PMID- 29997716 TI - A qualitative study of barriers to genetic counseling and potential for mobile technology education among women with ovarian cancer. AB - Background: National guidelines recommend genetic counseling for all ovarian cancer patients because up to 20% of ovarian cancers are thought to be due to hereditary cancer syndromes and effective cancer screening and prevention options exist for at-risk family members. Despite these recommendations, uptake of genetic counselling and testing is low. The goal of this study was to identify barriers to and motivators for receipt of genetic counseling along with preferences regarding potential use of a mobile application to promote genetic counseling. Methods: Three focus groups were conducted including 14 women with a diagnosis of epithelial ovarian, primary peritoneal or fallopian tube cancer. Topics included understanding of genetic counseling, perceived pros and cons, preferences for receiving health information, and familiarity with mobile phone technology. Transcripts were analyzed using standard procedures of qualitative thematic text analysis and descriptive coding techniques. Results: Six major themes regarding barriers to and motivators of genetic counseling and use of mobile technology in promoting genetic counseling emerged: (1) need for information, (2) relevance, (3) emotional concerns, (4) family concerns, (5) practical concerns, and (6) mobile application considerations. Conclusions: These data reiterate previously reported barriers to genetic counseling as observed in other populations. Participants were supportive of the use of mobile technology for promoting uptake of genetic counseling. PMID- 29997715 TI - Irisin Maternal Plasma and Cord Blood Levels in Mothers with Spontaneous Preterm and Term Delivery. AB - Irisin, an adipomyokine identified in 2012, has been investigated in association with common pregnancy complications, including gestational diabetes mellitus, preeclampsia, and intrauterine growth restriction. The objective of this study is to examine the potential role of irisin in preterm birth (PTB) by comparing its level between mothers with term and preterm labor. Maternal peripheral blood and cord blood samples were collected from 30 mothers who delivered prematurely and from 35 mothers who delivered at term. Irisin concentrations were measured in all samples using ELISA, and four common single nucleotide polymorphisms in the irisin gene were determined (rs16835198, rs726344, rs3480, and rs1746661). Univariable and multivariable regression modeling was applied to evaluate maternal and cord blood irisin concentrations in relation to preterm/term labor. Irisin concentration in umbilical cord blood was found to be associated with PTB in the univariable model (p = 0.046). On the other hand, no differences in maternal blood irisin levels between mothers with preterm and term deliveries were established. To the best of our knowledge, this is the first study determining irisin levels in term and preterm deliveries in maternal peripheral blood and umbilical cord blood. Our study shows a possible association between cord blood irisin concentration and PTB occurrence. PMID- 29997717 TI - Melorheostosis of a rib. AB - Melorheostos is a rare sclerosing bone dysplasia, characterized by cortical and medullary hyperostosis with typical "dripping candle wax" appearance, usually involving the long bones. Here, we present a case of melorheostosis of a rib, incidentally discovered in an asymptomatic adult patient. PMID- 29997718 TI - Detection of transplant renal artery stenosis with contrast-enhanced ultrasound. AB - Transplant renal artery stenosis (TRAS) is a vascular complication occurring during the first 2 years after kidney transplantation, with an incidence and a prevalence ranging from 1% to 23%, and from 1.5% to 4%, respectively. Detection of TRAS is the key, since most stenoses may progress to renal graft loss, however it may be difficult to detect due to its nonspecific clinical manifestations. Although Doppler ultrasound has become a primary imaging technique, digital subtraction angiography (DSA) remains the gold standard for diagnosing TRAS. We present a case of delayed graft function following kidney transplantation complicated by a lateral by-pass with prosthesis upstream and downstream of renal anastomosis, TRAS criteria were unclear using Doppler ultrasound, contrast enhanced computed tomography-scan, and DSA. Only contrast-enhanced ultrasound (CE US), observing a delayed and pulsating contest impregnation of renal parenchyma, supported the hypothesis of TRAS that was confirmed by the measurement of trans anastomosis pressure gradient during DSA. PMID- 29997719 TI - Anomalous development of the inferior vena cava: Case reports of agenesis and hypoplasia. AB - We reported the cases of two adult male patients who were admitted to our emergency room with abdominal pain and dyspnea caused by gallstones and pulmonary embolism respectively. During the radiological investigations, as collateral findings, we found two anomalous development of the inferior vena cava. These conditions affect about 4% of population and, although asymptomatic or mildly symptomatic, are associated with thrombotic manifestations as deep vein thrombosis and pulmonary embolism. The prompt recognition of these anomalies is necessary in order to prevent the complications associated with these conditions and to set the best therapy for patients. PMID- 29997720 TI - Symptomatic cholelithiasis in an ectopic retrocolic retroduodenal subhepatic duplicated gallbladder. AB - Gallbladder duplication is a rare anatomic variant of biliary anatomy, which can present diagnostic and treatment challenges. In this case, a 49-year-old male presented with classic symptoms of biliary colic to his primary care physician, and while computed tomography (CT) noted the presence of gallstones, neither CT nor ultrasound was able to locate a gallbladder within the gallbladder fossa. Initial surgery found and cauterized a rudimentary gallbladder, but symptoms persisted, requiring a second surgery and secondary analysis of CT, ultrasound, and magnetic resonance imaging with magnetic resonance cholangiopancreatography. Imaging helped clarify the diagnosis of gallbladder duplication (ductular type), where the first gallbladder's cystic duct inserted high on the common hepatic duct, and the second retroplaced gallbladder's cystic duct inserted into the midportion of the common bile duct. Thorough understanding of the numerous gallbladder duplication variants, careful interpretation of modern imaging, and close collaboration between surgeon and radiologist are essential for optimal management of patients with gallbladder duplications. PMID- 29997721 TI - Do High-Quality Kindergarten and First-Grade Classrooms Mitigate Preschool Fadeout? AB - Prior research shows that short-term effects from preschool may disappear, but little research has considered which environmental conditions might sustain academic advantages from preschool into elementary school. Using secondary data from two preschool experiments, we investigate whether features of elementary schools, particularly advanced content and high-quality instruction in kindergarten and first grade, as well as professional supports to coordinate curricular instruction, reduce fadeout. Across both studies, our measures of instruction did not moderate fadeout. However, results indicated that targeted teacher professional supports substantially mitigated fadeout between kindergarten and first grade but that this was not mediated through classroom quality. Future research should investigate the specific mechanisms through which aligned preschool-elementary school curricular approaches can sustain the benefits of preschool programs for low-income children. PMID- 29997722 TI - The Influence of Body Armor on Balance and Movement Quality. AB - Body armor is essential to the protection of military personnel; however, body armor may impede the users balance and movement quality. A better understanding of the influence of body armor on balance and movement quality may help in the development of new guidelines for training standards and procedures to mitigate the risk of injury associated with wearing of body armor in warfighters. The purpose of this study was to identify the effects of body armor (combat boots, tactical vest and combat helmet) on balance and movement quality in male military cadets and personnel. Twelve male participants completed the Functional Movement Screen (FMS) and Star Excursion Balance Test (SEBT) under two separate conditions, body armor and non-body armor. Results indicated a significant difference in FMS composite score between the non-body armor and body armor conditions (p =.012), with the non-body armor condition resulting in significantly higher FMS scores than the body armor condition. Additionally, the FMS item score for shoulder mobility was significantly higher (2.25+/-0.62) in the non-body armor condition than the body armor condition (p= 0.03). The SEBT composite and the three individual reach distances were not significantly different between conditions. Based on the current findings, body armor within a 4.8 kg - 5.3 kg range does appear to impact movement quality as evaluated using the FMS in male military personnel and cadets. More research is needed to determine a threshold of compensatory movement patterns relative to an increase in body armor weight. PMID- 29997723 TI - Stability of Resistance Training Implement alters EMG Activity during the Overhead Press. AB - Kettlebells often replace dumbbells during common resistance training exercises such as the overhead press. When performing an overhead press, the center of mass of a dumbbell is in line with the glenohumeral joint. In comparison, the center of mass of the kettlebell is posterior to the glenohumeral joint. Posterior displacement of the kettlebell center of mass may result in less stability during the pressing motion. The purpose of this study was to examine muscle activity during an overhead press with resistance training implements of differing stability. Surface electromyography (EMG) for the anterior deltoid and pectoralis major was analyzed for 21 subjects. Technique and pace of the overhead press were standardized and monitored. Filtered EMG data were collected, normalized, and average peak amplitude as a percentage of MVIC was calculated for each repetition. A repeated-measures analysis of variance was used to compare EMG values for the anterior deltoid and pectoralis major across implements. A statistically significant increase in normalized EMG activity (p < .05) was identified in the anterior deltoid when using the dumbbell (63.3+/-13.3%) compared to the kettlebell (57.9+/-15.0%). In this study, EMG activity was augmented in the anterior deltoid when using the more stable implement, the dumbbell. PMID- 29997724 TI - Lower Extremity Joint Kinematics of Shod, Barefoot, and Simulated Barefoot Treadmill Running. AB - Barefoot running is considered to decrease injury risk, but is not always practical, particularly while running on a fitness center treadmill. The purpose of this study was to compare the kinematics of shod, barefoot, and simulated barefoot running. Twelve subjects (age = 21.1 +/- 1.2 years) who regularly run on a treadmill for fitness participated in the study. After a warm up, each runner ran on a Biodex RTM 400 treadmill set at 7.4 mph (approximately 3.3 m/s) in their own shoes, barefoot, and while running "like they were barefoot" in their own shoes. Sixteen reflective markers were affixed to each subject to use PlugInGait (Vicon) to determine three-dimensional body landmark coordinates and to compute lower extremity joint angles. Values at touchdown and during stance were averaged over ten strides for analysis. Repeated measures ANOVA was implemented to determine differences based on running condition (p < 0.05) and post hoc testing was performed with an adjustment for multiple comparisons (p<0.05/3). At touchdown, ankle angle values significantly differed based on condition (6.2 +/- 5.9 degrees vs. -4.0 +/- 12.0 degrees vs, -0.2 +/- 13.3 degrees ; p = 0.004 for shod, barefoot and simulated barefoot running, respectively) indicating that when simulating barefoot running the subjects altered their foot strike pattern. Stride frequency differed between shod and barefoot running (1.415+/-0.068 Hz vs. 1.457+/-0.065 Hz; p = 0.001) but the simulated barefoot condition did not differ from the shod condition. The runners were able to simulate an important element of barefoot running, but they did not completely mimic their barefoot running pattern. PMID- 29997725 TI - The Effect of Stance Width and Anthropometrics on Joint Range of Motion in the Lower Extremities during a Back Squat. AB - The purpose of this study was to assess whether changing the stance width has an effect on the range of motion of hip flexion, knee flexion, and ankle dorsiflexion during an unloaded back squat, and whether these joint movements are affected by anthropometric differences. Thirty-two healthy, young adults performed unloaded back squats at three different stance widths, normalized to pelvic width. Joint angles were assessed using electromagnetic motion capture sensors on the sacrum, and thigh, shank and foot of the dominant leg. ANOVA comparison of joint angles for the three stance widths, at 10 degrees intervals of thigh orientation during the squat, indicated that joint angles tended to be larger when stance width was narrower, with the most significant effects on ankle dorsiflexion. A greater trunk/thigh length ratio (relatively long trunk) also tended to be associated with lower ankle and knee angles, while a greater thigh/shank length ratio (relatively long thigh) tended to be associated with higher ankle and knee angles, for the two narrower stance widths. The most practical implication of our findings is that individuals with limited ankle dorsiflexion, or with particularly long legs / thighs, may benefit from a wider stance width when squatting. PMID- 29997726 TI - Peak Power Output in Loaded Jump Squat Exercise is Affected by Set Structure. AB - A priority in strength and power exercise might be to train with as high quality as possible for the shortest possible duration. In this context, peak power output could reflect quality. Designing an exercise session as a cluster set structure, as compared to a traditional set structure, may be a way to obtain higher peak power output in the session. But it is unknown whether that is obtainable for non-elite individuals performing loaded jump squat exercise. The aim of the present study was therefore to test the hypothesis that peak power output would be highest in a jump squat exercise session, which was structured with cluster sets, as compared to traditional sets. Ten individuals (2 women, 8 men; 26.5 +/- 4.8 years, 1.81 +/- 0.08 m, 90.9 +/- 13.2 kg) performed two loaded jump squat exercise sessions structured with cluster sets and traditional sets, respectively. The sessions were performed on two separate days, in counterbalanced order. The position of the barbell was used to calculate derived values including peak power output. Values calculated as averages across the entire exercise sessions showed peak power output to be 178 +/- 181 W, corresponding to 4.1% +/- 4.9%, higher in the session with cluster set structure, as compared to the session with traditional set structure (p = 0.005). It was concluded that for non-elite individuals, peak power output was approximately 4% higher in a loaded jump squat exercise session structured with cluster sets as compared to an exercise session structured with traditional sets. PMID- 29997727 TI - Strength and Stability Analysis of Rehabilitated Anterior Cruciate Ligament Individuals. AB - The anterior cruciate ligament (ACL) serves as a vital stabilizer for the human knee, yet it is one of the most injured ligaments in the body. Function of the knee is restored through reconstruction and physical therapy, but long term functional deficits persist in some individuals. To better understand the influence of post rehabilitation outcomes on dynamic balance performance, this study evaluated bilateral differences in strength and stability in 11 participants who have rehabilitated from an ACL reconstruction or repair. The Y Balance Test and an isokinetic strength assessment using the Biodex dynamometer were used to measure dynamic knee stability and strength, respectively. No significant differences were found in the strength test measurements. However, side to side differences in Y-Balance Test composite score (-2.8+/-3.1%, p = 0.014), maximal anterior reach (-2.8+/-2.4 cm, p = 0.01), and posterolateral reach (-2.75+/-3.5 cm, p = 0.02) were found to be significantly impaired in participants' involved limbs compared to the uninvolved limbs. PMID- 29997728 TI - Effects of Very Short-Term Dynamic Constant External Resistance Exercise on Strength and Barbell Velocity in Untrained Individuals. AB - This study examined the effect of an upper body dynamic constant external resistance (DCER) exercise (barbell bench press [BP]), using the very short-term training (VST) model on strength and barbell velocity. Ten (5 females, 5 males) subjects (mean +/- SD age: 21.4 +/- 2.8 yrs; height: 1.75 +/- 0.12 m; body mass: 83 +/- 8.8 kg) completed two pre-test visits (pre-test 1 and pretest 2) to serve as the within subjects control, three training visits, and one post-test visit. The subject's 1 repetition maximum (1RM) for the BP as well as the mean (BPMV) and peak (BPPV) barbell velocities were determined during pre-test 1, pre-test 2 and post-test visits. The barbell bench press throw (BT) mean (BTMV) and peak (BTPV) velocities were also measured utilizing 35% of the subject's BP 1RM as resistance. The three training visits consisted of 5 sets of 6 repetitions, at 65% of the subject's 1RM. Statistical analyses included one-way repeated measures ANOVAs and paired samples t-tests (alpha level of p<=0.05). The post-test 1RM, BTMV, and BTPV were all significantly greater than pre-test 1 (p=0.002, p=0.0001, and p=0.002) and pre-test 2 (p=0.008, p=0.034, and p=0.015), with no significant differences seen between pre-test 1 and pre-test 2 for any of the variables. The posttest BPMV and BPPV were significantly greater than pre-test 1 (p=0.024 and p=0.005), but not pre-test 2 (p=0.131 and p=0.069). These findings showed the VST model, utilizing an upper body DCER exercise improved strength and barbell velocity in untrained subjects. PMID- 29997729 TI - Effects of Prior Fasting on Fat Oxidation during Resistance Exercise. AB - Prior research has demonstrated that the percentage of fuel utilization contributed by CHO compared to fat rises with an increase in exercise intensity. The role of food intake prior to exercise has been well studied and fasting prior to exercise generally increases reliance on fat as fuel. However, data on the role of fasting prior to resistance exercise is limited. Therefore, the purpose of this study was to assess the effects of one bout of resistance training in a fasted state compared to ingestion of standardized meal on fat and carbohydrate utilization. Twelve female (n = 12, age = 20.1 +/- 0.79 yrs, height = 67.0 +/- 2.63 in, weight = 143 +/- 21.8 lbs) NCAA Division 1 athletes participated in the study. Each participant completed one 10 hour fasted resistance training session and one postprandial resistance training session. The respiratory exchange ratio (RER) and METs were measured using a Cosmed K4b2 portable metabolic cart (Cosmed, Rome, Italy) and heart rate was measured by a Polar H1 heart rate monitor. Participants consumed the prescribed food, waited 15 minutes, and then completed three sets of five repetitions of bench press, back squat, and military press at 60% of their 1-repetition maximum. The mean fasted RER was significantly lower than postprandial for back squat (p=0.01) and military press (p=0.02), but not bench press (p=0.19). There was no difference in METs, RPE, or HR between fasted and postprandial trials for any exercise. Results suggest that fasted resistance exercise relies more heavily on fat metabolism than carbohydrate. PMID- 29997730 TI - Relative Handgrip Strength as a Simple Tool to Evaluate Impaired Heart Rate Recovery and a Low Chronotropic Index in Obese Older Women. AB - The aim of the present study was to compare differences in heart rate response following a treadmill exercise test in elderly obese women categorized into groups based on relative handgrip strength. Eighty-eight obese elderly women who were between the ages of 60 and 87 participated in the study and were categorized and enrolled to one of two groups based on lower (< 1.51 m2) or higher (>= 1.51 m2) relative handgrip strength, respectively. The heart rate recovery in the first and second minutes following the treadmill exercise test and the chronotropic index were compared between groups. The higher relative handgrip strength group presented a significantly higher peak heart rate during exercise and a quicker heart rate recovery following exercise versus the lower relative handgrip strength group (p<0.05). Furthermore, there was a tendency (p=0.059) toward a significantly greater chronotropic index in the higher versus the lower relative handgrip strength group. In conclusion, elderly women with greater relative handgrip strength also demonstrated a better heart rate response during and following exercise, possibly indicating better autonomic balance. The relative handgrip strength might be an important and inexpensive tool for the elderly obese women to indirect assess cardiovascular health. PMID- 29997731 TI - The Effects of PCSO-524(r), a Patented Marine Oil Lipid derived from the New Zealand Green Lipped Mussel (Perna canaliculus), on Pulmonary and Respiratory Muscle Function in Non-asthmatic Elite Runners. AB - Habitual endurance training may be associated with mild airway inflammation and subsequent deterioration in lung function. PCSO-524TM (Lyprinol(r)/Omega-XL(r)), a supplement extracted from the New Zealand green-lipped mussel (Perna canaliculus), has been shown to moderate airway inflammation in asthmatic subjects. The purpose of this study was to determine whether supplementation with PCSO-524TM improves pulmonary and respiratory muscle function in non-asthmatic elite runners. Sixteen male, non-asthmatic elite runners were randomly assigned to either a treatment (PCSO-524TM; 1 capsule contains 50 mg n-3 polyunsaturated fatty acids and 100 mg olive oil, n=8) or placebo (1 capsule contains 150 mg olive oil; n=8) group. During the supplementation period, subjects ingested 8 capsules of either treatment or placebo per day for 12 weeks. Resting pulmonary and respiratory muscle function testing were assessed at baseline and every two weeks throughout the 12 week supplementation period. No significant between-or within-subjects main effects were observed in forced vital capacity, forced expiratory volume in 1-second, forced expiratory flow from 25-75% of lung volume (FEF25-75), peak expiratory flow, maximal voluntary ventilation, maximal inspiratory mouth pressure, and closing volume (p>0.05). A significant within subjects main effect was observed in maximal expiratory mouth pressure (PEmax) (p=0.024) and lung diffusion capacity (DLCO) (p<0.0001), but no significant between-subjects main effects were observed for PEmax and DLCO (p>0.05). A significant treatment by time interaction was observed in FEF25-75 (p=0.026) and DLCO (p=0.024), but no other significant interactions were observed (all p>0.05). Supplementation with PCSO-524TM (Lyprinol(r)/Omega-XL(r)) does not improve pulmonary or respiratory muscle function in non-asthmatic elite runners. PMID- 29997732 TI - A Two-test Protocol for the Precise Determination of the Maximal Lactate Steady State. AB - The purpose of this study was to determine the efficacy of a two-test method for precisely identifying the Maximal Lactate Steady State (MLSS). Eight male competitive cyclists performed two bouts on a cycle ergometer. Following a maximal oxygen consumption (VO2max) test (66.91 +/- 5.29 mL.kg-1.min-1) we identified the lactate deflection point using the visual deflection (TVis), Log Log (TLog), Dmax (TDmax), RER = 1.00 (TRER), ventilatory threshold (TVent), and the 1.0 mmol.L-1 increase above baseline (T+1) methods. The second incremental test (SIT) consisted of 6-7 stages (5 min each) starting 20-30 W below to 20-30 W above the predetermined deflection point, in 10 W increments. Comparison of the two tests yielded different threshold estimates (range 11-46W) for all methods (P = 0.001-0.019) except the TLog (P = 0.194) and TRER (P = 0.100). The SIT resulted in significantly (P = 0.007) more narrow range of thresholds (27.5 +/- 11.01W) compared to the VO2max test (70 +/- 42.51W). The TVis from the SIT was identified as the MLSS and was verified using three 45-minute steady-state exercise bouts at 95%, 100%, and 105% of MLSS intensity (average increment 12.8 W). Blood lactate and VO2 were recorded every 5 minutes and differed between the three intensities at every time point (P < 0.001). VO2 increased from the 5th to the 45th minute by 7.02 mL.kg-1.min-1 (100% MLSS), 3.63 mL.kg-1.min-1 (95% MLSS) and 7.5 mL.kg-1.min 1 (105% MLSS, to the 30th minute). These results indicate that the MLSS was identified correctly by the SIT, the single incremental test overestimated the MLSS intensity, and the TVis provides a very accurate determination of the lactate breakpoint. The use of a second submaximal test is required for a precise identification of MLSS. PMID- 29997733 TI - Selecting the Best of the Best: Associations between Anthropometric and Fitness Assessment Results and Success in Police Specialist Selection. AB - To successfully complete specialist police selection, officers must be physically fit. The aim of this study was to investigate the relationship between performance on selected anthropometric and fitness tests and successful selection into a specialist police unit. Thirty-two male police officers (mean age = 29.48+/-4.99 years) participated in a Barrier Fitness Assessment (BFA), followed by a Specialist Selection Course (SSC). The BFA spanned two consecutive days of testing (pull-ups, push-ups, seven-stage sit-ups, a timed loaded pack march, a Multi-Stage Fitness Test, an agility run, a lift and carry task and a 300m swim assessment). The SSC occurred 4 weeks later and consisted of 8 days of intense police training. Officers who successfully completed the SSC were graded based on their performance and this determined their ultimate selection. Data were categorized into four participant groups: Group 1 - Did not complete the BFA; Group 2 - Completed the BFA but not the SSC; Group 3 - Completed the SSC and were not selected; and Group 4 - Completed the SSC and were selected. A Spearman's rank order correlation analysis was conducted to assess the strengths of the relationships between selection stage achieved and scores on each of the predictor variables, with significance set at 0.05. Height (p=0.011), body weight (p=0.011), pull-ups (p=0.021) and push-ups (p=0.016), seven-stage sit-up scores (p=0.042) and lift and carry speed (p=0.010) were significantly and positively correlated with level of selection success. Results suggest that candidates wishing to attempt selection into specialist police units would benefit from being tall and training to optimize musculoskeletal strength and muscular endurance. PMID- 29997734 TI - The Impact of an External Load of Football Equipment on Dynamic Balance as Assessed by the Modified Star Excursion Balance Test. AB - Ankle sprains are common injuries, especially for football players, and may result in ankle instability, which can limit performance and increase injury risk. Ankle stability return to play criteria is often assessed under loaded conditions, even though previous research suggests loaded conditions affect dynamic balance. The purpose of this study was to evaluate dynamic balance under loaded conditions. A modified Star Excursion Balance Test (SEBT), incorporating anterior, posterior medial and posterior lateral reach directions under the loaded condition of NCAA Division III football equipment was evaluated. Thirty male collegiate football players completed the modified SEBT under loaded and non loaded conditions. Scores for the three reach directions on the SEBT were computed for loaded and non-loaded conditions. Repeated measures ANOVA was used to compare reach directions under loaded and non-loaded. Under loaded conditions, participants had significantly shorter posterior lateral reach distances for the left (98.05 +/- 12.73 cm vs. 89.30 +/- 10.45 cm, p = 0.00) and right (103.77 +/- 12.78 cm vs. 99.07 +/- 13.50 cm, p = 0.00) legs and significantly shorter reach distances for the right leg in both the anterior direction (84.58 +/- 5.64 cm vs. 80.57 +/- 13.73 cm, p = 0.02) and composite dynamic balance score (105.99 +/- 12.99 vs. 102.30 +/- 14.28, p = 0.009). The addition of 6.2 kg of external load significantly affected dynamic balance assessed by the modified Star Balance Excursion Test. These findings suggest that return to support assessments should involve sport-specific conditions when determining readiness of return to play. PMID- 29997735 TI - Acute Cardiometabolic Responses to Medicine Ball Interval Training in Children. AB - Medicine ball interval training (MBIT) has been found to be an effective exercise modality in fitness programs, yet the acute physiological responses to this type of this exercise in youth are unknown. The purpose of this study was to examine the acute cardiometabolic responses to MBIT in children. Fourteen children (mean age 10.1 +/- 1.3 yr) were tested for peak oxygen uptake (VO2peak) on a treadmill and subsequently (> 48 hours later) performed a progressive 10 min MBIT protocol of 5 exercises (EX): standing marches (EX1), alternating lunges (EX2), squat swings (EX3), chest passes (EX4) and double arm slams (EX5). A 2.3 kg medicine ball was used for all trials and each exercise was performed twice for 30 sec with a 30 sec rest interval between sets and exercises. Participants exercised while connected to a metabolic system and heart rate (HR) monitor. During the MBIT protocol, mean HR significantly (p<0.05, eta2 = 0.89) increased from 121.5 +/- 12.3 bpm during EX1 to 178.3 +/- 9.4 bpm during EX5 and mean VO2 significantly (p<0.05, eta2= 0.88) increased from 15.5 +/- 2.9 ml * kg-1 * min-1 during EX1 to 34.9 +/- 5.1 ml * kg-1 * min-1during EX5. Mean HR and VO2 values during MBIT ranged from 61.1% to 89.6% of HRpeak and from 28.2% to 63.5% of VO2peak. These descriptive data indicate that MBIT can pose a moderate to vigorous cardiometabolic stimulus in children. PMID- 29997736 TI - An External Focus of Attention is Effective for Balance Control when Sleep deprived. AB - The purpose of our study was to examine if the beneficial effects of an external focus are effective for balance control when sleep-deprived. Sleep-deprived participants (27 hours awake) completed three blocks of five separate 30 second trials on a dynamic balance board. All participants were given internal, external, and control instruction. For the internal focus trials, participants focused on their feet; whereas, for the external focus trials, participants focused on the balance board. Participants' time in balance was significantly greater during the external focus compared to the internal focus and control. These findings suggest that external focus instructions are effective when participants are sleep-deprived. PMID- 29997737 TI - Field Test Performance of Junior Competitive Surf Athletes following a Core Strength Training Program. AB - Lower body and core muscular strength are essential for optimal performance in many sports and competitive surfers have similar strength demands when maneuvering a surfboard to achieve competition success. Presently, the use of unstable surfaces is excessively utilized by surf coaches and trainers and to date, research does not support this as an effective training method for long term improvements. Therefore, the purpose of this study was to determine the effectiveness of an 8-week Core Strength Training Program (CSTP) on a battery of field tests specific to assessing core musculature and lower body strength for junior competitive surf athletes. Nineteen American junior competitive surf athletes (age:15.7+/-1.01yrs, height:1.77+/-0.007m, mass:64.67+/-9.08kg) completed pre- and post-tests with a transitional pre-season to in-season 8-week CSTP intervention. The battery of tests included: rotational power (RP), time to peak acceleration (TP), maximal acceleration (Ma), maximal countermovement jump (CMJ), estimated peak power (PP), core strength (CS), core endurance (CE), and rotational flexibility (RF). Means, standard deviations, RMANOVA with a significance level of p < 0.05, and effect sizes were computed. Results demonstrated significant improvements in L.RP, TP, CMJ, PP, CS, and RF. Based on the results, the CSTP is an effective training program for surf coaches and strength and conditioning professionals to improve strength in the core musculature and lower body. In addition, we conclude implementation of the CSTP enhances athletic performance measurements which will likely increase competition success. PMID- 29997738 TI - Carbohydrate Mouth Rinse Improves Relative Mean Power During Multiple Sprint Performance. AB - Multiple investigations have confirmed carbohydrate mouth rinse (CMR) enhances high intensity endurance performance lasting under 1 hour, but the effects of CMR on high intensity intermittent exercise has received less attention. This study examined the effect of CMR on high intensity multiple sprint performances in a protocol designed to emulate a cyclocross or mountain biking event. Seven trained men (28.2 +/- 6.8 years, 185 +/- 9 cm, 85.3 +/- 14.8 kg, VO2peak 51.4 +/- 7.3 ml/kg*min-1) completed two, 48 min high intensity intermittent cycling protocols that consisted of 6 bouts of 5 min cycling at 50% VO2 peak followed by sets of three, 10-s Wingate sprints with 50 s of recovery between sprints. Prior to each set of Wingate sprints, either a 6.4% carbohydrate solution (CMR) or placebo (PLA) were rinsed for 10 s using a counterbalanced crossover design. There was a significant main effect (CMR 10.51 +/- 0.82, PLA 10.33 +/- 0.87 W/kg; p < 0.05 ES=0.21) for mean power, but post hoc tests only revealed statistically significant performance improvement with CMR during the 6th bout (CMR 10.5 +/- 0.75, PLA 10.22 +/- 0.92 W/kg; p = 0.01 ES=0.33). No treatment effect was exhibited for peak power, fatigue index, ratings of perceived exertion, or blood glucose. Most team sport situations provide multiple opportunities for access to beverages, but gastrointestinal distress associated with fluid intake may reduce desire for significant beverage consumption. Under such circumstances, a small but practical ergogenic advantage may be exhibited if the fluid rinsed in the mouth contains carbohydrates. PMID- 29997739 TI - Behavior of Heart Rate Variability After 10 Repetitions Maximum Load Test for Lower Limbs. AB - The purpose of this study was to analyze the acute heart rate variability behavior after 10 repetitions maximum load test for back squat, leg press, leg extension, and leg flexion in normotensive subjects. Eight recreationally trained women (age: 21.8 +/- 2.2 yrs; height: 167.6 +/- 6.3 cm; weight: 61.6 +/- 10.1 kg) performed two 10 repetitions maximum testing days with 48-hours rest between each one. Heart rate variability was measured in baseline and postexercise (15-, 30-, 45-, and 60-minutes) for time and frequency domain. A significant difference was identified in RMSSDms (p = 0.010; effect size = -1.3), MRRms (p = 0.026; effect size = -1.3), MHR (p = 0.006; effect size = 1.4), and PNN50% (p = 0.006; effect size = -1.6) when compared 15 minutes postexercise with baseline. For all others comparison and index were no differences (p > 0.05). The present study demonstrates that load test, although works with maximum intensities, did not generate an exacerbated postexercise sympathetic activity. Thus, it seems to be safe for cardiovascular healthy individuals. As a practical application, these results can encourage exercise practitioners to do a maximum load test to resistance training loads prescription. PMID- 29997740 TI - Pacing of an Untrained 17-Year-Old Teenager in a Marathon Attempt. AB - Although there has been increased scientific interest for physiological responses to endurance running and pacing, limited information exists for adolescents participating in endurance events. We are reporting the case of an untrained 17 year-old female teenager (body mass 50.6 kg, height 167 cm and body mass index 18.1 kg/m2) who intended to run a marathon within 6 hours without preparation. The young woman missed her goal by just 2 km. When the average running speed per hour was analysed, there was a major effect of race hour on running speed (p = 0.013, eta2 = 0.320), where the running speed in the fifth hour (6.3 +/- 0.2 km/h) was lower than in the second hour (6.9 +/- 0.1 km/h). Despite a progressive decrease in running speed, she was still able to put on a final spurt, indicated by a 4th degree non-linear regression (R2=0.55). Creatine-kinase reached the initial value again after 5 days and the fall of hemoglobin and hematocrit indicated expansion of plasma volume. Running a marathon as a teenager did not impair physical health, especially when a self-selected pace was adopted. Laboratory parameters during running showed similar changes as have been reported for teenagers and adults after running a marathon. Increased values returned to base line within a few days. In summary, a female teenager at the age of 17 years without specific running preparation is able to achieve nearly a marathon distance during 6 hours of continuous running without harmful effects on health. PMID- 29997741 TI - Validation of PiezoRx Pedometer Derived Sedentary Time. AB - Although pedometers are valid tools for measuring physical activity, to date they have not been used to assess sedentary time. The primary purpose of this study was to determine if the PiezoRx pedometer is a valid and reliable measure of sedentary time compared to the hip-worn Actical accelerometer. A secondary purpose was to compare sedentary time derived via the Fitbit Flex with that of the Actical. Finally, a third purpose was to compare sedentary time derived from the above devices, with that of the ActivPAL inclinometer. Thirty-five participants ages 11-69 years (Mage= 23.3; 21 Female) wore five devices for up to one week: two PiezoRx pedometers, an Actical, an ActivPAL and a Fitbit Flex. Participants recorded daily wear-time of each device using a log sheet. The average sedentary time calculated from the PiezoRx (716+/-137.68 min/day) was not different from the Actical (694 +/-136.11 min/day, p>0.05), although it was higher than the ActivPAL (475+/-171.52 min/day) and Fitbit Flex (530+/-149.94 min/day, all p<0.001). Sedentary time from all devices were significantly correlated with each other, with the strongest relationship seen between the Actical and PiezoRx (R2=0.93, p<0.001). In comparison to the ActivPAL, error in PiezoRx- (R2=0.96), Actical- (R2=0.96) and Fitbit Flex- (R2=0.34) determined sedentary time was strongly associated with standing time (all p<0.001). Sedentary time derived using the PiezoRx pedometer may be statistically equivalent to the Actical accelerometer, but not the ActivPAL inclinometer or Fitbit Flex. PMID- 29997742 TI - Correction to: Complete genome of a novel virulent phage ST0 lysing Escherichia coli H8. AB - [This corrects the article DOI: 10.1186/s40793-017-0304-9.]. PMID- 29997743 TI - Comparative cytogenetics and derived phylogenic relationship among Sitophilus grain weevils (Coleoptera, Curculionidae, Dryophthorinae). AB - Cytogenetic characteristics and genome size are powerful tools for species characterization and identification of cryptic species, providing critical insights into phylogenetic and evolutionary relationships. Sitophilus Linnaeus, 1758 grain weevils can benefit from such tools as key pest species of stored products and also as sources of archeological information on human history and past urban environments. Moreover, the phylogenetic relationship among these weevil species remains controversial and is largely based on single DNA fragment analyses. Therefore, cytogenetic analyses and genome size determinations were performed for four Sitophilus grain weevil species, namely the granary weevil Sitophilus granarius (Linnaeus, 1758), the tamarind weevil S. linearis (Herbst, 1797), the rice weevil S. oryzae (Linnaeus, 1763), and the maize weevil S. zeamais Motschulsky, 1855. Both maize and rice weevils exhibited the same chromosome number (2n=22; 10 A + Xyp). In contrast, the granary and tamarind weevils exhibited higher chromosome number (2n=24; 11 A + Xyp and 11 A + neo-XY, respectively). The nuclear DNA content of these species was not proportionally related to either chromosome number or heterochromatin amount. Maize and rice weevils exhibited similar and larger genome sizes (0.730+/-0.003 pg and 0.786+/ 0.003 pg, respectively), followed by the granary weevil (0.553+/-0.003 pg), and the tamarind weevil (0.440+/-0.001 pg). Parsimony phylogenetic analysis of the insect karyotypes indicate that S. zeamais and S. oryzae were phylogenetically closer than S. granarius and S. linearis, which were more closely related and share a more recent ancestral relationship. PMID- 29997744 TI - Children in the 2015 South Indian floods: community members' views. AB - Little is known about children's experiences and involvement in disaster preparation and recovery, in particular in low- and middle-income countries. Eliciting community members' perspectives on the 2015 floods in Tamil Nadu, India, may generate useful insights for improving services in low-resource settings. This qualitative study aimed to understand how children in Chennai experienced the floods, as reported by the adults in their community, and to explore children's involvement in disaster preparedness, response and recovery efforts as reported from the adults' perspective. We conducted in-depth, semi structured interviews (N = 48) with family members (n = 36), and with staff of non-governmental organizations (NGOs) (n = 12) who actively participated in relief and recovery efforts. We also conducted two focus group discussions (n = 14) with NGO staff about a year after the 2015 South Indian floods in Chennai, India. Six broad themes regarding children's experiences and behaviours during and after the floods emerged: (1) unexpectedness of the floods; (2) children's safety - barriers and facilitators; (3) parents' reactions - helplessness, fear and pride; (4) children's reactions - helping hands, fun and fear; (5) barriers to a return to 'normal'; and (6) a determination to be prepared for next time. Children and families were deeply impacted by the floods, in part owing to a lack of preparation, as perceived by the study participants. It was also clear from the data analysis that caste and socioeconomic status played an important role in the families' ability to evacuate safely. Helplessness on the part of the parents was apparent, as was children's concern over recurrence of the flood. Similarly, gender appeared to affect child safety, recovery and other outcomes such as continued education. Priorities for future efforts involve the development and evaluation of child-centred education about flood awareness, child participation and safety. PMID- 29997745 TI - The threat of colistin resistance among carbapenem-resistant Klebsiella pneumoniae isolates in Iran. PMID- 29997746 TI - Prevalence of biofilm formation and vancomycin-resistant genes among Enterococcus faecium isolated from clinical and environmental specimens in Lorestan hospitals. AB - Background and Objectives: The antibiotic resistance among Enterococcus faecium strains has increased worldwide. Additionally, biofilm-forming isolates of E. faecium play an important role in human infections. This study was conducted to investigate the prevalence of virulence and antibiotic resistance genes between biofilm-producing and non-biofilm-producing E. faecium strains. Materials and Methods: In this study, 228 E. faecium isolates from clinical and environmental specimens were obtained from different wards of hospitals in Lorestan province (Iran). Then, the pattern of antibiotic resistance and minimum inhibitory concentration (MIC) against beta-lactams, glycopeptides, aminoglycosides and other common antibiotics was investigated using disk diffusion and agar dilution methods. Biofilm formation was investigated using polystyrene microtiter plates. PCR assay was conducted for antibiotic resistance and biofilm related genes. Pulse field gel electrophoresis (PFGE) was used to determine the clonal spread of isolates. Results: Most of isolates (78%) were resistant to penicillin, but all were susceptible to linezolid and tigecycline. The biofilm-producing isolates were more resistant to beta-lactams, glycopeptides and aminoglycosides compared to non-biofilm-producing strains. In biofilm-producing isolates, pilA, pilB, efaAfm and esp were the dominant virulence genes and vanA and pbp5 genes were the dominant resistant genes. PFGE analysis exhibited a similar pattern between the clinical and environmental isolates, suggesting the presence of a common origin of the infection by E. faecium. Conclusion: The results of the antibiotic resistance, biofilm assay, and PFGE analysis suggest that there is a common clone of persistent and biofilm-producing strains of E. faecium, which could rapidly disseminate in patients and the environment. PMID- 29997747 TI - Genetic diversity of Staphylococcus aureus strains from a teaching hospital in Isfahan, Iran: The emergence of MRSA ST639- SCCmec III and ST343- SCCmec III. AB - Background and Objectives: Staphylococcus aureus is an important pathogen that can be colonized in the nose and increase the risk of spreading infections in hospitals. The present study aimed at determining the phenotypic and genotypic characterization of S. aureus strains isolated from patients and healthcare workers (HCWs) from a teaching hospital in Isfahan, Iran. Materials and Methods: This cross-sectional study was performed on 262 nasal swabs and 23 clinical isolates that were collected from a teaching hospital during February and April 2016. Staphylococcal cassette chromosome mec (SCCmec) and multilocus sequence typing (MLST) were performed for selected isolates. Results: Overall, 23% and 18% of healthcare workers and patients were carriers, respectively. Methicillin resistant S. aureus (MRSA) rate was 13%, 33% and 52% in nasal HCWs, nasal patients, and clinical samples, respectively. The molecular typing of MRSA isolates revealed that the most common SCCmec type is SCCmec type III (88%). The highest rate of resistance was observed against tetracycline and erythromycin, with 48.7%. The most frequently detected toxin genes among S. aureus isolates were hla (99%) and sea (44%), moreover, pvl genes were detected in (40%) of MRSA isolates. The results of MLST showed 7 different sequence types (STs): ST859 (2/9), ST6 (2/9), ST639 (1/9), ST343 (1/9), ST239 (1/9), ST291 (1/9) and ST25 (1/9). Conclusion: Our results revealed that ST clones associated with healthcare associated MRSA (HA-MRSA) are actively circulating among nasal carriage in our healthcare setting, and thus, effective infection control policies are needed to reduce nasal carriage in healthcare settings. PMID- 29997748 TI - Assessment of disinfectant and antibiotic susceptibility patterns and multi-locus variable number tandem repeat analysis of Staphylococcus epidermidis isolated from blood cultures. AB - Background and Objectives: Variable number tandem repeat (VNTR) patterns and resistance against three commonly used hospital disinfectants [0.5% (w/w) chlorhexidine digluconate (CHG) and 75% (w/w) alcohol (A), CHG-A; Quaternary ammonium compounds (QACs) and biguanides (B), QAC-B; and 70% (w/w) isopropanol (ISP) and 0.25% (w/w) QACs, ISP-QAC], as well as frequently used antibiotics, were evaluated among 115 Staphylococcus epidermidis blood isolates recovered from a children's hospital in Tehran, Iran. Materials and Methods: Multi-locus variable number tandem repeat analysis (MLVA) was performed using primers targeting 5 VNTR loci on the genome of S. epidermidis isolates. Micro-broth dilution method and detection of qacA/B and smr genes were carried out for evaluating resistance against the disinfectants. Results: Out of the 115 isolates, 115 (100%) and 113 (98.3%) were susceptible to linezolid and quinupristin/dalfopristin, respectively. A total of 55.7% of the isolates were found to be multidrug resistant (MDR). All isolates had MICs of CHG-A and ISP-QAC of 8 folds lower and MIC of QAC-B 6 folds lower than that suggested by the manufacturers. The genes qacA/B and smr were found in 28 (24.3%) and 14 (12.2%) isolates, respectively. MLVA typing of the S. epidermidis isolates resulted in 106 VNTR patterns and 102 MLVA types for the 112 S. epidermidis isolates, considering that 3 were not typeable. Conclusion: MLVA typing of S. epidermidis isolates show a great diversity and that the isolates are still susceptible to the concentrations of disinfectants recommended for use by the manufacturers. In addition, the relatively high percentage of the MDR S. epidermidis isolates could cause MDR infections and act as reservoirs to transfer resistance determinants to S. aureus population. Therefore, it is important that suitable infection control strategies are employed to avoid the distribution of MDR isolates between personnel and patients in this medical centre. PMID- 29997749 TI - First detection of New Delhi metallo-beta-lactamases variants (NDM-1, NDM-2) among Pseudomonas aeruginosa isolated from Iraqi hospitals. AB - Background and Objectives: Multidrug resistance and in particular, carbapenem resistant Gram-negative bacteria is spreading worldwide at an alarming rate. Among the clinically significant carbapenemases, the New Delhi Metallo-beta lactamase (NDM) is one of the most formidable. NDM efficiently hydrolyses beta lactams and is the last-resort among carbapenems. Hence, therapeutic options for NDM producer bacteria become restricted to a handful of antibiotics. The present study was undertaken to detect the prevalence of the blaNDM-variants Metallo beta lactamases (MBLs) among isolates of Pseudomonas aeruginosa recovered from various clinical samples of hospitalized patients in Baghdad, Iraq. Materials and Methods: A total of 100 isolates of Gram-negative bacteria obtained from various clinical samples were subjected to antibiotic susceptibility testing by the disc diffusion method against meropenem (10 MUg), imipenem (10 MUg), doripenem (10 MUg), polymyxin B (10 MUg), colistin (10 MUg), amikacin (30 MUg), gentamicin (10 MUg), aztreonam (30 MUg), ciprofloxacin (5 MUg), levofloxacin (5 MUg), ofloxacin (5 MUg), cefepime (30 MUg), ceftazidime (30 MUg), piperacillin-tazobactam (100?10 MUg), tigecycline (15 MUg) and tetracycline (10 MUg). The results were interpreted according to the guidelines suggested by the Clinical Laboratory Standards Institute. Presence of blaNDM was detected by PCR and it was confirmed by DNA sequencing of the gene present in the isolates that exhibited carbapenem resistance. Results: In the present study, four isolates of P. aeruginosa carried the blaNDM, three isolates harboured blaNDM-1 and one isolate harboured blaNDM-2. All isolates were resistant to imipenem and meropenem. The blaNDM-1 carrying isolates remained susceptible to colistin and beta-lactamase inhibitors piperacillin-tazobactam. Conclusion: We are reporting emergence of the P. aeruginosa carrying the blaNDM-variant, which exhibited resistance to imipenem and meropenem for the first time in Iraq. PMID- 29997750 TI - Molecular detection of class 1, 2 and 3 integrons and some antimicrobial resistance genes in Salmonella Infantis isolates. AB - Background and Objectives: Multidrug resistant Salmonella strains have been observed around the world in recent years. Many mechanisms contribute to the spread of antimicrobial resistance genes. This study aimed at determining the distribution and transmission of class 1, 2 and 3 integrons among MDR Salmonella isolates collected from a selection of chicken broilers in the north of Iran. Materials and Methods: PCR assays were used to detect genes for tetracyclines (tetA, tetB and tetG), chloramphenicol (cat1 and floR), and streptomycin (strA). Also, the presence of class 1, 2 and 3 integrons in all MDR isolates was evaluated using specific primers for the integrase genes of integrons intI1, intI2 and intI3. Results: Class 1, 2 and 3 integrons were present in 36%, 42% and 4% of the MDR isolates, respectively. Out of the tetracyclines resistant isolates, 47 (100%) and 5 (10.6%) carried tetA, tetB genes, respectively, while no isolate was positive for the tetG gene. All 36 chloramphenicol-resistant strains carried floR and cat1 genes. Nine (18%) Salmonella Infantis isolates harbored the strA gene, conferring resistance to sterptomycin. Conclusion: This study found a high frequency of antimicrobial resistance genes among Salmonella isolates; therefore, management strategies are needed to prevent food-borne diseases caused by MDR Salmonella from food supplies. PMID- 29997751 TI - Study of seminal infection among an infertile male population in Qom, Iran, and its effect on sperm quality. AB - Background and Objectives: There are very few analysis tools to examine seminal fluid specimens, so bacterial infections on male infertility has always been the subject of discussion. These infectious processes lead to deterioration of spermatogenesis, impairment of sperm function, and/or obstruction of the seminal tract. In this study, we aimed at determining the role of bacterial infection on semen parameters including motility, count and normal morphology in infertile male patients. Materials and Methods: In this cohort study, 150 infertile males having abnormal semen parameters (study group) and 150 healthy fertile males (control group) were included. A total of 300 semen samples were collected after 3 to 5 days of sexual abstinence. Volume, pH, concentration, normal morphology, and motility were evaluated. Samples were seeded using a calibrated loop on agar and EMB plates, which were incubated overnight. The microorganisms were identified by Gram staining technique, catalase and coagulase tests. Results: The prevalence of seminal infection among infertile males in Qom was 21%. Among these infected samples 61.9%, 14.28%, 14.28% and 9.25% were contaminated with Staphylococcus aureus, coagulase negative staphylococci, Streptococcus and Escherichia coli, respectively. All the identified bacteria except Streptococcus caused a significant decrease in sperm concentration. Sperm motility was significantly lower in E. coli contaminated samples than in the control group, and the presence of E. coli and S. aureus led to a decline in normal morphology of the sperms. Conclusion: Sperm bacterial contamination is quite frequent and could contribute to the deterioration of the sperm quality of infertile males. PMID- 29997752 TI - Effectiveness of an inactivated paratuberculosis vaccine in Iranian sheep flocks using the Mycobacterium avium subsp paratuberculosis 316F strain. AB - Background and Objectives: Paratuberculosis (PTb) (John's disease) is an incurable chronic intestinal infection that mainly affects ruminants. PTb is caused by Mycobacterium avium subspecies paratuberculosis (MAP) with a global distribution. Despite evidences on MAP contribution in Crohn's disease its causal role is still a matter of controversy. In ruminant farming, vaccination is broadly accepted as an effective control measure of PTb. This article describes preparation and field trial of an inactivated PTb vaccine made from the MAP 316F strain. Materials and Methods: Formulation of the vaccine was conducted based on the method traditionally used in the UK. Identity of the MAP strain was authenticated by PCR-IS900 and PCR-F57 tests. In the field, a group of 100 lambs (3-8 weeks old) were subcutaneously inoculated with the vaccine preparation under study. These animals, pre-vaccination, were all PTb ELISA negative. Serum level of antibody was determined by ELISA on days 0, 30, 60, 120 and 240, post vaccination. Results: In PCR-900 and PCR-F57, the MAP 316F strain produced two fragments of 560 and 704 bp length respectively, a confirmation of its identity as MAP bacterium. In the field trial and at the arranged time intervals, the achieved blood serum levels of antibody, attributable to the vaccine formulation, displayed considerably high values. Conclusion: Given that the PTb-caused economical losses in the Iranian environment are dramatically high and also the fact that future of state policy on control of PTb remains unknown, we belive vaccination of animals is the best recommendable practice. PMID- 29997753 TI - Screening and characterization of in-vitro probiotic criteria of Saccharomyces and Kluyveromyces strains. AB - Background and Objectives: Probiotics are defined as live micro-organisms conferring a health benefit on the host. Although most probiotics are bacteria, some yeasts such as Saccharomyces and Kluyveromyces, has been found to have effective probiotic properties. The objective of this study was to isolate and identify indigenous Saccharomyces and Kluyveromyces yeast strains and to compare some probiotic characteristics between these two strains in vitro. Materials and Methods: Strains were isolated on yeast glucose chloramphenicol agar medium from 205 samples and identified by morphological, physiological and biochemical assays. The effects of different conditions such as pH and temperature on the survival and growth of the isolates were studied. In addition, resistance to acidic pH (1.5, 2, 3 and 5), pepsin and different concentrations of bile salts (1%, 3% and 5%), as well as proteolytic, lipolytic and hemolytic activity of selected isolates were assessed. Finally, the best isolates were selected for investigation of their viability in samples of dairy products. Results: 126 isolates were identified using biochemical and molecular techniques as yeast strains. Five isolates were found to have effective probiotic properties, belonging to Kluyveromyces marxianus (S97, S101 and S106) and Saccharomyces cerevisiae (S28, S34). These isolates were able to grow at 37 degrees C, pH=1.5, withstand to concentration of 5% oxbile and pepsin and exhibit the proteolytic activity. The isolates of K. marxianus showed better viability in dairy (yogurt). Conclusion: In the in-vitro comparative experiments, the isolates of K. marxianus showed better probiotic potentials. PMID- 29997754 TI - Culturable rare actinomycetes from Indian forest soils: Molecular and physicochemical screening for biosynthetic genes. AB - Background and Objectives: Rare actinomycetes are a promising source of novel metabolites of pharmaceutical importance. The current study focussed on selective isolation of specific genera of rare actinomycetes and screening the isolates for biosynthetic genes particularly polyketide synthases (PKS) and non ribosomal peptide synthetases (NRPS). Materials and Methods: The soil samples were subjected to various pre-treatments like 1.5% phenol treatment, 0.3% chloramine T treatment, benzethonium chloride treatment, etc. and plated on selective media supplemented with specific antibiotics targeting rare genera of actinomycetes. The putative rare actinomycete isolates were screened for bioactivity using agar cross streak method and agar well diffusion method. The ability of the isolates to produce anti-quorum sensing compounds was tested against Serratia marcescens. The isolates were also screened for the presence of biosynthetic gene clusters associated with PKS-I, PKS-II and NRPS pathways using the degenerate primer sets K1F-M6R, KSalpha/KSbeta and A3FA7R, respectively. The expression of these gene clusters was tracked by physicochemical screening of the extracts of isolates using spectroscopic and chromatographic techniques. Results: In this study, 1.5% phenol treatment was found to be the most promising followed by heat treatment and chloramine treatment. Our studies showed that ISP5 agar was the best for isolation of rare genera followed by ISP7, Starch Caesin agar and ISP2 supplemented with antibiotics like gentamicin, nalidixic acid and streptomycin. Micromonospora was the most abundant genus followed by Dactylosporangium. Actinomadura, Nocardiopsis and Actinoplanes were almost equal in number. Primary screening showed that 92% of the isolates were active against one of the test organisms. Thirty seven isolates were found to produce anti-quorum sensing (QS) compounds. NRPS sequences were detected in thirty nine isolates (42.8%), whereas PKS-I and PKS-II sequences were detected in seventeen and twenty eight strains (18.6% and 30.7%), respectively. Conclusion: Nine type I and type II polyketide producing isolates as well as six peptide-producing isolates were found. The peptide extract of isolate KCR3 and a polyketide extract of isolate NCD10 were found to possess anti-tumor activity exhibiting an IC50 value of 3 MUg/ml and 2.5 MUg/ml against HeLa cells. PMID- 29997755 TI - A survey of the frequency of cytomegalovirus-associated diarrhea in immunocompromised patients using a non-invasive method. AB - Background and Objectives: Cytomegalovirus (CMV) infection is the most common viral opportunistic infection causing gastrointestinal diseases such diarrhea and colitis in immunocompromised patients. The development and performance of a robust and sensitive PCR assay are usually evaluated to detect CMV DNA in human fecal specimens. In this study, our aim was to detect CMV DNA in stool samples taken from patients with HIV/AIDS, cancer, and transplant recipient patients with chronic and persistent diarrhea using a non-invasive method. Materials and Methods: A total of 633 immunocompromised patients (451 males and 182 females) suffering from persistent or chronic diarrhea were included in this study. Among them, 392 were HIV/AIDS patients, 151 had cancer and were receiving chemotherapy, and 90 were recipients of a solid organ or bone marrow transplant. CMV genome was extracted from the stool samples using phenol: chloroform: isoamyl alcohol method. CMV DNA was identified by polymerase chain reaction using sequence specific primers on genomic DNA. Results: Looking at the frequency of CMV DNA in 392 HIV/AIDS patients, we found that only 5 patients (1.27%) were positive for CMV genome, while this frequency was 4.63% (7/151) and 5.5% (5/90) in patients with cancer receiving chemotherapy and in those with solid organ or bone marrow transplant, respectively. Conclusion: The results of this study revealed that the cause of chronic or persistent diarrhea in HIV/AIDS, cancer, and graft recipient patients might be related to CMV infection. Accordingly, we recommend a non invasive method, such as stool sample, as a first line of diagnosis of enteritis when the physician suspects that a patient has CMV infection. PMID- 29997756 TI - Comparison the Effectiveness of Breastfeeding, Oral 25% Dextrose, Kangaroo-Mother Care Method, and EMLA Cream on Pain Score Level Following Heal Pick Sampling in Newborns: a randomized clinical trial. AB - Background: Today, it is considered that infants can feel pain, and it can have several adverse effects on their development. Although different interventions, such as skin-to-skin contact (kangaroo mother care method), glucose solutions, breastfeeding, and local anesthetic agents, have been evaluated to reduce infants' pain, there is no clinical trial available to identify the best method. Objective: The aim of this study was to compare the efficacy of four methods of relieving infants' pain, i.e., breastfeeding, oral 25% dextrose, kangaroo mother care method (KMCM), and EMLA cream based on a pain score level following heal prick sampling in term newborns. Methods: In this double-blind, controlled, randomized clinical trial, full term, and healthy infants in Shahid Motahhari Hospital, Marvdasht, Shiraz Province, Iran were studied. Infants were randomly allocated to four groups of interventions, i.e., A: breast milk feeding (n=42), B: oral 25% dextrose (n=40), C: KMCM (n=38), and D: KMCM ointment (n=40). All interventions were applied 15 minutes before heel-prick sampling. To evaluate the pain level in infants, the Neonatal Infant Pain Scale (NIPS) questionnaire was used. The data were analyzed with SPSS version 16 by ANOVA and the chi-squared tests. Results: One hundred and sixty-one infants (93 males, 68 females) with an age range of 3 to 5 days were studied. There was no significant difference between the groups in terms of gender (p=0.113), weight (p=0.059), and baseline pain score level (p=0.904). The breastfeeding method showed the lowest pain score in comparison to the other interventions (A=5.52+/-2.22, B=6.45+/-1.88, C=6.84+/ 1.96, D=7.37+/-1.95; p=0.001) after the heel-prick sampling. Conclusion: It seems that, among the four methods of interventions in this study, the most effective method of lowering perceived pain in infants undergoing painful procedures was proven to be breastfeeding. Trial Registration: This study is registered in the Iranian Registry of Clinical Trials with the registration number of IRCT20151201253256N1. Funding: This research was supported financially by the Research Council of the International Campus of Shiraz University of Medical Sciences. PMID- 29997757 TI - Effectiveness of the mindfulness-acceptance-commitment-based approach on athletic performance and sports competition anxiety: a randomized clinical trial. AB - Background: Improving sports performance and reducing anxiety is one of the most important goals of athletes. Recurrence of symptoms and treatment cessation are common problems with common interventions. Approaches based on mindfulness acceptance-commitment (MAC) can be a response to these limitations. Objective: The main purpose of the present study was to determine effectiveness of the mindfulness-acceptance-commitment-based approach to athletic performance enhancement and sports competition anxiety in students who have had athletic experience for 3 to 5 years. Methods: This randomized clinical trial was conducted at the Faculty of Educational Sciences of Iran University of Medical Sciences in Tehran, Iran, from May 1, 2017 to September 15, 2017. A total of 31 students were randomly assigned to experimental (n=15) and control groups (n=16). The experimental group received the protocol Mindfulness-Acceptance-Commitment (MAC) for 8 sessions. Subjects completed the Charbonneau Sports Performance Questionnaire, Action and Acceptance Questionnaire (AAQ) and Sports Competition Anxiety Test (SCAT) Questionnaire. Data analysis was conducted by using multivariate covariance analysis (MANCOVA) by SPSS-22. Results: The results of the study indicated that the MAC approach increases significantly the performance of basketball playing athletes (p<0.05). Furthermore, the MAC approach decreases significantly experiential avoidance and sports anxiety in athletes (p<0.05). The size of the difference between the groups is moderate (Eta squared). Conclusions: This study revealed that the mindfulness-acceptance-commitment-based approach is an effective intervention to increasing athletic performance and reducing experiential avoidance and sports anxiety in athletes. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT20170409033333N1. Funding: This study has been financially supported by the Research Deputy of Iran University of Medical Sciences (Code: 95-04-185-29333). PMID- 29997758 TI - Comparison of vaginal misoprostol, laminaria, and isosorbide dinitrate on cervical preparation and labor duration of term parturient: a randomized double blind clinical trial. AB - Background: Cervical ripening plays an important role in successful labor induction. Objective: This study aimed to compare the effects of misoprostol, laminaria tent, and isosorbide dinitrate (ISDN) on cervical ripening. Methods: This double-blind three-armed clinical trial was conducted at Shahidan Mombini Teaching Hospital in Sabzevar, Iran, in 2016 on 96 singleton term pregnant women. Participants were randomly allocated to receive either two 20-mg ISDN tablets vaginally every 4 hours for a maximum of three doses or 25 mcg misoprostol vaginally every 6 hours for a maximum of two doses or laminaria tent for a maximum of 12 hours. The method of randomization was covariate adaptive randomization and the primary outcome measures were Bishop Score changes and labor duration. SPSS software version 18 was used for statistical analyses. Kruskal-Wallis, chi-square and ANOVA tests were applied for data analyses. Results: Bishop Score changes were higher in the misoprostol group than in the two other groups (p=0.014). Time from start of medication to active phase of labor and delivery were 6.22+/-3.11 and 11.78+/-5.3 minutes in the misoprostol group, 11.25+/-3.07 and 17.62+/-4.07 minutes in the laminaria group, and 10.12+/ 3.48 and 17.37+/-4.79 minutes in the ISDN group respectively (p<0.001). Cesarean rate was higher in the misoprostol group than the two other groups (p=0.016). No significant differences were observed between the study groups in terms of Apgar score and meconium-stained amniotic fluid. Conclusions: Use of misoprostol results in more improvement of Bishop Score and reduced length of labor phases in comparison to laminaria tent and ISDN. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT2016050527643N2 in the Iranian Registry of Clinical Trials IRCT2015040921670N1. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 29997759 TI - Effectiveness of intervention due to feedback on errors arising from inappropriate transportation and storage of blood bags in hospitals: a quasi experimental study. AB - Background: The limited supply of red blood cells (RBCs) for transfusion has clinical implications, and can lead to the introduction of different approaches in decreasing blood wastage and the safe and effective delivery of blood products. Objective: To identify the influences of feedback-based intervention on inappropriate temperatures during transportation and storage of blood bags. Methods: This was a quasi-experimental pretest-posttest design with a non equivalent control group that was carried out on 200 RBC. The study was conducted in a teaching hospital in Mashhad, Iran, and in two periods during the same season: winter of 2015 (pre-intervention period) and winter of 2016 (post intervention period). Staff of the blood bank department, as the intervention group, received the intervention including feedback regarding the inappropriate temperature in the blood bank during the pre-intervention period. The control group included personnel and nurses from the OR, CSICU, and transportation department, who did not receive any feedback. The effect of the intervention on the RBCs' temperature was evaluated by comparing the percentage of inappropriate temperature of RBC bags before and after the implementation of the intervention. Results: Inappropriate temperature in the blood bank decreased from 30% to 12% after the intervention was implemented (relative reduction of 60%). Meanwhile, there was even an increase in inappropriate temperature in the control group including OR (from 6.5% to 20.5%), CSICU (from 1% to 2.5%) and transportation (from 0.6% to 16.6%). Conclusion: The implementation of a feedback-based intervention to increase the awareness of the staff of critical conditions can improve conditions of blood storage and transport. The use of various interventions along with this type of intervention seems necessary to increase effectiveness. Funding: This research was part of the first author's MSc thesis which was supported by a grant from Mashhad University of Medical Science Research Council (Ref. no.: 950116; Date: September 7, 2016). PMID- 29997760 TI - Pediatric self-inflicted eye trauma due to a major depressive disorder. AB - Self-inflicted eye trauma is a serious form of self-harm as it may lead to irreversible visual disability. Diagnosing self-inflicted ocular injuries, in all its forms, can be quite challenging. In this report, we are presenting a 5-year old girl presented to Sohag University Outpatient Clinic with a history of repeated attacks of bilateral eye redness with blood-tinged strands removed from her eyes. After ocular examination, inferior bulbar conjunctival injection with blood-tinged strands were found. After careful examination of the strands, it was discovered that they were actual threads of cloth due to self-inflicted eye injury. Following psychiatric consultation, the patient was diagnosed as having a major depressive disorder. The case was subject to pharmacological and psychotherapeutic treatment, and showed significant improvement within two months of starting treatment as regard to depressive symptoms and self-injury behaviors. Although self-inflicted ocular injuries due to pediatric mood disorders are rare, it should be suspected in any case of unexplained chronic conjunctivitis. PMID- 29997761 TI - Dobutamine stress-induced ischemic right ventricular dysfunction in patients with three-vessel coronary artery disease. AB - Background: Dobutamine stress echocardiography (DSE) is a non-invasive technique to detect coronary artery diseases (CAD). There are limited studies on evaluation of the right ventricular function by stress echocardiography. The appropriate evaluation of RV function and early diagnosis of its failure can help to improve outcomes for the patients undergoing cardiac surgery. Objective: To determine right ventricular dysfunction in patients with three-vessel CAD by using DSE. Methods: This cross-sectional study was among 13 patients who were candidates for coronary artery bypass grafting (CABG) referred to Ghaem Hospital, Mashhad, Iran; from September 2015 to May 2016. After a physical examination and initial measures, DSE was performed and echocardiographic parameters were recorded by a cardiologist. Paired-samples t-test was performed using SPSS Software v.16.0 for data analysis. Results: The study included 13 patients (9 males) with a mean age of 65.4+/-7.6 years. The mean of TAPS was 16.9+/-4.5 mm and 15.7+/-2.9 mm before and after stress echocardiography, respectively (p=0.69). Systolic right ventricular (SRV) peak increased from before DSE compared with after DSE (8.0+/ 2.2 vs. 13.7+/-4.2 mm/s, p<0.001). In addition, after dobutamine injection, right ventricular (RV) cardiac output decreased in 7 patients and one patient was affected by post-ejection shortening. Conclusion: It seems that TAPS and RV cardiac output after injection of dobutamine, can be used as markers for the recognition of ischemic RV dysfunction. PMID- 29997762 TI - Pattern of chronic urticaria and value of autologous serum skin test in Sohag Province, Upper Egypt. AB - Background: Chronic urticaria (CU) is a debilitating disorder with variable clinical course. It is characterized by hives occurring for at least 6 weeks, and is classified as spontaneous or inducible. Objective: The aim of this study was to detect the pattern of CU, to study association between results of autologous serum skin test (ASST) and urticaria severity score (USS), and to detect serum levels of anti IgE receptors antibodies. Methods: This study included all patients attending the Dermatology Outpatient Clinic, Sohag University Hospital, who were diagnosed as CU from April 2015 to March 2016. ASST and serum level of anti IgE receptor antibodies was assessed using ELISA. Data were analyzed by SPSS version 16, using descriptive statistics, Kruskal-Wallis and Mann-Whitney U test. Results: A total of 108 patients with CU were included in the study. Females with mean age 33+/-12.4 years were more affected. A total of 58.3% complained of CSU, 6.5% physical urticaria and 35.2% mixed type of CU. According to USS, mild score represented 20.4%, moderate 46.3% and severe in 33.3%. ASST showed positive in 38% of patients. There was a statistically significant relation between ASST and USS and duration of CU. This indicates that more severe symptoms and prolonged duration of CU are observed in positive ASST (autoreactive type). In all, 91% of the anti IgE receptor antibodies positive patients had positive ASST. Conclusion: In conclusion, chronic urticaria is not an uncommon disease in our locality which represented 1.13% of our patients. Urticaria severity score and duration of urticaria was higher in positive ASST patients and hence the autoreactive type. PMID- 29997763 TI - Evaluation of oxidative stress indices after exposure to malathion and protective effects of ascorbic acid in ovarian tissue of adult female rats. AB - Background: Malathion is one of organophosphate pesticides that is extensively used in farming and crops to control pests. Malathion induces oxidative stress in the various tissues such as the reproductive system. Objective: To determine the effects of malathion on malondialdehyde (MDA) level and glutathione (GSH) content in female rat ovary tissue as well as to assess the protective role of Ascorbic Acid. Methods: This study was carried out at the Department of Anatomy and Cell Biology (School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran) in 2015. In this experimental study, 30 adult, female, Wistar rats (weight range: 200-250 g) were divided into five groups, each group consisting of six rats: control group (no interventions), sham group (normal saline 0.9% 50 mg/kg), experimental group 1 (Ascorbic Acid 200 mg/kg), experimental group 2 (malathion 50 mg/kg), and experimental group 3 (malathion 50 mg/kg + Ascorbic Acid 200 mg/kg). Malathion, solvents and Ascorbic Acid were injected intraperitoneally. After two weeks, the animals were anaesthetized with intraperitoneal ketamine/xylazine (60 and 6 mg/kg, respectively) and then scarified, and the right ovarian was used to measure levels of MDA, a marker of lipid peroxidation, and GSH content. Data were analyzed by SPSS version 16, using descriptive statistics, One Way ANOVA, and Tukey-Kramer test. A p-value <0.05 was set as significance level. Results: This study has shown that malathion increased MDA level and reduced GSH content compared with the control group (p<0.001). Also, administration of malathion in combination with Ascorbic Acid, reduced MDA level and increased the GSH content in rat ovarian tissue. Conclusion: Malathion induced lipid peroxidation and Oxidative stress in the ovarian of Rats. In addition, it appears that Ascorbic Acid, due to its antioxidant, can recover malathion-induced poisonous changes. PMID- 29997764 TI - A conceptual model of the impacts of quality components of a health department website on students' health literacy at Semnan University of Medical Sciences. AB - Background: People with poor health literacy are those who have less knowledge about disease management and health promotion behaviors, and generally have poorer health status. Objective: The aim of this study was to investigate the impact of qualitative components of the health website of Semnan University of Medical Sciences on the students' health literacy. Methods: This study was performed on 529 medical and allied health students in schools affiliated to Semnan University of Medical Sciences, Iran in 2016-2017. A researcher-made questionnaire and standard questionnaire were used. Descriptive statistics and regression test were used by SPSS 19 to analyze data in significance level of 0.01. Results: The findings showed that there were poor relationships between communications in the health website and health literacy (R2=0.265, B=0.50), between understanding of concepts in the health website and health literacy (R2=0.259, B=0.38) and patient centeredness in the health website and health literacy (R2=0.241, B=0.30). Conclusion: It is concluded that the empowerment of students' health literacy through the University Health Department website can be realized when the health department website is used as a tool for learning and the website is much more active in social marketing in the field of health. PMID- 29997765 TI - Exploration of nurses' perception about professionalism in home care nursing in Iran: a qualitative study. AB - Background: Professionalism is one of the basic concepts of home care nursing, as a growing model of community-based nursing. This phenomenon results from the nurse-patient interaction in home and community environments with multiple dimensions. Objective: The purpose of this study was to explore the professional experiences of home care nurses in Iran. Methods: In this study, the qualitative content analysis method was used based on the 2004 Graneheim & Lundman approach. The study was conducted between September 2016 and September 2017 in Khorasan Razavi province, Iran. Participants were selected by Purposeful Sampling. The main method of data collection was semi-structured interviews with 21 nurses who had home-based care experience. Eventually, after reaching saturation, the data were analyzed in-depth. Results: In total, 3 main categories and 11 subcategories were extracted. Generally, nurses considered the concept of professionalism in home care nursing by attention to basic values, social capital, and maintaining quality and standards of care. Conclusion: Professionalism in home care nursing is one of today's challenges in the health system of the country, and professionalism requires more attention and conditions for its prosperity. PMID- 29997766 TI - Exploring the experiences of Iranian adolescent mothers about the maternal role: a qualitative study. AB - Background: Early motherhood is one of the most important issues in developing countries. Adolescent mothers are not sufficiently prepared to accept the maternal role. How to achieve success in the maternal role should be studied. Objective: To explore the experiences of Iranian adolescent mothers about the maternal role. Methods: This qualitative study was conducted through a conventional content analysis approach from March to December 2016. Face to face in-depth semi-structured interviews were conducted with 18 Iranian teenage mothers in Kerman province, Iran. Participants were selected purposefully and with maximum variation of the age of the first birth, child's age, place of residence and financial status. Data collection continued until data saturation and MAXQDA software was utilized to analyze the collected data. Results: Data analysis resulted in the extraction of the two main categories including optimizing the process of the maternal experience (use of maximum individual capabilities, planning and management of conditions, efforts to acquire maternal competency, and reliance on spirituality) and supporters for the acceptance of the maternal role (social support, professional services of health care providers, time lapse, care history). Conclusion: Early motherhood is not merely an unpleasant experience; if appropriate strategies and facilitators are used, it can have positive consequences. Health care providers should provide satisfactory services in care, education and support with adequate knowledge of adolescent characteristics. Opportunities in the community should also be directed to support this vulnerable group. PMID- 29997767 TI - Awareness of and attitude towards blood donation in students at the Semnan University of Medical Sciences. AB - Background: Despite the increasing demands for blood and its products, some people, especially the youth, have little interest in donating blood. Objective: This study aimed to assess the university students' awareness of and attitude towards blood donation. Methods: In this cross-sectional study, a descriptive analytical approach was used to examine awareness of and attitude towards blood donation among students in Semnan University of Medical Sciences, Semnan, Iran. The study was performed in 2015-2016. A total of 749 university students participated in this study. A special questionnaire was used to collect demographic information and the participants' awareness of and attitude towards blood donation. Before beginning the main phase of the study, the reliability and validity of the questionnaire were examined and verified. The SPSS software, version 16, was used for statistical analysis. We used descriptive statistics, specifically chi-square and Friedman tests, to analyze the data. A p-value of <0.05 was considered significant. Results: 63.55% of the participants were female. Only 9.74% of the participants had a history of blood donation. Based on the results, 253 participants (35.33%) had low awareness, 352 participants (49.16%) had moderate awareness, and 111 participants (15.5%) had good awareness of blood donation. In addition, 176 participants (23.59%) had negative attitude, 438 participants (58.71%) had moderate attitude, and only 132 participants (17.69%) had good attitude towards blood donation. Results also showed a statistically significant relationship between gender and awareness of the history of blood donation (p=0.047). However, there was no significant relationship between gender and attitude towards blood donation (p=0.27). When asked about their favorite method of receiving information about blood donation, 376 participants (50.2%) preferred social media. Conclusion: A considerable percentage of students have low awareness of and negative attitude towards blood donation. The low awareness and negative attitude towards blood donation can be considered as important factors contributing to the lack of interest and poor participation in blood donation among this population. Therefore, there is a critical need for training and culture building activities and programs in order to increase university students' awareness and improve their attitude towards blood donation. PMID- 29997768 TI - Hospital Information Systems: The status and approaches in selected countries of the Middle East. AB - Background and aim: Since hospital information systems (HISs) are among the most important information systems in the health sector, the present study aimed to shed light upon the situation of HISs in selected countries of the Persian Gulf region to reflect national strategies and activities in the case of HISs. Methods: In this descriptive cross-sectional study, the information about HISs status of the selected countries of the Persian Gulf region were obtained through approaches including review of national and international resources. Then, according to aspects included in HIS status, content analysis was performed. Information obtained from content analysis after several stages of reading, was categorized and then findings, presented. Results: The findings revealed that the surveyed countries have widely used HISs since the 1980s. HIS use and development vary to a certain extent. Since the middle of the first decade of the 21st century, Ministry of Health officials of the studied countries have considered the importance of HIS's integration and creating Electronic Health Record where, Oman, Bahrain and UAE are among the leading countries. Conclusion: Since the emergence of HISs in healthcare centers, these countries have employed various approaches. In any case, in order to avoid wasting important resources, including financial and human ones, the use of successful experiences of other countries along with the formulation of a comprehensive plan is highly recommended while considering all HIS aspects, including national and international standards. PMID- 29997769 TI - Comparison of health behaviors among students of Iranian medical and human sciences universities. AB - Background and aim: Health risk behaviors are major and threatening problems of societies. The aim of this study was to determine and compare health behaviors among students of Iranian medical and human sciences universities. Methods: In this cross-sectional study, 570 senior medical and human sciences students of Ilam universities (Ilam, Iran) were selected during the period between October 2015 and October 2016, using the stratified random sampling method. The research tool was the self-assessment health questionnaire which consists of personal information, understanding the concept of health and health behaviors. Descriptive statistics and Mann-Whitney U, independent samples t-test and Pearson product-moment correlation tests were used in SPSS version 16. Results: The scores obtained by both groups of medical sciences and human sciences students were low. There was no significant relationship between field of study and the score of understanding the concept of health (p=0.289); but the relationship between field of study and the score on health behaviors (p=0.001) and between health behaviors and understanding the concept of health were significant for both the students of medicine (r=0.259, p=0.01) and the students of human sciences (r=0.493, p=0.001). Conclusion: Students' health behaviors were not at a desirable level. Conducting interventions in the form of research projects have been recommended. PMID- 29997770 TI - Exploring the perception of women with epilepsy about pregnancy concerns: a qualitative study. AB - Background and aim: Epilepsy is a common neurological disorder in pregnancy, which is associated with increased maternal and fetal adverse outcomes. This study aimed to explore the reproductive healthcare needs of women with epilepsy before, during and after childbirth. Methods: This was a qualitative study using a content analysis method. The study population was marital women with epilepsy in reproductive age (15-45 years) referred to Imam Hossein Hospital, Tehran, Iran. Participants were 16 women chosen using purposive sampling with the consideration of maximum variation in sampling. Semi-structured interviews were held with the participants until data saturation was reached. The data were analyzed using the content analysis method. The MAXQDA software, version 2010, was used for the management of data. Results: The data analysis led to the development of two categories. The first one is named 'resilience against threats to safe pregnancy' and has the following subcategories: (1) real physical complications and perceived (mental) conditions due to unwanted pregnancies, (2) the predisposing factors of anxiety related to safe pregnancy, (3) perceived consequences of pregnancy', and (4) the approach to encounter perceived consequences of pregnancy. The second category is called 'adverse experiences under inefficient supportive systems' and has the following subcategories: (1) the insufficiency of reproductive healthcare services for women with epilepsy, (2) doubt about the advantages and disadvantages of breastfeeding, (3) stigma as a block to the treatment of the postpartum depression, and (4) playing the motherhood role under the shadow of self-esteem to lack of self-esteem. Conclusion: In the prenatal, natal and postnatal duration, because of supportive system disruption and not receiving proper consultation, participants were often worried about not being able to get favorable conditions for safe pregnancy and controlling process of their pregnancy. Therefore, they often experienced unwanted pregnancy. They were also concerned about the adverse fetal outcomes. In postpartum period, they often experienced postpartum depression and were very doubtful about breastfeeding. PMID- 29997771 TI - Resilience and therapeutic regimen compliance in patients undergoing hemodialysis in hospitals of Hamedan, Iran. AB - Background: The relationship between resilience, one of the important issues in mental health, and therapeutic regimen compliance, the key in the successful management of chronic disease such as chronic kidney disease, is unclear. Objective: The aim of this study was to determine the relationship between resilience and therapeutic regimen compliance in ESRD patients, undergoing hemodialysis. Methods: In this cross-sectional study, 107 hemodialysis patients referred to Besat and Shahid Beheshti Hospitals of Hamedan, Iran were selected through systematic sampling method from January to April 2013. The tool was Connor-Davidson Resilience Scale (CD-RISC). The criteria for compliance were: mean of interdialytic weight gain less than 5.7% to the dry weight, serum potassium 5.5 mEq/L or less, serum phosphorus of 6 mg/dL or less and no more than 3 absences in dialysis sessions. For data analysis, statistical tests such as independent t-test and Logistic regression were performed. Results: Fifty-seven (53.3%) patients were males and the mean age of subjects was 49.96+/-17.39 years. The difference in the mean scores of resilience between compliance or non compliance patients was statistically significant (p=0.032). Only resilience and age were significant factors related to regimen compliance. In those subjects with greater resilience for 1 score, the chance of compliance with the therapeutic regimen would be 5.4% higher (OR=1.054, CI 95%: 1.01-1.103). In addition, the elderly patients were more likely to comply with the regimen (OR=1.072, CI 95 %: 1.033, 1.113). Conclusion: According to the results, the patients with greater scores of resilience were more likely to comply with the therapeutic regimen. PMID- 29997772 TI - Epidemiology of road traffic accidents in Rafsanjan city, Iran. AB - Introduction: Injury is recognized as a major health problem in most high and low income countries. Rafsanjan is considered as one of the accident-prone areas in Kerman province. Objective: To study the epidemiology of traffic accidents in the Rafsanjan city. Methods: This cross-sectional study was conducted, by using the data from the Emergency Department (ED) of Aliebn Abitaleb Hospital in Rafsanjan city. The population included all people who had had a traffic accident in the city of Rafsanjan from March 21, 2014 through February 18, 2015. The sample included those who had been injured and transferred to the ED of Aliebn Abitaleb Hospital. Data were analyzed using Chi-square, independent-samples t-test, and logistic regression. SPSS software version 19 was used for data analysis. P< 0.05 was considered statistically significant. Results: Age, gender and location of accident, had significant association with the number of mortalities (p=0.02), and other results of this study suggest that there was a significant relationship between the status of the injured and the gender (p<0.001), the accident location (p<0.001), and the type of injury (p<0.001). Conclusion: The rate of accidents in one year in Rafsanjan city was high. Moreover, young people and motorcyclists had most accidents. Teaching the laws and regulations to the people of the city, is the most effective method in reducing accidents and mortality. PMID- 29997773 TI - The study of work-family conflict and job satisfaction among nurses' state hospitals in Tehran city. AB - Introduction: Since nurses work in various wards, job satisfaction evaluation and work-family conflict investigation among them regarding the ward they work in is highly crucial, because on one hand, there are ample requests for changes in wards, shifts, hospitals, and even job abandonment, and on the other hand, family conflicts and clashes have increased among nurses. Methods: This correlational research was conducted on 280 nurses who worked in special and general wards of state hospitals in Tehran in 2015. In this study, samples were selected randomly among state hospitals subsidiary to Tehran and Shahid Beheshti universities and social security hospitals in Tehran. Data were collected by means of demographic questionnaire, Smith's job satisfaction questionnaire, and Net Mayer and Mc Marian's Work-Family conflict questionnaire. In order to analyze the data, SPSS version 21 software was employed and also descriptive statistics methods, correlation coefficient, t-test, regression, and ANOVA were applied. Results: According to the study's findings, job satisfaction average scores in the supervisor dimension in special and general wards were medium (44.15, 43.868) (p=0.771), job satisfaction average scores in the work dimension in both special and general wards were relatively medium (30.869, 31.520), job satisfaction scores in promotion opportunity aspect in both special and general wards were weak (14.31, 14.187), also work-family conflict average score was 26.07 in special wards and 25.51 in general wards (p=0.519), and work-family conflict average scores in special wards was 15.71 and in general wards was 14.87 (p=0.420), these differences were not significant. Conclusion: The study outcomes reveal that nurses' job satisfaction is at the medium level. It is noteworthy that the highest percentage of nurses' job satisfaction in both general wards and special wards are associated with being satisfied with their head nurse, and work family conflict is equal in both sets of wards (general and special). It is recommended that more studies in the realm of nurses' job satisfaction and work family conflict should be done. PMID- 29997774 TI - Analysis of the reasons for nurses' confusion in relation to the concept of brain death from clinical and legal points of view. AB - Background: Nurses in intensive care units (ICU) play a key role in taking care of brain dead patients and they are often in contact with such patients given the high rate of brain deaths. Consequently, they are in a challenging and stressful condition, which may be aggravated due to the need for increased organ donation, and this may also affect the quality of care provided for these patients. Objective: This review analyzes the different studies on the concept of brain death from both medical and legal points of view. The aim of this study was to identify the challenges the nurses face with the perception of the concept of brain death and its effects on the care provided for the patients suffering from brain death, as well as organ donation. Methods: This Narrative review study summarizes the information obtained from relevant literature through a targeted search of library texts and electronic resources including Science Direct, PubMed, Google Scholar, Scientific Information Database (SID), IranMedex, and Magiran databases during 2000-2017 in English and Persian, on the subject of interest by keywords such as brain death, organ donation, care, legal, regulations and nursing. Finally, a total of 44 relevant articles were reviewed. Results: Nurses play an important role in taking care of brain dead patients; therefore, recognizing challenges can be the first step in taking accurate care of these patients and subsequently maintaining the organs' health for transplants. Although there are clinical and legal uncertainties regarding the concept of brain death, nurses have an important effect on taking care of brain dead patients as well as the rate of organ donation. Conclusion: Nurses in intensive care units should have a clear understanding of the concept of brain death in order to be able to take care of brain dead patients by avoiding psychological effects. In this regard, it is recommended that a comprehensive educational program be designed on the dimensions of brain death. Therefore, the nurses' awareness of brain death and their ability to clarify this concept to the patients' relatives would have a great effect on the decrease in the challenges and the stress imposed on the nurses. Also, there would be an increase in the quality of the care given to brain dead patients and even the rate of organ donation. PMID- 29997775 TI - Sc3N@Ih -C80 as a novel Lewis acid to trap abnormal N-heterocyclic carbenes: the unprecedented formation of a singly bonded [6,6,6]-adduct. AB - The reaction between an N-heterocyclic carbene (NHC), namely 1,3 bis(diisopropylphenyl)-imidazol-2-ylene (1), and Sc3N@Ih -C80 successfully affords a Lewis acid-base pair (2a). Single crystal X-ray crystallographic results unambiguously reveal the unexpected structure of 2a where the abnormal carbene center of the NHC is connected to a triple-hexagon-junction (THJ) carbon atom of Sc3N@Ih -C80via a single bond. Theoretical calculations reveal that selective entrapment of the abnormal carbene 1 is caused by the steric hindrance between the normal NHC moiety and the fullerene cage, which precludes the formation of normal carbene adducts. Furthermore, the analysis of the electronic density distribution on the cage of Sc3N@Ih -C80 indicates that THJ carbons bear relatively low negative charge densities and, accordingly, are easily attacked by the electron-rich NHC 1 to form the singly bonded [6,6,6]-adduct 2a instead of the corresponding [5,6,6]-adduct 2b. It is thus confirmed that the regioselective formation of 2a is a synergistic effect of both cage size and electron density distribution. Sc3N@Ih -C80, although with a highly charged cage, is proven to show excellent Lewis acidity, opening a wide avenue toward carbon-based Lewis acids taking into account the diversity of endohedral metallofullerenes. PMID- 29997776 TI - Isolation of Au-, Co-eta1PCO and Cu-eta2PCO complexes, conversion of an Ir eta1PCO complex into a dimetalladiphosphene, and an interaction-free PCO anion. AB - Sodium phosphaethynolate reacts with [MCl(PDI)] (M = Co, Ir; PDI = pyridinediimine) to give metallaphosphaketenes, which in the case of iridium rearranges into a dimetalladiphosphene, via CO migration from phosphorus to the metal. Two different bonding modes of the PCO anion to CAAC-coinage metal complexes [CAAC: cyclic (alkyl)(amino)(carbene)] are reported, one featuring a strong Au-P bond and the other an eta2 coordination to copper. The gold complex appears to be mostly unreactive whereas the copper complex readily reacts with various organic substrates. A completely free PCO anion was structurally characterized as the [Cu(La)2]+ (OCP)- salt. It results from the simple displacement of the PCO unit of the cationic (CAAC)Cu(PCO) complex by a second equivalent of CAAC. PMID- 29997777 TI - Simple and ultrastable all-inclusive pullulan tablets for challenging bioassays. AB - Many biodetection systems employ labile enzymes and substrates that need special care, making it hard to routinely use them for point-of-care or field applications. In this work we provide a simple solution to this challenging problem through the creation of all-inclusive pullulan assay tablets. The proposed tablet system not only enhances the long-term stability of both enzymes and organic substrates, but also simplifies the assay procedure. The enhanced stability is attributed to two factors: the restriction of the molecular motion of proteins and impermeability to molecular oxygen afforded by the tables. These tablets dissolve rapidly upon addition to testing samples, making the test very easy to perform. Using the ATP-detecting luciferase-luciferin system as an example, we show that the tablet-based assay can achieve highly sensitive detection of ATP in biological samples and that the activity of the assay tablets remains unchanged for over a month at room temperature. PMID- 29997778 TI - HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat. AB - Histone deacetylase inhibitors (HDACi) and panobinostat in particular are currently in the focus of intensive investigation as latency reversing agents against the human immunodeficiency virus (HIV). Regretfully, HDACi have dose limiting side-effects making controlled, optimized methods for delivery of panobinostat highly warranted. This has proven to be highly challenging, predominantly because panobinostat has no readily available classic sites for bioconjugation. In this work, we address this challenge and present the first macromolecular prodrugs of panobinostat engineered using self immolative linkers (SIL) and a disulfide trigger for drug release upon cell entry. Synthetic methodology involved the development of a novel monomer with functionalities of SIL and activated ester for one-step polymer-analogous conjugation to drugs. In agreement with the design set forward, copolymers were stable in buffered solutions and released panobinostat at reducing conditions. Synthesized polymers were highly efficacious as latency reversing agents as monitored in three cell lines harboring latent HIV, at no expense to the cytotoxicity of treatment. The data presented herein provide broad pre-in vivo characterization of a promising prodrug system developed to address a global healthcare challenge, safe and efficient reversal of HIV latency. PMID- 29997779 TI - Multi-luminescent switching of metal-free organic phosphors for luminometric detection of organic solvents. AB - Metal-free organic phosphors can be an attractive smart optical sensing materials since, in such compounds, intersystem crossing (ISC) and the phosphorescence process are placed in subtle competition with fluorescence, internal conversion (IC), and non-radiative decay pathways. Here, we report a unique environment dependent multi-luminescence switching behavior of metal-free organic phosphorescent materials. Through combined photophysical measurements and computational electronic structure analysis, we systematically investigated how physicochemical properties of organic solvents affect the photophysical pathways of the metal-free organic phosphors. By rationally adapting the finding into phosphor-doped electrospun polymer fibers, we developed a new luminometric sensory platform and achieved selective detection of eight different common organic solvents. The presented finding provides new possibilities for metal-free organic phosphors to be a novel class of smart optical sensory materials. PMID- 29997780 TI - Electrochemical fingerprint of street samples for fast on-site screening of cocaine in seized drug powders. AB - We report on a wearable fingertip sensor for on-the-spot identification of cocaine and its cutting agents in street samples. Traditionally, on-site screening is performed by means of colour tests which are difficult to interpret and lack selectivity. By presenting the distinct voltammetric response of cocaine, cutting agents, binary mixtures of cocaine and street samples in solution and powder street samples, we were able to elucidate the electrochemical fingerprint of all these compounds. The new electrochemical concept holds considerable promise as an on-site screening method. PMID- 29997781 TI - Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action. AB - Our study demonstrates that Pt(iv) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)2(PhB)2Cl2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(iv) derivatives of cisplatin with either two hydroxido, two acetato or two valproato ligands. The high potency of this compound (and some others) is due to several factors including enhanced internalization, probably driven by "synergistic accumulation" of both the Pt moiety and the phenylbutyrate, that correlates with enhanced DNA binding and cytotoxicity. ctc-[Pt(NH3)2(PhB)2Cl2] inhibits 60-70% HDAC activity in cancer cells, at levels below the IC50 values of PhB, suggesting synergism between Pt and PhB. Mechanistically, ctc-[Pt(NH3)2(PhB)2Cl2] induces activation of caspases (3 and 9) triggering apoptotic signaling via the mitochondrial pathway. Data also suggest that the antiproliferative effect of ctc-[Pt(NH3)2(PhB)2Cl2] may not depend of p53. Pt(iv) derivatives of cisplatin with either two axial PhB or valproate ligands are more potent than their oxaliplatin analogs. ctc [Pt(NH3)2(PhB)2Cl2] is significantly more potent than its valproate analog ctc [Pt(NH3)2(VPA)2Cl2]. These compounds combine multiple effects such as efficient uptake of both Pt and PhB with DNA binding, HDAC inhibition and activation of caspases to effectively kill cancer cells. PMID- 29997782 TI - Separated-pair approximation and separated-pair pair-density functional theory. AB - Multi-configuration pair-density functional theory (MC-PDFT) has proved to be a powerful way to combine the capabilities of multi-configuration self-consistent field theory to represent the an electronic wave function with a highly efficient way to include dynamic correlation energy by density functional theory. All applications reported previously involved complete active space self-consistent field (CASSCF) theory for the reference wave function. For treating large systems efficiently, it is necessary to ask whether good accuracy is retained when using less complete configuration interaction spaces. To answer this question, we present here calculations employing MC-PDFT with the separated pair (SP) approximation, which is a special case (defined in this article) of generalized active space self-consistent-field (GASSCF) theory in which no more than two orbitals are included in any GAS subspace and in which inter-subspace excitations are excluded. This special case of MC-PDFT will be called SP-PDFT. In SP-PDFT, the electronic kinetic energy and the classical Coulomb energy, the electronic density and its gradient, and the on-top pair density and its gradient are obtained from an SP approximation wave function; the electronic energy is then calculated from the first two of these quantities and an on-top density functional of the last four. The accuracy of the SP-PDFT method for predicting the structural properties and bond dissociation energies of twelve diatomic molecules and two triatomic molecules is compared to the SP approximation itself and to CASSCF, MC-PDFT based on CASSCF, CASSCF followed by second order perturbation theory (CASPT2), and Kohn-Sham density functional theory with the PBE exchange-correlation potential. We show that SP-PDFT reproduces the accuracy of MC-PDFT based on the corresponding CASSCF wave function for predicting C-H bond dissociation energies, the reaction barriers of pericyclic reactions and the properties of open-shell singlet systems, all at only a small fraction of the computational cost. PMID- 29997783 TI - Dehydrocoupling of phosphine-boranes using the [RhCp*Me(PMe3)(CH2Cl2)][BArF4] precatalyst: stoichiometric and catalytic studies. AB - We report a detailed, combined experimental and computational study on the fundamental B-H and P-H bond activation steps involved in the dehydrocoupling/dehydropolymerization of primary and secondary phosphine-boranes, H3B.PPhR'H (R = Ph, H), using [RhCp*(PMe3)Me(ClCH2Cl)][BArF4], to either form polyphosphino-boranes [H2B.PPhH] n (Mn ~ 15 000 g mol-1, PDI = 2.2) or the linear diboraphosphine H3B.PPh2BH2.PPh2H. A likely polymer-growth pathway of reversible chain transfer step-growth is suggested for H3B.PPhH2. Using secondary phosphine boranes as model substrates a combined synthesis, structural (X-ray crystallography), labelling and computational approach reveals: initial bond activation pathways (B-H activation precedes P-H activation); key intermediates (phosphido-boranes, alpha-B-agostic base-stabilized boryls); and a catalytic route to the primary diboraphosphine (H3B.PPhHBH2.PPhH2). It is also shown that by changing the substituent at phosphorus (Ph or Cy versust Bu) different final products result (phosphido-borane or base stabilized phosphino-borane respectively). These studies provide detailed insight into the pathways that are operating during dehydropolymerization. PMID- 29997784 TI - Selective capture of hexavalent chromium from an anion-exchange column of metal organic resin-alginic acid composite. AB - We report an anion exchange composite material based on a protonated amine functionalized metal-organic framework, denoted Metal Organic Resin-1 (MOR-1), and alginic acid (HA). MOR-1-HA material shows an exceptional capability to rapidly and selectively sorb Cr(vi) under a variety of conditions and in the presence of several competitive ions. The selectivity of MOR-1-HA for Cr(vi) is shown to be the result of strong O3CrVI...NH2 interactions. The composite sorbent can be successfully utilized in an ion-exchange column, in contrast to pristine MOR-1 which forms fine suspensions in water passing through the column. Remarkably, an ion exchange column with only 1% wt MOR-1-HA and 99% wt sand (an inert and inexpensive material) is capable of reducing moderate and trace Cr(vi) concentrations to well below the acceptable safety limits for water. The relatively low cost of MOR-1-HA/sand column and its high regeneration capability and reusability make it particularly attractive for application in the remediation of Cr(vi)-bearing industrial waste. PMID- 29997785 TI - Construction of homogeneous antibody-drug conjugates using site-selective protein chemistry. AB - Systemic chemotherapy, the current standard of care for the treatment of cancer, is rarely curative and is often accompanied by debilitating side effects. Targeted drug delivery stands as an alternative to chemotherapy, with the potential to improve upon its low efficacy and systemic toxicity. Among targeted therapeutic options, antibody-drug conjugates (ADCs) have emerged as the most promising. These conjugates represent a new class of biopharmaceuticals that selectively deliver potent cytotoxic drugs to cancer cells, sparing healthy tissue throughout the body. Despite this promise, early heterogenous ADCs suffered from stability, pharmacokinetic, and efficacy issues that hindered clinical development. Recent advances in antibody engineering, linkers for drug release, and chemical site-selective antibody conjugation have led to the creation of homogenous ADCs that have proven to be more efficacious than their heterogeneous predecessors both in vitro and in vivo. In this minireview, we focus on and discuss recent advances in chemical site-selective modification strategies for the conjugation of drugs to antibodies and the resulting potential for the development of a new generation of homogenous ADCs. PMID- 29997787 TI - Sensitive and fast identification of bacteria in blood samples by immunoaffinity mass spectrometry for quick BSI diagnosis. AB - Bloodstream infections rank among the most serious causes of morbidity and mortality in hospitalized patients, partly due to the long period (up to one week) required for clinical diagnosis. In this work, we have developed a sensitive method to quickly and accurately identify bacteria in human blood samples by combining optimized matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MS) and efficient immunoaffinity enrichment/separation. A library of bacteria reference mass spectra at different cell numbers was firstly built. Due to a reduced sample spot size, the reference spectra could be obtained from as few as 10 to 102 intact bacterial cells. Bacteria in human blood samples were then extracted using antibodies-modified magnetic beads for MS fingerprinting. By comparing the sample spectra with the reference spectra based on a cosine correlation, bacteria with concentrations as low as 500 cells per mL in blood serum and 8000 cells per mL in whole blood were identified. The proposed method was further applied to positive clinical blood cultures (BCs) provided by a local hospital, where Escherichia coli and Staphylococcus aureus were identified. Because of the method's high sensitivity, the BC time required for diagnosis can be greatly reduced. As a proof of concept, whole blood spiked with a low initial concentration (102 or 103 cells per mL) of bacteria was cultured in commercial BC bottles and analysed by the developed method after different BC times. Bacteria were successfully identified after 4 hours of BC. Therefore, an entire diagnostic process could be accurately accomplished within half a day using the newly developed method, which could facilitate the timely determination of appropriate anti-bacterial therapy and decrease the risk of mortality from bloodstream infections. PMID- 29997786 TI - From curiosity to applications. A personal perspective on inorganic photochemistry. AB - Over the past several decades, the photochemistry and photophysics of transition metal compounds has blossomed from a relatively niche topic to a major research theme. Applications arising from the elucidation of the fundamental principles defining this field now range from probing the rates and mechanisms of small molecules with metalloproteins to light activated molecular machines. Offered here is a personal perspective of metal complex photochemistry drawn from this author's long involvement with this field. Several examples are described. Topics include characterizing key excited states and tuning these to modify chemical reactivity and/or photoluminescence properties, as well as using photoreactions as an entry to reactive intermediates relevant to homogeneous catalysts. This is followed by discussions of applying these concepts to developing precursors and precursor-antenna conjugates for the photochemical delivery of small molecule bioregulators to physiological targets. PMID- 29997788 TI - Interplay between surface chemistry and performance of rutile-type catalysts for halogen production. AB - Catalytic HBr oxidation is an integral step in the bromine-mediated functionalisation of alkanes to valuable chemicals. This study establishes the relationships between the mechanism of HBr oxidation over rutile-type oxides (RuO2, IrO2, TiO2) and their apparent catalytic performance. Comparison with the well-studied HCl oxidation revealed distinct differences in surface chemistry between HBr and HCl oxidation that impact the stability and activity of the catalysts. The kinetic fingerprints of both oxidation reactions over the three rutile-type oxides investigated are compared using temporal analysis of products, which substantiates the energy profiles derived from density functional theory. The quantitative determination of the halogen uptake under operando conditions using prompt gamma activation analysis demonstrates that RuO2 suffers from extensive subsurface bromination upon contact with hydrogen bromide, particularly at low temperature and low O2 : HBr ratios, which negatively affects the stability of the catalyst. TiO2 exhibits intrinsically low halogen coverage (30 50%) under all the conditions investigated, due to its unique defect-driven mechanism that renders it active and stable for Br2 production. On the contrary, for HCl oxidation TiO2 is inactive, and the chlorination of the highly active RuO2 is limited to the surface. Differences in the extent of surface halogenation of the materials were also confirmed by high-resolution transmission electron microscopy and explained by the DFT calculations. These insights into the molecular-level processes taking place under working conditions pave the way for the design of the next generation catalysts for bromine production. PMID- 29997789 TI - Metal-responsive structural transformation between artificial DNA duplexes and three-way junctions. AB - DNA three-way junctions (3WJs) are essential structural motifs for DNA nanoarchitectures and DNA-based materials. We report herein a metal-responsive structural transformation between DNA duplexes and 3WJs using artificial oligonucleotides modified with a 2,2'-bipyridine (bpy) ligand. A mixture of bpy modified DNA strands and natural complementary strands were self-assembled exclusively into duplexes without any transition metal ions, while they formed 3WJs in the presence of NiII ions. This transformation was induced by the formation of an interstrand NiII(bpy)3 complex, which served as a template for the 3WJ assembly. Altering the amount and identity of the metal ion regulated the 3WJ induction efficiency. Removal of the metal using EDTA quantitatively regenerated the duplexes. The metal-dependent structural conversion shown here has many potential applications in the development of stimuli-responsive DNA materials. PMID- 29997790 TI - Improvement of enzyme-linked immunosorbent assay for the multicolor detection of biomarkers. AB - An enzyme-linked immunosorbent assay that is dependent on enzyme amplification has dominated the current field of protein detection; however, limited multiple detection ability and susceptible enzymatic reactions, and low sensitivity may severely hinder its application. Here, we report a new signal amplification scheme based on allochroic molecule modified carboxyl graphene oxide (cGO), which can be used to develop a multicolor immunoassay named as allochroic-cGO linked immunosorbent assay (ALISA). Thanks to high adsorption levels and a wide selection of allochroic molecules, the simultaneous colorimetric detection of diagnostic biomarkers at a picogram level can be successfully achieved for the first time. In addition, the color change triggered by acidic or basic water can provide a simple, rapid, stable and economical signal output, further meeting the growing biodetection requirements. Moreover, with the help of ALISA, we demonstrate that the combined detection of three tumor biomarkers, including carcino-embryonic antigen, neuron-specific enolase, and cytokeratin-19 fragment, is more valuable for differentiating lung cancer patients than the detection of a single biomarker, further manifesting the superiority of ALISA. All in all, this straightforward approach not only opens up new prospects for multicolor immunoassays, but also has great potential for applications in resource constrained settings. PMID- 29997791 TI - A pillar[5]arene-based [2]rotaxane lights up mitochondria. AB - Subcellular organelle-specific reagents for simultaneous targeting, imaging and treatment are highly desirable for cancer therapy. However, it remains a challenge to fabricate a single molecular platform containing a targeting group, imaging and therapeutic agents through traditional synthesis. Due to their superior sensitivity and photostability, fluorescent probes with aggregation induced emission (AIE) characteristics have attracted more and more attention in studying the process of translocation, drug release, and excretion of nanomedicines in vitro or in vivo. We construct a pillar[5]arene-based [2]rotaxane (R1) by employing tetraphenylethene (TPE) and triphenylphosphonium (TPP) moieties as stoppers; the TPE unit retains the aggregation-induced emission (AIE) attribute and the TPP group is used as a mitochondria-targeting agent. R1 exhibits enhanced AIE, high specificity to mitochondria, and superior photostability. By introducing doxorubicin (DOX) into R1, prodrug R2 is constructed as a dual-fluorescence-quenched Forster resonance energy transfer (FRET) system, in which the TPE-based axle acts as a donor fluorophore and the DOX unit acts as the acceptor. Upon hydrolysis of R2 in endo/lysosomes, the fluorescences of the carrier and the drug recover. R1 is further utilized as a drug delivery platform to conjugate other anticancer drugs containing amine groups through imine formation to prepare prodrugs. The anticancer drugs are released from these prodrugs in the cells upon hydrolysis of the pH-responsive imine bonds. PMID- 29997792 TI - A multi-dimensional quasi-zeolite with 12 * 10 * 7-ring channels demonstrates high thermal stability and good gas adsorption selectivity. AB - A novel quasi-zeolite PKU-15, with a rare 3-dimensional structure containing interconnected large (12-ring), medium (10-ring) and small (7-ring) multi-pore channels, was hydrothermally synthesised and characterised. A unique tri-bridging O2- anion is found to be encapsulated in the cage-like (Ge,Si)12O31 building unit and energetically stabilises the PKU-15 framework. The removal of this oxygen atom would convert PKU-15 into a hypothetical zeolite PKU-15H. Thus, PKU-15 can be considered as a unique 'quasi-zeolite', which bridges porous germanates and zeolites. Owing to the absence of terminal Ge-OH groups in its structure, PKU-15 shows a remarkably high thermal stability of up to 600 degrees C. PKU-15 is also the first microporous germanate that exhibits permanent porosity, with a BET area of 428 m2 g-1 and a good adsorption affinity toward CO2. PMID- 29997793 TI - Chemoselective nitro reduction and hydroamination using a single iron catalyst. AB - The reduction and reductive addition (formal hydroamination) of functionalised nitroarenes is reported using a simple and bench-stable iron(iii) catalyst and silane. The reduction is chemoselective for nitro groups over an array of reactive functionalities (ketone, ester, amide, nitrile, sulfonyl and aryl halide). The high activity of this earth-abundant metal catalyst also facilitates a follow-on reaction in the reductive addition of nitroarenes to alkenes, giving efficient formal hydroamination of olefins under mild conditions. Both reactions offer significant improvements in catalytic activity and chemoselectivity and the utility of these catalysts in facilitating two challenging reactions supports an important mechanistic overlap. PMID- 29997794 TI - Benzo-thia-fused [n]thienoacenequinodimethanes with small to moderate diradical characters: the role of pro-aromaticity versus anti-aromaticity. AB - Open-shell singlet diradicaloids have recently received much attention due to their unique optical, electronic and magnetic properties and promising applications in materials science. Among various diradicaloids, quinoidal pi conjugated molecules have become the prevailing design. However, the need for a fundamental understanding on how the fusion mode and pro-aromaticity/anti aromaticity affect their diradical character and physical properties remains unaddressed. In this work, a series of pro-aromatic benzo-thia-fused [n]thienoacenequinodimethanes (Thn-TIPS (n = 1-3) and BDTh-TIPS) were synthesized and compared with the previously reported anti-aromatic bisindeno-[n]thienoacenes (Sn-TIPS, n = 1-4). The ground-state geometric and electronic structures of these new quinoidal molecules were systematically investigated by X-ray crystallographic analysis, variable temperature NMR, ESR, SQUID, Raman, and electronic absorption spectroscopy, assisted by DFT calculations. It was found that the diradical character index (y0) increased from nearly zero for Th1-TIPS to 2.4% for Th2-TIPS, 18.2% for Th3-TIPS, and 38.2% for BDTh-TIPS, due to the enhanced aromatic stabilization. Consequently, with the extension of molecular size, the one-photon absorption spectra are gradually red-shifted, the two-photon absorption (TPA) cross section values increase, and the singlet excited state lifetimes decrease. By comparison with the corresponding anti-aromatic analogues Sn-TIPS (n = 1-3), the pro-aromatic Thn-TIPS (n = 1-3) exhibit larger diradical character, longer singlet excited state lifetime and larger TPA cross section value. At the same time, they display distinctively different electronic absorption spectra and improved electrochemical amphotericity. Spectroelectrochemical studies revealed a good linear relationship between the optical energy gaps and the molecular length in the neutral, radical cationic and dicationic forms. Our research work discloses a significant difference between the pro-aromatic and anti-aromatic quinoidal compounds and provides guidance for the design of new diradicaloids with desirable properties. PMID- 29997795 TI - Strong Bronsted acid promoted asymmetric hydrogenation of isoquinolines and quinolines catalyzed by a Rh-thiourea chiral phosphine complex via anion binding. AB - Rhodium catalyzed asymmetric hydrogenation of both isoquinolines and quinolines provides a new method to synthesize chiral tetrahydroisoquinolines and tetrahydroquinolines. By introducing strong Bronsted acid HCl, anion binding between the substrate and the ligand was established to achieve high reactivity and high enantioselectivity (up to 99% conversion and 99% ee). An NMR study suggests an anion binding between the catalyst and the substrate. Deuterium labeling experiments reveal a plausible reaction pathway. PMID- 29997796 TI - Multi-scale imaging of anticancer platinum(iv) compounds in murine tumor and kidney. AB - Nano-scale secondary ion mass spectrometry (NanoSIMS) enables trace element and isotope analyses with high spatial resolution. This unique capability has recently been exploited in several studies analyzing the subcellular distribution of Au and Pt anticancer compounds. However, these studies were restricted to cell culture systems. To explore the applicability to the in vivo setting, we developed a combined imaging approach consisting of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), NanoSIMS and transmission electron microscopy (TEM) suitable for multi-scale detection of the platinum distribution in tissues. Applying this approach to kidney and tumor samples upon administration of selected platinum(iv) anticancer prodrugs revealed uneven platinum distributions on both the organ and subcellular scales. Spatial platinum accumulation patterns were quantitatively assessed by LA-ICP-MS in histologically heterogeneous organs (e.g., higher platinum accumulation in kidney cortex than in medulla) and used to select regions of interest for subcellular-scale imaging with NanoSIMS. These analyses revealed cytoplasmic sulfur-rich organelles accumulating platinum in both kidney and malignant cells. Those in the tumor were subsequently identified as organelles of lysosomal origin, demonstrating the potential of the combinatorial approach for investigating therapeutically relevant drug concentrations on a submicrometer scale. PMID- 29997797 TI - Overall water splitting by Pt/g-C3N4 photocatalysts without using sacrificial agents. AB - We report the direct splitting of pure water by light-excited graphitic carbon nitride (g-C3N4) modified with Pt, PtO x , and CoO x as redox cocatalysts, while pure g-C3N4 is virtually inactive for overall water splitting by photocatalysis. The novelty is in the selective creation of both H2 and O2 cocatalysts on surface active sites of g-C3N4via photodeposition triggering the splitting of water for the simultaneous evolution of H2 and O2 gases in a stoichiometric ratio of 2 : 1, irradiated with light, without using any sacrificial reagents. The photocatalyst was stable for 510 hours of reaction. PMID- 29997798 TI - What determines if a ligand activates or passivates a superatom cluster? AB - Quantum confinement in small metal clusters leads to a bunching of states into electronic shells reminiscent of shells in atoms, enabling the classification of clusters as superatoms. The addition of ligands tunes the valence electron count of metal clusters and appears to serve as protecting groups preventing the etching of the metallic cores. Through a joint experimental and theoretical study of the reactivity of methanol with aluminum clusters ligated with iodine, we find that ligands enhance the stability of some clusters, however in some cases the electronegative ligand may perturb the charge density of the metallic core generating active sites that can lead to the etching of the cluster. The reactivity is driven by Lewis acid and Lewis base active sites that form through the selective positioning of the iodine and the structure of the aluminum core. This study enriches the general knowledge on clusters including offering insight into the stability of ligand protected clusters synthesized via wet chemistry. PMID- 29997799 TI - Direct observation by time-resolved infrared spectroscopy of the bright and the dark excited states of the [Ru(phen)2(dppz)]2+ light-switch compound in solution and when bound to DNA. AB - The [Ru(phen)2(dppz)]2+ complex (1) is non-emissive in water but is highly luminescent in organic solvents or when bound to DNA, making it a useful probe for DNA binding. To date, a complete mechanistic explanation for this "light switch" effect is still lacking. With this in mind we have undertaken an ultrafast time resolved infrared (TRIR) study of 1 and directly observe marker bands between 1280-1450 cm-1, which characterise both the emissive "bright" and the non-emissive "dark" excited states of the complex, in CD3CN and D2O respectively. These characteristic spectral features are present in the [Ru(dppz)3]2+ solvent light-switch complex but absent in [Ru(phen)3]2+, which is luminescent in both solvents. DFT calculations show that the vibrational modes responsible for these characteristic bands are predominantly localised on the dppz ligand. Moreover, they reveal that certain vibrational modes of the "dark" excited state couple with vibrational modes of two coordinating water molecules, and through these to the bulk solvent, thus providing a new insight into the mechanism of the light-switch effect. We also demonstrate that the marker bands for the "bright" state are observed for both Lambda- and Delta-enantiomers of 1 when bound to DNA and that photo-excitation of the complex induces perturbation of the guanine and cytosine carbonyl bands. This perturbation is shown to be stronger for the Lambda-enantiomer, demonstrating the different binding site properties of the two enantiomers and the ability of this technique to determine the identity and nature of the binding site of such intercalators. PMID- 29997800 TI - Remarkably selective and enantiodifferentiating sensing of histidine by a fluorescent homochiral Zn-MOF based on pyrene-tetralactic acid. AB - A highly luminescent and water-stable homochiral Zn-MOF, i.e., Zn-PLA, has been developed based on a pyrene-tetralactic acid, which inherently features concave shapes for guest inclusion, to explore sensing of amino acids by fluorescence quenching; the solid-state fluorescence quantum yield of the MOF was found to be 46%. The fluorescence of an aqueous suspension of Zn-PLA was shown to be quenched specifically by histidine amongst all the other amino acids. Selective sensing of histidine is of prime importance due to its relevance in a variety of biological functions. The lack of quenching of fluorescence of Zn-PLA by all the amino acids other than histidine has been rationalized based on the exchange of the cationic dimethylammonium species in the MOF crystals with histidine that is protonated in water; the latter is envisaged to quench the fluorescence via charge transfer in the excited state. Furthermore, the homochiral crystals of Zn-PLA were found to permit enantiodiscrimination in the quenching by the d- and l-forms such that the ratio of enantioselectivity, i.e., Kd/Kl, is 1.8, as determined by Stern-Volmer quenching plots. The highly selective as well as enantiodifferentiating sensing of amino acids by MOFs is unprecedented for any sensor type. PMID- 29997801 TI - Rational design of supramolecular hemin/G-quadruplex-dopamine aptamer nucleoapzyme systems with superior catalytic performance. AB - The rational design of a set of hemin/G-quadruplex (hGQ)-dopamine binding aptamer (DBA) conjugates, acting as nucleoapzymes, is described. The nucleoapzyme constructs consist of a hGQ DNAzyme as a catalytic unit and DBA as a substrate binding unit that are brought into spatial proximity by a duplex scaffold composed of complementary oligonucleotide strands. When the hGQ unit is linked to the duplex scaffold via a single-strand DNA tether of variable length, the resulting nucleoapzymes reveal a moderate catalytic enhancement toward the H2O2 mediated oxidation of dopamine to aminochrome as compared to the process stimulated by the separated hGQ and DBA units (5-7 fold enhancement). This limited enhancement is attributed to inappropriate spatial positioning of the hGQ in respect to the dopamine binding site, and/or to the flexibility of the tether that links the hGQ catalytic site to the double-stranded scaffold. To solve this, rigidification of the hGQ/DBA conjugates by triplex oligonucleotide structures that anchor the hGQ to a duplex domain associated with the DBA units was achieved. By the sequential, programmed, triplex-controlled rigidification of the hGQ/DBA structure, a nucleoapzyme with superior catalytic activity toward the oxidation of dopamine to aminochrome is identified (30-fold catalytic enhancement). Molecular dynamics simulations reveal that in the resulting highly active rigidified nucleoapzyme structure, the hGQ catalytic site is positioned in spatial proximity to the opening of the DBA substrate binding site, thus rationalizing and supporting the enhanced catalytic functions of the system. Finally, the most active nucleoapzyme system was subjected to fuel- and anti-fuel strands that separate and re-assemble the nucleoapzyme structure, allowing "ON" and "OFF" switching of the nucleoapzyme catalytic functions. PMID- 29997802 TI - Accessing low-oxidation state taxanes: is taxadiene-4(5)-epoxide on the taxol biosynthetic pathway? AB - We have shown for the first time that taxadiene (3) can be epoxidised in a regio- and diastereoselective manner to provide taxadiene-4(5)-epoxide (12) as a single diastereoisomer, and that this epoxide can be rearranged to give taxa 4(20),11(12)-dien-5alpha-ol (4). Furthermore, the epoxide 12 rearranges under acidic conditions to give taxa-4(20),11(12)-dien-5alpha-ol (4), the known bridged ether OCT (5) and the new oxacyclotaxane (OCT2) 15. Contrary to previous speculation, taxadiene-4(5)-epoxide (12) is susceptible to rearrangement when exposed to an ironIII porphyrin, and these observations justify consideration of epoxide 12 as a chemically competent intermediate on the taxol biosynthetic pathway. PMID- 29997803 TI - Stable luminescent iridium(iii) complexes with bis(N-heterocyclic carbene) ligands: photo-stability, excited state properties, visible-light-driven radical cyclization and CO2 reduction, and cellular imaging. AB - A new class of cyclometalated Ir(iii) complexes supported by various bidentate C deprotonated (C^N) and cis-chelating bis(N-heterocyclic carbene) (bis-NHC) ligands has been synthesized. These complexes display strong emission in deaerated solutions at room temperature with photoluminescence quantum yields up to 89% and emission lifetimes up to 96 MUs. A photo-stable complex containing C deprotonated fluorenyl-substituted C^N shows no significant decomposition even upon irradiation for over 120 h by blue LEDs (12 W). These, together with the strong absorption in the visible region and rich photo-redox properties, allow the bis-NHC Ir(iii) complexes to act as good photo-catalysts for reductive C-C bond formation from C(sp3/sp2)-Br bonds cleavage using visible-light irradiation (lambda > 440 nm). A water-soluble complex with a glucose-functionalized bis-NHC ligand catalysed a visible-light-driven radical cyclization for the synthesis of pyrrolidine in aqueous media. Also, the bis-NHC Ir(iii) complex in combination with a cobalt catalyst can catalyse the visible-light-driven CO2 reduction with excellent turnover numbers (>2400) and selectivity (CO over H2 in gas phase: >95%). Additionally, this series of bis-NHC Ir(iii) complexes are found to localize in and stain endoplasmic reticulum (ER) of various cell lines with high selectivity, and exhibit high cytotoxicity towards cancer cells, revealing their potential uses as bioimaging and/or anti-cancer agents. PMID- 29997804 TI - Proton-triggered switch based on a molecular transistor with edge-on gate. AB - The manipulation of charge transport through single molecules so that electronic information can be controlled is a basic challenge that is important for both fundamental understanding of the mechanisms and the potential applications in single-molecule technologies. This paper reports the influence of protonation on the gating effect in a series of molecular wires utilizing a pyridinoparacyclophane (PPC) moiety as the edge-on gate. It was found that the molecular conductance, transition voltage, and the corresponding tunnelling barriers can be reversibly switched by the protonation/deprotonation process of the nitrogen atom on the PPC pyridine ring. It was found that protonation levels off the tunnelling barrier of different molecules and converts p-type molecular wires into n-type, reversibly. PMID- 29997805 TI - Iridium(iii)-bis(imidazolinyl)phenyl catalysts for enantioselective C-H functionalization with ethyl diazoacetate. AB - The intermolecular enantioselective C-H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(iii)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities. PMID- 29997806 TI - Directing group assisted meta-hydroxylation by C-H activation. AB - meta-Hydroxylated cores are ubiquitous in natural products. Herein, we disclose the first template assisted meta-hydroxylation reaction. Experimental and in silico studies helped us to gain valuable mechanistic insights, including the role of the hexafluoroisopropanol (HFIP) solvent, during C-H hydroxylation. The reactive intermediates, prior to the C-H activation, have been detected by spectroscopic techniques. Additionally, the C-O bond formation has been extended to meta-acetoxylation. The preparation of a phase II quinone reductase activity inducer and a resveratrol precursor illustrated the synthetic significance of the present strategy. PMID- 29997807 TI - High yielding synthesis of 2,2'-bipyridine macrocycles, versatile intermediates in the synthesis of rotaxanes. AB - We present an operationally simple approach to 2,2'-bipyridine macrocycles. Our method uses simple starting materials to produce these previously hard to access rotaxane precursors in remarkable yields (typically >65%) across a range of scales (0.1-5 mmol). All of the macrocycles reported are efficiently converted (>90%) to rotaxanes under AT-CuAAC conditions. With the requisite macrocycles finally available in sufficient quantities, we further demonstrate their long term utility through the first gram-scale synthesis of an AT-CuAAC [2]rotaxane and extend this powerful methodology to produce novel Sauvage-type molecular shuttles. PMID- 29997808 TI - When the inhibitor tells more than the substrate: the cyanide-bound state of a carbon monoxide dehydrogenase. AB - Carbon monoxide dehydrogenase (CODH) is a key enzyme for reversible CO interconversion. To elucidate structural and mechanistic details of CO binding at the CODH active site (C-cluster), cyanide is frequently used as an iso-electronic substitute and inhibitor. However, previous studies revealed conflicting results on the structure of the cyanide-bound complex and the mechanism of cyanide inhibition. To address this issue in this work, we have employed IR spectroscopy, crystallography, site directed mutagenesis, and theoretical methods to analyse the cyanide complex of the CODH from Carboxydothermus hydrogenoformans (CODHII Ch ). IR spectroscopy demonstrates that a single cyanide binds to the Ni ion. Whereas the inhibitor could be partially removed at elevated temperature, irreversible degradation of the C-cluster occurred in the presence of an excess of cyanide on the long-minute time scale, eventually leading to the formation of [Fe(CN)6]4- and [Ni(CN)4]2- complexes. Theoretical calculations based on a new high-resolution structure of the cyanide-bound CODHII Ch indicated that cyanide binding to the Ni ion occurs upon dissociation of the hydroxyl ligand from the Fe1 subsite of the C-cluster. The hydroxyl group is presumably protonated by Lys563 which, unlike to His93, does not form a hydrogen bond with the cyanide ligand. A stable deprotonated epsilon-amino group of Lys563 in the cyanide complex is consistent with the nearly unchanged C[triple bond, length as m-dash]N stretching in the Lys563Ala variant of CODHII Ch . These findings support the view that the proton channel connecting the solution phase with the active site displays a strict directionality, controlled by the oxidation state of the C cluster. PMID- 29997809 TI - High-resolution measurement of long-range distances in RNA: pulse EPR spectroscopy with TEMPO-labeled nucleotides. AB - Structural information at atomic resolution of biomolecular assemblies, such as RNA and RNA protein complexes, is fundamental to comprehend biological function. Modern spectroscopic methods offer exceptional opportunities in this direction. Here we present the capability of pulse EPR to report high-resolution long-range distances in RNAs by means of a recently developed spin labeled nucleotide, which carries the TEMPO group directly attached to the nucleobase and preserves Watson Crick base-pairing. In a representative RNA duplex with spin-label separations up to 28 base pairs (~8 nm) we demonstrate that the label allows for a model-free conversion of inter-spin distances into base-pair separation (Deltabp) if broad band pulse excitation at Q band frequencies (34 GHz) is applied. The observed distance distribution increases from +/-0.2 nm for Deltabp = 10 to only +/-0.5 nm for Deltabp = 28, consistent with only small deviations from the "ideal" A-form RNA structure. Molecular dynamics (MD) simulations conducted at 20 degrees C show restricted conformational freedom of the label. MD-generated structural deviations from an "ideal" A-RNA geometry help disentangle the contributions of local flexibility of the label and its neighboring nucleobases and global deformations of the RNA double helix to the experimental distance distributions. The study demonstrates that our simple but strategic spin labeling procedure can access detailed structural information on RNAs at atomic resolution over distances that match the size of macromolecular RNA complexes. PMID- 29997810 TI - Size controllable redispersion of sintered Au nanoparticles by using iodohydrocarbon and its implications. AB - Downsizing large Au particles into small particles with controllable size remains challenging. In this study, we redispersed large sintered Au particles on activated carbon (Au/C) to highly dispersed nanoparticles with uniform distribution and controllable size after treatment with iodohydrocarbons. The Au/C catalyst was conducted for a number of deactivation/regeneration cycles with negligible deterioration in catalytic performance for acetylene hydrochlorination. The redispersion behavior reveals a reverse agglomeration process in the presence of iodohydrocarbons under mild conditions. This behavior is significantly related to the C-I bond dissociation energy (BDE) and adsorption of iodic species on Au particles. A novel protocol for controlling the size and predicting the redispersion efficiency of Au particles is established by correlating with the C-I BDEs of iodohydrocarbons. The molecular-level interpretation of redispersion provides a thorough mechanism based on experimental results. This study presents an efficient method for the easy regeneration of sintered Au-based catalysts for practical applications. PMID- 29997811 TI - Unprotected and interconnected Ru0 nano-chain networks: advantages of unprotected surfaces in catalysis and electrocatalysis. AB - Seedless, surfactantless and support-free unprotected, metallic, interconnected nano-chain networks of ruthenium nanoparticles (NPs) were successfully synthesized via the reduction of ruthenium(iii) chloride (RuCl3) with sodium borohydride (NaBH4) at three different temperatures, viz. 30 degrees C, 45 degrees C and 60 degrees C. The molar ratio of RuCl3 solution and borohydride was optimized to be 1 : 1.5 to produce stable colloids with the optimum final solution pH of 9.7 +/- 0.2. Average diameters of the interconnected nano-chain networks prepared at 30 degrees C (Ru-30), 45 degrees C (Ru-45) and 60 degrees C (Ru-60) were 3.5 +/- 0.5 nm, 3.0 +/- 0.2 nm and 2.6 +/- 0.2 nm respectively. The morphology and composition dependent catalytic and electrocatalytic activities of these unprotected Ru nano-chain networks (Ru-30, Ru-45 and Ru-60) were studied in detail. The catalysis study was performed by investigating the transfer hydrogenation of several substituted aromatic nitro compounds. It was observed that Ru-60 was relatively more active compared to Ru-30 and Ru-45, which was reflected in their rate constant values. The electrocatalytic activities of Ru-30, Ru-45 and Ru-60 were screened for anodic water splitting in alkaline medium (0.1 M NaOH) and it was found that all of them showed almost the same activity which required an over-voltage of 308 +/- 2 mV to obtain an anodic current density of 10 mA cm-2. The catalytic and electrocatalytic performances of these unprotected Ru0 networks were compared with Ru0 nanomaterials prepared under similar conditions with three different surfactants, viz. CTAB, SDS and TX 100, which revealed that unprotected Ru0 networks are better catalysts than those stabilized with surfactants. The superior catalytic and electrocatalytic performance is due to the availability of unprotected Ru0 surfaces. The present route may provide a new possibility of synthesizing other surfactant-free, unprotected metal colloids for enhanced catalytic and electrocatalytic applications. PMID- 29997812 TI - Identification of "sarsasapogenin-aglyconed" timosaponins as novel Abeta-lowering modulators of amyloid precursor protein processing. AB - The inhibition of amyloid beta (Abeta) peptide production is a key approach in the development of therapeutics for the treatment of Alzheimer's disease (AD). We have identified that timosaponins consisting of sarsasapogenin (SSG) as the aglycone can effectively lower the production of Abeta peptides and stimulate neurite outgrowth in neuronal cell cultures. Structure-activity relationship studies revealed that the cis-fused AB ring, 3beta-configuration, spiroketal F ring and 25S-configuration of SSG are the essential structural features responsible for the Abeta-lowering effects and neurite-stimulatory activity. New synthetic derivatives that retain the SSG scaffold also exhibited an Abeta lowering effect. Treatment of cells with timosaponins led to modulation of amyloid precursor protein (APP) processing through the suppression of beta cleavage and preferential lowering of the production of the 42-amino acid Abeta species (Abeta42) without affecting another gamma-secretase substrate. The SSG and "SSG-aglyconed" timosaponins also penetrated brain tissue and lowered brain Abeta42 levels in mice. Our studies demonstrate that timosaponins represent a unique class of steroidal saponins that may be useful for the development of AD therapeutics. PMID- 29997813 TI - Competition-driven selection in covalent dynamic networks and implementation in organic reactional selectivity. AB - Competition among reagents in dynamic combinatorial libraries of increased complexity leads to reactional self-sorting (improved regioselectivity) in mixtures of aldehydes and oligoamines. High selectivity of a given library component is transferred to a different reacting component of low selectivity through a network of underlying equilibrating reactions which provide component exchange between all species. The selectivity of various carbonyl compounds in reactions with amines was also assessed towards the formation of defined sequences of residues along oligoamine chains. The approach was further exploited for defining selective dynamic protecting groups (DPGs), based on the reversible linkage between the substrate and the protecting group. They represent an intermediate approach between the conventional protecting groups and the protecting-group-free approach in organic synthesis. Removal of the protecting group is effected via dynamic exchange trapping by formation of a more stable product. The establishment of equilibrium eliminates the need for isolation and purification of the dynamically protected intermediate(s) and enables as well the selective sequential derivatisation of oligoamines. The DPG concept can be generalised to other reversible reactions and can thus represent a valuable alternative in the design of total synthesis of complex molecules. PMID- 29997814 TI - Fabrication of a mercaptoacetic acid pillar[5]arene assembled nanochannel: a biomimetic gate for mercury poisoning. AB - Mercury ion binding blocks potassium ion channels, which leads to toxicity in vivo. It is challenging to design a simple and efficient artificial system to mimic the sophisticated biological process of mercury poisoning. Herein, based on biomimetic strategies, a tunable mercury(ii) ion-gate modulated by mercaptoacetic acid-pillar[5]arene (MAP5) is reported. By virtue of the unique design of the host-guest competition, potassium ion transport can actualize the reversible switching between "on" and "off" in the absence and presence of mercury ions. Moreover, the MAP5-immobilized nanochannel is highly effective at distinguishing Hg2+ from other metal ions and can be used to detect Hg2+ and act as an excellent and robust gate valve for developing integrated circuits and nanoelectronic logic devices. This study paves a new way for better understanding the physiological phenomenon of mercury toxicity and shows great promise for biomedical research. PMID- 29997816 TI - Dynamic helical cyclophanes with two quadruply-bridged planes arranged in an "obverse and/or reverse" relation. AB - We describe the design of two types of cyclophanes that generate dynamic helicity through the twisting of two planes in a clockwise or counterclockwise direction to give (M)- or (P)-helicity. We used a rectangular and anisotropic plane of 1,2,4,5-tetrakis(phenylethynyl)benzene (TPEB), since it can be stacked in pairs in two ways, in parallel or orthogonally, to be identified as distinct cyclophane molecules. We adopted a synthetic strategy for obtaining these two cyclophanes as a mixture using a macrocyclic intermediate that possessed two rotatable phenyl rings. We introduced necessary parts into the rotators to give a mixture of rotational isomers leading to a parallel or orthogonal arrangement of TPEBs, and then doubly bridged two planes of TPEB to form quadruply-bridged cyclophanes. We consider that such two planes in each cyclophane are in an "obverse and/or reverse" relation. In each cyclophane, we found unique dynamic helical forms with (M)- or (P)-helicity as well as an inherently non-chiral form. Normally, the screw-sense preference of dynamic helicity would be controlled through the intramolecular or supramolecular transmission of central chirality, when a chiral auxiliary is attached to the cyclophanes or a chiral guest is allowed to form a complex with the cyclophanes. In a case where two different substitution groups were used on bridging units to generate planar chirality in each cyclophane, the screw-sense preference was controlled through the arrangement of these substitution groups, and did not depend on the transmission of central chirality. Two different substitution groups desymmetrize the enantiomeric forms with (M)- or (P)-helicity generated in each dynamic helical cyclophane so that two dynamic helical forms with (M)- or (P)-helicity can be in a diastereomeric relation. Thus, a particular screw sense of dynamic helicity can be preferred, regardless of whether or not the two substitution groups possess some chiral element. PMID- 29997815 TI - Water-soluble allyl sulfones for dual site-specific labelling of proteins and cyclic peptides. AB - Water-soluble allyl sulfones provide convenient site-specific disulfide rebridging of native proteins and cyclic peptides. The site-selective functionalization of (a) the peptide hormone somatostatin, (b) the interchain disulfide of bovine insulin and (c) functionalization of the proteins GFP and lysozyme with allyl sulfones proceeds in aqueous solution. Allyl sulfones offer three functionalizable sites that react with thiol containing molecules in a step wise fashion. Dual labeling of proteins and cyclic peptides is achieved i.e. the attachment of a chromophore and an affinity tag in a single reaction step, which is of great significance for the construction of precise multifunctional peptide and protein conjugates. PMID- 29997817 TI - Minimization of dynamic effects in the evolution of dihydrofolate reductase. AB - Protein isotope labeling is a powerful technique to probe functionally important motions in enzyme catalysis and can be applied to investigate the conformational dynamics of proteins. Previous investigations have indicated that dynamic coupling is detrimental to catalysis by dihydrofolate reductase (DHFR) from the mesophile Escherichia coli (EcDHFR). Comparison of DHFRs from organisms adapted to survive at a wide range of temperatures suggests that dynamic coupling in DHFR catalysis has been minimized during evolution; it arises from reorganizational motions needed to facilitate charge transfer events. Contrary to the behaviour observed for the DHFR from the moderate thermophile Geobacillus stearothermophilus (BsDHFR), the chemical transformation catalyzed by the cold adapted bacterium Moritella profunda (MpDHFR) is only weakly affected by protein isotope substitutions at low temperatures, but the isotopically substituted enzyme is a substantially inferior catalyst at higher, non-physiological temperatures. QM/MM studies revealed that this behaviour is caused by the enzyme's structural sensitivity to temperature changes, which enhances unfavorable dynamic coupling at higher temperatures by promoting additional recrossing trajectories on the transition state dividing surface. We postulate that these motions are minimized by fine-tuning DHFR flexibility through optimization of the free energy surface of the reaction, such that a nearly static reaction-ready configuration with optimal electrostatic properties is maintained under physiological conditions. PMID- 29997818 TI - Oriented assembly of invisible probes: towards single mRNA imaging in living cells. AB - Due to the complexity of biological systems and the ultralow concentration of analytes, improving the signal-to-noise ratio and lowering the limit of detection to allow highly sensitive detection is key to biomolecule analysis, especially intracellular analysis. Here, we present a method for highly sensitive imaging of mRNA in living cells by using novel invisible oriented probes to construct a turn on signal generation mechanism from zero background. Two DNA probes (S1 and S2) are asymmetrically modified on two small gold nanoparticles (AuNPs) with a diameter of 20 nm. The hybridization of the two DNA probes with a single target mRNA leads to the formation of an AuNP dimer which shows a prominent plasmonic coupling effect. It generates a strong scattering signal from zero-background under a dark-field spectral analysis system. The unique design of the oriented assembly dimer has the ability to easily discriminate the target signal from the inherent cellular background noise in intracellular detection, thus making this approach a valuable technique for imaging single survivin mRNA and monitoring the distribution of survivin mRNA in tumor cells. PMID- 29997819 TI - Evaluation of the coordination preferences and catalytic pathways of heteroaxial cobalt oximes towards hydrogen generation. AB - Three new heteroaxial cobalt oxime catalysts, namely [CoIII(prdioxH)(4tBupy)(Cl)]PF6 (1), [CoIII(prdioxH)(4Pyrpy)(Cl)]PF6 (2), and [CoIII(prdioxH)(4Bzpy)(Cl)]PF6 (3) have been studied. These species contain chloro and substituted tert-butyl/pyrrolidine/benzoyl-pyridino ligands axially coordinated to a trivalent cobalt ion bound to the N4-oxime macrocycle (2E,2'E,3E,3'E)-3,3'-(propane-1,3-diylbis(azanylylidene))bis(butan-2-one)dioxime, abbreviated (prdioxH)- in its monoprotonated form. Emphasis was given to the spectroscopic investigation of the coordination preferences and spin configurations among the different 3d6 CoIII, 3d7 CoII, and 3d8 CoI oxidation states of the metal, and to the catalytic proton reduction with an evaluation of the pathways for the generation of H2via CoIII-H- or CoII-H- intermediates by mono and bimetallic routes. The strong field imposed by the (prdioxH)- ligand precludes the existence of high-spin configurations, and 6-coordinate geometry is favored by the LSCoIII species. Species 1 and 3 show a split CoIII/CoII electrochemical wave associated with partial chemical conversion to a [CoIII(prdioxH)Cl2] species, whereas 2 shows a single event. The reduction of these CoIII complexes yields LSCoII and LSCoI species in which the pyridine acts as the dominant axial ligand. In the presence of protons, the catalytically active CoI species generates a CoIII-H- hydride species that reacts heterolytically with another proton to generate dihydrogen. The intermediacy of a trifluoroacetate-bound CoIII/CoII couple in the catalytic mechanism is proposed. These results allow for a generalization of the behavior of heteroaxial cobalt macrocycles and serve as guidelines for the development of new catalysts based on macrocyclic frameworks. PMID- 29997820 TI - Small molecule regulated dynamic structural changes of human G-quadruplexes. AB - The changes in structure and dynamics of oncogenic (c-MYC) and telomeric (h-TELO) G-rich DNA sequences due to the binding of a novel carbazole derivative (BTC) are elucidated using single-molecule Forster resonance energy transfer (sm-FRET), fluorescence correlation spectroscopy (FCS) and NMR spectroscopy. In contrast to the previous reports on the binding of ligands to pre-folded G-quadruplexes, this work illustrates how ligand binding changes the conformational equilibria of both unstructured G-rich DNA sequences and K+-folded G-quadruplexes. The results demonstrate that K+ free c-MYC and h-TELO exist as unfolded and partially folded conformations. The binding of BTC shifts the equilibria of both investigated DNA sequences towards the folded G-quadruplex structure, increases the diffusion coefficients and induces faster end-to-end contact formation. BTC recognizes a minor conformation of the c-MYC quadruplex and the two-tetrad basket conformations of the h-TELO quadruplex. PMID- 29997821 TI - Emergence of comparable covalency in isostructural cerium(iv)- and uranium(iv) carbon multiple bonds. AB - We report comparable levels of covalency in cerium- and uranium-carbon multiple bonds in the iso-structural carbene complexes [M(BIPMTMS)(ODipp)2] [M = Ce (1), U (2), Th (3); BIPMTMS = C(PPh2NSiMe3)2; Dipp = C6H3-2,6-iPr2] whereas for M = Th the M[double bond, length as m-dash]C bond interaction is much more ionic. On the basis of single crystal X-ray diffraction, NMR, IR, EPR, and XANES spectroscopies, and SQUID magnetometry complexes 1-3 are confirmed formally as bona fide metal(iv) complexes. In order to avoid the deficiencies of orbital based theoretical analysis approaches we probed the bonding of 1-3via analysis of RASSCF- and CASSCF-derived densities that explicitly treats the orbital energy near-degeneracy and overlap contributions to covalency. For these complexes similar levels of covalency are found for cerium(iv) and uranium(iv), whereas thorium(iv) is found to be more ionic, and this trend is independently found in all computational methods employed. The computationally determined trends in covalency of these systems of Ce ~ U > Th are also reproduced in experimental exchange reactions of 1-3 with MCl4 salts where 1 and 2 do not exchange with ThCl4, but 3 does exchange with MCl4 (M = Ce, U) and 1 and 2 react with UCl4 and CeCl4, respectively, to establish equilibria. This study therefore provides complementary theoretical and experimental evidence that contrasts to the accepted description that generally lanthanide-ligand bonding in non-zero oxidation state complexes is overwhelmingly ionic but that of uranium is more covalent. PMID- 29997822 TI - Synthesis, structure, spectroscopy and reactivity of new heterotrinuclear water oxidation catalysts. AB - Four heterotrinuclear complexes containing the ligands 3,5-bis(2 pyridyl)pyrazolate (bpp-) and 2,2':6',2''-terpyridine (trpy) of the general formula {[RuII(trpy)]2(MU-[M(X)2(bpp)2])}(PF6)2, where M = CoII, MnII and X = Cl , AcO- (M = CoII, X = Cl-: Ru2Co-Cl2 ; M = MnII, X = Cl-: Ru2Mn-Cl2 ; M = CoII, X = AcO-: Ru2Co-OAc2 ; M = MnII, X = AcO-: Ru2Mn-OAc2 ), have been prepared for the first time. The complexes have been characterized using different spectroscopic techniques such as UV-vis, IR, and mass spectrometry. X-Ray diffraction analyses have been used to characterize the Ru2Mn-Cl2 and Ru2Mn-OAc2 complexes. The cyclic voltammograms (CV) for all four complexes in organic solvent (CH3CN or CH2Cl2) display three successive reversible oxidative waves corresponding to one-electron oxidations of each of the three metal centers. The oxidized forms of the complexes Ru2Co-OAc2 and Ru2Mn-OAc2 are further characterized by EPR and UV-vis spectroscopy. The magnetic susceptibility measurements of all complexes in the temperature range of 2-300 K reveal paramagnetic properties due to the presence of high spin Co(ii) and Mn(ii) centers. The complexes Ru2Co-OAc2 and Ru2Mn-OAc2 act as precatalysts for the water oxidation reaction, since the acetato groups are easily replaced by water at pH = 7 generating the active catalysts, {[Ru(H2O)(trpy)]2(MU-[M(H2O)2(bpp)2])}4+ (M = CoII: Ru2Co-(H2O)4 ; M = MnII: Ru2Mn-(H2O)4 ). The photochemical water oxidation reaction is studied using [Ru(bpy)3]2+ as the photosensitizer and Na2S2O8 as a sacrificial electron acceptor at pH = 7. The Co containing complex generates a TON of 50 in about 10 minutes (TOFi = 0.21 s-1), whereas the Mn containing complex only generates a TON of 8. The water oxidation reaction of Ru2Co-(H2O)4 is further investigated using oxone as a sacrificial chemical oxidant at pH = 7. Labelled water oxidation experiments suggest that a nucleophilic attack mechanism is occurring at the Co site of the trinuclear complex with cooperative involvement of the two Ru sites, via electronic coupling through the bpp- bridging ligand and via neighboring hydrogen bonding. PMID- 29997823 TI - Asymmetric synthesis of allylic amines via hydroamination of allenes with benzophenone imine. AB - Rhodium-catalyzed highly regio- and enantioselective hydroamination of allenes is reported. Exclusive branched selectivities and excellent enantioselectivities were achieved applying a rhodium(i)/Josiphos catalyst. This method permits the practical synthesis of valuable alpha-chiral allylic amines using benzophenone imine as ammonia carrier. PMID- 29997824 TI - Peptidines: glycine-amidine-based oligomers for solution- and solid-phase synthesis. AB - Efforts to emulate biological oligomers have given rise to a host of useful technologies, ranging from solid-phase peptide and nucleic acid synthesis to various peptidomimetic platforms. Herein we introduce a novel class of peptide like oligomers called "peptidines" wherein each carbonyl O-atom within poly-N alkyl glycine oligomers is replaced with a functionalized N-atom. Compared to peptoids or peptides, the presence of this amidine N-substituent in peptidines effectively doubles the number of diversification sites per monomeric unit, and can decrease their overall conformational flexibility. We have developed iterative solution- and solid-phase protocols for the straightforward assembly of peptidines containing diverse backbone and amidine substituents, derived from readily available primary and secondary amines. We have also performed crystallographic and computational studies, which demonstrate a strong preference for the trans (E) amidine geometry. Given their straightforward synthetic preparation and high functional group density, peptidines have the potential to serve as useful tools for library generation, peptide mimicry, and the identification of biologically active small molecules. PMID- 29997825 TI - Stapling of unprotected helical peptides via photo-induced intramolecular thiol yne hydrothiolation. AB - Peptide stapling emerged as a versatile strategy to recapitulate the bioactive helical conformation of unstructured short peptides in water to improve their therapeutic properties in targeting intracellular "undruggable" targets. Here, we describe the development of photo-induced intramolecular thiol-yne macrocyclization for rapid access to short stapled peptides with enhanced biophysical properties. This new peptide stapling technique provides rapid access to conformationally constrained helices with satisfying functional group tolerance. Notably, the vinyl sulfide linkage shows distinct lipophilicity with reduced membrane toxicity compared to the corresponding all-hydrocarbon analogue. As a proof of principle, we constructed stabilized helices modulating intracellular estrogen receptor (ER)-coactivator interactions with a nanomolar binding affinity, enhanced serum stability, a diffuse cellular distribution and selective cytotoxicity towards ER-positive MCF-7 cells. PMID- 29997826 TI - Optical control of neuronal firing via photoinduced electron transfer in donor acceptor conjugates. AB - A series of porphyrin-fullerene linked molecules has been synthesized to evaluate the effects of substituents and molecular structures on their charge-separation yield and the lifetime of a final charge-separated state in various hydrophilic environments. The selected high-performance molecule effectively achieved depolarization in a plasma cell membrane by visible light as well as two-photon excitation using a near-infrared light laser. Moreover, it was revealed that the depolarization can trigger neuronal firing in rat hippocampal neurons, demonstrating the potential and versatility for controlling cell functions using light. PMID- 29997827 TI - Phosphorescent soft salt for ratiometric and lifetime imaging of intracellular pH variations. AB - In contrast to traditional short-lived fluorescent probes, long-lived phosphorescent probes based on transition-metal complexes can effectively eliminate unwanted background interference by using time-resolved luminescence imaging techniques, such as photoluminescence lifetime imaging microscopy. Hence, phosphorescent probes have become one of the most attractive candidates for investigating biological events in living systems. However, most of them are based on single emission intensity changes, which might be affected by a variety of intracellular environmental factors. Ratiometric measurement allows simultaneous recording of two separated wavelengths instead of measuring mere intensity changes and thus offers built-in correction for environmental effects. Herein, for the first time, a soft salt based phosphorescent probe has been developed for ratiometric and lifetime imaging of intracellular pH variations in real time. Specifically, a pH sensitive cationic complex (C1) and a pH insensitive anionic complex (A1) are directly connected through electrostatic interaction to form a soft salt based probe (S1), which exhibits a ratiometric phosphorescent response to pH with two well-resolved emission peaks separated by about 150 nm (from 475 to 625 nm). This novel probe was then successfully applied for ratiometric and lifetime imaging of intracellular pH variations. Moreover, quantitative measurements of intracellular pH fluctuations caused by oxidative stress have been performed for S1 based on the pH-dependent calibration curve. PMID- 29997828 TI - Understanding the origin of photoelectrode performance enhancement by probing surface kinetics. AB - Photoelectrochemical (PEC) water splitting holds the potential to meet the challenges associated with the intermittent nature of sunlight. Catalysts have often been shown to improve the performance of PEC water splitting, but their working mechanisms are not well understood. Using intensity modulated photocurrent spectroscopy (IMPS), we determined the rate constants of water oxidation and recombination at the surface of three different hematite-based photoanodes. It was found that the best performing electrodes, in terms of photocurrent onset potential, exhibited the slowest water oxidation rate constants, which was a surprise. The performance of these photoelectrodes was enabled by the slow surface recombination. When amorphous NiFeO x , a water oxidation catalyst, was present, the rate of surface hole transfer actually slowed down; what was slowed more was the recombination rate at the hematite surface, resulting in better water oxidation performance. As such, NiFeO x primarily serves as a passivation layer rather than a catalytic layer. Together a better understanding of the role of catalytic overlayers for water oxidation has been achieved. PMID- 29997830 TI - Innovative catalyst design for the oxygen reduction reaction for fuel cells. AB - A combination of chemical and electrochemical catalysis is introduced herein as a new approach to overcome one of the most challenging and persistent issues in fuel cell cathodes. Demonstrated using hematite (alpha-Fe2O3) nanoparticles modified glassy carbon electrode, this bifunctional fuel cell catalyst system prevails the slow kinetics of the oxygen reduction reaction by rapid heterogeneous disproportionation of hydrogen peroxide. Whilst the catalytic efficiency of glassy carbon is limited to the two-electron reduction of oxygen, modification with hematite drastically improves it to equivalent to the four electron pathway. This is due to regeneration of the cathodic fuel through the rapid decomposition of hydrogen peroxide. The importance of such system is stressed as the formation of water rather than hydrogen peroxide is essential to maximize the energy output of the fuel cell. Cycling of oxygen reduction/regeneration boosts the activity of a low-cost catalyst to be comparable to that of platinum and concurrently reduces the risk of cell degradation. PMID- 29997829 TI - Highly efficient blue thermally activated delayed fluorescent OLEDs with record low driving voltages utilizing high triplet energy hosts with small singlet triplet splittings. AB - The high driving voltage of blue organic light-emitting diodes (OLEDs) based on emitters with thermally activated delayed fluorescence (TADF) remains a constraint for their portable application. A major reason for this is that the high triplet (T1) of the host required to match the blue TADF emitters would always lead to inferiority in terms of carrier injection. Therefore, a suitable host should possess not only a high T1 but also a relatively low singlet (S1) for improved carrier injection, indicating that small singlet-triplet splittings (DeltaESTs) are highly desired. Here, four carbazolyl benzonitrile derivatives are facilely prepared in a one-step approach with restrained conjugate lengths to maintain high triplet energies while their highly twisted structures spatially separate the frontier orbital distribution to achieve relatively low DeltaESTs. Meanwhile, the charge transporting mobilities of these hosts are effectively tuned by the different linker types of the host moieties. Consequently, high triplet-energy hosts with favorable carrier injection/transporting abilities are realized, endowing blue TADF devices with a maximum external quantum efficiency of 21.5%, a maximum power efficiency of 42.0 lm W-1 and an ultra-low onset voltage of 2.8 V. It is noteworthy that a driving voltage of 4.9 V is achieved at a practical luminance of 1000 cd m-2, which is the lowest among the doped blue TADF OLEDs reported until now. This work suggests that manipulation of the molecular topologies not only leads to the flexible and feasible design of novel bipolar host materials, but also affords a promising method for fine-tuning physical properties and thus obtaining state-of-the-art device performances. PMID- 29997831 TI - Dynamic covalent synthesis of aryleneethynylene cages through alkyne metathesis: dimer, tetramer, or interlocked complex? AB - A dynamic covalent approach towards rigid aryleneethynylene covalent organic polyhedrons (COPs) was explored. Our study on the relationship of the COP structures and the geometry of their building blocks reveals that the topology of aryleneethynylene COPs strongly depends on the size of the building blocks. A tetramer (D2h symmetric), dimer, or interlocked complex can be formed from monomers with the same face-to-edge angle but in different sizes. As alkyne metathesis is a self-exchange reaction and non-directional, the cyclooligomerization of multi-alkyne monomers involves both intramolecular cyclization and intermolecular metathesis reaction, resulting in complicated thermodynamic process disturbed by kinetic competition. Although a tetrahedron shaped tetramer (Td symmetric) has comparable thermodynamic stability to a D2h symmetric tetramer, its formation is kinetically disfavored and was not observed experimentally. Aryleneethynylene COPs consist of purely unsaturated carbon backbones and exhibit large internal cavities, which would have interesting applications in host-guest chemistry and development of porous materials. PMID- 29997832 TI - Surfactant-facilitated crystallisation of water-soluble foldamers. AB - X-ray crystallography has played a major role in the advancement of foldamer research, however, obtaining well-formed single crystals of suitable quality for structure determination by X-ray diffraction methods is often rather challenging. Towards this end, we report here the ability of common surfactants to promote the crystallisation of a series of water-soluble oligourea foldamers which had previously proven highly resistant to crystallisation. Four high-resolution crystal structures are reported, suggesting certain surfactants could be potentially useful tools for the crystallisation of intractable water-soluble foldamers (or peptides). PMID- 29997833 TI - Highly selective catalytic trans-hydroboration of alkynes mediated by borenium cations and B(C6F5)3. AB - The trans-hydroboration of terminal alkynes mediated by borenium cations [NHC(9 BBN)]+ (NHC = N-heterocyclic carbene, 9-BBN = 9-borabicyclo(3.3.1)nonane) exclusively affords Z-vinylboranes. NHCs and chelating dialkyl substituents on the borenium cation and "non"-basic anions were essential to preclude alternative reactions including dehydroboration. Deuterium labelling studies indicate the mechanism involves addition of the boron electrophile to the alkyne and transfer of hydride to the opposite face of the activated alkyne. trans-Hydroboration proceeds with only catalytic amounts of B(C6F5)3 or [Ph3C][B(C6F5)4] to activate the (NHC)9-BBN(H) precursor with the borenium regenerated in the hydride transfer step. The NHC can be removed from the trans-hydroborated products by the addition of Et2O-BF3 providing access to vinylBBN species effective for Suzuki-Miyaura couplings to generate Z-alkenes. Combinations of catalytic B(C6F5)3 and stoichiometric [HB(C6F5)3]- also lead to trans-hydroboration of terminal alkynes to form Z-isomers of [arylCH[double bond, length as m-dash]CHB(C6F5)3]-. PMID- 29997834 TI - A single cation or anion dendrimer-based liquid electrolyte. AB - We propose here a novel liquid dendrimer-based single ion conductor as a potential alternative to conventional molecular liquid solvent-salt solutions in rechargeable batteries, sensors and actuators. A specific change from ester ( COOR) to cyano (-CN) terminated peripheral groups in generation-one poly(propyl ether imine) (G1-PETIM)-lithium salt complexes results in a remarkable switchover from a high cation (tLi+ = 0.9 for -COOR) to a high anion (tPF6- = 0.8 for -CN) transference number. This observed switchover draws an interesting analogy with the concept of heterogeneous doping, applied successfully to account for similar changes in ionic conductivity arising out of dispersion of insulator particle inclusions in weak inorganic solid electrolytes. The change in peripheral group simultaneously affects the effective ionic conductivity, with the room temperature ionic conductivity of PETIM-CN (1.9 * 10-5 Omega-1 cm-1) being an order of magnitude higher than PETIM-COOR (1.9 * 10-6 Omega-1 cm-1). Notably, no significant changes are observed in the lithium mobility even following changes in viscosity due to the change in the peripheral group. Changes in the peripheral chemical functionality directly influence the anion mobility, being lower in PETIM-COOR than in PETIM-CN, which ultimately becomes the sole parameter controlling the effective transport and electrochemical properties of the dendrimer electrolytes. PMID- 29997835 TI - Heteronanowires of MoC-Mo2C as efficient electrocatalysts for hydrogen evolution reaction. AB - Exploring efficient noble-metal free electrocatalysts for the hydrogen evolution reaction (HER) is one of the most promising pathways for facing the energy crisis. Herein, MoC-Mo2C heteronanowires composed of well-defined nanoparticles were accomplished via controlled carbonization, showing excellent HER activity, fast kinetic metrics and outstanding stability in both acid and basic electrolytes. In particular, the optimal one consisting of 31.4 wt% MoC displayed a low overpotential (eta10 = 126 and 120 mV for reaching a current density of -10 mA cm-2), a small Tafel slope (43 and 42 mV dec-1) and a low onset overpotential (38 and 33 mV) in 0.5 M H2SO4 and 1.0 M KOH, respectively. Such prominent performance, outperforming most of the current noble-metal free electrocatalysts, was ascribed to the carbide surface with an optimized electron density, and the consequently facilitated HER kinetics. This work elucidates a feasible way toward efficient electrocatalysts via heteronanostructure engineering, shedding some light on the exploration and optimization of catalysts in energy chemistry. PMID- 29997836 TI - Fatty acids' double role in the prebiotic formation of a hydrophobic dipeptide. AB - In search of a connection between prebiotic peptide chemistry and lipid compartments, the reaction of a 5(4H)-oxazolone with leucinamide was extensively explored under buffered aqueous conditions, where diverse amphiphiles and surfactants could form supramolecular assemblies. Significant increases in yield and changes in stereoselectivity were observed when fatty acids exceeded their critical aggregation concentration, self-assembling into vesicles in particular. This effect does not take place below the fatty acid solubility limit, or when other anionic amphiphiles/surfactants are used. Data from fluorimetric and Langmuir trough assays, complementary to the main HPLC results reported here, demonstrate that the dipeptide product co-localizes with fatty acid bilayers and monolayers. Additional experiments in organic solvents suggest that acid-base catalysis operates at the water-aggregate interface, linked to the continuous proton exchange dynamics that fatty acids undergo at pH values around their effective pKa. These simple amphiphiles could therefore play a dual role as enhancers of peptide chemistry under prebiotic conditions, providing soft and hydrophobic organic domains through self-assembly and actively inducing catalysis at their interface with the aqueous environment. Our results support a systems chemistry approach to life's origin. PMID- 29997837 TI - Construction of spirocarbocycles via gold-catalyzed intramolecular dearomatization of naphthols. AB - A highly efficient, gold-catalyzed intramolecular dearomatization reaction of naphthols via 5-endo-dig cyclization is described. This facile and direct approach furnishes spirocarbocycles in excellent yields under mild conditions. PMID- 29997838 TI - Towards a general ruthenium-catalyzed hydrogenation of secondary and tertiary amides to amines. AB - A broad range of secondary and tertiary amides has been hydrogenated to the corresponding amines under mild conditions using an in situ catalyst generated by combining [Ru(acac)3], 1,1,1-tris(diphenylphosphinomethyl)ethane (Triphos) and Yb(OTf)3. The presence of the metal triflate allows to mitigate reaction conditions compared to previous reports thus improving yields and selectivities in the desired amines. The excellent isolated yields of two scale-up experiments corroborate the feasibility of the reaction protocol. Control experiments indicate that, after the initial reduction of the amide carbonyl group, the reaction proceeds through the reductive amination of the alcohol with the amine arising from collapse of the intermediate hemiaminal. PMID- 29997839 TI - Genetic engineering of inorganic functional modular materials. AB - Since the launch of the Materials Genome Initiative by the US government in 2011, many computer techniques have been developed to predict the structures and properties of advanced materials, providing important guidance for laboratory experimentation and a promising new direction for future materials innovation. However, lots of inorganic materials are difficult for computers to process because of their complex three-dimensionally extended structures. Fortunately, many of these materials are built from well-defined stacking layer modules, and the stacking sequences of their layer modules unambiguously determine their three dimensional structures. Such one-dimensional stacking sequence representation is naturally accessible for computer processing, easing the problems not only of structure elucidation, but also in the enumeration, evaluation, and screening of a large number of unknown materials with desired properties. More importantly, with the aid of various computational methods, we may reveal the relationship between the stacking sequences and the properties of these materials, which is a key prerequisite for function-led targeted synthesis. This Minireview covers the most recent progress in this emerging area. PMID- 29997840 TI - C-Linked 8-aryl guanine nucleobase adducts: biological outcomes and utility as fluorescent probes. AB - Aryl radical species derived from enzymatic transformations of aromatic mutagens preferentially react at the 8-site of the guanine (G) nucleobase to afford carbon linked 8arylG adducts. The resulting lesions possess altered biophysical and genetic coding properties compared to the precursor G nucleoside in B-form DNA. Unlike other adducts, these lesions also possess useful fluorescent properties, since direct attachment of the 8aryl ring extends the purine pi-system to afford G mimics with red-shifted excitation maxima and emission that can be sensitive to the microenvironment of the 8arylG base within nucleic acid structures. In B-form DNA, 8arylG adducts are disruptive to duplex formation because they prefer to adopt the syn-conformation about the bond connecting the nucleobase to the deoxyribose backbone, which perturbs Watson-Crick (WC) H-bonding with the opposing cytosine (C). Thus, in a B-form duplex, the emissive properties of 8arylG adducts can be employed as a tool to provide insight into adduct conformation, which can be related to their biological outcomes. However, since Gs preferentially adopt the syn-conformation in left-handed Z-DNA and antiparallel G-quadruplex (GQ) structures, 8arylG lesions can be inserted into syn-G positions without disrupting H-bonding interactions. In fact, 8arylG lesions can serve as ideal fluorescent probes in an antiparallel GQ because their emission is sensitive to GQ folding. This perspective outlines recent developments in the biological implications of 8arylG formation together with their utility as fluorescent G analogs for use in DNA-based diagnostic systems. PMID- 29997841 TI - The Raman fingerprint of cyclic conjugation: the case of the stabilization of cations and dications in cycloparaphenylenes. AB - Radical cations and dications of [n]CPP from n = 5 to n = 12 have been studied by Raman spectroscopy and density functional theory. Small [n]CPP dications owe their stability to the closed-shell electronic structure imposed by cyclic conjugation surpassing the destabilizing effect of ring strain and of the electron deficiency of the charged states. Large [n]CPP dications mitigate cyclic strain by forming diradicals. The Raman spectra reflect the balance among cyclic conjugation, cyclic strain and biradicaloid stabilization by finding an unexpected turning point in the frequency behavior of the G vibrational modes as a function of size. These Raman data represent the vibrational fingerprint of this rare form of conjugation which is central to stabilize both cations and dications of [n]CPP macrocycles. PMID- 29997842 TI - Porous single-crystalline AuPt@Pt bimetallic nanocrystals with high mass electrocatalytic activities. AB - Au-Pt bimetallic structures can effectively improve the activity and stability of catalysts in several fuel cell related electrochemical reactions. However, most of the methods for the preparation of Au-Pt nanocrystals (NCs) with core-shell structures are step-wise syntheses, which are adverse for reducing the production costs and the scale-up process. This paper describes a one-pot synthesis of rhombic dodecahedral AuPt@Pt bimetallic nanocrystals with dendritic branches. The dendritic branches on the surfaces were grown through oriented attachment and the whole particle exhibited a single-crystal structure. The thickness of the dendritic Pt shell can be controlled by tuning the introduced Pt precursor. With the Au-enhancement effect arising from the Au-Pt bimetallic core and high atom utilization efficiency provided by the porous structure, the AuPt@Pt bimetallic NCs exhibited greatly enhanced electrocatalytic properties (e.g. oxygen reduction reaction and formic acid oxidation) than those of the commercial Pt/C catalyst. PMID- 29997843 TI - Enhancement of dye regeneration kinetics in dichromophoric porphyrin-carbazole triphenylamine dyes influenced by more exposed radical cation orbitals. AB - Reduction kinetics of oxidized dyes absorbed on semiconductor surfaces and immersed in redox active electrolytes has been mainly modeled based on the free energy difference between the oxidation potential of the dye and the redox potential of the electrolyte. Only a few mechanisms have been demonstrated to enhance the kinetics by other means. In this work, the rate constant of the reduction of oxidized porphyrin dye is enhanced by attaching non-conjugated carbazole triphenylamine moiety using iodine/triiodide and tris(2,2' bispyridinium)cobalt II/III electrolytes. These results are obtained using transient absorption spectroscopy by selectively probing the regeneration kinetics at the porphyrin radical cation and the carbazole triphenylamine radical cation absorption wavelengths. The enhancement in the reduction kinetics is not attributed to changes in the driving force, but to the more exposed dye cation radical orbitals of the dichromophoric dye. The results are important for the development of high efficiency photo-electrochemical devices with minimalized energy loss at electron transfer interfaces. PMID- 29997844 TI - Tunable and highly efficient light-harvesting antenna systems based on 1,7 perylene-3,4,9,10-tetracarboxylic acid derivatives. AB - We report the synthesis and excited-state dynamics of a series of five bichromophoric light-harvesting antenna systems, which are capable of efficient harvesting of solar energy in the spectral range of 350-580 nm. These antenna systems have been synthesized in a modular fashion by the covalent attachment of blue light absorbing naphthalene monoimide energy donors (D1, D2, and D3) to green light absorbing perylene-3,4,9,10-tetracarboxylic acid derived energy acceptors, 1,7-perylene-3,4,9,10-tetracarboxylic tetrabutylester (A1), 1,7 perylene-3,4,9,10-tetracarboxylic monoimide dibutylester (A2), and 1,7-perylene 3,4,9,10-tetracarboxylic bisimide (A3). The energy donors have been linked at the 1,7-bay-positions of the perylene derivatives, thus leaving the peri positions free for further functionalization and device construction. A highly stable and rigid structure, with no electronic communication between the donor and acceptor components, has been realized via an all-aromatic non-conjugated phenoxy spacer between the constituent chromophores. The selection of donor naphthalene derivatives for attachment with perylene derivatives was based on the effective matching of their respective optical properties to achieve efficient excitation energy transfer (EET) by the Forster mechanism. A comprehensive study of the excited-state dynamics, in toluene, revealed quantitative and ultrafast (ca. 1 ps) intramolecular EET from donor naphthalene chromophores to the acceptor perylenes in all the studied systems. Electron transfer from the donor naphthalene chromophores to the acceptor perylenes has not been observed, not even for antenna systems in which this process is thermodynamically allowed. Due to the combination of an efficient and fast energy transfer along with broad absorption in the visible region, these antenna systems are promising materials for solar-to-electric and solar-to-fuel devices. PMID- 29997845 TI - Electronic structure and reactivity of nickel(i) pincer complexes: their aerobic transformation to peroxo species and site selective C-H oxygenation. AB - The study is aimed at a deeper understanding of the electronic structure of the T shaped nickel(i) complex [LigiPr(iso)Ni] (1b), bearing the iso-PyrrMeBox (bis(oxazolinylmethylidene)pyrrolidinido) pincer ligand, and its CO adduct [LigiPr(iso)Ni(CO)] (2b) as well as to provide insight into the mechanism of autoxidation of the different nickel peroxo species of this ligand type. CO was found to react reversibly with complex 1b resulting in the corresponding CO adduct 2b. The EPR data as well as the results of DFT modeling revealed significant differences in the electronic structure of 1b and 2b. Reaction of [LigPh(iso)Ni] and [LigiPr(iso)Ni] (1a and b) with dioxygen yielded the 1,2-MU peroxo complexes [Lig(iso)NiO]23a and b which reacted with hydrogen peroxide to give the hydroperoxo complexes [Lig(iso)NiOOH] 5a and b. Thermal aerobic decomposition of the peroxo species 3a and 5a in the presence of O2 led to a C-H activation of the ligand at the benzylic position of the oxazoline ring forming diastereomeric cyclic peroxo complexes 6 and 6'. For the 1,2-MU-peroxo complex 3b the autoxidation of the pincer in the absence of O2 occurred at the tertiary C-H bond of the iPr-group and led to a selective formation of the terminal hydroxo complex [LigiPr(iso)NiOH] 7b and the cyclic alkoxy complex 8 in equimolar quantities, while the corresponding cyclic peroxo species 9 was formed along with 7b in the presence of oxygen. Whether or not O-O bond cleavage occurred in the generation of 9 was established upon performing labeling experiments which indicate that the transformation does not involve an initial O-O bond cleaving step. Based on these observations and a series of stoichiometric transformations a tentative proposal for the processes involved in the anaerobic and aerobic decomposition of 3b has been put forward. Finally, the nickel(ii) methyl complex [LigPh(iso)NiMe] 14 reacted with O2 to give the methylperoxo complex [LigPh(iso)NiOOMe] 15 which slowly converted to a mixture of near equal amounts of the formato and the hydroxo complexes, [LigPh(iso)NiOOCH] 16 and [LigPh(iso)NiOH] 7a, along with half an equivalent of methanol. The formato complex 16 itself decomposed at elevated temperatures to CO2, dihydrogen as well as the nickel(i) species 1a. PMID- 29997847 TI - Insight into the mechanism and outcoupling enhancement of excimer-associated white light generation. AB - Fundamental insight into excimer formation has been gained by using 9,10-bis[4-(9 carbazolyl)phenyl]anthracene] (Cz9PhAn) as a probe. Cz9PhAn exhibits a highly emissive blue fluorescence in solution and is found to emit a panchromatic white light spectrum (400-750 nm) in film, powder and single crystal, in which an additional excimer band appears at ~550 nm. Detailed structural analyses, emission relaxation dynamics and a theoretical approach conclude the formation of an anthracene*/phenyl ring excimer through an overlap between pi* (anthracene) and pi (phenyl ring) orbitals in a face-to-edge stacking orientation. The rate of excimer formation is determined to be 2.2 * 109 s-1 at room temperature, which requires coupling with lattice motion with an activation energy of 0.44 kcal mol 1. Exploiting Cz9PhAn as a single emitter, a fluorescent white organic light emitting diode (WOLED) is fabricated with a maximum external quantum efficiency (etaext) of 3.6% at 1000 cd m-2 (4.2 V) and Commission Internationale de L'Eclairage (CIE) coordinates of (0.30, 0.33). The white-light Cz9PhAn reveals a preferred orientation of the transition dipole moment in the emitting layer to enhance light outcoupling. This non-doped, single component (Cz9PhAn) WOLED greatly reduces the complexity of the fabrication process, rendering a green and cost-effective alternative among the contemporary display/lighting technologies. PMID- 29997848 TI - Carbogenic nanodots derived from organo-templated zeolites with modulated full color luminescence. AB - Hydrophilic N-doped carbogenic nanodots (denoted as CNDs) have been prepared from a N-methylpiperazine-templated zeolite precursor by calcination and NaOH treatment. The isolated CNDs exhibit tunable photoluminescence according to the concentration and pH value of aqueous dispersions of the CNDs. Fine-tuning of the fluorescence emission wavelength across the entire visible spectrum can be easily achieved by varying the concentration of the CND dispersions. Meanwhile, both the emission wavelength and intensity of the photoluminescence can be tuned by controlling the pH value of the CND dispersion. The pyrolysis of organic templates confined in nanoporous zeolites represents a new approach to controlling the optical properties of CNDs, which may open more opportunities in applications such as multimodal sensing and full-color displays. PMID- 29997846 TI - Ring-fusion as a perylenediimide dimer design concept for high-performance non fullerene organic photovoltaic acceptors. AB - A series of perylenediimide (PDI) dimers are evaluated as acceptors for organic photovoltaic (OPV) cells. The materials are characterized using a wide variety of physical and computational techniques. These dimers are first linked at the bay position of each PDI molecule via an aromatic spacer; subsequent photocyclization affords ring-fused dimers. Thus, photocyclization of the thiophene-linked dimer 2,5-bis-[N,N'-bis-perylenediimide-1-yl]-thiophene (T1) affords the twisted acceptor [2,3-b:2',3'-d]-bis-[N,N'-bis-perylenediimide-1,12-yl]-thiophene (T2), while photocyclization of the thienothiophene-linked dimer, 2,5-bis-[N,N'-bis perylenediimide-1-yl]-thienothiophene (TT1) affords the planar acceptor [2,3 b:2',3'-d]-bis-[N,N'-bis-perylenediimide-1,12-yl]-thienothiophene (TT2). Furthermore, a dimer linked by a phenylene group, 1,4-bis-[N,N'-bis perylenediimide-1-yl]-benzene (Ph1), can be selectively photocyclized to form either the twisted dimer, [1,2:3,4]-bis-[N,N'-bis-perylenediimide-1,12-yl] benzene (Ph1a) or the planar dimer [1,2:4,5]-bis-[N,N'-bis-perylenediimide-1,12 yl]-benzene (Ph2b). Ring-fusion results in increased electronic coupling between the PDI units, and increased space-charge limited thin film electron mobility. While charge transport is efficient in bulk-heterojunction blends of each dimer with the polymeric donor PBDTT-FTTE, in the case of the twisted dimers ring fusion leads to a significant decrease in geminate recombination, hence increased OPV photocurrent density and power conversion efficiency. This effect is not observed in planar dimers where ring fusion leads to increased crystallinity and excimer formation, decreased photocurrent density, and decreased power conversion efficiency. These results argue that ring fusion is an effective approach to increasing OPV bulk-heterojunction charge carrier generation efficiency in PDI dimers as long as they remain relatively amorphous, thereby suppressing excimer formation and coulombically trapped charge transfer states. PMID- 29997849 TI - Water vs. cucurbituril rim: a fierce competition for guest solvation. AB - The impact of remote substituents on the affinity of cucurbit[n]urils (CB[n]) towards a homologous series of guests, which differ from one another only by a single substituent, and adopt the same geometry within the cavity of the macrocycle, is presented for the first time, and is used to decipher the competition between water and the carbonylated portal of CB[7] for the stabilization of positively charged guests. Binding affinities of CB[7] towards substituted N-benzyl-trimethylsilylmethylammonium cations relative to the unsubstituted member (X = H) range from 0.9 (X = CH3) to 3.1 (X = SO2CF3), and correlate very precisely with a linear combination of Swain-Lupton field/inductive (F; 67%) and resonance (R; 33%) parameters tabulated for each substituent. We show that this subtle sensitivity results exclusively from the balance between two competing mechanisms, on which the substituents exert an approximately 11 times greater impact: (1) the solvation of the ammonium unit and its immediate surroundings by water in the free guests, and (2) the coulombic attraction between the ammonium unit and the rim of CB[7] in the complexes. PMID- 29997850 TI - "Inverse" thermoresponse: heat-induced double-helix formation of an ethynylhelicene oligomer with tri(ethylene glycol) termini. AB - An ethynylhelicene oligomer [(M)-d-4]-C12-TEG with six tri(ethylene glycol) (TEG) groups at the termini was synthesized, and double-helix formation was studied using CD, UV-Vis, vapor pressure osmometry, dynamic light scattering, and 1H NMR. [(M)-d-4]-C12-TEG reversibly changed its structure between a double helix and a random coil in response to heating and cooling in aromatic solvents, non-aromatic polar organic solvents, and aqueous solvent mixtures of acetone/water/triethylamine. Notably, [(M)-d-4]-C12-TEG in acetone/water/triethylamine (1/2/1) formed a double helix upon heating and disaggregated into random coils upon cooling. The double helix/random coil ratio sharply changed in response to temperature changes. This is an unprecedented "inverse" thermoresponse, which is opposite to the "ordinary" thermoresponse in molecular dimeric aggregate formation. This phenomenon was explained by the dehydration of the terminal TEG groups and the formation of condensed triethylamine domains upon heating. PMID- 29997851 TI - Violation of DNA neighbor exclusion principle in RNA recognition. AB - DNA intercalation has been very useful for engineering DNA-based functional materials. It is generally expected that the intercalation phenomenon in RNA would be similar to that in DNA. Here we note that the neighbor-exclusion principle is violated in RNA by naphthalene-based cationic probes, in contrast to the fact that it is usually valid in DNA. All the intercalation structures are responsible for the fluorescence, where small naphthalene moieties are intercalated in between bases via pi-pi interactions. The structure is aided by hydrogen bonds between the cationic moieties and the ribose-phosphate backbone, which results in specific selectivity for RNA over DNA. This experimentally observed mechanism is supported by computationally reproducing the fluorescence and CD data. MD simulations confirm the unfolding of RNA due to the intercalation of probes. Elucidation of the mechanism of selective sensing for RNA over DNA would be highly beneficial for dynamical observation of RNA which is essential for studying its biological roles. PMID- 29997852 TI - Zeolite-derived hybrid materials with adjustable organic pillars. AB - Porous organic-inorganic materials with tunable textural characteristics were synthesized using the top-down process by intercalating silsesquioxanes and polyhedral oligomeric siloxanes of different types between crystalline zeolite derived layers. The influence of key parameters such as (i) linker nature (pure hydrocarbon, S-, N-containing); (ii) chain length in alkyl- and aryl bis(trialkoxysilyl) derivatives; (iii) denticity of the organic precursor molecules; (iv) nature and size of side chain in mono(trialkoxysilyl) substrates; (v) rigidity of the chain (saturated vs. unsaturated, aliphatic vs. aromatic); (vi) nature and size of leaving group on the structural and textural properties of formed hybrids was carefully addressed. It was established, that the optimal silsesquioxane appropriate for the formation of zeolite-derived hybrids with high textural characteristics should possess short alkyl or long aryl chains, relatively small leaving groups and denticity larger than 3. Addition of polydentate low-molecular binder improved the structural and textural characteristics of hybrids, especially when using bulky or hydrophilic linkers. PMID- 29997853 TI - Conjugated polymer-enhanced enantioselectivity in fluorescent sensing. AB - A new strategy to use conjugated polymers to conduct fluorescent enhancement sensing has been developed. Chiral 1,1'-bi-2-naphthol-based binding sites are linked by p-phenylene units to construct a conjugated polymer whose fluorescence is quenched by the aldehyde groups introduced at each binding site. Interaction of this polymer with chiral amino alcohols in the presence of Zn(ii) leads to highly enantioselective fluorescent enhancement. It is found that the chiral conjugated polymer shows greatly enhanced enantioselectivity over the corresponding small molecular sensor under the same conditions. This work provides the first example that a conjugated polymer is used to greatly increase the enantioselectivity of a small molecular sensor in chiral recognition. Simultaneous determination of the concentration and enantiomeric composition of chiral substrates by a fluorescent measurement has been achieved by combining the polymer with salicylaldehyde in the assay. PMID- 29997854 TI - Triplet excited state properties in variable gap pi-conjugated donor-acceptor donor chromophores. AB - A series of variable band-gap donor-acceptor-donor (DAD) chromophores capped with platinum(ii) acetylide units has been synthesized and fully characterized by electrochemical and photophysical methods, with particular emphasis placed on probing triplet excited state properties. A counter-intuitive trend of increasing fluorescence quantum efficiency and lifetime with decreasing excited state energy (optical gap) is observed across the series of DAD chromophores. Careful study of the excited state dynamics, including triplet yields (as inferred from singlet oxygen sensitization), reveals that the underlying origin of the unusual trend in the fluorescence parameters is that the singlet-triplet intersystem crossing rate and yield decrease with decreasing optical gap. It is concluded that the rate of intersystem crossing decreases as the LUMO is increasingly localized on the acceptor unit in the DAD chromophore, and this result is interpreted as arising because the extent of spin-orbit coupling induced by the platinum heavy metal centers decreases as the LUMO is more localized on the acceptor. In addition to the trend in intersystem crossing, the results show that the triplet decay rates follow the Energy Gap Law correlation over a 1.8 eV range of triplet energy and 1000-fold range of triplet decay rates. Finally, femtosecond transient absorption studies for the DAD chromophores reveals a strong absorption in the near-infrared region which is attributed to the singlet excited state. This spectral band appears to be general for DAD chromophores, and may be a signature of the charge transfer (CT) singlet excited state. PMID- 29997855 TI - Energy harvesting from enzymatic biowaste reaction through polyelectrolyte functionalized 2D nanofluidic channels. AB - Effective recycling of biowaste energy in a compact system remains a great challenge. Here, we report a graphene-based energy harvesting system powered by enzymatic biowaste reaction through two-dimensional (2D) nanofluidic channels. The integrated 2D nanofluidic generator shows distinct advantages such as flexibility, low cost, and high output in ionic currents. PMID- 29997856 TI - Oxadendralenes in asymmetric organocatalysis for the construction of tetrahydroisochromenes. AB - Oxadendralenes are integrated in a novel manner into a one-pot cascade utilizing synergistic catalysis for the construction of valuable and complex bicyclic heterocyclic scaffolds. The construction is based on the organocatalytic activation of the oxadendralenes generating a vinylogous iminium-ion intermediate which is set-up for a 1,6-addition with an enamine formed from an aldehyde and the same organocatalyst. This reaction generates a cyclic oxadendralenic intermediate, which acts as an electron-deficient heterodiene reacting in a Lewis acid catalyzed hetero-Diels-Alder reaction with vinyl ethers to form tetrahydroisochromenes with five continuous stereocenters in high yields, >20 : 1 dr and 99% ee. This synergistic organo- and Lewis-acid catalysed system also displays high tolerance for variation in oxadendralenes and aldehydes, which provides tetrahydroisochromenes with high diversity in the substituent pattern and the same excellent stereoselectivities. Mechanistic studies have been performed to account for the activation modes and stereochemical outcome of the reaction. The reaction concept has been extended to also include a sequential organocatalytic reaction of oxadendralenes with aldehydes, in which the enamine formed from the aldehyde and the organocatalyst act both in the first catalytic cycle forming the cyclic oxadendralenic intermediate and in a second catalytic cycle leading to tetrahydroisochromenes in good yields and excellent stereoselectivities. Mechanistic studies reveal that the stereochemistry of the organocatalyst has an influence on the diastereoselectivity of the reaction sequence. Some transformations of the tetrahydroisochromenes are also presented. The chiral tetrahydroisochromenes formed might be applied in the diversified synthesis of important drugs. PMID- 29997857 TI - Paving the way for methane hydrate formation on metal-organic frameworks (MOFs). AB - The presence of a highly tunable porous structure and surface chemistry makes metal-organic framework (MOF) materials excellent candidates for artificial methane hydrate formation under mild temperature and pressure conditions (2 degrees C and 3-5 MPa). Experimental results using MOFs with a different pore structure and chemical nature (MIL-100 (Fe) and ZIF-8) clearly show that the water-framework interactions play a crucial role in defining the extent and nature of the gas hydrates formed. Whereas the hydrophobic MOF promotes methane hydrate formation with a high yield, the hydrophilic one does not. The formation of these methane hydrates on MOFs has been identified for the first time using inelastic neutron scattering (INS) and synchrotron X-ray powder diffraction (SXRPD). The results described in this work pave the way towards the design of new MOF structures able to promote artificial methane hydrate formation upon request (confined or non-confined) and under milder conditions than in nature. PMID- 29997858 TI - On the origin of high ionic conductivity in Na-doped SrSiO3. AB - Understanding the local structure and ion dynamics is at the heart of ion conductor research. This paper reports on high-resolution solid-state 29Si, 23Na, and 17O NMR investigation of the structure, chemical composition, and ion dynamics of a newly discovered fast ion conductor, Na-doped SrSiO3, which exhibited a much higher ionic conductivity than most of current oxide ion conductors. Quantitative analyses reveal that with a small dose (<10 mol%) of Na, the doped Na integrates into the SrSiO3 structure to form Na x Sr1-x SiO3-0.5x , and with >10 mol% Na doping, phase separation occurs, leading to the formation of an amorphous phase beta-Na2Si2O5 and a crystalline Sr-rich phase. Variable temperature 23Na and 17O magic-angle-spinning NMR up to 618 degrees C have shown significant changes in Na ion dynamics at high temperatures but little oxide ion motion, suggesting that Na ions are responsible for the observed high ionic conductivity. In addition, beta-Na2Si2O5 starts to crystallize at temperatures higher than 480 degrees C with prolonged heating, resulting in reduction in Na+ motion, and thus degradation of ionic conductivity. This study has contributed critical evidence to the understanding of ionic conduction in Na-doped SrSiO3 and demonstrated that multinuclear high-resolution and high-temperature solid-state NMR is a uniquely useful tool for investigating ion conductors at their operating conditions. PMID- 29997859 TI - Towards pi-extended cycloparaphenylenes as seeds for CNT growth: investigating strain relieving ring-openings and rearrangements. AB - Despite significant multidisciplinary effort over many years, the preparation of uniform carbon nanotubes (CNTs) is still an unsolved problem in the scientific community. This inaccessibility hampers the commercial use of CNTs in electronic devices due to the sensitive connection between their electronic properties and molecular structure. The [n]cycloparaphenylenes ([n]CPPs), the smallest horizontal segment of an armchair CNT, hold great promise as "seeds", or templates, for the preparation of homogenous batches of CNTs. Initial reports towards this goal, however, suggest that it would be advantageous to pi-extend these structures through traditional organic synthesis before their use in CNT growth. Towards this, several strategies have been reported attempting to utilize the Scholl reaction on aryl-substituted cycloparaphenylenes to yield a small CNT for use as a template for larger tubes. Prominently used in polyaromatic hydrocarbon chemistry, the Scholl reaction has afforded numerous extraordinary targets, such as graphene nanoribbons and graphene propellors. In this work, both experimental and computational studies are provided to unravel the complex cationic rearrangements and ring-openings associated with the Scholl reaction in the context of the cycloparaphenylenes-systems that are thermodynamically and kinetically different from flat graphene fragments. Additionally, this work demonstrates the unique reactivity of cycloparaphenylenes in the context of cationic or radical cationic intermediates, which are common reaction pathways for numerous transformations. PMID- 29997860 TI - Redirecting immunity via covalently incorporated immunogenic sialic acid on the tumor cell surface. AB - Techniques eliciting anti-tumor immunity are of interest for immunotherapy. We herein report the covalent incorporation of a non-self immunogen into the tumor glycocalyx by metabolic oligosaccharide engineering with 2,4-dinitrophenylated sialic acid (DNPSia). This enables marked suppression of pulmonary metastasis and subcutaneous tumor growth of B16F10 melanoma cells in mice preimmunized to produce anti-DNP antibodies. Located on the exterior glycocalyx, DNPSia is well positioned to recruit antibodies. Given the high levels of natural anti-DNP antibodies in humans and ubiquitous sialylation across many cancers, DNPSia offers a simplified route to redirect immunity against diverse tumors without recourse to preimmunization. PMID- 29997861 TI - Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human O-GlcNAcase. AB - The modification of nucleocytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc) plays diverse roles in multicellular organisms. Inhibitors of O-GlcNAc hydrolase (OGA), the enzyme that removes O-GlcNAc from proteins, lead to increased O-GlcNAc levels in cells and are seeing widespread adoption in the field as a research tool used in cells and in vivo. Here we synthesize and study a series of tight binding carbohydrate-based inhibitors of human OGA (hOGA). The most potent of these 2'-aminothiazolines binds with a sub-nanomolar Ki value to hOGA (510 +/- 50 pM) and the most selective has greater than 1 800 000-fold selectivity for hOGA over mechanistically related human lysosomal beta hexosaminidase. Structural data of inhibitors in complex with an hOGA homologue reveals the basis for variation in binding among these compounds. Using linear free energy analyses, we show binding of these 2'-aminothiazoline inhibitors depends on the pKa of the aminothiazoline ring system, revealing the protonation state of the inhibitor is a key driver of binding. Using series of inhibitors and synthetic substrates, we show that 2'-aminothiazoline inhibitors are transition state analogues of hOGA that bind to the enzyme up to 1-million fold more tightly than the substrate. These collective data support an oxazoline, rather than a protonated oxazolinium ion, intermediate being formed along the reaction pathway. Inhibitors from this series will prove generally useful tools for the study of O GlcNAc. The new insights gained here, into the catalytic mechanism of hOGA and the fundamental drivers of potency and selectivity of OGA inhibitors, should enable tuning of hOGA inhibitors with desirable properties. PMID- 29997862 TI - Coupling fullerene into porous aromatic frameworks for gas selective sorption. AB - A lot of investigations calculate that fullerene would be an excellent unit for porous adsorbents for gas sorption and separation. Although the conjugated structure and symmetrical shape of fullerene makes it an ideal building block, there is no facile strategy to achieve fullerene-based porous materials. Herein, we adopt a novel acid catalyzed coupling reaction to bind the fullerene molecules together in a one-step synthesis. After synthesizing the adducts as models, the atomic connectivity between the fullerene molecules is determined clearly. We then prepared a series of fullerene-based porous aromatic frameworks (PAFs). The targeted products adsorb H2 and CO2, and they exhibit some selectivity of CO2 over N2 and CH4. The good performance of the PAFs indicates that we could combine the gas binding ability of the building block and the porous nature of PAF materials together to give a better adsorbent. PMID- 29997863 TI - Palladium-catalyzed difluoromethylthiolation of heteroaryl bromides, iodides, triflates and aryl iodides. AB - A palladium-catalyzed difluoromethylthiolation of heteroaryl halides and triflates under mild conditions was described. A vast range of heteroaryl halides such as pyridyl, quinolinyl, benzothiazolyl, thiophenyl, carbazolyl and pyazolyl halides could be difluoromethylthiolated efficiently, thus providing medicinal chemists with new tools for their search of new lead compounds for drug discovery. Likewise, aryl iodides were difluoromethylthiolated in high yields under a modified reaction condition. PMID- 29997864 TI - Tuning ESIPT fluorophores into dual emitters. AB - Dyes undergoing excited-state intramolecular proton transfer (ESIPT) are known to present large Stokes shifts as a result of the important geometrical reorganisation following photon absorption. When the ESIPT process is not quantitative, one can obtain dual emitters characterised by two distinct fluorescence bands, observed due to emissions from both the canonical and ESIPT isomers. However, dual emission generally requires to maintain a very specific balance, as the relative excited-state free energies of the two tautomers have to be within a narrow window to observe the phenomenon. Consequently, simple chemical intuition is insufficient to optimise dual emission. In the present contribution, we investigate, with the help of quantum-mechanical tools and more precisely, time-dependent density functional theory (TD-DFT) and algebraic diagrammatic construction (ADC), a wide panel of possible ESIPT/dual emitters with various substituents. The selected protocol is first shown to be very robust on a series of structures with known experimental behaviour, and next is applied to novel derivatives with various substituents located at different positions. This work encompasses the largest chemical library of potential ESIPT compounds studied to date. We pinpoint the most promising combinations for building dual emitters, highlight unexpected combination effects and rationalise the impact of the different auxochromes. PMID- 29997865 TI - Aryl transition metal chemical warheads for protein bioconjugation. AB - The past seven years have witnessed the burgeoning of protein bioconjugation reactions highlighting aryl transition metal reagents as coupling partners. This new bioorthogonal organometallic chemistry, which sets the scene for stoichiometric processes in place of the catalytic procedures that developed in parallel, already enabled the forging of C-S and C-C bonds onto protein substrates, respectively in their native state or equipped with pre-installed non natural terminal alkene or alkyne appendages. Although not yet applied to proteins, related transformations pointing to the creation of C-N bonds have, in addition, just been disclosed by targeting peptide lysine residues. Central to this research was the selection of ligands attached to the transition metal, in order to confer to metal complexes, not only their stability in aqueous medium, but also the desired chemoselectivity. We summarize here this body of work, which has already put in the limelight elaborated palladium and gold complexes equipped with biologically relevant appendages, such as fluorescent and affinity tags, as well as drug molecules. This research holds much promise, not only for the study of proteins themselves, but also for the design of new protein-based biotherapeutics, such as protein-drug conjugates or constrained analogs resulting from macrocyclisation reactions. PMID- 29997866 TI - Tropylium-promoted carbonyl-olefin metathesis reactions. AB - The carbonyl-olefin metathesis (COM) reaction is a highly valuable chemical transformation in a broad range of applications. However, its scope is much less explored compared to analogous olefin-olefin metathesis reactions. Herein we demonstrate the use of tropylium ion as a new effective organic Lewis acid catalyst for both intramolecular and intermolecular COM and new ring-opening metathesis reactions. This represents a significant improvement in substrate scope from recently reported developments in this field. PMID- 29997867 TI - Active learning with non-ab initio input features toward efficient CO2 reduction catalysts. AB - In a conventional chemisorption model, the d-band center theory (augmented sometimes with the upper edge of the d-band for improved accuracy) plays a central role in predicting adsorption energies and catalytic activity as a function of the d-band center of solid surfaces, but it requires density functional calculations that can be quite costly for the purposes of large scale screening of materials. In this work, we propose to use the d-band width of the muffin-tin orbital theory (to account for the local coordination environment) plus electronegativity (to account for adsorbate renormalization) as a simple set of alternative descriptors for chemisorption which do not require ab initio calculations for large-scale first-hand screening. This pair of descriptors is then combined with machine learning methods, namely, neural network (NN) and kernel ridge regression (KRR). We show, for a toy set of 263 alloy systems, that the CO adsorption energy on the (100) facet can be predicted with a mean absolute deviation error of 0.05 eV. We achieved this high accuracy by utilizing an active learning algorithm, without which the accuracy was 0.18 eV. In addition, the results of testing the method with other facets such as (111) terrace and (211) step sites suggest that the present model is also capable of handling different coordination environments effectively. As an example of the practical application of this machine, we identified Cu3Y@Cu* as an active and cost-effective electrochemical CO2 reduction catalyst to produce CO with an overpotential ~1 V lower than a Au catalyst. PMID- 29997868 TI - Copper mediated C-H amination with oximes: en route to primary anilines. AB - Here we report an efficient Cu(i)-mediated C-H amination reaction with oximes as amino donors to introduce NH2 groups directly. Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were tolerated well. The potential utility was further demonstrated in a late stage modification of telmisartan (an antagonist for the angiotensin II receptor). PMID- 29997869 TI - Red-emissive azabenzanthrone derivatives for photodynamic therapy irradiated with ultralow light power density and two-photon imaging. AB - Photodynamic therapy has proved to be an effective strategy for cancer therapy, and advanced photosensitizers for image-guided photodynamic therapy require biocompatibility, intense absorption, high ROS generation efficiency, phototoxicity, low irradiation power density and efficient emission. In this work, four red emissive azabenzanthrone derivatives have been designed and synthesized, which generally exhibit efficient aggregated state emission. Through structural optimization, 3-diphenylamino-11-azabenzanthrone was found to show satisfactory photo-induced ROS generation and high emission efficiency in the aggregated state. Under the irradiation of a white LED lamp with an ultralow power density of 1.67 mW cm-2, this compound demonstrates significant photo induced cytotoxicity toward HeLa cells. Moreover, deep tissue penetration can be realized by two-photon imaging of mouse brain vessels with these azabenzanthrone derivatives at vertical depths of up to 280 MUm, attributed to the large emission wavelength and efficient emission. PMID- 29997870 TI - Pyrene hydrogel for promoting direct bioelectrochemistry: ATP-independent electroenzymatic reduction of N2. AB - Enzymatic bioelectrocatalysis often requires an artificial redox mediator to observe significant electron transfer rates. The use of such mediators can add a substantial overpotential and obfuscate the protein's native kinetics, which limits the voltage of a biofuel cell and alters the analytical performance of biosensors. Herein, we describe a material for facilitating direct electrochemical communication with redox proteins based on a novel pyrene modified linear poly(ethyleneimine). This method was applied for promoting direct bioelectrocatalytic reduction of O2 by laccase and, by immobilizing the catalytic subunit of nitrogenase (MoFe protein), to demonstrate the ATP-independent direct electroenzymatic reduction of N2 to NH3. PMID- 29997871 TI - Rechargeable aluminum-selenium batteries with high capacity. AB - Rechargeable aluminum (Al) batteries are emerging as a promising post lithium-ion battery technology. Herein, we demonstrate a conceptually new design of rechargeable aluminum-selenium (Al-Se) batteries by understanding the selenium chemistry and controlling the electrode reaction. The Al-Se battery consists of a composite cathode including selenium nanowires and mesoporous carbon (CMK-3) nanorods, an Al metal anode and chloroaluminate ionic liquid electrolyte. The working mechanism of the Al-Se battery is the reversible redox reaction of the Se2Cl2/Se pair confined in the mesopores of CMK-3 nanorods. Al-Se batteries deliver a high reversible capacity of 178 mA h g-1 (by Se mass), high discharge voltages (mainly above 1.5 V), and good cycling/rate performances. PMID- 29997872 TI - Oncosis-inducing cyclometalated iridium(iii) complexes. AB - Oncosis is a non-apoptotic form of programmed cell death (PCD), which differs from apoptosis in both morphological changes and inner pathways, and might hold the key to defeating a major obstacle in cancer therapy - drug-resistance, which is often a result of the intrinsic apoptosis resistance of tumours. However, despite the fact that the term "oncosis" was coined and used much earlier than apoptosis, little effort has been made to discover new drugs which can initiate this form of cell death, in comparison to drugs inducing apoptosis or any other type of PCD. So herein, we present the synthesis of a series of mitochondria targeting cyclometalated Ir(iii) complexes, which activated the oncosis-specific protein porimin and calpain in cisplatin-resistant cell line A549R, and determined their cytotoxicity against a wide range of drug-resistant cancer types. To the best of our knowledge, these complexes are the very first metallo components to induce oncosis in drug-resistant cancer cells. PMID- 29997873 TI - Facile synthesis of alpha-aminoboronic acids from amines and potassium acyltrifluoroborates (KATs) via trifluoroborate-iminiums (TIMs). AB - We report the facile formation of trifluoroborate-iminiums (TIMs) from potassium acyltrifluoroborates (KATs) and the transformation of TIMs to alpha aminotrifluoroborates by reduction or Grignard additions. Conditions for the hydrolysis of alpha-aminotrifluoroborates to alpha-aminoboronic acids, which are important biologically active compounds, were established. This new methodology allows access to sterically demanding alpha-aminoboronic acids that are not easily prepared with currently available methods. This work also introduces TIMs, that can be easily prepared and handled, as a new category of functional groups that serve as precursors to valuable organic compounds. PMID- 29997875 TI - Preparative microdroplet synthesis of carboxylic acids from aerobic oxidation of aldehydes. AB - Single liquid-phase and liquid-liquid phase reactions in microdroplets have shown much faster kinetics than that in the bulk phase. This work extends the scope of microdroplet reactions to gas-liquid reactions and achieves preparative synthesis. We report highly efficient aerobic oxidation of aldehydes to carboxylic acids in microdroplets. Molecular oxygen plays two roles: (1) as the sheath gas to shear the aldehyde solution into microdroplets, and (2) as the sole oxidant. The dramatic increase of the surface-area-to-volume ratio of microdroplets compared to bulk solution, and the efficient mixing of gas and liquid phases using spray nozzles allow effective mass transfer between aldehydes and molecular oxygen. The addition of catalytic nickel(ii) acetate is shown to accelerate further microdroplet reactions of this kind. We show that aliphatic, aromatic, and heterocyclic aldehydes can be oxidized to the corresponding carboxylic acids in a mixture of water and ethanol using the nickel(ii) acetate catalyst, in moderate to excellent yields (62-91%). The microdroplet synthesis is scaled up to make it preparative. For example, aerobic oxidation of 4-tert butylbenzaldehyde to 4-tert-butylbenzoic acid was achieved at a rate of 10.5 mg min-1 with an isolated product yield of 66%. PMID- 29997874 TI - Enhancement of CO2 binding and mechanical properties upon diamine functionalization of M2(dobpdc) metal-organic frameworks. AB - The family of diamine-appended metal-organic frameworks exemplified by compounds of the type mmen-M2(dobpdc) (mmen = N,N'-dimethylethylenediamine; M = Mg, Mn, Fe, Co, Zn; dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) are adsorbents with significant potential for carbon capture, due to their high working capacities and strong selectivity for CO2 that stem from a cooperative adsorption mechanism. Herein, we use first-principles density functional theory (DFT) calculations to quantitatively investigate the role of mmen ligands in dictating the framework properties. Our van der Waals-corrected DFT calculations indicate that electrostatic interactions between ammonium carbamate units significantly enhance the CO2 binding strength relative to the unfunctionalized frameworks. Additionally, our computed energetics show that mmen-M2(dobpdc) materials can selectively adsorb CO2 under humid conditions, in agreement with experimental observations. The calculations further predict an increase of 112% and 124% in the orientationally-averaged Young's modulus E and shear modulus G, respectively, for mmen-Zn2(dobpdc) compared to Zn2(dobpdc), revealing a dramatic enhancement of mechanical properties associated with diamine functionalization. Taken together, our calculations demonstrate how functionalization with mmen ligands can enhance framework gas adsorption and mechanical properties. PMID- 29997876 TI - Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket. AB - Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain give rise to several cancers including Non-Small Cell Lung Cancer (NSCLC). Small molecule inhibitors targeted at these mutants have proven to be clinically successful drugs. These molecules are ATP competitive and rapidly result in the emergence of resistance. Recently Jia et al. [Nature, 2016, 534, 129-132] reported a small molecule inhibitor (called EAI045) that binds at an allosteric pocket, does not compete with ATP and displays high potency and selectivity towards certain activating mutants (L858R, T790M, L858R/T790M) of EGFR, with IC50 values ranging from 3 nM to 49 nM. We present here a study combining extensive molecular dynamics simulations with binding assays to provide a structural basis underlying the mechanism of binding of this molecule. It appears that in mutants, conformational destabilization of the short helix (that carries Leu858 in the wildtype), is key to the exposure of the allosteric pocket which otherwise is occluded by a set of sidechains including L858. We extend this hypothesis to show that a similar mechanism would enable the molecule to inhibit EGFRL861Q which is another oncogenic mutant and validate this with binding experiments. The screening of the human structural kinome revealed at least 12 other oncogenic kinases which carry at least one activating mutant in this disorder-prone region and hence would be amenable to allosteric inhibition by molecules such as EAI045. Our study characterizes a druggable allosteric pocket which appears to be specific to certain oncogenic mutants of the EGFR and holds therapeutic potential. PMID- 29997877 TI - Dehydrogenative coupling of 4-substituted pyridines mediated by a zirconium(ii) synthon: reaction pathways and dead ends. AB - The mechanism of the reductive homocoupling of pyridine derivatives mediated by the ZrII synthon [(PNP)Zr(eta6-toluene)Cl] (1) has been investigated. Selective transformation into three different types of product complexes has been observed, depending on the N-heterocyclic substrate employed: the bipyridyl complexes 3-R (R = Me, Et, t Bu, Bn, Ph, CHCHPh), which are the homocoupling products, the eta2 ((4-dimethylamino)pyridyl) complex 4 as well as the bis(isoquinolinyl) complex 5. By deuterium labelling experiments the participation of the ligand backbone in the pyridine coupling reaction via potential cyclometallation steps was ruled out. Based on DFT modelling of the possible reaction sequences a reaction mechanism for the coupling sequence could be identified. The latter is initiated by a reductive syn C-C coupling rather than based on an initial C-H activation of the pyridine substrate. PMID- 29997878 TI - Norbornene chaotropic salts as low molecular mass ionic organogelators (LMIOGs). AB - Phenylalanine functionalised norbornene (9:Na) functions as a potent, low molecular-mass (MW = 333 Da) ionic organogelator with a minimum gelating concentration of 0.5 wt% in THF, i-PrOH, 1,4-dioxane and n-BuOH. Fibrous crystals form in the gel and X-ray crystallography identified a cation mediated helical assembly process controlled by the chirality of the phenylalanine. In addition to excellent gelating properties 9:Na readily forms aqueous biphasic and triphasic systems. PMID- 29997879 TI - Rationally designed upconversion nanoprobe for simultaneous highly sensitive ratiometric detection of fluoride ions and fluorosis theranostics. AB - For many years, fluorosis has been known as a worldwide disease which seriously diminishes quality of life through skeletal embrittlement and hepatic damage. Aiming to develop novel drugs for simultaneous fluorosis diagnosis and therapy, in this work we explore the feasibility of a novel pyrogallic acid-titanium(iv) complex-modified upconversion nanoprobe (UCNP-PA-Ti) for F- capture and real-time quantification. Utilizing the strong interaction between Ti4+ and F-, the modified PA-Ti decomposes in F--containing solution, which not only weakens the FRET but results in upconversion luminescence (UCL) recovery. Both in vitro and in vivo experiments demonstrate a highly sensitive F- UCL response and therapeutic efficiency, which was promising for successful UCL image monitoring and the therapeutic process. Long blood circulation time and low toxicity ensured their safe application for fluorosis theranostics. Our work provides a new possibility for F- concentration detection within fluorosis therapeutic periods and encourages the development of novel drugs for fluorosis theranostics. PMID- 29997880 TI - Exceptionally rapid oxime and hydrazone formation promoted by catalytic amine buffers with low toxicity. AB - Hydrazone and oxime bond formation between alpha-nucleophiles (e.g. hydrazines, alkoxy-amines) and carbonyl compounds (aldehydes and ketones) is convenient and is widely applied in multiple fields of research. While the reactants are simple, a substantial drawback is the relatively slow reaction at neutral pH. Here we describe a novel molecular strategy for accelerating these reactions, using bifunctional buffer compounds that not only control pH but also catalyze the reaction. The buffers can be employed at pH 5-9 (5-50 mM) and accelerate reactions by several orders of magnitude, yielding second-order rate constants of >10 M-1 s-1. Effective bifunctional amines include 2-(aminomethyl)imidazoles and N,N-dimethylethylenediamine. Unlike previous diaminobenzene catalysts, the new buffer amines are found to have low toxicity to human cells, and can be used to promote reactions in cellular applications. PMID- 29997881 TI - The morphology and surface charge-dependent cellular uptake efficiency of upconversion nanostructures revealed by single-particle optical microscopy. AB - The cellular uptake efficiency of nanostructures has been demonstrated to be highly dependent on the surface charge, size and shape although the cellular internalization process is still far from being well-understood. In this work, a series of NaYF4:Yb3+, Er3+ upconversion nanoparticles (UCNPs) with different morphologies and surface coatings were prepared to explore the influence of surface charge and morphology on the cellular internalization process with single particle fluorescence microscopy. It is found that the higher the surface charge and larger the surface-to-volume ratio of the nanoparticles, the more efficient the cellular uptake will be. Particularly, the surface charge is demonstrated to be the primary influence factor for small sized nanoparticles on the cellular uptake process. By blocking the endocytosis routes with temperature modulation (from 37 to 4 degrees C) or introduction of chemical inhibitors (dynasore and genistein), multiplexed mechanisms are found to be involved in the cellular uptake process, including clathrin- and caveolae-mediated endocytosis, physical adhesion and penetration, and so on. Moreover, in the aspect of size effect, an energy-dependent endocytosis process plays a more important role for larger size particles. In short, this study presents a pattern of cellular internalization pathway for the nanoparticles with different morphologies and surface charges, which would provide useful information for the development of robust drug delivery systems. PMID- 29997882 TI - Mechanically triggered reversible stepwise tricolor switching and thermochromism of anthracene-o-carborane dyad. AB - A novel single organic molecule-carborane conjugate, CAN, was synthesized in a high yield via a modified nickel-catalyzed cross-coupling reaction incorporating an anthracene unit and an o-carborane moiety. CAN exhibits multiple functions of tricolored mechanochromism and mechanically triggered thermochromism. The fluorescence could be switched from blue to bright yellow then to pink by grinding. The robust and reversible thermochromic process was triggered by the mechanical force. The locally excited (LE) state emission, intermolecular excimer formation and twisted intermolecular charge transfer (TICT) are the primary origins of this tricolor switching property. High temperature sensitivity of the heavily ground CAN powders contribute to the mechanical force induced TICT emission enhancement and color switching. PMID- 29997883 TI - Directed nickel-catalyzed 1,2-dialkylation of alkenyl carbonyl compounds. AB - A nickel-catalyzed conjunctive cross-coupling of non-conjugated alkenes, alkyl halides, and alkylzinc reagents is reported. Regioselectivity is controlled by chelation of a removable bidentate 8-aminoquinoline directing group. Under optimized conditions, a wide range of 1,2-dialkylated products can be accessed in moderate to excellent yields. To the best of our knowledge, this report represents the first example of three-component 1,2-dialkylation of non conjugated alkenes to introduce differentiated alkyl fragments. PMID- 29997884 TI - Copper-catalyzed enantioselective 1,2-borylation of 1,3-dienes. AB - A highly enantioselective Cu-catalyzed borylation of 2-substituted 1,3-dienes is reported. The use of a chiral phosphanamine ligand is essential in achieving high chemo-, regio-, diastereo- and enantioselectivity. It provides access to a variety of homoallylic boronates in consistently high yield and enantiomeric excess with 2-aryl and 2-heteroaryl 1,3-dienes as well as sterically demanding 2 alkyl 1,3-dienes. Preliminary investigations based on a non-linear effect study point to a mechanism involving more than one metal center. PMID- 29997885 TI - Carboxylate-directed C-H allylation with allyl alcohols or ethers. AB - A [Ru(p-cymene)Cl2]2 catalyst activates allyl alcohols and ethers for the regioselective ortho-C-H allylation of aromatic and heteroaromatic carboxylates. The reaction is orthogonal to most C-H functionalisations with allyl alcohols in that allyl arenes rather than carbonyl compounds are obtained. A wide range of substrates are thus smoothly transformed to allylarenes at 50 degrees C in phosphate-buffered 2,2,2-trichloroethanol. The reaction concept combines the use of abundant reagents and directing groups in a sustainable, waste-minimised method for C-C bond formation. PMID- 29997886 TI - Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes. AB - Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles. PMID- 29997887 TI - The impact of cold on the respiratory tract and its consequences to respiratory health. AB - The increasing use, and sometimes the abuse, particularly in industrialized countries of air conditioning at home, in car, hotel and shopping centres has highlighted new emerging public health issues, resulting from exposure of the airways to cool air or, more properly, resulting from sudden temperature changes. This is part of a wider problem, relating to air quality in indoor environment, such as homes or offices, where people spend more than 90% of their time. In particular, if indoor exposure occurs quickly and without any gradual adaptation to a temperature 2 degrees -3 degrees lower than the external temperature and especially with a 5 degrees difference (avoiding indoor temperature below 24 degrees ) and an humidity between 40 and 60%, there is a risk of negative consequences on the respiratory tract and the patient risks to be in a clinical condition characterized by an exacerbation of the respiratory symptoms of his chronic respiratory disease (asthma and COPD) within a few hours or days. Surprisingly, these effects of cold climate remain out of the focus of the media unless spells of unusually cold weather sweep through a local area or unstable weather conditions associated with extremely cold periods of increasing frequency and duration. Moreover, the energy consumed by air conditioning induces an increase of CO2 in atmosphere with increase of global warming. There is a need to better define the consequences of repeated exposure to cold air and the mechanisms by which such exposure could modify airway function and affect the outcomes of patients with pre-existing airway disease. This could help to promote adequate policy and public health actions to face the incoming challenges induced by climate change and global warming. PMID- 29997888 TI - Early nonreactivity in the conjunctival provocation test predicts beneficial outcome of sublingual immunotherapy. AB - Background: Clinical practice needs a common parameter that can provide an early, reliable estimation of the outcome of sublingual immunotherapy (SLIT) in an upcoming pollen season. We investigated whether the conjunctival provocation test (CPT) can predict the beneficial outcome of SLIT in patients with allergic rhinoconjunctivitis after 4 weeks of treatment. Methods: We conducted two separate prospective, randomized, double-blind, placebo-controlled, multicenter trials. Adults 18-75 years of age received placebo or SLIT tablets containing tree or grass pollen allergoids and underwent CPTs. Participants receiving SLIT were divided into two groups (reactive, nonreactive) according to their CPT reactions after 4 weeks of treatment. These two groups were compared with regard to clinical outcome parameters (total combined score, rhinoconjunctivitis total symptom score, total rescue medication score, well days) assessed during the pollen season for the 14-day (tree) or 30-day (tree/grass) peaks and for the entire 60-day seasons. Participants' global evaluations of therapy after completing treatment were also compared. Results: The tree pollen trial randomized 188 participants; 182 participants were evaluable, 76 of whom received SLIT and were suitable for this post hoc analysis. The grass pollen trial included 90 participants; 82 participants were evaluable, 44 of whom underwent SLIT. Comparing SLIT participants who reacted to the CPT after 4 weeks (tree: 77.6%; grass: 79.5%) with those who ceased to show a reaction (tree: 22.4%; grass: 20.5%) (tree: P = 0.0001; grass: P = 0.003), the total combined score for the 14-day (P = 0.017) and 30-day peaks (P = 0.042) as well as the rhinoconjunctivitis total symptom score assessed for the 14-day peak (P = 0.024) were significantly lower in the nonreactive group of the tree pollen trial. In the grass pollen trial, the nonreactive group rated their SLIT treatment significantly better (P = 0.019). Conclusions: Using clinically meaningful outcome parameters during the pollen season, both trials independently led to similar results when comparing participants' reactions to the CPT 4 weeks after beginning SLIT. These results suggest that CPT allows an early estimation of allergic rhinoconjunctivitis symptoms before an upcoming season. Thus, the CPT can be used as a valuable parameter to predict the beneficial outcome of ongoing SLIT. Trial registration: Both trials registered with the Medical Ethics Committee of the North Rhine Medical Council (EudraCT numbers 2012-004916-79 (grass pollen trial) and 2013-002129-43 (tree pollen trial)) and the German Federal Ministry of Health (Paul-Ehrlich-Institut). PMID- 29997890 TI - Genomic analyses reveal two distinct lineages of Corynebacterium ulcerans strains. AB - Corynebacteriumulcerans is an important zoonotic pathogen which is causing diphtheria-like disease in humans globally. In this study, the genomes of three recently isolated C. ulcerans strains, 4940, 2590 and BR-AD 2649, respectively from an asymptomatic carrier, a patient with pharyngitis and a canine host, were sequenced to investigate their virulence potential. A comparative analysis was performed including the published genome sequences of 16 other C. ulcerans isolates. C. ulcerans strains belong to two lineages; 13 strains are grouped together in lineage 1, and six strains comprise lineage 2. Consistent with the zoonotic nature of C. ulcerans infections, isolates from both the human and canine hosts clustered in both the lineages. Most of the strains possessed spaDEF and spaBC gene clusters along with the virulence genes cpp, pld, cwlH, nanH, rpfI, tspA and vsp1. The gene encoding Shiga-like toxin was only present in one strain, and 11 strains carried the tox gene encoding the diphtheria-like toxin. However, none of strains 4940, 2590 and BR-AD 2649 carried any toxin genes. These strains varied in the number of prophages in their genomes, which suggests that they play an important role in introducing diversity in C. ulcerans. The pan genomic analyses revealed a variation in the number of membrane-associated and secreted proteins that may contribute to the variation in pathogenicity among different strains. PMID- 29997891 TI - First isolation of Mycoplasma canis from human tissue samples after a dog bite. AB - Mycoplasma canis is an opportunistic bacterial pathogen that may colonize dogs and cattle. In the present case, we report for the first time the isolation of M. canis from a wound tissue specimen of a 62-year-old woman after a dog bite. PMID- 29997889 TI - Risk factors for hospitalized patients with resistant or multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis. AB - Background: Identifying risk factors predicting acquisition of resistant Pseudomonas aeruginosa will aid surveillance and diagnostic initiatives and can be crucial in early and appropriate antibiotic therapy. We conducted a systematic review examining risk factors of acquisition of resistant P. aeruginosa among hospitalized patients. Methods: MEDLINE(r), EMBASE(r), and Cochrane Central were searched between 2000 and 2016 for studies examining independent risk factors associated with acquisition of resistant P. aeruginosa, among hospitalized patients. Random effects model meta-analysis was conducted when at least three or more studies were sufficiently similar. Results: Of the 54 eligible articles, 28 publications (31studies) examined multi-drug resistant (MDR) or extensively drug resistant (XDR) P. aeruginosa and 26 publications (29 studies) examined resistant P. aeruginosa. The acquisition of MDR P. aeruginosa, as compared with non-MDR P. aeruginosa, was significantly associated with intensive care unit (ICU) admission (3 studies: summary adjusted odds ratio [OR] 2.2) or use of quinolones (4 studies: summary adjusted OR 3.59). Acquisition of MDR or XDR compared with susceptible P. aeruginosa was significantly associated with prior hospital stay (4 studies: summary adjusted OR 1.90), use of quinolones (3 studies: summary adjusted OR 4.34), or use of carbapenems (3 studies: summary adjusted OR 13.68). The acquisition of MDR P. aeruginosa compared with non-P. aeruginosa was significantly associated with prior use of cephalosporins (3 studies: summary adjusted OR 3.96), quinolones (4 studies: summary adjusted OR 2.96), carbapenems (6 studies: summary adjusted OR 2.61), and prior hospital stay (4 studies: summary adjusted OR 1.74). The acquisition of carbapenem-resistant P. aeruginosa compared with susceptible P. aeruginosa, was statistically significantly associated with prior use of piperacillin-tazobactam (3 studies: summary adjusted OR 2.64), vancomycin (3 studies: summary adjusted OR 1.76), and carbapenems (7 studies: summary adjusted OR 4.36). Conclusions: Prior use of antibiotics and prior hospital or ICU stay was the most significant risk factors for acquisition of resistant P. aeruginosa. These findings provide guidance in identifying patients that may be at an elevated risk for a resistant infection and emphasize the importance of antimicrobial stewardship and infection control in hospitals. PMID- 29997892 TI - 'Helcococcus massiliensis' sp. nov., a new bacterial species isolated from the vaginal sample of a woman with bacterial vaginosis living in Dielmo, Senegal. AB - We report here the isolation of a new bacterial species 'Helcococcus massiliensis' strain Marseille P4590 (CSURP4590), isolated from the vaginal sample of a woman with bacterial vaginosis. PMID- 29997893 TI - What are the barriers to, and facilitators of, implementing and receiving MHPSS programmes delivered to populations affected by humanitarian emergencies? A qualitative evidence synthesis. AB - Background: Humanitarian emergencies can impact people's psychosocial well-being and mental health. Providing mental health and psychosocial support (MHPSS) is an essential component of humanitarian aid responses. However, factors influencing the delivery MHPSS programmes have yet to be synthesised. We undertook a systematic review on the barriers to, and facilitators of, implementing and receiving MHPSS programmes delivered to populations affected by humanitarian emergencies in low- and middle-income countries. Methods: A comprehensive search of 12 bibliographic databases, 25 websites and citation checking was undertaken. Studies published in English from 1980 onwards were included if they contained evidence on the perspectives of adults or children who had engaged in or programmes providers involved in delivering, MHPSS programmes in humanitarian settings. Thirteen studies were critically appraised and analysed thematically. Results: Community engagement was a key mechanism to support the successful implementation and uptake of MHPSS programmes. Establishing good relationships with parents may also be important when there is a need to communicate the value of children and young people's participation in programmes. Sufficient numbers of trained providers were essential in ensuring a range of MHPSS programmes were delivered as planned but could be challenging in resource-limited settings. Programmes need to be socially and culturally meaningful to ensure they remain appealing. Recipients also valued engagement with peers in group-based programmes and trusting and supportive relationships with providers. Conclusion: The synthesis identified important factors that could improve MHPSS programme reach and appeal. Taking these factors into consideration could support future MHPSS programmes achieve their intended aims. PMID- 29997894 TI - Internalized HIV stigma, bullying, major depressive disorder, and high-risk suicidality among HIV-positive adolescents in rural Uganda. AB - Background: Studies conducted in sub-Saharan Africa suggest a high prevalence of depression and suicidality among adolescents living with HIV (ALWH). This is an important public health issue because depression is known to compromise HIV treatment adherence. However, the drivers of depression and suicidality in this population are unclear. We conducted a cross-sectional study to estimate the associations between internalized stigma, bullying, major depressive disorder, and suicidality. Methods: We conducted a cross-sectional survey between November 2016 and March 2017, enrolling a consecutive sample of 224 ALWH aged 13-17 years. We collected information on demographic characteristics, internalized HIV-related stigma (using the six-item Internalized AIDS-Related Stigma Scale), bullying victimization (using the nine-item Social and Health Assessment Peer Victimization Scale), major depressive disorder [using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID)], and suicidality (also using the MINI-KID). We fitted multivariable logistic regression models to estimate the associations between stigma, bullying, major depressive disorder, and suicidality. Results: Thirty-seven participants (16%) had major depressive disorder, 30 (13%) had suicidality, and nine (4%) had high risk suicidality. Ninety-one participants (41%) had high levels of internalized stigma, while 97 (43%) reported two or more bullying events in the past year. In multivariable logistic regression models, major depressive disorder had a statistically significant association with bullying (AOR = 1.09; 95% CI 1.00 1.20; p = 0.04); while suicidality (low, moderate, high risk) had statistically significant associations with both bullying (AOR = 1.09; 95% CI 1.01-1.17; p = 0.02) and stigma (AOR = 1.30; 95% CI 1.03-1.30; p = 0.02). Conclusions: Among ALWH in rural Uganda, stigma and bullying are strongly associated with major depressive disorder and suicidality. There is a need to incorporate psychological interventions in the mainstream HIV care to address these challenges for optimal management of HIV among ALWH. PMID- 29997895 TI - Risk of perpetrating intimate partner violence amongst men exposed to torture in conflict-affected Timor-Leste. AB - Background: A key issue in need of empirical exploration in the post-conflict and refugee mental health field is whether exposure to torture plays a role in generating risk of intimate partner violence (IPV), and whether this pathway is mediated by the mental health effects of torture-related trauma. In examining this question, it is important to assess the impact of socio-economic hardship which may be greater amongst survivors of torture in low-income countries. Methods: The study data were obtained from a cohort of 870 women (recruited from antenatal clinics) and their male partners in Dili district, Timor-Leste. We conducted bivariate and path analysis to test for associations of men's age, socioeconomic status, torture exposure, and mental disturbance, with IPV (the latter reported by women). Results: The path analysis indicated positive paths from a younger age, torture exposure, and lower socio-economic status amongst men leading to mental disturbance. Mental disturbance, in turn, led to IPV. In addition, younger age, lower socio-economic status, torture exposure, and mental disturbance were directly associated with IPV. Conclusions: Our data provide the first systematic evidence of an association between torture and IPV in a low income, post-conflict country, confirming that low socio-economic status, partly related to being a torture survivor, adds to the risk. The high prevalence of IPV in this context suggests that other structural factors, such as persisting patriarchal attitudes, contribute to the risk of IPV. Early detection and prevention programs may assist in reducing the risk of IPV in families in which men have experienced torture. PMID- 29997896 TI - Revert to the original: time to re-establish delayed umbilical cord clamping as the standard approach for preterm neonates. AB - Delayed cord clamping, the common term used to denote placental-to-newborn transfusion at birth, is a practice now endorsed by the major governing bodies affiliated with maternal-newborn care. Despite considerable evidence, delayed cord clamping, not early cord clamping, continues to be viewed as the "experimental" intervention category when discussed in research studies. We provide a brief overview of placental-to-newborn transfusion in relation to birth transitional physiology and discuss areas where we may need to modify our interpretation of "normal" vital signs and laboratory values as delayed cord clamping becomes standardized. We also assert that delayed cord clamping should now be viewed as the standard of care approach, especially given that multiple randomized controlled trials have revealed that early cord clamping, which lacks evidence-based support, is associated with a greater risk for morbidity and mortality than delayed cord clamping. PMID- 29997897 TI - Delayed cord clamping during elective cesarean deliveries: results of a pilot safety trial. AB - Background: Delayed cord clamping (DCC) results in decreased iron deficiency in infancy. The American College of Obstetrics and Gynecology has called for research on the optimal time to clamp the cord during cesarean deliveries (CD). Our objective was to conduct a pilot trial examining the safety of delayed cord clamping (DCC) for maternal-infant dyads during elective cesarean delivery (CD). Methods: We enrolled 39 dyads [23 at 90 s, 16 at 120 s; (DCC Pilot)] between 10/2013 and 9/2014. We abstracted data from the electronic medical record (EMR) for historical controls (HC) birthing between 1/2012-6/2013 for whom DCC was not performed (n = 112). Results: Available data for 37 mothers and 30 infants compared to HC revealed 174 (95% CI: 61-286) mL lower mean estimated maternal blood loss [(EBL) mean (SD) mL]: DCC Pilot 691(218) vs. HC 864(442), p = 0.003 and lower incidence of maternal transfusions, DCC Pilot 2.7% vs. HC 18.8%, p = 0.016. There was no significant between group difference between DCC Pilot and HC in other a priori definitions of excess maternal blood loss: a) EBL > 800 ml, 21.6% vs. 38.8%, p = 0.07 or b) post-op hgb/pre-op hgb < 80%, 16.7% vs. 20.6%, p = 0.81. There were also no statistically significant between group differences in rates of NICU admission DCC Pilot 8.1% vs. HC 7.1%, p = 1.0., but there was a higher rate of newborn cold stress or hypothermia <=36.2 degrees C in study subjects, DCC Pilot 27.0% vs. HC 11.9%, p = 0.038.Prevalence of newborn anemia was decreased [DCC pilot 3.3% (1 of 30) vs. HC 40.0% (4 of 10 infants with data), p = 0.012. No infants were polycythemic. Conclusions: These pilot data suggest cord clamping can be delayed to 120 s during elective CD without increased risk of excessive maternal blood loss. More aggressive prevention of infant heat loss may be warranted. A randomized trial to evaluate long-term maternal and infant outcomes is indicated. Trial registration: Clinical trials.gov, NCT02229162; registered: 1 September, 2014. PMID- 29997899 TI - Requirements for the collection of electronic PROMS either "in clinic" or "at home" as part of the PROMs, PREMs and Effectiveness Programme (PPEP) in Wales: a feasibility study using a generic PROM tool. AB - Background: The patient-reported outcome measures (PROMs), patient-reported experience measure (PREMs) and Effectiveness Programme (PPEP) launched with the aim of supporting all National Health Service Wales (NHS Wales) organisations to collect PROMs and PREMs across a range of conditions. The aim is to collect generic and condition-specific PROMs and PREMs electronically from every secondary care patient in Wales to provide a measure that can be used to determine the clinical and cost-effectiveness of treatments and services. This study reports on the experience of the PPEP in developing an electronic platform suitable for large-scale data collection, storage, analysis and reporting and identifies the problems encountered and solutions implemented using a generic PROM survey as an example. Methods: The generic PROM survey is available in English and Welsh and consists of a consent section and three components: the EQ 5D-5L tool, the Work Productivity and Activity Impairment (WPAI) tool and a number of "about you" questions. The "about you" questions are designed to assess factors which may affect patient health and outcomes such as information on height, weight, smoking history, exercise levels and alcohol consumption. A dedicated PROM database was built, and links between the e-PROM platform and other key clinical databases within NHS Wales were developed. Results: Pilot testing of the unvalidated sections of the generic electronic PROM found that most of the questions were well understood and easy to answer: however, feedback suggested some improvements and changes were required, specifically around questions relating to alcohol and exercise.Electronic PROM collection has been initiated in six of the seven health boards in Wales and at-home collection initiated in three health boards. More than 9300 patients have completed a PROM survey. Early results from one Health Board show that patients took approximately 10 min to complete the questionnaire with most patients answering an average of 94.7% of the questions. Conclusions: Successful implementation of a PROM collection programme is dependent on a number of factors including close collaboration with clinicians, analysts, IT specialists and patients to ensure that any electronic system of PROM collection is fit for purpose and user friendly both for patients and clinicians. PMID- 29997898 TI - A feasibility study to develop and test a Spanish patient and provider intervention for managing osteoarthritis in Hispanic/Latino adults (PRIMO Latino). AB - Background: Arthritis affects approximately 50 million adults in the USA. Hispanics/Latinos have a higher prevalence of arthritis-attributed activity limitations primarily related to osteoarthritis (OA). Hispanic/Latinos are less likely to receive hip replacement independent of health care access, and they are less likely to receive knee replacement. There have been few interventions to improve OA treatment among the Hispanic/Latino population in the USA. In our study, we aimed to develop and test a telephone delivered culturally appropriate Spanish behavioral intervention for the management of OA in Hispanic/Latino adults. Methods: We conducted a feasibility study in an academic health center and local community in Durham, North Carolina. We enrolled self-identified Spanish speaking overweight/obese adults (>= 18) with OA of the knee and/or hip under the care of a primary health care provider. The 12-month patient intervention focused on physical activity, weight management, and cognitive behavioral pain management skills. The patient intervention was delivered via telephone with calls scheduled twice per month for the first 6 months, then monthly for the last 6 months (18 sessions). The one-time provider intervention included delivery of patient-specific OA treatment recommendations, based on patients' baseline data and published guidelines. The primary measures were metrics of feasibility, including recruitment and intervention delivery. We also assessed pain, stiffness, and function using the Spanish-Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results: A total of 1879 participants were identified for potential enrollment. Of those, 1864 did not meet inclusion criteria, were not able to be reached or refused. Fifteen participants enrolled in the intervention. The mean number of phone calls completed was 14.7. Eighty percent completed more than 16 calls. The mean WOMAC baseline score (SD) was 39 (20); mean improvement in WOMAC scores between baseline and 12 months, among 11 participants who completed the study, was - 13.27 [95% CI, - 25.09 to - 1.46] points. Conclusion: Recruitment of Hispanics/Latinos, continues to be a major challenge. A Spanish-based telephone delivering lifestyle intervention for OA management in Hispanic/Latino adults is feasible to deliver and may lead to improved OA symptoms. Future research is needed to further test the feasibility and effectiveness of this type of intervention in this segment of the population. Trial registration: NCT01782417. PMID- 29997900 TI - Patient, physician, and caregiver perspectives on ovarian cancer treatment decision making: lessons from a qualitative pilot study. AB - Background: Ovarian cancer is the deadliest gynecologic malignancy and the fifth leading cause of cancer death among women living in the USA. Treatment for ovarian cancer that follows the guidelines published by the National Comprehensive Cancer Network is associated with a 33% decrease in disease specific mortality, yet fewer than 40% of women with ovarian cancer receive guideline-adherent treatment. Little is known about the process by which women with ovarian cancer, their unpaid caregivers, and physicians make decisions about ovarian cancer treatment. We are planning to conduct a population-based study examining the ovarian cancer treatment decision-making process from the perspective of women with ovarian cancer, their caregivers, and physicians using a qualitative approach. Prior to embarking on a large-scale study, we determined it would be beneficial to pilot test our unpaid caregiver recruitment protocol and identify preliminary topics for the main study's interview guide. Methods: We conducted a cross-sectional descriptive study using a qualitative approach. Data were collected via unstructured, individual interviews. Data were analyzed using modified grounded theory methods. Results: We interviewed six women with ovarian cancer, four unpaid caregivers, and three physicians. The recruitment protocol successfully recruited patient participants but did not allow for direct recruitment of unpaid caregivers, which presented logistical difficulties. The interview guide was adequate to elicit participants' discussion of the major topics of interest; however, the opening statement needed modification to account for physician participants' specialties. Patient and caregiver participants identified three major categories of concepts describing the process of ovarian cancer treatment decision making: (a) choosing a provider, (b) choosing a facility, and (c) choosing a treatment. All three groups of participants addressed the influence of geographic location on treatment decisions, while physicians described encounters with patients declining recommended treatment. Conclusions: This pilot study met our objectives of testing unpaid caregiver recruitment procedures and identifying topics to include in the interview guide for a planned grounded theory study. Although the thematic results of this study are preliminary, the categories of concepts described by participants provide a framework for the exploration of patient, unpaid caregiver, and physician perspectives of ovarian cancer treatment decision making. PMID- 29997901 TI - Platelet-rich plasma (PRP) therapy for knee arthritis: a feasibility study in primary care. AB - Background: Platelet-rich plasma (PRP) is a concentrate of autologous blood growth factors which has been shown to provide some symptomatic relief in early osteoarthritis (OA) of the knee. The objective of this study was to test the feasibility and efficacy potential of platelet rich plasma (PRP) in primary care. Methods: Feasibility study to assess safety of the intervention procedures and assess primary and secondary outcome measures. Consecutive patients presenting with symptomatic knee OA were recruited in a primary care setting in Ireland. All participants received three injections of PRP 4 weeks apart. The following self reported clinical outcomes were evaluated before and after therapy (4 months): Pain and disability (ICOAP questionnaire); health utility (EUROQol); adverse events; patient satisfaction and goal-orientated outcomes. Results: Seventeen potential patients were identified of whom 14 were eligible to participate. Twelve consented and completed the intervention and all outcome measures. There were no losses to follow-up. One patient reported pain and stiffness for 2 days after the first injection but did complete the study. No growth was detected from nine consecutive samples sent for microbiology analysis. Changes in constant, intermittent and total pain scores were reported; pain fully resolved in two patients. In addition, health utility, patient satisfaction and goal-orientated outcomes also demonstrated improvement. Conclusions: Platelet-rich plasma therapy is a simple and minimally invasive intervention which is feasible to deliver in primary care to treat osteoarthritis of the knee joint. Well-designed randomised controlled trials are needed to measure outcomes, durability of effect and cost effectiveness. PMID- 29997902 TI - Improving shared decision-making in advanced Parkinson's disease: protocol of a mixed methods feasibility study. AB - Background: In advanced stages of Parkinson's disease (PD), patients and neurologists regularly face complex treatment decisions. Shared decision-making (SDM) can support the process where evidence, the clinician's expertise and the patient's preferences jointly contribute to reach an optimal decision. Here, we describe the rationale of our feasibility study protocol.The aim of the study is to test the feasibility of the SDM intervention by (1) analysing the acceptability of the intervention by users (i.e. professionals and patients), (2) assessing the level of implementation, (3) testing efficacy on a small scale and (4) evaluating the study procedures. Methods: Using an uncontrolled before-after mixed methods design, patients in the pre-intervention group will receive information and decisional support as usual. Patients in the post-intervention group will receive the SDM intervention, consisting of an Option GridTM patient decision aid and a website with supplementary information plus a value clarification tool for both patients and professionals. An Option Grid is a one page, evidence-based summary of available options, listing the frequently asked questions that patients consider when making treatment decisions. A value clarification tool helps patients identify which option he/she prefers based on attributes in the treatment decision context. Neurologists and PD nurse specialists will receive a 1-h instruction on SDM and how to use the SDM intervention.Through purposive sampling, neurologists and PD nurse specialists will be recruited from both specialised neurology clinics and community-based hospitals. Included professionals will invite consecutive patients who are eligible for the advanced therapies.Data will be collected using questionnaires, interviews and audio observations of the consultations and by tracking users' logging behaviour of the website. Data will be analysed using a mixed methods design. Discussion: The mixed methods design will create a deeper understanding of how the SDM intervention affects the interactions between professionals (a neurologist and/or a PD nurse specialist) and the patient, when an advanced treatment is chosen. The results of the study will inform the design of an RCT to test the effectiveness of the SDM intervention. Trial registration: NTR6649, retrospectively registered 28 August 2017. PMID- 29997903 TI - An alternative approach to implementing patient-reported outcome measures. AB - Background: Obtaining patients' views of their health and outcomes of interventions utilising patient-reported outcome measures (PROMs) is a well established method, but there is still uncertainty about the impact of PROMs on services and patient care. Studies are now needed of alternative ways of implementing PROMs. This paper describes a case study of the introduction of a new PROM to assess musculoskeletal (MSK) problems, known as the Musculoskeletal Health Questionnaire (MSK-HQ). Methods: Following an invitation from the Arthritis Research UK (ARUK), 11 groups and organisations agreed to become 'partners' in piloting the MSK-HQ. Twenty-nine interviews and a focus group were carried out with key informants from the partners. Interviews were supplemented with some documentary evidence of partners' meetings. Data were coded and analysed with NVivo software V.10. Analysis was carried out via a framework method. Results: Participants reported positive evidence that the MSK-HQ is feasible and practical for use in patient care with content that helped health professionals identify and address patients' main presenting problems. Although mediated and reported through health professionals' judgments, the questionnaire was also seen as very relevant and acceptable to a wide spectrum of patients.There was also broad support for the view that whilst the MSK-HQ is relevant to individual patient care, it could also, when aggregated, reflect the experiences of patients as a group and be used as evidence for third parties concerned with the provision and commissioning of services.The main difficulties revealed by the case study were in the form of logistics and sustainability. It was recognised that electronic systems would be more effective for administration and data processing but they were not feasible to develop and implement within reasonable timelines and available budgets. A sustainable approach to using the PROM required significant long-term commitment of budget, a coherent system, and active support from diverse organisations. Conclusions: The current study supports the view that a bottom-up approach is a promising method to generate PROM-related insights that are relevant to patients and health professionals. The partnership approach to developing and using PROMs may have wider relevance and potential as a model of implementation. PMID- 29997905 TI - Animal roles and traces in the history of medicine, c.1880-1980. AB - This paper argues for the need to create a more animal-centred history of medicine, in which animals are considered not simply as the backdrop for human history, but as medical subjects important in and of themselves. Drawing on the tools and approaches of animal and human-animal studies, it seeks to demonstrate, via four short historical vignettes, how investigations into the ways that animals shaped and were shaped by medicine enables us to reach new historical understandings of both animals and medicine, and of the relationships between them. This is achieved by turning away from the much-studied fields of experimental medicine and public health, to address four historically neglected contexts in which diseased animals played important roles: zoology/pathology, parasitology/epidemiology, ethology/psychiatry, and wildlife/veterinary medicine. Focusing, in turn, on species that rarely feature in the history of medicine - big cats, tapeworms, marsupials and mustelids - which were studied, respectively, within the zoo, the psychiatric hospital, human-animal communities and the countryside, we reconstruct the histories of these animals using the traces that they left on the medical-historical record. PMID- 29997904 TI - A brief early intervention for adolescent depression that targets emotional mental images and memories: protocol for a feasibility randomised controlled trial (IMAGINE trial). AB - Background: Adolescent depression is common and impairing. There is an urgent need to develop early interventions to prevent depression becoming entrenched. However, current psychological interventions are difficult to access and show limited evidence of effectiveness. Schools offer a promising setting to enhance access to interventions, including reducing common barriers such as time away from education. Distressing negative mental images and a deficit in positive future images, alongside overgeneral autobiographical memories, have been implicated in depression across the lifespan, and interventions targeting them in adults have shown promise. Here, we combine techniques targeting these cognitive processes into a novel, brief psychological intervention for adolescent depression. This feasibility randomised controlled trial will test the feasibility and acceptability of delivering this imagery-based cognitive behavioural intervention in schools. Methods/design: Fifty-six adolescents (aged 16-18) with high symptoms of depression will be recruited from schools. Participants will be randomly allocated to the imagery-based cognitive behavioural intervention (ICBI) or the control intervention, non-directive supportive therapy (NDST). Data on feasibility and acceptability will be recorded throughout, including data on recruitment, retention and adherence rates as well as adverse events. In addition, symptom assessment will take place pre intervention, post-intervention and at 3-month follow-up. Primarily, the trial aims to establish whether it is feasible and acceptable to carry out this project in a school setting. Secondary objectives include collecting data on clinical measures, including depression and anxiety, and measures of the mechanisms proposed to be targeted by the intervention. The acceptability of using technology in assessment and treatment will also be evaluated. Discussion: Feasibility, acceptability and symptom data for this brief intervention will inform whether an efficacy randomised controlled trial is warranted and aid planning of this trial. If this intervention is shown in a subsequent definitive trial to be safe, clinically effective and cost-effective, it has potential to be rolled out as an intervention and so would significantly extend the range of therapies available for adolescent depression. This psychological intervention draws on cognitive mechanism research suggesting a powerful relationship between emotion and memory and uses imagery as a cognitive target in an attempt to improve interventions for adolescent depression. Trial registration: ISRCTN85369879. PMID- 29997906 TI - The Brazilian health system at crossroads: progress, crisis and resilience. AB - The Unified Health System (Sistema Unico de Saude (SUS)) has enabled substantial progress towards Universal Health Coverage (UHC) in Brazil. However, structural weakness, economic and political crises and austerity policies that have capped public expenditure growth are threatening its sustainability and outcomes. This paper analyses the Brazilian health system progress since 2000 and the current and potential effects of the coalescing economic and political crises and the subsequent austerity policies. We use literature review, policy analysis and secondary data from governmental sources in 2000-2017 to examine changes in political and economic context, health financing, health resources and healthcare service coverage in SUS. We find that, despite a favourable context, which enabled expansion of UHC from 2003 to 2014, structural problems persist in SUS, including gaps in organisation and governance, low public funding and suboptimal resource allocation. Consequently, large regional disparities exist in access to healthcare services and health outcomes, with poorer regions and lower socioeconomic population groups disadvantaged the most. These structural problems and disparities will likely worsen with the austerity measures introduced by the current government, and risk reversing the achievements of SUS in improving population health outcomes. The speed at which adverse effects of the current and political crises are manifested in the Brazilian health system underscores the importance of enhancing health system resilience to counteract external shocks (such as economic and political crises) and internal shocks (such as sector specific austerity policies and rapid ageing leading to rise in disease burden) to protect hard-achieved progress towards UHC. PMID- 29997908 TI - Impact of MRSA on the Military Medical Service and Diagnostic Point-of-Care Options for the Field Setting. AB - Methicillin-resistant Staphylococcus aureus (MRSA) poses an infection risk for international military deployments. In the presented mini-review, the history of MRSA in the medical service and modern warfare is highlighted. To allow rapid diagnosis, various molecular diagnostic point-of-care solutions are available. Most evaluation studies, however, are focused on screening swabs rather than clinical materials and evaluation data from harsh environments are widely lacking. Accordingly, studies with complex sample materials under difficult environmental conditions, e.g., in the desert or in the tropics, are desirable to close this gap of knowledge regarding the diagnostic reliability of such modern molecular point-of-care devices. PMID- 29997907 TI - Performance of verbal autopsy methods in estimating HIV-associated mortality among adults in South Africa. AB - Introduction: Verbal autopsy (VA) can be integrated into civil registration and vital statistics systems, but its accuracy in determining HIV-associated causes of death (CoD) is uncertain. We assessed the sensitivity and specificity of VA questions in determining HIV status and antiretroviral therapy (ART) initiation and compared HIV-associated mortality fractions assigned by different VA interpretation methods. Methods: Using the WHO 2012 instrument with added ART questions, VA was conducted for deaths among adults with known HIV status (356 HIV positive and 103 HIV negative) in South Africa. CoD were assigned using physician-certified VA (PCVA) and computer-coded VA (CCVA) methods and compared with documented HIV status. Results: The sensitivity of VA questions in detecting HIV status and ART initiation was 84.3% (95% CI 80 to 88) and 91.0% (95% CI 86 to 95); 283/356 (79.5%) HIV-positive individuals were assigned HIV-associated CoD by PCVA, 166 (46.6%) by InterVA-4.03, 201 (56.5%) by InterVA-5, and 80 (22.5%) and 289 (81.2%) by SmartVA-Analyze V.1.1.1 and V.1.2.1. Agreement between PCVA and older CCVA methods was poor (chance-corrected concordance [CCC] <0; cause specific mortality fraction [CSMF] accuracy <=56%) but better between PCVA and updated methods (CCC 0.21-0.75; CSMF accuracy 65%-98%). All methods were specific (specificity 87% to 96%) in assigning HIV-associated CoD. Conclusion: All CCVA interpretation methods underestimated the HIV-associated mortality fraction compared with PCVA; InterVA-5 and SmartVA-Analyze V.1.2.1 performed better than earlier versions. Changes to VA methods and classification systems are needed to track progress towards targets for reducing HIV-associated mortality. PMID- 29997909 TI - Anti-inflammatory Effects of the Octapeptide NAP in Human Microbiota-Associated Mice Suffering from Subacute Ileitis. AB - The octapeptide NAP is well known for its neuroprotective properties. We here investigated whether NAP treatment could alleviate pro-inflammatory immune responses during experimental subacute ileitis. To address this, mice with a human gut microbiota were perorally infected with one cyst of Toxoplasma gondii (day 0) and subjected to intraperitoneal synthetic NAP treatment from day 1 until day 8 postinfection (p.i.). Whereas placebo (PLC) control animals displayed subacute ileitis at day 9 p.i., NAP-treated mice exhibited less pronounced pro inflammatory immune responses as indicated by lower numbers of intestinal mucosal T and B lymphocytes and lower interferon (IFN)-gamma concentrations in mesenteric lymph nodes. The NAP-induced anti-inflammatory effects were not restricted to the intestinal tract but could also be observed in extra-intestinal including systemic compartments, given that pro-inflammatory cytokines were lower in liver, kidney, and lung following NAP as compared to PLC application, whereas at day 9 p.i., colonic and serum interleukin (IL)-10 concentrations were higher in the former as compared to the latter. Remarkably, probiotic commensal bifidobacterial loads were higher in the ileal lumen of NAP as compared to PLC-treated mice with ileitis. Our findings thus further support that NAP might be regarded as future treatment option directed against intestinal inflammation. PMID- 29997910 TI - Effects of Live and Heat-Inactivated E. coli Strains and Their Supernatants on Immune Regulation in HT-29 Cells. AB - Probiotics are considered to have a beneficial impact on humans, but in some cases, administration of live microorganisms might be risky. In the present study, immunomodulatory effects of different Escherichia coli strains and their super-natants were examined under different inflammatory conditions with living and heat-inactivated strains. HT-29 cells were incubated with E. coli strains (S2 G1, S2-G3, S2-G4 and S2-G8) and their supernatants with or without stimulation with tumor necrosis factor alpha (TNF-alpha) or interleukin (IL)-1beta. Quantification of IL-8 secretion and gene expression was performed by enzyme linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). IL-8 secretion by TNF-alpha- and IL-1beta-stimulated cells was attenuated by all four live strains. In contrast, heat inactivation resulted in an elevated IL-8 expression and secretion in unstimulated cells and did not maintain the anti inflammatory effect of live bacteria in cytokine-stimulated cells. The supernatant of the live S2-G3 led to an elevated IL-8 secretion in unstimulated and IL-1beta-stimulated cells but not in TNF-alpha-stimulated cells. Live bacteria of all strains might induce an immunosuppressive effect after stimulation of HT-29 cells, whereas heat inactivation and the supernatant seem to induce an elevated immune response. These findings might have an impact depending on the indication and purpose of administration. PMID- 29997911 TI - Diagnostics as Prevention - A Rapid Testing-Based Strategy of Sex Workers against Sexual HIV Exposure. AB - Introduction: German sex workers have illegally established a prevention strategy, which consists of testing potential sexual partners with human immunodeficiency virus (HIV)-specific rapid diagnostic tests (RDTs) prior to engaging in unprotected sexual intercourse eventually performed in case of a negative test result. Based on a recently established modeling approach, the effectiveness of this strategy regarding the risk of HIV exposure was compared with protection provided by condom use. Methods: Based on a literature search, the following assumptions were used for the calculations: an averaged 80% exposure risk reduction with a condom used during sexual intercourse, usage of a well-characterized 4th-generation HIV RDT, and a 10 day post-infection period without any measurable viral load in peripheral blood followed by a sero conversion period of about 3 weeks with 12.3% test sensitivity (antigen-specific) and only afterwards 97.3% (antibody-specific) test sensitivity. Results: In most constellations, the HIV exposure risk in case of RDT-based prevention was lower than with condom use. Conclusions: The RDT-based HIV exposure prevention as established by sex workers is effective in most situations. A notable weakness of the strategy is the RDTs' poor sensitivity in spite of a high transmission risk during the seroconversion stage. PMID- 29997912 TI - Peroral Low-Dose Toxoplasma gondii Infection of Human Microbiota-Associated Mice A Subacute Ileitis Model to Unravel Pathogen-Host Interactions. AB - Within 1 week following high-dose Toxoplasma gondii infection, mice develop lethal necrotizing ileitis. However, data from a subacute T. gondii-induced ileitis model are scarce. Therefore, mice harboring a human gut microbiota were perorally infected with one cyst of T. gondii. Within 9 days post-infection, the intestinal microbiota composition shifted towards higher loads of commensal enterobacteria and enterococci. Following T. gondii infection, mice were clinically only mildly affected, whereas ~60% of mice displayed fecal blood and mild-to-moderate ileal histopathological changes. Intestinal inflammation was further characterized by increased apoptotic intestinal epithelial cells, which were accompanied by elevated proliferating gut epithelial cell numbers. As compared to naive controls, infected mice displayed elevated numbers of intestinal T lymphocytes and regulatory T-cells and increased pro-inflammatory mediator secretion. Remarkably, T. gondii-induced apoptotic and pro-inflammatory immune responses were not restricted to the gut, but could also be observed in extra-intestinal compartments including kidney, liver, and lung. Strikingly, low dose T. gondii infection resulted in increased serum levels of pro- and anti inflammatory cytokines. In conclusion, the here presented subacute ileitis model following peroral low-dose T. gondii infection of humanized mice allows for detailed investigations of the molecular mechanism underlying the "menage a trois" of pathogens, human gut microbiota, and immunity. PMID- 29997913 TI - A commemoration of my mentor, Professor Thomas Patrick Joseph Hennessy. PMID- 29997914 TI - Esophageal cancer in patients under 50: a SEER analysis. AB - Background: Concomitant with rising rates of esophageal adenocarcinoma, there has been a significant increase of diagnoses among relatively younger individuals. However, most studies that focus on esophageal cancer (EC) in younger patients have had small sample sizes of patients treated at a single institute. The aim of this study was to analyze the clinical characteristics, outcomes and independent prognostic factors for EC in patients under 50-year-old using a large, multi center dataset. Methods: The national Surveillance, Epidemiology, and End Results (SEER) database was analyzed for EC reported from 2004 to 2013. Patients were divided into two groups, those under 50-year-old and those 50 years or older, and comparisons were made regarding demographics, histology, stage distribution, treatment, overall survival (OS), and esophageal cancer-specific survival (ECSS). Multivariate Cox proportional hazard regression analyses were also used to identify independent prognostic factors. Results: Among the 16,544 eligible patients, 1,385 (8.37%) were under 50 and 15,159 (91.63%) were over 50. Compared with the older group, patients under 50 were characterized by a higher frequency of males, lower esophagus involvement, adenocarcinoma histology, stage III/IV disease, and receiving esophagectomy or radiation therapy. The stage-wise OS and ECSS were significantly better in the younger group (P<0.001). The multivariate analysis indicated that African-American heritage, grade III or IV, later stage, and not undergoing surgical or radiation therapy were independent negative prognostic factors of ECSS for patients under 50. Conclusions: EC patients under 50-year-old had distinctive clinicopathological characteristics compared with patients over 50-year-old. Despite more often presenting with stage III and IV disease, survival rates were better in the younger cohort. Prognostic factors for ECSS in patients under 50 differed from those in all age patients. PMID- 29997915 TI - Correlation of triglycerides with myocardial infarction and analysis of risk factors for myocardial infarction in patients with elevated triglyceride. AB - Background: This study aims to investigate the associations of different (low/medium/high) levels of fasting triglyceride (TG) levels with cardiovascular endpoints. Methods: This cohort study comprised of in-service and retired employees of the Kailuan Coal Mine Group, who participated in the health examination conducted in 11 hospitals in the Kailuan region from June 2006 to October 2007 (n=100,271). The study population was divided into five groups according to different TG levels. Logistic regression analysis was used to analyze the risk factors for myocardial infarction (MI) in patients with elevated TG, and Cox proportional hazards regression analysis was used to analyze the effects of different TG levels on endpoint events. Results: After a median follow up of 7 years, 961 patients developed MI and 3,142 subjects died. The multivariate logistic regression analysis revealed that elevated TG, an age of >=65 years old, body mass index (BMI) >25 kg/m2, fasting blood glucose (FBG) >=6.1 mmol/L and high density lipoprotein cholesterol (HDL-C) <1.5 mmol/L were all risk factors for MI (P<0.05). Furthermore, Cox proportional hazards regression model revealed that after controlling for gender, age and other factors, with the increase in TG level, the relative risk of MI also increased. Compared to the TG1 group, the risk of MI increased to 1.32 folds in the TG4 group (95% CI: 1.05-1.66, P=0.018) and 1.61 folds in the TG5 group (95% CI: 1.21 1.93, P=0.004). Furthermore, the risk of MI combined with all-cause death and all cause death also increased, but the differences were not all statistically significant. Conclusions: In the study population of the Kailuan region, elevated fasting TG increases the risk of MI, particularly in populations with an age of >=65 years old, BMI >25 kg/m2, FBG >=6.1 mmol/L and HDL-C <1.5 mmol/L. PMID- 29997916 TI - Calpain and spectrin breakdown products as potential biomarkers in tuberculous pleural effusion. AB - Background: Early diagnosis of tuberculous pleural effusion (TPE) remains difficult. Calpain is a family of calcium-dependent endopeptidase that plays an important role in extracellular matrix (ECM) remodeling and collagen synthesis. The aim of this study was to explore the diagnostic value of pleural fluid angiotensin-converting enzyme (ACE), calpain-1, spectrin breakdown products (SBDP), and matrix metalloproteinase-1 (MMP-1) in TPE and malignant pleural effusion (MPE). Methods: The study included 47 patients with TPE, 28 patients with MPE, and 10 patients with transudate of non-tuberculous and non-malignant origin as controls. Calpain-1, ACE, SBDP, and MMP-1 levels in pleural fluid were measured by the ELISA method. Results: ACE, calpain-1, SBDP, and MMP-1 levels were higher in TPE than MPE and transudate (all, P<0.05). On multivariate logistic regression analysis, adenosine deaminase (ADA) >=40 IU/mL, calpain-1 >=787 ng/mL, and SBDP >=2.745 ng/mL were independent factors associated with TPE. The predicted probability of TPE based on these three predictors had an area under the receiver operating characteristic (ROC) curve of 0.985, with 97.9% sensitivity and 86.6% specificity under a cut-off value of 0.326. In patients with TPE, residual pulmonary thickening (RPT) was associated with significantly higher calpain-1, SBDP, and MMP-1 levels (all, P<0.05) versus cases without RPT. Conclusions: Our results suggest that the overproduction of calpain-1 and SBDP is associated with pleural fibrosis in tuberculous pleurisy. While ADA is a conventional marker for diagnostic TPE, the simultaneous measurement of calpain-1 and SBDP l in pleural fluid may improve the diagnostic efficacy. PMID- 29997917 TI - Laryngeal mask for airway management in open tracheal surgery-a retrospective analysis of 54 cases. AB - Background: Airway management in tracheal resections presents many challenges. The aim of this retrospective analysis is to report the efficacy and complications associated with the use of the laryngeal mask airway in this procedure. Methods: The charts of 54 consecutive patients operated for tracheal stenosis during the period 2009-2016 were reviewed. This cohort included only resections of the trachea. We evaluated total success rate of laryngeal mask insertion (%), insertion success rate on the first attempt, the quality of intraoperative ventilation through the laryngeal mask, the quality of fibre optic view through the device, incidence of bleeding during the first 24 h, signs of dehiscence of the anastomosis within 48 h and 30-day mortality. Results: The laryngeal mask airway provided a patent airway throughout the procedure in 52 (96.4%) patients. Insertion of the device failed in 1 (1.8%) patient due to abnormal upper airway anatomy. Another patient (1.8%) developed laryngeal mask malposition during intraoperative neck extension subsequently requiring tracheal intubation. Fibre optic view through the devices including insertion of the flexible bronchoscope was satisfactory in 52 (96.4%) patients. Serious complications, such as pulmonary aspiration, early postoperative bleeding or suture dehiscence were not observed in this cohort. Conclusions: Based on this analysis of 54 patients, we would consider the laryngeal mask airway a feasible alternative to the tracheal tube for airway management and ventilation during open tracheal surgery. PMID- 29997918 TI - Long non-coding RNA DANCR promotes cell proliferation, migration, invasion and resistance to apoptosis in esophageal cancer. AB - Background: Long non-coding RNAs (lncRNAs) have important effects on the development and progression of multiple carcinomas. Our studies aimed to investigate the expression of lncRNA DANCR in esophageal squamous cell carcinoma (ESCC) tissues and paracancerous tissues, and to explore its effect on the cell biological characteristics of ESCC ECA109 cells. Methods: The expression of DANCR was detected by qRT-PCR in human ESCC tissues and paracancerous normal tissues in ESCC patients. Small interfering RNA (siRNA) was transfected to knock down the expression of DANCR and interference efficiency was analyzed by qRT-PCR in ECA109 cells. MTT, wound healing, Transwell, TUNEL and flow cytometry (FCM) assay was used to measure the influence of DANCR on proliferation, invasion, migration and apoptosis in ECA109 cells, respectively. Results: The expression of DANCR in ESCC tissues and ESCC cells was significantly higher compared with that in the adjacent normal tissues (P<0.05). Furthermore, cell proliferation, migration and invasion were significantly suppressed by knock-down mediated down-regulation of DANCR expression. On the contrary, cell apoptosis was promoted by silencing of DANCR. Conclusions: According to our research, the expression of DANCR was up regulated in human ESCC tissues, and the important role that DANCR played in ESCC cells was similar to an oncogene. Therefore, silencing of lncRNA DANCR could have potentially beneficial effects on the prognostic and therapy for ESCC in the future. PMID- 29997919 TI - Effect of nicotine dependence on quality of life and sleep quality in patients with lung cancer who continue to smoke after diagnosis. AB - Background: Hundreds of millions of Chinese individuals continue to smoke and rates of lung cancer still continue to rise. However, there were few studies that examined the effects of nicotine dependence on quality of life (QOL) and sleep quality in lung cancer patients. This study aimed to investigate the effect of nicotine dependence on QOL and sleep quality in lung cancer patients who continue to smoke after diagnosis. Methods: This cross-sectional survey study included 202 patients with lung cancer. Smokers were separated into two groups based on the Fagerstrom Test for Nicotine dependence: the low dependence (LD) (<4 score) group (n=59) and the high dependence (HD) (>=4 score) group (n=143). Both Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) and Chinese version of Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the two groups of lung cancer patients. Then we analyzed the difference of QOL and sleep quality between two distinct nicotine dependence groups. Results: Physical functioning, role functioning, emotional functioning, cognitive functioning, global health status and social functioning items in the LD group were significantly higher than the HD group (P<0.001). Fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, diarrhea and financial problems in the LD group were significantly lower than those in the HD group (P<0.001). Significantly higher scores in the HD group were found concerning the three sleep components including sleep duration, sleep efficiency and daytime function. The mean global PSQI score in the HD group was significantly higher than the LD group (P=0.014). Conclusions: These findings suggest that lung cancer patients who continue to smoke after diagnosis should receive health education in order to improve their QOL and quality of sleep after the word education. This can be useful for clinicians and nurses who are trying to motivate smokers to quit smoking. PMID- 29997920 TI - Independent risk factors for postoperative AKI and the impact of the AKI on 30 day postoperative outcomes in patients with type A acute aortic dissection: an updated meta-analysis and meta-regression. AB - Background: This meta-analysis aims to investigate the effects of postoperative acute kidney injury (AKI) on 30-day postoperative outcomes and the independent risk factors for postoperative AKI in patients with type A acute aortic dissection (TAAD). Methods: Relevant reports published between January 1, 2011 and May 31, 2017 were searched in multiple electronic literature databases. A total of seven eligible articles were included in the meta-analysis. Results: Postoperative AKI was associated with 249% increase in 30-day postoperative mortality [odds ratio (OR): 3.49; 95% confidence interval (CI): 2.17-5.59; P<0.0001]. Subgroup analysis revealed that patients with stage II/III AKI showed 445% increase in 30-day postoperative mortality compared with the control group (OR: 5.45; 95% CI: 2.87-10.36; P<0.0001). Postoperative AKI was also associated with 143%, 432%, and 126% increase in the incidences of 30-day postoperative stroke, bleeding, and respiratory complications, respectively. Notably, high body mass index (BMI), advanced age, and perioperative sepsis were independent risk factors for postoperative AKI in patients with TAAD. Conclusions: This meta analysis firstly provided clinical evidence showing the adverse effects of postoperative AKI on 30-day postoperative outcomes in patients with TAAD and identified high BMI, advanced age, and perioperative sepsis as the independent risk factors for postoperative AKI. These findings suggest that preventive or therapeutic methods to effectively manage postoperative AKI may improve 30-day postoperative outcomes in patients with TAAD. PMID- 29997921 TI - Evaluation of the performance of serum miRNAs as normalizers in microRNA studies focused on cardiovascular disease. AB - Background: Few study has been done to evaluate the stability and superiority of normalizers for serum microRNA (miRNA) study in cardiovascular disease. Therefore, the aim of this study is to assess the suitability of several common normalizers (miR-16, SNOU6, 5S, miR-19b, miR-24, miR-15b, let 7i) in cardiovascular disease. Methods: We evaluated the stability of the seven circulating miRNAs as reference genes in the blood samples from patients with cardiovascular disease [heart failure (HF) and hypertension] and healthy people. Stability was quantified by combining BestKeeper, NormFinder and comparative delta Cq analysis. Results: A total of 62 subjects were included in this study, of which 25 patients were with HF, 10 patients were with hypertension, and 27 were healthy people. The analysis from both BestKeeper and comparative delta ct analysis demonstrated that let-7i and miR-16 showed the best performance [the standard deviations (SD) in BestKeeper for let-7i and miR-16 were 0.60 and 0.72, and the mean SD in comparative delta ct analysis for let-7i and miR-16 were 1.79 and 1.82, respectively], while SNOU6 and 5S had the highest variability. In NormFinder analysis, miR-15 show best stability (rho=0.029), followed by miR-19b (rho=0.037), let-7i (rho=0.064), SNOU6 (rho=0.064), 5S (rho=0.064), miR-16 (rho=0.064), while miR-24 (rho=0.075) showed worst stability. Conclusions: This study pointed out that in the serum studies focused on cardiovascular disease, let-7i and miR-16 had the best performance, while SNOU6 and 5S were not suitable as reference gene. This study indicate that the selection of an optimal reference genes is important to get an accurate result in serum miRNA studies, the findings are of clinical significance to guide the further miRNA studies or tests. PMID- 29997922 TI - Risk factors for mortality in ICU patients with Acinetobacter baumannii ventilator-associated pneumonia: impact of bacterial cytotoxicity. AB - Background: Acinetobacter baumannii (A. baumannii) ventilator-associated pneumonia (VAP) in intensive care unit (ICU) is associated with high morbidity and mortality in patients with critical illness. However, the literatures that focused on the short-term prognosis and the risk factors for mortality are limited. The aim of this study was to evaluate the risk factors for mortality in ICU patients with A. baumannii VAP. Methods: A retrospective cohort study was conducted in the medical/surgical ICU at Zhongshan Hospital in Shanghai, China. Adult patients meeting the criteria of A. baumannii VAP from January 2012 to October 2015 were enrolled. Apart from collecting clinical and microbiologic data, we performed biofilm-formation and cytotoxicity testing using A. baumannii strains which are isolated from patients. Multivariate logistic regression analysis was used to determine the independent risk factors for 30-day mortality in ICU. Results: Seventy-eight patients were included in this study. The 30-day mortality rate in ICU for the patients was 37.2%. Multivariate analysis revealed that short-term mortality was significantly associated with prior surgery [OR, 0.277; 95% confidence interval (CI), 0.089-0.866; P=0.027], higher APACHEII score (OR, 1.140; 95% CI, 1.007-1.291; P=0.038) and an increased bacterial cytotoxicity (OR, 1.029 ; 95% CI, 1.001-1.058; P=0.047). Conclusions: The main finding of our study was that increased bacterial cytotoxicity might be a risk factor for short term mortality in ICU patients with A. baumannii VAP. PMID- 29997923 TI - Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. AB - Background: Defective airway host-defense (e.g., altered mucus properties, ciliary defects) contributes to the pathogenesis of bronchiectasis. This study aims to determine whether genetic mutations associated with defective airway host defense are implicated in the pathogenesis of bronchiectasis. Methods: Based on the systematic screening of 32 frequently reported bronchiectasis-associated genes, we performed next-generation sequencing (NGS) on peripheral blood samples from 192 bronchiectasis patients and 100 healthy subjects. The variant distribution frequency and pathogenicity of mutations were analyzed. Results: We identified 162 rare variants in 192 bronchiectasis patients, and 85 rare variants among 100 healthy subjects. Among bronchiectasis patients, 25 (15.4%), 117 (72.2%) and 18 (11.1%) rare variants were associated with cystic fibrosis transmembrane receptor (CFTR), epithelial sodium channel, and primary ciliary dyskinesia genes, respectively. Biallelic CFTR variants were detected in four bronchiectasis patients but none of the healthy subjects. Carriers of homozygous p.M470 plus at least one CFTR rare variant were detected in 6.3% of bronchiectasis patients (n=12) and in 1.0% of healthy subjects (n=1, P=0.039). Twenty-six patients (16 with idiopathic and 6 with post-infectious bronchiectasis) harbored biallelic variants. Bronchiectasis patients with biallelic DNAH5 variants, or biallelic CFTR variants plus an epithelial sodium channel variant, tended to have greater disease severity. Conclusions: Genetic mutations leading to impaired host-defense might have implicated in the pathogenesis of bronchiectasis. Genetic screening may be a useful tool for unraveling the underlying causes of bronchiectasis, and offers molecular information which is complementary to conventional etiologic assessment for bronchiectasis. PMID- 29997924 TI - Next generation sequencing-based molecular profiling of lung adenocarcinoma using pleural effusion specimens. AB - Background: Molecular profiling of non-small cell lung cancer (NSCLC) is essential for therapeutic decision-making. Pleural effusion obtained by a non invasive, repeatable procedure may provide an opportunity for molecular profiling and thereby possibly provide information enabling targeted therapy. In this study, we aimed to evaluate the diagnostic performance of pleural effusion as a specimen for molecular analysis. Methods: Thirty patients with paired malignant pleural effusion and thoracic biopsy specimens were included. Clinically actionable mutations were assessed using a validated targeted next generation sequencing assay. EGFR/KRAS/ALK mutation status in thoracic biopsy specimens was tested using ARMS PCR. Results: The concordance rate between gene status identified by ARMS and next-generation sequencing (NGS) analysis in the thoracic biopsy and pleural effusion samples was 86.7% (26/30). Compared with the thoracic biopsy specimens, the diagnostic performance of pleural effusion showed a sensitivity of 92.3%, a specificity of 50.0%, and a positive predictive value of 92.3%. Therefore, cases with a low percentage of tumor cells (<5%) can successfully be used to detect actionable mutations in pleural effusion specimens. Conclusions: These results suggest that pleural effusions are suitable specimens for oncogene mutation analysis and enable targeted therapy for patients with advanced NSCLC. PMID- 29997925 TI - The role of virtual-assisted lung mapping in the resection of ground glass nodules. AB - Background: Virtual-assisted lung mapping (VAL-MAP), a bronchoscopic multi-spot dye-marking technique, was tested for its ability to resect ground glass nodules (GGNs) in sublobar lung resections. Methods: All patients were prospectively registered in the multi-institutional lung mapping (MIL-MAP) study using VAL-MAP. The data were retrospectively analyzed, focusing on GGNs. GGN characteristics, pathological findings, operation type, and the surgical contribution of VAL-MAP were evaluated. Results: The 370 GGNs in 299 patients included 257 pure and 113 mixed GGNs. There were 146 wedge resections (43.6%), 99 simple segmentectomies (29.6%), and 60 complex segmentectomies (18.0%). The largest number of marks were used in complex segmentectomy (4.05+/-0.74), followed by simple segmentectomy (3.35+/-0.97) and wedge resection (2.96+/-0.80). The overall successful resection rate was 98.6%. Multiple [2-5] GGNs were concurrently targeted by VAL-MAP in 53 patients (17.7%) with 123 GGNs. Two concurrent resections were conducted in 36 patients (12.1%), most commonly wedge resection and segmentectomies (21 patients). Among 190 sub-centimeter GGNs, 24 out of 51 GGNs <=5 mm in diameter (47.1%) and 113 of 139 GGNs >5 mm in diameter (81.3%) were primary lung cancer (P<0.0001). Regarding the contribution of VAL-MAP to successful resection, wedge resection and pure GGNs were graded higher than both other resection types and mixed GGNs. Conclusions: VAL-MAP enabled thoracoscopic limited resection of GGNs. Its multiple marks facilitated resections of multi-centric GGNs. Resected suspicious GGNs >5 mm in diameter are likely to be lung cancer. VAL-MAP may impact decision-making regarding the indications and type of surgery for suspicious small GGNs. PMID- 29997926 TI - Long-term survival of the middle and lower thoracic esophageal cancer patients after surgical treatment through left or right thoracic approach. AB - Background: Esophageal cancer is one of the most prevalent malignancies with a high incidence and mortality in China, the main treatment for esophageal cancer at present is still surgery-based multimodality treatment, and surgery is still the most effective measure. However, the modes of surgical treatment for esophageal cancer have been diverse. The surgical approaches can be mainly divided into the left thoracic approach and right thoracic approach in China. The long-term survival of the patients treated through right approach was reported better than that through left thoracic approach, but until now no statistically significant difference was found between two approaches, especially, for those with middle and lower thoracic esophageal cancer without suspected upper mediastinal lymph node metastasis in preoperative examinations, no definite conclusion have been made on selection of the approach, therefore, this studies try to compare the long-term survival between two approaches . Methods: The data of 402 cases with complete resection and two-field lymph node dissection from January, 2011 to December, 2011 in the Cancer Hospital, Chinese Academy of Medical Sciences was retrospectively reviewed and analyzed. Propensity score matching (PSM) analysis and life-table in SPSS 22.0 and Stata 14.0 were used to analyze the survival. Results: Totally, 402 cases were surgically treated either via left or right thoracic approach. The overall 5-year survival rate of this series was 38%, it was 37% in 281 cases surgically treated through left approach, and 39% in 121 cases through right approach (P=0.908). The 5-year survival of 256 patients without suspected lymph node metastasis in the upper mediastinum based on the preoperative examinations surgically treated through left approach was 38% versus 43% of 88 cases through right approach (P=0.404). After PSM, the 5-year survival of 110 cases surgically treated through left approach was 32% versus 40% of another matched 110 cases through right approach (P=0.146). for the patients without suspected lymph node metastasis in the upper mediastinum based on preoperative examinations, the 5-year survival of 88 surgically treated through left approach was 33% versus 44% of another matched 88 cases through right approach (P=0.239). Conclusions: For the middle and lower thoracic esophageal cancer patients, whether or not who has suspected lymph node metastasis in the upper mediastinum based on preoperative CT and EUS, the surgical treatment through right thoracic approach can achieve better but not significantly better overall survival than that through left thoracic approach. Further prospective randomized clinical trials are still needed to verify this disputed issue on approach selection. PMID- 29997927 TI - On-pump beating heart versus conventional coronary artery bypass grafting: comparative study on early and long-term clinical outcomes. AB - Background: We reviewed our experience with on-pump beating (OPB) heart coronary artery bypass grafting (CABG) to evaluate the impacts of obviating aortic cross clamping and cardioplegic arrest on clinical outcomes compared with conventional CABG (C-CABG). Methods: Between 2006 and 2012, elective isolated cardiopulmonary bypass (CPB)-assisted CABG was consecutively performed in 645 patients (mean patient age 63.3+/-9.1 years, 471 women) with 254 (39.4%) undergoing OPB-CABG and 391 (60.6%) undergoing C-CABG. The early and long-term clinical outcomes were compared between the two groups after adjusting for risk profiles through propensity score (PS) analyses. Results: The OPB-CABG group presented significant morbidities more frequently than the C-CABG group, including severe chronic kidney disease (CKD) (P=0.026), severe chest pain (P<0.001), and poor left ventricular function (P<0.001). Early mortality occurred in 6 (2.4%) and 2 (0.5%) patients in the OPB- and C-CABG group, respectively (P=0.087). The number of distal anastomosis was comparable between the two groups (3.0+/-0.9 vs. 3.0+/ 1.0, P=0.816). After PS matching, the incidence of major complications such as stroke (P>0.99) and new-onset dialysis (P=0.109) was comparable. During a median follow-up of 81.0 months (quartiles 1-3, 66.6-95.0 months), 118 patients died and the PS-matched models showed no significant between-group differences in the risk of overall death [hazard ratio (HR), 1.19; 95% confidence interval (CI), 0.72 1.95; P=0.507] and major adverse cardiac events (MACE) (HR, 1.49; 95% CI, 0.67 3.31; P=0.328). Conclusions: The OPB strategy may be as safe and effective as the conventional strategy during CABG among patients with similar risk profiles. A prospective randomized trial is warranted to better ascertain the beneficial impact of OPB-CABG as both a viable and a durable alternative strategy to C-CABG. PMID- 29997928 TI - Multi-level analysis of bacteria isolated from inpatients in respiratory departments in China. AB - Background: With the different situation for clinical antibiotic usage and its management in different regions and medical institutions, the antimicrobial resistance varied in different level. However, the epidemiological data of multi drug resistant (MDR) strains from the department of respiration is limited. Thus, this study aims to investigate the epidemiology of bacteria isolated from inpatients of respiratory departments, and analyze the distribution variation of major multi-drug resistant bacteria in China. Methods: Based on data from China Antimicrobial Resistance Surveillance System (CARSS) in 2015, 50,417 non duplicate isolates obtained from inpatients of respiratory departments from 91 general hospitals in seven regions of China were enrolled in the study. The distribution of methicillin-resistant Staphylococcus aureus (MRSA), carbapenem resistant Escherichia coli (CREC) and Klebsiella pneumoniae (CRKP), carbapenem resistant Pseudomonas aeruginosa (CRPA) and Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamases-producing E. coli (ESBL-EC) and K. pneumoniae (ESBL-KP), were further analyzed by geographic regions, age groups, wards and specimen types. Results: The major specimens type were sputum (81.6%, 41,131/50,417), followed by blood (5.3%, 2,649/50,417), urine (4.5%, 2,249/50,417) and bronchoalveolar lavage fluid (BALF) (3.2%, 1,620/50,417). The top four bacteria species isolated from sputum and BALF were similar: K. pneumonia (18.9% and 14.8%, respectively), P. aeruginosa (13.6% and 22.2%, respectively), A. baumannii (11.3% and 11.9%, respectively) and S. pneumonia (11.1% and 9.6%, respectively). The four most common bacteria species were K. pneumonia (17.2%), P. aeruginosa (12.1%), A. baumannii (10.4%) and S. pneumonia (10.1%) in tertiary hospitals but K. pneumonia (20.8%), P. aeruginosa (16.3%), E. coli (11.3%) and A. baumannii (6.9%) in secondary hospitals. The top four bacteria species in respiratory intensive care unit (RICU) were A. baumannii (25.8%), P. aeruginosa (13.1%), K. pneumonia (12.2%) and S. aureus (9.2%). The prevalence of CRKP, CRPA and CRAB in tertiary hospitals was significantly higher than that in secondary hospitals (5.2% vs. 2.5%, 23.8% vs. 12.8% and 53.5% vs. 33.9%, respectively) (all P<0.05). However, the prevalence of ESBL-EC in secondary hospitals was higher than in tertiary ones (63.9% vs. 55.0%, P=0.011). The prevalence of MRSA, CRKP, CRAB, CRPA, ESBL-EC, ESBL-KP in RICU were higher than that in non-ICU respiratory departments (76.5% vs. 35.7%, 20.1% vs. 4.1%, 90.6% vs. 45.5%, 64.2% vs. 19.3%, 47.2% vs. 28.3% and 43.0% vs. 11.2%, respectively) (all P<0.01). Among seven regions in China, central area had the highest detection rates of MRSA (70.3%, 237/337), CRPA (30.9%, 376/1,218), CRAB (71.8%, 487/678) and ESBL-KP (38.8%, 241/621). The prevalence of ESBL-EC and ESBL KP in pediatric group (68.2% and 55.3%, respectively) was higher than that in geriatric group (54.2% and 27.1%, respectively) and adult group (51.1% and 15.1%, respectively) (all P<0.001). Conclusions: In China, the predominant bacterial pathogens in the respiratory ward were Enterobacteriaceae and non-fermentative bacteria. High prevalence of ESBL-EC and ESBL-KP isolated from lower respiratory tract (LRT) was revealed in primary hospitals and pediatric patients. PMID- 29997930 TI - Evaluating and assessing the prevalence of bedside ultrasound in emergency departments in China. AB - Background: To survey the prevalence of bedside ultrasound assessment in emergency departments (EDs) in China. Methods: We designed an online survey for emergency physicians based in the China. The questionnaire included sixteen items querying common ED bedside ultrasound practices. Respondents were recruited via weblinks sent through social media and a popular Chinese emergency medicine website. Survey data was collected from April through June, 2016. Results: Four hundred and twenty-eight physicians responded to this survey; more than 80% of respondents reported working clinically in the ED. Ninety-eight percent of respondents agreed on the clinical importance and value of bedside ultrasound. However, less than half of participants' EDs had ultrasound devices, and less than half of the respondents said they knew how to perform bedside ultrasound. Less than 20% of respondents reported having had formal training in bedside ultrasound. Conclusions: There is a strong interest in bedside ultrasound in Chinese EDs. Emergency physicians participating in this study considered bedside ultrasound a necessary skill, but, because there is a lack of training, most emergency physicians reported they did not know how to perform bedside ultrasonography. There is likely an acute desire and need for bedside ultrasound training for Chinese emergency physicians. PMID- 29997929 TI - High-resolution computed tomography features and CT-guided microcoil localization of subcentimeter pulmonary ground-glass opacities: radiological processing prior to video-assisted thoracoscopic surgery. AB - Background: With the rapid development of high-resolution computed tomography (HRCT), low-dose CT scanning and video-assisted thoracoscopic surgery (VATS), smaller pulmonary nodules can be detected. Subcentimeter ground-glass opacities (GGOs) are extremely difficult to diagnose and accurately locate during VATS and in surgically resected specimens. Methods: From September 2013 to September 2017, 42 subcentimeter GGO lesions (<=1 cm) in 31 patients who underwent CT-guided microcoil insertion followed by VATS resection were included. All HRCT images were assessed by two experienced radiologists, and CT-guided microcoil localization procedures were performed by two experienced interventional radiologists. Results: A total of 42 subcentimeter GGOs included 28 malignancies (66.7%) and 14 benign lesions (33.3%). The diameter of malignant GGOs (8.52+/ 1.46 mm) was significantly larger than that of benign lesions (7.04+/-1.52 mm) (P<0.05). Seven patients had more than one GGO nodule. There were no significant differences in the location, composition, shape, margins, presence of air bronchograms, presence of the pleural indentation sign and presence of the vascular convergence sign between benign and malignant GGOs (P>0.05). All the localization procedures were performed successfully. A small pneumothorax occurred in 9 patients (21.4%), and minor hemorrhage in the lung parenchyma occurred in 8 patients (19.0%). All GGOs were easily identified during VATS and were definitively diagnosed. Conclusions: Common HRCT features cannot be used as criteria for the differential diagnosis of subcentimeter benign and malignant pulmonary GGOs. CT-guided microcoil marking of these lesions prior to VATS is a feasible, safe, and effective procedure for the localization of subcentimeter pulmonary GGOs. PMID- 29997931 TI - Long-term outcome after resection for recurrent oesophageal cancer. AB - Background: The efficacy of surgical resection for lymph node (LN) or distant recurrence of oesophageal cancer has not been sufficiently investigated. The objective of this study was to reveal appropriate indications for a surgical approach. Methods: A total of 42 patients who underwent resection for recurrent or residual oesophageal squamous cell carcinoma after surgery or definitive chemoradiotherapy (dCRT) between April 2004 and August 2016 were identified. These resections did not include salvage oesophagectomy. The long-term outcomes of these patients were retrospectively analysed. Results: Thirty-three patients underwent LN resection, 6 patients underwent lung resection, and 3 patients underwent resection for other recurrent tumours. The 5-year overall survival (OS) of patients who underwent salvage abdominal lymphadenectomy after dCRT was significantly better than that of patients who underwent salvage cervical or mediastinal lymphadenectomy (46.9% vs. 0.0%, P=0.006). The 5-year OS of patients who underwent salvage resection for LNs outside the radiation field was significantly better than that of patients who underwent resection inside the radiation field (47.6% vs. 8.9%, P=0.027). The 5-year OS of patients who underwent salvage resection for recurrent LNs was significantly better than that of patients who underwent salvage resection for residual LNs (21.7% vs. 0.0%, P<0.001). Among the 42 patients, 9 survived more than 3 years: 4 after salvage abdominal lymphadenectomy, 3 after resection for solitary lung recurrence, and 2 others. Conclusions: The use of the appropriate surgical approach might improve the prognosis of patients with abdominal LN recurrence, LN recurrence outside the radiation field, or a solitary lung recurrence of oesophageal cancer. PMID- 29997932 TI - Effect of Liuweibuqi capsules on CD4+CD25+Foxp3+ regulatory T cells, helper T cells and lung function in patients with stable chronic obstructive pulmonary disease complicated with lung Qi deficiency. AB - Background: Chronic obstructive pulmonary disease (COPD) is predicted to become the fifth leading cause of disability and the third leading cause of death around the world by 2020. Though it is potentially treatable and preventable, evidence of brain structural alterations in COPD remains sparse and conflicting. We aim to investigate the effect of Liuweibuqi capsules on CD4+CD25+ Forkhead box protein 3+ (Foxp3+) regulatory T cells (Tregs), helper T cells (Th) and lung function in patients with stable COPD complicated with lung Qi deficiency. Methods: COPD patients with lung Qi deficiency [458] were assigned into non-smoking COPD (NS COPD), non-smoking control (NS-control), smoking COPD (S-COPD) and smoking control (S-control) groups, and healthy volunteers [245] into the non-smoking healthy (NSH) and smoking healthy (SH) groups. Levels of inflammatory cytokines were detected by Enzyme-linked immunoassay (ELISA). Contents of inflammatory cells, inflammatory marker, and CD4+CD25+Fox3+Tregs were measured by flow cytometry. FEV1/FVC (%) and FEV1 (%) were detected by pulmonary function test apparatus. Correlation between FEV1 (%) and Th1, Th2, Th17, Th1/Th2 or CD4+CD25+Fox3+Tregs was analyzed by Spearman rank correlation test. The related factors affecting treatment efficacy was assessed by logistic analysis. Results: COPD patients and smoking people showed higher level of INF-gamma, IL-4, IL-17, Th1, Th2, Th17 and Th1/Th2 but lower level of CD4+CD25+Fox3+Tregs. Liuweibuqi capsules could decrease level of inflammatory cells, cytokines, and markers (especially Th17 and IL-17), and increase level of CD4+CD25+Fox3+Tregs. FEV1 (%) negatively correlated with Th1, Th2, Th17 and Th1/Th2 but positively correlated with CD4+CD25+Fox3+Tregs, and smoking may strengthen their correlation, but Liuweibuqi capsules may weaker their correlation. Levels of inflammatory cytokines, cells, marker, CD4+CD25+Fox3+Tregs, FEV1/FVC (%), FEV1 (%), smoking and Liuweibuqi capsules are factors affecting efficacy. Conclusions: Taken together, our data support the notion that smoking is an important factor to induce and aggravate COPD. Liuweibuqi capsules could stimulate proliferation of CD4+CD25+Fox3+Tregs and decrease Th17 expression to improve the lung function in stable COPD patients with lung Qi deficiency, and it had obvious efficacy for smoking COPD patients. PMID- 29997933 TI - It is safe and feasible to omit the chest tube postoperatively for selected patients receiving thoracoscopic pulmonary resection: a meta-analysis. AB - Background: To access the feasibility and safety of no chest tube (NCT) placement after thoracoscopic pulmonary resection. Methods: A comprehensive search of online databases (PubMed, Embase, Web of Science, and Cochrane library) was performed. Studies investigating the safety and feasibility of NCT compared with chest tube placement (CTP) after VATS pulmonary resection were eligible for our meta-analysis. Perioperative outcomes were extracted and synthesized. Specific subgroups (wedge resection) were examined. The methodological quality of the included articles was evaluated with the methodological index for non-randomized studies (MINORS) tool. Results: Analysis of 9 studies including a total of 918 patients was performed. Four hundred sixty-one patients underwent NCT and 457 patients underwent CTP. The length of stay (LOS) postoperatively in the NCT group was significant shorter than in the CTP group [standardized mean difference (SMD) = -0.80; 95% confidence interval (CI), -1.13 to -0.47, P=0.000]. Patients in the NCT group experienced slighter pain than patients in the CTP group in postoperative day (POD) one (SMD = -0.41; 95% CI, -0.75 to -0.07, P=0.02), and POD two (SMD = -0.41; 95% CI, -0.75 to -0.07, P=0.02). While, there was no significant difference about the 30-day morbidity for patients who underwent NCT and CTP [relative ratio (RR) =1.01; 95% CI, 0.59-1.74, P=0.04) and the rate of re intervention (RR =0.89; 95% CI, 0.33-2.40, P=0.57). No perioperative mortality was observed in both groups. The sensitivity analysis suggested that the relative effects between 2 groups have already stabilized. Subgroup analysis revealed an effect modification by operation approach regarding perioperative morbidity, but not for LOS. Conclusions: This meta-analysis conforms that it is feasible and safe to omit chest tube after thoracoscopic pulmonary resection for patients carefully selected. Randomized controlled trails (RCTs) are urgently needed to verify this conclusion. PMID- 29997934 TI - Lung volume reduction surgery does not increase daily physical activity in patients with severe chronic obstructive pulmonary disease. AB - Background: Lung volume reduction surgery (LVRS) is a treatment option for selected patients with severe chronic obstructive pulmonary disease (COPD) and emphysema. The positive effects of LVRS on exercise capacity are well known. In contrast, the effect of LVRS on daily physical activity (PA) is less clear. Methods: In a prospective case-control study we evaluated selected patients with severe COPD and emphysema who underwent LVRS and COPD patients following usual care. Controls were matched for age, severity of airflow obstruction (FEV1) and hyperinflation [residual volume to total lung capacity (RV/TLC)]. Treatment effect of LVRS on activity parameters was analysed using univariable regression model adjusting for treatment group. Results: A total of 19 patients underwent LVRS and 16 COPD patients without a surgical intervention during the study period were included. The median (quartile) FEV1%pred was 28% (range, 21-33%), RV/TLC was 69% (range, 64-73%) in cases while controls had a median (quartile) FEV1%pred of 33% (range, 28.5-49.5%) and a RV/TLC of 58% (range, 49-61%). Age and body mass index (BMI) were comparable between both groups. Number of steps per day following LVRS was comparable to before the intervention (mean change: -115, 95% CI: -994.6 to 764.3, P=0.779) and was not significantly different to the change in control subjects (mean treatment effect: 931.4, 95% CI: -252.4 to 2,115.1, P=0.117). Conclusions: The results from this study reveal that patients undergoing LVRS did not increase their daily level of PA despite improvement of exercise capacity and symptoms. PMID- 29997935 TI - Safety and efficacy of airway stenting in patients with malignant oesophago airway fistula. AB - Background: Close anatomical relationships between the oesophagus and the bronchial tree can lead to the formation of oesophageal fistula particularly in patients with advanced lung or oesophageal carcinoma. Stenting is a most often used treatment in such patients, but data regarding the relative value of unilateral (US) vs. double stenting (DS) are scarce. Methods: Retrospective analysis of hospital records of patients with oesophageal fistula who underwent stenting between 2008 and 2016. In those in whom airway stenosis was >30%, double stenting (oesophagus and bronchial tree) was performed, whereas in those with lesser airway stenosis unilateral stenting (i.e., oesophagus only) was performed. In all patients, the degree of dysphagia, the degree of dyspnoea and the quality of life were assessed before and after the stenting. Results: There were 46 patients, analysed, including 26 who underwent DS and 20 patients who underwent US. Both, DS and US resulted in significant improvement of dysphagia (2.72 vs. 1.2, P=0.0001 and 2.65 vs. 1.0, P=0.0001), dyspnoea (2.89 vs. 0.34, P=0.0001 and 1.71 vs. 0.09, P=0.0001) and performance score (53.2 vs. 66.3, P=0.0001 and 54.3 vs. 62.38, P=0.0001). Neither fistula type, nor stenting method, weight loss and gain, and BMI, had an effect on survival (P=0.34). Disease progression and recurrence of fistula requiring re-intervention occurred in 9 patients (19.5%). Conclusions: Double and unilateral stenting is an effective measure to alleviate dysphagia and dyspnoea in patients treated with malignant oesophageal fistula. In those with airway stenosis of <=30%, stenting of the oesophagus only, instead of DS, is a safe method of treatment. PMID- 29997936 TI - Qualitative coronary artery calcium assessment on CT lung screening exam helps predict first cardiac events. AB - Results: A total of 1,513 individuals underwent CTLS. Downstream data, pre-test cardiac risk factors and CAC scores were available for 88.3% (1,336/1,513). The average length of follow-up was 2.64 (SD +/-0.72) years. There were a total of 43 events, occurring in 1.55% (6/386) of patients with mild CAC, 3.24% (11/339) of patients with moderate CAC, and 8.90% (26/292) of patients with marked CAC. There were no events among patients with no reported CAC (0/319). Using multivariable logistic modeling, the increased odds of an initial cardiac event was 2.56 (95% CI, 1.76-3.92, P<0.001) for mild CAC, 6.57 (95% CI, 3.10-15.4, P<0.001) for moderate CAC, and 16.8 (95% CI, 5.46-60.3, P<0.001) for marked CAC, as compared to individuals with no CAC. Time to event analysis showed distinct differences among the four CAC categories (P<0.001). Conclusions: Qualitative coronary artery calcification scoring of CTLS exams may provide a novel method to help select individuals at elevated risk for an initial cardiac event. PMID- 29997937 TI - Pyrroloquinoline quinone attenuates cachexia-induced muscle atrophy via suppression of reactive oxygen species. AB - Background: Cachexia, a wasting syndrome, is most commonly observed in individuals with advanced cancer including lung cancer, esophageal cancer, liver cancer, etc. The characteristic sign of cachexia is muscle atrophy. To date, effective countermeasures have been still deficiency to alleviate muscle atrophy. Reactive oxygen species (ROS) are important regulators of muscle atrophy. Therefore, the effects of a naturally antioxidant, pyrroloquinoline quinone (PQQ), were explored on muscle atrophy induced by cachexia in the present study. Methods: Tumor necrosis factor-alpha (TNF-alpha) induced C2C12 myotubes atrophy model was constructed. The atrophied C2C12 myotubes were dealt with the presence or absence of N-acetyl-L-cysteine (NAC, an antioxidant for ROS abolition) (5 mM) or PQQ (80 uM) for 24 hours. ROS content was determined by dichlorodihydrofluorescein diacetate (DCFH-DA) staining. The diameter of myotubes was analyzed by myosin heavy chain (MHC) staining. The protein levels of MHC, muscle atrophy F-box (MAFbx) and muscle RING finger-1 (MuRF-1) in each group were observed by Western blotting. Results: First, ROS generation was enhanced in C2C12 myotubes treated with TNF-alpha. NAC treatments significantly avoided the reduction in the diameter of C2C12 myotubes, and concomitantly increased MHC levels, and decreased ROS contents, MuRF1 and MAFbx levels. These data suggested that the increased ROS induced by TNF-alpha might play a central role in muscle wasting. PQQ (a naturally occurring antioxidant) administration inhibited C2C12 myotubes atrophy induced by TNF-alpha, as evidenced by the increase of the diameter of C2C12 myotubes, together with increased MHC levels and decreased ROS, MAFbx and MuRF-1 levels. Conclusions: PQQ resists atrophic effect dependent on, at least in part, decreased ROS in skeletal muscle treated with TNF-alpha. PMID- 29997938 TI - Effect of lung protective ventilation on coronary heart disease patients undergoing lung cancer resection. AB - Background: Mechanical ventilation, especially large tidal volume (Vt) one-lung ventilation (OLV), can cause ventilator-induced lung injury (VILI) that can stimulate cytokines. Meanwhile, cytokines are considered very important factor influencing coronary heart disease (CHD) patient prognosis. So minimization of pulmonary inflammatory responses by reduction of cytokine levels for CHD undergoing lung resection during OLV should be a priority. Because previous studies have demonstrated that lung-protective ventilation (LPV) reduced lung inflammation, this ventilation approach was studied for CHD patients undergoing lung resection here to evaluate the effects of LPV on pulmonary inflammatory responses. Methods: This is a single center, randomized controlled trial. Primary endpoint of the study are plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-10 and C-reactive protein (CRP). Secondary endpoints include respiratory variables and hemodynamic variables. 60 CHD patients undergoing video-assisted thoracoscopic lung resection were randomly divided into conventional ventilation group [10 mL/kg Vt and 0 cmH2O positive end expiratory pressure (PEEP), C group] and protective ventilation group (6 mL/kg Vt and 6 cmH2O PEEP, P group; 30 patients/group). Hemodynamic variables, peak inspiratory pressure (Ppeak), dynamic compliance (Cdyn), arterial oxygen tension (PaO2) and arterial carbon dioxide tension (PaCO2) were recorded as test data at three time points: T1-endotracheal intubation for two-lung ventilation (TLV) when breathing and hemodynamics were stable; T2-after TLV was substituted with OLV when breathing and hemodynamics were stable; T3-OLV was substituted with TLV at the end of surgery when breathing and hemodynamics were stable. The concentrations of TNF-alpha, IL-6, IL-10 and CRP in patients' blood in both groups at the very beginning of OLV (beginning of OLV) and the end moment of the surgery (end of surgery) were measured. Results: The P group exhibited greater PaO2, higher Cdyn and lower Ppeak than the C group at T2, T3 (P<0.05). At the end moment of the surgery, although the P group tended to exhibit higher TNF-alpha and IL-10 values than the C group, the differences did not reach statistical significance(P=0.0817, P=0.0635). Compared with C group at the end moment of the surgery, IL-6 and CRP were lower in P group, the differences were statistically significant (P=0.0093, P=0.0005). There were no significant differences in hemodynamic variables between the two groups (P>0.05). Conclusions: LPV can effectively reduce the airway pressure, improve Cdyn and PaO2, reduce concentrations of IL-6 and CRP during lung resection of CHD patients.Trial registration: The trial was registered in the Chinese Clinical Trial Registry. PMID- 29997939 TI - ypT0N+: the unusual patient with pathological complete tumor response but with residual lymph node disease after neoadjuvant chemoradiation for esophageal cancer, what's up? AB - Background: Little is known about the prognostic significance of residual nodal disease in otherwise complete pathologic responders (ypT0N+) after neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC). The purpose is to analyze the long-term outcomes of EC patients with ypT0N+ following nCRT and esophagectomy. Methods: From a single institution database, 466 consecutive EC patients undergoing esophagectomy after nCRT were collected (1996-2016). ypT0N+ responders were compared to pathological complete responders (ypT0N0) and to pathological non-complete responders (ypT+N0 and ypT+N+). Results: There were 149 ypT0N0, 31 ypT0N+, 141 ypT+N0 and 145 ypT+N+. Median overall survival (OS) was worse in ypT0N+ (21.7 months) and ypT+N+ (16.8 months) compared to ypT0N0 (55.2 months) and ypT+N0 (42.0 months). Stratification by histology revealed a significant difference in prevalence of ypT0: 62.5% in 184 squamous cell carcinomas (SCC) compared to 23.0% in 282 adenocarcinomas (ADC) (P<0.0001) but not in ypT0N+ (15% vs. 22% respectively, P=0.25). In ADC, locoregional recurrence in ypT0N+ (43%) was comparable to ypT+N+ (31%) and more common compared to ypT0N0 (7%) and ypT+N0 (10%), reflected in median OS rates of 20.6, 17.5, 53.0 and 36.6 months respectively. Median OS in ADC is significantly determined by number of positive lymph nodes, being 21.7 months for pN1 and 2.7 months for pN2/3 (P=0.005) in ypT0N+ and 33.7 months for pN1 and 16.2 months for pN2/3 (P=0.031) in ypT+N+. In SCC, locoregional recurrences were found in 17% of ypT0N+, 33% of ypT+N+, 11% of ypT0N0 and 22% in ypT+N0 and median OS was 26.6, 15.6, 55.2 and 43.8 months respectively. In SCC ypN+ number of affected lymph nodes showed no difference on OS. Conclusions: ypT0N+ in EC patients following nCRT has a poor prognosis and behaves similar to ypT+N+. However, stratification by histology shows that this is especially true in ADC but seems determined by the number of involved lymph nodes. PMID- 29997940 TI - EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma. AB - Background: It is urgent to explore an effective potential therapeutic strategy for ESCC. In recent years, cell-based cancer immunotherapy has become a potentially close for carcinoma therapy. Chimeric antigen receptor (CAR) T cell technology is a kind of adoptive cell therapy technique which has been developed rapidly. We sought to obtain EphA2.CAR-T cell and revealed the ability of EphA2.CAR-T cells to kill esophageal squamous cell carcinoma (ESCC) cells in vitro. Methods: Firstly, the expression and location of EphA2 in ESCC tissues and cells was tested by immunohistochemistry staining and Western blot. Secondly, the second generation of EphA2.CAR was constructed via molecular biology technology, and transduced into T cells to obtain the EphA2.CAR-T cell. The transduction efficacies were assessed using flow cytometry (FCM). Thirdly, the effect of cell killing of EphA2.CAR-T cell on ESCC cells in vitro was detected by co-culture experiments. The productions of cytokines (TNF-alpha and IFN-gamma) by EphA2.CAR T cell after co-culture with ESCC cells were analyzed by ELISA assay. Results: The expression of EphA2 was significantly upregulated in ESCC tissues and cells (P<0.05). EphA2 was expressed on the membrane of ESCC cells, so it could be served as tumor-associated surface antigens (TAA) of CAR for ESCC treatment. The EphA2.CAR-T cell was obtained successfully, and its' transduction efficacies was 61.4% by FCM. The ability of cell killing of EphA2.CAR-T cell was better than that of T cells (P<0.01), and demonstrated a dose-dependent cell killing. The results of ELISA assay showed that the levels of TNF-alpha and IFN-gamma in EphA2.CAR-T cells were notably raised compared with T cells (P<0.05). Conclusions: We firstly constructed the second generation of EphA2.CAR and established EphA2.CAR-T cells. The EphA2.CAR-T cells showed a dose-dependent cell killing of ESCC cells, and promoted the production of cytokines in vitro. These findings open a new way for treatment of ESCC by immunotherapy in the future. PMID- 29997941 TI - The correlation of pulmonary arterial hypertension with late recurrence of paroxysmal atrial fibrillation after catheter ablation. AB - Background: Paroxysmal atrial fibrillation (PAF) is one of the most common clinical arrhythmias. Although radiofrequency catheter ablation (RFCA) for the treatment of atrial fibrillation has continuously matured and developed in recent years, some patients treated with RFCA continued to have atrial fibrillation recurrence, and the recurrence rate was high. Determining indicators to predict the recurrence of PAF after RFCA is significantly important for improving the surgical success rate and guiding clinical work. This study aimed to investigate the influence of pulmonary arterial hypertension (PAH) on the late recurrence of PAF after RFCA. Methods: A total of 300 patients with PAF, who underwent RFCA for the first time at the Department of Cardiology of Fujian Union Medical College Hospital from January 2013 to October 2016, were retrospectively studied. These patients were regularly followed-up from 3 months at least to 3 years and clinical data were collected. In order to observe the 100 PAF patients with PAH were assigned into the observation group, and 200 PAF patients without PAH were assigned as the control group. PAH and its related clinical characteristics were evaluated by univariate analysis of variance (ANOVA) and logistic regression analysis. Results: The follow-up results revealed that 34 patients had early recurrence, and the early arrhythmia recurrence rate was 11.3%. Furthermore, 22 patients had late recurrence, including 19 patients with atrial fibrillation and three patients with atrial flutter; and the late recurrence rate was 7.3%. The univariate ANOVA revealed that PAH (P=0.001), early recurrence (P=0.014) and Left atrial diameter (LAD) (P=0.023) had significant effects on late recurrence after PAF ablation. Furthermore, logistic regression analysis revealed that PAH (P=0.049, OR =1.053, 95% CI: 1.000-1.109) was independently correlated to late recurrence of PAF. Conclusions: PAH is a predictive factor for late recurrence of PAF after RFCA. PMID- 29997942 TI - Pathologic complete response after induction therapy-the role of surgery in stage IIIA/B locally advanced non-small cell lung cancer. AB - Background: Pathologic complete response (pCR) is dominant prognostic factor determining favorable outcome in locally advanced non-small cell lung cancer (NSCLC) after induction therapy (IT). There is no non-operative diagnostics that adequately estimates the pCR. Aim of this retrospective study was to assess the correlation between clinical and pathological factors in patients with pCR. Methods: Twenty-five patients with pCR after curative lung resection following IT were assessed using univariate and multivariate Cox regression and descriptive analysis. The survival rate was estimated by Kaplan-Meier method. Results: The IT included chemoradiation with median doses of 50.4 Gy (range, 45-59.4 Gy) combined with platinum-based chemotherapy in 23 patients (92%) and induction platinum based chemotherapy in 2 patients (8%). Clinical tumor stage before IT was IIIA in 21, IIIB in 4 patients. Mean interval between IT and surgery was 8.1+/-3.0 weeks. Perioperative morbidity and 30-day mortality was 32% and 4%, respectively. There was no significant correlation of pCR and different clinical and pathological factors. The estimated 5-year long-term survival (LTS) and progressive-free survival (PFS) was 57% and 54%, respectively. The median LTS and PFS was not reached. Conclusions: pCR in patients with locally advanced NSCLC following IT is an independent prognostic factor, without correlation with pathological and clinical factors. Non-operative accurate assessment of pCR is currently impossible. Surgical resection enables secure identification of pCR and might improve the patient stratification for additive therapy. PMID- 29997943 TI - Suppression of mitochondrial respiration with local anesthetic ropivacaine targets breast cancer cells. AB - Background: Retrospective studies on cancer patients who have received local anesthesia show a favorable decrease in tumor metastasis and recurrence. However, the mechanisms underlying the benefits of local anesthesia on cancer recurrence are not well understood. Methods: In this study, we investigated the biological effects of ropivacaine on breast cancer cells and the mechanisms of its action with emphasis on mitochondrial respiration. Results: Ropivacaine significantly inhibited growth, survival, and anchorage-independent colony formation in two human breast cancer cell lines. It also acted synergistically with a 5-FU in breast cancer cells. Mechanistically, ropivacaine was found to inhibit mitochondrial respiration by suppressing mitochondrial respiratory complex I and II activities, leading to energy depletion, and oxidative stress and damage. The inhibitory effects of ropivacaine in breast cancer cells were abolished in mitochondrial respiration-deficient rho0 cells, indicating that mitochondrial respiration is essential for the mechanism of action of ropivacaine. Ropivacaine inhibited phosphorylation of Akt, mTOR, rS6, and EBP1 in breast cancer cells, suggesting the association between Akt/mTOR signaling pathway and mitochondrial functions in breast cancer. Conclusions: Our work clearly demonstrates the inhibitory effects of ropivacaine in breast cancer by disrupting mitochondrial function. Our findings provide a proper understanding of how local anesthetics reduce the risk of tumor recurrence, and thus, support the use of ropivacaine for surgery and to control pain in patients with breast cancer. PMID- 29997944 TI - Interaction between treatment delivery delay and stage on the mortality from non small cell lung cancer. AB - Background: The aim of this study is to evaluate the interaction between treatment delay and stage on the mortality from non-small cell lung cancer (NSCLC). Methods: We performed a survival analysis in a cohort of patients admitted to the reference cancer center. The following data were collected: age, gender, smoking status, tumor staging, type of lung cancer, and time from the date when the patient was diagnosed with cancer to the starting date of effective treatment. Univariable and multivariable Cox proportional hazard models were used to investigate the association between potential confounders identified during the study design. After the final adjusted model was determined, tests for interaction among all predictors were performed. Results: Inclusion criteria were met by 359 patients. In the adjusted analysis, delayed treatment delivery was a protective factor for the risk of death, with a crude hazard ratio (HR) =0.75 (0.59-0.97; P=0.02) and an adjusted HR =0.59 (0.46-0.77; P<0.001). However, a statistically significant interaction with mortality was observed between timely treatment and tumor stage. Patients with stage II disease who received delayed treatment had a higher risk of death [HR =3.08 (1.05-9.0; P=0.04)]. On the other hand, stage IV patients who received delayed treatment had a 52% reduction in mortality [HR =0.48 (0.35-0.66; P<0.001)]. Conclusions: Stage of disease influenced the association between start of the treatment and mortality, and only the subgroup of stage II patients seemed to benefit from early treatment. PMID- 29997945 TI - Mitral valve repair versus replacement in patients with ischemic mitral regurgitation. AB - Background: The optimal management of ischemic mitral regurgitation (IMR) is controversial. The aim of this study was to examine our eight years' experience of surgical treatment in patients with IMR, and to compare outcomes of mitral valve repair versus replacement with concomitant coronary artery bypass grafting (CABG). Methods: A retrospective, observational, cohort study was undertaken to collect data on consecutive patients with IMR and coronary artery disease who received CABG and mitral valve surgery in our hospital between January 2008 and December 2015. Basic patient characteristics, operative data, and postoperative clinical outcomes were examined. Results: The series included 22 consecutive patients (21 male; 1 female). The mean age was 62.1+/-11.4 years old. The mean preoperative left ventricular ejection fraction (LVEF) was 33.4%+/-15.4%. The mean cardiopulmonary bypass (CPB) time was 165.4+/-38.4 minutes, and the mean aortic cross clamp time was 113.8+/-33.6 minutes. Eighteen patients underwent CABG plus mitral valve repair, and four patients underwent CABG plus mitral valve replacement (MVR). There were three early in-hospital mortalities: two in the mitral valve repair group, and one in the replacement group. The follow-up was complete in all patients, with a mean follow-up duration of 3.1+/-2.3 years. The mean last LVEF was 35.3%+/-17.7%. There were 2 late mortalities. Both were from the repair group. The overall late survival rate was 81.6%, with 83.0% in the repair group and 75.0% in the replacement group. In patients with echocardiography follow-up of more than or equal to 1 year duration, the residual or recurrent mitral regurgitation rates were 0.0% in the replacement group and 57.1% in the repair group. One patient in the repair group later underwent MVR due to severe regurgitation postoperatively. Conclusions: Our preliminary findings showed that the surgical outcome of mitral valve repair might be comparable to that of MVR in terms of early mortality and long-term survival. However, mitral valve repair was associated with a higher residual or recurrent mitral regurgitation rate. According to the latest literature, the role of MVR can justifiably be indicated for severe IMR. As for moderate IMR, CABG alone without mitral valve intervention may provide similar clinical outcomes. PMID- 29997947 TI - The effect of delayed adjuvant chemotherapy on relapse of triple-negative breast cancer. AB - Background: For triple negative breast cancer (TNBC), the optimal time from surgery to initiation of adjuvant chemotherapy is controversial. We investigated the influence of time to adjuvant chemotherapy on outcome in TNBC patients. Methods: Female patients with stage I-IIIa operable TNBC between 2006 and 2008 in our institutions were included. A total of 331 patients were divided into 3 groups according to the time to adjuvant chemotherapy: <=30, 31-60, and >60 days. Relapse free survival (RFS) were calculated and compared. Results: Prolonged delay of initiation of adjuvant chemotherapy (<=30 versus >60 days) significantly decreased the RFS in our TNBC cohort [adjusted hazard ratio (HR) of 2.39; 95% confidence interval (CI), 1.13-5.07, P=0.02]. While a moderate delay (<=30 versus 31-60 days) did not significantly influence RFS in all TNBC patients, it did compromise survival in lymph node positive patients (P=0.04). Conclusions: Longer delay of adjuvant chemotherapy was associated with worse survival in TNBC patients. Early initiation of adjuvant chemotherapy should be considered, especially for relatively high risk node positive TNBCs. PMID- 29997946 TI - Prophylactic continuous positive airway pressure after pulmonary lobectomy: a randomized controlled trial. AB - Background: Despite advances in perioperative care and surgical techniques, patients undergoing pulmonary lobectomy are still at high risk for postoperative complications. Among interventions expected to reduce complications, continuous positive airway pressure (CPAP) is a discussed option. This trial aims to test the hypothesis whether prophylactic application of CPAP following pulmonary lobectomy can reduce postoperative complications. Methods: The study was designed as a prospective, randomized, controlled trial. Patients with clinical stage I non-small cell lung cancer scheduled for pulmonary lobectomy were eligible and were trained for the use of CPAP interface. The control group received standard postoperative pain management and physiotherapy; in addition, the study group received CPAP (PEEP 8-12 cmH2O, 2 hours thrice daily for three days). Results: After the appropriate selection, 163 patients were considered for the analysis: 82 patients constituted the control group, 81 the study group. The two groups were substantially comparable for preoperative parameters. The rate of postoperative complications was lower in the study group (24.7% vs. 43.9%; P=0.015) as well as the hospital stay (6 vs. 7 days; P=0.031). The stepwise logistic regression model identified: CPAP [odd ratio (OR): 0.3026, CI: 0.1389 0.6591], smoke habits [OR: 2.5835, confidence interval (CI): 1.0331-6.4610] and length of surgery in minutes (OR: 1.0102, CI: 1.0042-1.0163) as regressors on postoperative complications. Conclusions: The present trial demonstrated that prophylactic application of CPAP during the postoperative period after pulmonary lobectomy for stage I non-small cell lung cancer was effective in prevent postoperative complications. PMID- 29997948 TI - Myasthenia gravis as a prognostic marker in patients with thymoma. AB - Background: Thymoma is the most common mediastinal tumor, representing <1% of all cancers. It is usually associated with paraneoplastic disorders, mainly myasthenia gravis (MG). The aim of the present study was to describe patients with thymoma and the differences between those with MG and those without it. Methods: A retrospective 10-year database of the patients with thymoma treated at a single cancer referral hospital (National Institute of Cancer, Mexico City), was analyzed. Results: Sixty-four files from patients with thymoma were analyzed, 18 of them had MG. The symptoms that occurred most frequently in patients with MG were ptosis, diplopia, appendicular weakness, dysphonia and dysphagia. The most frequent Myasthenia Gravis Foundation of America (MGFA) stage was IIIb followed by stage I. Almost all the patients with MG had positive Acetylcholine Receptor antibodies (P<0.001), with not specified antibodies in four patients. The median overall survival showed a trend to be higher among the patients with MG, but there were no significant differences. Conclusions: In patients with thymoma MG manifests with different clinical and autoimmune traits, but not survival differences. A larger multi-centric study should be encouraged to evaluate the prognostic implications of having MG in patients with thymoma. PMID- 29997949 TI - Management of lung nodules in Brazil-assessment of realities, beliefs and attitudes: a study by the Brazilian Society of Thoracic Surgery (SBCT), the Brazilian Thoracic Society (SBPT) and the Brazilian College of Radiology (CBR). AB - Background: Pulmonary nodules are common; some are inconsequential while others are malignant. Management of solitary pulmonary nodule (SPN) in Brazil appears to be highly variable, potentially leading to suboptimal outcomes. Assessment of the variability and the association with the degree of availability of resources can provide a foundation for development of clinical guidelines for management of SPN specific for the Brazilian setting. Methods: A web-based survey was developed by thoracic surgeons, pulmonologists and radiologists to evaluate SPN perception and management. This survey was sent to their respective national societies members and answers collected between August and December 2016. That included multiple choice questions regarding age, specialty, SPN management, accessibility to exams and interventional procedures characterizing public (SUS) and supplementary private working settings. Results: A total of 461 questionnaires were answered. More than half of participants live in cities with over one million people. Specialties were reasonable equilibrated with 43.5% radiologists, 33.5% thoracic surgeons, 20.3% pulmonologists and 2.6% others. Most of the respondents work in both public and private sector (72.7%). Private has a similar reality compared to well-developed nations regarding exams accessibility and interventions. SUS setting has a significant variability access according to the participants. CT is only easily available in 31.9% of cases, PET-CT is easily available in 24.4%, bronchoscopy is easily available for 42.8%, transthoracic needle biopsy is only easily available in 13.9% and video-assisted thoracoscopic surgery (VATS) biopsy is not available in 19.5%. When there is a probability of malignancy of 50% or higher, 46.5% of participants would be comfortable recommending surgical biopsy. When the probability is higher than 10%, only 36.9% would be comfortable following up radiologically. Conclusions: Brazil has a very different setting for public and private patients regarding exams accessibility and management options. That might explain why participants have a higher tendency to choose interventional diagnosis and explains why current guidelines may not be applicable to developing countries reality. PMID- 29997950 TI - Can lobe-specific lymph node dissection be an alternative to systematic lymph node dissection in treating early-stage non-small cell lung cancer: a comprehensive systematic review and meta-analysis? AB - Background: Whether lobe-specific lymph node dissection (L-SLND) could serve as an alternative to systematic lymph node dissection (SLND) in treating early-stage non-small cell lung cancer (NSCLC) remains unclear. Therefore, we conducted this comprehensive meta-analysis to compare the effect of L-SLND with that of SLND in treating early-stage NSCLC. Methods: A systematic literature search in PubMed and Embase was conducted to identify relevant studies up to 30 November 2017. Data including 5-year overall survival (OS) and disease-free survival (DFS) rates, recurrence rates, and morbidity rate were extracted and analysed. Results: A total of six studies [one randomized controlled trial (RCT) and five retrospective cohort studies] consisting of 2,037 patients with early-stage NSCLC were included for analysis. Meta-analysis showed that there was no significant difference of 5-year OS [81.7% and 79.5%, respectively; risk ratio (RR) =1.021; 95% confidence interval (CI), 0.977-1.068; P=0.352] and DFS (76.4% and 69.9%, respectively; RR =1.061; 95% CI, 0.999-1.128; P=0.054) between patients treated with L-SLND and those with SLND. Moreover, there was also no significant difference of total recurrence rates (24.3% and 25.8%, respectively; RR =0.892; 95% CI, 0.759-1.048; P=0.166) and loco-regional recurrence rates (7.9% and 9.3%, respectively; RR =0.851; 95% CI, 0.623-1.162; P=0.310) between patients treated with L-SLND and those with SLND. However, patients treated with L-SLND yielded a significant lower morbidity rate than those treated with SLND (10.2% and 13.5%, respectively; RR =0.681; 95% CI, =0.521-0.888; P=0.005). Conclusions: L-SLND yielded a significantly lower risk of morbidity compared to SLND without compromising long-term oncologic outcomes based on available studies with relatively poor quality. L-SLND may serve as an alternative to SLND in treating early-stage NSCLC. Further well-conducted RCTs, however, are badly needed to confirm and update our conclusions. PMID- 29997951 TI - Systemic blood pressure trends and antihypertensive utilization following continuous-flow left ventricular assist device implantation: an analysis of the interagency registry for mechanically assisted circulatory support. AB - Background: Elevated systemic blood pressure (SBP) has been linked to complications in Continuous-flow left ventricular assist devices (CF-LVADs), including stroke and pump thrombosis. We queried Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to describe the response of SBP to CF-LVAD implantation and to delineate contemporary trends in antihypertensive (AH) utilization for patients with these pumps. Methods: We identified all CF-LVAD implantations in patients older than 18 years from 2006 2014, excluding those whose durations were less than 30 days. Pre-implant patient demographics and characteristics were obtained for each record. SBPs [i.e., mean arterial pressures (MAPs)], AH-use data, and vital status were tabulated, extending up to 5 years following implantation. Results: A total of 10,329 CF LVAD implantations were included for study. Post-implant, SBPs increased rapidly during the first 3 months but plateaued thereafter; AH utilization mirrored this trend. By 6 months, mean MAPs climbed 12.2% from 77.6 mmHg (95% CI: 77.4-77.8) pre-implantation to 87.1 mmHg (95% CI: 86.7-87.4) and patients required a mean of 1.8 AH medications (95% CI: 1.75-1.78) -a 125% increase from AH use at 1-week post-implantation (0.8 AHs/patient, 95% CI: 0.81-0.83) but a 5.3% decrease from pre-implant utilization (1.9 AHs/patient, 95% CI: 1.90-1.92). Once medication changes stabilized, the most common AH regimens were lone beta blockade (15%, n=720) and a beta blocker plus an ACE inhibitor (14%, n=672). Conclusions: SBP rises rapidly after CF-LVAD implantation, stabilizing after 3 months, and is matched by concomitant changes in AH utilization; this AH use has increased over consecutive implant years. PMID- 29997952 TI - Robotic-assisted mediastinal surgery: the first Chinese series of 167 consecutive cases. AB - Background: To report the first and largest series of robotic-assisted mediastinal surgeries performed in a single center by the same surgical team in mainland China. Methods: From May 2009 to June 2017, 167 patients (100 males, 67 females), with a mean age of 50.2 years (range, 12-78 years), underwent robotic surgery for the treatment of a mediastinal mass. Data regarding the operation time, docking time, blood loss, conversion rate, morbidity, mortality and survival follow-up were collected and analyzed. Results: The mean operation time and docking time were 70.01+/-29.49 and 10.12+/-2.77 min. There were 56 thymomas, 52 cysts, 17 schwannomas, 9 bronchogenic cysts, 6 thymic hyperplasias, 6 foregut cysts, 4 squamous carcinomas and 17 others. The mean drainage on the first day after operation was 122.83+/-107.58 mL, and the mean post-operative drainage duration and post-operative hospital stay were 2.95 days, ranging from 1-7 days, and 4.09 days, ranging from 2-10 days, respectively. The post-operative complication rate was 3%, and the conversion rate was 1.8%. No perioperative mortality occurred. One patient died due to tumor recurrence. Conclusions: Our experience indicates that this robotic surgical system is a safe and established technique for mediastinal mass resection. PMID- 29997953 TI - Comparison of clinical manifestations and treatment outcome according to age groups in adult patients with miliary tuberculosis. AB - Background: After the introduction of chemotherapy, miliary tuberculosis (TB) has been more prevalent in adults than in children. However, adult patients have a wide age range and may have different characteristics across the age span. Thus, clinical manifestations and treatment outcome may differ according to age groups in adult patients with miliary TB. However, there is limited information regarding this issue. Methods: Adult patients with miliary TB were retrospectively reviewed and were categorized into young (18-40 years), middle aged (41-64 years), and old adults (>=65 years). The clinical manifestations and treatment outcome were compared among the three adult groups. Results: Of 150 patients, 27, 35, and 88 patients composed the young, middle-aged, and old adult groups, respectively. Overall clinical manifestations were comparable among the three groups. Treatment completion was significantly lower and overall TB deaths were significantly higher in the old group than in the young group. However, deaths in the young and middle-aged groups were all TB-related deaths, whereas deaths in the old group were more attributable to TB-unrelated deaths rather than TB-related deaths. In multivariate analysis, underlying chronic condition, lower hemoglobin levels, and acute respiratory failure were independent predictors for TB-related deaths in the adult group <65 years, and lower albumin levels and acute respiratory failure were those in the adult group >=65 years. Conclusions: The present study suggests that treatment completion, the cause of death, and risk factors for TB-related deaths may be different according to age groups in adult patients with miliary TB. PMID- 29997954 TI - The painless combination of anatomically contoured titanium plates and porcine dermal collagen patch for chest wall reconstruction. AB - Background: A plethora of new biomaterials and dedicated rib fixator implant systems have been introduced into the field of chest wall reconstruction. The aim of our study is to evaluate the surgical outcomes of a novel combination of the anatomically contoured titanium rib implant and porcine dermal collagen patch for chest wall reconstruction. Methods: We performed a retrospective review of eight consecutive patients who underwent chest wall resection and reconstruction between January 2014 to August 2015 in a single institution. MatrixRib Fixation System and Permacol Surgical Implant were utilized to achieve chest wall reconstruction. Results: The indication for reconstruction was malignant infiltration in 50% of patients. Three other subjects (37.5%) had chest wall resections to achieve adequate and safe surgical exposure. One patient had a right lung apical mycetoma with chest wall invasion. All patients underwent lung resections with the removal of 2 to 6 (median 3) ribs. Reconstruction was performed using the MatrixRib system, with a median of 2.5 (range, 2-4) ribs fixed in each patient. There was no post-operative mortality. One patient had a superficial wound infection which resolved with one week of oral antibiotics. Upon discharge, the pain scores were near zero with minimal analgesic requirements. None of the patients required repeat surgery or removal of their implants. Conclusions: Our early experience indicates that the combination of the MatrixRib system and Permacol patch for chest wall reconstruction is safe and feasible with promising results in terms of anatomical restoration of the chest wall mechanics, infection and pain. PMID- 29997955 TI - Risk factors of neuropathic pain after thoracic surgery. AB - Background: This study aimed to clarify the incidence and risk factors of neuropathic pain after thoracic surgery, focusing especially on patients who underwent complete video-assisted thoracoscopic surgery (VATS). Methods: We retrospectively identified 185 patients who underwent thoracic surgery at our hospital over a 2-year period. Logistic regression analysis was used to analyze the association of various factors with postoperative neuropathic pain. Results: Forty-eight (25.9%) patients developed postoperative neuropathic pain, and 9 (18.8%) of these patients reported persistent pain 1 year postoperatively. The median interval from surgical treatment to the onset of neuropathic pain was 7 days, and the duration was 50 days. Multivariate logistic regression analysis revealed a significant positive correlation between postoperative neuropathic pain and preoperative use of hypnotic medication [odds ratio (OR), 5.45; 95% confidence interval (CI); 2.52-12.17] and duration of surgery >=2.5 hours (OR, 2.72; 95% CI, 1.27-6.09), and a significant negative association with the complete VATS approach (OR, 0.18; 95% CI, 0.073-0.42). Conclusions: Preoperative use of hypnotic medication, the thoracotomy approach, and duration of surgery >=2.5 hours are associated with increased risk of neuropathic pain after thoracic surgery. The complete VATS approach could decrease the incidence of postoperative neuropathic pain, regardless of the duration of surgery. PMID- 29997956 TI - A predictor for mitral valve repair in patient with rheumatic heart disease: the bending angle of anterior mitral leaflet. AB - Background: Mobility and flexibility of anterior mitral leaflet (AML) are considered to be the important factor for mitral valve (MV) repair in rheumatic population, we try to use the bending angle of AML to quantify its' mobility and flexibility and investigate whether it can predict the success of rheumatic MV repair or not. Methods: Total 54 patients underwent rheumatic MV surgeries with mild lesions of subvalvular apparatus from August, 2017 to November, 2017 at the author institution, we divided the patients into MV repair and MV replacement groups which included directly MV replacement and repair attempt but failed repairing transfer to replacement intraoperatively. Patients' MV structure was carefully evaluated on transthoracic echocardiography (TTE) and scored by the Wilkins score (WS) preoperatively. The bending angle of AML was measured during systole and diastole at different level before surgery. Results: The differences of patients' demographic characteristics between repair group and replacement group were not statistically significant (P value >0.05) and the differences among B-angle, T-angle, Bs-angle, C-angle of AML between repair group and replacement groups were not statistically significant (P value >0.05). Only BT angle in repair group was significantly larger than that of replacement group (21.56 degrees +/-3.84 degrees , 10.29 degrees +/-6.02 degrees , respectively, P<0.001), therefore the BT-angle was tested as a predictor of reparability by observing the receiver operating characteristic (ROC) curve (ROC area: 0.944, standard error: 0.06, 95% CI: 0.826-1), BT-angle of AML on preoperative transthoracic echo of 15.5 degrees or more predicts feasibility of rheumatic MV repair with 100% sensitivity and 85.7% specificity in patients with mild lesions of subvalvular apparatus. Logistic regression for a single area of calcification (diameter <0.8 cm) at commissure were shown that: beta: 0.08, Exp (beta): 1.083, P: 0.777>0.05, the minor single calcified area at commissure had no effect on reparability of rheumatic MV disease. The differences of total WS and each component score between repair group and replacement group were not statistically significant (P value >0.05). By observing the ROC curve for total WS (ROC area: 0.508), the WS cannot be a predictor for the rheumatic MV repair. Conclusions: The bending angle of AML which was considered as quantification of mobility and flexibility of AML can be a predictor for MV repair in patients with rheumatic heart disease (RHD). The small single area of commissural calcification had no effect on reparability of rheumatic MV disease. WS cannot appropriately predict the outcome of rheumatic MV repair. PMID- 29997957 TI - Lung function in the late postoperative phase and influencing factors in patients undergoing pulmonary lobectomy. AB - Background: Lung function in the late postoperative phase after pulmonary lobectomy is insufficiently characterized. This study aimed to appraise lung function in the late postoperative phase according to vital capacity (VC) and forced expiratory volume in 1 second (FEV1) in patients who underwent pulmonary lobectomy. Methods: Pre- and postoperative VC and FEV1 were reviewed in 112 patients who underwent pulmonary lobectomy. Postoperative lung volume was assessed >1 year after surgery. Postoperative decreases in VC and FEV1 were compared with preoperative predicted values among patients who underwent resection of specific lobe. Determinants effecting a decrease in lung function were also investigated. Results: A mean postoperative decreased VC of 10.5%+/ 1.8% was recorded in patients who underwent right upper lobectomy (RU), 7.2%+/ 1.5% for right middle lobectomy (RM), 14.3%+/-2.3% for right lower lobectomy (RL), 16.6%+/-3.0% for left upper lobectomy (LU), and 14.7%+/-2.5% for left lower lobectomy (LL). Corresponding FEV1 values were 14.8%+/-1.8% for RU, 11.9%+/-4.0% for RM, 14.9%+/-2.3% for RL, 17.9%+/-2.9% for LU, and 15.1%+/-2.4% for LL. The actual decreasing rate of VC was overestimated in patients who underwent RU, RL, LU, and LL. In contrast, FEV1 was overestimated only in patients who underwent RL and LL. Patients with chronic obstructive pulmonary disease (COPD) exhibited significantly better preservation of FEV1. Conclusions: Patients scheduled for RL and LL, or those with COPD, appeared to exhibit preserved lung function in the late postoperative phase after pulmonary lobectomy. PMID- 29997958 TI - Three-field versus two-field lymph node dissection for thoracic esophageal squamous cell carcinoma: a propensity score-matched comparison. AB - Background: For the surgery of esophageal cancer, cervical, mediastinal, and abdominal lymph node dissection (three-field lymph node dissection, 3FLND) is still controversial in most countries. This study aims to provide additional evidence of this procedure comparing with mediastinal-abdominal lymph node dissection (two-field lymph node dissection, 2FLND) from a high volume center in China, and also attempts to identify routes to reduce postoperative complications associated with 3FLND. Methods: From January 2009 to December 2013, 348 consecutive patients received esophagectomy with 3FLND and 1,406 patients received Ivor-Lewis with 2FLND in Fudan University Shanghai Cancer Center. After propensity-score matching, 282 pairs of cases without neoadjuvant treatment were selected. Postoperative outcomes and survival of the two groups were analyzed. Results: Operative morbidity and mortality rates were 34.8% and 0.4% for 3FLND group; and 25.5% and 0.7% for 2FLND group. Compared with the 2FLND group, the 3FLND group reported more cases of anastomotic leakage (14.9% vs. 4.3%, P<0.001). Multivariate analysis showed that an independent factor of anastomotic leakage was the anastomotic location [HR =0.096 (0.037-0.247), P<0.001] rather than the extent of lymph node dissection. The intrathoracic anastomosis subgroup of 3FLND showed a similar leakage rate as the 2FLND group (4.2% vs. 4.3%). At a median follow-up of 42 months, no significant difference was observed in overall survival between the groups (P=0.529). A subgroup of patients with N1 status who underwent 3FLND showed a better survival trend than those who underwent 2FLND (P=0.093). No significant difference was observed in overall survival between the intrathoracic anastomosis subgroup and cervical anastomosis subgroup (P=0.334). Conclusions: Intrathoracic anastomosis may reduce the incidence of anastomotic leakage in esophagectomy with 3FLND, with no compromise on overall survival. Compared with the 2FLND, patients with N1 status might benefit more from the 3FLND technique. PMID- 29997959 TI - Video-assisted thoracic surgery for tiny pulmonary nodules with real-time image guidance in the hybrid theatre: the initial experience. AB - Background: Localization of tiny lung nodules during video-assisted thoracic surgery (VATS) resection can be challenging. Real-time image-guided hookwire localization of the target lesions immediately followed by VATS lung resection in the hybrid operating theatre setting is an emerging approach. Methods: We retrospectively reviewed our experience with this form of hybrid operating theatre image-guided VATS (iVATS) for lung nodules 1.5 cm or less, or soft in consistency. These patients were compared with matched cohort who received standard hookwire localization in the radiology department. Results: From February 2014 to September 2017, lung nodules of indeterminate nature in 32 consecutive patients with mean size 9.1+/-4.6 mm underwent iVATS. All were accurately localized by hookwire and successfully resected. There was no postoperative mortality. There were 21 (66%) malignant lesions, all with adequate resection margins. Major outcomes were compared with a comparable cohort of 8 patients who received standard hookwire localization and VATS (sVATS) performed at separate departments operation suites. sVATS groups has significantly longer 'at-risk' period for pneumothorax progression and hookwire dislodgement (109.5+/ 57.1 minutes for sVATS vs. 41.1+/-15.0 minutes for iVATS, P=0.011), and a higher risk of hookwire dislodgement (25% for sVATS vs. 0 for iVATS, P=0.036). Conclusions: Real-time image-guided hookwire localization in the hybrid theatre setting is an effective facilitator of VATS resection of tiny lung nodules in selected patients, and may have added advantages in terms of safety and localization accuracy over the conventional sVATS method. PMID- 29997960 TI - Combined lipiodol marking and video-assisted thoracoscopic surgery in a hybrid operating room. AB - Background: The development of diagnostic technology has led to detection of an increasing number of small pulmonary nodules (SPNs), which can be difficult to locate intraoperatively. Here, we report our experience performing single-stage lipiodol localization and surgical resection in a hybrid operating room (OR). Methods: Between June 2016 and August 2017, 30 patients with 32 SPNs underwent sliding gantry-based multidetector computed tomography (MDCT)-guided lipiodol marking followed by video-assisted thoracoscopic surgery (VATS) in a hybrid OR. After induction of general anesthesia, all nodules were marked with 0.2 mL lipiodol under MDCT fluoroscopic guidance, followed by immediate VATS. Results: The mean SPN diameter and distance from the pleural surface were 10.7+/-4.5 mm (range, 5.0-21.0 mm) and 18.0+/-9.0 mm (range, 2.8-32.0 mm) respectively. The MDCT-guided localization procedure required 15.8+/-6.0 min (range, 8.0-32.0 min). All the nodules were marked with lipiodol and detected during fluoroscopy as a clear spot. The median deviation between the radio-opaque nodule and the target nodule was 7.8+/-3.6 mm (range, 3.0-20.0 mm). In two cases, MDCT scans performed after completion of marking revealed mild pneumothorax, which did not need further intervention. VATS resection was converted to thoracotomy in two patients because of strong pleural adhesions and intraoperative bleeding from the pulmonary vein. No other complications occurred during the combined approach, and there was no intra- or post-operative mortality or morbidity. Conclusions: These results suggest that a combined approach using MDCT-guided lipiodol marking followed by VATS is feasible and has acceptable accuracy in resection of SPNs. PMID- 29997961 TI - The correlation between crizotinib efficacy and molecular heterogeneity by next generation sequencing in non-small cell lung cancer. AB - Background: Non-small cell lung cancer (NSCLC) patients with EML4-ALK fusion exhibited various durations of response to crizotinib. Molecular heterogeneity is also one of the factors associated with resistance to crizotinib. This study investigated the relevance of molecular heterogeneity to the clinical efficacy of crizotinib using next-generation sequencing (NGS). Methods: A total of 52 ALK positive advanced NSCLC patients were enrolled. The genetic variation was revealed by NGS. We identified different ALK fusion types, allelic fraction (AF) and additional coexisting mutations (ACMs) and evaluated the correlation between the above three factors and clinical response to crizotinib. Results: Among the group that was detected with ALK+ fusion by immunohistochemistry (IHC), patients detected as ALK- fusion by the NGS method were associated with a shorter progression-free survival (PFS) compared with ALK+ patients by NGS. Moreover, for different ALK fusion types, the median PFS of variant 1/2/3 and other uncommon variants were 305, 557, 242 and 370 days, respectively. Although there was no statistically significant difference (P=0.201), patients with ALK variant 2 appeared to display a longer PFS than other types of variants in this study. There was no significant difference in the relationship between ALK fusion AF and PFS (P=0.639). Additionally, there was no correlation between ACMs and PFS in the three groups (IHC+, IHC+/NGS-, and IHC+/NGS+, P=0.738, 0.801 and 0.550). We analysed the relationship between TP53/FAT3 and PFS in the IHC+/NGS+ group, and there was no statistically significant difference (P=0.712/0.631). Conclusions: It is necessary to use multiple methods together to detect ALK fusion, and we can continue to carry out the study of the correlation between the different contents of heterogeneity of gene mutations and TKI effects using the NGS method. PMID- 29997962 TI - Percutaneous coronary intervention versus optimal medical therapy for patients with chronic total occlusion: a meta-analysis and systematic review. AB - Background: It was under debate whether chronic total occlusion (CTO) patients could benefit from percutaneous coronary intervention (PCI). We sought to compare clinical outcomes of PCI and optimal medical therapy (OMT) in these patients. Methods: PubMed, Embase and Cochrane Library were searched for studies enrolling patients with CTO who accepted PCI or OMT. The meta-analysis was performed by using a random-effect model. In addition, subgroup analyses were performed, including patients after propensity-matching and patients with CTO in infarct related artery (IRA), respectively. Results: We identified 5 studies enrolling 4,761 participants in this meta-analysis. In the main analysis, when compared with OMT, PCI was associated with significant improvement in all-cause death [risk ratio (RR) 0.41, 95% CI: 0.35-0.48], cardiac death (RR 0.44, 95% CI: 0.35 0.55) and major adverse cardiac events (MACE) (RR 0.64, 95% CI: 0.43-0.97). But there were no differences in myocardial infarction (MI) and stroke. The results of the propensity-matched subgroup were somewhat consistent with those of the main analysis (all-cause death: RR 0.57, 95% CI: 0.26-0.89; MI: RR 0.54, 95% CI: 0.32-0.77; and MACE: RR 0.76, 95% CI: 0.33-1.18). In IRA subgroup, PCI reduced risks of mortality (all-cause death: RR 0.41, 95% CI: 0.34-0.49; cardiac death: RR 0.44, 95% CI: 0.35-0.56) and MACE (RR 0.71, 95% CI: 0.46-1.10). But no difference was observed in MI. Conclusions: PCI was associated with improved survival and reduced MACE relative to OMT. PMID- 29997964 TI - A comparison between two types of indwelling pleural catheters for management of malignant pleural effusions. AB - Background: Malignant pleural effusion (MPE) is a common cause of quality of life deterioration in patients with advanced cancer. Management options include chemical pleurodesis with a sclerosing agent such as doxycycline or talc powder, surgery, and also the placement of tunneled indwelling pleural catheters (IPCs). Two different IPC types are mostly used in the USA. Methods: We conducted a single-center retrospective study with the objective to compare the efficacy and safety profiles of two IPC systems. Patients with a diagnosis of malignancy, who received IPCs by the interventional radiology department of our hospital from January 2013 to March 2015, were identified in the local database and a chart review was performed to record characteristics and outcomes. Patients without a diagnosis of malignancy or with pleural effusions of cardiac origin were excluded from the study. Results: We identified 27 patients with a median age of 59.0 years. Eighty patients received Aspira catheter while nine patients received PleurX catheter, and seven patients achieved spontaneous pleurodesis. The median length of stay (LOS) was 9 days for the Aspira group (AG), as compared to 13 days for the PleurX group (PG) (overall median LOS was 10 days; range, 2-62 days). The rate of catheter-related complications (pain, obstruction, loculations, infection, hemorrhage) was 39% (seven patients) for the AG and 33% (three patients) for the PG (overall ten patients, 37%). Conclusions: In our study, outcomes and safety were similar for patients receiving either type of IPC, Aspira or PleurX. PMID- 29997963 TI - Native T1 and T2 mapping by cardiovascular magnetic resonance imaging in pressure overloaded left and right heart diseases. AB - Background: Pulmonary arterial hypertension (PAH) and severe aortic valve stenosis (AS) are diseases characterized by increased afterload of the right and left heart, respectively. Our study aims to investigate the differences of myocardial tissue characteristics in the pressure overloaded left and right hearts, especially in the shared interventricular septum, as detected by native T1 and T2 relaxation times. Methods: Eighteen patients with PAH and 19 patients with severe AS in addition to 5 healthy volunteers underwent 1.5-T CMR examination with native T1 and T2 mapping. Mean T1 and T2 value were measured at the right ventricular (RV) free wall, superior RV insertion, inferior RV insertion, interventricular septum and left ventricular (LV) lateral wall. Results: Compared with controls and AS group, T1 was significantly elevated in the RV insertion in PAH group (P=0.015), while no statistically significant differences were seen in other segments among the three groups. There was an increase of T2 in the RV insertion in AS and PAH groups (P=0.01). Significant T2 elevation was also observed in the RV free wall of PAH group, and the LV lateral wall of AS group compared with the control group. RV insertion T2 was significantly correlated with RV end-diastolic volume index (r=0.608, P=0.016) and RV mass index (r=0.57, P=0.026) in the PAH group. LV lateral wall T2 and RV insertion T2 were significantly correlated with aortic valve mean gradients in the AS group (r=0.56, P=0.02; r=0.58, P=0.01, respectively). Conclusions: In pressure overload diseases, both T1 and T2 values increase in the myocardium. The alterations seen in the RV insertion sites in the septum was more pronounced with RV pressure overload. T2 values also correlated with structural and functional remodeling in both diseases. Combining T1 and T2 mapping may help to better characterize the alternation of myocardial composition in pressure overloaded heart diseases. PMID- 29997965 TI - Inter-relationship among myasthenia gravis, WHO histology, and Masaoka clinical stage and effect on surgical methods in patients with thymoma: a retrospective cohort study. AB - Background: The aim of study is to analyze the inter-relationship among WHO histology, myasthenia gravis (MG) and Masaoka stage and to assess the feasibility of thoracoscopic surgery in thymoma patients. Methods: Data from 142 consecutive thymoma patients from January 2009 to March 2016 were retrospectively reviewed in our institution. Histological classification and clinical staging were assessed by WHO histology criteria and Masaoka stage. We investigated the clinical characteristics, inter-relationship among WHO histology, MG and Masaoka stage, and compared the feasibility and safety of thoracoscopic thymectomy by comparison of open thymectomy. Results: Among 142 patients, the incidence of MG was 29.6%. Compared with A and AB-type thymomas, a higher prevalence of advance clinical stage was in B1 to C-type thymomas (37/63 vs. 9/43, P<0.001), and there was an increased trend of Masaoka stage from A to C-type thymomas (P<0.001). The incidence of MG was significantly higher in AB, B1 and B2-type thymomas than other type thymomas (23/63 vs. 6/44, P=0.009) and in early Masaoka clinical stage than advanced Masaoka clinical stage (29/80 vs. 12/59, P=0.042). Thoracoscopic surgery could significantly decrease blood loss in patients with (104.06+/-137.36 vs. 350.91+/-560.79 mL, P=0.001) or without MG (91.90+/-77.70 vs. 266.32+/-292.60 mL, P=0.02), with comparable complications. Additionally, thoracoscopic surgery could achieve an equal effect on the remission of MG with open surgery (7/11 vs. 10/14, P=1.000), and Masaoka stage was significantly associated with the remission of MG after thymectomy. Conclusions: Our study suggests that WHO histology, MG, and Masaoka stage interrelate with one another, and Masaoka stage is an important prognostic factor in remission of MG after thymectomy in thymoma patients. Thoracoscopic thymectomy could achieve an equal efficacy to open thymectomy and should be recommended as a routine surgery for patients with early Masaoka stage. PMID- 29997966 TI - TP53 mutations predict for poor survival in ALK rearrangement lung adenocarcinoma patients treated with crizotinib. AB - Background: Advanced non-small cell lung cancer (NSCLC) patients who harbor anaplastic lymphoma kinase (ALK) rearrangement are sensitive to an ALK inhibitor (crizotinib), but not all ALK-positive patients benefit equally from crizotinib treatment. We analyze the impact of TP53 mutations on response to crizotinib in patients with ALK rearrangement NSCLC. Methods: Sixty-six ALK rearrangement NSCLC patients receiving crizotinib were analyzed. 21 cases were detected successfully by the next generation sequencing validation FFPE before crizotinib. TP53 mutations were evaluated in 8 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: TP53 mutations were observed in 2 (25.00%), 1 (12.50%), 1 (12.50%) and 4 (50.00%) patients in exons 5, 6, 7 and 8, respectively. The majority of patients were male (75.00%, 6/8), less than 65 years old (62.50%, 5/8) and never smokers (75.00%, 6/8). ORR and DCR for crizotinib in the entire case series were 61.90% and 71.43%, respectively. Statistically significant difference was observed in terms of PFS and OS between TP53 gene wild group and mutation group patients (P=0.038, P=0.021, respectively). Conclusions: TP53 mutations reduce responsiveness to crizotinib and worsen prognosis in ALK rearrangement NSCLC patients. PMID- 29997967 TI - Pleural catheters after thoracoscopic treatment of malignant pleural effusion: a randomized comparative study on quality of life. AB - Background: Malignant pleural effusion (MPE) complicates many neoplasms and its incidence is expected to rise in parallel with the aging population and longer survival of cancer patients. Although a clear consensus exists on indwelling catheters in patients with poor performance status, no study has hitherto compared different devices in patients requiring temporary or definitive drainage following talc poudrage. Methods: This is a prospective, two-arm, pilot study on patients with MPE undergoing talc poudrage, comparing two different catheters (PleurX(r) versus Pleurocath(r)) positioned because of the inefficacy of the procedure or the high risk of short-term failure. End points of the study were quality of life (QoL), median dyspnea and chest pain assessment by EORTC questionnaires and a 100 mm visual analog scale, total in-hospital length of stay and frequency of serious adverse events. Results: No difference was observed between the two groups in in mean dyspnea and mean chest pain in any questions of the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Duration of the procedure was significantly longer in the PleurX(r) group versus the Pleurocath(r) group (72+/ 33 versus 44+/-13 minutes; P=0.03). No difference was observed between the two groups in total length of hospital stay (P=1.00) or complication rate (P=1.00). Conclusions: For the cohort of patients still needing indwelling pleural catheters (PC) after thoracoscopic talc poudrage, PleurX(r) is suggested when drain removal is unlikely due to short life expectancy or the high chance of pleurodesis failure. Conversely, Pleurocath(r) should be recommended in all other patients as it is faster to place and easier to remove. Keywords: Malignant pleural effusion (MPE); talc poudrage; indwelling pleural catheter (indwelling PC). PMID- 29997968 TI - Prognostic prediction of clinical stage IA lung cancer presenting as a pure solid nodule. AB - Background: Clinical stage IA lung cancer presenting as a ground glass opacity (GGO) on imaging is known to be associated with a good prognosis. Conversely, the prognosis of lung cancer presenting as a pure solid nodule is less favorable. The purpose of this study was to identify the predictive factors affecting prognosis in pure solid nodule lung cancer. Methods: A total of 328 consecutive patients undergoing curative resection of clinical stage IA pure solid nodule lung cancer were reviewed retrospectively. Recurrence, survival and risk factors for nodal upstaging were analyzed. Results: Of the 328 patients, 277 patients (84.6%) underwent lobectomy (or greater) and 51 patients (15.6%) underwent sublobar resection. Mediastinal lymph node dissection or sampling was performed in 278 patients (84.8%). The 5-year recurrence-free survival rate was 70.0% and the disease-specific survival rate was 86.5%. Intraoperative mediastinal lymph node dissection was the only significant related factor for recurrence and cancer related death in a multivariate analysis [hazard ratio (HR) =0.485, P=0.020; HR =0.342, P=0.014]. A total of 217 patients underwent lobectomy with mediastinal lymph node dissection and nodal upstaging occurred in 36 patients (16.6%). There were no significant predictive factors for nodal upstaging in a multivariate analysis. Visceral pleural invasion, lymphovascular invasion, and small cell carcinoma histology were the only identified risk factors for nodal upstaging (HR =3.858, P=0.006; HR =8.792, P<0.001; HR =45.908, P=0.017). Conclusions: There were no definite factors predictive of prognosis in clinical stage IA pure solid nodule lung cancer. Only accurate pathologic staging and adequate intraoperative lymph node dissection were shown to be related to prognosis. PMID- 29997969 TI - New dynamic viewing of mast cells in pulmonary arterial hypertension (PAH): contributors or outsiders to cardiovascular remodeling. AB - Background: In patients with pulmonary arterial hypertension (PAH), mast cells (MCs) are extensively observed around pulmonary vessels. However, their temporal and spatial variation during PAH development remains obscure. This study investigated the dynamic evolution of MCs in lungs and right ventricles (RV) to illuminate their role in pulmonary vascular and RV remodeling. Methods: The PAH model was established by a single intra-peritoneal injection of monocrotaline (MCT, 60 mg/kg) in rats. On day 0, 3, 7, 14, and 28 after MCT injection, lung and RV tissues were harvested for staining with hematoxylin and eosin (HE), Gomori aldehyde fuchsin (GAF), toluidine blue (TB) and picrosirius red (PSR). Immunohistochemistry was performed to evaluate the levels of alpha-SMA, CD68 and tryptase. A simple RV remolding model was produced as well by pulmonary artery banding (PAB). RV tissues were collected to determine the degree of MCs infiltration. Results: After MCT challenge, elevated mean pulmonary arterial pressure (mPAP), increased RV systolic pressure (RVSP), pulmonary arterial media hypertrophy as well as distal vascular muscularization gradually occurred with time. MCs recruitment along with CD68+ macrophages accumulation was observed around distal pulmonary vessels and in alveolar septa. Excessive infiltration and degranulation of MCs were detected in MCT-treated group in lung tissues but not in RV. In addition, no exacerbation of MCs infiltration and degranulation in RV was noted in PAB-treated rats, suggesting few contributions of MCs to RV remodeling. Conclusions: Our findings implied a crucial role of MCs in the remodeling of pulmonary vessels, not RV, which probably through releasing cytokines such as tryptase. The present study enriches the knowledge about PAH, providing a potential profile of MCs as a switch for the treatment of PAH. PMID- 29997970 TI - Mechanical interventricular dependency supports hemodynamics in tako-tsubo cardiomyopathy. AB - Background: Although morphological abnormalities of the heart appear to be remarkable, most patients with tako-tsubo cardiomyopathy (TTC) remain clinically stable. We investigate real time changes in the left ventricular (LV) and right ventricular (RV) mechanics and function to explore the mechanism to preserve hemodynamics. Methods: With deformation and Doppler echocardiography, we evaluated myocardial mechanics and ventricular function/hemodynamics simultaneously in 103 consecutive TTC patients admitted from 01/01/2008 through 12/31/2015. The coronary angiography and left ventriculography were performed to rule out culprit coronary artery stenosis (CAS). We included 66 patients in a control group with matched age, sex, and risk factors for coronary artery disease (CAD), and 41 patients in a group of myocardial infarction induced cardiogenic shock, who required circulatory supporting devices to maintain hemodynamic stability. Results: Although systolic myocardial strain in most of the LV segments was significantly impaired, 4 basal LV segments remained functionally active during acute stage of TTC. The impairment in the myocardial strain of the RV apex could extend to the middle segments, but basal RV systolic strain was also preserved. Despites comparable apical to basal strain gradients, LV and RV displayed discrepant functional/hemodynamic status. In contrast to LV, RV functional/hemodynamic parameters appeared to be hyper-dynamic. This unique RV strain pattern remained unchanged in patients with atypical (mid-LV cavity) TTC. In 41 patients with myocardial infarction induced cardiogenic shock, RV exhibited comparable mechanic and functional features with those in TTC patients. Conclusions: The identified LV and RV mechanic changes appear to support interventricular hemodynamic dependence during TTC, which may represent a universal rescue mechanism in a jeopardized or injured heart. PMID- 29997972 TI - Medical thoracoscopy removal of a self-expandable metallic stent migration into pleural cavity. AB - Pleuroscopy, also known as medical thoracoscopy (MT), is an important tool for pleural disease management. Removal of foreign body (FB) by MT was reported in a few reports because it can identify the position of a FB in the pleural cavity and can be used for its urgent removal. In this study, we describe the case of a male patient with a ruptured lung abscess and a rare complication of self expandable metallic stent (SEMS) migration into the pleural cavity via a bronchopleural fistula after the management of obstructive airway disease. An experienced pulmonologist successfully removed the SEMS from the pleural cavity using semi-rigid pleuroscopy under local anesthesia and conscious sedation in a bronchoscopy suite. PMID- 29997973 TI - Extended right upper sleeve lobectomy with double-barrel segmental bronchoplasty. PMID- 29997971 TI - The Society for Translational Medicine: the assessment and prevention of venous thromboembolism after lung cancer surgery. PMID- 29997974 TI - Intraoperative descending aortic dissection during aortic root replacement: successful management. PMID- 29997975 TI - Application of the Montgomery T-tube in subglottic tracheal benign stenosis. PMID- 29997976 TI - An alternative chest tube placement after uniportal video-assisted thoracic surgery. PMID- 29997977 TI - Mechanism of death: there's more to it than sudden cardiac arrest. PMID- 29997978 TI - Relationship between free and total malondialdehyde, a well-established marker of oxidative stress, in various types of human biospecimens. AB - Background: Oxidative stress is involved in thoracic diseases and health responses to air pollution. Malondialdehyde (MDA) is a well-established marker of oxidative stress, but it may be present in unconjugated and conjugated forms. To our knowledge, no studies have conducted a systemic evaluation of both free MDA (unconjugated MDA) and total MDA (the sum of both unconjugated and conjugated MDA) across various types of human biospecimens. Methods: Free MDA and total MDA were simultaneously measured in a range of human biospecimens, including nasal fluid (N=158), saliva (N=158), exhaled breath condensate (N=40), serum (N=232), and urine (N=429). All samples were analyzed using an HPLC-fluorescence method with high sensitivity and specificity. Due to the right skewed distribution of free MDA and total MDA, we performed natural-log transformation before subsequent statistical analyses. The relationship between the natural log of free and total MDA was evaluated by R2 of simple linear regression. T test was used for comparisons of means between two groups. One-way analysis of variance was used in combination with Tukey's test to compare the natural log of the ratio of free MDA to total MDA across various types of biospecimens. Results: For exhaled breath condensate, serum, urine, nasal fluid and saliva samples, the R2 between free and total MDA were 0.61, 0.22, 0.59, 0.47 and 0.06, respectively; the medians of the free MDA to total MDA ratio were 48.1%, 17.4%, 9.8%, 5.1% and 3.0%, respectively; the free MDA to total MDA ratio in EBC > serum > urine > nasal fluid > saliva (P<0.001 for pairwise comparisons). Conclusions: For exhaled breath condensate and urine samples, using either free or total MDA can provide information regarding the level of oxidative stress; however, that is not the case for serum, nasal fluid, and saliva given the low correlations between free and total MDA. PMID- 29997979 TI - An unusual foreign body aspiration requiring an unusual retrieval technique. AB - Foreign body aspiration during medical procedures has been reported in the literature. These iatrogenic incidents could be related to instruments malfunction or to accidental occurrences during medical treatment. In this paper, we present a report of a woman coming for a laparoscopic abdominal hysterectomy who developed intraoperative bronchospasm. In an attempt to administer aerosolized albuterol, the resident anesthesia provider fractured the Luer-lock tip of the 60-cc syringe, which he was using to hold the albuterol nebulizer. The plastic tip was dislodged into the endotracheal tube (ETT). On further inspection with a fiberoptic instrument the plastic tip was located loosely adherent to the distal part of the ETT and was held in place by the moisture, which had precipitated in the distal tube. An intraoperative consult with interventional pulmonary medicine was obtained after unsuccessfully attempting to retrieve the foreign body with a grasper. The syringe tip was then removed using a Fogarty balloon catheter that was threaded through the hole of the plastic tip. PMID- 29997980 TI - Management of drug-resistant tuberculosis in special sub-populations including those with HIV co-infection, pregnancy, diabetes, organ-specific dysfunction, and in the critically ill. AB - Tuberculosis remains a major problem globally, and is the leading cause of death from an infectious agent. Drug-resistant tuberculosis threatens to marginalise the substantial gains that have recently been made in the fight against tuberculosis. Drug-resistant TB has significant associated morbidity and a high mortality, with only half of all multidrug-resistant TB patients achieving a successful treatment outcome. Patients with drug-resistant TB in resource-poor settings are now gaining access to newer and repurposed anti-tuberculosis drugs such as bedaquiline, delamanid and linezolid. However, with ever increasing rates of co-morbidity, there is little guidance on how to manage complex patients with drug-resistant TB. We address that knowledge gap, and outline principles underpinning the management of drug-resistant TB in special situations including HIV co-infection, pregnancy, renal disease, liver disease, diabetes, and in the critically ill. PMID- 29997982 TI - Malignancies after lung transplantation. AB - Lung transplantation has become an efficient life-saving treatment for patients with end stage respiratory disease. The increasing good outcome following lung transplantation may be explained by growing experience of transplant teams and availability of potent immunosuppressive drugs. Nevertheless, the latter carries an inherent risk for malignancy besides other common side effects such as systemic hypertension, diabetes and renal dysfunction. Malignancies occur in a smaller proportion of patients but explain for a large proportion of deaths following transplantation. From the first year post-transplantation they will represent the third cause of death with an increasing incidence along post lung transplant survival. In this chapter, we will browse the different types of malignancies arising following lung transplantation. According to the different techniques for lung transplantation, specific types of bronchogenic carcinoma will be described in the explanted lung, in the native lung, and in the graft. Risk factors associated to immunosuppressive therapy, but also to occupational and environmental factors, especially smoking, will be discussed. Eventually, we will strive at integrating recommendations for the treatment of malignancies following lung transplantation. PMID- 29997981 TI - miRNAs as biomarkers and for the early detection of non-small cell lung cancer (NSCLC). AB - Lung cancer is the most frequently diagnosed cancer and the most common cause of cancer death globally, of which 85% is non-small cell lung cancer (NSCLC). Early detection of NSCLC is essential to identify potential individuals for radical cure. Although low-dose computed tomography (LDCT) is recommended as standard screening with a mortality reduction of 20%, it displays a high false positive rate that poses an issue of overdiagnosis. MicroRNAs (miRNAs) are a group of small non-coding RNAs acting as important regulators in post-transcriptional gene expression and have been studied for their extensive role as novel biomarkers in NSCLC. Herein, we discuss the miRNA biology, its role in cancer, the potential of biomarkers both in cancer and NSCLC, and promising current publications of diagnostic biomarkers for early detection in NSCLC, especially studies in order to complement LDCT screening. PMID- 29997984 TI - Is "lung repair centre" a possible answer to organ shortage?-transplantation of left and right lung at two different centres after ex vivo lung perfusion evaluation and repair: case report. AB - Ex vivo lung perfusion (EVLP) has become a reality as a technique to evaluate and recondition lungs from marginal donors. We report the first case on the use of EVLP followed by separate transplantation in two different centres. The local organ procurement organization proposed the lungs of a 53-year-old non-smoker donor who died for cerebral haemorrhage. P/F ratio was 294 after lung recruitment manoeuvres. Oto score was 10. Two centres accepted the grafts for two single transplantations under the condition of EVLP evaluation. After usual retrieval, the bi-pulmonary block was transferred to Centre 1 and EVLP was run as previously described. At the end of the procedure the two lungs were evaluated separately and both judged suitable for transplantation. After cooling and storage on ice, the block was separated on the back table. The left lung was transplanted in a patient with pulmonary fibrosis at Centre 1; surgery was complicated by cardiac arrhythmias that required several defibrillations. The right lung was transferred on ice to Centre 2, 250 km away from Centre 1, and transplanted in a patient with idiopathic pulmonary fibrosis. Thirty months after transplantations Patient 1 and Patient 2 are both alive, in good clinical conditions. This is the first report of the separate use of lungs after EVLP for non-urgent recipients in two different centres. This experience opens the door to a new allocation model with great potentials on organ shortage. Actually, we demonstrated that the perspective of a 'lung repair centre' is feasible and effective. PMID- 29997985 TI - Case study-based time-course analysis of symptoms of respiratory syncytial virus infections followed by acute sinusitis in otherwise-healthy adults. AB - Reports on respiratory syncytial virus (RSV) infections are abundant in pediatric and geriatric populations but not many in healthy adults, and particularly, those which demonstrated the illness throughout its time course are rare. We report two otherwise-healthy adult cases, showing a number of evidence essential for confirmation of exclusive infections with RSV, and document their clinical features from the onset of the disease to recovery, including secondary sinusitis with magnetic resonance (MR) and computed tomography (CT) images. The infection was proven by isolating RSV belonging to subgroup B and by observing elevated anti-RSV antibody titer in the paired sera. Possible contribution of other pathogens including almost all respiratory viruses and representative bacteria, was excluded by negative results in multiplex PCR examination. In the first case, illness initiated with pharyngeal pain, followed by symptoms of sneezing, severe rhinorrhea and coughing, which peaked at approximately 5-7 days and persisted for 12 days. The patient experienced a slight chill, but the body temperature did not exceed 37 degrees C during illness. The patient showed no significant finding but only a slight increase in serum C-reactive protein level in the routine clinical laboratory examinations. On the 9th day of illness, a dull headache started persisting for at least a week after which it gradually waned. Sinusitis was found by chance on MR images of maxillary sinus 8 days after the headache started, and the finding disappeared on CT images taken after 6 months. In the second case, the symptoms included severe rhinorrhea and dull facial pain around the upper nose; the pain also occurred on the 9th day of illness and the symptom was clinically diagnosed to be acute sinusitis during a visit to a physician. PMID- 29997986 TI - Surgical removal of an intrapulmonary aberrant needle: report of a case. PMID- 29997987 TI - Ochronosis of the aortic valve. AB - Ochronosis is the bluish-black discolouration of connective tissue, including heart valves, joints, kidney and the skin. It is due to the deposition of homogentisic acid (HGA) commonly found in alkaptonuria. Ochronosis in the aortic valve is a rare occurrence and there is limited data available on the most appropriate choice of valve prosthesis in these patients. This case involves a 72 year-old male with symptomatic aortic stenosis and on echocardiogram a severe calcific trileaflet aortic stenosis with normal ejection fraction. Intraoperative aortic cannulation was routine and uncomplicated, and bluish-black discolouration of aortic valve was noted. Thorough decalcification was undertaken and a bioprosthetic valve was chosen in accordance with patient's age and preference. There were no complications post-operatively and the patient reported being well. Ochronosis affecting the aortic valve is a rare condition and there is limited data on the recurrence rate as well as the natural history of the disease. This case reports aims to provide data to facilitate further research to better understand the natural history of aortic valve ochronosis and rates of recurrence following bioprosthetic aortic valve replacement (AVR). PMID- 29997988 TI - Acute attack of recurrent esophageal duplication cyst in an adult: case report and literature review. PMID- 29997983 TI - New frontiers in immunosuppression. AB - Immunosuppressive therapy is arguably the most important component of medical care after lung transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term allograft function. However, the benefits of immunosuppressive therapy must be balanced against the side effects and major toxicities of these medications. Immunosuppressive agents can be classified as induction agents, maintenance therapies, treatments for acute rejection and chronic rejection and antibody directed therapies. Although induction therapy remains an area of controversy in lung transplantation, it is still used in the majority of transplant centers. On the other hand, maintenance immunosuppression is less contentious; but, unfortunately, since the creation of three-drug combination therapy, including a glucocorticoid, calcineurin inhibitor and anti-metabolite, there have been relatively modest improvements in chronic maintenance immunosuppressive regimens. The presence of HLA antibodies in transplant candidates and development of de novo antibodies after transplantation remain a major therapeutic challenge before and after lung transplantation. In this chapter we review the medications used for induction and maintenance immunosuppression along with their efficacy and side effect profiles. We also review strategies and evidence for HLA desensitization prior to lung transplantation and management of de novo antibody formation after transplant. Finally, we review immune tolerance and the future of lung transplantation to limit the toxicities of conventional immunosuppressive therapy. PMID- 29997989 TI - Carcinoembryonic antigen-positive pleural effusion in early stage non-small cell lung cancer without pleural infiltration. AB - Carcinoembryonic antigen (CEA) is a tumor marker for detecting recurrences of adenocarcinomas such as colon cancer. In lung adenocarcinoma, CEA elevation can be found in both serum and malignant pleural effusion. However, CEA elevation in cytologically negative pleural effusion in the presence of adenocarcinoma without pleural infiltration has not been described. We here present the case of an 82 year-old man with incidental early stage adenocarcinoma of the right upper lobe showing CEA elevation in pleural fluid and serum despite negative cytological findings. Due to limited lung reserve the tumor was removed by wide wedge resection, but the visceral pleura was not affected and infiltration of the parietal pleura was ruled out by pleural biopsies. Serum and pleural CEA levels declined postoperatively as measured at 1 and 2 months follow-up. This case shows CEA elevation in serum and pleural fluid in early stage lung adenocarcinoma with negative cytology and no sign of pleural infiltration. Previous research revealed that CEA level in pleural effusion correlates to serum CEA and is significantly higher in adenocarcinoma of the lung than in other lung cancer entities. Firstly, this case suggests that determination of CEA levels can increase the diagnostic sensitivity in cases with cytologically negative pleural effusion suspicious of malignant origin and secondly, it contributes valuable information to the decision whether follow-up of pulmonary nodules or continuative diagnostics such as video-assisted thoracoscopic surgery (VATS) wedge resection is indicated. PMID- 29997990 TI - Anomalous origin of the left coronary artery from the pulmonary artery diagnosed during transcatheter treatment of severe pulmonary branch stenoses: a potentially life-threatening situation. AB - We report an 8-year-old female undergoing interventional catheterization for treatment of pulmonary artery stenoses, atrial septal defect and patent ductus arteriosus. Anomalous left coronary artery arising from the pulmonary artery was diagnosed during the procedure. We highlight the importance of recognizing this rare anomaly to avoid the risk of myocardial ischaemia consecutively to abrupt decrease of right ventricular pressure after dilation of pulmonary branches. PMID- 29997991 TI - Acute gastroesophageal intussusception in a patient with pneumomediastinum, pneumoperitoneum, and extensive subcutaneous emphysema resulting from iatrogenic colonic perforation. AB - Acute gastroesophageal intussusception is a rare condition in which the stomach invaginates into the adjacent esophagus. We report a case of acute gastroesophageal intussusception with massive pneumomediastinum, pneumoperitoneum, and subcutaneous emphysema, effectively treated with conservative management. PMID- 29997992 TI - Secondary pulmonary alveolar proteinosis predominant in the transplanted lung in patients with idiopathic interstitial pneumonia: an autopsy case. AB - A man in his 40 s with idiopathic interstitial pneumonia underwent cadaveric left single-lung transplantation from a brain-dead donor in October 2014. In October 2015, chest high-resolution computed tomography revealed centrilobular ground glass opacities (GGOs) predominantly in the transplanted left lung, and subsequently, the shadows progressed to a geographic GGO without crazy paving. Bronchoalveolar lavage fluid analysis revealed an opaque and milky appearance, and cytopathology demonstrated foamy alveolar macrophages and abundant granular, acellular, eosinophilic, and amorphous material in the background. There was no evidence of infection. Serum anti-granulocyte-macrophage colony-stimulating factor antibody testing was negative. We diagnosed the patient with secondary pulmonary alveolar proteinosis (PAP) following lung transplantation. Autopsy revealed PAP findings predominant in the transplanted left lung, which also had dilated lymphatic vessels. In addition to defects in alveolar macrophage function from immunosuppressive therapy, impaired lymphatic drainage due to transplantation would contribute to the onset of secondary PAP in the transplanted lung. PMID- 29997993 TI - A new application for argon beam coagulation: the thymoma patient with pleural recurrence. AB - Thymomas are enigmatic tumors for which surgical resection is the mainstay of treatment. However, there are still many debates about resected thymomas with pleural recurrence. Repetitive operations for thymomas involving pleural recurrence are still the treatment of choice. Herein, we present a case with a suitable performance status for re-operation with a new application for argon beam coagulation. Both our experience and the currently available evidence suggest that surgical resection could be considered for patients with advanced thymomas, even for patients with locally advanced or Masaoka-Koga stage IV thymomas. Multimodality or multimodal, treatments resulted in better oncological outcomes for these patients. In this case, we proved that the new application of argon beam coagulation for a thymoma patient with pleural recurrence is safe and feasible. Additional evidence should be collected, and patients should be followed to assess long-term benefits. PMID- 29997995 TI - Complete excision of acute necrotic regression of thymoma mimicking an infected mediastinal cyst with mediastinitis using video-assisted thoracoscopic technique. PMID- 29997994 TI - Lung adenocarcinoma patient with an EGFR kinase domain duplication (KDD) and the response to icotinib. PMID- 29997996 TI - Non-pyothorax-associated primary pleural lymphoma without pleural effusion in an immunocompetent patient: a case report and literature review. PMID- 29997997 TI - A surgical case of lung cancer with poor general status associated with parathyroid hormone-related protein. AB - Parathyroid hormone-related protein (PTHrP), which is released in the presence of malignant disease, is associated with hypercalcemia. Complete resection of the tumor in such patients is rarely performed because of their poor general condition. We herein report a case of lung cancer associated with PTHrP in a patient whose condition dramatically improved after surgery. We also review the literature on the benefits of various surgical options. Although only a few cases of complete resection in such patients have been reported, the mental and physical condition of the patients improved postoperatively and the median survival time was longer than 12 months. A poor general status is frequently considered a contraindication for surgery, even in a palliative setting; however, we conclude that resection of lung cancer may lead to improved symptom control and survival when the patient's condition is induced by hypercalcemia secondary to PTHrP secretion from the tumor. PMID- 29997998 TI - Three-port mediastino-laparoscopic esophagectomy (TPMLE) for an 81-year-old female with early-staged esophageal cancer: a case report of combining single port mediastinoscopic esophagectomy and reduced port laparoscopic surgery. PMID- 29997999 TI - Situs inversus uniportal video-assisted thoracoscopic right anatomic segmentectomy S1-S2 and S6. AB - Situs inversus totalis (SIT) is an extremely rare condition where the major organs are reversed or mirrored from their usual positions. There are few reports in the literature describing thoracoscopic major surgery in patients with this unusual anomaly. Here we report a 48-year old female with two small early stage lung cancer lesions located in the apicoposterior segment of the right upper lobe and in the dorsal segment of the right lower lobe. The patient underwent a uniportal approach through a 3 cm incision and combined anatomic segmentectomies in the upper and lower lobes. The postoperative course was uneventful. This is the first report of an anatomic segmentectomy in a patient with a situs inversus condition. PMID- 29998000 TI - Transcatheter aortic valve implantation for patients with lung cancer and aortic valve stenosis. AB - Many patients who require lung resection have cardiovascular and cerebrovascular comorbidities. It has been recommended that surgical aortic valve replacement (SAVR) should precede lung resection in patients with severe aortic valve stenosis (AS). However, by first undergoing transcatheter aortic valve implantation (TAVI), the patient may undergo lung resection more safely. We present two patients with both severe AS and lung cancer who underwent TAVI and lung resection without any complications. PMID- 29998001 TI - Right sleeve pneumonectomy via uniportal video-assisted thoracoscopic approach. PMID- 29998002 TI - Xiaoxin Chen: funding remains the greatest challenge to research due to constant improvement of technologies. PMID- 29998003 TI - New perspectives in multidisciplinary treatment of esophageal cancer: the "First East Asian Conference on Multidisciplinary Treatment of Esophageal Cancer" held in Chengdu, Sichuan Province. PMID- 29998004 TI - Erratum to uncontrolled and under-diagnosed asthma in a Damascus shelter during the Syrian crisis. AB - [This corrects the article DOI: 10.21037/jtd.2017.08.86.]. PMID- 29998005 TI - Immune profiling of microsatellite instability-high and polymerase epsilon (POLE) mutated metastatic colorectal tumors identifies predictors of response to anti-PD 1 therapy. AB - Background: Microsatellite instability-high (MSI-H) and polymerase epsilon (POLE) mutated metastatic colorectal cancer (mCRC) represent hypermutated and ultramutated tumor phenotypes, respectively, that may predict benefit to checkpoint blockade [anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1)]. Methods: Immune profiling through multispectral fluorescent immunohistochemistry (IHC) using a multi-marker staining panel was performed on pretreatment tumor specimens from a cohort of MSI-H or POLE-mutated mCRC patients treated with PD-1 blockade at our institution to identify candidate predictors of response to checkpoint inhibitors. Results: From 4/2013 to 1/2017, a total of 237 mCRC patients with molecularly profiled tumors were screened. Five MSI-H and three POLE-mutated mCRC patients were treated with checkpoint inhibitors. Immune profiling identified higher CD8+ tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME) of responders (CR or PR as best response) than nonresponders (SD or PD as best response). Responders had significantly higher densities of CD8+ PD-1+ TILs than nonresponders (P=0.0007). PD-L1 expression (P=0.73), CD4+ T-cell density (P=0.39), and CD4+ FOXP3+ T-cell density (P=0.68) did not significantly differ, but the percentage of CD4+ Tbet+ T-cells (Th1 phenotype) was also significantly higher in responders than nonresponders (P=0.0007). Conclusions: Higher densities of CD8+ TILs, PD-1-expressing CD8+ TILs, and tumor-infiltrating immune cells with a Th1 phenotype in the TME may predict response to checkpoint inhibitors in MSI-H and POLE-mutated mCRC. PMID- 29998006 TI - Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines. AB - Background: The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines. Methods: Between 2011 and 2017, 67 patients with GI malignancies were genotyped for DPYD variants. Fluoropyrimidines associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Fisher's exact test was used for statistical analysis. Results: DPYD variants were identified in 17 out of 67 (25%) patients. One patient was homozygous for DPYD*9A variant and one patient was double heterozygous for DPYD*9A and DPYD*9B variants. In patients with identified DPYD variants, 13/17 (76%) patients had DPYD*9A variant, 3/17 (18%) patients had DPYD*2A variant and 2/17 (12%) patient had DPYD*9B variant. Only patients genotyped prior to 2015 were genotyped for DPYD*9A variant (N=28). Of those, 13/28 patients (46%) had DPYD*9A variant. Grade 3-4 diarrhea was associated with DPYD*9A variant in patients treated with full dose fluoropyrimidines (P=0.0055). Conclusions: In our cohort, DPYD*9A variant was the most common diagnosed variant. The correlation between DPYD*9A genotype and DPD deficiency in clinical phenotype was noticeable in patients who received full dose fluoropyrimidines as they all experienced grade 3-4 toxicities (diarrhea). PMID- 29998007 TI - Cost-utility analysis of 5-fluorouracil and capecitabine for adjuvant treatment in locally advanced rectal cancer. AB - Background: Adjuvant chemotherapy at concurrent time with radiation therapy (RT) or at adjuvant time alone in locally advanced rectal cancer (LARC) is used with several regimens. The cost-utility analysis was conducted to compare administration of two 5-FU regimens and capecitabine in the aspect of provider and societal viewpoint. Methods: Stage II or III rectal cancer patients who received pre-operative or post-operative concurrent chemoradiotherapy and adjuvant chemotherapy were compared by using decision tree model between (I) 5-FU plus leucovorin (LV) for 5 days per cycle (Mayo Clinic regimen); (II) 5-FU continuous infusion (CI) for 120-h per cycle (CAO/ARO/AIO-94 protocol); (III) standard regimen of capecitabine. All probability data were extracted from landmark study. Direct medical costs were the cost from database of Drug Medical Supply Information Center, while direct non-medical cost and utility were interviewed from stage II and III rectal cancer patients. The time horizon of this study was 5 years. Incremental cost-effectiveness ratio (ICER) was the final result in this study, which determined as the numerator of the difference of costs among three drug regimens, and the difference of quality-adjusted life years (QALYs) from each drug was the denominator. Results: 5-FU plus LV was the cheapest and least efficacy for adjuvant treatment of LARC in both provider and societal viewpoint. In provider viewpoint, the ICERs of 5-FU CI and capecitabine were 334,550 THB/QALY (US $9,840/QALY) and 189,935 THB/QALY (US $5,586/QALY), respectively, with the corresponding societal viewpoint of 264,447 THB/QALY (US $7,778/QALY) and 119,120 THB/QALY (US $3,504/QALY) when 5-FU plus LV was used as comparator. The most influential parameter for value of treatment was acquisition cost of capecitabine. At the willingness to pay for one QALY gained in Thailand (160,000 THB or US $4,706), 5-FU plus LV, 5-FU CI and capecitabine had probabilities of cost-effectiveness of 63%, 2% and 35%, respectively. Conclusions: Capecitabine was the most expensive regimen but produced the higher effectiveness than 5-FU plus LV and 5-FU CI. The most influential parameter in the model was acquisition cost of capecitabine. PMID- 29998008 TI - Preferential use of imaging modalities in staging newly diagnosed rectal cancer: a survey of US radiation oncologists. AB - Background: Accurate staging is crucial for management of patients with newly diagnosed rectal cancer. Endorectal ultrasound (EUS) has been the standard modality in the United States for decades, with magnetic resonance imaging (MRI) now preferred by national guidelines. Positron emission tomography (PET), conversely, is not recommended. The current utilization of imaging modalities by American radiation oncologists in staging newly diagnosed rectal cancer is unknown. Methods: American radiation oncologists completed an anonymous institutional review board-approved online survey probing their imaging preferences for initial staging of rectal cancer patients. Results: We received 220 responses from American radiation oncologists, with 39% in academic centers and with 45% seeing more than 10 rectal cancer patients per year. Most respondents utilize all three imaging modalities for rectal cancer staging-EUS, MRI and positron emission tomography/computed tomography (PET/CT). Fifty-two percent and 38% of respondents are high utilizers of EUS and MRI, respectively, defined as ordering these tests at least 75% of the time. Forty seven percent were high PET utilizers. The latter was associated with practice in a private setting (P=0.015) and being within 10 years from residency training completion (P<0.01). Conclusions: Our analysis reveals a dramatic discordance among national guidelines and the practice patterns among American radiation oncologists. More rely on PET for initial staging of rectal cancer patients than on pelvic MRI. Further research needs to determine the most effective imaging work-up of patients with an initial diagnosis of rectal cancer. PMID- 29998009 TI - Does a fine line exist between regional and metastatic pelvic lymph nodes in rectal cancer-striking discordance between national guidelines and treatment recommendations by US radiation oncologists. AB - Background: Management of rectal cancer with involved lateral pelvic lymph nodes (LPLNs) at the time of diagnosis-the stage we refer institutionally to as Stage 3.5-is controversial. The American Joint Committee on Cancer's 7th edition classifies internal iliac lymph nodes (LNs) as regional (Stage III), but both external and common iliac LNs as metastatic (Stage IV). However, in many Asian countries all LPLNs are considered regional and patients are treated with curative intent, with literature supporting improved outcomes with LPLN dissection. Management patterns of these patients by US radiation oncologists (ROs) are unknown. Methods: American ROs completed an anonymous institutional review board-approved online questionnaire regarding rectal cancer management. Results: Among the 220 completed responses, 45% treat more than 10 patients annually and 39% work in academia. We found 10.5% and 34.2% recommend biopsy of clinically involved internal and common iliac LNs, respectively. The vast majority of responders-98.6% and 94.5%-treat involved internal and common iliac LNs with curative intent, respectively. Respondents recommend treatment intensification to involved internal iliac LNs by dissection of the nodal basin (88.2%) and radiation therapy (RT) boost (59.1%), and treatment intensification to involved common iliac LNs by LN dissection (76.4%) and RT boost (63.6%). Conclusions: Our analysis reveals that the vast majority of US ROs approach patients with involved LPLNs, both regional (internal iliac) and metastatic (common iliac), with curative intent. They recommend treatment intensification with surgical resection and/or RT boost to involved nodes. Prospective clinical trials need to determine the appropriate management of patients with Stage 3.5 rectal cancer. PMID- 29998010 TI - Single nucleotide polymorphism rs4648298 in miRNAs hsa-miR21 and hsa-miR590 binding site of COX gene is a strong colorectal cancer determinant. AB - Background: Genetic determinants are considered as driving forces in development colorectal cancer (CRC), a malignancy that ranks as the second cause of cancer death in the world. Single nucleotide polymorphisms (SNPs), are considered as the main genetic factor in cancers susceptibility. MicroRNAs are critical players in posttranslational gene regulation by binding to their specific recognition sequences located at 3' untranslated region (UTR) of mRNAs. In present study we have elucidated the role of 9,850 A > G (rs4648298), in development of sporadic CRC in Iranian population. Methods: A case-control study using 88 CRC patients and 88 noncancerous counterparts was undertaken in order to determine rs4648298 genotypes using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Also, a meta-analysis was performed based on 9 articles accessed via the MEDLINE, Cochrane review, Google Scholar and Scopus databases. Results: AA genotype was determined to be associated with significant decreased risk of CRC in our study population [odds ratio (OR) =0.14; 95% confidence interval (CI), 0.05-0.34; P<0.001]. In a meta-analysis on 6 risk estimates for the AG versus AA genotype, we found a significant inverse association between AG SNPs and risk of gastric adenocarcinoma, CRC, breast cancer and prostate cancer (OR =0.86; 95% CI, 0.76-0.98; P<0.02). Conclusions: Our results suggest significant correlation between rs4648298 polymorphism and CRC risk in Iranian population. PMID- 29998011 TI - Demographic characteristics and the first program of colorectal cancer (CRC) screening in north of Iran (2016). AB - Background: Colorectal cancer (CRC) is one of the most common types of gastrointestinal cancers. This study aimed to determine the demographic characteristics and their relationships with the results of the first screening program for CRC in people over 50 years old in northern Iran. Methods: This cross sectional study was conducted in 2016 on 924 eligible people over 50 years old. Initial screening was done by IFOBT and then colonoscopy was performed if the results were positive. The demographic characteristics of individuals including age, sex, place of residence, marital status, body mass index (BMI) and education level were investigated with the results of the colonoscopy and the test results. Results: The mean age of participants was 59.38 years, and the participation of women (57.0%) and rural residents (54.2%) were higher in the screening program. According to the demographic variables, age was considered as a strong independent predictor variable, so that the prevalence of positive test results was more than 2 times higher in subjects older than 70 compared with subjects aged <=60 (OR =2.05; 95% CI, 1.18-3.55, P=0.010). Also, the chance of positive test result in the age group <=55 years old was 23%, with an increase of 64% in the age group above 75 years (P<0.001). Among the positive test subjects, 118 cases underwent colonoscopy. Conclusions: The prevalence of IFOBT positivity was increased with age. Therefore, given the aging population of the country, it is recommended to emphasize on the screening of older people in the general population. PMID- 29998012 TI - Utilization of intensity modulated radiation therapy for anal cancer in the United States. AB - Background: Chemoradiotherapy for anal cancer (AC) can incur substantial treatment-related toxicities. Whereas radiotherapy (RT) for AC has historically been delivered with two- or three-dimensional conformal RT (2D/3DCRT) techniques, intensity-modulated RT (IMRT) is associated with improved target conformality and lower doses to organs-at-risk (OARs). This is the first investigation to date evaluating trends of IMRT utilization in the United States. Methods: The National Cancer Data Base (NCDB) was queried [2004-2015] for AC patients receiving definitive chemoradiotherapy with a defined RT technique (3DCRT versus IMRT). Following analysis based on temporal trends, multivariate logistic regression determined factors associated with receipt of IMRT. Secondarily, Kaplan-Meier analysis compared OS between the 3DCRT and IMRT groups, and Cox proportional hazards modeling determined variables associated with OS. Results: Altogether, 11,396 patients met study criteria; 1,288 (11%) were treated with 3DCRT and 10,108 (89%) with IMRT. Temporally, utilization of IMRT rose significantly, from 28% in 2004 to 96% in 2015, corresponding with a progressive decrease in 3DCRT usage. IMRT was more likely delivered in node-positive disease, at academic centers, and in southern/western regions (P<0.05 for all). T3-4 disease was less likely to receive IMRT (P<0.05). As expected, there were no OS differences based on RT technique (P=0.402). Predictors of worse OS included advancing age, male gender, increasing comorbidities, advanced T-stage, and nodal positivity (P<0.05 for all). In addition to racial- and insurance-related factors, receipt of therapy at academic centers independently predicted for improved OS (P<0.05 for all). Conclusions: Based on findings from this large, contemporary dataset, IMRT is now the most widely utilized RT technique for AC, and 3DCRT is used in a very small minority of patients. IMRT utilization is impacted by multiple characteristics, such as disease- and regional-related factors. These observations have implications for payers and insurance coverage; improved survival at academic centers has ramifications for patient counseling. PMID- 29998013 TI - The platelets-neutrophils to lymphocytes ratio: a new prognostic marker in metastatic colorectal cancer. AB - Background: The cancer micro-environment is recognized as having an increasing importance in cancer progression. Immune cells originating from the peripheral blood are important elements of this environment. Thrombocytosis, neutrophilia and lymphocytopenia have been found to be negative prognostic indicators in many cancers. This study aims to evaluate the potential of the use of a novel hematological marker, the platelet-neutrophil to lymphocyte ratio (PNLR) as a practical, reliable, and inexpensive prognostic tool in metastatic colorectal adenocarcinomas. Methods: Charts from 305 patients with colorectal cancer were retrospectively reviewed. Of these, 152 had metastatic disease with complete follow-up data on progression and survival. Data were extracted and stratified by a PNLR cut-off point of 2,000. Baseline parameters of the two groups were evaluated and compared with the chi2 test. Univariate and multivariate Cox proportional-hazards regression analyses were performed on variables of interest. Results: A total of 102 (67.1%) patients had a PNLR of less than 2,000 while the index for 50 (32.9%) patients was 2,000 or higher. Patients with a PNLR above 2,000 had a shorter median progression-free survival (PFS) [6.5 vs. 13.3 months; hazard ratio (HR), 2.05; 95% CI, 1.32-3.19, P=0.001] than in patients with a PNLR below the threshold. Similar results were observed for median overall survival (OS) (9.6 vs. 21.8 months; HR, 2.33; 95% CI, 1.44-3.79, P=0.001). PNLR had a higher predictive HR than Eastern Cooperative Oncology Group (ECOG) performance status (PS). Conclusions: In this retrospective analysis of metastatic colorectal cancer patients, PNLR had prognostic value for both OS and PFS. While other variables held significance for poorer prognosis, PNLR had the highest HR and the highest significance in multivariate analysis for both PFS and OS. Thus, it represents a powerful and objective prognostic tool in the evaluation of metastatic colorectal cancer patients that is readily available and does not require any additional expenses. PMID- 29998015 TI - Palliative care and end-of-life health care utilization in elderly patients with pancreatic cancer. AB - Background: Palliative care has been associated with improved survival and quality of life, with lower rate of end-of-life health care utilization and cost. We examined trends in palliative care utilization in older pancreatic cancer patients. Methods: Pancreatic cancer patients with and without palliative care consults were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database between 2000 and 2009. Trend of palliative care use was studied. Emergency room/intensive care unit (ICU) utilization and costs in the last 30 days of life were compared between both groups using propensity score-matched (PSM) analysis. Results: Of the 54,130 patients, 3,166 (5.8%) received palliative care and 70% received it in the last 30 days of life. The proportion of patients receiving palliative care increased from 1.4% in 2000 to 7.4% in 2009 (P<0.001). Patients with palliative care were more likely to be older, Asian and women. In the unmatched and PSM population, the average visits to the ER in the last 30 days of life were significantly higher for patients who received palliative care, and had a significantly higher cost of care. Similarly, ICU length of stay in the last 30 days of life was higher in patients who did not receive palliative care in both PSM and unmatched patients. Cost of care and number of ICU admissions were not different between palliative and non-palliative care groups in PSM and unmatched patients. Conclusions: In this study of Medicare patients with pancreatic cancer, palliative care use has increased between 2000 and 2009. Palliative care was largely offered close to the end of life and was not associated with reduced health care utilization or cost. PMID- 29998014 TI - Adjuvant radiation provides survival benefit for resected pancreatic adenocarcinomas of the tail. AB - Background: The appropriate adjuvant treatment for resected pancreatic cancer remains a controversy. We sought to determine the effect of adjuvant treatment on overall survival (OS) in patients with pancreatic tail adenocarcinoma. Methods: Retrospective review of patients with upfront surgically resected pancreatic tail cancer treated at our institution between 2000-2012 was performed to determine outcomes of patients treated with and without adjuvant radiation therapy (RT). Survival curves were calculated according to the Kaplan-Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the Cox proportional hazards model. Results: Thirty-four patients met inclusion criteria. 79% received adjuvant chemotherapy, either concurrent with RT or alone. The groups were well matched, with the only significant difference being patient sex. On both UVA and MVA there was significantly worse survival in patients with a post-op CA19-9 >90 [hazard ratio (HR) 5.55; 95% confidence interval (CI): 1.20 25.7, P=0.03] and improved survival in patients treated with adjuvant RT (HR 0.15; 95% CI: 0.04-0.58, P=0.006). The median and 2-year OS were 21.6 months and 47% for patients treated with adjuvant RT compared with 11.3 months and 21% for those treated without RT. Conclusions: Although few in patient numbers, this data suggests integration of adjuvant RT in resected pancreatic tail adenocarcinoma may improve OS. PMID- 29998016 TI - Disparities in major surgery for esophagogastric cancer among hospitals by case volume. AB - Background: The purpose of this study was to characterize disparities among centers performing major surgery for esophageal or gastric cancer stratified by case volume. Methods: The National Cancer Data Base (NCDB) was queried for cases of esophagectomy or total gastrectomy. Centers were compared based on number of cases during 2004-2013: low volume [1-99], middle [100-200], and high [>200]. Results: For esophagectomy, 17,547 patients were included; 73.5% were treated in low volume centers, 14.6% in middle, and 11.9% in high. For gastrectomy, 20,059 patients were included, with 87.5%, 8.3%, and 4.3%, respectively. Patients treated at low volume centers were more likely to be of racial/ethnic minorities, uninsured, and have lower socioeconomic status. Overall survival (OS) was superior for patients treated at high volume centers. On multivariable analysis for either procedure, a higher number of disparate factors was identified in the low and middle volume centers compared to the high volume centers, which were associated with poorer OS. Conclusions: This study identified higher numbers of disparate patient factors associated with low/middle volume centers compared to high volume centers, which were associated with worse OS, and further makes the case for performance of esophagectomy and total gastrectomy at high volume centers. PMID- 29998017 TI - Clinical impact of underutilization of adjuvant therapy in node positive gastric adenocarcinoma. AB - Background: Adjuvant therapy for gastric adenocarcinoma has shown a survival advantage, though it may be underutilized. The purpose of this study is to examine how infrequently adjuvant therapy is administered with curative intent gastrectomy for node positive gastric cancer and the long-term effects to patients. Methods: The National Cancer Database was queried from 2006-2013 for patients with node positive gastric adenocarcinoma undergoing a potentially curative gastrectomy. Overall survival was compared between patients who received adjuvant chemotherapy or chemoradiation and those who did not. Results: Of 2,565 patients, 793 (30.9%) patients did not receive any adjuvant chemotherapy or radiation therapy, while 147 (5.7%) received peri-operative chemotherapy and 723 (28.2%) received post-operative chemoradiation. From 2006-2013, the percentage of patients receiving peri-operative chemotherapy rose from 1.1% to 9.9%, while those receiving post-operative chemoradiation decreased from 39.7% to 21.6%. The adjusted restricted mean survival time over 5 years for no adjuvant therapy was 27.7 months, peri-operative chemotherapy was 39.6 months, and post-operative chemoradiation was 37.7 months (P<0.0001). Conclusions: Approximately one third of patients treated for node positive gastric cancer undergo surgical resection without adjuvant therapy. This is associated with poorer survival, highlighting the need for improvement in multimodality care and cancer outcomes. PMID- 29998018 TI - Chemoradiotherapy versus chemotherapy alone for unresected intrahepatic cholangiocarcinoma: practice patterns and outcomes from the national cancer data base. AB - Background: Current guidelines recommend chemotherapy (CT) with or without radiotherapy (RT) for unresected intrahepatic cholangiocarcinoma (IC). Although there is currently lack of consensus, previous smaller studies have illustrated the efficacy of local therapy for this population. This investigation evaluated outcomes of chemoradiotherapy (CRT) versus CT alone in unresected IC using a large, contemporary national database. Methods: The National Cancer Data Base (NCDB) was queried for primary IC cases (2004-2013) receiving CT alone or CRT. Patients undergoing resection or not receiving CT were excluded, as were those with M1 disease or unknown M classification. Logistic regression analysis ascertained factors associated with CRT administration. Kaplan-Meier analysis evaluated overall survival (OS) between both groups. Cox proportional hazards modeling assessed variables associated with OS. Results: In total, 2,842 patients were analyzed [n=666 (23%) CRT, n=2,176 (77%) CT]. CRT was less likely delivered at community centers, in more recent time periods (2009-2013), to older patients, and in certain geographic locations. Median OS in the CRT and CT groups were 13.6 vs. 10.5 months, respectively (P<0.001). On multivariate analysis, poorer OS was associated with age, male gender, increased comorbidities, treatment at a community center, and treatment at earlier time periods (2004-2008) (P<0.05 for all). Notably, receipt of CRT independently predicted for improved OS (P<0.001). Conclusions: As compared to CT alone, CRT was independently associated with improved survival in unresected IC. These findings support a randomized trial evaluating this question that is currently accruing. PMID- 29998019 TI - Non-surgical management of patients with intrahepatic cholangiocarcinoma in the United States, 2004-2015: an NCDB analysis. AB - Background: Surgical resection is the standard of care for intrahepatic cholangiocarcinoma (ICC), but only a minority of patients are managed surgically. Other modalities, including external beam radiation (XRT), radiofrequency ablation (RFA), and radioactive implants (RIs) have been employed with significant heterogeneity of prognosis reported in the literature. The aim of this study was to evaluate the demographics of patients with ICC managed non surgically and compare prognosis in patients managed surgically to those that underwent XRT, RFA, or RI. Methods: All patients diagnosed with ICC from 2004 to 2015 in the National Cancer Database (NCDB) were reviewed. Patient demographics, treatments, and survival outcomes were analyzed. Results: Of the 6,140 patients with ICC, 4,374 (71%) did not undergo surgery. Patients managed non-surgically were typically older, treated at community centers, more likely to have severe fibrosis or cirrhosis, and present with higher stage disease. The strongest association to receipt of XRT, RI, or RFA modalities was treatment at an academic center. Increased clinical stage was associated with decreased use of RFA; a significantly higher proportion of patients with stage IV disease were given no local therapy. RFA associated with a statistically significant survival benefit over no local therapy only in stage I disease (2.1 vs. 0.7 years, P=0.012) as well as XRT over no local therapy (1.7 vs. 0.7 years, P=0.009). No survival benefit was realized for any treatment in stage II disease. Patients with stage III disease had a survival benefit from XRT versus no local therapy (0.9 vs. 0.6 years, P=0.029) and RI over no local therapy (1.2 vs. 0.6 years, P=0.013). Patients with stage IV disease only demonstrated survival benefit from RI over no local therapy (0.9 vs. 0.3 years, P=0.014). Conclusions: The majority of patients with ICC in the United States continue to be managed non-surgically. RFA was associated with improved survival only in stage I disease. XRT was associated with improved survival in stage I & III disease, while RI was associated with improved survival in stage III and IV disease. PMID- 29998020 TI - Viral hepatitis associated hepatocellular carcinoma outcomes with yttrium-90 radioembolization. AB - Background: Viral associated (VA) malignancies have recently been correlated with improved outcomes. We sought to evaluate outcomes of patients with hepatocellular carcinoma (HCC) with and without viral hepatitis (hepatitis B and C) treated with lobar yttrium-90 radioembolization (Y-90 RE). Methods: After IRB approval, an institutional database of patients with HCC who received RE between 2009-2014 was queried and 99 patients were identified that received a total of 122 lobar RE. Charts were reviewed to capture previous treatments, viral hepatitis status, alpha-fetoprotein values (AFP), Child-Pugh class (CP), albumin-bilirubin score (ALBI), portal vein thrombosis (PVT), volumes treated and doses delivered. Comparison was made with Chi-square and Mann-Whitney U test. Intrahepatic control (IHC), extrahepatic control (EHC), progression free survival (PFS), and overall survival (OS) were calculated according to the Kaplan-Meier method stratified by cause of underlying liver disease (viral vs. non-viral) and survival differences were assessed via the log-rank test. Hazard ratios were calculated using Cox regression. Results: Median follow up for VA HCC and non-VA (NVA) HCC patients was 10.9 months (range, 0.8-46.7 months) and 11.8 months (range, 1.1-62.8 months), respectively. Patients with VA HCC (n=44) were younger (P<0.001) and had smaller pretreatment liver volumes (P<0.001); however, there was no difference with respect to gender, pre-treatment AFP, CP, ALBI, PVT, extrahepatic disease, previous treatment, or dose delivered. Median doses for VA and NVA HCC patients were 129.5 Gy (range, 90-215.8 Gy) and 131 Gy (range, 100.9-265 Gy), respectively (P=0.75). One year IHC showed a strong trend to better control for VA HCC at 67% versus 34% for NVA HCC (P=0.067) but 1 year EHC was significantly worse at 63% for VA HCC versus 86% for NVA HCC (P=0.027). There were no significant differences in survival, with a 1-year PFS of 45% for VA HCC versus 31% for NVA HCC (P=0.56) and 1 year OS of 46% versus 55% (P=0.55). Patients that received salvage treatments, CP A, no PVT, and those without extrahepatic disease had improved OS. Conclusions: Patients with VA HCC had a trend to improved IHC and significantly worse EHC. Prospective investigation of novel systemic therapies following Y-90 RE in patients with VA HCC is warranted to potentially further extend survival in VA HCC patients by addressing extra-hepatic disease. PMID- 29998021 TI - Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance. AB - Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life. PMID- 29998022 TI - Refining the management of resectable esophagogastric cancer: FLOT4, CRITICS, OE05, MAGIC-B and the promise of molecular classification. AB - The multidisciplinary management of locoregional esophagogastric cancers (GCs) has evolved significantly over the past two decades. While perioperative chemotherapy, adjuvant chemotherapy, and postoperative chemotherapy with chemoradiation (CRT) have demonstrated improved survival when compared to surgery alone, there is no universal standard for resectable gastroesophageal cancer. Current global management patterns vary by geographic region, partly related to phase III data originating from each global region. Herein we detail the landmark phase III trials that support the various multimodality treatment paradigms in resectable GC, with particular focus on findings from more recent phase III gastroesophageal cancer trials including FLOT4, MAGIC-B, OE05, and CRITICS. We highlight important ongoing and future approaches including the potential of molecular subtyping, predictive biomarkers, and immunotherapy as avenues to further improve outcomes in resectable gastroesophageal cancer. PMID- 29998023 TI - Gastrointestinal stromal tumours: advances in surgical and pharmacological management options. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. The stomach is most commonly affected. Advances in immunopathology have identified a mutation in the c-KIT proto-oncogene, leading to the development of the tyrosine-kinase inhibitor Imatinib as targeted therapy for advanced disease. Surgery, however, remains the only curative treatment of resectable primary GIST. This review article aims at reviewing the management of primary GISTs, investigating recurrences, exploring the role of surgery in metastatic disease and looking into combined surgery and molecular therapy for GISTs. PMID- 29998024 TI - Uncovering the barriers to undergoing screening among first degree relatives of colorectal cancer patients: a review of qualitative literature. AB - First degree relatives (FDRs) of colorectal cancer (CRC) patients are at higher risks of developing the disease, but screening rates amongst this group remains dismal. We undertook a systematic review of qualitative studies to identify the barriers surrounding CRC screening among FDRs from both the FDRs' and the healthcare professionals' perspectives. A comprehensive search of major bibliographic databases from January 2000 till February 2017 was performed to answer the above research questions. Pre-determined inclusion and exclusion criteria were applied. Thematic analysis was used to derive the commonalities across the studies. COREQ checklist was used to evaluate the quality of the included studies. Eight qualitative studies were included. Some of the barriers reported by FDRs included the fear of diagnosis of cancer and socio-cultural barriers. The most important barrier was the FDRs' negative perceptions towards screening test such as discomfort, embarrassment, cost of procedure and accessibility to healthcare resources. Likewise, the lack of awareness amongst FDRs that they are at increased risk of developing CRC was also found to be a barrier. On the other hand, healthcare providers are keen for patients themselves to be advocates for CRC screening of their family members as constraints posed by their daily workload impede their time to advocate screening. Lack of knowledge of the physicians on CRC screening guidelines is another notable barrier. A lack of awareness of being at higher risk of developing CRC coupled with negative attitude towards colonoscopy are the main barriers faced by the FDRs of CRC patients. Healthcare providers are more comfortable with patients being the advocates of screening among their family members. PMID- 29998025 TI - Oxaliplatin-induced bronchiolitis obliterans organizing pneumonia following hyperthermic intraperitoneal chemotherapy. AB - Oxaliplatin given systemically is associated with pneumonitis in less than 1% of cases. This case report describes acute respiratory failure, due to bronchiolitis organising pneumonia, in a patient with colorectal carcinoma being treated with hyperthermic intraperitoneal chemotherapy which included oxaliplatin and CPT-11 (irinotecan). The clinical course, the lack of an identifiable infectious agent and the complete response to corticosteroids suggested a drug-induced cause. After ruling out CPT-11, oxaliplatin was considered to be the causal agent. The unusual feature of this case was that pneumonitis developed after intraperitoneal administration of oxaliplatin. Oxaliplatin-associated respiratory complications can occur whatever route the drug is administered. PMID- 29998026 TI - An Atypical HNF4A Mutation Which Does Not Conform to the Classic Presentation of HNF4A-MODY. AB - Objective: To present the case of an atypical Hepatocyte Nuclear Factor 4 Alpha (HNF4A) mutation that is not consistent with the classically published presentation of HNF4A-Mature Onset Diabetes of the Young (MODY). Methods: Clinical presentation and literature review. Results: A 43-year-old nonobese man was referred to the endocrinology clinic for evaluation of elevated fasting blood glucose (FBG) measurements. Laboratory review revealed prediabetes and hypertriglyceridemia for the previous decade. Testing of autoantibodies for type 1 diabetes was negative. Genetic testing showed an autosomal dominant, heterozygous missense mutation (c.991C>T; p.Arg331Cys) in the HNF4A gene, which is correlated with HNF4A-MODY. Phenotypically, patients with an HNF4A-MODY tend to have early-onset diabetes, microvascular complications, low triglyceride levels, increased birth weight, fetal macrosomia, and less commonly neonatal hyperinsulinemic hypoglycemia. The patient did not demonstrate any of these features but instead presented with late-onset diabetes, an elevated triglyceride level, and a normal birth weight. Conclusion: Our patient likely represents an atypical variant of HNF4A-MODY with a milder clinical presentation. Patients with atypical, less-severe presentations of HNF4A-MODY may be largely undiagnosed or misdiagnosed, but identification is important due to implications for treatment, pregnancy, and screening of family members. PMID- 29998027 TI - Uterine Necrosis after Uterine Artery Embolization for Symptomatic Fibroids. AB - Introduction: Uterine artery embolization (UAE) is a minimally invasive intervention that is used in the treatment of fibroids. UAE can lead to complications including postembolization syndrome, postprocedure pain, infection, endometrial atrophy leading to secondary amenorrhea, and uterine necrosis. Uterine necrosis after UAE is very rare and hence poses a clinical dilemma for any clinician in its identification and management. We document a case of uterine necrosis after UAE and conduct a literature review on its causation, clinical features, and management principles. Case: A patient presented one month after UAE with abdominal pain and abdominal vaginal discharge. Her work-up revealed features of possible uterine necrosis with sepsis and she was scheduled for a laparotomy and a subtotal hysterectomy was performed. She was subsequently managed with broad spectrum antibiotic and recovered well. Conclusion: Uterine necrosis after UAE is a rare occurrence and we hope the documentation of this case will add to the body of knowledge around it. Theories that explain its occurrence include the use of small particles at embolization, the use of Contour SE a spherical poly-vinyl alcohol, and lack of collateral supply to the uterus. Its symptoms may be nonspecific but unremitting abdominal pain is invariably present. Finally although conservative management may be successful at times, surgical management with hysterectomy will be required in some cases. The prognosis is good after diagnosis and surgical management. PMID- 29998028 TI - First Report of Eight Milkcap Species Belonging to Lactarius and Lactifluus in Korea. AB - Lactarius and Lactifluus are milkcaps that are characterized by the secretion of latex. These two genera are part of a globally distributed cosmopolitan group of ectomycorrhizal fungi that is an important food resource in various ecosystems. Recently, the taxonomy of Lactarius and Lactifluus has been revised based on molecular phylogenetics. Despite the importance of these taxa, Korean species of both genera are poorly understood. In an effort to describe milkcap species that are indigenous to Korea, a long-term study has been initiated. During a recent survey, eight species of milkcaps that were previously unrecorded in Korea were detected based on morphological observation and sequence analysis of the internal transcribed spacer region: five Lactarius species (Lactarius atromarginatus, L. austrotorminosus, L. kesiyae, L. tabidus, and L. vietus) and three Lactifluus species (Lactifluus acicularis, Lf. pilosus, and Lf. pinguis). Detailed morphological descriptions and phylogenetic relationships of these species are provided in this article. PMID- 29998029 TI - Guild Patterns of Basidiomycetes Community Associated With Quercus mongolica in Mt. Jeombong, Republic of Korea. AB - Depending on the mode of nutrition exploitation, major fungal guilds are distinguished as ectomycorrhizal and saprotrophic fungi. It is generally known that diverse environmental factors influence fungal communities; however, it is unclear how fungal communities respond differently to environment factors depend on fungal guilds. In this study, we investigated basidiomycetes communities associated with Quercus mongolica using 454 pyrosequencing. We attempted to detect guild pattern (ectomycorrhizal or saprotrophic fungal communities) by comparing the influence of geography and source (root and surrounding soil). A total of 515 mOTUs were detected from root (321) and soil (394) of Q. mongolica at three sites of Mt. Jeombong in Inje County. We found that patterns of diversity and community structure were different depending on the guilds. In terms of alpha diversity, only ectomycorrhizal fungi showed significant differences between sources. In terms of community structure, however, geography significantly influenced the ectomycorrhizal community, while source appeared to have a greater influence on the saprotrophic community. Therefore, a guild-based view will help to elucidates novel features of the relationship between environmental factors and fungal communities. PMID- 29998030 TI - Yield, Nutritional Content, and Antioxidant Activity of Pleurotus ostreatus on Corncobs Supplemented with Herb Residues. AB - Improper disposal of herb residues in China has caused severe problems to the surrounding environment and human safety. Three herb residues, i.e., compound Kushen injection residues (CKI) and part one and part two of Qizhitongluo Capsule residues (QC1 and QC2, respectively), were used for the cultivation of Pleurotus ostreatus. The effect of the supplementation of corncobs (CC) with different herb residues on yield, nutritional composition, and antioxidant activity of P. ostreatus was investigated. Compared to the control, the higher mycelial growth rate was observed on substrates CC +30% CKI and CC +30% QC1, while the higher yield was obtained from substrates CC +30% QC2 and CC +30% CKI. Moreover, chemical analysis of fruit bodies revealed that the addition of herb residues to CC significantly increased proteins, amino acids, ashes, minerals (Na and Ca), and total phenolic contents but significantly reduced carbohydrates and IC50 values of DPPH radicals. In addition, no heavy metals (Pb, Cd, and As) were detected in the fruiting bodies harvested from different substrate combinations. These results demonstrated that mixtures of CC with herb residues might be utilized as a novel, practical, and easily available substrate for the cultivation of P. ostreatus, which is beneficial for the effective management of herb residues. PMID- 29998031 TI - Screening and Evaluation of Yeast Antagonists for Biological Control of Botrytis cinerea on Strawberry Fruits. AB - Gray mold (Botrytis cinerea) is one of the most common diseases of strawberries (Fragaria * ananassa Duchesne) worldwide. Although many chemical fungicides are used for controlling the growth of B. cinerea, the risk of the fungus developing chemical resistance together with consumer demand for reducing the use of chemical fungicides have necessitated an alternative method to control this pathogen. Various naturally occurring microbes aggressively attack plant pathogens and benefit plants by suppressing diseases; these microbes are referred to as biocontrol agents. However, screening of potent biocontrol agents is essential for their further development and commercialization. In this study, 24 strains of yeast with antagonistic ability against gray mold were isolated, and the antifungal activity of the volatile and diffusible metabolites was evaluated. Putative mechanisms of action associated with the biocontrol capacity of yeast strains against B. cinerea were studied through in vitro and in vivo assays. The volatile organic compounds produced by the Galactomyces candidum JYC1146 could be useful in the biological control of plant pathogens and therefore are potential alternative fungicides with low environmental impact. PMID- 29998032 TI - Antifungal Effects of Silver Phytonanoparticles from Yucca shilerifera Against Strawberry Soil-Borne Pathogens: Fusarium solani and Macrophomina phaseolina. AB - In the present study, the characterization and properties of silver nanoparticles from Yucca shilerifera leaf extract (AgNPs) were investigated using UV-visible spectroscopic techniques, zeta potential, and dynamic light scattering. The UV visible spectroscopic analysis showed the absorbance peaked at 460 nm, which indicated the synthesis of silver nanoparticles. The experimental results showed silver nanoparticles had Z-average diameter of 729 nm with lower stability (195.1 mV). Additionally, our dates revealed that AgNPs showed broad spectrum antagonism (p <= .05) against Fusarium solani (83.05%) and Macrophomina phaseolina (67.05%) when compared to the control after nine days of incubation. Finally, AgNPs from leaf extracts of Y. shilerifera may be used as an agent of biocontrol of microorganism of importance. However, further studies will be needed to fully understand the agronanotechnological potentialities of AgNPs from Yucca schidigera. PMID- 29998033 TI - Biocontrol Activity of Volatile-Producing Bacillus megaterium and Pseudomonas protegens Against Aspergillus and Penicillium spp. Predominant in Stored Rice Grains: Study II. AB - In our previous studies, Bacillus megaterium KU143, Microbacterium testaceum KU313, and Pseudomonas protegens AS15 have been shown to be antagonistic to Aspergillus flavus in stored rice grains. In this study, the biocontrol activities of these strains were evaluated against Aspergillus candidus, Aspergillus fumigatus, Penicillium fellutanum, and Penicillium islandicum, which are predominant in stored rice grains. In vitro and in vivo antifungal activities of the bacterial strains were evaluated against the fungi on media and rice grains, respectively. The antifungal activities of the volatiles produced by the strains against fungal development and population were also tested using I plates. In in vitro tests, the strains produced secondary metabolites capable of reducing conidial germination, germ-tube elongation, and mycelial growth of all the tested fungi. In in vivo tests, the strains significantly inhibited the fungal growth in rice grains. Additionally, in I-plate tests, strains KU143 and AS15 produced volatiles that significantly inhibited not only mycelial growth, sporulation, and conidial germination of the fungi on media but also fungal populations on rice grains. GC-MS analysis of the volatiles by strains KU143 and AS15 identified 12 and 17 compounds, respectively. Among these, the antifungal compound, 5-methyl-2-phenyl-1H-indole, was produced by strain KU143 and the antimicrobial compounds, 2-butyl 1-octanal, dimethyl disulfide, 2-isopropyl-5 methyl-1-heptanol, and 4-trifluoroacetoxyhexadecane, were produced by strain AS15. These results suggest that the tested strains producing extracellular metabolites and/or volatiles may have a broad spectrum of antifungal activities against the grain fungi. In particular, B. megaterium KU143 and P. protegens AS15 may be potential biocontrol agents against Aspergillus and Penicillium spp. during rice grain storage. PMID- 29998034 TI - The Uneven Distribution of Mating Type Genes in Natural and Cultivated Truffle Orchards Contributes to the Fructification of Tuber indicum. AB - The aim of this study was to investigate the pattern of distribution of mating type (MAT) genes of Tuber indicum in ectomycorhizosphere soils from natural T. indicum-producing areas and cultivated truffle orchards and ascocarp samples from different regions. Quantitative real-time PCR and multiplex PCR were used to weight the copy numbers of MAT1-1-1 and MAT1-2-1 in natural truffle soils and cultivated orchard soils. The effect of limestone on the pattern of truffle MAT genes and the correlation between soil properties and the proportion of MAT genes were also assessed. These results indicated that an uneven and nonrandom distribution of MAT genes was common in truffle-producing areas, cultivated truffle orchards, and ascocarps gleba. The competition between the two mating type genes and the expansion of unbalanced distribution was found to be closely related to truffle fructification. Limestone treatments failed to alter the proportion of the two mating type genes in the soil. The content of available phosphorus in soil was significantly correlated with the value of MAT1-1-1/MAT1-2 1 in cultivated and natural ectomycorhizosphere soils. The application of real time quantitative PCR can provide reference for monitoring the dynamic changes of mating type genes in soil. This study investigates the distributional pattern of T. indicum MAT genes in the ectomycorhizosphere soil and ascocarp gleba from different regions, which may provide a foundation for the cultivation of T. indicum. PMID- 29998035 TI - Development of a Molecular Marker for Fruiting Body Pattern in Auricularia auricula-judae. AB - The fruiting body pattern is an important agronomic trait of the edible fungus Auricularia auricula-judae, and an important breeding target. There are two types of fruiting body pattern: the cluster type and the chrysanthemum type. We identified the fruiting body pattern of 26 test strains, and then constructed two different near-isogenic pools. Then, we developed sequence characterized amplified region (SCAR) molecular markers associated with the fruiting body pattern based on sequence-related amplified polymorphism (SRAP) markers. Ten different bands (189-522 bp) were amplified using 153 pairs of SRAP primers. The SCAR marker "SCL-18" consisted of a single 522-bp band amplified from the cluster type strains, but not the chrysanthemum strains. This SCAR marker was closely associated with the cluster-type fruiting body trait of A. auricula-judae. These results lay the foundation for further research to locate and clone genes controlling the fruiting body pattern of A. auricula-judae. PMID- 29998036 TI - Laccase Activity and Azo Dye Decolorization Potential of Podoscypha elegans. AB - Azo dyes containing effluents from different industries pose threats to the environment. Though there are physico-chemical methods to treat such effluents, bioremediation is considered to be the best eco-compatible technique. In this communication, we discuss the decolorization potentiality of five azo dyes by Podoscypha elegans (G. Mey.) Pat., a macro-fungus, found growing on the leaf litter layer of Bethuadahari Wildlife Sanctuary in West Bengal, India. The fungus exhibited high laccase and very low manganese peroxidase activities under different culture conditions. Decolorization of five high-molecular weight azo dyes, viz., Orange G, Congo Red, Direct Blue 15, Rose Bengal and Direct Yellow 27 by the fungus was found to be positive in all cases. Maximum and minimum mean decolorization percentages were recorded in Rose Bengal (70.41%) and Direct Blue 15 (24.8%), respectively. This is the first record of lignolytic study and dye decolorization by P. elegans. PMID- 29998037 TI - The Contribution of Untreated and Treated Anxiety and Depression to Prenatal, Intrapartum, and Neonatal Outcomes. AB - Objective To determine independent perinatal associations of anxiety and depression in women who were and were not treated with psychotropic drugs in comparison to unaffected pregnancies. Study Design From 2013 to 2014, 978 (6.3%) cases of anxiety/depression, of which 35% used psychotropic drugs, were compared with 14,514 (93.7%) unaffected pregnancies using logistic regression. Results Subjects were more likely to be Non-Hispanic Whites, use tobacco and illegal substances, be unmarried, use public insurance, and have medical complications of pregnancy. For independent maternal outcomes, untreated anxiety/depression was associated with labor induction (adjusted odds ratio [aOR] = 2.02), cesarean deliveries (aOR = 1.69), longer length of stay (aOR = 1.96), readmission (aOR = 2.40), fever (aOR = 2.03), magnesium exposure (aOR = 1.82), and postpartum hemorrhage (aOR = 2.57), whereas treated cases were associated with increased blood transfusion (aOR = 4.81), severe perineal lacerations (aOR = 2.93), and postpartum hemorrhage (aOR = 3.85), but decreased risk of cesarean deliveries (aOR = 0.59). Independent neonatal outcomes included small for gestational age (aOR = 3.04), meconium-stained fluid (aOR = 1.85; 2.61), respiratory failure (aOR = 5.84), neonatal adaptation syndrome (aOR = 11; 10.2), and neonatal seizures (aOR = 12.3) in treated cases, whereas untreated cases were associated with hypoxia (aOR = 2.83), low Apgar score (aOR = 3.82), and encephalopathy (aOR = 18.3). Exposure to multiple psychotropic medications independently increased the risk of neonatal adaptation syndrome, neonatal length of stay, and hypoglycemia. Conclusion Untreated cases were associated with increased maternal adverse outcomes, whereas treated cases were associated with more adverse neonatal outcomes when compared with unaffected pregnancies. PMID- 29998038 TI - Prediction of off-target activities for the end-to-end design of CRISPR guide RNAs. AB - The CRISPR-Cas9 system provides unprecedented genome editing capabilities. However, off-target effects lead to sub-optimal usage and additionally are a bottleneck in the development of therapeutic uses. Herein, we introduce the first machine learning-based approach to off-target prediction, yielding a state-of-the art model for CRISPR-Cas9 that outperforms all other guide design services. Our approach, Elevation, consists of two interdependent machine learning models-one for scoring individual guide-target pairs, and another which aggregates these guide-target scores into a single, overall summary guide score. Through systematic investigation, we demonstrate that Elevation performs substantially better than competing approaches on both tasks. Additionally, we are the first to systematically evaluate approaches on the guide summary score problem; we show that the most widely-used method performs no better than random at times, whereas Elevation consistently outperformed it, sometimes by an order of magnitude. We also introduce an evaluation method that balances errors between active and inactive guides, thereby encapsulating a range of practical use cases; Elevation is consistently superior to other methods across the entire range. Finally, because of the large scale and computational demands of off-target prediction, we have developed a cloud-based service for quick retrieval. This service provides end-to-end guide design by also incorporating our previously reported on-target model, Azimuth. (https://crispr.ml:please treat this web site as confidential until publication). PMID- 29998039 TI - Sexual harassment: The most challenging issue of medical professionalism in Japan. PMID- 29998040 TI - Tomojiro Nagai, founder of the Association of the Medical Practitioners (Jicchi ika no tame no kai) in Japan. AB - Obituary: Tomojiro Nagai, founder of the Association of the Medical Practitioners (Jicchi-ika no tame no kai) in Japan. PMID- 29998041 TI - Overdiagnosis or not? 2017 ACC/AHA high blood pressure clinical practice guideline: Consequences of intellectual conflict of interest. AB - American Heart Association/the American College of Cardiology and nine other professional organizations have issued a new hypertension clinical practice guideline (CPG) on November 2017, which has lowered the hypertension threshold to 130/80 mmHg. American Academy of Family Medicine has decided to not endorse this new CPG for various reasons including flaws in CPG development process and a limited additional benefit for lower treatment targets. The major concern was intellectual conflict of interest (COI). Substantial weight was given to SPRINT trial, which provided the basis for the recommended change in blood pressure targets. It is a serious intellectual COI that the Chair of the SPRINT trial steering committee was commissioned as chair of the guideline panel. The new threshold would lead to 46 percent of the U.S. adult population being categorized as having hypertension, while using the previous threshold that figure would be 32 percent. Should we call this change as overdiagnosis? PMID- 29998042 TI - Development and efficacy of a clinician-targeted refresher course for treating nonpneumonia respiratory tract infections. AB - Background: In 2017, the Japanese government published an evidence-based manual describing the appropriate use of antibiotics in outpatient settings to tackle the problem of antimicrobial resistance. To fill the evidence-practice gap, we developed a clinician-targeted course aimed at improving clinician skills in the daily clinical practice of treating acute respiratory tract infections (RTIs) based on the manual. The aim of this study was to evaluate the efficacy of the course. Methods: This course consisted of lectures using illness scripts and checklists, as well as interactive communication skills training using role playing. We performed a vignette-based evaluation of the changes in the knowledge and attitudes of the course participants toward prescribing antibiotics for nonpneumonia RTIs, using pre- and postcourse questionnaires. The questionnaires also included course feedback via the use of a 5-point Likert scale. Results: Thirty-eight clinicians were included in the analyses, and 90% of these participants had graduated >=20 years ago. We found statistically significant reductions in the intention to prescribe antibiotics for four of the six nonpneumonia RTI vignettes: acute bronchitis (-47.2%; 95% confidence interval [CI] -66.3 to -28.1%), common cold (-16.2%; 95% CI -30.8 to -1.6%), acute pharyngitis (-27.0%; 95% CI -49.0 to -5.0%), and acute rhinosinusitis (-33.3%; 95% CI -53.3 to -13.3%). The course seemed to be satisfactory for experienced doctors who were the relevant target population of such a workshop. Conclusions: The refresher course was helpful for reducing the participants' intensions to prescribe antibiotics for nonpneumonia RTIs. PMID- 29998043 TI - An atypical case of atypical pneumonia. AB - Atypical pneumonia has been thought to account for 7%-20% of community-acquired pneumonia (CAP). The treatment for the pathogens that cause atypical pneumonia is different from that of other bacterial pneumonia. Therefore, identification of the causative pathogen in a primary care situation is crucial for adequate treatment of CAP. Mycoplasma infection is prevalent in the general population, but Mycoplasma pneumoniae with extrapulmonary symptoms is relatively rare. Herein, we report a case of CAP because of M. pneumoniae that presented with a wide variety of extrapulmonary diseases. Delayed administration of appropriate antibiotics may contribute to development of extrapulmonary manifestations. PMID- 29998044 TI - A rare case of full neurological recovery from severe nonexertional heatstroke during a bedrock bath. AB - We report a rare case of full neurological recovery in a 77-year-old woman with an initial Glasgow Coma Scale of 3 while taking a bedrock bath. Severe heatstroke was quickly diagnosed, and intensive treatment was immediately provided. Laboratory data showed multi-organ failure, and her electroencephalogram showed very low amplitude, indicating a poor prognosis; however, she gradually recovered consciousness, and her electroencephalogram normalized, showing a Glasgow Coma Scale of 15 at discharge. This case demonstrated that physicians should pay careful attention when withholding treatment from a patient with severe heatstroke accompanied by a poor initial electroencephalogram result and laboratory data. PMID- 29998045 TI - A typical case of giant cell arteritis with vision loss due to delayed diagnosis. AB - A 75-year-old woman lost vision because of delayed recognition of GCA. Early diagnosis and treatment of GCA are important for preventing visual complications. Physicians must remember to evaluate the entire body, not just a single organ/system. PMID- 29998046 TI - Hyperglycemia and chorea. AB - (A) Computed tomography of the brain showing no abnormal finding. (B) Magnetic resonance imaging of the brain showing a T1-weighted area of hyperintensity in the left putamen, caudate nucleus, and globus pallidum with sparing of the internal capsule (arrow). (C) T2*-weighted image showing hypointensity in the left putamen, caudate nucleus, and globus pallidum (arrowhead). (D) T2-weighted image showing no abnormal finding. PMID- 29998048 TI - Psoas sign of pneumoperitoneum. AB - Gastrointestinal perforation with psoas sign was diagnosed by abdominal radiography. Although CT is most useful modality for diagnosing gastrointestinal perforation, clinic doctors need to also swim abdominal radiography. PMID- 29998047 TI - Septic arthritis of the cervical facets: Unusual cause of neck pain. AB - Sagittal T2-weighted fat saturation magnetic resonance imaging reveals erosion and a high-intensity area around the C3-C4 facet joint. PMID- 29998049 TI - Antimicrobial stewardship without infectious disease physician. PMID- 29998050 TI - Author Reply to the Letter to the Editor: Antimicrobial stewardship without infectious disease physician. AB - We were pleased to read the letter to our article and decided to respond to the letter. PMID- 29998051 TI - In silico analysis of the alpha-amylase family GH57: eventual subfamilies reflecting enzyme specificities. AB - Glycoside hydrolases (GHs) have been classified in the CAZy database into 153 GH families. Currently, there might be four alpha-amylase families: the main family GH13, the family GH57 with related GH119 and, eventually, also GH126. The family GH57 was established in 1996 as the second and smaller alpha-amylase family. In addition to alpha-amylase, it contains 4-alpha-glucanotransferase, alpha-glucan branching enzyme, amylopullulanase, dual-specificity amylopullulanase cyclomaltodextrinase, non-specified amylase, maltogenic amylase and alpha galactosidase. The family GH57 enzymes employ the retaining reaction mechanism, share five typical conserved sequence regions and possess catalytic (beta/alpha)7 barrel succeeded by a four-helix bundle with the catalytic machinery consisting of catalytic nucleophile and proton donor (glutamic acid and aspartic acid at strands beta4 and beta7, respectively). The present bioinformatics study delivers a detailed sequence comparison of 1602 family GH57 sequences with the aim to highlight the uniqueness of each enzyme's specificity and all eventual protein groups. This was achieved by creating the evolutionary tree focused on both the enzyme specificities and taxonomical origin. The substantial increase of numbers of sequences from recent comparisons done more than 5 years ago has allowed to refine the details of the sequence logos for the individual enzyme specificities. The study identifies a new evolutionary distinct group of alpha-galactosidase related enzymes with until-now-undefined enzyme specificity but positioned on the evolutionary tree on a branch adjacent to alpha-galactosidases. The specificity of alpha-galactosidase is, moreover, the only one of the entire family GH57 for which there is no structural support for the proposal of the proton donor based on sequence analysis. The analysis also suggests a few so-called "like" protein groups related to some family GH57 enzyme specificities but lacking one or both catalytic residues. PMID- 29998053 TI - Up in smoke: An unusual case of diffuse alveolar hemorrhage from marijuana. AB - Diffuse alveolar hemorrhage (DAH) can be a serious and life threating condition. Illicit substance use has been associated with DAH, with cocaine being the most widely reported. Marijuana use has been associated with pulmonary complications in the form of pneumomediatsium, pneumothorax, bullous disease, and pulmonary aspergillosis. We present a case of diffuse alveolar hemorrhage (DAH) resulting from marijuana inhalation, a finding rarely described in the literature. A 21 year-old male presented with several episodes of hemoptysis after drinking alcohol and smoking marijuana. He reported smoking 5-8 joints per day of marijuana (he denied use of bongs or other inhalant aids). His respiratory exam revealed bilateral fine rales. Laboratory evaluation included leukocytosis with left shift, normal platelets, coagulation profile, and a urine toxicology screen positive for tetrahydocanabinoid (THC). Chest CT revealed bilateral diffuse alveolar infiltrates suggestive of DAH. A bronchoscopy with BAL of bilateral upper lobes consistent with DAH with negative microbiologic studies, hemosiderin laden macrophages were present. Additional workup included a normal Echocardiogram, negative autoimmune serologies. His hemoptysis resolved with supportive care. DAH is a potentially fatal disease that has been associated with illicit substance use, most commonly cocaine. Recently, reports have surfaced associating marijuana use with DAH, though these cases have all involved the use of bongs or other inhalant aids, leading to the hypothesis that combustibles and inhaled particles may be the etiologic factor. This is the second report of DAH developing after smoking only marijuana, though the etiology for the association between marijuana use and DAH remains uncertain. PMID- 29998052 TI - Neighbourhood deprivation, smoking, and race in South Africa: A cross-sectional analysis. AB - Research on the role of neighbourhood-level deprivation in low- and middle-income countries with respect to tobacco use is relatively nascent. In South Africa, where race and deprivation are closely linked due to the history of apartheid, smoking disparities exist by individual risk factors such as gender, race, and socioeconomic status. However, less is known about how community-level factors affect smoking disparities in the country, or how the relationship between deprivation and smoking differs by race. We used data from the 2008 South African National Income Dynamics Study (NIDS) and Poisson generalised estimating equations to assess the relationship between neighbourhood deprivation and current smoking for individuals nested within neighbourhoods, while controlling for individual-level and household-level covariates. Subgroup analyses for racial categories Black and Coloured were performed. We found that the relationship between neighbourhood deprivation and smoking prevalence was non-linear: the smoking prevalence ratio was highest among those in the middle range for our deprivation index, and lower at extremely high and low levels of deprivation. Both Black and Coloured subsamples exhibited this inverted U-shape, although the relationship was weaker in the latter group. That the relationship between neighbourhood deprivation and smoking is non-linear contrasts with what has been found in high-income countries, where the relationship between neighbourhood deprivation and smoking is linear. Moreover, these findings are relevant to assess the potential differential impact of smoking interventions as a function of socioeconomic and environmental context. PMID- 29998054 TI - Tocilizumab-effective multicentric Castleman's disease with infiltration of eosinophil and IgG4-positive plasma cells: A case report. AB - A 67-year-old woman with fever and cough was diagnosed with eosinophilic pneumonia because of eosinophilia and increased eosinophil levels in the bronchoalveolar lavage fluid and transbronchial biopsy lung specimens. However, prednisolone therapy at a previous hospital was ineffective. Histological findings from thoracoscopic lung and lymph node biopsies were consistent with multicentric Castleman's disease (MCD). Since specimens also showed prominent eosinophil and IgG4-positive plasma cell infiltration, it was difficult to distinguish IgG4-related disease (IgG4-RD) from MCD. Administration of prednisolone plus tocilizumab improved the symptoms and lung lesions, and prednisolone administration was successfully reduced and then terminated. The present case highlights the difficulty in diagnosing MCD and IgG4-RD, and suggests that combined administration of tocilizumab and prednisolone might be effective in such a case. PMID- 29998055 TI - Dysphonia and dyspnea in idiopathic hypereosinophilic syndrome treated with Mepolizumab. AB - Hypereosinophilic syndrome (HES) is characterized by a persistently elevated eosinophil count associated with eosinophil-related end-organ damage and thromboembolic events, in the absence of an identifiable cause. We present a case of idiopathic HES with evidence of peripheral and tissue eosinophilia while on high dose prednisone, associated with muscle tension dysphonia, colitis, and jackhammer esophagus. The patient was treated with the interleukin-5 inhibitor, Mepolizumab, with resolution of symptoms including dyspnea, diarrhea and dysphonia. PMID- 29998056 TI - Pulmonary embolism and deep vein thrombosis in eosinophilic granulomatosis with polyangiitis successfully treated with rivaroxaban. AB - A 41-year-old woman presented complaining of cough and purpura for one month. On her first visit, a blood test demonstrated peripheral blood eosinophilia, but chest radiography showed no abnormalities. However, 2 days after the first visit, she went to the emergency room because of fever and right-sided chest pain. Contrast-enhanced computed tomography of the chest showed pulmonary embolism and air space consolidation. Thrombosis was present in the popliteal vein. Bronchoscopy revealed alveolar hemorrhage and increased eosinophils in the bronchoalveolar lavage fluid, and a skin biopsy demonstrated a perivascular eosinophilic infiltrate. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). We started steroid therapy and low molecular-weight heparin (LMWH). The chest pain and fever disappeared, and the peripheral eosinophil count normalized. However, the thrombosis in the leg worsened. It was dramatically improved by changing from LMWH to oral rivaroxaban. The thrombogenic risk of eosinophilia should be recognized. This case suggests that oral rivaroxaban is useful when thrombosis is uncontrolled by LMWH in a patient with EGPA. PMID- 29998057 TI - Tumor necrosis factor- and interleukin-6-producing high-grade B-cell lymphoma, not otherwise specified in the pleura. AB - A 65-year-old man was admitted to our hospital with left-sided chest and back pain and dyspnea. Computed tomography demonstrated a marked circumferential left pleural thickening. A thoracoscopic pleural biopsy led to a diagnosis of high grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Lymphoma cells were positive for tumor necrosis factor (TNF) and interleukin-6. This is the first case report of TNF- and IL-6-producing aggressive HGBL, NOS in the pleura, in which radiological findings mimicked pleural mesothelioma. The aggressive tumor progression in the present case may have been caused by abnormal cytokine production from lymphoma cells. PMID- 29998058 TI - Secondary pure red cell aplasia in multiple myeloma treated with lenalidomide. AB - Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide. PMID- 29998059 TI - Resting-state fMRI reveals network disintegration during delirium. AB - Delirium is characterized by inattention and other cognitive deficits, symptoms that have been associated with disturbed interactions between remote brain regions. Recent EEG studies confirm that disturbed global network topology may underlie the syndrome, but lack an anatomical basis. The aim of this study was to increase our understanding of the global organization of functional connectivity during delirium and to localize possible alterations. Resting-state fMRI data from 44 subjects were analyzed, and motion-free data were available in nine delirious patients, seven post delirium patients and thirteen non-delirious clinical controls. We focused on the functional network backbones using the minimum spanning tree, which allows unbiased network comparisons. During delirium a longer diameter (mean (M) = 0.30, standard deviation (SD) = 0.05, P = .024) and a lower leaf fraction (M = 0.32, SD = 0.03, P = .027) was found compared to the control group (M = 0.28, SD = 0.04 respectively M = 0.35, SD = 0.03), suggesting reduced functional network integration and efficiency. Delirium duration was strongly related to loss of network hierarchy (rho = -0.92, P = .001). Connectivity strength was decreased in the post delirium group (M = 0.16, SD = 0.01) compared to the delirium group (M = 0.17, SD = 0.03, P = .024) and the control group (M = 0.19, SD = 0.02, P = .001). Permutation tests revealed a decreased degree of the right posterior cingulate cortex during delirium and complex regional alterations after delirium. These findings indicate that delirium reflects disintegration of functional interactions between remote brain areas and suggest long-term impact after the syndrome resolves. PMID- 29998061 TI - Urethral diverticulum repair using diverticulum wall: A new technique for preparing covering flap layer. PMID- 29998060 TI - Pneumococcal urinary antigen test: A tool for pneumococcal aortitis diagnosis? AB - Introduction: Aortitis is rare. The etiological diagnosis is difficult but essential for treatment. Even with appropriate treatment mortality remains high. We present a case of pneumococcal aortitis followed by a brief review of the literature. Presentation of Case: In this case, the aortic disease was characterized by multiple inflammatory aneurysms. Blood cultures were negative but urine was tested for the presence of pneumococcal urinary antigen postoperatively was positive. Treatment consisted of antibacterial therapy and both surgical and endovascular procedures. The patient was discharged and is well. Discussion: Preoperative determination of etiology is crucial in implementing a specific treatment. Pneumococcus is a common bacterium in infectious aortitis. Identification of the causative microbe is necessary to guide antimicrobial therapy. Blood cultures are frequently sterile. The pneumococcal urinary antigen test may be more sensitive than blood cultures, as is the case in pneumococcal pneumonia. Conclusions: The pneumococcal urinary antigen test may was a useful diagnostic tool in establishing the cause for aortitis in this case. Its potential value should be assessed in furthers studies. PMID- 29998062 TI - Recurrent bladder trichobezoars in a quadriplegic patient. PMID- 29998063 TI - Total endoscopic management of a patient with urinary bladder leiomyosarcoma presenting with dysuria: A case report. AB - The pathophysiology of bladder leiomyosarcoma, a rare disease with aggressive mesenchymal tumor, is not certain, but its main symptoms are hematuria, dysuria and abdominal pain. Cases described in the literature are few. This report describes a case of a leiomyosarcoma of the urinary bladder in a 49-year-old woman. After CT scanning revealed a heterogeneously enhanced 4-cm mass involving the bladder neck and anterior wall, further examinations detected no metastatic lesion. Cystoscopy and transurethral resection of bladder tumor (TURBT) were performed. The histopathological diagnosis was leiomyosarcoma. Postoperative period was uneventful. The patient experienced complete resolution of urologic symptoms. Repeat-TURBT was performed 70 days after first surgery. The patient has remained disease-free 18 months after surgery. PMID- 29998064 TI - Surgical excision of an acutely symptomatic subpubic cartilaginous cyst in a 70 year old male. PMID- 29998065 TI - Robotic partial cystectomy for venous malformation of the bladder. PMID- 29998066 TI - The impact of an adrenal incidentaloma algorithm on the evaluation of adrenal nodules. AB - Objective: To determine the impact of the use of an electronic medical record tool on the evaluation of adrenal incidentalomas. Methods: Retrospective chart review was used to compare rates of hormone testing and follow up imaging for adrenal incidentalomas. Patients whose radiology reports contained an algorithm with recommendations, based on our 2013 clinical guideline for the workup of these nodules, were compared to those whose imaging reports did not contain the algorithm. Results: For patients whose Radiology reports contained the algorithm, 69% had hormonal testing versus 43% of controls (p < 0.0001). By contrast, 57% of study group patients had a follow up imaging study, compared to 51% of controls (p = 0.1000). However, when the 18% of controls that were given guidance by the radiologist to perform follow-up imaging were excluded from those who received no guidance, there was a statistically significant difference in the rate of follow up imaging (57% vs 48%, p < 0.0001). Conclusion: Implementation of a clinical algorithm for the evaluation of adrenal incidentalomas in radiology reports and on the intranet site of a major clinical center led to improved rates of hormone testing. There was also a significant increase in the rate of follow up imaging, compared to when no guidance was given. Additional efforts to further improve performance are needed to increase the detection of clinically significant lesions, particularly hormone secreting tumors that should be removed. PMID- 29998067 TI - A sandwich enzyme-linked immunosorbent assay for the quantitation of human plasma ferritin. AB - There is a lack of published enzyme linked immunosorbent assay (ELISA) protocols which use commercially available reagents for the measurement of ferritin in human plasma for research purposes. ELISA kits are often expensive and do not always provide detailed information about reagents included. A commercially available antibody pair was used to develop an in-house ELISA to measure ferritin in small (25 MUl) volumes of human plasma. ELISA results were compared to ferritin levels measured using a commercial immune-assay system. The sensitivity, intra and inter assay variation of the ELISA assay were also determined. ELISA measurements of plasma ferritin ranged between 3.2-232 ng/mL and were comparable to those measured by a commercial immunoassay system (Pearson correlation r = 0.93 P < 0.0001). Ferritin levels as low as 0.5 ng/mL were detectable and samples with both low and normal ferritin levels showed low inter and intra-assay variation. This ELISA protocol allows the accurate, reliable and cost-effective quantitative determination of plasma ferritin levels from small volumes of human plasma. *No published protocols detail how to measure ferritin by ELISA using commercially available antibodies.*ELISA kits are expensive and information on antibodies included are often lacking.*We have identified a commercially available antibody pair to measure plasma ferritin using a cost-effective ELISA. PMID- 29998068 TI - Automated 3D EBSD for metallic powders. AB - Metallic powders are commonly used in additive manufacturing processes. While their post-process consolidated properties are widely studied, there is little research on the properties of the powders prior to consolidation. Understanding the powder characteristics before use in additive manufacturing processes could lead to fine-tuning properties of additively manufactured materials. The three dimensional grain structure of metals can be useful in predicting their properties and microstructure. Powder particles are much smaller and more difficult to fixture and polish than their bulk counterparts, hence typical protocols are difficult to use when serially sectioning them. This method describes a recommendation as to how to fixture, mill, and image metallic powder particles using a Xe P-FIB to mill and take EBSD measurements. It is based on milling and imaging techniques used for bulk materials, but with the specific advantage of how to fixture the powder sample. Our modifications include: *the method of fixturing the specimen to the holder.*the method of protecting the sample during milling. PMID- 29998069 TI - Quantitative determination of perfluoroalkyl substances (PFAS) in soil, water, and home garden produce. AB - This data article includes details on the simple and efficient analytical methods used to measure perfluoroalkyl substances (PFASs) in water, soil, and produce from home gardens in Minnesota. PFASs in water were analyzed via direct injection. PFASs were extracted from homogenized soil using sonication, and from produce using dispersive solid phase extraction. Isotope dilution was used for quantitation in all methods. The method performance parameters and quality control measures are described. The methods described are applicable for a PFAS ranging from C4-C8 and the produce method was used on a wide variety of produce. For further details and experimental findings, please refer to the article "Occurrence of perfluoroalkyl substances (PFAS) in garden produce at homes with a history of PFAS-contaminated drinking water" The key benefits of this method are: *This method adapts dispersive solid phase extraction for the analysis of PFAS in produce.*The method can be used to analyze PFAS ranging from 4 to 8 carbons in a variety of produce types. PMID- 29998070 TI - RemScan: A tool for monitoring the bioremediation of Total Petroleum Hydrocarbons in contaminated soil. AB - Total Petroleum Hydrocarbons (TPH) represent major environmental contaminants which pose a significant risk to ecosystems and humans heath if left untreated. Bioremediation represents a simple, cheap and environmentally-safe approach to clean up TPH-contaminated sites. Traditional TPH analysis is expensive and time consuming. Here we assess, for the first time, the potential of RemScan as a fast, accurate and cost-effective portable device to be used as a tool to monitor the bioremediation process. A variety of TPH-contaminated soils were subject to TPH quantitative analysis using RemScan. The TPH values obtained were validated and compared against the results obtained from an accredited external laboratory, which uses Gas Chromatography / Mass Spectrometry (GC/MS) for TPH analysis. *RemScan showed a correlation coefficient (R2) of 0.998 in comparison with the traditional methods, but importantly with a significant reduction in both time and cost.*RemScan was successfully used to measure TPH concentrations in bioremediated, weathered-contaminated and highly contaminated soil samples with TPH concentrations varying from 100 to 100,000 mg kg-1.*The RemScan Laboratory Station was used to minimize the source of errors associated with human manual handling. PMID- 29998071 TI - Single-cell cloning enables the selection of more productive Drosophila melanogaster S2 cells for recombinant protein expression. AB - The generation of monoclonal cell lines is an important early process development step for recombinant protein production. Although single-cell cloning is an established method in mammalian cell lines, straightforward protocols are not yet available for insect cells. We describe a new method for the generation of monoclonal insect cells without using fetal bovine serum and/or feeder cells pretreated by irradiation or exposure to mitomycin. Highly productive clones of Drosophila melanogaster S2 cells were prepared in a two-step procedure, comprising the establishment of a polyclonal population and subsequent single cell isolation by limiting dilution. Necessary growth factors were provided by co cultivation of single transformants with untransfected feeder cells, which were later removed by antibiotic selection. Enhanced expression of EGFP and two target peptides was confirmed by flow cytometry and dot/western blotting. Highly productive clones were stable, showed a uniform expression profile and typically a sixfold to tenfold increase in cell-specific productivity. PMID- 29998072 TI - Effect of salicylic acid and methyl jasmonate in the production of phenolic compounds in plant cell suspension cultures of Thevetia peruviana. AB - The objective was to enhance the production of the phenolic compounds in plant cell suspension cultures of T. peruviana at shake flask scale. The effects of salicylic acid (SA), methyl-jasmonate (MeJA) and the combination of both (SA/MeJA) were studied. Elicitor concentration, elicitation time and harvest time of cells were optimized. Phenolic compound content (PCC), flavonoid content (FC) and antioxidant activity (AA) were determined by the folin-ciocalteu method, flavonoid-aluminum complexation method and the ABTS assay, respectively. Differences between intracellular metabolite profiles due to the mentioned treatments were analyzed by Thin-layer chromatography and High-performance liquid chromatography. Highest PCC, FC and AA were obtained under the following treatments: 3 MUM MeJA > 3 MUM MeJA/300 MUM SA > 300 MUM SA > control, when elicited on the 4th day and harvested 96-h post-elicitation. It was demonstrated that exposure to 3 MUM MeJA increase 1.49-fold of PCC, 1.66-fold of AA and 2.55 fold of FC compared to the control culture. PMID- 29998073 TI - Nipple sparing mastectomy: indications and reconstruction. PMID- 29998074 TI - Evidence based outcomes of the American Society of Breast Surgeons Nipple Sparing Mastectomy Registry. AB - Background: The American Society of Breast Surgeons (ASBrS) Nipple Sparing Mastectomy Registry (NSMR) is a prospective, non-randomized, IRB approved, multi institutional registry. The purpose of this Registry is to provide a large, prospective, non-randomized database of patient characteristics, tumor characteristics, surgical technique, and outcome (both aesthetic and oncologic) of the nipple sparing mastectomy (NSM). Methods: Data is entered into the ASBrS NSMR, housed within the Mastery of Surgery Program, after patients consent to participation. Each investigator routinely offers NSM in their practice has obtained IRB approval and completed forms of agreement to participate in the ASBrS NSMR. Results: This data set represents a total of 1,935 NSMs performed on 1,170 patients by 98 investigators from 70 institutions/sites. Of the 1,935 NSMs: 833 were performed for an indication of cancer [594 invasive carcinoma and 239 for ductal carcinoma in situ (DCIS)] and 1,102 were prophylactic. Of the 1,170 total patients, 352 underwent a unilateral and 818 underwent a bilateral NSM. Recurrence at a mean follow-up of 31 months/median follow-up of 27 months, with a range of 9.7 to 58.3 months since surgery was 1.4% with no recurrences at the nipple or nipple areola complex (NAC). Cancer occurrence (0.3%) also did not involve the nipple/NAC. Overall patient satisfaction of excellent/good: 94.9% and overall cosmesis (surgeon rated) of excellent/good was 96.4%. Overall infection rates included flap infection of 4.4%, NAC complication rate of 4.5% (defined as necrosis/other or ischemia/epidermolysis requiring surgery), and a 10% rate of NAC epidermolysis with full recovery. Conclusions: NSMs were performed on breasts with a variety of sizes and degrees of ptosis, via multiple incisions, dissection and reconstruction techniques with low complication rates and high patient satisfaction and surgeon rated cosmesis. PMID- 29998075 TI - Nipple sparing mastectomy and direct to implant breast reconstruction, validation of the safe procedure through the use of laser assisted indocyanine green fluorescent angiography. AB - Background: Nipple sparing mastectomy (NSM) is a psychologically effective and oncological safe procedure followed by immediate breast reconstruction. Methods: Between January 2015 and September 2015 the authors conducted a retrospective review of 40 patients divided into two groups depending on breast volume and weight of mastectomy: group A, 20 patients with small breast; group B, 20 patients with medium breast for nipple sparing mastectomy and direct to implant (DTI) breast reconstruction using strict patient selection and a standardized surgical technique. The nipple areola complex/flap viability were analysed intraoperatively through the use of laser assisted indocyanine green (ICG) fluorescent angiography. Results: A total of 44 procedures were followed-up for 24 months. Nineteen patients were assisted in DTI breast reconstruction by acellular dermal matrix (ADM) for inferior/lateral part of the implant coverage. Encouraging results are presented with a unique case of implant failure. Conclusions: We report our retrospective experience corroborated by intraoperative laser assisted ICG fluorescent angiography to demonstrate the safety and reliability of the oncoplastic procedure proposed. We also advocate the central role of oncoplastic surgeon as "one man band" to manage breast cancer from the oncological procedure to the breast reconstruction. PMID- 29998076 TI - Nipple sparing mastectomy and the evolving direct to implant breast reconstruction. AB - In this paper, we describe the evolving use of the nipple-sparing mastectomy (NSM) and direct to implant breast reconstruction according to existing literature and our own experience. The surgical method enables superior aesthetic results resembling that of a natural breast while maintaining oncologic safety. Acellular dermal matrix enables direct to implant breast reconstruction by serving as a hammock and can be used with acceptable rates of complications. A successful nipple-sparing mastectomy and direct to implant breast reconstruction approach with acceptable postoperative complication rates relies upon quality of the mastectomy skin flaps and correct patient selection. The surgical method has developed with a rapid pace and expected to evolve further in terms of technical modalities, safety measure and lasting results. PMID- 29998077 TI - Nipple sparing mastectomy techniques: a literature review and an inframammary technique. AB - Nipple sparing mastectomy (NSM) has quickly become an accepted technique for patients with selected cancers and for risk reducing surgery. Much of its surgical acceptance over the last decade has been based on the low risk of nipple areolar complex (NAC) occurrence in breast cancer patients. Improved patient satisfaction due to improved cosmetic outcomes with reconstruction have also driven its popularity. We reviewed current English journals to determine the NSM techniques which achieve the lowest complications, best outcomes, and best patient satisfaction. We researched studies showing reductions in complications with improved surgical techniques and patient selection which have been implicated in improved results. In the studies reviewed, incision placement, away from the nipple, resulted in the lowest rates of ischemic nipple complications and the best cosmetic outcomes. The effect of other factors such as surgeon experience and thickness of skin flap development were more difficult to prove. Leaving a 2-3 mm rim of tissue around the nipple bundle was shown to help preserve the nipple vascularity. Lower complication rates with improved outcomes and patient satisfaction were reported in the literature in patients with B or smaller cup sizes, non-smokers, and patients with lower body mass index (BMI). Incision placement, away from the nipple, with preservation of a 2-3 mm rim of tissue around the nipple bundle along with careful patient selection were the most significant variables reviewed which helped to lower complications rates of NSM. Coordinated surgical planning with the breast and plastic surgeons to determine the best surgical approach for each individual patient is necessary to obtain the best results. Although short-term oncologic follow-up seems to be acceptable, longer follow-up will still be needed to define the best breast cancer surgical candidates for the nipple sparing approach. PMID- 29998079 TI - Evaluation of skin viability in nipple sparing mastectomy (NSM). AB - Nipple sparing mastectomy (NSM) is quickly becoming the standard of care due to earlier stage of breast cancer diagnosis, increased prevalence of prophylactic mastectomies, improved surgical techniques, and the desire of women to keep their nipples. However, the procedure is plagued with problems of nipple and skin necrosis due to the inherent ischemic nature of mastectomy. Indocyanine green (ICG) technologies offer surgeons new information that is helpful in the battle to reduce these devastating complications. PMID- 29998078 TI - Overview of indications for nipple sparing mastectomy. AB - The introduction of more targeted systemic therapies, better screening modalities with earlier diagnosis and dramatically improved reconstructive techniques has allowed more minimally invasive approaches to breast surgery. The recent introduction of nipple sparing mastectomy (NSM) has dramatically improved the cosmetic outcomes and quality of life (QoL) for patients undergoing mastectomy. This technique involves preservation of both the skin envelope including the nipple areolar complex commonly through a barely visible inframammary skin incision followed by immediate breast reconstruction. An ideal candidate includes women with small breasts, absence of ptosis, low BMI and not actively smoking. High risk patients include those with radiation treatment, active smokers, macromastia, high BMI >30 kg/m2, grade 2 or 3 ptosis and active smokers. There are several new techniques to approach complex high risk patients which have expanded the candidates for NSM. PMID- 29998080 TI - The evolution of mastectomy surgical technique: from mutilation to medicine. AB - Breast surgeries for cancer and tumors were first described approximately 3,000 years ago, and since that time the standard of management has changed dramatically. From Egyptian papyri to Hippocratic theory, from Galen's dissections to Halsted's radical mastectomy, and from sentinel lymph node mapping to the development of nipple-sparing mastectomies, this review starts at the beginning and highlights breakthroughs and innovation in technique and medicine that have fundamentally changed the way breast cancer is managed. The progression depicted in this review acts as a proxy to the management of other complex diseases. Breast cancer was initially managed with operative extirpation alone, but now requires a multidisciplinary team across various surgical, medical, psychological, and social specialties in order to produce the best outcomes for our patients. PMID- 29998081 TI - Autologous reconstruction following nipple sparing mastectomy: a comprehensive review of the current literature. AB - As surgical methods continue to evolve and patients become more educated consumers of their medical care, both oncologic breast surgeons and reconstructive plastic surgeons should understand the current options for surgical management of breast cancer. This review evaluates the current autologous breast reconstruction options following nipple sparing mastectomy (NSM). A comprehensive review of the current literature discussing autologous reconstruction after NSM was performed. Fat grafting alone has been used to reconstruct small to medium sized-breasts over multiple injection sessions. Goldilocks mastectomy-like reconstructions can be used for larger, more ptotic breasts. Pedicled latissimus dorsi (LD) flaps can be used, but usually need to be modified to ensure sufficient breast volume. While the lower abdominal tissue remains the most common donor site in free tissue transfer, other donor sites can be used if there is insufficient volume or inadequate perforators. Periareolar incisions are associated with the highest rates of overall complications and nipple areola complex necrosis. It has not been determined whether implant-based or autologous reconstructions have lower complication rates. Both prior radiation and large, ptotic breasts present unique challenges during reconstruction. Overall, there is a high rate of patient satisfaction with breast reconstruction following NSM. Autologous breast reconstruction after NSM is a safe method of breast cancer surgical management with aesthetically excellent results. Multiple techniques have been described along the reconstructive ladder. Special consideration should be given to choices of incision, previously irradiated breasts, and large, ptotic breasts. PMID- 29998082 TI - Nipple-sparing mastectomy in women at high risk of developing breast cancer. AB - Nipple-sparing mastectomy is a valuable addition to the options available for women at high risk of developing breast cancer. In this review, we summarize current knowledge about the high-risk genes, BRCA1, BRCA2 and TP53 and the associated guidelines with regard to risk-reducing surgery. We consider other genetic risks and high-risk lesions. We discuss the literature on bilateral mastectomy for breast cancer risk-reduction, and the results of nipple-sparing mastectomy in particular. Finally, we report on patient satisfaction with these procedures and the impact that nipple-sparing mastectomy may have on women at high-risk of breast cancer. PMID- 29998083 TI - Utilizing large volume fat grafting in breast reconstruction after nipple sparing mastectomies. AB - Nipple sparing mastectomy (NSM) has gained popularity especially in prophylactic mastectomies allowing improved cosmetics. Traditionally reconstruction has utilized implants or autologous tissue. With the development of large volume fat grafting additional reconstructive techniques can be utilized in NSM reconstruction. This can either complement a technique or be a standalone form of reconstruction. This paper is intended to serve as a broad overview of fat grafting and its potential role in reconstructing the breast following nipple sparing mastectomies. PMID- 29998085 TI - MAP1203 Promotes Mycobacterium avium Subspecies paratuberculosis Binding and Invasion to Bovine Epithelial Cells. AB - Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's disease, chronic and ultimately fatal enteritis that affects ruminant populations worldwide. One mode of MAP transmission is oral when young animals ingest bacteria from the collostrum and milk of infected dams. The exposure to raw milk has a dramatic impact on MAP, resulting in a more invasive and virulent phenotype. The MAP1203 gene is upregulated over 28-fold after exposure of the bacterium to milk. In this study, the role of MAP1203 in binding and invasion of the bovine epithelial cells was investigated. By over-expressing the native MAP1203 gene and two clones of deletion mutant in the signal sequence and of missense mutations changing the integrin domain from RGD into RDE, we demonstrate that MAP1203 plays a role in increasing binding in more than 50% and invasion in 35% of bovine MDBK epithelial cells during early phase of infection. Furthermore, results obtained suggest that MAP1203 is a surface-exposed protein in MAP and the signal sequence is required for processing and expression of functional protein on the surface of the bacterium. Using the protein pull-down assay and far Western blot, we also demonstrate that MAP1203 interacts with the host dihydropyrimidinase-related protein 2 and glyceraldehyde 3-phosphate dehydrogenase proteins, located on the membrane of epithelial cell and involved in the remodeling of the cytoskeleton. Our data suggests that MAP1203 plays a significant role in the initiation of MAP infection of the bovine epithelium. PMID- 29998084 TI - NOTCH1 Aberrations in Chronic Lymphocytic Leukemia. AB - Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by highly variable clinical outcomes. In recent years, genomic and molecular studies revealed a remarkable heterogeneity in CLL, which mirrored the clinical diversity of this disease. These studies profoundly enhanced our understanding of leukemia cell biology and led to the identification of new biomarkers with potential prognostic and therapeutic significance. Accumulating evidence indicates a key role of deregulated NOTCH1 signaling and NOTCH1 mutations in CLL. This review highlights recent discoveries that improve our understanding of the pathophysiological NOTCH1 signaling in CLL and the clinical impact of NOTCH1 mutations in retrospective and prospective trials. In addition, we discuss the rationale for a therapeutic strategy aiming at inhibiting NOTCH1 signaling in CLL, along with an overview on the currently available NOTCH1-directed approaches. PMID- 29998086 TI - The Infection Process of Yersinia ruckeri: Reviewing the Pieces of the Jigsaw Puzzle. AB - Finding the keys to understanding the infectious process of Yersinia ruckeri was not a priority for many years due to the prompt development of an effective biotype 1 vaccine which was used mainly in Europe and USA. However, the gradual emergence of outbreaks in vaccinated fish, which have been reported since 2003, has awakened interest in the mechanism of virulence in this pathogen. Thus, during the last two decades, a large number of studies have considerably enriched our knowledge of many aspects of the pathogen and its interaction with the host. By means of both conventional and a variety of novel strategies, such as cell GFP tagging, bioluminescence imaging and optical projection tomography, it has been possible to determine three putative Y. ruckeri infection routes, the main point of entry for the bacterium being the gill lamellae. Moreover, a wide range of potential virulence factors have been highlighted by specific gene mutagenesis strategies or genome-wide transposon/plasmid insertion-based screening approaches, such us in vivo expression technology (IVET) and signature tagged mutagenesis (STM). Finally, recent proteomic and whole genomic analyses have allowed many of the genes and systems that are potentially implicated in the organism's pathogenicity and its adaptation to the host environmental conditions to be elucidated. Altogether, these studies contribute to a better understanding of the infectious process of Y. ruckeri in fish, which is crucial for the development of more effective strategies for preventing or treating enteric redmouth disease (ERM). PMID- 29998087 TI - Molecular Characterization of Dengue Virus Serotype 2 Cosmospolitan Genotype From 2015 Dengue Outbreak in Yunnan, China. AB - In 2015, a dengue outbreak with 1,067 reported cases occurred in Xishuangbanna, a city in China that borders Burma and Laos. To characterize the virus, the complete genome sequence was obtained and phylogenetic, mutation, substitution and recombinant analyses were performed. DENV-NS1 positive serum samples were collected from dengue fever patients, and complete genome sequences were obtained through RT-qPCR from these serum samples. Phylogenetic trees were then constructed by maximum likelihood phylogeny test (MEGA7.0), followed by analysis of nucleotide mutation and amino acid substitution. The recombination events among DENVs were also analyzed by RDP4 package. The diversity analysis of secondary structure for translated viral proteins was also performed. The complete genome sequences of four amplified viruses (YNXJ10, YNXJ12, YNXJ13, and YNXJ16) were 10,742, 10,742, 10,741, and 10,734 nucleotides in length, and phylogenetic analysis classified the viruses as cosmopolitan genotype of DENV-2. All viruses were close to DENV Singapore 2013 (KX380828.1) and the DENV China 2013 (KF479233.1). In comparison to DENV-2SS (M29095), the total numbers of base substitutions were 712 nt (YNXJ10), 809 nt (YNXJ12), 772 nt (YNXJ13), and 841 nt (YNXJ16), resulting in 109, 171, 130, and 180 amino acid substitutions in translated regions, respectively. In addition, compared with KX380828.1, there were 44, 105, 64, and 116 amino acid substitutions in translated regions, respectively. The highest mutation rate occurred in the prM region, and the lowest mutation rate occurred in the NS4B region. Most of the recombination events occurred in the prM, E and NS2B/3 regions, which corresponded with the mutation frequency of the related portion. Secondary structure prediction within the 3,391 amino acids of DENV structural proteins showed there were 7 new possible nucleotide-binding sites and 6 lost sites compared to DENV-2SS. In addition, 41 distinct amino acid changes were found in the helix regions, although the distribution of the exposed and buried regions changed only slightly. Our findings may help to understand the intrinsic geographical relatedness of DENV-2 and contributes to the understanding of viral evolution and its impact on the epidemic potential and pathogenicity of DENV. PMID- 29998088 TI - Protective Role of Rabbit Nucleotide-Binding Oligomerization Domain-2 (NOD2) Mediated Signaling Pathway in Resistance to Enterohemorrhagic Escherichia coli Infection. AB - Nucleotide-binding oligomerization domain 2 (NOD2), a member of the NOD-like receptors (NLRs) family that is well-known to play a key role in innate immune responses and is involved in innate antibacterial responses. In this study, rabbit NOD2 (rNOD2) was cloned from rabbit kidney (RK) cells. It was distributed in various tissues, and the highest level of rNod2 was detected in spleen. Moreover, the expression of rNod2 was significantly upregulated in the heart, liver, and spleen induced by enterohemorrhagic Escherichia coli (EHEC). Overexpression of rNOD2 induced the expression of pro-inflammatory cytokine, including Il1beta, Il6, Ifn-gamma, and Tnf, as well as defensins, including Defb124, Defb125, and Defb128 through the nuclear factor (NF)-kappaB signaling pathway. Furthermore, overexpression of rNOD2 inhibited the growth of EHEC, and knockdown of rNOD2 or inhibition of the NF-kappaB pathway promoted its replication. In addition, our results suggest that rNOD2 can significantly activate NF-kappaB signaling and trigger antibacterial defenses to increase the expression of pro-inflammatory cytokine and defensins after stimulation by EHEC. These findings are useful to further understanding the innate immune system of rabbits and providing a new perspective for the prevention of bacterial diseases in rabbits. PMID- 29998090 TI - Tei Index Is the Best Echocardiographic Parameter for Assessing Right Ventricle Function in Patients With Unrepaired Congenital Heart Diseases With Outflow Tract Obstruction. AB - Objective: Magnetic resonance imaging (MRI) and cardiac catheterization are diagnostic tools for right ventricle dysfunction (RVD), but those are expensive and often unavailable techniques. Thus, our objective was to identify clinical and/or echocardiographic variables capable of predicting a catheterization-based diagnosis of RVD. Design: This was cross-sectional, diagnostic test accuracy study, considering the catheterization-based diagnosis of RVD as the gold standard. Patients: Pediatric patients with non-repaired CHD with overload pressure were evaluated. Clinical variables (edema and functional class), transthoracic echocardiography (right heart dimensions, systolic and diastolic function, Doppler velocities), and cardiac catheterization (pressures and right ventricle systolic work measurements) were obtained during the same hospitalization. Results: We included 253 patients with tetralogy of Fallot (39.9%), pulmonary atresia with ventricular septal defect (33.9%), type C Ebstein's anomaly (15.8%), or pulmonary stenosis (10.4%). Among clinical (vascular congestion, functional class derangement) and echocardiographic (indexed right ventricle diameter, fractional area change, tricuspid annular plane systolic excursion, S' wave, Tei index) variables, the Tei index (defined as the ratio of isovolumetric contraction time to ejection time) was the sole variable that exhibited high diagnostic capability, with 98.5% sensitivity, 97.4% specificity, 97.8% positive predictive value, and 98.3% negative predictive value, with 98.0% overall performance. Multivariate logistic regression confirmed that Tei index alone predicted the catheterization-based diagnosis of RVD. Conclusions: Tei index is the best parameter that can be employed for the non invasive identification of RVD in patients with CHD. PMID- 29998089 TI - Biomarkers of Cutaneous Leishmaniasis. AB - Cutaneous leishmaniasis (CL) is an immune-mediated skin pathology caused mainly by Leishmania (L.) major, Leishmania tropica, Leishmania braziliensis, L. mexicana, and L. amazonensis. The burden of CL in terms of morbidity and social stigmas are concentrated on certain developing countries in Asia, Africa, and South America. People with asymptomatic CL represent a large proportion of the infected individuals in the endemic areas who exhibit no lesion and can control the infection by as yet not fully understood mechanisms. Currently, there is no approved prophylactic control measure for CL. Discovery of biomarkers of CL infection and immunity can inform the development of more precise diagnostics tools as well as curative or preventive strategies to control CL. Herein, we provide a brief overview of the state-of-the-art for the biomarkers of CL with a special emphasis on the asymptomatic CL biomarkers. Among the identified CL biomarkers so far, direct biomarkers which indicate the actual presence of the infection as well as indirect biomarkers which reflect the host's reaction to the infection, such as alterations in delayed type hypersensitivity, T-cell subpopulations and cytokines, adenosine deaminase, and antibodies against the sand fly saliva proteins are discussed in detail. The future avenues such as the use of systems analysis to identify and characterize novel CL biomarkers are also discussed. PMID- 29998091 TI - Knowledge, Attitude, Awareness, and Barriers Toward Influenza Vaccination Among Medical Doctors at Tertiary Care Health Settings in Peshawar, Pakistan-A Cross Sectional Study. AB - Objective: This study intends to evaluate the knowledge, attitude and awareness of medical doctors toward influenza vaccination and the reasons for not getting vaccinated. Methods: A cross-sectional study was carried out among medical doctors in three major tertiary care health settings in Peshawar, Khyber Pakhtunkhwa (KP), Pakistan. A web-based, pre-tested questionnaire was used for data collection. Results: A total of (n = 300) medical doctors were invited, however only (n = 215) participated in the study with a response rate of 71.7%. Among the participants, 95.3% (n = 205) were males with a mean age of 28.67 +/- 3.89 years. By designation, 121(56.3%) were trainee medical officers and 40 (18.6%) were house officers. The majority 102(47.4%) had a job experience of 1-2 years. Of the total sample, 38 (17.7%) doctors reported having received some kind of vaccination, whereas only 19 (8.84%) were vaccinated against influenza. The results identified that the major barriers toward influenza vaccinations included (1) Unfamiliarity with Influenza vaccination availability (Relative Importance Index RII = 0.830), (2) Unavailability of Influenza vaccines due to lack of proper storage area in the institution (RII = 0.634), (3) Cost of vaccine (RII = 0.608), and (4) insufficient staff to administer vaccine (RII = 0.589). Additionally, 156 (72.6%) of doctors were not aware of the influenza immunization recommendation and guidelines published by the Advisory Committee on Immunization Practices (ACIP) and Centre for Disease Control and Prevention (CDC). Physicians obtained a high score (8.27 +/- 1.61) of knowledge and understanding regarding influenza and its vaccination followed by medical officers (8.06 +/- 1.37). Linear Regression analysis revealed that gender was significantly associated with the knowledge score with males having a higher score (8.0+/- 1.39) than females (6.80 +/- 1.61 beta = -1.254 and CI [-2.152 to -0.355], p = 0.006). Conclusion: A very low proportion of doctors were vaccinated against influenza, despite the published guidelines and recommendations. Strategies that address multiple aspects like increasing awareness and the importance of the influenza vaccine, the international recommendations and enhancing access and availability of the vaccine are needed to improve its coverage and health outcomes. PMID- 29998092 TI - Impact of a Healthy Weight Intervention Embedded Within a National Home Visiting Program on the Home Food Environment. AB - Purpose: To determine whether a lifestyle intervention embedded within Parents as Teachers (PAT), a national child development and parenting home visiting program, helped families make food-related home environment changes. Design: Secondary data analysis of a stratified randomized pragmatic trial. (Trial Registration: This study is registered at www.clinicaltrials.gov NCT01567033). Setting: Participant homes in St. Louis, Missouri. Subjects: Women (n = 179 with pre-post data, of 230 with baseline) participating in standard PAT, with overweight or obesity, and at least one preschool child with BMI percentile >=60%. Intervention: PAT + Healthy Eating and Active Living Taught at Home (HEALTH), embedded elements of the Diabetes Prevention Program within the standard PAT curriculum. PAT + HEALTH addressed specific behaviors that impact caloric intake (e.g., sugar-sweetened beverages), focusing on behavioral and environmental strategies. Consistent with PAT practice, the frequency, number, and focus (i.e., time spent on intervention components) of home visits were determined by the family's needs; dose structure was flexible [on average intervention: 23 (SD = 9), usual care: 13 (SD = 6) visits]. Measures: Food availability/accessibility and distractions in the home were assessed with items drawn largely from the HomeSTEAD Survey. Analysis: Generalized estimating equations (GEEs) were used to test equality of changes between baseline and 24 months in the intervention and usual care groups. Results: The only significant difference in the pattern of change between usual care and intervention was soda availability/accessibility (p = 0.013). Conclusion: This embedded intervention successfully reduced availability/accessibility of sugar-sweetened beverages in the home. However, given the limited impact on other food-related home environment factors, future interventions could seek to more effectively intervene on all aspects of the home environment. PMID- 29998093 TI - Microbial Interaction as a Determinant of the Quality of Supply Drinking Water: A Conceptual Analysis. AB - This conceptual analysis elucidates the microbial interaction inside municipal distribution pipes, subsequent deterioration in the quality of the supply water, and its impacts on public health. Literature review involved a total of 21 original reports on microbiological events inside the water distribution system were studied, summarizing the current knowledge about the build-up of microbes in treated municipal water at various points of the distribution system. Next, original reports from the microbiological analysis of supply water from Bangladesh were collected to enlist the types of bacteria found growing actively. A schematic diagram of microbial interaction among the genera was constructed with respect to the physical, chemical, and microbiological quality of the supply water. Finally latest guidelines and expert opinions from public health authorities around the world are reviewed to keep up with using cutting-edge molecular technology to ensure safe and good quality drinking water for municipal supply. PMID- 29998094 TI - A Theoretical Study of the Benzoylformate Decarboxylase Reaction Mechanism. AB - Density functional theory calculations are used to investigate the detailed reaction mechanism of benzoylformate decarboxylase, a thiamin diphosphate (ThDP) dependent enzyme that catalyzes the nonoxidative decarboxylation of benzoylformate yielding benzaldehyde and carbon dioxide. A large model of the active site is constructed on the basis of the X-ray structure, and it is used to characterize the involved intermediates and transition states and evaluate their energies. There is generally good agreement between the calculations and available experimental data. The roles of the various active site residues are discussed and the results are compared to mutagenesis experiments. Importantly, the calculations identify off-cycle intermediate species of the ThDP cofactor that can have implications on the kinetics of the reaction. PMID- 29998095 TI - Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity. AB - Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease. PMID- 29998096 TI - Covalent Attachment of Enzymes to Paper Fibers for Paper-Based Analytical Devices. AB - Due to its unique material properties, paper offers many practical advantages as a viable platform for sensing devices. In view of paper-based microfluidic biosensing applications, the covalent immobilization of enzymes with preserved functional activity is highly desirable and ultimately challenging. In the present manuscript, we report an efficient approach to achieving the covalent attachment of certain enzymes on paper fibers via a surface-bound network of hydrophilic polymers bearing protein-modifiable sites. This tailor-made macromolecular system consisting of polar, highly swellable copolymers is anchored to the paper exterior upon light-induced crosslinking of engineered benzophenone motifs. On the other hand, this framework contains active esters that can be efficiently modified by the nucleophiles of biomolecules. This strategy allowed the covalent immobilization of glucose oxidase and horseradish peroxidase onto cotton linters without sacrificing their bioactivities and performance upon surface binding. As a proof-of-concept application, a microfluidic chromatic paper-based glucose sensor was developed and achieved successful glucose detection in a simple yet efficient cascade reaction. PMID- 29998097 TI - Editorial: The Chemistry of Imaging Probes. PMID- 29998098 TI - The "Dysplastic Nevus" Conundrum: A Look Back, a Peek Forward. PMID- 29998099 TI - An Unusual Case of Facial Steatocystoma Multiplex: A Clinicopathologic and Dermoscopic Report. AB - Background: Steatocystoma multiplex is a benign skin disorder originating from the sebaceous and nevoid ducts. Commonly classified under hamartomas, they are distributed over the trunk, neck, axillae, and groin. Methods: A 28-year-old male patient complained of multiple, asymptomatic skin-colored nodules over the face of 10-year duration. Clinical examination confirmed the historic findings of nontender, polysized, flesh-colored papules and nodules over the said distribution. Results: On histopathology, a cyst was noted in the mid-dermis, lined by stratified squamous, agranular epithelium, which contained degenerated keratin. Nonpolarized dermoscopy showed a structureless, cream-colored area, and polarized dermoscopy revealed a distinctive, well-circumscribed, yellowish hue which was superimposed over the facial pseudoreticular pigmentary pattern. The findings were compatible with steatocystoma multiplex, and the patient was taken up for radiofrequency ablation. Conclusion: Herein, we report a rare variant of steatocystoma multiplex limited to the face and scalp subjected to dermatoscopy and characteristic histological correlation. To the best of our knowledge and following a literature search, dermoscopic features of this condition have not been reported thus far. PMID- 29998100 TI - An Unusual Morphological Presentation of Cutaneous Squamous Cell Carcinoma Mimicking Microcystic Adnexal Carcinoma: A Diagnostic Pitfall. AB - Cutaneous squamous cell carcinoma (SCC) exhibiting microcystic adnexal carcinoma like differentiation is an extremely rare tumor that shows both squamous and ductal differentiation. This tumor is often misdiagnosed clinically and histologically and is confused with other malignant and benign cutaneous neoplasms. It usually occurs in middle-aged to older adults. Here, we report a case of SCC with microcystic adnexal carcinoma-like differentiation on the left chin of a 71-year-old male. The histopathological examination revealed a nodular tumor infiltrating the dermis, subcutaneous fat, and striated muscle tissue, consisting of both prominent atypical squamous differentiation and foci of duct like structures. PMID- 29998101 TI - Sign of Leser-Trelat and Cutaneous T-Cell Lymphoma: A Rare Association. AB - Sign of Leser-Trelat is a rare paraneoplastic cutaneous manifestation, characterized by the sudden appearance and rapid increase in size and number of seborrheic keratoses, accompanied by pruritus. Edmund Leser and Ulysse Trelat described this sign in 1890. Since their first description, their conclusions have been considered controversial and some authors assert the absence of a causal link. It seems to be frequently associated with solid tumors and in particular gastrointestinal cancer. Here, we describe a new case associated with a cutaneous T-cell lymphoma and a partial response to extracorporeal photopheresis. PMID- 29998102 TI - Nail Unit Glomus Tumor with Myxoid and Symplastic Change Presenting with Longitudinal Erythronychia. AB - Glomus tumors are soft tissue neoplasms, which are most frequently encountered in the nail unit and generally straightforward to diagnose by histopathology. The typical clinical presentation is that of a circular violaceous or erythematous lesion within the nail bed. However, there are rare variants of glomus tumors which may pose diagnostic challenges because of the presence of unusual histologic features. Herein we report such a glomus tumor that demonstrates the rare combination of both myxoid and symplastic change. The clinical presentation of longitudinal erythronychia, as seen with this case, can occur with glomus tumors, but it is unusual, as longitudinal erythronychia on a single nail usually is caused by an onychopapilloma. The distinct nuclear atypia characteristic of symplastic change can raise alarm for a malignant process but the clinical course is benign. It is essential for dermatopathologists to be aware of this unusual variant of a glomus tumor in order to avoid overdiagnosis of atypia, which could result in unnecessary aggressive surgery. While unusual, there is good clinicopathologic correlation of the glomus tumor presenting with longitudinal erythronychia. PMID- 29998103 TI - Cutaneous Adnexal Cysts Revisited: What We Know and What We Think We Know. AB - Cutaneous cysts have been classified by dermatopathologists in many different ways. Here, we propose a novel classification of cutaneous adnexal cysts according to their origin in the folliculosebaceous unit and the sweat glands. By examining the lining of the cystic structure, its origin can be easily identified. Epidermal cysts have an epithelial wall containing a granular layer with lamellar keratinization, indicating an infundibular origin. Tricholemmal cysts have an undulating epithelial wall with no granular layer and a compact keratinization, showing an isthmic origin. In steatocystoma, dermoid cyst, and folliculosebaceous hamartoma, the epithelial lining shows a crenulated appearance which is seen in the sebaceous duct. Hidrocystoma shows the characteristic cuboidal epithelial lining of sweat glands with decapitation secretion in its apocrine forms. The hair matrix cyst wall is composed of basaloid cells maturing to squamoid cells, as seen in the normal hair matrix and shadow cells in the lumen. Metabolizing acquired dioxin-induced skin hamartoma (MADISH) is a cystic lesion with lamellar keratinization, and no sebaceous glands. The classification proposed here aims to simplify the complexity of cutaneous adnexal cysts, and to facilitate a better understanding of the origin of cystic lesions of the skin. PMID- 29998104 TI - Machine Learning in Orthopedics: A Literature Review. AB - In this paper we present the findings of a systematic literature review covering the articles published in the last two decades in which the authors described the application of a machine learning technique and method to an orthopedic problem or purpose. By searching both in the Scopus and Medline databases, we retrieved, screened and analyzed the content of 70 journal articles, and coded these resources following an iterative method within a Grounded Theory approach. We report the survey findings by outlining the articles' content in terms of the main machine learning techniques mentioned therein, the orthopedic application domains, the source data and the quality of their predictive performance. PMID- 29998106 TI - Vaccine Immunotherapy for Celiac Disease. AB - Autoimmune and allergic disorders are highly prevalent conditions in which an altered or abnormal immune response is mounted against self- or environmental antigens, respectively. Antigen-based immunotherapy is a therapeutic option aimed at restoring the specific immune tolerance toward pathogenic antigens while leaving the rest of the immune system unaffected. This strategy proved efficacy especially in allergic diseases, including asthma, allergic rhinitis, and food allergies, but still has shortcomings for the treatment of autoimmune diseases. However, there are no available therapies, currently, in clinical practice for restoring the physiological tolerance that is typically lost in autoimmune diseases. In celiac disease, which is a common immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals, antigen-based immunotherapy could be a feasible option thanks to our deep understanding of the pathogenic mechanisms underpinning this condition. In fact, the immunodominant gluten epitopes are well-characterized and are recognized by pathogenic CD4+ T-cells that could be desensitized with immunotherapy. Moreover, the intestinal damage occurring in celiac disease (i.e., villous atrophy) is reversible upon gluten withdrawal. Only recently the results of a phase I trial of an intradermal, adjuvant-free, formulation of three specific gluten peptides (Nexvax2) showed a good safety profile, albeit its efficacy still needs to be demonstrated. More results are awaited, as they may radically change patients' quality of life that is constrained by the lifelong gluten-free diet and by the potential onset of life-threatening complications. PMID- 29998105 TI - Ion Channel Function During Oocyte Maturation and Fertilization. AB - The proper maturation of both male and female gametes is essential for supporting fertilization and the early embryonic divisions. In the ovary, immature fully grown oocytes that are arrested in prophase I of meiosis I are not able to support fertilization. Acquiring fertilization competence requires resumption of meiosis which encompasses the remodeling of multiple signaling pathways and the reorganization of cellular organelles. Collectively, this differentiation endows the egg with the ability to activate at fertilization and to promote the egg-to embryo transition. Oocyte maturation is associated with changes in the electrical properties of the plasma membrane and alterations in the function and distribution of ion channels. Therefore, variations on the pattern of expression, distribution, and function of ion channels and transporters during oocyte maturation are fundamental to reproductive success. Ion channels and transporters are important in regulating membrane potential, but also in the case of calcium (Ca2+), they play a critical role in modulating intracellular signaling pathways. In the context of fertilization, Ca2+ has been shown to be the universal activator of development at fertilization, playing a central role in early events associated with egg activation and the egg-to-embryo transition. These early events include the block of polyspermy, the completion of meiosis and the transition to the embryonic mitotic divisions. In this review, we discuss the role of ion channels during oocyte maturation, fertilization and early embryonic development. We will describe how ion channel studies in Xenopus oocytes, an extensively studied model of oocyte maturation, translate into a greater understanding of the role of ion channels in mammalian oocyte physiology. PMID- 29998108 TI - Objective vs. Subjective Health in Very Advanced Ages: Looking for Discordance in Centenarians. AB - Background: Living beyond 100 years of age is associated with several functional and health constraints but their impact depends on one's perception of the situation. Associations between self-rated health (SRH) with sociodemographic and psychosocial variables have been explored in several studies, revealing that one's health appraisal depends of factors beyond the objective health condition. There is a large body of literature concerning SRH in later life but lack of evidence about centenarians' perception of health and its associated factors, which could increase the available knowledge on the strengths and resources individuals in very advanced ages have for facing daily life limitations. Objective and Methods: This study aims to analyse the relationship between subjective and objective health status in a sample of centenarians (n = 127). Subjective health was assessed by a single-item health measure, and objective health by considering the number of reported diseases and a functional capacity scale (BADL and IADL). Main health characteristics are described as well as examined the association between objective and subjective health. Results: 46.5% of the sample has a good, very good, or excellent appraisal of their own health. SRH was associated (p < 0.05) with BADL and IADL scores and with the total number of diagnosis; when analyzing SRH according to the level of functional capacity, results revealed that most individuals with severe and moderate dependence have a reasonable to excellent SRH (p > 0.05). Conclusion: Having diseases and functional dependence at 100 years old may not mean to have a bad SRH. The high variability in SRH and the discordance between objective and subjective measures are a proof of centenarian's capacity of adaptation and the existence of individual resources, which may be decisive for one' perception and handling of health situation at such an advanced age. PMID- 29998107 TI - Oral Photoprotection: Effective Agents and Potential Candidates. AB - Electromagnetic radiation in the ultraviolet, visible, and infrared ranges produces biologic effects in humans. Where some of these effects are beneficial, others are harmful to the skin, particularly those stemming from ultraviolet radiation (UVR). Pharmacological photoprotection can be topical or systemic. Systemic photoprotection is often administered orally, complementing topical protection. New and classic oral agents (e.g., essential micronutrients as vitamins, minerals, polyphenols, carotenoids) are endowed with photoprotective and anti-photocarcinogenic properties. These substances bear the potential to increase systemic protection against the effects of electromagnetic radiation in the UV, visible, and infrared ranges. Protective mechanisms vary and include anti oxidant, anti-inflammatory, and immunomodulatory effects. As such, they provide protection against UVR and prevent photo-induced carcinogenesis and aging. In this review, we present state of the art approaches regarding the photoprotective effects of vitamins and vitamin derivatives, dietary botanical, and non-botanical agents. A growing body of data supports the beneficial effects of oral photoprotection on the health of the skin. More studies will likely confirm and expand the positive impact of oral dietary botanicals as complementary measures for photoprotection. PMID- 29998109 TI - Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant. AB - A cohort of 141 males (18-80 yo, 42.9 +/- 12.9) strongly suspected of being Insulin Resistant (IR) was prospectively studied by determining their insulin sensitivity (Pancreatic Suppression Test, PST) and testicular function (total testosterone and SHBG). The subjects were labeled as IR when the Steady State Plasma Glucose (SSPG) was >=150 mg/dL and Non-Insulin Resistant (NIR) when SSPG was <150 mg/dl; similarly, the subjects were labeled as Hypogonadal (HYPOG) when total testosterone was <=3.0 ng/mL and Eugonadal (EUG) when total testosterone was >3.0 ng/mL. Two out of three subjects turned out to be IR, while around one in four subjects were HYPOG. Contingency analysis indicated a significant interdependence between insulin resistance and hypogonadism (chi-square was 4.69, p = 0.0303). Age (>43 yo) predicted hypogonadism (AUROC 0.606, p = 0.0308). Twice as many HYPOG subjects were IR as compared with EUG subjects. Also, HYPOG subjects exhibited higher SSPG values as compared with EUG subjects. Statistically, neither Weight nor BMI predicted hypogonadism, while Waist Circumference (>110 cm) was only a mediocre predictor (AUROC 0.640, p = 0.009). SSPG (>224 mg/dL) on the other hand, was the best predictor of hypogonadism (AUROC 0.709, p = 0.002), outperforming Waist Circumference (half of the subjects with an SSPG >224 mg/dL were HYPOG). Age did not predict insulin resistance, while Weight (>99 kg), BMI (>29), and especially, Waist Circumference (>99 cm, AUROC 0.812, p < 0.0001) were all predictors of insulin resistance. Almost 90% of the subjects with a waist circumference >99 cm was IR. As a logical consequence of the selection criteria (various clues suggesting insulin resistance), most subjects with normal weight in this cohort were IR (53.3%) while 20% were HYPOG. On the other hand, 13.6% of the obese subjects were NIR, and 2 out of 3 of them were both NIR and EUG. In conclusion, Waist Circumference predicted both insulin resistance (>99 cm) and hypogonadism (>110 cm), suggesting that the first hit of abdominal obesity is insulin resistance and the second hit is male hypogonadism. Normal weight did not protect from IR, while a relevant proportion of obese subjects were NIR (with 2/3 being also EUG). PMID- 29998110 TI - Sensory Assessment by Consumers of Traditional and Potentially Probiotic Green Spanish-Style Table Olives. AB - This work presents the sensory characterization by consumers of traditionally and potentially probiotic green Spanish-style table olives. To this aim, green Manzanilla olives from the same lot were debittered, washed, and brined in the same way; then, one sub-lot was allowed fermenting spontaneously while another one was inoculated with a putative probiotic bacterium (Lactobacillus pentosus TOMC-LAB2). After fermentation, the olives from both sub-lots were packed with fresh brine to reach 5.5 g/100 mL NaCl and 0.6 g lactic acid/100 mL in the equilibrium. The stabilized olives were then subjected to sensory evaluation by 200 consumers, and the results were analyzed by ANOVA and multivariate statistical techniques. In a first approach, consumers perceived the spontaneously fermented olives as similar to the potentially probiotic product. However, a biplot based on Canonical Variate Analysis (CVA) showed differences between them in the Salty and Overall score. When data from the consumer test were assessed by PLS analysis, regardless of the fermentation system, Overall score, and Buying predisposition were significantly driven by Appearance, Odor, Salty (negatively), Hardness, and Crispness. PMID- 29998111 TI - Characterization of a Novel Mitochondrial Ascorbate Transporter From Rat Liver and Potato Mitochondria. AB - The Mitochondrial Ascorbic Acid Transporter (MAT) from both rat liver and potato mitochondria has been reconstituted in proteoliposomes. The protein has a molecular mass in the range of 28-35 kDa and catalyzes saturable, temperature and pH dependent, unidirectional ascorbic acid transport. The transport activity is sodium independent and it is optimal at acidic pH values. It is stimulated by proton gradient, thus supporting that ascorbate is symported with H+. It is efficiently inhibited by the lysine reagent pyridoxal phosphate and it is not affected by inhibitors of other recognized plasma and mitochondrial membranes ascorbate transporters GLUT1(glucose transporter-1) or SVCT2 (sodium-dependent vitamin C transporter-2). Rat protein catalyzes a cooperative ascorbate transport, being involved two binding sites; the measured K0.5 is 1.5 mM. Taking into account the experimental results we propose that the reconstituted ascorbate transporter is not a GLUT or SVCT, since it shows different biochemical features. Data of potato transporter overlap the mammalian ones, except for the kinetic parameters non-experimentally measurable, thus supporting the MAT in plants fulfills the same transport role. PMID- 29998113 TI - Sequence Analysis of Drug Target Genes with Suicidal Behavior in Bipolar Disorder Patients. AB - Background: A number of genes have been implicated in recent genome-wide association studies of suicide attempt in bipolar disorder. More focused investigation of genes coding for protein targets of existing drugs may lead to drug repurposing for the treatment and/or prevention of suicide. Methods: We analyzed 2,457 DNA variants across 197 genes of interest to GlaxoSmithKline across the pipeline in our sample of European patients suffering from bipolar disorder (N = 219). We analyzed these variants for a possible association with the suicide severity score (ranging from suicidal ideation/plan to serious suicide attempt) from the Schedule for Clinical Assessment in Neuropsychiatry. We conducted tests of individual variants and gene-based tests. Results: We found a number of DNA variants in the transforming growth factor beta receptor 1 gene (TGFBR1) to be suggestively associated with suicide severity scores (p < 0.005). The gene-based tests also pointed to TGFBR1 to be associated with suicide severity (p = 0.0001). However, these findings were not replicated in an independent bipolar disorder sample. Conclusions: We report no significant association between DNA sequences of drug target genes and suicidal behavior. Additional larger sequencing studies could further interrogate associations between variants in drug target genes and suicidal behavior. PMID- 29998112 TI - New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy. AB - Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the DNA damaging effects of chemotherapy or ionizing radiation treatments to combat cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in personalized medicine, but it remains to be optimized. A new target in cancer therapy is DNA unwinding enzymes known as helicases. Helicases play critical roles in all aspects of nucleic acid metabolism. We and others have investigated small molecule targeted inhibition of helicase function by compound screens using biochemical and cell-based approaches. Small molecule-induced trapping of DNA helicases may represent a generalized mechanism exemplified by certain topoisomerase and PARP inhibitors that exert poisonous consequences, especially in rapidly dividing cancer cells. Taking the lead from the broader field of DNA repair inhibitors and new information gleaned from structural and biochemical studies of DNA helicases, we predict that an emerging strategy to identify useful helicase-interacting compounds will be structure-based molecular docking interfaced with a computational approach. Potency, specificity, drug resistance, and bioavailability of helicase inhibitor drugs and targeting such compounds to subcellular compartments where the respective helicases operate must be addressed. Beyond cancer therapy, continued and new developments in this area may lead to the discovery of helicase-interacting compounds that chemically rescue clinically relevant helicase missense mutant proteins or activate the catalytic function of wild-type DNA helicases, which may have novel therapeutic application. PMID- 29998114 TI - Association of Novel ALX4 Gene Polymorphisms with Antidepressant Treatment Response: Findings from the CO-MED Trial. AB - Genome-wide association studies (GWAS) were conducted in participants of the CO MED (Combining Medications to Enhance Depression Outcomes) trial, a randomized, 3 treatment arm clinical trial of major depressive disorder (MDD) designed to identify markers of differential treatment outcome (response and remission). The QIDS-SR (Quick Inventory of Depressive Symptomatology, Self-Reported version) was used to measure response at week 6 (QIDS-SR <=5) and remission at week 12 (QIDS SR <=6 and <=8 at the last two study visits). Three treatment groups (escitalopram monotherapy, escitalopram + bupropion, and venlafaxine + mirtazapine) were evaluated. GWAS identified a potentially regulatory SNP rs10769025 in the ALX4 gene on chromosome 11 with a strong association (p value = 9.85925E-08) with response to escitalopram monotherapy in Caucasians. Further, haplotype analysis on 7 ALX4 variants showed that a regulatory haplotype CAAACTG was significantly associated (odds ratio = 3.4, p = 2.00E-04) with response to escitalopram monotherapy at week 6. Ingenuity pathway analyses in the present study suggest that ALX4 has an indirect connection with antidepressant gene pathways in MDD, which may account for the genetic association with treatment outcome. Functional genomics studies to investigate the role of ALX4 in antidepressant treatment outcome will be an interesting future direction. PMID- 29998115 TI - Dominant-Negative DISC1 Alters the Dopaminergic Modulation of Inhibitory Interneurons in the Mouse Prefrontal Cortex. AB - A truncated disrupted in schizophrenia 1 (Disc1) gene increases the risk of psychiatric disorders, probably affecting cortical interneurons. Here, we sought to determine whether this cell population is affected in mice carrying a truncated (Disc1) allele (DN-DISC1). We utilized whole cell recordings to assess electrophysiological properties and modulation by dopamine (DA) in two classes of interneurons: fast-spiking (FS) and low threshold-spiking (LTS) interneurons in wild-type and DN-DISC1 mice. In DN-DISC1 mice, FS interneurons, but not LTS interneurons, exhibited altered action potentials. Further, the perineuronal nets that surround FS interneurons exhibited abnormal morphology in DN-DISC1 mice, and the DA modulation of this cell type was altered in DN-DISC1 mice. We conclude that early-life manipulation of a gene associated with risk of psychiatric disease can result in dysfunction, but not loss, of specific GABAergic interneurons. The resulting alteration of excitatory-inhibitory balance is a critical element in DISC1 pathophysiology. PMID- 29998116 TI - Further Evidence of an Association between NCAN rs1064395 and Bipolar Disorder. AB - Genome-wide association studies suggest that rs1064395 in the neurocan gene (NCAN) is a potential risk factor for bipolar disorder (BPD), and further replication analyses in larger independent samples are needed. We herein analyzed rs1064395 in a Han Chinese sample of 1,146 BPD cases and 2,031 controls, followed by a meta-analysis of BPD samples from worldwide populations including a total of 15,318 cases and 91,990 controls. The meta-analysis found that rs1064395 showed a genome-wide significant association with BPD (p = 4.92 * 10-9, OR = 1.126 for the A allele), although it did not reach the significance level in the Han Chinese sample (p = 0.415, OR = 1.070 for the A allele). We also examined the association between the single nucleotide polymorphisms and major depressive disorder (MDD) given the presumed genetic overlap between BPD and MDD, and rs1064395 was also associated with MDD (p = 0.0068, OR = 1.067 for the A allele) in a meta-analysis of 14,543 cases and 14,856 controls. Our data provide further evidence for the involvement of NCAN in the genetic susceptibility to BPD and also implicate its broader role in major mood disorders. PMID- 29998117 TI - Recent Advances in the Genetics of Schizophrenia. AB - The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novomicron variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries. PMID- 29998119 TI - Novel Insights into Crystal-Induced Kidney Injury. AB - Background: The entity of crystal nephropathies encompasses a spectrum of different kidney injuries induced by crystal-formed intrinsic minerals, metabolites, and proteins or extrinsic dietary components and drug metabolites. Depending on the localization and dynamics of crystal deposition, the clinical presentation can be acute kidney injury, progressive chronic kidney disease, or renal colic. Summary: The molecular mechanisms involving crystal-induced injury are diverse and remain poorly understood. Type 1 crystal nephropathies arise from crystals in the vascular lumen (cholesterol embolism) or the vascular wall (atherosclerosis) and involve kidney infarcts or chronic ischemia, respectively. Type 2 crystal nephropathies arise from intratubular crystal deposition causing obstruction, interstitial inflammation, and tubular cell injury. NLRP3 inflammasome and necroptosis drive renal necroinflammation in acute settings. Type 3 is represented by crystal and stone formation in the draining urinary tract, i.e., urolithiasis, causing renal colic and chronic obstruction. Key Messages: Dissecting the types of injury is the first step towards a better understanding of the pathophysiology of crystal nephropathies. Crystal-induced acti-vation of the inflammasome and necroptosis, crystal adhesion, crystallization inhibitors, extratubulation, and granulo-ma formation are only a few of certainly many involved pathomechanisms that deserve further studies to eventually form the basis for innovative cures for these diseases. PMID- 29998118 TI - The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease. AB - While accounting for only 2% of the body's weight, the brain utilizes up to 20% of the body's total energy. Not surprisingly, metabolic dysfunction and energy supply-and-demand mismatch have been implicated in a variety of neurological and psychiatric disorders. Mitochondria are responsible for providing the brain with most of its energetic demands, and the brain uses glucose as its exclusive energy source. Exploring the role of mitochondrial dysfunction in the etiology of psychiatric disease is a promising avenue to investigate further. Genetic analysis of mitochondrial activity is a cornerstone in understanding disease pathogenesis related to metabolic dysfunction. In concert with neuroimaging and pathological study, genetics provides an important bridge between biochemical findings and clinical correlates in psychiatric disease. Mitochondrial genetics has several unique aspects to its analysis, and corresponding special considerations. Here, we review the components of mitochondrial genetic analysis nuclear DNA, mitochon-drial DNA, mitochondrial pathways, pseudogenes, nuclear mitochondrial mismatch, and microRNAs - that could contribute to an observable clinical phenotype. Throughout, we highlight psychiatric diseases that can arise due to dysfunction in these processes, with a focus on schizophrenia and bipolar disorder. PMID- 29998120 TI - IgA Nephropathy: A European Perspective in the Corticosteroid Treatment. AB - Background: IgA nephropathy (IgAN) is detected in Europe in 22% of glomerular diseases diagnosed by biopsy. The frequency of IgAN as cause of ESRD in Europe has increased in the last decades, accounting for 35% of young and adult transplanted patients. These data justify the interest for risk factors and a possible therapeutic approach. Summary: Insight into a European perspective of IgAN was allowed by the multicenter study VALIGA, on 1,147 patients, almost all Caucasians, with follow-up of 4.7 years. The predictive value of mesangial hypercellularity (M), segmental sclerosis (S), tubular atrophy interstitial fibrosis (T) as independent biomarkers of progression was validated. Endocapillary hypercellularity was predictive of increased follow-up proteinuria. Two groups of patients selected by a propensity score to perfectly match for histologic features (MEST) and clinical data treated with renin-angiotensin system blockers (RASBs) and corticosteroids, or RASBs alone were compared and a beneficial effect of corticosteroids in addition to RASB was found in patients with proteinuria > 1 g/day, with an initial eGFR < 50 mL/min/1.73 m2. On the contrary, the STOP-IgAN RCT found that immunosuppressive therapy in addition to optimal supportive care did not provide substantial kidney-related benefits in European patients with IgAN, because there was no difference in the rate of decrease in eGFR, although corticosteroid/immunosuppressive therapy induced complete remission of proteinuria more frequently than supportive care alone. The NEFIGAN trial evaluated a targeted release formulation of budesonide (TRF budesonide) delivering the drug in the distal ileum. TRF budesonide, additionally to optimized RAS blockade, reduced proteinuria and maintained eGFR in IgAN patients, suggesting a reduced risk of future progression to ESRD. Key Messages: In Europe, there is a reasoned search of a balanced approach to corticosteroid therapy for patients with IgAN, with particular attention to selecting the patients at risk of progression while limiting the unwanted systemic adverse events. PMID- 29998121 TI - The Genetic and Environmental Factors of Primary Membranous Nephropathy: An Overview from China. AB - Background: Primary membranous nephropathy (pMN) is the most common cause of nephrotic syndrome in adults. The discovery of the 2 autoantigens, M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A), has defined pMN as an autoimmune disease. A remarkable increase in the frequency of pMN in primary glomerular disease was witnessed in China. The genetic and environmental contributors to disease susceptibility have been investigated in these patients. Summary: We reviewed recent publications in genetic and environmental studies of pMN, focusing mainly on those undertaken in China. Following a genome-wide association study, the gene-gene interaction between the 2 most significant risk factors, PLA2R1 and DQA1, was validated in Chinese patients with MN. Fine mapping on human leukocyte antigen (HLA) locus found that DRB1*1501 and DRB1*0301 were risk alleles. Three amino acid residues on positions 13 and 71 of HLA-DRbeta1 chain may confer the susceptibility to pMN by presenting T-cell epitopes on PLA2R. Another study found that DRB3*0202 was the most likely culprit allele for the signal at DRB1*0301. One environmental risk factor for pMN has been identified as the long-term exposure to high levels of PM2.5 in Chinese patients with MN. Each 10 MUg/m3 increase in PM2.5 concentration was associated with 14% higher odds for pMN in the regions with PM2.5 above 70 MUg/m3. Key Message: A gene-environment interaction is suspected as an underlying mechanism for the increasing trend of pMN in China. PMID- 29998122 TI - An Overview on Renoprotective Effects of Thymoquinone. AB - Background: Kidneys as vital organs remove waste material from blood. Additionally, they may also have a role in the electrolyte balance, regulation of blood pressure, and red blood cell genesis. Kidney diseases may be caused by several factors such as ischemia/reperfusion injury, diabetes, and nephrotoxic agents. Oxidative stress and inflammation are involved in the pathogenesis and progression of kidney diseases. Traditionally, natural antioxidants are used for treatment of renal failure in various countries. Summary: People usually select natural antioxidants since they have an opinion that herbal medicine has not any important side effects. Nigella sativa is a flavoring herb that is widely used as a condiment and as a remedy for many disorders. Thymoquinone (TQ), the most important component of black seeds, mainly oil, is considered as an active agent responsible for a lot of the seed's useful effects. This review describes the protective roles and related mechanisms of TQ against renal disorders. The search terms, including TQ, antioxidant, renal ischemia-reperfusion, diabetic nephropathy, and nephrotoxic agent were searched in scientific databases. TQ showed anti-inflammatory and antioxidant properties in animal and in vitro models of several renal diseases caused by inflammation and oxidative stress. Key Messages: Experimental studies have shown beneficial effects of TQ against renal diseases; however, well-designed clinical trials in humans are required to confirm these effects. PMID- 29998123 TI - Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction. AB - Background: We previously reported that the NLRP3 inflammasome played an important role in mediating the podocyte injury induced by aldosterone. However, more studies on the role of the NLRP3 inflammasome in the pathogenesis of podocytopathy are still required. The present study was undertaken to study the role of the NLRP3 inflammasome in angiotensin II (Ang II)-induced podocyte injury, as well as the potential mechanisms. Methods: In this study, we used an Ang II infusion model in NLRP3-/- mice. In cultured podocytes, we used siRNA to silence NLRP3; then we treated the podocytes with Ang II. Results: Following Ang II treatment, we found that the NLRP3 inflammasome was significantly activated in line with mitochondrial dysfunction in a dose- and time-dependent manner. Silencing NLRP3 by siRNA transfection ameliorated podocyte apoptosis, attenuated the loss of the podocyte proteins nephrin and podocin, and protected mitochondrial function. Ang II infusion activated the NLRP3 inflammasome, caused albuminuria, and induced podocyte damage, which was all blocked in the NLRP3-/- mice. At the same time, NLRP3 deletion also ameliorated the mitochondrial dysfunction induced by Ang II infusion. However, the deletion of NLRP3 did not affect the Ang II hypertension. Conclusion: Taken together, these results demonstrate an important role of the NLRP3 inflammasome in mediating Ang II induced podocyte injury and mitochondrial dysfunction, suggesting that the NLRP3 inflammasome might be an effective therapeutic target against podocytopathy. PMID- 29998124 TI - Canonical Wnt Signaling Promotes Macrophage Proliferation during Kidney Fibrosis. AB - Background: Wnt/beta-catenin, an evolutionary conserved signaling pathway, plays an essential role in modulating kidney injury and repair. Our previous studies demonstrated that Wnt/beta-catenin signaling could stimulate macrophage M2 polarization and contribute to kidney fibrosis. However, whether canonical Wnt signaling activation leads to macrophage proliferation during kidney fibrosis remains to be determined. Methods: In this study, a mouse model with macrophage specific beta-catenin gene deletion was generated and a unilateral ureter obstruction (UUO) model was created. Results: In a mouse model with UUO nephropathy, deletion of beta-catenin in macrophages attenuated macrophage proliferation and accumulation in kidney tissue. Wnt3a, a well-known canonical Wnt signaling stimulator, could markedly promote macrophage proliferation, whereas blocking canonical Wnt signaling with ICG-001 or ablating beta-catenin could largely inhibit macrophage colony-stimulating factor-stimulated macrophage proliferation. Wnt3a treatment could time-dependently upregulate cyclin D1 protein expression and blocking beta-catenin signaling could downregulate it. Conclusion: These results demonstrate that Wnt/ beta-catenin signaling is essential for promoting macrophage proliferation during kidney fibrosis. PMID- 29998125 TI - Importance of AST-120 (Kremezin(r)) Adherence in a Chronic Kidney Disease Patient with Diabetes. AB - We report herein an adult case of chronic kidney disease (CKD) associated with diabetes. The patient had been treated with insulin injection for diabetes 10 years ago. At the time of his first visit to our division for further examinations, we diagnosed him as CKD: cause (C) diabetes; glomerular filtration rate (GFR) (G) G5 (estimated [e] GFR, 10.2 mL/min/1.73 m2; serum creatinine of 4.90 mg/dL); and albuminuria (A) A3 (2.62 g/gCr) by the Japanese Society of Nephrology (JSN) CGA classification. Because he had complained of severe constipation and kidney function, i.e., eGFR was not improved by previous medications, we added on a minimal dosage (2 g/day) of AST-120 (Kremezin(r); ordinary dose 6 g/day). After 3 months of AST-120 therapy, eGFR was increased to 17.8 mL/min/1.73 m2 (serum creatinine of 2.90-2.72 mg/dL). Although the patient used some laxative products, he could not continue to take Kremezin and completely stopped 8 months after starting this drug. Kidney function then abruptly declined and progressed to end-stage kidney disease (ESKD). In June 2017, he was introduced to hemodialysis. It appears that the adherence of Kremezin is very important for inhibiting the progression to ESKD for patients with CKD with diabetes. PMID- 29998126 TI - Postembolization Intratumoral Chronic Bleeding, without the Classic CT Feature of Active Extravasation, in Tuberous Sclerosis Complex-Related Renal Angiomyolipoma: Two Case Reports. AB - Two patients with tuberous sclerosis complex each had multiple bilateral renal angiomyolipomas. After undergoing embolization for a ruptured angiomyolipoma, patient 1 experienced long-lasting abdominal fullness; contrast-enhanced computed tomography (CECT) revealed a large chronic hematoma without contrast extravasation. Patient 2 underwent embolization for the largest right renal angiomyolipoma which contained a chronic hematoma. 2 weeks later, the symptom of abdominal fullness presented, and CECT revealed that the preexisting hematoma had enlarged without contrast extravasation. In both cases, a second embolization of the angiomyolipomas resulted in shrinking of the intratumoral hematomas and alleviation of the associated symptoms. Therefore, chronic postembolization intratumoral bleeding from renal angiomyolipoma may present as a persistently large or growing hematoma with an associated symptom of abdominal fullness but without the typical CECT feature of active extravasation. PMID- 29998127 TI - Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome. AB - Cardiomyopathies (CMs) are a group of cardiac pathologies caused by an intrinsic defect within the myocardium. The relative contribution of genetic mutations in the pathogenesis of certain CMs, such as hypertrophic cardiomyopathy (HCM), arrythmogenic right/left ventricular cardiomyopathy (ARVC) and left ventricular non-compacted cardiomyopathy (LVNC) has been established in comparison to dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). The aim of this article is to review mutations in the non-coding parts of the genome, namely, microRNA, promoter elements, enhancer/silencer elements, 3'/5'UTRs and introns, that are involved in the pathogenesis CMs. Additionally, we will explore the role of some long non-coding RNAs in the pathogenesis of CMs. PMID- 29998129 TI - Development of a Multidimensional Proteomic Approach to Detect Circulating Immune Complexes in Cattle Experimentally Infected With Mycobacterium bovis. AB - Objective: To evaluate a high-resolution method to identify pathogen-specific biomarkers in serum of calves infected with Mycobacterium bovis. Methods: Serum samples from four calves infected with M. bovis were collected before and after infection at weeks 9, 14, 15, 31, and 36. Immune-complex-associated mycobacterial antigens in the serum were enriched using an immunochromatography method termed, dual path platform (DPP). All regions of antigen capture zones, that consisted of monospecific rabbit polyclonal antibodies raised against M. tuberculosis lysates, on DPP strips were excised and analyzed by multidimensional proteomics. The resulting proteins were then passed through 4 rigorous peptide quality filters false-hits, decoys, non-M. tuberculosis complex proteins were all removed followed by individual quality check of those remaining. Peptides were then checked on NCBI's BLASTp for M. tuberculosis complex specificity. Results: Proteins in 2 of the animals passed the multipronged-highly stringent peptide quality analysis. Animal#54 had 7 unique M. tuberculosis complex proteins at week 14 post-infection, while animal#56 had 4 at week 36 post-infection along with 1 immunoglobulin. Conclusion:M. tuberculosis complex -specific peptides identified in this study were identified in 2 animals and at 2 separate time points post infection. Further studies with better enrichment protocols and using larger sample sizes and replications are required to develop a TB-specific diagnostic tool for bovine tuberculosis. PMID- 29998128 TI - Tissue Specific Origin, Development, and Pathological Perspectives of Pericytes. AB - Pericytes are mural cells surrounding blood vessels, adjacent to endothelial cells. Pericytes play critical roles in maturation and maintenance of vascular branching morphogenesis. In the central nervous system (CNS), pericytes are necessary for the formation and regulation of the blood-brain barrier (BBB) and pericyte deficiency accompanies CNS diseases including multiple sclerosis, diabetic retinopathy, neonatal intraventricular hemorrhage, and neurodegenerative disorders. Despite the importance of pericytes, their developmental origins and phenotypic diversity remain incompletely understood. Pericytes express multiple markers and the origin of pericytes differs by tissue, which may cause difficulty for the identification and understanding of the ontogeny of pericytes. Also, pericytes have the potential to give rise to different tissues in vitro but this is not clear in vivo. These studies indicate that pericytes are heterogeneous in a tissue- and context- dependent manner. This short review focuses on recent studies about identification of pericytes, heterogeneous origin of pericytes during development and in adults, and the differentiation capacity of pericytes, and pericytes in pathological settings. PMID- 29998130 TI - Low Birth Weight Impairs Acquisition of Spatial Memory Task in Pigs. AB - In commercial pig farming, an increasing number of low birth weight (LBW) piglets are born, due to selection for large litter sizes. While LBW piglets have a higher risk of pre-weaning mortality, a considerable number of these piglets survive to slaughter age. In humans, LBW is a risk factor for long-term cognitive impairments. In pigs, studies examining the post-weaning effects of LBW on cognition have reported contradictory results. Therefore, the current study aimed to assess the effects of LBW on cognitive development in pigs using an improved study design, by (1) testing a larger sample size than previous studies, (2) assessing acute and chronic stress responses to account for a potential altered stress response in LBW pigs, and (3) testing both female and male pigs to account for potential confounding effects of sex. Learning and memory of 20 LBW pigs and 20 normal birth weight (NBW) pigs, both groups consisting of 10 females and 10 males, were compared using a spatial holeboard task. In this task, pigs had to learn and remember the locations of hidden food rewards. After a pig had successfully acquired the task, it was presented with two successive reversal phases during which it was presented with a new configuration of reward locations. The holeboard allows for simultaneous assessment of working and reference memory, as well as measures of motivation, exploration, and behavioral flexibility. Mixed model ANOVAs revealed a transiently impaired reference memory performance of LBW pigs, implying they had more difficulty learning their reward configuration in the holeboard. Also, LBW piglets showed increased pre-weaning hair cortisol concentrations compared to their NBW siblings. No other effects of LBW were found. Sex had no direct or interaction effects on any measures of holeboard performance or stress. It is possible that the enriched housing conditions applied during our study had an ameliorating effect on our pigs' cognitive development. Overall, our results suggest LBW has a negative effect on post-weaning cognitive performance in pigs. This could have welfare consequences as cognitive skills are required for pigs to learn how to correctly respond to their environment. PMID- 29998131 TI - Impact of Coordinated-Bilateral Physical Activities on Attention and Concentration in School-Aged Children. AB - Purpose: This study examined the effects of 4-week, daily 6-minute coordinated bilateral physical activity (CBPA) breaks in classroom on attention and concentration in school-aged children. Methods: Participants (n=116) in fifth grade from two elementary schools were assigned to three groups: two intervention groups (n= 60) and one control group (n = 56). All three groups were pre- and post-tested with the d2 Test of Attention (d2 test). One intervention group (n = 31) took part in six minutes of daily classroom-based coordinated-bilateral physical activity (CBPA) break for four weeks. Another intervention group (n = 29), the Fitbit Only (Fitbit-O), wore Fitbits per day during a school, five days per week for four weeks without CBPA breaks. A 2 * 3 ANOVA was conducted, followed by the post hoc comparisons. Results: The CBPA showed significant increases in processing speed (F1 = 6.876, p = .010), focused attention (F1 = 10.688, p = .002), concentration performance (F1 = 26.46, p = .000), and attention span (F1 = 14.090, p = .000) over the control, but not in accuracy (Error %). The CBPA showed significant improvement in concentration performance (F1 = 24.162, p = .000) and attention span (F1 = 6.891, p = .011), compared to the Fitbit-O. No significant changes in all five attention parameters were found between the Fitbit-O and the control. Conclusion: It was concluded that daily brief coordinated-bilateral activities can improve attention and concentration in fifth-grade students over the course of four weeks. PMID- 29998132 TI - The Female Athlete's Heart: Comparison of Cardiac Changes Induced by Different Types of Exercise Training Using 3D Echocardiography. AB - We aimed to characterize female athlete's heart in elite competitors in the International Federation of Bodybuilding and Fitness (IFBB) Bikini Fitness category and compare them to athletes of a more dynamic sport discipline and healthy, sedentary volunteers using 3D echocardiography. Fifteen elite female fitness athletes were recruited and compared to 15 elite, age-matched female water polo athletes and 15 age-matched healthy, nontrained controls. Using 3D echocardiography, left ventricular (LV) and right ventricular (RV) end-diastolic volume index (EDVi) and LV mass index (LVMi) were measured. Fitness athletes presented similar LV and RV EDVi compared to healthy, sedentary volunteers. Water polo athletes, however, had higher LV and also RV EDVi (fitness versus water polo versus control; LVEDVi: 76 +/- 13 versus 84 +/- 8 versus 73 +/- 8 ml/m2, ANOVA p = 0.045; RVEDVi: 61 +/- 12 versus 86 +/- 14 versus 55 +/- 9 ml/m2, p < 0.0001). LVMi was significantly higher in the athlete groups; the hypertrophy, however, was even more prominent in water polo athletes (78 +/- 13 versus 91 +/- 10 versus 57 +/- 10 g/m2, p < 0.0001). To the best of our knowledge, this is the first study to characterize female athlete's heart of IFBB Bikini Fitness competitors. The predominantly static exercise regime induced a mild, concentric-type LV hypertrophy, while in water polo athletes higher ventricular volumes and eccentric LV hypertrophy developed. PMID- 29998133 TI - Custom-Made Direct Metal Laser Sintering Titanium Subperiosteal Implants: A Retrospective Clinical Study on 70 Patients. AB - Purpose: To present a digital technique for the fabrication of custom-made subperiosteal implants and to report on the survival and complication rates encountered when using these fixtures. Methods: The data used for this retrospective clinical study were derived from the medical records of five different private dental practices. Inclusion criteria were patients over the age of 60, treated with custom-made direct metal laser sintering (DMLS) titanium subperiosteal implants (Eagle-Grid(r), BTK, Dueville, Vicenza) during a two-year period (2014-2015) and restored with fixed restorations; all enrolled patients needed to have complete pre- and postoperative clinical and radiographic documentation, with at least 2 years of follow-up. Exclusion criteria were smoking and bruxism. The main outcomes looked at were implant survival and complications. Results: Seventy patients (39 males and 31 females, aged 62-79 years) who had been treated with custom-made DMLS titanium subperiosteal implants were enrolled in this study. After 2 years of follow-up, three implants were lost due to recurrent, untreatable infections; the survival rate was therefore 95.8% (67/70 implants). Four patients reported pain/discomfort/swelling after implant placement; the incidence of immediate postoperative complications was therefore 5.7% (4/70 implants). During the follow-up period, one patient suffered from recurrent infections classified as a biologic complication; the incidence of biologic complications was therefore 1.4% (1/67 surviving implants). Finally, four patients experienced prosthetic problems with their implant-supported restorations during the provisional phase (fracture of the acrylic restoration) and two patients had ceramic chipping of the definitive restoration; the incidence of prosthetic complications was therefore 8.9% (6/67 surviving implants). Conclusions: Within the limits of the present study (limited follow-up time and low number of patients treated, retrospective design), the application of custom-made DMLS titanium subperiosteal implants showed satisfactory implant survival (95.8%) and low complication rates. Further studies are needed to confirm the positive outcomes found in this research. PMID- 29998134 TI - Clinical and Biological Signature of Osteochondritis Dissecans in a Cross Sectional Study. AB - The healing potential of knee osteochondritis dissecans (OCD) focal lesions is not well defined. We performed a cross-sectional study correlating local and systemic biological characteristics with the patients' characteristics. We evaluated both local tissue markers (CD34, CD146, CD166, and tartrate-resistant acid phosphatase (TRAP)) and systemic serum biomarkers (fragments or propeptide of type II collagen: C2C, CTX-II, CPII, and TRAP5b) on histologically scored osteochondral fragments or serum from OCD patients. These biological features were associated with the patients' characteristics (IKDC subjective score, age, and body mass index (BMI)). Histological cartilage tissue score correlated with patients' IKDC and C2C and CPII biomarkers. CPII correlated also with histological bone tissue score. The percentage of CD146 positive cells in cartilage and CD34 positive cells in bone highly correlated with the patient's age and BMI, respectively. The percentage of TRAP in bone was directly correlated with both IKDC and age. Multivariate statistical analysis evidenced that only four parameters significantly predicted IKDC. In conclusion, a complete picture of OCD knee characteristics, defined by local and systemic markers of cartilage and bone remodeling, together with the patients' characteristics, might help to better understand the healing potential of each patient and to target and improve current OCD treatments. PMID- 29998135 TI - Comparison of Aggressive Surgical Treatment and Palliative Treatment in Elderly Patients with Poor-Grade Intracranial Aneurysmal Subarachnoid Hemorrhage. AB - Objective: To compare the current treatment approach in elderly patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) and identify the independent predictors of the outcome after aggressive surgical treatment. Method: This prospective, multicenter cohort study included 104 poor-grade aneurysmal SAH elderly patients, 60 years or older, treated in our institution from October 2010 to March 2013. Patients were grouped according to three treatment arms. Neurological outcome was assessed using the Glasgow Outcome Scale (GOS) at baseline and at a 12-month follow-up. Univariate and multivariate analysis were performed using the following factors: sex, age, smoking history, breathing ability, alcohol consumption, cerebral hernia, aneurysm location, aneurysm diameter, WFNS grade, CT Fisher grade, treatment approach, and the timing of the aneurysm surgery. Results: At the 12-month follow-up, patients in the coiling group and clipping group had better prognosis than patients in the palliative treatment group. Univariate analysis confirmed that the treatment approach, WFNS grade, CT Fisher grade, and age are critical factors for neurological outcomes in poor-grade SAH. Multivariate analysis indicated that WFNS grade V, CT Fisher grades 3-5, and palliative treatment were independent predictors of poor prognoses. Conclusion: Aggressive surgical treatment improves the prognoses in poor-grade aneurysm elderly patients with SAH. Elderly Patients of WFNS grade IV and CT Fisher grades 1-2 are more likely to have a better outcome. PMID- 29998136 TI - The Role of Combination Maintenance with Pemetrexed and Bevacizumab for Advanced Stage Nonsquamous Non-Small Cell Lung Cancer: A Systematic Review and Meta Analysis. AB - Purpose: To evaluate the effect of combination maintenance therapy of pemetrexed plus bevacizumab for patients with advanced non-small cell lung cancer. Methods: We identified relevant studies by electronic search (Embase, PubMed, Cochrane, and Web of Science from 1 January 1960 to 29 October 2016) and manual search. The primary outcome of interest was progression-free survival (PFS) and secondary end point included overall survival (OS) and toxicities. The data was pooled for quantitative analysis and the final effect size was reported as hazard ratio (HR) for survival outcomes and relative risk (RR) for safety outcomes, both with a random-effects model. Results: Three randomized controlled trials enrolling 1302 patients with advanced non-small cell lung cancer were included in this meta analysis. An evident PFS improvement (HR = 0.73, 95% CI = 0.63-0.83, P < 0.01) was observed in patients with pemetrexed and bevacizumab combination maintenance therapy compared with single-agent maintenance therapy, yet it did not subsequently lead to a significant improvement in OS (HR = 0.97, 95% CI = 0.84 1.10, P = 0.66). Our analysis also showed statistically increased risks for provoking grade 3-4 adverse events in patients managed using pemetrexed plus bevacizumab combination (RR = 1.59, 95% CI = 1.07-2.36, P = 0.022). Conclusions: Pemetrexed plus bevacizumab combination maintenance therapy leads to significant improvement in PFS but not in OS for patients with advanced non-small cell lung cancer, which also increases the risks of grade 3-4 adverse events. Yet, in view of the limitation of existing studies and this meta-analysis, current evidence is not adequate to support routine use of pemetrexed-bevacizumab maintenance. PMID- 29998137 TI - Lactobacillus plantarum with Functional Properties: An Approach to Increase Safety and Shelf-Life of Fermented Foods. AB - Lactobacillus plantarum (widespread member of the genus Lactobacillus) is one of the most studied species extensively used in food industry as probiotic microorganism and/or microbial starter. The exploitation of Lb. plantarum strains with their long history in food fermentation forms an emerging field and design of added-value foods. Lb. plantarum strains were also used to produce new functional (traditional/novel) foods and beverages with improved nutritional and technological features. Lb. plantarum strains were identified from many traditional foods and characterized for their systematics and molecular taxonomy, enzyme systems (alpha-amylase, esterase, lipase, alpha-glucosidase, beta glucosidase, enolase, phosphoketolase, lactase dehydrogenase, etc.), and bioactive compounds (bacteriocin, dipeptides, and other preservative compounds). This review emphasizes that the Lb. plantarum strains with their probiotic properties can have great effects against harmful microflora (foodborne pathogens) to increase safety and shelf-life of fermented foods. PMID- 29998139 TI - Group versus Individual Care in Patients with Long-Standing Type 1 and Type 2 Diabetes: A One-Year Prospective Noninferiority Study in a Tertiary Diabetes Clinic. AB - Aims: To explore the feasibility and noninferiority of group care in a diabetes outpatient clinic in comparison with individual care. Methods: In this prospective, randomized, nonblinded, one center (university hospital) trial, 60 patients (28 with type 1 and 32 with type 2 diabetes) with a mean duration of diabetes of 22.5 +/- 11.7 years were randomly assigned to group (6 patients per group) or individual care for one year. The primary endpoints were the change in HbA1c and visits to outpatient clinics. The secondary endpoints were changes in body mass index, blood pressure levels, waist circumference, non-HDL cholesterol, diabetes-related and well-being index questionnaires, and the number of hospitalizations. Results: Group care was not inferior to individual care for any of the above parameters except for the number of visits to a primary care physician. Conclusion: Group care is feasible in a diabetes clinic and is as effective as individual care. Implementation of group care may facilitate access to specialized care to a larger population of patients with diabetes type 1 and 2. PMID- 29998140 TI - The Usefulness of SPECT/CT in Sentinel Node Mapping of Early Stage Breast Cancer Patients Showing Negative or Equivocal Findings on Planar Scintigraphy. AB - Objectives: This study sought to determine the diagnostic yield of SPECT/CT in localizing axillary sentinel lymph nodes (SLNs) in early breast cancer patients where planar scintigraphy (PS) was equivocal or negative. Methods: Prospective analysis of early stage breast cancer patients with non-palpable axillary nodes undergoing SLN localization prior to nodal sampling for axillary staging. PS findings were categorized as: Category A: non-visualization of SLN; Category B: unusual uptake location; Category C: equivocal uptake / difficult interpretation. The K-coefficient of Cohen was used to evaluate the correlation between PS and SPECT/CT results. PS and SPECT/CT images were interpreted separately, and SLN identification on each of the modalities was correlated to BMI (Body mass index) and peroperative radio guided results. Results: Between April 2015 and January 2017, 1028 early breast cancer cases underwent sentinel lymphoscintigraphy. Of total, 134 (13%) patients underwent SPECT/CT in addition to PS. All were females with mean age of 48.15 years (range: 26-82 years). Right sided in 68, left in 64 and 2 with bilateral carcinoma. By TNM classification: 49 (37%) T1, 78 (58%) T2 and 7 (5%) had DCIS/Paget's disease.Overall SLNs were detected on both PS and SPECT/CT in 60% cases. Of category A (n=54); 35/54 (64%) SLN localized on SPECT/CT; 32 were level-I; 2 Level-II; 1 Level-III nodes. In 19, SLN was not localized. Of category B (n=18), 5 had prior lumpectomy, SPECT/CT localized tracer uptake to 17 level-I sentinel nodes, 3 level-II and level III / IMC in 9. Of category C (n=62), 29 had prior lumpectomy. SPECT/CT confirmed SLN in all the cases. Radio-guided surgery confirmed SPECT/CT results. The correlation between the two techniques was low (K=0.34). Where PS was negative; SPECT/CT localized nodes in statistically significant number of cases (=0.01). PS identified SLN uptakes in 80/134 (60%) cases with a mean BMI of 21.6+/-4.8 kg/m2 while SPECT/CT detected ''hot'' nodes in 115/134 (86%) cases with a mean BMI of 29.6+/-5.6 kg/m2. For overweight/obese patients (n=59) (BMI>25 kg/m2), PS failed to identify SLNs in 49 and SPECT/CT failed to do so in 18 (<0.001). Conclusion: SPECT/CT has diagnostic yield and helps in precise SLN localization where planar imaging is negative or shows unusual site of uptake. PMID- 29998141 TI - The Status of Stress Myocardial Perfusion Imaging Using 99mTc Pharmaceuticals in Japan: Results from a Nationwide Survey. AB - Objectives: To appropriately use one-day myocardial perfusion imaging (MPI) with 99mTc radiopharmaceuticals (i.e. to avoid shine-through artifacts), injection doses need to be optimized and dose ratios between the 1st and 2nd scans should be maintained at >= 3. However, the current state of practice in Japan is unclear. Thus, the aim of this study was to clarify the details of MPI protocols using 99mTc radiopharmaceuticals in Japan. Methods: A nationwide survey was conducted in June and July 2016. Questionnaires about stress MPI protocols using 99mTc radiopharmaceuticals were sent to 641 nuclear medicine facilities. Results: Responses were received from 246 facilities. One-day protocols were used in 97.1% of the facilities. The most common injection dose ratio was 2.5. Only 18.2% of facilities achieved the recommended injection dose ratio. Stress-only protocols were performed in only 1.7% of facilities; the primary reasons for not performing stress-only protocols were as follows: 1) "The reading-physician cannot interpret the image just after the first scan," and 2) "Preparation of radiopharmaceuticals and scan arrangements turn out to be complicated." Conclusion: Approximately 80% of nuclear medicine facilities do not follow the recommended injection dose ratio. Stress-only protocols are ideal, but are performed at very few facilities. Both optimization and standardization of stress MPI protocols using 99mTc radiopharmaceuticals are needed in Japan. PMID- 29998138 TI - Evolution of Therapeutic Antibodies, Influenza Virus Biology, Influenza, and Influenza Immunotherapy. AB - This narrative review article summarizes past and current technologies for generating antibodies for passive immunization/immunotherapy. Contemporary DNA and protein technologies have facilitated the development of engineered therapeutic monoclonal antibodies in a variety of formats according to the required effector functions. Chimeric, humanized, and human monoclonal antibodies to antigenic/epitopic myriads with less immunogenicity than animal-derived antibodies in human recipients can be produced in vitro. Immunotherapy with ready to-use antibodies has gained wide acceptance as a powerful treatment against both infectious and noninfectious diseases. Influenza, a highly contagious disease, precipitates annual epidemics and occasional pandemics, resulting in high health and economic burden worldwide. Currently available drugs are becoming less and less effective against this rapidly mutating virus. Alternative treatment strategies are needed, particularly for individuals at high risk for severe morbidity. In a setting where vaccines are not yet protective or available, human antibodies that are broadly effective against various influenza subtypes could be highly efficacious in lowering morbidity and mortality and controlling unprecedented epidemic/pandemic. Prototypes of human single-chain antibodies to several conserved proteins of influenza virus with no Fc portion (hence, no ADE effect in recipients) are available. These antibodies have high potential as a novel, safe, and effective anti-influenza agent. PMID- 29998142 TI - Brain Single Photon Emission Computed Tomography Scan (SPECT) and functional MRI in Systemic Lupus Erythematosus Patients with Cognitive Dysfunction: A Systematic Review. AB - Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide range of clinical manifestations. Cognitive dysfunction is one of the manifestations that could present prior to the emergence of any other neuropsychiatric involvements in SLE. Cognitive dysfunction is a subtle condition occurring with a high frequency. However, there is no data on the correlation of cognitive dysfunction with central nervous system (CNS) imaging findings, in particular single-photon emission computed tomography scan (SPECT) and functional MRI. We decided to perform a systematic review of brain SPECT and fMRI in SLE patients with cognitive dysfunction. Methods: PubMed, Scopus, and Google Scholar databases were searched until April 2017 with the following keywords: "SLE OR systemic lupus erythematous OR lupus" AND "functional MRI OR functional magnetic resonance imaging OR fMRI OR SPECT or SCAN". A total of 1,767articles were found. Two rheumatologists reviewed the articles and finally 14 articles were selected for the final systematic review. Results: The fMRI and SPECT imaging techniques could provide valuable information regarding the SLE patients with cognitive dysfunction at the early stages of the disease. Conclusion: Brain SPECT scan and fMRI are used as functional imaging tools in SLE. Both of these diagnostic modalities are sensitive in reflecting the subtle brain damages in SLE patients with cognitive dysfunction. Brain fMRI and SPECT scan could be significantly beneficial in the diagnosis and initial management of cognitive dysfunction in SLE. Nevertheless, prospective studies could be useful in confirming the application of these diagnostic modalities in the clinical setting. PMID- 29998143 TI - Comparison of Treatment Response Achieved by Tablet Splitting Versus Whole Tablet Administration of Levothyroxine in Patients with Thyroid Cancer. AB - Objectives: TSH suppression by Levothyroxine consumption is a mainstay of thyroid cancer treatment. Tablet-splitting is a worldwide approach in dose adjustment in patients. However, it is highly recommended to evaluate the validity of tablet splitting for each distinctive drug by clinical trials before routinely using tablet halves in clinical practice. In this study we compared the effect of 150 ug dose of Levothyroxine by use of a100 and a 50 ug tablets or one and half 100 ug tablets in Differentiated thyroid cancer (DTC) patients. Methods: One hundred DTC patients treated with one and half 100 ug Levothyroxine tablets were randomly divided into two groups. The first group continued taking medication as before and the second group received the same daily dose by taking one 100 and one 50 microgram Levothyroxine tablets. The mean changes in TSH and T3 levels and patients weight were compared between the groups. Results: 91 patients completed the study. Levothyroxine consumption pattern, age, gender distribution, weight and TSH levels were comparable between groups at the beginning of the study. The mean change of body weights, serum levels of T3 and TSH showed no significant difference between groups in different time points during the study (P>0.05). Conclusion: This study showed similar efficacy of tablet splitting and two tablets administration for Levothyroxine; however, patients preferred two tablets at the end of the study. It can be concluded that tablet splitting can be used as an alternative way when the 50 ug tablet is not available. PMID- 29998144 TI - A Comparison of 2D and 3D Kidney Absorbed Dose Measures in Patients Receiving 177Lu-DOTATATE. AB - Objectives: To investigate and compare quantitative accuracy of kidney absorbed dose measures made from both 2D and 3D imaging in patients receiving 177Lu DOTATATE (Lutate) for treatment of neuroendocrine tumours (NETs). Methods: Patients receiving Lutate therapy underwent both whole body planar imaging and SPECT/CT imaging over the kidneys at time points 0.5, 4, 24, and 96-120 hours after injection. Planar data were corrected for attenuation using transmission data, and were converted to units of absolute activity via two methods, using either a calibration standard in the field of view or relative to pre-voiding image total counts. Hand drawn regions of interest were used to generate time activity curves and kidney absorbed dose estimates in OLINDA-EXM. Fully quantitative SPECT data were generated using CT-derived corrections for both scatter and attenuation, before correction for dead time and application of a camera specific sensitivity factor to convert data to units of absolute activity. Volumes of interest were defined for kidney using the co-registered x-ray CT, before time activity curves and absorbed dose measures were generated in OLINDA EXM, both with and without corrections made to the model for patient specific kidney volumes. Quantitative SPECT data were also used to derive dose maps through dose kernel convolution (DKC), which was treated as the gold standard. Results: A total of 50 studies were analysed, corresponding to various cycles of treatment from 21 patients. Planar absorbed dose estimates were consistently higher than SPECT derived estimates by, on average, a factor of 3. Conclusion: Quantitative SPECT is considered the gold standard approach for organ specific dosimetry however often relies on in house software. As such planar methods for estimating absorbed dose are much more widely available, and in particular, are often the only source of reference in previously published data. For the case of Lutate dosimetry, planar measures may lead to a three-fold increase in measures of kidney absorbed dose. PMID- 29998145 TI - Evaluation of the Reconstruction Parameters of Brain Dopamine Transporter SPECT images Obtained by a Fan Beam Collimator: A Comparison with Parallel-hole Collimators. AB - Objectives: The purpose of this study was to examine the optimal reconstruction parameters for brain dopamine transporter SPECT images obtained with a fan beam collimator and compare the results with those obtained by using parallel-hole collimators. Methods: Data acquisition was performed using two SPECT/CT devices, namely a Symbia T6 and an Infinia Hawkeye 4 (device A and B) equipped with fan beam (camera A-1 and B-1), low- and medium-energy general-purpose (camera A-2 and B-2), and low-energy high-resolution (camera A-3 and B-3) collimators. The SPECT images were reconstructed using filtered back projection (FBP) with Chang's attenuation correction. However, the scatter correction was not performed. A pool phantom and a three-dimensional (3D) brain phantom were filled with 123I solution to examine the reconstruction parameters. The optimal attenuation coefficient was based on the visual assessment of the profile curve, coefficient of variation (CV) [%], and summed difference from the reference activity of the pool phantom. The optimal Butterworth filter for the 3D-brain phantom was also determined based on a visual assessment. The anthropomorphic striatal phantom was filled with 123I solution at striatum-to-background radioactivity ratios of 8, 6, 4, and 3. The specific binding ratio (SBR) of the striatum (calculated by the CT method) was used to compare the results with those of the parallel-hole collimators. Results: The optimal attenuation coefficients were 0.09, 0.11, 0.05, 0.05, 0.11, and, 0.10 cm-1 for cameras A-1, A-2, A-3, B-1, B-2, and B-3, respectively. The cutoff frequencies of the Butterworth filter were 0.32, 0.40, and 0.36 cycles/cm for camera A, and 0.46, 0.44, and 0.44 cycles/cm for camera B, respectively. The recovery rates of the SBRmean with camera A were 51.2%, 49.4%, and 45.6%, respectively. The difference was not statistically significant. The recovery rates of the SBR with camera B were 59.2%, 50.7%, and 50.8%, respectively. Camera B-1 showed significantly high SBR values. Conclusion: As the findings indicated, the optimal reconstruction parameters differed according to the devices and collimators. The fan beam collimator was found to provide promising results with each device. PMID- 29998147 TI - Validation of Optimum ROI Size for 123I-FP-CIT SPECT Imaging Using a 3D Mathematical Cylinder Phantom. AB - Objectives: The partial volume effect (PVE) of single-photon emission computed tomography (SPECT) on corpus striatum imaging is caused by the underestimation of specific binding ratio (SBR). A large ROI (region of interest) set using the Southampton method is independent of PVE for SBR. The present study aimed to determine the optimal ROI size with contrast and SBR for striatum images and validate the Southampton method using a three-dimensional mathematical cylinder (3D-MAC) phantom. Methods: We used ROIs sizes of 27, 36, 44, 51, 61, 68, and 76 mm for targets with diameters 40, 20, and 10 mm on reference and processed images reconstructed using the 3D-MAC phantom. Contrast values and SBR were compared with the theoretical values to obtain the optimal ROI size. Results: The contrast values in the ROI with diameters of 51 (target: 40 mm in diameter) and 44 (target: 20 mm in diameter) mm matched the theoretical values. However, this value did not correspond with the 10-mm-diameter target. The SBR matched the theoretical value with an ROI of > 44 mm in the 20-mm-diameter target; but, it was under- and overestimated under any other conditions. Conclusion: These results suggested that an ROI should be 2-4 folds larger than the target size without PVE, and that the Southampton method was remarkably accurate. PMID- 29998146 TI - Development of an 123I-metaiodobenzylguanidine Myocardial Three-Dimensional Quantification Method for the Diagnosis of Lewy Body Disease. AB - Objectives: We recently developed a new uptake index method for 123I metaiodobenzylguanidine (123I-MIBG) heart uptake measurements by using planar images (radioisotope angiography and planar image) for the diagnosis of Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the diagnostic accuracy of the uptake index was approximately equal to that of the heart-to-mediastinum ratio (H/M) for the discrimination of the LBD and non-LBD patients. A simple and pain-free uptake index method using 123I-MIBG SPECT images by modifying the uptake index method may show better diagnostic accuracy than the planar uptake index method. We hypothesized that the development of a new uptake index method for the determination of 123I-MIBG using single-photon emission computed tomography (SPECT) imaging would provide a reliable and reproducible diagnostic tool for clinical application. Regarding this, the purpose of this study was to develop a new uptake index method with a simple protocol to determine 123I-MIBG uptake on SPECT. Methods: The 123I-MIBG input function was determined from the input counts of the pulmonary artery, assessed by analyzing the pulmonary artery time-activity curves. The 123I-MIBG output function was obtained from 123I-MIBG SPECT counts on the polar map. The uptake index was calculated through dividing the output function by the input function (SPECT uptake method). For the purpose of the study, 77 patients underwent 123I-MIBG SPECT, with an average of 31.5 min after clinical assessment and injection of the tracer. The H/M values, as well as planar and SPECT uptake indices were calculated, and then correlated with clinical features. Results: According to the results, values obtained for LBD were significantly lower than those for non-LBD in all analyses (P<0.01). The overlap of the H/M values between the LBD and non-LBD cases ranged from 2.06 to 2.50. Furthermore, the overlap in uptake index values between LBD and non-LBD cases in planar image analysis was 1.05-1.29. The SPECT uptake index method showed the least overlap of 1.23-1.25, with the highest value for LBD patients clearly distinguished from the lowest value for the non-LBD patients. Conclusion: The new 123I-MIBG SPECT quantification method, developed by the input counts of the pulmonary artery, clearly distinguished LBD from non-LBD. Therefore, this method may be appropriate for routine clinical study. PMID- 29998148 TI - Radiosynthesis of 11C-phenytoin Using a DEGDEE Solvent for Clinical PET Studies. AB - Objectives: Phenytoin is an antiepileptic drug that is used worldwide. The whole body pharmacokinetics of this drug have been extensively studied using 11C phenytoin in small animals. However, because of the limited production amounts that are presently available, clinical 11C-phenytoin PET studies to examine the pharmacokinetics of phenytoin in humans have not yet been performed. We aimed to establish a new synthesis method to produce large amounts of 11C-phenytoin to conduct human studies. Methods: [11C] methane was produced using an in-house cyclotron by the 14N (p, alpha) 11C nuclear reaction of 5 % of hydrogen containing 95 % of nitrogen gas. About 30 GBq of 11C-methane was then transferred to a homogenization cell containing Fe2O3 powder mixed with Fe granules heated at 320 0C to yield 11C-phosgene. Xylene, 1,4-dioxane, and diethylene glycol diethyl ether (DEGDEE) were investigated as possible reaction solvents. Results: The ratio of 11C-phenytoin radioactivity to the total 11C radioactivity in the reaction vessel (reaction efficiency) was 7.5% for xylene, 11% for 1,4-dioxane, and 37% for DEGDEE. The synthesis time was within 45 min from the end of bombardment until obtaining the final product. The radioactivity produced was more than 4.1 GBq in 10 mL of saline at the end of synthesis. The specific activity of the product ranged from 1.7 to 2.2 GBq/MUmol. The quality of the [11C] phenytoin injection passed all criteria required for clinical use. Conclusion: The use of DEGDEE as a solvent enabled the production of a large amount of 11C-phenytoin sufficient to enable PET studies examining the human pharmacokinetics of phenytoin. PMID- 29998149 TI - The Value of Technetium-99m Labeled Alpha-Melanocyte-Stimulating Hormone (99mTc alpha-MSH) in Diagnosis of Primary and Metastatic Lesions of Malignant Melanoma. AB - Objectives: Malignant melanoma is the most lethal type of skin cancers with unfavorable prognosis. Alpha-MSH peptide analogues have a high affinity for melanocortine-1 (MC1) receptors on melanocytes over expressing in malignant melanoma cells. Pre-clinical studies have shown promising results for radiolabeled MSH imaging in this malignancy. The purpose of this study is to assess the diagnostic value of 99mTc-alpha-MSH imaging in malignant melanoma. Methods: Twenty-one patients (13 men) with pathologically confirmed malignant melanoma with or without metastatic distribution were included in this study. 740 1110 MBq 99mTc-alpha-MSH was injected and whole body scans were performed 20, 120 and 240 minutes post injection and were assessed both qualitatively and semi quantitatively using target (T) to background (BG) ratio. Results: The T/BG ratio for the primary tumor bed was 2.51+/-2.26, 2.56+/-2.48 and 1.92+/-1.79 minutes in the whole body scans 20, 120 and 240 minutes post injection, respectively. The sensitivity, specificity, negative and positive predictive values were 75%, 80%, 50% and 92% for primary lesion and 25%, 100%, 68% and 100% for distant metastasis, respectively. Conclusion: 99mTc-alpha-MSH is a newly introduced agent for diagnosis of tumoral lesions in malignant melanoma. Our study showed a high sensitivity with this modality in primary lesions as well as lymph node involvements. However the detection rate was not high in distant metastasis. The preliminary results are promising especially as a new complementary imaging method in management of malignant melanoma. PMID- 29998150 TI - Feasibility of High-dose Iodine-131-metaiodobenzylguanidine Therapy for High-risk Neuroblastoma Preceding Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation: a Study Protocol. AB - Objectives: High-risk neuroblastoma is a childhood cancer with poor prognosis despite modern multimodality therapy. Internal radiotherapy using 131I metaiodobenzylguanidine (MIBG) is effective for treating the disease even if it is resistant to chemotherapy. The aim of this study is to evaluate the safety and efficacy of 131I-MIBG radiotherapy combined with myeloablative high-dose chemotherapy and hematopoietic stem cell transplantation. Methods: Patients with high-risk neuroblastoma will be enrolled in this study. A total of 8 patients will be registered. Patients will receive 666 MBq/kg of 131I-MIBG and after safety evaluation will undergo high-dose chemotherapy and hematopoietic stem cell transplantation. Autologous and allogeneic stem cell sources will be accepted. After engraftment or 28 days after hematopoietic stem cell transplantation, the safety and response will be evaluated. Conclusion: This is the first prospective study of 131I-MIBG with high-dose chemotherapy and hematopoietic stem cell transplantation in Japan. The results will be the basis of a future nationwide clinical trial. PMID- 29998151 TI - Sagliker Syndrome in a Patient with Secondary Hyperparathyroidism and Chronic Renal Insufficiency: A Case Report. AB - Sagliker syndrome is a rare form of renal osteodystrophy resulted from untreated secondary hyperparathyroidism. It is described by severe skeletal deformities, high level of PTH in patients with chronic renal failure, and deformed face. This paper reports a 44-year-old male patient with the mentioned characteristics. In addition to the unique clinical features, high levels of ALP and PTH hormones encouraged us to search for syndrome-like a disease, which clinically and paraclinically matched the Sagliker syndrome. This case highlights the importance of clinicians' attention for early monitoring and appropriate treatment as it is shown to be effective in preventing irreversible complications such as soft tissue and bone abnormalities and cardiovascular impairment in patients with Sagliker syndrome. Therefore, considering the syndrome is recommended as one of the diagnostic hypothesis in young patients with renal insufficiency, secondary hyperparathyroidism, and skeletal deformities. PMID- 29998152 TI - Utility of 99mTc-Sestamibi SPECT/CT in the Early Localization of Metastatic Parathyroid Carcinoma. AB - Parathyroid carcinoma is very rare, with only a few documented cases. Hence, metastatic lesions are infrequently documented on scintigraphic imaging. We present a case of a 63-year-old female presenting with elevated serum levels of ionized calcium and parathyroid hormone (PTH) who was referred to our department for a parathyroid scan with SPECT/CT. Parathyroid scintigraphy showed a focus of increased 99mTc-sestamibi uptake corresponding to a solid mass with calcification in the inferior pole of the right thyroid lobe; tracer retention was noted on delayed images. Incidentally, focal uptake was also seen in a soft tissue mass on the 7th right rib. The patient soon underwent total thyroidectomy, with biopsy revealing parathyroid carcinoma on the right lobe. A bone scan done 7 months after surgery confirmed the presence of metastatic bone disease. The concomitant detection of intrathyroidal and extrathyroidal sestamibi-avid masses on parathyroid scintigraphy should increase clinical suspicion of a metastatic process from parathyroid carcinoma. PMID- 29998153 TI - Adrenocortical Oncocytic Carcinoma and Papillary Thyroid Carcinoma Incidentally Detected in an Asymptomatic Patient by F-18 FDG PET/CT. AB - F-18 FDG is the most widely used tracer in molecular imaging and it is applied for many purposes mainly in malignant diseases. Incidental finding are common in FDG-PET/CT imaging and includes benign and malignant lesions. Among the rare tumors, adrenal oncocytomas are uncommon findings and incidental findings of thyroid malignancies are not rare. Oncocytoma is a rare adrenocortical tumor and majority of bulky adrenal tumors are benign with uncertain incident of malignancy. In this study, we are reporting a 37-year-old man with two incidental malignancies detected by FDG-PET-CT. He has no symptoms has no blood and hormonal abnormalities. The scan demonstrated intense heterogeneous FDG uptake within the bulky oval shaped lesion in the left adrenal gland. Accordingly, open adrenalectomy was performed and diagnosis of adrenocortical carcinoma oncocytic type was established. Furthermore, a focal FDG uptake was identified in the right thyroid lobe and histopathology findings were consistent with well-differentiated papillary thyroid cancer. FDG plays a great role in identifying primary rare lesions and also detection of incidental findings at unexpected sites. PMID- 29998154 TI - Letter to the Editor. PMID- 29998155 TI - Response to the Letter to Editor. PMID- 29998156 TI - Autoimmune septin-5 cerebellar ataxia. AB - Objective: To report a form of autoimmune cerebellar ataxia in which antibodies target septin-5, a guanosine triphosphate (GTP)-binding neural protein involved in neurotransmitter exocytosis. Methods: Archived sera and CSF specimens with unclassified synaptic antibodies were re-evaluated by tissue-based indirect immunofluorescence assay. Autoantigens were identified by Western blot and mass spectrometry. Recombinant protein assays (Western blot, cell based, and protein screening array) confirmed antigen specificity. Results: Serum and CSF from 6 patients produced identical synaptic immunoglobulin G (IgG) staining patterns of synaptic regions (neuropil) of the mouse cerebrum and cerebellum. The molecular layer of the cerebellum and the thalamus demonstrated stronger immunoreactivity than the midbrain, hippocampus, cortex, and basal ganglia. The antigen revealed by mass spectrometry analysis of immunoprecipitated cerebellar proteins and confirmed by recombinant protein assays was septin-5. All 4 patients with records available had subacute onset of cerebellar ataxia with prominent eye movement symptoms (oscillopsia or vertigo). None had cancer detected. Improvements occurred after immunotherapies (2) or spontaneously (1). One patient died. Conclusion: Septin-5 IgG represents a biomarker for a potentially fatal but treatable autoimmune ataxia. PMID- 29998157 TI - VZV-associated acute retinal necrosis in a patient with MS treated with natalizumab. PMID- 29998158 TI - Paraneoplastic NMOSD associated with EG junction adenocarcinoma expressing unprotected AQP4. PMID- 29998159 TI - Tumefactive demyelination with a transient appearance of oligoclonal bands in MS under fingolimod. PMID- 29998160 TI - Colonoscope Insertion: Is the Future Underwater. PMID- 29998161 TI - Can Water Exchange Improve Patient Tolerance in Unsedated Colonoscopy A Prospective Comparative Study. AB - Background & Aims: Unsedated colonoscopy can be painful, poorly tolerated by patients, and associated with unsatisfactory technical performance. Previous studies report an advantage of water exchange over conventional air insufflation in reducing pain during unsedated colonoscopy. Our goal was to analyze the impact of water exchange colonoscopy on the level of maximum pain reported by patients submitted to unsedated colonoscopy, compared to conventional air insufflation. Methods: We performed a single-center, patient-blinded, prospective randomized comparative study, where patients were either allocated to the water group, in which the method of colonoscopy used was water exchange, or the standard air group, in which the examination was accomplished with air insufflation. Results: A total of 141 patients were randomized, 70 to the water and 71 to the air group. The maximum level of pain reported by patients during unsedated colonoscopy, measured by a numeric scale of pain (0-10), was significantly lower in the water group (3.39 +/- 2.32), compared to the air group (4.94 +/- 2.10), p < 0.001. The rate of painless colonoscopy was significantly higher in the water group (12.9 vs. 1.4%, p = 0.009). There were no significant differences between the two groups regarding indications for the procedure, quality of bowel preparation, cecal intubation time, withdrawal time, number of position changes, adenoma detection rate, and postprocedural complications. Only the number of abdominal compressions was significantly different, showing that water exchange decreases the number of compressions needed during colonoscopy. Conclusions: Water exchange was a safe and equally effective alternative to conventional unsedated colonoscopy, associated with less intraprocedural pain without impairing key performance measures. PMID- 29998162 TI - Lymphoproliferative Disorders in Inflammatory Bowel Disease Patients: Is It the Drugs or the Disease. AB - Introduction: Systemic inflammatory diseases are related to an increased risk of lymphoproliferative disorders. Although inflammatory bowel disease (IBD) was also associated with these conditions, population-based studies failed to demonstrate this relationship, and most studies only identified a very small number of cases. In the last few years, concerns arose regarding the role of thiopurines and tumour necrosis factor-alpha (TNF-alpha)-blocking agents in the development of lymphoma, influencing therapeutic decisions in IBD patients. The aim of this study was to describe a case series of IBD patients who developed a lymphoproliferative disorder in our tertiary referral centre. Material and Methods: The clinical records of all IBD patients who were observed in our unit between January 2007 and December 2016 were retrospectively reviewed, and IBD subjects who were diagnosed with a lymphoproliferative disorder were selected. Clinical and demographic data regarding both conditions were collected. Results: Six IBD patients were diagnosed with a lymphoma - 4 Hodgkin lymphomas and 2 B cell non-Hodgkin lymphomas - of which 3 corresponded to primary colonic lymphomas. Immunohistochemical analysis detected the presence of Epstein-Barr virus in the tumour cells of 2 patients, both of them with Hodgkin lymphomas. Only 2 patients were previously treated with thiopurines or anti-TNF-alpha drugs; none of the remaining had any history of immunosuppressive treatment. Discussion and Conclusions: Despite major attention being currently focused on the effect of treatment, which may play the main role in the increased susceptibility to lymphoma in IBD patients, and although it may be difficult to demonstrate, IBD itself may contribute to the development of lymphoproliferative disorders, particularly primary intestinal lymphomas. PMID- 29998163 TI - Unusual Cause of Epigastric Pain: Intra-Abdominal Focal Fat Infarction Involving Appendage of Falciform Ligament - Case Report and Review of Literature. AB - Torsion of the fatty appendage of the falciform ligament, part of the spectrum of conditions known as intra-abdominal focal fat infarction (IFFI), is very rare with less than 20 cases reported on imaging so far. Here we report a case of torsion of the lipomatous appendage of the falciform ligament in a middle-aged female, diagnosed on ultrasound and computed tomography (CT). CT showed classical "hyperattenuating rim" sign in the anterior perihepatic space adjacent to the falciform ligament. We re-emphasize the importance of "hyperattenuating rim" sign on CT in recognizing IFFI in locations other than the pericolic region. PMID- 29998164 TI - Eosinophilic Enterocolitis: An Exceedingly Rare Entity. AB - Eosinophilic enterocolitis is an exceptionally rare condition with few described cases in the literature, representing the least frequent manifestation of the wide spectrum of eosinophilic gastrointestinal disorders. We describe a case of a young male patient presenting with a panmural form of the disease, manifested by abdominal pain, distention, and watery diarrhea with 4 days of evolution, bowel wall thickening, and ascites. Eosinophilic ascites is probably the most unusual presentation form of this entity. It poses a diagnostic challenge because of its nonspecific symptoms, associated with the absence of standardized histological criteria, hence requiring a high level of suspicion. There is also no consensus regarding treatment: it should be individualized according to the patient's age and severity of symptoms. PMID- 29998166 TI - Adenosquamous Carcinoma of the Ampulla of Vater: A Rare Cause of Obstructive Jaundice. PMID- 29998167 TI - Dasatinib-Induced Colitis in a Patient with Chronic Myelogenous Leukemia. PMID- 29998165 TI - A Complex Case of Cholestasis in a Patient with ABCB4 and ABCB11 Mutations. AB - The low-phospholipid-associated cholelithiasis (LPAC) syndrome is a form of symptomatic cholelithiasis occurring in young adults, characterized by recurrence of symptoms after cholecystectomy and presence of hepatolithiasis. The case refers to a healthy 39-year-old Caucasian male who presented with abdominal pain and jaundice. His blood tests showed conjugated hyperbilirubinemia and elevated liver enzymes (total bilirubin 6.65 mg/dL, gamma-glutamyltransferase 699 IU/L) and abdominal computed tomography revealed dilation of common bile duct and left intrahepatic ducts. Magnetic resonance cholangiopancreatography identified choledocholithiasis, retrieved by endoscopic retrograde cholangiopancreatography, after which there was a worsening of jaundice (total bilirubin 23 mg/dL), which persisted for several weeks, possibly due to ciprofloxacin toxicity. After an extensive workup including liver biopsy, the identification of two foci of hepatolithiasis on reevaluation abdominal ultrasound raised the hypothesis of LPAC syndrome and the patient was started on ursodeoxycholic acid, with remarkable improvement. Genetic testing identified the mutation c.1954A>G (p.Arg652Gly) in ABCB4 gene (homozygous) and c.1331T>C (p.Val444Ala) in ABCB11 gene (heterozygous). In conclusion, we describe the unique case of an adult male with choledocholithiasis, hepatolithiasis, and persistent conjugated hyperbilirubinemia after retrieval of stones, fulfilling the criteria for LPAC syndrome and with possible superimposed drug-induced liver injury, in whom ABCB4 and ABCB11 mutations were found, both of which had not been previously described in association with LPAC. PMID- 29998168 TI - Pancreatic Mucinous Cystadenoma Mimicking Intraductal Papillary Mucinous Neoplasm. PMID- 29998169 TI - Fleeting Angiodysplasia. PMID- 29998170 TI - Colonic Necrosis Induced by Calcium Polystyrene Sulfonate. PMID- 29998171 TI - Endoscopic Submucosal Dissection of Gastric Adenocarcinoma Involving the Pylorus Circumference. PMID- 29998172 TI - An Uncommon Cause of Cholangitis and Cholecystitis. PMID- 29998173 TI - A Metal Stent in a Colostomy Obstruction. PMID- 29998174 TI - Expression of pro-apoptotic markers is increased along the osteochondral junction in naturally occurring osteochondrosis. AB - Osteochondrosis (OC) is a naturally occurring disease of the articular-epiphyseal cartilage and subchondral bone layers, leading to pain and decreased mobility. The objective of this study was to characterize gene and protein expression of apoptotic markers in chondrocytes surrounding cartilage canals and along the osteochondral junction of osteochondrosis (OC)-affected and normal cartilage, using naturally occurring disease in horses. Paraffin-embedded osteochondral samples (6 OC, 8 normal controls) and cDNA from chondrocytes captured with laser capture microdissection (4 OC, 6 normal controls) were obtained from the lateral trochlear ridge of femoropatellar joints in 14 immature horses (1-6 months of age). Equine-specific caspase-3, caspase-8, caspase-10, Fas, Bcl-2, BAG-1, TNFalpha, cytochrome C, thymosin-beta10, and 18S mRNA expression levels were evaluated by two-step real-time quantitative PCR. Percentage of cell death was determined using the TUNEL method. Protein expression of caspase-10, Fas, cytochrome C, and thymosin-beta10 was determined following immunohistochemistry. Statistical analysis was performed using the Wilcoxon rank sum test or two-sample t-test (p < 0.05). In OC samples, there was significantly increased gene expression of caspase-10, Fas, cytochrome C, and thymosin-beta10 in chondrocytes along the osteochondral junction and increased Fas gene expression in chondrocytes adjacent to cartilage canals, compared to controls. In OC samples, higher matrix Fas and cytochrome C protein expression, lower mitochondrial cytochrome C protein expression, and a trend for higher cytoplasmic caspase-10 protein expression were found. Collectively, these results suggest that both extrinsic and intrinsic apoptotic pathways are activated in OC cartilage. Increased apoptosis of osteochondral junction chondrocytes may play a role in OC, based on increased gene expression of several pro-apoptotic markers in this location. PMID- 29998176 TI - Pigmented actinic lichen planus (PALP) mimicking lentigo maligna melanoma: Usefulness of in vivo reflectance confocal microscopy in diagnosis and follow-up. PMID- 29998175 TI - Pancreatic cancer occurrence in Ferguson-Smith syndrome. PMID- 29998177 TI - Two reports of malignant melanoma arising within a new vitiligo-like depigmented patch. PMID- 29998178 TI - Recalcitrant lip verrucous carcinoma successfully treated with acitretin after carbon dioxide laser ablation. PMID- 29998179 TI - Enhancement of the aesthetic outcome of scleroderma en coup de sabre with botulinum toxin injection. PMID- 29998180 TI - Piezogenic pedal papules treated successfully with deoxycholic acid injection. PMID- 29998181 TI - Drug-induced dermatomyositis after lacosamide: A case report. PMID- 29998182 TI - Resilience, hope and flourishing are inversely associated with burnout among members of the Society for Gynecologic Oncology. AB - Purpose: In this study we sought to: 1) determine rates of burnout and other associated indices of psychosocial distress such as alcohol and substance abuse, 2) establish the baseline performance of gynecologic oncologists on several positive psychology metrics, 3) determine if increased hope, resilience, and flourishing are associated with decreased burnout. Methods: A survey of members of the Society of Gynecologic Oncology (SGO) was conducted in spring of 2017. Participants were sent an electronic questionnaire consisting of 82 items measuring burnout, depression, substance abuse, flourishing, resilience, hope, and psychological wellbeing. Results: A total of 1745 members were invited and 374 (21.4%) responded. Overall, 23.0% of respondents scores above clinical cutoffs indicating burnout. Almost 50.0% of participants screened positive for depression, 17.0% screened positive for alcohol abuse and 12.0% screened positive for substance abuse. Respondents meeting criteria for burnout were more likely to screen positive for depression (p < .001) and substance abuse (p < .001). Participants not meeting criteria for burnout had higher resilience, flourishing, hope, and wellbeing scores (p < .001). Male respondents had higher levels of hope, resilience, and wellbeing while married participants had higher flourishing and wellbeing scores than their unmarried counterparts. Parents had higher levels of resilience and wellbeing compared to non-parents. Conclusions: Burnout and associated indices of physiological distress continue to affect a large segment of SGO membership. Participants not meeting the criteria for burnout had higher scores on resilience, flourishing, hope, and wellbeing metrics. This suggests new targets for evidence-based interventions to mitigate burnout among members of SGO. PMID- 29998183 TI - Pelvic exenteration by robotically-assisted laparoscopy: A feasibility series of 6 cases. AB - After concomitant chemo-radiation therapy, 20 to 30% of advanced cervical cancers recur in irradiated territory. Pelvic exenteration remains a therapeutic option for selected patients. However, this procedure remains complex because of tissue fragility after radiotherapy and their associated co-morbidities. Minimally invasive surgery such as robotically assisted laparoscopy may overcome these surgical challenges. The objective of this study was to evaluate the feasibility of pelvic exenteration with robotically assisted laparoscopy. Patients who underwent this procedure between 2015 and 2016 were included. Patients characteristics, treatment indication, intraoperative events, immediate and late complications, and histological outcomes were recorded. The data of 6 patients were analyzed. The primary cancer staging ranged from IB1 to IIB. All cases were loco-regional recurrence and 2 cases presented with with vesico-vaginal fistula. All patients had a history of pelvic irradiation. The mean operative time was 6.7 h. No complications occurred during surgery. The average hospital stay was 11.5 days. Immediate complications were mostly represented by urinary tract infections (4/5). Histological margins were clear in 67% (4/6), and a focal involvement was found in 33% (2/6) of cases. Late complications occurred within 82 days on average and included stenosis of ileal anastomosis, wound infection, acute renal failure, and pulmonary embolism. Revision surgery was necessary in 2 cases. There were 3 local recurrences occurring within an average of 215 days. In the light of these results, pelvic exenteration by robotically assisted laparoscopy may represent a valuable treatment modality of recurrent cervical cancer with low immediate postoperative morbidity. PMID- 29998184 TI - Treatment of recurrent granulosa cell tumor with metformin and letrozole, a case report. AB - *Cytotoxic chemotherapy has questionable efficacy against granulosa cell tumor.*Aromatase inhibitors may provide alternative treatment for granulosa cell tumors.*Metformin may be a beneficial adjunct in treating recurrent granulosa cell tumors. PMID- 29998185 TI - Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series. AB - Tumors deficient in DNA mismatch repair are known to display increased susceptibility to immune checkpoint inhibitors due to accumulation of DNA damage and increased neoantigen load. This suggests that deficiency in the BRCA-related DNA repair mechanism may also be a surrogate marker for immunotherapy response. The aim of this study was to examine the efficacy of the immune checkpoint inhibitor, nivolumab, in women with BRCA gene mutations and recurrent mullerian cancer. This retrospective case series followed six BRCA carriers who received nivolumab monotherapy (3.0 mg/kg, intravenous, day 1 and 15, every 4 weeks) as salvage therapy for recurrent epithelial ovarian (n = 5) and fallopian tubal (n = 1) cancers. Toxicity, treatment response, and survival were examined. Median age was 57 (range 51-64). BRCA1 and 2 mutations were equally distributed. All had high-grade serous histology, and all but one had advanced-stage disease at initial diagnosis. The majority had platinum-resistant disease (n = 4). All received salvage therapy prior to nivolumab therapy (median 3 lines), including PARP inhibitors (n = 3). The median number of nivolumab treatment cycles was 9, including 2 women receiving 18 cycles. Three women developed nivolumab-related toxicities, most commonly grade 2 hypothyroidism (n = 2). Median follow-up time was 13.4 months, and there were 3 complete responses, 1 partial response, and 2 patients with progressive disease. Objective response rate was 67% (4 out of 6). In conclusion, our study suggests that nivolumab monotherapy is well-tolerated and may be an effective salvage therapy for BRCA mutation carriers with recurrent epithelial ovarian, fallopian tubal, and primary peritoneal cancers. PMID- 29998186 TI - Definitive radiation therapy for cervical cancer: Non-white race and public insurance are risk factors for delayed completion, a pilot study. AB - This is a pilot study to assess whether racial disparities exist in time to initiation and completion of external beam pelvic radiation therapy and brachytherapy in cervical cancers treated with definitive chemoradiation. A retrospective analysis was conducted on all cervical cancer patients treated with definitive radiotherapy between 2006 and 2016 at a single institution. Patient demographics including age, race, insurance status and stage at diagnosis were obtained. Analyses were performed according to the following definitions of wait times: interval from pathologic diagnosis of cervical cancer to (Siegel et al., 2016) initiation of radiation therapy, (Yoo et al., 2017) completion of external beam radiation therapy and (DeSantis et al., 2016) completion of external beam radiation therapy plus brachytherapy if indicated. Of 50 women, 21 self identified as white, 25 as black and 4 as Hispanic. Due to small numbers, Hispanic women were included with black women as a non-white group. The average age was 52 years for women in this cohort. Mean days to initiation of radiation therapy were 41.8 days: 33.7 days among white patients versus 47.8 days for non white patients (p-value 0.101). Mean days from diagnosis to completion of external beam pelvic radiation therapy were 81.3 days: 70.9 days among white patients versus 88.9 days among non-white patients (p-value 0.006). Non-white patients were more likely to have public insurance, which was also associated with a longer time to completion of radiation treatment. We conclude that non white patients experienced delays to completing external beam radiation therapy, which was no longer present after adjusting for insurance status. PMID- 29998187 TI - The known roots of a known problem. PMID- 29998188 TI - Overlapping geographic clusters of food security and health: Where do social determinants and health outcomes converge in the U.S? AB - We identified overlapping geographic clusters of food insecurity and health across U.S. counties to identify potential shared mechanisms for geographic disparities in health and food insecurity. By analyzing health variables compiled as part of the 2014 Robert Wood Johnson Foundation County Health Rankings, we constructed four health indices and compared their spatial patterns to spatial patterns found in food insecurity data obtained from 2014 Feeding America's County Map the Meal Gap data. Clusters of low and high food security that overlapped with clusters of good or poor health were identified using Local Moran's I statistics. Next, multinomial logistic regressions were estimated to identify sociodemographic, urban/rural, and economic correlates of counties lying within overlapping clusters. In general, poor health and high food insecurity clusters, "unfavorable cluster overlaps", were present in the Mississippi Delta, Black Belt, Appalachia, and Alaska. Overlapping good health and low food insecurity clusters, "favorable cluster overlaps", were less common and located in the Corn Belt and New England. Counties with higher black populations and higher poverty were associated with an increased likelihood of lying within overlapping clusters of poor health and high food insecurity. Generally consistent patterns in spatial overlaps between food security and health indicate potential for shared causal mechanisms. Identified regions and county-level characteristics associated with being located inside of overlapping clusters may be used in future place-based intervention and policy. PMID- 29998189 TI - The association between self-reported varenicline adherence and varenicline blood levels in a sample of cancer patients receiving treatment for tobacco dependence. AB - Introduction: The degree to which smokers quit successfully with varenicline is strongly associated with their adherence to the medication regimen. Thus, measuring varenicline adherence to identify smokers needing additional intervention is a priority. Few studies, however, have examined the validity of self-reported varenicline adherence, using a biological assessment of adherence as a reference. No study has examined this issue among cancer patients trying to quit smoking, who may show unique patterns of adherence given their medical comorbidity. Methods: This study used data from 76 cancer patients who received varenicline and provided self-reported varenicline adherence data (pill count) and a blood sample to determine varenicline metabolites 4 weeks after initiating varenicline. Results: Receiver operating characteristic (ROC) curve analyses of plasma varenicline levels showed that 4 ng/ml was the optimal cut-point for differentiating adherence with significant (p's < 0.04) area under the curve values, ranging from 0.73-0.80 for 3-day, 7-day, and 4-week self-reported pill count; specificity values ranged from 0.63-0.78 and sensitivity values ranged from 0.82-0.94. Using this cut-point, adherence was high (88%). However, plasma varenicline levels were weakly correlated with 3-day and 4-week pill count and total pill count (12 weeks) was not correlated with plasma varenicline levels. Patients with head and neck cancer, gastrointestinal cancer, and more advanced disease showed lower varenicline adherence and lower plasma varenicline. Conclusions: Using the 4 ng/ml cut-point, this study suggests validity of short term self-reported varenicline adherence among cancer patients undergoing tobacco dependence treatment in contrast to studies in the general population, which supported 12-week pill count. PMID- 29998190 TI - Preclinical Development of Oncolytic Immunovirotherapy for Treatment of HPVPOS Cancers. AB - Immunotherapy for HPVPOS malignancies is attractive because well-defined, viral, non-self tumor antigens exist as targets. Several approaches to vaccinate therapeutically against HPV E6 and E7 antigens have been adopted, including viral platforms such as VSV. A major advantage of VSV expressing these antigens is that VSV also acts as an oncolytic virus, leading to direct tumor cell killing and induction of effective anti-E6 and anti-E7 T cell responses. We have also shown that addition of immune adjuvant genes, such as IFNbeta, further enhances safety and/or efficacy of VSV-based oncolytic immunovirotherapies. However, multiple designs of the viral vector are possible-with respect to levels of immunogen expression and method of virus attenuation-and optimal designs have not previously been tested head-to-head. Here, we tested three different VSV engineered to express a non-oncogenic HPV16 E7/6 fusion protein for their immunotherapeutic and oncolytic properties. We assessed their profiles of efficacy and toxicity against HPVPOS and HPVNEG murine tumor models and determined the optimal route of administration. Our data show that VSV is an excellent platform for the oncolytic immunovirotherapy of tumors expressing HPV target antigens, combining a balance of efficacy and safety suitable for evaluation in a first-in-human clinical trial. PMID- 29998192 TI - The epithelial-mesenchymal transition induced by transcription factor LEF-1 is independent of beta-catenin. AB - Transcription factor lymphoid-enhancer-binding factor 1 (LEF-1) is a key molecule in the Wnt/beta-catenin signaling pathway. Slug is one of the Wnt/beta-catenin target genes and can induce epithelial-mesenchymal transition (EMT). Previously, we have shown that not only wild-type LEF-1 but also LEF-1 lacking the amino terminal beta-catenin-binding region can induce EMT, suggesting that LEF-1 acts independently of beta-catenin. Because it has been reported that LEF-1 interacts with beta-catenin outside the amino-terminal domain, namely, in the middle part of the molecule, the possible participation of beta-catenin has not been formally ruled out. To determine the involvement of beta-catenin in the LEF-1-induced EMT, we produced MDCK cells with a deletion of the beta-catenin gene and then expressed LEF-1 in the cells. We found that LEF-1 induced EMT in those cells. In the absence of beta-catenin, gamma-catenin has been shown to take over the role of beta-catenin. To examine this possibility, we first established MDCK cells with a double knockout of beta-catenin and gamma-catenin genes and then expressed LEF-1 in these cells. We found that LEF-1 can induce EMT in these cells; therefore, we conclude that neither beta-catenin nor gamma-catenin expression is necessary for the LEF-1-mediated induction of EMT. PMID- 29998191 TI - Mass media exposure and its impact on malaria prevention behaviour among adult women in sub-Saharan Africa: results from malaria indicator surveys. AB - Background: Mass media exposure plays a pivotal role in health communication and adoption of a healthy lifestyle. In this study, we aimed to measure the prevalence of malaria prevention behaviour among adult women in eight malaria endemic countries in sub-Saharan Africa (SSA), and assess the influence of mass media exposure in the adoption of those behaviours. Methods: For this study, we collected cross-sectional data on 46,822 women aged between 15 and 49 years from the Malaria Indicator Surveys (MIS) conducted in Burkina Faso, Ghana, Mali, Malawi, Kenya, Nigeria, Sierra Leone and Uganda. As the outcome variable, malaria prevention behaviour was proxied by the use of insecticide treated nets (ITNs) and uptake of antimalarial drugs in last pregnancy. Results: The overall prevalence of sleeping under ITN and that of taking antimalarial drug during the last pregnancy was respectively 67.9% (95%CI = 66.6-69.2) and 72.8% (95%CI = 71.3 74.2). However, there were disparities in the prevalence of using ITN and antimalarial drug use across the study countries. In the multivariable regression analysis, not receiving malaria related information from radio, poster/billboards, community events, and health workers were found to be significantly associated with reduction in the odds of using ITN the previous night. For the use of antimalarial drugs during last pregnancy, the odds were 23% [OR = 0.773, 95%CI = 0.625-0.956] lower for those who did not receive malaria information on radio compared with those who received. Conclusions: These findings indicate a potentially important role of malaria information received through mass media on utilisation of ITN among women in SSA. More research is needed to explore the factors that limit the accessibility to malaria information through mass media. PMID- 29998193 TI - Epitope mapping of anti-mouse podoplanin monoclonal antibody PMab-1. AB - Mouse podoplanin (mPDPN) is a type I transmembrane sialoglycoprotein, which is expressed on lymphatic endothelial cells, podocytes of the kidney, and type I alveolar cells of the lung. mPDPN is known as a platelet aggregation-inducing factor and possesses four platelet aggregation-stimulating (PLAG) domains: PLAG1, PLAG2, and PLAG3 in the N-terminus and PLAG4 in the middle of the mPDPN protein. mPDPN overexpression in cancers has been reportedly associated with hematogenous metastasis through interaction with the C-type lectin-like receptor 2 of platelets. We previously reported a rat anti-mPDPN monoclonal antibody clone PMab 1, which was developed by immunizing the PLAG2 and PLAG3 domains of mPDPN. PMab-1 is very useful in flow cytometry, western blot, and immunohistochemical analyses to detect both normal cells and cancers. However, the binding epitope of PMab-1 remains to be clarified. In the present study, flow cytometry, enzyme-linked immunosorbent assay, and immunohistochemical analyses were utilized to investigate the epitope of PMab-1. The results revealed that the critical epitope of PMab-1 is Asp39 and Met41 of mPDPN. These findings can be applied to the production of more functional anti-mPDPN monoclonal antibodies. PMID- 29998194 TI - Immune responses to vaccine-preventable diseases among toddlers and preschool children after primary immunization and first booster in Northwestern Algiers, Algeria. AB - Objectives: To determine immune responses to selected vaccine-preventable communicable diseases: pertussis, diphtheria and Haemophilus influenzae type b (Hib) in Algerian toddlers and preschool children after primary vaccination and first booster, recruited from three local healthcare facilities in Northwestern Algiers. Methods: The information of demographic characteristics and vaccination status were collected for each subject by questionnaire. Specific antibody levels and Hib antibody avidity were determined using commercial ELISA kits. Results: A total of eighty-one subjects aged between 19 and 55 months were studied. Almost all subjects were fully protected against diphtheria (76/81; 93.83%; 95% CI: 86.35-97.33) and invasive Hib disease (29/30; 96.67%; 95% CI: 83.33-99.41), while only 20/78 (25.64%; 95% CI: 17.26-36.31) had anti-PT (pertussis toxin) antibody levels above 25 IU/ml. A significant decrease of anti-PT antibody levels was observed until the age of 36 months (p = 0.02). GMTs (geometric mean titers) of anti-PT antibodies were low, but remain significantly higher in children <=36 months of age (p = 0.02). Both GMT and rates of >=0.15 MUg/ml, >=1 MUg/ml, and >=5 MUg/ml titers were significantly higher in Hib-vaccinated subjects (p < 0.01). Relative Hib-avidity index (>=50%) and GMAI (geometric mean avidity index) were high in both Hib-vaccinated and -unvaccinated groups. Conclusions: As shown in the present study, young children were fully protected against diphtheria and Hib, but showed low immunity to pertussis. Further sero-epidemiological studies including a large number of subjects with a wider range of age are needed to explore the immunity level in older children, adolescents and adults. PMID- 29998195 TI - Human brain gene expression profiles of the cathepsin V and cathepsin L cysteine proteases, with the PC1/3 and PC2 serine proteases, involved in neuropeptide production. AB - Proteases are required to generate active peptide neurotransmitters, known as neuropeptides, from pro-neuropeptides. Model animal systems have recently illustrated roles for the cathepsin V (CTSV) and cathepsin L (CTSL) cysteine proteases, combined with the serine proteases PC1/3 (PCSK1) and PC2 (PCSK2), and exopeptidases in the production of neuropeptides. There is notable interest in the human-specific cathepsin V gene which is not present in rodent and other animal models used in prior studies of neuropeptide production. A gap in the field is knowledge of the human brain gene expression patterns of these neuropeptide-producing protease systems. Therefore, the goal of this study was to characterize the expression profiles of these pro-neuropeptide processing proteases in human brain. Quantitative gene expression microarray data for 169 human brain regions was obtained from the Allen Institute Human Brain Atlas resource, analyzed as log2 of gene expression intensity normalized to the mean of human genes (21,245 genes) expressed in human brain. These proteases had log2 values of 2-12, indicating expression levels above the average of all genes in the human brain, with varying expression levels among the 169 brain regions. CTSV and CTSL displayed moderate to high expression values of 1.9-8.6 and 7.1-10.6, respectively. Interestingly, CTSV and CTSL showed high expression in white matter composed of myelinated axons, consistent with the knowledge that neuropeptide production occurs in axons within transported neuropeptide secretory vesicles to nerve terminals. PCSK1 had a broad range of moderate to very high expression with log2 of 2-12. PCSK2 had somewhat lower expression levels than PCSK1. The exopeptidase genes RNPEP, CTSH, and CPE each showed fairly even levels of expression throughout the brain, with CPE displaying high expression. The prevalence of these processing proteases throughout human brain regions, including areas rich in neuropeptides such as hypothalamus, is consistent with their roles for neuropeptide production. Further, proenkephalin and NPY precursors, substrates of CTSV and CTSL shown in prior model animal studies, were co-expressed with CTSV and CTSL. These data demonstrate that the human brain expresses the neuropeptide-producing cysteine and serine proteases, with exopeptidases, throughout a multitude of brain regions. PMID- 29998197 TI - Aftershock analysis of the 2015 Gorkha-Dolakha (Central Nepal) earthquake doublet. AB - On 25 April 2015, a large earthquake with moment-magnitude (Mw) 7.8 occurred at Gorkha (latitude 28.23 degrees N and longitude 84.73 degrees E) in Central Nepal. Just 17 days later, another large earthquake of Mw 7.3 occurred at Dolakha (latitude 27.80 degrees N and longitude 86.06 degrees E), about 140 km away from the previous epicenter. In this study, we deal with the aftershocks of these two earthquakes that occurred in the region (27 degrees -28.5 degrees N, 84 degrees -87 degrees E) spanning the period from 25 April 2015 to 28 May 2016 to find the spatiotemporal distribution patterns, the size distribution (b-value), and the aftershock decay rate (p-value) of this sequence. Aftershock epicenters of the 2015 Gorkha-Dolakha earthquake doublet are distributed over an area approximately 170 km in length and 70 km in width and largely confined in a depth range from 5 to 25 km. The spatial distribution of epicenters and known geological structures in this study reveals that aftershocks are limited on the east by the surface trace of the Everest lineament and on the south side by the surface trace of the segment of the Main Boundary Thrust (MBT). The estimated b and p-values of this seismic sequence are 0.93 +/- 0.03 and 0.79 +/- 0.24, respectively. This b-value is higher than the b-value estimated by the previous studies, while the p-value corresponds in general with the p-value obtained by recent study in the region. PMID- 29998196 TI - Transgenic overexpression of the SUR2A-55 splice variant in mouse heart reduces infract size and promotes protective mitochondrial function. AB - ATP-sensitive potassium channels found in both the sarcolemma (sarcKATP) and mitochondria (mitoKATP) of cardiomyocytes are important mediators of cardioprotection during ischemic heart disease. Sulfonylurea receptor isoforms (SUR2), encoded by Abcc9, an ATP-binding cassette family member, form regulatory subunits of the sarcKATP channel and are also thought to regulate mitoKATP channel activity. A short-form splice variant of SUR2 (SUR2A-55) was previously shown to target mitochondria and display diaxoxide and ATP insensitive KATP activity when co-expressed with the inward rectifier channels Kir6.2 and Kir6.1. We hypothesized that mice with cardiac specific overexpression of SUR2A-55 would mediate cardioprotection from ischemia by altering mitoKATP properties. Mice overexpressing SUR2A-55 (TGSUR2A-55) in cardiomyocytes were generated and showed no significant difference in echocardiographic measured chamber dimension, percent fractional shortening, heart to body weight ratio, or gross histologic features compared to normal mice at 11-14 weeks of age. TGSUR2A-55 had improved hemodynamic functional recovery and smaller infarct size after ischemia reperfusion injury compared to WT mice in an isolated hanging heart model. The mitochondrial membrane potential of TGSUR2A-55 mice was less sensitive to ATP, diazoxide, and Ca2+ loading. These data suggest that the SUR2A-55 splice variant favorably affects mitochondrial function leading to cardioprotection. These data support a role for the regulation of mitoKATP activity by SUR2A-55. PMID- 29998198 TI - Cross-talk between the transcription factor Sp1 and C/EBPbeta modulates TGFbeta1 production to negatively regulate the expression of chemokine RANTES. AB - RANTES is a key chemokine for atherosclerosis, and obesity is associated with progression of atherosclerosis. Substance P (SP) increases glucose uptake and accumulation of lipids in adipocytes, and SP may upregulate RANTES expression. This study investigated the mechanism of RANTES expression by human M1 macrophages stimulated with SP. SP upregulated RANTES protein expression, whereas aprepitant (an NK1R antagonist) blunted this response. Pretreatment of macrophages with BIRB796 (a combined p38gamma/p38delta inhibitor) led to a significant decrease of RANTES expression. Next, we investigated the effect of several NK1R internalization factors on RANTES expression, including GRK2, beta arrestin 2, dynamin, ROCK, and TGFbeta1. Exposure of macrophages to SP upregulated TGFbeta1 expression. Silencing of beta-arrestin 2 or GRK2 significantly enhanced the RANTES protein level after stimulation by SP, whereas TGFbeta1/2/3 siRNA or dynasore (a dynamin inhibitor) decreased RANTES and Y-27632 (a ROCK inhibitor) had no effect. Surprisingly, silencing of transcription factor specificity protein 1 (Sp1) or inhibition of Sp1 activity by mithramycin led to significant upregulation of TGFbeta1 protein and corresponding enhancement of RANTES expression (by ELISA or western blotting), whereas siRNA for C/EBPbeta attenuated expression of both TGFbeta1 and RANTES. Next, we investigated transcriptional cross-talk among Sp1 and C/EBPbeta, TIF1beta, or Fli-1 in relation to RANTES expression. Compared with TIF1beta or Fli-1 siRNA, C/EBPbeta siRNA showed significantly stronger inhibition of RANTES production by Sp1 siRNA transfected macrophages after stimulation with SP. In conclusion, transcription factor Sp1 engages in cross-talk with C/EBPbeta and modulates TGFbeta1 production to negatively regulate RANTES expression in macrophages stimulated with SP. In conclusion, cross-talk between the transcription factor Sp1 and C/EBPbeta modulates TGFbeta1 production to negatively regulate expression of the atherogenic chemokine RANTES in SP-stimulated macrophages, while RANTES is upregulated by SP via the p38gammadeltaMAPK/C/EBPbeta/TGFbeta1 signaling pathway. PMID- 29998199 TI - Sugar glass fugitive ink loaded with calcium chloride for the rapid casting of alginate scaffold designs. AB - Alginate-based hydrogels are widely used for the development of biomedical scaffolds in regenerative medicine. The use of sugar glass as a sacrificial template for fluidic channels fabrication within alginate scaffolds remains a challenge because of the premature dissolution of sugar by the water contained in the alginate as well as the relatively slow internal gelation rate of the alginate. Here, a new and simple method, based on a sugar glass fugitive ink loaded with calcium chloride to build sacrificial molds, is presented. We used a dual calcium cross-linking process by adding this highly soluble calcium source in the printed sugar, thus allowing the rapid gelation of a thin membrane of alginate around the sugar construct, followed by the addition of calcium carbonate and gluconic acid delta-lactone to complete the process. This innovative technique results in the rapid formation of "on-demand" alginate hydrogel with complex fluidic channels that could be used in biomedical applications such as highly vascularized scaffolds promoting pathways for nutrients and oxygen to the cells. PMID- 29998200 TI - An accurate assessment tool based on intelligent technique for suitability of soybean cropland: case study in Kebumen Regency, Indonesia. AB - In the last few years, the decrease in the land use of soybean affected the reduced of soybean production. Land suitability assessment is an effort to increase the soybean production since the manual method was less accurate. This study aims to apply fuzzy sets and AHP to improve the accuracy of the assessment process of land suitability for soybean crops. The value of five sub-criteria converted into fuzzy sets for standardization process. The weighting by AHP performed to determine the importance level of sub-criteria. Suitability index and final land suitability classes were obtained from the calculation of the fuzzy membership function values and the weights of each sub-criteria before being overlaid with spatial data to produce land suitability map for soybeans. The results of this work showed that 81.42% of the total area was moderate suitability (S2), 11.25% was marginally suitable (S3) and of 7.33% was not suitable (N). From the results of land suitability assessment for soybean crops has been tested and has good correlation with the yield conditions. This study showed that the proposed tool based on Fuzzy sets and AHP were accurate to assess the land suitability of soybean and can be used as the basis for agricultural planning to optimize the land use and soybean production. PMID- 29998201 TI - Selection of reference genes for quantitative real-time PCR normalization in Narcissus pseudonarcissu in different cultivars and different organs. AB - Quantitative real-time PCR (qRT-PCR) has been a widely used accurate technique for gene expression analysis in various species. However, its results require data normalization by reliable reference genes. Despite the horticultural importance of Narcissus pseudonarcissu, and genome sequence has become available for the species, no gene expression study based on the stability of reference genes in qRT-PCR has been conducted. To boost the use of qRT-PCR in N. pseudonarcissu, we uncovered eight commonly used candidate reference genes for their stability. The expression levels of the eight genes were detected for the normalization in five different organs (bulbs, scapes, leaves, perianths and coronas) of three N. pseudonarcissu cultivars ('Marieke', 'Pinza' and 'Slim Whitman') by qRT-PCR. Subsequently, three commonly used computational programs were applied for evaluating the stability of the candidate reference gene's expressions. It turned out that for all the samples and most subgroups, ACT and GAPDH were the most suitable reference genes for normalization. However, the best reference genes were found not always the same one across diverse samples by different computational programs. Our study was the first reference gene evaluation in N. pseudonarcissu and will promote future studies on gene expression levels of N. pseudonarcissu. PMID- 29998202 TI - Patterns of benzodiazepines use in primary care adults with anxiety disorders. AB - Background: Benzodiazepines are among the most commonly prescribed drugs for anxiety disorders. While they are indicated as adjunctive treatment for short term use according to clinical practice guidelines, previous studies have shown patterns of long-term use of benzodiazepines, which is problematic due to side effects, dependence and potential of abuse. The aims of this study were to examine among a large sample of primary care adults suffering from anxiety disorders: 1) benzodiazepine use patterns; and 2) correlates of long-term benzodiazepine use. Methods: Data were drawn from the "Dialogue" project, a large primary care study conducted in 64 primary care clinics in the province of Quebec, Canada. Following a mental health screening in waiting rooms, patients at risk of anxiety or depression completed the Composite International Diagnostic Interview-Simplified (CIDIS). A sample of 740 adults meeting DSM-IV criteria for Generalized Anxiety Disorder, Panic Disorder or Social Anxiety Disorder in the past 12 months took part in this study. Results: Benzodiazepines were used by 22.6% of participants with anxiety disorders in our primary care sample. A large majority of benzodiazepine users (88.4%) met our indicator of long-term use, as defined by utilization for more than 12 weeks including regular and as-needed use. Based on a logistic regression model, individual correlates associated with long-term benzodiazepine use included: being 30 years or older, having a comorbid physical illness, meeting criteria for comorbid agoraphobia, reporting the use of sleep-aids, and concurrent SSRI utilization. Limitation: Data collection with self-reported questionnaires may be subject to information bias. Conclusions: Despite knowledge of the risks of long-term use of benzodiazepines, this remains a pervasive problem. Clinicians need to be mindful of patterns and risk factors leading to long-term use of benzodiazepines in patients with anxiety disorders. Results of this study should raise awareness regarding appropriate prescription practices for benzodiazepines, including decision-making in initiation, duration of prescription, and use of strategies for discontinuation in current long-term benzodiazepine users. PMID- 29998203 TI - The Participant Recruitment Outcomes (PRO) study: Exploring contemporary perspectives of telehealth trial non-participation through insights from patients, clinicians, study investigators, and study staff. AB - Background: Telehealth has been proposed as an alternative means to providing traditional modes of care while alleviating the need for participant travel and reducing overall healthcare costs. The purpose of this study was to explore contemporary perspectives of patients and stakeholders regarding non participation in telehealth trials. Methods: We undertook a two-phase exploratory qualitative study to understand the reasons behind patient non-participation in telehealth. Data were collected through semi-structured interviews with non participating patient participants (n = 8) and stakeholders (n = 27) including clinicians, study investigators, and study staff. An analysis of interview data were undertaken and guided by a qualitative descriptive approach. Findings: Patients and stakeholders reported many barriers to telehealth participation including technological barriers, limited understanding of disease, and an understated need for services. Both groups had some overlap in their concerns but also provided unique insights. Conclusion: The analysis of study findings revealed perspectives of patients and stakeholders including barriers to participation as well as suggestions for future telehealth initiatives. Further research is needed to explore non-participation including patient readiness to assist in the development of future telehealth programs. PMID- 29998204 TI - Traumatic brain injury reduction in athletes by neck strengthening (TRAIN). AB - Reporting of sports-related concussions (SRCs) has risen dramatically over the last decade, increasing awareness of the need for treatment and prevention of SRCs. To date most prevention studies have focused on equipment and rule changes to sports in order to reduce the risk of injury. However, increased neck strength has been shown to be a predictor of concussion rate. In the TRAIN study, student athletes will follow a simple neck strengthening program over the course of three years in order to better understand the relationship between neck strength and SRCs. Neck strength of all subjects will be measured at baseline and biannually over the course of the study using a novel protocol. Concussion severity and duration in any subject who incurs an SRC will be evaluated using the Sports Concussion Assessment Tool 5th edition, a questionnaire based tool utilizing several tests that are commonly affected by concussion, and an automated eye tracking algorithm. Neck strength, and improvement of neck strength, will be compared between concussed and non-concussed athletes to determine if neck strength can indeed reduce risk of concussion. Neck strength will also be analyzed taking into account concussion severity and duration to find if a strengthening program can provide a protective factor to athletes. The study population will consist of student-athletes, ages 12-23, from local high schools and colleges. These athletes are involved in a range of both contact and non contact sports. PMID- 29998205 TI - Favorable outcomes of adequate laser photocoagulation and salvage bevacizumab treatment for aggressive posterior retinopathy of prematurity. AB - Purpose: To evaluate the effect of salvage therapy with bevacizumab after laser photocoagulation for infants with recurrence of zone I aggressive-posterior retinopathy of prematurity (AP-ROP). Methods: This was a retrospective case series documenting the 2-year outcomes of 8 patients diagnosed with zone I AP-ROP and treated with bevacizumab for recurrence after laser photocoagulation. Prior to intravitreal bevacizumab, additional laser treatment was performed when any skip areas on the avascular retina remained. Anatomical and functional outcomes were evaluated. Results: The median gestational age at birth was 23.7 weeks and the median birth weight was 541.5 g. The median time of initial laser treatment and intravitreal bevacizumab treatment were 32.1 weeks and 36.7 weeks' postmenstrual age, respectively. All 14 eyes developed a normal macular appearance and all 8 patients had visual responses. Visual acuity was measurable in 13 eyes (92%) between the chronological ages of 12-24 months. Conclusions: and Importance: Adequate laser treatment and salvage intravitreal bevacizumab achieved favorable anatomical and functional outcomes in AP-ROP patients with recurrence. PMID- 29998206 TI - Bilateral exudative retinal detachments due to thrombotic microangiopathy associated with intravenous abuse of Opana ER. AB - Purpose: To report the only known case, to our knowledge, of bilateral exudative retinal detachments in the setting of thrombotic microangiopathy associated with intravenous abuse of extended-release oxymorphone (Opana ER). Observations: A 35 year-old male presented with headaches and acute, painless vision loss in the context of daily IV abuse of crushed oral Opana ER. The patient was found to have microangiopathic hemolytic anemia (MAHA), acute kidney injury in conjunction with hypertensive crisis and bilateral exudative retinal detachments. Conclusions and importance: Bilateral exudative retinal detachments are rare ophthalmic complications that have been reported with thrombotic thrombocytopenic purpura (TTP). Non-TTP thrombotic microangiopathy, initially described as a "TTP-like illness" consisting of MAHA and thrombocytopenia, has been associated with the IV abuse of Opana ER. We report a case of bilateral exudative retinal detachments due to thrombotic microangiopathy in the setting of IV abuse of Opana ER. PMID- 29998207 TI - Retinal racemose hemangioma with retinal artery macroaneurysm: Optical coherence tomography angiography (OCTA) findings. AB - Purpose: To describe a rare case of retinal racemose hemangioma (RRH) with retinal artery macroaneurysm (RAM) and its optical coherence tomography angiography (OCT-A) finding before and after treatment. Observations: Congenital arteriovenous (AV) communications or RRH is a rare developmental anomaly associated with various ocular conditions. RRH alone is usually asymptomatic, and vision loss occurs when associated with other ocular complications like retinal vein occlusion, hemmorage, macular edema and macroaneurysm. In this communication we describe a case of a 44-year-old female having RRH who presented with active, leaking RAM with subretinal hemmorage. OCT-A through the lesion demonstrated an active aneurysm which on subsequent treatment with anti VEGF and focal laser photocoagulation showed involution of aneurysm. Conclusions and importance: RRH is usually asymptomatic and may be associated with vision threatening ocular complications like RAM. OCT-A helps in giving additional dynamic blood flow information in RAM. PMID- 29998208 TI - Intraoperative optical coherence tomography-assisted retrocorneal fibrous membrane biopsy and excision. AB - Purpose: We report a case of retrocorneal fibrous membrane (RCFM) formation following penetrating keratoplasty (PK) and intraoperative optical coherence tomography (OCT)-guided excision of this membrane. Observations: A 68-year-old woman with primary open angle glaucoma and corneal decompensation of the right eye secondary to tube shunt presented for 3-month follow-up of PK. On examination of the right eye, the patient was noted to have a glassy pupillary membrane with traction on the iris. Anterior segment OCT confirmed a membrane connecting the iris to host cornea. The patient underwent biopsy and excision of the membrane assisted by intraoperative OCT. Pathological examination was consistent with Descemet's membrane proliferation. We suspect that this membrane represents retained host's Descemet's membrane following corneal transplantation. Conclusions: This case highlights the existence of RCFM formation in the context of retained host cornea following PK and the role of intraoperative OCT in management. PMID- 29998209 TI - The use of bevacizumab and ranibizumab for branch retinal vein occlusion in medicare beneficiaries. AB - Purpose: To describe the frequency and variation of intravitreal bevacizumab and ranibizumab use for branch retinal vein occlusion (BVO) in the United States (US). Methods: We obtained a 5% random sample of Medicare beneficiaries from the Medicare Denominator and Physician/Supplier Part B claims files from 2010 to 2013 and identified all beneficiaries with an ICD-9-CM code for branch retinal vein occlusion (BVO, 362.36). Patient age, gender, race, state of residence and Charlson Comorbidity Index (CCI) scores were collected. Healthcare Common Procedure Coding System (HSCPS) codes for bevacizumab (J3590, J9035, and J3490) and for ranibizumab (J2778) were used to identify the mode of treatment for each patient. Patients who met the following criteria were excluded from this study: (1) under 65 years of age; (2) residence outside of the 50 United States or the District of Columbia; (3) no Part-B coverage or with HMO coverage that was not processed by Centers for Medicare & Medicaid Services (CMS); (4) concomitant diagnosis of diabetic edema (ICD-9: 362.07) or central retinal vein occlusion (ICD-9: 362.35); and (5) received both or none of the above two treatments. Geographic variation was examined by comparing injection frequencies across the nine US census divisions using Chi-squared analysis. Results: During 2010-2013, a majority of the 3944 BVO patients who met the inclusion criteria received bevacizumab compared to ranibizumab (76.7% vs 23.3%). Most patients were aged 75 79 (22.0%) or 80-84 (22.0%), female (61.5%), white (88.3%), and had a CCI score of 1-2 (39.8%). The frequencies of bevacizumab and ranibizumab injections for BVO varied significantly between the US census divisions (p < 0.0001). The highest frequencies of bevacizumab use were in the Mountain (90.6%) and Pacific (82.7%) divisions while the highest frequencies of ranibizumab use were in the West North Central (37.9%) and Mid Atlantic (32.7%) divisions. Conclusions and Importance: A majority of Medicare beneficiaries with BVO received bevacizumab compared to ranibizumab from 2010 to 2013, with significant geographic variation in the use of the two anti-VEGF agents. Future research into factors driving geographic variation in the use of these agents may help direct cost-effective strategies for the management of BVO. PMID- 29998210 TI - Delayed-onset Candida parapsilosis cornea tunnel infection and endophthalmitis after cataract surgery: Histopathology and clinical course. AB - Purpose: To describe a patient with late post-operative endophthalmitis and clear cornea tunnel infection caused by Candida parapsilosis that was masquerading as chronic anterior uveitis. Observations: A 62-year old woman with history of uncomplicated cataract surgery 7 months prior and chronic postoperative anterior uveitis, presented with an endothelial plaque, hypopyon, and infiltrates in the capsular bag and within the clear corneal tunnel. Anterior chamber cultures identified C. parapsilosis and pathology of the endothelial plaque showed fungus. Anterior chamber washout, scraping of the endothelial plaque, serial intracameral and intravitreal injections with amphotericin B (10 mcg) failed to control the infection. Pars plana vitrectomy, removal of the intraocular lens and capsular bag, a corneal patch graft, and administration of intravitreal antifungal agents were performed. One year later the patient remains free of recurrence and her best-corrected vision is 20/25 with a rigid gas permeable contact lens. Conclusions: and Importance: Persistent intraocular and intracorneal inflammation after cataract surgery should raise suspicion of endophthalmitis caused by fungi non-responsive to topical and intravitreal antibiotics. Surgical intervention and removal of the nidus of infection, which is often the intraocular lens and capsular bag, may be necessary for a successful outcome. PMID- 29998211 TI - Long term treatment with infliximab in pediatric Vogt-Koyanagi-Harada disease. AB - Purpose: To report a case of pediatric Vogt-Koyanagi-Harada (VKH) successfully treated with infliximab and methotrexate for ten years. Observations: A 9-year old Hispanic girl with VKH disease, was successfully treated with oral methotrexate 15 mg/week and oral prednisone 40 mg/day (1mg/kg/day). But when oral prednisone was tapered to 10 mg/day over a 3-month period, inflammation recurred. Patient was considered as corticosteroid-dependent thus infliximab 7mg/kg/pulse was started on days 0, 15, 60 and every 60 days thereafter. Six months after, infliximab was increased to 10mg/kg/pulse as cells in the anterior chamber were still observed. After four months of treatment, ocular inflammation was fully controlled, oral prednisone was tapered to discontinuation over a period of 10 months and methotrexate was maintained at 15 mg/week. At 1-year follow up, infliximab was reduced to 6 mg/kg/pulse as patient remained stable on examination. After being treated for 3-years it was decided to discontinue infliximab however, 2 + anterior chamber cells recurred after a dose was skipped thus infliximab was restarted. After 10 years treatment with infliximab 6 mg/kg/pulse every 60 days and methotrexate 15 mg/week associated, no relapsing inflammatory episodes and resolution of physical features of Cushing's syndrome were observed. Conclusion and importance: Combined therapy of infliximab and methotrexate for up to 10 years was efficacious in this girl in controlling recurrent inflammation without associated side effects. To the best of our knowledge, this is the longest reported clinical follow up of a pediatric VKH case supporting the use of infliximab and methotrexate without steroids treatment. PMID- 29998212 TI - AftD functions as an alpha1 -> 5 arabinofuranosyltransferase involved in the biosynthesis of the mycobacterial cell wall core. AB - Arabinogalactan (AG) is an essential structural macromolecule present in the cell wall of Mycobacterium tuberculosis, serving to connect peptidoglycan with the outer mycolic acid layer. The D-arabinan segment is a highly branched component of AG and is assembled in a step-wise fashion by a variety of arabinofuranosyltransferases (AraT). We have previously used Corynebacterium glutamicum as a model organism to study these complex processes which are otherwise essential in mycobacteria. In order to further our understanding of the molecular basis of AG assembly, we investigated the role of a fourth AraT, now termed AftD by generating single (DeltaaftD) and double deletion (DeltaaftB DeltaaftD) mutants of C. glutamicum. We demonstrate that AftD functions as an alpha(1 -> 5) AraT and reveal the point at which it exerts its activity in the AG biosynthetic pathway. PMID- 29998213 TI - Simultaneous Emission-Transmission Tomography in an MRI Hardware Framework. AB - Multi-modality imaging is essential for diagnosis and therapy in challenging cases. A Holy Grail of medical imaging is a hybrid imaging system combining computed tomography (CT), nuclear imaging, and magnetic resonance imaging (MRI) to deliver registered morphological, functional, and cellular/molecular information simultaneously and quantitatively for precision medicine. Recently, a unique imaging approach was demonstrated that combines nuclear imaging with polarized radiotracers and MRI-based spatial encoding. The detection scheme exploits the directional preference of gamma-rays emitted from the polarized nuclei, and the result is a concentration image with resolution that can outperform standard nuclear imaging at a sensitivity significantly higher than that of MRI. However, the method does not calculate the attenuation image. Here we propose to obtain MRI-modulated gamma-ray data for simultaneous image reconstruction of emission and transmission parameters, which could serve as a stepping stone toward simultaneous CT-SPECT-MRI. This method acquires synchronized datasets to provide insight into morphological features and molecular activities with accurate spatiotemporal registration. We present a complete overview of the system design and the formulation for tomographic reconstruction when the distribution of polarized radiotracers is either global or limited to a region of interest (ROI). Numerical results support the feasibility of our approach and suggest further research topics. PMID- 29998215 TI - It is time to accelerate building local vaccine adjuvant manufacturing capacity. PMID- 29998214 TI - PET/MRI: a frontier in era of complementary hybrid imaging. AB - With primitive approaches, the diagnosis and therapy were operated at the cellular, molecular, or even at the genetic level. As the diagnostic techniques are more concentrated towards molecular level, multi modal imaging becomes specifically essential. Multi-modal imaging has extensive applications in clinical as well as in pre-clinical studies. Positron Emission Tomography (PET) has flourished in the field of nuclear medicine, which has motivated it to fuse with Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) for PET/CT and PET/MRI respectively. However, the challenges in PET/CT are due to the inability of simultaneous acquisition and reduced soft tissue contrast, which has led to the development of PET/MRI. Also, MRI offers the better soft tissue contrast over CT. Hence, fusion of PET and MRI results in combining structural information with functional image from PET. Yet, it has many technical challenges due to the interference between the modalities. Also, it must be resolved with various approaches for addressing the shortcomings of each system and improvise on the image quantification system. This review elaborates on the various challenges in the present PET/MRI system and the future directions of the hybrid modality. Also, the different data acquisition and analysis techniques of PET/MRI system are discussed with enhanced details on the software tools. PMID- 29998216 TI - The influence of radiation in the context of developing combination immunotherapies in cancer. AB - In addition to tumouricidal activity, radiotherapy is now recognized to display potent immunostimulatory properties that can contribute to the generation of anti cancer immune responses. Treatment with radiation can induce a variety of pro immunogenic and phenotypic changes in malignant cells, and recalibrate the immune contexture of the tumour microenvironment, leading to enhanced activation of the innate immune system, and priming of tumour-specific T-cell immunity. The immune dependent effects of radiotherapy provide a sound rationale for the development of combination strategies, whereby the immunomodulatory properties of radiation can be exploited to augment the activity of immunotherapeutic agents. Encouraged by the recent success of breakthrough therapies such as immune checkpoint blockade, and a wealth of experimental data demonstrating the efficacy of radiotherapy and immunotherapy combinations, the clinical potential of this approach is now being explored in numerous trials. Successful translation will require careful consideration of the most suitable dose and fractionation of radiation, choice of immunotherapy and optimal sequencing and scheduling regimen. Immunological control of cancer is now becoming a clinical reality. There is considerable optimism that the development of effective radiotherapy and immunotherapy combinations with the capacity to induce durable, systemic immunity will further enhance patient outcome and transform the future management of cancer. PMID- 29998217 TI - Bispecific antibodies in cancer immunotherapy. AB - Following the clinical success of immune checkpoint antibodies targeting CTLA-4, PD-1 or PD-L1 in cancer treatment, bispecific antibodies are now emerging as a growing class of immunotherapies with potential to further improve clinical efficacy and safety. We describe three classes of immunotherapeutic bispecific antibodies: (a) cytotoxic effector cell redirectors; (b) tumor-targeted immunomodulators; and (c) dual immunomodulators. Cytotoxic effector cell redirectors are dominated by T-cell redirecting compounds, bispecific compounds engaging a tumor-associated antigen and the T-cell receptor/CD3 complex, thereby redirecting T-cell cytotoxicity to malignant cells. This is the most established class of bispecific immunotherapies, with two compounds having reached the market and numerous compounds in clinical development. Tumor-targeted immunomodulators are bispecific compounds binding to a tumor-associated antigen and an immunomodulating receptor, such as CD40 or 4-1BB. Such compounds are usually designed to be inactive until binding the tumor antigen, thereby localizing immune stimulation to the tumor environment, while minimizing immune activation elsewhere. This is expected to induce powerful activation of tumor-specific T cells with reduced risk of immune-related adverse events. Finally, dual immunomodulators are bispecific compounds that bind two distinct immunomodulating targets, often combining targeting of PD-1 or PD-L1 with that of LAG-3 or TIM-3. The rationale is to induce superior tumor immunity compared to monospecific antibodies to the same targets. In this review, we describe each of these classes of bispecific antibodies, and present examples of compounds in development. PMID- 29998218 TI - Healthcare-associated infections: potential for prevention through vaccination. AB - The challenge of healthcare-associated infections is compounded by the higher incidence of resistant organisms and the decreasing utility of antimicrobial agents. Historic and current vaccines have already contributed to reductions in healthcare-associated infections, and future vaccines have the potential to reduce these infections further. Through examples of bacterial and viral vaccines, this review will attempt to chart the way forward. PMID- 29998220 TI - Introducing Therapeutic Advances in Ophthalmology. PMID- 29998219 TI - Novel tumour antigens and the development of optimal vaccine design. AB - The interplay between tumours and the immune system has long been known to involve complex interactions between tumour cells, immune cells and the tumour microenvironment. The progress of checkpoint inhibitors in the clinic in the last decade has highlighted again the role of the immune system in the fight against cancer. Numerous efforts have been undertaken to develop ways of stimulating the cellular immune response to eradicate tumours. These interventions include the identification of appropriate tumour antigens as targets for therapy. In this review, we summarize progress in selection of target tumour antigen. Targeting self antigens has the problem of thymic deletion of high-affinity T-cell responses leaving a diminished repertoire of low-affinity T cells that fail to kill tumour cells. Thymic regulation appears to be less stringent for differentiation of cancer-testis antigens, as many tumour rejection antigens fall into this category. More recently, targeting neo-epitopes or post-translational modifications such as a phosphorylation or stress-induced citrullination has shown great promise in preclinical studies. Of particular interest is that the responses can be mediated by both CD4 and CD8 T cells. Previous vaccines have targeted CD8 T-cell responses but more recently, the central role of CD4 T cells in orchestrating inflammation within tumours and also differentiating into potent killer cells has been recognized. The design of vaccines to induce such immune responses is discussed herein. Liposomally encoded ribonucleic acid (RNA), targeted deoxyribonucleic acid (DNA) or long peptides linked to toll-like receptor (TLR) adjuvants are the most promising new vaccine approaches. These exciting new approaches suggest that the 'Holy Grail' of a simple nontoxic cancer vaccine may be on the horizon. A major hurdle in tumour therapy is also to overcome the suppressive tumour environment. We address current progress in combination therapies and suggest that these are likely to show the most promise for the future. PMID- 29998221 TI - An imaging-based treatment algorithm for posterior focal retinitis. AB - Background: In this paper, our aim was to describe an imaging-based empirical approach for categorizing and initiating treatment of immunocompetent patients with posterior focal retinitis, prior to the availability of results of expensive laboratory investigations. Materials and methods: The hospital records of 13 patients with posterior focal retinitis were reviewed. Results: Of the 13 patients, 9 were women and 4 were men. The mean age was 24 +/- 8 years. Based on similarities in clinical presentation and imaging, we categorized our cases into three groups with different first-line therapeutic strategies. In the first group, patients had presumed toxoplasmosis (treated with oral cotrimoxazole); in the second group, patients had presumed viral (herpetic) etiology (treated with oral valacyclovir); and in the third group, patients had presumed nonherpetic, nontoxoplasma retinitis (treated with oral doxycycline). Positive serology results included Rickettsia (two patients), Borrelia (one patient), Toxoplasma (two patients), and herpes simplex virus (one patient). Conclusion: An empirical approach for early initiation of therapy in retinitis cases based on imaging features is described. PMID- 29998223 TI - Women in Vision UK strive for gender equality in ophthalmology and vision sciences. PMID- 29998222 TI - Regenerative medicine in the retina: from stem cells to cell replacement therapy. AB - Following the fast pace of the growing field of stem cell research, retinal cell replacement is finally emerging as a feasible mean to be explored for clinical application. Although neuroprotective treatments are able to slow the progression of retinal degeneration caused by diseases such as age-related macular degeneration and glaucoma, they are insufficient to fully halt disease progression and unable to recover previously lost vision. Comprehensive, technological and intellectual advances over the past years, including the in vitro differentiation of retinal cells at manufacturing scale from embryonic stem (ES) cell and induced pluripotent stem (iPS) cell cultures, progress within the area of retinal disease modeling, and the first clinical trials have started to shape the way towards addressing this treatment gap and translating retinal cell replacement to the clinic. Here, summarize the most recent advances within retinal cell replacement from both a scientific and clinical perspective, and discuss the remaining challenges towards the delivery of the first retinal cell products. PMID- 29998224 TI - Low vision services: a practical guide for the clinician. AB - Low vision has been defined by best-corrected visual acuity worse than 20/40 in the better eye, substantial visual field loss, or substantial loss of contrast sensitivity that cannot be corrected by refraction, medical treatment, or surgery. In the United States, low vision is most commonly caused by age-related macular degeneration, glaucoma, and diabetic retinopathy. Most patients with low vision are elderly, although patients of all ages - including pediatric patients may be affected. Low vision may decrease a patient's quality of life substantially, leading to emotional distress and possibly depression. Low vision specialists aim to maximize the remaining vision of a patient by providing optical aids, orientation and mobility training, psychosocial support, and other methods of rehabilitation. Innovations in technology and devices offer additional options in low vision rehabilitation. Clinicians should consider referral to low vision specialists when a patient has difficulty with reading, mobility, driving, recognizing faces, or suffers from emotional distress due to low vision. Early referral may lead to improved outcomes. PMID- 29998226 TI - Edaravone: a new hope for deadly amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a fatal motor neuron degenerative disorder leading to paralysis and eventual death. At present, we do not have any specific cure for this deadly disorder. Current drug therapy can only reduce morbidity in ALS patients. In 1995, riluzole was the first drug approved by the U.S. Food and Drug Administration (FDA) for ALS. After a long gap of 22 years, Mitsubishi Tanabe Pharma America got U.S. FDA approval for edaravone (Radicava) in May 2017 for the management of ALS. Edaravone, a novel neuroprotective agent, is indicated to slow down progression of ALS. In 2015, Mitsubishi Tanabe Pharma launched edaravone (Radicut) for the treatment of stroke and ALS in Japan. The U.S. FDA approved edaravone following clinical evidence from three clinical trials conducted in 368 ALS patients in Japan. Edaravone is awaiting approval by the European Medicines Agency (EMA) in Europe. Edaravone (60 mg) is administered by very slow intravenous infusion (60 minutes) in 28-day cycles. It has been shown to slow down the loss of physical function in ALS patients by 33% as compared to placebo. Edaravone is a strong antioxidant that prevents oxidative stress from inducing motor neuron death in ALS patients. Being a potent free radical scavenger, it has been shown to inhibit nitration of tyrosine residues in the cerebrospinal fluid and improve motor functions in mouse models of ALS. The product has been patented and the FDA has not approved any generic version of edaravone. This article discusses the preclinical pharmacology, pharmacokinetics, safety profile, clinical studies and drug interactions of edaravone (Radicava) in ALS. PMID- 29998225 TI - Salivary Cortisol Does Not Correlate with Metabolic Syndrome Markers or Subjective Stress in Overweight Children. AB - Objective: Being overweight is a risk factor for metabolic syndrome in children, but not all overweight children develop metabolic syndrome. Cortisol excess from chronic psychological stress has been proposed as an independent risk factor for metabolic syndrome in this already at-risk population. The present study assesses the relationship of biochemical and body composition radiographic markers of metabolic syndrome to salivary cortisol and self-report of chronic psychological stress in a cohort of overweight children. Methods: This cross-sectional study took place in a multi-disciplinary pediatric obesity clinic at a tertiary care hospital, and involved fifteen children with BMI at or above the 85th percentile for age and sex, 10 of whom provided salivary cortisol samples. The main outcomes measured were salivary bedtime cortisol, first-waking cortisol, and cortisol awakening response (CAR-the rise in cortisol in the first half hour after waking); fasting serum triglycerides, HDL cholesterol, glucose and insulin for HOMA-IR; the ratio of abdominal fat to total body fat by DXA scan; and scores of validated stress and bullying questionnaires (PANAS-C, PSS, and SEC-Q). Results: In this pilot study, no correlation was found between salivary cortisol measures and questionnaire scores of subjective stress or bullying, and no correlation was found between any of these measures and markers of metabolic syndrome (dyslipidemia, insulin resistance, increased abdominal fat). Conclusions: These results suggest that measures of psychological stress, whether biochemical or subjective, do not appear to predict risk of metabolic syndrome in overweight children. While ease of collection and demonstrated utility both in detection of pediatric Cushing disease and in adult psychological research make salivary cortisol assessment an attractive clinical tool, further investigation into the value of salivary measures in pediatric stress research is needed. PMID- 29998227 TI - Letermovir for prophylaxis of cytomegalovirus in allogeneic hematopoietic stem cell recipients. AB - Letermovir is a new antiviral agent with activity against human cytomegalovirus (CMV). Letermovir works as an inhibitor of the CMV DNA terminase complex which further inhibits viral DNA processing and packaging. Letermovir is available both orally and intravenously in 480-mg and 240-mg dosage forms, and is approved for use in the prophylaxis of CMV infection and disease in CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT) over the age of 18. The recommended dose is 480 mg p.o./i.v. once daily initiated between day 0 through day 28 post-allogeneic HSCT and continued through day 100 post transplantation; the dose should be reduced to 240 mg daily if coadministered with cyclosporine. Letermovir is metabolized primarily by hepatic OATP1B1/3 and is not recommended for patients with severe hepatic impairment (Child-Pugh class C). Renal dosage adjustments are not warranted until a creatinine clearance (CrCl) of less than 10 mL/min; however, serum creatinine should be monitored when administered to patients with a CrCl of less than 50 mL/min. Cross-resistance with other useful antiviral agents in the treatment of CMV has not been observed. Additionally, letermovir is active against DNA polymerase inhibitor-resistant viral strains. Letermovir has shown promising clinical efficacy and is generally well tolerated, thus providing a favorable new option in the prophylaxis of CMV infection and disease. PMID- 29998228 TI - Osimertinib for the treatment of patients with EGFR mutation-positive non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) mutations, mostly seen in exon 19 or exon 21, are present in roughly 50% of patients with advanced non-small cell lung cancer (NSCLC) of Asian ethnicity compared with 12% in Caucasians. EGFR-mutated NSCLC patients have an increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib or afatinib, showing superior response, progression-free survival and overall survival rates with EGFR-TKIs than with platinum doublet chemotherapy, which makes EGFR-TKIs the standard of care in this subgroup of NSCLC patients. This has been the most important step toward molecular-guided precision therapy for NSCLC. Despite the initial rapid and durable clinical responses, acquired resistance to EGFR-TKIs has been found to eventually develop in most cases, with disease progression observed mostly within 9-12 months after treatment. One of the most important mechanisms for resistance to EGFR-TKI therapy is the substitution of threonine to methionine (T790M) on exon 20 of the EGFR gene, which occurs in 49% to 60% of patients. Osimertinib mesylate (formerly AZD-9291) is a potent third-generation TKI which irreversibly inhibits mutated EGFR alleles, including T790M. This review summarizes osimertinib's pharmacology, pharmacokinetics, safety, side effects and clinical utility in the treatment of EGFR-mutated advanced NSCLC. PMID- 29998229 TI - Life sciences licensing deals in the first quarter of 2018: updates and trends. AB - During the first quarter of 2018, Cortellis Competitive Intelligence registered 879 new deals (excluding mergers and acquisitions) with a total disclosed deal value of approximately USD 35.2 billion as part of its ongoing coverage of licensing activity in the life sciences sector. This compares to 1,203 and USD 26.2 bil-lion in the fourth quarter of 2017, and 1,158 and USD 31.8 billion in the first quarter of 2017. This meant a significant increase in the total disclosed deal value compared to these two previous periods (+34% and +10.7%, respectively), and included the USD 5.8 billion pact between Merck and Co. and Eisai which became the highest-value deal in the last 4-year opening quarters. However, during the first quarter of 2018 there was not a high number of signed agreements versus the fourth quarter of 2017 and the first quarter of 2017 (-27% and -24%, respectively), reaching a number similar to that in the first quarter of 2014 with a total of 931 agreements covered. PMID- 29998230 TI - Phenylene-bridged cross-conjugated 1,2,3-trisilacyclopentadienes. AB - 1,2,3-Trisilacyclopentadienes are obtained from the reactions of cyclotrisilene c Si3R4 (R = iPr3C6H2) with phenyl and diphenyl acetylene, respectively. With 1,4 diethynyl benzene the cross-conjugated bridging of two of the Si3C2 cycles by a para-phenylene linker is achieved. UV/vis spectroscopy indicates a small but significant effect of cross-conjugation, which is confirmed by TD-DFT calculations. The formation mechanism of the 1,2,3-trisilacyclopentadienes is elucidated by VT NMR. PMID- 29998232 TI - Recovery of xenon from air over ZIF-8 membranes. AB - Continuous ZIF-8 membranes effectively separated air/Xe gas mixtures. These membranes showed air permeances as high as 3.94 * 10-8 mol m-2 s-1 Pa-1 and separation selectivities as high as 12.4 for an air/Xe molar feed composition of 9 : 1. These membranes separated air from Xe via molecular sieving, preferential adsorption, and diffusivity differences. PMID- 29998234 TI - Photoinduced Curtius rearrangements of fluorocarbonyl azide, FC(O)N3: a QM/MM nonadiabatic dynamics simulation. AB - Upon either photolysis or pyrolysis, carbonyl azide can eliminate molecular nitrogen along with the formation of isocyanate. Though two different pathways (namely stepwise versus concerted) have been proposed, the detailed decomposition mechanism is still elusive to date. Herein, we have employed combined electronic structure calculations and nonadiabatic dynamics simulations to study the radiationless deactivation and rearrangement mechanisms of FC(O)N3 in the S3, S2, S1, and S0 states in an argon matrix. On the basis of QM(CASPT2)/MM calculations, we found that, upon 193 nm irradiation, the excited-state decay of FC(O)N3 from the S3 state via S2 and S1 to the S0 state is an ultrafast process and could be completed within 100 fs, and a subsequent Curtius rearrangement occurs in the period of ~300 fs; the elimination of N2 and the formation of fluorocarbonyl nitrene FC(O)N could take place in both S1 and S0 states rather than in higher excited states; the isomerization from FC(O)N to FNCO involves a stepwise mechanism and could only be found in the S0 state. This mechanistic scenario has been verified by both electronic structure calculations and full-dimensional trajectory-based "on the fly" QM(CASPT2)/MM nonadiabatic dynamics simulations. Finally, the currently calculated results provide important mechanistic insights for similar carbonyl azides. PMID- 29998233 TI - Photoelectron spectroscopic and computational studies of [EDTA.M(iii)]- complexes (M = H3, Al, Sc, V-Co). AB - Metal-EDTA complexes commonly exist as biological redox reagents. We have generated a series of such complexes, [EDTA.M(iii)]- (M = Al, Sc, V-Co), via electrospray ionization and characterized them by cryogenic mass-selected negative ion photoelectron spectroscopy (NIPES) and quantum chemical computations. Experiments clearly revealed one more spectral band at low electron binding energy for transition metal complexes with d electrons (M = V-Co) compared to those without d electrons (M = Al and Sc). Quantum chemical calculations suggested that all of the metal complexes possess hexacoordinated metal-ligand binding motifs, from which the calculated adiabatic/vertical detachment energy (ADE/VDE) and band gaps are in good agreement with experimental values. Direct spectrum and electronic structure analyses indicted that [EDTA.V(iii)]- can be easily oxidized to [EDTA.V(iv)] with the smallest ADE/VDE of 3.95/4.40 eV among these metal complexes, but further oxidation is hindered by the existence of a 2.30 eV band gap, a fact that accords with the special redox behavior of vanadium-containing species in biological cells. Spin density and molecular orbital analyses reveal that [EDTA.V(iii)]- was overwhelmingly detached from the vanadium atom, in stark contrast to [EDTA.Sc(iii)/Al(iii)]-, where the detachment occurred from the EDTA ligand. For all other metal complex anions, from M = Cr to Co, the detachment process is derived from contributions from both the metal and ligand. The intrinsic electronic and geometric structures of these complexes, obtained in this work, provide a molecular foundation to better understand their redox chemistries and specific metal bindings in condensed phases and biological cells. PMID- 29998236 TI - Nickel foam derived nitrogen doped nickel sulfide nanowires as an efficient electrocatalyst for the hydrogen evolution reaction. AB - Ni3S2 has been validated as an effective electrocatalyst for the oxygen evolution reaction, attributable to its suitable electronic configuration. However, pure Ni3S2 towards the hydrogen evolution reaction (HER) exhibits relatively low catalytic activity. Herein, a one-step annealing strategy is demonstrated for the synthesis of Ni3S2 nanowires on nickel foam (NF) through N doping towards vigorous HER performance both in acid and alkaline solution. The 1D N-Ni3S2 nanowires, integrated onto a 3D NF electrode, show a high catalytic current density of 10 mA cm-2 at a low overpotential of 196 mV and a small Tafel slope of 63 mV dec-1 in an acid electrolyte. In an alkaline medium, the N-Ni3S2 NWs exhibit a low overpotential of 105 mV at the current density of 10 mA cm-2, which is lower than other reported Ni3S2-based HER catalysts. The superior HER catalytic performance is attributed to its unique structural features, both the morphology and electronic structure. Our work provides profound guidance for the design and optimization of electrocatalysts for an efficient HER. PMID- 29998237 TI - Thermal reduction of ceria nanostructures on rhodium(111) and re-oxidation by CO2. AB - The thermal reduction of cerium oxide nanostructures deposited on a rhodium(111) single crystal surface and the re-oxidation of the structures by exposure to CO2 were investigated. Two samples are compared: a rhodium surface covered to ~60% by one to two O-Ce-O trilayer high islands and a surface covered to ~65% by islands of four O-Ce-O trilayer thickness. Two main results stand out: (1) the thin islands reduce at a lower temperature (870-890 K) and very close to Ce2O3, while the thicker islands need higher temperature for reduction and only reduce to about CeO1.63 at a maximum temperature of 920 K. (2) Ceria is re-oxidized by CO2. The rhodium surface promotes the re-oxidation by splitting the CO2 and thus providing atomic oxygen. The process shows a clear temperature dependence. The maximum oxidation state of the oxide reached by re-oxidation with CO2 differs for the two samples, showing that the thinner structures require a higher temperature for re-oxidation with CO2. Adsorbed carbon species, potentially blocking reactive sites, desorb from both samples at the same temperature and cannot be the sole origin for the observed differences. Instead, an intrinsic property of the differently sized CeOx islands must be at the origin of the observed temperature dependence of the re-oxidation by CO2. PMID- 29998239 TI - Polycarboxylate-directed semi-rigid pyridyl-amide-based various NiII complexes: electrochemical properties and enhancements of photocatalytic activities by calcination. AB - In this work, four new NiII coordination polymers (CPs) based on a bi-methylene bridged semi-rigid bis-pyridyl-bis-amide ligand and various polycarboxylates, namely, [Ni(4-bmbpd)(H2O)4].(TPD) (1), [Ni2(4-bmbpd)2(1,3-BDC)2(H2O)4].5H2O (2), [Ni2(4-bmbpd)2(MIP)2(H2O)2].3H2O (3) and [Ni3(4-bmbpd)3(BTC)2(H2O)4].4H2O (4) [4 bmbpd = N,N'-bis(4-methylenepyridin-4-yl)-1,4-benzenedicarboxamide, H2TPD = 2,5 thiophenedicarboxylic acid, 1,3-H2BDC = 1,3-benzenedicarboxylic acid, H2MIP = 5 methylisophthalic acid and 1,3,5-H3BTC = 1,3,5-benzenetricarboxylic acid] have been hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction analyses, thermal gravimetric (TG) analyses, IR spectroscopy and powder X-ray diffraction (PXRD). In complex 1, the MU2-bridging 4-bmbpd ligands connect adjacent NiII ions leading to a 1D [Ni-4-bmbpd]n wave-like chain, while the TPD anions act as discrete counter ions. Complexes 2 and 3 are similar 2D 4-connected grid networks derived from [Ni-4-bmbpd]n chains and [Ni-L]n (L = BDC or MIP) chains. 4 shows a 3D (2,3,4,4)-connected framework, which contains [Ni-1,3,5-BTC]n 1D double chains, [Ni-(4-bmbpd)]n linear chains and [Ni2(4 bmbpd)2] rings. The 1D chains for 1 and the 2D networks for 2 and 3 are finally extended into 3D supramolecular architectures by hydrogen bonding interactions. The role of polycarboxylates in the assembly and structures of the target compounds was discussed. Moreover, photoluminescence properties, electrochemical properties of complexes 1-4 and the photocatalytic activities of calcination products of 1 and 4 (Ni@NC1 and Ni@NC4) were investigated. More importantly, the photocatalytic performances of Ni@NC1 and Ni@NC4 are enhanced compared with the title complexes 1 and 4. PMID- 29998240 TI - Phase miscibility and dynamic heterogeneity in PMMA/SAN blends through solvent free reactive grafting of SAN on graphene oxide. AB - The spatial distribution of nanoparticles in a particular host polymer matrix can be improved by using brush coated nanoparticles. In this work we have grafted styrene-acrylonitrile (SAN) onto the surface of graphene oxide (GO) and investigated as to how the demixing temperature, morphology and volume cooperativity of PMMA/SAN blends are influenced. Grafting of polymer chains on the surface of nanoparticles usually involves the use of large amounts of solvents, many which are detrimental to the environment besides involving cumbersome processes. SAN-g-GO was prepared by a robust solvent-free strategy wherein the cyano group in SAN was replaced by oxazoline groups during melt mixing in the presence of zinc acetate and ethanol amine. These newly created oxazoline groups reacted with the COOH group of GO under melt extrusion resulting in grafting of SAN on the surface of GO sheets. The effect of SAN-g-GO nanoparticles on the demixing, local segmental motions and morphology evolution for different annealing times was carefully investigated in a classical LCST system, PMMA/SAN blend, using melt rheology, modulated DSC and AFM, respectively. The changes in viscoelastic behavior in the vicinity of demixing are investigated systematically for the control, and blends with GO and SAN-g-GO. Various models were used to gain insight into the spinodal decomposition temperatures of the blends. Interestingly, the demixing temperature determined rheologically and the spinodal decomposition temperature increased significantly in the presence of polymer grafted nanoparticles in comparison to the control and blends with GO. The evolution of the morphology, interfacial driven coarsening as a function of temperature and the localization of nanoparticles were assessed using atomic force microscopy. The cooperatively re-arranging regions estimated from calorimetric measurements begin to suggest enhanced dynamic heterogeneity in the presence of GO and SAN-g-GO in the blends. Taken together, our study reveals that the solvent-free approach of grafting SAN onto GO delays demixing, suppresses coalescence and alters cooperative relaxation in PMMA/SAN blends. PMID- 29998241 TI - Copper-catalyzed decarboxylative propargylation/hydroamination reactions: access to C3 beta-ketoester-functionalized indoles. AB - A copper-catalyzed reaction of ethynyl benzoxazinanones with readily accessible beta-ketoesters via a decarboxylative propargylation/hydroamination sequence has been developed. This protocol furnished a diverse range of C3 beta-ketoester functionalized indoles in good to excellent yields. PMID- 29998242 TI - Constructing reactive Fe and Co complexes from isolated picolyl-functionalized N heterocyclic carbenes. AB - We report the isolation of free picolyl-functionalized N-heterocyclic carbenes (NHCs), which serve as versatile precursors to access low coordinate iron and cobalt complexes. The reactivities of these new iron and cobalt complexes towards catalytic hydrosilylation of ketones have also been explored. For example, low loadings (0.05-1 mol%) of a four-coordinate iron complex bearing two deprotonated picolyl-NHC ligands can effect the fast catalytic reduction of ketones using the inexpensive industrial byproduct polymethylhydrosiloxane (PMHS) as the reductant at ambient temperature. PMID- 29998246 TI - Conformational change and suppression of the Theta-temperature for solutions of polymer-grafted nanoparticles. AB - We determine the conformational change of polystyrene chains grafted to silica nanoparticles dispersed in deuterated cyclohexane using small-angle neutron scattering. The cyclohexane/polystyrene system exhibits an upper-critical solution temperature below which the system phase separates. By grafting the polystyrene chains to a nano-sized spherical silica particle, we observe a significant suppression in the Theta-temperature, decreasing from ~38 degrees C for free polystyrene chains in d12-cyclohexane to ~34 degrees C for the polystyrene-grafted nanoparticles. Above this temperature, the grafted chains are swollen and extended from the particle surface, resulting in well-dispersed grafted nanoparticles. Below this temperature, the grafted chains fully expel the solvent and collapse on the particle surface, destabilizing the nanoparticle suspension and leading to aggregation. We attribute the suppression of the Theta temperature to a competition between entropic and enthalpic energies arising from the structure of the polymer-grafted nanoparticle in which the enthalpic terms appear to dominate. PMID- 29998247 TI - Comparative metabolomic analysis reveals global cadmium stress response of Lactobacillus plantarum strains. AB - Our previous work demonstrated the protective effects of Lactobacillus plantarum (L. plantarum) strains against cadmium (Cd) toxicity in vivo, and also indicated that the Cd tolerance of the strains played an important role in this protection. The goal of this study was to investigate the Cd resistance mechanism of L. plantarum by liquid chromatography-mass spectrometry (LC-MS) based metabolomic analysis, with a focus on the global Cd stress response. L. plantarum CCFM8610 (strongly resistant to Cd) and L. plantarum CCFM191 (sensitive to Cd) were selected as target strains, and their metabolomic profiles with and without Cd exposure were compared. The underlying mechanisms of the intra-species distinction between CCFM8610 and CCFM191 in terms of Cd tolerance can be attributed to the following aspects: (a) CCFM8610 possesses a higher intracellular content of osmolytes; (b) CCFM8610 can induce more effective biosynthesis of extracellular polymeric substance (EPS) to sequestrate Cd; PMID- 29998254 TI - 3D molecular network and magnetic ordering, formed by multi-dentate magnetic couplers, bis(benzene)chromium(i) and [1,2,5]thiadiazolo[3,4 c][1,2,5]thiadiazolidyl. AB - The reaction between bis(benzene)chromium(0), Cr0(C6H6)2, and [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazole (abbreviated as TDTD) formed single crystals of the 1 : 1 salt, [CrI(C6H6)2]+[TDTD]-. The crystal structure of [Cr(C6H6)2][TDTD] belongs to the monoclinic P21/c space group, and involves a CdSO4-type network (or quartz dual net), which is formed by CHN hydrogen bonds between [Cr(C6H6)2]+ (S = 1/2) and [TDTD]- (S = 1/2). In addition to this network, the two components form an alternating chain crystal with a pi-pi overlap along the [110] and [11[combining macron]0] directions. The theoretical calculations for the pairwise intermolecular magnetic exchange interactions in [Cr(C6H6)2][TDTD] reveal the presence of 3D interactions, ranging from an antiferromagnetic interaction of -8.96 cm-1 to a ferromagnetic one of 1.70 cm-1. The temperature dependence of the paramagnetic susceptibility chip indicates the dominance of an antiferromagnetic interaction with a negative Weiss constant of 4.8 K and a magnetic ordering at 8 K, which can be characterized in terms of weak ferromagnetism. PMID- 29998253 TI - The aerolysin nanopore: from peptidomic to genomic applications. AB - The aerolysin pore (ARP) is a newly emerging nanopore that has been extensively used for peptide and protein sensing. Recently, several groups have explored the application of ARP in detecting genetic and epigenetic markers. This brief review summarizes the current applications of ARP, progressing from peptidomic to genomic detection; the recently reported site-directed mutagenesis of ARP; and new genomic DNA sensing approaches, and their advantages and disadvantages. This review will also discuss the perspectives and future applications of ARP for nucleic acid sequencing and biomolecule sensing. PMID- 29998261 TI - A versatile strategy for ultrathin SnS2 nanosheets confined in a N-doped graphene sheet composite for high performance lithium and sodium-ion batteries. AB - In this work, few-layer SnS2 nanosheets confined in a nitrogen-doped graphene sheet composite (SnS2/NGS) are successfully synthesized via a facile thermal decomposition method. SnS2/NGS demonstrates sufficient nitrogen-doping and full graphene encapsulation. When evaluated as an anode material for lithium/sodium ion batteries, it exhibits an excellent electrochemical performance. PMID- 29998264 TI - TiO(OH)2 can exceed the critical limit of conventional CO2 sorbents: modification needed for high capacity and selectivity. AB - High-performance CO2 sorbents typically contain both alkaline compounds and inert supporting materials. The convention is broken by TiO(OH)2. The CO2 sorption capacity of nanostructured TiO(OH)2 reaches 6.1 mmol g-1, while its CO2 sorption selectivity for CO2/N2 mixtures is much higher than that of state-of-the-art sorbents, activated carbon and zeolite, which is another surprise. PMID- 29998263 TI - Nucleus-targeted DNA tetrahedron as a nanocarrier of metal complexes for enhanced glioma therapy. AB - A negatively-charged and nucleus-targeted DNA tetrahedron is rationally designed and used as a nanocarrier of positively-charged metal complexes. This tetrahedron speeds up the translocation of metal complexes into the cell nucleus, and inhibits the growth and invasion of glioma cells by triggering vascular mimicry associated signaling pathways, thus achieving precise glioma treatment. PMID- 29998262 TI - Quantitative and multiplex microRNA assays from unprocessed cells in isolated nanoliter well arrays. AB - MicroRNAs (miRNAs) have recently emerged as promising biomarkers for the profiling of diseases. Translation of miRNA biomarkers to clinical practice, however, remains a challenge due to the lack of analysis platforms for sensitive, quantitative, and multiplex miRNA assays that have simple and robust workflows suitable for translation. The platform we present here utilizes functionalized hydrogel posts contained within isolated nanoliter well reactors for quantitative and multiplex assays directly from unprocessed cell samples without the need of prior nucleic acid extraction. Simultaneous reactor isolation and delivery of miRNA extraction reagents is achieved by sealing an array of wells containing the functionalized hydrogel posts and cells against another array of wells containing lysis and extraction reagents. The nanoliter well array platform features >100* better sensitivity compared to previous technology utilizing hydrogel particles without relying on signal amplification and enables >100 parallel assays in a single device. These advances provided by this platform lay the groundwork for translatable and robust analysis technologies for miRNA expression profiling in samples with small populations of cells and in precious, material-limited samples. PMID- 29998265 TI - Theoretical exploitation of acceptors based on benzobis(thiadiazole) and derivatives for organic NIR-II fluorophores. AB - Small-molecule dyes with fluorescence emission in the second near-infrared (NIR II) region (1000-1700 nm) have attracted considerable attention in the biomedical and bioimaging fields due to their greater imaging depths, better spatial resolution, and higher signal-to-background ratios. However, currently reported organic NIR-II fluorophores are still limited and there is great demand to develop other novel NIR-II fluorophores besides benzobisthiadiazole (BBT)-based fluorophores. More importantly, there is a lack of an appropriate level of theory capable of providing both efficient and accurate predictions of the electronic structures of organic NIR-II fluorophores. In this work, successful application of time-dependent density functional theory (TDDFT) using optimally-tuned range separated functionals for calculations of both absorption and fluorescence spectral properties has been demonstrated, compared with the available experimental data. A series of thiadiazole-based acceptors (A) and derivatives based on the D-A-D skeleton are designed coupled with the triphenylamine donor (D). The structure-property relationships for these fluorophores are thus revealed by analyzing their ground (S0) and excited (S1) state geometries, frontier molecular orbitals (HOMO and LUMO), HOMO-LUMO energy gaps, oscillator strengths, hole-electron distributions and fluorescence wavelengths. It is suggested that the existence of a hypervalent structure leading to a much lower LUMO level and accompanying significant hole-electron separation plays a key role in the red-shift of fluorescence emission in the NIR-II region. In addition, the substitution of BBT oligomers and analogues as acceptor cores is an efficient way to achieve both red-shifted fluorescence wavelengths and enhanced oscillator strengths. The present work provides a reliable and efficient theoretical tool for predicting the related electronic and spectral properties of organic fluorophores and future screening out of potential candidates for excellent NIR II molecular fluorophores. PMID- 29998266 TI - Reversible 1,1-hydroaluminations and C-H activation in reactions of a cyclic (alkyl)(amino) carbene with alane. AB - Varying the reaction ratio of cyclic (alkyl)(amino) carbene (cAACEt) with AlH3.NEtMe2 leads to the isolation of (cAACEtH)AlH2.NEtMe21 and (cAACEtH)2Al(MU H)2AlH2.NEtMe22 and the first example of a monomeric dialkyl-aluminum hydride (cAACEtH)2AlH 3. VT and 1H-1H EXSY NMR experiments of 3 demonstrated the isomerization of the diastereomers of 3via the first instance of reversible hydride migration between the Al and the C center. In addition, heating solutions of 3 at 100 degrees C affords (cAACEtH)Al(CHC(Et)2CH2C(Me)2NC6H3(iPr)C(Me)CH2) 4 with loss of H2. PMID- 29998268 TI - Relaxation dynamics of saturated and unsaturated oriented lipid bilayers. AB - We present experimental measurements and analysis of the dynamics and the phase behaviour of saturated DMPC and unsaturated DOPC oriented multi-lamellar bilayers. Elastic and inelastic neutron scattering were used to directly probe the dynamical processes of these membrane systems on time and length scales relevant to the internal and localized motion of lipid monomers. Mobility in this regime can be informative in elucidating the local interactions responsible for material properties of these fluid lipid systems. DMPC and DOPC are structurally similar in terms of their membrane hydrophobic thickness; however, they exhibit different mechanical properties in terms of both elastic compressibility and bending moduli. The analyses suggest that the constraint imposed by the double bonds in DOPC acyl chains restricts atomic motion in both liquid and gel phases compared to DMPC. We discuss applications of molecular dynamics to further elucidate the atomic details of the dynamical processes. Such an understanding may suggest how membrane properties can be tuned using a variety of different lipid species. PMID- 29998269 TI - Bridge-bonded methylthiolate on Au(111) observed with the scanning tunneling microscope. AB - We report the discovery of bridge-bonded methylthiolate, SCH3, along the step edges of the Au(111) surface. Real-space imaging with a scanning tunnelling microscope reveals the presence of bridge-bonded SCH3 along both the [11[combining macron]0] and the [112[combining macron]] oriented step edges. The nearest neighbour distances of SCH3 along these steps are 2a and , respectively. The Au(111) terrace is covered with the usual CH3SAuSCH3 staples. The bridge bonded alkanethiolate is expected to play a rather significant role in the formation of thiol-passivated Au nanoclusters because of the high fraction of atoms in similar low-coordination sites. PMID- 29998270 TI - Substrate-induced enhancement of the chemical reactivity in metal-supported graphene. AB - Graphene is commonly regarded as an inert material. However, it is well known that the presence of defects or substitutional hetero-atoms confers graphene promising catalytic properties. In this work, we use first-principles calculations to show that it is also possible to enhance the chemical reactivity of a graphene layer by simply growing it on an appropriate substrate. Our comprehensive study demonstrates that, in strongly interacting substrates like Rh(111), graphene adopts highly rippled structures that exhibit areas with distinctive chemical behaviors. According to the local coupling with the substrate, we find areas with markedly different adsorption, dissociation and diffusion pathways for both molecular and atomic oxygen, including a significant change in the nature of the adsorbed molecular and dissociated states, and a dramatic reduction (~60%) of the O2 dissociation energy barrier with respect to free-standing graphene. Our results show that the graphene-metal interaction represents an additional and powerful handle to tailor the graphene chemical properties with potential applications to nano patterning, graphene functionalization and sensing devices. PMID- 29998271 TI - A highly fluorescent turn-on probe in the near-infrared region for albumin quantification in serum matrix. AB - Developing sensitive and selective near-infrared fluorescent bio-probes for serum albumin detection is an ambitious and highly rewarding task. Herein, we report a styryl based fluorophore for serum albumin detection, which displays an exceptional turn-on emission enhancement of ~500 fold, the highest reported so far in the near-infrared region, and more importantly enables quantification of albumin in the complex serum matrix. PMID- 29998272 TI - Spontaneous domain formation in disordered copolymers as a mechanism for chromosome structuring. AB - Motivated by the problem of domain formation in chromosomes, we studied a co polymer model where only a subset of the monomers feel attractive interactions. These monomers are displaced randomly from a regularly-spaced pattern, thus introducing some quenched disorder in the system. Previous work has shown that in the case of regularly-spaced interacting monomers this chain can fold into structures characterized by multiple distinct domains of consecutive segments. In each domain, attractive interactions are balanced by the entropy cost of forming loops. We show by advanced replica-exchange simulations that adding disorder in the position of the interacting monomers further stabilizes these domains. The model suggests that the partitioning of the chain into well-defined domains of consecutive monomers is a spontaneous property of heteropolymers. In the case of chromosomes, evolution could have acted on the spacing of interacting monomers to modulate in a simple way the underlying domains for functional reasons. PMID- 29998273 TI - Synthesis, structure, and photophysical and electrochemical properties of Ru(ii) complexes of arylene-vinylene terpyridyl conjugates. AB - A series of arylene-vinylene pi-conjugated terpyridyl ruthenium(ii) complexes, [Ru(PPh3)2Cl(tpy-C6H4-CH[double bond, length as m-dash]CH-Ar)][PF6] (1-4; tpy = 2,2':6',2''-terpyridyl, where Ar = phenyl, tolyl, 1-naphthyl and 9-anthracenyl as substituents at the 4' position of tpy), have been synthesized and characterized by multinuclear NMR, IR, HRMS and single crystal X-ray crystallography. The influence of the electronic nature of arylene groups on their photophysical and electrochemical properties has been investigated to understand the electronic interaction between the metal-organic redox centers. Furthermore, a sigma-donor phenylacetylide group has been incorporated to accomplish [Ph-C[triple bond, length as m-dash]C-Ru(PPh3)2(tpy-C6H4-CH[double bond, length as m-dash]CH Ar)][PF6] (5-8) complexes by the substitution of a coordinated chloride ligand and to investigate the change in their redox and photophysical properties. DFT studies have been performed to gain an insight into their electronic properties by determining the HOMO-LUMO energy levels and frontier molecular orbitals of all the synthesized Ru(ii) complexes. PMID- 29998274 TI - Epigallocatechin gallate induces GLUT4 translocation in skeletal muscle through both PI3K- and AMPK-dependent pathways. AB - Our previous report demonstrated that epigallocatechin gallate (EGCg) promotes translocation of glucose transporter 4 (GLUT4) in skeletal muscle. In this study, we investigated the molecular mechanism of GLUT4 translocation by EGCg at the physiological concentration range. In L6 cells, EGCg induced phosphorylation of phosphatidylinositide 3'-kinase (PI3K) and downstream protein kinase C (PKC) lambda/xi without affecting the phosphorylation of insulin receptor and Akt. EGCg induced GLUT4 translocation was suppressed by RNA interference-mediated knockdown of PI3K and treatment with PKC inhibitor Go6983. Moreover, EGCg increased Rac1 activity and actin remodelling as downstream events of PKClambda/xi. These results indicate that EGCg induced GLUT4 translocation through a PI3K-dependent pathway, but its mode of action differed from that of insulin. EGCg also induced GLUT4 translocation through a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway. 67 kDa laminin receptor, which is a target molecule of EGCg, was not involved in EGCg-induced glucose uptake in L6 cells. The oral administration of EGCg suppressed postprandial hyperglycaemia accompanied by GLUT4 translocation through both PI3K- and AMPK-dependent pathways, and promoted glycogen accumulation in skeletal muscle of ICR mice. EGCg promotes GLUT4 translocation through both PI3K- and AMPK-dependent pathways and glycogen accumulation in skeletal muscle. PMID- 29998275 TI - Highly concentrated electrolyte solutions for 4 V class potassium-ion batteries. AB - Stable cycling of a 4 V-class potassium-ion battery is demonstrated with a highly concentrated potassium bis(fluorosulfonyl)amide 1,2-dimethoxyethane solution as an electrolyte. Not only graphite and K2Mn[Fe(CN)6] half cells but also graphite//K2Mn[Fe(CN)6] full cells filled with the electrolyte exhibit higher coulombic efficiency and better cyclability than those of KPF6/carbonate ester solutions. PMID- 29998276 TI - A photo-responsive poly(amide-triazole) physical organogel bearing azobenzene residues in the main chain. AB - The synthesis of a click poly(amide-triazole) bearing multiple azobenzene units along the main chain was reported. The polymer was found to form strong physical polymer organogels. This structural design facilitates a much more efficient photomechanical effect upon photochemical excitation, and a highly reversible sol gel transformation can be smoothly triggered by light irradiation and thermal treatment. PMID- 29998277 TI - Nano-confinement of block copolymers in high accuracy topographical guiding patterns: modelling the emergence of defectivity due to incommensurability. AB - Extreme ultraviolet interference lithography (EUV-IL) is used to manufacture topographical guiding patterns to direct the self-assembly of block copolymers. High-accuracy silicon oxide-like patterns with trenches ranging from 68 nm to 117 nm width are fabricated by exposing a hydrogen silsesquioxane (HSQ) resist layer using EUV-IL. We investigate how the accuracy, the low line width roughness and the low line edge roughness of the resulting patterns allow achieving DSA line/space patterns of a PS-b-PMMA (polystyrene-block-poly methyl methacrylate) block copolymer of 11 nm half-pitch with low defectivity. We conduct an in-depth study of the dependence of the DSA pattern morphology on the trench width and on how the neutral brush covers the guiding pattern. We identify the relation between trench width and the emergence of defects with nanometer precision. Based on these studies, we develop a model that extends available free energy models, which allows us to predict the patterning process window. PMID- 29998278 TI - Copper(i)-catalyzed N-H olefination of sulfonamides for N-sulfonyl enaminone synthesis. AB - This communication reports copper-catalyzed N-H olefination of sulfonamides for enaminone synthesis using saturated ketones as olefin sources. With TEMPO derivatives and O2 as oxidants, this method provided an efficient way to produce various enaminones in good yields. Mechanistic studies helped figure out the stable intermediates and develop novel methodologies for the difunctionalization of saturated ketones. PMID- 29998279 TI - Probing translational and rotational dynamics in hydrophilic/hydrophobic anion based imidazolium ionic liquid-water mixtures. AB - In this investigation, we examine the effect of water concentration and temperature on the dynamical properties of [Hmim][Cl] and [Hmim][NTf2] ionic liquids (ILs). The dynamical properties such as translational diffusion coefficients, ion-pair lifetimes, and rotational correlation times are calculated using molecular dynamics simulations. The simulations predict that water concentration also significantly impacts the magnitude of dynamical properties. At low, intermediate and high water concentrations, the following trend in diffusion coefficients is seen: Cl- > Hmim+; Cl- > NTf2-; Hmim+ ([Hmim][Cl]) > Hmim+ ([Hmim] [NTf2]). At ultra-low water concentrations of [Hmim][Cl] IL, several bridge like configurations form between water molecules and Cl- anions, which are supported by a complex distribution of water clusters. The effect of an increase in the water concentration leads to a decrease in ion-pair lifetimes between the Hmim+ cations and Cl-/NTf2- anions, which strongly correlates with the trends observed from the diffusion coefficients. A biexponential function was found to be the best fit for the RACF at neat/ultra-low water concentrations of [Hmim][Cl] and [Hmim][NTf2] ILs, whereas a single exponential function was sufficient to fit the RACF at low, intermediate and high water concentrations. The rotational relaxation time of the Hmim+ cations is larger in neat [Hmim][Cl] compared to that in neat [Hmim][NTf2] with an opposite trend seen with hydration. The rotational correlation time of water molecules is larger in [Hmim][Cl] compared to that in [Hmim][NTf2] at low and intermediate water concentrations, with similar correlation times observed at high water concentrations. PMID- 29998280 TI - Optimization of Pediatric Surgical Care Is Not the Same as Regionalization. PMID- 29998281 TI - Optimization of Pediatric Surgical Care Is Not the Same as Regionalization-Reply. PMID- 29998282 TI - Acute Abdominal Pain in a Postmenopausal Woman. PMID- 29998283 TI - Are Technical Factors Important in Reducing the Risk of Delayed Gastric Emptying After Pancreatoduodenectomy? PMID- 29998284 TI - Error in Results and Figures 1, 2, and 3. PMID- 29998285 TI - Association Between Simulation Curriculum and Learners' Confidence and Interest in Cardiothoracic Surgery. PMID- 29998286 TI - Perioperative Opioid Management-An Opportunity to Put the Genie Back Into the Bottle. PMID- 29998288 TI - Use of Video Review to Investigate Technical Factors That May Be Associated With Delayed Gastric Emptying After Pancreaticoduodenectomy. AB - Importance: Technical proficiency at robotic pancreaticoduodenectomy (RPD) and video assessment are promising tools for understanding postoperative outcomes. Delayed gastric emptying (DGE) remains a major driver of cost and morbidity after pancreaticoduodenectomy. Objective: To determine if technical variables during RPD are associated with postoperative DGE. Design, Setting, and Participants: A retrospective study was conducted of technical assessment performed in all available videos (n = 192) of consecutive RPDs performed at a single academic institution from October 3, 2008, through September 27, 2016. Exposures: Video review of gastrojejunal anastomosis during RPD. Main Outcomes and Measures: Delayed gastric emptying was classified according to International Study Group of Pancreatic Surgery criteria. Video analysis reviewed technical variables specific in the construction of the gastrojejunal anastomosis. Using multivariate analysis, DGE was correlated with known patient variables and technical variables, individually and combined. Results: Of 410 RPDs performed, video was available for 192 RPDs (80 women and 112 men; mean [SD] age, 65.7 [11.1] years). Delayed gastric emptying occurred in 41 patients (21.4%; grade A, 15; grade B, 14; and grade C, 12). Patient variables contributing to DGE on multivariate analysis were advanced age (odds ratio [OR] 1.11; 95% CI, 1.05-1.16; P < .001), small pancreatic duct size (OR, 0.84; 95% CI, 0.72-0.98; P = .03), and postoperative pseudoaneurysm (OR, 17.29; 95% CI, 2.34-127.78; P = .005). However, technical variables contributing to decreased DGE on multivariate analysis included the flow angle (within 30 degrees of vertical) between the stomach and efferent jejunal limb (OR, 0.25; 95% CI, 0.08-0.79; P = .02), greater length of the gastrojejunal anastomosis (OR, 0.40; 95% CI, 0.20-0.77; P = .006), and a robotic-sewn anastomosis (robotic suture vs stapler: OR, 0.30; 95% CI, 0.09-0.95; P = .04). Conclusions and Relevance: This study examines modifiable technical factors through the use of review of video obtained at the time of operation and suggests ways by which the surgical construction of the gastrojejunal anastomosis during RPD may reduce the incidence of DGE as a framework for prospective quality improvement. PMID- 29998289 TI - Evaluation of Bedside Diagnostic Accuracy, Learning Curve, and Challenges for a Novice Reflectance Confocal Microscopy Reader for Skin Cancer Detection In Vivo. PMID- 29998290 TI - Self-Esteem, Self-Efficacy, and Social Support as Predictors of Communicative Participation in Adults Who Stutter. AB - Purpose: This study aimed to identify contributors to communicative participation in adults who stutter. Specifically, it was of interest to determine whether psychosocial variables of self-esteem, self-efficacy, and social support were predictive of communicative participation beyond contributions of demographic and speech-related variables. Method: Adults who stutter (N = 339) completed an online survey that included measures of communicative participation, self-esteem, self-efficacy, social support, self-reported speech-related variables (speech usage, number of years stuttering, history of treatment and self-help support group participation for stuttering, and physical speech disruption severity), and demographics (age, sex, living situation, education, and employment status). Hierarchical regression was performed for prediction of communicative participation, in addition to calculating Spearman correlations between social roles variables, communicative participation, and physical speech disruption severity. Results: After controlling for demographic and speech-related variables, self-esteem, self-efficacy, and social support each significantly predicted communicative participation in adults who stutter. Large correlations were observed between communicative participation and measures of social roles, whereas medium correlations were observed between physical speech disruption severity and measures of social roles. Conclusions: Communicative participation in adults who stutter is associated with a variety of demographic, speech related, and psychosocial variables. Speech-language pathologists should be aware of predictors of communicative participation such as self-esteem, self-efficacy, and social support, in addition to severity of physical speech disruptions. They should consider and evaluate these factors in clients who stutter and target them in treatment if necessary. PMID- 29998291 TI - The Obesity Paradigm and Lifetime Risk of Cardiovascular Disease. PMID- 29998287 TI - DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons: Meta-analysis of Multiethnic Epigenome-wide Studies. AB - Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. Design, Setting, and Participants: To date, the first cross-ethnic meta analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 * 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 * 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 * 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 * 10-03) and of ARHGEF3 in fibroblasts (effect, 0.48; P = 9.8 * 10-04) was associated with major depression. Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects. PMID- 29998292 TI - Economic Analysis of a Noninvasive Molecular Pathologic Assay for Pigmented Skin Lesions. AB - Importance: A recently described noninvasive gene expression test (the pigmented lesion assay [PLA]) with adhesive patch-based sampling has the potential to rule out melanoma and the need for surgical biopsy of pigmented lesions suggestive of melanoma with a negative predictive value of 99% compared with 83% for the histopathologic standard of care. The cost implications of using this molecular test vs visual assessment followed by biopsy and histopathologic assessment (VAH) have not been evaluated. Objective: To determine potential cost savings of PLA use vs the VAH pathway. Design, Setting, and Participants: This health economic analysis performed from a US payer perspective was based on consensus treatment guidelines and fee schedules from the Centers for Medicare & Medicaid Services. Data for model input were derived from routine use of the test in US dermatology practices and literature. Participants included patients with primary cutaneous pigmented lesions suggestive of melanoma. Data were analyzed from February 8 to December 1, 2017. Main Outcomes and Measures: The primary analysis consisted of the relative reduction in costs of diagnostic surgical procedures for PLA vs VAH management. Additional analyses included stage-related treatment costs associated with delays in diagnosis. Results: In the cost analysis for this economic model, the relative reduction in surgical procedure costs (biopsy and subsequent excision), assuming $0 for the PLA to facilitate multiple comparison scenarios, was -$395 compared with VAH. The relative reduction in stage-related treatment costs associated with the PLA was -$433 compared with VAH, primarily associated with avoidance of delays due to false-negative diagnoses. Surveillance costs were reduced by -$119 with the PLA. The total cost of fully adjudicating a lesion suggestive of melanoma by VAH was $947. At a mean selling price reference point for PLA of $500, cost savings of $447 (47%) per lesion tested could be realized. Conclusions and Relevance: The results of this analysis suggest that the PLA reduces cost and may improve the care of patients with primary pigmented skin lesions suggestive of melanoma. PMID- 29998293 TI - Anthony Fauci, MD: Working to End HIV/AIDS. PMID- 29998295 TI - Is Heart Failure Inherited?: Beyond the Cardiomyopathies, Genetics Do Matter. PMID- 29998294 TI - Associations of Asthma and Asthma Control With Atrial Fibrillation Risk: Results From the Nord-Trondelag Health Study (HUNT). AB - Importance: Asthma, a chronic inflammatory airway disease, and atrial fibrillation (AF) share several common pathophysiological mechanisms. Research on the association between asthma and atrial fibrillation is lacking, and to our knowledge, no previous studies have assessed the dose-response association between levels of asthma control and AF. Objective: To assess the association between asthma, levels of asthma control, and AF. Design, Setting, and Participants: This prospective population cohort analyzed data on adults from a second and third iteration of the survey-based Nord-Trondelag Health Study (HUNT) in Norway. All included participants were free from AF at baseline. Atrial fibrillation was ascertained by linking HUNT data with hospital records from the 2 hospitals in Nord-Trondelag County. Data analysis was completed from May 2017 to November 2017. Exposures: Self-reported asthma was categorized into 3 groups: those who had ever had asthma, those who self-report being diagnosed with asthma, and those who had active asthma. Asthma control was defined according to Global Initiative for Asthma guidelines and was categorized into controlled, partly controlled, and uncontrolled cases. Main Outcomes and Measures: Atrial fibrillation. Results: A total of 54 567 adults were included (of whom 28 821 [52.8%] were women). Of these, 5961 participants (10.9%) reported ever having asthma, 3934 participants (7.2%) reported being diagnosed with asthma, and 2485 participants (4.6%) reported having active asthma. During a mean (SD) follow-up of 15.4 (5.8) years, 2071 participants (3.8%) developed AF. Participants with physician-diagnosed asthma had an estimated 38% higher risk of developing AF (adjusted hazard ratio, 1.38 [95% CI, 1.18-1.61]) compared with participants without asthma. There was a dose-response association between levels of asthma control and risk of AF with the highest risk for AF in participants with uncontrolled asthma (adjusted hazard ratio, 1.74 [95% CI, 1.26-2.42]; P for trend < .001). Conclusions and Relevance: Asthma and lack of asthma control were associated with moderately increased risks of AF in a dose-response manner. Further studies are needed to explore the underlying mechanisms and clarify causal pathways between asthma and AF. PMID- 29998296 TI - A Swedish Nationwide Adoption Study of the Heritability of Heart Failure. AB - Importance: Heart failure (HF) aggregates in families, but the heritability of HF has not been determined. Discerning the genetic and environmental contributions to HF risk is important to further helping to identify individuals at risk. Adoption studies may establish the genetic contribution to HF. Objective: This nationwide adoption study aimed to determine the heritability of HF. Design, Setting, and Participants: This case-control study and cohort study design used logistic regression for calculating risks of HF in adoptees. Adoptees who were born in Sweden between 1942 and 1990 were linked to their adoptive parents and biological parents. The Swedish Multi-Generation Register was linked to the Swedish Patient Register for information on hospital inpatient and outpatient admissions and to the Swedish Cause of Death Register for the period 1964 through 2015. Heritability (h2 with a standard error) for HF was determined both with Falconer regression and with tetrachoric correlation. Data analysis was completed from July 2017 to April 2018. Exposures: Heart failure in biological parents and/or adoptive parents. Main Outcomes and Measures: Heritability; risk of HF, expressed as odds ratios. Results: A total of 21 643 adoptees were included (of whom 10 626 [49.1%] were female), as well as 35 016 adoptive parents (14 872 [42.5%] female) and 43 286 biological parents (21 643 [50.0%] female). There were 194 cases of HF in adoptees, 3972 cases of HF in adoptive parents, and 3657 cases of HF in biological parents. The cohort study odds ratio (OR) for heart failure was 1.45 in adoptees (95% CI, 1.04-2.03) for biological parents with HF, compared with those without an affected biological parent. If cardiomyopathies were excluded, this OR was 1.58 (95% CI, 1.03-2.42). The corresponding OR associated with an affected adoptive parent were nonsignificant, both with cardiomyopathies included (OR, 0.83 [95% CI, 0.57-1.20]) and with cardiomyopathies excluded (OR, 0.79 [95% CI, 0.49-1.29]). The heritability of HF per Falconer regression (h2) was 26% (SE, 14%). With exclusion of cardiomyopathies the heritability using Falconer regression was 34% (SE, 18%). Conclusions and Relevance: Heart failure in a biological parent is an HF risk factor that is worth clinical consideration. The increased heritability of HF suggests that genetic factors are important in HF pathogenesis. PMID- 29998298 TI - The Obesity Paradigm and Lifetime Risk of Cardiovascular Disease-Reply. PMID- 29998297 TI - Risk Assessment for Cardiovascular Disease With Nontraditional Risk Factors: US Preventive Services Task Force Recommendation Statement. AB - Importance: Cardiovascular disease (CVD) is the most common cause of death among adults in the United States. Treatment to prevent CVD events by modifying risk factors is currently informed by the Framingham Risk Score, the Pooled Cohort Equations, or similar CVD risk assessment models. If current CVD risk assessment models could be improved by adding more risk factors, treatment might be better targeted, thereby maximizing the benefits and minimizing the harms. Objective: To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on using nontraditional risk factors in coronary heart disease risk assessment. Evidence Review: The USPSTF reviewed the evidence on using nontraditional risk factors in CVD risk assessment, focusing on the ankle-brachial index (ABI), high sensitivity C-reactive protein (hsCRP) level, and coronary artery calcium (CAC) score; the health benefits and harms of CVD risk assessment and treatment guided by nontraditional risk factors combined with the Framingham Risk Score or Pooled Cohort Equations compared with using either risk assessment model alone; and whether adding nontraditional risk factors to existing CVD risk assessment models improves measures of calibration, discrimination, and risk reclassification. Findings: The USPSTF found adequate evidence that adding the ABI, hsCRP level, and CAC score to existing CVD risk assessment models results in small improvements in discrimination and risk reclassification; however, the clinical meaning of these changes is largely unknown. Evidence on adding the ABI, hsCRP level, and CAC score to the Pooled Cohort Equations is limited. The USPSTF found inadequate evidence to assess whether treatment decisions guided by the ABI, hsCRP level, or CAC score, in addition to risk factors in existing CVD risk assessment models, leads to reduced incidence of CVD events or mortality. The USPSTF found adequate evidence to conceptually bound the harms of early detection and interventions as small. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the ABI, hsCRP level, or CAC score in risk assessment for CVD in asymptomatic adults to prevent CVD events. Conclusions and Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of adding the ABI, hsCRP level, or CAC score to traditional risk assessment for CVD in asymptomatic adults to prevent CVD events. (I statement). PMID- 29998299 TI - High-Flow Nasal Cannula System: Not Just Another Nasal Cannula. PMID- 29998302 TI - Viewing the Value of Coronary Artery Calcium Testing From Different Perspectives. PMID- 29998300 TI - Trends and Scope of Dermatology Procedures Billed by Advanced Practice Professionals From 2012 Through 2015. AB - Importance: Advanced practice professionals (APPs) such as nurse practitioners and physician assistants independently perform a large number and variety of dermatologic procedures, but little is known about how the number and scope of these procedures have changed over time. Objective: To examine the trends in scope and volume of dermatology procedures billed by APPs over time. Design, Setting, and Participants: A longitudinal study was conducted using the Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File from 2012 through 2015. The data encompass nearly all outpatient procedures paid by Medicare Part B in the United States and include the type of clinician under which procedures were billed. Main Outcomes and Measures: For each type of dermatology procedure, the total number performed by APPs and the total number performed by dermatologists each year. Results: The total number (and percentage) of all dermatologic procedures performed by APPs increased from 2.69 million of 30.7 million (8.8%) in 2012 to 4.54 million of 33.9 million (13.4%) in 2015. The most common procedures performed by APPs in 2015 were destructions of benign neoplasms (3.6 million), biopsies (788 834), and destructions of malignant neoplasms (48 982). The numbers of patch tests, removals of benign and malignant neoplasms, intermediate and complex repairs, flaps, and surgical pathologic specimen examinations by APPs also increased each year from 2012 through 2015. Conclusions and Relevance: The number and scope of dermatologic procedures performed by APPs appear to be increasing over time. These procedures can be difficult and invasive. This study suggests that further studies are needed to determine what association these procedures have with patient outcomes and the potential need for more formal training. PMID- 29998301 TI - Nontraditional Risk Factors in Cardiovascular Disease Risk Assessment: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Incorporating nontraditional risk factors may improve the performance of traditional multivariable risk assessment for cardiovascular disease (CVD). Objective: To systematically review evidence for the US Preventive Services Task Force on the benefits and harms of 3 nontraditional risk factors in cardiovascular risk assessment: the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) level, and coronary artery calcium (CAC) score. Data Sources: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for studies published through May 22, 2017. Surveillance continued through February 7, 2018. Study Selection: Studies of asymptomatic adults with no known cardiovascular disease. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers. Main Outcomes and Measures: Cardiovascular events, mortality, risk assessment performance measures (calibration, discrimination, or risk reclassification), and serious adverse events. Results: Forty-three studies (N = 267 244) were included. No adequately powered trials have evaluated the clinical effect of risk assessment with nontraditional risk factors on patient health outcomes. The addition of the ABI (10 studies), hsCRP level (25 studies), or CAC score (19 studies) can improve both discrimination and reclassification; the magnitude and consistency of improvement varies by nontraditional risk factor. For the ABI, improvements in performance were the greatest for women, in whom traditional risk assessment has poor discrimination (C statistic change of 0.112 and net reclassification index [NRI] of 0.096). Results were inconsistent for hsCRP level, with the largest analysis (n = 166 596) showing a minimal effect on risk prediction (C statistic change of 0.0039, NRI of 0.0152). The largest improvements in discrimination (C statistic change ranging from 0.018 to 0.144) and reclassification (NRI ranging from 0.084 to 0.35) were seen for CAC score, although CAC score may inappropriately reclassify individuals not having cardiovascular events into higher-risk categories, as determined by negative nonevent NRI. Evidence for the harms of nontraditional risk factor assessment was limited to computed tomography imaging for CAC scoring (8 studies) and showed that radiation exposure is low but may result in additional testing. Conclusions and Relevance: There are insufficient adequately powered clinical trials evaluating the incremental effect of the ABI, hsCRP level, or CAC score in risk assessment and initiation of preventive therapy. Furthermore, the clinical meaning of improvements in measures of calibration, discrimination, and reclassification risk prediction studies is uncertain. PMID- 29998304 TI - Myths, Truths, and Clinical Relevance of Comedogenicity Product Labeling. PMID- 29998303 TI - Prevalence of Preoperative Opioid Use and Characteristics Associated With Opioid Use Among Patients Presenting for Surgery. AB - Importance: Patterns of preoperative opioid use are not well characterized across different surgical services, and studies in this patient population have lacked important self-reported data of pain and affect. Objectives: To assess the prevalence of preoperative opioid use and the characteristics of these patients in a broadly representative surgical cohort. Design, Setting, and Participants: Cross-sectional, observational study of patients undergoing surgery at a tertiary care academic medical center. Data were collected as a part of large prospective institutional research registries from March 1, 2010, through April 30, 2016. Exposures: Preoperative patient and procedural characteristics, including prospectively assessed self-reported pain and functional measures. Main Outcomes and Measures: Patient-reported opioid use before surgery. Results: Of the total 34 186 patients recruited (54.2% women; mean [SD] age, 53.1 [16.1] years), preoperative opioid use was reported in 7894 (23.1%). The most common opioids used were hydrocodone bitartrate (4685 [59.4%]), tramadol hydrochloride (1677 [21.2%]), and oxycodone hydrochloride (1442 [18.3%]). Age of 31 to 40 years (adjusted odds ratio [aOR], 1.26; 95% CI, 1.10-1.45), tobacco use (former use aOR, 1.32 [95% CI, 1.22-1.42]; current use aOR, 1.62 [95% CI, 1.48-1.78]), illicit drug use (aOR, 1.74; 95% CI, 1.16-2.60), higher pain severity (aOR, 1.33; 95% CI, 1.31-1.35), depression (aOR, 1.22; 95% CI, 1.12-1.33), higher Fibromyalgia Survey scores (aOR, 1.06, 95% CI, 1.05-1.07), lower life satisfaction (aOR, 0.95, 95% CI, 0.93-0.96), and more medical comorbidities (American Society of Anesthesiology score aOR, 1.47 [95% CI, 1.37-1.58]; Charlson Comorbidity Index aOR, 1.29 [95% CI, 1.18-1.41]) were all independently associated with preoperative opioid use. Preoperative opioid use was most commonly reported by patients undergoing orthopedic (226 [65.1%]) and neurosurgical spinal (596 [55.1%]) procedures and least common among patients undergoing thoracic procedures (244 [15.7%]). After adjusting for patient characteristics, the patients undergoing lower extremity procedures were most likely to report preoperative opioid use (aOR, 3.61; 95% CI, 2.81-4.64), as well as those undergoing pelvic (excluding hip) (aOR, 3.09; 95% CI, 1.88-5.08), upper extremity (aOR, 3.07; 95% CI, 2.12-4.45), and spinal or spinal cord (aOR, 2.68; 95% CI, 2.15-3.32) procedures, with the group undergoing intrathoracic surgery as the reference group. Conclusions and Relevance: In this large study of preoperative opioid use that includes patient-reported outcome measures, more than 1 in 4 patients presenting for surgery reported opioid use. These data provide important insights into this complicated patient population that would appear to help guide future preoperative optimization and perioperative opioid weaning interventions. PMID- 29998305 TI - Uncertainty. PMID- 29998306 TI - Association of Lichen Planopilaris With Dyslipidemia. PMID- 29998307 TI - Comparison of the Safety Planning Intervention With Follow-up vs Usual Care of Suicidal Patients Treated in the Emergency Department. AB - Importance: Suicidal behavior is a major public health problem in the United States. The suicide rate has steadily increased over the past 2 decades; middle aged men and military veterans are at particularly high risk. There is a dearth of empirically supported brief intervention strategies to address this problem in health care settings generally and particularly in emergency departments (EDs), where many suicidal patients present for care. Objective: To determine whether the Safety Planning Intervention (SPI), administered in EDs with follow-up contact for suicidal patients, was associated with reduced suicidal behavior and improved outpatient treatment engagement in the 6 months following discharge, an established high-risk period. Design, Setting, and Participants: Cohort comparison design with 6-month follow-up at 9 EDs (5 intervention sites and 4 control sites) in Veterans Health Administration hospital EDs. Patients were eligible for the study if they were 18 years or older, had an ED visit for a suicide-related concern, had inpatient hospitalization not clinically indicated, and were able to read English. Data were collected between 2010 and 2015; data were analyzed between 2016 and 2018. Interventions: The intervention combines SPI and telephone follow-up. The SPI was defined as a brief clinical intervention that combined evidence-based strategies to reduce suicidal behavior through a prioritized list of coping skills and strategies. In telephone follow-up, patients were contacted at least 2 times to monitor suicide risk, review and revise the SPI, and support treatment engagement. Main Outcomes and Measures: Suicidal behavior and behavioral health outpatient services extracted from medical records for 6 months following ED discharge. Results: Of the 1640 total patients, 1186 were in the intervention group and 454 were in the comparison group. Patients in the intervention group had a mean (SD) age of 47.15 (14.89) years and 88.5% were men (n = 1050); patients in the comparison group had a mean (SD) age of 49.38 (14.47) years and 88.1% were men (n = 400). Patients in the SPI+ condition were less likely to engage in suicidal behavior (n = 36 of 1186; 3.03%) than those receiving usual care (n = 24 of 454; 5.29%) during the 6-month follow-up period. The SPI+ was associated with 45% fewer suicidal behaviors, approximately halving the odds of suicidal behavior over 6 months (odds ratio, 0.56; 95% CI, 0.33-0.95, P = .03). Intervention patients had more than double the odds of attending at least 1 outpatient mental health visit (odds ratio, 2.06; 95% CI, 1.57-2.71; P < .001). Conclusions and Relevance: This large-scale cohort comparison study found that SPI+ was associated with a reduction in suicidal behavior and increased treatment engagement among suicidal patients following ED discharge and may be a valuable clinical tool in health care settings. PMID- 29998308 TI - Missing Affiliation. PMID- 29998309 TI - Missing Information About Study Funding. PMID- 29998311 TI - Gua Sha, or Coining Therapy. PMID- 29998312 TI - Tesla and the Violet Ray. PMID- 29998313 TI - Striking White Hair. PMID- 29998315 TI - An Atrophic and Spiny Eruption of the Palms. PMID- 29998316 TI - The Obesity Paradigm and Lifetime Risk of Cardiovascular Disease. PMID- 29998317 TI - Victimization, Bullying, and Emotional Competence: Longitudinal Associations in (Pre)Adolescents With and Without Developmental Language Disorder. AB - Purpose: Victimization is a common problem for many children but is exacerbated for children with a developmental language disorder (DLD). However, the severity of communication problems does not explain their victimization rates. In children without DLD, difficulties with emotional competence are a risk factor for victimization and also increase the risk of bullying. In this longitudinal study, we examined the extent to which the level and development of emotional competence (understanding of one's own emotions and levels of anger, sadness, and fear) contributed to the prediction of victimization and bullying in children with and without DLD, over and above the type and severity of communication problems of children with DLD. Method: Clinically referred youngsters (8-16 years old) with (n = 112; 48% girls, 52% boys) and without (n = 233; 58% girls, 42% boys) DLD completed self-reports 3 times over an 18-month period. Parents of children with DLD reported on their children's communication problems. Results: Participants with DLD reported more victimization but comparable levels of bullying behavior compared with peers without DLD. Higher levels of sadness and fear were risk factors for more victimization in both groups. Better understanding of one's own emotions had a larger effect on less victimization in children with DLD, independent of their communication problems. In addition, increased levels of anger and lower levels of understanding of one's own emotions explained more bullying in both groups. Conclusion: Outcomes indicate that secondary difficulties in emotional competence in children with DLD make these children more vulnerable to victimization and warrant specific support and interventions. PMID- 29998318 TI - Oral Sodium Sensor for Hypertension Management. PMID- 29998319 TI - Immunotherapy Leads to Complete Regression in Late-Stage Breast Cancer. PMID- 29998320 TI - Progressive Weakness and Memory Impairment in a Middle-aged Man. PMID- 29998321 TI - Intravenous Alteplase for Mild Nondisabling Acute Ischemic Stroke: A Bridge Too Far? PMID- 29998322 TI - Evaluating Health Technology Through Pragmatic Trials: Novel Approaches to Generate High-Quality Evidence. PMID- 29998323 TI - Screening for Atrial Fibrillation With a Wearable Device. PMID- 29998326 TI - New Ebola Outbreak in Africa Is a Major Test for the WHO. PMID- 29998324 TI - Ankle-Brachial Index Screening and Improving Peripheral Artery Disease Detection and Outcomes. PMID- 29998327 TI - Current Comment: The Hen and Her Imitators. PMID- 29998328 TI - Testosterone Prescribing in the United States, 2002-2016. PMID- 29998329 TI - Low-Fat vs Low-Carbohydrate Diets and Weight Loss. PMID- 29998330 TI - Low-Fat vs Low-Carbohydrate Diets and Weight Loss. PMID- 29998331 TI - Importance of Intelligence and Emotional Intelligence for Physicians. PMID- 29998332 TI - Importance of Intelligence and Emotional Intelligence for Physicians. PMID- 29998333 TI - Importance of Intelligence and Emotional Intelligence for Physicians. PMID- 29998334 TI - Low-Fat vs Low-Carbohydrate Diets and Weight Loss-Reply. PMID- 29998335 TI - Importance of Intelligence and Emotional Intelligence for Physicians-Reply. PMID- 29998336 TI - Effect of a Home-Based Wearable Continuous ECG Monitoring Patch on Detection of Undiagnosed Atrial Fibrillation: The mSToPS Randomized Clinical Trial. AB - Importance: Opportunistic screening for atrial fibrillation (AF) is recommended, and improved methods of early identification could allow for the initiation of appropriate therapies to prevent the adverse health outcomes associated with AF. Objective: To determine the effect of a self-applied wearable electrocardiogram (ECG) patch in detecting AF and the clinical consequences associated with such a detection strategy. Design, Setting, and Participants: A direct-to-participant randomized clinical trial and prospective matched observational cohort study were conducted among members of a large national health plan. Recruitment began November 17, 2015, and was completed on October 4, 2016, and 1-year claims-based follow-up concluded in January 2018. For the clinical trial, 2659 individuals were randomized to active home-based monitoring to start immediately or delayed by 4 months. For the observational study, 2 deidentified age-, sex- and CHA2DS2 VASc-matched controls were selected for each actively monitored individual. Interventions: The actively monitored cohort wore a self-applied continuous ECG monitoring patch at home during routine activities for up to 4 weeks, initiated either immediately after enrolling (n = 1364) or delayed for 4 months after enrollment (n = 1291). Main Outcomes and Measures: The primary end point was the incidence of a new diagnosis of AF at 4 months among those randomized to immediate monitoring vs delayed monitoring. A secondary end point was new AF diagnosis at 1 year in the combined actively monitored groups vs matched observational controls. Other outcomes included new prescriptions for anticoagulants and health care utilization (outpatient cardiology visits, primary care visits, or AF-related emergency department visits and hospitalizations) at 1 year. Results: The randomized groups included 2659 participants (mean [SD] age, 72.4 [7.3] years; 38.6% women), of whom 1738 (65.4%) completed active monitoring. The observational study comprised 5214 (mean [SD] age, 73.7 [7.0] years; 40.5% women; median CHA2DS2-VASc score, 3.0), including 1738 actively monitored individuals from the randomized trial and 3476 matched controls. In the randomized study, new AF was identified by 4 months in 3.9% (53/1366) of the immediate group vs 0.9% (12/1293) in the delayed group (absolute difference, 3.0% [95% CI, 1.8%-4.1%]). At 1 year, AF was newly diagnosed in 109 monitored (6.7 per 100 person-years) and 81 unmonitored (2.6 per 100 person-years; difference, 4.1 [95% CI, 3.9-4.2]) individuals. Active monitoring was associated with increased initiation of anticoagulants (5.7 vs 3.7 per 100 person-years; difference, 2.0 [95% CI, 1.9-2.2]), outpatient cardiology visits (33.5 vs 26.0 per 100 person years; difference, 7.5 [95% CI, 7.2-7.9), and primary care visits (83.5 vs 82.6 per 100 person-years; difference, 0.9 [95% CI, 0.4-1.5]). There was no difference in AF-related emergency department visits and hospitalizations (1.3 vs 1.4 per 100 person-years; difference, 0.1 [95% CI, -0.1 to 0]). Conclusions and Relevance: Among individuals at high risk for AF, immediate monitoring with a home-based wearable ECG sensor patch, compared with delayed monitoring, resulted in a higher rate of AF diagnosis after 4 months. Monitored individuals, compared with nonmonitored controls, had higher rates of AF diagnosis, greater initiation of anticoagulants, but also increased health care resource utilization at 1 year. Trial Registration: ClinicalTrials.gov Identifier: NCT02506244. PMID- 29998337 TI - Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. AB - Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1 2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02072226. PMID- 29998339 TI - Screening for Peripheral Artery Disease With Ankle-Brachial Index. PMID- 29998338 TI - Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial. AB - Importance: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors and often result in therapy discontinuation. Small studies suggest that acupuncture may decrease aromatase inhibitor-related joint symptoms. Objective: To determine the effect of acupuncture in reducing aromatase inhibitor related joint pain. Design, Setting, and Patients: Randomized clinical trial conducted at 11 academic centers and clinical sites in the United States from March 2012 to February 2017 (final date of follow-up, September 5, 2017). Eligible patients were postmenopausal women with early-stage breast cancer who were taking an aromatase inhibitor and scored at least 3 on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain). Interventions: Patients were randomized 2:1:1 to the true acupuncture (n = 110), sham acupuncture (n = 59), or waitlist control (n = 57) group. True acupuncture and sham acupuncture protocols consisted of 12 acupuncture sessions over 6 weeks (2 sessions per week), followed by 1 session per week for 6 weeks. The waitlist control group did not receive any intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52. Main Outcomes and Measures: The primary end point was the 6-week BPI-WP score. Mean 6-week BPI-WP scores were compared by study group using linear regression, adjusted for baseline pain and stratification factors (clinically meaningful difference specified as 2 points). Results: Among 226 randomized patients (mean [SD] age, 60.7 [8.6] years; 88% white; mean [SD] baseline BPI-WP score, 6.6 [1.5]), 206 (91.1%) completed the trial. From baseline to 6 weeks, the mean observed BPI-WP score decreased by 2.05 points (reduced pain) in the true acupuncture group, by 1.07 points in the sham acupuncture group, and by 0.99 points in the waitlist control group. The adjusted difference for true acupuncture vs sham acupuncture was 0.92 points (95% CI, 0.20-1.65; P = .01) and for true acupuncture vs waitlist control was 0.96 points (95% CI, 0.24 1.67; P = .01). Patients in the true acupuncture group experienced more grade 1 bruising compared with patients in the sham acupuncture group (47% vs 25%; P = .01). Conclusions and Relevance: Among postmenopausal women with early-stage breast cancer and aromatase inhibitor-related arthralgias, true acupuncture compared with sham acupuncture or with waitlist control resulted in a statistically significant reduction in joint pain at 6 weeks, although the observed improvement was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT01535066. PMID- 29998341 TI - On Breaking Bad News. PMID- 29998343 TI - Screening for Peripheral Artery Disease Using the Ankle-Brachial Index: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Peripheral artery disease (PAD) is associated with a high risk for cardiovascular events and poor ambulatory function, even in the absence of symptoms. Screening for PAD with the ankle-brachial index (ABI) may identify patients in need of treatment to improve health outcomes. Objective: To systematically review evidence for the US Preventive Services Task Force on PAD screening with the ABI, the diagnostic accuracy of the test, and the benefits and harms of treatment of screen-detected PAD. Data Sources: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant English-language studies published between January 2012 and May 2, 2017. Surveillance continued through February 7, 2018. Study Selection: Studies of unselected or generally asymptomatic adults with no known cardiovascular disease. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers. Main Outcomes and Measures: Cardiovascular morbidity; PAD morbidity; mortality; health-related quality of life; diagnostic accuracy; and serious adverse events. Results: Five studies (N = 5864 participants) were included that examined the indirect evidence for the benefits and harms of screening and treatment of screen detected PAD. No population-based screening trials evaluated the direct benefits or harms of PAD screening with the ABI alone. A single diagnostic accuracy study of the ABI compared with magnetic resonance angiography gold-standard imaging (n = 306) found low sensitivity (7%-34%) and high specificity (96%-100%) in a screening population. Two adequately powered trials (n = 4626) in asymptomatic populations with and without diabetes with a variably defined low ABI (<=0.95 or <=0.99) showed no statistically significant effect of aspirin (100 mg daily) for composite CVD outcomes (adjusted hazard ratio [HR], 1.00 [95% CI, 0.81-1.23] and HR, 0.98 [95% CI, 0.76-1.26]). One trial (n = 3350) demonstrated no statistically significant increase in major bleeding events with the use of aspirin (adjusted HR, 1.71 [95% CI, 0.99- 2.97]) and no statistically significant increase in major gastrointestinal bleeding (relative risk, 1.13 [95% CI, 0.44-2.91]). Two exercise trials (n = 932) in screen-relevant populations reported no differences in quality of life, Walking Impairment Questionnaire walking distance, or symptoms at 12 and 52 weeks; no harms were reported. Conclusions and Relevance: There was no direct evidence and limited indirect evidence on the benefits of PAD screening with the ABI in unselected or asymptomatic populations. Available studies suggest low sensitivity and lack of beneficial effect on health outcomes, but these studies have important limitations. PMID- 29998344 TI - Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment With the Ankle-Brachial Index: US Preventive Services Task Force Recommendation Statement. AB - Importance: Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the lower limbs. It can impair walking and, in severe cases, can lead to tissue loss, infection, and amputation. In addition to morbidity directly caused by PAD, patients with PAD are at increased risk for cardiovascular disease (CVD) events, because atherosclerosis is a systemic disease that also causes coronary and cerebrovascular events. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on screening for PAD and CVD risk with the ankle-brachial index (ABI). Evidence Review: The USPSTF reviewed the evidence on whether screening for PAD with the ABI in generally asymptomatic adults reduces morbidity or mortality from PAD or CVD. The current review expanded on the previous review to include individuals with diabetes and interventions that include supervised exercise and physical therapy intended to improve outcomes in the lower limbs. Findings: The USPSTF found few data on the accuracy of the ABI for identifying asymptomatic persons who can benefit from treatment of PAD or CVD. There are few studies addressing the benefits of treating screen-detected patients with PAD; 2 good-quality studies showed no benefit of using the ABI to manage daily aspirin therapy in unselected populations, and 2 studies showed no benefit from exercise therapy. No studies addressed the harms of screening, although the potential exists for overdiagnosis, labeling, and opportunity costs. Studies that addressed the harms of treatment showed nonsignificant results. Therefore, the USPSTF concludes that the current evidence is insufficient and that the balance of benefits and harms of screening for PAD with the ABI in asymptomatic adults cannot be determined. Conclusions and Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for PAD and CVD risk with the ABI in asymptomatic adults. (I statement). PMID- 29998346 TI - Stroke Rehab Lacking. PMID- 29998345 TI - Pool-Related Infections. PMID- 29998347 TI - USPSTF Recommendations for Assessment of Cardiovascular Risk With Nontraditional Risk Factors: Finding the Right Tests for the Right Patients. PMID- 29998348 TI - Investigating the Use of a Nonspeech Task to Measure Tongue-Jaw Differentiation: Findings Across Typical Development. AB - Purpose: Clinically, a task of alternating tongue lateralization has been used to evaluate the ability to independently control the tongue and jaw, with jaw movement interpreted as a sign of poor tongue-jaw differentiation. However, there is a lack of normative data regarding jaw movement during this task and whether this changes over the course of development. This study quantified relative tongue and jaw movement during alternating tongue lateralization for typical speakers across age ranges and examined whether degree of jaw movement varies as a function of age. Method: Participants were 39 typical children, adolescents, and adults ranging from 6 to 29 years old. A motion capture system was used to track tongue and jaw movement during an alternating tongue lateralization task, and the average relative contribution of the jaw to tongue lateralization was determined for each participant. Results: Age did not correlate significantly with the average relative contribution of the jaw to tongue lateralization. Typical children, adolescents, and adults exhibited wide variability in the degree of jaw movement during this task. Conclusion: Variability among typical speakers in alternating tongue lateralization performance makes it challenging to determine if/when performance should be considered atypical. Clinical findings from this task must be interpreted with caution. Supplemental Material: https://doi.org/10.23641/asha.6626222. PMID- 29998351 TI - Mitteilungen DGKFO. PMID- 29998349 TI - Dual contributions of noradrenaline to behavioural flexibility and motivation. AB - INTRODUCTION: While several theories have highlighted the importance of the noradrenergic system for behavioral flexibility, a number of recent studies have also shown a role for noradrenaline in motivation, particularly in effort processing. Here, we designed a novel sequential cost/benefit decision task to test the causal influence of noradrenaline on these two functions in rhesus monkeys. METHODS: We manipulated noradrenaline using clonidine, an alpha-2 noradrenergic receptor agonist, which reduces central noradrenaline levels and examined how this manipulation influenced performance on the task. RESULTS: Clonidine had two specific and distinct effects: first, it decreased choice variability, without affecting the cost/benefit trade-off; and second, it reduced force production, without modulating the willingness to work. CONCLUSIONS: Together, these results support an overarching role for noradrenaline in facing challenging situations in two complementary ways: by modulating behavioral volatility, which would facilitate adaptation depending on the lability of the environment, and by modulating the mobilization of resources to face immediate challenges. PMID- 29998352 TI - Three-dimensional versus two-dimensional laparoscopic right colectomy: a systematic review and meta-analysis. AB - BACKGROUND: Three-dimensional (3D) vision technology has recently been validated for the improvement of surgical skills in a simulated setting. Clinical studies on specific operations have been published in the field of general, urologic, and gynecologic laparoscopic surgery. We hypothesized that 3D vision laparoscopic right colectomy has better intra and short-term postoperative outcomes than two dimensional (2D) vision. AIM: The outcomes of this review and meta-analysis were to compare the 3D vision and the 2D vision laparoscopic right colectomy. METHODS: A systematic search of the literature was performed on Pubmed, WOS, Google Scholar, and Scopus databases (Prospero reg. nr. 42016047704) for comparative studies between 2D and 3D laparoscopic right colectomy. Primary endpoints were safety issues and secondarily patients' related and surgeons' comfort outcomes. Meta-analyses, when possible, were conducted with a random-effects model. RESULTS: Two retrospective comparative studies (for a total of 56 patients in the 2D arm and 52 patients for the 3D arm) were selected out of 680 screened records. Methodological quality was fair. Three-dimensional laparoscopic right colectomy has similar safety and secondary outcomes when compared to 2D, with not statistically significant shorter operating times (mean difference 11.81 min). The results are comparable also for anastomosis leakage. The results for other outcomes were not aggregated for heterogeneity. CONCLUSIONS: 3D laparoscopic right colectomy shows equivalent patients' outcomes compared to 2D operation, but the scarce clinical data and the potential amelioration of surgeons' skills, especially on difficult intracorporeal tasks like suturing, suggest the publication of further trials. PMID- 29998350 TI - Sound frequency affects the auditory motion-onset response in humans. AB - The current study examines the modulation of the motion-onset response based on the frequency-range of sound stimuli. Delayed motion-onset and stationary stimuli were presented in a free-field by sequentially activating loudspeakers on an azimuthal plane keeping the natural percept of externalized sound presentation. The sounds were presented in low- or high-frequency ranges and had different motion direction within each hemifield. Difference waves were calculated by contrasting the moving and stationary sounds to isolate the motion-onset responses. Analyses carried out at the peak amplitudes and latencies on the difference waves showed that the early part of the motion response (cN1) was modulated by the frequency range of the sounds with stronger amplitudes elicited by stimuli with high frequency range. Subsequent post hoc analysis of the normalized amplitude of the motion response confirmed the previous finding by excluding the possibility that the frequency range had an overall effect on the waveform, and showing that this effect was instead limited to the motion response. These results support the idea of a modular organization of the motion onset response with the processing of primary sound motion characteristics being reflected in the early part of the response. Also, the article highlights the importance of specificity in auditory stimulus design. PMID- 29998353 TI - Robot-guided neuromapping during nerve-sparing taTME for low rectal cancer. AB - PURPOSE: Intraoperative pelvic neuromapping with electrophysiological evaluation of autonomic nerve preservation during robotic total mesorectal excision (TME) for rectal cancer is conventionally performed by the bedside assistant with a hand-guided probe. Our goal was to return autonomy over the neuromonitoring process to the colorectal surgeon operating the robotic console. METHODS: A recently described prototype microfork electrostimulation probe was evaluated intraoperatively during abdominal robotic-assisted transanal TME (taTME) surgery for low rectal cancer in three consecutive male patients. RESULTS: An intraoperative video demonstrates the good control and maneuverability of the prototype probe with electrophysiological confirmation of bilateral pelvic autonomic nerve preservation. CONCLUSIONS: This study presents the first in situ application of a new microfork probe for fully robot-guided neuromapping in three patients undergoing TME surgery for low rectal cancer. PMID- 29998354 TI - Comparison of Robot-Assisted Versus Open Simple Prostatectomy for Benign Prostatic Hyperplasia. AB - PURPOSE OF REVIEW: Recent advancements in minimally invasive approaches for prostate surgery have provided numerous options for surgical management of benign prostatic hyperplasia (BPH). In the setting of a large prostate, an open simple prostatectomy was previously considered the gold standard surgical treatment. However, the recently updated American Urological Association (AUA) guidelines on surgical management of BPH now consider both open and minimally invasive approaches to simple prostatectomy viable alternatives for treating large glands, depending on expertise with the techniques. The purpose of our review is to discuss the minimally invasive robot-assisted approach and compare it to the classic open approach to simple prostatectomy. RECENT FINDINGS: Despite longer operative times, the robotic approach is associated with shorter hospital stay and lower morbidity profile. The morbidity of an open approach remains significant. Blood transfusions are 3-4 times as likely compared to a robotic approach and major complications are twice as likely. Consistent with previous literature, our review shows functional outcome improvements like flow rate and symptom score to be comparable between the robotic and open approach. The amount of adenoma resected and PSA decline is also similar among robotic and open cases. Robot-assisted simple prostatectomy is a safe and effective procedure for BPH secondary to a large prostate gland. Appropriately, it is no longer deemed "investigational" by the latest AUA guidelines on BPH and recommended as an alternative to the open approach. PMID- 29998355 TI - Efficacy of Nd-YAG laser for treatment of pyogenic granuloma on the fingers and toes. AB - Pyogenic granuloma (PG) is a common benign vascular proliferation which often occurs on the head, neck, hands, and feet. Among the various treatment options for PG, surgical excision is the most effective treatment which offers the lowest overall recurrence rates and also provides the exact diagnosis. However, it could have difficulties to do the surgery when lesions are located on the fingers and toes, especially very near to the nails, so laser may be a very good alternative choice. In this article, we evaluated the clinical efficacy and safety of neodymium-yttrium aluminum garnet (Nd:YAG) laser for treatment of PG located on the fingers and toes. Twenty-one patients with 21 PGs located on the fingers and toes were treated by multispot Nd-YAG laser. We chose monopulse (pulse width 10.5 13.5 ms; energy 100-125 J/cm2); treatment interval was 3-4 weeks. All lesions disappeared after one or two treatments. There was no apparent scar formation, no impact on the function of the fingers and toes, no damage to nail growth, and no recurrence in more than 12-month follow-up. Nd-YAG is an effective and safety treatment option for treatment of PG located on the fingers and toes. PMID- 29998356 TI - Low-level laser therapy (830 nm) on orthodontic pain: blinded randomized clinical trial. AB - The objective of this research was to compare the effect single low-level laser therapy (LLLT) irradiation on pain perception in patients having fixed appliance treatment in the clinic of orthodontics. Sixty-two patients were recruited to participate in this randomized, double-blinded, placebo-controlled study. The patients were assigned to four groups: group I-laser on the right side; group II placebo on the right side; group III-laser on the left side; group IV-placebo on the left. The laser or placebo was applied before separation, 24 and 48 h after separation of their first permanent molars in the lower arch. Just after the separation, the average of the pain for the placebo group was 1.6, significantly greater than the average of 1.1 registered for the laser group (p = 0.013). After 24 h and before the new irradiation, the values registered among the different groups did not show any differences. In relation to the gender, only after the first irradiation in placebo group, the female had a level of pain (0.1) significantly higher (p = 0.04) compared to male, and after 48 h, the group where the laser was applied had a difference (p = 0.04) among the gender with a value of lower pain for men (0.6) than for women (1.6).The laser irradiation to minimize the pain was only effective when applied immediately after treatment and separation. In general way, there were no differences between the genders, except after the first placebo group irradiation in which the female had a significantly higher level of pain compared to male and after 48 h. The pain cycle observed in this study had its peak in 24 h, both for laser's and placebo's group. PMID- 29998358 TI - Left Ventricular Diastolic Myocardial Stiffness and End-Diastolic Myofibre Stress in Human Heart Failure Using Personalised Biomechanical Analysis. AB - Understanding the aetiology of heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction requires knowledge of biomechanical factors such as diastolic myocardial stiffness and stress. Cine CMR images and intra-ventricular pressure recordings were acquired in 8 HFrEF, 11 HFpEF and 5 control subjects. Diastolic myocardial stiffness was estimated using biomechanical models and found to be greater in HFrEF (6.4 +/- 1.2 kPa) than HFpEF (2.7 +/- 0.6 kPa, p < 0.05) and also greater than control (1.2 +/- 0.4 kPa, p < 0.005). End-diastolic mid ventricular myofibre stress derived from the personalised biomechanics model was higher in HFrEF (2.9 +/- 0.3 kPa) than control (0.9 +/- 0.3 kPa, p < 0.01). Chamber stiffness, measured from the slope of the diastolic pressure-volume relationship, is determined by the intrinsic tissue properties as well as the size and shape of the heart, and was unable to distinguish between any of the three groups (p > 0.05). Personalised biomechanical analysis may provide more specific information about myocardial mechanical behaviour than global chamber indices, which are confounded by variations in ventricular geometry. PMID- 29998357 TI - A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models. AB - BACKGROUND: Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. METHODS: In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg with planar nuclear medicine imaging was used in a mechanically ventilated ovine model. To measure tobramycin concentrations by intravenous and nebulised tobramycin 400 mg (4 ml, 100 mg/ml) administration in the lung interstitial space (ISF) fluid and blood of mechanically ventilated sheep, the microdialysis technique was used over an 8-h duration. RESULTS: Tobramycin 100 mg/ml achieved a higher lung dose (121.3 mg) compared to 40 mg/ml (41.3 mg) solution. The imaging study with labelled tobramycin indicated that nebulised tobramycin distributed more extensively into each lung zone of the mechanically ventilated sheep than intravenous administration. A higher lung ISF peak concentration of tobramycin was observed with nebulised tobramycin (40.8 mg/l) compared to intravenous route (19.0 mg/l). CONCLUSIONS: The research methods appear promising to describe lung pharmacokinetics for formulations intended for nebulisation during mechanical ventilation. These methods need further validation in an experimental pneumonia model to be able to contribute toward optimising dosing regimens to inform clinical trials and/or clinical use. PMID- 29998359 TI - Optimal inspiratory pressure for face mask ventilation in paralyzed and unparalyzed children to prevent gastric insufflation: a prospective, randomized, non-blinded study. AB - BACKGROUND: Gastric insufflation is common during face mask ventilation and results in unfavourable respiratory events in children. The purpose of this study was to evaluate the effect of a muscle relaxant on gastric insufflation and determine the optimal inspiratory pressure during face mask ventilation in children. METHODS: Children aged one month to five years were randomly assigned to neuromuscular blocker (NM) or non-neuromuscular blocker (non-NM) groups. After administering intravenous anesthetics, face mask ventilation commenced via pressure-controlled mechanical ventilator. Initial inspiratory pressure was 10 cmH2O and was increased by 2 cmH2O until gastric insufflation was detected via gastric ultrasonography or epigastric auscultation. The primary outcome was the difference in the inspiratory pressure that causes gastric insufflation between the two groups. Diagnostic methods that detect gastric insufflation first were also evaluated. RESULTS: There was no significant difference in the median [interquartile range] inspiratory pressure inducing gastric insufflation between the non-NM (n = 52) and NM groups (n = 60) (18 [16-18] cmH2O vs 18.0 [16-20] cmH2O; median difference, 0 cmH2O; 95% confidence interval [CI], 0 to 2; P = 0.57). The incidence of gastric insufflation increased with increasing inspiratory pressure. Gastric insufflation was detected first by ultrasonography in 44% and by epigastric auscultation in 19% of the non-NM group (difference in percentage, 25%; 95% CI, 6 to 42; P = 0.006) and by ultrasonography in 73% and by epigastric auscultation in 7% of the NM group (difference in percentage, 66%; 95% CI, 50 to 78; P < 0.001). CONCLUSIONS: A neuromuscular blocking agent has minimal effect on the inspiratory pressure that causes gastric insufflation during face mask ventilation in children. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02471521); registered 15 June 2015. PMID- 29998360 TI - Correction to: Fungal Secretome Analysis Via PepSAVI-MS: Identification of the Bioactive Peptide KP4 from Ustilago maydis. AB - In the article "Fungal Secretome Analysis via PepSAVI-MS: Identification of the Bioactive Peptide KP4 from Ustilago maydis", acknowledgement of financial support was inadvertently omitted. The authors apologize for this oversight. PMID- 29998361 TI - Mass Spectral Detection of Forward- and Reverse-Hydrogen/Deuterium Exchange Resulting from Residual Solvent Vapors in Electrospray Sources. AB - Characterizing glycans is analytically challenging since glycans are heterogeneous, branched polymers with different three-dimensional conformations. Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) has been used to analyze native conformations and dynamics of biomolecules by measuring the mass increase of analytes as labile protons are replaced with deuterium following exposure to deuterated solvents. The rate of exchange is dependent on the chemical functional group, the presence of hydrogen bonds, pH, temperature, charge, and solvent accessibility. HDX-MS of carbohydrates is challenging due to the rapid exchange rate of hydroxyls. Here, we describe an observed HDX reaction associated with residual solvent vapors saturating electrospray sources. When undeuterated melezitose was infused after infusing D2O, samples with up to 73% deuterium exchange were detected. This residual solvent HDX was observed for both carbohydrates and peptides in multiple instruments and dependent on sample infusion rate, infusion time, and deuterium content of the solvent. This residual solvent HDX was observed over several minutes of sample analysis and persisted long enough to alter the measured deuterium labeling and possibly change the interpretation of the results. This work illustrates that residual solvent HDX competes with in-solution HDX for rapidly exchanging functional groups. Thus, we propose conditions to minimize this effect, specifically for top-down, in electrospray ionization, and quench-flow HDX experiments. Graphical Abstract ?. PMID- 29998362 TI - Simulation of Unidirectional Ion Ejection in an Asymmetric Half-Round Rod Electrode Linear Ion Trap Mass Analyzer. AB - An asymmetric trapping field was generated from an asymmetric half-round rod electrode linear ion trap (A-HreLIT), and its performance of unidirectional ion ejection was studied. Two different asymmetric structures of A-HreLITs were constructed, one rotating y electrode pairs toward an x electrode with an angle theta, and the other stretching one x electrode with a distance alpha. The center of trapping field was displaced away from the geometrical center of the ion trap, defined to be the midpoint along the axis of y between x electrodes, which leads to unidirectional ion ejection through one x electrode. Computer simulations were used to investigate the relationship between asymmetric geometric parameter of theta (or alpha) and analytical performance. Both structures could result in similar asymmetric trapping fields, which mainly composed of dipole, quadrupole, and hexapole fields. The dipole and hexapole fields were approximately proportional to the asymmetric geometric parameter of rotation angle theta (or stretch distance alpha). In simulation, ion trajectories and ion kinetic energy were calculated. For ions with m/z 609 Th, the simulation results showed that mass resolution of over 2400 (FWHM) and ion unidirectional ejection efficiency of nearly 90% were achieved in an optimized A-HreLIT. Ion detection efficiency of A HreLIT could be improved significantly with only one ion detector, while maintaining a considerable mass resolution. Furthermore, the A-HreLIT could be driven by a traditional balanced RF power supply. These advantages make A-HreLIT suitable for developing miniaturized mass spectrometer with high performance. Graphical Abstract ?. PMID- 29998363 TI - Large-Area Graphene Films as Target Surfaces for Highly Reproducible Matrix Assisted Laser Desorption Ionization Suitable for Quantitative Mass Spectrometry. AB - Due to the known sweet-spot issues that intrinsically arise from inhomogeneous formation of matrix-analyte crystals utilized as samples in matrix-assisted laser desorption ionization (MALDI) mass spectrometry, its reproducibility and thus its applications for quantification have been somewhat limited. In this paper, we report a simple strategy to improve the uniformity of matrix-analyte crystal spots, which we realized by adapting large-area graphene films, i.e., non-inert, interacting surfaces, as target surfaces. In this example, the graphitic surfaces of the graphene films interact with excess matrix molecules during the sample drying process, which induces spontaneous formation of optically uniform MALDI sample crystal layers on the film surfaces. Further, mass spectrometric imaging reveals that the visible uniformity is indeed accompanied by reproducible MALDI ionization over an entire sample spot, which greatly suppresses the appearance of sweet spots. The results of this study confirm that the proposed method achieves good linear responses of ion intensity to the analyte concentration (R2 > 0.99) with small relative standard deviations (sigma < 10%), which is a range applicable for quantitative measurements using MALDI mass spectrometry. Graphical Abstract ?. PMID- 29998364 TI - The marine natural product Scalarin inhibits the receptor for advanced glycation end products (RAGE) and autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. AB - Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Although combination therapies are showing improvements in treatment, the survival rate for pancreatic cancer five years post diagnosis is only 8%, stressing the need for new treatments. The receptor for advanced glycation end products (RAGE) has recently emerged as a chemotherapeutic target in KRAS driven pancreatic cancers both for treatment and in chemoprevention. RAGE appears to be an important regulator of inflammatory, stress and survival pathways that lead to carcinogenesis, resistance to chemotherapy, enhanced proliferation and the high metastatic potential of pancreatic cancer. RAGE expression has been demonstrated in pancreatic cancer tumors but not in adjacent epithelial tissues. Its presence is associated with increased proliferation and metastasis. In an effort to identify novel inhibitors of RAGE among our collection of marine-derived secondary metabolites, a cell-based screening assay utilizing flow cytometry was developed. This effort led to the identification of scalarin as the active compound in a marine sponge identified as Euryspongia cf. rosea. Scalarin is a sesterterpene natural product isolated previously from a different marine sponge. Scalarin reduces the levels of RAGE and inhibits autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. Its IC50 for cytotoxicity ranges between 20 and 30 MUM in the AsPC-1, PANC-1, MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. Inhibition of autophagy limits tumor growth and tumorigenesis in pancreatic cancer, making scalarin an interesting compound that may merit further study. PMID- 29998365 TI - Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial. AB - Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m2 bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis. Circulating tumor cells (CTCs) were determined pretherapeutically by immunohistochemical identification after enrichment with immunomagnetic separation. Results Thirty patients were evaluable at six dose levels. 900 mg/m2 bid were determined as MTD for capecitabine based on dose-limiting toxicities: cutaneous in two patients and vascular in another. The most severe (Grade (G)3/4) drug-related treatment-emergent adverse events (toxicities) belonged to the categories gastrointestinal, vascular, cutaneous, cardiovascular, metabolic/nutritional or hematological. G3 toxicities occurred in 14 (47%), G3 + G4 in a single (3%) patient. 2 out of 28 patients (7%) exerted partial response, 17 (61%) stable disease. Pharmacokinetic evaluation revealed lack of drug-drug interaction between capecitabine and erlotinib and their metabolites. Presence of CTCs was associated with shorter progression-free survival (p = 0.009). Conclusions The study met the primary objective. RP2D was capecitabine 800 mg/m2 bid continuously, erlotinib 150 mg daily, and bevacizumab 10 mg/kg q 2 weeks. The regimen could be applied safely, but demonstrated limited efficacy. PMID- 29998366 TI - Development of aptamer fluorescent switch assay for aflatoxin B1 by using fluorescein-labeled aptamer and black hole quencher 1-labeled complementary DNA. AB - Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins and draws great concern in health and food safety. A DNA aptamer against AFB1 having a stem-loop structure shows high binding affinity to AFB1 and promise in assay development for AFB1 detection. Based on the structure-switching property of the aptamer, we report an aptamer fluorescence assay for AFB1 detection. Aptamer with fluorescein (FAM) label at 5' end was used as affinity ligand, while its short complementary DNA (cDNA) with BHQ1 (black hole quencher 1) label at 3' end was used as a quencher. In the absence of AFB1, FAM-labeled aptamer hybridized with BHQ1 labeled cDNA, forming a duplex of cDNA and aptamer, resulting in fluorescence quenching of FAM. When AFB1 bound with aptamer, the BHQ1-labeled cDNA was displaced from aptamer, causing fluorescence restoration of FAM. We tested a series of FAM-labeled aptamers and BHQ1-labeled cDNAs with different lengths. The lengths of the aptamer stem and the cDNA, Mg2+ in binding buffer, and temperature had significant influence on the performance of the assay. Under optimized conditions, we achieved sensitive detection of AFB1 by using a 29-mer FAM-labeled aptamer and a 14-mer BHQ1-labeled cDNA, and the detection limit of AFB1 reached 0.2 nM. The maximum fluorescence recovery rate of FAM-labeled aptamer caused by AFB1 was about 69-fold. This method enabled the detection of AFB1 in complex sample matrix, e.g., diluted wine samples and maize flour samples. This aptamer based fluorescent assay for AFB1 determination shows potential for broad applications. Graphical abstract ?. PMID- 29998367 TI - A complementary forensic 'proteo-genomic' approach for the direct identification of biological fluid traces under fingernails. AB - Violent contact between individuals during a crime can result in body fluids becoming trapped under the fingernails of the individuals involved. The traces under fingernails represent valuable forensic evidence because DNA profiling can indicate from whom the trace originated and proteomic methods can be used to determine the type of fluid in the trace, thus providing evidence as to the circumstances surrounding the crime. Here, we present an initial study of an analytical strategy that involves two complementary techniques, direct PCR DNA profiling and direct mass spectrometry-based protein biomarker detection, for the comprehensive examination of traces of biological fluids gathered from underneath fingernails. With regard to protein biomarker detection, direct MALDI-ToF MS/MS is very sensitive, allowing results to be obtained from biological material present on only a few fibres plucked from a microswab used to collect the traces. Human cornulin, a protein biomarker for vaginal fluid, could be detected up to 5 h after it had been deposited under fingernails whereas haemoglobin, a biomarker for blood, is somewhat more persistent under fingernails and could be detected up to 18 h post-deposition. Bottom-up tandem mass spectrometry techniques were used to provide a high level of confidence in assigning the identity of protein biomarkers. nLC-ESI-qToF MS/MS offered higher levels of confidence and the ability to detect traces that had been present under fingernails for longer periods of time, but this performance came with the cost of longer analysis time and a more laborious sampling approach. Graphical abstract ?. PMID- 29998368 TI - Serum BAFF and APRIL levels in Indian patients with Takayasu arteritis. AB - Despite many studies focused on involvement of T cell in pathogenesis of Takayasu arteritis (TaK), very few have explored the role of B cells. Hence, we sought evidence of B cell involvement in a large cohort of TaK by measuring serum levels of B cell survival factors activation factor (BAFF) and A proliferation inducing ligand (APRIL). Serum BAFF and APRIL levels were measured by ELISA in 50 patients and 48 healthy individuals, and further assessed for correlation with outcome measures, such as Indian Takayasu Clinical Activity Score-ESR (ITAS-ESR) and Takayasu arteritis Damage score (TADS). Forty women and ten men of median age 26 (11-52) and disease duration of 3 years (0.1-22) were studied. Type V disease was the most common subset (n = 31), while type I, II, III, and IV was seen in ten, four, three, and two patients respectively. Serum APRIL levels were raised in patients as compared to healthy controls [2087.5 pg/ml (1480.0-2279.0) vs. 1288.64 pg/ml, (844.2-1632.9) p = 0.01]. Median serum APRIL level was also raised in patients with active disease (n = 24) as compared to inactive disease (n = 26) 2098.79 pg/ml, (1930.75-2768.75) vs. 1802.5 pg/ml, (1066.75-2098); p = 0.03). Serum BAFF levels were not raised in patients with TaK when compared to healthy Individuals. Neither BAFF, nor APRIL levels correlated with disease activity (ITAS-ESR) or TADS. Elevated APRIL levels in active TaK suggest probable role of B cells in pathogenesis. PMID- 29998369 TI - Decreased serum thrombospondin-1 and elevation of its autoantibody are associated with multiple exacerbated clinical manifestations in systemic lupus erythematosus. AB - The pathological effects of thrombospondin-1 (TSP-1) have been studied in many preclinical tumor models and rheumatoid arthritis. However, the role of TSP-1 and anti-thrombospondin-1 autoantibodies (ATSA) in systemic lupus erythematosus (SLE) has not been specifically defined. In this study, we investigated the clinical relevance and functional significance of TSP-1 and ATSA in SLE patients. Serum levels of TSP-1 and ATSA were measured by ELISA in 138 adult SLE patients and 60 healthy controls. Blood cell counts, rheumatoid factor (RF), immunoglobulins, erythrocyte sedimentation rate (ESR), complements, and SLE-related autoantibodies were measured by standard laboratory techniques. Disease activity was assessed by systemic lupus erythematosus disease activity index (SLEDAI). TSP-1 concentrations were significantly lower in SLE patients compared with those in healthy controls. A significant difference of TSP-1 was observed in the patients with serositis, C3 decrease, RF positive, leukocytopenia, and thrombocytopenia. The levels of TSP-1 showed a positive correlation with the number of leukocyte and thrombocyte, while a negative correlation with anti-dsDNA antibody, IgG, ESR, and SLEDAI. ATSA was observed in 58.7% (81/138) of SLE patients, which was significantly higher than that in healthy controls (7/60, p < 0.05). Patients with active SLE showed higher ATSA positivity (67.1%) than those with inactive disease (47.1%, p < 0.05). ATSA was positively correlated with anti-rRNP antibody, IgG, total protein, and C4. This study revealed the opposite clinical relevance of TSP-1 and its autoantibody in SLE for the first time. TSP-1 may play an anti-inflammatory and immunoregulatory role in SLE autoimmunity. ATSA increased more frequently in disease-active patients and was associated with more severe clinical manifestations, which implicated its antagonistic role on TSP-1 and its involvement in the pathogenesis of SLE. PMID- 29998370 TI - Characteristics of Dapagliflozin Responders: A Longitudinal, Prospective, Nationwide Dapagliflozin Surveillance Study in Korea. AB - INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors, such as dapagliflozin, have demonstrated favorable effects in patients with type 2 diabetes (T2D). However, there are limited reports in the literature regarding the glucose-lowering effects of SGLT2 inhibitors in actual clinical settings. METHODS: The post-marketing surveillance data from a longitudinal prospective study of 2007 patients with T2D who were prescribed dapagliflozin (10 mg/day) were analyzed (ClinicalTrials.gov, NCT02252224). RESULTS: After 12 weeks of dapagliflozin treatment, glycated hemoglobin (HbA1c) and body mass index were significantly decreased (P < 0.001) from 8.1 +/- 1.3% to 7.5 +/- 1.2% and from 28.1 +/- 4.4 to 27.6 +/- 4.2 kg/m2, respectively. Both body weight and HbA1c were reduced in 67.7% of patients, and HbA1c was lowered in 75.1%. Younger age, male sex, shorter diabetes duration, higher baseline HbA1c and estimated glomerular filtration rate (eGFR), and having dapagliflozin as add-on therapy were associated with stronger HbA1c reductions after dapagliflozin use (all P < 0.05). Moreover, subgroup analysis of eGFR of subjects with renal hyperfiltration (eGFR >= 120 ml/min/1.73 m2) showed the largest reduction in glucose level (% change, - 9.5; 95% CI - 6.8 to - 12.3 for HbA1c; P < 0.001). Multivariable logistic regression analysis showed that recent T2D diagnosis and higher HbA1c at baseline in patients who received an add-on regimen of dapagliflozin were statistically significantly associated with a dapagliflozin response (all P < 0.05). CONCLUSIONS: Dapagliflozin provides benefits for glycemic control and body weight. Patients in a relatively early stage of the course of diabetes with renal hyperfiltration might be more suitable for and gain maximal benefit from dapagliflozin treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02252224. FUNDING: AstraZeneca. PMID- 29998371 TI - Recent update on basic mechanisms of spinal cord injury. AB - Spinal cord injury (SCI) is a life-shattering neurological condition that affects between 250,000 and 500,000 individuals each year with an estimated two to three million people worldwide living with an SCI-related disability. The incidence in the USA and Canada is more than that in other countries with motor vehicle accidents being the most common cause, while violence being most common in the developing nations. Its incidence is two- to fivefold higher in males, with a peak in younger adults. Apart from the economic burden associated with medical care costs, SCI predominantly affects a younger adult population. Therefore, the psychological impact of adaptation of an average healthy individual as a paraplegic or quadriplegic with bladder, bowel, or sexual dysfunction in their early life can be devastating. People with SCI are two to five times more likely to die prematurely, with worse survival rates in low- and middle-income countries. This devastating disorder has a complex and multifaceted mechanism. Recently, a lot of research has been published on the restoration of locomotor activity and the therapeutic strategies. Therefore, it is imperative for the treating physicians to understand the complex underlying pathophysiological mechanisms of SCI. PMID- 29998373 TI - Icterus and abdominal pain: an unexpected, rare sonographic finding in a Peruvian Emergency Department. AB - BACKGROUND: The use of point-of-care ultrasound (POCUS) has become increasingly important in resource-limited settings. It can rapidly diagnose both tropical infectious diseases and more common pathology at the bedside. In these practice settings, POCUS can have a significant impact on management strategies and patient care. Ultrasonography has been the gold standard for the diagnosis and staging of Echinococcus disease. However, even in the "classic" clinical scenario and setting, the clinician must maintain a broad differential diagnosis. Point-of care ultrasound can be helpful in performing the rapid diagnosis and therefore direct appropriate treatment strategies based on the results. CASE PRESENTATION: We present a case of a 27-year-old woman presenting to an emergency department in Peru with jaundice and abdominal pain. Initially given the region of her origin, the working diagnosis was an Echinococcus cyst. However, when POCUS was performed, the findings were not consistent with hydatid disease. Ultimately, surgical pathology revealed a choledochal cyst, a rare finding in adulthood. CONCLUSIONS: This case initially appears as a "classic" finding of Echinococcus disease. It is important for the clinician sonographer to appreciate the features consistent with Echinococcus cysts and distinguish from those features that are more consistent with other pathology. PMID- 29998372 TI - A comprehensive and precise set of intervarietal substitution lines to identify candidate genes and quantitative trait loci in oilseed rape (Brassica napus L.). AB - KEY MESSAGE: A set of intervarietal substitution lines were developed in rapeseed by recurrent backcrossing and marker-assisted selection and employed for mapping both qualitative and quantitative traits. Intervarietal substitution lines (ISLs) may be assembled into advanced secondary mapping populations that have remarkable potential for resolving trait loci and mapping candidate genes. To facilitate the identification of important genes in oilseed rape (canola, Brassica napus), we developed 89 ISLs using an elite cultivar 'Zhongyou 821' (ZY821) as the recipient and a re-synthesized line 'No.2127' as the donor. In the whole process of ISLs development, the target chromosome segments were selected based on the genotypes of 300 microsatellite markers evenly distributed across the genome. Eighty-nine ISLs fixed at BC5F4 were genotyped by sequencing using double digestion to survey the lengths of target substitution segments from the donor parent and the background segments from the recurrent parent. The total length of the substituted chromosome segments was 3030.27 Mb, representing 3.56 * of the Darmor bzh reference genome sequence (version 4.1). Gene mapping was conducted for two qualitative traits, flower colour and seed-coat colour, and nine quantitative traits including yield- and quality-related traits, with 19 QTLs identified for the latter. Overlapping substitution segments were identified for flower colour and seed-coat colour loci, as well as for QTLs consistently detected in 2 or 3 years. These results demonstrate the value of these ISLs for locus resolution and subsequent cloning, targeted mutation or editing of genes controlling important traits in oilseed rape. PMID- 29998374 TI - Synthesis and structure-activity relationship of N-(piperidin-4-yl)benzamide derivatives as activators of hypoxia-inducible factor 1 pathways. AB - Guided by bioisosterism and pharmacokinetic parameters, we designed and synthesized a series of novel benzamide derivatives. Preliminary in vitro studies indicated that compounds 10b and 10j show significant inhibitory bioactivity in HepG2 cells (IC50 values of 0.12 and 0.13 MUM, respectively). Compounds 10b and 10j induced the expression of HIF-1alpha protein and downstream target gene p21, and upregulated the expression of cleaved caspase-3 to promote tumor cells apoptosis. PMID- 29998376 TI - The Effects of Interprofessional Education in Mental Health Practice: Findings from a Systematic Review. AB - OBJECTIVE: The aim of this study was to conduct a systematic review of studies describing the effects of interprofessional education (IPE) on undergraduate healthcare students' educational outcomes, compared with conventional clinical training in mental health. METHODS: MEDLINE, CINAHL, PsychINFO, and EMBASE were searched for studies published in January 2001-August 2017. All retrieved papers were assessed for methodological quality; Kirkpatrick's model was employed to analyze and synthesize the included studies. The following search terms were used: undergraduate, interprofessional education, and educational outcomes. RESULTS: The eight studies that met the inclusion criteria were highly diverse regarding the studied IPE interventions, methods, and outcomes. Participants included students receiving clinical training in mental health from the following professions: medicine, nursing, occupational therapy, physiotherapy, psychology, and social work. The results of the studies suggest that students respond well to IPE in terms of more positive attitudes toward other professions and improvement in knowledge and collaborative skills. Limited evidence of changes in behavior, organizational practice, and benefits to patients was found. CONCLUSION: Based on the eight included studies, IPE interventions appear to have an impact regarding positive attitudes toward other professions and increased knowledge of and skills in collaboration compared to conventional clinical training. However, further study of both the processes and the long-term impacts of undergraduate IPE in mental health is needed. The authors recommend that service users are involved in the implementation and evaluation of IPE interventions in mental health to undergraduate healthcare students. PMID- 29998375 TI - Microenvironmental derived factors modulating dendritic cell function and vaccine efficacy: the effect of prostanoid receptor and nuclear receptor ligands. AB - Dendritic cells (DCs) are widely used in DC-based immunotherapies because of their capacity to steer immune responses. So far treatment success is limited and more functional knowledge on how DCs initiate and stably drive specific responses is needed. Many intrinsic and extrinsic factors contribute to how DCs skew the immune response towards immunity or tolerance. The origin and type of DC, its maturation status, but also factors they encounter in the in vitro or in vivo microenvironment they reside in during differentiation and maturation affect this balance. Treatment success of DC vaccines will, therefore, also depend on the presence of these factors during the process of vaccination. Identification and further knowledge of natural and pharmacological compounds that modulate DC differentiation and function towards a specific response may help to improve current DC-based immunotherapies. This review focuses on factors that could improve the efficacy of DC vaccines in (pre-)clinical studies to enhance DC-based immunotherapy, with a particular emphasis on compounds acting on prostanoid or nuclear receptor families. PMID- 29998377 TI - Impact of Nesiritide Infusion on Early Postoperative Recovery After Total Cavopulmonary Connection Surgery. AB - OBJECTIVE: The purpose of the study is to compare the effects of nesiritide on the discharge time and pleural effusion in children with total cavopulmonary connection (TCPC), and to provide a more reasonable clinical method for these children. METHODS: Forty-four who children underwent cavopulmonary connection between January 2016 and 2017 were retrospectively collected, and 5 children were excluded from analysis due to postoperative thrombosis or second Fontan surgery due to high pulmonary hypertension. Thirteen children received nesiritide (3-11 days) plus conventional treatment as the nesiritide group, continuous infusion of nesiritide with the dose of 0.01 ug kg-1 min-1. Twenty-six children with the conventional treatment as the conventional treatment group. The length of stay in hospital and the retention time of chest drainage tube were compared between two groups. RESULTS: There were no significant differences in the time of cardiopulmonary bypass, postoperative ventilation time, ICU time, and vasoactive inotropic drug scores in the two groups. There were no hospital deaths in two groups. The median hospital stay was 20 days in the nesiritide group (11-56 days, means 25 days), and the median length of hospital stay was 28 days in the routine treatment group (9-95 days, means 34 days). There is no statistically significant difference between two groups with regard to the length of stay in hospital (P = 0.281). Regarding the thoracic drainage duration, the median was 17 days (9-55 days, means 22 days) in the nesiritide group and 23 days in the conventional treatment group (7-91 days, means 31 days) (P = 0.294). All the patients had no severe complications such as excessive fluid load, intractable hypotension, and liver or kidney injury. CONCLUSION: Nesiritide is safe in children who underwent cavopulmonary connection surgery. Compared with the conventional treatment group, postoperative nesiritide is not associated with improved early clinical outcomes after TCPC surgery. PMID- 29998378 TI - Impact of workplace bullying on missed nursing care and quality of care in the eldercare sector. AB - PURPOSE: To analyze the long-term impact of bullying among healthcare providers (T1) on missed nursing care and quality of care 2 years later (T2) and to test the potential mediating effect of affective organizational commitment. METHODS: Survey data from healthcare providers in the eldercare sector in 2006 (T1) and 2008 (T2). At T1, 9212 employees participated in the survey and 5202 participated in both T1 and T2. Including only participants who were directly engaged in the provision of care yielded 4000 providers, who were employed in 268 workgroups at T1 and T2. Associations between exposure to bullying (predictor) and the two outcomes (missed nursing care and quality of care) were investigated using multi level linear regression analysis. Included covariates were age, gender, job position, work place and tenure. RESULTS: We found a significant association between workplace bullying at T1 and missed nursing care at T2 but not for quality of care at T2. Affective organizational commitment did not mediate the association between bullying and the two outcomes. However, affective organizational commitment at T1 was associated with quality of care at T2. CONCLUSION: Exposure to bullying at work may cause the provider to miss nursing care for clients. To improve, care administrators should consider implementing bullying prevention strategies at three levels: organizational, work group and individual. PMID- 29998380 TI - A cell culture device equipped with a micro-needle electrode array fabricated using backside exposure mold and resin casting. AB - A cell culture device equipped with a micro-needle electrode array was fabricated for the signal analysis of cell spheroids, cell masses, and cell sheets. For the analysis, sharp needle electrodes with a high aspect ratio for facilitating easy penetration into the cell mass and a small pitch for fine spatial resolution were required. Microelectromechanical systems (MEMS) technology is one of the common solutions for the fabrication of devices. However, an additional process, such as anisotropic etching or electro-polishing, is required for fabricating sharp needles. Tapered needles were fabricated using backside exposure for coating a layer of thick resist film on a glass substrate. The incident beam from mask apertures were diffracted and attenuated in the medium, resulting in tapered intensity distribution. A needle-like shape was obtained after performing resist development without using additional MEMS process. In this study, the theoretical analysis of optical intensity distribution and design and fabrication process of the device were described. Finally, the effectiveness of the device was evaluated by adding cultured cell mass on the needle array. Signals with spikes and fluctuations were observed in the electrode covered with cell mass, whereas only noise was observed on the non-covered electrode, demonstrating the signal pick-up ability of the device during cell culture. PMID- 29998379 TI - The complexity of mitochondrial outer membrane permeability and VDAC regulation by associated proteins. AB - Previous studies have shown that class II beta-tubulin plays a key role in the regulation of oxidative phosphorylation (OXPHOS) in some highly differentiated cells, but its role in malignant cells has remained unclear. To clarify these aspects, we compared the bioenergetic properties of HL-1 murine sarcoma cells, murine neuroblastoma cells (uN2a) and retinoic acid - differentiated N2a cells (dN2a). We examined the expression and possible co-localization of mitochondrial voltage dependent anion channel (VDAC) with hexokinase-2 (HK-2) and betaII tubulin, the role of depolymerized betaII-tubuline and the effect of both proteins in the regulation of mitochondrial outer membrane (MOM) permeability. Our data demonstrate that neuroblastoma and sarcoma cells are prone to aerobic glycolysis, which is partially mediated by the presence of VDAC bound HK-2. Microtubule destabilizing (colchicine) and stabilizing (taxol) agents do not affect the MOM permeability for ADP in N2a and HL-1 cells. The obtained results show that betaII-tubulin does not regulate the MOM permeability for adenine nucleotides in these cells. HL-1 and NB cells display comparable rates of ADP activated respiration. It was also found that differentiation enhances the involvement of OXPHOS in N2a cells due to the rise in their mitochondrial reserve capacity. Our data support the view that the alteration of mitochondrial affinity for ADNs is one of the characteristic features of cancer cells. It can be concluded that the binding sites for tubulin and hexokinase within the large intermembrane protein supercomplex Mitochondrial Interactosome, could be different between muscle and cancer cells. PMID- 29998381 TI - Use of Opioid Analgesics Before and After Gastric Bypass Surgery in Sweden: a Population-Based Study. AB - BACKGROUND: Little is known regarding the use of opioid analgesics among patients who have undergone bariatric surgery. The Roux-en-Y gastric bypass (RYGB) procedure has been shown to significantly increase the rate of absorption of and exposure to morphine, raising concerns regarding the potentially increased risk of side-effects and the development of substance-use disorder. OBJECTIVES: The aim of this study was to describe the pattern of opioid use over time following RYGB and to see if the pattern differs between patients with a high opioid consumption (HOC) prior to surgery and those with a low consumption (LOC). SETTING: University Hospital of Orebro, Sweden. METHODS: The study was a descriptive retrospective population-based cohort study where two registers with complete coverage were cross-matched. RESULTS: The study population comprised 35,612 persons (1628 HOC, and 33,984 LOC). After surgery, the number of HOC patients increased to 2218. Mean daily opioid consumption in the total population and the LOC group increased after surgery (p < .0005). In the HOC group, there was no difference between mean daily consumption before and after surgery. CONCLUSION: In this nationwide study, we have showed that there is an increase in consumption of opioid analgesics after gastric bypass surgery in Sweden. The increase in the number of individuals with high opioid consumption in the total population was mainly due to an increase in the group of patients with a low consumption prior to surgery. PMID- 29998382 TI - Separation and purification of alpha-ketoglutarate and pyruvate from the fermentation broth of Yarrowia lipolytica. AB - A strategy to achieve the efficient co-production of alpha-ketoglutarate (KGA) and pyruvate (PYR) via Yarrowia lipolytica fermentation was established in our previous work. The next big challenge is to achieve an efficient separation of the two keto acids. A strategy for simultaneously separating and purifying KGA and PYR based on their different boiling points was established, leading to the efficient separation and purification of the two keto acids from the fermentation broth of Y. lipolytica. The purity and yield of KGA/PYR reached 99.3/99.5 and 79.8/80.6%, respectively. Application of the separation method on industrial scale could further decrease the cost of the production of the two keto acids by biotechnological routes. PMID- 29998383 TI - "If One Does Not Fulfil His Duties, He Must Not Be a Man": Masculinity, Mental Health and Resilience Amongst Sri Lankan Tamil Refugee Men in Canada. AB - Refugee men face unique mental health stressors in the pre- and post-migratory periods. However, there has been little in-depth research on the mental health of refugee men in Canada. Given this situation, the overall aim of this study is to explore the psycho-social experience of Sri Lankan Tamil refugee men in Canada. Particular objectives include better understanding any inter-relationship between war-trauma, migration, concepts of masculinity and mental health. The study employed a two-phase participatory action research design based on the grounded theory approach. Phase 1 involved an 8-month ethnography conducted in Sri Lanka. Phase 2 consisted of qualitative interviews with 33 Sri Lankan Tamil refugee men living in Canada. Consistent with grounded theory, analysis was conducted inductively and iteratively. Four specific themes emerged from the data (i) gendered helplessness of war: participants commonly reported ongoing negative rumination regarding experiences where they were unable to adequately protect loved ones from physical suffering or death; (ii) reduced capacity: participants frequently felt unable to fulfill culturally sanctioned duties, such as supporting their family, due to ongoing pre- and post-migratory stress; (iii) redundancy: many participants felt that they were useless in Canada, as they could not fulfill typical masculine social roles (e.g. provider) due to factors such as unemployment and underemployment; (iv) intimate criticism: some participants reported that their spouses would often attempt to 'shame' them into greater achievement by constantly reminding them of their 'failures'. Many found this distressing. These various failures culminated in a state that we label "depleted masculinity", which participants linked to emotional and behavioural problems. Participants reported that they actively tried to rebuild their masculine identity, for example by adopting leadership roles in community organizations, which fostered resiliency. Results suggest a need to review and rebuild masculine identity to support the mental health of refugee men. PMID- 29998384 TI - Magic Moments: Determinants of Stress Relief and Subjective Wellbeing from Visiting a Cultural Heritage Site. AB - We provide an experimental evaluation of the impact of aesthetic experiences in terms of stress reduction (cortisol levels) and wellbeing increase. The test experience is a visit to the vault of the Sanctuary of Vicoforte, Italy. Data have been collected using a double step method. A structured interview in relation to the individual subjective well-being has been administered to a sample of 100 subjects. In addition, a sample of their saliva has been taken, and its cortisol level measured, before and after the experience, and likewise for momentary wellbeing measured on a Visual Analogous Scale. Subjects reported an average increase of 40% in wellbeing and a decrease of the 60% in the cortisol level. The recorded cortisol level values dropped on average well beyond the decrease normally associated to its circadian cycle. The modulating role of various variables has been appreciated, and profiling of the typical subjects who are wellbeing respondents/non-respondents and cortisol respondents/non respondents has been carried out. We conclude that aesthetic experience seems to have a noticeable impact on individual physical and mental health. In both dominions, cultural participation intensity is significantly correlated to the response. The study underlines the potential of the arts and culture as a new platform for public health practices and new approaches to welfare policy design. PMID- 29998385 TI - Prognosis of septic cavernous sinus thrombosis remarkably improved: a case series of 12 patients and literature review. AB - PURPOSE: Septic cavernous sinus thrombosis (CST) is a rare complication of infections in the head and neck area. CST is notorious for its bad prognosis, with high mortality and morbidity rates described in literature. However, these rates are based on old series. We question whether the prognosis of CST is currently still as devastating. The primary purpose of this study is to assess the mortality and morbidity of CST. METHODS: Using the databases of all relevant specialties in our tertiary referral hospital, we collected all the patients treated for CST in the period 2005-2017. In addition, a PubMed search, using the mesh term 'cavernous sinus thrombosis', was performed. RESULTS: We found 12 patients with CST in the study period. Of the 12 patients, 11 survived and 9 recovered without any permanent deficits. Seven patients were treated with anticoagulation, and in none of the patients we saw hemorrhagic complications. In literature, older articles describe higher mortality rates (14-80%), but more recent articles report mortality and morbidity rates similar to our results. CONCLUSIONS: The prognosis of CST nowadays is more favorable than previously described. Anticoagulation seems to be a safe addition to antibiotic and surgical treatment, at least in patients without central nervous system infection. PMID- 29998386 TI - A microwell culture system that allows group culture and is compatible with human single media. AB - PURPOSE: A microwell culture system that facilitates group culture, such as well of-the-well (WOW), improves embryonic development in an individual culture. We examined the effect of WOW on embryonic development in vitro with commercially available human single culture media. METHODS: Using four different commercial human single culture media, in vitro development and imprinted gene expression of bovine embryos cultured in WOW were compared to droplet culture (one zygote per drop). To determine the effects of microwell and group culture on embryonic development, different numbers of embryos were cultured in droplet or WOW. Diffusion simulation of accumulating metabolites was conducted using the finite volume method. RESULTS: WOW had a positive effect on bovine embryonic development, regardless of the type of single culture media. Imprinted gene expression was not different between droplet- and WOW-derived blastocysts. The microwell and group cultures in WOW showed a significant positive effect on the rate of total blastocysts and the rate of development to the expanded and hatching blastocyst stages. The assumed cumulative metabolite concentration of WOW with one embryo was 1.47 times higher than that of droplet culture with one embryo. Furthermore, the concentration of WOW with three embryos was 1.54 times higher than that of WOW with one embryo. CONCLUSIONS: In using human single culture media, a microwell culture system that allows group culture could be a powerful clinical tool for improving the success of assisted reproductive technologies. PMID- 29998387 TI - Follicular factors determining granulosa cell number and developmental competence of porcine oocytes. AB - PURPOSE: Granulosa cell (GC) number in follicles is a simple characteristic of follicles. The present study examined the hypothesis that follicular fluid (FF) determines GC number and oocyte developmental ability and revealed the molecular background determining the number of follicular GCs. METHODS: FF was collected from antral follicles (3-5 mm in diameter), after which the number of GCs per follicle was determined for each donor gilt using real time PCR targeting single copy gene. GCs were analyzed by next-generation RNA sequencing and IPA pathway analysis. RESULTS: When oocyte cumulus cell-oocyte-complexes (COCs) were cultured in maturation medium containing 10% of each individual FF, the rate of development to the blastocyst stage was significantly correlated with the number of GCs in the donor gilt. In addition, when GCs were cultured in medium containing FF, the proliferative activity of the GCs was also significantly correlated to the number of GCs in the donor gilt. Moreover, when the FFs were categorized based on the number of GCs in the follicle, it was found that supplementation of culture media with GC-rich FF improved the developmental ability of oocytes compared to those supplemented with GC-poor FF. RNA sequencing and a pathway analysis of GCs from GC-rich and -poor follicles revealed the key regulatory pathway determining GC number in follicles. CONCLUSION: GC number may be a useful marker for "good" follicles and oocytes, and the characteristics of the FFs determine granulosa cell number and oocyte developmental ability. PMID- 29998389 TI - NSAID administration post colorectal surgery increases anastomotic leak rate: systematic review/meta-analysis. AB - BACKGROUND: Current enhanced recovery guidelines suggest that opioid sparing medications should be used for analgesia whenever possible following colorectal surgery. The present study aims to assess whether post-operative NSAID use is associated with an increased anastomotic leak rate after a colonic or rectal anastomosis. METHODS: A systematic review was performed for studies investigating anastomotic leak rate following NSAID use vs control after colonic or rectal anastomosis. Meta-analysis was performed to assess for overall risk of anastomotic leak with NSAID use, as well as sub-group analysis to compare selective vs non-selective NSAIDs and drug-specific NSAID safety profiles. RESULTS: Seven studies were included in the final review. Use of an NSAID post operatively was associated with an overall increased risk of anastomotic leakage [OR 1.58 (1.23, 2.03), P = 0.0003]. Non-selective NSAIDs were associated with an increased risk [OR 1.79 (1.47, 2.18), P < 0.00001], but selective NSAIDs were not. The non-selective NSAID diclofenac was associated with an increased leak rate [OR 2.79 (1.96, 3.96), P < 0.00001], but ketorolac was not [OR 1.36 (0.89, 2.06), P = 0.16]. CONCLUSIONS: Great caution must be taken when prescribing NSAIDs following colonic or rectal anastomotic creation. The safety profile varies within the NSAID class and further research is needed to clarify which NSAIDs are safe for use and which are not. PMID- 29998388 TI - Examination of novel Aureobasidium pullulans isolates dominating apple microflora and assessing their potential for apple juice spoilage. AB - There is very little up to date information regarding apple microflora so in the current study we decided to address that issue and assess whether dominant fungi which reside in fruit might spoil apple juice. Microorganisms were isolated from apples of Koksa Gorska harvested in the middle of October in 2016 and 2017. Identification of isolates was based on the sequencing of ribosomal DNA. Some isolates were characteristic for a particular year but in both years apple microflora was dominated by Aureobasidium pullulans. Based on phylogenetic analysis it was stated that only one isolate (LW81) was closely related to strains which are already described in available databases. All other isolates collected in the current study differed significantly from sequences stored in databases, tending to form a common cluster. It was possible to predict secondary structure of ITS2 region only for the isolate LW81, while we managed to establish the length and location of 5.8S gene in Rfam database for all sequences. A. pullulans is known exopolysaccharide producer so obtained microorganisms were tested for their ability to synthesise those substances on Czapek-Dox agar. The strain which proved to be the most significant exopolysaccharide producer (isolate LW14) was inoculated in the sterilised apple juice at three different initial cell number (100, 1000 and 10,000 cfu/ml) and subjected to pasteurisation. In all cases pasteurisation eliminated fungal growth effectively, therefore A. pullulans strains should not pose any risk to the quality of pasteurised apple juices. PMID- 29998390 TI - Outcomes of laparoscopic management of multicompartmental pelvic organ prolapse. AB - BACKGROUND: Pelvic organ prolapse (POP) is an increasing medical problem with complex diagnostics and controversial surgical management. It causes a series of dysfunctions in the gynecological, urinary, and anorectal organs. Numerous procedures have been proposed to treat these conditions, but in recent years, ventral mesh rectocolposacropexy (VMRCS) has emerged as the procedure of choice for the surgical treatment of POP, especially by a laparoscopic approach. This surgical technique limits the risk of autonomic nerve damage, and the colpopexy allows the correction of concomitant prolapse of the middle compartment. However, symptoms derived from anterior compartment prolapse remain a major morbidity and sometimes require an additional procedure. The aim of this study is to evaluate the results of laparoscopic prosthetic rectocolposacropexy (LRCS) and colposacropexy (LCS) procedures performed to manage combined multicompartmental POP. METHODS: Between November 2008 and December 2017, 38 patients with symptomatic POP underwent rectocolposacropexy (RCS) or colposacropexy (CS) by a laparoscopic approach. Demographics, mortality, morbidity, hospital stay, and functional outcomes were retrospectively analyzed. RESULTS: The median operating time was 200 min (IQR 160-220). Additional simultaneous surgery for POP was performed in nine cases: five suburethral slings and four hysterectomies were performed. No mortality was recorded. The conversion rate was 7.89%. There were two intraoperative complications (5.26%): one enterotomy and one urinary bladder tear. Late complications occurred in 5.26% of cases. After a mean follow-up of 20 months, constipation was completely resolved or improved in 83.33% of patients, urinary stress incontinence was resolved or improved in 52.94%, and gynecological symptomatology was resolved or improved in 93.75%. The recurrence rate was 5.26%. CONCLUSIONS: Laparoscopic mesh rectocolposacropexy and colposacropexy are safe and effective techniques associated with very low morbidity. In the medium term, they provide good results for POP and associated symptoms, but urinary symptomology has a worse outcome. PMID- 29998391 TI - Defining the learning curve for transanal total mesorectal excision for rectal adenocarcinoma. AB - BACKGROUND: Early observational data suggest that this approach is safe and feasible, but it is technically challenging and the learning curve has not yet been determined. The objective of this study was to determine the number of cases required achieve proficiency in transanal total mesorectal excision (TA-TME) for rectal adenocarcinoma. METHODS: All TA-TME cases performed from 03/2012-01/2017 at a single high-volume tertiary care institution for rectal adenocarcinoma were included. A cumulative summation (CUSUM) analysis was performed to determine the number of cases required to reach proficiency, defined as high-quality TME (complete or near-complete mesorectal envelope, negative distal (DRM), and circumferential resection (> 1 mm; CRM) margin). The acceptable and unacceptable rates of good quality TME were defined based on the incidence of high-quality TME in laparoscopic (unacceptable rate = 81.7%) and open (acceptable rate = 86.9%) arms of the ACOSOG Z6051 trial. RESULTS: A total of 87 consecutive cases were included with mean tumor height 4.8 cm (SD 2.7) and 80% (70/87) received neoadjuvant chemoradiation. Post-operative morbidity occurred in 44% (38/87) of cases, including 21% (18/87) readmissions. Median length of stay was 4 days [IQR 3-8]. A good quality TME was performed in 95% (83/87) of cases including 98% (85/87) negative CRM, 99% (86/87) negative DRM, and 99% (86/87) complete or near complete mesorectal envelope. CUSUM analysis reported that the good quality TME rate reaches an acceptable rate after 51 cases overall, and 45 cases if abdominoperineal resections are excluded. CONCLUSION: TA-TME is a complex technique that requires a minimum of 45-51 cases to reach an acceptable incidence of high-quality TME and lower operative duration. PMID- 29998392 TI - Reduced port minimally invasive distal pancreatectomy: single-port laparoscopic versus robotic single-site plus one-port distal pancreatectomy. AB - BACKGROUND: Minimally invasive surgery appears to be developing in multiple directions, including single-port laparoscopic (SPL), single-port robotic, reduced port laparoscopic, or single-site plus one-port robotic approach. The aim of study was to compare the short-term perioperative variables and outcomes of patients undergoing reduced port minimally invasive distal pancreatectomy (DP) via the SPL, or robotic single-site plus one-port (RSS + 1) approach. METHODS: The medical records of 35 patients were retrospectively reviewed, who underwent SPL-DP (n = 22) or RSS + 1 DP (n = 13) at Korea University Ansan Hospital and Yonsei University Severance Hospital. RESULTS: The mean operation time in SPL group was significantly higher than that of RSS + 1 group (281 vs 192, p = .001). The mean blood loss in SPL was significantly larger than that of RSS + 1 group (163 vs 12, p = .002). The mean length of free resection margin in SPL group was significantly longer than that of RSS + 1 group (2.1 vs 0.4 cm, p = .001). Spleen was significantly preserved in SPL group (54.5 vs 7.7%, p = .001). All RSS + 1 cases had tumors located near spleen hilum (p < .001). SPL approach had significantly grade IIIa complications (p = .014). Moreover, the mean hospital stay in SPL group was significantly longer than that of RSS + 1 group (14.4 vs 7.4 days, p = .004). Postoperative pancreatic fistula (POPF) was significantly observed in longer operation time (p = .043) and smaller tumor size (p = .037) in the univariate analysis. Higher BMI was significantly important factor for prolonged operation time (p = .034) in the multivariate analysis. Prolonged hospital stay was related to spleen preservation (p = .014) in the multivariate analysis. CONCLUSIONS: Both SPL and RSS + 1 are technically feasible and safe. RSS + 1-DP is superior to SPL-DP in terms of operation time, blood loss, severe complications, and hospital stay. SPL-DP shows advantages in terms of single wound site, less trocar usage, higher rate of spleen preservation, and wider range of operative field. PMID- 29998393 TI - Preoperative anemia: a common finding that predicts worse outcomes in patients undergoing primary hiatal hernia repair. AB - BACKGROUND: The increased incidence of anemia in patients with hiatal hernias (HH) and resolution of anemia after HH repair (HHR) have been clearly demonstrated. However, the implications of preoperative anemia on postoperative outcomes have not been well described. In this study, we aimed to identify the incidence of preoperative anemia in patients undergoing primary HHR at our institution and sought to determine whether preoperative anemia had an impact on postoperative outcomes. METHODS: Using our IRB-approved institutional HH database, we retrospectively identified patients undergoing primary HHR between January 2011 and April 2017 at our institution. We identified patients with anemia, defined as serum hemoglobin levels less than 13 mg/dL in men and 12 mg/dL in women, measured within two weeks prior to surgery, and compared this group to a cohort of patients with normal preoperative hemoglobin. Perioperative outcomes analyzed included estimated blood loss (EBL), operative time, perioperative blood transfusions, failed postoperative extubation, intensive care unit (ICU) admission, postoperative complications, length of stay (LOS), and 30-day readmission. Outcomes were compared by univariable and multivariable analyses, with significance set at p < 0.05. RESULTS: We identified 263 patients undergoing HHR. The median age was 66 years and most patients were female (78%, n = 206). Seventy patients (27%) were anemic. In unadjusted analyses, anemia was significantly associated with failed postoperative extubation (7 vs. 2%, p = 0.03), ICU admission (13 vs. 5%, p = 0.03), postoperative blood transfusions (9 vs. 0%, p < 0.01), and postoperative complications (41 vs. 18%, p < 0.01). On adjusted multivariable analysis, anemia was associated with 2.6-fold greater odds of postoperative complications (OR 2.57; 95% CI 1.36-4.86; p < 0.01). CONCLUSIONS: In this study, anemia had a prevalence of 27% in patients undergoing primary HHR. Anemic patients had 2.6-fold greater odds of developing postoperative complications. Anemia is common in patients undergoing primary HHR and warrants consideration for treatment prior to elective repair. PMID- 29998394 TI - Robotic-assisted unilateral adrenalectomy: risk factors for perioperative complications in 303 consecutive patients. AB - BACKGROUND: There is no consensus about the utility of using the robotic platform to perform a unilateral lateral transabdominal adrenalectomy in comparison with conventional laparoscopy. In some groups, obese patients (Body Mass Index > 30 kg/m2) and patients with tumor size > 5 cm have been considered as good candidates for robotic adrenalectomy. However, evaluation of incidence and risk factors for perioperative complications is currently lacking in large series of patients. The aim of this study was to evaluate incidence and predictive factors for intraoperative (conversion and capsular rupture) and postoperative complications (morbidity) after unilateral robotic-assisted transabdominal lateral adrenalectomy. METHODS: From 2001 to 2016, consecutive patients undergoing unilateral lateral transabdominal robotic adrenalectomy were included in a prospectively maintained database and analyzed retrospectively (clinicaltrials.gov NCT03410394). RESULTS: A total of 303 consecutive patients were analyzed. Between the first and last 100 of patients, mean tumor size increased from 2.9 to 4.2 cm (p < 0.001) and mean operating time decreased from 99 to 77 min (p < 0.001). Postoperative complications occurred in 28 patients (9.2%) and no postoperative death was observed. Nine patients (3%) were converted to open laparotomy and capsular rupture was observed in nine patients (3%). BMI was not a significant risk factor for conversion, capsular rupture, or postoperative complication. Tumor size > 5 cm remained the only predictive factor for conversion to laparotomy (OR 7.47, 95% CI 1.81-30.75; p = 0.005). History of upper gastrointestinal surgery was the only predictive factor for capsular rupture (OR 13.6, 95% CI 2.33-80.03; p = 0.004). Conversion to laparotomy (OR 8.35, 95% CI 1.99-35.05; p = 0.003) and patient age (OR 1.039, 95% CI 1.006 1.072; p = 0.019) remained independent predictive factors for postoperative complications. CONCLUSIONS: This study identified independent risk factors for perioperative complications after robotic-assisted unilateral adrenalectomy. These factors should be taken into account when evaluating robotic-assisted transabdominal lateral adrenalectomy. PMID- 29998395 TI - A comparison of short-term outcomes between laparoscopic and open emergent repair of perforated peptic ulcers. AB - BACKGROUND: We compared 30-day outcomes in patients undergoing emergent open and laparoscopic repair of perforated peptic ulcers in a large multicenter cohort. METHODS: Prospectively obtained data in the American College of Surgeons National Surgical Quality Improvement Program public use files from 2010 to 2016 were reviewed. Perioperative risks and outcomes were compared in unmatched and propensity-matched groups using parametric/non-parametric statistical tests as appropriate. RESULTS: A total of 4210 procedures were identified 345 (8.2%) laparoscopic and 3865 (91.8%) open. Laparoscopic repairs increased from 4.5% of 2010 cases to 11.4% of 2016 cases (p < .001). Open repair patients had more acute presentation including higher rates of ASA class, hypoalbuminemia, preoperative septic shock, dyspnea, and mechanical ventilation (all p < .01). Laparoscopic operations were longer than open procedures (p < .001). Mortality (8.5 vs. 3.5%), median length of stay (7 vs. 5 days), transfusion rates (13.7 vs. 7.0%), renal failure (3.7 vs. 1.2%), and respiratory failure (15.5 vs. 5.2%) were all worse in the unmatched open group (all p < .01). Propensity matching resulted in 342 laparoscopic and 626 open cases of similar ulcer type, demographics, ASA class, preoperative SIRS/sepsis, hypoalbuminemia, and wound class. Mortality was similar between matched groups (5.0 vs. 3.5%, p = .331). Median length of stay was longer in the open group (6 vs. 5 days, p < .001), which also had higher rates of prolonged ventilation/reintubation (9.6 vs. 5.3%, p = .019) and abdominal wall wound occurrences (6.2 vs. 2.3%, p = .042). Return to the operating room and 30 day readmissions did not differ between the matched groups. CONCLUSIONS: Emergent laparoscopic repair of perforated peptic ulcer is increasingly being performed, is safe relative to open repair (in patients without preoperative septic shock), and confers a modest benefit in terms of length of stay, respiratory, and abdominal wall wound complications. PMID- 29998396 TI - Gliomatosis cerebri: a consensus summary report from the Second International Gliomatosis cerebri Group Meeting, June 22-23, 2017, Bethesda, USA. AB - Gliomatosis cerebri (GC) is an aggressive glioma characterized by an invasive growth pattern and a dismal prognosis. The low incidence and non-specific symptoms at presentation pose unique challenges for early diagnosis and disease specific research. There is no standard of care for the treatment of patients with a GC phenotype. Understanding the biology of this entity is a critical step in determining effective treatments. Toward this end, the Second International GC Group convened at National Institutes of Health, Bethesda on June 22nd-23rd 2017. This paper summarizes the main conclusions and recommendations for research priorities to fight this fatal condition. PMID- 29998397 TI - Epigenetic Control of the Notch and Eph Signaling Pathways by the Prion Protein: Implications for Prion Diseases. AB - Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrPC molecules are converted into abnormally folded scrapie isoforms termed PrPSc. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrPC as a critical relay of prion induced neuronal cell demise. A current consensual view is that the conversion of PrPC into PrPSc in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrPC. We further show that both prion infection and PrPC depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrPC-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms. PMID- 29998398 TI - Inhibition of the Nrf2/HO-1 Axis Suppresses the Mitochondria-Related Protection Promoted by Gastrodin in Human Neuroblastoma Cells Exposed to Paraquat. AB - Mitochondria are double-membrane organelles involved in the transduction of energy from different metabolic substrates into adenosine triphosphate (ATP) in mammalian cells. The oxidative phosphorylation system is comprised by the activity of the respiratory chain and the complex V (ATP synthase/ATPase). This system is dependent on oxygen gas (O2) in order to maintain a flux of electrons in the respiratory chain, since O2 is the final acceptor of these electrons. Electron leakage from this complex system leads to the continuous generation of reactive species in the cells. The mammalian cells exhibit certain mechanisms to attenuate the consequences originated from the constant exposure to these reactive species. In this context, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and one of the enzymes whose expression is modulated by Nrf2, heme oxygenase-1 (HO-1), take a central role in inducing cytoprotection in humans. Mitochondrial abnormalities are observed during intoxication and in certain diseases, including neurodegeneration. Mitochondrial protection promoted by natural compounds has attracted the attention of researchers due to the promising effects these agents induce experimentally. In this regard, we examined here whether and how gastrodin (GAS), a phenolic glucoside, would prevent the paraquat (PQ)-induced mitochondrial impairment in the SH-SY5Y cells. The cells were exposed to GAS (25 MUM) for 4 h prior to the challenge with PQ at 100 MUM for additional 24 h. The silencing of Nrf2 by siRNA or the inhibition of HO-1 by ZnPP IX suppressed the GAS-elicited cytoprotection. Therefore, GAS promoted mitochondrial protection by an Nrf2/HO-1-dependent manner. PMID- 29998399 TI - SPECT/CT Imaging of Mycobacterium tuberculosis Infection with [125I]anti-C3d mAb. AB - PURPOSE: Diagnosis and therapeutic monitoring of chronic bacterial infection requires methods to detect and localize sites of infection accurately. Complement C3 activation fragments are generated and covalently bound to selective bacterial pathogens during the immune response and can serve as biomarkers of ongoing bacterial infection. We have developed several probes for detecting tissue-bound C3 deposits, including a monoclonal antibody (mAb 3d29) that recognizes the tissue-bound terminal processing fragments iC3b and C3d but does not recognize native circulating C3 or tissue-bound C3b. PROCEDURES: To determine whether mAb 3d29 could be used to detect chronic Mycobacterium tuberculosis infection non invasively, aerosol-infected female C3HeB/FeJ mice were injected with [125I]3d29 mAb and either imaged using single-photon emission computed tomography (SPECT)/X ray computed tomography (CT) imaging at 24 and 48 h after radiotracer injection or being subjected to biodistribution analysis. RESULTS: Discrete lesions were detected by SPECT/CT imaging in the lungs and spleens of infected mice, consistent with the location of granulomas in the infected animals as detected by CT. Low-level signal was seen in the spleens of uninfected mice and no signal was seen in the lungs of healthy mice. Immunofluorescence microscopy revealed that 3d29 in the lungs of infected mice co-localized with aggregates of macrophages (detected with anti-CD68 antibodies). 3d29 was detected in the cytoplasm of macrophages, consistent with the location of internalized M. tuberculosis. 3d29 was also present within alveolar epithelial cells, indicating that it detected M. tuberculosis phagocytosed by other CD68-positive cells. Healthy controls showed very little retention of fluorescent or radiolabeled antibody across tissues. Radiolabeled 3d29 compared with radiolabeled isotype control showed a 3.5:1 ratio of increased uptake in infected lungs, indicating specific uptake by 3d29. CONCLUSION: 3d29 can be used to detect and localize areas of infection with M. tuberculosis non-invasively by 24 h after radiotracer injection and with high contrast. PMID- 29998400 TI - Long-term experience with setup and implementation of an IHE-based image management and distribution system in intersectoral clinical routine. AB - PURPOSE: Sharing of medical data is crucial for the proper treatment of patients as it could reduce the risk of duplicated medical tests and speed up the care process if all documents are readily available. Despite great technical progress, sharing patient data while maintaining full control over the process in an intersectoral (in Germany, this describes the different actors in the healthcare system consisting of clinic, ambulatory care, etc.) setting remains a particular challenge. This paper focuses on the successful implementation of a privacy compliant, standards-based image-management component of a personal electronic health record. METHODS: Over a 5-year period, a sharing system based on readily available IHE profiles constructed around XDS has been built. It was necessary to create interfaces for the existing hospital sub-systems to become part of the network. Specifically, the imaging workflow had to be adapted to allow for fast and easy access to DICOM images utilizing a flexible web-based image viewer. In addition to the standard XDS workflow, an Imaging Cache was established which combines the Imaging Document Source and Consumer to guarantee fast and streaming based access to all images in the network observing the high security standards of the hospital network. RESULTS: The authors of this paper have proven that it is possible to build a fast and reliable sharing system based on IHE profiles using most of the transactions of XDS-I with some adaptions to the clinical workflow. Primary hospital systems were enabled by building adapters to overcome lack of IHE compatibility. The established system embraces the existing security mechanisms in hospital networks while connecting patients and referring physicians from outside in a secure and convenient manner. CONCLUSIONS: A state of-the-art sharing system that is used in a productive clinical environment has been established and is ready to grow with more partners. The system is the basis for an elaborated interdisciplinary collaboration where data, and in particular images, can now be shared between medical professionals. PMID- 29998401 TI - Colors of night: climate-morphology relationships of geometrid moths along spatial gradients in southwestern China. AB - Color lightness of insects is an important ecological trait affecting their performance through multiple functions such as thermoregulation, UV protection and disease resistance. The geographical pattern of color lightness in diurnal insects are relatively well understood and largely driven by thermal melanism through the enhancement of insect activity. In nocturnal insects, however, the ecological function of color lightness in response to climatic factors is poorly understood, particularly at small spatial scales. In this study, we investigated color lightness of nocturnal moth assemblages along environmental gradients. Using geometrid moths collected with comparable methodologies (light trapping), we examined assemblage-level changes in color lightness across elevational gradients and vertical strata (canopy vs understory) across three climatically different locations in Yunnan, China. The results showed that moths are darker in color at higher elevations. Such patterns are most apparent in canopy assemblages. In addition, the strength of the elevational pattern on color lightness varied across location, being most pronounced in the canopy of the subalpine site. These patterns are likely driven by UV protection and/or thermoregulation. Our study highlights the importance of abiotic factors such as temperature and solar radiation in structuring morphological patterns of nocturnal ectothermic assemblages along elevational gradients of climatically harsh environments. PMID- 29998402 TI - High levels of abiotic noise in volatile organic compounds released by a desert perennial: implications for the evolution and ecology of airborne chemical communication. AB - Plants release airborne volatile organic compounds (VOCs) in response to abiotic and biotic stimuli, including herbivory. These chemicals are used by insect parasitoids as sources of information that aid in finding hosts. It is unclear how biotic and abiotic factors interact to affect blend composition and the ability of insects to interpret signals. Here, we present a novel stimulus-space model, and use it to examine patterns of VOC emission. In field experiments, we manipulated herbivory levels and collected VOCs in a population of wild Datura wrightii, while simultaneously measuring key abiotic factors. We mirrored field experiments under controlled conditions in the lab, and used both sets of data to test predictions made by our proposed model. VOC blends were structured mainly by variation in abiotic factors, not herbivory. However, linear discriminant analysis showed that it is possible to distinguish different herbivory levels. We show that most compounds produced by D. wrightii are invariant, or respond solely to environmental variation or herbivory. Our results suggest that blend composition may be under selection for noise reduction, to maximize responses from potential receivers, and that abiotic variation can act as potentially strong sources of noise in chemical communication displays. PMID- 29998403 TI - Hepatic encephalopathy changes mitochondrial dynamics and autophagy in the substantia nigra. AB - Hepatic encephalopathy (HE) has been reported in more than 40% of patients with cirrhosis in clinical practice. HE changes mitochondrial dysfunction. Mitochondrial dynamics and autophagy are important for maintaining and removing damaged mitochondria. We used molecular biology and morphology methods to evaluate changes in mitochondrial dynamics and autophagy of the substantia nigra (SN) and prefrontal cortex (PFC) in HE. In this study, we observed that HE increased mitochondrial dynamics and autophagy in the SN, which was not seen in the PFC. HE stimulated dynamin-related protein 1 (DRP1) transformation from the cytosolic to the mitochondria within SN cells, which increased mitochondrial fission and the number of mitochondria. The fusion protein L-OPA1 (long isoforms of OPA1) was increased in the SN of HE mice. HE also increased the levels of autophagy proteins PINK1/PARKIN and P62/LC3-B in the SN, which can selectively remove damaged mitochondria and cell, respectively. Additionally, we used electron microscopy to directly observe changes in mitochondrial morphology in the SN of HE mice and found the number of mitochondria was increased. However, there were no significant changes in the fission, fusion or autophagy proteins in PFC-purified mitochondrial proteins in HE mice. The number of mitochondria also did not show alterations in the PFC of HE mice compared with that in a sham group. These results illustrate that mitochondria can protect themselves by changing the dynamics and autophagy in the SN of HE mice. Changes in the mitochondrial dynamics and autophagy related to HE can help repair damaged mitochondria and provide a further understanding of the mechanisms of hepatic encephalopathy. PMID- 29998404 TI - Cetacea are natural knockouts for IL20. AB - The Cetacea infraorder comprises a very unique group within the mammalian lineage. While sharing common ancestors with terrestrial mammals, their exclusive dependence on aquatic environments makes them attractive models to explore the landscape of molecular shifts in radical habitat transitions. Among their diverse anatomical and physiological solutions, we find detectable genetic remodeling of the immune system. In agreement, here we show that the gene sequence of interleukin-20 (IL20) displays unambiguous signs of inactivation with several disruptive mutations, including stop codons, insertions, and a conserved trans species mutation abolishing a canonical splice site, in nine analyzed cetacean genomes. Considering the suggested role of IL20 in skin immunity processes, including inflammation, epithelization, and remodeling, we propose that gene inactivation follows specific adaptations of cetacean skin to the aquatic environment, in frame with the less-is-more hypothesis. PMID- 29998406 TI - Risk Factors for Postoperative Chylothorax After Radical Subtotal Esophagectomy. AB - BACKGROUND: Chylothorax is one of the complications of esophagectomy for esophageal cancer. The treatment of this condition has been well discussed, but the risk factors for postoperative chylothorax remain unclear. METHODS: A retrospective review of 294 patients who underwent esophagectomy for esophageal cancer was conducted. These were patients with squamous cell carcinoma or adenocarcinoma of the esophagus including Siewert type I tumor of the esophagogastric junction who underwent subtotal esophagectomy with two-field or three-field lymphadenectomy. Of these, 24 patients who were diagnosed with chylothorax as a postoperative complication were allocated to the chylothorax group and the other 270 patients were allocated to the nonchylothorax group. RESULTS: Univariate analysis showed a significant difference in three factors: resection of thoracic duct, post-chemoradiotherapy, and high intraoperative fluid balance. Multivariate analysis revealed that post-chemoradiotherapy [hazard ratio (HR) = 3.430; 95% confidence interval (CI) 1.364-8.625] and high intraoperative fluid balance (HR = 1.569; 95% CI 1.2.7-2.039) were independent factors predicting chylothorax. In addition, resection of the thoracic duct may be a predictor of chylothorax after esophagectomy (HR = 3.389; 95% CI 0.941-12.201, p = 0.062). Receiver operating characteristic curve analysis of intraoperative fluid revealed that the sensitivity was 62.5%, specificity was 74.1%, and the cutoff value was 6.55 mL/kg/h. CONCLUSIONS: This study revealed that post chemoradiotherapy and high intraoperative fluid balance are predictors of chylothorax after esophagectomy. The elucidation of clinicopathological factors that can predict the incidence of chylothorax will help to establish more effective perioperative management for esophageal cancer patients. PMID- 29998407 TI - Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark. AB - BACKGROUND: An estimated 5-10% of breast and ovarian cancers are due to hereditary causes such as hereditary breast and ovarian cancer (HBOC) syndrome. Medicare, the third-party payer that covers 44 million patients in the United States, has implemented a set of clinical criteria to determine coverage for the testing of the BRCA1 and BRCA2 genes. These criteria, developed to identify carriers of BRCA1/2 variants, have not been evaluated in the panel testing era. This study investigated a series of Medicare patients undergoing genetic testing for HBOC to determine the efficacy of genetic testing criteria in identifying patients with hereditary risk. METHODS: This study retrospectively examined de identified data from a consecutive series of Medicare patients undergoing genetic testing based on personal and family history of breast and gynecologic cancer. Ordering clinicians indicated whether patients did or did not meet established criteria for BRCA1/2 genetic testing. The genetic test results were compared between the group that met the criteria and the group that did not. Patients in families with known pathogenic (P) or likely pathogenic (LP) variants were excluded from the primary analysis. RESULTS: Among 4196 unique Medicare patients, the rate of P/LP variants for the patients who met the criteria for genetic testing was 10.5%, and for those who did not, the rate was 9% (p = 0.26). CONCLUSIONS: The results of this study indicate that a substantial number of Medicare patients with clinically actionable genetic variants are being missed by current testing criteria and suggest the need for significant expansion and simplification of the testing criteria for HBOC. PMID- 29998408 TI - Correction to: Organized simultaneous displays facilitate learning of complex natural science categories. AB - The affiliation for Dr. Paulo F. Carvalho is listed incorrectly in this paper, The correct affiliation is Carnegie Mellon University, Pittsburgh, PA, USA. PMID- 29998405 TI - 3D Printing in Pharmaceutical and Medical Applications - Recent Achievements and Challenges. AB - Growing demand for customized pharmaceutics and medical devices makes the impact of additive manufacturing increased rapidly in recent years. The 3D printing has become one of the most revolutionary and powerful tool serving as a technology of precise manufacturing of individually developed dosage forms, tissue engineering and disease modeling. The current achievements include multifunctional drug delivery systems with accelerated release characteristic, adjustable and personalized dosage forms, implants and phantoms corresponding to specific patient anatomy as well as cell-based materials for regenerative medicine. This review summarizes the newest achievements and challenges of additive manufacturing in the field of pharmaceutical and biomedical research that have been published since 2015. Currently developed techniques of 3D printing are briefly described while comprehensive analysis of extrusion-based methods as the most intensively investigated is provided. The issue of printlets attributes, i.e. shape and size is described with regard to personalized dosage forms and medical devices manufacturing. The undeniable benefits of 3D printing are highlighted, however a critical view resulting from the limitations and challenges of the additive manufacturing is also included. The regulatory issue is pointed as well. PMID- 29998410 TI - Steroid phosphate esters and phosphonosteroids and their biological activities. AB - Steroid phosphate esters are very rare natural lipids that have been comparatively recently isolated from fractions of polar lipids of marine sponges and starfish. These steroids exhibit interesting biological activities. When using the PASS computer program, we showed that many of steroid phosphate esters showed antifungal, antihypercholesterolemic, anesthetic, and other activities with a confidence of 73 to 93%. In addition, some of them can be used as inhibitors of cholesterol synthesis and show hepatoprotection properties. Phosphonosteroids demonstrate antineoplastic and antihypercholesterolemic activities with a certainty of 85 to 90%. And also, they can be used as ovulation inhibitors or female steroid contraceptives with confidence from 86 to 98%. PMID- 29998409 TI - Effects of histone acetyltransferase inhibitors on L-DOPA-induced dyskinesia in a murine model of Parkinson's disease. AB - Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6 hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD. PMID- 29998411 TI - Copper and palladium nanostructures: a bacteriogenic approach. AB - Copper nanoparticles (CuNPs) and palladium nanoparticles (PdNPs) have attracted wide attention owing to their multifaceted utility in catalysis, sensors, and biomedical applications. Their therapeutic spectrum includes anticancer, antiviral, antibacterial, antifungal, antidiabetic, antioxidant potential which rationalizes the exploration of diverse physical, chemical, and biological routes for fabrication. In this article, we focused on bacterium-assisted design of nanostructured copper and palladium for applications in therapy against multidrug resistant pathogens, dehalogenation of diatrizoate, Heck coupling of iodobenzene, polymer electric membrane fuel cell, metal recovery, and electronic waste management. Further, hypothesis behind microbial synthesis of PdNPs in E. coli containing [NiFe] hydrogenase Hyd-1 is discussed. Similarly, detailed mechanism of synthesis and stabilization in Cyanobacteria is also documented. Both CuNPs and PdNPs act as potent chemotherapeutic agents that can further be enhanced by conjugation with drugs and/or fluorophores and ligands for simultaneous diagnosis and targeted drug delivery to the cancer site or infection. These bacteriogenic nanoparticles can be used in sensors and pollution control. PMID- 29998412 TI - Enhancing catalytic stability and cadaverine tolerance by whole-cell immobilization and the addition of cell protectant during cadaverine production. AB - A whole-cell (cadaverine-producing strain, Escherichia coli AST3) immobilization method was developed for improving catalytic activity and cadaverine tolerance during cadaverine production. Cell-immobilized beads were prepared by polyvinyl alcohol (PVA) and sodium alginate (SA) based on their advantages in biocatalyst activity recovery and mechanical strength. The following optimal immobilization conditions were established using response surface methodology: 3.62% SA, 4.71% PVA, 4.21% CaCl2, calcification, 12 h, and freezing for 16 h at - 80 degrees C, with a cell concentration of 0.3% (g dry cell weight (DCW) per 100 mL) of immobilized beads. After a 2-h bioconversion, the immobilized beads maintained 85% of their original biocatalyst activity, which was 1.8-fold higher than that of free cells. Furthermore, the effects of cell protectants on immobilized biocatalyst activity were examined by fed-batch bioconversion experiments. The results showed that the addition of polyvinylpyrrolidone (PVP) into the immobilized matrix effectively protected biocatalyst activity, with 95% of the relative activity remaining after the 2-h bioconversion. The performance of PVA SA-PVP-immobilized E. coli AST3 showed continuous production of cadaverine, with an average cadaverine yield of 29 +/- 1 g gDCW-1 h-1 after 12 h, suggesting that this method is capable of industrial scale cadaverine production. PMID- 29998413 TI - Evidence for the participation of an extra alpha-helix at beta-subunit surface in the thermal stability of Co-type nitrile hydratase. AB - Nitrile hydratase (NHase) has attracted considerable attention since it can efficiently catalyze the hydration of nitriles to valuable amides. However, the poor stability of NHase is one of the main drawbacks in the industrial application. In this study, we compared the structural difference between Fe-type and Co-type NHase and found that an extra alpha helix existed at the beta-subunit surface of Co-type NHase (defined as the beta-6th helix). Then, the effects of the beta-6th helix were investigated on the thermal stability and the catalytic kinetics of a Co-type NHase from Aurantimonas manganoxydans ATCC BAA-1229 (NHase1229). When the beta-6th helix was deleted or disrupted, the thermal stability of NHase1229 was reduced to 17.6 and 12.9% of that of wild NHase1229, respectively. Thus, the beta-6th helix is important for the thermal stability of Co-type NHase. Based on the structural characteristics of Co-type NHase, the beta 6th helix may be interacted with another helix at the alpha-subunit (defined as the alpha-2nd helix) by hydrophobic network just as a "magnetic suction buckle" on the enzyme surface to stabilize the binding of alpha- and beta-subunits. The beta-6th helix is located at the mouth of the substrate and product tunnel, so it plays crucial roles in catalytic process. Furthermore, the beta-6th helix in NHase1229 was swapped with a thermophilic NHase fragment from Pseudonocardia thermophila JCM3095 (NHase1229-Swap). The thermal stability of NHase1229-Swap was significantly improved, and the half-life was approximately 2.4-fold at 40 degrees C than that of the wild NHase1229. The knowledge is useful for improving the stability of NHases by restriction fragment swapping. PMID- 29998414 TI - Xenoligophoroides cobitis (Ergens, 1963) n. g., n. comb. (Monogenea: Ancyrocephalidae), a parasite of Gobius cobitis Pallas (Perciformes: Gobiidae) from the Mediterranean and Black seas. AB - Based on an integrative taxonomic approach, combining morphological characters and partial sequences of the nuclear 28S rRNA gene, a new genus and combination for the species Xenoligophoroides cobitis (Ergens, 1963) is proposed, to accommodate ancyrocephalid monogeneans, parasites on the gills of Gobius cobitis Pallas (Gobiidae) from the western Mediterranean Sea and the northern Black Sea. A morphological comparison of newly collected material with the descriptions of Ancyrocephalus cobitis Ergens, 1963 and Haliotrema cupensis Sasal, Pages & Euzet, 1998, recently synonymised and named as Haliotrema cobitis (Ergens, 1963), confirms their similarity and belonging to the same species. However, characters of this species, as the vas deferens not looping the caecal branch, the bilobed base of the male copulatory organ and the marginal hooks with an upright thumb, do not correspond to the diagnosis of Haliotrema Johnston & Tiegs, 1922. Morphologically, this species is close to members of Ligophorus Euzet & Suriano, 1977 and Kriboetrema Sarabeev, Rubtsova, Yang & Balbuena, 2013, but differs from the former in the accessory piece articulated with MCO and two prostatic reservoirs, and from the latter in the uncoiled MCO with bilobed base and the dextral vaginal pore. Moreover, all species of Ligophorus and Kriboetrema are parasites of grey mullets. A 28S rDNA-based phylogenetic analysis of sequences derived from specimens of X. cobitis from the Mediterranean and Black seas, along with sequences from several closely related genera of the Ancyrocephalidae, suggested the occurrence of a new taxonomic unit, which corresponded to the X. cobitis specimens. This finding supports the establishment of the new genus for the ancyrocephalid parasites on the gills of G. cobitis from the western Mediterranean Sea and the northern Black Sea. PMID- 29998415 TI - A Numerical Preoperative Planning Model to Predict Arterial Deformations in Endovascular Aortic Aneurysm Repair. AB - Endovascular aneurysm repair is rapidly emerging as the primary preferred method for treating abdominal aortic aneurysm. In this image-guided interventional procedure, to obtain the roadmap and decrease contrast injections, preoperative CT images are overlaid onto live fluoroscopy images using various 2D/3D image fusion techniques. However, the structural changes due to the insertion of stiff tools degrade the fusion accuracy. To correct the mismatch and quantify the intraoperative deformations, we present a patient-specific biomechanical model of the aorto-iliac structure and its surrounding tissues. The predictive capability of the model was evaluated against intraoperative data for a group of four patients. Incorporating the perivascular tissues into the model significantly improved the results and the mean distance between the real and simulated endovascular tools was 2.99 +/- 1.78 mm on the ipsilateral side and 4.59 +/- 3.25 mm on the contralateral side. Moreover, the distance between the deformed iliac ostia and their corresponding landmarks on intraoperative images was 2.99 +/- 2.48 mm. PMID- 29998416 TI - Impact of Retriever Passes on Efficacy and Safety Outcomes of Acute Ischemic Stroke Treated with Mechanical Thrombectomy. AB - BACKGROUND AND PURPOSE: In patients with acute ischemic stroke treated with thrombectomy, additional retriever passes may increase the likelihood of recanalization, but also the risk of intracranial hemorrhage. This multicenter retrospective register study aimed to evaluate the impact of retriever passes on treatment efficacy and safety outcomes in patients treated with mechanical thrombectomy. MATERIALS AND METHODS: Patients with ischemic stroke due to large artery occlusion in anterior circulation and treated with mechanical thrombectomy were enrolled. The primary efficacy outcome was a favorable functional outcome defined as modified Rankin Scale score of 0-2 at 90 days. Major safety outcome was symptomatic intracranial hemorrhage (SICH) and mortality. Multivariate logistic regression was used to analyze the impact of retriever passes on efficacy and safety outcomes. RESULTS: Of the 472 enrolled patients, the likelihood of favorable outcome declined in patients with more than three retriever passes (44.4% in patients with three passes, 26.3% with four passes, 14.8% with five or more passes). Multivariate logistic regression analysis identified three or less passes as an independent predictor for favorable functional outcomes (OR 2.44, 95% CI 1.10-5.45, P = 0.029). More than three passes was associated with an increased risk of SICH (OR 2.24, 95% CI 1.16-4.33, P = 0.016). CONCLUSIONS: More than three retriever passes may increase the rate of recanalization, but not the likelihood of favorable functional outcomes in ischemic stroke patients treated with mechanical thrombectomy. Notably, multiple retriever passes may also increase the risk of intracranial hemorrhage. EVIDENCE BASED MEDICINE: Level of Evidence: Level 4, Case Series. PMID- 29998417 TI - Micelle-like nanoparticles as siRNA and miRNA carriers for cancer therapy. AB - Gene therapy has emerged as an alternative in the treatment of cancer, particularly in cases of resistance to chemo and radiotherapy. Different approaches to deliver genetic material to tumor tissues have been proposed, including the use of small non-coding RNAs due to their multiple mechanisms of action. However, such promise has shown limits in in vivo application related to RNA's biological instability and stimulation of immunity, urging the development of systems able to overcome those barriers. In this review, we discuss the use of RNA interference in cancer therapy with special attention to the role of siRNA and miRNA and to the challenges of their delivery in vivo. We introduce a promising class of drug delivery system known as micelle-like nanoparticles and explore their synthesis and advantages for gene therapy as well as the recent findings in in vitro, in vivo and clinical studies. PMID- 29998418 TI - Heavy metal accumulation in vegetable species and health risk assessment in Serbia. AB - Continuous monitoring of heavy metal content in vegetables is of high priority for population nutrition control, as well as risk assessment for human health. The chemical composition of plants is a reliable indicator of their contamination by hazardous substances accumulated in the environment as a consequence of inadequately applied agro-technology. The main goal of this study was to examine the quality of vegetables that reach consumer markets as a function of growth location. Samples of 11 of the most common vegetable species used in the human diet were collected during a 4-year survey. Vegetables originated from local farm producers who cultivated them at different locations in Vojvodina Province, Serbia. Many vegetable samples contained disturbingly high levels of the investigated metals: cadmium, lead, nickel, and chromium. The plant species with the highest Cd accumulation was spinach, where Cd leaves exceeded the maximum permissible concentrations (MPCs) in more than half of the analyzed samples from different localities (54%). Pb concentrations in spinach were also higher than MPC values (according to Serbian law 3.0 MUg/g) in 46% of all analyzed samples. Results showed that Cr levels in all tested vegetable species were below MPC values recommended by the FAO/WHO organization. The largest chromium accumulator was spinach, with average values of 2.3 MUg/g, followed by beetroot and parsnips with an average concentration of 1.4 MUg/g. The highest average content of Ni in all analyzed vegetable species was also recorded in spinach leaves, with an average value of 2.2 MUg/g, followed by broccoli (1.7 MUg/g) and tomatoes (1.5 MUg/g). PMID- 29998419 TI - 223Ra-Dichloride in castration-resistant metastatic prostate cancer: improving outcomes and identifying predictors of survival in clinical practice. AB - PURPOSE: We first assessed whether the pattern of referrals to a nuclear medicine clinic improved as experience with 223Ra-dichloride increased, and whether referral patterns affected patient outcomes, and second assessed the value of bone scintigraphy, total alkaline phosphatase (tALP) and lymphadenopathy as prognostic factors in patients receiving 223Ra-dichloride. METHODS: A total of 57 patients eligible to receive 223Ra-dichloride over a 2-year period (March 2014 to March 2016) were retrospectively assessed and prospectively followed (median follow up 298 days). 223Ra-Dichloride was administered at 4-week intervals for a maximum of six injections. The numbers of patients in years 1 and 2 referred in relation to extent of bone disease (EOBD) category and overall survival (OS) were determined. The prognostic factors EOBD category, baseline tALP (tALPBL), tALP response, greatest percentage reduction in tALP from baseline in any treatment cycle (ALPmax; among patients with elevated ALPBL), and the presence of lymphadenopathy were assessed as predictors of OS. RESULTS: The proportion of patients with EOBD1 was higher in year 2 than in year 1 (29% and 4%, respectively), and in year 2 there was a lower rate of symptomatic skeleton related events, a higher proportion of patients completing six cycles, and longer (albeit nonsignificant) OS (p = 0.55). There were significant differences in OS between EOBD4 patients and those in all other groups and between EOBD1 and EOBD3 patients (p < 0.05). OS was longer in patients with normal tALPBL than in those with elevated tALPBL (p = 0.01), in ALP responders than in nonresponders (p < 0.05), and in patients without lymphadenopathy than in those with lymphadenopathy (p = 0.29). OS was correlated with ALPmax (r2 = 0.24). CONCLUSION: A collaborative multidisciplinary referrals pathway, together with increased experience with 223Ra-dichloride, led to improved outcomes. In patients with elevated tALPBL, tALP dynamics may be useful for monitoring response and predicting OS. Imaging and prognostic markers may therefore be of value for individualizing 223Ra-dichloride treatment and planning retreatment; however, further studies are required. PMID- 29998420 TI - Comparison of the clinical performance of upper abdominal PET/DCE-MRI with and without concurrent respiratory motion correction (MoCo). AB - PURPOSE: To compare the clinical performance of upper abdominal PET/DCE-MRI with and without concurrent respiratory motion correction (MoCo). METHODS: MoCo PET/DCE-MRI of the upper abdomen was acquired in 44 consecutive oncologic patients and compared with non-MoCo PET/MRI. SUVmax and MTV of FDG-avid upper abdominal malignant lesions were assessed on MoCo and non-MoCo PET images. Image quality was compared between MoCo DCE-MRI and non-MoCo CE-MRI, and between fused MoCo PET/MRI and fused non-MoCo PET/MRI images. RESULTS: MoCo PET resulted in higher SUVmax (10.8 +/- 5.45) than non-MoCo PET (9.62 +/- 5.42) and lower MTV (35.55 +/- 141.95 cm3) than non-MoCo PET (38.11 +/- 198.14 cm3; p < 0.005 for both). The quality of MoCo DCE-MRI images (4.73 +/- 0.5) was higher than that of non-MoCo CE-MRI images (4.53+/-0.71; p = 0.037). The quality of fused MoCo PET/MRI images (4.96 +/- 0.16) was higher than that of fused non-MoCo PET/MRI images (4.39 +/- 0.66; p < 0.005). CONCLUSION: MoCo PET/MRI provided qualitatively better images than non-MoCo PET/MRI, and upper abdominal malignant lesions demonstrated higher SUVmax and lower MTV on MoCo PET/MRI. PMID- 29998422 TI - Function and Regulation of Agrobacterium tumefaciens Cell Surface Structures that Promote Attachment. AB - Agrobacterium tumefaciens attaches stably to plant host tissues and abiotic surfaces. During pathogenesis, physical attachment to the site of infection is a prerequisite to infection and horizontal gene transfer to the plant. Virulent and avirulent strains may also attach to plant tissue in more benign plant associations, and as with other soil microbes, to soil surfaces in the terrestrial environment. Although most A. tumefaciens virulence functions are encoded on the tumor-inducing plasmid, genes that direct general surface attachment are chromosomally encoded, and thus this process is not obligatorily tied to virulence, but is a more fundamental capacity. Several different cellular structures are known or suspected to contribute to the attachment process. The flagella influence surface attachment primarily via their propulsive activity, but control of their rotation during the transition to the attached state may be quite complex. A. tumefaciens produces several pili, including the Tad-type Ctp pili, and several plasmid-borne conjugal pili encoded by the Ti and At plasmids, as well as the so-called T-pilus, involved in interkingdom horizontal gene transfer. The Ctp pili promote reversible interactions with surfaces, whereas the conjugal and T-pili drive horizontal gene transfer (HGT) interactions with other cells and tissues. The T-pilus is likely to contribute to physical association with plant tissues during DNA transfer to plants. A. tumefaciens can synthesize a variety of polysaccharides including cellulose, curdlan (beta-1,3 glucan), beta 1,2 glucan (cyclic and linear), succinoglycan, and a localized polysaccharide(s) that is confined to a single cellular pole and is called the unipolar polysaccharide (UPP). Lipopolysaccharides are also in the outer leaflet of the outer membrane. Cellulose and curdlan production can influence attachment under certain conditions. The UPP is required for stable attachment under a range of conditions and on abiotic and biotic surfaces. Other factors that have been reported to play a role in attachment include the elusive protein called rhicadhesin. The process of surface attachment is under extensive regulatory control and can be modulated by environmental conditions, as well as by direct responses to surface contact. Complex transcriptional and post-transcriptional control circuitry underlies much of the production and deployment of these attachment functions. PMID- 29998421 TI - Histology of Barrett's Metaplasia: Do Goblet Cells Matter? AB - This review has provided a summary of the biology of goblet cell metaplasia in CLE as it pertains to BE. Goblet cells are terminally differentiated nonproliferative cells that have many overlapping histochemical characteristics with mucinous columnar cells and pseudogoblet cells. There is an abundance of evidence that suggests that use of goblet cells as a biomarker of BE, and its progression to malignancy, is problematic. Some of these limitations include the fact that the background non-goblet epithelium in most patients with CLE is biologically intestinalized and contains molecular abnormalities similar to goblet cell CLE, goblet cells fluctuate with time and decrease in number with progression of neoplasia, and pathologists have problems with interpretation, and distinction, of goblet cells from other types of cells in the esophagus. Sampling error results in sensitivity and specificity issues that limit its positive predictive value. Goblet cells are fewest in number in the same population of patients with CLE that are hardest to detect endoscopically (i.e., those with short or ultrashort CLE). Nevertheless, the risk of cancer in patients with short segment BE, a condition difficult to distinguish from the stomach, is very low regardless of the presence or absence of goblet cells so it is unclear what the role of goblet cells is in these patients as a biomarker. Nevertheless, if the answer to the following question, "Would you as a gastroenterologist recommend surveillance for a patient with clear endoscopic evidence of CLE, particularly if it is >= 3 cm in length, but in which goblet cells were not reported to be present by the pathologist," is yes, then the US requirement for goblet cells as part of the criteria for "BE" is superfluous. PMID- 29998423 TI - Assessment of the value of gastroenterologists' activity in the outpatient setting: applying the "Moneyball" approach to clinical care. AB - BACKGROUND: With the emergence of alternative payment systems replacing the traditional funding models, the value of physician activity is scrutinized more closely. Attempts have been made to quantify the value of endoscopists' activity; there is little in the medical literature describing gastroenterologists' value in the outpatient setting. AIMS: To characterize the value of clinical activity of gastroenterologists in the outpatient setting. METHODS: The value of clinical activity of ten gastroenterologists in an academic medical center was estimated. Value was defined as Q (quality of clinical care) divided by TA (duration of outpatient visit adjusted for complexity level); TA served as a surrogate measure of the cost of the clinician's services. Medical records of each patient's clinical visit were reviewed and graded independently by three staff gastroenterologists; each reviewer was blinded to the identity of the physician and to other reviewers' scores. RESULTS: Over consecutive weeks, the clinical records of 307 patients who were seen by ten gastroenterologists were reviewed and graded for quality (Q) and complexity (C); the duration of each visit (T) was recorded. Each physician saw a mean of 31 patients; mean physician value varied from 0.28 to 0.87. More senior physicians demonstrated higher levels of value. CONCLUSION: Measurement of the value of clinical activity represents an important component of gastroenterologists' performance. There was a threefold variation among physician levels of value with more experienced clinicians demonstrating higher value levels. Further studies will be required to more clearly define valid metrics for physician value. PMID- 29998425 TI - Early Epileptiform Discharges and Clinical Signs Predict Nonconvulsive Status Epilepticus on Continuous EEG. AB - BACKGROUND: Critical care continuous electroencephalography (CCEEG) represents the gold standard for detection of nonconvulsive status epilepticus (NCSE) in neurological critical care patients. It is unclear which findings on short-term routine EEG and which clinical parameters predict NCSE during subsequent CCEEG reliably. The aim of the present study was to assess the prognostic significance of changes within the first 30 min of EEG as well as of clinical parameters for the occurrence of NCSE during subsequent CCEEG. METHODS: Systematic analysis of the first 30 min and the remaining segments of prospective CCEEG recordings according to the ACNS Standardized Critical Care EEG Terminology and according to recently proposed NCSE criteria as well as review of clinical parameters of 85 consecutive neurological critical care patients. Logistic regression and binary classification tests were used to determine the most useful parameters within the first 30 min of EEG predicting subsequent NCSE. RESULTS: The presence of early sporadic epileptiform discharges (SED) and early rhythmic or periodic EEG patterns of "ictal-interictal uncertainty" (RPPIIIU) (OR 15.51, 95% CI 2.83 84.84, p = 0.002) and clinical signs of NCS (OR 18.43, 95% CI 2.06-164.62, p = 0.009) predicted NCSE on subsequent CCEEG. Various combinations of early SED, early RPPIIIU, and clinical signs of NCS showed sensitivities of 79-100%, specificities of 49-89%, and negative predictive values of 95-100% regarding the incidence of subsequent NCSE (p < 0.001). CONCLUSIONS: Early SED and early RPPIIIU within the first 30 min of EEG as well as clinical signs of NCS predict the occurrence of NCSE during subsequent CCEEG with high sensitivity and high negative predictive value and may be useful to select patients who should undergo CCEEG. PMID- 29998426 TI - Intracerebral Hemorrhage in Women: A Review with Special Attention to Pregnancy and the Post-Partum Period. AB - Non-traumatic intracranial hemorrhage includes subarachnoid hemorrhage, subdural hemorrhage, and intracerebral hemorrhage (ICH), which can be classified as primary or secondary. Primary ICH is due to arterial hypertension or cerebral amyloid angiopathy, and secondary ICH is due to cerebral vascular malformations, coagulopathies, infectious complications, brain tumors, and illicit stimulant drug use. This review explores the epidemiology and management of non-traumatic ICH in women, with a focus on pregnancy and the post-partum period, defined as 6 weeks post-delivery. PMID- 29998424 TI - Primary small bowel adenomas and adenocarcinomas-recent advances. AB - The small intestine represents 75% of the length and 90% of the absorptive surface area of the gastrointestinal tract (GIT), yet only 2% of digestive system cancers occur at this site. Adenocarcinoma accounts for half of small bowel malignancies. There have been a number of important recent advances in our understanding, classification and treatment of small bowel tumours. Over recent years, ampullary tumours have become recognised as a form of small bowel carcinoma, distinct from head of pancreas and lower biliary tract tumours. This is reflected in separate TNM systems and increasing interest in separating intestinal from pancreatobiliary subtypes. The recognition of the importance of microsatellite (MSI) status and the advent of molecular pathology has also changed our approach to these neoplasms. PMID- 29998427 TI - Infection Prevention in the Neurointensive Care Unit: A Systematic Review. AB - Hospital-acquired infections are common in neurointensive care units. We sought to review interventions which may reduce infection rates in neurocritically ill populations. We conducted a systematic review of studies targeting adult patients in neuro-intensive care units (neuro-ICUs) with an intervention designed to prevent ICU-acquired infections. Our outcome of interest was change in the prevalence or rates of infection between active and control arms of these studies. We excluded studies based on the following criteria: no English full text version available; pediatric population; non-neurosciences ICU population; pre- or intraoperative methods to prevent infection; lack of discrete data for infection rates/prevalence; studies that were purely observational in nature and did not test an intervention; and studies performed in resource limited settings. We initially retrieved 3716 results by searching the following databases: PubMed/MEDLINE, EMBASE via Ovid, and Cochrane CENTRAL via Ovid. No date or language limits were used in the search. Computerized deduplication was conducted using EndNote followed by a confirmatory manual review resulting in 3414 citations. An additional 19 manuscripts were identified through review of references. The screening process followed a standard protocol, using two screeners at the title/abstract level to determine relevance and at the full-text level to determine eligibility for inclusion. The 3427 titles/abstracts were independently screened by two board-certified neurointensivists to determine relevance for full-text review, and 3248 were rejected. The remaining 179 abstracts were reviewed in full text using predetermined inclusion/exclusion criteria. Ultimately, 75 articles met our inclusion criteria and were utilized in the final analysis. The reviewed literature highlights the need for collaborative, multi-disciplinary, and multi-pronged approaches to reduce infections. Rates of VRI, SSI, VAP, CAUTI, and CLABSI can approach zero with persistence and a team-based approach. PMID- 29998428 TI - Prediction of Delayed Cerebral Ischemia with Cerebral Angiography: A Meta Analysis. AB - OBJECT: Cerebral catheter angiography is the gold standard for diagnosing cerebral artery vasospasm (vasospasm) in aneurysmal subarachnoid hemorrhage (SAH). We have previously published a meta-analysis of prediction of delayed cerebral ischemia (DCI) from transcranial Doppler (TCD) evidence of vasospasm. Analogous data relating to prediction of DCI have not been previously collated for cerebral angiography nor reconciled against TCD. METHODS: We searched PUBMED, the Cochrane database, and clinicaltrials.gov for studies that used cerebral angiography for diagnosis of vasospasm and evaluated DCI in patients with SAH. We performed a random-effects meta-analysis of prediction of DCI with cerebral angiography, reconciling its accuracy against that of TCD. We also report quality of evidence for the value of cerebral angiography and TCD in SAH based on pooled data from our meta-analyses. RESULTS: A total of 15 studies (n = 5463) were included in the meta-analysis. Sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of cerebral angiography for prediction of DCI are 57, 68, 32, and 90%. These metrics for TCD, based on our previous meta-analysis, are 90, 71, 57, and 92%. We report that test accuracy estimates are "moderate" for TCD and "low" for angiography based on pooled data from our meta-analyses. CONCLUSION: TCD evidence of vasospasm is a better predictor of DCI than angiographic vasospasm. Future comparative effectiveness studies can better define the value of these diagnostic tools in patients with SAH. PMID- 29998429 TI - Cerebral Herniation from Hyperammonemic Cerebral Edema: A Potentially Reversible Neurological Emergency. PMID- 29998430 TI - Racial/Ethnic Differences in the Utilization of Infertility Services: A Focus on American Indian/Alaska Natives. AB - Objectives Previous studies have identified racial/ethnic disparities in infertility care, but patterns among American Indian/Alaska Natives (AI/AN) have not been reported. Our objective was to evaluate infertility services use in the US by race/ethnicity using data from the National Survey of Family Growth (NSFG). Methods We analyzed female respondent data from the pooled NSFG cycles 2002, 2006 2010 and 2011-2013. Respondents reported use of infertility services and types of services. We calculated weighted crude and adjusted prevalence proportion ratios (PPR) and 95% confidence intervals (95% CI) using modified Poisson regression with robust error variances accounting for the complex survey design to compare infertility services use across race/ethnicities. Results Overall, 8.7% of women reported using medical services to get pregnant. The prevalence of using any medical service to help get pregnant was lower for American Indian/Alaska Native (AI/AN) (PPR: 0.60, 95% CI 0.43-0.83) and black (PPR: 0.53, 95% CI 0.44-0.63) compared to white women and in Hispanic compared to non-Hispanic women (PPR: 0.57, 95% CI 0.48-0.67). The prevalence of accessing treatment, testing, and advice also differed by race and ethnicity. Conclusions for Practice We observed disparities in accessing services to get pregnant among AI/AN and black women and reduced use of advice among Asian/Pacific Islanders compared to whites. We also observed reduced service utilization for Hispanic compared to non-Hispanic women. Differential utilization of specific services suggests barriers to infertility care may contribute to reproductive health disparities among underserved populations. PMID- 29998431 TI - Decreasing delta13C and delta15N values in four coastal species at different trophic levels indicate a fundamental food-web shift in the southern North and Baltic Seas between 1988 and 2016. AB - Marine ecosystems are exposed to increasing human pressures and climatic change worldwide. It has therefore become essential to describe ecosystem statuses with respect to multinational protection schemes, often necessitating long-term monitoring programmes. Changes in the food-web structure, which can be monitored via stable isotope measurements, represent an important descriptor of the status of marine ecosystems. We investigated long-term changes (29 years) in isotopic values (delta13C and delta15N) in four indicative organisms at different trophic levels in the southern North and Baltic Seas: bladderwrack (Fucus vesiculosus), blue mussel (Mytilus ssp.), eelpout (Zoarces viviparus), and herring gull (Larus argentatus). Time series analyses using generalised additive models revealed largely consistent declines in delta13C and delta15N throughout all trophic levels of the coastal food web at all study sites, indicating a clear change in these coastal regions from 1988 to 2016. There were no clear long-term patterns in egg biometrics for herring gulls, except for a consistent increase in eggshell thickness. The declines in stable isotope values were in line with the results of previous long-term studies of single higher-trophic-level species, which suggested that the noted changes were mainly caused by altered foraging patterns of the studied species. The current results demonstrate that declines in delta13C and delta15N have occurred throughout the whole food web, not just in particular species. We discuss the possible reasons for the decrease in stable isotope values, including decreasing eutrophication and an increase in terrestrial carbon sources. PMID- 29998433 TI - Cost Conversations Between Primary Care Providers and Patients with Expanded Medicaid Coverage. PMID- 29998432 TI - Predictors for grade 6 reading in children at familial risk of dyslexia. AB - The present study investigates whether grade 6 reading outcomes, reading fluency, and reading comprehension can be predicted by grade 3 reading fluency, familial risk of dyslexia (FR), and grade 3 reading related skills: rapid automatized naming (RAN), phonological awareness (PA), and vocabulary. In a sample of 150 children, of whom 83 had a parent with dyslexia, correlation and regression analyses were performed. FR, measured on a continuous scale, was by itself related to all outcomes. However, FR did not explain any variance on top of grade 3 reading fluency. Grade 3 reading fluency strongly predicted grade 6 reading fluency and was also related to reading comprehension. RAN improved the prediction of grade 6 reading fluency, though the additional explained variance was small. Vocabulary and PA fully explained the variance that grade 3 reading fluency explained in grade 6 reading comprehension. Vocabulary explained a substantial amount of variance in grade 6 reading comprehension making it an interesting clinical target. As we used continuous measures of reading fluency and FR, our findings are not biased by distinct diagnostic criteria. PMID- 29998435 TI - Capsule Commentary on Grant et al., Which Complex Patients Should Be Referred for Intensive Care Management? A Mixed Methods Analysis. PMID- 29998436 TI - Racial/Gender Biases in Student Clinical Decision-Making: a Mixed-Method Study of Medical School Attributes Associated with Lower Incidence of Biases. AB - BACKGROUND: Accumulating evidence suggests that clinician racial/gender decision making biases in some instances contribute to health disparities. Previous work has produced evidence of such biases in medical students. OBJECTIVE: To identify contextual attributes in medical schools associated on average with low levels of racial/gender clinical decision-making biases. DESIGN: A mixed-method design using comparison case studies of 15 medical schools selected based on results of a previous survey of student decision-making bias: 7 schools whose students collectively had, and 8 schools whose students had not shown evidence of such biases. PARTICIPANTS: Purposively sampled faculty, staff, underrepresented minority medical students, and clinical-level medical students at each school. MAIN MEASURES: Quantitative descriptive data and qualitative interview and focus group data assessing 32 school attributes theorized in the literature to be associated with formation of decision-making and biases. We used a mixed-method analytic design with standard qualitative analysis and fuzzy set qualitative comparative analysis. KEY RESULTS: Across the 15 schools, a total of 104 faculty, administrators and staff and 21 students participated in individual interviews, and 196 students participated in 29 focus groups. While no single attribute or group of attributes distinguished the two clusters of schools, analysis showed some contextual attributes were seen more commonly in schools whose students had not demonstrated biases: longitudinal reflective small group sessions; non accusatory approach to training in diversity; longitudinal, integrated diversity curriculum; admissions priorities and action steps toward a diverse student body; and school service orientation to the community. CONCLUSIONS: We identified several potentially modifiable elements of the training environment that are more common in schools whose students do not show evidence of racial and gender biases. PMID- 29998434 TI - Barriers to Healthcare Access and Long-Term Survival After an Acute Coronary Syndrome. AB - BACKGROUND: Barriers to healthcare are common in the USA and may result in worse outcomes among hospital survivors of an acute coronary syndrome (ACS). OBJECTIVE: To examine the relationship between barriers to healthcare and 2-year mortality after hospital discharge for an ACS. DESIGN: Longitudinal study. SETTING: Survivors of an ACS hospitalization were recruited from 6 medical centers in central Massachusetts and Georgia in 2011-2013. PATIENTS: Study participants with a confirmed ACS reported whether they had a financial-related healthcare barrier, no usual source of care, or a transportation-related healthcare barrier around the time of hospital admission. INTERVENTIONS: None. MEASUREMENTS: Cox regression analyses calculated adjusted hazard ratios (aHRs) for 2-year all-cause mortality for the three healthcare barriers while controlling for several demographic, clinical, and psychosocial characteristics. RESULTS: The mean age of study participants (n = 2008) was 62 years, 33% were women, and 77% were non-Hispanic white. One third of patients reported a financial barrier, 17% lacked a usual source of care, and 12% had a transportation barrier. Five percent (n = 100) died within 2 years after hospital discharge. Compared to patients without these barriers, those lacking a usual source of care and with barriers to transportation experienced significantly higher mortality (aHRs 1.40, 95% CI 1.30 to 1.51 and 1.46, 95% CI 1.13 to 1.89, respectively). Financial barriers were not associated with all-cause mortality (aHR 0.79, 95% CI 0.60 to 1.06). LIMITATIONS: Observational study with other unmeasured potentially confounding prognostic factors. CONCLUSIONS: Absence of an established usual source of care and inconsistent transportation availability were associated with a higher risk for dying after an ACS. Patients with these barriers to follow-up care may benefit from more intensive follow-up and support. PMID- 29998437 TI - Influence of Low-Intensive Red Light on the Myocardium in Experimental Asphyxia. AB - We studied the effects of low-intensity broadband red light on electrical activity of the heart and oxidative modification of proteins in the myocardium of rats after asphyxia. It was shown that low-intensity red light reduced the content of oxidatively modified proteins in rat heart after oxidative stress caused by asphyxia. Exposure to low-intensity red light normalized ECG parameters in rats after asphyxia. PMID- 29998438 TI - Effect of Calcium on Slow Force Responses in Isolated Right Ventricle Preparations of Healthy and Hypertrophied Myocardium in Male and Female Rats. AB - Effect of different Ca2+ concentrations in the bathing solution [Ca2+]o on the parameters of single isometric contraction and slow force response to stretching was studied in isolated preparations of healthy and hypertrophied myocardium of male and female Wistar rats. In all groups of experimental animals, the increase in calcium concentration was followed by a decrease in the myocardium slow response intensity. We revealed a complementary relationship between the current and medium-term systems of myocardial contractility regulation by the length of the myocardium aimed at the maintenance of the constant level during adaptation to the load. Slow responses of the hypertrophied rat heart myocardium were suppressed in comparison with those in the healthy myocardium and their intensity did not depend on animal sex. PMID- 29998439 TI - Hypolipidemic and Hepatoprotective Effects of a Polyprenol-Containing Drug in Patients with Acute Coronary Syndrome. AB - In a double-blind placebo-controlled trial POLYNCOR (registration No. NCT03122340 at clinicaltrials.gov ), lipid-lowering and hepatoprotective effects of polyprenol-containing drug Ropren were evaluated in patients with acute coronary syndrome. After 2-months therapy, total cholesterol and ALT in the patients receiving Ropren were significantly (p<0.05) lower than in the control group. The number of patients who needed to discontinue or reduce the dose of atorvastatin due to an increase in the level of transaminases in the main group was significantly (p<0.05) lower than in the control group: 0 (0%) vs. 5 (33.3%). The more pronounced decrease in cholesterol level and hepatoprotective effect of Ropren allowed recommending this preparation to patients with acute coronary syndrome in addition to standard therapy. PMID- 29998440 TI - Effect of Metabolic Stress on Lysosomal Proteolysis in the Liver and Brain of Rats Receiving Q10-Enriched Ration. AB - Activation of lysosomal proteolysis and increased coenzyme Q10 level were revealed in the liver and brain of rats with individual typological features under conditions of food deprivation. Changes in cathepsin B activity in these tissues were different in behaviorally active and passive animals. We observed indirect modulating effect of coenzyme Q10 in the regulation of activity of lysosomal endopeptidases in the brain of animals with different behavior during adaptation to metabolic stress. PMID- 29998441 TI - Influence of Caffeine Consumption by Pregnant Rats on Behavior and Learning in Their Offspring. AB - We studied the effect of long-term prenatal administration of caffeine on the behavior and learning of rats in postnatal ontogeny. Experiments were carried out on male rats born by females receiving caffeine solution as the only source of fluid throughout gestation. The control group consisted of pups obtained from females receiving drinking water throughout pregnancy. It was found that long term caffeine intake by female rats during pregnancy determined increased locomotor activity of the offspring. Rat pups born from mothers treated with caffeine during pregnancy faster reached the underwater platform in the Morris maze, i.e. demonstrated better spatial memory formation than control animals. PMID- 29998442 TI - Correlations between Extracellular Matrix Components in Mouse Lungs during Chronic BCG-Induced Granulomatosis. AB - Correlations between extracellular matrix components in mouse lungs were examined during various terms of BCG-induced granulomatosis (on postinfection days 3, 30, 60, 90, and 180). During the development of pathological process, the revealed dynamic interrelations between structural units of proteoglycans and hydroxyproline weakened. Most correlations were observed on postinfection day 180. They reflect the relationships not only between the structural units of proteoglycans but also between collagens, presumably determining the maximum degree of fibrosis at this period. The established correlations characterize the systemic nature of reactions in extracellular matrix and its versatile implications determined by the processes going on in the organs and tissues during the onset and development of generalized pathology. PMID- 29998443 TI - Physical property investigation of contemporary glass ionomer and resin-modified glass ionomer restorative materials. AB - OBJECTIVES: The objective of this study was to investigate selected physical properties of nine contemporary and recently marketed glass ionomer cement (GIC) and four resin-modified glass ionomer cement (RMGI) dental restorative materials. MATERIALS AND METHODS: Specimens (n = 12) were fabricated for fracture toughness and flexure strength using standardized, stainless steel molds. Testing was completed on a universal testing machine until failure. Knoop hardness was obtained using failed fracture toughness specimens on a microhardness tester, while both flexural modulus and flexural toughness was obtained by analysis of the flexure strength results data. Testing was completed at 1 h, 24 h, 1 week, and then at 1, 3, 6, and 12 months. Mean data was analyzed with Kruskal-Wallis and Mann-Whitney (p = 0.05). RESULTS: Physical properties results were material dependent. Physical properties of the GIC and RMGI products were inferior at 1 h compared to that at 24 h. Some improvement in selected physical properties were noted over time, but development processes were basically concluded by 24 h. A few materials demonstrated improved physical properties over the course of the evaluation. CONCLUSIONS: Under the conditions of this study: 1. GIC and RMGI physical property performance over time was material dependent; 2. Polyalkenoate maturation processes are essentially complete by 24 h; 3. Although differences in GIC physical properties were noted, the small magnitude of the divergences may render such to be unlikely of clinical significance; 4. Modest increases in some GIC physical properties were noted especially flexural modulus and hardness, which lends support to reports of a maturing hydrogel matrix; 5. Overall, GIC product physical properties were more stable than RMGI; 6. A similar modulus reduction at 6 months for both RMGI and GIC produced may suggest a polyalkenoate matrix change; and 7. Globally, RMGI products demonstrated higher values of flexure strength, flexural toughness, and fracture toughness than GIC materials. CLINICAL RELEVANCE: As compared to RMGI materials, conventional glass ionomer restorative materials demonstrate more stability in physical properties. PMID- 29998444 TI - Water quality guideline values for aluminium, gallium and molybdenum in marine environments. AB - Revised water quality guideline values (WQGVs) are presented for the metals aluminium (Al), gallium (Ga) and molybdenum (Mo) in receiving marine environments. These elements are commonly found in elevated concentrations in alumina refinery waste streams, yet current WQGVs fail to accurately assess the environmental risk. Here, chronic biological effects data we have generated over the course of several years were combined with toxicity data from the open literature to construct species sensitivity distributions (SSDs) which enabled the computation of revised WQGVs for Al, Ga and Mo in marine environments. These procedures are in accordance with internationally recommended derivation procedures, and newly computed WQGVs may be incorporated in regulatory frameworks aimed at sustainable exploitation of environmental resources and ongoing protection of the marine estate. Where the available datasets allowed such distinction, separate SSDs were constructed for temperate and tropical environments and zone-specific WQGVs derived. Extrapolated from the SSDs, WQGVs of 56 MUg Al L-1, 800 MUg Ga L-1 and 3.88 mg Mo L-1 (in the 0.45-MUm filtered fraction) for 95% species protection were recommended for implementation in both temperate and tropical receiving environments. Currently, there is insufficient validation to separate the tropical from the temperate data and in most cases, application of the generic WQGVs is recommended. PMID- 29998445 TI - Enhanced biodiesel industry wastewater treatment via a hybrid MBBR combined with advanced oxidation processes: analysis of active microbiota and toxicity removal. AB - In the present study, a multistage route is proposed for the treatment of biodiesel industry wastewater (BWW) containing around 1000 mg L-1 of total organic carbon (TOC), 3500 mg L-1 of chemical oxygen demand (COD), and 1325 mg L 1 of oil and grease. Initially, BWW aerobic biodegradability was assessed via Zhan-Wellens biodegradability test to confirm the appropriate treatment route. Then, a hybrid moving bed bioreactor (MBBR) system was chosen as the first treatment stage. The hybrid MBBR achieved 69 and 68% removal of COD and TOC removals, respectively, and provided great conditions for biomass growth. The bacterial community present in the hybrid MBBR was investigated by PCR-DGGE and potential biodegraders were identified such as: members of Desulfuromonadales, Nocardioidaceae and Pseudomonadaceae. Since biodegradation in the hybrid MBBR alone was unable to meet quality requirements, advanced oxidation processes, such as Fenton and photo-Fenton, were optimized for application as additional treatment stages. Physicochemical properties and acute toxicity of BWW were analyzed after the multistage routes: hybrid MBBR + Fenton, hybrid MBBR + photo Fenton and hybrid MBBR + UV-C254nm/H2O2. Hybrid MBBR + Fenton or photo-Fenton showed overall COD removal efficiencies greater than 95% and removed acute toxicity, thus being appropriate integrated routes for the treatment of real BWW. Graphical abstract ?. PMID- 29998446 TI - Detection, extinguishing, and monitoring of a coal fire in Xinjiang, China. AB - Coal fire is a global catastrophe. Xinjiang suffers the most severe coal fire in China and even in the world. Coal firefighting work has been being conducted for decades in Xinjiang. In this paper, coal fire detection, extinguishing, and monitoring approaches that were derived from coal firefighting experience are introduced in detail by taking the Fifth Fire Area (FFA) of the Heshituoluogai coal fire for instance. We first introduce the geology and fire situation in the FFA. Before developing efficient strategies to extinguish it, magnetic and self potential methods are adopted to delineate the extent of the fire. A composite index is proposed to better indicate the fire. The comprehensive coal firefighting method is illustrated in detail, which consists of surface cooling, excavation and leveling, borehole drilling, borehole water injection and grouting, and loess backfill. The subsequent temperature and CO monitoring records show that the fire is extinguished successfully without burnback. The methodology presented here provides guidance and reference for putting out other coal fires around the world. PMID- 29998447 TI - Colloidal mobilization from soil and transport of uranium in (sub)-surface waters. AB - An analytical methodology was developed to characterize the colloidal distribution of trace elements of interest in environmental waters sampled in a same site and enables the different colloidal distributions from waters to be compared. The purpose was to provide consistent information related to the origin and nature of colloids responsible for the transport of trace element(s). The work was motivated by the observed enhanced mobility of uranium in soil. The colloidal size continuum was investigated by a multi-technique approach involving asymmetric flow field-flow fractionation (AF4) coupled with ultraviolet spectroscopy (UV), multi angle light scattering (MALS), and atomic mass spectrometry (ICPMS). To take into consideration the size and shape variability specific to each sample, the size distributions were established from the gyration radii measured from MALS, also considering the size information from standard nanospheres fractionated by AF4. A new parameter called "shape index" was proposed. It expresses the difference in hydrodynamic behavior between analytes and spherical particles taken as reference. Under AF4 diffusion conditions, it can be considered as an evaluator of the deviation from the sphericity of the fractionated analytes. AF4-UV-MALS-ICPMS enabled the dimensional and chemical characteristics of the colloidal size continuum to be obtained. As a "proof of concept", the developed methodology was applied at a field scale, in a reference study site. In order to have a "dynamic understanding", the investigation was based on the joint characterization of colloids from surface waters and soil leachates from static and dynamic processes. In the water samples of the study site, the continuum of gyration radius ranged from a few nanometers up to 200 nm. Colloids containing iron, aluminum, and organic carbon were involved in the uranium transport in the soil column and surface waters. The colloidal uranium concentration in the surface water increased from the upstream location (approximately 13 ng (U) L-1) to the downstream location (approximately 60 ng (U) L-1). PMID- 29998448 TI - Development of immunochromatographic assays for the detection of imidacloprid in soil chemical barrier. AB - A soil chemical barrier is the most important and common way to control termites; fast and on-site detection methods are significant tools to verify pesticide content meeting the standard requirements. In this study, conventional and enhanced immunochromatographic assays (ICAs) containing two test lines (TLs) were developed to semi-quantitatively detect imidacloprid in soil chemical barrier, and detection results were quantified by a smart phone. According to the results, the disappearance concentrations of first TL (TL-1) and second TL (TL-2) in an enhanced ICA and conventional ICA were 5 and 20 ng/mL and 20 and 80 ng/mL with the naked eye. The sensitivity of TL-2 was four times that of TL-1 in both ICAs, consistent with the maximum and minimum concentration differences for imidacloprid in Jiangsu province's "the technical regulation of assay and evaluation on chemical soil barrier of termite prevention treatment in buildings". The results of TLs can be used to judge whether the amount of imidacloprid in soil chemical barrier meets the standard. Enhanced and conventional ICAs were available for further quantitative testing with a smart phone, and the limit of detection (LOD) was 0.74 and 3.17 ng/mL, respectively. Moreover, some soil chemical barrier samples from several areas in Wuxi, Jiangsu province, were used to test by ICAs and high-performance liquid chromatography (HPLC), and the results of ICAs correlated well with HPLC. PMID- 29998449 TI - S-incorporated TiO2 coatings grown by plasma electrolytic oxidation for reduction of Cr(VI)-EDTA with sunlight. AB - The plasma electrolytic oxidation (PEO) technique was used to prepare photocatalytic S-TiO2 coatings on Ti sheets; the incorporation of the S ions was possible from the electrolyte for modifying the structural and optics characteristics of the material. In this work, substrates of Ti (ASME SB-265 of 20 * 20 * 1 mm) were used in a PEO process in 10 min, using constant voltage pulses of 340 V with frequency of 1 kHz and duty cycles of 10% and of 30%. Solutions with H2SO4 (0.1 M) and CH4N2S (52 and 79 mM) were used as electrolytes. X-ray diffraction, scanning electron microscopy, and energy dispersive spectroscopy (EDS) were utilized to analyze the surface morphology, crystalline phase, and chemical composition of the samples. According to the results, the catalyst coatings had microporous structure and contained anatase-rutile TiO2 nanocrystalline mixture, until 73.2% rutile and 26.8% anatase in the samples grown with 30% duty cycle and the lowest concentration of CH4N2S. From the EDS measurements, the incorporation of sulfur ions to the coatings was 0.08 wt%. 99.5% reduction efficiency of Cr(VI)-EDTA with sunlight was observed after 2 h; it was determined by diphenyl carbazide spectrophotometric method. These coatings have potential for effective sunlight heterogeneous photoreduction of this toxic, cumulative, and non-biodegradable heavy metal that contaminates the soil and water and is a serious risk to sustainability, ecosystems, and human health. PMID- 29998450 TI - The Real-World Cost-Effectiveness of Coronary Artery Bypass Surgery Versus Stenting in High-Risk Patients: Propensity Score-Matched Analysis of a Single Centre Experience. AB - BACKGROUND: There are limited economic evaluations comparing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for multi vessel coronary artery disease (MVCAD) in contemporary, routine clinical practice. OBJECTIVE: The aim was to perform a cost-effectiveness analysis comparing CABG and PCI in patients with MVCAD, from the perspective of the Australian public hospital payer, using observational data sources. METHODS: Clinical data from the Melbourne Interventional Group (MIG) and the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) registries were analysed for 1022 CABG (treatment) and 978 PCI (comparator) procedures performed between June 2009 and December 2013. Clinical records were linked to same-hospital admissions and national death index (NDI) data. The incremental cost-effectiveness ratios (ICERs) per major adverse cardiac and cerebrovascular event (MACCE) avoided were evaluated. The propensity score bin bootstrap (PSBB) approach was used to validate base-case results. RESULTS: At mean follow-up of 2.7 years, CABG compared with PCI was associated with increased costs and greater all-cause mortality, but a significantly lower rate of MACCE. An ICER of $55,255 (Australian dollars)/MACCE avoided was observed for the overall cohort. The ICER varied across comparisons against bare metal stents (ICER $25,815/MACCE avoided), all drug-eluting stents (DES) ($56,861), second-generation DES ($42,925), and third-generation of DES ($88,535). Moderate-to-low ICERs were apparent for high risk subgroups, including those with chronic kidney disease ($62,299), diabetes ($42,819), history of myocardial infarction ($30,431), left main coronary artery disease ($38,864), and heart failure ($36,966). CONCLUSIONS: At early follow-up, high-risk subgroups had lower ICERs than the overall cohort when CABG was compared with PCI. A personalised, multidisciplinary approach to treatment of patients may enhance cost containment, as well as improving clinical outcomes following revascularisation strategies. PMID- 29998451 TI - Hypothesis Testing of the Q-matrix. AB - The recent surge of interests in cognitive assessment has led to the development of cognitive diagnosis models. Central to many such models is a specification of the Q-matrix, which relates items to latent attributes that have natural interpretations. In practice, the Q-matrix is usually constructed subjectively by the test designers. This could lead to misspecification, which could result in lack of fit of the underlying statistical model. To test possible misspecification of the Q-matrix, traditional goodness of fit tests, such as the Chi-square test and the likelihood ratio test, may not be applied straightforwardly due to the large number of possible response patterns. To address this problem, this paper proposes a new statistical method to test the goodness fit of the Q-matrix, by constructing test statistics that measure the consistency between a provisional Q-matrix and the observed data for a general family of cognitive diagnosis models. Limiting distributions of the test statistics are derived under the null hypothesis that can be used for obtaining the test p-values. Simulation studies as well as a real data example are presented to demonstrate the usefulness of the proposed method. PMID- 29998452 TI - Cytological differentiation and cell wall involvement in the growth mechanisms of articulated laticifers in Tabernaemontana catharinensis A.DC. (Apocynaceae). AB - The cellular mechanisms of laticifer growth are of particular interest in plant biology but are commonly neglected. Using transmission electron microscopy and immunocytochemical methods, we recorded cytological differentiation and evaluated the cell wall involvement in the growth of articulated laticifers with intrusive growth in the mature embryo and plant shoot apex of Tabernaemontana catharinensis. The incorporation of adjacent meristematic cells into the laticifer system occurred in the embryo and plant shoot apex, and the incorporated cells acquired features of laticifer, confirming the laticifers' action-inducing mechanism. In the embryo, this was the main growth mechanism, and began with enlargement of the plasmodesmata and the formation of pores between laticifers and meristematic cells. In the plant shoot apex, it began with loose and disassembled walls and the reorientation of the cortical microtubules of the incorporated cell. Plasmodesmata were absent in these laticifers. There was stronger evidence of intrusive growth in undifferentiated portions of the plant shoot apex than in the embryo. The numerous plasmodesmata in laticifers of the embryo may have been related to the lower frequency of intrusive growth. Intrusive growth was associated with presence of arabinan (increasing wall flexibility and fluidity), and absence of galactan (avoiding wall stiffness), and callose (as a consequence of reduction in symplastic connections) in the laticifer walls. The abundance of low de-methyl-esterified homogalacturonan in the middle lamella and corners may reestablish cell-cell bonding in the laticifers. The cell wall features differed between embryo and plant shoot apex and are directly associated to laticifer growth mechanisms. PMID- 29998453 TI - Exploring the optimal experimental setup for surface flow velocity measurements using PTV. AB - Advances in flow monitoring are crucial to increase our knowledge on basin hydrology and to understand the interactions between flow dynamics and infrastructures. In this context, image processing offers great potential for hydraulic monitoring, allowing acquisition of a wide range of measurements with high spatial resolution at relatively low costs. In particular, the particle tracking velocimetry (PTV) algorithm can be used to describe the dynamics of surface flow velocity in both space and time using fixed cameras or unmanned aerial systems (UASs). In this study, analyses allowed exploration of the optimal particle seeding density and frame rate in different configurations. Numerical results provided useful indications for two field experiments that have been carried out with a low-cost quadrocopter equipped with an optical camera to record RGB videos of floating tracers manually distributed over the water surface. Field measurements have been carried out using different natural tracers under diverse hydraulic and morphological conditions; PTV's processed velocities have been subsequently benchmarked with current meter measurements. The numerical results allowed rapid identification of the experimental configuration (e.g., required particle seeding density, image resolution, particle size, and frame frequency) producing flow velocity fields with high resolution in time and space with good agreement with the benchmark velocity values measured with conventional instruments. PMID- 29998455 TI - The Development of Heuristics for Evaluation of Dashboard Visualizations. AB - BACKGROUND: Heuristic evaluation is used in human-computer interaction studies to assess the usability of information systems. Nielsen's widely used heuristics, first developed in 1990, are appropriate for general usability but do not specifically address usability in systems that produce information visualizations. OBJECTIVE: This article develops a heuristic evaluation checklist that can be used to evaluate systems that produce information visualizations. Principles from Nielsen's heuristics were combined with heuristic principles developed by prior researchers specifically to evaluate information visualization. METHODS: We used nominal group technique to determine an appropriate final set. The combined existing usability principles and associated factors were distributed via email to a group of 12 informatics experts from a range of health care disciplines. Respondents were asked to rate each factor on its importance as an evaluation heuristic for visualization systems on a scale from 1 (definitely don't include) to 10 (definitely include). The distribution of scores for each item were calculated. A median score of >=8 represented consensus for inclusion in the final checklist. RESULTS: Ten of 12 experts responded with rankings and written comments. The final checklist consists of 10 usability principles (7 general and 3 specific to information visualization) substantiated by 49 usability factors. Three nursing informatics experts then used the checklist to evaluate a vital sign dashboard developed for home care nurses, using a task list designed to explore the full functionality of the dashboard. The experts used the checklist without difficulty, and indicated that it covered all major usability problems encountered during task completion. CONCLUSION: The growing capacity to generate and electronically process health data suggests that data visualization will be increasingly important. A checklist of usability heuristics for evaluating information visualization systems can contribute to assuring high quality in electronic data systems developed for health care. PMID- 29998454 TI - Outcomes and Management of the Ileal Pouch-Anal Anastomosis in the Elderly. AB - PURPOSE OF REVIEW: Ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients undergoing colectomy to maintain intestinal continuity. Earlier studies have suggested that outcomes are worse in elderly patients who underwent IPAA. However, more recent reports have shown that IPAA outcomes in the elderly are comparable to younger patients. We review the recent medical literature regarding outcomes and treatments for common complications in elderly IPAA patients. RECENT FINDINGS: Compared to younger patients, IPAA in the elderly is not associated with increased major surgical complications, but is associated with increased length of stay and re-admission rate for dehydration in older patients. Rates of fecal incontinence after IPAA were similar between younger and older patients. Sacral nerve stimulation has shown early promise as a possible treatment for fecal incontinence after IPAA, but more research is needed. Pouchitis is a common complication, and antibiotics remain first-line treatment options. Other treatment options include mesalamines, steroids, immunomodulators, and biologics. The efficacy of newer biologics such as vedolizumab and ustekinumab has been reported, but more data is needed. IPAA is safe in the elderly with high self-reported patient satisfaction. However, the elderly IPAA patient warrants special consideration regarding outcomes and management. PMID- 29998456 TI - Creation and Use of an Electronic Health Record Reporting Database to Improve a Laboratory Test Utilization Program. AB - OBJECTIVES: Laboratory-based utilization management programs typically rely primarily on data derived from the laboratory information system to analyze testing volumes for trends and utilization concerns. We wished to examine the ability of an electronic health record (EHR) laboratory orders database to improve a laboratory utilization program. METHODS: We obtained a daily file from our EHR containing data related to laboratory test ordering. We then used an automated process to import this file into a database to facilitate self-service queries and analysis. RESULTS: The EHR laboratory orders database has proven to be an important addition to our utilization management program. We provide three representative examples of how the EHR laboratory orders database has been used to address common utilization issues. We demonstrate that analysis of EHR laboratory orders data has been able to provide unique insights that cannot be obtained by review of laboratory information system data alone. Further, we provide recommendations on key EHR data fields of importance to laboratory utilization efforts. CONCLUSION: We demonstrate that an EHR laboratory orders database may be a useful tool in the monitoring and optimization of laboratory testing. We recommend that health care systems develop and maintain a database of EHR laboratory orders data and integrate this data with their laboratory utilization programs. PMID- 29998457 TI - Effects of genistein on insulin pathway-related genes in mouse differentiated myoblast C2C12 cell line: evidence for two independent modes of action. AB - INTRODUCTION: Genistein (plant isoflavone) is a well-known anti-cancer drug with estrogenic-like properties. Genistein also regulates sugar and lipid metabolism; thus, it has anti-diabetic properties. The aim of the study was to evaluate in vitro effects of genistein on glucose transport, fatty acids oxidation, activation of PKB, and expression of genes related to insulin pathway in differentiated myoblast C2C12 mouse cell line. MATERIAL AND METHODS: Differentiated myoblast C2C12 mouse cell line was used to assess the effects of different genistein concentrations on glucose transport and fatty acids oxidation measured by radioactivity technique, activation of PKB, and expression of selected genes related to insulin signaling pathway (IR-a, IR-b, IRS-1, PKB, GLUT 4, PP2A, SH-PTP2) at the mRNA and protein levels. Cells were incubated with various concentrations of genistein under standard conditions for 0-48 hours. RESULTS: Genistein in low concentrations (0.1-1 MUM) significantly increased glucose transport and decreased fatty acids oxidation in C2C12 cells after 48 h of incubation. High concentration of genistein (50 MUM) had the opposite effect. Genistein stimulated PKB phosphorylation during the first 5-10 minutes of incubation. There was no significant impact on the protein expression of selected genes (IR-a, IR-b, IRS-1, PKB, GLUT-4, PP2A-Ca, ER-a and ER-b) after 48 h treatment. We observed inverse correlation between genistein concentration and the expression of SH-PTP2 protein. Genistein affected the expression pattern of mRNAs for genes related to the insulin pathway, however, not the expression of the encoded proteins. CONCLUSIONS: The results of this study showed that depending on the concentration and time of incubation genistein significantly affects glucose and lipid metabolism and at low concentration modifies expression pattern of a few genes in C2C12 cells. PMID- 29998458 TI - Improvements in mentalization predict improvements in interpersonal distress in patients with mental disorders. AB - OBJECTIVES: Associations between interpersonal problems and mentalization have rarely been investigated. In this study, we explored patterns of interpersonal problems, mentalization, symptom severity, and attachment during inpatient treatment and at follow-up. Additionally, we investigated whether mentalization predicts a decrease in interpersonal distress. METHOD: We analyzed time-series data from patients with mental disorders. Data were collected at the beginning and at the end of inpatient treatment, and approximately 6 months after discharge from hospital. RESULTS: Patterns of correlations were stable from admission to the hospital until follow-up. Treatment significantly increased the levels of mentalization and decreased the levels of interpersonal problems and symptom severity, whereas attachment was only partially targeted. Improvements in mentalization significantly predicted reduction in interpersonal distress at each point in time. CONCLUSION: Results revealed characteristic patterns of interpersonal problems, mentalization, symptom severity, and attachment. Mentalization was found to play a key role in the reduction of interpersonal distress. PMID- 29998459 TI - Ornithine decarboxylase is involved in methyl jasmonate-regulated postharvest quality retention in button mushrooms (Agaricus bisporus). AB - BACKGROUND: In the present study, we investigated the role of ornithine decarboxylase (ODC) in the methyl jasmonate (MeJA)-regulated postharvest quality maintenance of Agaricus bisporus (J. E. Kange) Imbach button mushrooms by pretreating mushrooms with a specific irreversible inhibitor called alpha difluoromethylornithine (DFMO) before exposure to MeJA vapor. RESULTS: Mushrooms were treated with 0 or 100 umol L-1 MeJA or a combination of 120 umol L-1 DFMO and 100 umol L-1 MeJA, respectively, before storage at 4 degrees C for 21 days. Treatment with MeJA alone induced the increase in ODC activity whereas this effect was greatly suppressed by pretreatment with DFMO. alpha Difluoromethylornithine strongly attenuated the effect of MeJA on decreasing cap opening, slowing the decline rate of soluble protein and total sugar, and accumulating total phenolics and flavonoids. alpha-Difluoromethylornithine pretreatment also counteracted the ability of MeJA to inhibit polyphenol oxidase and lipoxygenase activities, and malondialdehyde production, and to stimulate superoxide dismutase and catalase activities. It also largely downregulated MeJA induced accumulation of free putrescine (Put). CONCLUSION: These results reveal that ODC is involved in MeJA-regulated postharvest quality retention of button mushrooms, and this involvement is likely to be associated with Put levels. (c) 2018 Society of Chemical Industry. PMID- 29998461 TI - Zwitterionic codeine-derived methacrylate monoliths for enantioselective capillary electrochromatography of chiral acids and chiral bases. AB - Thiol-ene click reaction of N-acetyl-L-cysteine methyl ester to codeine, followed by reaction with allyl isocyanate and hydrolysis to the corresponding zwitterionic chiral selector and its subsequent bonding to the surface of a methacrylate monolith provided a new chiral capillary column for enantiomer separation of chiral acids and chiral bases. First, the epoxy groups of a poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith were converted into amine residues, followed by reaction with allylglycidyl ether. In this way, a spacer arm was bonded to the surface before coating and cross-linking poly(3 mercaptopropyl methylsiloxane) (PMPMS) via radical addition (thiol-ene click reaction) to the surface. In order to improve the performance of the monolithic chiral stationary phase, thio ether and residual thiol groups were oxidized to sulfonyl and sulphonate groups, respectively. This novel chiral stationary phase (CSP) was evaluated by capillary electrochromatography (CEC) using two chiral model compounds, namely N-3,5-dinitrobenzoyl-R,S-leucine (retained by anion exchange mechanism) and mefloquine (by cation-exchange process). The ion-exchange retention mechanism on the CSP was characterized for these two counterionic model solutes by varying the mobile phase composition, including the nature of solvents, the concentration of counter-ions and co-ions, and the acid-to-base ratio. A series of chiral beta-blockers and amino acid derivatives was used to further check the performance of the modified monolith under the optimal conditions. Several enantiomers were baseline resolved with reasonable peak efficiencies (up to 60,000 theoretical plates per meter for the second eluted enantiomer). PMID- 29998460 TI - Nanopore label-free detection of single-nucleotide deletion in Baxalpha/BaxDelta2. AB - Baxalpha, a key tumor suppressor gene, will not be expressed correctly as a result of single nucleotide mutation in its microsatellite region; Instead, BaxDelta2, an isoform of Baxalpha, is often produced. In addition, lack of the exon 2 due to an alternative splicing, BaxDelta2 has the same sequence as Baxalpha except single base deletion from eight continuous guanines (G8) to G7. Most of the currently available methods for Bax?2 detection are inefficient and time-consuming, and/or require the use of labels or dyes. In this work, we reported a label-free nanopore sensing strategy to differentiate between Baxalpha and BaxDelta2 with a DNA polymer as a molecular probe based on alternative spliced sequences. Two DNA molecules were designed to selectively detect Baxalpha and BaxDelta2, respectively. The method was rapid, accurate, and highly sensitive: picomolar concentrations of target nucleic acids could be detected in minutes. Our developed simple and fast nanopore-based detection strategy is not only useful for distinguishing between Baxalpha and Bax?2, but also provides a useful tool for detection of other single-base mutations in genetic diagnosis. PMID- 29998462 TI - Hepatic steatosis is highly prevalent across the paediatric age spectrum, including in pre-school age children. AB - BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children is 8% in the general population, and 34% in the context of obesity. There is a paucity of data on the prevalence of hepatic steatosis in healthy children in Ontario. AIMS: To determine the prevalence of hepatic steatosis using abdominal computed tomography (CT) scans in a cohort of previously healthy children across the paediatric age spectrum in Ontario, Canada, and to determine any association between measures of abdominal adiposity and hepatic steatosis. METHODS: Retrospective review of the SickKids Trauma Database from 2004-2015. Previously healthy children ages 1-17 years having undergone an abdominal CT scan as a part of routine trauma assessment were included, and those with an intra abdominal injury excluded. Steatosis was defined as a difference between liver and spleen attenuation <=-25HU. The percentage of the total area occupied by abdominal subcutaneous adipose and visceral adipose tissue was measured. Anthropometrics and baseline demographics were collected. RESULTS: A total of 503 (51% male) children with mean (+/-SD) age 9.5 +/- 4.5 years and weight z-score of 0.37 +/- 1.05 were studied. Seventy-seven (15%, 95% CI [12%-18%]) had hepatic steatosis; no differences found between sexes or across age quartiles. The abdominal subcutaneous adipose tissue area was greater in those with hepatic steatosis compared to those without (32% [22-42] vs 24% [17-36], P = 0.003). The visceral adipose tissue area was significantly greater in older children >=9.8 years with hepatic steatosis (7.7% [5.1-10] vs 6.6% (4.9-8.5), P = 0.04). CONCLUSION: Hepatic steatosis was highly prevalent in previously healthy children in Ontario, including children of pre-school age. We found an association between hepatic steatosis and abdominal subcutaneous adipose tissue, and in older children with visceral adipose tissue. PMID- 29998463 TI - Genetic tests reveal extra-pair paternity among Gentoo penguins (Pyogoscelis papua ellsworthii) at Loveland Living Planet Aquarium: Implications for ex situ colony management. AB - Maintenance of ex situ populations for species conservation is a collaborative effort involving multiple agencies, institutions, and individuals around the world. Gentoo penguins (Pyogoscelis papua) are one species involved in such a conservation effort, and a Species Survival Plan (SSP) has been put in place by the Association of Zoos and Aquariums (AZA) to foster their long-term sustainability. As a part of their SSP, a Breeding and Transfer Plan has been created to support interagency exchanges of specimens. These transfers are vital to the demographic health and stability of ex situ populations, as well as the maintenance of genetic diversity. In populations such as the Gentoo, where social monogamy exists, paternal inferences of offspring are usually made through observation of birds' social behavior. However, social monogamy does not guarantee reproductive monogamy. In this study, we utilize Illumina high throughput DNA sequencing to genetically test the postulated paternity of Gentoo penguins born at Loveland Living Planet Aquarium (LLPA) in Draper, UT. While our data support the majority of the postulated relationships, we did identify two offspring that were the result of extra-pair paternity (EPP). The results of this research highlight the importance of genetic tests to validate pedigrees used in SSPs, to provide more-accurate data for the support of species conservation. PMID- 29998464 TI - Implications of treatment providers' varying conceptions of the disease model of addiction: A response. PMID- 29998465 TI - Prevalence of depressive symptoms in elderly cancer patients receiving chemotherapy and influencing factors. AB - BACKGROUND: Depression is one of the most prevalent causes of distress in the geriatric population. The purpose of this study was to examine the prevalence of depressive symptoms in elderly cancer patients and to determine the possible associated factors. METHODS: Cancer patients 65 years or older and on active chemotherapy completed the Yesavage Geriatric Depression Scale. We examined the relationship of depressive symptoms with age, gender, marital status, educational background, type of cancer, stage of disease, comorbidities, types of treatment for cancer, the duration after diagnosis of cancer, social support, and pain status. RESULTS: The study included 170 patients with a mean age of 71 years, and 47.1% were women. The prevalence of a high depressive symptom score was 19.4%. Of the patients who had a high depressive symptom score based on the Yesavage Geriatric Depression Scale, 18.2% had already been diagnosed with depression and used antidepressants. The mean pain score was significantly higher in patients who had a high depressive symptom score compared to others (P = 0.012). CONCLUSION: The prevalence of depressive symptoms in elderly cancer patients receiving chemotherapy was similar to that in the geriatric population without cancer. It was also consistent with previous studies on elderly cancer population. Pain was found to be a factor related to depressive symptoms. The prevalence of depression may be reduced by pain control. The treatment of depression may both improve the patient's quality of life and enhance their compliance with treatment. PMID- 29998466 TI - The efficacy of polidocanol sclerotherapy in mucocele of the minor salivary gland. AB - OBJECTIVES: Mucocele of the minor salivary gland is usually caused when the duct is injured, mucus leaks into the tissue space and the mucous gland are obstructed, which lead to cystic lesion formation and dilatation. Currently, there are multiple therapeutic methods available with various outcomes. This study aims to provide clinical evidence of polidocanol sclerotherapy for the treatment of mucocele of the minor salivary gland. METHODS: In this study, we injected polidocanol into 112 patients who were diagnosed with mucocele of the minor salivary gland and evaluated the treatment efficacy and safety systematically. RESULTS: Of the 122 cases, 102 cases were cured, eight cases showed remarkable remission, and two cases had partial remission. No recurrence was found during follow-up, and none of the cases showed an invalid effect, resulting in a total cure rate of 91.07%. No severe side effects were observed during treatment or the follow-up period. No significant difference in efficacy between different genders was found (P = 0.490). Polidocanol sclerotherapy for mucocele on the lower lip was more effective compared to mucocele on the inferior surface of the lingual apex (P = 0.035). CONCLUSION: Polidocanol sclerotherapy showed satisfying curative effects for mucocele of the minor salivary gland without causing side effects of anesthesia, trauma, or severe pain. PMID- 29998467 TI - Amphetamine use in the fourth decade of life: Social profiles from a population based Australian cohort. AB - INTRODUCTION AND AIMS: To estimate the prevalence and frequency of amphetamine use in a cohort of Australians aged in their mid-30s. DESIGN AND METHODS: Cross sectional analysis of wave 10 data collected in 2014 from the Victorian Adolescent Health Cohort Study: a sample of 1435 persons originally selected in a stratified, random community survey of secondary school students from the state of Victoria that commenced in 1992. Weighted multinomial regression models were used to evaluate the social, health and other substance-use correlates of lifetime and current (12-month) amphetamine use and current frequency of use. RESULTS: Lifetime amphetamine use was reported by 23.2% (95% confidence interval 21.0-25.5%) of respondents, and 6.5% (95% confidence interval 5.2-7.8%) reported current (12-month) use. A quarter (26%) of those currently using amphetamines, 1.7% (95% confidence interval 1.0-2.4%) of all respondents, reported frequent (at least weekly) use. Men reported greater amphetamine use than women. Current amphetamine use was associated with disrupted family circumstances, socioeconomic adversity, polydrug use and high levels of drug use within the social and familial environment. Frequent use was associated with greater likelihood of multiple adversity, unemployment, anxiety disorders and use of mental health services. DISCUSSION AND CONCLUSIONS: The current results show that lifetime, current and frequent amphetamine use was common amongst adults in the fourth decade of life in this cohort, and associated with the experience of social disadvantage, poor mental health and living in a social context in which drug use is the norm. PMID- 29998468 TI - Three cases of clear-cell adenocarcinoma arising from endometrioma during hormonal treatments. AB - Endometrioma is known to be an occurrence site of ovarian cancer, but there is no evidence on how to reduce the risk of canceration. Here, we report three cases of ovarian cancer arising from endometrioma during hormone therapies of GnRH analogue and tamoxifen, low-dose estrogen-progestin (LEP) and dienogest. In all cases, each hormonal treatment was effective in shrinking the size of the endometrioma. During hormonal treatments, solid parts inside endometrioma were observed, which was followed by surgery. The histology of the solid parts was clear-cell adenocarcinoma in all cases. An immunohistochemistry study demonstrated that the estrogen receptor (ER) and progesterone receptor (PR) were positive in the endometriosis part but negative in the cancer part, while the human EGF receptor (HER) 2 was negative or very weak in the benign part and positive in the malignant part in all three cases. Even though hormonal treatments seem to be effective to regulate endometrioma, careful observation is needed to follow-up patients with endometrioma. PMID- 29998469 TI - Effect of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogels on frozen-thawed human ovarian tissue in a xenograft model. AB - AIM: Ovarian tissue cryopreservation before cancer treatment is the only option to preserve fertility under some circumstances. However, tissue ischemia after transplantation while awaiting angiogenesis induces dysfunctional folliculogenesis and reduces ovarian reserve and is one of the disadvantages of frozen-thawed ovarian tissue transplantation. Basic fibroblast growth factor (bFGF) is a major regulator of angiogenesis. However, bFGF rapidly loses biological activity when its free form is injected in vivo. This study investigated whether administration of active bFGF helps establish a nurturing environment for follicular survival. METHODS: A sheet form of a sustained release drug delivery system for bFGF was developed using biodegradable acidic gelatin hydrogel (bFGF sheet). The bFGF sheets or phosphate-buffered saline sheets, as a negative control, were transplanted with frozen-thawed human ovarian tissues subcutaneously into the backs of severe combined immunodeficient mice. Neovascularization, cell proliferation, fibrosis and follicular survival of ovarian grafts were analyzed at 6 weeks after xenografting. RESULTS: The bFGF sheets were optimized to release bFGF for at least 10 days. The transplantation of bFGF sheets with frozen-thawed ovarian tissues significantly increased human and mouse CD31-positive areas and stromal and endothelial cell proliferations. The administration of bFGF also significantly decreased the percentage of the fibrotic area in the graft, resulting in a significant increase in primordial and primary follicular density. CONCLUSION: Local administration of a sustained release of biologically active bFGF induced neovascularization in frozen-thawed ovarian tissue grafts, which could establish the nurturing environment required for follicular survival in heterotopic xenografts. PMID- 29998471 TI - The functions of foliar nyctinasty: a review and hypothesis. AB - Foliar nyctinasty is a plant behaviour characterised by a pronounced daily oscillation in leaf orientation. During the day, the blades of nyctinastic plant leaves (or leaflets) assume a more or less horizontal position that optimises their ability to capture sunlight for photosynthesis. At night, the positions that the leaf blades assume, regardless of whether they arise by rising, falling or twisting, are essentially vertical. Among the ideas put forth to explain the raison d'etre of foliar nyctinasty are that it: (i) improves the temperature relations of plants; (ii) helps remove surface water from foliage; (iii) prevents the disruption of photoperiodism by moonlight; and (iv) directly discourages insect herbivory. After discussing these previous hypotheses, a novel tritrophic hypothesis is introduced that proposes that foliar nyctinasty constitutes an indirect plant defence against nocturnal herbivores. It is suggested that the reduction in physical clutter that follows from nocturnal leaf closure may increase the foraging success of many types of animals that prey upon or parasitise herbivores. Predators and parasitoids generally use some combination of visual, auditory or olfactory cues to detect prey. In terrestrial environments, it is hypothesised that the vertical orientation of the blades of nyctinastic plants at night would be especially beneficial to flying nocturnal predators (e.g. bats and owls) and parasitoids whose modus operandi is death from above. The movements of prey beneath a plant with vertically oriented foliage would be visually more obvious to gleaning or swooping predators under nocturnal or crepuscular conditions. Such predators could also detect sounds made by prey better without baffling layers of foliage overhead to damp and disperse the signal. Moreover, any volatiles released by the prey would diffuse more directly to the awaiting olfactory apparatus of the predators or parasitoids. In addition to facilitating the demise of herbivores by carnivores and parasitoids, foliar nyctinasty, much like the enhanced illumination of the full moon, may mitigate feeding by nocturnal herbivores by altering their foraging behaviour. Foliar nyctinasty could also provide a competitive advantage by encouraging herbivores, seeking more cover, to forage on or around non-nyctinastic species. As an added advantage, foliar nyctinasty, by decreasing the temperature between plants through its effects on re-radiation, may slow certain types of ectothermic herbivores making them more vulnerable to predation. Foliar nyctinasty also may not solely be a behavioural adaptation against folivores; by discouraging foraging by granivores, the inclusive fitness of nyctinastic plants may be increased. PMID- 29998470 TI - Systematic gene overexpression in Candida albicans identifies a regulator of early adaptation to the mammalian gut. AB - Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonisation, we competitively challenged growth of 572 signature-tagged strains (~10% genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonisation. Using clues from genome-wide expression and gene-set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37 degrees C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonisation of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome-wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase and cell-wall protein-encoding genes, suggesting a link with cell-wall function. We show that CRZ2 overexpression alters cell-wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment. PMID- 29998473 TI - The scope and conventions of evidence-based medicine need to be widened to deal with "too much medicine". AB - In order that evidence-based medicine can prevent "too much medicine", it has to provide evidence in support of "gold standard" findings for use as diagnostic criteria, on which the assessment of other diagnostic tests and the outcomes of randomized controlled trials depend. When the results of such gold standard tests are numerical, cut-off points have to be positioned, also based on evidence, to identify those in whom offering a treatment can be justified. Such a diagnosis depends on eliminating conditions that mimic the one to be treated. The distributions of the candidate gold standard test results in those with and without the required outcome of treatment are then used with Bayes rule to create curves that show the probabilities of the outcome with and without treatment. It is these curves that are used to identify a cut-off point for offering a treatment to a patient and also to inform the patient's decision to accept or reject the suggested treatment. This decision is arrived at by balancing the probabilities of beneficial outcomes against the probabilities of harmful outcomes and other costs. The approach is illustrated with data from a randomized controlled trial on treating diabetic albuminuria with an angiotensin receptor blocker to prevent the development of the surrogate end-point of "biochemical nephropathy". The same approach can be applied to nonsurrogate outcomes such as death, disability, quality of life, relief of symptoms, and their prevention. Those with treatment-justifying diagnoses such as "diabetic albuminuria" usually form part of a broader group such as "type 2 diabetes mellitus". Any of these can be made the subject of evidence-based differential diagnostic strategies. PMID- 29998472 TI - Expansions of key protein families in the German cockroach highlight the molecular basis of its remarkable success as a global indoor pest. AB - The German cockroach, Blattella germanica, is a worldwide pest that infests buildings, including homes, restaurants, and hospitals, often living in unsanitary conditions. As a disease vector and producer of allergens, this species has major health and economic impacts on humans. Factors contributing to the success of the German cockroach include its resistance to a broad range of insecticides, immunity to many pathogens, and its ability, as an extreme generalist omnivore, to survive on most food sources. The recently published genome shows that B. germanica has an exceptionally high number of protein coding genes. In this study, we investigate the functions of the 93 significantly expanded gene families with the aim to better understand the success of B. germanica as a major pest despite such inhospitable conditions. We find major expansions in gene families with functions related to the detoxification of insecticides and allelochemicals, defense against pathogens, digestion, sensory perception, and gene regulation. These expansions might have allowed B. germanica to develop multiple resistance mechanisms to insecticides and pathogens, and enabled a broad, flexible diet, thus explaining its success in unsanitary conditions and under recurrent chemical control. The findings and resources presented here provide insights for better understanding molecular mechanisms that will facilitate more effective cockroach control. PMID- 29998474 TI - Simultaneous enantioseparation of methcathinone and two isomeric methylmethcathinones using capillary electrophoresis assisted by 2-hydroxyethyl beta-cyclodextrin. AB - Methcathinone (ephedrone), 4-methylmethcathinone (mephedrone), and 3 methylmethcathinone (metaphedrone) are toxicologically-important cathinone derivatives used commonly as designer drugs. In this work we show the first method allowing to separate simultaneously all these molecules in a chiral medium, ensuring good resolution between all enantiomers. Eight cyclodextrins have been tested as potential chiral selectors, the best results were obtained with 2-hydroxyethyl-beta-cyclodextrin, unreported so far for efficient separation of cathinones. After optimization, the method was calibrated and validated with and without the use of internal standard. The addition of standard improved an overall repeatability and precision, the use of electrophoretic mobility ratio was especially favorable (RSD < 1%). It was demonstrated that the method may be easily extended by introducing the additional cathinone-related drugs to the sample, maintaining satisfactory separation efficiency. PMID- 29998475 TI - Pediatric Wells syndrome (eosinophilic cellulitis) after vaccination: A case report and review of the literature. AB - A 4-year-old boy presented with erythematous vesicular plaques, ulceration, edema, and pruritus on the left foot and ankle 10 days after receiving the tetanus, diphtheria, pertussis, and polio; measles, mumps, rubella, and varicella; and hepatitis A/B vaccines. Biopsy showed eosinophilic infiltrates and flame figures, suggesting Wells syndrome. Patch testing showed a 1+ reaction to neomycin and aluminum hydroxide, with a recall reaction of Wells syndrome of the feet bilaterally. We report a rare case of pediatric Wells syndrome triggered by nonthimerosal vaccine components confirmed by patch testing. PMID- 29998476 TI - Mechanisms of blood pressure control following acute exercise in adolescents: Effects of exercise intensity on haemodynamics and baroreflex sensitivity. AB - NEW FINDINGS: What is the central question of this study? What are the autonomic and vascular components of the baroreflex during hypotension following different exercise intensities in adolescents? What is the main finding and its importance? Hypotension after high-intensity exercise lasted 60 min, whereas following moderate-intensity exercise, blood pressure was restored after 20 min. Stroke volume and peripheral resistance responses were different between intensities. Post both exercise intensities, baroreflex sensitivity was lowered mainly due to the autonomic component, which returned to baseline 60 min post-exercise. The different haemodynamic stimuli indicate potential differences in cardiovascular health benefits of exercise intensity in healthy adolescents. ABSTRACT: This work aimed to investigate the time course of changes in baroreflex sensitivity (BRS) and its vascular and autonomic components after different exercise intensities in adolescents. Thirteen male adolescents (age 13.9 +/- 0.5 years) completed on separate days in a counterbalanced order (1) high-intensity interval exercise (HIIE): 8 * 1 min running at 90% of maximal aerobic speed with 75 s of active recovery; (2) moderate-intensity interval exercise (MIIE): 10-12 bouts of 1 min running at 90% of gas exchange threshold with 75 s of active recovery; and (3) resting as a control. Supine heart rate and blood pressure were monitored continuously at baseline, and 5 and 60 min following the conditions. A cross spectral method (low frequency gain; LFgain ) was used to determine BRS gain. Arterial compliance (AC) was assessed as the BRS vascular component. LFgain /AC was used as the autonomic component. LFgain decreased 5 min post-exercise bouts (HIIE P < 0.001; MIIE P = 0.002), but returned to baseline at 60 min post exercise. AC increased at 5 min post-exercise for all conditions (P = 0.048), and returned to baseline at 60 min post-exercise. LFgain /AC decreased 5 min post exercise bouts (HIIE P = 0.001; MIIE P = 0.004), but returned to baseline values at 60 min post-exercise. Mean arterial pressure was lowered by both exercise intensities at 5 min post-exercise, but remained decreased at 60 min post exercise following HIIE only. In conclusion, BRS decreases 5 min following exercise in adolescents independent of exercise intensity and is mainly driven by a lowered autonomic response. At 60 min post-exercise, the ability of BRS to regulate blood pressure is restored after MIIE but not after HIIE, indicating exercise intensity-dependent mechanisms. PMID- 29998478 TI - Nanoparticle-induced enzyme pretreatment method for increased glucose production from lignocellulosic biomass under cold conditions. AB - BACKGROUND: Appropriate pretreatment strategies that fractionate sugarcane bagasse (SB) are essential for the successful use of this feedstock in ethanol production. In this paper, we investigate a purely enzymatic process to achieve increased production of reducing sugars (RS) from SB in the presence of MgO nanoparticles (MgN) subjected to a three-step sequential enzyme treatment. RESULT: Pretreatment of SB with protease activated by magnesium oxide nanoparticles (MgN-pro) at 95 degrees C showed an increase in amino acid production by 6.18-fold compared to the untreated enzyme set at the same temperature. High-performance liquid chromatography (HPLC) studies showed an 18 fold removal of lignin from the samples subjected to protease (+ MgN) treatment compared to untreated samples. When the MgN-pro pretreated samples were subjected to pretreatment with xylanase activated by magnesium oxide nanoparticles (MgN xyl), more than 30-fold increased RS was produced at 8 degrees C compared to cellulase (cel) pretreated samples. Xylanase pretreated SB samples produced 1.82- and 1.91-fold increased reducing sugar and glucose respectively at 8 degrees C in the presence of MgN compared to untreated samples at the same temperature. CONCLUSION: The results presented here show the efficiency of the proposed method for improving the enzymatic digestibility of SB and explain the pretreatment action mechanism. These findings have potential implications in bio-ethanol, bio fuel, and agro industries. (c) 2018 Society of Chemical Industry. PMID- 29998477 TI - The incidence and prognosis of thromboembolism associated with oral contraceptives: Age-dependent difference in Japanese population. AB - AIM: We analyzed the incidence and prognosis of thromboembolism associated with combined oral contraceptives (COCs) by age groups in Japan. METHODS: A total of 581 events of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with COCs were analyzed from the Pharmaceuticals and Medical Devices Agency database from 2004 to 2013. In a statistical analysis, a good-prognosis group included recovery cases and a poor-prognosis group involved unrecovered cases with some sequela and fatal cases. The significant difference between these two groups was calculated by Pearson's chi-square test, and the age-specific tendency and the trend of differences in prognosis according to different hormonal contraceptives were examined by Cochran-Armitage trend test. RESULTS: A total of 543 events were analyzed except 38 events due to unknown age, in which DVT only was the most frequent, followed by cerebral infarction, PE with DVT, PE only, cerebral vein thromboses. ATE ratio for overall thromboembolism tended to increase with advancing age (P = 0.0041). Good-prognosis group was common (291 cases in VTE and 83 cases in ATE), followed by poor-prognosis group (46 cases in VTE and 34 cases in ATE). All ATE cases had a significantly poorer prognosis in comparison with all VTE cases (P < 0.0001). Types of progestin and age difference, however, showed no trend in the differences between good-prognosis group and poor-prognosis group (P = 0.3548 and P = 0.6097). CONCLUSION: Thromboembolic events were the most frequent in the 40s. The ATE ratio for overall thromboembolism tended to increase with advancing age. All ATE cases had a significantly poorer prognosis in comparison with all VTE cases. PMID- 29998480 TI - Responding to hurricanes in Puerto Rico-A public health disaster. PMID- 29998479 TI - Thinking inside the mouth: Public health nurses solve the dental crisis. PMID- 29998481 TI - The shape of things to come: Early life stress stunts brainstem microglia, with lasting implications for cardiorespiratory control and plasticity. PMID- 29998482 TI - Combination of microwave endometrial ablation and postoperative dienogest administration is effective for treating symptomatic adenomyosis. AB - AIM: Menorrhagia and dysmenorrhea are common symptoms. Uterine adenomyosis is one of the causes of menorrhagia and dysmenorrhea. These symptoms often decrease the quality of life in women. Microwave endometrial ablation (MEA) is a recently developed procedure that enables endometrial ablation. Dienogest has long been used to suppress endometrium development and reduce adenomyosis-related dysmenorrhea. However, some cases could be resistant to dienogest. In this study, we evaluated the efficacy of a combination of MEA and postoperative dienogest in reducing adenomyosis-related dysmenorrhea and menorrhagia. METHODS: Ten patients with hormone treatment-resistant symptomatic adenomyosis underwent MEA and were administered oral dienogest after the procedure. The primary endpoints were reduction in pain recurrence and anemia. The secondary endpoint was a change in the adenomyosis lesion and its symptomatic recurrence. RESULTS: Statistically significant improvements were seen in the visual analog scale score and hemoglobin levels in women post-treatment. The difference in myometrial thickness pre- and post-MEA was statistically significant. There were no cases of symptomatic recurrence. CONCLUSION: The combination of MEA and postoperative dienogest is useful for treating uterine adenomyosis with menorrhagia and dysmenorrhea. PMID- 29998483 TI - Covariate adjustment and estimation of mean response in randomised trials. AB - Analyses of randomised trials are often based on regression models which adjust for baseline covariates, in addition to randomised group. Based on such models, one can obtain estimates of the marginal mean outcome for the population under assignment to each treatment, by averaging the model-based predictions across the empirical distribution of the baseline covariates in the trial. We identify under what conditions such estimates are consistent, and in particular show that for canonical generalised linear models, the resulting estimates are always consistent. We show that a recently proposed variance estimator underestimates the variance of the estimator around the true marginal population mean when the baseline covariates are not fixed in repeated sampling and provide a simple adjustment to remedy this. We also describe an alternative semiparametric estimator, which is consistent even when the outcome regression model used is misspecified. The different estimators are compared through simulations and application to a recently conducted trial in asthma. PMID- 29998484 TI - Exposure to whole chicken carcasses may present a greater risk of campylobacteriosis compared to exposure to chicken drumsticks. AB - In New Zealand, the major risk factor for campylobacteriosis has been identified as poultry consumption. New Zealanders consume different types of chicken meat which undergo different processing before entering the retail chain. The manipulations and jointing of chicken carcasses into pieces and the subsequent processing and packaging have the potential to cross-contaminate and reshuffle bacterial pathogens among the different products sold. The aim of this study was to analyse: (a) the differences in the viable count and population genetic structure between Campylobacter isolated from chicken drumsticks and whole carcass meat for retail sale over a 1-year period; and (b) the genetic relatedness of human and chicken isolates collected concurrently. Enumeration of Campylobacter was performed using a spiral plater combined with manual spread plating. Campylobacter isolates were identified by polymerase chain reaction and typed by multilocus sequence typing (MLST). C. jejuni was the dominant species among both whole carcasses (63.5%) and drumsticks samples (73.8%), followed by C. coli (27% and 23.1%, respectively). After sample weight adjustment, whole carcasses showed significantly higher Campylobacter counts than drumsticks, with a significant difference in the counts between the commercial suppliers in both types of retail meat. MLST revealed 28 different sequence types among the two types of meat. Using permutational multivariate analysis of variance, statistically significant differences in the population genetic structures were observed between different suppliers but were not observed between the two types of chicken retail meat. In conclusion, we found differences in Campylobacter viable counts, suggesting consumption of whole carcasses may determine an exposure to a higher number of Campylobacter bacteria than consumption of chicken drumsticks. The Campylobacter population genetic structure did not differ between the two types of chicken retail meat. Therefore, source attribution studies based on MLST are unlikely to be biased by the selection of these types of retail meat during sampling. PMID- 29998485 TI - ASK1 inhibitor treatment suppresses p38/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis. AB - Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun amino terminal kinase (JNK) is prominent in human crescentic glomerulonephritis. p38 and JNK inhibitors suppress crescentic disease in animal models; however, the upstream mechanisms inducing activation of these kinases in crescentic glomerulonephritis are unknown. We investigated the hypothesis that apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) promote p38/JNK activation and renal injury in models of nephrotoxic serum nephritis (NTN); acute glomerular injury in SD rats, and crescentic disease in WKY rats. Treatment with the selective ASK1 inhibitor, GS-444217 or vehicle began 1 hour before nephrotoxic serum injection and continued until animals were killed on day 1 (SD rats) or 14 (WKY rats). NTN resulted in phosphorylation (activation) of p38 and c-Jun in both models which was substantially reduced by ASK1 inhibitor treatment. In SD rats, GS-444217 prevented proteinuria and glomerular thrombosis with suppression of macrophage activation on day 1 NTN. In WKY rats, GS-444217 reduced crescent formation, prevented renal impairment and reduced proteinuria on day 14 NTN. Macrophage activation, T-cell infiltration and renal fibrosis were also reduced by GS 444217. In conclusion, GS-444217 treatment inhibited p38/JNK activation and development of renal injury in rat NTN. ASK1 inhibitors may have therapeutic potential in rapidly progressive glomerulonephritis. PMID- 29998486 TI - Use of the ACTIVLIM-CP questionnaire: gauging daily performance in children with cerebral palsy. PMID- 29998487 TI - Presence and distribution of leptin and its receptor in the gut of adult zebrafish in response to feeding and fasting. AB - Leptin is an anorectic hormone secreted mainly by peripheral adipocytes but also by other central and peripheral tissues. It acts by means of a receptor called OB R, influencing not only appetite and body mass but being also involved in many fields like endocrinology, metabolism and reproduction. Immunohistochemistry and qRT-PCR techniques were, respectively, used to demonstrate the presence of leptin and its receptor in the gut of adult zebrafish and to evaluate the leptin gene expression response to feeding and fasting. Immunoreactivity for the antibodies utilized was demonstrated in feeding but not in fasting fish, and the gene expression analysis corroborates the data obtained by immunohistochemistry. Therefore, all the obtained results support the hypothesis of the role of this hormone in food regulation in zebrafish. PMID- 29998489 TI - The longitudinal effects of induction on beginning teachers' stress. AB - BACKGROUND: Teaching is a stressful profession especially for beginning teachers. Induction programmes can support beginning teachers. Little is known concerning which elements of induction programmes can influence (the change in) teachers' stress over time. AIMS: This study aims to investigate the growth of stress causes and stress responses during the first 3 years of professional practice and to reveal the influence of induction arrangement elements on the initial level as well as the change in stress levels over the 2 years that followed. SAMPLE: Longitudinal data from a sample of 393 beginning teachers (56.5% female) were collected at three measurement occasions. All teachers were offered four different induction arrangement elements. METHOD: Results of multiple group confirmatory factor analysis confirmed longitudinal measurement invariance. Multivariate latent growth curve modelling (MLGM) was conducted to examine the initial status, the subsequent linear growth, and the influence of the individual induction arrangement elements on the stress causes and stress responses. RESULTS: MLGM results show that perceived stress caused by high psychological task demands increases over time (d = 0.22), whereas perceived stress caused by negative pupil aspects decreases over time (d = -0.52). Further, workload reduction decreases the level of perceived high psychological task demands, negative social aspects, and all the stress responses. Perceived support for effective teaching behaviour decreases the level of perceived negative emotions and discontent. Further, school enculturation has an influence on the change in perceived discontent over time. CONCLUSIONS: Perceived stress causes and stress responses can change over time. Specific induction arrangement elements appear to be powerful elements to reduce the level, and the change over time, of specific perceived stress causes and stress responses. PMID- 29998488 TI - Induction of NAD (P)H: Quinone reductase 1 (QR1) and antioxidant activities in vitro of 'Toranja Burarama' (Citrus maxima [Burm.] Merr.). AB - Toranja 'Burarama', Citrus maxima (Burm.) Merr. (Citrus grandis), is a new citrus discovered in the State of Espirito Santo, Brazil. As several varieties of citrus are known to possess antioxidant and cancer chemopreventive properties, the aim of the study was to evaluate in vitro if this Toranja possess these properties. The antioxidant activity, the potential to induce quinone reductase 1, and the influence on cell viability were measured. ESI(-)FT-ICR MS analysis was also performed and identified flavonoids, coumarins, and fatty acids in the extract. The ethyl acetate and methanolic extracts of the peels presented the highest antioxidant activity in vitro by DPPH (IC50 = 298.3 +/- 2.6 MUg/ml and 303.8 +/- 0.4 MUg/ml), ABTS assay (IC50 = 298.2 +/- 6.4 MUg/ml and 296.4 +/- 2.5 MUg/ml), and FRAP (IC50 = 234.6 +/- 1.8 MUg/ml and 398.1 +/- 3.8 MUg/ml). The ethyl acetate extract of the peel induced quinone reductase 1 activity in Hepa1c1c7 cells, indicating that C. maxima exhibited cancer chemopreventive properties. PMID- 29998490 TI - Current dorsal myelographic column and dural diameter reduction rules do not apply at the cervicothoracic junction in horses. AB - Previously published myelographic studies do not report findings at the junction between the seventh cervical (C7) and first thoracic vertebrae (T1). Modern digital radiographic equipment allows improved visualization of C7-T1. Based on clinical experience, we hypothesized that 50% reduction of the dorsal myelographic column or 20% reduction of the dural diameter, criteria commonly used as a supportive finding for spinal cord compression in the cervical vertebral column, do not apply at C7-T1. A myelographic study was performed on 12 healthy, neurologically normal horses. Our hypothesis was confirmed; using established criteria eight of 12 horses would have been classified as having evidence of spinal cord compression at C7-T1. The dorsal myelographic column reduction at C7-T1 was 48 +/- 12%, while the C6-C7 dorsal myelographic column reduction was 33 +/- 17% (mean +/- standard deviation) (P = 0.010). The dural diameter reduction at C7-T1 (22.0 +/- 6.7%) was significantly greater than the dural diameter reduction at C6-C7 (13.2 +/- 9.5%) (P = 0.0007). Further measurements and comparisons suggested that the apparent greater reduction of dorsal myelographic column and dural diameter at C7-T1 was due to larger intravertebral measurements at C7 rather than smaller intervertebral values at C7 T1. Based on these findings, alternative criteria should be used at C7-T1 when assessing clinical cases for cervical stenotic myelopathy. Reduction of the dorsal myelographic column by 60% or of the dural diameter by 30% would avoid high numbers of false positive myelographic cases at C7-T1. PMID- 29998491 TI - Technical Note: Retrospective reduction in systematic differences across scanner changes by accounting for noise floor effects in diffusion tensor imaging. AB - PURPOSE: The purpose of this study was to determine if retrospective correction for noise floor effects can reduce systematic differences and improve reproducibility across major scanner changes. Changes in scanner configuration can negatively impact quantitative MRI studies by introducing systematic differences between measurements that are due to the instrument, not biology. Noise floor rectification is a potential source of systematic differences in diffusion tensor imaging (DTI). METHODS: Healthy volunteers were scanned before and after a major scanner change at four sites. DTI-based measures of tissue microstructure were calculated using a standard approach that ignores noise floor effects and using a maximum likelihood estimation (MLE) approach that accounts for the noise floor. Voxelwise estimates of systematic differences and reproducibility were evaluated. RESULTS: Accounting for noise floor effects can reduce the extent of systematic differences and can improve reproducibility. However, when signal levels are high, accounting for the noise floor can have a deleterious effect. An empirical metric constructed to reflect the magnitude of noise floor effects signal-to-noise-floor ratio (SNFR). The MLE approach improves reproducibility for SNFR < 3. CONCLUSIONS: Accounting for noise floor effects can boost the robustness of DTI measurements in the presence of scanner changes, potentially improving the reliability of DTI for studies of neurological disease. PMID- 29998492 TI - Factors that promote new or continuous participation in social group activity among Japanese community-dwelling older adults: A 2-year longitudinal study. AB - AIM: Identifying factors that influence participation in social group activities in older adults might be helpful in promoting social participation in this population. We examined factors related to new or continuous participation in social group activities according to group type. METHODS: We carried out a community-based, longitudinal study with a 2-year follow-up period. Of 7608 older adults aged >=65 years, 3380 completed the follow-up survey and were included in the analysis. We examined private group (hobbies, sports and volunteering; PrG) and public group (neighborhood associations and senior citizen clubs; PuG) activity. RESULTS: For PrG, 39.6% of the participants were engaged at baseline, 25.5% initiated participation and 9.5% withdrew during the study period. For PuG, 20.8% of the participants were engaged at baseline, 10.8% initiated participation and 31.5% withdrew during the study period. Logistic regression analysis showed mental health, self-rated health, employment, relationships with neighbors, subjective economic status, educational attainment and participation in PuG were related to new participation in PrG. Mental health, employment and relationships with neighbors were significantly related to continuous participation. For PuG, mental health, sex and relationships with neighbors were significantly related to new participation, whereas sex, relationships with neighbors and educational attainment were related to continuous participation. CONCLUSIONS: The rate of new and continuous participation in PrG was higher than that in PuG, and different related factors were identified as existing between social group types. Geriatr Gerontol Int 2018; 18: 1259-1266. PMID- 29998493 TI - Photokeratitis among restaurant workers: A case series. AB - This case report highlights the challenges associated with the diagnosis and workplace evaluation of occupationally acquired ultraviolet (UV) radiation induced photokeratitis and associated skin burns in a group of restaurant workers. UV-C spectrum bulbs were inadvertently shipped and installed in insect light traps. Ocular and dermal symptoms were reported in 18 of 85 restaurant employees to varying degrees of severity over a 2-day period. One patient was formally diagnosed with a chemical burn/irritation of the cornea. More severe symptoms were reported by individuals working in close proximity to the lights. This clinical picture can resemble mass chemical or irritant exposure when multiple individuals are affected, and a multidisciplinary approach was required for rapid identification of the source to limit morbidity. Prevention strategies for similar events should be considered which can include limiting hardware compatibility and improving warning labels. PMID- 29998494 TI - Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia. AB - BACKGROUND: Beta thalassaemia is a common inherited blood disorder. The need for frequent blood transfusions in this condition poses a difficult problem to healthcare systems. The most common cause of morbidity and mortality is cardiac dysfunction from iron overload. The use of iron chelation therapy has reduced the severity of systemic iron overload but specific, non-toxic treatment is required for removal of iron from the myocardium. OBJECTIVES: To assess the effects of calcium channel blockers combined with standard iron chelation therapy in people with transfusion-dependent beta thalassaemia on the amount of iron deposited in the myocardium, on parameters of heart function, and on the incidence of severe heart failure or arrhythmias and related morbidity and mortality. SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials databases, and the reference lists of relevant articles and reviews.Date of last search: 24 February 2018. SELECTION CRITERIA: We included randomised controlled trials of calcium channel blockers combined with standard chelation therapy compared with standard chelation therapy alone or combined with placebo in people with transfusion dependent beta thalassaemia. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria for the selection of trials. Two authors assessed the risk of bias of trials and extracted data and a third author verified these assessments. The authors used the GRADE system to assess the quality of the evidence. MAIN RESULTS: Two randomised controlled trials (n = 74) were included in the review; there were 35 participants in the amlodipine arms and 39 in the control arms. The mean age of participants was 24.4 years with a standard deviation of 8.5 years. There was comparable participation from both genders. Overall, the risk of bias in included trials was low. The quality of the evidence ranged across outcomes from low to high, but the evidence for most outcomes was judged to be low quality.Cardiac iron assessment, as measured by heart T2*, did not significantly improve in the amlodipine groups compared to the control groups at six or 12 months (low-quality evidence). However, myocardial iron concentration decreased significantly in the amlodipine groups compared to the control groups at both six months, mean difference -0.23 mg/g (95% confidence interval -0.07 to -0.39), and 12 months, mean difference -0.25 mg/g (95% confidence interval -0.44 to -0.05) (low-quality evidence). There were no significant differences between treatment and control groups in serum ferritin (low-quality evidence), liver T2* (low-quality evidence), liver iron content (low quality evidence) and left ventricular ejection fraction (low-quality evidence). There were no serious adverse events reported in either trial; however, one trial (n = 59) reported mild adverse events, with no statistically significant difference between groups (low-quality evidence). AUTHORS' CONCLUSIONS: The available evidence does not clearly suggest that the use of calcium channel blockers is associated with a reduction in myocardial iron in people with transfusion-dependent beta thalassaemia, although a potential for this was seen. There is a need for more long-term, multicentre trials to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should be designed to compare commonly used iron chelation drugs with the addition of calcium channel blockers to investigate the potential interplay of these treatments. In addition, the role of baseline myocardial iron content in affecting the response to calcium channel blockers should be investigated. An analysis of the cost-effectiveness of the treatment is also required. PMID- 29998495 TI - Mitochondrial ataxia is genetically and phenotypically heterogeneous. PMID- 29998496 TI - Effect of pre-storage removal of different parts of the scape top on the biochemical changes of two garlic cultivars during controlled atmosphere storage. AB - BACKGROUND: This study highlights the effect of removing different plant parts on the biochemical changes in the garlic scape of cultivars G064 and G025 during controlled atmosphere storage (O2 = 2%-5%, CO2 = 3%-6%) at temperature = 0 +/- 0.5 degrees C, Relative Humidity (RH) RH = 85%-95%, for 168 day. Total polyphenols (TP), total flavonoids (TF), the concentration of allicin, ethylene production and the antioxidant potential were evaluated and analyzed by using four different assays. Statistically significant differences were observed between different treatments. RESULTS: Total polyphenols, allicin concentration, and ethylene production were the highest in G064, while the total flavonoid concentration was the highest in G025. Removing the top resulted in the highest levels of total polyphenols, total flavonoids, allicin, and ethylene in both cultivars. The antioxidant capacity was also significantly higher when the top was removed than with other treatments in both cultivars. 2,2-Diphenyl-1 picrylhydrazyl (DPPH), hydroxyl radical scavenging activity (HRSC), ferric ion reducing antioxidant power (FRAP) and metal-chelating capacity (MCC) were higher in cultivar G064 compared to G025. CONCLUSION: Overall, the results suggest that the removing the tops of the scapes of G025 and G064 is the best treatment to maintain these biochemical changes. (c) 2018 Society of Chemical Industry. PMID- 29998498 TI - Editorial: proton pump inhibitors (PPIs) and primary liver cancer. PMID- 29998497 TI - Do bednets including piperonyl butoxide offer additional protection against populations of Anopheles gambiae s.l. that are highly resistant to pyrethroids? An experimental hut evaluation in Burkina Fasov. AB - Malaria control is dependent on the use of longlasting insecticidal nets (LLINs) containing pyrethroids. A new generation of LLINs containing both pyrethroids and the synergist piperonyl butoxide (PBO) has been developed in response to increasing pyrethroid resistance in African malaria vectors, but questions remain about the performance of these nets in areas where levels of pyrethroid resistance are very high. This study was conducted in two settings in southwest Burkina Faso, Vallee du Kou 5 and Tengrela, where Anopheles gambiae s.l. (Diptera: Culicidae) mortality rates in World Health Organization (WHO) discriminating dose assays were < 14% for permethrin and < 33% for deltamethrin. When mosquitoes were pre-exposed to PBO in WHO tube assays, mortality rates increased substantially but full susceptibility was not restored. Molecular characterization revealed high levels of kdr alleles and elevated levels of P450s previously implicated in pyrethroid resistance. In cone bioassays and experimental huts, PBO LLINs outperformed the pyrethroid-only equivalents from the same manufacturers. Blood feeding rates were 1.6-2.2-fold lower and mortality rates were 1.69-1.78-fold greater in huts with PBO LLINs vs. non-PBO LLINs. This study indicates that PBO LLINs provide greater personal and community-level protection than standard LLINs against highly pyrethroid-resistant mosquito populations. PMID- 29998499 TI - Editorial: post-operative complications in elderly onset inflammatory bowel disease-what is surgery, what is disease, and what is delay of surgery? PMID- 29998500 TI - Editorial: ustekinumab and Crohn's disease-what can we learn from long-term extension studies? PMID- 29998501 TI - Letter: vedolizumab drug levels in cord and maternal blood in women with inflammatory bowel disease-authors' reply. PMID- 29998502 TI - Letter: vedolizumab drug levels in cord and maternal blood in women with inflammatory bowel disease. PMID- 29998503 TI - Editorial: role of leucine-metformin-sildenafil combination in the treatment of nonalcoholic fatty liver disease (NAFLD). PMID- 29998504 TI - Editorial: post-operative complications in elderly onset inflammatory bowel disease-what is surgery, what is disease, and what is delay of surgery? Authors' reply. PMID- 29998505 TI - Editorial: is sofosbuvir-based therapy suitable for patients with advanced chronic kidney disease? PMID- 29998506 TI - Elevated ST2 levels are associated with antibody-mediated rejection in heart transplant recipients. AB - Soluble ST2 (sST2) is a novel biomarker of inflammation and fibrosis. Elevated sST2 levels (>=35 ng/mL) are associated with worse outcomes in patients with heart failure (HF). There are sparse data regarding the significance of sST2 levels after heart transplantation (HTx). The study aims were to evaluate trends in soluble ST2 levels after the resolution of HF status with HTx and association between post-HTx sST2 levels and outcomes. Plasma sST2 levels were measured at baseline (median [IQR] of 118 days pre-HTx) and 12 months post-HTx in 62 subjects who were stratified into two groups by post-HTx sST2 levels < or >=35 ng/mL: "Group 1" or "Group 2," respectively. Plasma sST2 levels were elevated in 58% of patients pre-HTx and in 50% of patients post-HTx. There was no association between elevated sST2 levels before and after HTx, and no significant differences in baseline characteristics between Group 1 and Group 2 patients. Group 2 as compared to Group 1 HTx recipients had significantly higher incidence of antibody mediated rejection (AMR) for the entire post-transplant follow-up period (32% vs 4%, P = 0.006). There was no association between post-HTx sST2 level status and other post-HTx outcomes including survival. In conclusion, elevated plasma sST2 levels after HTx are associated with increased risk for AMR. PMID- 29998507 TI - Medical staff tend to underestimate the quality of life in children and adolescents with inflammatory bowel disease. AB - AIM: We evaluated how well medical staff or parents understood patients with inflammatory bowel disease (IBD) by comparing their evaluation of the patients' quality of life (QoL) with the patients' self-reported QoL. METHODS: This study was carried out at Severance Children's Hospital in Seoul, Korea, in 2017. The children with IBD were recruited from August 2017 to December 2017, and they had a mean age of 16.4 (range 9.3-18.9) years. We asked the 64 children (38 boys), 58 mothers, 16 fathers, three physicians and one IBD nurse to answer the IMPACT-III questionnaire, which measures QoL, and compared the scores. RESULTS: The intraclass correlation coefficient of the total IMPACT-III score was highest for the patient and their father (0.824) and then for the patient and their mother (0.689), physician (0.625) and IBD nurse (0.499). Parents and medical staff thought the patients' QoL was lower than the patients themselves. The differences in the IMPACT-III scores of the patients were -10.09 +/- 17.86 for physicians, 9.87 +/- 15.80 for mothers, -5.72 +/- 17.04 for nurses and -3.81 +/- 11.82 for fathers. CONCLUSION: Parents and medical staff showed some correlation with the QoL documented by adolescent IBD patients, but tended to underestimate the levels. PMID- 29998508 TI - Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1. AB - BACKGROUND AND PURPOSE: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), caused by mutations in gap junction protein beta 1 (GJB1), is characterized by various central nervous system symptoms and gender differences of clinical severity. The aim of this study was to identify the frequency and mutation spectrum of CMTX1 patients in Japan and to demonstrate their phenotypic diversities. METHODS: Using three high-throughput sequencing systems, targeted gene panel sequencing on 1483 unrelated index patients with suspected Charcot Marie-Tooth (CMT) disease was performed. The peripheral and central nervous system involvements of all patients with GJB1 variants were assessed retrospectively and a detailed gender comparison was conducted with the CMT examination score. RESULTS: Twenty-three novel and 36 described GJB1 variants were identified from 88 pedigrees, in which 34 female and 78 male patients were enrolled. Mean age at onset of the male patients was much younger than the females, 21.56 +/- 17.63 years vs. 35.53 +/- 23.72 years (P = 0.007). Male patients presented with more severe phenotypes in every examination item, but statistical differences were observed only in motor dysfunctions of the lower extremities and vibration sensation. No significant sensory difference was identified between genders, either clinically or electrophysiologically. Central nervous system dysfunctions were found in 15 patients from 12 pedigrees. Therein, six patients developed stroke-like phenotypes, with dysarthria as the leading symptom. CONCLUSIONS: A relatively lower frequency of CMTX1 (5.9%) was demonstrated and a broad mutation spectrum of GJB1 was described. Detailed clinical differences between genders and various central nervous system symptoms were also illustrated, even in the same pedigree. PMID- 29998509 TI - Influence of initial mathematical competencies on the effectiveness of a classroom-based intervention. AB - BACKGROUND: Students commonly struggle with mathematics and mathematical problem solving. Therefore, it is necessary to design and implement interventions aimed at improving these essential components of learning. Furthermore, the outcomes of these interventions can vary significantly and appear to be a function of a student's initial competencies in mathematics. AIM: This study attempts to analyse the influence of initial levels of mathematics competency with respect to the benefits of a specific intervention known as the Integrated Dynamic Representation (IDR). SAMPLE: Participants were 288 students (aged 6-8 years) who were divided according to their levels of mathematics competency (low-medium high). METHODS: Students were assigned to the two primary intervention groups, experimental group (EG; students who received the IDR intervention) and control group (CG; students who followed the traditional instructional methods). All participants completed the Test of Early Mathematics Abilities (TEMA-3) both before and after the intervention. RESULTS AND CONCLUSIONS: Although all the three competency levels of the EG improved, the progression was different for each level. Results showed that students with low competency level improved substantially more than the students with medium and/or high baseline competency level. PMID- 29998510 TI - Hexavalent chromium in tattoo inks: Dermal exposure and systemic risk. AB - BACKGROUND: The presence of hexavalent chromium (Cr[VI]), which is carcinogenic to humans and a dermal sensitizer, in tattoo inks may represent a serious health concern. The level of this impurity is limited to 0.2 mg/kg in tattoo inks by the European Resolution ResAP(2008)1. OBJECTIVES: To analyse 29 tattoo inks, produced in Europe and the United States, of different colours and brands, for Cr(VI) to assess their conformity with ResAP(2008)1 and to characterize dermal and systemic risks. METHODS: Ion chromatography and inductively coupled plasma mass spectrometry were used to determine the levels of Cr(VI) in inks; risk characterization was performed by calculating the systemic exposure dosage (SED) and margin of safety (MoS). RESULTS: Ninety per cent of inks contained Cr(VI) (range: 0.22-4.09 mg/kg), ie, above the maximum allowed level, and no information appeared on the label. More than 1 mg/kg Cr(VI) was detected in 27.6% of inks; these might represent a possible cause of dermal adverse reactions. Exposure to Cr(VI) in inks resulted in negligible SED values and MoS values of >100 (safety threshold), indicating no appreciable systemic risk. CONCLUSIONS: The minimization of Cr(VI) contamination and the use of technology compliant with good manufacturing practices is recommended to increase the safety of tattoo inks. PMID- 29998511 TI - Lenalidomide for treatment of recurrent oral aphthae in Adamantiades-Behcet's disease. PMID- 29998513 TI - VORWORT. PMID- 29998512 TI - Praxis der Teledermatologie. AB - HINTERGRUND: Teledermatologische Anwendungen werden im deutschen Versorgungssystem in den nachsten Jahren erheblich an Bedeutung gewinnen. Das vorliegende Empfehlungspapier wurde als Expertenkonsens auf der Basis einer qualifizierten Literaturrecherche und eines strukturierten Entscheidungsprozesses der Autorengruppe entwickelt. ZIELSETZUNG: a) die IST-Analyse zum Einsatz der Telemedizin in der Dermatologie, b) die Bewertung der Evidenz ihres Nutzens und ihrer Sicherheit und, c) die Entwicklung von Verfahrensstandards fur die arztliche Praxis in den deutschsprachigen Landern. Auf der Basis dieser Erkenntnisse soll durch einen Expertenkonsens eine Handlungsorientierung fur den Einsatz der Teledermatologie gegeben werden. METHODEN: Dreistufiges Vorgehen: 1) Systematische Literaturrecherche in den internationalen medizinischen Onlinedatenbanken Pubmed und Embase, 2) Weitere, teils manuelle Recherchen, 3) Expertenkonsens mit einem systematischen Entscheidungsverfahren mit 21 Teilnehmern. ERGEBNISSE: In der strukturierten Literaturrecherche fanden sich 204 wissenschaftliche Originalarbeiten, in denen Anwendungen der Telemedizin bei Hautkrankheiten thematisiert wurden. Diese wurden systematisch aufgearbeitet, analysiert und bewertet. In der zweiten Stufe wurden in einer Handsuche zusatzliche relevante Schriften identifiziert und ebenfalls ausgewertet. Das Expertengremium entwickelte dann auf der Basis der externen Evidenz sowie der internen Diskussion Handlungsempfehlungen fur die Praxis. Schlussfolgerung der wissenschaftlichen Studienlage ist, dass die telemedizinische Unterstutzung der dermatologischen Behandlung und Pravention bei Einsatz leistungsfahiger Systeme, Kenntnis ihrer Anwendung sowie Beachtung der Indikationen und Kontrainidikationen einen erheblichen Mehrnutzen darstellt. SCHLUSSFOLGERUNGEN: Die Teledermatologie hat in den deutschsprachigen Landern wie auch weltweit einen zunehmenden Stellenwert und bietet aufgrund des hohen Innovationsgrades eine Vorreiter- und Vorbildfunktion fur weitere telemedizinische Anwendungen anderer Fachrichtungen. Eine qualitatsgesicherte teledermatologische Behandlung ist in den deutschsprachigen Landern praktikabel und kann zu einem relevanten Mehrnutzen in der Versorgung fuhren. Ihr Einsatz ist immer dann in Erwagung zu ziehen, wenn relevante Zusatznutzen fur die Patienten ohne relevante Nachteile fur sie und fur die Versorgenden zu erwarten sind. Fur die teledermatologische Behandlung wurden mit dem vorliegenden Konsensuspapier praxisrelevante Mabetagaben festgelegt. Etwaige situationsabhangige Limitationen in der Versorgung sind stets zu beachten. PMID- 29998514 TI - All-Organic Dual Spin Valves with Well-Resolved Four Resistive-States. AB - The formation of all-organic dual spin valves (DSVs) with three organic spin selective layers, that is, spin-injection, spin-detection, and an additional spin filtering layer at the intermediate, is reported. As spin-selective layers, manganese- and cobalt phthalocyanines, which are well-known single-molecule magnets, are used in their immobilized forms, so that all-organic DSVs can be prefabricated for characterization. The three spin-selective layers have provided four configurations with at most two spin-flip interfaces enforcing spin-flipping at the two nonmagnetic organic spacer layers, for which copper phthalocyanine is used. Since a couple of the four configurations have exhibited similar resistivities, the degeneracy in the resistive-states is broken through asymmetric spin-injection and spin-detection layers and also through asymmetric thickness of the nonmagnetic spacer layers. When both the spin-flip interfaces are made operative independently, a 2-bit logic with four distinct resistive states can be achieved. PMID- 29998516 TI - Corrigendum. PMID- 29998515 TI - Corrigendum. PMID- 29998517 TI - Association between workplace discrimination and depressive symptoms among firefighters in South Korea. AB - BACKGROUND: Workplace discrimination is associated with poor mental health. However, there is a lack of studies examining the effects of discrimination on depressive symptoms among firefighters. METHODS: We analyzed a national cross sectional survey of 6369 firefighters in South Korea. Workplace discrimination during the past year was measured and main reasons for the discriminatory experience (gender, birth region, age, education, field/office work, job division) were identified separately by gender and job division. Depressive symptoms during the previous week were measured by the CES-D11. RESULTS: Overall, 30.3% of firefighters experienced workplace discrimination and the main reasons for discrimination differed by gender and job division. Firefighters who experienced workplace discrimination had a higher likelihood of depressive symptoms than those who did not after adjusting for potential confounders (PR: 1.73; 95%CI: 1.55, 1.92). CONCLUSIONS: This finding suggests that experience of workplace discrimination could aggravate the mental health of firefighters who provide an important public service. PMID- 29998518 TI - Towards High-Efficiency Hydrogen Production through in situ Formation of Well Dispersed Rhodium Nanoclusters. AB - Rh-based materials have emerged as potential candidates for hydrogen revolution from electrolyzing water or ammonia borane (AB) hydrolysis. Nevertheless, most of the catalysts still suffer from the complex synthetic procedures combined with limited catalytic activity. Additionally, the facile syntheses of Rh catalysts with high efficiencies for both electrochemical water splitting and AB hydrolysis are still challenging. Herein, we develop a simple, green, and mass-producible ion-adsorption strategy to produce a Rh/C pre-catalyst (pre-Rh/C). The ultrafine and clean Rh nanoclusters immobilized on carbon are achieved via the in situ reduction of the pre-Rh/C during the hydrogen-evolution process. The resulting in situ Rh/C catalyst presents an outstanding electrocatalytic performance with low overpotentials of 8 and 30 mV at 10 mA cm-2 in 1.0 m KOH and 0.5 m H2 SO4 , respectively, outperforming the state-of-the-art Pt catalysts. Furthermore, the in situ Rh/C is also highly active for AB hydrolysis to produce hydrogen with a high turnover frequency of 1246 mol H2 molRh-1 min-1 at 25 degrees C. The in situ-formed ultrafine Rh nanoclusters are responsible for the observed superior catalytic performance. This facile in situ strategy to realize a highly active catalyst shows promise for practical applications. PMID- 29998519 TI - Reply to "Low prevalence of diabetes with chronic complications in patients with Takotsubo syndrome". PMID- 29998520 TI - ALIGNed on adherence: subanalysis of adherence in immune-mediated inflammatory diseases in the DACH region of the global ALIGN study. AB - BACKGROUND: Non-adherence to medication is a challenging problem in daily clinical practice. OBJECTIVE: To assess reasons for non-adherence in patients with chronic immune-mediated inflammatory diseases (IMIDs) in a direct comparison including evaluation of treatment necessity and concerns. METHODS: ALIGN was a non-interventional, multicountry, multicentre, self-administered, cross sectional, epidemiologic survey study. Here, we investigate the German, Austrian and Swiss (DACH) cohort. Six hundred thirty-one patients with different IMIDs (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis) under systemic therapies were evaluated concerning adherence, beliefs of necessity and concerns towards treatment in patients with IMIDs. RESULTS: The DACH cohort had significantly different levels of adherence depending on the IMID (P < 0.05) and the type of therapy (P < 0.05). Based on the significant influence of concerns on treatment adherence (P < 0.05) and the high belief of treatment necessity, patients could be classified in four attitudinal segments, which were unequally distributed throughout various IMIDs. High concerns had a significant influence on non adherence, whereas necessity did not. Older age, female sex, TNFi mono-, conventional combination and TNFi combination therapy are positively associated with adherence. CONCLUSIONS: In the DACH region, patients are less concerned about medication and believe in the necessity of treatment. Therefore, we suggest adapting the communication in the various patient groups. PMID- 29998521 TI - Regulatory B cell phenotype and mechanism of action: the impact of stimulating conditions. AB - A diverse population of regulatory B (Breg) cells reportedly exhibits significant immunomodulatory effects in various models of inflammatory responses and infectious diseases caused by bacteria, viruses or parasites. Breg cells contribute to maintenance of homeostasis via IL-10 production and multiple IL-10 independent mechanisms. The current review describes various phenotypic and functional subsets of Breg cells in autoimmune and infectious diseases and discusses the impacts of experimental conditions that have been found to drive Breg cell differentiation. PMID- 29998522 TI - Incidence and spontaneous clearance of hepatitis C virus (HCV) in people who inject drugs at the Stockholm Needle Exchange-Importance for HCV elimination. AB - The major transmission route for hepatitis C virus (HCV) is through sharing of unsterile injection equipment among people who inject drugs (PWID). The WHO strategy for HCV elimination by 2030 proposes increased efforts to treat PWID populations that drive the HCV epidemic. Among participants in the Stockholm needle exchange programme (NEP), the HCV prevalence is 60%. We aimed to study HCV incidence, spontaneous HCV clearance rate, and predictors associated with new HCV infections and reinfections in NEP participants. All 2320 patients enrolled in the programme between 8 April 2013 and 23 September 2016 were tested for HCV at baseline, and responded to a questionnaire regarding sociodemographic data and injection risk behaviour. Tests for HCV were repeated at an interval of 3-6 months. The anti-HCV prevalence in the NEP participants at baseline was 77%, and the prevalence of HCV RNA was 57%. 24% of the anti-HCV positive were HCV RNA negative with a spontaneously cleared HCV infection. The overall HCV incidence rate was 22/100 PY. The HCV incidence rate in the HCV naive group was 26/100 PY, and in the spontaneously cleared group 19/100. Although there were no significant differences in becoming HCV infected between the two groups (31% vs 29%), the rate of spontaneous HCV clearance was significantly lower in the HCV naive group, 20% vs 44%, (P < 0.05). A high HCV incidence rate was noted among the PWID indicating that treatment needs to be scaled up in conjunction with harm reduction measures to achieve HCV elimination goals set by WHO. This includes high coverage needle exchange programmes and effective addiction treatment for substance users, including opiate substitution treatment. PMID- 29998523 TI - Teenage night owls or early birds? Chronotype and the mental health of adolescents. AB - Evidence suggests that the timing of sleep (chronotype) impacts mental health in young people, but previous studies have not accounted for sleep duration or school start time in this association, or examined a broad range of mental outcomes. In this study, we investigated the association between chronotype and mental health in a representative sample of adolescents from the 2014 Canadian Health Behaviour in School-Aged Children survey (29,635 students, 362 schools). We examined positive and negative aspects of mental health, using scores for emotional problems (range 0-33), emotional well-being (0-22), behavioural problems (0-28) and prosocial behaviours (0-25). We estimated chronotype using the time of mid-sleep on weekends and examined the associations using multilevel regressions, adjusted for sleep duration, school start time, individual, family and geographic characteristics. The average time of mid-sleep (chronotype) was 04:11 hr. An hour delay in mid-sleep time was associated with more emotional problems (0.34 [95% confidence interval 0.23, 0.45] point higher score), more behavioural problems (2.0% [95% confidence interval 1.4%, 2.6%] higher score), less emotional well-being (0.19 [95% confidence interval 0.09, 0.20] point lower score), and fewer prosocial behaviours (0.18 [95% confidence interval 0.08, 0.29] point lower score). A later chronotype was associated with poorer mental health, independent of sleep duration and school start time, and across internalizing and externalizing mental health domains. Further research is needed to clarify the mechanisms underlying this association. The timing of sleep, and not just its duration, may be an additional consideration for youth mental health. PMID- 29998524 TI - Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema. AB - BACKGROUND: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. OBJECTIVE: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA(r) ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. METHODS: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. RESULTS: C1-INH functional activity following C1 INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour-1 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (Ctrough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in Ctrough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher Ctrough levels than IV dosing. PMID- 29998525 TI - Synthesis and Reactivity of Multiple Phosphine-Functionalized Nonagermanide Clusters. AB - Herein we report on the synthesis of the first multiple phosphine-substituted nonagermanide clusters in a one-step reaction from K4 Ge9 . Their reactions towards various transition metal complexes show a large variety of reactive sites. The novel threefold phosphine-functionalized [Ge9 ] clusters [Ge9 {PRRI }3 ]- {R: Ni Pr2 ; RI : Ni Pr2 (1 a) or t Bu (2 a)} are obtained by reaction of pristine [Ge9 ]4- clusters with the respective chlorophosphines. Subsequent reactions with NHCDipp CuCl yield neutral compounds (NHCDipp Cu)[Ge9 {P(Ni Pr2 )2 }3 ] (3) and (NHCDipp Cu)[Ge9 {P(Ni Pr2 )t Bu}3 ] (4), respectively. The reaction of neutral compound 3 with Cr(CO)5 (thf) yields the first uncharged fivefold substituted [Ge9 ] cluster (NHCDipp Cu)2 [Ge9 {P(Ni Pr2 )2 }2 Cr(CO)5 ] (5) via a ligand exchange reaction at the [Ge9 ] cluster core. Compounds 3 and 5 are characterized by single crystal structure determination. PMID- 29998526 TI - Fifteen years' experience of implantable cardioverter defibrillator in children and young adults: Mortality and complications study. AB - BACKGROUND: Young implantable cardioverter defibrillator (ICD) recipients have a high rate of complications, some of which seem to be underestimated. We report our clinical experience with ICD therapy in children and young adults during a 15 year follow up. METHODS: We reviewed the database of ICD recipients at the present institution and chose 73 consecutive patients who underwent implantation at age 6-21 years. We analyzed intervention rate, mortality, rate and characteristics of complications and treatment options. RESULTS: A total of 20/73 patients (27.4%) received >=1 episode of appropriate therapy (AT) for ventricular tachycardia/ventricular fibrillation (anti-tachycardia pacing or shock) and 24/73 patients (32.8%) had one or multiple episodes of inappropriate therapy (IT). Eight patients (11%) had both interventions: AT + IT. A total of 15/73 patients (20.5%) had ventricular lead dysfunction, with 13 re-implantations (17.8%) of a new system. Four of 73 patients (5.5%) had infection: endocarditis or device pocket infection. A total of 2/73 patients (2.7%) died due to ventricular lead dysfunction, while 22/73 patients (30.1%) needed elective device replacement, five of them twice (6.8%). CONCLUSION: Endocardial ICD implantation in children and young adults is a feasible and life-saving procedure, according to the present 15 year follow up. The rate of complications including IT was high: 72.8% in the young ICD recipients. Re-implantation of a new system was often required due to ventricular lead dysfunction or infection in 25% of the patients. PMID- 29998527 TI - Blistering of the hands following a manicure at a nail salon. PMID- 29998528 TI - Upper jaw development in the absence of teeth: New insights for craniodental evo devo integration. AB - In p63-null mice (p63-/- ), teeth fail to form but the mandible forms normally; conversely, the upper jaw skeleton is malformed. Here we explored whether lack of dental tissues contributed to midfacial dysmorphologies in p63-/- mice by testing if facial prominence defects appeared before odontogenesis failed. We also investigated gene dose effects by testing if one wild type (WT) p63 allele (p63+/ ) was sufficient for normal upper jaw skeleton formation. We micro-CT scanned PFA-fixed p63-/- , p63+/- , and WT (p63+/+ ) adult and embryonic mice aged E10 E14. Next, we landmarked mandibular (MdP), maxillary (MxP) and nasal prominences (NPs), and facial bones. 3D landmark data were assessed using Principal Component, Canonical Variate, Partial Least Squares, and other statistical analyses. The p63-/- embryos showed MxP and NP malformations by E12, despite the presence of dental tissues. MdP shape was comparable among p63-/- , p63+/- , and p63+/+ embryos. Upper jaw shape was comparable between p63+/+ and p63+/- adults. The upper jaw and its dentition both require p63 signaling, but not each other's presence, to form properly. One WT p63 allele enables normal midfacial morphogenesis; gene dose may be a target for jaw macroevolution. Jaw-specific genetic mechanisms likely integrate the evo-devo of dentitions with upper versus lower jaws. PMID- 29998529 TI - Extracellular prolyl oligopeptidase derived from activated microglia is a potential neuroprotection target. AB - Prolyl oligopeptidase (PREP) is an abundant peptidase in the brain and periphery, but its physiological functions are still largely unknown. Recent findings point to a role for PREP in inflammatory processes. This study assessed the cellular and extracellular PREP activities in cultures of mouse primary cortical neurons, microglial cells and astrocytes, and immortalized microglial BV-2 cells under neuroinflammatory conditions induced by lipopolysaccharide (LPS) and interferon gamma (IFNgamma). Furthermore, we evaluated the neuroprotective effect of a specific PREP inhibitor, KYP-2047, in a neuroinflammation model based on a coculture of primary cortical neurons and activated BV-2 cells. The inflammatory insult reduced intracellular and increased extracellular PREP activity specifically in microglial cells, suggesting that activated microglia excretes active PREP. A targeted proteomics approach revealed up-regulation in PREP protein levels in BV-2 cell growth medium but down-regulation in crude membrane bound PREP after LPS+IFNgamma. In the coculture of BV-2 cells and primary neurons, an increase in extracellular PREP activity was also detected after inflammation. KYP-2047 (10 MUmol/L) significantly protected neurons against microglial toxicity and reduced the levels of the pro-inflammatory cytokine tumour necrosis factor alpha. In conclusion, these data point to an extracellular role for microglial PREP in the inflammatory process. Inhibition of PREP during neuroinflammation is a potential target for neuroprotection. Thus, PREP inhibitors may offer a novel therapeutic approach for the treatment of neurodegenerative disorders with an inflammatory component including Parkinson's and Alzheimer's diseases. PMID- 29998531 TI - SUMO enters the ring: the emerging role of SUMOylation in Magnaporthe oryzae pathogenicity. PMID- 29998530 TI - Effect of diet-induced weight loss on angiopoietin-like protein 4 and adipose tissue lipid metabolism in overweight and obese humans. AB - Angiopoietin-like protein 4 (ANGPTL4) plays a role in lipid partitioning by inhibiting lipoprotein lipase (LPL)-dependent plasma clearance of triacylglycerol in adipose tissue. We investigated the effects of diet-induced weight loss on plasma ANGPTL4 concentrations in relation to in vivo adipose tissue LPL activity and lipolysis and adipose tissue ANGPTL4 release in overweight/obese participants. Sixteen individuals (BMI: 28-35 kg/m2 ; 10 women) were randomized to a dietary intervention composed of either a low-calorie diet (1250 kcal/day) for 12 weeks (n = 9) or a very low-calorie diet (500 kcal/day) for 5 weeks, followed by a 4-week weight stable period. Before and after the intervention, we measured arteriovenous concentration differences in combination with adipose tissue blood flow before and after intake of a high-fat mixed meal with [U-13 C] palmitate to assess in vivo adipose tissue LPL activity and lipolysis. The intervention significantly reduced body weight (-8.6 +/- 0.6 kg, P < 0.001). Plasma ANGPTL4 concentrations were unaffected. Significant postprandial adipose tissue ANGPTL4 release into the circulation was observed (P < 0.01). No association was observed between plasma ANGPTL4 and in vivo LPL activity. After intervention, fasting and postprandial plasma ANGPTL4 concentrations were positively associated with adipose tissue nonesterified FA (NEFA) and glycerol release, reflecting in vivo adipose tissue lipolysis (fasting NEFA: P = 0.039 and postprandial NEFA: P = 0.003). In conclusion, plasma ANGPTL4 is unaffected by weight loss and is secreted from human adipose tissue after a high-fat meal in overweight/obese participants. Plasma ANGPTL4 concentrations were not related to in vivo adipose tissue LPL activity, but were positively associated with in vivo adipose tissue lipolysis after weight loss. PMID- 29998532 TI - Nate G. McDowell. PMID- 29998533 TI - Bytes and boots to understand the future of the Amazon forest. PMID- 29998534 TI - Deriving pattern from complexity in the processes underlying tropical forest drought impacts. PMID- 29998535 TI - Corrigendum. PMID- 29998536 TI - Clinical Lipidology and the Prevention of Vascular Disease: Time for Personalized Therapy. AB - Genetic, metabolic, and lifestyle modifications can cause elevations of lipoproteins that contribute to atherosclerotic lesions over time. In the modern world with life extension from many improvements in medicine and public health, most humans live long enough to develop atherosclerosis with concentrations of blood plasma lipoproteins that are very common. Familial abnormalities are prevalent and provide additional challenges in identifying unhealthy but treatable values of low-density (LDL) and very low-density lipoproteins (VLDL). Multiple community studies and clinical trials have provided guidance on selecting targets and new tools that make possible effective goals of treatment. Lipid-lowering drugs are making it possible to achieve those goals and place responsibility on physicians to master the art of preventing atherosclerotic events. Lipoprotein management remains a very focused effort and requires an artful individualized approach for each patient. Few skills are more important for healthcare providers in primary care and cardiovascular medicine. PMID- 29998538 TI - Focus on sleep-disordered breathing and central nervous hypersomnolence. PMID- 29998537 TI - Digital health - a new medical cosmology? The case of 23andMe online genetic testing platform. AB - This article argues that commercial digital health platforms and devices commodify participatory features of the digital creating a new medical cosmology. Drawing on sociology on medical cosmologies, research on digital media and marketing and an analysis of the 23andMe online genetic testing platform, I identify three features of this cosmology. First, digital health seeks to foment 'flow' or enjoyable, continuous immersion in health. Second, digital health configures its consumers as 'co-creators' of health data and knowledge together with companies and other consumers. Third, digital health frames medical knowledge as tentative, up for revision and scepticism by expert and lay science. The way in which digital health configures consumers as immersed, creative and sceptical gives it an open-ended and participatory air. However, the conceptual discussion and the analysis of the 23andMe platform highlight that these features represent commercial capture of the lifeworld, even if they appear radical against classical medical cosmologies. PMID- 29998539 TI - Promoting functional independence in people with Alzheimer's disease: Outcomes of a home-based occupational therapy intervention in Spain. AB - Nonpharmacologic therapies such as occupational therapy (OT) are promising for people with Alzheimer's disease (AD). However, more research is needed to better understand the effectiveness of home-based OT programs. This pilot study aimed to assess the effects of a home-based, high-intensity and multicomponent OT intervention on the activities of daily living of people with AD in Spain. The secondary objective was to examine its impact on the cognitive functions. A multiple-baseline intrasubject design was used. Twenty-one community-dwelling older adults with mild AD (mean age 78.6 years) and their primary caregivers participated in a 12-week home-based OT program. This intervention was replicated for 8 weeks after a 1.5-month intervention withdrawal period. The intervention followed a holistic, biopsychosocial and client-centred approach and consisted of the following components: meaningful activities/tasks, cognitive stimulation, activation of psychomotor and sensory skills, home modification, caregiver counselling and training in daily living skills. Functional independence was the primary outcome (Barthel Index). The cognitive functions were assessed by the Loewenstein Occupational Therapy Cognitive Assessment-Geriatric (LOTCA-G). Data were analysed using nonparametric tests. Main results showed that after completing the OT program, 6.5 months after the moment of inclusion, the level of functional independence improved significantly and the effect size was large. Moreover, there was a significant moderate-to-substantial improvement in several cognitive functions after each of the two intervention periods: place orientation, time orientation and attention/concentration. In summary, the findings give a great deal of information as a basis for further research. This study provides evidence that an intensive home-based OT intervention has a positive influence on daily activities and some cognitive functions, suggesting that this program may be beneficial as a nonpharmacological supplementary tool in health and social care for people with AD living in the community. PMID- 29998540 TI - Porous Ionic Liquids or Liquid Metal-Organic Frameworks? AB - Porous liquids can be prepared from the dispersion metal-organic frameworks (MOFs) in ionic liquids (ILs). Porous liquids prepared from 5 % of ZIF-8 in a phosphonium-based ionic liquid are capable of absorbing reversibly up to 150 % more nitrogen and 100 % more methane than the pure ionic liquid. PMID- 29998541 TI - Evaluating resistant brassica trap crops to manage Heterodera schachtii (Schmidt) infestations in eastern England. AB - BACKGROUND: The beet cyst nematode (BCN), Heterodera schachtii Schmidt, is a plant parasitic nematode that causes severe yield losses in sugar beet. Resistant brassicas (radish and mustard) have been bred to be planted after harvest of the main crop, for example a cereal, and encourage BCN juvenile hatching. The resistant plants stimulate juvenile hatching but are not suitable hosts. Juveniles are unable to complete their lifecycle and thus populations are lowered. This research aimed to investigate the effectiveness of a range of brassicas in terms of BCN control when grown in infested fields in eastern England. RESULTS: Experiments used four different radish cultivars, which differed in their resistance to BCN, and one resistant mustard variety. Field experiments were sown in early September in 2016 and 2017. Significant reductions in BCN populations were found only following resistant mustard and the radish with the greatest resistance level. CONCLUSIONS: Further research is needed to understand how best to utilize brassicas and whether they are economically viable when alternative management options for BCN are available. Time of planting may be crucial to fully achieve their BCN-reducing potential. (c) 2018 Society of Chemical Industry. PMID- 29998542 TI - Tuning Zeolite Properties for a Highly Efficient Synthesis of Propylene from Methanol. AB - A series of nanosized ZSM-5 samples was synthesized at 170, 150, 120, and 100 degrees C. Experimental data show that the decrease of crystallization temperature leads to significant changes in zeolite properties. Crystals synthesized at 100 degrees C exhibit many framework defects with lower acid-site density, strength, and a larger external surface area. The selectivity to light olefins and the propylene-to-ethylene ratio increases as the crystallization temperature decreases. A propylene-to-ethylene ratio of above 6 with the highest selectivity to propylene of 53 % was obtained over ZSM-5 catalyst prepared at 100 degrees C. The stability of the nanosized zeolite in methanol to olefins (MTO) was also improved compared to the industrial sample with a similar Si/Al ratio. This catalytic performance is a result of the decrease in the acid-site density, strength, and the crystals' size, providing a shorter diffusion path and larger external surface area. The presence of structural defects and a different external surface in the crystals has been shown to play an important role in the MTO catalyst performance. PMID- 29998544 TI - Corrigendum. PMID- 29998545 TI - Staff members and managers' views of the conditions for the participation of adults with profound intellectual and multiple disabilities. AB - BACKGROUND: Participation is a central aspect of quality of life, and it is indicative of high-quality outcomes for people with intellectual disabilities. However, participation is difficult to achieve for adults with profound intellectual and multiple disabilities. AIM: To describe staff members' perceptions of what participation means for adults with profound intellectual and multiple disabilities. METHOD: Using a phenomenographic approach, 27 interviews were analysed resulting in variations in the conditions for participation. RESULTS: The interviews revealed conditions for participation at individual, staff and organisational levels. CONCLUSION: Participation appears to be an un reflected phenomenon, and several conditions must be met to achieve it. The conditions are experienced being fundamental for adults within the target group to achieve any kind of participation. The staff members and managers' perceptions of participation as conditional can make it more difficult for adults within the target group to achieve the Swedish disability policy goal of participation. PMID- 29998546 TI - Examining the dimensionality of the Fear of Cancer Recurrence Inventory. AB - OBJECTIVE: Fear of cancer recurrence (FCR) is a common concern among cancer survivors, and the Fear of Cancer Recurrence Inventory (FCRI) is a frequently used measure to assess FCR. Given that the dimensionality of FCR has received recent debate, the overall goal of this secondary analysis was to re-examine the dimensionality of the FCRI using confirmatory factor analyses (CFA) to compare models of FCR, using data from a large sample of cancer survivors. METHODS: Three models of FCR (including unidimensional and multidimensional models of the FCRI) were informed by the literature and proposed a priori. Separate CFAs were conducted to test the fit of each model to the data, and models with acceptable fits were compared. RESULTS: Of all the tested FCR models, a multidimensional first-order model aligned with the originally developed 7-subscale FCRI revealed the best fit to the data (chi2 = 3359.135, P < .0001, df = 795, RMSEA = 0.057 [0.055, 0.059], CFI = 0.897, TLI = 0.888). When this 7-factor structure was loaded onto a single, second-order factor of overall FCR, the model fit statistics were slightly poorer (chi2 = 3459.632, P < .0001, df = 807, RMSEA = 0.058 [0.056, 0.060], CFI = 0.893, TLI = 0.886). However, the difference between the models was significant (chi-square difference = 103.142, P < .0001, df = 12) indicating that the first-order model was a better fit to the data. CONCLUSIONS: These results align with empirical and theoretical literature that supports the use of the FCRI as a multidimensional scale. Implications of results are discussed in light of FCR conceptualization and measurement. PMID- 29998543 TI - Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake. AB - INTRODUCTION: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake. METHODS: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened. RESULTS: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E-08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes. CONCLUSIONS: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition. PMID- 29998547 TI - Quality of life in patients with acquired pigmentation: An observational study. PMID- 29998548 TI - Strain-Induced Double Carbon-Carbon Bond Activations of Cycloparaphenylenes by a Platinum Complex: Application to the Synthesis of Cyclic Diketones. AB - The carbon-carbon (C-C) bond activation of [n]cycloparaphenylenes ([n]CPPs) by a transition-metal complex is herein reported. The Pt0 complex Pt(PPh3 )4 regioselectively cleaves two C-C sigma bonds of [5] CPP and [6]CPP to give cyclic dinuclear platinum complexes in high yields. Theoretical calculations reveal that the relief of ring strain drives the reaction. The cyclic complex was further transformed into a cyclic diketone by using a CO insertion reaction. PMID- 29998550 TI - Elevated temperature reduces wheat grain yield by increasing pests and decreasing soil mutualists. AB - BACKGROUND: Climate warming is known to affect species' phenology, abundance, and their interactions with other species. Understanding how cultivated plants, their associated community members (including pest insects, natural enemies, soil microbes), and their interactions respond to warming to influence crop yields is critical to current and future food security. We conducted a two-year field study on the effects of elevated temperature on winter wheat growth and grain quality, insect pests, natural enemies, ground arthropods, weeds, and arbuscular mycorrhizal fungi (AMF). RESULTS: Elevated temperature shortened the period of wheat growth, decreased grain yield, and reduced grain quality by increasing fiber and decreasing wet gluten, protein, total soluble sugars, and starch. Elevated temperature also increased aphid abundance while decreasing AMF colonization rates. Structural equation modeling indicated that the direct negative effect of warming on wheat yield was augmented by indirect negative effects via increased aphid and weed abundances along with decreased AMF colonization. CONCLUSION: Climate change can potentially affect crop production and quality both directly and indirectly by modifying interactions with aboveground and belowground organisms. Future studies on the effects of climate change on crops should consider the responses of aboveground and belowground biotic community members and their interactions with crop plants. (c) 2018 Society of Chemical Industry. PMID- 29998549 TI - A sensitive, high-throughput, and eco-friendly analysis of daidzein and its valine carbamate prodrug in rat plasma by supercritical fluid chromatography with tandem mass spectrometry. AB - A valine carbamate prodrug of daidzein was synthesized to improve its bioavailability because of the poor solubility and low permeability of daidzein. To evaluate the pharmacokinetic behavior of the prodrug, a sensitive and high throughput method was developed and validated for the simultaneous determination of daidzein and its prodrug in rat plasma. The samples were extracted by ethyl acetate and then analyzed by a supercritical fluid chromatography with electrospray ionization tandem mass spectrometry method. The separation was achieved by an ACQUITY UPC2 TM BEH 2-EP column maintained at 40 degrees C using carbon dioxide (>=99.99%) and methanol within 3.0 min by gradient elution. The mass transition ion pairs were m/z 254.8->136.7, 398.0->254.9, and 271.0->91.07 for daidzein, the prodrug, and genistein, respectively. The calibration curves were linear over the concentration ranges of 2-500 (r > 0.997) and 10.0-5000.0 ng/mL (r > 0.996) with lower limits of quantification of 2 and 10 ng/mL for daidzein and the prodrug, respectively. The intra- and interday accuracy and precision were within +/-15% for all quality control samples. This developed method enabled high specificity, low cost, low solvent consumption, and a brief analysis time and was successfully applied to a bioavailability evaluation of daidzein and its carbamate prodrug. PMID- 29998552 TI - Enhanced Base-Free Formic Acid Production from CO2 on Pd/g-C3 N4 by Tuning of the Carrier Defects. AB - CO2 hydrogenation is attracting increasing attention as a sustainable route to produce formic acid, a commodity and potential energy vector. Here, bifunctional catalysts comprising metal nanoparticles deposited on bulk graphitic carbon nitride were assessed under base-free conditions, identifying supported Pd as the best performer. The catalyst productivity was enhanced by maximizing the edge defects of the g-C3 N4 carrier, amino groups able to activate CO2 , and by generating welldispersed 5 nm Pd particles, required to split H2 . Bottom-up synthesis methods, that is, hard-templating and carbon enrichment upon polymerization, and top-down strategies, that is, thermal exfoliation of the as prepared solid, were explored to boost the defects, the nature and density of which were evaluated by thermal and (in situ) spectroscopic techniques. After optimization of temperature, pressure, and reaction time, a 20 times higher turnover frequency compared with the best Pd/g-C3 N4 catalyst reported producing formic acid from CO2 without base was attained. This activity level was retained upon recycling with intermediate catalyst regeneration at mild temperature. PMID- 29998551 TI - Persistence of Escherichia coli in the soil of an organic mixed crop-livestock farm that integrates sheep grazing within vegetable fields. AB - Mixed crop-livestock farms (MCLF) integrate livestock and crops using their animals to graze crop residues and/or cover crops. MCLF are considered sustainable because grazing and the manure deposited by livestock enhance soil fertility and recycles farm nutrients. However, livestock manure may introduce enteric foodborne pathogens to the soil, which could contaminate fresh produce. Organic farmers in the United States follow the USDA National Organic Program (NOP) standards, which require 90 or 120 days between incorporating raw manure into the soil and harvest. Although not specifically addressed in NOP, organic farmers using grazing within production fields may also use this standard. The objectives of this study were to generate preharvest data to assess the die-off of generic Escherichia coli (E. coli) in the soil, after cover crops were grazed by sheep; and assess the genetic relatedness of generic E. coli isolates between soil and sheep faecal samples. We conducted a repeated observational study to evaluate the persistence of generic E. coli, as an indicator of faecal contamination and surrogate for STEC, in the soil of two fields (A and B) on an organic MCLF. Results showed a 3.70 log10 reduction in mean generic E. coli concentration MPN in the soil of field A from the highest of 3.70 log10 MPN/g on 48 day postsheep grazing (DPS) to -0.70 log10 MPN/g on 139 DPS. Field B showed a 3.51 log10 reduction in mean generic E. coli concentration in the soil from the highest mean of 3.51 log10 MPN/g on 14 DPS to the lowest mean -0.35 log10 MPN/g on 112 DPS. STEC prevalence in the sheep flock was 4.17% (1/24). Closely related generic E. coli strains were found between soil and faecal samples. Developing research-based waiting periods between grazing and harvest is important to inform best practices for farmers and food safety regulators. PMID- 29998555 TI - Birth Planning and Women's and Men's Health in Malawi. AB - Despite the frequency with which it occurs, we know little about unintended fertility in sub-Saharan Africa and even less about its implications for the health of the women and men who experience it. We use longitudinal data from southern Malawi to explore how young adults report on the planning of their births and to identify changes in their self-rated health and subjective well being associated with having more- or less-planned births. Our data feature a comprehensive scale of pregnancy planning, the London Measure of Unplanned Pregnancy (LMUP), that extends beyond the conventional focus on timing-based pregnancy intentions to incorporate information about contraception, desires, intentions, partner discussion, and preconception preparations. Women and men have similar bimodal distributions on the LMUP, with the majority of births clearly unplanned or planned but a sizeable minority that falls in the middle. Change score models demonstrate that, for women, an unplanned birth is associated with a decline in self-rated health. In contrast, men whose births were ambivalently-planned experience a decline in subjective well-being. Our findings highlight the value of considering the full spectrum of birth planning and demonstrate the health consequences of unplanned fertility for both women and men in this sub-Saharan context. PMID- 29998554 TI - Specific downregulation of cystathionine beta-synthase expression in the kidney during obesity. AB - Hydrogen sulfide (H2 S) is recognized as a novel gasotransmitter involved in the regulation of nervous system, cardiovascular functions, inflammatory response, gastrointestinal system, and renal function. Cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) are the major enzymes responsible for H2 S production through desulfuration reactions. H2 S is reported to play a protective role in both high-fat diet (HFD)-induced obese and diabetic mice. However, the synthesizing enzyme involved is not clearly elucidated. The current study was aimed to investigate the regulation of CBS and CSE in different tissues including the kidney, liver, and epididymal fat in C57BL/6 mice after a HFD (60% kcal fat) for 24 weeks. The protein and mRNA expression of CBS was specifically decreased in the kidney while CSE remained unchanged, which was further confirmed in db/db mice. In the liver, CSE expression was downregulated after HFD accompanied with unchanged CBS. Moreover, CSE expression was even upregulated in epididymal fat. The specific downregulation of renal CBS may contribute to decreased H2 S production, which could be a pathogenic mechanism of obesity. Increased CSE/H2 S pathway in epididymal fat possibly resulted in impaired glucose uptake and aggravated insulin resistance. In conclusion, our results revealed that CBS was selectively downregulated in both diet and gene-induced obesity models. PMID- 29998553 TI - Retinal perfusion changes in radiation retinopathy. AB - PURPOSE: To investigate retinal blood flow and oxygen saturation changes in patients diagnosed with retinopathy following plaque radiation treatment to treat choroidal melanoma. METHODS: Eight patients (mean age 55.75 years, SD 12.58 years) who have developed unilateral ischaemic radiation-related retinopathy as confirmed by wide-field fluorescein angiography were recruited for the study. The fellow eye with no other ocular or retinal pathology was used as control. Both eyes underwent measurement of total retinal blood flow (TRBF) and retinal blood oxygen saturation using prototype methodologies of Doppler Spectral Domain Optical Coherence Tomography (OCT) and Hyperspectral Retinal Camera, respectively. RESULTS: The average TRBF in the retinopathy eye was significantly lower compared to the fellow eye (33.48 +/- 12.73 MUl/min versus 50.37 +/- 15.26 MUl/min; p = 0.013). The arteriolar oxygen saturation (SaO2 ) and venular oxygen saturation (SvO2 ) were higher in the retinopathy eye compared to the fellow eye (101.11 +/- 4.26%, versus 94.45 +/- 5.79%; p = 0.008) and (62.96 +/- 11.05% versus 51.24 +/- 6.88%, p = 0.051), respectively. CONCLUSION: The ionizing radiation seems to have an impact on the TRBF, SaO2 and SvO2 , clinically presenting similar to a rapidly developing diabetic retinopathy. The results show an altered retinal vascular physiology in patients with radiation-related retinopathy. PMID- 29998556 TI - Extracellular matrix proteins in the gastrointestinal tract: more than a supporting role. PMID- 29998557 TI - Left coronary artery anomaly in a patient with severe aortic regurgitation and subvalvular membrane. PMID- 29998558 TI - Testing the light:nutrient hypothesis: Insights into biofilm structure and function using metatranscriptomics. AB - Aquatic biofilms are hotspots of biogeochemical activity due to concentrated microbial biomass (Battin, Kaplan, Newbold, & Hansen, ). However, biofilms are often considered a single entity when their role in biogeochemical transformations is assessed, even though these biofilms harbour functionally diverse microbial communities (Battin, Besemer, Bengtsson, Romani, & Packmann, ; Veach, Stegen, Brown, Dodds, & Jumpponen, ). Often overlooked are the biotic interactions among biofilm components that can affect ecosystem-scale processes such as primary production and nutrient cycling. These interactions are likely to be especially important under resource limitation. Light is a primary resource mediating algal photosynthesis and both phototrophic and heterotrophic production due to bacterial reliance on C-rich algal exudates (Cole, ). However, current understanding of function-structure linkages in streams has yet to unravel the relative degree of these microbial feedbacks under resource availability gradients. In this issue of Molecular Ecology, Bengtsson, Wagner, Schwab, Urich, and Battin () studied stream biofilm responses to light availability to understand its impact across three domains of life. By integrating biogeochemical rate estimation and metatranscriptomics within a microcosm experiment, they were able to link primary production and nutrient uptake rates to algal and bacterial metabolic processes and specify what taxa contributed to gene expression. Under low light, diatoms and cyanobacteria upregulated photosynthetic machinery and diatom-specific chloroplast rRNA suggesting heightened transcriptional activity under light limitation to maintain phototrophic energy demands. Under high light, heterotrophic bacteria upregulated mRNAs related to phosphorous (P) metabolism while biofilm P uptake increased indicating high bacterial-specific P demand when algal biomass was high. Together, these results indicate that biogeochemical function is mediated by complex microbial interactions across trophic levels. PMID- 29998559 TI - The gap between current knowledge and clinical practice in childhood disability. PMID- 29998560 TI - Characterization of airborne viromes in cheese production plants. AB - AIMS: To characterize airborne virus-like particles isolated from two cheese production plants in order to reveal their complexity in terms of viral communities and microbial genes potentially mobilized by viruses. METHODS AND RESULTS: Airborne virus-like particles have been isolated from Grana Padano and Gorgonzola PDO cheese production plants and ripening cellars. A shotgun metagenomics analysis of the isolated viromes highlighted a high complexity of the viral communities both in terms of viral taxonomy and phage-host associations. Bacterial reads in each of the viromes were confirmed to be abundant and their taxonomy appeared to be associated with the environmental parameters and the technological processes that characterize the sampling area. Antibiotic resistance genes have been identified in each virome thus confirming that phages could be involved in the mobilization of antimicrobial resistances among bacterial populations. Interestingly human viruses were also identified even if the contamination source was not revealed. CONCLUSIONS: The environmental conditions, which are imposed by the technology of the dairy process, seam to shape the viral populations as a consequence of the adaptation of microbial taxa to those environments. The identification of sequences belonging to Legionella pneumophila and to the human papillomavirus, raised some considerations about the safety of cheese-ripening cellars. SIGNIFICANCE AND IMPACT OF THE STUDY: In conclusion, the analysis of the dairy airborne viromes, has revealed a high complexity of the viral communities even if the environments where the samples were collected were confined environments. Metagenomics of airborne viral population could be a promising monitoring tool for the biological characterization of dairy environments. PMID- 29998561 TI - Bayesian placement of fossils on phylogenies using quantitative morphometric data. AB - Jointly developing a comprehensive tree of life from living and fossil taxa has long been a fundamental goal in evolutionary biology. One major challenge has stemmed from difficulties in merging evidence from extant and extinct organisms. While these efforts have resulted in varying stages of synthesis, they have been hindered by their dependence on qualitative descriptions of morphology. Though rarely applied to phylogenetic inference, traditional and geometric morphometric data can improve these issues by generating more rigorous ways to quantify variation in morphological structures. They may also facilitate the rapid and objective aggregation of large morphological datasets. I describe a new Bayesian method that leverages quantitative trait data to reconstruct the positions of fossil taxa on fixed reference trees composed of extant taxa. Unlike most formulations of phylogenetic Brownian motion models, this method expresses branch lengths in units of morphological disparity, suggesting a new framework through which to construct Bayesian node calibration priors for molecular dating and explore comparative patterns in morphological disparity. I am hopeful that the approach described here will help to facilitate a deeper integration of neo- and paleontological data to move morphological phylogenetics further into the genomic era. PMID- 29998563 TI - Attempt XYZ: airway management at the opposite end of the alphabet. PMID- 29998562 TI - CTL-associated and NK cell-associated immune responses induce different HBV DNA reduction patterns in chronic hepatitis B patients. AB - The activation of hepatitis B virus (HBV)-related hepatitis is associated with both natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). We analyzed the association between the immune response and changes in the proportion of Pre S deletion variants. We quantified Pre-S deleted HBV (HBV-del) and wild-type HBV (HBV-wt) DNA levels in sera obtained from HBV-infected mice and chronic hepatitis B patients. In chronic hepatitis B patients, the HBV-del proportion usually increased during or after ALT elevation but did not occur during all ALT elevations. To clarify this difference in the immunological responses, we performed in vivo analyses using HBV-infected human hepatocyte chimeric mice. Although HBV-del proportions did not change in mice with NK cell-associated hepatitis or in mice treated with entecavir, the proportions sharply increased in mice with CTL-associated hepatitis. Furthermore, the number of patients in which HBV-del proportions were greater than 5% was significantly higher in chronic hepatitis B patients than in asymptomatic carriers (P = 0.023). We identified associations between virological response in chronic hepatitis B patients and two different immune responses. The proportion of HBV-del variants could be a useful biomarker for distinguishing between chronic hepatitis and asymptomatic carriers. PMID- 29998564 TI - In vitro interactions between 17-AAG and azoles against Exophiala dermatitidis. AB - BACKGROUND: Exophiala dermatitidis causes a variety of illnesses in humans which are always refractory to available treatment modalities. Hsp90 governs crucial stress responses, cell wall repair mechanisms and antifungal resistance in pathogenic fungi. Thus, targeting Hsp90 with specific inhibitors holds considerable promise as combination strategy. OBJECTIVES: To investigate the antifungal effect of 17-AAG alone or combined with azoles against E. dermatitidis. METHODS: In vitro interactions of 17-AAG, a Hsp90 inhibitor, and azoles including itraconazole, voriconazole and posaconazole against E. dermatitidis were evaluated via broth microdilution chequerboard technique, adapted from the CLSI M38-A2 method. A total of 18 clinical strains were studied. Candida parapsilosis (ATCC22019) was included to ensure quality control. RESULTS AND CONCLUSIONS: 17-AAG alone exhibited minimal antifungal activity against all tested isolates. However, synergistic effects between 17-AAG and posaconazole, itraconazole or voriconazole were observed against 15 (83.3%), 12 (66.7%) and 1 (5.6%) isolates of E. dermatitidis, respectively. The effective working ranges of 17-AAG in synergistic combinations were mostly within 2-8 MUg/mL. No antagonism was observed. In conclusion, harnessing fungal Hsp90 with 17-AAG might prove a potential antifungal regimen for E. dermatitidis infections. However, due to the host toxicity of 17-AAG, more efforts are needed to develop fungal specific Hsp90 inhibitors. PMID- 29998565 TI - Cost-effectiveness and health-related outcomes of screening for hepatitis C in Korean population. AB - BACKGROUND/AIM: In the era of direct-acting antivirals (DAA), active screening for hidden hepatitis C virus (HCV) infection is important for HCV elimination. This study estimated the cost-effectiveness and health-related outcomes of HCV screening and DAA treatment of a targeted population in Korea, where anti-HCV prevalence was 0.6% in 2015. METHODS: A Markov model simulating the natural history of HCV infection was used to examine the cost-effectiveness of two strategies: no screening vs screening and DAA treatment. Screening was performed by integration of the anti-HCV test into the National Health Examination Program. From a healthcare system's perspective, the cost-utility and the impact on HCV related health events of one-time anti-HCV screening and DAA treatment in Korean population aged 40-65 years was analysed with a lifetime horizon. RESULTS: The HCV screening and DAA treatment strategy increased quality-adjusted life years (QALY) by 0.0015 at a cost of $11.27 resulting in an incremental cost effectiveness ratio (ICER) of $7435 per QALY gained compared with no screening. The probability of the screening strategy to be cost-effective was 98.8% at a willingness-to-pay of $27 205. Deterministic sensitivity analyses revealed the ICERs were from $4602 to $12 588 and sensitive to screening costs, discount rates and treatment acceptability. Moreover, it can prevent 32 HCV-related deaths, 19 hepatocellular carcinomas and 15 decompensated cirrhosis per 100 000 screened persons. CONCLUSIONS: A one-time HCV screening and DAA treatment of a Korean population aged 40-65 years would be highly cost-effective, and significantly reduce the HCV-related morbidity and mortality compared with no screening. PMID- 29998566 TI - Evaluating the experimental cultivation of peppers in low-energy-demand greenhouses. An interdisciplinary study. AB - BACKGROUND: Photovoltaics (PV) provide an alternative solution to cover energy demands in greenhouses. This study evaluates the effect of PV panels installed on the roofs of greenhouses, and the partial shading that they cause, on the growth parameters and growth indicators of the experimental cultivation of peppers (Capsicum annuum cv. California Wonder). The growth of the plants, the antioxidant profile, radical scavenging activity, total phenolic content, and the phenolic and metabolic profiles (using LC-MS spectrometry and NMR spectroscopy) are evaluated. RESULTS: Data are presented from a full cultivation period. Results indicated that indoor temperatures were similar for both glass and glass PV (glass with PV panels installed) greenhouses during the day and the night. The production yield was higher for the glass-PV greenhouses. The pepper fruits' weight, dimensions, and thickness were similar in both cases. Comparison of the pepper fruit extracts in terms of total phenolic content, antioxidant, and antiradical activities indicated differences that were not statistically significant. Photometric and spectroscopic studies both showed a smaller distribution of values in the case of the glass-PV greenhouse, probably indicating a more consistent phytochemical profile. CONCLUSION: Covering only a small proportion (ca. 20%) of the greenhouse roof with photovoltaic panels contributes considerably to its energy demands without affecting plant growth and quality. (c) 2018 Society of Chemical Industry. PMID- 29998567 TI - A stomatal control model based on optimization of carbon gain versus hydraulic risk predicts aspen sapling responses to drought. AB - Empirical models of plant drought responses rely on parameters that are difficult to specify a priori. We test a trait- and process-based model to predict environmental responses from an optimization of carbon gain vs hydraulic risk. We applied four drought treatments to aspen (Populus tremuloides) saplings in a research garden. First we tested the optimization algorithm by using predawn xylem pressure as an input. We then tested the full model which calculates root zone water budget and xylem pressure hourly throughout the growing season. The optimization algorithm performed well when run from measured predawn pressures. The per cent mean absolute error (MAE) averaged 27.7% for midday xylem pressure, transpiration, net assimilation, leaf temperature, sapflow, diffusive conductance and soil-canopy hydraulic conductance. Average MAE was 31.2% for the same observations when the full model was run from irrigation and rain data. Saplings that died were projected to exceed 85% loss in soil-canopy hydraulic conductance, whereas surviving plants never reached this threshold. The model fit was equivalent to that of an empirical model, but with the advantage that all inputs are specific traits. Prediction is empowered because knowing these traits allows knowing the response to climatic stress. PMID- 29998569 TI - Patients admitted via the emergency department to the intensive care unit: An observational cohort study. AB - OBJECTIVE: Timely and appropriate assessment and management within the ED impacts patient outcomes including in-hospital mortality and length of stay (LOS). Within the ED, several processes facilitate timely recognition of the need for intensive care unit (ICU) admission. This study describes characteristics and outcomes for patient presentations admitted to ICU from ED, categorised by Australasian Triage Score (ATS), ICU admission time and ICU admission source. METHODS: A retrospective observational cohort study with linked health data of adult ICU admissions during 2012. Outcomes measured included: ED, ICU and hospital LOS, time to see ED clinician, ICU readmission and ICU and hospital mortality rates. RESULTS: In total, 423 ICU admissions occurred within 24 h of ED arrival; 395 were admitted directly to ICU; 28 were admitted to the ward before ICU admission. ATS 3/4/5 patients comprised 26.7% of ICU admissions and experienced longer waits to be seen, longer total ED LOS, shorter ICU LOS and a lower mortality rate than those triaged ATS 1/2. Compared to ICU admissions during business hours, admissions outside hours did not differ significantly for any outcome measured. Patients admitted to the ward before ICU experienced longer waits to be seen and longer ED LOS. CONCLUSION: Most patients are appropriately identified in ED as requiring ICU admission, although around one in four were triaged ATS 3/4. Patients admitted to the ward first tended to have poorer outcomes than those directly admitted to ICU. Factors predicting the need for ICU admission should be identified to support clinical decision-making. PMID- 29998570 TI - The Relation Between Factual and Counterfactual Conditionals. AB - What is the relation between factual conditionals: If A happened then B happened, and counterfactual conditionals: If A had happened then B would have happened? Some theorists propose quite different semantics for the two. In contrast, the theory of mental models and its computer implementation interrelates them. It postulates that both can have a priori truth values, and that the semantic bases of both are possibilities: states that are possible for factual conditionals, and that were once possible but that did not happen for counterfactual conditionals. Two experiments supported these relations. Experiment 1 showed that, like factual conditionals, certain counterfactuals are true a priori, and others are false a priori. Experiment 2 replicated this result and showed that participants selected appropriate paraphrases, referring, respectively, to real and to counterfactual possibilities, for the two sorts of conditional. These results are contrary to alternative accounts of conditionals. PMID- 29998568 TI - Clinical presentation of patients with suspected obstructive sleep apnea and self reported physician-diagnosed asthma in the ESADA cohort. AB - Obstructive sleep apnea (OSA) and asthma are often associated and several studies suggest a bidirectional relationship between asthma and OSA. This study analyzed the characteristics of patients with suspected OSA from the European Sleep Apnea Database according to presence/absence of physician-diagnosed asthma. Cross sectional data in 16,236 patients (29.1% female) referred for suspected OSA were analyzed according to occurrence of physician-diagnosed asthma for anthropometrics, OSA severity and sleepiness. Sleep structure was assessed in patients studied by polysomnography (i.e. 48% of the sample). The prevalence of physician-diagnosed asthma in the entire cohort was 4.8% (7.9% in women, 3.7% in men, p < 0.0001), and decreased from subjects without OSA to patients with mild moderate and severe OSA (p = 0.02). Obesity was highly prevalent in asthmatic women, whereas BMI distribution was similar in men with and without physician diagnosed asthma. Distribution of OSA severity was similar in patients with and without physician-diagnosed asthma, and unaffected by treatment for asthma or gastroesophageal reflux. Asthma was associated with poor sleep quality and sleepiness. Physician-diagnosed asthma was less common in a sleep clinic population than expected from the results of studies in the general population. Obesity appears as the major factor raising suspicion of OSA in asthmatic women, whereas complaints of poor sleep quality were the likely reason for referral in asthmatic men. PMID- 29998572 TI - Basic skin care in atopic dermatitis - new and established treatment options. AB - Basic skin care (basic therapy) is a mainstay in the treatment of atopic dermatitis, irrespective of disease severity and current disease activity. Consistent application of basic skin care plays a key role in restoring skin barrier function and reducing xerosis as well as pruritus. Moreover, it has been shown that concurrent basic therapy has steroid-sparing effects in acute disease flares. In long-term atopic dermatitis management, the use of basic skin care is associated with prolonged recurrence-free intervals. Recent studies have also demonstrated that early initiation of basic skin therapy has protective effects in infants at risk of developing atopic dermatitis. The present review addresses these topics with a focus on established treatments and new developments. PMID- 29998571 TI - Individual differences in early body mass affect thermogenic performance and sibling interactions in litter huddles of the house mouse. AB - We asked whether within-litter differences in early body mass are associated with differences in house mouse pups' thermogenic performance and whether such variation predicts individual differences in competitive interactions for thermally more advantageous positions in the huddle. We explored pups' thermogenic performance in isolation by measuring changes in (maximal) peripheral body temperatures during a 5-min thermal challenge using infrared thermography. Changes in peripheral body temperature were significantly explained by individual differences in body mass within a litter; relatively lighter individuals showed an overall quicker temperature decrease leading to lower body temperatures toward the end of the thermal challenge compared to heavier littermates. Within the litter huddle, relatively lighter pups with a lower thermogenic performance showed consistently more rooting and climbing behavior, apparently to reach the thermally advantageous center of the huddle. This suggests that within-litter variation in starting body mass affects the pups' thermal and behavioral responses to environmental challenges. PMID- 29998573 TI - Evaluation of compounded aqueous milbemycin oxime: issues with formulation potency and reproducibility. AB - OBJECTIVES: To determine the potency and reproducibility of milbemycin oxime when compounded as an aqueous suspension (20 mg/mL). MATERIALS AND METHODS: Preparation choice reflected current prescribing practices. Samples were acquired by prescription from two national veterinary compounding pharmacies at three time points. Two different storage conditions were evaluated and sampled at four time points from the order date (day 7, 14, 21 and 28). Milbemycin oxime recovery was performed by solid-phase extraction and concentration strength measured via high performance liquid chromatography. RESULTS: The average concentration on day 7 for Pharmacy A samples was 16.29 mg/mL [confidence interval (CI): 15.66 to 16.92] with a coefficient of variation (CV) = 11%, while for Pharmacy B it was 20.46 mg/mL (CI: 19.83 to 21.08) with CV = 22%. The mean decrease in concentration over 28 days for Pharmacy A was 22% (CI: 9% to 34%) while Pharmacy B was 18% (CI: 2% to 35%). CLINICAL SIGNIFICANCE: The compounded milbemycin oxime suspensions evaluated in this study deviated by more than 10% from their labelled strength in five of the six lots. Clinical efficacy of compounded milbemycin oxime suspensions remains unknown and the use of these products should be discouraged at this time. PMID- 29998574 TI - CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel. AB - CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11 13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P = 0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24 hours after ticagrelor ingestion than the controls (43% vs. 21%; P = 0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect. PMID- 29998575 TI - Nitric oxide plays a pivotal role in cardioprotection induced by pomegranate juice against myocardial ischemia and reperfusion. AB - Pomegranate juice (Pg) has demonstrated cardiovascular beneficial effects. The current research intends to investigate the roles of nitric oxide (NO) and antioxidants in Pg-induced cardioprotection against ischemia and reperfusion (I/R). Isolated hearts from anesthetized rats were subjected to 30-min global ischemia followed by 120-min reperfusion. The hearts in the test groups were treated with Pg, NG -nitro-L-arginine methyl ester (L-NAME) or both throughout the experiment. In Pg group, left ventricular developed pressure, rate of rise in left ventricular pressure (dp/dt max), and rate pressure product were 83%, 55%, and 127%, respectively, higher than those of the control group (p < 0.05). The infarct size declined to less than 40% (p < 0.0001), and biomarkers of myocardial damage including creatine kinase-MB, lactate dehydrogenase, and troponin-I, showed significant reductions (59%, 36%, and 94%, respectively) compared with the control. Furthermore, the indices of oxidative status including superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde showed significant improvement (2.4, 1.7, 1.9, and 2.4 fold, respectively). Most of these effects were mainly blocked by L-NAME. These results suggest potent cardioprotective effects for Pg against myocardial I/R injury. The current results suggest a key role for NO for this cardioprotection; however, other mechanisms seem to be also involved. PMID- 29998576 TI - Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor. AB - Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 degrees C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods. PMID- 29998577 TI - Pathways into and out of overweight and obesity from infancy to mid-childhood. AB - OBJECTIVES: To investigate whether high weight in infancy predicts obesity in childhood. METHOD: Data from two UK cohorts (Newcastle Growth and Development N = 795, Gateshead Millennium N = 393) and one Finnish (Tampere N = 1262) were combined. Z scores of weight at 3 and 12 months and body mass index (BMI) at 5 and 8 years were categorized as raised/overweight (1 to <2 SD) or high/obese (>=2 SD). RESULTS: The majority of infants with raised or high weight at birth tended to revert to normal by 3 months and to track in the same category from 3 to 12 months. Although infants with high weight were five times more likely to have BMI >= 2 SD at 8 years (p < 0.001), only 22% went on to have BMI >= 2 SD, while 64% of infants with raised weight had normal BMI at 8 years. Of children with BMI >= 2 SD aged 8 years, only 22% had raised weight in infancy and half had BMI >= 2 SD for the first time at that age. CONCLUSIONS: Infants with raised weight in infancy tend to remain so, but most children who go on to have BMI >= 2 SD were not unusually heavy infants and the majority of infants with high weight reverted to overweight or normal weight in childhood. PMID- 29998578 TI - Salivary S100A8/A9 in Sjogren's syndrome accompanied by lymphoma. AB - BACKGROUND: Sjogren's syndrome (SS) is an autoimmune inflammatory disease that affects the exocrine glands. The absence of early diagnostic markers contributes to delays in its diagnosis. Identification of changes in the protein profile of saliva is considered one of the promising strategies for the discovery of new biomarkers for SS. OBJECTIVE: To identify salivary protein biomarkers with potential for use in discriminating between different lymphoma risk subgroups of SS. METHOD: Parotid and whole mouth saliva samples were collected from patients with SS, including those in subgroups at higher risk of developing or with confirmed lymphoma, non-SS sicca disease controls and healthy subjects. An initial proteomics analysis by mass spectrometry (LCMSMS) identified S100A8/A9 as a biomarker and was followed by validation with an enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant differences were found in levels of S100A8/A9 in parotid saliva but not whole mouth saliva between patients with SS compared with healthy and disease control subjects (P = 0.001 and 0.031, respectively). Subgroups of patients with SS based on lymphoma risk showed significant differences in salivary levels of S100A8/A9. CONCLUSION: The results suggest that salivary levels of S100A8/A9 can aid in differentiating between SS, disease control and healthy control subjects, especially the subgroups of SS with lymphoma or at higher risk of lymphoma. PMID- 29998579 TI - User opinions for the Veterinary Radiology & Ultrasound journal differ among demographic groups. AB - Meeting the changing needs of journal users is important for veterinary editors. The objective of this prospective survey study was to analyze user opinions for the journal Veterinary Radiology & Ultrasound. An online survey was developed based on a consensus among the journal's Editor-in-Chief and Editorial Board members, an industrial organizational psychologist, Executive Council members for the journal's owner organization, representatives of the journal's publisher, and members of the authors' University Institutional Review Board. The online survey link was sent via email to members of the journal's five represented organizations and responses were collected from January 2016 to June 2016. The survey response rate was 38.5% (478 survey responses received/1241 emails sent). Private practitioners were significantly more likely than academicians to consider the reviewer feedback to be accurate (U = 5855, P < 0.05). Respondents from North America were significantly more likely than Europeans to consider the reviewer feedback to be insightful (U = 6212, P < 0.05). A majority of respondents (75.1%) agreed or strongly agreed that the journal should change to a double-blinded peer review system, which has been implemented. Perceptions of quality and satisfaction with the journal were highly correlated to each other (r = 0.68, P < 0.01) and positively correlated with respondent age. Findings indicated that opinions of Veterinary Radiology & Ultrasound users are diverse and differ among some demographic groups. These results may be used to guide future strategic planning to ensure that journal content and Editorial Board membership are representative of these diverse points of view. PMID- 29998581 TI - Treatment of tricuspid regurgitation and para-ring leak in tetralogy of Fallot with oversized SAPIEN 3 valve-in-ring implantation. AB - A 40-year-old female with previously repaired tetralogy of Fallot had recurrent severe tricuspid regurgitation with a para-ring leak after annuloplasty ring placement. Because of multiple prior sternotomies and co-morbidities, she was not felt to be a surgical candidate. Percutaneous placement of an oversized SAPIEN 3 valve-in-ring in the tricuspid position successfully treated the regurgitation and para-ring leak. PMID- 29998580 TI - Cerebrospinal fluid non-pleocytosis in pediatric enteroviral meningitis: Large scale review. AB - BACKGROUND: Lack of cerebrospinal fluid (CSF) pleocytosis has been reported in some children with enteroviral meningitis (EVM). The aim of this paper was to investigate the clinical spectrum and related factors in EVM with CSF non pleocytosis. METHODS: The databases of children diagnosed with EVM on CSF polymerase chain reaction between 2011 and 2014 were retrospectively reviewed. CSF pleocytosis was defined at each age using the criteria. Clinical and laboratory variables were compared between patients with CSF pleocytosis and non pleocytosis. RESULTS: Of the 802 children of EVM, 25.4% (204/802) had CSF non pleocytosis. In particular, CSF non-pleocytosis was found in 63.3% of the neonates versus in 22.2% of the children aged >=1 year old, indicating that the ratio of CSF non-pleocytosis had a negative correlation with age (P < 0.001). As the main symptoms, fever (91.8% vs 86.8%, P = 0.038), headache (80.3% vs 63.7%, P < 0.001), and vomiting (75.9% vs 61.8%, P < 0.001) were significantly more frequent in CSF pleocytosis than in CSF non-pleocytosis. Patients with CSF non pleocytosis had much lower peripheral leukocytosis (10 656 +/- 3,662 vs 12 403 +/ 4,207/mm3 , P = 0.014) and C-reactive protein (0.7+/-0.8 vs 1.2+/-1.5 mg/dL, P < 0.001), and earlier lumbar puncture <24 h after onset (42.6% vs 21.4%, p<0.001). No significant difference during the summer and autumn months was seen between the two groups (76.9% vs 81.9%, P = 0.169). CONCLUSION: CSF non-pleocytosis in childhood EVM was frequently observed, especially in young infants, regardless of season. We propose that CSF PCR testing for enterovirus can be helpful to recognize EVM in children with CSF non-pleocytosis. PMID- 29998582 TI - Agency, activation and compatriots: the influence of social networks on health seeking behaviours among Sri Lankan migrants and Anglo-Australians with depression. AB - The nexus between social networks and illness behaviours is important in uptake of health care, however scant research has explored this relationship in South Asian migrants living with mental illness. We explored the interplay between culture, social networks and health seeking in Sri Lankan migrants and Anglo Australians living with depression. Forty-eight in-depth interviews were conducted and data were analysed through the theoretical prism of the network episode model. Results showed that social networks were important in negotiating care. Decisions to initiate care occurred along a continuum of choice and agency; some took charge of their care, others were coerced into care, however some Sri Lankan migrants were led through various informal channels of care. Selective activation of compatriots - those perceived to understand mental illness-became increasingly important to participants through their illness careers. Compatriots were considered of greater benefit as participants progressed through depression than otherwise meaningful social networks based on ethnicity, culture and kinship. We argue that the role of social networks is pivotal in uptake of formal care, and engaging with communities to improve responses of social networks to mental illnesses may provide a bottom-up avenue for improving uptake of mental health services in migrant communities. PMID- 29998583 TI - Knowledge and Assertion in Korean. AB - Evidence from life science, cognitive science, and philosophy supports the hypothesis that knowledge is a central norm of the human practice of assertion. However, to date, the experimental evidence supporting this hypothesis is limited to American anglophones. If the hypothesis is correct, then such findings will not be limited to one language or culture. Instead, we should find a strong connection between knowledge and assertability across human languages and cultures. To begin testing this prediction, we conducted three experiments on Koreans in Korean. In each case, the findings replicated prior results observed in Americans and were corroborated by key findings from new replication studies on Americans using materials back-translated from Korean. These findings support the theory that there is a core, cross-culturally robust human practice of assertion and that, according to the rules of this practice, assertions should express knowledge. PMID- 29998584 TI - Comparative histomorphological and ultrastructural study of the luminal epithelium of the isthmus in laying and moulting domestic fowls (Gallus domesticus). AB - This study describes ciliated, nonciliated and mitochondrial luminal epithelial cells of the isthmus in laying and moulting domestic fowls using histological and ultrastructural techniques. The ciliated cells were nonsecretory, while numerous electron-dense secretory granules were present in the nonciliated cells of laying birds. Mitochondrial cells, occurring in two morphologically distinct forms, constituted the third type of epithelial cell present in the isthmus. The SEM study showed that the luminal epithelium was dominated by ciliated cells, the cilia of which partially obscured adjacent nonciliated cells. The involution of the luminal epithelium in moulting birds occurred via autophagy, apoptosis and necrosis. Autophagic inclusions, which included autophagosomes and autolysosomes, were present in the early degenerative phases of ciliated, nonciliated and mitochondrial cells. Nonciliated cells underwent degeneration via apoptosis, which was characterized by nuclear and cytoplasmic condensation. Apoptotic and necrotic ciliated cells were evident during the intermediate and advanced stages of regression. The presence of apoptotic cell death was confirmed using the TUNEL assay. Loss of cilia via the formation of cilia packets was observed using TEM and SEM. Necrotic cell death occurred in mitochondrial cells during the intermediate and late stages of degeneration. In conclusion, the findings of the study on isthmus involution in moulting birds suggest that autophagy is a process confined to the early stages of degeneration, while apoptosis and/or necrosis occur in the terminal stages of regression. PMID- 29998585 TI - Correction of a severe pectus carinatum by sterno-costo-chondroplasty with double osteotomy and triple rib bridge fixation. PMID- 29998586 TI - Biosorption of copper by endophytic fungi isolated from Nepenthes ampullaria. AB - : Copper (Cu) tolerance was observed by endophytic fungi isolated from the carnivorous plant Nepenthes ampullaria (collected at an anthropogenically affected site, Kuching city; and a pristine site; Heart of Borneo). The fungal isolates, capable of tolerating Cu up to 1000 ppm (11 isolates in total), were identified through molecular method [internal transcribed spacer 4+5 (ITS4+5); ITS1+NL4; beta-tubulin region using Bt2a + Bt2b], and all of them grouped with Diaporthe, Nigrospora, and Xylaria. A Cu biosorption study was then carried out using live and dead biomass of the 11 fungal isolates. The highest biosorption capacity of using live biomass was achieved by fungal isolates Xylaria sp. NA40 (73.26 +/- 1.61 mg Cu per g biomass) and Diaporthe sp. NA41 (72.65 +/- 2.23 mg Cu per g biomass), NA27 (59.81 +/- 1.15 mg Cu per g biomass) and NA28 (56.85 +/- 4.23 mg Cu per g biomass). The fungal isolate Diaporthe sp. NA41 also achieved the highest biosorption capacity of 59.33 +/- 0.15 mg g-1 using dead biomass. The living biomass possessed a better biosorption capacity than the dead biomass (P < 0.05) and the roadside fungal strains showed higher Cu biosorption capacities using live biomass compared to the jungle fungal strains (P < 0.05). SIGNIFICANCE AND IMPACT OF THE STUDY: Our study highlights that fungal biosorption capacity is highly dependent on the sampling area (roadside vs jungle) with roadside fungal strains showing significantly higher copper (Cu) biosorption capacities using living biomass compared to fungal strains originating from plants collected in virgin jungle (P < 0.05). It also highlights that different biosorption mechanisms (alive - metabolic dependent and dead biomass - metabolic independent) result in different amounts of Cu being removed from the solutions. The living biomass possessed a better biosorption capacity than the dead biomass (P < 0.05). PMID- 29998587 TI - Electronic assessment of cardiovascular potentially inappropriate medications in an administrative population database. AB - AIM: To explore the feasibility of the electronic assessment of potentially inappropriate medication (PIM) criteria in a large administrative database and to explore the validity of the cardiovascular subset of PIM criteria, by studying the association with relevant outcome. METHOD: A cohort study using administrative data from Stockholm County, Sweden (VAL database). Eligible for inclusion were community-dwelling older people (>=65 years), alive in Stockholm County on 31 December 2015. We applied PIM criteria pertaining to the cardiovascular medication group (first-level ATC C group), and we assessed the association between PIM use and mortality and hospitalisation. RESULTS: Patients' (n = 315 120) mean age was 74.0 years (range 65-114), and 54.7% were women. There were 111 cardiovascular PIM criteria in the repository, from which 44 were not registered or prescribed in our population. We excluded another 43 requiring information not available in the database, or duplicates, resulting in 24 applicable criteria. The prevalence of polypharmacy (>= five medications) was 25.5% and the prevalence of at least one PIM use was 8.3%, including 2.8% underuse and 5.3% misuse. Patients with intake of >=10 medications had 38% increased mortality risk compared to those with 0-4 medications. Unplanned hospitalisation and emergency department visits were positively associated with underuse (12% and 25%, respectively) and misuse (13% and 12%, respectively). CONCLUSION: It was feasible to select a subset of cardiovascular PIM criteria originating from different PIM lists and to apply this subset in an administrative database. Additionally, by applying this subset, we showed significant associations with clinical outcome. PMID- 29998588 TI - Technology-induced bias in the theory of evidence-based medicine. AB - Designing trials and studies to minimize confounding and bias is central to evidence-based medicine (EBM). The widespread use of recent technologies such as machine learning, smartphones, and the World Wide Web to collect, analyse, and disseminate information can improve the efficiency, reliability, and availability of medical research. However, it also has the potential to introduce new sources of significant, technology-induced evidential bias. This paper assesses the extent of the impact by reviewing some of the methods by and principles according to which evidence is collected, analysed, and disseminated in EBM, supported by specific examples. It considers the effect of personal health tracking via smartphones, the current proliferation of research data and the influence of search engine "filter bubbles", the possibility of machine learning-driven study design, and the implications of using machine learning to seek patterns in large quantities of data, for example from observational studies and medical record databases. It concludes that new technology may introduce profound new sources of bias that current EBM frameworks do not accommodate. It also proposes new approaches that could be incorporated in to EBM theory to mitigate the most obvious risks, and suggests where further assessment of the practical implications is needed. PMID- 29998589 TI - Volatile organic compounds produced by castor bean cake incorporated into the soil exhibit toxic activity against Meloidogyne incognita. AB - BACKGROUND: This study showed, for the first time, the effect of volatile organic compounds (VOCs) emitted by castor bean cake added to soil on the plant-parasitic nematode Meloidogyne incognita. Identification of nematotoxic volatiles increases the chance of identifying molecules for use in commercial nematicides. RESULTS: VOCs produced after the incorporation of castor bean cake in the soil resulted in immobility (>97.3%) and death (>96.9%) of M. incognita second-stage juveniles (J2) and reduction in M. incognita egg-hatch (>74.3%) at all concentrations of cake tested (1.5-6.0%). A similar reduction in M. incognita infectivity and reproduction was observed when nematodes were exposed to these VOCs and inoculated into tomato plants or exposed directly upon contact with the soil. We identified 32 VOCs produced by castor bean cake when incorporated into soil by using solid phase micro-extraction gas chromatography coupled with mass spectrometry (SPME-GC-MS). Four of the most intense peaks in the chromatogram represented the compounds phenol, 4-methylphenol, gamma-decalactone, and skatole. When M. incognita J2 were exposed to these compounds, all of the compounds demonstrated nematicidal activity with low median lethal concentration (LC50 ) values. CONCLUSION: Castor bean cake incorporated into the soil produces volatile compounds which are toxic to M. incognita. These substances show potential for application in the nematicide-producing industry. (c) 2018 Society of Chemical Industry. PMID- 29998590 TI - Effects of howler monkey reintroduction on ecological interactions and processes. AB - Rewilding has been an increasingly popular tool to restore plant-animal interactions and ecological processes impaired by defaunation. However, the reestablishment of such processes has seldom been assessed. We investigated the restoration of ecological interactions following the reintroduction of the brown howler monkey (Alouatta guariba) to a defaunated Atlantic forest site. We expected the reintroduction to restore plant-animal interactions and interactions between howlers and dung beetles, which promote secondary seed dispersal. We estimated the number of interactions expected to be restored by the reintroduction to provide the baseline interaction richness that could be restored. We followed the reintroduced howler monkeys twice a week for 24 months (337 hours total) to assess their diet. We used howler monkey dung in secondary seed dispersal experiments with 2484 seed mimics to estimate the removal rates by dung beetles and collected the beetles to assess community attributes. We compared the potential future contribution of howler monkeys and other frugivores to seed dispersal based on the seed sizes they disperse in other areas where they occur. In 2 years, howler monkeys consumed 60 animal-dispersed plant species out of the 330 estimated. Twenty-one dung beetle species were attracted to experimentally provided dung; most of them were tunnelers, nocturnal, and large sized (>10 mm). On average 30% (range 0-100%) of the large seed mimics (14 mm) were moved by dung beetles. About 91% of the species consumed by howlers (size range 0.3-34.3 mm) overlapped in seed size with those removed by dung beetles. In our study area, howler monkeys may consume more large-seeded fruit species than most other frugivores, highlighting their potential to affect forest regeneration. Our results show reintroductions may effectively restore ecological links and enhance ecological processes. PMID- 29998591 TI - Biological activities of extracts from Aspidosperma subincanum Mart. and in silico prediction for inhibition of acetylcholinesterase. AB - Species of Aspidosperma are traditionally used to treat malaria, leishmaniasis, microbial, and inflammatory diseases. Aspidosperma subincanum Mart. known as "guatambu" is used in Brazilian traditional medicine to treat diabetes, hypercholesterolemia, and digestive diseases. Its tonic properties have been employed by the indigenous populations to stimulate the circulatory and genitourinary tracts and to improve respiratory function as well as to relieve spasms and to reduce fever. The species is known to contain antitumoural and antimalarial indole alkaloids. In the present study, various less explored biological activities of extracts from leaves and branches of A. subincanum were investigated, that is, inhibition of acetylcholinesterase as well as antioxidant and antibacterial activity. Twenty-one known indole alkaloids from this species were targeted for predicting the inhibition of acetylcholinesterase, and their biological activities were collected from the literature. Through in silico the prediction, the indole alkaloids uleine and derivatives demonstrated a strong probability of being able to inhibit the acetylcholinesterase enzyme, as well as the olivacine derivatives 3,4-dihydroolivacine and N-methyl-tetrahydro-olivacine (guatambuine), and the subincanadines C and E. Indeed, the extracts of A. subincanum showed acetylcholinesterase inhibitory activity, antioxidant activity in the lipid peroxidation assay, and antimicrobial activity against Staphylococcus aureus ATCC 25923, and their pharmacological properties should be explored further. PMID- 29998592 TI - Mortality, liver transplantation and hepatic complications in patients with treatment-naive chronic hepatitis B treated with entecavir vs tenofovir. AB - Few studies have directly compared the long-term clinical outcomes of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). This study aimed to compare the risk of mortality, liver transplantation and hepatic complications including hepatocellular carcinoma (HCC) and hepatic decompensation between these drugs in treatment-naive chronic hepatitis B (CHB). We performed a longitudinal observational analysis of data from 1325 consecutive adult CHB patients with a cumulative adherence of >=80% to treatment with ETV (n = 721) or TDF (n = 604) at a tertiary referral hospital in Ulsan, Korea, from 1 January 2007 through 31 April 2017. Among the patients, 708 were analysed using propensity score matching with a ratio of 1:1. In the follow-up period of up to 5 years, five patients (0.4%) died, three patients (0.2%) underwent liver transplantation (LT) and 54 patients (4.1%) developed HCC. Hepatic decompensation occurred in 24 (1.8%) patients. ETV therapy did not significantly differ from TDF therapy regarding the risk of liver-related death or LT (HR 0.96; 95% CI, 0.23-4.07; log-rank P = 0.955), HCC (HR, 1.36; 95% CI, 0.72-2.56; log-rank P = 0.340) and hepatic decompensation (HR, 1.64; 95% CI, 0.67-4.00; log-rank P = 0.276). In the 708 propensity-matched pairs, ETV and TDF were also not significantly different with respect to the risk of mortality, LT and hepatic complications. In this longitudinal observational study of 1325 patients with CHB, ETV and TDF therapies were not significantly different regarding the risk of mortality, HCC, LT and hepatic decompensation. PMID- 29998594 TI - Lymph node ratio is an independent prognostic factor for rectal cancer after neoadjuvant therapy: A meta-analysis. AB - OBJECTIVE: With neoadjuvant therapy increasingly used in advanced rectal cancer, the lymph node ratio (LNR) has been strongly considered to indicate cancer specific survival in recent years, and a comprehensive evaluation of a large number of studies is deficient. The objective of our study is to pool enough eligible studies to assess the relationship between LNR and prognosis of advanced rectal cancer after neoadjuvant therapy. METHODS: A systematic search was done in the PubMed and EmBase databases (through 1 March 2017) that reported LNR in colorectal cancer after neoadjuvant therapy. The first two authors independently conducted the study selection and data extraction. All statistical analyses were conducted using STATA 13.0 (College Station, Texas). RESULTS: Thirteen studies with 4023 participants were included in the meta-analysis, and all were published after 2011. A high LNR was assessed to be a predictor of poor overall survival in rectal cancer after neoadjuvant therapy (HR: 2.94, 95% CI:1.97 to 3.91, P < 0.001). Similarly, a high LNR was related to poor disease-free survival (HR: 2.83, 95% CI: 1.82 to 3.85, P < 0.001). With respect to recurrence, the HRs of 3.25, 1.93, and 2.11 also showed a strong relationship between high LNR and poor local, distant, and total recurrences. CONCLUSIONS: Our present study demonstrates that a high LNR can predict poor survival in advanced rectal cancer. We suggest well-designed clinical trials to prospectively assess LNR as an independent predictor of rectal cancer survival. PMID- 29998593 TI - Hierarchical Titanium Dioxide Nanowire/Metal-Organic Framework/Carbon Nanofiber Membranes for Highly Efficient Photocatalytic Degradation of Hydrogen Sulfide. AB - Photocatalysis is an efficient approach to degrade hydrogen sulfide (H2 S) and titanium dioxide (TiO2 ) is commonly used as a catalyst for H2 S degradation. However, the low separation rate of photoinduced carriers and low gas adsorption ability of TiO2 limit its H2 S photocatalytic decomposition rate. In this paper, single-crystalline TiO2 nanowires are assembled on one-dimensional carbon nanofibers (CNFs) and a tunable metal-organic framework (MOF) coating is fabricated on the surface of the TiO2 nanowires using a versatile step-by-step self-assembly strategy. The excellent photocatalytic properties of the resulting membrane originate from the ability of the CNFs to rapidly transport charge carriers and the high and regenerable H2 S adsorption ability of the MOF. The photocatalytic mechanism of the as-prepared material was also discussed. Therefore, this work provides a promising method to improve the photocatalytic performance of H2 S degradation. PMID- 29998595 TI - Ultrasonography does not consistently detect parathyroid glands in healthy cats. AB - Ultrasound is used to evaluate the parathyroid glands of several species but there are limited reports of its use in cats. With this prospective anatomic study, we hypothesized that ultrasound could identify two parathyroid glands as hypoechoic nodules associated with each thyroid lobe and that a normal size range could be established. Six cat cadavers were imaged with ultrasound and histopathology of the thyroid and parathyroid tissue was performed for comparison. In addition, clinically healthy adult cats were prospectively recruited and placed in Group 1 (2-6 years; n = 11) or Group 2 (7-13 years; n = 9). Ultrasound of the cervical region was performed using a 7-15 MHz linear transducer. Number, size, and location of all hypoechoic nodules within or immediately adjacent to the thyroid lobes were documented. Ultrasound identified between 0-6 hypoechoic nodules per thyroid lobe in cat cadavers and between 0-3 hypoechoic nodules per thyroid lobe in clinically healthy cats, which does not correlate with the normal anatomy. In conclusion, parathyroid glands were frequently not ultrasonographically observed or were not distinguishable from thyroid tissue and this problem was worse in older cats because of the prevalence of nodular thyroid lesions, which primarily included foci of adenomatous hyperplasia. PMID- 29998596 TI - Position paper: Telemedicine in occupational dermatology - current status and perspectives. AB - Teledermatology is the use of telecommunication technologies to exchange medical information for diagnosis, consultation, treatment and teaching in dermatology. While its use has been evaluated in a wide range of dermatological diagnoses, only few studies exist on its validity, diagnostic precision, feasibility, and cost-effectiveness in occupational dermatology. However, these studies show a considerable potential for diagnosis, prevention, treatment support and follow-up of patients with occupational skin diseases. Asynchronous (store and forward; SAF) or synchronous dermatology teleconsults could assist occupational medicine specialists not only in occupational preventive care, but also in the context of skin cancer screening in outdoor workers. Thus, teledermatology might contribute to earlier prevention and notification of occupational skin diseases. Modern smartphone apps with artificial intelligence technologies may also facilitate self-monitoring in employees working in high-risk jobs. PMID- 29998597 TI - Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell mediated pregnancy loss in mice. AB - OBJECTIVE: Tokishakuyakusan (TSS) is a traditional herbal medicine that has been used empirically to prevent recurrent pregnancy loss. Its mode of action remains unclear. With their potent capacity to produce cytokines, invariant natural killer (iNKT) cells are involved in the control of fetomaternal immunity in early gestation. This study aimed to clarify the effect of TSS on iNKT cell activities in a well-studied murine miscarriage model. METHODS: Pregnant mice were fed 1% TSS-containing or control diet from the day of vaginal plug formation. Alpha galactosylceramide (AGC) was administered intraperitoneally to the pregnant mice at day 9.5 postcoitus (pc) to stimulate iNKT cells. Peripheral cytokine levels were evaluated using cytokine arrays. The percentage of iNKT cells among splenocytes was examined by flow cytometric analysis. The incidence of pregnancy loss was assessed at day 12.5 pc. RESULTS: The ratio of fetal resorptions to total conceptuses was significantly higher in the group exposed to TSS (34%) than in controls (78%). A rapid and robust surge in inflammatory cytokines, including IFN-gamma and TNF-alpha, was detected in the peripheral blood of control animals 2 hours after AGC administration. This peripheral cytokine induction was significantly attenuated in the TSS-fed group compared with the control. The percentage of iNKT cells among total splenocytes was lower in the TSS-fed group than in controls. CONCLUSION: The findings in this study suggest that the inhibitory effects of TSS on pregnancy loss may involve immune modulation of iNKT cells during early pregnancy. PMID- 29998598 TI - Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. AB - OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with >=50%, >=75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with >=50%, >=75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE. PMID- 29998599 TI - Dynamic Covalent Identification of an Efficient Heparin Ligand. AB - Despite heparin being the most widely used macromolecular drug, the design of small-molecule ligands to modulate its effects has been hampered by the structural properties of this polyanionic polysaccharide. Now a dynamic covalent selection approach is used to identify a new ligand for heparin, assembled from extremely simple building blocks. The amplified molecule strongly binds to heparin (KD in the low MUm range, ITC) by a combination of electrostatic, hydrogen bonding, and CH-pi interactions as shown by NMR and molecular modeling. Moreover, this ligand reverts the inhibitory effect of heparin within an enzymatic cascade reaction related to blood coagulation. This study demonstrates the power of dynamic covalent chemistry for the discovery of new modulators of biologically relevant glycosaminoglycans. PMID- 29998600 TI - Feasting on terrestrial organic matter: Dining in a dark lake changes microbial decomposition. AB - Boreal lakes are major components of the global carbon cycle, partly because of sediment-bound heterotrophic microorganisms that decompose within-lake and terrestrially derived organic matter (t-OM). The ability for sediment bacteria to break down and alter t-OM may depend on environmental characteristics and community composition. However, the connection between these two potential drivers of decomposition is poorly understood. We tested how bacterial activity changed along experimental gradients in the quality and quantity of t-OM inputs into littoral sediments of two small boreal lakes, a dark and a clear lake, and measured the abundance of operational taxonomic units and functional genes to identify mechanisms underlying bacterial responses. We found that bacterial production (BP) decreased across lakes with aromatic dissolved organic matter (DOM) in sediment pore water, but the process underlying this pattern differed between lakes. Bacteria in the dark lake invested in the energetically costly production of extracellular enzymes as aromatic DOM increased in availability in the sediments. By contrast, bacteria in the clear lake may have lacked the nutrients and/or genetic potential to degrade aromatic DOM and instead mineralized photo-degraded OM into CO2 . The two lakes differed in community composition, with concentrations of dissolved organic carbon and pH differentiating microbial assemblages. Furthermore, functional genes relating to t-OM degradation were relatively higher in the dark lake. Our results suggest that future changes in t-OM inputs to lake sediments will have different effects on carbon cycling depending on the potential for photo-degradation of OM and composition of resident bacterial communities. PMID- 29998601 TI - An improved DNA method to unambiguously detect small hive beetle Aethina tumida, an invasive pest of honeybee colonies. AB - The scavenger and invasive species Aethina tumida threatening the honey bee has been recently introduced in Europe. We present a new, reliable and rapid multiplex real-time PCR for efficient diagnostics enabling surveillance programs. (c) 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29998602 TI - Elastically Flexible Crystals have Disparate Mechanisms of Molecular Movement Induced by Strain and Heat. AB - Elastically flexible crystals form an emerging class of materials that exhibit a range of notable properties. The mechanism of thermal expansion in flexible crystals of bis(acetylacetonato)copper(II) is compared with the mechanism of molecular motion induced by bending and it is demonstrated that the two mechanisms are distinct. Upon bending, individual molecules within the crystal structure reversibly rotate, while thermal expansion results predominantly in an increase in intermolecular separations with only minor changes to molecular orientation through rotation. PMID- 29998603 TI - Early Cognitive Precursors of Children's Mathematics Learning Disability and Persistent Low Achievement: A 5-Year Longitudinal Study. AB - Mathematical difficulties have been distinguished as mathematics learning disability (MLD) and persistent low achievement (LA). Based on 1,880 Finnish children who were followed from kindergarten (age 6) to fourth grade, this study examined the early risk factors for MLD and LA. Distinct groups of MLD (6.0% of the sample) and LA (25.7%) children were identified on the basis of their mathematics performance between first and fourth grades with latent class growth modeling. Impairment in the same set of cognitive skills, including language, spatial, and counting skills, was found to underlie MLD and LA. The finding highlights the importance of monitoring mathematical development across the early grades and identifying early cognitive precursors of MLD and LA for screening and intervention efforts. PMID- 29998604 TI - Why Choo-Choo Is Better Than Train: The Role of Register-Specific Words in Early Vocabulary Growth. AB - Across languages, lexical items specific to infant-directed speech (i.e., 'baby talk words') are characterized by a preponderance of onomatopoeia (or highly iconic words), diminutives, and reduplication. These lexical characteristics may help infants discover the referential nature of words, identify word referents, and segment fluent speech into words. If so, the amount of lexical input containing these properties should predict infants' rate of vocabulary growth. To test this prediction, we tracked the vocabulary size in 47 English-learning infants from 9 to 21 months and examined whether the patterns of growth can be related to measures of iconicity, diminutives, and reduplication in the lexical input at 9 months. Our analyses showed that both diminutives and reduplication in the input were associated with vocabulary growth, although measures of iconicity were not. These results are consistent with the hypothesis that phonological properties typical of lexical input in infant-directed speech play a role in early vocabulary growth. PMID- 29998605 TI - Effect of methyl jasmonate (MeJA)-induced defenses in rice against the rice leaffolder Cnaphalocrocis medinalis (Guenee) (Lepidoptera: Pyralidae). AB - BACKGROUND: Methyl jasmonate (MeJA) activates host defense mechanisms against insect pests of agricultural importance, and regulates defense responses against living and non-living stresses in various plant species. Rice leaf-folder (Cnaphalocrocis medinalis Guenee, Lepidoptera: Pyralidae) feeding activity and mortality were evaluated after MeJA treatment of rice plants ASD-16. RESULTS: Rice plant resistance was activated through the topical application of MeJA to rice leaves. Feeding deterrence occurred with application of 2.5 and 5 mm MeJA solution. Feeding activity and consumption rates were significantly different, being reduced compared with controls post MeJA treatment. Significantly greater mortality was seen in second instars post treatment with 2.5 and 5 mm MeJA. Survival was significantly reduced for larvae and adults post treatment. CONCLUSION: Application of MeJA as a topical spray onto rice plants significantly altered the biology and survival of the leaf-folder, having an effect on all life stages. (c) 2018 Society of Chemical Industry. PMID- 29998607 TI - Hemodialysis improves skin moisture and sebum secretion but not elasticity in chronic renal disease patients. PMID- 29998606 TI - Clinical characteristics associated with therapeutic nonadherence of the patients with major depressive disorder: A report on the National Survey on Symptomatology of Depression in China. AB - AIMS: Nonadherence is one of the leading challenges to treatment of the major depressive disorder (MDD). Few studies have systematically analyzed the relationship between clinical characteristics, especially symptoms of depressive patients and their therapeutic nonadherence over a relatively large sample. This study aimed to investigate factors of nonadherence in a nationwide survey in China. METHODS: Participants with MDD who met the criteria of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) were recruited from 32 sites throughout China. Patients were all over 16 years old. A doctor rating questionnaire with 64 symptoms based on DSM-IV was constructed to evaluate depression-related feeling and behavior. Single-factor logistic regression was utilized to screen variables, and multifactor logistic regressive analysis was used to identify which factors were risk or protective for nonadherence. We included 882 patients of poor adherence and 857 patients of good adherence. RESULTS: Recurrence, untreated first episode, tricyclic antidepressant (TCA) treated first episode, antidepressant-only-treated current episode, decrease or loss of interest, more somatic symptoms, and "atypical" symptoms were risk factors for nonadherence, whereas selective noradrenaline reuptake inhibitor (SNRI)-treated first episode was a protecting factor. CONCLUSION: Clinical characteristics may play an important role in predicting nonadherence. Doctors may have to pay much attention on patients with these factors and should keep on discussing them with patients. PMID- 29998609 TI - Autophagy and its role in plant abiotic stress management. AB - Being unable to move, plants are regularly exposed to changing environmental conditions, among which various types of abiotic stress, such as heat, drought, salt, and so forth. These might have deleterious effects on plant performance and yield. Plants thus need to adapt using appropriate stress responses. One of the outcomes of abiotic stress is the need to degrade and recycle damaged proteins and organelles. Autophagy is a conserved eukaryotic mechanism functioning in the degradation of proteins, protein aggregates, and whole organelles. It was previously shown to have a role in plant abiotic stress. This review will describe the current knowledge regarding the involvement of autophagy in plant abiotic stress response, mechanisms functioning in autophagy induction during stress, and possible direction for future research. PMID- 29998608 TI - Lippia gracilis essential oil in beta-cyclodextrin inclusion complexes: an environmentally safe formulation to control Aedes aegypti larvae. AB - BACKGROUND: One of the most efficient ways to prevent arboviruses, such as dengue fever, yellow fever, chikungunya and Zika, is by controlling their vector, the Aedes aegypti. Because this vector is becoming resistant to most larvicides used, the development of new larvicides should be considered. beta-Cyclodextrin (beta CD) complexes have been investigated as an interesting way of enabling the use of essential oils in water as larvicides. This study comprised the development of Lippia gracilis essential oil (LGEO) and beta-CD inclusion complexes for control of Ae. aegypti. RESULTS: Thermal analysis clearly showed the formation of complexes using kneading and co-evaporation methods. Gas chromatography analysis showed that kneading without co-solvent (KW) gave the highest content (~ 15%) of the LGEO major component. Moreover, KW showed that the complex had a 50% lethal concentration (LC50 ; 33 ppm) lower than that of pure LGEO (39 ppm); in other words, complexing LGEO with beta-CD improved the larvicidal activity. In addition, LGEO complexed with beta-CD (KW) was not harmful to non-target organisms at the concentrations needed to control Ae. aegypti larvae. CONCLUSION: The inclusion complex with LGEO was a feasible formulation, being economically viable, easy-to-apply and without impact on non-target organisms and, therefore, is a potential alternative larvicide for Ae. aegypti control. (c) 2018 Society of Chemical Industry. PMID- 29998610 TI - Post cardiac surgery stunning reduces stroke work, but leaves cardiac power output unchanged in patients with normal ejection fraction. AB - This study assesses positional changes in cardiac power output and stroke work compared with classic hemodynamic variables, measured before and after elective coronary artery bypass graft surgery. The hypothesis was that cardiac power output was altered in relation to cardiac stunning. The study is a retrospective analysis of data from two previous studies performed in a tertiary care university hospital. Thirty-six patients scheduled for elective coronary artery bypass graft surgery, with relatively preserved left ventricular function, were included. A pulmonary artery catheter and a radial artery catheter were placed preoperatively. Cardiac power output and stroke work were calculated through thermodilution both supine and standing prior to induction of anesthesia and again day one postoperatively. Virtually all systemic hemodynamic parameters changed significantly from pre- to postoperatively, and from supine to standing. Cardiac power output was maintained at 0.9-1.0 (+/-0.3) W both pre- and postoperatively and from supine to standing on both days. Stroke work fell from pre- to postoperatively from 1.1 to 0.8 J (P < 0.001), there was a significant fall in stroke work with positional change preoperatively from 1.1 to 0.9 J (P < 0.001). Postoperatively the stroke work remained at 0.8 J despite positional change. Cardiac power output was the only systemic hemodynamic variable which remained unaltered during all changes. Stroke work appears to be a more sensitive marker for temporary cardiovascular dysfunction than cardiac power output. Further studies should explore the relationship between stroke work and cardiac performance and whether cardiac power output is an autoregulated intrinsic physiological parameter. PMID- 29998611 TI - Computed tomographic features of destructive granulomatous rhinitis with intracranial extension secondary to leishmaniasis in a cat. AB - A 5-year-old castrated male Domestic Shorthair cat presented for evaluation of chronic history of nasal discharge and nasal stridor. On computed tomography (CT), a destructive ill-defined mass of soft tissue attenuation was occupying the right nasal cavity and extending into the left nasal cavity, nasopharynx, and rostral cranial cavity. Histopathology of the rhinoscopically excised samples consisted with destructive granulomatous rhinitis secondary to Leishmania spp. Chronic granulomatous rhinitis with intracranial and nasopharyneal extension secondary to Leishmania spp. infection should be included as a differential diagnosis for a destructive nasal mass of soft tissue attenuation, especially in endemic regions for leishmaniasis. PMID- 29998612 TI - Role of AMPA and NMDA receptors on vasopressin and oxytocin secretion induced by hypertonic extracellular volume expansion. AB - Vasopressin (AVP) and oxytocin (OT) are essential for the control of extracellular fluid osmolality and volume. Secretion of these hormones is modulated by several mechanisms, including NMDA and AMPA L-glutamate receptors in magnocellular cells of paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei. Thus, to better understand the participation of L-glutamate on the neuroendocrine control of AVP and OT, this work evaluated the effects of intracerebroventricular (icv) NMDA and AMPA receptor antagonists on plasma AVP and OT levels induced by extracellular volume expansion (EVE). Cannulated rats received icv NMDA (AP5) and AMPA (NBQX) antagonists in 10 and 30nmol/5MUl/rat doses and were subjected to either isotonic (0.15 M NaCl, 2ml/100g) or hypertonic (0.30 M NaCl, 2ml/100g) EVE. Blood samples were collected for plasma AVP and OT determination. Isotonic EVE did not change plasma AVP and OT levels, but hypertonic EVE increased both AVP and OT plasma levels. AP5 reduced plasma AVP, but it did not change the OT level induced by hypertonic EVE. On the other hand, NBQX reduced plasma OT, but did not alter the AVP plasma level. Our data shows that L-glutamate controls the secretion of neurohypophyseal hormones through the NMDA receptor for AVP release, and through the AMPA receptor for OT release, both in response to hypertonic EVE. This article is protected by copyright. All rights reserved. PMID- 29998613 TI - Intestinal macrophages and their interaction with the enteric nervous system in health and inflammatory bowel disease. AB - Over the past decades, there has been an increasing understanding of cellular and molecular mechanisms that mediate modulation of the immune system by the autonomic nervous system. The discovery that vagal nerve stimulation (VNS) attenuates endotoxin-induced experimental sepsis paved the way for further studies investigating neuro-immune interaction. In particular, great attention is now given to intestinal macrophages: several studies report the existence of both intrinsic and extrinsic neural mechanisms by which intestinal immune homoeostasis can be regulated in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. Given the important role of inflammation in numerous disease processes, such as inflammatory bowel disease (IBD), cholinergic anti-inflammatory mechanisms are under intense investigation both from a basic and clinical science perspective in immune-mediated diseases such as IBD. This review discusses recent insights on the cross-talk between enteric neurons and the immune system, especially focusing on macrophages, and provides an overview of basic and translational aspects of the cholinergic anti inflammatory response as therapeutic alternative to reinstall immune homoeostasis in intestinal chronic inflammation. PMID- 29998614 TI - Management of acute appendicitis in an acute surgical unit: a cost analysis. AB - BACKGROUND: The acute surgical unit (ASU) model of acute general surgery care offers efficient patient assessment, improved clinical outcomes and has been demonstrated to be cost-efficient. Despite this, the management of acute appendicitis in our ASU was found to be highly cost-negative. This study sought to identify the drivers of increased cost. METHODS: A retrospective cost analysis of all patients with uncomplicated acute appendicitis in 2016 was undertaken to investigate the drivers of increased cost. The patient-level costing approach was used to assign cost to patients. RESULTS: The ASU management of uncomplicated appendicitis was found to have made a net loss of $625 000 in 2016. This study identified that the three largest cost drivers in appendicitis care were hospital overheads, bed day length of admission cost and operating theatre costs. Radiology, pathology and pharmacy costs did not affect total cost significantly. CONCLUSION: Two key targets for improvement were identified. First, reduced theatre turnaround times will allow more efficient theatre utilization. Second, improved after-hours and weekend theatre availability will reduce preoperative waiting time-related cost. PMID- 29998615 TI - Pre-clinical evaluation of proteasome inhibitors for canine and human osteosarcoma. AB - Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed. PMID- 29998617 TI - Sexual behaviour and extra-genital colonisation in women treated for recurrent Candida vulvo-vaginitis. AB - OBJECTIVE: This study analyses a relation between sexual habits and the presence of Candida in extra-genital locations as well as a potential effect on therapy response. MATERIAL AND METHODS: Candida cultures were obtained from mouth, nose, anus, urine and perineum of 117 women enrolled in a RVVC treatment trial (ReCiDiF). Sexual behaviour and carriage rates of extra-genital Candida of women responding well to treatment were compared to that of non-responders. RESULTS: Most respondents were heterosexual. All but one practiced vaginal sex. Regular receptive oral sex was not related to multiple site colonisation with Candida (OR = 1.27; CI95% 0.36-4.48), nor to non-response to therapy (OR = 1.3; CI 95% 0.41 4.73). Also, masturbation was not related to response to therapy (OR 0.8; CI95% 0.31-1.84), nor was anal sex (OR = 0.54; CI95% 0.11-2.72). CONCLUSION: Neither oral nor casual anal sex, nor masturbation can be held responsible for the association of the multiple site/anal colonisation with Candida and inferior response to fluconazole maintenance therapy. Changing sexual behaviour during fluconazole maintenance treatment for RVVC in otherwise healthy women should not be advocated. Also, treatment of asymptomatic sexual partners of women with RVVC is not recommended. PMID- 29998616 TI - Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development. AB - BACKGROUND: One of the defining moments of human life occurs early during embryonic development, when individuals sexually differentiate into either male or female. Perturbation of this process can lead to disorders/differences of sex development (DSD). Chromobox protein homolog 2 (CBX2) has two distinct isoforms, CBX2.1 and CBX2.2: the role of CBX2.1 in DSD has been previously established, yet to date the function of the smaller isoform CBX2.2 remains unknown. METHODS: The genomic DNA of two 46,XY DSD patients was analysed using whole exome sequencing. Furthermore, protein/DNA interaction studies were performed using DNA adenine methyltransferase identification (DamID) to identify putative binding partners of CBX2. Finally, in vitro functional studies were used to elucidate the effect of wild-type and variant CBX2.2 on selected downstream targets. RESULTS: Here, we describe two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT). We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development, leading to a severe 46,XY DSD defect, likely because of a defective expression of EMX2 in the developing gonad. CONCLUSION: Our study indicates a distinct function of the shorter form of CBX2 and by identifying several of its unique targets, can advance our understanding of DSD pathogenesis and ultimately DSD diagnosis and management. PMID- 29998618 TI - CyberKnife(r) fixed cone and IrisTM defined small radiation fields: Assessment with a high-resolution solid-state detector array. AB - PURPOSE: The challenges of accurate dosimetry for stereotactic radiotherapy (SRT) with small unflattened radiation fields have been widely reported in the literature. In this case, suitable dosimeters would have to offer a submillimeter spatial resolution. The CyberKnife(r) (Accuray Inc., Sunnyvale, CA, USA) is an SRT-dedicated linear accelerator (linac), which can deliver treatments with submillimeter positional accuracy using circular fields. Beams are delivered with the desired field size using fixed cones, the InCiseTM multileaf collimator or a dynamic variable-aperture IrisTM collimator. The latter, allowing for field sizes to be varied during treatment delivery, has the potential to decrease treatment time, but its reproducibility in terms of output factors (OFs) and dose profiles (DPs) needs to be verified. METHODS: A 2D monolithic silicon array detector, the "Octa", was evaluated for dosimetric quality assurance (QA) for a CyberKnife system. OFs, DPs, percentage depth-dose (PDD) and tissue maximum ratio (TMR) were investigated, and results were benchmarked against the PTW SRS diode. Cross plane, in-plane and 2 diagonal dose profiles were measured simultaneously with high spatial resolution (0.3 mm). Monte Carlo (MC) simulations with a GEANT4 (GEometry ANd Tracking 4) tool-kit were added to the study to support the experimental characterization of the detector response. RESULTS: For fixed cones and the Iris, for all field sizes investigated in the range between 5 and 60 mm diameter, OFs, PDDs, TMRs, and DPs in terms of FWHM measured by the Octa were accurate within 3% when benchmarked against the SRS diode and MC calculations. CONCLUSIONS: The Octa was shown to be an accurate dosimeter for measurements with a 6 MV FFF beam delivered with a CyberKnife system. The detector enabled real time dosimetric verification for the variable aperture Iris collimator, yielding OFs and DPs consistent with those obtained with alternative methods. PMID- 29998619 TI - Pre-exposure prophylaxis for men who have sex with men in China: challenges for routine implementation. PMID- 29998620 TI - Treatment of HER2-positive early breast cancer: How to best balance efficacy and toxicity? PMID- 29998621 TI - Commentary on Litt et al. (2018): Identifying treatment-targeted mechanisms-aim and measure the bullseye. PMID- 29998622 TI - Commentary on Schluter et al. (2018): Revisiting the core elements of addiction using a lay epidemiology approach. PMID- 29998623 TI - Commentary on Madden et al. (2018): 'It's not only about the destination... it's also about the journey!' Consumer perspectives on a model of open-access MAT provision. PMID- 29998624 TI - Commentary on Ritter et al. (2018): Making research active in policy-engaging in ontological politics and evidence events. PMID- 29998625 TI - Probing Interfacial Electronic and Catalytic Properties on Well-Defined Surfaces by Using In Situ Raman Spectroscopy. AB - Heterogeneous metal interfaces play a key role in determining the mechanism and performance of catalysts. However, in situ characterization of such interfaces at the molecular level is challenging. Herein, two model interfaces, Pd and Pt overlayers on Au single crystals, were constructed. The electronic structures of these interfaces as well as effects of crystallographic orientation on them were analyzed by shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) using phenyl isocyanide (PIC) as a probe molecule. A clear red shift in the frequency of the C=N stretch (nuNC ) was observed, which is consistent with X-ray photoelectron spectroscopy (XPS) data and indicates that the ultrathin Pt and Pd layers donate their free electrons to the Au substrates. Furthermore, in situ electrochemical SHINERS studies showed that the electronic effects weaken Pt-C/Pd C bonds, leading to improved surface activity towards CO electrooxidation. PMID- 29998627 TI - The science and art of dietetics: Why science needs to underpin our practice. PMID- 29998626 TI - Dietetics students' construction of competence through assessment and placement experiences. AB - AIM: Competency standards are widely adopted as a framework to describe standards of performance required in the workplace. Little is known, however, about how students construct competence. This qualitative study aimed to explore how dietetics students ready to graduate construct the concept of competence and the role of assessment in developing professional competence. METHODS: A qualitative description was used to gather data from a convenience sample of students ready to graduate from universities with accredited dietetics programs across Australia (10 out of 15 at the time of the study). A total of 11 focus groups were conducted to explore perspectives of competence and experiences of 'competency based' assessment. Data were audio-recorded, transcribed and analysed using a thematic analysis approach. RESULTS: A total of 81 (n = 81) participants across 10 universities representing 22% of total students participated in the focus groups. Themes revealed that: (i) there is no shared understanding of competence; (ii) current work placement experiences may not reflect current standards or workforce needs; (iii) assessment approaches may not fully support the development of competence; and (iv) the competent performance of supervising dietitians/clinical educators in the workplace influences the construction of competence. CONCLUSIONS: There is a need to work towards a shared understanding of dietetic entry-level competence in the profession. 'Work-based' learning experiences may need to be modified to ensure students meet current competency standards. Practitioners involved in student supervision need to acknowledge the influential role they have in the development of the future workforce. PMID- 29998628 TI - Plasma Exchanges for Refractory Evans Syndrome. PMID- 29998629 TI - Low- and high-protein diets do not alter ex vivo insulin action in skeletal muscle. AB - A low-protein high carbohydrate (LPHC) diet and a high-protein low carbohydrate (HPLC) diet have been reported to positively and negatively regulate whole-body glucose tolerance and insulin sensitivity, respectively. Skeletal muscle is quantitatively the most important tissue clearing glucose in the postprandial state, but it is unclear if LPHC and HPLC diets directly influence insulin action in skeletal muscle. To test this, mice were placed on control chow diet, LPHC and HPLC diets for 13.5 weeks at which time the submaximal insulin-stimulated glucose transport and insulin signaling were evaluated in ex vivo incubated oxidative soleus and glycolytic EDL muscle. At the whole-body level, the diets had the anticipated effects, with LPHC diet improving glucose tolerance and insulin sensitivity whereas HPLC diet had the opposite effect. However, neither insulin stimulated Akt/TBC1D4 signaling and glucose transport ex vivo, nor cell signaling in vivo were altered by the diets. These data imply that skeletal muscle insulin sensitivity does not contribute to the whole-body effects of LPHC and HPLC diets on glucose metabolism. PMID- 29998630 TI - Disaster Nursing Development in China and Other Countries: A Bibliometric Study. AB - PURPOSE: China is a country with frequent disasters, and nurses play indispensable roles in the disaster process. The Chinese disaster nursing specialty developed with several deficiencies. This study aimed to identify the limitations in the development of disaster nursing in China and to provide a reference for the future by comparing relevant studies between China and other countries. DESIGN: A systematic literature review was conducted in English and Chinese databases to identify disaster nursing articles published from January 1, 2000, to December 31, 2016. METHODS: This study followed the systematic literature collection tactic and bibliometric method. Basic information such as country, number of publications, and discussed disaster types were described through frequency distributions. Article themes were extracted and divided into the four phases of the International Council of Nurses Framework of Disaster Nursing Competencies. FINDINGS: 1,384 articles were included in the analysis, containing 781 written in Chinese and 603 written in English (with 56 of them written by Chinese researchers). The number of Chinese disaster nursing articles and other publications increased sharply between 2007 and 2009 but dropped significantly afterwards, while the total number of articles in other countries fluctuated, with a general upward trend. Compared to other countries, there were fewer research methods used and less focus on disaster prevention and preparedness in China, an imbalanced focus on disaster types, and a lack of focus on prevention, preparedness, and recovery phases. CONCLUSIONS: In China, there is a lack of stable development of disaster nursing research, a lack of study types, and less focus on disaster prevention, preparedness, and recovery. Varied study methods and an increased focus on disaster prevention and preparedness are required in the future. CLINICAL RELEVANCE: This study analyzed the deficiencies in Chinese disaster nursing, which led to recommendations and proposed directions for future studies and a clinical focus in this field, in compliance with the United Nations guidelines for disaster management. PMID- 29998631 TI - Individuals with obesity but no other metabolic risk factors are not at significantly elevated all-cause mortality risk in men and women. AB - Studies have examined mortality risk for metabolically healthy obesity, defined as zero or one metabolic risk factors but not as zero risk factors. Thus, we sought to determine the independent mortality risk associated with obesity or elevated glucose, blood pressure or lipids in isolation or clustered together. The sample included 54 089 men and women from five cohort studies (follow-up = 12.8 +/- 7.2 years and 4864 [9.0%] deaths). Individuals were categorized as having obesity or elevated glucose, blood pressure or lipids alone or clustered with obesity or another metabolic factor. In our study sample, 6% of individuals presented with obesity but no other metabolic abnormalities. General obesity (hazard ratios [HR], 95% CI = 1.10, 0.8-1.6) and abdominal obesity (HR = 1.24, 0.9-1.7) in the absence of metabolic risk factors were not associated with mortality risk compared to lean individuals. Conversely, diabetes, hypertension and dyslipidaemia in isolation were significantly associated with mortality risk (HR range = 1.17-1.94, P < 0.05). However, when using traditional approaches, obesity (HR = 1.12, 1.02-1.23) is independently associated with mortality risk after statistical adjustment for the other metabolic risk factors. Similarly, metabolically healthy obesity, when defined as zero or one risk factor, is also associated with increased mortality risk (HR = 1.15, 1.01-1.32) as compared to lean healthy individuals. Obesity in the absence of metabolic abnormalities may not be associated with higher risk for all-cause mortality compared to lean healthy individuals. Conversely, elevation of even a single metabolic risk factor is associated with increased mortality risk. PMID- 29998633 TI - ? PMID- 29998632 TI - The Role of Optical Coherence Tomography in Differentiating Optic Disc Drusen from Optic Disc Edema. AB - An elevated optic nerve head can be an ominous sign, sometimes signifying an underlying basis for raised intracranial pressure. Alternatively, patients may harbor a different mechanism for this optic nerve head appearance, including optic disc drusen (ODD), which does not confer any life-threatening implications. It is important to refine the approach to distinguishing ODD from papilledema because this is a relatively common, and important, conundrum encountered in clinical practice. Optical coherence tomography (OCT) is a noninvasive, readily accessible, and cost-effective ocular imaging technique that can improve the diagnostic accuracy for detecting ODD; or, instead, increase the index of suspicion for papilledema, thus prompting additional investigations needed to identify (or exclude) potential causes of raised intracranial pressure. In this review, we will discuss the value of OCT in the diagnostic approach to cases of mild optic disc elevation, with acknowledgment of the potential pearls and pitfalls of this imaging technology. In particular, we will emphasize the helpful role OCT can play in differentiating cases of ODD from mild papilledema in the context of idiopathic intracranial hypertension (IIH). PMID- 29998634 TI - [Management of a first-time dislocation in the athlete]. AB - Management of a first-time dislocation in the athlete patient is challenging. This patient population has important requirements with high expectations and deadlines to meet, especially if the trauma occurs during high season. As initial management is usually conservative with immobilization followed by rehabilitation, some authors support the role of primary surgical treatment in high risk athletes. Indication for surgery and choice of surgical technique is based on an algorithm incorporating risk factors for recurrence and the presence of concomitant bony lesions on the humeral and glenoid sides. Return to sport varies from 3 to 6 months depending on the type of sport practiced. PMID- 29998635 TI - [The acute management of muscle injuries in 2018]. AB - Acute muscle lesions are frequent conditions in sports traumato-logy. Intrinsic traumatic mechanism (excessive stretch) is more prevalent that extrinsic mechanism (direct shock or lacerations). The diagnosis is generally based on the injury mechanism description together with the clinical examination. The ultrasonography is helpful in order to evaluate the severity of the lesion and the time to sports resumption. The initial management is based on the POLICE acronym: Protection, Optimal loading, Ice, Compression, and Elevation. For high grade muscle lesions, patients might benefit from either ultrasound-guided hematoma evacuation or surgical repair. Non-steroid anti-inflammatory drugs should be avoided within the first days. The rehabilitation should begin 48h after the trauma, whatever the severity of the lesion. PMID- 29998636 TI - [Return to sport and to competition after anterior crusiate ligament reconstruction.] AB - The return to sport (RTS) and return to competition (RTC) after anterior cruciate ligament reconstruction (ACLR) in the recreational and professionnel sports population remains a challenge. Previous level of activity, associated injuries, the type of reconstruction, and rehabilitation associated factors such as strength, neuromuscular control, and mobility all influence the RTS and RTC. Psychologic aspects, overall fitness, and patient's expectations equally play an important role. ACLR rehabilitation needs ideally a multi-disciplinary setting and follows functional steps rather than chronological time-lines, with passing criteria until RTS and RTC. Standardized and sport-specific tests are mandatory to evaluated optimal readiness for RTS and RTC. PMID- 29998637 TI - [Adolescent sport medicine : do simple injuries really exist in youth athletes ?] AB - Offering an interdisciplinary approach to the athletic adolescent helps to expand the evaluation framework when investigating a medical complaint. It is important to use the opportunity of each consultation to take not only a detailed history of the sporting practice, but also to investigate the social and familial context as well as healthy lifestyle of the young athlete. Considering young athletes within the larger picture of their developmental context of adolescence offers an opportunity to better respect the psychological and physical needs of this life phase. These needs are strongly related to the promotion of a good health among young athletes. PMID- 29998638 TI - [Hamstring injury prevention]. AB - Hamstring muscle injury is the first diagnosis of injury in sports involving sprints. Its prevention represents a fundamental challenge for the technical and health professionals around the athletes. Risk factors have been described and can be used for screening at-risk individuals (age, history of hamstring injury, strength deficit). Although every determinant of the occurrence of these injuries has not yet been determined, and currently available preventive measures are not fully effective (eccentric muscle strengthening and strength deficit screening), these preventive measures do exist and must be implemented to the benefit of athletes before more comprehensive approaches are developed and demonstrate greater efficiency. PMID- 29998639 TI - [The necessary dialogue between medicine and anti-doping for the integrity of sport and the athlete]. AB - In the light of recurring anti-doping news, this article discusses some special cases and extends to the future prospects of developing effective anti-doping strategies. After recalling the current principles of the fight against doping, the use of substances tole-rated at a certain threshold, and the therapeutic use exemptions (TUE) are discussed. Authorized substances with a health risk for athletes are discussed before concluding on the development of the athlete's biological passport as a future common ground for anti-doping and medical follow up of athletes. In conclusion, this approach emphasizes the imperative dialogue between anti-doping organizations and sports medicine in order to defend good practices preserving the intrinsic value of sport. PMID- 29998641 TI - ? PMID- 29998640 TI - [Why a post-intensive care consultation ?] AB - The progress of intensive care medicine allows the survival of patients with severe critical illness. However, the quality of life of patients with a prolonged stay in intensive care unit (ICU) can be poor. The physical and psychological consequences are due more to the intensive care than the primary diagnoses. Moreover, a stay of a beloved in an ICU impacts heavily on the relatives. The service of Geneva ICU developed a specific model of care for patients with a prolonged stay and seeks to establish a follow-up consultation for these patients. The aim would be to fill the memory gaps, explain the events during their stay, and detect potential complications. This project fits in the follow-up of complex situations in tight collaboration with the family doctors of such patients. PMID- 29998642 TI - ? PMID- 29998644 TI - ? PMID- 29998643 TI - ? PMID- 29998645 TI - ? PMID- 29998646 TI - ? PMID- 29998647 TI - Whole brain vascular imaging in a mouse model of Alzheimer's disease with two photon microscopy. AB - Given known correlations between vascular health and cognitive impairment, the development of tools to image microvasculature in the whole brain could help investigate these correlations. We explore the feasibility of using an automated serial two-photon microscope to image fluorescent gelatin-filled whole rodent brains in three-dimensions (3-D) with the goal of carrying group studies. Vascular density (VD) was computed using automatic segmentation combined with coregistration techniques to build a group-level vascular metric in the whole brain. Focusing on the medial prefrontal cortex, cerebral cortex, the olfactory bulb, and the hippocampal formation, we compared the VD of three age groups (2-, 4.5-, and 8-months-old), for both wild type mice and a transgenic model (APP/PS1) with pathology resembling Alzheimer's disease (AD). We report a general loss of VD caused by the aging process with a small VD increase in the diseased animals in the somatomotor and somatosensory cortical regions and the olfactory bulb, partly supported by MRI perfusion data. This study supports previous observations that AD transgenic mice show a higher VD in specific regions compared with WT mice during the early and late stages of the disease (4.5 to 8 months), extending results to whole brain mapping. PMID- 29998648 TI - Investigating optical path and differential pathlength factor in reflectance photoplethysmography for the assessment of perfusion. AB - Photoplethysmography (PPG) is an optical noninvasive technique with the potential for assessing tissue perfusion. The relative time-change in the concentration of oxyhemoglobin and deoxyhemoglobin in the blood can be derived from DC part of the PPG signal. However, the absolute concentration cannot be determined due to the inadequate data on PPG optical paths. The optical path and differential pathlength factor (DPF) for PPG at red (660 nm) and infrared (880 nm) wavelengths were investigated using a heterogeneous Monte Carlo model of the human forearm. Using the simulated DPFs, the absolute time-change in concentrations were determined from PPG signals recorded from the same tissue site. Results were compared with three conditions of approximated DPFs. Results showed the variation of the optical-path and DPF with different wavelengths and source-detector separations. Approximations resulted in significant errors, for example, using NIRS DPF in PPG led to "cross talk" of -0.4297 and 0.060 and an error of 15.16% to 25.18%. Results confirmed the feasibility of using the PPG (DC) for the assessment of tissue perfusion. The study also identified the inappropriateness of the assumption that DPF is independent of wavelength or source-detector separations and set the platform for further studies on investigating optical pathlengths and DPF in PPG. PMID- 29998649 TI - How to assist in emergency tracheal intubation. PMID- 29998650 TI - [An Assessment of PM2.5-Related Health Risks and Associated Economic Losses in Chinese Cities]. AB - It is important to carry out research on health risks and associated economic losses caused by air pollution using a large sample city in order to control air pollution and improve public health literacy. Using environmental health risk and environmental value assessment methods, the health risks of PM2.5 pollution in 2015, as well as the corresponding economic losses, were estimated in this study using the environmental monitoring data of 62 key cities as samples. The results show that significant impacts due to PM2.5 pollution occurred in 2015, including about 125.1[95% confidence interval (CI):33.29-205.90] thousand premature deaths and 10.10 (95% CI:4.70-15.02) million cases of illness, hospital admissions, and outpatients, which accounted for 3.53% (95% CI:1.64%-5.26%) of the total urban population. The total economic loss associated with the health risks was approximately 570.6 (95% CI:193.08-874.21) billion yuan, which accounts for 1.53% (95% CI:0.52%-2.35%) of the total GDP in 2015. The per capita loss was 1970 (95% CI:667-3018) yuan for these cities. Among the four major urban agglomerations of Beijing-Tianjin-Hebei, the Yangtze River Delta, the Pearl River Delta, and Northeast China, Beijing-Tianjin-Hebei has the highest health risks, associated economic losses, the proportion of associated economic losses to GDP, and associated economic loss per capita because of its high concentration of PM2.5 and dense population than other three urban agglomerations. Among the three economic areas of Eastern, Central, and Western China, the health risks and associated economic losses were highest in the former. However, economic loss per capita did not differ greatly in the three economic areas. The difference in economic losses was very small between South and North China. However, the proportion of economic loss to GDP and per capita loss were much higher in the North than in the South. As to specific cities, the problems of health risks and economic losses were outstanding in Baoding, Zhengzhou, Jinan, and Beijing, which have higher PM2.5 concentrations. PMID- 29998651 TI - [Impact of the Electric Power Industry on Air Quality in Winter of Urban Agglomerations Along the Middle Reaches of the Yangtze River]. AB - A WRF-CAMx-PSAT model was applied to analyze the impact of the electric power industry on urban agglomerations along the middle reaches of the Yangtze River. A high-resolution emission inventory based on a bottom-up approach was developed for air quality simulation. A typical month with heavy air pollution in this region (i.e., January) was chosen for simulation, and two mitigation scenarios were set for assessing lower capacity power units' impact on regional air quality. One scenario was for shutting down the lower capacity power units, and the other was for replacing lower capacity power units with higher capacity power units. Results showed that lower capacity power units contributed bigger pollutant concentrations to the regional contribution of the electric power industry. The concentration contributions of SO2, NOx, and PM2.5 in the two mitigation scenarios were reduced by 36.2%-39.8%,30.5%-33.5%, and 25.9%-30.7%, respectively, than those under the current situation. Meanwhile, the decreases in pollutant concentration contribution for different regions were very similar for the two mitigation scenarios. In addition, lower capacity power units in four regions (i.e., northwest of Hubei province, west of Hunan province, Xiang-Jing-Yi economic belt region, and Hefei-centered urban agglomerations) contributed obviously to the regional pollutant concentration contributions of the electric power industry. Regional pollutant concentration contributions in the two mitigation scenarios were reduced by 40%-70%. Therefore, lower capacity power units make a bigger impact on the air quality of urban agglomerations along the middle reaches of the Yangtze River and should be paid special attention to achieve better regional air quality. PMID- 29998652 TI - [Capacity Simulation Method Based on Regional Transfer Matrix and PM2.5 Concentration Target Constraint]. AB - Atmospheric environmental capacity is an important reference in environmental planning. To meet the PM2.5 standard, a new method is proposed to balance the capacity among cities of Guangdong, with screening of the most unfavorable meteorological year and combining it with the regional transportation calculated by the CAMx-PSAT module. Pollutant overloading and capacity scenarios were also calculated. The results showed that, under the constraints of the cities' annual PM2.5 <= 35 MUg.m-3, the capacities of SO2, NOx, NH3, and PM2.5 in Guangdong were about 6.8*105 tons, 1.35*106 tons, 4.6*105 tons, and 5.1*105 tons, respectively. Based on the benchmark scenario, SO2 emissions in Guangdong were overloaded by 10%, and the emissions of NOx, NH3, and PM2.5 exceeded by 12%, 9%, and 20%, respectively, compared to those of the capacity scenario. Ranked by the number of overloaded species in Guangdong, the cities of Guangzhou, Foshan, Zhongshan, and Qingyuan were on top. When achieving the capacity scenario, the annual PM2.5 concentration in Guangdong was about 30 MUg.m-3, which meets the national secondary ambient air quality standard. PMID- 29998653 TI - [Analysis of Chemical Composition of the Fine Particulate Matter in Summer in Tianjin City via a Single Particle Aerosol Mass Spectrometer (SPAMS)]. AB - As an important megacity of the Beijing-Tianjin-Hebei air pollution transmission channel and the Bohai Sea Economic Zone, Tianjin is influenced by air pollution in recent years, thus research on the fine particulate matter in Tianjin is of vital value. In this study, single particle aerosol mass spectrometry (SPAMS) was used to measure data of Jinnan District in Tianjin during August 2017, to describe the chemical features of fine particles in summer ambient air and estimate the potential pollution sources of fine particles. By using the ART-2a clustering method, 12 classes of PM were acquired, such as elemental carbon particles, Fe-NO3 particles, Na-K particles, and metal particles. After monitoring the size distribution and diurnal variation of fine particles, it was concluded that the ratio of EC particles decreased as the size increased, whereas dust particles and Fe-NO3 particles showed the opposite trend; three types of EC particles varied differently in a day according to the photochemical reaction; and the ratio of Fe-NO3 particles was elevated in the daytime because of industrial production during that period. Backward trajectories of daily airflow at the measured spot were also calculated. When the monitoring site was affected by the air mass from the southwest, coal-burning particles may have contributed more; whereas, when the air mass from the southeast occurred more frequently, biomass burning and sea salt particles possibly contributed more. PMID- 29998654 TI - [Pollution Characteristics of Organic Carbon and Elemental Carbon in Atmospheric Aerosols in Beibei District, Chongqing]. AB - To study the pollution characteristics of atmospheric carbon aerosols, aerosol samples were collected via a cascade impactor (Andersen) from March 2014 to February 2015 in Beibei District, Chongqing. Organic carbon (OC) and element carbon (EC) were detected using a DRI 2001A carbon analyzer. The results showed that the annual average concentrations of OC and EC in PM2.1 were (16.3+/-7.6) and (1.8+/-0.7), respectively, and (25.0+/-9.6), and (3.2+/-1.3) MUg.m-3, respectively, in PM9.0. The concentrations of both OC and EC were higher in winter and spring than in summer and autumn for PM2.1, whereas, for PM9.0, the concentration of OC was higher in summer and spring than in winter and autumn and that of EC was higher in winter and spring than in summer and autumn. The particle size distributions of OC and EC for the study year were analyzed, and it was found that those of OC were bimodal, with peaks in the size ranges of 0.43 0.65 MUm for fine particles and 4.7-5.8 MUm for coarse particles, and those of EC were trimodal, with peaks in the size ranges of 0.43-0.65 MUm for fine particles and 4.7-5.8 MUm for coarse particles and a concurrent significant peak in the particle size range of 2.1-3.3 MUm. In addition, the correlations between OC and EC were analyzed and the SOC in PM2.1 was estimated. It was found that the average concentration of SOC was (6.3+/-5.9) MUg.m-3, which accounted for 33.5%+/ 22.6% of the OC concentration in Beibei District. Furthermore, OC and EC were significantly correlated. Finally, the pollution sources of atmospheric aerosols in Beibei were analyzed, and it was found that the pollution in Beibei mainly came from the exhaust gas of gasoline vehicles, biomass combustion, and coal combustion. PMID- 29998655 TI - [Characteristics and Source Analysis of Atmospheric Carbonaceous Aerosols in the Cities of Hangzhou and Ningbo]. AB - To investigate the seasonal variations and sources of carbonaceous aerosols in the cities of Hangzhou and Ningbo, field PM2.5 sampling was conducted at four representative sites (two urban, one suburban, and one rural) in this region from December 2014 to November 2015. A thermal/optical carbon analyzer was employed to analyze both organic carbon (OC) and elemental carbon (EC) contents in PM2.5 by identifying eight different carbon fractions, including OC1, OC2, OC3, OC4+OPC, EC1-OPC, EC2, and EC3. Based on these fractions, OC and EC were defined as OC1+OC2+OC3+OC4+OPC and EC1+EC2+EC3-OPC, respectively; total carbon (TC) was calculated as the sum of OC and EC; and total carbonaceous aerosols (TCAs) were quantified via the sum of organic aerosols (OAs; converted from OC) and EC. The results showed the following. 1The annual average level of TC in this region was (14.3+/-4.1) MUg.m-3, accounting for (26.2+/-6.5)% of the annual average PM2.5 concentration. The annual average OC and EC concentrations were (11.3+/-3.4) MUg.m-3 and (3.0+/-0.9) MUg.m-3, respectively. The highest TC level was observed in winter among the four seasons. 2The annual average TCA concentration in this region was (25.6+/-7.5) MUg.m-3, contributing (42.2+/-10.0)% of PM2.5. In addition, secondary organic carbon (SOC) was also estimated by the commonly applied EC method. It was found that SOC contributed (41.1+/-5.5)% to OC on an annual average basis. 3The sources of carbonaceous aerosols were determined using the correlation between OC and EC, OC/EC mass ratio, and different carbon fraction characteristics. The annual average OC/EC ratio in this region was 4.7+/ 1.7, which falls in the diagnostic ratio range for vehicular emissions, coal combustion, and biomass burning, indicating these sources are probably the major contributors of the regional carbonaceous aerosols. Moreover, a higher char EC/soot-EC ratio was observed during winter and autumn at all sites, possibly implying the enhanced biomass burning activities during these two seasons. PMID- 29998656 TI - [Emission Characteristics and Chemical Components of PM2.5 from Open Burning of Municipal Solid Waste]. AB - Source emission measurements were employed to investigate open burning of municipal solid waste (MSW). Both barrel and natural pile-up burning of MSW were investigated using a self-designed dilution sampling system. PM2.5 was collected for three types of waste, including rubber and plastic, paper, and wood and bamboo. Then, components in the samples were analyzed and emission factors of PM2.5, organic carbon (OC), elemental carbon (EC), water-soluble ions and inorganic elements were calculated. The PM2.5 emission factor was highest for wood and bamboo, and lowest for paper, and was calculated to be (7.44+/-0.76) g.kg-1 and (2.72+/-0.52) g.kg-1, respectively. Barrel burning resulted in much higher pollutant emissions. The PM2.5 emission factor for barrel burning was 2.5 3.5 times that of natural pile-up burning. OC and EC were the main components of PM2.5, with a proportion of 46.6%-67.2%. MSW composition had a greater effect on the OC/EC ratios than burning mode. The ratios could be helpful in the analysis of the emission contributions of different MSW components. The proportions of NH4+ and Cl- were the highest in water-soluble ions, accounting for 2.28%-6.35% and 1.04%-14.31%, respectively. Among inorganic elements, Ca, K, Fe, and Ba showed high emission factors. The emission factor of Zn was the highest among heavy metals, and other elements such as Cu, Cr, Sb, and Pb were also enriched. Zn emission was mainly determined by the burning mode; emissions from barrel combustion were approximately 20 times more than that of natural pile-up burning. PMID- 29998657 TI - [Size-resolved Emission Factors of Carbonaceous Particles from Domestic Coal Combustion in China]. AB - China is one of the most important contributors to the global burden of carbonaceous aerosols, of which domestic coal combustion occupies a large fraction. Uncertainty in the emission factors (EFs) directly influences the accuracy of corresponding emission inventories. In the present study, based on domestic burning tests with a dilution sampling system, nine size-segregated particle classes emitted from the burning of three kinds of honeycomb coals (under flaming and smoldering burning conditions) and four kinds of chunk coals, including bituminous and lignite, were collected via a cascade impactor (FA-3). Organic and elemental carbon (OC and EC, respectively) were analyzed using the thermal-optical method. The EFs of particulate matter (PM), OC, and EC for nine size ranges were obtained. For honeycomb coals, the EFs of OC and EC in PM2.1 were 0.07 g.kg-1 and 0.002 g.kg-1, respectively, under flaming burning conditions and 0.10 g.kg-1 and 0.001 g.kg-1, respectively, under smoldering burning conditions. Carbonaceous particles exhibited higher EFs under flaming burning conditions. For chunk coals, the EFs of OC and EC in PM2.1 were 1.4 g.kg-1 and 0.02 g.kg-1, respectively, which are about one magnitude higher than those for honeycomb coal burning. Particulate matter and its associated carbonaceous components preferred to concentrate in fine particles. The EFs of carbonaceous components peaked at the size of <= 0.43 MUm and 0.43-0.65 MUm for honeycomb coal burning and chunk coal burning, respectively. PMID- 29998658 TI - [Characteristics and Source Analysis of Non-methane Hydrocarbons(NMHC)in Dalian]. AB - Non-methane hydrocarbon (NMHC) play a very important role in the formation of ozone. The concentrations, compositions, and diurnal variation of NMHC were measured in July and August of 2014 in Dalian City. Continuous samples were collected in Dalian and were analyzed via gas chromatography. The results show that the annual mean concentration of total NMHC (TNMHC) concentrations was 80.7*10-9+/-62*10-9. Alkanes were the most abundant components, accounting for 64% of the TNMHC, followed by alkenes, aromatics, and acetylene, which accounted for 19%, 16%, and 1%, respectively. n-Decane, ethene, and octane were the top three species in Dalian City, and the diurnal variation of NMHC in this area was obvious. The ozone formation potential (OFP) results show that the contribution of aromatics to the OFP in Dalian was the largest, and ethylene, m-ethyltoluene, and p-ethyltoluene were the most important contributors to the OFP in this area. Principal component analysis (PCA) was used to identify the sources of the VOCs. Six sources were resolved by the PCA:solvent usage, LPG, traffic sources, biogenic sources, petrochemical refining, and aged air transportation. PMID- 29998659 TI - [Scenario Analyses of the Volatile Organic Compound Emission Allowance and Allocation in the 13th Five-Year Period]. AB - China implemented the emission allowance and allocation strategy in 2016 to achieve effective control of volatile organic compounds (VOCs). An inventory of VOCs emissions for 2015 and future emissions for 2020 were developed and predicted, respectively, using emission factors and regression analysis. The results showed that anthropogenic VOCs emission in 2015 was 31117.0 kt. VOCs emission in 2020 under the business-as-usual scenario is predicted to be 41737.2 kt, an increase of 34.13% from that in 2015. Based on the Outline of the 13th Five-Year Plan, a total amount control target and pollution reduction task of about 28005.3 kt and 13731.9 kt, respectively, were proposed. Additionally, three control scenarios, i.e., implementing VOCs emission reduction strategies in all the key areas, in all the key industries, and in the key industries of the key areas, were established for the 13th Five-Year Plan using a scenario analysis method. The results showed that some differences exist between the potential mitigation of VOCs emissions and the emission reduction target for the three control scenarios, it is difficult to realize the emission allowance target. It is necessary to devote greater efforts to control VOCs. Moreover, reducing emissions of VOCs by implementing large-scale control projects is recommended. Further, regulation of VOC emissions in key areas and industries should be emphasized. PMID- 29998660 TI - [Pollution Characteristics and Emission Coefficients of Volatile Organic Compounds from the Packaging and Printing Industry in Zhejiang Province]. AB - This paper presents the raw material composition and VOC treatment status of the packaging and printing industry in Zhejiang Province based on the survey data obtained in 2015 of 254 packaging and printing enterprises. To analyze the emission characteristics and calculate the emission coefficients of the packaging and printing industry, 100 typical enterprises were further screened according to different printing processes. The results showed that about two-thirds of packaging and printing enterprises failed to effectively dispose of VOCs; meanwhile, solvent-based materials were still commonly used in the packaging and printing industry. The main emission pollution factors of VOCs in the packaging and printing industry were ethyl acetate, isopropanol, ethanol, propyl acetate, and n-butyl acetate. The VOC emission coefficient of the packaging and printing industry in Zhejiang Province was 0.485 kg.kg-1, of which the gravure printing was the primary source with VOCs emission coefficient of 0.634 kg.kg-1. Compared with the material balance method, the error value from the emission coefficient method was less than 15%. PMID- 29998661 TI - [Emission Characteristics and Characteristic Substance Identification of Volatile Odorous Organic Compounds in Industries Using Organic Solvents]. AB - To study the emission characteristics of volatile organic malodorous compounds and identify the characteristic substances of associated industries, the components of VOCs of typical industries were detected and analyzed in an industrial area of south China. The results showed that there are certain differences in the material composition among different companies, and there are also certain differences in the composition of different processes in the same company. For the automobile manufacturing industry, alcohols and esters were the main substances in the spraying workshop, accounting for 21.87% and 21.62%, respectively, and aromatic hydrocarbons were the typical substances in the drying workshop, accounting for 41.14%. Concerning the electronic components industry, esters were the main substances, accounting for 67.99% in the spraying and coating workshop. Regarding the coating production industry, esters were the main substances in the two paint companies, but the emission ratio of aromatic hydrocarbons was the second highest in one company and the emission ratio of ketone was the second highest in the other company. For the printing industry, alcohols were the characteristic substances, accounting for 99.32%. Concerning the refrigeration industry, alkanes were the most abundant compounds, accounting for 83.01%. Esters (ethyl acetate, butyl acetate, and isobutyl acetate), aromatic hydrocarbons (toluene, ethylbenzene, and styrene), and alcohol ketones (ethanol, methyl isobutyone, and 2-butanone) were preliminarily identified as characteristic malodorous compounds of the industries using organic solvents. PMID- 29998662 TI - [Analysis of Aerosol Optical Depth Variation Characteristics for 10 years in Urumqi Based on MODIS_C006]. AB - Based on the MYD04_L2_C006 dataset gained from Moderate resolution imaging spectroradiometer MODIS Level 2 at 10 km resolution of NASA's EOS (Earth Observing System) from 2006 to 2015, the aerosol optical depths (AODs) for 10 years under the condition of mild above atmospheric pollution (including mild) were analyzed for Urumqi City. The results showed that the average AODs in Urumqi were unimodally distribution over the 10 years. From January to April, the AODs gradually increased. During a year, the annual peak of 0.37+/-0.19 was in April, and the lowest value of 0.22+/-0.20 was in October. Owing to the frequent occurrence of dust weather conditions in spring, the largest seasonal variation of AOD was in spring, as the air pollution in the entire area was very serious, followed by summer and winter, with the smallest in autumn. In addition, the urban area was the high AOD value area in Urumqi, as its air pollution was more severe than that in the suburbs. The average value of AOD during the 10 years was 0.293. The highest value of AOD was 0.33 in 2006, and the lowest value of 0.24 was in 2008, which declined to 23.3% of that in 2007. The annual change in AOD in Urumqi over the 10 years rose steadily. Compared with previous studies, the lowest and highest values were both higher to different degrees. Despite the deduction trend in 2015, air pollution in Urumqi was serious in the studied decade, and thus control of such needs to be strengthened. PMID- 29998663 TI - [Motor Vehicle Pollution Control Scenarios of Beijing Subsidiary Administrative Center Based on Road Traffic Flow]. AB - In this study, the scenario analysis method was used to establish motor vehicle exhaust emission inventories based on road-traffic-flow information of the Beijing subsidiary administrative center under different scenarios, with a base year of 2015. The pollutant emissions in 2020 and 2025 were forecast by calculating the motor vehicle pollutant emission inventories of future road traffic-flow information and various scenarios. The results showed that the kilometers travelled via motor vehicles and the road network density of the Beijing subsidiary administrative center both will increase continuously over the next 10 years. Compared with the baseline scenario, each control scenario had a certain degree of reduction in pollutant emissions, and the reduction rates increased with the strengthening of the measures. The emission reductions of pollutants were significant in the new energy vehicle promotion scenario, especially for NOx and PM. The effect of emission reduction of every pollutant was significant in the outgoing vehicle restriction scenario. Elimination of highly polluting vehicles had a significant effect in the short term, but the effect of long-term reduction was weak. The combined scenario achieved the best reduction rate of pollutant emissions, with CO, NOx, HC, and PM decreasing by 39.0%, 58.7%, 49.2%, and 55.5%, respectively. PMID- 29998665 TI - [Temporal and Spatial Changes in Sediment Nutrients and Heavy Metals of the Danjiangkou Reservoir Before and After Water Division of the Mid-route Project]. AB - Reservoir/lake sediments are potential pollutant acceptors and sources of pollution. The Danjiangkou Reservoir, as the largest drinking water source in China, is the source water area for the Mid-route Project of the South-North Water Diversion. To illustrate the temporal and spatial changes in the environmental risks of both nutrients and heavy metals in the surface sediments of Danjiangkou Reservoir, the levels of pH, OM, TP, TN, and six kinds of metal elements during the period 2011-2016 were measured at five ecological sites. Canadian freshwater sediment quality guidelines for aquatic environments (from the CCME) were used to assess the potential ecological risks. The results showed that the contents of OM, TP, and TN in the surface sediments were 25.85, 0.57, and 1.34 g.kg-1, respectively, and those of Cr, Mn, Cu, Zn, Cd, and Pb were 57.96, 521.78, 13.91, 195.74, 0.37, and 12.92 mg.kg-1, respectively. The contents of both Zn and Cd were under the corresponding II-level standards of soil environmental quality, but the contents of the other four heavy metals were lower than their corresponding I-level standards. After water diversion of the Mid route Project, the OM, TN, Mn, and Zn contents increased, and the TP and other heavy metal contents displayed downward trends. Excluding the pH value, the distribution of measured nutrients and heavy metals in the surface sediments of the Danjiangkou Reservoir reached the extremely significant level (P<0.01). OM in the sediments was negatively correlated with TN and Pb, but had positive correlations with the other indicators measured. The results from the potential ecological risk assessment showed that:1Cd, Cu, and Pb had no harmful effects on organisms; 2 OM had low ecological risk in most years; 3 the risk of TP was between zero and low ecological risk; and 4Cr, Zn, and TN had low ecological risk in most cases. The K and H sites had higher ecological risk for Cr, Zn, and TN, thus attention should be paid to those cases. These results illustrate the effects of human activities on nutrients and heavy metals in surface sediments. PMID- 29998664 TI - [Air Pollution Characteristics and Jogger Inhalation Exposure in Typical Running Area of Beijing]. AB - To investigate the exposure to major air pollutants of runners while running in Beijing, the concentrations of PM2.5, CO, O3, and NO2 were constantly monitored at typical park running areas (Tiantan Park and Olympic Sports Center), roadside running areas (Qianmen East Street and Yongding Inner Street), and a background area (Dinglin) during April, June, and October of 2016 and in January 2017. The concentration variation characteristics for the pollutants in different areas and at different times were analyzed. Using a numerical model of human respiratory exposure, 102 joggers were studied, as was the temporal-spatial variation of inhalation dose of pollutants. At typical running areas, the concentrations of CO, NO2, and PM2.5 were relatively higher in winter, whereas the concentrations of O3 were higher in spring and summer. The concentrations of CO, NO2, and PM2.5 were lower in the afternoon (16:00-18:00), whereas the concentrations of O3 were lower in the morning (06:00-08:00) and evening (18:00-20:00). There was a linear correlation between concentrations roadside to those in nearby parks, as the concentrations of CO roadside were generally consistent with those in parks (croad/cpark=1.01, R2=0.93), the concentrations of NO2 and PM2.5 roadside were higher than those in parks (croad/cpark were 0.56 and 1.19, respectively), and the concentrations of O3 roadside were lower than those in parks (croad/cpark=0.74, R2=0.97). During moderate or higher pollution conditions, 92% of joggers halted outdoor activities, 62.7% chose to jog in parks, 66.7% chose to jog at night, and 64.7% of joggers had single run mileages of 10-20 km. When people chose to jog in the afternoon and evening, the inhalation of CO, NO2, and PM2.5 were relatively lower, whereas the inhalation of O3 was higher. During spring and summer, night running after 20:00 reduced the O3 inhalation dose. Running roadside led to higher inhalation of CO, NO2, and PM2.5 than that in parks; however, O3 inhalation was lower. PMID- 29998666 TI - [Fluorescence Characteristics and Environmental Significance of Organic Matter in the Northern Part of Lake Taihu in Spring and Winter]. AB - Organic matter (OM), rich in carbon, nitrogen, phosphorus and other biogenic elements, has numerous geochemical and ecological functions in all kinds of water bodies, and is highly valued in ecological studies of both marine and inland environments. The formation, transformation, and fate of OM, and its accompanying nutrient regeneration process are key links in the biogeochemical cycling of nutrients in aquatic ecosystems. Furthermore OM, as a provider of nutrients, also plays a very significant role during the outbreak of algal blooms in inland lakes. Two extensive sampling campaigns were conducted at the same site (n=17) in Lake Taihu in February and May of 2015, and 34 (17*2) samples were collected. Excitation-emission matrix (EEM) fluorescence was combined with parallel factor analysis (PARAFAC) to characterize the spatial-temporal variations in the components and sources of particulate (POM) and dissolved (DOM) organic matter. Moreover, the correlations between fluorescence intensity and Chla were studied. Significant differences between the fluorescence peaks, fluorescence positions, and fluorescence intensities of POM and DOM indicated that the components of POM were more complex than those of DOM. Fluorescence intensities and fluorescence indices indicated that POM and DOM possessed endogenous characteristics and that estuaries possessed obvious exogenous characteristics. Five types of fluorophores were present in POM (C1p-C5p) and DOM (C1d-C5d):tyrosine-like fluorophores (C1 and C2), humic-like fluorophores (C3 and C4), and tryptophan-like fluorophores (C5). The fluorescent components of POM and DOM differed significantly. C3p was the dominant fluorophore in POM during spring and winter, and fluorescence intensities of C1p-C5p were higher in the Meiliang Bay and the central part of thelake than in other areas. C2d, C1d, and C5d were the dominant fluorophores in DOM during spring and winter, and fluorescence intensities of C1d-C5d were higher in the Zhushan Bay than in other areas. In spring, positive correlations were observed between C1d and C2d (P<0.01), C3d and C4d (P<0.01), C1p and C4p (P<0.05), and C2p and C5p (P<0.01). Remarkably, C3p and C3d (P<0.01) and C3p and C4d (P<0.05) were positively correlated, suggesting that these two forms of OM were correlated. Similarly, highly significant, positive correlations were observed between C1d and C2d (P<0.01), C3d and C4d (P<0.01), C1p and C2p (P<0.01), and C1d and C2p (P<0.01) during winter. Furthermore, Chla and C5d were significantly and positively correlated (P<0.01). However, both Chla/C2d and Chla/C3p were negatively correlated in spring. Furthermore, Chla and C4d were negatively correlated in winter. PMID- 29998667 TI - [Contamination Levels and Ecological Risk Assessment of Phthalate Esters (PAEs) in the Aquatic Environment of Key Areas of Taihu Lake]. AB - To better understand phthalate esters (PAEs) pollution in key areas of Taihu Lake, water and sediment samples were collected for content analysis. The concentrations of ?PAEs in water samples from wet, dry, and normal seasons ranged 1.6-11.2 MUg.L-1 (mean:3.68 MUg.L-1), nd-6.21 MUg.L-1 (mean:1.3 MUg.L-1), and nd 1.72 MUg.L-1 (mean:0.48 MUg.L-1), respectively. No differences were found between upstream and downstream samples. DEHP was the predominant component in water samples, whereas DBP exceeded the national surface water environmental quality standards. The total PAE concentration in the sediment ranged between 0.74 and 6.90 MUg.g-1 (mean:2.64 MUg.g-1), with DBP and DEHP the predominant PAEs. The risk quotient (RQ) results showed that DBP and DEHP contributed the most potentially adverse effects to the aquatic environment in the key areas. The contents of PAEs in sediment were all less than the ERLs, thus posing no significant threat to aquatic organisms. The overall level of PAEs in the study area was moderate compared to those in other areas, including rivers, lakes, and estuaries from cities worldwide. Industrial pollution and urban activities are the major sources of PAEs in the aquatic environment of key areas of Taihu Lake. PMID- 29998669 TI - [Geochemical Characteristics and Genesis Analyses of High-arsenic Groundwater in the Pearl River Delta]. AB - To determine the main factors affecting the migration, enrichment, and sources of arsenic in the shallow groundwater of the Pearl River Delta (PRD), clustering analysis was used to partition the study area and then analyze the abnormal distribution of arsenic and groundwater storage environment in each part area based on the data obtained from the investigation of groundwater pollution in the PRD region. The results showed, in the study area, arsenic was mainly represented by As(III), and its concentration ranged from under the detection limit to 560 MUg.L-1. High-arsenic groundwater was mainly distributed in the plain area covered by Quaternary loose sediment, with the Shunde District in Foshan City having the highest, followed by Zhongshan City and central Guangzhou. The hydrochemical type of groundwater in the study area was mainly HCO3-Ca type water. The high-arsenic groundwater had the characteristics of high pH value; high concentrations of NH4+, Fe, and Mn; and a high permanganate index, in addition to a low concentration of NO3-. Based on scatter plot and factor analysis of various indicators of arsenic in groundwater and the impact of human activities on the groundwater environment of the PRD, it was concluded in this study that under the common influence of natural sedimentary environment and pollution input, a neutral or weak-alkaline-reducing environment, which was conducive to the occurrence of high-arsenic groundwater, was formed in the plain area. The role of microorganisms and the input of organic pollutants in the shallow groundwater led to the reduction and dissolution of arsenic-containing Fe Mn oxide, resulting in the release of arsenic. The source of arsenic contamination in the groundwater was mainly the industrial pollution in Shunde and other areas in southern Foshan City. PMID- 29998668 TI - [Nitrogen and Phosphorous Adsorption Characteristics of Suspended Solids Input into a Drinking Water Reservoir via Typhoon Heavy Rainfall]. AB - During typhoon "Mujigae" in October 2015, water samples and surface sediments were collected from Gaozhou Reservoir, a drinking water reservoir, for simulation and analysis of the kinetics of suspended solids adsorption to nitrogen and phosphorus and the adsorption isotherms of suspended solids with different particle sizes and different concentrations. The results showed no obvious nitrogen adsorption of suspended solids of Gaozhou Reservoir. However, the adsorption effect to phosphorus by suspended solids was significant and the equilibrium time of phosphorus adsorption was 10 hours. The adsorption capacity of phosphorus increased with the decrease of sediment particle size when particle sizes were less than 0.25 mm, whereas it increased with the increase of suspended solids concentration when the concentration was in the range of 0.2-2.0 kg.m-3. The adsorption isotherm of suspended solids to phosphorus conformed to the Langmuir and Freundlich models, and the maximum adsorption capacity increased with the decrease of suspended solids particle sizes, which increased with the increase of suspended solids concentrations. The maximum adsorption capacity of suspended solids to phosphorus was 0.073-1.776 mg.g-1. These results indicated that the increase of suspended solids concentration due to the heavy rainfall of the typhoon promoted the adsorption of suspended solids to phosphorus, which reduced eutrophication in Gaozhou Reservoir. PMID- 29998670 TI - [Effects of Organic Pollutants on the Bacterioplankton Community in Hangzhou Bay]. AB - Hangzhou Bay suffers from intensive anthropogenic disturbances and a huge amount of terrestrial inputs, and thus has become one of the most seriously contaminated coastal zones in China. There is evidence that microbes play a dominant role in pollutant biodegradation and serve as biomarkers for pollution levels. However, it remains unclear how the bacterioplankton communities respond to organic contaminants. To fill this knowledge gap, we collected surface water samples (0.5 m below the surface layer) from 13 sites across Hangzhou Bay and 8 control sites across its adjacent offshore areas. Using Illumina sequencing based on analysis of the bacterial 16S rRNA gene, we explored the effects of increasing organic pollution levels on the bacterioplankton community compositions (BCCs). The results revealed that the organic pollution level (A) in Hangzhou Bay (13.2+/ 1.6) was significantly (P<0.001) higher than in the control zone (5.4+/-3.0). The distribution and diversity of bacterioplankton communities were significantly distinct between the two zones. The dominant bacterioplankton lineages in Hangzhou Bay were gamma-Proteobacteria (24.4%+/-5.5%), alpha-Proteobacteria (16.5%+/-7.7%), and Planctomycetes (13.9%+/-8.6%), whereas those in the adjacent zones were Cyanobacteria (20.1%+/-7.5%), Bacteroidetes (18.4%+/-1.5%), Actinobacteria (17.5%+/-4.2%), gamma-Proteobacteria (16.6%+/-1.2%), and alpha Proteobacteria (14.3%+/-1.7%). Multivariate regression tree (MRT) analysis showed that the bacterioplankton community diversity was primarily affected by suspended particulates (SP), nitrite, oil, and organic pollutants, which respectively explained 22.0%, 6.5%, 6.0%, and 5.5% of the variance in diversity. Redundancy analysis (RDA) illustrated that the bacterioplankton community distribution was controlled by organic pollutants, COD, Chla, TN, nitrate, and salinity, which cumulatively governed 71.0% of the variation in BCCs. Organic pollutants alone controlled 6.5% variance, which was higher than any other single factor. Additionally, 35 sensitive species were identified via the indicator value method and their relative abundances were significantly associated (P<0.05 in each case) with the organic pollution level, thereby indicating their potential for evaluating coastal pollution. Collectively, our work demonstrates that BCCs are sensitive to coastal pollution and provides biomarkers for elevated pollution levels. PMID- 29998671 TI - [Bacterioplankton Community Structure in the Lancang River Basin and the Analysis of Its Driving Environmental Factors]. AB - In order to explore the bacterioplankton diversity community structure in the Lancang River basin, as well as to study the relationship between the bacterial diversity and environmental factors, MiSeq high-throughput sequencing was used to analyze and compare the bacterial diversity and community composition of samples in February 2017. Furthermore, Pearson correlation analysis and redundancy analysis (RDA) were used to identify the key environmental factors for the change of bacterial community structure in the natural river and reservoirs of the Lancang river. The results show that the ACE index and Shannon index of the natural river are higher than those of the reservoir, and the main environmental factors causing the diversity of planktonic bacteria in natural river and reservoir segments are water temperature (WT), dissolved oxygen (DO), turbidity (Tur), permanganate index, pH, and total nitrogen (TN). Overall, 26772 optimized reads were obtained from samples based on the high-throughput sequencing of the V3 and V4 region of the 16S rRNA gene. The bacterial species detected in these samples cover 45 phyla and 965 genera. Taxonomic assignment analysis indicated that Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria are the abundant phyla. Among them, the Proteobacteria content is relatively rich, accounting for 36%-94% of the bacterial community. The predominant groups are alpha-Proteobacteria, beta-Proteobacteria, and gamma-Proteobacteria, at the genus level, with Proteobacteria ratios of 0.39%-21.56%, 0.39%-55.80% and 31.09% 99.18%, respectively. The environmental factors affecting the community structure of planktonic bacteria are different in natural river and reservoir. DO and Tur are the key environmental factors affecting the community structure of planktonic bacteria in the natural river, while the community structure of planktonic bacteria in reservoirs is mainly affected by WT, permanganate index, and TN. PMID- 29998672 TI - [Bacterial Community Structure Characteristics in the Biliuhe Reservoir and Its Key Driving Factors]. AB - In order to understand the bacterial community structure and its diversity in the Biliuhe Reservoir, the impact of environmental factors must be explored. Using 16S rDNA high-throughput sequencing technology, the bacterial community structure and diversity differences in four seasons were analyzed and compared from 2016 to 2017. Redundancy analysis (RDA) was used to investigate the relationship between the environmental factors in water and bacterial diversity. The analysis of bacterial diversity index (Shannon-Wiener index) showed that the bacterial community diversity index reached 6.9 in the whole year, with the following pattern:Winter < summer < spring < autumn. Sequence alignment results show that although the flora status was not clear and rare flora were seen, a total of 44 bacterial phyla, 115 classes, 184 orders, 368 families, and 865 genera were found. The dominant bacteria phyla were:Proteobacteria (34.16%), Cyanobacteria (24.35%), Actinobacteria (13.35%), Bacteroidetes (12.42%). The dominant class of bacteria in the dominant phylum (Proteobacteria) was beta-Proteobacteria (18.34%), and the dominant strain was unidentified_Chloroplast (17.73%). The results of RDA showed that different bacterial communities were affected by environmental factors. Total suspended solids (TSS), transparency (SD), pH, active phosphorus (ADP), dissolved oxygen (DO), total phosphorus (TP), and nitrite nitrogen (NO2--N) were the main environmental factors influencing community distribution. The bacterial community during the summer was positively correlated with NO2--N, ADP, TP, and TSS. PMID- 29998673 TI - [Analysis of the Temporal and Spatial Distribution of the Diversity of the Denitrifying Anaerobic Methane-Oxidizing Bacterial Community in the Sediments of the Hunhe River and Its Relationship with Environmental Factors]. AB - 16S rRNA and pmoA functional genes were used as biomarker genes to investigate the temporal and spatial distribution of community diversity of Candidatus Methylomirabilis oxyfera (M. oxyfera) in the sediments of the Hunhe River by clone library technology. The dependence relationship between the physicochemical property of water and sediment samples and the diversity characteristics of the M. oxyfera community were analyzed by multivariate direct gradient analysis. Among the examples collected in September 2014, the OTU number of the 16S rRNA gene of M. oxyfera was 2-5, the Shannon-Wiener diversity index was 0.21-1.4, and the distribution characteristics in the middle reaches > upstream > downstream were presented. The OTU number and Shannon-Wiener diversity index of the pmoA functional gene in upstream samples are significantly higher than those in the middle and lower reach samples, and the Shannon-Wiener diversity indices in the upstream samples are 3.5 times and 2.3 times higher than that of the middle and the downstream samples, respectively. The community diversity of M. oxyfera showed a distinct regional distribution. Samples were collected at 3 sampling points in March 2015. The OTU values of 16S rRNA and pmoA for M. oxyfera are 6 and 5 respectively, which were obviously higher than those in September 2014. The Shannon-Wiener index is also higher than that in September 2014 (1.4>0.68; 57>0.00). The community diversity of M. oxyfera showed obvious seasonal distribution characteristics. Multivariate direct gradient analysis results showed that the concentration of DOC in water, sediment conductivity, TOC concentration, and nitrite concentration in the sediment are the main environmental factors affecting the community diversity of M. oxyfera. PMID- 29998674 TI - [Influences of Anthropogenic Activities on the Community Structure of N-DAMO Bacteria in the North Canal]. AB - Stream ecosystems are the primary receivers of nutrients and organic carbon exported from terrestrial ecosystems and are profoundly influenced by the land of the surrounding landscape. Anthropogenic activities increased the nutrient and organic carbon levels in both stream and benthic biofilms, which are closely related to the differences in the N-DAMO (Nitrate/nitrite-dependent anaerobic methane oxidation) bacterial communities. We studied N-DAMO bacterial communities in streams flowing through anthropogenic land in the city of Beijing. The results showed that anthropogenic activities increase the nutrient and organic carbon levels both midstream and downstream; these are closely related to the difference in the N-DAMO bacterial communities. Phylogenetic analysis revealed that most of the cloned 16S rRNA and pmoA sequences in the North Canal were similar to those recovered from activated sludge and wastewater. The effect of nitrogen on N-DAMO bacteria in the North Canal mainly depended on the main form of available nitrogen and the source of pollutant. Moreover, N-DAMO bacteria present downstream of the North Canal, had a more connected and modular microbial network than those present midstream, where bacterial communities with tightly connected species that were shown to be more vulnerable and sensitive to various disturbances were found. PMID- 29998675 TI - [Impact of Exogenous Nitrogen Import on Sediment Denitrification and N2O Emissions in Ditches Under Different Land Uses]. AB - Farmland drainage ditch soil can consume part of the agricultural non-point nitrogen through nitrification-denitrification processes. Paddy fields, vegetable land, and orchards are the main types of land uses in the Taihu Lake region, and many drainage ditches are distributed across these lands. The way exogenous nitrogen is imported to drain ditches under different land uses differs significantly, which can directly affect the nitrogen consumption ability of the channels. A soil incubation experiment was conducted under laboratory conditions to study the denitrification loss and N2O emissions of drainage ditch soil under different land uses. In this study, drainage ditch sediment was collected from orchards, paddy fields, and vegetable land in the Taihu Lake region. Five different NO3--N content import levels were set:0, 0.5, 1.0, 5.0, and 10 mg.L-1, which were denoted as N0, N1, N2, N3, and N4, respectively. The results showed that exogenous nitrogen input stimulated sediment denitrification in the drainage ditches. The sediment denitrification rates of the three types of channels increased significantly with the increase of input NO3--N concentration (P<0.05). There was a significant linear positive correlation between the cumulative denitrification loss and input NO3--N concentration (R2>0.75). Excluding for the vegetable land sediment, the N2O emission rate and cumulative emissions did not increase significantly with the increase of input NO3--N concentration (P>0.05). There was no significant difference in the denitrification and N2O emissions among the three kinds of channel sediment, with no or low exogenous nitrogen input (N0and N1) (P>0.05). As the input NO3--N concentration increased, especially under the condition of high exogenous nitrogen input (N3and N4), the nitrogen consumed via denitrification in orchard and paddy field sediment was significantly higher than that in vegetable land sediment (P<0.05), whereas the N2O emissions of drainage ditch sediment from the vegetable land was significantly higher than that of the other two channel sediments (P<0.05). The mineralization rate of ditch soil organic carbon had a positive correlation with denitrification rate (n=15), and microbial mineralization (CO2-C) promoted the nitrification and denitrification of the drainage ditch soils. PMID- 29998676 TI - [Sedimentation Characteristics and Pollutant Content Distribution of Storm Drainage Sediments]. AB - To determine the characteristics of precipitation and pollutant content in storm drainage sediments, samples of sediment from building areas (including residential areas), roads, and green spaces in Wuhan were collected and analyzed. The settling velocity results show that particles with high settling velocity weight occupied a larger proportion in the sediment; the settling velocity distribution of sediments in building areas and roads was more stable than that in green spaces; and the proportion of particles with settling velocity over 3.00 cm.s-1 in building areas, roads, and green spaces decreased in turn. The particle size distribution indicated sediment size had a wide variation range, with most particles concentrated in the range 13-628 MUm, and that the particle size distribution in sediment from the same land type could differ greatly. Each sample was divided into seven groups according to settling velocity. The contents of chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) were tested. The results indicate that pollutant contents in groups containing particles with settling velocity over 3.00 cm.s-1 or below 0.025 cm.s-1 were lower than those in other groups. Most pollutants were concentrated in particles with high settling velocity.The COD concentration declined in green spaces, roads, and building areas, in turn, for most cases. The nitrogen content in the drainage sediment of roads was lower than those in the two other kinds of land, whereas the phosphorus content in the drainage sediment of building areas was higher than those in the two other kinds of land. In the storm drainage sediment, the ratio of COD:TN was between (51-89):1 and that of COD:TP was between (102 186):1. PMID- 29998677 TI - [Effect of Cr(VI) on Coagulation Process of Different Coagulants]. AB - In this study, the effect of Cr(VI) in industrial wastewater on the coagulation of different aluminum forms under the influence of different particle concentrations was investigated. The coagulation efficiency was determined by examining the removal rate of turbidity, residual aluminum, and residual chromium and by using the residual pH value, zeta potential, and floc properties of the coagulation to reveal the coagulation mechanism of Cr(VI) in water under different turbidities. The experimental results show that under low turbidity conditions, Cr(VI) greatly influences the coagulation process of highly polymerized Alb, yet has no obvious effect on oligomeric Ala. Under high turbidity conditions, particulate matter will adsorb part of the Cr(VI) in high turbidity water, thus reducing its interaction with Alb. The main role Alb plays in coagulation is charge neutralization. It plays the same role in the stability of the particles and floc regeneration. The main role of Alc formed by hydrolysis of Ala is bridging effects and sweep flocculation, which plays an important role in floc production and strength factor. At the same time, the existence of Cr(VI) enhances the strength factor of Al13 flocs, but the consumption of some of the positive charge will lead to a reduction in the floc recovery factor. PMID- 29998678 TI - [Enhancement of Photoelectrocatalytic Degradation of Bisphenol A with Peroxymonosulfate Activated by a Co3O4/BiVO4 Composite Photoanode]. AB - A nanostructured Co3O4/BiVO4 composite photoanode was synthesized using a facile electrospinning method and applied to photoelectrochemical (PEC) degradation of bisphenol A (BPA) with the assistance of peroxymonosulfate (PMS). Results show that PMS obviously enhanced the photoelectrocatalytic degradation of BPA by the Co3O4/BiVO4 composite photoanode. When at 0.25 V bias potential and visible light irradiation, with 2 mmol.L-1 PMS addition, 96% of BPA was removed within 2 h, and the corresponding kinetic constant was 0.4714 min-1. The effects of initial PMS concentration and bias potential on the BPA degradation were studied. Results show that BPA could be efficiently degraded at lower PMS concentrations and lower bias potentials. SO4.- and.OH were identified as the primary free radicals using an electron spin resonance spectrometer. Free radical quenching experiments were carried out, and the photogenerated hole, SO4.-, and.OH proved to be responsible for the BPA oxidation. There was no metal ion leaching detected in the solution after the reactions, which means the secondary pollution could be avoided. PMID- 29998679 TI - [Preparation and Characterization of a Calcium Alginate/Biochar Microsphere and Its Adsorption Characteristics and Mechanisms for Pb(II)]. AB - A microsphere (CA/BC) was prepared using biochar (BC) encapsulated with calcium alginate (CA) as a green adsorbent for Pb(II) removal from aqueous solution. The effects of the initial Pb(II) concentration, initial pH value of the Pb(II) solution, and equilibrium contact time were investigated. The isothermal thermodynamic data of the BC and CA/BC conformed to the Langmuir model. The maximum adsorption capacities of the BC and CA/BC from the Langmuir equation were 93.20 mg.g-1 and 155.04 mg.g-1 respectively, at pH=5. The adsorption of Pb(II) by the BC was in good agreement with the pseudo-second-order equation, indicating that chemisorption was the rate-controlling step. The adsorption of Pb(II) by the CA/BC was in good agreement with the pseudo-first-order model, which suggested that the rate-limiting step was governed by diffusion. Mechanism studies for Pb(II) removal by the CA/BC showed that the nature of Pb(II) abstraction took place through ion exchange between Ca(II) and Pb(II) as well as via the formation of a coordination complex. PMID- 29998680 TI - [Behaviors and Mechanisms of CIP and OFL Adsorption by Magnetic Biochar]. AB - A magnetic reed biochar (MBC) was fabricated through chemical coprecipitation first and subsequent pyrolysis of reed stalk powder precipitated with Fe2+/Fe3+ at 873.15 K. The structure and properties of the MBC were characterized using SEM, BET, FTIR, and VSM. Adsorption experiments were carried out to investigate the adsorption behaviors and mechanisms of ciprofloxacin (CIP) and ofloxacin (OFL) onto the MBC. The MBC possessed roughness and pores within its structure and contained a large amount of oxygen-containing functional groups on the surface. The BET surface area of the MBC was 254.6 m2.g-1, and the total pore volume was 0.257 cm3.g-1, thus the MBC exhibited a relatively high porosity. The adsorption process was found to be pH and temperature dependent. The relative contributions of adsorbate species (cations, zwitterions, and anions) to overall adsorption varied for different pH values. Thermodynamic parameters indicated that the CIP and OFL adsorption onto MBC was a spontaneous, endothermic, and entropy-increasing process. Kinetics and isotherm data of CIP and OFL adsorption onto MBC were well depicted by the pseudo-second-order model and the Langmuir model. The equilibrium adsorption capacities of CIP and OFL onto MBC were 27.84 mg.g-1 and 22.00 mg.g-1, respectively. Pore-filling effects, pi-pi interaction between electron donors and acceptors, hydrogen bonding formation, hydrophobic interaction, and electrostatic interaction may be important mechanisms for CIP and OFL adsorption onto the MBC. PMID- 29998681 TI - [Optimization and Validation of the Analytical Method to Detect New Psychoactive Substances in Wastewater]. AB - New psychoactive substances (NPS) are emerging continuously, as the crackdown against traditional drugs becomes stricter. Metabolites of NPSs and the unchanged drugs enter wastewater through urine and are collected and treated by wastewater treatment plants before being discharged into the aquatic environment. Based on previous research, solid phase extraction (SPE) and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) were used and the detection method of 11 NPSs was optimized. Influences of wastewater pretreatment procedures, including SPE columns; pH values of water samples; and processes of flushing and redissolving on NPS recoveries were compared. It was shown that the best recovery was achieved when Oasis MCX columns were used and the pH value of wastewater samples was adjusted to 2. A flushing process with 2 mL water at pH=2 followed by 2 mL methanol was needed. Redissolution of the residue after evaporation was best achieved with 400 MUL of a 20% methanol water solution. It was indicated by retention times, recoveries, matrix effects, limits of detection, limits of quantification, as well as precision that C18-UPLC-MS/MS and the optimized method are efficient and valid. Influent and effluent samples from 11 municipal wastewater treatment plants in Beijing were analyzed using the optimized method for validation. The validated method can be used as an important reference for monitoring NPSs via wastewater-based epidemiology and for assessing the risk of NPS abuse in China. PMID- 29998682 TI - [Effect of Hybrid Process of Pre-ozonation and CNT Modification on Hollow Fiber Membrane Fouling Control]. AB - Polyvinylidene fluoride (PVDF) hollow fiber ultrafiltration membranes were modified with carbon nanotube (CNT). Combined with the ozonation process, the effect of the hybrid pre-ozonation and CNT modification on fouling alleviation was investigated. The impacts of CNT loading mass and ozone dosage on the variation of flux and antifouling ability of the membrane modules were evaluated. Under a critical flux of 144 L.(m2.h)-1, CNT loading mass of 3 g.m-2, and ozone dosage(O3/DOC) of 0.22 mg.mg-1, the results revealed that the filtration volume of the hybrid process was promoted to 850 L.m-2, which was about 4.5 times higher than that of the original unmodified membrane. With a flux of 18 L.(m2.h)-1 and 15 day operation, the filtration volume was promoted to 3000 L.m-2, which was 10 times that of the unmodified membrane. The fouling membrane surface was observed using confocal laser scanning electron microscopy (CLSM). The results demonstrated that more living bacteria were present on the membrane surface of the unmodified membrane, which showed a rapid transmembrane pressure (TMP) increase. Both pre-ozonation and CNT modification decreased the total amount of microorganisms and the amount of the living bacteria as well, which mitigated the increase in TMP. After pre-ozonation, the presence of a CNT layer on the membrane surface further decreased the number of living bacteria. Although the CNT layer captured some dead bacteria, it had no obvious relationship with the increase in TMP. PMID- 29998683 TI - [Bioregeneration of Anion Exchange Resin Used in Nitrate Removal]. AB - Anion exchange resin is a feasible adsorbent for nitrate removal because of its high efficiency and cost-effectiveness, but brine regeneration complicates subsequent wastewater procedures. Bioregeneration degrades the nitrate from the nitrate-laden resin, which can decrease brine solution usage and waste discharge. In this study, based on investigation of the effect of carbon source, for example, glucose, sodium acetate, sodium lactate, and methanol, on bioregeneration, nitrate-laden resin was employed to investigate the effects of inoculum amount and salt concentration on bioregeneration with sodium acetate as the carbon source. The results showed that the bioregeneration process comprised chemical desorption and biological denitrification and was limited by the biological process. With increasing inoculum amount, the bioregeneration time was remarkably reduced. Nitrate on the resin could be completely biodegraded within 10 h when the inoculum amount (measured as VSS) was higher than 0.6 g.L-1. Furthermore, higher NaCl concentrations improved the chemical desorption of nitrate, resulting in a sharp increase in soluble nitrate. However, the denitrification process of bioregeneration was also eventually limited by the biological process. When the concentration of NaCl was higher than 20 g.L-1, bioactivity of the denitrifying bacteria was limited and the bioregeneration time increased to more than 10 h. The result of multi-cycle adsorption-bioregeneration experiment showed that the NO3--N adsorption capacity of bioregenerated resin was stable at 30-35 mg.g-1. PMID- 29998684 TI - [Preparation of Prussian Blue@Yeast Catalyst and Its Heterogeneous Fenton Performance]. AB - A novel heterogeneous Fenton catalyst, Prussian blue@yeast (PB@yeast), was prepared via facile self-assembly synthesis. The as-synthesized composite was characterized by field emission scanning electron microscopy (FE-SEM), energy dispersive spectroscopy (EDS), powder X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). All of the results indicated that PB nanoparticles were uniformly dispersed on the surface of yeasts with stable core shell morphology. Degradation of the model anionic fluorescent whitening agent CXT indicated that the PB@yeast catalyst presented a synergistic effect of adsorption and heterogeneous Fenton performance. Owing to the high adsorption capacity of yeast, the CXT molecules were easy to move to the active site of the catalyst, promoting the electron transfer between Fe(III) and Fe(II) and then enhancing the catalytic activity of the Fenton reaction effectively. Furthermore, the yeast support could improve the dispersity and stability of PB nanoparticles, which maintained excellent catalytic activity and stability after being recycled four times. PMID- 29998685 TI - [Nitrogen Removal of Double-bacteria-layer System via PN/A Process]. AB - Nitrification and anaerobic ammonia oxidation (ANAMMOX) sludge was acclimated via SBR and MBR reactors respectively, both of which were embedded with microbial immobilization technology and spliced together to construct a PN/A double bacteria-layer system. A short-term experiment proved that ammonia-oxidizing bacteria (AOB) and ANAMMOX bacteria in the system played dominant roles separately in different stages, which maintained the acid-base balance and achieved efficient removal of NH4+-N (98.8%). A long-term experiment showed that the PN/A double-bacteria-layer system improved the utilization of dissolved oxygen (DO) and enhanced the stability and nitrogen removal efficiency, with limited dissolved oxygen. The nitrogen removal efficiency of the PN/A double bacteria-layer system remained stable at~80% when the influent NH4+-N was 200 mg.L-1 or 400 mg.L-1 in the presence of 1.0 mg.L-1 DO, whereas those of the control group were only 58.1% and 61.4%, respectively. When influent NH4+-N and DO were 400 mg.L-1 and 3.0 mg.L-1, respectively, the PN/A double-bacteria-layer system achieved a nitrogen removal efficiency, nitrogen loading rate (NLR), and nitrogen removal rate (NRR) of 87.9%, 0.4 kg.(m3.d)-1, and 12.8 mg.(g.h)-1, respectively. PMID- 29998686 TI - [Inhibitory Effect of Phenol on Phosphorus Removal Performance of an EBPR System]. AB - An SBR reactor was operated to study the inhibitory effect of different concentrations of phenol (5, 10, 30, 50, 100, 150, and 200 mg.L-1) on the phosphorus removal performance of an EBPR system. The results showed that when the phenol concentration was no higher than 50 mg.L-1, the removal efficiencies of COD and PO43--P were above 85%. The system showed efficient pollutant removal performance. However, when phenol was higher than 100 mg.L-1, phosphorus removal performance of the reactor decreased drastically. When phenol concentration was 200 mg.L-1, the system lost phosphorus removal performance after only 22 cycles. The average COD removal efficiency dropped to 61.3%, and high removal performance recovery was not observed in the short term. Meanwhile, it was found that long term dosing of phenol inhibited phosphorus removal of the sludge subjected to EBPR. Furthermore, the inhibition on aerobic phosphate uptake was greater than that on anaerobic phosphate release. In addition, the limited sludge bulking disappeared gradually owing to acclimation of the sludge to toxicity with a low phenol concentration (<= 50 mg.L-1). However, high concentration of phenol induced sludge bulking was difficult to recover. The short-term impact experiments showed that effluent COD and phosphorus fluctuation caused by phenol could be recovered gradually by removing phenol, suggesting that the inhibitory effect of phenol on phosphorus removal was reversible. PMID- 29998687 TI - [Treatment of Old Landfill Leachate via a Denitrification-Partial Nitritation ANAMMOX Process]. AB - To research the performance of removing nitrogen and organics from old landfill leachate via denitrification-partial nitritation-ANAMMOX (DN-PN-ANAMMOX) process, an integrated reactor seeded with mature ANAMMOX sludge and nitritation sludge connected to a denitrification (DN) reactor was studied. The result showed that before the pre-denitrification reactor was connected, the PN-ANAMMOX reactor achieved a nitrogen removal rate (NRR) of 1.88 kg.(m3.d)-1 and a nitrogen removal efficiency (NRE) of 90.3% when the concentration of influent ammonia nitrogen and COD were 600 mg.L-1 and 483 mg.L-1, respectively. The NRR of the PN-ANAMMOX process dropped to 1.50 kg.(m3.d)-1 when the concentration of influent COD>483 mg.L-1, which corresponds to C/N>0.8. To relieve the influence of organic matter on ANAMMOX, a DN reactor was put in front of the PN-ANAMMOX reactor. The DN-PN ANAMMOX process achieved an NRR and NRE of 1.37 kg.(m3.d)-1 and 98.6%, respectively, under the conditions of influent ammonia nitrogen and COD concentrations of 1100 mg.L-1 and 1150 mg.L-1, respectively. The NRR of ANAMMOX reached 15.6 kg.(m3.d)-1. The whole system realized a highly efficient and deep removal of nitrogen without any additional carbon source. When treating old landfill leachate, most of the biodegradable organics can be removed by the system. PMID- 29998688 TI - [Denitrification Characteristics and Functional Genes of Denitrifying Bacteria Under Aerobic or Anaerobic Conditions]. AB - An efficient aerobic denitrifying bacterium was isolated from the sediments of the Jin Pen Reservoir in Xi'an. The strain was identified by morphological features and 16S rDNA sequences as Pseudomonas stutzeri and named it KK99. The denitrification characteristics of the strain and the expression level of the functional genes narG, nirS, and nosZ in aerobic/anaerobic conditions were investigated. The results showed that the strain can carry out both anaerobic and aerobic denitrification and has a high efficiency of denitrification, which occurs under both aerobic and anaerobic conditions; after 24 h, the removal rates of total nitrogen (TN) were 85.08% and 89.05%, respectively. Under both the conditions, the expression levels of the functional genes nosZ and nirS are high. nosZ plays a vital role in denitrification in the aerobic pathway, nirS plays a vital role in denitrification in the anaerobic pathway, and narG expression is low under both the conditions. At the same time, simultaneous nitrification and denitrification (SND) capacity of the strain was observed when nitrate and ammonium salts were the nitrogen sources, with the total nitrogen removal rate being 76% within 24 h in aerobic conditions. The P. stutzeri KK99 strain can be used for controlling eutrophication of micro-polluted water, and the application of total nitrogen reduction engineering. PMID- 29998689 TI - [Characteristic of Benzo[a]pyrene Anaerobic Degradation by Phenol Co-substrate and Microbial Communities from Two Types of Sludge]. AB - Benzo[a]pyrene (BaP) is a typical representative of PAHs in coking wastewater and priority-controlled pollutants in the coking industry; its response characteristics with microorganisms and the methods to promote its degradation are worth studying. On the other hand, because the inoculated sludge for the adjustment and operation of newly-constructed coking wastewater treatment plants comes from municipal sludge or other coking plants, currently, the study of the microbial properties of different sludges', sludge availability, and the conditions that influence these properties are lacking. On account of the above perspectives, an experiment to study and compare the durability of municipal sludge and coking sludge, and their ability to degrade BaP was carried out. An anaerobic reactor was selected for the experiment and anaerobic-activated sludges were collected from a coking wastewater processing unit and a municipal wastewater plant. Then, 10 mg.L-1 of BaP alone and BaP with phenol as a co metabolic carbon source was added to the coking and municipal sludge samples, respectively, for comparison experiments to study the microbial degradation of BaP and its dynamics. Moreover, high-throughput sequencing technology was also used to analyze the changes in the microbial community structure before and after the degradation experiment. The results showed that:1 Both sludges were capable of degrading BaP, but municipal sludge showed a higher degradation efficiency than coking sludge; 2 Adding phenol as co-substrate promoted the biodegradation of BaP in both sludges. When BaP was the sole carbon source, the half-life of BaP in the two sludges was 155.41 d and 116.3 d respectively. After the addition of phenol, the half-life was reduced to 81.25 d and 38.44 d, respectively; 3 According to the analysis of the microbial community structure, the community composition in both sludges changed markedly. Moreover, the microbial community in the municipal sludge showed a more evident change than that of the coking sludge. In the coking sludge, the dominant bacteria community changed a little after acclimation, most of the observed bacteria were previously reported common PAH-degrading strains. In contrast, the dominant bacteria community in the municipal sludge varied greatly after acclimation, and the most abundant bacteria were not common PAH-degrading strains. In addition, some frequently reported PAHs degrading bacteria such as Bacillus sp., Pseudomonas, Achromobacter, and Sphingomonas sp., were identified in both the sludges and were present in high abundance. The results indicated that municipal sludge utilized BaP more actively than coking sludge; this phenomenon can be explained by the fact that municipal sludge contained a higher diversity of microbes that were involved in the degradation of BaP. Furthermore, the presence of phenol promoted the degradation of PAHs like BaP. Therefore, we proposed that the PAHs in coking sludge discharge might be reduced by the addition phenol and municipal wastewater. PMID- 29998690 TI - [Spectroscopic Characterization of DOM During Hyperthermophilic Composting of Sewage Sludge]. AB - Spectroscopy methods such as three-dimensional excitation-emission (3D-EEM) fluorescence spectroscopy were applied to analyze the structures and changes of DOM in hyperthermophilic composting of sewage sludge to fully understand the advantages of hyperthermophilic composting in promoting sludge maturity. The results showed that the temperature reached its peak value at 90C and remained over 80C for 5 d. The thermophilic period more than 50C lasted for 22 d. This indicated that the microorganisms were metabolically active during the composting. The parameters of UV-visible (UV-Vis), including E253/E203, SUVA280, and S275-295, significantly changed from days 0 to 23, showing that the aromaticity degree of DOM and the humification degree of the compost gradually strengthened. Combined with the fluorescence regional integration (FRI), the 3D EEM analysis results illuminated that the protein-like materials in DOM were completely degraded during days 0 to 6 of the hyperthermophilic composting and a large amount of humic acid-like and fulvic-like materials formed from days 0 to 23, indicating the compost was mature at the hyperthermophilic stage. This was consistent with the germination index (GI) on day 23 (GI=98.5%) as well. Based on the correlation analysis between spectroscopic parameters, PV,n/PIII,n showed close relationship with others (r >= 0.68), showing their potential as indicators for maturity of hyperthermophilic composting. The results above confirmed that fermentation time could be greatly shortened to about 20 d by using the hyperthermophilic composting, which has great potential for application in organic solid waste management. PMID- 29998691 TI - [Effects of Biochar on Nitrous Oxide Fluxes and the Abundance of Related Functional Genes from Agriculture Soil in the North China Plain]. AB - To explore the effect and mechanism of biochar application in reducing nitrous oxide (N2O) content in agricultural soil, from March 27 to June 5 2015, pot experiments were conducted to study the effects of biochar application rates (CK, C1:5%, C2:10%, C3:15%, and C4:30%) (mass fraction) on soil N2O fluxes and the functional marker genes ammonia monooxygenase (amoA), nirK, nirS, and nosZ, which are responsible for nitrification and denitrification. The results revealed the following. 1The application of low doses of biochar (5%) promoted N2O emission. The application of middle and high doses of biochar reduced N2O emission. Furthermore, the application of biochar (15%) was found to be the best practice to reduce N2O emission. 2 At the beginning of the experiment, biochar had a significant effect on the abundance of soil amoA and denitrification bacteria gene. Furthermore, the abundance of AOA and nirS had a significant positive correlation with the biochar rate, and the abundance of nirK gene and biochar rate were significant. There was a significant negative correlation between AOB and nosZ gene abundance and biochar rate. At the end of the experiment, AOA abundance correlated negatively with biochar rate, while there was a significantly positive relationship between AOB abundance and biochar rate. 3 At the beginning of the experiment, the N2O fluxes exhibited a significant negative correlation with AOA and nirS gene, indicating that N2O production was controlled by the abundance of AOA and nirS gene under high soil moisture content. At the end of the experiment, there was a significant positive correlation between N2O flux and nosZ gene, indicating that the production of N2O was regulated by the abundance of nosZ gene under low soil water content. The results of this study showed that the application of biochar altered the abundance of amoA and denitrification bacteria genes, and reduced N2O emission. These results provide a theoretical basis for a rational application of biochar in farmland. PMID- 29998692 TI - [Nitrous Oxide Production in Response to Oxygen in a Solar Greenhouse Vegetable Soil]. AB - To explore the sources of peak nitrous oxide (N2O) flushes in solar greenhouse vegetable field, an experiment was conducted with two conventional vegetable soils under different initial volume fractions of oxygen (O2) (0%, 1%, 3%, 5%, and 10%). A robotized incubation system was employed to analyze the gas kinetics[O2, N2O, nitric oxide (NO), nitrogen (N2), and carbon dioxide (CO2)] every 6 or 8 h and calculate the N2O/(NO+N2O+N2) index. Sodium chlorate (NaClO3) was used to inhibit the oxidation of NO2- to further explore the relationship between N2O and nitrite (NO2-). A parallel off-line incubation in triplicates was conducted under similar conditions to measure the dynamic changes in inorganic nitrogen content[ammonia (NH4+), nitrate (NO3-), and NO2-]. The results showed that N2O production under anaerobic condition was significantly higher than that under aerobic condition. The peak value of N2O in the soil collected from a straw added plot (DIS) was significantly higher than that in the soil from non-straw added plot (DI) (P<0.01) when the volume fraction of oxygen was <= 1%. Oxygen can directly affect N2O production by delaying or inhibiting N2O reduction, with significant increase in N2O production rate under oxygen-depleted condition. However, the N2production rate decreased significantly with increase in initial oxygen volume fraction (P<0.01). When the initial volume fraction of oxygen was between 1% and 5%, a continuous accumulation of NO2- was observed during the incubation period, resulting in the significantly higher N2O/(NO+N2O+N2) index than that in either anaerobic or 10% of oxygen treatments. Furthermore, a linear correlation was observed between NO2- and N2O at 5% and 10% of oxygen with the addition of NaClO3 (R2 >= 0.85). Incomplete denitrification and nitrifier denitrification from NO2- induction co-occurred in the range of 1% and 5% volume fractions of oxygen, significantly increasing the soil N2O production and N2O/(NO+N2O+N2) index. In addition, N2O production under anaerobic condition was significantly higher than that under aerobic condition (P<0.01). PMID- 29998693 TI - [Comprehensive Study of Lead Speciation and Its Bioavailability in Soils From a Lead/Zinc Mining Area by Micro X-Ray Fluorescence and X-Ray Absorption Near-Edge Structure]. AB - Lead species significantly influences its mobility and bioavailability. In this study, improved BCR procedure, laboratory culture, laboratory micro X-ray fluorescence (MU-XRF), and synchrotron radiation X-ray absorption near-edge structure (XANES) were used to investigate the distribution, speciation, and bioavailability of Pb in soils from a Pb/zinc (Zn) mining area contaminated with heavy metals. The results showed that 1 Pb was mainly distributed in the reducible[which binds to oxides of iron (Fe) and manganese (Mn)], acid soluble, residual, and oxidizable fractions, 2 Pb content in plant tissues correlated with acid-soluble Pb content in soil, 3 MU-XRF results indicated that Pb was distributed heterogeneously, and correlated with the hot spot with high concentration of Mn. In some area, Pb also correlated with Fe, and 4 Pb was predominantly present as Pb-goethite (41%-46%), Pb3(PO4)2(36%-55%), and Pb MnO2(3%-24%) in soil samples. The results of this study showed that oxides of Fe and Mn, and Pb3(PO4)2precipitate mainly comprise the pool of Pb in soils. PMID- 29998694 TI - [Assessment of Heavy Metal Pollution in Soil and Its Bioaccumulation by Dominant Plants in a Lead-Zinc Mining Area, Nanjing]. AB - To identify plants with potential application in phytoremediation, the concentration of cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), lead (Pb), and zinc (Zn) in soil and 14 dominant plants sampled from a lead-zinc mining area in Nanjing City was measured. Furthermore, the heavy metal contamination of soil, and bioaccumulation and translocation of the 6 heavy metals by the 14 plants were evaluated. The results showed that the principal contaminants were Cd, Mn, Zn, and Pb, and their single factor pollution index was 45.71, 11.68, 10.40, and 4.46, respectively. Furthermore, the Nemerow index of this area was 33.45, which indicated that the mining area was severely polluted. All the 14 dominant plant species were metal-tolerant, although the concentration of metal varied between different spices. Among them, Pteris multifida and Trachelospermum jasminoides significantly accumulated the heavy metals. The concentration of Zn in all the dominant plants was beyond the normal range; however, the bio-concentration factor (BCF) of only Digitaria sanguinalis for Zn was>1, while the BCF of the remaining species for the 6 heavy metals was<1. Furthermore, the heavy metal bio-transfer factor (BTF) of the 14 species was generally high. The BTF of Helianthus tuberosus and Dendranthema indicum for the 6 heavy metals was>1. According to the mechanism of heavy metal accumulation, the 14 plant species were classified into 3 types:accumulators (H. tuberosus, D. indicum, Phytolacca americana, Justicia procumbens, D. sanguinalis, Sonchus brachyotus, Solanum nigrum, and Setaria viridis), root compartment (P. multifida and T. jasminoides), and excluders (Solidago decurrens, Duchesnea indica, Carex breviculmis, and Cyrtomium fortunei). PMID- 29998695 TI - [Preparation of Iron-Aluminum Modified Diatomite and Its Immobilization in Cadmium-Polluted Soil]. AB - To improve the in-situ immobilization effect of diatomite on cadmium (Cd) contaminated soil, diatomite was modified by hydroxyl iron-aluminum (Fe-Al). The soil incubation experiments were carried out to investigate the effect of Fe/Al molar ratio, OH/cation of molar ratio, pillaring agent aging time, (Fe+Al)/diatomite ratio, pillaring temperature, and pillaring product aging time on the immobilization of Cd in soils. The changes in properties of diatomite before and after modification were analyzed by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The results showed that:the optimal preparation conditions for modification were:Fe/Al molar ratio=1:8, OH/cation molar ratio 2.0-2.2, pillaring agent aging time=2 d, (Fe+Al)/diatomite ratio=10 mmol.g-1, pillaring temperature=60C, pillaring product aging time=2 d. The hydroxyl-Fe-Al-modified diatomite significantly reduced the content of exchangeable Cd in soil, and the modification reduced soil exchangeable Cd from 11.83% to 39.52%. The SEM and FTIR analyses of hydroxyl-Fe-Al-modified diatomite revealed increase in the specific surface area of diatomite and the amount of the Si-O-H groups. After modification, the hydroxyl-Fe-Al successfully exchanged into the diatom shell forming available pillars, thus increasing channel spacing and enhancing the microporous surface activity. The modification with hydroxyl-Fe-Al increased the immobilization effect of diatomite on Cd in soil. The modification methods and data from this study will help increase the application of diatomite materials for the immobilization of soil containing heavy metals. PMID- 29998696 TI - [Transfer of Soil Organic Carbon to Inorganic Carbon in Arid Oasis Based on Stable Carbon Isotope Technique]. AB - The northern margin oasis of the Tarim Basin in the central arid region of Asia was selected as the study area. The study analyzed the delta13C values of the SIC(soil inorganic carbon) and distinguished the pedogenic carbonate in soil from the total SIC using the stable carbon isotope techniques and models. Based on the relationship between soil organic carbon and inorganic carbon contents in soil, the transfer of SOC to SIC was discussed. The results showed that the delta13C values of the SIC of 4 types of arid oasis soil were significantly different (P<0.01), the delta13C values of the SIC of aeolian sandy soil was (0.32+/ 0.04)0/00, which increased with increase in depth. This indicates that the lithogenic carbonates of the sandy soil are advantageous. The delta13C values of the SIC of irrigated desert soil, brown desert soil, and saline soil were ( 0.30+/-0.24)0/00, (-1.96+/-0.66)0/00 and (-1.24+/-0.49)0/00, respectively, and decreased with increase in depth. This indicates that the lithogenic carbonates dominated the irrigated desert soil, and the pedogenic carbonates dominated brown desert and saline soils. In the aeolian sandy, irrigated desert, brown desert, and saline soils, pedogenic carbonate accounted for 1.33%, 4.72%, 15.01%, and 35.71% of SIC, respectively, which were less than 50%. This shows that the level of soil pedogenic carbonates was low in arid oasis. During pedogenic carbonate formation or recrystallization, the aeolian sandy, irrigated desert, brown desert, and saline soils fixed 0.30, 2.44, 4.96, and 12.40 g.kg-1 of soil CO2, respectively, the average amount of CO2 fixed from the atmosphere was 0.18, 0.79, 1.45, and 8.67 g.kg-1, respectively. Furthermore, the transfer of SOC to SIC was 0.06, 0.83, 1.62, and 1.86 g.kg-1, respectively. The total transfer of SOC to SIC was between 0.03 and 2.38 g.kg-1, with an average of 1.09 g.kg-1 of CO2. This shows that the proportion of soil pedogenic carbonates and the contribution of SOC were not high in the arid oasis area. PMID- 29998697 TI - [Environmental Filters Drive the Assembly of the Soil Fungal Community in the Larix principis-rupprechtii Forests of the Guandi Mountains]. AB - The community assembly process, which purports that the trade-off between the stochastic process and the deterministic process, is the central issue of community ecology, and is one of the most controversial ecological issues. The current research investigated the fungal community in the Larix principis rupprechtii forests of the Guandi Mountains and elucidated the relative role of the stochastic and deterministic processes in the assembly of soil fungal community on a local scale. The correlation analysis and redundancy analysis of the physicochemical factors in soil and dominant fungal phyla, as well as the structural equation model analysis, showed that these physicochemical factors and aboveground vegetation diversity had significant effects on fungal communities. The direct effect of vegetation diversity on fungal community structure was the most (1.1858). It is inferred that the determination process (environmental selection) has a certain influence on the assembly of fungal communities. The beta-diversity of fungal community shows a distance-decay pattern; thus, it can be concluded that the stochastic process (dispersal limitation) has a certain effect on the assembly of fungal communities. Null model analysis confirmed that the deterministic process was the main driving factor for the assembly of the fungal communities in the study area, and their relative importance varied along with altitudinal gradient. The null deviations in the study area were negative, suggesting that habitat filtering was the driving factor of the assembly of fungal communities. Overall, the deterministic versus stochastic processes jointly drive the assembly of fungal communities in the study area, while the deterministic processes triumph. PMID- 29998698 TI - [Effects of Transgenic Maize with cry1Ab and Epsps Genes C0030.3.5 on the Abundance and Community Structure of Soil Nitrogen-fixing Bacteria]. AB - In order to evaluate the potential risk of planting transgenic corn on soil nitrogen-fixing microorganisms, in 2015, rhizosphere and non-rhizosphere soil samples were collected at the jointing stage, tassel stage, milky stage, and ripening stage, and the effects of transgenic maize with the cry1Ab and epsps genes on the abundance and diversity of soil nitrogen-fixing bacteria were studied by real-time quantitative PCR and T-RFLP. The results showed that the copy number of the diazotrophic nifH gene in the rhizosphere and non-rhizosphere soil of transgenic maize with the cry1Ab and epsps genes (C0030.3.5) and its parental maize (DBN318) showed a trend where it first increased and then decrease with the growth stages, ranging between 2.99*107 and 7.02*107 copies.g-1. The abundance of the diazotrophic nifH gene in the rhizosphere soil and non rhizosphere soil gene showed no significant difference between TM and PM in the same growth stage (P>0.05). The correlation analysis showed that the abundance of the diazotrophic nifH gene was positively correlated with the content of organic matter, but negatively correlated with water content. T-RFLP analysis yielded 14 T-RFs of different lengths, and 43-bp and 155-bp fragments were the dominant population. The community composition of nitrogen-fixing bacteria was the same as that of TM and PM in the rhizosphere soil and non-rhizosphere soil, and there was no significant difference between the TM and PM populations in the same growth period (P>0.05). The Shannon index and Evenness index of the diazotrophic nifH gene showed a trend where they first increased and then decreased with the growth period, and there was no significant difference in the Shannon index and Evenness index in the same growth stage between the rhizosphere and non-rhizosphere soil samples. Principal component analysis(PCA) indicated that the composition of nitrogen-fixing bacteria was not different between TM and PM. Redundancy analysis (RDA) showed that soil ammonium, nitrogen, and pH were significantly correlated with composition of nitrogen-fixing bacteria. PMID- 29998700 TI - [Effects of Long-term Fertilization on Enzyme Activities in Profile of Paddy Soil Profiles]. AB - The enzyme activity, which is closely related to soil material cycling (mineralization, transformation, etc.), can reflect soil quality and nutrient status. In order to explore the effect of long-term fertilization on the enzyme activity in paddy soil profile (0-40 cm), soils with organic fertilizer and inorganic fertilizer, and non-fertilized soils were selected, and the carbon and nitrogen contents, and the activities of beta-1,4-glucosidase (BG), and beta-1,4 N-acetylglucosaminidase (NAG) in 10cm depths of soil were analyzed. The results showed that the activities of BG and NAG in the soils treated with inorganic fertilizer and organic fertilizer increased by 0.73-47.87 nmol.(g.h)-1 and 1.33 128.81 nmol.(g.h)-1, and 0.19-9.72 nmol.(g.h)-1 and 0.92-57.66 nmol.(g.h)-1, respectively, compared to those for non-fertilized soil. Soil enzyme activity decreased with increasing soil depth. Soil enzyme activity in soil from 0-20 cm was significantly higher than that of soil from 20-40 cm. Soil enzyme activities were significantly affected by long term fertilization at different soil depths. RDA analysis showed that soil carbon and nitrogen contents had significant positive relationships with the activities of BG and NAG in the 0-20 cm soil profiles, however, negative relationships were observed in the 20-40 cm soil profiles. The long-term application of organic fertilizer significantly increased soil biomass and enzyme activity, both of which decreased with the increase in soil depth. Long-term fertilization could increase soil nutrient contents, microbial biomass, and extracellular enzyme activities, which has important theoretical significance for optimizing farmland fertilizer management and improving soil productivity. PMID- 29998699 TI - [Effects of Gypsum on CH4 Emission and Functional Microbial Communities in Paddy Soil]. AB - In this study, the effects of gypsum (FGD) on CH4 emission and functional microbial community in paddy soil were identified under five treatments, including FGDG0(0 t.hm-2), FGDG1(2 t.hm-2), FGDG2(4 t.hm-2), FGDG3(8 t.hm-2), and FGDG4(16 t.hm-2). The methane flux was determined using static chamber and chromatography. Bacterial community structure and its effect on soil bacterial community structure, and the abundance of methanogenic and methanotrophs were measured via high-throughput sequencing and quantitative PCR. The results showed that after treatment with desulfurated gypsum, pH of the soil increased significantly (P<0.05). Redox potential, organic carbon, and available potassium content increased, with no significant difference (P>0.05). The average emission flux of CH4 reduced with the increase of desulfurated gypsum content, following the following trend:FGDG1 > FGDG2 > FGDG3 > FGDG4. They decreased by 31.56%, 57.30%, 83.60%, and 90.66%, respectively, compared with the control. Compared with the control, FGDG1 and FGDG2 increased the richness and variety of soil bacteria. However, when the application amount exceeds 4 t.hm-2, the richness and variety of soil bacteria decrease. Compared with the control, the relative abundance of sulfate-reducing bacteria in paddy soil increased significantly by 6.98%-13.56%. The abundance of the methane-oxidizing bacteria pmoA gene increased by 0.3%-6.2%. The abundance of the methanogen gene, mrcA decreased significantly by 2.4%-15.8%, while the abundance ratio (pmoA/mcrA)increased with the increase of the amount of desulfurated gypsum. Correlation analysis showed that the average emission of CH4 was markedly negatively correlated with the relative abundance of the sulfate-reducing bacteria and pmoA/mcrA percentage in soil, and significantly positively correlated with methanogenic gene, mcrA. In summary, desulfurated gypsum can improve the diversity of bacterial communities and reduce the emission of CH4 in the paddy soils. PMID- 29998701 TI - [Effects of Sediment Burial and Exogenous Cd Input on Biomass Allocation and Antioxidative Enzyme Activities of Suaeda salsa in the Coastal Wetland of the Yellow River Delta]. AB - The Yellow River Delta has been facing the threat of functional degradation during the recent years. The Water-Sediment Regulation Project not only supplements abundant freshwater, but also alters the sediment burial and heavy metal levels, which affects vegetation growth. Thus, we selected the pioneer species Suaeda salsa, to study the effects of different sediment burial depths (0, 3, 6, 12 cm) and exogenous Cd inputs (0, 0.5, 1.0, 1.5 mg.kg-1) on biomass allocation and activities of antioxidative enzymes in the coastal wetlands of the Yellow River delta. The results showed that a shallow or moderate burial depth had a stimulatory effect on chlorophyll content, while an excessive burial depth inhibited the growth of Suaeda salsa and chlorophyll content. With increasing Cd input, chlorophyll content and dry mass decreased. At a lower Cd input and moderate burial depth, activities of CAT and SOD increased, and at high levels, SOD activities decreased, while activities of CAT at a 12 cm burial depth and 1.0 mg.kg-1, 1.5 mg.kg-1 Cd input were higher than those for the control (62.66% and 58.56%). CAT activities reached high values (15.76 U.mg-1) at a high Cd input (1.5 mg.kg-1) and burial depth (12 cm). Analysis of variance showed that Cd input had a significant effect on protein content, and CAT and SOD activities, and sediment burial depth had a significant effect on the protein content and SOD activities. Interaction between Cd input and sediment burial depth had a significant effect on CAT and SOD activities (P<0.05). These results demonstrated that sediment burial depth and Cd input had a great influence on the growth of Suaeda salsa, and to some extent, Suaeda salsa could change its biomass allocation and antioxidative enzyme activities to adapt to severe environments. PMID- 29998702 TI - [Pollution Characteristics and Health Risk Assessment of Heavy Metals in Wheat Grains Cultivated in Kaifeng Irrigation Area of the Yellow River]. AB - In order to monitor heavy metal pollution in agricultural soils and assess the corresponding health risk in the Yellow River irrigation area, this study applied the Nemero index and the health risk index to evaluate heavy metal pollution in wheat grains and the health risks for residents in the lower reaches of the Yellow River. Four towns in Kaifeng, which are within the lower reaches of the Yellow River, were selected as the study area. The examination of wheat samples revealed that the average contents of Cd, Cr, Pb, Cu, Zn, Ni, and Hg in the wheat grains were 0.034, 0.428, 0.279, 5.363, 29.605, 0.305, and 0.003 mg.kg-1, respectively. Among the heavy metals, Pb and Zn exceeded the national food hygiene standards. The pollution indices of Pb and Zn in the wheat grains contributed significantly to the comprehensive pollution index, as each was greater than 1 (1.985), although the pollution indices of the other heavy metals were less than 1. The comprehensive pollution index of wheat in each town ranged from 1.116 to 1.847. The health risk indices of non-carcinogenic heavy metals (Pb, Cu, Zn, and Hg) for adults and children were 1.0558 and 0.5450, respectively. The health risk indices of carcinogenic heavy metals (Cd, Cr, and Ni) for adults and children were higher than the maximum acceptable risk level (1*10-4) recommended by the USEPA, which suggests that residents of the study area have a high risk of developing various forms of cancer. PMID- 29998704 TI - [Effects of Organic Substrates on ANAMMOX-MFC Denitrification Electrogenesis Performance]. AB - An anaerobic ammonium oxidation microbial fuel cell (ANAMMOX-MFC) was successfully started by inoculating anaerobic ammonium oxide sludge into the anode of a microbial fuel cell and then used to study the effect of glucose and phenol on ANAMMOX-MFC denitrification electrogenesis performance. The results showed that the ANAMMOX bacteria promoted ANAMMOX-MFC denitrification when the concentration of glucose was low (100-200 mg.L-1). At that time, the chemical oxygen demand (COD) concentration of the reactor was not significant. The electrogenesis production performance and NH4+-N removal rate gradually decreased when the glucose concentration was higher than 300 mg.L-1, but the NO2--N removal rate generally remained unchanged. The COD concentration was also reduced, indicating that the activity of the ANAMMOX bacteria was inhibited and the activity of denitrification bacteria began to increase. The polarization curve fitting degree was low, and the change in COD concentration had little effect on the battery internal resistance. When the concentration of phenol was low (50-100 mg.L-1), there was little effect on ANAMMOX-MFC denitrification electrogenesis performance. When the concentration of phenol exceeded 200 mg.L-1, ANAMMOX-MFC denitrification performance was gradually inhibited. Overall, in the process, the COD concentrations of the water influent and effluent changed little, the polarization curve fitting degree was low, and the apparent internal resistance increased slowly. PMID- 29998703 TI - [Effect of Graphene Oxide on Algal Toxicity of Dibutyl Phthalate]. AB - Marine microalgae, Platymonas helgolondica var. tsingtaoensis, were used as experimental subjects to study the acute toxic effects of graphene oxide (GO) and dibutyl phthalate (DBP), both individually and together. The growth of algae cells, production of photosynthetic pigments, cell permeability, and oxidative stress were investigated. The effects of GO on the algal toxicity of DBP were evaluated. The results showed that low concentrations of GO (0.1-10 mg.L-1) had no significant effect on algae density and chlorophyll production of Platymonas helgolondica var. tsingtaoensis (P<0.05). However, the algae cell permeability increased significantly with GO concentration (P<0.05) and reached 2.2 times that of the control group at 10 mg.L-1. The EC50, 96 h value of DBP for Platymonas helgolondica var. tsingtaoensis was (11.14+/-0. 80) mg.L-1, which, in terms of toxicity, was much higher than that of GO (EC50, 96 h>100 mg.L-1). At a GO concentration of 1 mg.L-1, the EC50, 96 h value of DBP decreased to (4.93+/-2.14) mg.L-1, showing that low concentrations of GO enhanced the algae toxicity of DBP. When 1 mg.L-1 of GO was added, low concentrations of DBP (0.1-2 mg.L-1) did not have any significant effect on algae density, chlorophyll production, cell permeability, ROS, and SOD. However, the inhibitory effects of high concentrations of DPB (4 mg.L-1) on algae density and chlorophyll production were enhanced by GO, thereby increasing the average ROS and SOD in algae cells by 21% and 7%, respectively. SEM images showed that GO was the primary factor responsible for increasing the coverage and packing of, and the aggregation effect on, algae cells, which could be the reasons for the increased toxicity of DBP. The results of our study can provide data to reveal the risk of novel carbon nanomaterial pollutants to marine organisms. PMID- 29998705 TI - [Well-to-Wheels Fossil Energy Consumption and CO2 Emissions of Hydrogen Fuel Cell Vehicles in China]. AB - Hydrogen fuel cell vehicles (FCVs) have the advantage of high energy efficiency and zero tailpipe emissions. They have been progressively commercialized in recent years. Hydrogen production has diversified technological pathways, which vary greatly in terms of energy and environmental impacts. In this study, the life cycle assessment (LCA) method was applied to evaluate well-to-wheels (WTW) fossil energy consumption and carbon dioxide (CO2) emissions of FCVs using various hydrogen production pathways. The greenhouse gases, regulated emissions, and energy use in transportation (GREET) model, developed by the Argonne National Laboratory, was applied as the assessment tool, and a China-specific database was investigated and developed to evaluate typical hydrogen production pathways. Then, we compared the WTW fossil energy consumption and CO2 emissions of FCVs with those of gasoline vehicles (GVs), hybrid electric vehicles (HEVs), and battery electric vehicles (BEVs). The results indicated that renewable-energy based electrolysis of water and biomass gasification are two prospective hydrogen production pathways with significant WTW energy and climate benefits which can help FCVs reduce fossil energy consumption and CO2 emissions by approximately 90% more than GVs. Among the current pathways with mass adoption, hydrogen production from coke oven gas (COG) has substantial energy and CO2 mitigation benefits, which enables FCVs to achieve a lower WTW fossil energy consumption than HEVs and lower WTW CO2 emissions than HEVs and BEVs. Considering the resource reserves and technological maturity in China, hydrogen production from COG and other industrial by-products is recommended for hydrogen energy and FCV development in the short term. In the medium and long terms, utilization of renewable energy to produce hydrogen should be promoted. PMID- 29998706 TI - [Secondary Organic Aerosols from Aqueous Reaction of Aerosol Water]. AB - Liquid water (cloud/fog droplets and aerosols) is ubiquitous in the atmosphere and can provide an important reaction media for aqueous-phase chemical reactions. Gaseous precursors (mainly VOCs) or their gas-phase initial or first-generation oxidation products (including intermediate-volatility and semi-volatile organic compounds; I/SVOCs) can undergo chemical reactions in the atmospheric condensed phase (aqueous phase) to form low-volatility, highly oxidized organic matter[e.g., some key tracer species such as organosulfates (OSs) and organonitrogens (ONs)]. These products largely remain in the particle phase upon water evaporation and are referred to as aqueous secondary organic aerosols (aqSOAs). aqSOAs have been emerging as a research hot topic in atmospheric chemistry, as they can contribute significantly to OAs and thus have important impacts on the environment, climate, and human health. Despite considerable progress, so far, aqSOAs remain poorly understood owing to their complex formation mechanisms. In this review, we focus mainly on the relevant research results on the SOAs formed in aerosol water-aqueous aerosol SOAs (aaSOAs) including gas-phase precursors, formation mechanisms, laboratory simulations, and field observations, as well as SOA yield and contribution to OAs. Meanwhile, we propose future directions regarding studies of sources and formation mechanisms of aaSOAs, including identification of unknown aaSOA precursors and tracer products, photosensitizer-triggered radical chemistry, formation pathways of OS and ON compounds, field observations and model simulations of aaSOAs. PMID- 29998707 TI - Pigmented porokeratosis with dermal deposits of amyloid: the different chromatic features. PMID- 29998708 TI - Post-inflammatory hypopigmentation due to ferrous sulphate. PMID- 29998709 TI - Scar-related basal cell carcinoma in a case series: clinical and dermoscopical findings. PMID- 29998710 TI - Serum levels of tumor necrosis factor-alpha in patients with psoriasis before, during and after narrow-band UVB phototherapy: a reply. PMID- 29998711 TI - Meeting a rare disease: a case of bullous ichthyosiform erythroderma. PMID- 29998712 TI - Evaluation of the costs of topical treatments for actinic keratosis based on lesion response and the affected area. AB - BACKGROUND: The cost of topical treatments for actinic keratosis (AK) has never been evaluated with respect to the actual cancerization field treated and the corresponding lesion response rate. Traditionally, evaluation in AK has been done in the context of patient response rate alone. The current study aimed to develop an economic model assessing the cost of topical treatments for the management of AK in Italy. METHODS: Data from Italian patients (N.=100) with five or more mild/moderate lesions on the face and/or scalp was used. The efficacy of the topical treatments which are available for the treatment of AK in Italy was considered. The outcome of interest was lesion response rates at three months and was based on published literature. The cost of each treatment was estimated according to the approval status of the drug and the cancerization area that required treatment. The analysis was replicated for four other European countries. RESULTS: The average costs of treatment with c-PDT, DL PDT, DHA, InMeb and IMQ were ? 364.2, ? 255.5, ? 848.7, ? 1039.1, and ? 628.3, respectively. Taking into account the number of lesions cleared per patient, the cancerization area treated, and the number of visits required with each treatment, the total costs per lesion treated per patient were estimated at ? 37.9, ? 29, ? 264.7, ? 103.5, and ? 115.4, respectively. The analysis produced consistent results when it was replicated for other countries. CONCLUSIONS: Daylight therapy with methyl aminolevulinate (DL PDT) is an effective treatment option for AK management with a favourable value for money profile. PMID- 29998713 TI - New insights into mechanism of Notch signalling in hidradenitis suppurativa. PMID- 29998714 TI - Leiomyoma of the finger in a patient affected by cutaneous Kaposi's sarcoma. PMID- 29998715 TI - Treatment of keloid-scar under polarized dermoscopy. PMID- 29998716 TI - Considerations on 18FDG PET/CT and sentinel lymph node biopsy in AJCC stages I and II of melanoma. PMID- 29998717 TI - Pathogenesis and causations of systemic contact dermatitis. AB - Systemic contact dermatitis (SCD) describes a hypersensitivity reaction following systemic re-exposure of the inciting allergen in previously sensitized individuals. Plants, drugs, and metals are the most common causes of SCD. In individuals with obstinate dermatitis, it is imperative to deliver and history focused patch testing with subsequent avoidance and elimination of the compound. PMID- 29998719 TI - A study of an ointment from a late 17th century Italian medicine chest. PMID- 29998718 TI - A chemical study of a'Terra Sigillata' medicinal tablet from a late 17th century Italian medicine chest. PMID- 29998720 TI - The Indian Lancet. PMID- 29998721 TI - The Rise and Fall of the Liverpool Apothecaries Company 1836 to 1904. PMID- 29998722 TI - Physical and verbal violence against health care workers. PMID- 29998723 TI - The Rise and Fall of the Liverpool Apothecaries Company 1836 to 1904. PMID- 29998724 TI - A Trial of Blood-Pressure Reduction in Black Barbershops. PMID- 29998725 TI - A Trial of Blood-Pressure Reduction in Black Barbershops. PMID- 29998726 TI - A Trial of Blood-Pressure Reduction in Black Barbershops. PMID- 29998727 TI - Portable, Self-Powered, and Light-Addressable Photoelectrochemical Sensing Platforms Using pH Meter Readouts for High-Throughput Screening of Thrombin Inhibitor Drugs. AB - In this work, a self-powered, portable, and light-addressable photoelectrochemical sensor (P-LAPECS) is developed for efficient drug screening using a handheld pH meter readout. The sensor, which employs thrombin inhibitors as the drug model, is constructed by evenly immobilizing biotin-labeled and thrombin-cleavable peptides on eight separated sensing zones of a single gold film electrode. The incubation of each peptide sensing zone with thrombin leads to the reduction of binding sites for streptavidin-labeled fullerene (C60) PEC bioprobes, which directly reflects the activity of thrombin by the variation of both photocurrent and photovoltage, and therefore allows the screening of thrombin inhibitors using either a single-channel electrochemical analyzer or a portable pH meter. Consequenty, the inhibition efficiency evaluation of multiple thrombin inhibitors can be achieved by just one electrode, and the screening result obtained by the pH meter is very close to that acquired by the electrochemical analyzer. Moreover, P-LAPECS can realize the light-addressable detection of thrombin with a detection limit as low as 0.05 pM. The present work thus demonstrates the possibility of constructing portable, inexpensive, sensitive, and high-throughput biosensing platforms using ubiquitous pH meters for laboratories all over the world. PMID- 29998729 TI - Enzymatic Synthesis of Structured Monogalactosyldiacylglycerols Enriched in Pinolenic Acid. AB - We enzymatically prepared structured monogalactosydiacylglycerols (MGDGs) enriched in pinolenic acid (PLA). PLA-enriched free fatty acids (FFAs) containing ~86 mol % PLA were produced from an FFA fraction obtained from pine nut oil (PLA content, ~13 mol %) by urea crystallization. Commercial MGDGs (5 mg) were acidolyzed with PLA-enriched FFAs using four commercial immobilized lipases as biocatalysts. The reaction was performed in acetone (4 mL) in a stirred-batch reactor. Lipozyme RM IM (immobilized Rhizomucor miehei lipase) was the most effective biocatalyst for the reaction. Structured MGDGs containing 42.1 mol % PLA were obtained under optimal reaction conditions: temperature, 25 degrees C; substrate molar ratio, 1:30 (MGDGs/PLA-enriched FFAs); enzyme loading, 20 wt % of total substrates; and reaction time, 36 h. The structured MGDGs were separated from the reaction products at a purity of 96.6 wt % using silica column chromatography. The structured MGDGs could be possibly used as emulsifiers with appetite-suppression effects. PMID- 29998728 TI - Evaluation of Current and Emerging Antimalarial Medicines for Inhibition of Toxoplasma gondii Growth in Vitro. AB - Toxoplasma gondii is a common zoonotic infection of humans, and estimates indicate that 1-2 billion people are chronically infected. Although largely asymptomatic, chronic infection poses risk of serious disease due to reactivation should immunity decline. Current therapies for toxoplasmosis only control acute infection caused by actively proliferating tachyzoites but do not eradicate the chronic tissue cyst stages. As well, there are considerable adverse side effects of the most commonly used therapy of combined sulfadiazine and pyrimethamine. Targeting the folate pathway is also an effective treatment for malaria, caused by the related parasites Plasmodium spp., suggesting common agents might be used to treat both infections. Here, we evaluated currently approved and newly emerging medicines for malaria to determine if such compounds might also prove useful for treating toxoplasmosis. Surprisingly, the majority of antimalarial compounds being used currently or in development for treatment of malaria were only modestly effective at inhibiting in vitro growth of T. gondii tachyzoites. These findings suggest that many essential processes in P. falciparum that are targeted by antimalarial compounds are either divergent or nonessential in T. gondii, thus limiting options for repurposing of current antimalarial medicines for toxoplasmosis. PMID- 29998730 TI - Visible Light-Erasable Oxide FET-Based Nonvolatile Memory Operated with a Deep Trap Interface. AB - A new concept of a tunneling oxide-free nonvolatile memory device with a deep trap interface floating gate is proposed. This device demonstrates a high on/off current ratio of 107 and a sizable memory window due to deep traps at the interface between the channel and gate dielectric layers. Interestingly, irradiation with 400 nm light can completely restore the program state to the initial one (performing an erasing process), which is attributed to the visible light-sensitive channel layer. Device reproducibility is enhanced by selectively passivating shallow traps at the interface using in situ H2 plasma treatment. The passivated memory device shows highly reproducible memory operation and on-state current during retention bake tests at 85 degrees C. One of the most significant advantages of this visible light-erasable oxide field-effect transistor-based nonvolatile memory is its simple structure, which is free from deterioration due to the frequent tunneling processes, as compared to conventional nonvolatile memory devices with tunneling oxides. PMID- 29998731 TI - Identification and Characterization of l-Malate Dehydrogenases and the l-Lactate Biosynthetic Pathway in Leuconostoc mesenteroides ATCC 8293. AB - One putative l-lactate dehydrogenase gene (l- ldh) and three putative d- ldh genes from Leuconostoc mesenteroides ATCC 8293 were overexpressed, and their enzymatic properties were investigated. Only one gene showed d-LDH activity, catalyzing pyruvate and d-lactate interconversion, whereas the other genes displayed l- and d-malate dehydrogenase (MDH) activity, catalyzing oxaloacetate and l- and d-malate interconversion, suggesting that strain ATCC 8293 may not harbor an l- ldh gene. Putative phosphoenolpyruvate carboxylase (PEPC)- and malolactic enzyme (MLE)-encoding genes were identified from strain ATCC 8293, and sequence analysis showed that they could exhibit PEPC and MLE activities, respectively. l-Lactate production and transcriptional expression of the mle gene in this strain were highly increased in the presence of l-malate. We propose that in strain ATCC 8293, which lacks an l- ldh gene, l-lactate is produced through sequential enzymatic conversions from phosphoenolpyruvate to oxaloacetate, then l malate, and finally l-lactate by PEPC, l-MDH, and MLE, respectively. PMID- 29998732 TI - Aquivion-Carbon Composites with Tunable Amphiphilicity for Pickering Interfacial Catalysis. AB - A key demand in biomass conversion is how to achieve high reactivity with immiscible reagents with the use of neither cosolvents nor additives. Pickering interfacial catalysis encompassing the design of amphiphilic catalysts behaving concomitantly as emulsifiers offers an elegant solution. In this study, we prepared a systematic series of amphiphilic Aquivion-carbon composites by the hydrothermal carbonization of guar gum with Aquivion perfluorosulfonic superacid. By tuning the Aquivion-carbon composition, materials with tunable hydrophilic lipophilic properties could be prepared, showing high versatility for conducting biphasic reactions without stirring. In particular, an optimal formulation based on 5:1 Aquivion-carbon could be developed, showing high activity in the transesterification reaction of glyceryl trioleate with methanol at 100 degrees C with good reusability due to the genesis of stable Pickering emulsions. PMID- 29998733 TI - Anaerobic Transformation of the Iodinated X-ray Contrast Medium Iopromide, Its Aerobic Transformation Products, and Transfer to Further Iodinated X-ray Contrast Media. AB - The iodinated X-ray contrast medium (ICM) iopromide and its aerobic transformation products (TPs) are frequently detected in the effluents of wastewater treatment plants and in different compartments of the aquatic environment. In this study, the anaerobic transformation of iopromide and its aerobic TPs was investigated in water-sediment systems. Iopromide, its final aerobic TP didespropanediol iopromide (DDPI), and its primary aniline desmethoxyacetyl iopromide (DAMI) were used as model substances. Five biologically formed anaerobic TPs of iopromide and DAMI and six of DDPI, and the respective transformation pathways, were identified. The TPs were formed by successive deiodination and hydrolysis of amide moieties. Quantification of the iodinated TPs was achieved by further development of a complementary liquid chromatography (LC)-quadrupole time-of-flight mass spectrometry (Q-ToF-MS) and LC inductively coupled plasma - mass spectrometry (ICP-MS) strategy without needing authentic standards, despite several TPs coeluting with others. A database with predicted anaerobic TPs of ICMs was derived by applying the transformation rules found for the anaerobic transformation pathways of iopromide and diatrizoate to further ICMs (iomeprol and iopamidol) and their aerobic TPs already reported in the literature. The environmental relevance of the identified transformation pathways was confirmed by identifying an experimental TP and two predicted TPs using suspect screening of water taken from anaerobic bank filtration zones. PMID- 29998734 TI - Synthesis of (-)-Cytisine Using a 6- endo aza-Michael Addition. AB - An asymmetric synthesis of (-)-cytisine has been achieved. The piperidine C-ring was formed using a stereodivergent intramolecular 6- endo aza-Michael addition. The B-ring was established by intramolecular pyridine N-alkylation. The absolute stereochemistry was established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded with an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone pair. PMID- 29998735 TI - Observation of Gap Opening in 1T' Phase MoS2 Nanocrystals. AB - Two-dimensional (2D) transition metal dichalcogenides (TMDs) manifest in various polymorphs, which deliver different electronic properties; the most prominent among them include the semiconducting 2H phase and metallic 1T (or distorted 1T' phase) phase. Alkali metal intercalation or interface strain has been used to induce semiconductor-to-metal transition in a monolayer MoS2 sheet, leading to exotic quantum states or improved performance in catalysis. However, the direct growth of 1T or 1T' phase MoS2 is challenging due to its metastability. Here, we report MBE growth of isolated 1T' and 2H MoS2 nanocrystals on a Au substrate; these nanocrystals can be differentiated unambiguously by their electronic states using scanning tunneling microscopy (STM) and scanning tunneling spectroscopy (STS). By studying the initial stages of nucleation during molecular beam epitaxy (MBE) of MoS2, we could identify atomic clusters (30-50 atoms) with intralayer stacking corresponding to 1T' and 2H separately, which suggests a deterministic growth mechanism from initial nuclei. Furthermore, a topological insulator type behavior was observed for the 1T' MoS2 crystals, where an energy gap opening of 80 meV was measured by STS in the basal plane at 5 K, with the edge of the nanocrystals remaining metallic. PMID- 29998736 TI - Photoactivated Specific mRNA Detection in Single Living Cells by Coupling "Signal on" Fluorescence and "Signal-off" Electrochemical Signals. AB - The spatiotemporal detection of a target mRNA in a single living cell is a major challenge in nanoscience and nanomedicine. We introduce a versatile method to detect mRNA at a single living cell level that uses photocleavable hairpin probes as functional units for the optical (fluorescent) and electrochemical (voltammetric) detection of MnSOD mRNA in single MCF-7 cancer cells. The fluorescent probe is composed of an ortho-nitrophenylphosphate ester functionalized hairpin that includes the FAM fluorophore in a caged configuration quenched by Dabcyl. The fluorescent probe is further modified with the AS1411 aptamer to facilitate the targeting and internalization of the probe into the MCF 7 cells. Under UV irradiation, the hairpin is cleaved, leading to the intracellular mRNA toehold-stimulated displacement of the FAM-functionalized strand resulting in a switched-on fluorescence signal upon the detection of the mRNA in a single cell. In addition, a nanoelectrode functionalized with a methylene blue (MB) redox-active photocleavable hairpin is inserted into the cytoplasm of a single MCF-7 cell. Photocleavage of the hairpin leads to the mRNA mediated toehold displacement of the redox-active strand associated with the probe, leading to the depletion of the voltammetric response of the probe. The parallel optical and electrochemical detection of the mRNA at a single cell level is demonstrated. PMID- 29998737 TI - Mechanistic Insight through Irreversible Inhibition: DNA Polymerase theta Uses a Common Active Site for Polymerase and Lyase Activities. AB - DNA polymerase theta (Pol theta) is a multifunctional enzyme. It is nonessential in normal cells, but its upregulation in cancer cells correlates with cellular resistance to oxidative damage and poor prognosis. Pol theta possesses polymerase activity and poorly characterized lyase activity. We examined the Pol theta lyase activity on various abasic sites and determined that the enzyme is inactivated upon attempted removal of the oxidized abasic site commonly associated with C4' oxidation (pC4-AP). Covalent modification of Pol theta by the DNA lesion enabled determination of the primary nucleophile (Lys2383) responsible for Schiff base formation in the lyase reaction. Unlike some other base excision repair polymerases, Pol theta uses a single active site for polymerase and lyase activity. Mutation of Lys2383 significantly reduces both enzyme activities but not DNA binding. Demonstration that Lys2383 is required for polymerase and lyase activities indicates that this residue is an Achilles heel for Pol theta and suggests a path forward for designing inhibitors of this attractive anticancer target. PMID- 29998738 TI - Cervical cancer, human papillomavirus (HPV), and HPV vaccination: exploring gendered perspectives, knowledge, attitudes, and cultural taboos among Mexican American adults. AB - BACKGROUND: Gendered perspectives may be particularly important in shaping norms and values around HPV and HPV vaccination, as previous research suggests that sexuality taboos (e.g. promiscuity) may contribute to low perceived risk among adolescent and young adult Hispanic females. However, research to date focuses primarily on Hispanic mothers, adolescent females, and women of HPV vaccine eligible age. Hispanic father's perspectives are relatively unknown despite father's important role in shaping norms for their female children. OBJECTIVE: To close this gap, this study examines gendered perspectives in knowledge, beliefs, and attitudes about HPV and HPV vaccination from Hispanic parents (mothers and fathers), women of vaccine-eligible age (18-26 years old), and women eligible for Pap Test screening (>26 years old) living in two counties along the Texas-Mexico border. DESIGN: We conducted eight focus groups. Research staff transcribed audio recordings verbatim and uploaded them into Atlas(ti) 5.0 for analysis. The research team analyzed the data for content, meaning, patterns and themes using the constant comparison approach. RESULTS: Perspectives were highly gendered. Women's (all groups combined) beliefs focused on misconceptions around how the HPV virus is contracted (e.g. toilet surfaces). Women also linked HPV-related sexual risk to adultery and indiscretion of male partners. Fathers (men) were more likely to link risk to female promiscuity. Fathers also worried that HPV vaccination might increase promiscuity. All groups believe that HPV vaccination is a way to protect Hispanic females in the face of beliefs around sexual behavior and risk of contracting HPV. CONCLUSION: Results suggest gendered differences in risk beliefs concerning HPV among Hispanics living along the Texas Mexico border. Researchers can use these findings to address barriers to HPV vaccination, as well as to create culturally appropriate prevention messages that may help reduce disparities in HPV among Hispanic women. PMID- 29998739 TI - Preceptor Perceptions of Team Quality Improvement Projects Conducted With the Educating Pharmacists in Quality Program. PMID- 29998740 TI - The impact of implementation support on the use of a social engagement intervention for children with autism in public schools. AB - Several interventions have demonstrated efficacy in improving social outcomes for children with autism; however, few have been successfully implemented in schools. This study compared two implementation strategies to improve the use of a social engagement intervention for children with autism in public schools. In total, 31 children with autism in grades K-5 and 28 school personnel participated in a randomized controlled trial. Schools were randomized to (1) training in Remaking Recess, a social engagement intervention, or (2) training in Remaking Recess with implementation support. Linear regression with random effects was used to test the intervention effects on implementation fidelity and social outcomes (peer engagement, social network inclusion, and friendship nominations). In both groups, implementation fidelity improved after training but remained low. Children in the Remaking Recess with implementation support condition had significantly higher social network inclusion and received more friendship nominations than children in the Remaking Recess-only condition (p = 0.03). Children in both groups experienced reduced solitary engagement (p < 0.001) and increased joint engagement (p < 0.001). The results suggest that implementation supports may have an effect on outcomes above and beyond the intervention, and that further research is needed into the active intervention mechanisms. PMID- 29998741 TI - Osteochondritis Dissecans of the Knee: Etiology and Pathogenetic Mechanisms. A Systematic Review. AB - Objective The purpose of this manuscript is to analyze the evidence regarding etiopathogenesis of knee osteochondritis dissecans (OCD) lesions through a systematic review, so to summate the current understanding of the origin and progression of this pathologic articular processes. Design A systematic review of the literature was performed on the PubMed and Cochrane databases on October 2017 by 2 independent authors and included all levels of evidence. This included all English language literature, pertaining specifically to etiopathology of knee OCD with exclusions for review articles and expert opinion. Of 965 identified records, 154 full-text articles were assessed for eligibility and 86 studies met the inclusion criteria. Results According to these studies, the etiology of OCD can be of a biological or mechanical origin: 40 articles proposed a biological hypothesis, including genetic causes (27), ossification center deficit (12), and endocrine disorders (9); conversely, 52 articles supported a mechanical hypothesis, including injury/overuse (18), tibial spine impingement (5), discoid meniscus (16), and biomechanical alterations (20) as the cause of the onset of OCD. The pathogenic processes were investigated by 36 of these articles, with a focus on subchondral bone fracture and ischemia as the ultimate events leading to OCD. Conclusions Biological and mechanical factors are found to result in subchondral bone remodeling alterations, acting independently or more likely synergically in the progression of knee OCD. The former includes genetic causes, deficit of ossification centers and endocrine disorders; the latter, tibial spine impingement, discoid meniscus, and biomechanical alterations, together with injuries and overuse. The resultant subchondral bone ischemia and/or fracturing appears to determine the onset and progression of OCD. Level of Evidence Systematic review of level II-IV studies, level IV. PMID- 29998742 TI - Exploratory and Confirmatory Factor Analysis of the Universal Nonverbal Intelligence Test-Second Edition: Testing Dimensionality and Invariance Across Age, Gender, Race, and Ethnicity. AB - This study examined key assumptions underlying the interpretation of one of the most widely used multidimensional nonverbal tests of intelligence, the Universal Nonverbal Intelligence Test-Second Edition (UNIT2). Specifically, we examined the dimensionality of the UNIT2 and the interpretive relevance of its factors. We also examined the invariance of constructs measured by the UNIT2 across age groups, gender, race, and ethnicity. Structural analyses were conducted using data from 1,802 individuals aged 5 to 21 years who participated in the norming of the UNIT2. Results indicate that the UNIT2 is primarily a measure of psychometric g. Tests of invariance indicate that the factors measured by the UNIT2 are calibrated differently across age, gender, and racial groups. The Memory, Quantitative, and Reasoning factors represent psychometric g quite well. However, there is insufficient unique, reliable variance for the interpretation of the index scores reflecting the Memory, Quantitative, and Reasoning factors. Based on the results of this study, we question whether the administration of multidimensional nonverbal tests of intelligence is worth the time and effort when unidimensional tests may provide the same information. PMID- 29998743 TI - The effectiveness of psychological interventions with adoptive parents on adopted children and adolescents' outcomes: A systematic review. AB - Adopted children and adolescents are at an increased risk of experiencing emotional, behavioural and relational difficulties compared to their non-adopted peers. This systematic review aimed to establish the effectiveness of interventions with adoptive parents on adopted children and adolescents' psychological well-being, behavioural functioning and parent-child relationship. A systematic search was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), including studies that assessed the effects of interventions with adoptive parents on adopted child and adolescent outcomes. Electronic databases, key journals, grey literature sources, reference and citation lists were searched and published authors in the field were contacted; 19 papers describing 15 interventions were included. The findings from this review provide preliminary support for the use of interventions with adoptive parents for improving adopted children's emotional and behavioural outcomes. However, overall, the studies were found to have a high risk of bias, and the significant heterogeneity across the studies limits the conclusions that can be drawn. Further research is required to provide conclusive recommendations regarding the effectiveness of interventions with adoptive parents on the outcomes of adopted children. PMID- 29998745 TI - Osteochondritis Dissecans in the Knee of Skeletally Immature Patients: Rates of Persistent Pain, Osteoarthritis, and Arthroplasty at Mean 14-Years' Follow-Up. AB - Objective Osteochondritis dissecans (OCD) is a knee disorder of predominately pediatric populations. Because of low incidence, it has traditionally been difficult to study OCD. The purpose of this study was to report long-term outcomes of skeletally immature OCD lesions and determine risk factors for persistent knee pain at final follow-up. Design A geographic database of more than 500,000 patients was reviewed to identify patients with knee OCD. Clinical course including operative management, persistent knee pain, and total knee arthroplasty (TKA) were analyzed through review of radiographs, magnetic resonance images, and physician notes. Results A total of 95 skeletally immature patients (70 male, 25 female, mean age 12.5 +/- 2.0 years) were followed for a mean of 14 years (range, 2-40 years). Fifty-three patients were treated operatively and 42 were treated nonoperatively. At final follow-up, 13 patients noted persistent knee pain, 8 treated operatively versus 5 treated nonoperatively. Risk factors for knee pain were female gender, patellar lesions, and unstable lesions. Four patients (8%) treated operatively and 2 patients (5%) treated nonoperatively developed symptomatic osteoarthritis at a mean of 28.6 years following diagnosis. Three patients underwent TKA at a mean age of 52 years, significantly younger than that observed for primary TKA at our institution ( P = 0.004). Conclusions Skeletally immature OCD patients have promising histories, with an estimated 14% risk of persistent knee pain, 6% symptomatic osteoarthritis, and 3% conversion to TKA at 14 years' mean follow-up. Females, patellar lesions, and unstable lesions demonstrated increased persistent knee pain risk. Patients with OCD undergo TKA at a significantly younger age than the general population. PMID- 29998744 TI - Nondestructive Assessment of Articular Cartilage Electromechanical Properties after Osteochondral Autologous and Allogeneic Transplantation in a Goat Model. AB - Objective To determine the applicability of a minimally invasive diagnostic device to evaluate the quality of articular cartilage following autologous (OAT) and allogeneic (OCA) osteochondral graft transplantation in goat model. Design OAT grafts were harvested from lateral femoral condyles (LFCs) and transplanted into osteochondral defects created in medial femoral condyles (MFCs) of contralateral knees. OCA grafts were transplanted into MFC condyles after in vitro storage. Autologous platelet-rich plasma (PRP) was administered intraarticularly after the surgery and at 1 and 2 months postoperatively. OAT and OCA grafts were evaluated macroscopically (Oswestry arthroscopy score [OAS]), electromechanically (quantitative parameter, QP), and histologically (O'Driscoll score, safranin O staining intensity) at 3 and 6 months after transplantation. Results were compared with preoperative graft evaluation. Results Transplanted cartilage deteriorated within 6 months in all groups. Cartilage quality was better retained in OAT group compared with a decline in OCA group. QP and OAS scores were comparable in OAT and OCA groups at 3 months, but superior in OAT group at 6 months, according to all the methods applied. PRP injections significantly improved QP and OAS score at 6 months compared with 3 months in OAT group. QP moderately correlated with OAS, O'Driscoll score, and safranin O staining intensity. Conclusions Grafts did not retain preoperative quality parameters at 6 months follow-up; however, OAT were superior to OCA grafts. PRP may have a beneficial effect on macroscopic and electromechanical properties of cartilage; however, histological improvement is yet to be proved. Electromechanical diagnostic device enables reliable assessment of transplanted cartilage. PMID- 29998746 TI - The Consequences of Crime in Company: Co-Offending, Victim-Offender Relationship, and Quality of Violence. AB - Peers influence offending, both directly through co-offending and indirectly through information and advice. Despite such findings, there has been only limited research into the ways in which the presence of other offenders (i.e., accomplices) may impact criminal behavior, especially violence. Drawing on research on small group behavior, this study explores the relationship between the presence of co-offenders and offense severity, focusing on weapon use and victim injury. More specifically, this research hypothesizes that, owing to a diffusion of responsibility and other group processes, crimes committed by groups are more severe than crimes committed by a single offender and that crimes committed by large co-offending groups are particularly severe. This research also proposes that anonymity is an important mechanism behind this relationship and tests the hypothesis that the relationship between groups and offense severity varies according to the victim-offender relationship. Using National Incident-Based Reporting System (NIBRS) data, the results indicate that (a) offenses committed by groups of offenders are more likely than offenses committed by a single offender to be severe (i.e., involve a weapon, result in injury); (b) as the size of the co-offending group increases, the likelihood of offense severity also increases; and PMID- 29998747 TI - Gerald Klatskin (1910-1986): A pioneer in hepato-biliary disorders and biopsy techniques. AB - The widespread use of liver biopsies underscores its utility and significance within the field of medicine. Dr. Gerald Klatskin's pioneering work on liver biopsy techniques, as well as his study of liver histopathology, paved the way for its diagnostic and therapeutic applications around the world. His attention to detail as well as meticulous account of hilar cholangiocarcinoma has had a lasting impact on the medical community. Eponymously, the tumor was named after him-Klatskin's tumor. Klatskin was also well known and respected for his commitment and devotion to his fellows who themselves went on to hold prestigious academic positions and make significant contributions of their own. The life and work of Klatskin documents a pioneering hepatologist and devoted teacher. PMID- 29998748 TI - Clinical feature and visual prognosis of acute retinal necrosis according to the initially involved zone and extent: 10-year experience. AB - PURPOSE: We aimed to analyze the visual prognosis and clinical characteristics of acute retinal necrosis according to the initially involved zone and extent. STUDY DESIGN: Retrospective, consecutive, cross-sectional study. METHODS: We retrospectively reviewed acute retinal necrosis patients who were treated with systemic antiviral treatment, and assessed the visual prognosis of acute retinal necrosis following antiviral treatment based on the initially involved zone and the extent of acute retinal necrosis at the time of diagnosis. Moreover, we evaluated whether prophylactic laser photocoagulation had preventive effects on retinal detachment. RESULTS: A total of 43 eyes from 35 patients with acute retinal necrosis were included. Eyes with zone I involvement/extensive retinal lesions showed poor visual prognosis (logMAR: 1.17 +/- 0.97 vs 0.49 +/- 0.81; p = 0.014) and a higher incidence of retinal detachment (9/30 (30.0%) vs 0/13 (0%); p = 0.039) after treatment. Retinal detachment was observed in 20.9% of cases, and its incidence was significantly lower in eyes that had undergone prophylactic laser photocoagulation. CONCLUSION: The overall visual prognosis of acute retinal necrosis is poor and can be determined at the time of diagnosis. Prophylactic laser photocoagulation exhibits preventive effects with regard to the development of retinal detachment. Therefore, laser photocoagulation should be actively considered in eyes with extensive retinal lesions to prevent retinal detachment and thus eventually improve the overall visual prognosis of acute retinal necrosis. PMID- 29998749 TI - Oskar Kobylinski (1856-1926) and the first description of Noonan syndrome in the medical literature. AB - While a student of University in Dorpat (now Tartu, Estonia) Oskar Kobylinski published an article reporting on his 22-year-old patient Leisar Eischikmann, who suffered from a congenital deformity of the neck. Kobylinski described this rare anomaly and called it "flughautige Verbreitung des Halses" (wing-like extension of the neck). It was only in 1902 when the name pterygium colli was introduced, and it has been in use ever since. This malformation is part of some congenital syndromes, most prominently, Turner syndrome and, more rarely, of Noonan syndrome. As Opitz et al. pointed out, the patient described in the 1883 article from Archiv fur Anthropologie is probably the first person with Noonan syndrome to have been pictured in the medical literature. The article was signed only by "O. v. Kobylinski, student of medicine." Further archival research was needed to identify this physician and provide more details about his unusual career. PMID- 29998750 TI - Interpretation of Retrospective BG Measurements. AB - BACKGROUND: This study investigates blood glucose (BG) measurement interpolation techniques to represent intermediate BG dynamics, and the effect resampling of retrospective BG data has on key glycemic control (GC) performance results. GC protocols in the ICU have varying BG measurement intervals ranging from 0.5 to 4 hours. Sparse data pose problems, particularly in comparing GC performance or model fitting, and thus interpolation is required. METHODS: Retrospective data from SPRINT in Christchurch Hospital Intensive Care Unit (ICU) (2005-2007) were used to analyze several interpolation techniques. Piecewise linear, spline, and cubic interpolation functions, which force interpolation through measured data, as well as 1st and 2nd Order B-spline basis functions, are used to identify the interpolated trace. Dense data were thinned to increase sparsity and obtain measurements (Hidden Measurements) for comparison after interpolation. Performance is assessed based on error in capturing hidden measurements. Finally, the effect of minutely versus hourly sampling of the interpolated trace on key GC performance statistics was investigated using retrospective data received from STAR GC in Christchurch Hospital ICU, New Zealand (2011-2015). RESULTS: All of the piecewise functions performed considerably better than the fitted interpolation functions. Linear piecewise interpolation performed the best having a mean RMSE 0.39 mmol/L, within 2 standard deviations of the BG sensor error. Minutely sampled BG resulted in significantly different key GC performance values when compared to raw sparse BG measurements. CONCLUSION: Linear piecewise interpolation provides the best estimate of intermediate BG dynamics and all analyses comparing GC protocol performance should use minutely linearly interpolated BG data. PMID- 29998751 TI - Exposure to Family and Friend Homicide in a Nationally Representative Sample of Youth. AB - This study examines the lifetime prevalence and distribution of family/friend homicide exposure among children and adolescents age 2 to 17 in the United States, and assesses the impact of family/friend homicide on emotional and behavioral outcomes, while controlling for potential co-occurring factors. Data were collected by telephone about the experiences of youth in 2008, 2011, or 2014, as part of the National Surveys of Children's Exposure to Violence (NatSCEV). Analyses are based on a pooled sample ( n =11,771) from these three surveys. Approximately 8% of all children and youth ages 2 to 17 were exposed to a family/friend homicide. Older adolescents, Black youth, those living in single parent and nonparent family households, those from lower socioeconomic status households, and youth living in large cities were overrepresented among youth experiencing family or friend homicide. Exposed youth were also substantially more likely to be poly-victims, experience other major adversities, and live in neighborhoods with more community disorder. Exposure to family/friend homicide was significantly related to trauma symptoms. However, when other co-occurring factors were taken into account, only family/friend homicide that occurred within the last 2 years remained significant. With respect to delinquency, only nonfamily homicide exposure remained significant with these other factors controlled. Findings suggest that family/friend homicide represents a powerful marker for a broad level of victimization risk and adversity, demonstrating that family/friend murder is often just one relatively small part of a more complicated life of adversity. Although recent exposure is certainly distressing to youth, it is the wider, co-occurring context of poly-victimization and other types of adversity that appears most impactful in the longer term. PMID- 29998752 TI - Philip Harker Newman (1911-1994): Dunkirk hero, war psychologist and orthopaedic surgeon to Sir Winston Churchill. AB - Philip Harker Newman an orthopaedic surgeon and a major in the Royal Army Medical Corps was left behind to man a casualty clearing station during the evacuation of Dunkrik in 1940. Newman was made a Prisoner of War and studied the adverse psychological effects of incarceration on his fellow officers. He escaped from Germany eventually returning to Europe for its liberation in 1944. He was awarded the Distinguished Service Order and Military Cross for his bravery. In 1946, Philip Newman was appointed consultant orthopaedic surgeon to The Middlesex Hospital and The Royal National orthopaedic Hospital, London. He became an internationally recognised authority on the management of spinal conditions including spondylolisthesis. In 1962, he operated with Sir Herbert Seddon (1903 1977) on Sir Winston Churchill who had sustained a fractured neck of femur following a fall in the South of France. Newman became President of The British Orthopaedic Association in 1976 and chairman of the Editorial Board of The Journal of Bone and Joint Surgery. In 1976, he was also awarded a CBE and wrote his wartime memoirs, Safer than a Known Way published in 1983. PMID- 29998753 TI - Overcoming Stigma and Discrimination: Challenges for Reinsertion of Gang Members in Developing Countries. AB - This article is an effort to better understand the discrimination mechanisms that ex-gang members perceive upon leaving the gang and seeking to reinsert themselves into a society marked by high levels of violence and inequality, as in Central America. Based on 24 in-depth interviews with former members of MS-13, the 18th Street gang, and other street gangs in El Salvador, this article analyzes the different mechanisms of discrimination perceived by respondents as a result of the stigma of past gang membership. This article also documents how these perceptions of discrimination can affect individuals who are searching for employment opportunities and seeking to reinsert themselves into society. PMID- 29998755 TI - A Comparative Study of Totalitarian Style Partner Control in Seoul and Beijing: Confucian Sex Role Norms, Secrecy, and Missing Data. AB - Totalitarian style partner control is seldom studied apart from intimate partner violence (IPV) independently as an outcome. This article uses a comparative study of Beijing and Seoul to begin to address this gap in the research. We collected three-stage probability proportional to size cluster samples of married/partnered women from Beijing ( n = 301) and Seoul ( n = 459), using refusal conversion to keep response rates high. We hypothesized (1) totalitarian style partner control will be positively associated with Confucian sex role norms at the (a) individual and (b) neighborhood levels, (2) totalitarian style partner control will be positively associated with IPV secrecy at the (a) individual and (b) neighborhood levels, and (3) totalitarian style partner control will be positively associated with the need for refusal conversion. Mixed effects (multilevel) regression models supported all three hypotheses at the individual level. Surprisingly, neighborhood socioeconomic status was positively associated with totalitarian style partner control. The combined data conceal important differences between Beijing and Seoul. The rate of totalitarian style partner control is more than 5 times higher in Seoul, and Confucian sex role norms, at both the individual and neighborhood levels, predict totalitarian style control there. Based on our findings, we infer that cultural emphases on face may play very different roles in the etiology of totalitarian partner control in the two cities. PMID- 29998756 TI - Intimate Partner Violence Victimization and Perpetration in a Turkish Female Sample: Rejection Sensitivity and Hostility. AB - Intimate partner violence (IPV) against women is one of the most alarming social problems all over the world. Recently, IPV research focuses on the bidirectional nature of the phenomenon, which underlines that both women and men can equally be victims and perpetrators of IPV, especially in community samples. The cycle of violence theory asserts that child abuse and neglect (CAN) is a vulnerability factor for being both a victim and perpetrator of IPV while developmental mechanisms perspective assesses mediators explaining this association. The purpose of the current study was to investigate whether CAN and each type of CAN (emotional maltreatment, physical abuse and neglect, and sexual abuse) would be associated with victimization of and perpetration by women via the multiple mediator roles of rejection sensitivity and hostility after controlling for co occurring CAN types. The sample ( N = 288) included Turkish women who were currently married or in a romantic relationship or in one of these statutes in the past year. Participants were recruited via online survey to fill out the related questionnaires. The results of Bootstrap analyses showed that the total CAN scores were associated with being a victim and perpetrator of IPV in the past year. Rejection sensitivity mediated the association between CAN and being a victim of IPV while hostility was a mediator between CAN and perpetration of IPV. Childhood emotional maltreatment (CEM) was the only trauma type which predicted victimization by rejection sensitivity and perpetration by hostility above and beyond the effects of co-occurring trauma types. The present study findings contributed to the growing literature that women exposed to childhood traumas can also be perpetrators of violence that was a demonstrated risk factor for the repeated victimization. Results implied that developmental and process variables should be taken into account rather than a strict gendered analysis of IPV in research and clinical practice. PMID- 29998757 TI - Perioperative Pain Control in Upper Extremity Surgery: Prescribing Patterns, Recent Developments, and Opioid-Sparing Treatment Strategies. AB - BACKGROUND: Perioperative pain management in hand and upper extremity surgery has become increasingly challenging following recent efforts to accelerate postoperative recovery, decrease length of stay, and maximize the number and complexity of surgical interventions provided in an ambulatory setting. This issue has been further complicated by the growing opioid epidemic in the United States and increasing insights into its detrimental effects on society. Practicing hand surgeons must acknowledge this ongoing public health crisis and adapt their clinical practices to minimize and optimize distribution of prescription opioids. METHODS/RESULTS: This review outlines current opioid prescribing patterns, recent developments, and treatment strategies designed to maintain effective perioperative analgesia in orthopedic upper extremity surgery while minimizing opioid delivery available for diversion, misuse, and abuse. CONCLUSIONS: The authors advise hand surgeons to utilize the strategies discussed in this review to assist in forming a unique, patient-specific postoperative analgesic regimen. PMID- 29998754 TI - Artificial Pancreas: Clinical Study in Latin America Without Premeal Insulin Boluses. AB - BACKGROUND: Emerging therapies such as closed-loop (CL) glucose control, also known as artificial pancreas (AP) systems, have shown significant improvement in type 1 diabetes mellitus (T1DM) management. However, demanding patient intervention is still required, particularly at meal times. To reduce treatment burden, the automatic regulation of glucose (ARG) algorithm mitigates postprandial glucose excursions without feedforward insulin boluses. This work assesses feasibility of this new strategy in a clinical trial. METHODS: A 36-hour pilot study was performed on five T1DM subjects to validate the ARG algorithm. Subjects wore a subcutaneous continuous glucose monitor (CGM) and an insulin pump. Insulin delivery was solely commanded by the ARG algorithm, without premeal insulin boluses. This was the first clinical trial in Latin America to validate an AP controller. RESULTS: For the total 36-hour period, results were as follows: average time of CGM readings in range 70-250 mg/dl: 88.6%, in range 70-180 mg/dl: 74.7%, <70 mg/dl: 5.8%, and <50 mg/dl: 0.8%. Results improved analyzing the final 15-hour period of this trial. In that case, the time spent in range was 70-250 mg/dl: 94.7%, in range 70-180 mg/dl: 82.6%, <70 mg/dl: 4.1%, and <50 mg/dl: 0.2%. During the last night the time spent in range was 70-250 mg/dl: 95%, in range 70 180 mg/dl: 87.7%, <70 mg/dl: 5.0%, and <50 mg/dl: 0.0%. No severe hypoglycemia occurred. No serious adverse events were reported. CONCLUSIONS: The ARG algorithm was successfully validated in a pilot clinical trial, encouraging further tests with a larger number of patients and in outpatient settings. PMID- 29998758 TI - Toward longitudinal studies of hemodynamically induced vessel wall remodeling. AB - INTRODUCTION:: Autogenous arteriovenous fistula is the preferred vascular access for hemodialysis, but it has high rates of non-maturation and early failure due to vascular stenosis. Convincing evidence supports a key role of local hemodynamics in vascular remodeling, suggesting that unsteady and disturbed flow conditions may be related to stenosis formation in arteriovenous fistula. The purpose of our study was to explore the feasibility of coupling contrast-free magnetic resonance imaging and computational fluid dynamics in longitudinal studies to identify the role of local hemodynamic changes over time in inducing vessel wall remodeling in arteriovenous fistula. METHODS:: We acquired contrast free magnetic resonance imaging of arm vasculature at 1 week and 6 weeks after arteriovenous fistula creation in a 72-year-old patient. We then generated three dimensional models and evaluated lumen cross-sectional area of arteriovenous fistula limbs. We performed high-resolution computational fluid dynamics to evaluate changes in local hemodynamics over time. RESULTS:: Our contrast-free magnetic resonance imaging protocol provided good quality images in a short scan duration. We observed a homogeneous dilatation in the proximal artery, while there was a more pronounced lumen dilatation in the venous outflow as compared to a limited dilatation in the juxta-anastomotic vein. Furthermore, we observed a slight stabilization of the flow pattern over time, suggesting that vascular outward remodeling accommodates the flow to a more helicoidally phenotype. CONCLUSION:: Coupling contrast-free magnetic resonance imaging and high resolution computational fluid dynamics represents a promising approach to shed more light in the mechanisms of vascular remodeling and can be used for prospective clinical investigations aimed at identifying critical hemodynamic factors contributing to arteriovenous fistula failure. PMID- 29998759 TI - The Safety and Benefits of the Semisterile Technique for Closed Reduction and Percutaneous Pinning of Pediatric Upper Extremity Fractures. AB - BACKGROUND: Closed reduction and percutaneous pinning (CRPP) is traditionally performed following full surgical prep and draping. The semisterile technique utilizes minimal prep and draping, which was proven to be a viable alternative when treating pediatric supracondylar humerus fractures. The purpose of this study was to investigate the safety and benefits of the semisterile technique for CRPP of pediatric upper extremity fractures. METHODS: A retrospective cohort study was conducted of pediatric patients who underwent CRPP of an upper extremity fracture over a 4-year period. Demographic data, fracture type/location, and the type of prep technique (full-prep vs semisterile) were recorded. Qualities of intraoperative care were assessed, and postoperative care parameters were compared. Patient outcomes for the 2 techniques were compared using bivariate analyses. RESULTS: In total, 219 patient records were reviewed including 160 in the semisterile group and 59 in the full-prep group. When comparing intraoperative parameters between the full-prep and semisterile techniques, the average room setup time was similar (20.6 vs 18.8 minutes, P = .52). However, the procedure times (32.1 vs 26.9 minutes, P = .04) were significantly shorter in the semisterile group. Nearly a 10-minute decrease in total time in the operating room was present while utilizing the semisterile technique (62.8 vs 53.6 minutes, P < .01). There were no statistical differences in complication rates between prep groups ( P = .31), and there were no infections while utilizing the semisterile technique. CONCLUSIONS: The semisterile technique is a safe and efficient alternative that may be used when performing CRPP of pediatric upper extremity fractures. PMID- 29998760 TI - First User Experiences With a Novel Touchscreen-Based Insulin Pump System in Daily Life of Patients With Type 1 Diabetes Experienced in Insulin Pump Therapy. AB - INTRODUCTION: A new insulin pump system was tested under everyday conditions for user evaluation and safety assessment prior to its launch in Europe. This insulin pump is focused on easy handling and uses prefilled cartridges. METHODS: The pump system was used by 35 adult subjects with type 1 diabetes, experienced in insulin pump therapy, under everyday conditions for approximately one month each. All subjects rated various aspects of the system after home use; technical issues and safety parameters were assessed throughout the study. RESULTS: All 35 subjects completed the study as planned and used the system for a total of 1013 days. After home use, 74% of the subjects were very satisfied or quite satisfied with the new pump. The subjects confirmed that the system is easy to use, especially considering general handling, bolus delivery and basal rate settings, infusion set, and cartridge change. Potential for improvements was seen in the touchscreen, warnings and alarms, the blind bolus function, the availability of a bolus calculator (was not available at time of study), and the cartridge size as rated by the study participants. Safety analysis did not raise any concerns for the use of this system. CONCLUSION: The majority of the users testing the system were satisfied with the novel insulin pump system and the system was safe for use under everyday conditions by this study population. PMID- 29998761 TI - Male-on-Female Sexual Homicides in Sweden, 1990 to 2013: A Population-Based Controlled Study of Incidents, Victims, and Offenders. AB - To date, systematic studies of sexual homicides from Europe are scarce, in which none have been conducted in Sweden. This study aims to describe male-on-female sexual homicides in Sweden and differentiate from corresponding nonsexual homicides. Unsolved and solved sexual homicide ( n = 33) cases were identified in a database containing all homicides in Sweden between 1990 and 2013 ( N = 2,126), and subsequently data from forensic psychiatric evaluations were collected for convicted offenders. Male-on-female sexual homicides constituted 1.6% of all homicides and the clearance rate was 82%, which is comparable with the 83% overall clearance rate but took longer time to solve. Three factors differentiated sexual from nonsexual homicides: strangulation, younger age of the victim, and the absence of eyewitnesses. In solved cases, distance from the offender's home to the crime scene was strongly correlated with time to clearance. A majority of the offenders suffered from personality disorders, while other diagnoses were uncommon. PMID- 29998762 TI - The Process of Adjusting to Divorce After Leaving Violent Marriages: A Case Study of Iranian Women. AB - Despite growing international attention to Intimate Partner Violence (IPV), there is little systemic information available regarding the process of adjusting to divorce after leaving violent marriages among Iranian women. Despite the strong religious discouragement and social stigma associated with divorce in Iran, divorce has always been recognized as a possible outcome of marriage. This qualitative study was conducted to understand the process that nine Iranian women who left violent marriages went through after divorce. The data came from two interviews with each participant and interviewer's notes that were taken during the interview. The data were analyzed using phenomenology and themes related to adjusting to divorce after experiencing IPV were identified. The process of adjusting to divorce seemed to occur in phases, that is, "initial experience after divorce," "searching for stability/challenges/resources," and "the process of developing new identity but still not being at peace." Each phase consists of subthemes and boundaries between these phases were fluid and adjustment was an ongoing process. This process was a journey for these Iranian IPV victims, which was dependent on their financial situation, emotional support, having a child or not, and their psychological health. These findings can help Iranian women who are in the process of adjustment to divorce to make sense of their experience. Also, findings provide a framework for researchers and clinicians in their work with female survivors of violent marriages. By testing these findings, researchers will be able to develop a theory regarding healing and disentanglement process. Clinicians need to understand the role of internalized stigma and how they can help their clients who are seeking to adjust after leaving violent marriages in Iran to reduce internalized stigma of divorce and challenge some of negative cultural beliefs against divorced women. Implications and suggestions for future research and clinicians are provided. PMID- 29998763 TI - Pressure difference between radial and femoral artery pressure in minimally invasive cardiac surgery using retrograde perfusion. AB - OBJECTIVE: To investigate whether radial artery pressure is a reliable surrogate measure of central arterial pressure as approximated by femoral artery pressure in minimally invasive cardiac surgery with retrograde perfusion via femoral cannulation. METHOD: Fifty-two consecutive patients undergoing minimally invasive cardiac surgery were prospectively included in this study. Cardiopulmonary bypass was established via a femoral artery cannulation and femoral vein. Radial and femoral arterial pressures were recorded continuously, and the pressure differential between them was calculated for both systolic and mean arterial pressures. The agreement between measurements from the two arteries was compared using Bland-Altman plots. An interval of 95% limits of agreement of less than 20 mm Hg was set as satisfactory agreement. RESULTS: Average age was 65 +/- 14 years. With respect to systolic arterial pressure, 28 patients (54%) had a peak pressure differential between radial and femoral arteries ?20 mm Hg. With respect to mean arterial pressure, only five patients (9%) had a peak pressure differential ?20 mm Hg. The pressure differential changed with time. Pressure differential in systolic arterial pressure was 5 +/- 8 mm Hg until aortic declamping, then increased to a peak of 23 +/- 16 mm Hg when cardiopulmonary bypass was turned off. The femoral systolic arterial pressures were significantly greater than radial systolic arterial pressures from time of aortic declamping to 20 min after cardiopulmonary bypass. The Bland-Altman plots revealed large biases and poor agreement in this period. CONCLUSION: Radial and femoral systolic artery pressure readings can differ significantly in minimally invasive cardiac surgery with retrograde perfusion. Intraoperative arterial pressure management based solely on radial systolic arterial pressure readings should be avoided. PMID- 29998764 TI - Neural precursor cell-expressed developmentally down-regulated 4-like: a new biomarker in the pathophysiology of endometrial cancer. AB - Objectives Endometrial cancer is the most frequent tumor of the female genital tract. Ubiquitin is a small protein (8.5 kDa) found in all eukaryotic cells, binds to substrate proteins via a three-phase enzymatic pathway referred to as ubiquitination and plays an important role in cellular stability. Neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) functions in the last phase of this enzymatic process. In this study, we investigated NEDD4L protein expression in endometrial cancer. Methods The study participants were divided into patients with benign endometrial pathologies (Group 1, n = 23), patients with endometrial hyperplasia (Group 2, n = 21) and patients with endometrial cancer (Group 3, n = 20). NEDD4L expression was detected by immunohistochemical staining and H scores were calculated to standardize staining intensity. Statistical analysis was performed using SPSS 16.0. Results NEDD4L expression levels according to H scores were significantly lower in patients diagnosed with endometrial cancer compared with those with benign endometrial pathologies. Conclusion NEDD4L is involved in maintaining cell stability, and reduced NEDD4L expression as a result of gene mutation may disrupt this balance in favor of tumorigenesis. PMID- 29998765 TI - Strategies to Improve Information Transfer for Multitrauma Patients. AB - The aim of this multiphase mixed-method study was to improve access, flow, and consistency of information transfer for multitrauma patients leaving the Emergency Department. Methods included literature review, focus group interviews, chart audits, staff surveys, and a review of international trauma forms to inform an intervention developed with a researcher-led, clinician stakeholder group. Analysis included descriptive and inferential statistics. Baseline data revealed variability existed in patient-care documentation, showing little standardization. Improvement strategies implemented included a gold standard for information embedded in handover tools, raising staff awareness of complexities for information transfer. Improvement was seen in communication between wards coordinating transfer, improved documentation, decreased information duplication, improved legibility, and increased ease and efficiency in navigating to key information. Improvement in communication at patient transition is essential to continuity of safe, effective care, and is impacted by complex interactions between multiple factors. Difficulty increases for patients with high acuity. PMID- 29998766 TI - Selection of surgical intervention for congenital dacryocystocele. AB - PURPOSE: To evaluate the surgical intervention and its effect on congenital dacryocystocele. METHODS: A total of 531 children with congenital dacryocystocele admitted to the Department of Ophthalmology of Beijing Children's Hospital, Shanghai Aier Eye Hospital, Nanjing Aier Eye Hospital, and the First Affiliated Hospital of Jinzhou Medical University between January 2007 and January 2017 were retrospectively analyzed. RESULTS: A total of 531 patients were followed up for 3 24 months, with an average of 13.3 months. No serious intraoperative complications (such as bleeding and tissue damage) and postoperative complications (bleeding, infection, and hole atresia) were found. We classified the outcomes into three categories based on the signs (overflowing tears and empyema) and objective routine follow-up by endoscopy. Cure indicated that mass, overflow of tears, and breathing difficulties disappeared, and 81.5% cases (433/531) were postoperatively cured. Improvement indicated disappearance of mass, overflow empyema, and the presence of residual tears (due to trocar and tears puncture), and 18.5% cases (98/531) were postoperatively improved. Unhealed indicated overflowing pus and tears, and 0% cases did not heal after surgery. CONCLUSIONS: Nasal endoscopic surgery is relatively safe, with high success rate for treatment of congenital dacryocystocele. Systematic training is required to promote the application of nasal endoscopy, so that more ophthalmologists can learn this technique. PMID- 29998767 TI - The RELIEF study: Tolerability and efficacy of preservative-free latanoprost in the treatment of glaucoma or ocular hypertension. AB - PURPOSE: To assess tolerability and efficacy following a switch from benzalkonium chloride-latanoprost to preservative-free latanoprost in patients with glaucoma or ocular hypertension. METHODS: A total of 140 patients with glaucoma or ocular hypertension controlled with benzalkonium chloride-latanoprost for at least 3 months were switched to treatment with preservative-free latanoprost. Assessments were made on days 15, 45, and 90 (D15, D45, and D90) and included best-corrected visual acuity, intraocular pressure, slit lamp examination, fluorescein staining, tear film break-up time, patient symptom evaluation, and subjective estimation of tolerability. RESULTS: Mean best-corrected visual acuity remained unchanged during the study. Mean intraocular pressure compared with baseline (D0) remained stable throughout the study (D0, 15.9 mmHg (standard deviation = 2.6); D90, 15.3 mmHg (standard deviation = 2.4); p < 0.006). Tear film break-up time improved or remained unchanged relative to baseline in 92% of patients at D45 and in 93% at D90. Moderate-to-severe conjunctival hyperemia was seen in 56.8% of patients at D0, but this figure decreased to 13.7%, 2.2%, and 1.6% at D15, D45, and D90, respectively. Subjective assessment of tolerability (0-10 scale) indicated improvement with change of therapy (mean score: 5.3 (standard deviation = 2.2) at D0 versus 1.9 (standard deviation = 1.7) at D90; p < 0.0001). CONCLUSION: Preservative-free latanoprost has at least the same intraocular pressure-lowering efficacy as benzalkonium chloride-latanoprost, with a better tolerability profile. This may translate into greater control of treatment and improved quality of life. PMID- 29998768 TI - Manufacturing, oxidation, mechanical properties and clinical performance of highly cross-linked polyethylene in total hip arthroplasty. AB - Ultra-high molecular weight polyethylene (UHMWPE) continues to be the gold standard bearing surface in total hip arthroplasty (THA) for nearly 5 decades. Highly cross-linked UHMWPE (HXLPE) was adapted for routine use in the early 2000s to reduce the revision rates related to wear, osteolysis, and aseptic loosening resulting from conventional UHMWPE wear. Since its inception, consistent evidence showing reduced wear rates and osteolysis supports the use of HXLPE in THA. High quality studies demonstrating the advantage in long term survivorship of HXLPE over conventional UHMWPE are emerging. Though retrieval studies have demonstrated evidence of in vivo oxidation and fatigue related damage at the rim of the first generation HXLPE liners, clinical significance of this remains to be seen. Second generation sequentially annealed and vitamin E containing HXLPE liners demonstrate improved mechanical properties, resistance to oxidation, and equivalent wear rates in comparison to their first-generation counterparts, but long term success remains to be seen. PMID- 29998769 TI - MDCKpred: a web-tool to calculate MDCK permeability coefficient of small molecule using membrane-interaction chemical features. AB - Structure-based models to understand the transport of small molecules through biological membrane can be developed by enumerating intermolecular interactions of the small molecule with a biological membrane, usually a dimyristoylphosphatidylcholine (DMPC) monolayer. This ADME (absorption, distribution, metabolism, and excretion) property based on Madin-Darby Canine Kidney (MDCK) cell line demonstrates intestinal drug absorption of small molecules and correlated to human intestinal absorption which acts as a determining factor to forecast small-molecule prioritization in drug-discovery projects. We present here the development of MDCKpred web-tool which calculates MDCK permeability coefficient of small molecule based on the regression model, developed using membrane-interaction chemical features. The web-tool allows users to calculate the MDCK permeability coefficient (nm/s) instantly by providing simple descriptor inputs. The chemical-interaction features are derived from different parts of the DMPC molecule viz. head, middle, and tail regions and accounts overall intermolecular contacts of the small molecule when passively diffused through the phospholipid-rich biological membrane. The MDCKpred model is both internally (R2 = .76; [Formula: see text]= .68; Rtrain = .87; Rtest = .69) and externally (Rext = .55) validated. Furthermore, we used natural molecules as application examples to demonstrate its utility in lead exploration and optimization projects. The MDCKpred web-tool can be accessed freely at http://www.mdckpred.in . This web-tool is designed to offer an intuitive way of prioritizing small molecules based on calculated MDCK permeabilities. PMID- 29998770 TI - A Randomized Controlled Study of a Cognitive Behavioral Planning Intervention for College Students With ADHD: An Effectiveness Study in Student Counseling Services in Flanders. AB - OBJECTIVE: The effectiveness of a short (six session) individual cognitive behavioral planning intervention for college students with attention deficit/hyperactivity disorder (ADHD) was tested. METHOD: In three student counseling services in Flanders, individuals with ADHD ( N = 58) were randomized to the intervention or waitlist condition. Pre- and posttreatment assessments were conducted, and within the intervention group, a 4-month follow-up was conducted. Primary outcomes were ADHD symptoms and study skills; secondary outcomes were comorbid symptoms and planning skills on a neuropsychological task. RESULTS: Intent-to-treat analyses showed a significant interaction on one outcome: inattention symptoms. The treatment condition improved from pretest to posttest, whereas the waitlist did not. Other measures showed large significant time effects (improved skills, reduction of symptoms in both groups) but no interactions. Stability analyses were not possible due to substantial dropout at follow-up. CONCLUSION: Specific treatment effects are on one outcome (inattention) and modest; for further implementation, the treatment needs adaptation. PMID- 29998771 TI - Cardioprotective effects of insulin on carbon monoxide-induced toxicity in male rats. AB - Carbon monoxide (CO) poisoning is a significant cause of death especially in developing countries. The current study investigated cardioprotective effects of insulin in CO-poisoned rats. Male rats were exposed to 3000 ppm CO for 1 h. Insulin (100 and 120 U/kg intraperitoneally) was immediately administered after CO exposure and on the next 4 days, on a daily basis (a total of 5 doses). On day 5, animals were euthanized, and the hearts were harvested for Western blotting and histopathological studies. The electrocardiograms (ECG) were recorded postexposure to CO and after the completion of insulin treatment period. Histopathological evaluations showed reduction of myocardial necrosis in insulin treated animals compared to controls. BAX/BCL2 ratio, as a proapoptotic index, was significantly reduced in treatment groups ( p < 0.01). The ECG findings showed no differences among groups; also, compared to control animals, myocardial Akt levels were not markedly affected by insulin. The current study showed that insulin significantly reduces myocardial necrotic and apoptotic indices in CO poisoned rats. PMID- 29998772 TI - Prospective Evaluation of a Single Corticosteroid Injection in Radial Tunnel Syndrome. AB - BACKGROUND: The role of corticosteroid injections in the treatment of radial tunnel syndrome (RTS) has not been evaluated in depth. The purpose of this study was to evaluate the utility of a single corticosteroid injection as a therapeutic modality for RTS. METHODS: We enrolled 40 patients with a clinical diagnosis of RTS. Our primary outcome was the quick Disabilities of the Arm, Shoulder and Hand (qDASH) score at 1 year. Each patient was then treated with a single corticosteroid injection in the proximal forearm at the posterior interosseous nerve (PIN). Patient follow-up occurred at 2 weeks, 3 months, and 1 year. RESULTS: The cohort had a mean age of 49 years, and 35 patients completed 1 year of follow-up. Outcomes based on qDASH and visual analog scale (VAS) showed significant improvement from baseline, with mean qDASH decreasing from 49.4 +/- 7.0 points to 35.8 +/- 7.5 points ( P = .03) and 28.5 +/- 7.3 points ( P = .01) at 12 and 52 weeks, respectively, and VAS decreasing from 6.0 +/- 0.8 points to 3.4 +/- 0.9 points ( P = .005) and 2.9 +/- 0.8 points ( P = .003) at 12 and 52 weeks, respectively. During the study period, 8 of 35 patients (23%) failed nonoperative treatment and went on to surgical decompression of the PIN. A minimal clinically important difference in qDASH was achieved in 57% of subjects at 1-year follow-up. CONCLUSIONS: Nonoperative management with corticosteroid injection can be used as a therapeutic measure with potential long-term benefits in the treatment of RTS. PMID- 29998773 TI - Patient Loss to Follow-up After Upper Extremity Surgery: A Review of 2563 Cases. AB - BACKGROUND: Postoperative care is essential to optimizing patient outcome. We sought to determine the incidence and associated demographic and surgical factors of postoperative patient loss to follow-up following hand and upper extremity surgery. METHODS: In all, 2834 surgical cases (2467 patients) were retrospectively reviewed. All surgical cases from July 2014 to June 2015 at a single practice with five surgeons were assessed. Charts were reviewed for compliance with postoperative follow-up. Variables were described with proportions and compared using logistic regression analysis. RESULTS: In total, 2563 cases (2388 patients) met the inclusion criteria. Overall loss to follow-up rate was 26%. Patients lost to follow-up based on insurance type were 13% for worker's compensation, 22% for private insurance, 21% for Medicare, 38% for Medicaid, and 44% for self-pay. Patients with expected short-term follow-up were lost at a 23% rate. Expected mid- and long-term follow-up patients were lost at 34% and 20% rates, respectively. Patients below 30 years old were lost to follow up at a 42% rate compared to patients 30 to 64 years old (26%) and greater than or equal to 65 years (13%). Males had a higher rate of loss to follow-up, 32%, compared with females (22%). Patients living greater than 50 miles from our surgery center were lost to follow-up at a rate of 31%, compared with those who lived less than 50 miles (25%). CONCLUSIONS: We have identified demographic variables associated with patients being lost to follow-up after hand and upper extremity surgery. With this knowledge, we hope to develop methods of either improving in-office follow-up rates or discover new avenues to deliver postoperative care. PMID- 29998774 TI - Effect of blade curvature on the hemolytic and hydraulic characteristics of a centrifugal blood pump. AB - AIMS:: Impeller design has a significant impact on the overall performance of a blood pump. In this study, the effect of the blade curvature was investigated by performing in silico and in vitro studies on a recently developed centrifugal blood pump. METHODS:: A computational fluid dynamics study was performed for the flow rates of 3-5 L/min at 2000 r/min. The computational fluid dynamics model was also applied on the US Food and Drug Administration (FDA) benchmark blood pump to validate our computational method. The relative hemolysis index was calculated with the Eulerian hemolysis estimation method for five impellers with the wrap angles ranging from 0 degrees to 240 degrees . Hydraulic experiments were conducted for the validation of computational fluid dynamics results. In addition, the curved-blade impeller (120 degrees ) and the straight-blade impeller (0 degrees ) were evaluated with in vitro hemolysis tests using human blood. RESULTS:: The wrap angle of 120 degrees provided the best hydraulic and hemolytic performance. Pump achieved the physiologic operating pressures and flows with 85-115 mmHg at 2.5-5.9 L/min. Compared to the straight-blade impeller, the 120 degrees model reduces the relative hemolysis index and the plasma-free hemoglobin near 72.8% and 56.7%, respectively. Comparison of in silico and in vitro results indicated the similar trend to the blade curvature. CONCLUSION:: Introducing a blade curvature enhanced the hydrodynamic and hemolytic performance compared to the straight-blade configuration for the investigated centrifugal blood pump. The findings of this study provide new insights into centrifugal blood pump design by examining the influence of the blade curvature. PMID- 29998775 TI - Predictors of red blood cell transfusion and its association with prognosis in patients undergoing extracorporeal membrane oxygenation. AB - PURPOSE: Few data are available on the potential benefits and risks of red blood cell transfusion in patients undergoing extracorporeal membrane oxygenation. The aim of this study was to identify the determinants and prognosis of red blood cell transfusion in patients undergoing extracorporeal membrane oxygenation, with a special focus on biological parameters during extracorporeal membrane oxygenation treatment. METHODS: We conducted a single-center retrospective cohort study including all consecutive patients who underwent extracorporeal membrane oxygenation between January 2010 and December 2015. RESULTS: The 201 evaluated patients received a median of 0.9 [0.5-1.7] units of red blood cell per day. Significant and clinically relevant variables that best correlated with units of red blood cell transfused per day of extracorporeal membrane oxygenation were lower median daily prothrombin time in percentage (Quick) ( t = -0.016, p < 0.0001), higher median daily free bilirubin level ( t = 0.016, p < 0.0001), and lower pH ( t = -2.434, p < 0.0001). In multivariate analysis, red blood cell transfusion was associated with a significantly higher rate of in-intensive care unit mortality (per red blood cell unit increment; adjusted odds ratio: 1.07, 95% confidence interval: 1.02-1.12, p = 0.005). It was also associated with higher rates of acute renal failure ( p = 0.025), thromboembolic complications ( p = 0.0045), and sepsis ( p = 0.015). CONCLUSION: This study suggests that red blood cell transfusion may be associated with a higher mortality rate and with severe complications. However, we cannot conclude a direct causal relationship, as red blood cell transfusion may be only a marker of poor outcome. We recommend that physicians correct acidosis and hemolysis in patients undergoing extracorporeal membrane oxygenation whenever possible. PMID- 29998776 TI - Hospital Vertical Integration Into Subacute Care as a Strategic Response to Value Based Payment Incentives, Market Factors, and Organizational Factors: A Multiple Case Study. AB - This study explores the extent to which payment reform and other factors have motivated hospitals to adopt a vertical integration strategy. Using a multiple case study research design, we completed case studies of 3 US health systems to provide an in-depth perspective into hospital adoption of subacute care vertical integration strategies across multiple types of hospitals and in different health care markets. Three major themes associated with hospital adoption of vertical integration strategies were identified: value-based payment incentives, market factors, and organizational factors. We found evidence that variation in hospital adoption of vertical integration into subacute care strategies occurs in the United States and gained a perspective on the intricacies of how and why hospitals adopt a vertical integration into subacute care strategy. PMID- 29998777 TI - Cautery selection for oculofacial plastic surgery in patients with implantable electronic devices. AB - PURPOSE: To discover oculofacial plastic surgeon practice patterns for cautery selection in the setting of implantable electronic devices and present guidelines based on a review of current literature. METHODS: A 10-Question web-based survey was sent to the email list serve of the American Society of Ophthalmic Plastic and Reconstructive Surgery to determine surgeon cautery preference in the setting of various implantable electronic devices and comfort level with the guidelines for cautery selection in their practice or institution. The relationship between survey questions was assessed for statistical significance using Pearson's Chi square tests. RESULTS: Two hundred ninety-three (41% response rate) surveys were completed and included for analysis. Greater than half of respondents either had no policy (36%) or were unaware of a policy (19%) in their practice or institution regarding cautery selection in patients with a cardiac implantable electronic device. Bipolar cautery was favored for use in patients with a cardiac implantable electronic device (79%-80%) and this number dropped in patients with implantable neurostimulators (30%). Overall, one-third of respondents did not feel comfortable with their practice/institution policy. CONCLUSION: Choices and comfort level among oculofacial plastic surgeons for cautery selection in patients with implantable electronic devices vary considerably, and some choices may increase the risk for interference-related complications. Practice patterns vary significantly in the setting of a neurostimulator or cochlear implant, where interference can cause thermal injury to the brain and implant damage, respectively. Guidelines are proposed for cautery selection in patients with implantable electronic devices undergoing oculofacial plastic surgery. PMID- 29998778 TI - Self-assembly and directed assembly of lipid nanocarriers for prevention of liver fibrosis in obese rats: a comparison with the therapy of bariatric surgery. AB - AIM: Whether the obesity prevention by chemicals or surgeries in already obese patients is the better choice remains controversial. We aimed to compare the effect of orally silibinin-loaded nanocarriers and Roux-en-Y gastric bypass surgery on hepatic fibrosis in high-fat feeding-induced obese rats. METHODOLOGY: The developed nanocarriers included self-emulsifying drug delivery system (SNEDDS) and nanostructured lipid carriers (NLC). RESULTS: A significant decrease in collagen production and lipid droplet formation was observed upon nanosystem and bariatric surgery than the rats treated with silibinin control suspension. Stage 3 fibrosis was present in 33% of the obese rats. This percentage could be minimized to 0% by SNEDDS and NLC. Following oral administration, SNEDDS and NLC resulted in 3.5- and 2.9-fold increase, respectively, in bioavailability compared with the reference suspension. CONCLUSION: Nanomedicine prevention provided a comparable efficiency to ameliorate liver steatosis as Roux-en-Y gastric bypass due to the improvement of silibinin dissolution and gastrointestinal permeation. PMID- 29998779 TI - Nanoparticle crossing of blood-brain barrier: a road to new therapeutic approaches to central nervous system diseases. PMID- 29998780 TI - When Nursing Care and Clinical Trials Coincide: A Qualitative Study of the Views of Nordic Oncology and Hematology Nurses on Ethical Work Challenges. AB - This study investigated the kinds of ethical challenges experienced by nurses in oncology and hematology when nursing care and research overlap in clinical trials, and how the nurses handle such challenges. Individual interviews with 39 nurses from Sweden, Denmark, and Finland indicated that all nurses were positive about research, considering it essential for developing the best care. Ethical challenges exist, however; the most difficult were associated with the end-of life patients, no longer responsive to standard therapy, who eagerly volunteer for cutting-edge drug trials in the hope of gaining therapeutic benefit. Many nurses lacked systematic strategies for addressing such challenges but found support from their nursing colleagues and relied on the research protocols to guide them. PMID- 29998781 TI - Charles Scott Sherrington's origins. AB - James Norton Sherrington who is normally described as the father of Charles Scott Sherrington, winner of the 1932 Nobel Prize for Medicine, died at least eight years before Charles was born. The article discusses whether Charles was born in India of unknown parents or was the illegitimate child of Caleb Rose and Anne Sherrington. PMID- 29998782 TI - Fluorescence of Deep Infiltrating Endometriosis During Laparoscopic Surgery: A Preliminary Report on 6 Cases. AB - BACKGROUND: The standard treatment of rectovaginal deep infiltrating endometriosis nodules (RVDIEN) consists in their surgical removal. RVDIEN are anatomically neovascularized. Indocyanine green (ICG) reveals vascularized structures when becoming fluorescent after exposure to near-infrared (NIR) light. This study aims to evaluate if fluorescence-guided surgery can improve the laparoscopic resection of RVDIEN, thus avoiding a rectal perforation. MATERIALS AND METHODS: Patients with a symptomatic RVDIEN, scheduled for a laparoscopic rectal shaving, were enrolled in the study. Technically, the RVDIEN was targeted and removed with the help of the NIR imager device Image 1 Spies (Karl Storz GmBH & Co KG, Tuttlingen, Germany) or Visera Elite II (Olympus Europe SE & Co KG, Hamburg, Germany), after an intraoperative, intravenous injection of ICG (0.25 mg/kg). RESULTS: Six patients underwent a fluorescence-guided laparoscopic shaving procedure for the treatment of a nonobstructive RVDIEN. Fluorescence of the RVDIEN was observed in all the patients. In one patient, once the main lesion was removed, the posterior vaginal fornix still appeared fluorescent and was removed. No intraoperative rectal perforation occurred. The postoperative hospital stay was 2 days. No postoperative rectovaginal fistula occurred within a median follow-up of 16 months (range = 2-23 months). CONCLUSION: In this preliminary study, fluorescence-guided laparoscopy appeared to help in separating the RVDIEN from the healthy rectal tissue, without rectal perforation. Moreover, this technique was helpful in deciding if the resection needed to be enlarged to the posterior vaginal fornix. PMID- 29998783 TI - Laparoscopic Common Bile Duct Exploration Is a Safe and Effective Strategy for Elderly Patients. AB - PURPOSE: Laparoscopic common bile duct exploration (LCBDE) has been widely used to remove common bile duct (CBD) stones. However, surgery is not considered as the first treatment choice for elderly patients with CBD stones because of the potential risk of postoperative complications. This study aims to evaluate the safety and efficiency of LCBDE for elderly patients. METHODS: From April 2011 to October 2016, 265 consecutive patients underwent LCBDE. We performed a retrospective study and divided these patients into 2 groups. The younger group was younger than 70 years old (n = 179), and the elderly group was 70 years old or older (n = 86). We compared patient demographics, clinical characteristics, intraoperative parameters, postoperative complications, and incidence of recurrent stone between the 2 groups. RESULTS: The elderly patients had higher preoperative morbidity of chronic diseases, such as pulmonary diseases, heart diseases, arterial hypertension, and abdominal operation history ( P < .05). There were no significant differences between the 2 groups in terms of operation time, intraoperative blood loss, conversion rate to open surgery, total cost, overall complications, and incidence of recurrent stone ( P > .05). CONCLUSION: LCBDE can also be carried out as a safe and effective approach to remove CBD stones in elderly patients, although they have higher risk of chronic diseases. PMID- 29998784 TI - Frank Utten Purchas 1861-1909: Physician in Wales and descendant of slave owners. AB - Frank Utten Purchas was born into a family which had a long history of benefitting from slavery. He was born in Jamaica where both his paternal and maternal lines owned slaves who were forced to work on their sugar plantations. Purchas left this life behind him, however, trained in medicine in Edinburgh and became a respected and committed physician in Wales. He married into a prominent local family, and lived through a time that saw significant political, religious and medical changes. He contributed to the founding of an infirmary that exists to this day although he himself did not live to see its opening. PMID- 29998785 TI - Endoscopic Hematoma Evacuation for Acute Subdural Hematoma in the Elderly: A Preliminary Study. AB - AIM: Endoscopic surgery for acute subdural hematoma (ASDH) has recently been performed in elderly patients. Unlike other reported procedures, we used the endoscope's fixation device to ensure hemostasis because the surgeon can then use a surgical instrument with each hand. To date, there have no reports that prove lesser invasiveness or noninferiority of endoscopic surgery based on direct comparison with a large craniotomy. In this study, we investigated whether our endoscopic procedure was effective and safe. MATERIALS AND METHODS: We performed 6 cases of endoscopic surgical procedures in elderly patients over the past year. First, our surgical outcomes were evaluated. Second, the outcomes were compared between our endoscopic surgery and our large craniotomy procedures. Third, the outcomes were compared between our endoscopic surgery and other reported endoscopic surgeries. RESULTS: The outcomes of our endoscopic surgery were generally satisfactory without complications or rebleeding. Mean hematoma evacuation percentage was 91.6 +/- 4%. Compared with a large craniotomy, operative time was significantly shorter ( P = .01), and the hospital costs were significantly less for endoscopic surgery ( P = .008). There was no inferiority of outcomes when compared with other reported endoscopic surgeries. CONCLUSION: Our surgical procedure is safe and effective when performed with strict operative indications. Endoscopic surgery for ASDH in elderly adults may be an alternative to a large craniotomy in simple-type hematomas. PMID- 29998786 TI - Sibyl Horner, Sydney Alexander Henry, and occupational skin disease. AB - Occupational skin disease was, and remains, a major cause of morbidity, accounting for many thousands of hours lost from work each year. Investigating the causes, and seeking preventive measures, occupied much of the time of the early Medical Inspectors of Factories. Two of the inspectors, Sydney Henry and Sibyl Horner, became specialists in certain types of skin disease. PMID- 29998787 TI - Women's Views About a Paternal Consent Requirement for Biomedical Research in Pregnancy. AB - Clinical research to inform the evidence base to guide nonobstetrical care during pregnancy is critically important for the well-being of women and their future offspring. Conversations about regulations for such research, including whether paternal consent should ever be required, should be informed by the perspectives of those most affected, namely, pregnant women. We conducted in-depth interviews with 140 pregnant women living with or at risk of HIV-70 in Malawi, 70 in the United States-exploring their views on requiring paternal consent for pregnant women's participation in trials offering the prospect of direct benefit solely to the fetus. The majority of women supported such a requirement; others raised concerns. A trio of themes-the father's or pregnant woman's rights, fetal protection, and gender/relationship dynamics-characterized views both supporting and against a paternal consent requirement, expanding the range of considerations that should inform approaches to paternal involvement in research with pregnant women. PMID- 29998788 TI - Individual Differences in Locomotor Function Predict the Capacity to Reduce Asymmetry and Modify the Energetic Cost of Walking Poststroke. AB - Changes in the control of the lower extremities poststroke lead to persistent biomechanical asymmetries during walking. These asymmetries are associated with an increase in energetic cost, leading to the possibility that reducing asymmetry can improve walking economy. However, the influence of asymmetry on economy may depend on the direction and cause of asymmetry. For example, impairments with paretic limb advancement may result in shorter paretic steps, whereas deficits in paretic support or propulsion result in shorter nonparetic steps. Given differences in the underlying impairments responsible for step length asymmetry, the capacity to reduce asymmetry and the associated changes in energetic cost may not be consistent across this population. Here, we identified factors explaining individual differences in the capacity to voluntarily reduce step length asymmetry and modify energetic cost during walking. A total of 24 individuals poststroke walked on a treadmill, with visual feedback of their step lengths to aid explicit modification of asymmetry. We found that individuals who took longer paretic steps had a greater capacity to reduce asymmetry and were better able to transfer the effects of practice to overground walking than individuals who took shorter paretic steps. In addition, changes in metabolic cost depended on the direction of asymmetry, baseline cost of transport, and reductions in specific features of spatiotemporal asymmetry. These results demonstrate that many stroke survivors retain the residual capacity to voluntarily walk more symmetrically on a treadmill and overground. However, whether reductions in asymmetry reduce metabolic cost depends on individual differences in impairments affecting locomotor function. PMID- 29998789 TI - Perceptions of Caring Between Slovene and Russian Members of Nursing Teams. AB - PURPOSE: To measure the perceptions of caring between Slovene and Russian members of nursing teams and compare the results with earlier findings in other European Union countries. METHOD: A cross-sectional study that included nurses and nursing assistants in Slovenia ( n = 294) and Russia ( n = 531). Data were collected using the 25-item Caring Dimensions Inventory. RESULTS: The most endorsed item for Slovene and Russian members of nursing teams was an item related to medication administration. All items that were endorsed by Russian participants were also endorsed by Slovenian participants; however, they ascribed a different level of importance to individual aspects of caring. DISCUSSION: Compared with other European Union countries, such as the United Kingdom and Spain, Slovenian and Russian members of nursing teams endorsed more technical aspects of nursing duties as caring, suggesting cultural differences and previous influences of the biomedical model on nursing education and practice. PMID- 29998790 TI - "Stop Talking to People; Talk with Them": A Qualitative Study of Information Needs and Experiences Among Genetic Research Participants in Pakistan and Denmark. AB - This article explores how research participants experienced information practices in an international genetic research collaboration involving the collection of biomaterial and clinical data in both Pakistan and Denmark. We investigated how people make sense of their research participation and the types of information they need and desire. We found great variation in what information exchange does and what participants experience as meaningful. For example, information practices could serve as a source of respect and recognition (in Denmark) or of hope, understanding or help when dealing with suffering (in Pakistan). Policies aimed at harmonizing ethics standards for international research do not encapsulate some of the most important aspects of information practices for the research participants involved. We suggest shifting the focus from standards of one-way information delivery to a more process-oriented form of research ethics, where the contextual exploration of local needs through a mutual engagement with participants gains more ground. PMID- 29998791 TI - Early Care and Education Teacher's Role in Obesity Prevention and Healthy Development of Young American Indian Children. AB - INTRODUCTION: The purpose of this study was to develop an understanding of how stakeholders, specifically early care and education (ECE) teachers, perceive their role in the development of young American Indian children, and envision working with health care providers and parents in order to enhance children's health. METHODOLOGY: Twenty tribally affiliated ECE teachers from Oklahoma participated in interviews. Thematic analysis was conducted, and three main themes, each with two to three subthemes, emerged. RESULTS: Teachers felt that nutrition and physical activity were important to children's health. Teachers had little professional interaction with health care providers but desired more. Parental empowerment was conveyed as essential to actualize positive changes in their child's behavior. DISCUSSION: Teachers of tribally affiliated ECE centers are important stakeholders in promoting the health and well-being of young American Indian children. Additional efforts are needed to more effectively integrate teachers and nurses in order to create effective interventions. We propose a stakeholder partnership to guide the development of future interventions. PMID- 29998792 TI - Ventral hernia repair in rat using nanofibrous polylactic acid/polypropylene meshes. AB - AIM: In the present study, we combined a nanofibrous polylactic acid (PLA) scaffold fabricated by electrospinning with a polypropylene (PP) material to generate a new type of mesh for hernia repair. MATERIALS & METHODS: The PLA/PP mesh was tested with tensile testing, in vitro cytocompatibility and degradation. A total of 90 rats were randomly allocated to PLA/PP, PP and polyester (PE) mesh groups for the in vivo study to evaluate the properties of PLA/PP mesh. RESULTS: PLA/PP mesh had superior mechanical properties. It also resulted in less inflammation adhesion formation (p < 0.05), which was related to the TGF beta1/Smad pathway. The distribution of collagen I and III in PLA/PP mesh was also superior to those in the other two groups (p < 0.05). CONCLUSION: The PLA/PP mesh would be suitable for ventral hernia repair in the future. PMID- 29998793 TI - Does Risk Adjustment Reduce Vaccination in the Elderly? Evidence From Medicare Advantage. AB - To combat risk selection, it is becoming increasingly common for payments to insurers (and providers) to adjust for patients' chronic conditions. A possible unintended negative consequence is to reduce insurers' (and providers') incentives to prevent chronic conditions. This study examined the effect of Medicare's risk adjustment for payments to Medicare Advantage plans, first introduced in 2004, on pneumonia and influenza vaccination for the elderly. The analysis used the 2000 through 2010 waves of the Medicare Current Beneficiary Survey and a difference-in-differences approach. Presumably by decreasing Medicare Advantage plans' positive influence on vaccination, Medicare's risk adjustment policy was estimated to have reduced pneumonia vaccination rates by 2.9 percentage points (4%, p = .039) and to have possibly reduced influenza vaccination rates by 2.2 percentage points (3%, p = .096). The results clarify an argument against including vaccine-preventable conditions, like pneumonia, in a risk adjustment model. PMID- 29998794 TI - Biomimetic approaches for tissue engineering. AB - Advancement in medical technologies, emergence of new diseases and need for quick and effective treatments have increased the requirement for unique and distinct materials. A plethora of materials in various forms, shapes and sizes have been developed from polymers, metals and ceramics and extensively explored for both in vitro and in vivo applications. When used inside the body, biomaterials include metals, polymers and ceramics typically as implants, scaffolds, drug or gene carriers and also as protective agents. Although various materials are used for biomedical products, natural polymers are preferred over synthetic or metallic materials since they have better biocompatibility and ability to degrade in vivo without releasing toxic substances. In addition to the material, the structure and properties of the biomedical device/product plays a crucial role, particularly, when used for in vivo applications. It is desirable that the materials or products developed resemble the structure and replicate the biological functions in the body. For instance, 3D, nanofibrous structures similar to the extracellular matrix are considered suitable as tissue engineering scaffolds. Hence, extensive studies have been done to biomimic the biological systems and develop biomedical materials and devices using natural and synthetic polymers. For instance, successful replication of the biomineralization and bone formation and regeneration of tissue have been done. There are unlimited choice of materials, approaches and potential products that can be developed using the biomimetic approach. In this review, we provide an overview of the materials and methods used to develop biomimetic products for various medical applications. The objective of this study to provide readers with information on the various methods, materials and approaches that can be used to develop biomimetic materials to address the challenges and needs of the medicine and health care industries. This manuscript is restricted to discussions on biomimetic approaches for tissue engineering applications. However, there are considerable other medical applications of biomimetic materials which are not part of this review. PMID- 29998795 TI - Sexual Violence Risk Prediction in a Police Context. AB - Adoption of evidence-based approaches by police services offers a practical and scientific solution to ensure public safety and proper allocation of resources. Advances in the field of sexual violence risk prediction have the potential to inform policing practices. The present study examines the validity of existing actuarial measures to predict the future sexual violence behavior of 290 identified male perpetrators of sexual assault against adult victims (ages 16 and older). The Static-99R and Static-2002R were coded from police documentation, and the sample was followed up for at least 1 year with an average of 3.6 years. Both measures showed large effects for predicting any offending, violent offending, and sexual offending in the form of charges and convictions. The findings suggest that existing sex offender research can extend to police practice, and criminogenic factors used to predict recidivism among convicted offenders may apply to assessing the risk posed by perpetrators of police-reported sexual assaults. PMID- 29998796 TI - Call for Papers: Special Issue on International Developmental/Life-Course Perspectives and Research on Sexual Offending and Offenders. PMID- 29998797 TI - Sexual Abuse's New Person First Guideline. PMID- 29998798 TI - Promoting Accurate and Respectful Language to Describe Individuals and Groups. PMID- 29998799 TI - Crystal Engineering for Enhanced Solubility and Bioavailability of Poorly Soluble Drugs. AB - BACKGROUND: Crystal engineering is dealing with the creation of new structures and new properties in drug molecules through inter-molecular interactions. Researchers of pharmaceutical sciences have used this knowledge to alter the structure of crystalline medications in order to remedy the problems of more than 40% of the new designed drugs which suffer from low solubility and consequently, low bioavailability which have limited their clinical application. METHODS: This review covers a broad spectrum of aspects of the application of crystal engineering in pharmaceutics and includes a comprehensive wide range of different techniques used in crystal engineering of active pharmaceutical ingredients (API) to compensate the low water solubility and bioavailability of drugs related specially to class II of biopharmaceutical classification system (BCS). RESULTS: These techniques include; crystalline habit modification, polymorphism, solvates and hydrates, cocrystals, surface modification, crystallization, spherical agglomeration, liquisolid crystals and solid dispersions which are introduced and discussed in this review article. CONCLUSION: Each of these techniques has advantages and limitations which are emphasized on them. PMID- 29998800 TI - BPC 157 and Standard Angiogenic Growth Factors. Gastrointestinal Tract Healing, Lessons from Tendon, Ligament, Muscle and Bone Healing. AB - Commonly, the angiogenic growth factors signify healing. However, gastrointestinal ulceration is still poorly understood particularly with respect to a general pharmacological/pathophysiological role of various angiogenic growth factors implemented in growth factors wound healing concept. Thereby, we focused on the stable gastric pentadecapeptide BPC 157, a peptide given always alone vs. standard peptidergic angiogenic growth factors (EGF, FGF, VEGF), and numerous carriers. Further, we reviewed how the gastrointestinal tract healing could be generally perceived (i) in terms of angiogenic growth factors, and/or (ii) through the healing of extragastrointestinal tissues healing, such as tendon, ligament, muscle and bone, and vice versa. Respected were the beneficial effects obtained with free peptides or peptides with different carriers; EGF, FGF, VEGF, and BPC 157, their presentation along with injuries, and a healing commonality, providing their implementation in both gastrointestinal ulcer healing and tendon, ligament, muscle and bone healing. Only BPC 157 was consistently effective in all of the models of acute/chronic injury of esophagus, stomach, duodenum and lower gastrointestinal tract, intraperitoneally, per-orally or locally. Unlike bFGF-, EGF-, VEGF-gastrointestinal tract studies demonstrating improved healing, most of the studies on tendon, muscle and bone injuries provide evidence of their (increased) presentation along with the various procedures used to produce beneficial effects, compared to fewer studies in vitro, while in vivo healing has a limited number of studies, commonly limited to local application, diverse healing evidence with diverse carriers and delivery systems. Contrary to this, BPC 157 - using same regimens like in gastrointestinal healing studies - improves tendon, ligament and bone healing, accurately implementing its own angiogenic effect in the healing. Thus, we claim that just BPC 157 represents in practice a pharmacological and pathophysiological role of various peptidergic growth factors. PMID- 29998801 TI - HELLP Syndrome: Pathophysiology and Current Therapies. AB - BACKGROUND: HELLP syndrome is a disorder associated with serious maternal morbidity and mortality. Distinguishing HELLP from other pregnancy related disorders is often challenging and may result in delay of treatment. Differential diagnoses include acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, and hemolytic uremic syndrome, and are reviewed in this chapter. While there is not any current treatment for HELLP, the mainstay of treatment involves maternal stabilization and timely delivery. Various treatment strategies have been attempted to help decrease the morbidity and mortality of HELLP, including the maternal use of corticosteroids. The authors review the studies and controversies surrounding the maternal use of corticosteroids, plasma exchange, and low molecular weight heparin for the treatment of HELLP, as well as the role of the complement system in HELLP. Further large, well-designed, randomized controlled trials are needed to address the role corticosteroids may play in the treatment of women with HELLP and to help improve maternal and fetal outcomes. PMID- 29998802 TI - Elevated C-reactive Protein and Depressed High-density Lipoprotein Cholesterol are Associated with Poor Function Outcome After Ischemic Stroke. AB - AIMS: C-reactive protein is an established marker of inflammation that can impair the protective function of High Density Lipoprotein Cholesterol (HDL-C). The combined effect of Creactive protein and HDL-C on long-term outcomes in patients with stroke remains uncertain. METHODS: A total of 3124 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to CRP and HDL-C levels on admission. The primary outcome was a combination of death and major disability (modified Rankin Scale score >=3) at one year after stroke. RESULTS: Compared to participants with low CRP/ high HDL C, adjusted odd ratios for primary outcome for those with low CRP /low HDL-C, high CRP /high HDL-C and high CRP /low HDL-C were 1.06(0.81-1.39),1.78(1.31-2.41) and 2.03(1.46-2.80), respectively, after multiple adjustments. Adding serum CRP and HDL-C status to a model containing conventional stroke risk factors significantly improve risk reclassification for the combined outcome of death and major disability (NRI: 6.85%, P=0.005; IDI: 2.57%, P=0.002). Moreover, no interaction was observed between CRP and HDL-C in relation to stroke outcomes (P interaction >0.05 for all). CONCLUSIONS: High CRP with low HDL-C levels was associated with death and major disability within one year after ischemic stroke. The findings suggest that the ischemic patients with both high CRP and low HDL-C should be treated with reducing CRP and promoting HDL-C levels. PMID- 29998803 TI - Extracranial-to-Intracranial Bypass for Pressor Dependent Cerebrovascular Insufficiency: Modified Classification and Representative Case. AB - BACKGROUND: While some randomized clinical trials have reduced the indications for cerebral revascularization in the secondary prevention of ischemic stroke, a distinct subset of patients with blood pressure augmentation dependent cerebrovascular insufficiency due to large vessel occlusions remains unaddressed. With the recent paradigm shifts in acute ischemic stroke care, the role of extracranial to intracranial (EC-IC) bypass must be re-addressed when endovascular intervention is not a feasible option. We submit a refined classification of cerebrovascular insufficiency with a category called Pressor Dependent Cerebrovascular Insufficiency (PD-CVI) for whom EC-IC bypass may be indicated. CLINICAL PRESENTATION: A 61-year-old female former smoker presented with one day of intermittent left faciobrachial weakness and was found to have middle cerebral artery and cervical internal carotid artery occlusions. On admission to the intensive care unit, she was found to have PD-CVI with an intravenous pressor dependent blood pressure threshold over which she had near resolution of her neurological deficits. With endovascular intervention precluded given the ICA occlusion, she underwent an urgent right sided EC-IC bypass. The procedure was without complication, with careful attention to maintaining hypertension perioperatively. She required no pressors postoperatively and was neurologically intact at three months post-operatively. CONCLUSION: With recent advances in acute ischemic stroke care, there remains a need for careful consideration of cerebral revascularization surgery in patients with evidence of PD-CVI who may be precluded from or failed endovascular intervention. PMID- 29998804 TI - LncRNA MALAT1 is Neuroprotective in a Rat Model of Spinal Cord Ischemia Reperfusion Injury Through miR-204 Regulation. AB - BACKGROUND: This study was to investigate the neuroprotective effect of long noncoding RNAs Metastasis associated lung adenocarcinoma transcript-1 (lncRNA MALAT-1) in Spinal Cord Ischemic/Reperfusion Injury (SCIRI). METHODS: Quantitative real-time PCR (RT-qPCR) was used to examine the expressions of MALAT1, miR-204 and Bcl-2, while western blot was performed to examine Bcl-2. Besides, apoptosis was evaluated by the percentage of cell viability and apoptotic cells. Neurological evaluation was performed by measuring hindlimb locomotor function. RESULTS: The expression of MALAT1 and Bcl-2 was decreased, while miRNA-204 (miR-204) was up-regulated in rats SCIRI model and neurocyte lines under hypoxic conditions. Oxygen, Glucose Deprivation (OGD) promoted apoptosis of neurocytes, downregulated MALAT1 and Bcl-2 and elevated miR-204 expression, however, overexpression of MALAT1 notably reversed this trend. Nevertheless, knockdown of MALAT1 increased cell apoptosis, decreased MALAT1 and Bcl-2 but upregulated miR-204. MALAT1 overexpression-induced anti-apoptosis and knockdowninduced pro-apoptosis were obviously reversed by synchronously overexpression and knockdown of miR-204, respectively. MALAT1-treated SCIRI rats exhibited lower Motor Deficit Index (MDI) scores, higher levels of MALAT1 and Bcl 2 expression and lower miR-204 expression. CONCLUSION: Our data suggested that MALAT1 exerted neuroprotective effect in a rat model of SCIRI by regulating miR 204. PMID- 29998805 TI - Genetic Determinants of Cerebral Arterial Adaptation to Flow-loading. AB - BACKGROUND: In animal models, flow-loading is a necessary and sufficient hemodynamic factor to express the Cerebral Aneurysm (CA) phenotype. Using a rat model, this study characterizes the molecular events that comprise the cerebral arterial response to flow-loading and reveals their significance relating to the CA phenotype. OBJECTIVE: To characterize the molecular events that underlie expansive remodeling of cerebral arteries in two genetically distinct inbred rat strains with differential susceptibility to flow-dependent cerebrovascular pathology. METHODS: Thirty-two rats underwent bilateral common carotid artery ligation (BCL) (n=16) or Sham Surgery (SS) (n=16). Nineteen days later, vertebrobasilar arteries were harvested, histologically examined and analyzed for mRNA and protein expression. Flow-induced changes in histology, mRNA and protein expression were compared between BCL and SS rats. Differences between aneurysm prone (Long Evans, LE) and resistant (Brown Norway, BN) strains were evaluated. RESULTS: Basilar Artery (BA) medial thickness/luminal diameter ratio was significantly reduced in BCL rats, without significant differences between LE (2.02 fold) and BN (1.94 fold) rats. BCL significantly altered BA expression of mRNA and protein but did not affect blood pressure. Eight genes showed similarly large flow-induced expression changes in LE and BN rats. Twenty-six flow responsive genes showed differences in flow-induced expression between LE and BN rats. The Cthrc1, Gsta3, Tgfb3, Ldha, Myo1d, Ermn, PTHrp, Rgs16 and TRCCP genes showed the strongest flow responsive expression, with the largest difference between LE and BN rats. CONCLUSIONS: Our study reveals specific molecular biological responses involved in flow-induced expansive remodeling of cerebral arteries that may influence differential expression of flowdependent cerebrovascular pathology. PMID- 29998806 TI - Obtaining Microbiological and Pharmacokinetic Highly Predictive Equations. AB - In this paper, a Multilinear Regression (MLR) analysis has been carried out in order to accurately predict physicochemical properties and biological activities of a group of antibacterial quinolones by means of a set of structural descriptors called topological indices. The aim of this work is to develop prediction equations for these properties after collecting the maximum number of data from the literature on antibacterial quinolones. The five regression functions selected by presenting the best combination of various statistical parameters, subsequently validated by means of internal validation (intercorrelation, Y-randomization and leave-one-out cross-validation tests), allowed the reliable prediction of minimum inhibitory concentration 50 versus Staphylococcus aureus (MIC50Sa), Streptococcus pyogenes (MIC50Spy) and Bacteroides fragilis (MIC50Bf), Mean Residence Time (MRT) after oral administration and volume of distribution (VD). We conclude that the combination of molecular topology methods and MLR provides an excellent tool for the prediction of pharmacological properties. PMID- 29998808 TI - Neonatal and Long-Term Consequences of Fetal Growth Restriction. AB - Fetal Growth Restriction (FGR) is one of the most common noxious antenatal conditions in humans, affecting 10% of all pregnancies, inducing a substantial proportion of preterm delivery and leading to a significant increase in perinatal mortality, neurological handicaps and chronic diseases in adulthood. This review summarizes the current knowledge about the postnatal consequences of FGR, with a particular emphasis on the long-term consequences on respiratory, cardiovascular and neurological structures and functions. FGR represents a global health challenge, and efforts are urgently needed to improve our understanding of the critical factors leading to FGR and subsequent insults to the developing organs. PMID- 29998807 TI - Antibacterial Activity and Time-kill Kinetics of Positive Enantiomer of alpha pinene Against Strains of Staphylococcus aureus and Escherichia coli. AB - Research on new antimicrobial agents is needed, as more and more microorganisms that cause antibiotic-resistant diseases are emerging commercially. In this group, we can find strains of Staphylococcus aureus and Escherichia coli, which are highly opportunistic species. Faced with this perspective, research using essential oils present in plants is emerging as a therapeutic alternative for the treatment of antimicrobial infections. Many of these oils have, in their composition, monoterpene alpha-pinene, that shows to have antibacterial activity. The purpose of this research is to evaluate the antimicrobial activity of the positive enantiomer of alpha-pinene against strains of Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922. The methodologies used were: Disc diffusion test, broth microdilution and bacterial death kinetics, all of which were standardized by CLSI. As a result, inhibition halos of 11 mm was obtained for the gram-positive strain and 12 mm for the gram-negative strain, both at the same concentration, 160 ul / ml. In addition, it was possible to observe with the death curve that the concentrations (1.25 ul/mL and 2.5 ul/mL of the (+)-alpha pinene were able to eliminate the formation of bacterial colonies at one time of exposure of 2 hours for the E. coli strain. However, the death curve of the S. aureus strain was characterized by non-elimination of bacterial colonies at a 24 hours exposure time used for the experiment. Only amikacin evidenced its bacterial killing rate of all colonies within two hours of exposure. At the end, it was possible to verify the activity of the phytoconstituent against Escherichia coli strains ATCC 25922 and Staphylococcus aureus ATCC 25923, recommending the continuity of the studies with the use of different methodologies so that (+) - alpha-pinene in the future can be a compound used in antimicrobial therapy. PMID- 29998809 TI - The use of an ostial stent does not increase the success rate of endoscopic dacryocystorhinostomy. AB - OBJECTIVE: This prospective, controlled study assessed how placing a stent into a newly formed ostium affects ostial patency, success and complication rates in endoscopic dacryocystorhinostomy patients. METHODS: In group 1 (40 eyes of 36 patients), both silicone tube intubation and tube stenting were performed. In group 2 (36 eyes of 34 patients), only silicone tube intubation was performed. Success, operative time and post-surgical complications were investigated two months post-operatively in each group. RESULTS: The success rates were 92.5 per cent and 83.3 per cent for groups 1 and 2 respectively, but the difference was not statistically significant (p = 0.294). The complication rates also differed between the two groups, but this was again insignificant. CONCLUSION: Compared with the use of a silicone tube alone, the addition of an ostial stent did not significantly increase the success rate of endoscopic dacryocystorhinostomy. PMID- 29998810 TI - Hybrid approach for disconnected pulmonary arteries: never lose a pulmonary artery again! AB - Disconnection of a pulmonary artery needs early surgical treatment in order to support the growth of the vessel. However, owing to the high rate of re-stenosis after traditional surgical reconstruction, we developed a hybrid approach involving the creation of pulmonary artery continuity by using autologous or heterologous tissue supported by stent implantation. PMID- 29998811 TI - Analysis of corporate political activity strategies of the food industry: evidence from France. AB - OBJECTIVE: To identify the corporate political activity (CPA) of major food industry actors in France. DESIGN: We followed an approach based on information available in the public domain. Different sources of information, freely accessible to the public, were monitored.Setting/SubjectsData were collected and analysed between March and August 2015. Five actors were selected: ANIA (Association Nationale des Industries Agroalimentaires/National Association of Agribusiness Industries); Coca-Cola; McDonald's; Nestle; and Carrefour. RESULTS: Our analysis shows that the main practices used by Coca-Cola and McDonald's were the framing of diet and public health issues in ways favourable to the company, and their involvement in the community. ANIA primarily used the 'information and messaging' strategy (e.g. by promoting deregulation and shaping the evidence base on diet- and public health-related issues), as well as the 'policy substitution' strategy. Nestle framed diet and public health issues, and shaped the evidence base on diet- and public health-related issues. Carrefour particularly sought involvement in the community. CONCLUSIONS: We found that, in 2015, the food industry in France was using CPA practices that were also used by other industries in the past, such as the tobacco and alcohol industries. Because most, if not all, of these practices proved detrimental to public health when used by the tobacco industry, we propose that the precautionary principle should guide decisions when engaging or interacting with the food industry. PMID- 29998812 TI - Education in ear and hearing care in remote or resource-constrained environments. AB - BACKGROUND: At the heart of surgical care needs to be the education and training of staff, particularly in the low-income and/or resource-poor setting. This is the primary means by which self-sufficiency and sustainability will ultimately be achieved. As such, training and education should be integrated into any surgical programme that is undertaken. Numerous resources are available to help provide such a goal, and an open approach to novel, inexpensive training methods is likely to be helpful in this type of setting.The need for appropriately trained audiologists in low-income countries is well recognised and clearly goes beyond providing support for ear surgery. However, where ear surgery is being undertaken, it is vital to have audiology services established in order to correctly assess patients requiring surgery, and to be able to assess and manage outcomes of surgery. The training requirements of the two specialties are therefore intimately linked. OBJECTIVE: This article highlights various methods, resources and considerations, for both otolaryngology and audiology training, which should prove a useful resource to those undertaking and organising such education, and to those staff members receiving it. PMID- 29998813 TI - Fruit and vegetable intakes, associated characteristics and perceptions of current and future availability in Dutch university students. AB - OBJECTIVE: To investigate fruit and vegetable (F&V) intakes of university students and associated demographic and lifestyle characteristics, and students' perceptions of F&V availability and F&V intervention strategies in the university environment. DESIGN: Cross-sectional questionnaire data were collected; F&V intakes were measured using a food frequency tool. Multivariable linear regression analyses were used to analyse the associations between demographic and lifestyle characteristics and F&V intakes. SETTING: Universities in the Netherlands. SUBJECTS: University students (n 717). RESULTS: The majority of students did not adhere to Dutch F&V guidelines (71 % and 93 %, respectively). Fruit intake was lower among students who were male, living independently, enrolled in a technical study, not adhering to physical activity guidelines, and heavy to excessive alcohol drinkers. Vegetable intake was lower among students who were non-Dutch, living with their parents, not adhering to physical activity guidelines, and moderate and heavy to excessive alcohol drinkers. Most students perceived that their university environment offers sufficient healthy foods (60 %) and F&V (65 %), but also indicated that their F&V intakes would increase with interventions concerning affordable F&V in the university canteen (64 %) or university supermarket (60 %). Students were less disposed to indicate that weekly local farmers' markets, vegetable parcels or a vegetable garden would increase their F&V intakes. CONCLUSIONS: Dutch university students do not consume enough F&V. Future efforts that aim to promote students' F&V intakes should consider the differences between subgroups based on demographic and lifestyle characteristics and that affordable F&V in the university environment might be an effective strategy. PMID- 29998814 TI - Assessment of progress and competence in tonsillectomy surgery using cumulative sum analysis. AB - OBJECTIVE: To assess the feasibility of using cumulative sum analysis to show trainees' performance curves and highlight concerns in tonsillectomy surgery. METHODS: In this prospective study, the performance of eight otolaryngology trainees (in their first 6-12 months in the specialty) was compared to that of experts (over 150 tonsillectomies performed) in terms of operative time and post operative complications. Cumulative sum analysis curves were generated to highlight trainees' performance, and were updated after each performance. RESULTS: The average operative time was 23 minutes (standard deviation = 11) for experts and 38 minutes (standard deviation = 16) for trainees (p < 0.0001). Cumulative sum analysis charts for trainees' operative time initially rose and then started to plateau after a number of cases (range, 25-30), while that of experts remained low. Cumulative sum analysis charts for complications can be used to monitor performance. In this study, complications were combined (because of low incidence) to allow use of this outcome measure. CONCLUSION: The flexibility of the cumulative sum analysis makes it adaptable to any outcome. It is a strong adjunct in surgical training to monitor progress and competence. Its sensitivity also allows early detection of poor performance, to instigate intervention. PMID- 29998815 TI - Do children undergoing bilateral myringotomy with placement of ventilating tubes benefit from pre-operative analgesia? A double-blinded, randomised, placebo controlled trial. AB - OBJECTIVE: A double-blinded, randomised, placebo-controlled trial was conducted to determine whether routine pre-operative analgesia is beneficial in reducing post-operative ear pain following bilateral myringotomy and tube placement. METHODS: Forty-five children (aged 3-15 years) were randomised to receive either pre-operative analgesics (paracetamol and ibuprofen) (n = 21) or placebo (n = 24). All children underwent sevoflurane gas induction with intranasal fentanyl (2 mcg/kg) to reduce the incidence of emergence agitation. Post-operative pain scores were measured using the Wong-Baker Faces Pain Rating Scale. Median pain scores taken 90 minutes post-surgery, and the highest pain score recorded prior to 90 minutes, were analysed. RESULTS: There were no statistical differences between the median pain scores at 90 minutes or subsequent need for rescue analgesia. Emergence agitation did not occur in any child. Inadvertent ear trauma, use of an intravenous cannula or airway adjunct did not affect pain scores. CONCLUSION: Routine pre-operative analgesia does not reduce pain scores in the early post-operative period. Simple analgesics are effective for rescue analgesia in the minority of cases. PMID- 29998816 TI - Subjective well-being and oral discomfort in older people. AB - : ABSTRACTBackground:The study aims to assess the relationship between oral discomfort and subjective well-being (SWB) in older people. METHODS: A quantitative cross-sectional study was conducted in four Reference Centers for Social Welfare in Fortaleza, Northeastern Brazil. A census was held and individual interviews were carried out with all the older people (n = 246) enrolled in the centers. A questionnaire addressing sociodemographic data (age, gender, marital status, income, and education) and oral discomfort (dry mouth, difficulty in chewing and swallowing food, problems with the taste of food, burning mouth sensation, pain for no apparent reason, and mouth swelling) and the 62-item SWB scale were used. RESULTS: Participants were 246 people aged 60-89 years (mean of 69 +/- 6.9 years). The majority were women (n = 199; 80.9%), had incomplete primary education (n = 161; 65.4%), had an income of up to one minimum wage (n = 182; 74%), were retired (n = 169; 68.7%), were white (n = 100; 40.7%), and had no partner (n = 177; 72%). The mean SWB score (subscale 1) was associated with age (p = 0.010), gender (p = 0.019), health in the previous year (p = 0.027), systemic diseases (p = 0.007), speech problems (p = 0.016), vision problems (p = 0.006), number of teeth (p = 0.010), and dry mouth (p = 0.044). SWB (subscale 2) was associated with gender (p = 0.029), skin color (p = 0.023), general health (p < 0.001), health in the previous year (p < 0.001), systemic diseases (p = 0.001), drinking (p = 0.022), soft tissue problems (p = 0.001), and pain for no apparent reason (p = 0.025). CONCLUSION: The relationship between oral discomfort and SWB reveals that older people's poor oral health leads to physical, psychological, and/or social problems that directly interfere with their well-being. PMID- 29998817 TI - Implementation and results of a surgical training programme for chronic suppurative otitis media in Cambodia. AB - BACKGROUND: Chronic suppurative otitis media is a massive public health problem in numerous low- and middle-income countries. Unfortunately, few low- and middle income countries can offer surgical therapy. METHODS: A six-month long programme in Cambodia focused on training local surgeons in type I tympanoplasty was instigated. Qualitative educational and quantitative surgical outcomes were evaluated in the 12 months following programme completion. A four-month long training programme in mastoidectomy and homograft ossiculoplasty was subsequently implemented, and the preliminary surgical and educational outcomes were reported. RESULTS: A total of 124 patients underwent tympanoplasty by the locally trained surgeons. Tympanic membrane closure at six weeks post-operation was 88.5 per cent. Pure tone audiometry at three months showed that 80.9 per cent of patients had improved hearing, with a mean gain of 17.1 dB. The trained surgeons reported high confidence in performing tympanoplasty. Early outcomes suggest the local surgeons can perform mastoidectomy and ossiculoplasty as safely as overseas trained surgeons, with reported surgeon confidence reflecting these positive outcomes. CONCLUSION: The training programme has demonstrated success, as measured by surgeon confidence and operative outcomes. This approach can be emulated in other settings to help combat the global burden of chronic suppurative otitis media. PMID- 29998818 TI - Evaluation of reliable improvement rates in depression and anxiety at the end of treatment in adolescents. AB - BACKGROUND: Literature has focused on effect sizes rather than individual-level improvement rates to determine how effectively services address burgeoning numbers of adolescents with anxiety and depression.AimsTo consider how many adolescents report reliable improvement in anxiety, depression and comorbid depression and anxiety by end of treatment. METHOD: The primary outcome was reliable improvement (i.e. change greater than likely the result of measurement error) in self-reported anxiety and depression for N = 4464 adolescents (mean age 14.5 years, s.d. = 1.9; 75% female; 61% White) seen in specialist mental health services in England. RESULTS: In total, 53% of those with anxiety, 44% with depression, and 35% with comorbid depression and anxiety showed reliable improvement. CONCLUSIONS: Improvement rates were higher than previously reported, but lower than generally used in advice to the public. There may be a need to set more realistic expectations, including with young people who seek help.Declaration of interestAll authors were involved in the programme of service transformation that this report draws on. M.W. led the outcomes and evaluation group that agreed the approach to measurement used in the initiative. PMID- 29998820 TI - Creating boundaries to empower digital health technology. AB - SummaryThe potential of digital health tools such as smartphones and sensors to increase access to and enhance delivery of healthcare is well known. However, a lack of regulation and delineation between those technologies seeking to offer direct clinical diagnostics and treatments and those involving clinical care enhancements or direct-to-consumer resources has led to patient and clinician confusion about the appropriate use and role of digital health. Here, we propose that creating boundaries and better defining the scope of digital health technology will advance the field through matching the right use cases with the right tools. We further propose that ethical clinicians, as stewards of standard of care, are well suited to uphold these boundaries and to safeguard best practices in digital health.Declaration of interestH.H. is an employee of Verily Life Sciences and owns equity in this company. The views expressed here are those of the authors and are not official views of Verily Life Sciences. PMID- 29998819 TI - Quality assessment of systematic reviews of vitamin D, cognition and dementia. AB - BACKGROUND: There is conflicting evidence regarding the association of vitamin D with cognition performance and dementia.AimsWe aimed to summarise the evidence on the association of vitamin D with cognitive performance, dementia and Alzheimer disease through a qualitative assessment of available systematic reviews and meta analyses. METHOD: We conducted an overview of the systematic reviews of all study types with or without meta-analyses on vitamin D and either Alzheimer disease, dementia or cognitive performance up to June 2017. RESULTS: Eleven systematic reviews were identified, nine of which were meta-analyses with substantial heterogeneity, differing statistical methods, variable methodological quality and quality of data abstraction. A Measurement Tool to Assess Systematic Reviews checklist scores ranged from 4 to 10 out of 11, with seven reviews of 'moderate' and four of 'high' methodological quality. Out of six meta-analyses on the association between low serum concentration of 25-hydroxyvitamin D and risk of dementia, five showed a positive association. Results of meta-analyses on the association between low serum concentration of 25-hydroxyvitamin D and memory function tests showed conflicting results. CONCLUSIONS: This systematic evaluation of available systematic reviews provided a clearer understanding of the potential link between low serum vitamin D concentrations and dementia. This evaluation also showed that the quality of the available evidence is not optimal because of both the low methodological quality of the reviews and low quality of the original studies. Interpretation of these systematic reviews should therefore be made with care.Declaration of interestNone. PMID- 29998822 TI - Evaluating IBD-specific antiglycan antibodies in serum of patients with spondyloarthritis and rheumatoid arthritis: are they really specific? AB - OBJECTIVES: The presence of serological markers associated with inflammatory bowel disease (IBD) has been studied in spondyloarthritis with conflicting results. The anti-glycan antibodies: anti-laminaribioside, anti-chitobioside, and anti-mannobioside carbohydrate antibodies (ALCA, ACCA, and AMCA) are serological markers previously associated with IBD. We aim to investigate the prevalence of these antibodies in spondyloarthritis in comparison with rheumatoid arthritis (RA) patients. METHODS: Serum samples were obtained from consecutive patients with spondyloarthritis and were compared to RA and healthy controls. Anti-glycan antibodies - ALCA, ACCA and AMCA - were assessed using ELISA (Glycominds Ltd, Israel). Demographic characteristics, family history, disease pattern, skin evaluation (for PsA), disease activity and a questionnaire for gastrointestinal symptoms were recorded. RESULTS: Seventy patients were recruited: 36 ankylosing spondylitis (AS) and 28 psoriatic arthritis (PsA). No difference in ALCA or AMCA levels was observed between all the study groups. Significantly higher levels of ACCA were observed in RA patients, compared to healthy controls (p=0.002). One or more of the anti-glycan antibodies was found in 16.7%, and 3.6% of patients with AS and PsA, respectively, compared to 7.3% in healthy controls and 27% in RA (p=0.09). No correlation was found between the presence of anti-glycan antibodies and gastrointestinal symptoms. CONCLUSIONS: Our data fail to show an increased prevalence of anti-glycan antibodies in AS or PsA patients. ACCA were found to be significantly higher in RA patients than in controls, and may serve as an inflammatory biomarker. The present results do not support a role for antiglycan antibodies as biomarkers for spondyloarthritis. PMID- 29998821 TI - Second-generation antipsychotics and metabolic side-effects: Canadian population based study. AB - BACKGROUND: Use of second-generation antipsychotics (SGA) has increased in recent years; however, their use and effect on metabolic outcomes has been poorly characterised in population-level studies.AimsThis study aimed to determine the associations between SGA use and metabolic indicators in a general population. METHOD: We used data from the Canadian Health Measures Survey, a cross-sectional survey of Canadian households. Participants were Canadians aged 3-79 years, living in one of the ten provinces. Several metabolic indicators were examined, including weight, body mass index, waist circumference, hypertension, diabetes and two definitions of metabolic syndrome. RESULTS: The proportion of Canadians taking an SGA tripled over the study period. SGA use was significantly associated with hypertension (odds ratio 1.94, 95% CI 1.07-3.55) and abdominal obesity in adults, as defined by the National Cholesterol Education Program-Adult Treatment Panel III (odds ratio 2.62, 95% CI 1.45-4.71). CONCLUSIONS: Evidence of metabolic dysfunction with SGAs is seen in the Canadian population, along with a rapid increase in prevalence of use since 2007.Declaration of interestNone. PMID- 29998824 TI - Prevention of the progressive biochemical cartilage destruction under methotrexate therapy in early rheumatoid arthritis. AB - OBJECTIVES: The aim of the study was to investigate biochemical cartilage composition under methotrexate (MTX) therapy and to intra-individually assess the impact of inflammation severity on cartilage composition by using dGEMRIC MRI in patients with early rheumatoid arthritis (eRA). METHODS: dGEMRIC of MCP joints of the index and middle finger of 28 patients from the AthroMark cohort were examined prior to MTX-therapy as well as after 3 and 6 month. OMERACT RA MRI score and clinical parameters (CRP and DAS28) were registered at any time point. Each patient's second and third MCP joints were dichotomised into the joint with more severe synovitis versus the joint with less severe synovitis according to the RAMRIS synovitis subscore. RESULTS: MCP joints with more severe synovitis ('bad joints') demonstrated significantly lower dGEMRIC values compared to MCP joints with less severe synovitis ('good joints') at time-points 0 and 3 months (p=0.002; p=0.019, respectively). After 6 months of MTX therapy no significant difference of dGEMRIC index was found between good and bad joint (p=0.086). CONCLUSIONS: Under MTX therapy, biochemical cartilage integrity remains stable; no further cartilage destruction occurred if patients were treated early in the course of the disease. In addition, six months of MTX therapy triggered an alignment of dGEMRIC index of MCP joints with initially severe synovitis and less severe synovitis in an intra-individual assessment. This underlines the importance of an early treatment in eRA to reduce further cartilage damage of the inflamed joints. PMID- 29998823 TI - The prevalence and relevance of traditional cardiovascular risk factors in primary Sjogren's syndrome. AB - Accelerated atherosclerosis is a distinct feature of some inflammatory and autoimmune disorders and several specific autoimmune mechanisms and persistent inflammation have been identified to exert a pivotal role in precocious atherosclerotic damage in these disorders. Although increased atherosclerotic risk has been well established in some rheumatic autoimmune systemic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, reliable data regarding the prevalence and pathogenetic mechanisms associated with increased atherosclerotic damage in primary Sjogren's syndrome are scarse. Indeed, primary Sjogren's syndrome is an autoimmune disorder characterised by chronic inflammation and autoimmune dysregulation that shares many pathogenic mechanisms and clinical features with systemic lupus erythematosus and rheumatoid arthitis. Higher prevalence of subclinical atherosclerosis has been observed in primary Sjogren's syndrome patients and recent population-based studies demonstrated an increased risk of cardiovascular events in these patients in comparison to general population. Among mechanisms associated with atherosclerotic damage, the prevalence and the role of traditional cardiovascular risk factors have been poorly investigated. In particular, the issue of whether the presence of these cardiovascular risk factors is associated with an increased risk of cardiovascular events needs to be further explored. PMID- 29998825 TI - Rapid immunoprofiling of cytokines, chemokines and growth factors in patients with active rheumatoid arthritis using Luminex Multiple Analyte Profiling technology for precision medicine. AB - OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of unknown etiology, characterised by symmetric erosive synovitis, leading inevitably to the destruction of cartilage and bone as well as bursa and tendon sheaths of joints. Our aim of this study was to decipher the differential expression of cytokines, chemokines and growth factors in the plasma of RA patients with active disease, using magnetic bead-based Luminex Multiple Analyte Profiling (xMAP) technology, for precision medicine. METHODS: We obtained plasma samples from RA patients (n=25) from the Rheumatology Clinic at the King Abdulaziz University Hospital (KAUH), Jeddah, Kingdom of Saudi Arabia (KSA) after written informed consent for their inclusion in this study. Besides, we have used the plasma samples from inflammatory osteoarthritis (OA) patients (n=10) and healthy volunteers (n=10) for comparison analyses. Plasma samples were examined using the Human Cytokine Magnetic 30-plex panel (Novex(r)), Invitrogen, USA) and analysed by MAGPIX(r) instrument (Luminex Corporation, USA). RESULTS: Though several pro-inflammatory cytokines, chemokines and growth factors present in the 30plex magnetic bead panel were not significantly (p>0.05) increased in the plasma of RA patients, the levels of plasma Th1 associated proinflammatory cytokines TNFalpha, and IL-6 and Th2 associated cytokines such as IL-4, IL-5 and IL-13 were significantly (p<0.05) upregulated compared to OA and normal controls. The proinflammatory IL-12 as well as anti-inflammatory IL-10 and IL-1RA were significantly (p<0.05) upregulated in the plasma of RA patients compared to normal controls. Also, the chemokines such as IP-10, RANTES and IL-8 as well as growth factors such as EGF, and VEGF were significantly (p<0.05) increased in RA. CONCLUSIONS: The MAGPIX data showed that the cytokines, chemokines and growth factors were differentially regulated systemically in patients with active RA compared to OA and normal controls. Hence, the Luminex xMAP technology-based multiplex immunoassays offer clues to formulate effective therapeutic strategies for RA patients with active disease irrespective of their treatment regimen and duration of treatment and, thus, an indispensable tool in precision medicine. PMID- 29998827 TI - Survival and safety of infliximab bio-original and infliximab biosimilar (CT-P13) in usual rheumatology care. AB - OBJECTIVES: Reports to-date indicate similarity between infliximab biosimilar (IB) and infliximab bio-original (IO) in clinical efficacy and safety. This study examines the survival of IB and IO using routinely collected data over a 2-year period. METHODS: Routinely collected clinical data inputted directly in an electronic database at a large rheumatology centre were analysed. Adult patients taking IO or IB for any rheumatological diagnosis were included. Kaplan-Meier survival analyses were used to examine IB and IO survival, with a sub-group analysis among those starting infliximab from 2008 onwards. RESULTS: Out of 395 patients analysed, 53% (n=209) were female; the majority had rheumatoid arthritis (31%) followed by spondyloarthritis (28%). Ninety-nine patients had IB as the first infliximab drug. Patients who started on IB vs. IO as their first infliximab product, had better survival over the first 2 years (log rank=0.001). Discontinuation due to inefficacy was much commoner in IO versus IB users (18 vs. 5%). In patients switching from IO to IB, drug survival was better versus those receiving IB as the first infliximab drug (log rank=0.073). CONCLUSIONS: IB was well-tolerated and comparable to IO, with no additional safety signals identified. The results suggest superior survival of IB over IO over the first 2 years. PMID- 29998826 TI - Limited efficacy of targeted treatments in Sjogren's syndrome: why? PMID- 29998828 TI - Successful treatment with tofacitinib for renal disorder due to amyloid A amyloidosis and immunoglobulin A nephropathy in a patient with rheumatoid arthritis. PMID- 29998830 TI - Redundant modulatory effects of proinflammatory cytokines in human osteoblastic cells in vitro. AB - OBJECTIVES: The aim of our study was to investigate possible interaction of IL 17, TRAIL, and TNF-alpha in the modulation of osteoblast homeostasis in vitro, using human differentiated osteoblastic Saos-2 cells as in vitro model. METHODS: The effects of these cytokines on osteoblastic cell viability were assessed, by MTT assay, alone or in combination, at different times and concentrations. The effects of IL-17 and TNF-alpha on the regulatory system of osteoclast activity RANK/RANKL/ OPG were evaluated by Western blot and ELISA techniques in cell culture media. Quantitative expression of RANKL, OPG and pro-inflammatory factors were analysed at the mRNA level by quantitative real time RT-PCR. RESULTS: Effects of IL-17, TNF-alpha and TRAIL on osteoblastic cell viability indicated that IL-17 alone, or in combination with TNF-alpha did not alter Saos-2 cell viability. On the other hand, TRAIL, as expected, exhibited time- and concentration-dependent cytotoxicity. The expression both RANKL and OPG were increased at the mRNA level and protein release by IL-17 and TNF-alpha, either alone or in combination. The analysis of IL-17 and TNF-alpha on pro-inflammatory molecules mRNA expression, such as CXC family chemokines CXCL-1 and CXCL-5, COX-2 and IL-6 demonstrated an increase in these pro-inflammatory cytokines with cooperative effects of the combination. CONCLUSIONS: Overall, these results suggest that IL-17, TRAIL and TNF-alpha sustain bone tissue inflammation associated with decrease of calcified component. To do so, they act redundantly each other, to amplify the inflammatory response in the bone. In conclusion, unravelling novel molecular targets within the bone-cytokine network represents a platform for innovative treatment of bone diseases due to immunological diseases such as psoriatic arthritis. PMID- 29998829 TI - Efficacy and safety of mycophenolate mofetil and tacrolimus combination therapy in patients with lupus nephritis: a nationwide multicentre study. AB - OBJECTIVES: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (TAC) may be an option for lupus nephritis (LN) patients that do not adequately respond to initial treatment. We evaluated the efficacy and safety of the combination treatment of MMF and TAC in LN patients with suboptimal response to prior MMF or TAC treatments. METHODS: In this multicentre study, we retrospectively enrolled 62 patients with class III, IV, or V LN who inadequately responded to MMF or TAC treatment. Those patients were then treated with a combination of MMF and TAC for 6 months. The primary outcome was complete remission (CR) at 6 months, and secondary outcomes included overall response and adverse events. RESULTS: After 6 months of treatment with the drug combination, CR was achieved in 14 of 62 patients (22.6%), and 35 (56.5%) patients responded. A significant reduction in proteinuria and lupus disease activity score was observable after 3 months. After 1 year, the CR rate increased to 36.4% (20 of 55 patients), and the overall response rate (n=38, 69.1%) also increased from 6 months. Twenty-one patients reported 29 adverse events, including severe infection requiring hospitalisation (n=3, 10.3%), infection not requiring hospitalisation (n=2, 6.9%), and herpes zoster (n=4, 13.8%). CONCLUSIONS: Our findings suggest that a combined MMF and TAC treatment, with a favourable adverse-event profile, may be a beneficial option for LN patients with inadequate response to either MMF or TAC treatments. PMID- 29998831 TI - Comparison between the efficacy of combination therapy and monotherapy in connective tissue disease associated pulmonary arterial hypertension: a systematic review and meta-analysis. AB - OBJECTIVES: Although the efficacy of combined treatment targeting pulmonary arterial hypertension (PAH) has been suggested to be preferable, the comparative efficacy of combination therapy versus monotherapy in connective tissue disease (CTD)-associated PAH (CTD-PAH) remains undetermined. We performed a meta-analysis regarding this topic. METHODS: The Cochrane Library, MEDLINE, PubMed, and EMBASE databases were searched for randomised controlled trials (RCTs) that directly compared the efficacies of combination therapy and monotherapy targeting PAH in patients with CTD-PAH. The risk of the clinical worsening of PAH and changes in 6 minute walk distance (6MWD) were evaluated. The Mantel-Hansel method was used to pool the results with a random-effects model. RESULTS: Six RCTs with 963 patients were included. The results of the meta-analysis showed that combination therapy significantly reduced the risk of clinical worsening events by 27% (pooled relative risk of 0.73, 95% confidence interval (CI) [0.60-0.89], p=0.002) with no significant heterogeneity (I2=13%, Ph=0.33) and tended to increase 6MWD by 21.38 m (95% CI [-20.38 to 63.14]; p=0.32; I2=58, Ph=0.09). No significant heterogeneity was indicated with funnel plots. CONCLUSIONS: Combination therapy targeting PAH may confer preferable therapeutic efficacy compared with monotherapy in patients with CTD-PAH as evidenced by a more remarkable reduction in the risk of clinical worsening and a probable improvement of exercise capacity in these patients. PMID- 29998832 TI - Does early seronegative arthritis develop into rheumatoid arthritis? A 10-year observational study. AB - OBJECTIVES: To investigate the 10-year clinical course of patients with seronegative arthritis with the emphasis of reclassification of diagnoses when applicable. METHODS: A total of 1030 patients including 435 seronegative cases were classified as early RA in 1997-2005 at Jyvaskyla Rheumatology Centre and prospectively scheduled for a ten-year follow-up. Clinical data from the follow up visits and the case-reports until and including the 10-year visit or death, whichever happened earlier, were retrospectively collected and reviewed with re classification of the cases when applicable. Descriptive statistics were used. RESULTS: Among the 435 seronegative cases (69 % women, baseline mean age was 59 years), 13 (13/435 [3%]) could be reclassified as seropositive or erosive RA: 4 turned seropositive (2 for ACPA and 2 for RF [> 2x reference level]) and 9 developed erosions typical for RA. Reclassification revealed 68 (16%) cases of polymyalgia rheumatica, 46 (11%) psoriatic arthritis, 45 (10%) osteoarthritis, 38 (8.7%) spondyloarthritis, 15 (3.4%) plausible reactive arthritis, 10 (2.3%) gout, 17 (3.9%) pseudogout, 6 (1.4%) paraneoplastic arthritis, 6 (1.4%) juvenile arthritis, 2 (0.5%) haemochromatosis, 3 (0.7%) ankylosing spondylitis, 2 (0.5%) giant cell arteritis, and 8 miscellaneous diagnoses. The other 140 patients (32%) could not be reclassified in any clear-cut diagnosis and had features of transient arthritis (n=41), seronegative spondyloarthritis (n=47), while 49 remained unspecified. CONCLUSIONS: Over a 10-year follow-up period, reclassification revealed significant heterogeneity in the diagnosis of seronegative RA. Therefore, seronegative arthritis should not be studied as a homogenous entity. PMID- 29998833 TI - Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients. AB - OBJECTIVES: Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients. METHODS: Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinicalparameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti SSA/Ro and anti-SSB/La), complement, and disease activity (SLEDAI and BILAG) were studied. RESULTS: SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetemcomitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity. CONCLUSIONS: Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients. These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to lupus therapies. PMID- 29998834 TI - Clinical characteristics and mortality rate of Thai elderly-onset systemic sclerosis. AB - OBJECTIVES: To identify the clinical differences and mortality rate between adult and elderly onset systemic sclerosis (SSc). METHODS: We conducted a historical cohort study of SSc patients during January 2007-December 2011. The SSc patients were 60 and over classified as elderly onset SSc. Cox regression analysis was used to estimate the probability of survival and for assessing the factors associated with mortality. RESULTS: The medical records of 350 SSc patients were reviewed; 53 (15.1%) had elderly onset SSc. According to the multivariate analysis, elderly onset SSc has a higher WHO functional class, more frequent weakness, more frequent hyperCKaemia, and less pulmonary fibrosis than adult onset SSc (p=0.004, 0.02, 0.02, 0.02, respectively). The incidence of mortality was 3.8 per 100 person-year with a median survival rate of 15.9 years (95%CI 12.4 17.3). The mortality rate of elderly SSc onset was significantly higher than that of adult SSc onset (HR 5.71; 95%CI 3.54-9.20). The median survival of elderly and adult onset SSc was 4.9 years and 16.1 years, respectively. The Cox regression analysis indicated that presence of digital ulcer and tendon friction rub had a respective HR of 7.39 (95%CI 1.28-42.60) and 37.23 (95%CI 2.10-659.09) for predicting mortality of elderly onset SSc. CONCLUSIONS: Myopathy and limitation of physical activity were frequently found among elderly onset SSc over against pulmonary involvement than in adult onset SSc. Mortality of elderly onset SSc was 5.7 times higher, and median survival was 11 years shorter, than adult onset SSc. PMID- 29998835 TI - The majority of patients with psoriatic arthritis are not eligible for randomised clinical trials. AB - OBJECTIVES: To identify the proportion of patients with psoriatic arthritis (PsA) who would meet inclusion criteria of the randomised clinical trials that were performed leading up to registration of the tumour necrosis factor inhibitors (TNFi). METHODS: Data from 329 patients with PsA were obtained from an Icelandic database, ICEBIO, medical records at the University Hospital of Iceland, and the private out-patient clinic Laeknasetrid Ltd. The patients were classified according to whether they met the inclusion criteria of the clinical trials that were performed ahead of the registration of each respective TNFi. The reasons for exclusion were also explored. RESULTS: 34% of the patients with complete data available met the inclusion criteria. Clinical data in respect to exclusion and inclusion criteria were incomplete for 13% of the cases. The proportion of patients who met the inclusion criteria was highest among those who received adalimumab and etanercept (53%). Patients who received in iximab had the lowest inclusion rate (23%). The main reason why patients did not meet the inclusion criteria was too few swollen and/or tender joints, or in 45% of excluded cases. CONCLUSIONS: Our results demonstrate that two thirds of patients with PsA in Iceland who are treated with TNFi would not have qualified for the randomised clinical trials performed leading up to the registration of the medications. Further studies with regards to whether outcomes are different between those who met the inclusion criteria and those who did not remain to be performed. PMID- 29998836 TI - Quantification of skin stiffness in patients with systemic sclerosis using real time shear wave elastography: a preliminary study. AB - OBJECTIVES: To assess the diagnostic value of shear wave elastography (SWE) quantification in patients with systemic sclerosis (SSc) and healthy controls. METHODS: Skin elastic modulus (E) values and thicknesses were measured at 6 skin sites between the SSc (n=37) and control (n=37) groups. Thickness and E values were converted into T- and E-scores, to allow skin thickness and stiffness of different regions to be quantified based on a single standard. T- and E-scores were compared with the modified Rodnan skin score (mRSS). RESULTS: E values were significantly higher in SSc patients than healthy controls at all measured sites (p<0.001), whereas skin thickness increased significantly only at fingers and forearms (p<0.001). E-score analysis revealed mRSS differences within 1.0 at most sites, while T- score evaluation only showed differences between mRSS 0 and mRSS 1 at fingers. Interestingly, mRSS correlated more closely with skin stiffness (r=0.889, p<0.001) than skin thickness (r=0.465, p=0.002). CONCLUSIONS: In patients with SSc, SWE is more sensitive to detect subtle skin changes than B mode ultrasound (US), and reflect the degree of skin involvement. As a non invasive and operator-independent technique, SWE may provide a new and valuable method to evaluate the degree and changes of skin involvement in SSc patients. PMID- 29998837 TI - Reduction of peripheral natural killer cells in patients with SAPHO syndrome. AB - OBJECTIVES: Little is known about the roles of peripheral immune cell subsets in synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome. Up to now, just a few studies have focused on this issue. We aimed to analyse the distribution and phenotype of T cell subsets and natural killer (NK) cells in the peripheral blood of patients with SAPHO syndrome. METHODS: The proportion and absolute counts of circulating immune cells were assessed in 19 patients diagnosed as SAPHO syndrome and 19 healthy controls. CD4+T cell subsets were also analysed in 9 untreated SAPHO patients and 9 healthy volunteers by flow cytometry. RESULTS: The proportion and absolute counts of NK cells were significantly reduced in SAPHO patients in comparison with the controls (proportion, 10% vs. 18%, p<0.001; absolute counts, 231/MUl vs. 307/MUl, p=0.014). Conversely, the proportion and absolute counts of Th17 cells in untreated SAPHO patients were significantly higher than that in the healthy controls (proportion, 1.49% vs. 0.93%, p=0.004; absolute counts, 14.36/MUl vs. 5.14/MUl, p<0.001). Similarly, Th17/Th1 cells were significantly increased (proportion, 0.45% vs. 0.33%, p=0.024; absolute number, 5.47/MUl vs. 1.98/MUl, p<0.001), but there was no significant difference between the percentage and number of Treg cells in patients with SAPHO syndrome and healthy controls. Thus, the ratio of Th17/Treg was increased in SAPHO patients (0.68 vs. 0.17, p=0.004). CONCLUSIONS: Our data suggested that the immune inflammation in SAPHO patients may be related to the depletion of NK cells and the imbalance of Th17 and Treg cells. A reduction of peripheral NK cells may exacerbate the disease progression by not being inhibited Th17 cells. PMID- 29998838 TI - Down-regulation of serum miR-151a-3p is associated with renal tissue activity in class IV lupus nephritis. AB - OBJECTIVES: The aim of this study was to explore the value of serum miRNA for evaluating renal tissue activity in patients with class IV lupus nephritis (LN). METHODS: First, we used a microRNA array to identify miRNAs differentially expressed between class IV LN patients and healthy volunteers (n=4/group). Then, we analysed the association between these identified miRNAs and renal tissue activity in class IV LN patients. Finally, to validate the results, 20 class IV LN patients (confirmed by renal biopsy) and 20 healthy control volunteers were further studied. RESULTS: We found 23 miRNAs to be significantly differentially expressed between the 2 groups. We selected 5 of these miRNAs (miR-3165, miR-4762 5p, miR-146a-5p, miR-151a-3p, and miR-21-5p) for further experiments. In validation experiments, expression of miRNA-151a-3p was significantly down regulated in the class IV LN group compared to that in the control group (p<0.01) and was negatively correlated with the activity index (AI) in the class IV LN group(r=-0.526, p=0.017); the internal correlation was described with a linear fitting equation (p<0.01). CONCLUSIONS: Serum miR-151a-3p expression was decreased in class IV LN patients compared with healthy control volunteers and was negatively correlated with renal tissue activity. Thus, miR-151a-3p may play a employed for diagnosing class IV LN and evaluating renal tissue activity. PMID- 29998839 TI - Paediatric Behcet's disease in Iran: report of 204 cases. AB - OBJECTIVES: This study proposed to report the characteristics of paediatric Behcet's disease (PED-BD) in a cohort of patients from Iran's registry and compare them with different reports throughout the world. METHODS: From a cohort of 7504 Iranian patients with Behcet's disease those diagnosed before the age of 16 years were included in this study. Data were collected on a standard protocol comprising 105 items, including demographic features, type of presentation, and different clinical and laboratory findings. RESULTS: PED-BD was seen in 2.7% of patients. The male/female ratio was 1.02/1, and the mean age at onset was 10.5+/ 3.4. Positive familial history was present in 9.9%. As a first manifestation, oral aphthosis was the most frequent (75%) followed by ocular lesions in 19.1%. The prevalence rates of various manifestations were as follows: oral aphthosis: 91.7%; genital ulcer: 42.2%; skin: 51.5% (pseudofolliculitis: 43.1%, erythema nodosum: 10.3%); ocular lesions: 66.2% (anterior uveitis 52%, posterior uveitis 58.3%, retinal vasculitis 39.7%); articular manifestations: 30.9%; neurological involvement: 4.9%; vascular involvement: 6.4% (venous 4.9%, arterial 2.5%); gastrointestinal manifestations: 5.9%; epididymo-orchitis: 8.7% (boys); high ESR (>=20): 50.8%; abnormal urine: 14.1%; positive pathergy test: 57%; HLA-B5/51: 48.7%. ICBD criteria have the highest sensitivity for the classification of PED BD patients in Iran (91.7%). CONCLUSIONS: The clinical spectrum of PED-BD in Iran in this study was similar to that of other reports; however, genital ulcers, skin lesions (notably erythema nodosum), and gastrointestinal involvement were noticed to occur less frequently, while ocular lesions were more frequent and more severe compared to other reports. PMID- 29998840 TI - What is metacarpophalangeal joint swelling in psoriatic arthritis? Ultrasound findings and reliability assessment. AB - OBJECTIVES: To evaluate by ultrasound (US) the frequency and reliability of peritenon extensor tendon inflammation (PTI) and intra articular synovitis (IAS) in metacarpophalangeal joints (MCPj) of psoriatic arthritis (PsA) patients. METHODS: 27 PsA patients with clinical involvement of MCPj were consecutively included. Presence of PTI and IAS were evaluated by grey-scale (GS) and power Doppler (PD). Longitudinal and transverse 3-5 second videos of US examinations were recorded for reliability assessments by five readers. Consensus on positive US results was achieved when at least three readers agreed. RESULTS: Clinical swelling was present in 60 joints whereas US detected IAS and/or PTI in 75 MCPj. GS PTI in at least one MCPj was found in 19 patients and 41 joints, concurring with clinical swelling in 30/41. GS IAS in at least one MCPj was found in 23 patients and 63 joints, concurring with clinical swelling in 37/63. The inter reader reliability was good for PD PTI and moderate for GS PTI. CONCLUSIONS: Our study identifies that both IAS and PTI cause MCPj swelling, where PTI is almost as frequent as IAS as a cause of swelling. The reliability of PTI is at least as good as for IAS. PMID- 29998841 TI - Short-term costs associated with non-medical switching in autoimmune conditions. AB - OBJECTIVES: To estimate short-term costs associated with non-medical switch (NMS) from originator biologics to biosimilars among stable patients with autoimmune conditions in rheumatology, gastroenterology, and dermatology from a US provider's and third-party payer's perspective. METHODS: An economic model was constructed to estimate switching costs related to physician time and healthcare resource utilisation (HRU) at the initial NMS visit and over 3 months. The proportion of patients with relevant conditions treated with originators and expected NMS rate, physician time, HRU, and payer reimbursement were derived from a physician survey. Switching costs were estimated for a practice of 1,000 patients with relevant conditions by therapeutic area and for an insurance plan with 1 million individuals by therapeutic area and all areas combined. Switching cost drivers were assessed with one-way sensitivity analyses. RESULTS: Physicians expected extra 6 minutes for the NMS visit and 22 minutes over 3 months; NMS rates of 14.4%, 15.5%, and 17.7%; and 11.3%, 16.2%, and 33.2% of time not reimbursed for gastroenterology, rheumatology, and dermatology, respectively. The total switching costs for payer's were $771,460 (for n = 3,609 patients with an NMS rate of 16.6%), mostly due to follow-up visits and additional laboratory tests/procedures. In sensitivity analyses, the NMS rate was the main cost driver. Increasing the NMS rate to 25% and 50% increased payer's total switching costs to $1.19 and $2.39 million, respectively. CONCLUSIONS: Originator-to-biosimilar NMS in stable patients with autoimmune conditions could result in considerable switching costs for both providers and payers. PMID- 29998842 TI - Ultrasound detection of subclinical synovitis in rheumatoid arthritis patients in clinical remission: a new reduced-joint assessment in 3 target joints. AB - OBJECTIVES: The ability of ultrasound (US) to identify subclinical joint inflammation in rheumatoid arthritis (RA) patients in remission has been already reported. Nonetheless, current studies present a lack of homogeneity in patient's characteristics and number of joints assessed by US. The aim of this study was to identify a reduced set of target joints to be scanned in RA patients in clinical remission in order to detect subclinical synovitis. METHODS: Forty RA patients in clinical remission (DAS28 <=2.6) for at least 3 months underwent an US examination of 18 joints: wrist, II-III-IV-V metacarpophalangeal (MCP) and II-III IV-V metatarsophalangeal joints bilaterally. The presence of synovial hypertrophy (SH) and power-Doppler (PD) signal was registered following the OMERACT definitions and was graded according to a 4-point scale (0-3). Then, by applying a process of data reduction based on the frequency of joint involvement, a reduced assessment was obtained. RESULTS: Twenty (50%) subjects had at least one joint affected by active synovitis; 17.5% presented grade 1 PD and 32.5% grade 2 PD. The joints most frequently affected by active synovitis were the wrists (75%) and the II MCP joints (55%). After data reduction, the evaluation of 3 joints (both wrists and the II MCP of the dominant hand) obtained a sensitivity of 90% for the detection of subclinical synovitis. CONCLUSIONS: The US scan of 3 target joints showed a high sensitivity in detecting subclinical active synovitis in RA patients in clinical remission and can be feasible in the routine assessment of these patients. PMID- 29998843 TI - Duration of anti-TNF treatment in vascular Behcet's disease: better to prolong treatment? PMID- 29998844 TI - Overweight and obesity affect clinical assessment of synovitis in rheumatoid arthritis: comparison of ultrasonography and clinical exam. AB - OBJECTIVES: Body mass index (BMI) might affect rheumatoid arthritis (RA) outcomes. Clinical assessment of swollen joint count (SJC) might also be affected by obesity in terms of obesity-related excess adipose tissue. In this study, we compared ultrasonography (US) and clinical examination in assessing the effect of BMI on RA disease activity assessment. METHODS: This was a single-centre study including RA (ACR/EULAR criteria) patients. US assessment was performed by one trained rheumatologist blinded to clinical data. US synovitis was defined as grey scale score >=2 and/or power Doppler score >=1. The primary outcome measure was difference in SJC (DeltaSJC) between clinical and US assessment (US-clinical examination). The secondary outcome was to evaluate the difference between clinical and US assessment of the Disease Activity Score in 28 joints (DeltaDAS28) in the 3 BMI subgroups according to the WHO classification. RESULTS: We included 76 RA patients (mean age 53.8 +/- 11.8 years; 67% female). Overall, 28 (36.8%), 33 (43.4%) and 15 (19.7%) were normal weight, overweight and obese, respectively. Baseline characteristics did not differ between the 3 BMI subgroups. US-determined SJC was significantly higher than clinical-determined SJC for overweight and obese RA patients: p=0.001 and p=0.049, respectively. The DAS28 was higher with US than clinical examination within the overweight group only (p=0.002). One-way analysis of variance (ANOVA) revealed a significant difference between DeltaDAS28 among the 3 BMI subgroups (p=0.046). CONCLUSIONS: In high BMI RA patients both SJC and DAS28 seem to be undervalued by clinical assessment when compared to US. PMID- 29998845 TI - Why male patients with Behcet's disease prone to thrombosis? A rotational thromboelastographic analysis. AB - OBJECTIVES: To investigate whether there is a difference between male and female patients with Behcet's disease (BD) in terms of hypercoagulability by using modified rotational thromboelastograhic (ROTEM) analysis. METHODS: 126 BD patients (71 male, 55 female; mean age: 41+/-9 yrs) who met ISSG criteria for BD were included into the study. 23 patients with vasculitis (16 female, 7 male; mean age 49+/-16 yrs), and 25 healthy individuals (11 female, 14 male; mean age: 37+/-10 yrs) were included to the study as disease and healthy control (HC) group, respectively. Clotting time (CT), clot formation time (CFT) and maximum clot firmness (MCF) were determined by INTEM and EXTEM analyses. As a marker of vascular endothelial injury, along with inflammatory markers, vWFag levels were investigated in patients and HC group. RESULTS: Extem-CFT was shorter in only vasculitic group compared to HC group. Intem-CFT was found to be shorter in BD patients and vasculitis group compared to HC. Intem-MCF was significantly longer in male BD patients than female BD patients. Extem-CFT was found to be shorter in male BD patients compared to female BD patients. Extem-MCF was statistically longer in male BD patients. In inactive male BD patients, while Intem-CFT was shorter than HC individuals, Intem-MCF and Extem-MCF were statistically longer than HC (p<0.02, p<0.03), respectively. However, no significant differences were found between inactive female BD patients and HC in terms of all ROTEM parameters. CONCLUSIONS: These results support that male BD patients have a hypercoagulable state compared to female BD patients, which may explain why male patients are prone to thrombotic complications. PMID- 29998846 TI - Valid molecular dynamics simulations of human hemoglobin require a surprisingly large box size. AB - Recent molecular dynamics (MD) simulations of human hemoglobin (Hb) give results in disagreement with experiment. Although it is known that the unliganded (T[Formula: see text]) and liganded (R[Formula: see text]) tetramers are stable in solution, the published MD simulations of T[Formula: see text] undergo a rapid quaternary transition to an R-like structure. We show that T[Formula: see text] is stable only when the periodic solvent box contains ten times more water molecules than the standard size for such simulations. The results suggest that such a large box is required for the hydrophobic effect, which stabilizes the T[Formula: see text] tetramer, to be manifested. Even in the largest box, T[Formula: see text] is not stable unless His146 is protonated, providing an atomistic validation of the Perutz model. The possibility that extra large boxes are required to obtain meaningful results will have to be considered in evaluating existing and future simulations of a wide range of systems. PMID- 29998847 TI - Magnetic imaging of a single ferromagnetic nanowire using diamond atomic sensors. AB - Recent advances in nanorobotic manipulation of ferromagnetic nanowires bring new avenues for applications in the biomedical area, such as targeted drug delivery, diagnostics or localized surgery. However, probing a single nanowire and monitoring its dynamics remains a challenge since it demands high precision sensing, high-resolution imaging, and stable operations in fluidic environments. Here, we report on a novel method of imaging and sensing magnetic fields from a single ferromagnetic nanowire with an atomic-scale sensor in diamond, i.e. diamond nitrogen-vacancy (NV) defect center. The distribution of static magnetic fields around a single Co nanowire is mapped out by spatially distributed NV centers and the obtained image is further compared with numerical simulation for quantitative analysis. DC field measurements such as continuous-wave ODMR and Ramsey sequence are used in the paper and sub Gauss level of field sensing is demonstrated. By imaging magnetic fields at a single nanowire level, this work represents an important step toward tracking and probing of ferromagnetic nanowires in biomedical applications. PMID- 29998848 TI - Anomalous effect of UV light on the humidity dependence of photocurrent in perovskite solar cells. AB - Effect of oxygen on the humidity dependence of photocurrent in the presence of UV light has been studied for perovskite solar cells. We observed that the magnitude of photocurrent increases with decreasing humidity initially, but below a certain level, the photocurrent starts to decrease when the humidity is reduced by sending dry nitrogen gas. If we decrease the humidity by sending dry air (keeping nitrogen to oxygen ratio same), then this effect is absent. This phenomenon is related to the presence of oxygen in the environment. When humidity is decreased by flowing dry nitrogen, the oxygen present in the environment of perovskite solar cell also reduces. We found that in the reduced oxygen condition, the presence of UV light helps to remove oxygen from the surface of the mesoporous TiO2 which is responsible for the reduction of photocurrent. In the presence of white light, this effect is not observed. To understand the phenomenon we studied low-frequency noise and current-voltage characteristics, and the dielectric properties of perovskite solar cells under various conditions. PMID- 29998849 TI - Nickel stamp origination from generic SU-8 nanostructure arrays patterned with improved thermal development and reshaping. AB - In this study, we show that rapid, reliable, and scalable custom-input colour patterning and eye-readable data storage can be achieved through high-throughput nanoimprinting-exposure-thermal-treatment (NETT) and thermal development and reshaping (TDR) techniques. The main impediment for commercial realization of high-resolution metasurfaces using NETT and TDR is the cost and speed of stamp origination as well as the quality and durability of the fabricated stamp. In order to accelerate the patterning process, lower the fabrication costs, and obtain patterns with high-resolution, we introduce and optimize a new method for origination of durable Ni stamps by electroplating on an SU-8 master fabricated according to custom-input colour patterns via NETT and TDR. In these processes, laser exposure is used to locally activate the generic RGB pixels fabricated on SU-8 via thermal nanoimprint lithography (NIL), according to the custom design. Upon TDR treatment, the exposed regions crosslink while the unexposed areas flatten. TDR is optimized to find the fastest processing condition that results in minimum nanocone height reduction and maximum diffraction efficiency. AFM results show that the TDR-processed nanocones in all red, green, and blue subpixels witness minimal shrinkage in comparison with the corresponding as imprinted RGB pixels. Among three different sets of direct baking and ramping temperature TDR experiments, direct 55 degrees C-10 min TDR is found to be the optimal recipe. As a proof-of-concept, the originated stamp was employed to replicate colour images on PET and glass substrates using UV-thermal NIL. The reproduced colour image, photographed at pre-defined lighting and viewing angles, bears vivid diffractive colours with different RGB ratios that are in good match with the custom-input image. Furthermore, the red, green, and blue diffraction peaks from the TDR-55 degrees C-baked sample exhibit either trivial or no distinguishable difference as compared to the corresponding peaks in the as imprinted sample. PMID- 29998850 TI - Dodecagonal plasmonic quasicrystals for phage-based biosensing. AB - In this work, we fabricate and characterize a novel sensitive two-dimensional surface enhanced Raman spectroscopy (SERS) substrate made of plasmonic nanocavities in a photonic quasicrystal arrangement characterized by a 12-fold rotational symmetry. Our SERS device is capable of detecting chemisorbed bacteriophages at a femtomolar range. Most importantly, the paper presents for the first time a study on the procedure to functionalize the plasmonic quasicrystal with bacteriophages of the Podoviridae family. The immobilization of the phages on the plasmonic substrate has been studied and verified through SERS measurements. A new stable peak, visible in the SERS spectra at 1326 cm-1 at a greater than 60 times amplification, confirms the immobilization of the phages on the substrate. This functionalization approach can be used also for other types of phages or plasmonic sensors and hence, our achievements could allow the development of novel systems for the specific detection of different species of bacteria. PMID- 29998851 TI - Re-inspiring the genetic algorithm with multi-level selection theory: multi-level selection genetic algorithm. AB - Genetic algorithms are integral to a range of applications. They utilise Darwin's theory of evolution to find optimal solutions in large complex spaces such as engineering, to visualise the design space, artificial intelligence, for pattern classification, and financial modelling, improving predictions. Since the original genetic algorithm was developed, new theories have been proposed which are believed to be integral to the evolution of biological systems. However, genetic algorithm development has focused on mathematical or computational methods as the basis for improvements to the mechanisms, moving it away from its original evolutionary inspiration. There is a possibility that the new evolutionary mechanisms are vital to explain how biological systems developed but they are not being incorporated into the genetic algorithm; it is proposed that their inclusion may provide improved performance or interesting feedback to evolutionary theory. Multi-level selection is one example of an evolutionary theory that has not been successfully implemented into the genetic algorithm and these mechanisms are explored in this paper. The resulting multi-level selection genetic algorithm (MLSGA) is unique in that it has different reproduction mechanisms at each level and splits the fitness function between these mechanisms. There are two variants of this theory and these are compared with each other alongside a unified approach. This paper documents the behaviour of the two variants, which show a difference in behaviour especially in terms of the diversity of the population found between each generation. The multi-level selection 1 variant moves rapidly towards the optimal front but with a low diversity amongst its children. The multi-level selection 2 variant shows a slightly slower evolution speed but with a greater diversity of children. The unified selection exhibits a mixed behaviour between the original variants. The different performance of these variants can be utilised to provide specific solvers for different problem types when using the MLSGA methodology. PMID- 29998852 TI - Hierarchical C/SiO x /TiO2 ultrathin nanobelts as anode materials for advanced lithium ion batteries. AB - TiO2-based nanomaterials are demonstrated to be a promising candidate for next generation lithium ion batteries due to their stable performance and easy preparation. However, their inherent low capacity impedes their wide application compared to commercial carbon nanomaterials. Here we present a unique in situ grafting-graphitization method to achieve a ternary nanocomposite of C/SiO x /TiO2 ultrathin nanobelts with a core-shell heterostructure. The obtained ternary nanocomposite integrates the merits of high specific capacity of SiO x , the excellent mechanical stability of graphite-like carbon and the high reactivity of TiO2. Cyclic voltammetric curves and cycling performance manifest the optimal ternary nanocomposite and deliver a very high initial specific capacity of ~1196 mA h g-1 with both good rate capability (~200 mA h g-1 up to 10 C) and especially enhanced cycle stability. Our work demonstrates that building hierarchical core shell heterostructures is an effective strategy to improve capacity and cycling performance in other composite anodes for electrochemical energy storage materials. PMID- 29998853 TI - A small number of objective function weight vectors is sufficient for automated treatment planning in prostate cancer. AB - Current practice for treatment planning optimization can be both inefficient and time consuming. In this paper, we propose an automated planning methodology that aims to combine both explorative and prescriptive approaches for improving the efficiency and the quality of the treatment planning process. Given a treatment plan, our explorative approach explores trade-offs between different objectives and finds an acceptable region for objective function weights via inverse optimization. Intuitively, the shape and size of these regions describe how 'sensitive' a patient is to perturbations in objective function weights. We then develop an integer programming-based prescriptive approach that exploits the information encoded by these regions to find a set of five representative objective function weight vectors such that for each patient there exists at least one representative weight vector that can produce a high quality treatment plan. Using 315 patients from Princess Margaret Cancer Centre, we show that the produced treatment plans are comparable and, for [Formula: see text] of cases, improve upon the inversely optimized plans that are generated from the historical clinical treatment plans. PMID- 29998854 TI - Graphitic carbon nitride nano sheets functionalized with selected transition metal dopants: an efficient way to store CO2. AB - Proficient capture of carbon dioxide (CO2) is considered to be a backbone for environment protection through countering the climate change caused by mounting carbon content. Here we present a comprehensive mechanism to design novel functional nanostructures capable of capturing a large amount of CO2 efficiently. By means of van der Waals corrected density functional theory calculations, we have studied the structural, electronic and CO2 storage properties of carbon nitride (g-C6N8) nano sheets functionalized with a range of transition metal (TM) dopants ranging from Sc to Zn. The considered TMs bind strongly to the nano sheets with binding energies exceeding their respective cohesive energies, thus abolishing the possibility of metal cluster formation. Uniformly dispersed TMs change the electronic properties of semiconducting g-C6N8 through the transfer of valence charges from the former to the latter. This leaves all the TM dopants with significant positive charges, which are beneficial for CO2 adsorption. We have found that each TM's dopants anchor a maximum of four CO2 molecules with suitable adsorption energies (-0.15 to -1.0 eV) for ambient condition applications. Thus g-C6N8 nano sheets functionalized with selected TMs could serve as an ideal sorbent for CO2 capture. PMID- 29998855 TI - A new high performance MSM hybrid plasmonic photodetector based on nanogratings and dual mode horn shape waveguide. AB - A new metal-semiconductor-metal photodetector (MSM-PD) based on a hybrid plasmonic and extra ordinary transmission (EOT) phenomenon is proposed. In the designed structure, we demonstrate that light transmission is improved by means of a new shape of surface nanograting and by optimizing the physical parameters of the metal. In this work the optical transfer parameters are strongly interrelated and all the parameters are optimized and the light transmission is enhanced by 55 times compared to the reference structure. Furthermore, the output port of the subwavelength slit in the presented MSM-PD has a dual horn shape and improves absorption light in the active layer of the structure. Also, by filling this port with the same type of material as that of the active layer, the absorption becomes greater than before. Moreover, the confinement region of the light in the active layer is reduced by using the hybrid plasmonic effect and therefore, the probability of the photon absorption is 101 times greater than that of the reference structure. Thus, the transmission and absorption enhancement improves the quantum efficiency and the electrical response of the presented MSM-PD. A high performance new photodetector is identified as an ultra fast MSM-PD and because of its thin film active layer can be used as a low-noise one. PMID- 29998856 TI - Self-controlled multilevel writing architecture for fast training in neuromorphic RRAM applications. AB - Memristor crossbar arrays naturally accelerate neural networks applications by carrying out parallel multiply-add operations. Due to the abrupt SET operation characterizing most RRAM devices, on-chip training usually requires either from iterative write/read stages, large and variation-sensitive circuitry, or both, to achieve multilevel capabilities. This paper presents a self-controlled architecture to program multilevel devices with a short and fixed operation duration. We rely on an ad hoc scheme to self-control the abrupt SET, choking the writing stimulus as the cell addresses the desired level. To achieve this goal, we make use of the voltage divider concept by placing a variable resistive load in series with the target cell. We validated the proposal against thorough simulations using RRAM cells fitting extremely fast physical devices and a commercial 40 nm CMOS technology, both exhibiting variability. For every case the proposed architecture allowed progressive and almost-linear resistive levels in each [Formula: see text] and [Formula: see text] crossbars structures. PMID- 29998857 TI - Defect-free InAsSb nanowire arrays on Si substrates grown by selective-area metal organic chemical vapor deposition. AB - We report the realization of defect-free InAsSb nanowire (NW) arrays on Si substrates by selective-area metal-organic chemical vapor deposition. We studied the effects of growth temperature and the morphology of patterned Si/SiO2 substrates on the formation of InAsSb NW arrays, and found that both the morphology and the yield of the NW arrays were sensitive to the growth conditions. By optimizing the growth conditions, we achieved high-quality InAsSb NW arrays, which exhibited a pure zinc-blende crystal structure without any defects. In addition, based on the as-grown NWs, we fabricated back-gated field effect transistors devices that showed an electron mobility of 2000 cm2 V-1 s-1 at room temperature. PMID- 29998858 TI - Gamma-ray spectroscopy for probing highly radioactive items behind thick shields? AB - In favourable circumstances, including the availability of prior knowledge, a potential use of gamma-ray spectroscopy with an HPGe detector for probing highly radioactive items behind thick shields is described. PMID- 29998859 TI - High-performance photodetector based on hybrid of MoS2 and reduced graphene oxide. AB - 2D materials are a promising new class of materials for next generation optoelectronic devices owing to their appealing optical and electrical properties. Pristine molybdenum disulfide (MoS2) is widely used in next generation photovoltaic and optoelectronic devices, but its low photo-dark current ratio prevents its use in highly efficient photo detection applications. Here, we decorated crumpled reduced graphene oxide (rGO) particles on a large area vertically aligned MoS2 flake network to enhance the performance of the MoS2 based photodetector by forming multiple nanoscale p-n heterojunctions. The rGO/MoS2 device exhibited a significantly improved photoresponsivity of ~2.10 A W 1 along with a good detectivity of ~5 * 1011 Jones (Jones = cm Hz1/2/W) compared to that of the pristine MoS2 photodetector in ambient atmosphere. Moreover, the rGO/MoS2 photodetector showed a fast response of ~18 ms with excellent stability and reproducibility in ambient air even after three months. The high performance of the photodetector is attributed to enhanced photoexcited carrier density and suppressed photo generated electron-hole recombination due to the strong local built-in electric field developed at the rGO/MoS2 interface. Our results showed that integration of rGO with MoS2 provides an efficient platform for photo detection applications. PMID- 29998860 TI - Strain-induced dimensional phase change of graphene-like boron nitride monolayers. AB - We investigate the coupling between the electronic bandgap and mechanical loading of graphene-like boron nitride (h-BN ) monolayers up to failure strains and beyond by means of first-principles calculations. We reveal that the kinks in the bandgap-strain curve are coincident with the ultimate tensile strains, indicating a phase change. When the armchair strain is beyond the ultimate tensile strain, h BN fails with a phase transformation from 2D honeycomb to 1D chain structure, characterized by the 'V'-shape bandgap-strain curve. Large biaxial strains can break the 2D honeycomb structures into 0D individual atoms and the bandgap closes. PMID- 29998861 TI - Autologous noncultured melanocyte-keratinocyte transplantation in stable vitiligo: A randomized comparative study of recipient site preparation by two techniques. AB - Background: Accurate preparation of recipient area is a critical step in melanocyte-keratinocyte transplantation procedure for vitiligo. It is an important potential step for adaptation in the quest to achieve better results and ablative lasers potentially offer excellent precision over margin and depth control in achieving that. Objective: To compare between the two techniques used for recipient site preparation: Er:YAG laser ablation and mechanical dermabrasion for melanocyte-keratinocyte transplantation procedure in terms of re-pigmentation achieved and adverse effects seen. Methods: A randomized comparative trial was performed among 32 patients of stable vitiligo undergoing melanocyte-keratinocyte transplantation procedure. In Group A (n = 15), recipient site preparation was done with Er:YAG laser, and in Group B (n = 17), it was done with a motorized dermabrader. Patients of both groups were objectively assessed for re pigmentation at 1, 3 and 6 months. Results: A total of 253.696 cm2 of depigmented surface was operated upon and re-pigmentation of 125.359 cm2 (49.4%) was achieved. On comparison between two groups, no statistical difference was found with respect to total re-pigmentation achieved (Group A: 54.67% vs Group B: 48.841%, P = 0.663) and grades of re-pigmentation achieved (P = 0.796). Occurrence of adverse events was also statistically similar in both the groups. Conclusion: This study did not reveal any statistically different outcome (in terms of re-pigmentation and adverse effects) between the two methods of recipient site preparation - motorized dermabrasion and Er:YAG ablation. Limitations: This study is small and larger studies are needed to ascertain the benefit of Er:YAG for recipient site preparation. Future studies may also ascertain variables such as time taken to prepare the recipient area, nature of bleeding, postoperative healing, difficulties in specific area, cost of the procedure, patient comfort and ease of the surgeon, rather than comparing the re pigmentation alone. PMID- 29998863 TI - Isotretinoin and dermatosurgical procedures. AB - Several early reports suggested that performance of dermatosurgical procedures in patients on oral isotretinoin is associated with abnormal skin healing, keloid or hypertrophic scar formation. However, this association has been recently questioned in some studies. This review examines this issue, analyzes the studies published and concludes that the recommendation made earlier about the need to avoid dermatosurgical procedures in patients on isotretinoin is based on inadequate and insufficient evidence and hence needs revision. The review also suggests that recent studies on the subject establish that performing such procedures is safe. PMID- 29998862 TI - Reduced immunohistochemical expression of CCN3 in vitiligo. AB - Background: Defective adhesion seems to be involved in the chronic loss of melanocytes observed in vitiligo. Recent findings showed an association of genetic variants of an adhesion gene with vitiligo and reduced immunohistochemical expression of some adhesion molecules in vitiligo skin. Aims: To compare CCN3 immunohistochemical expression in lesional and non-lesional epidermis of individuals with vitiligo. Methods: A total of 66 skin specimens from 33 volunteers with vitiligo were analyzed by immunohistochemistry using anti CCN3 antibodies. Absence of topical or systemic treatment for vitiligo over the previous 30 days and availability of an area of non-lesional skin for biopsy at least 15 cm away from any vitiliginous macules were the main inclusion criteria. Results: A significant reduction of CCN3 expression was observed in lesional skin as compared to non-lesional skin (P = 0.001). Limitations: Paraffin embedded skin samples do not allow investigation by molecular biology methods. Not all samples allowed analysis due to the lamina preparation technique. Complete clinical data was not available for all patients. Conclusion: Our results support the hypothesis of impaired cell adhesion in vitiligo suggested by genetic studies. The pattern of immunohistochemical expression suggests that vitiligo might be an epithelial disease and not just a melanocyte disorder. PMID- 29998864 TI - Safety of important dermatological drugs (retinoids, immune suppressants, anti androgens and thalidomide) in reproductively active males with respect to pregnancy outcome: A brief review of literature. AB - Paternally transmitted damage to offspring is recognized as a complex issue. Each parent contributes 23 chromosomes to a child; hence, it is necessary to know the effects of both maternal and paternal pre-and peri-conceptional exposure to drugs on pregnancy outcome. While there are many studies on the effects of maternal drug exposure on pregnancy outcome, literature on paternal exposure is scarce. Of late however, paternal exposure has been receiving increasing attention. We present a brief review on the safety of commonly used drugs in dermatology, focused on retinoids, immune suppressants, anti androgens and thalidomide. PMID- 29998865 TI - Universal health coverage in India: Progress achieved & the way forward. PMID- 29998866 TI - World immunization week 2018: What lessons for India? PMID- 29998867 TI - Analyzing lipids in the liver & in the red blood cell membrane in liver diseases. PMID- 29998868 TI - Chronic obstructive pulmonary disease in non-smokers - Is it a different phenotype? PMID- 29998869 TI - Oxidative stress as a possible pathogenic cofactor of post-menopausal osteoporosis: Existing evidence in support of the axis oestrogen deficiency-redox imbalance-bone loss. AB - Post-menopausal osteoporosis (PO) is one of the major health issues associated with menopause-related oestrogen withdrawal. Despite the intense research and the relevant progress achieved in the last two decades, the pathogenic mechanism underlying PO is still poorly understood. As a consequence of this gap in the knowledge, such disorder and the related complications are still difficult to be effectively prevented. A wealth of experimental and epidemiological/clinical evidence suggests that the endocrine change associated to menopausal transition might lead to a derangement of redox homeostasis, that is, the prelude to the health-threaten condition of oxidative stress (OxS). In turn, this (bio)chemical stress has been widely hypothesized to contribute, most likely in synergy with inflammation, to the development of menopause-related diseases, including PO. The main aim of this review is to discuss the current literature evidence on the association between post-menopausal oestrogen withdrawal, OxS and PO. It is also aimed to provide a critical overview of the most significant epidemiological studies on the effects of dietary antioxidants on bone health and to devise a strategy to overcome the limitations emerged and controversial results. PMID- 29998870 TI - Erythrocyte membrane fatty acid profile & serum cytokine levels in patients with non-alcoholic fatty liver disease. AB - Background & objectives: Fatty acids may affect the expression of genes, and this process is influenced by sex hormones. Cytokines are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), so this study was aimed to assess the association of erythrocyte membrane fatty acids with three cytokines and markers of hepatic injury in NAFLD patients and to explore whether these associations were the same in both sexes. Methods: In this cross-sectional study, 62 consecutive patients (32 men and 30 women) with NAFLD during the study period. Tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), aspartate aminotransferase and alanine aminotransferase were measured in a fasting serum sample, and Fibroscan was conducted for each individual. Gas chromatography was used to measure erythrocyte membrane fatty acids. Univariate and multiple linear regressions were used to analyze data. Results: In men, IL-6 had a significant (P <0.05) positive association with total omega-3 polyunsaturated fatty acids (PUFAs). In women, TNF alpha had a significant positive association with total omega-3 (P <0.05) and omega-6 (P <0.01) PUFAs, IL-6 had a significant (P <0.05) positive association with total monounsaturated fatty acids and MCP-1 had a significant positive association with total trans-fatty acids (P <0.05). No significant associations were observed between erythrocyte membrane fatty acids and liver enzymes or Fibroscan report in both sexes. In this study, women were significantly older than men [51 (42.75-55) vs 35.5 (29-52), P <0.01], so the associations were adjusted for age and other confounders. Interpretation & conclusions: Erythrocyte membrane fatty acid profile was not associated with serum liver enzymes or Fibroscan reports in NAFLD patients, but it had significant associations with serum TNF-alpha, IL-6 and MCP-1 and these associations were probably sex dependent. PMID- 29998871 TI - Expression analysis of apolipoproteins AI & AIV in hepatocellular carcinoma: A protein-based hepatocellular carcinoma-associated study. AB - Background & objectives: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. The objective of this study was to find out the differential expression of apolipoproteins (ApoAI and ApoAIV) in HCC and cases of liver cirrhosis and chronic hepatitis (controls) without HCC and to compare ApoAI and ApoAIV expression with alpha-foetoprotein (AFP), the conventional marker in HCC. Methods: Fifty patients with HCC and 50 controls comprising patients with liver cirrhosis (n=25) and chronic hepatitis (n=25) without HCC were included in this study. Total proteins were precipitated using acetone precipitation method followed by albumin and IgG depletion of precipitated protein using depletion kit. Proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expression changes of ApoAI and ApoAIV were confirmed by western blotting using specific primary and secondary polyclonal antibodies followed by densitometric protein semi-quantitative estimation. ApoAI, ApoAIV and AFP were measured in the plasma samples by ELISA method. Results: Semi quantitative densitometric image analysis of the western blot images and the comparison between HCC patients with those without HCC (control) revealed differential expression of ApoAI and ApoAIV. Levels of ApoAI were significantly higher in patients with HCC compared to controls without HCC (0.279+/-0.216 vs 0.171+/-0.091 and 0.199+/-0.014; P <0.001). Levels of ApoAIV were significantly lower in patients of HCC compared to controls without HCC (0.119+/-0.061 vs 0.208+/-0.07 and 0.171+/-0.16; P <0.01). ELISA assays of apolipoproteins (ApoAI and ApoAIV) revealed similar results of expression of ApoAI and ApoAIV as detected in western blotting densitometric image analysis. Interpretation & conclusions: Increased expression of ApoAI and decreased expression of ApoAIV in HCC patients compared to controls without HCC revealed the abnormalities in HCC. These molecules need to be studied further for their use as potential biomarkers in the future diagnostic tools along with other conventional biomarkers for screening of HCC cases. It needs further analysis in higher number of patient population. PMID- 29998872 TI - Development of a screening instrument for autism spectrum disorder: Chandigarh Autism Screening Instrument. AB - Background & objectives: There is a paucity of trained professionals for the diagnosis of autism spectrum disorder (ASD), and a large number of cases go undetected and are diagnosed only during adolescence. There is no screening instrument specifically developed for screening of Indian population for ASD. This study was undertaken to develop a screening instrument to screen ASD in north Indian Hindi speaking population by multipurpose health workers. Methods: A 37-item instrument in Hindi with dichotomous yes/no responses [Chandigarh Autism Screening Instrument (CASI)] was developed to be applied on children aged 1.5-10 yr. The instrument was pilot tested and then reliability and validity of this instrument were tested. The sample included children with intellectual disability (n=75), ASD (n=83), other developmental disorders (n=87) and typically developing children (n=160). Results: Reliability, construct and content validity testing of the instrument were performed, and a score of 10 as cut-off had sensitivity of 89.16 per cent, specificity of 89.13 per cent, positive predictive value of 67.89 per cent and negative predictive value of 96.96 per cent. A shorter four-item version (CASI Bref) has also been developed with good sensitivity (73.49%) and specificity (90.68%) at a cut-off score of 2. Interpretation & conclusions: CASI was found to be a valid instrument for screening general Hindi speaking population of north India with adequate sensitivity and specificity. PMID- 29998873 TI - Lymphopenia-induced proliferation of CD4 T-cells is associated with CD4 T lymphocyte exhaustion in treated HIV-infected patients. AB - Background & objectives: Under the lymphopenic condition, T-cells divide to maintain their peripheral pool size. Profound chronic lymphopenia in some treated HIV-infected patients, characterized by poor T-cell recovery, might result in intensive homeostatic proliferation and can cause T-cell exhaustion and/or senescence. The present study was undertaken to evaluate the homeostatic proliferation of CD4+T-cells in treated HIV-infected individuals, and to determine the amount of phenotypically exhausted and senescent CD4 T-lymphocytes. Methods: Thirty seven treated HIV-infected patients with suppressed HIV viral load (<50 copies/ml) were studied. Patients were divided into two groups: immunological non-responders (INRs) with CD4+T-cells <350/MUl (n=16) and immunological responders (IRs) with CD4+T-cells >350/MUl (n=21). T-cell subsets [naive, central memory (CM), and effector memory (EM)] and proportions of cycling (Ki-67+), senescent (CD57+) and exhausted (PD-1+) T-lymphocytes were assessed using flow cytometry. Results: CD4+T-cell cycling rate was higher in INRs than in IRs due to more extensive proliferation of CM, 4.7 vs 2.7 per cent (P <0.01) and EM, 4.8 vs 3.2 per cent (P <0.05). The percentages of CD4+Ki-67+ CM and EM T lymphocytes were inversely related to the CD4+T-cell counts in the appropriate subset, r=-0.584 (P <0.001) and r=-0.556, (P <0.001), respectively. Exhaustion [24.2 vs 16.7% (P <0.01)], but not senescence [7.1 vs 10.8% (P>0.05)] was more pronounced in the INR group than in the IR group. The frequency of CD4+Ki-67+ CM T-cells was related to the proportion of CD4+PD-1+ cells of the same subset, r=0.789 (P <0.001). The numbers of CD4+Ki-67+PD-1+ CM and EM T-cells were substantially higher in INRs than in IRs. Interpretation & conclusions: The present data indicated that intensive homeostatic proliferation contributed to the T-cell exhaustion in HIV-infection. PMID- 29998874 TI - Plasma & urinary catecholamines & urinary vanillylmandelic acid levels in patients with generalized vitiligo. AB - Background & objectives: Vitiligo is an acquired skin disease characterized by depigmented areas of the skin. Increased release of catecholamines from autonomic nerve endings in microenvironment of melanocytes in affected skin might be involved in the aetiopathogenesis of vitiligo. Levels of catecholamines are considered as being related to onset or worsening of the disease. Therefore, in this study, the role of catecholamines was evaluated in mapping disease stability and outcome of vitiligo patients undergoing melanocyte transfer. Methods: In this study, circulatory and urinary levels of catecholamine (CA) and vanillylmandelic acid (VMA) were determined in 45 individuals (30 vitiligo patients and 15 healthy controls) using ELISA. Results: A significant increase for plasma and urinary catecholamines along with VMA was observed as compared to healthy controls. When the pre- and post-intervention levels were analyzed in responders and non responders, respectively, only dopamine showed significant decline in urine, rest of the molecules in plasma as well as urine showed non-significant decline except VMA which showed insignificant increase. Interpretation & conclusions: Levels of plasma/urinary epinephrine, and plasma dopamine, could not be established as biomarkers for disease stability or successful outcome of autologous melanocyte transfer in generalized vitiligo patients. However, dopamine (urine) might be of help in determining the stability in patients with generalized vitiligo undergoing melanocyte transfer. Further studies need to be done on a large sample of patients to confirm our findings. PMID- 29998875 TI - Detection of parvovirus B19 in selected high-risk patient groups & their phylogenetic & selection analysis. AB - Background & objectives: Human parvovirus B19V (B19V) is known to be associated with erythema infectiosum commonly in children, aplastic crisis, especially in persons with underlying haemolytic disorders, hydrops fetalis in pregnancies and arthritis. This cross-sectional study was aimed to determine the presence of B19V infection in childhood febrile illnesses, association of B19V with arthropathies and in adult patients with end-stage renal disease (ESRD) on dialysis. The genetic diversity among the sequences was also analysed. Methods: A nested polymerase chain reaction (nPCR) assay was used for B19V DNA targeting VP1/VP2 region and used for testing 618 patients and 100 healthy controls. Phylogenetic analysis on nucleotide and amino acid sequences was carried out to compare our sequences with other Indian strains and global strains. Results: Among 618 samples tested, seven (1.13%) were found positive. The phylogenetic analysis revealed that all the seven sequences belonged to genotype 1 and showed low genetic diversity. The clustering pattern of seven sequences was similar both by nucleotide and by predicted amino acid sequences. The fixed effects likelihood analysis showed no positive or negatively selected sites. Interpretation & conclusions: Seven samples (4 from non-traumatic arthropathies, 2 from patients with ESRD and 1 from febrile illness patient) were found positive by nPCR. When our seven sequences were compared with global strains, the closest neighbour was other Indian strains followed by the Tunisian strains. PMID- 29998876 TI - Association of furanone C-30 with biofilm formation & antibiotic resistance in Pseudomonas aeruginosa. AB - Background & objectives: Pseudomonas aeruginosa is an opportunistic pathogen that can cause nosocomial bloodstream infections in humans. This study was aimed to explore the association of furanone C-30 with biofilm formation, quorum sensing (QS) system and antibiotic resistance in P. aeruginosa. Methods: An in vitro model of P. aeruginosa bacterial biofilm was established using the standard P. aeruginosa strain (PAO-1). After treatment with 2.5 and 5 MUg/ml of furanone C 30, the change of biofilm morphology of PAO-1 was observed, and the expression levels of QS-regulated virulence genes (lasB, rhlA and phzA2), QS receptor genes (lasR, rhlR and pqsR) as well as QS signal molecule synthase genes (lasI, rhlI, pqsE and pqsH) were determined. Besides, the AmpC expression was quantified in planktonic and mature biofilm induced by antibiotics. Results: Furanone C-30 treatment significantly inhibited biofilm formation in a dose-dependent manner. With the increase of furanone C-30 concentration, the expression levels of lasB, rhlA, phzA2, pqsR, lasI, rhlI pqsE and pqsH significantly decreased in mature biofilm bacteria while the expression levels of lasR and rhlR markedly increased. The AmpC expression was significantly decreased in both planktonic and biofilm bacteria induced by imipenem and ceftazidime. Interpretation & conclusions: Furanone C-30 may inhibit biofilm formation and antibiotic resistance in P. aeruginosa through regulating QS genes. The inhibitory effect of furanone C-30 on las system appeared to be stronger than that on rhl system. Further studies need to be done with different strains of P. aeruginosa to confirm our findings. PMID- 29998877 TI - Pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative infections: A pilot study. AB - Background & objectives: There is little information concerning intravenously (i.v.) administered colistin in patients with multidrug-resistant (MDR) Gram negative infections. Thus, this pilot prospective study was undertaken to characterize efficacy and pharmacokinetics of colistin in patients with MDR Gram negative infections. Methods: Nine patients with age >12 yr and MDR Gram-negative infections were included, of whom six were given colistin at the doses of 2 MU, while three patients were given 1 MU i.v. dose every 8 h. Blood samples were collected at different time intervals. Determination of colistin concentration was done by a ultra-high-performance liquid chromatography/mass spectrometry/selected reaction monitoring assay. Results: The area under the plasma concentration-versus-time curve over eight hours (AUC0-8) for colistin after the 1st dose ranged from 3.3 to 16.4 mg*h/l (median, 4.59). After the 5th dose, AUC0-8for colistin ranged from 4.4 to 15.8 mg*h/l (median, 6.0). With minimal inhibitory concentration (MIC) value of 0.125 mg/l, AUC0-8/MIC ranged from 26.7 to 131.4 (median, 36.7) and 35.5 to 126.0 (median, 48.0) after the 1st and the 5th doses of 2 MU every 8 h, respectively. Interpretation & conclusions: As there is a paucity of information on AUC/MIC for colistin, it may not be possible to conclude whether AUC/MIC values in our patients were adequate. There is a microbiological clearance of organism, which goes in favour of the dosing schedule being adequate. Further studies need to be done to understand the pharmacokinetics of colistin in patients with infections. PMID- 29998878 TI - AdeR-AdeS mutations & overexpression of the AdeABC efflux system in ciprofloxacin resistant Acinetobacter baumannii clinical isolates. AB - Background & objectives: : Overexpression of efflux pumps is a cause of acquired resistance to fluoroquinolones in Acinetobacter baumannii. The present study was done to investigate the presence and overexpression of AdeABC efflux system and to analyze the sequences of AdeR-AdeS regulatory system in ciprofloxacin resistant A. baumannii isolates. Methods: : Susceptibility of 50 clinical A. baumannii isolates to ciprofloxacin, imipenem, ceftazidime, cefepime and gentamicin antimicrobials was evaluated by agar dilution method. Isolates were screened for the evidence of active efflux pump. Isolates were also examined for adeR-adeS and adeB efflux genes by polymerase chain reaction (PCR). The adeR and adeS regulatory genes were sequenced to detect amino acid substitutions. Expression of adeB was evaluated by quantitative reverse-transcriptase PCR. Results: : There were high rates of resistance to ciprofloxacin (88%), ceftazidime (88%), cefepime (74%) and imipenem (72%) and less resistance rate to gentamicin (64%). Phenotypic assay showed involvement of active efflux in decreased susceptibility to ciprofloxacin among 16 isolates. The 12.27-fold increase and 4.25-fold increase were found in adeB expression in ciprofloxacin full-resistant and ciprofloxacin-intermediate-resistant isolates, respectively. Several effective mutations, including A91V, A136V, L192R, A94V, G103D and G186V, were detected in some domains of AdeR-AdeS regulators in the overexpressed ciprofloxacin-resistant isolates. Interpretation & conclusions: The results of this study indicated that overexpression of the AdeABC efflux pump was important to reduce susceptibility to ciprofloxacin and cefepime in A. baumannii that, in turn, could be triggered by alterations in the AdeR-AdeS two-component system. However, gene expression alone does not seem adequate to explain multidrug resistance phenomenon. These results could help plan improved active efflux pump inhibitors. PMID- 29998879 TI - Identification of a case of SRD5A3-congenital disorder of glycosylation (CDG1Q) by exome sequencing. PMID- 29998880 TI - An older male with fever-induced Brugada Syndrome. PMID- 29998881 TI - Glomerular Filtration Rate is Associated with Hemorrhagic Transformation in Acute Ischemic Stroke Patients without Thrombolytic Therapy. AB - Background: Whether there is a relationship between glomerular filtration rate (GFR) and hemorrhagic transformation (HT) after acute ischemic stroke (AIS) is still under debate. The aim of our study was to determine whether the GFR level is a predictor of HT in AIS patients without thrombolytic therapy (TT). Methods: Consecutive AIS patients without TT were included in this prospective study from January 2014 to December 2016 in the First Affiliated Hospital of Chongqing Medical University. We divided them into two groups (HT and non-HT group) and meticulously collected baseline characteristics and laboratory and imaging data of interested individuals. Multivariate regression analysis was performed to assess the correlation between GFR and HT in stroke patients without TT. Results: Among 426 consecutive patients, 74 (17.3%) presented HT (mean age: 65 +/- 12 years, number of male patients: 47) on the follow-up scans. In multivariate regression analysis, HT was significantly associated with low GFR (odds ratio [OR] = 3.708, confidence interval [CI] = 1.326-10.693, P = 0.013), atrial fibrillation (AF; OR = 2.444, CI = 1.087-5.356, P = 0.027), large cerebral infarction (OR = 2.583, CI = 1.236-5.262, P = 0.010), and hypoalbuminemia (HA; OR = 4.814, CI = 1.054-22.153, P = 0.037) for AIS patients without TT. Conclusions: The present study strongly showed that lower GFR is an independently predictor of HT; in addition, large infarct volume, AF, and HA are also important risks of HT for AIS patients without TT, which offered a practical information that risk factors should be paid attention or eliminated to prevent HT for stroke patients though the level of evidence seems to be unstable. PMID- 29998882 TI - Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients: A Randomized, Multicenter, Phase IIIb Open-Label Study (POTENT Study). AB - Background: Until now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short term antiviral treatment. Methods: Between June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis. Results: HBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA <2000 U/L (28.8% vs. 28.8%, t = 0.10, P = 1.000) was not different in sequential and mono treatment groups at 24 weeks of Peg-INF. Viral response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) was not different in the two groups (12.1% vs. 16.7%, t = 1.83, P = 0.457). Baseline HBV-DNA level (7 log10U/ml vs. 7.5 log10U/ml, t = 1.70, P = 0.019) and hepatitis B surface antigen titer (3.6 log10U/ml vs. 4.0 log10U/ml, t = 2.19, P = 0.020) were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively. Conclusions: The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens. Trial Registration: ClinicalTrials.gov, NCT01220596; https://clinicaltrials.gov/ct2/show/NCT01220596?term=NCT01220596&rank=1. PMID- 29998883 TI - Identification of Newly Diagnosed Diabetes and Prediabetes Using Fasting Plasma Glucose and Urinary Glucose in a Chinese Population: A Multicenter Cross Sectional Study. AB - Background: Although fasting plasma glucose (FPG) has been highly recommended as the sole test for diabetes screening, the efficacy of FPG alone for diabetes screening is potentially limited due to its low sensitivity. The aim of this study was to improve the efficacy of FPG for diabetes screening using urinary glucose (UG). Methods: This study was initiated on November 12, 2015, and ended on June 28, 2016. A representative sample of individuals aged between 18 and 65 years, with no history of diabetes, from 6 cities in Jiangsu Province participated in this study. A 75-g oral glucose tolerance test was used to diagnose diabetes. All urine samples were collected within 2 h of oral glucose loading to measure UG. Partial correlation analyses were used to evaluate the associations between UG and other glycemic variables, including FPG, 2-h plasma glucose (2h-PG), and glycated hemoglobin A1c, after adjustment for age. The performance of UG was evaluated using a receiver operating characteristic (ROC) curve analysis. Results: Of the 7485 individuals included, 8% were newly diagnosed with diabetes and 48.7% had prediabetes. The areas under the ROC curves for UG were 0.75 for estimation of 2h-PG >=7.8 mmol/L and 0.90 for 2h-PG >=11.1 mmol/L, respectively. The sensitivity and specificity of UG were 52.3% and 87.8%, respectively, for 2h-PG >=7.8 mmol/L (cutoff point >=130 mg), and 83.5% and 87.5%, respectively, for 2h-PG >=11.1 mmol/L (cutoff point >=178.5 mg). The combination of FPG and UG demonstrated a significantly higher sensitivity than that of FPG alone for the identification of diabetes ([483/597] 80.9% vs. [335/597] 56.1%, chi2 = 85.0, P < 0.001) and glucose abnormalities ([2643/4242] 62.3% vs. [2365/4242] 55.8%, chi2 = 37.7, P < 0.001). Conclusions: The combination of UG and FPG substantially improves the efficacy of using FPG alone for diabetes screening; this combination might be a practical screening tool and is worth being recommended in the future. PMID- 29998884 TI - Clinical Analysis of 1593 Patients with Infectious Endophthalmitis: A 12-Year Study at a Tertiary Referral Center in Western China. AB - Background: Infectious endophthalmitis is a severe ocular inflammation which can cause devastating visual loss. The aim of the study was to identify the demographic and clinical features of infectious endophthalmitis in Western China for better prophylaxis and treatment of this disease. Methods: A. : retrospective, cross-sectional study was conducted based on the medical records of inpatients having infectious endophthalmitis in a tertiary referral center in Western China between 2005 and 2016. Results: The common cause of infectious endophthalmitis was trauma (82.6%), endogenous (7.8%), ophthalmic surgery (6.9%), and corneal ulcer with perforation (2.7%). These four etiological groups differed in age, gender, enucleation rate, visual outcome, etc. The number of cases in the first 6 years accounted for 38.7% of the total collection, which in the second 6 years accounted for 61.3%. The etiology patterns were different between these two periods. Altogether 51.3% of patients received pars plana vitrectomy, 13.9% of patients underwent evisceration, and the remaining 34.8% received other treatments. Of the 670 cases that had culture results, 266 (39.7%) were culture positive and 177 (66.5%) were Gram-positive organisms, 64 (24.1%) were Gram negative organisms, 11 (4.1%) had fungal infection, and 14 (5.3%) were infected by multiple pathogens. Conclusions: There was an upward trend of the occurrence of infectious endophthalmitis in Western China for the past decade. The demographic and clinical characteristics of infectious endophthalmitis in Western China had its own characteristics and differed from those of developed countries. Here, open globe trauma was the most common cause of endophthalmitis, most traumatic endophthalmitis patients were male, and most of the injuries were work related, implicate that we should strengthen the education and application of ocular safety regulation specifically targeting the workplace. PMID- 29998885 TI - Diagnostic Performance and Interobserver Consistency of the Prostate Imaging Reporting and Data System Version 2: A Study on Six Prostate Radiologists with Different Experiences from Half a Year to 17 Years. AB - Background: One of the main aims of the updated Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2) is to diminish variation in the interpretation and reporting of prostate imaging, especially among readers with varied experience levels. This study aimed to retrospectively analyze diagnostic consistency and accuracy for prostate disease among six radiologists with different experience levels from a single center and to evaluate the diagnostic performance of PI-RADS v2 scores in the detection of clinically significant prostate cancer (PCa). Methods: From December 2014 to March 2016, 84 PCa patients and 99 benign prostatic shyperplasia patients who underwent 3.0T multiparametric magnetic resonance imaging before biopsy were included in our study. All patients received evaluation according to the PI-RADS v2 scale (1-5 scores) from six blinded readers (with 6 months and 2, 3, 4, 5, or 17 years of experience, respectively, the last reader was a reviewer/contributor for the PI-RADS v2). The correlation among the readers' scores and the Gleason score (GS) was determined with the Kendall test. Intra-/inter-observer agreement was evaluated using kappa statistics, while receiver operating characteristic curve and area under the curve analyses were performed to evaluate the diagnostic performance of the scores. Results: Based on the PI-RADS v2, the median kappa score and standard error among all possible pairs of readers were 0.506 and 0.043, respectively; the average correlation between the six readers' scores and the GS was positive, exhibiting weak-to-moderate strength (r = 0.391, P = 0.006). The AUC values of the six radiologists were 0.883, 0.924, 0.927, 0.932, 0.929, and 0.947, respectively. Conclusion: The inter-reader agreement for the PI-RADS v2 among the six readers with different experience is weak to moderate. Different experience levels affect the interpretation of MRI images. PMID- 29998886 TI - Natural History of Seroma Following the Immediate Latissimus Dorsi Flap Method of Breast Reconstruction. AB - Background: The latissimus dorsi (LD) flap procedure remains a popular and useful breast reconstruction tool in China and Western countries, and donor site seroma formation is the main complication. This study was conducted in Chinese patients to determine whether stable cases of seromas would resolve without treatment. Methods: A. : retrospective review of 45 consecutive cases of immediate breast reconstruction with LD flap from April 2012 to February 2017 was conducted. The scope of the seroma was demarcated with a marker pen, and cases that remained stable over time (i.e. the size of the seroma did not increase) were observed without treatment. The measured outcomes included the incidence of seromas, the volume and duration of postoperative wound drainage, and other demographic characteristics. Results: Twenty-four patients (53.3%) developed a seroma at the donor site. Of these, 21 patients (87.5%) did not require treatment, and the seroma resolved over time. The mean duration of a sustained seroma was 6.8 +/- 1.4 weeks (range: 4-9 weeks). Conclusions: This study observed the scope and progression of the seromas and found that seromas at the LD donor sites resolved over time without treatment. PMID- 29998887 TI - Placement of a Jejunal Feeding Tube via an Ultrasound-Guided Antral Progressive Water Injection Method. AB - Background: Jejunal feeding tube allows the nutrition of critical care patients more easy and safe. However, its placement remains a challenge. This study aimed to introduce a jejunal feeding tube through an ultrasound-guided antral progressive water injection method and subsequently to examine its efficacy. Methods: Between April 2016 and April 2017, 54 patients hospitalized in the Department of Critical Care Medicine, Peking Union Medical College Hospital, China who needed nutritional support through a jejunal feeding tube were recruited for this study. Patients who applied ultrasound-guided antral progressive water injection method were classified into the experimental group. Patients who applied conventional method were registered as control group. Results: No significant differences were found in age, body mass index, and Acute Physiology and Chronic Health Evaluation score, but a significant difference in operation time was found between the experimental group and the control group. Of the 24 individuals in the control group, 17 displayed clear catheter sound shadows once the tube entered the esophagus. In comparison, of the 30 individuals in the experimental group, all harbored catheter sound shadows through the esophageal gas injection method. Subsequent observation revealed that in the control group (via ultrasonographic observation), 15 individuals underwent successful antral tube entry, for a success rate of 63%. In the experimental group (via antral progressive water injection), 27 individuals underwent successful antral tube entry, for a success rate of 90%. There was a significant difference between the success rates of the two groups (chi2 = 5.834, P = 0.022). Conclusion: The antral progressive water injection method for the placement of a jejunal feeding tube is more effective than the traditional ultrasonic placement method. PMID- 29998888 TI - Curcumin Inhibits Lipopolysaccharide-Induced Mucin 5AC Hypersecretion and Airway Inflammation via Nuclear Factor Erythroid 2-Related Factor 2. AB - Background: Excess mucus production is an important pathophysiological feature of chronic inflammatory airway diseases. Effective therapies are currently lacking. The aim of the study was to evaluate the effects of curcumin (CUR) on lipopolysaccharide (LPS)-induced mucus secretion and inflammation, and explored the underlying mechanism in vivo and in vitro. Methods: For the in vitro study, human bronchial epithelial (NCI-H292) cells were pretreated with CUR or vehicle for 30 min, and then exposed to LPS for 24 h. Next, nuclear factor erythroid 2 related factor 2 (Nrf2) was knocked down with Nrf2 small interfering RNA (siRNA) to confirm the specific role of Nrf2 in mucin regulation of CUR in NCI-H292 cells. In vivo, C57BL/6 mice were randomly assigned to three groups (n = 7 for each group): control group, LPS group, and LPS + CUR group. Mice in LPS and LPS + CUR group were injected with saline or CUR (50 mg/kg) intraperitoneally 2 h before intratracheal instillation with LPS (100 MUg/ml) for 7 days. Cell lysate and lung tissue were obtained to measured Mucin 5AC (MUC5AC) and Nrf2 mRNA and protein expression by a real-time polymerase chain reaction and Western blotting. Bronchoalveolar lavage fluid (BALF) was collected to enumerate total cells and neutrophils. Histopathological changes of the lung were observed. Data were analyzed by one-way analysis of variance. Student's t-test was used when two groups were compared. Results: CUR significantly decreased the expression of MUC5AC mRNA and protein in NCI-H292 cells exposed to LPS. This effect was dose dependent (2.424 +/- 0.318 vs. 7.169 +/- 1.785, t = 4.534, and 1.060 +/- 0.197 vs. 2.340 +/- 0.209, t = 7.716; both P < 0.05, respectively) and accompanied by increased mRNA and protein expression of Nrf2 (1.952 +/- 0.340 vs. 1.142 +/- 0.176, t = -3.661, and 2.010 +/- 0.209 vs. 1.089 +/- 0.132, t = -6.453; both P < 0.05, respectively). Furthermore, knockdown of Nrf2 with siRNA increased MUC5AC mRNA expression by 47.7%, compared with levels observed in the siRNA-negative group (6.845 +/- 1.478 vs. 3.391 +/- 0.517, t = -3.821, P < 0.05). Knockdown of Nrf2 with siRNA also markedly increased MUC5AC protein expression in NCI-H292 cells. CUR also significantly decreased LPS-induced mRNA and protein expression of MUC5AC in mouse lung (1.672 +/- 0.721 vs. 5.961 +/- 2.452, t = 2.906, and 0.480 +/- 0.191 vs. 2.290 +/- 0.834, t = 3.665, respectively; both P < 0.05). Alcian blue/periodic acid-Schiff staining also showed that CUR suppressed mucin production. Compared with the LPS group, the numbers of inflammatory cells (247 +/- 30 vs. 334 +/- 24, t = 3.901, P < 0.05) and neutrophils (185 +/- 22 vs. 246 +/- 20, t = 3.566, P < 0.05) in BALF decreased in the LPS + CUR group, as well as reduced inflammatory cell infiltration in lung tissue. Conclusion: CUR inhibits LPS-induced airway mucus hypersecretion and inflammation through activation of Nrf2 possibly. PMID- 29998889 TI - Effect of Dandelion Extracts on the Proliferation of Ovarian Granulosa Cells and Expression of Hormone Receptors. AB - Background: In the current society, infertility related to age has become a social problem. The in vitro fertilization (IVF) success rate in women with poor ovarian response (POR) is very low. Dandelion extract T-1 (DE-T1) is an effective component of the extract from the leaves and stems of Taraxacum officinale, which is one of the medicines used in some patients with POR, but its molecular mechanism remains unclear. Methods: Following IVF, ovarian granulosa cells (GCs) of sixty patients were extracted and divided into normal ovarian response (NOR) and POR groups. GCs were cultured in a dose-dependent and time-dependent manner with DE-T1, proliferation of GCs was determined by Cell Counting Kit-8 assay, and mRNA levels of insulin-like growth factor 1 receptor (IGF-1R), luteotropic hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), LHR, and CYP19A1 (aromatase) were determined by quantitative polymerase chain reaction. Progesterone and estradiol (E2) concentrations were determined by enzyme-linked immunosorbent assay. Results: The cell viability gradually increased with the progressive increase in the DE-T1 concentration. Compared with the control group (without DE-T1), the mRNA expressions of FSHR, LHR, IGF-1R, and CYP19A1 were upregulated after the addition of DE-T1, especially in the 2.5% DE-T1 group (P < 0.01). The expression of IGF-1R was upregulated approximately 25 times (24.97 +/- 4.02 times) in the POR group with 2.5% DE-T1. E2 and progesterone levels increased with the increasing DE-T1 concentration. There were highly significant differences in the E2 and progesterone secretion between the NOR and POR groups (P < 0.01). Conclusion: DE-T1 may promote steroid hormone synthesis by promoting GC proliferation and upregulating GC receptor expression, thereby improving ovarian endocrine function. PMID- 29998890 TI - Effect of Autophagy Inhibition on the Protection of Ischemia Preconditioning against Myocardial Ischemia/Reperfusion Injury in Diabetic Rats. AB - Background: Ischemia preconditioning (IPC) remains the most powerful intervention of protection against myocardial ischemia/reperfusion injury (IRI), but diabetes can weaken or eliminate its cardioprotective effect and detailed mechanisms remain unclear. In this study, we aimed to explore whether changes of autophagy in the diabetic condition are attributable to the decreased cardioprotective effect of IPC. Methods: Sixty diabetic male Sprague-Dawley rats were randomly divided into the control (C), IRI, rapamycin (R), wortmannin (W), rapamycin + IPC (R + IPC), and wortmannin + IPC (W + IPC) groups. The in vivo rat model of myocardial IRI was established by ligaturing and opening the left anterior descending coronary artery via the left thoracotomy. Durations of ischemia and reperfusion are 30 min and 120 min, respectively. Blood samples were taken at 120 min of reperfusion for measuring serum concentrations of troponin I (TnI) and creatine kinase isoenzyme MB (CK-MB) using the enzyme-linked immunosorbent assay. The infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining. The expressions of LC3-II, beclin-1, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and P-Akt/Akt ratio in the ischemic myocardium were assessed by Western blotting. Results: Compared to the IRI group, infarct size (56.1% +/- 6.1% vs. 75.4 +/- 7.1%, P < 0.05), serum cTnI (0.61 +/- 0.21 vs. 0.95 +/- 0.26 ng/ml, P < 0.05), and CK-MB levels (6.70 +/- 1.25 vs. 11.51 +/- 2.35 ng/ml, P < 0.05) obviously decreased in the W + IPC group. Compared with the C group, myocardial expressions of LC3-II (0.46 +/- 0.04 and 0.56 +/- 0.04 vs. 0.36 +/- 0.04, P < 0.05) and beclin-1 (0.34 +/- 0.08 and 0.38 +/- 0.07 vs. 0.24 +/- 0.03, P < 0.05) evidently increased, and myocardial expressions of mTOR (0.26 +/- 0.08 and 0.25 +/- 0.07 vs. 0.38 +/- 0.06, P < 0.05), PI3K (0.29 +/- 0.04 and 0.30 +/- 0.03 vs. 0.38 +/- 0.02, P < 0.05), and P Akt/Akt ratio (0.49 +/- 0.10 and 0.48 +/- 0.06 vs. 0.72 +/- 0.07, P < 0.05) markedly decreased in the IRI and R groups, indicating an increased autophagy. Compared with the IRI group, myocardial expression of beclin-1 (0.26 +/- 0.03 vs. 0.34 +/- 0.08, P < 0.05) significantly decreased, and myocardial expressions of mTOR (0.36 +/- 0.04 vs. 0.26 +/- 0.08, P < 0.05), PI3K (0.37 +/- 0.03 vs. 0.29 +/ 0.04, P < 0.05), and P-Akt/Akt ratio (0.68 +/- 0.05 vs. 0.49 +/- 0.10, P < 0.05) increased obviously in the W + IPC group, indicating a decreased autophagy. Conclusions: Increased autophagy in the diabetic myocardium is attributable to decreased cardioprotection of IPC, and autophagy inhibited by activating the PI3K Akt-mTOR signaling pathway can result in an improved protection of IPC against diabetic myocardial IRI. PMID- 29998891 TI - Constructing a Novel Three-Dimensional Biomimetic Corneal Endothelium Graft by Culturing Corneal Endothelium Cells on Compressed Collagen Gels. AB - Background: Endothelium allotransplantation is the primary treatment for corneal decompensation. The worldwide shortage of donor corneal tissue has led to increasing pressure to seek an alternative for surgical restoration of corneal endothelium. Compressed collagen (CC) gels have excellent biocompatibility, simple preparation course and easy to be manipulated. This study aimed to form a new biomimetic endothelium graft by CC. Methods: We expanded bovine corneal endothelial cells (B-CECs) on laminin-coated CC to form a biomimetic endothelium graft. Scanning electron microscope was used for ultrastructural analysis and tight junction protein ZO-1 expression was tested by immunohistochemistry. Results: The biomimetic endothelium graft, we conducted had normal cell morphology, ultrastructure and higher cell density (3612.2 +/- 43.4 cells/mm2). ZO-1 localization at B-CECs membrane indicated the bioengineered graft possess the basic endothelium function. Conclusions: A. : biomimetic endothelium graft with B-CECs expanded on CC sheet was constructed, which possessed cells' morphology similar to that of in vivo endothelial cells and specific basic function of endothelium layer. This method provided the possibility of using one donor's cornea to form multiple uniformed endothelium grafts so as to overcome the shortage of cadaveric cornea tissue. PMID- 29998892 TI - Inhibitory Effects of Sulfur Dioxide on Rat Myocardial Fibroblast Proliferation and Migration. AB - Background: Myocardial fibrosis is an important pathological change in many heart diseases, but its pathogenesis is very complex and has not yet been fully elucidated. The study was designed to examine whether endogenous sulfur dioxide (SO2) is a novel myocardial fibroblast proliferation and migration inhibitor. Methods: Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase (AAT1 and AAT2) knockdown lentivirus or empty lentivirus. SO2 content in the supernatant was determined with high-performance liquid chromatography, and the expressions of AAT1, AAT2, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated protein kinase (p-ERK), and total ERK (T-ERK) in the cells were detected. Cell migration was detected by wound healing test. Independent sample t-test (for two groups) and one-way analysis of variance (three or more groups) were used to analyze the results. Results: Both AAT1 and AAT2 knockdown significantly reduced SO2levels (F = 31.46, P < 0.01) and AAT1/2 protein expression (AAT1, t = 12.67, P < 0.01; AAT2, t = 9.61, P < 0.01), but increased PCNA expression and Cell Counting Kit-8 (CCK-8) activity as well as the migration in rat primary myocardial fibroblasts (P < 0.01). Supplementation of SO2rather than pyruvate significantly inhibited the increase in proliferation and migration caused by AAT knockdown (P < 0.01). Mechanistically, the ratio of p-ERK to T-ERK was significantly increased in the AAT1/2 knockdown groups compared with that in the empty lentivirus group (AAT1, t = -7.36, P < 0.01; AAT2, t = -10.97, P < 0.01). Whereas PD98059, an inhibitor of ERK activation, successfully blocked AAT knockdown-induced PCNA upregulation (F = 74.01, P > 0.05), CCK-8 activation (F = 50.14, P > 0.05), and migration augmentation in myocardial fibroblasts (24 h, F = 37.08, P > 0.05; 48 h, F = 58.60, P > 0.05). Conclusion: Endogenous SO2might be a novel myocardial fibroblast proliferation and migration inhibitor via inhibiting the ERK signaling pathway. PMID- 29998893 TI - Effects of Dandelion Extract on the Proliferation of Rat Skeletal Muscle Cells and the Inhibition of a Lipopolysaccharide-Induced Inflammatory Reaction. AB - Background: Dandelion is commonly used in traditional Chinese medicine with several active compounds found in extracts. It has a variety of pharmacological effects, such as a reduction in swelling and inflammation, and detoxification. The mechanism by which dandelion extract inhibits the inflammatory response in skeletal muscle cells remains unknown; therefore, the aim of this study was to investigate the effects of dandelion extract root on the proliferation of skeletal muscle cells and the alleviation of lipopolysaccharide (LPS)-induced inflammatory response in vitro. Methods: Rat skeletal muscle cells were isolated from Sprague-Dawley rat and cultured in vitro which were cultured in basal medium, or medium containing LPS or dandelion extract. Cell counting kit-8 (CCK 8) was employed to measure cell proliferation; meanwhile, the optimal concentration of dandelion extract and treatment time were selected. Crystal violet staining was used to detect the proliferation of muscle cells. Western blotting analysis was used to detect the levels of inflammatory factors, myogenic factor, and p-AKT protein expression. Results: The optimal concentration and treatment time of dandelion extract for the following study were 5 mg/ml and 4 days, respectively. Dandelion extract was found to increase proliferation of rat skeletal muscle cells (t = 3.145, P < 0.05), with the highest effect observed at 5 mg/ml. LPS was found to decrease proliferation of skeletal muscle cells (t = 131.959, P < 0.001), and dandelion extract could against this affection (t = 19.466, P < 0.01). LPS could induce expression of inflammatory factors, including interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha (IL-1beta: t = 9.118, P < 0.01; IL-6: t = 4.346, P < 0.05; TNF-alpha: t = 15.806, P < 0.05), and dandelion extract was shown to reduce LPS-induced expression of IL-1beta, IL-6 and TNF-alpha (IL-1beta: t = -2.823, P < 0.05; IL-6: t = -3.348, P < 0.01; and TNF-alpha: t = -3.710, P < 0.01). Furthermore, LPS was also shown to decrease expression of myogenic factor, including myod1 and myogenin (MyoD1: t = 4.039, P < 0.05 and myogenin: t = 3.300, P < 0.01), but dandelion extract was shown to against this effect of LPS (MyoD1: t = -3.160, P < 0.05 and myogenin: t = -3.207, P < 0.01). And then, LPS was found to increase expression of p-AKT protein (p AKT/AKT: t = 4.432, P < 0.05). Moreover, expression of p-AKT protein was found to decrease, with 5 mg/ml of dandelion extract (p-AKT/AKT: t = -3.618, P < 0.05). Conclusions: The findings indicate that dandelion extract plays an important role in skeletal muscle cells viability regulation, promote cells proliferation by increasing level of p-AKT protein expression, and reduce LPS-induced expression of inflammatory factors, inhibiting the inflammatory response of rat skeletal muscle cells. PMID- 29998894 TI - Pulmonary Embolism in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - Objective: In most countries, nearly 6% of the adults are suffering from chronic obstructive pulmonary disease (COPD), which puts a huge economic burden on the society. Moreover, COPD has been considered as an independent risk factor for pulmonary embolism (PE). In this review, we summarized the existing evidence that demonstrates the associations between COPD exacerbation and PE from various aspects, including epidemiology, pathophysiological changes, risk factors, clinical features, management, and prognosis. Data Sources: We searched the terms "chronic obstructive pulmonary disease," "pulmonary embolism," "exacerbations," and "thromboembolic" in PubMed database and collected the results up to April 2018. The language was limited to English. Study Selection: We thoroughly examined the titles and abstracts of all studies that met our search strategy. The data from prospective studies, meta-analyses, retrospective studies, and recent reviews were selected for preparing this review. Results: The prevalence of PE in patients with COPD exacerbation varied a lot among different studies, mainly due to the variations in race, sample size, study design, research setting, and enrollment criteria. Overall, whites and African Americans showed significantly higher prevalence of PE than Asian people, and the hospitalized patients showed higher prevalence of PE compared to those who were evaluated in emergency department. PE is easily overlooked in patients with COPD exacerbation due to the similar clinical symptoms. However, several factors have been identified to contribute to the increased risk of PE during COPD exacerbation. Obesity and lower limb asymmetry were described as independent predictors for PE. Moreover, due to the high risk of PE, thromboprophylaxis has been used as an important treatment for hospitalized patients with COPD exacerbation. Conclusions: According to the previous studies, COPD patients with PE experienced an increased risk of death and prolonged length of hospital stay. Therefore, the thromboembolic risk in patients with acute exacerbation of COPD, especially in the hospitalized patients, should carefully be evaluated. PMID- 29998896 TI - Unilateral Isolated Basal Vein Thrombosis Associated with Deep Cerebral Venous Infarction. PMID- 29998897 TI - Successful Treatment of Erlotinib on Metastatic Adenoid Cystic Carcinoma of the Lacrimal Gland. PMID- 29998895 TI - Ten Things to be Considered in Practicing Critical Care Echocardiography. PMID- 29998898 TI - Reverse Postulation for "Disruption of Brain Networks" Hypothesis of Schizophrenia. PMID- 29998899 TI - Effect of Education by Messaging Software on the Quality of Bowel Preparation for Colonoscopy. PMID- 29998900 TI - Successful Management of a Rare Case of Humerus Non-Hodgkin's Lymphoma in Rapid Progress. PMID- 29998901 TI - Acute Pancreatitis as a Long-term Complication of Pancreatectomy. PMID- 29998902 TI - Hybrid Management for Supraceliac Aortic Aneurysm in a High-Risk Patient. PMID- 29998903 TI - Influence of the Anatomy of the Collecting System Upon Percutaneous Nephrolithotomy for Removal of Renal Staghorn Stones. PMID- 29998904 TI - Acquired Syphilis in a Chinese Family among Three Generations. PMID- 29998905 TI - Diagnosis-Related Groups' Payment Reform in Beijing. PMID- 29998906 TI - Corrigendum: Genistein Improves Liver Damage in Male Mice Exposed to Morphine. AB - [This corrects the article DOI: 10.4103/0366-6999.235117]. PMID- 29998908 TI - Light is required for proper female mate choice between winged and wingless males in Drosophila. AB - In many animal species, females choose potential mating partners according to their own preferences. Thus, female preference-based mate choice affects intraspecific mating success and prevents interspecific mating. To clarify the neuronal basis of female mate choice, it is essential to identify the important relevant sensory cues. In the fruitfly Drosophila melanogaster, the courtship song of males promotes female sexual receptivity. When wild-type virgin females can freely choose one of two types of courting males (winged or wingless males), they prefer to mate with winged males. Here, we report a crucial sensory cue relevant to this female mate choice. In a female choice test, female receptivity toward winged and wingless males was markedly reduced when females had auditory impairments, although females with visual or olfactory impairments showed normal receptivity similar to wild-type females. However, females with visual impairments did not show clear mate preference toward winged males. Thus, these findings suggest that females utilize visual cues in mate choice between winged and wingless males in Drosophila. PMID- 29998907 TI - The scallop IGF2 mRNA-binding protein gene PyIMP and association of a synonymous mutation with growth traits. AB - Insulin-like growth factor 2 mRNA-binding proteins (IMPs) function in localization, stability and translational control of their target RNAs. In this study, we identified an IMP gene (PyIMP) from Yesso scallop, Patinopecten yessoensis. The complete DNA sequence of PyIMP was 22,875 bp, consisting of seventeen exons and sixteen introns. The full-length cDNA sequence was 3,293 bp, with an open reading frame of 1,776 bp, encoding 592 amino acids. PyIMP exhibited characters typical of IMPs, namely two RNA recognition motifs and four hnRNP K homology domains. Real-time quantitative reverse transcription PCR analysis indicated that PyIMP was universally expressed, with higher expression levels in the gonad of adult scallops, and in gastrulae and trochophore larvae at developmental stages. A synonymous mutation SNP, c.852A>G, which showed significant associations with growth traits of Yesso scallop, was identified in this gene. Scallops with the AA genotype at this locus had significantly higher trait values than those with the GG genotype for shell length, shell height, body weight, soft tissue weight and striated muscle weight (P < 0.05). Meanwhile, the expression of PyIMP in AA type scallops was significantly higher than that in the GG type, implying a positive effect of PyIMP on scallop growth. PyIMP represents the first mRNA-binding protein gene characterized in mollusks, and SNP c.852A>G will be useful for a better understanding of the role of mRNA-binding proteins in bivalves and for scallop breeding. PMID- 29998909 TI - Ethylenecarbodiimide-fixed splenocytes carrying whole islet antigens decrease the incidence of diabetes in NOD mice via down-regulation of effector memory T cells and autoantibodies. AB - Type 1 diabetes mellitus (T1DM) is a syndrome of loss of glucose homeostasis caused by the loss of beta cell chronic autoimmunity against islet cells. Islet specific epitopes coupled antigen presenting cells by Ethylenecarbodiimide (ECDI) is a promising strategy to induce antigen-specific tolerance. However, single epitope induced tolerance is insufficient to prevent the onset of T1DM. The aim of this study is to evaluate the efficacy of whole islet antigens in preventing the onset and progression of T1DM and identify the underlying immune mechanism in NOD mice. In this study, the whole islet antigens, derived from islet lysate isolated from BALB/c mice, were coupled to splenocytes of BALB/c mice by ECDI fixation (SP-Islet lysate), and then intravenously administrated to NOD mice. The results showed that, compared with control group, SP-Islet lysate group significantly decreased T1DM incidence and improved the survival of NOD mice. SP Islet lysate treated mice had reduced insulitis score and autoantibody levels, and improved glucose tolerance and insulin/glucagon production. Furthermore, the effector memory T cells (TEMs) were downregulated and regulatory T cells (Tregs) were upregulated by the SP-Islet lysate treatment, with reduced populations of Th1&Th17 cells. In conclusion, ECDI-fixed splenocytes carrying whole islet antigens effectively prevented the onset of T1DM in NOD mice, via suppressing the production of autoantibodies and inducing anergy of autoreactive T cells. PMID- 29998911 TI - [The 138th Regional Meeting (Kanto Area)]. PMID- 29998910 TI - IRS2 depletion inhibits cell proliferation and decreases hormone secretion in mouse granulosa cells. AB - Insulin receptor substrate 2 (IRS2) is a component of the insulin/insulin-like growth factor 1 (IGF1) signaling cascade, which plays an important role in mouse hypothalamic and ovarian functions. The present study was conducted to investigate the role of IRS2 in steroidogenesis, apoptosis, cell cycle and proliferation in mouse granulosa cells (GCs). Flow cytometry and CCK8 assay showed that IRS2 knockdown inhibited cell proliferation, reduced cell viability, and increased apoptosis in GCs. The study also revealed that the expression of Cyclin A1, Cyclin B1 and Bcl2 was downregulated, while the expression of Bax, Cyclin D1 and Cyclin D2 was upregulated. ELISA analysis showed that IRS2 knockdown decreased the concentrations of estradiol (E2) and progesterone (P4), which was further validated by the decreased expression of Star, Cyp11a1, and Cyp19a1. Moreover, IRS2 knockdown altered the expression of Has2 and Ptgs2, which are essential for folliculogenesis. In addition, we found that IRS2-mediated cell viability and hormone secretion are dependent on the PI3K/AKT signaling pathway. Collectively, this study demonstrated that IRS2 plays an important role in the regulation of cell proliferation and steroidogenesis in mouse GCs via the PI3K/AKT signaling pathway. PMID- 29998912 TI - Post-prandial Remnant Lipoprotein Metabolism in Sitosterolemia. AB - AIM: We aimed to clarify post-prandial accumulation of remnant-like particles (RLP) in patients with sitosterolemia. METHODS: Oral fat tolerance test cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (m2); blood sampling was performed at 2 h intervals up to 6 h. Plasma lipoprotein fractions and RLP fractions were determined in four sitosterolemic subjects with double mutations in ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene (mean age=18 yr, median low-density lipoprotein cholesterol [LDL C]=154 mg/dL), six heterozygous carriers (mean age=31 yr, median LDL-C=105 mg/dL), and five subjects with heterozygous familial hypercholesterolemia (FH, mean age=32 yr, median LDL-C=221 mg/dL). The incremental area under curve (iAUC) of lipids, including LDL-C, apolipoprotein B-48 (apoB48), RLP cholesterol (RLP C), and RLP triglyceride (RLP-TG) were evaluated. RESULTS: After oral fat load, there was no significant difference of the iAUC of LDL-C between sitosterolemia and heterozygous FH, whereas the iAUC of apoB48 was significantly larger in the sitosterolemic subjects compared with that of heterozygous FH (2.9 ug/mL*h vs. 1.3 ug/mL*h, p<0.05). Under these conditions, the iAUCs of RLP-C and RLP-TG levels were significantly larger in the sitosterolemic subject compared with those of heterozygous FH (9.5 mg/dL*h vs. 5.7 mg/dL*h, p<0.05; 149 mg/dL*h vs. 40 mg/dL*h, p<0.05, respectively), whereas those of heterozygous carriers were comparable with those with heterozygous FH. CONCLUSIONS: Post-prandial lipoprotein metabolism in sitosterolemia appeared to be impaired, leading to their elevation in serum sterol levels. (UMIN Clinical Trials Registry number, UMIN000020330). PMID- 29998914 TI - Incidence Rate, Subtype Frequency, and Occurrence Site of Malignant Lymphoma in the Gastrointestinal Tract: Population-Based Analysis in Miyagi, Japan. AB - Primary gastrointestinal lymphoma (PGIL) has been reported in many studies of lymphomas of the gastrointestinal tract worldwide. However, there have been few accurate population-based reports on lymphomas, and it is difficult to apply the strict definition of PGIL to all lymphomas occurring in the gastrointestinal tract. Accordingly, instead of using PGIL, this study included newly diagnosed lymphomas with biopsy or excision specimens obtained from the gastrointestinal tract (GI-related lymphomas) and aimed at presenting the incidence rate, subtype frequency, and occurrence site of GI-related lymphomas. Additionally, we examined GI-related lymphomas diagnosed using flow cytometry (FCM) analysis, cytogenetics analysis, and molecular analysis (multimetric and/or integrated analysis). We extracted data on GI-related lymphomas from 2,098 lymphoma cases registered from the entire Miyagi Prefecture in Japan. The number of GI-related lymphomas was 350, and the incidence rate was 2.97 per 100,000 persons. Diffuse large B-cell lymphoma was the most common subtype (47.4%), followed by extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (32.6%) and follicular lymphoma (8.3%). The stomach was the most common site (62.6%), followed by the large intestine (15.4%), small intestine (14.3%), and duodenum (6.0%). Of the 350 included cases, 111 were diagnosed using multimetric and/or integrated analysis, in which the proportions of positive results for FCM analysis, cytogenetics analysis, and molecular analysis were 81%, 33%, and 51%, respectively. These results may provide a representation of lymphomas occurring in the gastrointestinal tract in Japan. Multimetric and/or integrated analysis of GI related lymphomas could enable us to acquire useful information for the diagnosis. PMID- 29998915 TI - Alamandine Protects the Heart Against Reperfusion Injury via the MrgD Receptor. AB - BACKGROUND: Alamandine differs from angiotensin-(1-7) in a single N-terminal alanine residue. The aim of this study was to investigate whether alamandine protects the heart against reperfusion injury. Methods and Results: After euthanizing Sprague-Dawley rats, hearts were perfused with Krebs-Henseleit buffer for a 20-min pre-ischemic period with or without alamandine, followed by 20 min global ischemia and 50 min reperfusion. Alamandine (0.1 mg/kg) improved the postischemic left ventricular developed pressure and +/-dP/dt, decreased the infarct size, and decreased the lactate dehydrogenase levels in the effluent. Alamandine increased the coronary flow and the amount of atrial natriuretic peptide (ANP) in the coronary effluent, and it decreased the expression of apoptotic proteins and increased the expression of antioxidative proteins. Pretreatment with the MrgD receptor antagonist or PD123319, but not the angiotensin type 1 receptor antagonist, attenuated the cardioprotective effects of alamandine. A similar cardioprotective effect with alamandine was also observed with high plasma ANP levels in an in vivo study. Alamandine directly stimulated ANP secretion from isolated atria, which was completely blocked by pretreatment with the MrgD receptor antagonist and was partially blocked by PD123319. CONCLUSIONS: These results suggest that the cardioprotective effects of alamandine against I/R injury are, in part, related to the activation of antioxidant and antiapoptotic enzymes via the MrgD receptor. PMID- 29998916 TI - Physical Activity Does Not Reduce Aortic Valve Stenosis Incidence. AB - BACKGROUND: Physical activity is associated with lower risk of coronary and cerebrovascular disease but its potential role in prevention of aortic valve stenosis (AVS) is unclear. Methods and Results: We investigated whether physical activity influences AVS risk in a cohort of 69,288 adults. During a mean follow up of 15.3 years, 1,238 AVS cases were diagnosed. No associations were observed between AVS and walking/bicycling (>=1 h/day vs. almost never: hazard ratio 0.92, 95% CI 0.74-1.15) or exercise (>=4 hs/week vs. <1 h/week: hazard ratio 1.18, 95% CI 0.97-1.43). CONCLUSIONS: Physical activity did not reduce the incidence of AVS. PMID- 29998913 TI - Pathophysiology of Diabetic Dyslipidemia. AB - Accumulating clinical evidence has suggested serum triglyceride (TG) is a leading predictor of atherosclerotic cardiovascular disease, comparable to low-density lipoprotein (LDL)-cholesterol (C) in populations with type 2 diabetes, which exceeds the predictive power of hemoglobinA1c. Atherogenic dyslipidemia in diabetes consists of elevated serum concentrations of TG-rich lipoproteins (TRLs), a high prevalence of small dense low-density lipoprotein (LDL), and low concentrations of cholesterol-rich high-density lipoprotein (HDL)2-C. A central lipoprotein abnormality is an increase in large TG-rich very-low-density lipoprotein (VLDL)1, and other lipoprotein abnormalities are metabolically linked to increased TRLs. Insulin critically regulates serum VLDL concentrations by suppressing hepatic VLDL production and stimulating VLDL removal by activation of lipoprotein lipase. It is still debated whether hyperinsulinemia compensatory for insulin resistance is causally associated with the overproduction of VLDL. This review introduces experimental and clinical observations revealing that insulin resistance, but not hyperinsulinemia stimulates hepatic VLDL production. LDL and HDL consist of heterogeneous particles with different size and density. Cholesterol-depleted small dense LDL and cholesterol-rich HDL2 subspecies are particularly affected by insulin resistance and can be named "Metabolic LDL and HDL," respectively. We established the direct assays for quantifying small dense LDL-C and small dense HDL(HDL3)-C, respectively. Subtracting HDL3-C from HDL-C gives HDL2-C. I will explain clinical relevance of measurements of LDL and HDL subspecies determined by our assays. Diabetic kidney disease (DKD) substantially worsens plasma lipid profile thereby potentiated atherogenic risk. Finally, I briefly overview pathophysiology of dyslipidemia associated with DKD, which has not been so much taken up by other review articles. PMID- 29998917 TI - Measurements of body surface area and volume in laboratory rabbits (New Zealand White rabbits) using a computed tomography scanner. AB - The body surface area (BSA) of an organism is one of the important parameters for evaluating physiological functions. In drug development, normalization by BSA is an appropriate method for extrapolating doses between species. The BSA of animals has generally been estimated by multiplying the k value by 2/3 of the power of the body weight (BW) (Meeh's formula). In mathematics, if it is assumed that the density and body shape of the animals are essentially constant, the BSA is proportional to BW2/3. In this study, we measured the BSA and volume (V) of 72 laboratory rabbits (48 males and 24 females of New Zealand White rabbits [NZW]), using a computed tomography scanner. After BSA and V determination, the k value, density, and sphericity were calculated. We analyzed variations in the k value, density, and body shape of laboratory rabbits. The mean k value of the 72 NZW was 11.0. We advocate using Meeh's formula, as follows, for estimating BSA of laboratory rabbits (NZW): 100 * BSA [m2] = 11.0 * BW [kg]2/3. PMID- 29998918 TI - Job Stress Factors Affect Workplace Resignation and Burnout among Japanese Rural Physicians. AB - Shortage of healthcare workers is a global problem. It is important to clarify factors, including job stress, that influence workplace resignation and factors that cause burnout among rural physicians. The study was designed as a cross sectional questionnaire survey. We sent questionnaires to town or village hospitals and clinics (n = 1,898) in Hokkaido, Tohoku, Shikoku, and Kyushu and Okinawa. The number of participants was 509. Of these 7.7% were female and 21.6% were < 50 years. Internal or general medicine physicians were asked about personal and job factors, job stress based on the demand-control-support model, intention to resign from current position, and burnout evaluated using the Maslach Burnout Inventory-General Survey. Overall, 10.4% of the participants intended to resign, and 21.8% was defined as burnout positive. In the multivariate logistic regression analysis, dissatisfaction with income (OR, 3.63; 95% CI, 1.63-8.10), having one's hometown in another town or village in the same prefecture (OR, 3.53; 95% CI, 1.18-10.62) were significantly related to intention to resign, while high job control (OR, 0.72; 95% CI, 0.58-0.88) had a significantly protective effect. In the multivariate analysis, high job demand (OR, 1.48; 95% CI, 1.28-1.72) was significantly related to burnout, and high job control (OR, 0.66; 95% CI, 0.55-0.78) and high support from co-workers (OR 0.88, 95% CI, 0.78-1.00) had a significantly protective effect. Improving job stress factors, especially job control, and taking into consideration physicians' hometown and income may be important factors to prevent resignation from a current position and burnout among Japanese rural physicians. PMID- 29998919 TI - Serum 1,25-Dihydroxyvitamin D Level Is Inappropriate for Use in Prospective Studies of Cancer Incidence. PMID- 29998920 TI - Serum 1,25-Dihydroxyvitamin D Level Is Inappropriate for Use in Prospective Studies of Cancer Incidence - Reply. PMID- 29998921 TI - Early-Phase Vascular Healing of Bioabsorbable vs. Durable Polymer-Coated Everolimus-Eluting Stents in Patients With ST-Elevation Myocardial Infarction - 2 Week and 4-Month Analyses With Optical Coherence Tomography. AB - BACKGROUND: Despite the revolution of coronary stents, there remain concerns about the risk of stent thrombosis, especially in patients with ST-elevation myocardial infarction (STEMI). The present study compared early vascular healing as a contributing factor to reducing stent thrombosis between Xience everolimus eluting stents (X-EES) and Synergy everolimus-eluting stents (S-EES) in patients with STEMI. Methods and Results: The present study included 47 patients with STEMI requiring primary percutaneous coronary intervention with X-EES (n=25) or S EES (n=22). Optical coherence tomography (OCT) assessments of the stented lesions were performed 2 weeks and 4 months after stent implantation. Neointimal strut coverage, malapposition and the frequency of thrombus formation were evaluated. In the 2-week OCT analysis, the proportion of covered struts in S-EES (42.4+/ 15.4%) was significantly higher than in X-EES (26.3+/-10.1%, P<0.001). In the 4 month OCT analysis, the proportion of covered struts in S-EES (72.2+/-17.9%) was still significantly higher than in X-EES (62.0+/-14.9%, P=0.04). CONCLUSIONS: Compared with X-EES, S-EES showed a higher proportion of covered struts in the early phase after stent implantation for STEMI patients. PMID- 29998922 TI - Limited Extent of Pleiotropic Effects Mediated by Dipeptidyl Peptidase-4 Inhibitors in Patients With Diabetes Mellitus. PMID- 29998923 TI - Emotional exhaustion and innovation in the workplace-a longitudinal study. AB - Emotional exhaustion and innovation at work are two major topics of interest to organization researchers, employees and employers. However, working conditions that foster innovation may also heighten employees' emotional exhaustion. By conducting a two-wave, longitudinal online study among the German working population (N=320), we analyzed the longitudinal impact of qualitative overload, unreasonable tasks, social support from a supervisor, and task variety on emotional exhaustion and innovation based on the categorization approach from the job demands-resources model research. Longitudinal structural equation modeling revealed that unreasonable tasks predicted emotional exhaustion (gamma=0.111, p<0.01) and that task variety predicted individual innovation (gamma=0.126, p<0.01) over time. Social support from a supervisor and qualitative overload, however, did not have any longitudinal influence on either emotional exhaustion or individual innovation. Rather unexpectedly, and in contrast to our hypotheses, no diverging effects from working conditions on emotional exhaustion or innovation could be found. The results demonstrate that the presence of unreasonable tasks impairs employees' psychological well-being and that a high task variety at work leads to innovation. Implications for practice and future studies are discussed. PMID- 29998924 TI - Detection of Felis catus papillomavirus type 2 within multicentric basosquamous carcinoma in a domestic cat. AB - A 12-year-old neutered male domestic shorthair cat was presented with a 3-year history of multiple nonpruritic, ulcerated, plaque-like skin lesions but no other clinical signs. A systemic examination revealed mild lymphadenopathy. Histopathologic analysis of the skin lesions revealed multicentric basosquamous carcinoma (BSC). Immunohistochemical analysis, PCR, and sequencing detected Felis catus papillomavirus type 2 (FcaPV-2) within the tumors. As BSC is rare in cats, clinical behavior has not been established. To our knowledge, this is the first case report to demonstrate detection of FcaPV-2 within a BSC in a domestic cat. PMID- 29998925 TI - Retrospective Analysis of Air Handling by Contemporary Oxygenators in the Setting of Cardiac Surgery. AB - PURPOSE: Cardiac surgery with the use of extracorporeal circulation is associated with a significant risk for gaseous microemboli (GME) despite excellent surgical techniques and highest operative standards. GME are associated with postoperative neurocognitive dysfunction and negative clinical outcome. This study determines whether oxygenator design has influence on perioperative outcome after cardiac surgery. METHODS: Three different oxygenator models with integrated arterial filter (HiliteAF 7000, Fusion Affinity, and Synthesis) were retrospectively evaluated in 55 patients undergoing elective cardiac surgery with the use of extracorporeal circulation. The two-channel ultrasound bubble counter BCC200 was used to detect GME in real time. RESULTS: All three oxygenators differ in terms of structural specifications and have different rates of number and volume GME reduction. The Fusion Affinity had the lowest arterial GME volume (1.81 uL +/- 0.23 uL), which was statistically significant compared to the Synthesis (3.37 uL +/- 0.71 uL, p = 0.014). However, the Synthesis had lower absolute numbers at the venous GME count (31771 uL +/- 6579 uL) versus the Fusion Affinity (49304 uL +/- 8196 uL). However, with regard to clinical outcome after cardiac surgery (duration of invasive and non-invasive mechanical ventilation, incidence of delirium, stroke, acute renal failure, or new myocardial infarction), we found no differences between groups. CONCLUSION: Despite significant differences in the design specifications, all oxygenators eliminated relevant GME volumes safely. PMID- 29998926 TI - Physiological properties and genetic analysis related to exopolysaccharide (EPS) production in the fresh-water unicellular cyanobacterium Aphanothece sacrum (Suizenji Nori). AB - The clonal strains, phycoerythrin(PE)-rich- and PE-poor strains, of the unicellular, fresh water cyanobacterium Aphanothece sacrum (Suringar) Okada (Suizenji Nori, in Japanese) were isolated from traditional open-air aquafarms in Japan. A. sacrum appeared to be oligotrophic on the basis of its growth characteristics. The optimum temperature for growth was around 20 degrees C. Maximum growth and biomass increase at 20 degrees C was obtained under light intensities between 40 to 80 MUmol m-2 s-1 (fluorescent lamps, 12 h light/12 h dark cycles) and between 40 to 120 MUmol m-2 s-1 for PE-rich and PE-poor strains, respectively, of A. sacrum . Purified exopolysaccharide (EPS) of A. sacrum has a molecular weight of ca. 104 kDa with five major monosaccharides (glucose, xylose, rhamnose, galactose and mannose; >=85 mol%). We also deciphered the whole genome sequence of the two strains of A. sacrum. The putative genes involved in the polymerization, chain length control, and export of EPS would contribute to understand the biosynthetic process of their extremely high molecular weight EPS. The putative genes encoding Wzx-Wzy-Wzz- and Wza-Wzb-Wzc were conserved in the A. sacrum strains FPU1 and FPU3. This result suggests that the Wzy-dependent pathway participates in the EPS production of A. sacrum. PMID- 29998928 TI - [Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 38, Number 6, June 25, 2018]. PMID- 29998927 TI - [Proposal of Criteria for Release of Patients and Use of the Normal Ward in 64Cu ATSM Internal Radiotherapy]. AB - Cu-ATSM [Cu-diacetyl-bis(N4-methylthiosemicarbazone)] is a small molecule chelate of radioactive Cu with ATSM ligand, and has been developed as a radiopharmaceutical for positron-emission tomography (PET) imaging to detect hypoxic regions in tumors. Among the radioactive Cu, 64Cu has a unique feature that it emits not only positron for PET imaging, but also beta- particles and Auger electrons that can damage tumor cells. Therefore, 64Cu-ATSM can be developed as an internal radiotherapy agent against tumors. Particularly for malignant brain tumors, a clinical PET study has reported that Cu-ATSM shows high tumor accumulation; and a non-clinical study has demonstrated that 64Cu-ATSM treatment shows high anti-tumor effects. Based on these findings, clinical development for 64Cu-ATSM internal radiotherapy is expected. Therefore, this paper is prepared to propose the timing to release a patient administered 64Cu ATSM from dedicated internal radiotherapy rooms to protect the general public and carers from the radiation. The special consideration for the radiation protection is also proposed to treat patients in the normal ward after the administration of 64Cu-ATSM. PMID- 29998929 TI - Transplantation of Endothelial Progenitor Cells Overexpressing miR-126-3p Improves Heart Function in Ischemic Cardiomyopathy. AB - BACKGROUND: In a previous study, a low level of miR-126-3p in endothelial progenitor cells (EPCs) was linked to the outcome of ischemic cardiomyopathy (ICM) patients. However, it remains unclear whether transplantation with miR-126 3p-overexpressing EPCs (MO-EPCs) can improve the cardiac function of ICM animal models. Methods and Results: miR-126-3p overexpression by lentiviral vector significantly increased migration and tube-like structures of EPCs from ICM patients. MO-EPCs or non-modified EPCs (NM-EPCs) were transplanted into nude rats with ICM induced by coronary artery ligation. MO-EPC transplantation increased capillary density and EPC survival rate in myocardial tissues of nude rats. Cytokines were also assessed by antibody array and real-time RT-PCR. G-CSF, VEGF A, IL-3, IL-10, IGF-1, angiogenin, HGF, TIMP-1 and TIMP-2 were upregulated, and IL-8, MCP-1, MCP-2, TNF-alpha, TNF-beta and MIP-1beta were downregulated after miR-126-3p overexpression in EPCs. The same results were obtained in infarction tissues of nude rats after MO-EPC transplantation. Eight weeks after MO-EPC transplantation, left ventricular function improved significantly with clearly decreased infarction size, increased anterior wall thickness, and inhibition of inflammation compared with the results for NM-EPC transplantation. However, MO EPC transplantation showed no increase in survival time of nude rats with ICM during 8 weeks of observation. CONCLUSIONS: miR-126-3p can restore the biology of EPCs from ICM patients. Moreover, MO-EPC transplantation improves cardiac function effectively, representing a promising future treatment for ICM. PMID- 29998930 TI - Amniotic Fluid Natriuretic Peptide Levels in Fetuses With Congenital Heart Defects or Arrhythmias. AB - BACKGROUND: We have previously demonstrated that umbilical cord plasma natriuretic peptide (NP) levels reflect the severity of heart failure (HF) in fetuses with congenital heart defects (CHD). The aim of this study was to evaluate the significance of amniotic fluid (AF) NP levels in the assessment of HF in fetuses with CHD or arrhythmia. Methods and Results: This was a prospective observational study at a tertiary pediatric cardiac center. A total of 95 singletons with CHD or arrhythmia, and 96 controls from 2012 to 2015 were analyzed. AF concentrations of atrial NP (ANP), B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) at birth were compared with ultrasonographic assessment of fetal HF using the cardiovascular profile (CVP) score. Multivariate analysis showed that a CVP score <=5 and preterm birth are independently associated with high AF NT-proBNP levels. AF NT-proBNP levels of fetuses with CHD or arrhythmia inversely correlated with CVP score (P for trend <0.01). In contrast, AF concentrations of ANP and BNP were extremely low, and it was difficult to assess the degree of fetal HF based on them. CONCLUSIONS: AF NT-proBNP concentrations increase in stepwise fashion with the severity of HF in fetuses with CHD or arrhythmia; it was the optimal NP for assessing the fetal HF. PMID- 29998931 TI - Pulmonary Artery Wall Thickness Assessed by Optical Coherence Tomography Correlates With Pulmonary Hemodynamics in Children With Congenital Heart Disease. AB - BACKGROUND: Pulmonary arterial (PA) wall thickening evaluated by optical coherence tomography (OCT) has been reported in adults with PA hypertension. The purpose of this study was to evaluate the feasibility of OCT for preoperative assessment of the PA wall in children with congenital heart disease (CHD). Methods and Results: Participants comprised 39 patients with ventricular septal defect, atrial septal defect, or patent ductus arteriosus. Attempts were made to evaluate vessels of various diameters using OCT. Clearly observed vessels that were optimal for evaluation were selected and classified into 4 subgroups by diameter of the lumen. Optimal depiction was obtained in 80 of 156 vessels in total, and 25 (64.1%), 34 (87.1%), 17 (43.6%), and 4 vessels (10.3%) in each of the 1.0-<2.0 mm, 2.0-<3.0 mm, 3.0-<4.0 mm, and 4.0-5.0 mm subgroups, respectively. Arterial walls in the 2.0-<3.0 mm subgroup were the most frequently delineated, and wall thickness correlated significantly with mean PA pressure, pulmonary vascular resistance index, pulmonary-to-systemic flow ratio, and PA capacitance index (r=0.56, 0.52, 0.37, and -0.49, respectively). The 3-layered appearance was delineated in 29 of 80 vessels (36.2%). This feature had no significant correlation with pulmonary hemodynamics. CONCLUSIONS: OCT represents a promising tool for evaluating the PA wall in children with CHD. PMID- 29998932 TI - Assessment of Congenital Vascular and Organ Anomalies in Subjects With Thalidomide Embryopathy Using Non-Contrast Magnetic Resonance Angiography. AB - BACKGROUND: To determine the type and frequency of vascular and organ malformations in adults with thalidomide embryopathy (TE) using non-contrast magnetic resonance angiography (MRA) and to assess the effect of the observed malformations on renal function. Methods and Results: The institutional ethics committee approved this prospective study and written informed consent was given by all 78 subjects (50 females) with TE (mean age: 55+/-1.1 years), who were examined by non-contrast MRA at 3T. ECG-triggered balanced turbo field echo images of the chest, abdomen and pelvis were obtained in coronal and sagittal orientations. Two observers assessed the frequency of vascular and organ malformations. Serum creatinine and estimated glomerular filtration rate (eGFR) were obtained to assess renal function. In 58 subjects, 99 vascular anomalies were observed, including 68 arterial (69%) and 31 venous anomalies (31%); 15 patients had 16 abdominal organ malformations including 12 kidney anomalies and 4 cases of gallbladder agenesis. Most vascular anomalies affected the renal vessels (n=66, 67%) or supraaortic arteries (n=28, 28%). Serum creatinine and eGFR revealed normal renal function in all subjects. CONCLUSIONS: Vascular and organ anomalies occurred in a high number of subjects with TE without evidence of renal dysfunction. Information about the presence of malformations may be important for future surgical interventions in subjects with TE. PMID- 29998933 TI - Pedicle Galeo-pericranial Flap Augmentation in Salvage Frontotemporal Cranioplasty: Additional 'Neurosurgeon-friendly' Reconstruction Technique of Aesthetic Neurosurgery in Superficial Temporal Artery Branch Compromised Host. AB - This technical note aims to demonstrate the usefulness, indications and its limitations of augmentation technique by bipedicle galeo-pericranial rotation flap and by monopedicle galeo-pericranial flap, both in STA (superficial temporal artery) branch compromised hosts in salvage frontotemporal cranioplasty. Although these flaps are not always idealistically vascularized owing to accidental injuries to the STA branches during previous surgeries, they are properly augmenting after salvage frontotemporal craniotomy when infection is not active. The procedure is indicated for salvage frontotemporal craniotomy when vasculature is needed at the surgical site, such as beneath the skin incision line in a thin injured scalp, onto the titanium plates or beneath the fragile fibrous scar. We do not apply this technique by neurosurgeons alone where infection is active or if the host is irradiated. This technique is recommended as a reconstructive aesthetic neurosurgical procedure. It is a 'neurosurgeon-friendly' simple procedure, as it does not require any special tools or complicated techniques. PMID- 29998934 TI - Flow Alteration Therapy for Ruptured Vertebral Artery Dissecting Aneurysms Involving the Posterior Inferior Cerebellar Artery. AB - Surgery for- and endovascular treatment of vertebral artery (VA) dissecting aneurysms involving the origin of the posterior inferior cerebellar artery (PICA) remain challenging. Their ideal treatment is complete isolation of the aneurysm by surgical or endovascular trapping plus PICA reconstruction. However, postoperative lower cranial nerve palsy and medullary infarction are potential complications. We report four patients with VA dissecting aneurysms involving the PICA origin who were treated by occipital artery (OA)-PICA bypass followed by proximal occlusion of the VA and clip ligation of the PICA origin instead of trapping. There were no procedural or ischemic complications. In all patients, angiography performed 2-3 weeks later showed good patency of the bypass graft and complete obliteration of the aneurysm. During the follow-up period ranging from 1 to 14 years, none experienced bleeding. Although retrograde blood flow to the dissecting aneurysm persisted in the absence of trapping, iatrogenic lower cranial nerve injury could be avoided. The decrease in aneurysmal flow might elicit spontaneous thrombosis and prevent aneurysmal rerupture. Our technique might be less invasive than aneurysmal trapping and help to prevent rebleeding. PMID- 29998935 TI - Neurosurgical Management and Outcomes of Cerebrovascular Disease in Pediatric Patients with Heart Disease. AB - Antithrombotic treatment has substantial risks, even in pediatric patients. We retrospectively evaluated the management and outcomes of consecutive pediatric patients who underwent neurosurgical treatment for cerebrovascular disease with cardiovascular disease between 1998 and 2017. Patients were divided into patients with comorbid cardiovascular disease (group I); and patients with cardiovascular disease as a primary disease of intracranial complication, without (group IIa) or with (group IIb) extracorporeal circulations. Postoperative resumption of antithrombotic agents was generally initiated within 48 h. Our study included 26 patients; five were categorized as group I, 15 as group IIa, and six as group IIb. All intracranial diseases in groups IIa and IIb were exclusively hemorrhagic. Preoperative anticoagulation therapy was used in one patient (20%) in group I, 13 patients (86.7%) in group IIa, and six patients (100%) in group IIb. Postoperative intracranial hemorrhagic events were observed in one patient (20%) in group I, three patients (20%) in group IIa, and four patients (66.7%) in group IIb. Re-operations were conducted in two (13.3%) and three patients (50%) in groups IIa and IIb, respectively. Death occurred in five (33.3%) and four patients (66.7%) in groups IIa and IIb, respectively. The remaining two patients in group IIb returned to candidate status for implantation. Emergent surgery for patients with intracranial hemorrhage associated with cardiovascular disease has a high risk of postoperative hemorrhagic events and high rate of re-operations with poor vital outcomes, especially in patients with extracorporeal circulations. We should consider maximum neurosurgical treatment achievable with optimal management of antithrombotic treatment. PMID- 29998936 TI - MEG-BMI to Control Phantom Limb Pain. AB - A brachial plexus root avulsion (BPRA) causes intractable pain in the insensible affected hands. Such pain is partly due to phantom limb pain, which is neuropathic pain occurring after the amputation of a limb and partial or complete deafferentation. Previous studies suggested that the pain was attributable to maladaptive plasticity of the sensorimotor cortex. However, there is little evidence to demonstrate the causal links between the pain and the cortical representation, and how much cortical factors affect the pain. Here, we applied lesioning of the dorsal root entry zone (DREZotomy) and training with a brain machine interface (BMI) based on real-time magnetoencephalography signals to reconstruct affected hand movements with a robotic hand. The DREZotomy successfully reduced the shooting pain after BPRA, but a part of the pain remained. The BMI training successfully induced some plastic changes in the sensorimotor representation of the phantom hand movements and helped control the remaining pain. When the patient tried to control the robotic hand by moving their phantom hand through association with the representation of the intact hand, this especially decreased the pain while decreasing the classification accuracy of the phantom hand movements. These results strongly suggested that pain after the BPRA was partly attributable to cortical representation of phantom hand movements and that the BMI training controlled the pain by inducing appropriate cortical reorganization. For the treatment of chronic pain, we need to know how to modulate the cortical representation by novel methods. PMID- 29998937 TI - Transmittance of visible and blue light through zirconia. AB - The aim of this study was to evaluate the transmittance of visible light (VL) (lambda: 400-700 nm) and blue light (BL) (lambda: 360-540 nm) through six CAD/CAM zirconia blanks (ZiB) in comparison to a lithium disilicate ceramic (LS2). Disks of the zirconia materials Bruxzir (BX), Cercon (CE), Lava Frame (LF), Lava Plus (LP), Prettau (PT), Zenostar (ZS) and LS2 (EM) were manufactured and the transmittance was measured in a spectrophotometer. ZS, followed by CE, PT, LP, LF, and BX showed the lowest transmittance of VL and BL. The highest transmittance was shown by EM. The transmittance of BL was lower than that of VL in all groups. EM ceramics showed higher transmittance than all zirconia materials and the thickness of zirconia materials influenced the transmittance values. Knowledge about VL and BL transmittance would help clinicians to individually tailor the selection of material to the specific indication and to make the right choice regarding the luting procedure and light curing duration. PMID- 29998938 TI - Hard and soft tissue responses to implant made of three different materials with microgrooved collar in a dog model. AB - The objective of the present study was to assess hard and soft tissue around dental implants made of three different materials with microgrooves on the collar surface. Microgrooved implants were inserted in the mandibles of five male beagles. Implants were made of three kinds of material; titanium (Ti), yttria stabilized tetragonal zirconia polycrystals (Y-TZP) and ceria partially stabilized zirconia/alumina nanocomposite (Ce-TZP/Al2O3). The animals were euthanatized at three months after implantation, and harvested tissue was analyzed by means of histology. All kinds of implant were osseointegrated, and there were no significant differences in any histomorphometric parameters among the three groups of microgrooved implants made of different materials. Within the limitations of this study, implants with microgrooves integrated into the surrounding bone tissue, without statistically significant differences among the three tested materials, Ti, Y-TZP, and Ce-TZP/Al2O3. PMID- 29998939 TI - Surface properties and color stability of dental flowable composites influenced by simulated toothbrushing. AB - This study evaluated surface gloss, roughness and color change of six current flowable composites after simulated toothbrushing, including four traditional flowable composites (i.e. GrandioSO Flow, Arabesk Flow, Kerr Revolution Formula 2 and Gradia Direct LoFlo), one self-adhering flowable composite (Kerr Vertise Flow) and one universal injectable composite (G-aenial Universal Flo). Forty eight dimensionally standardized specimens (n=8/group) were made from six composites. Before and after 1 h toothbrushing simulation, surface gloss was measured with a glossmeter, and surface roughness was evaluated with a profilometer, and color was measured with a spectrophotometer. In this study, G aenial Universal Flo, termed as universal injectable composite by the manufacturer, presented excellent surface properties after toothbrush abrasion; Gradia Direct LoFlo showed excellent color stablity after toothbrush abrasion; color alteration of composites caused by toothbrush abrasion was acceptable on the premise that 3.3?E units were considered as acceptable threshold values. PMID- 29998940 TI - Novel self-etching and antibacterial orthodontic adhesive containing dimethylaminohexadecyl methacrylate to inhibit enamel demineralization. AB - Enamel demineralization is one of the most undesired side effects of fixed orthodontic treatment, which will lead to white spot lesions (WSLs) on tooth surfaces. The development of WSLs is due to prolonged accumulation of bacterial plaque and associated acid production. Self-etching adhesives have been used in orthodontic treatments with several advantages over the more traditional acid etch method. However, current self-etching adhesives in orthodontic treatments have no antibacterial activity. The objectives of this study were to develop a self-etching and antibacterial orthodontic adhesive, and to investigate its enamel bond strength and antibacterial properties. A novel quaternary ammonium monomer dimethylaminohexadecyl methacrylate (DMAHDM) was incorporated into a commercial self-etching adhesive (Adper Easy One, 3M). It showed that the 5% DMAHDM appeared to be optimal in obtaining the strongest antibacterial function without compromising the enamel bond strength both at 15 min and after 30 days of immersion plus thermal cycling. PMID- 29998941 TI - Mechanical properties of "two generations" of teeth aligners: Change analysis during oral permanence. AB - Aim of this in vitro study was to analyze structural properties of two different polymeric orthodontic aligners, Exceed30 (EX30) and Smart Track (LD30), before and after use. Forty patterns of aligners were randomly selected: 20 LD30 and 20 EX30, worn intra-orally for 14+/-3 days, 22 h/day. From each aligner, 10 specimens were prepared from buccal surfaces of the incisor region by the cutting of samples 5*5 mm under a stereomicroscope. All samples were subjected to Fourier transform infrared spectroscopy, micro-Raman spectroscopy, X-ray diffraction, tensile and indentation strength test. LD30 appeared more homogeneous, with a crystalline fraction lower than EX30 and exhibited a higher elastic behavior and a lower tendency to warp after use than EX30. LD30 demonstrated better adaptability to the dental arch and greater consistency of application of orthodontic forces than produced with EX30. However, both materials showed structural modifications that resulted in increased sample hardness and hyper plasticity. PMID- 29998942 TI - Influence of a cylindrical crosshead on shear bond testing of composite-tooth interfaces. AB - The effect of a cylindrical crosshead on shear bond strength of composite to dentin was assessed by finite element analysis (FEA) after shear bond testing thirty mandibular molars restored with composite cylinders (Tetric EvoCeram-3 mm diameter) perpendicular to conditioned dentin. Cross-sectional geometric models were created with quadrilateral linear plane stress elements. Stress distributions for normal, shear, and major principal stresses were plotted. Mean shear bond strength for the experimental group was 23.9 MPa (+/-4.54), about 15 75% higher than values reported with other methods. FEA showed localized 'hot spots' (+/-16-20 MPa) at the corners of the base of the adhesive layer under a 20 N vertical load. Principal stresses across the composite-dentin interface were lower (+/-12-16 MPa), but significantly homogenous, approximating closely the nominal strength value. With uniform stress distributions across the adhesive layer, FEA confirmed that a cylindrical crosshead may be an optional tool to improve shear bond testing of dental materials. PMID- 29998943 TI - Effect of fluoride mouthrinse on adhesion to bovine root dentin. AB - The purpose of this study was to evaluate the effect of fluoride mouthrinses on dentin bonding performance of a two-step selfetch adhesive; Clearfil SE Bond. Bovine root dentin surface was treated with either 450, 900, or 9,000 ppm F solutions for 30 s (immediate), and continually treated for one month (one month) before the bonding procedures. Microtensile bond strength (uTBS) test and scanning electron microscopic (SEM) observation of the acid-base resistance zone (ABRZ) were performed. Chemical state of fluorine on dentin surface was analyzed by X-ray absorption fine structure (XAFS). The 450 and 900 ppm F fluoride mouthrinses did not influence the uTBS to dentin, while the 9,000 ppm F fluoride solution adversely affected the uTBSs. The fluoride application to dentin significantly enhanced acid resistance at the adhesive/dentin interface including the ABRZ. The XAFS analysis indicated different concentrations of fluoride might create different chemical compounds on the dentin surface, influencing the uTBS results. PMID- 29998944 TI - Effect of immediate dentin sealing applications on bonding of CAD/CAM ceramic onlay restoration. AB - The effects of immediate dentin sealing (IDS) applications on the bonding of computer-aided design/computer-aided manufacturing (CAD/CAM) ceramic onlay restorations after cyclic loading were examined. Standardized mesial-distal occlusal-palatal cavities in 32 extracted human molars were prepared. The cavities were divided into four groups: those receiving thin-layered (T), slope shaped (S), and base-shaped (B) sealing, and the non-sealing group (N) as a control. The intra-cavity dentin walls of the T, S, and B groups were sealed with an all-in-one adhesive and a flowable composite. All cavities were scanned; hence, CAD/CAM onlays were fabricated using ceramic blocks and bonded with a resin cement system. Cyclic loading was applied and the microtensile bond strength (MU-TBS) was measured. It was found that IDS application improved not only the MU-TBS, but also the bonding reliability and durability of the CAD/CAM restoration. In particular, the S restoration exhibited the highest-performance as regards both robust bond strength and stable bonding. PMID- 29998945 TI - Novel self-etch adhesive with antibacterial and protein-repellent functions to prevent enamel demineralization. AB - Enamel demineralization is the most undesired side-effect of fixed orthodontic treatments. This study were to develop a novel adhesive that is self-etching instead of using the traditional etching method, and to form a sealant on the enamel to prevent demineralization. 2-methacryloyloxyethyl phosphorylcholine (MPC) and quaternary ammonium dimethylaminohexadecyl methacrylate (DMAHDM) were mixed into a self-etch adhesive (Adper Easy One, 3M, St. Paul, MN, USA; referred to as AEO). Enamel shear bond strength (SBS) was measured. Protein adsorption onto the resins was measured. An oral microcosm biofilm model with saliva was tested. Incorporation of 7.5% MPC and 5% DMAHDM into AEO did not reduce the SBS (p>0.1). AEO with 7.5% MPC+5% DMAHDM had protein adsorption that was only 1/18 that of AEO control. AEO with 7.5% MPC+5% DAMHDM had much stronger antibacterial properties (p<0.05). In conclusion, the new self-etch adhesive with MPC and DAMHDM greatly reduced protein adsorption and inhibited biofilm viability. PMID- 29998946 TI - [Role of histamine in sepsis-induced organ dysfunction: study using knockout mice of histamine-related genes]. AB - Sepsis is the leading cause of death in critically ill patients, and its incidence continues to rise. Sepsis is now defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Histamine assumes a critical role as a major mediator of many pathologic disorders with inflammation and immune reactions. However, direct evidence has not been provided showing the involvement of histamine in the development of multiple organ dysfunction or failure in sepsis. We have found that sepsis-induced major end-organ (lung, liver, and kidney) injury is attenuated in histidine decarboxylase (HDC) gene knockout mice. H1/H2-receptor gene-double knockout mice apparently behave similar to HDC knockout mice in reducing sepsis-related pathologic changes. Here we provide an overview on the role of endogenous histamine as an aggregating mediator that could contribute to the development of major end-organ injury in sepsis. PMID- 29998947 TI - [Analysis of brain histamine clearance using genetically engineered mice]. AB - Histamine acts as a neurotransmitter to regulate various physiological functions in CNS. Recent reports showed the involvement of histaminergic dysfunction in neurological disorders. Neurotransmitter clearance is essential to determine brain neurotransmitter concentration. However, molecular mechanism of brain histamine clearance remains largely unknown. First, we examined the molecular mechanism of histamine clearance in primary human astrocytes. We demonstrated that extracellular histamine was transported through organic cation transporter (OCT) 3 and plasma membrane monoamine transporter (PMAT), and subsequently intracellular histamine was inactivated by histamine N-methyltransferase (HNMT) in cytosol. Next, we generated HNMT knockout (HNMT KO) mice to investigate the role of HNMT in vivo. HNMT deficiency dramatically enhanced brain histamine concentration, indicating the important role of HNMT in histamine inactivation. HNMT KO mice showed high aggression via abnormal histamine H2 receptor (H2R) activation and the disrupted sleep-wake cycle via excessive H1R activation. These observations show that HNMT plays a pivotal role in regulating brain histamine concentration, and modulates aggression as well as the sleep-wake cycle. Although importance of OCT3 and PMAT in histaminergic nervous system remains still unknown, our preliminary data show the contribution of PMAT to brain histamine concentration. We also try to find novel inhibitors targeting brain histamine clearance. We hope our study could lead a better understanding of neuropsychiatric disorders and the development of new drugs inhibiting HNMT, OCT3 and PMAT activity. PMID- 29998948 TI - [Advances in methods for analyzing IP3 signaling and understanding of coupled Ca2+ and IP3 oscillations]. AB - Inositol 1,4,5-trisphosphate (IP3) is an important intracellular messenger produced by phospholipase C via the activation of G-protein-coupled receptor- or receptor-tyrosine-kinase-mediated pathways, and is involved in numerous responses to hormones, neurotransmitters, and growth factors through the releases of Ca2+ from intracellular stores via IP3 receptors. IP3-mediated Ca2+ signals often exhibit complex spatial and temporal organizations, such as Ca2+ oscillations. Recently, new methods have become available to measure IP3 concentration ([IP3]) using AlphaScreen technology, fluorescence polarization, and competitive ligand binding assay (CFLA). These methods are useful for the high throughput screening in drug discovery. Calcium ions generate versatile intracellular signals such as Ca2+ oscillations and waves. Fluorescent sensors molecules to monitor changes in [IP3] in single living cells are crucial to study the mechanism for the spatially and temporally regulated Ca2+ signals. In particular, FRET-based IP3 sensors are useful for the quantitative monitoring intracellular [IP3], and allowed to uncovered the oscillatory IP3 dynamics in association with Ca2+ oscillations. A mathematical model of coupled Ca2+ and IP3 oscillations predicts that Ca2+ oscillations are the result of modulation of the IP3 receptor by intracellular Ca2+, and that the period is modulated by the accompanying IP3 oscillations. These model predictions have also been confirmed experimentally. At present, however, usefulness of FRET-based IP3 sensors are limited by their relatively small change in fluorescence. Development of novel IP3 sensors with improve dynamic range would be important for understanding the regulatory mechanism of Ca2+ signaling and for in vivo IP3 imaging. PMID- 29998949 TI - [In vivo analysis for mechanism of drug action by juxtacellular recording]. AB - Electrophysiological methods are commonly used in neuroscience and pharmacology to reveal the mechanisms of drug action. In vivo analysis of the mechanisms of drug action is a particularly important method in neuropharmacology. Here, we show the juxtacellular recording method to characterize the electrophysiological and neurochemical properties of neurons. Using juxtacellular recording, researchers can record the membrane potential from single neurons, and examine action potential parameters, such as the width and coefficient variance of inter spike intervals. Additionally, recorded neurons can be labeled using neurobiotin, and neurochemical properties can be revealed by a combination of immunohistochemical staining and in situ hybridization. We introduce an experiment testing the effects of a phosphodiesterase 4 (PDE4) inhibitor on the fronto-striatal circuit using juxtacellular recording. The cerebral cortex nucleus accumbens (NAcc)-external segment of globus pallidus (GPe)-subthalamic nucleus (STN)-substantia nigra pars reticulata (SNr) pathway is the neurobiological basis of many neuropsychiatric disorders. Several components of this pathway are particularly important for the regulation of motor action and cognitive function: 1) STN-SNr pathway (hyperdirect pathway), 2) NAcc-SNr pathway (direct pathway), and 3) GPe-STN-SNr pathway (indirect pathway). Researchers can record tri-phasic responses reflecting these pathways using electro-stimulation in cerebral cortex. A PDE4 inhibitor, roflumilast, affected the 2) direct pathway as well as the 3) indirect pathway, but not the 1) hyperdirect pathway. The current findings suggest that PDE4 inhibition could be considered as a possible treatment for cognitive deficits related to fronto-striatal disorders such as attention deficit/hyperactivity disorder, and Parkinson's disease. PMID- 29998950 TI - [Development of innovative three-dimensional tissues and their application for pharmaceutical assays]. AB - Three-dimensional (3D) cardiac myoblast tissues derived from iPS cells were constructed by cell coating technology with nanometer-sized extracellular matrix. Vascularized 3D-cardiac tissues were also fabricated by employing cardiac endothelial cells. These 3D-cardiac tissues are expected to apply to pharmaceutical assays. PMID- 29998951 TI - [Preclinical and clinical properties of Bezlotoxumab (ZINPLAVA(r) 25 mg/mL concentrate for solution for infusion), novel therapeutic agent for Clostridium difficile infection]. AB - Clostridium difficile (C. difficile), an enterobacteria, flourishes and produces potent toxins, toxin A (TcdA) and toxin B (TcdB), after the disruption of the normal colonic microbiota by antibiotic therapy. C. difficile infection (CDI) may induce life-threatening complications such as fulminant colitis through damage of the intestinal wall by the toxins, therefore the prevention of CDI recurrence is the most important in CDI treatment. Bezlotoxumab is a human monoclonal antibody that neutralizes the activity of TcdB directly. The antibody inhibited cytotoxicity by TcdB derived from various ribotypes of C. difficile at a concentration (EC50) of 1/150 or less of the serum concentration (Cmax: 169 MUg/mL) in CDI patients at the clinical dose. Moreover the anti-cytotoxicity effects of the antibody were also observed against 81 clinically isolated C. difficile strains (incl. 018 [smz] and 369 [trf]: Japanese prevalent ribotypes; 027: hypervirulent ribotype) obtained in Japan and western countries. The antibody prolonged survival time of hamster and rat CDI models in a dose dependent manner. In clinical phase III studies (MODIFY I and II), the recurrence rate of CDI up to 12 weeks after administration of the bezlotoxumab group was significantly lower (P<0.0001) than the placebo group. Bezlotoxumab is the world's first drug with an indication for reduce recurrence of CDI. In Japan, bezlotoxumab was approved for marketing in September, and launched in December in 2017. Bezlotoxumab is effective for broad ribotypes of C. difficile, therefore it expects to contribute to CDI treatment through the reduce recurrence of the CDI. PMID- 29998952 TI - [Development of imaging-based diagnostic procedures for brain protein aging using a mouse model of tauopathy]. AB - An increasing age is the greatest risk factor for dementia and related disorders. Therefore, much attention has been focus on researches to understand mechanisms of disease-related brain aging. Neurodegenerative diseases including Alzheimer's disease (AD), dementia with lewy bodies, and frontotemporal lobar degeneration are mostly diagnosed by neuropathological features with protein inclusions such as Abeta, tau, alpha-synuclein, TDP-43, and FUS. These proteins are expected to lose physiological functions and mutual interaction with functional molecule with aging. Consecutively, acquired pathogenicities of aged proteins are accumulated and propagated in neural cells. The research for "Brain protein aging" is developed for understanding the mechanisms of initiation and pathogenicity of aging. Tau protein is one of major components of neurofibrillary tangles, which are closely associated with the severity of brain function loss of AD. To investigate tau protein's Brain protein aging, we have currently developed the in vivo multimodal imaging techniques for visualizing the progression of tau pathology. In this review, we will introduce such a novel imaging-based diagnostic procedures on a mouse model of tauopathy. PMID- 29998953 TI - [Neuroregeneration by in vivo direct reprogramming]. PMID- 29998954 TI - Analytical System Using Lipid Bilayers to Immobilize Biofunctional Compounds. PMID- 29998955 TI - Recent Progress in the Development of Microfluidic Vascular Models. AB - The blood vessel is part of the circulatory system, and systemic circulation provides the blood supply to all tissues. Arteries are pathways through which the blood is carried, and the capillaries have a key role in material exchange to maintain the tissue environment. Blood vessels have structures appropriate for their functions, and their sizes and cell types are different. In this review, we introduced recent studies of the microfluidic vascular models. The model structures are classified mainly as poly(dimethylsiloxane) and hydrogel microchannels and self-assembled networks. Basic phenomena and functions were realized in vascular models, including fluid shear stress, cell strain, interstitial flow, endothelial permeation, angiogenesis, and thrombosis. In some models, endothelial cells were co-cultured with smooth muscle cells, pericytes, and fibroblasts in an extracellular matrix. Examples of vascular models involving the brain, lung, liver, kidney, placenta, and cancer were also introduced. PMID- 29998956 TI - Verification of the Universal Versatility of a Quantitative Protein Measurement Technique Using a Metal Mesh Device. AB - When proteins are attached to microstructures such as a metal mesh device, changes in their optical properties occur. These changes have been characterized based on actual measurements in the infrared region of the spectrum. We have previously theoretically and experimentally demonstrated the optical changes associated with streptavidin. Here, we investigate three types of proteins: avidin, BSA, and lysozyme. The three proteins were adsorbed onto three types of metal mesh devices having different resonant frequencies, and the corresponding spectra were measured in the infrared region. The change in the frequency of the dip point in the spectrum was extracted to quantitatively determine the quantity of protein; these results were correlated with the quantitative measurements obtained by electrophoresis. By examining three types of different proteins, it was verified that a variety of proteins can be measured based on the optical characteristics of metal mesh devices. PMID- 29998957 TI - Determination of Ophthalmic Drug Proparacaine Using Multi-walled Carbon Nanotube Paste Electrode by Square Wave Stripping Voltammetry. AB - Proparacaine, one of the most common local anesthetics to facilitate diagnosis and treatment of eye diseases, was assayed by square wave voltammetry using a paste electrode prepared with carbon nanotubes. In cyclic voltammetric studies, proparacaine has exhibited a single irreversible anodic peak at around + 900 mV vs. Ag/AgCl in pH 6.0 Britton-Robinson buffer solution. It was suggested that the peak had appeared due to the oxidation of the NH2 group on the proparacaine molecule. Prior to the determination of the proparacaine by square wave stripping voltammetry (SWSV) on the fabricated multi-walled carbon nanotube paste electrode (MWCNTPE), the accumulation potential (Eacc), accumulation time (tacc), pulse amplitude (DeltaE), step potential (DeltaEs) and frequency (f ) parameters were optimized. The peak currents plotted in the range of 0.5 - 12.5 mg/L proparacaine exhibited two linear sections with a detection limit of 0.11 mg/L. The results for the determination of proparacaine on a pharmaceutical local anesthetic (Alcaine(r)) showed that relative standard deviation (RSD) and relative error (RE) were 4.1 and -2.0%, respectively. Selectivity has also been investigated and results showed recoveries of 5.0 mg/L proparacaine in the presence of 5.0 mg/L dopamine, ascorbic acid and uric acid as 106.9 +/- 0.8, 99.9 +/- 1.2 and 94.1 +/- 0.7, respectively. PMID- 29998958 TI - Flow-Injection Chemiluminescence Method for Sensitive Determination of Ascorbic Acid in Fruit Juices and Pharmaceutical Samples Using a Luminol Cetyltrimethylammonium Chloride Reversed Micelle System. AB - A highly sensitive flow-injection (FI) method was developed for the determination of ascorbic acid using chemiluminescence (CL) based detection. This method involved the following processes: (1) reduction of tetrachloroaurate(III) in hydrochloric acid with ascorbic acid; (2) on-line extraction of the residual Au(III) with rhodamine B from the aqueous hydrochloric acid solution into toluene, followed by the separation of the Au(III)-containing organic phase from the aqueous phase through a microporous Teflon membrane in the flow system; and (3) the measurement of CL produced in a flow cell upon mixing of the extract stream of Au(III) in toluene with luminol in the reversed micellar medium of cetyltrimethylammonium chloride-water in 1-hexanol-cyclohexane, which was injected into a CL reagent stream. In this procedure, a reduction in the CL intensity occurred due to the addition of ascorbic acid to the Au(III) solution. The CL signal of Au(III) decreased with increasing concentration of ascorbic acid in the aqueous sample solution. The proposed procedure allowed the indirect quantitative determination of ascorbic acid in the range of 1.0 * 10-12 to 1.0 * 10-7 M with a correlation coefficient of 0.987 and relative standard deviation of 2.1% (n = 6) at 1.0 * 10-9 M. The proposed FI-CL methodology was successfully applied for quantitative determination of ascorbic acid in fruit juices and pharmaceutical samples. PMID- 29998959 TI - Comparison of Direct and Mediated Electron Transfer in Electrodes with Novel Fungal Flavin Adenine Dinucleotide Glucose Dehydrogenase. AB - Direct and mediated electron transfer (DET and MET) in enzyme electrodes with a novel flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) from fungi are compared for the first time. DET is achieved by placing a single-walled carbon nanotube (CNT) between GDH and a flat gold electrode where the CNT is close to FAD within the distance for DET. MET is induced by using a free electron transfer mediator, potassium hexacyanoferrate, and shuttles electrons from FAD to the gold electrode. Cyclic voltammetry shows that the onset potential for glucose response current in DET is smaller than in MET, and that the distinct redox current peak pairs in MET are observed whereas no peaks are found in DET. The chronoamperometry with respect to a glucose biosensor shows that (i) the response in DET is more rapid than in MET; (ii) the current at more than +0.45V in DET is larger than the current at the current-peak potential in MET; (iii) a DET electrode covers the glucose concentration range for clinical requirements and is not susceptible to interfering agents at +0.45 V; and (iv) a DET electrode with the novel fungal FAD-GDH does not affect sensing accuracy in the presence of up to 5 mM xylose, while it often shows a similar response level to glucose with other conventionally used fungus-derived FAD-GDHs. It is concluded that our DET system overcomes the disadvantage of MET. PMID- 29998960 TI - Development of Titania Nanotube-based Electrochemical Immunosensor and Determination of Prostate Specific Antigen. AB - Early diagnosis of cancer is the most important factor that increases the success of treatment. Therefore, the development of new diagnostic tools is a necessity. In this study, a new electrode surface was developed via modification of a disposable titanium electrode with anodic oxidation and coating of gold nanoparticle and chitosan. Titanium electrodes were anodized by several anodization parameters to obtain a nanoporous surface and characterized by scanning electron microscopy. Electrodes anodized in optimum conditions were modified with gold nanoparticles and chitosan for enhancing conductivity and functionalizing the surface of electrode, respectively. To detect prostate specific antigen (PSA), anti-PSA was bound onto the functional electrode surface. Modified electrodes were characterized with scanning electron microscopy and cyclic voltammetry and used for chronoamperometric detection of PSA. Limit of detection (LOD) of the designed electrode was found to be 7.8 ng mL-1 for PSA in a linear range of 0 - 100 ng mL-1. PMID- 29998961 TI - Paper-based DPPH Assay for Antioxidant Activity Analysis. AB - We report on a paper-based 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH) assay for a simple, inexpensive, low reagent and sample consumption and high throughput analysis of antioxidant activity. The paper-based device was fabricated using a lamination method to create a 5-mm in diameter circular test zone that was embedded with a DPPH reagent. The analysis was carried out in one step by dropping an antioxidant/sample onto the test zone. After reduction by the antioxidant, the DPPH radicals become stable DPPH molecules, resulting in a change in color from deep violet to pale yellow. The violet color intensity of DPPH was inversely proportional to the antioxidant activity of the samples, and was measured using imaging software. A high precision and a low limit of detection were found in the analysis of six standard antioxidants including gallic acid, trolox, ascorbic acid, caffeic acid, vanilliic acid and quercetin. The device was then validated against the traditional spectrophotometric DPPH assay by analyzing the antioxidant activity of 7 tea samples. The results showed no significant difference for gallic acid equivalent for all 7 samples obtained from the two methods at the 95% confidence level, indicating that the developed method was reliable for antioxidant activity analysis of real samples. Finally, the paper-based DPPH device was found to be stable over 10 days when stored in a refrigerator (2 - 4 degrees C), making it an easy-to-use device for end-users. PMID- 29998962 TI - Simultaneous Determination of Inorganic Cations and Anions in Microchip Electrophoresis Using High-voltage Relays. AB - A new and simple method for the simultaneous determination of cations and anions by microchip electrophoresis with capacitively coupled contactless conductivity detection (ME-C4D) is described. The best analytical performance was found by applying a sinusoidal wave with 800 kHz frequency and 20 Vpp amplitude. An optimized background electrolyte (BGE) composed of 20 mM His/MES and 0.01 mM CTAB was chosen for the simultaneous analysis. Samples containing K+, Na+, and Li+ as the cations and Cl-, F- and PO43- as anions were analyzed simultaneously in a single run (within 3 min). The reproducibility obtained by the method was compared with those obtained in previous studies that had employed simultaneous analysis of anions and cations by ME-C4D. The proposed simultaneous determination method is inexpensive, simple, fast, easy to operate, and offers a high degree of integration. PMID- 29998963 TI - Effects of Functional Group Density in Stylene-Divinylbenzene Copolymer Phase and of Supporting Electrolyte Concentration in Aqueous Phase on Performance of Iminodiacetate-type Chelating Resin in Terms of Contribution of Ion-Exchange Mechanism. AB - The effects of the functional group density in the stylene-divinylbenzene copoymer phase and of the supporting electrolyte concentration in the aqueous phase on the perfomance of the iminodiacetate (IDA)-type chelating resin were studied in terms of contribution of an ion-exchange mechanism. High hydrophobicity of the resin having a low functional group density interfered with penetration of aqueous solutions into the resin phase to slow the acid-base reaction and the adsorption reaction. Uptake of the cation in the supporting electrolyte into the resin phase was clearly indicated in each of two acid dissociation reactions. The high concentration of the supporting electrolyte enhanced acid dissociation of the IDA group, and a singly deprotonated species interacting with the supporting electrolyte cation strongly interfered with adsorption by the ion-exchange mechanism, while only slightly interfering with adsorption by the complexation. Both the complexed and ion-exchanged species respectively involving two or more IDA groups were destabilized to reduce the adsorption capacity of the resin having the low functional group density. PMID- 29998964 TI - Smart Aptamer and Protein Functionalized Poly(N-isopropylacrylamide) Materials for Selective Extraction of Riboflavin in Beer. AB - Materials which can be combined with riboflavin specifically based on smart functionalized polymer were studied for their ability to selectively extract riboflavin from beer. The extraction was done directly by the affinity interaction of riboflavin with the riboflavin aptamer or riboflavin binding protein (RBP). Poly(N-isopropylacrylamide) (PNIPAAm) was introduced as a carrier and modified with riboflavin aptamer and RBP, respectively, in order to be conducive to the separation of riboflavin originally present in the beer. The produced complexes can be readily separated from the aqueous phase and benefited from the temperature sensitive property of this smart polymer. The study showed riboflavin could be selectively removed from a standard solution and beer satisfactorily and the nonspecific binding was almost negligible. In the manufacturing process of beer, this separation method has a great potential to prolong the storage period of beer and improve the quality of the products. PMID- 29998966 TI - Determination of Sulfur in Grape and Apricot Samples Using High-resolution Continuum Source Electrothermal Molecular Absorption Spectrometry. AB - The determination of sulfur in apricot and grape samples was performed by using high-resolution continuum source electrothermal molecular absorption spectrometry based on vaporization of the carbon monosulfide (CS) molecule. CS forms in the gas phase without the addition of any molecule-forming element, since graphite cuvette contains plenty of carbon as well as food samples. A mixture of 15 MUg Pd + 10 MUg Mg was used in solution as the chemical modifier. The best sensitivity was obtained at 900 degrees C of the pyrolysis temperature with a K2SO4 calibration solution. The calibration plot drew a linear path between 50 and 1600 ng of sulfur, and the limit of detection was found to be 23 ng. The accuracy of the method was confirmed with the use of a standard reference material (Rice Flour, NIST SRM 1568a). The sulfur content in chemically dried apricot samples (1987 +/- 45 mg/kg) was determined to be higher than that of apricot samples dried under sunshine. PMID- 29998965 TI - A Selective Joint Determination of Salicylic Acid in Actinidia chinensis Combining a Molecularly Imprinted Monolithic Column and a Graphene Oxide Modified Electrode. AB - A new combination between selective polymer monolith microextraction (PMME) and sensitive differential pulse voltammetry (DPV) was developed for the determination of the phytohormone salicylic acid (SA) in Actinidia chinensis. A molecularly imprinted monolithic column (MIMC) thermally in-situ polymerized in a micropipette tip by using SA as a template, 4-vinyl pyridine (4-VP) as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker in the mixed porogen of toluene and dodecanol, was employed for the microextraction of SA. The prepared MIMC was characterized by a Fourier transform infrared spectrometer (FI-TR), scanning electron microscope (SEM) and thermo gravimetric analysis (TGA). The results confirmed the binary continuous structure of the porous network. The extracted SA was determined by DPV on a graphene oxide (GO) modified electrode. The joint conditions between MIMC and DPV were investigated practically. Under the optimum conditions, SA could be determined selectively and sensitively in a linear range from 0.1 to 60.0 MUg g-1. The limit of detection was 0.03 MUg g-1 and the recoveries were between 86.2 and 105.2%. The proposed joint method was successfully used to determine SA in Actinidia chinensis. PMID- 29998967 TI - Melanin Radicals in Paraffin-embedded Melanoma Investigated Using Surface-type Dielectric Resonator for X-band EPR. AB - We investigated melanin radicals in paraffin-embedded malignant melanoma (MM) using a surface-type dielectric resonator for X-band electron paramagnetic resonance (EPR) and analyzed the radical species. The surface-type resonator's performance was examined using 5 - 10 MUL of 0.1 mM 4-hydroxy-2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPOL) aqueous solution in a 1.0-mm (i.d.) glass capillary as well as 1,1-diphenyl-2-picrylhydrazyl (DPPH) powder. The surface type detection has approximately two times poorer S/N ratio than commercial insertion-type detection. A sample of the paraffin-embedded MM specimen was used for the radical detection. We obtained an EPR spectrum of melanin radicals in the paraffin-embedded melanoma sample (size ~3 * 4 * 3 mm). A single line (~0.64 mT peak-to-peak line-width) with a small shoulder was observed and was identified as a pheomelanin-related radical. The pheomelanin radical can be directly related to the MM. Thus, the present results were a good indication for noninvasive measurement, as well as for detailed analyses of melanin radicals in human MM. PMID- 29998968 TI - Sensitive Analysis of Sialic Acid and Related Compound by Hydrophilic Interaction Liquid Chromatography Using Fluorescence Detection after Derivatization with DBD PZ. AB - N-Acetylneuraminic acid (NANA) has been reported to react with hydrogen peroxide in vitro to produce 4-(acetylamino)-2,4-dideoxy-D-glycero-D-galacto-octonic acid (ADOA). We labeled NANA and ADOA with 4-(N,N-dimethylaminosulfonyl)-7-piperazino 2,1,3-benzoxadiazole (DBD-PZ) for simultaneous detection. The derivatized NANA and ADOA were separated using hydrophilic interaction liquid chromatography (HILIC) with fluorescence detection. The calibration curves of DBD-PZ-derivatized NANA and ADOA showed good linearity in the range of 221 fmol to 1.5 nmol, and 44 fmol to 1.5 nmol, respectively. This analytical method has high specificity and is useful for the detection of NANA and ADOA in saliva and serum. PMID- 29998969 TI - Generalized Two-dimensional Correlation Analysis for Unimodal Waveforms Modeled by Quadratic Polynomials. AB - We describe further potential of generalized 2D correlation analysis, aiming to realize the automation of the sequential order determination of signal variations. By modeling unimodal waveforms using quadratic functions, we can analytically express 2D correlation functions to yield an index to determine the sequential order. Based on the obtained results, we find an exception for determining the sequential order of signal variations. To resolve the exception, we suggest an extended way of interpreting the sequential order of signal intensity changes. PMID- 29998970 TI - Determination of Nickel by Flame Atomic Absorption Spectrometry after Preconcentration by Coprecipitation with Aluminum Hydroxide. AB - A method for nickel preconcentration by coprecipitation using Al(OH)3, followed by centrifugation and dissolution with HNO3 prior to a determination by flame atomic absorption spectrometry (FAAS), was investigated. Preconcentration factors of 30 and 200 were tested, and the detection limit (3 * sd/m, n = 10) was 0.05 MUg L-1. The method was applied to real samples, and the results agreed with those obtained directly by graphite furnace atomic absorption spectrophotometry. PMID- 29998971 TI - Application and Validation of a Determination Method Using Post-column Reaction Gas Chromatography of Nitrogen-containing Organic Compounds. AB - In this work, we applied post-column reaction gas chromatography (GC) using a flame ionization detector (FID) system to study nitrogen-containing organic compounds (NOCs). The results were subsequently validated. After separation by column, the target components were converted to carbon dioxide using an oxidizing catalyst and then reduced to methane, followed by detection using an FID. SI traceable testing mixtures containing NOCs (isoprocarb, napropamide, and pendimethalin) were prepared by the gravimetric blending method. These mixtures were analyzed using a post-column reaction GC-FID system; standard materials of hydrocarbons were used as calibrants in this analysis. The determined values were compared with the values obtained for samples prepared at the corresponding concentrations, and statistical analyses were performed in all cases. It was shown that the determined and prepared values agreed well with each other within the uncertainty limits. PMID- 29998973 TI - Erratum: Analytical Sciences, 2017, Vol. 33, No. 12, p. 1441. PMID- 29998974 TI - Highlights: Focus on Bone Marrow Pathology. PMID- 29998976 TI - Histopathology in the diagnosis of high-risk myelodysplastic syndromes. PMID- 29998975 TI - Histological evaluation of myeloproliferative neoplasms. AB - In 2017, the revised World Health Organization was published. Regarding myeloproliferative neoplasms, histological findings of bone marrow biopsy is becoming more important for diagnosis. This article highlights particularly the morphology of megakaryocytes and evaluation of myelofibrosis for pathological diagnosis, and immunohistochemistry which can detect somatic mutation. PMID- 29998977 TI - The histopathology of myeloma in the bone marrow. AB - Myeloma is characterized by the neoplastic proliferation of monoclonal plasma cells. A diagnosis of myeloma is based on the criteria proposed by the International Myeloma Working Group and the pathological findings.Myeloma cells are classified into four types: mature, immature, pleomorphic, and plasmablastic. There are three patterns in which myeloma infiltrates bone marrow - nodular, interstitial, and diffuse. Dutcher bodies are highly specific to neoplastic myeloma cells. On immunohistochemical staining, the specificity of CD138 is high for plasma cells. As a clear image is often not obtained from the immunohistochemical staining of the immunoglobulin light chain, in situ hybridization is recommended. Abnormal expression of CD56 is seen in 70-80% of cases by flow cytometry analysis. CD56 expression definitively indicates myeloma, suggesting its high diagnostic value. Evaluation of the infiltration pattern, monoclonality, and abnormal antigen expression of plasma cells is more important than the plasmocytic ratio to determine whether a case is reactive or neoplastic.Multiple gene abnormalities function in the onset and progression of myeloma. In our department, we analyze CCND1, FGFR3, MAF, and del (17p13) by FISH for all myeloma cases. None of the cases with genetic abnormalities were recognized by G-banding. Therefore, FISH is more effective than G-banding for the evaluation of genetic abnormalities in myeloma. PMID- 29998978 TI - The histopathology of bone marrow failure in children. AB - Bone marrow failure (BMF) is a rare but life-threatening disorder that usually manifests as (pan)cytopenia. BMF can be caused by a variety of diseases, but inherited BMF (IBMF) syndromes are a clinically important cause, especially in children. IBMF syndromes are a heterogeneous group of genetic disorders characterized by BMF, physical abnormalities, and predisposition to malignancy. An accurate diagnosis is critical, as disease-specific management, surveillance, and genetic counselling are required for each patient. The major differential diagnoses of IBMF syndromes are acquired aplastic anemia (AA) and refractory cytopenia of childhood (RCC). These diseases have overlapping features, such as BM hypocellularity and/or dysplastic changes, which make the differential diagnosis challenging. RCC has been defined as a histomorphologically distinct entity. Therefore, understanding the BM histopathology of these diseases is essential for the differential diagnosis. However, the BM histopathological features have not been characterized in detail, as descriptions of BM histopathology are very limited due to the rarity of the diseases. This review provides a detailed description of the BM histopathology in cases of RCC, AA, and the four most common IBMF syndromes: Fanconi anemia (FA), dysketatosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). An overview, including the clinical features and diagnosis, is also provided. PMID- 29998980 TI - [Review of small bowel disease (non-CD) -tumor, inflammation, and rare disease]. PMID- 29998979 TI - The expression of PD-1 ligands and IDO1 by macrophage/microglia in primary central nervous system lymphoma. AB - Recent progress in anti-tumor immunotherapy has focused on the significance of the tumor microenvironment in tumor progression and resistance to chemo/radio therapy. Myeloid cells such as macrophages are predominant stromal components in hematological malignancies. In the present study, we investigated the regulation of programmed death-1 (PD-1) ligand expression in primary central nervous system lymphoma (PCNSL) using PCNSL cell lines and human monocyte-derived macrophages. TK PCNSL cell line-derived soluble factors induced overexpression of PD-1 ligands, indoleamine 2,3-dioxygenase (IDO1), and several other cytokines in macrophages. The expression of PD-1 ligands was dependent on the activation of signal transducer and activator of transcription 3. PD-L1 and IDO1 were overexpressed by macrophage/microglia in PCNSL tissues, and gene expression profiling indicated that IDO1 expression was positively correlated with the expression of macrophage and lymphocyte markers. Macrophage-derived factors did not influence the proliferation or chemo-sensitivity of cell lines. These data suggest that the expression of immunosuppressive molecules, including PD-1 ligands and IDO1, by macrophage/microglia may be involved in immune evasion of lymphoma cells. PMID- 29998981 TI - [Overview of small bowel vascular diseases]. PMID- 29998982 TI - [Review of small bowel tumors]. PMID- 29998983 TI - [Review of the small intestinal mucosal lesion]. PMID- 29998985 TI - ? PMID- 29998984 TI - [The overview of small intestinal lesions in systemic diseases]. PMID- 29998986 TI - [Epidemiological investigation of colonic diverticulosis detected by computed tomography colonography]. AB - Among 586 patients who underwent computed tomography colonography (CTC) from May 2012 to September 2017, 333 were diagnosed with colonic diverticulosis. The incidence of colonic diverticulosis increases with age. Despite a high frequency of ascending colonic diverticulosis, multiple diverticulosis (>10 in a colonic segment) were the most frequent in the sigmoid colon. In previous studies, the frequency of detection of colonic diverticulosis by CTC was higher than that by colonoscopy and barium enema. In addition, using CTC, the detection rate of colonic diverticulosis has been recently increasing, suggesting that CTC is the most sensitive procedure for detecting colonic diverticulosis. PMID- 29998987 TI - [Clinical features of 60 patients with ischemic colitis]. AB - Clinical features of 60 patients with ischemic colitis diagnosed at our hospital were analyzed. Ischemic colitis developed in 58 patients (97%) shortly after the evening meal, and in 52 patients (87%), it occurred while the patients were asleep from night to daybreak. The supine position while sleeping resulted in a decrease in the blood flow to the colonic wall and an increase in the intraluminal pressure due to a delay in excretion of the contents of the gut. In addition, increased peristalsis and intraluminal pressure after the evening meal triggered ischemic colitis. Ischemic colitis in the young adult group (<40 years) was more frequently mild because they did not experience arteriosclerosis-related diseases and constipation, and these intestinal factors were considered to contribute to the onset of the disease. In the elderly group (>=70 years), ischemic colitis was more severe than that in the young adult group because ischemic colitis in the elderly group was caused by both vascular and intestinal factors. The severity score evaluated by endoscopic findings revealed a marked correlation with age, clinical symptoms, leukocyte count, and CRP value. The final linear regression model determined leukocyte count, age, and digestive symptoms as substantial independent predictors. In several cases in our study, ischemic colitis occurred more often when exposed to a high percentage of humidity;thus, we speculated that high humidity played an essential role in the pathogenesis of ischemic colitis. PMID- 29998988 TI - [Conservative management of gastric emphysema and hepatic portal venous gas: a case report]. AB - A 69-year-old Japanese man underwent successful percutaneous endoscopic gastrostomy (PEG) without any intra-procedural adverse event. However, 3 days postoperatively, he presented with melena and bloody discharge from the gastrostomy tube. Computed tomography revealed gastric emphysema, hepatic portal venous gas, portal vein thrombosis, and swelling of the ascending colon. We administered antibiotics and discontinued enteral feeding; this resulted in resolution of gastric emphysema, hepatic portal venous gas, and portal vein thrombosis and an improvement in the swelling of the ascending colon. To the best of our knowledge, till date, only three patients have been reported to develop gastric emphysema and hepatic portal venous gas after PEG. All previously reported patients were treated with antibiotics and/or discontinuation of enteral feeding, exhibiting recovery within 6-14 days. Although the occurrence of gastric emphysema and hepatic portal venous gas after a PEG procedure is rare, conservative management can ensure recovery in such patients. PMID- 29998989 TI - [Hip joint synovitis associated with daclatasvir plus asunaprevir combination therapy to treat chronic HCV infection in elderly patients: a case report]. AB - An 81-year-old woman was treated with Daclatasvir (DCV) and Asunaprevir (ASV) for chronic HCV infection. Although she developed a fever 13 days after treatment initiation, the administration of these drugs was continued under careful observation. After 33 days of treatment initiation, she developed a high fever and hip joint pain that led to hospitalization. Following MRI studies and examination of her hip joint fluid, we suspected that she had developed hip joint synovitis secondary to the use of DCV and ASV. Consequently, we discontinued the administration of both DCV and ASV, resulting in an immediate improvement in her symptoms. Eventually, she attained a sustained virological response 24 despite discontinuing the administration of DCV and ASV. Hence, unexpected adverse events, such as hip joint synovitis, should be considered in the differential diagnosis, particularly in elderly patients (>=80 years) who are treated with DCV and ASV for chronic HCV infection. PMID- 29998990 TI - [Diagnosis of reactive lymphoid hyperplasia of the liver and difficulty in its differentiation from a malignant tumor: a case report]. AB - A 79-year-old woman presented with a chief complaint of abdominal pain. Imaging findings suggested hepatocellular carcinoma although the serum levels of tumor markers were within the normal range. Thus, we performed hepatectomy of S5 and components separation. Histologically, the tumor was diagnosed as reactive lymphoid hyperplasia of the liver. In reactive lymphoid hyperplasia of the liver, a preoperative diagnosis of a malignant tumor was made followed by a definitive diagnosis after resection. Hence, it is imperative to consider reactive lymphoid hyperplasia as a type of liver tumor that is distinct from hepatocellular carcinoma. PMID- 29998991 TI - Increase in the hydroxyl radical-scavenging activity of Panax ginseng and ginsenosides by heat-processing. AB - Panax ginseng C.A. Meyer (Araliaceae), mainly cultivated in Korea and Northeast China, is processed before use based on its long history of ethnopharmacological evidence. Ginsenosides have been regarded as the main active components responsible for the pharmacological activities of ginseng. Although the Maillard reaction is known as a major source of compounds related to enhanced antioxidant activity by heat treatment in various crude drugs or foods, the chemical and free radical-scavenging activity changes of ginsenosides brought about by the Maillard reaction have not yet been elucidated. This paper gives a review of our recent findings, with emphasis on the hydroxyl radical (*OH)-scavenging activity changes of ginsengs and ginsenosides by heat-processing using an electron spin resonance spectrometer. 20(S)- Rg3 showed the strongest activity, and the next was in the decreasing order of Rb1, Rg1, Rc, Rb2, and Rd. The *OH-scavenging activities of ginsenosides were related to the ferrous metal ion-chelating activities of their aglycone, 20(S)-protopanaxadiol. In addition, the ferrous metal ion-chelating activities of ginsenosides were thought to be influenced by their types of hydrophilic sugar moieties. Moreover, Rb1 was changed into 20(S)-Rg3, 20(R)-Rg3, Rk1, and Rg5 by heat-processing, and the sugar moieties at carbon-20 were separated. The generated amount of 20(S)-Rg3 was higher than when Rb1 was heat processed without amino acids, and a significant increase in Maillard reaction products was noted. Based upon chemical and *OH-scavenging activity tests using Maillard reaction model experiments, the scientific evidence underlying the increase in free radical-scavenging activity of ginseng induced by heat processing was elucidated. PMID- 29998992 TI - Inhibitory effects of alpha-cyclodextrin and its derivative against sucrose induced hyperglycemia in an in vivo evaluation system. AB - Cyclodextrins (CyDs) are cyclic oligosaccharides consisting of six to eight glucose residues. Administration of alpha-CyD (six glucose residues) inhibits sucrose-induced hyperglycemia in humans. Here we show that oral administration of alpha-CyD and dimethyl alpha-CyD suppresses sucrose-induced hyperglycemia in an in vivo evaluation system using silkworms. On the other hand, beta-CyD (seven glucose residues), gamma-CyD (eight glucose residues), and their derivatives did not show the suppressive effect. These findings suggest that dimethyl alpha-CyD is a new inhibitor against sucrose-induced hyperglycemia and the silkworm system is useful for evaluation of suppressive activities of alpha-CyD derivatives against postprandial hyperglycemia. PMID- 29998993 TI - Tooth whitening efficacy of pigmented rice gels containing carbamide peroxide. AB - Carbamide peroxide (CP) is commonly used as a tooth whitening agent. However, efficacy of CP can be enhanced if it is in the suitable delivery system. In the present study, CP loaded in pigmented rice gels were developed and investigated for their physicochemical properties and tooth whitening efficacy. The modified pigmented rice of two varieties, Homnil (HN) and Doisket (DS) were prepared and used as a gelling agent. The outer appearance of the obtained rice gels containing 10% CP (CP-HN and CP-DS, respectively) were transparent and homogeneous texture. The pH of both rice gel bases was neutral but became slightly acidic after incorporating with CP. The adhesive property of HN gel was significantly higher than DS gels. In vitro drug release profile exhibited that the release of CP from CP-DS was significantly higher than CP-HN and the commercial gel (CP-CG), respectively. In vitro tooth whitening efficacy in 45 normal teeth revealed that the tooth whitening efficacy of the gels was time dependent. At the end of the treatment, CP-HN showed significantly higher tooth whitening efficacy than CP-DS and CP-CG, respectively. It is concluded that the physicochemical properties, particularly the adhesive and dissolution properties, play an important role in the tooth whitening efficacy of the CP gels. PMID- 29998994 TI - Effects of Piper betle fractionated extracts on inhibition of Streptococcus mutans and Streptococcus intermedius. AB - The overgrowth of certain strains of normal flora in oral cavity can cause many kinds of oral infections or diseases such as carries, periodontitis, and gingivitis. Prevention and treatment of these diseases are usually achieved by chemical antiseptics. However, these chemicals are found as negative impacts of human health hazards and accession of microbial resistance. The present study explores the potential of Piper betle extracts on inhibition of two oral pathogenic bacteria; Streptococcus mutans DMST 41283 and Streptococcus intermedius DMST 42700. P. betle demonstrated significantly higher inhibitory activity against both pathogenic strains than Acacia catechu, Camellia sinensis, Coccinia grandis, Solanum indicum, and Streblus asper. Among fractionated extracts of P. betle from several solvents, the extract from ethyl acetate (Pb EtOAc) possessed the widest inhibition zone of 11.0 +/- 0.1 and 11.3 +/- 0.4 mm against both bacterial strains, respectively. Pb-EtOAc showed the same minimum inhibitory concentration of 0.5 mg/mL against both strains, whereas its minimum bactericidal concentrations were 2.0 and 0.5 mg/mL against S. mutans and S. intermedius, respectively. HPLC analysis demonstrated that the major active compound of Pb-EtOAc was 4-allylpyrocatechol. It was found that the killing kinetics of Pb-EtOAc against both test strains were time and dose dependent. Scanning electron microscopy micrographs showed the morphological changes and depletion of the tested pathogens indicating cell destruction after exposure to Pb-EtOAc. It is confirmed that Pb-EtOAc is potentially effective against both oral pathogens and might be used as natural alternative agents in prevention and treatment of oral infections caused by oral pathogenic bacteria. PMID- 29998995 TI - D-cycloserine nasal formulation development for anxiety disorders by using polymeric gels. AB - D-cycloserine (DCS), a partial agonist at N-methyl-D-aspartate (NMDA) receptors, is used as an enhancer of exposure therapy for anxiety disorders. The purpose of the present study was to investigate the feasibility of using polymeric gels to increase the viscosity of the formulation and thereby increase the nasal residence time and sustained release of DCS in vitro. Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and methyl cellulose (MC) were prepared at concentrations of 0.5 to 5% w/v. Pluronic F-127 (PF-127) was prepared at concentrations of 15 to 35% w/v. pH, viscosity and in vitro DCS release behavior of the formulated gels were analyzed. All four gels that were tested, demonstrated sustained DCS release behavior over a 24-hour period, but with different rates. Based on the results of this study, HPMC, HPC, MC, and PF 127 are capable of increasing the viscosity of nasal gel formulations and of releasing DCS in sustained manner. Therefore, these polymeric gels can be suitable carriers for DCS nasal gel formulation. PMID- 29998996 TI - Clinical effect of long-term administration of tolvaptan in patients with heart failure and chronic kidney disease. AB - The effectiveness of long-term administration of tolvaptan in heart failure (HF) patients with chronic kidney disease (CKD) has not been fully studied. Hence, in this study, we investigated the effects of chronic administration of tolvaptan on patients with HF and CKD. We consecutively enrolled 31 patients with acute HF syndrome (AHFS) who were administrated tolvaptan as a long-term medication (TLV group). All patients had a history of prior HF admission and CKD. We also consecutively enrolled 27 patients with AHFS, a prior history of HF and CKD (conventional group). We compared renal function and outcomes between the two groups at discharge for AHFS and after 6 months of follow-up. The estimate glomerular filtration rate (eGFR) was maintained at approximately the same level in the TLV group exhibited approximately the same eGFR (-1.1 +/- 8.3 mL/min/1.73 m2) but decreased in the conventional group (-7.4 +/- 10.4 mL/min/1.73 m2). There was a significant difference in the changes observed in eGFR between the conventional and TLV groups (p = 0.01). There were no significant differences in the frequencies of rehospitalization and death. Long-term administration of tolvaptan may prevent increased renal dysfunction in HF patients with CKD. This conclusion should be confirmed in a large-scale prospective study. PMID- 29998997 TI - Characteristics of gut microbiota and its response to a Chinese Herbal Formula in elder patients with metabolic syndrome. AB - Alterations in gut microbiota have been known to play a critical role in metabolic syndrome. However, the microbial features in elderly patients with metabolic syndrome remain unclear. A traditional Chinese Herbal Formula, Yangyin Tiluo Decoction (YTD), can alleviate metabolic syndrome and cardiovascular disease. To characterize gut microbiota in elder patients and effects of YTD on gut microbiota during treatment of metabolic syndrome, 11 healthy elderly persons and 12 elderly persons (aged 60-90 years) with metabolic syndrome were enrolled. The patients were randomly assigned to receive YTD for 4 weeks (200 mL of the decoction two times daily). The microbial composition in healthy control, pre- and post- YTD treatment group were analyzed by 16S rRNA sequencing of fecal DNAs. Biochemical measurements were conducted for elderly patients. The results showed a high inter-individual variation of gut microbiota in elderly persons. The gut microbiota was dominated by phylum Firmicutes and Actinobacteria, which was distinct from the previously defined microbiota in Irish elderly persons. The elderly patients with metabolic syndrome had higher proportions of Lactobacillus and Bifidobacterium, and lower proportions of Anaerostipes, Coprococcus, Ruminococcus than healthy controls. YTD treatment reduced the abundance of genus Bacteroidales Incertae Sedis and species Enterobacteriaceae Incertae Sedis. The concentration of plasma lipoprotein (a) was also reduced, which was negatively correlated with the abundance of an Acinetobacter species. These results reveal a remarkable dominance of Firmicutes and Actinobacteria, and highlight the distinct gut microbiota in elderly patients with metabolic syndrome, which may be involved in pathogenesis. Furthermore, the benefits of YTD treatment were observed, providing an approach to improve metabolic syndrome in elderly patients. PMID- 29998998 TI - Exploring the causes of peripheral intravenous catheter failure based on shape of catheters removed from various insertion sites. AB - The risk of peripheral intravenous catheter failure varies according to the insertion site. This study examined catheter shape just after removal to evaluate the causes of catheter failure according to site. This study was a secondary analysis of previous study data. Our observational study was conducted during a 6 month period at The University of Tokyo Hospital. Participants were hospitalized adults who received infusion therapy via a short peripheral catheter. We acquired ultrasound images of blood vessels and surrounding tissues at the catheter insertion site before catheter removal and clinical images of the removed catheters. We analyzed 184 catheters from 142 participants. There were no significant differences in the catheter failure rate (29.9%) among insertion sites. Curvature in the middle of the catheter was present in 9.2% of cases; the median bend angle at the catheter base was 9.1 degrees (range: 0.0 degrees -68.3 degrees ). The bend angle of catheters inserted in the upper arm was significantly greater than of catheters in the forearm (p = 0.013). Catheter curvature was related to catheter failure (14.8% of failed catheters had curvature; p = 0.035) and occlusion (35.3% of occluded catheters had curvature; p = 0.008) in upper arm and forearm placements. The median distance from the elbow to the insertion site was shorter for failed catheters than for surviving catheters. To prevent catheter failure, especially occlusion resulting from catheter curvature, a catheter should be inserted at an appropriate insertion site far from the antecubital fossa. PMID- 29998999 TI - A study on yogurt consumption: A case of industry-academia collaboration in Fukushima and Tokyo. AB - This paper proposes a new product development of yogurt project based on industry academia collaboration between Teikyo University and Tohoku Kyodo Milk Industry and discusses the possible economic impact of this project on the Tohoku region as well as the Tama area in Tokyo. We also introduce a preliminary survey to partially clarify the consumption patterns for yogurt among students at Teikyo University. The survey reveals that most of our respondents consume yogurt regularly. The stated reason for yogurt consumption is to enjoy yogurt as a dessert rather than as a health food. We also find that the most significant determinant factors for purchasing yogurt are taste, price, and quantity. Based on the data, respondents are willing to pay between 100 JPY and 145 JPY for yogurt. In response to these findings, we discuss some additional surveys that need to be conducted in the future. PMID- 29999000 TI - Evaluation of the global action plan on antimicrobial resistance in Japan during its first eighteen months. AB - Antimicrobial resistance (AMR) has garnered the most attention among public health concerns worldwide. Japan formulated a national action plan for AMR in April 2016. The plan seeks to reduce the amount of antimicrobials used in 2020 to two-thirds of the use recorded in 2013. Prescription surveillance (PS) is being used to monitor trends in the amount of antimicrobials used. PS estimates the number of patients prescribed an antimicrobial each day. The number of patients who were prescribed an antimicrobial under the action plan was analyzed by including dummy variables with other control variables. Data from April 1, 2011 to 30 September 30, 2017 were analyzed. When the number of patients with an infectious disease (1 of 13 specified diseases) served as a dummy variable, estimates indicated that the coefficient of that dummy variable was not significant. If the number of patients with an infectious disease (1 of 13 specified diseases) was excluded as an explanatory variable, then the estimated coefficient was significant. The global action plan in Japan might not reduce the amount of antimicrobials used. The current results indicated that the number of patients who were prescribed an antimicrobial did not decrease significantly after initiation of the action plan. This finding does not exclude the possibility that the average amount of antimicrobials used per patient has decreased. PMID- 29999003 TI - Dental education: Unwanted sixth-formers. PMID- 29999002 TI - Management of odontogenic infection at a district general hospital. PMID- 29999001 TI - Genistein and Myd88 Activate Autophagy in High Glucose-Induced Renal Podocytes In Vitro. AB - BACKGROUND Renal podocyte damage plays a crucial role in the development of diabetic nephropathy. Genistein is derived from a leguminous plant, and MyD88 and TRIF are adaptor molecules in the Toll-like receptor (TLR) signaling pathway, which may play a role in autophagy. In this study, we utilized an in vitro high glucose (HG)-treated podocyte model to investigate the effects and underlying mechanisms of Genistein and MyD88 or TRIF siRNA induced autophagy and renal protection. MATERIAL AND METHODS An immortalized mouse podocyte cell line was treated with HG, Genistein, chloroquine, and/or transfected with specific Myd88 and TRIF siRNAs. The formation of autophagosomes and related autophagic vacuoles were monitored by transmission electron microscopy. The expression of autophagy related factors and podocyte structure and functional markers, including LC3, p62, p-mTOR, synaptopodin, and nephrin, were measured by Western blot, and LC3 and p-mTOR expression were also assessed by immunofluorescence. RESULTS We showed that HG transiently (after 6-h exposure) induced expression of the autophagy activation marker LC3-II in podocytes. Genistein treatment induced autophagy in both normal and HG-treated podocytes through inactivating mTOR signaling. Moreover, Genistein protected podocytes against chloroquine in HG-cultured conditions in vitro by maintaining the level of autophagy-related proteins. In addition, MyD88 siRNA downregulated expression of autophagy-related proteins, whereas Genistein treatment reversed these effects. CONCLUSIONS This study demonstrated that Genistein-induced autophagy could be a potential treatment strategy for glomerular diseases. PMID- 29999004 TI - The art and science of minimal intervention dentistry and atraumatic restorative treatment. PMID- 29999005 TI - Oral and maxillofacial: A quick scale and fracture. PMID- 29999006 TI - Dr Coupland 4 May 1901 - 12 May 1936. AB - Little is known about Dr Coupland, despite the use of his instruments in everyday dental practice. The aim of this article is to inform the reader about the life, works and inventions of Dr Coupland. PMID- 29999007 TI - The price of everything. PMID- 29999008 TI - A new way to motivate your patients. PMID- 29999009 TI - One big happy family. PMID- 29999011 TI - An advocate for the profession. PMID- 29999010 TI - BOS response to article on 'Hold that smile' campaign. AB - The British Orthodontic Society launched a campaign called 'Hold that smile' to highlight to patients the importance of wearing retainers as a means of reducing relapse following orthodontic treatment. This opinion piece, on behalf of the British Orthodontic Society, is written in response to an article entitled 'British Orthodontic Society's initiative on orthodontic retention, A GDP's perspective' ( 2018; 224: 481-486). In this short opinion article, we take the opportunity to clarify the aims of the campaign, which set out to educate patients about orthodontic relapse and to highlight the importance of wearing, and taking responsibility for, retainers long-term. PMID- 29999012 TI - Sugar roundup: Mission accomplished? Not yet. PMID- 29999013 TI - Prevalence and severity of dental caries in foster-care children and adolescents. AB - A high prevalence of dental caries was found in foster-care children. PMID- 29999014 TI - Knocking mouth cancer for six. PMID- 29999015 TI - Add value to your practice. PMID- 29999016 TI - Qualitative exploration of barriers and facilitators of dental service utilisation of pregnant women: A triangulation approach. AB - Understanding perceived barriers of dental service utilisation during pregnancy can be helpful when planning care in countries with developing oral healthcare systems. PMID- 29999017 TI - Tier 2 NHS services in primary dental care - where are the risks? AB - NHS England and the Office of the Chief Dental Officer have set out plans for the accreditation of Tier 2 services in primary care, the first of which will be endodontics. This Opinion article examines the unintended consequences of the development of this service whose need has arisen for a number of reasons including the current UDA activity-based NHS dental contract, undergraduate training and the quality and quantity of endodontic services being delivered in primary dental care. PMID- 29999018 TI - Clinical cases in early orthodontic treatment: an atlas of when, how and why to treat. PMID- 29999019 TI - Correction. AB - This corrects the article DOI: 10.1038/sj.bdj.2018.357. PMID- 29999020 TI - Management of fractured endodontic instruments: a clinical guide. PMID- 29999021 TI - Call out to community dentists. PMID- 29999022 TI - Paediatrics: Breastfeeding and dental health. PMID- 29999023 TI - Award winning extraoral imaging. PMID- 29999025 TI - Endodontic software for the 3D imaging era. PMID- 29999024 TI - Hall technique reviewed. PMID- 29999026 TI - Anxiety and anger of homeless people coping with dental care. AB - Homeless people have difficulty coping with dental care. PMID- 29999027 TI - Hypophosphatasia and the importance of the general dental practitioner - a case series and discussion of upcoming treatments. AB - Hypophosphatasia (HPP) is an inherited metabolic disorder that results in poorly mineralised bones and teeth. Clinical symptoms vary widely from mild dental anomalies to fatal fetal defects. The most common dental symptoms include exfoliation of the primary incisors before the age of three with little or no root resorption, large pulp chambers, alveolar bone loss and thin dentinal walls. There is generally minimal periodontal inflammation associated with the bony destruction and tooth loss. The general dental practitioner is usually the first clinician to spot signs of the milder forms of HPP. Patients diagnosed with dental symptoms in childhood can go on to develop significant morbidity in middle age with chronic bone pain and stress fractures of the long bones. The primary dental care clinician is the key to early diagnosis of such cases, whether they present in childhood or adulthood. Emerging enzyme replacement therapy has considerably changed the landscape of the disease, resulting in astonishing improvements in bone mineralisation and a significant reduction in mortality and morbidity. It is increasingly likely that primary and secondary care clinicians will treat patients with the severe forms of HPP, who would previously not have survived infancy. PMID- 29999029 TI - The (first) British Dental Conference and Dentistry Show. PMID- 29999028 TI - Big data is or big data are. PMID- 29999030 TI - Conference report: 'Bish bash bosh' Dental Trauma UK's Annual Conference. PMID- 29999031 TI - Consistently high quality care. PMID- 29999032 TI - Orthodontic brackets you can rely on. PMID- 29999033 TI - Cohort study of HIV-positive and -negative methamphetamine users. AB - Lifestyle contributed more to destructive periodontal disease than methamphetamine use. PMID- 29999034 TI - Redefining corporate dentistry. PMID- 29999036 TI - A definitive fixed solution. PMID- 29999035 TI - Diagnostics: The woman who found worms in her mouth. PMID- 29999037 TI - Postgraduate diploma in implantology. PMID- 29999039 TI - Clarification. PMID- 29999038 TI - Technology: Artificial intelligence. PMID- 29999041 TI - The ultimate guide to restoration longevity in England and Wales. Part 4: resin composite restorations: time to next intervention and to extraction of the restored tooth. PMID- 29999042 TI - Teeth at the Wellcome Collection. PMID- 29999043 TI - Teaching posterior resin composites in UK and Ireland dental schools: do current teaching programmes match the expectation of clinical practice arrangements? PMID- 29999044 TI - Reply to the 'Comment on "A quantitative definition of hypervalency"' by R. D. Harcourt and T. M. Klapotke, Chem. Sci., 2016, 7, DOI: ; 10.1039/C5SC04866D. AB - The Lewis and quantum mechanical theories of chemical bonding are compared and contrasted, with a view to clarifying the relationship between Harcourt's 'increased valence' quantum approach and the recently proposed quantitative definition of hypervalency. PMID- 29999045 TI - Comment on "A quantitative definition of hypervalency" by M. C. Durrant, Chem. Sci., 2015, 6, 6614. AB - Consideration is given to (electronically) hypervalent increased-valence structures, which possess 2c-1e bonds, fractional 2c-2e bonds, and usually normal 2c-2e bonds. For singlet-spin electron-rich systems, increased-valence structures, with Heitler-London 2c-2e bond wavefunctions, are equivalent to resonance between non-hypervalent Kekule and Dewar (or singlet diradical) type Lewis structures. Dewar structures are not considered in the Chem. Sci. 2015, 6, 6614 Edge article on hypervalency. Using one-electron delocalizations from lone pair atomic orbitals into separate bonding molecular orbitals, increased-valence structures for PCl5, O3, SO42-, NO3-, N2O4 and SN2 reactions are derived from the Edge-article's Kekule-type Lewis structures, and compared with the Edge article's hypervalent structures with 2c-2e bonds. It is also shown that Durrant's method to determine the gamma parameter for XAY-type systems that possess a symmetrical 3c-4e bonding unit is related to the A-atom charge density. PMID- 29999046 TI - Fluorescence hyperspectral imaging for live monitoring of multiple spheroids in microfluidic chips. AB - Tumor spheroids represent a realistic 3D in vitro cancer model because they provide a missing link between monolayer cell culture and live tissues. While microfluidic chips can easily form and assay thousands of spheroids simultaneously, few commercial instruments are available to analyze this massive amount of data. Available techniques to measure spheroid response to external stimuli, such as confocal imaging and flow cytometry, are either not appropriate for 3D cultures, or destructive. We designed a wide-field hyperspectral imaging system to analyze multiple spheroids trapped in a microfluidic chip in a single acquisition. The system and its fluorescence quantification algorithm were assessed using liquid phantoms mimicking spheroid optical properties. Spectral unmixing was tested on three overlapping spectral entities. Hyperspectral images of co-culture spheroids expressing two fluorophores were compared with confocal microscopy and spheroid growth was measured over time. The system can spectrally analyze multiple fluorescent markers simultaneously and allows multiple time points assays, providing a fast and versatile solution for analyzing lab on a chip devices. PMID- 29999047 TI - Green synthesis of a plant-derived protein protected copper quantum cluster for intrauterine device application. AB - Fluorescent copper quantum clusters (CuQCs) have received great interest in recent times due to their attractive features, such as water solubility, low cost, wide availability of Cu and good biocompatibility. Recently, considerable efforts have been devoted to the preparation and applications of CuQCs. Herein, we report a simple one-pot green method for the preparation of fluorescent CuQCs using a plant-derived protein, gluten, as a stabilizing agent. Gluten, a naturally abundant, low-cost and sustainable plant-protein derived from wheat, was employed both as a reducing and stabilizing agent to produce blue emitting CuQCs. The CuQCs were characterized by UV-Vis absorption, fluorescence, FT-IR, TEM, and XPS. We further incorporated CuQCs into a polymer to study the release rate of Cu2+ ions from a CuQC-polymer composite, since copper ions are well known for their fungicidal properties and contraceptive action in copper-T (CuT). The CuQCs were incorporated into a model polymer, polyurethane (PU), by melt compounding, and the mixtures were extruded in the form of a wire. It was observed that the CuQCs were uniformly dispersed within the polymer matrix. An in vitro experiment was carried out to quantify the potential release of Cu(ii) ions for contraceptive applications. The developed nanocomposite releases Cu(ii) ions for 90 days, which suggests the potential application of the CuQCs in the medical field like the development of short-term intrauterine devices (IUDs). Compared to conventional IUDs, here the CuQC-PU nanocomposite reduces the burst release of the Cu2+, and the release rates can be tuned by changing the composition of the materials. These results suggest that the CuQC-PU nanocomposites have great potential to replace current commercial intrauterine devices. PMID- 29999048 TI - A light-up fluorescence assay for tumor cell detection based on bifunctional split aptamers. AB - Light-up aptamers have attracted growing attention due to their advantages of being label-free and having low fluorescence background. In this work, we developed a light-up fluorescence assay for label-free detection of tumor cells based on a bifunctional split aptamer (BFSA) that contained two DNA strands (BFSA a and BFSA-b). BFSA-a and BFSA-b were constructed by combining aptamers ZY11 and ThT.2-2, which could specifically bind to the tumor cell SMMC-7721 and activate the fluorescence of thioflavin T (ThT). A Helper strand was introduced to hybridize with BFSA-b, and then BFSA-a and BFSA-b were separated if the target cell was absent. Only when the target cell is present can BFSA-a approach and hybridize with BFSA-b due to the 'induced-fit effect', which made the Helper strand dissociate. Then ThT bound to BFSA and the fluorescence of ThT was activated. The results indicated that this fluorescence assay had a good linear response to the target cells in the range of 250-20 000 cells in 100 MUL binding buffer; the lowest cell number actually detected was 125 cells in 100 MUL buffer. This assay also displayed excellent selectivity and was successfully applied to detect target cells in 20% human serum samples. The design of bifunctional split aptamers realized no-washing, label-free, low-cost, one-step detection of tumor cells, which could generate detectable fluorescence signals just by mixing nucleic acid aptamers and fluorescent reporter molecules with target cells. Such a design of aptamer probes also has the potential to construct stimuli-responsive controlled drug delivery systems. PMID- 29999049 TI - Photochemical upconversion is suppressed by high concentrations of molecular sensitizers. AB - Photochemical upconversion uses sensitized triplet-triplet annihilation in bimolecular compositions to convert lower energy photons to higher energy photons. For high efficiency under low illumination, usually a high sensitizer concentration is desirable. However, here we show that the upconversion sensitizer can reduce the emitter triplet lifetime by dynamic quenching, with rate constants on the order 106 M-1 s-1, leading to diminishing returns beyond a certain concentration. These results serve as a warning to designers of photochemical upconvertors that higher concentrations of sensitizers are not necessarily beneficial to upconversion performance. PMID- 29999051 TI - Tetraarylpyrrolo[3,2-b]pyrroles as versatile and responsive fluorescent linkers in metal-organic frameworks. AB - The first examples of crystalline coordination polymers containing the tetraarylpyrrolo[3,2-b]pyrrole (TPP) fluorophore are presented. We have prepared three new TPP ligands L1, H2L2 and H2L3, containing nitrile, carboxylate and mixed imidazole-carboxylate donor functionality, respectively. The ligands themselves each show significant fluorescence in the solution phase, with the nitrile species exhibiting solvatofluorochromism and the two carboxylate containing compounds exhibiting concentration-dependent emission colour suggesting aggregation processes in solution. Three 3-dimensional polymeric structures are then presented. The compound poly-[AgL12]SbF6.3THF.2H2O 1 is an eightfold-interpenetrated diamondoid material, while poly-[Zn4O(L2)3].20DMA.10H2O 2 is a porous Metal-Organic Framework with pcu topology, and both 1 and 2 show notable luminescence in the solid state. Complex 2 readily undergoes guest exchange accompanied by a reversible switching in emission colour with no change in chemical structure. While complex poly-[CdL3].2.5DMA.3.5H2O 3 is non-emissive, it displays a twofold interpenetrated pts topology with hexagonal symmetry and an extremely long hexagonal pitch of 100.3 A, and shows an impressive 22 wt% CO2 uptake capacity at 278 K and 1 bar. PMID- 29999052 TI - Mixed-valence dimolybdenum complexes containing hard oxo and soft carbonyl ligands: synthesis, structure, and electrochemistry of Mo2(O)(CO)2(MU-kappa2 S(CH2)nS)2(kappa2-diphosphine). AB - Mixed-valence dimolybdenum complexes Mo2(O)(CO)2{MU-kappa2-S(CH2)nS}2(kappa2 Ph2P(CH2)mPPh2) (n = 2, 3; m = 1, 2) (1-4) have been synthesized from one-pot reactions of fac-Mo(CO)3(NCMe)3 and dithiols, HS(CH2)nSH, in the presence of diphosphines. The dimolybdenum framework is supported by two thiolate bridges, with one molybdenum carrying a terminal oxo ligand and the second two carbonyls. The dppm (m = 1) products exist as a pair of diastereomers differing in the relative orientation of the two carbonyls (cis and trans) at the Mo(CO)2(dppm) center, while dppe (m = 2) complexes are found solely as the trans isomers. Small amounts of Mo(CO){kappa3-S(CH2CH2S)2}(kappa2-dppe) (5) also result from the reaction using HS(CH2)2SH and dppe. The bonding in isomers of 1-4 has been computationally explored by DFT calculations, trans diastereomers being computed to be more stable than the corresponding pair of cis diastereomers for all. The calculations confirm the existence of Mo[triple bond, length as m-dash]O and Mo Mo bond orders and suggest that the new dimeric compounds are best viewed as Mo(v)-Mo(i) mixed-valence systems. The electrochemical properties of 1 have been investigated by CV and show a reversible one-electron reduction associated with the Mo(v) centre, while two closely spaced irreversible oxidation waves are tentatively assigned to oxidation of the Mo(i) centre of the two isomers as supported by DFT calculations. PMID- 29999053 TI - Theoretical studies on the oxidation states and electronic structures of actinide borides: AnB12 (An = Th-Cm) clusters. AB - As B12 clusters exhibit significant structural stability due to double aromaticity, metal doped-B12 clusters often prefer a half sandwich structure. Herein, we report a systematic theoretical study on the geometric and electronic structures, and chemical bonding of the half sandwich AnB12 (An = Th to Cm) clusters to explore the stability and extent of covalency of the An-B bonds of these actinide borides. We have shown that in the gas-phase clusters, the significant stability of AnB12 is determined by electrostatic and orbital interactions between the An 5f6d7s orbitals and pi-type molecular orbitals from B 2p orbitals of the B12 unit. A change-over of An-B bond length from An = Th to Cm is found at An = Pa as a result of actinide contraction combined with weakening An-B bonding due to an energy decrease and orbital localization of the 5f orbitals. Consistently, the oxidation states of the An atoms at first increase from Th(f0)IV to Pa(f0)V, and then due to the 5f-AO contraction, they smoothly decline to U(f2)IV, Np(f4)III and Pu(f5)III, and then eventually to Am(f7)II but Cm(f7)III, both with a half-filled 5f shell. PMID- 29999054 TI - Fluorinated cyclopropanes: synthesis and chemistry of the aryl alpha,beta,beta trifluorocyclopropane motif. AB - A general route to aryl alpha,beta,beta-trifluorocyclopropanes is reported and aryl oxidation gave the corresponding alpha,beta,beta-trifluorocyclopropane carboxylic acid. Reactions of the corresponding amides with phenol/thiophenol resulted in HF elimination and then conjugate addition. The partially fluorinated cyclopropane has a similar lipophilicity to -CF3 despite three carbon atoms, and it emerges as a novel motif for drug discovery. PMID- 29999050 TI - Microfluidic fabrication of microparticles for biomedical applications. AB - Droplet microfluidics offers exquisite control over the flows of multiple fluids in microscale, enabling fabrication of advanced microparticles with precisely tunable structures and compositions in a high throughput manner. The combination of these remarkable features with proper materials and fabrication methods has enabled high efficiency, direct encapsulation of actives in microparticles whose features and functionalities can be well controlled. These microparticles have great potential in a wide range of bio-related applications including drug delivery, cell-laden matrices, biosensors and even as artificial cells. In this review, we briefly summarize the materials, fabrication methods, and microparticle structures produced with droplet microfluidics. We also provide a comprehensive overview of their recent uses in biomedical applications. Finally, we discuss the existing challenges and perspectives to promote the future development of these engineered microparticles. PMID- 29999055 TI - Amorphous graphene: a constituent part of low density amorphous carbon. AB - In this paper, we provide evidence that low density nano-porous amorphous carbon (a-C) consists of interconnected regions of amorphous graphene (a-G). We include experimental information in producing models, while retaining the power and accuracy of ab initio methods with no biasing assumptions. Our models are highly disordered with predominant sp2 bonding and ring connectivity mainly of sizes 5 8. The structural, dynamical and electronic signatures of our 3-D amorphous graphene are similar to those of monolayer amorphous graphene. We predict an extended x-ray absorption fine structure (EXAFS) signature of amorphous graphene. Electronic density of states calculations for 3-D amorphous graphene reveal similarity to monolayer amorphous graphene and the system is non conducting. PMID- 29999056 TI - Theoretical evidence of low-threshold amplified spontaneous emission in organic emitters: transition density and intramolecular vibrational mode analysis. AB - Organic gain materials are highly attractive for lasing due to their chemical tunability and large stimulated emission cross sections. In previous reports, the radiative decay rate kr was considered as an important factor to determine outstanding amplified spontaneous emission (ASE) performance of organic molecules. In this study, we use quantum mechanics to reveal the influential factors on photophysical properties of organic emitters, and give insight into the effect of kr on ASE performance. Based on the theoretical analysis of three molecules with similar structure, calculated results show that large kr derives from enhanced transition density rho between the electronic wave functions of the ground-state and the lowest excited singlet state as well as a handful of low frequency torsional modes with small Huang-Rhys factor S, further, kr values are calculated depending on molecular vibration terms. In addition, through the analysis of non-radiative decay rate knr considering vibration terms (vibronic coupling constants), the comparison of kr and knr shows that the radiative decay process is promoted in the three molecules. The two aspects are desired for outstanding ASE performance. Our work shows that the roles of transition density and vibrational modes are crucial to clarify the photophysical properties, which govern the ASE performance in organic light emitters. PMID- 29999057 TI - K11RbB28O48: a new triple-layered borate with an unprecedented [B28O57] fundamental building block. AB - A new mixed-alkali borate, K11RbB28O48, has been obtained using the high temperature solution method. It features a new [B28O57] fundamental building block. Meanwhile, these units further polymerize to form unusual triple-layered anionic groups. Thermal analysis, optical property measurement, and theoretical calculations were performed. PMID- 29999058 TI - An asymmetric graphene oxide film for developing moisture actuators. AB - Although Janus films of different compositions have been commonly utilized to develop moisture actuators due to the different capabilities of swelling in materials, a sole material with a distinct structural design is also able to provide moisture-actuation. In this study, we simply used graphene oxide (GO) to fabricate a sole GO film with an asymmetric structure which consisted of a wavy layer and a smooth layer. Due to the asymmetric structure and excellent hygroscopicity of the GO material, the asymmetric graphene oxide (AGO) film (2.5 * 0.5 cm2) was responsive to moisture and showed a maximum bending angle change of ~1800 degrees as the relative humidity (RH) changed. Compared with other reports about moisture actuators, the AGO film exhibited a superior bending capability. Furthermore, we propose a novel mechanism for moisture actuation of the AGO film based on our detailed observations, and a wavy structure has been introduced for showing great potential in bending deformation. Finally, the AGO film was used as a grabber to grab a leaf and it exhibited good capability to twine around a plastic rod. This work provides a novel pathway for the development of moisture-responsive materials for potential applications in robotics, artificial muscles and switches. PMID- 29999059 TI - A multi-electron transfer ferrocene derivative positive redox moiety with improved solubility and potential. AB - Rational molecular structure modification towards high performance redox couples attracts great concern. A ferrocene derivative N-(pyridin-2-ylmethylene)-1-(2 (diphenylphosphino) ferrocenyl) ethanamine (FeCp2PPh2RCN) with improved solubility and potential as well as multi-electron transfer behavior is designed and fabricated. Benefitting from the high operating current density and capacity of the battery, FeCp2PPh2RCN demonstrates promising prospects as a positive redox moiety. PMID- 29999060 TI - Direct kinetics study of CH2OO + methyl vinyl ketone and CH2OO + methacrolein reactions and an upper limit determination for CH2OO + CO reaction. AB - Methyl vinyl ketone (MVK) and methacrolein (MACR) are important intermediate products in atmospheric degradation of volatile organic compounds, especially of isoprene. This work investigates the reactions of the smallest Criegee intermediate, CH2OO, with its co-products from isoprene ozonolysis, MVK and MACR, using multiplexed photoionization mass spectrometry (MPIMS), with either tunable synchrotron radiation from the Advanced Light Source or Lyman-alpha (10.2 eV) radiation for photoionization. CH2OO was produced via pulsed laser photolysis of CH2I2 in the presence of excess O2. Time-resolved measurements of reactant disappearance and of product formation were performed to monitor reaction progress; first order rate coefficients were obtained from exponential fits to the CH2OO decays. The bimolecular reaction rate coefficients at 300 K and 4 Torr are k(CH2OO + MVK) = (5.0 +/- 0.4) * 10-13 cm3 s-1 and k(CH2OO + MACR) = (4.4 +/- 1.0) * 10-13 cm3 s-1, where the stated +/-2sigma uncertainties are statistical uncertainties. Adduct formation is observed for both reactions and is attributed to the formation of a secondary ozonides (1,2,4-trioxolanes), supported by master equation calculations of the kinetics and the agreement between measured and calculated adiabatic ionization energies. Kinetics measurements were also performed for a possible bimolecular CH2OO + CO reaction and for the reaction of CH2OO with CF3CHCH2 at 300 K and 4 Torr. For CH2OO + CO, no reaction is observed and an upper limit is determined: k(CH2OO + CO) < 2 * 10-16 cm3 s-1. For CH2OO + CF3CHCH2, an upper limit of k(CH2OO + CF3CHCH2) < 2 * 10-14 cm3 s-1 is obtained. PMID- 29999061 TI - Transition metal-free, chemoselective arylation of thioamides yielding aryl thioimidates or N-aryl thioamides. AB - Reactions of secondary thioamides with diaryliodonium salts under basic, transition metal-free conditions resulted in chemoselective S-arylation to provide aryl thioimidates in good to excellent yields. Equimolar amounts of thioamide, base and diaryliodonium salt were sufficient to obtain a diverse selection of products within short reaction times. Reactions with thiolactams delivered N-arylated thioamides in good yield at room temperature. PMID- 29999062 TI - Biomimetic tumor microenvironments based on collagen matrices. AB - The extracellular matrix (ECM) establishes the basis for the cell's microenvironment providing structural and mechanical support to cells and tissues, and regulating multiple cell functions including gene expression, cell cycle, apoptosis, morphogenesis, and migration. Tumor development can be considered as a process where the cells are subjected to mutations. However, changes in the microenvironment of tumor cells can strongly impact the growth, invasion and survival of tumor cells. This specialized microenvironment is known to have an abundance of inflammatory cells and activated fibroblasts both expressing ECM components and growth factors that support the survival and proliferation of tumor cells in a paracrine fashion. Growing evidence points towards a key role of the ECM in the modulation of tumor progression and metastasis, even influencing therapeutic pharmacosensitivity. Accordingly, to better understand the mechanisms of tumor cell behavior, e.g. proliferation, invasion and survival, in dependence on microenvironmental cues as well as the cell-microenvironment interaction, it is necessary to engineer well-defined 3D matrices to closely mimic in vivo like microenvironments in a controlled in vitro setting. In that way the full repertoire of high-resolution, in-depth analytical technologies available for in vitro settings can be applied to reveal the underlying molecular mechanisms in an in vivo like ECM microenvironment. This review provides an overview of the current bioengineering techniques of defined biomimetic 3D models with a focus on naturally derived biopolymer components for the investigation of tumor cell behavior in vitro. PMID- 29999063 TI - Towards molecular electronic devices based on 'all-carbon' wires. AB - Nascent molecular electronic devices based on linear 'all-carbon' wires attached to gold electrodes through robust and reliable C-Au contacts are prepared via efficient in situ sequential cleavage of trimethylsilyl end groups from an oligoyne, Me3Si-(C[triple bond, length as m-dash]C)4-SiMe3 (1). In the first stage of the fabrication process, removal of one trimethylsilyl (TMS) group in the presence of a gold substrate, which ultimately serves as the bottom electrode, using a stoichiometric fluoride-driven process gives a highly-ordered monolayer, Au|C[triple bond, length as m-dash]CC[triple bond, length as m dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CSiMe3 (Au|C8SiMe3). In the second stage, treatment of Au|C8SiMe3 with excess fluoride results in removal of the remaining TMS protecting group to give a modified monolayer Au|C[triple bond, length as m-dash]CC[triple bond, length as m dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CH (Au|C8H). The reactive terminal C[triple bond, length as m-dash]C-H moiety in Au|C8H can be modified by 'click' reactions with (azidomethyl)ferrocene (N3CH2Fc) to introduce a redox probe, to give Au|C6C2N3HCH2Fc. Alternatively, incubation of the modified gold substrate supported monolayer Au|C8H in a solution of gold nanoparticles (GNPs), results in covalent attachment of GNPs on top of the film via a second alkynyl carbon-Au sigma-bond, to give structures Au|C8|GNP in which the monolayer of linear, 'all-carbon' C8 chains is sandwiched between two macroscopic gold contacts. The covalent carbon-surface bond as well as the covalent attachment of the metal particles to the monolayer by cleavage of the alkyne C-H bond is confirmed by surface-enhanced Raman scattering (SERS). The integrity of the carbon chain in both Au|C6C2N3HCH2Fc systems and after formation of the gold top-contact electrode in Au|C8|GNP is demonstrated through electrochemical methods. The electrical properties of these nascent metal monolayer-metal devices Au|C8|GNP featuring 'all-carbon' molecular wires were characterised by sigmoidal I-V curves, indicative of well-behaved junctions free of short circuits. PMID- 29999064 TI - Microfluidics within a well: an injection-molded plastic array 3D culture platform. AB - Polydimethylsiloxane (PDMS) has been widely used in fabricating microfluidic devices for prototyping and proof-of-concept experiments. Due to several material limitations, PDMS has not been widely adopted for commercial applications that require large-scale production. This paper describes a novel injection-molded plastic array 3D culture (IMPACT) platform that incorporates a microfluidic design to integrate patterned 3D cell cultures within a single 96-well (diameter = 9 mm) plate. Cell containing gels can be sequentially patterned by capillary guided flow along the corner and narrow gaps designed within the 96-well form factor. Compared to PDMS-based hydrophobic burst valve designs, this work utilizes hydrophilic liquid guides to obtain rapid and reproducible patterned gels for co-cultures. When a liquid droplet (i.e. cell containing fibrin or collagen gel) is placed on a corner, spontaneous patterning is achieved within 1 second. Optimal dimensionless parameters required for successful capillary loading have been determined. To demonstrate the utility of the platform for 3D co-culture, angiogenesis experiments were performed by patterning HUVEC (human umbilical endothelial cells) and LF (lung fibroblasts) embedded in 3D fibrin gels. The angiogenic sprouts (with open lumen tip cells expressing junctional proteins) are comparable to those observed in PDMS based devices. The IMPACT device has the potential to provide a robust high-throughput experimental platform for vascularized microphysiological systems. PMID- 29999065 TI - Uranium biomineralization induced by a metal tolerant Serratia strain under acid, alkaline and irradiated conditions. AB - It has become increasingly apparent that the environmental microorganisms residing in uranium (U) enriched sites offer the possibility of understanding the biological mechanisms catalyzing the processes important for uranium bioremediation. Here, we present the results of uranium biomineralization over a wide pH range by a metal tolerant Serratia sp. strain OT II 7 isolated from the subsurface soil of a U ore deposit at Domiasiat in India. The Serratia cells actively expressed acid and alkaline phosphatase enzymes which hydrolyzed differential amounts of phosphate from an organophosphate substrate in the presence of uranium between pH 5 to 9. These cells precipitated ~91% uranium from aqueous solutions supplemented with 1 mM uranyl nitrate at pH 5 within 120 h. More rapid precipitation was observed at pH 7 and 9 wherein the cells removed ~93 94% of uranium from solutions containing 1 mM uranyl carbonate within 24 h. The aqueous uranyl speciation prevalent under the studied pH conditions influenced the localization of crystalline uranyl phosphate precipitates, which in turn, impacted the cell viability to a great extent. Furthermore, the cells tolerated up to ~1.6 kGy 60Co gamma radiation and their uranium precipitation abilities at pH 5, 7 and 9 were uncompromised even after exposure to a high dose of ionizing radiation. Overall, this study establishes the ecological adaptation of a natural strain like Serratia in a uranium enriched environment and corroborates its contribution towards uranium immobilization in contaminated subsurfaces through the formation of stable uranyl phosphate minerals over a wide pH range. PMID- 29999066 TI - Formation of uniform mesoporous TiO2@C-Ni hollow hybrid composites. AB - Highly efficient bifunctional metallic nickel nanoparticles (NPs) are highly desired for practical applications in catalysis and adsorption. However, the low surface area and the aggregation often lead to their poor activities during catalysis and adsorption. Here, we have developed a facile strategy to synthesize monodisperse magnetic mesoporous TiO2(mTiO2)@C-Ni hollow spheres using carboxyl functionalized polystyrene (CPS) spheres as sacrificial templates, which exhibit excellent performance during both catalysis of 4-nitrophenol (4-NP) and good affinity towards His-rich proteins. The enhanced activity of hybrid mTiO2@C-Ni composites could be related to their hollow structure, large surface area, high density of nickel NPs, and the monodisperse morphology. The results reported here may open a new avenue for the construction of advanced nanostructures for promising applications in catalysis, adsorption, energy storage, etc. PMID- 29999067 TI - Illuminating nanostructured gold electrode: surface plasmons or electron ejection? AB - Recently, the photoelectric effect in metals in electrolyte environments has aroused the interest of researchers. However, direct evidence for surface plasmons-enhanced electrochemical reactions involving classic outer-sphere reactions of reversible redox couples is seldom reported. We used a surface plasmons-active gold-mushroom-array as a working electrode and observed enhanced faradaic current from ferrocenemethanol following illumination with a xenon lamp. The photoelectric current behaved differently in the presence and absence of oxygen in the solution. The preliminary results are discussed with consideration of the possible mechanisms of electron transfer, although they are very complex, due to the lack of direct evidence. Some consideration was also taken of the research on photoelectrochemical reactions on metallic electrodes. PMID- 29999068 TI - Redox-enhanced hemilability of a tris(tert-butoxy)siloxy ligand at cerium. AB - The stabilizing effect of a tris(tert-butoxy)siloxy ligand on cerium(iv) is revealed by electrochemical and computation methods as well as by targeted redox chemistry. Ceric homoleptic complex Ce[OSi(OtBu)3]4 was obtained by the reaction of [Et4N]2[CeCl6] with NaOSi(OtBu)3 at ambient temperature in acetonitrile, while cerous ion-separated complex [Ce{OSi(OtBu)3}4][K(2.2.2-crypt)] was readily synthesized from [Ce{OSi(OtBu)3}4K] and cryptand. The solid-state structures of monocerium complexes Ce[OSi(OtBu)3]4 and Ce[OSi(OtBu)3]4(THF) show 5- and 6 coordinate CeIV centers (one kappa2-bonded siloxy ligand), while complex [Ce{OSi(OtBu)3}4][K(2.2.2-crypt)] exhibits a 4-coordinate CeIII center (all terminal siloxy coordination). A comparative electrochemical study of Ce[OSi(OtBu)3]4 and [Ce{OSi(OtBu)3}4][K(2.2.2-crypt)] suggests a redox-modulated molecular rearrangement process, featuring oxidation-state dependent formation and release of a CeOtBu coordination. While the overall stabilization of CeIV by the siloxy ligand is evident, significant extra stabilization is gained if the siloxy ligand coordinates in a chelating fashion, which is further supported by DFT calculations. Natural bond orbital (NBO) analysis indicates an enhanced donation of the siloxy ligand electron density into the unfilled CeIV 6s, 4f, and 5d orbitals. CeIV to CeIII reduction readily occurs when homoleptic complex Ce[OSi(OtBu)3]4 is treated with cobaltocene, affording the separated ion pair [Ce{OSi(OtBu)3}4][CoCp2], featuring exclusive terminal siloxy bonding in the solid-state, similar to that detected for [Ce{OSi(OtBu)3}4][K(2.2.2-crypt)]. PMID- 29999069 TI - Enhancement of CO2 adsorption on oxygen-functionalized epitaxial graphene surface under near-ambient conditions. AB - The functionalization of graphene is important in practical applications of graphene, such as in catalysts. However, the experimental study of the interactions of adsorbed molecules with functionalized graphene is difficult under ambient conditions at which catalysts are operated. Here, the adsorption of CO2 on an oxygen-functionalized epitaxial graphene surface was studied under near ambient conditions using ambient-pressure X-ray photoelectron spectroscopy (AP XPS). The oxygen-functionalization of graphene is achieved in situ by the photo induced dissociation of CO2 with X-rays on graphene in a CO2 gas atmosphere. The oxygen species on the graphene surface is identified as the epoxy group by XPS binding energies and thermal stability. Under near-ambient conditions of 1.6 mbar CO2 gas pressure and 175 K sample temperature, CO2 molecules are not adsorbed on the pristine graphene, but are adsorbed on the oxygen-functionalized graphene surface. The increase in the adsorption energy of CO2 on the oxygen functionalized graphene surface is supported by first-principles calculations with the van der Waals density functional (vdW-DF) method. The adsorption of CO2 on the oxygen-functionalized graphene surface is enhanced by both the electrostatic interactions between the CO2 and the epoxy group and the vdW interactions between the CO2 and graphene. The detailed understanding of the interaction between CO2 and the oxygen-functionalized graphene surface obtained in this study may assist in developing guidelines for designing novel graphene based catalysts. PMID- 29999070 TI - Sub-molecular spectroscopy and temporary molecular charging of Ni-phthalocyanine on graphene with STM. AB - In this study, the self-assembled molecular network and electronic properties of Ni-phthalocyanine (NiPc) molecules on monolayer graphene (MLG)/6H-SiC(0001) were studied by room temperature Scanning Tunnelling Microscopy (STM) and Density Functional Theory (DFT) calculations. In this study, a very weak electronic coupling between the graphene and the NiPc molecules is found. This is due to the very small charge transfer of only 0.035e- per molecule. The weak molecule graphene interaction has two observable consequences: sub-molecular resolution was obtained in the STM spectroscopy at room-temperature with the molecules adsorbed directly on the graphene, and the occupied and unoccupied molecular resonance peaks were observed to shift their position in energy as a function of the tip-surface distance. This is due to the temporary local charging (either positive or negative) that is achieved by decreasing the surface voltage under the STM tip. This may have important consequences for future studies of the opto electronic properties of such hybrid graphene-molecule systems. PMID- 29999071 TI - New insights into the sensing mechanism of a phosphonate pyrene chemosensor for TNT. AB - As security needs have increased, mechanism investigation has become of high importance in the development of new sensitive and selective chemosensors for chemical explosives. This study details a theoretical investigation of the sensing mechanism of a new phosphonate pyrene chemosensor for trinitrotoluene (TNT), suggesting a different interaction mode between the probe and TNT from the one previously reported. The invalidity of the mechanism of binding TNT through intermolecular hydrogen bonds was proved using the Gibbs free energy profile and 1H NMR analysis. Frontier molecular orbitals (FMOs) analysis was used to show that photo-induced electron transfer (PET) is the underlying mechanism behind the luminescence quenching of the probe upon exposure to TNT, the rationality of which was further confirmed by the recording of a high charge transfer rate. We also found the existence of an energy level crossing between the local excited (LE) state and charge transfer (CT) state of a complex of the probe and TNT, which was confirmed using energy profile calculations along the linearly interpolated internal coordinate (LIIC) pathway. PMID- 29999072 TI - Effect of transition-metal-ion dopants on the oxygen evolution reaction on NiOOH(0001). AB - Iron-doped nickel oxyhydroxide has been identified as one of the most active alkaline oxygen evolution reaction (OER) catalysts, exhibiting an overpotential lower than values observed for state-of-the-art precious metal catalysts. Several computational investigations have found widely varying effects of doping on the theoretical overpotential of the OER on NiOx. Comparisons of these results are made difficult by the numerous differences in the structural and computational parameters used in these studies. In this work, within a consistent framework, we calculate the theoretical overpotentials for reactions occurring on the most stable, basal plane of undoped and doped beta-NiOOH. We compare the activities of Fe(iii), Co(iii), and Mn(iii) doping using density functional theory with Hubbard like U corrections on the transition-metal d orbitals. We compare the effect of surface and subsurface doping in order to establish whether the dopants act as new active sites for the reaction or whether they induce more widespread changes in the material. The results of our study find only a small reduction in the overpotential (~0.1 and <=0.05 V when doped in the surface and subsurface layers, respectively) for the three dopants, if doped in the dominant basal plane. This is much less than the reductions of 0.3 V experimentally observed for the most active Fe-doped systems. Furthermore, the magnitudes of reductions in overpotentials for the three dopants are similar. This work therefore disqualifies the possibility of enhancing the activity of the dominant exposed basal plane of beta-NiOOH through substitutional doping. PMID- 29999073 TI - Supramolecularly self-assembled nano-twin drug for reversing multidrug resistance. AB - Multidrug resistance (MDR) is one of the most important reasons for the failure of clinical chemotherapy treatment of cancer patients. Although several strategies have been proposed to overcome MDR, their contributions in improving therapeutic efficacy are not adequate. Herein, we constructed a nano-twindrug using a supramolecular self-assembling strategy, with the aim of efficiently reversing MDR. Due to the supramolecular interactions, doxorubicin (DOX) and vorinostat (SAHA) could self-assemble into stable spherical nanoparticles with a size of ~160 nm. Since the antitumor drugs were not modified by nontherapeutic drug carriers, our strategy ensured a drug-loading efficacy of 100%. Furthermore, our study revealed that the DOX-SAHA nano-twin drug could enter drug-resistant cancer cells and inhibit their proliferation more effectively in vitro than single DOX, SAHA, or a DOX/SAHA mixture. In the meantime, the DOX-SAHA nano-twin drug could accumulate at the tumor site in vivo and show higher antitumor efficacy accompanied by low side effects. PMID- 29999074 TI - Access to 1H-indazoles, 1H-benzoindazoles and 1H-azaindazoles from (het)aryl azides: a one-pot Staudinger-aza-Wittig reaction leading to N-N bond formation? AB - The synthesis of various substituted 1H-indazoles is reported through N-N bond formation from an iminophosphorane derivative. Supported by control experiments, an original Staudinger-aza-Wittig tandem mechanism is proposed for this transformation. PMID- 29999075 TI - Nanoscale electrochemical movies and synchronous topographical mapping of electrocatalytic materials. AB - Techniques in the scanning electrochemical probe microscopy (SEPM) family have shown great promise for resolving nanoscale structure-function (e.g., catalytic activity) at complex (electro)chemical interfaces, which is a long-term aspiration in (electro)materials science. In this work, we explore how a simple meniscus imaging probe, based on an easily-fabricated, single-channeled nanopipette (inner diameter ~ 30 nm) can be deployed in the scanning electrochemical cell microscopy (SECCM) platform as a fast, versatile and robust method for the direct, synchronous electrochemical/topographical imaging of electrocatalytic materials at the nanoscale. Topographical and voltammetric data are acquired synchronously at a spatial resolution of 50 nm to construct maps that resolve particular surface features on the sub-10 nm scale and create electrochemical activity movies composed of hundreds of potential-resolved images on the minutes timescale. Using the hydrogen evolution reaction (HER) at molybdenite (MoS2) as an exemplar system, the experimental parameters critical to achieving a robust scanning protocol (e.g., approach voltage, reference potential calibration) with high resolution (e.g., hopping distance) and optimal scan times (e.g., voltammetric scan rate, approach rate etc.) are considered and discussed. Furthermore, sub-nanoentity reactivity mapping is demonstrated with glassy carbon (GC) supported single-crystalline {111}-oriented two-dimensional Au nanocrystals (AuNCs), which exhibit uniform catalytic activity at the single-entity and sub single entity level. The approach outlined herein signposts a future in (electro)materials science in which the activity of electroactive nanomaterials can be viewed directly and related to structure through electrochemical movies, revealing active sites unambiguously. PMID- 29999076 TI - Growth of boron nitride nanotubes from magnesium diboride catalysts. AB - The difficulty in synthesizing boron nitride nanotubes (BNNTs) in a conventional horizontal tube furnace by chemical vapor deposition (CVD) may be ascribed to the failure to identify suitable catalysts and nucleation particles. This report demonstrates that magnesium diboride (MgB2) can effectively catalyze the growth of BNNTs in such a tube furnace from various boron sources, including boron oxide (B2O3), boric acid (H3BO3), and a mixture of boron (B) and calcium oxide (CaO). This catalyst is more efficient than the possible magnesium oxide (MgO) or magnesium nitride (Mg3N2) catalysts. MgB2 efficiently catalyzes the formation of BNNTs by maintaining a liquid state and showing a dissolving capacity for B2O3 at the growth temperature, thus satisfying the criteria for the vapor-liquid-solid (VLS) mechanisms of one-dimensional nanomaterials. First-principles simulations demonstrate that B2O3 can be dissolved into the MgB2 nanoparticle. We believe that the strong catalytic behavior of MgB2 can be attributed to its robust nucleation for BNNTs and dissolubility for B2O3. PMID- 29999077 TI - Sustained production of H2O2 in alkaline water solution using borate and phosphate-modified Au/TiO2 photocatalysts. AB - UV irradiation of Au/TiO2 photocatalysts in the presence of borate and phosphate anions can produce H2O2 at a millimolar level in alkaline water solution. The positive effect of the anions is ascribed to the anion-mediated hole transfer from Au/TiO2 to an electron donor which thus accelerates the two-electron reduction of O2 to H2O2. PMID- 29999078 TI - Long-lived luminescence of colloidal silicon quantum dots for time-gated fluorescence imaging in the second near infrared window in biological tissue. AB - Boron (B) and phosphorus (P) codoped silicon quantum dots (Si QDs) are dispersible in polar solvents without organic ligands and exhibit photoluminescence (PL) in the first (NIR-I) and second (NIR-II) near infrared (NIR) windows in biological tissues due to the optical transition from the donor to acceptor states. We studied the relationship between the PL wavelength, lifetime and quantum yield (QY) of the colloidal solution and the composition of the starting material for the preparation. We found that the PL lifetime and the QY are primarily determined by the composition, while the PL wavelength is mainly determined by the growth temperature. By optimizing the composition, we achieved QYs of 20.1% and 1.74% in the NIR-I and NIR-II regions, respectively, in methanol. We demonstrate the application for time-gated imaging in the NIR-II range. PMID- 29999079 TI - Theoretical insight into the mechanism, regioselectivity, and substituent group effect of Rh-catalyzed synthesis of 1,2-benzothiazines from NH-sulfoximines and diazo compounds. AB - This work presents a computational study of RhIII-catalyzed synthesis of 1,2 benzothiazines from NH-sulfoximines and diazo compounds reported by Bolm et al. (Angew. Chem., Int. Ed., 2015, 54, 12349). The reaction involves five sequent processes: elimination of dinitrogen, C-H activation, carbene insertion, protonation, and dehydration, and the C-H activation is identified as the rate determining step with a barrier of 33.1 kcal mol-1. Phenyl sulfoximine is found to be the most favorable substrate with the lowest barrier in comparison with methoxybenzene sulfoximine and nitrobenzene sulfoximine. The noncovalent interaction is indicated to be mainly responsible for the experimentally observed regioselectivity. The theoretical results are expected to provide valuable guidance and assistance for the synthesis of 1,2-benzothiazines. PMID- 29999080 TI - Imaging large amplitude out-of-plane motion in photoexcited pentafluorobenzene using time-resolved photoelectron spectroscopy: a computational study. AB - Excited-state dynamics of pentafluorobenzene is studied in detail for a quartic vibronic coupling model including the six b1 vibrational modes of the molecule and the two lowest excited electronic states. The study analyzes the influence of the large-amplitude out-of-plane vibrational motion on the electronic dynamics and extends to the simulation of the emerging time-resolved photoelectron spectra. The mapping of coherent non-separable electron-nuclear motion into oscillatory photoelectron signals is discussed. PMID- 29999081 TI - Shear-induced parallel and transverse alignments of cylinders in thin films of diblock copolymers. AB - Coarse-grained Langevin dynamics simulations were performed to investigate the alignment behavior of monolayer films of cylinder-forming diblock copolymers under steady shear, a structure of significant importance for many technical applications such as nanopatterning. The influences of shear conditions, the interactions involved in the films, and the initial morphology of the cylinder forming phase were examined. Our results showed that above a critical shear rate, the cylinders can align either along the shearing direction or transverse (log rolling) to the shearing direction depending on the relative strength between the interchain attraction in the cylinders (epsilonAA) and the surface attraction of the confining walls with the film (epsilonBW). To understand the underlying mechanism, the microscopic properties of the films under shear were systematically investigated. It was found that at low epsilonAA/epsilonBW, the majority blocks of the diblock polymer that are adsorbed on the confining walls prefer to move synchronously with the walls, inducing the cylinder-forming blocks to align along the flow direction. When epsilonAA/epsilonBW is above a threshold value, a strong attraction between the cylinder-forming blocks restrains their movement during shear, leading to the log-rolling motions of the cylinders. To predict the threshold epsilonAA/epsilonBW, we developed an approach based on equilibrium thermodynamics data and found good agreement with our shear simulations. PMID- 29999082 TI - Hydrogen atom induced magnetic behaviors in two-dimensional materials: insight on origination in the model of alpha-MoO3. AB - Atomic layered two-dimensional (2D) materials have become fascinating research topics due to their intriguing performances, but the limitation of nonmagnetic properties hinders their further applications. Developing versatile strategies endowing 2D materials with ferromagnetism is one of the main trends in current research studies. Herein, a hydrogen plasma strategy is introduced to dope hydrogen (H) atoms into the prototypical layered alpha-MoO3 nanosheets, by which ferromagnetic and exchange bias (EB) effects can be induced by H atom doping into alpha-MoO3 to form HxMoO3. These effects were interpreted by density functional theory (DFT) calculations. We find that H atom doping can introduce unoccupied states and induce a net magnetic moment localized on the d orbital of the Mo atom, because of the generated asymmetric distribution of electronic states on the Mo atom near the Fermi level. Moreover, the saturation magnetization and the EB field (He) of hydrogenated alpha-MoO3 are found to be tunable through altering the amount of H dopant. This work provides new perspectives for the effective manipulation of ferromagnetism and exchange interaction through H doping. We hope that the presented hydrogenation strategy is applicable for other kinds of 2D materials. PMID- 29999083 TI - Phase separation in binary mixtures of active and passive particles. AB - We study binary mixtures of small active and big passive athermal particles interacting via soft repulsive forces on a frictional substrate. Athermal self propelled particles are known to phase separate into a dense aggregate and a dilute gas-like phase at fairly low packing fractions. Known as motility induced phase separation, this phenomenon governs the behaviour of binary mixtures for small to intermediate size ratios of the particle species. An effective attraction between passive particles, due to the surrounding active medium, leads to true phase separation for large size ratios and volume fractions of active particles. The effective interaction between active and passive particles can be attractive or repulsive at short range depending on the size ratio and volume fractions of the particles. This affects the clustering of passive particles. We find three distinct phases based on the spatial distribution of passive particles. The cluster size distribution of passive particles decays exponentially in the homogeneous phase. It decays as a power law with an exponential cutoff in the clustered phase and tends to a power law as the system approaches the transition to the phase separated state. We present a phase diagram in the plane defined by the size ratio and volume fraction of passive particles. PMID- 29999085 TI - Photoinduced three-component coupling reactions of electron deficient alkenes, dienes and active methylene compounds. AB - The irradiation of aqueous acetonitrile solutions, containing electron deficient alkenes, dienes and active methylene compounds along with sodium or cesium carbonate and catalytic amounts of phenanthrene or pyrene, gives rise to the formation of novel three-component coupling products and diene dimers. Cinnamonitrile and benzylidenemalononitrile and its derivatives serve as electron acceptors; 2,5-dimethyl-2,4-hexadiene and malononitrile anion serve as electron donors in this process. Based on the results of UV-vis absorption spectroscopy and the calculated DeltaG values for single electron transfer (SET), mechanisms are proposed for the coupling reaction involving photoinduced electron transfer (PET) between the electron deficient alkenes and dienes or malononitrile anion via direct excitation of electron deficient alkenes or redox photosensitization using phenanthrene or pyrene serving as a photosensitizer. PMID- 29999084 TI - Mechanics of cellular packing of nanorods with finite and non-uniform diameters. AB - To understand the mechanics of cellular/intracellular packing of one-dimensional nanomaterials, we performed theoretical analysis and molecular dynamics simulations to investigate how the morphology and mechanical behaviors of a lipid vesicle are regulated by encapsulated rigid nanorods of finite and non-uniform diameters, including a cylindrical rod, a rod with widened ends, a cone-shaped rod, and a screwdriver-shaped rod. As the rod length increases, the vesicle evolves from a sphere into different shapes, such as a lemon, a conga drum, a cherry, a bowling pin, or a tubular shape for long and thick rods. The contact between the vesicle protrusion and the rod plays an important role in regulating the vesicle tubulation, membrane tension, and axial contact force on the rod. Our analysis provides a theoretical basis to understand a wide range of experiments on morphological transitions that occur in cellular packing of actin or microtubule bundles, mitotic cell division, and intracellular packing of carbon nanotubes. PMID- 29999086 TI - Efficient syntheses and anti-cancer activity of xenortides A-D including ent/epi stereoisomers. AB - A one-pot, two-step, total synthesis of naturally occurring xenortides A, B, C and D, (Xens A-D) isolated from the bacterium Xenorhabdus nematophila, and an entire complementary set of stereoisomers, has been achieved. Compounds were synthesized utilizing an isocyanide-based Ugi 4-CR followed by facile N-Boc deprotection. The reaction sequence took advantage of the chiral pool of N-Boc protected amino acids (l-Leu/Val and d-Leu/Val) with aryl isocyanides, phenyl acetaldehyde and methylamine giving the desired Xens A-D (A and B >98% ee) and all subsequent stereoisomers in reasonable yields upon deprotection followed by separation of diastereomers. Also, detailed mechanistic insights for diastereoselectivity of (-)-Xen A, as a model in the Ugi 4-CR, has been described. Moreover, for the first time, this focused library was screened for cytotoxicity against a panel of epithelial cancer cell lines as well as normal cell lines with an MTT proliferation assay. The structure-activity relationship (SAR) study demonstrated that tryptamides Xen B and D were more active than phenylethylamides Xen A and C. Furthermore, (-)-Xen B (IC50 = 19-25 MUM) and ent (+)-Xen D (IC50 = 21-26 MUM) gave the highest cytotoxicity and they were also found to be non-toxic toward normal cells. Importantly, the SAR results indicate that the stereochemistry at C8 and C11 in (-)-Xen B and ent-(+)-Xen D play a critical role in cytotoxic activity. PMID- 29999087 TI - Considerably enhanced exciton emission of CsPbCl3 perovskite quantum dots by the introduction of potassium and lanthanide ions. AB - The photoluminescence quantum yield (PLQY) of blue-violet emission of CsPbCl3 quantum dots (QDs) is still low, which has limited their application in multi colour displays. It is important to search for efficient perovskite phosphors within this wavelength range. In this work, we first considerably enhanced the photoluminescence quantum yield (PLQY) of the CsPbCl3 QDs from 3.2 to 10.3% by the introduction of potassium ions (K+). Then, various lanthanide elements (La, Y, Eu, Lu) were further doped into KxCs1-xPbCl3 QDs. The lanthanide doped KxCs1 xPbCl3 QDs still demonstrated emissions around 408 nm and the PLQY was further improved to 31%. Finally, we carried out anion exchange by gradually substituting chlorine with bromine. Efficient and tunable emissions ranging from 408-495 nm were obtained, with a maximum PLQY of 90%. This work provides a new approach to improve the efficiency of the blue-violet light of perovskite QDs. PMID- 29999088 TI - PdO/PdO2 functionalized ZnO : Pd films for lower operating temperature H2 gas sensing. AB - Noble metals and their oxide nano-clusters are considered to be the most promising candidates for fabricating advanced H2 gas sensors. Through this work, we propose a novel strategy to grow and modulate the density of PdO/PdO2 nanoparticles uniformly on nanostructured Pd-doped ZnO (ZnO : Pd) films by a one step solution approach followed by thermal annealing at 650 degrees C, and thus to detect ppm-level H2 gas in a selective manner. The gas sensing properties of such hybridized materials showed that the PdO-functionalized ZnO samples offer significantly improved H2 gas sensing properties in an operating temperature range of 25-200 degrees C. The deposition of ZnO : Pd films via a simple synthesis from chemical solutions (SCS) approach with an aqueous bath (at relatively low temperatures, <95 degrees C) is reported. Furthermore, the functionalization of palladium oxide nanoclusters by a simple but highly effective approach on ZnO : Pd film surfaces was performed and is reported here for the first time. The morphological, structural, vibrational, optical, chemical, and electronic properties were studied in detail and the mixed phases of palladium oxide nanoclusters on the ZnO surface were found. Sensor studies of the ZnO : Pd samples (in the range of 25-350 degrees C operating temperature) showed good selectivity to H2 gas, especially in the range of higher temperatures (>150 degrees C, up to 350 degrees C); however, the PdO/PdO2 mixed phases of the nanocluster-modified surface ZnO : Pd films showed a much better selectivity to H2 gas, even at a lower operating temperature, in the range of 25-150 degrees C. For such PdO-functionalized ZnO : Pd films, even at room temperature, a gas response of ~12.7 to 1000 ppm of H2 gas was obtained, without response to any other reducing gases or tested vapors. The large recovery time of the samples at room temperatures (>500 s) can be drastically reduced by applying higher bias voltages. Furthermore, we propose and discuss the gas sensing mechanism for these structures in detail. Our study demonstrates that surface functionalization with PdO/PdO2 mixed phase nanoclusters-nanoparticles (NPs) is much more effective than only the Pd doping of nanostructured ZnO films for selective sensing applications. This approach will pave a new way for the controlled functionalization of PdO/PdO2 nanoclusters on ZnO : Pd surfaces to the exact detection of highly explosive H2 gas under various atmospheres by using solid state gas sensors. PMID- 29999089 TI - Phosphine-catalysed alpha-umpolung addition of nucleophiles to delta-acetoxy allenoates: stereoselective synthesis of 2,4-dienoates. AB - The first example of phosphine-catalyzed alpha-umpolung addition of nucleophiles to allenoates is described, which features the use of delta-acetoxy allenoate to generate a 3-phosphonium-2,4-dienoate intermediate, thus facilitating the alpha umpolung addition of nucleophiles. Both sulfinate and diarylphosphine oxide are competitive nucleophiles, affording highly activated conjugated dienes with good to excellent stereoselectivities. PMID- 29999090 TI - Visualization of diffusion limited antimicrobial peptide attack on supported lipid membranes. AB - Understanding the mechanism of action of antimicrobial peptides (AMP) is fundamental to the development and design of peptide based antimicrobials. Utilizing fast-scan atomic force microscopy (AFM) we detail the attack of an AMP on both prototypical prokaryotic (DOPC:DOPG) and eukaryotic (DOPC:DOPE) model lipid membranes on the nanoscale and in real time. Previously shown to have a favourable therapeutic index, we study Smp43, an AMP with a helical-hinge-helical topology isolated from the venom of the North African scorpion Scorpio maurus palmatus. We observe the dynamic formation of highly branched defects being supported by 2D diffusion models and further experimental data from liposome leakage assays and quartz crystal microbalance-dissipation (QCM-D) analysis, we propose that Smp43 disrupts these membranes via a common mechanism, which we have termed 'diffusion limited disruption' that encompasses elements of both the carpet model and the expanding pore mechanism. PMID- 29999091 TI - Luminescence phenomena of carbon dots derived from citric acid and urea - a molecular insight. AB - In this report, we present the results of our investigations into the elucidation of the chemical structure of moieties responsible for the blue and green luminescence of CDs derived from the microwave-assisted pyrolysis of citric acid in the presence of urea. The molecular fluorophore that forms during the synthesis of green fluorescing CDs is 4-hydroxy-1H-pyrrolo[3,4-c]pyridine 1,3,6(2H,5H)-trione (HPPT). PMID- 29999092 TI - Probing the nanoscale light emission properties of a CVD-grown MoS2 monolayer by tip-enhanced photoluminescence. AB - Two-dimensional transition metal dichalcogenides are gaining increasing interest due to their promising optical properties. In particular, molybdenum disulfide (MoS2) which displays a band-gap change from indirect at 1.29 eV for bulk materials to direct at 1.8 eV for the material monolayer. This particular effect can lead to a strong light interaction which can pave the way for a new approach to the next generation of visible light emitting devices. In this work we show the nanoscale variation of light emission properties by tip-enhanced photoluminescence microscopy and spectroscopy in the MoS2 monolayer, grown by chemical vapour deposition. The variations of the light emission properties are due to different effects depending on the shape of the MoS2 single layer, for instance, a different concentration of point defect in an irregularly shaped flake and the presence of a nanoscale terrace in a triangular monolayer. Simultaneously, atomic force microscopy reveals indeed the presence of a nanometric terrace, composed of an additional layer of MoS2, and tip-enhanced PL intensity imaging shows a localized intensity decrease. PMID- 29999093 TI - Correction: Metabolomic profiles delineate the potential role of glycine in gold nanorod-induced disruption of mitochondria and blood-testis barrier factors in TM 4 cells. AB - Correction for 'Metabolomic profiles delineate the potential role of glycine in gold nanorod-induced disruption of mitochondria and blood-testis barrier factors in TM-4 cells' by Bo Xu et al., Nanoscale, 2014, 6, 8265-8273. PMID- 29999094 TI - Lipid extraction by boron nitride nanosheets from liquid-ordered and liquid disordered nanodomains. AB - Atomically thin boron nitride nanosheets are important two-dimensional nanomaterials with great potential in biomedical applications. Understanding the basic interaction mechanisms between lipid domains and boron nitride nanosheets can help clarify the potential risks of these nanomaterials and thus provide guidance on the design of safe biomedical applications. Using molecular dynamics simulations, we demonstrate that the BNNS can disrupt the liquid disordered lipid bilayers much more easily compared to the liquid ordered phases. The potential of mean force profiles calculated from umbrella sampling further explain this adsorption preference. When the BNNS is placed at the boundary of the liquid ordered and liquid disordered nanodomains, disruption of the liquid ordered domains becomes much easier due to the presence of adjacent liquid disordered domains. Our findings provide new insights into the cytotoxicity of boron nitride nanosheets interacting with cellular membranes. PMID- 29999095 TI - Realization of an all-optically controlled dynamic superlattice for exciton polaritons. AB - Exciton-polaritons, formed by the strong coupling between excitons and cavity confined photons, are the building blocks of polaritonic devices. In this work, we report experimental realization of an all-optically controlled dynamic superlattice for polaritons working in the ultraviolet wavelength range at room temperature. The optical superlattice was realized on a one-dimensional (1D) ZnO microrod using an array of periodically arranged laser spots. Polaritonic mini band features were clearly observed by both momentum- and real-space imaging spectroscopy. By controlling the periodicity of the laser spots, we demonstrated that the band structures of polaritons can be well controlled by external lasers. Theoretically, by extending the Kronig-Penney model to the polariton system, we calculated the polaritonic mini-bands and found it to be in good agreement with our experimental observations. By imaging the polariton flow in real space, the lifetime of polaritons and their relationship with their exitonic fractions were also extracted. The polaritonic superlattices demonstrated in this work are fully reconfigurable and optically controlled, and our results could thus stimulate the development of polaritonic all-optical devices. PMID- 29999096 TI - [Thromboelastography and classical coagulation tests in the preoperative period of liver transplantation]. AB - BACKGROUND: Compared to standard coagulation essays (SCE), such as international normalized ratio (INR), prothrombin activated partial thromboplastin time (aPTT), or platelet count, thromboelastograhy (TEG) offers precise and real-time information about hemostasis. TEG tests both platelet function and coagulation by assaying several parameters of clot formation dynamically in whole blood. AIM: To evaluate hemostasis in cirrhotic patients undergoing liver transplantation and determine the positive and negative predictive values of SCE for alterations of TEG. MATERIAL AND METHODS: Preoperative SCE and TEG were prospectively analyzed in 25 patients. Results were categorized as normal, laboratory alteration or clinical alteration. SCE results were compared with TEG parameters to determine positive (PPV) and negative predictive values (NPV). RESULTS: Hemostasis was abnormal and laboratory abnormalities were observed in all patients. One patient had clinical signs of excessive bleeding. SCE were abnormal in all patients and TEG was normal in nine patients. The most common alteration in TEG was hypocoagulability, in some cases associated with hypercoagulability and hyperfibrinolysis. Two patients had solely hypercoagulability. PPV of INR, aPTT, platelet count and fibrinogenemia were 0, 0, 0.5 and 0.17 respectively. NPV of the same tests were 1, 1, 0.34 and 1 respectively. CONCLUSIONS: Hypocoagulability was the most common laboratory alteration, however, clinical signs of coagulopathy were rarely present. SCE had a poor predictive value to diagnose o discard hemostatic abnormalities. PMID- 29999098 TI - [Evolution of mortality, retention and loss to follow up of HIV infected subjects followed in a special clinic]. AB - BACKGROUND: The HIV epidemic reached Chile in late 1980s and as an early response, AIDS care centers were organized. Fundacion Arriaran (FA) was the first center. Free antiretroviral therapy (ART) was later provided with progressive coverage and complexity over the years. AIM: To quantify evolution of mortality, retention and loss to follow up (LTFU) over 25 years according to different periods of access to ART, from no availability to full coverage with current drugs at FA center. MATERIAL AND METHODS: Retrospective analysis of FA database of 5,080 adults admitted between 1990 and 2014. The sample was distributed in 7 groups: A: no ART (1990-92), B: monotherapy, C: dual therapy, D: dual/triple ART, E: early triple therapy with incomplete coverage, F same as E but with complete coverage and G: contemporary ART (2008-14). Mortality, retention and LTFU were evaluated at 1, 3, 5, 7 and 10 years and at 31/12/2015. RESULTS: Mortality varied from 40% to 2%, and 62% to 7% at 1 and 5 years, for groups A and G respectively; from 71% to 16% at 10 years for groups A and E, respectively. Retention at 5 years were 28%, 23%, 39%, 62%, 75%, 75% and 77% for groups A to G, respectively. LTFU was 10%, 19%, 15%, 17%, 9% 12% and 10% at 5 years for same groups, respectively. At 12/31/2015 22% of patients had died, 11% were LTFU, 60% were retained in care and 6% had been transferred. CONCLUSIONS: There is a marked reduction in mortality and increase in retention of HIV patients' concomitant to expanded access to modern therapy, although LTFU remains a problem. PMID- 29999097 TI - [Risk of recurrence in differentiated thyroid cancer]. AB - BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with a favorable prognosis. Its treatment requires surgery, selective use of radioiodine and levothyroxine, and its intensity must be adjusted to the initial risks of mortality and recurrence. AIM: To validate the risk of recurrence classification developed by the Chilean Ministry of Health in 2013 (MINSAL 2013), and compare it with the American Thyroid Association (ATA) 2009 and 2015 classifications. MATERIAL AND METHODS: Retrospective study of 362 patients with DTC aged 44.3 +/- 13.4 years (84% women), treated with total thyroidectomy, selective radioiodine ablation and levothyroxine and followed for a median of 4.2 years (range 2.0 7.8). Risk of recurrence was estimated with MINSAL 2013, ATA 2009 and ATA 2015 classifications, and risk of mortality with 7th and 8th American Joint Committee on Cancer (AJCC)/TNM systems. Clinical data obtained during follow-up were used to detect structural and biochemical persistence/recurrence. RESULTS: A mean dose of 104 +/- 48 mCi radioiodine was received by 91% of patients. MINSAL 2013 classified 148 (41%), 144 (40%), 67 (19%) and 3 (1%) patients as very low, low, intermediate and high risk of recurrence, respectively. Forty-five (12.4%) patients had persistence or recurrence during follow-up: 33 structural and 12 biochemical. Rates of persistence/recurrence on each category of MINSAL 2013 were 4.1%, 7.6%, 37.3% and 100%, respectively (p < 0.01). Areas under Receiver Operating Characteristic curves for persistence or recurrence of MINSAL 2013, ATA 2009 and ATA 2015 were 0.77 vs 0.73 vs 0.72, respectively. CONCLUSIONS: MINSAL 2013 classifies appropriately DTC patients and estimates correctly their risk of persistence or recurrence. PMID- 29999099 TI - Assessment of the Hospital Anxiety and Depression Scale for cancer patients. AB - BACKGROUND: Depression and anxiety are common in patients with cancer. AIM: To adapt and validate the Hospital Anxiety and Depression Scale (HADS) for adult Chilean cancer patients, and to provide information about their prevalence of anxiety and depression. MATERIAL AND METHODS: Two hundred fifteen patients with cancer answered an adapted version of HADS for Chilean population. The language adjustment of the scale was carried out with the opinions of 10 expert linguists and with a pilot study on 17 cancer patients. The Depression and Anxiety subscales of the DASS-21 were also applied to verify the convergent validity of HADS: Results: The confirmatory factor analysis indicated that the data fits the model of two correlated factors (anxiety and depression), chi2 = 98.608; df = 76;p < 0.05; chi2/df= 1.23, RMSEA = 0.037; CFI = 0.99; TLI = .98. Reliability analysis showed an adequate internal consistency of both subscales (.76 for anxiety and .84 for depression) and the general scale (.87). Correlations between HADS and DASS-21 scores were significant for both anxiety (r =.514, p < 0.001) and depression (r = 0.600, p < 0.001). Prevalence rates were approximately 30% for depression (actual = 12%, possible = 22.8%) and approximately 20% for anxiety (actual = 7%, possible = 8.4%). CONCLUSIONS: We conclude that HADS is a reliable and valid instrument for screening clinically relevant anxiety and depression symptoms in Chilean cancer patients. PMID- 29999100 TI - [Development of an instrument to assess cultural beliefs about physicians]. AB - BACKGROUND: Beliefs about professionals' healthcare may influence healthcare behaviors. Such beliefs are in part the result of the interactions that professionals have with their patients. Recent studies highlight the importance of beliefs about physicians, their effect on health-care behaviors, and the requirement of culturally appropriate tools to measure such beliefs. AIM: To develop and validate a culturally appropriate instrument to measure beliefs about physicians. MATERIAL AND METHODS: Based on a "bottom-up" methodology, a culturally pertinent scale of beliefs about physicians was developed and then validated by expert judges. The resulting scale, with 26 items, was applied to 337 participants aged 31 +/- 7 years (85% women). RESULTS: Two factors, grouping 24 items, emerged from the exploratory factor analysis. The first was called negative beliefs about doctors (Cronbach's alpha = 0.96) and the second was called positive beliefs about doctors (Cronbach's alpha = 0.95). Both factors explain 70 % of the scale variance. CONCLUSIONS: The devised instrument has adequate psychometric properties and is also culturally relevant. It allows the assessment of cultural beliefs about physicians. PMID- 29999101 TI - [Cognitive reserve, depression and social support. Analysis of 206 older adults]. AB - BACKGROUND: Cognitive reserve (CR) is a protective factor in aging. Depression and perceived social support are associated with cognitive performance in older adults. However, their role in the relationship between CR and cognitive functioning is less clear. AIM: To determine the relationship between CR and cognitive functioning and whether this relationship is mediated by depression and moderated by social support. MATERIAL AND METHODS: CR, depression, perceived social support, and cognitive functioning scales were applied to a convenience sample of 206 older adults, aged 69 +/- 1 years (77% women). Structural equation analysis and moderate mediation analysis were performed. RESULTS: There was a direct effect of CR in cognitive functioning (beta = 0.223, p = 0.005), which was not mediated by depression (beta = 0.040, p = 0.096). High CR scores were associated with lower depression scores (beta = -0.203, p = 0.002). Higher depression scores were associated with worse cognitive functioning (beta = 0.168, p = 0.040). The effect of CR on depression was moderated by social support (beta = -0.161, p = 0.032) controlling for income and age. CONCLUSIONS: The relationship between CR and cognition in older adults allows an early assessment of cognitive dysfunction risk. Depression is an independent risk factor for cognitive functioning. Social support protects individuals with high CR from developing depression. PMID- 29999102 TI - [Association of asthma control with psychological factors in women]. AB - BACKGROUND: Asthma is a chronic multifactorial disease with a fast-growing global prevalence. Its association with psychological factors is not completely elucidated. AIM: To analyze features associated with not well-controlled asthma and to test the association of psychological factors with asthma control criteria. PATIENTS AND METHODS: Cross-sectional study that analyzed data from clinical records of asthmatic women under care in the Adult Respiratory Diseases Programs (ERA, in Spanish) and the Mental Health Program of Family Care Health Centers in the city of Arica. According to the asthma control score, patients were classified as having adequate control or not. RESULTS: A total of 60 women were analyzed and 62% had a not well-controlled asthma. Factors associated with not well-controlled asthma were moderate depression (Odds ratio (OR) = 6.84;p < 0.01), emotional lability (OR = 0.14; p = 0.02) and domestic violence (OR = 5.75; p = 0.05). The psychological factors associated with asthma control criteria were fear, emotional instability, domestic violence, sleep disorders, mixed anxiety depressive disorders, and moderate depression. CONCLUSIONS: Psychological factors and violence exposure were consistently associated with asthma control. PMID- 29999103 TI - [Cultural adaptation and translation of the Woman Abuse Screening Tool]. AB - BACKGROUND: The Woman Abuse Screening Tool (WAST) is a screening tool for domestic violence used in Unites States. AIM: To carry out the cultural adaptation of the WAST instrument for early detection of domestic violence in primary health care. MATERIAL AND METHODS: Qualitative techniques for cultural adaptation were used in stages 1 and 2 and quantitative techniques were used in stage 3. The validity of content was assessed using judge tests carried out with experts in the field. Linguistic adaptation was carried out using a focal group technique to ensure semantic and language comprehension. Finally, the culturally adapted instrument was applied to 16 women who were victims of violence and to 28 women without a history of violence. RESULTS: For cultural adaptation, the judges' test added the item of economic violence to the instrument. According to the focus groups, some words were changed to facilitate understanding by the subjects. According to the scores obtained in women with and without a history of violence, a cut-off point of 15 points was defined to determine a history of domestic violence with a sensitivity of 100% and a specificity of 96%. The Cronbach Alpha of the questionnaire was 91%. CONCLUSIONS: WAST is an effective and easily applied instrument for the early detection of domestic violence. PMID- 29999104 TI - [Objective structured clinical evaluation to assess clinical skills of international medical graduates]. AB - BACKGROUND: Our institution adopted the Objective Structured Clinical Evaluation (OSCE) format to assess clinical skills of International Medical Graduates (IMGs) aiming to practice in Chile. The OSCE has clear advantages over oral exams due to its objective and structured nature. AIM: To report our experience with OSCE. MATERIAL AND METHODS: A team consisting of clinical specialists and medical educators with expertise in clinical simulation organized this OSCE cycle. IMGs were required to pass four clinical examinations (Internal Medicine, Surgery, Pediatrics and Obstetrics & Gynecology) where their respective general medical competences were evaluated. The latter were carefully selected from those issued by the Chilean Medical Evaluation policy-making body (EUNACOM). Each OSCE consisted of ten stations. Initially conceived to last five minutes each, they were afterwards expanded to seven minutes, after it was realized that most candidates had never been exposed to an OSCE examination before. A post-hoc analysis according to qualitative and psychometric quality criteria followed each OSCE. RESULTS: The proportion of candidates passing the first two examinations of the cycle, were 65 and 75% respectively and reached 100% in the last ones. Lack of IMG familiarity with the OSCE system initially hampered their full expression of competencies. Extending the stations' duration to seven minutes subsequently rectified this situation, as well as potential adverse impacts on the validity of results. CONCLUSIONS: This evaluative process, which entails important consequences for the community and the IMGs, requires a meticulous and coordinated planning and post-hoc quality control. PMID- 29999105 TI - [Estimation of glomerular filtration rate with creatinine]. AB - Glomerular filtration rate (GFR) is the best approximation to global renal function and its estimation is of great relevance for clinical practice. Since the measurement of GFR by reference methods is complex, costly and not widely available, its routine evaluation is performed using endogenous biomarkers. Within these, creatinine is the most commonly used. It allows the estimation of GFR by means of its clearance or by formulas based on its concentration on plasma. Creatinine measurement should be performed using enzimatic methods as they confer more accurate values than Jaffe methods, especially for normal and low creatinine levels. PMID- 29999106 TI - [Autoimmune encephalitis. A review]. AB - Autoimmune encephalitis are one of the emergent causes of subacute changes in the level of consciousness, behavior, cognitive impairment and seizures, mainly in young people. They are a consequence of inflammation or dysfunction of parts of the brain caused by antibodies against specific brain antigens, usually located in the limbic system, resulting in clinical presentation as a limbic encephalitis. The objectives of this article are to show the clinical presentation, complementary studies and treatment of this entity, considering that the patient's prognostic depends on a high level of clinical suspicion, and on an early initiation of immunosuppressive therapy. We did a nonsystematic review of the literature on autoimmune encephalitis between 2005 and 2017. We conclude that the prevalence of autoimmune encephalitis is increasing, even surpassing infectious causes of encephalitis in developed countries. Clinical presentation includes sub-acute cognitive and behavioral impairment, with or without alterations in consciousness and seizures. Fever and inflammation of the cerebrospinal fluid are less common than in the infectious causes but psychiatric symptoms are more frequent. There are specific clinical presentations according to the particular type of antigen/antibody present, which also determines the association with cancer, constituting a paraneoplastic syndrome only in some cases. Immunosuppressive therapy has been standardized in steps, and should be initiated early to improve prognosis. PMID- 29999107 TI - [Exercise and oxidative stress in type 2 diabetes mellitus]. AB - Sedentarism, overweight and malnutrition generate an increase in the production of reactive oxygen species leading to a state of chronic oxidative stress. In patients with type 2 diabetes mellitus, oxidative stress alters pancreatic insulin secretion and the actions of the hormone on target cells, contributing to the development of micro and macrovascular complications. During physical exertion a state of transient oxidative stress occurs. As a consequence, the organism generates multiple physiological adaptations to these repetitive stimuli. Physical exercise is beneficial for type 2 diabetes mellitus but there is a paucity of information about the effects of physical exercise on biomarkers of oxidative stress in patients with the disease. We herein try to elucidate if the effects of exercise on oxidative stress can help in the prevention and treatment of type 2 diabetes mellitus and which is the most effective modality of physical exercise to reduce oxidative stress markers. PMID- 29999108 TI - [Ethical problems in scientific publications]. AB - Ethical problems have always been present in scientific publications. Since the founding of medical journals, in the XIX Century, until today they are a source of concern because one main purpose of medical scientific publications is to add new, reliable information that could guide or modify medical decisions and public health policies. Since 1997, Revista Medica de Chile has published several articles clarifying this situation and emphasizing the need to avoid ethical misbehavior. The present review reminds that the main sources of information dealing with publication ethics appear in the web sites of ICMJE, COPE and WAME. Misconduct have been detected in Revista Medica de Chile in a few cases of redundant publications, plagiarism, lack of recognition of conflicts of interest mainly with pharmaceutical companies, and one attempt of forging the publication of an article that had been previously rejected. In handling situations identified as ethical misbehavior, the editors of this journal have successfully followed rules established by COPE. This article reviews and reinforces recommendations to avoid ethical misbehavior in biomedical research and in manuscripts submitted for publication. PMID- 29999110 TI - [Origin and development of the book Medical Semiology]. AB - Semiotics and Semiology share a similar etymology and meaning: the study of signs. In Medicine, signs are objective manifestations of disease, as opposed to the subjective nature of symptoms. Medical semiology comprises the study of symptoms, somatic signs and laboratory signs, history taking and physical examination (in English-speaking countries is known as Bedside diagnostic examination or Physical diagnosis). The first edition of Medical Semiology dates from 1987, and new editions appeared in 1999, 2010, and 2017. The book is devoted to semiology proper with clinical orientation. Its origin, however, dates back to 1937, when the University of Chile appointed Dr. Hernan Alessandri (1900-1981), the eminent Chilean medical educator, Professor in Semiology at the Internal Medicine Section of the Hospital del Salvador in Santiago. The authors of the present book served as Dr. Alessandri's teaching assistants for decades. The two semester course in semiology had a tutorial character: each teaching assistant was assigned five students whom engaged daily in practical activities in the hospital wards for a total of four hours, in addition to a 45- minute lecture on the theoretical aspects of the subject. The 720-page fourth edition of the book brings together teaching method and clinical experience of more than 50 years. The book consists of six Sections: "Cardinal manifestations of disease", "Major clinical syndromes", "History taking and Physical examination", "Clinical diagnosis and the patient-physician relationship", "Laboratory clinical tests and Instrumental exploration of the body," and "Glossary of diseases." In its forty Chapters, a total of 207 issues are described in detail. PMID- 29999109 TI - [Psychometric properties of a newly developed occupational identity questionnaire for university teachers]. AB - BACKGROUND: Occupational identity is defined as the perception of occupational interests, abilities, goals, and values, and the structure of the meanings that link these self-perceptions to career role. We developed an occupational identity questionnaire suitable to be used with university teachers. AIM: To evaluate the psychometric properties of the Occupational Identity Questionnaire (OIQ) and relate its results with those of the Teaching Practices questionnaire. MATERIAL AND METHODS: The OIQ and Teaching Practices Questionnaire were answered by 311 university teachers along Chile, who were selected through a non-probabilistic volunteer sampling. An exploratory factor analysis was performed and the internal consistency of each factor was calculated with Cronbach's Alpha. Spearman correlations were used to explore the relationship between the two questionnaires. RESULTS: Two factors were identified in OIQ: Teaching Vocation and Sense of Competence. Cronbach's Alpha was 0.75 for teaching vocation and 0.82 for the sense of competence. There was a moderate direct relationship between teaching vocation, sense of competence and the results of the Teaching Practices Questionnaire. CONCLUSIONS: OIS has an adequate internal consistency, its factorial structure showed two different types of identities and it is directly related to the results of the Teaching Practices Questionnaire. PMID- 29999111 TI - [Symmetrical rib fractures associated with chronic cough. Report of one case]. AB - Cough may be associated with complications such as syncope, urinary incontinence, pneumothorax, and less frequently, pulmonary hernia and costal fractures. Chronic cough is a cause of rib fractures and when they occur it is likely to affect more than one rib. We report a 53 year-old obese male in treatment with enalapril 10 mg for hypertension with a dry cough lasting five months. He consulted for bilateral chest pain and a Chest X ray examination showed symmetrical fractures in the seventh left and right ribs. Enalapril was discontinued, cough and pain subsided in two weeks. PMID- 29999112 TI - [Successful oral desensitization to levothyroxine. Report of one case]. AB - We report a 39-year-old female who underwent a total thyroidectomy as treatment for a thyroid papillary cancer. She suffered several episodes of mild angioedema in lips and tongue, after using different commercial Levothyroxine formulations, with and without excipients. Given the need to use this drug, the patient was admitted in our hospital and we proceeded to desensitize her with oral Levothyroxine. The patient fasted throughout the whole procedure, was properly monitored and had an adequate peripheral venous access. On the first day of the procedure, a 15-step protocol was performed, first administering placebo and then, compounded formulations of Levothyroxine starting from 0.01 ug, followed by doubling doses every 15 minutes until the cumulative dose of 111.95 ug was completed, corresponding to the daily dose of Levothyroxine her endocrinologist prescribed (112 ug). The patient was monitored at baseline, between each dose and up to 3 hours after the procedure was completed. There were no incidents such as urticaria, angioedema, or others. On the second day, the patient received a single-full dose of 112 ug on an empty stomach. The medication was successfully tolerated and she was discharged. Thereafter, she tolerates daily Levothyroxine. PMID- 29999113 TI - [Acquired aplastic anemia during pregnancy. Report of one case]. AB - Aplastic anemia (AA) or acquired aplastic anemia is an uncommon and potentially fatal disease. It is defined as reduction of at least two peripheral blood series, associated with persistent bone marrow hypocellularity. It's association with pregnancy is even more uncommon, and it may result in high mortality for the mother and the child. We report an adolescent female with aplastic anemia, which worsened during pregnancy. Her hemoglobin was 5.2 g/dl, her leukocytes were 1,833/ul and her platelets were 19,000/ul. She was initially treated with cyclosporine and horse antithymocyte globulin without hematologic improvement. At 36 weeks of pregnancy methylprednisolone and platelet transfusions were used and a cesarean section was performed. Six month later she continues to require red blood cell and platelet transfusions. PMID- 29999114 TI - [Validation of the questionnaire "Evaluation of Chronic Disease Care for patients"]. PMID- 29999115 TI - [Forty years later: Return to Alma-Ata]. PMID- 29999116 TI - [Prognostic value of PET/CT in pancreatic cancer]. PMID- 29999117 TI - [Clinical and functional variables associated to long-term mortality in COPD patients]. PMID- 29999118 TI - [The joint effect of sitting time and obesity on the odds of developing type 2 diabetes]. PMID- 29999119 TI - [Comparison of the physical activity levels during the university life]. PMID- 29999120 TI - [Physical activity and health implications of the CicloRecreoVia program in Chile]. PMID- 29999121 TI - [Results of extended transsternal thymectomy for Myasthenia gravis. Experience with 58 patients]. AB - BACKGROUND: Thymectomy improves clinical outcomes and decreases the need for medical treatment in patients with myasthenia gravis (MG). AIM: To describe the immediate and long-term results of extended transsternal thymectomy (ETT) in patients with MG. MATERIAL AND METHODS: A review of databases, surgical protocols, clinical records and interviews of patients subjected to extended transsternal thymectomy for MG between 1990 and 2016. Perioperative clinical characteristics, anticholinesterase treatment, immediate and remote surgical results were analyzed and patients were followed from one to 10years. RESULTS: We studied 58 patients aged 35 +/- 14years (72%) women. In the preoperative period, according to Osserman classification, nine patients (15,5%) were in grade I, eight (13,8%) in grade IIA 8 and 40 (69%) in grade IIB. The pathological study of the surgical piece showed thymic hyperplasia in 39 cases (67,2%). Four patients had postoperative complications but none died. In the Follow-up at 1, 3, 5, 8 and 10years the Masaoka palliation rate was 71.7, 77.5, 67.7, 70.0 and 70,6% respectively. The figures for remission rate were 13.0, 15.0,19.4, 35.0 and 35,3% respectively. The figures for Zielinski positive results were 79.6, 87.5, 87.1, 90.0 and 82,4% respectively. The DeFilippi score improved by 80.4, 87.5, 87.1, 90.0 and 82.4% respectively. The Myasthenia Gravis Foundation of America Post Intervention State improved by 67.4, 77.5, 77.5, 75.0 and 70,6% respectively. Mean Myasthenia Gravis Activities of daily living (MGADL) and Myasthenia Gravis Quality of life scale 15 (MGQOL 15) were 1.65 and 6.31 respectively. CONCLUSIONS: In selected patients with MG, extended transsternal thymectomy in MG has good immediate and long-term results. PMID- 29999122 TI - [Symptoms during sleep among patients with obstructive sleep apnea]. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a frequent sleep-related breathing disorder being associated with cardiovascular, metabolic and neurobehavioral consequences. Most patients with OSAS are untreated because they are not timely diagnosed. AIM: to determine the association of sleep symptoms and body mass index in patients with OSAS diagnosed by polysomnography. MATERIAL AND METHODS: We studied 144 patients aged 47 +/- 14 years (75% males) in whom a polysomnography was done. These patients answered a sleep symptom questionnaire and the Epworth sleepiness scale. Their weight and body mass index was also recorded. RESULTS: Snoring and the presence of pauses during breathing were the symptoms with the higher sensitivity to predict the presence of OSAS. Body mass index was significantly higher among patients with OSAS. No differences in the Epworth scale were observed between patients with and without OSAS. CONCLUSIONS: Snoring and apneas while sleeping are symptoms that should lead to the suspicion of the presence of OSAS. PMID- 29999123 TI - [Screening depressive episodes in adolescents. Validation of the Patient Health Questionnaire-9 (PHQ-9)]. AB - BACKGROUND: There is a paucity of validated instruments for screening depression in adolescent populations in Chile. AIM: To determine the diagnostic accuracy of the adolescent version of Patient Health Questionnaire-9 (PHQ-9). MATERIAL AND METHODS: The PHQ-9 was transculturally adapted and administered to adolescents aged 15 to 19 years residing in Santiago de Chile, who were then evaluated with a semi structured interview (Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version or K-SADS-PL) and the Beck Depression Inventory. Internal validity, concurrent validity, and discriminatory power of the PHQ-9 were analyzed. RESULTS: We evaluated 245 adolescents aged 16.2 +/- 1 years (71% females). Two hundred and ten presented with a depressive episode and 35 were healthy. The sensitivity and specificity of the scale were 86.2 and 82.9% for 11 points, with a positive likelihood ratio of 5.02. CONCLUSIONS: The PHQ-9 is sensitive and specific enough to be used as a screening tool in adolescents with suspected depression. At a 11-point cut-off score as proposed, the likelihood to find a positive result in a subject with depression is five times higher. PMID- 29999124 TI - [Deaths due to oral cancer in Chile in the period 2002-2012]. AB - BACKGROUND: Oral cancer is the 15th most common cause of cancer death in the world. In Chile, 1% of all cancer deaths are related to oral and pharyngeal cancer. AIM: To determine mortality rates for oral cancer in Chile and its regions between 2002-2012. MATERIAL AND METHODS: Deaths and their causes between the years 2002-2012 were obtained from the Chilean National Statistics Institute. Crude and adjusted rates by age and sex were calculated for the country and its regions. The denominator was Chilean population on June 30, 2012 and the WHO standard population. RESULTS: In the period studied, 1,611 individuals with a mean age of 67.6 years (63% men) died because of oral cancer. The most common location of the tumor was the tongue in 27% of cases and the parotid gland in 16%. The adjusted mortality rate in Chile was 0.85 / 100,000 inhabitants (1.13 and 0.58 in men and women, respectively). The regions with the highest rates were Antofagasta (1.51), Aysen (1.22) and Magallanes (1.17). Deaths among men occurred at younger ages than women. CONCLUSIONS: Mortality rates due to oral cancer in Chile are lower than abroad. The highest rates observed in some regions may be influenced by environmental factors such as arsenic contamination in Antofagasta and the lack of specialists and specialized care centers in Aysen and Magallanes. PMID- 29999125 TI - [Psychiatric sick leave]. AB - There is no consensus amongst physicians, social security representatives and researchers about optimum sick leaves. This is an indication that should maximize positive outcomes and minimize potential side effects, both for the patient and society. The use of sick leaves during the last decade rose steadily, particularly in the psychiatric field. The most important causes of this increase are: changes in public policies, overuse of psychiatric diagnosis to cover up unmet social needs, and modifications to labour structure. It is analysed the impact that this situation has implied for physician patient relationship as well as for health budget. Even though sick leave diminishes presentism associated to a psychiatric disorder, published evidence about the effect of prolonged sick leave shows that damage overruns potential benefits: augmented morbidity and mortality, workplace phobia, economic loss, among others. PMID- 29999126 TI - [Sepsis hyperglycemia in the ICU: from the mechanism to the clinic]. AB - Stress hyperglycemia is frequently diagnosed in septic patients in critical care units (ICU) and it is associated with greater illness severity and higher morbimortality rates. In response to an acute injury, high levels of counterregulatory hormones such as glucocorticoids and catecholamines are released causing increased hepatic gluconeogenesis and insulin resistance. Furthermore, during sepsis, proinflammatory cytokines also participate in the pathogenesis of this phenomenon. Septic patients represent a subtype of the critical ill patients in the ICU: this metabolic disarrangement management strategies and insulin therapy recommendations had been inconsistent. In this article, we describe the pathophysiological mechanisms of stress hyperglycemia in critical patients including the action of hormones, inflammatory cytokines and tissue resistance to insulin. In addition, we analyzed the main published studies for the treatment of acute hyperglycemia in critical patients. PMID- 29999127 TI - [Involuntary psychiatric hospital admissions]. AB - The United Nations Convention on the Rights of Persons with Disabilities Article 12 General Commentary, explicitly states that persons with mental illnesses must always have full exercise of their legal rights in all their aspects. Assistants or support persons must not substitute or have undue influence on the decisions of persons with disabilities, including the expression of their consent. However, the number of involuntary psychiatric hospitalizations appears to be increasing globally and in our country. This article reviews the national and international context of involuntary hospitalizations, including the Chilean legislation and administrative rules, the published evidence about patients' outcomes and clinician attitudes. The authors conclude that the conflict in this issue is not limited to the respect for autonomy and the obligation to provide care. We are now experiencing a new way of caring patients. The complex local, social and cultural realities, require a renewed knowledge and documentation of experiences. PMID- 29999128 TI - [Partial disclosure of information in the presence of presumable nocebo effects: an ethical analysis]. AB - When prescribing a treatment, the physician should give truthful information about the likely benefits and the potential adverse effects, allowing the patient to make an autonomous decision about whether to take the treatment. However, the mere expectation of adverse effects may precipitate the corresponding symptoms. This is called "nocebo effect", which in contrast to the placebo effect, can lead to harm to the patient due to psychological factors. Nocebo effects are common and clinically significant, although often unnoticed. This situation generates conflicts in medical ethics guiding principles, namely the moral obligation to disclose all possible effects of the prescribed drug as opposed to the duty of avoiding the harm of side effects that are likely to occur in a case. In other words, the physician faces a dilemma between the due respect for autonomy and the duty of non-maleficence. This article reflects about this conflict, by exploring the limits of the principle of autonomy and how to balance it with the principle of non-maleficence. We suggest an interpretation of the principle of autonomy from a patient-centered perspective, suggesting that it is ethically sound to give a prudential, partial disclosure of information to the patient, for the sake of avoiding potential nocebo effects. The article concludes with some cautionary considerations to be considered about this decision. PMID- 29999129 TI - [Toxic epidermal necrolysis during a hemophagocytic syndrome secondary to Hodgkin lymphoma. Report of one case]. AB - Toxic epidermal necrolysis (TEN) is a lethal entity, characterized by extensive epidermal necrosis and multiorgan failure. Hemophagocytic syndrome (HFS) is also a rare and lethal syndrome characterized by hyperinflammation that leads to the appearance of fever, pancytopenia, organomegaly and hemophagocytosis. The concomitance of these diseases is extremely uncommon. We report a 38 years old female, who during the course of a HFS secondary to Hodgkin Lymphoma (HL), presented a TEN secondary to antibiotics. She was admitted due to a consumptive syndrome, lymphadenopathy, visceromegaly and severe pancytopenia. Laboratory and bone marrow tests confirmed HFS. Due to constant fever, imipenem was indicated. On the third day she started with pain and skin rash. She evolved with positive Nikolsky sign. Cutaneous biopsy was concordant with extensive TEN, which was managed with intravenous immunoglobulin and dexamethasone. A complete response and normalization of the blood count were achieved. Finally, the lymph node biopsy showed HL of mixed cellularity type, which was managed with 8 cycles of ABVD chemotherapy, achieving complete remission. PMID- 29999130 TI - [Hemoptysis as the initial manifestation of Behcet's disease. Report of two cases]. AB - Arterial involvement in Behcet's disease (BD) is less common than venous lesions. The most commonly affected arteries are: the aorta, lower extremity arteries, mesenteric, femoral, coronary, renal, subclavian and pulmonary arteries. The rupture of pulmonary arteries is the main cause of death of patients with EB and the presence of aneurysms is a bad prognostic factor. We report two patients with arterial involvement in BD. A 14 years old male presenting with hemoptysis lasting three days. A chest computed tomography showed an aneurismal dilatation of the right interlobar artery, bilateral intramural thrombi and alveolar hemorrhage. A right lobar pulmonary resection was performed but hemoptysis recurred. Suspecting a BD, prednisone was started and hemoptysis subsided. A 42 years old male presenting with chest pain and hemoptysis. A chest CT scan showed thrombi in pulmonary veins and anticoagulant therapy was started. Two months later he was admitted again due to a massive hemoptysis. The CT scan showed aneurisms in pulmonary arteries, mural thrombi and pulmonary infarction. With the diagnosis of BD, methylprednisolone, followed by prednisone and cyclophosphamide were used, with a good clinical response. PMID- 29999131 TI - [Oligoarthritis, panniculitis and pyoderma gangrenosum associated with non Hodgkin lymphoma. Report of one case]. AB - An assortment of clinical and laboratory abnormalities may occur as paraneoplastic syndromes in lymphomas. Rheumatological and dermatological manifestations such as paraneoplastic arthritis and pyoderma gangrenosum must be underscored. We report a 28 years old woman who developed pyoderma gangrenosum and two years later presented with arthritis of knees and ankles associated with panniculitis interpreted as erythema induratum that was pathologically confirmed. She developed a reactivation of pyoderma gangrenosum, that was refractory to treatment. Complementary studies showed a pulmonary nodule and a right paravertebral mass with involvement of the psoas muscle. Biopsies of both masses and a new pathological skin study demonstrated a large B-cell non-Hodgkin's lymphoma. PMID- 29999132 TI - [Teaching and evaluating empathy in clinical practice]. PMID- 29999134 TI - [The new inmigration wave in Chile. An opportunity for growing]. PMID- 29999133 TI - [Intercultural communicative competence: a challenge for health care professionals in Chile]. PMID- 29999135 TI - [Update on management of cow's milk protein allergy: Available milk formulas and other juices]. AB - Cow's milk protein allergy (CMPA) is a common disease with a prevalence of 2-7%, increasingly so. It is characterized by an allergic reaction to one or more cow's milk proteins. There are not pathog nomonic clinical symptoms, and these will depend on the type of immune reaction involved. A good diagnostic approach avoids under and over diagnosis and, therefore, under and over treatment. The CMPA treatment is the elimination of cow's milk protein from the diet. A restricted diet in a child does not require it or who has developed tolerance can alter growth, quality of life, including unne cessary costs. The objective of this review is to present the different milk formulas available in Chile to treat CMPA in those cases where breastfeeding with exclusion diet is not possible. For this purpose, nutritional composition, ingredients and other relevant characteristics of all the milk formulas and juices marketed in Chile as CMPA treatment were reviewed. The information was obtained from the official distributors or sellers or failing that, from the official websites. There are multiple milk formulas and beverages used for the treatment of CMPA, and not all of them are nutritionally or immunologically secure. Knowing them in detail will help the pediatrician to indicate them in a more informed way according to their benefits and their deficiencies for the proper management of this pathology. PMID- 29999136 TI - [Association of health-related quality of life and suicidal risk in adolescents: A cross-sectional study]. AB - INTRODUCTION: Health-related quality of life (HRQoL) deterioraton is a risk factor for suicide in adults, however, this aspect has been little studied in adolescents. OBJECTIVE: To evaluate the asso ciation between HRQoL (measured with EQ-5D-5L) and suicidal risk in adolescents and its capacity for cross-sectional detection of suicidal risk. PATIENTS AND METHOD: 128 adolescents (15-19 years old) from Puerto Aysen (Chile) responded to the EQ-5D-5L questionnaire, the Okasha Suicide Scale and two anchoring questions of imminent suicide risk. A suicide risk case was considered to have a > 5 score on the Okasha scale or the affirmative answer to one of the anchoring questions. The index value of EQ-5D-5L was calculated and Odds Ratios (ORs) were estimated with confidence intervals (95% CI), adjusted for confounders. Areas under the ROC curve (AUC-ROC) were calculated to assess the discriminatory performance of EQ-5D-5L. RESULTS: 21 (16.4%) adolescents were at suicidal risk. Controlling for confounders, the EQ-5D 5L dimensions associated with suicidal risk were pain/ discomfort (OR: 2.5; 95% CI 1.1-6.1) and anxiety/depression (OR: 2.2; 95% CI 1.3-3.6). The AUC- ROC for both dimensions was 85% (95% CI 0.75-0.91) and 81% for the EQ-5D-5L index value (95% CI 0.72-0.89). CONCLUSIONS: HRQoL could be a risk factor for suicide in adolescents and in this way, the EQ-5D-5L could help in searching for high risk and hidden cases of suicidal risk. PMID- 29999137 TI - [Weight decrease in full-term newborns in the first 48 hours post natal]. AB - INTRODUCTION: It is known that the newborn (NB) presents weight loss immediately after birth. The magnitude of the weight loss is a controversial subject and there are no data in our sphere. Objecti ves: To determine the percentage of daily weight decrease in healthy full-term newborns in the first 48 hours of life. To specify whether factors such as gender, type of delivery, adequacy for gestational age, and use of milk formula influence weight loss. PATIENTS AND METHOD: Prospective study in healthy full-term newborns with > 37 weeks of gestational age during their stay in the nursery (puerperium). Weight data were collected at birth, 24 and 48 hours after birth, and the percentages of weight loss were calculated from the daily nursing record. In addition, gender, type of delivery, adequacy to the birth and type of feeding of the NB, either exclusive breastfeeding, artificial formula or mixed (breast milk and formula) were recorded. To standardize the measurements, weights were expressed in grams and subsequently the percentage of weight loss was calculated in relation to the birth and the previous day. The maximum percentage of weight loss per day variable was analyzed. A multivariate regression model was performed for the weight loss percentages evolution. RESULTS: 2960 NB were analyzed. The average weight loss on the first day was 4.43% (SD: 1.96), the second day 2.51% (SD: 1.86) and the total loss at 48 hours was of 6.85% (DS: 1.92). The determining factor in weight loss was the type of delivery. The NBs by cesarean section showed a greater weight loss in the first 24 to 48 hours. The use of milk formula determines a smaller weight loss in the NB compared with those fed with breast milk (BM). CONCLUSIONS: The percentage of weight loss per day of the NB in our center is similar to that reported in the international literature. Cesarean delivery is the factor associated with greater weight loss. The use of milk formula results in less weight loss. PMID- 29999138 TI - [Spirometric caracterization of cystic fibrosis patients]. AB - INTRODUCTION: The prognosis of patients with cystic fibrosis (CF) has remarkably improved. The as sessment of the disease progression is based on the measurement of the FEV1 (Forced Expiratory Volume in one second). OBJECTIVES: 1. To describe forced expiratory flows and volumes and com pare their interpretation according to different reference standards (Knudson, Gutierrez, and multi ethnic GLI); 2. To describe bronchodilator response. PATIENTS AND METHOD: The medical records and spirometries of all patients with CF controlled at the Dr. Sotero del Rio Hospital were reviewed. Demographic background, sweat test results, genetic study , and bacteriological study were obtained. In addition, Forced Vital Capacity (FVC) was recorded as well as FEV1 and FEV1/FVC ratio. Re sults: Data from 14 patients, were analyzed, seven males, aged 6-24 years, median 15 years, median BMI 18.15 (range 14.6-23.3), median sweat chloride test 76 mEq/l (range 50,2-119 mEq/l), seven patients with at least one F508del mutation. Using multi-ethnic and Gutierrez predictive formulas, lung function involvement occurred previously in relation to the use of Knudson equations. None of the patients had a significant bronchodilator response. CONCLUSION: The group of patients descri bed mostly presents functional respiratory involvement and had no bronchodilator response. The interpretation of functional respiratory involvement varies according to the theoretical values used. PMID- 29999139 TI - [Description of capsule endoscopy use in a pediatric public hospital]. AB - INTRODUCTION: Capsule endoscopy (CE) is a non-invasive technique that allows visualization of small intestine mucosa. It is used for diagnosis of lesions not accessible with other tests. Our goal was to describe the experience using CE in a pediatric public hospital in Chile. PATIENTS AND METHOD: A retrospective study was carried out to review the cases in which CE was used at Dr. Luis Calvo Mac- kenna Hospital from 2010 to date. Demographic and clinical data, findings, complications, diagnosis and treatment were recorded. RESULTS: Twenty procedures were performed in 16 patients, 11 men (69%), median age 12 years (range 3 to 15 years). Indications included polyposis study (60%), sus pected Crohn disease (20%), obscure gastrointestinal bleeding (15%) and undiagnosed anemia (5%). Seventeen studies were altered (85%) and 11 led to a diagnosis or clinical behavior change (55%). There were no complications. CONCLUSIONS: CE is a useful and safe technique in children, feasible to perform in a pediatric public hospital. PMID- 29999140 TI - [Proinflammatory state in obese children]. AB - INTRODUCTION: Obesity is a chronic disease that affects adults as well as children and is associated with insulin resistance, type 2 diabetes and cardiovascular disease. One of the reasons for the presence of low-grade inflammation in these patients could be that adipose tissue of the obese produces proin flammatory molecules that favor the development of atherosclerosis. OBJECTIVE: To determine serum levels of soluble CD40 ligand (sCD40L), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), Tumor Necrosis Factor alpha (TNF-alpha) and high sensitivity CRP (hsCRP), in an obese chil dren population compared to a control group, also to analyze the correlation of these molecules with the anthropometric and metabolic variables. PATIENTS AND METHOD: A cross-sectional, observational study was carried out on 37 obese children, aged 8 to 12 years, and 20 children with normal weight. Serum levels of sCD40L, MCP-1, IL-6, TNF-alpha and hsCRP were determined. Data were expressed as the median and interquartil range and Spearman coefficient was used to investigate correlations between variables. RESULTS: Compared to the control group, obese children presented significantly higher values of sCD40L, MCP-1, IL-6, TNF-alpha, and hsCRP than control group. Body mass index and waist circumference correlated positively with sCD40L and MCP-1. CONCLUSION: Elevated levels of the studied molecules studied suggest the presence of low-grade inflammation associated with obesity in this population. PMID- 29999141 TI - [Grooming, Cyberbullying and Sexting in Chile according of sex and school management or administrative dependency]. AB - INTRODUCTION: Children, teenagers and young men are increasingly experiencing their well-being related to the internet and the new digital technologies. The objective of this study is to describe the presence of Cyberbullying, Sexting and Grooming in students in Chile according to gender and type of school management or administrative dependency. SUBJECTS AND METHOD: Exploratory and descriptive study. The sample design was non-probabilistic by quotas in 60 transactional establish ments. The sample was weighted considering the age range and gender according to national data. The Digital Literacy Questionnaire "Divergente SerDigital" (2010) was applied to a sample of 12,926 students, aged 5 to 18 years. 4,790 men and 8,136 women. Average age 13.17 years. Frequencies were analyzed and the Chi-squared contrast statistic was used to determine statistically significant differences. RESULTS: The item Total Grooming (cheating) is presented as the main risk, 12.6% in municipal dependent schools (MDS), 8.2% in subsidized private schools (SPS), and 8.4% in private schools (PS). When considering gender, Grooming is observed mainly in Men, 20.4% in MDS, 19.9% in SPS and, 16.9% in PS. It is noteworthy that Women perform less Cyberbullying (active) according to school administration with 4.2% in MDS, 2.4% in SPS and, 2.6% in PS, with statistically significant differences (p < 0.05) in relation to Men. It also highlights the indicator Sexting (send) in Men, higher in PS with 10.6%. CONCLUSION: Grooming, Cyberbullying and Sexting risks are presented in the three types of administration with specific characteristics. These data can be a guide to work in promotion and prevention as well as in the schematization of cases according to type of school administration. PMID- 29999142 TI - [Cardiac Magnetic Resonance in long term follow-up of Tetralogy of Fallot]. AB - INTRODUCTION: Tetralogy of Fallot (TOF) is the most frequent cyanotic congenital heart disease. Pulmonary regurgitation (PR) and right ventricle (RV) enlargement and dysfunction are the most common long-term complications. Cardiac magnetic resonance (CMR) is the gold standard for RV evaluation. OBJECTIVE: To analyze CMR results in the follow-up of TOF patients. PATIENTS AND METHOD: All CMR performed between 2007 and 2012 in TOF patients with transannular patch (TAP) repair or infundibular widening, and without pulmonary valve replacement (PVR) were included. Pulmonary regurgitant fraction (PRF), ventricular end-diastolic (EDV) and end-systolic volume (ESV), and ejection fraction (EF) were examined. RESULTS: 122 CMR were performed in 114 patients. Average age at CMR was 15.4+/-7.4 years. 53.3% of them presented severe PR (> 40%). RVEDV was 157.3 +/- 38.6 ml/m2, RVESV was 85.3 +/- 27 ml/m2 and RVEF was 46.4 +/- 7.1%. RVEDV was > 150 ml/ m2 in 48.4% and > 170 ml/m2 in 32.8% of patients. Patients with TAP showed larger RV volumes compared with those with infundibular widening. RVEDV > 170 ml/m2 showed worse RVEF that those with lower RVEDV (47.9 +/- 7% vs 43.2 +/- 6.4%, p < 0.01). CONCLUSION: Almost half of the pa tients showed significant RV enlargement, demonstrating that the indication of CMR is late in their follow-up. TAP was associated with higher RVEDV and RVESV, but no worse RVEF. PMID- 29999143 TI - [Iatrogenic Cushing's syndrome in a infant due to prolonged use of topical corticosteroids. Case report]. AB - INTRODUCTION: Cushing's syndrome (CS) is an endocrine disease by to glucocorticoids excess, depen dent or independent of adrenocorticotropic hormone (ACTH). The main cause is iatrogenic due to excessive use of glucocorticoids. OBJECTIVE: To show the association between prolonged use of topical corticosteroids and the development of CS. CLINICAL CASE: An infant treated with topical corticosteroids due to seborrheic dermatitis. Due to long-term unsupervised use, he develops Cushing's syndrome characterized by obesity and compromised growth rate. Topical use of corticosteroids was discontinued and physiological replacement therapy was initiated with descending doses, achieving clinical improvement. DISCUSSION: Topical corticosteroids are widely used in clinical practice for management of dermatological pathologies. These are available in various presentations with va riable efficiency. The main determining factors in its action are the characteristics of the skin, the active principle of the drug, the potency and application technique, so that the adverse effects are observed more frequently in the use due to diaper dermatitis. The main adverse effect of long-term use is Cushing's syndrome which can be prevented through supervised use and progressive decrease. CONCLUSION: The rational and careful use of topical corticosteroids is essential to take advantage of the beneficial effects and avoid adverse effects. PMID- 29999144 TI - [Beta-hCG-producing thymic teratoma: an uncommon cause of peripheral precocious puberty]. AB - INTRODUCTION: Among the causes of peripheral precocious puberty in men are the beta-human cho rionic gonadotropin (Beta-HCG)-secreting tumors, such as hepatoblastomas, dysgerminomas, chorio carcinomas, and immature teratomas. In pediatrics, the mediastinal teratomas are rare, representing the 7-10% of extragonadal teratomas. OBJECTIVE: To describe the case of a patient with peripheral precocious puberty due to a Beta-HCG -secreting thymic teratoma. CLINICAL CASE: A seven-years-old schoolboy presents a three-months history of voice changes, gynecomastia, pubic hair appearance, and increased genital volume. In the exams, bone age of nine years, total testosterone 9.33ng/ml (< 0.4ng/ml), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), and normal adrenocorticotropic hormone (ACTH) test stand out; luteinizing hormone (LH) and follicle stimulating hormone (FSH) with low basal levels, Beta-HCG 39.5mU/ml (< 2.5 mUI/ml), alpha feto protein (alpha-FP) 11,2ng/ml (0.6-2.0 ng/ml). Imaging study to determine the origin of Beta-HCG secretion shows normal testicular ultrasound and thoracic, abdominal, and pelvic computerized axial tomo graphy (CAT); brain and sellar resonance without significant findings. The positron emission tomography/computed scan (PET SCAN) shows a tumor image in the anterosuperior mediastinum. The tumor is resected, and the biopsy shows an immature cystic teratoma in the thymus. Post-operatory evolution was satisfactory, with normalization of hormonal levels. CONCLUSION: The appearance of a teratoma in a pediatric patient is rare, even more if it is immature, with thymic location and P-HCG- secretor. It is important to consider it within the differential diagnosis facing precocious puberty, as a better way to handle appropriately. PMID- 29999145 TI - [Onychomadesis secondary to hand-foot-mouth disease: a frequent manifestation and cause of concern for parents]. AB - INTRODUCTION: Nail alterations in children are an important cause of parent anxiety and derive in multiple and unnecessary consultations. The onychomadesis corresponds to the complete and pain less detachment of the nail plate from the proximal fold. This self-resolving nail finding has been described as a late complication of hand-foot-mouth disease, a frequent viral exanthema in the pedia tric age. OBJECTIVE: To describe a classic pediatric case of hand-foot-mouth disease with subsequent onychomadesis. CLINICAL CASE: A 3-years-old male patient with an acute presentation of acute erythe matous perioral papulovesicles, which extend to upper extremities and hands, buttocks, thighs and feet, asymptomatic, and without compromising general condition. Skin lesions resolve completely, but after one month, he develops detachment of the nails, with subsequent complete recovery. Con clusions: The recognition of this association will allow primary care physicians to guide the parents about a benign and self-resolving process that may occur as part of the evolution of hand-foot-mouth disease, thus avoiding unnecessary anxiety, referral and treatments. PMID- 29999146 TI - [Propofol Infusion Syndrome in a refractory epileptic status case]. AB - INTRODUCTION: Propofol Infusion Syndrome (PRIS) is a rare but potentially lethal adverse reaction secondary to the continuous intravenous infusion of this drug. The diagnosis is based on the com bination of metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, hyperli pidemia, arrhythmias, and rapidly progressive heart failure. OBJECTIVE: To report a case of PRIS and literature review. CLINICAL CASE: A 6-year-old female patient with history of epilepsy secondary to large malformation of cortical development of the right hemisphere. The patient presented a refractory status epilepticus that required admission to the Intensive Care Unit for life support and treatment, which included continuous intravenous infusion of propofol at 10 mg/kg/h. She developed hemo dynamic instability, and after 24 h of treatment an increase of creatine phosphokinase (CPK) levels, metabolic acidosis and elevated lactacidemia were observed. After ruling out other causes, PRIS was diagnosed; therefore, the drug was suspended, achieving hemodynamic stabilization after 24 hours. DISCUSSION: The diagnosis of PRIS is complex and should be considered in patients who are receiving this drug and present metabolic acidosis or heart failure. The factors that most influence mortality are the cumulative dose of the drug, the presence of fever, and cranial brain injury. In the case described, the patient received a dose higher than 4 mg/kg/h, which is the maximum recommended dose, and responded favorably 12 hours after stopping the drug. PMID- 29999147 TI - [Psychosocial impact of type 1 diabetes mellitus in children, adolescents and their families. Literature review]. AB - Type 1 diabetes mellitus is the most common chronic endocrine pathology among children. Treatment includes diet, physical activity, insulin medication, and proper self-control. This self-control may be difficult, resulting in children, adolescents and their families suffering diverse psychosocial complications. There is an inverse relationship between self-control and psychosocial complications, the main problems being anxiety and depression, where adolescents are 2.3 times more likely to have mental health problems. Families are initially affected, in the debut period by a state of shock, with feelings of distress and anger. The necesary changes in habits and lifestyles can lead to psychosocial problems, including anxiety, depression and eating disorders. Subsequently, the child or adolescent and his or her family group may move into new balance characterized by good self-control and adherence to tratment, or deepen individual and group disorders which may reappear, especially in adolescence. The comprehensive treatment of type 1 diabetes mellitus requires addressing these aspects through multidisciplinary teams which include medical and phychosocial professionals. This review analyses the main aspects related to the psychosocial impact of diabetes mellitus type 1 among children, adolescents and their families. PMID- 29999148 TI - [Collagen VI related myopathies. When to suspect, how to identify. The contribution of muscle magnetic resonance]. AB - Myopathies secondary to collagen VI mutations (COLVI-M) are the most frequent in the northern hemisphere, affecting the adult and pediatric population. There are no data on its prevalence in Latin America. They are characterized by a great clinical variability, from severe phenotypes, such as Ullrich congenital muscular dystrophy (UCMD), to intermediate and mild ones such as Bethlem myopathy (BM). Its onset is also variable and extends from the neonatal period to adulthood. Given the presence of joint hypermobility, the differential diagnosis should be made with various connective tissue diseases. The classical diagnostic algorithm in many patients has been insufficient to guide the genetic study in an adequate way, and from this the muscular magnetic resonance imaging has emerged as a very useful tool for a better diagnostic approach of this and other muscular pathologies. This ob jective of this review is to study the forms of presentation, clinical characteristics, specific diagnostic study, differential diagnosis and management of one of the most frequent hereditary muscular patho logies, with emphasis on the contribution of muscle magnetic resonance imaging. PMID- 29999149 TI - [Contrast-enhanced spectral mammography. Experience in 465 examinations]. AB - BACKGROUND: Contrast-enhanced spectral mammography or "contrast mammography" has a better cost effectiveness than breast magnetic resonance for confirmation of suspicious lesions detected on breast screening programs. AIM: To report the experience of a single center in Santiago. MATERIAL AND METHODS: All patients referred for contrast mammography between July 2015 and October 2017 were studied. We recorded the patient risk factors for breast cancer. In 85 patients with suspicious lesions, biopsy results were available. RESULTS: We analyzed 465 contrast mammographies. The most common clinical indications were suspicion of cancer and previous inconclusive studies. Mass type lesions were detected in 33% of the studies. Non-mass-type lesions were observed in 10% of cases and findings compatible with papillomatosis in 2%. Fifty five percent of the studies had no visible lesions. In the 85 patients with a pathological study of the biopsy, the sensitivity of the contrast mammography was 100%, with a diagnostic accuracy of 85%, positive and negative predictive values of 82 and 100% respectively. CONCLUSIONS: Contrast mammography can be of great use for the assessment of patients with an altered conventional mammography, before indicating a magnetic resonance imaging or a percutaneous biopsy. PMID- 29999150 TI - Smoking promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients. AB - BACKGROUND: The dual potential to promote tolerance or inflammation when facing self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. There is an association between smoking and DCs maturation in patients with rheumatoid arthritis (RA). However, ethnicity is a key factor in autoimmune disorders. AIM: To evaluate phenotypic and functional alterations of DCs obtained from Chilean patients with RA as compared to healthy controls (HC). In second term, to compare the inflammatory behaviour of DCs between smoker and non-smoker patients. MATERIAL AND METHODS: Monocyte-derived DCs and T-cells were obtained from blood samples isolated from 30 HC and 32 RA-patients, 14 of which were currently smokers and 18 non-smokers. Several maturation surface markers were evaluated in DCs, including HLA-DR, CD40, CD80, CD83 and CD86. Furthermore, autologous co-cultures of DCs and T-cells were carried out and then T-cell proliferation, and expansion of Th1, Th17 and Tregs were analysed. RESULTS: Compared with HC, RA-patients displayed increased HLA-DR expression in DCs, which was manifested mainly in patients with moderate-to- high disease activity scores (DAS28). Furthermore, RA-patients presented a stronger Th17-expansion and a correlation between DAS28 and Th1-expansion. Both effects were mainly observed in patients in remission or with a low DAS28. Moreover, smoker RA-patients displayed enhanced HLA-DR and CD83 expression in DCs as well as an exacerbated Th17 expansion and a correlation between DAS28 and Th1-expansion. CONCLUSIONS: These findings suggest that smoking enhances the inflammatory behaviour of DCs and the consequent Th1 and Th17-mediated response in patients with RA. PMID- 29999151 TI - [Evaluation of clinical communication skills in medical students with simulated patients]. PMID- 29999152 TI - [Pattern of smoking and socioeconomic status in two cohorts of young adults]. AB - BACKGROUND: One in five deaths that occur in Chile can be attributed to smoking whose prevalence remains high, despite interventions aimed at reducing it. AIM: To compare the prevalence of smoking and its intensity among young adults born 15 years apart and determine their association with socioeconomic status (SES). MATERIAL AND METHODS: Two cohorts of young adults living in the Valparaiso Region of Chile were evaluated in the third decade of life. Cohort 1 was evaluated between 2000 and 2002 (n = 1232) and cohort 2 between 2014 and 2017 (n = 1078). RESULTS: In cohort 1, 57.5% (95% Confidence Interval (CI) 54.6-58.7) of the subjects reported smoking, with a median of 3 (Interquartile range (ICR:1-6) cigarettes/day. This percentage fell to 40.2% (CI: 37.5-43.1) with a similar median in cohort 2. Analyzing cohort 2, the odds ratio (OR) for smoking was 2.24 (CI 1.48-3.38) in the medium SES, compared with the medium high SES. The figures for low medium and low SES were 2.72 (CI: 1.85-3.99) and 3.01 (1.85-4.88). Similarly, in this cohort there was a significantly higher risk of being a heavy smoker in lower SES. No associations between smoking or its intensity and SES were observed in cohort 1. CONCLUSIONS: Smoking behavior has decreased among young adults evaluated at the same age in two generational cohorts in the third decade of life. In the most recent cohort analyzed, smoking and its intensity increase along with a decrease in SES. PMID- 29999153 TI - [Acquired aplastic anemia. Experience in a public hospital]. AB - BACKGROUND: The first line treatment for patients < 40 years old with aplastic anemia (AA) is allogeneic HLA-identical sibling donor transplantation (SCT). Immunosuppressive therapy (IST) with a combination of Thymoglobuline (ATG) and cyclosporine is used for older patients or those without a donor. Five year overall survival (OS) for both therapies is > 70%. AIM: To report the experience with SCT and ATG for AA in a public hospital. PATIENTS AND METHODS: AA was diagnosed in 42 patients between 1998 and 2016, according to Camitta criteria. Thirty eight (90%) received treatment, 7 (18%) under 40 years old received SCT, and 31 (82%) IST. The rest were not treated. OS was calculated from date of diagnosis until last control, death or loss from follow up. RESULTS: Complete or partial hematologic response, was obtained in 71% and 58% of cases with SCT and IS, respectively. Five year OS was 71% and 55% with SCT and IST, respectively. No difference in response was observed between horse and rabbit ATG. CONCLUSIONS: SCT from an HLA-identical sibling donor had a high response rate and survival. IST instead, had a lower response and survival, due to an initial high mortality rate. PMID- 29999154 TI - [Outcome of surgery for Crohn's colitis. Review of 28 cases]. AB - BACKGROUND: Exclusive involvement of the colon or rectum in Crohn's disease, called Crohn's colitis, (CC) occurs in about 25% of these patients. AIM: To analyze early surgical results and long-term outcomes of patients undergoing surgery for CC. MATERIAL AND METHODS: Review of a prospective database, identifying patients with Crohn's disease operated between 2003 and 2015 and excluding those with ileocecal disease. We analyzed demographic data, pre and postoperative pharmacological treatment, operations, morbidity and the need for a second bowel resection at follow-up. RESULTS: We reviewed data from 28 patients aged 17 to 72 years (15 men). Twenty-seven (96.4%) had previous pharmacological treatment, 11 received monoclonal antibodies. The most common indications for surgical treatment were failure of medical treatment in 15 cases, acute severe colitis in 12 and anemia/malnutrition in eight. Total colectomy was performed in 17 (61%) patients, proctocolectomy in 8 (29%) and segmental colectomies in 3 (11%). Sixteen (57%) were operated laparoscopically. Major postoperative complications were observed in 5 (18%). Four needed a reintervention. There was no operative mortality. During a 55 months median follow-up of 27 patients, seven (26%) required a second bowel resection, one of them for recurrence. Nineteen (70%) patients had an ostomy, which was permanent in 11. Fifteen patients are without medical treatment. CONCLUSIONS: Most of the reviewed patients required total colectomy for the control of the disease with a low surgical morbidity. Two thirds required an ileostomy, which became permanent in half of them. PMID- 29999155 TI - [Reliability of an automatic monitor for blood pressure measurement]. AB - : Background A correct blood pressure (BP) measurement is essential for the diagnosis and control of high BP. AIM: To evaluate the agreement and repeatability of BP measurements with the OMRON HEM-7320-LA device compared to a mercury sphygmomanometer. MATERIAL AND METHODS: A cross-sectional study comparing BP measurements made by two randomly selected trained nurses and an automatic oscillometric device. The mercurial sphygmomanometer was connected to the automated device via a "T" type connector and a dual-head stethoscope was used, allowing simultaneous measurements. The results were analyzed with one-factor analysis of variance, Bland-Altman's test, repeatability coefficient (RC), and intra-class correlation coefficient (ICC). RESULTS: Forty-nine participants aged 56 +/- 19 years were included. Nineteen had hypertension (38%). We did not observe a significant difference in either systolic (SBP) or diastolic blood pressure (DBP) pressure measurements between the observers and the device. The mean difference was -0.09 mmHg (95% confidence intervals (CI)-0.9 to 0.7) for SBP and -0.9 mmHg (95% CI -1.7 to -0.13) for DBP. The RC for SBP (6.2, 5.2 and 5.8 mmHg) and DBP (4.7, 4.2 y 5.2 mmHg) was similar between the observers and the device. The ICC for SBP was 0.990 (95% CI 0.983 to 0.995, p < 0.01) and 0.986 (95% CI 0.977 to 0.991, p < 0.01) for DBP. CONCLUSIONS: There was a high level of agreement and similar measurement repeatability in the measurements performed by the automatic device and the mercurial sphygmomanometer. No differences in BP measurements were observed. PMID- 29999156 TI - [Thoracic trauma. Experience of three decades]. AB - BACKGROUND: Trauma is the leading cause of death in young patients and thoracic trauma (TT) is responsible for 25-35% of trauma deaths. AIM: To describe and compare features, trauma severity indexes and morbidity of patients admitted for TT in the past three decades. MATERIAL AND METHODS: Review of a TT database, operative notes and medical records of patients. These were separated by decade of admission (1981-1990, 1991-2000, 2001-2010). TT characteristics were compared. Injury Severity Score (ISS), Revised Trauma Score (RTS-T) and Trauma Injury Severity Score (TRISS) were calculated. RESULTS: A total of 3,068 TT were reviewed. In the 1981-1990 period, 604 cases of TT were registered (19.7%), in the 1991-2000 period, 1,070 cases (34.9%) and in the 2001-2010 period, 1,394 cases (45.4%) (p < 0.05). The ages of patients in each of these periods were 34.9 +/- 15.5, 33.9 +/- 16.2 and 35.7 +/- 18.2 years respectively (p < 0.05). The proportion of patients aged 65 years or more were 6.6, 7.7 and 10.1% respectively, the proportion of females was 6.1, 9.4 and 12.0%, respectively. The causing agents per decade were knife wounds in 51.5, 61.1 and 60.0% of cases respectively, firearms in 2.5, 3.3 and 5.0% of cases respectively, multiple trauma in 13.9, 14.5 and 9.0% respectively and morbidity in 18.7, 19.7 and 11.7%, respectively. The ISS per decade was 11.9 +/- 6.5, 12.9 +/- 6.9 and 10.4 +/- 6.8 respectively. No significant difference were found in mortality (1.5, 3.0, 2.0% respectively) or TRISS score (2.7, 3.2 and 3.8% respectively). CONCLUSIONS: An increase in the number of hospital admission for TT has occurred in the last three decades, with an increase in the proportion of admissions of subjects aged 65 years or more, females and with firearm injuries. PMID- 29999157 TI - [Predatory journals: a new threat to scientific publications]. AB - The goal of the Open Access movement is to promote free access to scientific literature. From its creation in the nineties it has been a fundamental support to the democratization of knowledge. In the last years, however, a new fraud model has been detected: journals that use open access publications as "Predatory Journals", which do not fulfill minimal quality standards and profit with the model. To inform the Latin American community about such editorial malpractice, we have reviewed the literature about this issue, aiming to explain what predatory journals are, how to detect them and how they contact authors. One of this article's main conclusion is that students, academics and researchers need to develop skills to recognize this or any other kinds of publication fraud. PMID- 29999158 TI - [Workplace violence among health care workers]. AB - The aim of this review is to describe and to analyze scientific reports about occupational violence in the health area. A systematic review of the literature on Academic Search Complete (EBSCO Host), Medline, Pubmed, Scielo, Scopus and Web of Science was performed and 23 articles were selected for analysis. Most studies are quantitative, measuring workplace violence and its consequences, including multi-stratum samples. They mainly measure psychological and external violence and their subjects are hospital workers. Violence is conceived as coming from organizational dimensions. Facilitators of violence are related to the nature of the job and the most commonly studied consequences are related to mental health. The main consequences of the phenomenon are depressive symptoms, post-traumatic stress disorder (PTSD) and work stress. The nature of the job as a facilitator of violence relates primarily to the place of work and to the profession. Most of the studies are carried out with multi-stratum samples and combine workers from different services. However, studies in psychiatric services and with nursing staff are also common. PMID- 29999159 TI - [Exposure to nitrates in drinking water and its association with thyroid gland dysfunction]. AB - BACKGROUND: Nitrate exposure may be associated with thyroid gland dysfunction. AIM: To review the available evidence about the relationship between nitrates in drinking water and thyroid gland dysfunction. MATERIAL AND METHODS: A wide search was performed using Medline, Cochrane, Lilacs, IBECS and Scielo databases using pertinent keywords, finding a total of 66 related studies. After filtering and in depth reviewing, a total of 12 studies were included in this review. RESULTS: The main results reveal the importance of this ion for human health, finding evidence both in animals and human beings that suggest pathological changes in the gland as its relationship with the occurrence of subclinical hypothyroidism, and potentially cancer of the thyroid gland. In Chile, nitrate is not considered a critical contaminant so its regular measuring and control is not enforced. CONCLUSIONS: In light of the present review we believe that there is evidence to consider nitrate as a critical contaminant whose measurement, registration and correct implementation of valid policies would have a direct benefit for the population of this country. Without this information, it is not possible to quantify the damage to human health, especially in vulnerable groups residing in areas at greatest risk of exposure. PMID- 29999160 TI - [A collaborative objective structured clinical examination for title revalidation by foreign medical graduates in Chile]. AB - BACKGROUND: Title revalidation of foreign medical graduates to practice medicine in Chile is a complex and expensive process. According to the legislation they are required to approve the Unique National Exam of Medical Knowledge (EUNACOM), which has a theoretical and a practical section. AIM: To demonstrate that a collaborative and standardized examination of the practical section of EUNACOM is more effective and efficient than traditional practical examinations. MATERIAL AND METHODS: The faculties of Medicine of the Catholic University of Chile, University of Chile and University of Concepcion were associated to implement an examination proposal, framed in the legislation. The EUNACOM board supported and funded the initiative which consisted in the implementation of Objective Structured Clinical Examination (OSCE) for each basic specialty of medicine, applied to 40 designated candidates. This format was selected because of the wide experience and evidence at the international level in the certification of medical professionals. RESULTS: A collaborative and standardized OSCE reduces to less than half the time spent by examiners, providing more evidence of validity, reliability and objectivity. It also allows to visualize the real costs per applicant, which proved to be higher than those currently charged by EUNACOM, but comparatively lower than the examination used in the United States. CONCLUSIONS: A collaborative OSCE responds to the ethical principle of justice by being more valid, reliable, objective and cost efficient. PMID- 29999161 TI - [Renal involvement in antineutrophil cytoplasmic antibodies (ANCA) associated vasculitides. Recommendations of the Chilean Societies of Nephrology and Rheumatology]. AB - Renal involvement is a frequent complication in antineutrophil cytoplasmic antibodies (ANCA)associated vasculitides, adding morbidity and mortality, such as chronic kidney disease and the need for renal replacement therapy. With the aim of reaching a consensus on relevant issues regarding the diagnosis, treatment and follow-up of patients with these diseases, the Chilean Societies of Nephrology and Rheumatology formed a working group that, based on a critical review of the available literature and their experience, raised and answered consensually a set of questions relevant to the subject. This document includes aspects related to the clinical diagnosis, the histological characteristics, the therapeutic alternatives to induce and maintain the remission of the disease, relapse surveillance strategies and complementary therapies. PMID- 29999162 TI - [Neisseria meningitidis pneumonia. A case report]. AB - Few cases of bacteremic pneumonia by Neisseria meningitidis (NM) have been described worldwide; mostly in elderly patients or those with comorbidities. They appear clinically indistinguishable from other acute infectious pneumoniae, that do not develope the syndrome of meningococcemia. We report a 17-years-old male, without prior medical history, consulting in the emergency department with a 7 day history of productive cough, right pleural pain, fever and dyspnea. He was admitted to the ICU due to septic shock and respiratory distress. He was managed with vasoactive drugs and prone positioning ventilation for 48 hours. Chest radiography showed a right superior lobe condensation. The electrocardiogram and echocardiogram suggested septic myocarditis. Blood cultures demonstrated the presence of serogroup W135-NM. A lumbar puncture ruled out meningitis, and a 10 day ceftriaxone therapy was completed favorably. PMID- 29999163 TI - [Atypical hemolytic uremic syndrome. Report of two cases treated with Eculizumab]. AB - Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy where organic damage predominates in the kidney. Atypical HUS (aHUS) is a rare disease that affects young adults and causes terminal chronic renal failure ending in dialysis, in most cases. It also recurs after kidney transplantation. aHUS is associated with genetic defects of the alternative complement pathway or its activation by other factors such as drugs, autoimmune diseases, infections, malignant hypertension and ischemia-reperfusion. We report two women aged 17 and 25 years old with catastrophic aHUS. In both cases, complement amplifying factors (drugs and infections) were added and acted on a genetic vulnerability to precipitate complement activation and produce aHUS. Both patients developed terminal renal failure and had to undergo hemodialysis. Fortunately, after a broad etiological study, it was possible to make the diagnosis of aHUS and start treatment with Eculizumab, a monoclonal antibody that changed the natural history of aHUS. It inhibits complement activity controlling microangiopathy and preventing the development of end-stage renal disease. It also improves the success rate in kidney transplantation. In the case of our patients, both discontinued dialysis after chronic treatment with Eculizumab. PMID- 29999164 TI - [Extracorporeal cardiopulmonay resuscitation: case report on an out-of-hospital cardiopulmonary arrest]. AB - Out-of-hospital cardiopulmonary arrest (OHCA) is highly lethal. Although overall survival is increasing, hospital discharge with good neurological prognosis remains low and highly variable. In some countries, protocols are being implemented, which include techniques in cardiopulmonary resuscitation, allowing a better neurological prognosis for those patients who undergo an OHCA. Following these new techniques and the incorporation of these new protocols already accepted in the guidelines of advanced cardiopulmonary resuscitation, we report a 54 years old male who presented an OHCA and received advanced cardiopulmonary by a professional team in situ. He was transferred to the emergency department, where optimal advanced resuscitation was continued, until the connection to extracorporeal cardiopulmonary support, with the aim of reestablishing blood flow, a technique known as cardiopulmonary resuscitation (ECPR: extracorporeal cardiopulmonary resuscitation). The patient was discharged from the hospital 25 days later. PMID- 29999165 TI - [Interpreting an atypical clinical case: the timing of events determines the diagnosis and impacts the prognosis of non-Hodgkin lymphomas]. PMID- 29999166 TI - [Measures of association in a study of risk factors associated with the development of hypertension in Chile]. PMID- 29999167 TI - [Proposal to use of an abbreviated mini mental examination to detect dementia in older people]. PMID- 29999169 TI - Reevaluating the role of megalin in renal vitamin D homeostasis using a human cell-derived microphysiological system AB - The role of megalin in the regulation of renal vitamin D homeostasis has previously been evaluated in megalin-knockout mice and rat proximal tubule epithelial cells. We revisited these hypotheses that were previously tested solely in rodent models, this time using a 3-dimensional proximal tubule microphysiological system incorporating primary human proximal tubule epithelial cells. Using this human cell-derived model, we confirmed that 25OHD3 is transported into the human proximal tubule epithelium via megalin-mediated endocytosis while bound to vitamin D binding protein. Building upon these findings, we then evaluated the role of megalin in modulating the cellular uptake and biological activity of 1alpha,25(OH)2D3. Inhibition of megalin function decreased the 1alpha,25(OH)2D3-mediated induction of both cytochrome P450 24A1 protein levels and 24-hydroxylation activity following perfusion with vitamin D binding protein and 1alpha,25(OH)2D3. The potential for reciprocal effects from 1alpha,25(OH)2D3 on megalin expression were also tested. Contrary to previously published observations from rat proximal tubule epithelial cells, 1alpha,25(OH)2D3 did not induce megalin gene expression, thus highlighting the potential for meaningful interspecies differences in the homeostatic regulation of megalin in rodents and humans. These findings challenge a recently promoted hypothesis, predicated on the rodent cell data, that attempts to connect 1alpha,25(OH)2D3-mediated regulation of renal megalin expression and the pathology of chronic kidney disease in humans. In addition to providing specific insights related to the importance of renal megalin in vitamin D homeostasis, these results constitute a proof-of-concept that human-derived microphysio logical systems are a suitable replacement for animal models for quantitative pharmacology and physiology research. PMID- 29999168 TI - A human population-based organotypic in vitro model for cardiotoxicity screening. AB - Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (beta-adrenergic receptor agonist/positive inotrope), propranolol (beta adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses, and can be expanded to other cell types for which in vitro populations can be derived from iPSCs. PMID- 29999170 TI - Distribution of bile acid receptor TGR5 in the gastrointestinal tract of dogs. AB - Takeda-G-protein-receptor-5 (TGR5) is a receptor for bile acids and its expression has been described in a variety of tissues and species. Characterization of TGR5 distribution and function has been investigated in drug discovery for the treatment of metabolic diseases in humans. Because dogs are one of the species used in biomedical research and share some similarities with human gastrointestinal diseases, the objective of this study was to characterize the distribution of TGR5 receptor in the canine species. This study characterizes the distribution of TGR5 receptor in the gastrointestinal tract, liver, gallbladder, and pancreas of 8 dogs. The distribution of TGR5 antigen and mRNA expression was investigated using immunohistochemistry and RNA in situ hybridization, respectively. TGR5 immunolabeling was located in the cell membrane or in the cell membrane and cytoplasm. TGR5 immunolabeling was broadly distributed in macrophages, endothelial cells, ganglion cells, and leiomyocytes throughout all the examined tissues. Epithelial cells from tongue, stomach to rectum, as well as from gallbladder, biliary and pancreatic ducts demonstrated TGR5 immunolabeling. In endocrine cells, TGR5 immunolabeling was observed in intestinal enteroendocrine cells and islets of Langerhans in the pancreas. The hepatocytes had a unique pattern of immunolabeling located on the canalicular surface of the cell membrane. TGR5 mRNA expression was located mainly in the nucleus and the only negative cells throughout all examined tissues were striated muscle from tongue and esophagus, muscularis mucosae, esophageal glands, and hepatic sinusoids. These findings indicate that the bile acid receptor TGR5 is ubiquitously distributed in the canine gastrointestinal tract. PMID- 29999171 TI - [Influence on the prescription of antiepileptic drugs in Spain (2006-2017) after evaluations of committees or commissions]. AB - INTRODUCTION: The drug evaluation in a defined market becomes more important if we manage to objectify the impact of it on health care professionals. SUBJECTS AND METHODS: It has been collected all the information related to the autonomic committees of evaluation of drugs in a period of time (from April 2006 to May 2017) and in those who have produced reports related to the N3A therapeutic group (antiepileptics) and it has been measured the quantitative impact of their evaluations on the prescription habits of specialists in each of the autonomous communities and globally in Spain. RESULTS: The impact was measured by analyzing the sales data in units (IQVIA) by provinces and at national level of each product evaluated. CONCLUSIONS: The impact of the work carried out by the autonomous evaluation committees and by the therapeutic positioning reports in relation to the antiepileptic drugs has been practically non-existent or null. We consider from this forum the suitability or not to keep the investment of time, personnel and other resources in this type of approach. PMID- 29999172 TI - [Perceived stress and subjective memory complaints in young adults: the mediating role of the executive functions]. AB - INTRODUCTION: Previous studies have shown that executive functions can be mediators between perceived stress and subjective memory complaints. However, it has not been evaluated which executive functions are those that most mediate this relationship. AIM: To determine if executive functions have a mediating role in the relationship between perceived stress and subjective memory complaints, and which ones have the greatest explanatory power. PATIENTS AND METHODS: The sample consisted of 743 university students (76.4% women), with an average age of 22.24 +/- 3.64 years. The subjective memory complaints were evaluated with the Memory Failure of Everyday Questionnaire, the stress with the Perceived Stress Scale, and the executive functions with the Prefrontal Symptoms Inventory. RESULTS: The executive functions and the perceived stress explained altogether 57% of the subjective memory complaints, being the attentional problems and the executive control problems the two variables with a greater weight in the model. On the other hand, the executive control problems, attentional problems and social behaviour problems showed a mediating effect between perceived stress and subjective memory complaints. CONCLUSIONS: The executive control problems and the attentional problems could be factors of choice for clinical intervention, since they act on their own as generators of subjective memory complaints and, moreover, are involved in mediation processes of perceived stress. PMID- 29999173 TI - Functional magnetic resonance imaging in the study of multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS), a neuroinflammatory and demyelinating disease, modifies the normal connectivity among different brain regions involved in specific functions. Functional magnetic resonance imaging (fMRI), based on local changes in oxygen level as a response to the increase in neural activity, provides an approach to neural connectivity and brain dynamics which give us an overview on visual, motor and cognitive dysfunction and their mechanisms. DEVELOPMENT: An advanced search was performed using PubMed. Terms 'fMRI', 'visual', 'motor', 'cognitive' and 'multiple sclerosis' included in title and abstract were considered. We focus on original articles available in English. Articles were included based on their abstracts, looking for those potentially useful for understanding functional changes in MS. An important amount of studies have used fMRI as a complementary tool in the study of MS and clinically relevant alterations compromising visual, motor and cognitive domains. Since the earliest stages of the disease, local activity, and global neural dynamics appear to be compromised. Even when functional performance is still preserved, a different recruitment of neural resources arises as a compensatory response to disconnection observed in the disease. CONCLUSIONS: The main findings of fMRI applied to MS are strongly related to the demyelinating nature of the disease and provide an adequate insight into the mechanisms that underlie functional alterations reported in this disease. fMRI also appears to be useful for studying disease evolution and response to treatment in MS and other disorders. PMID- 29999175 TI - [Bilateral Wallerian degeneration of pontocerebellar fibres secondary to pontine infarction]. PMID- 29999176 TI - Provocative proposal for a revised nomenclature for allergy and other hypersensitivity diseases. PMID- 29999177 TI - Enantiomeric quality control of R-Tofisopam by HPLC using polysaccharide-type chiral stationary phases in polar organic mode. AB - A novel, fast and economic chiral HPLC method was developed and validated for the resolution of the four isomers of tofisopam. The separation capacity of eleven different chiral columns: six polysaccharide-type including three amylose-based (Chiralpak AD, Chiralpak AD-RH and Chiralpak AS) and three cellulose-based (Chiralcel OD, Chiralcel OJ and Lux Cellulose-4); three cyclodextrin- (Quest-BC, Quest-C2 and Quest-CM) and two macrocyclic glycopeptide antibiotic-type (Chirobiotic T and Chirobiotic TAG) were screened using polar organic or reversed phase mode. Chiralpak AD, based on amylose tris(3,5-dimethylphenylcarbamate) as chiral selector with neat methanol was identified as the most promising system. In order to improve resolution, an orthogonal experimental design was employed, altering the concentration of 2-propanol, column temperature, and flow rate in a multivariate manner. Using the optimized method (85/15 v/v methanol/2-propanol, 40 degrees C, flow rate: 0.7 mL/min) we were not only able to separate the four isomers but also detect 0.1% S-enantiomer as chiral impurity in R-tofisopam. This is important since the latter is under development as a single enantiomeric agent. Thermodynamic investigation revealed an unusual entropy and enthalpy entropy co-driven controlled enantioseparation on Chiralcel OJ and on Chiralpak AD column, respectively. Our newly developed HPLC method was validated according to the ICH guidelines and its application was tested on a pharmaceutical formulation containing the racemic mixture of the drug. As a further novelty, a separate circular dichroism method was applied for the investigation of the interconversion kinetics of tofisopam conformers, which proved to be crucial for sample preparation and method validation. PMID- 29999178 TI - Cultivation of black soldier fly larvae on almond byproducts: impacts of aeration and moisture on larvae growth and composition. AB - BACKGROUND: The increasing production of almonds worldwide has resulted in the significant generation of byproduct streams that require end uses. One potential use for byproducts is for cultivation of additional food sources including insects. Studies were performed to determine if black soldier fly larvae (Hermetia illucens L.) could be cultivated on almond byproducts (hulls and shells) and to examine the effect of aeration and moisture on larvae growth and hull composition. RESULTS: Increasing aeration from 0.04 to 0.36 mL min-1 g dry weight-1 tripled the harvest weight of larvae and increased larvae yield by a factor of five. Larvae calcium content increased by 18% with an increase in aeration from 0.04 to 0.95 mL min-1 g dry weight-1 . Moisture content also affected harvest dry weight and yield; increasing moisture content from 480 g kg 1 (wet basis) to 680 g kg-1 increased harvest weight by 56% and yield by a factor of 2. Variables did not affect larvae methionine and cysteine content. Low moisture content and aeration rate yielded an environment that supported microbial consumption of hulls over larvae consumption and growth. CONCLUSIONS: The results demonstrate that almond hulls are a suitable feedstock for larvae production under controlled management of moisture content and aeration. (c) 2018 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29999179 TI - Examining the Unanticipated Adverse Consequences of Youth Suicide Prevention Strategies: A Literature Review with Recommendations for Prevention Programs. AB - OBJECTIVE: Youth suicide is a public health problem in the United States. Suicide prevention programs have been shown to be beneficial; however, knowledge of unanticipated adverse consequences of programs is limited. The objective of this review is to present what is known about these consequences so informed decisions and appropriate planning can be made prior to implementation of suicide prevention interventions. METHOD: A narrative but systematic review was conducted assessing what is known about adverse consequences utilizing a comprehensive keyword search of EBSCO and PubMed databases. Study populations beyond youth were included. RESULTS: Unanticipated adverse consequences of suicide prevention interventions were included in 22 publications. Consequences occur at three levels: at the level of the youth, those who identify or intervene with at-risk youth, and at the system level. While rare, unanticipated adverse consequences include an increase in maladaptive coping and a decrease in help-seeking among program targets, overburden or increased suicide ideation among program implementers, and inadequate systemic preparedness. CONCLUSIONS: Overall, the benefits of youth suicide prevention outweigh the unanticipated adverse consequences. Nevertheless, these results may be utilized for informed decision making regarding suicide prevention programming, and to ensure appropriate infrastructure is in place prior to prevention efforts. PMID- 29999180 TI - Psychometric properties and reference data for Danish versions of Free and Cued Selective Reminding Test, Category Cued Memory Test and Logical Memory. AB - Memory assessment is a key element in neuropsychological testing. Gold standard evaluation is based on updated normative data, but in many small countries (e.g. in Scandinavia) such data are sparse. In Denmark, reference data exist for non verbal memory tests and list-learning tests but there is no normative data for memory tests which capture narrative recall and cued recall. In a nation-wide study, Free and Cued Selective Reminding Test (FCSRT), WMS-III Logical Memory (LM) and a newly developed test Category Cued Memory Test (CCMT-48) were applied in 131 cognitively intact persons (aged 60-96 years). Regression-based reference data for Danish versions of FCSRT, CCMT-48 and LM adjusted for age, education and gender are provided. Gender and age-group had a significant impact on the expected scores, whereas the effect of education had a limited effect on expected scores. Test performances were significantly correlated in the range 0.21-0.51. Based on these findings and previous results it may be relevant to assess both free recall, cued recall and recognition to tap the earliest changes associated with neurodegeneration, and this study therefore provides an important supplement to existing Danish normative data. Future studies should investigate the discriminative validity of the tests and the clinical utility of the presented reference data. PMID- 29999181 TI - What growth sounds like: Redemption, self-improvement, and eudaimonic growth across different life narratives in relation to well-being. AB - OBJECTIVE: We disentangled three growth-relevant concepts (redemption, self improvement, and eudaimonic growth) in personal narratives of high, low, and turning points and tested their relations to well-being. METHOD: In two studies, participants (Study 1 n = 111, Study 2 n = 206; overall ages 17-83, 56% women, 75% white) wrote narratives of high points, low points, and turning points. Researchers coded each narrative for redemption sequences (i.e., affectively valenced changes in life from bad to good), self-improvement sequences (i.e., affectively valenced changes in oneself for the better), and themes of eudaimonic growth (i.e., values or motives for cultivating meaningful activities or relationships, helping others, or wisdom). Participants also self-reported well being. RESULTS: Redemption sequences in low points predicted higher well-being but in high points predicted lower well-being. Self-improvement sequences and growth themes each predicted higher well-being in each life event (and interacted in high points). Growth themes consistently mediated predicted relations between both redemption and self-improvement sequences and well-being. Findings held when controlling for global narrative affect, self-reported growth motivation, and big five traits. CONCLUSIONS: Thematic motives for eudaimonic growth were more closely tied to well-being than were affective evaluations of either changes from bad to good (redemption) or one's becoming better (self-improvement). PMID- 29999182 TI - High exposure mining occupations are associated with obstructive lung disease, National Health Interview Survey (NHIS), 2006-2015. AB - BACKGROUND: The association between mining occupation categories and obstructive lung disease (OLD) has not been well explored in the United States. METHODS: National Health Interview Survey (NHIS) data from 2006 to 2015 was used to determine the relationship between mining occupations and diagnosis of chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), and asthma. We classified occupations into low, moderate, high, and very high dust exposure groups. Extraction workers were categorized as very high dust exposure. RESULTS: We found 4.5% of miners had chronic bronchitis, 3.3% had emphysema, 6.2% had COPD, and 9.9% had asthma. In fully adjusted models, extraction workers had significantly increased odds of having chronic bronchitis (OR = 2.18 [95%CI: 1.02, 4.64]), emphysema (OR = 7.85 [95%CI: 1.70, 36.27]), and COPD (OR = 2.56 [95%CI: 1.29, 5.12]) compared to lower exposure occupations. CONCLUSIONS: Occupation is an important predictor of OLD in the mining industry. PMID- 29999183 TI - Analysis of apparent demonstrations of responding in accordance with relational frames of sameness and opposition. AB - We evaluated whether contextual control over equivalence and nonequivalence and responding by exclusion can explain the outcomes of relational frame theory (RFT) studies on sameness and opposition relations. We trained nine college students to maintain and reverse conditional discriminations with X1 and X2 as contextual stimuli. In Experiment 1, X1 and X2 controlled derived stimulus relations (DSR) analogous to those controlled by Same and Opposite in RFT studies. These results can be explained by at least two hypotheses: X1 and X2 were cues for equivalence and nonequivalence and responding by exclusion, or for sameness and opposition. In Experiment 2, X1 and X2 controlled DSR predicted by the hypothesis that they were cues for equivalence and nonequivalence and responding by exclusion, and not predicted by the hypothesis that they were cues for sameness and opposition. The results of Experiment 2 and the functional equivalence of X1 and X2 with Same and Opposite in Experiment 1 suggest that Same and Opposite were cues for equivalence and nonequivalence and responding by exclusion in RFT studies. PMID- 29999184 TI - The SNP g.4667G>A at 3'-UTR of IFNG gene is associated with susceptibility to bovine tuberculosis in Mediterranean water buffalo (Bubalus bubalis). PMID- 29999185 TI - Brief group-based acceptance and commitment therapy for stroke survivors. AB - OBJECTIVES: To date, the efficacy of acceptance and commitment therapy (ACT) for stroke survivors has not been established. The aim of this study was to evaluate the efficacy of group-based ACT for stroke survivors in comparison with treatment as usual (TAU) controls. METHODS: Fifty-three participants were randomly assigned either to group-based ACT (ACTivate Your Life after Stroke) or to a TAU control group (60% male; mean age: 63 years). The ACT intervention consisted of four weekly 2-hr didactic group sessions. Therapeutic effects were measured by examining changes in depression (primary outcome), anxiety, hope, health-related quality of life, self-rated health status, and mental well-being. Measures were completed at pre-treatment, post-treatment, and 2-month follow-up. A mixed-design repeated-measures multivariate ANOVA was conducted to analyse the findings. RESULTS: Analysis based on intention to treat found that compared to participants in the TAU control, group-based ACT significantly reduced depression and increased self-rated health status and hopefulness in stroke survivors, with medium effect sizes. Significantly more participants reached clinically significant change of depression in the ACT intervention in comparison with the control group. CONCLUSIONS: The results correspond with previous studies of group based ACT with other long-term conditions. The findings from this current study suggest group-based ACT may have promising utility and could offer a suitable low intensity psychological intervention for stroke survivors. However, further large scale research is required. PRACTITIONER POINTS: Acceptance and commitment therapy (ACT), delivered didactically to groups of stroke survivors, proved feasible and acceptable. ACT had benefits, relative to treatment as usual, for depression, health status, and hope. Several secondary outcome variables did not show dependable benefit for ACT: anxiety; health-related quality of life; and mental well-being. Results should be treated as preliminary as the sample size was small, blinding was not possible, concomitant treatments were not monitored, and there was no attention control condition. Despite these limitations, group based ACT merits further study as a potentially effective intervention. PMID- 29999186 TI - The role of birth weight on the causal pathway to child and adolescent ADHD symptomatology: a population-based twin differences longitudinal design. AB - BACKGROUND: Available evidence points towards lower birth weight as a risk factor for the development of attention deficit/hyperactivity disorder (ADHD) symptoms. We probed the causal nature of this putative effect of birth weight on ADHD symptoms using the twin differences design, which accounts for genetic and shared environmental confounds. METHOD: In a large population-based twin sample - 3,499 monozygotic (MZ) and 6,698 dizygotic (DZ) pairs - parents, teachers or twins rated the twins' ADHD symptoms at nine assessment waves (2-16 years). We implemented the twin differences design, which completely accounts for shared environmental and genetic confounding in MZ twins. We tested whether: (a) the lighter-born twins had elevated ADHD symptoms compared to the heavier-born twins, by regressing within-pair differences of ADHD symptoms on within-pair differences of birth weight among MZ twins; (b) the effect of birth weight on ADHD was moderated by gender, gestational age and low birth weight; (c) this effect changed with age at ADHD assessment using adapted latent growth curve models; and (d) results differed for inattention and hyperactivity/impulsivity. RESULTS: Birth weight significantly predicted ADHD symptoms from early childhood to late adolescence. The lighter-born twin had more ADHD symptoms than the heavier-born cotwin among MZ twins across assessment waves and raters. No moderation effect was detected. The magnitude of the effect of birth weight decreased significantly across time for hyperactivity/impulsivity, but the decrease failed to reach significance for inattention. Estimates for inattention were significantly larger than for hyperactivity/impulsivity at each time point, implying stronger effect of birth weight on inattention symptoms. CONCLUSIONS: Our findings provide stringent evidence for environmental effect of lower birth weight on the causal pathway to elevated ADHD symptoms. Effect of birth weight persists across a 14 year period from childhood into late adolescence, in particular for inattention symptoms. PMID- 29999187 TI - Prevalence of patients with self-reported hidradenitis suppurativa in a cohort of Danish blood donors: a cross-sectional study. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflamed nodules. No pathognomonic test is available for HS; hence the diagnosis is based on three clinical criteria. OBJECTIVES: To estimate the cross-sectional prevalence and characterize patients with HS in the Danish Blood Donor Study cohort. METHODS: A questionnaire previously developed containing HS screening questions, the Major Depression Inventory, the Short Form 12, as well as questions about height, weight and drinking habits was answered by 27 765 blood donors. RESULTS: The prevalence of HS was 1.8% [95% confidence interval (CI) 1.6-2.0%] in the cohort of Danish blood donors. Donors with HS were on average 4.7 years younger (P < 0.001), had 1.3 kg m-2 higher mean body mass index (BMI) (P < 0.001) and were significantly more likely to smoke [odds ratio (OR) 1.44, 17.9% vs. 13.1%, P = 0.002] compared with donors without HS. Furthermore, significantly more donors with HS were classified as having moderate depression (3.2% vs. 0.7%, P < 0.001). Also, significantly more patients with HS were apprenticeship educated, received educational support and sickness or cash benefits. CONCLUSIONS: The prevalence of HS in the cohort of blood donors was estimated to 1.8% (95% CI 1.6-2.0%). Donors with HS reported characteristics similar to those reported for hospital-based patients with HS such as higher BMI, smoking rates and lower socioeconomic status than donors without HS. PMID- 29999188 TI - Re: Donkelaar CS, Rosier PFWM, de Kort L: Comparison of three methods to analyze detrusor contraction during micturition in men over 50 years of age. Neurourol Urodyn 2017;36:2153-2159. PMID- 29999189 TI - Re: Gammie A et al. What are the additional signs and symptoms in patients with detrusor underactivity and coexisting detrusor overactivity? PMID- 29999190 TI - Meta-analysis of the prognostic role of perioperative platelet count in posthepatectomy liver failure and mortality. AB - BACKGROUND: Emerging evidence suggests that the perioperative platelet count (PLT) can predict posthepatectomy liver failure (PHLF). In this systematic review and meta-analysis, the impact of perioperative PLT on PHLF and mortality was evaluated. METHODS: MEDLINE and Web of Science databases were searched systematically for relevant literature up to January 2018. All studies comparing PHLF or mortality in patients with a low versus high perioperative PLT were included. Study quality was assessed using methodological index for non randomized studies (MINORS) criteria. Meta-analyses were performed using Mantel Haenszel tests with a random-effects model, and presented as odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: Thirteen studies containing 5260 patients were included in the meta-analysis. Two different cut-off values for PLT were used: 150 and 100/nl. Patients with a perioperative PLT below 150/nl had higher PHLF (4 studies, 817 patients; OR 4.79, 95 per cent c.i. 2.89 to 7.94) and mortality (4 studies, 3307 patients; OR 3.78, 1.48 to 9.62) rates than patients with a perioperative PLT of 150/nl or more. Similarly, patients with a PLT below 100/nl had a significantly higher risk of PHLF (4 studies, 949 patients; OR 4.65, 2.60 to 8.31) and higher mortality rates (7 studies, 3487 patients; OR 6.35, 2.99 to 13.47) than patients with a PLT of 100/nl or greater. CONCLUSION: A low perioperative PLT correlates with higher PHLF and mortality rates after hepatectomy. PMID- 29999191 TI - Transsynaptic tracing to dissect supraspinal serotonergic input regulating the bladder reflex in rats. AB - AIMS: This study was designed to determine specific cell groups of the raphe nuclei (RN) that give rise to supraspinal serotonergic projections regulating the bladder reflex. METHODS: Anesthetized rats underwent surgery to open the abdomen and expose the bladder. A total of 6 uL transsynaptic neuronal tracer pseudorabies virus (PRV-152), encoding for green fluorescent protein (GFP), was injected into the bladder detrusor. After 72 or 96 h, animals were perfused and the brain was dissected for processing transverse and sagittal sections. Subsequently, fluorescent immunohistochemistry for GFP and Serotonin (5 hydroxytryptamine [5-HT]) was performed in the brain sections. Under the microscope, each RN subset was characterized individually from caudal to rostral according to the atlas. GFP+ or GFP/5-HT double labeled neurons in each subset were quantified for statistical analysis. RESULTS: At 72-h post-infection, very few GFP+ or GFP/5-HT double-labeled neurons appeared in the brainstem and beyond. In contrast, many labeled neurons were found at these levels after 96 h. Quantitative analysis showed that the majority of infected 5-HT+ neurons were located in the pallidus, obscurus, and magnus nuclei. Conversely, very few infected neurons were found in other raphe subsets, that is the pontis, median, dorsal, or linear nuclei. Overall, the raphe magnus had the highest number of GFP labeled and GFP/5-HT double-labeled cells. CONCLUSIONS: The caudal subsets of RN, especially the raphe magnus, are the main sources of serotonergic input to the lower spinal cord controlling bladder activity. PMID- 29999192 TI - Impact of breast cancer grade discordance on prediction of outcome. AB - AIMS: Histological grade is an independent prognostic variable in breast cancer (BC). Previous concordance studies of BC grade have reported moderate levels of agreement; a typical finding in morphological assessment of biological variables. This study aimed to investigate the impact of discordance on the prognostic value of grade and to identify the best reporting approach in borderline cases. METHODS AND RESULTS: A large (n = 1675) well-characterised annotated cohort of BC, originally graded in routine practice using glass slides, was re-graded twice by an expert breast pathologist using virtual microscopy with a 3-month washout period. Outcome was assessed using breast cancer-specific and distant metastasis free survival (median follow-up = 135 months). Fifty-eight per cent of the cases showed absolute agreement in the three separate grading sessions, whereas grades 1/2 and 2/3 discordance were observed in 21% and 21%, respectively. Absolute intra-observer agreement using virtual microscopy was observed in 77% of the cases, whereas 13% and 10% showed grades 1/2 and 2/3 discordance, respectively. Despite the concordance, outcome analysis revealed significant associations between tumour grade and patients' outcome in the three grading sessions. Grades 1/2 and 2/3 discordant cases showed intermediate survival between grades 1 and 2 tumours and grades 2 and 3 tumours, respectively. Grades 1/2 discordant cases showed a worse outcome when compared with grade 1 tumours (P = 0.008) but no statistical difference was identified when compared with grade 2 tumours. Similarly, grades 2/3 discordant cases showed a significant difference from grade 2 tumours (P < 0.001), but no statistical difference was identified when compared with grade 3 tumours. CONCLUSIONS: Breast cancer grade discordance is probably a reflection of biologically, and hence morphologically, borderline tumours. Cases with borderline features for grade are more likely to behave similarly to the higher-grade category. Repeating histological grade of borderline cases or double reporting may improve correlation with outcome. PMID- 29999193 TI - Evaluating the Feasibility and Effectiveness of an Australian Safety Planning Smartphone Application: A Pilot Study Within a Tertiary Mental Health Service. AB - OBJECTIVE: The purpose of this study was to examine the feasibility and effectiveness of a suicide prevention smartphone application. METHOD: Thirty-six non-Aboriginal Australians aged between 16 and 42 years (67% female) were recruited from a tertiary mental health service where they were receiving treatment for suicide risk. Participants were asked to use the BeyondNow safety planning smartphone application to manage their suicide safety plan during a 2 month trial, as an adjunct to treatment as usual. A survey battery designed to measure feasibility and effectiveness of the smartphone app plus treatment as usual intervention was completed at baseline and follow-up. RESULTS: A vast majority of participants used the app to view and edit their safety plans and reported that the app was easy to use. A reduction was observed in participant severity and intensity of suicide ideation, and suicide-related coping increased significantly. No significant changes were observed in suicide resilience. CONCLUSIONS: The BeyondNow safety planning smartphone application was shown to be feasible and effective as an adjunct to mental health treatment among patients at risk of suicide. PMID- 29999194 TI - Effect of milled flaxseed and storage conditions on sensory properties and selected bioactive compounds in banana and cinnamon muffins used in a clinical trial. AB - BACKGROUND: Muffins containing 0, 20, and 30 g of flaxseed were developed for a randomized, controlled cross-over trial on low-density lipoprotein (LDL) cholesterol lowering. The effect of milled flaxseed and storage (-20 degrees C for 1 and 6 months) of banana and cinnamon muffins on sensory attribute intensities, selected physical properties, bioactive concentrations, and acceptability by two groups - clinical trial participants and consumers - was investigated. RESULTS: The addition of flax increased flax aroma and flavor, sour aroma, and cohesiveness of mass and brown color, and decreased sweet aroma and flavor, banana and cinnamon aroma and flavor, springiness and mouth dryness. Alpha-linolenic acid and secoisolariciresinol diglucoside were significantly increased when flax was increased from 20 to 30 g. Clinical trial participants generally found the muffins more acceptable than the consumers. Consumers reported significantly decreased acceptability when flax at any level was added to muffins, with 30 g the least acceptable. CONCLUSIONS: Muffins with 20 g flaxseed generally had higher mean acceptability values compared to muffins with 30 g. Neither flavoring nor storage at -20 degrees C for 6 months appreciably changed muffin attributes or acceptability. Future work will optimize the ingredients as well as the amount of flax needed to provide the required amount of bioactive to positively affect LDL cholesterol level and to produce acceptable muffins. (c) 2018 Society of Chemical Industry. PMID- 29999195 TI - Transforming growth factor beta mediates communication of co-cultured human nucleus pulposus cells and mesenchymal stem cells. AB - Intervertebral disc (IVD) consists of surrounding tissue annulus fibrosus and central nucleus pulposus, which are partially degenerative in scoliotic IVDs. Successful regeneration of scoliotic alterations requires cognition of critical paracrine mediators of cell-to-cell contact in the IVD. In this work, we hypothesized that transforming growth factor beta (TGF-beta) is involved in the intercellular communication of nucleus pulposus cells (NPCs) and mesenchymal stem cells (MSCs). We observed that in cultured NPCs TGF-beta1 stimulated COL1A1 expression, encoding collagen I, and in MSCs stimulated COL1A1 and SOX9 expressions. We subsequently co-cultured NPCs and MSCs together using direct and indirect transwell systems. The expression of miR-140 and miR-145 were decreased in co-cultured NPCs. We observed that direct co-culture system stronger than the indirect system decreased expression of three miRNA. The expression of COL1A1, ACAN, encoding aggrecan, and SOX9 genes was increased in MSCs co-cultured with NPCs. Co-cultures were incubated with two inhibitors of TGF-beta type I receptor: SB-431542 and SB-525334. In co-cultured NPCs, SB-431542 and SB-525334 annulated downregulation of miR-140 and miR-145. In MSCs these inhibitors diminished stimulation of COL1A1, ACAN, and SOX9. We concluded that stimulation of COL1A1, ACAN, and SOX9 in co-cultured MSCs and regulation of miR-140 and miR-145 in NPCs were TGF-beta-dependent and TGF-beta is involved in the communication of NPCs and MSCs in co-culture. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29999196 TI - Thermoresponsive Alignment Media in NMR Spectroscopy: Helix Reversal of a Copolyaspartate at Ambient Temperatures. AB - Poly(aspartic acid esters) are known to form either right-or left-handed alpha helices depending on the ester group in the side chain, on solvent and/or on temperature. Polyphenethyl-l-aspartates (PPLA) exhibit a helix reversal from the right- to the left-handed form with increasing temperature. We have recently reported the application of polyphenethylaspartates as helically chiral alignment media. The thermoresponsivity observed for these polymers offers the possibility to measure different orientations of analytes before and after helix reversal of the alignment medium at 373 K. Herein we present a synthesized copolymer of phenethyl- and benzylaspartate as a new alignment medium undergoing this helix reversal at 303-313 K. Thus, the measurement of residual dipolar couplings (RDC) before and after the helix reversal is allowed for at ambient temperatures. A complete sign change of all 1 H-13 C RDCs was observed, which is close to the highest possible difference in NMR spectra. PMID- 29999197 TI - Clinical studies evaluating abametapir lotion, 0.74%, for the treatment of head louse infestation. AB - BACKGROUND: There is a need for better control of head louse infestations. Abametapir is an inhibitor of metalloproteinases critical for louse survival and egg development. The efficacy of abametapir lotion, 0.74%, was assessed for its ability to clear head louse infestations after a single application. METHODS: Two randomized, double-blind, multicenter, vehicle-controlled studies were conducted in subjects aged 6 months and older to compare the effectiveness of abametapir lotion versus vehicle control for eliminating head louse infestations without nit combing. Abametapir lotion was applied to dry hair for 10 minutes on day 0 and then rinsed with water. The primary endpoint was the proportion of index subjects (youngest household member with >= 3 live lice at screening) in the intent-to treat population who were louse free at all follow-up visits through day 14. Older household members with one or more live lice at screening were designated as nonindex subjects and treated as per the index subject within their household. RESULTS: In the intent-to-treat population (index subjects, N = 216), 81.5% of subjects treated with abametapir lotion were louse free through day 14 after a single treatment, versus 49.1% with vehicle (P < 0.001). For the combined index and nonindex population (N = 704), 85.9% were louse free through day 14 in the abametapir group, versus 61.3% in the vehicle group (P < 0.001). The most frequently reported adverse events were erythema (4.0%), rash (3.2%), and skin burning sensation (2.6%). CONCLUSION: Abametapir lotion, 0.74%, was effective at clearing active head louse infestations through day 14 in subjects aged 6 months and older. All adverse events (including one serious but unrelated to study drug) resolved uneventfully. PMID- 29999198 TI - Survival of children and young adults with skin cancer: Analysis of a population based Florida cancer registry: 1981-2013. AB - BACKGROUND/OBJECTIVES: Although pediatric and young adult skin cancer is uncommon, recent epidemiologic studies have shown pediatric melanoma to be on the rise in the United States. Using a population-based cancer registry, this study examined skin cancer burden and survival disparities in children and young adults. METHODS: Linked data from the Florida Cancer Data System and U.S. Census were analyzed to elucidate skin cancer burden distribution and survival disparities in 1543 Florida children (0-9 years), adolescents (10-19 years), and young adults (20-24 years). These disparities were assessed according to sociodemographic groups such as sex, race, ethnicity, and neighborhood level socioeconomic status. A multivariable Cox regression model adjusted for sociodemographic, clinical, and tumor characteristics was used to predict survival. RESULTS: Boys had a slightly greater burden of skin cancer among children (50.9%), whereas girls had the greatest burden for adolescents (54.5%) and young adults (60%). Survival differed between white, black, and other races; 1-year survival was 91.5% for whites and 77.9% for blacks. Average 3- and 5-year survival was comparable for blacks and whites. "Other" race had a 1- and 3-year survival of 96.2%. CONCLUSION: Because skin cancer is on the rise, it is important to elucidate the burden and determinants associated with survival outcomes to identify high-risk pediatric and young adult populations. Understanding these factors in the Florida pediatric population may provide a base for future endeavors to create culturally competent cancer prevention programs through screening, health promotion, and literacy. PMID- 29999199 TI - Employment status of patients with chronic inflammatory demyelinating polyradiculoneuropathy. AB - It has been previously shown that patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are unemployed or retired have worse quality of life. The aim of this study was to assess predictors of early retirement in CIDP. One hundred five patients with CIDP were included. Following measures were used: questionnaire on employment status, Medical Research Council Sum Score, INCAT disability score, Beck Depression Inventory, and Krupp's Fatigue Severity Scale. At the moment of testing, 2% of patients were students, 15% were employed, 9% were unemployed due to CIDP, 9% were unemployed but not due to CIDP, 28% were retired early due to disability caused by CIDP, and finally 37% were in old-age pension. Mean age when patients retired due to CIDP was 50 +/- 8 years. Mean time from CIDP onset to retirement was 2.7 +/- 2.3 years. Older age at onset, lower education, and more severe weakness at the time of diagnosis were significant predictors of early retirement due to CIDP. Retired patients were 12 times more likely to suffer from depression, compared to employed patients (OR = 12.2, 95% CI = 1.41-100, P < 0.01), and eight times more likely to have fatigue (OR = 8.2, 95% CI = 1.89-35.82, P < 0.01). Older patients with lower education and more severe weakness at the time of diagnosis were most likely retired due to CIDP. Early retirement was associated with depression and fatigue. Therefore, maintaining employment should be an important aim in the management of CIDP patients. PMID- 29999200 TI - Recent Progress on Manganese-Based Nanostructures as Responsive MRI Contrast Agents. AB - Manganese-based nanostructured contrast agents (CAs) entered the field of medical diagnosis through magnetic resonance imaging (MRI) some years ago. Although some of these Mn-based CAs behave as classic T1 contrast enhancers in the same way as clinical Gd-based molecules do, a new type of Mn nanomaterials have been developed to improve MRI sensitivity and potentially gather new functional information from tissues by using traditional T1 contrast enhanced MRI. These nanomaterials have been designed to respond to biological environments, mainly to pH and redox potential variations. In many cases, the differences in signal generation in these responsive Mn-based nanostructures come from intrinsic changes in the magnetic properties of Mn cations depending on their oxidation state. In other cases, no changes in the nature of Mn take place, but rather the nanomaterial as a whole responds to the change in the environment through different mechanisms, including changes in integrity and hydration state. This review focusses on the chemistry and MR performance of these responsive Mn-based nanomaterials. PMID- 29999201 TI - Probiotics promoted head growth in extremely low birthweight infants in a double blind placebo-controlled trial. AB - AIM: This study evaluated if oral supplementation with the probiotic bacterium Lactobacillus reuteri DSM 17938 improved enteral feeding tolerance and growth rates in extremely low birthweight (ELBW) infants. METHOD: A randomised, double blind, placebo-controlled trial comprising 134 ELBW (<1000 g) infants born before gestational week 28 + 0. Daily supplementation of L. reuteri (1.25 * 108 bacteria/day) or placebo started within 3 days and continued until gestational week 36 + 0. Primary outcome was feeding tolerance and secondary outcome growth rate calculated as z-score development. RESULTS: Feeding tolerance was similar in the probiotic and placebo group. Time to full enteral feeds was 15 days in both groups. The z-score of the head circumference decreased in both groups from birth to day 28 of life, but it decreased less in the L. reuteri group compared to the placebo group: -1.2 SD (95% CI: -1.4 to -1.0) versus -1.7 SD (95% CI: -2.0 to 1.5; p = 0.001). Other growth parameters were similar in the study groups. CONCLUSION: Lactobacillus reuteri did not reduce time to reach full enteral feeds in ELBW infants. The L. reuteri supplemented infants, however, had a better growth rate of the head during the first month of life. PMID- 29999202 TI - Exercise capacity and clinical outcomes in adults followed in the Cooperative Study of Sickle Cell Disease (CSSCD). AB - OBJECTIVES: To determine the factors associated with exercise capacity in adults with sickle cell disease (SCD) and its relationship to hospitalizations and mortality. METHODS: A total of 223 participants in the Cooperative Study of Sickle Cell Disease (CSSCD) (64% female, 70% hemoglobin SS/Sbeta0 thalassemia, mean age 43.3 +/- 7.5 years) underwent maximal exercise testing using a treadmill protocol with a mean duration of 11.6 +/- 5.2 minutes. RESULTS: Female sex (beta = -3.34, 95% CI [-1.80, -4.88], P < 0.001), older age (beta = -0.14, 95% CI [ 0.24, -0.04], P = 0.005), higher body mass index (beta = -0.23, 95% CI [-0.37, 0.10]; P = 0.001), and lower hemoglobin (beta = 0.56, 95% CI [0.08, 1.04], P = 0.02) were independently associated with lower fitness, while there was a trend with abnormal pulmonary function testing (beta = -1.42, 95% CI [-2.92, 0.07]; P = 0.06). Lower percent-predicted forced expiratory volume in 1 second (FEV1 ) was independently associated with lower fitness (beta = 0.08, 95% CI [0.03, 0.13], P = 0.001). Genotype and hospitalization rates for pain and acute chest syndrome (ACS) prior to testing were not associated with exercise capacity. Baseline exercise capacity predicted neither future pain or ACS nor survival in our cohort. Adults with SCD tolerated maximal exercise testing. CONCLUSIONS: Prospective studies are needed to further evaluate the impact of regular exercise and improved fitness on clinical outcomes and mortality in SCD. PMID- 29999203 TI - Seeing the site of treatment improves habitual pain but not cervical joint position sense immediately after manual therapy in chronic neck pain patients. AB - BACKGROUND: Visual analgesia refers to the phenomena where people report decreased pain intensity when they see the painful or painfully stimulated body part. Alongside pain, sensorimotor impairment (i.e., disturbed proprioception) is also evident in chronic pain. This study aims to investigate whether real-time visual feedback offers additional pain relief and proprioceptive improvement when used in combination with recommended therapies in neck pain patients who received manual therapy with or without real-time visual feedback. METHODS: A total of 29 neck pain patients were recruited in an outpatient physical therapy practice. Patients were randomly allocated to receive manual therapy of the cervical spine with real-time visual feedback or to a control group where patients received manual therapy without real-time visual feedback. Habitual pain intensity, the pressure pain threshold at the zygapophyseal joint of C2-C3 and the superior angle of the scapulae and cervical proprioception were assessed before and immediately after the intervention by a blinded assessor. RESULTS: A between group comparison revealed a significant reduction in habitual pain in the real time visual feedback group. No differences were found for the pressure pain threshold or proprioceptive performance. CONCLUSIONS: Real-time visual feedback combined with manual therapy enhanced the analgesic effect of manual therapy in neck pain patients, but had no positive effect on the pressure pain threshold and cervical joint position sense. The technical demands for integrating real-time visual feedback into daily practice to reduce habitual pain are low, have low costs and are easy to apply. SIGNIFICANCE: Real-time visual feedback reduces habitual pain immediately after the intervention. Due to its easy integration, it may be an effective adjunct to recommended interventions (i.e., manual therapy) in patients with neck pain. PMID- 29999205 TI - Oral 5-aminolevulinic acid-mediated photodynamic diagnosis using fluorescence cystoscopy for non-muscle-invasive bladder cancer: A multicenter phase III study. AB - OBJECTIVE: To confirm the reproducibility of the effectiveness and safety in photodynamic diagnosis of non-muscle-invasive bladder cancer using 5 aminolevulinic acid in a prospective multicenter non-randomized phase III trial. METHODS: A total of 61 patients with primary or recurrent non-muscle-invasive bladder cancer were prospectively enrolled from five hospitals between May 2015 and March 2016. 5-Aminolevulinic acid (20 mg/kg) was orally administered 3 h before transurethral resection of bladder tumors using white light or fluorescent light. Of 60 evaluable patients, 511 specimens were obtained from tumor suspicious lesions and normal-looking mucosa. The primary end-point was sensitivity. The secondary end-points were specificity, positive and negative predictive values, and safety. RESULTS: The sensitivity of the fluorescent light source (79.6%) was significantly higher (P < 0.001) than that of the white light source (54.1%). In total, 25.4% (46/181) of tumor specimens were diagnosed as positive with only the fluorescent light source. In nine (15%) of 60 patients, the risk classification and recommended treatment after transurethral resection of bladder tumors were changed depending on the additional types of tumor diagnosed by the fluorescent light source. The specificity of the fluorescent light versus white light source was 80.6% versus 95.5%. No grade 4-5 adverse event was noted. Hypotension and urticaria were severe adverse events whose relationship to oral 5-aminolevulinic acid could not be excluded. CONCLUSIONS: These findings confirm the diagnostic efficacy and safety of photodynamic diagnosis with 20 mg/kg of oral 5-aminolevulinic acid, and show that transurethral resection of bladder tumors with a fluorescent light source using oral 5-aminolevulinic acid is well tolerated. PMID- 29999204 TI - Use of the NESMA Filter to Improve Myelin Water Fraction Mapping with Brain MRI. AB - BACKGROUND AND PURPOSE: Myelin water fraction (MWF) mapping permits direct visualization of myelination patterns in the developing brain and in pathology. MWF is conventionally measured through multiexponential T2 analysis which is very sensitive to noise, leading to inaccuracies in derived MWF estimates. Although noise reduction filters may be applied during postprocessing, conventional filtering can introduce bias and obscure small structures and edges. Advanced nonblurring filters, while effective, exhibit a high level of complexity and the requirement for supervised implementation for optimal performance. The purpose of this paper is to demonstrate the ability of the recently introduced nonlocal estimation of multispectral magnitudes (NESMA) filter to greatly improve the determination of MWF parameter estimates from gradient and spin echo (GRASE) imaging data. METHODS: We evaluated the performance of the NESMA filter for MWF mapping from clinical GRASE imaging data of the human brain, and compared the results to those calculated from unfiltered images. Numerical and in vivo analyses of the brains of three subjects, representing different ages, were conducted. RESULTS: Our results demonstrated the potential of the NESMA filter to permit high-quality in vivo MWF mapping. Indeed, NESMA permits substantial reduction of random variation in derived MWF estimates while preserving accuracy and detail. CONCLUSIONS: In vivo estimation of MWF in the human brain from GRASE imaging data was markedly improved through use of the NESMA filter. The use of NESMA may contribute to the goal of high-quality MWF mapping in clinically feasible imaging times. PMID- 29999206 TI - Myc protein overexpression is a feature of progression and adverse prognosis in multiple myeloma. AB - OBJECTIVE: Prognostic and predictive markers in multiple myeloma are continuously explored because of the heterogeneity of the tumor biology. Myc protein is the final product from activating MYC oncogene, but the prognostic impact in multiple myeloma is not well described. METHODS: In a population-based cohort of 194 untreated, newly diagnosed patients with multiple myeloma, we assessed myc protein expression using CD138/myc immunohistochemical double stain and collected clinicopathological data. RESULTS: Cases with myc protein expression >=40% (mycHIGH ) had a median overall survival of 11 months compared to 48 months in cases of myc protein expression <40% (mycLOW ) (P < 0.01). MycHIGH was significantly correlated to R-ISS, high proliferation index, high percentage of plasma cell in bone marrow, plasmablastic morphology, high calcium level, and abnormal karyotype. In multivariate survival analyses, mycHIGH was independently associated with inferior overall survival with a hazard ratio of 2.5. CONCLUSION: Our results indicate myc protein overexpression to be associated with advanced multiple myeloma and poor prognosis. PMID- 29999207 TI - Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple, NRAS and BRAF mutation-negative nodules. AB - We report the case of a newborn boy with multinodular NRAS and BRAF mutation negative congenital melanocytic nevi and cerebral lesions compatible with congenital intraparenchymal melanosis. Histopathology from skin lesions showed atypical nodular melanocytic proliferation with marked melanocytic atypia and a large number of mitoses and apoptosis, indicating aggressive proliferation. The child developed several new subcutaneous tumors and multiple internal lesions, which were confirmed to be metastases, and died at 5 months of age. This case may represent an infantile melanoma developing from a giant congenital melanocytic nevus or a congenital melanoma. PMID- 29999208 TI - Adjunctive laser-stimulated stem-cells therapy to primary reperfusion in acute myocardial infarction in humans: Safety and feasibility study. AB - BACKGROUND: Low-level laser therapy (LLLT) has photobiostimulatory effects on stem cells and may offer cardioprotection. This cell-based therapy may compliment primary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVE: In this randomized control trial, our primary objective was to determine the safety and feasibility of LLLT application to the bone marrow in patients with STEMI undergoing PPCI. METHODS: We randomly assigned patients undergoing PPCI to LLLT or non-laser therapy (NLT). In the LLLT group, 100 s of laser therapy was applied to the tibia bone prior to PPCI, as well as 24 and 72 h post-PPCI. In the control group, the power source was turned off. The primary outcome was the difference in door-to-balloon (D2B) time, and additional outcomes included differences in circulating cell counts, cardiac enzymes, and left-ventricular ejection fraction (LVEF) at pre-specified intervals post-PPCI. RESULTS: Twenty-four patients were randomized to LLLT (N = 12) or NLT (N = 12). No adverse effects of the treatment were detected. The D2B time was not significantly different between the groups (41 +/- 8 vs 48 +/- 1 min; P = 0.73). Creatinine Phosphokinase area under the curve, was lower after LLLT (22 +/- 10) compared to NLT (49 +/- 12), but this was not statistically significant (P = 0.08). Troponin-T was significantly lower after LLLT (2.7 +/- 1.4 ng/mL) in comparison to NLT (5.2 +/- 1.8 ng/mL. P < 0.05). At 9 months, LVEF improved in both groups without a significant difference between LLLT (55 +/- 9%) and NLT (52 +/- 9%; P = 0.90). CONCLUSION: LLLT is a safe and feasible adjunctive cell-based therapy to PPCI that may benefit ischemic myocardium. PMID- 29999209 TI - Congenital-type juvenile xanthogranuloma: A case series and literature review. AB - BACKGROUND/OBJECTIVES: Congenital juvenile xanthogranulomas are infrequently described in the medical literature. We report three previously unpublished cases and systematically review the literature to better characterize this variant. METHODS: We surveyed English-language articles indexed in MEDLINE (1951-March 2017) and EMBASE (1974-March 2017) for cases of congenital-onset juvenile xanthogranulomas confirmed on histopathology. Cases were divided into two categories: cutaneous only or cutaneous with systemic involvement. RESULTS: We identified 31 cases of congenital juvenile xanthogranulomas involving only the skin and 16 cases with systemic involvement. Congenital juvenile xanthogranulomas involving only the skin were large (> 3 cm), presented with various clinical morphologies, and showed signs of regression by 1 year of age. Atypical clinical presentations included exophytic tumors, infiltrative plaques, agminated plaques, and subcutaneous tumors. Complications included ulceration and anetodermic scarring. Infants with congenital cutaneous juvenile xanthogranulomas who also had systemic involvement typically had multiple cutaneous tumors and hepatic involvement and showed signs of spontaneous regression independent of treatment. CONCLUSIONS: The medical literature supports that congenital juvenile xanthogranulomas behave in a fashion similar to that of juvenile xanthogranulomas of infancy or childhood. Congenital cutaneous juvenile xanthogranulomas with or without systemic involvement spontaneously regress. The varied clinical presentations in the skin may lead to misdiagnosis, inappropriate examination, and unnecessary treatments. Infants with multiple congenital cutaneous juvenile xanthogranulomas should be evaluated for systemic involvement, with a particular focus on the liver, because 72.2% of these children were found to have hepatic juvenile xanthogranulomas. PMID- 29999210 TI - Simultaneous chiral analysis of amphetamine-type stimulants and ephedrine by capillary electrophoresis coupled to time-of-flight mass spectrometry. AB - This study focused on the chiral characteristics of methamphetamine seizures in Shanghai for inferring the synthetic pathways of drugs. Capillary electrophoresis coupled to time-of-flight mass spectrometry was used for simultaneous chiral separation of amphetamine-type stimulants and ephedrine, including S(+) amphetamine/R(-)-amphetamine, S(+)-methamphetamine/R(-)-methamphetamine, (+/-) MDA (3,4-methylenedioxyamphetamine), (+/-)-MDMA (3,4 methylenedioxymethamphetamine), (+/-)-MDEA (3,4-methylenedioxy-N ethylamphetamine), d,l-N-ethylamphetamine, methylephedrine/methylpseudoephedrine, and 1S,2R(+)-ephedrine/(-)-ephedrine. The running buffer was 50-mM ammonium formate (pH 2.2 was adjusted by 1-M formic acid) containing 0.26% highly sulfated gamma-cyclodextrin as the chiral selector. All enantiomers were well resolved within 40 minutes by capillary electrophoresis at 20 kV in an uncoated fused silica capillary (50-MUm I.D. * 375-MUm O.D. * 90-cm length) and detected by micro time-of-flight mass spectrometry. Twenty seized methamphetamine samples were determined by the established method. They were classified into two groups through their chiral characteristics. PMID- 29999211 TI - Over-diagnosis of cognitive deficits in psychiatric patients may be the result of not controlling for hearing sensitivity and auditory processing. PMID- 29999212 TI - Chemopreventive effect of sulindac in combination with epigallocatechin gallate or kaempferol against 1,2-dimethyl hydrazine-induced preneoplastic lesions in rats: A Comparative Study. AB - A systematic investigation of the chemopreventive effect of sulindac (SL) in combination with either epigallocatechin gallate (EGCG) or kaempferol similar (KMP) has been carried out 1,2-dimethyl hydrazine-treated rats (DMH). Those SL combinations with KMP and EGCG have enhanced the SL activity producing greater antioxidant, anti-inflammatory, antiproliferating, and apoptotic activities in both combinations than SL alone. The chemopreventive effects of SL with both EGCG and KMP were demonstrated by a decrease in thiobaribituric acid reactive substances level, tissue nitric oxide (NO), serum, and tissue beta-catenin as well as a reduction in the multiplicity of aberrant crypt foci (ACF) with alleviation in the dysplastic changes that resulted from DMH administration. Down regulation of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX 2) were also confirmed by immunohistochemical staining. The current study paves the way for the use of sulindac combination with kaempferol or EGCG as potential chemopreventive agents against colon cancer with more effect in combination with EGCG. PMID- 29999213 TI - Sirolimus as initial therapy for kaposiform hemangioendothelioma and tufted angioma. AB - BACKGROUND: Sirolimus has been used to manage various complex vascular anomalies. Kaposiform hemangioendothelioma and tufted angioma may develop Kasabach-Merritt phenomenon in infancy. METHODS: We retrospectively reviewed the clinical and laboratory data of eight patients with kaposiform hemangioendothelioma and tufted angioma who were initially treated using oral sirolimus in our center, including six with Kasabach-Merritt phenomenon. RESULTS: Five girls and three boys seen between September 2012 and March 2015 were included. Age at initiation of sirolimus ranged from 30 days to 14 weeks (mean+/-SD 8.6 +/- 3.5 weeks). Six of these eight patients had kaposiform hemangioendothelioma, and two had a tufted angioma. Platelet count before start of oral sirolimus ranged from 5 * 109 /L to 189 * 109 /L ((78.8 +/- 65.2)*109 /L) and fibrinogen level from 68 to 215 mg/dL (123.1 +/- 50.5 mg/dL). All patients received standard doses of sirolimus (0.05 mg/kg orally, twice daily) as initial therapy. All patients with thrombocytopenia or hypofibrinogenemia reached a normal platelet count and a normal fibrinogen level within 3 to 4 weeks after sirolimus treatment. Length of treatment ranged from 12 to 79 weeks (39.9 +/- 15.3 weeks). Two patients developed grade 2 oral mucositis during treatment. CONCLUSION: Sirolimus as first-line therapy shows great promise in the treatment of kaposiform hemangioendothelioma and tufted angioma. PMID- 29999214 TI - Developing and testing a web-based intervention to encourage early help-seeking in people with symptoms associated with lung cancer. AB - OBJECTIVES: To detail the development method used to produce an online, tailored, theory-based, user-centred intervention to encourage help-seeking for potential lung cancer symptoms. DESIGN: Intervention development was structured around the person-based approach. The feasibility study involved a randomized controlled trial design. METHODS: Intervention development drew on qualitative inquiries, the Theory of Planned Behaviour (TPB), and identifying concrete mechanisms of change to implement in the intervention (Behaviour Change Techniques). The final intervention involved two key features: (1) tailoring and (2) 'TPB components' to target beliefs about help-seeking. In an online feasibility study, we recruited people reporting potential lung cancer symptoms using mailing lists, social media, websites, and Google AdWords. Participants were randomized to the intervention, a tailored comparison group (CG) without TPB-components, an untailored CG with TPB components, or a CG with neither. Following treatment, participants clicked a button to indicate whether they wished to make an appointment and completed a TPB questionnaire. RESULTS: A total of 130 participants reporting relevant symptoms were recruited (24% of website visitors). Participants in the intervention group reported higher intention to seek help than those who received tailored information without TPB components (p = .03). User comments indicate more support is needed for people who sought help for symptoms, but felt dismissed. CONCLUSIONS: The potential for differential dropout in online randomized trials requires careful consideration. Future help seeking interventions should provide support for those who have previously felt dismissed by health professionals. The feasibility study provides some evidence that our 'TPB components' were effective, but validation in a powered trial is necessary. Statement of contribution What is already known on this subject? People with lung cancer often delay presenting symptoms to health services. Some patients (or their family/friends) look up symptoms online before their diagnosis, to decide whether they should see a doctor. Interventions are needed to ensure people can find useful information online that will encourage them to seek help for relevant symptoms. What does this study add? Theory-mapping and user involvement facilitated systematic intervention development. Lung cancer help-seeking interventions should address salient beliefs and personal relevance. The potential for differential dropout in online randomized trials requires careful consideration. PMID- 29999216 TI - Prospective, randomized controlled study of the preventive effect of fosfomycin tromethamine on post-transurethral resection of bladder tumor urinary tract infection. PMID- 29999217 TI - Predictive validity of verbal and non-verbal communication and mother-child turn taking at 12 months on language outcomes at 24 and 36 months in a cohort of infants experiencing adversity: a preliminary study. AB - BACKGROUND: Parent-reported measures of early communication have limitations for use with infants experiencing adversity. Observational measures of early non verbal and verbal communicative behaviours and mother-child turn-taking may provide a complementary method of capturing early communication skills for these children. AIMS: To explore the predictive validity of verbal and non-verbal behaviours and mother-child conversational turn-taking (fluency and connectedness) at child age 12 months in relation to language measures at 24 and 36 months in a cohort of infants experiencing adversity. METHODS & PROCEDURES: Pregnant women experiencing adversity were recruited from maternity hospitals in Australia. At 12 months, 190 infants were videoed during mother-child free-play. Verbal and non-verbal communicative behaviours and fluency and connectedness were measured from the 12-month videos. Predictive validity of 12-month behaviours was calculated in relation to mean length of utterance and number of unique words at 24 months and Clinical Evaluation of Language Fundamentals Preschool-Second Edition (CELF-P2) Core Language scores at 36 months. OUTCOMES & RESULTS: All 12 month behaviours had adequate specificity but poor sensitivity when compared with other predictive validity studies using published early language measures. However, in adjusted regression models, fluency and connectedness and verbal behaviours at 12 months predicted unique words at 24 months. Fluency and connectedness also predicted CELF-P2 scores at 36 months. CONCLUSIONS & IMPLICATIONS: Findings reconfirm the difficulty in early identification of children at risk of later language difficulties. All 12-month measures were more accurate at identifying those children who will have better language than those children who will not. As fluency and connectedness was the only measure to predict 24- and 36-month language in adjusted regression models, it may be an important factor to consider when measuring early language skills for infants experiencing adversity. Future research could combine observational measures of early communication and fluency and connectedness with other predictors of language to try to increase prediction accuracy. PMID- 29999218 TI - Helmuth Mohwald (1946-2018). AB - Helmuth Mohwald, Founding Director of the Max Planck Institute for Colloids and Interfaces, Potsdam-Golm, passed away on March 27, 2018, at the age of 72. Mohwald's scientific achievements included the development of the layer-by-layer (LbL) technique to prepare ultrathin organized organic films, and its application in the coating of colloidal particles. PMID- 29999219 TI - One potato, two potato,... assessing carbohydrate counting accuracy in adolescents with type 1 diabetes. AB - BACKGROUND/OBJECTIVE: Carbohydrate (CHO) counting is a recommended daily practice to help manage blood glucose levels in type 1 diabetes. Evidence suggests that CHO estimates should be within 10 to 15 g of the actual meal for optimal postprandial blood glucose control. The objective of this study was to assess accuracy of CHO counting in adolescents with type 1 diabetes. METHODS: Adolescents (aged 12-18 years) with type 1 diabetes who self-identified as regular CHO counters were recruited from the SickKids Diabetes Clinic, Toronto, Canada. Adolescents completed the PedsCarbQuiz (PCQ) and estimated CHO content of test trays (three meals and three snack trays) that were randomly assigned. Analyses were conducted to identify factors associated with accuracy of counting and CHO counting knowledge (PCQ score). RESULTS: A total of 140 adolescents (78 females, mean age 14.7, SD = 1.8) participated. The average PCQ score was 81 +/- 10%. Forty-two percent of adolescents were accurate in estimating meal trays (ie, within 10 g of the actual CHO content), 44% estimated inaccurately (within 10-20 g), while 14% were significantly inaccurate counters (>20 g variation). PCQ scores were higher in teens who CHO counted accurately than in those with significant inaccuracy (>20 g) (P < 0.05), and a longer duration of diabetes corresponded significantly with a lower PCQ score. No demographics correlated significantly with CHO counting accuracy. CONCLUSIONS: Less than half of the teens in our study were accurate CHO counters. These results indicate the need for regular clinical accuracy check and reeducation. PMID- 29999220 TI - Mechanistic Studies on the Organocatalytic alpha-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates. AB - Herein we report the isolation and characterization of aminal intermediates in the organocatalytic alpha-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed. PMID- 29999221 TI - High-Throughput Metabolomics by 1D NMR. AB - Metabolomics deals with the whole ensemble of metabolites (the metabolome). As one of the -omic sciences, it relates to biology, physiology, pathology and medicine; but metabolites are chemical entities, small organic molecules or inorganic ions. Therefore, their proper identification and quantitation in complex biological matrices requires a solid chemical ground. With respect to for example, DNA, metabolites are much more prone to oxidation or enzymatic degradation: we can reconstruct large parts of a mammoth's genome from a small specimen, but we are unable to do the same with its metabolome, which was probably largely degraded a few hours after the animal's death. Thus, we need standard operating procedures, good chemical skills in sample preparation for storage and subsequent analysis, accurate analytical procedures, a broad knowledge of chemometrics and advanced statistical tools, and a good knowledge of at least one of the two metabolomic techniques, MS or NMR. All these skills are traditionally cultivated by chemists. Here we focus on metabolomics from the chemical standpoint and restrict ourselves to NMR. From the analytical point of view, NMR has pros and cons but does provide a peculiar holistic perspective that may speak for its future adoption as a population-wide health screening technique. PMID- 29999222 TI - ISPAD Clinical Practice Consensus Guidelines 2018: Insulin treatment in children and adolescents with diabetes. PMID- 29999224 TI - The paradox of low B-type natriuretic peptide levels in obesity revisited: does sex matter? PMID- 29999223 TI - Electronic Clinical Decision Support System for allergic rhinitis management: MASK e-CDSS. AB - BACKGROUND: Allergic rhinitis (AR) management has changed in recent years following the switch from the concept of disease severity to the concept of disease control, publication of the AR clinical decision support system (CDSS) and development of mobile health (m-health) tools for patients (eg Allergy Diary). The Allergy Diary Companion app for healthcare providers is currently being developed and will be launched in 2018. It incorporates the AR CDSS to provide evidence-based treatment recommendations, linking all key stakeholders in AR management. OBJECTIVE: To produce an electronic version of the AR CDSS (e CDSS) for incorporation into the Allergy Diary Companion, to describe the app interfaces used to collect information necessary to inform the e-CDSS and to summarize some key features of the Allergy Diary Companion. METHODS: The steps involved in producing the e-CDSS and incorporating it into the Allergy Diary Companion were (a) generation of treatment management scenarios; (b) expert consensus on treatment recommendations; (c) generation of electronic decisional algorithms to describe all AR CDSS scenarios; (d) digitization of these algorithms to form the e-CDSS; and (e) embedding the e-CDSS into the app to permit easy user e-CDSS interfacing. RESULTS: Key experts in the AR field agreed on the AR CDSS approach to AR management and on specific treatment recommendations provided by Allergy Diary Companion. Based on this consensus, decision processes were developed and programmed into the Allergy Diary Companion using Titanium Appcelerator (JavaScript) for IOS tablets. To our knowledge, this is the first time the development of any m-health tool has been described in this transparent and detailed way, providing confidence, not only in the app, but also in the provided management recommendations. CONCLUSION: The Allergy Diary Companion for providers provides guideline and expert-endorsed AR management recommendations. [MASK paper No 32]. PMID- 29999225 TI - There is something about Power-a gap in Rehabilitation and injury reduction strategies? PMID- 29999226 TI - Quantifying pesticide deposits and spray patterns at micro-scales on apple (Malus domesticus) leaves with a view to arthropod exposure. AB - BACKGROUND: Pesticides used in commercial crop systems can adversely affect non target arthropod populations. The spatial distribution of pesticide residues is rarely studied at scales relevant to these populations. Here, we combine two methods for assessing pesticide spray deposits at spatial scales relevant to non target arthropods found in apple orchards. Pesticide residues were determined on individual apple leaves through conventional residue analysis; water-sensitive paper was used to investigate spatial distributions in deposits at the micro scale. We also evaluated how accurately a digital image analysis program estimated pesticide residues. RESULTS: We found that mean pesticide spray coverage on water-sensitive paper varied by up to 6.1% (95% CI 9.4%, 2.7%) within an apple orchard, and leaf residues varied by up to 0.95 (95% CI 0.54, 1.36) mg kg-1 within a tree. Leaf residues based on analytical chemistry were six times lower than pesticide deposition estimated through image analysis of water sensitive paper, although these correlated strongly. This correlation allowed estimation of actual residues by application of a correction factor. CONCLUSION: Our method demonstrates accurate estimation of pesticide deposits at the individual leaf scale through digital analysis of water-sensitive paper and is a low-cost, rapid alternative to conventional residue analysis techniques. (c) 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29999227 TI - Obesity and mortality risk in heart failure: when adipose tissue distribution matters. PMID- 29999228 TI - ISPAD Clinical Practice Consensus Guidelines 2018: Type 2 diabetes mellitus in youth. PMID- 29999229 TI - Gene drive systems: do they have a place in agricultural weed management? AB - There is a pressing need for novel control techniques in agricultural weed management. Direct genetic control of agricultural pests encompasses a range of techniques to introduce and spread novel, fitness-reducing genetic modifications through pest populations. Recently, the development of CRISPR-Cas9 gene editing has brought these approaches into sharper focus. Proof of concept for CRISPR-Cas9 based gene drives has been demonstrated for the control of disease-vectoring insects. This article considers whether and how gene drives may be applied in agricultural weed management, focusing on CRISPR-Cas9-based systems. Population suppression drives might be employed to introduce and proliferate deleterious mutations that directly impact fitness and weediness, whereas population sensitizing drives would seek to edit weed genomes so that populations are rendered more sensitive to subsequent management interventions. Technical challenges relating to plant transformation and gene editing in planta are considered, and the implementation of gene drives for timely and sustainable weed management is reviewed in the light of weed population biology. The technical, biological, practical and regulatory challenges remain significant. Modelling based studies can inform how and if gene drives could be employed in weed populations. These studies are an essential first step towards determining the utility of gene drives for weed management. (c) 2018 The Author. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29999231 TI - Long-Acting Reversible Contraception. PMID- 29999230 TI - Stagnating trends in complementary feeding practices in Bangladesh: An analysis of national surveys from 2004-2014. AB - Bangladesh has experienced steady socio-economic development. However, improvements in child growth have not kept pace. It is important to document complementary feeding (CF) practices-a key determinant of children's growth-and their trends over time. The study aims to examine trends in CF practices in children aged 6-23 months using data from Bangladesh Demographic and Health Surveys conducted in 2004, 2007, 2011, and 2014. Multilevel logistic regression models were applied to identify independent predictors of four CF practice indicators among children 6-23 months, namely, timely introduction of complementary foods, minimum meal frequency, minimum dietary diversity, and minimum acceptable diet. Introduction of complementary foods was achieved among 64-71% of children between 2004 and 2014. The proportion meeting minimum meal frequency increased from 2004 to 2007 (71-81%) and declined and held steady at 65% from 2011 to 2014. The proportion meeting minimum dietary diversity in 2011 and 2014 was low (25% and 28%), and so was minimum acceptable diet (19% and 20%). From 2007 to 2014, child dietary diversity decreased and the most decline was in the consumption of legumes and nuts (29% to 8%), vitamin A-rich fruits and vegetables (54% to 41%), and other fruits and vegetables (47% to 20%). Young child age (6-11 months), poor parental education, household poverty, and residence in the Chittagong and Sylhet independently predicted poorer feeding practices. Dietary diversity and overall diet in Bangladeshi children are strikingly poor. Stagnation or worsening of feeding practices in the past decade are concerning and call for decisive policy and programme action to address inappropriate child feeding practices. PMID- 29999232 TI - Surface-Assisted Self-Assembly of a Hydrogel by Proton Diffusion. AB - Controlling supramolecular growth at solid surfaces is of great importance to expand the scope of supramolecular materials. A dendritic benzene-1,3,5 tricarboxamide peptide conjugate is described in which assembly can be triggered by a pH jump. Stopped-flow kinetics and mathematical modeling provide a quantitative understanding of the nucleation, elongation, and fragmentation behavior in solution. To assemble the molecule at a solid-liquid interface, we use proton diffusion from the bulk. The latter needs to be slower than the lag phase of nucleation to progressively grow a hydrogel outwards from the surface. Our method of surface-assisted self-assembly is generally applicable to other gelators, and can be used to create structured supramolecular materials. PMID- 29999233 TI - The Photosensitising Clinical Agent Verteporfin Is an Inhibitor of SPAK and OSR1 Kinases. AB - STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative-stress responsive kinase 1 (OSR1) are two serine/threonine protein kinases that play key roles in regulating ion homeostasis. Various SPAK and OSR1 mouse models exhibited reduced blood pressure. Herein, the discovery of verteporfin, a photosensitising agent used in photodynamic therapy, as a potent inhibitor of SPAK and OSR1 kinases is reported. It is shown that verteporfin binds the kinase domains of SPAK and OSR1 and inhibits their catalytic activity in an adenosine triphosphate (ATP)-independent manner. In cells, verteporfin was able to suppress the phosphorylation of the ion co-transporter NKCC1; a downstream physiological substrate of SPAK and OSR1 kinases. Kinase panel screening indicated that verteporfin inhibited a further eight protein kinases more potently than that of SPAK and OSR1. Although verteporfin has largely been studied as a modifier of the Hippo signalling pathway, this work indicates that the WNK-SPAK/OSR1 signalling cascade is also a target of this clinical agent. This finding could explain the fluctuation in blood pressure noted in patients and animals treated with this drug. PMID- 29999235 TI - Assessment of pain in chronic wounds: A survey of Australian health care practitioners. AB - Pain associated with chronic wounds can delay wound healing, affects quality of life, and has a major impact on physical, emotional, and cognitive function. However, wound-related pain is often under-assessed and may therefore be suboptimally managed. The aim of this study was to describe the assessment practices used to assess chronic wound pain by health practitioners in Australia. A structured self-administered questionnaire was posted to members of an Australian national wound care organisation, whose membership represents various health practitioners involved in wound management. A total of 1190 (53%) members completed the survey. Overall, wound pain assessment was most commonly conducted at every consultation or wound dressing change (n = 718/1173, 61%). Nurses were more likely to assess wound-related pain before, during, and after the wound dressing procedures compared with other health care practitioners. In contrast, podiatrists assessed wound pain only when the patient complained about the pain. The most common assessment method was simply talking to the patient (n = 1005/1180, 85%). Two-thirds of practitioners used a validated pain assessment tool. The most commonly used tool was the numerical analogue scale (n = 524/1175, 46%). In summary, these findings suggest that there is no consistent method for the assessment of wound-related pain, and there are substantial variations in how and when wound-related pain is assessed between different professions. PMID- 29999234 TI - Organization of projection from brainstem auditory nuclei to the inferior colliculus of Japanese house bat (Pipistrellus abramus). AB - OBJECTIVES: Echolocating bats show remarkable specialization which is related to analysis of echoes of biosonars in subcortical auditory brainstem pathways. The inferior colliculus (IC) receives inputs from all lower brainstem auditory nuclei, i.e., cochlear nuclei, nuclei of the lateral lemniscus, and superior olivary complex, and create de novo responses to sound, which is considered crucial for echolocation. Inside the central nucleus of the IC (ICC), small domains which receive specific combination of extrinsic inputs are the basis of integration of sound information. In addition to extrinsic inputs, each domain is interconnected by local IC neurons but the cell types related to the interconnection are not well-understood. The primary objective of the current study is to examine whether the ascending inputs are reorganized and terminate in microdomains inside the ICC. METHODS: We made injection of a retrograde tracer into different parts of the ICC, and analyzed distribution of retrogradely labeled cells in the auditory brainstem of Japanese house bat (Pipistrellus abramus). RESULTS: Pattern of ascending projections from brainstem nuclei was similar to other bat species. Percentages of labeled cells in several nuclei were correlated each other. Furthermore, within the IC, we identified that large GABAergic (LG) and glutamatergic neurons made long-range connection. CONCLUSIONS: Synaptic organization of IC of Japanese house bat shows specialization which is likely to relate for echolocation. Input nuclei to the IC make clusters which terminate in specific part of the ICC, implying the presence of microdomains. LG neurons have roles for binding IC microdomains. PMID- 29999236 TI - Biodegradable, Drug-Loaded Nanovectors via Direct Hydration as a New Platform for Cancer Therapeutics. AB - The stabilization and transport of low-solubility drugs, by encapsulation in nanoscopic delivery vectors (nanovectors), is a key paradigm in nanomedicine. However, the problems of carrier toxicity, specificity, and producibility create a bottleneck in the development of new nanomedical technologies. Copolymeric nanoparticles are an excellent platform for nanovector engineering due to their structural versatility; however, conventional fabrication processes rely upon harmful chemicals that necessitate purification. In engineering a more robust (copolymeric) nanovector platform, it is necessary to reconsider the entire process from copolymer synthesis through self-assembly and functionalization. To this end, a process is developed whereby biodegradable copolymers of poly(ethylene glycol)-block-poly(trimethylene carbonate), synthesized via organocatalyzed ring-opening polymerization, undergo assembly into highly uniform, drug-loaded micelles without the use of harmful solvents or the need for purification. The direct hydration methodology, employing oligo(ethylene glycol) as a nontoxic dispersant, facilitates rapid preparation of pristine, drug-loaded nanovectors that require no further processing. This method is robust, fast, and scalable. Utilizing parthenolide, an exciting candidate for treatment of acute lymphoblastic leukemia (ALL), discrete nanovectors are generated that show strikingly low carrier toxicity and high levels of specific therapeutic efficacy against primary ALL cells (as compared to normal hematopoietic cells). PMID- 29999238 TI - Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells. AB - The hematopoietic system has a very well-studied hierarchy with the long-term (LT) hematopoietic stem cells (HSCs) taking the top position. The pool of quiescent adult LT-HSCs generated during the fetal and early postnatal life acts as a reservoir to supply all the blood cells. Therefore, the maintenance of this stem cell pool is pivotal to maintaining homeostasis in hematopoietic system. It has long been known that external cues, along with the internal genetic factors influence the status of HSCs in the bone marrow (BM). Hypoxia is one such factor that regulates the vascular as well as hematopoietic ontogeny from a very early time point in development. The metabolic outcomes of a hypoxic microenvironment play important roles in functional regulation of HSCs, especially in case of adult BM HSCs. Anaerobic metabolic pathways therefore perform prominent role in meeting energy demands. Increased oxidative pathways on the other hand result in loss of stemness. Recent studies have attributed the functional differences in HSCs across different life stages to their metabolic phenotypes regulated by respective niches. Indicating thus, that various energy production pathways could play distinct role in regulating HSC function at different developmental/physiological states. Here, we review the current status of our understanding over the role that energy production pathways play in regulating HSC stemness. (c) 2018 IUBMB Life, 70(7):612-624, 2018. PMID- 29999239 TI - Orexins Facilitates Osteogenic Differentiation of MC3T3-E1 Cells. AB - Dysfunction of osteoblastic bone formation and matrix mineralization plays a key role in the pathological development of osteoporosis. The orexin peptide orexin A, a highly excitatory neuropeptide hormone, possesses various biological functions by activating its specific G protein-coupled receptors, orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R). Here, we report that OX1R but not OX2R was expressed in MC3T3-E1 cells. Importantly, we found that orexin-A accelerated osteoblast differentiation and matrix mineralization in MC3T3-E1 cells, as manifested by elevation of physiological markers of osteoblastic differentiation [alkaline phosphatase (ALP) and osteogenic genes] and Alizarin Red staining, respectively. Importantly, our findings indicated that orexin-A significantly increased the expression of runt-related transcription factor 2 (Runx-2), which is the central transcriptional factor. Orexin-A treatment phosphorylated the kinase p38 mitogen-activated protein kinase (MAPK) in a dose- and time-dependent manner. Also, orexin-induced increase in gene expression (Runx 2, ALP, osteocalcin, and osterix) and matrix mineralization were prevented by the p38 MAPK specific inhibitor SB203580. Additionally, we also revealed that protein kinase D (PKD) is involved in the effects of Orexin-A on p38 MAPK activation and Runx-2 expression. Finally, we found that Orexin-A-induced osteoblastic formation and matrix mineralization and the activation of the PKD/p38 MAPK pathway are mediated by OX1R. Based on these findings, we concluded that activation of OX1R by orexin-A might possess a therapeutic strategy for bone disease. (c) 2018 IUBMB Life, 70(7):633-641, 2018. PMID- 29999240 TI - The Neurovascular Protective Effect of S14G-Humanin in a Murine MCAO Model and Brain Endothelial Cells. AB - Endothelial dysfunction is fundamental to ischemic stroke and brain injury. The humanin analogue S14G-humanin (HNG) has been shown to be a cytoprotective derivative. In this study, we investigated the neuroprotective effects of HNG in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) stroke model, HNG ameliorates cerebral infarction and suppresses the production of TNF alpha, IL-1beta, IL-6 and MCP-1 cytokines. HNG inhibits the expression of vascular adhesion molecules such as VCAM-1 and ICAM-1 in the cortex tissue. In mouse brain endothelial cells bEnd.3, HNG protects cell survival under oxygen deprivation (OGD) conditions. HNG suppresses ROS production as well as that of the same panel of cytokines and vascular adhesion molecules induced by OGD. HNG also reduces the numbers of THP-1 cells attached to bEnd.3 by OGD. Mechanistically, we show that HNG exerts its effect via inhibition of the NF- kappaB pathway factor IKKalpha, activation of IkappaBalpha and accumulation of p65 in the nucleus. Our data conclude that S14G-humanin serves as a neuroprotective factor, especially in brain vascular disorders. (c) 2018 IUBMB Life, 70(7):691-699, 2018. PMID- 29999241 TI - Response to "A Successful Standardized Academic Inter-professional Post-licensure Education Program Exists to Train MSK Professionals to Become Advanced Practitioners in Arthritis Care: Lessons Learned from the ACPAC Program". AB - With tremendous gratitude, we thank Drs. Lundon and Shupak for their interest in the recently published article "Core Curriculum to Facilitate the Expansion of a Rheumatology Practice to Include Nurse Practitioners and Physician Assistants". They have very thoughtfully reviewed the article and highlighted the need to continue to grow the rheumatology workforce to increase access to care for people with rheumatic disease. Our congratulations for the success of the Advanced Clinician Practitioner in Arthritis Care (ACPAC) program, and we applaud and recognize their ongoing efforts. This article is protected by copyright. All rights reserved. PMID- 29999242 TI - Left atrial appendage occlusion for stroke prevention in diabetes mellitus patients with atrial fibrillation: Long-term results. AB - BACKGROUND: Concomitant diabetes mellitus (DM) in atrial fibrillation (AF) may increase the risk of thromboembolism. Left atrial appendage occlusion (LAAO) is an alternative treatment in AF patients in whom antithrombotic therapy is ineffective or contraindicated. The aim of this study was to evaluate the long term efficacy of LAAO in DM patients with AF. METHODS: A retrospective study was conducted in 139 patients who had undergone LAAO and were categorized into two groups: 28 patients with DM and 111 patients without DM. Overall, the follow-up period was 530 patient-years. RESULTS: Mean CHADS2 and CHA2 DS2 -VASc scores were higher in patients with than without DM (2.6 vs 1.7 [P < 0.001] and 3.5 vs 2.8 [P = 0.056], respectively). There were no significant differences between the two groups in terms of HAS-BLED scores and other patient factors (sex, age, heart failure, hypertension, previous stroke or transient ischemic attack, peripheral vascular disease) that may increase the risk of thromboembolism based on CHA2 DS2 -VASc. The mean follow-up period was 51.6 and 50 months in patients with DM and without DM, respectively. Comparing patients with and without DM, there were no significant differences in thromboembolic events (4% vs 1.9%), severe bleeding (0% vs 3.1%), or mortality (4% vs 5.9%). The estimated reductions in thromboembolic and bleeding risk were 77% and 100%, respectively, for patients with DM, compared with 85% and 62%, respectively, for patients without DM. CONCLUSION: The present study indicates that LAAO in AF patients with DM has similar safety endpoints and long-term efficacy as LAAO in patients without DM. PMID- 29999243 TI - High-Performance, Ultrathin, Ultraflexible Organic Thin-Film Transistor Array Via Solution Process. AB - Ultrathin organic thin-film transistors (OTFTs) have received extensive attention due to their outstanding advantages, such as extreme flexibility, good conformability, ultralight weight, and compatibility with low-cost and large-area solution-processed techniques. However, compared with the rigid substrates, it still remains a challenge to fabricate high-performance ultrathin OTFTs. In this study, a high-performance ultrathin 2,7-dioctyl[1]benzothieno[3,2 b][1]benzothiophene (C8-BTBT) OTFT array is demonstrated via a simple spin coating method, with mobility as high as 11 cm2 V-1 s-1 (average mobility: 7.22 cm2 V-1 s-1 ), on/off current ratio of over 106 , switching current of >1 mA, and a good yield ratio as high as 100%. The ultrathin thickness at ~380 nm and the ultralight weight at ~0.89 g m-2 enable the free-standing OTFTs to imperceptibly adhere onto human skin, and even a damselfly wing without affecting its flying. More importantly, the OTFTs show good electrical characteristics and mechanical stability when conformed onto the curved surfaces and even folded in a book after 100 folding cycles. These results illustrate the broad application potential of this simply fabricated ultrathin OTFT in next-generation electronics such as foldable displays and wearable devices. PMID- 29999244 TI - The Risk of Ischemic and Haemorrhagic Stroke in Idiopathic Inflammatory Myopathies: a Swedish population-based cohort study. AB - OBJECTIVE: To study the occurrence of ischemic (IS) and haemorrhagic stroke (HS) in idiopathic inflammatory myopathies (IIM) compared to the general population and to investigate how it varies by sex, age, clinical sub-diagnosis and time since IIM diagnosis. METHODS: All newly diagnosed IIM patients in Sweden were identified from the National Patient Register and general population comparators were identified from the Total Population Register. The study population was followed prospectively until death, emigration, December 2013 or first incident stroke. Incidence rates, rate differences and hazard ratios (HR) comparing IIM to the general population were estimated and stratified by age, sex, type of IIM and time since diagnosis. To account for the competing risk of death, the sub distribution HR was estimated using Fine and Gray models. RESULTS: We observed 34 and 229 stroke events in 663 IIM and 6673 comparators, respectively. The HR was elevated for IS, 2.1 (95%CI 1.4-3.0). Few HS events were identified but an increased risk was observed, 1.9 (95%CI 0.7-5.5). The association remained elevated for both outcomes when taking the competing risk of death into account. For IS, the rate difference was highest in the oldest age group (>=68 years) while the HR was highest in the youngest (<56 years). CONCLUSION: Our findings indicate that the risk of both IS and HS is elevated for individuals with IIM but it should be kept in mind that stroke is a rare event. Focus on prevention should be directed towards groups with the highest absolute risk, especially older patients. This article is protected by copyright. All rights reserved. PMID- 29999245 TI - Progress Curve Analysis Within BioCatNet: Comparing Kinetic Models for Enzyme Catalyzed Self-Ligation. AB - The estimation of kinetic parameters provides valuable insights into the function of biocatalysts and is indispensable in optimizing process conditions. Frequently, kinetic analysis relies on the Michaelis-Menten model derived from initial reaction rates at different initial substrate concentrations. However, by analysis of complete progress curves, more complex kinetic models can be identified. This case study compares two previously published experiments on benzaldehyde lyase-catalyzed self-ligation for the substrates benzaldehyde and 3,5-dimethoxybenzaldehyde to investigate 1) the effect of using different kinetic model equations on the kinetic parameter values, and 2) the effect of using models with and without enzyme inactivation on the kinetic parameter values. These analyses first highlight possible pitfalls in the interpretation of kinetic parameter estimates and second suggest a consistent strategy for data management and validation of kinetic models: First, Michaelis-Menten parameters need to be interpreted with care, complete progress curves are necessary to describe the reaction dynamics, and all experimental conditions have to be taken into consideration when interpreting parameter estimates. Second, complete progress curves should be stored together with the respective reaction conditions, to consistently annotate experimental data and avoid misinterpretation of kinetic parameters. Such a data management strategy is provided by the BioCatNet database system. PMID- 29999246 TI - A Successful Standardized Academic Inter-professional Post-licensure Education Program Exists to Train MSK Professionals to Become Advanced Practitioners in Arthritis Care: Lessons Learned from the ACPAC Program. AB - We read with interest the article in the most recent issue of Arthritis Care & Research "Core Curriculum to Facilitate the Expansion of a Rheumatology Practice to Include Nurse Practitioners and Physician Assistants" by Benjamin J. Smith et al., Vol 70(5) May 2018: pp 672-678. We can all agree that rapid access to rheumatology care has become increasingly important as early aggressive treatment with disease modifying anti-rheumatic drugs (DMARDs) and/or biologic agents can prevent irreversible joint damage and long-term disability in patients with inflammatory arthritis (IA). We were surprised, however, that reference to the efforts and successes of an already existing curricular-based and rigorously evaluated inter-professional, post-licensure education program- the Advanced Clinician Practitioner in Arthritis Care (ACPAC) Program1-3 )-went unacknowledged in this paper. This article is protected by copyright. All rights reserved. PMID- 29999248 TI - What is the evidence to support the association between metabolic syndrome and osteoarthritis? - A systematic review. AB - OBJECTIVE: There is conflicting evidence on the association between metabolic syndromes (MetS) with risk of osteoarthritis (OA). We aimed to systemically summarize the empirical evidence and discuss challenges in research methodologies in addressing this question. METHODS: We performed a systemic literature review based on PUBMED, EMBASE, Web of Science and Cochrane systemic review databases on published epidemiological studies that examined the association between MetS and risk of OA. We included cross-sectional studies, case control studies and cohort studies with appropriate covariate adjustments. We extracted information on prevalence, incidence, crude and adjusted effect estimates and the 95% confidence intervals from the articles or provided by the authors. We listed main methodological issues existing in current literature and provide recommendations for future research on this topic. RESULTS: We identified seven eligible studies on knee OA, three on hip OA, and three on hand OA. In studies which adjusted for BMI or weight, MetS was not significantly associated with risk of knee OA. No significant associations were reported for hip OA. For hand OA, the data were sparse and insufficient to reach a conclusion. Studies were mostly cross sectional, exposure with only one time measurement, few with incident outcomes, and covariate adjustment was often insufficient. CONCLUSION: Our review was unable to reach a definitive conclusion due to insufficient data although data suggest that knee and hip OA are not associated with MetS. Future longitudinal studies with incident OA cases, repeated measurement of MetS, and appropriate covariate adjustment are needed. This article is protected by copyright. All rights reserved. PMID- 29999247 TI - Combination of resveratrol and 5-azacytydine improves osteogenesis of metabolic syndrome mesenchymal stem cells. AB - Endocrine disorders have become more and more frequently diagnosed in humans and animals. In horses, equine metabolic syndrome (EMS) is characterized by insulin resistance, hyperleptinemia, hyperinsulinemia, inflammation and usually by pathological obesity. Due to an increased inflammatory response in the adipose tissue, cytophysiological properties of adipose derived stem cells (ASC) have been impaired, which strongly limits their therapeutic potential. Excessive accumulation of reactive oxygen species, mitochondria deterioration and accelerated ageing of those cells affect their multipotency and restrict the effectiveness of the differentiation process. In the present study, we have treated ASC isolated from EMS individuals with a combination of 5-azacytydine (AZA) and resveratrol (RES) in order to reverse their aged phenotype and enhance osteogenic differentiation. Using SEM and confocal microscope, cell morphology, matrix mineralization and mitochondrial dynamics were assessed. Furthermore, we investigated the expression of osteogenic-related genes with RT-PCR. We also investigated the role of autophagy during differentiation and silenced PARKIN expression with siRNA. Obtained results indicated that AZA/RES significantly enhanced early osteogenesis of ASC derived from EMS animals. Increased matrix mineralization, RUNX-2, collagen type I and osteopontin levels were noted. Furthermore, we proved that AZA/RES exerts its beneficial effects by modulating autophagy and mitochondrial dynamics through PARKIN and RUNX-2 activity. PMID- 29999249 TI - Influence of acid hydrolysis, saponification and sample clean-up on the measurement of phytosterols in dairy cattle feed using GC-MS and GC with flame ionization detection. AB - The fortification of processed foods including dairy products is increasingly commonplace with phytosterols among many compounds used to improve the nutritional value of food products. It is also increasingly common practice for some dairy cattle feeds to be fortified for their potential to increase phytosterol levels in milk. In this study, a combined, streamlined protocol using acid hydrolysis, saponification and sample clean-up was developed to enable the rapid and reliable measurement of phytosterols. The method was developed with focus on streamlining the overall technique to make it suitable for commercial laboratories, to reduce labor and consumable costs, while maintaining accuracy. A total of 12 different feed types commonly used in the dairy industry were analyzed with the highest and lowest sterol contents found in cotton seed oil and tannin with average phytosterol contents of 256 and <30 mg per 100 g, respectively. With a limit of reporting of 30 mg/kg for individual sterols and a correlation coefficient > 0.99, the method was validated for milk to enable feed comparison studies with respect to the total phytosterol content in raw milk. PMID- 29999250 TI - "Smart" Nanoprobes for Visualization of Tumor Microenvironments. AB - Physiological parameters in tumor microenvironments, including hypoxia, low extracellular pH, enzymes, reducing conditions, and so on, are closely associated with the proliferation, angiogenesis, invasion, and metastasis of cancer, and impact the therapeutic administrations. Therefore, monitoring the tumor microenvironment is significant for diagnosing tumors, predicting the invasion potential, evaluating therapeutic efficacy, planning the treatment, and cancer prognostics. Noninvasive molecular imaging technologies combined with novel "smart" nanoparticle-based activatable probes provide a feasible approach to visualize tumor-associated microenvironment factors. This review summarizes recent achievements in the designs of "smart" molecular imaging nanoprobes responding to the tumor microenvironment-related features, and highlights the state of the art in tumor heterogeneity imaging. PMID- 29999251 TI - Fluorophobic Effect Promoting Lamellar Self-Assembly of Donor Acceptor Dyes. AB - To combine liquid crystalline and linear optical properties in the same molecule, the fluorophobic effect was probed for the first time in donor acceptor dyes. Thus, a series of mono-, bi-, and tricyclic donor acceptor dyes with 1H,1H perfluorinated alkyl chains of different lengths as donor units and nitrile, malononitrile or barbiturate as acceptor units was synthesized in 5 steps and 1.4 6.6 % overall yield. UV/Vis and fluorescence spectroscopy, cyclic voltammetry and DFT calculations revealed that absorption and emission maxima, Stokes shifts and LUMO energies were mainly governed by the chromophore size and acceptor strengths. The perfluorinated chain was electronically almost decoupled from the remaining chromophore and induced only slight changes of the absorption maxima as compared to the alkyl substituted counterparts. However, in contrast to the non mesomorphic alkyl donor-substituted derivatives, the perfluorinated donors resulted in self-assembly into partially interdigitated SmA bilayers according to differential scanning calorimetry (DSC), polarizing optical microscopy (POM), X ray diffraction (WAXS, SAXS) studies and electron density profile calculations. PMID- 29999252 TI - The Effect of Pre-appointment Consult Triage on Patient Selection and Revenue Generation in a University Rheumatology Practice. AB - OBJECTIVE: To evaluate the effectiveness of pre-appointment consult screening to identify patients with autoimmune and inflammatory rheumatic diseases (AIRD) and to evaluate the revenue implications of routine outpatient care of AIRD patients compared to non-AIRD patients. METHODS: Using data recorded in the electronic medical record, all new outpatient rheumatology consults sent during a 9 month period were retrospectively analyzed for final diagnosis and revenue generation for routine outpatient care over one year following consult review or initial evaluation. RESULTS: A total of 961 consults were received and underwent pre appointment triage. Overall, 673 consults were approved for AIRD evaluation and 288 consults were declined to be seen. Patients were seen an average of 13 days after consult review. Of approved consults, 597 came for evaluation with 357 diagnosed as having an AIRD and 240 with a non-AIRD. Of the declined consults, 128 had one year followup data with 6 patients eventually diagnosed as having an AIRD (consult triage sensitivity 98%, positive predictive value 60%). The consult triage system allowed more AIRD patients to be seen over a one year period. Revenue data for outpatient care was available for 318/357 AIRD patient and 192/240 non-AIRD patients showing that care of AIRD patients generates 44 times more revenue compared to non-AIRD patients ($5877/AIRD pt vs $134/non-AIRD pt, p< 0.001). CONCLUSION: Pre-appointment consult screening is an effective method to identify patients with an AIRD. This enables timely access to care for patients with the highest need of evaluation and results in significantly more revenue generation. This article is protected by copyright. All rights reserved. PMID- 29999253 TI - Validation of a windowing protocol for accurate in vivo tooth segmentation using i-CAT cone beam computed tomography. AB - BACKGROUND: Validation of three-dimensional (3D) reconstructions of full dental arches with crowns and roots based on cone beam computed tomography (CBCT) imaging represents a key issue in 3D digital dentistry. OBJECTIVES: The aim of the study was to search for the most accurate in vivo windowing-based manual tooth segmentation using CBCT. The null hypothesis was that all applied windowing protocols were equivalent in terms of in vivo tooth volume measurement using CBCT. MATERIAL AND METHODS: This retrospective study was based on preoperative CBCT images from patients who underwent further tooth extractions for reasons independent of this study. Written informed consent was obtained from all the participants, and the study was approved by the Ethics Committee of Cliniques Universitaires Saint Luc (Brussels, Belgium). The radiological protocol was I-CAT CBCT, 0.3 mm slice thickness, 8 cm * 16 cm field of view, 120 kVp, and 18 mAs. A total of 36 teeth were extracted from 14 patients between the ages of 18 and 68 years. Using 3D Slicer software, segmentations were performed twice by 2 independent observers, with a 1-month time period between the 2 segmentations to study intraand inter-observer repeatability and reproducibility. Four windowing protocols (level/window) were applied: 1. 1131/1858, 2. 2224/4095, 3. 1131/4095, and 4. AUTO, an automatic protocol provided by default by the software. A total of 576 segmentations were performed. Tooth volumes were automatically calculated using the software. To compare the volumes obtained from CBCT segmentations with a gold-standard method, we laser-scanned the extracted teeth. RESULTS: Excellent intraand inter-observer intraclass correlations were found for all of the protocols used. The best windowing protocol was 1131/1858 for both observers. Tooth volumes were obtained by manual segmentation of the CBCT images and using windowing protocol 1131/1858. No significantly different tooth volumes were found by laser scanning. CONCLUSIONS: Our null hypothesis was rejected. Only windowing protocol 1131/1858 allowed for significantly closer 3D in vivo segmentation of a tooth compared to I-CAT CBCT, with excellent intra-observer repeatability and inter-observer reproducibility. PMID- 29999254 TI - Parkinson Disease: Current and Emerging Treatment Strategies. AB - Although levodopa is effective for treating Parkinson disease, physicians and patients face significant management challenges related to disease progression. Patients may develop fluctuations in motor symptoms and dyskinesias as well as nonmotor symptoms. Review this CME Brief Report activity to learn about new and emerging treatment options to manage patients' symptoms. PMID- 29999255 TI - A novel solution to the nursing workforce crisis: recruitment of overseas nurses living locally. AB - Aneurin Bevan University Health Board has recruited nurses from overseas from within and outside the European economic area. This article describes an innovative recruitment initiative that has focused on nurses who trained overseas and are living and working in the local community, but cannot work in a registered nurse role without financial and practical support. It provides an overview of the robust selection processes used, which are in line with the Nursing and Midwifery Council registration requirements, and the stepwise employment offer made to successful applicants. PMID- 29999256 TI - Informing Consent: Medical Malpractice and the Criminalization of Pregnancy. AB - Since the early 1990s, jurisdictions around the country have been using civil child abuse laws to penalize women for using illicit drugs during their pregnancies. Using civil child abuse laws in this way infringes on pregnant women's civil rights and deters them from seeking prenatal care. Child Protective Services agencies are key players in this system. Women often become entangled with the Child Protective Services system through their health care providers. Providers will drug test pregnant women without first alerting them to the potential negative consequences stemming from a positive drug test. Doing so is a breach of these providers' duties to obtain informed consent from their patients before administering medical tests. Malpractice liability can deter providers from forcing women into the Child Protective Services system and forestall the use of civil child protective laws to criminalize pregnancy. PMID- 29999257 TI - One pharmacy world-view 1963-74 using perspectives of SchUtz. PMID- 29999258 TI - Stream of Consciousness. PMID- 29999259 TI - Historical Evidence of Treating Vitiligo in Persia. PMID- 29999260 TI - Stream of Consciousness. PMID- 29999261 TI - The impact of rabies and its treatment until the 19th Century: a lesson from the past. PMID- 29999263 TI - Learning on the Job for People with Disabilities. AB - Possessing the skills needed to successfully perform higher-paying jobs in the 21st century remains a significant barrier to employment for people with disabilities. (1) The labor participation rate for people with disabilities is 20 percent, compared to 68 percent for those without a disability. (2) The U.S. Army offers a summer apprenticeship program for high school students from groups historically under-represented in science, technology, engineering and math subjects, including students with disabilities. PMID- 29999264 TI - The First Hu ndred Year s of Western Pharmacy in Coloni al Hong Kong ( 1841-1940). PMID- 29999265 TI - Two 17th century skin balms for warts and pimples? PMID- 29999266 TI - 'Golden Liberty': A Remarkable Time for the Apothecaries of Krakow in the Early Modern Era (16th to 18th centuries). PMID- 29999268 TI - Sergeant Peter Irvine, Pharmaceutical Chemist, RAMC (1876-1949). PMID- 29999267 TI - Persistent Polypharmacy: the case of Lady Allen's Water. PMID- 29999269 TI - Qairooti (Cerate or Cera Beeswax Salve) in Medieval Persia. PMID- 29999270 TI - Edward John Waring (1819-1891) in India. PMID- 29999271 TI - Examining Scope of Practice for Health Care Workers. AB - Twenty-eight states have enacted scope of practice legislation since 2015. (1) Nearly 80 percent of nurse practitioners deliver primary care. (2) In rural and underserved areas, physician assistants may be the primary care providers at clinics where a physician is present only a few days a week. PMID- 29999272 TI - 'Baqaee Collection': A Qarabadin book of the 18th century. PMID- 29999273 TI - Patient Perspectives of Obstetrician-Gynecologists as Primary Care Providers. AB - OBJECTIVE: To examine women?s perceptions of their obstetrician/gynecologist (ob gyn) as primary care provider (PCP) and comfort in receiving primary care services in an ob-gyn setting. STUDY DESIGN: Survey regarding women?s use of their ob-gyn provider as a PCP, their desire and comfort in receiving primary care services from them, and their perceptions of their ob-gyn?s delivery of primary care. Associations were assessed between use of an ob-gyn as PCP and various demographic and attitudinal factors, as well as patients? perceptions of primary care performance RESULTS: The response rate was 48% (1,404/2,916). Overall, the majority of participants responded that routine primary care services are available at their ob-gyn office and that they were comfortable receiving those services from their ob-gyn. Twenty percent of respondents considered their ob-gyn as their PCP, 52% considered another provider their PCP, and 28% of women did not identify a PCP. Women who were pregnant, mothers of newborns, and patients without a chronic health condition were more likely to identify their ob-gyn as their PCP. CONCLUSION: A substantial proportion of women consider their ob-gyn their primary care provider and do not visit another provider regularly. While ob-gyns may not consider themselves as PCPs, they are often perceived as such by patients. PMID- 29999274 TI - Do Different Modes of Labor Induction Affect the Overall Success and Risk of Trial of Labor After Cesarean Section? AB - OBJECTIVE: To determine whether different modes of labor induction impact the success rate and perinatal morbidity in women undergoing trial of labor after cesarean (TOLAC).STUDY DESIGN: Retrospective review of the Consortium on Safe Labor electronic database from 2002?2008; women with a prior cesarean birth, desiring TOLAC, and requiring induction of labor were included. Oxytocin and Foley bulb induction methods were compared to amniotomy alone. Prostaglandin use was also reviewed but, given the small numbers, was not the focus of this study.RESULTS: Univariate analysis showed significantly greater incidence of hemorrhage >1,000 mL (p=0.0030) and transfusion (p=0.0076) with Foley bulb use. All methods of induction for TOLAC decreased repeat cesarean sections (OR 0.34, 95% CI 0.23?0.52, p<0.01).CONCLUSION: Induction of labor does not alter the success rate for TOLAC candidates, regardless of mode of induction. When choosing induction methods, one should be mindful of the apparent additional risk of increased blood loss and transfusion with intracervical Foley bulb usage. PMID- 29999275 TI - Is There a Role for Hyperglycosylated hCG in the Diagnosis of Ectopic Pregnancy in Women with a Pregnancy of Unknown Location? AB - OBJECTIVE: To examine the potential use of hyperglycosylated human gonadotropin (hCG-H) in identifying ectopic pregnancies in pregnancies of unknown location (PULs) on ultrasound scan.STUDY DESIGN: This was a prospective observational study. An additional blood sample was taken from women whose initial transvaginal ultrasound scan showed none of the following: intact intrauterine pregnancy, retained placental tissue, or ectopic pregnancy. Parallel sandwich ELISAs were performed using sheep monoclonal antibodies to the 12F6 epitope for detection of total hCG and to the 4D8 epitope for hCG-H detection, and an automated immunoassay technique was used for progesterone and serum beta-hCG measurements. Patients were managed accord-ing to our standard clinical protocol.RESULTS: hCG-H was significantly higher in ectopic pregnancies (85.6 ng/mL) than in viable intrauterine pregnancies (26.8 ng/mL) and spontaneously resolving pregnancies (23.2 ng/mL). The ability to distinguish ectopic pregnancies from nonectopic pregnancies, expressed as area under the curve, was 0.816 for hCG-H and 0.824 for total hCG.CONCLUSION: Women with an underlying ectopic pregnancy tended to have higher hCGs, whichever assay was used. However, the current study does not support a role for a single measurement of hCG-H in the diagnosis of ectopic pregnancy within the PUL population. PMID- 29999276 TI - Increased Expression of Thioredoxin-1 Binding Protein-2 in Placentas in Preeclampsia. AB - OBJECTIVE: To examine the expressions of thioredoxin-1 (TRX-1) and thioredoxin-1 binding protein-2 (TBP-2) in placentas affected by preeclampsia.STUDY DESIGN: We examined the mRNA levels of TRX-1, TBP-2, cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-alpha) in preeclamptic (n=20) and normal placentas (n=18) by quantitative reverse transcriptase-polymerase chain reaction.RESULTS: We found the mRNA level of TRX-1 was significantly decreased (p<0.005), while the mRNA levels of TBP-2, COX-2, and TNF-alpha were significantly increased in the placentas in preeclampsia when compared to the normal group (p<0.005).CONCLUSION: These data suggest that TBP-2 may play roles in the pathophysiology of preeclampsia, probably by contributing to oxidative stress and inflammation. Thus, TBP-2 may be a potential therapeutic target for preeclampsia. PMID- 29999277 TI - Human Trafficking and the Health Care System. AB - (1) Human trafficking in the United States is believed to be on the rise, although comprehensive data is hard to come by. (2) At least 22 states have established funds to enhance their efforts to eradicate human trafficking. (3) Some states are working to educate the public about the National Human Trafficking Hotline, 1-888-373-7888 (TTY: 711). PMID- 29999278 TI - Effects of Levonorgestrel Intrauterine System on Patients with Female Sexual Dysfunction. AB - OBJECTIVE: To examine the effects of a levonorgestrel-releasing intrauterine device (LID) in patients with female sexual dysfunction and who were using this device for contraception.STUDY DESIGN: The results before device application and at the 6-month follow-up were compared using the female sexual function index (FSFI) test on a sample of 36 patients with female sexual dysfunction who had requested the use of the LID for contraception.RESULTS: The FSFI scores before the placement of an LID and at 6-month follow-up were determined to be 19.3+/-4.8 and 21.1+/-3.8 (p<0.001), respectively. In addition, the visual analog scale scores and menstruation duration were determined to be statistically significantly different before and after placement. When the FSFI subgroup evaluations were performed, the desire and arousal parameters before and after the application were determined to be statistically significantly different.CONCLUSION: The use of an LID for contraception resulted in positive effects in patients with female sexual dysfunction. PMID- 29999279 TI - Attributes That Fellowship Directors Value in the Selection of Reproductive Endocrinology and Infertility Fellows. AB - OBJECTIVE: To investigate which attributes of reproductive endocrinology and infertility (REI) fellowship applicants are most valued by fellowship program directors during the match process.STUDY DESIGN: An electronic survey was administered to determine characteristics most favored by program directors in the selection of REI fellows. A 5-point Likert scale was utilized to rank characteristics, with 1 being "most important" and 5 being" least important." The main outcome measures were factors desired by REI fellowship directors.RESULTS: The overall response rate was 61%. Objective factors that ranked highly were training at a competitive obstetrics and gynecology (OB/GYN) residency program, and clinical or basic science research experience. First authorship research ranked favorably regardless of whether it was in the form of a peer-reviewed paper, oral presentation, or poster abstract. Personal interview and perceived ability to work well with others were subjective factors considered favorably by REI fellowship directors.CONCLUSION: When selecting REI fellows for interviews, fellowship directors value candidates who have trained at competitive OB/GYN residency programs, who have clinical or basic science research experience, and who have contributed to scientific literature as first author. When subsequently ranking fellowship applicants, however, the most important factors are those found in the interview process, such as identification as a "team player". PMID- 29999280 TI - Conservative Treatment for Patients with Carcinoma in Situ-Positive Margins After a Loop Electroexcisional Procedure: Is It Safe? AB - OBJECTIVE: To investigate the clinical significance of and appropriate treatments for carcinoma in situ (CIS)-positive margin after a loop electroexcisional procedure (LEEP) in the management of squamous carcinoma in situ (SCIS), adenocarcinoma in situ (ACIS), and microinvasive carcinoma (MIC).STUDY DESIGN: We analyzed 232 patients who underwent a hysterectomy for CIS-positive margin. We investigated the relationship between residual lesions after hysterectomy and clinical parameters, including age, LEEP method, histologic grade of conized cervix, location of the positive margin after LEEP, results of endocervical curettage (ECC), and size of the conized specimen.RESULTS: Age, LEEP method, proximal endocervical margin positivity, and ECC positivity differed significantly between patients with residual lesions and those with no residual lesions. In a comparison between groups with residual disease of a higher or lower grade than MIC, age, LEEP method, ECC positivity, and histologic grade of conized cervix were significantly different. Age, histologic grade of conized cervix, and ECC positivity were clinical parameters significantly contributing to invasive residual lesion in multivariate regression analysis. There were no residual invasive (MIC or advanced invasive cancer) lesions observed in women <50 years old who had SCIS conized lesions after hysterectomy.CONCLUSION: Conservative treatment with close follow-up or reconization for women <50 years old who have conized SCIS lesions without ECC positivity is acceptable. However, this study does not present sufficient evidence for the conservative treatment of conized ACIS or MIC lesions with CIS-positive margins. PMID- 29999281 TI - Postpartum Contraception Use Rates of Patients Participating in the Centering Pregnancy Model of Care Versus Traditional Obstetrical Care. AB - OBJECTIVE: To examine whether postpartum contraceptive rates are higher in the CenteringPregnancy population as compared to patients who choose to participate in traditional prenatal care. Centering Pregnancy is a model of obstetrical care that allows for enhanced contraceptive education.STUDY DESIGN: All patients who were delivered within the Florida State University College of Medicine Obstetrics and Gynecology residency from October 31, 2010, to October 31, 2011, were included in the study. A retrospective chart review was undertaken to compare the postpartum contraceptive use of patients in traditional obstetric care versus patients in CenteringPregnancy.RESULTS: A total of 472 obstetrical charts were reviewed, with 350 women participating in traditional care and 122 women in CenteringPregnancy. Using Fisher's exact test, the 2 groups' postpartum contraceptive use was compared. Analysis revealed that 57.4% of CenteringPregnancy patients returned for postpartum contraception, vs. 37.7% of traditional prenatal care patients. Furthermore, 24.5% of CenteringPregnancy patients chose long-acting reversible contraception as compared to only 8.28% of traditional patients.CONCLUSION: Centering Pregnancy leads to an increase in use of postpartum contraception when compared to traditional prenatal care. Long acting reversible contraceptive usage rates were also significantly higher among CenteringPregnancy patients and were the most frequently chosen method of family planning. PMID- 29999282 TI - Comparison of Connexin43 in Cumulus Cells Between Poor and Non-Poor Responders Undergoing in Vitro Fertilization. AB - OBJECTIVE: To detect expression of connexin43 in cumulus cells and compare the differences between poor and non-poor ovarian responders undergoing in vitro fertilization (IVF), and to determinate whether the expression of connexin43 correlates with pregnancy outcome.STUDY DESIGN: A total of 152 infertile women undergoing IVF were included in this study. Patients were divided into 2 groups: poor ovarian responders and non-poor ovarian responders. Cumulus cells were collected from oocytes and were analyzed by Western blot for connexin43. Meanwhile, clinical data were obtained.RESULTS: The incidence of poor ovarian response was 18.42% (28/152). Connexin43 was detected in the cumulus cells of all the patients. The relative quantity of connexin43 in the poor responder group (1.11 [0.34, 2.11]) was much lower than that of the non-poor responder group (2.68 [1.41, 4.96]). There was significant difference in connexin43 between pregnant women and non-pregnant women. When adjusting for ovarian response, it yielded similar results.CONCLUSION: Expression of gap junction protein correlates with quantity of oocytes retrieved and might be related to pregnancy outcome. This study suggests that lack of connexin43 expression may contribute to poor ovarian response. PMID- 29999283 TI - [Progress of Detection Technology of Ultra-Broadband THz Time-Domain Spectroscopy]. AB - Terahertz Time-Domain Spectroscopy (THz-TDS) is one of the effective coherent detection techniques. It has been widely applied in materials, chemistry, biology, security and other fields due to its capabilities such as high signal-to noise ratio (SNR), broadband detection, working at room temperature, time resolved measurement and others. Limited by the spectrum bandwidth of THz radiation and detection techniques, the measuring range of the traditional THz TDS system is generally less than several THz, thus the spectral information of high frequencies cannot be obtained. In order to expand its application, there is an urgent need for the development of ultra-broadband (>=10 THz) THz-TDS detection techniques. This paper reviews the development and applications of main detection techniques in ultra-broadband THz-TDS. The advantages and disadvantages of these techniques are also analyzed. PMID- 29999284 TI - Sugary Beverage Consumption Among California Children and Adolescents. AB - This policy brief examines patterns of sugary beverage consumption among children and adolescents in California. Using data from the California Health Interview Survey (CHIS), this study found that while sugary beverage consumption decreased among adolescents ages 12-17 between 2011-12 and 2013-14, it increased among children under age 12 between 2009 and 2013-14. The trend among children under age 12 may be attributed to a shift in sugary beverage consumption from soda to sports and energy drinks. Establishing and strengthening policies that focus on reducing consumption of sugary beverages could counter the increasing consumption trend among younger children as well as result in further reductions in consumption among teens. PMID- 29999285 TI - [Atmospheric Correction for HJ-1 CCD Data Coupling with Aerosol Models of Beijing Tianjin-Hebei Region]. AB - Current atmospheric correction of HJ-1 CCD does not take the aerosol models of Chinese specific regions into consideration. This paper proposes a method of atmospheric correction coupling local aerosol models. Choosing Beijing-Tianjin Hebei region as the study area, aerosol model parameters of the method on the foundation of AERONET inversion are analyzed and four types of aerosol model parameters of Beijing-Tianjin- Hebei regions are clustered to build the lookup table for the inversion of aerosol optical thickness. Lack of SWIR (2.12 MUm) in the bands of HJ-1 CCD , the blue(0.43~0.52 MUm) and red(0.63~0.69 MUm) cannot be calculated like the MODIS. So the ratio of blue and red is used as the basis of error equation for aerosol optical depth retrieval, with no need of ground target reflectance. HJ-1 CCD data after atmospheric correction are compared with MODIS surface product data (MOD09) and ASD measurements. The results show that the reflectance obtained by the atmospheric correction is close to the ASD measurement results, and there is a strong correlation with MOD09, the average correlation coefficient in the red band reached more than 0.8, the one of blue band affected by molecule mostly is up to 0.75. PMID- 29999286 TI - Crosstalk between gonadotropins and thyroid axis. AB - Gonadotropins and thyroid hormones are essential, respectively, for reproduction and metabolism. The classical endocrinological approach is based on the detection of axes that start from the hypothalamus and arrive at the final effector organ, in this case gonads and thyroid. However, several clues suggest that these axes do not work in parallel, but they dialogue with each other. In this article, we review evidences demonstrating crosstalk between gonadotropins and thyroid axis. Firstly, there is an undeniable structural similarity of both hormones and receptors, maybe due to a common ancient origin. This structural similarity leads to possible interaction at the receptor level, explaining the influence of thyroid stimulating hormone on gonadal development and vice versa. Indeed, altered levels of thyroid hormones could lead to different disorders of gonadal development and function throughout entire life, especially during puberty and fertile life. We here report the current knowledge on this item both in males and in females. In particular, we deepen the interaction between thyroid and gonads in two situations in females: polycystic ovary syndrome, the most frequent cause of menstrual alteration, and pregnancy. PMID- 29999287 TI - beta-arrestins and biased signaling in gonadotropin receptors. AB - Gonadotropin receptors include the follicle stimulating hormone receptor (FSHR) and the luteinizing hormone/choriogonadotropin receptor (LHCGR), both belong to the G protein-coupled receptor (GPCR) superfamily and are essential to reproduction. FSHR is activated by follicle stimulating hormone (FSH) while LHCGR is activated by either luteinizing hormone (LH) or choriogonadotropin (CG). Upon ligand binding, gonadotropin receptors undergo conformational changes that lead to the activation of the heterotrimeric G protein, resulting in the production of different second messengers. Gonadotropin receptors can also recruit and bind beta-arrestins. This particular class of scaffold proteins were initially identified to mediate GPCRs desensitization and recycling, but it is now well established that beta-arrestins can also initiate Gs-independent signaling by assembling signaling modules. Furthermore, new advances in structural biology and biophysical techniques have revealed novel activation mechanisms allowing beta arrestins and G proteins to control signaling in time and space. The ability of different ligands to preferentially elicit G- or beta-arrestin-mediated signaling is known as functional selectivity or biased signaling. This new concept has switched the view of pharmacology efficacy from monodimensional to multidimensional. Biased signaling offers the possibility to separate therapeutic benefits of a drug from its adverse effects. The proof of concept that gonadotropin receptors can be subjected to biased signaling is now established. The challenge will now be the design of molecules that can specifically activate beneficial signaling pathway at gonadotropin receptors while reducing or abolishing those leading to side effects. Such strategy could for instance lead to improved treatments for infertility. PMID- 29999288 TI - Update on oogenesis in vitro. AB - INTRODUCTION: Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. Alternately to the autologous transplantation, the development of culture systems that support oocyte development from the primordial follicle stage represent a valid strategy to restore fertility. The aim of this study is to review the most recent data regarding oogenesis in vitro and to provide an up-to-date on the contemporary knowledge of follicle growth and development in vitro. EVIDENCE ACQUISITION: A comprehensive systematic MEDLINE search was performed since February 2018 for English-language reports by using the following terms: "ovary," "animal and human follicle," "in vitro growth and development," "ovarian tissue culture," "fertility preservation," "IVM," "oocyte." Previous published reviews and recent published original articles were preferred in order to meet our study scope. EVIDENCE SYNTHESIS: Over time, many studies have been conducted with the aim to optimize the characteristics of ovarian tissue culture systems and to better support the three main phases: 1) activation of primordial follicles; 2) isolation and culture of growing preantral follicles; 3) removal from the follicle environment and maturation of oocyte cumulus complexes. While complete oocyte in vitro development has been achieved in mouse, with the production of live offspring, the goal of obtaining oocytes of sufficient quality to support embryo development has not been completely reached into higher mammals despite decades of effort. CONCLUSIONS: Over the years, many improvements have been made on ovarian tissue cultures with the future purpose that patients will be provided with a greater number of developmentally competent oocytes for fertility preservation. PMID- 29999289 TI - Programmed cell death in the human ovary. AB - During a woman's reproductive life, only about 400 primordial follicles will develop into a preovulatory follicle and undergo ovulation, releasing an oocyte available for fertilization. The process of formation and selection of these follicles is complex and involves a multistep process characterized by a balance between survival and death of the oocytes and the surrounding follicular cells. Although the mechanisms underlying such process are not completely clarified yet, it is common idea that they can occur through various types of programmed cellular death (PCD). Since atresia is the principal destiny of the ovarian follicles, it is relevant to understand how this process takes place and how it is regulated. In this review, after a summary description of folliculogenesis in humans, the main mechanisms of atresia reported to occur during folliculogenesis from birth to adult age, in the human ovary and in other mammals when appropriate, are described. PMID- 29999290 TI - Association Between Ovarian Volume-Related Dynamic Parameters and Outcomes of IVF. AB - OBJECTIVE: To investigate the relationship between ovarian volume-related parameters and in vitro fertilization (IVF) outcomes in order to establish an accurate and reliable method of determining ovarian response or IVF outcomes.STUDY DESIGN: A total of 142 women undergoing controlled ovarian stimulation with gonadotropin-releasing hormone agonist were retrospectively analyzed. In each ovary, diameters in 2 perpendicular planes were measured and calculated by applying the formula for an ellipsoid: (D1xD2x(D1+D2/2)xpi/6). The total basal ovarian volume (BOV) was calculated as the sum of the bilateral ovarian volume. Total follicular volume (TFV) was defined as sum of bilateral follicular volume. The study subjects were grouped by TFV/BOV and by TFV/BOV/stimulation days.RESULTS: A significantly higher number of oocytes was retrieved in the participants with a higher TFV/BOV (p=0.002). The patients with higher TFV/BOV/stimulation days also demonstrated a significantly higher serum estradiol level on the hCG day and a higher number of retrieved oocytes (p=0.04 and 0.02, respectively). In a multivariate analysis, the TFV/BOV/stimulation days had a significant independent effect on the number of transferred embryos (p=0.01).CONCLUSION: Ovarian volume-related dynamic parameters play an important role in predicting ovarian response and IVF outcomes. PMID- 29999291 TI - Applicability of sentinel lymph node biopsy in papillary thyroid cancer. AB - BACKGROUND: The optimal surgical management of papillary thyroid cancer (PTC) for T1-T2 tumors without pre or intrasurgical evidence of lymph node metastasis (cN0) remains controversial, since approximately 40% of patients have lymph node involvement (pN1) which becomes evident when a prophylactic lymphadenectomy (PL) is performed. The aim of this study was to investigate the feasibility of sentinel lymph node (SLN) identification with SPECT/CT lymphoscintigraphy imaging along with intraoperatory image techniques in early stages of PTC undergoing PL of central neck compartment (CNC). METHODS: A single-center, prospective consecutive study was designed for SLN mapping in patients with high suspicion of PTC (Bethesda V or VI) in early stage (cT1-2, cN0). Twenty-four patients underwent SLN identification with preoperative SPECT/CT and planar images (99mTc nanocolloid albumin intratumoral injection). During surgery, SLN located in CNC was found by means of a gamma probe and portable gamma camera, and excised. Afterwards, CNC lymphadenectomy was performed in all cases without modifying the established protocol. RESULTS: SLNs were identified and accurately located in 23 (95.8%) patients. Nodal metastases (pN1) were confirmed in 9 (37.5%) patients, with one false negative case. The sensitivity was 88.9% and negative predictive value (NPV) was 93.3%, would have allowed to avoid PL in more than half of cases, a higher proportion than those found in other similar studies. No complications associated with the procedure were observed. CONCLUSIONS: Our results support that SLN biopsy by SPECT/CT along with intraoperatory image techniques is applicable in early stages of PTC (cT1-2, cN0), allowing to avoid unnecessary PL. PMID- 29999292 TI - Vaginal Progesterone Gel for Luteal Support After Cleavage Stage Embryo Transfer: Once or Twice a Day? AB - OBJECTIVE: To determine whether twice daily dosing of progesterone vaginal gel (PVG) is better for luteal phase support (LPS) than once daily dosing.STUDY DESIGN: Retrospective study including 456 women aged <=42 years who underwent assisted reproductive technology with long GnRH agonist protocol. Blastocyst transfers and difficult embryo transfers were excluded. LPS was started with 90 mg PVG once daily on the evening of oocyte retrieval and continued until negative pregnancy test or 10th week of pregnancy in both groups. PVG dosage was doubled on the day of embryo transfer in the twice-daily group.RESULTS: Age, duration of infertility, and number of oocytes collected were similar. Numbers of embryos transferred were 2.9 and 2.8 in the once-daily and twice-daily groups, respectively (p=0.04). Embryo implantation (23.96% vs. 27.95%) and clinical pregnancy (50.9% vs. 56.5%) rates favored twice-daily dosage; however, differences were statistically nonsignificant, and the study had 20% power to demonstrate significance. When our results were pooled with a prior trial comparing once and twice daily dosing, twice daily dosing seemed to significantly increase clinical pregnancy rate (rate ratio: 1.18, 95% CI 1.01-1.38).CONCLUSION: Trends favoring twice daily dosing are encouraging findingsand require further investigation. PMID- 29999293 TI - Intimate Partner Violence During Pregnancy and Maternal and Neonatal Health Among Hispanic Women. AB - OBJECTIVE: To examine the prevalence and the effect of intimate partner violence (IPV) during pregnancy on maternal and neonatal health outcomes among Hispanics.STUDY DESIGN: A cross-sectional survey was conducted among Hispanic women who delivered at a Houston hospital between January 2011 and October 2012; 613 women completed self-administered questionnaires in the postpartum window prior to discharge. Indices of maternal and neonatal health were compared between women with and without reports of IPV during the most recent pregnancy.RESULTS: Approximately 11% of the surveyed population reported having experienced IPV during the most recent pregnancy. Among non-U.S. born participants, women who experienced IPV reported longer U.S. stay (11.4+/-7.3 years) as compared to women who did not (9.2+/-6.3 years). They were more likely to be unhappy about their pregnancy and to have evidence of depres-sion. Reported IPV was also associated with later initiation of prenatal care, a greater likelihood of delivery before 34 weeks' gestational age, lower infant birth weight, and lower likelihood of planning to breastfeed beyond 12 months (aOR 0.43, CI 0.21-0.83; p=0.02).CONCLUSION: IPV during pregnancy is associated with adverse maternal and neonatal health outcomes. Prenatal programs should assess Hispanic women for IPV during pregnancy with the goal of mitigating its long-term health consequences. PMID- 29999294 TI - Septic Shock and Multiple Organ Failure After Office Endometrial Sampling. AB - BACKGROUND: Office endometrial biopsy with a Pipelle cannula is the main method for sampling the endometrial lining. The Pipelle biopsy is safe, efficient, and cost effective. This office endometrial sampling method is also an accurate and safe procedure for endometrial sampling of patients with endometrial carcinoma. It is associated with minimal pain and does not require anesthesia.CASE: Pipelle is the most common method used for sampling the endometrial lining. No data are available of infectious complications related to endometrial biopsy. The incidence is presumed to be negligible. We present an unusual case of a 52-year old woman who experienced septic shock and multiple organ failure following Pipelle endometrial sampling.CONCLUSION: Lower abdominal pain is the cardinal presenting symptom in woman with pelvic infection. Our case emphasizes that an atypical symptom such as abdominal pain after endometrial biopsy could be a sign of infectious complications. PMID- 29999295 TI - Mirror Syndrome Associated with 18p Deletion Syndrome. AB - BACKGROUND: Mirror syndrome is defined as the development of maternal edema in association with fetal hydrops. This rare disease is called mirror syndrome due to the presence of maternal edema that "mirrors" the fetal and placental condition.CASE: We report the first case of mirror syndrome associated with 18p deletion.CONCLUSION: Cytogenetic analysis should be considered in mirror syndrome to identify the underlying cause. PMID- 29999296 TI - Purtscher-like Retinopathy After Placental Abruption. AB - BACKGROUND: Pregnant women are susceptible to visual disturbances, particularly with hypertension. Vision generally recovers postpartum within hours to days. A rare condition known as Purtscher-like retinopathy presents abruptly postpartum with visual field defects and blindness. Recovery of vision is unpredictable, occurring over several weeks and months.CASE: A 38-year-old woman presented at 34 weeks' gestation with contractions and heavy bleeding. Placental abruption was confirmed after a repeat cesarean was performed. Hours after delivery, she complained of central vision loss despite normal blood pressure and preeclamptic laboratory results. The diagnosis of Purtscher-like retinopathy was made, presumably from multiple infarcts to the retina caused by the placental abruption.CONCLUSION: Recovery from Purtscher-like retinopathy may result in permanent visual impairment. PMID- 29999297 TI - A Further Application of Detachable Snare Loops (Endoloop) for Repair of Bladder Injury. AB - BACKGROUND: Complications of operative laparoscopy and laparoscopic hysterectomy were once repaired by laparotomy. Their laparoscopic repair still offers challenges, most especially in the presence of inflammation, scarring, and tissue distortion. This report presents a new application, under high-risk conditions, of a simple and effective method for repair of inadvertent cystotomy.CASE: A 29 year-old woman undergoing laparoscopic hysterectomy for a vaginal mass experienced an incidental bladder injury in the context of a retained foreign body, extensive inflammatory changes, and scarring. A novel use of a standard laparoscopic tool produced a rapid, effective bladder repair.CONCLUSION: Simple and effective cystotomy repair is possible even under extremely complex conditions. PMID- 29999298 TI - Paraurethral Leiomyoma. AB - BACKGROUND: Paraurethral vaginal leiomyoma is a rare and solid tumor of unknown etiology. We present a case of successfully treated paraurethral leiomyoma.CASE: A 49-year old woman, G4P2A2, was admitted to our clinic with complaints of vaginal mass and dyspareunia. During pelvic examination a 4x4-cm-sized, solid mass with hard consistency was detected at the paraurethral area in the front wall of the vagina. In the histopathological examination the mass was found to be compatible with leiomyoma.CONCLUSION: Paraurethral leiomyoma is a rare, hormone dependent, benign tumor of mesenchymal origin. Surgical excision is necessary for discrimination from sarcoma. One should be cautious of urethral injury during the excision. PMID- 29999299 TI - Bladder Calculus at Cesarean Delivery in a Patient with Previous Cystotomy Repair. AB - BACKGROUND: The cesarean delivery rate continues to rise in the United States. The majority of cesarean deliveries are performed secondary to a previous cesarean delivery. Bladder injury at the time of a repeat cesarean delivery is a known risk.CASE: A 28-year-old woman sustained an incidental cystotomy during her second cesarean delivery, which was repaired at that time. During her third cesarean delivery she was noted to have a 6x5-cm calculus in her bladder. This large bladder calculus was removed through a cystotomy and her bladder was repaired without incident.CONCLUSION: Women with a previous bladder injury undergoing repeat cesarean delivery should have their bladder carefully inspected for any further urologic complications. PMID- 29999300 TI - Vulvar Pyogenic Granuloma (Lobular Capillary Hemangioma). AB - BACKGROUND: Pyogenic granuloma (PG) is a common vascular lesion of the skin and subcutaneous tissue and is usually found on the face, trunk, and limbs. It is well known by general surgeons.CASE: A 42-year-old woman attended our clinic due to a rapidly growing, glistening, ulcerative, pedunculated vulvar mass. The mass was excised and subsequent histopathology revealed it as PG, which was completely unexpected. We reviewed the previous reported cases to investigate its clinical behavior, incidence, and management.CONCLUSION: PG of the vulva is a common clinical misdiagnosis. It is the third most common vulvar vascular lesion, but all the reported cases were diagnosed after histopathological examination. Gynecologists should include PG among the differential diagnoses of vulvar polypoid mass. PMID- 29999301 TI - Mass Spectrometry Reveals a Multifaceted Role of Glycosaminoglycan Chains in Factor Xa Inactivation by Antithrombin. AB - Factor Xa (fXa) inhibition by antithrombin (AT) enabled by heparin or heparan sulfate is critical for controlling blood coagulation. AT activation by heparin has been investigated extensively, while interaction of heparin with trapped AT/fXa intermediates has received relatively little attention. We use native electrospray ionization mass spectrometry to study the role of heparin chains of varying length [hexa-, octa-, deca-, and eicosasaccharides (dp6, dp8, dp10, and dp20, respectively)] in AT/fXa complex assembly. Despite being critical promoters of AT/Xa binding, shorter heparin chains are excluded from the final products (trapped intermediates). However, replacement of short heparin segments with dp20 gives rise to a prominent ionic signal of ternary complexes. These species are also observed when the trapped intermediate is initially prepared in the presence of a short oligoheparin (dp6), followed by addition of a longer heparin chain (dp20), indicating that binding of heparin to AT/fXa complexes takes place after the inhibition event. The importance of the heparin chain length for its ability to associate with the trapped intermediate suggests that the binding likely occurs in a bidentate fashion (where two distinct segments of oligoheparin make contacts with the protein components, while the part of the chain separating these two segments is extended into solution to minimize electrostatic repulsion). This model is corroborated by both molecular dynamics simulations with an explicit solvent and ion mobility measurements in the gas phase. The observed post-inhibition binding of heparin to the trapped AT/fXa intermediates hints at the likely role played by heparan sulfate in their catabolism. PMID- 29999302 TI - Strategic Design of Vacancy-Enriched Fe1- xS Nanoparticles Anchored on Fe3C Encapsulated and N-Doped Carbon Nanotube Hybrids for High-Efficiency Triiodide Reduction in Dye-Sensitized Solar Cells. AB - A new class of hybrids with the unique electrocatalytic nanoarchitecture of Fe1- xS anchored on Fe3C-encapsulated and N-doped carbon nanotubes (Fe1- xS/Fe3C NCNTs) is innovatively synthesized through a facile one-step carbonization sulfurization strategy. The efficient synthetic protocols on phase structure evolution and dynamic decomposition behavior enable the production of the Fe1- xS/Fe3C-NCNT hybrid with advanced structural and electronic properties, in which the Fe vacancy-contained Fe1- xS showed the 3d metallic state electrons and an electroactive Fe in +2/+3 valence, and the electronic structure of the CNT was effectively modulated by the incorporated Fe3C and N, with the work function decreased from 4.85 to 4.63 eV. The meticulous structural, electronic, and compositional control unveils the unusual synergetic catalytic properties for the Fe1- xS/Fe3C-NCNT hybrid when developed as counter electrodes (CEs) for dye sensitized solar cells (DSSCs), in which the Fe3C- and N-incorporated CNTs with reduced work function and increased charge density provide a highway for electron transport and facilitate the electron migration from Fe3C-NCNTs to ultrahigh active Fe1- xS with the electron-donating effect, and the Fe vacancy-enriched Fe1 xS nanoparticles exhibit ultrahigh I3- adsorption and charge-transfer ability. As a consequence, the DSSC based on the Fe1- xS/Fe3C-NCNT CE delivers a high power conversion efficiency of 8.67% and good long-term stability with a remnant efficiency of 8.00% after 168 h of illumination, superior to those of traditional Pt. Furthermore, the possible catalytic mechanism toward I3- reduction is creatively proposed based on the structure-activity correlation. In this work, the structure engineering, electronic modulation, and composition control opens up new possibilities in constructing the novel electrocatalytic nanoarchitecture for highly efficient CEs in DSSCs. PMID- 29999303 TI - Ultrafast Multiplexed-Allergen Detection through Advanced Fluidic Design and Monolithic Interferometric Silicon Chips. AB - A silicon-based miniaturized sensor chip combined with an advanced microfluidic module for the simultaneous, label-free immunochemical determination of four allergens, bovine milk protein, peanut protein, soy protein, and gliadin, is presented. The sensor chip consists of an array of 10 broad-band Mach-Zehnder interferometers (BB-MZIs) monolithically integrated on silicon, along with their respective broad-band light sources. The BB-MZIs were biofunctionalized with the targeted allergens and their responses during immunoreaction were monitored by multiplexing their transmission spectra through an external miniaturized spectrometer. The assay is performed by running mixtures of calibrators or samples with the antibodies against the four allergens followed by an antispecies specific antibodies solution. Employing a fluidic module of nearly one dimensional geometry, that provided for uniform delivery of the reagents, CV values <6% were achieved for the responses of the 10 BB-MZIs, allowing for reliable multianalyte determinations. The analysis is completed in 6.5 min, and the detection limits were 0.04 MUg/mL for bovine k-casein, 1.0 MUg/mL for peanut protein, 0.80 MUg/mL for soy protein, and 0.10 MUg/mL for gliadin. The assays were accurate (recoveries 88-118%) and repeatable (intra- and interassay CVs <7% for all four allergens). Finally, the sensor was evaluated by analyzing samples from a cleaning in place system (CIP) of a dairy industry and the results obtained were in good agreement with those received by the respective ELISAs. The analytical characteristics of the sensor combined with the short analysis time and the small chip size make the proposed system an ideal tool for on-site multianalyte determinations. PMID- 29999305 TI - Nitrosyl Myoglobins and Their Nitrite Precursors: Crystal Structural and Quantum Mechanics and Molecular Mechanics Theoretical Investigations of Preferred Fe -NO Ligand Orientations in Myoglobin Distal Pockets. AB - The globular dioxygen binding heme protein myoglobin (Mb) is present in several species. Its interactions with the simple nitrogen oxides, namely, nitric oxide (NO) and nitrite, have been known for decades, but the physiological relevance has only recently become more fully appreciated. We previously reported the O nitrito mode of binding of nitrite to ferric horse heart wild-type (wt) MbIII and human hemoglobin. We have expanded on this work and report the interactions of nitrite with wt sperm whale (sw) MbIII and its H64A, H64Q, and V68A/I107Y mutants whose dissociation constants increase in the following order: H64Q < wt < V68A/I107Y < H64A. We also report their X-ray crystal structures that reveal the O-nitrito mode of binding of nitrite to these derivatives. The MbII-mediated reductions of nitrite to NO and structural data for the wt and mutant MbII-NOs are described. We show that their FeNO orientations vary with distal pocket identity, with the FeNO moieties pointing toward the hydrophobic interiors when the His64 residue is present but toward the hydrophilic exterior when this His64 residue is absent in this set of mutants. This correlates with the nature of H bonding to the bound NO ligand (nitrosyl O vs N atom). Quantum mechanics and hybrid quantum mechanics and molecular mechanics calculations help elucidate the origin of the experimentally preferred NO orientations. In a few cases, the calculations reproduce the experimentally observed orientations only when the whole protein is taken into consideration. PMID- 29999304 TI - Direct-qPCR Assay for Coupled Identification and Antimicrobial Susceptibility Testing of Neisseria gonorrhoeae. AB - Multidrug-resistant gonorrhea has become an urgent issue for global public health. As the causative agent of gonorrhea, Neisseria gonorrhoeae, has been progressively developing resistance to nearly all prescribed antimicrobial drugs, monitoring its antimicrobial resistance on a broader scale has become a crucial agenda for effective antibiotic stewardship. Unfortunately, gold standard antimicrobial susceptibility testing (AST) relies on time and labor-intensive phenotypic assays, which lag behind the current diagnostic workflow for N. gonorrhoeae identification based on nucleic acid amplification tests (NAAT). Newer assay technologies based on NAAT can rapidly identify N. gonorrhoeae from clinical specimen but fundamentally lack the capacity to provide phenotypic AST information. Herein, we propose a direct-quantitative PCR (direct-qPCR) assay that enables pathogen-specific identification and phenotypic AST via quantitative measurement of N. gonorrhoeae growth directly from a liquid medium without any sample preprocessing. The assay has an analytical sensitivity of 102 CFU/mL and is highly specific to N. gonorrhoeae in the presence of urogenital flora and clinical swab eluent. We tested seven N. gonorrhoeae strains against three antibiotic agents, penicillin, tetracycline, and ciprofloxacin, and achieved 95.2% category agreement and 85.7% essential agreement with the FDA-approved E test. The assay presented in this work has the unique ability to identify N. gonorrhoeae and provide phenotypic AST directly from the liquid medium with cell densities as low as 102 CFU/mL, demonstrating an accelerated, sensitive, and scalable workflow for performing both identification and AST of N. gonorrhoeae. PMID- 29999306 TI - Dynamic States of the Ligand-Free Class A G Protein-Coupled Receptor Extracellular Side. AB - G protein-coupled receptors (GPCRs) make up the largest family of drug targets. The second extracellular loop (ECL2) and extracellular end of the third transmembrane helix (TM3) are basic structural elements of the GPCR ligand binding site. Currently, the disulfide bond between the two conserved cysteines in the ECL2 and TM3 is considered to be a basic GPCR structural feature. This disulfide bond has a significant effect on receptor dynamics and ligand binding. Here, molecular dynamics simulations and experimental results show that the two cysteines are distant from one another in the highest-population conformational state of ligand-free class A GPCRs and do not form a disulfide bond, indicating that the dynamics of the GPCR extracellular side are different from our conventional understanding. These surprising dynamics should have important effects on the drug binding process. On the basis of the two distinct ligand-free states, we suggest two kinetic processes for binding of ligands to GPCRs. These results challenge our commonly held beliefs regarding both GPCR structural features and ligand binding. PMID- 29999307 TI - Alignment of Thermally Conducting Nanotubes Making High-Performance Light-Driving Motors. AB - Light-actuating devices that can produce selective motions at small scales are highly desired for on-demand manipulation. For conventional photothermal motors that mostly encounter the homogenous light-induced heat diffusion at the liquid/air interface, it is challenging to effectively control the actuating direction and enhance the actuating speed. To this end, here, we explore aligned thermally conducting one-dimensional nanomaterials to make light-driving motors where the light-induced heat can be transmitted to the water surface along the length direction of the aligned one-dimensional nanomaterials to generate a localized surface tension gradient for high spatial resolution propulsion. When multiwalled carbon nanotubes were studied as a demonstration, the aligned active layer generated sufficient propulsion to drive a centimeter-sized motor that was 10 000 times higher in mass of the actuating layer on water. In addition, the actuating direction had been accurately controlled by varying the illuminated region of the active aligned nanotube layer. The resulting light-driving motors can move as fast as 4.19 cm/s (or 5.2 body length per second), which exceeded the previous motors based on the light activation. PMID- 29999308 TI - Patterning Islandlike MnO2 Arrays by Breath-Figure Templates for Flexible Transparent Supercapacitors. AB - Although plenty of active materials could be used as supercapacitor electrodes, only limited ones have been engineered to construct transparent supercapacitors. Specially, it is a great challenge to make opaque metal oxides, which often own high energy density, into transparent films. Here, we demonstrate a novel approach to fabricate transparent MnO2 films for flexible transparent supercapacitors. By utilizing breath-figure polymer films with ordered pores as template, arrays of MnO2 islands were electrochemically deposited, with high light transmission. The thickness and interspace distance of MnO2 island arrays could be adjusted by tuning deposition time so that the capacitance and transparency of the electrodes are changed accordingly. Such island array structure can effectively eliminate the internal stress existing in the composite film to avoid cracks during bending operation. The assembled transparent supercapacitor shows a transmittance of 44% at 550 nm and can yield a high capacitance of 4.73 mF/cm2 at a current density of 50 MUA/cm2, demonstrating high flexibility and stability. PMID- 29999310 TI - Modulation of Lithium Plating in Li-Ion Batteries with External Thermal Gradient. AB - Li-ion battery safety is often threatened by undesirable lithium metal electrodeposition or dendrite growth, during charging. The unpredictable and complex onset of widely ranging lithium morphologies limits reproducibility, making prevention and detection strategies difficult to assess. This work blends the fundamentals of classical metallurgical dendrite growth with traditional Li ion battery charging, to prove the ability to modulate lithium metal deposition through an applied interelectrode thermal gradient. With NMC (nickel-manganese cobalt) cathode warmed to 40 degrees C and graphite anode cooled to 0 degrees C, irreversible lithium plating is observed within 10 cycles, and complete cell deactivation within 20 cycles. The stages of failure over these first 20 cycles are assessed with electrochemical impedance spectroscopy. This work provides a technique for accelerated aging and the reliable study of lithium deposition in Li-ion batteries. PMID- 29999309 TI - Correlating Crystal Thickness, Surface Morphology, and Charge Transport in Pristine and Doped Rubrene Single Crystals. AB - The relationship between charge transport and surface morphology is investigated by utilizing rubrene single crystals of varying thicknesses. In the case of pristine crystals, the surface conductivities decrease exponentially as the crystal thickness increases until ~4 MUm, beyond which the surface conductivity saturates. Investigation of the surface morphology using optical and atomic force microscopy reveals that thicker crystals have a higher number of molecular steps, increasing the overall surface roughness compared with thin crystals. The density of molecular steps as a surface trap is further quantified with the subthreshold slope of rubrene air-gap transistors. This thickness-dependent surface conductivity is rationalized by a shift from in-plane to out-of-plane transport governed by surface roughness. The surface transport is disrupted by roughening of the crystal surface and becomes limited by the slower vertical crystallographic axis on molecular step edges. Separately, we investigate surface doping of rubrene crystals by using fluoroalkyltrichrolosilane and observe a different mechanism for charge transport which is independent of surface roughness. This work demonstrates that the correlation between crystal thickness, surface morphology, and charge transport must be taken into account when measuring organic single crystals. Considering the fact that these molecular steps are universally observed on organic/inorganic and single/polycrystals, we believe that our findings can be widely applied to improve charge transport understanding. PMID- 29999311 TI - Advantageous Units in Antimony Sulfides: Exploration and Design of Infrared Nonlinear Optical Materials. AB - The exploration of infrared (IR) nonlinear optical (NLO) materials remains attractive because of the urgent requirements in the laser field. Meanwhile, the deepened cognition of structure-property relationships is necessary to help guide the exploration of IR NLO materials. So far, the family of antimony sulfides is an important system with a lot of attention, and a series of antimony sulfides are reported. However, it is urgent to reveal how different Sb-S units, like SbS3, SbS4, and more complex combinations, affect apparent properties. Here, taking ternary metal antimony sulfides as examples, the sources of some essential optical properties, such as second harmonic generation (SHG) and birefringence, are systematically analyzed through first-principles calculations, and the mechanisms of the performances with various magnitudes are also presented to clarify the structure-property relationships. The results indicate that the SbS4 unit among antimony sulfides is an advantageous NLO-active unit, which can balance the contradiction between the band gap and SHG response. Introduction of transition metals in the Sb-S anionic frameworks can tune the magnitude of birefringence. Besides, the substitution of a cation from a transition metal to an alkali metal can notably enlarge the band gap and maintain a large SHG response. These design strategies are beneficial to explore potential IR NLO materials with Sb-S units. PMID- 29999312 TI - Oxidative Rearrangement Mechanism of Pentalenolactone F Catalyzed by Cytochrome P450 CYP161C2 (PntM). AB - The CYP161C2 (PntM) from Streptomyces arenae is a member of the cytochrome P450 enzymes, which catalyzes the unusual oxidative rearrangement of pentalenolactone F (1) to the sesquiterpenoid antibiotic pentalenolactone (3). On the basis of the crystal structure of PntM bound with substrate, quantum mechanical/molecular mechanics (QM/MM) calculations have been performed to explore the detailed mechanism of PntM-catalyzed oxidative rearrangement. The conversion from pentalenolactone F (1) to pentalenolactone (3) involves the stereospecific removal of the H-1 si from 1, the syn-1,2-migration of the 2 si methyl group, and the antarafacial loss of H-3 re. The abstraction of H-1 si by Cpd I is calculated to be rate limiting with an energy barrier of 20.3 kcal/mol, which basically agrees with the estimated free energy barrier from experiments (18.6 kcal/mol). It is the unfavorable geometry of Fe-OH-C1 that blocks the oxygen rebound reaction, and the subsequent intramolecular syn-1,2-methyl migration is accompanied by an electron transfer from the substrate to the porphyrin ring via an Fe-OH group, generating the carbocation intermediate. Owing to the positive charge, the intermediate can easily lose a proton to form the final products. Our calculation results indicate that both the carboxyl group of porphyrin and Fe-OH can act as bases to accept the proton of the substrate. The target product pentalenolactone and the three isomeric byproducts correspond to four different modes of deprotonation. PMID- 29999313 TI - Copper-Catalyzed Cascade Synthesis of 2-Aryl-3-cyanobenzofuran and Dibenzo[ b, f]oxepine-10-carbonitrile Derivatives. AB - The copper-catalyzed reaction of aryl aldehydes with 2-iodobenzylcyanides afforded 2-aryl-3-cyanobenzofurans in isolated yields of up to 74% in a cascade manner, which involves Knoevenagel condensation, aryl hydroxylation, oxa-Michael addition, and aromatization reactions. Conversely, 2-halo benzaldehydes as reacting partners with 2-iodobenzylcyanide regioselectively furnished dibenzo[ b,f]oxepine-10-carbonitrile derivatives up to 85% isolated yields via tandem Knoevenagel condensation, aryl hydroxylation, and Ullmann coupling reactions. PMID- 29999314 TI - Spontaneous Additive Nanopatterning from Solution Route Using Selective Wetting. AB - Nanopatterns of functional materials have successfully led innovations in a wide range of fields, but further exploration of their full potential has often been limited because of complex and cost-inefficient patterning processes. We here propose an additive nanopatterning process of functional materials from solution route using selective wetting phenomenon. The proposed process can produce nanopatterns as narrow as 150 nm with high yield over large area at ultrahigh process speed, that is, the speed of solution dragging, of up to ca. 4.6 m.min-1. The process is highly versatile that it can utilize a wide range of solution materials, control vertical structures including pattern thickness and multistacks, and produce nanopatterns on various substrates with emerging form factors such as foldability and disposability. The solution patterning in nanoscale by selective wetting is enabled by corresponding surface energy patterns in high contrast that are achieved by one-step imprinting onto hydrophobic/hydrophilic bilayers. The mechanisms and control parameters for the solution patterning are revealed by fluid-dynamic simulation. With the aforementioned advantages, we demonstrate 25 400 pixel-per-inch light-emitting pixel arrays and a plasmonic color filter of 10 cm * 10 cm area on a plastic substrate as potential applications. PMID- 29999316 TI - Pseudomonas aeruginosa Quorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives. AB - Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multidrug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to coordinate virulence gene expression, is a potential target that has been intensively investigated over the past decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems ( las, rhl, and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective. PMID- 29999317 TI - Conversion of Imine to Oxazole and Thiazole Linkages in Covalent Organic Frameworks. AB - Imine-linked ILCOF-1 based on 1,4-phenylenediamine and 1,3,6,8-tetrakis(4 formylphenyl)pyrene was converted through consecutive linker substitution and oxidative cyclization to two isostructural covalent organic frameworks (COFs), having thiazole and oxazole linkages. The completeness of the conversion was assessed by infrared and solid-state NMR spectroscopies, and the crystallinity of the COFs was confirmed by powder X-ray diffraction. Furthermore, the azole-linked COFs remain porous, as shown by nitrogen sorption experiments. The materials derived in this way demonstrate increased chemical stability, relative to the imine-linked starting material. This constitutes a facile method for accessing COFs and linkages that are otherwise difficult to crystallize due to their inherently limited microscopic reversibility. PMID- 29999318 TI - Predicting the Prevalence of Alternative Warfarin Tautomers in Solution. AB - Warfarin, a widely used oral anticoagulant, is prescribed as a racemic mixture. Each enantiomer of neutral Warfarin can exist in 20 possible tautomeric states leading to complex pharmacokinetics and uncertainty as to the relevant species under different conditions. Here, the ability of alternative computational approaches to predict the preferred tautomeric form(s) of neutral Warfarin in different solvents is examined. It is shown that varying the method used to estimate the heat of formation in vacuum (direct or via homodesmic reactions), whether entropic corrections were included, and the method used to estimate the free enthalpy of solvation (i.e., PCM, COSMO, or SMD implicit models or explicit solvent) lead to large differences in the predicted rank and relative populations of the tautomers. In this case, only a combination of the enthalpy of formation using homodesmic reactions and explicit solvent to estimate the free enthalpy of solvation yielded results compatible with the available experimental data. The work also suggests that a small but significant subset of the possible Warfarin tautomers are likely to be physiologically relevant. PMID- 29999319 TI - A Scalable "Junction Substrate" to Engineer Robust DNA Circuits. AB - Versatile building blocks are essential for building complex and scaled-up DNA circuits. In this study, we propose a conceptually new scalable architecture called a "junction substrate" (J-substrate) that is linked by prepurified double stranded DNA molecules. As a proof-of-concept, this novel type of substrate has been utilized to build multi-input DNA circuits, offering several advantages over the conventional substrate (referred to as a "linear substrate", L-substrate). First, the J-substrate does not require long DNA strands, thus avoiding significant synthetic errors and costs. Second, the traditional PAGE purification method is technically facilitated to obtain high-purity substrates, whereby the initial leakage is effectively eliminated. Third, the asymptotic leakage is eliminated by introducing the "junction". Finally, circuits with the optimized J substrate architecture exhibit fast kinetics. We believe that the proposed architecture constitutes a sophisticated chassis for constructing complex circuits. PMID- 29999320 TI - Comparing Surfactant Structures at "Soft" and "Hard" Hydrophobic Materials: Not All Interfaces Are Equivalent. AB - The interfacial structures of a range of amphiphilic molecules are studied with both "soft" and "hard" hydrophobic substrates. Neutron reflection and quartz crystal microbalance with dissipation measurements highlight the differences between the adsorbed structures adopted by sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (C16TAB), and the "AM1" surface active peptide. At the soft siloxane/water interface, small molecular surfactants form loosely packed layers, with the hydrophobic tails penetrating into the oily layer, and an area per surfactant molecule that is significantly less than previously reported for the air/water interface. Neutron reflection measurements, supported by quartz crystal microbalance studies, indicate that for C16TAB, approximately 30 +/- 8% of the alkyl tail penetrates into the poly(dimethylsiloxane) (PDMS) layer, whereas 20 +/- 5% of the alkyl tail of SDS is located in the PDMS. For the engineered peptide surfactant AM1 (21 residues), it was found that one face of the alpha helix penetrated into the PDMS film. In contrast, penetration of the surfactant tails was not observed against hard solidlike hydrophobic surfaces made from octadecyltrichlorosilane (OTS) for any of the molecular species studied. At the OTS/water interface, C16TAB and SDS were seen to adsorb as larger aggregates and not as monolayers. Amphiphilic adsorption (amount, structural conformation) at the PDMS/water interface is shown to be different from that at both the air/water interface and the hard OTS/water interface, illustrating that interfacial structures cannot be predicted by the surfactant packing parameter alone. The bound PDMS layer is shown to be a useful proxy for the oil/water interface in surface and stabilization studies, with hydrophobic components of the molecules able to penetrate into the oily PDMS. PMID- 29999321 TI - Self-Assembly, Thermotropic, and Lyotropic Phase Behavior of Guerbet Branched Chain Maltosides. AB - Five synthetic beta-d-maltosides derived from Guerbet branched alcohols, whose total hydrocarbon chain length ranged from C8 to C24, were synthesized to a high anomeric purity, and their thermal properties, liquid-crystalline phases, and structures were characterized using differential scanning calorimetry, optical polarizing microscopy, and small-angle X-ray scattering. Thermal investigations of all anhydrous Guerbet maltosides showed that they do not form solid crystals but undergo a glass transition upon temperature change in the range of 35-53 degrees C. The glassy crystalline structure turns into the liquid-crystalline structure upon heating or addition of water. In thermotropic studies, the lamellar phase formation is prominent in shorter-chain-length analogues, whereas the longer-chain compounds exhibit a more frustrated form of self-assembly in the formation of a metastable state, polymorphism, and inverse bicontinuous cubic structure ( Ia3 d). The excess water conditions show that the phase formation is dominated by the lamellar phase for the longer-chain compounds. Normal micellar solution was observed in the shortest-chain-length maltosides because of the enlargement of hydrated maltose headgroups. The self-assembly of both dry and fully hydrated Guerbet maltosides, which exhibited glass-forming abilities and showed surface activity and also the ability to act as membrane-stabilizing compounds, makes them ideal candidates for practical use in industry as well as biomedical research. PMID- 29999322 TI - Cross Photoreaction of Glyoxylic and Pyruvic Acids in Model Aqueous Aerosol. AB - Aerosols of variable composition, size, and shape are associated with public health concerns as well as with light-particle interactions that play a role in the energy balance of the atmosphere. Photochemical reactions of 2-oxocarboxylic acids in the aqueous phase are now known to contribute to the total secondary organic aerosol (SOA) budget. This work explores the cross reaction of glyoxylic acid (GA) and pyruvic acid (PA) in water, the two most abundant 2-oxocarboxylic acids in the atmosphere, under solar irradiation and dark thermal aging steps. During irradiation, PA and GA are excited and initiate proton-coupled electron transfer or hydrogen abstraction and alpha-cleavage reactions, respectively. The time series of photoproducts is studied by ion chromatography (IC) with conductivity and electrospray ionization (ESI) mass spectrometry (MS) detection, direct ESI-MS analysis in the negative ion mode, and nuclear magnetic resonance spectroscopy (NMR). The use of one-dimensional (1H and 13C NMR) and two dimensional NMR techniques includes gradient correlation spectroscopy (gCOSY) and heteronuclear single quantum correlation (HSQC). The aging of photoproducts in the dark is monitored by UV-visible spectroscopy. The periodicity in the time domain of the optical properties is explained in terms of chromophores that undergo alternating thermochromism and photobleaching between nighttime and daytime cycles, respectively. A reaction mechanism for the cross reaction of GA and PA explaining the generation of trimers with general formulas C5H8O5 (148 Da), C6H10O5 (162 Da), and C5H8O6 (164 Da) is provided based on all experimental observations. PMID- 29999323 TI - Poly( N-isopropylacrylamide- co-1-vinyl-3-alkylimidazolium bromide) Microgels with Internal Nanophase-Separated Structures. AB - Microgels with internal nanophase-separated structures were fabricated by surfactant-free emulsion copolymerization of N-isopropylacrylamide (NIPAm) and ionic liquid comonomers, namely, 1-vinyl-3-alkylimidazolium bromide (VIM nBr) with various lengths n of long alkyl side chain, in an aqueous solution at 70 degrees C using N, N'-methylenebisacrylamide as the cross-linker. Combined techniques of transmission electron microscopy, dynamic and static light scattering, differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WAXD), small-angle X-ray scattering (SAXS), and polarized optical microscopy were employed to systematically investigate the sizes, morphologies, and properties of the obtained microgels as well as the microstructures and phase transition of nanophases inside the microgels. The obtained P(NIPAm/VIM nBr) microgels are spherical with narrow size distributions, and the nanophases have a radius of about 8-12 nm and are randomly distributed inside the microgels. The cooperative competition of the hydrophilic quaternary vinylimidazole moieties and hydrophobic long alkyl side chains determines the thermal sensitive behavior of the P(NIPAm/VIM nBr) microgels. DSC and WAXD results reveal that the nanophases consist of the ordered alkyl side chains with a layered crystalline structure at low temperature, which exhibit a low melting temperature and a broad melting transition. SAXS results further show that the nanophases form a layered liquid crystalline structure at high temperature for the microgel suspensions and freeze dried microgels. PMID- 29999324 TI - Long-Term Stability of n-Alkane-in-Water Pickering Nanoemulsions: Effect of Aqueous Solubility of Droplet Phase on Ostwald Ripening. AB - High-pressure microfluidization is used to prepare a series of oil-in-water Pickering nanoemulsions using sterically-stabilized diblock copolymer nanoparticles as the Pickering emulsifier. The droplet phase comprised either n octane, n-decane, n-dodecane, or n-tetradecane. This series of oils enabled the effect of aqueous solubility on Ostwald ripening to be studied, which is the primary instability mechanism for such nanoemulsions. Analytical centrifugation (LUMiSizer instrument) was used to evaluate the long-term stability of these Pickering nanoemulsions over time scales of weeks/months. This technique enables convenient quantification of the fraction of growing oil droplets and confirmed that using n-octane (aqueous solubility = 0.66 mg dm-3 at 20 degrees C) leads to instability even over relatively short time periods. However, using n-tetradecane (aqueous solubility = 0.386 MUg dm-3 at 20 degrees C) leads to significantly improved long-term stability with respect to Ostwald ripening, with all droplets remaining below 1 MUm diameter after 6 weeks storage at 20 degrees C. In the case of n-dodecane, the long-term stability of these new copolymer-stabilized Pickering nanoemulsions is significantly better than the silica-stabilized Pickering nanoemulsions reported in the literature by Persson et al. ( Colloids Surf., A, 2014, 459, 48-57). This is attributed to a much greater interfacial yield stress for the former system, as recently described in the literature (see P. J. Betramo et al. Proc. Natl. Acad. Sci. U.S.A., 2017, 114, 10373-10378). PMID- 29999325 TI - Ruthenium- and Rhodium-Catalyzed Chemodivergent Couplings of Ketene Dithioacetals and alpha-Diazo Ketones via C-H Activation/Functionalization. AB - Chemodivergent coupling of alpha-acylketene dithioacetals with diazo compounds has been realized under catalyst control. The Ru(II)-catalyzed C-H activation occurred at the olefinic position, and 1:2 coupling with alpha-diazoketoesters leads to furfurylation. In contrast, the Rh(III)-catalyzed C-H functionalization occurred at both the olefinic and the ortho C(aryl)-H positions, and [4 + 2] annulation afforded naphthalenones. Synthetic applications have been performed to demonstrate the usefulness of the coupling system. PMID- 29999326 TI - Isomerizations of Propargyl 3-Acylpropiolates via Reactive Allenes. AB - Thermal isomerizations of various propargyl 3-acylpropiolates are described. Many result in the formation of 3-acylbutenolides. These reactions appear to proceed through intermediate 2,3-dehydropyrans (strained cyclic allenes), which then isomerize in a previously unobserved fashion. Competitive processes that provide additional mechanistic insights are also described. PMID- 29999327 TI - The Electronic Structures of CoGe n-/0 ( n = 1-3) Clusters from Multiconfigurational CASSCF/CASPT2 and RASSCF/RASPT2 Calculations. AB - Density functional theory and multiconfigurational CASPT2 and RASPT2 methods are employed to investigate the low-lying states of CoGe n-/0 ( n = 1-3) clusters. With the RASPT2 approach, the active space is extended to 14 orbitals for CoGe /0, 17 orbitals for CoGe2-/0, and 20 orbitals for CoGe3-/0. These active spaces include the 3d, 4s, and 4d of Co and 4p of Ge. The 4d of Co is incorporated into these active spaces in order to account for the important double-shell effect of Co. The structural parameters, vibrational frequencies, and relative energies of the low-lying states of CoGe n-/0 ( n = 1-3) are reported. The ground states of CoGe n- ( n = 1-3) are computed to be 3Phi of linear CoGe-, 3B1 of cyclic CoGe2-, and 3B1 of cyclic CoGe3- isomer. The ground states of the neutral clusters are calculated to be 2Delta of linear CoGe, 4B1 of cyclic CoGe2, and 4A" of tetrahedral CoGe3 isomer. The calculated adiabatic and vertical detachment energies of the anionic ground states are in agreement with the experimental values as observed in the 266 nm anion photoelectron spectra. PMID- 29999328 TI - Membrane Charging and Swelling upon Calcium Adsorption as Revealed by Phospholipid Nanodiscs. AB - Direct binding of calcium ions (Ca2+) to phospholipid membranes is an unclarified yet critical signaling pathway in diverse Ca2+-regulated cellular phenomena. Here, high-pressure-liquid-chromatography, small-angle X-ray scattering (SAXS), UV-vis absorption, and differential refractive index detections are integrated to probe Ca2+-binding to the zwitterionic lipid membranes in nanodiscs. The responses of the membranes upon Ca2+-binding, in composition and conformation, are quantified through integrated data analysis. The results indicate that Ca2+ binds specifically into the phospholipid headgroup zone, resulting in membrane charging and membrane swelling, with a saturated Ca2+-lipid binding ratio of 1:8. A Ca2+-binding isotherm to the nanodisc is further established and yields an unexpectedly high binding constant K = 4260 M-1 and a leaflet potential of ca. 100 mV based on a modified Gouy-Chapman model. The calcium-lipid binding ratio, however, drops to 40% when the nanodisc undergoes a gel-to-fluid phase transition, leading to an effective charge capacity of a few MUF/cm2. PMID- 29999329 TI - Puzzling Aqueous Solubility of Guanine Obscured by the Formation of Nanoparticles. AB - Dissolution of guanine in neutral solutions was obscured by peculiar behavior of guanine, indicating an apparent dependence of solubility on the amount of solid guanine used. Here, we demonstrate that the problem is caused by the formation of tiny guanine nanoparticles that tend to grow forming stable particles of ca. 800 nm size. This effect can be minimalized by using small quantities of guanine powder for dissolution. We also show that assuming a constant, independent of pH, concentration of neutral form of guanine, at 25 degrees C equal 25.4 MUM, and applying known p Ka values related to its dissociation or protonation, it is possible to calculate the concentrations of all conjugate acids and bases of guanine at the given pH value, and by summing them up, the guanine solubility. PMID- 29999330 TI - Evaluating autonomy, beneficence, and justice with substance-using populations: Implications for clinical research participation. AB - Narrow inclusion criteria regarding substance use are commonplace in clinical research. This is due, in part, to assumptions about capacity to make "rational" decisions regarding participation by these populations. This study evaluated decision-making and perceptions surrounding each of the Belmont principles among individuals with cocaine use histories, cigarette smokers without illicit substance use histories, and controls without cigarette or illicit substance use histories. Cocaine (n = 124), cigarette (n = 128), and control (n = 145) groups were recruited using Amazon's Mechanical Turk. Participants completed measures evaluating research participation after reading two hypothetical study vignettes varying in risk. Assays assessed capacity to consent, perceived research burden, and endorsement of research participation by various populations. Individuals reporting cocaine use showed a reduced capacity to consent compared to controls, but this effect was small and largely explained by sociodemographic differences (e.g., race) rather than substance use history. Perceived research burden in the cigarette group was lower than in the cocaine group, but this difference was of a small to medium effect size. All groups reported substantively lower endorsement of research participation by individuals with illicit substance use histories relative to healthy adults, with less support indicated by control and cigarette groups compared to the cocaine group. Few differences were observed by substance use history regarding perceptions of and decision-making surrounding research participation. These data highlight the need for the continued study of evidence based ethics and support more widespread acceptance of research participation by individuals with substance use histories in clinical research. (PsycINFO Database Record PMID- 29999331 TI - The relative importance of parent-child dynamics and minority stress on the psychological adjustment of LGBs in China. AB - This cross-sectional study examined how minority stress (i.e., internalized homonegativity, self-concealment, and rejection sensitivity) and positive parent child relationship dynamics (i.e., respect for parents and perceived parental support for sexual orientation) were associated with the psychological adjustment of lesbian, gay, and bisexual (LGB) individuals in China. Based on survey responses from 277 self-identified Chinese LGB young adults, results from structural equation modeling showed that minority stress was not a significant predictor of psychological maladjustment, whereas respect for parents and perceived parental support for sexual orientation were associated with positive psychological adjustment. Tests of gender differences partially confirmed whether Confucian traditions may burden sexual minority men more than women. Gender differences were found in the correlations between minority stress and each measure of positive parent-child relationship dynamics. However, the associations between independent variables and psychological maladjustment were not different between men and women in the sample. Our results suggest that culture-specific variables, such as parent-child factors within the context of China, may be especially important when working with LGB individuals in research and clinical practice. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29999332 TI - Construction and validation of the Multicultural Orientation Inventory-Group Version. AB - Given the continued racial/ethnic diversification of the United States, it is not uncommon for therapy groups to consist of members with diverse racial/ethnic backgrounds and various cultural identities. Scholars have underscored how this cultural diversity can directly impact many processes and outcomes of group-based interventions (Chen, Kakkad, & Balzano, 2008). However, there is presently a paucity of empirical research testing the relationship between cultural processes of therapy groups and members' outcomes. Moreover, no psychometrically sound measure of the cultural process that unfolds in group therapy currently exists. As such, this study sought to adapt the Multicultural Orientation Inventory to develop and validate the Multicultural Orientation Inventory-Group Version (MCO G), a measure assessing the cultural humility, cultural comfort, and cultural missed opportunities in therapy groups. Data for this validation study consisted of 208 members of 49 therapy groups across 10 university counseling centers. Confirmatory factor analyses supported a 3-factor structure of the MCO-G Inventory, wherein the 3 factors corresponded with the underlying constructs of cultural humility, cultural comfort, and cultural missed opportunities. This study provides initial evidence for the estimated internal and convergent validity of the MCO-G, as measured by clients' perceptions of a higher-order group therapeutic factor and improvement in therapy. Results provide initial support for the psychometric properties of the MCO-G. Moreover, groups' cultural humility and cultural missed opportunities were related to members' improvement in therapy. Clinical implications and future research are discussed. (PsycINFO Database Record PMID- 29999333 TI - Within-person relationship between career goal feedback and career-related stress: A weekly survey study. AB - Based on social-cognitive and general self-regulation theories, this study examined the underlying mechanisms of the within-person relationship between negative career goal feedback and career-related stress. Using a sample of young adults and a weekly survey study with four measurements (212 observations), we found that negative feedback on career progress and poor feedback on improvements needed for career progress related to more career stress, and that career-related self-efficacy mediated the link between feedback on improvements needed and stress. In addition, trait optimism buffered the link between negative feedback on progress and stress. These findings highlight important roles for career feedback and optimism in young people's career self-regulation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29999334 TI - Consumer perspectives on physical activity interventions within assertive community treatment programs. AB - OBJECTIVE: The purpose of this study was to identify strategies for encouraging greater levels of physical activity among community-dwelling individuals living with serious mental illness participating in assertive community treatment (ACT). METHOD: Eighteen individuals living with serious mental illness participated in focus group interviews. Participants were recruited from an ACT provider located in the Midwestern United States. A semistructured interview protocol was developed specifically for this study. Participants responded to a series of questions on ACT physical activity programming, providing (a) information about their personal experiences with physical activity-related interventions and (b) suggestions for intervention strategies that may enhance physical activity participation in this population. Consensual qualitative research conventions, a qualitative methodology used in social sciences, were followed for organizing, coding, quantifying, and interpreting participant responses. RESULTS: Several unique themes emerged from the data. Participants identified a variety of strategies used by their ACT provider to encourage physical activity, such as group physical activities and incentive programs. A number of recommendations related to skills training, intervention characteristics, and motivational strategies were identified by the participants as well. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Physical activity is an important part of successful treatment for individuals with serious mental illness. In this study, participants identified a variety of strategies that may be useful for incorporating within the ACT treatment paradigm. Participant responses were frequently consistent with the tenets of popular health behavior theory (e.g., self-determination theory). Future research should focus on the efficacy of the recommended intervention strategies and their implementation within ACT treatment settings. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29999335 TI - The social identity approach to disability: Bridging disability studies and psychological science. AB - Although mainstream psychology has received numerous critiques for its traditional approaches to disability-related research, proposals for alternative theory that can encompass the social, cultural, political, and historical features of disability are lacking. The social identity approach (SIA) offers a rich framework from which to ask research questions about the experience of disability in accordance with the critical insights found in disability studies (DS), the source for many of the most compelling critiques of disability psychology research. We review existing research considering the complementary social identity (Tajfel & Turner, 1979) and self-categorization (Turner, Hogg, Reicher, & Wetherell, 1987) theories to support our contention that the disability social category is a significant driving force in the psychological experience of disability and to demonstrate the theoretical utility of the SIA. We suggest that a bridge between the critical epistemological perspectives found in disability studies and the methodological rigor and theoretical breadth and parsimony of a social identity approach is essential for examining the social psychological experience of disability in the 21st century. To conclude we explore the emergent possibilities for research in psychological science that can follow from a social identity approach to disability. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29999336 TI - Who is trustworthy? Predicting trustworthy intentions and behavior. AB - Existing trust research has disproportionately focused on what makes people more or less trusting, and has largely ignored the question of what makes people more or less trustworthy. In this investigation, we deepen our understanding of trustworthiness. Across six studies using economic games that measure trustworthy behavior and survey items that measure trustworthy intentions, we explore the personality traits that predict trustworthiness. We demonstrate that guilt proneness predicts trustworthiness better than a variety of other personality measures, and we identify sense of interpersonal responsibility as the underlying mechanism by both measuring it and manipulating it directly. People who are high in guilt-proneness are more likely to be trustworthy than are individuals who are low in guilt-proneness, but they are not universally more generous. We demonstrate that people high in guilt-proneness are more likely to behave in interpersonally sensitive ways when they are more responsible for others' outcomes. We also explore potential interventions to increase trustworthiness. Our findings fill a significant gap in the trust literature by building a foundation for investigating trustworthiness, by identifying a trait predictor of trustworthy intentions and behavior, and by providing practical advice for deciding in whom we should place our trust. (PsycINFO Database Record PMID- 29999337 TI - Reciprocal support and daily perceived control: Developing a better understanding of daily support transactions across a major life transition. AB - A paradox of social support has been well documented: believing that support is available and perceiving high levels of it has well-established mental health benefits, but the actual receipt of support is often found to be ineffective and even detrimental (see Gleason & Iida, 2015). Researchers have suggested that support receipt may be associated with negative mood because it is linked with a lack of self-efficacy or perceived control (Bolger & Amarel, 2007). Research on daily support transactions found that reciprocal emotional support exchanges counteracted the negative effects associated with support receipt, but there was significant variation between individuals in their reactions to support exchanges suggesting that a potential moderating variable of the support pattern exists. Using a daily diary study of 78 couples approaching a shared stressor, the transition to parenthood, associations between control, self- and partner reported support, and mood were investigated. Couples were asked to complete three weeks of daily diaries at three different time points. Previous support pattern effects on mood were replicated for partners, but whereas reciprocity was beneficial for mothers, support receipt alone was not negative. Perceived control was found to be a moderator of this process such that the greater an individual's sense of perceived control, the more one is buffered from any negative effects of support transactions. Exploratory analyses also suggest that overall patterns of supportive reciprocity influence marital satisfaction across the transition to parenthood. (PsycINFO Database Record PMID- 29999338 TI - The dark core of personality. AB - Many negatively connoted personality traits (often termed "dark traits") have been introduced to account for ethically, morally, and socially questionable behavior. Herein, we provide a unifying, comprehensive theoretical framework for understanding dark personality in terms of a general dispositional tendency of which dark traits arise as specific manifestations. That is, we theoretically specify the common core of dark traits, which we call the Dark Factor of Personality (D). The fluid concept of D captures individual differences in the tendency to maximize one's individual utility-disregarding, accepting, or malevolently provoking disutility for others-accompanied by beliefs that serve as justifications. To critically test D, we unify and extend prior work methodologically and empirically by considering a large number of dark traits simultaneously, using statistical approaches tailored to capture both the common core and the unique content of dark traits, and testing the predictive validity of both D and the unique content of dark traits with respect to diverse criteria including fully consequential and incentive-compatible behavior. In a series of four studies (N > 2,500), we provide evidence in support of the theoretical conceptualization of D, show that dark traits can be understood as specific manifestations of D, demonstrate that D predicts a multitude of criteria in the realm of ethically, morally, and socially questionable behavior, and illustrate that D does not depend on any particular indicator variable included. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29999339 TI - Pediatric primary care providers' reported likelihood to refer to mental health specialists. AB - INTRODUCTION: Pediatric primary care providers (PPCPs) play an increasingly important role in addressing mental health concerns. Yet PPCPs are limited in the services they can provide because of constraints in training, time, and reimbursement. Whereas some patients may be appropriately treated in primary care, others require referrals to mental health specialists. The current study evaluated patient, clinician, and situational factors associated with PPCPS' reported likelihood to refer hypothetical patients with mental health concerns to mental health specialists. METHOD: The sample included 106 PPCPs from Massachusetts and Indiana who read one of two vignettes of hypothetical patients (one with symptoms of attention-deficit hyperactivity disorder (ADHD) and one with symptoms of depression) and then completed surveys regarding patient diagnosis and treatment decisions. RESULTS: Results indicated that PPCPs who read the depression vignette were significantly more likely to report intentions to refer the patient to a mental health specialist than those who read the ADHD vignette as were PPCPs with less confidence in treating mental health concerns. PPCPs who read the depression vignette were also more likely to report intentions to refer to psychologists and social workers as opposed to PPCPs who read the ADHD vignette, who reported intentions to refer to psychiatrists. Training in developmental and behavioral pediatrics was not related to reported likelihood of referring. CONCLUSION: These findings illuminate potential areas for future research on referral patterns from primary care to mental health specialists. (PsycINFO Database Record PMID- 29999340 TI - Parent-adolescent dyadic diabetes distress: Associations with A1c and diabetes related strengths. AB - INTRODUCTION: This study examined concordance and discordance between parent adolescent report of diabetes-specific emotional distress and associations with A1c and diabetes-related strengths. Diabetes strengths refer to adaptive behaviors and attitudes that enhance resilience in living with diabetes. METHOD: One thousand two hundred sixteen adolescent-parent dyads completed measures of diabetes distress and adolescent-reported diabetes strengths. Polynomial regression with response surface analysis assessed concordant and discordant reports of adolescent-parent distress and independent associations of each reporter's distress on measures of diabetes strengths and A1c. RESULTS: A1c was lower in concordantly lower distress dyads compared to concordantly higher distress dyads. For discordant dyadic reports, A1c was higher when distress was higher for parents and lower for adolescents compared to low-parent-high adolescent distress. Greater diabetes-related strengths were reported when distress was concordantly low among dyads and fewer strengths were reported when distress was concordantly higher. Greater strengths were reported when distress was lower for adolescents and higher for parents compared to high-adolescent/low parent distress. Dyadic distress for both A1c and diabetes strengths were robust when adjusted for significant demographic predictors of outcome including age, race, income, pump use, and continuous glucose monitoring use. DISCUSSION: A1c and diabetes strengths are associated with degree of concordant and discordant reports of diabetes distress among adolescent-parent dyads. Programmatic interventions should target parents and adolescents, particularly when diabetes distress is higher among both adolescents and their parents. (PsycINFO Database Record PMID- 29999341 TI - The role of partner autonomy support in motivation, well-being, and weight loss among women with higher baseline BMI. AB - INTRODUCTION: The association of partner autonomy support with women's motivation for healthy eating, weight-related health behavior change, and psychological well being has been largely overlooked. Results of 2 studies showed that the positive association between autonomy support and a variety of motivational and psychological outcomes was especially pronounced for women with high body mass index (BMI) (+1 SD) compared to low BMI (-1 SD). METHOD: In Study 1, autonomy support was measured as male partners' report of their behavior in a cross sectional design. In Study 2, autonomy support was measured as female participants' perceptions of their partners' behavior in a longitudinal home environment-based behavioral weight loss intervention. RESULTS: Study 1 showed that autonomy support from partners was associated with greater self-determined motivation for healthy eating and self-reported well-being among women with higher BMI. Study 2 showed that changes in partner autonomy support over 18 months of a home-based weight loss intervention were associated with increases in motivation for treatment and greater weight loss, especially for women who had higher baseline BMI. DISCUSSION: Both studies demonstrated that autonomy support was associated with adaptive functioning across weight status but that it was especially potent for women with higher BMI. This pattern of findings is explained in terms of the pressures women with higher BMI may feel about their weight-related behaviors. (PsycINFO Database Record PMID- 29999342 TI - A qualitative enquiry of hypoglycemia and the social determinants of health: The InHypo-DM study, Canada. AB - INTRODUCTION: A significant body of research exists on the impact of the social determinants of health (SDoHs) on diabetes care and general health outcomes. However, less is known about health care practitioners' (HCPs') perspectives and experiences regarding the impact of the SDoHs on their patients with Type I and Type 2 diabetes mellitus and how this affects the prevention and treatment of hypoglycemia. METHOD: A descriptive qualitative study, derived from the InHypo-DM (Canada) research program. A purposive sampling technique was used to recruit participants residing in southwestern Ontario, Canada, for a 30- to 45-min semistructured interview. Individual and team analysis of interviews was conducted to identify overarching and subthemes. Twenty HCP participants, including endocrinologists, family physicians, and allied health care practitioners, were recruited. Seven were Certified Diabetes Educators. RESULTS: Participants articulated 2 overarching components of the SDoHs: patients' socioeconomic issues and psychosocial issues. They highlighted two socioeconomic issues: occupation type and poverty. Participants also emphasized 3 areas pertaining to patients' psychosocial issues: stage in the life cycle (e.g., elderly), social isolation, and mental health. DISCUSSION: This study emphasizes the need for conducting detailed and comprehensive social histories during clinical diabetes assessments, as well as the necessity of adequate clinical time and resources for HCPs and patients to address these issues in the context of hypoglycemia management. (PsycINFO Database Record PMID- 29999343 TI - Is relationship quality linked to diabetes risk and management?: It depends on what you look at. AB - : Although the quality of marriage and marriage-like relationships (e.g., cohabitation) has been linked to the risk of developing diabetes and being able to effectively manage the disease once developed, it is unclear which aspects of marital quality drive these associations. METHOD: Using nationally representative data (Midlife in the United States, N = 800), the present study therefore examines how aspects of marriage (e.g., strain, support, marital risk, and constructive communication) are linked to diabetes outcomes and whether these links vary as a function of sociodemographic characteristics related to health (e.g., gender, race, and income). RESULTS: Strain and marital risk were linked to an increased risk of developing diabetes and strain and poor communication were linked to an increased risk of poor diabetes management. Finally, marital support was linked to a lower risk of diabetes but only for those with lower income. DISCUSSION: These findings inform prevention and intervention programs focusing on social support mechanisms to potentially reduce the risk of developing diabetes (e.g., reduced marital strain and marital instability) and improving diabetes control (e.g., improved communication and reduced marital strain). (PsycINFO Database Record PMID- 29999344 TI - Family health and income: A two-sample replication. AB - The current study examined psychological and family health predictors of change over time in household income, using data from longitudinal studies of African American (N = 889, 93.5% female) and Mexican origin (N = 674, 100% female) families. Participants self-reported their household income, as well as their emotional, personality, and cognitive resources. Participant behavioral and physical resources were coded from observed family interactions. Although income did not predict change in any personal resources, all five classes of personal resources (i.e., emotional, personality, cognitive, behavioral, physical) predicted change in income across a 10-year span (Study 1) and a 6-year span (Study 2). Income is potentially caused by these personal resources, or both income and these personal resources share a common cause. The dominant approach of assuming income causes personal and family health needs stronger support. (PsycINFO Database Record PMID- 29999345 TI - Aspects of the parent-adolescent relationship and associations with adolescent risk behaviors over time. AB - Parents' actions and knowledge of adolescents' whereabouts play key roles in preventing risk behaviors in early adolescence, but what enables parents to know about their adolescents' activities and what links there are to adolescent risk behaviors, such as substance use and delinquent behavior, remain unclear. In this study, we investigated whether different aspects of the parent-adolescent relationship predict parental knowledge, and we examined the direct and indirect longitudinal associations between these aspects of the parent-adolescent relationship and adolescents' self-reported delinquent behavior and substance use. The participants were 550 parents and their adolescent children from two small and two midsized municipalities in Sweden. Parental data were collected when the adolescents were 13 years old (mean), and adolescent data on risk behaviors were collected on two occasions, when they were 13 and 14 years of age (mean). Structural path analyses revealed that adolescent disclosure, parental solicitation, and parental control predicted parental knowledge, with adolescent disclosure being the strongest source of parental knowledge and the strongest negative predictor of adolescent risk behaviors. Parenting competence and adolescents' connectedness to parents were indirectly, through adolescent disclosure and parental solicitation and parental control, associated with substance use and delinquent behavior. Some paths differed for boys and girls. In conclusion, confident parenting and a close parent-adolescent relationship in which adolescent disclosure is promoted, seem protective of adolescent engagement in risk behaviors. (PsycINFO Database Record PMID- 29999346 TI - Family rituals when children have cancer: A qualitative study. AB - Family rituals serve important functions for families, especially at times of change and stress, such having a child diagnosed with cancer. No studies have investigated how family rituals may be impacted during pediatric cancer treatment. This qualitative study explored the impact of pediatric cancer and its treatment on family rituals. Semistructured interviews with 19 mothers of children with cancer, ages 8-17 years old, were conducted and analyzed using grounded theory strategies. The interviews revealed two main types of changes in rituals: Loss; and Transformation. The Loss of Family Rituals included two subcategories (Nonattendance at Ongoing Family Rituals, Disruption of Family Rituals). The Transformation of Family Rituals included three subcategories (Readjustment of Family Rituals, Creation of New Family Rituals, Reestablishing Old Family Rituals). Seven general functions of family rituals were identified (Celebrating, Family Cohesion, Family Communication, Respite, Sense of Predictability, Sense of Security, Rhythm of Life) and five illness-related functions (Grounding in Life, Hope, Marking the Course of Treatment, Sense of Normalcy, Treatment Adherence). Although pediatric cancer may compromise family rituals (nonattendance and/or disruption) and their functions, families develop adaptive strategies (readjustment, creation, and/or reestablish) to transform rituals and facilitate their potentially protective functions. Discussion of rituals can be integrated into interventions to optimize family interactions in the adverse context of pediatric cancer, via the readjustment of existing rituals, the creation of new ones and the reestablishing of old rituals. (PsycINFO Database Record PMID- 29999347 TI - Gold Medal Award for Life Achievement in the Application of Psychology: Marvin Goldfried. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2018 recipient of the Gold Medal Award for Life Achievement in the Application of Psychology is Marvin Goldfried, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 126th Annual Convention of the American Psychological Association on August 10, 2018, at 4:00 p.m. Members of the 2018 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president; W. Bruce Walsh, PhD, secretary; Richard C. McCarty, PhD, treasurer; Camilla Benbow, EdD; Dorothy W. Cantor, PsyD; Connie S. Chan, PhD; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; and Stewart E. Cooper, PhD, American Psychological Association Board of Directors liaison. (PsycINFO Database Record PMID- 29999348 TI - Gold Medal Award for Life Achievement in the Practice of Psychology: David H. Barlow. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2018 recipient of the Gold Medal Award for Life Achievement in the Practice of Psychology is David H. Barlow, PhD, ABPP. President of the APF, Terence M. Keane, will present the APF Gold Medal Awards at the 126th Annual Convention of the American Psychological Association on August 10, 2018, at 4:00 p.m. Members of the 2018 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president; W. Bruce Walsh, PhD, secretary; Richard C. McCarty, PhD, treasurer; Camilla Benbow, EdD; Dorothy W. Cantor, PsyD; Connie S. Chan, PhD; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; and Stewart E. Cooper, PhD, American Psychological Association Board of Directors liaison. (PsycINFO Database Record PMID- 29999349 TI - Gold Medal Award for Life Achievement in Psychology in the Public Interest: James M. Jones. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2018 recipient of the Gold Medal Award for Life Achievement in Psychology in the Public Interest is James M. Jones, PhD. The president of the APF, Terence M. Keane, PhD, will present the APF Gold Medal Awards at the 126th Annual Convention of the American Psychological Association on August 10, 2018, at 4:00 p.m. Members of the 2018 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president; W. Bruce Walsh, PhD, secretary; Richard C. McCarty, PhD, treasurer; Camilla Benbow, EdD; Dorothy W. Cantor, PsyD; Connie S. Chan, PhD; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; and Stewart E. Cooper, PhD, APA Board of Directors liaison. (PsycINFO Database Record PMID- 29999350 TI - Charles L. Brewer Award for Distinguished Teaching of Psychology: Stephen L. Chew. AB - The American Psychological Foundation (APF) Charles L. Brewer Award for Distinguished Teaching of Psychology recognizes exemplary career contributions to the teaching of psychology. The 2018 recipient of the Charles L. Brewer Award for Distinguished Teaching of Psychology is Stephen L. Chew, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Charles L. Brewer Award for Distinguished Teaching of Psychology at the 126th Annual Convention of the American Psychological Association on August 10, 2018, at 4:00 p.m. Members of the 2018 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president; W. Bruce Walsh, PhD, secretary; Richard C. McCarty, PhD, treasurer; Camilla Benbow, EdD; Dorothy W. Cantor, PsyD; Connie S. Chan, PhD; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; and Stewart E. Cooper, PhD, American Psychological Association Board of Directors liaison. (PsycINFO Database Record PMID- 29999351 TI - Gold Medal Award for Life Achievement in the Science of Psychology: Constance L. Hammen. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2018 recipient of the Gold Medal Award for Life Achievement in the Science of Psychology is Constance L. Hammen, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 126th Annual Convention of the American Psychological Association on August 10, 2018, at 4:00 p.m. Members of the 2018 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president; W. Bruce Walsh, PhD, secretary; Richard C. McCarty, PhD, treasurer; Camilla Benbow, EdD; Dorothy W. Cantor, PsyD; Connie S. Chan, PhD; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; and Stewart E. Cooper, PhD, American Psychological Association Board of Directors liaison. (PsycINFO Database Record PMID- 29999353 TI - Summary Report of Journal Operations, 2017. AB - Presents a summary report of journal operations compiled from the 2017 annual reports of the Council of Editors and from Central Office records. Also includes a summary report of division journal operations compiled from the 2017 annual reports of the division journal editors. (PsycINFO Database Record PMID- 29999352 TI - The strength of the causal evidence against physical punishment of children and its implications for parents, psychologists, and policymakers. AB - The question of whether physical punishment is helpful or harmful to the development of children has been subject to hundreds of research studies over the past several decades. Yet whether causal conclusions can be drawn from this largely nonexperimental research and whether the conclusions generalize across contexts are issues that remain unresolved. In this article, the authors summarize the extent to which the empirical research on physical punishment meets accepted criteria for causal inference. They then review research demonstrating that physical punishment is linked with the same harms to children as is physical abuse and summarize the extant research that finds links between physical punishment and detrimental outcomes for children are consistent across cultural, family, and neighborhood contexts. The strength and consistency of the links between physical punishment and detrimental child outcomes lead the authors to recommend that parents should avoid physical punishment, psychologists should advise and advocate against it, and policymakers should develop means of educating the public about the harms of and alternatives to physical punishment. (PsycINFO Database Record PMID- 29999354 TI - Unconscious processing: Comment on Hornsey and Fielding (2017). AB - The goals of this comment are to emphasize the positive contribution made by Hornsey and Fielding (2017) and to present reasons why their contribution is neither theoretic nor transtheoretic. This comment seeks to provide a theoretic and transtheoretic explanation that involves unconscious processing. It indicates that connectionist neural network models provide relevant mechanism information for how unconscious processing works. (PsycINFO Database Record PMID- 29999355 TI - Not all motivated rejection of science is unconscious: Reply to Tryon (2018). AB - Tryon (2018) states that our proposed attitude roots are "effectively and functionally unconscious" (p. 685) and proposes connectionist neural network models as a mechanism for explaining these unconscious processes. In our response, we disagree with the presumption that our attitude roots necessarily operate at an unconscious level. Although some attitude roots may exert their influence through an unconscious process, others exert their influence as a result of explicit and mindful reasoning, and others still operate at a "preconscious" level: outside conscious awareness but accessible if required. Finally, we clarify that we did not claim in our article to have developed a theory or a metatheory. Rather, we drew on numerous established theories to make the case for the role of attitude roots and did so using a transtheoretical language that we hope can be useful in terms of integrating insights and developing concrete persuasion strategies. (PsycINFO Database Record PMID- 29999356 TI - Voice-only does not meaningfully improve detection of emotions: Comment on Kraus (2017). AB - Kraus (2017) claims that voice-only communication allows more accurate detection of emotions than does voice-plus-visual communication. The present author reanalyzes the data from Kraus's five experiments to reveal that the voice-only advantage is so slight as to not be of any practical importance. (PsycINFO Database Record PMID- 29999357 TI - What is a meaningful improvement in emotion detection? Reply to Rossiter (2018). AB - In his comment, Rossiter (2018) claims that voice-only communication elicits improvements in empathic accuracy that are "so slight as to not be of any practical importance" (p. 689). In this reply, I acknowledge that the reported experiments from Kraus (2017) produced small effects and are limited in terms of what they can conclude about empathic accuracy. Nevertheless, determining the practical importance of any effect is an empirical question worthy of further scrutiny. (PsycINFO Database Record PMID- 29999358 TI - A new look for addiction training in psychology programs: Comment on Dimoff, Sayette, and Norcross (2017). AB - Dimoff, Sayette, and Norcross (2017) documented a serious omission in the education of psychologists. Their research showed a paucity of addiction training in doctoral programs despite the growing prevalence of addictions. Although their article briefly discussed possible explanations and barriers to explain this finding, the article itself was shaped by implicit assumptions about addiction training that contribute to the field's failure to embrace such training. The current article identifies these assumptions and offers elements of an alternative approach to addiction training better suited to psychologists. (PsycINFO Database Record PMID- 29999359 TI - Addiction training and multiple treatments for all clinical psychologists: Reply to Freimuth (2018). AB - The authors agree with Freimuth (2018) that addiction training among clinical psychologists would be enhanced by offering addiction-related training to all clinical students, including those who do not aim to specialize in substance abuse. It is argued that Freimuth's points in fact support Dimoff, Sayette, and Norcross's (2017) recommendation that clinical programs bolster their addiction training but, contrary to Freimuth, in all evidence-based (abstinence and nonabstinence) treatments predicated on patient needs, not on practitioner preferences. (PsycINFO Database Record PMID- 29999360 TI - Duane M. Rumbaugh (1929-2017). AB - Presents an obituary of Duane M. Rumbaugh (1929-2017). Rumbaugh was an experimental psychologist known for his many contributions toward understanding primate learning and behavior. His ape-language research with Lana and other chimpanzees, comparative studies of quantitative and qualitative hallmarks of primate intelligence, and numerous methodological innovations helped usher in the field of comparative cognition. Rumbaugh's scientific legacy is extensive. The computerized language keyboard invented for the Lana Project would subsequently be employed to teach other nonhuman primates, as well as humans with intellectual challenges to communicate. (PsycINFO Database Record PMID- 29999361 TI - Elizabeth Deutsch Capaldi Phillips (1945-2017). AB - Presents an obituary for Elizabeth Deutsch Capaldi Phillips (1945-2017). Always known as Betty, she was an important contributor to the scientific literature and a force in higher education. Beginning as an assistant professor at Purdue University in 1969, Betty rose through the ranks and served as head of the Department of Psychological Sciences (1983-1988) and assistant dean of the Graduate School (1982-1986). Academic administration suited her: After moving to the University of Florida as a professor in 1988, she was appointed provost (1996 1999). Four years later she moved to the University of Buffalo as provost (2000 2003) and subsequently subsequently was appointed vice chancellor and chief of staff at the State University of New York (2003-2006). Betty's final academic position was as provost of Arizona State University (2006-2013). Throughout her career, Betty conducted research on the psychology of eating. She published over 80 articles and chapters and edited two books (both published by the American Psychological Association). (PsycINFO Database Record PMID- 29999362 TI - James (Jim) Georgoulakis (1948-2017). AB - Presents an obituary for James (Jim) Georgoulakis (1948-2017). Georgoulakis was a psychologist, soldier, and scholar. An international consultant, leader, and well respected advocate, he fought behind the scenes for decades, particularly on issues related to psychology and Medicare. He held several leadership positions with the U.S. Army, including director of the largest outpatient mental health program in the Department of Defense and Director of ambulatory care research for six military facilities. Jim's most substantial contribution to the profession of psychology was representing the American Psychological Association (APA) on the AMA's Relative Update Committee (RUC) for 20 years. Among his many awards, Jim was inducted into the MBA National Business Honor Society and named a distinguished scholar in law school. In 2005, he was honored with an APA Presidential Citation for contributions to psychology. He was laid to rest with full military honors at Fort Sam Houston. (PsycINFO Database Record PMID- 29999363 TI - Mary E. Reuder (1923-2017). AB - Presents an obituary for Mary E. Reuder (1923-2017). Mary was a member of the American Psychological Association (APA) for more than 60 years. A fellow of seven APA divisions (1, 2, 3, 6, 32, 36, and 52), she was also a member of eight other divisions (5, 8, 10, 15, 20, 24, 26, and 51). She was an exceptional statistician, experimental psychologist, and licensed clinical psychologist, unusual at a time when women were sparse in academia. She worked for the U.S. Navy as a management specialist and as research psychologist for the Adjunct General's Office of the U.S. Army before accepting a position at Queens College of the City University of New York (1954). The Florence Denmark and Mary E. Reuder Award in APA Division 52 (International Psychology) was created in recognition of her scholarly contributions, international outlook, and outstanding mentoring. Among her other awards, Mary was particularly pleased with the William James Award from the New York State Psychological Association for outstanding contributions to psychology. Her research was primarily in the areas of anxiety and locus of control. (PsycINFO Database Record PMID- 29999364 TI - Diane T. Marsh (1941-2016). AB - Presents an obituary for Diane T. Marsh (1941-2016). A retired faculty member at the University of Pittsburgh-Greensburg, she made substantial contributions to children's mental health, families affected by mental illness, and psychology education. During her 33 years at Pitt-Greensburg, Diane mentored many faculty members. She offered coauthorships to junior faculty on her book contracts, advised them on teaching, and helped many reach higher levels of research and professionalism. As a recipient of the Catherine Acuff Congressional Fellowship in 2003, Diane had the opportunity to influence public policy while working for U.S. Sen. Jeff Bingaman. One example of her influence was a Medicare law cosponsored by Bingaman that improved preventative and mental health services and enhanced benefits to low-income and rural populations. (PsycINFO Database Record PMID- 29999365 TI - Dennis "Denny" Drotar (1945-2017). AB - Presents an obituary for Dennis "Denny" Drotar (1945-2017). Denny was a brilliant and revered scholar who authored more than 350 papers, eight books, and many chapters that serve as a foundation for the field of pediatric psychology. Editor of the Journal of Pediatric Psychology from 2007-2013, he served as president of the Society of Pediatric Psychology (SPP), Division 54 of the American Psychological Association (APA), and was the first psychologist to serve as president of the Society for Developmental and Behavioral Pediatrics. Denny spent his career in academic medical centers, including Rainbow Babies and Children's Hospital, MetroHealth Medical Center, Cincinnati Children's Hospital Medical Center, and Boston Children's Hospital. He "semi-retired" in 2014 but continued to be involved in research and training until his death. (PsycINFO Database Record PMID- 29999367 TI - Critical consciousness moderates the relationship between transphobia and "bathroom bill" voting. AB - In recent years, antitransgender legislation that focuses on gender and the use of public restrooms-so-called bathroom bills-has been considered in many states in the United States. The present study was designed to extend research on transphobic attitudes and elucidate links between religious fundamentalism, social dominance orientation, transphobia, and voting for bathroom bills. Further, we examined the moderating influence of critical consciousness on the relationship between transphobic attitudes and voting on a hypothetical bathroom bill. Results of a moderated mediation multinomial logistic regression path analysis using data from a sample of 282 college students (154 women and 128 men) indicated that religious fundamentalism and social dominance orientation were associated with transphobic attitudes. Transphobia was associated with lower likelihood to vote against or abstain from voting on the bill, compared to voting for it. Critical consciousness was also associated with greater likelihood of voting against the bill rather than for it. The interaction between transphobia and critical consciousness was associated with voting against rather than for the bill, such that at higher levels of transphobia, those higher in critical consciousness were more likely to vote against the bill rather than for it. Implications for incorporating critical consciousness into advocacy efforts to promote transgender rights are discussed. (PsycINFO Database Record PMID- 29999366 TI - Sherri McCarthy (1958-2017). AB - Presents an obituary for Sherri McCarthy (1958-2017). A Professor of Educational Psychology at Northern Arizona University-Yuma, Sherry was instrumental in establishing their Human Relations Graduate Program. She was a fellow of Division 52 (International Psychology) of the American Psychological Association and active in Divisions 2 (Teaching of Psychology) and 48 (Peace Psychology). Sherri was particularly involved in service-oriented, community-oriented, and humanity oriented fields of psychology, and was a tireless collaborator on research, educational, and counseling projects around the world. She was a leader and cofounder of the series of international conferences on psychology education that began in St. Petersburg, Russia (2002). Sherri's editorial leadership produced three volumes, Teaching of Psychology Around the World (2007, 2009, 2012). Her commitment to international peace and human rights is well illustrated by her substantial contributions to the Springer Peace series volumes on International Handbook on War, Torture, and Terrorism (2013; as coeditor and chapter author) and International Handbook on Peace and Reconciliation (2013) to which she contributed extensively. (PsycINFO Database Record PMID- 29999368 TI - Socialization and well-being in multiracial individuals: A moderated mediation model of racial ambiguity and identity. AB - Scholarly interest in racial socialization is growing, but researchers' understanding of how and when racial socialization relates to well-being is underdeveloped, particularly for multiracial populations. The present study investigated moderated mediation models to understand whether the indirect relations of egalitarian socialization to subjective well-being and self-esteem through integrated multiracial identification were conditional on phenotypic racial ambiguity among 383 multiracial adults. Tests of moderated mediation in primary analyses were significant for subjective well-being and self-esteem. Consistent with the hypotheses, egalitarian socialization was linked to a stronger multiracial integrated identity, which was positively associated with subjective well-being and self-esteem for those with moderate and high phenotypic racial ambiguity. This indirect effect was not significant for those reporting low phenotypic racial ambiguity. Results suggested a positive role of egalitarian socialization in relation to integrated identity and well-being for multiracial adults. This study highlights a culturally relevant pathway through which egalitarian socialization impacts well-being through racial identification for multiracial adults and the conditions of phenotypic racial ambiguity that contextualize this indirect effect. (PsycINFO Database Record PMID- 29999369 TI - Work as a calling: A theoretical model. AB - Perceiving work as a calling has been positioned as a key pathway to enhancing work-related well-being. However, no formal theory exists attempting to explain predictors and outcomes of living a calling at work. To address this important gap, this article introduces a theoretical, empirically testable model of work as a calling - the Work as Calling Theory (WCT) - that is suitable for the contemporary world of work. Drawing from research and theory in counseling, vocational, multicultural, and industrial-organizational psychology, as well as dozens of quantitative and qualitative studies on calling, the WCT is presented in three parts: (a) predictors of living a calling, (b) variables that moderate and mediate the relation of perceiving a calling to living a calling, and (c) positive (job satisfaction, job performance) and potentially negative (burnout, workaholism, exploitation) outcomes that result from living a calling. Finally, practical implications are suggested for counselors and managers, who respectively may seek to help clients and employees live a calling. (PsycINFO Database Record PMID- 29999370 TI - When in doubt, sit quietly: A qualitative investigation of experienced therapists' perceptions of self-disclosure. AB - Using consensual qualitative research (CQR), we analyzed 13 interviews of experienced psychotherapists about general intentions for therapist self disclosure (TSD), experiences with successful TSDs, experiences with unsuccessful TSDs, and instances of unmanifested urges to disclose. For TSD generally (i.e., not about a specific instance), typical intentions were to facilitate exploration and build and maintain the therapeutic relationship. Therapists typically reported becoming more comfortable using TSD over time. In successful TSDs, the typical content was accurate, relevant similarities between therapist and client; typical consequences were positive. In unsuccessful TSDs, the typical antecedent was countertransference reactions; the typical intention was to provide support; typical content involved therapists mistakenly perceiving similarities with clients; and the general consequences were negative. In instances when therapists repressed the urge to disclose, the typical antecedent was countertransference and the content typically seemed relevant to the client's issues. We conclude that effective use of TSD requires general attunement to the client's dynamics, attunement to the client's readiness in the moment, ability to manage countertransference, and ability to use a specific TSD appropriately. Implications for practice, training, and research are discussed. (PsycINFO Database Record PMID- 29999371 TI - Client laughter in psychodynamic psychotherapy: Not a laughing matter. AB - We studied 814 client laughter events nested within 330 sessions nested within 33 clients nested within 16 therapists at one community clinic in which doctoral student therapists provided psychodynamic psychotherapy to adult community clients. Each laughter event in Sessions 1 to 5 and 16 to 20 was rated for cheerfulness, politeness, reflectiveness, contemptuousness, and nervousness. Across all clients, there was an average of about one laughter even per session. The average laughter event lasted 3.5 seconds, and was characterized primarily by politeness and reflectiveness. Overall amount of client laughter and the characteristics of client laughter did not change across sessions. Most of the variance in the laughter characteristics was at the session level, with less variance attributable to clients and therapists. When client attachment avoidance was high, laughter was less cheerful and more contemptuous. When client attachment anxiety was high, laughter was more nervous. Sessions with more reflective laughter were evaluated more positively by clients, and therapists whose clients had more reflective laughter had more positive client session evaluations. Furthermore, within a therapist's caseload, clients with the most nervous and contemptuous laughter evaluated sessions most positively. Implications are discussed. (PsycINFO Database Record PMID- 29999372 TI - Unmet social support needs among college students: Relations between social support discrepancy and depressive and anxiety symptoms. AB - Social support is a widely studied construct due to its associations with physical and emotional well-being outcomes (Uchino, 2006). However, little research examines the context within which receiving support may be helpful (Picard, Lee, & Hunsley, 1997). Whereas examinations of support adequacy are present in the literature (e.g., Song et al., 2012), limited research considers the difference between support needs and support received when the 2 are separated as distinct constructs. The current study consisted of 428 undergraduate college students and examined how the relation between social support needs and received social support relates to depressive and anxiety symptoms via a statistical approach suggested for need-actual discrepancy analysis (polynomial multiple regression, PMR, with response surface analysis; Edwards, 1994; Shanock, Baran, Gentry, Pattison, & Heggestad, 2010). Results indicated that greater discrepancy between needed support and received support was related to greater depressive, but not anxiety, symptoms. Specifically, when emotional support needs exceeded emotional support received, depressive symptoms tended to be highest. Moreover, perceptions of needed support were significantly greater than perceptions of received support, suggesting that college students in general perceive receiving less support than they need, and this discrepancy is related to greater depressive symptoms. (PsycINFO Database Record PMID- 29999373 TI - Firm father figures: A moderated mediation model of perceived authoritarianism and the intergenerational transmission of gender messages from fathers to sons. AB - How do men develop sexist attitudes, gender role conflict, and subjective masculinity stress? These questions have been given little attention in the literature. Given the strong relationships between these variables and men's poorer mental health, it is essential to understand their antecedents. This study seeks to elucidate the manner in which perceptions of fathers may influence sons' gender attitudes and experiences. Using a sample of 170 undergraduate men, the authors proposed a model in which perceived paternal modeling of masculine norms and perceived paternal sexist communication mediate the relationship between perceived paternal authoritarianism and our three outcome variables: sons' sexism, gender role conflict, and subjective masculinity stress. They also hypothesized that the father-son relationship quality would moderate these mediating relations. Results were consistent with a model in which both perceived paternal modeling of masculine norms and perceived paternal sexist communication mediated the relationship between perceived paternal authoritarianism and sons' sexism. However, only the indirect effects from perceived paternal authoritarianism to gender role conflict and subjective masculinity stress through perceived paternal sexist communication were significant. Two significant moderated mediation findings underscore the complexities of the father-son relationship-the quality of this relationship was a risk factor for sons' sexism but a protective factor for sons' subjective masculinity stress. These results suggest an intricate portrait of the perceived influence of fathers on their sons' gender development and stress. Practical implications for counseling psychologists as they relate to both counseling and prevention are discussed. (PsycINFO Database Record PMID- 29999374 TI - The working alliance, beliefs about the supervisor, and counseling self-efficacy: Applying the relational efficacy model to counselor supervision. AB - There is need for closer examination of how counselors' efficacy beliefs develop and function within actual counseling or supervisory relationships. We adapted Lent and Lopez's (2002) model of relational efficacy beliefs to the context of counseling supervision, examining possible linkages of counselors' self-efficacy to beliefs about how their supervisor perceives their (counselors') efficacy (termed relation-inferred self-efficacy [RISE]), beliefs about the supervisor's efficacy (other-efficacy), and perceptions of the supervisory working alliance. Two hundred forty graduate student counselors completed the relational efficacy belief measures in relation to a particularly challenging client on their caseloads. Path analysis findings suggested that the hypothesized model provided good fit to the data. In particular, counselors' RISE beliefs regarding their supervisors were well-predicted by the supervisory working alliance, other efficacy beliefs about the supervisor, amount of clinical experience, and perceived client distress level. RISE beliefs (along with amount of clinical experience), in turn, predicted counselors' self-efficacy. In addition, the strength of the relationship between RISE and counselor self-efficacy was moderated by other-efficacy, suggesting that supervisors' clinical credibility, from the perspective of their supervisees, plays an important role in their ability to promote the efficacy of their supervisees. (PsycINFO Database Record PMID- 29999375 TI - Patient financial distress and treatment outcomes in naturalistic psychotherapy. AB - Although psychotherapy is on the whole an effective health care practice, treatment efficacy for patients with varying levels of reported financial distress is less clear. The purpose of this study was to examine the impact of patient self-reported financial distress on psychotherapy outcomes using a large, naturalistic psychotherapy dataset of college students who sought psychotherapy services (n = 5,078 patients, n = 238 therapists). Multilevel models accounted for the nesting of patients within therapists and treatment outcome was assessed using the Outcome Questionnaire-45. Patients on the whole showed treatment effects in the moderate to large range (d = 0.73). However, patients with higher financial distress at baseline were more likely to drop out of treatment after 1 session and, when controlling for baseline severity, had worse outcomes at the end of treatment. Though the effects were small, these findings held when controlling for age, gender, and treatment length. Further, the relationship between baseline financial distress and treatment retention (but not treatment outcome) varied between therapists, though the effects were also small. Patients' financial distress specifically and social class more generally may be patient contributors to psychotherapy outcome (and therapist effects) that warrant further attention. (PsycINFO Database Record PMID- 29999376 TI - Cultural humility: Pilot study testing the social bonds hypothesis in interethnic couples. AB - The purpose of this study was to explore factors associated with relationship quality in interethnic couples. Specifically, we tested the social bond hypotheses of humility in a sample of 155 individual participants currently in an interethnic relationship. Using a cross-sectional design, participants completed an online survey that included measures of demographics, conflict in their relationship, cultural humility, and relationship quality. We predicted that perceptions of one's partner's cultural humility would mediate the relationship between culturally based ineffective arguing and relationship satisfaction and commitment. Results indicated that cultural humility was positively related to both relationship satisfaction and commitment and negatively related to ineffective arguing. Mediation analyses revealed that approximately 26% of the variance in relationship satisfaction and about 8% of the variance in commitment was explained by the effect of ineffective arguing through cultural humility. Results of this study add to the growing body of evidence for the social bond hypothesis of humility and advance the field of research on interethnic couples by providing quantitative support for themes noted in previous qualitative studies on interethnic couples. (PsycINFO Database Record PMID- 29999377 TI - Examining the utility of the Personality Assessment Screener in three criminal justice samples. AB - Many individuals in forensic/correctional settings experience significant mental health problems, yet effective screening tools to identify such difficulties are in relatively short supply. This study investigates the clinical utility of the Personality Assessment Screener (PAS; Morey, 1997), a 22-item self-report measure of risk for emotional and behavioral dysfunction, across three archival criminal justice samples (incarcerated sex offenders, prison inmates housed in general population and psychiatric units, and jail detainees). The PAS is derived from the Personality Assessment Inventory (PAI; Morey, 1991, 2007), a more comprehensive measure of emotional and behavioral disturbances that is widely used in forensic/correctional settings. The PAS total score effectively identified those with clinically significant elevations on the PAI and also significantly correlated with various criterion measures tapping psychological dysfunction. Existing interpretive ranges and labels used to describe PAS scores in general clinical settings were problematic, however, and may require revision for use in these contexts. (PsycINFO Database Record PMID- 29999378 TI - Quantifying explained variance in multilevel models: An integrative framework for defining R-squared measures. AB - Researchers often mention the utility and need for R-squared measures of explained variance for multilevel models (MLMs). Although this topic has been addressed by methodologists, the MLM R-squared literature suffers from several shortcomings: (a) analytic relationships among existing measures have not been established so measures equivalent in the population have been redeveloped 2 or 3 times; (b) a completely full partitioning of variance has not been used to create measures, leading to gaps in the availability of measures to address key substantive questions; (c) a unifying approach to interpreting and choosing among measures has not been provided, leading to researchers' difficulty with implementation; and (d) software has inconsistently and infrequently incorporated available measures. We address these issues with the following contributions. We develop an integrative framework of R-squared measures for MLMs with random intercepts and/or slopes based on a completely full decomposition of variance. We analytically relate 10 existing measures from different disciplines as special cases of 5 measures from our framework. We show how our framework fills gaps by supplying additional total and level-specific measures that answer new substantive research questions. To facilitate interpretation, we provide a novel and integrative graphical representation of all the measures in the framework; we use it to demonstrate limitations of current reporting practices for MLM R squareds, as well as benefits of considering multiple measures from the framework in juxtaposition. We supply and empirically illustrate an R function, r2MLM, that computes all measures in our framework to help researchers in considering effect size and conveying practical significance. (PsycINFO Database Record PMID- 29999379 TI - Computing Bayes factors from data with missing values. AB - The Bayes factor is increasingly used for the evaluation of hypotheses. These may be traditional hypotheses specified using equality constraints among the parameters of the statistical model of interest or informative hypotheses specified using equality and inequality constraints. Thus far, no attention has been given to the computation of Bayes factors from data with missing values. A key property of such a Bayes factor should be that it is only based on the information in the observed values. This article will show that such a Bayes factor can be obtained using multiple imputations of the missing values. After introduction of the general framework elaborations for Bayes factors based on default or subjective prior distributions and Bayes factors based on priors specified using training data will be given. It will be illustrated that the approach proposed can be applied using R packages for multiple imputation in combination with the Bayes factor packages Bain and BayesFactor. It will furthermore be illustrated that Bayes factors computed using a single imputation of the data are very inaccurate approximations of the correct Bayes factor. (PsycINFO Database Record PMID- 29999380 TI - Remembering or knowing how we felt: Depression and anxiety symptoms predict retrieval processes during emotional self-report. AB - Researchers and clinicians routinely rely on patients' retrospective emotional self-reports to guide diagnosis and treatment, despite evidence of impaired autobiographical memory and retrieval of emotional information in depression and anxiety. To clarify the nature and specificity of these impairments, we conducted two large online data collections (Study 1, N = 1,983; Study 2, N = 900) examining whether depression and/or anxiety symptoms would uniquely predict the use of self-reported episodic (i.e., remembering) and/or semantic (i.e., knowing) retrieval when rating one's positive and negative emotional experiences over different time frames. Participants were randomly assigned to one of six time frames (ranging from at this moment to last few years) and were asked to rate how intensely they felt each of four emotions, anxious, sad, calm, and happy, over that period. Following each rating, they were asked several follow-up prompts assessing their perceived reliance on episodic and/or semantic information to rate how they felt, using procedures adapted from the traditional "remember/know" paradigm (Tulving, 1985). Across both studies, depression and anxiety symptoms each uniquely predicted increased likelihood of remembering across emotion types, and decreased likelihood of knowing how one felt when rating positive emotion types. Implications for the theory and treatment of emotion-related memory disturbances in depression and anxiety, and for dual-process theories of memory retrieval more generally, are discussed. (PsycINFO Database Record PMID- 29999381 TI - Forecasting the duration of emotions: A motivational account and self-other differences. AB - This research investigates the forecasts that people make about the duration of positive versus negative emotions, and tests whether these forecasts differ for self versus for others. Consistent with a motivated thinking framework, six studies show that people make optimistic, asymmetric forecasts that positive emotions will last longer than negative ones. However, for other people, wishful thinking is absent, and therefore people make less optimistic, more symmetric forecasts. Potential implications of these motivated forecasts and self-other differences are discussed. (PsycINFO Database Record PMID- 29999382 TI - Paradoxical associations between familial affective responsiveness, stress, and amygdala reactivity. AB - Studies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving maps onto individual differences in threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development. (PsycINFO Database Record PMID- 29999383 TI - Cultural religiosity as the moderator of the relationship between affective experience and life satisfaction: A study in 147 countries. AB - People in different cultures may give different weights to emotional experience when evaluating their lives. In modern secularized cultures, people are more likely to focus on maximizing the experience of positive emotions and minimizing the experience of negative emotions to achieve well-being. In contrast, in traditional religious cultures, people are more likely to use religious standards to evaluate their lives. Therefore, the present study predicted that the frequency of positive and negative affect would be a better predictor of life satisfaction in secular (vs. religious) cultures. A sample of 295,933 participants from 147 countries was used to test this prediction. The data were extracted from the Gallup World Poll. As expected, the results of multilevel modeling showed that the association between affect and life satisfaction was weaker in religious than secular cultures. Therefore, the socioreligious context partly determines the extent to which affective information is relied on in life evaluation. (PsycINFO Database Record PMID- 29999384 TI - Exercise and emotion dynamics: An experience sampling study. AB - Though it has been widely demonstrated that regular exercise is associated with better emotional wellbeing, the nature of this association remains unclear. The present study explored the relationship between voluntary exercise and the temporal dynamics of daily emotions, and thus how voluntary exercise could be impacting emotional reactivity and recovery in naturalistic contexts. Seventy-six young adults participated simultaneously in this ecological momentary assessment study, and received 75 prompts over the course of 15 days. Emotional inertia (persistence of emotional states), emotional variability (intensity of emotional fluctuations), and emotional instability (tendency for emotional fluctuations) were considered. Past research has shown that low wellbeing tends to be associated with high inertia, variability, and instability. Each prompt included ratings of present emotions (anxiety, sadness, cheerfulness, contentment) and any recent physical activity. Greater average exercise time was significantly associated with less inertia (reduced autocorrelation) of anxiety. Exercise was not significantly associated with inertia of the other emotions, although results were in the same direction. Exercise habits were unrelated to emotional variability and instability. Results suggest that exercise may buffer against prolonged or persistent negative affective states and consequently could benefit a person's ability to self-regulate or recover from changes in the environment and internal emotional experiences, rather than simply reducing the frequency or intensity of anxious emotions. (PsycINFO Database Record PMID- 29999385 TI - Facial mimicry and play: A comparative study in chimpanzees and gorillas. AB - Play fighting, a common form of mammalian play, can escalate into aggression if playful motivation is misinterpreted and not shared by players. In primates, playful facial expressions and mimicry can be performed to signal and share playful motivation. Here we compare play facial expressions (play face [PF]: lower teeth exposed; full play face [FPF]: upper and lower teeth exposed) and their mimicry in captive chimpanzees and lowland gorillas, during play fighting. These two species have different social dynamics, with social cohesion being lower-and play possibly riskier-in gorillas than in chimpanzees. Thus, we hypothesized that gorillas would perform redundant PFs more often to avoid misunderstanding (Prediction 1). However, the two species are phylogenetically very close and possess a similar biology. Thus, we hypothesized that both species could perform rapid facial mimicry (RFM: response within 1 s) and delayed facial mimicry (DFM: response occurring between 1 s and 5 s), which may have different roles in play modulation (Prediction 2). Gorillas performed more FPF than chimpanzees and FPFs lasted longer than the less intense PF (Prediction 1 supported). RFM was present in both species, whereas DFM was present only in chimpanzees (Prediction 2 not fully supported). DFM may be performed by chimpanzees to modulate the session at a later stage of the interaction and favor interindividual cohesion. RFM prolonged play sessions and may be performed to communicate playful motivation to the playmate thus demonstrating that animals integrate contextual information into their understanding of others' states and intentions. (PsycINFO Database Record PMID- 29999386 TI - Fear and happiness, but not sadness, motivate attentional flexibility: A case for emotion influencing the ability to split foci of attention. AB - One prominent and consistent effect is that negative emotions with high motivational intensity, such as fear, narrow attention. However, recent data concerning how fear influences vision may suggest that fear could make attention flexible. Thus, the goal of the present study was to examine whether fear, like happiness, enhances attentional flexibility when multiple targets are present in noncontiguous locations. Fear, happiness, or sadness was induced followed by participants completing an attentional task that required splitting foci of attention to noncontiguous regions of space in the presence (Exp. 1) or absence (Exp. 2) of distractors or both (Exp. 3). Fear and happiness enhanced the reporting of targets in unattended locations demonstrating greater attentional flexibility. Sadness facilitated the splitting of attention through the suppression of irrelevant locations. The effects were replicated in a third experiment using a within-subjects design of distractor presence and an inclusion of a neutral condition. Taken together, results suggest fear and happiness increase attentional flexibility by impairing the suppression of irrelevant locations, which may allow for faster reallocation of attention facilitating detection of potential threats/rewards in one's environment. (PsycINFO Database Record PMID- 29999387 TI - Experiences in bullying and/or peer victimization of vulnerable, marginalized, and oppressed children and adolescents: An introduction to the special issue. AB - This is an introduction to the special issue "Bullying and Peer Victimization of Vulnerable, Marginalized, and Oppressed Youth." The study findings included in this special issue reveal that bias-based bullying and harassment are global social problems. Each article identifies suggestions for interventions, policy, and future research. Each study presented in this special issue contributes to the bullying and school violence scholarship, which can provide avenues for serious discussions on best ways to address not only bullying but also racism, sexism, heteronormativity, homophobia, ableism, classism, and Eurocentrism, all of which accompany bias-based bullying. (PsycINFO Database Record PMID- 29999388 TI - Bullying and mental health amongst Australian children and young people with cystic fibrosis. AB - Currently, there is little research investigating how schools can support the mental health and social development of young people with cystic fibrosis (CF), given their heightened risk of mental illness. Few studies have examined the relationship between bullying and mental health in populations of children with CF. This study describes the peer bullying experiences of young people with CF, and examines associations between school bullying and the psychological well being of these young people. A sequential mixed-methods approach was used to collect data from 26 young people with CF (10-16 years of age). These data were compared with large samples of healthy children. Following an online survey, 11 young people, through online focus groups, expanded on the survey findings, describing their experiences within the school environment. Young people with CF reported lower involvement in bullying victimization and perpetration relative to the comparison population. For older adolescents with CF, victimization was associated with less connectedness to school and less peer support, and more school loneliness, anxiety, and depression. Young people with CF reported they generally liked the school environment, and were happy with their friendships, whereas some older adolescents reported that bullying evoked anxiety and mood problems. Reported bullying was primarily verbal and targeted characteristics of their CF, including their coughing, noninvolvement in certain activities because of shortness of breath, use of medication, and being underweight (for boys only). The findings provide some recommendations for interventions to promote mental health and school engagement among young people with CF. (PsycINFO Database Record PMID- 29999389 TI - Examining suicidality, bullying, and gun carrying among Latina/o youth over 10 years. AB - Latino/a youth have reported the highest rates of suicide attempts compared to White and African American youth for over 40 years. The data from the Youth Risk Behavior Surveillance System (YRBSS) cross-sectional subsamples of Latino/a youth (N = 13,378) at every year of data collection between 2005 and 2015 were examined for bullying, gun carrying, and suicidality. Results indicate that Latina girls are significantly more likely than boys to make a suicide attempt and report more bullying and more cyberbullying, but are less likely to carry a gun. Being bullied or carrying a gun were significantly associated with greater likelihood of suicide attempt among both boys and girls. Youth who carried a gun overall had higher rates of suicide attempts whether they were bullied or not, whereas youth who did not carry a gun were significantly more likely to attempt suicide if they were bullied. Over the past 10 years, gun carrying has decreased significantly for Latino boys and suicide attempts have decreased significantly for Latina girls. Findings have important implications of considering intersections of race and gender when developing antibullying and suicide prevention strategies. There are important policy implications for considering the mental well-being of youth who are caught carrying guns at school and considering that victimization varies by ethnicity and gender. (PsycINFO Database Record PMID- 29999390 TI - Gain without pain: Glucose promotes cognitive engagement and protects positive affect in older adults. AB - When faced with a cognitively demanding task, older adults tend to disengage and withdraw effort. At the same time, their usual processing preference for positive information disappears. Providing glucose as an energy resource is known to improve cognitive performance and reinstate older adults' positivity preference. Here, we examined whether glucose can help older adults to exert more effort under high difficulty conditions, and if so, whether such increase is accompanied by a change in positive affect. Fifty-three young and 58 older adults consumed a glucose or a placebo drink and completed a memory-search task at three levels of difficulty. Cognitive engagement was measured through changes in heart rate (HR) and self-reported effort. After each memory-search block, participants completed an implicit emotion-assessment task. In both age groups, glucose produced increased HR (indicating higher task engagement) relative to placebo. In older but not in young adults, glucose also improved cognitive performance and increased positive affect. Subjective effort, in contrast, did not differ between the older-glucose and older-placebo groups. These results suggest that in older adults, glucose improves cognitive performance by promoting higher cognitive engagement while mitigating the subjective costs of effortful exertion. (PsycINFO Database Record PMID- 29999391 TI - Visual-vestibular integration during self-motion perception in younger and older adults. AB - Younger adults integrate visual and vestibular cues to self-motion in a manner consistent with optimal integration; however, little is currently known about whether this process changes with older age. Our objective was to determine whether older adults, like younger adults, display evidence of optimal visual vestibular integration, including reductions in bimodal variance (Visual + Vestibular) compared with unimodal variance (visual or vestibular alone), and reliability-based cue weighting. We used a motion simulator and a head-mounted display to introduce a 2-interval forced-choice heading estimation task. Older (65+ years) and younger adults (18-35 years) judged which of two movements was more rightward. Movements consisted of vestibular cues (passive movement in darkness), visual cues (optic flow), or both cues combined. The combined condition contained either congruent cues or incongruent cues (either a subtle 5 degrees or larger 20 degrees conflict). Results demonstrated that older adults had less reliable visual heading estimates than younger adults but comparable vestibular heading estimates. During combined, congruent conditions, both age groups exhibited reductions in combined variance, consistent with predicted optimal integration. During subtle cue conflicts, only younger adults exhibited combined variance consistent with predicted optimal integration, but both age groups displayed reliability-based cue weighting. During larger spatial conflicts, neither group demonstrated optimal reductions in variance. Younger adults displayed reliability-based cue weighting but older adults' heading estimates were biased toward the less reliable visual estimate. Older adults' tendency to incorporate spatially conflicting and unreliable visual cues into their self-motion percept may affect their performance on mobility-related tasks like walking and driving. (PsycINFO Database Record PMID- 29999392 TI - The impact of exposure to war and terror on individuals with disabilities. AB - BACKGROUND: Exposure to war or to a terror event is associated with mental health problems among the general population; however, less is known about its impact on people with lifelong disabilities. OBJECTIVE: The aim of the present study was to determine the impact of war and terror on people with lifelong physical and sensory disabilities. METHOD: Self-report questionnaires assessing exposure to war or terror, history of traumatic life events, presence of posttraumatic stress symptoms (PTSS), and depression symptoms were used to compare PTSS and depression symptoms among individuals with lifelong disabilities, who had been exposed to war or to terror events, individuals without disabilities exposed to war or to terror events, and individuals with disabilities without such exposure (N = 438). RESULTS: The findings indicated that individuals with lifelong disabilities, who had been exposed to war or terror events, were at higher risk for developing PTSS (95% CI [-13.189, -6.60]), but not depression symptoms (95% CI [5.007, 13.173]). PTSS was predicted by previous traumatic events, the presence of disability, and exposure to war (R2 = .12). In addition, within the disability groups, previous traumatic events did not predict any depressive symptoms. CONCLUSIONS: In times of political threat, a lifelong disability is a risk factor for elevated stress related symptomatology but not for depressive symptoms. The findings emphasize the need to be aware of the effects of life-threatening situations on vulnerable groups, such as people with lifelong disabilities, and to provide services to reduce the level of distress among this population. (PsycINFO Database Record PMID- 29999393 TI - More is not always better: Strategies to regulate negative mood induction in women with borderline personality disorder and depressive and anxiety disorders. AB - Individuals with borderline personality disorder (BPD) have difficulties regulating emotions, which may be a consequence of using less effective emotion regulation (ER) strategies to lessen the intensity of their negative emotions. It is not yet known whether people with BPD utilize particular ER strategies to modulate specific mood states and if these strategies are different from those used by individuals with depressive and anxiety disorders. In the present study, 90 participants (30 BPD, 30 anxiety and/or depressive disorders, and 30 healthy controls) underwent a mood induction procedure and specified which ER strategies they used and their perceived difficulty regulating mood following induction. Compared with healthy controls, BPD endorsed higher negative mood prior to, immediately following, and 4 min after neutral and negative mood inductions; more maladaptive ER strategies (e.g., rumination); and more perceived difficulty regulating negative mood. Compared with anxiety and/or depressive disorders, BPD endorsed similar ER strategies and subjective difficulty during mood inductions, endorsed higher negative mood following a neutral video and 1 negative video, and recorded higher RSA reactivity during and following 2 negative videos. Results suggest that individuals with BPD use a higher number of maladaptive ER strategies compared with healthy controls, which may lead to less effective modulation of negative mood and higher reports of difficulty regulating emotions. In addition, physiological measurements indicated that individuals with BPD may have higher RSA reactivity in response to negative mood induction compared with other mental disorders, which may reflect inefficient or disorganized attempts to regulate emotional arousal. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29999394 TI - A randomized controlled trial of a mentalization-based intervention (MBT-FACTS) for families of people with borderline personality disorder. AB - This article reports a delayed-treatment randomized controlled trial of a mentalization-based intervention for families or significant others living with or supporting a person with borderline personality disorder (BPD). In all, 56 family members/significant others living with/supporting people with a diagnosis of BPD were randomized either to immediate mentalization-based Families and Carers Training and Support, a supportive and skills-based program consisting of five 1.5- to 2-hr evening meetings, delivered by trained family members, or to delayed intervention. The primary outcome was adverse incidents reported by the family member in relation to the person with BPD. Secondary outcomes included self-reported family well-being, empowerment, burden, and levels of anxiety and depression. Family members randomized to immediate intervention showed a significant reduction in reported adverse incidents between themselves and the identified patient in the second phase of treatment compared with those randomized to delayed intervention. Analysis of the rate of change indicated a significantly steeper decline for the immediate-treatment group compared with the delayed-intervention group (beta = -1.07, 95% confidence interval [-1.40, -0.74], z = -6.3, p < .000). Secondary outcome measures showed family functioning and well-being improved more in the immediate-treatment group; changes were maintained at follow-up. There were no differences in depression, total anxiety, and total burden; both groups showed improvement on all these measures. Findings show that the mentalization-based Families and Carers Training and Support program delivered by families to families supporting a person with BPD reduces reported adverse incidents within the family. Further studies are needed to show whether this reduction improves outcomes for the individual with BPD. (PsycINFO Database Record PMID- 29999395 TI - "Complementary exploratory and confirmatory factor analyses of the French WISC-V: Analyses based on the standardization sample": Correction to Lecerf and Canivez (2018). AB - Reports an error in "Complementary exploratory and confirmatory factor analyses of the French WISC-V: Analyses based on the standardization sample" by Thierry Lecerf and Gary L. Canivez (Psychological Assessment, 2018[Jun], Vol 30[6], 793 808). In the original article a production error resulted in the deletion of subtests in the "French WISC-V subtest" column and the misalignment of factor names in the "Eigenvalue" column of Table 1. The corrected table is included in this erratum. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-57791-001.) Interpretation of the French Wechsler Intelligence Scale for Children-Fifth Edition (French WISC-V; Wechsler, 2016a) is based on a 5-factor model including Verbal Comprehension (VC), Visual Spatial (VS), Fluid Reasoning (FR), Working Memory (WM), and Processing Speed (PS). Evidence for the French WISC-V factorial structure was established exclusively through confirmatory factor analyses (CFAs). However, as recommended by Carroll (1995); Reise (2012), and Brown (2015), factorial structure should derive from both exploratory factor analysis (EFA) and CFA. The first goal of this study was to examine the factorial structure of the French WISC-V using EFA. The 15 French WISC-V primary and secondary subtest scaled scores intercorrelation matrix was used and factor extraction criteria suggested from 1 to 4 factors. To disentangle the contribution of first- and second-order factors, the Schmid and Leiman (1957) orthogonalization transformation (SLT) was applied. Overall, no EFA evidence for 5 factors was found. Results indicated that the g factor accounted for about 67% of the common variance and that the contributions of the first-order factors were weak (3.6 to 11.9%). CFA was used to test numerous alternative models. Results indicated that bifactor models produced better fit to these data than higher order models. Consistent with previous studies, findings suggested dominance of the general intelligence factor and that users should thus emphasize the Full Scale IQ (FSIQ) when interpreting the French WISC-V. (PsycINFO Database Record PMID- 29999396 TI - Responses improve the accuracy of confidence judgements in memory tasks. AB - How do we assess what we remember? Previous work on metacognition suggests that confidence judgments are more accurate when given after than before a response to a perceptual task. Here we present two experiments that investigate the influence of decision and response on metacognitive accuracy in a memory task so as to establish what kind of information people use to assess their memory content. Participants were asked to remember lists of words and then to decide which of two target words had previously been presented. In both experiments, participants rated their confidence either after or before the response. However, the experiments differed in the amount of information provided for confidence rating. In Experiment 1, before confidence rating, participants were either presented with both target words and asked to decide between them, or they were only presented with a cue (first letter of the subsequent target words). In Experiment 2, participants were always presented with a target word before confidence rating. The results of both experiments showed that although task accuracy correlated with confidence ratings in both conditions, this relationship was weaker when confidence was assessed before response to a memory task. We argue that metacognitive judgments are influenced by processing information that is not available at the time of primary response. We discuss the implications for theories of confidence and metacognition. (PsycINFO Database Record PMID- 29999397 TI - Determining the developmental requirements for hebb repetition learning in young children: Grouping, short-term memory, and their interaction. AB - The Hebb repetition paradigm has recently attracted attention as a measure of serial order learning, which underlies word-form learning abilities. Although children are good vocabulary learners, it is surprising that previous Hebb learning studies with young children show rather weak Hebb effects. In this study, we conducted two experiments to identify developmental factors that drive an increase of the size of the Hebb effect in young children. Motivated by evidence from adult work, we focused on an ability to group a sequence into consistent subsequences and on phonological short-term memory (STM) capacity. In Experiment 1 (N = 98), it was shown that 3- to 5-year-old children with high phonological STM capacity showed a Hebb effect, particularly in the later experimental trials. In Experiment 2 (N = 97), temporal grouping of the sequences in 2-2 subsequences further encouraged children with high phonological STM capacity to show the Hebb effect even in the earlier experimental trials and children with low STM capacity to show a trend toward a Hebb effect in the later trials. Moreover, across Experiments 1 and 2 we found robust evidence of transfer of the Hebb effect to recall of new sequences that partially overlapped in item by-item pairings with the Hebb sequence, indicating that children use consistent grouping strategies when learning above-span Hebb sequences. These findings indicate that phonological STM, grouping consistency, and their interaction are developmental requirements for the Hebb effect to emerge. (PsycINFO Database Record PMID- 29999398 TI - Forced fixations, trans-saccadic integration, and word recognition: Evidence for a hybrid mechanism of saccade triggering in reading. AB - Recent studies using the gaze-contingent boundary paradigm reported a reversed preview benefit-shorter fixations on a target word when an unrelated preview was easier to process than the fixated target (Schotter & Leinenger, 2016). This is explained via forced fixations-short fixations on words that would ideally be skipped (because lexical processing has progressed enough) but could not be because saccade planning reached a point of no return. This contrasts with accounts of preview effects via trans-saccadic integration-shorter fixations on a target word when the preview is more similar to it (see Cutter, Drieghe, & Liversedge, 2015). In addition, if the previewed word-not the fixated target determines subsequent eye movements, is it also this word that enters the linguistic processing stream? We tested these accounts by having 24 subjects read 150 sentences in the boundary paradigm in which both the preview and target were initially plausible but later one, both, or neither became implausible, providing an opportunity to probe which one was linguistically encoded. In an intervening buffer region, both words were plausible, providing an opportunity to investigate trans-saccadic integration. The frequency of the previewed word affected progressive saccades (i.e., forced fixations) as well as when trans-saccadic integration failure increased regressions, but, only the implausibility of the target word affected semantic encoding. These data support a hybrid account of saccadic control (Reingold, Reichle, Glaholt, & Sheridan, 2012) driven by incomplete (often parafoveal) word recognition, which occurs prior to complete (often foveal) word recognition. (PsycINFO Database Record PMID- 29999399 TI - Cognate effects on anaphor processing. AB - There are numerous studies demonstrating facilitated processing of cognates relative to noncognates for bilinguals, providing evidence that bilingual lexical access is language nonselective. We tested whether cross-language activation affects comprehension of larger units of meaning, focusing specifically on comprehension of anaphoric references. Highly proficient, Spanish-English bilinguals read sentences either in English (Experiment 1) or Spanish (Experiment 2) while their eye movements were recorded. Sentences consisted of an initial clause with 2 nouns that were either cognates or noncognates, and a later clause with an anaphor that either referred to the first or second noun. In the English experiment, cognate status facilitated selection of the sentence's foundational noun, reflected by shorter reading times for cognate nouns in the first position. Processing of pronouns was facilitated when they referred to cognates, reflected by higher skipping rates and shorter reading times. Final selection of cognate referents was also facilitated, reflected by total reading shorter total reading times, but only when the pronoun referred to the first noun. In the Spanish experiment, total reading times for cognate nouns were shorter, irrespective of their order of mention, reflecting a general cognate facilitation effect that was not affected by which noun was selected as the foundational structure. Spillover fixations from anaphors referring to cognates were shorter than noncognates, but only when they were the second-mentioned noun, suggesting that cognate status affected coreferencing for the more recently encountered noun. Implications for theories of cross-language activation and anaphoric reference are discussed. (PsycINFO Database Record PMID- 29999400 TI - Item-to-item associations in typing: Evidence from spin list sequence learning. AB - Associations are formed among the items in a sequence over the course of learning, but these item-to-item associations are not sufficient to reproduce the order of the sequence (Lashley, 1951). Contemporary theories of serial order tend to omit these associations entirely. The current paper investigates whether item to-item associations play a role in serial order, specifically focusing on whether these associations influence how typists order their keystrokes. To address this question, participants completed variants of the spin list learning procedure (Ebenholtz, 1963). In these experiments, participants practiced typing nonword anagram sequences, and the order of the letters between anagrams was manipulated. Between half of the anagram sequences, both absolute and relative letter order were made inconsistent by scrambling the letters according to a balanced Latin square. For the other half, the letters were instead spun, making absolute order inconsistent but keeping relative order consistent. Learning was faster for anagram sequences with consistent relative order (Experiment 1). Practice on spun sequences with consistent relative order transferred to unpracticed sequences with the same relative order (Experiment 2). Transfer to unpracticed sequences did not depend on the absolute position of the letters in the unpracticed sequences (Experiment 3). However, transfer disappeared if letter order was reversed (Experiment 4). These results suggest that typing does make use of item-to-item associations, at least when associative interference is minimized. Although not sufficient, item-to-item associations are a necessary component of serial order in typing. (PsycINFO Database Record PMID- 29999401 TI - Planning and coordination of utterances in a joint naming task. AB - Dialogue requires speakers to coordinate. According to the model of dialogue as joint action, interlocutors achieve this coordination by corepresenting their own and each other's task share in a functionally equivalent manner. In two experiments, we investigated this corepresentation account using an interactive joint naming task in which pairs of participants took turns naming sets of objects on a shared display. Speaker A named the first, or the first and third object, and Speaker B named the second object. In control conditions, Speaker A named one, two, or all three objects and Speaker B remained silent. We recorded the timing of the speakers' utterances and Speaker A's eye movements. Interturn pause durations indicated that the speakers effectively coordinated their utterances in time. Speaker A's speech onset latencies depended on the number of objects they named, but were unaffected by Speaker B's naming task. This suggests speakers were not fully incorporating their partner's task into their own speech planning. Moreover, Speaker A's eye movements indicated that they were much less likely to attend to objects their partner named than to objects they named themselves. When speakers did inspect their partner's objects, viewing times were too short to suggest that speakers were retrieving these object names as if they were planning to name the objects themselves. These results indicate that speakers prioritized planning their own responses over attending to their interlocutor's task and suggest that effective coordination can be achieved without full corepresentation of the partner's task. (PsycINFO Database Record PMID- 29999402 TI - Exploring the effects of knowledge of writing on reading Chinese characters in skilled readers. AB - Knowledge about how characters are written has been argued to play a particularly important role in how children learn to read Chinese. In the current study, we investigate the role that knowledge about writing characters plays in visual word processing in skilled adult readers. While there is clear neuropsychological evidence against the strong version of the hypothesis that reading depends on writing in Chinese even once literacy is acquired, it is still possible that writing could have a modulatory influence on how visually presented Chinese characters are processed in literate readers. The present study addressed this hypothesis using a visual same/different judgment task on pairs of characters that vary in how similar the 2 characters are visually and how similar they are in terms of motor plan, using 24 expert readers and writers of Chinese and 24 naive participants with no prior experience with written Chinese as subjects. The results of linear mixed-effects modeling indicate that the speed of same/different judgments is influenced by visual similarity, but not by how similar they are written, even in the group of skilled readers. These results suggest that knowledge of how Chinese characters are written does not influence visual character processing in skilled readers. (PsycINFO Database Record PMID- 29999403 TI - Are we attracted by losses? Boundary conditions for the approach and avoidance effects of losses. AB - The majority of the literature on the psychology of gains and losses suggests that losses lead to an avoidance response. Several studies, however, have shown that losses can also lead to an approach response, whereby an option is selected more often when it produces losses. In five studies we examine the boundary conditions for these contradictory approach and avoidance effects. The results show that an approach response emerges only when losses are produced by a highly advantageous choice alternative and when participants have ample unbiased direct or vicarious experience with this alternative. Additionally, the avoidance response to losses is also not ubiquitous and emerges when alternatives producing losses are experienced as disadvantageous. Thus, the findings suggest that both the approach and avoidance effects of losses exist and can be accounted for by increased investment of cognitive resources with losses (i.e., loss attention). Additionally, the findings clarify the loss attention account in indicating that losses increase exploitative behavior based on experienced outcomes, a process which can be locally optimal. (PsycINFO Database Record PMID- 29999404 TI - Effect of maternal depression and anxiety on mother's perception of child and the protective role of social support. AB - OBJECTIVE: The purpose of this study was to investigate the impact of postpartum depressive and anxiety symptoms on maternal perception of the infant and the protective role of social support. BACKGROUND: Adverse effects of perinatal depression on mother-child interaction are well documented; however, the role of maternal perception has not been examined. METHODS: We used the data of 431 women enrolled in a prospective study in a single maternity unit. Depressive and anxiety symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS), the State Trait Anxiety Inventory (STAI), and the mother's perception of infant with the Mother's Object Relation Scale (MORS). We used Multidimensional Scale of Perceived Social Support (MSPSS) in order to measure social support. RESULTS: Depressive and anxiety symptoms were positively associated to less positive emotions and a more dominant attitude of child as perceived by mothers. This association was even more significant in the case of trait anxiety. Perceived social support has been found to be a protective factor which was able to reduce this tendency. CONCLUSION: The findings have potential implications for our understanding of the impact of maternal depressive and anxiety symptoms on the developing mother-infant relationship. PMID- 29999405 TI - Bioactive edible films for food applications: mechanisms of antimicrobial and antioxidant activity. AB - In order to improve the quality of food and to extend their shelf life, a new generation of active edible films is being especially intended after the incorporation of organic acids, enzymes, antimicrobial proteins, phenolic compounds, or other functional ingredients such as probiotics, flavors, vitamins and nutraceuticals. These active compounds have different mechanisms of action related to their structure, their concentration, the nature of micro-organism targeted, the process of encapsulation or incorporation in the biopolymer film networks. The application of the active films by direct contact or indirect contact via the head space also affects the bioactivity of these compounds. This article critically reviews the published work on active edible-films and their applications for food preservation. The classes of active compounds and their action mechanisms are firstly discussed. Then, an extended overview on their effect on model food (simulants) or on real food during storage was also addressed. Edible films offer two main advantages over the direct incorporation of the antimicrobial or antioxidant agents into the bulk food: 1) to control the diffusion of active compounds at the surface of the food and 2) to reduce the amount of preservatives added in the food. PMID- 29999406 TI - Baseline Investigation of HIV-1 Primary Drug Resistance Among Newly Diagnosed Treatment-Naive HIV-1 Individuals in Hebei, China. AB - Human immunodeficiency virus (HIV) primary drug resistance (PDR) has influenced the long-term therapeutic effects of antiretroviral drugs. However, for the overall PDR prevalence in China, no report was found in published articles. In our study, an extensive cross-sectional investigation based on all newly diagnosed treatment-naive HIV-infected individuals was conducted. The overall prevalence of HIV-1 PDR among newly diagnosed treatment-naive HIV-1 individuals was 8.3% (60/720), obviously beyond the warning line (5.0%) set by WHO. The prevalence of PDR to PIs, nucleoside reverse transcriptase inhibitors, and non nucleoside reverse transcriptase inhibitors was 4.9% (35/720), 0.4% (3/720), and 2.5% (18/720), respectively. Moreover, the occurrence of HIV-1 PDR strains was random among different prefectures. HIV-1 PDR strains were extensively circulating among the sexual contact population inside and outside the Hebei province, especially between neighboring provinces and Hebei. Hebei province has become the moderate level PDR epidemic area. Enhanced surveillance for PDR is necessary among treatment-naive individuals in Hebei, and we must take effective measures to cut off the spread of HIV PDR strains. PMID- 29999407 TI - Sphingosine-1-phosphate induces airway smooth muscle cell proliferation, migration, and contraction by modulating Hippo signaling effector YAP. AB - Sphingosine-1-phosphate (S1P), a bioactive lipid, has been shown to be elevated in the airways of individuals with asthma and modulates the airway smooth muscle cell (ASMC) functions, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue. S1P induced yes-associated protein (YAP) dephosphorylation and nuclear localization via the S1PR2/3/Rho-associated protein kinase (ROCK) pathway, and this in turn increased forkhead box M1 (FOXM1) and cyclin D1 expression leading to ASMC proliferation, migration, and contraction. Pretreatment of cells with S1PR2 antagonist JTE013, S1PR3 antagonist CAY10444, or ROCK inhibitor Y27632 blocked S1P-induced alterations of YAP, FOXM1, cyclin D1, and ASMC proliferation, migration, and contraction. In addition, prior silencing of YAP or FOXM1 with siRNA reversed the effect of S1P on ASMC functions. Taken together, our study indicates that S1P stimulates ASMC proliferation, migration, and contraction by binding to S1PR2/3 and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma. PMID- 29999408 TI - The effects of phytochemicals on circadian rhythm and related diseases. AB - A circadian rhythm is any biological activity rhythm driven by internal circadian clocks (~24 h) and entrained by external signals. Its disruption leads to the development of many diseases, including obesity, metabolic syndrome, and cancer. However, not many medical treatments for circadian rhythm disorder has been applied. Several phytochemicals demonstrate the ability to prevent or even treat circadian-related diseases and function as circadian modulators. In this review, we briefly summarize the molecular architecture of circadian rhythm in mammals and circadian-related diseases. The effects of various phytochemicals such as caffeine, quercetin, cinnamic acid, and resveratrol on circadian clocks are highlighted. Potential application of diet therapy for circadian disorder and future research directions are also discussed. PMID- 29999409 TI - Roles for endothelial zinc homeostasis in vascular physiology and coronary artery disease. AB - The discovery of the roles of nitric oxide (NO) in cardiovascular signaling has led to a revolution in the understanding of cardiovascular disease. A new perspective to this story involving zinc (Zn) is emerging. Zn and its associated Zn transporter proteins are important for the integrity and functions of both the large conduit vessels and the microvascular resistance vessels. The Zn and NO pathways are tightly coordinated. Zn ions are required for the dimerization of endothelial nitric oxide synthase and subsequent generation of NO while generation of NO leads to a rapid mobilization of endothelial Zn stores. Labile Zn may mediate important downstream actions of NO including vascular cytoprotection and vasodilation. Several vascular disease risk factors (including aging, smoking and diabetes) interfere with Zn homeostatic mechanisms and both hypozincaemia and Zn transporter protein abnormalities are linked to atherosclerosis and microvascular disease. Some vegetarian diets and long-term use of certain anti-hypertensives may also impact on Zn status. The available evidence supports the existence of a Zn regulatory pathway in the vascular wall that is coupled to the generation and actions of NO and which is compromised in Zn deficiency with consequent implications for the pathogenesis and therapy of vascular disease. PMID- 29999410 TI - Seeking relational information sources in the digital age: A study into information source preferences amongst family and friends of those with dementia. AB - Despite an increasing number of sources providing information and advice about dementia, those living with the condition feel inadequately informed. The reasons for this remain unclear. This study has three aims: to identify where people with dementia and their carers currently access dementia-related information from; to determine how accessible, credible and comprehensible people with dementia and their carers consider the available sources of information; and to determine how people with dementia and their carers would like to receive information. An online or postal survey was completed by 171 female and 41 male participants with a close family member or friend with dementia. Accessibility above quality held the greatest influence over an individual's use of an information source. Participants preferred relational sources such as healthcare professionals as these were able to give individualised information, yet these were poorly accessible and lacked dementia specific knowledge. Therefore, individuals used non-relational sources such as the internet. However, increased use of the internet was linked to feeling overwhelmed by information. It was not the end result of the information search but the effort taken to reach the information that influenced participant's perception of information gathering. Future research should look at ways of designing and providing accessible information sources that act and feel like relational contact. PMID- 29999411 TI - A visual and creative approach to exploring people with dementia's experiences of being students at a school in Denmark. AB - In dementia research, there is limited knowledge about how people with dementia experience their daily life including how they experience the services they attend. This means a lack of knowledge about how people with dementia judge the quality of services provided for them. In this study visual and creative methods were used to understand the experience of people with early stage dementia who attend an adult school, Voksenskolen for Undervisning og Kommunikation (VUK) in Denmark. The study explored the students' experience of being a student at VUK and what it means to engage in life-long learning. Alongside the aim to evaluate the service provided for them, seen from their perspective. Photo-elicitation was used, with cameras provided to each student, who took photographs of their school and home life. Students' photographs were used to support focus group discussions, with the images integral to the process of talking about and recalling stories. Ten students were recruited to participate in four weekly sessions. Two groups were run with five students in each group. Each session was video recorded, these sessions were then transcribed and analysed using Braun and Clarke's thematic analysis. Visual images were found to support the students' memory of current experiences and prompted reminiscences about the past, leading to rich descriptions about being a student at VUK and their experiences of living with dementia. Being able to attend VUK was found to be important for these students with dementia, providing them with a sense of purpose, a way to support their cognitive function and also to develop new friendships. The method provided a way for people with dementia to be active in the research process and provide their perspective about a novel service, which promotes an ethos of learning and development. PMID- 29999412 TI - HIV-1 Infection and Type 1 Interferon: Navigating Through Uncertain Waters. AB - HIV-1 remains a chronic viral infection of global health importance. Although HIV 1 replication can be controlled by antiretroviral therapy (ART), there is no cure due to persistence of a long-lived latent reservoir. In addition, people living with HIV-1 who are taking ART still bear signatures of persistent immune activation that include continued type 1 interferon (IFN) signaling. Paradoxically, type 1 IFN exerts a limited role on the control of chronic HIV-1. Indeed, recent reports from humanized mice suggest that type 1 IFN may partly maintain the latent reservoir. In this review, we discuss the molecular interactions between HIV-1 and the type 1 IFN signaling pathway, and examine the efficacy of type 1 IFNs in vivo. We also explore whether limited type 1 IFN manipulation may have a therapeutic role. PMID- 29999414 TI - Near Full-Length Genome Sequence of a Novel HIV-1 Recombinant Form (CRF01_AE/07_BC) Detected Among Men Who Have Sex with Men in Zhejiang, China. AB - The prevalence of HIV type 1 among men who have sex with men (MSM) is increasing in China. We report here a novel HIV-1 recombinant form (CRF01_AE/CRF07_BC) detected from a male patient infected with HIV-1 by homosexual behavior in Zhejiang Province of eastern China. The near full-length genome analyses showed that the unique HIV-1 recombinant isolate (16ZJ305) has two recombinant breakpoints observed in the env and tat/rev gene regions. To date, several novel CRF01_AE/CRF07_BC recombinant forms have been identified, which may imply an active transmission network of HIV-1 infection among MSM. Further studies of the molecular epidemiology of the HIV-1 epidemic among MSM are necessary to gain a better understanding of the transmission network and track the genetic evolution. PMID- 29999413 TI - The Human Brain Traverses a Common Activation-Pattern State Space Across Task and Rest. AB - Much of our lives are spent in unconstrained rest states, yet cognitive brain processes are primarily investigated using task-constrained states. It may be possible to utilize the insights gained from experimental control of task processes as reference points for investigating unconstrained rest. To facilitate comparison of rest and task functional magnetic resonance imaging data, we focused on activation amplitude patterns, commonly used for task but not rest analyses. During rest, we identified spontaneous changes in temporally extended whole-brain activation-pattern states. This revealed a hierarchical organization of rest states. The top consisted of two competing states consistent with previously identified "task-positive" and "task-negative" activation patterns. These states were composed of more specific states that repeated over time and across individuals. Contrasting with the view that rest consists of only task negative states, task-positive states occurred 40% of the time while individuals "rested," suggesting task-focused activity may occur during rest. Together our results suggest that brain activation dynamics form a general hierarchy across task and rest, with a small number of dominant general states reflecting basic functional modes and a variety of specific states potentially reflecting a wide variety of cognitive processes. PMID- 29999415 TI - Biomedical applications of Aloe vera. AB - Over the last centuries, Aloe vera, a plant species belonging to the genus Aloe, have been extensively studied for various therapeutic activities, including anti bacterial, anti-viral, anti-cancer activity, as well as immunoregulative and hepatoprotective properties, although some of these claimed efficacies are controversial as demonstrated by some of the recent studies. In spite of the intensive historic and recent use of this herb and its extracts in various areas, a well-balanced, systematic review seems crucial in order to gain in-depth comprehensive knowledge about this plant and to reflect and revive the use of Aloe vera in biomedical sciences. This review will focus on summarization of the pharmacological activities and clinical studies of Aloe and various extracts, as well as its extensive application in food chemistry, and will also discuss the future prospects of biomedical applications of this herb. PMID- 29999416 TI - Algae in food: a general review. AB - Algae are common all over the Earth. Due to their rich chemical composition and content of bioactive substances they have been used in many fields of industry. Their gelling, thickening and stabilizing properties have led to the development of such products as agar, alginate and carrageenan. Moreover, algae are used in the food industry as food supplements and an addition to functional food. Algae are also added to meat products, such as pasty, steaks, frankfurters and sausages, as well as to fish, fish products, and oils, to improve their quality. Cereal-based products, such as pasta, flour and bread, are another group of products enriched with algae. Due to their properties algae may also be used for construction of fermented functional food. Fermented products containing algae are, most of all, dairy products, such as cheese, cream, milk deserts, yoghurt, cottage cheese, and processed cheese. Combination of fermented products offering a high content of lactic acid bacteria with algae possessing biologically active metabolites of natural origin allows not only to compose products with a high content of nutrients, but also to create a brand new segment of fermented food. PMID- 29999417 TI - To follow a rule? On frontline clinicians' understandings and embodiments of hospital-acquired infection prevention and control rules. AB - This article reports on a study of clinicians' responses to footage of their enactments of infection prevention and control. The study's approach was to elicit clinicians' reflections on and clarifications about the connections among infection control activities and infection control rules, taking into account their awareness, interpretation and in situ application of those rules. The findings of the study are that clinicians responded to footage of their own infection prevention and control practices by articulating previously unheeded tensions and constraints including infection control rules that were incomplete, undergoing change, and conflicting; material obstructions limiting infection control efforts; and habituated and divergent rule enactments and rule interpretations that were problematic but disregarded. The reflexive process is shown to elicit clinicians' learning about these complexities as they affect the accomplishment of effective infection control. The process is further shown to strengthen clinicians' appreciation of infection control as necessitating deliberation to decide what are locally appropriate standards, interpretations, assumptions, habituations and enactments of infection control. The article concludes that clinicians' 'practical wisdom' is unlikely to reach its full potential without video-assisted scrutiny of and deliberation about in situ clinical work. This enables clinicians to anchor their in situ enactments, reasonings and interpretations to local agreements about the intent, applicability, limits and practical enactment of rules. PMID- 29999418 TI - A step forward in resolving an old issue: treatment of heart failure with preserved ejection fraction and renal dysfunction? PMID- 29999419 TI - Immigrant Women's Mental Health in Canada in the Antenatal and Postpartum Period. AB - Immigrant women constitute a relatively large sector of Canadian society. In 2011, immigrant women made up a fifth of Canada's female population, the highest proportion in 100 years; based on the current trends of immigration, this proportion is expected to grow over the next 20 years. As women immigrate and find themselves simultaneously experiencing an unfamiliar environment, being unacquainted with societal norms, and lacking vital social networks, they become vulnerable to mental health problems. This article aims to undertake a narrative review of the literature on immigrant women's mental health in Canada during antenatal and postpartum care by employing the transnational theory as a theoretical framework. The article starts with an overview of the theoretical framework, followed by a discussion on a literature review that particularly talks about culture, isolation and social support network, social determinants of health, and access to health care as elements to consider in avoiding mental health problem among immigrant women in antenatal and postpartum care. The literature shows a high number of depression among immigrant women, and mental health problems are higher among visible minorities than Caucasians. The highest antenatal and postpartum depression recorded are 42% and 13%, respectively. As Canada has long been and continues to be the land of immigrants, addressing the multiple factors affecting immigrant women's mental health is paramount to Canada truly achieving "health for all." PMID- 29999420 TI - An indigenous framework of the cycle of fetal alcohol spectrum disorder risk and prevention across the generations: historical trauma, harm and healing. AB - OBJECTIVE: To build on Evans-Campbell's [2008. "Historical Trauma in American Indian/Native Alaska Communities: A Multilevel Framework for Exploring Impacts on Individuals, Families, and Communities." Journal of Interpersonal Violence 23 (3): 316-338. doi:10.1177/0886260507312290.] multilevel framework of historical trauma and health by focusing on the cycle of fetal alcohol spectrum disorders (FASD) in the socio-cultural, historical, and interpersonal context of trauma shared by American Indian and Alaska Native (AI/AN) peoples. METHODS: We analyzed qualitative data from focus groups with seventy four urban AI/ANs who were 15 years of age and older. Community-based participatory research methods were used for data collection and analysis. Our study explored knowledge and attitudes about FASD, perspectives on FASD risk factors, and culturally relevant approaches to FASD prevention and healthcare. RESULTS: According to our study's participants, efforts to address FASD among urban AI/ANs should align with and emerge from community values, promote healing, consider the broader context that influences behaviors, and reflect the community's understanding that FASD risk behaviors are inextricably linked with historical and contemporary trauma. CONCLUSION: Effective, multiple-level FASD prevention approaches for AI/ANs may include prioritizing Indigenous culture, supporting intergenerational cohesion, focusing on non-stigmatic healing of traumas, and authentically engaging community knowledge. This work draws on community and cultural strengths in an effort to reduce the occurrence of substance-exposed pregnancies, and encourages transformational changes in systems that serve AI/AN peoples to promote a healthy and thriving community and future generations. PMID- 29999422 TI - Brain Hyperconnectivity >10 Years After Cisplatin-Based Chemotherapy for Testicular Cancer. AB - Chemotherapy for testicular cancer (TC) has been associated with neurotoxic effects shortly post-treatment. Late effects of chemotherapy on brain function in this patient group are still unknown. In this study, we investigated differences between patients with and without chemotherapy in functional brain networks at rest and during an affective processing functional magnetic resonance imaging (fMRI) task on average >14 years post-treatment. In addition, we report on changes in cognitive functioning during survivorship by comparing present and previous performance on a neuropsychological test battery on average 11 years earlier (3 years post-treatment). Twenty-eight chemotherapy (43.1 +/- 7.5 years) and 23 surgery-only (48.2 +/- 9.5 years) TC survivors were examined using neurocognitive tests and 3T-fMRI >10 years after treatment end. Brain functional networks were identified using dual regression independent component analysis. Task fMRI was analyzed using a block design. Standardized domain change scores were calculated for each individual to assess cognitive change. TC patients in the chemotherapy group showed functional hyperconnectivity at rest in the precuneus network, sensory and motor function network, executive control network, and the ventral stream network when compared with surgery-only patients. Furthermore, hypoactivation was found when performing the affective processing task. Cognitive data revealed that both groups showed comparable patterns of change from 3 to 14 years after initial treatment. This study provides novel insights on the possible underlying neurobiological mechanisms of late neurotoxic effects of cisplatin-based chemotherapy. Present findings reveal that functional hyperconnectivity is widespread, possibly to compensate for the pathophysiological disturbances. This concurs with our previous findings of structural hyperconnectivity in white matter. Longitudinal multimodal imaging studies are warranted to further investigate the association between long-term structural and functional network connectivity data, as well as its relationship with cognitive changes. PMID- 29999423 TI - Controversy on the correlation of red and processed meat consumption with colorectal cancer risk: an Asian perspective. AB - This study aimed to investigate the relationship between meat intake and colorectal cancer risk from an Asian, particularly Korean, perspective. A report by the International Agency for Research on Cancer (IARC) published in 2015 concluded that intake of processed and red meat increases the risk of developing colorectal cancer. We conducted an in-depth analysis of prospective, retrospective, case-control and cohort studies, systematic review articles, and IARC monograph reports, which revealed that the IARC/WHO report weighted the results of studies based in Western countries more and that the correlation between intake of processed meat products and colorectal cancer incidence in Asians is not clearly supported. Among 73 epidemiological studies, approximately 76% were conducted in Western countries, whereas only 15% of studies were conducted in Asia. Furthermore, most studies conducted in Asia showed that processed meat consumption is not related to the onset of cancer. Moreover, there have been no reports showing significant correlation between various factors that directly or indirectly affect colorectal cancer incidence, including processed meat products types, raw meat types, or cooking methods. Further epidemiological studies taking each country's food culture into consideration are required to reliably elucidate the effects of processed meat product intake, especially on cancer incidence. PMID- 29999421 TI - Street-involved youth engaged in sex work at increased risk of syringe sharing. AB - Syringe sharing places street-involved young people at risk of acquiring HIV and hepatitis C. While markers of economic marginalization, such as homelessness, have been linked with syringe sharing and have led to targeted interventions, the relationship between syringe sharing and other markers of economic vulnerability, such as sex work, are not well documented among young people. This study examines whether those engaged in sex work are at increased risk of syringe borrowing and syringe lending among street-involved youth who use injection drugs in Vancouver, Canada. Between September 2005 and May 2014, data was collected from the At-Risk Youth Study (ARYS), a prospective cohort of street involved youth aged 14-26. Generalized estimating equations with a confounding model building approach was used to examine the relationship between sex work and syringe borrowing and lending. 498 youth reported injecting drugs at some point during the study period and were therefore included in the analysis. In multivariable analysis, youth who engaged in sex work were at an elevated risk of both syringe borrowing (Adjusted Odds Ratio (AOR) = 2.17, 95% Confidence Interval [CI] = 1.40-3.36) and syringe lending (AOR = 1.66, 95% CI = 1.07-2.59). Our study found that youth engaged in street-based sex work were at a significantly higher risk of both syringe borrowing and lending among youth who use injection drugs in Vancouver. Ready access to clean syringes, safer working conditions for sex workers to enable risk reduction measures, and increased access to addiction treatment are identified as promising opportunities for reducing syringe sharing in this setting. PMID- 29999424 TI - Recent advances in banana (musa spp.) biofortification to alleviate vitamin A deficiency. AB - Vitamin A deficiency (VAD) is one of the most prevalent micronutrient deficiencies that disproportionately affects low income populations in developing countries. Traditional breeding and modern biotechnology have significant potential to enhance micronutrient bioavailability in crops through biofortification. Bananas (Musa spp.) are economically important fruit crops grown throughout tropical and sub-tropical regions of the world where VAD is most prevalent. Some banana genotypes are rich in provitamin A carotenoids (pVACs), providing an opportunity to use bananas as a readily available vehicle for provitamin A delivery. This review summarizes the progress made in carotenoid research in bananas relative to banana diversity and the use of conventional breeding and transgenic approaches aimed at banana biofortification to address vitamin A deficiency. Existing reports on sampling strategies, pVAC retention and bioavailability are also evaluated as essential components for a successful banana biofortification effort. The wide variability of pVACs reported in banana cultivars coupled with recent advances in unraveling the diversity and genetic improvement of this globally important but often-neglected staple fruit crop underscores their importance in biofortification schemes. PMID- 29999425 TI - Finding meaningful work in difficult circumstances: A study of prison healthcare workers. AB - Prisons are rigidly structured institutions housing-in some cases-violent and unstable residents. To discover the positive job attributes and perceived challenges in this extreme practice environment, we employed exploratory qualitative content analysis on the written-in responses of 269 prison health workers in one state's Department of Corrections. Two researchers independently analyzed and coded the data. Using an iterative process, we categorized the responses into themes and critical underlying meanings. Positive job attributes included meaningful work, stability, variety of ailments treated, and feelings of support. Perceived challenges included ineffective leadership, constraints on the ability to effectively execute the role, perceived inequity, and organizational culture. The results of our study suggest that there are lessons to be learned from correctional health workers that could inform policy and management outside of the prison walls specifically as it pertains to motivating and engaging providers through meaningful work. Specifically, health organizations would improve the experience of their clinicians by offering a broader scope of practice experience, schedule stability, reducing bureaucratic redundancies, and ultimately-restoring the sense of purpose within the work itself. PMID- 29999426 TI - MUC16 as a novel target for cancer therapy. AB - INTRODUCTION: MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy. PMID- 29999427 TI - A pharmacoeconomic evaluation of cholinesterase inhibitors and memantine for the treatment of Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) results in progressively worsening cognitive decline, leading to loss of functional ability, behavior/mood disturbances, institutionalization, and death. Current pharmaceutical therapies only treat the symptoms of cognitive decline yet can be expensive for payers. Areas covered: The authors undertook a systematic review of economic evaluations of pharmaceutical therapies for AD. The literature search encompassed English language studies indexed in PubMed (Medline), Cochrane Library Current, and Web of Science. The search included articles published between 1 January 1995 and 10 February 2018. The literature suggested AD medications generally dominated comparator treatments (e.g. placebo). Expert opinion: The authors noted several limitations of the included economic evaluations. These limitations suggest the results of the economic evaluations should be interpreted with caution. Many economic models were not transparent with respect to sources of probabilities and cost data, and data collected in certain jurisdictions were applied to other jurisdictions without considering the validity of such applications. Measuring health utilities in cognitively impaired populations raises questions about the validity of quality-adjusted life years, but this issue was unaddressed in the included studies. Most included studies were sponsored by industry and the results tended to overwhelmingly support the manufacturer's product. PMID- 29999428 TI - Misconceptions and issues regarding allometric scaling during the drug development process. AB - INTRODUCTION: Allometry is the study of size and its consequences. The simple hypothesis of allometric scaling is that all physiological parameters are proportional to body size or body mass. This review examines the development of theory-based allometry or fixed exponents (0.75 and 1.0 for basal metabolic rate and volume, respectively) and the evidence for or against the theory. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the concept of theory-based allometry in biology, physiology, and pharmacokinetics. Areas covered: In this review, the history of the development of theoretical allometry and the strong evidence against theory based allometry demonstrated by experimental data is provided. During drug development, allometry is applied to both inter-species (from animals to humans) and intra-species (adults to children) scaling. These two forms of allometric scaling in the context of theory-based allometry are discussed and provide insight on scientific progress that refute theory-based allometry. Expert opinion: Theory-based allometry is a mere theory and experimental data and real life observations strongly negate the existence of such a theory. Pharmacostatistical and physiological models based on theory-based allometry can be misleading and incorrect because the theory-based allometric exponent 0.75 is not universal. The exponents of allometry are data dependent and are not fixed in the universe. PMID- 29999429 TI - Fistula-associated anal carcinoma in Crohn's disease. AB - INTRODUCTION: Fistula-associated anal carcinoma in patients with Crohn's disease (CD) is a rare condition. More recently, this entity has been increasingly reported likely due to increased recognition, and the incidence may be greater than once appreciated. There remains a paucity of data regarding the incidence, diagnosis, treatment, and outcome of fistula-associated anal carcinoma. Area covered: This review evaluates the clinical features, pathology, treatment, and prognosis of fistula-associated anal carcinoma in patients with CD. A strategy for surveillance of this carcinoma is proposed by the authors based on the evidence obtained from this review. Expert commentary: Clinicians caring for patients with CD and perianal involvement need to be aware of the rare yet extremely important association of long-standing perianal disease and fistula associated carcinoma. Only through awareness, a high level of suspicion will be diagnosed in a timely manner. This involves a thorough history, a proper, and complete anorectal examination, along with early imaging and examination under anesthesia. Through this approach, it is hoped that early diagnose can be achieved in at-risk patients and change the significant morbidity and mortality associated with this diagnosis. PMID- 29999430 TI - The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics. AB - S-Acylation (commonly referred to as S-palmitoylation) is a post-translational modification consisting in the covalent attachment of an acyl chain to a cysteine residue of the target protein. The lability of the resulting thioester bond gives S-acylation an essential characteristic: its reversibility. S-acylation dynamically regulates different aspects in the life of a protein (including stability, localization, interactome, and function) and, thus, plays critical roles in cellular physiology. For long, the reversibility of S-acylation has been neglected and thereby its potential as a regulatory mechanism for protein function undervalued. Thanks to technological advances, the field has now entered its golden era. A great diversity of interesting targets is being identified, the physio-pathological importance of the modification is starting to be revealed, structural information on the enzymes is becoming available, and the regulatory dynamics are gradually being understood. Here we will review the most recent literature in the S-acylation field, with a special focus on the molecular aspects of the modification, its regulation, and its consequences. PMID- 29999432 TI - Corrigendum. PMID- 29999431 TI - Efficacy of antibody-drug conjugate brentuximab vedotin in treating Hodgkin's lymphoma. AB - INTRODUCTION: Hodgkin's lymphoma (HL) patients refractory to first-line therapy or relapsed after autologous stem cell transplantation have a dismal prognosis, and their treatment represents an unmet medical need. Brentuximab vedotin (BV) is a second-generation antibody-drug conjugate (ADC) constituted by an anti-CD30 antibody linked to the cytotoxic drug monomethyl auristatin E. The first administration of BV in relapsed and refractory HL patients in a phase I study showed an impressive antilymphoma activity and prompted development of the drug. Areas covered: This article reviews pharmaceutical characteristics of ADC and specific chemical features of BV related to mechanism of action and mechanism of resistance. Administration recommendation and main toxicities will also be described. Antilymphoma efficacy of BV alone and in combination with conventional chemotherapy and new compounds in different settings of HL patients will be examined. Expert opinion: BV seems to be an effective and safe option for treatment of HL patients. BV alone or in association with chemotherapy as salvage regimen or as bridge to autologous or allogeneic transplant showed encouraging results. Exploration of new drug combinations and new settings of treatment is warranted in order to reduce long-term therapy-related toxicities and ameliorate survival of poor prognosis patients. PMID- 29999433 TI - Use of MALDI-TOF mass spectrometry in the battle against bacterial infectious diseases: recent achievements and future perspectives. PMID- 29999434 TI - The nasal microbiome: opening new clinical research avenues for allergic disease. PMID- 29999435 TI - Length of stay and hospitalization costs for patients undergoing lung surgery with Progel pleural air leak sealant. AB - AIM: Progel Pleural Air Leak Sealant (Progel) is currently the only sealant approved by the FDA for the treatment of air leaks during lung surgery. This study was performed to determine whether Progel use improves hospital length of stay (LOS) and hospitalization costs compared with other synthetic/fibrin sealants in patients undergoing lung surgery. METHODS: The US Premier hospital database was used to identify lung surgery discharges from January 1, 2010 to June 30, 2015. Eligible discharges were categorized as "Progel Sealant" or "other sealants" using hospital billing data. Propensity score matching (PSM) was performed to control for hospital and patient differences between study groups. Primary outcomes were hospital LOS and all-cause hospitalization costs. Clinical outcomes, hospital re-admissions, and sealant product use were also described. RESULTS: After PSM, a total of 2,670 discharges were included in each study group; baseline characteristics were balanced between groups. The hospital LOS (mean days +/- standard deviation, median) was significantly shorter for the Progel group (9.9 +/- 9.6, 7.0) compared with the other sealants group (11.3 +/- 12.8, 8.0; p < .001). Patients receiving Progel incurred significantly lower all cause hospitalization costs ($31,954 +/- $29,696, $23,904) compared with patients receiving other sealants ($36,147 +/- $42,888, $24,702; p < .001). LIMITATIONS: It is not possible to say that sealant type alone was responsible for the findings of this study, and analysis was restricted to the data available in the Premier database. CONCLUSIONS: Among hospital discharges for lung surgery, Progel use was associated with significantly shorter hospital LOS and lower hospitalization costs compared with other synthetic/fibrin sealants, without compromising clinical outcomes. PMID- 29999436 TI - Percutaneous ablation of the tumor feeding artery for hypervascular hepatocellular carcinoma before tumor ablation. AB - OBJECTIVE: To evaluate the efficiency and safety of percutaneous ablation of the tumor feeding artery (PAA) before radiofrequency ablation (RFA) for hypervascular hepatocellular carcinoma (HCC) under ultrasound guidance. PATIENTS AND METHODS: In total, 94 patients with hypervascular HCC and tumor feeding artery visible by contrast-enhanced ultrasound were prospectively randomized to receive either PAA combined with RFA (RFA + PAA) or RFA alone. This study was registered at the clinical trials registry website (No. NCT03143140). The mean tumor size was 3.2 +/- 0.9 cm (2.0-5.0 cm). The mean follow-up was 23.7 +/- 9.7 months (4-44 months). The technical success, local tumor progression and intrahepatic distant recurrence rates were compared. Survival analysis was performed using the Kaplan Meier method and compared with the log-rank test. RESULTS: The local tumor progression rate was significantly lower for the PAA + RFA group than for the RFA group (8.5% vs 21.3%, p < .001). No significant differences in the technical success and intrahepatic distant recurrence rates were observed between the two groups (97.9% vs 91.5%, p = .203 and 40.4% vs 42.6%, p = .834). The 1- and 3-year local tumor progression-free survival rates were 91.5% and 69.9% vs 68.1% and 52.1% for the PAA + RFA vs RFA groups, respectively (p = .052). The 1- and 3-year overall survival rates were 95.7% and 69.1% vs 89.4% and 66.6% in the PAA + RFA vs RFA groups, respectively (p = .744). The major complication rate was 4.3% in both groups. CONCLUSIONS: PAA appears to be an effective and safe technique for the treatment of hypervascular HCC, with a lower local tumor progression rate than that of conventional RFA. PMID- 29999437 TI - Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma. AB - INTRODUCTION: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M HNSCC) is rapidly evolving. Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC. Expert commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel. Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1. PMID- 29999438 TI - Do individual versus illness belief schema differ in the prediction of post stroke recovery? AB - This longitudinal observational study examined how individual versus illness belief schema compare as predictors of post-stroke recovery. A total of 42 stroke survivors (mean age = 66.9 years/range = 29-96 years; 68% male) were involved. The primary outcome, Health-Related Quality of Life was measured using EQ-5D-5L, mood using Patient Health Questionnaire-9 and disability using Nottingham Extended Activities of Daily Living Scale. Stroke Illness Perception Questionnaire-Revised measured illness beliefs. Linear regressions showed that individual illness beliefs significantly explained more of the variance in 3 month post-stroke recovery than schema (7.4%-22.5% versus 1.9%-9.9%). Individual versus illness belief schema predict outcomes differently, but which approach predicts outcomes better remains unclear. PMID- 29999439 TI - Barotrauma after liquid nitrogen ingestion: a case report and literature review. AB - A 25-year-old man developed a gastric perforation after ingesting a homemade drink containing liquid nitrogen. Surgical repair had to be postponed to seek consultations with experts because the available practitioners in this case, including emergency physicians, surgeons, and anesthesiologists, had little experience and knowledge about the source of the patient's pneumothorax and subcutaneous emphysema. The patient ultimately underwent exploratory laparotomy with general anesthesia, considering that delaying the operation would lead to a longer duration of bacterial peritonitis and delay the standard treatment of postoperative systemic infectious complications. Our literature review revealed that barotrauma is the unique injury mechanism underlying liquid nitrogen ingestion. Injuries to the airway and esophagus are rare. PMID- 29999440 TI - Disseminated intravascular coagulation: an update on pathogenesis and diagnosis. AB - INTRODUCTION: Activation of the hemostatic system can occur in many clinical conditions. However, a systemic and strong activation of coagulation complicating clinical settings such as sepsis, trauma or malignant disease may result in the occurrence disseminated intravascular coagulation (DIC). Areas covered: This article reviews the clinical manifestation and relevance of DIC, the various conditions that may precipitate DIC and the pathogenetic pathways underlying the derangement of the hemostatic system, based on clinical and experimental studies. In addition, the (differential) diagnostic approach to DIC is discussed. Expert commentary: In recent years a lot of precise insights in the pathophysiology of DIC have been uncovered, leading to a better understanding of pathways leading to the hemostatic derangement and providing points of impact for better adjunctive treatment strategies. In addition, simple diagnostic algorithms have been developed and validated to establish a diagnosis of DIC in clinical practice. PMID- 29999441 TI - Women in neurosurgery: inequality redux. PMID- 29999443 TI - Microhemorrhagic transformation of ischemic lesions on T2*-weighted magnetic resonance imaging after Pipeline embolization device treatment. AB - OBJECTIVE The authors sought to demonstrate that hemorrhagic transformation of ischemic lesions is the main cause of delayed intracerebral hemorrhage (ICH) after Pipeline embolization device (PED) treatment and to estimate the rate of hemorrhagic transformation of new postprocedure ischemic lesions. METHODS Patients who underwent PED placement (PED group) from November 2015 to March 2017 or stent-mediated embolization (EN group) from December 2010 to October 2015 were retrospectively analyzed. Pre- and postprocedural MR images and 6-month follow-up MR images for each patient were scored for the presence of postprocedural bland ischemic and hemorrhagic lesions using diffusion-weighted MRI (DWI) and T2* weighted MRI (T2*WI), respectively. RESULTS The PED group comprised 28 patients with 30 intracranial aneurysms, and the EN group comprised 24 patients with 27 intracranial aneurysms. The mean number of ischemic lesions on DWI 1 day postprocedure was higher in the PED group than in the EN group (5.2 vs 2.7, p = 0.0010). The mean number of microbleeds detected on T2*WI 6 months postprocedure was higher in the PED group than in the EN group (0.6 vs 0.15, p = 0.028). A total of 36.7% of PED-treated patients exhibited new microbleeds on T2*WI at 6 months postprocedure, with at least 77.8% of these lesions representing hemorrhagic transformations of the new ischemic lesions observed on day 1 postprocedure. The rate of adjunctive coil embolization (27.3% vs 0.0%, p = 0.016) and the mean number of ischemic lesions observed 1 day postprocedure (6.6 vs 4.3, p = 0.020) were predictors of subsequent microbleeds in the PED group. CONCLUSIONS New microbleeds detected using T2*WI at 6 months postprocedure were more common after PED treatment than after stent-mediated embolization. Approximately three-quarters of these lesions were hemorrhagic transformations of new ischemic lesions observed on day 1 postprocedure. Prevention of intraprocedural or postprocedural infarcts is necessary to reduce the risk of hemorrhagic complications following PED placement. PMID- 29999444 TI - Letter to the Editor. Influence of rare RNF213 variants other than p.R4810K on the clinical outcomes of moyamoya disease. PMID- 29999442 TI - Utilizing proteomics to understand and define hypertension: where are we and where do we go? AB - INTRODUCTION: Hypertension is a complex and multifactorial cardiovascular disorder. With different mechanisms contributing to a different extent to an individual's blood pressure, the discovery of novel pathogenetic principles of hypertension is challenging. However, there is an urgent and unmet clinical need to improve prevention, detection, and therapy of hypertension in order to reduce the global burden associated with hypertension-related cardiovascular diseases. Areas covered: Proteomic techniques have been applied in reductionist experimental models including angiotensin II infusion models in rodents and the spontaneously hypertensive rat in order to unravel mechanisms involved in blood pressure control and end organ damage. In humans proteomic studies mainly focus on prediction and detection of organ damage, particularly of heart failure and renal disease. While there are only few proteomic studies specifically addressing human primary hypertension, there are more data available in hypertensive disorders in pregnancy, such as preeclampsia. We will review these studies and discuss implications of proteomics on precision medicine approaches. Expert commentary: Despite the potential of proteomic studies in hypertension there has been moderate progress in this area of research. Standardized large-scale studies are required in order to make best use of the potential that proteomics offers in hypertension and other cardiovascular diseases. PMID- 29999445 TI - Utilizing preprocedural CT scans to identify patients at risk for suboptimal external ventricular drain placement with the freehand insertion technique. AB - OBJECTIVE Freehand insertion of external ventricular drains (EVDs) using anatomical landmarks is considered the primary method for placement, although alternative techniques have shown improved accuracy in positioning. The purpose of this study was to retrospectively evaluate which features of the baseline clinical history and preprocedural CT scan predict EVD positioning into suboptimal and unsatisfactory locations when using the freehand insertion technique. METHODS A retrospective chart review was performed evaluating 189 consecutive adult patients who received an EVD via freehand technique through an anterior burr hole between January 1, 2014, and December 31, 2015, at a Level 1 trauma facility in Edmonton, Alberta, Canada. The primary outcome measures included features associated with suboptimal positioning (Kakarla grade 1 vs Kakarla grades 2 and 3). The secondary outcome measures were features associated with unsatisfactory positioning (Kakarla grades 1 and 2 vs Kakarla grade 3). RESULTS Fifty-one EVDs (27%) were suboptimally positioned. Fifteen (8%) EVDs were placed into eloquent cortex or nontarget CSF spaces. Admitting diagnosis, head height-to-width ratio in axial plane, and side of predominant pathology were found to be significantly associated with suboptimal placement (p = 0.02, 0.012, and 0.02, respectively). A decreased height-to-width ratio was also associated with placement into only eloquent cortex and/or nontarget CSF spaces (p = 0.003). CONCLUSIONS Freehand insertion of an EVD is associated with significant suboptimal positioning into parenchyma and nontarget CSF spaces. The likelihood of inaccurate EVD placement can be predicted with baseline clinical and radiographic features. The patient's height-to-width ratio represents a novel potential radiographic predictor for malpositioning. PMID- 29999446 TI - Timing of surgery in traumatic brachial plexus injury: a systematic review. AB - OBJECTIVE Ideal timeframes for operating on traumatic stretch and blunt brachial plexus injuries remain a topic of debate. Whereas on the one hand spontaneous recovery might occur, on the other hand, long delays are believed to result in poorer functional outcomes. The goal of this review is to assess the optimal timeframe for surgical intervention for traumatic brachial plexus injuries. METHODS A systematic search was performed in January 2017 in PubMed and Embase databases according to the PRISMA guidelines. Search terms related to "brachial plexus injury" and "timing" were used. Obstetric plexus palsies were excluded. Qualitative synthesis was performed on all studies. Timing of operation and motor outcome were collected from individual patient data. Patients were categorized into 5 delay groups (0-3, 3-6, 6-9, 9-12, and > 12 months). Median delays were calculated for Medical Research Council (MRC) muscle grade >= 3 and >= 4 recoveries. RESULTS Forty-three studies were included after full-text screening. Most articles showed significantly better motor outcome with delays to surgery less than 6 months, with some studies specifying even shorter delays. Pain and quality of life scores were also significantly better with shorter delays. Nerve reconstructions performed after long time intervals, even more than 12 months, can still be useful. All papers reporting individual-level patient data described a combined total of 569 patients; 65.5% of all patients underwent operations within 6 months and 27.4% within 3 months. The highest percentage of >= MRC grade 3 (89.7%) was observed in the group operated on within 3 months. These percentages decreased with longer delays, with only 35.7% >= MRC grade 3 with delays > 12 months. A median delay of 4 months (IQR 3-6 months) was observed for a recovery of >= MRC grade 3, compared with a median delay of 7 months (IQR 5-11 months) for <= MRC grade 3 recovery. CONCLUSIONS The results of this systematic review show that in stretch and blunt injury of the brachial plexus, the optimal time to surgery is shorter than 6 months. In general, a 3-month delay appears to be appropriate because while recovery is better in those operated on earlier, this must be considered given the potential for spontaneous recovery. PMID- 29999447 TI - Sequelae and management of radiation vasculopathy in neurosurgical patients. AB - The term "radiation vasculopathy" defines a heterogeneous and poorly defined complex of vessel injury due to radiation. Radiation vasculopathy remains underrecognized and poorly treated with respect to head and neck radiotherapy. Distinct injury patterns to small (<= 100-MUm), medium (> 100-MUm), and large (> 500-MUm) vessels can occur, resulting in carotid stenosis, intracranial stenosis, and vascular anomalies (e.g., cavernous malformations, aneurysms). Because of the lack of clinical evidence and guidelines, treatment plans involve medical management, carotid endarterectomy, and carotid artery stenting and are developed on a patient-by-patient basis. In this review, the authors discuss the current pathophysiology, imaging, clinical impact, and potential treatment strategies of radiation vasculopathy with clinical pertinence to practicing neurosurgeons and neurologists. A review of 4 patients with prior head and neck tumors in whom delayed radiation vasculopathy developed after radiotherapy demonstrates the application of various treatment options in a case-by-case manner. Earlier recognition of radiation vasculopathy disease patterns may enable earlier initiation of treatment and monitoring for complications. Standardized terminology and treatments may assist with improving clinical outcomes. PMID- 29999449 TI - Letter to the Editor. Multimodal opioid-minimizing pain management regimens following transsphenoidal surgery. PMID- 29999448 TI - Rates and predictors of seizure outcome after corpus callosotomy for drug resistant epilepsy: a meta-analysis. AB - OBJECTIVE Corpus callosotomy is a palliative surgery for drug-resistant epilepsy that reduces the severity and frequency of generalized seizures by disconnecting the two cerebral hemispheres. Unlike with resection, seizure outcomes remain poorly understood. The authors systematically reviewed the literature and performed a meta-analysis to investigate rates and predictors of complete seizure freedom and freedom from drop attacks after corpus callosotomy. METHODS PubMed, Web of Science, and Scopus were queried for primary studies examining seizure outcomes after corpus callosotomy published over 30 years. Rates of complete seizure freedom or drop attack freedom were recorded. Variables showing a potential relationship to seizure outcome on preliminary analysis were subjected to formal meta-analysis. RESULTS The authors identified 1742 eligible patients from 58 included studies. Overall, the rates of complete seizure freedom and drop attack freedom after corpus callosotomy were 18.8% and 55.3%, respectively. Complete seizure freedom was significantly predicted by the presence of infantile spasms (OR 3.86, 95% CI 1.13-13.23), normal MRI findings (OR 4.63, 95% CI 1.75 12.25), and shorter epilepsy duration (OR 2.57, 95% CI 1.23-5.38). Freedom from drop attacks was predicted by complete over partial callosotomy (OR 2.90, 95% CI 1.07-7.83) and idiopathic over known epilepsy etiology (OR 2.84, 95% CI 1.35 5.99). CONCLUSIONS The authors report the first systematic review and meta analysis of seizure outcomes in both adults and children after corpus callosotomy for epilepsy. Approximately one-half of patients become free from drop attacks, and one-fifth achieve complete seizure freedom after surgery. Some predictors of favorable outcome differ from those in resective epilepsy surgery. PMID- 29999451 TI - Letter to the Editor. "Burned out" at work but satisfied with one's job: anatomy of a false paradox. PMID- 29999450 TI - Tumour necrosis factor-related apoptosis-inducing ligand expression in patients with diabetic nephropathy. AB - OBJECTIVE: The objective of this study was to evaluate the expression profile of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in patients with diabetic nephropathy (DN). METHODS: A total of 126 Chinese subjects were enrolled in this study, including 42 patients with diabetes mellitus (DM), 42 patients with DN and 42 healthy controls. Real-time polymerase chain reaction was performed to analyze levels of TRAIL mRNA in peripheral blood mononuclear cells (PBMCs). Serum levels of soluble TRAIL (sTRAIL) and various cytokines were detected with a commercially available enzyme-linked immunosorbent assay kit. RESULTS: Compared with the control group, the levels of TRAIL mRNA in PBMCs and sTRAIL in sera were both significantly decreased in the DM and DN patients ( P < 0.05). Conversely, levels of interleukin (IL)-1, IL-6, tumour necrosis factor alpha and monocyte chemotactic protein-1 were higher in the DN group than in the control group. Serum levels of TRAIL positively correlated with TRAIL mRNA levels in all of the subjects examined ( P < 0.05). CONCLUSIONS: These results provide support and a theoretical basis for further research of TRAIL in regard to the pathogenesis of DN. PMID- 29999452 TI - Application of a LC-MS/MS method for multi-mycotoxin analysis in infant formula and milk-based products for young children commercialized in Southern Brazil. AB - An analytical method based on liquid chromatography-tandem mass spectrometry (LC MS/MS) was validated and applied for the analysis of aflatoxin M1 (AFM1), ochratoxin A (OTA) and deoxynivalenol (DON) in infant formula and milk-based products for young children commercialized in Brazil. A total of 38 samples were evaluated, including 12 infant formula, 14 follow-on formula and 12 samples of milk-based products. AFM1 was detected in 12 (32%) samples, and seven (18%) samples contained AFM1 levels above the method limit of quantification in a concentration range between 0.013 and 0.067 ng mL-1 (0.026 +/- 0.019). Two samples of milk-based products exceeded the maximum level (ML) fixed by the European Union for AFM1 in baby foods, however, all samples were in agreement with the levels established by the Brazilian regulation. OTA and DON were not detected in any of the analyzed samples. PMID- 29999453 TI - A printed information leaflet about MRI and radiologists improves neuroradiology patient health literacy. AB - PURPOSE: To determine the health literacy benefit of a printed informational leaflet for patients scheduled to undergo brain magnetic resonance imaging (MRI) scans. METHODS AND MATERIALS: A two-page leaflet that provided an overview of MRI and the role of radiologists was prepared and given to outpatients scheduled to undergo brain MRI examinations while in the waiting room. A survey composed mainly of yes/no and Likert scale questions pertaining to the leaflet, as well as patient demographics, was administered to the patients. RESULTS: A total of 147 patients completed the survey, of which 110 (75%) had undergone a prior MRI scan, 120 (82%) stated that their ordering provider explained the reason for the MRI scan, and less than 1% reported having referenced online resources related to MRI. The average score for how well patients understood the MRI scan procedure and how it is reviewed was 4.16/5 (standard deviation 1.18) before versus 4.39/5 (standard deviation 1.08) after reading the leaflet, which was a statistically significant improvement based on the Wilcoxon signed-rank test ( P < 0.01). The score for how helpful the reading material was for explaining what is MRI was 4.06/5 (standard deviation 1.02) and the score for how helpful the reading material was for explaining what is a radiologist was 4.18/5 (standard deviation 0.98). CONCLUSION: A printed leaflet about MRI and radiologists can serve as an opportunity to educate patients about certain aspects of their scans during their stay in the waiting room. PMID- 29999454 TI - A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo. AB - Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts. We show that ATG5i mice recapitulate many of the previously described phenotypes of tissue-specific knockouts. While restoration of autophagy in the liver rescues hepatomegaly and other pathologies associated with autophagy deficiency, this coincides with the development of hepatic fibrosis. These results highlight the need to consider the potential side effects of systemic anti-autophagy therapies. PMID- 29999455 TI - Cortical Spreading Depression Denotes Concussion Injury. AB - Cortical spreading depression (CSD) has been described after moderate-to-severe traumatic brain injury (TBI). It is uncertain, however, whether CSD occurs after mild, concussive TBI and whether it relates to brain pathology and functional outcome. Male C57BL6/J mice (n = 62) were subjected to closed head TBI with a 25 g weight (n = 11), 50 g weight (n = 45), or sham injury (n = 6). Laser Doppler flowmetry and optical intrinsic signal imaging were used to determine cerebral blood flow dynamics after concussive CSD. Functional deficits were assessed at baseline, 2 h, 24 h, and 48 h. TUNEL and Prussian blue staining were used to determine cell death and presence of cerebral microbleeds at 48 h. No CSD was observed in mice subjected to a 25 g weight drop whereas 58.9% of mice subjected to a 50 g weight drop developed a CSD. Mice with concussive CSD displayed significantly greater numbers of apoptotic cell profiles in the ipsilesional hemisphere compared with mice without a CSD that underwent the same 50 g weight drop paradigm (p < 0.05, each). All investigated animals had at least one cerebral microbleed (range 1 to 24). Compared with mice without a CSD, mice with a CSD had significantly more microbleeds in the traumatized hemisphere (p < 0.05, each) and showed impaired functional recovery (p < 0.05). Incidence of CSD after mild TBI depended on impact severity and was associated with histological and behavioral outcomes. These observations indicate that concussive CSD may serve as viable marker for concussion severity and provide novel avenues for outcome prediction and therapeutic decision making. PMID- 29999456 TI - Assessment of blood flow velocities and venous pressures using a dual-sensor guidewire in symptomatic dural sinus stenoses. AB - Lateral venous sinus stenoses have been associated with idiopathic intracranial hypertension and venous pulsatile tinnitus. Venous pressure measurement is traditionally performed to assess the indications for stenting in patients with idiopathic intracranial hypertension. However, its reliability has recently been questioned by many authors. The dual-sensor guidewire was first developed for advanced physiological assessment of fractional and coronary flow reserves in coronary artery stenoses. It allows measurement of both venous pressure and blood flow velocities. The authors used this device in 14 consecutively treated patients to explore for symptomatic lateral sinus stenosis. They found that venous blood flow was significantly accelerated inside the stenotic lesion. This acceleration, as well as the pulsatile tinnitus, resolved in all patients following stent placement. According to the authors' results, this guidewire can be helpful for establishing an indication for stenting in patients with pulsatile tinnitus and idiopathic intracranial hypertension. PMID- 29999457 TI - Variability with Astroglial Glutamate Transport Genetics Is Associated with Increased Risk for Post-Traumatic Seizures. AB - Excitotoxicity contributes to epileptogenesis after severe traumatic brain injury (sTBI). Demographic and clinical risk factors for post-traumatic seizures (PTS) have been identified, but genetic risk remains largely unknown. Thus, we investigated whether genetic variation in astroglial glutamate transporter genes is associated with accelerated epileptogenesis and PTS risk after sTBI. Adults (n = 267) 18-75 years old were assessed over a three-year period post-TBI. Single nucleotide polymorphisms (SNPs) throughout the SLC1A2 and SLC1A3 genes were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure frequencies by genotype. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HRs) for genotypes significant in Kaplan Meier analyses. Thirty-nine tagging SNPs were examined (SLC1A2: n = 21, SLC1A3: n = 18). PTS developed in 57 (21.4%) individuals. Of those with PTS, n = 20 (35.7%) had an immediate/early seizure within the first seven days, and n = 36 (64.3%) had a late seizure occurring between eight days and three years post-TBI. When adjusting for multiple comparisons, rs4869682 genotypes (SLC1A3, GG vs. T carriers) were associated with time to first seizure (p = 0.003). Median time until first seizure was 20.4 days for individuals with a GG genotype and 44.8 days for T-carriers. After adjusting for covariates, rs4869682 GG-homozygotes had a 2.05 times increased PTS risk versus T-carriers (aHR = 2.08, 95% confidence interval: 1.20, 3.62, p = 0.009). Variation within SLC1A3 is associated with accelerated epileptogenesis and clinical PTS development after sTBI. Future studies should validate these findings and examine how genetic variation at rs4869682 may be a target for PTS prevention and treatment. PMID- 29999458 TI - Letter to the Editor. How to provide intraoperative brain relaxation in patients undergoing craniotomy for supratentorial brain tumor resection. PMID- 29999459 TI - Complications associated with microscopic and endoscopic transsphenoidal pituitary surgery: experience of 1153 consecutive cases treated at a single tertiary care pituitary center. AB - OBJECTIVE Pituitary adenomas (PAs) are benign neoplasms that are frequently encountered during workup for endocrinopathy, headache, or visual loss. Transsphenoidal surgery remains the first-line approach for PA resection. The authors retrospectively assessed complication rates associated with transsphenoidal PA resection from an institutional database. METHODS A retrospective analysis of 1153 consecutive transsphenoidal pituitary adenoma resections performed at the Keck Hospital of USC between November 1992 and March 2017 was conducted. Microscopic transsphenoidal resection was performed in 85.3% of cases, and endoscopic transsphenoidal resection was performed in 14.7%. Analysis of perioperative complications and patient and tumor risk factors was conducted. RESULTS The overall median hospital stay was 3 days. There was 1 perioperative death (0.1%). Surgical complications included postoperative cerebrospinal fluid leak (2.6%), epistaxis (1.1%), postoperative hematoma (1.1%), meningitis (1.0%), cranial nerve paresis (0.8%), hydrocephalus (0.8%), vision loss (0.6%), stroke (0.3%), abdominal hematoma or infection (0.2%), carotid artery injury (0.1%), and vegetative state (0.2%). Perioperative medical complications included bacteremia/sepsis (0.5%), pneumonia (0.3%), myocardial infarction (0.3%), and deep venous thrombosis/pulmonary embolism (0.1%). Endocrine complications were the most frequent, including transient diabetes insipidus (4.3%), symptomatic hyponatremia (4.2%), new hypopituitarism (any axis) (3.6%), permanent diabetes insipidus (0.3%), and adrenal insufficiency (0.2%). There were no significant differences between microscopic and endoscopic approaches with regard to surgical complications (6.4% vs 8.8%, p = 0.247) or endocrine complications (11.4 vs 11.8%, p = 0.888). Risk factors for surgical complications included prior transsphenoidal surgery (11.4% vs 6.8%, p = 0.025), preoperative vision loss (10.3% vs 6.8%, p = 0.002), and presence of PA invasion on MRI (8.5% vs 4.4%, p = 0.007). CONCLUSIONS In this single tertiary center study assessing complications associated with transsphenoidal PA resection, the rate of death or major disability was 0.26%. Risk factors for complications included prior surgical treatment and PA invasion. No differences in complication rates between endoscopic and microscopic surgery were observed. When performed at experienced pituitary centers, transsphenoidal surgery for PAs may be performed with a high degree of safety. PMID- 29999461 TI - Amyotrophic Lateral Sclerosis and a "Death With Dignity". AB - The Oregon "Death With Dignity" Act (DWD Act) allows a terminally ill patient with 6 months to live to ask a physician for medication to end their life. To receive the medication, the DWD Act requires the patient to verbally request the prescription twice 2 weeks apart as well as in writing. Patients with amyotrophic lateral sclerosis have three main barriers to using DWD: (a) the ability to communicate their informed consent as the disease progresses further, (b) the possibility of dementia which may affect their decisional capacity, and (c) given the nature and speed of amyotrophic lateral sclerosis, limited time is available for patients to self-administer the prescription and may rush the time line for the death. This article reviews the current knowledge and addresses the need for adjustments to existing law and recommendations for states considering a DWD law. PMID- 29999460 TI - Does Visual Attention Impact on Decision Making in Complex Dynamic Events? AB - In recent years, several publications examined the underlying mechanisms that might have an impact on decision-making processes under time pressure. This study investigated how individual differences in attentional capability relate to decision making in complex dynamic offside events. A total of 24 professional football assistant referees (ARs) performed an offside decision-making task and an attention-demanding task. ARs with higher attentional capability along the horizontal meridian of their attentional focus made fewer mistakes when judging offside situations in football than ARs with lower capability. This implies that being able to rely on high-attentional capabilities in situations requiring conscious perception of multiple processes is likely to be beneficial for the ultimate decision-making performance. PMID- 29999462 TI - Air Sac Nematode ( Serratospiculum tendo) Infection in an Austral Peregrine Falcon ( Falco peregrinus cassini) in Argentina. AB - We report a case of air sac nematode ( Serratospiculum tendo) infection in an adult male Austral Peregrine Falcon ( Falco peregrinus cassini) admitted to a rehabilitation center in Mendoza Province, Argentina, in September 2017. This case of air sac nematodes reported in an Argentine raptor is only the second report of S. tendo in South America. We recommend examination of all raptors, especially those falcon species that include insects in their diet and inhabit open lands and those in rehabilitation centers or kept for falconry, education, or captive breeding. Fecal analysis and microscopic examination of oral swabs for evidence of parasites are simple noninvasive diagnostic procedures that allow easy detection of these parasites under field and captive circumstances. PMID- 29999463 TI - GUT PARASITE LEVELS ARE ASSOCIATED WITH SEVERITY OF RESPONSE TO IMMUNE CHALLENGE IN A WILD SONGBIRD. AB - Life history trade-offs have been posited to shape wild animals' immune responses against microparasites (e.g., bacteria, viruses). However, coinfection with gut helminths may bias immune phenotypes away from inflammatory responses and could be another mechanism underlying variation in immune responses. We examined how the magnitude of a common and costly response to microparasites, the acute phase response (APR), varied with helminth coinfection at both the individual and the population levels in Song Sparrows ( Melospiza melodia). The APR includes fever and sickness behaviors, like lethargy and anorexia, and provides a whole-organism metric of immune activation. We combined data on fever and lethargy in response to an immune challenge (lipopolysaccharide) with postmortem data assessing helminth burdens and data on malarial parasite infection from blood samples in sparrows from two populations: southern California and western Washington, USA. We predicted that birds with higher helminth burdens would express less severe APRs, at both the individual and population levels. Furthermore, we predicted that these reduced immune responses would diminish resistance against malarial parasites and would thus be associated with higher prevalences of such parasites. Previously, Song Sparrows from Washington have been shown to mount less severe APRs than those from California. In our study, Washington birds also exhibited higher helminth burdens and a higher prevalence of one type of avian malarial parasite. Because of low variation in helminth burdens in California (median=0, range=0-3), we tested within-population relationships only in birds from Washington, where the severity of fever and lethargy correlated negatively with helminth burden. These results suggested that helminth coinfection could help mediate immune responsiveness in wild songbirds. PMID- 29999464 TI - Morphologic Observations and Novel 18S rDNA Sequences of Abbreviata hastaspicula and Abbreviata antarctica from Varanus spp. Lizards in Australia. AB - The nematodes Abbreviata antarctica von Linstow, 1899, and Abbreviata hastaspicula Jones, 1979, are predominant spirurid nematodes in species of Varanus lizards in Australia. However, genetic knowledge of these two species of nematode is lacking. In this study, nematodes removed from Varanus gouldii were examined using integrated morphologic and molecular methods. We extracted DNA from A. hastaspicula and A. antarctica for PCR and sequencing. Specific 18S small subunit ribosomal RNA (rRNA) primers were designed on the basis of existing 18S rRNA sequences of Physalopterinae strains. Species of Abbreviata, which are closely similar morphologically, may be misidentified, especially the larvae of different species of Abbreviata that cannot be differentiated. The findings of this study will improve the accuracy in identification of A hastaspicula and A. antarctica, both morphologically and molecularly. PMID- 29999465 TI - Encephaloduroarteriosynangiosis for hemorrhagic moyamoya disease: long-term outcome of a consecutive series of 95 adult patients from a single center. AB - OBJECTIVE The objective of this study was to investigate long-term outcomes after encephaloduroarteriosynangiosis (EDAS) for the treatment of hemorrhagic moyamoya disease (MMD) and identify the risk factors for recurrent hemorrhages. METHODS The authors retrospectively reviewed 95 patients with hemorrhagic MMD who were treated with EDAS at 307th Hospital PLA. Clinical features, angiographic findings, and clinical outcomes were investigated. Rebleeding incidences were compared between anterior or posterior hemorrhagic sites. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to estimate rebleeding risks after EDAS. RESULTS The average age at symptom onset was 37.1 years (range 20-54 years) for adult patients. The ratio of female to male patients was 1.16:1. In 61 of 95 hemorrhagic hemispheres (64.2%), the anterior choroidal artery (AChA) or posterior communicating artery (PCoA) was extremely dilated, with extensive branches beyond the choroidal fissure, which only occurred in 28 of 86 nonhemorrhagic hemispheres (32.6%). Fifty-seven incidences were classified as anterior hemorrhages and 38 as posterior. Sixteen of 95 patients (16.8%) suffered cerebral rebleeding after a median follow-up duration of 8.5 years. The annual rebleeding rate was 2.2% per person per year. The incidence rate was higher for the posterior group than for the anterior group, but this difference was not statistically significant (p > 0.05). Cox regression analysis revealed that the age of symptom onset (OR 1.075, 95% CI 1.008-1.147, p = 0.028) was a predictor of rebleeding strokes. CONCLUSIONS Through long-term follow up, EDAS proved beneficial for patients with hemorrhagic MMD. Dilation of the AChA-PCoA is associated with the initial hemorrhage of MMD, and rebleeding is age-related. Patients with hemorrhagic MMD should undergo follow-up over the course of their lives, even when neurological status is excellent. PMID- 29999466 TI - Lattice Microarchitecture for Bone Tissue Engineering from Calcium Phosphate Compared to Titanium. AB - Additive manufacturing of bone tissue engineering scaffolds will become a key element for personalized bone tissue engineering in the near future. Several additive manufacturing processes are based on extrusion where the deposition of the filament will result in a three-dimensional lattice structure. Recently, we studied diverse lattice structures for bone tissue engineering realized by laser sintering of titanium. In this work, we used lithography-based ceramic manufacturing of lattice structures to produce scaffolds from tricalcium phosphates (TCP) and compared them in vivo to congruent titanium scaffolds manufactured with the identical computer-aided design data to look for material based differences in bony healing. The results show that, during a 4-week period in a noncritical-size defect in a rabbit calvarium, both scaffolds with the identical microarchitecture performed equally well in terms of bony regeneration and bony bridging of the defect. A significant increase in both parameters could only be achieved when the TCP-based scaffolds were doped with bone morphogenetic protein-2. In a critical-size defect in the calvarial bone of rabbits, however, the titanium scaffold performed significantly better than the TCP-based scaffold, most likely due to its higher mechanical stability. We conclude that titanium and TCP-based scaffolds of the same microarchitecture perform equally well in terms of bone regeneration, provided the microarchitecture meets the mechanical demand at the site of implantation. PMID- 29999467 TI - Outcomes following transsphenoidal surgical management of incidental pituitary adenomas: a series of 52 patients over a 17-year period. AB - OBJECTIVE Incidental pituitary adenomas (IPAs) are commonly discovered during cranial imaging evaluations obtained for unrelated indications. The optimal management of IPA remains controversial. The authors investigated the outcomes and safety of the surgical treatment of IPAs at their institution. METHODS Clinical outcome data for 1692 patients surgically treated for pituitary adenomas at the Keck Medical Center of USC/USC Pituitary Center over a 17-year period (1999-2016) were reviewed to identify all cases with surgically managed IPAs. Clinical characteristics reviewed in this retrospective analysis included patient demographics, endocrine laboratory data, visual field examinations, and MRI results. Intraoperative data reviewed included requirement for CSF leak repair, surgical complications, and estimated extent of resection. Postoperative data collected included pathology results, length of stay, postoperative complications, endocrine outcomes, readmission rates, and long-term outcomes, including extent of resection noted on postoperative imaging studies and tumor progression and/or recurrence. RESULTS Fifty-two patients (3.1% of all cases) underwent transsphenoidal surgery for IPA. The median age at surgery was 61 years (range 31-86 years). The most common reasons for neuroimaging included trauma (19%), stroke/transient ischemic attack (15%), and sinonasal disease (15%). Visual field deficits were present in 15% of bedside examinations, and among the 22 patients sent for formal testing, 54.5% were noted to have deficits. Preoperative endocrine function was normal in 69% of patients, which includes 3 patients (5.8%) having isolated hyperprolactinemia consistent with a stalk effect without other hormonal dysfunction. The average maximal tumor diameter was 20.9 mm (8-50 mm; data available in 35 patients). The most common primary indication for surgery was compression of the chiasm or vision loss (52%); other major considerations included tumor growth, a young patient age, and identified endocrine abnormalities. Intraoperative CSF leak repair was performed in 56% of patients, and 1 patient (2%) developed postoperative CSF rhinorrhea treated with lumbar drainage. The median hospital stay was 2 days. There were no deaths or major complications. Three patients (5.8%) developed transient diabetes insipidus. Over a mean follow-up of 61 months, 4 patients (50.0%) reported improved headaches and 6 (54.5%) reported improvement in their visual deficits. Four patients (25%) had improved endocrine function, including one with resumption of menstruation and another with remission of acromegaly. One patient (2.4%) reported new postoperative headache, and none experienced worsened vision. Four patients (10.5%) developed new single-axis hypopituitarism and 1 (2.6%) developed new panhypopituitarism. The overall recurrence/progression rate on neuroimaging was 9.6% at a mean of 80 months. CONCLUSIONS Transsphenoidal resection of IPAs, when appropriate, can be performed safely at experienced treatment centers. Incidental pituitary adenomas should be evaluated and treated as indicated, especially in younger patients at risk for endocrine or visual dysfunction. PMID- 29999468 TI - Risk of subsequent stroke, with or without extracranial-intracranial bypass surgery: a nationwide, retrospective, population-based study. AB - OBJECTIVE Although no benefits of extracranial-intracranial (EC-IC) bypass surgery in preventing secondary stroke have been identified previously, the outcomes of initial symptomatic ischemic stroke and stenosis and/or occlusion among the Asian population in patients with or without bypass intervention have yet to be discussed. The authors aimed to evaluate the subsequent risk of secondary vascular disease and cardiac events in patients with and without a history of this intervention. METHODS This retrospective nationwide population based Taiwanese registry study included 205,991 patients with initial symptomatic ischemic stroke and stenosis and/or occlusion, with imaging data obtained between 2001 and 2010. Patients who underwent EC-IC bypass (bypass group) were compared with those who had not undergone EC-IC bypass, carotid artery stenting, or carotid artery endarterectomy (nonbypass group). Patients with any previous diagnosis of ischemic or hemorrhagic stroke, moyamoya disease, cancer, or trauma were all excluded. RESULTS The risk of subsequent ischemic stroke events decreased by 41% in the bypass group (adjusted hazard ratio [HR] 0.59, 95% CI 0.46-0.76, p < 0.001) compared with the nonbypass group. The risk of subsequent hemorrhagic stroke events increased in the bypass group (adjusted HR 2.47, 95% CI 1.67-3.64, p < 0.001) compared with the nonbypass group. CONCLUSIONS Bypass surgery does play an important role in revascularization of the ischemic brain, while also increasing the risk of hemorrhage in the early postoperative period. This study highlights the fact that the high risk of bypass surgery obscures the true benefit of revascularization of the ischemic brain and also emphasizes the importance of developing improved surgical technique to treat these high-risk patients. PMID- 29999469 TI - Regression after subtotal resection of an optic pathway glioma in an adult without adjuvant therapy: case report. AB - Optic pathway gliomas (OPGs) are relatively common and benign lesions in children; however, in adults these lesions are nearly always malignant and hold a very poor prognosis. In this report the authors present the case of an adult patient with a benign OPG who underwent subtotal resection without adjuvant therapy and has had no tumor progression for more than 20 years. A 50-year-old woman presented with a 2-year history of personality changes, weight gain, and a few months of visual disturbances. Ophthalmological evaluation showed incomplete right homonymous hemianopsia. MRI demonstrated a 2.5 * 2.5 * 2.5-cm enhancing left-sided lesion involving the hypothalamus with extension into the suprasellar cistern, extending along the left optic tract and anterior to the level of the optic chiasm. A biopsy procedure revealed a juvenile pilocytic astrocytoma. A subtotal resection of approximately 80% of the tumor was performed. Postoperatively, the patient experienced complete resolution of her personality changes, and her weight decreased back to baseline. Ophthalmological examination showed increased right homonymous hemianopsia. In the years following her surgery, there was a spontaneous decrease in tumor size without adjuvant therapy. The patient continues to have an excellent quality of life despite a visual field defect, and no further tumor growth has been observed. PMID- 29999470 TI - Editorial. Time to repair and outcome after traumatic brachial plexus injury: is sooner always better? PMID- 29999471 TI - Modelling the long-term feed-to-fillet transfer of leuco crystal violet and leuco malachite green in Atlantic salmon (Salmo salar). AB - Leuco crystal violet (LCV) and leuco malachite green (LMG) are the main metabolites of two dyes that are forbidden for use in food production, but can be present at low background concentration in novel Atlantic salmon feed ingredients such as processed animal proteins (animal by-product [ABP]). In this study, the potential transfer of dietary LCV or LMG to the fillet of farmed Atlantic salmon was investigated. The uptake and elimination rate kinetics were determined in seawater-adapted Atlantic salmon (initial weight 587 +/- 148 g) fed two levels of either LCV- or LMG-enriched diets (~500 and 4000 ug kg-1, respectively) for 40 days, followed by a 90-day depuration period with feeding on control diets (<0.15 MUg kg-1 LCV and LMG). A three-compartmental model was developed, based on a fillet fat, fillet muscle and a central body compartment comprising all other tissues. Model calibrations showed a good fit with measured values during overall uptake and elimination period; however, the model poorly predicted the short-term (days) peak measured values at the end of the exposure period. The model was used to simulate the long-term (>16 months) LCV and LMG feed-to-fillet transfer in Atlantic salmon under realistic farming conditions such as the seasonal fluctuations in feed intake, growth and fillet fat deposition. The model predictions gave highest expected LCV and LMG fillet concentrations of approximately 0.12 and 0.45 MUg kg-1, depending on the dietary levels of ABP and background level of LCV and LMG contamination. These levels are under the reference point for action of 2 ug kg-1 for the sum of MG and LMG that EFSA assessed as adequate to protect public health. However, for LCV, the predicted highest levels exceed the analytical decision limit (CCalpha) of 0.15 ug kg-1 for the method used in this paper. PMID- 29999472 TI - Taxonomy, phylogeny, and divergence time estimation for Apiosphaeria guaranitica, a Neotropical parasite on bignoniaceous hosts. AB - Apiosphaeria guaranitica, the causal agent of brown crust disease of several bignoniaceous hosts, among them Handroanthus and Tabebuia species, has been traditionally placed in Phyllachoraceae, based exclusively on morphological studies, without supporting molecular evidence. Here, we provide molecular data for the link between sexual and asexual states of the fungus and elucidate the phylogeny of A. guaranitica. The multilocus phylogenetic analyses employed sequences from the 18S subunit (18S), 28S subunit (28S), and nuclear internal transcribed spacers (ITS1-5.8S-ITS2 = ITS) of the nuc rDNA, second-largest subunit of RNA polymerase II (RPB2), and translation elongation factor 1-alpha (TEF1) genetic loci. Estimates of the divergence time of this lineage were supported by fossil calibration (FC) and secondary calibration (SC) strategies. Our results indicate a natural placement of Apiosphaeria within Diaporthaceae (Diaporthales), where it represents an ancient lineage of the crown group of Diaporthaceae, diverging during the late Paleocene at 61.15 (FC) and 60.63 (SC) million years ago. This divergence time estimate within Diaporthales is based on Spataporthe taylori, a diaporthaceous fossil. PMID- 29999473 TI - The Role of Continuous Cerebrospinal Fluid Pulsation Stress in the Remodeling of Artificial Vertebral Laminae: A Comparison Experiment. AB - The physiological reconstruction of artificial vertebral laminae without epidural scar tissue formation or spinal cord compression has been challenging. Mechanical stimulations have been reported to play an important role in bone formation and bone remodeling. In this study, we designed a comparison study to investigate the effect of continuous cerebrospinal fluid pulsation (CSFP) stress on the remodeling of artificial vertebral laminae. Mesenchymal stem cells derived from rabbit umbilical cord Wharton's Jelly were induced for osteogenic differentiation for 3 weeks before seeding on the hydroxyapatite-collagen I scaffolds to construct the tissue-engineered laminae (TEL). TEL were then implanted into the fifth rabbit lumbar vertebrae in both CSFP group (n = 36) and non-CSFP group (n = 36). De novo laminae were examined through histological and radiographic analysis in the 2nd, 4th, 8th, 12th, 16th, and 24th weeks postimplantation. Our results showed that the osteogenic gene expression levels and cancellous microstructure parameters of newborn laminae in the CSFP group reached the peak and the complete newborn laminae formed in the 12th week. Then the osteoclastic gene expression and osteoclast number of newborn laminae in the CSFP group increased greatly in the 12th week, and were significantly higher compared with the non-CSFP group. After 16 weeks of implantation, the arrangement of trabeculae became organized, and the dura surface of newborn laminae in the CSFP group showed similar curvature and smoothness as the native laminae. In conclusion, continuous CSFP stress played an important role in the physiological reconstruction of artificial vertebral laminae by promoting the remodeling abilities of TEL. PMID- 29999474 TI - A Biomechanical Shoulder Strain Index Based on Stabilizing Demand of Shoulder Joint. AB - Work-related shoulder joint disorders contribute considerably to absenteeism in the workplace. To identify the tasks that are stressful to the shoulder joint, a strain index was formulated based on the concept of concavity compression - a shoulder stabilizing mechanism. The magnitude and direction of the shoulder joint reaction forces were used in formulating the strain index. A two phase experiment was conducted. In phase 1, participants performed 30 different manual handling tasks. The tasks were categorized into low, medium, and high strain tasks based on their strain index values. In phase 2, out of the 30 tasks, repetitive exertions of three tasks (low, medium and high strain index values) were simulated using three external loads (0.91kg, 1.81kg, and 2.72kg). The muscle activity data recorded from eight shoulder muscles showed that tasks with higher strain index values induced significantly greater activation and muscle fatigue than tasks with lower strain index values. Practitioner Summary: The strain index developed in this study is a conclusive estimation of the concavity compression required for shoulder joint stabilization. It can be used to identify the activities that may contribute to the risks of shoulder disorders. PMID- 29999476 TI - Phytochemical characterization and antioxidant, antibacterial and antimutagenic activities of aqueous extract from leaves of Alchornea glandulosa. AB - Plant extracts exist as a complex matrix which serves as a source of numerous bioactive metabolites. The ultra performance liquid chromatography with diode array detection-coupled electrospray ionization-mass spectrometry/mass spectrometry technique was used to characterize the aqueous extract from leaves of Alchornea glandulosa (EAG), a species popularly used to treat gastrointestinal problems as an antiulcer agent. Quantification of phenolic derivatives was determined using Folin-Ciocalteu and aluminum trichloride (AlCl3) methods. In addition, antioxidant (2,2-diphenyl-1-picrylhydrazyl [DPPH*] radical scavenging, beta-carotene-linoleic acid, and lipid peroxidation), antibacterial (agar well diffusion method and minimum inhibitory concentration), antimutagenic (Ames test), and antigenotoxic (plasmid cleavage) assays were also performed on this plant extract. The ellagitannin tris-galloyl-hexahydroxydiphenic acid-glucose was identified as the predominant compound along with tannins as majority metabolites. EAG showed high antioxidant activity accompanied by moderate antibacterial activity against Staphylococcus aureus. The highest antimutagenic activity was observed for TA97 strain without metabolic activation (S9) and with metabolic activation, TA100 and TA102 were completely inhibited. In addition, EAG exhibited potential signs of antigenotoxic action. The high antioxidant and antimutagenic activity observed for EAG suggests important therapeutic uses that still need to be verified in future studies. PMID- 29999475 TI - Rapid Detection of Shear-Induced Damage in Tissue-Engineered Cartilage Using Ultrasound. AB - Previous investigations have shown that tissue-engineered articular cartilage can be damaged under a combination of compression and sliding shear. In these cases, damage was identified in histological sections after a test was completed. This approach is limited, in that it does not identify when damage occurred. This especially limits the utility of an assay for evaluating damage when comparing modifications to a tissue-engineering protocol. In this investigation, the feasibility of using ultrasound (US) to detect damage as it occurs was investigated. US signals were acquired before, during, and after sliding shear, as were stereomicroscope images of the cartilage surface. Histology was used as the standard for showing if a sample was damaged. We showed that US reflections from the surface of the cartilage were attenuated due to roughening following sliding shear. Furthermore, it was shown that by scanning the transducer across a sample, surface roughness and erosion following sliding shear could be identified. Internal delamination could be identified by the appearance of new echoes between those from the front and back of the sample. Thus, it is feasible to detect damage in engineered cartilage using US. PMID- 29999477 TI - Future year ozone source attribution modeling study using CMAQ-ISAM. AB - To achieve the current United States National Ambient Air Quality Standards (NAAQS) attainment level for ozone or particulate matter, current photochemical air quality models include tools to determine source apportionment and/or source sensitivity. Previous studies by the authors have used the Ozone and Particulate Matter Source Apportionment Technology and Higher-order Decoupled Direct Method probing tools in CAMx to investigate these source-receptor relationships for ozone. The recently available source apportionment for CMAQ, referred to as the Integrated Source Apportionment Method (ISAM), was used in this study to conduct future year (2030) source attribution modeling. The CMAQ-ISAM ozone source attribution results for selected cities across the U.S. showed boundary conditions were the dominant contributor to the future year highest July maximum daily 8-hour average (MDA8) ozone concentrations. Point sources were generally larger contributors in the eastern U.S. than in the western U.S. The contributions of on-road mobile emissions were around 5 ppb at most of the cities selected for analysis. Off-road mobile source contributions were around 20 ppb or nearly 30%. Since boundary conditions play an important role in future year ozone levels, it is important to characterize future year boundary conditions accurately. The current implementation of ISAM in CMAQ 5.0.2 requires significant computing resources for ozone source attribution, making it difficult to conduct long-term simulations for large domains. The computing requirements for PM source attribution are even more onerous. CMAQ 5.2 was released after this study was completed, and does not include ISAM. If an efficient version of ISAM becomes available, it could be used in long-term ozone and PM2.5 studies. Implications: Ozone source attribution results provide useful information on important emission source contribution categories and provide some initial guidance on future emission reduction strategies. This study explains a new source apportionment technique, CMAQ-ISAM, and compares it to CAMx OSAT. The techniques have similar results: ozone's highest source contributor is boundary conditions, followed by point sources, then off-road mobile sources. The current version of ISAM in CMAQ 5.0.2 requires significant computing resources for ozone source attribution, while the computing requirements for PM source attribution are even more onerous. CMAQ 5.2 was released after this study was completed, and does not include ISAM. PMID- 29999478 TI - A bilayer scaffold prepared from collagen and carboxymethyl cellulose for skin tissue engineering applications. AB - Treatment of chronic skin wound such as diabetic ulcers, burns, pressure wounds are challenging problems in the medical area. The aim of this study was to design a bilayer skin equivalent mimicking the natural one to be used as a tissue engineered skin graft for use in the treatments of problematic wounds, and also as a model to be used in research related to skin, such as determination of the efficacy of transdermal bioactive agents on skin cells and treatment of acute skin damages that require immediate response. In this study, the top two layers of the skin were mimicked by producing a multilayer construct combining two different porous polymeric scaffolds: as the dermis layer a sodium carboxymethyl cellulose (NaCMC) hydrogel on which fibroblasts were added, and as the epidermis layer collagen (Coll) or chondroitin sulfate-incorporated collagen (CollCS) on which keratinocytes were added. The bilayer construct was designed to allow cross talk between the two cell populations in the subsequent layers and achieves paracrine signalling. It had interconnected porosity, high water content, appropriate stability and elastic moduli. Expression of vascular endothelial growth factor (VEGF), basic-fibroblast growth factor (bFGF) and Interleukin 8 (IL 8), and the production of collagen I, collagen III, laminin and transglutaminase supported the attachment and proliferation of cells on both layers of the construct. Attachment and proliferation of fibroblasts on NaCMC were lower compared to performance of keratinocyte on collagen where keratinocytes created a dense and a stratified layer similar to epidermis. The resulting constructs succesfully mimicked in vitro the natural skin tissue. They are promising as grafts for use in the treatment of deep wounds and also as models for the study of the efficacy of bioactive agents on the skin. PMID- 29999479 TI - Comparative Characterization of Ischemia-Induced Brain Multipotent Stem Cells with Mesenchymal Stem Cells: Similarities and Differences. AB - Mesenchymal stem cells (MSCs) are multipotent stem cells localized to the perivascular regions of various organs, including bone marrow (BM). While MSC transplantation represents a promising stem cell-based therapy for ischemic stroke, increasing evidence indicates that exogenously administered MSCs rarely accumulate in the injured central nervous system (CNS). Therefore, compared with MSCs, regionally derived brain multipotent stem cells may be a superior source to elicit regeneration of the CNS following ischemic injury. We previously identified ischemia-induced multipotent stem cells (iSCs) as likely originating from brain pericytes/perivascular cells (PCs) within poststroke regions. However, detailed characteristics of iSCs and their comparison with MSCs remains to be investigated. In the present study, we compared iSCs with BM-derived MSCs, with a focus on the stemness and neuron-generating activity of each cell type. From our results, stem and undifferentiated cell markers, including c-myc and Klf4, were found to be expressed in iSCs and BM-MSCs. In addition, both cell types exhibited the ability to differentiate into mesoderm lineages, including as osteoblasts, adipocytes, and chondrocytes. However, compared with BM-MSCs, high expression of neural stem cell markers, including nestin and Sox2, were found in iSCs. In addition, iSCs, but not BM-MSCs, formed neurosphere-like cell clusters that differentiated into functional neurons. These results demonstrate that iSCs are likely multipotent stem cells with the ability to differentiate into not only mesoderm, but also neural, lineages. Collectively, our novel findings suggest that locally induced iSCs may contribute to CNS repair by producing neuronal cells following ischemic stroke. PMID- 29999480 TI - Does sports club participation contribute to physical activity among children and adolescents? A comparison across six European countries. AB - AIMS: Insufficient physical activity (PA) is one of the largest public health challenges of our time and requires a multisectoral public-health response. PA recommendations state that all children and adolescents should accumulate at least 60 minutes of moderate-to-vigorous PA (MVPA) daily and carry out vigorous PA (VPA) three times weekly. While participation in sports club activities is known to enhance the probability of reaching the recommended overall PA level, less is known about the contribution of sports club participation to VPA, and few cross-national comparisons have been carried out. The purpose of this paper is to study whether participation in sports club activities is associated with meeting the overall PA and VPA recommendations among children and adolescents across six European countries, namely Belgium (Flanders), Czech Republic, Finland, France, Ireland and Sweden. METHODS: Analyses were carried out on existing self-reported national data sets using descriptive statistics and logistic regression. RESULTS: Results indicate that approximately two-thirds of children and adolescents take part in sports club activities in the given countries. Sports club participants were more likely to meet the overall PA recommendations (OR 2.4-6.4) and VPA recommendation (OR 2.8-5.0) than non-participants. CONCLUSIONS: The extent to which overall PA and/or VPA is gained through sports club participation versus other settings needs to be further studied. Nonetheless, it can be argued that sports clubs have an important position in PA promotion for younger populations. PMID- 29999481 TI - A mechanical hand for prosthetic applications: multibody model and contact simulation. AB - The dynamical behavior study of a mechanical hand is a fundamental issue to verify its possible application as a prosthetic hand. Simulation approaches are widely used to predict the dynamics of mechanical components. In the context of mechanical hands, the multibody model represents a useful tool to predict the finger dynamics and therefore the phalanx rotations before the prototyping. The phalanx rotations drive the finger closure sequence and, consequently, influence the grasping ability of the whole mechanical hand. This article discusses the main theoretical aspects dealing with the design of a mechanical hand for prosthetic application and the solutions offered by multiple simulation approaches. PMID- 29999482 TI - Complex Yearlong Associations Between Mental Toughness and Sport-Specific Practice Among Adolescent Estonian Volleyball Players. AB - This study tested the reciprocal associations between mental toughness (MT) and sport-specific practice (SSP) among 163 adolescent Estonian volleyball players who completed self-reported measures of MT and SSP within a 2-year, three-wave longitudinal research design. Higher MT was associated with higher SSP hours at baseline, and changes in MT and SSP were also significantly interrelated across data from both males and females. These findings have implications for the importance of SSP to increase MT, though future research should replicate this study with other participant samples. PMID- 29999483 TI - Applicability increases the effect of misattribution on judgment. AB - Feelings and cognitions influence judgment through attribution. For instance, the attribution of positive feelings and cognitions to a stimulus leads to a positive judgment of that stimulus. We examined whether misattribution is moderated by the applicability of a distractor to the judgment question. For instance, when are people more likely to attribute to a target person the affective and cognitive experiences triggered by a kitten - when trying to judge the person's cuteness or trustworthiness? The kitten triggers experiences specifically relevant to cuteness, but people might more easily suspect the kitten's potential influence when judging cuteness rather than trustworthiness. Using the Affect Misattribution Procedure, we found that applicability increases the effect of misattribution on valenced judgments. The results emphasise the importance of specific information (rather than only general valence) in attribution and suggest that high applicability of distractors to the judgment question does not elicit effective correction. PMID- 29999485 TI - Consider the Adhesives of Wound Dressings. PMID- 29999484 TI - The Diagnosis and Treatment of Primary CNS Lymphoma. AB - BACKGROUND: Primary central nervous system lymphoma is a diffuse large B celllymphoma with exclusive manifestation in the central nervous system (CNS), leptomeninges, and eyes. Its incidence is 0.5 per 100 000 persons per year.Currently, no evidence-based standard of care exists. METHODS: This review is based on pertinent publications (2000-2017) retrieved by aselective search in PubMed. RESULTS: The clinical and neuroradiological presentation of primary CNS lymphoma isoften nonspecific, and histopathological confirmation is obligatory. The disease, if left un- treated, leads to death within weeks or months. If the patient's general condition permits, treatment should consist of a high-dose chemotherapy based on methotrexate (HD- MTX) combined with rituximab and other cytostatic drugs that penetrate the blood-brain barrier. Long-term survival can be achieved in patients under age 70 by adding non- myeloablative consolidation chemotherapy or high-dose chemotherapy with autologous stem cell transplantation (HD-AST) to the induction therapy. Clinical trials comparing the efficacy and toxicity of these two treatment strategies are currently underway. Con- solidation whole-brain radiotherapy is associated with the risk of severe neurotoxicity and should be reserved for patients who do not qualify for systemic treatment. Some 30% of patients are refractory to primary treatment, and at least 50% relapse. In patients who are still in good general condition, relapse can be managed with HD-AST. Re- exposure to conventional HD-MTX-based polychemotherapy is another option, if the initial response was durable. The 5-year survival rate of all treated patients is 31%,according to registry data. CONCLUSION: Current recommendations for the treatment of primary CNS lymphomaare based on only a small number of prospective clinical trials. Patients with this disease should be treated by interdisciplinary teams in experienced centers, andpreferably as part of a controlled trial. PMID- 29999486 TI - Lukewarm Tap Water. PMID- 29999487 TI - In Reply. PMID- 29999488 TI - Tuberculosis Cutis Luposa (Lupus Vulgaris). PMID- 29999489 TI - Helicobacter Pylori Infection. AB - BACKGROUND: Infection with Helicobacter pylori (H. pylori) is a major pathogenic factor for gastroduodenal ulcer disease and gastric carcinoma, as well as for other types of gastric and extragastric disease. As a result of changing epidemiologic conditions (e.g., immigration), changing resistance patterns with therapeutic implications, and new knowledge relating to the indications for pathogen eradication, the medical management of H. pylori is a dynamic process in need of periodic reassessment. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and the Cochrane Database, with particular attention to three international consensus reports and the updated German S2k guideline. RESULTS: H. pylori is now dealt with as an infection, whether or not the infected individual has symptoms or suffers from and H.-pylori-induced illness. H.-pylori-associated dyspepsia and functional dyspepsia are distinct entities that can only be diagnosed when competing elements in the differential diagnosis have been ruled out. H. pylori can be detected with noninvasive methods (13C-urea breathing test, stool antigen detection) and with invasive methods (histology, culture, rapid urease test). An important consideration for treatment is that primary clarithromycin resistance is common in many groups of patients; in Germany, its prevalence is now 10.9%. Primary treatment can be with either standard triple therapy (clarithromycin and amoxicillin or metronidazole) or bismuth-containing quadruple therapy. Treatment for 10 to 14 days is more likely to eradicate the pathogen than treatment for 7 days. When H. pylori infection is initially diagnosed in a patient over age 50, gastritis risk stratification should be performed by means of endoscopic biopsy and histologic examination. CONCLUSION: The new, clinically relevant developments that are presented and commented upon in this review now enable evidence-based management of H. pylori infection. PMID- 29999490 TI - Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions. AB - Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8 to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation. PMID- 29999493 TI - Optimized I-values for use with the Bragg additivity rule and their impact on proton stopping power and range uncertainty. AB - Novel imaging modalities can improve the estimation of patient elemental compositions for particle treatment planning. The mean excitation energy (I value) is a main contributor to the proton range uncertainty. To minimize their impact on beam range errors and quantify their uncertainties, the currently used I-values proposed in 1982 are revisited. The study aims at proposing a new set of optimized elemental I-values for use with the Bragg additivity rule (BAR) and establishing uncertainties on the optimized I-values and the BAR. We optimize elemental I-values for the use in compounds based on measured material I-values. We gain a new set of elemental I-values and corresponding uncertainties, based on the experimental uncertainties and our uncertainty model. We evaluate uncertainties on I-values and relative stopping powers (RSP) of 70 human tissues, taking into account statistical correlations between tissues and water. The effect of new I-values on proton beam ranges is quantified using Monte Carlo simulations. Our elemental I-values describe measured material I-values with higher accuracy than ICRU-recommended I-values (RMSE: 6.17% (ICRU), 5.19% (this work)). Our uncertainty model estimates an uncertainty component from the BAR to 4.42%. Using our elemental I-values, we calculate the I-value of water as 78.73 +/- 2.89 eV, being consistent with ICRU 90 (78 +/- 2 eV). We observe uncertainties on tissue I-values between 1.82-3.38 eV, and RSP uncertainties between 0.002%-0.44%. With transport simulations of a proton beam in human tissues, we observe range uncertainties between 0.31% and 0.47%, as compared to current estimates of 1.5%. We propose a set of elemental I-values well suited for human tissues in combination with the BAR. Our model establishes uncertainties on elemental I-values and the BAR, enabling to quantify uncertainties on tissue I values, RSP as well as particle range. This work is particularly relevant for Monte Carlo simulations where the interaction probabilities are reconstructed from elemental compositions. PMID- 29999491 TI - How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion. AB - Dengue virus (DV) is a compact, icosahedrally symmetric, enveloped particle, covered by 90 dimers of envelope protein (E), which mediates viral attachment and membrane fusion. Fusion requires a dimer-to-trimer transition and membrane engagement of hydrophobic 'fusion loops'. We previously characterized the steps in membrane fusion for the related West Nile virus (WNV), using recombinant, WNV virus-like particles (VLPs) for single-particle experiments (Chao et al., 2014). Trimerization and membrane engagement are rate-limiting; fusion requires at least two adjacent trimers; availability of competent monomers within the contact zone between virus and target membrane creates a trimerization bottleneck. We now report an extension of that work to dengue VLPs, from all four serotypes, finding an essentially similar mechanism. Small-molecule inhibitors of dengue virus infection that target E block its fusion-inducing conformational change. We show that ~12-14 bound molecules per particle (~20-25% occupancy) completely prevent fusion, consistent with the proposed mechanism. PMID- 29999494 TI - Suggested reference values for regional blood volumes in children and adolescents. AB - Estimates of regional blood volumes (BVs) in humans are needed in dosimetric models of radionuclides and radiopharmaceuticals that decay in the circulation to a significant extent. These values are also needed to refine models of tissue elemental composition in computational human phantoms of both patients and exposed members of the general public. The International Commission on Radiological Protection (ICRP) in its Publication 89 provides reference values for total blood content in the full series of their reference individuals, to include the male and female newborn, 1 year-old, 5 year-old, 10 year-old, 15 year old, and adult. Furthermore, Publication 89 provides reference values for the percentage distribution of total blood volume in 27 different blood-filled organs and tissues of the reference adult male and adult female. However, no similar distribution values are provided for non-adults. The goal of the present study is to present a volumetric scaling methodology to derive these values for the same organs and tissues at ages younger than the reference adult. Literature data on organ-specific vascular growth in the brain, kidneys, and skeletal tissues are also considered. PMID- 29999492 TI - E-cadherin binds to desmoglein to facilitate desmosome assembly. AB - Desmosomes are adhesive junctions composed of two desmosomal cadherins: desmocollin (Dsc) and desmoglein (Dsg). Previous studies demonstrate that E cadherin (Ecad), an adhesive protein that interacts in both trans (between opposing cells) and cis (on the same cell surface) conformations, facilitates desmosome assembly via an unknown mechanism. Here we use structure-function analysis to resolve the mechanistic roles of Ecad in desmosome formation. Using AFM force measurements, we demonstrate that Ecad interacts with isoform 2 of Dsg via a conserved Leu-175 on the Ecad cis binding interface. Super-resolution imaging reveals that Ecad is enriched in nascent desmosomes, supporting a role for Ecad in early desmosome assembly. Finally, confocal imaging demonstrates that desmosome assembly is initiated at sites of Ecad mediated adhesion, and that Ecad L175 is required for efficient Dsg2 and desmoplakin recruitment to intercellular contacts. We propose that Ecad trans interactions at nascent cell-cell contacts initiate the recruitment of Dsg through direct cis interactions with Ecad which facilitates desmosome assembly. PMID- 29999495 TI - LEFMIS: locally-oriented evaluation framework for medical image segmentation algorithms. AB - This article proposes a novel framework for the locally-oriented evaluation of segmentation algorithms (LEFMIS). The presented approach is robust and takes into account local inter/intra-observer variability and the anisotropy of medical images. What is more, the framework makes it possible to distinguish types of error locally. These features are crucial in the context of cancer image data. The proposed framework is based on use of the signed anisotropic Euclidean distance transform and the distance projection. It can be used easily in many different applications with or without additional expert outlines (both inter- and intra-observer variability). The performance of the proposed framework is depicted using both artificial and kidney cancer CT data with experts' manual outlines. In the article, in the case of artificial data, it is presented that the manual outlines dispersion is symmetric in relation to the truth border. The effectiveness of the selected segmentation algorithm was analysed in the context of kidney cancer using computed tomography data. For the calculated local inter observer variability, 80.11% of the surface points generated by the kidney segmentation algorithm are within one expert outline standard deviation and 97.96% are within five. An error distribution shift in the direction of type I error equivalent was also observed. Finally, the significance of the local estimation of error type differences is presented. The article shows the greater usefulness and flexibility of the proposed framework in comparison to the state of-the-art methods. The exemplary usage of the LEFMIS with or without inter /intra-observer variability is also presented. PMID- 29999497 TI - Suitability of low density materials for 3D printing of physical breast phantoms. AB - Breast physical phantoms are a basic tool for the assessment and verification of performance standards in daily clinical practice of x-ray breast imaging modalities. They are also invaluable in testing and evaluation of new x-ray breast modalities to be potentially established, e.g. breast computed tomography, dual-energy breast CT and phase-contrast mammography and tomography. Nowadays, there is a lack or there are only a limited number of breast physical phantoms available for this purpose. The aim of this study is to explore a range of 3D printing materials such as resins, PLA, ABS, Nylon etc, to determine their attenuation and refractive properties, and to finally compare them to the properties of the breast tissues: adipose, glandular and skin. To achieve this goal, step-wedge phantoms were computationally modeled and then manufactured using stereolithographic and fused-deposition modeling technologies. X-ray images of the phantoms were acquired, using monochromatic beam at ID17, ESRF, Grenoble for three energies-30 keV, 45 keV and 60 keV. Experimental data were further processed to obtain the linear attenuation coefficients of these materials. Comparison with theoretical data for the linear attenuation coefficients and the refractive indexes for breast tissues was performed. From the studied materials, most of the resins, Nylon, Hybrid, PET-G show absorption properties close to the glandular tissue, while ABS shows absorption characteristics close to these of the adipose tissue. For phase-contrast imaging, it turns out that the ABS combined with resin-based materials to represent the adipose and glandular tissues, respectively may be a good combination for manufacturing of a phantom suitable for these studies. These results can be used for the design and the construction of a new physical anthropomorphic phantom of the breast with improved anatomical and radiological characteristics dedicated for advanced mammography imaging techniques implemented at higher photon energies. PMID- 29999496 TI - Flexible optically stimulated luminescence band for 1D in vivo radiation dosimetry. AB - In vivo dosimetry helps ensure the accuracy of radiation treatments. However, standard techniques are only capable of point sampling, making it difficult to accurately measure dose variation along curved surfaces in a continuous manner. The purpose of this work is to introduce a flexible dosimeter band and validate its performance using pre-clinical and clinical x-ray sources. Dosimeter bands were fabricated by uniformly mixing BaFBr:Eu storage phosphor powders into a silicone based elastomer. An optical readout device with dual-wavelength excitation was designed and built to correct for non-uniform phosphor density and extract accurate dose information. Results demonstrated significant correction of the non-uniform readout signal and excellent dose linearity up to 8 Gy irradiation using a pre-clinical 320 kV x-ray system. Beam profile measurements were demonstrated over a long distance of ~30 cm by placing multiple dosimeters in a single line and stitching the results. The performance of the dosimeters was also tested using a clinical linear accelerator (6 MV) and compared to radiochromic film. Once bias corrected, the bands displayed a linear dose response over the 1.02-9.36 Gy range (R 2 > 0.99). The proposed system can be further improved by reducing the size of the readout beam and by more uniformly mixing the phosphor powder with the elastomer. We expect this technique to find application for large-field treatments such as total-skin irradiation and total body irradiation. PMID- 29999498 TI - Type I superconductivity in Dirac materials. AB - Superconductivity of the second kind was observed in many 3D Weyl and Dirac semi metals while in the PdTe2, superconductivity is clearly of the first kind. This is very rare in Dirac semi-metals, but is expected in clean conventional metallic superconductors with 3D parabolic dispersion relation. The conduction bands in this material exhibit the linear (Dirac) dispersion only along two directions, while in the third direction the dispersion is parabolic. Therefore the 'hybrid' Dirac-parabolic material is intermediate between the two extremes. A microscopic pairing theory is derived for arbitrary tilt parameter of the 2D cone and used to determine anisotropic coherence lengths, the penetration depths and applied to recent extensive experiments. Magnetic properties of these superconductors are then studied in the parallel to the layers magnetic field on the basis of microscopically derived Ginzburg-Landau effective theory for the order parameter. PMID- 29999499 TI - Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement. AB - OBJECTIVE: Although previous studies have shown associations between patient symptoms/outcomes and the spontaneous tympanic membrane displacement (spTMD) pulse amplitude, the contribution of the underlying intracranial pressure (ICP) signal to the spTMD pulse remains largely unknown. We have assessed the relative contributions of ICP and arterial blood pressure (ABP) on spTMD at different frequencies in order to determine whether spTMD contains information about the ICP above and beyond that contained in the ABP. APPROACH: Eleven patients, who all had invasive ICP and ABP measurements in situ, were recruited from our intensive care unit. Their spTMD was recorded and the power spectral densities of the three signals, as well as coherences between the signals, were calculated in the range 0.1-5 Hz. Simple and multiple coherences, coupled with statistical tests using surrogate data, were carried out to quantify the relative contributions of ABP and ICP to spTMD. MAIN RESULTS: Most power of the signals was found to predominate at respiration rate, heart rate, and their harmonics, with little outside of these frequencies. Analysis of the simple coherences found a slight preference for ICP transmission, beyond that from ABP, to the spTMD at lower frequencies (7/11 patients at respiration, 7/10 patients at respiration 1st harmonic) which is reversed at the higher frequencies (2/11 patients at heart rate and its 1st harmonic). Both ICP and ABP were found to independently contribute to the spTMD. The multiple coherence reinforced that ICP is preferentially being transmitted at respiration and respiration 1st harmonic. SIGNIFICANCE: Both ABP and ICP contribute independently to the spTMD signal, with most power occurring at clear physiological frequencies-respiration and harmonics and heart rate and harmonics. There is information shared between the ICP and spTMD that is not present in ABP. This analysis has indicated that lower frequencies appear to favour ICP as the driver for spTMD. PMID- 29999501 TI - alphav Integrins regulate germinal center B cell responses through noncanonical autophagy. AB - Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through TLRs on B cells promotes many aspects of GC B cell responses, including affinity maturation, class switching, and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here, we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by alphav integrins and noncanonical autophagy. Using B cell-specific alphav-KO mice, we show that loss of alphav-mediated TLR regulation increased GC B cell expansion, somatic hypermutation, class switching, and generation of long-lived plasma cells after immunization with virus-like particles (VLPs) or antigens associated with TLR ligand adjuvants. Furthermore, targeting alphav-mediated regulation increased the magnitude and breadth of antibody responses to influenza virus vaccination. These data therefore identify a mechanism of regulation of GC B cells that can be targeted to enhance antibody responses to vaccination. PMID- 29999503 TI - Editorial Epigenetics: A Missing Link Between Periodontitis and Peri-implantitis? AB - No abstract available. PMID- 29999502 TI - Bibliographical Characteristics of North Korean Medical Journals and Articles. AB - The aim of our work was to analyze the bibliographical characteristics of 9 North Korean medical journals and articles. All journals show only ten pieces of information, such as publication dates and table of contents, and do not provide submission guidelines and journal policy. Most of the journals were published four times a year. Editorials often share government policy. Research articles are very short and compressed. The journals often publish articles on oriental medicine and medical information useful to the public. In conclusion, the journals were published in their own unique style and format, which are far from the global standard. PMID- 29999504 TI - Lactose malabsorption and intolerance: a review. AB - Food lactose and lactose intolerance are today hot topics in the field of food and nutrition. About 70% of the adult world population is lactose-intolerant, due to low levels of intestinal lactase, also called lactase-phlorizin hydrolase (LPH), a beta-d-galactosidase found in the apical surface of the intestinal microvilli. This may be due to the loss of intestinal lactase in adulthood, a condition transmitted by an autosomal recessive gene, which differs in humans according to race. According to the cultural-historical hypothesis, the mutation that allows the metabolization of lactose appeared about 10 000 years ago in the inhabitants of Northern Europe where mammalian milk continued in the diet after weaning, and lactase-persistent populations were genetically selected in some areas. Many intolerant individuals can tolerate low levels of lactose in their daily diet. Probiotics have also been proposed as an alternative that could avoid some symptoms of lactose intolerance. Many products are marketed nowadays as alternatives to dairy products for lactose-intolerant individuals. However, the rules for low-lactose foods are currently not harmonised in the European Union. As scientific knowledge on lactose intolerance has notably advanced in recent decades, the aim of this work was to review the current state of the knowledge on lactose and lactose intolerance, its diagnosis and clinical management, and the various food products that are offered specifically for non-tolerant individuals. PMID- 29999500 TI - Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype. AB - GWAS have repeatedly mapped susceptibility loci for emphysema to genes that modify hedgehog signaling, but the functional relevance of hedgehog signaling to this morbid disease remains unclear. In the current study, we identified a broad population of mesenchymal cells in the adult murine lung receptive to hedgehog signaling, characterized by higher activation of hedgehog surrounding the proximal airway relative to the distal alveoli. Single-cell RNA-sequencing showed that the hedgehog-receptive mesenchyme is composed of mostly fibroblasts with distinct proximal and distal subsets with discrete identities. Ectopic hedgehog activation in the distal fibroblasts promoted expression of proximal fibroblast markers and loss of distal alveoli and airspace enlargement of over 20% compared with controls. We found that hedgehog suppressed mesenchymal-derived mitogens enriched in distal fibroblasts that regulate alveolar stem cell regeneration and airspace size. Finally, single-cell analysis of the human lung mesenchyme showed that segregated proximal-distal identity with preferential hedgehog activation in the proximal fibroblasts was conserved between mice and humans. In conclusion, we showed that differential hedgehog activation segregates mesenchymal identities of distinct fibroblast subsets and that disruption of fibroblast identity can alter the alveolar stem cell niche, leading to emphysematous changes in the murine lung. PMID- 29999505 TI - Silk fibroin nanoparticles as biocompatible nanocarriers of a novel light responsive CO-prodrug. AB - [Mn(CO)3(2,2'-bipyridine)(PPh3)](ClO4) (1), a novel photoactive CO-releasing molecule, has been prepared and fully characterized. Besides, silk fibroin nanoparticles (SFNs) have been used, for the first time, as vehicles of 1 leading to the hybrid material 1@SFNs that shows an enhanced CO-delivery. PMID- 29999506 TI - PEG-copolymer-coated iron oxide nanoparticles that avoid the reticuloendothelial system and act as kidney MRI contrast agents. AB - In vitro experiments have shown the great potential of magnetic nanocarriers for multimodal imaging diagnosis and non-invasive therapies. However, their extensive clinical application is still jeopardized by a fast retention in the reticuloendothelial system (RES). The other issue that restrains their potential performance is slow degradation and excretion, which increases their risks of toxicity. We report a promising case in which multicore iron oxide nanoparticles coated with a poly(4-vinylpyridine) polyethylene glycol copolymer show low RES retention and high urinary excretion, as confirmed by single photon emission computerized tomography (SPECT), gamma counting, magnetic resonance imaging (MRI) and electron microscopy (EM) biodistribution studies. These iron oxide-copolymer nanoparticles have a high PEG density in their coating which may be responsible for this effect. Moreover, they show a clear negative contrast in the MR imaging of the kidneys. These nanoparticles with an average hydrodynamic diameter of approximately 20 nm were nevertheless able to cross the glomerulus wall which has an effective pore size of approximately 6 nm. A transmission electron microscopy inspection of kidney tissue revealed the presence of iron containing nanoparticle clusters in proximal tubule cells. This therefore makes them exceptionally useful as magnetic nanocarriers and as new MRI contrast agents for the kidneys. PMID- 29999507 TI - Unique selectivity trends of highly permeable PAP[5] water channel membranes. AB - Artificial water channels are a practical alternative to biological water channels for achieving exceptional water permeability and selectivity in a stable and scalable architecture. However, channel-based membrane fabrication faces critical barriers such as: (1) increasing pore density to achieve measurable gains in permeability while maintaining selectivity, and (2) scale-up to practical membrane sizes for applications. Recently, we proposed a technique to prepare channel-based membranes using peptide-appended pillar[5]arene (PAP[5]) artificial water channels, addressing the above challenges. These multi-layered PAP[5] membranes (ML-PAP[5]) showed significantly improved water permeability compared to commercial membranes with similar molecular weight cut-offs. However, due to the distinctive pore structure of water channels and the layer-by-layer architecture of the membrane, the separation behavior is unique and was still not fully understood. In this paper, two unique selectivity trends of ML-PAP[5] membranes are discussed from the perspectives of channel geometry, ion exclusion, and linear molecule transport. PMID- 29999508 TI - Surface functionalisation significantly changes the physical and electronic properties of carbon nano-dots. AB - Biomolecule functionalisation of carbon nano-dots (CDs) greatly enhances their biocompatibility and applicability, however, little is known about their molecular structure. Using an arsenal of spectroscopic and analytical techniques, we provide new insights into the physical and electronic structure of uncoated and glycan-functionalised CDs. Our studies reveal that surface functionalisation does not always result in a homogenous corona surrounding the core, and the choice of carbohydrate significantly affects the electronic structure of the surface CD states. Further, the average surface coverage of an ensemble of CDs can be probed via transient absorption spectroscopy. These findings have implications for CDs targeted at interactions with biological systems or local sensors. PMID- 29999510 TI - Fatty acid positional distribution in colostrum and mature milk of women living in Inner Mongolia, North Jiangsu and Guangxi of China. AB - In order to investigate the fatty acid composition and distribution in colostrum and mature milk, breast milk samples and 24 h food records were obtained from 65 lactating women across three regions in China (Inner Mongolia, North Jiangsu and Guangxi). Fatty acid methyl esters were prepared by standard methods and separated and identified by gas chromatography. Compared with the Chinese breast milk fatty acid data 10 years ago, SFA and trans fatty acids (TFA) in breast milk decreased, while PUFA increased in the present study. Most SFA (C16:0, C15:0, C14:0), cis-C16:1 and several LC-PUFA (C22:5n-3 and C22:6n-3) were predominantly acylated at the sn-2 position. The cis-C17:1 and C22:6n-3 were distributed equally in three positions of triacylglycerol (TAG). Whereas, TFA, conjugated linoleic acids (CLA), cis-C18:1, C18:2n-6, C18:3n-3 and C20:5n-3 were acylated at the sn-1, 3 positions of TAG in human milk. The composition of fatty acids in breast milk was closely related to the diet of lactating mothers. PUFA in breast milk was negatively correlated with the intake of protein, fat and meat, but positively correlated with the intake of carbohydrates. MUFA of human milk was negatively correlated with the intake of dairy products, eggs, fish and shrimp. SFA in breast milk was positively correlated with the maternal intake of meat. In addition, the present results showed that the composition of total fatty acids and sn-2 fatty acids in breast milk varied with the lactation period and the geographical regions in China; however, the regiospecific fatty acid profile seemed not to be affected by the lactation time and regions, although the quantities at each position could be changed. PMID- 29999509 TI - 'AND'-based fluorescence scaffold for the detection of ROS/RNS and a second analyte. AB - Traditionally, fluorescence probes have focused on the detection of a single biomarker for a specific process. In this work, we set out to develop a number of fluorescence probes that enable the detection of a chosen analyte in the presence of reactive oxygen/nitrogen species (ROS/RNS). These fluorescence probes when activated result in the formation of the highly fluorescent pink dye, resorufin. Therefore, we have labelled these fluorescent probes as 'Pinkments'. Our first 'Pinkment' was shown to detect biologically relevant concentrations of ONOO- and have an excellent selectivity against other ROS/RNS. Pinkment-OH was developed to provide a core unit which could be easily functionalised to produce a range of 'AND' based fluorescence probes for the detection of ROS/RNS and a second analyte. For proof of concept, we synthesised Pinkment-OTBS and Pinkment-OAc. These 'AND'-based probes were successfully shown to detect ROS/RNS and F- or esterase, respectively. PMID- 29999511 TI - Topologically protected interface phonons in two-dimensional nanomaterials: hexagonal boron nitride and silicon carbide. AB - We perform both lattice dynamics analysis and molecular dynamics simulations to demonstrate the existence of topologically protected phonon modes in two dimensional, monolayer hexagonal boron nitride and silicon carbide sheets. The topological phonon modes are found to be localized at an in-plane interface that divides these systems into two regions of distinct valley Chern numbers. The dispersion of this topological phonon mode crosses over the frequency gap, which is opened through analogy with the quantum valley Hall effect by breaking the inversion symmetry of the primitive unit cells. Consequently, vibrational energy with frequency within this gap is topologically protected, resulting in wave propagation that exhibits minimal backscattering, is robust with regard to structural defects such as sharp corners, and exhibits excellent temporal stability. Our findings open up the possibility of actuating and detecting topological phonons in two-dimensional nanomaterials. PMID- 29999512 TI - Structural tailoring of nanoporous anodic alumina optical microcavities for enhanced resonant recirculation of light. AB - A comprehensive study about the structural engineering of high quality nanoporous anodic alumina optical microcavities (NAA-MUCVs) fabricated by rationally designed anodisation strategies to enhance the light-confining capabilities of these photonic crystal (PC) structures is presented. Two types of NAA-MUCV architectures are produced: (i) GIF-NAA-MUCVs composed of a cavity layer featuring straight nanopores that is sandwiched between two gradient-index filters (GIFs) with sinusoidally modulated porosity in depth, and (ii) DBR-NAA MUCVs formed by sandwiching a cavity layer with straight nanopores between two distributed Bragg reflectors (DBRs), in which the porosity is engineered in a stepwise fashion. The geometric features of GIF-NAA-MUCVs and DBR-NAA-MUCVs are engineered and optimised through a systematic modification of the anodisation parameters (i.e. cavity anodisation time, cavity anodisation current density, anodisation period and number of anodisation pulses, and pore widening time). This methodology enables fine-tuning of the optical properties of GIF-NAA-MUCVs and DBR-NAA-MUCVs, such as quality factor and position and width of resonance band, to generate NAA-MUCVs with unprecedented quality factors (i.e. 170 +/- 8 and 206 +/- 10 for the first and second order resonance bands - threefold and fourfold quality enhancement as compared to previous studies). Our results demonstrate that an optimal design of the geometric features and the nanoporous architecture of NAA-MUCVs can significantly enhance resonant recirculation of light within these PC structures, creating new opportunities to develop ultrasensitive optical platforms, highly selective optical filters, and other photonic devices. PMID- 29999513 TI - Base excision repair initiated rolling circle amplification-based fluorescent assay for screening uracil-DNA glycosylase activity using Endo IV-assisted cleavage of AP probes. AB - Uracil-DNA glycosylase (UDG) is a crucial damage repair enzyme that initiates the cellular base excision repair pathway that maintains the integrity of the genome. Abnormal UDG activity may induce the malfunction of uracil excision repair that is directly related to a range of diseases including cancers, genotypic diseases, and human immunodeficiencies. In this work, a simple, robust and cost effective biosensing platform for the ultrasensitive detection of UDG activity is established based on the combination of base excision repair-initiated primer generation for rolling circular amplification (RCA) with Endo IV-assisted signal amplification. In the presence of target UDG, UDG can catalyze the removal of uracil on a hairpin probe (HP) leaving an apurinic/apyrimidinic (AP site) which can be cleaved by Endo IV to generate a primer for triggering the RCA reaction. Subsequently, numerous AP site-embedded signal probes, acting as fluorescence quenched probes, combine with the RCA products to perform signal transduction and quadradic signal amplification through an Endo IV-catalyzed cleavage reaction, thus significantly enhancing the fluorescence signal, which can be used for UDG activity screening. Under optimum conditions, this biosensor exhibits improved sensitivity toward target UDG with a detection limit of as low as 9.3 * 10-5 U mL 1 and a wide detection range across 5 orders of magnitude. Additionally, our biosensor demonstrates high selectivity toward UDG for simple, rapid, and low cost detection. Furthermore, by redesigning the modification of HP and using of suitable endonuclease enzymes, this RCA coupled with Endo IV-assisted signal amplification strategy might be applied for the detection of various other targets, such as thymine DNA glycosylase, 8-oxoguanine DNA glycosylase, DNA methyltransferase, and so on. Hence, the proposed strategy provides a useful and versatile biosensing platform for the ultrasensitive detection of UDG activity and related fundamental biomedicine research and clinical diagnosis. PMID- 29999514 TI - A fluorescence-enhanced chemosensor based on multifarene[2,2] and its recognition of metal cations. AB - A selective and sensitive fluorescent chemosensor based on an anthracene functionalized triazole-linked multifarene[2,2] was successfully synthesized and investigated with regard to the recognition of metal ions using fluorescence spectroscopy, 1H NMR titration, and IR spectroscopy. The proposed sensor exhibited desirable properties for potential fluorescence enhanced chemosensor applications, including selective affinity and low Zn2+ and Cd2+ detection limits compared with other metal ions. Quantum chemical calculations described the synthesized chemosensor's static structure and its coordination to Zn2+ and Cd2+. Frontier molecular orbital distribution and energy changes suggested a possible mechanism for increased receptor fluorescence intensity with Zn2+ and Cd2+ addition. PMID- 29999515 TI - Meta-analysis of prognostic factors for overall survival in patients with resected hilar cholangiocarcinoma. AB - BACKGROUND: Hilar cholangiocarcinoma is staged using the AJCC staging system. Numerous other prognostically important histopathological and demographic characteristics have been reported. The objective of this meta-analysis was to assess statistically the effect of postresectional tumour characteristics on overall survival of patients undergoing attempted radical curative resection for hilar cholangiocarcinoma. METHODS: Relevant studies were identified by searching the Ovid MEDLINE and PubMed databases. The search was limited to studies published between 2009 and 2017. Papers referring to intrahepatic or distal cholangiocarcinoma were excluded from review. Data extraction used standard Parmar modifications to determine pooled univariable hazard ratios (HRs). RESULTS: Twenty-four articles, containing 4599 patients, were assessed quantitatively. In pooled analyses, age (HR 1.16, 95 per cent c.i. 1.04 to 1.28), T category (HR 1.49, 1.30 to 1.70), lymph node involvement (HR 1.78, 1.65 to 1.93), microvascular invasion (HR 1.49, 1.34 to 1.68), perineural invasion (HR 1.54, 1.40 to 1.68) and tumour differentiation (HR 1.54, 1.38 to 1.72) were significant prognostic factors, with low heterogeneity. Portal vein resection (HR 1.54, 1.15 to 1.70) and resection margin status (HR 1.77, 1.57 to 1.99) had significant effects, but with high heterogeneity. Sex, tumour size and preoperative carbohydrate antigen 19-9 levels did not have a statistically significant effect on postoperative prognosis. CONCLUSION: Several tumour biological variables not included in the seventh edition of the AJCC classification affect overall survival. These require incorporation into prognostic models to ensure a personalized approach to prognostication and treatment. PMID- 29999516 TI - Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes. AB - Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 * 10-5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 * 10-4 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 * 10-4 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN. PMID- 29999518 TI - Outcomes of patients receiving a massive transfusion for major trauma. AB - BACKGROUND: The benefits of high transfusion ratios (plasma to red blood cells and platelets to red blood cells) on survival in injured patients who receive massive transfusions remain uncertain. This study aimed to assess the association between transfusion ratios and adverse events and survival in patients undergoing massive transfusion for major trauma. METHODS: A retrospective observational study was conducted on patients who had major trauma using a Japanese national administrative database. The associations between transfusion ratios and outcomes (in-hospital mortality and incidence of adverse events) were analysed using a non linear logistic generalized additive model (GAM). In a logistic generalized estimating equation model, adjusted for patient and hospital-level confounders, transfusion ratios were included as continuous or categorical variables (low, transfusion ratio 0.75 or less; intermediate, over 0.75 to 1.25; high, over 1.25). RESULTS: Some 1777 patients were included in the analysis, of whom 602 died in hospital. GAM plots of the transfusion ratios for in-hospital mortality demonstrated a downward convex unimodal curve. In-hospital mortality was similar with increasing transfusion ratios for plasma (adjusted odds ratio (OR) 1.13, 95 per cent c.i. 0.82 to 1.55; P = 0.446) and platelets (adjusted OR 0.84, 0.66 to 1.08; P = 0.171). Both plasma to red blood cell ratio (adjusted OR 1.77, 1.32 to 2.37; P < 0.001) and platelet to red blood cell ratio (adjusted OR 1.71, 1.35 to 2.15; P < 0.001) were significantly associated with a higher incidence of adverse events. No significant differences in in-hospital mortality were observed between the three transfusion categories (low, medium and high). CONCLUSION: In this study, transfusion strategies with high plasma to red blood cell and platelet to red blood cell ratios did not have survival benefits, but were associated with an increase in adverse events. PMID- 29999517 TI - Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer. AB - BACKGROUND: Preoperative immunonutrition has been proposed to reduce the duration of hospital stay and infective complications following major elective surgery in patients with gastrointestinal malignancy. A multicentre 2 * 2 factorial RCT was conducted to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with oesophageal cancer. METHODS: Patients were randomized before oesophagectomy to immunonutrition (IMPACT(r) ) versus standard isocaloric/isonitrogenous nutrition, then further randomized after operation to immunonutrition versus standard nutrition. Clinical and quality-of-life outcomes were assessed at 14 and 42 days after operation on an intention-to-treat basis. The primary outcome was the occurrence of infective complications. Secondary outcomes were other complications, duration of hospital stay, mortality, nutritional and quality-of-life outcomes (EuroQol EQ-5D-3 LTM, European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-OES18). Patients and investigators were blinded until the completion of data analysis. RESULTS: Some 278 patients from 11 Australian sites were randomized; two were excluded and data from 276 were analysed. The incidence of infective complications was similar for all groups (37 per cent in perioperative standard nutrition group, 51 per cent in perioperative immunonutrition group, 34 per cent in preoperative immunonutrition group and 40 per cent in postoperative immunonutrition group; P = 0.187). There were no significant differences in any other clinical or quality-of-life outcomes. CONCLUSION: Use of immunonutrition before and/or after surgery provided no benefit over standard nutrition in patients undergoing oesophagectomy. Registration number: ACTRN12611000178943 ( https://www.anzctr.org.au). PMID- 29999519 TI - WASPnest: a worldwide assessment of social Polistine nesting behavior. AB - Cooperative breeding decreases the direct reproductive output of subordinate individuals, but cooperation can be evolutionarily favored when there are challenges or constraints to breeding independently. Environmental factors, including temperature, precipitation, latitude, high seasonality, and environmental harshness have been hypothesized to correlate with the presence of cooperative breeding. However, to test the relationship between cooperation and ecological constraints requires comparative data on the frequency and variation of cooperative breeding across differing environments, ideally replicated across multiple species. Paper wasps are primitively social species, forming colonies composed of reproductively active dominants and foraging subordinates. Adult female wasps, referred to as foundresses, initiate new colonies. Nests can be formed by a single solitary foundress (noncooperative) or by multiple foundress associations (cooperative). Cooperative behavior varies within and among species, making paper wasps species well suited to disentangling ecological correlates of variation in cooperative behavior. This data set reports the frequency and extent of cooperative nest founding for 87 paper wasp species. Data were assembled from more than 170 published sources, previously unpublished field observations, and photographs contributed by citizen scientists to online natural history repositories. The data set includes 25,872 nest observations and reports the cooperative behavioral decisions for 45,297 foundresses. Species names were updated to reflect modern taxonomic revisions. The type of substrate on which the nest was built is also included, when available. A smaller population-level version of this data set found that the presence or absence of cooperative nesting in paper wasps was correlated with temperature stability and environmental harshness, but these variables did not predict the extent of cooperation within species. This expanded data set contains details about individual nests and further increases the power to address the relationship between the environment and the presence and extent of cooperative breeding. Beyond the ecological drivers of cooperation, these high-resolution data will be useful for future studies examining the evolutionary consequences of variation in social behavior. This data set may be used for research or educational purposes provided that this data paper is cited. PMID- 29999520 TI - Survival and risk of breast cancer recurrence after breast reconstruction with deep inferior epigastric perforator flap. AB - BACKGROUND: Women who undergo autologous breast reconstruction have been reported to have an increased risk of breast cancer recurrence compared with those who have mastectomy alone. It has been suggested that more extensive surgery possibly activates dormant micrometastases. The aim of this study was to evaluate whether delayed unilateral deep inferior epigastric perforator (DIEP) flap reconstruction after mastectomy increases the risk of breast cancer recurrence or affects mortality among women previously treated for breast cancer. METHODS: This was a matched retrospective cohort study including women with a previous unilateral invasive breast cancer who received a delayed DIEP flap breast reconstruction and a control cohort of individually matched women with unilateral breast cancer who underwent mastectomy but no autologous breast reconstruction. Matching criteria comprised: year of diagnosis (+/-3 years), age at diagnosis (+/-5 years), type of cancer and demographic region. The primary endpoints were local recurrence or distant metastasis, and overall mortality was a secondary endpoint. Absolute risk of recurrent disease and mortality was analysed, and relative risks were estimated using Cox proportional hazards analysis. RESULTS: There were 225 women in the DIEP cohort and 450 in the no-DIEP cohort. The median follow-up time was 125 months. There was no difference in absolute risk of recurrence between the cohorts. The hazard ratio for breast cancer recurrence in DIEP versus no-DIEP cohorts was 0.76 (95 per cent c.i. 0.47 to 1.21). CONCLUSION: There is no increased risk in breast cancer recurrence after delayed DIEP flap reconstruction compared with mastectomy alone. PMID- 29999522 TI - Reciprocal plant-mediated interactions between a virus and a non-vector herbivore. AB - Vector-borne viruses alter many physical and chemical traits of their plant hosts, indirectly affecting the fitness and behavior of vectors in ways that promote virus transmission. However, it is unclear whether viruses induce plant mediated shifts in the behavior and fitness of non-vector herbivores, or if non vectors affect the dynamics of vector-borne viruses. Here we evaluated reciprocal interactions between Pea enation mosaic virus (PEMV), a pathogen transmitted by the aphid Acrythosiphon pisum, and a non-vector weevil, Sitona lineatus. In the field, PEMV-infected plants experienced more defoliation from S. lineatus than uninfected plants; behavioral assays similarly showed S. lineatus adults preferred to feed on infected plants. In turn, infectious A. pisum preferred plants damaged by S. lineatus, and S. lineatus herbivory led to increased PEMV titer. These interactions may be mediated by plant phytohormone levels, as S. lineatus induced jasmonic acid, while PEMV induced salicylic acid. Levels of abscisic acid were not affected by attack from either PEMV or S. lineatus alone, but plants challenged by both had elevated levels of this phytohormone. As plant viruses and their vectors often exist in diverse communities, our study highlights the importance of non-vector species in influencing plant pathogens and their vectors through host-mediated effects. PMID- 29999524 TI - Myofibromatosis presenting as reticulated vascular changes and subcutaneous atrophy in a patient with somatic mosaicism of PDGFRB mutation. PMID- 29999523 TI - Proteome analysis of human CD56neg NK cells reveals a homogeneous phenotype surprisingly similar to CD56dim NK cells. AB - NK cells lacking CD56 (CD56neg ) were first identified in chronic HIV-1 infection. However, CD56neg NK cells also exist in healthy individuals, albeit in significantly lower numbers. Here, we provide an extensive proteomic characterisation of human CD56neg peripheral blood NK cells of healthy donors and compare them to their CD56dim and CD56bright counterparts. Unbiased large-scale surface receptor profiling clustered CD56neg cells as part of the main NK cell compartment and indicated an overall CD56dim -like phenotype. Total proteome analyses of CD56neg NK cells further confirmed their similarity with CD56dim NK cells, and revealed a complete cytolytic inventory with high levels of perforin and granzyme H and M. In the present study, twelve proteins discriminated CD56neg NK cells from CD56dim NK cells with nine up-regulated and three down-regulated proteins in the CD56neg NK cell population. Those proteins were functionally related to lytic granule composition and transport, interaction with the extracellular matrix, DNA transcription or repair, and proliferation. Corroborating these results, CD56neg NK cells showed modest cytotoxicity, degranulation, and IFN-gamma secretion as compared to CD56dim NK cells. In conclusion, CD56neg NK cells constitute functionally competent cells sharing many features of bona fide CD56dim NK cells in healthy individuals, but with some distinct characteristics. PMID- 29999521 TI - Hypothalamic AMPK and energy balance. AB - AMP-activated protein kinase (AMPK) is the main cellular energy sensor. Activated following a depletion of cellular energy stores, AMPK will restore the energy homoeostasis by increasing energy production and limiting energy waste. At a central level, the AMPK pathway will integrate peripheral signals (mostly hormones and metabolites) through neuronal networks. Hypothalamic AMPK is directly implicated in feeding behaviour, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). It also participates in other metabolic functions: glucose and muscle metabolisms, as well as hepatic function. Numerous anti-obesity and/or antidiabetic agents, such as nicotine, metformin and liraglutide, are known to induce their effects through a modulation of AMPK pathway, either at central or at peripheral levels. Moreover, the weight gaining side effects of antipsychotic drugs, such as olanzapine, are also mediated by hypothalamic AMPK. Therefore, considering hypothalamic AMPK as a therapeutic target in metabolic diseases appears as an interesting strategy due to its implication in feeding and energy expenditure, the two sides of the energy balance equation. PMID- 29999525 TI - Neuroticism confers vulnerability in response to experimentally induced feelings of thwarted belongingness and perceived burdensomeness: Implications for suicide risk. AB - OBJECTIVE: This study investigated the role of individual differences in neuroticism in conferring increased reactivity to the interpersonal antecedents for suicide proposed by the interpersonal theory of suicide. METHOD: Undergraduate students (N = 113) were screened and selected to form high (n = 58) and low (n = 55) neuroticism groups, and an experimental computer task was used to manipulate participants' experience of thwarted belongingness and perceived burdensomeness. Participants' self-reported desire to persist in the face of this induced interpersonal adversity was measured. RESULTS: Results indicate that high neuroticism confers increased reactivity to the experimental induction of the interpersonal antecedents of suicidal ideation: Thwarted belongingness and perceived burdensomeness. Furthermore, this vulnerability corresponds to a diminished desire to persist with the task in the face of interpersonal adversity. CONCLUSIONS: Neuroticism confers vulnerability for suicidal desire via an increased reactivity to the proximal, causal risk factors proposed by the interpersonal theory of suicide. This has implications for considering how personality risk factors such as neuroticism may interact with proximal interpersonal risk factors to increase suicidal ideation. PMID- 29999526 TI - Letter to the Editor regarding Fujioka-Kobayashi et al. 2017 (JOP-16-0443.R1). PMID- 29999527 TI - Automated noninvasive epithelial cell counting in phase contrast microscopy images with automated parameter selection. AB - Cell counting is commonly used to determine proliferation rates in cell cultures and for adherent cells it is often a 'destructive' process requiring disruption of the cell monolayer resulting in the inability to follow cell growth longitudinally. This process is time consuming and utilises significant resource. In this study a relatively inexpensive, rapid and widely applicable phase contrast microscopy-based technique has been developed that emulates the contrast changes taking place when bright field microscope images of epithelial cell cultures are defocused. Processing of the resulting images produces an image that can be segmented using a global threshold; the number of cells is then deduced from the number of segmented regions and these cell counts can be used to generate growth curves. The parameters of this method were tuned using the discrete mereotopological relations between ground truth and processed images. Cell count accuracy was improved using linear discriminant analysis to identify spurious noise regions for removal. The proposed cell counting technique was validated by comparing the results with a manual count of cells in images, and subsequently applied to generate growth curves for oral keratinocyte cultures supplemented with a range of concentrations of foetal calf serum. The approach developed has broad applicability and utility for researchers with standard laboratory imaging equipment. PMID- 29999528 TI - Progranulin is highly expressed in patients with chronic periodontitis and protects against experimental periodontitis in rats. AB - BACKGROUND: The autocrine growth factor progranulin (PGRN) plays a crucial role in the physiological and pathological processes. However, its function in chronic periodontitis (CP) remains unclear. METHODS: Forty-five CP patients and 43 healthy controls were recruited. Expressions of PGRN in gingival biopsies were assessed by reverse transcription-quantitative polymerase chain reaction (RT qPCR) and immunohistochemistry, respectively. The levels of PGRN, tumor necrosis factor alpha (TNF-alpha), and interleukin-1 beta (IL-1beta) in the gingival crevicular fluid (GCF) before and after non-surgical periodontal treatment were quantified by ELISA. In addition, recombinant human PGRN (rhPGRN) or its vehicle was injected into the gingiva of rats with ligature-induced experimental periodontitis to test its influence on the disease process. Local inflammatory cell infiltration and alveolar bone loss were assessed by histomorphometric analysis, and the expression levels of TNF-alpha and IL-1beta in the gingiva were determined by RT-qPCR and ELISA. RESULTS: PGRN expression was increased in the gingiva and GCF of patients with CP compared with healthy controls. With the decline of periodontal clinical indices, the molar ratio of PGRN to TNF-alpha in GCF at 1 month after non-surgical treatment was significantly higher than at baseline (35.31 +/- 22.09 vs 25.67 +/- 16.19, P < 0.01). In rats with experimental periodontitis, local administration of rhPGRN attenuated inflammatory cell infiltration (P < 0.05), inhibited alveolar bone loss (P < 0.05) and decreased TNF-alpha and IL-1beta levels (both P < 0.01) compared with the vehicle treatment group. CONCLUSION: These findings suggest that progranulin is highly expressed in the gingiva and GCF of patients with CP and protects against experimental periodontitis in rats. PMID- 29999530 TI - Liquid phase extraction and separation of natural compounds. PMID- 29999529 TI - The salivary microbiome of diabetic and non-diabetic adults with periodontal disease. AB - BACKGROUND: A comparison of the salivary microbiome of non-diabetic and diabetic cohorts having periodontal health, gingivitis and periodontitis could reveal microbial signatures unique to each group that will increase understanding of the role of oral microbiota in the pathogenesis of disease, and assist with diagnosis and risk assessment for both periodontal disease and diabetes. METHODS: A group of individuals diagnosed with type 2 diabetes (T2D) was compared with a group without T2D. For both the diabetic and non-diabetic cohorts, three subgroups were established: periodontal health, gingivitis, and periodontitis. Salivary DNA was extracted (n = 146), polymerase chain reaction was performed to amplify 16S rRNA hypervariable region V3-V4, and constructed libraries were sequenced and subjected to bioinformatic and statistical analyses. RESULTS: Microbiome analysis resulted in 88 different genus level operational taxonomic units (OTUs) for differential abundance testing. Results were largely described by two trends. Trend 1 showed OTUs that increased in abundance with increasing periodontal disease, and in diabetics relative to non-diabetics. Trend 1 OTUs comprised a mix of primarily anaerobic commensals and potential periodontopathogens. Trend 2 was driven primarily by genera that decreased in abundance in those with diabetes relative to those without diabetes, which included other anaerobes associated with periodontal disease. Overall, oral microbial diversity decreased in diabetics and increased with progression of periodontal disease compared with periodontally healthy controls. CONCLUSION: Although select microbiota increased in both diabetes and periodontal disease progression, these genera decreased in co-existing diabetes and periodontal disease. These findings suggest that the genera abundance continues to change with additional stress imposed by co existing conditions. PMID- 29999531 TI - Similarity of vocational interest profiles within families: A person-centered approach for examining associations between circumplex profiles. AB - OBJECTIVE: Our study addressed three questions concerning the similarity of vocational interests within families: (a) How similar are vocational interests of mothers and fathers? (b) How similar are vocational interests of parents and their children? (c) Is the inference about parent-child profile similarity affected by mother-father profile similarity? METHOD: Data from N=1,624 tenth graders and their parents were used to analyze interest profile similarity by means of a pseudo-coupling approach. Similarity was assessed on the level of observed profiles and model-based circumplex profiles. RESULTS: Interest profiles of mother-father and parent-child dyads were more similar to each other than those of corresponding arbitrarily paired dyads. However, when the similarity between the parents' interest profiles was accounted for, only same-sex parent child dyads were more similar to each other than would be expected by chance. All findings were mirrored on the level of observed profiles and model-based circumplex profiles. CONCLUSIONS: In sum, our findings support the validity of the circumplex model of vocational interests and emphasize the benefits of explicitly considering its implications when analyzing profile similarity. Moreover, we were able to show that the statistical evaluation of profile similarities must account for normative profile components. PMID- 29999532 TI - Coping trajectories in emerging adulthood: The influence of temperament and gender. AB - OBJECTIVE: The study of coping has far-reaching implications for understanding psychopathology and resilience, as well as for the treatment of psychological disorders. Developmental work has examined how the ability to cope changes across time in children and adolescents; however, work in emerging adulthood is still lacking. Coping is thought to emerge from basic biological and psychological processes, such as temperament and gender, which may influence the trajectory of coping use over time. METHOD: Using a sample of college students (N = 1,000), our 4-year longitudinal study with yearly assessments sought to (a) examine the trajectory of coping styles in emerging adulthood and to (b) examine the influence of temperament and gender on these coping trajectories. RESULTS: Our findings suggest that young adults' use of avoidance strategies decreased slightly over college, whereas the use of approach strategies and social support seeking remained stable. Temperament (BIS/BAS) and gender were related to certain coping styles at baseline and appeared to have an influence on some of these trajectories over time, though these associations were complex. CONCLUSIONS: This work may inform intervention research attempting to promote adaptive coping because it may help identify young adults most in need of such interventions. PMID- 29999533 TI - Engineered GH11 xylanases from Orpinomyces sp. PC-2 improve techno-functional properties of bread dough. AB - BACKGROUND: Endo-1,4-beta-xylanases have marked hydrolytic activity towards arabinoxylans. Xylanases (xynA) produced by the anaerobic fungus Orpinomyces sp. strain PC-2 have been shown to be superior in specific activity, which strongly suggests their applicability in the bakery industry for the processing of whole wheat flour containing xylans. In the present study, two xylanases from this source, the small wild-type xylanase SWT and the small mutant xylanase SM2 (V108A, A199T), were expressed in Escherichia coli, purified, characterized, tested for their ability to hydrolyze whole-wheat flour and applied in dough processing. RESULTS: Both purified SM2 and SWT showed high specific activity against oat spelt xylan and wheat arabinoxylan, exhibiting maximum activity at pH 3-7 and 60 degrees C. SM2 was more thermostable than SWT, which suggests that the mutations enhanced its stability. Both SWT and SM2 were able to hydrolyze whole-wheat flour, and evaluation of their applicability in dough processing by the sponge method indicated that use of these enzymes increased dough volume by 60% and reduced texture hardness by more than 50%, while gumminess and chewiness were reduced by 40%. CONCLUSION: The recombinant xylanases showed potential for application in bakery processing and can improve techno-functional properties in sponges. (c) 2018 Society of Chemical Industry. PMID- 29999534 TI - Integrating whole trait theory and self-determination theory. AB - We explore and explicate some promising points of integration between self determination theory (SDT) and whole trait theory (WTT). Integrating SDT and WTT can offer an example for navigating challenges that have long confronted integrating trait-descriptive and motivational-explanatory views of personality. We review SDT and WTT in turn. The review of SDT is organized around the emergence of its six mini-theories. The review of WTT will introduce the descriptive and explanatory elements as aspects of whole traits, and it will also provide a functional view of traits as tools for goal pursuit. For integrating the two, we point out the many instances in which SDT motivational concepts are interpretive or goal activation processes that act as intermediaries between the inputs and outputs WTT describes. Because WTT has focused on outputs as trait manifestations, we can begin to link SDT's need satisfaction processes to traits and their manifestations. This integration leads to a key proposition that traits are tools for satisfying basic psychological needs; basic psychological needs can (partially) explain traits. This then paves the way to novel research questions. PMID- 29999535 TI - Uniconazole and diethyl aminoethyl hexanoate increase soybean pod setting and yield by regulating sucrose and starch content. AB - BACKGROUND: Uniconazole (S3307) and diethyl aminoethyl hexanoate (DA-6) are known plant growth regulators (PGRs). However, it is unknown if their regulation of sucrose and starch content can affect pod setting and yield in soybean. Herein, S3307 and DA-6 were foliar sprayed on soybean Hefeng50 and Kangxian6 at the beginning of the bloom cycle in field tests conducted over two years. RESULTS: PGRs promoted the accumulation and distribution of plant biomass and significantly improved leaf photosynthetic rates. Sucrose and starch content increased after PGR treatment across organs and varieties. Accumulation and allocation of sucrose and starch content in soybean source organs are enhanced by PGRs, which supply high levels of assimilate to sink organs. Moreover, sucrose and starch contents in source and sink organs are positively correlated. S3307 and DA-6 also significantly increased pod setting rates and reduced flower and pod abscission rates, leading to increased yield. CONCLUSION: S3307 and DA-6 promoted the accumulation and availability of sucrose and starch content in source organs and increased sucrose and starch content in flowers and pods or seeds, thereby maintaining the balance between source and sink organs and contributing to increased pod setting rates and soybean yield. (c) 2018 Society of Chemical Industry. PMID- 29999536 TI - Nanoencapsulation of carotenoids extracted from tomato peels into zein fibers by electrospinning. AB - BACKGROUND: The processing of tomatoes generates significant amounts of tomato waste, which has a high potential to be used in food industry as a natural food colorant, antioxidant, and food supplement providing health benefits. However, it is difficult to incorporate the carotenoids into different food formulations because they are relatively unstable in food systems. Hence, this novel study investigated the use of an electrospinning technique for the encapsulation of carotenoids extracted from tomato peel into zein nanofibers to improve its thermal and storage stability, and antioxidant activity. RESULTS: Composite zein nanofibers containing the carotenoids extracted from tomato peel (TP) were successfully produced with above 90% encapsulation efficiency by electrospinning. Scanning electron microscope (SEM) analysis revealed that the extract-loaded fibers exhibited morphology similar to the neat zein fibers with a bead-free, smooth, and homogeneously-distributed morphology. Differential scanning calorimetry (DSC) thermograms showed that the thermal stability of the extract was enhanced by nanoencapsulation. No significant changes in the Fourier transform infrared (FTIR) spectra of extract-loaded zein fibers were observed compared to neat zein fiber, showing that the TP extract could be entrapped into the zein fibers. Compared to non-encapsulated extract, the encapsulated one inside zein fibers had better retention of lycopene and antioxidant activity (AA) during 14-days' storage. More interestingly, the AA of the extract increased about 11-fold by nanoencapsulation. CONCLUSION: This study showed that nanoencapsulation by electrospinning is an effective way to stabilize carotenoids, which is promising for their use in food processing. (c) 2018 Society of Chemical Industry. PMID- 29999537 TI - How does meaning in life predict proactive coping? The self-regulatory mechanism on emotion and cognition. AB - OBJECTIVE: This study examined the effectiveness of a photographic intervention method on meaning in life (MIL) and further investigated the self-regulatory mechanism responsible for the effect of MIL in the promotion of proactive coping. METHOD: Participants were 145 Chinese adults (Mage = 27.82; 71.3% female), who were randomly assigned into one of three conditions: An intervention (taking photos and writing expressively), a taking-photos-only control, or an assessment only control. MIL, positive affect, future temporal focus, and proactive coping were measured before and after the intervention, with follow-up assessments conducted 1 week and 1 month later. Additionally, daily assessments were conducted during the intervention week. RESULTS: MIL improved daily in the intervention condition, an effect that was also found post-intervention and at follow-up. Significant increases in positive affect, future temporal focus, and proactive coping were also observed after the intervention. Hierarchical linear modeling demonstrated that daily MIL positively predicted daily future temporal focus and positive affect. Furthermore, longitudinal mediation analysis confirmed that future temporal focus and positive affect mediated the relationship between MIL and proactive coping. CONCLUSIONS: MIL's self-regulatory mechanism is reflected in both cognitive (future temporal focus) and emotional (positive affect) dimensions, which promotes proactive coping with future stressors. PMID- 29999538 TI - Acquired cyclic neutropenia associated with cocaine-induced anti-neutrophil cytoplasmic antibodies binding to human neutrophil elastase. PMID- 29999539 TI - Synthesis of three triterpene series and their activity against respiratory syncytial virus. AB - The human respiratory syncytial virus (hRSV) is a leading cause of hospitalization due to acute lower respiratory infection especially in infants and young children, sometimes causing fatal cases. The monoclonal antibody palivizumab is one of the available options for preventing this virus, and at the moment there are several hRSV vaccine trials underway. Unfortunately, the only drug option to treat hRSV infection is ribavirin, which can be used in severe high-risk cases. For this reason, new medicines are needed and, in this context, the triterpenes and their derivatives are promising alternatives, since many of them have shown important antiviral activity, such as bevirimat. Therefore, we report three series of triterpene (betulin (BE), betulinic acid (BA), and ursolic acid (UA)) derivatives tested against hRSV. The derivatives were synthesized by using commercial anhydrides in an easy and inexpensive step reaction. For the antiviral assay, A549 cells were infected by hRSV and after 96 h of compound or ribavirin (positive control) treatment, the cell viability was tested by MTT assay. DMSO, non-infected cells and infected cells without treatment were used as negative control. The triterpene esterification at the hydroxyl group resulted in 17 derivatives. The 3,28-di-O-acetylbetulin derivative (1a) showed the best results for cell viability, and real-time PCR amplification was performed for 1a treatment. Remarkably, one new anti-hRSV prototype was obtained through an easy synthesis of BE, which shall represent an alternative for a new lead compound for anti-hRSV therapy. PMID- 29999540 TI - Effects of the prebiotic mannan oligosaccharide on the experimental periodontitis in rats. AB - AIM: To evaluate the effect of the prebiotic (PREB) mannan oligosaccharide (MOS) on the progression of the experimental periodontitis (EP) and intestinal morphology in rats. MATERIALS AND METHODS: Forty rats were randomly allocated into groups (n = 10): C (control), PREB, EP and EP-PREB. Groups PREB and EP-PREB received MOS incorporated into the feed daily. After 30 days, groups EP and EP PREB received a cotton ligature around their mandibular first molars, kept for 14 days. Morphometrical, histomorphometrical, microcomputed tomography, gene expression analyses and immunohistochemistry were performed. Data were statistically analysed (p < 0.05). RESULTS: Group EP-PREB showed less interproximal bone loss, area without bone in the furcation and bone porosity, and greater bone mineral density than group EP (p < 0.05). It was also observed a significant decrease in IL-10 and IFN-gamma gene expression, besides a decrease in TNF-alpha and IL-1beta and an increase in TGF-beta immunolabeling score for group EP-PREB. Group EP-PREB also presented villous height and crept depth values similar to group C, while group EP presented reduced values (p < 0.05). CONCLUSION: It can be concluded that the oral administration of MOS promotes a protective effect against alveolar bone loss caused by EP in rats, modifying histologic and immune-inflammatory parameters, in addition to protecting the intestine. PMID- 29999541 TI - Overground endoscopic findings and respiratory sound analysis in horses with recurrent laryngeal neuropathy after unilateral laser ventriculocordectomy. AB - BACKGROUND: Unilateral ventriculocordectomy (VeC) is frequently performed, yet objective studies in horses with naturally occurring recurrent laryngeal neuropathy (RLN) are few. OBJECTIVES: To evaluate respiratory noise and exercising overground endoscopy in horses with grade B and C laryngeal function, before and after unilateral laser VeC. STUDY DESIGN: Prospective study in clinically affected client-owned horses. METHODS: Exercising endoscopy was performed and concurrent respiratory noise was recorded. A left-sided laser VeC was performed under standing sedation. Owners were asked to present the horse for re-examination 6-8 weeks post-operatively when exercising endoscopy and sound recordings were repeated. Exercising endoscopic findings were recorded, including the degree of arytenoid stability. Quantitative measurement of left-to-right quotient angle ratio (LRQ) and rima glottidis area ratio (RGA) were performed pre and post-operatively. Sound analysis was performed, and measurements of the energy change in F1, F2 and F3 formants between pre- and post-operative recordings were made and statistically analysed. RESULTS: Three grade B and seven grade C horses were included; 6/7grade C horses preoperatively had bilateral vocal fold collapse (VFC) and 5/7 had mild right-sided medial deviation of the ary-epiglottic fold (MDAF). Right VFC and MDAF was still present in these horses post-operatively; grade B horses had no other endoscopic dynamic abnormalities post-operatively. Sound analysis showed significant reduction in energy in formant F2 (P = 0.05) after surgery. MAIN LIMITATIONS: The study sample size was small and multiple dynamic abnormalities made sound analysis challenging. CONCLUSIONS: RLN-affected horses have reduction in sound levels in F2 after unilateral laser VeC. Continuing noise may be caused by other ongoing forms of dynamic obstruction in grade C horses. Unilateral VeC is useful for grade B horses based on endoscopic images. In grade C horses, bilateral VeC, right ary epiglottic fold resection +/- laryngoplasty might be a better option than unilateral VeC alone. The Summary is available in Portuguese - see Supporting Information. PMID- 29999542 TI - Verification of the Heska Element Point-of-Care blood gas instrument for use with venous blood from alpacas and llamas, with determination of reference intervals. AB - BACKGROUND: The Heska Element POC ("EPOC") is a blood gas instrument intended for use with canine, feline, and equine whole blood; no verification for use with camelid specimens has been reported. OBJECTIVES: Using camelid specimens and commercial quality control materials (QCM), we investigatee EPOC analytical performance and establish EPOC camelid reference intervals (RIs). METHODS: Camelid blood (n = 124) was analyzed using the EPOC (pH, pCO2 , pO2 , HCO3 , base excess, SO2 , sodium, potassium, chloride, ionized calcium, TCO2 , anion gap, HCT, HGB, glucose, lactate, and creatinine); plasma was analyzed using a Roche Cobas c501 (sodium, potassium, chloride, TCO2 , anion gap, glucose, and creatinine). Method comparison data were assessed using Pearson's correlation, Passing-Bablok regression, and Bland-Altman plots. EPOC precision was evaluated using QCM and camelid blood. RESULTS: For all measurands except anion gap, the EPOC vs Cobas instrument correlation was r > .85. Except for pO2 and pCO2 , EPOC precision (QCM and blood) ranged from a repeatability CV <1%-6.3%. Mild constant bias for chloride, glucose, TCO2 , anion gap, and creatinine, and mild proportional bias for chloride, glucose, and anion gap were present. The total error (QCM data) for the EPOC instrument was below the ASVCP-recommended allowable total error. Alpacas had higher potassium and lactate, while llamas had higher creatinine, sodium, chloride, ionized calcium, pO2 , and SO2 . Statistical RIs based on alpaca (n = 74-96) and llama data (n = 12-17) are reported descriptively. CONCLUSIONS: The EPOC analyzer shows good performance with camelid blood. A lack of complete agreement with automated chemistry analyzers highlights the importance of interpreting patient data using instrument-specific RIs. PMID- 29999543 TI - Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses. AB - Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye, with a higher incidence documented in Haflinger horses. Recently, a missense variant in the gene damage specific DNA binding protein 2 (DDB2, p.Thr338Met) on ECA12 was identified as a risk factor for the development of limbal SCC in Haflinger horses. SCC also occurs on the nictitating membrane; therefore, investigating the role of this missense variant in nictitating membrane SCC is warranted. In this study, a common ancestor was identified among Haflinger horses affected with limbal SCC or with nictitating membrane SCC, thus supporting a recessive risk factor for the development of cancer at both ocular locations. Analysis of genotype data from Haflinger horses with and without nictitating membrane SCC revealed that the same region on ECA12 associated with limbal SCC was also associated with nictitating membrane SCC (P < 2.04 * 10-5 ). Fine mapping of this locus using 25 cases and 49 controls supported the hypothesis that DDB2:c.1013C>T, p.Thr338Met, is a risk factor for nictitating membrane SCC, as 88% of our cases were homozygous for this variant and no other polymorphism was more strongly associated (P = 4.13 * 10-14 ). These data indicate that the genetic risk is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses and validates utilization of genetic testing of the DDB2 variant for both clinical management and the guidance of mating decisions. PMID- 29999544 TI - Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. AB - In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead. PMID- 29999545 TI - The role of IL-20 in chronic kidney disease and diabetic nephropathy: Pathogenic and therapeutic implications. AB - Chronic kidney disease and its complications are a major public health problem worldwide. Diabetic nephropathy has become the main contributing cause of terminal renal failure. There are now evidences that different inflammatory molecules, including proinflammatory cytokines, play a critical role in the development of microvascular diabetic complications, including nephropathy. IL-20 is emerging as a potent angiogenic, chemotactic, and proinflammatory cytokine related to several chronic inflammatory disorders likes psoriasis, atherosclerosis, and renal failure. This review discusses the role of IL-20 as a pathogenic factor in renal injury, focusing on chronic kidney disease and diabetic nephropathy, and describes potential treatment strategies based on modulation of IL-20's function. PMID- 29999546 TI - Long-term reprogramming of the innate immune system. AB - During the last few years, a growing body of evidence has shown that immunological memory is not an exclusive trait of lymphocytes, as many inflammatory insults can alter the functionality and the responsiveness of the innate immune system in the long term. Innate immune cells, such as monocytes, macrophages, dendritic cells, and NK cells can be influenced by the encounters with inflammatory stimuli, undergoing functional reprogramming and developing changed responses to subsequent chellenges. The long-term reprogramming depends on the rewiring of cell metabolism and epigenetic processes, and they stay at the basis of induction of both innate immune memory (also termed trained immunity) and innate immune tolerance. Here, we review the central role that the effects of this long-term reprogramming of innate immune cells plays in a number of clinically relevant conditions such as vaccination, atherosclerosis, sepsis, and cancer. PMID- 29999547 TI - Known Unknowns of Mammalian Mitochondrial DNA Maintenance. AB - Mammalian mitochondrial DNA (mtDNA) replication and repair have been studied intensively for the last 50 years. Although recently advances in elucidating the molecular mechanisms of mtDNA maintenance and the proteins involved in these have been made, there are disturbing gaps between the existing theoretical models and experimental observations. Conflicting data and hypotheses exist about the role of RNA and ribonucleotides in mtDNA replication, but also about the priming of replication and the formation of pathological rearrangements. In the presented review, we have attempted to match these loose ends and draft consensus where it can be found, while identifying outstanding issues for future research. PMID- 29999548 TI - Computational fluid dynamics predictions of non-isothermal ventilation flow-How can the user factor be minimized? AB - The use of computational fluid dynamics (CFD) to solve indoor airflow problems has increased tremendously in the last decades. However, the accuracy of CFD simulations depends greatly on user experience, the available validation data, and the effort made to verify solutions. This study presents the results of a conference workshop, which assessed user influence on the CFD results obtained for a generic non-isothermal flow problem; ie, a backward-facing step flow problem with a heated wall below the supply. Fifty-five simulation sets were submitted by 32 teams. The results showed a very large spread in predicted penetration length (xre /(H - h)), location of maximum velocity in the lower part of the recirculation cell (xrm /(H - h)), and maximum velocity at this location (urm /u0 ). The turbulence model seemed to very strongly influence the results, with a statistically significant difference in the predictions yielded by the k epsilon and k-omega models. The results obtained using a single turbulence model generally also showed a spread in results; the level of spread depended on factors such as grid size and near-wall treatment. The statistical data strongly indicate the need for validation studies using experimental data (benchmarks) to ensure the accuracy, reliability, and trustworthiness of CFD simulations for indoor airflow problems. PMID- 29999549 TI - Cardiovascular autonomic neuropathy and bone metabolism in Type 1 diabetes. AB - AIM: To investigate the association between cardiovascular autonomic neuropathy and bone metabolism in people with Type 1 diabetes. METHODS: We assessed cardiovascular autonomic neuropathy in 329 people with Type 1 diabetes according to heart rate response to deep breathing, to standing and to the Valsalva manoeuvre, and 2-min resting heart rate. More than one pathological non-resting test was defined as cardiovascular autonomic neuropathy. Bone mineral density of the femoral neck (BMDfn) was assessed by dual energy X-ray absorptiometry. Serum parathyroid hormone levels and other bone markers were measured. RESULTS: The mean (sd) age of the participants was 55.6 (9.4) years, 52% were men, and the mean (sd) diabetes duration was 40 (8.9) years, HbA1c 62 (9) mmol/mol and estimated GFR 78 (26) ml/min/1.73m2 . In all, 36% had cardiovascular autonomic neuropathy. Participants with cardiovascular autonomic neuropathy had 4.2% (95% CI -8.0 to -0.2; P=0.038) lower BMDfn and 33.6% (95% CI 14.3 to 53.8; P=0.0002) higher parathyroid hormone levels compared with participants without cardiovascular autonomic neuropathy in adjusted models. Higher resting heart rate remained associated with higher parathyroid hormone level and lower BMDfn after additional adjustment for eGFR (P<0.0001 and P = 0.042, respectively). CONCLUSIONS: The presence of cardiovascular autonomic neuropathy was associated with reduced BMDfn and increased levels of parathyroid hormone. Kidney function may either confound or mediate these findings. Cardiovascular autonomic neuropathy could be associated with increased risk of osteoporosis in Type 1 diabetes. Whether cardiovascular autonomic neuropathy directly affects bone metabolism detrimentally or if this association is mediated via decreased kidney function should be investigated further. PMID- 29999550 TI - Why do the public support or oppose obesity prevention regulations? Results from a South Australian population survey. AB - ISSUE ADDRESSED: Australian policymakers have acknowledged that implementing obesity prevention regulations is likely to be facilitated or hindered by public opinion. Accordingly, we investigated public views about possible regulations. METHODS: Cross-sectional survey of 2732 persons, designed to be representative of South Australians aged 15 years and over. Questions examined views about four obesity prevention regulations (mandatory front-of-pack nutrition labelling for packaged foods; zoning restrictions to prohibit fast food outlets near schools; taxes on unhealthy high fat foods; and taxes on sugar-sweetened beverages). Levels of support (Likert scale) for each intervention and reasons for support/opposition were ascertained. RESULTS: Views about the regulations were mixed: support was highest for mandatory nutrition labelling (90%) and lowest for taxes (40%-42%). High levels of support for labelling were generally underpinned by a belief that this regulation would educate "Other" people about nutrition. Lower levels of support for zoning restrictions and taxes were associated with concerns about government overreach and the questionable effectiveness of these regulations in changing behaviours. Levels of support for each regulation, and reasons for support or opposition, differed by gender and socioeconomic status. CONCLUSIONS: Sociodemographic differences in support appeared to reflect gendered responsibilities for food provision and concerns about the material constraints of socioeconomic deprivation. Engagement with target populations may offer insights to optimise the acceptability of regulations and minimise unintended social consequences. SO WHAT?: Resistance to regulations amongst socioeconomically disadvantaged target populations warrants attention from public health advocates. Failure to accommodate concerns identified may further marginalise these groups. PMID- 29999551 TI - Configurational Analysis by Residual Dipolar Coupling Driven Floating Chirality Distance Geometry Calculations. AB - A new method implemented into a computer program (ConArch+ ) has been developed and applied to demonstrate the successful implementation of residual dipolar couplings (RDCs) in distance geometry (DG) calculations for the configurational assignment of chiral compounds. Unlike established protocols, the new approach combines floating chirality (fc) in 4D- and 3D-distance bounds driven dynamics (DDD) calculations with structural information from RDCs. Thus, relative configurations of chiral compounds were generated only by observables (e.g., NOEs, RDCs) rendering tedious evaluations of calculated structures against RDCs obsolete. We demonstrate the potential of this novel procedure by the simultaneous determination of the configuration and the conformation of three natural products, (-)-isopinocampheol (1), tubocurarine (2), and vincristine (3), as well as for diisopropylidene-beta-d-fructopyranose (4). PMID- 29999552 TI - Regulation and functions of MicroRNA-149 in human cancers. AB - MicroRNAs are small non-coding RNAs that play critical roles in the regulatory mechanisms involving cell differentiation, proliferation, apoptosis and tumorigenesis. Recent research efforts have been conducted to apply these discoveries into clinical functions, including the early diagnosis and therapeutic outcome of patients with cancer. Previous studies have shown that microRNA-149 (miR-149) is dysregulated in various human cancers and exerts its effects on tumorigenesis and tumour progression. In this review, we summarized the potential roles of miR-149 dysregulation and its target genes during tumorigenesis and clinical treatment of human cancers. PMID- 29999553 TI - Covalency and Ionicity Do Not Oppose Each Other-Relationship Between Si-O Bond Character and Basicity of Siloxanes. AB - Covalency and ionicity are orthogonal rather than antipodal concepts. We demonstrate for the case of siloxane systems [R3 Si-(O-SiR2 )n -O-SiR3 ] that both covalency and ionicity of the Si-O bonds impact on the basicity of the Si-O Si linkage. The relationship between the siloxane basicity and the Si-O bond character has been under debate since previous studies have presented conflicting explanations. It has been shown with natural bond orbital methods that increased hyperconjugative interactions of LP(O)->sigma*(Si-R) type, that is, increased orbital overlap and hence covalency, are responsible for the low siloxane basicity at large Si-O-Si angles. On the other hand, increased ionicity towards larger Si-O-Si angles has been revealed with real-space bonding indicators. To resolve this ostensible contradiction, we perform a complementary bonding analysis, which combines orbital-space, real-space, and bond-index considerations. We analyze the isolated disiloxane molecule H3 SiOSiH3 with varying Si-O-Si angles, and n-membered cyclic siloxane systems Si2 H4 O(CH2 )n-3 . All methods from quite different realms show that both covalent and ionic interactions increase simultaneously towards larger Si-O-Si angles. In addition, we present highly accurate absolute hydrogen-bond interaction energies of the investigated siloxane molecules with water and silanol as donors. It is found that intermolecular hydrogen bonding is significant at small Si-O-Si angles and weakens as the Si-O-Si angle increases until no stable hydrogen-bond complexes are obtained beyond phiSiOSi =168 degrees , angles typically displayed by minerals or polymers. The maximum hydrogen-bond interaction energy, which is obtained at an angle of 105 degrees , is 11.05 kJ mol-1 for the siloxane-water complex and 18.40 kJ mol-1 for the siloxane-silanol complex. PMID- 29999554 TI - Effect of microgravity on proliferation and differentiation of embryonic stem cells in an automated culturing system during the TZ-1 space mission. AB - OBJECTIVE: Despite a great number of studies analysing the effects of microgravity on stem cell proliferation and differentiation, few of them have focused on real-time imaging estimates in space. Herein, we utilized the TZ-1 cargo spacecraft, automatic cell culture equipment and live cell imaging techniques to examine the effects of real microgravity on the proliferation and differentiation of mouse embryonic stem cells (mESCs). MATERIALS AND METHODS: Oct4-GFP, Brachyury-GFP mESC and Oct4-GFP mESC-derived EBs were used as experimental samples in the TZ-1 spaceflight mission. These samples were seeded into chambers, cultured in an automatic cell culture device and were transported into space during the TZ-1 mission. Over 15 days of spaceflight, bright field and fluorescent images of cell growth were taken in micrography, and the medium was changed every day. Real-time image data were transferred to the ground for analysis. RESULTS: Space microgravity maintains stemness and long-term survival of mESCs, promising 3D aggregate formation. Although microgravity did not significantly prevent the migration of EBs on the ECM substrate, it did prevent terminal differentiation of cells. CONCLUSIONS: This study demonstrates that space microgravity might play a potential role in supporting 3D cell growth and maintenance of stemness in embryonic stem cells, while it may negatively affect terminal differentiation. PMID- 29999555 TI - Injectable Enzymatically Cross-linked Hydrogels with Light-Controlled Degradation Profile. AB - An advanced hydrogel that features facile formation and injectability as well as light-controlled degradation profile is reported here. By modifying 4-arm poly(ethylene glycol) (4-arm PEG) with 2-nitrobenzyl (NB) and phenol, the 4-arm PEG precursor solutions could form enzymatically cross-linked hydrogels in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2 O2 ). The gelation time, mechanical strength, and porous structure could be simply tuned by the concentration of HRP and H2 O2 . Moreover, the hydrogels underwent controlled degradation under UV light irradiation via photo-cleavage reaction of the NB ester bond. The hydrogels exhibited negligible cytotoxicity toward mouse fibroblast L929 cells in vitro and can be manipulated through injection in vivo. PMID- 29999556 TI - Carborane-BODIPY Dyads: New Photoluminescent Materials through an Efficient Heck Coupling. AB - A small library of carborane-BODIPY/aza-BODIPY dyads were efficiently synthesized by means of a novel convergent synthetic approach, the key step of which is a Pd catalyzed Heck coupling reaction. The structural characterization and photoluminescence properties of the newly synthesized dyads were evaluated. The presence of the carborane did not significantly alter the photophysical patterns of the BODIPY or aza-BODIPY in the final fluorophores, but it produced a decrease of the emission fluorescent quantum yields that was in the range from 1.4 % for aza-BODIPY to 48 % for BODIPY-dyads. The carborane-BODIPY dyads were successfully incorporated into cells, especially compounds 2, 4 and 13, demonstrating their cytoplasmic localization. The fluorescent and biocompatibility properties make these compounds good candidates for in vitro cell tracking. PMID- 29999558 TI - Heparin-Mimicking Sulfonated Polymer Nanoparticles via RAFT Polymerization Induced Self-Assembly. AB - Heparin plays a significant role in wound healing and tissue regeneration applications, through stabilization of fibroblast growth factors (FGF). Risks associated with batch-to-batch variability and contamination from its biological sources have led to the development of synthetic, highly sulfonated polymers as promising heparin mimics. In this work, a systematic study of an aqueous polymerization-induced self-assembly (PISA) of styrene from poly(2-acrylamido-2 methylpropane sodium sulfonate) (P(AMPS)) macro reversible addition-fragmentation chain transfer (macro-RAFT) agents produced a variety of spherical heparin mimicking nanoparticles, which were further characterized with light scattering and electron microscopy techniques. None of the nanoparticles tested showed toxicity against mammalian cells; however, significant hemolytic activity was observed. Nonetheless, the heparin-mimicking nanoparticles outperformed both heparin and linear P(AMPS) in cellular proliferation assays, suggesting increased bFGF stabilization efficiencies, possibly due to the high density of sulfonated moieties at the particle surface. PMID- 29999557 TI - Comprehensive molecular profiling of the B7 family in gastrointestinal cancer. AB - OBJECTIVES: B7 family has been identified as co-stimulatory or co-inhibitory molecules on T-cell response and plays an important role in tumour mortality and malignancy. In this study, the expression pattern of B7 family in gastrointestinal (GI) cancer was examined. Its upstream regulating mechanism, downstream targets and association with clinical parameters were also studied. MATERIALS AND METHODS: The expression level of B7 members was analysed by FIREHOUSE. The gene mutation, DNA methylation, association with clinical parameters and downstream network of B7 members were analysed in cBioportal. The mutation frequency was analysed by Catalogue of Somatic Mutations in Cancer (COSMIC) analysis. The phylogenetic tree was constructed in MEGA7. The interaction protein domain analysis was performed by Pfam 31.0. RESULTS: Differential expression of B7 family molecules was detected in different kinds of GI cancer. High-frequency gene alteration was found in tumour samples. There was negative correlation of promoter methylation and mRNA expression of B7 family members in tumour samples, suggesting the epigenetic basis of B7 family gene deregulation in GI cancer. The overexpression of B7-H1 in pancreatic cancer, B7 H5 in oesophageal cancer and B7-H6 in liver cancer were significantly associated with worse overall survival. Finally, by network analysis, we identified some potential interacting proteins for B7-1/2 and B7-H1/DC. CONCLUSIONS: Overall, our study suggested that B7 member deregulation was strongly involved in GI cancer tumorigenesis. PMID- 29999559 TI - Responsive Assembly of Upconversion Nanoparticles for pH-Activated and Near Infrared-Triggered Photodynamic Therapy of Deep Tumors. AB - Upconversion nanoparticle (UCNP)-mediated photodynamic therapy has shown great effectiveness in increasing the tissue-penetration depth of light to combat deep seated tumors. However, the inevitable phototoxicity to normal tissues resulting from the lack of tumor selectivity remains as a major challenge. Here, the development of tumor-pH-sensitive photodynamic nanoagents (PPNs) comprised of self-assembled photosensitizers grafted pH-responsive polymeric ligands and UCNPs is reported. Under neutral pH conditions, photosensitizers aggregated in the PPNs are self-quenched; however, upon entry into a tumor microenvironment with lower pH, the PPNs not only exhibit enhanced tumor-cell internalization due to charge reversal but also are further disassembled into well-dispersed nanoparticles in the endo/lysosomes of tumor cells, enabling the efficient activation of photosensitizers. The results demonstrate the attractive properties of both UCNP mediated deep-tissue penetration of light and high therapeutic selectivity in vitro and in vivo. PMID- 29999560 TI - Understanding the recruitment response of juvenile Neotropical trees to logging intensity using functional traits. AB - Selective logging remains a widespread practice in tropical forests, yet the long term effects of timber harvest on juvenile tree (i.e., sapling) recruitment across the hundreds of species occurring in most tropical forests remain difficult to predict. This uncertainty could potentially exacerbate threats to some of the thousands of timber-valuable tree species in the Amazon. Our objective was to determine to what extent long-term responses of tree species regeneration in logged forests can be explained by their functional traits. We integrate functional trait data for 13 leaf, stem, and seed traits from 25 canopy tree species with a range of life histories, such as the pioneer Goupia glabra and the shade-tolerant Iryanthera hostmannii, together with over 30 yr of sapling monitoring in permanent plots spanning a gradient of harvest intensity at the Paracou Forest Disturbance Experiment (PFDE), French Guiana. We anticipated that more intensive logging would increase recruitment of pioneer species with higher specific leaf area, lower wood densities, and smaller seeds, due to the removal of canopy trees. We define a recruitment response metric to compare sapling regeneration to timber harvest intensity across species. Although not statistically significant, sapling recruitment decreased with logging intensity for eight of 23 species and these species tended to have large seeds and dense wood. A generalized linear mixed model fit using specific leaf area, seed mass, and twig density data explained about 45% of the variability in sapling dynamics. Effects of specific leaf area outweighed those of seed mass and wood density in explaining recruitment dynamics of the sapling community in response to increasing logging intensity. The most intense treatment at the PFDE, which includes stand thinning of non-timber-valuable adult trees and poison-girdling for competitive release, showed evidence of shifting community composition in sapling regeneration at the 30-yr mark, toward species with less dense wood, lighter seeds, and higher specific leaf area. Our results indicate that high intensity logging can have lasting effects on stand regeneration dynamics and that functional traits can help simplify general trends of sapling recruitment for highly diverse logged tropical forests. PMID- 29999561 TI - Visual integration of objects and scenes increases recollection-based responding despite differential MTL recruitment in young and older adults. AB - Unitization, the process of encoding previously independent units as one coherent representation, improves associative memory in both young and older adults, or in some cases, differentially benefits older adults. Unitization of verbal associative pairs may reduce reliance on the hippocampus (HC) for successful encoding and recognition by shifting to familiarity-based processing mediated by perirhinal cortex (PRC). However, this shift was not observed in a recent study of visual associative memory, with equivalent activation in HC and PRC during encoding of visually integrated (unitized) and nonintegrated object and scene pairs. Furthermore, behavioral findings from this study suggested an increase in recollection rather than familiarity during recognition of visually integrated pairs. The present study extends our previous work by focusing on the influence of visual integration on fMRI activation during associative recognition, rather than encoding and these patterns between young and older adults. In contrast to our findings from encoding, visual integration reduced HC and PRC activation during retrieval of object and scene associative pairs across both age groups. However, visual integration increased the correlation between bilateral HC and left parahippocampal (PHC) activation and behavioral performance among older adults, consistent with an increased reliance on recollection. In contrast, visual integration reduced the correlation between HC activation and behavioral performance in young adults, more consistent with findings from the verbal unitization literature. Taken together, these results suggest that associative memory for visually integrated pairs may involve differential recruitment of medial temporal regions in young and older adults. PMID- 29999562 TI - A mid-century ecological forecast with partitioned uncertainty predicts increases in loblolly pine forest productivity. AB - Ecological forecasting of forest productivity involves integrating observations into a process-based model and propagating the dominant components of uncertainty to generate probability distributions for future states and fluxes. Here, we develop a forecast for the biomass change in loblolly pine (Pinus taeda) forests of the southeastern United States and evaluate the relative contribution of different forms of uncertainty to the total forecast uncertainty. Specifically, we assimilated observations of carbon and flux stocks and fluxes from sites across the region, including global change experiments, into a forest ecosystem model to calibrate the parameter distributions and estimate the process uncertainty (i.e., model structure uncertainty revealed in the residuals of the calibration). Using this calibration, we forecasted the change in biomass within each 12-digit Hydrologic (H12) unit across the native range of loblolly pine between 2010 and 2055 under the Representative Concentration Pathway 8.5 scenario. Averaged across the region, productivity is predicted to increase by a mean of 31% between 2010 and 2055 with an average forecast 95% quantile interval of +/-15 percentage units. The largest increases were predicted in cooler locations, corresponding to the largest projected changes in temperature. The forecasted mean change varied considerably among the H12 units (3-80% productivity increase), but only units in the warmest and driest extents of the loblolly pine range had forecast distributions with probabilities of a decline in productivity that exceeded 5%. By isolating the individual components of the forecast uncertainty, we found that ecosystem model process uncertainty made the largest individual contribution. Ecosystem model parameter and climate model uncertainty had similar contributions to the overall forecast uncertainty, but with differing spatial patterns across the study region. The probabilistic framework developed here could be modified to include additional sources of uncertainty, including changes due to fire, insects, and pests: processes that would result in lower productivity changes than forecasted here. Overall, this study presents an ecological forecast at the ecosystem management scale so that land managers can explicitly account for uncertainty in decision analysis. Furthermore, it highlights that future work should focus on quantifying, propagating, and reducing ecosystem model process uncertainty. PMID- 29999563 TI - Facebow Use in Clinical Prosthodontic Practice. AB - The use of a dental facebow in diagnosis and treatment by the restorative dentist has been controversial in recent years. Digital alternatives have been proposed and hold promise for the future; however, the traditional facebow still has practicality in a modern restorative practice. The purpose of this paper is to review facebow use in clinical prosthodontic practice. PMID- 29999564 TI - Herbivore-induced rice resistance against rice blast mediated by salicylic acid. AB - In agro-ecosystems, plants are important mediators of interactions between their associated herbivorous insects and microbes, and any change in plants induced by one species may lead to cascading effects on interactions with other species. Often, such effects are regulated by phytohormones such as jasmonic acid (JA) and salicylic acid (SA). Here, we investigated the tripartite interactions among rice plants, three insect herbivores (Chilo suppressalis, Cnaphalocrocis medinalis or Nilaparvata lugens), and the causal agent of rice blast disease, the fungus Magnaporthe oryzae. We found that pre-infestation of rice by C. suppressalis or N. lugens but not by C. medinalis conferred resistance to M. oryzae. For C. suppressalis and N. lugens, insect infestation without fungal inoculation induced the accumulation of both JA and SA in rice leaves. In contrast, infestation by C. medinalis increased JA levels but reduced SA levels. The exogenous application of SA but not of JA conferred resistance against M. oryzae. These results suggest that pre-infestation by C. suppressalis or N. lugens conferred resistance against M. oryzae by increasing SA accumulation. These findings enhance our understanding of the interactions among rice plant, insects and pathogens, and provide valuable information for developing an ecologically sound strategy for controlling rice blast. PMID- 29999565 TI - Context-dependent role of selective attention for change detection in multi speaker scenes. AB - Disappearance of a voice or other sound source may often go unnoticed when the auditory scene is crowded. We explored the role of selective attention for this change deafness with magnetoencephalography in multi-speaker scenes. Each scene was presented two times in direct succession, and one target speaker was frequently omitted in Scene 2. When listeners were previously cued to the target speaker, activity in auditory cortex time locked to the target speaker's sound envelope was selectively enhanced in Scene 1, as was determined by a cross correlation analysis. Moreover, the response was stronger for hit trials than for miss trials, confirming that selective attention played a role for subsequent change detection. If selective attention to the streams where the change occurred was generally required for successful change detection, neural enhancement of this stream would also be expected without cue in hit compared to miss trials. However, when listeners were not previously cued to the target, no enhanced activity for the target speaker was observed for hit trials, and there was no significant difference between hit and miss trials. These results, first, confirm a role for attention in change detection for situations where the target source is known. Second, they suggest that the omission of a speaker, or more generally an auditory stream, can alternatively be detected without selective attentional enhancement of the target stream. Several models and strategies could be envisaged for change detection in this case, including global comparison of the subsequent scenes. PMID- 29999566 TI - An Optimized System for Effective Derivation of Three-Dimensional Retinal Tissue via Wnt Signaling Regulation. AB - Effective derivation of three-dimensional (3D) retinal tissue from human-induced pluripotent stem cells (hiPSCs) could provide models for drug screening and facilitate patient-specific retinal cell replacement therapy. However, some hiPSC lines cannot undergo 3D self-organization and show inadequate differentiation efficiency to meet clinical demand. In this study, we developed an optimized system for derivation of 3D retinal tissue. We found that the Wnt signaling pathway antagonist Dickkopf-related protein 1 (DKK-1) rescued the inability of differentiated retinal progenitors to self-organize. By evaluating DKK-1 expression and supplying DKK-1 if necessary, retinal organoids were differentiated from six hiPSC lines, which were reprogramed from three common initiating cell types. Retinal tissues derived from the optimized system were well organized and capable of surviving for further maturation. Thus, using this system, we generated retinal tissues from various hiPSC lines with high efficiency. This novel system has many potential applications in regenerative therapy and precision medicine. Stem Cells 2018;36:1709-1722. PMID- 29999567 TI - Topological analyses of functional connectomics: A crucial role of global signal removal, brain parcellation, and null models. AB - Recently, functional connectome studies based on resting-state functional magnetic resonance imaging (R-fMRI) and graph theory have greatly advanced our understanding of the topological principles of healthy and diseased brains. However, how different strategies for R-fMRI data preprocessing and for connectome analyses jointly affect topological characterization and contrastive research of brain networks remains to be elucidated. Here, we used two R-fMRI data sets, a healthy young adult data set and an Alzheimer's disease (AD) patient data set, and up to 42 analysis strategies to comprehensively investigate the joint influence of three key factors (global signal regression, regional parcellation schemes, and null network models) on the topological analysis and contrastive research of whole-brain functional networks. At the global level, we first found that these three factors affected not only the quantitative values but also the individual variability profile in small-world related metrics and modularity, wherein global signal regression exhibited the predominant influence. Moreover, strategies without global signal regression and with topological randomization null model enhanced the sensitivity of the detection of differences between AD and control groups in small-worldness and modularity. At the nodal level, strategies of global signal regression dominantly influenced the spatial distribution of both hubs and between-group differences in terms of nodal degree centrality. Together, we highlight the remarkable joint influence of global signal regression, regional parcellation schemes and null network models on functional connectome analyses in both health and diseases, which may provide guidance for the choice of analysis strategies in future functional network studies. PMID- 29999568 TI - UHRF1 Licensed Self-Renewal of Active Adult Neural Stem Cells. AB - Adult neurogenesis in the brain continuously seeds new neurons throughout life, but how homeostasis of adult neural stem cells (NSCs) is maintained is incompletely understood. Here, we demonstrate that the DNA methylation adapter ubiquitin-like, containing PHD and RING finger domains-1 (UHRF1) is expressed in, and regulates proliferation of, the active but not quiescent pool of adult neural progenitor cells. Mice with a neural stem cell-specific deficiency in UHRF1 exhibit a massive depletion of neurogenesis resulting in a collapse of formation of new neurons. In the absence of UHRF1, NSCs unexpectedly remain in the cell cycle but with a 17-fold increased cell cycle length due to a failure of replication phase entry caused by promoter demethylation and derepression of Cdkn1a, which encodes the cyclin-dependent kinase inhibitor p21. UHRF1 does not affect the proportion progenitor cells active within the cell cycle but among these cells, UHRF1 is critical for licensing replication re-entry. Therefore, this study shows that a UHRF1-Cdkn1a axis is essential for the control of stem cell self-renewal and neurogenesis in the adult brain. Stem Cells 2018;36:1736 1751. PMID- 29999569 TI - Clinical characteristics of cognitive impairment in patients with Parkinson's disease and its related pattern in 18 F-FDG PET imaging. AB - This study aimed to characterize the clinical features and the related cerebral glucose metabolism pattern of cognitive impairments in Parkinson's disease (PD) with positron emission tomography (PET) imaging. We recruited 168 PD patients and 100 age-matched healthy controls of similar education and gender distribution. All of those enrolled underwent clinical assessment including the unified Parkinson's disease rating scale motor score, Hoehn and Yahr scale, and comprehensive neuropsychological tests including domains of executive function, attention, memory, visuospatial function, and language. Demographics and the results of cognitive measures were compared between patients and healthy controls. Cognition status was classified as PD patients with dementia (PD-D), PD patients with mild cognitive impairment (PD-MCI), or PD patients with normal cognition (PD-NC). In 53 PD patients who underwent 18 F-fluorodeoxyglucose (18 F FDG) PET imaging, correlations between Z-score values of the different cognitive domains and cerebral 18 F-FDG uptake were assessed using statistical parametric mapping (SPM8) corrected for age and motor severity. A total of 23.2% of PD patients were PD-MCI and 8.9% were PD-D. In the group of PD-MCI, 96.3% showed multiple-domain deficits, with executive function and attention impairment most predominantly involved. All the cognitive domain scores with the exception of language correlated with 18 F-FDG metabolisms, primarily in posterior temporo parieto-occipital association cortical areas. This study found that cognitive impairment in PD particularly encompasses frontal/executive deficits. Posterior cortical areas, containing multiple neurotransmitters and neural circuits, may play an important role in the pathogenesis of cognitive impairment in PD. PMID- 29999570 TI - Effect of Aging on Stained Monolithic Resin-Ceramic CAD/CAM Materials: Quantitative and Qualitative Analysis of Surface Roughness. AB - PURPOSE: The aim of this in vitro study was to measure the effect of staining and artificial aging on the surface roughness of commercially available resin-ceramic computer-aided design and computer-aided manufacturing (CAD/CAM) materials both quantitatively and qualitatively and to compare it to feldspathic material. MATERIALS AND METHODS: Test specimens (n = 15 per material) were prepared of CAD/CAM ingots from a resin nanoceramic (Lava Ultimate, LVU), a polymer infiltrated ceramic (Vita Enamic, ENA), and a resin nanoceramic (Cerasmart, CER). In the staining protocol, test specimens were (i) roughened in a standardized manner and (ii) stained with the manufacturer's recommended staining kit by means of photo-polymerization (Bluephase Polywave). The control specimens were prepared out of a feldspathic ceramic (Vita Mark II,VM2) and stained in a ceramic furnace. As negative control of each group, 15 specimens were prepared and polished in a standardized manner. Surface roughness (Ra) was measured after finishing procedures and after simulation of clinical service up to 5 years by means of toothbrushing. After each year of aging, one specimen per group was randomly selected for scanning electron microscopy (SEM) analysis. Kruskal-Wallis test and paired post-hoc test were applied to detect differences between treatment groups (alpha = 0.05). RESULTS: The mean roughness measurements of the stained CAD/CAM materials were 0.14 +/- 0.04 MUm (ENA), 0.15 +/- 0.03 MUm (LVU), 0.22 +/- 0.03 MUm (VM2), and 0.26 +/- 0.12 MUm (CER). In the polished CAD/CAM materials the measurements were 0.01 +/- 0.01 MUm (CER), 0.02 +/- 0.01 MUm (LVU), 0.02 +/- 0.00 MUm (VM2), and 0.03 +/- 0.01MUm (ENA). Irrespective of the restoration material, the applied staining protocol resulted in a higher surface roughness compared to the polished specimens (p < 0.001). After 5 years of simulated aging the mean surface roughness in the stained CAD/CAM materials were 0.22 +/- 0.03 MUm (VM2), 0.24 +/- 0.09 MUm (ENA), 0.25 +/- 0.06 MUm (CER), and 0.37 +/- 0.09 MUm (LVU). Aging had a significant effect on surface roughness in groups ENA and LVU (p < 0.001). SEM analysis showed that the staining layer on resin-ceramic CAD/CAM materials was partially removed over time. CONCLUSIONS: The applied staining protocol significantly increased surface roughness of CAD/CAM materials. Instability of the staining layer on resin-ceramic CAD/CAM materials could be anticipated over time as a consequence of toothbrushing, whereas feldspathic ceramic did not suffer from such aging effect. PMID- 29999571 TI - Aberrant O-glycosylation contributes to tumorigenesis in human colorectal cancer. AB - Aberrant O-glycosylation is frequently observed in colorectal cancer (CRC) patients, but it is unclear if it contributes intrinsically to tumorigenesis. Here, we investigated the biological consequences of aberrant O-glycosylation in CRC. We first detected the expression profile of Tn antigen in a serial of human CRC tissues and then explored the genetic and biosynthetic mechanisms. Moreover, we used a human CRC cell line (LS174T), which express Tn antigen, to assess whether aberrant O-glycosylation can directly promote oncogenic properties. It showed that Tn antigen was detected in around 86% human primary and metastatic CRC tissues. Bio-functional investigations showed that T-synthase and Cosmc were both impaired in cancer tissues. A further analysis detected an occurrence of hypermethylation of Cosmc gene, which possibly caused its loss-of-function and a consequent inactive T-synthase. Transfection of LS174T cells with WT Cosmc restored mature O-glycosylation, which subsequently down-regulated cancer cell proliferation, migration and apoptotic-resistant ability. Significantly, the expression of MUC2, a heavily O-glycosylated glycoprotein that plays an essential role in intestinal function, was uniformly reduced in human CRC tissues as well as in LS174T cells. These data suggest that aberrant O-glycosylation contributes to the development of CRC through direct induction of oncogenic properties in cancer cells. PMID- 29999572 TI - Cost-effectiveness of aprepitant in Japanese patients treated with cisplatin containing highly emetogenic chemotherapy. AB - Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse event in cancer chemotherapy. Although aprepitant is effective in preventing CINV, an increment in financial burden for uniform use of aprepitant is a concern. The aim of the present study was to define the cost-effectiveness of aprepitant from the perspective of the Japanese National Health Insurance system. Based on the results of a randomized phase II trial comparing an aprepitant-containing regimen versus a nonaprepitant regimen in Japanese patients who received cisplatin containing highly emetogenic chemotherapy, a decision analytic model was developed. The incremental cost-effectiveness ratio (ICER) was calculated both in the outpatient care setting (OCS) and in the inpatient care setting (ICS). The use of the aprepitant-containing regimen was associated with improved quality of life compared with the nonaprepitant regimen, with an increment in quality adjusted life years (QALY) of 0.0016. The incremental total medical costs associated with the use of the aprepitant regimen were lower in the OCS than in the ICS, 6192 JPY (56.92 USD) and 9820 JPY (90.27 USD), respectively. The ICER was calculated as 3 906 698 JPY (35 910 USD) per QALY gained in the OCS and 6 195 781 JPY (56 952 USD) per QALY gained in the ICS. Cost-effectiveness of the aprepitant-containing antiemetic therapy was limited to the OCS, considering the threshold of willingness-to-pay commonly accepted (5 million JPY [45 960 USD] in Japan and 50 000 USD in the USA). The efficacy of aprepitant offsets the costs for revisiting clinics or rehospitalization added with rescue medications in the OCS. PMID- 29999573 TI - Disentangling seasonal and interannual legacies from inferred patterns of forest water and carbon cycling using tree-ring stable isotopes. AB - Tree-ring carbon and oxygen isotope ratios have been used to understand past dynamics in forest carbon and water cycling. Recently, this has been possible for different parts of single growing seasons by isolating anatomical sections within individual annual rings. Uncertainties in this approach are associated with correlated climate legacies that can occur at a higher frequency, such as across successive seasons, or a lower frequency, such as across years. The objective of this study was to gain insight into how legacies affect cross-correlation in the delta13 C and delta18 O isotope ratios in the earlywood (EW) and latewood (LW) fractions of Pinus ponderosa trees at thirteen sites across a latitudinal gradient influenced by the North American Monsoon (NAM) climate system. We observed that delta13 C from EW and LW has significant positive cross correlations at most sites, whereas EW and LW delta18 O values were cross correlated at about half the sites. Using combined statistical and mechanistic models, we show that cross-correlations in both delta13 C and delta18 O can be largely explained by a low-frequency (multiple-year) mode that may be associated with long-term climate change. We isolated, and statistically removed, the low frequency correlation, which resulted in greater geographical differentiation of the EW and LW isotope signals. The remaining higher-frequency (seasonal) cross correlations between EW and LW isotope ratios were explored using a mechanistic isotope fractionation-climate model. This showed that lower atmospheric vapor pressure deficits associated with monsoon rain increase the EW-LW differentiation for both delta13 C and delta18 O at southern sites, compared to northern sites. Our results support the hypothesis that dominantly unimodal precipitation regimes, such as near the northern boundary of the NAM, are more likely to foster cross-correlations in the isotope signals of EW and LW, potentially due to greater sharing of common carbohydrate and soil water resource pools, compared to southerly sites with bimodal precipitation regimes. PMID- 29999575 TI - Highly Emissive Self-Trapped Excitons in Fully Inorganic Zero-Dimensional Tin Halides. AB - The spatial localization of charge carriers to promote the formation of bound excitons and concomitantly enhance radiative recombination has long been a goal for luminescent semiconductors. Zero-dimensional materials structurally impose carrier localization and result in the formation of localized Frenkel excitons. Now the fully inorganic, perovskite-derived zero-dimensional SnII material Cs4 SnBr6 is presented that exhibits room-temperature broad-band photoluminescence centered at 540 nm with a quantum yield (QY) of 15+/-5 %. A series of analogous compositions following the general formula Cs4-x Ax Sn(Br1-y Iy )6 (A=Rb, K; x<=1, y<=1) can be prepared. The emission of these materials ranges from 500 nm to 620 nm with the possibility to compositionally tune the Stokes shift and the self-trapped exciton emission bands. PMID- 29999574 TI - Exosome-mediated regulation of tumor immunology. AB - Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8+ T cells that show potent cytotoxic activity against tumor cells reside as an inactive naive form in the T cell zone of secondary lymphoid organs. Once receiving tumor-specific antigenic stimulation by dendritic cells (DC), CD8+ T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome-mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC-derived and regulatory T (Treg) cell-derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression. PMID- 29999577 TI - Differential responses of carbon-degrading enzyme activities to warming: Implications for soil respiration. AB - Extracellular enzymes catalyze rate-limiting steps in soil organic matter decomposition, and their activities (EEAs) play a key role in determining soil respiration (SR). Both EEAs and SR are highly sensitive to temperature, but their responses to climate warming remain poorly understood. Here, we present a meta analysis on the response of soil cellulase and ligninase activities and SR to warming, synthesizing data from 56 studies. We found that warming significantly enhanced ligninase activity by 21.4% but had no effect on cellulase activity. Increases in ligninase activity were positively correlated with changes in SR, while no such relationship was found for cellulase. The warming response of ligninase activity was more closely related to the responses of SR than a wide range of environmental and experimental methodological factors. Furthermore, warming effects on ligninase activity increased with experiment duration. These results suggest that soil microorganisms sustain long-term increases in SR with warming by gradually increasing the degradation of the recalcitrant carbon pool. PMID- 29999578 TI - Advances in Materials and Structures for Ingestible Electromechanical Medical Devices. AB - Ingestible biomedical devices that diagnose, prevent, or treat diseases has been a dream of engineers and clinicians for decades. The increasing apparent importance of gut health on overall well-being and the prevalence of many gastrointestinal diseases have renewed focus on this emerging class of medical devices. Several prominent examples of commercially successful ingestible medical devices exist. However, many technical challenges remain before ingestible medical devices can achieve their full clinical potential. This Minireview summarizes recent discoveries in this interdisciplinary topic including novel materials, advanced materials processing techniques, and select examples of integrated ingestible electromechanical systems. After a brief historical perspective, these topics will be reviewed with a dedicated focus on advanced functional materials and fabrication strategies in the context of clinical translation and potential regulatory considerations. Future perspectives, challenges, and opportunities related to ingestible medical devices will also be summarized. PMID- 29999576 TI - Self-medication with alcohol or drugs for mood and anxiety disorders: A narrative review of the epidemiological literature. AB - BACKGROUND: The comorbidity of mood and anxiety disorders (MD and AD) with substance use disorders (SUD) is common. One explanation for this comorbidity is the self-medication hypothesis, which posits that individuals with MD or AD use substances to cope with the difficult symptoms associated with the disorder. Over time, self-medication (SM) can develop into an independent SUD. This narrative review will present the prevalence and correlates of SM with alcohol and/or drugs for MD and AD and the relationship between SM and subsequent SUD using both cross sectional and longitudinal epidemiological data. METHODS: Scopus and PsycINFO were searched from January 1997 to April 2018 to identify original research articles that examined the prevalence and correlates of SM and the temporal relationship between MD/AD and SUD in the general population (n = 22). RESULTS: The prevalence of SM with alcohol and/or drugs among those with MD or AD ranged from 21.9% to 24.1%. Male sex, younger age, being separated, divorced or widowed, and being Caucasian were characteristics associated with higher proportions of respondents endorsing SM with alcohol/drugs for MD and AD. Longitudinal data supports the temporal onset of primary MD/AD and secondary SUD among those who self-report SM. CONCLUSION: Providing and promoting alternate coping strategies for those with MD/AD may reduce SM, the development of SUD, and the comorbidity of MD/AD with SUD. The concurrent treatment of MD/AD and substance use is the current "gold standard" model of care, and the results of this review support its use. PMID- 29999579 TI - Multi-omics analyses reveal epigenomics basis for cotton somatic embryogenesis through successive regeneration acclimation process. AB - Plant regeneration via somatic embryogenesis is time-consuming and highly genotype-dependent. The plant somatic embryogenesis process provokes many epigenetics changes including DNA methylation and histone modification. Recently, an elite cotton Jin668, with an extremely high regeneration ability, was developed from its maternal inbred Y668 cultivar using a Successive Regeneration Acclimation (SRA) strategy. To reveal the underlying mechanism of SRA, we carried out a genome-wide single-base resolution methylation analysis for nonembryogenic calluses (NECs), ECs, somatic embryos (SEs) during the somatic embryogenesis procedure and the leaves of regenerated offspring plants. Jin668 (R4) regenerated plants were CHH hypomethylated compared with the R0 regenerated plants of SRA process. The increase in CHH methylation from NEC to EC was demonstrated to be associated with the RNA-dependent DNA methylation (RdDM) and the H3K9me2 dependent pathway. Intriguingly, the hypomethylated CHH differentially methylated regions (DMRs) of promoter activated some hormone-related and WUSCHEL-related homeobox genes during the somatic embryogenesis process. Inhibiting DNA methylation using zebularine treatment in NEC increased the number of embryos. Our multi-omics data provide new insights into the dynamics of DNA methylation during the plant tissue culture and regenerated offspring plants. This study also reveals that induced hypomethylation (SRA) may facilitate the higher plant regeneration ability and optimize maternal genetic cultivar. PMID- 29999580 TI - Variations in the management of significant polyps and early colorectal cancer: results from a multicentre observational study of 383 patients. AB - AIM: The concept of significant polyps and early colorectal cancer (SPECC) encompasses complex polyps not amenable to routine snare polypectomy or where malignancy cannot be excluded. Surgical resection (SR) offers definitive treatment, but is overtreatment for the majority which are benign and amenable to less invasive endoscopic resection (ER). The aim of this study was to investigate variations in the management and outcomes of significant colorectal polyps. METHOD: This was a retrospective observational study of significant colorectal polyps, defined as nonpedunculated lesions of >= 20 mm size, diagnosed across nine UK hospitals in 2014. Inclusion criteria were endoscopically or histologically benign polyps at biopsy. RESULTS: A total of 383 patients were treated by primary ER (87.2%) or SR (12.8%). Overall, 108/383 (28%) polyps were detected in the Bowel Cancer Screening Programme (BCSP). Primary SR was associated with a significantly longer length of stay and major complications (P < 0.01). Of the ER polyps, 290/334 (86.8%) patients were treated without undergoing surgery. The commonest indication for secondary surgery was unexpected polyp cancer, and of these cases 60% had no residual cancer in the specimen. Incidence of unexpected cancer was 10.7% (n = 41) and was similar between ER and SR groups (P = 0.11). On multivariate analysis, a polyp size of > 30 mm and non BCSP status were independent risk factors for primary SR [OR 2.51 (95% CI 1.08 5.82), P = 0.03]. CONCLUSION: ER is safe and feasible for treating significant colorectal polyps. Robust accreditation within the BCSP has led to improvements in management, with lower rates of SR compared with non-BCSP patients. Standardization, training in polyp assessment and treatment within a multidisciplinary team may help to select appropriate treatment strategies and improve outcomes. PMID- 29999581 TI - Ovarian hormones modulate endothelin-1 receptor responses in young women. AB - OBJECTIVE: We recently demonstrated ETBR mediate vasodilation in young but not postmenopausal women; it is unclear if this is related to age or a decline in ovarian hormones. The purpose of this study was to test the hypothesis that ETBR responses are modulated by ovarian hormones. METHODS: We measured cutaneous vasodilatory responses in 12 young women (22 +/- 1 years, 23 +/- 1 kg/m2 ) during the ML (days 20-25) and EF (days 2-5) phases of the menstrual cycle. Cutaneous microdialysis perfusions of lactated Ringer (control), ETBR antagonist (BQ-788, 300 nmol/L), and ETAR antagonist (BQ-123, 500 nmol/L) were performed, followed by local heating to 42 degrees C. RESULTS: Serum estradiol (ML: 118 +/- 16 vs EF: 44 +/- 9 pg/mL, P < 0.05) and progesterone (ML: 8.3 +/- 1.0 vs EF: 0.7 +/- 0.2 ng/mL, P < 0.05) were higher during ML vs EF phase. ETBR blockade decreased vasodilation during ML (control: 91 +/- 2 vs BQ-788: 83 +/- 2%CVCmax, P < 0.05) but not EF (control: 89 +/- 2 vs BQ-788: 89 +/- 1%CVCmax). ETAR blockade also decreased vasodilation during ML (control: 91 +/- 2 vs BQ-123: 87 +/- 2%CVCmax, P < 0.05) but not EF (control: 89 +/- 2 vs BQ-123: 92 +/- 2%CVCmax). CONCLUSIONS: These data suggest that fluctuations in ovarian hormones modulate ETBR and ETAR responses in young women. PMID- 29999582 TI - Dependency of Antarctic zooplankton species on ice algae-produced carbon suggests a sea ice-driven pelagic ecosystem during winter. AB - How the abundant pelagic life of the Southern Ocean survives winter darkness, when the sea is covered by pack ice and phytoplankton production is nearly zero, is poorly understood. Ice-associated ("sympagic") microalgae could serve as a high-quality carbon source during winter, but their significance in the food web is so far unquantified. To better understand the importance of ice algae-produced carbon for the overwintering of Antarctic organisms, we investigated fatty acid (FA) and stable isotope compositions of 10 zooplankton species, and their potential sympagic and pelagic carbon sources. FA-specific carbon stable isotope compositions were used in stable isotope mixing models to quantify the contribution of ice algae-produced carbon (alphaIce ) to the body carbon of each species. Mean alphaIce estimates ranged from 4% to 67%, with large variations between species and depending on the FA used for the modelling. Integrating the alphaIce estimates from all models, the sympagic amphipod Eusirus laticarpus was the most dependent on ice algal carbon (alphaIce : 54%-67%), and the salp Salpa thompsoni showed the least dependency on ice algal carbon (alphaIce : 8%-40%). Differences in alphaIce estimates between FAs associated with short-term vs. long term lipid pools suggested an increasing importance of ice algal carbon for many species as the winter season progressed. In the abundant winter-active copepod Calanus propinquus, mean alphaIce reached more than 50% in late winter. The trophic carbon flux from ice algae into this copepod was between 3 and 5 mg C m-2 day-1 . This indicates that copepods and other ice-dependent zooplankton species transfer significant amounts of carbon from ice algae into the pelagic system, where it fuels the food web, the biological carbon pump and elemental cycling. Understanding the role of ice algae-produced carbon in these processes will be the key to predictions of the impact of future sea ice decline on Antarctic ecosystem functioning. PMID- 29999583 TI - A 627K variant in the PB2 protein of H9 subtype influenza virus in wild birds. AB - BACKGROUND: Wild birds are gaining increasing attention as gene-mixing reservoirs for influenza viruses. To investigate the molecular properties of the viruses isolated and epidemiological analysis of H9N2 subtype AIV in wild birds, we studied samples obtained over two years (2014-2015) from wetlands in Anhui province, China. METHODS: A total of 4534 samples were collected from migratory waterfowl in Anhui in 2014-2015, and 8 strains of H9 subtype AIV were isolated. RESULTS: Phylogenetic analysis showed different degrees of gene segment reassortment in H9 viruses between the Eurasian lineage and the North American lineage. Most importantly, two viruses harbored the E627K mutation in the polymerase PB2 (PB2) protein. This is the first report of the mutation of this virus from low pathogenicity to high pathogenicity in wild birds. CONCLUSIONS: The continued surveillance of wild birds, especially migratory birds, is important to provide early warning and control of AIV outbreaks. Our results highlight the high genetic diversity of AIV along the Eurasian-Australian migration flyway and the need for more extensive AIV surveillance in eastern China. PMID- 29999585 TI - Corrigendum. PMID- 29999584 TI - Heterogeneity of lipidomic profiles among lung cancer subtypes of patients. AB - Lung cancer is a leading cause of cancer-related deaths with an increasing incidence and poor prognoses. To further understand the regulatory mechanisms of lipidomic profiles in lung cancer subtypes, we measure the profiles of plasma lipidome between health and patients with lung cancer or among patients with squamous cell carcinomas, adenocarcinoma or small cell lung cancer and to correct lipidomic and genomic profiles of lipid-associated enzymes and proteins by integrating the data of large-scale genome screening. Our studies demonstrated that circulating levels of PS and lysoPS significantly increased, while lysoPE and PE decreased in patients with lung cancer. Our data indicate that lung cancer specific and subtype-specific lipidomics in the circulation are important to understand mechanisms of systemic metabolisms and identify diagnostic biomarkers and therapeutic targets. The carbon atoms, dual bonds or isomerism in the lipid molecule may play important roles in lung cancer cell differentiations and development. This is the first try to integrate lipidomic data with lipid protein associated genomic expression among lung cancer subtypes as the part of clinical trans-omics. We found that a large number of lipid protein-associated genes significantly change among cancer subtypes, with correlations with altered species and spatial structures of lipid metabolites. PMID- 29999586 TI - Custom-made facemask as a coadjuvant in the postoperative treatment of sport related facial trauma: Case report. AB - Maxillofacial injuries are a regular consequence of sport activities that can force athletes to take a long time off from training and competitions. One way to decrease the time that the athlete needs to get back to his or her training exercises after surgery is to use a custom facemask as a coadjuvant in the postoperative recovery phase. This case report describes the case of a 16-year old male athlete who suffered facial trauma (orbitozygomatic fractures) during a soccer game. After surgery, a facemask was used during the postoperative phase. He returned to his regular physical activities only 3 weeks after surgery. This simple and very efficient procedure is a good option for athletes who suffer facial injuries. PMID- 29999587 TI - Analysis of Differentially Expressed Proteins Involved in Autoimmune Cirrhosis and Normal Serum by iTRAQ Proteomics. AB - PURPOSE: In order to study the candidate biomarkers in autoimmune cirrhosis (AIC). EXPERIMENTAL DESIGN: Isobaric tags are first implemented for relative and absolute quantitation technology on proteins prepared from serum obtained from AIC and normal controls. Proteins found to be differentially expressed are identified with liquid chromatography electrospray ionization tandem mass spectrometry by using a Q Exactive classic ion trap mass spectrometer. RESULTS: 108 proteins (32 upregulated and 76 downregulated proteins) are identified from AIC samples, compared with the normal controls. Gene Ontology enrichment analysis, KEGG pathway analysis, and protein-protein interaction map by STRING show that they associate with multiple functional groups, including ion binding activity, peptidase activity, and enzyme regulator activity. Finally, the von Willebrand factor, insulin-like growth factor-binding protein complex acid labile subunit, transthyretin, adiponectin proteins are identified with western blot as candidate biomarkers for AIC. CONCLUSIONS AND CLINICAL RELEVANCE: These findings offer a comprehensive profile of the AIC proteome about candidate biomarkers and provide a useful basis for further analysis of the pathogenic mechanism of AIC. PMID- 29999588 TI - Compatibility between haemagglutinin and neuraminidase drives the recent emergence of novel clade 2.3.4.4 H5Nx avian influenza viruses in China. AB - Genetic reassortments between highly pathogenic avian influenza (HPAI) H5 subtype viruses with different neuraminidase (NA) subtypes have increased in prevalence since 2010 in wild birds and poultry from China. The HA gene slightly evolved from clade 2.3.4 to clade 2.3.4.4, raising the question of whether novel clade 2.3.4.4 HA broke the balance with N1 but is matched well with NAx to drive viral epidemics. To clarify the role of compatibility between HA and NA on the prevalence of H5Nx subtypes, we constructed 10 recombinant viruses in which the clade 2.3.4 or clade 2.3.4.4 HA genes were matched with different NA (N1, N2 and N8) genes and evaluated viral characteristics and pathogenicity. Combinations between clade 2.3.4 HA and N1 or between clade 2.3.4.4 HA and NAx, but not between clade 2.3.4.4 HA and N1, or between clade 2.3.4 HA and NAx, promoted viral growth, NA activity, thermostability, low-pH stability and pathogenicity in chicken and mice. These findings suggest that both clade 2.3.4 HA/N1 and clade 2.3.4.4 HA/NAx displayed a better match, which could promote the increased prevalence of clade 2.3.4 H5N1 AIV (prior to 2010) and clade 2.3.4.4 H5Nx AIV (since 2010) in China, respectively. PMID- 29999590 TI - Generation of Induced Cardiospheres via Reprogramming of Mouse Skin Fibroblasts. AB - Cardiospheres represent a more effective cell-based therapy for treatment of myocardial infarction than stem cells of non-cardiac origin. Unfortunately, their therapeutic application is limited by low yield of cell harvesting, declining quality and quantity during the aging process, and the need for highly invasive heart biopsy. Therefore, there is an emerging interest in generating cardiosphere like stem cells from somatic cells via somatic reprogramming. This novel approach would provide an unlimited source of stem cells with cardiac differentiation potential. Here we provide the detailed protocol for generating induced cardiospheres (iCS) for cardiac regeneration by somatic reprogramming of mouse fibroblasts using a panel of pluripotent transcription factors and cardiotrophic growth factors. (c) 2018 by John Wiley & Sons, Inc. PMID- 29999589 TI - Tubular epithelial C1orf54 mediates protection and recovery from acute kidney injury. AB - Acute kidney injury (AKI) incidence among hospitalized patients is increasing steadily. Despite progress in prevention strategies and support measures, AKI remains correlated with high mortality, particularly among ICU patients, and no effective AKI therapy exists. Here, we investigated the function in kidney ischaemia-reperfusion injury (IRI) of C1orf54, a newly identified protein encoded by an open reading frame on chromosome 1. C1orf54 expression was high in kidney and low in heart, liver, spleen, lung and skeletal muscle in healthy mice, and in the kidney, C1orf54 was expressed in tubular epithelial cells (TECs), but not in glomeruli. C1orf54 expression was markedly decreased on Day 1 after kidney IRI and then gradually recovered to baseline levels by Day 7. Notably, relative to wild-type mice, C1orf54-knockout mice exhibited impaired TEC proliferation and delayed recovery after kidney IRI, which led to deteriorated renal function and increased mortality. Conversely, adenovirus-mediated C1orf54 overexpression promoted TEC proliferation and ameliorated kidney pathology, which resulted in accelerated renal repair and improved renal function. Mechanistically, C1orf54 was found to promote TEC proliferation through PI3K/AKT signalling. Thus, C1orf54 holds considerable potential as a therapeutic target in kidney IRI. PMID- 29999591 TI - Plasma tyrosine and its interaction with low high-density lipoprotein cholesterol and the risk of type 2 diabetes mellitus in Chinese. AB - AIMS/INTRODUCTION: Metabolomic markers have the potential to improve the predicting accuracy of existing risk scores for type 2 diabetes mellitus. The present study aimed to test the associations between plasma tyrosine and type 2 diabetes mellitus with special attention to identifying possible cut-off points for type 2 diabetes mellitus, and its interactive effects with low high-density lipoprotein cholesterol (HDL-C) and/or high triglyceride for type 2 diabetes mellitus. METHODS: From 27 May 2015 to 3 August 2016, we retrieved the medical notes of 1,898 inpatients with type 2 diabetes mellitus as the cases, and 1,522 individuals without diabetes as the controls who attended annual medical checkups from the same tertiary care center in Jinzhou, China. Logistic regression analyses were carried out to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic spline analysis nested in the logistic regression analysis was used to identify possible cut-off points of tyrosine for type 2 diabetes mellitus. The additive interaction was used to estimate interactions between high tyrosine and low HDL-C in type 2 diabetes mellitus patients. RESULTS: The OR of tyrosine for type 2 diabetes mellitus did not increase until 46 MUmol/L and after that point, the OR rapidly rose with increasing tyrosine in a nearly linear manner. If 46 MUmol/L was used to define high tyrosine, high tyrosine was associated with an increased OR of type 2 diabetes mellitus (adjusted OR 1.88, 95% CI 1.44-2.45). The presence of low HDL-C greatly enhanced the ORs of tyrosine for type 2 diabetes mellitus from 1.11 (95% CI 0.82-1.51) to 54.11 (95% CI 33.96-86.22) with significant additive interaction. CONCLUSIONS: In Chinese adults, tyrosine >46 MUmol/L was associated with increased odds of type 2 diabetes mellitus, which was contingent on low HDL C. PMID- 29999593 TI - Inflammation in cystic fibrosis: An update. AB - Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF. PMID- 29999594 TI - Observational studies of vitamin D associations with asthma: Problems and pitfalls. PMID- 29999592 TI - Quality indicators for the diagnosis and management of chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) has been identified as a high-priority disease category for quality improvement. To this end, this study aimed to develop CRS-specific quality indicators (QIs) to evaluate diagnosis and management that relieves patient discomfort, improves quality of life, and prevents complications. METHODS: A guideline-based approach, proposed in 2012 by Kotter et al. was used to develop QIs for CRS. Candidate indicators (CIs) were extracted from 3 practice guidelines and 1 international consensus statement on the diagnosis and management of CRS. Guidelines were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Each CI and its supporting evidence was summarized and reviewed by an expert panel based on validity, reliability, and feasibility of measurement. Final QIs were selected from CIs utilizing the modified RAND Corporation-University of California, Los Angeles (RAND/UCLA) appropriateness methodology. RESULTS: Thirty-nine CIs were identified after literature review and evaluated by our panel. Of these, 9 CIs reached consensus as being appropriate QIs, with 4 requiring additional discussion. After a second round of evaluations, the panel selected 9 QIs as appropriate measures of high-quality care. CONCLUSION: This study proposes 9 QIs for the diagnosis and management of patients with CRS. These QIs can serve multiple purposes, including documenting the quality of care; comparing institutions and providers; prioritizing quality improvement initiatives; supporting accountability, regulation, and accreditation; and determining pay-for performance initiatives. PMID- 29999595 TI - Precision medicine: why surgeons deviate from "appropriateness criteria" in the management of chronic rhinosinusitis and effects on outcomes. AB - BACKGROUND: In uncomplicated chronic rhinosinusitis (CRS), a consensus regarding appropriate medical therapy (AMT) before surgical intervention has been published in the form of "appropriateness criteria" for endoscopic sinus surgery (ESS). We sought to determine why tertiary surgeons may deviate from the suggested criteria and evaluated whether those deviations result in change in outcomes. METHODS: Patients with uncomplicated CRS were prospectively enrolled over the course of 1 year. The 22-item Sino-Nasal Outcomes Test (SNOT-22), a general health outcome out of 100, and a physician form, indicating management pathway and decision making, was completed at each visit over a 6-month follow-up period. A descriptive analysis was used to quantify reasons for veering from the "appropriateness criteria," and repeated linear regression modeling was used to measure whether compliance impacted SNOT-22, general health, and Lund-Kennedy (LK) scores over the period of study. RESULTS: One hundred fifty-five patients were enrolled. Sixty-eight percent followed the appropriate management pathway based on their presentation and the suggested criteria. Disparate reasons were documented for deviation in the other 32%, and, despite establishing several predictive categories, "other" was the most common reason, with various explanations well documented. SNOT-22, general health, and LK scores were not statistically impacted by compliancy status (p > 0.05). CONCLUSION: The suggested "appropriateness criteria" predict a management pathway for the majority of CRS patients. However, in a tertiary sinus center, surgeons may deviate from that model with a significant minority of their patients, for multiple reasons, without causing a change in outcomes. PMID- 29999596 TI - Nasal high-frequency oscillatory ventilation and CO2 removal: A randomized controlled crossover trial. AB - OBJECTIVE: To compare short-term application of nasal high-frequency oscillatory ventilation (nHFOV) with nasal continuous positive airway pressure (nCPAP). WORKING HYPOTHESIS: nHFOV improves CO2 removal with respect to nCPAP in preterm infants needing noninvasive respiratory support and persistent oxygen supply after the first 72 h of life. STUDY DESIGN: Multicenter non-blinded prospective randomized crossover study. PATIENT SELECTION: Thirty premature infants from eight tertiary neonatal intensive care units, of mean +/- SD 26.4 +/- 1.8 weeks of gestational age and 921 +/- 177 g of birth weight. METHODOLOGY: Infants were randomly allocated in a 1:1 ratio to receive a starting treatment mode of either nCPAP or nHFOV delivered by the ventilator CNO (Medin, Germany), using short binasal prongs of appropriate size. A crossover design with four 1-h treatment periods was used, such that each infant received both treatments twice. The primary outcome was the mean transcutaneous partial pressure of CO2 (TcCO2 ) value during the 2-h cumulative period of nHFOV compared with the 2-h cumulative period of nCPAP. RESULTS: Significantly lower TcCO2 values were observed during nHFOV compared with nCPAP: 47.5 +/- 7.6 versus 49.9 +/- 7.2 mmHg, respectively, P = 0.0007. A different TcCO2 behavior was found according to the random sequence: in patients starting on nCPAP, TcCO2 significantly decreased from 50.0 +/- 8.0 to 46.6 +/- 7.5 mmHg during nHFOV (P = 0.001). In patients starting on nHFOV, TcCO2 slightly increased from 48.5 +/- 7.8 to 49.9 +/- 6.7 mmHg during nCPAP (P = 0.13). CONCLUSIONS: nHFOV delivered through nasal prongs is more effective than nCPAP in improving the elimination of CO2 . PMID- 29999597 TI - Effects of early postoperative nasal decongestant on symptom relief after septoplasty. AB - BACKGROUND: A randomized, prospective, double-blinded clinical study was conducted at a single, tertiary referral center. The aim of the study was to evaluate the effects of nasal decongestant use in the early postoperative period after septoplasty. METHODS: After septoplasty, patients who met the study inclusion criteria were randomized into 2 groups to receive either physiologic saline irrigation (saline group) or physiologic saline irrigation plus oxymetazoline hydrochloride 0.05% nasal spray (saline+oxymetazoline group). Visual analog scale (VAS) scores for bleeding, pain, and nasal crusting; Nasal Obstruction Symptom Evaluation (NOSE) scores; and rhinomanometric measurements were assessed pre- and postoperatively. RESULTS: The VAS scores for bleeding and nasal crusting of patients in the saline+oxymetazoline group were significantly lower compared with the saline group (p < 0.005). VAS scores for pain were similar between the groups (p > 0.05). Total nasal resistance and NOSE scores of patients in the saline+oxymetazoline group were significantly lower than in saline group after surgery (p < 0.005). CONCLUSION: The use of nasal decongestant sprays in the very early postoperative period is beneficial to reduce the postsurgical nasal crusting and bleeding symptoms and also for decreasing nasal resistance in this edematous period. PMID- 29999598 TI - Measures of respiratory inductance plethysmography (RIP) in children with neuromuscular disease. AB - BACKGROUND: Pulmonary function testing (PFT) is essential for the clinical assessment of respiratory problems. Respiratory inductance plethysmography (RIP) is a non-invasive method of PFT requiring minimal patient cooperation. RIP measures the volumetric change in the ribcage and abdomen, from which work of breathing (WOB) indices are derived. WOB indices include: phase angle (F), percent ribcage (RC%), respiratory rate (RR), and labored breathing index (LBI). Heart rate (HR) is collected separately. AIM: The goal of this study was to assess the utility of a newly developed RIP system, the pneuRIP, in an outpatient clinic setting in children with neuromuscular (NM) disease. METHOD: The pneuRIP system measures and displays the WOB indices in real-time on an iPad display. Forty-three subjects, 22 NM patients and 21 healthy children (ages: 5-18 years) were enrolled. RESULTS: Patients' means showed an increase of 119.8% for F, 15.7% for LBI, and 19.9% for HR compared with healthy subjects, when adjusted for age and gender. The study found significant differences between the mean values of the healthy subjects and patients in F (P = 0.000), LBI (P = 0.001), and HR (P = 0.001). No differences were noted for RC% and RR between groups. Data for F in NM patients were diffusely distributed as compared with healthy subjects based on analysis of histograms. CONCLUSION: Non-invasive pneuRIP testing provided instantaneous PFT results. As compared to healthy subjects, NM patients showed abnormal results with increased markers of thoracoabdominal asynchrony, WOB indices, and biphasic breathing patterns likely resulting from NM weakness. PMID- 29999599 TI - Correction to: Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells. PMID- 29999601 TI - Tunable Enzymatically Cross-Linked Silk Fibroin Tubular Conduits for Guided Tissue Regeneration. AB - Hollow tubular conduits (TCs) with tunable architecture and biological properties are in great need for modulating cell functions and drug delivery in guided tissue regeneration. Here, a new methodology to produce enzymatically cross linked silk fibroin TCs is described, which takes advantage of the tyrosine groups present in silk structure that are known to allow the formation of a covalently cross-linked hydrogel. Three different processing methods are used as a final step to modulate the properties of the silk-based TCs. This approach allows to virtually adjust any characteristic of the final TCs. The final microstructure ranges from a nonporous to a highly porous network, allowing the TCs to be selectively porous to 4 kDa molecules, but not to human skin fibroblasts. Mechanical properties are dependent both on the processing method and thickness of the TCs. Bioactivity is observed after 30 days of immersion in simulated body fluid only for the TCs submitted to a drying processing method (50 degrees C). The in vivo study performed in mice demonstrates the good biocompatibility of the TCs. The enzymatically cross-linked silk fibroin TCs are versatile and have adjustable characteristics that can be exploited in a variety of biomedical applications, particularly in guidance of peripheral nerve regeneration. PMID- 29999600 TI - Effects of PM2.5 on mucus secretion and tissue remodeling in a rabbit model of chronic rhinosinusitis. AB - BACKGROUND: According to epidemiologic studies, fine particulate matter (particulate matter <=2.5 MUm, PM2.5) is closely associated with increases in the incidence and severity of chronic rhinosinusitis (CRS). However, the role of PM2.5 in the pathophysiology of CRS remains largely unknown. In this study, we investigated the effects of PM2.5 on nasal cilia, tissue remodeling, and mucus hypersecretion in a rabbit model of CRS. METHODS: CRS rabbits were exposed to ambient PM2.5 via a PM2.5 inhalation exposure system. The degree of ciliary damage was evaluated using scanning electron microscopy (SEM). Histopathologic changes were determined using periodic acid-Schiff (PAS) staining of goblet cells and Masson trichrome (MT) staining for collagen in the nasal mucosa. MUC5AC expression was assessed by immunohistochemistry. RESULTS: PM2.5 exposure substantially aggravated ciliary disruption in rabbits with CRS. PM2.5 also significantly increased goblet cell hyperplasia and collagen deposition, as reflected by PAS and MT staining. The nasal mucosa of CRS rabbits displayed markedly elevated MUC5AC expression after PM2.5 exposure. CONCLUSION: Increases in ciliary disruption, nasal remodeling, and mucus hypersecretion may be the pathophysiologic mechanisms underlying the PM2.5-induced aggravation of CRS. PMID- 29999604 TI - Successful Medical School Accreditation. PMID- 29999602 TI - Novel Catechol Derivatives of Arylimidamides as Antileishmanial Agents. AB - Two novel bis-arylimidamide derivatives with terminal catechol moieties (9a and 10a) and two parent compounds with terminal phenyl groups (DB613 and DB884) were synthesized as dihydrobromide salts (9b and 10b). The designed compounds were hybrid molecules consisting of a catechol functionality embedded in an arylimidamide moiety. All compounds were examined for in vitro antiparasitic activity upon promastigotes of Leishmania major and L. infantum as well as axenic amastigotes of L. major. It was shown that conversion of terminal phenyl groups into catechol moieties resulted in more than 10-fold improvement in potency, coupled with lower cytotoxicity against fibroblast cells, compared to the corresponding parent compounds. The furan-containing analog 9a exhibited the highest activity with submicromolar IC50 values, ranging from 0.29 to 0.36 MUm, which is comparable in efficacy to the reference drug amphotericin B (IC50 0.28 - 0.33 MUm). The results justify further study of this class of compounds. It seems that the combination of catechol chelating groups with potent antiparasitic agents could improve the efficacy by presenting novel hybrid compounds. PMID- 29999605 TI - Aneurysm of the Splenomesenteric Portal Venous Confluence: A Case Report. AB - A 62-year-old Caucasian woman was found to have an aneurysm of the splenomesenteric portal venous confluence via computed tomography (CT) scan after presenting with left upper abdominal tenderness. Venous aneurysms typically occur in the popliteal, jugular, and saphenous veins, but visceral venous aneurysms are rare. These aneurysms most commonly arise from the main portal vein and the confluence of the splenic and superior mesenteric veins. There have been fewer than 50 reported cases of portal venous aneurysm. Evaluation involves imaging modalities such as ultrasound, CT, magnetic resonance imaging (MRI), and angiography. There is currently no clear guideline for management, but options include observation, resection, thrombectomy, or portal venous decompression. PMID- 29999603 TI - Sustained lung inflation at birth via short binasal prong in very low birth weight preterm infants: A retrospective study. AB - BACKGROUND AND OBJECTIVES: It is believed, that sustained lung inflation (SLI) at birth in preterm infants reduces the need for mechanical ventilation (MV) and improves respiratory outcomes. The aim of this study was to compare need for MV in preterm infants at high risk for respiratory distress syndrome (RDS) after prophylactic SLI via short binasal prongs at birth combined with early nasal continuous positive airway pressure (nCPAP) versus nCPAP alone. METHODS: Medical records of infants born at 260/7 to 296/7 weeks gestation through 2015 and 2017 were retrospectively assessed. Infants who get sustained inflations at 25 cmH2 O pressure for 15 s following delivery via binasal short prongs comprised the study group. Gestational age matched infants who was supported solely with nCPAP (6 cmH2 O PEEP) comprised the control group. Early rescue surfactant (200 mg/kg poractant alfa) was delivered using the less invasive surfactant administration technique in infants with established RDS. RESULTS: A total of 215 infants were analyzed. Fewer infants in the SLI group required MV within the first 72 h of life compared to the control group (25.7% vs 56.9%, P < 0.001). In multiple logistic regression analysis, SLI emerged as an independent factor for reduced MV need. Bronchopulmonary dysplasia (BPD) incidence including mild BPD was significantly lower in the SLI group (31.9% vs 48%, P = 0.01); however, moderate and severe BPD rates did not reach to a statistical significance (11.5% vs 20.6%, P = 0.06). CONCLUSION: Prophylactic SLI maneuver at birth for preterm infants with impending RDS reduces the need for MV with no adverse effects. PMID- 29999606 TI - Validating a Survey for Addiction Wellness: The Recovery Capital Index. AB - BACKGROUND: Evaluating addiction wellness encompasses more than sobriety. The Recovery Capital Index (RCI), developed by Face It TOGETHER (FIT), measures addiction wellness using three domains and 22 components providing a comprehensive baseline and assessment of intervention effectiveness to allow for the tracking of client progress and to tailor support. The RCI is a holistic, person-centered metric irrespective of a person's treatment modality, recovery, or wellness pathway. METHODS: FIT and Sanford Research set a goal to validate the RCI's effectiveness to measure the factors associated with addiction wellness through a retrospective cohort study of FIT clients with the disease of addiction to alcohol and/or other drugs. Study cohort included 154 client intake records with corresponding RCI scores. The RCI was subjected to descriptive analyses using stacked barplots and side-by-side boxplots. The Cronbach and correlation coefficients were used to check the reliability and validity of the components within each domain. Differences of RCI against clients' characteristics were examined using Tukey's test of multiple comparisons of means. RESULTS: The validation process verified the design of the RCI domains - personal, social, and cultural capital. Variables significantly related to addiction wellness, based on the RCI, are: primary addiction, addiction identification, employment, and income. The RCI accurately described the individual's current state of recovery. CONCLUSIONS: This project validated the RCI as a tool to measure addiction wellness. The RCI measures what it is intended to measure. The results allow FIT and Sanford Research to next validate the RCI instrument's predictive nature for measuring behavior change. PMID- 29999607 TI - The Role of Socioeconomic Status in Individuals that Leave Against Medical Advice. AB - INTRODUCTION: Individuals leaving against medical advice (AMA) are at risk for adverse health outcomes including a 40 percent increased mortality rate a year after self-discharge. Additionally, leaving AMA may dramatically increase medical costs due to failure to complete treatment resulting in higher risk of readmission with additional co-morbidities. METHODS: Retrospective study of inpatients utilizing the Healthcare Cost and Utilization Project (HCUP) 2012 National Inpatient Sample (NIS) database. Primary outcome of interest was discharge type (AMA versus non-AMA) examined against primary payer type, patient and hospital characteristics. Analysis performed on the weighted discharges using Proc Surverylogistic. Statistical significance set at p less than 0.05. All analysis was performed in SAS version 9.4 (SAS Institute). RESULTS: After adjustment for possible cofounders and socioeconomic factors, there were increased odds of leaving against medical advice in those that lacked insurance (ORadj = 4.16, p less than 0.001) or had Medicare (ORadj = 2.10, p less than 0.001) or Medicaid (ORadj = 2.94, p less than 0.001). Compared to individuals in the lower income brackets, groups with higher incomes had a 20-30 percent decrease in leaving AMA. However, in comparison to white individuals, black (ORadj = 1.023, p = 0.2688) and Native Americans (ORadj = 0.994, p=0.9322) were not at an increased risk of leaving AMA. Hispanic (ORadj = 0.665, p less than 0.001) and the Asian/Pacific Islander (ORadj = 0.56, p less than 0.001) groups had decreased odds of leaving AMA. CONCLUSION: Groups at risk for leaving AMA were individuals lacking insurance, having public insurance, and those within the 0-25th percentile in income. Although ethnicity does play a factor in leaving against medical advice, our data indicates that the gap is not as extreme as previously stated. Additional work needs to be done to help health care providers set targeted preventative measures to address those at increased risk for leaving AMA in order to provide a higher standard of care for the patient. PMID- 29999608 TI - It's Crowded Here - A Case of Cor Triatriatum Sinister. AB - The image presented is a still frame taken from a transesophageal echocardiogram of a 76-year-old male who was referred for evaluation of mitral valve disease. He was found to have a non-flow limiting membrane, dividing the left atrium into two sections, consistent with the diagnosis of cor triatriatum sinister. PMID- 29999609 TI - Acute Hemolytic Transfusion Reaction Due to Anti-Kpa Antibody. AB - BACKGROUND: Kpa (KEL3, Penney) is a red blood cell antigen within the Kell system, first described in 1957, that occurs in less than 2 percent of the population. Although anti-Kpa antibodies were identified in 2-5 percent of those with alloantibodies among patients requiring chronic transfusion, only five previously published case reports of anti-Kpa reactions were identified. CASE REPORT: Reported here is a case of an elderly female who experienced an acute hemolytic transfusion reaction due to this antigen. Following initiation of blood transfusion, she experienced a sudden onset of rigorous chills, accompanied by elevated temperature, tachycardia, and hypertension. Laboratory studies showed uremia, elevated creatinine, positive direct Coomb's, and low haptoglobin. Serology revealed anti-Kpa antibody. CONCLUSION: This report is only the sixth, to our knowledge, of a significant reaction attributable to anti-Kpa and only the second of an acute hemolytic reaction associated with it. It serves as a reminder of the potential of low incidence antigens causing severe reactions; this potential should be considered when evaluating acute hemolytic reaction. PMID- 29999610 TI - An Evaluation of SPOT Vision Screening Efficacy for Children in South Dakota. AB - BACKGROUND: Amblyopia is a preventable, sight stealing disorder with a prevalence of approximately 2-4 percent in the U.S. pediatric population. Identifying efficacious, early stage screening modalities is of critical importance to sustain quality of vision and quality of life. This project assessed the quality of screening methods used in the Children's Vision Screening Initiative (CVSI), administered by Northern Plains Eye Foundation in collaboration with Western South Dakota Lions Clubs, by comparing to data collected in follow-up appointments at professional eye care clinics. METHODS: Data from 120 cases for children ages 6 months-12 years collected between February 2014 to July 2016 were compared. Only cases that had undergone initial screening by CVSI using a SPOT photoscreener device and that attended a subsequently scheduled eye care professional referral follow-up appointment were evaluated. SPOT screening performance measures on detecting amblyopia risk factors and the accuracy of refractive error data were evaluated. RESULTS: Review of professional evaluations showed that 23 percent of cases referred by SPOT screening had detectable amblyopia and 82 percent of all cases referred were found to be in need of further therapy as a result of examination findings. The SPOT device showed fair sensitivity and good specificity in the detection of astigmatism (76 percent/86 percent), strabismus (50 percent/96 percent), and anisometropia (75 percent/90 percent). CONCLUSION: Vision screening performed using the SPOT device represents a valuable modality that is easily employable and can provide tremendous benefit to children in the state of South Dakota. PMID- 29999612 TI - Dyslipidemia. PMID- 29999611 TI - Perspective. PMID- 29999613 TI - Quality Focus: Hypertension: The Challenges of Appropriate Diagnosis and Treatment Continue. PMID- 30000461 TI - [A Methane Gas Sensor Based on Mid-Infrared Quantum Cascaded Laser and Multipass Gas Cell]. AB - According to the principle of mid-infrared absorption spectrum, the fundamental absorption characteristics at the wavelength of 7.5 MUm of methane (CH4) molecule was used to design a mid-infrared quantum cascaded laser (QCL) and multi-pass gas cell (MPC)-based methane gas sensor. This sensor uses a thermoelectrically cooled, pulse mode QCL whose central wavelength is 7.5 MUm. The QCL wavelength was scanned over CH4 absorption line (1 332.8 cm-1)through adjusting the injection current under the condition of room temperature. Meanwhile, a compact MPC (40 cm long and 800 mL sampling volume) was utilized to achieve an effective optical path length of 16 meters. Additionally, a reference gas cell was occupied and joined a spatial filtering optical structure to meet the requirement of MPC in incidence beam, effectively improved the beam quality, reduced the noise which is caused by the fluctuation of QCL and improved the detection sensitivity of this instrument under the guidance of differential optical absorption spectroscopy method. It indicated that the stability of this instrument is good by means of multiple measurements to the methane gas with different concentration, a detection limit of 1 MUmol.mol-1 will be obtained when the signal-to-noise ratio equals 1. PMID- 30000662 TI - [A New Method for Measurement of Laser-Induced Damage Threshold]. AB - With the development of the laser towards high-power and high energy, laser induced damage threshold of optics becomes one of the important parameters to evaluate the laser damage resistance of optics. Therefore, accurately measuring of the laser-induced damage threshold optics become the focal point studied. And the key to accurately measuring of the laser-induced damage threshold is whether the laser-induced damage can be accurately identified when it occurs. In order to solve low accuracy, long testing time, narrow scope of applications and complex operation of the common damage identification methods, a new testing method to diagnose the laser-induced damage of optics, called plasma diagnosis, is proposed in this paper. Based on this new method, the testing platform was set up, and the spectrum obtained by fiber spectrometer was analyzed under laser radiation by different laser energies. Take whether the spectral lines of the feature element contained in the measured optics occur as standard. The laser-induced damage threshold of K9 glass has been tested, and the test result was compared to that measured by the plasma flash method and the microscope method. The results show that, the plasma diagnosis method proposed in this paper has high-accurate judgment, high- testing speed, simple testing equipment, and easy to realization, which can greatly improve the testing efficiency of the laser-induced damage threshold of optics. PMID- 30000996 TI - [Multi-Pass Absorption Spectroscopy for CO Detection Using a Quantum Cascaded Laser]. AB - According to the fundamental absorption properties of Carbon Monoxide(CO) near 4.7 MUm, a novel CO sensor was designed using a Quantum Cascaded Laser (QCL) whose central wavelength is 4.75 MUm and Multi-pass Gas Cell (MGC). This sensor uses a QCL with the thermoelectrically cooled function and can work under pulse mode and room temperature, the exiting optical wavelength was located in a strong absorption line (2 103 cm-1)which is in the base band of CO through adjusting the injection current and temperature. Meanwhile, a novel MGC (40 cm long and 800 mL sampling volume) with 16 meters effective optical path length and mercury cadmium telluride mid-infrared detectors was used, thus effectively improved the sensitivity of this system. Additionally, a reference gas cell and a spatial filtering optical structure were occupied, resulting in effective improvement of the beam quality and reduction of the noise caused by the instability of QCL, the sensitivity of this system was improved furtherly. It indicated that the system works stably by means of multiple measurements to the carbon monoxide gas with different concentration, a detection limit of 5 MUmol.mol-1 can be obtained when the signal-to-noise ratio equals 1. PMID- 30000879 TI - [Research on the Distribution of Broad-Band Correlated Photon Spectra and the Measurement of Time-Correlation]. AB - The correlated photon technique makes it possible to achieve a radiation calibration processing without chain transferring. The study of the spectral radiation character and time correlation of the photon is of great significance for broad-band radiometric calibration. To absolutely calibrate quantum efficiency of photoelectric detector, it is necessary to extend calibration band from single band to more bands. According to the phase-matching condition of the spontaneous parametric down-conversion, non-collinear angle formula of correlated photon in the crystal is derived. The distribution of the photon spectrum is simulated. Meanwhile, the phase-matching angle of the crystal is optimized. The photon generated by the spontaneous parameters down-conversion has a broad spectral distribution and the correlated photon wavelength is corresponding to its emission angle. Based on the result of the simulation, the experimental measurement system of the spectral distribution and time-correlation of the correlated photon is established. The spectral distribution, the time-correlation and the polarization properties of the four pair photon were measured by using this system. The experimental results show that, (1) the spectral distribution of the measurements is 633~808 nm, where the maximum spectral distribution measurement bias is 1.51 mm. The experiment result is highly consistent with theoretical ones; (2) the correlation time of four pairs correlated photon is measured, during which "three coincidence-peaks" is observed and the minimum correlation time was 0.32 ns; (3) single photon count rate along with coincidence count rate of correlated photon vary with the polarization direction of the pump as sine function. The experimental result is shown that the correlated photon pairs are ranging from the visible to near infrared band distribution, and that the spectrum has time-correlation and polarization characteristic. The research result is firstly reported at home and abroad, and the results are promising for the application of the photoelectric detector in the multi-band radiometric calibration. PMID- 30000997 TI - [A Study of Lasing Spectrum of Dye-Doped Chiral Nematic Liquid Crystal Cell under Electric Field]. AB - The lasing spectrum of dye-doped chiral nematic liquid crystal under electric filed was investigated. Two kinds of electrodes were designed to apply transverse electric field to positive liquid crystal cell and longitudinal electric field to negative liquid crystal cell. A 532 nm Nd?YAG pulsed solid-state laser was used to pump the cell. When transverse electric field is applied to positive liquid crystal device, multi-wavelength laser output is obtained in the range of 630~660 nm. When longitudinal electric field is applied to negative liquid crystal cell, 18.5 nm tunable output lasing is obtained. The output characteristic of cell was analyzed from the texture of device and the photonic band gap. In the positive liquid crystal cell, the competition of electric moment with twisting moment causes the flow of LC molecule, and the flow of LC molecule leads to a floating photonic band gap. For this reason, not only at the edge of photonic band gap but in the photonic band gap can produce lasing. For negative liquid crystal cell, the pitch shrinks with the increase of electric field. The photonic band gap shows blue-shift with the decrease of pitch. and Lasing wavelength is blue shifted from 681.0 to 662.5 nm and the lasing at the edge of photonic band gap. Negative liquid crystal cell has better stability under electric field effect. PMID- 30000998 TI - [Quantum State-Resolved Energy Redistribution of CO2 from Collisions with Highly Vibrationally Excited NaH]. AB - Degenerate stimulated hyper-Raman pumping is used to excite high vibrational states of NaH. The full state-resolved distribution of scattered CO2(0000, J) molecules from collisions with excited NaH(nu"=14, J=21) was reported. The nascent number densities of NaH were determined from absorption measurements at times t=1 MUs as the laser to prepare NaH(nu", J"). Absorption signals were converted to NaH(nu", J") population using absorption coefficients and the transient Doppler-broadened linewidths. The nascent CO2(0000, J) population were obtained from transient overtone laser induced fluorescence line intensity measured at short times relative to the time between collisions. The scattered CO2(0000, J=2~80) molecules had a biexponential rotational distribution. Fitting the data with a two-component exponential model yielded CO2 product distributions with Trot=(650+/-80) and (1 531+/-150) K. The cooler distribution accounted for 79% of the scattered population and resulted from elastic or weakly inelastic collisions that induced very little rotational excitation in CO2. The hotter distribution involved large changes in CO2 rotational energy and accounted for 21% of collision. Nascent translational energy profiles for scattered CO2 (0000, J=60~80) were measured using high resolution transient overtone fluorescence. The relative translational energy of the scattered molecules increased as a function of final CO2 rotational state with =582 cm-1 for J=60, and 2 973 cm-1 for J=80. Energy transfer rates were determined for the full J-state distribution by monitoring the change of the nascent population. The total rate constant for appearance of scattered CO2(0000) was kapp=(7.2+/-1.8)*10(-10) cm(3).mol(-1).s( 1). The depletion for the low-J CO2 states was involved in the collisional energy transfer of the initial distribution. For J=2~38, the average rate constant for depletion of scattered CO2(0000) is =(6.9+/-1.7)*10(-10) cm(3). mol(-1).s( 1). PMID- 30000999 TI - [Characterization of Plasma Induced by Laser Effect on Coal Sample]. AB - With the output of an OPG/OPA pumped by the third harmonic output 355 nm of a pulsed Nd.YAG laser as radiation source, the emission spectrum of laser induced coal sample plasma is created. The emission spectral line shows the character of Lorenz profile. So Stark broadening is the main widening way of this plasma system. The spatial distribution of the plasma temperature and electron density is measured from the intensity and Stark broadening of the spectral lines. It is found that in the direction from vertical to plasma luminous flame, both plasma temperature and electron density are symmetrically relative to the center. While in the direction of parallel to plasma luminous flame, they are asymmetrically relative to the center. Plasma temperature and electron density is maximized in the centre of the flame, and the emission intensity of the plasma in the centre is also strong. So we ought to collect the emission spectrum in the plasma centre when using the technique of spectroscopy for the diagnosis of plasma characteristics. It is also found that there is a dip in the centre of some spectral lines. This indicates that there exists strong self-absorption in the plasma. The appearance of self-absorption varies with laser wavelength. It is most obvious when the wavelength is near to the center of the profile, because the transition probability is the largest at the center of the profile. Both emission intensity and self-absorption increase with laser energy. These experimental results can be interpreted as the increase of the particle density with laser energy. Thus we ought to select spectral lines with no self-absorption when measuring the parameters of the plasma with the technique of laser spectroscopy. This can ensure higher detection accuracy. PMID- 30001000 TI - [The Optics and Magnetic Properties of Cr Doped ZnO Thin Films]. AB - The precursor solution is sent to the ultrasonic nozzle directly through a needle tube to prepare Zn1-xCrxO (x=0, 0.01, 0.03 and 0.05)films on quartz substratesby ultrasonic spray method. The structures, optical and magnetic properties of the films were measured by X-ray diffracmeter(XRD), scanning electron microscope(SEM), fluorescence spectrometer, ultraviolet-visible light detector, vibrating sample magnetometer (VSM) and so on. The experimental results indicate that, the undopedZnO thin films exhibit the hexagonal wurtzite crystalline structure with a preferential orientation of (002); the Cr doping restrains the preferred orientation of C axis; the average grain sizes of the samples increase withCr doping, and thesize attains the maximum(31.4 nm) when x=3%. The SEMimages show that the Zn1-xCrxO (x=0, 0.01, 0.03 and 0.05) films are grain-like particles. And it exhibits a long strip shape when x=5%. Moreover, the doping of Cr makes the photoluminescence (PL) spectra of Zn1-xCrxO films change evidently. The undoped sample shows an ultraviolet emission peak at 378 nm as well as a defect related green peak at around 550 nm. However, for the doping samples, there is only a wide range of emission peak from 350 to 550 nm. By gaussian fitting,it is found that VZn, Zni and V-Zn defects exist in the Cr doping films, and VZn is largest when x=3%. The band gap increases with the doping of Cr, and reaches the maximum when x=3%. The doping of Cr hasthe band gap of the samples increase, and the band gapreachs themaximum(3.37 eV) when x=3%. Magnetic measured results show that threedoping samples Zn1-xCrxO(x=1%, 3% and 5%) are ferromagnetic at room temperature, and the magnetization of Zn1-xCrxO (x=3%) is the largest, which is corresponding to the most VZn defect. The experimental results also prove the the oretical prediction that the substitutive Cr in the oxidation state of +3 and the neutral Zn vacancy in the ZnO?Cr sample are the most favorable defect complex to maintain a high stability of ferromagnetic order. PMID- 30001001 TI - [Calibration Transfer of Near Infrared Spectrometric Models for Crude Protein of Protein Feed Materials]. AB - The near infrared spectrometric quantitative model of protein feed and its sharing in different instruments can greatly improve the utilization efficiency of the model and meet the needs of rapid development of feed industry. Considering the issue of applicability of near infrared spectrometric models for crude protein of protein feed materials, calibration transfer was explored among three types of instruments using spectral subtraction correction, direct standardization and piecewise directs standardization methods for the first time. Four kinds of protein feed raw materials were involved in the present study, corn protein powder, rapeseed meal, fish meal and distillers dried grains with soluble. The experimental instruments included MATRIX-I Fourier transform near infrared instrument (master instrument), Spectrum 400 Fourier transform near infrared instrument (slave 1 instrument), and SupNIR-2750 grating near infrared instrument (slave 2 instrument). Results showed that the spectral data difference for all the samples between the master and slave 2 instrument was relatively small, and the difference between the master and slave 1 instrument, and slave 1 and slave 2 instrument were relatively large. All the root mean square error of prediction and bias values after calibration transfer were lower than the values before calibration transfer, except that no improvement was found for the prediction of corn protein powder of slave 2 instrument corrected by piecewise direct standardization method. The relative prediction deviation (RPD) of corn protein powder, rapeseed meal and distillers dried grains with soluble transferred by all three methods were higher than 3, which indicated good predictions, while the RPD of fish meal were all higher than 2.5, which indicated relative good predictions. All three techniques used in the study were effective in the correction of the difference between different instruments for protein feed materials. This study is of important practical significance for the application of near infrared spectrometric models for crude protein of protein feed materials. PMID- 30001002 TI - [Optimizing Savitzky-Golay Parameters and Its Smoothing Pretreatment for FTIR Gas Spectra]. AB - In the smoothing pretreatment for the quantitative analysis of hydrocarbon mixed gases by Fourier transform infrared analysis (FTIR), the Savitzky- Golay filter is usually used as one of the smoothing preprocessing methods in the Fourier transform infrared spectrum data smoothing pretreatment. However, the parameters of the Savitzky-Golay filter such as the polynomial order and frame size are not easy to decide. There is no one unified choice basis. Users usually adopt multiple sets in the special data set to try, and then select a set of relatively optimal data as the optimizing parameters of the Savitzky-Golay filter. The optimal selection method of the Savitzky-Golay filter parameters was explored, and the concrete calculation equations were deduced according to the relation among the normalized cut-off frequency, the normalized beginning frequency of the stopband, the normalized first side lobe peak frequency of the stopband, the normalized first side lobe peak amplitude with the polynomial order and frame size of the Savitzky-Golay filter parameters. Then when the polynomial order and frame size are set as 8 and 11 respectively according the above conclusion and the characteristics of the actual spectral data, the Savitzky - Golay filter smoothing effect is optimum. Through the acquisition the concentration of 0.1%, 0.2%, 0.5%, 1%, 2%, 5% for the actual CH4 spectra, the relative maximum and minimum error of the raw spectra converted absorbance were 17.230 5% and 0.243 0% respectively, and the relative maximum and minimum error of the smooth spectra converted absorbance were 0.088 0% and 0.088 0% respectively in the second absorption peak. The relative error of converted absorbance was basically stable through the Savitzky-Golay filter after the spectral data preprocessing and it was relatively low, so, it laid a foundation for the late spectral data accurate qualitative and quantitative analysis. PMID- 30001003 TI - [Application of Wavelet Transform and Successive Projections Algorithm in the Non Destructive Measurement of Total Acid Content of Pitaya]. AB - The objective of present study was to find out an accurate, rapid and nondestructive method to detect total acid content (TA) of pitaya with visible/near-infrared spectrometry, wavelet transform (WT) and successive projections algorithm (SPA), which will provide scientific basis for non- destructive measurement of pitaya. Maya2000 fiber-optic spectrumeter was used to collect spectral data of pitaya on the wavelength in the range of 380~1 099 nm; and then with the methods of WT denosing pretreatment, SPA and partial least squares regression (PLSR) quantitative forecasting model of TA of pitaya was established. The result showed that the precision of WT-SPA-PLSR model, which combine the WT with SPA, was better than that of PLSR model based on the whole wave variables. The relation coefficient of the PLSR model (Rp) that predicted TA based on the original spectrum of all samples as the input variables was 0.851 394 and RMSEP was 0.086 848. The original spectrum variable of the all samples were processed by using wavelet function dbN(N=2, 3, ..., 10) for wavelet decomposition and de-noising. The optimal results of noise reduction were decomposed in level 2 using wavelet function db4 (db4-2). The Rp of WT-PLSR model was 0.915 635 and RMSEP was 0.066 752. The prediction of model using wavelet transform de-noising was improved significantly. After the original spectrum processed by db10-3 and SPA, 12 preferred variables were selected from 570 spectrum variables, such as 530, 545, 604, 626, 648, 676, 685, 695, 730, 897, 972, 1 016 nm spectrum variables. The WT-SPA-PLSR model based on these 12 variables as input variables was established. Rp of the WT-SPA-PLSR prediction model was 0.882 83 and RMSEP was 0.077 39. SPA algorithm was suitable for the selection of spectrum variables which could effectively obtain the spectrum variables which were strong correlation with TA and increase the accuracy and stability of the prediction model. The results indicated that the nondestructive detection for TA of pitaya based on the diffuse reflectance visible/near-infrared spectrometry, WT and SPA was feasible. PMID- 30001004 TI - [Study on the Nondestructive Detection Methods for Dynamica Change of Lipid Content in Chlorella sp.]. AB - Microalgae based biodiesel production requires a large amount of lipid accumulation in the cells, and the accumulation is greatly influenced by the environment. Therefore, it is necessary to find fast and non-destructive methods for lipid change detection. In this paper, Chlorella sp. was adopted as the objective, which was cultured under different light condition consisted of red and blue lights with different proportion. We applied the visible near-infrared spectroscopy (Vis/NIRs) technique to detect the dynamic change of lipid during the microalgae growth processes and utilized hyperspectral imaging technology for visualization of lipid distribution in the suspension. The transmittance and reflectance spectra of microalgae were acquired with Vis/NIRs and hyper spectroscopy, respectively. In the comparison of the transmittance and reflectance spectra, they showed some different characteristics. Meanwhile it also varied in terms of the number and the area of feature wavelengths obtained by successive projections algorithm (SPA) based on the different spectra. But the established multiple linear regression (MLR) model for lipid content prediction had similar results with rpre of 0.940, RMSEP of 0.003 56 and rpre of 0.932, RMSEP of 0.004 23, respectively. Based on the predictive model, we obtained the spectra and analyzed the lipid dynamic change in microalgae in one life cycle. In the life cycle, the lipid content in Chlorella sp. was relatively stable from the beginning of inoculation to exponential phase, the increase and accumulation of lipid phenomenon occurred in the late exponential phase. Combined with the MLR model and the hypersepctral images, we studied the visualization result of microalgae suspension in the steady phase. The stimulated images showed that the microalgae with higher lipid content appeared gathering. This study compared the difference and the feasibility of the Vis/NIRs and hyperspectral imaging technique in lipid content detection applied in microalgae growing microalgae. The results are meaningful for the fast and non-destructive detection of the growth information of microalgae. It has boththeoretical and practical significance for developing microalgal culture and harvest strategy in practice. PMID- 30001005 TI - [Study on the Discrimination of FTIR Spectroscopy of Gentiana Rigescens with Different Harvest Time]. AB - The harvest time of traditional Chinese medicine (TCM) is a very essential part for the production and quality of TCM which is the prerequisite for safe and effective clinical use of TCM. It is of great importance to carry out the research of timely harvest time of TCM. With Fourier transform infrared spectroscopy (FTIR) to study harvest time of Seventy-two Gentiana Rigescens samples. First derivative, second derivative, standard normal variate, multiplicative scatter correction and Savitaky-Golay(15,3) smoothing of all original spectra were pretreated with TQ8.0 software. Samples were divided into calibration set and prediction set at the ratio of 3?1. Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) model were established. The result indicated that after removing noise spectrum, the spectra range was from 1 800 to 600 cm-1, the method SNV combined with SD and SG present the best result of spectra pretreatment. The contribution rates of first three principal components were 92.47% with PCA. Small differences were found for the samples harvested in May, September and October. Same spectrum range was chosen and PLS-DA was applied to establish the model. The R2 and RMSEE were 0.967 8, 0.086 0, respectively, and the prediction accuracy is 100%. The methods of PCA and PLS-DA have good ability to classify and identify different harvest time of Gentiana Rigescens. It provided a basis for the identification of different harvest time of TCM. PMID- 30001006 TI - [Identification of Planting Area and Varieties of Rapeseeds by Infrared Spectroscopy Combing with Stepwise Discriminatory Analysis]. AB - The planting area and varieties of rapeseeds were studied based on Fourier transform infrared spectroscopy (FTIR) combining with stepwise discriminatory analysis. The FTIR of 188 rapeseed skin samples of 17 varieties from 5 planting areas was obtained and processed by OMINC 8.0 software. In order to distinguish their planting area and variety, 5 spectra in the range of 1 800~950 cm-1 for each variety from each producing area were selected as training samples arbitrarily with Fisher linear discriminatory criterion which was used to build model by means of stepwise discriminatory analysis by SPSS20.0 software. All the five discriminatory models based on Wilks'Lambda, Unexplained variance, Mahalanobis distance, Smallest F value and Rao's v can distinguish variety and planting area well, and the best one for identifying variety was on the base of Wilks'Lambda, which yielded correct rate of 97.9%, and the best one for distinguishing planting area was on the base of Unexplained variance with a correct rate of 98.4%. The results showed that discriminatory analysis based on the infrared spectrum of rapeseed skin is an efficient method for identification of rapeseed variety and planting area. PMID- 30001007 TI - [Study on the Discrimination of Gentiana Rigescens with Different Processing Methods by Using FTIR Spectroscopy]. AB - The Processing of traditional Chinese medicine (TCM) is the key to clinical application of TCM, and processing has functions such as enhancing the efficacy, attenuating the toxicity andmoderating medicine property. In order to the realizing safe, reasonable and effective use of medicine in clinical, research on identification of TCM processed products is of great significance. The Gentiana rigescens samples which processed with five different methods were discriminated by Fourier transform infrared spectroscopy (FTIR). Baseline correction and normalization were used to pretreat all original spectra and the noise was cut off. The spectra range was from 3 400 to 600 cm-1. The effect of multiple scattering correction and standard normal variable on the model were observed and compared. Samples were divided into calibration set and prediction set at the ratio of 3?1. The principal component analysis (PCA) was applied to reduce data dimensionality and discriminant analysis model was established. The result indicated that the main absorption peaks of samples were 3 378, 2 922, 1 732, 1 610, 1 417, 1 366, 1 316, 1 271, 1 068, 1 048 cm- 1 which 1 738, 1 643, 1 613, 1 420, 1 051 cm-1 as to gentiopicrin; 1 068, 1 048, 935 cm-1 as to carbohydrate. The accumulation contribution rate of first three principal components is 94.05%. Most of the information reflected the original data. There were differences among different samples. The result of discriminant analysis showed that the recognition rate of G. rigescens samples could achieve to 100% based on baseline correction and normalization treatment combined with MSC with the precondition of principal component scores being 10. In conclusion, FTIR is a feasible, rapid and non-destructive method to discriminate G. rigescens samples wtih different processing methods. It also provided reference for discrimination of processed products of medicine materials. PMID- 30001008 TI - [Research on Pyrolysis Process of Kevlar Fibers with Thermogravimetric Analysis coupled and Fourier Transform Infrared Spectroscopy]. AB - Modern industrial application and technologies require materials with superior mechanical and thermal properties. Kevlar fibers have been known as fibrous materials with good properties of high strength and high decomposition temperature which have become a hot research field in recent years. The properties of fibrous materials depend on their structures and compositions. Thermal decomposition processing of the materials is of great significance for their structures and thermal properties. As a new technique, thermogravimetric (TG) analysis coupled with Fourier transform infrared spectroscopy(FTIR), are able to analyze materials not only qualitatively but also quantitatively. This method has obvious advantages in researching the thermal decomposition of many materials. However, the thermal decomposition processing of Kevlar fibers is rarely reported in the literature, therefore, we firstly studied the pyrolysis behavior of Kevlar fibers with thermogravimetric analysis coupled with Fourier transform infrared spectroscopy at the temperature of 30~800 C. We not only obtained the processing of the Kevlar fibers' thermal decomposition with great details but also the products of every stage. Experimental results exhibited that the decomposition of Kevlar fibers has experienced three stages: 100~240, 240~420 and 420~800 C. The weight loss of Kevlar fibers was quite slow before 500 C. The third stage was the main stage of the decomposition, and the amount of residue finally reached to a mass percent of 56.21%. FTIR analysis illustrated that free water released from Kevlar fibers at the first stage, followed by the dehydration and depolymerization which made polymer chains short. Finally the fiber fragments further reacted and produced the gases of small molecular mass, and the main products were water, ammonia, carbon monoxide and carbon dioxide. Generation rate of water was increased; the emission of ammonia was at the same rate; carbon monoxide was only produced at the temperature of 515~630 C, then turned into carbon dioxide. The release of carbon dioxide was on rise because of the conversion process of carbon monoxide, and then dropped to a certain value. PMID- 30001009 TI - [Soil Moisture Monitoring Based on Angle Dryness Index]. AB - Soil moisture content (SMC) is one of the most important indicators influencing the exchange of energy and water among vegetation, soil, and the atmosphere. Accurate detection of soil moisture content is beneficial to improving the precision of crop yield evaluating and field management measures. In this paper, a novel method ADI (Angle Dryness Index) based on NIR-RED spectral feature space used for calculating SMC was proposed, which improved the accuracy of calculating SMC with red and near infrared band reflectance. It was found that an intermediate parameter theta in NIR-RED feature space was significantly related to SMC, and independent of vegetation coverage according to the linear decomposition of mixed pixel and the empirical correlation between SMC and red/NIR band reflectance which were achieved by previous researches. Then, ADI was proposed with the feature discovered in the paper. The mathematical expression on SMC is nonlinear, and the newton iterative method is applied to ADI for calculation SMC. Then, the newly proposed method was validated with two kinds of remote sensing imagery data (Thematic Mapper (TM) and moderate resolution imaging spectrometer (MODIS)) and the synchronous observed data in the field. Validation results revealed that the ADI- derived SMC was highly accordant with the in-situ results with high correlation (R2=0.74 with TM and R2=0.64 with MODIS data). We also calculated MPDI (Modified Perpendicular Drought Index) developed by Ghulam, which is also proposed with the red and near infrared reflectance. The result showed that the accuracy of MPDI was lower than that of ADI. The most likely reason was that ADI was insensitive to fv, but the calculation errors of fv would reduce the accuracy of SMC estimation. MODIS had a low spatial resolution, thus there may be more than two end members in a mixed pixel. In this case, the linear decomposition of mixed pixel was not applicable and the errors would finally be enlarged. ADI achieved good results in monitoring SMC in vegetated area because it was less influenced by vegetation coverage than other similar approaches. ADI only requires the satellite image data including the red and near infrared band which are available from most of the optical sensors. Therefore, it is an effective and promising method for monitoring SMC in vegetated area, and would be widely used in agriculture, meteorology, and hydrology. PMID- 30001010 TI - Lower readmission rates linked to Medicare's HRRP. PMID- 30001011 TI - [Experimental Study and DFT Calculation of FTIR, FT-Raman and THz-TDS Spectra of I and III Polymorphs of Chlorpropamide]. AB - The absorption spectra of I and III polymorphs of chlorpropamide were measured with terahertz time-domain spectroscopy (THz-TDS) technique, FT-IR and FT-Raman at room temperature. The results showed that there were distinct differences of I and III polymorphs of chlorpropamide in those spectra. The IR spectra of two polymorphs of chlorpropamide had showed differences both in the frequencies of the vibrational bands and in the relative band intensities. The obvious differences in Raman spectra of polymorphs of chlorpropamide were that the characteristic peaks of III- form were more than I-form in 100~1 800 cm-1 region. Absorption peaks observing in the terahertz spectra ofI-form were at 0.90, 1.09 and 1.29 THz and III-form were at 0.92, 1.11, 1.23 and 1.63 THz. The maximum difference between I-form and III-form was that the strong peak appeared at 1.63 THz of III-form. The characteristic absorption bands of two polymorphs of chlorpropamide were assigned based on the simulation results of DFT calculation. The simulation result is in accordance with the experiment. From simulation results, it is found that the vibration modes of I-form and III-form were similar in IR and Raman spectra, but there were more differences in terahertz spectra. The study can provide experimental and theoretical references for the application of FT-IR , FT-Raman and THz-TDS spectra techniques to detect pharmaceutical polymorphs. PMID- 30001012 TI - [Effects of Enhanced Ultraviolet B Irradiation on Photosynthetic and Antioxidant System of Sorghum Seedlings]. AB - The UV-B radiation on the surface of our planet has been enhanced due to gradual thinning of ozone layer. The change of solar spectrum UV-B radiation will cause damage to all kinds of terrestrial plants at certain degree. In this paper, taking breeding sorghum (Sorghum bicolor (L.Moench))variety Longza No.5 as sample, 40 MUW.cm-2 UV-B radiation treatment was conducted on sorghum seedlings at two-leaf and one-heart stage and different time courses; then after a 2 d recovering, photosynthetic parameters were measured with a photosynthetic apparatus; the activities of antioxidant enzymes were detected as well. Our results revealed that, as the dosages of UV-B increasing, leaf browning injury was aggravated, plants dwarfing and significantly were reduced fresh weight and dry weight were observed; anthocyanin content was significantly increased; chlorophyll and carotenoid content significantly were reduced and net photosynthetic rate and chlorophyll fluorescence parameters were decreased. Meanwhile, with the increase in UV-B dosages, stomatal conductance, intercellular CO2 concentration and transpiration rate showed "down - up - down" trend; the activities of SOD and GR presented "down - up" changes; activities of POD and CAT demonstrated "down - up - down", and APX, GPX showed an "up - down - up" pattern. It is worth to note that, under the four-dose treatment, a sharp decline in net photosynthesis in sorghum seedlings was observed at 6 h UV-B treatment (equals to 2.4 J.m-2), and an obvious turning point was also found for other photosynthetic parameters and activities of antioxidant enzymes at the same time point. In summary, the results indicated that the enhanced UV-B radiation directly accounted for the damages in photosynthesis system including photosynthetic pigment content, net photosynthetic rate and chlorophyll fluorescence parameters of sorghum; the antioxidant system showed different responses to UV-B radiation below or above 6 h treatment: ASA-GSH cycle was more sensitive to low-dose UV-B radiation, while high-dose UV-B radiation not only undermined the photosynthesis system, but also triggered plant enzymatic and non-enzymatic antioxidant systems, resulting in leaf browning and necrosis,biomass accumulation reduction, plant dwarfing and even death. PMID- 30001013 TI - [Rapid Detection of Ammonia Nitrogen in Water with Dual-Wavelength Spectroscopy]. AB - Ammonia nitrogen is an important indicator to measure the quality of surface water. In the process of detecting ammonia nitrogen content with Nessler's reagent spectrophotometry method (HJ535-2009), water sample pretreatment (flocculation method), residual turbidity and instrument baseline drifting will bring uncertainty to the process. Accordingly, a spectroscopic method based on dual-wavelength (420 and 650 nm) measurement is proposed, so as to subtract the absorbance of residual turbidity and instrument baseline-drifting to eliminate such interference. We first figure out k, the turbidity correction coefficient of the water sample at the wavelength 420 nm, then divide the product of absorbance of 650 and k by the absorbance of 420, and finally obtain the net absorption of ammonia nitrogen chromogenic reaction. Thus we can make accurate quantitative detection of ammonia nitrogen content and evaluate the precision and accuracy of dual-wavelength spectrometry. The results shows that, with single-wavelength method, the relative deviation can be up to 8.67% caused by the filtration process of flocculation and sedimentation, while the dual-wavelength method would not be affected by the deviation, since dual-wavelength method includes no filtration process. The accuracy standard deviation of dual-wavelength method could be as low as 1.58%, and the recovery is between 98.5% and 103%, which shows that the method is more accurate and reliable. Compared with the current Nessler's reagent spectrophotometric method, the present method not only omits the process of water sample pretreatment, but also avoids the interference of residual turbidity, which could significantly improve the efficiency of the experiment. Therefore, it is more suitable for rapid determination of ammonia nitrogen in large quantities of surface water samples. PMID- 30001014 TI - New staffing schedule unclogs PACU bottleneck. PMID- 30001015 TI - [Research on the Training Samples Selection for Spectral Reflectance Reconstruction Based on Principal Component Analysis]. AB - The composition of training samples set is an important influence factor of spectral reflectance reconstruction process. Representative color samples selection for learning-based spectral reflectance reconstruction is discussed in this paper. A method based on Principal Component Analysis (PCA) is proposed to perform sample selection. First of all, a part of samples are selected according to the minimum Euclidean distance criteria in terms of camera response value from a large number of samples, which aim to ensure the similarity between training samples and target samples. Then the PCA data processing method is applied to these samples after removing the duplicate samples. The samples with larger principal component loadings are regarded as the representative color samples. Different thresholds for each principal component are used to make decision whether the loading of sample is large enough. In order to validate the proposed method, the selected samples are used as training samples to recover the spectral reflectance of color patches. A real multi-channel imaging system by loading broadband color filters in front of lens is used in the experiment to acquire the multi-channel image dataset. In this paper the pseudo-inverse method is employed to reconstruct spectral reflectance of target color patches. It is shown that the proposed method is superior to the previous methods in spectral reconstruction accuracy and can meet the requirements of high precision color reproduction. PMID- 30001017 TI - [Synthesis of LaPO4?Ce, Tb Fluorescent Nanopowders and Their Applications in Nondestructive Development of Latent Fingerprints]. AB - LaPO4?Ce, Tb fluorescent nanopowders with high quality were synthesized via a hydrothermal method. The size, phase, and fluorescent property of as-prepared fluorescent nanopowders were then characterized by transmission electron microscopy (TEM), powder X-ray diffraction (XRD) measurements, and fluorescence spectroscopy (FS). The fluorescent nanopowders were well-dispersed and rod-like in shape, with an average diameter of about 20 nm and an average length of about 700 nm. The fluorescent nanopowders were of pure monoclinic LaPO4 structure. They could emit strong green fluorescence under the 254 nm ultraviolet excitation. The LaPO4?Ce, Tb fluorescent nanopowders were finally used as novel fluorescent labels for the nondestructive development of latent fingerprints on various smooth substrates, and the developing contrast, sensitivity, selectivity, as well as the background interference were also discussed in detail. The experimental results showed that the latent fingerprints labeled by LaPO4?Ce, Tb fluorescent nanopowders could give strong green emissions under 254 nm ultraviolet lights, and thus well-defined friction ridges with sharp edges and some detailed features could be clearly observed, with high contrast, high sensitivity, high selectivity, and low background interference. It was shown that our development procedure was facile, effective and well applicable with outstanding performance. More importantly, the extraction and detection of DNA in fingerprint residues could also be achieved after fingerprint development, which was almost impossible to achieve by using the traditional used developing powders including metal powder, metallic powder, and fluorescent powder. Therefore, our work provides beneficial references for the full utilization of both fingerprints and DNA evidences. PMID- 30001016 TI - [Monitor of Cyanobacteria Bloom in Lake Taihu from 2001 to 2013 Based on MODIS Temporal Spectral Data]. AB - Algal bloom highly impacts the ecological balance of inland lakes. Remote sensing provides real-time and large-scale observations, which plays an increasingly significant role in the monitoring of algal bloom. Various Vegetation Indices (VIs) derived from satellite images have been used to monitor algae. With threshold segmentation of VI, the area of algal bloom can be extracted from images. However, the result of threshold segmentation only reflects the condition of algae when images were generated. Compared to separated VI data obtained at a particular moment of time, temporal spectral VI data contains phonological information of algae, which may be used to evaluate algal bloom more accurately and comprehensively. This study chose MODIS NDVI data of the Lake Taihu from 2001 to 2013, and constructed temporal spectral data for each year. Then, we determined the feature temporal spectra of severe cyanobacteria bloom, moderate cyanobacteria bloom, slight cyanobacteria bloom and aquatic plants, and separated these four kinds of objects using SVM (Support Vector Machine) algorithm, getting the spatial distribution and area of them. In order to compare the results of our method with traditional threshold segmentation method, we chose 8 separated NDVI images from the temporal spectral data of 2007. With the threshold 0.2 and 0.4, cyanobacteria bloom was classified into three degrees: severe cyanobacteria bloom, moderate cyanobacteria bloom, and slight cyanobacteria bloom. By comparison, it showed that our method reflected cyanobacteria bloom more comprehensively, and could distinguish cyanobacteria and aquatic plants using the phonological information provided by NDVI temporal spectra. This study provides important information for monitoring the algal bloom trends and degrees of inland lakes, and temporal spectral method may be used in the forecast of algal bloom in the future. PMID- 30001018 TI - [Research on Remote Sensing Inversion of Suaeda Salsa's Biomass Based on TSAVI for OLI Band Simulation]. AB - Suaeda salsa(S.salsa) is a typical vegetation of coastal wetland in the north of Liaodong Bay. The S. salsa biomass assessment plays an important role in understanding the ecosystem productivity of coastal wetland and the formation of ecosystem structure and function. Usually the S.salsa coverage is inhomogeneous. The low S.salsa coverage can be found at a natural condition, the soil background has a strong influence on S.salsa spectral data. The Transformed Soil Adjusted Vegetation Index (TSAVI) used as independent variable was derived by the Landsat 8 OLI simulation data. The S.salsa biomass inversion models were built based on the regression analysis of TSAVI and ground measured biomass in this study. The correlation between TSAVI (600~687, 820~880 nm) and biomass was significant, the correlation coefficient was about 0.9, up to 0.92. The results of linear and quadratic models were better than those of logarithmic, exponential and power models, the determination coefficient r2 of linear and quadratic models were 0.83. Combined with F value and operation efficiency, the linear model was the best option for mature S.salsa biomass inversion. The linear model was applied to invert the S.salsa biomass by using the Landsat 8 OLI data in the study area and it was further validated using in-situ data. The correlation coefficient between the in-situ value and retrieved value was 0.962, the relative error was 0.106. For higher S.salsa coverage, the relative error was lower. The relative error of the low-cover S.salsa biomass inversion was around 0.18. The results showed that the established model has good accuracy for different coverage. In addition, with the introduction of +/-5% error of soil line parameters a and b, the average relative errors were relatively stable, and the correlation coefficients were reduced, but all the correlative coefficients were above 0.9. The results showed that the established model is stable. PMID- 30001019 TI - [Identification of Strawberry Ripeness Based on Multispectral Indexes Extracted from Hyperspectral Images]. AB - In order to establish new multispectral indexes for automatic identification of strawberry ripeness, hyperspectral imaging technology was applied in this paper. Eight indexes: Ind1=R730+R640-2*R680, Ind2=R680/(R640+R730), Ind3=R675/R800, IAD=log10(R720/R670), I1=R650/R550, I2=R650/R450, I3=R650/(R450+R550), I4=2*R650 (R550+R450) were calculated by extracting average spectral of strawberry samples and their identification effects of strawberry samples in three ripening stages(mature, nearly mature and immature) were judged with Fisher linear discriminant(FLD). The result showed that the identification effects of linear discriminant analysis model based on index I4 was the best among 8 indexes and the identification accuracy of modeling and prediction set was 90% and 91. 67% respectively. Three wavelengths (535, 675, 980 nm) related to strawberry ripeness were extracted based on average spectral of strawberry samples and 4 new indexes were established based on these three wavelengths: i1=2*R675- (R980+R535), i2=R675/(R980+R535), i3= (R675-R535)/(R675+R535), i4=[R675- (R535+R980)]/[R675+(R535+R980)]. The identification effects was judged with FLD and the results showed that the effects of linear discriminant analysis models based on i1, i2, i4 were better than index I4 and the identification accuracy of modeling and prediction set was 95.83%,95.83%,95.83% and 95%,95%,96.67% respectively. In conclusion, new established indexes i1, i2, i4 could be used in automatic identification of strawberry ripeness. PMID- 30001020 TI - START makes a good case for greater scheduling accuracy. PMID- 30001021 TI - [Inversion of Soil Organic Matter Content Using Hyperspectral Data Based on Continuous Wavelet Transformation]. AB - Soil organic matter content (SOMC) is an important parameter that reflect soil fertility available for crop production, and monitoring of the SOMC dynamically has shown great importance to promote the development of precision agriculture. In recent years, many researchers have tried to use proximal soil sensing, especially using the proximal hyperspectral techniques to acquire different kinds of spectral data under the field and laboratory conditions, and various new algorithms are also introduced to build inversion models to predict SOMC from spectra for different regions and different kinds of soils. In this paper, the hyperspectral reflectance of different soil samples was measured using the ASD FieldSpec3 spectrum analyzer. At the same time, the SOMC of each soil sample was analyzed using potassium dichromate external heating method in the laboratory. The correlation analyses between raw soil spectral reflectance (R) and SOMC were done, and it could select sensitive wavebands reflectance when the determination coefficients (R2) exceeded 0.15. A continuous wavelet transform (CWT) was also performed on R and the continuum removal curves (CR) to generate a wavelet power scalogram in different scales, the correlation analyses were done between wavelet power coefficients and SOMC, and it could select the sensitive wavelet coefficients when the R2 exceeded 0.3. Then, after extracting wavebands reflectance from R and wavelet power coefficients from R-CWT, CR-CWT, the estimation models for SOMC had been successfully built by partial least squares regression (PLSR), BP neural network (BPNN), support vector machine regression (SVMR), respectively. The results showed that, compared to the R2 between SOMC and R, the R2 between SOMC and R- CWT, CR-CWT wavelet coefficients were increased by about 0.15 and 0.2. The CR-CWT-SVMR model was the best, its R2, RMSE and RPD value of validation set were 0.83, 4.02, 2.48, which could estimate SOMC comprehensively and stably. For the CR-CWT-PLSR model, although there was a slight gap in the prediction accuracy with that CR-CWT-BPNN and CR-CWT-SVMR models, it also had its own unique advantages: the model was simple and thus the computation speed was reduced significantly. In the future, the results can provide good potential for field proximal sensing researching. PMID- 30001022 TI - [Experimental Study on Soil Moisture Remote Sensing Based on Polarization Spectrum]. AB - As a novel remote sensing technique, polarimetric detecting technology is a useful supplement to traditional hyperspectral remote sensing technology, which provides more information for remote sensing. By taking advantage of the polarization characteristics of the surface reflecting light of soil with different moisture, the polarization spectral method is applied to measure soil moisture. The spectropolarimeter was used to measure the polarized reflectance spectrum of different soil moisture. The correlation between soil moisture and polarization spectrum was analyzed. The polarization characteristics of soil surface reflecting light in different viewing angles were surveyed by experiments. The experimental results show that: in the higher soil moisture conditions, the polarization spectrum and soil moisture have a certain connection, especially in the 500~700 nm band and soil moisture is directly proportional to the degree of polarization; but in low soil moisture conditions, the correlation of polarization spectrum and soil moisture is not obvious; in addition, the polarization spectrum are influenced by viewing angles, for example, when the incident angle of source light is fixed at 50 degrees , while the viewing angle of instrument is between 20 degrees and 60 degrees , the degree of polarization increases with the viewing angle. When the viewing angle becomes wider,, the degree of polarization changed more significantly with the soil moisture. PMID- 30001024 TI - Top 10 Patient Safety Concerns for 2017. PMID- 30001023 TI - Preverence card cleanup projected to cut costs across departments. PMID- 30001025 TI - [Study on Photocatalytic Performance of LaPO4 Nanorods with Different Crystal Phases]. AB - Rare earth phosphate has a wide application in optical materials, laser materials and many fields with great development prospects. In this paper, LaPO4 nanorods with different crystalline phases are prepared with hydrothermal method, its photocatalytic performance are discussed, as well as the structure and UV diffuse reflectance spectroscopy. The research indicates that the hydrothermal temperature plays a key role in the crystal phase, while it is hexagonal at 120 C, monoclinic at 180 C and the mixed phase at 160 C. The UV absorption has no obvious change of each crystalline phase, and they all show nanorods. The photocatalytic activity of LaPO4 for the degradation of MB is studied; it is found that the monoclinic LaPO4 has the best photocatalytic activity. Furthermore, monoclinic LaPO4 could decrease the fluorescence quantum efficiency and increase the separation efficiency of electrons and holes, which improve the photocatalytic activity. Besides, the main active species are confirmed to be hydroxyl radicals with capture experiments during the photocatalytic process. PMID- 30001026 TI - Concider a sterilization subject matter expert to increase compliance. PMID- 30001027 TI - Choose the right linen service to match supply with demand. PMID- 30001028 TI - [Automatic Assessment of Facial Nerve Function Based on Infrared Thermal Imaging]. AB - Facial paralysis which is mainly caused by facial nerve dysfunction is a common clinical entity. It seriously devastates a patient's daily life and interpersonal relationships. A method of automatic assessment of facial nerve function is of critical importance for the diagnosis and treatment of facial paralysis. The contralateral asymmetry of facial temperature distribution is one of the newly symptoms of facial paralysis patients which can be captured by infrared thermography. This paper presents a novel framework for objective measurement of facial paralysis based on the automatic analysis of infrared thermal image. Facial infrared thermal image is automatically divided into eight regional areas based on facial temperature distribution specificity and edge detection, the facial temperature distribution features are extracted automatically, including the asymmetry degree of facial temperature distribution, effective thermal area ratio and temperature difference. The automatic classifier is used to assess facial nerve function based on radial basis function neural network (RBFNN). This method comprehensively utilizes the correlation and specificity of the facial temperature distribution,extracts efficiently the facial temperature contralateral asymmetry of facial paralysis in the infrared thermal imaging. In our experiments, 390 infrared thermal images were collected from subjects with unilateral facial paralysis. The results show: the average classification accuracy rate of our proposed method was 94.10%. It has achieved a better classification rate which is above 9.31% than K nearest neighbor (kNN) classifier and 4.87% above Support vector machine (SVM). This experiment results is superior to traditional House-Brackmann facial neural function assessment method. The classification accuracy of facial nerve function with the method is full compliance with the clinical application standard. A complete set of automated techniques for the computerized assessment of thermal images has been developed to assess thermal dysfunction caused by facial paralysis, and the clinical diagnosis and treatment of facial paralysis also will benefit by this method. PMID- 30001029 TI - Employee engagement: The path to better patient care--Part 1. PMID- 30001030 TI - [Automatic Method for Selecting Characteristic Lines Based on Genetic Algorithm to Quantify Laser-Induced Breakdown Spectroscopy]. AB - Selecting proper characteristic lines from enormous spectral intensities is crucially important to implement quantitative analysis of Laser-Induced Breakdown Spectroscopy using internal standard method. Manual selecting of characteristic lines by researchers is time consuming and energy consuming, which cannot guarantee the best result. An automatic method to select analytical and reference lines for internal standard method from the original spectra based on Genetic Algorithm was proposed in this paper. This method was utilized to select analytical and reference lines for internal standard methods from LIBS of Mn, Ni, Cr, Si and Fe of low alloy steels. The optimal characteristic lines optimized by this method were the analytical line 403.306 8 nm of Mn and the corresponding reference line 368.745 7 nm of Fe, the analytical line 288.157 7 nm of Si and the corresponding reference line 427.176 1 nm of Fe, the analytical line 286.510 0 nm of Cr and the corresponding reference line 272.753 9 nm of Fe and the analytical line 352.453 6 nm of Ni and the corresponding reference line 358.698 5 nm of Fe, respectively. Then these elements were quantified by the internal standard method using these selected lines. The results showed that this proposed method for selecting characteristic lines can automatically select the optimal analytical and reference lines and could guarantee the best quantitative result obtained by internal standard method. PMID- 30001031 TI - [Review on Analytical Methods of Doping Elements in Synthetic Crystals]. AB - During the synthesis of crystal material, specific dopant can enhance the qualities and performance of crystals, while the types, concentrations and distributions of doping elements also have significant influence on the structures and properties of artificial crystals. Hence, it is very important to determine the concentrations of doping elements for further improving the crystal material formulas, crystal growth process, andits quality control. Currently, the analysis techniques for doping elements' characterization include atomic spectrometry, X-ray fluorescence spectrometry, inorganic mass spectrometry, electron probe microanalysis, etc. The principles, advantages and disadvantages of these techniques are discussed in this paper. Considering the specialties and scope of application, it is necessary to choose the suitable methods to improve the efficiency and accuracy. Meanwhile, the developing trends of analysis methods for doping elements are also prospected. PMID- 30001032 TI - [Study on the Detection of Trace Sulphur in Diesel with Inductively Coupled Plasma Optical Emission Spectroscopy]. AB - The method to detect trace sulphur content in diesel with inductively coupled plasma optical emission spectrometry (ICP-OES) was established. Kerosene sample was directly diluted, and then trace sulphur content in the solution was analyzed directly with ICP-OES. High concentrations of organic solvents with high saturation vapor pressure can cause the increasing of the loading of plasma, which would interfere the determination. In order to keep the working stability of equipment, operating parameters, such as RF power, loading gas velocity, were being optimized. First, the axially-viewed technology was adopted to increase the sensitivity of determination. Second, the analysis spectral lines of sulfur are located in ultraviolet area; therefore the Ar was adopted as protective air, and increase Ar clean time to keep the pure of sight source. Third, the condensation and deposition of high concentrations of carbon could be avoided effectively by introducing O2 to plasma. Some detailed processes were used to further keep the stability of determinate signals such as: using element Y as internal standard to correct matrix effectives and compensate the errors caused by the spectral line shift, some automatic software were used to correct signal background. The results showed that the detection limits was 0.2 MUg.L-1, the relative standard deviation (RSD) was in range of 1.6%~2.1%, and the recovery of the methods was in range of 97.4%~101.8%. The method has the following advantages: simple sample pretreatment, fast analyzing speed, low detection limitation, high precision and accuracy, as well as wide linear dynamic range. It can be used for rapid analysis of trace sulfur in diesel. PMID- 30001033 TI - [Study on the Inorganic Components Elements in Rare and Endangered Plant Alsophila Spinulosa]. AB - A method for simultaneously analysis of inorganic elements in rare and endangered plant spinulose tree fern was established. Alsophila Spinulosa samples were pretreated by using the hermetic microwave digestion. Six elements Na, Mg, Al, P, K and Ca were determined by using the inductively coupled plasma optical emission spectrometry (ICP-OES) and ten elements V, Cr, Mn, Fe, Ni, Cu, Zn, Cd, Hg and Pb were determined by using inductively coupled plasma mass spectrometry (ICP-MS). The working conditions were optimized as well. In order to keep the stability of the experiment, low concentration of HCl was added into the sample during testing. Multicomponent Spectral Fitting (MSF) and dynamic reaction cell (DRC) were used to correct the spectral interference and mass interference. Under optimized conditions, the standard linear relationships were satisfactory and the detection limit ranged from 1.87 ng.L-1~12.31 MUg.L-1. Finally, the standard reference material NIST SRM 1 547 (peach leaves) was used to verify the proposed method. The obtained results were consistent with the reference method with the sameaccuracy and precision. Two Alsophila Spinulosa samples analysis results showed that Alsophila Spinulosa have higher concentrations of Na, Mg, K, Ca, Al, and P, and concentration of K is the highest. These results indicated that Alsophila Spinulosa have strong capability in K-enrichment. Alsophila Spinulosa have low concentrations of V, Cr, Mn, Fe, Cu, and Zn. Concentrations of Ni, Cd, Hg, and Pb are at very low trace levels, which indicated that the wild living environment is very healthy. This method has features of fast analyzing, high accuracy and convenience in operation, which can provide scientific basis for Alsophila Spinulosa inorganic elements contents measure. PMID- 30001034 TI - [Study on the Inorganic Components Elements in Rare and Endangered Plant Alsophila Spinulosa]. AB - A method for simultaneously analysis of inorganic elements in rare and endangered plant spinulose tree fern was established. Alsophila Spinulosa samples were pretreated by using the hermetic microwave digestion. Six elements Na, Mg, Al, P, K and Ca were determined by using the inductively coupled plasma optical emission spectrometry (ICP-OES) and ten elements V, Cr, Mn, Fe, Ni, Cu, Zn, Cd, Hg and Pb were determined by using inductively coupled plasma mass spectrometry (ICP-MS). The working conditions were optimized as well. In order to keep the stability of the experiment, low concentration of HCl was added into the sample during testing. Multicomponent Spectral Fitting (MSF) and dynamic reaction cell (DRC) were used to correct the spectral interference and mass interference. Under optimized conditions, the standard linear relationships were satisfactory and the detection limit ranged from 1.87 ng.L-1~12.31 MUg.L-1. Finally, the standard reference material NIST SRM 1 547 (peach leaves) was used to verify the proposed method. The obtained results were consistent with the reference method with the sameaccuracy and precision. Two Alsophila Spinulosa samples analysis results showed that Alsophila Spinulosa have higher concentrations of Na, Mg, K, Ca, Al, and P, and concentration of K is the highest. These results indicated that Alsophila Spinulosa have strong capability in K-enrichment. Alsophila Spinulosa have low concentrations of V, Cr, Mn, Fe, Cu, and Zn. Concentrations of Ni, Cd, Hg, and Pb are at very low trace levels, which indicated that the wild living environment is very healthy. This method has features of fast analyzing, high accuracy and convenience in operation, which can provide scientific basis for Alsophila Spinulosa inorganic elements contents measure. PMID- 30001036 TI - Hospital-academia partnerships steer new nurses to the OR. PMID- 30001035 TI - OR leader job analysis helps sort out roles, responsibilities. PMID- 30001037 TI - [Mapping Applications in Laser-Induced Breakdown Spectroscopy]. AB - LIBS mapping was used to analyze and detect the elemental distribution of iron ore surface with self-developed software and 532 nm Nd?YAG laser. Firstly, in order to illustrate the relationship between element content and spectral intensity, the calibration curve was established by scanning the surface of standard sample. Then, a self-made sample was homogeneously divided into three parts that was pressed by three different standard iron ore powders. For the purpose of validating the mapping technology, a two-dimensional concentration distribution profile was generated after scanning the sample surface which was compared with surface morphology phase of the sample. Finally, with the resolution of 100 microns, the surface scanning analysis of the natural iron ore within the scope of 14 mm*11 mm was implemented. With this basis, the distribution profile of the elements Ca, Al, Ti and Mn were obtained, and the analysis results were compared with the surface morphology phase of the natural iron ore. The results showed that LIBS mapping technology could be used to achieve the qualitative analysis of component gradient distribution of the heterogeneous sample surface. PMID- 30001038 TI - Conference keynote to highlight care coordination. PMID- 30001039 TI - PACU finds its flow in better patient management. PMID- 30001040 TI - [The Study of Organic Nitrogen Uptake by Soil Microorganisms Using Gas Chromatography-Mass Spectrometry and Double Isotope Labeling Technique]. AB - The direct absorption and utilization of low-molecular weight organic nitrogen (N) by soil microbial is a new subject in the research of microbial N nutrition. The study used gas chromatography-mass spectrometry to trace dual-labeled (13C, 15N) glycine from the soil solution and microorganisms. The results showed that glycine added to the soil was quickly taken up by soil microorganisms, with the half-life of glycine being 2.9 h. Withthe incubation of 4 h, the maximum amount of dual-labeled glycine in the microbial biomass was measured (equivalent to 10% of glycine added), indicating that added glycine was absorbed as intact molecular by soil microorganisms. The single labeled-Keto acid was detected in soil solution and in the microorganisms (decomposed production by double labeled glycine), but the content is extremely low, suggesting that added glycine mainly served as carbon (C) source for soil microbial life activities. This study demonstrated that compound specific stable dual labeled isotope analysis combined with chloroform fumigation technique was an effective method for detecting the low-molecular organic N utilized by soil microorganisms. PMID- 30001041 TI - Case cancellations drop dramatically with refined preop screening. PMID- 30001042 TI - [Adsorption Behavior of Pb(II) Ion Imprinted Magnetic Composite Adsorbent in Aqueous Solution by FAAS]. AB - Pb(II) Ion Imprinted Magnetic Composite Adsorbent (Pb(II)-MICA) was prepared for the quick separation of Pb(II) from aqueous solutions by bulk polymenrization with chitosan as the functional monomer, the magnetic iron oxide nano-particles as carrier and epichlorohydrin as the cross-link agent. The Pb(II)-MICA and MNICA were characterized by FTIR. The Effects of the adsorption process including pH, contact time, initial concentration and temperature were investigated by FAAS. It was found that with the increasing of PH value, the adsorption capacity of Pb(II) MICA for Pb(II) reached the peak in the range of pH 5.0~6.0. The maximum adsorption capacity was 32.48 mg.g-1 when the adsorption time was up to 120 min. The relative selectivity coefficient of Pb(II) and other metal ion on Pb(II) MICA were 28.11, 91.14, 76.54, 33.06 times compared with MNICA. The results show that the Pb(II)-MICA displayed strong affinity for Pb(II) in the solution and exhibited selectivity for Pb(II) ion in the presence of Cu2+,Cd2+,Ni2+ and Zn2+. The Langmuir adsorption isotherm models were fit to the adsorption equilibrium data well (r2=1, the saturation adsorption capacities were 33.87 mg.g-1). The adsorption dynamics and thermodynamics of Pb(II) -MICA for Pb(II) were investigated, the results indicated a Langmuir mono-layer mode process of Pb(II) on the Pb(II)-MICA was dominated by chemical action. An exothermic and spontaneous adsorption process of Pb(II) on the Pb(II)-MICA was driven by enthalpy. PMID- 30001043 TI - Adding new business to the ASC, one procedure at a time-Part 3. PMID- 30001044 TI - [Orthogonal Experiment for Optimization of the Sample Pretreatment Conditions for the Serum Cholesterol and Markers Determination by GC-MS]. AB - The objective is to use orthogonal experiment to optimize the pretreatment on the determination of serum cholesterol and its markers by GC-MS. And then the method is evaluated in a methodological perspective. The methodis to Use L16(211) orthogonal experiment design to observe the influence of three key steps,althogether seven factors of pretreatment, which are saponification (KOH ethanol solution concentration, temperature and time), extraction (dose) and derivatization (temperature , time and dose). As for the results,the conditions of optimal pretreatment are as follows:the ethanol solution is 1 mol.L-1 KOH, the saponification temperature is 70 C;the saponification time is 60 min;the Solvent quantity is 2 mL;the derivatization temperature is 70 C;the derivatization time is 60 min,and the derivatization agent is 100 MUL. Through the optimization by orthogonal design and methodological evaluation, the determination of serum cholesterol and its markers by GC-MS is excellent in terms of accuracy and precision, and methodological evaluation indexes are better than those reported in other papers. PMID- 30001045 TI - [Development of a Laser On-Line Cement Raw Material Analysis Equipment]. AB - In engineering construction, cement quality directly affects the safety of construction projects. So it is necessary that we use qualified cement in the engineering structure. It is of great signification that a method detects cement raw material rapidly to adjust the mixture ratio of raw ores to ensure the cement quality. Traditional detection method needs sampling, sample preparation and test, etc. With many procedures, the test results are seriously lagged behind the production process. This paper introduces a set of online analysis equipment to determinate elemental composition of cement powder timely based on laser induced breakdown spectroscopy. This equipment is composed of a LIBS detection system and a pneumatic system. The equipment can achieve the real-time measurement for it needn't sample preparation. Thus, it can guide cement raw material proportioning in time. In this paper, we have quantitatively analyzed the main components of Al2O3, CaO, Fe2O3, MgO and SiO2 in the cement raw materials using the full spectrum normalization method as well as the support vector machine. The corresponding maximum absolute errors were 0.34%, 0.35%, 0.07%, 0.14%, and 0.55%, respectively. Results showed that the measurement results of the newly developed LIBS equipment are in accord with those of the conventional chemical method. Furthermore, the measurement precision is in line with X-Ray fluorescence spectrometry. It is confirmed that the LIBS technique could be a prospect method for determination of elemental composition in the cement production industries. PMID- 30001047 TI - Conference speaker advocates a 'drama-free' OR. PMID- 30001050 TI - Evidence-based practice supports adopting ERAS protocols. PMID- 30001049 TI - [Nondestructive Analysis of Jingdezhen and Longquan Celadon Wares Excavated from Nanhai No.1 Shipwreck]. AB - The provenance study of ancient ceramics, as an important part in archaeological field, is the researching focus for researchers in scientific and technological archaeology. At present, the provenance study of ancient ceramics mainly depends on chemical analysis technologies while non-destructive physical structural analysis of ceramic glaze is relatively lacking. Therefore, it is difficult to have a comprehensive understanding of ancient ceramics. Optical coherence tomography (OCT) is an emerging non-destructive imaging technology with a high sensitivity. In this paper, the OCT combined with X-ray fluorescence spectroscopy (XRF) is employed firstly to analyze celadon wares of Jingdezhen and Longquan found in Nanhai No.1 shipwreck which is dated to early Southern Song dynasty non destructively. First, the glaze cross-section structures and decoration characteristics of the celadon wares of the two kilns, Jingdezhen and Longquan,are studied by OCT.The type,thickness of glaze, the glaze inclusions including bubbles, crystals, residual grains, and the cracks on the glaze surface are analyzed based on the OCT images obtained. The characteristics of glaze cross section structures for the celadon wares of two kilns are compared, and the decoration technologies of the celadon wares are also determined. Next, the chemical compositions of glaze and body of the celadon wares of the two kilns,Jingdezhen and Longquan, are obtained by XRF and compared. Then, the relationship between the differences of glaze cross-section structures and chemical compositions of glaze are discussed. The results show that the celadon wares from Jingdezhen and Longquan are different in glaze cross-section structures, and are the chemical compositions of the glaze and body. Meanwhile the differences of glaze chemical composition are relevant to the differences of glaze cross-section structures. This paper shows that the combination of OCT and XRF is validate as an effective method to identify the porcelains from different kilns. PMID- 30001051 TI - [The Characteristics and Significance of Deep Fault Gouge from the Weilasituo Zinc-Copper Polymetallic Deposit in Inner Mongolia]. AB - The six groups of fault gouge samples were collected in different middle-sections from the underground mine of the Weilasituo zinc-copper polymetallic deposit, Inner Mongolia. The samples were analyzed with X-ray diffraction (XRD) and near infrared spectrum (NIR)to explore the mineral composition features of the fault gouges and their relationship with mineralization. The results are as follows: (1) The fault gouge samples contain the clay minerals which were formed in the low temperature alteration (such as montmorillonite, kaolinite, dickite, chlorite etc.), the alteration minerals in the medium temperature or high temperature hydrothermal environment (such as graphite, black mica, pyrophyllite, barite, serpentine, tremolite, actinolite etc.), and also the mineral compositions which were closely related to mineralization (such as copper-zinc oxide, copper vanadium-chloride, azurite, bornite etc.). (2) The mineral compositions of the fault gouge from different depth are different. Shallow earth's surface is mainly consisted of the low metamorphic minerals, and deep underground is mainly consisted of the high metamorphic minerals. (3) The mineral composition, mineral genesis and law of development of evolution of fault gouges suggest that, they were formed in the ore and metallogenic tectonic hydrothermal activity period, and had experienced the supergene oxidation later. (4) Through the analysis of the mineral compositions and alteration mineral assemblage characteristics of the fault gouges we can speculate that, the ore deposit was formed in medium-high temperature hydrothermal environment which had experienced the process of silicide, kaolinite, chloritization, hotaru petrochemical and sericitization alteration. Therefore, the analysis of the mineral compositions and mineral assemblage characteristics of the fault gouges,not only have certain practical significance for prospecting, but also can provide important reference information to study the genesis of the deposit. PMID- 30001052 TI - Turnover times improve with multiphase approach. PMID- 30001053 TI - [Study on Technological Characteristic of the Proto-Porcelain on Western Zhou Dynasty Excavated from Zhouyuan Site in Shaanxi Province]. AB - In southern region, the proto- porcelain have been found in large number and its excavation sites are relatively concentrated, thus its processing technique and origin have been studied thoroughly. However, as to proto-porcelain in northern region, the unearthed sites are scattered in distribution and its quantity is less. So there is limited analysis as to the technology. Since shaanxi zhouyuan relics unearthed a large number of proto-porcelain, it is necessary to give detailed analysis to them. In order to explore the technological characteristic of proto-porcelain of Western Zhou Dynasty which was excavated from Zhouyuan site in Shaanxi province, in this article three-dimensional video microscopy system was used to observe the microstructure and energy dispersive X-ray Fluorescence Spectrometer was used to test the chemical composition of the proto-porcelain body and glaze. The results of microscopic observation indicated that the proto porcelain body quality was rough and had many unmelting particles and pores; the glaze layer was uneven and distributes many bubbles. The results of chemical composition in the body showed that the content of Al2O3 was between 11.8%~17.21%, SiO2 is 75%~80.5%, K2O is 3%~7.85%. However the content in the glaze of CaO is between 11.08%~23.94%, P2O5 is 1%~3.18%, MnO is 0.24%~1%; the content of MnO, P2O5, K2O in the glaze had improved greatly more than those in the body. The above results showed that the raw materials of proto-porcelain body may use the chinastone which contains more potassium; and the plant ash should be added in the calcareous glaze; the manufacturing characteristic of the proto porcelain found in Zhouyuan site was still at the primary stage in Chinese porcelain's history. PMID- 30001054 TI - Can infrared sensors reliably measure OR traffic? PMID- 30001055 TI - ASC reaps rewards of recycling and reprocessing. PMID- 30001056 TI - [A New Redshift Measuring Method for Low-Quality Galaxy Spectra Based on Multi Resolution Fusion Distance]. AB - The redshift measurement of galaxy spectrum is a key issue in large astronomical spectral survey. Its goal is to extract the redshift from spectrum, which is caused the Doppler Effect. With the development of the extragalactic sky survey project, the distance (redshift) of the observed targets is becoming further. As a result, the magnitude of the observed objects becomes darker and the spectral quality becomes poorer. Therefore, how to effectively and accurately measure the redshift from these low quality spectra is becoming an important problem in the extragalactic survey. Considering the spectral features and the data character, a new definition of multi-resolution fusion distance for low quality spectra is proposed. In this paper, we put forward a redshift measuring method for low quality galaxy spectra. This method combines the spectral features with different resolutions. The template spectrum and the spectrum to measure are reduced to the resolution and then a distance is computed by combining the offset of the above two spectra in different wavelengths. Then, a fusion distance is weighted averaged from the distances with different resolutions. In this paper, the effect of signal-to-noise ratio (SNR) on the measuring accuracy of the proposed method is discussed. The measuring accuracy is larger than 90% when the SNR is larger than 5. A large number of experiments show that the method proposed in this paper is very efficient in measuring the redshift of the low-quality galaxy spectra and the measuring error has nothing to do with the redshift value. The proposed method can be applied in redshift measurement of galaxies for the large-scale survey data. PMID- 30001057 TI - [Processing FBG Sensing Signals with Exponent Modified Gaussian Curve Fitting Peak Detection Method]. AB - The system based on Fiber Bragg Grating (FBG) sensor is used in various fields, because of its advantages of high detection accuracy, good repeatability and adaptability. While the FBG sensor is a wavelength modulation type sensor, so the outside parameter detection is the center wavelength of FBG detection. At the same time, the FBG center wavelength corresponding to the peak value of the FBG reflection spectrum. Therefore, the core of demodulation system is the demodulation of FBG reflection spectrum during peak-seeking, and the high precision peak detecting algorithm is the key technology of the system demodulation. The current peak detecting algorithms has a precondition for peak detection on FBG reflective spectrum, that the FBG reflective spectrum was a standard Gaussian model. But FBG reflective spectrum is not a standard Gaussian spectrum owing to the practical manufacture process and the individual environment; actually, it is an asymmetrical Gaussian spectrum. The experiment would achieve a lower accuracy because of this asymmetric property during peak seeking. Based on the defect of the existing algorithm, an Exponent Modified Gaussian (EMG) Curve Fitting peak detecting algorithm is proposed in this paper. In the proposed algorithm, the coarse location was first determined by three times judgments and it can remove the false peak and peak invalid at the same time. Based on this, as the center of the coarse localization point to reconstruct the spectrum, and using the integral to judge the peak bias; then according to different peak bias, it revised the peak by the prepared exponential modified function. Simulation results show that at normal temperature or under variable temperature conditions, by comparing with direct peak searching algorithm, Gaussian fitting algorithm and the algorithm proposed by literature, the error of EMG peak detection algorithm is the minimum and high peak detecting precision. The algorithm proposed in this paper considers the FBG reflection spectrum characteristic of asymmetric effect. From its spectrum character, the EMG algorithm solves the problem of the limits of traditional peak detecting algorithm, meanwhile also guarantees a high-precision peak search results. PMID- 30001058 TI - [Study on the Determination System of Tissue Optical Properties Based on Diffuse Reflectance Spectrum]. AB - The determination of tissue optical properties is the fundamental research field in biomedical optics. The ability to separately quantify absorption and scattering coefficients of tissue based on diffuse reflectance spectrum not only helps to gain physiological and structural properties of tissue but also provide insight into the mechanisms of tissue, which leads to the improvement in non invasive detecting, image diagnosis and photodynamic therapy. In the paper, a flexible and rapid method is developed to extract the absorption and reduced scattering coefficients of turbid medium such as human tissue with diffuse reflectance spectrum. The diffuse reflectance spectrum is measured by the system which includes a white light source, a spectrometer, and a fiber optic probe for delivery and collection of light. The collection efficiency and system transfer function are researched based on the fiber probe geometry. This paper outlines a method based on empirical forward model and non-linear modeling inverse model to extract the optical properties from diffuse reflectance spectrum. The approach includes four steps: (1) generating diffuse reflectance spectra for training inverse model; (2) training the inverse model; (3) measuring and processing the diffuse reflectance spectra of samples; (4) predicting the optical properties of samples. Since the forward and inverse models could be regarded as non-linearity, the Artificial Neural Networks (ANN) is employed to develop the forward and inverse models. The principal component analysis (PCA) is also employed in the inverse model to decompress the data dimension and suppress the spectral noise. With a single fiber optic probe and spectroscopy system, the diffuse reflectance spectrum is measured and preprocessed. The accuracy and robustness of this method are evaluated by measuring the phantoms with a wide range of optical properties. The results indicate that the absorption and scattering coefficients could be extracted accurately by measuring the diffuse reflectance spectrum of single source-detector distance. The mean RMS percentage error is 4.58% and 7.92%, respectively. As to the application of extracting concentration of different chromosphere, it is better to include the absorption peak of every chromosphere within the measuring wavelength range. This method is valid for a wide range of optical properties with the advantage of rapid measurement and simple system setup, which is important for the clinical application. PMID- 30001059 TI - [Study on the Design of Prism Hyperspectral Imaging System Based on Off-Axis Two Mirror Littrow Configuration]. AB - In order to meet the requirements of high spectral resolution and high image quality on the hyperspectral imaging system, and to meet the new demands of miniaturization, light weight, and high optical efficiency in practical applications, a prism known as hyperspectral imaging system based on Littrow configuration is designed. The use of off-axis two-mirror Littrow configuration is to reduce the size of the optical system and provide a collimated beam for the plane prisms. To avoid the optical path interference, the macro programming optimization is applied. The application of two correct lens and aspheric mirrors can correct the spectral smile and the keystone of the hyperspectral imaging system. It is indicated that the distortion is less than 2.1 MUm and the spectral bend is less than 1.3 MUm, both are controlled within 18% pixel. The analytical results indicate that the MTF in the visible-near infrared(VNIR) spectral region from 400 to 1 080 nm is above 0.9 while spectrum resolution is about 1.6~5.0 nm, the spectral transmittance more than 51.5%. The results show that the system has high transmittance and image quality within the whole spectral range. PMID- 30001060 TI - [Study on Coaxial Linear Dispersion Triplet Prisms of Wide Spectral Imaging Spectrometer]. AB - To overcome the difficulties of complex structure and serious nonlinear dispersion in prismatic imaging spectrometer the coaxial linear dispersion prismatic imaging spectrometer is investigated in this paper. A mathematical model of symmetric triple prisms' beam splitting system is constructed with prism's dispersion equation, and the prisms assemble of direct view is obtained. Then the factors affecting dispersion linearity are analyzed. The refractive index and dispersion rate of prism material impact dispersion linearity most while the influence of incident angle is very small. The way to improve dispersion linearity is given and the refractive index condition meeting the requirement of dispersion linearity of prisms is obtained. It provides important basis to select the initial structure for coaxial linear dispersion triplet prisms of imaging spectrometer. On condition that the working band of 400~1 000 nm, center wavelength deviation angle 0 degrees , the maximum dispersion angle 0.6 degrees , object numerical aperture 0.15 and spectral resolution 5 nm, we succeed in designing coaxial linear dispersion triplet prisms. Digital simulation with ZEMAX is performed, and the results are in accordance with theoretical analysis. PMID- 30001061 TI - [The Research of Spectral Polarization Imaging Detection System Based Dual AOTFs]. AB - Acousto-optic tunable filter (AOTF) has the advantages of small size, good stability, wide range of wavelength scanning, quick modulation speed and so on. So AOTF is widely used in spectral imaging. But the detection of spectral polarization imaging is seldom found by using AOTF individually., Anew method of spectral polarization imaging based on dual-AOTFs is proposed. This method shows that the incident light is firstly divided into two beams by splitting mirror, and then two beams of light are through two AOTFs respectively, and the polarization direction of +1 diffraction order formed by AOTF is at a 45 degrees against the other. The intensity of 0 degrees , 45 degrees , 90 degrees and 135 degrees can be obtained by +/-1 diffraction orders of dual-AOTFs. Finally, the Stokes parameters are obtained by +/-1 diffraction orders imaging of dual-AOTFs. They are S0 (the sum of light intensity between 0 degrees and 90 degrees ), S1(the difference of light intensity between 0 degrees and 90 degrees ) and S2 (the difference of light intensity between 45 degrees and 135 degrees ). The target degree of linear polarization (DoLP) and angle of linear polarization (AoLP) is realized by corresponding theoretical formula. Furthermore, the polarization imaging of different wavelengths is realized with frequency sweep of dual-AOTFs so as to ultimately detect the spectral polarization imaging. The experiment has been verified through polarization imaging of three different lights, such as lambda=500 nm, lambda=550 nm and lambda=600 nm. PMID- 30001062 TI - [Analysis and Design of Interference Imaging System in Fourier Transform Imaging Spectrometer Based on Multi-Micro-Mirror]. AB - To realize the static state and high throughput of Fourier transform imaging spectrometer (FTIS), a temporal spatial mixed modulated FTIS based on multi-micro mirror was put forward in this paper, whose interference system was based on Michelson interferometer with a multi-micro-mirror to replace the plane mirror. The remarkable characteristics of this FTIS were no movable parts and slit existing in this system, and the interferogram and image of object could be gained at the same time. The fore-optics system imaged the object on the plane mirror and multi-micro-mirror of the interference system, due to the structure feature of multi-micro-mirror, the optical path difference (OPD) of two imaging beam could be modulated. Through the reimaging system, the image of object with different interference order could be obtained. By means of the analysis to the spectrum signal-to-noise ratio (SNR) of interference system, the relationship between spectrum SNR and image SNR was definite, and the characteristic parameters of multi-micro-mirror were determined. To ensure the constancy of OPD corresponding to each step plane, by means of the analysis to the imaging process of fore-optics system, the optical path structure of telecentric in image space was determined. According to the calculation of the relationship between field of view and OPD, the design indexes of fore-optics system were determined and the optical design was completed. To ensure no extra OPD was introduced by reimaging system, through the analysis of the imaging feature by reimaging system, the optical path structure of double telecentric was determined. According to the calculation of the relationship between incidence aperture angle and step number, the optical system that satisfied the system requirement was designed. By means of the theory analysis and optical design to each unit system, this research can provide a novel development strategy for static and high throughput FTIS. PMID- 30001063 TI - [All-Fiber Mach-Zehnder Interferometer Based on Lateral-Offset and Peanut Shape Structure]. AB - A new in-fiber Mach-Zehnder interferometer (MZI) based on lateral-offset and peanut shape structure is proposed and demonstrated for the measure of curvature and liquid level. The sensor consists of lateral-offset structure and peanut shape structure. A section of single mode fiber (SMF) is spliced between them. A part of core mode in the single mode fiber is excited to cladding modes by lateral-offset. The cladding modes are re-coupled to the core mode by peanut shape structure and get interference with the core mode. A high-quality interference spectrum with a fringe visibility of about 12 dB is observed. The effective refractive indices of cladding mode would change with the external environment parameters, which further bring about a shift of the interference fringes. The liquid level or curvature can be measured by record the shift of the valley, because the shift of the valley shows a linear dependence with the variation of the liquid level or curvature theoretically. In the water level experiment, the water level changes from 1.00 to 5.00 cm and the wavelength valley shows a red shift. The sensitivity of the MZI with a length of 6.10 cm is 0.68 nm.cm-1. In the curvature experiment, the curvature changes from 0.3 to 1.2 and the wavelength valley shows a blue shift. The sensitivity of the MZI with a length of 2.10 cm is 22.47 nm.m. The lateral-offset structure and peanut shape structure are spliced to fabricate the MZI. The sensitivity of the MZI is high, especially in the curvature measurement, it is higher than that of other fiber curvature sensors. Moreover the MZI presented in this paper has advantages of low cost and easy fabrication, which can be a potential application in the liquid level and curvature measurement. PMID- 30001064 TI - [Bidirectional Reflectance Distribution Function of Space-Borne Quartz Volume Diffuser]. AB - Quartz Volume Diffuser(QVD) is used in the observing system of Space-Borne differential optical absorption spectrometer. The precision of observed solar spectrum directly influences the accuracy of the gas retrievals. Therefore the QVD is required for well Lambert feature to ensure the accuracy of full field solar spectrum, and it can provide uniformity source in the observing view of the instrument. Using bidirectional reflectance distribution function(BRDF) measurement instrument, adopting the powder pressboard of F4(polytetrafluoroethylene(PTFE)), QVD's BRDF is measured by choosing the relative measurement method. Four kinds of QVD's BRDF is obtained in the range of 180~880 nm, the observing view of -70 degrees ~+70 degrees . Two kinds of QVD which has a well Lambert feature are selected by analyzing the QVD's BRDF. The diffuse sunlight measured by QVD and F4 is compared, which show that QVD has well scattering properties with regard to solar spectrum and can be selected as the measuring diffuser. That supports for next Ultraviolet irradiation measurement, atomic oxygen erosion measurement and comparison measurement. PMID- 30001065 TI - Spectrum Quantitative Analysis Based on Bootstrap-SVM Model with Small Sample Set. AB - A new spectrum quantitative analysis method based on Bootstrap-SVM model with small sample set is proposed in this paper. To build the spectrum quantitative analysis model for bitumen penetration index, altogether 29 bitumen samples were collected from 6 companies. Based on the collected 29 bitumen samples, spectrum quantitative analysis model with proposed method for predicting bitumen penetration index has been built. To verify the feasibility and effectiveness of the proposed method, the comparative experiments of predicting the bitumen sample penetration index with the proposed method, partial least squares (PLS) and support vector machine (SVM) have also been done. Comparative experiment results have verified that the minimum prediction root mean squared error (RMSE) is achieved by using the proposed Bootstrap-SVM model with the small sample set. The proposed method provides a new way to solve the problem of building the spectrum quantitative analysis model with small sample set. PMID- 30001066 TI - A Comparison of Heterogeneous Reaction Kinetics of Oleic Acid Thin Film and Oleic Acid Coated Flyash with Ozone Using Vacuum FTIR. AB - Aerosol aging is the one of the research hotspots in the field of physical chemistry of atmospheric particulates at present. This study evaluates the impact of flyash in heterogenous reaction through the comparision of ozone oxidation reaction kinetics between the oleic acid (OA) thin film and oleic acid coated flyash which are observed by in situ vacuum FTIR for the first time. Except for the fingerprint region, the main bands of infrared spectrum of the fresh OA thin film and the fresh OA coated flyash are similar. When the two samples are exposed in the 20 ppm ozone concentration, room temperature and dry (RH~0%) conditions respectively, the =CH absorption peak (3 050 cm-1) decreases while The -OH stretch band (3 430 cm-1) increases. Moreover, The carboxylic C=O stretch band at 1 710 cm-1 decreases whereas a new ester group stretch band at 1 740 cm-1 appears and increases with increasing ozone exposure time. The OA component of the two samples can be gradually consumed and converted to some products containing hydroxyl and ester groups during the reactions through the changing trends of the infrared spectrum. The pseudo-first-order rate constant Kapp and the overall uptake coefficient gamma, are obtained through changes in the absorbance of C=O stretching bands at 1 740 cm-1. The ozonolysis reaction rate constant of OA coated flyash is nearly double to the OA thin film. Since the surface area-to volume ratio of OA coated flyash is larger than the OA thin film and the ozone concentrations are the same for the both reactions, the gamma values for ozone uptake on OA thin film and OA coated flyash are (2.70+/-0.11)*10-4 and (3.70+/ 0.13)*10-4. Rapid reaction rate of the flyash sample is due to the larger catalytic surface area and more valid catalytic effect compared to the OA thin film. This demonstrates that the flyash often easily leads to the secondary organic aerosols (SOAs) when the flyash unites with unsaturated organic acids and exposes to the ozone oxidation environment. PMID- 30001067 TI - Study on the Water Transfer of Magnesium Acetate Aerosols Led by the Rapid and Slow Change of Relative Humidity. AB - A combination of vacuum FTIR spectrometer (Vertex 80v, Bruker, German) and novel relative humidity (RH) adjusting equipment,which provides the pressure by pure water vapor, is used to study the hygroscopicity of magnesium acetate (Mg(CH3COO)2) aerosols. The RH can change not only rapidly but also slowly by the RH adjusting equipment. Because the RH is decided by the pure vapor, the real time RH can be gained by calculating the integrated intensity of a feature band of vapor in an IR spectrum. Such the synchronism between FTIR spectrum and RH canbe ensured. The high-quality spectra of aerosols are obtained and the water peak and feature peaks of Mg(CH3COO)2 are analyzed during the slow and rapid RH changing process. The result shows that the areas of acetate ions and water decreases continuously at constant high RHs. After a slow cycle of RH (1.05*104 minutes), the water area decreases from 1.5 to 1.1, which means that the water content decreases after a cycle of RH. This phenomenon is reported at first up to date. The detailed analysis suggests that the hydrolysis of Mg(CH3COO)2 at high RH produces acetic acid, which was put out from the aerosols owing to the decrease of the pressure around the aerosols droplets. Furthermore, the dynamic hygroscopicity of Mg(CH3COO)2 aerosols is studied by changing RH as a pulse mode. It reveals that there is only water transfer hysteresis and no water loss after a pulse (10 seconds) when the RH is above 70%. Compared to slow process, it can be concluded that the hydrolysis reaction rate is slower than that of a pulse RH. The water transfer limited on rapid process should rise from some species on the surface of aerosols. PMID- 30001068 TI - Interaction Study of Ferrocene Derivatives and Heme by UV-Vis Spectroscopy. AB - The interaction between ferrocene derivatives, such as Fc(COOH)2(lambdamax=286 nm), Fc(OBt)2(lambdamax=305 nm), Fc(Cys)(lambdamax=289 nm) and heme(lambdamax=386 nm) were studied by UV-Vis spectroscopy, respectively. The results show that, when the concentration of heme is fixed, the absorbance of heme increases with the increase of Fc(COOH)2 and Fc(Cys) concentration, the absorbance of heme almost keep the same when Fc(OBt)2 concentration increases; when the concentration of ferrocene derivatives are fixed, the absorbance of Fc(COOH)2 and Fc(Cys) also increases with the increase of heme concentration, the absorbance of Fc(OBt)2 almost keep the same when heme concentration increase. It is demonstrated that the hydrogen bonding interactions happen between Fc(COOH)2, Fc(Cys) and heme, none of Fc(OBt)2, the formation of hydrogen bonding lead to the growth of molecular chain, the bigger molecule can absorb more energy and increase the absorbance. Meanwhile, the stability of molecule is affected by the formation of hydrogen bonding, when the reaction time increases from 0.5 h to 18 h and 48 h, the absorbance at lambdamax=384 nm change from 2.64 to 2.53 and 2.51 with fixed concentration of Fc(COOH)2, the absorbance at lambdamax=384 nm change from 1.76 to 1.72 and 1.68 with fixed concentration of heme, the absorbance at lambdamax=397 nm change from 2.74 to 2.63 and 2.55 with fixed concentration of Fc(Cys), and the absorbance at lambdamax=397 nm change from 1.82 to 1.58 and 1.49 with fixed concentration of heme, respectively. PMID- 30001069 TI - Application of Empirical Mode Decomposition and Independent Component Analysis for the Interpretation of Rock-Mineral Spectrum. AB - Rock-mineral spectrum is a mixture of varied mineral spectra, through which we can obtain information about its components quickly and conveniently without any damage to the sample. Empirical mode decomposition (EMD) cannot directly decompose source signals from information of the mixture, and independent component analysis (ICA) requires the number of mixed signals to be no less than the number of source signals. Combining these two methods, mixed signals can be decomposed using EMD method to obtain intrinsic mode function (IMF), while certain IMFs together with mixed signals can be used as input data matrix of ICA to obtain the source signals. This method overcomes the shortcomings of IMF and ICA. Studies have shown that, the higher content of source signals contained in the mixed signal, the better estimation can be obtained through EMD and ICA. The number of IMFs that participate in ICA decomposition determines the number of approximation of source signals. The accuracy of source signal estimation increases with the correlation coefficient between IMF and mixed signals. By applying this method to quantitative analysis of rock-mineral spectrum, information of the component minerals in rock-mineral can be obtained, which improves the efficiency of component analysis in detecting rock-minerals outside. PMID- 30001070 TI - Study on the Multi-Spectral True Temperature Pyrometer for Explosion Transient of Thermo-Baric Explosives. AB - The high temperature and destructive power, made it difficult to test the explosion temperature of thermo-baric explosive. To effectively assess heat damage effect of thermo-baric explosive, multi-spectral high temperature measurement system is applied to transient high temperature test of thermo-baric explosive. The emissivity and the true temperature of explosion flame are calculated by using the secondary measurement method. In the data acquisition system, the test instrument achieves data collection and transmission 500 meters away in combination with optical fiber sensing technology and under the precondition to guarantee the participants safety. The measurement results show that the designed measurement system has the advantages of simple operation, high safety and better application prospect. PMID- 30001071 TI - Native Defect Luminescence of Zinc Oxide Films and Its Potential Application as White Light Sources. AB - ZnO light-emitting diodes (LEDs) have an enormous potential in lighting applications. The major issue to be resolved is the generating and control of light emissions. This issue arises from the variation and combination in LED wavelength. We found that defect luminescence of ZnO has a varied wide range of wavelength, which suits to an application of LED for white-light generation. We have shown both experimentally and theoretically that defect emission can be used in ZnO systems. This type of defect has the advantage of not requiring extensive and costly factory systems comparing with traditional doped materials and others. We not only propose potential application of native defect luminescence of Zinc Oxide film for white LEDs-flat light sources, but also have some methods to control defect origins, a certain center position and broad range of the emission band of ZnO film in the initial stage. According to different preparing method and certain experiment conditions, variant white such as whitish and bluish-white etc., primary and important colors- blue bands (455, 458 nm), green bands (517, 548 nm), red bands (613, 569 nm) are obtained respectively. This proved that it is a better road to one white light LED with one kind of material -ZnO. PMID- 30001072 TI - Hyperspectral Models and Forcasting of Physico-Chemical Properties for Salinized Soils in Northwest China. AB - Hyperspectral remote sensing data have special advantages, i.e., they have high spectral resolution and strong band continuity, and a great number of spectral information could be widely used in soil properties monitoring research. Using hyperspectral remote sensing technique to analyze saline soil properties makes great significance for the crop growth in the irrigation district and agricultural sustainable development. 221 soil samples were collected from Manasi River Basin to measure soil electrical conductivity (EC), soil organic matter (SOM) and 3 kinds of cation concentrations including Na+, Ca2+ and Mg2+, which were used to obtain sodium adsorption ration value (SAR). The soil hyperspectral curves were also measured. EC, SOM and SAR models were established based on the six spectral-related indices, including raw reflectance (R), standard normal variable (SNV), normalized difference vegetation index (NDVI), logarithm of the reciprocal (LR), the first derivative reflectance (FDR) and continuum-removal reflectance (CR) by the stepwise linear regression method. The results showed that, compared to the other five models, the model of log (EC)~R had the highest accuracy with r value of 0.782 and RMSE value of 0.256. The model of SOM vs. NDVI had the highest accuracy with r value of 0.670 and RMSE value of 5.352. The model of SAR vs. FDR had the highest accuracy with r value of 0.647 and RMSE value of 1.932. As to the model accuracy of the studied soil physico-chemical properties, the log(Ec) model was the most effective one, followed by the SOM model, the SAR model was the most inaccurate. The sensitive wavelengths for EC, SOM and SAR distributed in 395~1 801 nm, 352~1 144 nm and 394~1 011 nm, respectively. Since soil physico-chemical properties were highly spatially variable, there were large differences for the model establishment and validation of the soil properties. This research could be a reference of hyperspectral remote sensing monitoring of salinized soils. PMID- 30001073 TI - Color Enhancement by Diffusion of Beryllium in Dark Blue Sapphire. AB - Diffusion of beryllium was performed on dark blue sapphire from China and Australia. The samples were heated with beryllium as a dopant in a furnace at 1 600 C for 42 h in air. After beryllium diffusion, samples were analyzed by UV Vis, FTIR, and WD-XRF spectroscopy. After heat-treatment with Be as a catalyst, the irons of the ferrous state were changed to the ferric state. Therefore, reaction of Fe2+/Ti4+ IVCT was decreased. The absorption peaks at 3 309 cm-1 attributed to OH radical were disappeared completely due to carry out heat treatment. Consequently, the intensity of absorption band was decreased in the visible region. Especially, decreased absorption band in the vicinity of 570 nm was responsible for the lighter blue color. Therefore, we confirmed that the dark blue sapphires from China and Australia were changed to vivid blue. PMID- 30001074 TI - Role of Interfacial Viscosity and pH in L-Phenylalanine, L-Tryptophan Molecular Rotors. AB - Protein folding involves the aminoacid sequence to come forth and form an energy minimized structure. Recently molecular crowding leading to increase in viscosity is said to be one of the major concerns affecting protein folding. Many external fluorescent probes are used to detect such increases in viscosity. Since most of the protein sequences contain L-Phe and L-Trp, in this study we have used these aminoacids as probes to detect changes in viscosity. This study will help to advance the knowledge on molecular crowding effects in protein folding. PMID- 30001075 TI - Novel and Validated Spectrophotometric Matrix Matching Method for Simple and Rapid Determination of Chromium in Oily Media. AB - N,N'-bis(4-methoxysalicylidene) ethylenediamine is proposed as analytical reagent for the direct determination of chromium in original matrix of liquid oils. The method is based on the complexation of N,N'-bis(4-methoxysalicylidene) ethylenediamine and chromium in n-hexane?acetone (1?4) medium and spectrophotometric determination at 355 nm against reagent blank. Complexation of MSE and chromium is completed in 20 seconds at molar ratio 1?1. The molar absorptivity and the formation constant of the complex are determined as 9 740 L.mol-1.cm-1 and 3.6(+/-0.1)*105, respectively. Beer's law is obeyed in range 0.02~1.50 mg.L-1 chromium concentration. Limits of detection and quantification of the suggested method were 7.5 and 25.1 MUg.kg-1, respectively. The accuracy and precision of the method was checked by finding mean recovery and relative standard deviation by oil-based chromium standard analysis as 96.4%+/-1.4% and 1.5%, respectively. The practical applicability of elaborate method was tested using oil-based chromium standard spiked and unspiked corn, sunflower, soybean, olive and canola oils. PMID- 30001097 TI - Multi-Heteroatom-Doped Hollow Carbon Attached on Graphene Using LiFePO4 Nanoparticles as Hard Templates for High-Performance Lithium-Sulfur Batteries. AB - P, O, and N heteroatom-doped hollow carbon on graphene (PONHC/G) from nanosized LiFePO4 (LFP) as a hard template is shown to be a very efficient sulfur host for lithium-sulfur (Li-S) batteries. The PONHC/G made from LFP nanoparticles as hard materials provides sufficient voids with various pore sizes for sulfur storage, and doping of the carbon structures with various heteroatoms minimized dissolution/diffusion of the polysulfides. The obtained PONHC/G can store sulfur and mitigate diffusion of the dissolved polysulfide owing to the well-organized host structure and the strong chemical affinity for polysulfides because of the polarization effect of the heteroatom dopants. As a cathode, S@PONHC/G shows excellent cycle stability and rate capability, as confirmed by polysulfide adsorption analysis. Therefore, PONHC/G may show high potential as a sulfur scaffold in the commercialization of Li-S batteries through additional modification and optimization of these host materials. PMID- 30001098 TI - Optical Control of a Delayed Rectifier and a Two-Pore Potassium Channel with a Photoswitchable Bupivacaine. AB - Photoswitchable blockers of potassium channels can be used to optically control neuronal excitability and hold great promise for vision restoration. Here, we report a series of improved photoswitchable blockers that are furnished with a new pharmacophore based on the local anesthetic bupivacaine. These azobupivacaines (ABs) enable optical control over the delayed rectifier channel Kv2.1. and target the two-pore domain potassium channel TREK-1. For the first time, we have identified a compound that blocks conductance in the dark and potentiates it upon illumination. Using light as a trigger, ABs efficiently and reversibly silence action potential firing of hippocampal neurons in acute mouse brain slices. PMID- 30001099 TI - Halide Perovskite Nanopillar Photodetector. AB - Numerous studies have reported the use of halide perovskites as highly functional light-harvesting materials. The development of optimized compositions and deposition approaches has led to impressive improvements; however, no noticeable breakthrough in performance has been observed for these materials recently. Here, a breakthrough that enables the fabrication of vertically grown halide perovskite (VGHP) nanopillar photodetectors via a nanoimprinting crystallization technique is demonstrated. We used engraved nanopatterned polymer stamps to form VGHP nanopillars during the pressurized crystallization of the softly baked gel state of a methylammonium lead iodide (CH3NH3PbI3, denoted MAPI) film. The VGHP films exhibit much lower defect density and higher conductivity, as supported by current-voltage characteristic measurements and conductive atomic force microscopy measurements. Ultimately, two-terminal lateral photodetectors based on the VGHP nanopillar films show a greatly enhanced photoresponse compared with flat film-based photodetectors. We expect that the deposition method presented here will help surpass the technical limits and contribute to further improvements in various halide-perovskite-based devices. PMID- 30001100 TI - Novel Flexible Self-Standing Pt/Al2O3 Nanofibrous Membranes: Synthesis and Multifunctionality for Environmental Remediation. AB - In spite of intensive research investigating the prevalent Pt/Al2O3 catalysts, achieving macroscopic morphology beyond the powder form limitations remains highly challenging. Meanwhile, current impregnation-based preparation approaches show the drawbacks of tedious procedures and inefficient use of noble metals. Therefore, it is important to search for new methods for the fabrication of Pt/Al2O3 catalysts with a novel morphology. In this study, a novel Pt/Al2O3 nanofibrous membrane catalyst is fabricated via a facile one-pot electrospinning process. The embedding of Pt nanoparticles is performed simultaneously with the formation of Al2O3 nanofibers. The Pt/Al2O3 membranes show remarkable mechanical properties with tensile stresses as high as 44.14 MPa. Notably, the Pt/Al2O3 membranes exhibit multifunctionality with excellent performance characteristics. The catalytic experiments indicate that 100% of bisphenol A is removed within 60 min, and 100% of CO is completely converted to CO2 at 242 degrees C when Pt/Al2O3 membranes are used as catalysts. The membranes also exhibit excellent filtration performance, clearly decreasing the turbidity of water, and meet the high efficiency of particulate air filter standards. The excellent flexibility, satisfying mechanical property, and multifunctionality extend the range of potential application of the Pt/Al2O3 membranes. Moreover, the facile synthesis suggests new possibilities for the fabrication of many membrane-form Al2O3 supported catalysts. PMID- 30001101 TI - Spray-Coated CsPbBr3 Quantum Dot Films for Perovskite Photodiodes. AB - Large-area film deposition and high material utilization ratio are the crucial factors for large-scale application of perovskite optoelectronics. Recently, all inorganic halide perovskite CsPbBr3 has attracted great attention because of its high phase stability, thermal stability, and photostability. However, most reported perovskite devices were fabricated by spin-coating, suffering from a low material utilization ratio of 1% and a small coverage area. Here, we developed a spray-coating technique to fabricate a CsPbBr3 quantum dot (QD) film photodiode which had a high material utilization ratio of 32% and a deposition rate of 9 nm/s. The film growth process was studied, and substrate temperature and spray time were two key factors for the deposition of uniform and crack-free QD films. The spray-coated photodiode was demonstrated to be more suitable for working in the photodetector mode because a low dark current density of 4 * 10-4 mA cm-2 resulting from an extremely low recombination current contributed to a high detectivity of 1 * 1014 Jones. A high responsivity of 3 A W-1 was obtained at 0.7 V under 365 nm illumination, resulting from a low charge-transfer resistance and a high charge recombination resistance. We believe that the spray deposition technique will benefit the fabrication of perovskite QD film optoelectronics on a large scale. PMID- 30001102 TI - Microporous Polymer Networks for Carbon Capture Applications. AB - A new generation of porous polymer networks has been obtained in quantitative yield by reacting two rigid trifunctional aromatic monomers (1,3,5 triphenylbenzene and triptycene) with two ketones having electron-withdrawing groups (trifluoroacetophenone and isatin) in superacidic media. The resulting amorphous networks are microporous materials, with moderate Brunauer-Emmett Teller surface areas (from 580 to 790 m2 g-1), and have high thermal stability. In particular, isatin yields networks with a very high narrow microporosity contribution, 82% for triptycene and 64% for 1,3,5-triphenylbenzene. The existence of favorable interactions between lactams and CO2 molecules has been stated. The materials show excellent CO2 uptakes (up to 207 mg g-1 at 0 degrees C/1 bar) and can be regenerated by vacuum, without heating. Under postcombustion conditions, their CO2/N2 selectivities are comparable to those of other organic porous networks. Because of the easily scalable synthetic method and their favorable characteristics, these materials are very promising as industrial adsorbents. PMID- 30001104 TI - Assembly Pathway Selection of Designer Self-Assembling Peptide and Fabrication of Hierarchical Scaffolds for Neural Regeneration. AB - The self-assembling peptide (SAP) RADA 16-I has been modified with various functional motifs to improve its performances in biomedical applications. Nevertheless, the assembly mechanisms of designer functional RADA 16-I SAPs (F SAPs) have not been clearly illustrated. The main problem is the difficulty in preparing a completely molecular aqueous solution of F-SAP. In the current study, we demonstrated that different procedures for preparing the F-SAP solution could result in the formation of different conformations and consequently micro/macroscopic morphologies. F-SAP was molecularly dissolved in an appropriate solvent, such as hexafluoroisopropanol (HFIP), as evidenced by random coil conformation characterized by circular dichroism spectroscopy and morphologies under transmission electron microscopy. The monomers were induced into monolayers when the F-SAP solution in HFIP was adsorbed on mica as observed by atomic force microscopy. However, nanoscaled filaments containing beta-sheets dominated in the F-SAP aqueous solution, in which case water acted as a poor solvent of F-SAP. Furthermore, the results of molecular dynamics simulation implicated that water facilitated F-SAP aggregation, whereas HFIP inhibited it. The beta-sheet assemblies formed in water exhibited a high kinetic stability and did not disassemble rapidly after the addition of HFIP. Our study indicated that selecting the right assembly pathway of F-SAP required for targeted functions, for example, delivery of hydrophobic drugs in aqueous conditions, could be achieved by optimizing the preparation protocol in addition to molecular design. Moreover, hierarchical scaffolds mimicking the natural extracellular matrix could be fabricated by the direct electrospinning of F-SAP molecular solution in HFIP and biodegradable polymer for applications in neural regeneration by promoting neural differentiation, neurite outgrowth, and synapse formation. PMID- 30001103 TI - Fabrication of Activity-Reporting Glucose Oxidase Nanocapsules with Oxygen Independent Fluorescence Variation. AB - Glucose oxidase (GOx) has seen large-scale technological applications, and the determinations of its activity that is directly related to the enzymatic functions are extremely important. However, conventional methods to analyze the enzymatic activity involving high oxygen dependency and indirect redox reactions are usually tedious and restricted in complicated environments. For analyzing enzymatic activity by direct detection of the electron signals from the active centers, mediators are often used for facilitating the electron transfer. Differing from common methods of preparing electron mediators-contained GOx composites, a strategy aiming at remolding of the enzyme itself has been proposed in this work. Cofactor-like molecule 2'-diallyamino-ethyl flavin (DAA-flavin) derived from riboflavin is synthesized and incorporated as cross-linker into the polyacrylamide (PAAm) network around GOx surface by in situ polymerization to obtain enzyme nanocapsules termed as GOx@Fla-c-PAAm. The peripheral polymer shell confines the orientation of GOx and prevents it from denaturing, whereas incorporated DAA-flavin can replace the oxygen as an alternative electron acceptor to interact with the active centers of GOx in the presence of the substrate, thus giving the nanocapsules oxygen-independent characteristics. The introduced unlimited cofactor-like molecules endow the nanocapsules redox-related fluorescence, and the intensity variation is closely correlated with the enzymatic activity. There is a high goodness of fitting ( R2 ~ 0.990) between the slope of linear fluorescence-time plots and enzymatic activity, thereby making the nanocapsules a reliable activity-reporting enzymatic nanosystem with oxygen independent fluorescence variation for further extended potential application in biofuel cells and biosensors. PMID- 30001105 TI - Use and Future Prospects of in Vivo Microdialysis for Epilepsy Studies. AB - Epilepsy is a common neurological disease characterized by recurrent unpredictable seizures. For the last 30 years, microdialysis sampling has been used to measure changes in excitatory and inhibitory neurotransmitter concentrations before, during, and after seizures. These advances have fostered breakthroughs in epilepsy research by identifying neurochemical changes associated with seizures and correlating them to electrophysiological data. Recent advances in methodology may be useful in further delineating the chemical underpinnings of seizures. A new model of ictogenesis has been developed that allows greater control over the timing of seizures that are similar to spontaneous seizures. This model will facilitate making chemical measurements before and during a seizure. Recent advancements in microdialysis sampling, including the use of segmented flow, "fast" liquid chromatography (LC), and capillary electrophoresis with laser-induced fluorescence (CE-LIF) have significantly improved temporal resolution to better than 1 min, which could be used to measure transient, spontaneous neurochemical changes associated with seizures. Microfabricated sampling probes that are markedly smaller than conventional probes and allow for a much greater spatial resolution have been developed. They may allow the targeting of specific brain regions important to epilepsy studies. Coupling microdialysis sampling to optogenetics and light stimulated release of neurotransmitters may also prove useful for studying epileptic seizures. PMID- 30001106 TI - Targeted Perturbation of Nuclear Envelope Integrity with Vapor Nanobubble Mediated Photoporation. AB - The nuclear envelope (NE) has long been considered to dismantle only during mitosis. However, recent observations in cancer cells and laminopathy patient cells have revealed that the NE can also transiently rupture during interphase, thereby perturbing cellular homeostasis. Although NE ruptures are promoted by mechanical force and the loss of lamins, their stochastic nature and variable frequency preclude the study of their direct downstream consequences. We have developed a method based on vapor nanobubble-mediated photoporation that allows for deliberately inducing NE ruptures in a spatiotemporally controlled manner. Our method relies on wide-field laser illumination of perinuclear gold nanoparticles, resulting in the formation of short-lived vapor nanobubbles that inflict minute mechanical damage to the NE, thus creating small pores. We demonstrate that perinuclear localization of gold nanoparticles can be achieved after endocytic uptake or electroporation-facilitated delivery and that both strategies result in NE rupture upon laser irradiation. Furthermore, we prove that photoporation-induced nuclear ruptures are transient and recapitulate hallmarks of spontaneous NE ruptures that occur in A-type lamin-depleted cells. Finally, we show that the same approach can be used to promote influx of macromolecules that are too large to passively migrate through the NE. Thus, by providing unprecedented control over nuclear compartmentalization, nuclear photoporation offers a powerful tool for both fundamental cell biology research and drug delivery applications. PMID- 30001107 TI - Band Gap Engineering and Room-Temperature Ferromagnetism by Oxygen Vacancies in SrSnO3 Epitaxial Films. AB - Perovskite SrSnO3 (SSO) thin films were epitaxially grown on LaAlO3 (001) substrates by pulsed laser deposition at various oxygen pressures. X-ray diffraction was carried out to characterize the microstructure of the films, and the results showed that the unit-cell volume of the films increased gradually with lowering the growth oxygen pressures while remaining the perovskite structure. X-ray photoelectron spectroscopy results indicated that oxygen vacancies (OVs) existed in SSO thin films. Optical property measurements showed that all samples have a transmittance of more than 75% in the visible and near infrared wavelength region. Furthermore, the band gaps of SSO films were found to increase from 4.56 to 5.21 eV with the decrease of deposition oxygen pressures calculated by linear fitting absorption edges of optical transmittance. In order to further ascertain the effect of OVs on band gaps of SSO films, the as deposited 10 Pa film was annealed at 10-4 Pa oxygen pressures and the band gap was found to increase by more than 1 eV. Density functional theory was used to explain the effects of OVs on band gaps and the ferromagnetism of SSO films, and the results suggested that an impurity energy level of OVs appeared near the Fermi level, causing the widening of the band gaps, which is consistent with our experimental results. Meanwhile, the room-temperature ferromagnetism was observed in the SSO films, and saturation magnetization increased gradually from 4.46 to 7.69 emu/cm3 with decreasing the growth oxygen pressures. PMID- 30001108 TI - Desublimation Frosting on Nanoengineered Surfaces. AB - Ice nucleation from vapor presents a variety of challenges across a wide range of industries and applications including refrigeration, transportation, and energy generation. However, a rational comprehensive approach to fabricating intrinsically icephobic surfaces for frost formation-both from water condensation (followed by freezing) and in particular from desublimation (direct growth of ice crystals from vapor)-remains elusive. Here, guided by nucleation physics, we investigate the effect of material composition and surface texturing (atomically smooth to nanorough) on the nucleation and growth mechanism of frost for a range of conditions within the sublimation domain (0 degrees C to -55 degrees C; partial water vapor pressures 6 to 0.02 mbar). Surprisingly, we observe that on silicon at very cold temperatures-below the homogeneous ice solidification nucleation limit (<-46 degrees C)-desublimation does not become the favorable pathway to frosting. Furthermore, we show that surface nanoroughness makes frost formation on silicon more probable. We experimentally demonstrate at temperatures between -48 degrees C and -55 degrees C that nanotexture with radii of curvature within 1 order of magnitude of the critical radius of nucleation favors frost growth, facilitated by capillary condensation, consistent with Kelvin's equation. Our findings show that such nanoscale surface morphology imposed by design to impart desired functionalities-such as superhydrophobicity-or from defects can be highly detrimental for frost icephobicity at low temperatures and water vapor partial pressures (<0.05 mbar). Our work contributes to the fundamental understanding of phase transitions well within the equilibrium sublimation domain and has implications for applications such as travel, power generation, and refrigeration. PMID- 30001109 TI - Polydopamine@Gold Nanowaxberry Enabling Improved SERS Sensing of Pesticides, Pollutants, and Explosives in Complex Samples. AB - Surface-enhanced Raman scattering (SERS) is a promising analysis technique for detecting various analytes in complex samples due to its unique vibrational fingerprints and high signal enhancement. However, impurity interference and substrate unreliability are direct suppression factors for practical application. Herein, we synthesize polydopamine@gold (PDA@Au) nanowaxberry, where Au nanoparticles are deposited on the surface of PDA sphere with high density and uniformity. Seed-mediated synthesis is used for fabrication of nanowaxberry. Au seeds are deposited on the surface of PDA sphere, then I ion coordinating ligand is employed to form stable AuI4- complex with AuCl4-, which decreases reduction potential of AuCl4- and avails formation of shell structure. Such nanowaxberry has high density of voids and gaps in three-dimensional space, which could absorb analytes and benefit practical SERS detection. Using malachite green as a model analyte, nanowaxberry realizes highly sensitive detection with low limit of detection (1 pM) and good reproducibility (relative standard deviation of about 10%). Meanwhile, the nanowaxberry is employed for practical detection of thiram, benzidine, and 2,4-dinitrotoluene in the environmental water, juice, apple peel, and soil. The high performance makes nanowaxberry to be potentially used for pesticides detection, pollutants monitoring, and forbidden explosives sensing in complex samples. PMID- 30001111 TI - Steady-State Kinetics of Phytoglobin-Catalyzed Reduction of Hydroxylamine to Ammonium. AB - Phytoglobins are plant hexacoordinate hemoglobins with reversible coordination of a histidine side chain to the ligand binding site of the heme iron. They mediate electron transfer reactions such as nitric oxide scavenging and are particularly efficient at reducing nitrite and hydroxylamine. Previous work with phytoglobins has focused only on single turnovers of these reactions and has not revealed whether structural features, such as histidine hexacoordination, play a prominent role in the complete catalytic cycle. This work characterizes steady-state phytoglobin catalysis of reduction of hydroxylamine to ammonium using two different chemical reductants. Km and kcat values were measured for rice phytoglobin, horse myoglobin, human neuroglobin, and a rice phytoglobin mutant protein in which the hexacoordinating histidine has been replaced with leucine (Phyt:H73L). The results demonstrate that phytoglobin catalysis driven by benzyl viologen is limited only by the dissociation rate constant for the distal histidine. This is consistent with the rate limit in single-turnover experiments and demonstrates that the kinetics of hydroxylamine binding, and not phytoglobin reduction, ultimately governs the reaction. Catalysis by the other proteins that either lack or have tighter hexacoordination is much slower, suggesting that facile reversibility of the bond between the distal histidine and the heme iron is needed to allow both substrate binding and heme iron reduction. On the other hand, catalysis driven by dithionite is limited by SO2*- concentrations and is similar for all of these proteins, suggesting that dithionite is not a good reducing agent for evaluation of the catalytic properties of hemoglobins. PMID- 30001110 TI - Glutathione-Responsive Self-Assembled Magnetic Gold Nanowreath for Enhanced Tumor Imaging and Imaging-Guided Photothermal Therapy. AB - Designing nanomaterials with advanced functions and physical properties to improve cancer diagnosis and treatment has been an enormous challenge. In this work, we report the synthesis of magnetic gold nanowreaths (AuNWs) by combining wet-chemical synthesis with layer-by-layer self-assembly. The presence of Au branches, small junctions, and central holes in AuNWs led to improved photothermal effect compared with Au nanoring seeds and thick Au nanoring with smooth surface. The self-assembly of exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) on the surfaces of AuNWs not only effectively quenched the T1-weighted magnetic resonance imaging (MRI) ability due to the enhanced T2 decaying effect but also provided the responsiveness to glutathione (GSH). After intravenous injection, the T1 signal of magnetic AuNWs initially in the "OFF" state can be intelligently switched on in response to the relatively high GSH concentration in tumor, and the formation of larger assemblies of ES-MIONs improved their tumor delivery compared to ES-MIONs themselves. Thus, the magnetic AuNWs showed higher MRI contrast than ES-MIONs or commercial Magnevist in T1 weighted MR imaging of tumor. Furthermore, the magnetic AuNWs have absorption in near-infrared range, leading to strong photoacoustic signal and effective photoablation of tumor. Therefore, our GSH-responsive self-assembled magnetic AuNWs could enhance T1-weighted MRI and photoacoustic imaging of tumor and be used for imaging-guided photothermal therapy. PMID- 30001113 TI - Near-Infrared Light Excited and Localized Surface Plasmon Resonance-Enhanced Photoelectrochemical Biosensing Platform for Cell Analysis. AB - Under near-infrared (NIR) light of 810 nm wavelength for irradiation, a very simple and highly sensitive photoelectrochemical (PEC) biosensing platform has been established using the localized surface plasmon resonance effect of Au nanoparticles (NPs) as signal amplification for the nondestructive analysis of living cells. The water-dispersible Ag2S quantum dots (QDs) synthesized by a one pot method were employed as photoelectrochemically active species, and they exhibited excellent PEC properties irradiated with NIR light which was chosen due to the obvious absorption and fluorescent emission in the NIR light region. After the incorporation of Au NPs on the Ag2S QDs modified ITO electrode, the photoelectric conversion efficiency was greatly increased, at ~2.5 times that of the pure Ag2S QDs modified electrode. Additionally, 4-mercaptophenylboronic acid (MPBA) molecules, as recognition elements, self-assembled on the electrode surface through Au-S bonds. On the basis of the chemical reaction between sialic acid on the cytomembranes and boric acid of MPBA, the very simple PEC biosensing platform was used for the quantitative determination of MCF-7 cells and dynamic evaluation of cell surface glycan expression under the external stimulus of sialidase. Under NIR light of 810 nm and a potential of 0.15 V, this proposed strategy exhibited a wide linear range from 1 * 102 to 1 * 107 cells/mL, with an experimental detection limit of 100 cells/mL. Importantly, this work provided a promising application for NIR Ag2S QDs coupled with Au NPs in the development of a novel PEC biosensing platform for the nondestructive analysis of biological samples. PMID- 30001112 TI - Chemical Self-Assembly of Multifunctional Hydroxyapatite with a Coral-like Nanostructure for Osteoporotic Bone Reconstruction. AB - Bone defects/fractures are common in older people suffering from osteoporosis. Traditional hydroxyapatite (HA) materials for osteoporotic bone repair face many challenges, including limited bone formation and aseptic loosening of orthopedic implants. In this study, a new multifunctional HA is synthesized by spontaneous assembly of alendronate (AL) and Fe3O4 onto HA nanocrystals for osteoporotic bone regeneration. The chemical coordination of AL and Fe3O4 with HA does not induce lattice deformation, resulting in a functionalized HA (Func-HA) with proper magnetic property and controlled release manner. The Func-HA nanocrystals have been encapsulated in polymer substrates to further investigate their osteogenic capability. In vitro and in vivo evaluations reveal that both AL and Fe3O4, especially the combination of two functional groups on HA, can inhibit osteoclastic activity and promote osteoblast proliferation and differentiation, as well as enhance implant osseointegration and accelerate bone remodeling under osteoporotic condition. The as-developed Func-HA with coordinating antiresorptive ability, magnetic property, and osteoconductivity might be a desirable biomaterial for osteoporotic bone defect/fracture treatment. PMID- 30001114 TI - Methylation Products of 6beta- N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators. AB - Two 6beta- N-heterocyclic naltrexamine derivatives, NAP and NMP, have been identified as peripherally selective mu opioid receptor (MOR) antagonists. To further enhance the peripheral selectivity of both compounds, the 17-amino group and the nitrogen atom of the pyridine ring in both NAP and NMP were methylated to obtain dMNAP and dMNMP, respectively. Compared with NAP and NMP, the binding affinities of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor) dual selective and they acted as moderate efficacy partial agonists. The results from radioligand binding studies were further confirmed by molecular docking studies. In vivo studies demonstrated that dMNAP and dMNMP did not produce antinociception nor did they antagonize morphine's antinociceptive activity, indicating that these compounds did not act on the central nervous system. Meanwhile, both dMNAP and dMNMP significantly slowed down fecal excretion, which indicated that they were peripherally acting opioid receptor agonists. All together, these results suggested that dMNAP and dMNMP acted as peripheral mu/kappa opioid receptor modulators and may be applicable in the treatment of diarrhea in patients with bowel dysfunction. PMID- 30001115 TI - Highly Stable and Multiemissive Silver Nanoclusters Synthesized in Situ in a DNA Hydrogel and Their Application for Hydroxyl Radical Sensing. AB - Oligonucleotide-stabilized silver nanoclusters (AgNCs) show promising applications in bioimaging and bio-/chemo-sensing. However, their unsatisfactory photostability limits their practical applications. In this work, fluorescent AgNCs were synthesized in situ in a DNA hydrogel, consisting of cross-linked enzymatically amplified polymeric DNAs with cytosine-rich sequences in the presence of Ag+. The fluorescence property of the resultant AgNCs was optimized by a rational design of the DNA sequences to cover a broad spectrum with comparable green and red emissions. Under the protection of the DNA hydrogel, the AgNCs showed significantly improved photostability in an ambient oxygen environment, as well as low cytotoxicity even at a high concentration. Therefore, these properties show the rolling-circle-amplification-stabilized AgNCs to be a promising possible fluorescent probe for the detection of reactive oxygen/nitrogen species (ROS/RNS) in live cells because red-emitting species are susceptible to oxidation and consequently convert to green-emitting species. Finally, the as-prepared AgNCs were demonstrated to be a sensitive and specific probe for cellular imaging and the monitoring of ROS/RNS levels, which broadens the applications of AgNCs and provides a new tool for related biological investigations. PMID- 30001116 TI - Plasmonic Hot-Carrier-Mediated Tunable Photochemical Reactions. AB - Hot-carrier generation from surface plasmon decay has found applications in many branches of physics, chemistry, materials science, and energy science. Recent reports demonstrated that the hot carriers generated from plasmon decay in nanoparticles can transfer to attached molecules and drive photochemistry which was thought impossible previously. In this work, we have computationally explored the atomic-scale mechanism of a plasmonic hot-carrier-mediated chemical process, H2 dissociation. Numerical simulations demonstrate that, after photoexcitation, hot carriers transfer to the antibonding state of the H2 molecule from the nanoparticle, resulting in a repulsive-potential-energy surface and H2 dissociation. This process occurs when the molecule is close to a single nanoparticle. However, if the molecule is located at the center of the gap in a plasmonic dimer, dissociation is suppressed due to sequential charge transfer, which efficiently reduces occupation in the antibonding state and, in turn, reduces dissociation. An asymmetric displacement of the molecule in the gap breaks the symmetry and restores dissociation when the additional charge transfer is significantly suppressed. Thus, these models demonstrate the possibility of structurally tunable photochemistry via plasmonic hot carriers. PMID- 30001117 TI - The Molecular Proceedings of Biological Hydrogen Turnover. AB - Over the past two decades, the bioinorganic chemistry of hydrogenases has attracted much interest from basic and applied research. Hydrogenases are highly efficient metalloenzymes that catalyze the reversible reduction of protons to molecular hydrogen (H2) in all domains of life. Their iron- and nickel-based cofactors represent promising blueprints for the design of biomimetic, synthetic catalysts. In this Account, we address the molecular proceedings of hydrogen turnover with [FeFe]-hydrogenases. The active site cofactor of [FeFe] hydrogenases ("H-cluster") comprises a unique diiron complex linked to a [4Fe-4S] cluster via a single cysteine. Since it was discovered that a synthetic analogue of the diiron site can be incorporated into apoprotein in vitro to yield active enzyme, significant progress has been made toward a comprehensive understanding of hydrogenase catalysis. The diiron site carries three to four carbon monoxide (CO) and two cyanide (CN-) ligands that give rise to intense infrared (IR) absorption bands. These bands are sensitive reporters of the electron density across the H-cluster, which can be addressed by infrared spectroscopy to follow redox and protonation changes at the cofactor. Synthetic variation of the metal bridging dithiolate ligand at the diiron site, as well as site-directed mutagenesis of amino acids, provides access to the proton pathways toward the cofactor. Quantum chemical calculations are employed to specifically assign IR bands to vibrational modes of the diatomic ligands and yield refined H-cluster geometries. Here, we provide an overview of recent research on [FeFe] hydrogenases with emphasis on experimental and computational IR studies. We describe advances in attenuated total reflection Fourier transform infrared spectroscopy (ATR FTIR) and protein film electrochemistry, as well as density functional theory (DFT) calculations. Key cofactor species are discussed in terms of molecular geometry, redox state, and protonation. Isotope editing is introduced as a tool to evaluate the cofactor geometry beyond the limits of protein crystallography. In particular, the role of proton-coupled electron transfer (PCET) in the generation of catalytically relevant redox species is addressed. We propose that site-selective protonation of the H-cluster biases surplus electrons either to the [4Fe-4S] cluster or to the diiron site. Protonation of the [4Fe-4S] cluster prevents premature reduction at the diiron site and stabilizes a reactive, terminal hydride. The observed H-cluster species are assigned to rapid H2 conversion or to reactions possibly involved in activity regulation and cellular H2 sensing. In the catalytic cycle of [FeFe] hydrogenases, an H-cluster geometry is preserved that features a bridging CO ligand. PCET levels the redox potential for two steps of sequential cofactor reduction. The concept of consecutive PCET at a geometrically inert cofactor with tight control of electron and proton localization may inspire the design of a novel generation of biomimetic catalysts for the production of H2 as a fuel. PMID- 30001120 TI - Synthesis and Characterization of Dinuclear Salan Rare-Earth Metal Complexes and Their Application in the Homo- and Copolymerization of Cyclic Esters. AB - Four rare-earth-metal aryloxo complexes stabilized by a tetradentate Salan ligand were prepared, and their catalytic properties for the (co)polymerization of lactides and epsilon-caprolactone were elucidated. The proton-exchange reactions of (C5H5)3Ln(THF) with the Salan ligand N, N'-(CH2Ph)2- N, N'-[CH2(2-OH-C6H2-Me2 3,5)]2 (LH2) in a 1:1 molar ratio, and subsequently with 1 equiv of p methylphenol, gave the rare-earth-metal aryloxides [LLn(OC6H4-4-CH3)(THF) n]2 [ n = 0 and Ln = Y (1), Sm (2), and Nd (3); n = 1 and Ln = La (4)] in good isolated yields. These complexes were fully characterized by elemental analysis, IR, and NMR spectroscopy (for complexes 1 and 4). Solid-state structures of complexes 1-4 were confirmed by single-crystal X-ray diffraction analysis. Complexes 1-4 have dinuclear solid-state structures, with a Ln2O2 core bridging the Salan ligands. The coordination geometry around each of the metals is a slightly distorted octahedron in complexes 1-3, whereas it is a capped trigonal prism in complex 4. It was found that complexes 1-4 can initiate efficiently the homopolymerization of l-lactide (l-LA) and rac-lactide ( rac-LA) at 30 degrees C in tetrahydrofuran. The increasing activity of these complexes is in agreement with increasing ionic radii. A kinetic study revealed that seven-coordinated lanthanum complex 4 is more active for rac-LA polymerization compared with l-LA. A further study revealed that complex 4 was also an efficient initiator for the random copolymerization of l-LA and epsilon-caprolactone with the simultaneous addition of these two monomers, and the Tg values of the copolymers obtained increase linearly from -30.2 to +38.3 degrees C with an increase of the percentage of LA units. A mechanism study revealed that transesterification plays a crucial role in the formation of a random copolymer. PMID- 30001119 TI - Discovery of Unprecedented Hydrazine-Forming Machinery in Bacteria. AB - Recent studies described several different routes that facilitate nitrogen nitrogen bond formation in natural product biosynthesis. We report herein the identification of unprecedented machinery for hydrazine formation involved in the biosynthesis of s56-p1, a dipeptide natural product with a unique hydrazone unit. The gene cassette comprising this machinery is widespread across several bacterial phyla, highlighting the overlooked potential of bacteria to synthesize hydrazine. PMID- 30001121 TI - Visible-Light-Driven "On"/"Off" Photochromism of a Polyoxometalate Diarylethene Coordination Complex. AB - Herein we report the first photochromic polyoxometalate (POM)-based diarylethene (DAE) coordination complex, prepared by ligation of two cobalt(III)-incorporated borotungstates [BIIIWVI11O39CoIII]6- with the ditopic pyridyl-containing diarylethene (C25H16N2F6S2). The solution-state composition, structure, and stability of the assembly were probed using 1H and 19F nuclear magnetic resonance spectroscopy (NMR), electrospray ionization quadrupolar time-of-flight mass spectrometry (ESI-QTOF-MS), ultraviolet-visible spectroscopy (UV-vis), and small angle X-ray scattering (SAXS), revealing that the complex self-organizes to adopt a molecular dumbbell structure due to electrostatic and steric considerations. This conformation is a prerequisite for the photocyclization reaction. The assembly was found to be switchable between two states using visible light due to the perturbation of the DAE electronic structure on coordination to the POM. We present photophysical data, including the reaction quantum efficiency of the molecular switch in both directions measured using a custom-built quantum yield determination setup in addition to fatigue resistance on prolonged irradiation. PMID- 30001122 TI - Stability, Composition, and Core-Shell Particle Structure of Uranium(IV)-Silicate Colloids. AB - Uranium is typically the most abundant radionuclide by mass in radioactive wastes and is a significant component of effluent streams at nuclear facilities. Actinide(IV) (An(IV)) colloids formed via various pathways, including corrosion of spent nuclear fuel, have the potential to greatly enhance the mobility of poorly soluble An(IV) forms, including uranium. This is particularly important in conditions relevant to decommissioning of nuclear facilities and the geological disposal of radioactive waste. Previous studies have suggested that silicate could stabilize U(IV) colloids. Here the formation, composition, and structure of U(IV)-silicate colloids under the alkaline conditions relevant to spent nuclear fuel storage and disposal were investigated using a range of state of the art techniques. The colloids are formed across a range of pH conditions (9-10.5) and silicate concentrations (2-4 mM) and have a primary particle size 1-10 nm, also forming suspended aggregates <220 nm. X-ray absorption spectroscopy, ultrafiltration, and scanning transmission electron microscopy confirm the particles are U(IV)-silicates. Additional evidence from X-ray diffraction and pair distribution function data suggests the primary particles are composed of a UO2-rich core and a U-silicate shell. U(IV)-silicate colloids formation correlates with the formation of U(OH)3(H3SiO4)32- complexes in solution indicating they are likely particle precursors. Finally, these colloids form under a range of conditions relevant to nuclear fuel storage and geological disposal of radioactive waste and represent a potential pathway for U mobility in these systems. PMID- 30001124 TI - Laser-Induced Bipolar Electrochemistry-On-Demand Formation of Bipolar Electrodes in a Solid Polymer Light-Emitting Electrochemical Cell. AB - Bipolar electrochemistry (BPEC) is a versatile and powerful technique that has found applications in sensing, chemical synthesis, catalysis, fuel cells, and batteries, among others. In BPEC, the reactions of interest occur at a wireless, bipolar electrode (BPE). BPEC is most commonly carried out in an electrochemical cell that contains an electrolyte solution, in which a metallic BPE is immersed and polarized when the wired driving electrodes are biased. In this article, we demonstrate BPEC in a solid light-emitting electrochemical cell (LEC) that does not initially contain a BPE. Shining a focused laser beam onto the mixed conductor LEC film causes the illuminated spot to function as a BPE from which redox reactions are induced and visualized. Separate experiments using a photosensitizer (widely used in polymer solar cells) confirm that a BPE is formed on-demand via photoabsorption that causes the illuminated spot to have elevated photoconductivity. The simplicity of laser-induced BPEC offers exciting opportunities to explore sciences and applications of BPEC in the new realm of solid-state organic photonic devices. PMID- 30001123 TI - Secondary-Structure-Mediated Hierarchy and Mechanics in Polyurea-Peptide Hybrids. AB - Peptide-polymer hybrids combine the hierarchy of biological species with synthetic concepts to achieve control over molecular design and material properties. By further incorporating covalent cross-links, the enhancement of molecular complexity is achieved, allowing for both a physical and covalent network. In this work, the structure and function of poly(ethylene glycol) (PEG) network hybrids are tuned by varying peptide block length and overall peptide content. Here the impact of poly(epsilon-carbobenzyloxy-l-lysine) (PZLY) units on block interactions and mechanics is explored by probing secondary structure, PEG crystallinity, and hierarchical organization. The incorporation of PZLY reveals a mixture of alpha-helices and beta-sheets at smaller repeat lengths ( n = 5) and selective alpha-helix formation at a higher peptide molecular weight ( n = 20). Secondary structure variations tailored the solid-state film hierarchy, whereby nanoscale fibers and microscale spherulites varied in size depending on the amount of alpha-helices and beta-sheets. This long-range ordering influenced mechanical properties, resulting in a decrease in elongation-at-break (from 400 to 20%) with increasing spherulite diameter. Furthermore, the reduction in soft segment crystallinity with the addition of PZLY resulted in a decrease in moduli. It was determined that, by controlling PZLY content, a balance of physical associations and self-assembly is obtained, leading to tunable PEG crystallinity, spherulite formation, and mechanics. PMID- 30001125 TI - Total Synthesis of Onitin. AB - The total synthesis of the phenolic sesquiterpene onitin using dimethylated indanone as the key intermediate is reported. Key to the success of this synthesis route is the Suzuki-Miyaura cross-coupling reaction of aryl bromide to introduce the vinyl side chain followed by formyl selective Wacker oxidation to generate the aldehyde. The target aldehyde was also obtained in high overall yield via an acid-catalyzed pinacol-pinacolone-type rearrangement of the epoxide. The epoxide was generated from oxidation of a styrene derivative by oxone. Demethylation of the aldehyde followed by chemoselective reduction furnished onitin. PMID- 30001126 TI - Bioreduction of Antimonate by Anaerobic Methane Oxidation in a Membrane Biofilm Batch Reactor. AB - Employing a special anaerobic membrane biofilm batch reactor (MBBR), we demonstrated antimonate (Sb(V)) reduction using methane (CH4) as the sole electron donor. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and Raman and photoluminescence (PL) spectra identified that Sb2O3 microcrystals were the main reduced products. The Sb(V) reduction rate increased continually over the 111-day experiment, which supports the enrichment of the microorganisms responsible for Sb(V) reduction to Sb(III). Copy numbers of the mcrA gene and archaeal and bacterial 16 S rRNA genes increased in parallel. Clone library and Illumina sequencing of 16S rRNA gene demonstrated that Methanosarcina became the dominant archaea in the biofilm, suggesting that Methanosarcina might play an important role in Sb(V) reduction in the CH4-based MBBR. PMID- 30001127 TI - In Situ Measurement of Exciton Dynamics During Thin-Film Formation Using Single Shot Transient Absorption. AB - The exciton dynamics of pseudoisocyanine (PIC) is reported during the formation of a thin film dropcast from solution. Tilted pump pulses are used to spatially encode a pump-probe time delay, enabling the collection of a transient in a single shot. We demonstrate that a spatially encoded delay can be used to accurately measure exciton dynamics in thin-film samples, with a signal-to-noise ratio above 20 attained in 2 s. We report in situ linear absorption, fluorescence, and transient absorption measurements during the molecular aggregation of PIC. These measurements reveal a highly fluorescent intermediate stage during thin-film formation that we ascribe to J-aggregates, in contrast to the final, less fluorescent, dry thin film that exhibits photophysics indicative of disordered J-aggregates. The ability to measure exciton dynamics in situ during materials formation will provide a deeper understanding of how functional materials properties evolve, and will enable direct feedback for rational materials design. PMID- 30001118 TI - Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine. AB - Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field. PMID- 30001128 TI - Visualization of the Intrinsic Reaction Coordinate and Global Reaction Route Map by Classical Multidimensional Scaling. AB - A classical multidimensional scaling (CMDS) method is employed to visualize an intrinsic reaction coordinate (IRC) and a global reaction route map consisting of the equilibrium minima and transition state structures connected by the IRC network. As demonstrations, the method was applied to the IRCs of the intramolecular proton transfer in malonaldehyde and the SN2 reaction of OH- + CH3F -> CH3OH + F-, which are both well described by two principal coordinates. Next, the method was applied to the global reaction route map of the Au5 cluster; the resulting map shows appropriate positions of five minima and 14 transition states in a reduced 2- or 3-dimensional coordinate space successfully. PMID- 30001129 TI - Experimental and Modeling Studies on the Filtration of SiO2 Nanoparticles Aerosolized from Different Solvents. AB - The filtration performance of a fibrous filter in removing nano-SiO2 aerosols atomized using different solvents including methanol, ethanol, 1-propanol, water, and the ethanol/water mixture has been investigated. Through discrete element method (DEM) simulation and filtration experiments, the efficiency variation caused by the combinative interaction of the particle-filter adhesion and interparticle attraction has been analyzed and verified. The adhesion force between the solvent-coated nanoparticles and the filter is considered as the key factor to influence their initial filtration efficiency and can be balanced by their interparticle interaction. The stronger the adhesion, the higher the initial filtration efficiency. Primary aggregate is formed through the particle fiber interaction, and further agglomerate is caused by particle migration on the fibers, i.e. secondary aggregate. Hydrogen bonding interaction is considered as the main factor causing interparticle secondary agglomeration, and plenty of OH groups existing in the nano-SiO2 aerosols yielded from alcohol promotes the particle secondary aggregation. As a result, the Brown diffusion capture of the filter is significantly abated, and the as-formed agglomerate is scraped off the filter surface by the alcohol molecules, causing the filtration efficiency decreases. This study highlights the surface affinity properties of nanoaerosols and their balance between particle-particle and particle-fiber interactions in the filtration process. PMID- 30001130 TI - Molecular Mobility Effect on Magnetic Interactions in All-Organic Paramagnetic Liquid Crystal with Nitroxide Radical as a Hydrogen-Bonding Acceptor. AB - We synthesized new chiral all-organic liquid crystalline (LC) compounds with nitroxide (NO) and hydroxy (OH) groups, which form intermolecular hydrogen bonds between the NO and OH groups. The LC compounds show hexagonal columnar phases at room temperature, which solidify as LC glasses at low temperature. The experimental magnetic susceptibility of each of the compounds in the LC and isotropic phases is larger than that theoretically estimated on the simple assumption about the amount of the spins, whereas it accords with the theoretical one in the LC glass state. It is called magneto-LC effects. The difference between experimental and theoretical magnetic susceptibilities gradually increases as temperature increases through the LC glass state-to-LC phase transition. It suggests that molecular mobility is one of the origins of the magneto-LC effects. PMID- 30001131 TI - Importance of Solvents' Translational-Rotational Coupling for Translational Jump of a Small Hydrophobic Solute in Supercooled Water. AB - Despite clear evidence of sudden translational jump occurrence of a solute in supercooled water, a detailed mechanism of this jump is still lacking. A previous work [ Indra , S. ; Daschakraborty , S. Chem. Phys. Lett. 2017 , 685 , 322 - 327 ] put forward a mechanism of this jump from an initial solvent cage to a final one. The proposed mechanism is astoundingly similar to that of the electron/proton transfer reaction in aqueous solution. The above study identified the spatial prearrangement (rearrangement before the jump occurrence) of cage forming water solvent molecules as the actual reaction coordinate. However, the study completely ignored the contribution of the orientational prearrangement of solvent water molecules. In this study, we have monitored both the spatial and the orientational prearrangements of water solvent molecules at subzero temperatures during the jump occurrence of the solute. We have found overwhelming contributions of both the spatial and orientational prearrangements of water, which symmetrize the hydration structure at the initial and final cage positions to facilitate the jump event. Through a systematic temperature dependence study (from T = 240 to 270 K), we have found clear evidence that a strong synchronization between translational and rotational prearrangements of the solvent water molecules is crucial for the solute's jump from one solvent cage to another in supercooled water (below T = 252 K). The above translation-rotation synchronization is probably due to the cooperative movement of solvent water molecules forming clusters in the supercooled region. Since these cooperative dynamics are the consequence of the spatiotemporal heterogeneity in the medium, we infer that the large-amplitude translational jump of the nonpolar solute probably stems from the spatiotemporal heterogeneity of supercooled water. At temperatures above the melting point, this cooperativity is partly lost since the translational and orientational prearrangements become somewhat independent of each other. PMID- 30001132 TI - Hypoxia Remediation and Methane Emission Manipulation Using Surface Oxygen Nanobubbles. AB - Algal blooms in eutrophic waters often induce anoxia/hypoxia and enhance methane (CH4) emissions to the atmosphere, which may contribute to global warming. At present, there are very few strategies available to combat this problem. In this study, surface oxygen nanobubbles were tested as a novel approach for anoxia/hypoxia remediation and CH4 emission control. Incubation column experiments were conducted using sediment and water samples taken from Lake Taihu, China. The results indicated that algae-induced anoxia/hypoxia could be reduced or reversed after oxygen nanobubbles were loaded onto zeolite micropores and delivered to anoxic sediment. Cumulated CH4 emissions were also reduced by a factor of 3.2 compared to the control. This was mainly attributed to the manipulation of microbial processes using the surface oxygen nanobubbles, which potentially served as oxygen suppliers. The created oxygen-enriched environment simultaneously decreased methanogen but increased methanotroph abundances, making a greater fraction of organic carbon recycled as carbon dioxide (CO2) instead of CH4. The CH4/CO2 emission ratio decreased to 3.4 * 10-3 in the presence of oxygen nanobubbles, compared to 11 * 10-3 in the control, and therefore the global warming potential was reduced. This study proposes a possible strategy for anoxia/hypoxia remediation and CH4 emission control in algal bloom waters, which may benefit global warming mitigation. PMID- 30001133 TI - Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control. AB - A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a ubiquitous structural motif seen in many bioactive natural products, including di- and triterpenes and steroids. Installation of these centers has been a long-standing problem in organic chemistry. Few classes of compounds illustrate this problem better than serrulatanes and amphilectanes, which carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed asymmetric hydrovinylation (AHV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provides an exceptionally facile way of introducing these chiral centers. This Article documents our efforts to demonstrate the generality of AHV to access not only the natural products but also their various diastereoisomeric derivatives. Key to success here is the availability of highly tunable phosphoramidite Ni(II) complexes useful for overcoming the inherent selectivity of the chiral intermediates. The yields for hydrovinylation (HV) reactions are excellent, and selectivities are in the range of 92-99% for the desired isomers. Discovery of novel, configurationally fluxional, yet sterically less demanding 2,2'-biphenol-derived phosphoramidite Ni complexes (fully characterized by X-ray) turned out to be critical for success in several HV reactions. We also report a less spectacular yet equally important role of solvents in a metal-ammonia reduction for the installation of a key benzylic chiral center. Starting with simple oxygenated styrene derivatives, we iteratively install the various exocyclic chiral centers present in typical serrulatane [e.g., a (+)- p-benzoquinone natural product, elisabethadione, nor elisabethadione, helioporin D, a known advanced intermediate for the synthesis of colombiasin and elisapterosin] and amphilectane [e.g., A-F, G-J, and K,L pseudopterosins] derivatives. A concise table showing various synthetic approaches to these molecules is included in the Supporting Information. Our attempts to synthesize a hitherto elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A-F aglycones. PMID- 30001134 TI - One Million Percent Tunnel Magnetoresistance in a Magnetic van der Waals Heterostructure. AB - We report the observation of a very large negative magnetoresistance effect in a van der Waals tunnel junction incorporating a thin magnetic semiconductor, CrI3, as the active layer. At constant voltage bias, current increases by nearly one million percent upon application of a 2 T field. The effect arises from a change between antiparallel to parallel alignment of spins across the different CrI3 layers. Our results elucidate the nature of the magnetic state in ultrathin CrI3 and present new opportunities for spintronics based on two-dimensional materials. PMID- 30001135 TI - Fabrication of Biocompatible, Luminescent Supramolecular Structures and Their Applications in the Detection of Dopamine. AB - Supramolecular materials assembled by amide-functionalized surface active ionic liquid, N-dodecyl- N'-acetamido imidazolium bromide ([C12ImCONH2]Br), and europium-containing polyoxometalates (Eu-POM) were fabricated in aqueous solution by a one-step method via ionic self-assembly strategy. The [C12ImCONH2]Br/Eu-POM supramolecular structures exhibit favorable fluorescence properties and represent a 15-fold increase in quantum yield (~13.68%) compared to Eu-POM. Besides, more fluorescence was quenched obviously with the increasing concentration of dopamine (DA) (within the range of 0-100 MUM), based on which DA monitoring could be achieved. The detection limit was identified to be 0.1 MUM. The supramolecular nanoparticles are highly specific for the detection of DA. In addition, the hybrid assemblies display not only low cytotoxicity but also excellent biocompatibility to MC3T3-E1 cells. As a result, as-prepared supramolecular materials with these superior properties show the promising application in some fields such as biochemistry and biomedical science. PMID- 30001136 TI - Semiconducting van der Waals Interfaces as Artificial Semiconductors. AB - Recent technical progress demonstrates the possibility of stacking together virtually any combination of atomically thin crystals of van der Waals bonded compounds to form new types of heterostructures and interfaces. As a result, there is the need to understand at a quantitative level how the interfacial properties are determined by the properties of the constituent 2D materials. We address this problem by studying the transport and optoelectronic response of two different interfaces based on transition-metal dichalcogenide monolayers, namely WSe2-MoSe2 and WSe2-MoS2. By exploiting the spectroscopic capabilities of ionic liquid gated transistors, we show how the conduction and valence bands of the individual monolayers determine the bands of the interface, and we establish quantitatively (directly from the measurements) the energetic alignment of the bands in the different materials as well as the magnitude of the interfacial band gap. Photoluminescence and photocurrent measurements allow us to conclude that the band gap of the WSe2-MoSe2 interface is direct in k space, whereas the gap of WSe2/MoS2 is indirect. For WSe2/MoSe2, we detect the light emitted from the decay of interlayer excitons and determine experimentally their binding energy using the values of the interfacial band gap extracted from transport measurements. The technique that we employed to reach this conclusion demonstrates a rather-general strategy for characterizing quantitatively the interfacial properties in terms of the properties of the constituent atomic layers. The results presented here further illustrate how van der Waals interfaces of two distinct 2D semiconducting materials are composite systems that truly behave as artificial semiconductors, the properties of which can be deterministically defined by the selection of the appropriate constituent semiconducting monolayers. PMID- 30001138 TI - Nanowires for Biosensing: Lightguiding of Fluorescence as a Function of Diameter and Wavelength. AB - Semiconductor nanowires can act as nanoscaled optical fibers, enabling them to guide and concentrate light emitted by surface-bound fluorophores, potentially enhancing the sensitivity of optical biosensing. While parameters such as the nanowire geometry and the fluorophore wavelength can be expected to strongly influence this lightguiding effect, no detailed description of their effect on in coupling of fluorescent emission is available to date. Here, we use confocal imaging to quantify the lightguiding effect in GaP nanowires as a function of nanowire geometry and light wavelength. Using a combination of finite-difference time-domain simulations and analytical approaches, we identify the role of multiple waveguide modes for the observed lightguiding. The normalized frequency parameter, based on the step-index approximation, predicts the lightguiding ability of the nanowires as a function of diameter and fluorophore wavelength, providing a useful guide for the design of optical biosensors based on nanowires. PMID- 30001139 TI - Entropy-Driven Spontaneous Reaction in Cryogenic Ice: Dissociation of Fluoroacetic Acids. AB - Chemical reactions are extremely difficult to occur in ice at low temperature, where atoms and molecules are frozen in position with minimal thermal energy and entropy. Contrary to this general behavior, certain weak acids including fluoroacetic acids dissociate spontaneously and more efficiently in cryogenic ice than in aqueous solution at room temperaure. The enhanced reactivity of weak acids is an unexpected consequence of proton-transfer equilibrium in ice. The configurational entropy of protons in ice shifts the acid dissociation equilibrium forward. This configurational entropy, although a solid-state property, is comparatively large in magnitude with the entropy of vaporization and can effectively drive proton-transfer reactions in ice. PMID- 30001137 TI - Electronic Preresonance Stimulated Raman Scattering Microscopy. AB - Optical microscopy has generated great impact for modern research. While fluorescence microscopy provides the ultimate sensitivity, it generally lacks chemical information. Complementarily, vibrational imaging methods provide rich chemical-bond-specific contrasts. Nonetheless, they usually suffer from unsatisfying sensitivity or compromised biocompatibility. Recently, electronic preresonance stimulated Raman scattering (EPR-SRS) microscopy was reported, achieving simultaneous high detection sensitivity and superb vibrational specificity of chromophores. With newly synthesized Raman-active dyes, this method readily breaks the optical color barrier of fluorescence microscopy and is well-suited for supermultiplex imaging in biological samples. In this Perspective, we first review previous utilizations of electronic resonance in various Raman spectroscopy and microscopy. We then discuss the physical origin and uniqueness of the electronic preresonance region, followed by quantitative analysis of the enhancement factors involved in EPR-SRS microscopy. On this basis, we provide an outlook for future development as well as the broad applications in biophotonics. PMID- 30001140 TI - Orientational Epitaxy of van der Waals Molecular Heterostructures. AB - The shape of individual building blocks is an important parameter in bottom-up self-assembly of nanostructured materials. A simple shape change from sphere to spheroid can significantly affect the assembly process due to the modification to the orientational degrees of freedom. When a layer of spheres is placed upon a layer of spheroids, the strain at the interface can be minimized by the spheroid taking a special orientation. C70 fullerenes represent the smallest spheroids, and their interaction with a sphere-like C60 is investigated. We find that the orientation of the C70 within a close-packed C70 layer can be steered by contacting a layer of C60. This orientational steering phenomenon is potentially useful for epitaxial growth of multilayer van der Waals molecular heterostructures. PMID- 30001141 TI - Drug Repurposing Using Deep Embeddings of Gene Expression Profiles. AB - Computational drug repositioning requires assessment of the functional similarities among compounds. Here, we report a new method for measuring compound functional similarity based on gene expression data. This approach takes advantage of deep neural networks to learn an embedding that substantially denoises expression data, making replicates of the same compound more similar. Our method uses unlabeled data in the sense that it only requires compounds to be labeled by identity rather than detailed pharmacological information, which is often unavailable and costly to obtain. Similarity in the learned embedding space accurately predicted pharmacological similarities despite the lack of any such labels during training and achieved substantially improved performance in comparison with previous similarity measures applied to gene expression measurements. Our method could identify drugs with shared therapeutic and biological targets even when the compounds were structurally dissimilar, thereby revealing previously unreported functional relationships between compounds. Thus, our approach provides an improved engine for drug repurposing based on expression data, which we have made available through the online tool DeepCodex ( http://deepcodex.org ). PMID- 30001142 TI - NiO Nanoparticles for Exceptionally Stable DNA Adsorption and Its Extraction from Biological Fluids. AB - Selective extraction of a small amount of nucleic acids from complex biological samples containing a high concentration of proteins is critical for bioanalytical chemistry. A number of previously published studies have focused on long, double stranded DNA such as plasmid DNA. On the other hand, we are interested in short oligonucleotides. Nucleic acids have a negatively charged phosphate backbone that interacts with metal oxides strongly, and this may be used to distinguish them from proteins. In this work, a few metal oxide nanoparticles were screened, including NiO, CoO, ZnO, TiO2, CeO2, and Fe3O4 for DNA recovery. NiO had the highest DNA adsorption efficiency from mixtures containing bovine serum albumin or human blood serum. The adsorption of DNA by NiO was further characterized as a function of the pH, salt concentration, DNA length, and DNA sequence. The adsorption mechanism was studied by adding competing chemicals or denaturing agents. A striking observation was the extremely high adsorption affinity of NiO, much higher than that of the other tested oxides. Polyphosphate was the most effective agent for displacing adsorbed DNA, whereas simple inorganic phosphate was less effective. NiO was able to concentrate DNA from a serum mixture by 33- to 55-fold, depending on the serum concentration. NiO is thus a promising candidate for extracting DNA from biological samples. PMID- 30001143 TI - Modular Assembly of Plasmonic Nanoparticles Assisted by DNA Origami. AB - Arraying noble metal nanoparticles with nanoscale features is an important way to develop plasmonic devices with novel optical properties such as plasmonic chiral metamolecules, optical waveguides, and so forth. Along with top-down methods of fabricating plasmonic nanostructures, solution-based self-assembly provides an alternative approach. There are mainly two routes to organizing metal nanoparticles via self-assembly. One is directly linking nanoparticles through linker molecules, and the other is using nanoparticles to decorate a preformed template. We combine these two routes and herein report a strategy for the DNA origami-assisted modular assembly of gold nanoparticles into homogeneous and heterogeneous plasmonic nanostructures. For each module, we designed W-shaped DNA origami with two troughs as two domains. One domain is used to host a gold nanoparticle, and the other domain is designed to capture another gold nanoparticle hosted on a different module. By simply tuning the sequences of capture DNA strands on each module, gold nanoparticles including spherical and rod-shaped gold nanoparticles (denoted as AuNPs and AuNRs) could be well organized in a predefined manner to form versatile plasmonic nanostructures. Since the interparticle distances could be precisely controlled at the nanoscale, we also studied the plasma coupling among the assembled plasmonic nanostructures. This modular assembly strategy represents a simple yet general and effective design principle for DNA-assembled plasmonic nanostructures. PMID- 30001144 TI - New links for old: differential roles of filaggrin in the regulation of mucosal barriers? PMID- 30001145 TI - Muscarinic suppression of ATP-sensitive K+ channels mediated by the M3/Gq/11/phospholipase C pathway contributes to mouse ileal smooth muscle contractions. AB - ATP-sensitive K+ (KATP) channels are expressed in gastrointestinal smooth muscles, and their activity is regulated by muscarinic receptor stimulation. However, the physiological significance and mechanisms of muscarinic regulation of KATP channels are not fully understood. We examined the effects of the KATP channel opener cromakalim and the KATP channel blocker glibenclamide on electrical activity of single mouse ileal myocytes and on mechanical activity in ileal segment preparations. To explore muscarinic regulation of KATP channel activity and its underlying mechanisms, the effect of carbachol (CCh) on cromakalim-induced KATP channel currents ( IKATP) was studied in myocytes of M2 or M3 muscarinic receptor-knockout (KO) and wild-type (WT) mice. Cromakalim (10 uM) induced membrane hyperpolarization in single myocytes and relaxation in segment preparations from WT mice, whereas glibenclamide (10 uM) caused membrane depolarization and contraction. CCh (100 uM) induced sustained suppression of IKATP in cells from both WT and M2KO mice. However, CCh had a minimal effect on IKATP in M3KO and M2/M3 double-KO cells. The Gq/11 inhibitor YM-254890 (10 MUM) and PLC inhibitor U73122 (1 MUM), but not the PKC inhibitor calphostin C (1 MUM), markedly decreased CCh-induced suppression of IKATP in WT cells. These results indicated that KATP channels are constitutively active and contribute to the setting of resting membrane potential in mouse ileal smooth muscles. M3 receptors inhibit the activity of these channels via a Gq/11/PLC-dependent but PKC independent pathways, thereby contributing to membrane depolarization and contraction of smooth muscles. NEW & NOTEWORTHY We systematically investigated the regulation of ATP-sensitive K+ channels by muscarinic receptors expressed on mouse ileal smooth muscles. We found that M3 receptors inhibit the activity of ATP-sensitive K+ channels via a Gq/11/PLC-dependent, but PKC-independent, pathway. This muscarinic suppression of ATP-sensitive K+ channels contributes to membrane depolarization and contraction of smooth muscles. PMID- 30001146 TI - Vagus nerve cholinergic circuitry to the liver and the gastrointestinal tract in the neuroimmune communicatome. AB - Improved understanding of neuroimmune communication and the neural regulation of immunity and inflammation has recently led to proposing the concept of the "neuroimmune communicatome." This advance is based on experimental evidence for an organized and brain-integrated reflex-like relationship and dialogue between the nervous and the immune systems. A key circuitry in this communicatome is provided by efferent vagus nerve fibers and cholinergic signaling. Inflammation and metabolic alterations coexist in many disorders affecting the liver and the gastrointestinal (GI) tract, including obesity, metabolic syndrome, fatty liver disease, liver injury, and liver failure, as well as inflammatory bowel disease. Here, we outline mechanistic insights regarding the role of the vagus nerve and cholinergic signaling in the regulation of inflammation linked to metabolic derangements and the pathogenesis of these disorders in preclinical settings. Recent clinical advances using this knowledge in novel therapeutic neuromodulatory approaches within the field of bioelectronic medicine are also briefly summarized. PMID- 30001147 TI - A luminescent future for the study of bile acid transporters. PMID- 30001148 TI - Forward collision warning system impact. AB - OBJECTIVE: The objective of this research is to use historical crash data to evaluate the potential benefits of both high- and low-speed automatic emergency braking (AEB) with forward collision warning (FCW) systems. METHODS: Crash data from the NHTSA's NASS-General Estimates System (GES) and Fatality Analysis Reporting System (FARS) databases were categorized to classify crashes by the speed environment, as well as to identify cases where FCW systems would be applicable. RESULTS: Though only about 19% of reported crashes occur in environments with speeds greater than 45 mph, approximately 32% of all serious or fatal crashes occur in environments with speeds greater than 45 mph. The percentage of crashes where FCW systems would be relevant has remained remarkably constant, varying between about 21 and 26% from 2002 to 2015. In 2-vehicle fatal crashes where one rear-ends the other, the fatality rates are actually higher in the struck vehicle (33%) than the striking vehicle (26%). The disparity is even greater when considering size-class differences, such as when a light truck rear ends a passenger car (15 vs. 42% fatality rates, respectively). CONCLUSIONS: NHTSA and the Insurance Institute for Highway Safety (IIHS) proposed the Automatic Emergency Braking Initiative in 2015, which is intended to make AEB (also called crash-imminent braking) with FCW systems standard on nearly all new cars by September 2022. Twenty automakers representing 99% of the U.S. auto market voluntarily committed to the initiative. Though the commitment to safety is laudable, the AEB component of the agreement only covers low-speed AEB systems, with the test requirements set to 24 mph or optionally as low as 12 mph. The test requirements for the FCW component of the agreement include 2 tests that begin at 45 mph. Only 21% of relevant serious injury or fatal accidents occur in environments at speeds under 24 mph, whereas about 22% of serious or fatal crashes occur in environments with speeds greater than 45 mph. This means that the AEB with FCW systems as agreed upon will cover only 21% of serious or fatal crashes and will not cover 22% of serious or fatal crashes. Because these systems are protective not only for the occupants of the vehicle where they are installed but also other vehicles on the roads, the data indicate that these systems should be a standard feature on all cars for high-speed as well as low-speed environments for the greatest social benefit. PMID- 30001150 TI - Application of different nanocarriers for encapsulation of curcumin. AB - Curcumin is the main polyphenol of the curcuminoid class of turmeric, a well known spice belonging to the ginger family. In addition to its common applications like coloring and antioxidant agent as food additives, it has a broad range of favorable biological functions, such as anti-inflammatory, anti microbial, anti-diabetic activities, and anti-cancer potentials against various cancers. However, curcumin suffers from some limitations including short shelf life due to its poor chemical stability, low bioavailability due to its poor absorption, low water solubility, rapid metabolism and rapid systemic elimination. Nanoencapsulaion has been addressed as an innovative and emerging technology for resolving these shortcomings. In this review, the different delivery systems used for loading of curcumin have been considered and explained including lipid-based, chemical polymer and biopolymer-based, nature-inspired, special equipment-based and surfactant-based techniques. Also, implications of nanoencapsulated curcumin in food, pharmaceutical and cosmetic uses are discussed. In this sense, the relevant recent studies in the past few years along with upcoming challenges have been covered. Although incorporation of curcumin into nanocarriers can be a possible solution to overcome its inherent constraints, there are some rational concerns about their toxicological safety once they enter into the biological paths. Therefore, future investigations could focus on assessment of their biological fate during digestion and absorption within human body. PMID- 30001149 TI - A gender invariant model of disgust propensity in blood-injection-injury phobia in Latina/o individuals. AB - Latinas/os have been underrepresented in research investigating the role of disgust propensity in phobias. The current study was the first to examine associations between disgust propensity and Blood-Injection-Injury (BII) phobia, when acculturation was controlled for, in Latina/o Americans (n = 376). A structural model was developed with a BII fear latent variable consisting of fears of injection, blood, and sharp objects (causing injuries). The disgust propensity latent variable was formed with three domains of core, animal reminder, and contamination disgust elicitors. In the model, disgust propensity predicted BII fear when controlling for acculturation. A series of measurement and structural invariance tests demonstrated that the model was invariant between males and females. The current findings supported the hypothesis that disgust plays a role in BII fear symptoms similarly in Latinas and Latinos. The findings are expected to improve our understanding of mechanisms and treatment approaches for BII phobia symptoms in this underserved cultural group. PMID- 30001151 TI - The DigniCap Scalp Cooling System and its use in the treatment of chemotherapy induced alopecia. AB - Chemotherapy-induced alopecia remains an emotionally traumatic side effect for cancer patients that impacts the quality of life, may be protracted in duration and may influence treatment decisions. Scalp cooling has been shown to be effective in preventing chemotherapy-induced alopecia. The DigniCap Scalp Cooling System is designed to prevent hair loss by cooling the scalp to reduce the impact of chemotherapy on hair follicle cells. Recent studies have shown the safety, efficacy and low-grade toxicity of the DigniCap System with a 66.3% success rate in hair preservation (n = 106) relative to 0% in a nonrandomized control group according to a prospective pivotal study. Data also support improved quality of life in several domains. Two scalp cooling devices including the DigniCap are now US FDA cleared and can be offered as a part of standard of care. PMID- 30001152 TI - Effectiveness of wearing a bicycle helmet for impacts against the front of a vehicle and the road surface. AB - OBJECTIVE: To assess the effect of wearing a bicycle helmet using an adult headform in terms of the head injury criterion (HIC) when the frontal and lateral parts of the helmet impact a vehicle body and also when the frontal part of the helmet impacts the road surface. METHODS: The adult headform was made to impact the hood, windscreen, roof top, and roof side rail of a vehicle body at an impact velocity of 35 km/h, which is a common head-to-vehicle impact velocity in real world cyclist-vehicle collisions, in which the vehicle impacts the cyclist at 40 km/h. For the road surface impact experiments, we set a drop height of 1.5 m (impact velocity of 20 km/h). RESULTS: Helmet usage helped to reduce the HIC when the frontal and lateral parts of the helmet impacted vehicle parts other than the hood. The HIC reduction for the frontal impact was greater than that for the lateral impact. Moreover, the higher the stiffness index of the vehicle structure, the greater was the HIC reduction. However, helmet usage was ineffective for reducing skull fracture risk (HIC 2558) when the lateral part of the helmet impacted stiffer parts of the vehicle, such as the roof side rail close to the B-pillar. Helmet usage helped to reduce the HIC by 91% when the frontal part of the helmet impacted the road surface. CONCLUSIONS: Wearing a helmet reduces skull fracture risk when the frontal and lateral parts of the helmet impact vehicle parts (excluding the hood) at 35 km/h and the road surface at 20 km/h. However, when the lateral part of the helmet impacts the B-pillar, the helmet cannot effectively reduce the skull fracture risk at these real-world velocities. PMID- 30001153 TI - Disentangling Family Life and Hair Pulling: Trichotillomania and Relatedness. AB - Trichotillomania (hair pulling) remains a relatively unknown form of body-focused repetitive behavior (BFRB). Sufferers tend to conceal both the action and its effects from others because of stigmatization, which is strong in both public and domestic spheres. Negative responses from close family members can add significantly to the suffering. Based on fieldwork in the United Kingdom and United States, we explore how hair pulling troubles ties even among close family members. We show why ethnographic methods reveal impacts of hair pulling that structured assessments do not yet capture and argue for a more nuanced study of BFRBs through anthropologies of relatedness. PMID- 30001155 TI - Rejuvenation of the term Sarcopenia. PMID- 30001156 TI - Queen of the mountain: successful pregnancy while exercising up to 5,300 m. PMID- 30001157 TI - Metabolic homeostasis: Oxidative phosphorylation and the metabolic requirements of higher plants and animals. AB - A model of oxidative phosphorylation and its regulation is presented that is consistent with the experimental data on metabolism in higher plants and animals. The variables that provide real time control of metabolic status are: intramitochondrial [NAD+]/[NADH], energy state ([ATP]/[ADP][Pi]), and local oxygen concentration ([O2]). ATP consumption and respiratory chain enzyme content are tissue specific (liver vs heart muscle) and the latter is modulated by chronic alterations in ATP consumption (i.e. endurance training etc). ATP consumption affects the energy state, which increases or decreases as necessary to match synthesis with consumption. [NAD+]/[NADH], local [O2], and respiratory chain content determine the energy state at which match of synthesis and utilization is achieved. Tissues vary widely in their ranges of ATP consumption. Expressed as the turnover of cytochrome c, the rates may change little (7 to 12 sec-1) (liver) or a lot (1 to >300 sec-1) (flight muscle of birds, bats, and insects). Ancillary metabolic pathways, including creatine or arginine kinase, glycerol phosphate shuttle, fatty acid and citric acid cycle dehydrogenases, are responsible for meeting tissue specific differences in maximal rate and range in ATP utilization without displacing metabolic homeostasis. Intramitochondrial [NAD+]/[NADH], [ATP], and [Pi] are adjusted to keep [ADP] and [AMP] similar for all tissues despite large differences in ranges in ATP utilization. This is essential because [ADP] and [AMP], particularly the latter, have major roles in regulating the activity of many enzymes and signaling pathways (AMP deaminase, AMP dependent protein kinases, etc) common to all higher plants and animals. PMID- 30001154 TI - Blood pressure variability, heart functionality, and left ventricular tissue alterations in a protocol of severe hemorrhagic shock and resuscitation. AB - Autonomic control of blood pressure (BP) and heart rate (HR) is crucial during bleeding and hemorrhagic shock (HS) to compensate for hypotension and hypoxia. Previous works have observed that at the point of hemodynamic decompensation a marked suppression of BP and HR variability occurs, leading to irreversible shock. We hypothesized that recovery of the autonomic control may be decisive for effective resuscitation, along with restoration of mean BP. We computed cardiovascular indexes of baroreflex sensitivity and BP and HR variability by analyzing hemodynamic recordings collected from five pigs during a protocol of severe hemorrhage and resuscitation; three pigs were sham-treated controls. Moreover, we assessed the effects of severe hemorrhage on heart functionality by integrating the hemodynamic findings with measures of plasma high-sensitivity cardiac troponin T and metabolite concentrations in left ventricular (LV) tissue. Resuscitation was performed with fluids and norepinephrine and then by reinfusion of shed blood. After first resuscitation, mean BP reached the target value, but cardiovascular indexes were not fully restored, hinting at a partial recovery of the autonomic mechanisms. Moreover, cardiac troponins were still elevated, suggesting a persistent myocardial sufferance. After blood reinfusion all the indexes returned to baseline. In the harvested heart, LV metabolic profile confirmed the acute stress condition sensed by the cardiomyocytes. Variability indexes and baroreflex trends can be valuable tools to evaluate the severity of HS, and they may represent a more useful end point for resuscitation in combination with standard measures such as mean values and biological measures. NEW & NOTEWORTHY Autonomic control of blood pressure was highly impaired during hemorrhagic shock, and it was not completely recovered after resuscitation despite global restoration of mean pressures. Moreover, a persistent myocardial sufferance emerged from measured cardiac troponin T and metabolite concentrations of left ventricular tissue. We highlight the importance of combining global mean values and biological markers with measures of variability and autonomic control for a better characterization of the effectiveness of the resuscitation strategy. PMID- 30001158 TI - Therapeutic prospective of plant-induced silver nanoparticles: application as antimicrobial and anticancer agent. AB - Green synthesis approach for nanoparticle is environmental friendly, non hazardous and the nanoparticles have shown enhanced biocompatibility for application in healthcare. Previous reviews have mentioned about green synthesis methods for nanoparticles and their biological activities. This review not only covers the general information about green synthesis of silver nanoparticles and characterization, but also focused on recent uses of various medicinal and nonmedical plants based AgNPs synthesis and their broad-spectrum antimicrobial and anticancer activities. In addition, this review emphasizes on elaborating underlying mechanism of anti-pathogenic microbial and anticancer activities of plant based AgNPs. Thus, present article provides a comprehensive analysis of plant-mediated synthesis of AgNPs and their potential applications in biomedical field including their mode of action and challenges in a single window. PMID- 30001159 TI - Deconstructing progression of amyotrophic lateral sclerosis in stages: a Markov modeling approach. AB - OBJECTIVES: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine'til 9 (FT9) based on how many of the patient's ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King's, Milan-Torino system (MITOS) and FT9). METHODS: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks. RESULTS: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King's and FT9 stages were more balanced. Non-sequential progression was observed with King's system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage specific mortality. CONCLUSION: King's and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King's, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome. PMID- 30001161 TI - Discovering the Hidden Profiles of Employee Drinking Motives: An Application of Integrated Variable- and Person-Centered Latent Profile Analysis. AB - The drinking motives questionnaire (DMQ, Cooper, 1994) has been a very useful measurement tool for understanding why people drink alcohol. Recent attempts to examine drinking motives used the DMQ within a person-centered analysis framework. However, latent profiles identified in previous research largely presented level effects without strong shape effects, which consequently restricted meaningful interpretations and effective applications of drinking motive profiles. To address this limitation, we applied a new alternative methodology for the study of drinking motives that integrated variable- and person-centered approaches. Our research clearly demonstrated that controlling for an overarching general drinking-motive construct provided a clearer disaggregation of shape and level effects. Four latent profiles were identified that represented a combination of shape and level effects. Each profile predicted different patterns of alcohol use. Theoretical as well as practical implications are discussed. PMID- 30001160 TI - Role of putative voltage-sensor countercharge D4 in regulating gating properties of CaV1.2 and CaV1.3 calcium channels. AB - Voltage-dependent calcium channels (CaV) activate over a wide range of membrane potentials, and the voltage-dependence of activation of specific channel isoforms is exquisitely tuned to their diverse functions in excitable cells. Alternative splicing further adds to the stunning diversity of gating properties. For example, developmentally regulated insertion of an alternatively spliced exon 29 in the fourth voltage-sensing domain (VSD IV) of CaV1.1 right-shifts voltage dependence of activation by 30 mV and decreases the current amplitude several fold. Previously we demonstrated that this regulation of gating properties depends on interactions between positive gating charges (R1, R2) and a negative countercharge (D4) in VSD IV of CaV1.1. Here we investigated whether this molecular mechanism plays a similar role in the VSD IV of CaV1.3 and in VSDs II and IV of CaV1.2 by introducing charge-neutralizing mutations (D4N or E4Q) in the corresponding positions of CaV1.3 and in two splice variants of CaV1.2. In both channels the D4N (VSD IV) mutation resulted in a 5 mV right-shift of the voltage dependence of activation and in a reduction of current density to about half of that in controls. However in CaV1.2 the effects were independent of alternative splicing, indicating that the two modulatory processes operate by distinct mechanisms. Together with our previous findings these results suggest that molecular interactions engaging D4 in VSD IV contribute to voltage-sensing in all examined CaV1 channels, however its striking role in regulating the gating properties by alternative splicing appears to be a unique property of the skeletal muscle CaV1.1 channel. PMID- 30001162 TI - Deficient Response to Altered Auditory Feedback in Dyslexia. AB - Although dyslexia is characterized by a deficit in phonological representations, the nature of this deficit is debated. Previously, it was shown that adults with dyslexia respond differently to online manipulations of auditory feedback. In the present study, we found that individual differences in reading and reading related skills within a group of 30 children (10-13 years old) with dyslexia were associated with the response to altered feedback. The fractional anisotropy of the arcuate fasciculus/superior longitudinal fasciculus was not directly related to the response to altered feedback. This study corroborates that speech perception-production communication is important for phonological representations and reading. PMID- 30001163 TI - Pacritinib to treat myelofibrosis patients with thrombocytopenia. AB - INTRODUCTION: Treatment with ruxolitinib, a selective JAK1/2 inhibitor, has significantly improved the lives of patients with myelofibrosis. Unfortunately, this treatment is frequently limited by cytopenias, precluding a high-risk group characterized by baseline thrombocytopenia. Additionally, there are no approved treatments for patients who have progressed while receiving ruxolitinib. Pacritinib is a novel JAK2/FLT3 inhibitor associated with less treatment-related myelosuppression that has the potential to fill these unmet treatment needs. Areas covered: This review will describe the preclinical rationale for JAK2/FLT3 inhibition, review the pharmacology of pacritinib, and detail available clinical data for pacritinib treatment of myelofibrosis. The circumstances surrounding the full clinical hold temporarily placed on pacritinib will also be explored. Expert commentary: Pacritinib has demonstrated promising results in patients with myelofibrosis and thrombocytopenia. Improvements in splenomegaly and symptom burden were observed with the 200 mg twice-daily dose in PERSIST-2, including those with platelet counts <50,000 mm. Safety concerns pertaining to cardiovascular events and bleeding that arose in an early analysis of PERSIST-2 were likely related to the advanced disease state enrolled rather than clear attribution to pacritinib. The results of an ongoing dose-finding, phase II study are eagerly awaited in order to move this promising myelofibrosis therapy forward. PMID- 30001164 TI - Preliminary study of hearing protection and non-impact, blast-induced concussion in US military personnel. AB - PRIMARY OBJECTIVE: To examine the relationship between hearing protection and non impact, blast-induced concussion in US military personnel. RESEARCH DESIGN: Retrospective cohort study. METHODS AND PROCEDURES: A total of 501 US service members from the Expeditionary Medical Encounter Database with hearing protection status reported either 'worn' or 'not worn' were eligible for analysis. Clinical records were reviewed for concussion diagnoses. Univariate and multiple logistic regressions were performed. MAIN OUTCOMES AND RESULTS: Overall, 270 (53.9%) service members sustained non-impact, blast-induced concussion and 231 (46.1%) sustained other blast injuries. Only 39.6% (107 of 270) of service members with concussion wore hearing protection at the point of injury compared with 61.0% (141 of 231) of those with other injuries (p < 0.001). After adjusting for covariates, service members wearing hearing protection had significantly lower odds of concussion compared with those not wearing hearing protection (odds ratio = 0.42, 95% confidence interval = 0.29-0.62). CONCLUSIONS: To our knowledge, this preliminary study is the first to demonstrate that hearing protection is associated with lower odds of non-impact, blast-induced concussion. The benefits of using hearing protection in terms of force readiness could be significant since many service members wounded in recent conflicts were diagnosed with concussion. PMID- 30001165 TI - Everyone Else Is Doing It: The Association Between Social Identity and Susceptibility to Peer Influence in NCAA Athletes. AB - The authors examined athletes' conformity to teammates' risky behaviors through a performance-based manipulation paradigm. They hypothesized that athletes who strongly identified with their team would be at increased risk of conforming to teammates' behaviors. Athletes (N = 379) from 23 intact National Collegiate Athletic Association (NCAA) teams completed surveys (e.g., social identity) and reported the extent to which they would engage in risky behavior scenarios (e.g., drinking and driving). Then, researchers displayed ostensible responses that were manipulated to appear as though teammates reported high engagement in the risky behaviors. Finally, athletes again responded to the hypothetical scenarios and a conformity index was created. Results indicated that social identity, at both individual and group levels, positively predicted conformity-indicating that athletes with stronger social identities are more susceptible to peer influence. Although these findings highlight a pernicious aspect of social identity, they also provide insight into how group-level processes could be leveraged to prevent risky behaviors in student-athletes. PMID- 30001166 TI - Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress. AB - Diffuse gliomas often carry point mutations in isocitrate dehydrogenase ( IDH1mut), resulting in metabolic stress. Although IDHmut gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain-specific tumor-stroma interactions that can compensate for IDH-1 deficits. To elucidate the metabolic adjustments in clinical IDHmut gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next-generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH-1R132H mutation. Datasets were analyzed in R using Manhattan plots to calculate distance between expression profiles, Ward's method to perform unsupervised agglomerative clustering, and the Mann Whitney U test and Fisher's exact tests for supervised group analyses. The significance of transcriptome data was investigated by protein analysis, in situ enzymatic activity mapping, and in vivo magnetic resonance spectroscopy of orthotopic IDH1mut- and IDHwt-glioma xenografts. Gene set enrichment analyses of clinical IDH1mut gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDHwt gliomas, processing of glucose and glutamine are the predominant metabolic pathways. Further evidence of the differential metabolic activity in these cancers comes from in situ enzymatic mapping studies and preclinical in vivo magnetic resonance spectroscopy imaging. Our data support an evolutionary model in which IDHmut glioma cells exist in symbiosis with supportive neuronal cells and astrocytes as suppliers of glutamate and lactate, possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDHmut gliomas.-Lenting, K., Khurshed, M., Peeters, T. H., van den Heuvel, C. N. A. M., van Lith, S. A. M., de Bitter, T., Hendriks, W., Span, P. N., Molenaar, R. J., Botman, D., Verrijp, K., Heerschap, A., ter Laan, M., Kusters, B., van Ewijk, A., Huynen, M. A., van Noorden, C. J. F., Leenders, W. P. J. Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress. PMID- 30001167 TI - Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/beta-catenin pathway in mice. AB - Liver regeneration is a complicated pathophysiologic process that is regulated by a myriad of signaling pathways and transcription factors. The interaction among these pathways and factors, either cooperatively or antagonistically, may ultimately lead to recovery and restoration of liver function or permanent loss of liver function and liver failure. In the present study, we investigated the mechanism whereby the chromatin remodeling protein brahma related gene 1 (Brg1) regulates liver regeneration in mice. The Smarca4-Flox strain of mice was crossbred with the Alb-Cre strain to generate hepatocyte-specific Brg1 knockout mice. Liver injury was induced by partial hepatectomy (PHx). We report that Brg1 deletion in hepatocyte compromised liver regeneration and dampened survival after PHx in mice. Brg1 interacted with beta-catenin to potentiate Wnt signaling and promote hepatocyte proliferation. Mechanistically, Brg1 recruited lysine demethylase 4 (KDM4) to activate beta-catenin target genes. Our data suggest that Brg1 might play an essential role maintaining hepatic homeostasis and contributing to liver repair.-Li, N., Kong, M., Zeng, S., Hao, C., Li, M., Li, L., Xu, Z., Zhu, M., Xu, Y. Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/beta-catenin pathway in mice. PMID- 30001168 TI - Lack of p11 expression facilitates acidity-sensing function of TASK1 channels in mouse adrenal medullary cells. AB - External acidity induces catecholamine secretion by inhibiting TASK1-like channels in rat adrenal medullary (AM) cells. TASK channels can function as a heteromer or homomer in the TASK subfamily. In this study, we elucidate the molecular identity of TASK1-like channels in mouse AM cells using gene knockout. Genetic deletion of TASK1, but not TASK3, abolished the depolarizing inward current and catecholamine secretion in response to acidity, whereas it did not affect the resting current level. Immunocytochemistry revealed that AM cells exhibited predominantly TASK1-like and little TASK3-like immunoreactivity. A proximity ligation assay showed that TASK1/3 heteromeric channels were not formed in AM cells or PC12 cells. However, the exogenous expression of p11 in PC12 cells resulted in the heteromeric formation of TASK isoforms, which were mainly located in the cytoplasm, and p11 was not expressed in rat adrenal medullae or PC12 cells. In AM cells, genetic deletion of TASK1 resulted in enhancement of the immunoreactivity of the TALK2 channel, but not TASK3. The results indicate that TASK1 homomeric channels function as acidity sensors in AM cells, and that function is facilitated by the lack of p11 expression.-Inoue, M., Matsuoka, H., Lesage, F., Harada, K. Lack of p11 expression facilitates acidity-sensing function of TASK1 channels in mouse adrenal medullary cells. PMID- 30001169 TI - Creating Coherent Strategies to Combat the Crises of Opioid Scarcity and Abuse. PMID- 30001170 TI - IPH4102, a monoclonal antibody directed against the immune receptor molecule KIR3DL2, for the treatment of cutaneous T-cell lymphoma. AB - INTRODUCTION: Therapeutic options for mycosis fungoides and Sezary syndrome include a variety of immunomodulatory, epigenetic, and cytotoxic options; however, none has been demonstrated to be efficacious for all patients, or to deliver deep and durable responses to the majority of patients. In this review, we examine the monoclonal antibody, IPH4102, a novel agent for the treatment of cutaneous T-cell lymphoma. Areas covered: In this review, we examine data demonstrating the tissue specificity of KIR3DL2 receptor, which is highly expressed on the malignant cells in cutaneous T-cell lymphoma, including mycosis fungoides and Sezary syndrome. This specificity has led to the development of the agent IPH4102. Preclinical data showing efficacy of IPH4102 in vivo are outlined, as well as the results from Phase I clinical trials, which suggest that the agent is both efficacious and well-tolerated. Larger scale clinical trials are to follow. Expert Opinion: We examine the putative benefit of IPH4102 in comparison to established agents already in the clinic, highlighting its efficacy and relative safety. We also examine possible directions that may better define the role of IPH4102 in the treatment of T-cell lymphoma in the future. PMID- 30001171 TI - The Effect of Intravenous Selenium on Oxidative Stress in Critically Ill Patients with Acute Respiratory Distress Syndrome. AB - OBJECTIVE: To modulate the inflammatory response in respiratory distress syndrome (ARDS) with selenium. BACKGROUND: Selenium replenishes the glutathione peroxidase proteins that are the first line of defense for an oxidative injury to the lungs. METHODS: Forty patients with ARDS were randomized into two groups: the SEL+ group being administered sodium selenite and the SEL- group receiving normal saline for 10 days. Blood samples were taken on Day-0, DAY-7, and Day-14 for assessment of IL-1 beta, IL-6, C-reactive protein, GPx-3, and selenium. Ferric reducing antioxidant power (FRAP) was measured in the bronchial wash fluids. Pearson correlation and repeated measure analysis were performed to examine the effects of selenium on the inflammatory markers. RESULTS: Sodium selenite replenished selenium levels in the SEL+ group. Selenium concentrations were linearly correlated to serum concentrations of GPx3 (R value: 0.631; P < 0.001), and FRAP (R value: -0.785; P < 0.001). Serum concentrations of both IL 1-beta (R value: 0.624; P < 0.001) and IL-6 (R value: -0.642; P < 0.001) were inversely correlated to the serum concentrations of selenium. There was a meaningful difference between two groups in airway resistance and pulmonary compliance changes (P values 0.008 and 0.028, respectively). CONCLUSION: Selenium restored the antioxidant capacity of the lungs, moderated the inflammatory responses, and meaningfully improved the respiratory mechanics. Despite these changes, it had no effect on the overall survival, the duration of mechanical ventilation, and ICU stay. Selenium can be used safely; however, more trials are essential to examine its clinical effectiveness. PMID- 30001172 TI - Conservation of the Ca2+-permeability through the voltage sensor domain of mammalian CatSper subunit. AB - Cation channel of Spermatozoa (CatSper) is one of the voltage-gated ion channels consisting of voltage sensor domains (VSDs) and pore-gate domains. CatSper is exclusively expressed in spermatozoa and indispensable for Ca2+ influx into cytosol. Recently, we have reported that the VSD of ascidian CatSper induces Ca2+ permeable pathways in heterologous expression systems. However, it is not known whether ion permeability through the VSD of CatSper is conserved in mammals. In the present study, electrophysiology and fluorometry in Xenopus oocytes revealed that Ca2+-permeable paths are also formed by expressing the VSD of murine CatSper. We also examined the permeability to monovalent cations other than Na+ in the VSD of ascidian CatSper. PMID- 30001173 TI - Treponema denticola enolase contributes to the production of antibodies against ENO1 but not to the progression of periodontitis. AB - Autoantibodies against alpha-enolase (ENO1) are often detected in various infectious and autoimmune diseases. Anti-ENO1 antibody titers were reported to be associated with the severity of periodontitis in patients with rheumatoid arthritis. Because the enolase of the periodontal pathogen Treponema denticola (TdEno) has the highest homology with ENO1 among the enolases of human-associated bacteria, we hypothesized that anti-ENO1 autoantibodies produced during the immune response to TdEno may contribute to the progression of periodontitis and tested it in human and mouse systems. In human subjects with healthy periodontium or chronic periodontitis, a strong positive correlation between the levels of anti-TdEno and anti-ENO1 antibodies was observed. In addition, the purified anti TdEno antibodies recognized ENO1 as well as TdEno in a dot blot, confirming the cross-reactivity between TdEno and ENO1. However, anti-ENO1 antibody titers were not associated with the severity of periodontitis. To further investigate the role of TdEno in the production of anti-ENO1 antibodies and the progression of periodontitis, mice received an oral gavage of P. gingivalis alone, subcutaneous immunization with TdEno alone, or both P. gingivalis oral gavage and TdEno immunization. Immunization with TdEno induced not only anti-TdEno but also anti mouse Eno1 (mEno1) antibodies and increased the expression of TNFalpha in the gingival tissues. However, alveolar bone loss was not increased by TdEno immunization. In conclusion, autoreactive anti-ENO1/mEno1 antibodies that are produced as byproducts during the antibody response to TdEno play a minimal role in the progression of periodontitis in the absence of rheumatoid arthritis. PMID- 30001175 TI - The synaptic action of Degenerin/Epithelial sodium channels. AB - Degenerin/Epithelial Sodium Channels (DEG/ENaCs) are a large family of animal specific non-voltage gated ion channels, with enriched expression in neuronal and epithelial tissues. While neuronal DEG/ENaCs were originally characterized as sensory receptor channels, recent studies indicate that several DEG/ENaC family members are also expressed throughout the central nervous system. Human genome wide association studies have linked DEG/ENaC-coding genes with several neurologic and psychiatric disorders, including epilepsy and panic disorder. In addition, studies in rodent models further indicate that DEG/ENaC activity in the brain contributes to many behaviors, including those related to anxiety and long term memory. Although the exact neurophysiological functions of DEG/ENaCs remain mostly unknown, several key studies now suggest that multiple family members might exert their neuronal function via the direct modulation of synaptic processes. Here, we review and discuss recent findings on the synaptic functions of DEG/ENaCs in both vertebrate and invertebrate species, and propose models for their possible roles in synaptic physiology. PMID- 30001174 TI - IgM cleavage by Streptococcus suis reduces IgM bound to the bacterial surface and is a novel complement evasion mechanism. AB - Streptococcus suis (S. suis) causes meningitis, arthritis and endocarditis in piglets. The aim of this study was to characterize the IgM degrading enzyme of S. suis (IdeSsuis) and to investigate the role of IgM cleavage in evasion of the classical complement pathway and pathogenesis. Targeted mutagenesis of a cysteine in the putative active center of IdeSsuis abrogated IgM cleavage completely. In contrast to wt rIdeSsuis, point mutated rIdeSsuis_C195S did not reduce complement mediated hemolysis indicating that complement inhibition by rIdeSsuis depends on the IgM proteolytic activity. A S. suis mutant expressing IdeSsuis_C195S did not reduce IgM labeling, whereas the wt and complemented mutant showed less IgM F(ab')2 and IgM Fc antigen on the surface. IgM cleavage increased survival of S. suis in porcine blood ex vivo and mediated complement evasion as demonstrated by blood survival and C3 deposition assays including the comparative addition of rIdeSsuis and rIdeSsuis_C195S. However, experimental infection of piglets disclosed no significant differences in virulence between S. suis wt and isogenic mutants without IgM cleavage activity. This work revealed for the first time in vivo labeling of S. suis with IgM in the cerebrospinal fluid of piglets with meningitis. In conclusion, this study classifies IdeSsuis as a cysteine protease and emphasizes the role of IgM cleavage for bacterial survival in porcine blood and complement evasion though IgM cleavage is not crucial for the pathogenesis of serotype 2 meningitis. PMID- 30001176 TI - Burmese injecting drug users in Yunnan play a pivotal role in the cross-border transmission of HIV-1 in the China-Myanmar border region. AB - Injecting drug users (IDUs) are the major risk group for HIV-1 infection in the China-Myanmar border area. There are a large number of Burmese IDUs living in Yunnan (Yunnan-mIDUs) who might be associated with the cross-border transmission of HIV-1. From 2010 to 2013, 617 Yunnan-mIDUs were recruited from three counties of Yunnan, 19.0% of whom were detected to be HIV-1 positive by serological testing. Partial HIV-1 p17, pol, vif-env, and env genes were amplified from the positive samples and were sequenced. Phylogenetic and HIV-1 subtyping analyses revealed that HIV-1 recombinant forms (RFs), including RF_BC (36.4%), RF_01BC (26.1%), RF_01C (9.1%) and RF_01B (1.1%), were predominant among this cohort. Of the identified HIV-1 strains, 14.8%, 9.1% and 3.4% belonged to subtype C, CRF01_AE and subtype B, respectively. Transmission cluster analysis showed that sequences from the Yunnan-mIDUs formed transmission clusters not only with those from Burmese IDUs but also with those from Chinese IDUs, indicating that Yunnan mIDUs might acquire HIV-1 infection from or spread HIV-1 to both Burmese and Chinese IDUs. Phylogeographic analyses revealed three cross-border transmission patterns associated with Yunnan-mIDUs, in which Yunnan-mIDUs served as the crucial nodes linking the Burmese and Chinese IDUs. These results suggest that Yunnan-mIDUs are a potential viral reservoir for the diffusion of HIV-1 in Yunnan and play a pivotal role in the bidirectional cross-border transmission of HIV-1 in the China-Myanmar border region. More intervention efforts that focus on Yunnan-mIDUs are recommended in Yunnan's campaign against HIV/AIDS. PMID- 30001177 TI - Cumulative lifetime maternal stress and epigenome-wide placental DNA methylation in the PRISM cohort. AB - Evolving evidence links maternal stress exposure to changes in placental DNA methylation of specific genes regulating placental function that may have implications for the programming of a host of chronic disorders. Few studies have implemented an epigenome-wide approach. Using the Infinium HumanMethylation450 BeadChip (450K), we investigated epigenome-wide placental DNA methylation in relation to maternal experiences of traumatic and non-traumatic stressors over her lifetime assessed using the Life Stressor Checklist-Revised (LSC-R) survey (n = 207). We found differential DNA methylation at epigenome-wide statistical significance (FDR = 0.05) for 112 CpGs. Additionally, we observed three clusters that exhibited differential methylation in response to high maternal lifetime stress. Enrichment analyses, conducted at an FDR = 0.20, revealed lysine degradation to be the most significant pathway associated with maternal lifetimes stress exposure. Targeted enrichment analyses of the three largest clusters of probes, identified using the gap statistic, were enriched for genes associated with endocytosis (i.e., SMAP1, ANKFY1), tight junctions (i.e., EPB41L4B), and metabolic pathways (i.e., INPP5E, EEF1B2). These pathways, also identified in the top 10 KEGG pathways associated with maternal lifetime stress exposure, play important roles in multiple physiological functions necessary for proper fetal development. Further, two genes were identified to exhibit multiple probes associated with maternal lifetime stress (i.e., ANKFY1, TM6SF1). The methylation status of the probes belonging to each cluster and/or genes exhibiting multiple hits, may play a role in the pathogenesis of adverse health outcomes in children born to mothers with increased lifetime stress exposure. PMID- 30001179 TI - Mood impedes monitoring of emotional false memories: evidence for the associative theories. AB - In the present experiment, we investigated whether warnings provided at the time of retrieval would reduce emotional false memories in the Deese-Roediger McDermott (DRM) paradigm. The provision of retrieval warnings allowed us to test specific predictions based on the associative theories (e.g., Activation Monitoring Theory; AMT) and Fuzzy-Trace Theory (FTT) that have been used to account for false memories in the DRM paradigm. Participants were randomly assigned to either a no-warning group or a retrieval-warning group. In each group, mood-induction procedures were used to elicit a positive, negative, or neutral mood and participants were then presented with word lists comprised of positive, negative, or neutral words. Retrieval warnings reduced false recognition, regardless of the valence of the to-be-remembered information or participants' mood. Consistent with the associative theories' predictions, within the warning condition, positive moods yielded greater false recognition for positive critical lures, and negative moods yielded greater false recognition for negative critical lures, compared to neutral moods. These findings have important practical implications for our understanding of the effect of mood on memory. PMID- 30001180 TI - Association between knee-to-hip flexion ratio during single-leg vertical landings, and strength and range of motion in professional soccer players. AB - The aim of this study was to test the correlation between knee-to-hip flexion ratio during a single leg landing task and hip and knee strength, and ankle range of motion. Twenty-four male participants from a professional soccer team performed a continuous single leg jump-landing test during 10s, while lower limb kinematics data were collected using a motion analysis system. After biomechanical testing, maximal isometric hip (abduction, extension, external rotation), knee extension and flexion strength were measured. Maximum ankle dorsiflexion range of motion was assessed statically using the weight bearing lunge test. Pearson correlation coefficients were calculated to determine the associations between the predictor variables (knee and hip strength, and ankle ROM) and the main outcome measure (knee-to-hip flexion ratio). Correlation between knee-to-hip flexion ratio and hip abductors strength was significant (r = -0.47; p = 0.019). No other significant correlations were observed among the variables (p > 0.05). These results demonstrated that a lower hip abductors strength in male soccer players was correlated with a high knee-to-hip flexion ratio during landing from a single leg jump, potentially increasing knee overload by decreasing energy absorption at the hip. The results provide a novel proposal for the functioning of hip muscles to control knee overload. PMID- 30001181 TI - Transnational Social Work: Opportunities and Challenges of a Global Profession. PMID- 30001182 TI - Phage-Based Applications in Synthetic Biology. AB - Bacteriophage research has been instrumental to advancing many fields of biology, such as genetics, molecular biology, and synthetic biology. Many phage-derived technologies have been adapted for building gene circuits to program biological systems. Phages also exhibit significant medical potential as antibacterial agents and bacterial diagnostics due to their extreme specificity for their host, and our growing ability to engineer them further enhances this potential. Phages have also been used as scaffolds for genetically programmable biomaterials that have highly tunable properties. Furthermore, phages are central to powerful directed evolution platforms, which are being leveraged to enhance existing biological functions and even produce new ones. In this review, we discuss recent examples of how phage research is influencing these next-generation biotechnologies. PMID- 30001178 TI - Gene expression and DNA methylation changes in the hypothalamus and hippocampus of adult rats developmentally exposed to bisphenol A or ethinyl estradiol: a CLARITY-BPA consortium study. AB - Bisphenol A (BPA), an endocrine disrupting chemical (EDC), is a ubiquitous pollutant. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether exposure of Sprague Dawley rats to 2,500 MUg/kg/day BPA (BPA) or 0.5 MUg/kg/day ethinyl estradiol (EE) from gestational day 6 through postnatal day 21 induces behavior-relevant gene expression and DNA methylation changes in hippocampus and hypothalamus at adulthood. RNA and DNA were isolated from both regions. Expression of ten genes (Dnmt1, Dnmt3a, Dnmt3b, Esr1, Esr2, Avp, Ar, Oxt, Otr, and Bdnf) presumably altered by early-life BPA/EE exposure was examined. Three genes (Bdnf, Dnmt3b, and Esr1) were studied for DNA methylation changes in their putative 5' promoter regions. Molecular changes in hippocampus were correlated to prior Barnes maze performance, including sniffing correct holes, distance traveled, and velocity. Exposure to BPA and/or EE disrupted patterns of sexually dimorphic gene expression/promoter DNA methylation observed in hippocampus and hypothalamus of controls. In the hippocampus of female offspring, BPA exposure resulted in hypermethylation of the putative 5' promoter region of Bdnf, while EE exposure induced hypomethylation. Bdnf methylation was weakly associated with Bdnf expression in hippocampi of female rats. Hippocampal Bdnf expression in females showed a weak negative association with sniffing correct hole in Barnes maze. Hippocampal expression of Avp, Esr2, Oxt, and Otr was strongly associated with velocity of control rats in Barnes maze. Findings suggest BPA exposure induced non-EE-like gene expression and epigenetic changes in adult rat hippocampi, a region involved in spatial navigation. PMID- 30001183 TI - Breaking the Last Chains of Poliovirus Transmission: Progress and Challenges in Global Polio Eradication. AB - Since the launch of the Global Polio Eradication Initiative (GPEI), paralytic cases associated with wild poliovirus (WPV) have fallen from ~350,000 in 1988 to 22 in 2017. WPV type 2 (WPV2) was last detected in 1999, WPV3 in 2012, and WPV1 appeared to be localized to Pakistan and Afghanistan in 2017. Through continuous refinement, the GPEI has overcome operational and biological challenges far more complex and daunting than originally envisioned. Operational challenges had led to sustained WPV endemicity in core reservoirs and widespread dissemination to polio-free countries. The biological challenges derive from intrinsic limitations to the oral poliovirus vaccine: ( a) reduced immunogenicity in high-risk settings and ( b) genetic instability, leading to repeated outbreaks of circulating vaccine-derived polioviruses and prolonged infections in individuals with primary immunodeficiencies. As polio eradication enters its multifaceted endgame, the GPEI, with its technical, operational, and social innovations, stands as the preeminent model for control of vaccine-preventable diseases worldwide. PMID- 30001184 TI - The effect of increased shooting distance on energy flow in basketball jump shot. AB - The aim of this study is to clarify the effect of shooting distance on energy flow in basketball jump shot. Ten male right-handed basketball players participated in this study, and three successful shots at three different distances (short condition, equating to a free-throw; long condition, equating to a three-point shot; and mid condition, equating to the mid-point of the short- and long-condition shots) were recorded using a motion capture system and force platforms. Kinetic variables of joints during shooting were analysed using inverse dynamics method. Our results showed that the joint work was not significantly different for short- and mid-condition shots; however, the amount of energy transferred from the torso to the shooting arm by the shoulder joint force increased significantly for the mid-condition shots ([Formula: see text] as opposed to [Formula: see text] J/kg, [Formula: see text]), whereas between the mid- and long-conditions, it was found that the joint work in the lower limbs increased significantly ([Formula: see text] as opposed to [Formula: see text] J/kg, [Formula: see text]). These results suggest that sufficient energy transfer from the lower limbs to the shoot arms is important to keep the motions of the shooting arms approximately constant when shooting from various distances. PMID- 30001186 TI - The effect of processing load on loss of information from short-term memory. AB - We report an experiment in which we varied the nature of the articulatory suppression task being performed during a filled retention interval in serial recall. During the retention interval participants performed one of three computer-paced colour naming tasks designed to prevent subvocal rehearsal: A Stroop color-interference task with items presented at a rate of one every 750 ms, and two color-consistent control tasks at a rate of either 750 ms or 500 ms per item. Memory performance over a 12 s interval declined much more dramatically with the Stroop task and the 500 ms control task than with the 750 ms control. There was no difference between the Stroop condition and the 500 ms control. These results pose problems for models that assume that loss of information from memory is determined entirely by interference, as there are more interfering events in the control 500 ms condition than the 750 ms Stroop. They also pose problems for models relying solely on time-based decay and articulatory rehearsal because all three conditions should block rehearsal and produce equivalent performance. The results illustrate that articulatory suppression tasks are not all equivalent, and suggest that the rate of decay from short-term memory is strongly influenced by the resource demands of concurrent processing. PMID- 30001187 TI - Students report more positive attitudes toward older adults following an interprofessional service-learning course. AB - The aim of this study was to assess undergraduate students' perceptions of older adults over the semester in an interprofessional service-learning course that implemented a health promotion program called Bingocize(r) at community facilities for older adults. Students were surveyed at the beginning of the semester, at midterm, and at the conclusion of the course. Quantitative and qualitative data were collected to assess the students' perceptions and experiences. Results suggest that a course on aging that includes interprofessional service-learning in geriatric settings is associated with a significant increase in positive perceptions of the older adult population. Further research, however, is warranted to validate the findings. PMID- 30001185 TI - Archaeal imaging: leading the hunt for new discoveries. AB - Since the identification of the archaeal domain in the mid-1970s, we have collected a great deal of metagenomic, biochemical, and structural information from archaeal species. However, there is still little known about how archaeal cells organize their internal cellular components in space and time. In contrast, live-cell imaging has allowed bacterial and eukaryotic cell biologists to learn a lot about biological processes by observing the motions of cells, the dynamics of their internal organelles, and even the motions of single molecules. The explosion of knowledge gained via live-cell imaging in prokaryotes and eukaryotes has motivated an ever-improving set of imaging technologies that could allow analogous explorations into archaeal biology. Furthermore, previous studies of essential biological processes in prokaryotic and eukaryotic organisms give methodological roadmaps for the investigation of similar processes in archaea. In this perspective, we highlight a few fundamental cellular processes in archaea, reviewing our current state of understanding about each, and compare how imaging approaches helped to advance the study of similar processes in bacteria and eukaryotes. PMID- 30001189 TI - The Impact of a Care Recipient's Pet on the Instrumental Caregiving Experience. AB - Older adults report strong emotional bonds with their pets which often become increasingly important as health declines and dependence upon others increases. Individuals requiring assistance meeting their own needs are likely to need assistance in meeting the needs of their pet. The care recipient's pet may be an important, though presently overlooked, factor in the caregiving experience. This study measured the amount of care tasks/ activities informal caregivers of older adults devoted to their care recipients' pet. Caregivers for an individual aged 50 and older who did not consider the care recipient's pet to be his/her own animal completed an online questionnaire. Descriptive statistics and Pearson correlations were used in analyses. Caregivers (N = 34) performed an average of 14.9 (SD = 5.4) different pet care tasks/activities and an average of 11.21 (SD = 1.33) hours per week in pet care. The total number of tasks/activities performed was significantly and positively correlated with the care recipients' degree of functional limitation (r = 0.49, p = 0.004). Care recipients' pets may be a significant factor in shaping the instrumental caregiving experience. PMID- 30001188 TI - Investigation of mother-to-child transmission of HIV in pregnancy and among HIV exposed infants accessing care at a PMTCT clinic in southwest Nigeria. AB - BACKGROUND: Over 90% of infant acquired immunodeficiency syndrome (AIDS) cases have been through mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Consequent to this, prevention of mother-to-child transmission (PMTCT) programs have instituted as dual purposes for prevention of HIV transmission from mother to child and enrollment of infected pregnant women and their families into antiretroviral treatment (ART) program. However, there are still some breakthrough infections and challenges. Therefore, this study was designed to assess risk of HIV transmission among HIV-exposed infants on follow up at a PMTCT clinic in an antiretroviral (ARV) referral health facility in southwest Nigeria. METHODS: A cohort of 60 purposively recruited consenting pregnant women referred to PMTCT HIV clinic in Ibadan, southwest Nigeria were enrolled and followed up for 1 year (2015-2016). A well-structured epidemiological questionnaire was used to capture all relevant information. Data were then analyzed by SPSS version 21 (St. Louis, MO, USA), while bivariate and multivariate analyses were used to identify associations. RESULTS: A total of 44 mothers and their infants were available for the analysis with an attrition rate of 26.7%. The mean age of mothers at enrollment to follow-up was 32.9 years (SD = 4.2 years). Two (4.5%, 95% CI: 7.2-12.3%) of the infants were HIV positive by DNA PCR test. There was no linear relationship between age of the mothers with CD4 count or viral load both before and after delivery but there was a significant positive relationship with year on ARV (r = 0.318, 95% CI: 0.024-0.562). Infants of rural dwelling mothers were at 3.39 (adjusted odds ratio (AOR) = 3.39, 95% CI: 1.32, 2.29) times higher risk of vertical HIV transmission compared to those of urban dwelling mothers. Infants delivered at home had 2.61(AOR = 2.61, 95% CI: 1.59, 7.91) times higher risk of MTCT compared to those delivered at health institution. Mixed feeding was also another important predictor in which the risk of MTCT was about two (AOR = 2.21, 95% CI: 0.68, 9.97) times higher compared to exclusive breastfeeding. CONCLUSIONS: There was a high risk of MTCT of HIV among exposed infants on follow-up at the PMTCT clinic of Adeoyo Maternity Teaching referral hospital. Our findings will assist health policy makers in providing important information capable of enhancing assurance HIV control in such population and in raising the standard of PMTCT program in Nigeria. PMID- 30001190 TI - Pouteria ramiflora (Mart.) Radlk. extract: Flavonoids quantification and chemopreventive effect on HepG2 cells. AB - Pouteria ramiflora (Mart.) Radlk., popularly known as curriola, is commonly used in Brazil as medicinal plant to treat worm infections, dysentery, pain, inflammation, hyperlipidemia, and obesity. At present the safety of this extract when used therapeutically in human remains to be determined. Thus, the aim of this study was to examine cytotoxicity, antiproliferative, and antimutagenic actions of this extract. The hydroalcoholic extract from P. ramiflora leaves consisted of flavonoids identified and quantified as myricetin-3-O-beta-D galactopyranoside (13.55 mg/g) and myricetin-3-O-alpha-L-rhamnopyranoside (9.61 mg/g). The extract exhibited cytotoxicity at concentrations higher than 1.5 ug/ml in human hepatocarcinoma (HepG2)and 2.5 ug/ml in non-tumoral primary gastric (GAS) cells using the MTT assay, and at concentrations higher than 3 ug/ml in HepG2 and 3.5 ug/ml in GAS cells by the neutral red assay. The extract did not show antiproliferative effect as evidenced by the nuclear division index (NDI). However, in the presence of benzo[a]pyrene (BaP) (positive control), an enhanced cytostatic effect in the NDI and flow cytometry was noted. It is of interest that when the extract was co-incubated with BaP a significant decrease in DNA damage was observed indicating an antimutagenic action. This protective effect might be attributed to myricetin and gallic acid found in P. ramiflora extract. The low cytotoxicity action and protective effect observed in the present study encourage further studies regarding other biological effects of P. ramiflora, as well as its potential use as a chemopreventive agent. PMID- 30001191 TI - Promoting intergroup openness and support for equality in a new cultural context: Replicating the effects of internal criticism. AB - Exposure to an outgroup member voicing criticism of his or her own group fosters greater openness to the outgroup's perspective. Research suggests that this effect owes its influence to a serial process in which participants' perception of the risk involved in voicing internal criticism leads to an increase in the perceived credibility of the speaker. The credibility makes it possible for the speaker to be viewed as open-minded, which subsequently inspires greater hope. This process culminates in an increased openness to the outgroup. These findings have been restricted to the Israeli-Palestinian conflict, but here we examine their generalizability to racial conflict in the United States. Results reveal that White Americans exposed to internal criticism expressed by a Black authority figure express greater openness to African-American perspectives on race relations and are more willing to support policies of racial equality. Replicating past research, this effect is serially mediated by risk, credibility, and hope. PMID- 30001192 TI - Training with FES-assisted cycling in a subject with spinal cord injury: Psychological, physical and physiological considerations. AB - Context People with spinal cord injury (SCI) experience the effects of a sedentary lifestyle very early on. Literature data suggest that programs using FES-assisted cycling would contribute to reduce the consequences of physical inactivity. The objective was to assess the feasibility of 12-month training on a FES-assisted bike of a subject with paraplegia for 21 years, T3, Asia Impairment Scale (AIS) A. An evaluation of morbidity, self-esteem, satisfaction, quality of life and duration of pedaling was performed. The impact on pain, cardiorespiratory function, body composition and bone metabolism were also assessed. Findings The acceptability score of the training constraints increased from 51 to 59/65 and satisfaction was high around 8/10. The pedaling duration increased from 1' to 26' on the recumbent bike and from 1' to 15' on open terrain. No significant changes were found with BMD and cardiorespiratory measures during exercise tests. SF 36 showed significant improvement of more than 10% and the Rosenberg Self Esteem score rapidly improved from 36 to 39/40. At the end of the training, the patient reached the objective of the Cybathlon 2016 by covering 750 m in less than 8 minutes, at an average speed of 5.80 km/hr. Conclusion/Clinical relevance A person with high and complete level of SCI for more than 20 years can undertake this type of challenge if the prerequisites are met; this training is without danger if the safety precautions are respected; the challenge of participating in a competition had a powerful impact on JP's self esteem and perceived quality of life. PMID- 30001193 TI - Correction to: Acceptability of HIV self-sampling kits (TINY vial) among people of black African ethnicity in the UK: a qualitative study. AB - It has been highlighted that in the original article [1] there is a typesetting mistake in the name of I. Fakoya. This was incorrectly captured as F. Fakoya. This correction article clarifies the correct name of the author. PMID- 30001194 TI - Quantifying the unquantifiable: why Hymenoptera, not Coleoptera, is the most speciose animal order. AB - BACKGROUND: We challenge the oft-repeated claim that the beetles (Coleoptera) are the most species-rich order of animals. Instead, we assert that another order of insects, the Hymenoptera, is more speciose, due in large part to the massively diverse but relatively poorly known parasitoid wasps. The idea that the beetles have more species than other orders is primarily based on their respective collection histories and the relative availability of taxonomic resources, which both disfavor parasitoid wasps. Though it is unreasonable to directly compare numbers of described species in each order, the ecology of parasitic wasps specifically, their intimate interactions with their hosts-allows for estimation of relative richness. RESULTS: We present a simple logical model that shows how the specialization of many parasitic wasps on their hosts suggests few scenarios in which there would be more beetle species than parasitic wasp species. We couple this model with an accounting of what we call the "genus-specific parasitoid-host ratio" from four well-studied genera of insect hosts, a metric by which to generate extremely conservative estimates of the average number of parasitic wasp species attacking a given beetle or other insect host species. CONCLUSIONS: Synthesis of our model with data from real host systems suggests that the Hymenoptera may have 2.5-3.2* more species than the Coleoptera. While there are more described species of beetles than all other animals, the Hymenoptera are almost certainly the larger order. PMID- 30001195 TI - Effect of extra-amniotic Foley's catheter and vaginal misoprostol versus vaginal misoprostol alone on cervical ripening and induction of labor in Kenya, a randomized controlled trial. AB - BACKGROUND: The safest, most effective and fastest combined approaches to induction of labor is unknown. In an open-label randomized clinical trial we evaluated the efficacy of combination of extra-amniotic Foley's catheter and vaginal misoprostol compared to vaginal misoprostol alone for cervical ripening and induction of labor on the incidence of failed induction, induction-to delivery interval and adverse maternal and perinatal outcomes. METHODS: Pregnant women at gestational age of 28 weeks or greater admitted at Kenyatta National Hospital, Kenya for induction of labor were enrolled then randomized to either a combination of extra-amniotic Foley's catheter inflated by 30 cm3 of normal saline and 25 micrograms of vaginal misoprostol or 25 micrograms of vaginal misoprostol alone. Women underwent 6 hourly reviews and additional misoprostol inserted if required. The primary outcome was incidence of failed induction. Secondary outcomes were induction-to-delivery interval and adverse maternal and perinatal outcomes. We conducted an intent-to-treat analysis and compared means or medians using t-test or Wilcoxon rank, proportions using Chi-square or Fishers test as appropriate. Induction-to-delivery interval were compared using the log rank test. P-values of < 0.05 and 95% confidence intervals that excluded the null were considered statistically significant. RESULTS: Between February and May 2016, we enrolled 180 of 237 pregnant women admitted for induction of labor and randomized them to either a combination of extra-amniotic Foley's catheter and vaginal misoprostol (n = 90) or vaginal misoprostol alone (n = 90). The socio demographic and obstetric characteristics were similar between the two groups. Failed induction rates were lower but not statistically significant following combined extra-amniotic Foley's catheter and vaginal misoprostol (8.9%) versus vaginal misoprostol alone (11.1%). The mean induction-to-delivery time was 4.8 h shorter in the combined extra-amniotic Foley's catheter and vaginal misoprostol (mean 18.9, standard deviation (SD) 7.2 h) compared to misoprostol only group (mean 14.1, SD 6.9 h) (log-rank test, p < 0.001). Maternal and perinatal complications were similar between the two groups. CONCLUSIONS: Extra-amniotic Foley's catheter and vaginal misoprostol for cervical ripening and induction of labor did not significantly lower the incidence of failed induction but safely shortened induction-to-delivery time compared to vaginal misoprostol only. TRIAL REGISTRATION: Trial was retrospectively registered on 14-03-2016 PACTR201604001535825. PMID- 30001197 TI - Study of disease phenotype and its association with prognosis of paediatric inflammatory bowel disease in China. AB - BACKGROUND: To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. METHODS: We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn's disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. RESULTS: Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0-2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3-9 and 10 16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0-2 y and B3 phenotype; 0-2 y, B3 phenotype and steroid dependency were risk factors for early relapse. CONCLUSIONS: Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients. PMID- 30001196 TI - The functional interplay of low molecular weight thiols in Mycobacterium tuberculosis. AB - BACKGROUND: Three low molecular weight thiols are synthesized by Mycobacterium tuberculosis (M.tb), namely ergothioneine (ERG), mycothiol (MSH) and gamma glutamylcysteine (GGC). They are able to counteract reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). In addition, the production of ERG is elevated in the MSH-deficient M.tb mutant, while the production of MSH is elevated in the ERG-deficient mutants. Furthermore, the production of GGC is elevated in the MSH-deficient mutant and the ERG-deficient mutants. The propensity of one thiol to be elevated in the absence of the other prompted further investigations into their interplay in M.tb. METHODS: To achieve that, we generated two M.tb mutants that are unable to produce ERG nor MSH but are able to produce a moderate (DeltaegtD-mshA) or significantly high (DeltaegtB-mshA) amount of GGC relative to the wild-type strain. In addition, we generated an M.tb mutant that is unable to produce GGC nor MSH but is able to produce a significantly low level of ERG (DeltaegtA-mshA) relative to the wild-type strain. The susceptibilities of these mutants to various in vitro and ex vivo stress conditions were investigated and compared. RESULTS: The DeltaegtA-mshA mutant was the most susceptible to cellular stress relative to its parent single mutant strains (DeltaegtA and ?mshA) and the other double mutants. In addition, it displayed a growth-defect in vitro, in mouse and human macrophages suggesting; that the complete inhibition of ERG, MSH and GGC biosynthesis is deleterious for the growth of M.tb. CONCLUSIONS: This study indicates that ERG, MSH and GGC are able to compensate for each other to maximize the protection and ensure the fitness of M.tb. This study therefore suggests that the most effective strategy to target thiol biosynthesis for anti-tuberculosis drug development would be the simultaneous inhibition of the biosynthesis of ERG, MSH and GGC. PMID- 30001198 TI - Serum magnesium levels and lung cancer risk: a meta-analysis. AB - BACKGROUND: Whether serum magnesium levels were lower in patients with lung cancer than that in healthy controls is controversial. The aim of this study was to identify and synthesize all citations evaluating the relationship between serum magnesium levels and lung cancer. METHODS: We searched PubMed, WanFang, China National Knowledge Internet (CNKI), and SinoMed databases for relevant studies before December 31, 2017. Two authors independently selected studies, extracted data, and assessed risk of bias. RESULTS: Eleven citations comprising 707 cases with lung cancer and 7595 healthy controls were included in our study. Serum magnesium levels were not significantly lower in patients with lung cancer [summary SMD = 0.193, 95%CI = - 1.504 to 1.890] when compared to health controls, with significant heterogeneity (I2 = 99.6%, P < 0.001) found. Negative associations were found among Asian populations [summary SMD = 0.229, 95%CI = - 1.637 to 2.094] and European populations [summary SMD = - 0.168, 95%CI = - 0.482 to 0.147]. No publication bias was found using the test of Egger and funnel plot. CONCLUSIONS: Our study suggested that serum magnesium levels had no significant association on lung cancer risk. PMID- 30001201 TI - Correction to: Huddling remodels gut microbiota to reduce energy requirements in a small mammal species during cold exposure. AB - Following publication of the original article [1], the authors reported an error in the caption of Fig. 4. PMID- 30001200 TI - Correction to: Landraces of snake melon, an ancient Middle Eastern crop, reveal extensive morphological and DNA diversity for potential genetic improvement. AB - Following publication of the original article [1], the authors reported the need for a more detailed acknowledgement of the source of the samples that were analyzed and their coordinates, which are discussed in the 'Methods' section of the article. This Correction provides an addition to the 'Methods' section, and a subsequently revised 'Acknowledgements' and 'Availability of data and materials' section. PMID- 30001199 TI - DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells. AB - BACKGROUND: DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown. RESULTS: Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters. CONCLUSIONS: We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay. PMID- 30001202 TI - Low-level laser therapy for treatment of venous ulcers evaluated with the Nursing Outcome Classification: study protocol for a randomized controlled trial. AB - BACKGROUND: Different methods are available for the treatment of venous ulcers. Most current approaches focus on a combination of topical and compressive therapy. Adjuvant low-level laser therapy may be helpful in lesions with a protracted healing course, but evidence for its use is still limited. This paper describes the protocol of a randomized controlled trial designed to compare the effect of adjuvant low-level laser therapy versus conventional venous ulcer tissue repair, evaluated by a nurse using clinical indicators from the Nursing Outcomes Classification (NOC). METHODS/DESIGN: For this prospective randomized controlled trial, 40 adult patients of both sexes with active venous ulcers will be recruited. Subjects will be selected by the sealed-envelope method without any annotation or external identification that might refer to the type of study group. At the time of unblinding, a label with the description of the group to which the patient belongs (that is, control or intervention) will be found inside the envelope. Conventional treatment (topical medication and compressive therapy) will be offered to both groups. Additionally, the intervention group will receive adjuvant low-level laser therapy. All patients will be followed weekly until ulcer healing or for a maximum of 16 weeks. Evaluation of tissue repair will be based on 14 clinical indicators drawn from NOC for wound healing (secondary intention) and tissue integrity (skin and mucous membranes). The primary endpoint will be decreased wound size and scar formation. This laser therapy is expected to enhance the quality, speed, and effectiveness of the treatment of venous ulcers, a chronic condition. This should reduce associated costs to the health service and allow patients to resume their daily activities sooner. DISCUSSION: This randomized clinical trial will use a validated method to investigate the effect of a novel intervention for the treatment of venous ulcers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03229330 . Registered on July 2017. PMID- 30001203 TI - Does experience provide a permissive or instructive influence on the development of direction selectivity in visual cortex? AB - In principle, the development of sensory receptive fields in cortex could arise from experience-independent mechanisms that have been acquired through evolution, or through an online analysis of the sensory experience of the individual animal. Here we review recent experiments that suggest that the development of direction selectivity in carnivore visual cortex requires experience, but also suggest that the experience of an individual animal cannot greatly influence the parameters of the direction tuning that emerges, including direction angle preference and speed tuning. The direction angle preference that a neuron will acquire can be predicted from small initial biases that are present in the naive cortex prior to the onset of visual experience. Further, experience with stimuli that move at slow or fast speeds does not alter the speed tuning properties of direction selective neurons, suggesting that speed tuning preferences are built in. Finally, unpatterned optogenetic activation of the cortex over a period of a few hours is sufficient to produce the rapid emergence of direction selectivity in the naive ferret cortex, suggesting that information about the direction angle preference that cells will acquire must already be present in the cortical circuit prior to experience. These results are consistent with the idea that experience has a permissive influence on the development of direction selectivity. PMID- 30001205 TI - Are ADC values of readout-segmented echo-planar diffusion-weighted imaging (RESOLVE) correlated with pathological prognostic factors in rectal adenocarcinoma? AB - BACKGROUND: Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values as imaging biomarkers of rectal cancer are currently a hot research spot. The use of ADC values for preoperative judgment of pathological features in rectal cancer has been generally accepted. The image quality evaluation of conventional diffusion is severe deformation, and the measurement of ADC values can easily lead to bias. Readout-segmented echo-planar diffusion-weighted imaging (RESOLVE) provides high signal-to-noise ratio images and significantly reduces distortions caused by magnetosensitive effects. The purpose of this study was to explore the correlations between ADC values of RESOLVE and pathological prognostic factors in rectal adenocarcinoma. METHODS: We collected pathological data of 89 patients with pathologically confirmed rectal adenocarcinoma who directly underwent surgical resection without receiving adjuvant therapy. The patients were grouped according to the pathologic type, gross classification, degree of differentiation, TN stage, and immunohistochemical expression of epidermal growth factor receptor (EGFR). RESULTS: RESOLVE ADC values of rectal cancer were measured at b = 800, and correlations between the RESOLVE ADC values obtained in different groups were analysed. We found that RESOLVE ADC values in the ulcer-type group were significantly higher than those in the eminence-type group. CONCLUSION: RESOLVE ADC values in different pathologic types of rectal cancer were significantly different. RESOLVE ADC values in the EGFR-positive group were significantly lower than those in the EGFR-negative group. There was no significant difference in RESOLVE ADC values between different degrees of pathologic differentiation, TN stages, and positive or negative lymph nodes. The quantitative description of RESOLVE ADC values could be used to assess the biological behaviour of rectal adenocarcinoma. PMID- 30001206 TI - Alternative DNA secondary structure formation affects RNA polymerase II promoter proximal pausing in human. AB - BACKGROUND: Alternative DNA secondary structures can arise from single-stranded DNA when duplex DNA is unwound during DNA processes such as transcription, resulting in the regulation or perturbation of these processes. We identify sites of high propensity to form stable DNA secondary structure across the human genome using Mfold and ViennaRNA programs with parameters for analyzing DNA. RESULTS: The promoter-proximal regions of genes with paused transcription are significantly and energetically more favorable to form DNA secondary structure than non-paused genes or genes without RNA polymerase II (Pol II) binding. Using Pol II ChIP-seq, GRO-seq, NET-seq, and mNET-seq data, we arrive at a robust set of criteria for Pol II pausing, independent of annotation, and find that a highly stable secondary structure is likely to form about 10-50 nucleotides upstream of a Pol II pausing site. Structure probing data confirm the existence of DNA secondary structures enriched at the promoter-proximal regions of paused genes in human cells. Using an in vitro transcription assay, we demonstrate that Pol II pausing at HSPA1B, a human heat shock gene, is affected by manipulating DNA secondary structure upstream of the pausing site. CONCLUSIONS: Our results indicate alternative DNA secondary structure formation as a mechanism for how GC rich sequences regulate RNA Pol II promoter-proximal pausing genome-wide. PMID- 30001204 TI - Key role of piRNAs in telomeric chromatin maintenance and telomere nuclear positioning in Drosophila germline. AB - BACKGROUND: Telomeric small RNAs related to PIWI-interacting RNAs (piRNAs) have been described in various eukaryotes; however, their role in germline-specific telomere function remains poorly understood. Using a Drosophila model, we performed an in-depth study of the biogenesis of telomeric piRNAs and their function in telomere homeostasis in the germline. RESULTS: To fully characterize telomeric piRNA clusters, we integrated the data obtained from analysis of endogenous telomeric repeats, as well as transgenes inserted into different telomeric and subtelomeric regions. The small RNA-seq data from strains carrying telomeric transgenes demonstrated that all transgenes belong to a class of dual strand piRNA clusters; however, their capacity to produce piRNAs varies significantly. Rhino, a paralog of heterochromatic protein 1 (HP1) expressed exclusively in the germline, is associated with all telomeric transgenes, but its enrichment correlates with the abundance of transgenic piRNAs. It is likely that this heterogeneity is determined by the sequence peculiarities of telomeric retrotransposons. In contrast to the heterochromatic non-telomeric germline piRNA clusters, piRNA loss leads to a dramatic decrease in HP1, Rhino, and trimethylated histone H3 lysine 9 in telomeric regions. Therefore, the presence of piRNAs is required for the maintenance of telomere chromatin in the germline. Moreover, piRNA loss causes telomere translocation from the nuclear periphery toward the nuclear interior but does not affect telomere end capping. Analysis of the telomere-associated sequences (TASs) chromatin revealed strong tissue specificity. In the germline, TASs are enriched with HP1 and Rhino, in contrast to somatic tissues, where they are repressed by Polycomb group proteins. CONCLUSIONS: piRNAs play an essential role in the assembly of telomeric chromatin, as well as in nuclear telomere positioning in the germline. Telomeric arrays and TASs belong to a unique type of Rhino-dependent piRNA clusters with transcripts that serve simultaneously as piRNA precursors and as their only targets. Telomeric chromatin is highly sensitive to piRNA loss, implying the existence of a novel developmental checkpoint that depends on telomere integrity in the germline. PMID- 30001208 TI - Prediction of stone-free status after single-session retrograde intrarenal surgery for renal stones. AB - OBJECTIVE: To determine the possible factors effecting stone-free status (SFS) after single-session retrograde intrarenal surgery (RIRS) for renal stones. MATERIAL AND METHODS: We retrospectively analyzed the charts of 100 consecutive patients who underwent RIRS. Unilateral procedures performed for single renal stones were included in the study. The studied parameters included patient demographics, stone characteristics (size, volume, location and attenuation according to Hounsfield unit [HU]), operation time, presence of preoperative double-J stent (DJS), use of ureteral access sheath (UAS) and SFS. RESULTS: The study population consisted of 100 patients where 43 of them were stone free and remaining 57 had residual stones. The mean age of the patients was 47.2+/-13.4 years. The mean stone size (largest dimension), stone attenuation and stone volume were 14.8+/-5.8 mm, 1010+/-416 HU and 937+/-929 mm3, respectively. The mean operative time was 60.8+/-24.2 minutes. Mean stone size, volume and HU were higher in the RS group compared to SF group but without any statistically significant difference, 15.2+/-6.1 vs. 14.2+/-5.3 mm, 1056+/-1037 mm3 vs. 780+/ 745 mm3 and 1061+/-374 HU vs. 942+/-462 HU, respectively (p=0.490, p=0.135 and p=0.226). In multivariate regression analysis stone location and UAS use were found to be the significant predictors of SFS. Patients with lower pole stones are 2.25 times likely to have residual stones after RIRS compared to patient's having stones at other localizations (p<0.001). CONCLUSION: Stone volume could be a more reliable parameter than stone size in predicting RIRS success. Lower pole stone location and UAS use could be considered the most significant predictors of SFS after single session RIRS for single renal stones. PMID- 30001209 TI - Setup and initial testing of an endoscope manipulator system for assistance in transoral endoscopic surgery. AB - Purpose For the treatment of malignant diseases of the oral cavity and the larynx, a total or partial resection is the standard therapy, while in special cases chemo- and/or external radiation therapy is considered. Transoral access reduces trauma and hospitalization time. Transoral surgery is usually executed using external microscopic imaging. Therefore, the microscope is placed in the visual line of the opening of the mouth and throat. However, specific anatomical structures like the posterior commissure (dorsal end of the vocal cords) are not visible in these procedures. An endoscopic approach can improve this problem. We introduce a new prototype system for endoscopic assisted transoral surgery. Methods Based on clinical observation and discussions with professional users and surgeons, the clinical need was identified and specified. A general concept or an endoscopic manipulator to assist microlaryngeal surgery was designed. For that a steerable rigid endoscope was combined with an actuator that allows translational and rotational movement. A quick release fastener was designed allowing for fast change of the endoscope and independence from its shape and type. The actuator was fixed on a commercially available, semi-active medical holding arm for easy positioning. The holder can be fixed to the standard rails of the surgical table. The piezoelectric drives integrated in the actuator are activated with a foot pedal. This allows easy and fast fine positioning, while the hands are free to perform the surgery with standard instruments for microlaryngeal surgery. Results A prototype of the system for endoscopic assisted transoral surgery was developed. The entire technical setup was tested in terms of usability and performance in a simulated surgical scenario. A basic phantom, representing the throat and vocal cords was created and placed on a surgical table. The system was installed on the table and the clinical workflow of a simulated endoscopic assisted surgery on the vocal cords was performed. The performance of the setup and the procedure success was evaluated by clinical users. Conclusion Fixture of the system on the surgical table is fast and easy due to its low weight and compact design. The medical holder allows a fast initial positioning of the system in front of the phantom patient. An easy insertion and removal of the endoscope was realized using the quick release fastener. The developed endoscope fixation is universally adaptable and not limited to a single type of endoscope. The piezoelectric drives, combined with the foot pedal, allow a precise placement and readjustment of the endoscope during surgery. The use of a multi view endoscope enables a variable view on the surgical situs. The size and shape of the whole setup offer excellent access to the targeted structures. The development was classified beneficial by the clinical users. PMID- 30001207 TI - Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau. AB - Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser422) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cell-based immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1. PMID- 30001210 TI - A theoretical study of digital silicon photomultiplier utilization in diffuse optical imaging systems. AB - Digital silicon photomultiplier (dSiPM) is introduced for diffuse optical imaging (DOI) applications instead of conventional photomultiplier tubes and avalanche photodiodes (APDs) as a state-of-the-art detector. According to the low-level light regime in DOI applications, high sensitivity and high dynamic range (DR) image sensors are needed for DOI systems. dSiPM is proposed as a developing detector which can detect low-level lights. Also, an accurate equation is obtained for calculating the DR of dSiPMs. Different dSiPMs and the corresponding benefits are studied for DOI applications. Furthermore, a 120 dB DR dSiPM is chosen for use in DOI systems. It is shown that dSiPMs can be utilized in DOI configurations such as time domain (TD), frequency domain (FD) and continuous wave (CW) systems. Ultimately, by utilizing dSiPM in DOI systems, the DOI method can be used for thoracic imaging due to the high DR and signal-to-noise ratio (SNR) of the detector. PMID- 30001211 TI - Is FGF23 effective on insulin resistance in individuals with metabolic syndrome? AB - Purpose Metabolic syndrome (MetS) is a polymetabolic syndrome has high morbidity and mortality rates. Insulin resistance (IR) plays a key role in the increasing frequency of this situation and has been cited as being an important etiologic factor in MetS. In this study, the relationship between IR and fibroblast growth factor-23 (FGF23), was investigated in a population with MetS. Materials and methods Forty patients with diagnosis of MetS and 40 healthy volunteers with an equal number of males and females were included in the study and classified as patient group and control group. Blood samples were obtained after 12-h fasting period to study FGF23 and other parameters. MetS, defined according to the International Diabetes Federation (IDF) guidelines, FGF23 was studied by Enzyme Linked ImmunoSorbent Assay (ELISA) method and IR was calculated using the homeostatic model assessment-insulin resistance (HOMA-IR) formula. Results There was a statistically significant difference in HOMA-IR between the patient and control group as expected, while levels of FGF23 were similar. According to gender, levels of FGF23 was statistically significantly higher in male patients compared with controls (p = 0.037). A relationship was not detected between HOMA IR and FGF23 in the correlation analysis. Conclusion Although there are many studies suggesting the correlation between FGF23 and IR in different populations, we did not find any statistically significant relationship between IR and FGF23 levels in MetS in this study. PMID- 30001212 TI - Heuristic Modeling and 3D Stereoscopic Visualization of a Chlamydomonas reinhardtii Cell. AB - The structural modeling and representation of cells is a complex task as different microscopic, spectroscopic and other information resources have to be combined to achieve a three-dimensional representation with high accuracy. Moreover, to provide an appropriate spatial representation of the cell, a stereoscopic 3D (S3D) visualization is favorable. In this work, a structural cell model is created by combining information from various light microscopic and electron microscopic images as well as from publication-related data. At the mesoscopic level each cell component is presented with special structural and visual properties; at the molecular level a cell membrane composition and the underlying modeling method are discussed; and structural information is correlated with those at the functional level (represented by simplified energy producing metabolic pathways). The organism used as an example is the unicellular Chlamydomonas reinhardtii, which might be important in future alternative energy production processes. Based on the 3D model, an educative S3D animation was created which was shown at conferences. The complete workflow was accomplished by using the open source 3D modeling software Blender. The discussed project including the animation is available from: http://Cm5.CELLmicrocosmos.org. PMID- 30001214 TI - Klaus Riegel (1926-2018). PMID- 30001213 TI - Molecular genetics of tetrahydrobiopterin deficiency in Chinese patients. AB - Background The overall incidence of hyperphenylalaninemia (HPA) in China is 1:11,763, with tetrahydrobiopterin (BH4) deficiency accounting for 8.55% of patients with HPA in the mainland. Much progress has been made in the diagnosis and treatment of BH4 deficiency with the introduction of neonatal screening in China. However, the screening rate is still low and screening is not universally available. Methods A total of 44 BH4-deficient patients were enrolled in this study, of which 39 were diagnosed with BH4 deficiency, while the remaining five showed typical characteristics of BH4 deficiency at a later period. The entire coding regions and adjacent intronic regions of GCH1, PTS, PCBD1 and QDPR genes were analyzed using target sequencing. Results Nineteen (n=19) different mutations in the PTS gene including four novel mutations and one mutation in QDPR were identified. p.P87S, p.D96N, IVS1-291A>G, p.N52S, p.K91R, p.V56M, p.T106M and p.F40GfsX53 in PTS were the prevalent mutations with >=3% relative frequency. The mutation p.R221X in the QDPR gene was found with relatively lower frequencies (2.27%). The remaining 12 mutations in PTS were found at relative frequencies of 1.14%. Conclusions The results could be of value for genetic counseling and prenatal diagnosis in the patients' families and for the molecular diagnosis of BH4 deficiencies. Furthermore, four novel mutations expand and improve the PTS mutation database. PMID- 30001215 TI - The response to radiofrequency neurotomy of medial branches including a bipolar system for thoracic facet joints. AB - Background and aims The evidence for interventional treatment of thoracic facet joint pain remains limited. This is partly due to inconsistency of the path of thoracic medial branches and a lower incidence of thoracic facet pain among spine pain patients. The purpose of this study is to evaluate the efficacy of bipolar radiofrequency (RF) neurotomy of medial branches for treating chronic thoracic facet joint pain. Methods This is a retrospective record review of all patients diagnosed to have thoracic facet pain with diagnostic block and subsequently treated with bipolar RF neurotomy of medial branch between January 2012 and December 2015. The outcome measures were mean changes in Numeral Rating Scale (NRS) and Pain Disability Index (PDI). Results There were 71 patients with complete data available for analysis. The mean age of the patients was 57.9+/ 11.2 years. The mean duration of pain was 23+/-10.5 months. The majority of patients (82%) had pain reduction of more than 50% at 12 months after bipolar RF neurotomy. The NRS decreased significantly from baseline of 7.75+/-1.25 to 2.86+/ 1.53 at 3 months and 2.82+/-1.29 at 12 months post-procedure (p<0.001. p<0.001, respectively). The PDI improved significantly from 40.92+/-12.22 to 24.15+/-9.79, p<0.05). There were no serious adverse effects or complications of the procedure reported in this study. Conclusions Bipolar RF neurotomy of thoracic medial branch is associated with a significant reduction in thoracic facet joint pain. The promising findings from this case series merit further assessment with prospective, randomized controlled trial which will produce a more reliable and accurate finding for its clinical applications. PMID- 30001216 TI - Central and peripheral pain sensitization during an ultra-marathon competition. AB - Background and aims The participation in ultra-marathons and other ultra endurance events has increased exponentially over the past decade. There is insufficient data on variation in pain mechanisms in exercise overall but especially in the ultra-endurance athlete population. To further understand peripheral and central pain sensitization we have investigated pressure pain threshold and conditioned pain modulation during three separate ultra-marathon competitions. Methods Each ultra-marathon investigated was held in the state of Florida, USA, over flat, sandy and paved surfaces under generally warm to hot, humid conditions. Pressure pain threshold was measured utilizing a Baseline (c) Dolorimeter. The blunt end of the dolorimeter stylus was placed onto the distal dominant arm, equidistant between the distal radius and ulna, three times in a blinded manner to insure that the testing technician did not influence the subject's responses. Conditioned pain modulation was measured immediately after the PPT measures by placing the non-dominant hand in a cool water bath maintained at 15 degrees C. The same dolorimeter measurement was repeated two more times on the dominant arm while the non-dominant hand remained in the water. Data was analyzed with a paired t-test. Results Pressure pain threshold was significantly decreased (p<0.05) at 25, 50 and 100 miles. Conditioned pain modulation was also significantly decreased (p<0.05) at 25, 50 and 100 miles of an ultra-marathon competition. Conclusions Together these data suggest an increased peripheral and/or central pain sensitization starting at 25 miles and continuing throughout an ultra-marathon competition run in these conditions. This is the first study that provides evidence of a decreased peripheral pain threshold and decreased central pain inhibition from ultra-marathon running. Decreases in both the peripheral pain threshold and central inhibition may result from nociceptor plasticity, central sensitization or a combination of both. Implications Based on previous research that has indicated a central sensitization resulting from inflammation and the well-documented inflammatory response to the rigors of ultra marathon competition, we suggest the decreased peripheral pain threshold and decreased descending pain inhibition results from this inflammatory response of running an ultra-marathon. PMID- 30001217 TI - Hybrid complexes of high and low molecular weight hyaluronan delay in vitro replicative senescence of mesenchymal stromal cells: a pilot study for future therapeutic application. AB - Mesenchymal stem cells, a subpopulation of mesenchymal stromal cells (MSCs), are present in the stroma of several tissues. MSC in vitro cultivation for clinical treatments may greatly affect MSC properties. A primary handicap is replicative senescence that impairs MSC functions. Hyaluronan (HA) is present in the extracellular matrix that composes the stem cell niche environment and is under investigation as a key factor for in vitro stem cell growth. We evaluated the effect on MSC cultivation of HA hybrid cooperative complexes (HCC) that are obtained from high (H) and low (L) weight molecules (NAHYCOTM). We compared this HCC with H-HA and L-HA. We investigated the effects of these HAs on proliferation, cell cycle, apoptosis, senescence, and differentiation following the addition of the polymer solutions in the culture media at concentrations that did not drastically modify the medium viscosity. Interestingly, 0,16% HCC significantly delayed the senescence compared with the controls. This occurred without alteration of the cell cycle, cytotoxicity, or apoptosis. HCCs also promoted adipogenic and chondrogenic differentiation. Our finding could suggest a potential functional role of HCC above the updated scientific reports of its effects and pave the way to optimization of MSC cultivation for therapeutic application. PMID- 30001220 TI - Just the FACTS: The Role of Diagnostic Blocks in Lumbar Facet Interventions. PMID- 30001218 TI - Nicotine exposure impairs germ cell development in human fetal ovaries cultured in vitro. AB - In the present paper, we found that human fetal ovaries (at ~16 weeks) express the transcripts for several subunits of the nicotinic acetylcholine receptor (nAChR). Exposure to the drug in vitro resulted in the marked increase of apoptosis in the ovaries in a time and dose-dependent manner. Evidence that adverse nicotine effects are potentially due to an increased level of reactive oxygen species (ROS) and consequent DNA damage, both in the ovarian somatic cells and germ cells, are reported. After 4 days of culture, exposure to 1 mM and 10 mM nicotine caused a 50% and 75% decrease, respectively, in the number of oogonia/oocytes present in the fetal ovaries. These results represent the first indication that nicotine may directly cause apoptosis in cells of the fetal human ovary and may lead to a reduction of the ovarian reserve oocytes and consequent precocious menopause in mothers smoking during pregnancy. PMID- 30001221 TI - Impact of the Choice of Risk Model for Identifying Low-risk Patients Using the 2014 American College of Cardiology/American Heart Association Perioperative Guidelines. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The 2014 American College of Cardiology Perioperative Guideline recommends risk stratifying patients scheduled to undergo noncardiac surgery using either: (1) the Revised Cardiac Index; (2) the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator; or (3) the Myocardial Infarction or Cardiac Arrest calculator. The aim of this study is to determine how often these three risk-prediction tools agree on the classification of patients as low risk (less than 1%) of major adverse cardiac event. METHODS: This is a retrospective observational study using a sample of 10,000 patient records. The risk of cardiac complications was calculated for the Revised Cardiac Index and the Myocardial Infarction or Cardiac Arrest models using published coefficients, and for the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator using the publicly available website. The authors used the intraclass correlation coefficient and kappa analysis to quantify the degree of agreement between these three risk prediction tools. RESULTS: There is good agreement between the American College of Surgeons National Surgical Quality Improvement Program and Myocardial Infarction or Cardiac Arrest estimates of major adverse cardiac events (intraclass correlation coefficient = 0.68, 95% CI: 0.66 to 0.70), while only poor agreement between (1) American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator and the Revised Cardiac Index (intraclass correlation coefficient = 0.37; 95% CI: 0.34 to 0.40), and (2) Myocardial Infarction or Cardiac Arrest and Revised Cardiac Index (intraclass correlation coefficient = 0.26; 95% CI: 0.23 to 0.30). The three prediction models disagreed 29% of the time on which patients were low risk. CONCLUSIONS: There is wide variability in the predicted risk of cardiac complications using different risk-prediction tools. Including more than one prediction tool in clinical guidelines could lead to differences in decision-making for some patients depending on which risk calculator is used. PMID- 30001219 TI - Locus of control as a modifiable risk factor for cognitive function in midlife. AB - Few modifiable risk factors for cognitive decline have been identified. Despite an external locus of control (LoC) being adversely associated with many psychological and physical health outcomes, few studies have examined whether it is related to cognitive function in adulthood. In 1178 women from the Avon Longitudinal Study of Parents and Children, we examined whether LoC, and change in LoC over time, is associated with cognitive function in midlife. LoC was prospectively measured at mean ages 30 and 48 years using the validated Nowicki Strickland scale. Cognitive function was examined at mean age 51 years. At both time points, greater externality was associated with lower cognitive function. For example, the group of women classified as being external at mean age 48 years had, on average, a 0.18 lower cognitive function score (95% CI: (0.11 to 0.25) than the group classified as being internal (p<0.001). Participants who changed from external to internal over time, on average, had better cognitive function than those who remained external or changed to become external. In summary, an external LoC may be detrimental to cognitive function. Thus, interventions to increase internality may help to minimise the adverse consequences on cognitive health later in life. PMID- 30001222 TI - Associations between Changes in Activity and Sleep Quality and Duration over Two Years. AB - PURPOSE: Insufficient physical activity (PA) and inadequate sleep quality (SQ) and sleep duration (SD) are highly prevalent behaviors that increase the risk of developing many chronic health conditions. Evidence regarding bidirectional relationships between PA, SQ, and SD is inconsistent. As changes in one of these behaviors may impact on the other, it is important to understand the nature of the bidirectional relationship between PA and sleep. Therefore, the aim of this study was to examine the relationship between changes in PA, SQ, and SD over a 2 yr period in middle-age adults. METHODS: Participants were adults age 42 to 72 yr from Brisbane, Australia. Mail surveys were used to assess PA, SQ, SD, sociodemographic and health characteristics in 2011 and 2013 (n = 3649). Multinomial logistic regression analyses were conducted to examine the relationships between patterns of change in PA, SQ, and SD over the 2 yr. RESULTS: Improving or maintaining good SQ was associated with increasing or maintaining PA and maintaining PA was associated with maintaining or increasing SQ (P < 0.05). Changes in PA were not associated with changes in SD. CONCLUSIONS: A bidirectional relationship between PA and SQ was identified; however, no evidence of a relationship in any direction between PA and SD was found. Multibehavior interventions targeting both PA and SQ are warranted. Middle-age adults with poor SQ may benefit from increasing PA and improving SQ may promote higher levels of activity. PMID- 30001223 TI - Effect of Endurance Conditioning on Insulin-mediated Glucose Clearance in Dogs. AB - INTRODUCTION: Physical activity has been shown to improve insulin sensitivity in subjects with insulin resistance, but the effect of athletic conditioning on subjects with normal insulin sensitivity has received less scrutiny. Because strenuous exercise can be limited by the availability of substrates, it is reasonable to hypothesize that conditioning would increase the capacity for muscle uptake of substrates like glucose and to the extent that improvement in this process would include upregulation of the portions of the glucose uptake pathway in muscle, this increased capacity would also be reflected in insulin sensitivity. Therefore, we tested the hypothesis that conditioning for endurance exercise would result in increased insulin sensitivity using elite racing sled dogs. METHODS: A frequent-sampled intravenous glucose tolerance test was performed on these dogs before and after a full 7-month season of conditioning in preparation for a 1600-km race. RESULTS: Compared with the results in unconditioned dogs, conditioned dogs rapidly cleared the intravenous glucose bolus through increases in both glucose mediated (7.6%.min +/- 3.4%.min vs 3.0%.min +/- 2.2%.min, P = 0.008) and insulin-mediated (36.3 +/- 18.4 * 10 L.min.mU vs 11.5 +/- 8.0 * 10 L.min.mU, P = 0.007) mechanisms. The more modest increase in serum insulin after the intravenous glucose bolus in conditioned dogs failed to suppress lipolysis and serum concentrations of nonesterified fatty acids remained constant in the conditioned dogs throughout the 4-h test. CONCLUSIONS: These results, in particular the increase in insulin-independent peripheral uptake of glucose, describe novel alterations in metabolism induced by athletic conditioning that arguably result in near-continuous provision of oxidizable substrates to peripheral muscle in support of sustained muscular work typical of these dogs. PMID- 30001224 TI - Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis? PMID- 30001226 TI - Mapping alterations of gray matter volume and white matter integrity in children with autism spectrum disorder: evidence from fMRI findings. AB - This study aimed to identify the neuroanatomical substrates and white matter connectivity in children with autism spectrum disorder (ASD) and the association between gray matter and structural connectivity. A total of 36 children including patients with ASD and healthy controls between 6 and 15 years of age were enrolled in this study. High-resolution structural MRI and functional MRI were performed and analyzed using voxel-based morphometry and tract-based spatial statistics. The relationship between gray matter volume and structural connectivity was generated using Pearson correlation analysis. Voxel-based morphometry analysis showed significantly reduced areas of gray matter in the left cerebellum. Tract-based spatial statistics analysis showed white matter abnormalities in several distinct clusters within the right inferior frontal gyrus (opercular part), the left inferior parietal lobule, and the right mentary motor area. Neither ASD nor healthy controls showed a significant correlation between gray matter volume and white matter integrity. Our study confirmed the presence of several structural and regional abnormalities in ASD children. These findings suggest that there are significant differences in some brain regions in children with autism relative to healthy children, but no association between them. PMID- 30001225 TI - Evaluation of composite responder outcomes of pain intensity and physical function in neuropathic pain clinical trials: an ACTTION individual patient data analysis. AB - Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (rho = -0.22; P < 0.001) and nonsignificant in PHN (rho = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of >=50% improvement in pain intensity, or a >=20% improvement in pain intensity and >=30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of >=50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials. PMID- 30001227 TI - Che-1 inhibits oxygen-glucose deprivation/reoxygenation-induced neuronal apoptosis associated with inhibition of the p53-mediated proapoptotic signaling pathway. AB - Accumulating evidence suggests that Che-1 is a strong antiapoptotic protein and can protect cells against various insults. However, whether Che-1 is involved in the protection of neurons against cerebral ischemia/reperfusion injury remains unclear. In this study, we aimed to investigate the potential role of Che-1 in regulating cerebral ischemia/reperfusion injury-induced neuronal injury using the oxygen-glucose deprivation and reoxygenation (OGD/R) model in vitro. We found that Che-1 expression was induced in neurons following OGD/R treatment. Functional experiments showed that Che-1 knockdown aggravated OGD/R-induced neuronal apoptosis. In contrast, Che-1 overexpression exerted a protective effect against OGD/R-induced neuronal apoptosis. Moreover, our results showed that the protective effect of Che-1 was associated with the inhibition of p53-mediated proapoptotic genes, including Puma, Noxa, and Bax. In addition, we showed that Che-1 impeded the transcript activity of p53 toward apoptosis. Taken together, our results indicate that Che-1 alleviates OGD/R-induced neuronal apoptosis in vitro through inhibition of p53-mediated proapoptotic signaling. Our study suggests that Che-1 may serve as a potential therapeutic target for the treatment of cerebral ischemic/reperfusion injury in vivo. PMID- 30001229 TI - Central Nervous System Infections Caused by Mycobacterium abscessus: Ventricular Shunt Infection in Two Pediatric Patients and Literature Review. AB - A 4-year-old former 24-week gestation male and an 18-month-old former 26-week gestation female, both with history of intraventricular hemorrhage resulting in hydrocephalus, presented with Mycobacterium abscessus ventricular shunt infections affecting both the shunt track and the ventricular fluid. Both children required prolonged combination antimycobacterial therapy; the 4 year old required more than two months of triple intravenous antibiotics and intraventricular amikacin to sterilize the cerebrospinal fluid. Each infection came under control only after removal of all foreign material and multiple and extensive adjunctive surgical procedures to excise infected shunt track tissue. Central nervous system infections caused by M. abscessus are rare and their management is challenging: prolonged antimicrobial therapy is required, adverse effects from antibiotics are common, and rates of mortality and morbidity are high. PMID- 30001228 TI - Utility of Timed Up and Go in Outpatient Cardiology Clinics. AB - PURPOSE: The aim of the study was to examine if the Timed Up and Go (TUG) Test would be a feasible, reproducible, and valid measure in patients post-coronary artery bypass grafting (CABG). DESIGN: Cross-sectional study, controls and patients post-CABG, outpatient clinic. METHODS: Participants performed the TUG Test and the 6-Minute Walking Distance (6MWD) Test. Reliability was measured within observer on two occasions. FINDINGS: Patients and controls were similar in age. The patients had greater TUG mean (SD) of 14.4 seconds (4.9 seconds) and lower 6MWD of 358 m (76 m) compared with TUG of 8.2 seconds (2.7 seconds) and 6MWD of 487 m (56 m) in controls. In patients, intraclass correlation for the TUG was .98 (95% CI [.96, .98]) between the measurements. In patients, there was a high correlation between the TUG Test and the 6MWD Test, r = -.70, p < .001. CONCLUSION: The TUG Test demonstrated to be a feasible, reproducible, and valid measure in patients post-CABG. CLINICAL RELEVANCE: The TUG Test could serve as a screening tool for physical performance inside clinics. PMID- 30001230 TI - Tracking Changes in Vaccine Attitudes and Decisions: Results from 2008 and 2016 Parental Surveys. AB - To monitor parental vaccine attitudes, a survey was conducted in 2008 and in 2016. In both years (90%-89%) reported full immunization of their children, and a stable majority (71%-66%) supported documentation of vaccination before entering kindergarten. However, a declining confidence in official recommendations from 87% to 72% (p<0.0001) in 2008 and 2016 respectively was documented, requiring effort to rebuild it. PMID- 30001231 TI - Rhinovirus Species in Children with Severe Bronchiolitis: Multicenter Cohort Studies in the US and Finland. AB - In this analysis of two prospective multi-center, multi-year cohorts of children hospitalized for bronchiolitis in the US and Finland, 306 rhinovirus infections were genotyped. Rhinovirus-A and -C species were predominant in the US study while rhinovirus-C species was predominant in the Finland study. In both cohorts, there were no significant between-species differences in clinical characteristics, including acute severity measures. PMID- 30001232 TI - Comparing the Clinical Severity of Disease Caused by Enteroviruses and Human Parechoviruses in Neonates and Infants. AB - Comparison of children hospitalized with enterovirus (EV) or human parechovirus (HPeV) detected in their cerebrospinal fluid (CSF) revealed that HPeV infections presented with more persistent fever, irritability and feeding problems, more frequent leukopenia and lymphopenia, and higher admission rates to high dependency or intensive care units. Few HPeV cases were followed-up, further studies on long-term outcomes are needed. PMID- 30001234 TI - Intrahepatic Cholangiocarcinomas Have Histologically and Immunophenotypically Distinct Small and Large Duct Patterns. AB - Intrahepatic cholangiocarcinomas are histologically heterogenous. Using a cohort of 184 clinically defined, resected intrahepatic cholangiocarcinomas, we retrospectively classified the histology into 4 subtypes: large duct (LD), small duct (SD) (predominantly tubular [SD1] or predominantly anastomosing/cholangiolar, [SD2]), or indeterminate. Then, we tested the 4 subtypes for associations with risk factors, patient outcomes, histology, and immunophenotypic characteristics. SD was the most common (84%; 24% SD1 and 60% SD2) with lower proportions of LD (8%), and indeterminate (8%). Primary sclerosing cholangitis was rare (2%), but correlated with LD (P=0.005). Chronic hepatitis, frequent alcohol use, smoking, and steatosis had no histologic association. LD was associated with mucin production (P<0.001), perineural invasion (P=0.002), CA19-9 staining (P<0.001), CK7, CK19, CD56 immunophenotype (P=0.005), and negative albumin RNA in situ hybridization (P<0.001). SD was histologically nodular (P=0.019), sclerotic (P<0.001), hepatoid (P=0.042), and infiltrative at the interface with hepatocytes (P<0.001). Albumin was positive in 71% of SD and 18% of LD (P=0.0021). Most albumin positive tumors (85%) lacked extracellular mucin (P<0.001). S100P expression did not associate with subtype (P>0.05). There was no difference in disease-specific or recurrence-free survival among the subtypes. Periductal infiltration and American Joint Committee on Cancer eighth edition pT stage predicted survival by multivariable analysis accounting for gross configuration, pT stage, and histologic type. pT2 had worse outcome relative to other pT stages. Significant differences in histology and albumin expression distinguish LD from SD, but there is insufficient evidence to support further subclassification of SD. PMID- 30001233 TI - Cutaneous Non-Neural Granular Cell Tumors Harbor Recurrent ALK Gene Fusions. AB - Non-neural granular cell tumor (NNGCT; also known as primitive polypoid granular cell tumor) is a rare neoplasm composed of large ovoid cells with abundant granular cytoplasm, variable nuclear pleomorphism, and the potential for regional lymph node spread. In contrast to conventional granular cell tumor (GCT), NNGCT lacks S100 expression and can exhibit greater nuclear atypia and mitotic activity. Therefore, we investigated clinicopathologic features of 12 NNGCT, and also used next-generation sequencing to identify potential driver events in a subset of NNGCT and 6 GCT. NNGCT demonstrated mild-to-moderate nuclear pleomorphism, variable mitotic activity (0 to 10/10 high-power fields), and were S100. Genetic analysis of 5 cutaneous NNGCT revealed gene fusions involving the anaplastic lymphoma kinase gene (ALK) in 3 cases (60%). Specifically, an interstitial deletion of chromosome 2 resulting in an in-frame fusion of dyanactin 1 (DCTN1) to ALK was identified in 2 cases, and a translocation resulting in a fusion between sequestosome 1 (SQSTM1) on chromosome 5 and ALK was identified in one case. Two of 6 GCT (33%) showed gains of chromosome 7. No other molecular or chromosomal alterations were detected in NNGCT and GCT. ALK immunohistochemistry revealed weak-to-moderate positivity in 4/9 cutaneous NNCGT (44%) including all 3 tumors with ALK fusions. Three oral NNGCT lacked ALK expression. NNGCT with ALK immunostaining did not have morphologic features distinguishing them from those without ALK staining. Our results demonstrate that a subset of NNGCT harbor ALK fusions, suggest that NNGCT are molecularly diverse, and further substantiate NNGCT as distinct from GCT. PMID- 30001236 TI - Acquired Cystic Disease-associated Renal Cell Carcinoma (ACKD-RCC)-like Cysts. AB - Acquired cystic disease-associated renal cell carcinoma (ACKD-RCC), originally described by Tickoo and colleagues, is found exclusively in patients with end stage renal disease. Tickoo and colleagues noted: "Many of the tumors (16 of 24 dominant tumors) appeared to arise in a cyst, most often completely filling the cystic space. The cells lining such cysts were morphologically similar to those in the rest of the tumor." Subsequent literature lacks analysis of cysts lined by cells identical to ACKD-RCC, yet lacking areas of solid growth. The current study evaluates 16 cases ACKD-RCC-like cysts. All specimens were nephrectomies and occurred in the setting of end-stage renal disease. Of the 16 cases, 9 were in men. Patient's ages ranged from 32 to 66 years (median: 57). The cysts ranged in size from 0.2 to 2.5 cm. Twelve cases had unilateral cysts with the remaining 4 seen in both kidneys. Nine cysts were multilocular, 6 unilocular, and 1 consisted of closely clustered cysts. The atypical cysts showed architectural variation. One cyst was lined by a single layer of atypical cells (1/16), whereas in the majority these were either focally lined by 2 to 4 cell layers of atypical cells (6/16 cases) or showed occasional short papillary formations (9/16). Calcium oxalate crystals were noted in cyst walls in 7/16 cases. A total of 12/16 cases had separate RCCs (2 cases with 2 RCCs each; 1 case with 3). Carcinoma ranged in size from 3 mm to 5 cm in the largest dimension: 4 were pT1 ACKD-RCC; 5 were pT1 papillary RCC; 5 were pT1 clear cell papillary RCC; 1 was pT3 clear cell RCC; and 1 pT1 unclassified. Our study formally analyzes for the first time in the literature atypical cysts lined with vacuolated cells with eosinophilic cytoplasm that are likely the earliest precursors of ACKD-RCC. When these cysts are encountered, especially ones that are multilocular or clustered, they may be misdiagnosed as ACKD-RCC. ACKD-RCC-like cysts should be recognized as a distinct entity from ACKD-RCC, defined by the lack of any solid nodular growth within the cyst. PMID- 30001235 TI - Are Enterocolic Mucosal Mast Cell Aggregates Clinically Relevant in Patients Without Suspected or Established Systemic Mastocytosis? AB - The World Health Organization considers enterocolic mast cell aggregates with atypical morphologic and/or immunohistochemical features diagnostic of systemic mastocytosis mostly because published data are heavily influenced by inclusion of symptomatic patients with systemic disease. We occasionally encounter atypical mast cells in gastrointestinal biopsy samples from patients in whom systemic mastocytosis is not suspected. The aim of this study was to describe the clinicopathologic features and implications of atypical enterocolic mast cell aggregates in 16 patients without suspected or established systemic mastocytosis. Mast cell infiltrates were assessed for morphology, distribution, associated inflammatory cells, and CD117 and CD25 immunoexpression. Most (63%) patients were women; 15 underwent endoscopic examination for screening (n=7), abdominal pain (n=3), diarrhea (n=3), changing bowel habits (n=1), and dysphagia (n=1). Mast cell aggregates were detected in 1 colectomy specimen for cancer. Colonic involvement was most common (n=14) and resulted in polypoid (n=10), edematous (n=2), or normal (n=3) mucosae. All cases featured CD117/CD25, ovoid mast cells concentrated beneath the epithelium, or diffusely involving the entire mucosal thickness. Eosinophils were numerous and obscured mast cells in 63% of cases. Spontaneous resolution of symptoms occurred in all patients (mean follow-up: 54 mo), and asymptomatic patients remained symptom-free (mean follow-up: 17 mo). Of 4 patients evaluated for systemic mastocytosis, 3 had negative bone marrow biopsies and one lacked a KIT mutation in peripheral blood. We conclude that, although careful clinical assessment of patients with incidental enterocolic mast cell aggregates is reasonable, labeling them with a systemic hematologic disorder may not be justified. PMID- 30001238 TI - Loss of SATB2 Expression in Colorectal Carcinoma Is Associated With DNA Mismatch Repair Protein Deficiency and BRAF Mutation. AB - The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation. PMID- 30001239 TI - Mixed Adenoma Well-differentiated Neuroendocrine Tumor (MANET) of the Digestive System: An Indolent Subtype of Mixed Neuroendocrine-NonNeuroendocrine Neoplasm (MiNEN). AB - Mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) consisting of adenoma and well-differentiated neuroendocrine tumor (NET) has been recently defined as "MANET." However, the clinico-pathologic and pathogenetic features of this entity are not thoroughly studied. We examined the clinico-pathologic features of 12 MANETs by expanding their p53 and beta-catenin expression profiles as well as the presence of microsatellite instability and KRAS, BRAF, and PIK3CA mutations in the 2 tumor components. In all cases, the adenomatous component represented the larger part of the lesions and the NET was localized in the deep central portion of polyps. In 9 cases the latter was represented by NET G1, in 2 by NET G2, and in 1 by NET G3. In all cases, the glandular and NET components were intimately admixed, with zone of transition between the tumor components. The NET component was p53 negative in all cases and 3 of 8 cases showed variable nuclear positivity for beta-catenin. All patients with follow-up data were alive and free of disease after a mean follow-up time of 9 years. No mutations in KRAS, BRAF, and PIK3CA genes and no microsatellite instability were found in both tumor components. Review of the literature also identified 59 previously reported MANETs and no tumor-related death has been found. Like mixed adenoneuroendocrine carcinomas, a high-grade malignant form of MiNENs with a poorly differentiated neuroendocrine carcinoma component, a common origin for both tumor constituents may be hypothesized. Moreover, the current series provides evidence that MANET is an indolent disease that needs to be distinguished from aggressive high-grade MiNENs. PMID- 30001240 TI - Consistent Amplification of FRS2 and MDM2 in Low-grade Osteosarcoma: A Genetic Study of 22 Cases With Clinicopathologic Analysis. AB - Low-grade osteosarcoma (LGOS) encompasses low-grade central osteosarcoma (LGCOS) and parosteal osteosarcoma (POS). LGOSs are characterized by a supernumerary ring and giant rod chromosomes containing the 12q13-15 amplicon. The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4. Recent studies identified consistent amplification of FRS2 gene in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma. The aim of this study was to evaluate the frequency of FRS2 amplification and its relationship with the clinicopathologic features of LGOSs. The amplification of FRS2 and MDM2 genes were analyzed by fluorescence in situ hybridization using 22 LGOSs (3 LGCOSs, 14 classic POSs, and 5 dedifferentiated POSs) and 85 control samples of bone and soft tissue. The clinicopathologic features of the 22 LGOSs were described. Amplification of FRS2 was detected in 21/22 (95%) of the LGOSs, including 3 (100%) LGCOSs and 18 (95%) POSs. All 22 LGOSs showed MDM2 amplification (100%). The only MDM2/FRS2 LGOS was dedifferentiated POS (the dedifferentiated component was conventional osteosarcoma). In the control group, all of the atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcomas (DDLs) (10/10, 100%) were FRS2 amplified, whereas the remaining 75 control cases were FRS2-nonamplified. These findings indicate that the FRS2 gene is consistently amplified in classic and dedifferentiated LGOSs but not in their histologic mimics. These results offer another avenue for investigating the biology of LGOSs. Whether FRS2-nonamplified tumors exhibit unusual clinicopathologic features needs further investigation. Some so-called "high-grade osteosarcomas harboring 12q13-15 amplification" may be unrecognized dedifferentiated LGOSs. PMID- 30001237 TI - Uterine PEComas: A Morphologic, Immunohistochemical, and Molecular Analysis of 32 Tumors. AB - Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms that may show overlapping morphology and immunohistochemistry with uterine smooth muscle tumors. In this study, we evaluated the morphologic, immunohistochemical, and molecular features of 32 PEComas, including 11 with aggressive behavior. Two distinct morphologies were observed: classic (n=30) and those with a lymphangioleiomyomatosis appearance (n=2). In the former, patients ranged from 32 to 77 (mean: 51) years and 13% had tuberous sclerosis. Tumors ranged from 0.2 to 17 (mean: 5.5) cm with 77% arising in the corpus. Epithelioid cells were present in 100% and a spindled component was seen in 37%. Nuclear atypia was low (53%), intermediate (17%), or high (30%). Mitoses ranged from 0 to 36 (mean: 6) and 0 to 133 (mean: 19) per 10 and 50 high-power fields, with atypical mitoses present in 30%. Thin and delicate vessels were noted in 100%, clear/eosinophilic and granular cytoplasm in 93%, stromal hyalinization in 73%, necrosis in 30%, and lymphovascular invasion in 10%. All tumors were positive for HMB-45, cathepsin K, and at least one muscle marker, with most expressing melan-A (77%) and/or MiTF (79%). A PSF-TFE3 fusion was identified in one while another showed a RAD51B OPHN1 fusion. Follow-up ranged from 2 to 175 (mean: 41) months, with 63% of patients alive and well, 20% dead of disease, 13% alive with disease, and 3% dead from other causes. In the latter group (n=2), patients were 39 and 49 years old, one had tuberous sclerosis, while the other had pulmonary lymphangioleiomyomatosis. Both tumors expressed HMB-45, cathepsin K, and muscle markers, but lacked TFE3 and RAD51B rearrangements. The 2 patients are currently alive and well. Application of gynecologic-specific criteria (>=4 features required for malignancy: size >=5 cm, high-grade atypia, mitoses >1/50 high-power fields, necrosis, and lymphovascular invasion) for predicting outcome misclassified 36% (4/11) of aggressive tumors; thus, a modified algorithm with a threshold of 3 of these features is recommended to classify a PEComa as malignant. PMID- 30001241 TI - Pulmonary Carcinomas With Mucinous and Neuroendocrine Differentiation: Expanding the Spectrum of Amphicrine Carcinomas. AB - Amphicrine carcinoma is a distinct type of carcinoma characterized by synchronous exocrine and endocrine differentiation within the same tumor cell. Such tumors are exceedingly rare and most commonly recognized in the gastrointestinal tract. In the lung, sporadic descriptions of such lesions exist. This report presents 3 more such tumors, expanding the spectrum of amphicrine carcinomas in this organ. The patients were 3 men, 53 to 78 years of age (mean: 63 y) and all were current or former smokers. In one patient the tumor was an incidental finding, the others presented with lower respiratory symptoms. Microscopically, the lesions had an organoid pattern, consisting of nests of large tumor cells with peripheral palisading, vesicular nuclei and prominent nucleoli reminiscent of large cell neuroendocrine carcinoma. In addition, the tumor nests also showed glandular features, characterized by gland-like lumina filled with mucin and intracytoplasmic mucin droplets. Immunohistochemical studies showed diffuse reactivity of the tumor cells with synaptophysin and chromogranin and variable reactivity with TTF-1. Mucin stains highlighted extracellular and intracellular mucin deposition. Clinical follow-up demonstrated that one patient had died of his disease 12 months after surgery while another was alive and free of disease 21 months after surgery. The third patient was alive with widespread metastatic disease 8 months after diagnosis. This series highlights a rare variant of pulmonary carcinoma showing synchronous exocrine and endocrine differentiation. Recognition of this type of tumor is important in terms of tumor classification and to identify an entity with potential aggressive behavior. PMID- 30001242 TI - Dysplastic Lipoma: A Distinctive Atypical Lipomatous Neoplasm With Anisocytosis, Focal Nuclear Atypia, p53 Overexpression, and a Lack of MDM2 Gene Amplification by FISH; A Report of 66 Cases Demonstrating Occasional Multifocality and a Rare Association With Retinoblastoma. AB - In our routine and consultative pathology practices, we have repeatedly encountered an unusual subcutaneous fatty tumor with notable anisocytosis, single cell fat necrosis, and patchy, often mild, adipocytic nuclear atypia. Because of the focal atypia, consultative cases have most often been received with concern for a diagnosis of atypical lipomatous tumor. Similar tumors have been described in small series under the designations "subcutaneous minimally atypical lipomatous tumors" and "anisometric cell lipoma." Sixty-six cases of this tumor type were collected and reviewed. Immunohistochemistry for p53, MDM2, CDK4, Retinoblastoma 1 (RB1) protein, CD34, S100, and CD163 was performed. Cases were tested for MDM2 gene amplification and RB1 gene deletion with fluorescence in situ hybridization (FISH) and for TP53 mutations by Sanger sequencing. Next generation sequencing analysis using a panel of 271 cancer-related genes, including TP53, RB1, and MDM2, was also carried out. Our patient cohort included 57 male patients, 8 female patients, and 1 patient of unstated sex, who ranged in age from 22 to 87 years (mean: 51.2 y). All tumors were subcutaneous, with most examples occurring on the upper back, shoulders, or posterior neck (86.4%). Ten patients had multiple (2 to 5) lipomatous tumors, and the histology was confirmed to be similar in the different sites in 4 of them, including 1 patient who had a retinoblastoma diagnosed at age 1. The tumors were generally well circumscribed. At low magnification, there was notable adipocytic size variation with single cell fat necrosis in the background associated with reactive histiocytes. Adipocytic nuclear atypia was typically patchy and characterized by chromatin coarsening, nuclear enlargement, and focal binucleation or multinucleation. Focal Lochkern change was frequent. In most instances, the degree of atypia was judged to be mild, but in 3 instances, it was more pronounced. Spindle cells were sparse or absent, and when present, cytologically bland. Thick ropy collagen bundles were absent. In all cases, p53 immunoexpression was noted (range: 2% to 20% of adipocytic nuclei), characteristically highlighting the most atypical cells. Twenty of 50 cases had MDM2 immunoreactivity, usually in <1% of the neoplastic cells, but in 4 cases, up to 10% of the cells were positive. Of 32 cases tested, 22 showed a near total loss of RB1 immunoexpression, and the remainder showed partial loss. Three of 13 cases showed RB1 gene deletion in >45% of the cells by FISH (our threshold value for reporting a positive result) with an additional 3 cases being very close to the required cutoff value. MDM2 gene amplification was absent in all 60 cases tested, including those with the greatest MDM2 immunoexpression and most pronounced atypia. All 5 tested cases showed no TP53 mutation with Sanger sequencing. Because of material quality issues, next generation sequencing analysis could be performed in only 3 cases, and this did not reveal any recurrent mutations. All tumors were managed by simple local excision. Follow-up was available for 47 patients (range: 1 to 192 mo; mean: 27 mo) and revealed 2 local recurrences and no metastases. Dysplastic lipoma is a distinctive atypical fatty tumor variant that has p53 overexpression and RB1 gene abnormalities and lacks MDM2 gene amplification by FISH. These tumors have a strong male predominance and a notable tendency to involve the subcutaneous tissue of the shoulders, upper back and posterior neck. Multifocality is frequent (18.9% of patients with follow-up information), and there is a rare association with retinoblastoma. This tumor warrants separation from ordinary lipoma with fat necrosis, fat-rich spindle cell lipoma and the conventional form of atypical lipomatous tumor that features MDM2 gene amplification. PMID- 30001243 TI - Adverse fetal and infant outcomes among HIV-infected women who received either nonnucleoside reverse transcriptase inhibitor-based or protease inhibitor-based antiretroviral therapy for prevention of mother-to-child transmission. AB - BACKGROUND: For HIV-infected pregnant and breastfeeding women, antiretroviral therapy (ART) is known to reduce the mother's risk of passing the infection to her child. However, concerns remain about possible associations between various components of different ART regimens and adverse fetal and infant outcomes. As part of a clinical trial in western Kenya for the prevention of mother-to-child transmission (PMTCT) of HIV, pregnant women received one of two different ART regimens. METHODS: The original PMTCT study conducted in Kenya enrolled 522 HIV infected, ART-naive pregnant women. These women were assigned to receive an ART regimen that included either nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), or nelfinavir, a protease inhibitor. This substudy involves 384 women from the original study who had baseline CD4 cell counts at least 250 cells/MUl, and compares the risks of adverse fetal and infant outcomes between the two ART regimens. RESULTS: There were 386 live births (including multiples) and 7 (1.8%) stillbirths. Among live births, there were 67 preterm deliveries, 37 low-birth weight infants, and 14 infant deaths by 6 months. There were no statistically significant differences between the two ART regimens for any of the reported adverse outcomes. CONCLUSION: Although these data do not show significant differences between the NNRTI-based or protease inhibitor-based regimens in serious adverse fetal and infant outcomes, more studies need to be done and careful vigilance is needed to ensure infant safety. PMID- 30001245 TI - Impact of HIV on human papilloma virus-mediated cervical disease progression. PMID- 30001244 TI - Pregnancy outcomes and infant growth among babies with in-utero exposure to tenofovir-based preexposure prophylaxis for HIV prevention. AB - BACKGROUND: Global guidelines recommend preexposure prophylaxis (PrEP) use by women at risk for HIV, including during pregnancy, a period with heightened HIV risk. However, data to support safety of PrEP use during pregnancy are limited, particularly from women using PrEP throughout pregnancy. METHODS: In an open label delivery study of PrEP integrated with ART for high-risk HIV serodiscordant couples in Kenya and Uganda (the Partners Demonstration Project), women who became pregnant while using PrEP were offered the option to continue PrEP throughout pregnancy. We compared pregnancy outcomes and 1-year infant growth from pregnancies with exposure to PrEP throughout pregnancy to those without any exposure, with data from the placebo arm of a prior efficacy trial of PrEP conducted in the same setting. RESULTS: Outcomes from 30 women who elected to continue PrEP throughout pregnancy were compared with those from 96 pregnancies among PrEP-unexposed women. There were small nonsignificant decreases in the frequency of pregnancy loss [16.7% PrEP-exposed versus 23.5% PrEP-unexposed, adjusted odds ratio (aOR) = 0.59, P = 0.4] and preterm delivery [0 versus 7.7%, (aOR) = 0.54, exact P = 0.6]. No congenital anomalies occurred among PrEP-exposed infants. PrEP-exposed infants had slightly lower adjusted mean z-scores for length (-1.73 versus -0.79, P = 0.05) and head circumference (0.24 versus 1.07, P = 0.04) 1 month after birth but were comparable to PrEP-unexposed infants in these measurements 1 year after birth. CONCLUSION: This first evaluation among women using PrEP throughout pregnancy indicates no greater frequency of adverse pregnancy outcomes or restricted infant growth; these findings support recommendations permitting PrEP use during pregnancy. PMID- 30001246 TI - Severe cholestatic hepatitis related to abacavir/lamivudine/dolutegravir antiretroviral treatment in a HIV-1 infected subject. PMID- 30001247 TI - Differences in antiretroviral regimens do not impact safety or level of latency reversal in persons receiving romidepsin. PMID- 30001248 TI - Sexual Dysfunctions Induced by Pregabalin. AB - OBJECTIVES: Pregabalin (PGB) is a gabapentinoid (ie, GABA analog), which has been Food and Drug Administration-approved for treatment of partial epilepsy in adults and neuropathic pain. It also has off-label uses for the treatment of generalized anxiety disorders, fibromyalgia, and tension headache and prevention of migraine. Few cases were reported with sexual dysfunctions (SDs) as adverse effects of PGB and gabapentin, and the majority were dose related (>=900 mg/d for gabapentin). This study aimed to determine the frequency and types of SDs induced by PGB and the temporal relation to its use. METHODS: We presented case series of patients (n = 75) treated with PGB for different indications (sciatica, atypical facial pain, chronic tension headache, transformed migraine, fibromyalgia, and generalized anxiety disorder and developed different aspects of SDs). RESULTS AND CONCLUSIONS: In this case series, SDs were noticed with PGB in 41.33% (n = 31) (men, 13 [50%]; women, 18 [36.73%]), which included erectile dysfunction (n = 16, 51.61%), anorgasmia (n = 10, 32.26%), and loss of libido (n = 11, 35.48%). Sexual dysfunctions occurred within weeks after the use of PGB and were not dose related. They occurred with low therapeutic PGB doses (50-100 mg/d). Discontinuation of PGB resulted in improvement of SDs within weeks. To conclude, SDs are not infrequent adverse effects of PGB therapy. Pregabalin can induce erectile dysfunction, loss of libido, and anorgasmia. Sexual dysfunctions induced by PGB are not dose related. It is important for the clinician to acknowledge and encourage discussion regarding sexual function with patients and inquire about the impact of PGB on sexual function. PMID- 30001249 TI - Successful Intrathecal Baclofen Therapy for Intractable Paroxysmal Sympathetic Hyperactivity in Patient with Pontine Hemorrhage: A case report. AB - Paroxysmal sympathetic hyperactivity (PSH) is characterized by increased activity of the sympathetic nervous system. Although several treatments have been proposed for PSH, their efficacies are uncertain. We report a case of a patient with intractable PSH after pontine hemorrhage who was treated with intrathecal baclofen (ITB). A 61-year-old man was diagnosed with pontine hemorrhage expanding to the bilateral midbrain. Beginning 2 weeks after onset, he developed paroxysmal hyperthermia, tachycardia, tachypnea, hypertension, and generalized dystonic movements. Several medications were administered to the patient, including fentanyl patch, dantrolene, gabapentin, and beta blockers. Nevertheless, PSH episodes continued to occur more than twice per day. Seven months after onset, we performed a trial of ITB injection, which led to reduced severity and frequency of PSH. Therefore, the ITB therapy was implanted. Continuous ITB was initiated at a rate of 100 MUg/d, which was gradually increased up to 200 MUg/d. Oral medications were tapered off. No PSH episode occurred for 4 weeks. Our findings suggest that ITB therapy may be used to manage intractable PSH. Intrathecal baclofen may inhibit postsynaptic activity and suppress sympathetic activity via the stimulation of gamma-aminobutyric acid B receptors the brain. PMID- 30001250 TI - A New Data Resource to Examine Meals on Wheels Clients' Health Care Utilization and Costs. AB - BACKGROUND: Access to social services (eg, nutrition) can impact older adults' health care utilization and health outcomes. However, data documenting the relationship between receiving services and objective measures of health care utilization remain limited. OBJECTIVES: To link Meals on Wheels (MOW) program data to Medicare claims to enable examination of clients' health and health care utilization and to highlight the utility of this linked dataset. RESEARCH DESIGN: Using probabilistic linking techniques, we matched MOW client data to Medicare enrollment and claims data. Descriptive information is presented on clients' health and health care utilization before and after receiving services from MOW. SUBJECTS: In total, 29,501 clients were from 13 MOW programs. MEASURES: Clients' demographics, chronic conditions, and hospitalization, emergency department (ED), and nursing home (NH) utilization rates. RESULTS: We obtained a one-to-one link for 25,279 clients. Among these, 14,019 were Medicare fee-for-service (FFS) beneficiaries and met inclusion criteria for additional analyses. MOW clients had high rates of chronic conditions (eg, almost 90% of FFS clients were diagnosed with hypertension, compared with 63% of FFS beneficiaries in their communities). In the 6 months before receiving MOW services, 31.6% of clients were hospitalized, 24.9% were admitted to the ED and 13% received care in a NH. In the 6 months after receiving meals, 24.2% were hospitalized, 19.3% were admitted to the ED, and 9.5% received care in a NH. CONCLUSIONS: Linking MOW data to Medicare claims has the potential to shed additional light on the relationships among social services, health status, health care use, and benefits to clients' well being. PMID- 30001251 TI - Validation of the Combined Comorbidity Index of Charlson and Elixhauser to Predict 30-Day Mortality Across ICD-9 and ICD-10. PMID- 30001252 TI - Principles for Developing Innovative HIV Digital Health Interventions: The Case of Positive Health Check. PMID- 30001253 TI - Clinical and Health System Determinants of Venous Thromboembolism Event Rates After Hip Arthroplasty: An International Comparison. AB - BACKGROUND: Routinely collected hospital data provide increasing opportunities to assess the performance of health care systems. Several factors may, however, influence performance measures and their interpretation between countries. OBJECTIVE: We compared the occurrence of in-hospital venous thromboembolism (VTE) in patients undergoing hip replacement across 5 countries and explored factors that could explain differences across these countries. METHODS: We performed cross-sectional studies independently in 5 countries: Canada; France; New Zealand; the state of California; and Switzerland. We first calculated the proportion of hospital inpatients with at least one deep vein thrombosis (DVT) or pulmonary embolism by using numerator codes from the corresponding Patient Safety Indicator. We then compared estimates from each country against a reference value (benchmark) that displayed the baseline risk of VTE in such patients. Finally, we explored length of stay, number of secondary diagnoses coded, and systematic use of ultrasound to detect DVT as potential factors that could explain between country differences. RESULTS: The rates of VTE were 0.16% in Canada, 1.41% in France, 0.84% in New Zealand, 0.66% in California, and 0.37% in Switzerland, while the benchmark was 0.58% (95% confidence interval, 0.35-0.81). Factors that could partially explain differences in VTE rates between countries were hospital length of stay, number of secondary diagnoses coded, and proportion of patients who received lower limb ultrasound to screen for DVT systematically before hospital discharge. An exploration of the French data showed that the systematic use of ultrasound may be associated with over detection of DVT but not pulmonary embolism. CONCLUSIONS: In-hospital VTE rates after arthroplasty vary widely across countries, and a combination of clinical, data-related, and health system factors explain some of the variations in VTE rates across countries. PMID- 30001254 TI - A Cost Analysis of Icon Reusable Underwear Versus Disposable Pads for Mild to Moderate Urinary Incontinence. AB - OBJECTIVE: The objective of this study was to perform a cost analysis assessing the economic feasibility of reusable underwear as alternative for disposable pads for women with mild to moderate urinary incontinence. METHODS: A consumer perspective cost analysis was performed with the following assumptions: (1) consumers have mild to moderate urinary incontinence and use 2 pads per day (PPD); (2) consumers have a 2-week supply of underwear; (3) there is no difference in laundering cost between 2 incontinence options; (4) there is no difference in use of labor/other accessories of care; (5) there is no difference in skin complaints/associated cost; (6) cost of products are nonfluctuant with time; and (7) all incontinence products were purchased online. Sensitivity analyses were performed varying the longevity of underwear, price of regular underwear, price of pads, pads used per day, and shipping and handling. RESULTS: The total cost of disposable pads with regular underwear was US $392.40, whereas the cost of Icon underwear was US $380.80 over the course of 2 years. Icon costs less than using regular underwear with disposable pads as long as the cost of the regular underwear is at least US $2.17. Icon is economically inferior if the cost per pad is US $0.15 when using 3 PPD or if the cost per pad is US $0.24 when using less than 2 PPD. CONCLUSIONS: Reusable incontinence underwear can be an economically feasible alternative to disposable pads for light to moderate urinary incontinence after 2 years of use assuming underwear has a 2-year longevity and the consumer is using 2 PPD with regular underwear. PMID- 30001255 TI - A Brief Self-Directed Intervention to Reduce Office Employees' Sedentary Behavior in a Flexible Workplace. AB - OBJECTIVE: The aim of the study was to assess changes in employees' sedentary behavior after a brief self-directed intervention in a flexible workplace. METHODS: A total of 30 employees (69% female; 39.5 +/- 9 years) completed an online questionnaire before and after a 6-week intervention. The intervention comprised one group-based action planning session, using a smart activity tracker for self-monitoring, weekly email reminders, and a healthy living seminar. RESULTS: Total self-reported sitting time (including occupational and nonoccupational sitting) decreased nonsignificantly on days when working at the office (MDelta = -56 min/d, 95% confidence interval [CI], -128.5 to 17.0) and increased nonsignificantly when working at home (MDelta = 20.5 min/d, 95% CI, 64.5 to 105.5). The program had high acceptability in this participant group. CONCLUSIONS: Brief self-directed interventions using activity tracker devices show promise and may be highly acceptable in a flexible workplace. Additional strategies may be needed to create change in sedentary behavior. PMID- 30001256 TI - Initial Assessment of a Prototype 3D Cone-Beam Computed Tomography System for Imaging of the Lumbar Spine, Evaluating Human Cadaveric Specimens in the Upright Position. AB - OBJECTIVES: The aims of this study were to assess feasibility, image quality, and radiation dose and to estimate the optimal dose protocol for the lumbar spine of cadaveric specimens with different body mass indices (BMIs) in the upright position using a prototype 3-dimensional cone-beam computed tomography (CT) software implemented on a robotic x-ray system and compare with CT. MATERIALS AND METHODS: The lumbar spine of 5 formalin-fixed human cadaveric specimens (BMI, 22 35 kg/m) was prospectively assessed in the upright position using prototype software for 3-dimensional tomography implemented on a robotic x-ray system. Specimens were scanned with varying kilovolt values (70, 81, 90, 100, 109, 121 kV) and thereafter with 80 kV (BMI <=30 kg/m) and 121 kV (BMI >30 kg/m) and varying dose levels (DLs; 0.278, 0.435, 0.548, 0.696, 0.87, 1.09). Computed tomography data were acquired with a standard clinical protocol. Two independent readers rated visibility of the cortex, endplates, facet joints, trabeculae, neuroforamina, posterior alignment, and spinal canal as well as nerve roots. Radiation dose was measured with a cylindrical CTDI phantom. Descriptive statistics and analysis of variance were used (P < 0.05). RESULTS: Average intraclass correlation was excellent (0.94). The lowest technically possible kilovolt and the highest technically possible DL yielded the best image quality. In specimens with a BMI of 30 kg/m or less, depiction of all structures was good and comparable to CT, except for nerve roots. For specimens with a BMI greater than 30 kg/m, image quality was limited. CONCLUSIONS: Three-dimensional cone-beam CT of the lumbar spine in cadaveric specimens in the upright position is feasible. An optimal dose protocol was estimated. Depiction of osseous structures is comparable to CT in specimens with BMI of 30 kg/m or less. Image quality is limited for soft tissue structures and specimens with BMI greater than 30 kg/m. PMID- 30001257 TI - Experience With the Use of Rituximab for the Treatment of Rheumatoid Arthritis in a Tertiary Hospital in Spain: RITAR Study. AB - BACKGROUND/OBJECTIVE: There is evidence supporting that there are no relevant clinical differences between dosing rituximab 1000 mg or 2000 mg per cycle in rheumatoid arthritis (RA) patients in clinical trials, and low-dose cycles seem to have a better safety profile. Our objective was to describe the pattern of use of rituximab in real-life practice conditions. METHODS: Rituximab for RA in clinical practice (RITAR) study is a retrospective cohort study from 2005 to 2015. Eligibility criteria were RA adults treated with rituximab for active articular disease. Response duration was the main outcome defined as months elapsed from the date of rituximab first infusion to the date of flare. A multivariable analysis was performed to determine the variables associated with response duration. RESULTS: A total of 114 patients and 409 cycles were described, 93.0% seropositive and 80.7% women. Rituximab was mainly used as second-line biological therapy. On demand retreatment was used in 94.6% of cases versus fixed 6 months retreatment in 5.4%. Median response duration to on demand rituximab cycles was 10 months (interquartile range, 7-13). Multivariable analysis showed that age older than 65 years, number of rituximab cycles, seropositivity, and first- or second-line therapy were associated with longer response duration. The dose administered at each cycle was not significantly associated with response duration. CONCLUSIONS: Our experience suggests that 1000 mg rituximab single infusion on demand is a reasonable schedule for long-term treatment of those patients with good response after the first cycles, especially in seropositive patients and when it is applied as a first- or second-line biological therapy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30001258 TI - A Pilot Randomized Controlled Double-Blind Trial of High- Versus Low-Dose Weekly Folic Acid in People With Rheumatoid Arthritis Receiving Methotrexate. AB - BACKGROUND/OBJECTIVE: The aim of this study was to determine whether reducing the dose of supplemental folic acid used in conjunction with methotrexate (MTX) therapy in people with active rheumatoid arthritis (RA) improved disease control and/or increased MTX-related adverse effects. METHODS: A randomized double-blind randomized controlled trial comparing 5 mg/wk and 0.8 mg/wk folic acid was undertaken. Rheumatoid arthritis patients on MTX for 3 months or more at a stable dose for 1 month or more were recruited. All participants had DAS28 of 3.2 or greater or required a change in therapy determined by the treating clinician. Disease activity, full blood count, liver function tests, red blood cell (RBC) folate, and RBC MTX polyglutamates were assessed at weeks 0, 4, 8, 16, and 24 along with reports of adverse events. RESULTS: Forty participants were recruited. The mean (SD) change in RBC folate between week 0 and 24 was +87.9 (57.4) nmol/L in the high-dose group and -113.3 (65.7) nmol/L in the low-dose group (P < 0.05). There was no significant difference in the change in DAS28 between the high- and low-dose groups at 24 weeks (-0.13 [95% confidence interval, -0.69 to 0.43] vs 0.25 [-0.87 to 0.37], respectively [P = 0.78]). There was no significant difference in MTX-related adverse effects between the 2 groups. CONCLUSIONS: A reduction in RBC folate secondary to reduction in folic acid dose was not associated with a change in RA disease activity or MTX-related adverse effects. The prevention of MTX-related adverse effects remains the primary reason for coprescribing folic acid with MTX. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR12610000739011). PMID- 30001259 TI - Strategies to Recruit the Next Generation of Nursing Leadership Talent. AB - OBJECTIVE: The purpose of this study was to explore how generational differences contribute to challenges in recruiting the next generation of talent into nursing administration roles. BACKGROUND: The current workforce is aging. Nursing administrative roles, which for the purpose of this study are defined as nurse managers, are increasingly difficult to fill with leaders from upcoming Generations X and Y. METHODS: A descriptive, nonexperimental study was undertaken using a convenience sample. An electronic survey was distributed to explore the impact a set of interventions would have on recruiting into nursing administration roles. Then differences between generations were analyzed. RESULTS: Respondents indicated 45% of the interventions have a moderate to high impact on their consideration for a position in administration. Statistical significance between generations was identified on 4 interventions related to work-life harmony. CONCLUSIONS: Fiscally conservative interventions exist to assist hospital administrators with succession planning among nurse managers. When recruiting Generations X and Y candidates, interventions supporting work life harmony should be emphasized. PMID- 30001260 TI - Description and Factors Associated With Missed Nursing Care in an Acute Care Community Hospital. AB - OBJECTIVE: The aims of this study are to describe and evaluate the factors associated with missed nursing care in an acute care community hospital. BACKGROUND: Despite RNs' accountability for high-quality patient care in hospitals, missed nursing care is widespread, jeopardizing patient safety and health system costs. Better understanding of the factors associated with missed nursing care may provide nurse leaders with opportunities for improvement. METHODS: Using a cross-sectional correlational study design, 138 RNs were randomly sampled during May-June 2017. RESULTS: The extent of missed nursing care is consistent with other studies, was greater on medical-surgical and telemetry units compared with specialty units, and was negatively associated with staffing/resources, satisfaction with current position, and collegial nurse physician relationships. CONCLUSION: Findings suggest urgent nurse leader action and future research. PMID- 30001261 TI - Patient Trust of the Muslim Nurse. AB - OBJECTIVE: This quantitative study examined patients' trust of a nurse who represents the Muslim faith by wearing the hijab. BACKGROUND: Presumptions about nurse trustworthiness based on religious affiliation may impede the effectiveness of the nurse-patient relationship and diminish the ability of nursing care to promote patient's feelings of well-being. METHODS: Hospitalized participants were randomly given a picture of a nurse either wearing the hijab or not. They completed a survey to measure their level of trust considering the nurse in the picture. RESULTS: No difference was found in trust of the nurse between groups or in trust analyzed for between-group characteristics. In the hijab picture group, the older the patient, the lower the trust of the nurse. CONCLUSIONS: The results may reflect the general trust of nurses as an ethical and honest professional group. A high level of general trust may transcend stereotypes toward a Muslim nurse. PMID- 30001262 TI - Subjective Versus Objective Measures of Medication Adherence in Adolescents/Young Adults with Attention-Deficit Hyperactivity Disorder. AB - OBJECTIVE: To examine the frequency of medication nonadherence using both objective and subjective data and to compare the differences between these measures in adolescents and young adults (AYAs) with attention-deficit hyperactivity disorder (ADHD). METHOD: Fifty-four participants enrolled. Frequency (mean percent of prescribed doses not taken) of nonadherence was measured using subjective (visual analog scale) and objective (pill count and electronic monitoring) methods. Differences between measures were compared using t tests and analysis of variances. RESULTS: Objective measures showed that participants missed 40% to 43% of their prescribed doses. Contrastingly, subjective measures indicated that participants missed 25% of their prescribed doses. Frequency of nonadherence was significantly higher when relying on objective measures rather than on subjective measures (t[46] = -4.51, p < 0.01 for pill counts, and t[47] = -4.81, p < 0.01 for electronic monitoring). CONCLUSION: Nonadherence is high in AYAs with ADHD. These individuals tend to overestimate their adherence when self-reporting. Physicians should exercise caution when prescribing based on patient report of adherence and use objective measures when possible. PMID- 30001263 TI - Primary Modified Predescemetic Deep Anterior Lamellar Keratoplasty in Acute Corneal Hydrops. AB - PURPOSE: To report primary treatment of acute corneal hydrops (CH) with a modified technique of predescemetic deep anterior lamellar keratoplasty (pdDALK). METHODS: This prospective interventional case series included 9 eyes with acute CH that underwent pdDALK as primary treatment. Technique modifications included a bevel-up needle, creating tissue emphysema as a guide for dissection, using small aliquots of air directed away from break, manual deeper dissection using a blunt dissector, centripetal dissection leaving the area of Descemet membrane (DM) break for last, retention of minimal stroma above DM tear, and tamponade of DM tear with air in the anterior chamber. In eyes with extensive area of edema or thin residual stroma, an inked trephine mark was manually deepened with a sharp crescent blade, followed by other modifications. RESULTS: All patients underwent uneventful surgery without enlargement of DM tear. The average follow-up period was 18 +/- 13 months. All showed a clear, nonedematous graft with an area of DM defect seen and overlying cornea continuing to remain clear at final postoperative follow-up. ASOCT showed 90.8 +/- 32 MUm residual predescemetic host stroma on either side of the defect. CDVA improved from 0.002 +/- 0.005 preoperatively to 0.35 +/- 0.1 by an average of 2.3 +/- 0.8 weeks and to 0.52 +/- 0.13 at final postoperative follow-up. CONCLUSIONS: Primary pdDALK was possible as single-stage definitive treatment with early visual rehabilitation and avoidance of scarring in our case series. Simultaneous correction of pathology by closure of DM break, anatomical correction of ectasia and thinning, optical correction by improved corneal topography and by regaining corneal structure and transparency, and retention of host DM and endothelium are advantages. Advanced DALK surgeons may use this technique. PMID- 30001264 TI - Integrated texture parameter of 18F-FDG PET may be a stratification factor for the survival of nonoperative patients with locally advanced non-small-cell lung cancer. AB - OBJECTIVE: This study explored whether integrated texture parameter (ITP) of the fluorine-18-fluorodeoxyglucose PET (F-FDG PET) is a stratification factor for the survival of nonoperative patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Thirty-five patients with LA-NSCLC treated with chemoradiotherapy or radiotherapy were included in the retrospective study. Eight principal components (PCs) were extracted from 72 F-FDG PET texture features (TFs) using PC analysis. The survival rates between PC subgroups (group by median value) were compared using Kaplan-Meier method. Seventy-two factor loadings for PC7 were evaluated using t-test. Standardized values of the TFs with significant factor loading were multiplied by the corresponding PC7 component coefficient, and the products were added together to obtain ITP. The survival rates between ITP subgroups (group by median value) were compared using Kaplan Meier method. Patient characteristics between ITP subgroups were compared using chi -test, Mann-Whitney U-test, or t-test. RESULTS: The median follow-up time was 20.7 months. The median overall survival (OS) and progression-free survival (PFS) were 32.5 and 14.4 months, respectively. The patients with high PC7 value had lesser OS (P=0.006) and PFS (P=0.010) than those with lower value. Factor loadings of standardized uptake value kurtosis, run percentage, and zone percentage were significant for PC7 (P<0.01). The patients with high ITP value had lesser OS (P=0.001) and PFS (P=0.002) than those with lower value. There were no significant differences in patient characteristics between ITP subgroups (P>0.2). CONCLUSION: This study demonstrated that ITP might be a stratification factor for the survival of nonoperative patients with LA-NSCLC. PMID- 30001266 TI - Cognitive Function and Falls in Older Adults With Type 2 Diabetes Mellitus. AB - BACKGROUND AND PURPOSE: Cognitive impairments have been reported in older adults with type 2 diabetes (T2DM), which subsequently increases the risk of falling. However, the relationship between specific cognitive processes and falls has not been reported. Therefore, the purpose of this study was to describe the contribution of cognitive function on falls in older adults with T2DM and to describe any differences by age group. METHODS: A cross-sectional analysis was conducted of 1171 older adult respondents with T2DM from the 2010 wave of the Health and Retirement Study. Group assignment was based on age: younger group 65 to 74 years (N = 662) or older group (N = 509). Groupwise comparisons on demographic, cognitive, and mobility variables were completed, followed by logistic regression analyses to examine the contribution of specific cognitive processes on falls for the sample and then by group after controlling for demographic and mobility-related variables. RESULTS: Significant differences existed between groups in demographic, cognitive, and mobility variables and falls. Executive function was consistently identified as a predictor of falls in the whole sample (odds ratio [OR] = 1.06; 95% CI, 1.02-1.09) and within groups: younger group (OR = 1.06; 95% CI, 1.01-1.11) and older group (OR = 1.07; 95% CI, 1.01-1.13), while delayed recall was a much stronger predictor of falls in the older group (OR = 1.28; 95% CI, 1.03-1.59). Orientation and immediate recall were not predictors of falls. CONCLUSIONS: Executive function and delayed recall, 2 cognitive domains reported to influence glycemic control and disease management in those with T2DM, are associated with an increased fall risk and should be included in the assessment of fall risk in this population. PMID- 30001265 TI - Preoperative omental metastasis-related maximum standardized fluorine-18 fluorodeoxyglucose uptake value can predict chemosensitivity and recurrence in advanced high-grade serous ovarian cancer patients. AB - OBJECTIVE: The aim of this study was to explore the clinical and prognostic implication of preoperative fluorine-18-fluorodeoxyglucose uptake value of omental metastasis-related in advanced high-grade serous ovarian cancer patients (HGSC). PATIENTS AND METHODS: We retrospectively investigated HGSC patients with omental metastasis (International Federation of Gynecology and Obstetrics stage IIIB-IV) who underwent PET/CT before primary surgery in our hospital between January 2010 and January 2016. All patients were confirmed omental metastasis by postoperative pathology. None of these patients received neoadjuvant chemotherapy. PET/CT parameters, including maximum standardized uptake value of primary ovary tumor (SUVp), omental metastasis (SUVo), and omental metastasis-to primary tumor (SUVo/p) were measured. The relationships between PET/CT parameters and clinical characteristics were analyzed by t-test. Kaplan-Meier methods and log-rank tests were used to analyze progression-free survival (PFS) in univariate analysis. For multivariate analysis, COX regression analysis was used to assess the prognostic predictive value of PET/CT-derived variables. RESULTS: Totally 81 advanced HGSC patients with omental metastasis were enrolled in our study, and 49 (60.5%) patients experienced recurrence and disease progression. The median (range) follow-up time was 18.5 (7-72) months. Older patients showed higher level of SUVo/p (P=0.006). Chemosensitive patients had lower levels of SUVo (P=0.009) and SUVo/p (P<0.001) than those chemoresistant ones. In univariate analysis, patients with better PFS were associated with lower SUVo (P<0.001) and SUVo/p (P<0.001). Multivariate analysis found only SUVo/p was an independent factor for PFS (P=0.006). CONCLUSION: Preoperative SUVo/p measured by fluorine-18 fluorodeoxyglucose PET/CT appeared to be an independent predictive factor for recurrence in advanced HGSC patients. Chemosensitive patients had lower omentum related SUV values than those chemoresistant ones. PMID- 30001267 TI - Butyrate, a Gut Bacterial Metabolite, Lowers Intraocular Pressure in Normotensive But Not in Hypertensive Rats. AB - BACKGROUND: Accumulating evidence supports a role of gut bacterial metabolites in arterial blood pressure (BP) regulation. Since the mechanisms controlling intraocular pressure (IOP) and BP overlap, we hypothesized that butyrate, a bacterial metabolite, might affect both IOP and BP. METHODS: IOP, BP, and heart rate (HR) were measured at baseline and after the intraperitoneal administration of either butyrate or a vehicle (0.9% NaCl) in anaesthetized normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). RESULTS: At baseline, there was no significant difference between WKY and SHR in IOP and HR, whereas BP was significantly higher in SHR. In WKY administration of butyrate produced a significant decrease in IOP and BP, which lasted throughout the experiment. IOP response to butyrate was similar between sham WKY and WKY, which had undergone unilateral superior cervical ganglion excision. In contrast, in SHR butyrate treatment did not affect IOP and produced only a transient decrease in BP. WKY showed no significant changes in HR whereas SHR exhibited an increase in HR. CONCLUSIONS: Butyrate, a gut bacterial metabolite, lowers IOP in normotensive but not in hypertensive rats. The effect is independent of ocular sympathetic innervation. Given that changes in BP followed a different pattern than changes in IOP it seems that butyrate lowers IOP independently of BP changes. PMID- 30001270 TI - Performance Fatigability Is Not Regulated to A Peripheral Critical Threshold. AB - The critical threshold hypothesis proposes that performance fatigability during high-intensity exercise is tightly regulated by negative-feedback signals from the active muscles. We propose that performance fatigability is simply dependent on the exercise mode and intensity; the consequent adjustments, in skeletal muscle and the other physiological systems that support exercise, interact to modulate fatigue and determine exercise tolerance. PMID- 30001268 TI - Quantification of Changes in Visual Function During Disease Development in a Mouse Model of Pigmentary Glaucoma. AB - PURPOSE: We investigated the relationship between visual parameters that are commonly affected during glaucomatous disease progression with functional measures of retina physiology using electroretinography and behavioral measures of visual function in a mouse model of glaucoma. Electroretinogram components measuring retinal ganglion cell (RGC) responses were determined using the non invasive Ganzfeld flash electroretinography (fERG) to assess RGC loss in a mouse model of glaucoma. METHODS: Intraocular pressure (IOP), behaviorally assessed measures of visual function, namely visual acuity and contrast sensitivity as well as fERG responses were recorded in 4- and 11-month-old male DBA/2 mice. Scotopic threshold response (STR) and photopic negative response components as well as oscillatory potentials (OPs) were isolated from fERG responses and correlated with IOP, optomotor reflex measurements, and RGC counts. RESULTS: The 11-month-old DBA/2 mice had significantly elevated IOP, reduced visual performance, as assessed behaviorally, significant RGC loss, deficits in standardized fERG responses, reduced STRs, and differences in OP amplitudes and latencies, when compared with 4-month-old mice of the same strain. STRs and OPs correlated with some visual and physiological parameters. In addition, elevated IOP and RGC loss correlated positively with measures of visual function, specifically with surrogate measures of RGC function derived from fERG. CONCLUSIONS: Our data suggest that RGC function as well as interactions of RGCs with other retinal cell types is impaired during glaucoma. In addition, a later OP wavelet denoted as OP4 in this study was identified as a very reproducible indicator of loss of visual function in the glaucoma mouse model. PMID- 30001269 TI - Protective Effects of Exercise on Cognition and Brain Health in Older Adults. AB - Accelerated trajectories of cognitive decline in older adults may increase the risk of developing Alzheimer disease and related dementias (ADRD). Physical activity has potential modifying effects on these changes that could prevent or delay ADRD. This review explores the hypothesis that multiple, mutually complimentary, and interacting factors explain the positive association between exercise and the optimization of cognition in older adults. PMID- 30001271 TI - Modeling Overuse Injuries in Sport as a Mechanical Fatigue Phenomenon. AB - This paper postulates that overuse injury in sport is a biomechanical event resulting from the mechanical fatigue of biological tissue. A theoretical foundation and operational framework necessary to model overuse injury as a mechanical fatigue phenomenon is introduced. Adopting this framework may provide a more mechanistic understanding of overuse injury and inform training and preventive strategies to reduce their occurrence. PMID- 30001273 TI - Resistance Exercise's Ability to Reverse Cancer-Induced Anabolic Resistance. AB - Skeletal muscle has the dynamic capability to modulate protein turnover in response to anabolic stimuli, such as feeding and contraction. We propose that anabolic resistance, the suppressed ability to induce protein synthesis, is central to cancer-induced muscle wasting. Furthermore, we propose that resistance exercise training has the potential to attenuate or treat cancer-induced anabolic resistance through improvements in oxidative metabolism. PMID- 30001272 TI - Modulation of Energy Expenditure by Estrogens and Exercise in Women. AB - Reducing estrogen in women results in decreases in energy expenditure, but the mechanism(s) remain largely unknown. We postulate that the loss of estrogens in women is associated with increased accumulation of bone marrow-derived adipocytes in white adipose tissue, decreased activity of brown adipose tissue, and reduced levels of physical activity. Regular exercise may counteract the effects of estrogen deficiency. PMID- 30001274 TI - The Renin-Angiotensin System and Skeletal Muscle. AB - The renin-angiotensin system (RAS) plays a key role in the control of blood pressure and fluid homeostasis. Emerging evidence also reveals that hyperactivity of the RAS contributes to skeletal muscle wasting. This review discusses the key role that the RAS plays in skeletal muscle wasting due to congestive heart failure, chronic kidney disease, and ventilator-induced diaphragmatic wasting. PMID- 30001277 TI - Ketamine and Electroconvulsive Therapy for Depression. PMID- 30001276 TI - Can Cerebral Near-infrared Spectroscopy Predict Cerebral Ischemic Events in Neurosurgical Patients? A Narrative Review of the Literature. AB - Cerebral near-infrared spectroscopy (NIRS) is considered a valuable noninvasive modality for cerebral oxygenation monitoring during cardiovascular surgery and cardiac arrest. We assessed the capability of cerebral NIRS to predict cerebral desaturation and the related neurological outcomes in neurosurgical patients. A literature search in different electronic medical databases was performed from inception to January 2018. A total of 286 citations were found and finally 48 studies were retrieved, only 7 of these were eligible and included for review. A meta-analysis was not feasible because of high heterogeneity of patients' groups, different NIRS techniques used in the studies and different outcome criteria selected. The qualitative assessment showed controversial data on the threshold value of cerebral near-infrared spectroscopy used for detecting cerebral ischemia in neurosurgical patients. The evidence on the selected studies is not strong enough, at the moment, to recommend cerebral NIRS as a mandatory monitor to detect cerebral deoxygenation able to predict the future neurological outcome in neurosurgical patients. Further studies are needed to validate a threshold value for cerebral ischemia and the relationship between NIRS-detected cerebral desaturation and clinical outcome in the neurosurgical population. PMID- 30001278 TI - Prioritization of Reimplantation in Previously Successful Cochlear Implantation Following Natural Device Failure. AB - INTRODUCTION: Cochlear reimplantation procedures account for approximately 5% of all implant cases and may be caused by internal device failure, skin flap complications, or an unexpected decline in auditory performance. This issue, in concert with changing demographics, expanded audiometric candidacy criteria, adult bilateral implantation, and implantation for unilateral hearing loss, all place escalating pressure on device availability and resource allocation in a publically funded health care system. OBJECTIVE: The predictable and problematic access to a scare medical resource requires rigor in establishing program priority and formal policy. We present a single cochlear implant center's working reflections and an attempt at a principled approach to rationing health care decisions. METHODS: Different approaches to health care rationing are examined and discussed. We describe a method of allocation that is currently employed by a large Canadian quaternary care center and ground this method in important principles of distributive justice as they apply to health care systems. RESULTS: We elect to recognize device failure as analogous to sudden sensorineural hearing loss, with the associated need to expedite reimplantation. We consider this an ethical approach grounded in the egalitarian principle of equality of opportunity within cohorts of patients. CONCLUSION: Porting the practice from sudden sensorineural hearing loss, the time-sensitive need for hearing restoration, and maximized communication outcomes, dictates prioritization for this patient population. The predicted evolution of health systems globally and the shape of future medical practice will be heavily influenced by both the macro and micro level resource-dependent decisions implant centers currently face. PMID- 30001279 TI - Unilateral Brainstem Herniation Into a Bulbous Internal Auditory Canal, With Elevated Intracranial Pressure, Profound Hearing Loss, and Facial Palsy: Serial Imaging Findings. PMID- 30001275 TI - Dietary Nitrate Enhances the Contractile Properties of Human Skeletal Muscle. AB - Dietary nitrate, a source of nitric oxide (NO), improves the contractile properties of human muscle. We present the hypothesis that this is due to nitrosylation of the ryanodine receptor and increased NO signaling via the soluble guanyl cyclase-cyclic guanosine monophosphate-protein kinase G pathway, which together increase the free intracellular Ca concentration along with the Ca sensitivity of the myofilaments themselves. PMID- 30001280 TI - Sudden Sensorineural Hearing Loss Predicts Ischemic Stroke: a Longitudinal Follow Up Study. AB - OBJECTIVES: To investigate the risk of stroke in SSNHL patients. STUDY DESIGN: A longitudinal follow-up cohort study. SETTING: The Korean National Health Insurance Service-National Sample Cohort from 2002 to 2013. PATIENTS: The 4,944 SSNHL participants were matched with 19,776 controls for age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia. The SSNHL subjects were diagnosed (International Classification of Disease [ICD]-10: H91.2), underwent an audiometry examination, and were treated with steroids. The history of hemorrhagic stroke, ischemic stroke, hypertension, diabetes, dyslipidemia, ischemic heart disease, and depression was investigated based on the ICD-10. MAIN OUTCOME MEASURES: The hazard ratios (HRs) for hemorrhagic and ischemic stroke were analyzed using a Cox proportional hazard model. Subgroup analyses were conducted according to age (< 50 vs. >= 50 yr old) and sex. RESULTS: Participants diagnosed with ischemic stroke included 4.2% of SSNHL subjects and 3.5% of control subjects (p = 0.013). The adjusted HR of SSNHL for ischemic stroke was 1.22 (95% confidence interval [95% CI] = 1.05 - 1.43, p = 0.012). The >= 50-year old male SSNHL subgroup showed 1.40 adjusted HRs for ischemic stroke (95% CI = 1.10 - 1.78, p = 0.006). The rate of hemorrhagic stroke was 0.7% for SSNHL and 0.6% for control subjects. SSNHL did not elevate the risk of hemorrhagic stroke (p = 0.310). CONCLUSION: SSNHL elevated the risk of ischemic stroke in the general population. Older males with SSNHL demonstrated a high risk for ischemic stroke; however, SSNHL did not increase the risk of hemorrhagic stroke. PMID- 30001281 TI - Assessing Cochlear Implant Performance in Older Adults Using a Single, Universal Outcome Measure Created With Imputation in HERMES. AB - OBJECTIVE: In the era of big data, it is critical to aggregate results across different institutions. This is a major challenge for cochlear implant (CI) research given multiple, incompatible outcome measures. We use a large, national CI database to develop a formula to convert between the two most common measures: Consonant-Nucleus-Consonant word (CNCw) and Arizona Biomedical (AzBio). We then use this tool to analyze hearing outcomes in older adults with a single, universal outcome measure. STUDY DESIGN: Analysis of a prospective, national cochlear implant database (HERMES). SETTING: Multicentered, 32 US private practice and academic medical centers. PATIENTS: CI subjects (n = 386, n = 430 ears; 10-102 years old; mean: 65). MAIN OUTCOME MEASURE(S): CNCw, AzBio. RESULTS: Univariable linear regression equations were generated relating CNCw and AzBio scores at each time-point. Correlation (R) was 0.71 (3 mo), 0.69 (6 mo), 0.63 (12 mo), and 0.56 (24 mo) (all p < 0.01). Using these equations, missing outcomes (CNCw, n = 83 or AZBio, n = 96) were imputed (calculated). The average absolute difference between observed and imputed CNCw (when both present) was 10.5% (95% CI = 9.8-11.3). On multivariable regression, age was not a significant predictor of CNCw (p = 0.38) after controlling for sex, hearing loss duration, use, and postoperative follow-up duration. CONCLUSIONS: We generated simple linear regression equations to calculate CNCw scores from AzBio, and vice versa, with good accuracy. This allowed one of the largest analyses of CI performance in older adults to date. We confirm that older age is not a significant predictor of performance when controlling for confounders. PMID- 30001282 TI - Fluorescent Detection of Merlin-deficient Schwann Cells and Primary Human Vestibular Schwannoma Cells Using Sodium Fluorescein. AB - HYPOTHESIS: Merlin-deficient Schwann cells (MD-SC) and primary human vestibular schwannoma (VS) cells exhibit selective uptake of sodium-fluorescein (SF), allowing for fluorescent detection and improved visualization of tumor cells, when compared with Schwann cells (SC). BACKGROUND: SF is a fluorescent compound used for fluorescence-guided resection of gliomas. The utility of SF for VS surgery has not been assessed. METHODS: Mouse MD-SCs and rat SCs were cultured on 96-well plates at different cell densities and treated with SF at several drug concentrations and durations. Relative fluorescence units (RFU) were measured using a fluorometer to determine optimal treatment parameters in vitro. Subsequently, a four-point Likert scale for fluorescence visualization of pelleted cells was created and validated. Blinded observers rated SF-treated primary human VS and SC cultures, which were developed from deidentified specimens obtained from live and cadaveric donors, respectively. RESULTS: In contrast to SCs that showed low levels of fluorescence, MD-SCs demonstrated dose dependent increases in RFUs when treated with incremental dosages of SF as well as longer treatment and fluorescent excitation times. In addition, RFUs were higher at greater MD-SC densities. The Likert scale for fluorescence visualization was validated using nine blinded observers and there were excellent inter- and intrarater reliabilities (intraclass coefficients of 0.989 and >0.858, respectively). Using the Likert scale, human VS treated with SF received higher scores than human SCs (p < 0.001). CONCLUSION: Mouse MD-SC and human VS cells demonstrate preferential uptake of SF when compared with normal primary SCs. Observers detected differences in fluorescence using the validated Likert scale. Further investigations into the utility of SF-guidance in VS surgery are warranted. PMID- 30001283 TI - Adenomatous Neuroendocrine Tumors of the Middle Ear: A Multi-institutional Investigation of 32 Cases and Development of a Staging System. AB - OBJECTIVE: To date, less than 150 cases of middle ear adenomatous neuroendocrine tumors (MEANTs) have been reported in the English literature. The objective of this study was to provide a contemporary analysis of these rare lesions and develop a consensus-driven staging system. STUDY DESIGN: Multi-institutional retrospective histopathologic, radiologic, and clinical review. SETTING: Six tertiary referral centers. PATIENTS: Thirty-two patients with pathologically confirmed MEANT. INTERVENTION: Surgical resection, adjuvant therapy. MAIN OUTCOME MEASURES: Clinical manifestations, outcomes, staging system. RESULTS: Patients commonly presented with progressive conductive or mixed hearing loss (90%), aural fullness (50%), and tonal tinnitus (46%). Pulsatile tinnitus (16%), carcinoid syndrome (4%), and facial nerve paresis (4%) were less commonly observed. MEANTs frequently mimicked temporal bone paraganglioma (31%) and cholesteatoma (15%) at presentation. According to a novel T/N/M/S staging system (S = secretory tumor) proposed herein, there were 6 (19%) T1, 19 (59%) T2, and 7 (22%) T3 MEANTs. T3 tumors were significantly more likely to undergo subtotal or near total resection compared with lower staged tumors secondary to adherence to critical neurovascular structures such as the petrous internal carotid artery and facial nerve (p = 0.027). Patients with T3 MEANTs were more likely to experience multiple recurrences, require adjuvant therapy with a somatostatin analogue, or develop permanent facial nerve paresis compared with lower staged tumors. At last follow up, no patients with T1 MEANTs had developed recurrence, whereas 37% (7/19) of patients with T2 MEANT and 57% (4/7) of patients with T3 MEANT experienced either disease recurrence after gross total resection (GTR) or regrowth of known residual tumor requiring additional surgery at a median duration of 72 months (95% CI, 24-84). CONCLUSIONS: Patients with MEANTs can present with nonspecific symptomatology that overlaps with more commonly encountered middle ear lesions. MEANT exhibits a proclivity for recurrence according to T-stage and long-term clinical follow up is necessary, particularly for advanced stage tumors. PMID- 30001284 TI - Patients With Normal Hearing Thresholds but Difficulty Hearing in Noisy Environments: A Study on the Willingness to Try Auditory Training. AB - HYPOTHESIS: Persons with normal audiometric thresholds but excessive difficulty hearing in background noise will choose auditory training as a treatment option. BACKGROUND: Auditory training has traditionally been reserved for those with marked hearing loss. We investigated auditory training as a treatment option for those who have normal auditory thresholds but complain about hearing in noise-a population of patients for which no therapy or intervention currently exists. We also determined the willingness of this patient population to volunteer for a free auditory training program. METHODS: We administered a 14-item, telephone based questionnaire to assess perceived difficulty hearing in noise and willingness to volunteer for auditory training. We developed questions to identify those who consistently reported difficulty hearing in noise, but not quiet. RESULTS: The 11,938-person database included 2,299 patients with pure-tone averages less than 25. A total of 474 of these patients completed our questionnaire, 135 of who had normal audiometric thresholds at all octave frequencies 0.25 to 8 kHz. We found that difficulty hearing in noise was a graded problem. Our approach to find consistent reports about hearing in noise showed that the majority of people who consistently had difficulty hearing in noise, but not quiet, were the most likely to try auditory training. CONCLUSIONS: While relatively few patients with both normal hearing thresholds and complaints of severe difficulty hearing in noise were in the database, these patients were generally willing to volunteer for auditory training. Our results provide evidence that many in this underserved population would volunteer for auditory training. PMID- 30001286 TI - Enhanced exposure assessment and genome-wide DNA methylation in World Trade Center disaster responders. AB - DNA methylation has emerged as a promising target linking environmental exposures and cancer. The World Trade Center (WTC) responders sustained exposures to potential carcinogens, resulting in an increased risk of cancer. Previous studies of cancer risk in WTC-exposed responders were limited by the deficiency in quantitative and individual information on exposure to carcinogens. The current study introduces a new exposure-ranking index (ERI) for estimating cancer-related acute and chronic exposures, which aimed to improve the ability of future analyses to estimate cancer risk. An epigenome-wide association study based on DNA methylation and a weighted gene co-expression network analysis were carried out to identify cytosine-phosphate-guanosine (CpG) sites, modules of correlated CpG sites, and biological pathways associated with the new ERI. Methylation was profiled on blood samples using Illumina 450K Beadchip. No significant epigenome wide association was found for ERI at a false discovery rate of 0.05. Several cancer-related pathways emerged in pathway analyses for the top ranking genes from epigenome-wide association study as well as enriched module from the weighted gene co-expression network analysis. The current study was the first DNA methylation study that aimed to identify methylation signature for cancer-related exposure in the WTC population. No CpG sites survived multiple testings adjustment. However, enriched gene sets involved in cancer, were identified in both acute and chronic ERIs, supporting the view that multiple genes play a role in this complex exposure. PMID- 30001285 TI - Consumption of garlic and its interactions with tobacco smoking and alcohol drinking on esophageal cancer in a Chinese population. AB - Garlic consumption has been associated inversely with esophageal cancer (EC); however, its interactions with tobacco smoking and alcohol consumption have never been evaluated in an epidemiological study. We evaluated the potential interactions between garlic intake and tobacco smoking as well as alcohol consumption in a population-based case-control study with 2969 incident EC cases and 8019 healthy controls. Epidemiologic data were collected by face-to-face interviews using a questionnaire. The adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated and additive and multiplicative interactions were evaluated using unconditional logistic regression models, adjusting for potential confounding factors. Semi-Bayes (SB) adjustments were used to reduce potential false-positive findings. EC was associated inversely with raw garlic intake [SB adjusted OR for more than once a week=0.68, 95% CI: 0.57-0.80], with a strong dose-response pattern in the overall analysis and in the stratified analyses by smoking and drinking. EC was associated positively with smoking and alcohol drinking, with SB-adjusted OR of 1.73 (95% CI: 1.62-1.85) and 1.37 (95% CI: 1.28 1.46) in dose-response effects of increased intensity and longer duration of smoking/drinking. Moreover, garlic intake interacts with smoking [synergy index (S)=0.83, 95% CI: 0.67-1.02; ratio of OR=0.88, 95% CI: 0.80-0.98] and alcohol drinking (S=0.73, 95% CI: 0.57-0.93; ratio of OR=0.86, 95% CI: 0.77-0.95) both multiplicatively and additively. Our findings suggested that high intake of raw garlic may reduce EC risk and may interact with tobacco smoking and alcohol consumption, which might shed a light on the development of EC as well as a potential dietary intervention among high-risk smokers and drinkers for EC prevention in the Chinese population. PMID- 30001287 TI - Outcomes of Patients With Cirrhosis Undergoing Orthopedic Procedures: An Analysis of the Nationwide Inpatient Sample. AB - INTRODUCTION: The population of patients with cirrhosis is growing and shifting toward a more elderly demographic and thus are at risk of developing orthopedic complications. There is lack of data on safety of orthopedic procedures in this population. METHODS: We performed an analysis of the Nationwide Inpatient Sample from 2005 to 2011 for patients undergoing hip arthroplasty, knee arthroplasty, and spinal laminectomy/fusion, stratified by presence of cirrhosis. The primary endpoint was in-hospital mortality and secondary endpoints included length of stay (LOS) and costs. RESULTS: There were 693,610 inpatient stays for orthopedic procedures conducted during the study period, with 3014 (0.43%) patients coded as having cirrhosis. Patients with cirrhosis had a lower median age (62 vs. 66 y; P<0.001) and were more likely to be male (52.3% vs. 41.1%; P<0.001). The inpatient mortality rate was significantly higher in patients with cirrhosis (2.4% vs. 0.4%; P<0.001) as was median LOS (4 vs. 3 d; P<0.001) and mean costs ($19,321 vs. $18,833; P<0.001). Patients with decompensated cirrhosis (vs. compensated cirrhosis) had significantly higher inpatient mortality rates (5.8% vs. 1.1%; P<0.001) with higher LOS and costs (P<0.001). On multivariable analysis, cirrhosis was associated with an increased risk of mortality (odds ratio, 4.22; 95% confidence interval, 2.92-6.10). Hospital cirrhosis volume was inversely associated with mortality, while hospital orthopedic procedure volumes had an inconsistent impact on outcomes. CONCLUSIONS: Inpatient orthopedic procedures in patients with cirrhosis result in high postoperative mortality, LOS, and costs. Careful patient selection is warranted to optimize cirrhosis patient postoperative outcomes. PMID- 30001288 TI - A Randomized Controlled Trial Comparing Colonoscopic Enema With Additional Oral Preparation as a Salvage for Inadequate Bowel Cleansing Before Colonoscopy. AB - GOALS: The goal of this study was to evaluate the noninferiority of colonoscopic enema to additional oral preparation in salvage bowel cleansing for inadequate preparation for a morning colonoscopy. BACKGROUND: Colonoscopic enema, administering additional cathartics into the right colon through the colonoscope accessory channel, is suggested to rescue poor bowel preparation for a colonoscopy but lacking comparative study. STUDY: In this prospective, randomized, actively-controlled, parallel group, noninferiority trial, consecutive outpatients and health checkup recipients aged from 19 to 70 years with inappropriate bowel preparation during an elective colonoscopy were enrolled to receive either a colonoscopic enema of 1 L polyethylene glycol (PEG) (enema group) or additional oral intake of 2 L PEG (oral group). The primary endpoint was the proportion of adequate bowel preparation evaluated using the Boston Bowel Preparation Scale. RESULTS: Overall, 131 participants were randomized. Adequate bowel preparation was achieved in 53% (35/66) of the enema group, which was significantly inferior to the oral group (81.5%; 53/67) with a difference of 28.5% (95% confidence interval, -44.1, -12.9; P=0.001). The largest difference in the proportion of adequate bowel preparation was observed in the right colon (57.8% in the enema group vs. 86.9% in the oral group; P<0.001), followed by the transverse colon (85.9% vs. 98.4%; P=0.017) and the left colon (90.6% vs. 96.7%; P=0.274). CONCLUSIONS: The colonoscopic enema of 1 L PEG was inferior to the additional oral ingestion of 2 L PEG regarding efficacy as a salvage bowel preparation in adults with inadequate bowel cleansing for colonoscopy. PMID- 30001289 TI - The Microbiome and Pancreatic Cancer: An Evidence-based Association? AB - Many risk factors for pancreatic cancer are related with microbiome alteration. In the past few years, the human microbiome and its relation with the immune system have been linked with carcinogenesis of different organs distant from the gut, including the pancreas. Patterns of oral microbiome associated with periodontitis are associated with an increased risk of pancreatic cancer, possibly because of the increased systemic inflammatory response, or to the capacity of some specific bacteria to alter the host immune response, making it more favorable to cancer cells. Helicobacter pylori infection when affecting the gastric body mucosa with subsequent hypochlorhydria also seems associated with an increased risk of pancreatic cancer. The composition of the intestinal microbiome is different in animal models and in humans with pancreatic cancer who have a distinct microbiome population compared with controls. Some specific bacteria can migrate from the intestine to the pancreas, and their ablation restores the immune system activity through its reprogramming with a switch toward a Th1 response and displays a protective effect toward tumor growth. More research in this area might lead to progress in terms of pancreatic cancer prevention and treatment, possibly in association with immunotherapy. PMID- 30001290 TI - Effect of Consent and Educational Adjuncts to Consent on Patient Perceptions About Colonoscopy. AB - BACKGROUND AND AIMS: Informed consent is a vital preprocedural step for endoscopy but there are substantial variations in its delivery. We therefore sought to assess a multifaceted intervention to improve the consent process. METHODS: Gastroenterologists at a tertiary center were educated on the recommended components of informed consent. Following this, 3 cohorts of patients undergoing colonoscopy were surveyed before and after consent. In one cohort, the effect of optimized verbal consent alone was assessed. In the second and third groups, the effects of the addition of either a handout or a video describing colonoscopy and its risks were evaluated. The primary outcomes were the changes between preconsent and postconsent survey responses regarding confidence in understanding the procedure's purpose, likelihood of adverse events, and levels of anxiety. RESULTS: In total, 240 patients were included with 79 to 81 patients per group. There were no significant differences among the groups' survey responses. Compared with patients receiving verbal consent alone, fewer patients in the handout and video groups increased their perceived risk of adverse events following consent, but this difference did not reach significance (P=0.08). Examining all groups together, anxiety levels changed significantly after consent (P=0.003), with 31% of patients reducing their anxiety level, 8% increasing it, and 62% having no change. CONCLUSIONS: The consent process appears to decrease patient anxiety about colonoscopy. When used in conjunction with a high-quality verbal consent, written or video educational adjuncts provided on the day of colonoscopy likely have no effect on patient perceptions. PMID- 30001291 TI - Clinical Faceoff: What is the Role of Acromioplasty in the Treatment of Rotator Cuff Disease? PMID- 30001292 TI - Temporal Patterns of Motion in Flexion-extension and Pronation-supination in a Rat Model of Posttraumatic Elbow Contracture. AB - BACKGROUND: The elbow is highly susceptible to contracture, which affects up to 50% of patients who experience elbow trauma. Previously, we developed a rat model to study elbow contracture that exhibited features similar to the human condition, including persistently decreased ROM and increased capsule thickness/adhesions. However, elbow ROM was not quantitatively evaluated over time throughout contracture development and subsequent mobilization of the joint. QUESTIONS/PURPOSES: The purposes of this study were (1) to quantify the time dependent mechanics of contracture, including comparison of contracture after immobilization and free mobilization; and (2) to determine what changes occur in capsule and joint surface morphology that may support the altered joint mechanics. METHODS: A total of 96 male Long-Evans rats were randomized into control and injury (unilateral soft tissue injury/immobilization) groups. Flexion extension and pronation-supination joint mechanics (n = 8/group) were evaluated after 3, 7, 21, or 42 days of immobilization (IM) or after 42 days of IM with either 21 or 42 days of free mobilization (63 or 84 FM, respectively). After measuring joint mechanics, a subset of these limbs (n = 3/group) was prepared for histologic analysis and blinded sections were scored to evaluate capsule and joint surface morphology. Joint mechanics and capsule histology at 42 IM and 84 FM were reported previously but are included to demonstrate the full timeline of elbow contracture. RESULTS: In flexion-extension, injured limb ROM was decreased compared with control (103 degrees +/- 11 degrees ) by 21 IM (70 degrees +/- 13 degrees ) (p = 0.001). Despite an increase in injured limb ROM from 42 IM (55 degrees +/- 14 degrees ) to 63 FM (83 degrees +/- 10 degrees ) (p < 0.001), injured limb ROM was still decreased compared with control (103 degrees +/- 11 degrees ) (p = 0.002). Interestingly, ROM recovery plateaued because there was no difference between injured limbs at 63 (83 degrees +/- 10 degrees ) and 84 FM (73 degrees +/- 19 degrees ) (p > 0.999). In pronation-supination, increased injured limb ROM occurred until 7 IM (202 degrees +/- 32 degrees ) compared with control (155 degrees +/- 22 degrees ) (p = 0.001), representative of joint instability. However, injured limb ROM decreased from 21 (182 degrees +/- 25 degrees ) to 42 IM (123 degrees +/- 47 degrees ) (p = 0.001), but was not different compared with control (155 degrees +/- 22 degrees ) (p = 0.108). Histologic evaluation showed morphologic changes in the anterior capsule (increased adhesions, myofibroblasts, thickness) and nonopposing joint surfaces (surface irregularities with tissue overgrowth, reduced matrix), but these changes did not increase with time. CONCLUSIONS: Overall, flexion-extension and pronation-supination exhibited distinct time-dependent patterns during contracture development and joint mobilization. Histologic evaluation showed tissue changes, but did not fully explain the patterns in contracture mechanics. Future work will use this rat model to evaluate the periarticular soft tissues of the elbow to isolate tissue-specific contributions to contracture to ultimately develop strategies for tissue-targeted treatments. CLINICAL RELEVANCE: A rat model of posttraumatic elbow contracture quantitatively described contracture development/progression and reiterates the need for rehabilitation strategies that consider both flexion-extension and pronation-supination elbow motion. PMID- 30001293 TI - The Growing Executive-Physician Wage Gap in Major US Nonprofit Hospitals and Burden of Nonclinical Workers on the US Healthcare System. AB - BACKGROUND: In an era of increasing healthcare costs, the number and value of nonclinical workers, especially hospital management, has come under increased study. Compensation of hospital executives, especially at major nonprofit medical centers, and the "wage gap" with physicians and clinical staff has been highlighted in the national news. To our knowledge, a systematic analysis of this wage gap and its importance has not been investigated. QUESTIONS/PURPOSES: (1) How do wage trends compare between physicians and executives at major nonprofit medical centers? (2) What are the national trends in the wages and the number of nonclinical workers in the healthcare industry? (3) What do nonclinical workers contribute to the growth in national cost of healthcare wages? (4) How much do wages contribute to the growth of national healthcare costs? (5) What are the trends in healthcare utilization? METHODS: We identified chief executive officer (CEO) compensation and chief financial officer (CFO) compensation at 22 major US nonprofit medical centers, which were selected from the US News & World Report 2016-2017 Hospital Honor Roll list and four health systems with notable orthopaedic departments, using publicly available Internal Revenue Service 990 forms for the years 2005, 2010, and 2015. Trends in executive compensation over time were assessed using Pearson product-moment correlation tests. As institution specific compensation data is not available, national mean compensation of orthopaedic surgeons, pediatricians, and registered nurses was used as a surrogate. We chose orthopaedic surgeons and pediatricians for analysis because they represent the two ends of the physician-compensation spectrum. US healthcare industry worker numbers and wages from 2005 to 2015 were obtained from the Bureau of Labor Statistics and used to calculate the national cost of healthcare wages. Healthcare utilization trends were assessed using data from the Agency for Healthcare Quality and Research, the National Ambulatory Medical Care Survey, and the National Hospital Ambulatory Medical Care Survey. All data were adjusted for inflation based on 2015 Consumer Price Index. RESULTS: From 2005 to 2015, the mean major nonprofit medical center CEO compensation increased from USD 1.6 +/- 0.9 million to USD 3.1 +/- 1.7 million, or a 93% increase (R = 0.112; p = 0.009). The wage gap increased from 3:1 to 5:1 with orthopaedic surgeons, from 7:1 to 12:1 with pediatricians, and from 23:1 to 44:1 with registered nurses. We saw a similar wage-gap trend in CFO compensation. From 2005 to 2015, mean healthcare worker wages increased 8%. Management worker wages increased 14%, nonclinical worker wages increased 7%, and physician salaries increased 10%. The number of healthcare workers rose 20%, from 13 million to 15 million. Management workers accounted for 3% of this growth, nonclinical workers accounted for 27%, and physicians accounted for 5% of the growth. From 2005 to 2015, the national cost burden of healthcare worker wages grew from USD 663 billion to USD 865 billion (a 30% increase). Nonclinical workers accounted for 27% of this growth, management workers accounted for 7%, and physicians accounted for 18%. In 2015, there were 10 nonclinical workers for every one physician. The cost of healthcare worker wages accounted for 27% of the growth in national healthcare expenditures. From 2005 to 2015, the number of inpatient stays decreased from 38 million to 36 million (a 5% decrease), the number of physician office visits increased from 964 million to 991 million (a 3% increase), and the number of emergency department visits increased from 115 million to 137 million (a 19% increase). CONCLUSIONS: There is a fast-rising wage gap between the top executives of major nonprofit centers and physicians that reflects the substantial, and growing, cost of nonclinical worker wages to the US healthcare system. However, there does not appear to be a proportionate increase in healthcare utilization. These findings suggest a growing, substantial burden of nonclinical tasks in healthcare. Methods to reduce nonclinical work in healthcare may result in important cost-savings. LEVEL OF EVIDENCE LEVEL: IV, economic and decision analysis. PMID- 30001294 TI - Perinatally Acquired Chlamydia trachomatis Infection in Children. PMID- 30001295 TI - Re: "Perinatally Acquired Chlamydia trachomatis Infection in Children". PMID- 30001296 TI - Health Utility, Social Interactivity, and Peristomal Skin Status: A Cross Sectional Study. AB - PURPOSE: The objective of this study was to examine relationships among social interaction, health utility, and peristomal skin status in adults with ostomies. DESIGN: Cross-sectional, descriptive. SUBJECTS AND SETTING: 15,591 persons residing in the United States were randomly selected from 3 multinational proprietary databases of individuals who had undergone surgery. METHODS: The study was a cross-sectional assessment utilizing the SF36v2 survey instrument. Potential subjects were sent an e-mail letter of invitation that included instructions for completing the questionnaire, an informed consent form, and nontransferable link to an electronic survey. Health utility was derived from the SF6D, and the Hawthorne Friendship Scale was used to measure social connectivity. Social functioning was derived from the SF36v2. A minimally important social value of health (MISVH) is reported as the minimum quality-adjusted life-days to be of benefit (influence) within indices of social connectivity and function. A self-reported determinant of peristomal skin health was included. RESULTS: Increased social interactivity, defined as social functioning and social connectivity, was associated with increased health utility. In addition, health utility decreased as peristomal skin integrity worsened. A MISVH can be demonstrated. CONCLUSION: Findings indicate that peristomal skin complications are more than dermatologic issues. They negatively affect the well-being of those who must cope and adapt to their impact and the community at large. Social interaction is also negatively influenced. PMID- 30001297 TI - State Laws Related to Billing Third Parties for Health Care Services at Public Sexually Transmitted Disease Clinics in the United States. AB - BACKGROUND: Health departments (HDs) cite state laws as barriers to billing third parties for sexually transmitted disease (STD) services, but the association between legal/policy barriers and third-party HD billing has not been examined. This study investigates the relationship between laws that may limit HDs' ability to bill, clinic perceptions of billing barriers, and billing practices. METHODS: Two surveys, (1) clinic managers (n = 246), (2) STD program managers (n = 63), conducted via a multiregional needs assessment of federally funded HD clinics' capacity to bill for STD services, billing/reimbursement practices, and perceived barriers were combined with an analysis of state laws regarding third-party billing for STD services. Statistical analyses examined relationships between laws that may limit HDs' ability to bill, clinic perceptions, and billing practices. RESULTS: Clinic managers reported clinics were less likely to bill Medicaid and other third parties in jurisdictions with a state law limiting their ability to bill compared with respondents who billed neither or 1 payer (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.10-0.97) and cited practical concerns as a primary barrier to billing (OR, 2.83; 95% CI, 1.50-5.37). The STD program managers report that the staff believed that STD services should be free (OR, 0.34; 95% CI, 0.13-0.90) was associated with not billing (not sure versus no resistance to billing); confidentiality concerns was not a reported barrier to billing among either sample. CONCLUSIONS: Practical concerns and clinic staff beliefs that STD services should be free emerged as possible barriers to billing, as were laws to a lesser extent. Attempts to initiate HD billing for STD services may benefit from staff education as well as addressing perceived legal barriers and staff concerns. PMID- 30001298 TI - HIV Coinfection Among Persons Diagnosed As Having Sexually Transmitted Diseases, San Francisco, 2007 to 2014. AB - BACKGROUND: Early syphilis, gonorrhea, and chlamydia but not HIV infections have increased in San Francisco, primarily among men. METHODS: We linked records of persons reported with early syphilis, gonorrhea, and chlamydia to records of persons reported with HIV to measure the proportion and characteristics of San Francisco residents with HIV-sexually transmitted disease (STD) coinfection between 2007 and 2014. We measured trends in HIV coinfection separately for men and women for each STD. RESULTS: From 2007 to 2014, of the 5745 early syphilis, 18,037 gonorrhea, and 37,224 chlamydia diagnoses that were reported, 66%, 28%, and 15%, respectively, were among persons coinfected with HIV. Men accounted for most persons with early syphilis, gonorrhea, and chlamydia HIV coinfection. For early syphilis and HIV coinfection, among men who have sex with men (MSM), Latinos were more likely and Asian/Pacific Islanders were less likely to have HIV coinfection compared with whites. Older age at diagnosis and history of an STD were both also significantly associated with early syphilis and HIV coinfection. Transgender persons, older ages, Latino MSM compared with white MSM, and those with a history of STD were more likely to have HIV coinfection, whereas Asian/Pacific Islander MSM were less likely to have HIV coinfection for both gonorrhea and chlamydia, CONCLUSIONS: Our findings highlight the high burden of HIV-STD coinfection in San Francisco. To maintain the current declines in HIV incidence and turn the curve in rising STD incidence, there is an urgent need for collaborative HIV and STD prevention and control efforts. PMID- 30001299 TI - Partial Recovery of Limb Function Following End-to-Side Screw Anastomosis of Phrenic Nerve in Rats with Brachial Plexus Injury. AB - BACKGROUND Brachial plexus injury (BPI), a severe nervous system injury, is a leading cause of functional damages of the affected upper limb. Patients with BPI manifested with motor weakness or paralysis, sensory deficits, and pain. We established a BPI rat model to explore the in vivo effect of end-to-side screw anastomosis (ETSSA) of phrenic nerve on the recovery of limb function after BPI. MATERIAL AND METHODS After modeling, rats were treated with end-to-side anastomosis (ETSA) and ETSSA respectively. After 1 and 3 months, the behavioral changes of rats were observed using the Terzis grooming test, and the compound muscle action potential (CMAP) and muscle tension of biceps brachii were detected. The muscle weight recovery rate (MWRR) and cross-sectional area recovery rate (CARR) were calculated. Toluidine blue staining was used to observe the myelinated nerve fibers in the proximal phrenic nerve and distal musculocutaneous nerve of suture. The ratio of regenerated nerve traversing rate (NTR) was counted and motor endplate area of biceps brachii was measured. RESULTS The rats treated with ETSA and ETSSA exhibited elevated grading of Terzis grooming test with time. Although both the ETSSA and ETSA can reduce the MWRR, CARR and motor endplate area in BPI rats, ETSSA showed a better influence on the latency delayed rate (LDR) and amplitude recovery rate (ARR) of CMAP, muscular tension recovery rate (MTRR), MWRR, number of regenerated myelinated nerve fibers, NTR, and motor endplate area in BPI rats. CONCLUSIONS Our study provided evidence that ETSSA can restore the limb function recovery to a greater extent, and accelerate the regeneration of nerve fibers in rats with BPI; the effect of ETSSA was better than that of ETSA. PMID- 30001300 TI - Transplant ethical considerations: response from the trenches. PMID- 30001301 TI - The Zero Carbon Bill and the health of New Zealanders-help shape this crucial health law now. PMID- 30001302 TI - Comparing methamphetamine, MDMA, cocaine, codeine and methadone use between the Auckland region and four Australian states using wastewater-based epidemiology (WBE). AB - AIMS: To compare levels of drug use in Auckland with four Australian major cities using wastewater-based epidemiology (WBE). METHODS: A week of daily wastewater samples were selected from two Auckland and eight Australian urban wastewater treatment plants (WWTPs) during 2014 and 2015. Samples were analysed for drug residues using liquid chromatography-tandem mass spectrometry. Consumption of methamphetamine, methylenedioxymethamphetamine (MDMA), cocaine, codeine and methadone (mg/day/1,000 people) was estimated for each WWTP from mass loads using an internationally validated back-calculation formula. RESULTS: Cocaine was not detected at either of the two Auckland WTTPs, and MDMA was detected on only one day of the sampled week in each of the Auckland WWTPs. In contrast, cocaine and MDMA was detected on every day at all eight Australian WWTPs. Methamphetamine was detected on every day at both the New Zealand and Australian WWTPs. Levels of methamphetamine consumption at the Auckland WWTPs were lower than five of the Australian WWTPs. Lower levels of codeine and methadone consumption were detected in Auckland than Australian sites. CONCLUSIONS: MDMA and cocaine use is low in Auckland compared to sampled Australia cities. Both Auckland and the selected Australian cities have significant methamphetamine problems compared to many European cities. PMID- 30001304 TI - Chromoendoscopy versus standard colonoscopy for detection of nonpolypoid dysplasia in patients with inflammatory bowel disease. AB - AIM: Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer. Studies show that chromoendoscopy (CE) can increase the detection of dysplasia at surveillance colonoscopy, compared to standard white light endoscopy (WLE). We performed a retrospective cohort study to compare standard WLE to CE with targeted biopsies in detecting nonpolypoid dysplasia in IBD patients undergoing surveillance colonoscopy at a single tertiary centre. METHOD: Data was collected on 110 consecutive patients with IBD who underwent surveillance colonoscopy from 1 August 2015 to 31 July 2017 at Counties Manukau District Health Board, Auckland. Patients had either WLE or CE. Patient characteristics, endoscopic and histologic descriptions were reviewed. Rates of dysplasia detection by the different endoscopic techniques were compared using an exact Poisson test. RESULTS: 76/110 (69%) had WLE (mean age 56y; median disease duration 18y) and 34/110 (31%) had CE (median age 59y; median disease duration 19y). Nonpolypoid dysplasia was detected in 0/76 (0%) patients who had WLE. Seven nonpolypoid dysplastic lesions were detected in 4/34 (11.8%) patients who had CE. Dysplasia pick up rate was significantly higher in the CE group with a risk difference of 11.8%, 95% confidence interval (0.93, 22.59), p=0.008. Dysplasia detection rate per patient was also significantly higher in the CE group with a rate difference of 20.6 lesions per 100 patients, 95% confidence interval (5.3, 35.8), p=0.0003. As expected, there was no difference between the number of polypoid dysplastic lesions found between the two groups (p=0.12). CONCLUSION: In our cohort of IBD patients undergoing surveillance colonoscopy, CE with targeted biopsy is associated with a significantly increased nonpolypoid dysplasia detection rate when compared to WLE. These results are comparable to studies performed in the rest of the world. PMID- 30001303 TI - Trends in ischaemic heart disease: patterns of hospitalisation and mortality rates differ by ethnicity (ANZACS-QI 21). AB - AIM: To examine trends in ischaemic heart disease (IHD) events by ethnicity. METHODS: All IHD deaths and hospitalisations from 2006-2015 were identified using individual-linkage of national hospitalisation and mortality data. Age standardised IHD rates and average annual age-adjusted percent changes were estimated by ethnic group. Ratios of non-fatal to fatal events were calculated by dividing age-standardised hospitalisation by death rates. RESULTS: IHD mortality rates declined by 3.1-5.4% per year for most groups, except Pacific women, who experienced a non-significant decline of 1.3% per year. IHD hospitalisation rates declined significantly by 3.6-8.8% per year in all groups. IHD mortality rates were highest in Maori and Pacific people, but hospitalisation rates highest in Indians. Indians also had the highest ratio of hospitalisations to deaths. For every person who died from IHD in 2014/15, 7-8 Indians, but only 3-4 Maori or Pacific people, were hospitalised with IHD. CONCLUSION: Fatal and non-fatal IHD rates are declining in all groups, but Maori and Pacific people have disproportionately high rates of IHD mortality. The much lower ratio of IHD hospitalisations to deaths among Maori and Pacific people compared to others suggests there are still important barriers to preventive interventions and acute care for Maori and Pacific men and women. PMID- 30001305 TI - Institutional gastroenteritis outbreaks and time to notify public health services. AB - AIM: We report a quantification and visualisation of the association between the time to notify public health service (PHS) and the duration and size of institutional gastroenteritis outbreaks, and explore the seasonality and trend of the outbreaks. METHOD: Descriptive analysis was performed on institutional gastroenteritis outbreak data from a North Island PHS (1 January 2009-31 December 2014). Time-series analysis was used to explore the seasonality and trend of outbreaks. Multivariate analyses were performed to quantify the association between the time to notify PHS and the duration and size of outbreaks. RESULTS: One hundred and seventy-five gastroenteritis outbreaks (from 58 facilities) were included in descriptive analyses. A significant increasing trend (p=0.01) without seasonal pattern was confirmed by time-series analysis. Shorter notification time was associated with shorter duration and smaller size of outbreaks, eg, duration of outbreaks when time to notify was >=7 days, was 3.4 days (p=0.001, 95% CI=3.1 3.7) longer than baseline time to notify (0-1 day). CONCLUSION: Prompt notification to the PHS appears to be a factor associated with reduced outbreak duration and size. PMID- 30001306 TI - Pregabalin misuse: preventing potential problems in New Zealand. AB - AIMS: Pregabalin has not been used widely in New Zealand to this point as it has not been funded, but from May 2018 it will be available fully subsidised. This paper intends to highlight the issue of pregabalin misuse, a concern that will be unfamiliar to most clinicians in New Zealand. METHODS: A review of the literature of papers documenting the misuse of gabapentin and pregabalin was conducted with a specific focus on pregabalin. RESULTS: There is a growing body of evidence regarding the potential of misuse of pregabalin. It produces a range of sensations, including euphoria, sedation and dissociation. It is commonly used in conjunction with other drugs, most notably sedatives and opioids, which leads to an additive effect. Although generally safe when taken alone, pregabalin is a growing feature of drug-related deaths. CONCLUSIONS: Prescribers need to be alert to the potential of pregabalin misuse. This should be achieved through prescribing with great care (not prescribing to new or unknown patients; not in response to direct patient requests for it by name; supplying in limited quantities), regular review of patients and stopping treatment, by slow withdrawal, when lack of efficacy is seen. PMID- 30001307 TI - New Zealand transplant patients and organ transplantation in China: some ethical considerations. AB - In this viewpoint article we consider the situation of organ procurement from China, and address some of the ethical aspects arising for health professionals when New Zealand transplant patients contemplate traveling to China for an organ. We also consider some of the challenges facing health professionals involved in providing care to such patients. PMID- 30001309 TI - Applying the Reason Model to enhance health record research in the age of 'big data'. PMID- 30001308 TI - Traumatic haemorrhagic lumbar synovial facet cyst presenting as bilateral foot drop: a case report. PMID- 30001310 TI - On-call goes with the territory! PMID- 30001311 TI - Evaluation of the rapid molecular diagnostic test for the New Zealand Mycobacterium tuberculosis Rangipo strain in a clinical setting. PMID- 30001312 TI - Poor female representation at surgical conference. PMID- 30001313 TI - Response to: Poor female representation at surgical conference. PMID- 30001314 TI - Response to: A systematic review of leadership training for medical students. PMID- 30001315 TI - Why did so many women develop cancer? Part 3. PMID- 30001316 TI - Ikaros cooperates with Notch activation and antagonizes TGFbeta signaling to promote pDC development. AB - Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFbeta function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFbeta activation, suggesting that Ikaros is an upstream negative regulator of the TGFbeta pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with gamma-secretase inhibitors, which affects both TGFbeta-dependent and -independent pathways, but is Notch independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity. PMID- 30001318 TI - Revisiting the concept of Innovative Developing Countries (IDCs) for its relevance to health innovation and neglected tropical diseases and for the prevention and control of epidemics. AB - INTRODUCTION: Countries have traditionally been split into two major groups: developed or industrialized ("the North") and developing or underdeveloped ("the South"). Several authors and organizations have challenged this classification to recognize countries that have reached an intermediate stage of social and economic development. As proposed by Morel and collaborators in 2005, the concept of Innovative Developing Countries (IDCs) defines a group of nations with impactful scientific programs. Here, IDCs are reexamined by a variety of metrics to highlight their role in health innovation through research and development (R&D) programs on neglected tropical diseases (NTDs) that also positively impact epidemic preparedness. RESULTS: To address the global changes due to expanding globalization we updated the original indicator of the number of USPTO patents deposited by individual countries per GDP and per capita to the number of international patents applications, related to applicant residence and deposited under the Patent Cooperation Treaty (PCT) per GNI (or GDP) and per capita. A comparison of the originally described ranking of top innovative countries to those in the present study revealed new members that updated the list of IDCs and showed a prominent role now played by China. Analyzing scientific publications in international journals since the introduction of the IDC concept in 2005 we found that IDCs do prioritize Neglected Tropical Diseases (NTDs) as an area of research. Finally we investigated the role of IDCs in two major public health emergencies between 2012 and 2016, the outbreaks of Ebola in West Africa and Zika in South America. An analysis of the co-authorship country networks demonstrated an important role for IDC infrastructure and personnel in the prevention and control of these epidemics. DISCUSSION AND CONCLUSIONS: Different techniques can be used to evaluate and measure innovative performance of countries. Country rankings published by traditional indexes, such as the Bloomberg Innovation Index (BII) and the Global Innovation Index (GII), only include high income economies among the top 20 performers. This is in sharp contrast to our approach, which identified 8-9 IDCs among the first 25 with China occupying the top position. Through an analysis of the pros and cons of the different methodologies, the IDC concept challenges more conventional approaches to address and estimate the innovative capacity of countries. PMID- 30001319 TI - Snakebite envenomation in the Caribbean: The role of medical and scientific cooperation. PMID- 30001317 TI - Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays. AB - The protozoan parasite Leishmania causes leishmaniasis; a spectrum of diseases of which there are an estimated 1 million new cases each year. Current treatments are toxic, expensive, difficult to administer, and resistance to them is emerging. New therapeutics are urgently needed, however, screening the infective amastigote form of the parasite is challenging. Only certain species can be differentiated into axenic amastigotes, and compound activity against these does not always correlate with efficacy against the parasite in its intracellular niche. Methods used to assess compound efficacy on intracellular amastigotes often rely on microscopy-based assays. These are laborious, require specialist equipment and can only determine parasite burden, not parasite viability. We have addressed this clear need in the anti-leishmanial drug discovery process by producing a transgenic L. mexicana cell line that expresses the luciferase NanoLuc-PEST. We tested the sensitivity and versatility of this transgenic strain, in comparison with strains expressing NanoLuc and the red-shifted firefly luciferase. We then compared the NanoLuc-PEST luciferase to the current methods in both axenic and intramacrophage amastigotes following treatment with a supralethal dose of Amphotericin B. NanoLuc-PEST was a more dynamic indicator of cell viability due to its high turnover rate and high signal:background ratio. This, coupled with its sensitivity in the intramacrophage assay, led us to validate the NanoLuc-PEST expressing cell line using the MMV Pathogen Box in a two-step process: i) identify hits against axenic amastigotes, ii) screen these hits using our bioluminescence-based intramacrophage assay. The data obtained from this highlights the potential of compounds active against M. tuberculosis to be re-purposed for use against Leishmania. Our transgenic L. mexicana cell line is therefore a highly sensitive and dynamic system suitable for Leishmania drug discovery in axenic and intramacrophage amastigote models. PMID- 30001320 TI - Deconvolution of expression microarray data reveals 131I-induced responses otherwise undetected in thyroid tissue. AB - High-throughput gene expression analysis is increasingly used in radiation research for discovery of damage-related or absorbed dose-dependent biomarkers. In tissue samples, cell type-specific responses can be masked in expression data due to mixed cell populations which can preclude biomarker discovery. In this study, we deconvolved microarray data from thyroid tissue in order to assess possible bias from mixed cell type data. Transcript expression data [GSE66303] from mouse thyroid that received 5.9 Gy from 131I over 24 h (or 0 Gy from mock treatment) were deconvolved by cell frequency of follicular cells and C-cells using csSAM and R and processed with Nexus Expression. Literature-based signature genes were used to assess the relative impact from ionizing radiation (IR) or thyroid hormones (TH). Regulation of cellular functions was inferred by enriched biological processes according to Gene Ontology terms. We found that deconvolution increased the detection rate of significantly regulated transcripts including the biomarker candidate family of kallikrein transcripts. Detection of IR-associated and TH-responding signature genes was also increased in deconvolved data, while the dominating trend of TH-responding genes was reproduced. Importantly, responses in biological processes for DNA integrity, gene expression integrity, and cellular stress were not detected in convoluted data-which was in disagreement with expected dose-response relationships-but upon deconvolution in follicular cells and C-cells. In conclusion, previously reported trends of 131I induced transcriptional responses in thyroid were reproduced with deconvolved data and usually with a higher detection rate. Deconvolution also resolved an issue with detecting damage and stress responses in enriched data, and may reduce false negatives in other contexts as well. These findings indicate that deconvolution can optimize microarray data analysis of heterogeneous sample material for biomarker screening or other clinical applications. PMID- 30001321 TI - Use of an anionic collagen matrix made from bovine intestinal serosa for in vivo repair of cranial defects. AB - Polymeric biomaterials composed of extracellular matrix components possess osteoconductive capacity that is essential for bone healing. The presence of collagen and the ability to undergo physicochemical modifications render these materials a suitable alternative in bone regenerative therapies. The objective of this study was to evaluate the osteogenic capacity of collagen-based matrices (native and anionic after alkaline hydrolysis) made from bovine intestinal serosa (MBIS). Twenty-five animals underwent surgery to create a cranial defect to be filled with native and anionic collagen matrixes, mmineralized and non mineralized. The animals were killed painlessly 6 weeks after surgery and samples of the wound area were submitted to routine histology and morphometric analysis. In the surgical area there was new bone formation projecting from the margins to the center of the defect. More marked bone neoformation occurred in the anionic matrices groups in such a way that permitted union of the opposite margins of the bone defect. The newly formed bone matrix exhibited good optical density of type I collagen fibers. Immunoexpression of osteocalcin by osteocytes was observed in the newly formed bone. Morphometric analysis showed a greater bone volume in the groups receiving the anionic matrices compared to the native membranes. Mineralization of the biomaterial did not increase its osteoregenerative capacity. In conclusion, the anionic matrix exhibits osteoregenerative capacity and is suitable for bone reconstruction therapies. PMID- 30001322 TI - Molecular mechanism of the tree shrew's insensitivity to spiciness. AB - Spicy foods elicit a pungent or hot and painful sensation that repels almost all mammals. Here, we observe that the tree shrew (Tupaia belangeri chinensis), which possesses a close relationship with primates and can directly and actively consume spicy plants. Our genomic and functional analyses reveal that a single point mutation in the tree shrew's transient receptor potential vanilloid type-1 (TRPV1) ion channel (tsV1) lowers its sensitivity to capsaicinoids, which enables the unique feeding behavior of tree shrews with regards to pungent plants. We show that strong selection for this residue in tsV1 might be driven by Piper boehmeriaefolium, a spicy plant that geographically overlaps with the tree shrew and produces Cap2, a capsaicin analog, in abundance. We propose that the mutation in tsV1 is a part of evolutionary adaptation that enables the tree shrew to tolerate pungency, thus widening the range of its diet for better survival. PMID- 30001324 TI - Modelling how responsiveness to interferon improves interferon-free treatment of hepatitis C virus infection. AB - Direct-acting antiviral agents (DAAs) for hepatitis C treatment tend to fare better in individuals who are also likely to respond well to interferon-alpha (IFN), a surprising correlation given that DAAs target specific viral proteins whereas IFN triggers a generic antiviral immune response. Here, we posit a causal relationship between IFN-responsiveness and DAA treatment outcome. IFN responsiveness restricts viral replication, which would prevent the growth of viral variants resistant to DAAs and improve treatment outcome. To test this hypothesis, we developed a multiscale mathematical model integrating IFN responsiveness at the cellular level, viral kinetics and evolution leading to drug resistance at the individual level, and treatment outcome at the population level. Model predictions quantitatively captured data from over 50 clinical trials demonstrating poorer response to DAAs in previous non-responders to IFN than treatment-naive individuals, presenting strong evidence supporting the hypothesis. Model predictions additionally described several unexplained clinical observations, viz., the percentages of infected individuals who 1) spontaneously clear HCV, 2) get chronically infected but respond to IFN-based therapy, and 3) fail IFN-based therapy but respond to DAA-based therapy, resulting in a comprehensive understanding of HCV infection and treatment. An implication of the causal relationship is that failure of DAA-based treatments may be averted by adding IFN, a strategy of potential use in settings with limited access to DAAs. A second, wider implication is that individuals with greater IFN-responsiveness would require shorter DAA-based treatment durations, presenting a basis and a promising population for response-guided therapy. PMID- 30001325 TI - Stabilization of Bacillus subtilis Spx under cell wall stress requires the anti adaptor protein YirB. AB - Spx is a global transcriptional regulator present in low-GC Gram-positive bacteria, including the model bacterium Bacillus subtilis and various human pathogens. In B. subtilis, activation of Spx occurs in response to disulfide stress. We recently reported, however, that induction of Spx also occurs in response to cell wall stress, and that the molecular events that result in its activation under both stress conditions are mechanistically different. Here, we demonstrate that, in addition to up-regulation of spx transcription through the alternative sigma factor sigmaM, full and timely activation of Spx-regulated genes by cell wall stress requires Spx stabilization by the anti-adaptor protein YirB. YirB is itself transcriptionally induced under cell wall stress, but not disulfide stress, and this induction requires the CssRS two-component system, which responds to both secretion stress and cell wall antibiotics. The yirB gene is repressed by YuxN, a divergently transcribed TetR family repressor, and CssR~P acts as an anti-repressor. Collectively, our results identify a physiological role for the YirB anti-adaptor protein and show that induction of the Spx regulon under disulfide and cell wall stress occurs through largely independent pathways. PMID- 30001323 TI - A bidirectional relationship between sleep and oxidative stress in Drosophila. AB - Although sleep appears to be broadly conserved in animals, the physiological functions of sleep remain unclear. In this study, we sought to identify a physiological defect common to a diverse group of short-sleeping Drosophila mutants, which might provide insight into the function and regulation of sleep. We found that these short-sleeping mutants share a common phenotype of sensitivity to acute oxidative stress, exhibiting shorter survival times than controls. We further showed that increasing sleep in wild-type flies using genetic or pharmacological approaches increases survival after oxidative challenge. Moreover, reducing oxidative stress in the neurons of wild-type flies by overexpression of antioxidant genes reduces the amount of sleep. Together, these results support the hypothesis that a key function of sleep is to defend against oxidative stress and also point to a reciprocal role for reactive oxygen species (ROS) in neurons in the regulation of sleep. PMID- 30001327 TI - In vivo 13C-MRI using SAMBADENA. AB - Magnetic Resonance Imaging (MRI) is a powerful imaging tool but suffers from a low sensitivity that severely limits its use for detecting metabolism in vivo. Hyperpolarization (HP) methods have demonstrated MRI signal enhancement by several orders of magnitude, enabling the detection of metabolism with a sensitivity that was hitherto inaccessible. While it holds great promise, HP is typically relatively slow (hours), expensive (million $, ?) and requires a dedicated device ("polarizer"). Recently, we introduced a new method that creates HP tracers without an external polarizer but within the MR-system itself based on parahydrogen induced polarization (PHIP): Synthesis Amid the Magnet Bore Allows Dramatically Enhanced Nuclear Alignment (SAMBADENA). To date, this method is the simplest and least cost-intensive method for hyperpolarized 13C-MRI. HP of P13C > 20% was demonstrated for 5mM tracer solutions previously. Here, we present a setup and procedure that enabled the first in vivo application of SAMBADENA: Within seconds, a hyperpolarized angiography tracer was produced and injected into an adult mouse. Subsequently, fast 13C-MRI was acquired which exhibited the vena cava, aorta and femoral arteries of the rodent. This first SAMBADENA in vivo 13C-angiography demonstrates the potential of the method as a fast, simple, low cost alternative to produce HP-tracers to unlock the vast but hidden powers of MRI. PMID- 30001326 TI - BMP signaling downstream of the Highwire E3 ligase sensitizes nociceptors. AB - A comprehensive understanding of the molecular machinery important for nociception is essential to improving the treatment of pain. Here, we show that the BMP signaling pathway regulates nociception downstream of the E3 ubiquitin ligase highwire (hiw). hiw loss of function in nociceptors caused antagonistic and pleiotropic phenotypes with simultaneous insensitivity to noxious heat but sensitized responses to optogenetic activation of nociceptors. Thus, hiw functions to both positively and negatively regulate nociceptors. We find that a sensory reception-independent sensitization pathway was associated with BMP signaling. BMP signaling in nociceptors was up-regulated in hiw mutants, and nociceptor-specific expression of hiw rescued all nociception phenotypes including the increased BMP signaling. Blocking the transcriptional output of the BMP pathway with dominant negative Mad suppressed nociceptive hypersensitivity that was induced by interfering with hiw. The up-regulated BMP signaling phenotype in hiw genetic mutants could not be suppressed by mutation in wallenda suggesting that hiw regulates BMP in nociceptors via a wallenda independent pathway. In a newly established Ca2+ imaging preparation, we observed that up regulated BMP signaling caused a significantly enhanced Ca2+ signal in the axon terminals of nociceptors that were stimulated by noxious heat. This response likely accounts for the nociceptive hypersensitivity induced by elevated BMP signaling in nociceptors. Finally, we showed that 24-hour activation of BMP signaling in nociceptors was sufficient to sensitize nociceptive responses to optogenetically-triggered nociceptor activation without altering nociceptor morphology. Overall, this study demonstrates the previously unrevealed roles of the Hiw-BMP pathway in the regulation of nociception and provides the first direct evidence that up-regulated BMP signaling physiologically sensitizes responses of nociceptors and nociception behaviors. PMID- 30001328 TI - Characterized non-transient microbiota from stinkbug (Nezara viridula) midgut deactivates soybean chemical defenses. AB - The Southern green stinkbug (N. viridula) feeds on developing soybean seeds in spite of their strong defenses against herbivory, making this pest one of the most harmful to soybean crops. To test the hypothesis that midgut bacterial community allows stinkbugs to tolerate chemical defenses of soybean developing seeds, we identified and characterized midgut microbiota of stinkbugs collected from soybean crops, different secondary plant hosts or insects at diapause on Eucalyptus trees. Our study demonstrated that while more than 54% of N. viridula adults collected in the field had no detectable bacteria in the V1-V3 midgut ventricles, the guts of the rest of stinkbugs were colonized by non-transient microbiota (NTM) and transient microbiota not present in stinkbugs at diapause. While transient microbiota Bacillus sp., Micrococcus sp., Streptomyces sp., Staphylococcus sp. and others had low abundance, NTM microbiota was represented by Yokenella sp., Pantoea sp. and Enterococcus sp. isolates. We found some isolates that showed in vitro beta-glucosidase and raffinase activities plus the ability to degrade isoflavonoids and deactivate soybean protease inhibitors. Our results suggest that the stinkbugs' NTM microbiota may impact on nutrition, detoxification and deactivation of chemical defenses, and Enterococcus sp., Yokenella sp. and Pantoea sp. strains might help stinkbugs to feed on soybean developing seeds in spite of its chemical defenses. PMID- 30001330 TI - The anatomy of a nucleus: As revealed by chromosome painting. PMID- 30001329 TI - Condensin II drives large-scale folding and spatial partitioning of interphase chromosomes in Drosophila nuclei. AB - Metazoan chromosomes are folded into discrete sub-nuclear domains, referred to as chromosome territories (CTs). The molecular mechanisms that underlie the formation and maintenance of CTs during the cell cycle remain largely unknown. Here, we have developed high-resolution chromosome paints to investigate CT organization in Drosophila cycling cells. We show that large-scale chromosome folding patterns and levels of chromosome intermixing are remarkably stable across various cell types. Our data also suggest that the nucleus scales to accommodate fluctuations in chromosome size throughout the cell cycle, which limits the degree of intermixing between neighboring CTs. Finally, we show that the cohesin and condensin complexes are required for different scales of chromosome folding, with condensin II being especially important for the size, shape, and level of intermixing between CTs in interphase. These findings suggest that large-scale chromosome folding driven by condensin II influences the extent to which chromosomes interact, which may have direct consequences for cell-type specific genome stability. PMID- 30001332 TI - Flourishing and prosocial behaviors: A multilevel investigation of national corruption level as a moderator. AB - The current psychology literature defines flourishing as leading an authentic life that directs one towards the highest levels of both feeling good and functioning well. Numerous studies show that flourishing relates to a wide array of advantageous personal outcomes. However, the same literature says very little about the social outcomes of flourishing, even though an individual's pursuit of well-being does not happen in isolation of others. With the present research, we seek to address this void. Specifically, we argue that flourishing, in its psychological conceptualization, does not provide strong moral guidance. As such, flourishing is amoral when it comes to social outcomes such as prosocial behaviors. Drawing on social learning theory, we argue that flourishers' prosociality is at least somewhat contingent on the moral guidance of their society. To assess this, we tested society's corruption level as a moderator in the relation between flourishing and prosocial behavior. To that end, we conducted two studies using data from the European Social Survey (ESS), which were collected in 2006 (N1 = 50,504) from 23 countries and in 2012 (N2 = 56,835) from 29 countries. We generally find that corruption at the national level moderates the relation between flourishing and prosocial behaviors (i.e., helping close/distant others, charitable activities). Overall, our study suggests that moral guidance should factor into discussions about flourishing. PMID- 30001333 TI - Approximation processes in arithmetic in old adulthood. AB - Young and old adults estimated the results of multidigit multiplication problems relative to a reference number. Old adults were slower but slightly more accurate than young adults. They were less affected by the distance between the reference number and the exact answer than the young adults. The same strategies reported by past research-the approximated calculation strategy and the sense of magnitude strategy-were found here. The old adults showed a stronger preference toward the approximated calculation strategy than the young ones, and this probably led to the reduced effect of distance. These patterns are interpreted as reflecting two factors. The first is the extensive experience of the old adults with mental calculation, and the second is the decline in processing speed and in working memory resources with adulthood. The former is responsible for the more frequent use of the approximated calculation strategy and for the higher accuracy of the old adults, while the latter is responsible for their slower responses. PMID- 30001331 TI - Animal influence on water, sanitation and hygiene measures for zoonosis control at the household level: A systematic literature review. AB - INTRODUCTION: Neglected zoonotic diseases (NZDs) have a significant impact on the livelihoods of the world's poorest populations, which often lack access to basic services. Water, sanitation and hygiene (WASH) programmes are included among the key strategies for achieving the World Health Organization's 2020 Roadmap for Implementation for control of Neglected Tropical Diseases (NTDs). There exists a lack of knowledge regarding the effect of animals on the effectiveness of WASH measures. OBJECTIVES: This review looked to identify how animal presence in the household influences the effectiveness of water, hygiene and sanitation measures for zoonotic disease control in low and middle income countries; to identify gaps of knowledge regarding this topic based on the amount and type of studies looking at this particular interaction. METHODS: Studies from three databases (Medline, Web of Science and Global Health) were screened through various stages. Selected articles were required to show burden of one or more zoonotic diseases, an animal component and a WASH component. Selected articles were analysed. A narrative synthesis was chosen for the review. RESULTS: Only two studies out of 7588 met the inclusion criteria. The studies exemplified how direct or indirect contact between animals and humans within the household can influence the effectiveness of WASH interventions. The analysis also shows the challenges faced by the scientific community to isolate and depict this particular interaction. CONCLUSION: The dearth of studies examining animal-WASH interactions is explained by the difficulties associated with studying environmental interventions and the lack of collaboration between the WASH and Veterinary Public Health research communities. Further tailored research under a holistic One Health approach will be required in order to meet the goals set in the NTDs Roadmap and the 2030 Agenda for Sustainable Development. PMID- 30001334 TI - Effects of vehicle gap changes on fuel economy and emission performance of the traffic flow in the ACC strategy. AB - This paper focuses on the effects of vehicle gap changes on fuel and emission performance of the simulated traffic flow in the adaptive cruise control (ACC) strategy. Firstly, the close correlation of vehicle gap changes and the host car's behaviors was explored with the measured car-following data. Secondly, the correlation between the host car's velocity and vehicle gap changes with different memory steps was also explored to develop the nth car's optimal velocity function. Thirdly, a microscopic traffic simulation program was created for analyzing the traffic flow evolution process and approximately estimating the fuel consumptions and exhaust emissions. As a result, it was seen that vehicle gap changes with memory significantly affect fuel economy and emission performance of the simulated traffic flow in the ACC strategy, which can result in low fuel consumptions and exhaust emissions. This study is an incremental step forward for designing the control strategy of the ACC system. PMID- 30001337 TI - Loitering with intent-Catching the outlier vessels at sea. AB - Illegal, Unreported and Unregulated (IUU) fishing activities pose one of the most significant threats to sustainable fisheries worldwide. Identifying illegal behaviour, specifically fishing and at-sea transhipment, continues to be a fundamental hurdle in combating IUU fishing. Here, we explore the use of spatial statistical methods to identify vessels behaving anomalously, in particular with regard to loitering, using the Indonesian Exclusive Economic Zone (EEZ) and surrounding waters as a case-study. Using Automatic Identification System (AIS) for vessel tracking, we applied Generalized Additive Models to capture both the temporal and spatial nature of loitering behaviour. We identified three statistically anomalous loitering behaviours (based on time, speed and distance) and applied the models to 2700 vessels in the region. We were able to rank vessels for individual and joint probability of atypical behaviour, providing a hierarchical list of vessels engaging in anomalous behaviour. While identification of irregular behaviour does not mean vessels are definitely engaging in illegal activities, this statistical modelling approach can be used to prioritise the allocation of enforcement resources and assist authorities under the United Nations Food and Agricultural Organization Port State Measures Agreement for management and enforcement of IUU fishing associated activities. PMID- 30001335 TI - The noisy basis of morphogenesis: Mechanisms and mechanics of cell sheet folding inferred from developmental variability. AB - Variability is emerging as an integral part of development. It is therefore imperative to ask how to access the information contained in this variability. Yet most studies of development average their observations and, discarding the variability, seek to derive models, biological or physical, that explain these average observations. Here, we analyse this variability in a study of cell sheet folding in the green alga Volvox, whose spherical embryos turn themselves inside out in a process sharing invagination, expansion, involution, and peeling of a cell sheet with animal models of morphogenesis. We generalise our earlier, qualitative model of the initial stages of inversion by combining ideas from morphoelasticity and shell theory. Together with three-dimensional visualisations of inversion using light sheet microscopy, this yields a detailed, quantitative model of the entire inversion process. With this model, we show how the variability of inversion reveals that two separate, temporally uncoupled processes drive the initial invagination and subsequent expansion of the cell sheet. This implies a prototypical transition towards higher developmental complexity in the volvocine algae and provides proof of principle of analysing morphogenesis based on its variability. PMID- 30001336 TI - An efficient algorithm for estimating brain covariance networks. AB - Often derived from partial correlations or many pairwise analyses, covariance networks represent the inter-relationships among regions and can reveal important topological structures in brain measures from healthy and pathological subjects. However both approaches are not consistent network estimators and are sensitive to the value of the tuning parameters. Here, we propose a consistent covariance network estimator by maximising the network likelihood (MNL) which is robust to the tuning parameter. We validate the consistency of our algorithm theoretically and via a simulation study, and contrast these results against two well-known approaches: the graphical LASSO (gLASSO) and Pearson pairwise correlations (PPC) over a range of tuning parameters. The MNL algorithm had a specificity equal to and greater than 0.94 for all sample sizes in the simulation study, and the sensitivity was shown to increase as the sample size increased. The gLASSO and PPC demonstrated a specificity-sensitivity trade-off over a range of values of tuning parameters highlighting the discrepancy in the results for misspecified values. Application of the MNL algorithm to the case study data showed a loss of connections between healthy and impaired groups, and improved ability to identify between lobe connectivity in contrast to gLASSO networks. In this work, we propose the MNL algorithm as an effective approach to find covariance brain networks, which can inform the organisational features in brain-wide analyses, particularly for large sample sizes. PMID- 30001338 TI - Morphological and neurophysiological impairment of the nerve in type II macrodactyly. AB - BACKGROUND: Macrodactyly is a congenital malformation characterized by aggressive overgrowth of multiple tissues, including subcutaneous fat, nerves, and bones in digits or limbs. In type II macrodactyly, the peripheral nerve is enlarged; however, the morphological and functional characteristics of the affected peripheral nerves have rarely been evaluated. METHODS: In this research, six macrodactyly patients and three polydactyly patients (control) were studied. Pre operative sensory nerve action potential and intra-operative nerve action potential tests were performed. The microstructure and ultrastructure of the enlarged nerves were observed and neurofilament (NF) expression was evaluated using immunofluorescent staining. RESULTS: Axon impairment of the digital nerves originating from the median nerve (MN) was observed. A compensatory reinnervation from the ulnar nerve (UN) was found in two of the six patients, and significant morphological changes were observed in the enlarged nerve. The myelinated nerve fibers decreased, the lamellar structure of the myelin sheath changed, and the density of the NFs of the unmyelinated fibers decreased. There was aberrant distribution of NFs in the macrodactylous nerve tissues. In patients with compensatory UN reinnervation, the number of myelinated and unmyelinated fibers increased to normal levels; however, the diameter of the myelinated fibers apparently decreased. CONCLUSIONS: The morphology and function of the macrodactylous enlarged nerve was impaired in type II macrodactyly patients; however, the unaffected UN partially compensated for the lost function of the affected MN under specific situations. Electrophysiological tests should be performed to determine the function of the affected nerve and surgical treatment for type II macrodactyly could be refined. PMID- 30001339 TI - The Chicago School Readiness Project: Examining the long-term impacts of an early childhood intervention. AB - The current paper reports long-term treatment impact estimates for a randomized evaluation of an early childhood intervention designed to promote children's developmental outcomes and improve the quality of Head Start centers serving high violence and high-crime areas in inner-city Chicago. Initial evaluations of end of-preschool data reported that the program led to reductions in child behavioral problems and gains in measures of executive function and academic achievement. For this report, we analyzed adolescent follow-up data taken 10 to 11 years after program completion. We found evidence that the program had positive long-term effects on students' executive function and grades, though effects were somewhat imprecise and dependent on the inclusion of baseline covariates. Results also indicated that treated children had heightened sensitivity to emotional stimuli, and we found no evidence of long-run effects on measures of behavioral problems. These findings raise the possibility that developing programs that improve on the Head Start model could carry long-run benefits for affected children. PMID- 30001341 TI - Investigating global phase diagrams (GPDs) with reentrant transition behavior. AB - In this paper we calculate the global phase diagrams with the closed-loop behavior for the phase transition of physical systems by means of the transverse field Ising model with nearest neighbor interaction. The 3D graph plotted by the various physical parameters gives a clear appreciation and qualitative understanding of the reentrant phase behavior of the system. Meanwhile the results show the close correlation between experimental phenomena and our theoretical calculation for the closed-loop behavior for the phase transition of the systems. PMID- 30001340 TI - Clinical, environmental, and behavioral characteristics associated with Cryptosporidium infection among children with moderate-to-severe diarrhea in rural western Kenya, 2008-2012: The Global Enteric Multicenter Study (GEMS). AB - BACKGROUND: Cryptosporidium is a leading cause of moderate-to-severe diarrhea (MSD) in young children in Africa. We examined factors associated with Cryptosporidium infection in MSD cases enrolled at the rural western Kenya Global Enteric Multicenter Study (GEMS) site from 2008-2012. METHODOLOGY/PRINCIPAL FINDINGS: At health facility enrollment, stool samples were tested for enteric pathogens and data on clinical, environmental, and behavioral characteristics collected. Each child's health status was recorded at 60-day follow-up. Data were analyzed using logistic regression. Of the 1,778 children with MSD enrolled as cases in the GEMS-Kenya case-control study, 11% had Cryptosporidium detected in stool by enzyme immunoassay; in a genotyped subset, 81% were C. hominis. Among MSD cases, being an infant, having mucus in stool, and having prolonged/persistent duration diarrhea were associated with being Cryptosporidium positive. Both boiling drinking water and using rainwater as the main drinking water source were protective factors for being Cryptosporidium-positive. At follow-up, Cryptosporidium-positive cases had increased odds of being stunted (adjusted odds ratio [aOR] = 1.65, 95% CI: 1.06-2.57), underweight (aOR = 2.08, 95% CI: 1.34-3.22), or wasted (aOR = 2.04, 95% CI: 1.21-3.43), and had significantly larger negative changes in height- and weight-for-age z-scores from enrollment. CONCLUSIONS/SIGNIFICANCE: Cryptosporidium contributes significantly to diarrheal illness in young children in western Kenya. Advances in point of care detection, prevention/control approaches, effective water treatment technologies, and clinical management options for children with cryptosporidiosis are needed. PMID- 30001344 TI - Jatropha half-sib family selection with high adaptability and genotypic stability. AB - Jatropha (Jatropha curcas) has become one of the most important species for producing biofuels. Currently, Genotype x Environment (GxE) interaction is the biggest challenge that breeders should solve to increase the section accuracy in the plant breeding. Therefore, the objectives in this study were to estimate the parameters in the 180 half-sib families in Jatropha evaluated for five production years, to verify the significance of the GxE interaction variance, to evaluate the adaptability and stability for each family based on three prediction methods, to select superior half-sib families based on the adaptability and stability analyses, and to predict the accuracy for the sixth production year. Jatropha half-sib families were classified and selected using the follow adaptability and stability methods: linear regression, bi-segmented linear regression and mixed models concepts called harmonic mean of the relative performance of genetic values (HMRPGV). The prediction accuracy was estimated by the Pearson correlation between the predicted genetic values by adaptability and stability methods and the phenotypic value in the sixth production year. In result, most half-sib families were classified as general adaptability and general stability for the evaluated traits. The selection gain obtained via HMRPGV was higher than other methods. The prediction accuracy for the sixth production year was 0.45. Therefore, HMRPGV is efficient to maximize the genetic gain, and it can be a useful strategy to select genotype with high adaptability and stability in Jatropha breeding as well as other species that should be evaluated for many years to take a suitable selection accuracy. PMID- 30001342 TI - Nitrosporeusine analogue ameliorates Chandipura virus induced inflammatory response in CNS via NFkappab inactivation in microglia. AB - Chandipura Virus (CHPV), a negative-stranded RNA virus belonging to the Rhabdoviridae family, has been previously reported to bring neuronal apoptosis by activating several factors leading to neurodegeneration. Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues gets activated and starts secreting chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the effect of CHPV on microglia and the activation of cellular signalling pathways leading to chemokine expression upon CHPV infection. Protein and mRNA expression profiles of chemokine genes revealed that CHPV infection strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. CHPV infection triggered the activation of signalling pathways mediated by mitogen-activated protein kinases, including p38, JNK 1 and 2, and nuclear factor kappaB (NF-kappaB). CHPV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. Considering the important role of inflammation in neurodegeneration, we have targeted NF-kappaB using a newly synthesised natural product nitrosporeusine analogue and showed incapability of microglial supernatant of inducing apoptosis in neurons after treatment. PMID- 30001343 TI - Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth. AB - Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB. PMID- 30001345 TI - Reducing healthcare-associated infections incidence by a probiotic-based sanitation system: A multicentre, prospective, intervention study. AB - Healthcare Associated Infections (HAI) are a global concern, further threatened by the increasing drug resistance of HAI-associated pathogens. On the other hand, persistent contamination of hospital surfaces contributes to HAI transmission, and it is not efficiently controlled by conventional cleaning, which does not prevent recontamination, has a high environmental impact and can favour selection of drug-resistant microbial strains. In the search for effective approaches, an eco-sustainable probiotic-based cleaning system (Probiotic Cleaning Hygiene System, PCHS) was recently shown to stably abate surface pathogens, without selecting antibiotic-resistant species. The aim of this study was to determine whether PCHS application could impact on HAI incidence. A multicentre, pre-post interventional study was performed for 18 months in the Internal Medicine wards of six Italian public hospitals (January 1st 2016-June 30th 2017). The intervention consisted of the substitution of conventional sanitation with PCHS, maintaining unaltered any other procedure influencing HAI control. HAI incidence in the pre and post-intervention period was the main outcome measure. Surface bioburden was also analyzed in parallel. Globally, 11,842 patients and 24,875 environmental samples were surveyed. PCHS was associated with a significant decrease of HAI cumulative incidence from a global 4.8% (284 patients with HAI over 5,930 total patients) to 2.3% (128 patients with HAI over 5,531 total patients) (OR = 0.44, CI 95% 0.35-0.54) (P<0.0001). Concurrently, PCHS was associated with a stable decrease of surface pathogens, compared to conventional sanitation (mean decrease 83%, range 70-96.3%), accompanied by a concurrent up to 2 Log drop of surface microbiota drug-resistance genes (P<0.0001; Pc = 0.008). Our study provides findings which support the impact of a sanitation procedure on HAI incidence, showing that the use of a probiotic-based environmental intervention can be associated with a significant decrease of the risk to contract a HAI during hospitalization. Once confirmed in larger experiences and other target populations, this eco-sustainable approach might be considered as a part of infection control and prevention (IPC) strategies. Trial registration ISRCTN International Clinical Trials Registry, ISRCTN58986947. PMID- 30001346 TI - LMDIPred: A web-server for prediction of linear peptide sequences binding to SH3, WW and PDZ domains. AB - Protein-peptide interactions form an important subset of the total protein interaction network in the cell and play key roles in signaling and regulatory networks, and in major biological processes like cellular localization, protein degradation, and immune response. In this work, we have described the LMDIPred web server, an online resource for generalized prediction of linear peptide sequences that may bind to three most prevalent and well-studied peptide recognition modules (PRMs)-SH3, WW and PDZ. We have developed support vector machine (SVM)-based prediction models that achieved maximum Matthews Correlation Coefficient (MCC) of 0.85 with an accuracy of 94.55% for SH3, MCC of 0.90 with an accuracy of 95.82% for WW, and MCC of 0.83 with an accuracy of 92.29% for PDZ binding peptides. LMDIPred output combines predictions from these SVM models with predictions using Position-Specific Scoring Matrices (PSSMs) and string-matching methods using known domain-binding motif instances and regular expressions. All of these methods were evaluated using a five-fold cross-validation technique on both balanced and unbalanced datasets, and also validated on independent datasets. LMDIPred aims to provide a preliminary bioinformatics platform for sequence-based prediction of probable binding sites for SH3, WW or PDZ domains. PMID- 30001348 TI - Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1. AB - BACKGROUND AND PURPOSE: Moyamoya angiopathy is a progressive cerebral vasculopathy. The p.R4810K substitution in RNF213 has previously been linked to moyamoya disease in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1, this vasculopathy is frequently reported as moyamoya syndrome. Intriguingly, most cases of moyamoya-complicated neurofibromatosis type 1 have been described in Caucasians, inverting the population ratio observed in Asians, although prevalence of neurofibromatosis type 1 is constant worldwide. Our aim was to investigate whether, among Caucasians, additive genetic factors may contribute to the occurrence of moyamoya in neurofibromatosis type 1. METHODS: Whole exome sequencing was carried out on an Italian family with moyamoya-complicated neurofibromatosis type 1 to identify putative genetic modifiers independent of the NF1 locus and potentially involved in moyamoya pathogenesis. Results were validated in an unrelated family of German ancestry. RESULTS: We identified the p.P186S substitution (rs35857561) in MRVI1 that segregated with moyamoya syndrome in both the Italian and German family. CONCLUSIONS: The rs35857561 polymorphism in MRVI1 may be a genetic susceptibility factor for moyamoya in European patients with neurofibromatosis type 1. MRVI1 is a functional partner of ITPR1, PRKG1 and GUCY1A3, which are involved in response to nitric oxide. Mutations in GUCY1A3 have been recently linked to a recessive syndromic form of moyamoya with esophageal achalasia. PMID- 30001347 TI - Development of Trypanosoma cruzi in vitro assays to identify compounds suitable for progression in Chagas' disease drug discovery. AB - Chagas' disease is responsible for significant mortality and morbidity in Latin America. Current treatments display variable efficacy and have adverse side effects, hence more effective, better tolerated drugs are needed. However, recent efforts have proved unsuccessful with failure of the ergosterol biosynthesis inhibitor posaconazole in phase II clinical trials despite promising in vitro and in vivo studies. The lack of translation between laboratory experiments and clinical outcome is a major issue for further drug discovery efforts. Our goal was to identify cell-based assays that could differentiate current nitro-aromatic drugs nifurtimox and benznidazole from posaconazole. Using a panel of T. cruzi strains including the six major lineages (TcI-VI), we found that strain PAH179 (TcV) was markedly less susceptible to posaconazole in vitro. Determination of parasite doubling and cycling times as well as EdU labelling experiments all indicate that this lack of sensitivity is due to the slow doubling and cycling time of strain PAH179. This is in accordance with ergosterol biosynthesis inhibition by posaconazole leading to critically low ergosterol levels only after multiple rounds of division, and is further supported by the lack of effect of posaconazole on the non-replicative trypomastigote form. A washout experiment with prolonged posaconazole treatment showed that, even for more rapidly replicating strains, this compound cannot clear all parasites, indicative of a heterogeneous parasite population in vitro and potentially the presence of quiescent parasites. Benznidazole in contrast was able to kill all parasites. The work presented here shows clear differentiation between the nitro-aromatic drugs and posaconazole in several assays, and suggests that in vitro there may be clinically relevant heterogeneity in the parasite population that can be revealed in long-term washout experiments. Based on these findings we have adjusted our in vitro screening cascade so that only the most promising compounds are progressed to in vivo experiments. PMID- 30001350 TI - Using citizen science to describe the prevalence and distribution of tick bite and exposure to tick-borne diseases in the United States. AB - Tick-borne pathogens are increasing their range and incidence in North America as a consequence of numerous factors including improvements in diagnostics and diagnosis, range expansion of primary vectors, changes in human behavior, and an increasing understanding of the diversity of species of pathogens that cause human disease. Public health agencies have access to human incidence data on notifiable diseases e.g., Borrelia burgdorferi, the causative agent of Lyme disease, and often local pathogen prevalence in vector populations. However, data on exposure to vectors and pathogens can be difficult to determine e.g., if disease does not occur. We report on an investigation of exposure to ticks and tick-borne bacteria, conducted at a national scale, using citizen science participation. 16,080 ticks were submitted between January 2016 and August 2017, and screened for B. burgdorferi, B. miyamotoi, Anaplasma phagocytophilum, and Babesia microti. These data corroborate entomologic investigations of tick distributions in North America, but also identify patterns of local disease risk and tick contact with humans throughout the year in numerous species of ticks and associated pathogens. PMID- 30001349 TI - Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells. AB - Current anti-cancer strategy takes advantage of tumour specific abnormalities in DNA damage response to radio- or chemo-therapy. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of T-lymphocyte leukemic MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug induced changes in irradiated cells. VE-821 radiosensitized MOLT-4 cells, and furthermore 10 MUM VE-821 significantly affected proliferation of sham-irradiated MOLT-4 cells. We detected 623 differentially regulated phosphorylation sites. We revealed changes not only in DDR-related pathways and kinases, but also in pathways and kinases involved in maintaining cellular metabolism. Notably, we found downregulation of mTOR, the main regulator of cellular metabolism, which was most likely caused by an off-target effect of the inhibitor, and we propose that mTOR inhibition could be one of the factors contributing to the phenotype observed after treating MOLT-4 cells with 10 MUM VE-821. In the metabolomic analysis, 206 intermediary metabolites were detected. The data indicated that VE 821 potentiated metabolic disruption induced by irradiation and affected the response to irradiation-induced oxidative stress. Upon irradiation, recovery of damaged deoxynucleotides might be affected by VE-821, hampering DNA repair by their deficiency. Taken together, this is the first study describing a complex scenario of cellular events that might be ATR-dependent or triggered by ATR inhibition in irradiated MOLT-4 cells. Data are available via ProteomeXchange with identifier PXD008925. PMID- 30001351 TI - Gout and the risk of age-related macular degeneration in the elderly. AB - OBJECTIVE: To assess whether gout is associated with incident age-related macular degeneration (AMD). METHODS: We used the 5% Medicare claims data from 2006-12 for all beneficiaries who were enrolled in Medicare fee-for-service (Parts A, B) and not enrolled in a Medicare Advantage Plan, and resided in the U.S. People were censored at the occurrence of new diagnosis of AMD, death or the end of study (12/31/2012), whichever occurred first. We used multivariable-adjusted Cox regression analyses to assess the association of gout with incident AMD, adjusted for demographics, comorbidity, and use of medications for cardiovascular disease and gout. Hazard ratios and 95% confidence intervals were calculated. RESULTS: In this observational cohort study, of the 1,684,314 eligible people, 116,097 developed incident AMD (6.9%). Incidence rates of AMD per 1,000 person-years were 20.1 for people with gout and 11.7 for people without gout. In multivariable adjusted analyses, a diagnosis of gout was significantly associated with a higher risk of incident AMD with a hazard ratio of 1.39 (95% CI, 1.35, 1.43). This association was confirmed in sensitivity analyses that substituted Charlson Romano comorbidity index continuous score with either a categorical Charlson Romano comorbidity index score or individual Charlson-Romano index comorbidities plus hypertension, hyperlipidemia and coronary artery disease. Other covariates significantly associated with higher hazards of incident AMD were older age, female gender, White race/ethnicity, and higher Charlson-Romano comorbidity index score. CONCLUSIONS: We noted a novel association of gout with AMD in the elderly. Future studies should investigate the pathways that mediate this association. PMID- 30001352 TI - A robust gene regulatory network inference method base on Kalman filter and linear regression. AB - The reconstruction of the topology of gene regulatory networks (GRNs) using high throughput genomic data such as microarray gene expression data is an important problem in systems biology. The main challenge in gene expression data is the high number of genes and low number of samples; also the data are often impregnated with noise. In this paper, in dealing with the noisy data, Kalman filter based method that has the ability to use prior knowledge on learning the network was used. In the proposed method namely (KFLR), in the first phase by using mutual information, the noisy regulations with low correlations were removed. The proposed method utilized a new closed form solution to compute the posterior probabilities of the edges from regulators to the target gene within a hybrid framework of Bayesian model averaging and linear regression methods. In order to show the efficiency, the proposed method was compared with several well know methods. The results of the evaluation indicate that the inference accuracy was improved by the proposed method which also demonstrated better regulatory relations with the noisy data. PMID- 30001353 TI - Is infant arterial stiffness associated with maternal blood pressure in pregnancy? Findings from a UK birth cohort (Baby VIP study). AB - BACKGROUND: In adults, arterial stiffness measured by pulse wave velocity (PWV) is regarded as a predictor of cardiovascular disease. Infant vascular development depends on factors related to pregnancy, including maternal blood pressure (BP). This study assessed the association between maternal BP in pregnancy and infant brachio-femoral PWV at age 2-6 weeks. METHODS: The Baby Vascular health and Iron in Pregnancy (Baby VIP) study is a birth cohort which measured PWV and heart rate (HR) in 284 babies in Leeds, UK, at 2-6 weeks after birth. Maternal BP measurements at 12 and 36 weeks gestation was collected from antenatal clinical records. Multivariable linear regression models assessed associations between maternal systolic and diastolic BPs, and BP change from booking to 36 weeks, with infant PWV adjusting for covariables at both mother and baby level. RESULTS: There was no evidence of an association between infant PWV and maternal systolic BP at booking (adjusted regression coefficient -0.01 m/s per 10mmHg, 95% CI 0.11, 0.14, p = 0.84) or at 36 weeks (adjusted regression coefficient 0.00 m/s per 10mmHg, 95% CI -0.12, 0.11, p = 0.95). Change between 12 and 36 weeks gestation of more than 30 mmHg in systolic BP or 15 mmHg in diastolic BP was also not associated with infant PWV. There was an inverse relationship between infant HR and infant PWV (regression coefficient -0.14 m/s per 10 bpm, 95% CI -0.22, 0.05, p<0.01). CONCLUSIONS: This study has shown no evidence of association between infant PWV at 2-6 weeks of age and maternal BP in early or late pregnancy. Infant HR was inversely associated with infant PWV. Further studies are required to determine the predictors of infant PWV as well as the importance and long term implications of PWV measurements in infants. PMID- 30001354 TI - Cognitive frailty predicting all-cause mortality among community-living older adults in Taiwan: A 4-year nationwide population-based cohort study. AB - BACKGROUND: Cognitive frailty (CF) featured as frailty plus cognitive impairment was deemed to be a novel target for dementia and disable prevention. The study was intended to investigate the epidemiology of CF and the association between CF and all-cause mortality. METHODS: The national representative cohort study was comprised of 1,103 community-living middle-aged and older adults. CF was defined as the co-existence of dynapenia (weakness and/or slowness) and cognitive impairment (1.5 standard deviations below the age-, sex- and education-matched norms in cognitive tests) without known neurodegenerative diseases. Dynapenia was defined by the Asian Working Group for Sarcopenia and cognitive function was assessed by the Short Portable Mental Status Questionnaire. RESULTS: The prevalence of CF was 8.6% in this study. Subjects with CF were older, more likely to be women, having less regular exercise, fewer educational years, more depressive symptoms and greater multimorbidity. Compared to robust individuals, CF was significantly associated with all-cause mortality (HR: 3.1, 95% CI:1.3 7.7, p = 0.012). CONCLUSION: Dynapenia and cognitive impairment synergistically contribute to the mortality risk for the participants in this study. Further study is needed to explore the underlying pathophysiology and the reversibility of CF. PMID- 30001356 TI - Network-based risk measurements for interbank systems. AB - This paper focuses on evaluating the systemic risk in interbank networks, proposing a series of measurements: risk distance, risk degree and m-order risk degree. The proposed measurements are formally proven to have good basic and extended properties that are able to reflect the effect of bank size, liability size, liability distribution, and the discount factor on the default risk, not only of a single bank, but also of the entire system. Additionally, the abovementioned properties and the relationship between risk distance and financial contagion indicate the rationality embodied in the proposed measurements. This paper also provides some implications on how to decrease or prevent the systemic risk in an interbank system. PMID- 30001355 TI - Characteristics, treatment and quality of life of stable coronary artery disease patients with or without angina: Insights from the START study. AB - Data on contemporary management patterns of angina in patients with stable coronary artery disease (CAD) are scarce. We sought to describe the current presentation, management, and quality of life of stable CAD patients with or without angina, using the data from the START (STable Coronary Artery Diseases RegisTry) study. START was a prospective, observational, nationwide study aimed to evaluate the presentation, management, treatment and quality of life of stable CAD presenting to cardiologists during outpatient visits or discharged from cardiology wards. Among the 5070 consecutive stable CAD patients enrolled in 183 participating centers over a 3-month period, 3714 (73.2%) had no angina and 1356 (26.8%) presented with angina. Patients with angina underwent more frequently coronary angiography (92.7% vs 84.9%; p<0.0001) and other diagnostic imaging procedures compared to those without angina. In addition, patients with angina received more frequently different combinations of first line therapies and angina relief drugs compared to patients without angina. The quality of life, assessed with the EQ 5D-5L questionnaire, did not differ between the two groups, with the exception of the 'pain or worry' domain that was higher in patients with compared to those without angina (p<0.0001). Current management and treatment of stable CAD patients with angina is still suboptimal and different compared to those without angina. Our findings highlight the need for disseminating best practice patterns and improving guidelines adherence for the management of angina even among cardiologists. PMID- 30001357 TI - Peer effects on adolescent smoking: Are popular teens more influential? AB - Previous research on adolescent cigarette adoption has focused on peer influence and the perceived status gain from smoking but has ignored the status effects on peer influence. We analyze adolescent peer effects on cigarette consumption while considering the popularity of peers. The analysis is based on a four wave panel survey representative of American high school students. We measure peers' popularity by their eigenvector centrality in high school social networks. Using lagged peers' behavior, school fixed effects, and instrumental variables to control for homophily and contextual confounds, we find that the probability of smoking the following year increases with the mean popularity of smokers, while the popularity of non-smokers has the opposite effect. These effects persist seven and fourteen years later (wave 3 and 4 of the data). In addition, the probability of smoking increases with the smoking propensity of the 20% most popular teens and decreases with the smoking propensity of the bottom 80%. The results indicate the importance of knowing not only the smoking propensity within a school but also the location of smokers within the social hierarchy. PMID- 30001358 TI - Level of partograph utilization and its associated factors among obstetric caregivers at public health facilities in East Gojam Zone, Northwest Ethiopia. AB - INTRODUCTION: The discrepancy regarding maternal mortality continues to be a health concern between developing and developed countries. The majority of global maternal deaths occur in developing countries, specifically, in the sub-Sahara African region which alone accounts for more than half of these deaths. It has been indicated that utilization of the partograph was significantly associated with improved maternal and neonatal outcomes of labour and that is why the World Health Organization recommends the universal use of the tool during labour. Therefore, this study has assessed the level of partograph use and its associated factors among obstetric caregivers in East Gojam Zone, Northwest Ethiopia. METHODS: A health facility based cross-sectional study was conducted among randomly selected obstetric caregivers in Northwest Ethiopia. The data were collected using a self-administered questionnaire and a clinical observation checklist. The data were entered into Epidata version 3.1, and cleaned and analyzed using SPSS version 24.0 statistical software. RESULT: About three quarters, or 198 (72.53%), of the obstetric caregivers, had attained diploma level of education. However, 153 (56.04%) of the obstetric caregivers had what was considered to be good knowledge about the partograph, but utilization of the tool was slightly lower than their level of knowledge, 147 (53.85%). Utilization of the partograph was significantly higher among obstetric caregivers holding a Bachelor of Science degree and above, than Diploma holders (AOR (95% C.I) 2.07 (1.15-3.75)) and the use was higher among those who were regularly working in the delivery ward compared to those regularly working in the Adult Outpatient Department (AOR (95% C.I): 2.25 (1.07-4.72)). Moreover, caregivers who had a good knowledge about the partograph and who had received on the job training in obstetric care were also more likely to use the partograph during labour and delivery (AOR (95% C.I): 1.79 (1.05-3.06) and 4.85 (2.63-8.96)) respectively. CONCLUSION: The results of this study revealed that although more than half of obstetric caregivers had a good knowledge of the partograph, the actual utilization of the tool was slightly lower than the knowledge they had. Therefore, in this study, we suggest that providing on the job obstetric care training for obstetric caregivers, about the partograph in particular, would improve partograph utilization. PMID- 30001360 TI - Using search engine big data for predicting new HIV diagnoses. AB - BACKGROUND: A large and growing body of "big data" is generated by internet search engines, such as Google. Because people often search for information about public health and medical issues, researchers may be able to use search engine data to monitor and predict public health problems, such as HIV. We sought to assess the feasibility of using Google search data to analyze and predict new HIV diagnoses cases in the United States. METHODS AND FINDINGS: From 2007 to 2014, we collected search volume data on HIV-related Google search keywords across the United States. State-level new HIV diagnoses data were collected from the Centers for Disease Control and Prevention (CDC) and AIDSVu.org. We developed a negative binomial model to predict HIV cases using a subset of significant predictor keywords identified by LASSO. The Google search data were combined with state level HIV case reports provided by the CDC. We use historical data to train the model and predict new HIV diagnoses from 2011 to 2014, with an average R2 value of 0.99 between predicted versus actual cases, and average root-mean-square error (RMSE) of 108.75. CONCLUSIONS: Results indicate that Google Trends is a feasible tool to predict new cases of HIV at the state level. We discuss the implications of integrating visualization maps and tools based on these models into public health and HIV monitoring and surveillance. PMID- 30001362 TI - Is increased colorectal screening effective in preventing distant disease? AB - BACKGROUND: Screening in the average risk population for colorectal cancer (CRC) is expected to reduce the incidence of distant (i.e., metastatic) CRCs at least as much as less advanced CRCs. Indeed, since 2000, during which time colonoscopy became widely used as a screening tool, the overall incidence of CRC has been reduced by 29%. OBJECTIVE: The purpose of the current study was to determine whether the reduction of incidence rates is the same for all stages of disease. METHODS: We evaluated incidence data from the Surveillance, Epidemiology, and End Results (SEER) program from 2000-2014 for Localized, Regional, and Distant disease. Joinpoint models were compared to assess parallelism of trends. Data were stratified by race, age, tumor location, and sex to determine whether these subgroupings could explain overall trends. RESULTS: Inconsistent with the expectations of a successful screening program, the reduction in incidence rates of distant CRCs from 2000-2014 has been slower than the reductions in incidence rates of both regional and localized CRCs. This trend is evident even when the data are stratified by age at diagnosis, sex, race, or tumor location. CONCLUSIONS: The slower decrease in the incidence rate of distant disease is not consistent with a screening effect, that is, CRC screening may not be effective in preventing many distant CRCs. As a consequence, distant CRCs represent an increasing fraction of all CRCs, accounting for 21% of all CRCs in 2014. The analysis indicates that inadequate screening does not explain the slower decrease in incidence of distant CRCs. Consequently, we suggest that a subtype of CRC exists that advances rapidly, evading detection because screening intervals are too long to prevent it. Microsatellite unstable tumors represent a known subtype that advances more rapidly, and we suggest that another rapidly advancing subtype very likely exists that is microsatellite stable. PMID- 30001359 TI - Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts. AB - BACKGROUND: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. METHODS AND FINDINGS: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. CONCLUSIONS: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2. PMID- 30001363 TI - Role of the Streptococcus suis serotype 2 capsular polysaccharide in the interactions with dendritic cells is strain-dependent but remains critical for virulence. AB - Streptococcus suis serotype 2 is an important porcine bacterial pathogen and zoonotic agent responsible for sudden death, septic shock, and meningitis. However, serotype 2 strains are heterogeneous, composed of a multitude of sequence types (STs) whose distribution greatly varies worldwide. Of the virulence factors presently described for S. suis, the capsular polysaccharide (CPS) is a critical factor implicated in a multitude of functions, including in impairment of phagocytosis and innate immune cell activation by masking underlying bacterial components. However, these roles have been described using Eurasian ST1 and ST7 strains, which greatly differ from North American ST25 strains. Consequently, the capacity of the CPS to mask surface antigens and putative virulence factors in non-Eurasian strains remains unknown. Herein, the role of the S. suis serotype 2 CPS of a prototype intermediate virulent North American ST25 strain, in comparison with that of a virulent European ST1 strain, with regards to interactions with dendritic cells, as well as virulence during the systemic phase of infection, was evaluated. Results demonstrated that the CPS remains critical for virulence and development of clinical disease regardless of strain background, due to its requirement for survival in blood. However, its role in the interactions with dendritic cells is strain-dependent. Consequently, certain key characteristics associated with the CPS are not necessarily applicable to all S. suis serotype 2 strains. This indicates that though certain factors may be important for S. suis serotype 2 virulence, strain background could be as determining, reiterating the need in using strains from varying backgrounds in order to better characterize the S. suis pathogenesis. PMID- 30001361 TI - Atlas of tissue- and developmental stage specific gene expression for the bovine insulin-like growth factor (IGF) system. AB - The insulin-like growth factor (IGF) axis is fundamental for mammalian growth and development. However, no comprehensive reference data on gene expression across tissues and pre- and postnatal developmental stages are available for any given species. Here we provide systematic promoter- and splice variant specific information on expression of IGF system components in embryonic (Day 48), fetal (Day 153), term (Day 277, placenta) and juvenile (Day 365-396) tissues of domestic cow, a major agricultural species and biomedical model. Analysis of spatiotemporal changes in expression of IGF1, IGF2, IGF1R, IGF2R, IGFBP1-8 and IR genes, as well as lncRNAs H19 and AIRN, by qPCR, indicated an overall increase in expression from embryo to fetal stage, and decrease in expression from fetal to juvenile stage. The stronger decrease in expression of lncRNAs (average -16-fold) and ligands (average -12.1-fold) compared to receptors (average -5.7-fold) and binding proteins (average -4.3-fold) is consistent with known functions of IGF peptides and supports important roles of lncRNAs in prenatal development. Pronounced overall reduction in postnatal expression of IGF system components in lung (-12.9-fold) and kidney (-13.2-fold) are signatures of major changes in organ function while more similar hepatic expression levels (-2.2-fold) are evidence of the endocrine rather than autocrine/paracrine role of IGFs in postnatal growth regulation. Despite its rapid growth, placenta displayed a more stable expression pattern than other organs during prenatal development. Quantitative analyses of contributions of promoters P0-P4 to global IGF2 transcript in fetal tissues revealed that P4 accounted for the bulk of transcript in all tissues but skeletal muscle. Demonstration of IGF2 expression in fetal muscle and postnatal liver from a promoter orthologous to mouse and human promoter P0 provides further evidence for an evolutionary and developmental shift from placenta-specific P0-expression in rodents and suggests that some aspects of bovine IGF expression may be closer to human than mouse. PMID- 30001365 TI - Association of inflammatory genes in obstructive sleep apnea and non alcoholic fatty liver disease in Asian Indians residing in north India. AB - BACKGROUND: Previous studies have indicated that variants of the high sensitive C reactive protein (CRP), Interleukin (IL)-6 and leptin receptor (LEPR) genes are associated with the presence of obstructive sleep apnea (OSA) but not in non alcoholic fatty liver disease (NAFLD) in Asian Indians. The study was conducted to investigate the association of CRP rs1130864 (1444C/T), IL-6 rs1800795 ( 174G/C) and LEPR rs1137101 (Q223R) genes with OSA and NAFLD in Asian Indians residing in North India. METHODS: 240 overweight/ obese subjects [body mass index (BMI>23kg/m2)], 124 with OSA and with NAFLD (group 1), 47 with OSA without NAFLD (group 2), 44 without OSA and with NAFLD (group 3) and 25 without OSA and without NAFLD (group 4) were recruited in this study. The severity of NAFLD was based on abdomen liver ultrasound and of OSA on overnight polysomnography. Clinical details, anthropometry profile, body composition, biochemical parameters and inflammatory markers were measured. Polymerase chain reaction and restriction fragment length polymorphism of CRP, IL-6 and LEPR gene was performed. The associations of these polymorphisms with clinical, anthropometric and biochemical profiles were investigated. The genotypes were confirmed by DNA sequencing analysis. RESULTS: The C, T and R alleles of IL-6, CRP and LEPR genes was more frequent in OSA and NAFLD subjects and significantly correlated with higher protein levels. The prevalence of variant genotypes C/T of CRP, G/C of IL-6 and Q/R of LEPR genes was significantly higher in OSA subjects as compared to non OSA subjects. Further, C/C genotype of IL-6 (G/C), T/T of CRP (C/T) and RR genotype of LEPR (Q/R) was associated with significantly higher BMI, fat mass (kg), % body fat, waist circumference, serum triglycerides, total cholesterol, alkaline phosphate, aspartate transaminase and fasting insulin levels in OSA and NAFLD subjects. Using a multivariate analysis, the combined effect of three polymorphisms of CRP, IL-6 and LEPR gene variants on OSA and NAFLD risk was evaluated. Odds ratio for OSA and NAFLD with the combination of the three gene polymorphisms increased to 2.84 (95% CI: 1.08-6.54; p = 0.04) even when adjusted for sex, age and BMI. CONCLUSION: Polymorphisms of pro-inflammatory cytokine genes were associated with increased risk of OSA and NAFLD in Asian Indians. PMID- 30001366 TI - Individual variation in the transmission of UVB radiation in the young adult eye. AB - OBJECTIVES: Data obtained mostly from animal models and ex vivo samples show that a small portion of ultraviolet light (UV, 300-400 nm) penetrates the cornea and crystalline lens and impinges on the human retina. UV transmission to the retina appears to be unique to the young and some older pseudophakes. In this study, we determine the variation in UV transmission in a relatively homogenous sample of young adults. METHODS: 42 subjects were tested (M = 19 +/- 1.3 years). Absolute thresholds to UV radiation were collected (lambdamax = 315 nm, 305-325). Macular pigment optical density (MPOD, measured using heterochromatic flicker photometry) and iris color (using a standardized color scale) were also assessed as potential covariates. RESULTS: All of the subjects could detect UV radiation at 315 nm but individual variation was large (over a factor of 30). Higher MPOD and darker iridies were not related to UV sensitivity in this young sample. Males, however, were more sensitive to UV than the females (p<0.05). CONCLUSIONS: The large individual differences in UV reaching the retina of younger individuals suggests equally significant vulnerability to the actinic effects of this highly energetic light. PMID- 30001364 TI - Measuring bone stiffness using spherical indentation. AB - OBJECTIVES: Bone material properties are a major determinant of bone health in older age, both in terms of fracture risk and implant fixation, in orthopaedics and dentistry. Bone is an anisotropic and hierarchical material so its measured material properties depend upon the scale of metric used. The scale used should reflect the clinical problem, whether it is fracture risk, a whole bone problem, or implant stability, at the millimetre-scale. Indentation, an engineering technique involving pressing a hard-tipped material into another material with a known force, may be able to assess bone stiffness at the millimetre-scale (the apparent elastic modulus). We aimed to investigate whether spherical-tip indentation could reliably measure the apparent elastic modulus of human cortical bone. MATERIALS AND METHODS: Cortical bone samples were retrieved from the femoral necks of nineteen patients undergoing total hip replacement surgery (10 females, 9 males, mean age: 69 years). The samples underwent indentation using a 1.5 mm diameter, ruby, spherical indenter tip, with sixty indentations per patient sample, across six locations on the bone surfaces, with ten repeated indentations at each of the six locations. The samples then underwent mechanical compression testing. The repeatability of indentation measurements of elastic modulus was assessed using the co-efficient of repeatability and the correlation between the bone elastic modulus measured by indentation and compression testing was analysed by least-squares regression. RESULTS: In total, 1140 indentations in total were performed. Indentation was found to be repeatable for indentations performed at the same locations on the bone samples with a mean co-efficient of repeatability of 0.4 GigaPascals (GPa), confidence interval (C.I): 0.33-0.42 GPa. There was variation in the indentation modulus results between different locations on the bone samples (mean co-efficient of repeatability: 3.1 GPa, C.I: 2.2-3.90 GPa). No clear correlation was observed between indentation and compression values of bone elastic modulus (r = 0.33, p = 0.17). The mean apparent elastic modulus obtained by spherical indentation was 9.9 GPa, the standard deviation for each indent cycle was 0.11 GPa, and the standard deviation between locations on the same sample was 1.01 GPa. The mean compression apparent elastic modulus was 4.42 GPa, standard deviation 1.02 GPa. DISCUSSION: Spherical tip indentation was found to be a repeatable test for measuring the elastic modulus of human cortical bone, demonstrated by a low co-efficient of repeatability in this study. It could not, however, reliably predict cortical bone elastic modulus determined by platens compression testing in this study. This may be due to indentation only probing mechanical properties at the micro scale while platens compression testing assesses millimetre length-scale properties. Improvements to the testing technique, including the use of a larger diameter spherical indenter tip, may improve the measurement of bone stiffness at the millimetre scale and should be investigated further. PMID- 30001367 TI - Incidental pulmonary emboli in stage IV melanoma patients: Prevalence in CT staging examinations and improved detection with vessel reconstructions based on dual energy CT. AB - OBJECTIVES: Malignancy is the strongest predictor for venous thromboembolism. Dual energy CT (DECT) can support assessment of pulmonary emboli (PE) by providing vessel reconstructions (DECT-VR) and highlighting thrombi. Purpose was to determine prevalence and risk factors of PE in staging examinations of stage IV-melanoma patients and to evaluate the potential of DECT-VR to improve PE diagnosis. MATERIAL AND METHODS: This retrospective study was approved by IRB. Contrast-enhanced, conventional grey scale CT (cCT) and DECT-VR of 200 stage IV melanoma patients were reviewed by three radiologists in consensus. Overall prevalence was determined. One-sided Wilcoxon-test was performed to compare the number of detected emboli between cCT and cCT with supplementary DECT-VR. Frequencies of risk factors were compared with chi2 test. RESULTS: On cCT, 9 PE were detected (6 patients, correlating to 3% of the study population with 0.05 emboli per patient). With the supplementary DECT-VR, number of diagnosed emboli increased from 9 to 17 (p < 0.05) (in total 9 patients, correlating to 0.09 emboli per patient). Emboli on DECT-VR were mainly subsegmentally (7 of 8). There was no significant difference in the frequency of risk factors. CONCLUSIONS: The prevalence of pulmonary emboli in our cohort of 200 stage IV melanoma patients was 5%. DECT-VR improved significantly diagnosis of PE, especially when located subsegmentally. PMID- 30001368 TI - Downregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth. AB - Precision cancer therapy requires on the one hand detailed knowledge about a tumor's driver oncogenes and on the other hand an effective targeted therapy that specifically inhibits these oncogenes. While the determination of genomic landscape of a tumor has reached a very precise level, the respective therapy options are scarce. The application of small inhibitory (si) RNAs is a promising field of investigation. Here, we present the effective in vivo-treatment of colorectal cancer (CRC) xenograft tumors with antibody-complexed, endoribonuclease-prepared small inhibitory (esi)RNAs. We chose heterogeneous endoribonuclease-prepared siRNA pools (esiRNAs) against the frequently mutated genes PIK3CA and KRAS and coupled them to the anti-EGFR antibody cetuximab, which was internalized specifically into the tumor cells. esiRNA pools have been shown to exhibit superior specificity in target gene knockdown compared to classic siRNAs. We identified a significant decrease in tumor growth upon this treatment due to decreased tumor cell proliferation. The ex vivo-analysis of the xenograft CRC tumors revealed the expected downregulation of the intended direct targets PIK3CA and KRAS on protein level. Moreover, known downstream targets for EGFR signaling such as p-ERK, p-AKT, and c-MYC were decreased as well. We therefore propose the use of antibody-esiRNA complexes as a novel experimental treatment option against key components of the EGFR signaling cascade. PMID- 30001370 TI - A new targeted capture method using bacterial artificial chromosome (BAC) libraries as baits for sequencing relatively large genes. AB - To analyze a specific genome region using next-generation sequencing technologies, the enrichment of DNA libraries with targeted capture methods has been standardized. For enrichment of mitochondrial genome, a previous study developed an original targeted capture method that use baits constructed from long-range polymerase chain reaction (PCR) amplicons, common laboratory reagents, and equipment. In this study, a new targeted capture method is presented, that of bacterial artificial chromosome (BAC) double capture (BDC), modifying the previous method, but using BAC libraries as baits for sequencing a relatively large gene. We applied the BDC approach for the 214 kb autosomal region, ring finger protein 213, which is the susceptibility gene of moyamoya disease (MMD). To evaluate the reliability of BDC, cost and data quality were compared with those of a commercial kit. While the ratio of duplicate reads was higher, the cost was less than that of the commercial kit. The data quality was sufficiently the same as that of the kit. Thus, BDC can be an easy, low-cost, and useful method for analyzing individual genome regions with substantial length. PMID- 30001371 TI - Mining patterns of comorbidity evolution in patients with multiple chronic conditions using unsupervised multi-level temporal Bayesian network. AB - Over the past few decades, the rise of multiple chronic conditions has become a major concern for clinicians. However, it is still not known precisely how multiple chronic conditions emerge among patients. We propose an unsupervised multi-level temporal Bayesian network to provide a compact representation of the relationship among emergence of multiple chronic conditions and patient level risk factors over time. To improve the efficiency of the learning process, we use an extension of maximum weight spanning tree algorithm and greedy search algorithm to study the structure of the proposed network in three stages, starting with learning the inter-relationship of comorbidities within each year, followed by learning the intra-relationship of comorbidity emergence between consecutive years, and finally learning the hierarchical relationship of comorbidities and patient level risk factors. We also use a longest path algorithm to identify the most likely sequence of comorbidities emerging from and/or leading to specific chronic conditions. Using a de-identified dataset of more than 250,000 patients receiving care from the U.S. Department of Veterans Affairs for a period of five years, we compare the performance of the proposed unsupervised Bayesian network in comparison with those of Bayesian networks developed based on supervised and semi-supervised learning approaches, as well as multivariate probit regression, multinomial logistic regression, and latent regression Markov mixture clustering focusing on traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), depression (Depr), substance abuse (SuAb), and back pain (BaPa). Our findings show that the unsupervised approach has noticeably accurate predictive performance that is comparable to the best performing semi-supervised and the second-best performing supervised approaches. These findings also revealed that the unsupervised approach has improved performance over multivariate probit regression, multinomial logistic regression, and latent regression Markov mixture clustering. PMID- 30001369 TI - Body density of humpback whales (Megaptera novaengliae) in feeding aggregations estimated from hydrodynamic gliding performance. AB - Many baleen whales undertake annual fasting and feeding cycles, resulting in substantial changes in their body condition, an important factor affecting fitness. As a measure of lipid-store body condition, tissue density of a few deep diving marine mammals has been estimated using a hydrodynamic glide model of drag and buoyancy forces. Here, we applied the method to shallow-diving humpback whales (Megaptera novaeangliae) in North Atlantic and Antarctic feeding aggregations. High-resolution 3-axis acceleration, depth and speed data were collected from 24 whales. Measured values of acceleration during 5 s glides were fitted to a hydrodynamic glide model to estimate unknown parameters (tissue density, drag term and diving gas volume) in a Bayesian framework. Estimated species-average tissue density (1031.6 +/- 2.1 kg m-3, +/-95% credible interval) indicates that humpback whale tissue is typically negatively buoyant although there was a large inter-individual variation ranging from 1025.2 to 1043.1 kg m 3. The precision of the individual estimates was substantially finer than the variation across different individual whales, demonstrating a progressive decrease in tissue density throughout the feeding season and comparably high lipid-store in pregnant females. The drag term (CDAm-1) was estimated to be relatively high, indicating a large effect of lift-related induced drag for humpback whales. Our results show that tissue density of shallow diving baleen whales can be estimated using the hydrodynamic gliding model, although cross validation with other techniques is an essential next step. This method for estimating body condition is likely to be broadly applicable across a range of aquatic animals and environments. PMID- 30001372 TI - Spatial variability in the diversity and structure of faunal assemblages associated with kelp holdfasts (Laminaria hyperborea) in the northeast Atlantic. AB - Kelp species are ecologically-important habitat-formers in coastal marine ecosystems, where they alter environmental conditions and promote local biodiversity by providing complex biogenic habitat for an array of associated organisms. While it is widely accepted that kelps harbour significant biodiversity, our current understanding of spatiotemporal variability in kelp associated assemblages and the key environmental drivers of variability patterns remains limited. Here we examined the influence of ocean temperature and wave exposure on the structure of faunal assemblages associated with the holdfasts of Laminaria hyperborea, the dominant habitat-forming kelp in the northeast Atlantic. We sampled holdfasts from 12 kelp-dominated open-coast sites nested within four regions across the UK, spanning ~9 degrees in latitude and ~2.7 degrees C in mean sea surface temperature. Overall, holdfast assemblages were highly diverse, with 261 taxa representing 11 phyla recorded across the study. We examined patterns of spatial variability for sessile and mobile taxa separately, and documented high variability between regions, between sites within regions, and between replicate holdfasts for both assemblage types. Mobile assemblage structure was more strongly linked to temperature variability than sessile assemblage structure, which was principally structured by site-level variability in factors such as wave exposure. Patterns in the structure of both biogenic habitat and associated assemblages did not vary predictably along a latitudinal gradient in temperature, indicating that other processes acting across multiple spatial and temporal scales are important drivers of assemblage structure. Overall, kelp holdfasts in the UK supported high levels of diversity, that were similar to other kelp-dominated systems globally and comparable to those recorded for other vegetated marine habitats (i.e. seagrass beds), which are perhaps more widely recognised for their high biodiversity value. PMID- 30001373 TI - Mental profile mapping: A psychological single-candidate authorship attribution method. AB - Modern authorship attribution methods are often comprised of powerful yet opaque machine learning algorithms. While much of this work lends itself to concrete outcomes in the form of probability scores, advanced approaches typically preclude deeper insights in the form of psychological interpretation. Additionally, few attribution methods exist for single-candidate authorship problems, most of which require large amounts of supplemental data to perform and none of which rely upon explicitly psychological measures. The current study introduces Mental Profile Mapping, a new authorship attribution technique for single-candidate authorship questions that is founded on previous scientific research pertaining to the nature of language and psychology. In the current study, baseline expectations for results and performance are set using an advanced technique known as "unmasking" on the test case of Aphra Behn, a 17th century English playwright. Following this, Mental Profile Mapping is introduced and tested for its psychometric properties, tested using a "bogus insertion" method, and then applied to canonical Aphra Behn plays. Results from both attribution methods suggest that 2 of 5 questioned plays are likely to have been authored by Behn, with the remaining 3 plays exhibiting a poor fit for Behn's psychological fingerprint. Mental Profile Mapping results are then decomposed into deeper psychological interpretation, a quality unique to this new method. PMID- 30001374 TI - On the rules of continuity and symmetry for the data quality of street networks. AB - Knowledge or rule-based approaches are needed for quality assessment and assurance in professional or crowdsourced geographic data. Nevertheless, many types of geographic knowledge are statistical in nature and are therefore difficult to derive rules that are meaningful for this purpose. The rules of continuity and symmetry considered in this paper can be thought of as two concrete forms of the first law of geography, which may be used to formulate quality measures at the individual level without referring to ground truth. It is not clear, however, how much the rules can be faithful. Hence, the main objective is to test if the rules are consistent with street network data over the world. Specifically, for the rule of continuity we identify natural streets that connect smoothly in a network, and measure the spatial order of information (e.g. names, highway level, speed, etc.) along the streets. The measure is based on spatial auto-correlation indicators adapted for one dimension. For the rule of symmetry, we device an algorithm that recognize parallel road pairs (e.g. dual carriageways), and examine to what extent attributes in the pairs are identical. The two rules are tested against 28 cities selected from OpenStreetMap data worldwide; two professional data sets are used to show more insights. We found that the rules are consistent with street networks from a wide range of cities of different characteristics, and also noted cases with varying degrees of agreement. As a side-effect, we discussed possible limitations of the autocorrelation indicators used, where cautions are needed when interpreting the results. In addition, we present techniques that performed the tests automatically, which can be applied to new data to further verify (or falsify) our findings, or extended as quality assurance tools to detect data items that do not satisfy the rules and to suggest possible corrections according to the rules. PMID- 30001375 TI - Preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer: Meta-analysis with trial sequential analysis of long-term survival data. AB - BACKGROUND AND PURPOSE: The role of preoperative short-course radiotherapy (SCRT) in rectal cancer treatment, when compared to long-course radiochemotherapy (LCRT), is still controversial. Thus the meta-analysis with trial sequential analysis (TSA) was performed to evaluate the long-term survival of SCRT and LCRT as therapeutic regimens for locally advanced rectal cancer. MATERIAL AND METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to August 2017 for eligible studies. Hazard ratios (HRs) or odds ratios (ORs) of overall survival (OS), disease free survival (DFS) and local recurrence (LR) with the corresponding 95% confidence intervals (CIs) were calculated and TSA was applied. RESULTS: 11 studies with 1984 patients were included. There was no significant difference in OS (HR = 0.92, 95% CI: 0.75 1.13, p = 0.44), DFS (HR = 0.94, 95% CI: 0.79-1.12, p = 0.50) and LR (OR = 0.73, 95% CI: 0.49-1.08, p = 0.11) between SCRT and LCRT groups. TSA suggested firm evidence for lacking on average a -10% relative risk reduction (RRR) in 4-year OS but no statistical significance in 4-year DFS. CONCLUSIONS: Preoperative SCRT is as effective as LCRT for locally advanced colorectal cancer in long-term survival. SCRT could be preferential while facing long waiting lists or lacking medical resource. PMID- 30001376 TI - In Silico evaluation and identification of fungi capable of producing endo inulinase enzyme. AB - The enzyme endo-inulinase hydrolyzes inulin to short chain fructooligosaccharides (FOS) that are potential prebiotics with many health promoting benefits. Although the raw materials for inulin production are inexpensive and readily available, commercial production of FOS from inulin is limited due to inadequate availability of the enzyme source. This study aimed to identify the fungi capable of producing endo-inulinase based on the in silico analysis of proteins retrieved from non-redundant protein sequence database. The endo-inulinase of Aspergillus ficuum was used as reference sequence. The amino acid sequences with >90% sequence coverage, belonging to different fungi were retrieved from the database and used for constructing three-dimensional (3D) protein models using SWISS-MODEL and Bagheerath H. The 3D models of comparable quality as that of the reference endo-inulinase were selected based on QMEAN Z score. The selected models were evaluated and validated for different structural and functional qualities using Pro-Q, ProSA, PSN-QA, VERIFY-3D, PROCHECK, PROTSAV metaserver, STRAP, molecular docking, and molecular dynamic simulation analyses. A total of 230 proteins belonging to 53 fungal species exhibited sequence coverage >90%. Sixty one protein sequences with >60% sequence identity were modeled as endo-inulinase with higher QMEAN Z Score. The evaluations and validations of these 61 selected models for different structural and functional qualities revealed that 60 models belonging to 22 fungal species exhibited native like structure and unique motifs and residues as that of the reference endo-inulinase. Further, these models also exhibited similar kind of interaction between the active site around the conserved glutamate residue and substrate as that of the reference endo inulinase. In conclusion, based on the current study, 22 fungal species could be identified as endo-inulinase producer. Nevertheless, further biological assessment of their capability for producing endo-inulinase is imminent if they are to be used for commercial endo-inulinase production for application in FOS industry. PMID- 30001377 TI - Lower performance of Toxoplasma-infected, Rh-negative subjects in the weight holding and hand-grip tests. AB - BACKGROUND: Toxoplasma, a protozoan parasite of cats, infects many species of intermediate and paratenic hosts, including about one-third of humans worldwide. After a short phase of acute infection, the tissue cysts containing slowly dividing bradyzoites are formed in various organs and toxoplasmosis proceeds spontaneously in its latent form. In immunocompetent subjects, latent toxoplasmosis was considered asymptomatic. However, dozens of studies performed on animals and humans in the past twenty years have shown that it is accompanied by a broad spectrum of specific behavioural, physiological and even morphological changes. In human hosts, the changes often go in the opposite direction in men and women, and are mostly weaker or non-existent in Rh-positive subjects. METHODS: Here, we searched for the indices of lower endurance of the infected subjects by examining the performance of nearly five hundred university students tested for toxoplasmosis and Rh phenotype in two tests, a weight holding test and a grip test. RESULTS: The results confirmed the existence of a negative association of latent toxoplasmosis with the performance of students, especially Rh-negative men, in these tests. Surprisingly, but in an accordance with some already published data, Toxoplasma-infected, Rh-positive subjects expressed a higher, rather than lower, performance in our endurance tests. DISCUSSION: Therefore, the results only partly support the hypothesis for the lower endurance of Toxoplasma infected subjects as the performance of Rh-positive subjects (representing majority of population) correlated positively with the Toxoplasma infection. PMID- 30001378 TI - The evaluation of operating Animal Bite Treatment Centers in the Philippines from a health provider perspective. AB - BACKGROUND: The Philippine government has an extensive network of 513 Animal Bite Treatment Centers (ABTCs) to supply rabies post exposure prophylaxis (PEP), reaching over 1 million bite victims in 2016. The network was evaluated using a review of existing national and provincial data, key informant interviews and surveys in sample ABTCs to determine the cost-effectiveness of this network in preventing human rabies deaths. METHODOLOGY AND PRINCIPAL FINDINGS: One urban and one rural ABTC in each of three selected provinces were studied in more detail. PEP delivery generally followed national guidance based on best practices, but there was evidence of operational challenges in supplying all ABTCs with adequate biologics and recently trained staff. Funding was contributed by different levels of government and in some clinics, patients paid for a significant fraction of the total cost. From a health provider perspective including both fixed and variable costs, the average PEP course delivered cost USD 32.91 /patient across urban ABTCs (with higher patient throughput) and USD 57.21 /patient across rural ABTCs. These costs suggests that PEP provision in the Philippines cost USD 37.6 million in 2016, with a cost per life saved of USD 8,290. An analysis of the 2,239 suspected rabies deaths from 2008 to 2016 showed no significant decline, and from 2014-16 an average of 8,534 years of life were lost annually. The incidence of rabies deaths from 2014-16 was not clearly related to the provision of ABTCs (per 100,000 population) or human population density, but deaths were more common in higher income provinces. CONCLUSIONS/SIGNIFICANCE: In the context of comprehensive rabies control (including dog vaccination and public awareness) ways to reduce this high expenditure on PEP should be explored, to most cost effectively reach the elimination of human rabies deaths. This paper is accompanied by another containing data on the operation of ABTCs network from a patient perspective. PMID- 30001379 TI - Histogram analysis of DTI-derived indices reveals pontocerebellar degeneration and its progression in SCA2. AB - PURPOSE: To assess the potential of histogram metrics of diffusion-tensor imaging (DTI)-derived indices in revealing neurodegeneration and its progression in spinocerebellar ataxia type 2 (SCA2). MATERIALS AND METHODS: Nine SCA2 patients and 16 age-matched healthy controls, were examined twice (SCA2 patients 3.6+/-0.7 years and controls 3.3+/-1.0 years apart) on the same 1.5T scanner by acquiring T1-weighted and diffusion-weighted (b-value = 1000 s/mm2) images. Cerebrum and brainstem-cerebellum regions were segmented using FreeSurfer suite. Histogram analysis of DTI-derived indices, including mean diffusivity (MD), fractional anisotropy (FA), axial (AD) / radial (RD) diffusivity and mode of anisotropy (MO), was performed. RESULTS: At baseline, significant differences between SCA2 patients and controls were confined to brainstem-cerebellum. Median values of MD/AD/RD and FA/MO were significantly (p<0.001) higher and lower, respectively, in SCA2 patients (1.11/1.30/1.03*10-3 mm2/s and 0.14/0.19) than in controls (0.80/1.00/0.70*10-3 mm2/s and 0.20/0.41). Also, peak location values of MD/AD/RD and FA were significantly (p<0.001) higher and lower, respectively, in SCA2 patients (0.91/1.11/0.81*10-3 mm2/s and 0.12) than in controls (0.71/0.91/0.63*10 3 mm2/s and 0.18). Peak height values of FA and MD/AD/RD/MO were significantly (p<0.001) higher and lower, respectively, in SCA2 patients (0.20 and 0.07/0.06/0.07*10-3 mm2/s/year /0.07) than in controls (0.15 and 0.14/0.11/0.12/*10-3 mm2/s/year /0.09). The rate of change of MD median values was significantly (p<0.001) higher (i.e., increased) in SCA2 patients (0.010*10-3 mm2/s/year) than in controls (-0.003*10-3 mm2/s/year) in the brainstem cerebellum, whereas no significant difference was found for other indices and in the cerebrum. CONCLUSION: Histogram analysis of DTI-derived indices is a relatively straightforward approach which reveals microstructural changes associated with pontocerebellar degeneration in SCA2 and the median value of MD is capable to track its progression. PMID- 30001380 TI - Self-reported and objectively assessed knowledge of evidence-based practice terminology among healthcare students: A cross-sectional study. AB - BACKGROUND: Self-reported scales and objective measurement tools are used to evaluate self-perceived and objective knowledge of evidence-based practice (EBP). Agreement between self-perceived and objective knowledge of EBP terminology has not been widely investigated among healthcare students. AIM: The aim of this study was to examine agreement between self-reported and objectively assessed knowledge of EBP terminology among healthcare students. A secondary objective was to explore this agreement between students with different levels of EBP exposure. METHODS: Students in various healthcare disciplines and at different academic levels from Norway (n = 336) and Canada (n = 154) were invited to answer the Terminology domain items of the Evidence-Based Practice Profile (EBP2) questionnaire (self-reported), an additional item of 'evidence based practice' and six random open-ended questions (objective). The open-ended questions were scored on a five-level scoring rubric. Interrater agreement between self-reported and objective items was investigated with weighted kappa (Kw). Intraclass correlation coefficient (ICC) was used to estimate overall agreement. RESULTS: Mean self-reported scores varied across items from 1.99 ('forest plot') to 4.33 ('evidence-based practice'). Mean assessed open-ended answers varied from 1.23 ('publication bias') to 2.74 ('evidence-based practice'). For all items, mean self-reported knowledge was higher than that assessed from open-ended answers (p<0.001). Interrater agreement between self-reported and assessed open-ended items varied (Kw = 0.04-0.69). The overall agreement for the EBP2 Terminology domain was poor (ICC = 0.29). The self-reported EBP2 Terminology domain discriminated between levels of EBP exposure. CONCLUSION: An overall low agreement was found between healthcare students' self-reported and objectively assessed knowledge of EBP terminology. As a measurement tool, the EBP2 Terminology scale may be useful to differentiate between levels of EBP exposure. When using the scale as a discriminatory tool, for the purpose of academic promotion or clinical certification, users should be aware that self-ratings would be higher than objectively assessed knowledge. PMID- 30001382 TI - Between session reliability of heel-to-toe progression measurements in the stance phase of gait. AB - The objective of the current study was to determine the test-retest reliability of heel-to-toe progression measures in the stance phase of gait using intraclass correlation coefficient (ICC) analysis. It has been proposed that heel-to-toe progression could be used as a functional measure of ankle muscle contracture/weakness in clinical populations. This was the first study to investigate the test-retest reliability of this measure. Eighteen healthy subjects walked over the GAITRite(r) mat three times at a comfortable speed on two sessions (>= 48 hours apart). The reliability of the heel-to-toe progression measures; heel-contact time, mid-stance time and propulsive time were assessed. Also assessed were basic temporal-spatial parameters; velocity, cadence, stride length, step length, stride width, single and double leg support time. Reliability was determined using the ICC(3,1) model and, fixed and proportional biases, and measures of variability were assessed. Basic gait temporal-spatial parameters were not different between sessions (p > 0.05) and had excellent reliability (ICC(3,1) range: 0.871-0.953) indicating that subjects walked similarly between sessions. Measurement of heel-to-toe progression variables were not different between sessions (p > 0.05) and had excellent reliability (ICC(3,1) range: 0.845-0.926). However, these were less precise and more variable than the measurement of standard temporal-spatial gait variables. As the current study was performed on healthy populations, it represents the 'best case' scenario. The increased variability and reduced precision of heel-to-toe progression measurements should be considered if being used in clinical populations. PMID- 30001381 TI - Comparison of body composition assessment by DXA and BIA according to the body mass index: A retrospective study on 3655 measures. AB - BACKGROUND AND AIMS: Body composition assessment is often used in clinical practice for nutritional evaluation and monitoring. The standard method, dual energy X-ray absorptiometry (DXA), is hardly feasible in routine clinical practice contrary to Bioelectrical Impedance Analysis (BIA) method. We thus aimed to compare body composition assessment by DXA and BIA according to the body mass index (BMI) in a large cohort. METHODS: Retrospectively, we analysed DXA and BIA measures in patients followed in a Nutrition Unit from 2010 to 2016. Body composition was assessed under standardized conditions in the morning, after a fasting period of 12 h, by DXA (Lunar Prodigy Advance) and BIA (Bodystat QuadScan 4000, Manufacturer's equation). Bland-Altman test was performed for each class of BMI (kg/m2) and fat mass and fat free mass values were compared using Kruskal Wallis test. Pearson correlations were also performed and the concordance coefficient of Lin was calculated. RESULTS: Whatever the BMI, BIA and DXA methods reported higher concordance for values of FM than FFM. Body composition values were very closed for patients with BMI between 16 and 18,5 (difference < 1kg). For BMI > 18,5 and BMI < 40, BIA overestimated fat free mass from 3,38 to 8,28 kg, and underestimated fat mass from 2,51 to 5,67 kg compared with DXA method. For BMI >= 40, differences vary with BMI. For BMI < 16, BIA underestimated fat free mass by 2,25 kg, and overestimated fat mass by 2,57 kg. However, limits of agreement were very large either for FM and FFM values, irrespective of BMI. CONCLUSION: The small bias, particularly in patients with BMI between 16 and 18, suggests that BIA and DXA methods are interchangeable at a population level. However, concordance between BIA and DXA methods at the individual level is lacking, irrespective of BMI. PMID- 30001385 TI - Complexity of the relationship between life expectancy and overlap of lifespans. AB - Longevity has long been recognised as a key facilitator of reciprocal altruism because repeated cooperation of partners hinges on mutual survival. Although demographic tools can be used to quantify mutual survival and expected overlapping lifespans, studies on the evolutionary theory of cooperation take only limited advantage of demography. Overlap of lifespans depends on variation in survival across ages and can be high or low independently of high or low life expectancies. Here we develop formal demographic measures to study the complex relationships between shared life expectancy of two birth cohort peers, the proportion of their lives that they can expect to overlap, and longevity. We simulate age-specific mortality schedules using a Siler model to reveal how infant and senescent mortality, along with age-independent mortality, affect the relationship between the proportion of life shared and life expectancy. We find that while the proportion of life shared can vary vastly for similar life expectancies, almost all changes to mortality schedules that result in higher life expectancies also result in higher proportions of life shared. A distinct exception occurs if life expectancy increases due to lowering the rate of senescence. In this case the proportion of life shared decreases. Our work shows that almost all selective pressures that result in higher life expectancies also result in a larger proportion of life shared. Therefore, selective forces that extend life also improve the chances that a cooperative system would be stable in terms of reciprocal interactions. Since reciprocal interactions may also reduce mortality and result in a feedback loop with the evolution of longevity, our measures and findings can be used for future cross-species comparisons that aim to disentangle predecessor and successor in the evolution of longevity and cooperation. PMID- 30001383 TI - Proteomic analysis of canine oral tumor tissues using MALDI-TOF mass spectrometry and in-gel digestion coupled with mass spectrometry (GeLC MS/MS) approaches. AB - Oral tumors, including highly invasive and metastatic oral melanoma (OM), non tonsillar oral squamous cell carcinoma (OSCC) and benign tumors (BN), are common neoplasms in dogs. Although these tumors behave differently, limited data of their protein expression profiles have been exhibited, particularly at the proteome level. The present study aimed to i.) characterize peptide-mass fingerprints (PMFs) and identify potential protein candidates of OM, OSCC, BN and normal control subjects, using matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS), ii.) identify potential protein candidates associated with the diseases, using in-gel digestion coupled with mass spectrometric analysis (GeLC-MS/MS) and iii.) search for relationships between chemotherapy drugs and disease-perturbed proteins. A distinct cluster of each sample group and unique PMFs with identified protein candidates were revealed. The unique peptide fragment at 2,274 Da of sacsin molecular chaperone (SACS) was observed in early stage OM whereas the fragment at 1,958 Da of sodium voltage-gated channel alpha subunit 10 (SCN10A) was presented in early- and late-stage OM. The peptide mass at 2,316 Da of Notch1 appeared in early-stage OM and benign oral tumors while the peptide mass at 2,505 Da of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 3A (GRIN3A) was identified in all groups. Markedly expressed proteins from GeLC-MS/MS included Jumonji domain containing 1C (JMJD1C) in benign tumors, inversin (INVS) and rho guanine nucleotide exchange factor 28 (ARHGEF28) in OM, BTB domain-containing 16 (BTBD16) in OSCC, and protein tyrosine phosphatase non-receptor type 1 (PTPN1), BRCA2, DNA repair associated (BRCA2), WW domain binding protein 2 (WBP2), purinergic receptor P2Y1 and proteasome activator subunit 4 (PSME4) in all cancerous groups. The network connections between these proteins and chemotherapy drugs, cisplatin and doxorubicin, were also demonstrated. In conclusion, this study unveiled the unique PMFs and novel candidate protein markers of canine oral tumors. PMID- 30001384 TI - AIF1L regulates actomyosin contractility and filopodial extensions in human podocytes. AB - Podocytes are highly-specialized epithelial cells essentially required for the generation and the maintenance of the kidney filtration barrier. This elementary function is directly based on an elaborated cytoskeletal apparatus establishing a complex network of primary and secondary processes. Here, we identify the actin bundling protein allograft-inflammatory-inhibitor 1 like (AIF1L) as a selectively expressed podocyte protein in vivo. We describe the distinct subcellular localization of AIF1L to actin stress fibers, focal adhesion complexes and the nuclear compartment of podocytes in vitro. Genetic deletion of AIF1L in immortalized human podocytes resulted in an increased formation of filopodial extensions and decreased actomyosin contractility. By the use of SILAC based quantitative proteomics analysis we describe the podocyte specific AIF1L interactome and identify several components of the actomyosin machinery such as MYL9 and UNC45A as potential AIF1L interaction partners. Together, these findings indicate an involvement of AIF1L in the stabilization of podocyte morphology by titrating actomyosin contractility and membrane dynamics. PMID- 30001386 TI - Pre-pregnancy body mass index classification and gestational weight gain on neonatal outcomes in adolescent mothers: A follow-up study. AB - INTRODUCTION: Institute of Medicine gestational weight gain recommendations are based on body mass index (BMI) status using adult cut-off points for women of all ages, even though adolescents have specific criteria, like WHO and CDC, so adolescents can receive inadequate weight gain recommendations. OBJECTIVES: To estimate the proportion of classification disparity between the three criteria (WHO, CDC and IOM) of pre-pregnancy BMI status; and to analyze neonatal outcomes according to weight gain recommendation based on pre-pregnancy BMI using the three criteria. METHODS: Follow-up study in pregnant adolescents 12-19 years. Sociodemographic, anthropometric and pregnancy data were obtained. Percentage of pre-pregnancy BMI classification disparity was calculated between three criteria. Gestational weight gain was categorized in adequate, low and high according to IOM. Regression models were used to analyze negative neonatal outcomes. RESULTS: 601 pregnant adolescents were included, mean age was 16+/-1.4 years. For pre pregnancy BMI classification, 28.5% had classification disparity using IOM vs WHO, and 14% when comparing IOM vs CDC. Greater classification disparity was observed as BMI increased. When using WHO categories, a high weight gain was associated with increased risk of having a low birth weight baby (OR: 1.91, CI95%: 1.03-3.53). For CDC criteria, a low weight gain was associated with increased risk of having a preterm baby (OR: 2.65; CI95%: 1.16-6.08) and a high weight gain was associated with low birth weight (OR: 2.10; CI95%: 1.10-4.01). For IOM criteria, a weight gain either low or high were associated with increased risk of low birth weight and preterm birth. CONCLUSION: There is pre-pregnancy BMI classification disparity using criteria for adolescents compared to adult criteria. Nevertheless, with WHO and CDC only a high gestational weight gain was a risk for negative neonatal outcome. It is important to have a BMI classification system for adolescents that better predicts neonatal outcomes. PMID- 30001387 TI - Ki67, CD105, and alpha-SMA expression supports the transformation relevant dysplastic features in the atrophic epithelium of oral submucous fibrosis. AB - BACKGROUND: The grading of oral epithelial dysplasia is not possible in the atrophic epithelium of oral submucous fibrosis (OSMF). Recently, we found that features such as increased basal cell layer hyperplasia, abnormal superficial mitosis, increased nuclear-cytoplasmic ratio, increased nuclear size, and hyperchromasia represent transformation-relevant dysplastic features in the atrophic epithelium of OSMF. The presence of these features can be considered a high-risk feature for patients. However, these findings have not been tested and authenticated using markers relevant to oral carcinogenesis. METHOD: Paraffin embedded tissues from 30 normal oral mucosa (NOM) and 50 OSMF were retrieved from 2008 to 2016 and subjected to immunohistochemical expression using Ki67, CD105 and alpha-SMA antibodies. RESULTS: Ki67 LI showed significant increases from NOM (12.47+/-2.34) to LRED (23.47+/-3.75) to HRED (34.31+/-7.31) (<0.0001). Similarly, MVD was increased significantly from NOM (3.53+/-5.17) to LRED (27.57+/-12.25) to HRED (46.18+/-12.55) (p<0.0001). The expression of alpha-SMA was significantly increased from LRED (0.21+/-0.41) to HRED (1.13+/-0.56) (<0.0001). The Ki67 LI and alpha-SMA; MVD and alpha-SMA; and Ki67Ki67 LI and MVD in NOM, LRED and HRED showed a statistically significant positive correlation (P<0.0001). The increase in Ki67 LI was directly proportional to MVD and alpha SMA expression from NOM to LRED to HRED (P<0.0001). The connective tissue stroma of NOM lacks alpha-SMA expression. Mild myofibroblast expression was noted in 4 cases of LRED (14.28%) and in 18 cases of HRED (81.81%). Moderate expression was noted only in 4 cases of HRED (22.22%). CONCLUSION: Ki67 LI, CD105, and alpha-SMA expression showed significant differences between normal, LRED and HRED. These findings further support that features such as increased basal cell layer hyperplasia, abnormal superficial mitosis, increased nuclear-cytoplasmic ratio, and hyperchromasia could be transformation-relevant dysplastic features. PMID- 30001389 TI - Correction: Estimated hepatitis C prevalence and key population sizes in San Francisco: A foundation for elimination. AB - [This corrects the article DOI: 10.1371/journal.pone.0195575.]. PMID- 30001388 TI - Clinical correlation between erectile function and ejaculatory function in the Czech male population. AB - INTRODUCTION: This study explores the relationship between erectile function and ejaculatory function, to inform the clinical psychosexological and sexual medicine practice treatment protocols. MATERIALS AND METHODS: A total of 1,004 Czech males aged between 15 and 84 years (m = 42.8 yrs; sd = 17.6 years) completed a sexual behavior questionnaire. A cross-sectional design was adopted. Erectile function was measured with the International Index of Erectile Function (IIEF-5) and ejaculatory function measured using self-report intravaginal ejaculation latency time and the Index of Premature Ejaculation (IPE). Linear regression analyses were used to explore the relationships between premature ejaculation and erectile dysfunction. RESULTS: The sample mean self-reported intravaginal ejaculatory latency time was 9.34 minutes. The overall mean on the IPE was 19.44 (sd = 2.368). The Control domain mean was 81.13 (sd = 17.22); Sexual Satisfaction domain mean 78.60 (sd = 20.59); and the Distress domain mean was 86.86 (sd = 18.32). The mean score on the IIEF-5 was 19.28 (sd = 2.53). The results indicate a relationship between premature ejaculation and erectile dysfunction. With age significantly associated with all measures. CONCLUSIONS: Higher levels of erectile function are associated with a better control and sexual satisfaction, and less distress about ejaculation. This association supports the consideration of this relationship in the development of new clinical practice guidelines for erectile dysfunction and premature ejaculation. PMID- 30001390 TI - Mitochondrial Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes. AB - INTRODUCTION: Ca2+ release from sarcoplasmic reticulum (SR) is known to contribute to automaticity via the cytoplasmic Na+-Ca2+ exchanger (NCX). Mitochondria participate in Ca2+ cycling. We studied the role of mitochondrial Ca2+ flux in ventricular spontaneous electrical activity. METHODS: Spontaneously contracting mouse embryonic stem cells (ESC)-derived ventricular cardiomyocytes (CMs) were differentiated from wild type and ryanodine receptor type 2 (RYR2) knockout mouse ESCs and differentiated for 19-21 days. Automaticity was also observed in human induced pluripotent stem cell (hiPSC)-derived ventricular CMs differentiated for 30 days, and acute isolated adult mouse ventricular cells in ischemic simulated buffer. Action potentials (APs) were recorded by perforated whole cell current-clamp. Cytoplasmic and mitochondrial Ca2+ transients were determined by fluorescent imaging. RESULTS: In mouse ESC-derived ventricular CMs, spontaneous beating was dependent on the L-type Ca2+ channel, cytoplasmic NCX and mitochondrial NCX. Spontaneous beating was modulated by SR Ca2+ release from RYR2 or inositol trisphosphate receptors (IP3R), the pacemaker current (If) and mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU). In RYR2 knockout mouse ESC-derived ventricular CMs, mitochondrial Ca2+ flux influenced spontaneous beating independently of the SR Ca2+ release from RYR2, and the mitochondrial effect was dependent on IP3R SR Ca2+ release. Depolarization of mitochondria and preservation of ATP could terminate spontaneous beating. A contribution of mitochondrial Ca2+ flux to automaticity was confirmed in hiPSC derived ventricular CMs and ischemic adult mouse ventricular CMs, confirming the findings across species and cell maturity levels. CONCLUSIONS: Mitochondrial and sarcolemma NCX fluxes are required for ventricular automaticity. Mitochondrial Ca2+ uptake plays a modulatory role. Mitochondrial Ca2+ uptake through MCU is influenced by IP3R-dependent SR Ca2+ release. PMID- 30001391 TI - Impact of Leishmania donovani infection on the HLA I self peptide repertoire of human macrophages. AB - Macrophages are specialized antigen-presenting cells that process and present self-antigens for induction of tolerance, and foreign antigens to initiate T cell mediated immunity. Despite this, Leishmania donovani (LD) are able to parasitize the macrophages and persist. The impact of this parasitizing and persistence on antigen processing and presentation by macrophages remains poorly defined. To gain insight into this, we analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) and compared the HLA-I self-peptidomes, proteasome compositions, HLA expression and activation states of non-infected and LD infected THP1-derived macrophages. We found that, though both HLA-I peptidomes were dominated by nonapeptides, they were heterogeneous and individualized, with differences in HLA binding affinities and anchor residues. Non-infected and LD infected THP1-derived macrophages were able to sample peptides from source proteins of almost all subcellular locations and involved in various cellular functions, but in different proportions. In the infected macrophages, there was increased sampling of plasma membrane and extracellular proteins, and those involved in immune responses, cell communication/signal transduction and metabolism/energy pathways, and decreased sampling of nuclear and cytoplasmic proteins and those involved in protein metabolism, RNA binding and cell growth and/or maintenance. Though the activation state of infected macrophages was unchanged, their proteasome composition was altered. PMID- 30001392 TI - In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances. AB - It is usually recommended that flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free flucloxacillin concentrations after oral flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC0-infinity) ratio was 0.80 (p<0.01, 90% CI 0.70-0.92), the peak concentraton (Cmax) ratio 0.51 (p<0.001, 0.42-0.62) and the time to peak concentration (Tmax) ratio 2.2 (p<0.001, 1.87-2.55). The ratios for total flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63-0.87, fed inferior p<0.01), 0.95 (0.81-1.11, bioequivalent) and 1.15 (0.97-1.36, fed non inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC0-infinity and Cmax, and prolonged the Tmax of both free and total flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking flucloxacillin with food is unlikely to compromise efficacy in most circumstances. PMID- 30001393 TI - Effect of progesterone on Smad signaling and TGF-beta/Smad-regulated genes in lung epithelial cells. AB - The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone's effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-beta)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-beta-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-beta1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-beta1 inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-beta1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-beta1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-beta1-activated Smad signaling and TGF-beta1 regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-beta1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants. PMID- 30001394 TI - New diagnostic SNP molecular markers for the Mytilus species complex. AB - The development of diagnostic markers has been a long-standing interest of population geneticists as it allows clarification of taxonomic uncertainties. Historically, there has been much debate on the taxonomic status of species belonging to the Mytilus species complex (M. edulis, M. galloprovincialis and M. trossulus), and whether they are discrete species. We analysed reference pure specimens of M. edulis, M. galloprovincialis and M. trossulus, using Restriction site associated DNA (RAD) sequencing and identified over 6,000 SNP markers separating the three species unambiguously. We developed a panel of diagnostic SNP markers for the genotyping of Mytilus species complex as well as the identification of hybrids and interspecies introgression events in Mytilus species. We validated a panel of twelve diagnostic SNP markers which can be used for species genotyping. Being able to accurately identify species and hybrids within the Mytilus species complex is important for the selective mussel stock management, the exclusion of invasive species, basic physiology and bio-diversity studies. PMID- 30001395 TI - Correction: Physiological responses to acute cold exposure in young lean men. AB - [This corrects the article DOI: 10.1371/journal.pone.0196543.]. PMID- 30001396 TI - Hemilaterally masked arterial spin labeling by intentional magnetic field changes in the labeling area due to placement of material with high susceptibility. AB - BACKGROUND AND PURPOSE: Arterial spin labeling(ASL)with magnetic resonance imaging (MRI) is an effective method for estimating cerebral blood flow (CBF). Furthermore, assessing perfusion territories of arteries is useful for determining the treatment strategy of patients with carotid artery stenosis. ASL with selective vessel labeling is an effective method to obtain perfusion mapping, however, the application for selective labeling is not installed on all MR scanners. The purpose of this study is to establish a method to selectively mask in the labeling area using material with high susceptibility instead of selectively labeling to obtain a partial perfusion image. MATERIALS AND METHODS: ASL perfusion images were performed in five volunteers. Masking was applied by placing a stainless-steel bolt and nuts on the neck. The area of artifacts extended to the carotid artery was confirmed by the localizer image. In the obtained masked ASL, blood flow of the left and right cerebrum and cerebellum was measured and compared with control ASL without masking. By subtracting masked ASL from the control ASL, the perfusion territory of the carotid artery on the masked side was identified. RESULTS: Mean CBF which was 39.6 ml/(100 g * min) in control ASL decreased to 16.1 ml/(100 g * min) in masked ASL, and the masking ratio was 59.6%. There were no significant differences in the CBF of non-masked areas under the control ASL condition (39.6+/- 5.2 ml/[100 g * min]) btween that under the masked ASL condition (39.4 +/- 7.0 ml/[100 g * min]). By subtracting masked ASL from control ASL, we successfully visualized the hemilateral carotid artery's perfusion territory. CONCLUSION: Intentional susceptibility artifacts with non magnetic metals on the neck can mask spin labeling of the carotid artery. Furthermore, hemilateral carotid artery perfusion territories can be visualized in hemilaterally masked ASL. PMID- 30001397 TI - The effect of maternal decisional authority on children's vaccination in East Asia. AB - Even though they are important determinants for increasing vaccination rates in advanced and developing nations alike, maternal capacity and decisional authority have not been fully elucidated in diverse countries and cultural spheres. This study examined the effects of South Korean, Chinese, and Japanese mothers' health literacy, self-efficacy, mass media use, and decisional authority on their children's vaccination after adjustment for their socioeconomic statuses. Computer-assisted web interviews were conducted with married women in their 20s 40s of South Korean, Chinese, or Japanese nationality (n = 1,571). Dependent variables were generated for the following four vaccinations: BCG, diphtheria+pertussis+tetanus (DPT), poliomyelitis (polio), and measles. For statistical processing, cases where all four types of vaccines had been recorded were scored as 1 and other cases were processed as 0. According to the results of the pooled model, we found that for East Asian mothers, decisional authority, self-efficacy, and health literacy all increased the likelihood that they would vaccinate their children. Furthermore, women who searched for health information through media such as the radio were more likely to vaccinate their children. However, when elaborate analyses were conducted by country, there were considerable differences in those characteristics by country. Therefore, this study showed that it is necessary to establish locally tailored strategies in order to raise vaccination rates in the Global Vaccine Action Plan. This study also showed that social contexts must be taken into consideration in order to raise vaccination rates. PMID- 30001398 TI - Downregulation of splicing regulator RBFOX1 compromises visual depth perception. AB - Rbfox1 is a splicing regulator that has been associated with various neurological conditions such as autism spectrum disorder, mental retardation, epilepsy, attention-deficit/hyperactivity disorder and schizophrenia. We show that in adult rodent retinas, Rbfox1 is expressed in all types of retinal ganglion cells (RGCs) and in certain subsets of amacrine cells (ACs), within the inner nuclear (INL) and ganglion cell (GCL) layers. In the INL, all Rbfox1-positive cells were colocalized with GABAergic ACs, however not all GABAergic ACs were immunostained for Rbfox1. In the GCL, a vast majority of GABAergic dACs were Rbfox1 immunopositive. Furthermore, all cholinergic starburst ACs (SACs) in the INL (type a) and in the GCL (type b) were Rbfox1 positive. The expression of Rbfox1 in the retina significantly overlapped with expression of Rbfox2, another member of Rbfox family of proteins. Rbfox2, in addition to RGCs and ACs, was also expressed in horizontal cells. In developing retinas at E12 and E15, Rbfox1 is localized to the cytoplasm of differentiating RGCs and ACs. Between P0 and P5, Rbfox1 subcellular localization switched from cytoplasmic to predominantly nuclear. Downregulation of Rbfox1 in adult Rbfox1loxP/loxP mice had no detectable effect on retinal gross morphology. However, the visual cliff test revealed marked abnormalities of depth perception of these animals. RNA sequencing of retinal transcriptomes of control and Rbfox1 knockout animals identified a number of Rbfox1-regulated genes that are involved in establishing neuronal circuits and synaptic transmission, including Vamp1, Vamp2, Snap25, Trak2, and Slc1A7, suggesting the role of Rbfox1 in facilitating synaptic communications between ACs and RGCs. PMID- 30001399 TI - Reelin controls the positioning of brainstem serotonergic raphe neurons. AB - Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of serotonin signaling during critical periods is involved in developmental neurological disorders, such as schizophrenia and autism. In this study we focused on the consequences of defect reelin signaling for the development of the brainstem serotonergic raphe system. We observed that reelin signaling components are expressed by serotonergic neurons during the critical period of their lateral migration. Further, we found that reelin signaling is important for the normal migration of rostral, but not caudal hindbrain raphe nuclei and that reelin deficiency results in the malformation of the paramedian raphe nucleus and the lateral wings of the dorsal raphe nuclei. Additionally, we showed that serotonergic neurons projections to laminated brain structures were severely altered. With this study, we propose that the perturbation of canonical reelin signaling interferes with the orientation of tangentially, but not radially, migrating brainstem 5-HT neurons. Our results open the window for further studies on the interaction of reelin and serotonin and the pathogenesis of neurodevelopmental disorders. PMID- 30001401 TI - Brain haemorrhage detection using a SVM classifier with electrical impedance tomography measurement frames. AB - Brain haemorrhages often require urgent treatment with a consequent need for quick and accurate diagnosis. Therefore, in this study, we investigate Support Vector Machine (SVM) classifiers for detecting brain haemorrhages using Electrical Impedance Tomography (EIT) measurement frames. A 2-layer model of the head, along with a series of haemorrhages, is designed as both numerical models and physical phantoms. EIT measurement frames, taken from an electrode array placed on the head surface, are used to train and test linear SVM classifiers. Various scenarios are implemented on both platforms to examine the impact of variables such as noise level, lesion location, lesion size, variation in electrode positioning, and variation in anatomy, on the classifier performance. The classifier performed well in numerical models (sensitivity and specificity of 90%+) with signal-to-noise ratios of 60 dB+, was independent of lesion location, and could detect lesions reliably down to the tested minimum volume of 5 ml. Slight variations in electrode layout did not affect performance. Performance was affected by variations in anatomy however, emphasising the need for large training sets covering different anatomies. The phantom models proved more challenging, with maximal sensitivity and specificity of 75% when used with the linear SVM. Finally, the performance of two more complex classifiers is briefly examined and compared to the linear SVM classifier. These results demonstrate that a radial basis function (RBF) SVM classifier and a neural network classifier can improve detection accuracy. Classifiers applied to EIT measurement frames is a novel approach for lesion detection and may offer an effective diagnostic tool clinically. A challenge is to translate the strong results from numerical models into real world phantoms and ultimately human patients, as well as the selection and development of optimal classifiers for this application. PMID- 30001400 TI - Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation may reveal subclinical alterations in human T-cell lymphotropic virus type 1 associated myelopathy. AB - BACKGROUND: Vestibular-evoked myogenic potential triggered by galvanic vestibular stimulation (galvanic-VEMP) evaluates the motor spinal cord and identifies subclinical myelopathies. We used galvanic-VEMP to compare spinal cord function in individuals infected with human T-cell lymphotropic virus type 1 (HTLV-1) from asymptomatic status to HTLV-1-associated myelopathy (HAM). METHODOLOGY/PRINCIPAL FINDINGS: This cross-sectional study with 122 individuals included 26 HTLV-1 asymptomatic carriers, 26 individuals with possible HAM, 25 individuals with HAM, and 45 HTLV-1-seronegative individuals (controls). The groups were similar regarding gender, age, and height. Galvanic stimuli (duration: 400 ms; intensity: 2 mA) were applied bilaterally to the mastoid processes and VEMP was recorded from the gastrocnemius muscle. The electromyographic parameters investigated were the latency and amplitude of the short-latency (SL) and medium-latency (ML) responses. While SL and ML amplitudes were similar between groups, SL and ML latencies were delayed in the HTLV-1 groups compared to the control group (p<0.001). Using neurological examination as the gold standard, ROC curve showed an area under the curve of 0.83 (p<0.001) for SL and 0.86 (p<0.001) for ML to detect spinal cord injury. Sensibility and specificity were, respectively, 76% and 86% for SL and 79% and 85% for ML. Galvanic-VEMP disclosed alterations that were progressive in HTLV-1-neurological disease, ranging from SL delayed latency in HTLV-1-asymptomatic carriers, SL and ML delayed latency in possible HAM group, to absence of VEMP response in HAM group. CONCLUSIONS/SIGNIFICANCE: The worse the galvanic-VEMP response, the more severe the myelopathy. Galvanic-VEMP alteration followed a pattern of alteration and may be a prognostic marker of progression from HTLV-1-asymptomatic carrier to HAM. PMID- 30001402 TI - The deregulation of miR-17/CCND1 axis during neuroendocrine transdifferentiation of LNCaP prostate cancer cells. AB - Prostate carcinoma contain foci of neuroendocrine transdifferentiation, resulting in an increase of androgen-independent neuroendocrine-like (NE) tumor cells, whose number significantly correlates with tumor aggressiveness and thus lower survival rate. Neuroendocrine transdifferentiation of prostate cancer cells and a potential role of miRNAs within this process are poorly understood. MicroRNAs are small non-coding RNAs which post-transcriptionally regulate gene expression. The aim of this project was to identify new genes and miRNAs involved in neuroendocrine transdifferentiation. LNCaP prostate cancer cells were differentiated to NE-like cancer cells and microarray analyses were performed. Microarray results have been validated for the eight most deregulated mRNAs and microRNAs via qRT-PCR and analyzed with different algorithms to predict new targets for deregulated microRNAs. The induced CyclinD1 gene could be validated as new target gene for the repressed miR-17 family containing miR-17, miR-20a, miR-20b, miR-106a and miR-106b via reporter gene assays and Western Blot. Functional analysis of miR-17 family shows a high influence on cell proliferation, colony forming ability and apoptosis in LNCaP cells. Our data demonstrate wide changes in mRNA and microRNA expression during neuroendocrine transdifferentiation of LNCaP cells and confirm new mRNA-miRNA interactions with potential roles in NE-transdifferentiation of prostate carcinoma. PMID- 30001404 TI - Absence of IL-10 production by human PBMCs co-cultivated with human cells expressing or secreting retroviral immunosuppressive domains. AB - Immunosuppression by retroviruses including the human immunodeficiency virus-1 (HIV-1) is well known, however the mechanisms how retroviruses induce this immunosuppression is not fully investigated. It was shown that non-infectious retroviral particles as well as retroviral or recombinant retroviral transmembrane envelope (TM) proteins demonstrated immunosuppressive properties. The same was shown for peptides corresponding to a highly conserved domain in the TM protein. This domain is called immunosuppressive (ISU) domain and it induces modulation of the cytokine release of peripheral blood mononuclear cells (PBMCs) from healthy donors. In addition, it changes the gene expression of these cells. Common indications for the immunosuppressive activity were tumour growth in vivo and interleukin-10 (IL-10) release from human PBMCs in vitro. Single mutations in the ISU domain abrogated the immunosuppressive activity. In order to develop a new model system for the expression of the ISU domain and presentation to PBMCs which is not prone to possible endotoxin contaminations, two expression systems were developed. In the first system, designated pOUT, retroviral proteins containing the ISU domain were expressed and released into the cell culture medium, and in the second system, tANCHOR, the ISU domain was presented by a tetraspanin-anchored sequence on the cell surface of human cells. Both systems were exploited to express the wild-type (wt) ISU domains of HIV-1, of the porcine endogenous retrovirus (PERV) and of the murine leukaemia virus (MuLV) as well as to express mutants (mut) of these ISU domains. PERV is of special interest in the context of virus safety of xenotransplantation using pig organs. Expression of the TM proteins was demonstrated by confocal laser scanning microscopy, ELISA and Western blot analyses using specific antibodies. However, when cells expressing and releasing the ISU were co-incubated with human PBMCs, no increased production of IL-10 was observed when compared with the mutants. Similar results were obtained when the released TM proteins were concentrated by immunoprecipitation and added to PBMCs. We suggest that the absence of IL-10 induction can be explained by a low amount of protein, by the lack of a biologically active conformation or the absence of additional factors. PMID- 30001405 TI - Mechanistic modelling of interventions against spread of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) within a Danish farrow-to finish pig herd. AB - Knowledge on successful interventions against livestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA) within pig herds is sparse. In situations like this, a mechanistic simulation model can be a valuable tool for assessing the effect of potential intervention strategies, and prioritising which should be tested in the field. We have simulated on-farm interventions in a farrow-to-finish pig herd, with a previously published LA-MRSA spread model, within four different areas: 1) Reduced antimicrobial consumption, 2) Reduced number of pigs within each section, 3) Reduced mixing of pigs, and 4) Improved internal biosecurity. To model a decrease in the selective pressure, the transmission rates were reduced after LA-MRSA had become fully established within a herd, which resulted in a marked decrease in the prevalence within all stable units. However, LA-MRSA rarely disappeared completely from the herd; this was only observed in scenarios where the transmission rates were reduced to <= 30% of the original level. While changes in antimicrobial consumption patterns might be a very important step towards reducing the spread of LA-MRSA, the simulation results indicate that it may need to be paired with other preventive or intervention measures. Reducing the number of pigs within each section, reducing mixing of pigs, or improving internal biosecurity after LA-MRSA had become established within the herd only resulted in marginal changes in the median prevalence within the herd. However, these factors might be important in relation to being able to achieve or maintain a low level of antimicrobial consumption, and thus still indirectly influence the LA-MRSA prevalence within the herd. The results of a sensitivity analysis indicated the assumptions regarding the existence of pigs persistently shedding MRSA have a noticeable influence on the model results. The assumptions regarding transmission from sow to offspring at the day of birth also had a considerable influence on the MRSA prevalence within the farrowing unit but did not cause any marked changes in the simulated effect of interventions. Effects might differ between different farm types contaminated in different levels and this simulation study highlights a strong need for more knowledge from on-farm trials. PMID- 30001403 TI - Maternal total cell-free DNA in preeclampsia and fetal growth restriction: Evidence of differences in maternal response to abnormal implantation. AB - OBJECTIVES: Preeclampsia and fetal growth restriction are obstetrical syndromes associated with abnormal placental implantation and changes in the activation status of maternal leukocytes. This study is aimed to determine by a simple, rapid fluorescent assay the changes in maternal serum total cell-free DNA (t cfDNA) concentrations in women with preeclampsia and those with fetal growth restriction (FGR). STUDY DESIGN: A cross-sectional study was conducted measuring maternal serum t-cfDNA concentrations. Women were classified into the following groups: 1) patients with preeclampsia (n = 21); 2) FGR-estimated fetal weight below the 10thpercentile (n = 28); and 3) normal pregnancy (n = 39). Serum samples were directly assayed for t-cfDNA using a rapid fluorescent SYBR Gold assay. Elevated maternal serum t-cfDNA concentrations were defined as a cutoff>850ng/ml. Nonparametric statistics were used for analysis. RESULTS: Women with preeclampsia had a higher median maternal serum concentration (802 ng/ml, 400-2272 ng/ml) than women with a normal pregnancy (499 ng/ml, 0-1892 ng/ml, p = 0.004) and those with FGR (484 ng/ml, 72-2187 ng/ml, p = 0.012). Moreover, even patients with FGR <5th percentile and abnormal Doppler had a lower median maternal serum t-cfDNA than those with preeclampsia (median 487 ng/ml, 144-1971 ng/ml, p = 0.022). The median concentration of t-cfDNA did not differ between women with a normal pregnancy and those with FGR (p = 0.54), as well as those with fetuses <5th percentile and abnormal Doppler (p = 0.7). Women with preeclampsia had a higher proportion of elevated t-cfDNA than those with a normal pregnancy (p = 0.015) and patients with FGR (p = 0.025). CONCLUSIONS: Preeclampsia is associated with higher maternal serum t-cfDNA concentration than normal pregnancy or FGR. This observation may reflect an increased systemic activation of the maternal inflammation, rather than placental; this assumption is supported by the fact that we did not observe a significant change in the maternal serum t-cfDNA in patients with placental-mediated FGR. PMID- 30001406 TI - Mediterranean diet and physical functioning trajectories in Eastern Europe: Findings from the HAPIEE study. AB - BACKGROUND: Unhealthy diet may increase the risk of impaired physical functioning in older age. Although poor diet and limited physical functioning both seem to be particularly common in Eastern Europe, no previous study has assessed the relationship between these two factors in this region. The current analysis examined the association between overall diet quality and physical functioning in Eastern European populations. METHODS: We used data on 25,504 persons (aged 45-69 years at baseline) who participated in the Health Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study. Dietary assessment at baseline used food frequency questionnaire, and the overall diet quality was evaluated by the Mediterranean diet score (MDS). Physical functioning (PF) was measured by the physical functioning subscale (PF-10) of the 36-item Short-Form Health Survey at baseline and three subsequent occasions over a 10-year period. The cross sectional and longitudinal relationships between the MDS and PF were examined simultaneously using growth curve models. RESULTS: Men and women with higher adherence to the Mediterranean diet had significantly better PF at baseline; after multivariable adjustment, the regression coefficient per 1-unit increase in the MDS was 0.39 (95% CI: 0.25, 0.52) in men and 0.50 (0.36, 0.64) in women. However, we found no statistically significant link between baseline MDS and the subsequent slope of PF decline in neither gender; the coefficients were -0.02 ( 0.04, 0.00) in men and -0.01 (-0.03, 0.02) in women. DISCUSSION: Our results do not support the hypothesis that the Mediterranean diet has a substantial impact on the trajectories of physical functioning, although the differences existing at baseline may be related to dietary habits in earlier life. PMID- 30001408 TI - Identification of changes in dendritic cell subsets that correlate with disease severity in dengue infection. AB - Dengue virus (DENV) is the most prevalent arthropod-borne viral disease in humans. DENV causes a spectrum of illness ranging from mild to potentially severe complications. Dendritic cells (DCs) play a critical role in initiating and regulating highly effective antiviral immune response that include linking innate and adaptive immune responses. This study was conducted to comparatively characterize in detail the relative proportion, phenotypic changes, and maturation profile of subsets of both myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in children with dengue fever (DF), dengue hemorrhagic fever (DHF) and for purposes of control healthy individuals. The mDCs (Lin-CD11c+CD123lo), the pDCs (Lin-CD11c-CD123+) and the double negative (DN) subset (Lin-/HLA-DR+/CD11c-CD123 ) were analyzed by polychromatic flow cytometry. The data were first analyzed on blood samples collected from DENV-infected patients at various times post infection. Results showed that the relative proportion of mDCs were significantly decreased which was associated with an increase in disease severity in samples from DENV-infected patients. While there was no significant difference in the relative proportion of pDCs between healthy and DENV-infected patients, there was a marked increase in the DN subset. Analysis of the kinetics of changes of pDCs showed that there was an increase but only during the early febrile phase. Additionally, samples from patients during acute disease showed marked decreases in the relative proportion of CD141+ and CD16+ mDC subsets that were the major mDC subsets in healthy individuals. In addition, there was a significant decrease in the level of CD33-expressing mDCs in DENV patients. While the pDCs showed an up-regulation of maturation profile during acute DENV infection, the mDCs showed an alteration of maturation status. This study suggests that different relative proportion and phenotypic changes as well as alteration of maturation profile of DC subsets may play a critical role in the dengue pathogenesis and disease outcome. PMID- 30001407 TI - Modulation of the honey bee queen microbiota: Effects of early social contact. AB - As the sole reproductive female in a honey bee (Apis mellifera) colony, the queen's health is critical to colony productivity and longevity. Beekeeping operations typically rely on the commercial mass production of queens for colony multiplication, which involves manipulating and isolating the queens by confining them in cages during early development. Using common queen-rearing techniques, this study shows that segregating newly eclosed queens from their worker attendants for 72 hours using queen protector cages has a significant impact on the total amount of gut bacteria carried by those queens compared to queens that have unrestricted access to attendants upon eclosion. Isolated virgin queens sampled immediately after isolation at 4 days post eclosure had significantly more bacteria and a less consistent microbiota composition than their non isolated peers. Furthermore, this effect lasted into the mating life of queens, since mated queens that had been isolated after emergence and then sampled at 14 days post eclosure also had significantly more microbiota compared to non isolated mated queens of the same age. The causes and potential impacts of this alteration are not clear and deserve further investigation. This study also verifies earlier findings that honey bee queens lack the core microbiome found within honey bee workers. PMID- 30001409 TI - Increased skin blood flow during low intensity vibration in human participants: Analysis of control mechanisms using short-time Fourier transform. AB - AIM: Investigate the immediate effect of low intensity vibration on skin blood flow and its underlying control mechanisms in healthy human participants. MATERIALS AND METHODS: One-group pre-post design in a university laboratory setting. Nine adults underwent two bouts of 10-minute vibration (30Hz, peak acceleration 0.4g). Outcome measures include skin blood flow, and skin temperature on the right foot. To examine the control mechanisms underlying the vibration-induced blood flow response, SHORT-TIME Fourier analyses were computed to obtain the spectral densities for three frequency bands: metabolic (0.0095 0.02Hz), neurogenic (0.02-0.06Hz), and myogenic (0.06-0.15Hz). Non-parametric Friedman's tests were computed to compare changes of the outcome measures and control mechanisms over the course of vibration. RESULTS: Vibration increased skin blood flow during both bouts of vibration, however the effect did not last after vibration was terminated. Myogenic spectral density increased during both bouts of vibration, whereas the metabolic and neurogenic spectral densities increased only during the 2nd bout of vibration. Interestingly, only the metabolic spectral density remained elevated after vibration ended. CONCLUSION: Low intensity vibration produced acute increases in skin blood flow mediated in part by vascular control mechanisms of myogenic origin. Further investigation is warranted to determine whether low intensity vibration induces similar increases in skin blood flow in populations prone to developing chronic non-healing wounds, such as spinal cord injury and diabetes. PMID- 30001410 TI - Surfactant replacement therapy in combination with different non-invasive ventilation techniques in spontaneously-breathing, surfactant-depleted adult rabbits. AB - Nasal intermittent positive pressure ventilation (NIPPV) holds great potential as a primary ventilation support method for Respiratory Distress Syndrome (RDS). The use of NIPPV may also be of great value combined with minimally invasive surfactant delivery. Our aim was to implement an in vivo model of RDS, which can be managed with different non-invasive ventilation (NIV) strategies, including non-synchronized NIPPV, synchronized NIPPV (SNIPPV), and nasal continuous positive airway pressure (NCPAP). Forty-two surfactant-depleted adult rabbits were allocated in six different groups: three groups of animals were treated with only NIV for three hours (NIPPV, SNIPPV, and NCPAP groups), while three other groups were treated with surfactant (SF) followed by NIV (NIPPV+SF, SNIPPV+SF, and NCPAP+SF groups). Arterial gas exchange, ventilation indices, and dynamic compliance were assessed. Post-mortem the lungs were sampled for histological evaluation. Surfactant depletion was successfully achieved by repeated broncho alveolar lavages (BALs). After BALs, all animals developed a moderate respiratory distress, which could not be reverted by merely applying NIV. Conversely, surfactant administration followed by NIV induced a rapid improvement of arterial oxygenation in all surfactant-treated groups. Breath synchronization was associated with a significantly better response in terms of gas exchange and dynamic compliance compared to non-synchronized NIPPV, showing also the lowest injury scores after histological assessment. The proposed in vivo model of surfactant deficiency was successfully managed with NCPAP, NIPPV, or SNIPPV; this model resembles a moderate respiratory distress and it is suitable for the preclinical testing of less invasive surfactant administration techniques. PMID- 30001411 TI - Using MRI to predict the fate of excitotoxic lesions in rats. AB - Excitotoxic lesions are frequently used to assess the role of cerebral structures in cognitive processes in rodents. However, the precise site and extent of these lesions remain unknown without histological verifications. Using a 7-Teslas MRI system and a T2-weighted turbo-RARE sequence, MR images were acquired at several time points following NMDA lesions (1h, 6h, 24h, 48h, 1 week and 2 weeks). NMDA infusions into the parenchyma induced a clear and delineable hyperintense signal from 1h up to 1-week post-surgery. Hyperintensity volumes were compared with NeuN and Cresyl violet histological quantifications of the lesion magnitude. NMDA induced hypersignal is observed as soon as 1h post-injection and is a reliable estimate of the presence (or absence) of a lesion. Compared to NeuN, Cresyl violet staining underestimates the extent of the lesion in significant proportions. The MRI hyperintensity generated by NMDA instillation into the parenchyma can be used as a powerful tool to confirm the diffusion of the drug into the cerebral tissue, to ascertain the locus of injection and predict with a high success rate the fate of NMDA lesions as soon as 1h post-surgery. This approach could be very useful in a large variety of lesion studies in rodents. PMID- 30001412 TI - Supplementation stocking of Lake Trout (Salvelinus namaycush) in small boreal lakes: Ecotypes influence on growth and condition. AB - Supplementation stocking is a commonly used management tool to sustain exploited fish populations. Possible negative consequences of supplementation on local stocks are a concern for the conservation of wild fish populations. However, the direct impacts of supplementation on life history traits of local populations have rarely been investigated. In addition, intraspecific hybridization between contrasting ecotypes (planktivorous and piscivorous) has been seldom considered in supplementation plans. Here, we combined genetic (genotype-by-sequencing analysis) and life history traits to document the effects of supplementation on maximum length, growth rates, body condition and genetic admixture in stocked populations of two Lake Trout ecotypes from small boreal lakes in Quebec and Ontario, Canada. In both ecotypes, the length of stocked individuals was greater than local individuals and, in planktivorous-stocked populations, most stocked fish exhibited a planktivorous-like growth while 20% of fish exhibited piscivorous-like growth. The body condition index was positively related to the proportion of local genetic background, but this pattern was only observed in stocked planktivorous populations. We conclude that interactions and hybridization between contrasting ecotypes is a risk that could result in deleterious impacts and possible outbreeding depression. We discuss the implications of these findings for supplementation stocking. PMID- 30001413 TI - Correction: Carbon dioxide dynamics in a lake and a reservoir on a tropical island (Bali, Indonesia). AB - [This corrects the article DOI: 10.1371/journal.pone.0198678.]. PMID- 30001414 TI - Molecular characterization and sensitivity to demethylation inhibitor fungicides of Aspergillus fumigatus from orange-based compost. AB - Aspergillus fumigatus, the causal agent of human aspergilloses, is known to be non-pathogenic in plants. It is present as saprophyte in different types of organic matter and develops rapidly during the high-temperature phase of the composting process. Aspergilloses are treated with demethylation inhibitor (DMI) fungicides and resistant isolates have been recently reported. The present study aims to estimate the abundance, genetic diversity and DMI sensitivity of A. fumigatus during the composting process of orange fruits. Composting of orange fruits resulted in a 100-fold increase in A. fumigatus frequency already after 1 week, demonstrating that the degradation of orange fruits favoured the growth of A. fumigatus in compost. Most of A. fumigatus isolates belonged to mating type 2, including those initially isolated from the orange peel, whereas mating type 1 evolved towards the end of the composting process. None of the A. fumigatus isolates expressed simultaneously both mating types. The 52 investigated isolates exhibited moderate SSR polymorphisms by formation of one major (47 isolates) and one minor cluster (5 isolates). The latter included mating type 1 isolates from the last sampling and the DMI-resistant reference strains. Only few isolates showed cyp51A polymorphisms but were sensitive to DMIs as all the other isolates. None of the A. fumigatus isolates owned any of the mutations associated with DMI resistance. This study documents a high reproduction rate of A. fumigatus during the composting process of orange fruits, requesting specific safety precautions in compost handling. Furthermore, azole residue concentrations in orange-based compost were not sufficient to select A. fumigatus resistant genotypes. PMID- 30001415 TI - Exoskeleton robot control for synchronous walking assistance in repetitive manual handling works based on dual unscented Kalman filter. AB - Prolong walking is a notable risk factor for work-related lower-limb disorders (WRLLD) in industries such as agriculture, construction, service profession, healthcare and retail works. It is one of the common causes of lower limb fatigue or muscular exhaustion leading to poor balance and fall. Exoskeleton technology is seen as a modern strategy to assist worker's in these professions to minimize or eliminate the risk of WRLLDs. Exoskeleton has potentials to benefit workers in prolong walking (amongst others) by augmenting their strength, increasing their endurance, and minimizing high muscular activation, resulting in overall work efficiency and productivity. Controlling exoskeleton to achieve this purpose for able-bodied personnel without impeding their natural movement is, however, challenging. In this study, we propose a control strategy that integrates a Dual Unscented Kalman Filter (DUKF) for trajectory generation/prediction of the spatio temporal features of human walking (i.e. joint position, and velocity, and acceleration) and an impedance cum supervisory controller to enable the exoskeleton to follow this trajectory to synchronize with the human walking. Experiment is conducted with four subjects carrying a load and walking at their normal speed- a typical scenario in industries. EMG signals taken at two muscles: Right Vastus Intermedius (on the thigh) and Right Gastrocnemius (on the calf) indicated reduction in muscular activation during the experiment. The results also show the ability of the control system to predict spatio-temporal features of the pilots' walking and to enable the exoskeleton to move in concert with the pilot. PMID- 30001416 TI - Azithromycin therapy reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction: Potential therapeutic targets in ischemic heart disease. AB - INTRODUCTION: Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery. METHODS AND RESULTS: Male WT mice (C57BL/6, 6-8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45+/Ly6G /F4-80+/CD86+) and increase in anti-inflammatory (CD45+/Ly6G-/F4-80+/CD206+) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis. CONCLUSION: Azithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM. PMID- 30001417 TI - Effectiveness of robot therapy on body function and structure in people with limited upper limb function: A systematic review and meta-analysis. AB - Robot-Assisted Therapy (RT) is an innovative approach to neurological rehabilitation that uses intensive, repetitive, interactive, and individualized practice. This systematic review aimed to investigate the effectiveness of RT on the body function and structure of people with upper limb impairments (PROSPERO registration: CRD42017054982). A search strategy conducted on seven databases identified randomized controlled studies. Methodological quality was assessed using the PEDro scale. When possible, the data were pooled, the strength of evidence was assessed using the GRADE system, and the effect sizes were assessed using Cohen coefficient. Subgroup analyses investigated the impact on the estimated effects of the following parameters: methodological quality; portion of the assessed upper limb; duration of stroke; and intervention dose and duration. Thirty-eight studies involving 1174 participants were included. Pooled estimates revealed small effects of RT on motor control and medium effects on strength compared with other intervention (OI) at a short-term follow-up. Standardized differences in means were as follows: 0.3 (95% CI 0.1 to 0.4) and 0.5 (95% CI 0.2 to 0.8). Effects at other time points and on other investigated outcomes related to body function and structure were not found (p>0.05). The strength of the current evidence was usually low quality. Subgroup analyses suggested that the methodological quality, and duration and dose of RT may influence the estimated effects. In conclusion, RT has small effects on motor control and medium effects on strength in people with limited upper limb function. Poor methodological quality, and lower treatment dose and duration may impact negatively the estimated effects. PMID- 30001418 TI - Phenotypic characterization of Gardnerella vaginalis subgroups suggests differences in their virulence potential. AB - The well-known genotypic and phenotypic diversity of G. vaginalis resulted in its classification into at least four subgroups (clades) with diverse genomic properties. To evaluate the virulence potential of G. vaginalis subgroups, we analyzed the virulence-related phenotypic characteristics of 14 isolates of clade 1, 12 isolates of clade 2, 8 isolates of clade 4 assessing their in vitro ability to grow as a biofilm, produce the toxin vaginolysin, and express sialidase activity. Significant differences in VLY production were found (p = 0.023), but further analysis of clade pairs did not confirm this finding. The amount of biofim did not differ significantly among the clades. Analysis of sialidase activity indicated statistically significant differences among the clades (p < 0.001). Production of active recombinant G. vaginalis sialidase demonstrated the link between the sld gene and enzymatic activity, which may be differentially regulated at the transcriptional level. Statistical classification analysis (random forests algorithm) showed that G. vaginalis clades could be best defined by the profiles of two phenotypic characteristics: sialidase activity and vaginolysin production. The results of principal component analysis and hierarchical clustering suggested that all isolates can be subgrouped into three clusters, the structures of which are determined based on phenotypic characteristics of the isolates. Clade 4 was the most homogenous group, as all isolates were found in the same cluster, which is characterized by low production of all studied virulence factors. Clade 2 isolates were mainly distributed between two clusters, whereas clade 1 isolates were found in all three clusters that were characterized by a distinct profile of phenotypic characteristics. Our findings suggest that G. vaginalis subgroups with different virulence potential might play distinct roles in vaginal microbiota. PMID- 30001420 TI - A hierarchical Bayesian model to predict APOE4 genotype and the age of Alzheimer's disease onset. AB - In this work we use a hierarchical Bayesian paradigm to introduce a theoretical framework to determine an individual's Apolipoprotein epsilon4 (APOE4) genotype, which heavily influences both the age of onset and probability of acquiring Alzheimer's disease (AD). This calculation is based solely on an individual's family history. This APOE4 genotype estimation is then combined with a number of known factors that influence AD onset to produce a function that estimates the onset of AD as a function of age. We disseminated our Alzheimer's predictive tool online at http://www.alzheimerspredictor.com. PMID- 30001419 TI - MARCH1-mediated ubiquitination of MHC II impacts the MHC I antigen presentation pathway. AB - Major histocompatibility complex class II (MHC II) expression and turn-over are regulated via its ubiquitination by the membrane associated RING-CH 1 (MARCH1) E3 ligase. Unexpectedly, we show that MHC II ubiquitination also impacts MHC I. Lack of MARCH1 in B cells and dendritic cells (DCs) resulted in a significant reduction in surface MHC I expression. This decrease was not directly caused by changes in MARCH1 ubiquitination of MHC I but indirectly by altered MHC II trafficking in the absence of its ubiquitination. Deletion of MHC II in March1-/- cells restored normal MHC I surface expression and replacement of wild type MHC II by a variant that could not be ubiquitinated caused a reduction in MHC I expression. Furthermore, these cells displayed inefficient presentation of peptide and protein antigen via MHC I to CD8+ T cells. In summary, we describe an unexpected intersection between MHC I and MHC II such that the surface expression of both molecules are indirectly and directly regulated by MARCH1 ubiquitination, respectively. PMID- 30001421 TI - Improving comprehension of genetic counseling for hereditary breast and ovarian cancer clients with a visual tool. AB - OBJECTIVE: Genetic counseling and testing can be offered to individuals who are at high risk of carrying a breast cancer (BRCA) gene mutation. However, the content of genetic counseling could be difficult to understand due to complex medical information. The aim of this study was to investigate if comprehension can be improved with a new genetic counseling tool (NGCT hereafter; a tool that combines complex medical information with pictures, diagrams and tables) as compared to conventional oral-only genetic counseling (CGC). METHODS: 207 clients attended genetic counseling for hereditary breast and ovarian cancer at the Medical University of Vienna between February 2015 and February 2016. Seventy clients participated in this study and were allocated into two groups: the first 36 participants received conventional (oral only) genetic counseling (CGC) and the following 34 participants received genetic counseling using a new genetic counseling tool (NGCT), which combines complex information with pictures, diagrams and tables. After genetic counseling, all consenting participants were invited to complete a questionnaire with seven questions evaluating their comprehension of the medical information provided. RESULTS: Socio-demographic backgrounds were comparable in both groups. Correct responses were significantly higher in the NGCT group compared to the CGC group (p = 0.012). NGCT also statistically improves correct response of Q1 (p = 0.03) and Q7 (p = 0.004). CONCLUSION: The NGCT leads to an overall better understanding of the content of a genetic counseling session than CGC alone. PMID- 30001422 TI - Use of principle component analysis to quantitatively score the equine metabolic syndrome phenotype in an Arabian horse population. AB - Equine metabolic syndrome (EMS), like human metabolic syndrome, comprises a collection of clinical signs related to obesity, insulin dysregulation and susceptibility to secondary inflammatory disease. Although the secondary conditions resulting from EMS can be life-threatening, diagnosis is not straightforward and often complicated by the presence of other concurrent conditions like pituitary pars intermedia dysfunction (PPID). In order to better characterize EMS, we sought to describe the variation within, and correlations between, typical physical and endocrine parameters for EMS. Utilizing an unsupervised statistical approach, we evaluated a population of Arabian horses using a physical examination including body measurements, as well as blood plasma insulin, leptin, ACTH, glucose, and lipid values. We investigated the relationships among these variables using principle component analysis (PCA), hierarchical clustering, and linear regression. Owner-assigned assessments of body condition were one full score (on a nine-point scale) lower than scores assigned by researchers, indicating differing perception of healthy equine body weight. Rotated PCA defined two factor scores explaining a total of 46.3% of variation within the dataset. Hierarchical clustering using these two factors revealed three groups corresponding well to traditional diagnostic categories of "Healthy", "PPID-suspect", and "EMS-suspect" based on the characteristics of each group. Proxies estimating up to 93.4% of the composite "EMS-suspect" and "PPID suspect" scores were created using a reduced set of commonly used diagnostic variables, to facilitate application of these quantitative scores to horses of the Arabian breed in the field. Use of breed-specific, comprehensive physical and endocrinological variables combined in a single quantitative score may improve detection of horses at-risk for developing EMS, particularly in those lacking severe clinical signs. Quantification of EMS without the use of predetermined reference ranges provides an advantageous approach for future studies utilizing genomic or metabolomics approaches to improve understanding of the etiology behind this troubling condition. PMID- 30001423 TI - Participant perspectives of a home-based palliative approach for people with severe multiple sclerosis: A qualitative study. AB - BACKGROUND: We performed a qualitative study to investigate the experiences of participants in a multicentre randomized controlled trial on a home-based palliative approach (HPA) for adults with severe multiple sclerosis (MS) and their caregivers. Our aim was to explore the strengths and challenges of the intervention, and circumstances that may have influenced its efficacy. METHODS: Participants to the qualitative study were the patients, their caregivers, patient referring physicians, and the teams who delivered the HPA intervention. We performed semi-structured one-on-one interviews with 12 patients and 15 informal caregivers chosen using a maximum variation strategy, two focus group meetings with patient referring physicians (4 participants each), and one with the HPA teams (9 participants). RESULTS: From data analysis (framework method) 38 sub-categories emerged, which were grouped into 10 categories and 3 themes: 'expectations,' 'met and unmet needs', and 'barriers'. Intervention benefits were improved control of symptoms and reduced sense of isolation of the patient caregiver dyads. Limitations were: factors related to experimental design (difficulty of dyads in identifying examiner and team roles, additional burden for caregivers); team issues (insufficient team building /supervision, competing priorities); limitations of the intervention itself (insufficient length, lack of rehabilitation input); and external factors (resource limitations, under responsive services/professionals). The referring physician focus groups provided little experiential data. CONCLUSIONS: The HPA reduced patient symptoms and sense of isolation in patients and caregivers. The indirect role of the HPA teams, and insufficient length of the intervention were key limitations. The experimental design imposed additional burdens on the dyads. Key barriers were the paucity of available services, the demanding administrative procedures, and lack of networking facilities. These findings suggest that two major requirements are necessary for home palliative care to be effective in this patient population: HPA teams well-connected with MS rehabilitation services, and care delivered over the long-term, with variable intensity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN73082124 (Registered 19/06/2014). PMID- 30001424 TI - Two types of somatostatin-expressing GABAergic interneurons in the superficial layers of the mouse cingulate cortex. AB - Somatostatin-expressing (SOM+), inhibitory interneurons represent a heterogeneous group of cells and given their remarkable diversity, classification of SOM+ interneurons remains a challenging task. Electrophysiological, morphological and neurochemical classes of SOM+ interneurons have been proposed in the past but it remains unclear as to what extent these classes are congruent. We performed whole cell patch-clamp recordings from 127 GFP-labeled SOM+ interneurons ('GIN') of the superficial cingulate cortex with subsequent biocytin-filling and immunocytochemical labeling. Principal component analysis followed by k-means clustering predicted two putative subtypes of SOM+ interneurons, which we designated as group I and group II GIN. A key finding of our study is the fact that these electrophysiologically and morphologically distinct groups of SOM+ interneurons can be correlated with two neurochemical subtypes of SOM+ interneurons described recently in our laboratory. In particular, all SOM+ interneurons expressing calbindin but no calretinin could be classified as group I GIN, whereas all but one neuropeptide Y- and calretinin-positive interneurons were found in group II. PMID- 30001425 TI - DDX3 suppresses type I interferons and favors viral replication during Arenavirus infection. AB - Several arenaviruses cause hemorrhagic fever (HF) diseases that are associated with high morbidity and mortality in humans. Accordingly, HF arenaviruses have been listed as top-priority emerging diseases for which countermeasures are urgently needed. Because arenavirus nucleoprotein (NP) plays critical roles in both virus multiplication and immune-evasion, we used an unbiased proteomic approach to identify NP-interacting proteins in human cells. DDX3, a DEAD-box ATP dependent-RNA-helicase, interacted with NP in both NP-transfected and virus infected cells. Importantly, DDX3 deficiency compromised the propagation of both Old and New World arenaviruses, including the HF arenaviruses Lassa and Junin viruses. The DDX3 role in promoting arenavirus multiplication associated with both a previously un-recognized DDX3 inhibitory role in type I interferon production in arenavirus infected cells and a positive DDX3 effect on arenavirus RNA synthesis that was dependent on its ATPase and Helicase activities. Our results uncover novel mechanisms used by arenaviruses to exploit the host machinery and subvert immunity, singling out DDX3 as a potential host target for developing new therapies against highly pathogenic arenaviruses. PMID- 30001427 TI - Disease burden of hepatitis C in the Austrian state of Tyrol - Epidemiological data and model analysis to achieve elimination by 2030. AB - BACKGROUND: In 2016, the World Health Organization (WHO) and 69th World Health Assembly approved the first global health sector strategy (GHSS) on viral hepatitis with the goal to eliminate hepatitis C virus (HCV) infections worldwide. The aim is a 90% reduction of new infections and 65% reduction of HCV related deaths by 2030. AIM: This study reports on the epidemiology of HCV infections in the Austrian state of Tyrol (total population 750,000) and uses a predictive model to identify how the WHO strategy for elimination of HCV can be achieved. METHODS: We developed a regional disease burden model based on observed local diagnosis data from 2001 to 2016. Scenarios were developed to evaluate the impact of diagnosis and treatment on HCV-related outcomes (viremic prevalence, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths) from 2015 through 2030. RESULTS: In the last 15 years, 1,721 patients living in Tyrol have been diagnosed with chronic HCV infection. When ageing, mortality and treatment were factored in, there were an estimated 2,043 viremic HCV infections in 2016, of which 1,136 cases had been diagnosed. A baseline model predicts a decrease of 588 HCV cases from 2015 to 2030, which would not translate into the significant reduction of infections needed to achieve WHO global health recommendations. A total of 1,843 infected individuals need to be identified and treated to achieve the WHO goals by 2030 (1,254 averted cases as compared to baseline model). Implementation of this strategy would avoid 523 new HCV infections and decreases HCV-related mortality by 73%. CONCLUSION: HCV elimination and >65% reduction of associated mortality are possible for Tyrol, but requires a significant increase in new diagnoses and treatment rate. The model presented in this study could serve as an example for other regions to reliably predict regional disease burden and estimate how WHO goals can be met in the future. PMID- 30001426 TI - Reduced microbiome alpha diversity in young patients with ADHD. AB - ADHD is a psychiatric disorder which is characterized by hyperactivity, impulsivity and attention problems. Due to recent findings of microbial involvement in other psychiatric disorders like autism and depression, a role of the gut microbiota in ADHD pathogenesis is assumed but has not yet been investigated. In this study, the gut microbiota of 14 male ADHD patients (mean age: 11.9 yrs.) and 17 male controls (mean age: 13.1 yrs.) was examined via next generation sequencing of 16S rDNA and analyzed for diversity and biomarkers. We found that the microbial diversity (alpha diversity) was significantly decreased in ADHD patients compared to controls (pShannon = 0.036) and that the composition (beta diversity) differed significantly between patients and controls (pANOSIM = 0.033, pADONIS = 0.006, pbetadisper = 0.002). In detail, the bacterial family Prevotellacae was associated with controls, while patients with ADHD showed elevated levels of Bacteroidaceae, and both Neisseriaceae and Neisseria spec. were found as possible biomarkers for juvenile ADHD. Our results point to a possible link of certain microbiota with ADHD, with Neisseria spec. being a very promising ADHD-associated candidate. This finding provides the basis for a systematic, longitudinal assessment of the role of the gut microbiome in ADHD, yielding promising potential for both prevention and therapeutic intervention. PMID- 30001428 TI - Biodiversity of cultivable Burkholderia species in Argentinean soils under no till agricultural practices. AB - No-tillage crop production has revolutionized the agriculture worldwide. In our country more than 30 Mha are currently cultivated under no-till schemes, stressing the importance of this management system for crop production. It is widely recognized that soil microbiota is altered under different soil managements. In this regard the structure of Burkholderia populations is affected by soils management practices such as tillage, fertilization, or crop rotation. The stability of these structures, however, has not been evaluated under sustainable schemes where the impact of land practices could be less deleterious to physicochemical soils characteristics. In order to assess the structure of Burkholderia spp. populations in no-till schemes, culturable Burkholderia spp. strains were quantified and their biodiversity evaluated. Results showed that Burkholderia spp. biodiversity, but not their abundance, clearly displayed a dependence on agricultural managements. We also showed that biodiversity was mainly influenced by two soil factors: Total Organic Carbon and Total Nitrogen. Results showed that no-till schemes are not per se sufficient to maintain a richer Burkholderia spp. soil microbiota, and additional traits should be considered when sustainability of productive soils is a goal to fulfil productive agricultural schemes. PMID- 30001429 TI - Self-rated health status and illiteracy as death predictors in a Brazilian cohort. AB - Cohort studies assessing predictive values of self-rated health (SRH) and illiteracy on mortality in low-to-middle income countries are missing in the literature. Aiming to determine if these two variables were death predictors, an observational prospective population-based cohort study was conducted in a Brazilian small city. The cohort was established in 2002 with a representative sample of adults living in the city, and re-assessed in 2015. Sociodemographic (including illiteracy), anthropometric, lifestyle, previous CVD, and SRH data were collected. Cox proportional hazard models were designed to assess SRH and illiteracy in 2002 as death (all causes, CVD and non-CVD) predictors in 2015. From a total of 1066 individuals included in this study, 95(9%) died of non-CVD causes and 53(5%) from CVD causes. Mortality rates were higher among those with worse SRH in comparison to better health status categories for all causes of death, CVD and non-CVD deaths (p<0.001 for all outcomes). Similarly, illiterate individuals had higher mortality rates in comparison to non-illiterate for all causes of death (p<0.001), CVD (p = 0.004) and non-CVD death (p<0.001). Higher SRH negatively predicted CVD death (HR 0.44; 95%CI 0.44-0.95; p = 0.027) and all causes of death (OR 0.40; 95%CI 0.20-0.78; p = 0.008) while illiteracy positively predicted Non-CVD death (OR 1.59; 95%CI 1.03-2.54; p = 0.046). In conclusion, we found in this large Brazilian cohort followed for 13 years that better health perception was a negative predictor of death from all causes and CVD deaths, while illiteracy was a positive predictor of non-CVD deaths. PMID- 30001431 TI - Higher breast cancer prevalence associated with higher socioeconomic status in the South Korean population; Has it resulted from overdiagnosis? AB - Recently, breast cancer prevalence has increased in South Korea. In this study, we investigated the correlation between breast cancer prevalence and socioeconomic status. This study enrolled 27,331 people who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) IV-VI (2007 2015). In addition, we obtained data from the Korean Statistical Information Service (KSIS) on the breast cancer age-standardized incidence rate (AIR), the age-standardized mortality rate (AMR), the number of women screened, and the number of newly diagnosed patients. The KHANES data showed that breast cancer prevalence was significantly associated with educational level (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.08-3.77 for 10-12 vs. <= 6 years of education, and OR, 2.36; 95% CI, 1.10-5.06 for >= 13 vs. <= 6 years of education). However, there was no significant association of breast cancer prevalence with monthly household income. In a separate analysis of the AIR, AMR, and number of women screened for breast cancer, the AIR increased with the number of women screened, whereas the AMR did not. Furthermore, the number of newly diagnosed patients in all age groups increased over time. The present results demonstrate that the recently increased breast cancer prevalence documented in South Korea may be attributable to earlier detection rather than to a real increase in prevalence, and that breast cancer may be overdiagnosed. PMID- 30001430 TI - An easy, rapid, and sensitive method for detection of drug-resistant influenza virus by using a sialidase fluorescent imaging probe, BTP3-Neu5Ac. AB - Immunochromatographic kits and RT-PCR are widely used as diagnostic tools for influenza detection in clinical and hygiene fields. Immunochromatographic kits are useful for differential typing of influenza A and influenza B but cannot show if the detected virus strains have acquired drug resistance against neuraminidase inhibitors that target sialidase activity of viral neuraminidase. Although RT-PCR enables determination of drug-resistant mutants, its efficacy is limited to viruses carrying a known substitution in their neuraminidase genome sequence. In the present study, an easy, rapid and sensitive method for detection of drug resistant influenza viruses regardless of major antigenic changes or genomic mutations was developed. By using the method in combination with virus concentrated membranes in centrifugal filter units and a sialidase imaging probe, 2-(benzothiazol-2-yl)-4-bromophenyl-N-acetylneuraminic acid (BTP3-Neu5Ac), sialidase activity of influenza neuraminidase was visualized on membranes by the green fluorescence of produced hydrophobic BTP3 under UV irradiation with a handheld UV flashlight. Fluorescence images in the presence or absence of neuraminidase inhibitors clearly discriminated drug-resistant influenza viruses from drug-sensitive ones. The assay can be done within 15 min. The detection sensitivity was shown to be equal to or higher than the sensitivities of commercial immunochromatographic kits. The assay will be a powerful tool for screening and monitoring of emerging drug-resistant influenza viruses and would help clinicians decide effective antiviral treatment strategies when such mutants have become prevalent. PMID- 30001432 TI - FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis. AB - Focal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FAK Y397 in vivo we analyzed mice with 'non-phosphorylatable' Y-to-phenylalanine (F) and 'phospho mimicking' Y-to-glutamate (E) mutations in the germline. We found that FAK Y397F mice die early during embryogenesis with abnormal angiogenesis like FAK kinase dead mice. When Y397 is mutated to a glutamate mice survive beyond mid-gestation like mice where Y397 is lost by deletion of FAK exon 15. In culture, defects in proliferation, invasion and gene expression were more severe with the FAK Y397F than with the FAK Y397E mutation despite the inability of FAK Y397E to bind SRC. Conditional expression of FAK Y397F or Y397E in unchallenged avascular epidermis, however, resulted in no appreciable phenotype. We conclude that FAK Y397 is required for the highly dynamic tissue remodeling during development but dispensable for normal homeostasis of avascular epidermis. In contrast to the Y397F mutation, FAK Y397E retains sufficient biological activity to allow for development beyond mid-gestation. PMID- 30001434 TI - Retraction: 5-aminosalicylic acid improves lipid profile in mice fed a high-fat cholesterol diet through its dual effects on intestinal PPARgamma and PPARalpha. PMID- 30001433 TI - Three-dimensionally printed surface features to anchor endoluminal spring for distraction enterogenesis. AB - Spring-mediated distraction enterogenesis has been studied as a novel treatment for short bowel syndrome (SBS). Previous approaches are limited by multiple surgeries to restore intestinal continuity. Purely endoluminal devices require a period of intestinal attachment for enterogenesis. The purpose of this study is to modify the device to prevent premature spring migration in a porcine model. Two models were created in juvenile mini-Yucatan pigs for the placement of three dimensionally printed springs. (1) Two Roux-en-y jejunojenostomies with two Roux limbs were made. A spring with bidirectional hooked surface features was placed in one Roux limb and a spring with smooth surface was placed in the other Roux limb. (2) The in-continuity model had both hooked and smooth surface springs placed directly in intestinal continuity. Spring location was evaluated by weekly radiographs, and the intestine was retrieved after 2 to 4 weeks. Springs with smooth surfaces migrated between 1 to 3 weeks after placement in both porcine models. Springs with bidirectional hooked surface features were anchored to the intestine for up to 4 weeks without migration. Histologically, the jejunal architecture showed significantly increased crypt depth and muscularis thickness compared to normal jejunum. Bidirectional features printed on springs prevented the premature migration of endoluminal springs. These novel spring anchors allowed for their endoluminal placement without any sutures. This approach may lead to the endoscopic placement of the device for patients with SBS. PMID- 30001437 TI - A Chronologic Perspective on Sickle Cell Disease. PMID- 30001438 TI - Depression in Children and Adolescents: The Pediatrician at the Front Lines. AB - Pediatricians are the primary care providers for most children and adolescents in the United States, so they need to feel comfortable caring for children and teens with depression. This topic is an extremely important one because the top three reasons teens die or get injured are related to accidents (3.7 per 100,000 for those ages 5-14 years and 28.5 per 100,000 for those ages 15-24 years), suicide (1 per 100,000 in the younger age group, and 12.5 deaths per 100,000 in those ages 5-14 years), and homicide (0.7 per 100,000 in those age 5-14 years, and 10.8 per 100,000 in those age 15-24 years). Each year, 21% of children ages 9 to 17 years are diagnosed with a mental or addictive disorder associated with at least minimum impairment, with 11% of these children having significant functional impairment and another 5% demonstrating extreme functional impairment. We know that one-half of all lifetime cases of mental health disorders start by age 14 years. This includes serious adult psychiatric illnesses such as major depressive disorder, anxiety disorders, and substance abuse. Three-quarters are present by age 24 years; therefore, interventions aimed at prevention or early treatment need to focus on youth. [Pediatr Ann. 2018;47(7):e261-e265.]. PMID- 30001436 TI - Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV. AB - Human gammaherpesviruses are associated with malignancies in HIV infected individuals; in macaques used in non-human primate models of HIV infection, gammaherpesvirus infections also occur. Limited data on prevalence and tumorigenicity of macaque gammaherpesviruses, mostly cross-sectional analyses of small series, are available. We comprehensively examine all three-rhesus macaque gammaherpesviruses -Rhesus rhadinovirus (RRV), Rhesus Lymphocryptovirus (RLCV) and Retroperitoneal Fibromatosis Herpesvirus (RFHV) in macaques experimentally infected with Simian Immunodeficiency Virus or Simian Human Immunodeficiency Virus (SIV/SHIV) in studies spanning 15 years at the AIDS and Cancer Virus Program of the Frederick National Laboratory for Cancer Research. We evaluated 18 animals with malignancies (16 lymphomas, one fibrosarcoma and one carcinoma) and 32 controls. We developed real time quantitative PCR assays for each gammaherpesvirus DNA viral load (VL) in malignant and non-tumor tissues; we also characterized the tumors using immunohistochemistry and in situ hybridization. Furthermore, we retrospectively quantified gammaherpesvirus DNA VL and SIV/SHIV RNA VL in longitudinally-collected PBMCs and plasma, respectively. One or more gammaherpesviruses were detected in 17 tumors; generally, one was predominant, and the relevant DNA VL in the tumor was very high compared to surrounding tissues. RLCV was predominant in tumors resembling diffuse large B cell lymphomas; in a Burkitt-like lymphoma, RRV was predominant; and in the fibrosarcoma, RFHV was predominant. Median RRV and RLCV PBMC DNA VL were significantly higher in cases than controls; SIV/SHIV VL and RLCV VL were independently associated with cancer. Local regressions showed that longitudinal VL patterns in cases and controls, from SIV infection to necropsy, differed for each gammaherpesvirus: while RFHV VL increased only slightly in all animals, RLCV and RRV VL increased significantly and continued to increase steeply in cases; in controls, VL flattened. In conclusion, the data suggest that gammaherpesviruses may play a significant role in tumorogenesis in macaques infected with immunodeficiency viruses. PMID- 30001435 TI - Illuminating pathogen-host intimacy through optogenetics. AB - The birth and subsequent evolution of optogenetics has resulted in an unprecedented advancement in our understanding of the brain. Its outstanding success does usher wider applications; however, the tool remains still largely relegated to neuroscience. Here, we introduce selected aspects of optogenetics with potential applications in infection biology that will not only answer long standing questions about intracellular pathogens (parasites, bacteria, viruses) but also broaden the dimension of current research in entwined models. In this essay, we illustrate how a judicious integration of optogenetics with routine methods can illuminate the host-pathogen interactions in a way that has not been feasible otherwise. PMID- 30001439 TI - The Modern Day Critical Care Team and Their Charge. PMID- 30001440 TI - Acute Respiratory Failure in Children. AB - This article reviews the definition, pathophysiology, etiology, assessment, and management of acute respiratory failure in children. Acute respiratory failure is the inability of the respiratory system to maintain oxygenation or eliminate carbon dioxide. Acute respiratory failure is a common cause for admission to a pediatric intensive care unit. Most causes of acute respiratory failure can be grouped into one of three categories: lung parenchymal disease, airway obstruction, or neuromuscular dysfunction. Many patients with acute respiratory failure are managed successfully with noninvasive respiratory support; however, in severe cases, patients may require intubation and mechanical ventilation. [Pediatr Ann. 2018;47(7):e268-e273.]. PMID- 30001441 TI - Traumatic Brain Injury in the Pediatric Intensive Care Unit. AB - Head trauma is a leading cause of brain injury in children, and it can have profound lifelong physical, cognitive, and behavioral consequences. Optimal acute care of children with traumatic brain injury (TBI) requires rapid stabilization and early neurosurgical evaluation by a multidisciplinary team. Meticulous attention is required to limit secondary brain injury after the initial trauma. This review discusses pathophysiology, acute stabilization, and monitoring, as well as supportive and therapeutic measures to help minimize ongoing brain injury and optimize recovery in children with TBI. [Pediatr Ann. 2018;47(7):e274-e279.]. PMID- 30001443 TI - Acute Kidney Injury in Hospitalized Pediatric Patients. AB - Acute kidney injury (AKI) is pervasive, affecting a significant proportion of critically ill and noncritically ill children. Recent data demonstrate a clear independent association of escalating AKI severity with not only mortality, but also with longer-term disability and chronic kidney disease in children. The paradigm has shifted-patients are no longer dying with AKI, but rather from AKI. In this review, AKI is described in the paradigms of "past," "present," and "future" to stimulate a reassessment of our understanding of this organ dysfunction syndrome. Current treatment strategies as well as novel methodologies are discussed. A global effort is required to make progress in the fight against AKI and improve patient outcomes. [Pediatr Ann. 2018;47(7):e286-e291.]. PMID- 30001442 TI - Acquired Cardiac Disease in the Pediatric Intensive Care Unit. AB - This review focuses on the identification, evaluation, management, and stabilization of a variety of acquired cardiac conditions, such as cardiomyopathies, inflammatory cardiac disease, and Kawasaki disease, which commonly require care in the pediatric intensive care unit (PICU). Pediatric cardiomyopathies comprise a spectrum of acquired or congenital myocardial diseases in which there are abnormalities of cardiac size and ventricular wall thickness, along with ventricular performance. The inflammatory diseases of the heart include acute myocarditis and pericarditis. Cardiac sequelae of Kawasaki disease resemble a self-limited vasculitis, but in rare instances may present with hemodynamic instability requiring vasopressor support. Care in the PICU affords both monitoring and management opportunities. [Pediatr Ann. 2018;47(7):e280-e285.]. PMID- 30001444 TI - Pediatric Sepsis: A Primer for the Pediatrician. AB - Sepsis is the body's systemic response to infection and is a serious health care concern that affects neonatal, pediatric, and adult populations worldwide. Severe sepsis (sepsis that has progressed to cellular dysfunction and organ damage or evidence of hypoperfusion) and septic shock (sepsis with persistent hypotension despite adequate fluid resuscitation) are still associated with high mortality rates despite improvements in the management of infectious processes. The cellular processes that occur as a result of the inflammatory response in sepsis, including impaired perfusion and microcirculatory coagulation, can lead to organ system dysfunction. Early recognition of sepsis can help prompt treatment to improve patient care. Current pediatric guidelines emphasize early recognition, aggressive fluid resuscitation, and administration of antibiotics within the first hour for a better outcome. The practitioner needs to always be mindful of the possibility of sepsis when examining a patient with potential symptoms. [Pediatr Ann. 2018;47(7):e292-e299.]. PMID- 30001445 TI - Peanut Allergy: Changes in Dogma and Past, Present, and Future Directions. AB - The prevalence of food allergy in the pediatric population, specifically to peanuts, has been rising. Accidental exposure to peanuts in a person who is allergic may have life-threatening consequences. Previous recommendations regarding peanut allergy included a delay in introduction of peanut to infants. However, more recent studies have provided sufficient contrary evidence supporting early introduction of peanuts for prevention of peanut allergy. Therefore, prompt evaluation by a specialist should be considered in infants at high risk of developing peanut allergy. Current treatment is strict avoidance of the allergen; however, future therapies are being sought, including oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy. [Pediatr Ann. 2018;47(7):e300-e304.]. PMID- 30001446 TI - Enhanced-Fluence Pulsed-Light Iontophoresis Corneal Cross-linking: 1-Year Morphological and Clinical Results. AB - PURPOSE: To assess the safety and efficacy of a novel pulsed-light enhanced fluence iontophoresis corneal cross-linking (EF I-CXL) procedure in patients with progressive keratoconus. METHODS: This prospective interventional pilot study included 12 eyes of 10 patients. Iontophoresis with Ricrolin+ solution (Sooft, Montegiorgio, Italy) was used for stromal imbibition. The treatment energy dose (fluence) was optimized at 30% (from 5.4 J to 7 J/cm2) and ultraviolet-A (UV-A) power set at 18 mW/cm2 * 6.28 minutes of exposure time, pulsing the light 1 second on/1 second off with a total irradiation time of 12.56 minutes. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), Scheimpflug corneal tomography data, and corneal optical coherence tomography (OCT) at baseline and 1, 3, 6, and 12 months postoperatively were evaluated. RESULTS: Twelve-month statistically significant average data (P < .05) showed UDVA decreased from 0.50 +/- 0.10 to 0.36 +/- 0.08 logMAR, maximum keratometry decreased from 52.86 +/- 1.50 to 51.49 +/- 0.90 diopters (D), surface asymmetry index decreased from 2.34 +/- 0.36 to 2.13 +/- 1.12 D, symmetry index decreased from 4.22 +/- 1.01 to 3.56 +/- 0.90 D, and coma decreased from 0.25 +/- 0.05 to 0.14 +/- 0.06 MUm. Corneal OCT showed greater than 80% demarcation line detection at 295.8 +/- 20.2 MUm depth on average in the first postoperative month. CONCLUSIONS: The preliminary results of the EF I-CXL protocol demonstrate its capability to increase I-CXL efficacy closer to standard CXL. [J Refract Surg. 2018;34(7):438-444.]. PMID- 30001447 TI - Comparison of the Distribution of Lenticule Decentration Following SMILE by Subjective Patient Fixation or Triple Marking Centration. AB - PURPOSE: To investigate lenticule decentration following small incision lenticule extraction (SMILE) via the subjective patient fixation method or triple marking centration method and compare inductions of corneal higher order aberrations (HOAs) between the two methods. METHODS: This study analyzed decentration values obtained from the Keratron Scout (Optikon, Rome, Italy) tangential topography difference map of 110 eyes (110 patients) undergoing SMILE with the subjective patient fixation method (n = 55) or triple marking centration method (n = 55). Root mean square values of total HOAs, 3rd order coma aberration, and 4th order spherical aberration, as well as individual coefficients for vertical and horizontal coma, were measured preoperatively and 3 months postoperatively. Relationships between the magnitudes of decentration and induced corneal HOAs were assessed. RESULTS: There were significant differences in horizontal decentered displacement (P = .048), vertical decentered displacement (P = .002), and total decentered displacement (P = .001) between the two groups. Total HOAs, coma, vertical coma, and spherical aberration significantly increased in the subjective patient fixation method (all P < .001), whereas total HOAs (P = .002) and vertical coma (P = .005) increased in the triple marking centration method. Induction of total HOAs (mean values: 0.13 vs 0.07; P = .026), coma (0.09 vs 0.03; P = .032), and spherical aberration (0.08 vs 0.02; P = .013) was significantly greater in the subjective patient fixation method than in the triple marking centration method. Association between the total decentered displacement and induced vertical coma (P = .006) or induced spherical aberration (P = .018) was significant in the subjective patient fixation method. CONCLUSIONS: SMILE with the triple marking centration method can yield improved treatment centration and smaller induction of total HOAs, coma, and spherical aberrations. [J Refract Surg. 2018;34(7):446-452.]. PMID- 30001448 TI - Variation of Lenticule Thickness for SMILE in Low Myopia. AB - PURPOSE: To report the impact of increasing minimum lenticule thickness on the safety and efficacy of small incision lenticule extraction (SMILE) in low myopia up to -3.50 diopters (D). METHODS: SMILE was performed in 76 eyes of 76 patients. Thirty-eight eyes of 38 patients with low myopia were prospectively operated on with a programmed minimum lenticule thickness of 15 to 30 MUm (thicker lenticule group). Thirty-five eyes suitable for analysis were then retrospectively matched by spherical equivalent to 35 eyes operated on with a minimum standard setting of 10 MUm (standard thickness group), as provided in the database of the SMILE Eyes Clinic Linz, Linz, Austria. Comparison of outcomes was performed with the Standard Graphs for Reporting Refractive Surgery and by analysis of higher order aberrations as provided by Scheimpflug imaging. RESULTS: Apart from lenticule thickness, there was no significant difference in preoperative baseline or treatment parameters between both groups. Mean minimum lenticule thickness differed significantly (standard thickness = 10 +/- 0 MUm; thicker lenticule = 20 +/- 5 MUm; P < .0001). This also translated into a significant difference in maximum lenticule thickness (standard thickness: 54 +/- 11 MUm; thicker lenticule: 62 +/- 8 MUm; P = .0002). Mean SEQ preoperatively was -2.25 +/- 0.51 (standard thickness) and -2.24 +/- 0.46 (thicker lenticule) D, respectively, and changed to -0.11 +/- 0.50 (standard thickness) and +0.01 +/- 0.36 (thicker lenticule) D postoperatively (P < .0001 for both comparisons). Uncorrected postoperative visual acuity was -0.08 +/- 0.35 (standard thickness) versus -0.10 +/- 0.09 (thicker lenticule) logMAR (P = .706). After SMILE, the thicker lenticule group showed better safety (1.20 vs 1.08; P = .025) and efficacy (1.14 vs 0.96; P = .011) indices, translating into more eyes within +/-0.50 D from target (91% vs 77%) and with at least 0.0 logMAR visual acuity (97% vs 86%), and fewer eyes losing one (3% vs 17%) and two (0% vs 3%) lines. CONCLUSIONS: Increasing minimum lenticule border thickness seems to improve the safety and efficacy of SMILE in low myopia. [J Refract Surg. 2018;34(7):453-459.]. PMID- 30001449 TI - Impact of a Displaced Corneal Apex in Small Incision Lenticule Extraction. AB - PURPOSE: To evaluate the possible impact of a displaced corneal apex (point of maximum curvature) on visual results and tomographic parameters after small incision lenticule extraction (SMILE). METHODS: In this retrospective evaluation, eyes with uncomplicated SMILE for myopia correction were classified in two groups based on their preoperative distance between the corneal apex and corneal vertex (corneal intercept with the patient's line of sight) of 1 mm or greater (large A V distance) or less than 1 mm (small A-V distance). All surgeries were performed during the early learning curve of two surgeons. Visual outcome parameters included uncorrected (UDVA) and corrected (CDVA) distance visual acuity, manifest refractive spherical equivalent (MRSE), and refractive astigmatism 3 months postoperatively. Scheimpflug-derived tomographic outcome parameters included mean keratometry value, root mean square higher order aberrations (RMS HOAs), and optical zone decentration. RESULTS: The study comprised 94 eyes of 48 patients: 44 eyes in the large A-V distance group and 50 eyes in the small A-V distance group. Preoperative and postoperative RMS HOAs were significantly higher in the large A-V distance group than in the small A-V distance group (P = .002 and .008, respectively). Postoperative CDVA was significantly better in the small A-V distance group (P = .014). There were no statistically significant differences in postoperative UDVA, MRSE, refractive astigmatism, mean keratometry value, and optical zone decentration. CONCLUSIONS: After SMILE, CDVA was significantly worse in eyes with a preoperatively displaced corneal apex compared to eyes with a more central corneal apex. However, good visual results were achieved in both groups. [J Refract Surg. 2018;34(7):460-465.]. PMID- 30001450 TI - Transepithelial Photorefractive Keratectomy in Moderate to High Astigmatism With a Non-wavefront-Guided Aberration-Neutral Ablation Profile. AB - PURPOSE: To evaluate the outcomes of transepithelial photorefractive keratectomy (PRK) in moderate to high astigmatism with a non-wavefront-guided aberration neutral ablation profile using SmartPulse allocation. METHODS: In this retrospective study, myopic patients with a preoperative cylinder of 2.00 diopters (D) or greater were analyzed at 3 months of follow-up. Transepithelial PRK treatments were performed in each patient with the Amaris 1050RS laser (SCHWIND eye-tech-solutions, Kleinostheim, Germany) creating aspheric ablation profiles by applying a SmartPulse allocation. Standard examinations and wavefront analyses were included for low and high ocular residual astigmatism subgroups. RESULTS: Fifty-eight eyes (44 patients) were included in the cohort. The eyes were divided into separate ocular residual astigmatism subgroups: 17 eyes presented with less than 0.50 D (low ocular residual astigmatism) and 24 eyes with greater than 0.75 D (high ocular residual astigmatism). The mean refractive cylinder in the entire cohort was 2.84 +/- 0.86 D preoperatively and 0.40 +/- 0.39 D postoperatively, with 81% of the eyes within 0.75 D of the target astigmatism. At 3 months of follow-up, significant improvement (P < .05) was seen in terms of sphere, cylinder, spherical equivalent, and uncorrected (UDVA) and corrected (CDVA) distance visual acuity. CDVA improved in 40% of eyes and 3% of eyes lost one line of CDVA. No clinically relevant changes were seen in higher order aberrations. The refractive changes showed an excellent match with the keratometric changes. The difference between the low and high ocular residual astigmatism subgroups was not significant except for the change of Snellen lines of CDVA (P < .05). CONCLUSIONS: Transepithelial PRK using a non-wavefront-guided aberration-neutral ablation profile performed by applying SmartPulse allocation yielded excellent visual outcomes. The preoperative astigmatism was reduced to subclinical values. Both subgroups were effective in terms of UDVA, CDVA, spherical and astigmatic correction, and preserving higher order aberrations. However, the low ocular residual astigmatism subgroup was slightly more prone to gain lines of CDVA. [J Refract Surg. 2018;34(7):466-474.]. PMID- 30001451 TI - Changes of Functional Optical Zone After LASIK for Hyperopia and Hyperopic Astigmatism. AB - PURPOSE: To evaluate which factors may influence the size of the postoperative functional optical zone after hyperopic LASIK. METHODS: Thirty-three eyes with a mean spherical equivalent of +3.55 +/- 1.28 diopters (D) underwent LASIK with a Technolas 217 C-LASIK laser (Bausch & Lomb Surgical, Munich, Germany). After 1 week and 1, 4, and 12 months, the authors examined refraction, corneal refractive power by means of computerized videokeratography (Technomed C-Scan; Baesweiler, Germany), and uncorrected/corrected distance visual acuity (UDVA/CDVA). According to the degree of hyperopia, they were divided into low hyperopia (spherical equivalent <= 3.00 D) and high hyperopia (spherical equivalent > 3.00 D) groups. RESULTS: One year postoperatively, 82% of all eyes had a UDVA of 0.5 or better; in 88%, the spherical equivalent did not deviate more than 1.00 D from the attempted value. Three eyes were slightly undercorrected. After an initial overcorrection (-0.27 D) with subsequent regression, the refraction remained stable at +0.17 D from the fourth postoperative month (low hyperopia group: +0.14 D; high hyperopia group: +0.19 D after 1 year). After 1 year, the functional optical zone diminished by 32%; the reduction was more pronounced in eyes with higher hyperopia: -1.85 +/- 1.09 mm (range: +0.5 to -3.4 mm) in the low hyperopia group (P < .0001) and -2.25 +/- 1.24 mm (range: +1 to -3.9 mm) in the high hyperopia group (P < .0001). Preoperative spherical equivalent and preoperative corneal refractive power affected the postoperative size of the functional optical zone additively. CONCLUSIONS: An expected small functional optical zone in high hyperopia may not be regarded as a compelling exclusion criterion, but can induce possible side effects such as glare and halos. [J Refract Surg. 2018;34(7):476-481.]. PMID- 30001453 TI - Rotational Stability and Visual Outcomes of V4c Toric Phakic Intraocular Lenses. AB - PURPOSE: To investigate the clinical outcomes and rotational stability following implantation of V4c toric implantable collamer lenses (ICLs) (STAAR Surgical Company, Monrovia, CA) and to analyze the factors that influence rotational stability. METHODS: In this prospective observational case series, the authors analyzed the visual outcomes and rotational stability in 52 eyes of 52 patients immediately and 3 and 6 months after implantation. Postoperative rotation was defined as the angle between the adjusted axis and alignment axis. Central vaulting of the ICL was measured in a non-accommodative state using Visante optical coherence tomography (Carl Zeiss Meditec, Jena, Germany). Vector analysis of refractive astigmatism was performed. Regression analysis was used to investigate the association between the degree of rotation 6 months postoperatively and the associated variables. RESULTS: The mean efficacy index and safety index 6 months postoperatively were 1.35 +/- 0.19 and 1.38 +/- 0.22, respectively. In vector analysis, the magnitude of error was -0.20 diopters (D), indicating slight undercorrection. Absolute degree of rotation was 2.81 degrees +/- 1.87 degrees immediately after the operation and 3.75 degrees +/- 2.92 degrees and 3.87 degrees +/- 3.07 degrees at 3 and 6 months postoperatively, respectively (P = .009). Bonferroni-adjusted post-hoc comparison showed that the absolute degree of rotation immediately after the operation was significantly smaller than that after 3 (P = .043) and 6 (P = .023) months, with barely any change after 3 months. No explanatory variable relevant to the absolute degree of rotation was discovered. CONCLUSIONS: The V4c toric ICL is predictable, safe, and effective in correcting low and high levels of astigmatism, showing relatively good postoperative rotational stability. [J Refract Surg. 2018;34(7):489-496.]. PMID- 30001452 TI - Stereopsis Simulating Small-Aperture Corneal Inlay and Monovision Conditions. AB - PURPOSE: To analyze stereoscopic vision under a broad range of experimental conditions simulating small-aperture corneal inlay and monovision conditions. METHODS: A total of 10 patients participated in the study. The anisocoria generated by corneal inlays was simulated by using a small-aperture contact lens fitted on the non-dominant eye. Visual acuity, contrast sensitivity function, visual discrimination capacity (halo perception), and stereoacuity tests were performed under natural conditions or when the non-dominant eye wore the small aperture contact lens under two conditions: induced anisocoria and induced anisocoria combined with monovision (using two add-powers: +0.75 and +1.25 diopters [D]). Stereoscopic vision and binocular summation were analyzed under those experimental conditions and for far, intermediate, and near vision. RESULTS: The results showed a deterioration in stereoacuity with respect to natural conditions, being significant mainly for near and intermediate distances. Results with other visual functions showed a deterioration of the binocular summation and therefore of visual performance, although not in a generalized way for all distances. Binocular visual acuity under the conditions that used the small-aperture contact lens was comparable to that of the natural eye. CONCLUSIONS: The deterioration of stereopsis and other binocular functions found in this study may be acceptable for patients who had this surgical technique because it is similar to the deterioration found in other surgical procedures of emmetropization. [J Refract Surg. 2018;34(7):482-488.]. PMID- 30001454 TI - Problems With Different Meanings and Types of Refractive Lens Exchange. PMID- 30001455 TI - Retained Lenticule or Lenticular Fragments After SMILE. PMID- 30001456 TI - Multiple electrode aggregometry as a method for platelet function assessment according to the European guidelines. AB - Platelets play an essential role in haemostasis. Assessment of their function is vital for anaesthesiologists evaluating haemostatic potential, especially during emergency operations. The monitoring of platelets function had been implemented into the European recommendations for management of perioperative and posttraumatic bleeding. One of the diagnostic methods described in the recommendations is multiple electrode aggregometry. As antiplatelet therapy becomes more widely used in modern medicine, this method, in contrast to standard laboratory tests, can significantly help to identify patients with drug-induced thrombocytopaty. The aggregometry enables prompt evaluation of the platelets aggregation which is very useful for everyday decision-making in goal-directed hemostatic therapy. PMID- 30001457 TI - Diminished Canonical beta-Catenin Signaling During Osteoblast Differentiation Contributes to Osteopenia in Progeria. AB - Patients with Hutchinson-Gilford progeria syndrome (HGPS) have low bone mass and an atypical skeletal geometry that manifests in a high risk of fractures. Using both in vitro and in vivo models of HGPS, we demonstrate that defects in the canonical WNT/beta-catenin pathway, seemingly at the level of the efficiency of nuclear import of beta-catenin, impair osteoblast differentiation and that restoring beta-catenin activity rescues osteoblast differentiation and significantly improves bone mass. Specifically, we show that HGPS patient-derived iPSCs display defects in osteoblast differentiation, characterized by a decreased alkaline phosphatase activity and mineralizing capacity. We demonstrate that the canonical WNT/beta-catenin pathway, a major signaling cascade involved in skeletal homeostasis, is impaired by progerin, causing a reduction in the active beta-catenin in the nucleus and thus decreased transcriptional activity, and its reciprocal cytoplasmic accumulation. Blocking farnesylation of progerin restores active beta-catenin accumulation in the nucleus, increasing signaling, and ameliorates the defective osteogenesis. Moreover, in vivo analysis of the Zmpste24-/- HGPS mouse model demonstrates that treatment with a sclerostin neutralizing antibody (SclAb), which targets an antagonist of canonical WNT/beta catenin signaling pathway, fully rescues the low bone mass phenotype to wild-type levels. Together, this study reveals that the beta-catenin signaling cascade is a therapeutic target for restoring defective skeletal microarchitecture in HGPS. (c) 2018 American Society for Bone and Mineral Research. PMID- 30001458 TI - A DNA as a Substrate and an Enzyme: Direct Profiling of Methyltransferase Activity by Cytosine Methylation of a DNAzyme. AB - Inhibiting DNA methyltransferase (MTase) activity is crucial for cancer treatment. Evaluating drug candidates as inhibitors of MTase requires the measurement of its activity. However, direct profiling of MTase activity remains an analytical challenge, since a complicated hydrolysis step using methylation sensitive restriction enzymes (msRE) was inevitable in almost all previously reported methods. Taking advantage that DNA is the substrate of MTase and certain DNA sequences, known as DNAzymes, can also have enzyme-like activities, we herein developed an enzyme-free and label-free route for direct assaying MTase activity. Specifically, adding a cytosine at the meta-position of a peroxidase-mimicking DNAzyme can improve the catalytic activity of DNAzyme up to 5-fold. After methylation of the cytosine cap, the activity is further doubled. Based on these findings, direct assaying of MTase inhibitors was performed without the extra and complicated hydrolysis step. These new findings provide a helpful tool for screening drugs for cancer therapy. The idea of using the same DNA as a substrate and an enzyme could be a general way for assaying other enzymes. PMID- 30001459 TI - Sexual Dimorphism in Cortical and Trabecular Bone Microstructure Appears During Puberty in Chinese Children. AB - Distal forearm fractures during growth are more common in males than females. Because metaphyseal cortical bone is formed by coalescence of trabeculae emerging from the periphery of the growth plate, we hypothesized that the later onset of puberty in males produces a longer delay in trabecular bone formation and coalescence, which leaves a transient phase of high cortical porosity, low matrix mineral density, and high trabecular density relative to females. We quantified the nondominant distal radial microstructure using high-resolution peripheral quantitative computed tomography in 214 healthy Chinese boys and 219 Chinese girls aged between 7 and 17 years living in Hong Kong. Measurements of 110 slices (9.02 mm) were acquired 5 mm proximal to the growth plate of the nondominant distal radius. Porosity was measured using StrAx1.0 (Straxcorp, Melbourne, VIC, Australia) and trabecular plate and rod structure were measured using individual trabecula segmentation (ITS). Mechanical properties were estimated using finite element analysis (FEA). Results were adjusted for age, total bone cross-sectional area (CSA), dietary calcium intake, and physical activity. In boys, total bone CSA was 17.2% to 22.9% larger throughout puberty, cortical/total bone CSA was 5.1% smaller in Tanner stage 2 only, cortical porosity was 9.4% to 17.5% higher, and matrix mineral density was 1.0% to 2.5% lower in Tanner stage 2 to 5, than girls. Boys had higher trabecular rod BV/TV in Tanner stage 3 and 4, but higher trabecular plate BV/TV and plate to rod ratio in Tanner stage 5, than girls. Boys had 17.0% lower apparent modulus than girls in Tanner stage 2. A transient phase of higher porosity due to dissociation between bone mineral accrual and linear growth may contribute to higher distal radial bone fragility in Chinese boys compared to girls. (c) 2018 American Society for Bone and Mineral Research. PMID- 30001460 TI - Research Agenda 2018: The American Society for Parenteral and Enteral Nutrition. PMID- 30001461 TI - Feeding During Phases of Altered Mitochondrial Activity: A Theory. AB - Decisions surrounding the timing and dosing of nutrition support are made for thousands of ICU patients daily and yet remain a topic of controversy. Nutrition support designed to replenish resting energy expenditure (REE) early in critical illness has led to worse clinical outcomes in at least three recent prospective randomized clinical trials. Producing sufficient energy from nutrient substrates requires use of the mitochondrial electron transport chain (ETC). This process is functionally linked to the creation of a tightly regulated series of chemical messengers known as reactive oxygen species (ROS). In health, ROS are kept at low levels by a system of mitochondrial/cellular enzymes and antioxidants, allowing ROS to act as a signal for the redox health of the cell. In inflammatory conditions, however, this system is altered, leading to changes in the physiologic function of the ETC such that its usage produces greater ROS per unit of substrate. This increased ROS is capable of deactivating antioxidant systems, as well as activating further ROS-producing pathways and stimulating localized inflammatory activity. We propose that exacerbation of this process at this time by the forced influx of exogenously acquired nutrient substrates leads to mitochondrial damage, amplified ROS production, increased inflammation, decreased ATP-productive capacity, and, eventually, the death of the cell by either apoptosis or necrosis. Knowledge of this process is vital to determining the safe dosing and timing of nutrition support in the ICU. It is possible that the physiologic cost of meeting the REE under these conditions of mitochondrial stress may simply be too high. This paper details the proposed process by which inappropriately timed feeding in critically ill patients may damage the very mitochondria required for its utilization. PMID- 30001462 TI - Early Enteral Nutrition Is Associated With Significantly Lower Hospital Charges in Critically Ill Children. AB - BACKGROUND: Previous studies have shown that early enteral nutrition (EEN) is associated with lower mortality in critically ill children. The purpose of this study was to determine the association between EEN (provision of 25% of goal calories enterally over the first 48 hours) and pediatric intensive care unit (PICU) and hospital charges in critically ill children. METHODS: We conducted a supplementary study to our previous multicenter retrospective study of nutrition and outcomes in critically ill patients who had a PICU length of stay (LOS) >=96 hours for the years 2007-2008. From 2 centers, we obtained additional data for all charges incurred during the PICU and hospital stay, respectively, from administrative data sets at each institution. RESULTS: We obtained data for 859 patients who met the inclusion criteria (615 from the first center and 244 from the second center). In the combined data from both centers, total (P = .0006, adjusted for Pediatric Index of Mortality-2 [PIM-2] and center) and daily hospital charges (P < .001, adjusted for PIM-2 and center) were significantly lower in patients who met the EEN goal than in patients who did not. Hospital LOS did not differ between patients who met the EEN goal and patients who did not. A significant interaction between EEN and centers prevented any comparison of PICU charges, daily PICU charges, and PICU LOS between those patients who met the EEN goal and those who did not. CONCLUSION: In critically ill children who stay in the PICU >96 hours, EEN is associated with significantly lower hospital charges. PMID- 30001463 TI - Impact of Software Selection and ImageJ Tutorial Corrigendum on Skeletal Muscle Measures at the Third Lumbar Vertebra on Computed Tomography Scans in Clinical Populations. AB - BACKGROUND: There is growing interest in computed tomography (CT) measures of skeletal muscle cross-sectional area (CSA) for nutrition assessment. Multiple software programs are available, but little work has been done comparing programs. We aimed to determine if CT-derived measures of skeletal muscle CSA at the level of the L3 are influenced by the software program used. We also demonstrate the importance of the ImageJ corrigendum published in this journal. METHODS: Two software programs, National Institutes of Health ImageJ and Tomovision sliceOmatic, were compared. ImageJ measures were obtained using both the original tutorial and corrigendum instructions. Skeletal muscle CSA at the level of the L3 was measured in advanced heart failure and head and neck cancer populations by 3 different investigators. Intraclass correlation coefficients were used to calculate intrarater and interrater reliability. Bland-Altman analysis was used to assess agreement. RESULTS: Both software programs yielded excellent intrarater and interrater reliability scores (intraclass correlation coefficients, 0.985-1.000). The overall mean difference (ImageJ tutorial with corrigendum - sliceOmatic) for the entire sample (N = 51) was found to be 1.53 cm2 (95% CI, 0.59-2.47 cm2 ). The overall mean difference (ImageJ corrected - original) for the entire sample (N = 51) was found to be -11.35 cm2 (95% CI, 12.75 to -9.95 cm2 ). CONCLUSION: Measures of skeletal muscle CSA at the L3 were found to be ~1.53 cm2 higher with ImageJ than sliceOmatic. This difference was not found to affect interpretation against a published cut point. The importance of accounting for the ImageJ tutorial corrigendum was shown to be clinically significant when applied to published cut points. PMID- 30001464 TI - Insulin Instability in Parenteral Nutrition Admixtures. AB - BACKGROUND: Biosynthetic human recombinant short-acting insulin is added to parenteral nutrition (PN) admixtures to nourish glucose-intolerant patients. Insulin, however, is electrostatically attracted and inactivated by ethyl-vinyl acetate (EVA) bags and filling system tubes. Our aim was to verify and quantify the presence of insulin in PN with and without intravenous lipid emulsion (ILE), just after addition (T0) until the infusion's end (T24). METHODS: Four undiluted samples of 12 different PN complete admixtures (6 with ILE and 6 without), each containing 250 g of glucose in a 2000 mL volume, were taken and analyzed at T0 and T24 by an automated electrochemiluminescence immunoassay after the addition of biosynthetic human recombinant short-acting insulin at increasing doses (from 6 to 72 IU/bag) by an automated compounding device. Assay sensitivity was set at 2 MUIU/mL. Admixtures with and without ILE were compared in terms of insulin detected amounts at T0 and T24. RESULTS: Regardless of the amount initially provided, insulin was missing in PN without ILE. In admixtures with ILE, the greater the insulin and ILE doses initially included, the higher the insulin availability at T0 and T24, both in absolute terms and as a percentage of the initial amount (from 3 to 81% at T0 and from 2.5 to 72.5% at T24). ILE may prevent insulin attraction to plastic surfaces. CONCLUSIONS: Insulin is recovered in the presence of ILE in PN even though considerable amounts are untraceable. This aspect needs verification. Until then, insulin should safely be injected in a different manner in uncontrolled situations. PMID- 30001465 TI - Tube Feeding with a Diabetes-Specific Enteral Formula Improves Glycemic Control in Severe Acute Ischemic Stroke Patients. AB - BACKGROUND: Glycemic control is essential for managing acute stroke. This study evaluated the impact of a diabetes-specific formula (DSF) on glycemic control in severe acute ischemic stroke patients. METHODS: A randomized, prospective controlled trial was conducted in Nanjing Drum Tower Hospital. Acute ischemic stroke patients who scored > 10 on the National Institutes of Health Stroke Scale as well as had swallowing problems were randomized to group A, which received a diabetes-specific enteral formula, and group B, which received a standard formula. Glycemic parameters were assessed at baseline and 7 days after admission. RESULTS: One hundred four patients were enrolled in the study (group A, 53; group B, 51). Postprandial glucose parameters, including capillary glucose concentration from 8 hours to 16 hours after enteral nutrition (EN) consumption, incremental areas under the curve (iAUC0-16 h ), peak value, and mean glucose concentration, were significantly lower in group A than in group B following a 7 day intervention period. Moreover, changes in HOMAIR after the 7-day treatment were significantly higher in group A than in group B. No significant difference in the incidence of hypoglycemia, glycemic variability parameters, or nutrition parameters was found between the 2 groups, either at baseline or after treatment. There were no serious adverse events observed during the study. CONCLUSION: A diabetes-specific formula may improve acute-term glycemic control in severe acute ischemic stroke patients. PMID- 30001466 TI - Retinal photoreceptor and ganglion cell types and topographies in the red fox (Vulpes vulpes) and Arctic fox (Vulpes lagopus). AB - The red fox (Vulpes vulpes) is the carnivore with the widest distribution in the world. Not much is known about the visual system of these predominantly forest dwelling animals. The closely related Arctic fox (Vulpes lagopus) lives in more open tundra habitats. In search for corresponding adaptations, we examined the photoreceptors and retinal ganglion cells (RGCs), using opsin immunohistochemistry, lucifer yellow injections and Nissl staining. Both species possess a majority of middle-to-longwave-sensitive (M/L) and a minority of shortwave-sensitive (S) cones, indicating dichromatic color vision. Area centralis peak cone densities are 22,600/mm2 in the red fox and 44,800/mm2 in the Arctic fox. Both have a centro-peripheral density decrease of M/L cones, and a dorsoventrally increasing density of S cones. Rod densities and rod/cone ratios are higher in the red fox than the Arctic fox. Both species possess the carnivore typical alpha and beta RGCs. The RGC topography shows a centro-peripheral density gradient with a distinct area centralis (mean peak density 7,900 RGCs/mm2 in the red fox and 10,000 RGCs/mm2 in the Arctic fox), a prominent visual streak of higher RGC densities in the Arctic fox, and a moderate visual streak in the red fox. Visual acuity and estimated sound localization ability were nearly identical between both species. In summary, the red fox retina shows adaptations to nocturnal activity in a forest habitat, while the Arctic fox retina is better adapted to higher light levels in the open tundra. PMID- 30001467 TI - Phosphorylation of Extracellular Bone Matrix Proteins and Its Contribution to Bone Fragility. AB - Phosphorylation of bone matrix proteins is of fundamental importance to all vertebrates including humans. However, it is currently unknown whether increase or decline of total protein phosphorylation levels, particularly in hypophosphatemia-related osteoporosis, osteomalacia, and rickets, contribute to bone fracture. To address this gap, we combined biochemical measurements with mechanical evaluation of bone to discern fracture characteristics associated with age-related development of skeletal fragility in relation to total phosphorylation levels of bone matrix proteins and one of the key representatives of bone matrix phosphoproteins, osteopontin (OPN). Here for the first time, we report that as people age the total phosphorylation level declines by approximately 20% for bone matrix proteins and approximately 30% for OPN in the ninth decade of human life. Moreover, our results suggest that the decline of total protein phosphorylation of extracellular matrix (ECM) contributes to bone fragility, but less pronouncedly than glycation. We theorize that the separation of two sources of OPN negative charges, acidic backbone amino acids and phosphorylation, would be nature's means of assuring that OPN functions in both energy dissipation and biomineralization. We propose that total phosphorylation decline could be an important contributor to the development of osteoporosis, increased fracture risk and skeletal fragility. Targeting the enzymes kinase FamC20 and bone alkaline phosphatase involved in the regulation of matrix proteins' phosphorylation could be a means for the development of suitable therapeutic treatments. (c) 2018 American Society for Bone and Mineral Research. PMID- 30001468 TI - Analysis of Three Commonly Used Tibia Length Measurement Techniques. AB - This study analyzes three tibia length measurement techniques on a sample of 107 tibiae. Two of the techniques meet published criteria by resting the tibia on its posterior surface with the longitudinal axis parallel to an osteometric board. The third technique does not adequately keep the longitudinal axis parallel to the board. Statistical analyses show low levels of interobserver error for all techniques and statistically significant differences between the third technique and the other two techniques. Results report a maximum difference of 6 mm between measurement techniques with the third technique having greater than 95% directional bias. A survey sent out to the American Academy of Forensic Sciences forensic anthropology community reported more than 50% of respondents having been taught the third technique when an osteometric board with a slot/hole is not available. The intermixing of the third technique with the other two has likely contributed to higher levels of interobserver error in tibia length measurements. PMID- 30001469 TI - Serum 25-Hydroxyvitamin D and Intact Parathyroid Hormone Influence Muscle Outcomes in Children and Adolescents. AB - Increases in 25-hydroxyvitamin D concentrations are shown to improve strength in adults; however, data in pediatric populations are scant and equivocal. In this ancillary study of a larger-scale, multi-sited, double-blind, randomized, placebo controlled vitamin D intervention in US children and adolescents, we examined the associations between changes in vitamin D metabolites and changes in muscle mass, strength, and composition after 12 weeks of vitamin D3 supplementation. Healthy male and female, black and white children and adolescents between the ages of 9 and 13 years from two US states (Georgia 34 degrees N and Indiana 40 degrees N) were enrolled in the study and randomly assigned to receive an oral vitamin D3 dose of 0, 400, 1000, 2000, or 4000 IU/d for 12 weeks between the winter months of 2009 to 2011 (N = 324). Analyses of covariance, partial correlations, and regression analyses of baseline and 12-week changes (post-baseline) in vitamin D metabolites (serum 25(OH)D, 1,25(OH)2 D, intact parathyroid hormone [iPTH]), and outcomes of muscle mass, strength, and composition (total body fat-free soft tissue [FFST], handgrip strength, forearm and calf muscle cross-sectional area [MCSA], muscle density, and intermuscular adipose tissue [IMAT]) were assessed. Serum 25(OH)D and 1,25(OH)2 D, but not iPTH, increased over time, as did fat mass, FFST, forearm and calf MCSA, forearm IMAT, and handgrip strength (p < 0.05). Vitamin D metabolites were not associated with muscle strength at baseline nor after the 12-week intervention. Changes in serum 25(OH)D correlated with decreases in forearm IMAT, whereas changes in serum iPTH predicted increases in forearm and calf MCSA and IMAT (p < 0.05). Overall, increases in 25(OH)D did not influence muscle mass or strength in vitamin D-sufficient children and adolescents; however, the role of iPTH on muscle composition in this population is unknown and warrants further investigation. (c) 2018 American Society for Bone and Mineral Research. PMID- 30001470 TI - Bioclimatic factors at an intrabiome scale are more limiting than cyanobiont availability for the lichen-forming genus Peltigera. AB - PREMISE OF THE STUDY: Factors shaping spatiotemporal patterns of associations in mutualistic systems are poorly understood. We used the lichen-forming fungi Peltigera and their cyanobacterial partners Nostoc to investigate the spatial structure of this symbiosis at an intrabiome scale and to identify potential factors shaping these associations. METHODS: Ninety-three thalli were sampled in Quebec, Canada, along a south-north and an east-west transect of ~1300 km each. We identified the two main partners (Peltigera species and Nostoc phylogroups) using molecular markers and modeled the effects of environmental variables and partner occurrence on Peltigera-Nostoc distributions. KEY RESULTS: Peltigera species showed a high degree of specialization toward cyanobionts, whereas two Nostoc phylogroups dominated both transects by associating with several Peltigera species. Peltigera species had narrower ranges than these two main cyanobionts. Distributions of three Peltigera species were highly associated with precipitation and temperature variables, which was not detected for Nostoc phylogroups at this spatial scale. CONCLUSIONS: For these cyanolichens, factors driving patterns of symbiotic associations are scale dependent. Contrary to global-scale findings, generalist Peltigera species were not more widespread within the boreal biome than specialists. Nostoc availability was not the only driver of Peltigera species' geographic ranges; environmental factors also contributed to their intrabiome distributions. Climatic conditions (especially precipitation) limited the range of some Peltigera species more than the range of their cyanobacterial partners at an intrabiome (boreal) scale. PMID- 30001471 TI - Effects of the EXAT neuropsychological multilevel intervention on behavior problems in children with executive function deficits. AB - This is a clinical intervention study of children with executive function (EF) deficits. A neuropsychological multimodal group intervention called EXAT (rehabilitation of EXecutive function and ATtention) was developed at the Psychology Clinic of the University of Tampere. Based on the principles of neuropsychological rehabilitation and behavioral modification, EXAT combines child group training, parent training, and teacher consultations. The aims of this study were to investigate behavior problems before and after the intervention in children attending EXAT and in controls, and to compare intervention effects in hyperactive, inattentive, and EF subgroups based on the primary deficit described in the referral. The participants were 86 children (6 12 years) with a mean IQ of 91.4 attending EXAT and 45 controls. The participants' parents and teachers completed the Conners' Rating Scales-Revised. In addition, the Strengths and Difficulties Questionnaire was completed by the parents attending EXAT. The parents reported statistically significant decreases with medium effect sizes for the CPRS-R subscales for impulsivity, hyperactivity, and oppositional behavior. In the controls within the same time interval, there was increase in restless and impulsive behavior, and a decrease in total problems. The teachers reported positive changes after the intervention in ADHD symptoms and anxiousness/shyness, but the effects sizes were small. The intervention effects were larger in the hyperactive subgroup. Positive intervention effects were related to a younger age, lower IQ, and simultaneous learning support. In conclusion, EXAT - a structured multilevel group intervention - has positive effects on children's behavior regulation skills by decreasing impulsivity and restless behavior. PMID- 30001472 TI - Adsorbed Intermediates in Oxygen Reduction on Platinum Nanoparticles Observed by In Situ IR Spectroscopy. AB - The sluggish kinetics of oxygen reduction to water remains a significant limitation in the viability of proton-exchange-membrane fuel cells, yet details of the four-electron oxygen reduction reaction remain elusive. Herein, we apply in situ infrared spectroscopy to probe the surface chemistry of a commercial carbon-supported Pt nanoparticle catalyst during oxygen reduction. The IR spectra show potential-dependent appearance of adsorbed superoxide and hydroperoxide intermediates on Pt. This strongly supports an associative pathway for oxygen reduction. Analysis of the adsorbates alongside the catalytic current suggests that another pathway must also be in operation, consistent with a parallel dissociative pathway. PMID- 30001473 TI - Estimating the Temperature of Heat-exposed Bone via Machine Learning Analysis of SCI Color Values: A Pilot Study. AB - Determining maximum heating temperatures of burnt bones is a long-standing problem in forensic science and archaeology. In this pilot study, controlled experiments were used to heat 14 fleshed and defleshed pig vertebrae (wet bones) and archaeological human vertebrae (dry bones) to temperatures of 400, 600, 800, and 1000 degrees C. Specular component included (SCI) color values were recorded from the bone surfaces with a Konica-Minolta cm-2600d spectrophotometer. These color values were regressed onto heating temperature, using both a traditional linear model and the k-nearest neighbor (k-NN) machine-learning algorithm. Mean absolute errors (MAE) were computed for 1000 rounds of temperature prediction. With the k-NN approach, the median MAE prediction errors were 41.6 degrees C for the entire sample, and 20.9 degrees C for the subsample of wet bones. These results indicate that spectrophotometric color measurements combined with machine learning methods can be a viable tool for estimating bone heating temperature. PMID- 30001474 TI - Resolving the overall pattern of marattialean fern phylogeny. AB - PREMISE OF THE STUDY: Recent clarification of the distribution of Marattiales through time provides the impetus for "total evidence" phylogenetic analyses of a major fern clade with a rich fossil record. These analyses serve as empirical tests for results from systematic analyses of living species and also of the belief that relationships among living species accurately reflect the overall pattern of phylogeny for clades with an extensive fossil record and a large percentage of extinction. METHODS: Species of living and fossil Marattiaceae are analyzed employing a "total evidence approach" via maximum parsimony. Analyses were conducted using TNT implemented through WinClada. KEY RESULTS: Systematic analyses of living species and of living + extinct species provide roughly concordant topologies for living taxa. However, living species of Marattiales are only one component of a much larger clade with two major subclades. One consists of Psaroniaceae and extends through time to at least the Early Cretaceous. The other consists of Marattiaceae and includes all living species. Various analyses support the generic-level clades of living species from earlier analyses, but the arrangement of such clades varies from analysis to analysis. CONCLUSIONS: Marattiales is a monophyletic group that is extremely common in late Paleozoic and early Mesozoic deposits, with a stem group Psaroniaceae and a crown group Marattiaceae. Because Marattiaceae represents only a small component of overall marattialean diversity, living species alone neither account for evolutionary changes within the clade over time, nor accurately reflect the overall pattern of marattialean fern phylogeny. PMID- 30001475 TI - Labially impacted maxillary canines after the closed eruption technique and orthodontic traction: A split-mouth comparison of periodontal recession. AB - BACKGROUND: Labially impacted maxillary canines may lack periodontal tissue after orthodontic traction. This study evaluated the periodontal status of labially impacted maxillary canines after the closed eruption technique followed by orthodontic traction and investigated pretreatment variables affecting periodontal changes. METHODS: Patients with one labially impacted maxillary canine (impaction group) and one contralateral normal canine (control group) were selected retrospectively. Maxillary canine pretreatment variables (angle, depth, sector, and Nolla stage) were determined from initial panoramic radiography. Periodontal outcomes including sulcus probing depth, bone probing depth, keratinized gingiva width (KGW), attached gingiva width (AGW), clinical crown length (CCL), cemento-enamel junction to alveolar crest (CEJ-AC) distance, root length, and bone support were measured from radiographic and clinical examinations after treatment and compared between the two groups. Pretreatment variables affecting the periodontal outcomes were determined using linear regression analyses. RESULTS: Fifty-four patients (21 males and 33 females; mean age, 12.85 years) were enrolled. The KGW, AGW, and root length were shorter; the CCL and CEJ-AC distance were longer; and the bone support on the interproximal sides was less in the impaction group than in the control group (P < 0.05). The root length was shorter with higher Nolla stages and the distal alveolar crest was lower with deep and mesially angulated impaction (P < 0.01). CONCLUSIONS: After the closed eruption technique, impacted canines exhibited slight but clinically insignificant periodontal recession compared with the contralateral normal tooth. The root developmental stage and pretreatment depth and angle may influence periodontal recession. PMID- 30001476 TI - Nivolumab for adults with Hodgkin's lymphoma (a rapid review using the software RobotReviewer). AB - BACKGROUND: Hodgkin's lymphoma (HL) is a cancer of the lymphatic system, and involves the lymph nodes, spleen and other organs such as the liver, lung, bone or bone marrow, depending on the tumour stage. With cure rates of up to 90%, HL is one of the most curable cancers worldwide. Approximately 10% of people with HL will be refractory to initial treatment or will relapse; this is more common in people with advanced stage or bulky disease. Standard of care for these people is high-dose chemotherapy and autologous stem cell transplantation (ASCT), but only 55% of participants treated with high-dose chemotherapy and ASCT are free from treatment failure at three years, with an overall survival (OS) of about 80% at three years.Checkpoint inhibitors that target the interaction of the programmed death (PD)-1 immune checkpoint receptor, and its ligands PD-L1 and PD-L2, have shown remarkable activity in a wide range of malignancies. Nivolumab is an anti (PD)-1 monoclonal antibody and currently approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma and, since 2016, for classical Hodgkin's lymphoma (cHL) after treatment with ASCT and brentuximab vedotin. OBJECTIVES: To assess the benefits and harms of nivolumab in adults with HL (irrespective of stage of disease). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, International Pharmaceutical Abstracts, conference proceedings and six study registries from January 2000 to May 2018 for prospectively planned trials evaluating nivolumab. SELECTION CRITERIA: We included prospectively planned trials evaluating nivolumab in adults with HL. We excluded trials in which less than 80% of participants had HL, unless the trial authors provided the subgroup data for these participants in the publication or after we contacted the trial authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed potential risk of bias. We used the software RobotReviewer to extract data and compared results with our findings. As we did not identify any randomised controlled trials (RCTs) or non-RCTs, we did not meta-analyse data. MAIN RESULTS: Our search found 782 potentially relevant references. From these, we included three trials without a control group, with 283 participants. In addition, we identified 14 ongoing trials evaluating nivolumab, of which two are randomised. Risk of bias of the three included studies was moderate to high. All of the participants were in relapsed stage, most of them were heavily pretreated and had received at least two previous treatments, most of them had also undergone ASCT. As we did not identify any RCTs, we could not use the software RobotReviewer to assess risk of bias. The software identified correctly that one study was not an RCT and did not extract any trial data, but extracted characteristics of the other two studies (although also not RCTs) in a sufficient way.Two studies with 260 participants evaluated OS. After six months, OS was 100% in one study and median OS (the timepoint when only 50% of participants were alive) was not reached in the other trial after a median follow-up of 18 months (interquartile range (IQR) 15 to 22 months) (very low certainty evidence, due to observational trial design, heterogenous patient population in terms of pretreatments and various follow-up times (downgrading by 1 point)). In one study, one out of three cohorts reported quality of life. It was unclear whether there was an effect on quality of life as only a subset of participants filled out the follow-up questionnaire (very low certainty evidence). Three trials (283 participants) evaluated progression-free survival (PFS) (very low certainty evidence). Six-month PFS ranged between 60% and 86%, and median PFS ranged between 12 and 18 months. All three trials (283 participants) reported complete response rates, ranging from 12% to 29%, depending on inclusion criteria and participants' previous treatments (very low certainty evidence).One trial (243 participants) reported drug-related grade 3 or 4 adverse events (AEs) only after a median follow-up of 18 months (IQR 15 to 22 months); these were fatigue (23%), diarrhoea (15%), infusion reactions (14%) and rash (12%). The other two trials (40 participants) reported 23% to 52% grade 3 or 4 AEs after six months' follow-up (very low certainty evidence). Only one trial (243 participants) reported drug-related serious AEs; 2% of participants developed infusion reactions and 1% pneumonitis (very low certainty evidence).None of the studies reported treatment-related mortality. AUTHORS' CONCLUSIONS: To date, data on OS, quality of life, PFS, response rate, or short- and long-term AEs are available from small uncontrolled trials only. The three trials included heavily pretreated participants, which had previously undergone regimens of BV or ASCT. For these participants, median OS was not reached after follow-up times of at least 16 months (more than 50% of participants with a limited life expectancy were alive at this timepoint). Only one cohort out of three only reported quality of life, with limited follow-up data so that meaningful conclusions were not possible. Serious adverse events occurred rarely. Currently, data are too sparse to make a clear statement on nivolumab for people with relapsed or refractory HL except for heavily pretreated people, which had previously undergone regimens of BV or ASCT. When interpreting these results, it is important to consider that proper RCTs should confirm these findings.As there are 14 ongoing trials evaluating nivolumab, of which two are RCTs, it is possible that an update of this review will be published in the near future and that this update will show different results to those reported here. PMID- 30001478 TI - Protection from fentanyl exposure: New resources from NIOSH. PMID- 30001477 TI - A Mechanism-Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases. AB - Functional metagenomics has opened new opportunities for enzyme discovery. To exploit the full potential of this new tool, the design of selective screens is essential, especially when searching for rare enzymes. To identify novel glycosidases that employ cleavage strategies other than the conventional Koshland mechanisms, a suitable screen was needed. Focusing on the unsaturated glucuronidases (UGLs), it was found that use of simple aryl glycoside substrates did not allow sufficient discrimination against beta-glucuronidases, which are widespread in bacteria. While conventional glycosidases cannot generally hydrolyze thioglycosides efficiently, UGLs follow a distinct mechanism that allows them to do so. Thus, fluorogenic thioglycoside substrates featuring thiol based self-immolative linkers were synthesized and assessed as selective substrates. The generality of the approach was validated with another family of unconventional glycosidases, the GH4 enzymes. Finally, the utility of these substrates was tested by screening a small metagenomic library. PMID- 30001479 TI - From the Editors. PMID- 30001480 TI - Role of Activator Protein-1 Complex on the Phenotype of Human Osteosarcomas Generated from Mesenchymal Stem Cells. AB - Osteosarcoma (OS) is a highly aggressive bone tumor that usually arises intramedullary at the extremities of long bones. Due to the fact that the peak of incidence is in the growth spurt of adolescence, the specific anatomical location, and the heterogeneity of cells, it is believed that osteosarcomagenesis is a process associated with bone development. Different studies in murine models showed that the tumor-initiating cell in OS could be an uncommitted mesenchymal stem cell (MSC) developing in a specific bone microenvironment. However, only a few studies have reported transgene-induced human MSCs transformation and mostly obtained undifferentiated sarcomas. In our study, we demonstrate that activator protein 1 family members induce osteosarcomagenesis in immortalized hMSC. c-JUN or c-JUN/c-FOS overexpression act as tumorigenic factors generating OS with fibroblastic or pleomorphic osteoblastic phenotypes, respectively. Stem Cells 2018;36:1487-1500. PMID- 30001481 TI - Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing. AB - Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross coupling methods. PMID- 30001483 TI - Online High Throughput Measurements for Fast Catalytic Reactions Using Time Division Multiplexing Gas Chromatography. AB - Developing new catalysts is crucial for optimization of chemical processes. Thus, advanced analytical methods are required to determine the catalytic performance of new catalysts accurately. Usually, gas chromatographic methods are employed to analyze quantitatively the product distribution of volatile compounds generated by a specific catalyst. However, the characterization of rapidly changing catalysts, e.g., due to deactivation, still poses an analytical challenge because gas chromatographic methods are too slow for monitoring the change of the complex product spectra. Here, we developed a gas chromatographic technique based on the concept of multiplexing gas chromatography (mpGC) for fast and comprehensive analysis of the product stream from a catalytic testing unit. This technique is applied for the study of the catalytic reaction of methanol-to-olefins (MTO) conversion. For this method, the time distance between two measurements is chosen so that the chromatograms but not the peaks themselves are superimposed. In this way, stacked chromatograms are generated in which the components from successively injected samples elute baseline separated next to each other from the column. The peaks from different samples are interlaced, and for this reason, the method is referred to as time-division multiplexing gas chromatography (td mpGC). The peaks are analyzed by direct peak integration not requiring a Hadamard transformation for deconvolution of the raw data as usual for many mpGC applications. Therefore, the sample can be injected equidistantly. The integrated peaks have to be allocated to the correct retention times. The time distance between two measurements for studying the reaction and regeneration cycles of MTO catalysts is 4.3 min and 38 s, respectively. Column switching techniques such as back-flush and heart-cut are introduced as general tools for multiplexing gas chromatography. PMID- 30001482 TI - Constitutive Activation of the Nutrient Sensor mTORC1 in Myeloid Cells Induced by Tsc1 Deletion Protects Mice from Diet-Induced Obesity. AB - SCOPE: To test whether myeloid cells Tsc1 deletion and therefore constitutive activation of the nutrient sensor mTORC1 protects from high-fat diet (HFD) induced obesity, glucose intolerance, and adipose tissue inflammation. METHODS AND RESULTS: Mice with Tsc1 deletion in myeloid cells (MTsc1KO) and littermate controls (MTsc1WT) were fed with HFD for 8 weeks and evaluated for body weight, glucose homeostasis, and adipose tissue inflammation. MTsc1KO mice were protected from HFD-induced obesity and glucose intolerance. MTsc1KO, however, displayed, independently of the diet, abnormal behavior, episodes of intense movement, and muscle spasms followed by temporary paralysis. To investigate whether obesity protection was due to myeloid cells Tsc1 deletion, bone marrow was transplanted from MTsc1WT and MTsc1KO into irradiated C57BL6/J mice. Mice transplanted with MTsc1KO bone marrow displayed reduced body weight gain, adiposity, and inflammation, and enhanced energy expenditure, glucose tolerance and adipose tissue M2 macrophage content upon HFD feeding, in the absence of abnormal behavior. In vitro, Tsc1 deletion increased in a mTORC1-dependent manner macrophage polarization to M2 profile and mRNA levels of fatty acid binding protein 4 and PPARgamma. CONCLUSION: Constitutive mTORC1 activation in myeloid cells protects mice from HFD-induced obesity, adipose tissue inflammation, and glucose intolerance by promoting macrophage polarization to M2 pro-resolution profile and increasing energy expenditure. PMID- 30001484 TI - Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) Sequences: Scope, Limitation, and Computational Investigations. AB - Oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition-conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway. PMID- 30001485 TI - Method for Biomonitoring DNA Adducts in Exfoliated Urinary Cells by Mass Spectrometry. AB - Tobacco smoking contributes to about 50% of the bladder-cancer (BC) cases in the United States. Some aromatic amines in tobacco smoke are bladder carcinogens; however, other causal agents of BC are uncertain. Exfoliated urinary cells (EUCs) are a promising noninvasive biospecimen to screen for DNA adducts of chemicals that damage the bladder genome, although the analysis of DNA adducts in EUCs is technically challenging because of the low number of EUCs and limiting quantity of cellular DNA. Moreover, EUCs and their DNA adducts must remain viable during the time of collection and storage of urine to develop robust screening methods. We employed RT4 cells, a well-differentiated transitional epithelial bladder cell line, as a cell-model system in urine to investigate cell viability and the chemical stability of DNA adducts of two prototypical bladder carcinogens: 4 aminobiphenyl (4-ABP), an aromatic amine found in tobacco smoke, and aristolochic acid I (AA-I), a nitrophenanthrene found in Aristolochia herbaceous plants used for medicinal purposes worldwide. The cell viability of RT4 cells pretreated with 4-ABP or AA-I in urine exceeded 80%, and the major DNA adducts of 4-ABP and AA-I, quantified by liquid chromatography-mass spectrometry, were stable for 24 h. Thereafter, we successfully screened EUCs of mice treated with AA-I to measure DNA adducts of AA-I, which were still detected 25 days following treatment with the carcinogen. EUCs are promising biospecimens that can be employed for the screening of DNA adducts of environmental and dietary genotoxicants that may contribute to the development of BC. PMID- 30001486 TI - Exploring the Magnetic and Electric Side of Light through Plasmonic Nanocavities. AB - Light-matter interactions are often considered to be mediated by the electric component of light only, neglecting the magnetic contribution. However, the electromagnetic energy density is equally distributed between both parts of the optical fields. Within this scope, we experimentally demonstrate here, in excellent agreement with numerical simulations, that plasmonic nanostructures can selectively manipulate and tune the magnetic versus electric emission of luminescent nanocrystals. In particular, we show selective enhancement or decay of magnetic and electric emission from trivalent europium-doped nanoparticles in the vicinity of plasmonic nanocavities, designed to efficiently couple to either the electric or magnetic emission of the quantum emitter. Specifically, by precisely controlling the spatial position of the emitter with respect to our plasmonic nanostructures, by means of a near-field optical microscope, we record local distributions of both magnetic and electric radiative local densities of states (LDOS) with nanoscale precision. The distribution of the radiative LDOS reveals the modification of both the magnetic and electric optical quantum environments induced by the presence of the metallic nanocavities. This manipulation and enhancement of magnetic light-matter interaction by means of plasmonic nanostructures opens up new possibilities for the research fields of optoelectronics, chiral optics, nonlinear and nano-optics, spintronics, and metamaterials, among others. PMID- 30001487 TI - Magnetism-Resolved Separation and Fluorescence Quantification for Near Simultaneous Detection of Multiple Pathogens. AB - In the modern era of molecular evidence-based medicine and advanced biomedical technologies, the rapid, sensitive and specific assay of multiple pathogens is critical to, but largely absent from, clinical practice. Therefore, to improve the current ordinary separation and collection method, we report herein a strategy of magnetism-resolved separation and fluorescence quantification for near-simultaneous detection of multiple pathogens, followed by the direct antimicrobial susceptibility testing (AST). To accomplish this strategy, we utilized aptamer-modified fluorescent-magnetic multifunctional nanoprobes (apt FMNPs). FMNPs with intriguing different magnetic responses and excellent fluorescence quality were first self-assembled based on metal coordination interaction using (3-mercaptopropyl) trimethoxysilane, magnetic gamma-Fe2O3, and fluorescent quantum dots as matrix components. Then, aptamers, which specific to target pathogens of Escherichia coli O157:H7 ( E. coli) and Salmonella typhimurium ( S. typ), were conjugated with FMNPs to yield apt-FMNPs nanoprobes for multiple pathogens assay. Based on the discrepant magnetic response of pathogen@nanoprobes complex under the identical external magnetic field, the model bacteria were fished out by magnetic adsorption at different time points and subjected to fluorescence quantification with good linear ranges and detection limits within 1h. Multiple pathogens spiked in real samples were also effectively detected by the apt-FMNPs and sequentially fished out for AST assay, which showed similar results to that for pure pathogens. The apt-FMNPs-based strategy of near-simultaneous detection of multiple pathogens shows promise for the potential application in the diagnosis and treatment of pathogen-related infectious diseases. PMID- 30001489 TI - Visible Light Mediated Generation of trans-Arylcyclohexenes and Their Utilization in the Synthesis of Cyclic Bridged Ethers. AB - While accessible via UV-irradiation of cis-cyclohexene, trans-cyclohexene has thus far been an investigation driven by curiosity, and due primarily to its short lifespan, has until recently not been employed for productive synthesis. Herein, we present straightforward conditions that provide access to a class of trans-arylcyclohexenes and demonstrate their utility in the formation of oxabicyclic ethers, which are otherwise inaccessible from the corresponding cis cyclohexene. A key challenge to utilizing the incredible ca. 52 kcal/mol strain energy of trans-cyclohexene to drive synthesis was overcoming its short lifetime. Herein, we show that preorganization via hydrogen bonding between the substrate and the reaction partner prior to isomerization is a viable strategy to overcome the inherently short lifetime of trans-cyclohexene. PMID- 30001490 TI - Active {001} Facet Exposed TiO2 Nanotubes Photocatalyst Filter for Volatile Organic Compounds Removal: From Material Development to Commercial Indoor Air Cleaner Application. AB - TiO2 nanotubes (TNT) have a highly ordered open structure that promotes the diffusion of dioxygen and substrates onto active sites and exhibit high durability against deactivation during the photocatalytic air purification. Herein, we synthesized {001} facet-exposed TiO2 nanotubes (001-TNT) using a new and simple method that can be easily scaled up, and tested them for the photocatalytic removal of volatile organic compounds (VOCs) in both a laboratory reactor and a commercial air cleaner. While the surface of TNT is mainly composed of {101} facet anatase, 001-TNT's outer surface was preferentially aligned with {001} facet anatase. The photocatalytic degradation activity of toluene on 001 TNT was at least twice as high as that of TNT. While the TNT experienced a gradual deactivation during successive cycles of photocatalytic degradation of toluene, the 001-TNT did not exhibit any sign of catalyst deactivation under the same test conditions. Under visible light irradiation, the 001-TNT showed degradation activity for acetaldehyde and formaldehyde, while the TNT did not exhibit any degradation activity for them. The 001-TNT filter was successfully scaled up and installed on a commercial air cleaner. The air cleaner equipped with the 001-TNT filters achieved an average VOCs removal efficiency of 72% (in 30 min of operation) in a 8-m3 test chamber, which satisfied the air cleaner standards protocol (Korea) to be the first photocatalytic air cleaner that passed this protocol. PMID- 30001488 TI - Adaptive Multifunctional Supramolecular Assemblies of Glycopeptides Rapidly Enable Morphogenesis. AB - Despite the well-established biophysical principle of adhesion-guided in vitro morphogenesis, there are few single synthetic molecular species that can rapidly enable morphogenesis (e.g., a cell monolayer to cell spheroids) in a cell culture because adhesion inherently involves many signals. Here we show the use of adaptive multifunctional supramolecular assemblies of glycopeptides, consisting of cell adhesion sequence and saccharide, to induce cell spheroids rapidly from a monolayer of cells. Having a general architecture of N-terminal capping, glycosylation, and an integrin-binding sequence, the glycopeptides self-assemble to form a dynamic continuum of nanostructures (i.e., from nanoparticles to nanofibers) to affect the interactions of integrins, E-selectin, and cadherins with their natural ligands and to act adaptively according to the cellular environment. Such adaptive (i.e., context-dependent) interactions weaken cell substratum adhesion and enhance intercellular interactions, which rapidly and transiently induce cell spheroids. This work illustrates the use of supramolecular assemblies of simple glycopeptides to modulate biophysical conditions for regulating cell functions, which is a new approach for developing biomaterials. PMID- 30001491 TI - Inertial Microfluidic Syringe Cell Concentrator. AB - Low-cost, easy-to-use cell concentration tools are in urgent demand for biomedical diagnosis in resource-poor settings. Herein, we propose a novel inertial microfluidic syringe cell (IMSC) concentrator that employs inertial focusing to increase cell concentration through ordering the cell and removing the cell-free fluid. A three-part structure, consisting of a cap-shaped upper housing, a circular gasket, and a lower housing with a spiral channel, is adopted for simple fabricating and assembling, which enables the seamless translation of our IMSC concentrator into commercial outcomes without additional redesigning. The performance characterization indicates that our IMSC concentrator is capable of processing samples with different initial concentrations over a broad flow rate range. The satisfactory concentration performances over a broad driving flow rate range make it possible for our IMSC concentrator to be driven by pushing the syringe with single hand. Finally, pollen particles and MCF-7 cells are successfully concentrated at a high throughput of 3.0 mL/min (up to 4.2 * 107 counts/mL) under the hand-powered drive. We envision wide applications of our IMSC concentrator as "centrifugation on a syringe tip" to various cell concentration pretreatments in resource-poor settings. PMID- 30001492 TI - Resolving Mixtures in Solution by Single-Molecule Rotational Diffusivity. AB - Sensing the size of individual molecules in an ensemble has proven to be a powerful tool to investigate biomolecular interactions and association dissociation processes. In biologically relevant solution environments, molecular size is often sensed by translational or rotational diffusivity. The rotational diffusivity is more sensitive to the size and conformation of the molecules as it is inversely proportional to the cube of the hydrodynamic radius, as opposed to the inverse linear dependence of the translational diffusion coefficient. Single molecule rotational diffusivity has been measured with time-resolved fluorescence anisotropy decay, but the ability to sense different sizes has been restricted by the limited number of photons available or has required surface attachment to observe each molecule longer, and the attachment may be perturbative. To address these limitations, we show how to measure and monitor single-molecule rotational diffusivity by combining the solution-phase Anti-Brownian ELectrokinetic (ABEL) trap and maximum likelihood analysis of time-resolved fluorescence anisotropy based on the information inherent in each detected photon. We demonstrate this approach by resolving a mixture of single- and double-stranded fluorescently labeled DNA molecules at equilibrium, freely rotating in a native solution environment. The rotational diffusivity, fluorescence brightness and lifetime, and initial and steady-state anisotropy are simultaneously determined for each trapped single DNA molecule. The time resolution and precision of this method are analyzed using statistical signal analysis and simulations. We present key parameters that define the usefulness of a particular fluorescent label for extracting molecular size information from single-molecule rotational diffusivity measurements. PMID- 30001493 TI - The Lung Microbiome in Hematopoietic Stem Cell Transplant. Where the Money Lies. PMID- 30001494 TI - In Vitro Repair of Meniscal Radial Tear With Hydrogels Seeded With Adipose Stem Cells and TGF-beta3. AB - BACKGROUND: Radial tears of the meniscus are a common knee injury, frequently resulting in osteoarthritis. To date, there are no established, effective treatments for radial tears. Adipose-derived stem cells (ASCs) may be an attractive cell source for meniscal regeneration because they can be quickly isolated in large number and are capable of undergoing induced fibrochondrogenic differentiation mediated by transforming growth factor beta3 (TGF-beta3). However, the use of ASCs for meniscal repair is largely unexplored. HYPOTHESIS: ASC-seeded hydrogels with preloaded TGF-beta3 will improve meniscal healing of radial tears, as modeled in an explant model. STUDY DESIGN: Controlled laboratory study. METHODS: With an institutional review board-exempted protocol, human ASCs were isolated from the infrapatellar fat pads of 3 donors, obtained after total knee replacement, and characterized. ASCs were encapsulated in photocrosslinkable methacrylated gelatin hydrogels to form 3-dimensional constructs, which were placed into tissue culture. The effect of TGF-beta3-whether preloaded into the hydrogel or added as a soluble medium supplement-on matrix-sulfated proteoglycan deposition in the constructs was evaluated. A meniscal explant culture model was used to simulate meniscal repair. Cylindrical-shaped explants were excised from the inner avascular region of adult bovine menisci, and a radial tear was modeled by cutting perpendicular to the meniscal main fibers to the length of the radius. Six combinations of hydrogels-namely, acellular and ASC-seeded hydrogels supplemented with preloaded TGF-beta3 (2 ug/mL) or soluble TGF-beta3 (10 ng/mL) and without supplement-were injected into the radial tear and stabilized by photocrosslinking with visible light. At 4 and 8 weeks of culture, healing was assessed through histology, immunofluorescence staining, and mechanical testing. RESULTS: ASCs isolated from the 3 donors exhibited colony-forming and multilineage differentiation potential. Hydrogels preloaded with TGF-beta3 and those cultured in soluble TGF-beta3 showed robust matrix-sulfated proteoglycan deposition. ASC-seeded hydrogels promoted superior healing as compared with acellular hydrogels, with preloaded or soluble TGF-beta3 further improving histological scores and mechanical properties. CONCLUSION: These findings demonstrated that ASC-seeded hydrogels preloaded with TGF-beta3 enhanced healing of radial meniscal tears in an in vitro meniscal repair model. CLINICAL RELEVANCE: Injection delivery of ASCs in a TGF-beta3-preloaded photocrosslinkable hydrogel represents a novel candidate strategy to repair meniscal radial tears and minimize further osteoarthritic joint degeneration. PMID- 30001495 TI - Reconstruction of Premaxilla With Alveolar Distraction Osteogenesis in a Patient With Complete Cleft Lip and Palate: A Case Report. AB - This case report presents an early clinical evaluation of a patient with bilateral cleft lip and palate (CLP) treated with ArchWise Distraction Osteogenesis Technique and Appliance. A 16-year-old patient with a bilateral CLP had a chief complaint of missing upper anterior teeth and poor aesthetics. The patient had class III skeletal and dental relationships, maxillary hypoplasia, maxillary posterior arch constriction, premaxillary deficiency, multiple missing teeth due to an alveolar cleft, and a concave profile. Treatment plan consisted of maxillary expansion with quad helix appliance, leveling and aligning of the arches with fixed orthodontic appliances, and archwise distraction osteogenesis. Osteotomies were performed to mobilize the posterior segments. Activation of the distractors was continued until the lateral segments had contacted each other, and then sagittal distraction was performed in order to correct the sagittal discrepancy. Patient was referred to the oral surgeon and prosthodontist for the final restorations. A very large gap was successfully repaired using this protocol while maintaining the ideal arch form and generating new bone behind the distracted segments. PMID- 30001496 TI - Sex differences in cardiac electrophysiology. AB - Women have a longer QT interval than men, which appears to evolve after puberty suggesting that sex hormones have an influence on cardiac electrophysiology. Sex hormones do in fact regulate cardiac ion channels via genomic and nongenomic pathways. Women are at greater risk for life-threatening arrhythmias under conditions that prolong the QT interval. In addition, women exhibit greater sensitivity to QT interval-prolonging drugs. Female sex has also an impact on propensity to cardiovascular disease, including atrial fibrillation. However, ex vivo recorded atrial action potentials (APs) from female and male patients in atrial fibrillation did not exhibit significant differences in shape, except that APs from women had slower upstroke velocity. It is concluded that sex-related differences should be taken into account not only in the clinics, but also in basic research. PMID- 30001497 TI - Whole-genome resequencing of Ujumqin sheep to investigate the determinants of the multi-vertebral trait. AB - The Ujumqin sheep is one of the most profitable breeds in China, with unique multi-vertebral characteristics. We performed high-throughput genome resequencing of five multi-vertebral and three non-multi-vertebral sheep in an Ujumqin population. We identified the genomic regions that correlated with the germplasm characteristics to establish the cause of the "multi-vertebral" phenotype in this breed. Sequencing generated a total of 314 952 000 000 bp of raw data. The alignment rate of all the samples was between 98.53% and 99.11%, and the mean depth of coverage relative to the reference genome was between 11.58* and 14.92*. After comparing the differences between the two groups, we identified 21 homozygous single nucleotide polymorphisms (SNPs) in the mutant exons of 14 genes. Nineteen loci of 10 genes contained nonsynonymous mutations, while two loci contained synonymous mutations. Resequencing revealed homozygous mutations comprised of 44 indels located within exons of 19 genes. These indels included 37 frameshift mutations, 6 non-frameshift mutations, and 1 stopgain single nucleotide variation (SNV). Finally, comparisons of genotypic variations revealed 17 genes with homozygous mutations in their coding regions, 5 of which have previously been associated with vertebral development and the remaining 12 genes were newly identified in this study. PMID- 30001498 TI - Functional genetic discovery of enzymes using full-scan mass spectrometry metabolomics. AB - Our understanding of metabolic networks is incomplete, and new enzymatic activities await discovery in well-studied organisms. Mass spectrometric measurement of cellular metabolites reveals compounds inside cells that are unexplained by current maps of metabolic reactions, and existing computational models are unable to account for all activities observed within cells. Additional large-scale genetic and biochemical approaches are required to elucidate metabolic gene function. We have used full-scan mass spectrometry metabolomics of polar small molecules to examine deletion mutants of candidate enzymes in the model yeast Saccharomyces cerevisiae. We report the identification of 25 genes whose deletion results in focal metabolic changes consistent with loss of enzymatic activity and describe the informatic approaches used to enrich for candidate enzymes from uncharacterized open reading frames. Triumphs and pitfalls of metabolic phenotyping screens are discussed, including estimates of the frequency of uncharacterized eukaryotic genes that affect metabolism and key issues to consider when searching for new enzymatic functions in other organisms. PMID- 30001499 TI - Intraspecific mitogenomics of three marine species-at-risk: Atlantic, spotted, and northern wolffish (Anarhichas spp.). AB - High-resolution mitogenomics of within-species relationships can answer such phylogeographic questions as how species survived the most recent glaciation, as well as identify contemporary factors such as physical barriers, isolation, and gene flow. We examined the mitogenomic population structure of three at-risk species of wolffish: Atlantic (Anarhichas lupus), spotted (A. minor), and northern (A. denticulatus). These species are extensively sympatric across the North Atlantic but exhibit very different life history strategies, a combination that results in concordant and discordant patterns of genetic variation and structure. Wolffish haplogroups were not structured geographically: Atlantic and spotted wolffish each comprised three shallow clades, whereas northern wolffish comprised two deeper but unstructured lineages. We suggest that wolffish species survived in isolation in multiple glacial refugia, either refugia within refugia (Atlantic and spotted wolffish) or more distant refugia (northern wolffish), followed by secondary admixture upon post-glacial recolonisation of the North Atlantic. PMID- 30001500 TI - What's HIF Got to Do with It? HIF-2 Inhibition and Pulmonary Hypertension. PMID- 30001501 TI - Evidence-Based Best-Practice Guidelines for Preventing Anterior Cruciate Ligament Injuries in Young Female Athletes: A Systematic Review and Meta-analysis. AB - BACKGROUND: Injury prevention neuromuscular training (NMT) programs reduce the risk for anterior cruciate ligament (ACL) injury. However, variation in program characteristics limits the potential to delineate the most effective practices to optimize injury risk reduction. PURPOSE: To evaluate the common and effective components included in ACL NMT programs and develop an efficient, user-friendly tool to assess the quality of ACL NMT programs. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Study inclusion required (1) a prospective controlled trial study design, (2) an NMT intervention aimed to reduce incidence of ACL injury, (3) a comparison group, (4) ACL injury incidence, and (5) female participants. The following data were extracted: year of publication, study design, sample size and characteristics, and NMT characteristics including exercise type and number per session, volume, duration, training time, and implementer training. Analysis entailed both univariate subgroup and meta regression techniques using random-effects models. RESULTS: Eighteen studies were included in the meta-analyses, with a total of 27,231 participants, 347 sustaining an ACL injury. NMT reduced the risk for ACL injury from 1 in 54 to 1 in 111 (odds ratio [OR], 0.51; 95% CI, 0.37-0.69]). The overall mean training volume was 18.17 hours for the entire NMT (24.1 minutes per session, 2.51 times per week). Interventions targeting middle school or high school-aged athletes reduced injury risk (OR, 0.38; 95% CI, 0.24-0.60) to a greater degree than did interventions for college- or professional-aged athletes (OR, 0.65; 95% CI, 0.48 0.89). All interventions included some form of implementer training. Increased landing stabilization and lower body strength exercises during each session improved prophylactic benefits. A meta-regression model and simple checklist based on the aforementioned effective components (slope = -0.15, P = .0008; intercept = 0.04, P = .51) were developed to allow practitioners to evaluate the potential efficacy of their ACL NMT and optimize injury prevention effects. CONCLUSION: Considering the aggregated evidence, we recommend that ACL NMT programs target younger athletes and use trained implementers who incorporate lower body strength exercises (ie, Nordic hamstrings, lunges, and heel-calf raises) with a specific focus on landing stabilization (jump/hop and hold) throughout their sport seasons. CLINICAL RELEVANCE: Clinicians, coaches, athletes, parents, and practitioners can use the developed checklist to gain insight into the quality of their current ACL NMT practices and can use the tool to optimize programming for future ACL NMT to reduce ACL injury risk. PMID- 30001502 TI - Inhibition of adenosine deaminase and xanthine oxidase by valproic acid abates hepatic triglyceride accumulation independent of corticosteroids in female rats treated with estrogen-progestin. AB - Elevated circulating uric acid has been postulated to play an important pathophysiological role in estrogen-progestin combined oral contraceptive (COC) induced hypertension and endothelial dysfunction. We hypothesized that disruption of glucoregulation and liver triglyceride (TG) accumulation induced by COC use would be abated by valproic acid (VPA) treatment through suppression of adenosine deaminase (ADA) and xanthine oxidase (XO) activities. Female Wistar rats aged 9 10 weeks were treated with a combination of estrogen-progestin COC steroids (1.0 MUg ethinylestradiol and 5.0 MUg levonorgestrel; p.o.) with or without VPA (100.0 mg/kg; p.o.) daily for 6 weeks. The result shows that the disrupted glucoregulation and associated elevated hepatic ADA activity, plasma and hepatic XO activity, uric acid (UA), TG/HDL-cholesterol, total cholesterol, and malondialdehyde induced by COC treatment were attenuated by VPA treatment. However, VPA did not have any effect on plasma aldosterone, corticosterone, ADA, circulating and hepatic free fatty acid. Our results demonstrate that suppression of plasma and hepatic XO activities, along with hepatic ADA activity and UA by VPA treatment, protects against disrupted glucoregulation and increased liver TG by COC independent of elevated corticosteroids. The findings imply that VPA would provide protection against the development of cardiometabolic disorder via inhibition of the ADA/XO/UA-mediated pathway. PMID- 30001504 TI - Axon Guidance: Gained in Translation. AB - In this issue of Neuron, Cagnetta et al. (2018) describe a novel method to identify, in an unbiased manner, newly synthesized axonal proteins in response to axon guidance cues. They find that axons stimulated by different guidance cues (Netrin-1, BDNF, and Sema3A) show distinct and common signatures. PMID- 30001503 TI - Low-intensity resistance training with partial blood flow restriction and high intensity resistance training induce similar changes in the skeletal muscle transcriptome in elderly humans. AB - We aimed to investigate the mechanisms underlying muscle growth after 12 weeks of RT-BFR and HRT in older individuals. Participants were allocated into the groups HRT, RT-BFR and control (CG). High-throughput transcriptome sequencing was performed by the Illumina HiSeq2500 platform. HRT and RT-BFR presented similar increases in quadriceps femoris CSA and few genes were differently expressed between interventions. The small differences in gene expression between interventions suggest that similar mechanisms may underpin training-induced muscle growth. PMID- 30001505 TI - Setting the Stage for the Next Generation of Neuroscience. AB - Neuroscientists share their vision-spanning from the nanoscale to complex social behavior-for what is needed to take on the big challenges of the field. PMID- 30001506 TI - Dendritic Tau in Alzheimer's Disease. AB - The microtubule-associated protein tau and amyloid-beta (Abeta) are key players in Alzheimer's disease (AD). Abeta and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD. Recent work on site-specific modification of dendritic and more specifically post-synaptic tau has revealed new endogenous functions of tau that limits synaptic Abeta toxicity. Thus, molecular studies opened a new perspective on tau, placing it at the center of neurotoxic and neuroprotective signaling at the post-synapse. Here, we review recent advances on tau in the dendritic compartments, with implications for understanding and treatment of AD and related neurological conditions. PMID- 30001507 TI - Internally Generated Predictions Enhance Neural and Behavioral Detection of Sensory Stimuli in an Electric Fish. AB - Studies of cerebellum-like circuits in fish have demonstrated that synaptic plasticity shapes the motor corollary discharge responses of granule cells into highly-specific predictions of self-generated sensory input. However, the functional significance of such predictions, known as negative images, has not been directly tested. Here we provide evidence for improvements in neural coding and behavioral detection of prey-like stimuli due to negative images. In addition, we find that manipulating synaptic plasticity leads to specific changes in circuit output that disrupt neural coding and detection of prey-like stimuli. These results link synaptic plasticity, neural coding, and behavior and also provide a circuit-level account of how combining external sensory input with internally generated predictions enhances sensory processing. PMID- 30001508 TI - The Epigenetic State of PRDM16-Regulated Enhancers in Radial Glia Controls Cortical Neuron Position. PMID- 30001509 TI - Parvalbumin Interneurons Modulate Striatal Output and Enhance Performance during Associative Learning. PMID- 30001510 TI - mTOR'ing across the Cortex by Chopping the Cilia. AB - Somatic mutation of the MTOR gene is a genetic etiology of focal malformations of cortical development. In this issue of Neuron, Park et al. (2018) identify defective autophagy-dependent ciliogenesis/Wnt signaling as an underlying mechanism affecting neuronal migration and cortical lamination. PMID- 30001511 TI - Parallel Processing of Negative Feedback: E Unum Pluribus. AB - How do canonical computational elements interact to shape neural circuit function? In this issue of Neuron, Drinnenberg et al. (2018) show that parallel processing converts unitary negative feedback at the first synapse of the retina into diverse output signals to the brain. PMID- 30001513 TI - Are We There Yet? Identification of Reward-Selective Cells in the Hippocampus. AB - Navigation to a previously visited reward site requires a reliable and accurate spatial memory. In this issue of Neuron, Gauthier and Tank (2018) use two-photon calcium imaging to uncover a discrete hippocampal subpopulation specialized for encoding reward location. PMID- 30001514 TI - The Trojan Horse of the Plant Kingdom. AB - The advent of host-induced gene silencing (HIGS) technology for the development of pathogen-resistant cultivars led to the discovery of cross-kingdom RNA interference. In a recent Science paper, Cai et al. (2018) discovered that plant extracellular vesicles act as Trojan horses to deliver small RNAs into fungi to fight infection. PMID- 30001512 TI - Alzheimer's Disease-Associated beta-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. AB - Amyloid-beta peptide (Abeta) fibrilization and deposition as beta-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Abeta is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Abeta antimicrobial activities. Thus, infection can seed and dramatically accelerate beta-amyloid deposition. Here, we show Abeta oligomers bind herpesvirus surface glycoproteins, accelerating beta-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce beta-amyloidosis in brain. These data support the notion that Abeta might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Abeta amyloidosis. PMID- 30001515 TI - Next Generation of Plant-Associated Bacterial Genome Data. AB - Plants interact with numerous pathogenic and beneficial bacteria. In this issue of Cell Host & Microbe, Karasov et al. (2018) and Garrido-Oter et al. (2018) use NextGen sequencing and data analysis from more than 2,000 bacterial genomes to draw hypotheses about interactions and evolution of microbes with their plant hosts. PMID- 30001516 TI - Mother-to-Infant Microbial Transmission from Different Body Sites Shapes the Developing Infant Gut Microbiome. AB - The acquisition and development of the infant microbiome are key to establishing a healthy host-microbiome symbiosis. The maternal microbial reservoir is thought to play a crucial role in this process. However, the source and transmission routes of the infant pioneering microbes are poorly understood. To address this, we longitudinally sampled the microbiome of 25 mother-infant pairs across multiple body sites from birth up to 4 months postpartum. Strain-level metagenomic profiling showed a rapid influx of microbes at birth followed by strong selection during the first few days of life. Maternal skin and vaginal strains colonize only transiently, and the infant continues to acquire microbes from distinct maternal sources after birth. Maternal gut strains proved more persistent in the infant gut and ecologically better adapted than those acquired from other sources. Together, these data describe the mother-to-infant microbiome transmission routes that are integral in the development of the infant microbiome. PMID- 30001517 TI - Strain-Level Analysis of Mother-to-Child Bacterial Transmission during the First Few Months of Life. AB - Bacterial community acquisition in the infant gut impacts immune education and disease susceptibility. We compared bacterial strains across and within families in a prospective birth cohort of 44 infants and their mothers, sampled longitudinally in the first months of each child's life. We identified mother-to child bacterial transmission events and describe the incidence of family-specific antibiotic resistance genes. We observed two inheritance patterns across multiple species, where often the mother's dominant strain is transmitted to the child, but occasionally her secondary strains colonize the infant gut. In families where the secondary strain of B. uniformis was inherited, a starch utilization gene cluster that was absent in the mother's dominant strain was identified in the child, suggesting the selective advantage of a mother's secondary strain in the infant gut. Our findings reveal mother-to-child bacterial transmission events at high resolution and give insights into early colonization of the infant gut. PMID- 30001520 TI - Overcoming Barriers in the Path to a Universal Influenza Virus Vaccine. AB - Influenza viruses are important pathogens which pose an ongoing threat to public health due to their ability to mutate and evade immunity elicited by prior infection or vaccination. Their evolutionary diversity is facilitated by the plasticity of the antigenically variable head domain of the major surface glycoprotein, hemagglutinin (HA), which tolerates the accumulation of extensive mutations. To date, vaccines have focused on eliciting largely strain-specific immune responses toward the HA head. However, novel universal influenza vaccines aim to refocus immunity toward the immunosubdominant but conserved influenza virus HA stalk domain. Such vaccines could provide heterologous protection against diverse influenza viruses. PMID- 30001518 TI - Modular Traits of the Rhizobiales Root Microbiota and Their Evolutionary Relationship with Symbiotic Rhizobia. AB - Rhizobia are a paraphyletic group of soil-borne bacteria that induce nodule organogenesis in legume roots and fix atmospheric nitrogen for plant growth. In non-leguminous plants, species from the Rhizobiales order define a core lineage of the plant microbiota, suggesting additional functional interactions with plant hosts. In this work, genome analyses of 1,314 Rhizobiales isolates along with amplicon studies of the root microbiota reveal the evolutionary history of nitrogen-fixing symbiosis in this bacterial order. Key symbiosis genes were acquired multiple times, and the most recent common ancestor could colonize roots of a broad host range. In addition, root growth promotion is a characteristic trait of Rhizobiales in Arabidopsis thaliana, whereas interference with plant immunity constitutes a separate, strain-specific phenotype of root commensal Alphaproteobacteria. Additional studies with a tripartite gnotobiotic plant system reveal that these traits operate in a modular fashion and thus might be relevant to microbial homeostasis in healthy roots. PMID- 30001522 TI - Gut Bacteria Seize Control of the Brain to Prevent Epilepsy. AB - Why ketogenic diet (KD) effectively controls seizures in some people with epilepsy is unclear. In a recent issue of Cell, Olson et al. (2018) showed that KD prevents seizures by upregulating key bacterial species (Akkermansia muciniphila and Parabacteroides merdae). These bacteria synergize to decrease gammaglutamylation of amino acids, increase hippocampal GABA/Glutamate ratios, and, ultimately, prevent seizures. PMID- 30001523 TI - Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design. AB - Tuberculosis (TB) is a large global health problem, in part because of the long period of coevolution of the pathogen, Mycobacterium tuberculosis, and its human host. A major factor that sustains the global epidemic of TB is the lack of a sufficiently effective vaccine. While basic mechanisms of immunity that protect against TB have been identified, attempts to improve immunity to TB by vaccination have been disappointing. This Review discusses the mechanisms used by M. tuberculosis to evade innate and adaptive immunity and that likely limit the efficacy of vaccines developed to date. Despite multiple mechanisms of immune evasion, recent trials have indicated that effective TB vaccines remain an attainable goal. This Review discusses how knowledge from other systems can inform improvements on current vaccine approaches. PMID- 30001519 TI - Arabidopsis thaliana and Pseudomonas Pathogens Exhibit Stable Associations over Evolutionary Timescales. AB - Crop disease outbreaks are often associated with clonal expansions of single pathogenic lineages. To determine whether similar boom-and-bust scenarios hold for wild pathosystems, we carried out a multi-year, multi-site survey of Pseudomonas in its natural host Arabidopsis thaliana. The most common Pseudomonas lineage corresponded to a ubiquitous pathogenic clade. Sequencing of 1,524 genomes revealed this lineage to have diversified approximately 300,000 years ago, containing dozens of genetically identifiable pathogenic sublineages. There is differentiation at the level of both gene content and disease phenotype, although the differentiation may not provide fitness advantages to specific sublineages. The coexistence of sublineages indicates that in contrast to crop systems, no single strain has been able to overtake the studied A. thaliana populations in the recent past. Our results suggest that selective pressures acting on a plant pathogen in wild hosts are likely to be much more complex than those in agricultural systems. PMID- 30001521 TI - Immune Correlate-Guided HIV Vaccine Design. AB - Although vaccines have been successfully developed against several pathogens, designing an effective vaccine to protect against human immunodeficiency virus (HIV) has remained an intractable challenge. To address this, the research community has looked to human and non-human primate studies to understand the correlates of protective immunity, based on which a targeted vaccine strategy may be designed. Two distinct approaches, focused on different immune correlates of protection, have emerged. The first focuses on structure-based design of HIV envelope immunogens that are able to induce antibodies that neutralize the virus. The second focuses on strategies aimed at driving non-neutralizing polyclonal and polyfunctional antibodies that engage other arms of immunity to clear the virus. Here we review these two different vaccine design strategies and posit that ultimately the convergence of these two efforts will likely be necessary for the development of a globally protective HIV vaccine. PMID- 30001525 TI - STING: From Mammals to Insects. AB - STING is a key mediator of mammalian innate immunity in response to pathogens. In this issue of Cell Host & Microbe and the June 19th issue of Cell Reports, Liu et al. (2018) and Martin et al. (2018) reveal that Drosophila STING is required for antiviral and antibacterial defenses, respectively. PMID- 30001526 TI - Lipid Peroxidation Adds Fuel to Pyr(optosis). AB - Glutathione peroxidase 4 (GPX4) is an antioxidant enzyme that protects cells from lipid peroxidation. In this issue of Cell Host & Microbe, Kang et al. (2018) report that GPX4 is a negative regulator of the pyroptotic cell death pathway and plays an important role in inhibiting lethal inflammation associated with sepsis. PMID- 30001524 TI - Malaria Vaccines: Recent Advances and New Horizons. AB - The development of highly effective and durable vaccines against the human malaria parasites Plasmodium falciparum and P. vivax remains a key priority. Decades of endeavor have taught that achieving this goal will be challenging; however, recent innovation in malaria vaccine research and a diverse pipeline of novel vaccine candidates for clinical assessment provides optimism. With first generation pre-erythrocytic vaccines aiming for licensure in the coming years, it is important to reflect on how next-generation approaches can improve on their success. Here we review the latest vaccine approaches that seek to prevent malaria infection, disease, and transmission and highlight some of the major underlying immunological and molecular mechanisms of protection. The synthesis of rational antigen selection, immunogen design, and immunization strategies to induce quantitatively and qualitatively improved immune effector mechanisms offers promise for achieving sustained high-level protection. PMID- 30001527 TI - Linc00518 Contributes to Multidrug Resistance Through Regulating the MiR 199a/MRP1 Axis in Breast Cancer. AB - BACKGROUND/AIMS: Long non-coding RNAs (LncRNAs) have been validated to be pivotal mediators in multidrug resistance (MDR) of various cancers. This study aims to explore the roles and molecular mechanisms of linc00518 implicated in chemoresistance in breast cancer. METHODS: Expressions of linc00518, miR-199a and MRP1 were evaluated by RT-qPCR or western blot. IC50 values of adriamycin (ADR), vincristine (VCR) and paclitaxel (PTX) were determined by XTT assays and cell apoptosis was assessed by flow cytometry. Luciferase reporter and RIP assays were employed to detect the interaction of linc00518, miR-199a and MRP-1. RESULTS: linc00518 expression increased nearly 2 fold and MRP1 level elevated about 2.5 fold in breast cancer tissues as compared to that in adjacent normal tissues. Also, almost 2 fold upregulation of linc00518 and MRP-1 expressions was observed in MCF-7 cells than in MCF-10A cells. Additionally, linc00518 level was almost 2.5 fold higher and MRP1 level was about 2 fold increased in ADR-resistant MCF-7 cells (MCF-7/ADR) than in parental cell line MCF-7. Linc00518 knockdown enhanced chemosensitivity to ADR, VCR and PTX, and boosted ADR-, VCR- and PTX-induced apoptosis in MCF-7/ADR cells. miR-199a inhibitor conferred chemoresistance to ADR, VCR and PTX in MCF-7/ADR cells, and suppressing miR-199a reversed multi-drug susceptibility induced by linc00518 knockdown. Furthermore, linc00518 could act as a molecular sponge of miR-199a to repress MRP1 expression. MRP1 depletion increased the sensitivity of MCF-7/ADR cells to ADR, VCR and PTX, and this effect was attenuated following miR-199a inhibition or linc00518 overexpression. Also, linc00518 silencing increased ADR-mediated anti-tumor effect in vivo. CONCLUSIONS: linc00518 downregulation reduced MDR by regulating miR-199a/MRP1 axis in breast cancer. PMID- 30001528 TI - Expression of Endothelial Cell Injury Marker Cd146 Correlates with Disease Severity and Predicts the Renal Outcomes in Patients with Diabetic Nephropathy. AB - BACKGROUND/AIMS: Glomerular endothelial cell injury plays a crucial role in the development of diabetic nephropathy (DN). CD146, an endothelial marker, was shown to increase in chronic kidney disease (CKD), but its role in DN remains unknown. We aim to assess whether CD146 could be used to evaluate disease severity and predict renal outcomes in DN at early stages. METHODS: 159 non-dialysis type 2-DN patients from 2008 to 2015 were enrolled to measure the plasma concentration of soluble CD146 (sCD146). 94 type 2 diabetes mellitus patients without DN and 100 healthy subjects were used as controls. The patients with CKD stage 1-3 were referred as early stage patients. Another independent cohort of 48 patients with biopsy-proved DN was used for the immunohistochemistry study of CD146. Renal outcomes were defined as doubling of serum creatinine, initiation of renal replacement therapy or death. RESULTS: We found that plasma level of sCD146 was upregulated and associated with renal function in DN patients. sCD146 was proved to be a more optimal marker than urine albumin creatinine ratio to evaluate disease severity in these DN patients. The kidney expression of CD146 was co localized with endothelial marker CD31 and increased in DN. CD146 staining in kidney was correlated with the severity of pathological changes in DN patients. Survival analysis suggested that both plasma and biopsy expression of CD146 were correlated with renal outcomes. CONCLUSIONS: CD146 is associated with kidney injury and could be a good marker to predict renal outcomes in patients with early stages of DN. PMID- 30001531 TI - Long-Acting Growth Hormone in Idiopathic Short Stature. PMID- 30001529 TI - MicroRNA-34a Attenuates Metastasis and Chemoresistance of Bladder Cancer Cells by Targeting the TCF1/LEF1 Axis. AB - BACKGROUND/AIMS: Chemoresistance is largely responsible for relapses of bladder cancer during clinical therapy. However, the molecular mechanisms involved in the chemoresistance of bladder cancer are unclear. Growing evidence supports the theory that microRNAs (miRNAs) play an important role in chemotherapeutic drug resistance because they are downregulated in many malignancies that have been implicated in the regulation of diverse processes in cancer cells. More specifically, the extent and precise mechanism of the involvement of miR-34as in chemoresistance to epirubicin (EPI) in the treatment of bladder cancer remains unclear. METHODS: In this study, real-time quantitative polymerase chain reaction (PCR) was used to analyze the expression of miR-34a in bladder cancer cell line BIU87 and its EPI chemoresistant cell line BIU87/ADR. The miR-34a profiles in bladder cancer tissues were obtained from The Cancer Genome Atlas database. The effect of miR-34a on chemosensitivity was evaluated by cell viability assays, colony formation assays, and in vivo experimentation. Apoptosis and the cell cycle were examined by flow cytometry. A luciferase reporter assay was used to assess the target genes of miR-34a. Western blot and qPCR were used to analyze the expression of target proteins and downstream molecules. RESULTS: The downregulation of miR-34a in bladder cancer serves as an independent predictor of reduced patient survival. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to EPI, while miR-34a downregulation resulted in chemoresistance to EPI in vitro. Moreover, it was found that miR-34a increased the sensitivity of BIU87/ADR cells to chemotherapy in vivo. The luciferase reporter assay ascertained that TCF1 and LEF1 are direct target genes of miR-34a. It was found that miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis. CONCLUSIONS: The results of this study indicate that miR-34a contributes to the chemosensitivity of BIU87/ADR by inhibiting the TCF1/LEF1 axis. Consequently, miR-34a is a determinant of BIU87 chemosensitivity and may therefore serve as a potential therapeutic target in bladder cancer treatment. PMID- 30001532 TI - Gli2 Mediated Activation of Hedgehog Signaling Attenuates Acute Pancreatitis via Balancing Inflammatory Cytokines in Mice. AB - BACKGROUND/AIMS: Inflammatory response is a determinant in the pathological progression of acute pancreatitis (AP). Previous studies have shown that the activation of hedgehog (Hh) signaling is a remarkable change in caerulein-induced AP. However, the relationship between Hh signaling and inflammation is largely ambiguous. METHODS: The AP mouse model was induced by injection of cerulein, and histological staining and serum enzymology assays were used to evaluate the establishment of AP. Western blot assay was used to determine the protein levels, cleavage of apoptotic proteins, and activation of the NF-kappaB signaling pathway. Cytokine array was used to screen inflammatory cytokines, and target cytokines' transcriptional expression and serum levels were examined by real-time PCR and enzyme-linked immunosorbent assay, respectively. RESULTS: The key transcriptional factor in Hh signaling, Gli2, was upregulated in the pancreas and other tissues during the process of AP, and it seems to be a characteristic feature of local inflammation in pancreatic tissue and systemic inflammatory response in multiple organs. The inflammatory NF-kappaB pathway is required for the activation of Hh signaling, as blockade of the NF-kappaB pathway by pyrrolidine dithiocarbamate impaired the Gli2 upregulation. Manipulation of Gli2 expression altered the activation of the NF-kappaB pathway correspondingly, as well as the cell apoptosis in cerulein-induced AP. Moreover, Gli2 upregulation changed the cytokine expression profile in mouse pancreatic acinar cells, mainly decreasing the pro-inflammatory cytokines interleukin (IL)-6, interferon-gamma, and FasL. The anti-inflammatory cytokine IL-10 was upregulated by Gli2 overexpression. Interdiction of Gli2 by the Gli-specific inhibitor GANT61 exacerbated AP in mice and altered the balance of inflammatory cytokines. CONCLUSIONS: This study indicates that Hh activation during AP development is a negative feedback of the inflammatory response, restricting inflammatory injury to the pancreas and other tissues. Thus, manipulation of Hh signaling should shed light on limiting inflammation and alleviating AP damage. PMID- 30001530 TI - Nuclear Localization Leucine-Rich-Repeat Protein 1 Deficiency Protects Against Cardiac Hypertrophy by Pressure Overload. AB - BACKGROUND/AIMS: Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a cytoplasmic protein, involved in autoimmune diseases, mammalian reproduction, neuronal cell death, and stroke. However, the role of NLRP1 in cardiac hypertrophy remains unclear. We used in vivo and in vitro models to investigate the effects of NLRP1 on cardiac hypertrophy. METHODS: We used NLRP1-deficient mice and cultured neonatal rat cardiomyocytes with gain and loss of NLRP1 function. Cardiac hypertrophy was estimated by echocardiographic and hemodynamic measurements, and by pathological and molecular analysis. RESULTS: Eight weeks after aortic banding (AB), NLRP1 deficiency significantly inhibited aortic banding-induced cardiac hypertrophy, inflammation, and fibrosis. Activation of MAPK, NF-kappaB, and TGF-beta/Smad pathways was reduced in NLRP1-knockout (KO) mice compared with that in wild-type (WT) mice. Consistent with these results, in vitro studies, performed using cultured neonatal mouse cardiomyocytes, confirmed that NLRP1 deficiency protects against cardiomyocyte hypertrophy induced by isoproterenol (PE); this protective activity was associated with the arrest of MAPK and NF-kappaB signaling. CONCLUSIONS: Our data illustrates that NLRP1 plays a crucial role in the development of cardiac hypertrophy via positive regulation of the MAPK, NF-kappaB, and TGF-beta/Smad signaling pathways. PMID- 30001533 TI - Multilevel Analysis of Dental Caries in Swedish Children and Adolescents in Relation to Socioeconomic Status. AB - The objective was to investigate the variability in dental caries experience in Swedish children and adolescents, at two different area levels: dental clinics and SAMS (small areas for market statistics), with respect to multiple individual socioeconomic factors (SES). Records of manifest caries using the DMFT indices (decayed, missing, filled teeth, dependent variables) were collected from electronic dental records for 300,988 individuals aged 3-19 years (97.3% coverage) from the Region Vastra Gotaland, Sweden. SES data were obtained from official registers and covered ethnicity, wealth, parental education, and employment. The SES variables were used as an independent aggregated variable - an in dex - categorized in deciles. Age and gender were independently included in the multilevel models. Two-level logistic regression analyses explored the probability of a dental caries experience and the variability (intracluster correlation) within dental clinic areas and SAMS, respectively. The most deprived (10th decile, SAMS level) 3- to 6-year-old children had an OR of 5.00 (95% CI 4.61-5.43) for dental caries experience (deft), compared with children in the 1st to 5th deciles. For older children and adolescents (>=7 years), the corresponding OR (DFT) was 2.25 (95% CI 2.15-2.35). Small geographical areas explained more of the variance in caries experience compared with the more aggregated level dental clinics. SES was more strongly related to the risk of dental caries experience than age and gender. In conclusion, the associations between SES and dental caries experience in Swedish children and adolescents were strong in the study and strongest in young children at a low level. PMID- 30001535 TI - Parthenolide Influences Herpes simplex virus 1 Replication in vitro. AB - BACKGROUND/AIMS: Parthenolide is a sesquiterpene lactone that is present in plants of the Tanacetum genus, for which many biological effects have already been reported, including antiherpetic activity. Although the effectiveness of parthenolide against Herpes simplex virus 1 (HSV-1) has already been demonstrated, such findings are still controversial. The objective of this study was to investigate the ways in which parthenolide exerts anti-HSV-1 activity. METHODS: The cytotoxicity and antiviral activity of parthenolide were determined by the MTT method and plaque reduction assay, respectively. The expression of cell and viral proteins during the treatment of infected cells was investigated by Western blot. RESULTS: Both strains of HSV-1 were sensitive to parthenolide, and parthenolide was active only after penetration of the virus into the host cell. The expression of p65 protein decreased, the expression of caspases 8 and 9 increased, and the expression of c-Jun N-terminal kinase (JNK) and p38 protein was altered in infected cells after parthenolide treatment, resulting in lower cell survival. The low expression of viral proteins gB, gD, and ICP0 confirmed the reduction of HSV-1 particle production. CONCLUSION: Parthenolide exerts anti HSV-1 activity by impairing cell viability, which consequently interferes with the efficient infection and production of new viral particles. PMID- 30001536 TI - Modulation of the Epigenome by Nutrition and Xenobiotics during Early Life and across the Life Span: The Key Role of Lifestyle. PMID- 30001534 TI - Partially Hydrolyzed Whey Infant Formula: Literature Review on Effects on Growth and the Risk of Developing Atopic Dermatitis in Infants from the General Population. AB - Limited evidence is available regarding the effect of partially hydrolyzed whey based formula (pHF-W) on growth and atopic dermatitis (AD) risk reduction in infants within the general infant population, and without a familial history of allergy as an inclusion or exclusion criterion. We reviewed the current evidence available from studies using pHF-W in the general population and summarized the data on safety (growth) and efficacy outcomes (reduction of AD), comparing the studies side by side. A total of 8 clinical trials were identified from the literature search, 7 of which used the same pHF-W. Six out of 8 studies indicated a reduction of atopic manifestations using a specific pHF-W versus cow's milk formula (CMF) in the first years of life. Data were summarized and compared side by side for growth (3 studies) and efficacy (5 studies). In these diverse general populations, the results on growth and AD were consistent with the previous findings reported on infants with a family history of allergy, but numerous limitations to these studies were identified. This literature review confirms that pHF-W supports normal growth in infants, and suggests that the risk of AD may be reduced in not-fully breastfed infants from the general population when supplemented with a specific pHF-W when compared to CMF during the first 4-6 months of life. Further studies are warranted to confirm these results. PMID- 30001539 TI - Nomograms of the Fetal Sylvian Fissure and Insular Lobe throughout Gestation: A Multicentric, Ultrasonographic Cross-Sectional Study. AB - INTRODUCTION: Anomalies in cortical development are often associated with an adverse outcome, but prenatal diagnosis is often impeded by the limited knowledge about normal sulci biometries throughout fetal brain development. Our aim was to provide two-dimensional ultrasonographical (2D US) nomograms of the depth of the Sylvian fissure (SF) and insular lobe (IL), as well as of the SF ratio throughout gestation in a large number of fetuses. MATERIALS AND METHODS: This was a prospective cross-sectional study of 329 normal singleton pregnancies. Measurements of the SF, IL, and SF ratio were obtained in a standard transthalamic plane of the fetal head. The SF ratio was defined as SF?SF + IL. All measurements were expressed by regression equations as a function of gestational age (GA) according to the method described by Royston and Wright. The first 38 measurements were repeated twice by 2 examiners to assess the reproducibility through the intraclass correlation coefficient (ICC). RESULTS: A significant correlation was found between GA and SF (r = 0.79; p < 0.0001) as well as IL (r = 0.77; p < 0.0001). Similarly, the SF ratio also showed a significant correlation with GA (r = 0.39; p < 0.0001). When interobserver variability was assessed, ICC was 0.97. CONCLUSIONS: Prenatal 2D US measurements of SF and IL as well as the SF ratio may be feasible and reproducible using a standard view of the fetal head. Our nomograms may be used as a reference for assessing cortical development throughout pregnancy. PMID- 30001538 TI - Effects of Three Months of Aerobic Endurance Training on Motor Cortical Excitability in Schizophrenia Patients and Healthy Subjects. AB - BACKGROUND: Aerobic endurance training has been discussed to induce brain plasticity and improve cognitive functions in healthy subjects and patients with neuropsychiatric disorders. For schizophrenia, a motor cortical inhibitory deficit has been established as one aspect of impaired plasticity, especially involving impairments in GABAergic interneuron networks, but the possibility to restore these deficits via exercise-induced plasticity has not been evaluated yet. METHODS: 17 schizophrenia patients and 16 matched healthy controls underwent 3 months of aerobic endurance training (30 min, 3 times a week) on bicycle ergometers. After 6 weeks, computer-assisted cognitive remediation training (30 min, 2 times a week) was added. Transcranial magnetic stimulation of the left and right hemispheres was performed at baseline and at the end of the intervention. We evaluated the intensity to induce a motor-evoked potential of 1 mV (S1mV), the resting motor threshold (RMT), the cortical silent period (CSP) at an intensity of 120 and 150% of the individual RMT, short-latency interval intracortical inhibition (3 ms), and intracortical facilitation (7 and 15 ms). Depending on the variable and hemisphere, follow-up data was available for 7-15 schizophrenia patients and for 10-12 healthy controls. RESULTS: Repeated measures ANOVA revealed no significant time * group interactions for any of the analyzed variables. A significant increase in S1mV and CSP duration at 150% RMT of the left hemisphere could be observed in both groups over time. CONCLUSION: Regular ergometer training over 3 months increases motor cortical inhibition as displayed by an increase in CSP. The increase in S1mV may also indicate a higher degree of inhibition after the intervention. We could not establish a difference between schizophrenia patients and healthy controls. Due to the limited sample size, our results have to be considered as preliminary and need to be replicated in future trials. PMID- 30001537 TI - FOXO1 Inhibits Tumor Cell Migration via Regulating Cell Surface Morphology in Non Small Cell Lung Cancer Cells. AB - BACKGROUND/AIMS: Cell surface morphology plays pivotal roles in malignant progression and epithelial-mesenchymal transition (EMT). Previous research demonstrated that microvilli play a key role in cell migration of non-small cell lung cancer (NSCLC). In this study, we report that Forkhead box class O1 (FOXO1) is downregulated in human NSCLC and that silencing of FOXO1 is associated with the invasive stage of tumor progression. METHODS: The cell proliferation, migration, and invasion were characterized in vitro, and we tested the expression of the Epithelial-mesenchymal transition (EMT) marker by immunofluorescence staining and also identified the effect of FOXO1 on the microvilli by scanning electron microscopy (SEM). RESULTS: Functional analyses revealed that silencing of FOXO1 resulted in an increase in NSCLC cell proliferation, migration, and invasion; whereas overexpression of FOXO1 significantly inhibited the migration and invasive capability of NSCLC cells in vitro. Furthermore, cell morphology imaging showed that FOXO1 maintained the characteristics of epithelial cells. Immunofluorescence staining and western blotting showed that the E-cadherin level was elevated and Vimentin was reduced by FOXO1 overexpression. Conversely, the E cadherin level was reduced and Vimentin was elevated in cells silenced for FOXO1. Furthermore, scanning electron microscopy (SEM) showed that FOXO1 overexpression increased the length of the microvilli on the cell surface, whereas FOXO1 silencing significantly reduced their length. CONCLUSIONS: FOXO1 is involved in human lung carcinogenesis and may serve as a potential therapeutic target in the migration of human lung cancer. PMID- 30001540 TI - FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition. AB - BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. METHODS: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. RESULTS: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. CONCLUSIONS: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression. PMID- 30001541 TI - Effects of Selenium in the Microcirculation of Fructose-Fed Hamsters. AB - BACKGROUND AND AIMS: Fructose intake is directly related to vascular dysfunction and it is a risk factor for the development of metabolic and cardiovascular diseases, such as obesity, diabetes, and hypertension. Selenium, a component of antioxidant enzymes, improves hyperglycemia and vascular function in diabetic animals. The aim of this study was to evaluate the effects of dietary selenium supplementation on microcirculatory and metabolic parameters of fructose-fed hamsters. METHODS AND RESULTS: Male hamsters (Mesocricetus auratus) had their drinking water substituted or not by 10% fructose solution for 60 days, during which their microcirculatory function was evaluated in the cheek pouch preparation. Blood glucose and serum insulin levels were also tested. Microcirculatory responses to acetylcholine (an endothelium-dependent vasodilator) and to sodium nitroprusside (SNP, an endothelium-independent vasodilator), and macromolecular permeability increase induced by a 30-min ischemia/reperfusion (I/R) procedure, showed that endothelium-dependent and independent vasodilatation was significantly increased in animals that had high selenium supplementation, in both the control and fructose-fed groups. Selenium supplementation protected against plasma leakage induced by I/R in all control and fructose-fed groups. CONCLUSION: Our results indicate that dietary selenium supplementation reduces microvascular dysfunction by increasing endothelial dependent and independent dilatation and reducing macromolecular permeability increase in fructose-fed animals. PMID- 30001542 TI - Variable Vowel Metaphony in Asturian: An Acoustic Analysis. AB - BACKGROUND/AIMS: Vowel metaphony, a type of vowel harmony observed in Asturian, is characterized by the raising and/or centralization of stressed mid or low vowels in the presence of a high vowel in word-final position. Descriptions of Asturian metaphony have been based on data collected using exclusively auditory judgments. This study is the first to document the phenomenon acoustically. METHODS: The data were collected using a word elicitation task and sociolinguistic interviews of 40 speakers from the 2 geographic areas in which metaphony has been observed. Qualitative and quantitative analyses of vocalic distributions were performed. RESULTS: The results of the analyses show that: (1) while metaphony still occurs in Asturian, its implementation is highly variable; (2) metaphonized variants remain distinct from other vowels; and (3) the traditional distinction between 2 areas of metaphony cannot be maintained. CONCLUSION: This study provides the first acoustic characterization of vowel metaphony in Asturian, offering empirical evidence on which to build theoretical approaches to vowel metaphony. PMID- 30001543 TI - Antenatal Care of Preeclampsia: From the Inverted Pyramid to the Arrow Model? AB - The recent demonstration of the effectiveness of low-dose aspirin administered from the first trimester in the prevention of preeclampsia will probably lead to establishing and radicating the "inverted pyramid" screening model for preeclampsia. Such a multiparametric approach for the screening of preeclampsia in the first trimester, albeit highly sensitive in identifying early-onset disease, is poor at screening the forms of preeclampsia occurring close to term. Late-onset preeclampsia is 3 to 6 times more common than early-onset preeclampsia and currently represents the major determinant of maternal morbidity related to hypertensive disorders of the pregnancy. On this ground, we discuss our idea to construct a second "screening checkpoint" in the third trimester with the aim of reassessing the risk of preeclampsia of those women who screened negative in the first trimester. If implemented, the sequential screening model we propose would convert the "inverted pyramid model" into an "arrow model" for the antenatal care of preeclampsia. PMID- 30001544 TI - Retinal Toxicity of Medical Devices Used during Vitreoretinal Surgery: A Critical Overview. AB - : Retinal toxicity/biocompatibility of medical devices in direct contact with the retina is an important subject for clinicians and scientists. As these effects are not very frequent, there is also a relative lack of information for many clinicians. The past has taught us multiple times that there is a significant safety problem associated with severe loss of vision in affected patients. In this review, we want to classify medical products that are used in the back of the eye, describe recent examples of toxicity, critically reflect on the regulations that exist and suggest improvements that can be done to ensure patient safety without hindering innovation. METHODS: Critical review of the recent papers and personal experience of the authors in this issue. Medical devices used in the back of the eye and recent examples of toxicity are described, regulations that exist are critically reflected and improvements suggested that can ensure patient safety without hindering innovation. RESULTS: There is clear evidence of toxicity after intraocular surgery in any category. Some cytotoxic indirect methods have failed in detecting this toxicity. Some ISO rules do not seem appropriate. Postmarketing safety is missing. There is little data on this issue. CONCLUSIONS: The absence of a clear regulation of the production, purification and evaluation of the toxic effects of the medical devices supposes the possibility that products are not sufficiently safe to obtain the CE mark. PMID- 30001546 TI - Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro. AB - AIM: Treatment of exudative age-related macular degeneration by using vascular endothelial growth factor (VEGF) antagonists is the gold standard today. So far, several bioactive molecules have been approved for therapeutic use. In this study, we investigate the effects of ranibizumab (Lucentis(r)), bevacizumab (Avastin(r)), and aflibercept (Eylea(r)) on primary human retinal pigment epithelial (hRPE) cells in vitro. METHODS: hRPE cells were prepared from donor eyes and cultured under standard culture conditions. Scleral fibroblasts also prepared from donor tissue served as physiological controls. The impact of the anti-VEGF molecules on cell viability was investigated with the trypan blue exclusion assay, whereas proliferation was measured using the MTT assay. Biological activity of the molecules was quantified in a VEGF-enzyme-linked immunosorbent assay (ELISA). RESULTS: All tested substances were biologically active in vitro. They displayed no cytotoxicity on RPE cells or scleral fibroblasts. However, proliferation of RPE cells was significantly decreased after treatment with ranibizumab or bevacizumab but not with aflibercept. CONCLUSIONS: The humanized antibodies (fragments) interfered specifically with the RPE cells. The thereby measured inhibition of cell proliferation may indicate possible side effects on the physiology of RPE cells. PMID- 30001545 TI - Synergic Effects of CD40 and CD86 Silencing in Dendritic Cells on the Control of Allergic Diseases. AB - BACKGROUND: We previously reported that siRNA-induced CD40-silenced dendritic cells (DCs) inhibit allergic responses and symptoms. However, more potent therapies are needed. To our knowledge, synergic effects of gene silencing in DCs by >=2 siRNAs have not been reported to control allergic diseases. Therefore, we investigated the synergistic effects of the silencing of CD40 and CD86 in DCs on allergic responses. METHODS: Mice were treated with CD40/CD86-silenced DCs, which were transfected with CD40/CD86 siRNAs and pulsed with ovalbumin (OVA) antigen. The effects of these DCs on allergic symptoms and allergic responses were estimated. RESULTS: The administration of CD40/CD86-silenced OVA-pulsed DCs significantly inhibited the number of sneezes and nasal rubbing movements, the number of eosinophils in the nasal mucosa, and the level of OVA-specific IgE when compared with those for CD40- or CD86-silenced OVA-pulsed DCs alone (p < 0.01). These inhibitory effects were detected before sensitization as well as after the establishment of allergic rhinitis. CD40/CD86-silenced OVA-pulsed DCs did not inhibit KLH-induced allergies. Foxp3 gene expression was significantly upregulated in CD40-silenced DCs compared to in CD86-silenced DCs (p < 0.01). IL 4 production by T cells was suppressed more substantially when using CD86 silenced DCs than with CD40-silenced DCs (p < 0.01). CONCLUSIONS: These results indicate, for the first time, that siRNA-induced CD40/CD86-silenced antigen specific DCs have greater inhibitory effects against allergic responses than those of CD40- or CD86-silenced antigen-specific DCs alone. This study also suggests that the synergic effects of gene silencing in DCs by >=2 siRNAs are useful for the control of allergic diseases. Thus, owing to the synergistic effects, CD40 and CD86 silencing has the potential to substantially improve the treatment of allergic diseases. PMID- 30001547 TI - Effects of a Phonological Reading and Writing Remediation Program in Students with Dyslexia: Intervention for Specific Learning Disabilities. AB - OBJECTIVE: To determine the effects of a phonological remediation reading and writing program in individuals with dyslexia, through behavioral and objective evaluations. PATIENTS AND METHODS: Twenty children diagnosed with dyslexia, aged 8-14 years, were included in this study. Group I (GI) was composed of 10 children who took part in the program, and group II (GII) consisted of 10 subjects who did not take the remediation. The pre-testing evaluated phonological awareness, rapid naming, working memory, reading and writing of words and nonwords, thematic writing, and auditory evoked potential - P300. The type of stimulus used was the speech (20% of rare stimulus and 80% of frequent stimulus), intensity of 80 dBNa. The rare stimulus was the syllable /da/, and the frequent stimulus was the syllable /ba/. Next, the Phonological Reading and Writing Remediation Program was applied in 24 cumulative sessions, twice a week, each with a duration of 30 min. In the post-testing (at the end of the program), all the tests of the pre-testing were reapplied. RESULTS: There was a statistically significant difference (between pre- and post-testing) in phonological awareness, rapid naming, working memory, thematic writing, writing and reading words and nonwords, as well as in the latency of the P3 component of P300 in GI, while GII maintained the same difficulties. CONCLUSION: The phonological remediation program showed to be a therapeutic method of fast beneficial effects in written language of individuals with dyslexia. However, the wide age range and the size of the sample could be considered a limitation of this study - it interferes with the generalization of results. PMID- 30001548 TI - Typhoon-Related Post-Traumatic Stress Disorder and Trauma Might Lead to Functional Integration Abnormalities in Intra- and Inter-Resting State Networks: a Resting-State Fmri Independent Component Analysis. AB - BACKGROUND/AIMS: Functional connectivity studies based on region of interest approach suggest altered functional connectivity of the default mode network (DMN), executive control network (ECN), and salience network (SN). The aim of this study is to determine whether intranetwork and internetwork brain connectivity are altered in both post-traumatic stress disorder (PTSD) patients and traumatized subjects without PTSD using a data-driven approach. METHODS: Resting-state functional MRI data were acquired for 27 patients with typhoon related PTSD, 33 trauma-exposed controls (TEC), and 30 healthy controls (HC). Functional connectivity within the DMN, ECN, and SN as well as functional and effective connectivity between these resting-state networks were examined with independent component analysis (ICA), and then compared between groups by conducting analysis of variance. RESULTS: Within the DMN, the TEC group showed decreased and increased functional connectivity in the superior frontal gyrus compared with the PTSD group and the HC group, respectively. The TEC group showed increased angular functional connectivity within the DMN and decreased functional connectivity in the superior temporal gyrus/posterior insula within the SN relative to the HC group. Compared with the TEC group, the PTSD group showed increased functional connectivity in the middle frontal gyrus and supplementary motor area within the ECN as well as in the inferior frontal gyrus/anterior insula within the SN. The PTSD group showed decreased functional connectivity in the supplementary motor area within the SN relative to both control groups. Moreover, the PTSD showed increased excitatory influence from the ECN to DMN compared with both control groups, while the TEC group showed increased inhibitory influence from the DMN to ECN compared with the HC group. Intranetwork functional connectivity within the DMN and SN is altered in traumatized subjects irrespective of PTSD diagnosis. PTSD patients also showed altered intranetwork functional connectivity within the ECN. CONCLUSIONS: Distinct changes of effective connectivity between the DMN and ECN in the PTSD group and TEC group may reflect different compensatory mechanisms for rebalance of resting-state networks in the two groups. PMID- 30001550 TI - 3rd European Summer School on Nutrigenomics. PMID- 30001549 TI - Optimized Plasmid Construction Strategy for Cas9. AB - BACKGROUND/AIMS: The target genome editing technology not only plays an important role in basic biology studies but also holds a great promise for potential clinical applications. The new generation of engineered nuclease RGEN (RNA Guided EndoNuclease) is much easier to construct and modify, and attracts more attentions. In the current study, we compared different plasmid construction strategies of Cas9-gRNA (guide RNA). METHODS: Different plasmid construction strategies of Cas9-gRNA were compared. And more modifications were introduced into the plasmid construction strategy. RESULTS: The plasmid construction efficiency of expressing the gRNA and Cas9 in one plasmid was lower than expressing them in two separate plasmids. However, they showed the similar genome editing efficiency. We further introduced the Golden-gate assembly and blue-white screening approaches into the Cas9-gRNA construction procedures, without the process of vector digestion and gel purification. CONCLUSIONS: Combing with the optimized gRNA structure (gRNA-BL) we identified before, we established one more cost-effective, time-saving and efficient plasmid construction strategy for Cas9 gRNA. PMID- 30001551 TI - Appendix J Laboratory Conversion Factors. PMID- 30001552 TI - CD24 is a Potential Biomarker for Prognosis in Human Breast Carcinoma. AB - BACKGROUND/AIMS: CD24 is a highly glycosylated mucin-like antigen on the cell surface, which has recently emerged as a novel oncogene and metastasis promoter. We performed bioinformatics analysis to investigate whether CD24 can serve as a prognostic indicator in breast cancer. METHODS: CD24 expression was assessed using SAGE Genie tools and Oncomine analysis. The PrognoScan database, Kaplan Meier Plotter, and bc-GenExMiner were used to identify the prognostic roles of CD24 in breast cancer. RESULTS: We found that CD24 was more frequently overexpressed in breast cancer than in normal breast tissue and correlated with worse prognosis. Meanwhile, high CD24 expression was associated with increased risk of HER2, basal-like, triple-negative breast cancer, and higher Scarff-Bloom Richardson grade. Data mining in multiple big databases confirmed a positive correlation between CD24 mRNA expression and SDC1 mRNA expression in breast cancer tissue. CONCLUSIONS: Our findings suggest that CD24 overexpression is more common in breast cancer than in corresponding normal tissue. In addition, CD24 and SDC1 can serve as prognostic indicators for breast cancer. However, large scale and comprehensive research is needed to further confirm these results. PMID- 30001553 TI - The Association Between Three Genetic Variants in MicroRNAs (Rs11614913, Rs2910164, Rs3746444) and Prostate Cancer Risk. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules which play a significant role in transcriptional and translational regulation. Published data on the association between the miRNA SNPs and prostate cancer (PCa) risk are somewhat inconclusive. METHODS: We performed a meta-analysis of all available studies including 2,227 patients and 2,331 control subjects to evaluate the impact of three common genetic variants of microRNAs in prostate cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to investigate the strength of the association. RESULTS: For miR-499 polymorphism, a significant association was observed between the rs3746444 A>G polymorphism and PCa risk in heterozygote comparison and dominant genetic model, in particular in Asian population subgroup. For miR-146a polymorphism, the rs2910164 CC genotype was associated with decreased PCa risk in Asian population in homozygote comparison. In addition, rs2910164 CC genotype had a weekly higher percentage value in subgroup of Gleason score < 7. Similar results were also indicated in localized prostate cancer in subgroup analysis by tumor stage. For miR-196a2 polymorphism, no association was observed between this variant and PCa risk in the overall group. However, in stratified analysis by ethnicity, we found that rs11614913 T allele was a risk factor for Asian PCa patients. CONCLUSIONS: Polymorphisms of miR-196a2 rs11614913, miR-146a rs2910164, and miR-499 rs3746444 may contribute to the risk for developing prostate cancer in Asian descendants. Moreover, miR-146a rs2910164 polymorphism was related to PCa prognosis. PMID- 30001554 TI - Lower Emotion Awareness in Skin-Restricted Lupus Patients: A Case-Controlled Study. PMID- 30001555 TI - Follicular Penetration of Caffeine from Topically Applied Nanoemulsion Formulations Containing Penetration Enhancers: In vitro Human Skin Studies. AB - BACKGROUND/AIMS: This study aimed to investigate transfollicular delivery enhancement of caffeine from nanoemulsion formulations incorporating oleic acid (OA) and eucalyptol (EU) as chemical penetration enhancers. METHODS: Caffeine permeation was evaluated from nanoemulsions containing OA or EU and an aqueous control solution through excised human full-thickness skin with hair follicles opened, blocked, or left untreated. Differential tape stripping was performed, followed by cyanoacrylate skin surface biopsies to determine the amount of caffeine in the hair follicles, and skin extraction to determine the retention of caffeine in the skin. RESULTS: Nanoemulsions significantly increased caffeine permeation through open and untreated skin over control (untreated: 36- and 42 fold for OA and EU, respectively; open: 40- and 49-fold). The follicular route contributed 53.7% of caffeine permeation for the OA nanoemulsion and 51% for EU when follicles were opened. Nanoemulsions promoted 4- and 3.4-fold increases in caffeine retention in open follicles, for OA and EU, respectively. Retention of caffeine in the stratum corneum and skin was almost equal in all cases. CONCLUSIONS: This study demonstrated effective delivery of caffeine as a hydrophilic model drug into and through hair follicles and showed that follicles and surrounding regions may be targeted by optimised formulations for specific treatments. PMID- 30001556 TI - Right Ventricular Index for Risk Stratification of Patients with Pulmonary Arterial Hypertension. AB - BACKGROUND: Right ventricular (RV) dysfunction is a major prognostic predictor in pulmonary arterial hypertension (PAH). OBJECTIVES: The objective of this study was to assess the prognostic impact of a newly developed index merging haemodynamic parameters into 1 variable. METHODS: We retrospectively assessed 2 cohorts of 248 patients (164 from Hamburg and 84 from Heidelberg) with invasively diagnosed PAH. During a median follow-up time of 3.6 years (3.1 and 4.0 years for Hamburg and Heidelberg, respectively), the composite endpoint of all-cause mortality and lung transplantation occurred in 57 patients (53 and 4 patients for Hamburg and Heidelberg, respectively). The RV index was developed in the Hamburg cohort and validated in the Heidelberg cohort: (right atrial pressure * pulmonary vascular resistance)/mixed venous oxygen saturation. RESULTS: Patients with a high RV index had a higher incidence of the combined endpoint in Kaplan-Meier analyses in the Hamburg and Heidelberg cohort (p = 0.017 and p = 0.034, respectively). The calculated RV index cut-off value was 91 and identified patients with a worse outcome in the Hamburg cohort and showed a trend in the Heidelberg cohort (p < 0.001 and p = 0.089, respectively). The RV index in Cox regression hazard models was an independent predictor of outcomes after adjustment for sex and age in both cohorts (Hamburg: hazard ratio [HR] 1.26 [95% CI 1.08, 1.47], p = 0.0027; Heidelberg: HR 2.27 [95% CI 1.46, 3.51], p < 0.001). A nomogram based on these results allowed risk stratification. CONCLUSION: Merging 3 haemodynamic variables into 1 variable, the RV index increased the prognostic power up to an independent risk factor. The RV index is easy to calculate and allows the construction of a nomogram for an individualized risk assessment. PMID- 30001557 TI - Occupational Mercury Exposure at a Fluorescent Lamp Recycling Facility - Wisconsin, 2017. AB - On May 9, 2017, Public Health Madison & Dane County contacted the Wisconsin Division of Public Health for assistance with investigation of mercury exposure among workers at a fluorescent lamp recycling facility. Public Health Madison & Dane County had been contacted by the Wisconsin Department of Natural Resources as part of an investigation of potential environmental contamination at the facility. Fluorescent lamps are composed of a phosphor-coated glass tube containing mercury vapor and argon. During the recycling process, lamps are crushed, releasing mercury vapor and mercury-containing dusts. State and county health officials, in collaboration with Wisconsin Department of Natural Resources, conducted an investigation of mercury exposure of workers and an environmental assessment of the facility, surrounding areas, and worker vehicles. All five workers who were tested had urine mercury levels exceeding the American Conference of Governmental Industrial Hygienists (ACGIH) biologic exposure index of 20.0 MUg/g creatinine, and two had tremor on physical exam. Workers wore inadequate personal protective equipment (PPE). Mercury levels in indoor air varied within the building, with a maximum of 207.4 MUg/m3 at floor level on the crushing platform, approximately eightfold higher than the ACGIH threshold limit value of 25 MUg/m3 (1). Mercury also was found in workers' vehicles, indicating risk for take-home exposure. Workers at risk for mercury exposure need to have access to and consistently wear National Institute of Occupational Safety and Health (NIOSH)-approved respiratory protection for mercury vapor, nitrile or other suitable gloves to prevent contact exposure, and disposable suits with booties and change shoes before leaving the worksite to prevent take-home exposures. PMID- 30001560 TI - Notes from the Field: Overdose Deaths with Carfentanil and Other Fentanyl Analogs Detected - 10 States, July 2016-June 2017. PMID- 30001559 TI - Notes from the Field: Toxic Leukoencephalopathy Associated with Tianeptine Misuse - California, 2017. PMID- 30001558 TI - Hypertension Among Youths - United States, 2001-2016. AB - Hypertension is an important modifiable risk factor for cardiovascular morbidity and mortality, and hypertension in adolescents and young adults is associated with long-term negative health effects (1,2).* In 2017, the American Academy of Pediatrics (AAP) released a new Clinical Practice Guideline (3), which updated 2004 pediatric hypertension guidance? with new thresholds and percentile references calculated from a healthy-weight population. To examine trends in youth hypertension and the impact of the new guideline on classification of hypertension status, CDC analyzed data from 12,004 participants aged 12-19 years in the 2001-2016 National Health and Nutrition Examination Survey (NHANES). During this time, prevalence of hypertension declined, using both the new (from 7.7% to 4.2%, p<0.001) and former (from 3.2% to 1.5%, p<0.001) guidelines, and declines were observed across all weight status categories. However, because of the new percentile tables and lower threshold for hypertension (4), application of the new guideline compared with the former guideline resulted in a weighted net estimated increase of 795,000 U.S. youths being reclassified as having hypertension using 2013-2016 data. Youths who were older, male, and those with obesity accounted for a disproportionate share of persons reclassified as having hypertension. Clinicians and public health professionals might expect to see a higher prevalence of hypertension with application of the new guideline and can use these data to inform actions to address hypertension among youths. Strategies to improve cardiovascular health include adoption of healthy eating patterns and increased physical activity (3). PMID- 30001561 TI - QuickStats: Percentage of Adults Aged >=20 Years Told Their Cholesterol Was High Who Were Taking Lipid-Lowering Medications,* by Sex and Age Group - National Health and Nutrition Examination Survey, 2005-2006 to 2015-2016. PMID- 30001562 TI - Subjective Cognitive Decline Among Adults Aged >=45 Years - United States, 2015 2016. AB - Subjective cognitive decline (SCD) is the self-reported experience of worsening or more frequent confusion or memory loss within the previous 12 months (1,2) and one of the earliest noticeable symptoms of Alzheimer's disease (Alzheimer's), a fatal form of dementia (i.e., a decline in mental abilities severe enough to interfere with everyday life) (1). Alzheimer's is the most common form of dementia, although not all memory loss results from Alzheimer's (3). To examine SCD, CDC analyzed combined data from the 2015 and 2016 Behavioral Risk Factor Surveillance System (BRFSS) surveys. Overall, 11.2% of adults aged >=45 years reported having SCD, 50.6% of whom reported SCD-related functional limitations. Among persons living alone aged >=45 years, 13.8% reported SCD; among persons with any chronic disease, 15.2% reported SCD. Adults should discuss confusion or memory loss with a health care professional who can assess cognitive decline and address possible treatments and issues related to chronic disease management, medical care, and caregiving. PMID- 30001563 TI - [A rare tympanic lesion - paracentesis led to an interesting diagnosis]. PMID- 30001564 TI - Epilepsy in Biotinidase Deficiency Is Distinct from Early Myoclonic Encephalopathy. PMID- 30001565 TI - Shunt Dependency Syndrome after Cyst-Peritoneal Shunt Resolved by Keyhole Microsurgical Cyst Resection: Two Case Reports and Literature Review. AB - OBJECTIVE: Shunt dependency syndrome after cyst-peritoneal (CP) shunt is a rare but serious complication which leads to increased intracranial pressure and neurological deficit. The possible mechanism still remains in controversy. We present our experience on the treatment of the complication and attempt to find a better therapy strategy for the complication. METHODS: Two children with middle fossa arachnoid cysts underwent CP shunt with fixed pressure catheters at an opening pressure of 7 cmH2O and then developed dependency syndrome. Both patients were effectively treated by mini-invasive cyst wall excision with the shunts reserved. The clinical manifestation, radiological findings, treatment methods, and therapeutic outcomes were reviewed retrospectively. RESULTS: The time from shunt surgery to shunt dependency syndrome occurrence was 4 and 2 years, respectively. Computed tomography/magnetic resonance findings of the brain showed remarkably collapsed cysts with normal or small ventricles. Both patients underwent secondary mini-invasive cyst wall excision and shunt catheters were reserved. After the operations, their symptoms were resolved except one case with marginally improved visual impairment. CONCLUSION: Shunt dependency syndrome is a rare but dangerous complication of CP shunt and should be treated in time. Collapsed and thickened cyst wall intermittent covering the catheter head end, decreased brain compliance due to chronic fibrosis, as well as regression of cerebrospinal fluid absorption could be the pathogenesis. We suggest keyhole resection of the residual cyst wall as an effective and mini-invasive treatment option. PMID- 30001566 TI - Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study. AB - We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development. PMID- 30001567 TI - Effect of Prolonged Fasting Duration on 50 Gram Oral Glucose Challenge Test in the Diagnosis of Gestational Diabetes Mellitus. AB - The aim of this study was to investigate the association between fasting duration before screening with 50 g glucose challenge test (GCT) and the test outcome. For this cross-sectional study, we enrolled 508 low-risk pregnant women who underwent 50 g GCT between the 24 and 28 weeks of gestation. We excluded women with pregestational diabetes, multiple gestations or a history of gestational diabetes mellitus (GDM), and macrosomia. We evaluated fasting durations, GCT results, and demographic features. A significant positive correlation was found between fasting duration and 50 g GCT values (r=0.122; p=0.006), and the best cut-off value was found to be 6.5 h, with 85.85% sensitivity and 38.61% specificity (relative risk, 2.73; 95% CI, 1.893-3.936; p<0.0001). Further, we divided the patients into two groups: study (fasting, <6.5 h; n=146) and control (fasting,>6.5 h; n=362) groups. Notably, the mean glucose levels, number of patients with GCT>140 mg/dl, and rates of unnecessary 100 g loadings were significantly higher in the study group. We found no significant differences between the groups in terms of the fasting plasma glucose levels and GDM prevalence. According to our findings, fasting duration of>6.5 h resulted in 2.7 times more unnecessary 100 g glucose tolerance tests (GTT). We recommend that patients having fasted for>6.5 h receive a one-step 75 g GTT after completing 8-h fasting. PMID- 30001568 TI - DEGUM, OGUM, SGUM and FMF Germany Recommendations for the Implementation of First Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures. AB - First-trimester screening between 11 + 0 and 13 + 6 weeks with qualified prenatal counseling, detailed ultrasound, biochemical markers and maternal factors has become the basis for decisions about further examinations. It detects numerous structural and genetic anomalies. The inclusion of uterine artery Doppler and PlGF screens for preeclampsia and fetal growth restriction. Low-dose aspirin significantly reduces the prevalence of severe preterm eclampsia. Cut-off values define groups of high, intermediate and low probability. Prenatal counseling uses detection and false-positive rates to work out the individual need profile and the corresponding decision: no further diagnosis/screening - cell-free DNA screening - diagnostic procedure and genetic analysis. In pre-test counseling it must be recognized that the prevalence of trisomy 21, 18 or 13 is low in younger women, as in submicroscopic anomalies in every maternal age. Even with high specificities, the positive predictive values of screening tests for rare anomalies are low. In the general population trisomies and sex chromosome aneuploidies account for approximately 70 % of anomalies recognizable by conventional genetic analysis. Screen positive results of cfDNA tests have to be proven by diagnostic procedure and genetic diagnosis. In cases of inconclusive results a higher rate of genetic anomalies is detected. Procedure-related fetal loss rates after chorionic biopsy and amniocentesis performed by experts are lower than 1 to 2 in 1000. Counseling should include the possible detection of submicroscopic anomalies by comparative genomic hybridization (array-CGH). At present, existing studies about screening for microdeletions and duplications do not provide reliable data to calculate sensitivities, false-positive rates and positive predictive values. PMID- 30001569 TI - The pharmacokinetics and the pharmacodynamics of cannabinoids. AB - There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and pharmacodynamics to guide prescribers. Cannabis medicines contain a wide variety of chemical compounds, including the cannabinoids delta-9 tetrahydrocannabinol (THC), which is psychoactive, and the nonpsychoactive cannabidiol (CBD). Cannabis use is associated with both pathological and behavioural toxicity and, accordingly, is contraindicated in the context of significant psychiatric, cardiovascular, renal or hepatic illness. The pharmacokinetics of cannabinoids and the effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements. As both THC and CBD are hepatically metabolized, the potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. An important example is the CBD-mediated inhibition of clobazam metabolism. Pharmacodynamic interactions may occur if cannabis is administered with other central nervous system depressant drugs, and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations, such as older patients, may benefit from the potential symptomatic and palliative benefits of cannabinoids but are at increased risk of adverse effects. The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a 'start low and go slow' approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the actual patient populations for whom prescribing may be considered are needed, to derive a better understanding of these drugs and enhance safe and optimal prescribing. PMID- 30001570 TI - Determination of vortioxetine and its degradation product in bulk and tablets, by LC-DAD and MS/MS methods. AB - Vortioxetine hydrobromide (VOR), is a novel antidepressant used for the treatment of major depressive disorder. It has a chemical structure susceptible to degradation, therefore it is important to have suitable analytical methods to determine VOR in presence of its main degradation products (DP), because if the compound degrades, this could result in diminution of the therapeutic activity and safety. A simple HPLC method with photodiode array detection was developed and validated for determination of VOR in bulk and tablets, in the presence of its major DP. The drug was subjected to oxidative, hydrolytic, and photolytic stress conditions, showing significant degradation under oxidation with the formation of one DP, which was identified by ESI-MS/MS. A C18 column was used, with mobile phase consisting of acetonitrile and water with acetic acid and triethylamine in isocratic elution mode, with detection at 228 nm and 1.0 mL/min flow rate. The assay was linear in the 25-125 MUg/mL concentration range. For precision, the RSD was <1.8%, the recovery was 100.0-101.6%, and the method demonstrated adequate selectivity. The method was successfully applied to quantify VOR in tablets. The results showed that the method is useful for routine analysis and for quality control purposes. PMID- 30001572 TI - Football training over 5 years is associated with preserved femoral bone mineral density in men with prostate cancer. AB - This study investigated the association between long-term adherence to football training and retaining bone mineralization and physical capacity in men with prostate cancer (PCa) managed with androgen deprivation therapy (ADT). Patients completing follow-up at 32 weeks in the FC Prostate Randomized Controlled Trial (RCT) in 2012 or 2013 were invited to 5-year follow-up assessments in May 2017 (n = 30). Changes in physiological outcomes over time between the football participants (FTG) and nonparticipants (CON) were examined. Twenty-two men accepted the invitation of which 11, aged 71.3 +/- 3.8 years, had continued to play self-organized football 1.7 (SD 0.5) times per week for 41/2 years (+/-8 months). At 5 years, right femoral neck bone mineral density (BMD) had improved significantly in the FTG compared to CON (P = .028). No other significant between group differences were observed. In FTG, RHR decreased by 4.3 bpm (P = .009) with no changes in CON. Muscle mass, knee-extensor muscle strength, VO2 max, and postural balance decreased in both groups. In FTG, the fraction of training time with HR between 80%-90% or >90% of HRmax was 29.9% (SD 20.6) and 22.8% (SD 28.7), respectively. Average distance covered during 3 * 20 minutes of football training was 2524 m (SD 525). Football training over a 5-year period was associated with preserved femoral neck BMD in elderly men with PCa managed on ADT. Intensity during football training was >80% of HRmax for 51% of training time after 5 years. Body composition and physical capacity deteriorated over 5 years regardless of football participation. PMID- 30001571 TI - Determination of halquinol residual levels in animal-derived food products using liquid chromatography-tandem mass spectrometry. AB - A reliable and highly sensitive detection method based on liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry (LC-MS/MS) analysis has been developed for determination and quantification of halquinol, including 5,7-dichloroquinolin-8-ol and 5-chloroquinolin-8-ol. The target analytes were extracted from porcine muscle, egg, milk, eel, flatfish and shrimp using a mixture of acetonitrile and ethyl acetate followed by liquid-liquid purification with n-hexane. The analytes were separated on an Agilent Eclipse XDB C18 reversed-phase analytical column using 0.05% formic acid in distilled water and acetonitrile as mobile phases. Good linearity from six-point matrix-matched calibration was obtained with correlation coefficients (R2 ) >= 0.9904. Recoveries from three spiking levels (5, 10 and 20 MUg/kg) ranged between 70.6 and 101.7% in various matrices with relative standard deviations <=8.6%. Samples acquired from markets located in Seoul, Republic of Korea, tested negative for the target analytes. In conclusion, the proposed method is versatile and precise for the routine detection of halquinol residual levels in animal-derived food products intended for human consumption. PMID- 30001574 TI - [Preparation and Characterization of Recombinant HEV RNA-loaded MS2 Bacteriophage Capsid by Armored RNA Technology]. AB - The purpose of this study was to develop an effective control to be applied in hepatitis E virus(HEV)nucleic acid detection.Construction of an MS2/HEV gene was performed based on an "Armored RNA technology" protocol. The gene included a partial MS2 phage genome including the 5'UTR,the maturation protein, capsid protein and initiation site of the replicase and a partially conserved sequence derived from the HEV ORF2.The target genes were synthesized and amplified by PCR, and the purified target gene products subcloned into the pET-28 b prokaryotic expression vector to obtain the pET-28b-MS2/HEV recombinant plasmid. SDS-PAGE was used for expression analysis in E. coli BL21(DE3)cells harboring the pET-28b MS2/HEV plasmid. Centrifugal ultrafiltration was adopted for the purification and concentration of recombinant HEV RNA-loaded MS2 Bacteriophage Capsid (rHEPC). The morphological identification of the particles was subsequently performed by scanning electron microscopy. Stability of the rHEPC particles were evaluated by challenging with different concentrations of DNase I and RNase A, and also evaluated for long-term storage based on RT-PCR verification. SDS-PAGE results showed that the target MS2/HEV gene could express efficiently in recombinant E. coli BL21(DE3)and RT-PCR results revealed that the designed HEV conserved gene sequence was successfully packaged into MS2phage-like or rHEPC particles. Stability evaluation showed that the prepared rHEPC particles exhibited strong resistance to degradation by DNase I and RNase A and long-lasting protection of coated HEV RNA for at least seven months when stored at-20C.The prepared rHEPC particles in the present study meet the basic requirements to be used as a quality control material for routine HEV nucleic acid detection. PMID- 30001573 TI - [Construction of Recombinant Full-length Hepatitis E Virus Fused with EGFP and Assessment of Infectivity]. AB - The purpose of this study was to construct recombinant full-length hepatitis E virus(HEV)fused with enhanced green fluorescent protein(EGFP),and assess its infectivity in A549 cells. Two fragments from the full-length HEV genome and the EGFP gene were amplified by PCR. The EGFP gene was inserted downstream of the HEV ORF2 and then cloned into the pGEM(r) -7Zf(+)vector containing the T7 and SP6RNA polymerase promoters, producing pGEM-HEV-EGFP. The construction of the pGEM-HEV EGFP recombinant plasmid was confirmed by restriction enzyme digest and sequencing. The pGEM-HEV-EGFP recombinant plasmid was transfected into A549 cells to assess infectivity using Lipofectamine. EGFP expression was observed at 24hpost-transfection,and expression of the HEV ORF2 was detected by immunofluorescence, confirming the presence of the HEV ORF2 and EGFP fusion protein. Cytopathic effects were observed at day seven post-transfection. The infectivity of pGEM-HEV-EGFP was confirmed by the presence of fluorescence after three continuous passages. The recombinant pGEM-HEV-EGFP vector was successfully constructed and effectively infected A549 cells, which will facilitate future studies on the mechanisms of HEV infection and pathogenesis. PMID- 30001575 TI - [Cloning, Sequence Analysis and Expression of Recombinant E2 Protein of GB Virus C Genotype 7]. AB - The purpose of this study was to explore the potential of the GB virus C(GBV C)genotype 7E2 protein as a detection antigen for ELISA kit development. In this study, analyses of antigen epitopes, space structures and the linear B cell epitopes from the GBV-C genotype 7E2 protein were performed using an online analysis program. To establish a more reliable detection method for GBV-C studies, a 945bp gene fragment from GBV-C E2 was amplified by RT-PCR and ligated into the pET-32 a prokaryotic expression vector, which was then transformed into E. coli BL21 cells for protein expression. A protein with a molecular weight of 55 kDa was detected by 12% SDS-PAGE. The protein was found in inclusion bodies, and the His-tagged protein was detected by western blotting. The results showed that the cloned E2 gene sequence was 945 bp, and that the GBV-C E2 protein sequence had multiple antigenic epitopes. The recombinant protein formed inclusion bodies, which was consistent with expectations. These findings may provide the foundation for the development of a GBV-C detection kit. PMID- 30001576 TI - [Preparation and Cryo-EM Structure Determination of Human Papillomavirus 16 Pseudovirion Derived from Suspension-adapted HEK293 Cells]. AB - The goals of this study were to establish a scalable production method to prepare human papillomavirus(HPV)16pseudovirus (PsV) using suspension-adapted HEK-293 FT cells and to improve the purification efficiency of HPV PsV. Furthermore, we aimed to solve the cryo-electron microscopy (cryo-EM) structure of HPV16 PsV. The suspension f HEK-293 FT cells were generated from adherent cells by a stepwise decrease in serum content and the addition of an anti-clumping agent during culturing. The resultant HEK-293 FT suspension cells were transfected with an L1/L2 expression vector and pN31-EGFP plasmid to generate HPV16 PsV in the Wave Bioreactor. Following cell lysis,HPV16 PsV was purified by sucrose density gradient and subsequent CsCl iso-density gradient ultra-centrifugation The final titer of HPV16 PsV was 8.2 * 10(5) TCID(50)/MUL. Purified HPV16 PsV was comfirmed to as contain L1 and L2protein by western blotting, and the L1 concentration was determined to be 156.0 MUg/mL by quantitative ELISA. Finally, a FEI Tecnai G2F30 electron microscope and AUTO3 DEM were used to solve the cryoEM structure of HPV16 PsV at a resolution of 14 A.The structure shows that HPV16 PsV exists as a T=7dicosahedral lattice, with a diameter of 600 A. These results will be beneficial for neutralization assays and for anti-sera for HPV vaccines, the high resolution structure determination of HPV16 PsV, and the investigation of interactions between HPV L1 and L2. PMID- 30001577 TI - [Identification of the Transcriptional Activity Domain of EV71 3D(pol)]. AB - Enterovirus 71(EV71)is one of the major pathogens of hand, foot and mouth disease (HFMD). The EV71 genome encodes an RNA-dependent RNA polymerase(RdRp),3D(pol),which is critical for genome transcription and translation. However, how the 3D(pol) interacts with the host remains unclear. Yeast two-hybrid systems provide an effective approach for detecting protein protein interactions. In this report, we inserted the DNA sequence of 3D(pol) into the pGBKT7 vector as the bait plasmid for the yeast two-hybrid experiment and transformed the plasmid into the yeast AH109 strain. We detected the expression,cytotoxicity and self-activity of 3D(pol).The 3D(pol) expressed well without affecting cell growth but exhibited strong transcriptional activation in yeast cells. We further constructed a series of pGBKT7-3D(pol) deletion mutants and identified the shortest transcriptional activation domain(1-94aa)using a self activation assay. The results provide a molecular basis for screening the host proteins that interact with 3D(pol) using the yeast two hybrid system. PMID- 30001578 TI - [The Complete Sequence Analysis of 18 Strains of Coxsackievirus A6 in Guangdong Province of China]. AB - In this study, we examined the complete genome of coxsackievirus A6 (CVA6) from hand, foot, and mouth disease in Guangdong Province from 2013,and explored the genetic similarities and differences in epidemic and non-epidemic stains of CVA6.Eighteen strains of CVA6 were included in complete genome sequencing, and the sequences were subject to phylogenetic analysis,sequence alignment analysis and genetic recombination analysis using the software DNASTAR6.0,MEGA5.2and SimPlot3.5.1.The results showed that the complete genome of 18 Guangdong CVA6strains ranged from 7390bp to 7392bp.No insertions or deletions were detected in the coding region. There were several insertions and deletions in 5'UTR and 3'UTR.Phylogenetic analysis indicated that the nucleotide and amino acid sequence identity between the 18 complete genomes were 90.5%-99.6% and 97.5% 99.9%,respectively.The strains isolated in2013 could be further divided into two clusters, III and IV, while the strains isolated in 2011 were only present in the IV cluster. Genetic recombination analysis revealed that the Guangdong representative strain of CVA6,GD870/2013,had gene recombination in the P2 and P3regions,while the GD839/2013 strain did not show obvious genetic recombination. Genome-wide analysis of CVA6 revealed that there are two possible transmitted chains, III and IV, in epidemic strains from Guangdong Province in 2013.The transmitted chain III originated from the strain with genetic recombination in the P2 and P3regions,whichwas completely different from the chain IV. Transmission of chain IV of CVA6 was only observed in the nonepidemic 2011 strain. PMID- 30001579 TI - [Proteome Profiling of A549 Cells Infected with Influenza H7N9 Virus]. AB - To explore the mechanisms of influenza H7N9 virus pathogenesis, influenza H7N9 virus and H1N1 influenza A virus(H1N1pdm09)-infected A549 cellular models were established, and differential protein expression in A549 cells infected with the two strains were investigated.A549 cells were infected with H7N9 and H1N1pdm09influenza virus at a multiplicity of infection(MOI)of 0.001.The temporal response of A549 cells infected with the two strains was evaluated using the proteomics approaches(2DDIGE combined with MALDI-TOF-MS/MS)at 24,48 and 72hours post infection(hpi).There were 11,12 and 33proteins with significantly different expression at 24,48 and 72hpi,respectively.Compared with H1N1pdm09 infection, functional analysis revealed that the down-regulation of proteins in H7N9 infection including F-actin-capping protein subunit alpha-1(CapZ-alpha1), ornithine aminotransferase(OAT),poly(rC)-binding protein 1(PCBP1)and eukaryotic translation initiation factor 5A-1(eIF5A)produced cytopathic effects. The down regulation of platelet-activating factor acetylhydrolaseIb subunit beta(PAFAH1B2)in H7N9-infection may be related to the clinical symptoms of patients infected by the influenza H7N9 virus. PMID- 30001580 TI - [Analysis of Egg-adapted Mutations in Influenza A H1N1pdm09 Viruses in Hubei Province of China, 2013-2014]. AB - Influenza A H1N1pdm09 Virus; Chicken embryo; Phylogenetic tree; Egg-adaptation; Antigenic site; Drug-resistance site; Abstract: To investigate egg-adapted mutation in influenza A H1N1pdm09 viruses isolated from the Hubei influenza surveillance network, a comparative analysis was performed of three influenza A H1N1pdm09 viruses isolated in chicken embryo and the corresponding MDCK cell derived viruses. Analyses included examination of the phylogenetic tree, evolutionary rates, amino acid substitutions, egg-adapted mutation and homology modeling. We found differences between the egg-adapted viruses and MDCK cell derived viruses based on phylogenetic trees and evolutionary rates; the viruses showed a trend of " NA>HA>MP". Four amino acid substitutions(Q223R,V527 I,M19Iand H275Y)were found in three egg-adapted viruses.Q223 Rand V527Iwere present in the haemagglutinin protein, while M19I and H275Y were detected in neuraminidase.The Q223R mutation changed the structure of antigenic sites between Sb and Ca2. H275Y is a classic neuraminidase resistance mutation. The results suggest that the egg adapted mutations were introduced when influenza viruses were isolated in chicken embryos from the Hubei influenza surveillance network. These mutations may affect the selection of vaccine candidates and vaccine efficacy; therefore, monitoring of egg-adapted mutations should be strengthened in the influenza surveillance network. PMID- 30001581 TI - [Molecular Phylogenetic Analysis of a Highly Pathogenic H5N2 Avian Influenza Virus Isolated from Duck]. AB - In 2016,routine influenza virus surveillance was conducted in the live poultry markets of Wuhan, Hubei Province. An H5N2 subtype avian influenza virus(AIV)was isolated from ducks in Wuhan. The entire genome of this virus isolate was sequenced,and molecular phylogenetic analysis performed. The results indicated that the HA gene belonged to clade 2.3.4.4and contained multiple basic amino acids at the cleavage site, which is characteristic of highly pathogenic AIV. Sequence alignment revealed that the isolate shared a high degree of homology with different H5 subtype AIVs isolated from waterfowl in southern China in recent years. This isolate was likely a natural reassortant from different subtype AIVs. This study provides epidemiological evidence of influenza evolution. Continuation of molecular epidemiology studies of H5 subtype influenza viruses in live poultry markets is important for understanding their role in the variation and evolution of highly pathogenic AIVs and their potential hazardous effects on human health. Furthermore, this information is important for strengthening comprehensive AIV surveillance and control measures. PMID- 30001582 TI - [Prediction and Identification of Immunodominant Linear B Cell Epitopes in the Nucleocapsid Protein of SFTSV]. AB - In order to identify immunodominant linear B cell epitopes in the nucleocapsid protein N of severe fever with thrombocytopenia syndrome virus(SFTSV),bioinformatics programs were used to analyze antigenicity, hydrophilicity and surface probability of the amino acid sequence and predict possible linear B cell epitopes. PyMOL software was used to analyze the distribution of linear B cell epitopes in nucleocapsid protein N based on its crystal structure. Corresponding peptides were synthesized and examined in peptide enzyme-linked immunosorbent assay(Peptide-ELISA)individually to check whether they reacted with sera from SFTSV-infected patients. As a result, a total of six potential linear B cell epitopes were predicted as the following: A(40 KKLKETGGDDWVKDTK-55), B(71-ASGKMSNSGSKRL-83), C(94-ERAETRL-100),D(135-LKVENYPP 142),E(157-GVSEATT-163)and F(184-KMRGASKTEVYNSFRDP-200).All epitopes were located on the surface of the nucleocapsid protein N and contained flexible loops. Each of the six synthetic peptides reacted positively with sera from SFTSV-infected patients and were identified as immunodominant linear B cell epitopes. Linear regression analysis showed a positive correlation between each peptide-ELISA and commercialized N protein-based EIA. In this study, immunodominant linear B cell epitopes from the nucleocapsid protein N of SFTSV were successfully predicted and confirmed. These findings may help to establish the molecule basis of specific antigenicity and disease diagnosis. PMID- 30001583 TI - [Identification and Characterzation of the Porcine Epidemic Diarrhea Virus (PEDV) Isolates]. AB - To explore the porcine epidemic diarrhea virus(PEDV)epidemiology in domestic pigs, virus isolation and identification were carried out in pig herds in Shanghai and Jiangsu province. Based on sequences of PEDV strains in GenBank, a pair of primers targeting the M gene were designed for PEDV detection. Two clinical pig diarrhea samples were amplified and sequencing results confirmed that the fragments amplified were M gene. PEDV-positive samples were inoculated in Vero cells with different concentrations of trypsin. Our results showed that these two isolates could proliferate effectively in Vero cells with a specific concentration of trypsin. Twenty-second passages viruses were added to the feeding of newborn piglets, and animal regression test showed obvious clinical symptoms of diarrhea, confirming the the PEDV isolates, named as JSLS/PEDV/1/2014 and JS/PEDV/2/2014,were successfully obtained. Phylogenetic analysis of the M genes showed that JSLS/PEDV/1/2014 and JS/PEDV/2/2014 displayed the greatest similarity with the Chinese strains HLJ-2012 and BJ-2012-1,respectively.The S genes of the two isolates were classified in group I. There were 51 bases deletion in the ORF3 genes of these two isolates which were located in the same big branch with the DR13 strain rather than the CV777 strain. PMID- 30001584 TI - [Analysis of Polymorphisms in the HCMV UL144 Gene in Clinical Isolates from Children with Asymptomatic Infection]. AB - The purpose of this study was to examine polymorphisms in the human cytomegalovirus(HCMV)UL144gene in children with asymptomatic HCMV infection. PCR was performed to amplify the UL144 open reading frame(ORF)from urine specimens of asymptomatic HCMV-DNA positive children and both strands of the amplicon were sequenced. Sequence analysis was performed with software including BioEdit,DNAstar,Mega5.0and GeneDoc. Twenty-one of 50 clinical strains were successfully amplified and sequenced, giving a positive rate of detection of 42%.Nucleotide sequence homology ranged from 80.2%to100% and amino acid sequence homology ranged from 77.8%to 100%.The UL144 sequences were distributed among two genotypes, type A(47.61%)and type B(52.38%).The Expasy database was used to analyze the important functional motifs of the UL144 protein. These results revealed that there was a high level of conservation of post-translational modification sites including ASN, PKC, TNFR, and NCD3 G.UL144type B added a PROKAR-LIPOPROTEIN site and ZF-CTCHY site between amino acid residues 1 and 16 and between amino acid residues 30 and 96,respectively,as compared with type A.Compared to the UL144 gene from the Toledo strain, there was a high level of conservation in the CRD1 and CRD2of UL144 type A, while significantly more variability was observed in CRD1 and CRD2of UL144 type B. The transmembrane and cytoplasmic domains were highly conserved in both UL144 type A and type B. Variation in nucleotide sequences of UL144 type A and type B did not cause major changes to the predicted isoelectric point or secondary structure of the UL144 protein. The UL144 genotype of children with asymptomatic HCMV infection was divided into type A and type B, which was different from children with symptomatic HCMV infection. PMID- 30001585 TI - The essential nature of iron usage and regulation. PMID- 30001586 TI - Fate of antibiotic resistance genes and mobile genetic elements during anaerobic co-digestion of Chinese medicinal herbal residues and swine manure. AB - Swine manure is an important reservoir for antibiotic resistance genes (ARGs) but anaerobic co-digestion (AcoD) can potentially reduce the abundance of these ARGs. However, few studies have considered the effects of Chinese medicinal herbal residues (CMHRs) on the variations in ARGs and mobile genetic elements (MGEs) during AcoD. Thus, this study explored the fate of ARGs and MGEs during the AcoD of CMHRs and swine manure. The results showed that CMHRs effectively reduced the abundances of the main ARGs (excluding ermF, qnrA, and tetW) and four MGEs (by 36.7-96.5%) after AcoD. Redundancy analysis showed that changes in the bacterial community mainly affected the fate of ARGs rather than horizontal gene transfer by MGEs. Network analysis indicated that 17 bacterial genera were possible hosts of ARGs. The results of this study suggest that AcoD with CMHRs could be employed to remove some ARGs and MGEs from swine manure. PMID- 30001587 TI - Evaluation of engineered hydrochar from KMnO4 treated bamboo residues: Physicochemical properties, hygroscopic dynamics, and morphology. AB - In this study, a novel approach was developed to prepare engineered hydrochar from KMnO4 treated bamboo residues through hydrothermal carbonization. The hydrochar yields were within a specified range of 61.8-67.8% at 180 degrees C and 39.8-45.0% at 260 degrees C, respectively. The higher temperature led to the higher C content, lower H/C and O/C ratio, whereas the ash content increased with increasing KMnO4 concentration, causing the increase of solid yield as well as the decrease of C content. Pseudo-second kinetic model was optimal to describe bamboo hydrochar's hygroscopic dynamic, and the engineered hydrochar produced at 260 degrees C and 1.0 wt% concentration obtained the better hydrophobicity of 0.82%. SEM-EDS and XRD analysis confirmed the existence of manganese carbonate on the surface of engineered hydrochar, from which we inferred the chemical complexation between KMnO4 and hydrochar. PMID- 30001588 TI - Synergetic promotion of syntrophic methane production from anaerobic digestion of complex organic wastes by biochar: Performance and associated mechanisms. AB - Biochar was added to a mesophilic anaerobic digester to promote syntrophic volatile fatty acids (VFAs) oxidation and methane production from complex organic wastes. Compared with conventional operation, biochar addition effectively shortened the lag time by 27.5-64.4% and increased the maximum methane production rate by 22.4%-40.3%. With a biochar dosage of 15 g/L, the system performed well under an organic loading rate as high as 3 g substrate/g inoculums. Biochar showed a remarkable buffering capacity to alleviate pH decrease caused by VFAs accumulation. In order to gain knowledge on associated mechanisms, a specific experiment was conducted using butyrate as substrate. It was identified that syntrophic degradation of butyrate to acetate occurred under high H2 partial pressure. By microbial community analysis, it was further revealed that biochar addition brought about the enrichment of Anaerolineaceae and Methanosaeta, typical microorganisms for direct interspecies electron transfer. PMID- 30001589 TI - A study on microwave-assisted fast co-pyrolysis of chlorella and tire in the N2 and CO2 atmospheres. AB - The microwave-assisted fast co-pyrolysis of chlorella and tire with additive under N2 and CO2 atmospheres were investigated. The pyrolysis profiles, yields of three-phase, the chemical composition of liquid and the ultimate analyses of solid residues were gained. With the tire ratio increasing, all the characters had the changes. The finial temperature had a wave change. The yield of liquid decreased and the chemical composition obtained in liquid of oxygenates compounds decreased, while hydrocarbon compounds increased, among which aromatic hydrocarbons had the highest content. The yield of solid increased, the HHV had a wave change and the values of H/C decreased. Under CO2 atmosphere, the final temperatures were lower with 70% and 100% chlorella ratios, the yield difference of liquid reached the minimal with 70% and 30% chlorella ratios. According to the quantity and quality of liquid and solid, and the former results, 50% percentage of tire was the suitable ratio. PMID- 30001590 TI - Aerobic deterioration of corn stalk silage and its effect on methane production and microbial community dynamics in anaerobic digestion. AB - Ensilage is a commonly used method of preserving energy crops for biogas production. However, aerobic deterioration of silage is an inevitable problem. This study investigated the effect of aerobic deterioration on methane production and microbial community dynamics through anaerobic digestion (AD) of maize stalk silage, following 9days air exposure of silage. After air exposure, hydrolytic activity and methanogenic archaea amount in AD were reduced, decreasing the specific methane yield (SMY); whereas lignocellulose decomposition during exposure improved the degradability of silage in AD and enhanced SMY, partially compensating the dry matter (DM) loss. 29.3% of the DM and 40.7% of methane yield were lost following 0-9days exposure. Metagenomic analysis showed a shift from Clostridia to Bacteroidia and Anaerolineae in AD after silage deterioration; Methanosaetaceae was the dominant methanogenic archaea. PMID- 30001591 TI - Nitrate removal by combined heterotrophic and autotrophic denitrification processes: Impact of coexistent ions. AB - In this current study, sawdust and zero-valent iron (Fe0) were used as co electron donors to evaluate the effects of coexistent ions on the combined heterotrophic and autotrophic denitrification (HAD) processes. The results showed that HCO3- and SO42- drastically enhanced nitrate removal. The promotion effect derived from both biological and chemical process by HCO3- and chemical process by SO42-. However, Ca2+ ions would remarkably increase nitrate removal due to promoting the electron transfer and the metabolic activities of bacteria, whereas the Cu2+ ions inhibited the biological process due to the deleterious effect on bacteria. Meanwhile, Fe2+ and Fe3+ ions exhibited inhibition effect firstly because of their toxicity to bacteria and promotion subsequently due to their enhancement on Fe0 chemical denitrification. Moreover, byproducts such as nitrite, ammonium, dissolved organic carbon (DOC), etc. were also influenced by common ions. PMID- 30001592 TI - Does carbon-nitrogen ratio affect nitrous oxide emission and spatial distribution in subsurface wastewater infiltration system? AB - In order to evaluate the effects of carbon-nitrogen ratio (CNR) on nitrous oxide (N2O) emission and quantify N2O spatial distribution in subsurface wastewater infiltration system (SWIS), layered sampling method was introduced. Results showed that low N2O emission rate (1.43 mg/m2.h) and conversion rate (0.1% accounting for influent TN) were obtained when CNR increased up to as high as 10. The highest N2O emission (3.14 mg/m2.h) was observed at CNR of 6. Instead, independent of CNR variations, 0-75 cm was the main contributor for N2O emission. The results indicated that layered sampling method is necessary in revealing N2O spatial distribution in soil layers. Carbon source availability and nitrogen load and their ratio (i.e. CNR) determined N2O emission rate. CNR of medium level leads to an increase in N2O emission rate. PMID- 30001593 TI - Performance of co-composting sewage sludge and organic fraction of municipal solid waste at different proportions. AB - In this study, the co-composting performance of sewage sludge (SS) and organic fraction of municipal solid waste (OFMSW) at different proportions was investigated. Cornstalk was added at 15% (of total wet weight) to improve the co composting process. Results show that higher SS proportion could rapidly initialize the co-composting process; while increasing OFMSW percentage enhanced organic content for biodegradation, thus prolonging the thermophilic period and increasing the humification degree during co-composting. However, excessive OFMSW required longer co-composting period to ensure a desirable compost maturity and quality. Over 15days of rapid co-composting, adding 55-85% OFMSW aggravated compost quality by increasing the compost salinity (3.5-4.6mScm-1) and plant toxicity (indicated by the low germination index of 54.1-77.3%). Moreover, different proportions of SS and OFMSW varied gaseous emissions during co composting. Our results suggested that OFMSW should be less than 55% for rapid co composting with SS and cornstalk. PMID- 30001594 TI - Enhanced cellulosic ethanol production via consolidated bioprocessing by Clostridium thermocellum ATCC 31924?. AB - The production of bioethanol was studied by the cultivation of Clostridium thermocellum ATCC 31924 in MTC medium including crystalline cellulose as the sole substrate. The effects of key operational parameters that affect bioethanol production from microcrystalline cellulose were optimized. Under optimum conditions (pH 8.0, temperature 55 degrees C, inoculum size 4% (v/v) and 0.5% (w/v) substrate concentration), a maximum ethanol yield of 0.30 g ethanol/g cellulose consumed and 95.32% cellulose conversion was obtained. An inclusion of modest acetate concentration in the medium showed that carbon flux shifted away from lactate accompanied by 20% increase in ethanol production. It suggests that strain ATCC 31924 differed in its cellulose conversion efficacy and optimum pH requirements compared to the other reported strains of Clostridium thermocellum. The purified cellulosome of strain ATCC 31924 found to be rich in both cellulase and xylanase enzymes emphasizing the importance of this strain for the degradation of lignocellulosic biomass. PMID- 30001595 TI - Targeting and sensing of some cancer cells using folate bioreceptor functionalized nitrogen-doped graphene quantum dots. AB - In recent years, study of folate receptor (FR) expression related to targeting, drug delivery and counting of tumoral cells have been followed. In this work, a fast and simple strategy was reported to determine the FR expressed cancer cells based on the selective bonding of the folic acid/folate (FA) to the FR-positive tumor cells. The folate decorated Nitrogen-doped graphene quantum dots (N-GQDs) were utilized as selective targeting of the MKN 45 cells. Fluorescent microscopy imaging investigations revealed that the produced FA conjugated N-GQDs could specifically attach to the target FR-positive tumor cells. Due to the fluorescence emission of N-GQDs, the developed cytosensor is free from attaching any fluorescent ligand i.e. Rhodamine B to capture the florescence microscopy images and also flow cytometry analysis. The fabricated cytosensor possesses a dynamic range from 100 to 7.0 * 104 cell.mL-1 with high selectivity. Furthermore, the cytosensor also could visualized the MCF 7 and HT 29 cells where the dynamic ranges were 100 to 1.0 * 104 and 500 to 4.0 * 104 cells.mL-1, respectively. In vitro toxicity tests has shown low toxicity of the synthesized N-GQDs where the minimum viability is 68%. The proposed FA-N-GQDs based cytosensor provides a novel platform for detection of MKN 45, HT 29 and MCF 7 cancer cell lines which could be used in multi-channel cancer diagnosis biodevice. PMID- 30001596 TI - Influence of a nonionic surfactant on curcumin delivery of nanocellulose reinforced chitosan hydrogel. AB - Nanocellulose reinforced chitosan hydrogel was synthesized using chemical crosslinking method for the delivery of curcumin which is a poorly water-soluble drug. Curcumin extracted from the dried rhizomes of Curcuma longa was incorporated to the hydrogel via in situ loading method. A nonionic surfactant (Tween 20) was incorporated into the hydrogel to improve the solubility of curcumin. After the gas foaming process, hydrogel showed large interconnected pore structures. The release studies in gastric medium showed that the cumulative release of curcumin increased from 0.21% +/- 0.02% to 54.85% +/- 0.77% with the increasing of Tween 20 concentration from 0% to 30% (w/v) after 7.5 h. However, the entrapment efficiency percentage decreased with the addition of Tween 20. The gas foamed hydrogel showed higher initial burst release within the first 120 min compared to hydrogel formed at atmospheric condition. The solubility of curcumin would increase to 3.014 +/- 0.041 mg/mL when the Tween 20 concentration increased to 3.2% (w/v) in simulated gastric medium. UV-visible spectra revealed that the drug retained its chemical activity after in vitro release. From these findings, it is believed that the nonionic surfactant incorporated chitosan/nanocellulose hydrogel can provide a platform to overcome current problems associated with curcumin delivery. PMID- 30001597 TI - Eexopolysaccharide production of Pantoea sp. BCCS 001 GH: Physical characterizations, emulsification, and antioxidant activities. AB - The newly discovered exopolysaccharide (EPS) produced by Pantoea sp. BCCS 001 GH, isolated from nectarine fruit and some of its physical properties were characterized. This paper examines precipitation, rheological behavior, emulsification, and antioxidant activities of EPS. Particularly, the concentration of common salt (NaCl) affected on precipitation of EPS; while the low ratio (3 Vagent/V) of CaCl2 isopropanol to culture broth was required. The Zeta potential value of emulsified particles had a high surface charge -65.67 +/- 0.6 mV. The strong hydrogen bonds and/or hydrophobic interactions between the polysaccharide and the Congo red molecule showed the triple helical polysaccharide. The water solubility index and water holding capacity of the EPS were 15.6 +/- 0.22, 662 +/- 12.5%, respectively. The degradation temperature (Td) of 318 degrees C was observed from the TGA curve for the EPS. The rheological study indicated that the EPS had typically non-Newtonian pseudoplastic behavior. Among the EPS and Tween 80 tested against oils/hydrocarbons, EPS was found to be one the most effective emulsifying agent against kerosene, xylene, hexane and diesel (72.8, 74.5, 68.3 and 81.1%, respectively). It was found that changes in pH (2-12) significantly influenced the emulsification of kerosene and diesel. In vitro antioxidant activity of EPS against hydroxyl, 1,1-diphenyl-2-picryl hydrazyl radical (DPPH), and superoxide free radicals shown good antioxidant activities. These results indicate the favorable potential of the EPS from strain BCCS 001 GH in food and pharmaceutical fields. PMID- 30001598 TI - Conjugation of testo and testo-Pt(II) with serum proteins: Loading efficacy and protein conformation. AB - The potential application of hybrid anticancer molecules requires further investigation. There is a great interest in developing new site-specific anticancer agents able to efficiently destroy cancer cells with minimal toxic side effects. Serum proteins are known to play an important role as drug delivery system with important clinical applications. Hence, the conjugation of testo and testo-Pt(II) (two semi-synthetic testosterone derivatives) with human serum albumin HSA), bovine serum albumin (BSA) and beta-lactoglobulin (beta-LG) was investigated in aqueous solution at physiological pH. Multiple spectroscopic methods, thermodynamic analysis and modeling were used to determine the binding efficacy of these bioactive compounds to serum proteins. Drug-protein conjugation occurred via ionic contacts. BSA forms more stable conjugates than HSA and beta LG with the order of stability testo > testo-Pt(II). Major alterations of protein secondary structures were observed upon drug complexation. Serum proteins can be used to deliver these bioactive materials in vitro. PMID- 30001599 TI - Chemical characterization and serological properties of a unique O-polysaccharide of the Proteus mirabilis Sm 99 clinical strain - Identification of a new, O81, serotype. AB - The current serological classification scheme of the medically important bacteria from the genus Proteus consists of 80 O serogroups, the last four of which (O77 O80) were created from clinical strains from Lodz, Poland. There are more serologically unique strains isolated from patient that do not fit into the existing scheme, such as Proteus mirabilis strain Sm 99 isolated from urine of a 74-year-old woman in Lodz. Serological investigation involving ELISA and Western blotting failed to classify the Proteus mirabilis strain Sm 99 into any of the 80 Proteus O serogroups. Sugar analysis along with two-dimensional NMR spectroscopy showed that the O-polysaccharide is composed of branched pentasaccharide repeating units containing one residue each of d-Glc, d-GlcNAc, d-GalNAc, d glucuronic acid, and 4-[(R)-3-hydroxybutanoylamino]-4,6-dideoxy-d-glucose. The chemical and serological data show that the O antigen of P. mirabilis Sm 99 is unique among the known Proteus O antigens. Based on this finding, it is proposed to extend the current serological classification scheme of Proteus by adding a new serogroup, O81, which at present consists of P. mirabilis strain Sm 99 only. PMID- 30001600 TI - Study on interaction between human salivary alpha-amylase and sorghum procyanidin tetramer: Binding characteristics and structural analysis. AB - As one of receptors of the acquired membrane, human salivary alpha-amylase (HSA) plays an important role in the formation of caries. In vitro conditions, sorghum procyanidins (SPC) tetramer has a better inhibitory effect on the adhesion of Streptococcus mutans to hydroxyapatite than SPC-dimer and SPC-trimer. This study investigated the interaction mechanism between HSA and SPC-tetramer using spectroscopic techniques including fluorescence, UV-vis absorption, and circular dichroism (CD). Fluorescence data revealed that the fluorescence quenching of HSA by SPC-tetramer was a static quenching process, and that the SPC-tetramer was bound with HSA at the ratio of 1:1 in SPC-tetramer-protein complex. Meanwhile, the analysis of CD demonstrated that the conformation of HSA was altered in the presence of SPC-tetramer. The conformation changes of HSA might contribute to the reduction of the adhesion of cariogenic bacteria and finally decrease the occurrence of dental caries. PMID- 30001601 TI - Attenuation of Na/K-ATPase/Src/ROS amplification signal pathway with pNaktide ameliorates myocardial ischemia-reperfusion injury. AB - OBJECTIVES: Oxidative stress plays an important role in myocardial ischemia reperfusion (I/R) injury. And pNaKtide is known to inhibit Na/K ATPase/Src/reactive oxygen species (ROS) amplification signaling. Accordingly, we aimed to investigate the effect of pNaKtide on myocardial I/R injury. METHODS: We first determine the effect of pNaKtide on hypoxia- or cobalt chloride-induced injury in embryonic heart-derived H9c2 cells via measuring lactate dehydrogenase (LDH) level and trypan blue stain assay. In addition, TUNEL stain assay and western blot analysis of cleaved-PARP and cleaved-caspase3 were performed to detect apoptosis level. Meanwhile, ROS accumulation was assessed by dichlorofluorescin diacetate (DCFH-DA) assay. Then we conducted cell counting kit 8 (CCK-8) and flow cytometry to examine cell proliferation and cell cycle respectively. We next generated rat I/R model and determined the effect of pNaKtide by measuring serum LDH and evaluating heart pathology. At last, the activities of Src and ERK1/2 were examined via western blot to clarify molecular mechanism. RESULTS: In vitro, pNaKtide exposure significantly attenuated the H9c2 cells death and ROS accumulation induced by hypoxia or cobalt chloride. And no significant effect was detected on cell cycle and proliferation upon pNaKtide administration. In vivo, pNaKtide distinctly decreased serum LDH level and ameliorated I/R induced myocardial injury in the rats. Western blot analysis revealed pNaKtide decreased Src and ERK1/2 activities robustly. CONCLUSIONS: The results provided evidence that pNaKtide exhibited cardioprotective effect against hypoxia-induced injury in vitro and in vivo. And pNaKtide might be a potential molecular for therapy of I/R related heart disease. PMID- 30001602 TI - Selective mechanisms and molecular design of 2,4 Diarylaminopyrimidines as ALK inhibitors. AB - As an attractive therapeutic target for non-small-cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) has got increased attention, and the selectivity of ALK inhibitors is an enormous challenge. Recently, 2,4-Diarylaminopyrimidines with high inhibitory activity over InsR/IGF1R were reported as ALK inhibitors, which harboring phosphine oxide moiety. In this work, it is the first time to reveal that the incorporation of dimethylphosphine oxide moiety and the smaller active pocket of ALK is key factor in the selectivity of inhibitor 11q toward ALK over IGF1R/InsR. The results of molecular simulation indicate that the subtle change in the binding pocket of ALK is mainly associated with the flexibility of P-loop and the own residues K1150 and D1270. The replacement of the dimethylphosphine oxide and methylpiperazine of inhibitor 11q would alter the major inhibitory effects of binding and activation. The results further combined 3D-QSAR can not only profile the binding mechanism between the 2,4 Diarylaminopyrimidines inhibitors and ALK, but also supply the useful information for the rational design of a more potential small molecule inhibitor bound to ALK receptor. PMID- 30001603 TI - Rheological and functional properties of asafoetida gum. AB - The asafoetida gum was extracted and purified from oleo-gum-resin of Ferula assa foetida root and characterized by high pressure anions exchange chromatography after acidic hydrolysis. It was composed of Gal:Ara:Rha:GlcA with the ratio 11.5:5.0:2.1:1.0. This monosaccharide composition was found similar to that of a commercial Arabic gum which exhibited a Gal:Ara:Rha:GlcA ratio of 11.7:5.4:3.2:1.0. As the Arabic gum is currently used for its emulsifying properties, the two gums were evaluated for their functional and rheological behaviors. Surface and interfacial tensions values were lower for asafoetida gum compared to Arabic gum. Critical micelle concentration was achieved at concentrations of 0.5% w/w and 1% w/w for asafoetida and Arabic gums, respectively. Values of emulsion capacity, emulsion stability and foaming properties were considerably higher for asafoetida gum in contrast to emulsion activity index that was lower than that of Arabic gum. As those of Arabic gum, solutions of asafoetida gum (2-30% w/w) exhibited Newtonian flow behavior at shear rates between 1 and 500 s-1. Apparent viscosities of Arabic and asafoetida gums were close and logically decreased by increasing temperature (10-80 degrees C). Higher viscosities were achieved at higher pH and CaCl2 concentrations. PMID- 30001604 TI - Galactomannan endowed biogenic silver nanoparticles exposed enhanced cancer cytotoxicity with excellent biocompatibility. AB - Galactomannan isolated from the fruit rind of Punica granatum was previously reported to have excellent antioxidant, immunomodulatory and anticancer properties against both human and murine cancer cells. This polysaccharide was proved to be an anticancer agent either alone or as an adjuvant to chemotherapy. An exploration leads to the fabrication of silver nanoparticles with an average size around 30 nm and a negative surface charge of 35.2 mV using this biopolymer which acted both as reducing and capping agent and displayed good stability and biocompatibility. UV-vis spectrum of the aqueous medium containing silver nanoparticles showed an absorption peak at around 440 nm. The nanoparticles displayed an upgraded and selective cytotoxicity towards human adenocarcinoma, colorectal carcinoma and hepatocellular carcinoma cells. The induction of cancer cell toxicity was proved to be through the induction of programmed cell death pathway mediated with the active involvement of caspases. The significant anti metastatic properties will further favour the safer in vivo application of these silver nanoparticles against neoplasia. The nontoxic nature of polysaccharide endowed the resultant silver nanoparticles with excellent biocompatibility towards red blood cells and extended the biomedical potential of this candidate. Hence, the surfactant-free green method mediated orchestration of biogenic silver nanoparticles resembled a potential theransonstic nano-construct with synergistic anticancer and immunomodulatory potential in a single platform. PMID- 30001605 TI - Effect of ionic strength and arginine on aggregation of UV-irradiated muscle glycogen phosphorylase b. AB - In this work the effect of ionic strength and arginine on the kinetics of aggregation of UV-irradiated muscle glycogen phosphorylase b (UV-Phb) was studied using dynamic light scattering at 37 degrees C at various ionic strengths (0.02 0.7 M). Under these conditions the rate-limiting stage of the overall aggregation process is the structural reorganization of UV-Phb, which can be characterized by the first order rate constant kI. It was shown that an increase in NaCl concentration caused a decrease in the kI value, suggesting a slowdown of the UV Phb structural reorganization. Circular dichroism data confirmed this conclusion. Arginine is widely used in biotechnology as an agent suppressing protein aggregation. However, arginine is a charged molecule, and, when studying the action of arginine on protein aggregation, the effects of ionic strength should be taken into account. To evaluate the effect of arginine, experiments were conducted at fixed values of ionic strength (0.15 M and 0.5 M). It was shown that at a low ionic strength arginine (0-0.13 M) accelerated the process of protein aggregation, whereas at higher ionic strength arginine (0-0.48 M) acted as an aggregation suppressor. PMID- 30001606 TI - In vitro neuroprotective effects of naringenin nanoemulsion against beta-amyloid toxicity through the regulation of amyloidogenesis and tau phosphorylation. AB - Alzheimer's disease (AD) is an increasingly prevalent neurological disorder of the central nervous system. There is growing evidence that amyloidogenesis is a pathological hallmark for AD; this leads to the formation of senile plaques. Naringenin is a bioflavonoid which has neuroprotective effects through its antioxidant and anti-inflammatory properties. However, its clinical usage is limited due to its inefficient transport across biological membranes. In the present study, a naringenin nanoemulsion was prepared and its neuroprotective effects were tested against beta-amyloid induced neurotoxicity in a human neuroblastoma cell line (SH-SY5Y). The optimised, naringenin-loaded nanoemulsion formulation had a droplet size of 113.83 +/- 3.35 nm and around 50 nm, as assessed respectively by photon correlation spectroscopy and transmission electron microscopy. The preparation showed a low polydispersity index (0.312 +/- 0.003), a high zeta potential (12.4 +/- 1.05) and a high percentage transmittance (97.01%). The neuroprotective activity of naringenin nanoemulsions was determined by assessing their ability to protect SH-SY5Y neuroblastoma cells against the neurotoxic effect of beta amyloid (Abeta). Abeta-induced production of reactive oxygen species (ROS), amyloid precursor protein (APP), beta-secretase (BACE), total tau and phosphorylated tau (pT231) was also determined. The naringenin loaded nanoemulsion significantly alleviated the direct neurotoxic effects of Abeta on SH-SY5Y cells; this was associated with a down-regulation of APP and BACE expression, indicating reduced amyloidogenesis. Furthermore, it decreased the levels of phosphorylated tau in SH-SY5Y cells exposed to Abeta. These results suggest that a naringenin-loaded nanoemulsion could be a promising agent for the treatment of Alzheimer's disease. PMID- 30001607 TI - Improving antiproliferative effect of the nevirapine on Hela cells by loading onto chitosan coated magnetic nanoparticles as a fully biocompatible nano drug carrier. AB - The freshly prepared magnetic iron oxide nanoparticles (MIONPs) were coated with SiO2 and then modified with a Si-based linker (SiL) having chlorine atom at the end of its chain. The resulting chlorine functionalized MIONPs were bonded to chitosan (CT) in trimethylamine solution. Then nevirapine (Nev) drug was loaded into above CT-SiL-MIONPs system and resulting Nev-loaded magnetic nanoparticles, Nev@CT-SiL-MIONPs, studied using different techniques. Furthermore, the value of Nev loading efficiency and also controlled delivery effect of Nev@CT-SiL-MIONP particles was determined by UV-vis spectrometer. Interestingly, the above nanomaterial showed a superparamagnetic property with a saturation magnetization value of 35.66 emu/g, indicating that it has an excellent potential application in the treatment of cancer using magnetic targeting drug delivery technology. Furthermore, the in-vitro antiproliferative activity of Nev@CT-SiL-MIONPs against cancer cell line (Hela) was compared with nevirapine using MTT colourimetric assay. The Nev-loaded magnetic nanoparticles were shown to be more effective antiproliferative on Hela cancer cell lines than nevirapine itself. Moreover, in vitro ct-DNA binding studies were investigated by UV-Vis and competitive fluorescence spectroscopies. The results showed that DNA aggregated on Nev-loaded nanoparticles via groove binding mode. PMID- 30001608 TI - Halomonas smyrnensis as a cell factory for co-production of PHB and levan. AB - Levan is a fructan type polysaccharide that has long been considered as an industrially important biopolymer however its limited availability is mainly due to the bottlenecks associated with its large-scale production. To overcome such bottlenecks in the commercialization of this very promising polysaccharide, co production of levan with polyhydroxyalkanoates (PHAs) by halophilic Halomonas smyrnensis cultures has been proposed in this study for the first time. After in silico and in vitro assessment of PHA accumulation, fermentation profiles for levan and PHA concentrations were obtained in the presence of sucrose and glucose and the PHA granules observed by TEM were found to be poly(3-hydroxybutyrate) (PHB) after detailed structural characterization by GC-MS, DSC, FTIR and NMR. Six nutrient limitation strategies based on nitrogen (N) and phosphorus (P) were tested but highest levan and PHB yields were obtained under unlimited conditions. H. smyrnensis is proved to co-produce PHB and levan while using inexpensive carbon sources which is a commercially successful microbial cell factory system showing a great potential in lowering manufacturing costs and aiming for a zero waste policy within the biorefinery concept. PMID- 30001610 TI - Neuroprotective Effects of 6-Shogaol and Its Metabolite, 6-Paradol, in a Mouse Model of Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease characterized by progressive neuronal loss, neuroinflammation, axonal degeneration, and demyelination. Previous studies have reported that 6-shogaol, a major constituent of ginger (Zingiber officinale rhizome), and its biological metabolite, 6-paradol, have anti-inflammatory and anti-oxidative properties in the central nervous system (CNS). In the present study, we investigated whether 6-shogaol and 6-paradol could ameliorate against experimental autoimmune encephalomyelitis (EAE), a mouse model of MS elicited by myelin oligodendrocyte glycoprotein (MOG35-55) peptide immunization with injection of pertussis toxin. Once-daily administration of 6 shogaol and 6-paradol (5 mg/kg/day, p.o.) to symptomatic EAE mice significantly alleviated clinical signs of the disease along with remyelination and reduced cell accumulation in the white matter of spinal cord. Administration of 6-shogaol and 6-paradol into EAE mice markedly reduced astrogliosis and microglial activation as key features of immune responses inside the CNS. Furthermore, administration of these two molecules significantly suppressed expression level of tumor necrosis factor-alpha, a major proinflammatory cytokine, in EAE spinal cord. Collectively, these results demonstrate therapeutic efficacy of 6-shogaol or 6-paradol for EAE by reducing neuroinflammatory responses, further indicating the therapeutic potential of these two active ingredients of ginger for MS. PMID- 30001609 TI - ZFP36L1 and AUF1 Induction Contribute to the Suppression of Inflammatory Mediators Expression by Globular Adiponectin via Autophagy Induction in Macrophages. AB - Adiponectin, a hormone predominantly originated from adipose tissue, has exhibited potent anti-inflammatory properties. Accumulating evidence suggests that autophagy induction plays a crucial role in anti-inflammatory responses by adiponectin. However, underlying molecular mechanisms are still largely unknown. Association of Bcl-2 with Beclin-1, an autophagy activating protein, prevents autophagy induction. We have previously shown that adiponectin-induced autophagy activation is mediated through inhibition of interaction between Bcl-2 and Beclin 1. In the present study, we examined the molecular mechanisms by which adiponectin modulates association of Bcl-2 and Beclin-1 in macrophages. Herein, we demonstrated that globular adiponectin (gAcrp) induced increase in the expression of AUF1 and ZFP36L1, which act as mRNA destabilizing proteins, both in RAW 264.7 macrophages and primary peritoneal macrophages. In addition, gene silencing of AUF1 and ZFP36L1 caused restoration of decrease in Bcl-2 expression and Bcl-2 mRNA half-life by gAcrp, indicating crucial roles of AUF1 and ZFP36L1 induction in Bcl-2 mRNA destabilization by gAcrp. Moreover, knock-down of AUF1 and ZFP36L1 enhanced interaction of Bcl-2 with Beclin-1, and subsequently prevented gAcrp-induced autophagy activation, suggesting that AUF1 and ZFP36L1 induction mediates gAcrp-induced autophagy activation via Bcl-2 mRNA destabilization. Furthermore, suppressive effects of gAcrp on LPS-stimulated inflammatory mediators expression were prevented by gene silencing of AUF1 and ZFP36L1 in macrophages. Taken together, these results suggest that AUF1 and ZFP36L1 induction critically contributes to autophagy induction by gAcrp and are promising targets for anti-inflammatory responses by gAcrp. PMID- 30001611 TI - Single aortic branch device: the Mona LSA experience. AB - INTRODUCTION: Endovascular treatment of aortic arch pathologies is challenging due to its complex anatomical architecture and the presence of vital collateral branches. This paper aims to provide an overview of the currently available and future endovascular options for these diseases, particularly regarding branched stent-grafts and the Mona-LSA device. EVIDENCE ACQUISITION AND EVIDENCE SYNTHESIS: After discussing the indications for revascularization of supra-aortic trunks in endovascular aortic repair, we present the principles, benefits and drawbacks of the main modern methods to overcome an insufficient proximal landing zone, ie. hybrid repair with associated surgical bypass, chimney or snorkel grafts, fenestrated stent-grafts and branched stent-grafts. Subsequently, we detail the technical specifications of the two main branched stent-graft devices under study: the Valiant Mona-LSA (Medtronic, Santa Rosa, Calif) and the W.L. Gore (Flafstaff, AZ) arch branch device. The steps of the deployment procedure are described from examples of branched stent graft aortic repair of aortic dissection and aneurysm of the left subclavian artery. Finally, available results of the premarket trial on the Mona-LSA branched stent graft device are recalled. CONCLUSIONS: Branched stent grafts represent a promising therapeutic option for pathologies of the aortic arch with insufficient proximal landing zone or mandatory revascularization of supra-aortic trunks. Further studies are needed to specify their indications, long-term effectiveness and safety. PMID- 30001612 TI - Internal iliac artery preservation strategies in the endovascular treatment of aortoiliac aneurysms. AB - INTRODUCTION: Common iliac aneurysms are present in up to 40% of abdominal aortic aneurysms and frequently impair distal landing zones for endovascular aneurysm repair. Several techniques have been developed in order to overcome these issues, with different applications and conflicting results. Although long-term outcomes of hypogastric exclusion are favorable, the risks of pelvic ischemia and morbidity rates are high. We aim to review current hypogastric preservation strategies used in the endovascular treatment of aortoiliac aneurysms. EVIDENCE ACQUISITION: A thorough non-systematic review of the literature was conducted using PubMed/Medline. Forty-five articles were included, according to their scientific relevance and relation with the subject. EVIDENCE SYNTHESIS: The bell bottom technique can be used in common iliac arteries with up to 24 mm of diameter. Although apparently effective in the short-term, long-term durability is questionable with reported type 1b endoleak rates varying from 3.4-7.8% and high reintervention rates reported. Iliac branches have better long-term outcomes, with 90.4% patency rates and 91.8% freedom from re-intervention at 10 years' follow-up. Nonetheless, its widespread application is limited by complex anatomies and increased costs. Finally, parallel graft techniques are an effective option for hostile anatomies unsuitable for other techniques. Endoleak due to gutter development remains the biggest limitation for its long-term durability and solid evidence regarding its application is still lacking. CONCLUSIONS: When determining the appropriate hypogastric preservation strategy, several factors should be considered. Anatomic criteria, life expectancy as well as physical and sexual activity are the most important criteria. Procedure complexity and cost should also be accounted for. PMID- 30001613 TI - Proposal for improving the education and licensing examination for medical record administrators in Korea. PMID- 30001614 TI - Acquired Hemophilia in a Patient Presenting with Swollen Left Limb. AB - Acquired hemophilia is a rare, potentially life-threatening disease that usually remains under-recognized especially in a primary setting; thus, diagnosing this disease is very challenging. Given its prevalence in elderly patients, awareness and diagnosis of this condition in the aging population (particularly those with unexplained bleeding or prolonged activated partial thromboplastin time) should be improved and better managed by the clinicians. Early diagnosis and prompt treatment are usually effective in preventing the adverse outcomes of this disease. In this report, we discuss a case of an elderly patient with acquired hemophilia who initially presented with swelling of his lower left limb. The diagnosis of acquired hemophilia was made a month after the appearance of symptoms. Early diagnosis with proper treatment could have been provided to this patient, if the initial assessment had been thoroughly conducted. PMID- 30001615 TI - Accuracy of Endoscopic Diagnosis of Mild Atrophic Gastritis with Helicobacter pylori Infection. PMID- 30001616 TI - Prospective Assessment of the Performance of a New Fine Needle Biopsy Device for EUS-Guided Sampling of Solid Lesions. AB - BACKGROUND/AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) remains the most common EUS-guided tissue acquisition technique. This study aimed to evaluate the performance of a new Franseen tip fine needle biopsy (FNB) device for EUSguided sampling of solid lesions and compare it with the historical FNA technique. METHODS: Acquire(r) 22 G FNB needle (Boston Scientific Co., Natick, MA, USA) was used for solid tumor sampling (Study group). Tissue was collected for rapid on-site evaluation, and touch and crush preparations were made. Historical EUS-FNA samples obtained using Expect(r) 22 G FNA needle (Boston Scientific Co.) were used as controls (Control group). All specimens were independently evaluated by two cytopathologists blinded to the formal cytopathological diagnosis. RESULTS: Mean cell block histology scores were significantly higher (p=0.046) in the FNB group (51 samples) despite a significantly lower (p<0.001) mean number of passes compared to the FNA group (50 specimens). The overall diagnostic yields for the FNB vs. FNA groups were 96% vs. 88%. The degree of tumor differentiation was adequately assessed in all cell block qualifying lesions in the FNB group. Two patients developed post-FNB abdominal pain. CONCLUSION: The new Franseen tip FNB device provides histologically superior and cytologically comparable specimens to those obtained by FNA, but with fewer passes. PMID- 30001617 TI - Synthesis of Modular Brush Polymer-Protein Hybrids Using Diazotransfer and Copper Click Chemistry. AB - Proteoglycans are important brush-like biomacromolecules, which serve a variety of functions in the human body. While protein-bottlebrush hybrids are promising proteoglycan mimics, many challenges still exist to robustly produce such polymers. In this paper, we report the modular synthesis of protein-brush hybrids containing elastin-like polypeptides (ELP) as model proteins by copper-catalyzed azide-alkyne cycloaddition. We exploit the recently discovered imidazole-1 sulfonyl azide (ISA) in a diazotransfer reaction to introduce an N-terminal azide onto an ELP. Next, we use a click reaction to couple the azido-ELP to an alkyne terminated amine-rich polymer followed by a second diazotransfer step to produce an azide-rich backbone that serves as a scaffold. Finally, we used a second click reaction to graft alkyne-terminated poly(oligoethylene glycol methacrylate) (POEGMA) bristles to the azide-rich backbone to produce the final protein bottlebrush hybrid. We demonstrate the effectiveness of this synthetic path at each step through careful characterization with 1H NMR, FTIR, GPC, and diagnostic test reactions on SDS-PAGE. Final reaction products could be consistently obtained for a variety of different molecular weight backbones with final total grafting efficiencies around 70%. The high-yielding reactions employed in this highly modular approach allow for the synthesis of protein-bottlebrush hybrids with different proteins and brush polymers. Additionally, the mild reaction conditions used have the potential to avoid damage to proteins during synthesis. PMID- 30001618 TI - Tripeptide-Stabilized Oil-in-Water Nanoemulsion of an Oleic Acids-Platinum(II) Conjugate as an Anticancer Nanomedicine. AB - We report a nanoemulsion (NE) which is stabilized by self-assembling tripeptide lysine-tyrosine-phenylalanine (KYF) and encapsulates an oleic acids-platinum conjugate formed using simple Pt (II) coordination chemistry. The KYF-Pt-NE is evaluated both in cultured ovarian cancer cells and in an in vivo preclinical cancer model and shows pH dependent Pt (II) release, which is low at physiological pH and enhanced at tumoral pH. The biological activity of KYF-Pt NE, evaluated in multiple ovarian cancer cell lines, is significantly higher when compared to the analogous Pt (II) complex used in the clinic. Concurrently, the KYF-Pt-NE platform shows good compatibility with the immune system. Preliminary in vivo testing of KYF-Pt-NE with tumor bearing mice indicates efficient Pt (II) delivery to the tumor. Together, these results demonstrate the potential of peptide-stabilized nanoemulsions, specifically KYF-Pt-NE as an effective nanomedicine against cancer. PMID- 30001619 TI - Transition-Metal Dihydride Monolayers: A New Family of Two-Dimensional Ferromagnetic Materials with Intrinsic Room-Temperature Half-Metallicity. AB - Two-dimensional (2D) ferromagnetic materials with intrinsic half-metallicity are highly desirable for nanoscale spintronic applications. Here, we predict a new and stable family of 2D transition-metal dihydride (MH2; M = Sc, Ti, V, Cr, Fe, Co, Ni) monolayers with novel properties. Our density functional theory computation shows that CoH2 and ScH2 monolayers are ferromagnetic metals, while the others are antiferromagnetic semiconductors. In particular, the CoH2 monolayer is a perfect half-metal with a wide spin gap of 3.48 eV. The ScH2 monolayer can also possess half-metallicity through hole doping. Most importantly, our Monte Carlo simulations show that the CoH2 monolayer possesses an above-room-temperature Curie point (339 K), while that of the ScH2 monolayer can also reach 160 K. A synthetic approach is proposed to realize CoH2 and ScH2 monolayers in the laboratory. Notably, their half-metallicity can be well maintained on substrates. The new family of MH2 monolayers are promising functional materials for spintronic applications due to their novel magnetic properties. PMID- 30001620 TI - Influence of a "Dangling" Co(II) Ion Bound to a [MnCo3O4] Oxo Cubane. AB - Cobalt(II), in the presence of acetate and nitrate, quantitatively adds to the manganese-cobalt oxido cubane MnIVCoIII3O4(OAc)5(py)3 (1) to furnish the pentametallic dangler complex MnIVCoIII3CoIIO4(OAc)6(NO3)(py)3 (2). Complex 2 is structurally reminiscent of photosystem II's oxygen-evolving center, and is a rare example of a transition-metal "dangler" complex. Superconducting quantum interference device magnetometry and density functional theory calculations characterize 2 as having an S = 0 ground state arising from antiferromagnetic coupling between the CoII and MnIV ions. At higher temperatures, an uncoupled state dominates. The voltammogram of 2 has four electrochemical events, two more than that of its parent cubane 1, suggesting that addition of the dangler increases available redox states. Structural, electrochemical, and magnetic comparisons of complexes 1 and 2 allow a better understanding of the dangler's influence on a cubane. PMID- 30001621 TI - Electrodeposition of Zwitterionic PEDOT Films for Conducting and Antifouling Surfaces. AB - Conferring antifouling properties can extend the use of conducting polymers in biosensors and bioelectronics under complex biological conditions. On the basis of the antifouling properties of a series of zwitterionic polymers, we synthesized new thiophene-based compounds bearing a phosphorylcholine, carboxybetaine, or sulfobetaine pendant group. The monomers were synthesized by a facile reaction of thiol-functionalized 3,4-ethylenedioxythiophene with zwitterionic methacrylates. Electrochemical copolymerization was performed to deposit zwitterionic poly(3,4-ethylenedioxythiophene) (PEDOT) films with tunable conducting and antifouling properties on a conducting substrate. Electrochemical impedance spectroscopy showed that the conductivity and capacitance decreased with increasing zwitterionic content in the films. Protein adsorption and cell adhesion studies showed the effects of the type and content of zwitterions on the antifouling characteristics. Optimization of the electrodeposition conditions enabled development of both conducting and antifouling polymer films. These antifouling conjugated functional polymers have promising applications in biological environments. PMID- 30001622 TI - Designs of Zwitterionic Interfaces and Membranes. AB - Zwitterionic materials are the latest generation of materials for nonfouling interfaces and membranes. They outperform poly(ethylene glycol) derivatives because they form tighter bonds with water molecules and can trap more water molecules. This feature article summarizes our laboratory's fundamental developments related to the functionalization of interfaces and membranes using zwitterionic materials. Our molecular designs of zwitterionic polymers and copolymers, sulfobetaine-based, carboxybetaine-based, or phosphobetaine-based, are first reviewed. Then, the strategies used to functionalize surfaces/membranes by coating, grafting onto, grafting from, or in situ modification are examined and discussed, and the third part of this article shifts the focus to key applications of zwitterionic materials. Finally, some potential future directions for molecular designs, functionalization processes, and applications are presented. PMID- 30001623 TI - Kinetic Trapping of Folded Proteins Relative to Aggregates under Physiologically Relevant Conditions. AB - Anfinsen's thermodynamic hypothesis does not explicitly take into account the possibility of protein aggregation. Here, we introduce a cyclic-perturbation approach to prove that not only the native state but also soluble aggregates of most proteins can be highly populated under mild, physiologically relevant conditions, even at very low concentration. Surprisingly, these aggregates are not necessarily amyloid in nature and are usually not observed in bioactive proteins due to the extremely low kinetic flux from the native state toward a region of the chemical-potential landscape encoding aggregates. We first illustrate this concept for the representative model protein apomyoglobin-at room temperature and no denaturant-and demonstrate kinetic trapping of the native state relative to at least two different types of soluble, predominantly nonamyloid aggregates. The concentration and temperature dependence of aggregation confirm the above scenario. Extension of our analysis to the Escherichia coli proteome shows that the majority of the soluble bacterial proteome is also kinetically trapped in the nonaggregated state. Hence, the existence and low kinetic accessibility of large aggregates at room temperature and pH 6-7 is a general phenomenon. We also show that the average critical protein concentration for aggregation of most of the bacterial proteome is extremely small, much lower than the typical cellular protein concentration. Hence, the thermodynamic driving force for protein aggregation is large even if aggregation does not usually occur in healthy cells due to kinetic trapping. A broader view of Anfinsen's thermodynamic hypothesis encompassing all protein states, including aggregates, is necessary to understand the behavior of proteins in their natural environment. PMID- 30001624 TI - Unexpected Hard Protein Behavior of BSA on Gold Nanoparticle Caused by Resveratrol. AB - The understanding of the interactions between nanomaterials, biomolecules, and polyphenols is fundamental in food chemistry, toxicology, and new emerging fields, such as nanomedicine. Here, we investigated the effect of the resveratrol, a principal actor in drug-delivery application on the interaction between bovine serum albumin (BSA), employed as a vector for the delivery of polyphenol drugs, and gold nanoparticle (gNP), the most promising tool in theranostic applications. Through a combination of experimental techniques, which includes an initial evaluation by dynamic light scattering and surface plasmon resonance spectroscopy, we were able to evaluate the evolution of the gold nanoparticle aggregation with increasing ionic strength and the consequences of the BSA and resveratrol addition. To investigate the mechanisms of the interactions, we pursued at the single-molecule level using solid-state nanopore and fluorescence correlation spectroscopy. Our results show that without resveratrol, the BSA is adsorbed on the gNP in water or saline solution. In the presence of resveratrol, the BSA is normally absorbed on gNP in water, but the salt addition leads to its desorption. The resveratrol clearly plays a fundamental role, changing the protein behavior and making the BSA adsorption a reversible process in the presence of salt. PMID- 30001625 TI - Operando Direct Observation of Charge Accumulation and the Correlation with Performance Deterioration in PTB7 Polymer Solar Cells. AB - Polymer solar cells are one of the promising energy sources because of the easy solution-processable production with large area at a low cost without toxicity. Among the polymer materials, a donor-acceptor conjugated copolymer PTB7 has been extensively studied because of the typical high-performance polymer solar cells. Here, we show operando direct observation of charge accumulation in PTB7:PC71BM blend solar cells from a microscopic viewpoint using electron spin resonance spectroscopy. The accumulation of ambipolar charges in the PTB7-based cells is directly observed for the first time, which shows a clear correlation with the performance deterioration during device operation. The sites of the ambipolar charge accumulation are elucidated at the molecular level, whose information would be useful for improving the cell durability in addition to the performance improvement. PMID- 30001626 TI - Conductive and Chiral Polymer-Modified Metal-Organic Framework for Enantioselective Adsorption and Sensing. AB - We reported integration of conductivity, chirality, and porosity into MIL 101@chiral-PANI composite for synchronous chiral recognition, adsorption, and sensing toward enantiomers. The core-shell structure of MIL-101@chiral-PANI was characterized in detail by Fourier transform infrared and circular dichroism spectroscopy as well as scanning electron microscopy and transmission electron microscopy. Adsorption behaviors of carvone enantiomers over chiral PANI and MIL 101@chiral-PANI are satisfied with pseudo-first-order fitting. In comparison with chiral PANI, MIL-101@c-PANI exhibits a better enantioselectivity and much higher (>5-fold) adsorption amount over l-carvone than d-carvone. And MIL-101@c-PANI is able to recognize the chirality of carvone via electrochemical sensing, taking advantage of the electric conductivity of chiral PANI. Our result demonstrated the feasibility of applying achiral MOF for enantioselective sensing and adsorption via installing chiral and conductive gates. And this chiral polymer modification strategy represents a universal way to entitle achiral MOFs with chiral functions. PMID- 30001627 TI - SmMYB111 Is a Key Factor to Phenolic Acid Biosynthesis and Interacts with Both SmTTG1 and SmbHLH51 in Salvia miltiorrhiza. AB - Transcription factors that include myeloblastosis (MYB), basic helix-loop-helix (bHLH), and tryptophan-aspartic acid (WD)-repeat protein often form a ternary complex to regulate the phenylpropanoid pathway. However, only a few MYB and bHLH members involved in the biosynthesis of salvianolic acid B (Sal B) have been reported, and little is known about Sal B pathway regulation by the WD40 protein transparent testa glabra 1 (TTG1)-dependent transcriptional complexes in Salvia miltiorrhiza. We isolated SmTTG1 from that species for detailed functional characterization. Enhanced or reduced expression of SmTTG1 was achieved by gain- or loss-of-function assays, respectively, revealing that SmTTG1 is necessary for Sal B biosynthesis. Interaction partners of the SmTTG1 protein were screened by yeast two-hybrid (Y2H) assays with the cDNA library of S. miltiorrhiza. A new R2R3-MYB transcription factor, SmMYB111, was found through this screening. Transgenic plants overexpressing or showing reduced expression of SmMYB111 upregulated or deregulated, respectively, the yields of Sal B. Both Y2H and bimolecular fluorescent complementation experiments demonstrated that SmMYB111 interacts with SmTTG1 and SmbHLH51, a positive regulator of the phenolic acid pathway. Our data verified the function of SmTTG1 and SmMYB111 in regulating phenolic acid biosynthesis in S. miltiorrhiza. Furthermore, ours is the first report of the potential ternary transcription complex SmTTG1-SmMYB111-SmbHLH51, which is involved in the production of Sal B in that species. PMID- 30001628 TI - Cyanide Docking and Linkage Isomerism in Models for the Artificial [FeFe] Hydrogenase Maturation Process. AB - Linkage isomerization of the cyanide on the [2Fe] subsite of the [FeFe]-H2ase active site was reported to occur during the docking of various synthetic diiron complexes onto a carrier protein, apo-HydF, as the initial step for the artificial maturation of the [FeFe]-H2ase enzyme (Berggren et al., Nature, 2013, 499, 66-70). An investigation of our triiron organometallic models (FeFe-CN/NC Fe') revealed that, once a Fe-CN-Fe connection is formed, high barriers prevent such cyanide linkage isomerization ( Chem. Sci., 2016, 7, 3710-3719). To explore effects of variable oxidation states of the receiver unit, we introduce copper(I/II) fragments, precedented in Holm's models of cytochrome c oxidase to induce cyanide isomerization (Cu-CN/NC-Fe), to the diiron synthetic analogues of [FeFe]-H2ase. For comparison, a zinc variant of the cytochrome c oxidase model is also examined. According to the oxidation state of copper, a cyanide flip was induced during the formation of both Zn-NC-Cu and FeFe-CN-Cu complexes. Density functional theory calculations are used to predict the mechanisms for such linkage isomerization and account for optimal conditions including oxidation states of metals, spin states, and solvation. These results on synthetic paradigms imply a role for oxidation state control of cyanide isomerization during hydrogenase active site assembly. PMID- 30001629 TI - Design of hybrid molecular brushes with reversible surface adaptability on exposure to specific solvents. AB - Hybrid molecular brushes (HMBs) are macromolecules made of a linear backbone and polymeric side chains that differ in their chemical nature. The authors developed a new method of synthesis of HMB with chitosan (CHI) backbone. In the first step, chitosan-graft-polylactide (CHI-g-PLA) was synthesized by interfacial ring opening polymerization of lactide initiated from CHI. CHI-g-PLA is characterized for its molecular weight and structure. In the second step, polyvinylpyrrolidone (PNVP) or polyacrylamide (PAAm) is grafted by radical polymerization from the CHI in CHI-g-PLA to form CHI-g-PLA-g-PNVP and CHI-g-PLA-g-PAAm. This results in the formation of HMB, with hydrophobic PLA and hydrophilic PNVP or PAAm side chains grafted to CHI. The chemical structure and thermal behavior of the HMBs are characterized. The morphology of CHI-g-PLA as well as the HMBs is determined using atomic force microscopy (AFM). Both the HMBs tethered to separate surfaces exhibit reversible switching between the hydrophilic and hydrophobic polymers on exposure to specific solvents. This is studied by AFM and water contact angle measurements. Hence, the authors developed a method for synthesis of HMB that can be applied for surface modification. PMID- 30001630 TI - The specific role of O6-methylguanine-DNA methyltransferase inhibitors in cancer chemotherapy. AB - The DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), can confer resistance to guanine O6-alkylating agents. Therefore, inhibition of resistant MGMT protein is a practical approach to increase the anticancer effects of such alkylating agents. Numerous small molecule inhibitors were synthesized and exhibited potential MGMT inhibitory activities. Although they were nontoxic alone, they also inhibited MGMT in normal tissues, thereby enhancing the side effects of chemotherapy. Therefore, strategies for tumor-specific MGMT inhibition have been proposed, including local drug delivery and tumor-activated prodrugs. Over-expression of MGMT in hematopoietic stem cells to protect bone marrow from the toxic effects of chemotherapy is also a feasible selection. The future prospects and challenges of MGMT inhibitors in cancer chemotherapy were also discussed. PMID- 30001632 TI - The Dermatophagoides pteronyssinus Molecular Sensitization Profile of Allergic Rhinitis Patients in Central China. AB - Background House dust mites (HDMs) are the major aeroallergens in patients with rhinitis and/or asthma in China. However, the molecular sensitization of HDM is varied in different regions. Objective To investigate the Dermatophagoides pteronyssinus ( Der p) molecular sensitization profile of allergic rhinitis (AR) patients in Central China. Methods AR patients with positive skin prick tests to Der p were enrolled in our study. Specific immunoglobulin E (sIgE) for Der p, Dermatophagoides farinae ( Der f), Acarus siro ( Aca s), Blomia tropicalis ( Blo t), and Der p components Der p1, Der p2, and Der p10 were measured in all patients. Results A total of 130 patients were included. The overall prevalence of positive serum sIgE was 99.2% for Der p, 98.5% for Der f, 81.5% for Aca s, 83.1% for Blo t, 71.5% for Der p1, 64.6% for Der p2, and 11.5% for Der p10. HDM AR patients with asthma displayed significantly higher concentrations of sIgE to Der p, Der f, Der p1, and Der p2 than did those without asthma ( P < .001). The prevalence of asthma in HDM-AR patients was higher among the patients sensitized to both Der p1 and Der p2 (62.8%) than those sensitized to only 1 allergen ( Der p1 26.7% or Der p2 16.7%; P < .05) or nonsensitized to Der p1 and Der p2 (19.4%; P < .001). Conclusion Der p has high cross-reactivity with other mite species. Der p1 and Der p2 are the major components to induce Der p sensitization among AR patients in Central China. Sensitization to both Der p1 and Der p2 may be a risk factor for developing asthma in HDM-AR patients. PMID- 30001633 TI - Neuroprotective effect of agmatine (decarboxylated l-arginine) against oxidative stress and neuroinflammation in rotenone model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer's disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and nonmotor symptoms. The neuropathological hallmarks of PD are well reported, but the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, and neuroinflammation play vital roles in the progress of the disease. The current study was established to investigate the neuroprotective effect of agmatine on a rotenone (ROT)-induced experimental model of PD. Adult male Sprague Dawley rats were subcutaneously injected with ROT at a dose of 2 mg/kg body weight for 35 days. Agmatine was injected intraperitoneally at 50 and 100 mg/kg body weight, 1 h prior to ROT administration. ROT-treated rats that received agmatine showed better performance on beam walking and an elevated number of rears within the cylinder test. In addition, agmatine reduced midbrain malondialdehyde as an indication of lipid peroxidation, pro-inflammatory cytokines including tumor necrosis factor alpha and interleukin-1beta, and glial fibrillary acidic protein. Moreover, agmatine was responsible for preventing loss of tyrosine hydroxylase-positive neurons. In conclusion, our study showed that agmatine possesses a dose-dependent neuroprotective effect through its antioxidant and anti-inflammatory activities. These findings need further clinical investigations of agmatine as a promising neuroprotective agent for the future treatment of PD. PMID- 30001631 TI - Selective inhibition of carbonic anhydrase-IX by sulphonamide derivatives induces pH and reactive oxygen species-mediated apoptosis in cervical cancer HeLa cells. AB - Selective inhibition with sulphonamides of carbonic anhydrase (CA) IX reduces cell proliferation and induces apoptosis in human cancer cells. The effect on CA IX expression of seven previously synthesised sulphonamide inhibitors, with high affinity for CA IX, as well as their effect on the proliferation/apoptosis of cancer/normal cell lines was investigated. Two normal and three human cancer cell lines were used. Treatment resulted in dose- and time-dependent inhibition of the growth of various cancer cell lines. One compound showed remarkably high toxicity towards CA IX-positive HeLa cells. The mechanisms of apoptosis induction were determined with Annexin-V and AO/EB staining, cleaved caspases (caspase-3, caspase-8, caspase-9) and cleaved PARP activation, reactive oxygen species production (ROS), mitochondrial membrane potential (MMP), intracellular pH (pHi), extracellular pH (pHe), lactate level and cell cycle analysis. The autophagy induction mechanisms were also investigated. The modulation of apoptotic and autophagic genes (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin and LC3) was measured using real time PCR. The positive staining using gamma-H2AX and AO/EB dye, showed increased cleaved caspase-3, caspase-8, caspase-9, increased ROS production, MMP and enhanced mRNA expression of apoptotic genes, suggesting that anticancer effects are also exerted through its apoptosis inducing properties. Our results show that such sulphonamides might have the potential as new leads for detailed investigations against CA IX-positive cervical cancers. PMID- 30001634 TI - Two new tetracyclic triterpenoids from the endophytic fungus Hypoxylon sp. 6269. AB - Two new tetracyclic triterpenoids, integracide E (1) and isointegracide E (2), as well as three known secondary metabolites (i.e. integracide A (3), 2 deoxyintegracide A (4) and 2-deoxyintegracide B (5)), were isolated from mycelium of the endophytic fungus Hypoxylon sp. 6269. Structures were determined by a combination of 1D and 2D NMR techniques and mass spectrometry. All of the compounds were tested for their anti-HIV-1 integrase activities. PMID- 30001635 TI - Regulatory Roles of Osteopontin in Production of Monocyte-Origin MCP-1. AB - Osteopontin (OPN), expressed by various immune cells, plays a critical role in leukocyte migration. Although OPN was found to selectively induce the expression of proinflammatory chemokines, the molecular mechanisms that control OPN gene expression and its underlying mechanism for migration and recruitment of inflammatory cells remain largely unknown. In this study, real-time polymerase chain reaction and enzyme-linked immunosorbent assay were used to determine OPN and monocyte chemoattractant protein 1 (MCP-1) expression. Signaling and molecular events between OPN and MCP-1 were analyzed by Western blot. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Our data indicated that phosphoinositide 3-kinase (PI3K), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) that are activated upon stimulation with lipopolysaccharide were shown to upregulate OPN expression. Endogenous production of OPN was attributable to increased production of MCP-1, and this effect could be blocked by an anti-beta1 integrin antibody and JNK and p38 kinase inhibitors. Furthermore, we found that the effect of OPN on inflammatory cell migration was mediated through inducing the expression of MCP-1 in monocytes. These results support a role of OPN in monocyte migration via MCP 1, which may represent an additional mechanism for innate and adaptive immune responses. PMID- 30001636 TI - Interplay of Autophagy Inducer Rapamycin and Proteasome Inhibitor MG132 in Reduction of Foam Cell Formation and Inflammatory Cytokine Expression. AB - MG132 is a pivotal inhibitor of the ubiquitin-proteasome system (UPS), and rapamycin (RAPA) is an important inducer of autophagy. MG132 and RAPA have been shown to be effective agents that can cure multiple autoimmune diseases by reducing inflammation. Although individual MG132 and RAPA showed protective effects for atherosclerosis (AS), the combined effect of these two drugs and its molecular mechanism are still unclear. In this article we investigate the regulation of oxidative modification of low-density lipoprotein (ox-LDL) stress and foam cell formation in the presence of both proteasome inhibitor MG132 and the autophagy inducer RAPA to uncover the molecular mechanism underlying this process. We established the foam cells model by ox-LDL and an animal model. Then, we tested six experimental groups of MG132, RAPA, and 3MA drugs. As a result, RAPA-induced autophagy reduces accumulation of polyubiquitinated proteins and apoptosis of foam cells. The combination of MG132 with RAPA not only suppressed expression of the inflammatory cytokines and formation of macrophage foam cells, but also significantly affected the NF-kappaB signaling pathway and the polarization of RAW 264.7 cells. These data suggest that the combination of proteasome inhibitor and autophagy inducer ameliorates the inflammatory response and reduces the formation of macrophage foam cells during development of AS. Our research provides a new way to suppress vascular inflammation and stabilize plaques of late atherosclerosis. PMID- 30001637 TI - Estimate of ischemic stroke prevalence according to a novel 4-tiered classification of left ventricular hypertrophy: Insights from the general Chinese population. AB - BACKGROUND: Recently, a novel 4-tiered classification of left ventricular hypertrophy (LVH) based on ventricular dilatation (indexed LV end-diastolic volume [EDV]) and concentricity (mass/EDV0.67) has improved all-cause and cardiovascular mortality risk stratification. However, their possible association with ischemic stroke has not been extensively evaluated in the general population. METHODS: We evaluated a cross-sectional study of 11,037 subjects from the general population of China in whom echocardiographic and ischemic stroke data were available to subdivide patients with LVH into four geometric patterns: indeterminate, dilated, thick, and both thick and dilated hypertrophy. RESULTS: Compared with normal LV geometry, indeterminate and thick hypertrophy showed a higher prevalence of ischemic stroke (P < 0.05). Ischemic stroke was significantly greater in participants with indeterminate (adjusted odd ratio [OR]:1.635, 95% confidence interval [CI]: 1.115-2.398) and thick (2.143 [1.329 3.456]) hypertrophy but not significantly in those with dilated (1.251 [0.803 1.950]) and both thick and dilated hypertrophy (0.926 [0.435-1.971]) compared with normal geometry in multivariable analysis. CONCLUSIONS: Indeterminate and thick hypertrophy were significantly associated with the presence of ischemic stroke in the general Chinese population. The new 4-tiered categorization of LVH can permit a better understanding of which subjects are at high enough risk for ischemic stroke to warrant early targeted therapy. PMID- 30001638 TI - Evaluation of the effect of the 2011 Tsunami on coastal forests by means of multiple isotopic analyses of tree-rings. AB - The March 2011 Mega-Tsunami in eastern Japan damaged at different degrees the black pine (Pinus thunbergii) forests along the coast. In order to evaluate the recovery of black pine four years later, tree-ring samples from 9 trees for the period 2002-2014 were analyzed for ring growth and stable isotopes (delta13C, delta15N and delta18O). The results showed that annual tree-ring width decreased approximately 70 % from the year 2011 to 2014 compared to the period previous to the tsunami (2002-2010). The multiple isotopic analyses showed that the reduction in growth was caused by soil salinity that prompted stomatal closure and an abrupt increase of tree-ring delta13C. Sea water deposition in the soil did not affect tree-ring delta18O values. Two years after the tsunami, decreasing tree ring delta13C values caused by apparently photosynthetic recovery did not translate into radial tree-growth, indicating a possible shift in carbon allocation to foliage and mainly roots as a defense mechanism to sodium toxicity. The dual delta13C-delta18O model explains neither the limited growth nor the subsequent recovery in delta13C. Similarly tree-ring delta15N indicated that there was no difference in nitrogen availability before and after the tsunami, suggesting that nutrients were not a limitation but rather soil salinity. PMID- 30001639 TI - Hematoxylin: Mesoamerica's Gift to Histopathology. Palo de Campeche (Logwood Tree), Pirates' Most Desired Treasure, and Irreplaceable Tissue Stain. AB - Hematoxylin is a basic dye derived from the heartwood of Palo de Campeche ( Haematoxylum campechianum), the logwood tree native to Mexico and Central America. Haematoxylum means "bloodwood" in reference to its dark-red heartwood and campechianum refers to its site of origin, the coastal city of Campeche on the Yucatan Peninsula, Mexico. Hematoxylin is colorless but it turns into the color dye hematein after oxidation (ripening). The dyeing property of logwood was well-known to the natives of the Yucatan Peninsula before the arrival of the Spaniards who brought it to Europe shortly after the discovery of the Americas. An important trade soon developed related to growing and preparing hematoxylin for dyeing fabrics. Pirates discovered that one shipload of logwood was equivalent to a year's value from any other cargo, and by 1563, more than 400 pirate vessels wandered the Atlantic Ocean and attacked Spanish galleons transporting gold, silver, and logwood from the Americas to Europe. Hematoxylin and eosin is a staining method that dates back to the late 19th century. In 1865 and 1891, Bohmer and Meyer, respectively, first used hematoxylin in combination with a mordant (alum). Later, with the use of anilines by Ehrlich, the repertoire of stains expanded rapidly resulting in the microscopic descriptions of multiple diseases that were defined by their stainable features. Today hematoxylin, along with eosin, remains the most popular stain in histology. PMID- 30001640 TI - Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence. AB - PURPOSE: Evidence on the association between depression, antidepressant use and venous thromboembolism (VTE) risk is conflicting. We conducted a systematic review and meta-analysis of published observational studies evaluating the associations of depression and antidepressant use with VTE risk. DESIGN: Eligible studies were identified in a literature search of MEDLINE, Embase, Web of Science and reference list of relevant studies up to April 2018. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were aggregated using random effects models. RESULTS: Eight observational studies with data on 960 113 nonoverlapping participants and 9027 VTE cases were included. The pooled RR (95% CI) for VTE comparing antidepressant use with no antidepressant use was 1.27 (1.06-1.51). Tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants were each associated with an increased VTE risk; 1.16 (1.06 1.27), 1.12 (1.02-1.23), and 1.59 (1.21-2.09), respectively. In pooled analysis of three studies that compared patients with depression versus individuals without depression, the RR for VTE was 1.31 (1.13-1.53). CONCLUSIONS: Pooled observational evidence suggests that depression and use of antidepressants are each associated with an increased VTE risk. The effect of antidepressant drugs on VTE may be a class effect. The mechanistic pathways underlying these associations deserve further evaluation. Systematic review registration: PROSPERO 2018: CRD42018095595 Key messages Emerging evidence suggests that depression and antidepressant use may be associated with venous thromboembolism (VTE) risk, but the evidence is conflicting. This first systematic review and meta-analysis of observational studies shows that depression and use of antidepressants are each associated with an increased risk of VTE. There may be a class effect of antidepressant drugs on VTE. PMID- 30001641 TI - The Relationship Between Ictal Multi-Unit Activity and the Electrocorticogram. AB - During neocortical seizures in patients with epilepsy, microelectrode array recordings from the ictal core show a strong correlation between the fast, cellular spiking activities and the low-frequency component of the potential field, reflected in the electrocorticogram (ECoG). Here, we model the relationship between the cellular spike activity and this low-frequency component as the input and output signals of a linear time invariant system. Our approach is based on the observation that this relationship can be characterized by a so called sinc function, the unit impulse response of an ideal (brick-wall) filter. Accordingly, using a brick-wall filter, we are able to convert ictal cellular spike inputs into an output that significantly correlates with the observed seizure activity in the ECoG [Formula: see text], while ECoG recordings of subsequent seizures within patients also show significant, but lower, correlations [Formula: see text]. Furthermore, we can produce seizure-like output signals using synthetic spike trains with ictal properties. We propose a possible physiological mechanism to explain the observed properties associated with an ideal filter, and discuss the potential use of our approach for the evaluation of anticonvulsant strategies. PMID- 30001642 TI - Chinese Herbal Medicine for Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. AB - Chinese herbal medicine (CHM) has been widely used in the treatment of advanced non-small-cell lung cancer (NSCLC), but their efficacy and safety remain controversial. We sought to comprehensively aggregate and evaluate the available evidence on the efficacy and safety of the combination treatment with CHM and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients. Our exhausted and systematical searching strategy yielded 64 related randomized controlled trials involving 4384 patients. Compared with EGFR-TKIs therapy alone, meta-analysis showed significant differences favoring the combination treatment in progression-free survival ([Formula: see text]), median survival time ([Formula: see text]), one-year survival rate ([Formula: see text]), two-year survival rate ([Formula: see text]), probability of severe toxicities ([Formula: see text]), objective response rate ([Formula: see text]), Karnofsky performance status ([Formula: see text]), and improvement in percentage of CD3[Formula: see text] T lymphocyte ([Formula: see text]) and CD4[Formula: see text] T lymphocyte ([Formula: see text]). Though these results require further confirmation, they are prone to show a potential therapeutic value of CHM in improving the clinical effect, overcoming the drug resistance and toxicities as an adjunctive therapy to EGFR-TKIs. PMID- 30001643 TI - Administrations of Preoperative Shenmai Injection and Postoperative Shenfu Injection, Two Ginseng Containing TCM Formulas, Improve Cognitive Dysfunction in Aged Rats. AB - Postoperative cognitive dysfunction (POCD) is one of the major complications in patients who have undergone surgeries. Reduction of surgery-induced inflammation and perioperative stress responses may prevent the development of POCD. As recent experimental data have suggested, Shenmai and Shenfu injections, two ginseng containing formulations, may improve cognition. We designed this study using aged rats as an experimental model to determine the effect of combined perioperative Shenmai injection and Shenfu injection in preventing the development of POCD and exploring the underlying mechanism of this intervention. Aged rats were randomized into one of the two groups. Rats in the experiment group received preoperative Shenmai injection and postoperative Shenfu injection while those of the control group did not receive this treatment. Study results indicate that the memory and cognitive ability of rats in the experiment group were significantly better than those of the control group at postoperative day 1 as well as at day 3. Plasma levels of neuron-specific enolase (NSE), S-100 [Formula: see text] protein, interleukin-6 (IL-6), tumor necrosis factor-[Formula: see text] (TNF [Formula: see text]), cortisol (COR), aldosterone (ALD), and adenocorticotropic hormone (ACTH) were significantly lower in the experiment group than in those of the control group (day 1 postoperatively). The plasma level of NSE on postoperative day 3 remained lower in the experimental group than in those of the control group. Our experimental results indicate that preoperative Shenmai and postoperative Shenfu injections facilitate conscious recovery and prevent postoperative cognitive decline. This anti-POCD effect may be a result of minimizing surgery-induced inflammation and reduction of perioperative stress responses by these injections. PMID- 30001645 TI - Anion gap and base deficit are predictors of mortality in acute pesticide poisoning. AB - BACKGROUND: Acute pesticide poisoning has long been a serious problem as a method of suicide worldwide. This poisoning is a highly fatal condition that requires a rapid and precise diagnosis for adequate treatment. However, various studies on mortality predictor factors have been insufficient for whole pesticide treatments. We hypothesized that the initial plasma anion gap (AG) and base deficit (BD) are reliable prognostic factors. METHODS: A retrospective study analyzed 561 patients with a diagnosis of acute pesticide poisoning between January 1, 2014 and June 30, 2017. The initial AG and BD values were divided into quartiles according to the number of patients. Survival at 30 days from admission was estimated using the Kaplan-Meier survival analysis. Receiver-operator characteristic (ROC) curves were drawn, and the areas under the curve for AG and BD for mortality were calculated. RESULTS: Fifty-eight (10.3%) of 561 patients died within 30 days. The highest AG quartile (>22 mEq/L) was associated with an increased risk of 30-day hospital mortality. Compared to patients with an AG less than 14.7 mEq/L, these patients had a 4.18-fold higher risk of 30-day hospital mortality and the highest BD quartile (>7.9 mEq/L) was associated with an increased risk of 30-day hospital mortality. Compared to patients with a BD less than 1.4 mEq/L, these patients had 2.23-fold higher risk of 30-day hospital mortality. The areas under the ROC for AG and BD curve were 0.699 and 0.744, respectively. CONCLUSIONS: Initial high AG and BD values could predict mortality and require precise intensive care. PMID- 30001644 TI - Acupuncture Alleviates Rheumatoid Arthritis by Immune-Network Modulation. AB - Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory and debilitating disease that involves the systemic imbalance of the immune network. Previous studies have shown that acupuncture can help treat RA. However, its specific mechanisms are not fully understood. Thus, the present study was designed to clarify the mechanisms of acupuncture acted on RA via immune network modulation using complete Freund's adjuvant (CFA)-induced arthritic rats. Results revealed that manual acupuncture (MA) could alleviate the inflammation and pain of infected joints. Moreover, MA could effectively stimulate the innate immune cytokines (IL-1[Formula: see text], IL-1[Formula: see text], IL-6, IL-7, IL-18, TNF-[Formula: see text]) and adaptive immunity cytokines (IL-2, IL-12, IFN [Formula: see text], IL-4, IL-5, IL-10, IL-13, IL-17) as the main part of the immune response and repaired damage of RA. These complex immunomodulatory processes were analyzed quantitatively by cell-cell communication (CCC) networks. The CCC networks demonstrated that the immune networks were enhanced with the development of RA, while MA enhanced the immune networks in the early stage to act on RA and promoted the immune-network to a normal level at the late stage. Moreover, we found that monocyte/macrophage and endothelial cells were the key cells of innate immunity and body cells; TH1, TH2 and B cells were the key cells of adaptive immunity, which were also the main target cells for MA regulation. PMID- 30001646 TI - Repetitive head injury in adolescent mice: A role for vascular inflammation. AB - Repetitive mild traumatic brain injury during adolescence can induce neurological dysfunction through undefined mechanisms. Interleukin-1 (IL-1) contributes to experimental adult diffuse and contusion TBI models, and IL-1 antagonists have entered clinical trials for severe TBI in adults; however, no such data exist for adolescent TBI. We developed an adolescent mouse repetitive closed head injury (rCHI) model to test the role of IL-1 family members in post-injury neurological outcome. Compared to one CHI, three daily injuries (3HD) produced acute and chronic learning deficits and emergence of hyperactivity, without detectable gliosis, neurodegeneration, brain atrophy, and white matter loss at one year. Mature IL-1beta and IL-18 were induced in brain endothelium in 3HD but not 1HD, three hit weekly, or sham animals. IL-1beta processing was induced cell autonomously in three-dimensional human endothelial cell cultures subjected to in vitro concussive trauma. Mice deficient in IL-1 receptor-1 or caspase-1 had improved post-injury Morris water maze performance. Repetitive mild CHI in adolescent mice may induce behavioral deficits in the absence of significant histopathology. The endothelium is a potential source of IL-1beta and IL-18 in rCHI, and IL-1 family members may be therapeutic targets to reduce or prevent neurological dysfunction after repetitive mild TBI in adolescents. PMID- 30001647 TI - Microsurgical clipping and endovascular flow diversion of ruptured anterior circulation blood blister-like aneurysms. AB - BACKGROUND: Detection and treatment of blister-like intracranial aneurysms as a source of subarachnoid hemorrhage (SAH) can be challenging. In the past the results of both microsurgical and endovascular treatment were difficult. We present our experience with the treatment of blister-like aneurysms in the acute phase of SAH using microsurgical clipping, endovascular parent vessel occlusion or flow diversion. METHODS: A retrospective analysis of the cases of eight consecutive patients presenting in the acute phase after SAH from an intracranial blister aneurysm was performed. The demographic data of the patients, aneurysm characteristics, the clinical results of the treatment and the follow-up examinations were recorded. Procedural safety margins and aneurysm occlusion on follow-up digital subtraction angiography were the main interest of this evaluation. RESULTS: Between January 2012 and November 2017 a total of eight ruptured blister aneurysms were treated in our center, six patients endovascularly. Five patients were treated in the acute phase of SAH, four by flow diversion. All endovascular procedures were feasible and no procedure related complications were observed, especially no recurrent hemorrhage. In the first angiographic follow-up all blood blister-like aneurysms were completely occluded; two of the six patients treated by flow diverter implantation showed mild, transient intimal hyperplasia without clinical symptoms or the need for treatment. CONCLUSIONS: Endovascular flow diversion is a viable option in the acute phase after SAH due to the rupture of a blister aneurysm. Implants with reduced thrombogenicity, obviating dual-platelet function inhibition, and flow diverters for vessel bifurcations would extend the indications for this treatment modality. PMID- 30001649 TI - About the role of polysomnography in weaning and titration of home oxygen therapy in children with bronchopulmonary dysplasia. PMID- 30001648 TI - Mid-term 3T MRA follow-up of intracranial aneurysms treated with the Woven EndoBridge. AB - INTRODUCTION: Angiography is the standard follow-up modality for treated aneurysms with the Woven EndoBridge (WEB), and magnetic resonance angiography (MRA) is useful for extended follow-up. We present the results of WEB-treated aneurysms with angiographic follow-up at three months and at least 18 months' 3T MRA follow-up. MATERIALS AND METHODS: Included were 52 patients with 53 aneurysms treated with the WEB between February 2015 and July 2016. There were 29 women and 23 men with a mean age of 60 years (median 62, range 23-76). Mean aneurysm size was 6.2 mm (median 6, range 3-16 mm). RESULTS: 3T MRA follow-up was mean 19.6 months (median 18, range 18-36 months). One patient had an aneurysm remnant at three-month angiography that was additionally coiled and with stable complete occlusion at 18 months' 3T MRA follow-up. At three-month follow-up angiography, 44 aneurysms were completely occluded and eight had a neck remnant. At latest 3T MRA, stable complete occlusion was present in 43 aneurysms and stable neck remnant in eight. One posterior cerebral artery (PCA) dissection aneurysm was stable at three and six months but was enlarged and reopened at 18 months, confirmed with angiography. Focal signal loss by the proximal marker of the WEB was apparent in four patients without compromising diagnostic evaluation. CONCLUSION: WEB-treated aneurysms with adequate occlusion at three-month angiography remained stable during serial 3T MRA follow-up of 18-36 months. One PCA aneurysm reopened during the 6- to 18-month interval. Once the WEB-treated aneurysm is adequately occluded in the short term, later reopening is uncommon. PMID- 30001650 TI - Osteopontin-enriched formula feeding improves the T-cell-dependent humoral immune responses in infant rats. AB - Previous studies have shown that osteopontin (OPN) can enhance infant resistance to infection. However, the underlying mechanisms remain to be explored. Here, we studied the effects of OPN on the development and functions of immune cells in infant rats fed with OPN-enriched formula (OF) compared with regular formula (RF). After 21 days feeding, the proportion of infant rats' CD3+ T cells of lymph nodes in the OF group is significantly increased compared with the RF group. The proportion of CD4+ and CD8+ T cells of lymph nodes in the OF group is closer to the breast feeding (BF) group than to the RF group. Upon immunisation with the thymus-dependent antigen ovalbumin (OVA), the concentration of OVA-specific IgG in the OF group was significantly higher than that in the RF group. Altogether OPN-enriched infant formula feeding can promote the differentiation of CD3+ T cells and improve the T-cell-dependent humoral immune responses in infant rats. PMID- 30001651 TI - Understanding healthcare burden and treatment patterns among young adults with schizophrenia. AB - BACKGROUND: Schizophrenia is a serious public health problem that affects ~1% of the US population. AIMS: To examine treatment patterns and evaluate healthcare resource utilization (HRU) and costs among young adults (18-35 years) with schizophrenia who were early in the disease. MATERIALS AND METHODS: Patients aged 18-64 years with >=2 schizophrenia diagnoses in the identification period (January 1, 2012-September 30, 2015) and continuous enrollment for >=12 months pre- and post-index date were identified from the OptumInsight Clinformatics DataMart. Demographics, clinical characteristics, HRU, costs, and treatment patterns were compared between schizophrenia and non-schizophrenia "controls" cohorts and between young (18-35 years) and older adults (36-64 years) with schizophrenia. RESULTS: Among 9,889 schizophrenia patients, 23.70% were young adults (aged 18-35), had higher all-cause per-patient-per-year (PPPY) costs ($22,338 vs $7,332; p < .0001), higher inpatient costs ($8,857 vs $1,289; p < .0001), and longer inpatient length-of-stay (LOS) (5.0 vs 0.4 days, p < .0001; adjusted incidence rate ratio [aIRR] = 12.8; 95% confidence interval [CI] = 11.5 14.3) than controls. Among young adults with schizophrenia, there were more mental-health-related and fewer non-mental-health-related diagnoses compared to older adults with schizophrenia; 63.40% were male. Young adults with schizophrenia incurred higher inpatient costs ($15,692 vs $10,274; p < .0001) and longer inpatient LOS (9.6 vs 5.9 days, p < .0001; aIRR = 1.6; 95% CI = 1.4-1.8) compared to older adults with schizophrenia. A substantial proportion of patients were treated with oral antipsychotics vs long-acting injectables in both cohorts (young adults: 98.72% vs 9.71%; older adults: 98.10% vs 13.31%). LIMITATIONS: Claims data are collected for payment and not research. The presence of a prescription claim does not indicate medication was consumed or taken as prescribed. CONCLUSIONS: The economic burden for schizophrenia patients is substantial, especially among young adults. Based on this analysis, further research is warranted to better understand the association between adherent treatment patterns earlier in the disease and long-term health outcomes among patients with schizophrenia. PMID- 30001652 TI - Twelve tips for developing key-feature questions (KFQ) for effective assessment of clinical reasoning. AB - Clinical reasoning is the cognitive process that makes it possible for us to reach conclusions from clinical data. "A key feature (KF) is defined as a significant step in the resolution of a clinical problem. Examinations using key feature questions (KFQs) focus on a challenging aspect in the diagnosis and management of a clinical problem where the candidates are most likely to make errors." KFs have been used at different levels of medical education and practice, from undergraduate to certification examinations. KFQs illuminate the strengths and limits of an individual's clinical problem-solving ability. These types of items are more likely than other forms of assessment to discriminate among stronger or weaker candidates in the area of clinical reasoning. The 12 tips in this article will provide guidance to faculty who wish to develop KFQs for their tests. PMID- 30001653 TI - Prenatal diagnosis of tetralogy of Fallot with pulmonary atresia using: Fetal Intelligent Navigation Echocardiography (FINE). AB - Tetralogy of Fallot with pulmonary atresia, a severe form of tetralogy of Fallot, is characterized by the absence of flow from the right ventricle to the pulmonary arteries. This cardiac abnormality is challenging and complex due to its many different anatomic variants. The main source of variability is the pulmonary artery anatomy, ranging from well-formed, confluent pulmonary artery branches to completely absent native pulmonary arteries replaced by major aorto-pulmonary collateral arteries (MAPCAs) that provide all of the pulmonary blood flow. Since the four-chamber view is usually normal on prenatal sonography, the diagnosis may be missed unless additional cardiac views are studied. Fetal Intelligent Navigation Echocardiography (FINE) is a novel method developed recently that allows automatic generation of nine standard fetal echocardiography views in normal hearts by applying "intelligent navigation" technology to spatiotemporal image correlation volume datasets. We report herein for the first time, two different cases of tetralogy of Fallot with pulmonary atresia having variable sources of pulmonary blood flow in which the prenatal diagnosis was made successfully using the FINE method. Virtual Intelligent Sonographer Assistance (VIS-Assistance(r)) and automatic labeling (both features of FINE) were very helpful in making such diagnosis. PMID- 30001654 TI - Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis, skin fibrosis, and vasculopathy in systemic sclerosis: A potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors. AB - OBJECTIVES: We explored the interactions of osteoprotegerin (OPG) with biomarkers of bone turnover and cytokines, including soluble receptor activator for nuclear factor kappa beta ligand (sRANKL), tumor necrosis factor-related apoptosis induced ligand (TRAIL), and Wnt inhibitors in osteoporosis, vasculopathy and fibrosis related to systemic sclerosis (SSc). METHODS: The study included 46 SSc patients and 30 healthy controls. Skin thickness, pulmonary fibrosis and/or hypertension, digital ulcers, and calcinosis cutis of SSc patients were assessed. We determined bone mineral density (BMD), and OPG, sRANKL, TRAIL, secreted frizzled-related protein 1 (sFRP-1), Dickkopf-related protein 1 (DKK-1), sclerostin in the serum of both patients and controls. RESULTS: OPG, sclerostin, and sFRP-1 levels were similar between patients and controls (P > 0.05). Femoral neck and lumbar spine BMD and vitamin D levels were lower, and the OC, NTX, sRANKL, DKK1 and TRAIL levels were significantly higher, in patients than in controls (p < 0.05). In subgroup analysis, patients with higher modified Rodnan skin score (mRodnan) had higher DKK-1, sclerostin, and TRAIL levels (p < 0.05); those with diffuse SSc subtype had lower BMD values than those with limited SSc (p < 0.05). Skin and pulmonary fibrosis linked negatively with BMD measures. CONCLUSION: we showed that sRANKL levels were higher and correlated with bone turnover markers. It may be related to osteoporosis in SSc. The OPG level was unaltered in SSc patients. Higher TRAIL levels associated with skin thickness may indicate vascular dysfunction or injury. Higher DKK-1 and sclerostin levels may be related to a reactive increase in cells and be prominently linked to fibrosis in SSc. PMID- 30001655 TI - 2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis. AB - OBJECTIVE: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan. METHODS: The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements. RESULTS: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy. CONCLUSION: The revised CPG has demonstrated evidence-based treatment recommendations for AAV. PMID- 30001656 TI - Ethical Challenges of Early Identification of Advanced Chronic Patients in Need of Palliative Care: The Catalan Experience. AB - Palliative care must be early applied to all types of advanced chronic and life limited prognosis patients, present in all health and social services. Patients' early identification and registry allows introducing palliative care gradually concomitant with other measures. Patients undergo a systematic and integrated care process, meant to improve their life quality, which includes multidimensional assessment of their needs, recognition of their values and preferences for advance care planning purposes, treatments review, family care, and case management. Leaded by the National Department of Health, a program for the early identification of these patients has been implemented in Catalonia (Spain). Although the overall benefits expected, the program has raised some ethical issues. In order to address these challenges, diverse institutions, including bioethics and ethics committees, have elaborated a proposal for the program's advantages. This paper describes the process of evaluation, elaboration of recommendations, and actions done in Catalonia. PMID- 30001657 TI - Effect of chorionic villus sampling on placental volume and vascularization in the first trimester of pregnancy. AB - OBJECTIVE: To evaluate the effects of chorionic villus sampling (CVS) on placental volume (PV), perfusion, and vasculature in the first trimester of pregnancy. METHOD: Uterine artery pulsatility index (PI), PV, vascularization index (VI), flow index (FI), and Vascularization Flow Index (VFI) were serially measured in 38 pregnant women who underwent CVS. Thirty-eight women who did not undergo invasive prenatal diagnosis were recruited as controls. RESULTS: CVS was associated with a mild reduction of PI, a reduction of placental VI, FI, and VFI and with an increase in PV detected one week after the procedure. The outcome of pregnancy was similar between women of the two groups. CONCLUSION: Our findings showed that CVS is associated with mild placental vascular and morphological changes. However, these changes do not seem to be associated with adverse outcome. PMID- 30001658 TI - Prenatal diagnosis of closed spina bifida: multicenter case series and review of the literature. AB - OBJECTIVE: Closed spina bifida (CSB) is an abnormality of the posterior arch formation in which the defect is covered by the skin, without protrusion of nervous tissue. The prenatal diagnosis of CSB is very difficult, rarely diagnosed antenatally. METHODS: We present a multicenter case series of six prenatal diagnosis of CSB using two-dimensional (2D) ultrasonography complemented with three-dimensional (3D) ultrasonography and magnetic resonance imaging (MRI). All cases of prenatal diagnosis of CSB were confirmed in the postnatal period/termination of pregnancy by both clinical and/or imaging diagnosis (ultrasonography and MRI). RESULTS: 2D ultrasonography allowed the prenatal diagnosis of six cases. We observed two cases of subcutaneous lipomas, two cases of meningoceles, one case of fibrolipomas, and one case of false-positive CSB (meningomyelocele). 3D ultrasonography using rendering mode was important in one case of meningocele (case# 3). Three cases were delivered at term and one of them was submitted to corrective surgery. All these three newborns were discharged from the hospital well and without neurologic signs. Termination of pregnancy was performed in three cases. CONCLUSION: During prenatal evaluation, detailed ultrasonographic assessment of the entire spine with the identification of the position and morphology of the conus medullaris and absence of cranial signs of spinal dysraphism are the most valuable sonographic clues for the diagnostic of the CSB. PMID- 30001659 TI - The association of parental methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C > T and 1298A > C) and fetal loss: a case-control study in South Australia. AB - OBJECTIVE: To determine the association between parental MTHFR 677C > T (RS1801133) and 1298A > C (RS1801131), and fetal loss (FL). DESIGN: Case-control study. SETTING: Department of Obstetrics and Gynecology, Lyell McEwin Hospital (LMH), and the Women's and Children's Hospital (WCH) in Adelaide, Australia. PATIENTS: A total of 222 couples with FL and 988 couples with uncomplicated pregnancies. MEASUREMENTS: The main outcomes were FL and hyperhomocysteinemia (HHcy). All couples were tested for MTHFR 677C > T and 1298A > C. Fasting homocysteine was measured in the women with FL. RESULTS: The main finding was a significant difference between the FL group and controls in couples with >=4 abnormal alleles compared to <4 [p=.0232, OR 1.9 (95% CI 1.1-3.3)]. None of the couples with FL had zero abnormal alleles (both parents 677CC/1298 AA). However, this was also rare amongst the controls. Maternal carriage of both 677C > T and the 1298A > C polymorphisms was similar between the FL group and controls. The prevalence of paternal 677TT/1298AA and 677CC/1298AC was significantly higher in the FL group compared with controls. HHcy was significantly more common in the FL group compared with controls. CONCLUSION: The presence of parental MTHFR 677C > T and 1298A > C is associated with FL. The association between maternal MTHFR genotypes with FL is less pronounced than in previously published articles investigating first trimester miscarriages. Maternal HHcy is a significant risk factor for FL. PMID- 30001660 TI - Preeclampsia: risk factors and neonatal outcomes associated with early- versus late-onset diseases. AB - OBJECTIVE: This study examined the effects of early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) on short-term maternal and neonatal morbidity, as well as risk factors associated with early-onset and late-onset diseases. METHOD: This retrospective, cohort study included pregnant women who had been diagnosed with PE during pregnancy. Electronic medical records were reviewed for demographics and medical history, laboratory tests, and delivery data. The women were grouped according to EOPE (<34 weeks) and LOPE (>=34 weeks). Power analysis revealed that a sample size of 35 was sufficient for each PE group, under the assumptions of type I error (two-sided) of 5% and at least 80% power to detect a 30% difference in composite outcomes between EOPE and LOPE. RESULTS: Among 101 patients, 35 (34.7%) had EOPE and 66 (65.3%) developed LOPE. Alpha fetoprotein (AFP) and unconjugated estriol (UE3) were higher in the early-onset group (p = .015 and p= .002, respectively) and might be predictors of EOPE. There was a positive correlation between gestational age at PE diagnosis and gestational age at delivery. Patients with EOPE delivered earlier than patients with LOPE did (p<.0001). CONCLUSIONS: Patients who developed EOPE had higher of AFP and UE3 values at their second trimester biochemical screening. These parameters might be predictors of EOPE. We found a positive correlation between early gestational age at PE diagnosis and preterm delivery. PMID- 30001661 TI - Improving precision in prediction: Using kidney failure risk equations as a potential adjunct to vascular access planning. AB - The timing of referral for creation of vascular access in a patient with declining kidney function is difficult to predict. Current methods may result in patients undergoing unnecessary procedures and subsequent interventions on accesses that are never used. Multiple variables, including time for assessment, surgery and follow-up that considers the likelihood of access failure, and the estimated rate of kidney function decline, make vascular access planning challenging and difficult to balance. Better prediction tools that incorporate the risks of progressive decline in kidney function with the risk of access failure and the competing risk of death would facilitate decision-making in vascular access. The kidney failure risk equation is a validated, simple online tool that estimates the probability of the 2- and 5-year risk of reaching end stage kidney disease. While the use of the kidney failure risk equation has not been validated as an adjunct to planning vascular access, it has potential and may facilitate more individualised care and more appropriate allocation of resources. PMID- 30001662 TI - Inflammatory cytokine release from human peripheral blood mononuclear cells exposed to polyetheretherketone and titanium-6 aluminum-4 vanadium in vitro. AB - Objective To investigate the cytokine expression profiles of blood cells exposed to polyetheretherketone and titanium-6 aluminum-4 vanadium materials in vitro. Materials and methods Coin-shaped samples composed of titanium-6 aluminum-4 vanadium, polyetheretherketone, and blasted polyetheretherketone were manufactured. The surfaces of the coins were characterized using optical interferometry, scanning electron microscopy, and contact angle measurements. Peripheral blood mononuclear cells collected from 10 blood donors were cultured for one, three, and six days in the presence or absence of the coins, and then assayed for cytokine production. Quantification of the peripheral blood mononuclear cells attached to the coins was performed using confocal microscopy after immunofluorescence staining. Results The machined titanium-6 aluminum-4 vanadium coins had a smoother surface topography compared to the machined polyetheretherketone and blasted polyetheretherketone. The highest mean contact angle was noted for the blasted polyetheretherketone, followed by the machined polyetheretherketone and titanium-6 aluminum-4 vanadium. The peripheral blood mononuclear cells produced significantly more proinflammatory cytokines when exposed to the polyetheretherketone surface compared to the titanium-6 aluminum-4 vanadium surface, while the blasted polyetheretherketone induced the highest level of proinflammatory cytokine release from the peripheral blood mononuclear cells. Significantly more cells attached to both polyetheretherketone surfaces, as compared to the titanium-6 aluminum-4 vanadium surface. Conclusion Polyetheretherketone induces a stronger inflammatory response from peripheral blood mononuclear cells than does titanium-6 aluminum-4 vanadium. Surface topography has an impact on cytokine release from peripheral blood mononuclear cells. PMID- 30001663 TI - The role of adipocyte-specific IL-6-type cytokine signaling in FFA and leptin release. AB - High secretion of interleukin (IL)-6 from white adipose tissue may contribute to metabolic complications in obesity. We have recently shown that IL-6-type cytokine signaling in adipocytes is involved in the development of obesity associated hepatic insulin resistance and steatosis. In addition, we revealed that adipocyte-specific IL-6 signaling ameliorates glucose metabolism in obesity via enhancing insulin secretion. Mechanistically, IL-6 induces the release of free fatty acid (FFA) and leptin from adipocytes thereby affecting liver metabolism and pancreatic beta-cell function, respectively. This commentary further discusses the role of adipocyte-specific IL-6-type cytokine signaling in the regulation of FFA and leptin release. In particular, we outline depot specific differences in IL-6-induced basal release of the two aforementioned factors. Moreover, we provide evidence that insulin's effect on the release of FFA and leptin is adipose depot-dependent. We conclude that adipose depot specific targeting of the IL-6 signaling pathway may be a novel approach to blunt obesity-associated metabolic complications. PMID- 30001664 TI - Association between cigarette smoking during pregnancy and gestational diabetes mellitus: a meta-analysis. AB - AIMS: Several studies have been carried out to examine the association between cigarette smoking during pregnancy and risk of developing gestational diabetes mellitus (GDM), yet the findings are mixed. Therefore, we aimed to estimate the relationship between cigarette smoking during pregnancy and GDM risk. MATERIAL AND METHODS: PubMed, ScienceDirect, and Cochrane Library databases were searched up to December 2017. Studies on cigarette smoking during pregnancy and GDM were retrieved. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) for highest versus lowest level of cigarette smoking were calculated using a random-effects model. RESULTS: Compared to nonsmoking, the pooled ORs of cigarette smoking during pregnancy were 0.98 (95% CI: 0.88-1.10) for GDM. Specifically, the pooled ORs of light smoking and heavy smoking during pregnancy for GDM were 1.10 (95% CI: 0.97-1.25) and 1.02 (95% CI: 0.67-1.53), respectively. CONCLUSIONS: Our findings suggest that there is no significant association between cigarette smoking during pregnancy and risk of GDM. PMID- 30001666 TI - Influence of mode of delivery on outcomes in preterm breech infants presenting in labor. AB - OBJECTIVE: Rates of vaginal breech delivery at term have fallen significantly. We sought to examine rates of preterm vaginal breech delivery and outcomes associated with delivery route. METHODS: This retrospective cohort study was carried out at a large tertiary referral center serving an urban population, from 2001 to 2011. The primary objective was to compare outcomes of breech presenting preterm infants according to mode of delivery. The incidence of preterm breech delivery was examined as well as maternal and neonatal outcomes associated with vaginal and abdominal delivery of preterm breech infants. RESULTS: A total of 15% (413/2759) of breech presenting infants delivered prior to 37-week gestation. In extreme prematurity (<28 weeks) the majority (88%; 37/42) of those who presented in labor delivered vaginally, this rate fell to 47% (63/134) after 28 weeks. Infants delivered vaginally after 28 weeks were more likely to have an Apgar <7 at 5 min, than those who had a cesarean delivery (22.5% [16/71] versus 9% [25/278], p = .002; numbers needed to treat (NNT) = 4). Maternal blood loss >500 ml was more likely in those patients delivered by cesarean section (24.2% [74/305] versus 3.7% [4/108]; p < .0001; NNT =2). CONCLUSION: These results demonstrate that vaginal delivery of a preterm breech - presenting infant is a necessary skill for all birth attendants in contemporary practice, particularly prior to 28-week gestation. PMID- 30001667 TI - Economic burden of hospital malnutrition and the cost-benefit of supplemental parenteral nutrition in critically ill patients in Latin America. AB - AIM: Disease-related malnutrition (DRM) is a prevalent condition that significantly increases the risk of adverse outcomes in hospitalized patients, particularly those with critical illness. Limited data is available on the economic burden of DRM and the cost-benefit of nutrition therapy in high-risk populations in Latin America. The aims of the present study were to estimate the economic burden of DRM and evaluate the cost-benefit of supplemental parenteral nutrition (SPN) in critically ill patients who fail to receive adequate nutrient intake from enteral nutrition (EN) in Latin America. METHODS: Country-specific cost and prevalence data from eight Latin American countries and clinical data from studies evaluating outcomes in patients with DRM were used to estimate the costs associated with DRM in public hospitals. A deterministic decision model based on clinical outcomes from a randomized controlled study and country specific cost data were developed to examine the cost-benefit of administering SPN to critically ill adults who fail to reach >=60% of the calculated energy target with EN. RESULTS: The estimated annual economic burden of DRM in public hospitals in Latin America is $10.19 billion (range, $8.44 billion-$11.72 billion). Critically ill patients account for a disproportionate share of the costs, with a 6.5-fold higher average cost per patient compared with those in the ward ($5488.35 vs. $839.76). Model-derived estimates for clinical outcomes and resource utilization showed that administration of SPN to critically ill patients who fail to receive the targeted energy delivery with EN would result in an annual cost reduction of $10.2 million compared with continued administration of EN alone. LIMITATIONS: The cost calculation was limited to the average daily cost of stay and antibiotic use. The costs associated with other common complications of DRM, such as prolonged duration of mechanical ventilation or more frequent readmission, are unknown. CONCLUSIONS: DRM imposes a substantial economic burden on Latin American countries, with critically ill patients accounting for a disproportionate share of costs. Cost-benefit analysis suggests that both improved clinical outcomes and significant cost savings can be achieved through the adoption of SPN as a therapeutic strategy in critically ill patients who fail to receive adequate nutrient intake from EN. PMID- 30001665 TI - Synthesis, X-ray structure, in silico calculation, and carbonic anhydrase inhibitory properties of benzylimidazole metal complexes. AB - Three coordination compounds of formula {M(bmim)2Cl2} were synthetised (M = Co, Zn, and Hg) and fully characterised. Each complex incorporates 1-benzyl-2 methylimidazole (bmim) as ligand. The coordination polyhedron around the metal center for all complexes has a quasi-regular tetragonal geometry. Density functional theory calculations were carried out on the title compounds and as well on hypothetical complexes (Cu, Ni), in order to elucidate their electronic and molecular structure. The calculations reproduced the Co, Zn, and Hg experimental structures and could predict stable complexes in the case of Ni(II) and Cu(II) ions. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the three complexes were investigated. Only compound {Hg(bmim)2Cl2} (3) exhibited a modest inhibitory effect against hCA I, probably due to the affinity of Hg(II) for His residues at the entrance of the active site cavity. PMID- 30001668 TI - Impact of remote biometric monitoring on cost and hospitalization outcomes in peritoneal dialysis. AB - Introduction Peritoneal dialysis is a home-based therapy for individuals with end stage renal disease. Telehealth, especially remote monitoring, is making inroads in managing this cohort. Methods We examined whether daily remote biometric monitoring (RBM) of blood pressure and weight among peritoneal dialysis patients was associated with changes in hospitalization rate and hospital length of stay, as well as outpatient, inpatient and overall cost of care. Results Outpatient visit claim payment amounts (in US dollars derived from CMS data) decreased post intervention relative to pre-intervention for those at age 18-54 years. For certain subgroups, non- or nearly-significant changes were found among female and Black participants. There was no change in inpatient costs post-intervention relative to pre-intervention for females and while the overall visit claim payment amounts increased in the outpatient setting slightly (US$511.41 (1990.30) vs. US$652.61 (2319.02), p = 0.0783) and decreased in the inpatient setting (US$10,835.30 (6488.66) vs. US$10,678.88 (15,308.17), p = 0.4588), these differences were not statistically significant. Overall cost was lower if RBM was used for assessment of blood pressure and/or weight (US$-734.51, p < 0.05). Use of RBM collected weight was associated with fewer hospitalizations (adjusted odds ratio 0.54, 95% confidence interval 0.33-0.89) and fewer days hospitalized (adjusted odds ratio 0.46, 95% confidence interval 0.26-0.81). Use of RBM collected blood pressure was associated with increased days of hospitalization and increased odds of hospitalization. Conclusions RBM offers a powerful opportunity to provide care to those receiving home therapies such as peritoneal dialysis. RBM may be associated with reduction in both inpatient and outpatient costs for specific sub-groups receiving peritoneal dialysis. PMID- 30001669 TI - Cost comparison of fibrin sealant versus tack screws for mesh fixation in laparoscopic repair of inguinal hernia. AB - OBJECTIVES: Inguinal hernias of the abdominal wall are common accounting for 75% of all hernia defects. They can be treated with laparoscopic surgery using a transabdominal preperitoneal (TAPP) approach. However, in surgery there is some contention on how to conclude the hernia repair, as there are alternatives of using fibrin sealant (FS) or tack screws for fixation of a mesh implant over the defect in the abdominal wall. In this study, we evaluate the economic consequences of using FS vs. tacks for mesh fixation in TAPP inguinal hernia repair for the UK from a hospital perspective. METHODS: The model was populated with clinical inputs (theater time, hospitalization days, occurrence of seroma, and neuralgia) from a previously conducted study comparing FS and tack screws in patients who had undergone TAPP hernia repair, and cost inputs from official government sources. One-way sensitivity analyses were also conducted to evaluate key drivers of cost analyses. RESULTS: The average cost per case treated with FS 2 mL Tisseel(r) and tack screws (ProTackTM) was L1,098 and L1,348, respectively, for resource expenses paid by the healthcare system. This would suggest a potential savings achieved of L249 per surgery using FS for mesh fixation. The sensitivity analysis showed that the key drivers for the cost difference were a variation in time to complete the surgery, followed by hospitalization days, and lower adverse outcomes such as seroma and neuralgia in the two cohorts. CONCLUSION: Using FS resulted in cost savings in hospitals based on reduced time to complete surgery, hospitalization time post-op, and lower adverse outcomes. Indirect cost savings were also found in favor of FS when comparing the two alternatives from a societal perspective, as patients were able to return to work more promptly in the FS group versus the tack screws group. PMID- 30001670 TI - Effects of coat length and faecal hair removal on measured nutrient digestibility in cats. AB - Objectives This experiment was conducted to evaluate the effect of coat length and faecal hair removal on measured nutrient digestibility in longhair and shorthair cats. Methods A total of 14 adult domestic cats, with a mean +/- SD body weight of 4.5 +/- 1.21 kg and a mean +/- SD age of 3.3 +/- 1.38 years, were used for a nutrient digestibility trial. The nutrient digestibility of cats was measured by hair-included faeces and hair-removed faeces. Food was provided twice daily (09:00 h and 16:00 h) and water was provided ad libitum. Cats were adapted to a steel cage and diet for 16 days before a 10 day collection period. During the collection period, food offered, food refused and faecal output were measured daily and used for digestibility analysis. Results The digestibility of dry matter, crude protein and neutral detergent fibre (NDF) of longhair cats was underestimated by 8% ( P = 0.02), 9% ( P = 0.04) and 14% ( P = 0.04), respectively. In shorthair cats, the digestibility of dry matter, crude protein and crude ash increased by 4% ( P = 0.01), 5% ( P = 0.02) and 15% ( P <0.01), respectively, with hair-removed faeces. The nutrient digestibility between longhair and shorthair cats showed no difference when hair-included faeces were used. However, when using hair-removed faeces, the digestibility of NDF and amino acids in longhair cats were about 4-8% higher than in shorthair cats ( P <0.05). Conclusions and relevance This study showed that the nutrient digestibility values were affected by whether the hair in faeces was removed or not. Removing hairs from faeces is a more precise method with which to evaluate the apparent nutrient digestibility of domestic cats ( Felis catus). PMID- 30001671 TI - Evaluation of grooming behaviour and apparent digestibility method in cats. AB - Objectives This experiment was conducted to evaluate the behavioural time budget for grooming and grooming patterns for shorthair and longhair cats, and to assess the effect of grooming behaviour on apparent digestibility of nutrients in domestic cats ( Felis catus) by comparing hair-included faeces and hair-removed faeces. Methods A total of 10 adult domestic cats, with a mean +/- SD body weight of 4.3 +/- 0.89 kg and a mean +/- SD age of 3.5 +/- 1.38 years, were used for behavioural observation. Cats were housed individually in stainless steel cages at the animal hospital. The cats' behaviour was recorded on a webcam videotaping system for one 24 h period; then, faecal samples were collected and analysed to measure apparent digestibility. Results There was no significant difference between longhair and shorthair cats in behavioural time budget for grooming and grooming patterns. The apparent digestibility of dry matter, crude protein, crude ash, acid detergent fibre (ADF) and neutral detergent fibre (NDF) of hair-removed faeces was significantly higher than that of hair-included faeces: about 6% ( P <0.01), 7% ( P <0.01), 14% ( P <0.01), 12% ( P = 0.01) and 10% ( P <0.01), respectively. Conclusions and relevance There was no difference in grooming patterns between longhair cats and shorthair cats. Also, the digestibility of dry matter, crude protein, crude ash, ADF and NDF has been underestimated by approximately 6%, 7%, 14%, 12%, and 10%, respectively, when they have been calculated using the conventional digestibility method for domestic cats. PMID- 30001672 TI - Occupational balance among family members of people in palliative care. AB - BACKGROUND: Today people can live a long time with a chronic cancer diagnosis, and it affects the entire family. Family members to patients in palliative care often have to leave valued occupations due to lack of time and energy, while new roles are forced upon them, potentially affecting their health. OBJECTIVE: To explore occupational balance, needs and roles among family members to persons in palliative care. METHODS: Six semi-structured interviews were conducted with family members to terminally ill persons enrolled to specialized palliative care. A qualitative content analysis guided the data collection and analysis. RESULT: An overarching theme Striving for control while being in the disease, and two categories Changing roles and occupations in the family; and Handling emotions in the end of life emerged from the data. CONCLUSION: The findings suggest that family members could benefit from strategies to maintain valued roles and occupations, and that palliative care provision need to develop new ways to take family members needs into consideration. PMID- 30001673 TI - HbA1c method performance: The great success story of global standardization. AB - Diagnosing and monitoring the treatment of people with diabetes is a global issue and uses considerable resources in laboratories and clinics worldwide. Hemoglobin A1c (HbA1c) has been the mainstay of monitoring glycemic control in people with diabetes for many years and more recently it has been advocated as a diagnostic tool for type 2 diabetes mellitus (T2DM). Good analytical performance is key to the successful use of any laboratory test, but is critical when using the test to diagnose disease, especially when the potential number of diagnoses could exceed 500 million people. Very small variations in bias or increased imprecision could lead to either a missed diagnosis or overdiagnosis of the disease and given the scale of the global disease burden, this could mean erroneous categorization of potentially millions of people. Fundamental to good performance of diagnostic testing is standardization, with defined reference materials and measurement procedures. In this review, we discuss the historical steps to first harmonize HbA1c testing, followed by the global standardization efforts and provide an update on the current situation and future goals for HbA1c testing. PMID- 30001674 TI - Identification of novel long chain N-acylhomoserine lactones of chain length C20 from the marine phototrophic bacterium Rhodovulum sulfidophilum. AB - : Gram-negative bacterial quorum sensing is mainly regulated by an extracellularly produced N-acylhomoserine lactone (AHL). AHL consists of a lactone ring and an acyl chain, which generally varies from C4 to C18 in length and affords species-specific variety. In this study, we developed an ultra-high performance liquid chromatography tandem mass spectrometry system and detected two kinds of long chain AHLs with chain length C20 from the reverse-phase thin layer chromatography-fractionated cultured supernatant of the marine photosynthetic bacterium Rhodovulum sulfidophilum. By fragmentation search analysis to detect compounds with a homoserine lactone ring moiety for data dependent acquisition, a minor AHL, presumed to be 3-OH-C18-homoserine lactone (HSL), was also found. Among the detected C20-HSLs, 3-OH-C20-HSL was structurally identified and 3-OH-C20:1-HSL was strongly suggested. To our knowledge, this is the first report to show a novel AHL with the longest C20 acyl side chain found to date. ABBREVIATIONS: AGC: automatic gain control; AHL: N-acylhomoserine lactone; CD: cyclodextrin; CID: collision induced dissociation; DDA: data dependent acquisition; EPI: enhanced product ion; FISh: fragment ion search; HCD: high energy collisional dissociation; HSL: homoserine lactone; IT: injection time; LC: liquid chromatography; MS: mass spectrometry; PRM: parallel reaction monitoring; RP: reverse phase; SRM: selected reaction monitoring; TLC: thin layer chromatography; UHPLC: ultra high performance liquid chromatography. PMID- 30001675 TI - The role of social attention in older adults' ability to interpret naturalistic social scenes. AB - Age-related differences on theory of mind (ToM) tasks are well established. However, the literature has been criticised for predominantly relying on tasks with poor ecological validity, and consequently it remains unclear whether these age differences extend to tasks with greater realism. In addition, we currently have a limited understanding of the factors that may contribute to age-related declines in ToM. To address these issues, we conducted two studies that assessed age differences in ToM using multimodal social scene stimuli. Study 1 also examined eye movements to assess whether biases in visual attention may be related to age-related difficulties in ToM, and Study 2 included an assessment of social attention (as indexed by biological motion perception) and working memory to assess whether these capacities may explain age difficulties in ToM. In both studies, the results showed that older adults performed worse than their younger counterparts on the ToM tasks, indicating that age-related difficulties in ToM extend to measures that more closely represent everyday social interactions. The eye-tracking data in Study 1 showed that older adults gazed less at the faces of protagonists in the social scenes compared with younger adults; however, these visual biases were not associated with ToM ability. Study 2 showed that older age was associated with a reduced ability to detect biological motion cues, and this mediated age-related variance in ToM ability. These findings are discussed in relation to competing theoretical frameworks of ageing that predict either improvements or declines in ToM with age. PMID- 30001676 TI - Corrigendum. PMID- 30001678 TI - The Eyes Wide Shut Illusion. AB - The new "eyes wide shut" illusion uses a standard enlarging (shaving or makeup) mirror. Close one eye and look at the closed eye in the mirror; the eye should take up most of the mirror. Switch eyes to see the other closed eye. Switch back and-forth a few times, then open both eyes. You see an open eye. Which eye is it? To find out, close one eye. Whichever you close, that's the eye you see. How can this be possible? The brain is fusing two images of the two eyes! The illusion depends on (a) binocular fusion: The brain combines two images to a single percept; (b) symmetry: Mirrors don't affect appearance of left-right symmetric objects and the eyes are sufficiently left-right symmetric for the brain to combine them. Why aren't the lingering asymmetries sufficient to prevent fusion? (c) Only vision with scrutiny affords conscious access to scene details. Consistent with reverse hierarchy theory, vision at a glance grants conscious perception of the gist of the scene, integrating images of nonperfectly symmetric eyes. PMID- 30001679 TI - In Defence of Illusions: A Reply to Braddick (2018). PMID- 30001680 TI - Increase in the thermostability of Bacillus sp. strain TAR-1 xylanase using a site saturation mutagenesis library. AB - : Site saturation mutagenesis library is a recently developed technique, in which any one out of all amino acid residues in a target region is substituted into other 19 amino acid residues. In this study, we used this technique to increase the thermostability of a GH10 xylanase, XynR, from Bacillus sp. strain TAR-1. We hypothesized that the substrate binding region of XynR is flexible, and that the thermostability of XynR will increase if the flexibility of the substrate binding region is decreased without impairing the substrate binding ability. Site saturation mutagenesis libraries of amino acid residues Tyr43-Lys115 and Ala300 Asn325 of XynR were constructed. By screening 480 clones, S92E was selected as the most thermostable one, exhibiting the residual activity of 80% after heat treatment at 80 degrees C for 15 min in the hydrolysis of Remazol Brilliant Blue xylan. Our results suggest that this strategy is effective for stabilization of GH10 xylanase. ABBREVIATIONS: DNS: 3,5-dinitrosalicylic acid; RBB-xylan: Remazol Brilliant Blue-xylan. PMID- 30001681 TI - First synthesis of (+/-)-myristicyclin A. AB - The first synthesis of myristicyclin A, which was isolated from the Papua New Guinean plant Horsfieldia spicata, is described. The synthesis features acid mediated hydroarylation reaction to form a dihydrocoumarin moiety, construction of the 2,8-dioxabicyclo[3.3.1]nonane skeleton under acidic conditions, and regioselective Friedel-Crafts acylation at a later stage. PMID- 30001682 TI - Australian Media Messages: Critical Discourse Analysis of Two Intimate Homicides Involving Domestic Violence. AB - This study uses critical discourse analysis to examine news reporting of two cases of intimate partner violence in Australia. The fine-grained analysis of newswriting and news-editing practices focuses particularly on the lexical features and referential strategies used to represent the perpetrator and the victim, the crime, and the location of the crime. Findings show that reporting often omits social context, sensationalizes, and acts to shift blame in ways that do not increase public understanding of the nature of domestic violence. These results build on international findings and add to the evidence base about media reporting of violence against women. PMID- 30001683 TI - Efficacy of single dose albendazole and praziquantel drugs among helminth infected school children at Rural Bahir Dar, northwest Ethiopia. AB - The resistance of anthelminthic drugs makes helminth control difficult. The aim of our study was to assess the efficacy of single dose albendazole and praziquantel drugs among helminth-infected children. A cross-sectional study was conducted from April to June, 2017. Stool examination was done by the Formol Ether concentration technique. Students infected with geohelminths and s chistosoma mansoni were treated with a single dose of albendazole and praziquantel, respectively. Post-treatment stool examination was performed after two weeks. The magnitude of parasite infection, percentage of egg count reduction and cure rate following treatment were calculated using descriptive statistics. A total of 409 Sebatamet primary school students were included. The total prevalence of intestinal parasitosis was 58%. The cure rate of albendazole against hookworm was only 76.8%. Praziquantel had a 91.4% cure rate against Schistosoma mansoni. Therefore, periodic evaluation of the efficacy of anthelminthic drugs is required. PMID- 30001684 TI - Variable selection for random effects two-part models. AB - Random effects two-part models have been applied to longitudinal studies for zero inflated (or semi-continuous) data, characterized by a large portion of zero values and continuous non-zero (positive) values. Examples include monthly medical costs, daily alcohol drinks, relative abundance of microbiome, etc. With the advance of information technology for data collection and storage, the number of variables available to researchers can be rather large in such studies. To avoid curse of dimensionality and facilitate decision making, it is critically important to select covariates that are truly related to the outcome. However, owing to its intricate nature, there is not yet a satisfactory variable selection method available for such sophisticated models. In this paper, we seek a feasible way of conducting variable selection for random effects two-part models on the basis of the recently proposed "minimum information criterion" (MIC) method. We demonstrate that the MIC formulation leads to a reasonable formulation of sparse estimation, which can be conveniently solved with SAS Proc NLMIXED. The performance of our approach is evaluated through simulation, and an application to a longitudinal alcohol dependence study is provided. PMID- 30001685 TI - Estimating men's fertility from vital registration data with missing values. AB - Comparative perspectives on men's fertility are still rare, in part because vital registration data are often missing paternal age information for a substantial number of births. We compare two imputation approaches that attempt to estimate men's age-specific fertility rates and related measures for data in which paternal age information is missing for a non-negligible number of cases. Taking births with paternal age information as a reference, the first approach uses the unconditional paternal age distribution, while the second approach considers the paternal age distribution conditional on the maternal age. To assess the performance of these two methods, we conduct simulations that mimic vital registration data for Sweden, the United States, Spain, and Estonia. In these simulations, we vary the overall proportion and the age selectivity of missing values. We find that the conditional approach outperforms the unconditional approach in the majority of simulations and therefore should be generally preferred. PMID- 30001686 TI - The introduction of IMITATE-R and its comparison with the IMITATE treatment method in the naming ability of two Persian speaking aphasic patients. AB - Mirror neurons that have properties of audio/visual-acuity play a key role in imitation of movement performance. Since speech is a collection of coordinated movements in the producing organs, observing and imitation of speech movements can stimulate these neurons. In addition, observing hand movements trigger some actions related to the verbal cortex in the network of mirror neurons. According to the hypothesis of mirror neurons, new therapeutic approaches, including IMITATE, have been proposed for patients with aphasia. In the present study, using the IMITATE programme, a new therapeutic approach called IMITATE-R was planned based on observation of oral movements, hand gestures, and imitation of oral movements. Afterward, the IMITATE and IMITATE-R methods were compared with each other on naming skills of two Persian people with aphasia. The results showed that the rate of benefit from each treatment in each client was proportional to its individual and linguistic characteristics; however, in both patients, the IMITATE-R method was more effective in improving the naming skill. The results of this study were aimed at confirming the hypothesis of mirror neurons and the use of methods are based on action-observation for the treatment of patients with aphasia. PMID- 30001690 TI - Perspectives on Neuroscience and Behavior. PMID- 30001691 TI - Corrigendum to reporting the impact of inferior vena cava perforation by filters. AB - Wood EA, Malgor RD, Gasparis AP and Labropoulos N. Reporting the impact of inferior vena cava perforation by filters. Phlebology 2014; 29: 471-475. DOI: 10.1177/0268355513491723 The authors regret that conflicts of interest were omitted from the original published version of the above article. Antonios Gasparis would like to declare that at the time of authoring this paper he conducted work with Cook Medical and Bard Medical. PMID- 30001693 TI - trumpet: transcriptome-guided quality assessment of m6A-seq data. AB - BACKGROUND: Methylated RNA immunoprecipitation sequencing (MeRIP-seq or m6A-seq) has been extensively used for profiling transcriptome-wide distribution of RNA N6 Methyl-Adnosine methylation. However, due to the intrinsic properties of RNA molecules and the intricate procedures of this technique, m6A-seq data often suffer from various flaws. A convenient and comprehensive tool is needed to assess the quality of m6A-seq data to ensure that they are suitable for subsequent analysis. RESULTS: From a technical perspective, m6A-seq can be considered as a combination of ChIP-seq and RNA-seq; hence, by effectively combing the data quality assessment metrics of the two techniques, we developed the trumpet R package for evaluation of m6A-seq data quality. The trumpet package takes the aligned BAM files from m6A-seq data together with the transcriptome information as the inputs to generate a quality assessment report in the HTML format. CONCLUSIONS: The trumpet R package makes a valuable tool for assessing the data quality of m6A-seq, and it is also applicable to other fragmented RNA immunoprecipitation sequencing techniques, including m1A-seq, CeU-Seq, Psi-seq, etc. PMID- 30001695 TI - Xanthine calculi in a patient with Lesch-Nyhan syndrome and factor V Leiden treated with allopurinol: case report. AB - BACKGROUND: Lesch-Nyhan syndrome is a rare inborn error of purine metabolism marked by a complete deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Inherited as an X-linked recessive genetic disorder that primarily affects males, patients with Lesch-Nyhan syndrome exhibit severe neurological impairments, including choreoathetosis, ballismus, cognitive dysfunction, and self-injurious behavior. Uric acid levels are usually abnormally high, leading to kidney and bladder stones which often necessitate urological intervention. Factor V Leiden is an autosomal dominant disorder of blood clotting associated with hypercoagulability, thrombophilia, and renal disease. CASE PRESENTATION: We present the first reported case of xanthine calculi in a patient with Lesch-Nyhan syndrome and Factor V Leiden who was treated with allopurinol. A renal ultrasound and CT scan demonstrated bilateral staghorn calculi in the kidneys as well as nephrocalcinosis. Two years earlier the patient underwent cystoscopy with bilateral ureteroscopy and laser lithotripsy, and he was stone free afterwards. The patient subsequently underwent bilateral percutaneous nephrolithotomy (PCNL) and was stone free following the procedure. Patients with endogenous overproduction of uric acid who are being treated with allopurinol have a higher chance of developing xanthine stones. CONCLUSIONS: Pediatricians treating these children should be aware of these rare conditions and promptly manage the potential complications that may require medical or surgical intervention. PMID- 30001694 TI - Alternative empirical Bayes models for adjusting for batch effects in genomic studies. AB - BACKGROUND: Combining genomic data sets from multiple studies is advantageous to increase statistical power in studies where logistical considerations restrict sample size or require the sequential generation of data. However, significant technical heterogeneity is commonly observed across multiple batches of data that are generated from different processing or reagent batches, experimenters, protocols, or profiling platforms. These so-called batch effects often confound true biological relationships in the data, reducing the power benefits of combining multiple batches, and may even lead to spurious results in some combined studies. Therefore there is significant need for effective methods and software tools that account for batch effects in high-throughput genomic studies. RESULTS: Here we contribute multiple methods and software tools for improved combination and analysis of data from multiple batches. In particular, we provide batch effect solutions for cases where the severity of the batch effects is not extreme, and for cases where one high-quality batch can serve as a reference, such as the training set in a biomarker study. We illustrate our approaches and software in both simulated and real data scenarios. CONCLUSIONS: We demonstrate the value of these new contributions compared to currently established approaches in the specified batch correction situations. PMID- 30001696 TI - Is recession bad for your mental health? The answer could be complex: evidence from the 2008 crisis in Spain. AB - BACKGROUND: We explored the impact of 2008 recession on the prevalence of mental health problems in Spain. METHODS: Repeated cross-sectional survey design. Datasets from 2006 and 2011 were used, and temporal change was examined. The study was conducted on the economically active population (16-64 years old). The two surveys included 29,478 and 21,007 people, obtaining a 96 and 89.6% response rate, respectively. Multiple logistic regression models were adjusted to identify poor mental health risk factors. A standardisation analysis was performed to estimate the prevalence of people at risk of poor mental health (GHQ+). RESULTS: The prevalence of GHQ+ following the crisis increased in men and decreased in women. Two logistic regression analyses identified GHQ+ risk factors. From 2006 to 2011, unemployment rose and income fell for both men and women, and there was a decline in the prevalence of somatic illness and limitations, factors associated with a higher prevalence of GHQ+. After controlling for age, the change in employment and income among men prompted an increase in the prevalence of GHQ+, while the change in somatic illness and limitations tended to mitigate this effect. After the recession, unemployed men showed a better level of somatic health. The same effects were not detected in women. CONCLUSIONS: The economic recession exerted a complex effect on mental health problems in men. The reduction of prevalence in women was not associated with changes in socioeconomic factors related to the economic crisis nor with changes in somatic health. PMID- 30001697 TI - Interrelation between Tween and the membrane properties and high pressure tolerance of Lactobacillus plantarum. AB - Tween(r) 80 is a frequently used supplement of media for the cultivation of lactic acid bacteria. We investigated its effect on the cell physiology and stress tolerance of Lactobacillus (L.) plantarum. Data on the transcriptomic response to Tween 80 supplementation and its effects on cellular fatty acid profiles and growth characteristics are compared with data characterizing the effect of Tween 80, other Tween types and free fatty acids on the high hydrostatic pressure (HHP) tolerance of L. plantarum strain TMW 1.708. These include effects on cell viability, sub-lethal injury, metabolic activity, protein release and propidium iodide uptake. Tween 80 caused the downregulation of fatty acid biosynthesis and an increase in oleic acid and cyclopropane fatty acid levels in the cell membrane. Tween 20, Tween 80 and free oleic acid, but not Tween 40, Tween 60 and other free fatty acids, conferred resistance against HHP. Tween 80 diminished pressure-induced loss of metabolic activity, protein release and uptake of propidium iodide. However, loss of cell viability exceeded by far membrane permeabilization, suggesting that membrane permeabilization, which has frequently been postulated as a major factor in HHP inactivation of microbes, is not necessarily required for HHP-induced cell death of Lactobacillus plantarum. PMID- 30001698 TI - Challenges in supporting lay carers of patients at the end of life: results from focus group discussions with primary healthcare providers. AB - BACKGROUND: Family caregivers (FCGs) of patients at the end of life (EoL) cared for at home receive support from professional and non-professional care providers. Healthcare providers in general practice play an important role as they coordinate care and establish contacts between the parties concerned. To identify potential intervention targets, this study deals with the challenges healthcare providers in general practice face in EoL care situations including patients, caregivers and networks. METHODS: Focus group discussions with general practice teams in Germany were conducted to identify barriers to and enablers of an optimal support for family caregivers. Focus group discussions were analysed using content analysis. RESULTS: Nineteen providers from 11 general practices took part in 4 focus group discussions. Participants identified challenges in communication with patients, caregivers and within the professional network. Communication with patients and caregivers focused on non-verbal messages, communicating at an appropriate time and perceiving patient and caregiver as a unit of care. Practice teams perceive themselves as an important part of the healthcare network, but also report difficulties in communication and cooperation with other healthcare providers. CONCLUSION: Healthcare providers in general practice identified relational challenges in daily primary palliative care with potential implications for EoL care. Communication and collaboration with patients, caregivers and among healthcare providers give opportunities for improving palliative care with a focus on the patient-caregiver dyad. It is insufficient to demand a (professional) support network; existing structures need to be recognized and included into the care. PMID- 30001699 TI - Setting standards for empirical bioethics research: a response to Carter and Cribb. AB - This paper responds to the commentaries from Stacy Carter and Alan Cribb. We pick up on two main themes in our response. First, we reflect on how the process of setting standards for empirical bioethics research entails drawing boundaries around what research counts as empirical bioethics research, and we discuss whether the standards agreed in the consensus process draw these boundaries correctly. Second, we expand on the discussion in the original paper of the role and significance of the concept of 'integrating' empirical methods and ethical argument as a standard for research practice within empirical bioethics. PMID- 30001700 TI - Elimination of PCR duplicates in RNA-seq and small RNA-seq using unique molecular identifiers. AB - BACKGROUND: RNA-seq and small RNA-seq are powerful, quantitative tools to study gene regulation and function. Common high-throughput sequencing methods rely on polymerase chain reaction (PCR) to expand the starting material, but not every molecule amplifies equally, causing some to be overrepresented. Unique molecular identifiers (UMIs) can be used to distinguish undesirable PCR duplicates derived from a single molecule and identical but biologically meaningful reads from different molecules. RESULTS: We have incorporated UMIs into RNA-seq and small RNA-seq protocols and developed tools to analyze the resulting data. Our UMIs contain stretches of random nucleotides whose lengths sufficiently capture diverse molecule species in both RNA-seq and small RNA-seq libraries generated from mouse testis. Our approach yields high-quality data while allowing unique tagging of all molecules in high-depth libraries. CONCLUSIONS: Using simulated and real datasets, we demonstrate that our methods increase the reproducibility of RNA-seq and small RNA-seq data. Notably, we find that the amount of starting material and sequencing depth, but not the number of PCR cycles, determine PCR duplicate frequency. Finally, we show that computational removal of PCR duplicates based only on their mapping coordinates introduces substantial bias into data analysis. PMID- 30001701 TI - The CHIP-Family study to improve the psychosocial wellbeing of young children with congenital heart disease and their families: design of a randomized controlled trial. AB - BACKGROUND: Children with congenital heart disease (CHD) are at increased risk for behavioral, emotional, and cognitive problems. They often have reduced exercise capacity and participate less in sports, which is associated with a lower quality of life. Starting school may present more challenges for children with CHD and their families than for families with healthy children. Moreover, parents of children with CHD are at risk for psychosocial problems. Therefore, a family-centered psychosocial intervention for children with CHD when starting school is needed. Until now, the 'Congenital Heart Disease Intervention Program (CHIP) - School' is the only evidence-based intervention in this field. However, CHIP-School targeted parents only and resulted in non-significant, though positive, effects as to child psychosocial wellbeing. Hence, we expanded CHIP by adding a specific child module and including siblings, creating the CHIP-Family intervention. The CHIP-Family study aims to (1) test the effects of CHIP-Family on parental mental health and psychosocial wellbeing of CHD-children and to (2) identify baseline psychosocial and medical predictors for the effectiveness of CHIP-Family. METHODS: We will conduct a single-blinded randomized controlled trial comparing the effects of CHIP-Family with care as usual (no psychosocial intervention). Children with CHD (4-7 years old) who are starting or attending kindergarten or primary school (first or second year) at the time of first assessment and their families are eligible. CHIP-Family consists of a separate one-day workshop for parents and children. The child workshop consists of psychological exercises based on the evidence-based cognitive behavioral therapy Fun FRIENDS protocol and sports exercises. The parent workshop focuses on problem prevention therapy, psychoeducation, general parenting skills, skills specific to parenting a child with CHD, and medical issues. Approximately 4 weeks after the workshop, parents receive an individual follow-up session. The baseline (T1) and follow-up assessment (T2 = 6 months after T1) consist of online questionnaires filled out by the child, parents, and teacher (T2 only). Primary outcome measures are the CBCL for children and the SCL-90-R for parents. DISCUSSION: This trial aims to test the effects of an early family-centered psychosocial intervention to meet the compelling need of young children with CHD and their families to prevent (further) problems. If CHIP-Family proves to be effective, it should be structurally implemented in standard care. TRIAL REGISTRATION: Dutch Trial Registry; NTR6063 on 23 August, 2016. PMID- 30001702 TI - npInv: accurate detection and genotyping of inversions using long read sub alignment. AB - BACKGROUND: Detection of genomic inversions remains challenging. Many existing methods primarily target inzversions with a non repetitive breakpoint, leaving inverted repeat (IR) mediated non-allelic homologous recombination (NAHR) inversions largely unexplored. RESULT: We present npInv, a novel tool specifically for detecting and genotyping NAHR inversion using long read sub alignment of long read sequencing data. We benchmark npInv with other tools in both simulation and real data. We use npInv to generate a whole-genome inversion map for NA12878 consisting of 30 NAHR inversions (of which 15 are novel), including all previously known NAHR mediated inversions in NA12878 with flanking IR less than 7kb. Our genotyping accuracy on this dataset was 94%. We used PCR to confirm the presence of two of these novel inversions. We show that there is a near linear relationship between the length of flanking IR and the minimum inversion size, without inverted repeats. CONCLUSION: The application of npInv shows high accuracy in both simulation and real data. The results give deeper insight into understanding inversion. PMID- 30001703 TI - Positive STEPS - a randomized controlled efficacy trial of an adaptive intervention for strengthening adherence to antiretroviral HIV treatment among youth: study protocol. AB - BACKGROUND: HIV infection among youth in the United States is on the rise. A high level of antiretroviral therapy (ART) adherence is crucial to treatment success and can minimize the population burden of the disease. However, the overall rate of ART adherence among youth is generally suboptimal and no published efficacious interventions exist to address the specific needs of this population. This paper describes the design of a stepped-care, "adaptive" ART adherence intervention protocol for HIV-infected adolescents and young adults. METHODS: This is a randomized controlled trial (RCT) to establish the efficacy of "Positive STEPS," a behavioral and technology-based intervention to optimize ART adherence and viral suppression among HIV-infected youth, ages 16 to 29. Participants are equally randomized to 1) the Positive STEPS intervention, which begins with two way daily text messaging as a reminder system to take their medications; participants progress to a more intensive in-person counseling intervention if text messaging is not sufficient to overcome barriers; or 2) or standard of care (SOC). At randomization, all participants receive standardized ART adherence education. During the 4 major study assessment visits (baseline, 4-, 8-, and 12 months), participants have their blood drawn to measure HIV viral load and complete a mix of computer-based self-administered and interviewer-administered behavioral and psychosocial measures. The primary outcomes are improvements in viral load and ART adherence measured via a medication-tracking device (i.e., Wisepill) and self-report. DISCUSSION: Behavioral interventions are greatly needed to improve ART adherence among HIV-infected adolescents and young adults and prevent onward transmission. If effective, the intervention tested here will be one of the first rigorously-designed efficacy trials to promote ART adherence in this population, using an approach that holds promise for being readily integrated into real-world clinical settings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT03092531 , registered March 28, 2017. PMID- 30001705 TI - Preservation of kidney function in kidney transplant recipients by alkali therapy (Preserve-Transplant Study): rationale and study protocol. AB - BACKGROUND: Graft survival after kidney transplantation has significantly improved within the last decades but there is a substantial number of patients with declining transplant function and graft loss. Over the past years several studies have shown that metabolic acidosis plays an important role in the progression of Chronic Kidney Disease (CKD) and that alkalinizing therapies significantly delayed progression of CKD. Importantly, metabolic acidosis is highly prevalent in renal transplant patients and a recent retrospective study has shown that metabolic acidosis is associated with increased risk of graft loss and patient death in kidney transplant recipients. However, no prospective trial has been initiated yet to test the role of alkali treatment on renal allograft function. METHODS: The Preserve-Transplant Study is an investigator-initiated, prospective, patient-blinded, multi-center, randomized, controlled phase-IV trial with two parallel-groups comparing sodium bicarbonate to placebo. The primary objective is to test if alkali treatment will preserve kidney graft function and diminish the progression of CKD in renal transplant patients by assesing the change in eGFR over 2 years from baseline. Additionally we want to investigate the underlying pathomechanisms of nephrotoxicity of metabolic acidosis. DISCUSSION: This study has the potential to provide evidence that alkali treatment may slow or reduce the progression towards graft failure and significantly decrease the rate of end stage renal disease (ESRD), thus prolonging long-term graft survival. The implementation of alkali therapy into the drug regimen of kidney transplant recipients would have a favorable risk benefit ratio since alkali supplements are routinely used in CKD patients and represent a well-tolerated, safe and cost-effective treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03102996 . Trial registration was completed on April 6, 2017. PMID- 30001704 TI - Web-based intervention to improve quality of life in late stage bipolar disorder (ORBIT): randomised controlled trial protocol. AB - BACKGROUND: The primary objective of this randomised controlled trial (RCT) is to establish the effectiveness of a novel online quality of life (QoL) intervention tailored for people with late stage (>= 10 episodes) bipolar disorder (BD) compared with psychoeducation. Relative to early stage individuals, this late stage group may not benefit as much from existing psychosocial treatments. The intervention is a guided self-help, mindfulness based intervention (MBI) developed in consultation with consumers, designed specifically for web-based delivery, with email coaching support. METHODS/DESIGN: This international RCT will involve a comparison of the effectiveness and cost-effectiveness of two 5 week adjunctive online self-management interventions: Mindfulness for Bipolar 2.0 and an active control (Psychoeducation for Bipolar). A total of 300 participants will be recruited primarily via social media channels. Main inclusion criteria are: a diagnosis of BD (confirmed via a phone-administered structured diagnostic interview), no current mood episode, history of 10 or more mood episodes, no current psychotic features or active suicidality, under the care of a medical practitioner. Block randomisation will be used for allocation to the interventions, and participants will retain access to the program for 6 months. Evaluations will be conducted at pre- and post- treatment, and at 3- and 6- months follow-up. The primary outcome measure will be the Brief Quality of Life in Bipolar Disorder Scale (Brief QoL.BD), collected immediately post-intervention at 5 weeks (T1). Secondary measures include BD-related symptoms (mania, depression, anxiety, stress), time to first relapse, functioning, sleep quality, social rhythm stability and resource use. Measurements will be collected online and via telephone assessments at baseline (T0), 5 weeks (T1), three months (T2) and six months (T3). Candidate moderators (diagnosis, anxiety or substance comorbidities, demographics and current treatments) will be investigated as will putative therapeutic mechanisms including mindfulness, emotion regulation and self-compassion. A cost-effectiveness analysis will be conducted. Acceptability and any unwanted events (including adverse treatment reactions) will be documented and explored. DISCUSSION: This definitive trial will test the effectiveness and cost-effectiveness of a novel QoL focused, mindfulness based, online guided self-help intervention for late stage BD, and investigate its putative mechanisms of therapeutic action. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03197974 . Registered 23 June 2017. PMID- 30001706 TI - Gene expression profiles in neurological tissues during West Nile virus infection: a critical meta-analysis. AB - BACKGROUND: Infections with the West Nile virus (WNV) can attack neurological tissues in the host and alter gene expression levels therein. Several individual studies have analyzed these changes in the transcriptome based on measurements with DNA microarrays. Individual microarray studies produce a high-dimensional data structure with the number of studied genes exceeding the available sample size by far. Therefore, the level of scientific evidence of these studies is rather low and results can remain uncertain. Furthermore, the individual studies concentrate on different types of tissues or different time points after infection. A general statement regarding the transcriptional changes through WNV infection in neurological tissues is therefore hard to make. We screened public databases for transcriptome expression studies related to WNV infections and used different analysis pipelines to perform meta-analyses of these data with the goal of obtaining more stable results and increasing the level of evidence. RESULTS: We generated new lists of genes differentially expressed between WNV infected neurological tissues and control samples. A comparison with these genes to findings of a meta-analysis of immunological tissues is performed to figure out tissue-specific differences. While 5.879 genes were identified exclusively in the neurological tissues, 15 genes were found exclusively in the immunological tissues, and 44 genes were commonly detected in both tissues. Most findings of the original studies could be confirmed by the meta-analysis with a higher statistical power, but some genes and GO terms related to WNV were newly detected, too. In addition, we identified gene ontology terms related to certain infection processes, which are significantly enriched among the differentially expressed genes. In the neurological tissues, 17 gene ontology terms were found significantly different, and 2 terms in the immunological tissues. CONCLUSIONS: A critical discussion of our findings shows benefits but also limitations of the meta-analytic approach. In summary, the produced gene lists, identified gene ontology terms and network reconstructions appear to be more reliable than the results from the individual studies. Our meta-analysis provides a basis for further research on the transcriptional mechanisms by WNV infections in neurological tissues. PMID- 30001708 TI - Modelling population-level impact to inform target product profiles for childhood malaria vaccines. AB - BACKGROUND: The RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5-17-month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program. Work is ongoing to optimise this vaccine, with higher efficacy for a different schedule demonstrated in a phase 2a challenge study. The objective of our study was to investigate the population-level impact of a modified RTS,S/AS01 schedule and dose amount in order to inform the target product profile for a second generation malaria vaccine. METHODS: We used a mathematical modelling approach as the basis for our study. We simulated the changing anti-circumsporozoite antibody titre following vaccination and related the titre to vaccine efficacy. We then implemented this efficacy profile within an individual-based model of malaria transmission. We compared initial efficacy, duration and dose timing, and evaluated the potential public health impact of a modified vaccine in children aged 5-17 months, measuring clinical cases averted in children younger than 5 years. RESULTS: In the first decade of delivery, initial efficacy was associated with a higher reduction in childhood clinical cases compared to vaccine duration. This effect was more pronounced in high transmission settings and was due to the efficacy benefit occurring in younger ages where disease burden is highest. However, the low initial efficacy and long duration schedule averted more cases across all age cohorts if a longer time horizon was considered. We observed an age-shifting effect due to the changing immunological profile in higher transmission settings, in scenarios where initial efficacy was higher, and the fourth dose administered earlier. CONCLUSIONS: Our findings indicate that, for an imperfect childhood malaria vaccine with suboptimal efficacy, it may be advantageous to prioritise initial efficacy over duration. We predict that a modified vaccine could outperform the current RTS,S/AS01, although fourth dose timing will affect the age group that derives the greatest benefit. Further, the outcome measure and timeframe over which a vaccine is assessed are important when prioritising vaccine elements. This study provides insight into the most important characteristics of a malaria vaccine for at-risk groups and shows how distinct vaccine properties translate to public health outcomes. These findings may be used to prioritise target product profile elements for second-generation childhood malaria vaccines. PMID- 30001707 TI - LncRNA PVT1 triggers Cyto-protective autophagy and promotes pancreatic ductal adenocarcinoma development via the miR-20a-5p/ULK1 Axis. AB - BACKGROUND: Defective autophagy is thought to contribute to the pathogenesis of many diseases, including cancer. Human plasmacytoma variant translocation 1 (PVT1) is an oncogenic long non-coding RNA that has been identified as a prognostic biomarker in pancreatic ductal adenocarcinoma, but how PVT1 operates in the regulation of autophagy in pancreatic ductal adenocarcinoma (PDA) is unclear. METHODS: PVT1 expression level was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and hybridization in situ (ISH). Western blot or qRT-PCR was performed to assess the ULK1 protein or mRNA level. Autophagy was explored via autophagic flux detection under a confocal microscope and autophagic vacuoles investigation under a transmission electron microscopy (TEM). The biological role of PVT1 in autophagy and PDA development was determined by gain of-function and loss-of-function assays. RESULTS: We found that PVT1 levels paralleled those of ULK1 protein in PDA cancer tissues. PVT1 promoted cyto protective autophagy and cell growth by targeting ULK1 both in vitro and in vivo. Moreover, high PVT1 expression was associated with poor prognosis. Furthermore, we found that PVT1 acted as sponge to regulate miR-20a-5p and thus affected ULK1 expression and the development of pancreatic ductal adenocarcinoma. CONCLUSIONS: The present study demonstrates that the "PVT1/miR-20a-5p/ULK1/autophagy" pathway modulates the development of pancreatic ductal adenocarcinoma and may be a novel target for developing therapeutic strategies for pancreatic ductal adenocarcinoma. PMID- 30001709 TI - Evaluation of distance learning IMCI training program: the case of Tanzania. AB - BACKGROUND: The standard 11-days IMCI (Integrated Management of Childhood Illness) training course (standard IMCI) has faced barriers such as high cost to scale up. Distance learning IMCI training program was developed as an alternative to the standard IMCI course. This article presents the evaluation results of the implementation of distance learning IMCI training program in Tanzania. METHODS: From December 2012 to end of June 2015, a total of 4806 health care providers (HCP) were trained on distance learning IMCI from 1427 health facilities {HF) in 68 districts in Tanzania. Clinical assessments were done at the end of each course and on follow up visits of health facilities 4 to 6 weeks after training. The results of those assessments are used to compare performance of health care providers trained in distance learning IMCI with those trained in the standard IMCI course. Statistical analysis is done by comparing proportions of those with appropriate performances using four WHO priority performance indicators as well as cost of conducting the courses. In addition, the perspectives of health care providers, IMCI course facilitators, policy makers and partners were gathered using either focussed group discussions or structured questionnaires. RESULTS: Distance learning IMCI allowed clusters of training courses to take place in parallel, allowing rapid expansion of IMCI coverage. Health care providers trained in distance learning IMCI performed equally well as those trained in the standard IMCI course in assessing Main Symptoms, treating sick children and counselling caretakers appropriately. They performed better in assessing Danger Signs. Distance learning IMCI gave a 70% reduction in cost of conducting the training courses. CONCLUSION: Distance learning IMCI is an alternative to scaling up IMCI as it provides an effective option with significant cost reduction in conducting training courses. PMID- 30001710 TI - Effect of glutaraldehyde based cross-linking on the viscoelasticity of mitral valve basal chordae tendineae. AB - BACKGROUND: Mitral valve failure can require repair or replacement. Replacement bioprosthetic valves are treated with glutaraldehyde prior to implantation. The aim of this study was to determine the changes in mechanical properties following glutaraldehyde fixation of mitral valve chordae. METHODS: To investigate the impact of glutaraldehyde on mitral valve chordae, 24 basal chordae were dissected from four porcine hearts. Anterior and posterior basal (including strut) chordae were used. All 24 chordae were subjected to a sinusoidally varying load (mean level 2N, dynamic amplitude 2N) over a frequency range of 0.5-10 Hz before and after glutaraldehyde treatment. RESULTS: The storage and loss modulus of all chordal types decreased following glutaraldehyde fixation. The storage modulus ranged from: 108 to 119 MPa before fixation and 67.3-87.4 MPa following fixation for basal chordae; 52.3-58.4 MPa before fixation and 47.9-53.5 MPa following fixation for strut chordae. Similarly, the loss modulus ranged from: 5.47 to 6.25 MPa before fixation and 3.63-4.94 MPa following fixation for basal chordae; 2.60 2.97 MPa before fixation and 2.31-2.93 MPa following fixation for strut chordae. CONCLUSION: The viscoelastic properties of mitral valve chordae are affected by glutaraldehyde fixation; in particular, the reduction in storage moduli decreased with an increase in chordal diameter. PMID- 30001711 TI - Detecting germline BAP1 mutations in patients with peritoneal mesothelioma: benefits to patient and family members. AB - Germline mutations in the BRCA-1 associated tumor protein 1 (BAP1) increase susceptibility to mesothelioma and other cancers. We describe a patient with a family history of peritoneal mesothelioma, who developed malignant peritoneal mesothelioma at age 45 in the absence of known asbestos exposure. These findings lead us to hypothesize that the mesothelioma occurred in the setting of germline a BAP1 mutation. This was confirmed by genetic testing. The subsequent therapeutic choices for the patient and testing of at-risk family members highlight the importance of recognizing this genetic syndrome and screening for individuals at high risk. PMID- 30001712 TI - Anti-inflammatory duration of action of fluticasone furoate/vilanterol trifenatate in asthma: a cross-over randomised controlled trial. AB - BACKGROUND: Fluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action. METHODS: A single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naive adults with asthma. Participants with an FEV1 >= 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation. RESULTS: In the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42-212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61 0.86) with the maximum reduction occurring at day 14, 0.32 (0.27-0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59-1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment. CONCLUSIONS: The anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma. Funding GlaxoSmithKline (201499). TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov registry number NCT02712047 . PMID- 30001714 TI - A pilot study to profile salivary angiogenic factors to detect head and neck cancers. AB - BACKGROUND: Early diagnosis of head and neck squamous cell carcinoma (HNSCCs) is an appealing way to increase survival rates in these patients as well as to improve quality of life post-surgery. Angiogenesis is a hallmark of tumor initiation and progression. We have investigated a panel of angiogenic factors in saliva samples collected from HNSCC patients and controls using the Bio-Plex ProTM assays. METHODS: We have identified a panel of five angiogenic proteins (sEGFR, HGF, sHER2, sIL-6Ra and PECAM-1) to be elevated in the saliva samples collected from HNSCC patients (n = 58) compared to a control cohort (n = 8 smokers and n = 30 non-smokers). RESULTS: High positive correlations were observed between the following sets of salivary proteins; sEGFR:sHER2, sEGFR:HGF, sEGFR:sIL-6Ralpha, sHER2:HGF and sHER2:sIL6Ra. A moderate positive correlation was seen between FGF-basic and sEGFR. CONCLUSION: We have shown that angiogenic factor levels in saliva can be used as a potential diagnostic biomarker panel in HNSCC. PMID- 30001713 TI - Health outcomes associated with reallocations of time between sleep, sedentary behaviour, and physical activity: a systematic scoping review of isotemporal substitution studies. AB - BACKGROUND: During a 24-h day, each given period is spent in either sedentary behaviour, sleeping, light physical activity (LPA), or moderate-to-vigorous physical activity (MVPA). In epidemiological research most studies have traditionally analysed the associations of these behaviours in isolation from each other; that is, without taking into account the displacement of time spent in the remaining behaviours. In recent years, there has been a growing interest in exploring how all the behaviours across the energy expenditure spectrum influence health outcomes. A statistical model used to investigate these associations is termed an isotemporal substitution model (ISM). Considering the increasing number of ISM-based studies conducted in all age groups, the present paper aimed to: (i) review and summarise findings from studies that employed ISM in sleep, sedentary behaviour, and physical activity research; (ii) appraise the methodological quality of the studies; and (iii) suggest future research directions in this area. METHODS: A systematic search of ten databases was performed. The Newcastle-Ottawa scale was used to assess the methodological quality of the included studies. RESULTS: Fifty-six studies met the inclusion criteria, all being of moderate or high methodological quality. Associations were reported for exchanged time varying from one minute to 120 min/day across the studies, with 30 min/day being the most common amount of time reallocated. In total, three different ISM methodologies were used. The most commonly studied health outcomes in relation to isotemporal substitutions were mortality, general health, mental health, adiposity, fitness, and cardiometabolic biomarkers. It seems that reallocations of sedentary time to LPA or MVPA are associated with significant reduction in mortality risk. Current evidence appears to consistently suggest that reductions in mortality risk are greater when time spent sedentary is replaced with higher intensities of physical activity. For adiposity, it seems that reallocating sedentary time to physical activity may be associated with reduced body mass index, body fat percentage, and waist circumference in all age groups, with the magnitude of associations being greater for higher intensities of physical activity. While there is a relatively large body of evidence reporting beneficial associations between the reallocation of time from sedentary behaviour to LPA or MVPA and cardiometabolic biomarkers among adults, there is a lack of studies among children, adolescents, and older adults. Although some studies investigated general health, mental health, and fitness outcomes, further investigation of these topics is warranted. In general, it seems that the strongest association with health outcomes is observed when time is reallocated from sedentary behaviour to MVPA. Most studies did not account for sleep time, which is a major limitation of the current evidence. CONCLUSIONS: The current evidence indicates that time reallocation between sleep, sedentary behaviour, LPA, and MVPA may be associated with a number of health outcomes. Future studies should employ longitudinal designs, take into account all movement behaviours, and examine a wider range of health, psychological, social, economic, and environmental outcomes. PMID- 30001715 TI - Serial blood eosinophils and clinical outcome in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Blood eosinophils have been suggested as a potential biomarker in chronic obstructive pulmonary disease (COPD), and their stability over time has been investigated in a few studies. However, the association between the stability of blood eosinophils and long-term clinical outcomes in COPD patients has yet to be fully elucidated. This study aimed to evaluate the stability of blood eosinophils and its association with clinical outcomes in COPD patients. METHODS: In total, 299 COPD patients from the Korean Obstructive Lung Disease cohort with at least two blood eosinophil measurements were included. Patients were stratified according to a cut-off of 300 cells/MUL, and the association between eosinophil changes and all-cause mortality was analysed. The annual decline in forced expiratory volume in 1 s (FEV1), serial changes in St George's Respiratory Questionnaire score (SGRQ), and exacerbations during follow-up were compared among eosinophil groups. RESULTS: Patients were stratified into three groups according to the blood eosinophil cut-off: persistently < 300 cells/MUL (PL; n = 175), variable (V; n = 68), and persistently >=300 cells/MUL (PH; n = 56). There were no significant differences in baseline characteristics (age, sex, smoking, body mass index, use of inhaled corticosteroids, exacerbations in the previous year, FEV1 (L or % predicted), or emphysema score) among the groups. During a median follow-up of 6.0 years, the PH group had a better survival rate than the PL group (adjusted mortality rate ratio, 0.29; 95% confidence interval, 0.09-0.97; P = 0.045). The PH group also showed improved symptoms and impact domains of SGRQ score compared to the PL group. No difference was found in annual FEV1 decline or exacerbations during follow-up among the groups. CONCLUSIONS: Patients with persistently high blood eosinophils had a better survival rate than those with persistently low blood eosinophils. Serial follow-up of blood eosinophils could help to predict outcomes in COPD patients. PMID- 30001717 TI - Will artificial intelligence solve the human resource crisis in healthcare? AB - Artificial intelligence (AI) has the potential to ease the human resources crisis in healthcare by facilitating diagnostics, decision-making, big data analytics and administration, among others. For this we must first tackle the technological, ethical and legal obstacles.The human resource crisis is widening worldwide, and it is obvious that it is not possible to provide care without workforce. How can disruptive technologies in healthcare help solve the variety of human resource problems? Will technology empower physicians or replace them? How can the medical curriculum, including post-graduate education prepare professionals for the meaningful use of technology? These questions have been growing for decades, and the promise of disruptive technologies filling them is imminent with digital health becoming widespread. Authors of this essay argue that AI might not only fill the human resources gap, but also raises ethical questions we need to deal with today.While there are even more questions to address, our stand is that AI is not meant to replace caregivers, but those who use AI will probably replace those who don't. And it is possible to prepare for that. PMID- 30001716 TI - IL-33 receptor (ST2) deficiency downregulates myeloid precursors, inflammatory NK and dendritic cells in early phase of sepsis. AB - BACKGROUND: Sepsis is a life-threatening disease mediated by profound disturbances in systemic inflammatory response to infection. IL-33 is multifunctional regulator of numerous aspects of innate and adaptive immune response. The aim of this article was to further evaluate the role of IL-33 receptor (ST2) in different pathways of innate immunity during early polymicrobial sepsis. METHODS: Polymicrobial sepsis was induced using cecal ligation and puncture (CLP) model in ST2 deficient (ST2-/-) and wild type BALB/c mice. Peritoneal and spleen cells were isolated for further phenotyping. Apoptosis was determined by immunohistochemistry and flow cytometry. RESULTS: Deletion of ST2 leads to increased susceptibility to early manifestations of sepsis as evaluated by clinical signs and survival. These are accompanied by decrease in the total number of neutrophils, eosinophils and mast cells in peritoneal cavity 12 h after CLP. In early sepsis there was also low number of precursors of myeloid cells in particular CD11b+Ly6G+Ly6Clow cells in spleen of ST2-/- mice. Although the number of NK cells in the spleen was similar, there were significant differences in the presence of inflammatory IFN-gamma and IL-17 producing NK cells. Further, ST2 deletion affects the phenotype and maturation of dendritic cell in sepsis. The total number of dendritic cells in the spleen was lower as well as IL-12 expressing dendritic cells. Finally, there was higher frequency of active caspase-3 positive and early apoptotic cells, in particular CD11c positive cells, in spleen of septic ST2-/- mice. CONCLUSION: Taken together, our data provide the evidence that ST2 deficiency in early phase of sepsis downregulates myeloid precursors, inflammatory NK and dendritic cells. PMID- 30001718 TI - Distribution patterns of foot and ankle tumors: a university tumor institute experience. AB - BACKGROUND: Bone and soft tissue masses of the foot and ankle are not particularly rare but true neoplasia has to be strictly differentiated from pseudotumorous lesions. Diagnosis is often delayed as diagnostic errors are more common than in other regions. Awareness for this localization of musculoskeletal tumors is not very high and neoplasia is often not considered. The purpose of this study is to provide detailed information on the incidence and distribution patterns of foot and ankle tumors of a university tumor institute and propose a simple definition to facilitate comparison of future investigations. METHODS: As part of a retrospective, single-centre study, the data of patients that were treated for foot and ankle tumors between June 1997 and December 2015 in a musculoskeletal tumor centre were analyzed regarding epidemiologic information, entity and localization. Included were all cases with a true tumor of the foot and ankle. Exclusion criteria were incomplete information on the patient or entity (e.g. histopathological diagnosis) and all pseudotumoral lesions. RESULTS: Out of 7487 musculoskeletal tumors, 413 cases (5,52%) of tumors of the foot and ankle in 409 patients were included (215 male and 198 female patients). The average age of the affected patients was 36 +/- 18y (min.3y, max.92y). Two hundred sixty-six tumors involved the bone (64%), among them 231 (87%) benign and 35 (13%) malignant. There were 147 soft tissue tumors (36%), 104 (71%) were benign, 43 (29%) malignant. The most common benign osseous tumor lesions included simple bone cysts, enchondroma and osteochondroma. By far the most common malignant bone tumor was chondrosarcoma. Common benign soft tissue tumors included pigmented villo-nodular synovitis, superifcial fibromatosis and schwannoma whereas the most common malignant members were synovial sarcoma and myxofibrosarcoma. Regarding anatomical localization, the hindfoot was affected most often. CONCLUSIONS: Knowledge of incidence and distribution patterns of foot and ankle tumors will help to correctly assess unclear masses and initiate the right steps in further diagnostics and treatment. Unawareness can lead to delayed diagnosis and inadequate treatment with serious consequences for the affected patient. PMID- 30001719 TI - Anterior cervical discectomy and fusion with stand-alone anchored cages versus posterior laminectomy and fusion for four-level cervical spondylotic myelopathy: a retrospective study with 2-year follow-up. AB - BACKGROUND: The optimal treatment for multi-level cervical spondylotic myelopathy (CSM) remains controversial. Posterior approach is most commonly used, but complicated with insufficient decompression and postoperative axial neck pain. The anterior approach is effective in neural decompression with less surgical trauma. However, the profile of the plate or the possible construct failure may cause dysphagia after surgery. Recently, anterior cervical discectomy and fusion (ACDF) with self-anchored cage is reported to have a superior result over ACDF with anterior plates and screws in three-level CSM. The purpose of the study is to compare the clinical and radiological outcomes of ACDF using stand-alone anchored cages to that of laminectomy with fusion (LF) for treating four-level CSM. METHODS: Twenty-six patients underwent four-level ACDF (Group A) and 32 patients with four-level LF (Group B) were retrospectively reviewed and followed up for 24 months. Clinical efficacy was evaluated by comparing pre- and post operative Japanese Orthopedic Association (JOA) and Neck Disability Index (NDI) scores. Operative time, blood loss, fusion, lordosis change and complications were evaluated. RESULTS: There was significantly less blood loss in Group A (163.4 +/- 72.1 ml) than Group B (241.0 +/- 112.3 ml) (P < 0.05). Both groups demonstrated significant improvements in JOA and NDI scores after surgery with similar operative time. Improvements in cervical lordosis and fused segment lordosis were more pronounced in Group A (11.3 +/- 5.9 degrees , 9.7 +/- 5.3 degrees ) than Group B (5.8 +/- 4.6 degrees , 5.5 +/- 4.5 degrees ) (P < 0.05). Loss of lordosis in the cervical spine and fused segment was more prominent in Group A (11.7 +/- 2.2 degrees , 6.7 +/- 3.2 degrees ) than Group B (7.5 +/- 3.8 degrees , 3.7 +/- 3.4 degrees ) (P < 0.05) at the final follow-up. Complication rate in Group A and Group B was 57.69 and 18.75%, respectively. CONCLUSIONS: ACDF using a stand-alone anchored cage showed similar clinical results to LF for the treatment of four-level CSM, with better lordosis correction and less blood loss. However, ACDF was associated with more loss of lordosis after surgery and more non-unions. PMID- 30001720 TI - Diagnosis and mortality of emergency department patients in the North Denmark region. AB - BACKGROUND: Emergency departments handle a large proportion of acute patients. In 2007, it was recommended centralizing the Danish healthcare system and establishing emergency departments as the main common entrance for emergency patients. Since this reorganization, few studies describing the emergency patient population in this new setting have been carried out and none describing diagnoses and mortality. Hence, we aimed to investigate diagnoses and 1- and 30 day mortality of patients in the emergency departments in the North Denmark Region during 2014-2016. METHODS: Population-based historic cohort study in the North Denmark Region (580,000 inhabitants) of patients with contact to emergency departments during 2014-2016. The study included patients who were referred by general practitioners (daytime and out-of-hours), by emergency medical services or who were self-referred. Primary diagnoses (ICD-10) were retrieved from the regional Patient Administrative System. For non-specific diagnoses (ICD-10 chapter 'Symptoms and signs' and 'Other factors'), we searched the same hospital stay for a specific diagnosis and used this, if one was given. We performed descriptive analysis reporting distribution and frequency of diagnoses. Moreover, 1- and 30-day mortality rate estimates were performed using the Kaplan-Meier estimator. RESULTS: We included 290,590 patient contacts corresponding to 166 ED visits per 1000 inhabitants per year. The three most frequent ICD-10 chapters used were 'Injuries and poisoning' (38.3% n = 111,274), 'Symptoms and signs' (16.1% n = 46,852) and 'Other factors' (14.52% n = 42,195). Mortality at day 30 (95% confidence intervals) for these chapters were 0.86% (0.81-0.92), 3.95% (3.78 4.13) and 2.84% (2.69-3.00), respectively. The highest 30-day mortality were within chapters 'Neoplasms' (14.22% (12.07-16.72)), 'Endocrine diseases' (8.95% (8.21-9.75)) and 'Respiratory diseases' (8.44% (8.02-8.88)). CONCLUSIONS: Patients in contact with the emergency department receive a wide range of diagnoses within all chapters of ICD-10, and one third of the diagnoses given are non-specific. Within the non-specific chapters, we found a 30-day mortality, surpassing several of the more organ specific ICD-10 chapters. TRIAL REGISTRATION: Observational study - no trial registration was performed. PMID- 30001721 TI - The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4 mediated microglial inflammation. AB - BACKGROUND: The steroid hormone estrogen (17-beta-estradiol, E2) provides neuroprotection against cerebral ischemic injury by activating estrogen receptors. The novel estrogen receptor G protein-coupled receptor 30 (GPR30) is highly expressed in the brain and provides acute neuroprotection against stroke. However, the underlying mechanisms remain unclear. METHODS: In this study, ovariectomized female mice were subjected to middle cerebral artery occlusion (MCAO), and E2, G1, and ICI182780 were administered immediately upon reperfusion. The infarction volume, neurological scores, and neuronal injuries were examined. Primary microglial cells were subjected to oxygen-glucose deprivation (OGD), and the drugs were administered immediately upon reintroduction. The pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 in penumbra and microglia were assessed by ELISA. The cell viability and lactose dehydrogenase (LDH) release of neurons co-cultured with microglia were analyzed using cell counting kit-8 (CCK8) and LDH release assays. Microglial activation as well as GPR30, Iba1, and Toll-like receptor 4 (TLR4) protein expression and TLR4 mRNA expression were detected. Additionally, NF-kappaB activity was detected in lipopolysaccharide (LPS) activated microglia after the activation of GPR30. RESULTS: GPR30 was highly expressed in microglia and significantly increased after ischemic injury. The activation of GPR30 significantly reduced the infarction volume, improved the neurological deficit, and alleviated neuronal injuries. Moreover, GPR30 activation significantly reduced the release of TNF-alpha, IL-1beta, and IL-6 from ischemic penumbra and microglia subjected to OGD and alleviated neuronal injury as assessed using the CCK8 and LDH assays. Finally, the activation of GPR30 relieved microglial activation, reduced Iba1 and TLR4 protein expression and TLR4 mRNA levels, and inhibited NF-kappaB activity. CONCLUSIONS: Microglial GPR30 exerts acute neuroprotective effects by inhibiting TLR4-mediated microglial inflammation, which indicates that GPR30 may be a potential target for the treatment of ischemic stroke. PMID- 30001722 TI - Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury. AB - BACKGROUND: Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Exosomes from adipose derived stem cells (hASCs) containing the long noncoding RNA MALAT1 are a novel, cell-free regenerative approach to long-term recovery after traumatic brain injury (TBI) that have the potential to modulate inflammation at the genomic level. The long noncoding RNA MALAT1 has been shown to be an important component of the secretome of hASCs. METHODS: We isolated exosomes from hASC containing or depleted of MALAT1. The hASC-derived exosomes were then administered intravenously to rats following a mild controlled cortical impact (CCI). We followed the rats with behavior, in vivo imaging, histology, and RNA sequencing (RNA Seq). RESULTS: Using in vivo imaging, we show that exosomes migrate into the spleen within 1 h following administration and enter the brain several hours later following TBI. Significant recovery of function on motor behavior as well as a reduction in cortical brain injury was observed after TBI in rats treated with exosomes. Treatment with either exosomes depleted of MALAT1 or conditioned media depleted of exosomes showed limited regenerative effects, demonstrating the importance of MALAT1 in exosome-mediated recovery. Analysis of the brain and spleen transcriptome using RNA Seq showed MALAT1-dependent modulation of inflammation-related pathways, cell cycle, cell death, and regenerative molecular pathways. Importantly, our data demonstrates that MALAT1 regulates expression of other noncoding RNAs including snoRNAs. CONCLUSION: We demonstrate that MALAT1 in hASC-derived exosomes modulates multiple therapeutic targets, including inflammation, and has tremendous therapeutic potential for treatment of TBI. PMID- 30001723 TI - Evaluating the impact of multilevel evidence-based implementation strategies to enhance provider recommendation on human papillomavirus vaccination rates among an empaneled primary care patient population: a study protocol for a stepped wedge cluster randomized trial. AB - BACKGROUND: Each year, human papillomavirus (HPV) causes 30,000 cancers in the USA despite the availability of effective and safe vaccines. Uptake of HPV vaccine has been low and lags behind other adolescent vaccines. This protocol describes a multilevel intervention to improve HPV vaccination rates. METHODS: Using a cluster randomized trial, we will evaluate the independent and combined impact of two evidence-based implementation strategies with innovative enhancements on HPV vaccination rates for female and male patients. The clusters are six primary care sites providing care to pediatric populations. We will use a stepped-wedge cluster randomized design, including process evaluation, to test the hypothesis that compared with the current course of care and a practice-level intervention using reminder-recall interventions coupled with provider-level audit and feedback with education increases HPV vaccination rates in exposed clusters. The factorial design allows us to use a single trial to test these two interventions and to assess each individually and in combination. Our design has four 12-month steps. The first step will be a baseline period; data collected during it will provide a within-practice control group for each cluster. Second, two clusters will be randomly assigned to receive intervention 1 (reminder and recall), and two clusters will be randomly selected to receive intervention 2 (audit and feedback with education). Third, the other two clusters will be randomly allocated to intervention 1 or 2. Clusters initially with intervention 1 will be randomly allocated to 1 + 2 or 1; clusters initially with intervention 2 will be randomly allocated to 1 + 2 or 2. Fourth, all clusters will receive both interventions. To ensure balance of patient numbers across interventions, we will use block randomization at the first step, with the six clusters grouped into three pairs according to volume. Our primary outcome will be vaccination rates. DISCUSSION: Results of our clinical trial and process evaluation will provide evidence showing whether practice- and provider-level interventions improve HPV vaccination rates and will offer insight into contextual factors associated with direction and magnitude of trial outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03501992 , registered April 18, 2018. PMID- 30001725 TI - Relationships between the acoustic startle response and prepulse inhibition in C57BL/6J mice: a large-scale meta-analytic study. AB - Prepulse inhibition (PPI) is the suppression of a startle reflex response to a startle stimulus that occurs when a weak prepulse stimulus precedes the startle stimulus. PPI is measured to assess sensorimotor gating across species, including humans and rodents. Reduced PPI, which is thought to reflect dysfunction of sensorimotor gating, is reported in patients with psychiatric disorders, such as schizophrenia, bipolar disorder, and post-traumatic stress disorder (PTSD), and in animal models of these disorders. Individual differences in basal startle reactivity occur even in a genetically homogenous group of animals; however, there is limited information regarding whether basal levels of the startle response are associated with variations in PPI levels. Here, to explore the relationship between an acoustic startle response (ASR) and PPI, we performed a meta-analysis of data obtained from more than 1300 C57BL/6J male mice on the influence of an ASR to 110- and 120-dB startle stimuli on the PPI levels of the ASR at 74- and 78-dB prepulse intensities. Examination of scatter plots of the ASR amplitudes and PPI levels followed by correlation analyses indicated that there is no simple linear relationship between the two measures; when mice were divided into three groups on the basis of their startle amplitudes, there were positive correlations between the amplitude of the ASR to the 110-dB stimulus and PPI levels in a group of mice that showed lower ASR amplitudes among the genetically homogenous group, whereas no significant correlations were identified in groups of mice that showed intermediate and higher ASR amplitudes. As indicated by the correlation analysis, the lowest responders to the 110-dB stimulus exhibited lower levels of PPI than the intermediate or higher responders. In contrast, for the 120-dB stimulus, a negative correlation was identified between the amplitude of the ASR to the 120-dB stimulus and the PPI levels in the groups of mice that showed intermediate or higher ASR amplitudes. Lower and intermediate responders showed higher levels of PPI than higher responders to the 120-dB stimulus. These findings suggest that basal startle reactivity may affect PPI levels in male C57BL/6J mice, thus representing one potential confounding factor that may confuse the interpretation of PPI results. These findings emphasize the importance of careful examination of startle reactivity to ensure a reliable assessment of PPI. PMID- 30001724 TI - Pharmacokinetics of lotilaner following a single oral or intravenous administration in cats. AB - BACKGROUND: CredelioTM (lotilaner) is an oral ectoparasiticide from the isoxazoline class developed for the treatment of flea and tick infestations in cats. It is formulated as a pure S-enantiomer in flavoured chewable tablets. The pharmacokinetics of lotilaner were investigated after intravenous or oral administration and under fed or fasted conditions in cats. Twenty-six adult cats were enrolled in a pharmacokinetic study evaluating either intravenous or oral administration of lotilaner. Following the oral administration at a dosage of 6 mg/kg, under fed or fasted conditions, or intravenous administration of 3 mg/kg, blood samples were collected up to 35 days after treatment. Lotilaner blood concentrations were measured using a validated liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters were calculated by non compartmental analysis. In addition, in vivo enantiomer stability of lotilaner was evaluated in a separate bioanalytical study. RESULTS: Following oral administration in fed cats, lotilaner was readily absorbed and peak blood concentrations reached within four hours. The terminal half-life was 33.6 days. Food enhanced the absorption, providing close to 100% oral bioavailability and reduced the inter-individual variability. Following intravenous administration, lotilaner had a low clearance of 0.13 l/kg/day, large volumes of distribution Vz and Vss of 5.34 and 5.37 l/kg, respectively and a terminal half-life of 28.7 days. In addition, there was no in vivo racemization of lotilaner. CONCLUSIONS: The pharmacokinetic properties of lotilaner administered orally as a flavoured chewable tablet (CredelioTM) were studied in detail. With a Tmax of 4 h and a terminal half-life of 33.6 days under fed conditions, lotilaner provides a rapid onset of flea and tick killing activity with consistent and sustained efficacy for at least one month in cats. PMID- 30001726 TI - Autonomous multi-joint soft exosuit with augmentation-power-based control parameter tuning reduces energy cost of loaded walking. AB - BACKGROUND: Soft exosuits are a recent approach for assisting human locomotion, which apply assistive torques to the wearer through functional apparel. Over the past few years, there has been growing recognition of the importance of control individualization for such gait assistive devices to maximize benefit to the wearer. In this paper, we present an updated version of autonomous multi-joint soft exosuit, including an online parameter tuning method that customizes control parameters for each individual based on positive ankle augmentation power. METHODS: The soft exosuit is designed to assist with plantarflexion, hip flexion, and hip extension while walking. A mobile actuation system is mounted on a military rucksack, and forces generated by the actuation system are transmitted via Bowden cables to the exosuit. The controller performs an iterative force based position control of the Bowden cables on a step-by-step basis, delivering multi-articular (plantarflexion and hip flexion) assistance during push-off and hip extension assistance in early stance. To individualize the multi-articular assistance, an online parameter tuning method was developed that customizes two control parameters to maximize the positive augmentation power delivered to the ankle. To investigate the metabolic efficacy of the exosuit with wearer-specific parameters, human subject testing was conducted involving walking on a treadmill at 1.50 m s- 1 carrying a 6.8-kg loaded rucksack. Seven participants underwent the tuning process, and the metabolic cost of loaded walking was measured with and without wearing the exosuit using the individualized control parameters. RESULTS: The online parameter tuning method was capable of customizing the control parameters, creating a positive ankle augmentation power map for each individual. The subject-specific control parameters and resultant assistance profile shapes varied across the study participants. The exosuit with the wearer specific parameters significantly reduced the metabolic cost of load carriage by 14.88 +/- 1.09% (P = 5 * 10- 5) compared to walking without wearing the device and by 22.03 +/- 2.23% (P = 2 * 10- 5) compared to walking with the device unpowered. CONCLUSION: The autonomous multi-joint soft exosuit with subject specific control parameters tuned based on positive ankle augmentation power demonstrated the ability to improve human walking economy. Future studies will further investigate the effect of the augmentation-power-based control parameter tuning on wearer biomechanics and energetics. PMID- 30001727 TI - Laboratory evaluation of the efficacy and speed of kill of lotilaner (CredelioTM) against Ctenocephalides felis on cats. AB - BACKGROUND: Lotilaner is approved for dogs as a chewable tablet formulation. It has separately been developed for oral administration in cats (CredelioTM chewable tablets for cats) to meet the need for an easy to use, safe and rapidly effective parasiticide and as an alternative to topical products. This paper describes two pivotal laboratory studies assessing the efficacy and speed of kill of lotilaner in cats against Ctenocephalides felis fleas following a single oral administration, at the minimum recommended dose rate of 6 mg/kg. METHODS: Two GCP (Good Clinical Practice), blinded, randomized, negative-controlled, parallel groups, laboratory studies were performed. In both studies, lotilaner was administered once, per os, at the minimum recommended dose of 6 mg/kg. Study 1 evaluated the efficacy of lotilaner tablets for cats against adult C. felis in experimentally infested cats, 24 h after treatment and after new weekly infestations, until day 35. Study 2 evaluated the speed of kill of lotilaner against C. felis, in cats, 8 and 12 h after treatment and after each subsequent weekly infestation, through day 35. In both studies, for each assessed time point, animals were randomized 1:1 to a lotilaner-treated or a contemporaneous negative control group of 8 cats each. RESULTS: In both studies, the infestation in the control groups was adequate at all assessment times. In Study 1, efficacy at 24 h was 100% at all time points. In Study 2, efficacy was >= 97.4% at the 8 h and >= 98.6% at the 12 h time point, through one month. Lotilaner was well tolerated, with no product-related adverse events reported. CONCLUSIONS: Lotilaner administered orally to cats at the minimum recommended dose rate of 6 mg/kg was effective as early as 8 hours post-administration and at 8 hours after subsequent weekly infestations of adult C. felis for at least one month. The product was well-tolerated. PMID- 30001728 TI - Ethnobotanical knowledge of the lay people of Blouberg area (Pedi tribe), Limpopo Province, South Africa. AB - BACKGROUND: Limpopo province, South Africa, has a rich plant diversity and is referred to as one of the hotspots areas within the country. The aim of the current work was to identify and document medicinal plant species used by the indigenous Pedi people of Blouberg area, Limpopo Province, South Africa. METHODS: A total of 40 informants which includes both traditional healers and medicinal plant sellers were randomly selected and asked about the plant species used in treatment of variety of infections using a structured questionnaire. Follow-up visits and various field walks were also used to identify and document various plant species used in Traditional medicine (TM). The interviews were carried out from April 2008 to June 2016 using indigenous language (Sehananwa). RESULTS: A total of 82 medicinal plants species belonging to 42 families have been collected, identified and documented. About 46.34% of the plant species were herbs, followed by trees (25.61%), shrubs (20.73%) and climbers (7.32%). The most used plant parts are roots and rhizomes (58.58%). Peltophorum africanum Sond revealed frequency index of greater than 70 and is used in combination with other plants species to treat various pathogenic infections. Most of the plant species reported are used in the treatment of sexually transmitted infections (24), management of HIV-AIDS (15) and stomach ache (14). Our informants indicated that the use of plant medicines in combinations is also applied to cure pathogenic infections. CONCLUSION: The current study demonstrate that the indigenous people of Blouberg area, Limpopo Province harbours an important information about the vegetation around them. The plant species are used in the treatment of various pathogenic infections, offers fruits as additional source of food and form integral part of other medicinal products that may in turn produce income. PMID- 30001729 TI - Exploring organisational mechanisms in PRO-based follow-up in routine outpatient care - an interpretive description of the clinician perspective. AB - BACKGROUND: Patient-reported outcome (PRO)-based follow-up is a new model of service delivery, where PRO measures are used as the very basis for demand-driven outpatient follow-up in patients with chronic diseases. Adopting the clinicians' perspective, we aimed to explore what happens when PRO-based follow-up is implemented in routine clinical practice. We also aimed to identify organisational mechanisms related to PRO-based follow-up. METHODS: The methodological approach of this interview study is interpretive description, informed by a perspective of critical realism. Semi-structured interviews were conducted with 13 clinicians (eight nurses and five physicians) working with PRO based follow-up in outpatient care for epilepsy in the Central Denmark Region. RESULTS: PRO-based follow-up gave rise to ambivalence in clinicians. Seen from the clinicians' perspective, PRO-based follow-up could both increase and decrease the quality of follow-up. Moreover, PRO-based follow-up both enhanced and impaired clinicians' work experiences. Additionally, the clinicians used strategies to ease some of the perceived disadvantages. The clinicians did extra tasks and worked around the scope of PRO-based follow-up. Thus, clinicians constituted a professional buffer as they deflected some of the negative mechanisms associated with PRO-based follow-up. CONCLUSIONS: As a model of a service delivery, PRO-based follow-up is highly dependent on the clinicians' day to-day management of the system, and mechanisms related to routine use of PRO measures in outpatient follow-up are complex. Paying attention to the organisational settings is critical for PRO-based follow-up to improve quality of care and enhance patient-centred care. PMID- 30001730 TI - Tanshinone IIA promotes the differentiation of bone marrow mesenchymal stem cells into neuronal-like cells in a spinal cord injury model. AB - BACKGROUND: Spinal cord injury (SCI) is one of the most severe central nervous system injuries. Currently, transplanting bone marrow mesenchymal stem cells (BMSCs) is considered a therapeutic option for SCI. Tanshinone IIA (TIIA) is one of the extracts obtained from Salvia miltiorrhiza Bunge, which has been shown to have some protective effects against SCI. The present research was aimed to explore whether TIIA would influence the fate of transplanted BMSCs in a rat model of SCI, especially with regard to their differentiation into neuronal cells. METHODS: Bone marrow mesenchymal stem cells were obtained from immature rats and identified using flow cytometry. After SCI, 1.0 * 107 cells labeled with PKH67 were transfused into the injured spinal cord. TIIA was first injected into the tail vein (30 mg/kg) 1 h before surgery. From day 1 to day 7 post-SCI, TIIA was injected (20 mg/kg) per day at the same time. Recovery of locomotor function and histological regeneration of the spinal cord were compared among the groups, with the differentiation and distribution of BMSCs determined anatomically and biochemically by the expression of neural cell markers. RESULTS: Locomotor assessments showed that the rats in the BMSCs + TIIA group exhibited higher scores (19.33 +/- 0.58) than those in the other groups (13.67 +/- 1.53, 17.67 +/- 0.58, 18.00 +/- 1.73). The area of the cavity in the BMSCs + TIIA rats was smaller than that in the other groups (1.30 +/- 0.56, 10.39 +/- 1.59, 6.84 +/- 1.18, 4.36 +/- 0.69). Co-expression of glial fibrillary acid protein was observed in transplanted BMSCs, with a reduced rate in the BMSCs + TIIA group relative to that in the SCI group. In contrast, the expression levels of Nestin, neuron specific nuclear protein (NeuN) and neurofilament protein 200 (NF200) were greatest in the transplanted cells in the BMSCs + TIIA group. CONCLUSIONS: Tanshinone IIA treatment enhances the therapeutic effects of BMSC transplant on SCI, likely by promoting the differentiation of neuronal cells. PMID- 30001731 TI - Laboratory evaluation of the efficacy and speed of kill of lotilaner (CredelioTM) against Ixodes ricinus ticks on cats. AB - BACKGROUND: Lotilaner, approved for dogs as a chewable tablet formulation, has separately been developed for oral use in cats (CredelioTM chewable tablets for cats), to meet the need for an easy to use, safe and rapidly effective parasiticide. It is a valid cat- and owner-friendly alternative to topical products. This manuscript describes three pivotal laboratory studies assessing the efficacy and speed of kill of lotilaner in cats against Ixodes ricinus ticks following a single oral administration, at a dose rate close to 6 mg/kg. METHODS: In Studies 1 and 2, efficacy and safety were evaluated 48 h after treatment and post-treatment weekly infestations in 16 cats, against untreated controls, for 35 days. In Study 3, efficacy and safety were assessed in 8 lotilaner-treated cats until Day 35, before and after 24 h incubation of the female live ticks removed from the animals 12, 18 and 24 h after dosing and subsequent weekly infestations. RESULTS: Efficacy was > 99% on days 23 and 37, and 100% on all other timepoints in Study 1. In Study 2 it was > 98% on Days 9 and 37, and 100% on all other days. In Study 3, on Day 0, lotilaner was > 90% efficacious, pre- and post-incubation at all time-points. On Day 7, at 12 hours after infestation, efficacy was 100%, pre- and post-incubation. On Day 14, there was a 66.5% reduction in geometric mean live tick counts in treated cats compared to controls, increasing, after incubation, to 94.4%. Afterwards, efficacy decreased below 90% while tick counts in the treated groups remained significantly lower compared to controls. At 18 hours, lotilaner was >= 90% efficacious through Day 37, increasing to 100% at 24 hours, on all study days, with the exception of Day 28 (98.9 and 99.1% pre- and post-incubation, respectively). There were no treatment-related adverse events. CONCLUSIONS: At the minimum dose rate of 6 mg/kg, lotilaner was efficacious against I. ricinus ticks. In addition, lotilaner was effective against this tick within 12 hours of treatment, reaching 100% efficacy within 24 hours. Lotilaner sustained a rapid kill of newly infesting I. ricinus through 35 days. By quickly killing ticks that infest cats, lotilaner has the potential to contribute to the reduction of tick-borne pathogens transmission. PMID- 30001733 TI - Lotilaner - a novel formulation for cats provides systemic tick and flea control. PMID- 30001734 TI - Exosomal miR-9 inhibits angiogenesis by targeting MDK and regulating PDK/AKT pathway in nasopharyngeal carcinoma. AB - BACKGROUND: Exosomes are small vesicles containing a wide range of functional proteins, mRNA and miRNA. Exosomal miRNAs from cancer cells play crucial roles in mediating cell-cell communication and tumor-microenvironment cross talk, specifically in enabling metastasis and promoting angiogenesis. We focused on miR 9 that was identified as a tumor suppressor previously in nasopharyngeal carcinoma (NPC) tumorigenesis. METHODS: Differential centrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to isolate and identify exosomes. Quantitative PCR and western blotting analysis were used to detect miR-9, pri-miR-9, CD63, TSG101, MDK, P70S6K P-Ser424 and PDK1 P-Ser241 expression. Laser confocal microscopy was used to trace exosomal miR-9 secreted by NPC cells into HUVECs. The effect of exosomal miR-9 on cell migration and tube formation of HUVECs in vivo and vitro was assessed by using migration assay, tube formation assay and matrigel plug assay, respectively. Bioinformatics analysis and luciferase reporter assay were utilized to confirm the binding of exosomal miR-9 to the 3'untranslated region (3'-UTR) of MDK, while Phosphorylation Array was performed to identify AKT Pathway in HUVECs treated with exosomal miR-9. Furthermore, Immunohistochemistry (IHC) and in situ hybridization (ISH) was used to detected miR-9, CD31 and MDK expression in human NPC tumor samples. RESULTS: NPC cells transfected with miR-9-overexpressing lentivirus, released miR-9 in exosomes. Exosomal miR-9 directly suppressed its target gene - MDK in endothelial cells. Mechanistic analyses revealed that exosomal miR-9 from NPC cells inhibited endothelial tube formation and migration by targeting MDK and regulating PDK/AKT signaling pathway. Additionally, the level of MDK was upregulated in NPC tumor samples and was positively correlated with microvessel density. Notably, the level of exosomal miR-9 was positively correlated with overall survival, and MDK overexpression was positively associated with poor prognosis in NPC patients, suggesting the clinical relevance and prognostic value of exosomal miR-9 and MDK. CONCLUSIONS: Taken together, our data identify an extracellular anti-angiogenic role for tumor-derived, exosome-associated miR-9 in NPC tumorigenesis and prompt further investigation into exosome-based therapies for cancer treatment. PMID- 30001735 TI - Technical efficiency of public health centers in three districts in Ethiopia: two stage data envelopment analysis. AB - OBJECTIVE: The aim of the study was to measure technical and scale efficiency of public health centers in three districts of Jimma zone, Ethiopia. A two-stage data envelopment analysis was used. First, we estimated technical and scale efficiency of the health centers. In the second stage, institutional and environmental factors were against technical efficiency of the health centers to identify factors associated to efficiency of the health centers. RESULTS: Eight out of the 16 health centers in the study were found to be technically efficient, with an average score of 90% (standard deviation = 17%). This indicates that on average they could have reduce their utilization of all inputs by about 10% without reducing output. On the other hand, 8 out of 16 health centers were found to be scale efficient, with an average scale efficiency score of 94% (standard deviation = 9%). The inefficient health centers had an average scale score of 89%; implying there is potential for increasing total outputs by about 11% using the existing capacity/size. Catchment population and number of clinical staff were found to be directly associated with efficiency, while the number of nonclinical staff was found to be inversely associated with efficiency. PMID- 30001732 TI - The central mechanism of acupuncture treatment with a long-lasting effect for functional dyspepsia: study protocol for a randomized controlled trial. AB - BACKGROUND: The mechanism of the long-lasting effect and the relationship between the long-lasting effect and the deqi sensation, which is the key of achieving the acupuncture effect, has not been well investigated. This trial focuses on investigating the possible central mechanism of the long-lasting effect influenced by the deqi sensation. METHODS: A randomized controlled functional brain imaging trial is currently being conducted in Sichuan, China. In total 105 functional dyspepsia (FD) patients will be allocated into three groups: an acupuncture with deqi group, an acupuncture without deqi group, and a wait-list group. This trial will include a 2-week baseline period, a 4-week treatment period, and a 4-week follow-up period. During the 4-week treatment, patients in two acupuncture groups will receive 20 sessions of acupuncture treatment with or without deqi. The Nepean Dyspepsia Index (NDI) and the short form Leeds Dyspepsia Questionnaire (SF-LDQ) will be used to evaluate the clinical efficacy of acupuncture treatment at baseline, the end of treatment, and the end of the follow-up. Functional magnetic resonance imaging (fMRI) scans will be performed to detect cerebral functional changes in 25 patients in each group at three time points mentioned above. The clinical data and fMRI data will be analyzed, respectively. Correlation analysis will be conducted to investigate the relationship between cerebral functional changes and symptom improvement. DISCUSSION: The results of this trial will allow us to compare the changes of acupuncture therapeutic effect at three time points (the baseline vs. the end of treatment vs. the end of follow-up), and investigate the potential central mechanism of the long-lasting effect influenced by acupuncture with deqi. This trial aims to re-identify the long-lasting effect of acupuncture and investigate its central mechanism, and to further explore the central influence of deqi sensation on the long-lasting effect. TRIAL REGISTRATION: Chinese Clinical Trial Registry, IDF: ChiCTR-IOR-15006523 . Registered on 5 June 2015. PMID- 30001737 TI - Tracheostomy reversal years after patient lost to follow-up. AB - BACKGROUND: Pediatric tracheostomies occur for various reasons, including prologned intubation, and require a multidisciplinary approach with routine follow-up. CASE PRESENTATION: This report reviews the history and clinical outcome of a 29 year old female patient who was lost to follow-up for nearly two decades after a pediatric tracheostomy. When she presented to the Otolaryngology service as an adult the original indication for tracheostomy had resolved and decannulation was initiated, but a profound psychological dependence had developed. CONCLUSION: This case outlines the importance of regular follow-up for tracheostomy patients, as well as health care barriers faced in remote rural communities. PMID- 30001736 TI - Parkinson's disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naive and drug treated patients. AB - BACKGROUND: Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue. METHODS: We performed two cross-sectional studies in antiparkinson drug-treated and drug-naive PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency. RESULTS: PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naive CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-gamma and tumor necrosis factor-alpha by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naive patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity. CONCLUSIONS: The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics. PMID- 30001739 TI - Resilience to infection by Mycobacterium avium subspecies paratuberculosis following direct intestinal inoculation in calves. AB - Mycobacterium avium subspecies paratuberculosis (Map) is the cause of Johne's disease, a chronic enteritis of cattle. A significant knowledge gap is how persistence of Map within the intestinal tract after infection contributes to progression of disease. To address this, we exposed calves to Map by direct ileocecal Peyer's patch injection. Our objective was to characterize the persistence of Map in tissues, associated intestinal lesions, fecal Map shedding, and serum antibody responses, through the first 28-weeks post-inoculation (wpi). Previous work using this model showed 100% rate of Map infection in intestine and lymph node by 12 wpi. We hypothesized that direct inoculation of Map into the distal small intestine would induce intestinal Map infection with local persistence and progression towards clinical disease. However, our data show decreased persistence of Map in the distal small intestine and draining lymph nodes. We identified Map in multiple sections of distal ileum and draining lymph node of all calves at 4 and 12 wpi, but then we observed reduced Map in distal ileum at 20 wpi, and by 28 wpi we found that 50% of animals had no detectable Map in intestine or the lymph node. This provides evidence of resilience to Map infection following direct intestinal Map inoculation. Further work examining the immune responses and host-pathogen interactions associated with this infection model are needed to help elicit the mechanisms underlying resilience to Map infection. PMID- 30001738 TI - Molecular characterization of a putative serine protease from Trichinella spiralis and its elicited immune protection. AB - In our previous work, a Trichinella spiralis putative serine protease (TsSP) was identified from ES products of T. spiralis intestinal infective larvae (IIL) and adult worms (AW) by immunoproteomics: it was highly expressed in IIL compared with muscle larvae (ML). In this study, the TsSP biological characteristics in larval invasion and growth were identified and its potential as a vaccine target against Trichinella infection were investigated. Expression of TsSP at various developmental phases (newborn larvae, ML, IIL, and AW) was detected by qPCR, immunofluorescent test and Western blotting. The rTsSP could specifically bind to the intestinal epithelial cell (IEC) membrane and enter into the cytoplasm. Anti rTsSP serum suppressed the larval invasion of enterocytes in a dose-dependent mode, and killed newborn and ML of T. spiralis, decreased larval infectivity and development in the host by an ADCC-mediated mechanism. Immunization of mice with rTsSP produced a Th2 predominant immune response, and resulted in a 52.70% reduction of adult worms at 5 days post-infection (dpi) and a 52.10% reduction of muscle larvae at 42 dpi. The results revealed there was an interaction between TsSP and the host's IEC; TsSP might be a pivotal protein for the invading, growing and parasiting of this nematode in the host. Vaccination of mice with rTsSP elicited immune protection, and TsSP is a potential target molecule for vaccines against enteral Trichinella infection. PMID- 30001740 TI - The role of anti-citrullinated protein antibody reactivities in an inception cohort of patients with rheumatoid arthritis receiving treat-to-target therapy. AB - BACKGROUND: Anti-citrullinated protein antibody (ACPA) reactivities precede clinical onset of rheumatoid arthritis (RA), and it has been suggested that ACPA reactivities towards distinct target proteins may be associated with differences in RA phenotypes. We aimed to assess the prevalence of baseline ACPA reactivities in an inception cohort of patients with early RA, and to investigate their associations with disease activity, treatment response, ultrasound findings and radiographic damage. METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with early RA, classified according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, were included in the ARCTIC trial and assessed in the present analysis. During follow up, patients were monitored frequently and treatment was adjusted according to a predetermined protocol, starting with methotrexate monotherapy with prednisolone bridging. Analysis of 16 different ACPA reactivities targeting citrullinated peptides from fibrinogen, alpha-1 enolase, vimentin, filaggrin and histone was performed using a multiplex chip-based assay. Samples from 0, 3, 12 and 24 months were analysed. Controls were blood donors with similar characteristics to the patients (age, gender, smoking status). RESULTS: A total of 217 patients and 94 controls were included. Median [25, 75 percentile] number of ACPA reactivities in all patients was 9 [4, 12], and were most prevalent in anti-cyclic citrullinated peptide /rheumatoid factor-positive patients 10 [7, 12]. Disease activity measures and ultrasound scores at baseline were lower in ACPA reactivity-positive compared to ACPA reactivity-negative patients. ACPA reactivity levels decreased after 3 months of DMARD treatment, most pronounced for fibrinogenbeta 60-74 to 62% of baseline antibody level, with least change in filaggrin 307-324 to 81% of baseline antibody level, both p < 0.001. However, outcomes in disease activity measures, ultrasound and radiographic scores after 12 and 24 months were not associated with baseline levels or changes in ACPA reactivity levels and/or seroreversion after 3 months. CONCLUSIONS: The clinical relevance of analysing ACPA reactivities in intensively treated and closely monitored early RA was limited, with no apparent associations with disease activity, prediction of treatment response or radiographic progression. Further studies in larger patient materials are needed to understand the role of ACPA reactivities in patients with RA classified according to the 2010 ACR/EULAR criteria and treated according to modern treatment strategies. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01205854 . Registered on 21 September 2010. PMID- 30001742 TI - SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a poor prognosis. The epithelial-to-mesenchymal transition (EMT) is crucial for increasing the metastasis of OSCC. Recently, studies have indicated that sirtuin7 (SIRT7) is implicated in tumor genesis; however, the potential role of SIRT7 in the EMT and metastasis of OSCC has not been reported. METHODS: We investigated the cellular responses to SIRT7 silencing or overexpression in OSCC cell lines by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry. RESULTS: In the present study, we found that SIRT7 was significantly downregulated in OSCC cell lines and human OSCC/OSCC tissues with lymph node metastasis. Overexpression of SIRT7 decreased the proliferation and invasion of OSCC cells in vitro, whereas SIRT7 knockdown significantly increased OSCC cell growth and invasion. Upregulation of SIRT7 concomitantly increased the expression of E-cadherin, and decreased the expression of mesenchymal markers. SIRT7 overexpression also reduced the level of acetylated SMAD4 in OSCC cells. Moreover, SIRT7 overexpression significantly inhibited OSCC lung metastasis in vivo. CONCLUSION: Together, these findings suggested that SIRT7 suppressed EMT in OSCC metastasis by promoting SMAD4 deacetylation. PMID- 30001743 TI - FDG-PET/CT activity leads to the diagnosis of unsuspected TB: a retrospective study. AB - OBJECTIVE: Mycobacterium tuberculosis infection leads to latent or active tuberculosis (TB). Increased uptake on 18F-fluoro-2-deoxy-glucose-positron emission tomography/computed tomography (FDG-PET/CT) has been reported in the lungs and lymph nodes of individuals with recent infection and active TB, but not in individuals without known recent exposure or suggestive symptoms. We describe five patients with lung nodules not suspected to be due to TB in whom abnormalities on FDG-PET/CT scans ultimately were attributed to TB infection. RESULTS: Patient records were searched using the words "positron emission tomography/computed tomography" and 24 codes for TB between 2004 and 2013. Patients with a diagnosis of TB and a PET/CT scan were included. Clinical and radiographic data were retrieved. PET/CT images were reviewed by an experienced radiologist. FDG-PET/CT scans revealed elevated FDG-uptake in lungs of five patients subsequently diagnosed with active (n = 3) or clinically inactive (n = 2) tuberculosis. Uptake magnitude was unrelated to disease activity. These findings suggest that tuberculosis latency may include periods of percolating inflammation of uncertain relationship to future disease risk. PMID- 30001741 TI - Sex differences in the traumatic stress response: the role of adult gonadal hormones. AB - BACKGROUND: Our previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones? METHODS: For the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined. RESULTS: We now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females. CONCLUSIONS: We propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience. PMID- 30001744 TI - A randomized, controlled field study to assess the efficacy and safety of lotilaner (CredelioTM) in controlling fleas in client-owned cats in Europe. AB - BACKGROUND: Lotilaner is a new isoxazoline developed as an oral ectoparasiticide for cats and dogs. Its safety, rapid killing onset of action and sustained speed of fleas and ticks kill for a minimum of one month after administration, were demonstrated in a number of laboratory studies in cats. This study was performed to demonstrate the efficacy and safety of lotilaner flavored chewable tablets for cats (CredelioTM, Elanco) in controlling fleas under field conditions in European countries. METHODS: Seventeen veterinary practices in France and Spain, located in high flea prevalence regions, participated in the study. Households with a maximum of three cats and two dogs were randomized 2:1 to a lotilaner (minimum dose rate 6 mg/kg) or a topical fipronil/(S)-methoprene combination (Frontline Combo(r) Spot-on Cats, Merial) group (administered according to label). In each household, efficacy against fleas and flea allergy dermatitis (FAD) signs were assessed in one primary cat (bearing a minimum of five fleas on Day 0) while safety was evaluated in all cats. There were 121 households included in the lotilaner and 61 in the fipronil/(S)-methoprene groups, respectively. Treatments were administered by the cats' owners on Day 0. Flea counts and FAD assessments were made on Days 0, 14, and 28. Efficacy calculations were based on geometric mean percent reductions of live flea counts versus baseline pre-treatment counts. RESULTS: Lotilaner efficacy was 97.2 and 98.1% on Days 14 and 28, respectively. Corresponding efficacy for fipronil/(S)-methoprene was 48.3 and 46.4%. Lotilaner was superior to fipronil/(S)-methoprene at all post-Day 0 assessments and over the whole study period (P < 0.0001). At every post-administration evaluation, at least 81% of lotilaner-treated cats were flea-free as opposed to 25% in the fipronil/(S)-methoprene group. Lotilaner improved or eliminated clinical signs of FAD, including pruritus. Both products were well tolerated. CONCLUSIONS: Under field conditions in Europe, lotilaner flavored chewable tablets for cats displayed an efficacy against fleas higher than 97%; clinical signs of FAD were improved or eliminated. Lotilaner tablets were safe and provided superior flea control to fipronil/(S)-methoprene. PMID- 30001745 TI - Safety of lotilaner flavoured chewable tablets (CredelioTM) after oral administration in cats. AB - BACKGROUND: Lotilaner is a new member of the isoxazoline class for treatment of flea and tick infestations in cats. This laboratory study with lotilaner vanilla yeast flavoured chewable tablets (CredelioTM, Elanco) investigated the safety in healthy kittens starting at 8 weeks of age in a randomized, blinded, parallel group design. Lotilaner tablets were given orally once a month over eight months at one, three and five times the upper level of the maximum recommended dose range (26 mg/kg). METHODS: The safety of lotilaner flavoured chewable tablets was assessed in healthy kittens when administered orally every 4 weeks for 8 months at the highest recommended dose rates, i.e. 1* (26 mg/kg) and at elevated dose rates, i.e. 3* (78 mg/kg) and 5* (130 mg/kg). Sixteen male and 16 female healthy 8-week-old kittens, with a mean body weight of 0.79 kg and 0.75 kg, respectively, were randomized to an untreated control group or lotilaner groups at dose rates of 26 mg/kg (1*), 78 mg/kg (3*), or 130 mg/kg (5*) every four weeks over eight months. The control group was sham-dosed. All animals were fed within 30 minutes prior to treatment. Safety assessment included general health observations, detailed clinical observations, complete physical/neurological examinations, including ophthalmological examinations, electrocardiographic (ECG) and clinical pathology evaluations (haematology, clinical chemistry and urinalysis), food and water consumption, body weight, pharmacokinetic blood collections, organ macroscopic and microscopic examinations. RESULTS: Systemic exposure to lotilaner was confirmed during the course of the study in all treated animals with the exception of the control group. No treatment-related effects were seen on daily clinical observations, food consumption (wet), ophthalmoscopic, physical/neurological and microscopic examinations. Statistically significant differences were recorded in some of the clinical pathology parameters, body weights, food consumption (dry), electrocardiograms, and organ weights, but none of the recorded observations was considered to be of clinical relevance. CONCLUSIONS: Lotilaner, when administered once monthly over eight months at the highest recommended dose and overdoses of three- and five-fold, to 8-week-old healthy kittens, is well tolerated. PMID- 30001747 TI - Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies. AB - Mutation-derived neoantigens represent an important class of tumour-specific, tumour rejection antigens, and are attractive targets for TCR gene therapy of cancer. The majority of such mutations are patient-specific and targeting these requires a fully personalized approach. However, some mutations are found recurrently among cancer patients, and represent potential targets for neoantigen specific TCR gene therapy that is more widely applicable. Therefore, we have investigated if some cancer mutations found recurrently in hematological malignancies encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles and can form targets for TCR gene therapy. We initially focused on identifying HLA class I neoepitopes derived from calreticulin (CALR) exon 9 mutations, found in ~ 80% of JAK2wt myeloproliferative neoplasms (MPN). Based on MHC class I peptide predictions, a number of peptides derived from mutant CALR (mCALR) were predicted to bind to HLA-A*03:01 and HLA B*07:02. However, using mass spectrometry and ex vivo pMHC multimer staining of PBMC from MPN patients with CALR exon 9 mutations, we found no evidence that these peptides were naturally processed and presented on the surface of mCALR expressing target cells. We next developed a protocol utilizing pMHC multimers to isolate CD8+ T cells from healthy human donor PBMC that are specific for mCALR and additional putative neoepitopes found recurrently in hematological malignancies. Using this approach, CD8+ T cells specific for HLA-A*03:01- and HLA B*07:02-presented mCALR peptides and an HLA-A*11:01-presented mutant FBXW7 (mFBXW7) peptide were successfully isolated. TCRs isolated from mCALR-specific CD8+ T cell populations were not able to recognize target cells engineered to express mCALR. In contrast, mFBXW7-specific CD8+ T cells were able to recognize target cells engineered to express mFBXW7. In conclusion, while we found no evidence for mCALR derived neoepitope presentation in the context of the HLA class I alleles studied, our data suggests that the recurrent pR465H mutation in FBXW7 may encode an HLA-A*11:01 presented neoepitope, and warrants further investigation as a target for T cell based immunotherapy of cancer. PMID- 30001746 TI - A randomized, controlled field study to assess the efficacy and safety of lotilaner (CredelioTM) in controlling ticks in client-owned cats in Europe. AB - BACKGROUND: There is a continuing need for novel approaches to tick infestations treatment and control in cats. Lotilaner, an isoxazoline with rapid onset of action, has proven its efficacy against ticks in laboratory studies. A study was undertaken to confirm lotilaner's efficacy and safety in client-owned cats, at the minimum dose of 6.0 mg/kg, against the most common ticks infesting cats in Europe. METHODS: Twenty clinics in Germany, Hungary and Portugal participated in the study. Households with no more than three cats were randomized 2:1 to a lotilaner or fipronil group. The first household cat with at least three live, attached ticks was the primary cat. Treatments were dispensed on days 0, 28 and 56 for owner administration. Tick counts were performed on days 0, 7, 14, 21, 28, 42, 56, 70 and 84 (primary cats) and supplementary cats were assessed for safety only, on days 28, 56 and 84. Efficacy was assessed by comparing mean day 0 live attached tick counts with subsequent counts. RESULTS: Most frequently retrieved ticks were Ixodes ricinus, Rhipicephalus sanguineus and Dermacentor reticulatus, with Ixodes hexagonus also present. In the lotilaner group (n = 112) efficacy (based on geometric mean tick counts) was between 98.3-100%. For fipronil (n = 57), efficacy was between 89.6-99.6%, with live attached ticks present on some cats at all time points. Mean tick counts in lotilaner-treated cats were significantly lower than in fipronil-treated cats on days 21, 28, 42 and 56 (P < 0.05). The mean percent efficacy over all post-enrolment visits was 99.6% and 96.4% (lotilaner and fipronil group, respectively), (P < 0.0001). Lotilaner was superior to fipronil for efficacy averaged over all time points (P < 0.0001) and on individual assessment days (day 14 to 70, P < 0.0394); it was non-inferior to fipronil on the other days. Owners successfully administered all treatments, and both products were well tolerated. CONCLUSIONS: CredelioTM was effective and safe for the treatment of tick infestations in client-owned cats. Efficacy lasted one month and lotilaner was superior to fipronil on most assessment days. Cure rates ranged between 94.5-100% for lotilaner and 68.4-98.2% for fipronil. PMID- 30001748 TI - Factors associated with adherence to antiretroviral therapy among HIV infected children in Kabale district, Uganda: a cross sectional study. AB - OBJECTIVES: This study was set out to assess the level of adherence to antiretroviral therapy (ART) and its determinants among children receiving HIV treatment in Kabale district, south western Uganda, in order to inform interventions for improving pediatric ART adherence. RESULTS: Overall, 79% (121/153) of the children did not miss ART doses over the 7 days. Caregiver forgetfulness was the major reason for missing ART doses, 37% (13/35). Other reasons included transportation costs to the health facilities, 17%, (6/35) and children sitting for examinations in schools. Older children (11-14 years) were more likely to adhere to ART than the younger ones (0-10 years) (AOR = 6.41, 95% CI 1.31-31.42). Caregivers, who knew their HIV status, had their children more adherent to ART than the caregivers of unknown HIV status (AOR = 21.64: 95% CI 1.09-428.28). A significant proportion of children in two facilities 21.5% (32/153) missed ART doses within the previous week. Support for providers to identify clues or reminders to take drugs, extending HIV testing to caregivers and innovative models of ART delivery that alleviate transport costs to caregivers and allow sufficient drugs for children in school could enhance drug adherence among children. PMID- 30001749 TI - Feature optimization in high dimensional chemical space: statistical and data mining solutions. AB - OBJECTIVES: The primary goal of this experiment is to prioritize molecular descriptors that control the activity of active molecules that could reduce the dimensionality produced during the virtual screening process. It also aims to: (1) develop a methodology for sampling large datasets and the statistical verification of the sampling process, (2) apply screening filter to detect molecules with polypharmacological or promiscuous activity. RESULTS: Sampling from large a dataset and its verification were done by applying Z-test. Molecular descriptors were prioritized using principal component analysis (PCA) by eliminating the least influencing ones. The original dimensions were reduced to one-twelfth by the application of PCA. There was a significant improvement in statistical parameter values of virtual screening model which in turn resulted in better screening results. Further improvement of screened results was done by applying Eli Lilly MedChem rules filter that removed molecules with polypharmacological or promiscuous activity. It was also shown that similarities in the activity of compounds were due to the molecular descriptors which were not apparent in prima facie structural studies. PMID- 30001750 TI - Marked attenuation of the amplitude of transcranial motor-evoked potentials after intravenous bolus administration of ketamine: a case report. AB - BACKGROUND: It is believed that ketamine does not affect motor-evoked potential amplitude, whereas various anesthetic drugs attenuate the amplitude of transcranial motor-evoked potential. However, we encountered a patient with marked attenuation of motor-evoked potential amplitude after intravenous bolus administration of ketamine. CASE PRESENTATION: A 15-year-old Japanese girl with a diagnosis of adolescent idiopathic scoliosis was admitted to our hospital to undergo posterior spinal fusion at T4-L3. After induction of general anesthesia using a continuous infusion of propofol and remifentanil, we confirmed that transcranial electrical motor-evoked potentials were being recorded correctly. Ketamine 1.25 mg/kg was administered intravenously for intraoperative and postoperative analgesia. About 3 minutes later, the motor-evoked potential amplitude was markedly attenuated. No other drugs were administered except for ketamine. The patient's vital signs were stable, and the surgery had not yet started. The motor-evoked potential amplitude was recovered at about 6 minutes after administration of ketamine. The surgery was performed uneventfully, and the patient had no neurologic deficit when she emerged from general anesthesia. CONCLUSIONS: Although there is a widely held belief in the field of anesthesiology that ketamine does not affect motor-evoked potential amplitude, it has been suggested that ketamine could affect its monitoring. PMID- 30001751 TI - LINC01287/miR-298/STAT3 feedback loop regulates growth and the epithelial-to mesenchymal transition phenotype in hepatocellular carcinoma cells. AB - BACKGROUND: The long non-coding RNAs (lncRNAs) have participated in the promotion of hepatocellular carcinoma (HCC) initiation and progression. Nevertheless, the biological role and underlying mechanism of LINC01287 in HCC has never been reported. METHODS: The TGCA database was used to explore the abnormal expression of lncRNAs in HCC. Real-time PCR and in situ hybridization assays were used to examine the expression of LINC01287 in HCC tissues. The clinicopathological characteristics of HCC patients in relation to LINC01287 expression were then analyzed. Infection of cells with the si-LINC01287 lentiviral vector was performed to down-regulate LINC01287 expression in HCC cells. MTT and colony formation assays were performed to examine cell growth ability, and FACS analysis was performed to examine the cell cycle and apoptosis. A Boyden assay was used to examine HCC cell invasion ability, and RNA immunoprecipitation tested the interaction between LINC01287 and miR-298. A luciferase reporter assay was used to examine whether STAT3 was a direct target of miR-298, and chromatin immunoprecipitation (ChIP) was used to examine the potential binding of c-jun to the miR-298 promoter. RESULTS: We revealed that the expression of LINC01287 was increased in HCC cell lines, as well as tissues. Knockdown of LINC01287 decreased HCC cell growth and invasion both in vitro and in vivo. LINC01287 can negatively regulate miR-298 expression by acting as a ceRNA. miR-298 directly targeted STAT3 and inhibited its expression. LINC01287 exerted its function via the miR 298/STAT3 axis in HCC. Interestingly, STAT3 elevated LINC01287 expression via c jun, which bound to the LINC01287 promoter. A feedback loop was also discovered between LINC01287 and the miR-298/STAT3 axis. CONCLUSIONS: Our data indicated that LINC01287 played an oncogenic role in HCC growth and metastasis and that this lncRNA might serve as a novel molecular target for the treatment of HCC. PMID- 30001752 TI - Host B chromosomes as potential sex ratio distorters of intestinal nematode infrapopulations in the yellow-necked mouse (Apodemus flavicollis). AB - The yellow-necked mouse, Apodemus flavicollis, can be considered as a model for genetic polymorphism produced by the frequent presence of supernumerary or B chromosomes (Bs). Host genetic background is rarely taken into account in studies of parasite sex ratio. The main aim of this study was to investigate the range of infrapopulation sex ratios for nematode parasites of the yellow-necked mouse and to determine which factors most influence variation in parasite sex ratios. Six nematode species found in the collected yellow-necked mice were analysed. We confirmed the predominant pattern of female-biased sex ratios in vertebrate parasite infrapopulations. The presence of B chromosomes in host genomes played an important role in infrapopulations of Heligmosomoides polygyrus, Syphacia stroma and Trichuris muris, as hosts with B chromosomes carried a higher proportion of males. The relative increase of males in infrapopulations could result from a shift in parasite life history strategy, induced by adaptation to the specific host genotypes (Bs present). In a meta-analysis with previously published data, the sex determination system was demonstrated to play a significant role in nematode sex ratio variation, as well as specific life history patterns, such as the place of egg hatching. PMID- 30001754 TI - Leisure Activities and Motivational Profiles in Adaptation to Nursing Homes. AB - ABSTRACTBased on self-determination theory, this study examined the relationship between leisure activities, motivation, and adjustment to institutional living by older adults who live in nursing homes. We hypothesized that motivational profiles with higher levels of self-determined motivation represent the optimal profiles regarding participation in leisure activities, adaptation to nursing home living, and satisfaction with life. Participants completed questionnaires assessing motivation, leisure activity participation, life satisfaction, and adaptation to the nursing home. Results showed a relationship between the latter three factors. A latent profile analysis based on the different forms of motivation indicated four distinct profiles. Although no differences were found between the high self-determined profile (high self-determined motivation and low non-self-determined motivation) and the additive profile (high self-determined motivation and non-self-determined motivation), participants with a moderate profile and a low self-determined profile reported the lowest levels in leisure activity participation, adaptation to the nursing home, and satisfaction with life. PMID- 30001753 TI - Metabolic perturbations associated with the consumption of a ketogenic medium chain TAG diet in dogs with idiopathic epilepsy. AB - Consumption of diets containing medium-chain TAG (MCT) has been shown to confer neuroprotective effects. We aim to identify the global metabolic perturbations associated with consumption of a ketogenic diet (medium-chain TAG diet (MCTD)) in dogs with idiopathic epilepsy. We used ultra-performance liquid chromatography-MS (UPLC-MS) to generate metabolic and lipidomic profiles of fasted canine serum and made comparisons between the MCTD and standardised placebo diet phases. We identified metabolites that differed significantly between diet phases using metabolite fragmentation profiles generated by tandem MS (UPLC-MS/MS). Consumption of the MCTD resulted in significant differences in serum metabolic profiles when compared with the placebo diet, where sixteen altered lipid metabolites were identified. Consumption of the MCTD resulted in reduced abundances of palmitoylcarnitine, octadecenoylcarnitine, stearoylcarnitine and significant changes, both reduced and increased abundances, of phosphatidylcholine (PC) metabolites. There was a significant increase in abundance of the saturated C17 : 0 fatty acyl moieties during the MCTD phase. Lysophosphatidylcholine (17 : 0) (P=0.01) and PC (17:0/20:4) (P=0.03) were both significantly higher in abundance during the MCTD. The data presented in this study highlight global changes in lipid metabolism, and, of particular interest, in the C17 : 0 moieties, as a result of MCT consumption. Elucidating the global metabolic response of MCT consumption will not only improve the administration of current ketogenic diets for neurological disease models but also provides new avenues for research to develop better diet therapies with improved neuroprotective efficacies. Future studies should clarify the involvement and importance of C17 : 0 moieties in endogenous MCT metabolic pathways. PMID- 30001755 TI - Familial clustering of cardiac conditions in patients with anomalous aortic origin of a coronary artery and myocardial bridges. AB - BACKGROUND: Anomalous aortic origin of a coronary artery is the second leading cause of sudden cardiac arrest/death in young athletes in the United States of America. Limited data are available regarding family history in this patient population. METHODS: Patients were evaluated prospectively from 12/2012 to 02/2017 in the Coronary Anomalies Program at Texas Children's Hospital. Relevant family history included the presence of CHD, sudden cardiac arrest/death, arrhythmia/pacemaker use, cardiomyopathy, and atherosclerotic coronary artery disease before the age of 50 years. The presence of one or more of these in 1st- or 2nd-degree relatives was considered significant. RESULTS: Of 168 unrelated probands (171 patients total) included, 36 (21%) had significant family history involving 19 (53%) 1st-degree and 17 (47%) 2nd-degree relatives. Positive family history led to cardiology referral in nine (5%) patients and the presence of abnormal tests/symptoms in the remaining patients. Coronary anomalies in probands with positive family history were anomalous right (27), anomalous left (five), single right coronary artery (two), myocardial bridge (one), and anomalous circumflex coronary artery (one). Conditions present in their family members included sudden cardiac arrest/death (15, 42%), atherosclerotic coronary artery disease (14, 39%), cardiomyopathy (12, 33%), CHD (11, 31%), coronary anomalies (3, 8%), myocardial bridge (1, 3%), long-QT syndrome (2, 6%), and Wolff-Parkinson White (1, 3%). CONCLUSION: In patients with anomalous aortic origin of a coronary artery and/or myocardial bridges, there appears to be familial clustering of cardiac diseases in approximately 20% of patients, half of these with early occurrence of sudden cardiac arrest/death in the family. PMID- 30001757 TI - Stroke and Coronary Artery Disease Are Associated With Parkinson's Disease. AB - BACKGROUND: The relationship between vascular disease and Parkinson's disease (PD) is controversial. We performed a cross-sectional study to investigate the association of two common vascular diseases (stroke and coronary artery disease [CAD]) with Parkinson's disease. METHODS: We identified 63 and 62 PD cases in two population-based cohorts (Malu rural community and Wuliqiao urban community) and collected information of PD and non-PD by means of questionnaires. Logistic regression analysis was used to investigate the association between stroke, coronary artery disease and PD, after adjusting for age, sex, hypertension, diabetes mellitus, hypercholesterolemia, smoking status, alcohol consumption, tea consumption and body mass index. RESULTS: After adjustment for potential confounders, we found that CAD and stroke were associated with PD in the Malu rural community (CAD: odds ratio [OR]=7.11, 95% confidence intervals [CI]: 3.09 16.40, p<0.001; stroke: OR=6.77, 95% CI: 3.09-14.81, p<0.001) and stroke was associated with PD in the Wuliqiao urban community (OR=2.58, 95% CI: 1.36-4.89, p=0.004), especially in women. In a subgroup analysis of PD with age- and sex matched controls, the results were similar in the Malu rural community (CAD: OR=12.72, 95% CI: 2.92-55.32, p=0.001; stroke: OR=6.26, 95% CI: 1.83-21.42, p=0.003), whereas in the Wuliqiao urban community the results were different in that CAD (but not stroke) was found to be associated with PD (CAD: OR=2.44, 95% CI: 1.09-5.47, p=0.03; stroke: OR=1.79, 95% CI: 0.77-4.17, p=0.18). CONCLUSIONS: Our study suggested that stroke and CAD are associated with PD in two Chinese population-based cohorts, indicating a probable vascular component in the pathogenesis of PD. PMID- 30001756 TI - Seroprevalence and risk factors of Toxoplasma gondii infection in oral cancer patients in China: a case-control prospective study. AB - Over the recent years, potential associations between Toxoplasma gondii (T. gondii) infection and cancer risk have attracted a lot of attention. Nevertheless, the association between T. gondii infection and oral cancer remains relatively unexplored. We performed a case-control study of 861 oral cancer patients and 861 control subjects from eastern China with the aim to detect antibodies to T. gondii by enzyme-linked immunosorbent assay (ELISA) in these patients. The results showed that oral cancer patients (21.72%, 187/861) had a significantly higher seroprevalence than control subjects (8.25%, 71/861) (P < 0.001). Among them, 144 (16.72%) oral cancer patients and 71 (8.25%) control subjects were positive for IgG antibodies to T. gondii, while 54 (6.27%) oral cancer patients and 9 (1.05%) controls were positive for IgM antibodies to T. gondii. In addition, multiple logistic analysis showed that T. gondii infection in oral cancer patients was associated with blood transfusion history, keeping cats at home, and oyster consumption. To our knowledge, this is the first study that provided a serological evidence of an association between T. gondii infection and oral cancer patients. However, further studies are necessary to elucidate the role of T. gondii in oral cancer patients. PMID- 30001758 TI - Risk factors for surgical site infection after kidney and pancreas transplantation. AB - OBJECTIVE: To evaluate the incidence of surgical site infection (SSI) in a cohort of pancreas transplant recipients and assess predisposing risk factors for SSI DESIGN: Retrospective cohort study SETTING: Single transplant center in CanadaPatientsPatients who underwent any simultaneous pancreas and kidney (SPK) or pancreas after kidney (PAK) transplant procedures between January 2000 and December 2015 METHODS: In this retrospective cohort evaluation of SPK or PAK recipients, we assessed the incidence of SSI and risk factors associated with superficial, deep, and organ/space SSI. Multivariate logistic regression was used to identify independent risk factors for SSI in SPK and PAK recipients. RESULTS: In total, 445 adult transplant recipients were enrolled. The median age of these patients was 51 years (range, 19-71 years), and 64.9% were men. SSIs were documented in 108 patients (24.3%). Organ/space SSIs predominated (59 patients, 54.6%), followed by superficial SSIs (47 patients, 43.5%) and deep SSIs (3 patients, 2.8%). Factors predictive of SSIs in the multivariate analysis were cold pancreas ischemic time (odds ratio [OR], 1.002; P=.019) and SPK transplant (compared to PAK transplant recipients; OR, 2.38; P=.038). Patients with SSIs developed graft loss more frequently (OR, 16.99; P<.001). CONCLUSIONS: Organ/space SSIs remain a serious and common complication after SPK and PAK. Prolonged cold ischemic time and SPK transplant were the risk factors predictive of SSIs. Appropriate perioperative prophylaxis in high-risk patients targeting the potential pathogens producing SSIs in kidney and/or pancreas transplant recipients and a reduction in cold ischemia may prove beneficial in reducing these SSIs. PMID- 30001759 TI - START versus SALT Triage: Which is Preferred by the 21st Century Health Care Student? AB - : IntroductionWhile the art and science of disaster triage continue to evolve, the education of the US health care student in matters pertaining to disaster preparedness and response remains stifled. Unfortunately, these students will be assuming major decision-making responsibilities regarding catastrophes that will be complicated by climate change, nuclear threats, global terrorism, and pandemics. Meanwhile, Sort, Assess, Life-Saving Interventions, Treatment, and/or Transport (SALT) triage is being advocated over the globally popular Simple Triage and Rapid Treatment (START) algorithm for multiple reasons: (1) it's an all-hazard approach; (2) it has four medical interventions; and (3) it has an additional triage color for victims with non-survivable injuries.Hypothesis/ProblemAs present-day threats become more ominous and health care education emphasizes the needs of vulnerable populations and palliative care, the authors hypothesize that, when given a choice, health care students will prefer SALT triage. METHODS: A convenience sample of 218 interprofessional, disaster-naive health care students received just-in-time, unbiased education on both START and SALT triage systems. Students then completed a survey asking them to decide which triage system they believe would be most effective in their community. RESULTS: A total of 123 health care students (56.4%) preferred SALT while 95 (43.6%) preferred START; however, only the physician assistant students showed a statistically significantly preference (28 versus six, respectively; P=.042). Interestingly, there was also a statistically significant difference in preference by gender (Chi-square=5.02; P=.025) of the observed distribution versus expected distribution in SALT and START. The females preferred SALT (61.0%) while the males preferred START (55.9%).Among those who preferred START, START being easier to learn was the most important reason cited. Among those who preferred SALT, the most important reason cited was that the number of patient triage categories seemed more logical, comprehensible, and consistent with traditional medical care. CONCLUSION: While SALT's preference among females and physician assistant students was based on the addition of medical interventions and the provision of palliative care, START's preference was related to expediency. Based on this research, incorporating disaster concepts into US health care students' curricula encourages thoughtful consideration among the future health care leaders about the most effective approach to triage care. It is critical that further research be completed to determine, without reservation, which triage system will not only save the most lives but provide the most humane care to victims.Fink BN, Rega PP, Sexton ME, Wishner C. START versus SALT triage: which is preferred by the 21st century health care student? Prehosp Disaster Med. 2018;33(4):381-386. PMID- 30001760 TI - The Scarier the Better: Maximizing Exposure Therapy Outcomes for Spider Fear. AB - BACKGROUND: While exposure therapy effectively reduces anxiety associated with specific phobias, not all individuals respond to treatment and some will experience a return of fear after treatment ceases. AIMS: This study aimed to test the potential benefit of increasing the intensity of exposure therapy by adding an extra step that challenged uncontrollability (Step 15: allowing a spider to walk freely over one's body) to the standard fear hierarchy. METHOD: Fifty-one participants who had a severe fear of spiders completed two 60-min exposure sessions 1 week apart in a context that was either the same or different from the baseline and follow-up assessment context. Participants were categorized into groups based on the last hierarchy step they completed during treatment (Step 14 or fewer, or Step 15). RESULTS: Those who completed Step 15 had greater reductions in fear and beliefs about the probability of harm from baseline to post-treatment than those who completed fewer steps. Although completing Step 15 did not prevent fear from returning after a context change, it allowed people to maintain their ability to tolerate their fear, which earlier steps did not. Despite some fear returning after a context change, individuals who completed Step 15 tended to report greater reductions in fear from baseline to the follow up assessment than participants who completed 14 or fewer steps. CONCLUSIONS: Overall, these results suggest that more intensive exposure that directly challenges harm beliefs may lead to greater changes in fear and fear beliefs than less intensive exposure. PMID- 30001761 TI - Marital Status and Problem Gambling among Older Adults: An Examination of Social Context and Social Motivations. AB - ABSTRACTOlder adults represent the highest proportion of gamblers (Ontario Lottery and Gaming Corporation [OLG], 2012). Unpartnered older adults may be more socially isolated and lonely (Dykstra & de Jong Gierveld, 2004), thus more likely to be at risk for problem gambling (McQuade & Gill, 2012). We examined whether gambling to socialize or from loneliness and going to the casino with friends/family mediate the relation between marital status and problem gambling. Data from a random sample of older adults at gambling venues across Southwestern Ontario indicated that gambling with family/friends and gambling due to loneliness mediated the relationship between marital status and problem gambling. Relative to those married, unpartnered older adults were less likely to gamble with family/friends, more likely to gamble due to loneliness, and had higher problem gambling. Prevention and treatment initiatives should examine ways to decrease loneliness and social isolation among older adults and offer alternative social activities. PMID- 30001762 TI - First assessment of all-cause acute diarrhoea and rotavirus-confirmed cases following massive vaccination in Argentina. AB - Argentina incorporated rotavirus massive vaccination in 2015. No specific strategy has been designed to accurately measure the impact of this recent introduction on the diarrhoeal disease burden in our country. We assessed post vaccine introduction data (all-cause acute diarrhoea and rotavirus laboratory confirmed cases, and genotype distribution), compared with pre-vaccination period in children under 5 years of age in Argentina. Cross-sectional ecologic analysis was conducted with data from the Argentine Surveillance Health System. Endemic channel and global and seasonal incidence rates of pre- and post-vaccination periods were calculated and further compared. Conventional binary genotypification on rotavirus-positive samples was also performed. In post vaccination period, a global decrease of 20.8% in the rate of all-cause acute diarrhoea cases was found. The endemic channel showed that declination was more significant in the autumn/winter season. Rotavirus laboratory-confirmed cases showed 61.7% of reduction and the weekly distribution analyses indicated a significant flattening of the expected seasonal peak. G2P[4] was the most prevalent circulating genotype (57.2%). This study represents the first assessment of diarrhoeal disease burden since rotavirus massive vaccination strategy was implemented in Argentina. This introduction represented a successful intervention due to the significant decrease in all-cause acute diarrhoea cases and rotavirus laboratory-confirmed cases. PMID- 30001763 TI - Nutrition support and clinical outcome in advanced cancer patients. AB - Newly diagnosed cancer patients are frequently found suffering from a metastatic disease, which poses additional challenges to the delivery of effective therapies. Chemotherapy and radiotherapy are associated with side effects which reduce tolerance to treatment and likelihood of tumour response. Identifying preventable factors of reduced response to therapy would translate into better care of cancer patients. Among other factors, malnutrition, as diagnosed by non volitional weight loss, and cachexia, as revealed by sarcopenia, are universally recognised negative prognostic factors. Less certainty exists on the role of nutrition therapy in improving cancer patients' body composition and clinical outcome. The reasons for the lack of convincing evidence are manifold, mostly related to the poor design of nutritional trials. Metastatic cancer patients should receive a quantitatively and qualitatively adequate diet, and in case of reduced tolerance of food, artificial nutrition is indicated. Most importantly, nutritional care should target the underlying mechanisms of reduced food intake/impaired anabolic response, and aim at minimising the impact of catabolic crisis, to maximise the recovery phase. The combined and early use of supplemental energies and proteins, as well as modulators of inflammatory response has been shown to improve nutritional status and may also benefit clinical outcome. When part of early palliative care, nutrition therapy improves cancer patients' quality of life and may prolong survival at a fraction of the costs of developing new drugs. PMID- 30001764 TI - Safety of psychotropic medicines: looking beyond randomised evidence. PMID- 30001765 TI - Comparison of Unmanned Aerial Vehicle Technology-Assisted Triage versus Standard Practice in Triaging Casualties by Paramedic Students in a Mass-Casualty Incident Scenario. AB - : IntroductionThe proliferation of unmanned aerial vehicle (UAV) technology has the potential to change the way medical incident commanders (ICs) respond to mass casualty incidents (MCIs) in triaging victims. The aim of this study was to compare UAV technology to standard practice (SP) in triaging casualties at an MCI. METHODS: A randomized comparison study was conducted with 40 paramedic students from the Holland College Paramedicine Program (Charlottetown, Prince Edward Island, Canada). Using a simulated motor vehicle collision (MVC) with moulaged casualties, iterations of 20 students were used for both a day and a night trial. Students were randomized to a UAV or a SP group. After a brief narrative, participants either entered the study environment or used UAV technology where total time to triage completion, GREEN casualty evacuation, time on scene, triage order, and accuracy were recorded. RESULTS: A statistical difference in the time to completion of 3.63 minutes (95% CI, 2.45 min-4.85 min; P=.002) during the day iteration and a difference of 3.49 minutes (95% CI, 2.08 min-6.06 min; P=.002) for the night trial with UAV groups was noted. There was no difference found in time to GREEN casualty evacuation, time on scene, or triage order. One-hundred-percent accuracy was noted between both groups. CONCLUSION: This study demonstrated the feasibility of using a UAV at an MCI. A non-clinical significant difference was noted in total time to completion between both groups. There was no increase in time on scene by using the UAV while demonstrating the feasibility of remotely triaging GREEN casualties prior to first responder arrival.Jain T, Sibley A, Stryhn H, Hubloue I.Comparison of unmanned aerial vehicle technologyassisted triage versus standard practice in triaging casualties by paramedic students in a mass-casualty incident scenario. Prehosp Disaster Med. 2018;33(4):375-380. PMID- 30001767 TI - Portable Health Care Facilities in Disaster and Rescue Zones: Characteristics and Future Suggestions. AB - : IntroductionNatural and man-made disasters are becoming global concerns. Natural disasters appear to be growing in number and intensity due to global warming, population explosion, increased travel, and overcrowding of cities. In addition, man-made disasters do not seem to be diminishing.At disaster sites, an immediate response is needed. National and international organizations; nongovernmental, military, and commercial organizations; and even private donors enlist to provide humanitarian and medical support and to send supplies, shelters, and temporary health care facilities to disaster zones.ProblemThe literature is sparse regarding the design of portable health care facilities intended for disaster zones and their adaptability to the tasks required and site areas. METHODS: Data were collected from peer-reviewed literature, scientific reports, magazines, and websites regarding health care facilities at rescue and salvage situations. Information was grouped according to categories of structure and properties, and relative strengths and weaknesses. Next, suggestions were made for future directions. RESULTS: Permanent structures and temporary constructed facilities were the two primary categories of health care facilities functioning at disaster zones. Permanent hospitals were independent functioning medical units that were moved or transported to and from disaster zones as complete units, as needed. These facilities included floating hospitals, flying (airborne) hospitals, or terrestrial mobile facilities. Thus, these hospitals self-powered and contained mobility aids within their structure using water, air, or land as transporting media.Temporary health care facilities were transported to disaster zones as separate, nonfunctioning elements that were constructed or assembled on site and were subsequently taken apart. These facilities included the classical soft-type tents and solid containers that were organized later as hospitals in camp configurations. The strengths and weaknesses of the diverse hospital options are discussed. CONCLUSIONS: Future directions include the use of innovative materials, advanced working methods, and integrated transportation systems. In addition, a holistic approach should be developed to improve the performance, accessibility, time required to function, sustainability, flexibility, and modularity of portable health care facilities.Bitterman N, Zimmer Y. Portable health care facilities in disaster and rescue zones: characteristics and future suggestions. Prehosp Disaster Med. 2018;33(4):411-417. PMID- 30001768 TI - Contribution of drugs acting on the TLRs/MyD88 signaling pathway on colitis associated cancer. AB - Toll-like receptors play a particularly significant role in colitis-associated cancer (CAC). MyD88 is the mediator in TLRs signal transduction process and it is indispensable for TLRs signaling except for TLR3. The conclusion of studies about the role of TLRs/MyD88 signaling in colon cancer remains contradictory: on one hand, TLRs/MyD88 signaling contributes to colon tumor cell proliferation, invasion and metastasis and inhibition of the expression of TLRs or MyD88 could prevent the growth of colon cancer cells; on the other hand, activation of the TLRs/MyD88 signaling pathway could inhibit the proliferation of colon cancer cells. This article is based on the expression levels of TLRs or MyD88 and the activation degrees of TLRs/MyD88 signaling pathway in different periods of colon cancer and, reviews the roles of TLRs/MyD88 signaling in the tumorigenesis and procession of CAC and the clinical application of agonists and inhibitor of TLRs or MyD88. This article is intended to explore the diverse roles of TLRs/MyD88 signaling pathway in CAC and to reveal the related molecular mechanism. PMID- 30001769 TI - Characterization of bevacizumab by dynamic light scattering while maintaining its native structure. AB - Bevacizumab, is a humanized monoclonal antibody and patents on Avastin(r) (Bevacizumab, Roche) will expire in the US in 2019 and in Europe in 2022. Therefore, bevacizumab is a popular target for biosimilar developers. One of the most common problems in the formulation of antibody drugs is protein aggregation. Dynamic light scattering (DLS) is a well-established method for the determination of hydrodynamic dimensions, aggregates, and aggregation points of proteins. In contradistinction to other techniques that require diluted samples or specific conditions, proteins and aggregates can maintain their native structure during DLS measurements. In recent studies, bevacizumab was characterized by DLS using diluted samples. In this study, we aimed at investigating the hydrodynamic dimensions, aggregates, and aggregation onset of bevacizumab (Altuzan(r), Turkey, Roche) by DLS, while maintaining its native structure. The intensity, volume, and number-based particle size distribution profiles of the test samples were evaluated and the aggregation onset of the formulation was successfully determined against increasing temperature. It is shown that the preservation of the native structure of commercial formulations in DLS measurements provides an opportunity to the characterization of commercial products and development of biosimilars. PMID- 30001766 TI - Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018). AB - Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597 2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'. PMID- 30001770 TI - Plasma concentration profile of tolterodine and 5-hydroxymethyl tolterodine following transdermal administration of tolterodine in rats. AB - In this study, the plasma concentration profiles of tolterodine and its active metabolite, 5-hydroxymethyl tolterodine (5-HM tolterodine) were investigated in rats with tolterodine transdermal patches using liquid chromatography-tandem mass spectrometry. The plasma samples were extracted by a liquid-liquid extraction method, with an n-hexane/isopropyl alcohol mixture (9:1, v/v). Tiropramide was used as an internal standard (IS). Chromatographic separation was achieved using a C18 column (2.0 mm * 150 mm, 5 MUm), with a mobile phase consisting of 5 mM ammonium acetate in distilled water/acetonitrile (50:50, v/v). The precursor product ion pairs used for multiple reaction monitoring were m/z 326 -> 284 (tolterodine), m/z 342 -> 223 (5-HM tolterodine), and m/z 468 -> 367 (IS). Subsequently, the plasma concentration levels of tolterodine and 5-HM tolterodine were measured in rat plasma after oral or transdermal administration of tolterodine and the pharmacokinetic parameters were calculated. The Cmax of the patch was less than that of the oral administration but their AUC values were comparable. The resulting data suggested that a transdermal dose of tolterodine 3 times higher (9 mg/12 cm2) could yield comparable efficacy to a 10 mg/kg oral dose in rats. These results would provide useful information on dose optimization of tolterodine transdermal patch for further clinical studies. PMID- 30001771 TI - Long non-coding RNA DLEU1 contributes to the development of endometrial cancer by sponging miR-490 to regulate SP1 expression. AB - This study aimed to investigate the role of long non-coding RNA DLEU1 in endometrial cancer (EC) development. The DLEU1 expression in EC tissues and cells (HHUA, KLE, Ishikawa, and ECC-1) were detected. The expression of DLEU1 was suppressed by transfection with sh-DLEU1 and the effects of DLEU1 suppression on the malignant behaviors of Ishikawa cells, including cell viability, apoptosis, migration and migration were then detected. In addition, the interaction of DLEU1 and miR-490 as well as between miR-490 and SP1 in EC were investigated. Furthermore, the regulatory relationship between DLEU1 and PI3K/AKT/GSK-3beta pathway was explored. DLEU1 was upregulated in EC tissues and cells. Suppression of DLEU1 significantly inhibited Ishikawa cell viability, promoted cell apoptosis, decreased BCL-2 expression and increased the expression of Bax, cleaved-caspase-3 and cleaved-caspase-3, suppressed cell migration and invasion, and inhibited EMT via increasing the expression of E-cadherin and decreasing the expression of N-cadherin, Snail and Vimentin. In addition, DLEU1 could sponge miR 490 and miR-490 inhibition significantly reversed the effects of DLEU1 suppression on the malignant behaviors of Ishikawa cells. Furthermore, SP1 was verified as a target of miR-490, and SP1 knockdown could reverse the effects of miR-490 inhibition on the malignant behaviors of Ishikawa cells. Besides, suppression of DLEU1 inhibited PI3K/AKT/GSK-3beta pathway, while miR-490 inhibition activated this pathway that could be neutralized by SP1 knockdown. Our findings indicate that DLEU1 contributes to EC development by sponging miR-490 to regulate SP1 expression. DLEU1/miR-490/SP1 axis may provide a new strategy for EC therapy. PMID- 30001773 TI - The hepatoprotective effect of lycopene on Con A-induced liver injury in mice. AB - Lycopene, the main fat-soluble pigment responsible for the red color of ripe tomatoes, is a symmetrical tetraterpene comprising eight isoprene units. In vitro and in vivo studies have shown that lycopene acts as a potent antioxidant; it is 100 times more effective than vitamin E and 125 times more effective than glutathione as an antioxidant. Here, we divided BALB/c male mice into three equal groups: control, Concanavalin A (Con A), and Con A and lycopene. The control group mice received only vehicle by intraperitoneal injection, the Con A group mice were given Con A, and the Con A and lycopene group mice received Con A and lycopene. The results showed that Con A administration increased histopathological damage, and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin (IL)-6, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha were increased in serum samples whereas the levels of these compounds were significantly decreased in the Con A and lycopene group compared to the Con A group. Furthermore, we observed that lycopene led to an increase in cell viability and cell growth. The results of this study revealed that lycopene might be a useful hepatoprotective agent for reducing increased proinflammatory cytokine levels, and for increasing cell viability and cell growth. PMID- 30001772 TI - Overexpression of miR-4443 promotes the resistance of non-small cell lung cancer cells to epirubicin by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway. AB - We aimed to elucidate the roles and regulatory mechanism of miR-4443 in regulating the resistance of non-small cell lung cancer (NSCLC) cells to epirubicin (EPI). Fifty-four advanced NSCLC patients were classified as ''insensitive'' or ''sensitive'' according to patient's responses following EPI based chemotherapy and then the expression of miR-4443 was determined. The EPI resistant H1299 cells were collected and transfected with miR-4443 mimics, whereas parental H1299 cells were transfected with miR-4443 inhibitors. The inhibition of growth (IC50), cell cycle or apoptosis of different transfected groups were investigated. Additionally, the potential target of miR-3188 was identified and verified by luciferase reporter assay. Besides, the regulatory relationship between miR-3188 and JAK2/STAT3 pathway was explored. miR-4443 was highly expressed in insensitive NSCLC patients to EPT-based chemotherapy and EPI resistant H1299 cells. Inhibition of miR-4443 increased the sensitivity of EPI resistant H1299 cells to EPI by decreasing IC50 of EPI, inducing cell apoptosis and G0/G1 cell cycle arrest, while overexpression of miR-4443 promoted the resistance of parental H1299 cells to EPI. Furthermore, inositol polyphosphate 4 phosphatase type I gene (INPP4A) was a target of miR-4443 and its expression could be negatively regulated by miR-4443. Overexpression of miR-4443 promoted the resistance of parental H1299 cells to EPI by targeting INPP4A. Besides, overexpression of miR-4443 activated JAK2/STAT3 pathway in parental H1299 cells to EPI. Overexpression of miR-4443 may promote the resistance of NSCLC cells to EPI by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway. miR 4443 may serve as a drug target for NSCLC. PMID- 30001774 TI - Tanshinone IIA activates autophagy to reduce liver ischemia-reperfusion injury by MEK/ERK/mTOR pathway. AB - Autophagy is a highly conserved cell program in eukaryotic cells, which plays an important role for cells to deal with adverse external stimuli such as ischemia reperfusion. Tanshinone IIA (TanIIA) is well known for its protective effect on myocardial disease, and it is know that it also could regulate autophagy in different cells. As this has not yet been shown for hepatocytes, using a mice liver ischemia-reperfusion model, we detected the role of TanIIA in regulating autophagy and the subsequent protective effects on hepatocytes. Our data showed that TanIIA pretreatment could significantly enhance autophagy by the MEK/ERK/mTOR pathway in hepatocytes after liver ischemia-reperfusion, and the enhanced autophagy decreased ROS generation by clearing damaged mitochondria, providing a protective effect on liver ischemia-reperfusion. This protective effect is manifested as reduced serum enzyme levels, reduced liver tissue damage, decreased inflammatory cell infiltration, decreased inflammatory cytokines and reduced hepatocyte apoptosis. In brief, moderate TanIIA utilization might be a potential treatment approach for clinically liver ischemia-reperfusion. PMID- 30001775 TI - Curcumin inhibits proliferation and enhances apoptosis in A549 cells by downregulating lncRNA UCA1. AB - OBJECTIVE: Curcumin has been reported to possess anti-tumor effects on multiple cancers, including lung cancer. However, the mechanisms of its anti-tumor effect on lung cancer have not been fully elucidated. Our study attempted to identify the effect of curcumin on A549 cells and further explore the potential mechanism. METHODS: Different concentrations of curcumin were exposed to A549 cells for 24 h and cell viability was measured by CCK-8 assay. The expression of UCA1 was overexpressed in A549 cells by transfection with pEX-UCA1. Cell proliferation was determined by BrdU staining and assessing the expression of CyclinD1 using western blot and RT-PCR assay. Apoptotic cells were measured by flow cytometry assay. Western blot was performed to assess the expression of apoptosis-related, Wnt and mTOR pathways-related factors. RESULTS: Curcumin incubation dramatically reduced viability of A549 cells in a dosage-dependent manner. Curcumin (0.6 MUM) significantly reduced BrdU+-positive cells, declined the expression of CyclinD1, and enhanced cell apoptosis. Interestingly, we found that curcumin inhibited the expression of UCA1 and UCA1 overexpression abolished the effect of curcumin on cell apoptosis. In addition, we also found that curcumin inhibited Wnt and mTOR pathways through down-regulation of UCA1. CONCLUSION: We demonstrated that curcumin inhibited the growth of A549 cells through downregulation of UCA1, which might provide new insight for the treatment of lung cancer. PMID- 30001776 TI - Ginkgolic acid exerts an anti-inflammatory effect in human umbilical vein endothelial cells induced by ox-LDL. AB - This present investigation examined the mitigating impact of Ginkgolic acid in the organization on oxidized low-density lipoproteinox-LDL (ox- LDL) animated in HUVECs, and to clear up its fundamental molecular components. The levels of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines were measured by Griess examine and catalyst connected immunosorbent test. The declarations of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), mitogen-initiated protein kinases (MAPKs), and Akt were measured utilizing Western smearing. ox-LDL-instigated was utilized as the HUVECs cell model of inflammation. Ginkgolic acid significantly inhibited the production of NO, PGE2, and pro-inflammatory cytokines in a dose-dependent manner and suppressed the expression of iNOS and COX-2 in ox-LDL-stimulated HUVECs cells. Ginkgolic acid strongly suppressed NF-kappaB by preventing degradation of inhibitor of kappaB alpha as well as by inhibiting phosphorylation of Akt and MAPKs. Ginkgolic acid reduced LDL-stimulated inflammation in endothelial cells. These outcomes suggest that the anti-inflammatory properties of Ginkgolic acid are related to a down control of iNOS, COX-2, and master provocative cytokines through the restraint of NF-kappaB pathway in ox- LDL-animated endothelial cells. PMID- 30001777 TI - Anti-proliferative and anti-invasive effects of garcinol from Garcinia indica on gallbladder carcinoma cells. AB - Garcinol, a natural histone acetyltransferase inhibitor, has been reported to exhibit significant anti-proliferative activity in various cancer cell types. However, no information is available about the anti-cancer effects of garcinol on gallbladder carcinoma cells (GBC). In this study, GBC cells (GBC-SD and NOZ) were treated by garcinol and subjected to Cell Counting Kit-8 (CCK-8), and GBC-SD cells were selected for further transwell chamber assay, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Our results indicated that garcinol could significantly inhibit the growth of GBC cells in a dose- and time-dependent manner. It also inhibited the invasion of GBC-SD cells in a dose-dependent manner. Garcinol treatment decreased the activity of matrix metalloproteinase 2 (MMP2) and MMP9 by the downregulation of mRNA levels, and these two enzymes are critical to tumor invasion. Treatment with garcinol also decreased Stat3 and Akt activation in GBC-SD cells. Taken together, the effects of garcinol on GBC-SD cells may be associated with the suppression of Stat3 and Akt signaling pathways, which may contribute to inhibiting their downstream targets such as mRNA levels of MMP2 and MMP9. PMID- 30001778 TI - Acute lymphoblastic leukemia in a patient with IgG4-related disease. AB - IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated condition characterized by tumor-like lesions, fibrosis, and lymphoplasmacytic infiltration to every organ. Recently, an association between IgG4-RD and malignant tumors has been suggested and IgG4-RD is closely related to the occurrence of malignant hematologic diseases. In this report, we describe a rare complication of acute lymphoblastic leukemia in a patient with IgG4-RD. An 81-year-old Chinese man was diagnosed with the lymphadenopathy associated with IgG4-related disease. The histopathological study revealed multiple plasma cells infiltration and immunostaining for IgG and IgG4 was performed on plasma cells and the IgG/IgG4 ratio was more than 40%. Eight months later, he developed acute lymphoblastic leukemia. It has been suggested that the incidence of malignant hematologic diseases may be high in patients with IgG4-RD and increased Th2 cells and Treg cells cytokines may result in the occurrence of hematologic malignancies. Therefore, the importance of accurate diagnosis and intense medical follow-up should be emphasized. Once the patients develop hematologic malignancies, they need to receive treatment timely. PMID- 30001779 TI - Contribution of pharmacists with expertise in infectious diseases to appropriate individualized vancomycin dosing. AB - BACKGROUND/AIM: Dose adjustment of vancomycin (VCM) is important in improving clinical outcomes and avoiding adverse effects such as nephrotoxicity. Although pharmacist-managed VCM therapy has been reported to optimize treatment, there are no studies focused on pharmacist expertise to date. In this study, we compared the contribution of pharmacists trained for infectious diseases and general pharmacists to dose adjustment of VCM. PATIENTS AND METHODS: We retrospectively investigated VCM trough concentration after dose adjustment by both trained (n = 67) and general (without special training for infectious diseases; n = 85) pharmacists. We also compared the incidence of nephrotoxicity during VCM treatment in both groups. RESULTS: The rate of achieving therapeutic VCM trough concentration (10-20 MUg/mL) was higher in the trained group than in the control group (80.6 vs. 54.1%, p < 0.001). No significant differences in incidence of nephrotoxicity were observed between the two groups (p = 0.744). Trained pharmacists could contribute more successfully to the achievement of therapeutic VCM concentration ranges without increasing the risk of nephrotoxicity. PMID- 30001780 TI - Foreword. PMID- 30001783 TI - The Relationship Between Rheumatologic Disorders and Malignancies. AB - A variety of conditions mimicking rheumatologic syndromes may be associated with an underlying malignancy. Therefore, distinguishing these syndromes from more common, nonparaneoplastic rheumatologic conditions can be perplexing. Some autoimmune conditions and the medications used for their management can be associated with increased future risk of malignancy. Some cancers can directly involve the musculoskeletal structures, whereas others present with systemic manifestations at sites away from the tumor and its metastases. Better awareness and timely recognition of these associations may lead to earlier cancer detection and, it is hoped, better long-term survival. PMID- 30001782 TI - Sarcopenia: A Rheumatic Disease? AB - Sarcopenia refers to the age-related loss of muscle mass, muscle strength, and physical function. With an increase in the number and proportion of elderly in the population, sarcopenia is a growing global health concern due to its impact on morbidity, mortality, and health care expenditure. Despite its clinical importance, sarcopenia remains underrecognized and poorly managed in routine clinical practice. This is, in part, due to a lack of available diagnostic testing and uniform diagnostic criteria. This article provides the general practitioner or rheumatologist an overview of the pathophysiology, diagnosis, and management of this complex and critical entity. PMID- 30001785 TI - A Review of Osteoporosis in the Older Adult: An Update. AB - Osteoporosis in the elderly population is common. It results in more than 1.5 million fractures per year in the United States. The goal of managing osteoporosis is to prevent fractures. In men, osteoporosis is underrecognized and undertreated. More men than women die every year as a consequence of hip fractures. Bisphosphonates are the first-line treatment of men and women. In the past several years, advances in bone biology have resulted in major therapeutic advances. A review of diagnosis and treatment of osteoporosis is described. PMID- 30001781 TI - Pharmacotherapy Pearls in Rheumatology for the Care of Older Adult Patients: Focus on Oral Disease-Modifying Antirheumatic Drugs and the Newest Small Molecule Inhibitors. AB - Providing safe and effective pharmacotherapy to geriatric patients with rheumatologic disorders is challenging. Multidisciplinary care involving rheumatologists, primary care physicians, and other specialties can optimize benefit and reduce adverse outcomes. Oral disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, and the small molecule inhibitors tofacitinib and apremilast have distinctive monitoring requirements and specific adverse reaction profiles. This article provides clinically relevant pearls for use of these interventions in older patients. PMID- 30001786 TI - Regional Rheumatic Disorders and Rehabilitation in Older Adults: An Update. AB - Musculoskeletal problems are the most frequently reported complaints among older adults living in the community. The impact of the aging process on skeletal muscles and joints can have a profound effect on the ability of individuals to function. This article reviews the rehabilitation medicine approach to the evaluation of older adults with regional rheumatic disorders and the rehabilitation medicine considerations for clinical intervention. Future research is required to gain a greater understanding of the subject matter and its impact on the provision of care and patients' quality of life. PMID- 30001787 TI - Update on Cardiovascular Disease Risk in Patients with Rheumatic Diseases. AB - Cardiovascular disease (CVD) risk is 1.5-fold higher in rheumatoid arthritis (RA), partly due to subclinical atherosclerosis that develops before the diagnosis of RA. Dyslipidemia in RA is better quantified by lipoproteins and apolipoproteins than by cholesterol levels. Current risk factors likely underestimate CVD risk by underestimating prior risk factor levels. Some of the 2 fold higher risk of heart failure and total mortality in RA may be due to myocardial disease caused by inflammation. Per recent recommendations, to reduce CVD risk in RA, control disease activity, reduce inflammation, and aggressively treat CVD risk factors. PMID- 30001788 TI - Crystal-Induced Arthritides in the Elderly: An Update. AB - The prevalence of gout increases with age. After the serum concentration of urate exceeds the saturation or solubility point, it deposits in and around the joints. Presentation in the elderly is often atypical and challenging to diagnose. Treatment depends on disease stage, health status, and comorbidities. Elderly patients often have several confounding issues; treatment decisions can be complicated and therapeutic options limited. To prevent recurrence, serum concentration of urate should be maintained well below the saturation threshold of 6.8 mg/dL, leading to dissolution of urate deposits and preventing recurrence. PMID- 30001784 TI - Update on Sjogren Syndrome and Other Causes of Sicca in Older Adults. AB - Dry eye and dry mouth symptoms are each reported by up to 30% of persons more than 65 years of age, particularly in women. Medication side effects are the most common contributing factors. The evaluation of these symptoms requires measures of ocular and oral dryness. Sjogren syndrome is the prototypical disease associated with dryness of the eyes and mouth and predominantly affects women in their perimenopausal and postmenopausal years. In addition to topical treatment of the mucosal dryness, patients with Sjogren syndrome may require treatment with systemic immunomodulatory and immunosuppressive agents to manage a variety of extraglandular manifestations. PMID- 30001789 TI - Lumbar Spinal Stenosis in Older Adults. AB - Lumbar spinal stenosis (LSS) is a frequent cause of low back pain among adults, caused by a narrowing impinging on the spinal cord or nerve roots. Several conditions cause LSS, including disc herniation, spondylolisthesis, tumor, fractures, and other degenerative changes. Back pain is frequently experienced. MRI is the radiologic modality of choice. Radiographic evidence of LSS may not correlate well with symptoms. An increase in utilization of surgery has been noted. However, surgery has no significant benefit over more conservative options. An appropriate risk/benefit discussion between the patient and an interdisciplinary medical team is optimal. PMID- 30001790 TI - Nonsurgical Management of Osteoarthritis Knee Pain in the Older Adult: An Update. AB - Symptomatic knee osteoarthritis is a common complaint of many elderly patients in primary care offices. For those unable or unwilling to undergo knee replacement, the primary practitioners' understanding of the strengths and weaknesses of the available treatment modalities for pain relief is critical to successful in office counseling and expectation management. Treatment requires a multimodal approach of nonpharmacologic and pharmacologic therapies to achieve a maximal clinical benefit. The focus of this review is on the nonsurgical options for treatment of knee osteoarthritis in patients aged 65 and older. PMID- 30001791 TI - Rheumatic Diseases in Older Adults. PMID- 30001793 TI - Age-Related Deficits in Taste and Smell. AB - Disturbances in both the ability to smell and to taste are common in older persons. Such disturbances influence nutrition, safety, quality of life, and psychological and physical health. The anatomic and physiologic causes of age related disturbances are multiple and interacting, and depend on genetic and environmental factors. Frank losses of function, distortions, and hallucinations are common. Most distortions resolve over time, although this can take months or even years. Olfactory dysfunction occurs during the earliest stages of several neurologic disorders, most notably Alzheimer's disease and Parkinson's disease, likely heralding the onset of the underlying pathologies. PMID- 30001792 TI - Rheumatic Diseases in Older Adults. PMID- 30001794 TI - Geriatric Otolaryngology. PMID- 30001796 TI - Preface. PMID- 30001797 TI - Radiation-induced angiosarcoma of the breast in a Li-Fraumeni patient. PMID- 30001795 TI - Pyrrolizidine Alkaloids. AB - Naturally occurring pyrrolizidine alkaloids (PAs) are isolated from plants and other sources. The interest of the scientific community in these compounds owes itself to their high toxicity and biological activity, as well as to the challenge of synthesizing their pyrrolizidine scaffold. This review encompasses a wide range of topics found in the literature from 1995 to date, including the occurrence, biosynthesis, toxicity (hepatotoxicity, genotoxicity, and tumorigenicity), biological activity, and pharmacological properties (glycosidase inhibitory activity) of these secondary metabolites. Particular attention is given to the chemistry of PAs, addressing general strategies for formal and total syntheses via amino-based substrates, pyrroles, and pyrrolidine-based derivatives. PMID- 30001798 TI - RF - Epidermal Growth Factor Receptor Inhibitors and Skin Toxicity: The Search for a Management Protocol. PMID- 30001799 TI - Effects of music intervention on inflammatory markers in critically ill and post operative patients: A systematic review of the literature. AB - BACKGROUND: Music listening has been shown to reduce anxiety, stress, and patient tolerance of procedures. Music may also have beneficial effects on inflammatory biomarkers in intensive care and post-operative patients, but the quality of evidence is not clear. OBJECTIVES: We conducted a systematic review to evaluate the effects of music on inflammatory biomarkers in intensive care, and post operative patients. METHODS: A comprehensive search of the literature was performed. After screening 1570 references, full text review of 26 studies was performed. Fourteen studies were selected for inclusion. RESULTS: Seven studies showed a significant decrease in cortisol levels, but the level of evidence was low. Three studies had low risk of methodological bias, while 11 studies had high risk of bias. CONCLUSIONS: Music intervention may decrease cortisol levels, but other biomarkers remain unchanged. Given the low level of evidence, further research on music effects on inflammatory biomarkers is needed. PMID- 30001801 TI - The antitumor effect of TAT-DCF1 peptide in glioma cells. AB - BACKGROUND: Glioblastoma is one of the most malignant brain cancer, thus, establishing an effective therapy is paramount. Our previous results indicate that dendritic cell-derived factor (DCF1) is an attractive candidate for therapy against Glioblastoma, since its overexpression in Glioblastoma U251 cells leads to apoptosis. However, the delivery approach limits its clinical application, in this paper, we expressed TAT-DCF1 fusion protein in E.coli in order to surmount its current delivery problems. METHODS: The coding sequences of the different domains of DCF1 (full length, cytoplasmic, extracellular, 19-amino acid), together with the N-terminal transactivator of transcription (TAT) sequence, were amplified and subcloned into the bacterial expression vector pET30a(+) in order to produce (His)6-tagged fusion proteins. Coomassie blue-stained SDS-PAGE and Western blotting identification showed that purity of the fusion proteins. RESULTS: Immunofluorescence and flow cytometry show that U251 cells were efficiently transduced with the fusion proteins. Cell viability, proliferation, and migration assays suggest that the complete TAT-DCF1 fusion protein significantly decreased U251 proliferation and migration. Flow cytometry further reveals that TAT-DCF1 triggered cellular apoptosis. CONCLUSIONS: In conclusion, these findings suggest that the TAT-DCF1 fusion protein was efficiently transduced into Glioblastoma U251 cells and induced the antitumor effect and support further investigation into specific targeting and side effects of TAT DCF1 during drug delivery. PMID- 30001800 TI - Lectin histochemical studies on the olfactory gland and two types of gland in vomeronasal organ of the brown bear. AB - Olfaction is mediated by the vomeronasal and main olfactory systems, and the peripheral vomeronasal organ (VNO) processes species-specific chemicals that are associated with various behaviors in mammals. Sensory epithelial surfaces of the olfactory mucosa and VNO are covered by mucosal fluid that contains secretory products derived from associated glands, and glycoconjugates in the mucosal fluid are involved in odorant reception. The VNO of brown bears contains two types of glands; submucosal vomeronasal glands (VNG) and multicellular intraepithelial glands (MIG). The present study determined the labelling profiles of 21 lectins in the olfactory glands (OG), VNG and MIG of young male brown bears. The OG reacted with 12 lectins, and the VNG and MIG were positive for seven and eight lectins, respectively. Six lectins bound only to the OG, while four reacted with both or either of the VNG and MIG, but not the OG. The differences of lectin labelling pattern between the OG and glands in the VNO suggest that glycans in covering mucosal fluids differ between the olfactory mucosa and VNO. In addition, Bandeiraea simplicifolia lectin-I, Sophora japonica agglutinin and Jacalin reacted with the MIG but not the VNG, whereas Datura stramonium lectin and concanavalin A bound to the VNG, but not the MIG. These findings indicate that the properties of secretory substances differ between the two types of glands in the bear VNO, and that the various secretions from these two types of glands may function in the lumen of VNO together. PMID- 30001802 TI - The relationship between aggression and ability emotional intelligence: The role of negative affect. AB - This study aimed to contribute to the understanding of the mechanisms underlying the relationship between aggressive behaviour and individual levels of ability emotional intelligence (EI). Three hundred and ninety-five participants took part in this study. Participants were assessed on ability EI, negative affect (NA), and aggression by the Mayer-Salovey-Caruso Emotional Intelligence Test, the Positive and Negative Affect Schedule, and the Buss-Perry Aggression questionnaires, respectively. The results revealed a negative relationship between aggression and ability EI, but this relationship depended on multiple factors: the type of EI branches and aggression dimensions, the influence of NA, and gender. Emotional management ability showed a direct relationship with aggression, while emotional perception ability presented an indirect relationship with aggression through the effect of NA. These EI abilities were related to different aggression dimensions, highlighting the direct relationship with physical aggression. Moreover, gender differences showed that women possess greater EI abilities, higher levels of NA, less aggressive behaviour, and a lower relationship between NA and aggression compared with men. This research offers a better understanding of the psychological processes explaining aggression. The inclusion of our findings in the design of prevention and treatment programs could be of great help in the control of aggressive behaviour. PMID- 30001803 TI - Parents' Need-related Experiences and Behaviors When Raising a Child With Autism Spectrum Disorder. AB - PURPOSE: Research suggests that parenting a child with autism spectrum disorder (ASD) brings about major challenges to parents' own psychological resources. Considered through the lens of Self-Determination Theory (Ryan & Deci, 2017), parents rearing a child with ASD particularly face challenges to their psychological needs for autonomy, competence, and relatedness. In turn, these challenges potentially jeopardize parents' capacity to attune to their child. This qualitative study aims to advance insight into (the interplay between) parents' experiences and parenting behaviors when raising a child with ASD, thereby using SDT as a framework to understand how these experiences and behaviors relate to the psychological needs for autonomy, relatedness and competence. DESIGN AND METHODS: Fifteen parents of children with ASD, aged 6 to 17, participated in an interview concerning their behaviors and experiences in raisin their child with ASD. RESULTS: Four sets of parental behaviors and five sets of parental experiences were identified, with the majority being relevant to the psychological needs postulated by SDT. CONCLUSIONS: The findings of this study provide (1) a deeper understanding of the threats and opportunities for the well-being of parents of children with ASD, (2) an in-depth insight into how these parents adjust their parenting behaviors to their child, and (3) an understanding of how parents' need-related experiences and parenting behaviors are dynamically intertwined. PRACTICAL IMPLICATIONS: By structuring how parents perceive threats and opportunities when raising a child with ASD within the SDT framework, important targets for parent-support are identified. PMID- 30001804 TI - Mechanisms of Intra-Atrial Re-Entrant Tachycardias in Congenital Heart Disease: Types and Predictors. AB - Intra-atrial re-entrant tachycardia (IART) is a severe complication in patients with congenital heart disease (CHD). Cavotricuspid isthmus (CTI)-related IART is the most frequent mechanism. However, due to fibrosis and surgical scars, non-CTI related IART is frequent. The main objective of this study was to describe the types of IART, circuit locations, and to analyze predictors of CTI versus non-CTI related IART. This is an observational study that includes all consecutive patients with CHD who underwent a first IART ablation in a single referral tertiary hospital from January 2009 to December 2015 (94 patients; 39.4% women; age: 36.55 +/- 14.9 years, 40.4% with highly complex cardiac disease). During the study, 114 IARTs were ablated (1.21 +/- 0.41 IARTs per patient). CTI-related IART was the only arrhythmia in 51% (n = 48) of patients; non-CTI-related IART was the only mechanism in 27.7% (n = 26), and 21.3% of patients (n = 20) presented the two types of IART. Severe dilation of the systemic ventricle, absence of severe dilation of the venous atrium, highly complex cardiac defects, and nontypical electrocardiography (ECG) were related to non-CTI-related IART in univariate analysis. In multivariate analysis, nontypical ECG (odds ratio 3.64; 1.01 to 4.9; p = 0.049) and grade III CHD complexity (odds ratio 9.43; 1.44 to 11.7; p = 0.001) were predictors of non-CTI-related IART. In conclusion, in our population with a high proportion of complex CHD, CTI-related IART was the most frequent mechanism, although non-CTI-related IART was present in 49% (alone or with concomitant CTI-related IART). High-grade CHD complexity and nontypical ECG were strongly related to non-CTI IART. PMID- 30001805 TI - Consequences of short sleep duration on the dietary intake in children: A systematic review and metanalysis. AB - During the last years, a decline in the amount of hours of sleep has been observed in children. Sleep deficiency has been linked to an increase in calories, snacks, and fat intake. The objective of this study was to review the evidence between sleep duration and eating habits in children. We performed an electronic search in MEDLINE, The Cochrane Central Register, BIREME, EMBASE, LILACS, and Epistemonikos. Study selection criteria was: children aged 2-18 yrs within studies that aimed to associate sleep duration and eating habits. Quality of the included studies was assessed with the STROBE scale. Thirty studies were included, 10 in the metanalysis (n = 72,054). Odds ratio for unhealthy eating habits among children who had short sleep was OR 1.51 [95% CI: 1.24-1.85]. Snack consumption was associated with less sleep: OR 1.75 [95% CI 1.24-2.46]. The same figure for soda was OR 1.16 [CI 95% 1.09-1.25]. Adequate sleep duration was associated with intake of fruits and vegetables: OR 0.75 [CI 95% 0.65-0.86]. This systematic review showed an association between sleeping hours and eating habits in children. Education regarding sleep should be recommended in children in order to avoid unhealthy eating habits. PMID- 30001806 TI - The effect of surgical weight loss on obstructive sleep apnoea: A systematic review and meta-analysis. AB - This review aimed to examine the relationship between surgical weight loss and obstructive sleep apnoea (OSA) severity (i.e., apnoea-hypopnoea index [AHI]), and how this relationship is altered by the various respiratory events scoring (RES) criteria used to derive the AHI. A systematic search of the literature was performed up to December 2017. Before-and-after studies were considered due to a paucity of randomised controlled trials (RCTs) available to be reviewed in isolation. Primary outcomes included pre- and post-surgery AHI and body mass index (BMI). Secondary outcomes included sleep study type and RES criteria. Meta analysis was undertaken where possible. Overall, surgical weight loss resulted in reduction of BMI and AHI, however, OSA persisted at follow-up in the majority of subjects. There was high between-study heterogeneity which was largely attributable to baseline AHI and duration of follow-up when analysed using meta regression. There was insufficient data to evaluate the impact of different RES criteria on OSA severity. Therefore, more RCTs are needed to verify these findings given the high degree of heterogeneity and future studies are strongly encouraged to report the RES criteria used to enable fair and uniform comparisons of the impact of any intervention on OSA severity. PMID- 30001807 TI - Autophagy impairment in pancreatic acinar cells causes zymogen granule accumulation and pancreatitis. AB - Basal autophagy degrades many kinds of proteins and organelles to maintain quality and plays important roles in cellular homeostasis. However, the impact of basal autophagy on zymogen granules in pancreatic acinar cells is unknown. In the present study, we examined the influence of autophagy impairment in acinar cells on zymogen granules and homeostasis of the pancreas, using mice with pancreas specific autophagy impairment (Pdx1-Cre+/-Atg7fl/fl mice). The number of zymogen granules in acinar cells from these mice did not differ from that in acinar cells from their wild-type littermates at 3 weeks of age. However, the number of zymogen granules in acinar cells drastically increased at 4 weeks of age in mice with pancreas-specific autophagy impairment. In addition to the increased number of zymogen granules, serum lipase was elevated, and the pancreas became oedematous at 4 weeks of age, suggesting pancreatitis. After 5 weeks of age, acinar cell death was accelerated, and several histological features of chronic pancreatitis were observed, including glandular atrophy and pseudotubular complexes with fibrotic changes. In conclusion, the impairment of pancreas specific basal autophagy caused spontaneous zymogen granule accumulation in acinar cells and pancreatitis, which eventually led to chronic pancreatitis. PMID- 30001808 TI - NtRLK5, a novel RLK-like protein kinase from Nitotiana tobacum, positively regulates drought tolerance in transgenic Arabidopsis. AB - Receptor-like protein kinase (RLKs) plays pivotal roles in plant growth and development as well as stress responses. However, little is known about the function of RLKs in Nitotiana tobacum. In the present study, we present data on NtRLK5, a novel RLK-like gene isolated from Hongda (Nitotiana tobacum L.). Expression profile analysis revealed that NtRLK5 was strongly induced by drought and salt stresses. Transient expression of NtRLK5-GFP fusion protein in protoplast showed that NtRLK5 was localized to plasma membrane. Overexpression of NtRLK5 conferred enhanced drought tolerance in transgenic Arabidopsis plants, which was attributed to not only the lower malondialdehyde (MDA) and H2O2 contents, but also the higher antioxidant enzymes activities. Moreover, the expression of several antioxidation- and stress-related genes was also significantly up-regulated in NtRLK5 transgenic plants under drought condition. Taken together, the results suggest that NtRLK5 functions as a positive regulator in drought tolerance. PMID- 30001809 TI - Identification of antibodies against extracellular matrix proteins in human osteoarthritis. AB - We investigated the presence of autoantibodies against the extracellular matrix proteins thrombospondin-4 (TSP-4), cartilage oligomeric matrix protein (COMP), C type lectin domain family 3 member A (CLEC3A), collagen II, collagen VI, matrilin 3, and fibrillin-2 in the serum of osteoarthritis (OA) patients. We compared those results with the presence of such antibodies in rheumatoid arthritis (RA) patients and in healthy donors (HD). Our study examines whether antibodies against extracellular proteins can be used as potential biomarkers to support the clinical diagnosis of OA. 10 OA, 10 RA patients and 10 HD were enrolled in this explorative cross-sectional study. SDS-PAGE and immunoblot were used to investigate the presence of antibodies against extracellular matrix proteins. The serum of 5/10 OA patients but 0/10 HD exhibited TSP-4 IgG isotype antibodies (P = 0.033). The serum of 8/10 OA patients but only 1/10 HD exhibited IgG isotype antibodies against TSP-4 or COMP (P = 0.005). The serum of 9/10 OA patients but only 1/10 HD exhibited IgG isotype antibodies against TSP-4, COMP or CLEC3A (P = 0.005). We found strong evidence for the presence of IgG isotype autoantibodies against the cartilage extracellular matrix proteins TSP-4, COMP and CLEC3A in OA. The detection of IgG isotype autoantibodies against TSP-4, COMP and CLEC3A may support the clinical diagnosis of OA. OA with autoantibodies against cartilage extracellular matrix proteins defines a new OA subgroup suggesting that patients with high concentrations of autoantibodies may benefit from an immune suppressive therapy. PMID- 30001810 TI - Blood lipids during pregnancy: A progressively appreciated subject in basic and clinical research. PMID- 30001811 TI - Frenotomy for tongue-tie in newborn infants. AB - BACKGROUND: Tongue-tie (ankylglossia) occurs when there is an anterior attachment near the tip of the tongue resulting in restricted tongue movement. It is reported to be a cause of poor breastfeeding in infants and nipple pain in breastfeeding mothers. OBJECTIVES: The objectives of the study were to determine whether frenotomy is safe and effective in improving ability to feed orally among infants. INTERVENTION/METHODS: Frenotomy may correct the restriction of tongue movement and allow improved breast feeding and reduced maternal nipple pain. Randomised, quasi-randomised cluster-randomised controlled trials that compared frenotomy verses no frenotomy or frenotomy verses sham procedure were included in the review. Participants were infants with tongue-tie experiencing feeding problems, or whose breast feeding mothers were experiencing nipple pain. RESULTS: Five studies (N = 302) met the inclusion criteria. Pooled analysis of two studies showed no change following frenotomy (mean difference (MD) -0.1, 95% confidence interval (CI) -0.6 to 0.5 units on a 10-point feeding scale). A third study showed objective improvement on a 12-point feeding scale (MD 3.5, 95% CI 3.1 to 4.0 units of a 12-point feeding scale). Pooled analysis of three studies (n = 212) showed a reduction in maternal pain scores following frenotomy (MD -0.7, 95% CI -1.4 to -0.1 units on a 10-point pain scale). These studies had serious methodological shortcomings. CONCLUSION: Investigators did not find a consistent positive effect on infant breastfeeding following frenotomy. A short-term reduction in breast pain was found among breastfeeding mothers. Small trial numbers and methodological issues meant no definitive benefit for frenotomy in infants with tongue-tie could be proved. PMID- 30001812 TI - Robust observer-based Hinfinity control for uncertain discrete singular systems with time-varying delays via sliding mode approach. AB - In this paper, the issue of robust observer-based Hinfinity control for uncertain discrete singular systems with time-varying delays is investigated via sliding mode control (SMC). A sliding mode strategy is presented combined with the observer technique, since the system states are unmeasured. The distinguishing feature of the provided strategy is that a novel sliding surface is constructed based upon the estimated states such that the resulting full-order closed-loop system is generated. Furthermore, by employing Lyapunov-Krasovskii functional, new sufficient criteria in terms of a solvable linear matrix inequality (LMI) is derived, insuring that the closed-loop system is admissible with an Hinfinity norm bound. With the solution of the LMI, a corresponding sliding mode controller is obtained for reaching motion and reducing the chattering. At last, the theoretical results are verified in numerical tests. PMID- 30001814 TI - Confounding biases in the association between fentanyl use and hypotension after rapid sequence intubation. PMID- 30001813 TI - Infectious endocarditis: An update for emergency clinicians. AB - INTRODUCTION: Infectious endocarditis (IE) is a potentially deadly disease without therapy and can cause a wide number of findings and symptoms, often resembling a flu-like illness, which makes diagnosis difficult. OBJECTIVE: This narrative review evaluates the presentation, evaluation, and management of infective endocarditis in the emergency department, based on the most current literature. DISCUSSION: IE is due to infection of the endocardial surface, most commonly cardiac valves. Major risk factors include prior endocarditis (the most common risk factor), structural heart damage, IV drug use (IVDU), poor immune function (vasculitis, HIV, diabetes, malignancy), nosocomial (surgical hardware placement, poor surgical technique, hematoma development), and poor oral hygiene, and a wide variety of organisms can cause IE. Patients typically present with flu like illness. Though fever and murmur occur in the majority of cases, they may not be present at the time of initial presentation. Other findings such as Roth spots, Janeway lesions, Osler nodes, etc. are not common. An important component is consideration of risk factors. A patient with IVDU (past or current use) and fever should trigger consideration of IE. Other keys are multiple sites of infection, poor dentition, and abnormal culture results with atypical organisms. If endocarditis is likely based on history and examination, admission for further evaluation is recommended. Blood cultures and echocardiogram are key diagnostic tests. CONCLUSIONS: Emergency physicians should consider IE in the patient with flu-like symptoms and risk factors. Appropriate evaluation and management can significantly reduce disease morbidity and mortality. PMID- 30001815 TI - Skin mottling score and capillary refill time to assess mortality of septic shock since pre-hospital setting. AB - OBJECTIVES: The early identification of septic shock patients at high risk of poor outcome is essential to early initiate optimal treatments and to decide on hospital admission. Biomarkers are often used to evaluate the severity. In prehospital settings, the availability of biomarkers, such as lactate, is restricted. In this context, clinical tools such as skin mottling score (SMS) and capillary refill time (CRT) are more suitable. In this study, we describe prehospital SMS and CRT's ability to predict mortality of patients with septic shock initially cared in the prehospital setting by a mobile intensive care unit. METHODS: Patients with septic shock who received prehospital medical care admitted to the intensive care unit were retrospectively analyzed. RESULTS: Sixty three patients were included. The origin of sepsis was mainly pulmonary (67%). Overall mortality reached 36%. No significant difference was observed in the duration of prehospital medical care between alive and deceased patients. Mean prehospital value of SMS was 3 +/- 2 and mean prehospital value of CRT was 5 +/- 1 s. A significant association was found between mortality and prehospital SMS (p = 0.02, OR[CI95] = 1.50 [1.08-2.15]) and prehospital CRT (p = 0.04, OR[CI95] = 1.53 [1.04-2.37]). After adjusting for confounding factors using propensity score, the relative risk of death was 6.58 for SMS > 2 and 2.03 for CRT > 4 s. CONCLUSION: In this study, we report an association between prehospital SMS and CRT, and mortality of patients with septic shock. SMS and CRT are simple tools that could be used to optimize the triage and to decide early intensive care admission. PMID- 30001816 TI - Fixed dose 4-factor prothrombin complex concentrate for bleeding caused by long acting anticoagulant rodenticides. AB - Acute, unintentional drug-related poisonings lead to an estimated 418,313 ED visits in 2014, according to the latest statistics from the Center for Disease Control and Prevention. While most of these were opiate-related poisonings, anticoagulant rodenticides were the most common cause of rodenticide-related poisoning in the United States. Many clinical syndromes and treatment algorithms have been described for patients with anticoagulant rodenticide poisoning. We report a case of an acute ingestion of two anticoagulant rodenticides and successful reversal of coagulation parameters using 4-factor prothrombin complex concentrate in a fixed-dose approach. PMID- 30001817 TI - Prehospital advanced cardiac life support by EMT with a smartphone-based direct medical control for nursing home cardiac arrest. AB - OBJECTIVE: To compare the survival to discharge between nursing home (NH) cardiac arrest patients receiving smartphone-based advanced cardiac life support (SALS) and basic life support (BLS). METHODS: The SALS registry includes data on cardiac arrest from 7 urban and suburban areas in Korea between July 2015 and December 2016. We include adult patients (>18) with out-of-hospital cardiac arrest (OHCA) of medical causes and EMS attended and dispatched in. SALS is an advanced field resuscitation including drug administration by paramedics with video communication-based direct medical direction. Prehospital resuscitation method was key exposure (SALS, BLS). The primary outcome was survival to discharge. RESULTS: A total of 616 consecutive out-of-hospital cardiopulmonary resuscitation cases in NHs were recorded, and 199 (32.3%) underwent SALS. Among the NH arrest patients, the survival discharge rate was a little higher in the SALS group than the BLS group (4.0% vs 1.7%), but the difference was not significant (P = 0.078). Survival discharge with good neurologic outcome rates was 0.5% in the SALS group and 1.0% in the BLS group (P = 0.119). On the other hand, in the non-NH group, all outcome measures significantly improved when SALS was performed compared to BLS alone (survival discharge rate: 10.0% vs 7.3%, P = 0.001; good neurologic outcome: 6.8% vs 3.3%, P < 0.001). CONCLUSIONS: As a result of providing prehospital ACLS with direct medical intervention through remote video calls to paramedics, the survival to discharge rate and that with good neurologic outcome (CPC 1, 2) of non-NH patients significantly improved, however those of NH patients were not significantly increased. PMID- 30001818 TI - Beyond basic resuscitation: What are the next steps to improve the outcomes of resuscitation at birth when resources are limited? AB - Implementation of basic neonatal resuscitation in low- and middle-income settings consistently saves lives on the day of birth. What can be done to extend these gains and further improve the outcomes of infants who require resuscitation at birth when resources are limited? This review considers how resuscitation and post-resuscitation care can advance to help meet the survival goals of the Every Newborn Action Plan for 2030. A brief summary of the evidence for benefit from basic neonatal resuscitation training in low- and middle-income countries highlights key aspects of training, low-dose high-frequency practice, and implementation with single providers or teams. Reorganization of processes of care, as well as new equipment for training and selected clinical interventions can support further quality improvement in resuscitation. Consideration of the resuscitation algorithm itself focuses on important actions for all babies and special considerations for small babies and those not crying after thorough drying. Finally, an examination of the vital elements of assessment and continued stabilization/care in the health facility draws attention to the opportunities for prevention of intrapartum-related events and the gaps that still exist in postnatal care. Extending and improving implementation of basic resuscitation to make it available to all newborns will assure continued benefit to the largest numbers; once high coverage and quality of basic resuscitation are achieved, health systems with maturing capacity can extend survival gains with improved prevention, more advanced resuscitative interventions, and strengthened postnatal care. PMID- 30001819 TI - Animal models in neonatal resuscitation research: What can they teach us? AB - Animal models have made and continue to make important contributions to neonatal medicine. For example, studies in fetal sheep have taught us much about the physiology of the fetal-to-neonatal transition. However, whereas animal models allow multiple factors to be investigated in a logical and systematic manner, no animal model is perfect for humans and so we need to understand the fundamental differences in physiology between the species in question and humans. Although most physiological systems are well conserved between species, some small differences exist and so wherever possible the knowledge generated from preclinical studies in animals should be tested in clinical trials. However, with the rise of evidence-based medicine the distinction between scientific knowledge generation and evidence gathering has been confused and the two have been lumped together. This misunderstands the contribution that scientific knowledge can provide. Science should be used to guide the gathering of evidence by informing the design of clinical trials, thereby increasing their likelihood of success. While scientific knowledge is not evidence, in the absence of evidence it is likely to be the best option for guiding clinical practice. PMID- 30001821 TI - The role of Kupffer cells in hepatic iron and lipid metabolism. PMID- 30001820 TI - Clinical manifestations and location of brain metastases as prognostic markers. AB - BACKGROUND: Brain metastases (BM) are a frequent complication of cancer and are regularly seen in clinical practice. New treatment modalities are improving survival after diagnosis of BM. However, symptoms are rarely reported and their significance is not well established. The aim of the present study was to investigate neurologic indicators as prognostic markers in patients with brain metastases. PATIENTS AND METHODS: A prospectively acquired database from 2 referral centers was analyzed. All patients had had at least 2 neuro-oncologic consultations and magnetic resonance imaging to confirm the diagnosis. Patients were classified according to universally used prognostic scores, gender, primary tumor, localization of BM, and clinical complaints. Univariate and multivariate analysis was used to evaluate associations. RESULTS: A total of 570 patients were included; 71% were female, and 91% had solid tumors. Median survival was 11 months (95% confidence interval 9.4-12.6). Of 1322 parenchymal lesions, 78% were supratentorial, and were most commonly in the frontal lobe. The most common symptoms were headache, vision changes, and weakness. Brain metastases in the brainstem were associated with a worse prognosis (P = 0.04). Visual complaints (P = 0.005), altered mental status, (P < 0.0001) and cranial neuropathy (P 0.001) were also associated with a poor outcome, as were poor performance status, more than 1 brain metastases, meningeal carcinomatosis, and uncontrolled primary cancer. CONCLUSIONS: Both presenting symptoms and the location of brain metastases have prognostic significance and should be further studied, both as independent prognostic predictors and in conjunction with other factors used in prognostic scores. PMID- 30001822 TI - Perceived advantages and disadvantages of oral anticoagulants, and the trade-offs patients make in choosing anticoagulant therapy and adhering to their drug regimen. AB - OBJECTIVE: The objective of this study was to explore the perceived advantages and disadvantages of oral anticoagulant therapies (OAT), and the trade-offs patients make in choosing therapy and adhering to their drug regimen. METHODS: Five focus group sessions were conducted across Europe among patients with atrial fibrillation to identify the most important factors impacting OAT's value and adherence. RESULTS: The most frequently identified barriers to OAT were lack of knowledge; poor patient-physician relationships; distraction due to employment or social environment; prior bleeding event(s) or the fear of bleeding; and changes in routine. Factors identified as promoting adherence included patients' personality, motivation, attitudes, and medication-taking habits and routines, as well as good quality health services. Inconvenient aspects of vitamin-K antagonists, such as regular blood monitoring and diet restrictions, were not reported to influence adherence, but may trigger patients to switch to direct oral anticoagulants. CONCLUSION: Most patients reported that a mixture of modifiable and non-modifiable factors helps them to take their drugs as prescribed. Individual patients' particular needs and preferences regarding OAT vary. PRACTICE IMPLICATIONS: OAT adherence can be promoted if therapies are tailored to patients' needs and preferences. Patients should be supported to share their preferences with their clinician. PMID- 30001823 TI - Birth spacing and informed family planning choices after childbirth in Burkina Faso and the Democratic Republic of Congo: Participatory action research to design and evaluate a decision-making tool for providers and their clients. AB - OBJECTIVES: Postpartum family planning (PPFP) is essential for maternal and newborn health but is often not systematically addressed before or after childbirth. This article describes the development and field-testing of a PPFP counseling tool to support providers and women. METHODS: Participatory action research involving women, men, providers, policymakers, researchers, and contraceptive experts from Burkina Faso and the Democratic Republic of Congo. RESULTS: The tool consists of an A4-size flipchart with illustrations on the client side and clinical information and counseling tips on the provider side, and can be used during visits of the antenatal-delivery-postnatal care continuum. Qualitative results suggest that the tool is easily understandable, user friendly, relevant, and useful with regard to providing PPFP information to clients, and respectful of clients' rights and choices. It may have a positive influence on clients' attitudes towards PPFP and their decision to use contraception. CONCLUSIONS: The tool holds promise in guiding a systematic discussion on birth spacing options among providers and clients. Its impact on contraceptive uptake requires further research. PRACTICE IMPLICATIONS: If proven effective, the tool could be disseminated to Ministries of Health and local, regional, and global partners to strengthen national family planning and maternal and child health strategies in low-resource countries. PMID- 30001824 TI - Prostate Cancer Diagnostics Using a Combination of the Stockholm3 Blood Test and Multiparametric Magnetic Resonance Imaging. AB - BACKGROUND: More specific diagnostic for prostate cancer is needed to decrease overdetection and number of diagnostic procedures. OBJECTIVE: To assess the performance of combining a blood-based biomarker panel and magnetic resonance imaging (MRI)-targeted biopsies for prostate cancer detection. DESIGN, SETTING, AND PARTICIPANTS: We used a prospective, multicenter, paired diagnostic study design. A total of 532 men aged 45-74 yr referred for prostate cancer workup were included during 2016-2017. INTERVENTION: Participants underwent blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic polymorphisms, and clinical variables; 1.5 T MRI; systematic prostate biopsies; and MRI-targeted biopsies to lesions with Prostate Imaging Reporting and Data System version 2 >=3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcome was numbers of detected prostate cancer characterized by grade group (GG) and the number of performed biopsies using relative sensitivity (RS). RESULTS AND LIMITATIONS: Median prostate-specific antigen was 6.3 ng/ml, and mean age was 63.9 yr. Targeted and systematic biopsies detected 170 and 162 GG >=2 tumors, respectively (RS 1.05; 95% confidence interval [CI] 0.96-1.14). Compared with performing systematic biopsies on all men, performing targeted and systematic biopsies only on men with >10% risk of GG >=2 cancer, as predicted by the Stockholm3 test, required 62% (95% CI 58-66) of the biopsy procedures and detected 58% (95% CI 48-70) of GG 1 disease, with increased sensitivity for GG >=2 detection (RS 1.10; 95% CI 1.02-1.17). Performing only targeted biopsies in men with elevated Stockholm3 test altered these results only slightly. Compared with performing systematic and targeted biopsies on all men, performing this only for men with an elevated Stockholm3 test decreased detection of GG >=2 cancer slightly (RS 0.92; 95% CI 0.88-0.95). Limitations include lacking knowledge of true disease prevalence. CONCLUSIONS: These findings provide evidence that strategies combining the blood-based Stockholm3 test and MRI-targeted biopsies can be used to inform biopsy decision making. PATIENT SUMMARY: In this study, 532 men coming for prostate cancer workup underwent blood sampling, and both traditional and magnetic resonance imaging/fusion-guided prostate biopsies. We report that performing targeted biopsies only in men with an elevated risk as assessed by the Stockholm3 test saved biopsies, decreased overdetection, and maintained the number of detected high-grade cancers. PMID- 30001825 TI - FIGO-IDF joint statement and declaration on hyperglycemia in pregnancy. PMID- 30001827 TI - Perioperative use of cefazolin without preliminary skin testing in patients with reported penicillin allergy. PMID- 30001826 TI - Youth or Young Adults: Which Group Is at Highest Risk for Tobacco Use Onset? AB - PURPOSE: Historically, adolescence has been regarded as the time when most tobacco use initiation occurs. This study examines the initiation of tobacco product use, including cigarettes, e-cigarettes, cigar products, and hookah, among contemporary youth and young adults, to determine whether the developmental timing (youth vs. young adulthood) of initiation has changed. METHODS: Three cohort studies were used to examine the onset of ever use and current (past 30 days) use of each tobacco product among never-using youth (11 to <17 years) and young adults (18-24 years) at baseline (2013-2015) to one-year follow-up (2015 2016). These studies include the national Population Assessment of Tobacco and Health Study, and two Texas cohort studies, the Texas Adolescent Tobacco and Marketing Surveillance System (TATAMS), and the Marketing and Promotions Across Colleges in Texas (M-PACT) project. Estimations of onset were computed using generalized linear mixed models for TATAMS and M-PACT. The rates of initiation in Population Assessment of Tobacco and Health Study were compared to standardized incidence rates from TATAMS to M-PACT. RESULTS: Young adults had significantly higher incidence rates than youth to initiate ever and current use of each/all tobacco products for all comparisons. CONCLUSIONS: These findings extend prior research on the timing of the onset of tobacco use by using longitudinal analyses from three contemporary cohort studies to include not just cigarettes, but also e cigarettes, cigar products, and hookah. Among those who were never-users of tobacco products, young adults began to ever and currently use all tobacco products more than youth in these samples, a marked departure from prior decades of research. PMID- 30001828 TI - The Specific AC Score (SACS): a new and validated method of assessment of isolated acromioclavicular joint pathology. AB - BACKGROUND: Acromioclavicular (AC) joint (ACJ) pathology is a common cause of shoulder dysfunction, and treatment recommendations vary. When the efficacy of treatment is evaluated, the ability to measure outcomes specific to the population is essential. The aim of the current research was to develop and validate a specific ACJ questionnaire. METHODS: Items for the "Specific AC Score" (SACS) were generated through the use of an expert panel, existing questionnaires, and patient feedback. Preliminary data analysis identified redundancy of items resulting in the questionnaire being refined. The final SACS was evaluated in 125 patients requiring surgical intervention of the ACJ. Internal consistency (the Cronbach alpha and corrected item-total correlation), content validity, criterion validity, responsiveness, and test-retest reliability (intraclass correlation coefficient) were examined and compared with the Shoulder Pain and Disability Index, Oxford Shoulder Score, and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form. The minimum detectable change score was calculated. RESULTS: The Cronbach alpha for the total scale preoperatively and postoperatively was high (preoperatively = 0.91, postoperatively = 0.93). All 3 domains (Pain, Function, Quality of Life) demonstrated acceptable internal consistency (alpha > 0.70), and the correlation between items in each domain was satisfactory. The responsiveness was excellent (effect size, -2.32; standard response mean, -1.85) and was higher than the other general shoulder questionnaires. There were no relevant floor or ceiling effects. Reliability was high (intraclass correlation coefficient, 0.89) and the minimum detectable change was 6.5 points. DISCUSSION: This new ACJ-specific questionnaire has been robustly developed, has good measurement properties, and has excellent responsiveness. The SACS is recommended for measuring outcomes in ACJ patients. PMID- 30001830 TI - Updates on liver transplantation: vascular and biliary complications. AB - This article uses a practical approach to explain the imaging findings for vascular and biliary complications after total liver transplantation in adults, comparing them to the normal imaging findings after transplantation. It emphasizes the radiologic management of patients who have undergone transplantations and explains the treatment of the different complications by interventional radiology. The information provided comes from the authors' experience and a thorough, up-to-date review of the indexed literature. PMID- 30001829 TI - Non-invasive metabolomic profiling of culture media of ICSI- and IVF-derived early developmental cattle embryos via Raman spectroscopy. AB - The aim of the present study was to compare differences in composition between in vitro cultured early developmental embryos resulting from either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Non-invasive metabolomic profiling of culture media was conducted with laser tweezer Raman spectroscopy (LTRS), providing molecular information that was used to aid the diagnosis or treatment of embryos that were adversely affected by ICSI treatment, ultimately improving the ICSI embryonic developmental potential. Cattle embryos were generated via ICSI and IVF with development to the 2-, 4-, 8-, 16-,32-cell, and blastocyst stages with individual in vitro culturing occurring for 4 h. The culture media for embryos in different developmental stages were separately analyzed using LTRS. The resulting composition of culture media used for culturing IVF- and ICSI-derived embryos was mainly altered in contents of carbohydrates, lipids, DNA, and proteins. Bands at 1004 cm-1 (phenylalanine) and 1529 cm-1 (-C = C-carotenoid) had specific patterns related to the metabolicactivity of embryos; using LTRS, and these may be considered as biomarkers for embryonic development. Furthermore, the vibrations of lipids at different stages increased more with assessment of ICSI culture media than in IVF media. Discriminant function analysis can be utilized for the classification of culture media used for culture of ICSI- and IVF-derived embryos. In conclusion, LTRS can be used for development of an independent assay to assess embryo status during both ICSI and IVF procedures, which provides novel insights into differences in structure and components of single cells. PMID- 30001831 TI - The AIDS Pandemic: Searching for a Global Response. AB - Michael Merson, the second Director of the World Health Organization (WHO) Global Program on AIDS, and co-author Stephen Inrig have described, in gripping detail, the personal antagonisms, interpersonal wrangling, and bureaucratic intrigue that explained the failure of the first global response to the HIV epidemic (Merson & Inrig, 2018). However, I believe that the decision of WHO, Western researchers, and the media to ignore the role of reuse of contaminated syringes and needles in health care settings and to instead emphasize African people's sex with multiple partners was more critical in the explosion of HIV in Africa than personal animosities and bureaucratic disputes. Merson & Inrig (2018) euphemistically noted that. PMID- 30001832 TI - Physician Burnout, Well-being, and Work Unit Safety Grades in Relationship to Reported Medical Errors. AB - OBJECTIVE: To evaluate physician burnout, well-being, and work unit safety grades in relationship to perceived major medical errors. PARTICIPANTS AND METHODS: From August 28, 2014, to October 6, 2014, we conducted a population-based survey of US physicians in active practice regarding burnout, fatigue, suicidal ideation, work unit safety grade, and recent medical errors. Multivariate logistic regression and mixed-effects hierarchical models evaluated the associations among burnout, well-being measures, work unit safety grades, and medical errors. RESULTS: Of 6695 responding physicians in active practice, 6586 provided information on the areas of interest: 3574 (54.3%) reported symptoms of burnout, 2163 (32.8%) reported excessive fatigue, and 427 (6.5%) reported recent suicidal ideation, with 255 of 6563 (3.9%) reporting a poor or failing patient safety grade in their primary work area and 691 of 6586 (10.5%) reporting a major medical error in the prior 3 months. Physicians reporting errors were more likely to have symptoms of burnout (77.6% vs 51.5%; P<.001), fatigue (46.6% vs 31.2%; P<.001), and recent suicidal ideation (12.7% vs 5.8%; P<.001). In multivariate modeling, perceived errors were independently more likely to be reported by physicians with burnout (odds ratio [OR], 2.22; 95% CI, 1.79-2.76) or fatigue (OR, 1.38; 95% CI, 1.15 1.65) and those with incrementally worse work unit safety grades (OR, 1.70; 95% CI, 1.36-2.12; OR, 1.92; 95% CI, 1.48-2.49; OR, 3.12; 95% CI, 2.13-4.58; and OR, 4.37; 95% CI, 2.06-9.28 for grades of B, C, D, and F, respectively), adjusted for demographic and clinical characteristics. CONCLUSION: In this large national study, physician burnout, fatigue, and work unit safety grades were independently associated with major medical errors. Interventions to reduce rates of medical errors must address both physician well-being and work unit safety. PMID- 30001833 TI - Sites of distant metastases and overall survival in ovarian cancer: A study of 1481 patients. AB - OBJECTIVE: To assess the association between patterns of distant metastases and overall survival in metastatic ovarian cancer and identify prognostic factors for site-specific distant metastases. METHODS: Data was obtained from the SEER database between 2010 and 2014. Univariate and multivariate Cox proportional hazard models were used to identify variables associated with overall survival. Survival times between different groups were compared using Kaplan-Meier analysis and log-rank tests. RESULTS: We analyzed 1481 patients. The most common distant metastatic site was liver, followed by distant lymph nodes, lung, bone, and brain. The site of distant metastases was an independent prognostic factor for overall survival. Using liver metastases as reference, overall survival was lower for lung metastases (p = 0.0297) and higher for distant lymph node metastases (p = 0.0006). Using distant lymph nodes as reference, distant metastases to the liver (p = 0.0006), lung (p < 0.0001), brain (p = 0.0455), and bone (p = 0.0138) were all associated with worse overall survival. The number of metastatic sites did not affect overall survival. We also found that surgery and chemotherapy affected overall survival for patients with distant lymph node metastases only; age, histological subtype, surgery, and chemotherapy affected overall survival for patients with liver metastases only, while histological subtype and chemotherapy affected overall survival for patients with lung metastases only. CONCLUSIONS: The site of distant metastases affected overall survival in metastatic ovarian cancer. Patients with specific distant metastatic sites should receive special treatment and management. The identified prognostic factors can help clinician evaluate the prognosis for ovarian cancer patients with distant metastases. PMID- 30001834 TI - Interval between debulking surgery and adjuvant chemotherapy is associated with overall survival in patients with advanced ovarian cancer. AB - OBJECTIVE: Treatment for advanced epithelial ovarian cancer (EOC) consists of debulking surgery and (neo)adjuvant platinum-based chemotherapy. The aim of this study was to evaluate whether the time from surgery to adjuvant chemotherapy (TTC) was associated with clinical outcome. METHODS: We identified all Dutch patients who received optimal or complete debulking surgery for primary EOC (FIGO IIb-IV) between 2008 and 2015 from the Netherlands Cancer Registry. TTC was divided into three groups based on the interquartile range (IQR). Early (<25%) and prolonged (>75%) TTC were compared to intermediate TTC (25-75%). Logistic regression was used to identify factors associated with a prolonged TTC and multivariable Cox regression to evaluate the independent effect of treatment interval on overall survival (OS). Patients receiving primary debulking surgery (PDS) and patients receiving interval debulking surgery (IDS) were analyzed separately. RESULTS: 4097 patients were included, 1612 underwent PDS and 2485 IDS. Median TTC was 29 days (IQR 24-37). Age >= 65, complete debulking surgery, postoperative complications, and hospitalization >=10 days were independently associated with a longer TTC for both PDS and IDS. TTC in the longest quartile was associated with poor OS after both PDS (Hazard Rate (HR) 1.43, 95% CI 1.09 1.88) and NACT-IDS (HR 1.22 (1.02-1.47)) when compared to the intermediate TTC, but only in patients with no macroscopic residual disease after surgery. CONCLUSIONS: Our study provides evidence that delayed initiation of adjuvant chemotherapy is an independent prognostic factor for worse overall survival after complete (interval)debulking surgery. We advise to start adjuvant chemotherapy within five to six weeks after debulking surgery. PMID- 30001836 TI - Exercise and non-pharmacological treatment of POTS. AB - Recent research has demonstrated that cardiovascular deconditioning (i.e., cardiac atrophy and hypovolemia) contributes significantly to the Postural Orthostatic Tachycardia Syndrome (POTS) and its functional disability. Therefore, physical reconditioning with exercise training and volume expansion via increased salt and fluid intake should be initiated early in the course of treatment for patients with POTS if possible. The use of horizontal exercise (e.g., rowing, swimming, recumbent bike, etc.) at the beginning is a critical strategy, allowing patients to exercise while avoiding the upright posture that elicits their POTS symptoms. As patients become increasingly fit, the duration and intensity of exercise should be progressively increased, and upright exercise can be gradually added as tolerated. Supervised training is preferable to maximize functional capacity. Other non-pharmacological interventions, which include: 1) chronic volume expansion via sleeping in the head-up position; 2) reduction in venous pooling during orthostasis by lower body compression garments extending at least to the xiphoid or with an abdominal binder; and 3) physical countermeasure maneuvers, such as squeezing a rubber ball, leg crossing, muscle pumping, squatting, negative-pressure breathing, etc., may also be effective in preventing orthostatic intolerance and managing acute clinical symptoms in POTS patients. However, randomized clinical trials are needed to evaluate the efficacies of these non-pharmacological treatments of POTS. PMID- 30001835 TI - Inter-pathologist and pathology report agreement for ovarian tumor characteristics in the Nurses' Health Studies. AB - BACKGROUND: Grade and histotype of ovarian carcinomas are often used as surrogates of molecular subtypes. We examined factors affecting pathologists' reproducibility in two prospective studies. METHODS: Two pathologists independently reviewed slides from 459 incident ovarian cancers in the Nurses' Health Study (NHS) and NHSII. We described agreement on tumor characteristics using percent agreement and Cohen's standard kappa (kappa) coefficients. We used logistic regression, with disagreement as the outcome, to evaluate the contribution of case and tumor characteristics to agreement. RESULTS: Inter-rater agreement was 95% (kappa = 0.81) for carcinoma versus borderline, 89% (kappa = 0.58) for grade and 85% (kappa = 0.71) for histotype. Inter-rater grading disagreement was higher for non-serous histotypes (OR = 4.66, 95% CI 2.09-10.36) and lower for cancers with bizarre atypia (OR = 0.13, 95% CI 0.04-0.38). Agreement with original pathology reports was 94% (kappa = 0.73) for carcinoma versus borderline, 78% (kappa = 0.60) for histotype, and 79% (kappa = 0.24) for grade. Grading disagreement was significantly lower for tumors with 'solid, pseudoendometrioid or transitional' (SET) architecture (OR = 0.08, 95%CI 0.01 0.84). Date of original diagnosis, hospital type, number of slides available for review, tumor stage, and slide quality were not related to agreement. CONCLUSION: Overall, inter-rater agreement for tumor type and grade for archival tissue specimens was good. Agreement between the consensus review and original pathology reports was lower. Factors contributing to grading disagreement included non serous histotype, absence of bizarre atypia, and absence of SET architecture. PMID- 30001837 TI - Intrapleural hematoma and hyperinsuflation of the native lung in patient with lung transplantation. PMID- 30001838 TI - miR-141-3p commonly regulates human UGT1A isoforms via different mechanisms. AB - UDP-Glucuronosyltransferase (UGT) 1A enzymes catalyze the glucuronidation of various compounds. Since no correlation was observed between the protein and mRNA expression of some UGT1A isoforms in the human liver, the involvement of post transcriptional regulation was hypothesized. We examined whether microRNAs (miRNAs) regulate human UGT1A, focusing on the predicted miR-141-3p. A luciferase assay revealed that a miRNA recognition element for miR-141-3p in the 3' untranslated region of UGT1A mRNA was functional. Overexpression of miR-141-3p in HEK293 cells stably expressing UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, or UGT1A9 significantly decreased the protein expression of all UGT1As. The mRNA levels of the UGT1As, except for UGT1A9, were also decreased by miR-141-3p. This indicated that the regulation mechanisms by miR-141-3p were different between UGT1A9 and the other UGT1A isoforms. Overexpression of miR-141-3p in HuH-7 or Caco-2 cells significantly decreased 4-methylumbelliferone O-glucuronosyltransferase activities, suggesting that miR-141-3p down-regulates endogenous UGT1As. No correlation was observed between miR-141-3p and the UGT1A mRNA levels in a panel of human liver samples, suggesting that regulation by other factors could hide the contribution of miR-141-3p to the regulation of UGT1A constitutive expression in the human liver. In conclusion, this study revealed that the miR-141-3p is an additional modulator of human UGT1A expression. PMID- 30001839 TI - Reply to Hurlburt. AB - Hurlburt (2018) states that Brouwers et al. (2018) find a much lower frequency of reported inner speech while reading than we find in Moore and Schwitzgebel (2018), and he attributes the difference to methodological shortcomings in Moore and Schwitzgebel's method. However, the method in Brouwers et al. has complementary shortcomings, and an apples-to-apples comparison of the data between the two studies shows a considerably smaller difference in results than the top-line percentages that Hurlburt emphasizes. PMID- 30001840 TI - On investigating inner experience: Contrasting Moore & Schwitzgebel and Brouwers et al. AB - Moore and Schwitzgebel (this issue) reported that readers report innerly speak the text about 59% of the time. Brouwers et al. (2018) reported that readers innerly speak the text only about 3% of the time. I use this huge discrepancy as a case study to discuss important issues in the investigation of inner experience, including: the training of participants; ambiguity in the time being considered; ambiguity in the phenomenon; the desirability of investigating the phenomenon itself, not merely its frequency; bracketing presuppositions; the advantages and disadvantages of large and small sample sizes; influence by the investigator; and the slide from phenomena to reports of phenomena. PMID- 30001841 TI - A free will needs a free mind: Belief in substance dualism and reductive physicalism differentially predict belief in free will and determinism. AB - In this article, we show that lay people's beliefs about how minds relate to bodies are more complex than past research suggests, and that treating them as a multidimensional construct helps explain inconclusive findings from the literature regarding their relation to beliefs about whether humans possess a free will. In two studies, we found that items previously used to assess a unidimensional belief in how minds relate to bodies indeed capture two distinguishable constructs (belief in substance dualism and reductive physicalism) that differently predict belief in free will and two types of determinism (Studies 1 and 2). Additionally, we found that two fundamental personality traits pertaining to people's preference for experiential versus rational information processing predict those metaphysical beliefs that were theorized to be based on subjective phenomenological experience and rational deliberation, respectively (Study 2). In sum, beliefs about mind-body relations are a multidimensional construct with unique predictive abilities. PMID- 30001842 TI - Editorial midwifery special issue on education: A call to all the world's midwife educators! PMID- 30001843 TI - A case of refractory cytomegalovirus-related thrombocytopenia that achieved complete remission without antiviral therapy. AB - Cytomegalovirus (CMV) is one of the major infectious etiologies that induce thrombocytopenia. Although immune thrombocytopenic purpura (ITP) in children is often preceded by viral infections, thrombocytopenia associated with active CMV infection is considered CMV-related thrombocytopenia (CMV-thrombocytopenia), which can be distinguished from ITP. CMV-thrombocytopenia is reported to be less responsive to standard therapies for ITP and may require antiviral therapies. We herein report a case of refractory CMV-thrombocytopenia that achieved complete remission without antiviral therapy. A 20-month-old boy presented with a 2-day history of fever and systemic petechiae. There were no abnormal findings except for an extremely low platelet count (8000/MUl) on blood examinations. He was clinically diagnosed with ITP, and intravenous immunoglobulin was administered twice, but his platelet count did not increase. CMV infection was suspected serologically, and a high CMV DNA load was detected in serum by real-time quantitative polymerase chain reaction (PCR). Without antiviral treatment, the CMV DNA load decreased below the detection limit on the 11th day of admission, followed by complete remission of the thrombocytopenia. The present case suggests that spontaneous recovery of thrombocytopenia can be expected in immunocompetent patients with CMV-thrombocytopenia in whom decreased CMV DNA load is observed. PMID- 30001844 TI - Risk factors for surgical site infection after major hepatobiliary and pancreatic surgery. AB - Major hepatobiliary and pancreatic (HP) surgeries are complex procedures associated with a high incidence of surgical site infection (SSI) and are commonly performed in patients with cancer in Japan. This study was performed to investigate the risk factors for SSI, including incisional and organ/space SSI, in HP surgery. The following procedures were included in the study: hepatectomy with and without biliary tract resection, pancreatectomy [pancreaticoduodenectomy (PD), others], and open cholecystectomy. In total, 735 patients were analyzed. The incidence of SSI was 17.8% (incisional, 5.2%; organ/space, 15.5%; both 2.9%). The highest incidence of SSI was observed in patients who underwent hepatectomy with biliary tract resection (39.1%), followed by pancreatectomy (PD, 28.8%; others, 29.8%). Almost all SSIs after these three procedures were classified as organ/space (39.1%, 25.0%, and 27.7%, respectively), and these procedures were risk factors for not only total SSI but also organ/space SSI in the multivariate analysis. An American Society of Anesthesiologists physical status of >=3 was a risk factor for incisional SSI. Preoperative biliary drainage, prolonged surgery, concomitant surgery, and massive intraoperative bleeding were associated with SSI. In conclusion, the main type of SSI was organ/space SSI after HP surgery, and different risk factors were identified between organ/space and incisional SSI. Procedure-related factors and preoperative biliary drainage were independent risk factors for SSI. To prevent SSI, the indication for preoperative biliary drainage should be carefully evaluated in patients undergoing HP surgery. PMID- 30001845 TI - FDG-PET/CT for Assessing the Response to Neoadjuvant Chemotherapy in Bladder Cancer Patients. AB - PURPOSE: To determine the accuracy of 18F-fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET/CT) scans in assessing the response to neoadjuvant chemotherapy (NAC) in patients with bladder cancer scheduled to undergo radical cystectomy (RC). PATIENTS AND METHODS: All patients treated at our center for muscle-invasive bladder cancer (MIBC) were counseled and offered NAC before RC. FDG-PET/CT scans were performed before the initiation of chemotherapy and after completion of the regimen. Patients with disease with complete response to NAC were those who had (pT0) or residual carcinoma-in-situ (pTis) on final pathology. Those who were downstaged from MIBC to non-MIBC were considered to have a chemosensitive tumor. We used percentage reduction in standardized maximum uptake value (SUVmax) from PET/CT scans as our measure to correlate with the final pathology after cystectomy. RESULTS: Thirty-seven patients with MIBC who underwent NAC followed by RC were included in the final analysis. FDG-PET/CT had 75% sensitivity (89.66% specificity) in identifying those with complete pathologic response with a 100% change in SUVmax, and 83% sensitivity (94% specificity) for the detection of chemosensitive tumors. CONCLUSION: FDG-PET/CT can help determine the response of primary tumor to NAC in patients with MIBC and thus can more accurately predict the prognosis of the patients, or potentially the appropriate time for cystectomy. PMID- 30001846 TI - Design, synthesis, and evaluation of novel l-phenylglycine derivatives as potential PPARgamma lead compounds. AB - In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator activated receptor gamma (PPARgamma) activated activity, alpha-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 MUg.mL-1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 MUg.mL-1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC50) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARgamma lead molecule and developed a tangible strategy for antidiabetic drug development. PMID- 30001847 TI - The blindness of Georg Eberhard Rumphius. PMID- 30001848 TI - Application of botulinum toxin in Horner's muscle for the treatment of dry eye. AB - OBJECTIVE/METHODS: The aim of this study is to describe the use of botulinum toxin to increase tear retention in patients with dry eye, using the description of 2 cases. RESULTS: Patients with moderate to severe dry eye that were given an injection of type A botulinum toxin in the Horner's muscle. The results at one month and 3 months are reported. An assessment was made of the subjective perception of the patient as regards any improvement, as well as taking into account, the Ocular Surface Disease Index, superficial punctate keratitis, and the time of the tear rupture and tear meniscus. A significant improvement was observed in the subjective perception of the patient, the Ocular Surface Disease Index, superficial punctate keratitis, and the time of the tear rupture and tear meniscus at one month after treatment, and the good results still being maintained at the third month. There were no adverse events. DISCUSSION: The use of type A botulinum toxin can be considered as an alternative to increase tear retention in moderate to severe dry eye, with a good response during the first month, with an acceptable response still being maintained at the third month. Given the temporary effect of the drug, further treatments would be required. PMID- 30001849 TI - The value of ABPM and subclinical target organ damage parameters in diagnosis of resistant hypertension. AB - INTRODUCTION: We aimed to assess the effectiveness of ambulatory blood pressure monitoring (ABPM) and subclinical target organ damage parameters for diagnosis of resistant hypertension (RH). METHODS: We assessed demographic and anthropometric variables, the incidence of cardiovascular events and subclinical target organ damage (n=112). We also studied the relationship between these variables and the ABPM results. RESULTS: Of the 112 patients referred from primary care with a diagnosis of RH, 69 (61.6%) were confirmed by ABPM. We found statistically significant differences (P<.001) between patients with RH and pseudo-resistant hypertension in the appearance of subclinical target organ damage. A percentage of 84 of the patients had microalbuminuria: 66.25+/-30.7mg/dl); 44.9% had stage 3 chronic kidney disease: the average glomerular filtration was 59ml/min/1.73m2; and 56.5% had left ventricular hypertrophy on echocardiography. Fundoscopy revealed that 64% of the patients had hypertensive retinopathy. Three variables were associated with an increased HR risk: microalbuminuria, hypertensive retinopathy and left ventricular hypertrophy (OR 5.7, 6.2 and 11.2, respectively). CONCLUSIONS: This study shows that the systematic testing for target organ damage, particularly in terms of albuminuria, is a simple and inexpensive tool, with a high predictive value for RH (85%), which could be useful for prioritising patients who need ABPM. PMID- 30001850 TI - Physician training in Spain in the 21st century. PMID- 30001851 TI - Self-sensing cavitation detection in ultrasound-induced acoustic cavitation. AB - The generation of cavitation by ultrasound is used in a large number of processes in different scientific and industrial applications. Chemical reactions are made possible or accelerated by locally occurring high temperatures and pressures generated by the collapse of cavitation bubbles. Mixing or separating substances, emulsification, ultrasonic cleaning, degassing, and microbiological treatment of fluids are some more applications for ultrasonic generated cavitation. In most of these applications, an optical examination of the events within the cavitating medium is not possible. Non-transparent media or closed containers prevent an optical process monitoring. In addition, the use of sensors is often impossible for cost reasons, limited construction space or disturbance of the process. In order to still enable process monitoring, the authors follow a novel approach: the analysis of the electrical signals of the ultrasound transducer used for cavitation generation. The current signal of the ultrasound transducer is inspected for frequency components, known as acoustic cavitation indicators. For this, the time signal is recorded and transferred to the frequency domain for further processing and evaluation. In previous studies, acoustical sensors like hydrophones or microphones were used as reference for the self-sensing technique. In order to link cavitation events inside the fluid container to cavitation indicators in the current signal, a photo study of the cavitation events inside a transparent water container is conducted. In contrast to previous self-sensing attempts, the ultrasound transducer's transfer characteristic is also considered. The evaluation of the acquired data shows that a frequency component which is 3/2 times the driving frequency (~30 kHz) can be used to determine the onset of transient cavitation. Once the transient cavitation threshold has been exceeded, broad band noise levels show a good correlation with cavitation intensity. PMID- 30001852 TI - Improving broadband ultrasound attenuation assessment in cancellous bone by mitigating the influence of cortical bone: Phantom and in-vitro study. AB - The purpose of this work was to present a new approach that allows the influence of cortical bone on noninvasive measurement of broadband ultrasound attenuation (BUA) to be corrected. The method, implemented here at 1 MHz makes use of backscattered signal and once refined and clinically confirmed, it would offer an alternative to ionizing radiation based methods, such as DEXA (Dual-energy X-ray absorptiometry), quantitative computed tomography (QCT), radiographic absorptiometry (RA) or single X-ray absorptiometry (SXA), which are clinically approved for assessment of progress of osteoporosis. In addition, as the method employs reflected waves, it might substantially enhance the applicability of BUA from being suitable to peripheral bones only it would extend this applicability to include such embedded bones as hip and femoral neck. The proposed approach allows the cortical layer parameters used for correction and the corrected value and parameter of the cancellous bone (BUA) to be determined simultaneously from the single (pulse-echo) bone backscattered wave; to the best of the authors' knowledge such approach was not previously reported. The validity of the method was tested using acoustic data obtained from a custom-designed bone-mimicking phantom and a calf femur. The relative error of the attenuation coefficient assessment was determined to be 3.9% and 4.7% for the bone phantom and calf bone specimens, respectively. When the cortical shell influence was not taken into account the corresponding errors were considerably higher 8.3% (artificial bone) and 9.2% (calf femur). As indicated above, once clinically proven, the use of this BUA measurement technique in reflection mode would augment diagnostic power of the attending physician by permitting to include bones, which are not accessible for transmission mode evaluation, e.g. hip, spine, humerus and femoral neck. PMID- 30001853 TI - Maximizing wave attenuation in viscoelastic phononic crystals by topology optimization. AB - The viscoelasticity of constituent materials has a significant effect on the dispersion relation of waves in viscoelastic phononic crystals (PCs). This paper extends the bi-directional evolutionary structure optimization (BESO) method to the design of viscoelastic PCs with the maximum attenuation and stiffness. The attenuation factor is calculated by the k(omega)-method, and the effective elasticity matrix of composite PCs is extracted by the homogenization theory. The inverse design of viscoelastic PCs is formulated with a topology optimization problem, which is then solved by the proposed BESO method. Generally, BESO re distributes the material phases of viscoelastic PCs within the primitive unit cell step by step based on sensitivity analysis. The optimization process is stopped until the optimized viscoelastic PC with the maximum attenuation factor and the desirable bulk modulus is achieved. Numerical examples are systematically presented for the propagation of out-of-plane or in-plane waves, and combined out of-plane and in-plane waves at various frequencies. Novel topological patterns of the optimized viscoelastic PCs are obtained and discussed. PMID- 30001855 TI - [Evidence and practice: How do primary care physicians evaluate screening interventions? A questionnaire study]. AB - BACKGROUND: Patients receiving a screening intervention have to be informed about risks and benefits. On the part of the physician, it requires the understanding of statistical evidence and statistical literacy. OBJECTIVES: Do general practitioners (GPs) make different recommendations on screening interventions if they only rely on statistics compared to their decisions in everyday practice? Are the decisions relying on statistics and the decisions made in everyday practice consistent with official recommendations? Does the way of presenting the numbers (table versus pictogram) affect the decision? METHODS: Online survey among German GPs. The GPs were asked to make recommendations for three different screening scenarios which were based on statistical evidence of existing screening interventions. To avoid bias, statistics were not presented in relation to the actual diseases. The numbers were presented in either a table or a pictogram. Afterwards, the GPs were asked for their recommendations on the same screening interventions in everyday practice. RESULTS: Forty-three GPs were surveyed. Compared to everyday medical practice, participants were less likely to recommend a screening intervention when being confronted with the underlying statistical evidence (F (1, 3)=104.83, p=.002, etapartial2=.97). Most of the decisions in everyday practice were consistent with official recommendations, while their decisions relying on statistics were more likely to deviate from them (everyday practice, M=1.79, SD=0.77; scenario, M=1.44, SD=0.80; t (42)=-2.29, p=.03). The way the numbers were presented did not affect the decision (t (127)= 1.83, p=.07). CONCLUSIONS: In everyday practice, GPs' screening recommendations do not seem to be based on statistical evidence. Presumably they would be more reluctant to recommend screening interventions if they knew the statistical evidence. PMID- 30001856 TI - Interpretation of the switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10 in Belgium. PMID- 30001857 TI - Switch in a childhood pneumococcal vaccination programme from PCV13 to PCV10: a defendable approach? PMID- 30001854 TI - Stable-Isotope Probing of Human and Animal Microbiome Function. AB - Humans and animals host diverse communities of microorganisms important to their physiology and health. Despite extensive sequencing-based characterization of host-associated microbiomes, there remains a dramatic lack of understanding of microbial functions. Stable-isotope probing (SIP) is a powerful strategy to elucidate the ecophysiology of microorganisms in complex host-associated microbiotas. Here, we suggest that SIP methodologies should be more frequently exploited as part of a holistic functional microbiomics approach. We provide examples of how SIP has been used to study host-associated microbes in vivo and ex vivo. We highlight recent developments in SIP technologies and discuss future directions that will facilitate deeper insights into the function of human and animal microbiomes. PMID- 30001858 TI - Ultrasound guided erector spinae plane block as a cause of unintended motor block. AB - Erector spinae plane block (ESPB) as postoperative analgesia method has been successfully carried out in several surgical interventions. Postoperative pain treatment for cesarean section is considered one of the important challenges for anesthesiologists due to the risk of chronic pain development and even pospartum depression. Regional anesthesia techniques were effectively used to prevent the pain together with multimodal analgesia regimes in cesarean section. Formerly, successful erector spinae plane block was documented as postoperative analgesia treatment for cesarean section; however, no motor weakness was recorded as a side effect. In this case report, we present an unexpected motor weakness as a side effect of the erector spinae plane block after cesarean delivery operation in a 29 year old patient. To our knowledge, this is the first report of motor weakness related to the ESPB. PMID- 30001859 TI - Validity and reliability of different techniques of neck-shaft angle measurement. AB - AIM: To determine a valid and reliable neck-shaft angle (NSA) measurement method while rotating the pelvises in increments of 5 degrees in order to simulate patient malpositioning. MATERIALS AND METHODS: CT images of 17 patients were used to produce digitally reconstructed radiographs in frontal and lateral views and three-dimensional (3D)-reconstructions of the femurs, considered to be the reference standard. Malpositioning was simulated by axially rotating the frontal radiographs from 0 degrees to 20 degrees . Three operators measured in two dimensions the NSA using four different methods, three times each, at each axial rotation (AR) position. Method 1 (femoral neck axis drawn by joining the centre of the femoral head (CFH) to the median of the femoral neck base; femoral diaphysis axis drawn by joining the median of two lines passing through the medial and lateral edges of the femoral axis below the lesser trochanter) and method 2 (femoral axis taken as the median of a triangle passing through base of femoral neck and medial and lateral head-neck junction; femoral diaphysis as previous) were described for the first time; method 3 was based on a previous study; method 4 was a free-hand technique. Reliability, validity, and global uncertainty were assessed. RESULTS: Method 1 showed the best reliability and validity. The global uncertainty also showed minimal values for method 1, ranging from 7.4 degrees to 14.3 degrees across AR positions. CONCLUSION: Method 1, based on locating the CFH, was the most reliable and valid method and should be considered as a standardised two-dimensional NSA measurement method for clinical application. PMID- 30001860 TI - Exploring what patients think when answering the Interpersonal Skills Questionnaire (ISQ): A 'think aloud' study. AB - BACKGROUND: The Interpersonal Skills Questionnaire (ISQ) was developed to collect patient feedback on consultation skills of practitioners. However, it has not yet been evaluated with pharmacists. OBJECTIVE: To explore the thinking process of patients as they completed the ISQ following a consultation with a pharmacist. METHODS: A qualitative think aloud (TA) methodology was used to explore patients' thinking while completing the ISQ following a consultation with a pharmacist. The study was conducted in secondary care with outpatients >=18 years old. Interviews were carried out in rounds and were informally analysed (i.e., by writing notes while listening to recordings) to identify any associated major problem(s). Discussions were held between researchers to determine whether changes were needed based on patients' comments. RESULTS: Eight patients in total (50% females) participated in this study (mean age: 48 years). Three rounds of TA were conducted. Most items of the ISQ were interpreted similarly by all participants with no major problems necessitating refining the ISQ. CONCLUSIONS: Modification of the ISQ was unnecessary as interviews demonstrated no major problems with its use. The ISQ is thus a potentially suitable tool to collect patient feedback on pharmacists' consultations. PMID- 30001861 TI - Cardiology patients' medicines management networks after hospital discharge: A mixed methods analysis of a complex adaptive system. AB - INTRODUCTION: The complex healthcare system that provides patients with medicines places them at risk when care is transferred between healthcare organisations, for example discharge from hospital. Consequently, understanding and improving medicines management, particularly at care transfers, is a priority. OBJECTIVES: This study aimed to explore the medicines management system as patients experience it and determine differences in the patient-perceived importance of people in the system. METHODS: We used a Social Network Analysis framework, collecting ego-net data about the importance of people patients had contact with concerning their medicines after hospital discharge. Single- and multi-level logistic regression models of patients' networks were constructed, and model residuals were explored at the patient level. This enabled us to identify patients' networks with support tie patterns different from the general patterns suggested by the model results. Qualitative data for those patients were then analysed to understand their differing experiences. RESULTS: Networks comprised clinical and administrative healthcare staff and friends and family members. Networks were highly individual and the perceived importance of alters varied both within and between patients. Ties to spouses were significantly more likely to be rated as highly important and ties to community pharmacy staff (other than pharmacists) and to GP receptionists were less likely to be highly rated. Patients with low-value medicines management networks described having limited information about their medicines and a lack of understanding or help. Patients with high-value networks described appreciating support and having confidence in staff. CONCLUSIONS: Patients experienced medicines management as individual systems within which they interacted with healthcare staff and informal support to manage their treatment. Multilevel models indicated that there are unexplained variables impacting on patients' assessments of their medicines management networks. Qualitative exploration of the model residuals can offer an understanding of networks that do not have the typical range of support ties. PMID- 30001862 TI - [Clinical photography by smartphone in plastic surgery and protection of personal data: Development of a secured platform and application on 979 patients]. AB - BACKGROUND: The clinical photography in plastic and reconstructive surgery has known a numerical breakthrough. The storage of online data, massive means of analysis such as facial recognitions algorithms poses a serious issue when it comes to the protection of personal data. We will assess a platform's benefits in connection with the computerized medical record, which will allow keeping the photos filed and centralized in a smart and secure manner. METHOD: We interviewed 300 plastic surgeons about the role of smartphone in their clinical practice. Concomitantly, we developed an innovative platform called Surgeon(c), a secure way to index, file and send photographs with a smartphone on our hospital's server. Each photographic sequence was qualified using a specific form. We then collected prospectively, between May 1st 2017 and March 30th 2018, the number of patients photographed, the number of sequences and photographs taken and the average number of sequences per patient. RESULTS: Out of 86 French plastic surgeons surveyed, 81% say that they could not go on with their daily practice today without their smartphone. Photographs taken were stored in their smartphones (50%) or synced with virtual storage (25.6%). A majority (80.2%) would use a dedicated secured smartphone application. Our application allowed us to photograph 979 patients, or 2345 sequences and 8112 photographs, with an average of 2.28 sequences per patient. CONCLUSION: Thanks to its ergonomics and security, this platform can be set up in a hospital ward and beyond. PMID- 30001863 TI - Interleukin 29 inhibits RANKL-induced osteoclastogenesis via activation of JNK and STAT, and inhibition of NF-kappaB and NFATc1. AB - Interleukin (IL)-29 is known to modulate immune functions of monocytes or macrophages. In this study, we investigated the effect and its underlying mechanism of IL-29 on receptor activator of nuclear factor kappaB ligand (RANKL) induced osteoclastogenesis using murine macrophage cell line RAW264.7 cells and bone-marrow-derived monocyte/macrophage precursor cells (BMMs), and human peripheral blood mononuclear cells (PBMCs). In response to human recombinant IL 29, cell viability and apoptosis were assessed by Cell Counting Kit-8 and flow cytometry; the osteoclast formation and activity by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assay, respectively; the expression and activation of molecules that associated with osteoclastogenesis by real time PCR, immunoblotting or immunofluorescent analysis. IL-28 receptor alpha (IL 28Ralpha), a specific receptor of IL-29 was expressed on RAW264.7 cells. Although IL-29 did not affect the viability and apoptosis of RAW264.7 cells, it inhibited multinucleated cells in the differentiation of osteoclastogenesis, the bone resorbing activity of mature osteoclasts and osteoclastic specific genes expression including TRAP, cathepsin K (CTSK), nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), C-Fos and matrix metallopeptidase 9 (MMP-9). This inhibitory effect of IL-29 was confirmed on BMMs and PBMCs and mediated via IL 28Ralpha through the activation of Stat1 and 3 and the suppression of nuclear factor kappa B (NF-kappaB) and NFATc1 nuclear translocation in RAW264.7 cells. In conclusion, IL-29 inhibited osteoclastogenesis via activation of STAT signaling pathway, prevention of NF-kappaB activation and NFATc1 translocation, and suppression of downstream osteoclastogenic genes expression. PMID- 30001864 TI - Visfatin as marker of isolated coronary artery ectasia and its severity. AB - Several studies have demonstrated the relationship between visfatin and increased risk of diseases caused by inflammation, however, the relationship between visfatin and coronary artery ectasia (CAE) is still unknown. The aim of our study is to investigate the association between serum visfatin with presence of coronary ectasia and its severity. We enrolled 85 individuals including 35 CAE patients (mean age: 58.40 +/- 9.82 years) and 50 control persons (mean age: 53.24 +/- 8.81 years). These participants underwent some biochemical tests including visfatin, fasting blood glucose and lipid profiles. In univariate analysis, the serum level of visfatin was significantly associated with ectasia in all patients with CAE and CAD coexisting with CAE groups, but a trend toward significance in isolated CAE group. In multivariate analysis, visfatin showed independently significant association with presence of ectasia in all patients with ectasia and in CAD coexisting with ectasia groups, but not significant in isolated CAE group. Visfatin was also independently associated with severity of ectasia according to MARKIS classification. We conclude that visfatin independently can be the useful predictor for the presence and severity of coronary ectasia. PMID- 30001866 TI - Heart of ice. PMID- 30001865 TI - Visceral leishmaniasis: A novel nuclear envelope protein 'nucleoporins-93 (NUP 93)' from Leishmania donovani prompts macrophage signaling for T-cell activation towards host protective immune response. AB - The shift of macrophage and T-cell repertoires towards proinflammatory cytokine signalling ensures the generation of host-protective machinery that is otherwise compromised in cases of the intracellular Leishmania parasite. Different groups have attempted to restore host protective immunity. These vaccine candidates showed good responses and protective effects in murine models, but they generally failed during human trials. In the present study, we evaluated the effect of 97 kDa recombinant nucleoporin-93 of Leishmania donovani (rLd-NUP93) on mononuclear cells in healthy and treated visceral leishmaniasis (VL) patients and on THP-1 cell lines. rLd-NUP93 stimulation increased the expression of the early lymphocyte activation marker CD69 on CD4+ and CD8+ T cells. The expression of the host protective pro-inflammatory cytokines IFN-gamma, IL-12 and TNF-alpha was increased, with a corresponding down-regulation of IL-10 and TGF-beta upon rLd NUP93 stimulation. This immune polarization resulted in the up-regulation of NF kappaB p50 with scant expression of SMAD-4. Augmenting lymphocyte proliferation upon priming with rLd-NUP93 ensured its potential for activation and generation of strong T-cell mediated immune responses. This stimulation extended the leishmanicidal activity of macrophages by releasing high amounts of reactive oxygen species (ROS). Further, the leishmanicidal activity of macrophages was intensified by the elevated production of nitric oxide (NO). The fact that this antigen was earlier reported in circulating immune complexes of VL patients highlights its antigenic importance. In addition, in silico analysis suggested the presence of MHC class I and II-restricted epitopes that proficiently trigger CD8+ and CD4+ T-cells, respectively. This study reported that rLd-NUP93 was an effective immunoprophylactic agent that can be explored in future vaccine design. PMID- 30001867 TI - Right eyelid droop. PMID- 30001868 TI - The association between bowel obstruction and the management of cholelithiasis and cholecystitis in elderly patients: A population-based cohort study. AB - AIMS: This study aimed to evaluate the risk of bowel events among elderly patients treated using only PTGBD (Percutaneous Gallbladder Drainage), or a cholecystectomy on its own, or PTGBD combined with a subsequent cholecystectomy. METHODS: A retrospective population-based cohort study was conducted with newly diagnosed cholelithiasis and cholecystitis patients who had no bowel obstruction history and were aged over 65 years during the period of January 1, 2000 to December 31, 2010. These patients were placed into 3 separate study cohorts; PTGBD alone, cholecystectomy alone and PTGBD with subsequent laparoscopic cholecystectomy, with the cohort frequencies matched by age and gender. We defined the index date as the time of the initial cholelithiasis and cholecystitis diagnosis date and began observation and suspended follow-up when the patient had either withdrawn from their health insurance, developed bowel obstruction or reached the date of December 31, 2011. RESULTS: The incidences of bowel obstruction were 24.6, 19.2 and 13.6 per 1000 person-years for PTGBD cohort, cholecystectomy cohort and PTGBD respectively, with a subsequent laparoscopic cholecystectomy cohort. Compared with the PTGBD cohort, (which was adjusted for age, gender, CCI score and laparotomy history), the hazard ratio of bowel obstruction was 0.77 (95% Confidence Interval (CI) = 0.59-1.00) and 0.57 (95% CI = 0.43-0.76) for the cholecystectomy cohort and PTGBD with a subsequent laparoscopic cholecystectomy cohort respectively. CONCLUSION: For treatment of cholelithiasis and cholecystitis in elderly patients, PTGBD with a subsequent cholecystectomy could benefit patients by providing a lower risk of ileus or intestinal obstruction. PMID- 30001869 TI - Clinical impact of high-sensitivity C-reactive protein during follow-up on long term adverse clinical outcomes in patients with coronary artery disease treated with percutaneous coronary intervention. AB - INTRODUCTION: C-reactive protein (CRP) is an established marker for vascular inflammation and predictor of adverse cardiovascular events, but the prognostic value of preprocedural CRP in coronary artery disease (CAD) patients who have undergone percutaneous coronary intervention (PCI) remains controversial. Furthermore, the impact of CRP levels during follow-up in CAD patients after PCI on long-term adverse clinical outcomes is uncertain. We evaluated the association between high-sensitivity (hs)-CRP values at follow-up angiography and long-term clinical outcomes in CAD patients after coronary intervention. METHODS: We prospectively enrolled 3507 consecutive CAD patients who underwent first PCI between 1997 and 2011 at our institution. We identified 2509 patients (71.5%) who underwent follow-up angiography (6-8 months after PCI). Of those, 1605 patients (45.8%) who had data available for hs-CRP at follow-up angiography were stratified into three groups according to tertiles of hs-CRP level at the time of follow-up angiography. The primary endpoint was composite of all-cause death and non-fatal acute coronary syndrome (ACS). RESULTS: Median follow-up was 1716 days. The cumulative incidence of all-cause death and ACS differed significantly among groups (log-rank, p=0.0002). Multivariate Cox regression analysis showed that a higher hs-CRP level at follow-up angiography was associated with a greater risk of all-cause death and ACS [adjusted hazard ratio (HR) for all-cause death and ACS 2.14, 95% confidence interval (CI) 1.43-3.27, p=0.0002. CONCLUSION: Elevated hs-CRP levels during follow-up were significantly associated with higher frequencies of adverse long-term clinical outcomes in patients with CAD after PCI. PMID- 30001870 TI - Description and analysis of three Homo naledi incudes from the Dinaledi Chamber, Rising Star cave (South Africa). AB - This study describes three incudes recovered from the Dinaledi Chamber in the Rising Star cave system in South Africa. All three bones were recovered during sieving of excavated sediments and likely represent three Homo naledi individuals. Morphologically and metrically, the Dinaledi ossicles resemble those of chimpanzees and Paranthropus robustus more than they do later members of the genus Homo, and fall outside of the modern human range of variation in several dimensions. Despite this, when overall size is considered, the functional lengths in H. naledi and P. robustus are very similar to those predicted for a human with a similar-sized incus. In this sense, both taxa seem to show a relatively elongated functional length, distinguishing them from chimpanzees. The functional length in H. naledi is slightly longer in absolute terms than in P. robustus, suggesting H. naledi may already show a slight increase in functional length compared with early hominins. While H. naledi lacks the more open angle between the long and short processes found in modern humans, considered a derived feature within the genus Homo, the value in H. naledi is similar to that predicted for a hominoid with a similar-sized incus. Principal components analysis of size standardized variables shows H. naledi falling outside of the recent human range of variation, but within the confidence ellipse for gorillas. Phylogenetic polarity is complicated by the absence of incus data from early members of the genus Homo, but the generally primitive nature of the H. naledi incudes is consistent with other primitive features of the species, such as the very small cranial capacity. These ossicles add significantly to the understanding of incus variation in hominins and provide important new data on the morphology and taxonomic affinities of H. naledi. PMID- 30001871 TI - Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect. AB - Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects. PMID- 30001873 TI - Peptide Tk-PQ induces immunosuppression in skin allogeneic transplantation via increasing Foxp3+ Treg and impeding nuclear translocation of NF-kappaB. AB - Solid organ transplantation is used as the last resort for patients with end stage disease, but allograft rejection is an unsolved problem. Here, we showed that Tk-PQ, a peptide derived from trichosanthin, had an immune-suppressive effect without obvious cytotoxicity in vitro and in a mouse skin allo transplantation model. In vitro, treatment of Tk-PQ administrated type 2 T helper cell (Th2)/regulatory T-cell (Treg) cytokines, and increased the ratio of CD4+CD25+Foxp3+ Treg by repressing the PI3K/mTOR pathway. In addition, Tk-PQ decreased NF-kappaB activation to downregulate pro-inflammatory cytokines. Tk-PQ treatment in the mouse skin transplantation model also caused the similar molecular and cellular phenotypes. Furthermore, Tk-PQ enhanced the suppressive function of Treg by increasing Foxp3 expression, and substantially improved allograft survival. These finding demonstrate that Tk-PQ has the potential to be used in clinical allogeneic transplantation. PMID- 30001872 TI - Peripheral Tissue Chemokines: Homeostatic Control of Immune Surveillance T Cells. AB - Cellular immunity is governed by a complex network of migratory cues that enable appropriate immune cell responses in a timely and spatially controlled fashion. This review focuses on the chemokines and their receptors regulating the steady state localisation of immune cells within healthy peripheral tissues. Steady state immune cell traffic is not well understood but is thought to involve constitutive (homeostatic) chemokines. The recent discovery of tissue-resident memory T cells (TRM cells) illustrates our need for understanding how chemokines control immune cell mobilisation and/or retention. These studies will be critical to unravel novel pathways for preserving tissue function (aging) and preventing tissue disease (vaccination). PMID- 30001874 TI - The utility of geodemographic indicators in small area estimates of limiting long term illness. AB - Small area health data are not always available on a consistent and robust routine basis across nations, necessitating the employment of small area estimation methods to generate local-scale data or the use of proxy measures. Geodemographic indicators are widely marketed as a potential proxy for many health indicators. This paper tests the extent to which the inclusion of geodemographic indicators in small area estimation methodology can enhance small area estimates of limiting long-term illness (LLTI). The paper contributes to international debates on small area estimation methodologies in health research and the relevance of geodemographic indicators to the identification of health care needs. We employ a multilevel methodology to estimate small area LLTI prevalence in England, Scotland and Wales. The estimates were created with a standard geographically-based model and with a cross-classified model of individuals nested separately in both spatial groupings and non-spatial geodemographic clusters. LLTI prevalence was estimated as a function of age, sex and deprivation. Estimates from the cross-classified model additionally incorporated residuals relating to the geodemographic classification. Both sets of estimates were compared against direct estimates from the 2011 Census. Geodemographic clusters remain relevant to understanding LLTI even after controlling for age, sex and deprivation. Incorporating a geodemographic indicator significantly improves concordance between the small area estimates and the Census. Small area estimates are however consistently below the equivalent Census measures, with the LLTI prevalence in urban areas characterised as 'blue collar' and 'struggling families' being markedly lower. We conclude that the inclusion of a geodemographic indicator in small area estimation can improve estimate quality and enhance understanding of health inequalities. We recommend the inclusion of geodemographic indicators in public releases of survey data to facilitate better small area estimation but caution against assumptions that geodemographic indicators can, on their own, provide a proxy measure of health status. PMID- 30001875 TI - Randomization, randomized trials, and analyses using observational data: A commentary on Deaton and Cartwright. PMID- 30001876 TI - Impact of anaerobic digestion and centrifugation/decanting processes in bacterial communities fractions. AB - Sewage sludge can be treated by anaerobic processes that frequently are followed by physical separation processes. In this work, a high-throughput sequencing technology, based on variation in the bacterial 16S rRNA gene, has been used to characterise the bacterial populations present in samples taken from different points of an industrial anaerobic digestion process fed with sewage sludge. Relative abundances of phyla and classes throughout the biological process and the subsequent separation steps were determined. Results revealed that the Bacteroidetes, Firmicutes and Proteobacteria phyla were the most representative. However, significant changes in relative abundance were detected along treatments, showing the influence of operational parameters on the distribution of microorganisms throughout the process. After anaerobic digestion, phylum Firmicutes doubled its relative abundance, which seems to indicate that the anaerobic conditions and the nutrients favoured its growth, in contrast to other phyla that almost disappeared. After centrifugation, Proteobacteria went preferentially to the solid phase, in contrast to Firmicutes which was the dominant phylum in the liquid phase. After decanting the liquid phase during 45 h, an important growth of Proteobacteria, Spirochaetes and Tenericutes was detected. At class level, only significantly changes were observed for Proteobacteria classes being alpha-proteobacteria dominant in the digestate, while gamma-proteobacteria was the majority since this point to the final steps. To know the changes on the kind and abundance of microbial populations throughout the anaerobic and separation processes is very important to understand how the facilities design and operation conditions can influence over the efficiencies of next biological treatments. PMID- 30001877 TI - Comparative study of the insoluble and soluble Ulp1 protease constructs as Carrier free and dependent protein immobilizates. AB - In this study, we analyzed and compared the properties of yeast Ulp1 protease in active inclusion bodies (IBs) as special protein immobilizate, and the soluble Ulp1 via oriented immobilization. Fusion of the N-terminal self-assembling peptide GFIL8 to the Ulp1 increased production of active IBs in Escherichia coli. Attachment of the N-terminal cellulose-binding module facilitated the constructed protein immobilized on the regenerated amorphous cellulose (RAC) with a binding capacity up to about 235 mg protein per gram of RAC. Compared with the immobilized soluble construct, the insoluble Ulp1 showed higher resistance to limited proteolysis with trypsin digestion, lower leaky amount at different storage temperatures, but more rapid decrease in cleavage activity after stored at 4 degrees C for 8 days. The immobilized soluble Ulp1 maintained about 42% initial cleavage activity with repetitive use successively, whereas the aggregated Ulp1 lost its cleavage capacity after cleaving the protein substrate once. Crosslinking of IBs mediated by glutaraldehyde inactivated the Ulp1. Freshly prepared and used IBs showed similar resistance to protease-K digestion, and comparable binding capacity of Congo red and thioflavin T. Taken together, due to different advantages, the Ulp1 constructs as carrier-free and carrier dependent immobilizates are used under different conditions. PMID- 30001878 TI - Corrigendum to "Electron bifurcation mechanism and homoacetogenesis explain products yields in mixed culture anaerobic fermentations"[Water Res. 141(2018) 349-356]. PMID- 30001879 TI - Corrigendum to "Sources and mechanisms of nitrate and orthophosphate transport in urban stormwater runoff from residential catchments" [Water Res. 112 (2017) 176 184]. PMID- 30001880 TI - Omics research ethics considerations. AB - BACKGROUND: Pending revisions to the Common Rule include topics consistent with respect for persons, justice, and beneficence for research subjects in studies using omics technologies and are relevant to omics research. PURPOSE: Synthesize trends in bioethics, precision health, and omics nursing science for novice and experienced nursing scholars from which to consider bioethics questions. METHODS: Review topics addressed in the National Institute of Nursing Research (NINR) strategic plan, Common Rule pending revisions, and publications regarding human subjects protection policies. DISCUSSION: Omics research involves decisions regarding understandable informed consent, broad consent, data sharing, trust, equal benefit, equal access, societal variables, privacy, data security, and return of findings to participants. CONCLUSION: Principles of respect for persons, justice, and beneficence as articulated in the Belmont report and reflected in the American Nurses Association (ANA) Code of Ethics provide guidance for human subjects protection procedures to advance omics and nursing science. PMID- 30001881 TI - Ultrasound to improve both synthesis and pollutants degradation based on metal nanoparticles supported on TiO2. AB - Sonochemistry is based on acoustic cavitation, which consist in the formation, growth, and implosive collapse of bubbles within a liquid. Collapsing bubbles generate localized hot spots, characterized by temperatures up to 5000 K and pressures up to 1800 atm. These extreme conditions allow producing a variety of nanostructured and amorphous materials, as well as they are advantageous for chemical processes. Ultrasound requires inexpensive equipment and fewer steps than conventional methods. Combining ultrasound and photocatalysis enhances the performance of the processes, reduces reaction time, avoids the use of extreme physical conditions and improves the photocatalytic materials properties increasing their activity. Here, we reported the positive effect of US in synthesizing Me-modified TiO2 (Me = Ag, Cu, Mn) for pollutants degradation in gas phase; also, we proved the advantageous application of ultrasound for the photocatalytic removal of organic compounds in water. Ultrasound produced more efficient Me-doped TiO2, which showed higher activity in visible light. When combined with photocatalytic water treatment, the organic compounds degradation and mineralization increases. PMID- 30001882 TI - Skilled Nursing Facility Star Rating, Patient Outcomes, and Readmission Risk After Total Joint Arthroplasty. AB - BACKGROUND: This study examined the correlation between publicly reported indicators of skilled nursing facility (SNF) quality and clinical outcomes after primary total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: This retrospective analysis used Medicare claims from the Centers for Medicare and Medicaid Services 100% Standard Analytic File (2014-2015) that were linked to SNF quality star ratings from the Centers for Medicare and Medicaid Services Nursing Home Compare database. Overall SNF rating and subcomponents of the rating were evaluated for correlation to 30-day and 90-day risk of readmission. Ratings were based upon a 5-star rating system (1 representing the lowest quality). Cox proportional hazards regressions controlled for age, race, census division, hospital location, comorbidities, and SNF length of stay. RESULTS: A total of 9418 SNFs, 58,064 TKA patients, and 26,837 THA patients met criteria. As SNF overall star rating increased from 1 to 5, incidence of all-cause 30-day readmission decreased from 6.4% to 5.0% for TKA (relative reduction [RR] 22%; P < .001) and from 9.1% to 6.2% for THA (RR 32%; P < .001). As nurse staffing rating increased, incidence of all-cause readmission decreased from 6.8% to 4.7% for the TKA cohort (30.9% RR; P < .001), and from 7.7% to 6.0% for the THA cohort (22.1% RR; P = .003). Regression analysis demonstrated that a higher star rating was associated with decreased risk of readmission (both cohorts P < .05). CONCLUSIONS: For patients undergoing TKA or THA, the overall SNF star rating, nurse staffing ratios, and physical therapy intensity were significantly correlated with risk of readmission within 30 days of SNF admission. PMID- 30001883 TI - Cadmium intake and chronic kidney disease: Response to Kawada T. PMID- 30001884 TI - A novel anatomical thin titanium mesh plate with patient-matched bending technique for orbital floor reconstruction. AB - This study developed an anatomical thin titanium mesh (ATTM) plate for Asian orbital floor fracture based on the medical image database. The computer aided stamping analysis was performed on four hole/slot patterns included the control type without hole design, circular hole pattern, slot pattern and hole/slot hybrid patterns within the ATTM plate with upper/lower dies of averaged orbital cavity reconstruction models. The curved-fan ATTM plate with 0.4 mm thickness was manufactured and pre-bent using a patient matched stamping process to verify its feasibility and the interfacial fitness between the plate and bone on the orbital floor fracture model. The stamping analysis found that the hole/slot hybrid patterns design resulted in the most favorable performance among all designs owing to the lowest maximum von-Mises stress/strain and spring-back value. The interfacial adaption results test showed that the average patient-matched stamping bending gap size was only 0.821 mm and the operative time was about 8 s. This study concluded that the curved-fan ATTM plate with hole/slot hybrid pattern design and patient-matched pre-bent technique can fit the ATTM plate/orbital cavity interface well, decrease unstable fracture segment mobility and improve the overall reduction efficiency. PMID- 30001885 TI - Adjustable selective maxillary expansion combined with one-stage maxillomandibular surgery: A prospective study of osseous widening in fifty-five consecutive patients. AB - OBJECTIVE: SARME is often considered to be the only available treatment for significant or severe maxillary transverse palatal deficiencies (MTD) in skeletally-mature patients. Despite this observation, the aim of our study was to assess a new type of maxilla distraction osteogenesis. Using two innovative tools, we performed selective expansion: the site to be widened and the amount of increase were both pre-selected. Patients were treated in a single maxillomandibular procedure. Our study focuses primarily on the extent of osseous widening. STUDY DESIGN: Post-expansion computed tomography data from 55 non syndromic patients were included in a prospective study and analyzed in two planes for transverse skeletal widening. Of the 55 patients, 16 underwent isolated posterior distraction for severe posterior endognathia (group I), and 39 were treated in both segments (group II). Diastemas and anterior spaces permitted resolution of crowding and patients with a small, narrow, tapering arch were given a more rounded form. All patients underwent a complete Le Fort I with down fracture. Two novel devices were used: first, an adjustable distractor to achieve an angular opening; and secondly, in group II, new modular plates interlocked for osteosynthesis to provide stability and anterior expansion. RESULTS: In group I, analysis of the width of the gain showed significant posterior values decreasing from back to front, a result never achieved with the SARME procedure. The mean osseous gain at first molars was 7.1 mm. When anterior space was required in group II, it was created as wide as needed (mean 4.2 mm, at canine level) with good preservation of the 1st molar space gain (mean 6.8 mm). CONCLUSION: Total Le Fort I osteotomy associated with two innovative devices provides a new, segmental and adaptable approach for transverse distraction osteogenesis. We demonstrate a good match with the dental enlargement required. All patients were managed in a single orthognathic procedure for all the anomalies to be treated. Long-term results show good stability. PMID- 30001886 TI - Empowered communities or "cheap labour"? Engaging volunteers in the rationalised management of invasive alien species in Great Britain. AB - Volunteers are increasingly involved in the delivery of nature conservation policies, usually supported by a twofold rationale: volunteering can (a) enhance citizen participation in environmental governance and (b) ensure a workforce is in place to support conservation work in times of budget shortages. Here, we ask how these two rationales correspond to volunteers' own motivations to engage in a specific nature conservation activity, namely the control of invasive alien species (IAS). We use qualitative interviews with professional project managers, local group leaders, and volunteers to examine the interactions between policies aiming to rationalise the management of IAS and the motivations for and goals of volunteer engagement. Our findings suggest that although volunteering can lead to positive conservation outcomes, satisfying experiences and empowerment, the different interests do not always align in practice. We investigate the implications of strategies that aim to improve the efficiency of invasive species and volunteer management, and discuss organisational arrangements that reconcile different objectives. PMID- 30001887 TI - Comment on: 12-year trajectory of health-related quality of life in gastric bypass patients versus comparison groups. PMID- 30001888 TI - Clinical features of symptomatic hypoglycemia observed after bariatric surgery. AB - BACKGROUND: Literature directly looking at post-bariatric surgery hypoglycemia consists mostly of small case series. The rate, severity, and outcomes of treatment in a large bariatric population are less characterized. OBJECTIVE: To determine the rate of post-bariatric surgery hypoglycemia, its clinical features and management outcomes over a 13-year period at our institution. SETTING: An academic center in the United States. METHODS: Patients who underwent bariatric surgery at a single academic center between 2002 and 2015 and had a postdischarge glucose level of <=70 mg/dL were studied. RESULTS: Of 6024 patients who underwent bariatric procedure, 118 patients (2.0%) had a postoperative glucose level <=70 mg/dL. Eighty-three patients (1.4%) had symptomatic hypoglycemia. The known underlying causes of symptomatic hypoglycemia included postprandial hyperinsulinemic hypoglycemia (n = 32, 38%), infection (n = 8, 10%), diabetic medications (n = 8, 10%), and poor oral intake (n = 8, 10%). Overall, 9 patients required intervention for nutritional supplementation including enteral (n = 9) and intermittent parenteral (n = 2) nutrition. No patients required reversal of their bariatric surgeries or pancreatic resection for management of hypoglycemia. The majority of the symptomatic patients had resolution of their symptoms (n = 76, 92%). Thirty-two patients had postprandial hypoglycemia with a median onset of hypoglycemia after bariatric surgery of 790 days (interquartile range 388 1334). All 32 patients with postprandial hypoglycemia had dietary adjustment and 53% received pharmacotherapy, which resulted in complete resolution of hypoglycemia (n = 29, 91%) and resolution with minimal disability (n = 3, 9%). CONCLUSION: The rate of symptomatic hypoglycemia and postprandial hypoglycemia after bariatric surgery were 1.4% and .5%. The majority of patients were successfully managed with dietary counseling, nutritional intervention, and occasionally pharmacotherapy. No surgical reversal or pancreatic procedures were performed. PMID- 30001889 TI - Is bariatric surgery effective for co-morbidity resolution in the super-obese patients? AB - BACKGROUND: Type 2 diabetes (T2D), obstructive sleep apnea (OSA), hypertension (HTN), and hyperlipidemia (HLD) are common co-morbidities that are strongly associated with obesity. OBJECTIVE: The purpose of this study was to compare the rate of obesity-related co-morbidity remission and percent total body weight loss of super-obese patients with a body mass index (BMI) >=50 kg/m2 with bariatric patients who have a BMI of 30 to 49.9 kg/m2. SETTING: Academic hospital, United States. METHODS: A retrospective analysis of outcomes of a prospectively maintained database was done on obese patients with a diagnosis of >=1 co morbidity (T2D, OSA, HTN, or HLD) who at the time of initial visit had undergone either a sleeve gastrectomy or a Roux-en-Y gastric bypass at our hospital between 2011 and 2015. The patients were stratified based on their preoperative BMI class, BMI of 30 to 49.9 kg/m2 versus BMI >=50 kg/m2. RESULTS: Of the 930 patients, 732 underwent sleeve gastrectomy and 198 underwent Roux-en-Y gastric bypass. The 6-month follow-up co-morbidity remission rates for patients with a BMI of 30 to 49.9 kg/m2 (n = 759) versus super-obese patients (n = 171) were 46.0% and 36.7% (P = .348) for T2D; 75.0% and 73.2% (P = .772) for OSA; 35.0% and 22.0% (P = .142) for HTN; and 37.0% and 21.0% (P = .081) for HLD, respectively. The 1-year follow-up co-morbidity remission rates for patients with a BMI of 30 to 49.9 kg/m2 versus super-obese patients were 54.2% and 45.5% (P = .460) for T2D; 87.0% and 89.7% (P = .649) for OSA; 37.4% and 23.9% (P = .081) for HTN; and 43.2% and 34.6% (P = .422) for HLD, respectively. Furthermore, there was no difference in the mean percent total weight loss for patients with a preoperative BMI of 30 to 49.9 kg/m2 versus the super-obese at the 6-month (21.4%, 20.9%, P = .612) and 1-year (28.0%, 30.7%, P = .107) follow-ups. CONCLUSION: In our study, preoperative BMI did not have an impact on postoperative co-morbidity remission rates or percent total body weight loss. Future studies should investigate the effect of other factors, such as disease severity and duration. PMID- 30001890 TI - Early intake of solid food after Roux-en-Y gastric bypass and complications. A cohort study from the Scandinavian Obesity Surgery Registry. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure worldwide. There are few studies investigating how early return to solid food affects complications. OBJECTIVE: The aim of this study was to explore how oral intake was resumed in RYGB patients and how the postoperative food regimen affects outcomes, such as complications and length of stay. SETTING: Retrospective nationwide registry study. METHODS: The Scandinavian Obesity Surgery Registry included prospective data from RYGB patients operated in 2009 to 2014. A questionnaire assessed the postoperative reintroduction of solid food applied at each bariatric center. The postoperative regimen was established in 23,589 patients. Outcomes were recorded at 30-day follow-up according to the standard Scandinavian Obesity Surgery Registry routine. RESULTS: Nine percent of patients (n = 2074) returned to solid food within the first week after surgery. Most commonly solid food was resumed in week 4 (37%, n = 8659). Median length of stay was 2 days for all. Of all, 2.8% suffered from a severe complication (>Clavien-Dindo 3a). After adjusting for the annual volume of procedures at hospitals, there was no correlation that the timing of solid food affected complication rates. The odds ratio for a severe complication was significantly lower for intermediate- (odds ratio .64 95% confidence interval .48-.85) or high- (odds ratio .52 95% confidence interval .42-.66) volume centers. The rate of leaks and small bowel obstructions were evenly distributed between the different postoperative food regimens. CONCLUSION: Early return to solid food after RYGB did not affect the risk of severe complications. Patients operated at centers with an annual volume of >100 procedures have a lower risk of severe complications. PMID- 30001891 TI - Absolute neutrophil count as a diagnostic guide for the use of MRI in the workup of suspected appendicitis in children. AB - BACKGROUND/PURPOSE: To assess the additive value of magnetic resonance imaging (MRI) in the setting of an equivocal US (Eq-US) with or without an elevated absolute neutrophil count (ANC). METHODS: Single-institution, retrospective review of children ages 5-18 years who presented to the ER with suspected appendicitis from 9/2015 to 8/2016. US, ANC, and MRI results were reviewed. Imaging was identified as positive/suspicious, normal, or equivocal and ANC <8000/mm3 was defined as normal. RESULTS: 738 patients with a median age of 11 years (IQR 8-14) met inclusion criteria. US was equivocal in 61.4%. Among 304 (67.1%) patients with an Eq-US and normal ANC, only 5 (1.6%) had acute appendicitis. In contrast, 28 of 149 patients (18.8%) with Eq-US and elevated ANC had appendicitis. MRI was performed in 125 patients with Eq-US and was positive/suspicious in 2.9% (2/69) with normal ANC and 25.0% (14/56) with elevated ANC. MRI had 94.7% sensitivity and 100% specificity for acute appendicitis in patients with an Eq-US. CONCLUSIONS: MRI has high sensitivity and specificity for diagnosing acute appendicitis in children. Patients with Eq-US plus a normal ANC have a very low likelihood of appendicitis and do not typically require further imaging. MRI may have utility for children with Eq-US and elevated ANC. LEVEL OF EVIDENCE: Level III. PMID- 30001892 TI - Quality assurance in melanoma care: The EU-MELACARE study. AB - BACKGROUND: A significant disparity regarding survival outcome for melanoma among European regions is well recognized and access to high quality care for European melanoma patients needs to be improved. There is an unmet need for the implementation of minimal standard of care within defined clinical pathways and Quality Assurance (QA) indicators. OBJECTIVE: The EU-MELACARE study aims to identify shared variables for cutaneous melanoma cases recorded in melanoma registries across Europe. MATERIAL AND METHODS: Opinion leaders involved in melanoma data registration and care quality analysis in 34 European countries were invited to respond to an expert survey covering questions regarding the melanoma registration practice in their countries and the characteristics, coverage and variables collected by the relevant melanoma registries. RESULTS: Data regarding 13 melanoma registries from 11 European countries contributed to the study. The majority (61,5%) were population based registries and more than half (62%) had national coverage. The included registries collected a median of 38 variables (Interquartile Range, IRQ 21-76). We identified 24 shared variables available in >70% of registries. CONCLUSIONS: This study provides valuable specific information on information recorded for melanoma cases are registered within Europe. A core of shared variables has been identified, which will constitute the basis for a standardized set of QA indicators for assessing and monitoring melanoma care across European countries. PMID- 30001895 TI - Late diagnosis of HIV infection: Missed diagnostic opportunities. PMID- 30001894 TI - Microscopic polyangiitis and interstitial lung disease. PMID- 30001893 TI - Haematopoietic stem cell transplantation in paediatric patients with beta thalassaemia and sickle cell disease: An experience of the Spanish Working Group for Bone Marrow Transplantation in Children (GETMON). AB - BACKGROUND AND OBJECTIVES: A recently occurring increase of the prevalence of haemoglobinopathies, beta-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON). MATERIAL AND METHODS: Retrospective review of patients undergoing HSCT in the GETMON units until 2015. RESULTS: A total of 65 patients were analysed (43 patients were affected with TM and 22 with SCD), who received allo-HSCT in 6 GETMON units between November 1989 and December 2014. Event-free survival three years post-transplant was 81% and overall survival 92% in patients with TM. Event-free survival three years post transplant was 79% and overall survival 85% in patients with SCD. CONCLUSIONS: The results of this series are comparable to the results of other international series and offer a platform from which to continue trying to improve the evolution of these patients. PMID- 30001896 TI - Pseudoxanthoma elasticum. PMID- 30001897 TI - Myasthenia gravis and large granular lymphocytic leukemia. PMID- 30001898 TI - Meningeal cryptococcosis in a patient with angioimmunoblastic lymphoma treated with alemtuzumab. PMID- 30001899 TI - Axial heterogeneities in capillary ultrahigh pressure liquid chromatography columns: Chromatographic and bed morphological characterization. AB - We study axial heterogeneities in capillary ultrahigh pressure liquid chromatography (UHPLC) columns through kinetic performance and bed morphological analysis. Two columns are used in this work, a 75 MUm i.d. * 100 cm column packed with 1.3 MUm C18-silica particles and a 75 MUm i.d. * 45 cm column packed with 1.9 MUm C18-silica particles. The long column is chromatographically characterized and is afterwards sectioned into three segments, each analyzed individually. The column packed with the 1.9 MUm particles is subjected to a bed morphological analysis using confocal laser scanning microscopy near the inlet, center, and outlet of the column. Chromatographic and morphological characterizations reveal highest separation efficiency and most homogeneous bed microstructure towards the column outlet. Kinetic performance data for inlet and central packing segments indicate enhanced contributions from wall effects to a transcolumn flow heterogeneity. Bed morphological data reveal systematic changes in geometrical and frictional wall effects along the bed: from inlet to outlet, bed morphologies increasingly reflect packing microstructures associated with concentrated slurries. Variations in separation efficiency and bed morphology can be related to the constant-pressure packing mode; the decrease in packing rate along the bed leaves fewer chances for particle rearrangement and bed consolidation from inlet to outlet. It explains the relatively uniform bed morphology towards the outlet and also the relatively loose wall region near the inlet. Bed microstructural features are discussed in a context of previous observations made in the characterization of capillary UHPLC columns. PMID- 30001900 TI - An untargeted lipidomic strategy combining comprehensive two-dimensional liquid chromatography and chemometric analysis. AB - Untargeted lipidomic samples are extremely complex and often exceed the limits of peak capacity achievable by one-dimensional liquid chromatography (LC). Comprehensive two-dimensional liquid chromatography (LC * LC) appears as a promising alternative to overcome this drawback. Unfortunately, this approach generates highly complex datasets which untargeted analysis is challenging. In this work, a global methodological strategy combining LC * LC-MS/MS with chemometric data analysis is proposed for untargeted lipidomic studies. The feasibility of the proposed methodology is demonstrated by its application to assess the effects of arsenic exposure on the lipidome of growing rice samples. A two-dimensional chromatographic setup coupling reversed phase (RP) and hydrophilic interaction liquid chromatography (HILIC) modes together with a triple quadrupole mass detector (TQD) is proposed to analyze lipid extracts from rice samples at different experimental conditions. Chemometric tools were used for data compression, spectral and elution profiles resolution, feature detection and statistical analysis of the multidimensional LC * LC-MS/MS data. The obtained results revealed that the proposed methodology was useful to gather relevant information from untargeted lipidomic studies and detect potential biomarkers. PMID- 30001901 TI - Direct chromatographic study of the enantioselective biodegradation of ibuprofen and ketoprofen by an activated sludge. AB - The quantification of the enantiomeric fraction (EF) during the biodegradation process is essential for environmental risk assessment. In this paper the enantioselective biodegradation of ibuprofen, IBU, and ketoprofen, KET, two of the drugs most consumed, was evaluated. Biodegradation experiments were performed in batch mode using a minimal salts medium inoculated with an activated sludge (collected from a Valencian Waste Water Treatment Plant) and supplemented with the racemate of each compound. The inoculum activity was verified using fluoxetine as reference compound. The experimental conditions used (analyte concentration and volume of inoculum) were chosen according to OECD guidelines. In parallel, the optical density at 600 nm was measured to control the biomass growth and to connect it with enantioselectivity. Two RPLC methods for chiral separations of IBU and KET using polysaccharides-based stationary phases were developed. Novel calculations and adapted models, using directly the chromatographic peak areas as dependent variable, were proposed to estimate significant parameters related to the biodegradation process: biodegradation (BD) and EF values at given time, half-life times of (R)- and (S)-enantiomers, number of days to reach a complete BD and the minimum EF expected. The modelled BD and EF curves fitted adequately the data (R2 > 0.94). The use of these new equations provided similar results to those obtained using concentration data. However, the use of chromatographic peak areas data, eliminates the uncertainty associated to the use of the calibration curves. The results obtained in this paper indicate that an enantiorecognition towards IBU enantiomers by the microorganisms present in the activated sludge used in this study occurred, being the biodegradation of (R)-IBU higher than that of (S)-IBU. For KET, non-enantioselective biodegradation was observed. PMID- 30001902 TI - Deep brain stimulation electrode insertion and depression: Patterns of activity and modulation by analgesics. AB - BACKGROUND: An initial antidepressant effect when using deep brain stimulation (DBS) of the subcallosal area of the cingulate cortex (Cg25) to treat resistant depression that could be the result of electrode insertion has been described. We previously showed that electrode insertion into the infralimbic cortex (ILC; the Cg25 rodent correlate) provokes a temporally limited antidepressant-like effect that is counteracted by non-steroidal anti-inflammatory drugs, such as those routinely used for pain relief. OBJECTIVE: We characterized the effect of electrode insertion using functional neuroimaging and evaluated the impact of different analgesics on this effect. METHODS: The effect of electrode insertion into the ILC was evaluated by positron emission tomography. The effect of analgesics (ibuprofen, tramadol and morphine) on the behavioral effect induced by electrode insertion were evaluated through the forced swimming test and the novelty suppressed feeding test. Furthermore, glial fibrillary acidic protein (GFAP) and p11 expression were measured. RESULTS: Electrode implantation produces an antidepressant- and anxiolytic-like effect, a local decrease in glucose metabolism, and changes in several brain regions commonly related to depression and the antidepressant response. Ibuprofen counteracted the behavioral and molecular changes produced by electrode insertion (changes in GFAP and p11 protein expression). However, analgesics with no anti-inflammatory properties (e.g., tramadol) neither counteract the behavioral effects of electrode implantation nor the molecular mechanisms triggered. CONCLUSIONS: Analgesics without anti-inflammatory properties may not limit the transient benefit produced by electrode insertion reducing the time required to achieve remission in depressive DBS patients. PMID- 30001903 TI - Effect of Manual Therapy, Motor Control Exercise, and Inspiratory Muscle Training on Maximum Inspiratory Pressure and Postural Measures in Moderate Smokers: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study is to assess whether adding manual therapy to motor control exercises protocol with inspiratory muscle training (IMT) (combined intervention) resulted in a greater effect than IMT alone in enhancing maximum inspiratory pressure (MIP) in the short term. METHODS: This was a single-blind, randomized, controlled trial. Fifty-one healthy moderate smokers were randomized into 2 groups: (1) IMT and (2) combined intervention. All participants received 8 individual sessions, 2 per week during a 4-week period. The primary outcome (MIP) and the secondary outcome (pulmonary function, forward head posture, and thoracic kyphosis) were recorded at baseline and after the treatments. RESULTS: There were differences between groups in change score for MIP (mean, 23.8; 95% confidence interval [CI]: 16.48-31.12), forward head posture (-1.57; 95% CI: -2.79 to 0.35), and thoracic kyphosis (-0.92; 95% CI: -1.74 to -0.1). The combined intervention revealed statistically significant differences for MIP (mean, -34; 95% CI: -39.12 to -28.88) and for postural measures (forward head posture 2.31; 95% CI: 1.45-3.16; thoracic kyphosis, 1.39; 95% CI: 0.8-1.97), whereas the IMT was only observed for MIP (mean, -10.2; 95% CI: -15.42 to -4.98). In addition, the intraclass correlation coefficient and minimal detectable change for MIP were 0.96; 95% CI: 0.93-0.97, and 17.70, respectively. CONCLUSION: Inspiratory muscle training protocol combined with manual therapy and motor control exercise had greater effect in enhancing MIP than did IMT in isolation in moderate smokers in the short term. In addition, both groups experienced changes in MIP but not in lung function. PMID- 30001905 TI - Comment on subvesical bile duct injury resolved by percutaneous drainage. PMID- 30001906 TI - Caspase -1, -3, -8 and antioxidant enzyme genes are key molecular effectors following Vibrio parahaemolyticus and Aeromonas veronii infection in fish leukocytes. AB - Caspases are a family of proteases involved in many important biological processes including apoptosis and inflammation. In order to get insights into the caspase gene family and antioxidant enzymes in Totoaba macdonaldi during bacterial infection, an in vitro assay was performed involving three different types of caspases (Casp-1, Casp-3 and Casp-8) and antioxidant enzymes (catalase, gluthathione peroxidase 1 and 4) after Vibrio parahaemolyticus and Aeromonas veronii infection, using head-kidney and spleen leukocytes from the teleost fish totoaba at 12 and 24 h post-exposure. Characterization of caspases by bioinformatics analyses showed that TmCas-1, TmCas-3 and TmCas-8 shared overall sequence identities of 82-61%, 85-97% and 77-63%, respectively, with other teleost fish. Caspase-1, -3 and -8 proteins revealed a conserved penta-peptide sequence at the catalytic site and three amino acid residues involved in the catalysis (H, G and C), as well as two conserved domains. The expression levels of the three caspases were detected in a wide range of fish tissues; however, they varied among tissues and caspases, which were highly up-regulated in immune organs, such as head-kidney, liver and/or spleen. The pathogen-induced gene expression pattern revealed two interesting facts; first, that the expression of all the caspase genes and antioxidant enzyme genes evaluated in this study were strongly induced following V. parahaemolyticus infection; second, these up regulations reached a maximum level at 24 h post-infection in head-kidney whereas in spleen leukocytes, it was observed at 6-h post-infection. In conclusion, based on these observations, the acute toxic effects of V. parahaemolyticus are associated to cell death and release of free radicals. This information provides a better understanding of the effects and nature of early immune response against common bacterial infections in totoaba leukocytes. PMID- 30001907 TI - [Improving nursing training in cultural diversity with clinical simulation]. PMID- 30001908 TI - Maggie in Kyoto. PMID- 30001904 TI - Sink into the Epigenome: Histones as Repositories That Influence Cellular Metabolism. AB - Epigenetic modifications on chromatin are most commonly thought to be involved in the transcriptional regulation of gene expression. Due to their dependency on small-molecule metabolites, these modifications can relay information about cellular metabolic state to the genome for the activation or repression of particular sets of genes. In this review we discuss emerging evidence that these modifications might also have a metabolic purpose. Due to their abundance, the histones have the capacity to store substantial amounts of useful metabolites or to enable important metabolic transformations. Such metabolic functions for histones could help to explain the widespread occurrence of particular modifications that may not always be strongly correlated with transcriptional activity. PMID- 30001909 TI - To reveal or conceal? Adult patient perspectives on SUDEP disclosure. AB - OBJECTIVE: The study aimed to evaluate adult patient or caregiver feelings and viewpoints about sudden unexpected death in epilepsy (SUDEP) awareness. BACKGROUND: The decision to discuss SUDEP with patients and families has created much debate. Many healthcare providers (HCPs) are hesitant to discuss SUDEP because of the perception of evoking unnecessary fear in patients while others argue that informing patients about SUDEP may enhance patient compliance, improve seizure control, and aid in saving lives. This study quantifies patient viewpoints regarding their right to information, requirements of disclosure, and initial responses of fear and patient motivation toward behavioral change. DESIGN/METHODS: This was a prospective random sample survey of adult patients with epilepsy or their caregivers. Every third eligible adult patient with epilepsy or caregiver was given a one-page SUDEP information sheet promoted by the Epilepsy Foundation of America. Participants were then asked if they were interested in completing an eight-item questionnaire assessing their perception of the information. RESULTS: Ninety-four of ninety-six subjects completed the survey (98%). One hundred percent (n = 94) of responders felt they had a right to be informed about SUDEP, and 95% felt that their HCP should be required to inform them. Respondents also indicated that SUDEP awareness motivated them for better medication adherence (89%) and management of lifestyle factors that lower seizure threshold (88%). Thirty percent endorsed increased fear. However, 100% of those patients or caregivers who endorsed fear still felt it was their right to be informed. Patients who endorsed fear were also more likely to be interested in nonpharmacologic treatment options as a result of SUDEP disclosure. CONCLUSIONS: Patients and caregivers feel it is their right to be informed about SUDEP, irrespective of evoked fear. The vast majority of participants endorsed a requirement for HCPs to disclose related information. While some participants endorsed fear, most agreed that SUDEP awareness motivated them to better manage factors that trigger seizures. Patient education regarding SUDEP may play a key role in encouraging modifying lifestyle factors that lower seizure threshold and facilitate more aggressive interventions in patients with pharmacoresistant epilepsy. PMID- 30001911 TI - Cost-effectiveness of perampanel for the treatment of primary generalized tonic clonic seizures (PGTCS) in epilepsy: A Spanish perspective. AB - BACKGROUND: Persistent seizures are associated with physical injury, reduced quality of life, and psychosocial impairment. Perampanel is approved for the adjunctive treatment of primary generalized tonic-clonic seizures (PGTCS). OBJECTIVE: This study aimed to determine the cost-effectiveness of perampanel as adjunctive therapy to other antiepileptic drugs (AED) compared with AED maintenance therapy alone for the treatment of PGTCS. METHODS: We developed a Markov model for PGTCS where transitions were based on treatment response rates. The analysis was conducted over a 33-year time horizon from the Spanish National Health Service (NHS) and societal perspectives. Efficacy data were derived from clinical studies. Resource use, market shares, costs, and utilities were obtained from Kantar Health's National Health and Wellness Survey. Drug costs were obtained from the Consejo General de Colegios Oficiales de Farmaceuticos. One-way and probabilistic sensitivity analyses were performed. RESULTS: In the base case analysis from the NHS perspective, perampanel was associated with an incremental cost-effectiveness ratio (ICER) of ?16,557/quality-adjusted life year (QALY) relative to AED maintenance therapy for the treatment of PGTCS. Incremental costs were ?5475 and incremental QALYs were 0.33. In one-way sensitivity analyses, the ICERs were strongly influenced by discounting rate for costs and health effects, with little influence of other parameters, including perampanel cost and utilities. In probabilistic sensitivity analyses, the probability of perampanel being cost-effective at a willingness-to-pay threshold of ?30,000/QALY was 89.3%. From the societal perspective, perampanel provided a cost-savings of ?5288 per patient compared with AED maintenance therapy alone. CONCLUSION: Our study demonstrates that perampanel is likely to be a cost-effective option. PMID- 30001910 TI - Executive dysfunction is associated with an altered executive control network in pediatric temporal lobe epilepsy. AB - OBJECTIVES: Children with temporal lobe epilepsy (TLE) exhibit executive dysfunction on traditional neuropsychological tests. However, there is limited evidence of neural network alterations associated with this clinical executive dysfunction. The objective of this study was to characterize working memory deficits in children with TLE via activation of the executive control network on functional magnetic resonance imaging (fMRI) and determine the relationships to fMRI behavioral findings and traditional neuropsychological tests. EXPERIMENTAL DESIGN: Functional magnetic resonance imaging was conducted on 17 children with TLE and 18 healthy control participants (age 8-16 years) while they performed the N-back task in order to assess activation of the executive control network. N back accuracy, N-back reaction time, and traditional neuropsychological tests (Delis-Kaplan Executive Function System [D-KEFS] color-word interference and card sort test) were also assessed. PRINCIPAL OBSERVATIONS: Children with TLE exhibited executive dysfunction on D-KEFS testing, reduced N-back accuracy, and increased N-back reaction time compared with healthy controls; D-KEFS and N-back behavioral findings were significantly correlated. Children with TLE also exhibited significant reduction in activation of the frontal lobe within the executive control network compared to healthy controls. These alterations were significantly correlated with N-back behavioral findings and D-KEFS testing. CONCLUSIONS: Children with TLE exhibit executive dysfunction, which correlates with executive control network alterations. This lends validity to the theory that the executive control network contributes to working memory function. The findings also indicate that children with TLE have network alterations in nontemporal brain regions. PMID- 30001912 TI - Thirty-year trends in aortofemoral bypass for aortoiliac occlusive disease. AB - OBJECTIVE: Endovascular intervention has supplanted open bypass as the most frequently used approach in patients with aortoiliac segment atherosclerosis. We sought to determine whether this trend together with changing demographic and clinical characteristics of patients undergoing aortobifemoral bypass (ABFB) for aortoiliac occlusive disease (AOD) have an association with postoperative outcomes. METHODS: Using a prospectively maintained institutional database, we identified patients who underwent ABFB for AOD from 1985 to 2015. Patients were divided into two cohorts: the historical cohort (HC) included patients who underwent ABFB for AOD from 1985 to 1999 and the contemporary cohort (CC) who underwent ABFB for AOD from 2000 to 2015. Medical and demographic data, procedural information, postoperative complications, and follow-up data were extracted. Cox proportional hazards regression was used to evaluate associations with the end point of primary patency. A similar analysis was performed for major adverse limb events (MALEs; the composite of above-ankle amputation, major reintervention, graft revision, or new bypass graft of the index limb) in the subset of patients with critical limb ischemia. RESULTS: There were a total of 359 cases: 226 in the HC and 133 in the CC. The CC had more women (56.4% vs 43.8%; P = .02), smokers (87.2% vs 67.7%; P = .001), and patients who failed prior aortoiliac endovascular intervention (17.3% vs 4.8%; P = .0001), but fewer patients with coronary artery disease (32.3% vs 47.3%; P = .005). Thirty-day mortality was less than 1% in both cohorts, but 10-year survival was higher in the CC (67.7% vs 52.6%; P = .02). Five-year primary, primary-assisted, and secondary patency were higher in the HC (93.3% vs 82.2%; P = .005; 93.8% vs 85.7%; P = .02; 97.5% vs 90.4%; P = .02, respectively). CC membership, decreasing age, prior aortic surgery, and decreasing graft diameter were significant independent predictors of loss of primary patency after adjustment (hazard ratio [HR], 7.03; 95% confidence interval [CI], 2.80-17.63; P < .0001; HR, 0.93; 95% CI, 0.90-0.96; P < .0001; HR, 18.80; 95% CI, 5.94-59.58; P < .0001; and HR, 0.73; 95% CI, 0.55-0.95; P = .02, respectively). Similarly, CC membership, prior aortic surgery, and decreasing graft diameter were significant independent predictors of MALE in the critical limb ischemia cohort after adjustment (HR, 21.13; 95% CI, 4.20-106.40; P = .0002; HR, 40.40; 95% CI, 3.23-505.61; P = .004; and HR, 0.51; 95% CI, 0.30-0.86; P = .01, respectively). CONCLUSIONS: Compared with the pre endovascular era, demographic and clinical characteristics of patients undergoing ABFB for AOD in the CC have changed. Although long-term patency is slightly lower among patients in the CC during which a substantial subset of AOD patients are being treated primarily via the endovascular approach, durability remains excellent and limb salvage unchanged. After adjustment, the time period of index ABFB independently predicted primary patency and MALE, as did graft diameter and prior aortic surgery. These changing characteristics should be considered when counseling patients and benchmarking for reintervention rates and other outcomes. PMID- 30001914 TI - Use of dual-skin paddle anterolateral thigh perforator flaps in the reconstruction of complex defect of the foot and ankle. AB - BACKGROUND: Complex soft tissue defect around the ankle and foot remains a reconstructive challenge for orthopedic and plastic surgeons. This study describes our clinical experience with the application of dual-skin paddle anterolateral thigh perforator (ALTP) flap for reconstruction of complex defects around the ankle and foot. METHODS: From June 2010 to June 2015, we retrospectively analyzed 15 patients with complex defects in the ankle and foot. Three types of soft tissue defects include irregular defect (n = 1), nonadjacent defect (n = 4), and extensive defect (n = 10). All patients in this series had exposure of underlying vital structures including vessels, nerves, bones, and tendons. All patients in this series underwent reconstruction with the dual-skin paddle ALTP flap. RESULTS: The dual-skin paddle ALTP flaps were successfully harvested to reconstruct three types of soft tissue defects in the ankle and foot. All the flaps survived. Only one flap had partial flap necrosis. One case suffered minor wound edge necrosis. All donor sites were closed directly and healed well. The mean follow-up time was 24.46 (range: 12-54) months. The average static two-point discrimination (s2PD) of the flap was 33 (range: 27-38) mm. The mean visual analog scale (VAS) score for the aesthetic appearance of the reconstructed defects was 8.9 (range: 8-9.5). CONCLUSION: Our experience showed that the dual-skin paddle ALTP flap can provide two independent skin paddles for complex defect reconstruction while minimizing donor site morbidity. It is a reliable option for the reconstruction of complex defects in the ankle and foot. PMID- 30001913 TI - Genetic Rescue Reverses Microglial Activation in Preclinical Models of Retinitis Pigmentosa. AB - Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co administering the therapeutic intervention. PMID- 30001916 TI - Synthesis and antimicrobial activity of beta-carboline derivatives with N2-alkyl modifications. AB - beta-Carbolines constitute a vast group of indole alkaloids and exhibit various biological actions. The objective of this study was to investigate the structure activity relationships of beta-carboline derivatives on in vitro inhibitory effects against clinically relevant microorganisms. A series of beta-carboline dimers and their N2-alkylated analogues were therefore prepared and evaluated for their antimicrobial effects. Among these, a dimeric 6-chlorocarboline N2 benzylated salt exerted potent activity against Staphylococcus aureus at MICs of 0.01-0.05 MUmol/mL. Our work highlights that N1-N1 dimerization and N2 benzylation significantly enhanced the antimicrobial effects of compounds. PMID- 30001915 TI - Abnormal soft palate movements in patients with microtia. AB - INTRODUCTION: Microtia is a congenital malformation of the auricle, ranging in severity. It can be isolated or associated with (craniofacial) anomalies. Most of these anomalies together are described as being part of the oculo-auriculo vertebral spectrum (OAVS). Velar abnormalities have been described to occur in patients with OAVS; however, the incidence in patients with microtia without OAVS is largely unknown. The primary purpose of this study was to examine the prevalence of velar palsy in patients with isolated microtia and patients with microtia and signs of OAVS. The secondary purpose was to identify possible risk factors associated with the presence of velar palsy. METHODS: All patients with microtia presented to our department between January 2015 and March 2017 were retrospectively reviewed. Medical images, information of the palate, and demographic data were extracted from the patients' medical files. RESULTS: Velar palsy was present in 18 out of 42 patients with isolated microtia (43%; no signs of OAVS) and in 33 out of 41 patients with microtia and signs of OAVS (80%). Patients with signs of OAVS were found to be independently associated with a higher prevalence of velar palsy (OR: 4.8; 95% CI: 1.7-13). CONCLUSION: This study demonstrates a clear relationship between abnormal velar movement and microtia. We believe that isolated microtia should not be seen as a separate entity but as a part of OAVS. Abnormal velar movement can lead to velopharyngeal insufficiency (VPI), which can affect speech development in children. Physicians should examine the palate in all patients with microtia and not restrict to those with speech difficulties. PMID- 30001918 TI - Arthroscopic resection arthroplasty for septic hip with osteonecrosis of the femoral head in patients with multiple comorbidities: A report of two cases. PMID- 30001917 TI - Synthesis and biological evaluation of Complex I inhibitor R419 and its derivatives as anticancer agents in HepG2 cells. AB - In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50 = 5.2 +/- 0.9 MUM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50 = 2.8 +/- 0.4 MUM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I. PMID- 30001919 TI - Separate mechanisms for number reading and word reading: Evidence from selective impairments. AB - Do number reading and word reading use the same cognitive mechanisms? We examined this question through the looking glass of dissociations between impairments in number and word reading. We report two women with selective deficits in number reading, who read words normally. An examination of their impairment pattern indicated that the specific locus of their number reading deficits is in processes that handle the number's structure: both were impaired in parsing a digit string into triplets, and one of them was also impaired in generating the number's verbal structure. In contrast to their structural deficits in number reading, their word reading was completely intact, including the structural processes in word reading (morphological analysis and assembly). We present this dissociation in the framework of a broader effort to examine dissociations between specific components in number and word reading. We went beyond general word-number dissociations: we used detailed cognitive models for word reading and for number reading, and analyzed them in order to identify which components of the number reading process are homologous to which components of words reading. We then show that even these homologous processes are dissociable: an examination of previously-reported dissociations, completed by the case studies presented here, indicated that each of the specific homologous sub-processes of word/number reading can be selectively impaired. We conclude that although the word and number reading pathways show much similarity, they are almost entirely separate. PMID- 30001920 TI - Visual and linguistic components of short-term memory: Generalized Neural Model (GNM) for spoken and sign languages. AB - The question of apparent discrepancies in short-term memory capacity for sign language and speech has long presented difficulties for the models of verbal working memory. While short-term memory (STM) capacity for spoken language spans up to 7 +/- 2 items, the verbal working memory capacity for sign languages appears to be lower at 5 +/- 2. The assumption that both auditory and visual communication (sign language) rely on the same memory buffers led to the claims of impairment of STM buffers in sign language users. Yet, no common model deals with both the sensory and linguistic nature of spoken and sign languages. The authors present a generalized neural model (GNM) of short-term memory use across modalities, which accounts for experimental results in both sign and spoken languages. GNM postulates that during hierarchically organized processing phases in language comprehension, spoken language users rely on neural resources for spatial representation in sequential rehearsal strategy, i.e., the phonological loop. The spatial nature of sign language precludes signers from utilizing a similar 'overflow' strategy, which speakers rely on to extend their STM capacity. This model offers a parsimonious neuroarchitectural explanation for the conflict between spatial and linguistic processing in spoken language, as well as the differences observed in STM capacity for sign and speech. PMID- 30001921 TI - Visual imagination and the narrative image. Parallelisms between art history and neuroscience. AB - Understanding visually presented stories requires intense effort from our visual imagination. Artists and theoreticians from the Renaissance onwards suggested various ways to depict stories, either to enhance their understanding and enjoyment, or to help adjust the depictions to the aesthetic ideas of the era. Alberti's concept of istoria, Leonardo's practice of visual stimulation, Lessing's advice on how to choose the most fruitful moment of a story relied both on personal experience and the scientific knowledge of the era. Visual imagination is specially needed in non-figurative and sequential narratives in modern and contemporary art, which are supported by Arnheim's notion of stroboscopic motion. Recent developments in image-making technologies enable some clarification of the processes involved in human perception with regard to the understanding of painted scenes and visually presented stories. The objective of this paper is to find the counterparts of these art theoretical concepts in psychology and neuroscience. Through the phenomena of mirror neurons, scene perception, gist of scene, and face and object recognition, these findings establish parallelisms between art history and neuroscience. PMID- 30001922 TI - Engineering a New Era: Will Autogenous Tissue Remain the Gold Standard for Head and Neck Reconstruction? PMID- 30001924 TI - Fingolimod and CIDP: insights from negative results. PMID- 30001925 TI - Commentary on "Resilience and White Matter Integrity in Geriatric Depression". PMID- 30001923 TI - Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial. AB - BACKGROUND: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). METHODS: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0.5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4.5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (>=1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. FINDINGS: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0.91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. INTERPRETATION: Fingolimod 0.5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. FUNDING: Novartis Pharma. PMID- 30001926 TI - Charcot-Marie-Tooth disease type 4C in Norway: Clinical characteristics, mutation spectrum and minimum prevalence. AB - Autosomal recessive Charcot-Marie-Tooth disease (CMT) is considered rare and phenotypic descriptions are scarce for the different subgroups. Mutations in the SH3TC2 gene, causing recessive demyelinating CMT type 4C have been found in several Norwegian CMT patients over the last years. We aimed to estimate a minimum prevalence and to study the genotypic and phenotypic variability of CMT4C in Norway. Patients were selected from diagnostic registries in medical genetic centers in Norway for cases of CMT4C. All patients were invited to complete a questionnaire and give medical consent to the use of clinical data from medical hospital records. A total of 35 patients from 31 families were found with CMT4C, which gives a minimum prevalence of 0.7/100,000 in Norway. Six new mutations were identified. Most patients had debut in the first decade with foot deformities, distal limb paresis, sensory ataxia and scoliosis. Proximal lower limb paresis and cranial nerve involvement was seen in about half of the patients. CMT4C is the most common recessive CMT in Norway. In addition to the classic distal limb affection, early debut, scoliosis, proximal paresis, cranial nerve affection and sensory ataxia are the most prominent features of CMT4C. PMID- 30001927 TI - Ketoacidosis in Duchenne muscular dystrophy: A report on 4 cases. AB - The longer survival in Duchenne dystrophy can be associated with previously unrecognised medical issues, in particular cardiac and nutritional problems, which provide new challenges in the management of these patients. We describe a series of patients who have DMD presenting with severe acid base abnormalities due to ketoacidosis. The cases described all developed the abnormalities in the context of decreased dietary intake. In all cases, the acid-base derangement resolved with intravenous glucose infusion. We conclude that decreased calorific intake for any reason can lead to very severe acid-base derangement in patients with DMD. The treatment is relatively simple once the problem has been identified. An awareness of this potential complication is important for all clinicians involved in the acute care of these patients. PMID- 30001928 TI - Sensitivity and clinical utility of the anti-cytosolic 5'-nucleotidase 1A (cN1A) antibody test in sporadic inclusion body myositis: Report of 40 patients from a single neuromuscular center. AB - Sporadic inclusion body myositis (IBM) is the most common acquired myopathy affecting patients over age 50. The discovery of an autoantibody directed against a 43-44 kD protein (anti-cytosolic-5'-nucleotidase 1A or anti-cN1A) has provided support for the hypothesis of an immune-mediated pathogenesis. Previous studies have reported variable test sensitivity and specificity, and inconsistent results on the predictive value. In our cohort of 40 patients with clinico-pathologically or clinically defined IBM, we found the sensitivity of the anti-cN1A antibody test to be 50%. Comparing characteristics for test positive and test negative groups, we found that patients in our cohort testing positive for the anti-cN1A antibody were significantly more likely to be older than age 60 years at symptom onset. We found no positive association between anti-cN1A reactivity and other clinical, laboratory, and muscle histopathologic findings. Based on all clinical studies published to date including the present, the anti-cN1A antibody test shows high diagnostic specificity, moderate sensitivity, and a low predictive value in regards to age of onset, disease severity and other associated clinicopathological findings. PMID- 30001929 TI - Novel mutations in HINT1 gene cause autosomal recessive axonal neuropathy with neuromyotonia in two cases of sensorimotor neuropathy and one case of motor neuropathy. AB - Autosomal recessive axonal neuropathy with neuromyotonia (ARANNM) is a rare disease caused by mutations of histidine triad nucleotide binding protein 1 (HINT1) gene. ARANNM has been reported mainly in European countries but little reported so far in China. We describe novel mutations of HINT1 in three Chinese patients with ARANNM from unrelated families. Patient 1 was a 14-year-old girl who presented with progressive distal weakness of upper limbs at two years of age. After that, she reported weakness of both feet, and difficulty in muscle relaxation after making a fist. Patient 2 was an 18-year-old boy, who presented with progressive distal weakness of all limbs with foot drop at the age of ten with loss of ambulation at age 15. Patient 3 was a 26-year-old man who had been afflicted with weakness and atrophy of distal lower limbs since the age of 16 complaining about muscle stiffness of the lower limbs when standing and walking, and contraction of finger flexion muscles when releasing a forced grip. Electrodiagnostic testing revealed an axonal motor or sensorimotor neuropathy with or without myokymic discharges. Sural biopsy showed no pathological changes in patient 1 and mild axonal neuropathies with demyelination in patients 2 and 3. Genetic analysis revealed HINT1 with novel compound heterozygous c.112T > C (p.C38R) and c.171G > C (p.K57N) mutations in patient 1, homozygous c.112T > C (p.C38R) mutation in patient 2, as well as compound heterozygous c.112T > C (p.C38R) and c.98T > C (p.F33S) mutations in patient 3. Our study, for the first time, confirms ARANNM in the Chinese population. These genetic findings can help expand the genotypic spectrum of HINT1 mutations. PMID- 30001931 TI - Cognitive behavioural therapy for clozapine non-responders. PMID- 30001930 TI - Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. AB - BACKGROUND: Although clozapine is the treatment of choice for treatment refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia. METHODS: We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual. FINDINGS: From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0.89, 95% CI -3.32 to 1.55; p=0.48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2.40, -4.79 to -0.02; p=0.049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1.09, 95% CI 0.81 to 1.46; p=0.58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial related serious adverse event. INTERPRETATION: At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some. FUNDING: National Institute for Health Research Technology Assessment programme. PMID- 30001934 TI - Radiotherapy in Asia: Making progress step by step. PMID- 30001933 TI - NHL-ChirEx: An interprofessional cross-border education initiative in the Greater Region with a focus on radiation morbidity and patient safety. AB - NHL-ChirEx is an interprofessional cross-border education project that addresses the potential excess of radiation induced morbidity throughout the radiation planning and treatment process. NHL-ChirEx is supported by ESTRO and the University of the Greater Region and has been recently approved and funded under INTERREG VA Programme. PMID- 30001932 TI - Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities. AB - Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community. PMID- 30001935 TI - Doing it the other way round - Mapping motor function by intrinsic activity. PMID- 30001936 TI - Corrigendum to "The influence of polyethylene bearing thickness on the tibiofemoral kinematics of a bicruciate retaining total knee arthroplasty"[Knee 24 (2017) 751-760]. PMID- 30001937 TI - Participants at three months post-operative anterior cruciate ligament reconstruction (ACL-R) demonstrate differences in lower extremity energy absorption contribution and quadriceps strength compared to healthy controls. AB - BACKGROUND: The purpose of this study was to compare hip and knee energy absorption contribution (EAC) during a double limb squat (DLS) and quadriceps strength in patients three months post-operative ACL-R versus matched healthy controls. METHODS: Twenty-four ACL-R participants (Age = 15.5 +/- 1.3 yrs; Ht = 1.66 +/- .07 m; Mass = 66.3 +/- 15.5 kg) were compared to 24 age, sex, limb, and activity-matched healthy controls (Age = 15.5 +/- 1.2 yrs; Ht = 1.65 +/- .08 m; Mass = 59.0 +/- 9.8 kg). Lower extremity biomechanical data was collected at three months post-operative ACL-R during five consecutive DLS. EAC was calculated during DLS descent. Isokinetic quadriceps strength was collected at 60 degrees /s. Normalized quadriceps peak torque (QUADS) was averaged across five trials. Independent t-tests examined differences in group hip and knee EAC during each task. Separate Pearson product-moment correlations examined the relationship between QUADS and hip and knee EAC during the DLS. RESULTS: ACL-R demonstrated greater injured limb hip EAC (46.4 +/- 16.0) than Healthy (31.7 +/- 11.0) during a DLS (p = 0.001). ACL-R demonstrated less injured limb knee EAC (42.7 +/- 14.6) than Healthy (60.6 +/- 8.9) during DLS (p < 0.001). No differences were seen between uninjured limb hip (ACL-R = 0.0 +/- 14.2; Healthy = 33.4 +/- 9.1, p = 0.629) or knee (ACL-R = 56.9 +/- 15.6; Healthy = 59.1 +/- 9.8, p = 0.561) EAC and matched limbs. ACL-R injured limb QUADS was decreased compared to Healthy (ACL-R = 1.1 +/- 0.5; Healthy = 2.0 +/- 0.5, p < 0.001). No differences were seen in QUADS on the uninjured and matched limbs (ACL-R = 2.0 +/- 0.6; Healthy = 1.9 +/- 0.5, p = 0.894). There was a weak, negative correlation between injured limb QUADS and hip EAC (r = -0.471, p = 0.001) and moderate, positive correlation between injured limb QUADS and knee EAC (r = 0.615, p < 0.001). CONCLUSIONS: ACL R participants demonstrate different eccentric loading strategies during a DLS at three months postoperative compared to matched healthy controls. PMID- 30001938 TI - Three-Dimensional Reconstruction of Foot in the Weightbearing Position From Biplanar Radiographs: Evaluation of Accuracy and Reliability. AB - The initial assessment and postoperative monitoring of patients with various abnormalities of the foot in clinical routine practice is primarily based on the analysis of radiographs taken in the weightbearing position. Conventional x-ray imaging, however, only provides a 2-dimensional projection of 3-dimensional (3D) bony structures, and the clinical parameters assessed from these images can be affected by projection biases. In the present work, we addressed this issue by proposing an accurate 3D reconstruction method of the foot in the weightbearing position from low-dose biplanar radiographs with clinical index measurement assessment for clinical routine practice. The accuracy of the proposed reconstruction method was evaluated for both shape and clinical indexes by comparing 3D reconstructions of 6 cadaveric adult feet from computed tomographic images and from biplanar radiographs. For the reproducibility study, 3D reconstructions from the biplanar radiographs of the foot of 6 able-bodied subjects were considered, with 2 observers repeating each measurement of anatomic landmarks 3 times. Baseline assessment of important 3D clinical parameters was performed on 17 subjects (34 feet; mean age 27.7, range 20 to 52 years). The average point to surface distance between the 3D stereoradiographic reconstruction and the computed tomographic scan-based reconstruction was 1 mm (range 0mm to 6mm). The selected radiographic landmarks were highly reproducible (95% confidence interval <2.0 mm). The greatest interindividual variability for the clinical parameters was observed for the twisting angle (mean 87 degrees , range 73 degrees to 100 degrees ). Such an approach opens the way for routine 3D quantitative analysis of the foot in the weightbearing position. PMID- 30001939 TI - A Comparative Study of Mini-Scarf Versus Standard Scarf Osteotomy for Hallux Valgus Correction. AB - Scarf osteotomy is widely used for hallux valgus treatment. More recently, a trend has begun toward the use of minimally invasive techniques, including the mini-scarf osteotomy, in which the diaphyseal cut is shortened. We compared the mini-scarf and traditional scarf osteotomy to determine whether the mini-scarf osteotomy is as effective as the scarf osteotomy in correcting mild to moderate hallux valgus and improving clinical function. We reviewed the cases of 37 consecutive patients during a 2-year period. A total of 21 (56.8%) patients had undergone scarf osteotomy and 16 (43.2%) had undergone mini-scarf osteotomy. The intermetatarsal, hallux valgus, and distal metatarsal articular angles and medial sesamoid position of the 2 groups were measured at 12 weeks postoperatively. The Manchester Oxford Foot Questionnaire scores and patient satisfaction were recorded at 28 months postoperatively. All radiologic parameters and Manchester Oxford Foot Questionnaire scores had significantly improved in both groups (p < .05 and p < .01 for mini-scarf and scarf, respectively). The medial sesamoid position had improved in all patients, with similar satisfaction between the 2 procedures (p = .43). The results of the present study have shown that the mini scarf osteotomy for mild to moderate hallux valgus is as effective as the standard approach, with the potential benefit of a smaller scar and less soft tissue disruption. PMID- 30001940 TI - Black Bone Disease of the Foot: A Two-Year Follow-Up Case Study. AB - "Black bone disease" is a term commonly used to describe a condition characterized by a blue/green/brown discoloration to the bone that often resembles infracted or necrotic bone. The chronic use of minocycline or tetracycline has been reported in previous data as a cause of this discoloration to the skin, bone, and teeth. However, the occurrence in bone is rare, with few studies reported regarding the discoloration. We previously presented a case of this condition encountered during cheilectomy of the first metatarsophalangeal joint in a patient who had had long-term usage of minocycline for adult acne. Two years after the initial case, the patient returned for correction of a hammertoe deformity on the second left proximal phalanx of the same foot. We present the findings and photographs from the second surgery. In addition, we have provided the relevant case data and figures from the first case for ease of comparison. PMID- 30001941 TI - Dynamic risk stratification using serial measurements of plasma concentrations of natriuretic peptides in patients with heart failure. AB - BACKGROUND: Prognostic models for patients with chronic heart failure are generally based on a single assessment but treatment is often given with the intention of changing risk; re- evaluation of risk is an important aspect of care. The prognostic value of serial measurements of natriuretic peptides for the assessment of changes in risk is uncertain. AIMS: To evaluate the prognostic value of serial measurements of plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP) during follow-up of out-patients with chronic heart failure (CHF). METHODS: Patients diagnosed with CHF between 2001 and 2014 at a single out patient clinic serving a local community were included in this analysis. NT proBNP was measured at the initial visit and serially during follow-up. Only patients who had one or more measurements of NT-proBNP after baseline, at 4, 12 and/or 24 months were included. RESULTS: At baseline, amongst 1998 patients enrolled, the median age was 73 (IQR: 64-79) years, 70% were men, 31% were in NYHA class III/IV, and 77% had NT-proBNP >400 pg/mL. Median follow-up was 4.8 (IQR: 2.5-8.6) years. Serial measurements of NT-proBNP improved prediction of all cause mortality at 3 years (c- statistic = 0.71) compared with using baseline data only (c-statistic = 0.67; p < 0.001) but a model using only the most recent NT-proBNP had an even higher c-statistic (0.72; p < 0.001). Similar results were obtained based on long-term prediction of mortality using all available follow-up data. CONCLUSIONS: Serial measurement of NT-proBNP in patients with CHF improves prediction of all-cause mortality. However, using the most recent value of NT proBNP has similar predictive power as using serial measurements. PMID- 30001942 TI - Catheter ablation of atrial fibrillation with heart failure: An updated meta analysis of randomized trials. AB - INTRODUCTION: Atrial fibrillation (AF) and heart failure (HF) often coexist. We conducted this meta-analysis to assess the efficacy and safety of catheter ablation in this population. METHODS: Electronic databases were searched for all randomized clinical trials (RCTs) that evaluated catheter ablation in patients with left ventricular systolic dysfunction (LVSD). We calculated the weighted mean differences (MDs) and risk ratios (RRs) using a random-effects model. RESULTS: We included 7 RCTs with 851 patients (mean follow-up was 18 months). Catheter ablation in patients with LVSD was associated with significantly lower HF hospitalization rates (RR 0.57; 95% CI: 0.45-0.72; P < 0.01), reduced all cause mortality (RR 0.52; 95% CI: 0.35-0.76; P < 0.01), improved left ventricular ejection fraction (MD 7.40; 95% CI: 3.37-11.43; P < 0.01), increased 6-minute walk test (MD 26.96; 95% CI: 6.39-47.54; P = 0.01), and improved peak oxygen consumption (VO2) (MD 3.17; 95% CI: 1.05-5.28; P < 0.01), without significant increased risks of serious adverse events (RR 1.05; 95% CI: 0.96-1.16; P = 0.30) compared with medical treatment. CONCLUSIONS: In this meta-analysis of RCTs, catheter ablation was associated with significant improvements in the clinical, structural, and functional capacity of patients with AF and coexisting HF compared with medical treatment. PMID- 30001943 TI - In vivo vulnerability grading system of plaques causing acute coronary syndromes: An intravascular imaging study. AB - BACKGROUND: Autopsy studies shed light on the interplay between fatal acute coronary syndromes (ACS) and features of plaque vulnerability. This is a prospective pilot study designed for generating a new in vivo imaging grading system of plaque vulnerability. METHODS: We studied 87 coronary vessels in 63 consecutive patients: 48 with Acute Coronary Syndrome (ACS) and 15 with stable coronary artery disease using IntraVascular-Ultrasound Near-Infrared-Spectroscopy (IVUS-NIRS) and Optical Coherence Tomography (OCT). We identified 99 lesions: 21 were the ACS culprit lesions (18 ulcerations and 3 with intact fibrous cap), 78 were non-culprit lesions including plaques located in the same ACS culprit vessel (N12), plaques located in a non-culprit vessel in patients with ACS (28) and target lesions of stable patients (N 38). A second analysis focused on lipid plaques, comparing the 18 ACS culprit ulcerated lesions and the 55 non-culprit lesions. RESULTS: The co-presence of the following three features of vulnerability [Minimal Luminal Area (MLA) <4 mm2, Fibrous Cap Thickness (FCT) < 75 MUm and superficial macrophages] was by far more frequent in ACS culprit lesions than in controls (OR 40.6 for all lesions and OR 45.7 for ulcerated culprit lesions only). The triple-feature OCT grading identified vulnerable plaques with a much higher accuracy than that obtained applying each single feature of vulnerability. CONCLUSIONS: The co-presence of the 3 OCT features of vulnerability (MLA < 4 mm2, FCT < 75 MUm and superficial macrophages) identifies culprit ACS lesions with a very high odd ratio. This finding could set the basis for a new OCT vulnerability grading system including superficial macrophages. PMID- 30001944 TI - Surgical closure of a ventricular septal defect in early childhood leads to altered pulmonary function in adulthood: A long-term follow-up. AB - BACKGROUND: The long-term outlook after surgical closure of ventricular septal defect (VSD) has traditionally been considered benign. However, there is an increasing awareness of not only late cardiac dysfunction, but also pulmonary abnormalities. The primary aim of this study was to describe pulmonary function in adults with a surgically repaired VSD, and secondarily to determine the effects of salbutamol on the potential abnormalities. METHODS: All patients (operated for a VSD in early childhood) and controls (age- and gender-matched) underwent static and dynamic spirometry, impulse oscillometry, multiple breath washout, diffusion capacity for carbon monoxide, and cardiopulmonary exercise testing. In a double-blinded, cross-over study, participants were randomized to inhalation of either 900 MUg of salbutamol or placebo. The primary outcome was forced expiratory volume in 1 s. RESULTS: In total, 30 participants with a surgically closed VSD and 30 healthy controls were included. The VSD participants had a lower forced expiratory volume in 1 s (99 +/- 13% vs. 111 +/- 13%), p < 0.001, impaired forced vital capacity, (106 +/- 12% vs. 118 +/- 13%), p < 0.001, and lower peak expiratory flow, (95 +/- 18% vs. 118 +/- 19%), p < 0.001, than the control group. Also, the VSD group had a lower alveolar volume than the control group, (92 +/- 10% vs. 101 +/- 11%), p < 0.001, but there were no differences in the remaining pulmonary function parameters. Salbutamol reduced airway resistances in both groups, but exercise performance was not improved by salbutamol, however. CONCLUSIONS: Adults who have undergone surgical closure of a VSD in early childhood have reduced pulmonary function compared with controls, which is unaffected by inhalation of salbutamol. PMID- 30001945 TI - Changes to oral anticoagulant therapy and risk of death over a 3-year follow-up of a contemporary cohort of European patients with atrial fibrillation final report of the EURObservational Research Programme on Atrial Fibrillation (EORP AF) pilot general registry. AB - BACKGROUND: Contemporary European data regarding patients with atrial fibrillation (AF) allow us to assess the use of oral anticoagulants (OACs) and long-term outcomes. METHODS: Patients with AF presenting to cardiologists in 9 European Society of Cardiology participating countries were enrolled and followed up for 3-years. RESULTS: Among the 2119 patients (40.4% female; mean age 69 +/- 11 years) the prevalent types of AF at baseline were first-detected (30.5%) and paroxysmal AF (27.0%). The composite of stroke/TIA/peripheral embolism/all-cause death at 3-years occurred in 18.2%, with first detected AF and permanent AF reporting the highest event rates (22.5% and 27.3%, respectively; p < 0.0001). Age, diabetes mellitus, heart failure, restrictive cardiomyopathy, chronic kidney disease and no physical activity were significant predictors of all-cause death. Paroxysmal and persistent AF patients were more likely to be hospitalised than other types of AF (34.1% and 37.9%, p < 0.0001). At follow-up, OAC drugs were used in 80.1% of patients, with non-vitamin K antagonists (NOACs) accounting for 24.3% of patients. OAC treatment at follow-up visits changed throughout time, with a shift from VKA to NOACs reported in 5.4% of the cases, while the reverse shift (from NOACs to VKA) occurred in 8.6%. Discontinuation of OAC was recorded in while in 9.5% of visits. CONCLUSIONS: Patients outcomes at 3-years follow-up differ according to type of AF at baseline, with worse outcomes in patients presenting with first-detected or permanent AF. Changes in the type of OAC use with shifts from NOACs to VKA and vice-versa are not uncommon, as were interruptions of OAC. PMID- 30001946 TI - Importance of maintaining good oral health in cardiometabolic disorders. PMID- 30001947 TI - Clarifying the anatomy of the atrioventricular node artery. AB - BACKGROUND: Reports of conduction abnormalities necessitating permanent pacemaker implantation due to atrioventricular node artery injury and increasing evidence of stenosis of the atrioventricular node artery in cases of sudden death are of unsolved clinical importance. Unfortunately, technical issues associated with physical and virtual dissections of the atrioventricular conduction axis make it difficult to accurately assess its arterial supply. METHODS: We used a specialized dissection technique to gather anatomical information on the atrioventricular node artery and described them using attitudinally appropriate terminology. RESULTS: The mean number of atrioventricular node artery branches was 1.6 in 103 submacroscopic examinations and 2.3 in 17 histological reconstructions. The artery had 5 origins in the modified AHA anatomy guidelines: distal RCA (#3), 10.4%; right posterior interventricular artery (#4PI), 7.3%; proximal RCA posterolateral branch (proximal #4PL), 76.8%; distal RCA posterolateral branch detouring the coronary sinus (distal #4PL), 1.8%; distal LCX (#13), 3.7%. Histological examination revealed that most atrioventricular node arteries immediately left the distal compact node (71.8%), suggesting that they supply mainly the proximal part of the AV conduction axis. The artery to the atrioventricular node tended to originate from the medial and atrial aspect of RCA posterolateral branch, and supplied adjacent structures within the inferior pyramidal space before entering the compact atrioventricular node. CONCLUSIONS: Based on the visualisation of the atrioventricular conduction axis and its arterial supply, we herein provide the 'gold standard' for understanding the origin, course and distribution of the artery to the atrioventricular node. PMID- 30001948 TI - Tailoring acoustics and devices for gene therapy: Comment on 'Shock-wave induced permeabilization of mammalian cells' by Lopez-Marin et al. PMID- 30001949 TI - Electrocardiographic findings in elite professional cyclists: The 2017 international recommendations in practice. AB - OBJECTIVES: To categorize ECG findings into normal, borderline or abnormal in a team of professional elite cyclists according to the 2017 international recommendations. DESIGN: A cross-sectional study was performed. METHODS: Twelve lead ECGs collected between 2012 and 2015 as part of an annual routine examination for a team of professional elite cyclists were analysed, and findings classified as normal, borderline or abnormal according to the 2017 recommendations. Information on exercise capacity testing was also collected. RESULTS: A total of 43 professional cyclists, all Caucasian males ranging between 21 and 38years of age, were included. Given most were followed up for multiple years, a total of 103 ECGs were collected. Normal variations were found in 43 (100%) athletes; borderline findings in 4 (9.3%), and 2 (4.7%) athletes had abnormal findings. No pathology was identified on further investigation of the four cyclists with two concurrent borderline or any abnormal ECG findings, reflecting a false positive rate of 9.3%. CONCLUSIONS: In this team of professional cyclists, the prevalence of abnormal ECG findings requiring further investigation, and the false positive rate were low, despite a very high prevalence of normal variations expected in athletes. This may be as a result of heightened specificity of the new international recommendations for ECG interpretation in athletes. PMID- 30001950 TI - Development and External Validation of an Early Prognostic Model for Survivors of Out-of-hospital Cardiac Arrest. AB - INTRODUCTION AND OBJECTIVES: Despite therapeutic hypothermia, unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Our objective was to assess the usefulness of the variables obtained in the early moments after resuscitation in the prediction of 6-month prognosis. METHODS: A multicenter study was performed in 3 intensive cardiac care units. The analysis was done in 153 consecutive survivors of out-of-hospital cardiac arrest who underwent targeted temperature management between January 2007 and July 2015. Significant neurological sequelae at 6 months were considered to be present in patients with Cerebral Performance Categories Scale > 2. An external validation was performed with data from 91 patients admitted to a third hospital in the same time interval. RESULTS: Among the 244 analyzed patients (median age, 60 years; 77.1% male; 50.0% in the context of acute myocardial ischemia), 107 patients (43.8%) survived with good neurological status at 6 months. The prediction model included 5 variables (Shockable rhythm, Age, Lactate levels, Time Elapsed to return of spontaneous circulation, and Diabetes - SALTED) and provided an area under the curve of 0.90 (95%CI, 0.85-0.95). When external validation was performed, the predictive model showed a sensitivity of 73.5%, specificity of 78.6%, and area under the curve of 0.82 (95%CI, 0.73-0.91). CONCLUSIONS: A predictive model that includes 5 clinical and easily accessible variables at admission can help to predict the probability of survival without major neurological damage following out-of-hospital cardiac arrest. PMID- 30001951 TI - Both glypican-3/Wnt/beta-catenin signaling pathway and autophagy contributed to the inhibitory effect of curcumin on hepatocellular carcinoma. AB - AIM: The aim of this study is to investigate the role of glypican 3(GPC3)/wnt/beta-catenin signaling pathway and autophagy in the regulation of hepatocellular carcinoma (HCC) growth mediated by curcumin. METHODS: HepG2 cells were treated with various concentrations of curcumin and/or GPC3-targeting siRNA in the presence or absence of 3-MA. Cell proliferation and apoptosis were determined by MTT and TUNEL assay, respectively. Expression of GPC3, beta catenin, c-myc, LC3, and Beclin1 was determined by western blotting. In addition, curcumin was tested in tumor xenografts mice model, Caliper IVIS Lumina II was used to monitor the tumor growth, and GPC3/wnt/beta-catenin signaling proteins were determined by western blotting. RESULTS: Curcumin treatment led to proliferation inhibition and apoptosis induction in HepG2 cells in a concentration-dependent manner, and suppressed HCC tumor growth in vivo. Further analysis showed that curcumin treatment inactivated Wnt/beta-catenin signaling and decreased GPC3 expression, silencing of GPC3 expression promoted the effects of curcumin on Wnt/beta-catenin signaling. In addition, inhibiting autophagy by 3 MA relieved curcumin-dependent down-regulation of GPC3. CONCLUSION: Curcumin suppressed HCC tumor growth through down-regulating GPC3/wnt/beta-catenin signaling pathway, which was partially mediated by activation of autophagy. PMID- 30001952 TI - Gene expression profile of Dclk1+ cells in intestinal tumors. AB - BACKGROUND: Accumulating evidence has shown the existence of tumor stem cells with therapeutic potential. Previously, we reported that doublecortin like kinase 1 (Dclk1) marks tumor stem cells but not normal stem cells in the intestine of ApcMin/+ mice, and that Dclk1- and Lgr5-double positive tumor cells are the tumor stem cells of intestinal tumors. AIM: To investigate molecules highly expressed in the Dclk1+ normal intestinal and Dclk1+ tumor cells in ApcMin/+ mice. METHODS: We used microarray analyses to examine the gene expression profile of Dclk1+ cells in both mouse normal intestinal epithelium and ApcMin/+ mouse intestinal tumors. We also performed immunofluorescence analyses. RESULTS: Genes related to microtubules and the actin cytoskeleton (e.g., Rac2), and members of the Src family kinases (i.e., Hck, Lyn, Csk, and Ptpn6) were highly expressed in both Dclk1+ normal intestinal and Dclk1+ tumor cells. Phosphorylated Hck and phosphorylated Lyn were expressed in Lgr5+ cells in the intestinal tumors of Lgr5EGFP-IRES-CreERT2/+; ApcMin/+ mice. CONCLUSION: We revealed factors that are highly expressed in Dclk1+ intestinal tumor cells, which may help to develop cancer stem cell-targeted therapy in future. PMID- 30001953 TI - Investigating influencing factors of physical restraint use in China intensive care units: A prospective, cross-sectional, observational study. AB - OBJECTIVE: In this study, we characterised the use of physical restraints in three intensive care units (ICUs) in a general hospital in Nantong, China. Additionally, we explored risk factors potentially related to physical restraint use. BACKGROUND: Despite their numerous harmful effects, physical restraints are frequently used in ICUs worldwide. Few studies have investigated the factors that contribute to physical restraint use in Chinese hospitals. METHODS: We conducted a prospective, cross-sectional, observational study of 312 patients in three ICUs at a general hospital in China. The quantitative data were collected during a 5 month period using a physical restraint observation form and patient records. The data obtained were analysed using descriptive statistics. The independent risk factors for physical restraint use were assessed using a logistic regression model. RESULTS: Of the 312 patients in the three ICUs, 191 (61.2%) were restrained, and physical restraints were used more than once for 46 (24.1%) patients during their ICU stay. The median length of physical restrain use was 20 shifts (interquartile range = 10-36 shifts). Physical restraints were applied in 6664 of 12374 (53.9%) nurse shifts. The most common time at which physical restraints were applied was the beginning of the evening shift. According to the forward stepwise logistic regression analysis, delirium (P < 0.001), mechanical ventilation (P < 0.001), and age (P < 0.001) were independent risk factors for physical restraint use. The use of analgesics (P = 0.001) exerted an independent protective effect against physical restraint use. CONCLUSIONS: The overall prevalence of physical restraint use in Chinese ICUs was higher than that reported in previous investigations. The patients' nursing notes lacked complete physical restraint records, reflecting a need for standard guidelines and policies for physical restraint use in hospital ICUs in China. In addition, in this study, we explored the risk factors related to physical restraint use and found that age, delirium, mechanical ventilation, and analgesic use are associated with physical restraint use. PMID- 30001954 TI - Barriers to implementing expert safety recommendations for early mobilisation in intensive care unit during mechanical ventilation: A prospective observational study. AB - BACKGROUND: Early mobilisation in the intensive care unit (ICU) has been consistently reported as feasible and safe with minimal adverse events; however, invasive mechanical ventilation patients are rarely actively mobilised. An expert consensus group developed and published recommendations using a traffic light system on safety criteria to promote active mobilisation of invasive mechanical ventilation patients. OBJECTIVES: The aim of this study was to determine whether, in clinical practice, the safety consensus recommendations resulted in (1) increased early mobilisation in patients assessed as appropriate to mobilise based on the risk classification and (2) early mobilisation without adverse events. METHODS: A prospective observational study of 100 patients requiring invasive mechanical ventilation (IMV) for greater than 24 h admitted to the ICU at The Alfred Hospital. Patients were assessed daily (Monday to Friday) to determine their ability to perform early mobilisation. RESULTS: Data were collected on 100 patients, resulting in 280 physiotherapy-patient interactions during IMV. Of the 100 patients, five patients actively mobilised out of bed during IMV. No adverse event occurred during active physiotherapy-patient interactions. There were 15 physiotherapy-patient interactions that had a low risk of an adverse event, and on nine (60.0%) of these physiotherapy-patient interactions, patients were actively mobilised out of bed with the main reported barrier being time constraints. Of 208 physiotherapy-patient interactions where there were significant potential risks of an adverse event identified for mobilising, active out of bed mobilisation did not occur, with sedation being reported as the main barrier in 170 (82%) patients. CONCLUSIONS: The translation of expert consensus recommendations for early mobilisation into clinical practice was poor. Clinicians were safe and conservative in the implementation of early mobilisation during IMV. PMID- 30001955 TI - Patent foramen ovale may not always be benign in the elderly. PMID- 30001956 TI - Do they just look like spikes or are they actual spikes? PMID- 30001957 TI - Uhl's disease, a rare disease with an uncommon presentation. AB - Uhl's anomaly is a rare disease secondary to the selective but uncontrolled apoptosis of right ventricular myocytes during the perinatal period, following complete cardiac development. This explains the absence of the right ventricular myocardium and the direct apposition of endocardium to epicardium without a myocardial layer in between, resulting in right ventricular failure. This paper describes a case of Uhl's disease with an uncommon presentation. A 28-year-old man was admitted with dyspnea and cyanosis. Transthoracic echocardiography showed severe dilation of the right chambers, impaired right ventricular systolic function and a large ostium secundum atrial septal defect. Cardiac catheterization revealed pulmonary hypertension, with increased pulmonary capillary wedge pressure (mean 19 mmHg); pulmonary blood flow:systemic blood flow was 0.88:1. At this point, the authors felt that atrial septal defect as the primary diagnosis could not explain the clinical features or hemodynamic data. Primary right ventricular disease was the most likely hypothesis and cardiac magnetic resonance imaging was performed, revealing an extremely thin-walled right ventricle, with almost complete absence of the right ventricular free wall myocardium, which is compatible with Uhl's disease. PMID- 30001958 TI - Redesigning provider payment: Opportunities and challenges from the Hawaii experience. AB - OBJECTIVES: To describe the process of developing a new physician payment system based on value and transitioning away from a fee-for-service payment system STUDY DESIGN: Descriptive. This paper describes a recent initiative involving redesign of primary care provider payment in the State of Hawaii. While there has been extensive discussion about switching payment from volume to value in recent years, much of this change has happened at the organizational level and this initiative focused on changing the incentives for individual providers. METHODS: Descriptive paper. In this paper we discuss the approach taken to shift incentives from fee-for-service towards value using behavioral economics as a conceptual framework for program design. We summarize the new payment system, challenges in its design, and our approach to piloting of different behavioral economic strategies to improve performance. RESULTS: None. CONCLUSIONS: This paper will provide useful guidance to health plans or health delivery systems considering shifting primary care payment away from fee-for-service towards value highlighting some of the design challenges and necessary compromises in implementing such a system at scale. PMID- 30001971 TI - [Bone metastases radiotherapy: Multi-approaches literature review]. AB - External beam radiation therapy is an efficient treatment, which relieves pain associated with bone metastases, and is prescribed in worldwide. Although bone metastases palliative irradiation recommendations exist, international clinical practices remain variable. The purpose of this article is to show the clinical practices evolution though clinical trials, cost studies and techniques' progression. PMID- 30001972 TI - The centrality of cognitive symptoms and metacognition within the interacting network of symptoms, neurocognition, social cognition and metacognition in schizophrenia. AB - Schizophrenia involves a range of interrelated impairments in functioning due to symptoms and deficits in varying domains of cognition including neurocognition, social cognition and metacognition. Yet little is known whether certain symptoms or cognitive impairments play a more central role than others. To explore, we conducted a network analysis of five types of symptoms, six domains of neurocognition and multiple aspects of both social cognition and metacognition. Participants were 81 adults with a schizophrenia spectrum disorder in a non-acute phase of the disorder. Results of the network analysis suggest that the cognitive symptoms node is most central in the network, metacognition abilities have high strength centrality measures followed by visual learning and emotion identification. In addition, distinction between the four groups of variables was supported. This suggests the need for both cognitive remediation and metacognitively oriented therapies in order to promote recovery from schizophrenia. PMID- 30001973 TI - Shorter telomere length in schizophrenia: Evidence from a real-world population and meta-analysis of most recent literature. AB - Schizophrenia is a severe, chronic mental disorder. Schizophrenia is visualized as an accelerated cellular aging syndrome characterized by early onset of cardiovascular disease causing premature mortality. In human aging involves alterations in telomere length (TL). To investigate the presence of TL shortening in schizophrenia and psychiatric syndromes associated, this condition was studied in leukocytes (LTL) of a sample of patients suffering from schizophrenia and other psychotic disorders, and compared with a group of non-psychiatric controls. We explored the relationship between LTL and age, gender, and smoking habit with the aim to control whether these potential confounding factors may influence the rate of telomeres shortening. We also performed a new comprehensive meta-analysis including studies on LTL in schizophrenia patients compared to healthy subjects published in the last two years and the results of the present study. Our results suggest that a diagnosis of schizophrenia, more than gender, age, cigarette smoking or alcohol drinking, is the most important condition responsible of the LTL shortening. A strong LTL shortening was observed in patients affected by schizophrenia, Schizoaffective disorder, and Psychosis not otherwise specified when they were younger than 50 years, while in the group of older subjects no major differences were observed. Additional evidence supporting the causal link of schizophrenia with accelerated telomeres shortening came from the analysis of the updated meta-analysis. The availability of a personalized profile of mechanistic pathways, risk factors, and clinical features may pose the basis for a rehabilitative treatment addressing individual needs of the psychiatric patients. PMID- 30001974 TI - Is low postoperative cholesterol level really an independent risk factor of adverse outcomes after living donor liver transplantation? PMID- 30001975 TI - Editorial Comment. PMID- 30001976 TI - Editorial Comment. PMID- 30001977 TI - Editorial Comment. PMID- 30001979 TI - Intraoperative bone defect measurement in the acetabulum using a navigation system: The influence of bone porosity on the digitalization process. AB - The aim of the study was to evaluate how bone porosity affects intraoperative volume measurement of the acetabulum in a plastic bone model study and to validate the measurement method on cadaveric acetabula. Point cloud collection was performed using a navigation system and compared to CT measurements as well as theoretical calculations on sawbones with different porosities and validated on cadaveric specimens. The grade of porosity had a significant influence on the volume measurement. In high porous materials volume calculation (61.5 cm2) was overestimated when using a digitalizer, while in materials with low porosity the volume was underestimated (57.0 cm2) in comparison to the known size of the defect (59.4 cm2). Digitalization time of the acetabulum was between 1 and 4 min. Validating the measurement on cadaveric bones no statistical significant difference could be found between digitalized volumes and theoretically calculated volumes. As digitalization of the acetabulum can be carried out in a reasonable time it could be used as a measurement tool to estimate the amount of allografts needed for filling bone defects. PMID- 30001978 TI - Intraoperative thermal safety of endoscopic ear surgery utilizing a holder. AB - PURPOSE: Despite the ever-growing popularity of endoscopic ear surgery (EES), there are still concerns regarding the potential thermal risk associated with the use of light sources and also questions raised about the thermal safety of extended stationary applications of endoscopes with holders that allow the use of both hands in the middle ear. The temperature changes witnessed during EES when using different calipers on static endoscopes fitted with camera holders during true operations were measured, and effects of varying light source intensities, as well as the cooling effect of irrigation and suction, were investigated. METHODS: This study included 12 patients with chronic otitis who were scheduled to undergo myringoplasty surgery. Two of five different endoscopes with xenon light sources (4 mm-0 degrees , 3 mm-0 degrees , 2.7 mm-0 degrees , 3 mm-45 degrees and, 2.7 mm-30 degrees ) were used on each patient. Following irrigation and aspiration, gradually increasing heat measurements were recorded at two minute intervals using a thermocouple thermometer for the entire period the endoscope remained in the ear. Three measurements obtained within the final 6 min, all of which were the same and reached a plateau, were considered to be the peak heat value. Measurements were repeated twice in each patient at 100% and 50% light intensities. RESULTS: The highest heat was recorded by the 4 mm-0 degrees endoscope, with heats at 100% and 50% light intensity recorded as 48.4 degrees C and 43.2 degrees C, respectively. The highest heat was measured by the 2.7 mm-0 degrees endoscope, and heats recorded at 100% and 50% light intensities were 37.8 degrees C and 35.3 degrees C, respectively. CONCLUSION: Stationary use of endoscopes with 3 mm and smaller calipers without irrigation or aspiration, the heat in the middle ear would appear to be safe, and at a level that does not cause thermal trauma to tissue. The present study demonstrates that frequent aspiration or intermittent irrigation may prevent potential thermal damage, even in procedures performed using endoscopes of a 4 mm caliper. Light intensity settings of 50% can be adopted as a further safety measure against potential thermal risk without compromising visual acuity. PMID- 30001980 TI - A systematic review of orthodontic retention systems: The verdict. AB - INTRODUCTION: Retention during both the active and passive phases of treatment has given rise to numerous publications concerning its efficacy, the range of systems available and its variability over time. There are currently many different retention protocols regularly used by orthodontists; however, their efficacy and duration are still subject to debate. There is as yet no consensus as to which retention protocol is the most effective or for how long the retention device needs to be worn. The aim of this research was to perform a systematic review of the scientific literature in order to evaluate the efficacy of the different retention systems and clinical protocols among those most widely used, so as to make recommendations beneficial to both patient and practitioner. MATERIALS AND METHODS: A search of the literature was performed in the following databases: PubMed (MEDLINE), ScienceDirect and Cochrane Library. The search was limited to publications in English and French during the period 2006-2016. RESULTS: Out of 1952 references initially identified, 17 articles corresponded to our inclusion criteria. The results show that: fixed retention is more effective than removable retainers for the maintenance of incisor alignment during the first six months of retention; there is no significant difference in efficacy between the different fixed retention systems; there is no significant difference in efficacy between the vacuum-formed systems and the Hawley retainer; part-time use of removable retainers (between 8-10h/day) is sufficient; the most widely used retention protocol combines a vacuum-formed splint or Hawley retainer in the upper arch with mandibular fixed retention. CONCLUSION: Despite the large number of studies devoted to orthodontic retention only a few articles corresponded to the methodological criteria of bio statistical analysis. Also, on account of the variations in experimental protocols, the levels of proof relating to the efficacy of different systems are very weak. Research into this topic should first seek to normalize methods of analysis and then perform randomized controlled long-term trials to shed light on this problem. PMID- 30001981 TI - ? PMID- 30001982 TI - Comparison of dienogest effects upon 3,3'-diindolylmethane supplementation in models of endometriosis and clinical cases. AB - Dienogest (DNG) administration is a well-established treatment for endometriosis but bleeding irregularities remain its main disadvantage. Changes in diet, mainly to vegetable consumption, are beneficial in the treatment of estrogen-related pathologies but their use for endometriosis has been poorly studied. In this study, addition of the phytochemical 3,3'-diindolylmethane (DIM) to DNG therapy has been investigated in in vitro and ex vivo models for endometriosis and in a small cohort of women with endometriosis. Endometrial Ishikawa cells were treated with DNG or DIM at dosages from 10-10 M to 10-5 M for up to 72 h. Cell proliferation was measured by assessing BrdU incorporation. Endometrial tissue from women with endometriosis and controls was incubated with DNG or a combination of DNG and DIM. Tissue viability was determined using a modified colorimetric MTS assay. 17beta-estradiol secretion was quantified by an electro chemiluminescence immunoassay. Finally, DNG as monotherapy or in combination with DIM was randomly administered to women with endometriosis (n = 8) over 3 months. Bleeding patterns and associated pelvic pain were assessed by Visual Analogue Scale (VAS). DNG and DIM significantly reduced cell proliferation in Ishikawa cells. Ex vivo, DIM reduced viability and estradiol secretion specifically in endometriotic but not in normal endometrial tissue. This effect was enhanced by combination with DNG. Endometriosis associated pelvic pain was significantly reduced in patients taking the DNG-DIM combination therapy compared to those taking DNG alone. Bleeding pattern (number and duration of episodes) was significantly improved by addition of DIM to the DNG treatment. In conclusion, addition of DIM enhances effects of DNG ex vivo and may ameliorate bleeding patterns in endometriosis patients. PMID- 30001983 TI - Decay-accelerating factor promotes endometrial cells proliferation and motility under ovarian hormone stimulation. AB - The intent of the study was to explore the elevating expression of decay accelerating factor(DAF) exerts influence on biological behaviors of endometrial stromal cells except in classical immunology on the basis of bioinformatic statistics and clinical miscarriages findings suggesting its potential role in the establishment of endometrial receptivity. We confirmed that DAF locates on the cellular surface of endometrial epithelium and stroma. By using plasmid transfection to down-regulate DAF expression in primary endometrial stromal cells(ESCs), we discovered that DAF expression in ESCs increases in response to estradiol and progesterone stimulation in dose- and time-dependent manners; moreover, tamoxifen and RU486 stimulations to block estrogen receptors(ERs) and progesterone receptors(PRs) respectively result in reduced DAF mRNA and protein, and it is more obvious to block PRs. Meanwhile, knocked-down DAF in ESCs weakens the proliferation, migration and invasion of endometrial cells. Cell cycle analysis showed knocked-down DAF accumulates cells in S phase and diminishes cells in G0/G1 phase, which substantiates DAF mediates endometrial cells proliferation. In conclusion, DAF is a potential molecule involving in endometrial cellular proliferation and motility to verify up-expressed DAF during the WOI may facilitate endometrial physiobiological behavior changes, which shed light on DAF function and potential role in the endometrial receptivity establishment. PMID- 30001984 TI - Multiple Myeloma Patients Ineligible for Randomized Controlled Trials Have Poorer Outcomes Irrespective of Treatment. PMID- 30001985 TI - The Multiple Myeloma Drug Pipeline-2018: A Review of Small Molecules and Their Therapeutic Targets. AB - Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of < 900 kDa)-immunomodulators, proteasome inhibitors, and histone deacetylase blockers-have been introduced for the disease. Therapeutic options for MM expanded further in 2015 when 2 new monoclonal antibodies (daratumumab and elotuzumab) were approved by the Food and Drug Administration for MM. Although MM remains incurable, the cumulative effect of these advances has resulted in a near doubling of the 5-year survival rate since the late 1980s. Despite these advances, therapy for MM continues to pose substantial challenges because resistance to therapy frequently develops, and relapse and recurrence are all too common. The present review focused on the pipeline for new small molecules in various stages of development and their associated cellular targets. In addition to newer versions of alkylators, immunomodulators, proteasome inhibitors, and histone deacetylase inhibitors, the present review considered the prospects for adding new classes of small molecules to the MM armamentarium, which offer the potential for oral efficacy, relative simplicity of preparation, and prospects for improvement in the cost-to-benefit ratio. Included are agents that affect myeloma epigenetics and the ubiquitination-proteasome system and the unfolded protein response, apoptotic mechanisms, chromosomal abnormalities, nuclear protein transport, and various kinases involved in cellular signaling pathways. PMID- 30001986 TI - A Pilot Trial of Lirilumab With or Without Azacitidine for Patients With Myelodysplastic Syndrome. AB - BACKGROUND: Enhancement of natural killer cell activity by blocking interactions between killer immunoglobulin (Ig)-like receptors (KIRs) and human leukocyte antigen-C (HLA-C) molecules can improve outcomes in myeloid malignancies. Lirilumab is a human IgG4 monoclonal antibody that blocks KIR/HLA-C interaction. We designed a study to evaluate the safety and efficacy of lirilumab as a single agent and in combination with azacitidine in patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Adult patients with MDS who had not received previous hypomethylating agents were included. Lower-risk MDS patients received single-agent lirilumab (3 mg/kg); higher-risk patients received azacitidine (75 mg/m2/day for 7 days) in combination with lirilumab (3 mg/kg, on day 7), in a 28-day cycle. Responses were evaluated according to 2006 International Working Group criteria. RESULTS: A total of 10 patients including 8 with higher and 2 with lower-risk enrolled. The median age was 70 (range, 50-84) years and 4 (40%) had complex cytogenetics. Baseline molecular mutations included TP53 (n = 5), TET2 (n = 3), and NRAS (n = 2). Patients received a median of 4 (range, 2-13) and 9 (range, 5-14) cycles of treatment with azacitidine with lirilumab and single-agent lirilumab, respectively. Two patients achieved complete remission (CR), 5 marrow CR, and 3 had stable disease. The median event free survival for the entire cohort was 8 months (95% confidence interval, 4 months to not reached), and the median overall survival has not yet been reached. Five patients experienced 8 episodes of Grade >=3 adverse events attributable to study drug, with the most frequent being infection or neutropenic fever (75%). CONCLUSION: Lirilumab either as a single agent as well as used in combination with azacitidine has clinical activity in patients with MDS. Further studies are needed to confirm our findings. PMID- 30001988 TI - Targeting VEGF and EGFR: a combination worth re-exploring? PMID- 30001989 TI - Non-invasive image-guided targeted drug delivery. PMID- 30001987 TI - Pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma: an open-label, phase 1b and expansion study. AB - BACKGROUND: Angiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS: We did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m2 first dose and 250 mg/m2 in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT01716416, and it is ongoing but closed to accrual. FINDINGS: Between June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m2 on day 1 of cycle 1, then cetuximab 250 mg/m2 weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19.2-54.6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab resistant disease, and five (28%) of 18 patients with platinum-resistant disease. INTERPRETATION: Pazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials. FUNDING: GlaxoSmithKline and Novartis. PMID- 30001991 TI - Pulmonary Arterial Hypertension Associated With the Chinese Herb Indigo Naturalis for Ulcerative Colitis: It May Be Reversible. PMID- 30001990 TI - Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single centre, open-label, phase 1 trial. AB - BACKGROUND: Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound. METHODS: We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged >=18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment. FINDINGS: Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3.7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2.34 MUg/g (SD 0.93) immediately after drug infusion to 8.56 MUg/g (5.69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3-4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred. INTERPRETATION: The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy. FUNDING: Oxford Biomedical Research Centre, National Institute for Health Research. PMID- 30001993 TI - Cell culture keeps pace with influenza virus. PMID- 30001992 TI - At last a step forward toward ambulatory care for endocrine surgery in France? PMID- 30001994 TI - Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. AB - BACKGROUND: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline. METHODS: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. FINDINGS: 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4.0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25.4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12.6%) were reported, and there were 4612 deaths (24.8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0.35, 95% CI 0.28-0.46) and extensively drug-resistant tuberculosis (0.26, 0.18-0.38) compared with standard regimens. INTERPRETATION: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen. FUNDING: None. PMID- 30001995 TI - Bedaquiline use in South Africa reveals a lifesaving policy in action. PMID- 30001996 TI - Tropism, replication competence, and innate immune responses of influenza virus: an analysis of human airway organoids and ex-vivo bronchus cultures. AB - BACKGROUND: Human airway organoids are three-dimensional cultures derived from stem cells, which self-organise in ex-vivo conditions to form so-called mini airways. The cellular morphology of these cultures is physiologically similar to the human airway, with cilia, goblet cells, and club cells facing the inner lumen and basal cells situated at the outer layer. The aim of this study was to compare replication competence, tissue tropism, and host responses elicited by human and avian strains of influenza A virus in ex-vivo human bronchus and human airway organoids. METHODS: Between Sept 29, 2016, and Jan 4, 2017, we obtained ex-vivo cultures of the human bronchus and cultured human airway organoids from lung stem cells obtained from human lung tissues removed as part of the routine clinical care of patients undergoing surgical resection at the Department of Cardiothoracic Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong. We compared viral replication competence, tissue tropism, and cytokine and chemokine induction of avian influenza A viruses isolated from humans (Sh2/H7N9, H5N1/483, H5N6/39715), and human H1N1pdm/415742 in airway organoids and ex-vivo bronchus explant cultures. FINDINGS: Virus tropism and replication kinetics of human and avian influenza A viruses in human airway organoids mimicked those found in ex-vivo cultures of human bronchus explants. In both airway organoids and bronchus explants, influenza A H1N1 subtype (H1N1) and avian influenza A H7N9 viruses replicated to significantly higher titres than did the highly pathogenic avian influenza (HPAI) H5N1, whereas HPAI H5N6 replication was moderate. H1N1, H7N9, and H5N6 viruses infected ciliated cells and goblet cells, but not basal cells in both airway organoids and bronchus explants. The expression of cytokines, interleukin 6, and interferon beta, and the chemokine regulated-on activation, normal T-cell expressed and secreted, was significantly higher in human airway organoids infected with HPAI H5N1 virus than H1N1pdm/415742, Sh2/H7N9, and H5N6/39715 viruses, and the expression of monocyte chemoattractant protein-1 was significantly higher in human organoids infected with HPAI H5N1 virus than H1N1pdm/415742 and Sh2/H7N9 viruses. INTERPRETATION: Human airway organoid cultures provided results that were comparable to those observed in human ex-vivo bronchus cultures, and thus provide an alternative physiologically relevant experimental model for investigating virus tropism and replication competence that could be used to assess the pandemic threat of animal influenza viruses. FUNDING: US National Institute of Allergy and Infectious Diseases, Research Grants Council of the Hong Kong Special Administrative Region. PMID- 30001998 TI - Uncovering a Role for Electronic Personal Health Records in Reducing Disparities in Sexually Transmitted Infection Rates Among Students at a Predominantly African American University: Mixed-Methods Study. AB - BACKGROUND: Black youth continue to bear an overwhelming proportion of the United States sexually transmitted infection (STI) burden, including HIV. Several studies on web-based and mobile health (mHealth) STI interventions have focused on characterizing strategies to improve HIV-related prevention and treatment interventions, risk communication, and stigma among men who have sex with men (MSM), people who use substances, and adolescent populations. The Electronic Sexual Health Information Notification and Education (eSHINE) Study was an exploratory mixed-methods study among students at a historically black university exploring perceptions on facilitating STI testing conversations with partners using electronic personal health records (PHRs). OBJECTIVE: The purpose of this paper is to use eSHINE Study results to describe perceived impacts of electronic PHRs on facilitating STI testing discussions between sexual partners. METHODS: Semistructured focus groups and individual in-depth interviews were conducted on a heterogeneous sample of students (n=35) between May and July 2014. Qualitative phase findings guided development of an online survey instrument for quantitative phase data collection. Online surveys were conducted using a convenience sample of students (n=354) between January and May 2015. Online survey items collected demographic information, sexual behaviors, beliefs and practices surrounding STI testing communication between partners, and beliefs about the impact of electronic PHR access on facilitating these discussions with partners. Chi-square analysis was performed to assess gender differences across quantitative measures. A Wilcoxon signed rank sum test was used to test the null hypothesis that electronic PHRs are believed to have no effect on the timing of dyadic STI health communication. RESULTS: Participants described multiple individual and dyadic level factors that inhibit initiating discussions about STI testing and test results with partners. Electronic PHRs were believed to improve ability to initiate conversations and confidence in STI screening information shared by partners. Among online survey participants, men were more likely to believe electronic PHRs make it easier to facilitate STI talks with potential partners (59.9% vs 51.9%; chi2=3.93, P=.05). The Wilcoxon signed-rank test results indicate significant increases in perceived discussion timing before sex with electronic PHR access (61.0% vs 40.4%; P<.001). CONCLUSIONS: Findings suggest that electronic PHR access in STI screening settings among similar populations of Black youth may improve both motivation and personal agency for initiating dyadic STI health communication. Results from this study will likely inform novel interventions that use access to electronic PHRs to stimulate important health related discussions between sexual partners. Moving forward requires studying strategies for implementing interventions that leverage electronic PHRs to create new sexual health communication channels with providers, peers, and family among black youth. PMID- 30001997 TI - Barriers to and Facilitators of Engagement With Remote Measurement Technology for Managing Health: Systematic Review and Content Analysis of Findings. AB - BACKGROUND: Remote measurement technology refers to the use of mobile health technology to track and measure change in health status in real time as part of a person's everyday life. With accurate measurement, remote measurement technology offers the opportunity to augment health care by providing personalized, precise, and preemptive interventions that support insight into patterns of health-related behavior and self-management. However, for successful implementation, users need to be engaged in its use. OBJECTIVE: Our objective was to systematically review the literature to update and extend the understanding of the key barriers to and facilitators of engagement with and use of remote measurement technology, to guide the development of future remote measurement technology resources. METHODS: We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines involving original studies dating back to the last systematic review published in 2014. We included studies if they met the following entry criteria: population (people using remote measurement technology approaches to aid management of health), intervention (remote measurement technology system), comparison group (no comparison group specified), outcomes (qualitative or quantitative evaluation of the barriers to and facilitators of engagement with this system), and study design (randomized controlled trials, feasibility studies, and observational studies). We searched 5 databases (MEDLINE, IEEE Xplore, EMBASE, Web of Science, and the Cochrane Library) for articles published from January 2014 to May 2017. Articles were independently screened by 2 researchers. We extracted study characteristics and conducted a content analysis to define emerging themes to synthesize findings. Formal quality assessments were performed to address risk of bias. RESULTS: A total of 33 studies met inclusion criteria, employing quantitative, qualitative, or mixed-methods designs. Studies were conducted in 10 countries, included male and female participants, with ages ranging from 8 to 95 years, and included both active and passive remote monitoring systems for a diverse range of physical and mental health conditions. However, they were relatively short and had small sample sizes, and reporting of usage statistics was inconsistent. Acceptability of remote measurement technology according to the average percentage of time used (64%-86.5%) and dropout rates (0%-44%) was variable. The barriers and facilitators from the content analysis related to health status, perceived utility and value, motivation, convenience and accessibility, and usability. CONCLUSIONS: The results of this review highlight gaps in the design of studies trialing remote measurement technology, including the use of quantitative assessment of usage and acceptability. Several processes that could facilitate engagement with this technology have been identified and may drive the development of more person-focused remote measurement technology. However, these factors need further testing through carefully designed experimental studies. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) CRD42017060644; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=60644 (Archived by WebCite at http://www.webcitation.org/70K4mThTr). PMID- 30002001 TI - NHS England's plan to pull the plug on ineffective procedures. PMID- 30002002 TI - An unusual localised pigmented skin lesion on the nipple-areola complex. PMID- 30002000 TI - Effect of electroacupuncture at ST36 on the intestinal mucosal mechanical barrier and expression of occludin in a rat model of sepsis. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) at ST36 on the intestinal mucosal mechanical barrier and expression of the tight junction (TJ) protein, occludin, in a rat model of sepsis. METHODS: 60 male Wistar rats were randomly divided into six groups (n=10 rats each): Control, Control+EA, CLP (caecal ligation and puncture), CLP+EA, CLP+Sham-EA, and Sham-CLP. Rats of the CLP, CLP+EA and CLP+Sham-EA groups underwent CLP modeling of sepsis; those in the Sham-CLP underwent sham surgery and those in the Control and Control+EA groups remained unoperated. Rats in the CLP+EA and Control+EA groups received verum EA at ST36 and rats in the CLP+Sham-EA groups received EA at non-traditional acupuncture points. After three days, serum D-lactate concentrations were measured and ileal mucosa was collected for haematoxylin and eosin staining, morphological observation and Chiu's scoring. The intestinal epithelial cells were observed under transmission electron microscopy (TEM), while protein expression of occludin was measured by immunohistochemistry and Western blotting. RESULTS: TJs of the Control, Sham-CLP and Control+EA groups were continuous under TEM but discontinuous in the CLP, CLP+EA and CLP+Sham-EA groups. Plasma D-lactate levels were significantly higher in the CLP, CLP+EA and CLP+Sham-EA groups compared with the Control, Sham-CLP and Control+EA groups (P<0.01). Protein expression of occludin, reflected by immunohistochemistry scores (IHS) and the results of Western blotting, were significantly reduced in the CLP, CLP+EA and CLP+Sham-EA groups when compared with the Control, Sham-CLP and Control+EA groups (P<0.01). Compared with the CLP group, the IHS and Western blotting results of the CLP+EA group were both significantly higher (P<0.05), while those of the CLP+Sham-EA group were similar to the CLP group. CONCLUSIONS: Electrical stimulation at ST36 in rats with sepsis can increase protein expression of occludin, reduce serum D-lactate levels and increase permeability of the intestinal barrier. PMID- 30001999 TI - Measurement of Symptom Change Following Web-Based Psychotherapy: Statistical Characteristics and Analytical Methods for Measuring and Interpreting Change. AB - BACKGROUND: Accurate measurement of treatment-related change is a key part of psychotherapy research and the investigation of treatment efficacy. For this reason, the ability to measure change with accurate and valid methods is critical for psychotherapy. OBJECTIVE: The aims of this study were to (1) explore the underlying characteristics of depressive symptom change, measured with the nine item Patient Health Questionnaire (PHQ-9), following psychotherapy, and (2) compare the suitability of different ways to measure and interpret symptom change. A treatment sample of Web-based psychotherapy participants (n=1098) and a waitlist sample (n=96) were used to (1) explore the statistical characteristics of depressive symptom change, and (2) compare the suitability of two common types of change functions: linear and proportional change. METHODS: These objectives were explored using hypotheses that tested (1) the relationship between baseline symptoms and the rate of change, (2) the shape of symptom score distribution following treatment, and (3) measurement error associated with linear and proportional measurement models. RESULTS: Findings demonstrated that (1) individuals with severe depressive baseline symptoms had greater reductions in symptom scores than individuals with mild baseline symptoms (11.4 vs 3.7); however, as a percentage measurement, change remained similar across individuals with mild, moderate, or severe baseline symptoms (50%-55%); (2) positive skewness was observed in PHQ-9 score distributions following treatment; and (3) models that measured symptom change as a proportional function resulted in greater model fit and reduced measurement error (<30%). CONCLUSIONS: This study suggests that symptom scales, sharing an implicit feature of score bounding, are associated with a proportional function of change. Selecting statistics that overlook this proportional change (eg, Cohen d) is problematic and leads to (1) artificially increased estimates of change with higher baseline symptoms, (2) increased measurement error, and (3) confounded estimates of treatment efficacy and clinical change. Implications, limitations, and idiosyncrasies from these results are discussed. PMID- 30002003 TI - Shared decision making won't reduce uncertainty. PMID- 30002004 TI - A comparison of evidence-based medicine practices between primary care physicians in rural and urban primary care settings in Malaysia: a qualitative study. AB - OBJECTIVE: This study aimed to compare the evidence-based practices of primary care physicians between those working in rural and in urban primary care settings. RESEARCH DESIGN: Data from two previous qualitative studies, the Front line Equitable Evidence-based Decision Making in Medicine and Creating, Synthesising and Implementing evidence-based medicine (EBM) in primary care studies, were sorted, arranged, classified and compared with the help of qualitative research software, NVivo V.10. Data categories were interrogated through comparison between and within datasets to identify similarities and differences in rural and urban practices. Themes were then refined by removing or recoding redundant and infrequent nodes into major key themes. PARTICIPANTS: There were 55 primary care physicians who participated in 10 focus group discussions (n=31) and 9 individual physician in-depth interviews. SETTING: The study was conducted across three primary care settings-an academic primary care practice and both private and public health clinics in rural (Pahang) and urban (Selangor and Kuala Lumpur) settings in Malaysia. RESULTS: We identified five major themes that influenced the implementation of EBM according to practice settings, namely, workplace factors, EBM understanding and awareness, work experience and access to specialist placement, availability of resources and patient population. Lack of standardised care is a contributing factor to differences in EBM practice, especially in rural areas. CONCLUSIONS: There were major differences in the practice of EBM between rural and urban primary care settings. These findings could be used by policy-makers, administrators and the physicians themselves to identify strategies to improve EBM practices that are targeted according to workplace settings. PMID- 30002005 TI - Protocol for a systematic review of research on HPV and cervical cancer in Ghana, up until the year 2017: informing research and policy direction on cervical cancer prevention in Ghana. AB - INTRODUCTION: For a country that lacks a national cervical cancer screening/prevention programme, there is the need to assess the volume of country specific information, and the status of research on HPV and cervical cancer, in order to provide evidence that will inform policy and further research. The aim of this protocol is to plan an intended systematic review, which is to identify research gaps, prevent unnecessary duplication of work and enable collaboration. METHODS AND ANALYSIS: This protocol, developed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols statement and registered by PROSPERO (CRD42017075583), will apply a 13-point eligibility criteria to screening and selecting peer-reviewed research articles and grey literature. These will be obtained from searches in databases, including, among others, those of the National Centre for Biotechnology Information, Cochrane Central Register of Controlled Trials, Google Scholar and the digital collections database of research publications of Universities in Ghana. Collected data will be aggregated and summarised according to emerging themes and simple descriptive statistics. ETHICS AND DISSEMINATION: The study will use publicly available data and will not identify authors of the publication by name. In light of these and as has been indicted, research ethics clearance is not required for evidence syntheses in such reviews. The review will be published in peer-reviewed scientific journals and presented at local and internal conferences as the opportunity becomes available. PROSPERO REGISTRATION NUMBER: CRD42017075583. PMID- 30002006 TI - Perceptions of patient safety culture among medical students: a cross-sectional investigation in Heilongjiang Province, China. AB - OBJECTIVES: Medical school education plays an important role in promoting patient safety. In this study, we assess medical students' perceptions of patient safety culture, identify their educational needs and provide evidence on the most important content relating to patient safety for the medical school curriculum. METHOD: This cross-sectional study was conducted in four medical universities in Heilongjiang province. Medical students in the first through five years completed an anonymous questionnaire-the Attitudes toward Patient Safety Questionnaire III. We analysed the differences in responses across the four universities and their cohorts. RESULTS: The overall perceptions of patient safety culture across the four medical universities were positive. The highest positive response rate was for 'I have a good understanding of patient safety issues as a result of my undergraduate medical training' (range: 58.4%-99.8%), whereas the lowest positive response rate was for 'medical errors are a sign of incompetence' (14.7%-47.9%). Respondents in the earlier years of school tended to have more positive responses for items concerning working hours and team work; however, fourth and fifth year students had more positive responses for error inevitability. Items with the lowest positive response rates across the cohorts included items related to 'professional incompetence as a cause of error' and 'disclosure responsibility'. CONCLUSIONS: While students generally had positive views of patient safety culture, none of them had been exposed to any formal curriculum content on patient safety. Policymakers should focus more on how educational needs vary across schools and cohorts in order to establish appropriate curricula. PMID- 30002008 TI - Organisational interventions designed to reduce caesarean section rates: a systematic review protocol. AB - INTRODUCTION: There is a growing body of evidence to indicate that both primary and subsequent caesarean sections are associated with increased maternal and perinatal morbidity. Efforts to reduce the number of clinically unnecessary caesarean sections are urgently required. Our objective is to systematically review published evidence on the effectiveness of maternity service organisational interventions, such as models of maternity care, that aim to reduce caesarean section rates. METHODS AND ANALYSIS: Databases will be searched, including the Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, MEDLINE, Maternity and Infant Care, EMBASE and SCOPUS. Search terms related to caesarean section and organisational intervention will be used. Research published before 1980 will be excluded and only randomised controlled trials, cluster-randomised controlled trials, quasi randomised controlled trials, controlled before and after studies and interrupted time series studies will be included. Data extraction and quality assessments will be undertaken by two authors. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review. The results of this study will be disseminated via peer-reviewed publication and presentation at professional conferences. PROSPERO REGISTRATION NUMBER: CRD42016039458. PMID- 30002007 TI - Antivirals for influenza-Like Illness? A randomised Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4 E): the ALIC4 E protocol. AB - INTRODUCTION: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. METHODS AND ANALYSIS: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants >=1 year presenting with influenza-like illness (ILI), with symptom duration <=72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost effectiveness, benefits in subgroups according to age (<12, 12-64 and >64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (<=48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. ETHICS AND DISSEMINATION: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN27908921; Pre-results. PMID- 30002010 TI - Effect of the 2016 Kumamoto earthquakes on preventable hospital admissions: a retrospective cohort study in Japan. AB - BACKGROUND AND OBJECTIVES: The Kumamoto earthquakes struck Kumamoto prefecture, in the southwest part of Japan in April 2016. Physical and mental disorders presenting to hospital increased after the 2016 Kumamoto earthquakes. Impaired access to primary care due to the earthquakes may have contributed to this increase. However, it is not known whether the 2016 Kumamoto earthquakes affected access to primary care. The objective of the present study was to investigate the impact of the 2016 Kumamoto earthquakes on short-term health conditions by analysing ambulatory care sensitive conditions (ACSCs), using administrative data from Kumamoto prefecture. DESIGN: A retrospective cohort study. SETTING: Residents enrolled in National Health Insurance or Late Elders' Health Insurance from Kumamoto prefecture, Japan. PARTICIPANTS: All hospital admissions due to ACSCs between 15 March and 16 May in each year from 2013 to 2016. OUTCOME MEASURES: ACSCs are defined as conditions for which appropriate primary care interventions could prevent admission to the hospital. RESULTS: We identified a total of 7921, 18 763 and 85 436 admissions for vaccine, acute and chronic preventable ACSCs, respectively, during the study period. Admissions within 7 days after the 2016 Kumamoto earthquakes increased to 32.6% (10.2, 59.5), 44.1% (27.0, 63.5) and 27.7% (20.2, 35.6) for vaccine-preventable, acute and chronic ACSCs, respectively. However, admissions for ACSCs did not change significantly 30 days after the earthquakes. CONCLUSION: The 2016 Kumamoto earthquakes were associated with increased hospital admissions for ACSCs. The impact of the earthquakes on admissions for ACSCs did not persist for more than 7 days. PMID- 30002009 TI - What can we learn from top-cited articles in inflammatory bowel disease? A bibliometric analysis and assessment of the level of evidence. AB - BACKGROUND AND OBJECTIVES: Despite increasing number of publications in inflammatory bowel disease (IBD), no bibliometric analysis has been conducted to evaluate the significance of highly cited articles. Our objectives were to identify the top-cited articles in IBD, assessing their characteristics and determining the quality of evidence provided by these articles. DESIGN AND OUTCOME MEASURES: IBD and related terms were used in searching the Web of Science to identify English language articles. The 50 top-cited articles were analysed by year, journal impact factor (JIF), authorship, females in authorship, institute, country and grants received. The level of evidence was determined using the Oxford Centre for Evidence-Based Medicine guidelines. RESULTS: The number of citations varied from 871 to 3555 with a total of 74 638, and a median 1339.50 (IQR=587). No correlations were found between the number of citations and number of years since publication (r=0.042, p=0.771), JIF (r=0.186, p=0.196), number of authors (r=0.061, p=0.674), females in authorship (r=0.064, p=0.661), number of institutes (r=0.076, p=0.602), number of countries (r=0.101, p=0.483) or number of grants (r=-0.015, p=0.915). The first authors were from the USA (n=24), the UK (n=6), Germany (n=5), France (n=5), Belgium (n=3) and Canada (n=3). The levels of evidence were 12 articles at level 1b, 9 articles at level 3a and 15 articles at level 3b and fewer were at other levels. CONCLUSIONS: Research papers represented 66% of articles. The majority of items have reasonably high levels of evidence, which may have contributed to the higher number of citations. The study also shows a gender gap in authorship in this area. PMID- 30002011 TI - Diabetes Shared Care Program (DSCP) and risk of infection mortality: a nationwide cohort study using administrative claims data in Taiwan. AB - OBJECTIVE: The Diabetes Shared Care Program (DSCP) is an integrated care model in Taiwan that has been proven to improve the care quality of patients with diabetes. We aimed to evaluate the efficacy of DSCP in decreasing the hospital mortality of infectious diseases. METHODS: From 1 662 929 patients with type 2 diabetes newly diagnosed between 1999 and 2013, we retrieved a total of 919 patients who participated in the DSCP with the first hospitalisation for an infectious disease as the study cohort and 9190 propensity score-matched patients with type 2 diabetes who did not participate as the comparison.The efficacy of DSCP was evaluated via the following comparisons between the DSCP and non-DSCP cohorts: hospital mortality, 1-year medical cost prior to and during the hospitalisation, and complications, such as receiving mechanical ventilation and intensive care unit admission. The ratio (OR) for hospital mortality of the DSCP participants was calculated by logistical regression. Further stratification analyses were conducted to examine which group of patients with type 2 diabetes benefited the most from the DSCP during hospitalisation for infectious diseases. RESULTS: The DSCP cohort had a lower hospital mortality rate than the non-DSCP participants (2.18% vs 4.82%, p<0.001). The total medical cost during the hospitalisation was lower in the DSCP cohort than in the non-DSCP cohort (NT$72 454+/-30 429 vs NT$86 385+/-29 350) (p=0.006). In the logistical regression model, the DSCP participants exhibited a significantly decreased adjusted OR for hospital mortality (adjusted OR=0.42, 95% CI 0.26 to 0.66, p=0.0002). The efficacy of the DSCP was much more prominent in male patients with type 2 diabetes and in patients with lower incomes. CONCLUSION: Participation in the DSCP was associated with a lower risk of hospital mortality for infectious diseases. PMID- 30002012 TI - How does the UK childcare energy-balance environment influence anthropometry of children aged 3-4 years? A cross-sectional exploration. AB - OBJECTIVES: To assess the association between time spent in care, the childcare energy-balance environment, and preschool-aged children's body mass index z-score (z-BMI), waist-to-height ratio (WHR) and sum of skinfold thickness (SST). DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Children aged 3-4 years were recruited from 30 childcare centres in Cambridgeshire (UK) in 2013. MAIN OUTCOME MEASURES: Objectively measured height and weight was used to calculate z-BMI; waist circumference and height were used to generate WHR; subscapular and tricep skinfolds were used to calculate SST. Associations between childcare attendance, the nutrition, physical activity, and overall childcare environment, and three anthropometric outcomes were explored using two-level hierarchical regression models, adjusting for demographic and family based confounders. RESULTS: Valid data were available for 196 children (49% female). Time spent in care, the nutrition, physical activity and overall childcare environment were not associated with children's z-BMI, WHR and SST. CONCLUSIONS: Childcare environment and level of attendance were not associated with UK preschool-aged children's anthropometry. The childcare environment has been central to intervention efforts to prevent/reduce early childhood obesity, yet other factors, including child level, family level, wider environmental and policy-level factors warrant substantial attention when considering obesity prevention strategies for young children. PMID- 30002013 TI - An adapted instrument to assess informed consent comprehension among youth and parents in rural western Kenya: a validation study. AB - OBJECTIVE: To adapt and validate a questionnaire originally developed in a research setting for assessment of comprehension of consent information in a different cultural and linguistic research setting. DESIGN: The adaptation process involved development and customisation of a questionnaire for each of the three study groups, modelled closely on the previously validated questionnaire. The three adapted draft questionnaires were further reviewed by two bioethicists and the developer of the original questionnaire for face and content validity. The revised questionnaire was subsequently programmed into an audio computerised format, with translations and back translations in three widely spoken languages by the study participants: Luo, Swahili and English. SETTING: The questionnaire was validated among adolescents, their parents and young adults living in Siaya County, a rural region of western Kenya. PARTICIPANTS: Twenty-five-item adapted questionnaires consisting of close-ended, multiple-choice and open-ended questions were administered to 235 participants consisting of 107 adolescents, 92 parents and 36 young adults. Test-retest was conducted 2-4 weeks after first questionnaire administration among 74 adolescents, young adults and parents. OUTCOME MEASURE: Primary outcome measures included ceiling/floor analysis to identify questions with extremes in responses and item-level correlation to determine the test-retest relationships. Given the data format, tetrachoric correlations were conducted for dichotomous items and polychoric correlations for ordinal items. The qualitative validation assessment included face and content validity evaluation of the adapted instrument by technical experts. RESULTS: Ceiling/floor analysis showed eight question items for which >80% of one or more groups responded correctly, while for nine questions, including all seven open ended questions,<20% responded correctly. Majority of the question items had moderate to strong test-retest correlation estimates indicating temporal stability. CONCLUSIONS: Our study demonstrates that cross-cultural adaptation and validation of an informed consent comprehension questionnaire is feasible. However, further research is needed to develop a tool which can estimate a quantifiable threshold of comprehension thereby serving as an objective indicator of the need for interventions to improve comprehension. PMID- 30002015 TI - Recurrent lower respiratory tract infections in children. PMID- 30002014 TI - Comparison at the first prenatal visit of the maternal dietary intakes of smokers with non-smokers in a large maternity hospital: a cross-sectional study. AB - OBJECTIVES: Using detailed dietary and supplement questionnaires in early pregnancy, we compared the dietary intakes of micronutrients and macronutrients at the first prenatal visit of women who reported continuing to smoke during pregnancy with the intakes of women who were non-smokers. DESIGN: Cross-sectional study conducted between June 2014 and March 2016. SETTING: Stand-alone tertiary maternity hospital in an urban setting with approximately 8000 deliveries per year. PARTICIPANTS: Women were recruited at their convenience after sonographic confirmation of an ongoing singleton pregnancy (n=502). Detailed dietary and supplement information was available for 398 women. Women <18 years and those who did not speak English fluently were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The differences in dietary micronutrients and macronutrients and maternal folate levels between women who continued to smoke in pregnancy compared with non-smokers. RESULTS: Of the 502 women, the mean age was 30.5 (SD 5.6) years, 42.5% were nulliparas, 19.2% were obese and 398 (79.3%) completed the questionnaire satisfactorily. In the 50 (12.6%) current smokers, the micronutrients magnesium, iron, carotene and copper were lower (all p<0.005) whereas sodium and chloride were higher compared with the 348 (87.4%) non smokers. Smokers reported lower intakes of dietary total folate (p=0.006) compared with non-smokers (i.e., dietary folate equivalents; intake from natural and fortified dietary sources) (p=0.005). Smokers also reported lower intakes of fibre than non-smokers (13.1 g (IQR 7.7) vs 16.3 g (IQR 8.5), p<0.001). The dietary intakes of former smokers compared favourably with non-smokers. CONCLUSIONS: We found that women who continue to smoke during pregnancy have serious dietary inadequacies which could potentially aggravate fetal growth restriction associated with direct toxicity from cigarettes. This provides a further reason to promote smoking cessation interventions in pregnancy, and highlights the need for dietary and supplementation interventions in women who continue to smoke. PMID- 30002016 TI - Healthy people, healthy animals, and a healthy environment: One Health. PMID- 30002017 TI - Tests for diagnosing and monitoring non-alcoholic fatty liver disease in adults. PMID- 30002019 TI - ? PMID- 30002020 TI - Relapsing polychondritis case. PMID- 30002018 TI - Family medicine, fast and slow. PMID- 30002021 TI - Working together. PMID- 30002022 TI - Primary care and the RCMP: Unexpected partnership in opioid harm reduction. PMID- 30002024 TI - Radon gas-the hidden killer: What is the role of family doctors? AB - OBJECTIVE: To create awareness of the dangers of radon gas and to provide family physicians with updated, practical information to help educate patients. SOURCES OF INFORMATION: MEDLINE (1950 to February 2013), the Cochrane Database of Systematic Reviews (2005 to 2013), and the Cochrane Central Register of Controlled Trials (2005 to 2013) were searched using relevant terms. Guidelines, position statements, articles, and original research relevant to radon were selected. MAIN MESSAGE: Radon is the principal cause of lung cancer in non smokers and the second most common cause in smokers (1 in 20 and 1 in 3, respectively), and lifetime risk increases in a linear fashion with radon exposure. In outdoor air, radon is diluted and is not a health concern, but as it diffuses into houses, the gas accumulates, reaching high concentrations, and becomes a health hazard. The Canadian guideline for the maximum acceptable concentration for indoor air is 200 Bq/m3, and there are cost-effective methods available to reduce radon gas when high levels are found in dwellings. CONCLUSION: Family physicians play a fundamental role in the prevention of radon related lung cancer by educating their patients, guiding them about specific preventive actions, and advocating on patients' behalf. PMID- 30002023 TI - Approach to tinnitus management. AB - OBJECTIVE: To provide family physicians with an evidence-based and practical approach to managing patients with tinnitus. SOURCES OF INFORMATION: MEDLINE was searched for English-language tinnitus guidelines and reviews. All such articles published between 1980 and 2016 were reviewed, with most providing level II and III evidence. MAIN MESSAGE: Tinnitus affects more than 40% of Canadians at least once in their lifetimes, most commonly older adults. Tinnitus is the perception of sound without external stimulation. It can greatly affect a patient's physical and psychological quality of life. Clinical history taking is directed at eliciting whether symptoms have a pulsatile or nonpulsatile quality, whether symptoms are unilateral or bilateral, and whether there is associated hearing loss. For tinnitus that is pulsatile or unilateral, referral to an otolaryngologist is recommended, as these qualities might be associated with more serious underlying conditions. Most patients with tinnitus can be managed with reassurance, conservative measures, and hearing aids if substantial hearing loss exists. CONCLUSION: Family physicians play the primary role in managing patients with tinnitus and are well situated to address both the physiologic and the psychological manifestations. As tinnitus is very common, helping patients cope with the symptoms through conservative measures and reassurance can prove to have the best outcomes. PMID- 30002027 TI - Consciousness with cardiopulmonary resuscitation. PMID- 30002026 TI - Effect of human papillomavirus vaccination on sexual behaviour among young females. AB - Question At the time of implementation of human papillomavirus (HPV) vaccine immunization programs, concerns were raised by parents, clinicians, and public health professionals about HPV vaccination possibly leading to riskier sexual health choices among young females. If HPV vaccination influences sexual behaviour among vaccinated females, this might influence the effect of HPV vaccination programs. What is known about the effects of the HPV vaccination program on sexual behaviour among young females?Answer Human papillomavirus vaccination has not been associated with increased sexual risk behaviour among young females. However, currently available studies have some important limitations, and future studies should focus on a longitudinal design that includes a prevaccination baseline measurement, adjustment for possible confounders, and measurement of both clinical indicators and behavioural outcomes. PMID- 30002025 TI - Screening: when things go wrong. PMID- 30002028 TI - Disclosing a diagnosis of dementia. PMID- 30002029 TI - Evidence for THC versus CBD in cannabinoids. PMID- 30002031 TI - Gratitude. PMID- 30002032 TI - Practice sharing among residents in a family medicine teaching unit. PMID- 30002030 TI - Future practice of comprehensive care: Practice intentions of exiting family medicine residents in Canada. AB - OBJECTIVE: To describe exiting family medicine (FM) residents' reported practice intentions after completing a Triple C Competency-based Curriculum. DESIGN: The surveys were intended to capture residents' perceptions of FM, their perceptions of their competency-based training, and their intentions to practise FM. Entry (T1) and exit (T2) self-reported survey results were compared considering the influence of the curriculum change. Unmatched aggregate-level data were reviewed. The T1 survey was administered in the summer of 2012 and the T2 survey was administered in the spring of 2014. SETTING: Six Canadian FM residency programs across 4 provinces in Canada (Alberta, Saskatchewan, Ontario, and Quebec). PARTICIPANTS: Overall, 341 entering FM residents in 2012 responded to the T1 survey and 325 exiting FM residents completing their residency programs in spring 2014 responded to the T2 survey. MAIN OUTCOME MEASURES: Self-reported data on FM residents' future practice intentions related to comprehensive care, providing care across clinical domains and settings, and providing comprehensive care individually or in teams. RESULTS: A total of 341 (71.3%) residents responded to the T1 survey and a total of 325 (71.4%) residents responded to the T2 survey. Of these, 78.7% responded that they intended to provide comprehensive FM in multiple clinical settings in their future practices, with 70.8% indicating a comprehensive care practice with a special interest and 36.6% intending to provide care in a focused practice. Overall, 92.9% reported that they intended to work in group practice environments. Ninety percent reported they intended to work in interprofessional team practices. CONCLUSION: While an upward trend toward the practice of comprehensive care was demonstrated, findings also showed an increased trend toward providing care in focused practices. Further research is needed to better determine how FM residents understand the definition of comprehensive FM and its practice models. The survey provides an opportunity to explore questions related to practice intentions that could be helpful in work force planning. As the first study to compare entry and exit data from learners who have been exposed to a Triple C competency-based approach, this survey provides important baseline data for use by many. PMID- 30002033 TI - Defining the added value of family medicine. PMID- 30002034 TI - ? PMID- 30002035 TI - ? PMID- 30002036 TI - Progress on CFPC governance. PMID- 30002037 TI - ? PMID- 30002038 TI - ? PMID- 30002039 TI - ? PMID- 30002040 TI - ? PMID- 30002042 TI - Large pertussis outbreak in rural Canada: Lessons learned from Haida Gwaii. AB - OBJECTIVE: To present characteristics of and response to a large outbreak of pertussis on Haida Gwaii, BC, in 2014. DESIGN: Quantitative descriptive review. SETTING: Haida Gwaii, a remote island archipelago located 100 km off of British Columbia's west coast. PARTICIPANTS: All patients presenting with symptoms evaluated for pertussis on Haida Gwaii between February and August 2014. MAIN OUTCOME MEASURES: The primary outcome measures included the demographic characteristics, time course, and morbidity of the outbreak. The secondary outcome measures included the laboratory result reports, the effects on clinician workload, and the treatment and prophylaxis practices. Statistical analysis for significance of pertussis severity and immunization status was performed with a maximum-likelihood framework. RESULTS: Between February and August 2014, out of 873 clinical encounters, 579 patients were seen for pertussis-related care. Of these, 260 patients were reported to public health for case identification, contact tracing, and follow-up. There were 123 cases of probable and confirmed pertussis, a case rate of 2795 cases per 100 000 population. Of these 123 cases, 91 had a cough of more than 2 weeks' duration. A subset of patients presented with mild symptoms, atypical of pertussis. Nasopharyngeal swabs were collected on 221 occasions, 378 antibiotic prescriptions were written, and 248 prophylactic immunizations were given. The odds ratio that previous immunization protected against the development of classic pertussis was 0.23; however, statistical significance was not reached (P = .112). CONCLUSION: Pertussis is resurging. Physicians need to remain vigilant for its characteristic symptoms. Clear and standardized criteria for the declaration of an outbreak should be developed. To contain an outbreak, it is crucial to deploy resources commensurate with disease activity while coordinating public health and primary care. More research into why large outbreaks continue to occur, why endemic rates continue to rise, and how these can be most effectively prevented is essential. PMID- 30002041 TI - "People in regular society don't think you can be a good mother and have a substance use problem": Participatory action research with women with substance use in pregnancy. AB - OBJECTIVE: To work collaboratively with women accessing an integrated program for women with substance use in pregnancy to learn how services can be improved. DESIGN: Qualitative design using focus groups within a participatory action framework. SETTING: Sheway, a program located in the Downtown Eastside of Vancouver, BC. PARTICIPANTS: A total of 21 co-researchers who were women who had accessed Sheway services. METHODS: Semistructured focus groups were recorded and transcribed. Data analysis was iterative and reviewed weekly with focus group members. Themes were member checked and reviewed with co-researchers. The action phase of the project involved the co-researchers presenting their main findings to the Sheway staff members. The staff and women worked collaboratively to implement client-directed changes to the program. MAIN FINDINGS: Co-researchers described Sheway as family. They expressed concern about transitioning from the program to other community services and identified stereotypes and negative treatment by health care providers as barriers to their transition out of the program. One action project developed by the co-researchers was a "transition group" where women could connect to current and former Sheway clients. The women could retain the social support they gained through Sheway while learning about other resources. The co-researchers also prioritized developing peer-to-peer mentorship to support new clients. The findings of the research were disseminated to Sheway staff, the Department of Family Practice at the University of British Columbia, and local family medicine maternity care providers with the hope of improving care for women with substance use in pregnancy. CONCLUSION: A participatory action framework allowed women to engage as co-researchers. The co researchers emphasized the importance of relationships and a sense of family with other women as well as providers as positive aspects of their care. Women involved in this project identified negative attitudes of health care providers toward substance use in pregnancy as barriers. Co-researchers proposed transition support and peer-to-peer networking as action projects to improve their care. PMID- 30002044 TI - Roring ahead with DOCK2. PMID- 30002043 TI - ? PMID- 30002045 TI - FDG-PET in PMBCL: which heterogeneity? PMID- 30002046 TI - Prognosis interfered with by clonal interference. PMID- 30002048 TI - Internuclear bridging outside of primary myelodysplasia and congenital dyserythropoietic anemia. PMID- 30002047 TI - Progress with pathogen-reduced blood. PMID- 30002049 TI - Terness P, Navolan D, Opelz G, Roelcke D. Inverse association between IgG-anti kappa and antierythrocyte autoantibodies in patients with cold agglutination. Blood. 1999;94(12):4343-4346. PMID- 30002050 TI - Rheumatoid arthritis: goal should be remission or low disease activity, says NICE. PMID- 30002051 TI - Ultrafast Brain MRI Can Be Used for Indications beyond Shunted Hydrocephalus in Pediatric Patients. AB - BACKGROUND AND PURPOSE: Evaluation of shunted hydrocephalus is the most common indication for ultrafast brain MRI. Radiation-/sedation-free imaging capabilities make this protocol more desirable over CT and standard brain MRI. We hypothesized that ultrafast brain MRI can be used for selected indications beyond shunted hydrocephalus without adverse outcomes. MATERIALS AND METHODS: Ultrafast brain MRI was performed with axial, sagittal, and coronal HASTE. The radiology information system was used to identify pediatric patients (0-18 years of age) who underwent ultrafast brain MRI between March 2014 and May 2016. A retrospective chart review was completed to identify indications other than shunted hydrocephalus, such as ventriculomegaly, macrocephaly, or intracranial cyst. All ultrafast brain MRIs were evaluated by a certified neuroradiologist and a neurosurgeon. Ultrafast brain MRI was deemed of sufficient diagnostic value for these indications if no further standard brain MRI was required for the study indication or if additional imaging was performed for an alternate indication. RESULTS: The radiology information system identified 800 patients who had undergone an ultrafast brain MRI during the study period. One hundred twenty-two of these patients had ventriculomegaly, macrocephaly, or intracranial cyst as the study indication. Twenty-one of the 122 patients were excluded due to insufficient follow-up. Of the remaining 101 patients, only 5 had a standard brain MRI for the same indication, with no additional clinically significant information identified on those studies. CONCLUSIONS: These results suggest that ultrafast brain MRI is sufficient to evaluate ventriculomegaly, macrocephaly, or intracranial cyst. Ultrafast brain MRI is radiation- and sedation-free; therefore, we recommend its use as the primary screening neuroimaging study for these indications. PMID- 30002052 TI - Application of 3D Fast Spin-Echo T1 Black-Blood Imaging in the Diagnosis and Prognostic Prediction of Patients with Leptomeningeal Carcinomatosis. AB - BACKGROUND AND PURPOSE: Contrast-enhanced 3D fast spin-echo T1 black-blood imaging selectively suppresses the signal of blood flow and could provide a higher contrast-to-noise ratio compared with contrast-enhanced 3D ultrafast gradient recalled echo (contrast-enhanced gradient recalled echo) and 2D spin echo T1WI (contrast-enhanced spin-echo). The purpose of our study was to evaluate whether black-blood imaging can improve the diagnostic accuracy for leptomeningeal carcinomatosis compared with contrast-enhanced gradient recalled echo and contrast-enhanced spin-echo and, furthermore, to determine whether the grade of leptomeningeal carcinomatosis evaluated on black-blood imaging is a significant predictor of progression-free survival. MATERIALS AND METHODS: Leptomeningeal carcinomatosis (n = 78) and healthy (n = 31) groups were enrolled. Contrast-enhanced gradient recalled-echo, contrast-enhanced spin-echo, and black blood imaging were separately reviewed, and a diagnostic rating (positive, indeterminate, or negative) and grading of leptomeningeal carcinomatosis were assigned. The diagnostic accuracies of the 3 imaging sequences were compared in terms of leptomeningeal carcinomatosis detection. The Kaplan-Meier and the Cox proportional hazards model analyses were performed to determine the relationship between the leptomeningeal carcinomatosis grade evaluated on black-blood imaging and progression-free survival. RESULTS: Black-blood imaging showed a significantly higher sensitivity (97.43%) than contrast-enhanced gradient recalled-echo (64.1%) and contrast-enhanced spin-echo (66.67%) (P < .05). In terms of specificities, we did not find any significant differences among contrast-enhanced gradient recalled-echo (90.32%), contrast-enhanced spin-echo (90.32%), and black-blood imaging (96.77%) (P > .05). A Cox proportional hazards model identified the time to metastasis, Karnofsky Performance Scale status, and a combination of the leptomeningeal carcinomatosis grade with a linear pattern as independent predictors of progression-free survival (P < .05). CONCLUSIONS: Black blood imaging can improve the diagnostic accuracy and predict progression-free survival in patients with leptomeningeal carcinomatosis. PMID- 30002053 TI - Clinical Utility of a Novel Ultrafast T2-Weighted Sequence for Spine Imaging. AB - BACKGROUND AND PURPOSE: TSE-based T2-weighted imaging of the spine has long scan times. This work proposes a fast imaging protocol using variable refocusing flip angles, optimized for blurring and specific absorption rate. MATERIALS AND METHODS: A variable refocusing flip angle echo-train was optimized for the spine to improve the point spread function and minimize the specific absorption rate, yielding images with improved spatial resolution and SNR compared with the constant flip angle sequence. Data were acquired from 51 patients (35 lumbar, 16 whole-spine) using conventional TSE and the proposed sequence, with a single-shot variant for whole-spine. Noninferiority analysis was performed to evaluate the efficiency of the proposed technique. RESULTS: The proposed multishot sequence resulted in a 2* shorter scan time with a >1.5* lower specific absorption rate. The variable flip angle sequence was noninferior to the conventional TSE (P < .025) for all image-quality and clinical criteria except signal-to-noise ratio for the lumbar spine protocol. However, mean image scores for the TSE-variable refocusing flip angle were >=4.3 for all criteria, and concordance analysis showed high agreement (>90%) with the TSE, indicating clinical equivalence. The single-shot sequence resulted in 4* shorter whole-spine scans, and image scores were >=4.4 for all criteria, attesting to its clinical utility. CONCLUSIONS: We present a fast T2-weighted spine protocol using variable refocusing flip angles, including a single-shot variant. The sequences have better point spread function behavior than their constant flip angle counterparts and, being faster, should be less sensitive to patient motion, often seen in the longer TSE scans. PMID- 30002054 TI - Preoperative Mapping of the Supplementary Motor Area in Patients with Brain Tumor Using Resting-State fMRI with Seed-Based Analysis. AB - BACKGROUND AND PURPOSE: The supplementary motor area can be a critical region in the preoperative planning of patients undergoing brain tumor resection because it plays a role in both language and motor function. While primary motor regions have been successfully identified using resting-state fMRI, there is variability in the literature regarding the identification of the supplementary motor area for preoperative planning. The purpose of our study was to compare resting-state fMRI to task-based fMRI for localization of the supplementary motor area in a large cohort of patients with brain tumors presenting for preoperative brain mapping. MATERIALS AND METHODS: Sixty-six patients with brain tumors were evaluated with resting-state fMRI using seed-based analysis of hand and orofacial motor regions. Rates of supplementary motor area localization were compared with those in healthy controls and with localization results by task-based fMRI. RESULTS: Localization of the supplementary motor area using hand motor seed regions was more effective than seeding using orofacial motor regions for both patients with brain tumor (95.5% versus 34.8%, P < .001) and controls (95.2% versus 45.2%, P < .001). Bilateral hand motor seeding was superior to unilateral hand motor seeding in patients with brain tumor for either side (95.5% versus 75.8%/75.8% for right/left, P < .001). No difference was found in the ability to identify the supplementary motor area between patients with brain tumors and controls. CONCLUSIONS: In addition to task-based fMRI, seed-based analysis of resting-state fMRI represents an equally effective method for supplementary motor area localization in patients with brain tumors, with the best results obtained with bilateral hand motor region seeding. PMID- 30002055 TI - Clinically Relevant Imaging Features for MGMT Promoter Methylation in Multiple Glioblastoma Studies: A Systematic Review and Meta-Analysis. AB - BACKGROUND: O6-methylguanine methyltransferase (MGMT) promoter methylation status has been reported as a prognostic biomarker in clinical trials. PURPOSE: Our aim was to systematically evaluate imaging features of MGMT promoter methylated glioblastoma and to determine the diagnostic performance of MR imaging for prediction of MGMT promoter methylation in patients with newly diagnosed glioblastoma. DATA SOURCES: A computerized search of Ovid MEDLINE and EMBASE up to February 27, 2018, was conducted. STUDY SELECTION: We selected studies evaluating imaging features of MGMT promoter methylated glioblastoma and the diagnostic performance of MR imaging for prediction of MGMT promoter methylation. DATA ANALYSIS: Pooled estimates of sensitivity and specificity were calculated using a hierarchic logistic regression model. Meta-regression and sensitivity analysis were performed. DATA SYNTHESIS: Twenty-two articles including 2199 patients were included. MGMT promoter methylated glioblastoma is likely to show less edema, high ADC, and low perfusion. Ten articles including 753 patients were included in the meta-analysis. The summary sensitivity was 79% (95% CI, 72%-85%), and the summary specificity was 78% (95% CI, 71%-84%). In the meta-regression, MGMT promoter methylation and mean age were associated with heterogeneity. Sensitivity analysis excluding 1 study resolved the heterogeneity. LIMITATIONS: Included studies used a variety of different MR imaging techniques to predict MGMT promoter methylation. CONCLUSIONS: MGMT promotor methylated glioblastoma is likely to show less aggressive imaging features than MGMT promotor unmethylated glioblastoma. Despite the variety of different MR imaging techniques used, MR imaging in patients with newly diagnosed glioblastoma was shown to have the potential to predict MGMT promoter methylation noninvasively. PMID- 30002056 TI - Academics who raised concerns about research misconduct are threatened with lawsuit. PMID- 30002057 TI - Persuading the public that less is more. PMID- 30002058 TI - Abdominal Aortic Aneurysms Growth Is Associated With High Concentrations of Plasma Proteins in the Intraluminal Thrombus and Diseased Arterial Tissue. AB - Objective- Porosity of the intraluminal thrombus (ILT) is believed to convey biologically active components from the bloodstream toward the aneurismal wall. Accumulation of molecules in the abdominal aortic aneurysmatic tissue may influence vascular protein turnover and regulate abdominal aortic aneurysm growth. We sought to identify proteins with concentrations in the ILT and the abdominal aortic aneurysm wall which associate with aneurysmal expansion rate. Approach and Results- Proteomic analysis by liquid chromatography tandem-mass spectrometry of separated wall and ILT samples was correlated with preoperative aneurysmal growth rate in 24 individuals operated electively for infrarenal abdominal aortic aneurysm. The median preoperative growth rate was 3.8 mm/y (interquartile range, 3) and the mean observational time was 3.3+/-1.7 years. Plasma components dominated the group of proteins with tissue concentrations, which correlate positively with growth rates ( P<0.001, Fisher exact test, both in the ILT and the wall). In contrast, in the wall and thrombus samples, ECM (extracellular matrix) proteins were significantly more prevalent in the group of proteins with negative correlations to growth rates ( P<0.05, Fisher exact test). Similarly, a long series of proteins, related to cellular functions correlated negatively to growth rates. Conclusions- When the preoperative aneurysmatic growth rate has been high, the concentration of many plasma proteins residing in the ILT and the aneurysmatic tissue is also high, compatible with the hypothesis of increased tissue porosity and accumulation of plasma components as a driver of aneurysm expansion. Moreover, many matrix and cellular proteins which are found in high concentrations in slower-growing aneurysms provides new knowledge about potential treatment targets. PMID- 30002059 TI - Synthesis of Extracellular Pyrophosphate Increases in Vascular Smooth Muscle Cells During Phosphate-Induced Calcification. AB - Objective- Hydroxyapatite deposition on the medial layer of the aortic walls is the hallmark of vascular calcification and the most common complication in aging individuals and in patients with diabetes mellitus and those undergoing hemodialysis. Extracellular pyrophosphate is a potent physicochemical inhibitor of hydroxyapatite crystal formation. This study analyzed changes in extracellular pyrophosphate metabolism during the phosphate-induced calcification process. Approach and Results- Phosphate-induced calcification of ex vivo-cultured aortic rings resulted in calcium accumulation after 7 days. This accumulation was enhanced when aortic walls were devitalized. BMP2 (bone morphogenic protein 2) expression was associated with calcium accumulation in cultured aortic rings, as well as in cultured vascular smooth muscle cells (VSMCs) and in calcitriol induced calcification in rats. Hydroxyapatite dose dependently induced BMP2 overexpression in VSMCs. Moreover, TNAP (tissue nonspecific alkaline phosphatase) mRNA levels and activity were found to be downregulated in early phases and upregulated in later phases of calcification in all 3 models studied. eNPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) increased from early to later phases of calcification, whereas eNTPD1 (ectonucleoside triphosphate diphosphohydrolase 1) was downregulated during later phases. Synthesis of pyrophosphate in VSMCs increased significantly over time, in all 3 models studied. Because the rate of pyrophosphate hydrolysis was 10* slower than the rate of pyrophosphate synthesis, pyrophosphate synthesis is determined mainly by the ratio of eNPP1 to eNTPD1 activity. Hydroxyapatite also induces increments both in TNAP and eNPP1/eNTPD1 ratio in VSMCs. Conclusions- Pyrophosphate synthesis increases in VSMCs during phosphate-induced calcification because of compensatory regulation of extracellular pyrophosphate metabolism. PMID- 30002061 TI - Cystathionine gamma-Lyase Modulates Flow-Dependent Vascular Remodeling. AB - Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine gamma-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE -/- mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57BL/6J but not CSE-/- mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE-/- endothelial cells showed reduced NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE-/- mice showed reduced inward remodeling after partial carotid ligation. CSE-/- mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro 4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE-/- mice. Conclusions CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability. PMID- 30002060 TI - Investigating the Role of G Protein betagamma in Kv7-Dependent Relaxations of the Rat Vasculature. AB - Objective- In renal arteries, inhibitors of G protein betagamma subunits (Gbetagamma) reduce Kv7 activity and inhibit Kv7-dependent receptor-mediated vasorelaxations. However, the mechanisms underlying receptor-mediated relaxation are artery specific. Consequently, the aim of this study was to ascertain the role of Gbetagamma in Kv7-dependent vasorelaxations of the rat vasculature. Approach and Results- Isometric tension recording was performed in isolated rat renal, mesenteric, and cerebral arteries to study isoproterenol and calcitonin gene-related peptide relaxations. Kv7.4 was knocked down via morpholino transfection while inhibition of Gbetagamma was investigated with gallein and M119K. Proximity ligation assay was performed on isolated myocytes to study the association between Kv7.4 and G protein beta subunits or signaling intermediaries. Isoproterenol or calcitonin gene-related peptide-induced relaxations were attenuated by Kv7.4 knockdown in all arteries studied. Inhibition of Gbetagamma with gallein or M119K had no effect on isoproterenol mediated relaxations in mesenteric artery but had a marked effect on calcitonin gene-related peptide-induced responses in mesenteric artery and cerebral artery and isoproterenol responses in renal artery. Isoproterenol increased association with Kv7.4 and Rap1a in mesenteric artery which were not sensitive to gallein, whereas in renal artery, isoproterenol increased Kv7.4-AKAP (A-kinase anchoring protein) associations in a gallein-sensitive manner. Conclusions- The Gbetagamma Kv7 relationship differs between vessels and is an essential requirement for AKAP, but not Rap-mediated regulation of the channel. PMID- 30002063 TI - Health informatics: a required skill for 21st century clinicians. PMID- 30002062 TI - High-Density Lipoprotein Particles, Cell-Cholesterol Efflux, and Coronary Heart Disease Risk. AB - Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to prebeta-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal prebeta-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor prebeta-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (alpha-1+alpha-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) prebeta-1 concentrations than controls, but the functionality of their prebeta-1 particles (prebeta-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (alpha-1+alpha-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either prebeta-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal prebeta-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality. PMID- 30002065 TI - Thirty-Second Gold Standard Definition of Atrial Fibrillation and Its Relationship With Subsequent Arrhythmia Patterns: Analysis of a Large Prospective Device Database. AB - BACKGROUND: The Heart Rhythm Society consensus statement arbitrarily defines atrial fibrillation (AF) ablation failure as any episode >=30 seconds. However, if brief AF events are not correlated to longer events, the rationale for this end point is questionable. We determined the impact of AF episode duration threshold on AF incidence and burden. METHODS: Patients with a pacemaker in a prospective registry with device-detected AF and follow-up >30 days were analyzed. AF patterns were calculated for various AF duration thresholds (30 s; 2 and 6 minutes; 3.8, 5.5, and 24 hours) selected based on published consensus statements, established evidence of stroke risk, and device capabilities. Freedom from AF postdevice implant at each AF episode duration threshold was assessed, as was overall AF burden. RESULTS: Among 615 patients with pacemaker (aged 72.0+/ 11.8 years, 54.2% male, follow-up 3.7+/-2.2 years) with device-detected AF, 599 had >=1 AF episode of >=30 seconds duration (median, 22 episodes). At 12 months, freedom from AF was 25.5%, 30.1%, 34.6%, 52.6%, 56.5%, and 73.1% for duration thresholds of 30 seconds, 2 minutes, 6 minutes, 3.8 hours, 5.5 hours, and 24 hours, respectively. Of patients with a first episode of 30 seconds to 2 minutes, 35.8% were free from subsequent episode >2 minutes at 180 days. Median AF burden was significantly less for patients with first episodes between 30 seconds and 3.8 hours versus >3.8 hours (0.2% versus 9.5%, respectively; P<0.0001). CONCLUSIONS: Small differences in AF episode duration definition can significantly affect the perceived incidence of AF and impact reported outcomes, including AF ablation success. An initial AF episode of 30 seconds does not predict clinically meaningful AF patterns. PMID- 30002067 TI - Measuring Success in Ablation of Atrial Fibrillation: Time for a Paradigm Shift? PMID- 30002064 TI - Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death. AB - BACKGROUND: Sudden cardiac death because of ventricular fibrillation (VF) is commonly unexplained in younger victims. Detailed electrophysiological mapping in such patients has not been reported. METHODS: We evaluated 24 patients (29+/-13 years) who survived idiopathic VF. First, we used multielectrode body surface recordings to identify the drivers maintaining VF. Then, we analyzed electrograms in the driver regions using endocardial and epicardial catheter mapping during sinus rhythm. Established electrogram criteria were used to identify the presence of structural alterations. RESULTS: VF occurred spontaneously in 3 patients and was induced in 16, whereas VF was noninducible in 5. VF mapping demonstrated reentrant and focal activities (87% versus 13%, respectively) in all. The activities were dominant in one ventricle in 9 patients, whereas they had biventricular distribution in others. During sinus rhythm areas of abnormal electrograms were identified in 15/24 patients (62.5%) revealing localized structural alterations: in the right ventricle in 11, the left ventricle in 1, and both in 3. They covered a limited surface (13+/-6 cm2) representing 5+/-3% of the total surface and were recorded predominantly on the epicardium. Seventy-six percent of these areas were colocated with VF drivers (P<0.001). In the 9 patients without structural alteration, we observed a high incidence of Purkinje triggers (7/9 versus 4/15, P=0.033). Catheter ablation resulted in arrhythmia free outcome in 15/18 patients at 17+/-11 months follow-up. CONCLUSIONS: This study shows that localized structural alterations underlie a significant subset of previously unexplained sudden cardiac death. In the other subset, Purkinje electrical pathology seems as a dominant mechanism. PMID- 30002068 TI - Race and Socioeconomic Status Regulate Lifetime Risk of Atrial Fibrillation. PMID- 30002066 TI - Lifetime Risk of Atrial Fibrillation by Race and Socioeconomic Status: ARIC Study (Atherosclerosis Risk in Communities). AB - BACKGROUND: Limited information exists on the lifetime risk of atrial fibrillation (AF) in African Americans and by socioeconomic status. METHODS: We studied 15 343 participants without AF at baseline from the ARIC (Atherosclerosis Risk in Communities) cohort recruited in 1987 to 1989 from 4 communities in the United States when they were 45 to 64 years of age. Participants have been followed through 2014. Incidence rates of AF were calculated dividing the number of new cases by person-years of follow-up. Lifetime risk of AF was estimated by a modified Kaplan-Meier method considering death as a competing risk. Participants' family income and education were obtained at baseline. RESULTS: We identified 2760 AF cases during a mean follow-up of 21 years. Lifetime risk of AF was 36% (95% confidence interval, 32%-38%) in white men, 30% (95% confidence interval, 26%-32%) in white women, 21% (95% confidence interval, 13%-24%) in African American men, and 22% (95% confidence interval, 16%-25%) in African American women. Regardless of race and sex, incidence rates of AF decreased from the lowest to the highest categories of income and education. In contrast, lifetime risk of AF increased in individuals with higher income and education in most sex race groups. Cumulative incidence of AF was lower in those with higher income and education compared with their low socioeconomic status counterparts through earlier life but was reversed after age 80. CONCLUSIONS: Lifetime risk of AF in the ARIC cohort was ~1 in 3 among whites and 1 in 5 among African Americans. Socioeconomic status was inversely associated with cumulative incidence of AF before the last decades of life. PMID- 30002069 TI - Discrepancy in current central serous chorioretinopathy classification. AB - AIM: To report the discordance in central serous chorioretinopathy (CSCR) classification among practising retina specialists. METHODS: The study conducted was a multicentre survey. Multimodal retinal images along with relevant clinical details of 100 cases diagnosed as CSCR (from six centres) were circulated among six retina specialists across the globe. The image sets included colour fundus photographs, fundus autofluorescence images, optical coherence tomography b scans, fluorescein and indocyanine green angiography of the study and fellow eyes. The graders were asked to classify the disease of study eye, according to their own criteria. The graders were masked to the responses of other graders. The final analysis of the pooled response data was done based on the diagnosis of study eye only. The main outcome measure was degree of agreement between six independent observers using Fleiss Kappa statistics. RESULTS: Grading for 100 eyes of 100 patients (men, 93%) was included in the analysis. 20 patients had a history of steroid use. The graders provided 36 different terms to classify the disease, with poor agreement among graders (Fleiss Kappa=0.134). The consistency in diagnosing acute CSCR was statistically higher than for either chronic (p=0.012) or recurrent CSCR (p<0.0001). When collapsing descriptors into six main terms, agreement remained poor (Fleiss Kappa=0.218). CONCLUSION: The high discordance among experienced retina specialists in describing CSCR clinical subtypes is highlighted. The current work demonstrates the limitations of current empirical CSCR classification methods and the need for a more objective and refined system to bring uniformity in diagnosis and prognostication of the disease. PMID- 30002070 TI - Analysis of multiple genetic loci reveals MPDZ-NF1B rs1324183 as a putative genetic marker for keratoconus. AB - OBJECTIVE: To investigate the associations between 16 single-nucleotide polymorphisms (SNPs) in 14 genetic loci and keratoconus in an independent Chinese cohort. METHODS: This cross-sectional, case-control association study included a Chinese cohort of 133 patients with keratoconus and 371 control subjects. In a recent meta-analysis study, we identified association of 16 SNPs in 14 gene loci with keratoconus. In this study, we genotyped these 16 SNPs in all the patients and controls and analysed their association with keratoconus, its clinical severities and progression profiles. We also analysed the genotype-phenotype correlation between individual SNPs and steep keratometry, flat keratometry (Kf), average keratometry (Avg K) and best-fit sphere diameter (BFS) of the anterior and posterior corneal surface. RESULTS: Among the 16 selected SNPs, rs1324183 in the MPDZ-NF1B locus showed a significant association with keratoconus (OR=2.22; 95% CI 1.42 to 3.45, p=4.30*10-4), especially severe keratoconus (OR=5.10, 95% CI 1.63 to 15.93, p=0.005). The rs1324183 A allele was positively associated with anterior Kf (p=0.008), anterior Avg K (p=0.017), posterior Kf (p=0.01) and negatively associated with apex pachymetry (p=0.007) and anterior BFS (p=0.023) in keratoconus. The other 15 SNPs had no significant association with keratoconus or genotype-phenotype correlations. CONCLUSIONS: This study confirmed the association of SNP rs1324183 in MPDZ-NF1B with keratoconus and revealed the association of this SNP with keratoconus severity and corneal parameters. It is thus a putative genetic marker for monitoring the progression of keratoconus to a severe form and facilitating early intervention. PMID- 30002071 TI - Time trends, disease patterns and gender imbalance in the top 100 most cited articles in ophthalmology. AB - We analysed the 100 top cited articles in ophthalmology to identify and characterise the most influential articles of the past four decades. Two independent investigators searched the Scopus database to determine the 100 most frequently cited articles in ophthalmology (T100-Eye) and general non ophthalmology journals (T100-Gen) published from 1975 to December 2017. The T100 Eye list consisted of 83 original articles and 17 reviews, and the number of citations ranged from 582 to 2833. Seventy-eight of these articles were published in three journals alone (impact factor (IF): 5.05-8.2), led by the Archives of Ophthalmology The T100-Gen list consisted of 84 original articles and 16 reviews and the number of citations ranged from 358 to 3272. Forty-five of these articles were published in four journals alone (IF: 9.66-72.41). In both lists, majority of the first authors were from the USA (T100-Eye, n=80; T100-Gen, n=66), and were men (n=76 in T100-Eye; n=72 in T100-Gen). With regard to the article type, in the T100-Eye, among the 83 original research articles, most were randomised controlled trials (n=26) or clinical observational studies related to description of a new condition or new management (n=26). In the T100-Gen, of the 84 original research articles, many were clinical observational studies (n=27) or basic science research (n=26). In both lists, the most frequently examined diseases were age-related macular degeneration, diabetic retinopathy and glaucoma. Our analysis reveals landmark articles, trends and medical advancements in ophthalmology over the past four decades. It also highlights gender disparity and influence of the USA in seminal ophthalmic research. PMID- 30002072 TI - Patient characteristics and risk factors for central serous chorioretinopathy: an analysis of 811 patients. AB - AIMS: To determine the demographic and morphological characteristics of patients with central serous chorioretinopathy (CSC) and describe risk factors for CSC. METHODS: We retrospectively reviewed medical records of 811 patients with CSC and 816 healthy controls referred from 2002 to 2018. RESULTS: The female/male ratio of patients with CSC was 1/2.7. Mean age of onset was 45.2 years. The peak prevalence for men occurred at 45-49 years. Women had two prevalence peaks, the higher at 55-59 years and the other at 45-49 years. Of these patients, 56.8% had unilateral disease, 42.1% had bilateral disease and 1.1% had only one eye. 671 (82.7%) patients had spectral domain optical coherence tomography (SD-OCT) images and 598 (73.7%) had enhanced depth choroidal images. Pigment epithelial detachment (PED) was detected in 763 (80.7%) of 945 eyes with SD-OCT images. Chronic cases were more likely to be bilateral and multifocal and to have PED (all p<0.001). Subfoveal choroidal thickness (SFCT) did not differ between chronic and classic cases (p=0.74), but SFCT was greater in multifocal cases than unifocal cases (p<0.001). In multivariate regression analyses, older age of onset, longer duration of disease and hyperopia were positively associated with having chronic disease rather than classic disease, and myopia and thyroid hormone replacement were negatively associated. Steroid use, antidepressant or anxiolytic drug use, smoking, pregnancy and hyperopia were risk factors, and myopia was a protective factor for CSC. CONCLUSION: This is the largest case control study of CSC to evaluate demographic morphological characteristics and risk factors. Multiple factors are associated with CSC. PMID- 30002073 TI - A quantitative analysis of cohesin decay in mitotic fidelity. AB - Sister chromatid cohesion mediated by cohesin is essential for mitotic fidelity. It counteracts spindle forces to prevent premature chromatid individualization and random genome segregation. However, it is unclear what effects a partial decline of cohesin may have on chromosome organization. In this study, we provide a quantitative analysis of cohesin decay by inducing acute removal of defined amounts of cohesin from metaphase-arrested chromosomes. We demonstrate that sister chromatid cohesion is very resistant to cohesin loss as chromatid disjunction is only observed when chromosomes lose >80% of bound cohesin. Removal close to this threshold leads to chromosomes that are still cohered but display compromised chromosome alignment and unstable spindle attachments. Partial cohesin decay leads to increased duration of mitosis and susceptibility to errors in chromosome segregation. We propose that high cohesin density ensures centromeric chromatin rigidity necessary to maintain a force balance with the mitotic spindle. Partial cohesin loss may lead to chromosome segregation errors even when sister chromatid cohesion is fulfilled. PMID- 30002075 TI - Ca2+tapulting HSCs into action. AB - In this issue of JEM, Umemoto et al. (https://doi.org/10.1084/jem.20180421) demonstrate that calcium influx stimulates mitochondrial metabolism and initiates proliferation in hematopoietic stem cells (HSCs). Extracellular adenosine, sourced from surrounding hematopoietic progenitors, inhibits this calcium influx, thereby suppressing mitochondrial metabolism and promoting HSC quiescence. This is the first demonstration that a calcium-mitochondria pathway regulates HSC division. PMID- 30002076 TI - One of the proposed solutions of the EBM Manifesto Educate the public in evidence based healthcare to make informed decisions. PMID- 30002074 TI - Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. PMID- 30002077 TI - Shared decision is the only outcome that matters when it comes to evaluating evidence-based practice. PMID- 30002078 TI - Biotransformation of Ilaprazole in Human Liver Microsomes and Human: Role of CYP3A4 in Ilaprazole Clearance and Drug-Drug Interaction. AB - Ilaprazole is a new proton pump inhibitor and is currently marketed in China and South Korea for the treatment of gastric and duodenal ulcer. Ilaprazole has a favorable long half-life and minimal pharmacokinetic variability associated with CYP2C19 polymorphism. Sulfoxide oxidation of ilaprazole is catalyzed mainly by CYP3A4. Thus, it has been widely accepted that CYP3A4 plays a major role in the clearance of ilaprazole in humans. However, absorption, distribution, metabolism, and excretion data of radiolabeled ilaprazole in humans are not available. The primary goal of this study was to determine if sulfoxide oxidation is a major metabolic pathway of ilaprazole in humans. Metabolite profiles of ilaprazole, ilaprazole sulfide, and ilaprazole sulfone in human liver microsomes (HLMs) were characterized and quantitively analyzed by liquid chromatography (LC)/UV/high resolution mass spectrometry (HRMS). Moreover, metabolites of ilaprazole in human urine and feces were detected and identified by LC-HRMS. The results revealed that sulfoxide reduction to ilaprazole sulfide rather than sulfoxide oxidation was the major biotransformation pathway in HLMs. Sulfoxide reduction also occurred in HLMs without NADPH or in deactivated HLMs. Ilaprazole sulfide and its multiple oxidative metabolites were major drug-related components in human urine and feces, where there were no ilaprazole sulfone and its metabolites. A small amount of the parent drug was found in feces. Thus, we propose that nonenzymatic sulfoxide reduction rather than CYP3A4-medidated sulfoxide oxidation is the major metabolic clearance pathway of ilaprazole in humans. Consequently, it is predicted that ilaprazole has no significant drug-drug interaction via CYP3A4 inhibition or induction by a coadministered drug. PMID- 30002079 TI - Advantages and Adversities of the Weighted Toxicity Score. AB - It is imperative to develop a comprehensive toxicity score that will capture, convey, and compare adverse events of agents that are therapeutic options for the same disease state. The weighted toxicity score tool is a valuable aid in the shared decision-making process of therapeutic choice between patients and providers. Clin Cancer Res; 24(20); 4918-20. (c)2018 AACR See related article by Carbini et al., p. 4968. PMID- 30002082 TI - Study Reveals Genetics of Pancreatic Cancer. AB - In a recent study, researchers established that heritable germline mutations in six genes associated with pancreatic cancer were present in 5.5% of patients with the disease, findings that support broader genetic testing of patients with pancreatic cancer and their family members. PMID- 30002081 TI - Relationship Between Sequence Homology, Genome Architecture, and Meiotic Behavior of the Sex Chromosomes in North American Voles. AB - In most mammals, the X and Y chromosomes synapse and recombine along a conserved region of homology known as the pseudoautosomal region (PAR). These homology driven interactions are required for meiotic progression and are essential for male fertility. Although the PAR fulfills key meiotic functions in most mammals, several exceptional species lack PAR-mediated sex chromosome associations at meiosis. Here, we leveraged the natural variation in meiotic sex chromosome programs present in North American voles (Microtus) to investigate the relationship between meiotic sex chromosome dynamics and X/Y sequence homology. To this end, we developed a novel, reference-blind computational method to analyze sparse sequencing data from flow-sorted X and Y chromosomes isolated from vole species with sex chromosomes that always (Microtus montanus), never (Microtus mogollonensis), and occasionally synapse (Microtus ochrogaster) at meiosis. Unexpectedly, we find more shared X/Y homology in the two vole species with no and sporadic X/Y synapsis compared to the species with obligate synapsis. Sex chromosome homology in the asynaptic and occasionally synaptic species is interspersed along chromosomes and largely restricted to low-complexity sequences, including a striking enrichment for the telomeric repeat sequence, TTAGGG. In contrast, homology is concentrated in high complexity, and presumably euchromatic, sequence on the X and Y chromosomes of the synaptic vole species, M. montanus Taken together, our findings suggest key conditions required to sustain the standard program of X/Y synapsis at meiosis and reveal an intriguing connection between heterochromatic repeat architecture and noncanonical, asynaptic mechanisms of sex chromosome segregation in voles. PMID- 30002083 TI - Tripartite Chromatin Localization of Budding Yeast Shugoshin Involves Higher Ordered Architecture of Mitotic Chromosomes. AB - The spindle assembly checkpoint (SAC) is key to faithful segregation of chromosomes. One requirement that satisfies SAC is appropriate tension between sister chromatids at the metaphase-anaphase juncture. Proper tension generated by poleward pulling of mitotic spindles signals biorientation of the underlying chromosome. In the budding yeast, the tension status is monitored by the conserved Shugoshin protein, Sgo1p, and the tension sensing motif (TSM) of histone H3. ChIP-seq reveals a unique TSM-dependent, tripartite domain of Sgo1p in each mitotic chromosome. This domain consists of one centromeric and two flanking peaks 3 - 4 kb away, present exclusively in mitosis. Strikingly, this trident motif coincides with cohesin localization, but only at the centromere and the two immediate adjacent loci, despite that cohesin is enriched at numerous regions throughout mitotic chromosomes. Chromosome conformation capture assays reveal apparent looping at the centromeric and pericentric regions. The TSM-Sgo1p cohesin triad is therefore at the center stage of higher-ordered chromatin architecture for error-free segregation. PMID- 30002085 TI - Use of dual-energy CT to detect and depict bone marrow oedema in rheumatoid arthritis: is it ready to substitute MRI? PMID- 30002080 TI - Chromatin Loop Formation Induced by a Subtelomeric Protosilencer Represses EPA Genes in Candida glabrata. AB - Adherence, an important virulence factor, is mediated by the EPA (Epithelial Adhesin) genes in the opportunistic pathogen Candida glabrata Expression of adhesin-encoding genes requires tight regulation to respond to harsh environmental conditions within the host. The majority of EPA genes are localized in subtelomeric regions regulated by subtelomeric silencing, which depends mainly on Rap1 and the Sir proteins. In vitro adhesion to epithelial cells is primarily mediated by Epa1. EPA1 forms a cluster with EPA2 and EPA3 in the right telomere of chromosome E (E-R). This telomere contains a cis-acting regulatory element, the protosilencer Sil2126 between EPA3 and the telomere. Interestingly, Sil2126 is only active in the context of its native telomere. Replacement of the intergenic regions between EPA genes in E-R revealed that cis-acting elements between EPA2 and EPA3 are required for Sil2126 activity when placed 32 kb away from the telomere (Sil@-32kb). Sil2126 contains several putative binding sites for Rap1 and Abf1, and its activity depends on these proteins. Indeed, Sil2126 binds Rap1 and Abf1 at its native position and also when inserted at -32 kb, a silencing-free environment in the parental strain. In addition, we found that Sil@-32kb and Sil2126 at its native position can physically interact with the intergenic regions between EPA1-EPA2 and EPA2-EPA3 respectively, by chromosome conformation capture assays. We speculate that Rap1 and Abf1 bound to Sil2126 can recruit the Silent Information Regulator complex, and together mediate silencing in this region, probably through the formation of a chromatin loop. PMID- 30002086 TI - Response to: 'The use of dual-energy CT to detect and depict bone marrow oedema in rheumatoid arthritis: is it ready to substitute MRI?' by Wu et al. PMID- 30002084 TI - The importance of DNA methylation of exons on alternative splicing. AB - Alternative splicing (AS) contributes to proteome diversity. As splicing occurs cotranscriptionally, epigenetic determinants such as DNA methylation likely play a part in regulation of AS. Previously, we have shown that DNA methylation marks exons and that a loss of DNA methylation alters splicing patterns in a genome wide manner. To investigate the influence of DNA methylation on splicing of individual genes, we developed a method to manipulate DNA methylation in vivo in a site-specific manner using the deactivated endonuclease Cas9 fused to enzymes that methylate or demethylate DNA. We used this system to directly change the DNA methylation pattern of selected exons and introns. We demonstrated that changes in the methylation pattern of alternatively spliced exons, but not constitutively spliced exons or introns, altered inclusion levels. This is the first direct demonstration that DNA methylation of exon-encoding regions is directly involved in regulation of AS. PMID- 30002087 TI - A review of acute ischemic stroke triage protocol evidence: a context for discussion. AB - Endovascular thrombectomy (EVT) is now the standard of care for eligible patients with acute ischemic stroke (AIS) secondary to emergent large vessel occlusion (ELVO). However, there remains uncertainty in how hospital systems can most efficiently route patients with suspected ELVO for EVT treatment. Given the relative geographic distribution of centers with and without endovascular capabilities, the value of prehospital triage directly to centers with the ability to provide EVT remains debated. While there are no randomized trial data available to date, there is substantial evidence in the literature that may offer guidance on the subject. In this review we examine the available data in the context of improving the existing AIS triage systems and discuss how prehospital triage directly to endovascular-capable centers may confer clinical benefits for patients with suspected ELVO. PMID- 30002088 TI - Subcutaneous Injection of Nitroglycerin at the Radial Artery Puncture Site Reduces the Risk of Early Radial Artery Occlusion After Transradial Coronary Catheterization: A Randomized, Placebo-Controlled Clinical Trial. AB - BACKGROUND: Transradial coronary catheterization is widely used as a diagnostic or interventional procedure for coronary disease. However, it can lead to adverse complications, such as radial artery occlusion. We sought to determine whether preprocedural injection of nitroglycerin at the radial artery puncture site reduces radial artery occlusion. METHODS AND RESULTS: A total of 188 patients undergoing transradial coronary catheterization were randomized in a single-blind fashion to receive subcutaneous injection of 0.5 mL 0.1% nitroglycerin or a placebo at the radial artery puncture site. The participants underwent ultrasound examinations of the radial artery before and at 24 hours after the procedure. Of the 188 patients enrolled, 182 completed the study, as the procedure failed in 2 participants in the nitroglycerin-treated group and 4 in the placebo group. Baseline demographic and clinical characteristics were similar between 2 groups. Comparing the radial artery diameters before and after the operation, there was a statistically significant increase in the nitroglycerin-treated group (2.48+/ 0.45 versus 2.45+/-0.46 mm; P=0.003) but a decrease in the placebo control group (2.41+/-0.50 versus 2.46+/-0.49 mm; P<0.001). Importantly, the incidence of radial arterial occlusion was substantially lower in the nitroglycerin-treated group than in the placebo control group (5.4% versus 14.4%; P=0.04). There was not significant difference in other complications (forearm hematoma and radial artery pseudoaneurysm, respectively), and there was no incidence of cause hypotension or an intolerable headache. CONCLUSIONS: Subcutaneous injection of nitroglycerin at the radial artery puncture site dilates the radial artery and reduces the incidence of early radial artery occlusion post-catheterization. CLINICAL TRIAL REGISTRATION: URL: https://www.chictr.org.cn. Unique identifier: ChiCTR-IPR-15006559. PMID- 30002089 TI - Successful Percutaneous Closure of a Well-Developed Arteriovenous Coronary Fistula With a Giant Aneurysm. PMID- 30002090 TI - Vasodilators and Radial Artery Occlusion: A Concept to Reduce Radial Artery Occlusion? PMID- 30002091 TI - The Future of Circulation: Cardiovascular Interventions: Changing, Creating, and Maturing. PMID- 30002093 TI - Cormack-Lehane grading evolution to assess trainee's progress in laryngoscopy. PMID- 30002094 TI - A machine vision system for zooplankton behavioural studies: a case study on the phototactic behaviour of sea lice (Lepeophtheirus salmonis) during sound and ultrasound stimuli. AB - Machine vision represents an accurate and easily verifiable method for observing live organisms and this technology is constantly evolving in terms of accessibility and cost. Motivated by the complexity of observing small-sized aquatic organisms in experimental systems, and the difficulties related to real time observation, sampling and counting without interfering with the organisms, we here present a new method for observing behaviour and dispersion of non sessile zooplankton organisms using a custom-made tank with an associated machine vision system. The system was used in an experiment where the aim was to assess the effect of sound and ultrasound on the phototactic behaviour of copepodite stages of the salmon louse (Lepeophtheirus salmonis). The experimental set-up is described, including a triangular test tank designed to create a sound pressure gradient, a mechanized camera movement system and a vision system with dedicated image processing software. PMID- 30002092 TI - Uric acid stones, clinical manifestations and therapeutic considerations. AB - Uric acid stones account for 10%-15% of all urinary stones. Changes in dietary habits, environment or both can result in the increase of uric acid stones. The formation of uric acid stones is related to hyperuricosuria, low urinary volume and persistently low urinary pH. Diabetes and obesity also significantly increase the risk of stone formation. Dual-energy CT provides a convenient and reliable method for diagnosis. Stone composition analysis and 24-hour urine metabolic evaluations should be considered for further evaluation. Most small uric acid stones (diameter <2 cm) can be treated by pharmacotherapy or extracorporeal shock wave lithotripsy. However, ureteroscopy and other minimally invasive procedures should be reserved for larger stones (diameter >=2 cm), or patients with concomitant urinary tract obstruction and/or infections. Additionally, adjustment of potential pathophysiologic defects by pharmacotherapy and dietary modification is strongly recommended for the prevention of uric stone recurrence. PMID- 30002095 TI - Metabolic Mechanisms and a Rational Combinational Application of Carboxyamidotriazole in Fighting Pancreatic Cancer Progression after Chemotherapy. AB - The anticancer and anti-inflammatory effects of carboxyamidotriazole (CAI) have been demonstrated in several studies, but the underlying mechanisms remain to be elucidated. This study showed that CAI caused metabolic reprogramming of pancreatic cancer cells. The inhibition of mitochondrial oxidative metabolism by CAI led to increased glutamine-dependent reductive carboxylation and enhanced glycolytic metabolism. The presence of environmental substances that affect cellular metabolism, such as glutamine and pyruvate, attenuated the anticancer efficacy of CAI. Based on the action of CAI: 1) when glutamine was removed, the NAD+/NADH ratio was decreased, the synthesis of cellular aspartate was reduced, and autophagy flux was blocked; and 2) when glycolysis was pharmacologically inhibited, the ATP level was significantly decreased, the cell viability was greatly inhibited, and the compensatory rescue effect of glutamine was eliminated. When combined with chemotherapy, cotreatment with CAI and the glycolysis inhibitor 2-deoxyglucose (2-DG) inhibited the pancreatic cancer progression after chemotherapy. As the inhibition of mitochondrial oxidative metabolism can explain several anticancer activities of CAI reported previously, including inhibition of calcium entry and induction of reactive oxygen species, we demonstrate that inhibition of mitochondrial oxidative phosphorylation may be the fundamental mechanism of CAI. The combination of CAI and 2-DG causes energy depletion in cancer cells, eliminating the rescue effect of the metabolic environment. Inhibiting pancreatic cancer progression after chemotherapy is a rational application of this metabolism-disturbing combination strategy. PMID- 30002097 TI - Detection and Quantification of Carbohydrate-Deficient Transferrin by MALDI Compatible Protein Chips Prepared by Ambient Ion Soft Landing. AB - BACKGROUND: Transferrin is synthetized in the liver and is the most important iron-transport carrier in the human body. Severe alcohol consumption leads to alterations in glycosylation of transferrin. Mass spectrometry can provide fast detection and quantification of transferrin isoforms because they have different molecular masses. In this study, we used antibody chips in combination with MALDI TOF MS for the detection and quantification of transferrin isoforms. METHODS: Protein chips were prepared by functionalization of indium tin oxide glass using ambient ion soft landing of electrosprayed antitransferrin antibody. Two microliters of patient serum was applied on the antibody-modified spots, and after incubation, washing, and matrix deposition, transferrin isoforms were detected by MALDI-TOF MS. Peak intensities of each transferrin form were used to calculate total carbohydrate-deficient transferrin (CDT). The CDT values obtained by the MALDI chip method were compared with the results obtained by a standard capillary electrophoresis (CE). RESULTS: The chip-based MALDI-TOF MS method was used for enrichment and detection of CDT from human serum. A sample cohort from 186 patients was analyzed. Of these samples, 44 were positively identified as belonging to alcoholic patients, whereas 142 were negative by the MALDI chip approach. The correlation of the data obtained by the CE and the chip-based MALDI was r = 0.986, 95% CI. CONCLUSIONS: Functionalized MALDI chips modified by antitransferrin antibody prepared by ambient ion soft landing were successfully used for detection and quantification of CDT from human sera. PMID- 30002096 TI - Role of Interstitial Fluid Turnover on Target Suppression by Therapeutic Biologics Using a Minimal Physiologically Based Pharmacokinetic Model. AB - For therapeutic biologics against soluble ligands, the magnitude and duration of target suppression affect their therapeutic efficacy. Many factors have been evaluated in relation to target suppression but the interstitial fluid turnover rate in target tissues has not been considered. Inspired by the fact that etanercept exerts limited efficacy in Crohn's disease despite its high efficacy in rheumatoid arthritis, we developed a minimal physiologically based pharmacokinetic model to investigate the role of the tissue fluid turnover rate on soluble target suppression and assessed the interrelationships between binding constants and tissue fluid turnover. Interstitial fluid turnover rates in target tissues were found to strongly influence target binding kinetics. For tissues with low fluid turnover, stable binders (low koff) exhibit greater target suppression, but efficacy is often restricted by accumulation of the drug-target complex. For tissues with high fluid turnover, fast binders (high kon) are generally favored, but a plateau effect is present for antibodies with low dissociation rates (koff). Etanercept is often regarded as a fast tumor necrosis factor-alpha (TNF-alpha) binder (high kon) despite comparable binding affinity (KD, koff/kon) with adalimumab and infliximab. Crohn's disease largely involves the colon, a tissue with relatively slower fluid turnover than arthritis associated joint synovium; this may explain why etanercept exerts poor TNF-alpha suppressive effect in Crohn's disease. This study highlights the importance of tissue interstitial fluid turnover in evaluation of therapeutic antibodies bound to soluble antigens. PMID- 30002098 TI - Effects of Sacubitril/Valsartan Versus Irbesartan in Patients With Chronic Kidney Disease. AB - BACKGROUND: Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease are unknown. METHODS: The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR at 12 months using ANCOVA with adjustment for each individual's baseline measured GFR. All analyses were by intention to treat. RESULTS: In total, 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline measured GFR was 34.0 (SE, 0.8) and 34.7 (SE, 0.8) mL/min/1.73 m2, respectively. At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4-7.4) and 2.1 (95% CI, 1.0-3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8-23) and 18% (95% CI, 11-25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75-1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96-1.90), and potassium >=5.5 mmol/L (32% versus 24%, P=0.10) was not significantly different between randomized groups. CONCLUSIONS: Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but it has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com . Unique identifier: ISRCTN11958993. PMID- 30002100 TI - Understanding why we deliver unnecessary care. PMID- 30002101 TI - Heartbeat: Causes and consequences of atrial fibrillation. PMID- 30002099 TI - Myocardial Scar and Mortality in Severe Aortic Stenosis. AB - BACKGROUND: Aortic valve replacement (AVR) for aortic stenosis is timed primarily on the development of symptoms, but late surgery can result in irreversible myocardial dysfunction and additional risk. The aim of this study was to determine whether the presence of focal myocardial scar preoperatively was associated with long-term mortality. METHODS: In a longitudinal observational outcome study, survival analysis was performed in patients with severe aortic stenosis listed for valve intervention at 6 UK cardiothoracic centers. Patients underwent preprocedural echocardiography (for valve severity assessment) and cardiovascular magnetic resonance for ventricular volumes, function and scar quantification between January 2003 and May 2015. Myocardial scar was categorized into 3 patterns (none, infarct, or noninfarct patterns) and quantified with the full width at half-maximum method as percentage of the left ventricle. All-cause mortality and cardiovascular mortality were tracked for a minimum of 2 years. RESULTS: Six hundred seventy-four patients with severe aortic stenosis (age, 75+/ 14 years; 63% male; aortic valve area, 0.38+/-0.14 cm2/m2; mean gradient, 46+/-18 mm Hg; left ventricular ejection fraction, 61.0+/-16.7%) were included. Scar was present in 51% (18% infarct pattern, 33% noninfarct). Management was surgical AVR (n=399) or transcatheter AVR (n=275). During follow-up (median, 3.6 years), 145 patients (21.5%) died (52 after surgical AVR, 93 after transcatheter AVR). In multivariable analysis, the factors independently associated with all-cause mortality were age (hazard ratio [HR], 1.50; 95% CI, 1.11-2.04; P=0.009, scaled by epochs of 10 years), Society of Thoracic Surgeons score (HR, 1.12; 95% CI, 1.03-1.22; P=0.007), and scar presence (HR, 2.39; 95% CI, 1.40-4.05; P=0.001). Scar independently predicted all-cause (26.4% versus 12.9%; P<0.001) and cardiovascular (15.0% versus 4.8%; P<0.001) mortality, regardless of intervention (transcatheter AVR, P=0.002; surgical AVR, P=0.026 [all-cause mortality]). Every 1% increase in left ventricular myocardial scar burden was associated with 11% higher all-cause mortality hazard (HR, 1.11; 95% CI, 1.05-1.17; P<0.001) and 8% higher cardiovascular mortality hazard (HR, 1.08; 95% CI, 1.01-1.17; P<0.001). CONCLUSIONS: In patients with severe aortic stenosis, late gadolinium enhancement on cardiovascular magnetic resonance was independently associated with mortality; its presence was associated with a 2-fold higher late mortality. PMID- 30002102 TI - The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension. AB - Pulmonary endarterectomy (PEA) is the gold standard treatment for operable chronic thromboembolic pulmonary hypertension (CTEPH). However, a proportion of patients with operable disease decline surgery. There are currently no published data on this patient group. The aim of this study was to identify outcomes and prognostic factors in a large cohort of consecutive patients with CTEPH.Data were collected for consecutive, treatment-naive CTEPH patients at the Pulmonary Vascular Disease Unit of the Royal Hallamshire Hospital (Sheffield, UK) between 2001 and 2014.Of 550 CTEPH patients (mean+/-sd age 63+/-15 years, follow-up 4+/-3 years), 49% underwent surgery, 32% had technically operable disease and did not undergo surgery (including patient choice n=72 and unfit for surgery n=63), and 19% had inoperable disease due to disease distribution. The 5-year survival was superior in patients undergoing PEA (83%) versus technically operable disease who did not undergo surgery (53%) and inoperable due to disease distribution (59%) (p<0.001). Survival was superior in patients following PEA compared with those offered but declining surgery (55%) (p<0.001). In patients offered PEA, independent prognostic factors included mixed venous oxygen saturation, gas transfer and patient decision to proceed to surgery.Outcomes in CTEPH following PEA are excellent and superior to patients declining surgery, and strongly favour consideration of a surgical intervention in eligible patients. PMID- 30002103 TI - A systematic review of how patients value COPD outcomes. AB - Our objective was to summarise systematically all research evidence related to how patients value outcomes in chronic obstructive pulmonary disease (COPD).We conducted a systematic review (systematic review registration number CRD42015015206) by searching PubMed, Embase, PsycInfo and CINAHL, and included reports that assessed the relative importance of outcomes from COPD patients' perspective. Two authors independently determined the eligibility of studies, abstracted the eligible studies and assessed risk of bias. We narratively summarised eligible studies, meta-analysed utilities for individual outcomes and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach.We included 217 quantitative studies. Investigators most commonly used utility measurements of outcomes (n=136), discrete choice exercises (n=13), probability trade-off (n=4) and forced choice techniques (n=46). Patients rated adverse events as important but on average, less so than symptom relief. Exacerbation and hospitalisation due to exacerbation are the outcomes that COPD patients rate as most important. This systematic review provides a comprehensive registry of related studies. PMID- 30002104 TI - Lung function trajectories using different reference equations in a birth cohort study up to the age of 20 years. PMID- 30002105 TI - Recurrence rates in primary spontaneous pneumothorax: a systematic review and meta-analysis. AB - Primary spontaneous pneumothorax (PSP) recurrence rates vary widely in the published literature, with limited data describing the factors that influence recurrence. The aims of this systematic review were to determine an estimation of PSP recurrence rates and describe risk factors for recurrence.A systematic review was conducted of all studies reporting PSP recurrence. Electronic searches were performed to identify English language publications of randomised trials and observational studies. The population was adults with PSP, who underwent conservative management, pleural aspiration or chest drainage. The outcome of interest was recurrence. Articles were screened and data extracted from eligible studies by two reviewers.Of 3607 identified studies, 29 were eligible for inclusion, comprising 13 548 patients. Pooled 1-year and overall recurrence rates were 29.0% (95% CI 20.9-37.0%) and 32.1% (95% CI 27.0-37.2%), respectively. Female sex was associated with increased recurrence (OR 3.03, 95% CI 1.24-7.41), while smoking cessation was associated with a four-fold decrease in risk (OR 0.26, 95% CI 0.10-0.63). I2 for random effects meta-analysis was 94% (p<0.0001), reflecting high heterogeneity between studies.This systematic review demonstrates a 32% PSP recurrence rate, with greatest risk in the first year. Female sex was associated with higher risk, suggesting possible sex-specific pathophysiology. PMID- 30002106 TI - Is chronic breathlessness less recognised and treated compared with chronic pain? A case-based randomised controlled trial. PMID- 30002109 TI - The Relevance of Dosimetry in Precision Medicine. AB - The aim of this review is to provide an overview of the most recent technologic developments in state-of-the-art equipment and tools for dosimetry in radionuclide therapies. This includes, but is not restricted to, calibration methods for imaging systems. In addition, a summary of new developments that consider the influence of small-scale dosimetry and of biologic effects on radionuclide therapies is given. Finally, the current limitations of patient specific dosimetry such as bone-marrow dosimetry or dosimetry of alpha-emitters are discussed. PMID- 30002107 TI - Targeting of the cholecystokinin-2 receptor with the minigastrin analog 177Lu DOTA-PP-F11N: does the use of protease inhibitors further improve in vivo distribution? AB - Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog 177Lu-DOTA PP-F11N (177Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) performs better than reference analogs with varying in vivo stability, namely 177Lu-DOTA-MG11 (177Lu DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) and 177Lu-DOTA-PP-F11 (177Lu-DOTA (DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), and if the use of protease inhibitors further improves CCKR2-targeting. First human data on 177Lu-DOTA-PP-F11N are also reported. Methods: In vitro stability of all analogs was assessed against a panel of extra- and intra-cellular endoproteases, while their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon (PA) and thiorphan (TO) was assessed 4h post-injection in MZ-CRC-1 and A431 CCK2R(+) dual xenografts. Autoradiography of 177Lu-DOTA-PP-F11N (without and with PA) and nanoSPECT/CT images were performed. SPECT/CT images of 177Lu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. Results: natLu-DOTA-PP-F11N is less of a substrate for neprilysines than the other analogs, while intracellular cysteine proteases, like cathepsins-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors, compared to A431-CCK2R(+), apparently due to the higher number of binding sites on MZ-CRC-1 cells. 177Lu-DOTA-PP-F11N has the same biodistribution as 177Lu-DOTA PP-F11, however, the uptake in the MZ-CRC-1 tumors is almost double (20.7+/-1.71 vs 11.2+/-2.94 %IA/g, P = 0.0002). Co-administration of PA or TO increases significantly the 177Lu-DOTA-MG11 uptake in the CCK2R(+) tumors and stomach. Less profound is the effect on 177Lu-DOTA-PP-F11, while no influence or even reduction is observed for 177Lu-DOTA-PP-F11N (20.7+/-1.71 vs 15.6+/-3.80 (with PA) %IA/g, p<0.05 in MZ-CRC-1 tumors). First clinical data show high 177Lu-DOTA-PP-F11N accumulation in the tumors, stomach, kidneys and colon. Conclusion: The performance of 177Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance of 177Lu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight stomach as a potential dose-limiting organ beside the kidneys. PMID- 30002108 TI - Outcome after PSMA PET/CT based salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy: a bi-institutional retrospective analysis. AB - Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) detects prostate cancer recurrence at low PSA levels. Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival (BRFS). Thus, we hypothesized that PSMA PET/CT-guided salvage radiotherapy leads to improved BRFS. Methods: A total of 204 consecutive patients were referred for salvage radiotherapy following radical prostatectomy. PSMA PET/CT scans were performed and patients with PSA persistence (109 patients) or evidence of distant metastases (5 patients) were excluded from this analysis. Thus, the following analysis is based on a total of 90 patients who underwent PSMA PET/CT prior to radiotherapy due to biochemical recurrence and received salvage radiotherapy. In case of PET-positive findings, antiandrogen therapy was commenced before initiation of radiotherapy. BRFS (PSA <= 0.2 ng/ml) was defined as the study endpoint. Results: PET-positive lesions were detected in 42/90 (47%) patients: 24/42 (27%) fossa recurrence only, 12/42 (13%) pelvic lymph nodes only and 6/42 (7%) fossa and pelvic lymph node recurrence. Median PSA before radiotherapy was 0.44 (0.11 - 6.24). Cumulatively, a total dose of 70.0 Gy (67.2 - 72 Gy) was delivered to local macroscopic tumor, 66 Gy (59.4 - 70.2 Gy) to the prostatic fossa, 60.8 Gy (54 - 66 Gy) to PET positive lymph nodes and 50.4 Gy (45 - 50.4 Gy) to the lymphatic pathways. After a median follow-up of 23 months, BRFS was 78%. Antiandrogen therapy was ongoing in 4 patients at last follow-up. No significant difference in BRFS between PET positive (74%) vs. PET-negative patients (82%; p>0.05) was observed at last follow-up. Two patients had late genitourinary toxicity grade 3 and no patient had gastrointestinal toxicity >= 3 (NCI-CTCAE v4.03). Conclusion: PSMA PET/CT guided salvage radiotherapy is an effective and safe local treatment option. No difference in BRFS between PET-positive and PET-negative patients was observed, indicating effective targeting of PET-positive lesions. PSMA PET/CT when readily available should be offered to patients with PSA recurrence for treatment individualization. PMID- 30002110 TI - "Standing by" for Bystander Effects: Dual-Isotope Imaging of Antibody-Drug Conjugate and Payload Distribution. PMID- 30002111 TI - Assessment of Physiological Intracranial Calcification in Healthy Adults Using 18F-NaF PET/CT. AB - The aim of this research study was to determine the role of 18F-Sodium fluoride (NaF) PET/CT imaging in the assessment of physiologic molecular calcification in the intra-cranial structures. We also examined the association of NaF accumulation with age as well as Hounsfield unit (HU) in certain anatomical sites that are known to calcify with normal aging. Methods: A total of 78 healthy subjects from the Cardiovascular Molecular Calcification Assessed by 18F-NaF PET/CT (CAMONA) clinical trial (38 females and 40 males) were included in this retrospective study. The mean age was 45.28 +/-14.15 years (21-75). Mean standardized uptake values (SUVmean) was used to measure NaF accumulation in the choroid plexus and epithalamus (pineal gland and habenula). Maximum HU was also measured for each ROI. Correlation analysis was conducted to assess the association between parameters. Results: Mean SUVmean was 0.42 +/- 0.26 in the right choroid plexus, 0.39 +/-25 in the left choroid plexus, and 0.23+/-0.08 in the epithalamus. Significant positive correlations were present between NaF uptake and age in the right choroid plexus (r=0.61, P < 0.0001), left choroid plexus (r=0.63, p<0.0001), and epithalamus (r=0.36, P = 0.001). NaF uptake significantly correlated with HU in the right choroid plexus (r=0.52, P < 0.0001), left choroid plexus (r=0.57, p<0.0001), and epithalamus (r=0.25, P = 0.03). Conclusion: NaF could be used in the assessment of physiological calcification in several intracranial structures. We report significant associations between NaF uptake and aging as well as HU in the calcified choroid plexus and epithalamus. Our findings further support the growing interest to utilize NaF for detecting extra-osseous, molecular calcification, and this powerful probe has potential applications in the evaluation of various age related, neurodegenerative brain processes. PMID- 30002112 TI - 68Ga-PSMA is a novel PET-CT tracer for imaging of hepatocellular carcinoma: A prospective pilot study. AB - Background:68Ga-Prostate Specific Membrane Antigen (68Ga-PSMA), a positron emission tomography (PET) tracer that was recently introduce for imaging of prostate cancer, may accumulate in other solid tumors including Hepatocellular Carcinoma (HCC). The aim of the study was to assess the potential role of 68Ga PSMA PET-Computed Tomography (CT) for imaging of HCC. Material and Methods: A prospective pilot study in seven patients with HCC with 41 liver lesions: 37 suspected malignant lesions (tumor lesions) and 4 regenerative nodules. For each liver lesion, uptake of 68Ga-PSMA and 18F-FDG uptake were measured [standard uptake value (SUV) and lesion-to-liver background ratios (TBR-SUV)], and correlated with dynamic characteristics (HU and TBR-HU) obtained on contrast enhanced CT data. Immunohistochemistry staining of PSMA in the tumor tissue was analyzed in samples obtained from 5 patients with HCC and compared to control samples from 3 patients with prostate cancer. Results: Thirty-six of the 37 tumor lesions and none of the regenerative nodules showed increased 68Ga-PSMA uptake while only 10 lesions were 18F-FDG avid. Based on contrast enhancement, tumor lesions were categorized into 27 homogeneously enhancing lesions, nine lesions with "mosaic" enhancement composed of enhancing and non-enhancing regions in the same lesion and a single non-enhancing lesion, the latter being the only non-68Ga PSMA avid lesion. Using the Mann-Whitney test, 68Ga-PSMA uptake was found significantly higher in enhancing tumor areas compared to non-enhancing areas and in contrast, 18F-FDG uptake was higher in non-enhancing areas, P<0.001 for both. 68Ga-PSMA uptake (TBR SUVmax) was found to correlate with vascularity (TBR-HU) (Spearman r=0.866, p<0.001). Immunohistochemistry showed intense intra-tumoral microvessel staining for PSMA in HCC, in contrast with cytoplasmic and membranous staining, mainly in the luminal border, in prostate cancer samples. In two of the study patients 68Ga-PSMA PET-CT identified unexpected extrahepatic metastases. Four regenerative liver nodules showed no increased uptake of either of the PET tracers. Conclusion:68Ga-PSMA PET-CT is superior to 18F-FDG PET-CT in imaging patients with HCC. HCC lesions are more commonly hypervascular taking up 68Ga PSMA in tumoral micro-vessels. 68Ga-PSMA PET-CT is a potential novel modality for imaging patients with HCC. PMID- 30002113 TI - HeartLogic Multisensor Algorithm Identifies Patients During Periods of Significantly Increased Risk of Heart Failure Events: Results From the MultiSENSE Study. AB - BACKGROUND: Care of heart failure (HF) patients results in a high burden on healthcare resources, and estimating prognosis is becoming increasingly important to triage resources wisely. Natriuretic peptides are recommended prognosticators in chronic HF. Our objective was to evaluate whether a multisensor HF index and alert algorithm (HeartLogic) replaces or augments current HF risk stratification. METHODS AND RESULTS: MultiSENSE (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) enrolled 900 patients with cardiac resynchronization therapy defibrillators enabled for collection of heart sounds, respiration, thoracic impedance, heart rate, and activity data. The HeartLogic algorithm automatically calculated a daily HF index and identified periods IN or OUT of an active alert state relative to a configurable threshold. Patients experienced 192 independently adjudicated HF events (average rate, 0.20/patient-year [pt-yr]) during 1 year of follow-up. HF event rates while IN alert was 10-fold higher than OUT of alert (0.80 versus 0.08 events/pt-yr). Combined with NT-proBNP (N-terminal pro-B-type natriuretic peptide) at enrollment (relative to 1000 pg/mL threshold, event rate was 0.42 [HIGH] versus 0.07 [LOW] events/pt-yr), substratification found the lowest risk group (LOW NT-proBNP and OUT of alert) experienced 0.02 events/pt-yr, whereas the highest risk group (HIGH NT-proBNP and IN alert) was associated with a 50-fold increased risk of an HF event (1.00 events/pt-yr) relative to the lowest risk group. CONCLUSIONS: Dynamic assessment using implantable device sensors within HeartLogic by itself or in conjunction with NT proBNP measurements can identify time-intervals when patients are at significantly increased risk of worsening HF and potentially better triage resources to this vulnerable patient population. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01128166. PMID- 30002114 TI - Dermal Interstitial Alterations in Patients With Heart Failure and Reduced Ejection Fraction: A Potential Contributor to Fluid Accumulation? AB - BACKGROUND: Large networks of interstitial glycosaminoglycans help to regulate water and electrolyte homeostasis. The relation between dermal interstitial alterations and occurrence of edema in heart failure patients with reduced ejection fraction (HFrEF) is unknown. We hypothesize that in HFrEF patients (1) interstitial glycosaminoglycan density is increased, (2) changes in the interstitial glycosaminoglycan network are associated with interstitial fluid accumulation, and (3) there is a link between the interstitial glycosaminoglycan network and the renin-angiotensin-aldosterone system. METHODS AND RESULTS: Two punch biopsies of the skin were obtained in healthy subjects (n=18) and HFrEF patients (n=29). Alcian blue staining and immunostaining for the angiotensin II type 1 receptor was performed. After obtaining tissue water content, total interstitial glycosaminoglycan (uronic acid) and sulfated glycosaminoglycan were quantified. A venous blood sample, clinical examination, and echocardiography were obtained. A significantly higher interstitial glycosaminoglycan content was observed in HFrEF patients compared with healthy subjects (uronic acid: 13.0+/ 4.2 versus 9.6+/-1.6 MUg/mg; P=0.002; sulfated glycosaminoglycan: 14.1 [11.7; 18.1] versus 10.0 [9.1; 10.8] MUg/mg; P<0.001). Uronic acid and sulfated glycosaminoglycan density were strongly associated with tissue water content and peripheral edema (uronic acid: rho=0.66; P<0.0001 and sulfated glycosaminoglycan: tau=0.58; P<0.0001). Expression of the angiotensin II type 1 receptor was found on dermal cells, although use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker was associated with significantly lower levels of interstitial glycosaminoglycans in HFrEF patients. CONCLUSIONS: Interstitial glycosaminoglycan concentration is significantly increased in HFrEF patients compared with healthy subjects and correlated with tissue water content and clinical signs of volume overload. A better appreciation of the interstitial compartment might improve management of volume overload in HF. PMID- 30002115 TI - The Luck of Having a Cardiac Implantable Electronic Device. PMID- 30002116 TI - Regulation of Fluid Volume From the Outside: A Role of Glycosaminoglycans in the Skin Interstitium? PMID- 30002117 TI - Fresh approaches to vaccine development: New financial and economic models are required to bring more vaccines against a wider range of diseases to the market. PMID- 30002118 TI - Dual localized kinesin-12 POK2 plays multiple roles during cell division and interacts with MAP65-3. AB - Kinesins are versatile nano-machines that utilize variable non-motor domains to tune specific motor microtubule encounters. During plant cytokinesis, the kinesin 12 orthologs, PHRAGMOPLAST ORIENTING KINESIN (POK)1 and POK2, are essential for rapid centrifugal expansion of the cytokinetic apparatus, the phragmoplast, toward a pre-selected cell plate fusion site at the cell cortex. Here, we report on the spatio-temporal localization pattern of POK2, mediated by distinct protein domains. Functional dissection of POK2 domains revealed the association of POK2 with the site of the future cell division plane and with the phragmoplast during cytokinesis. Accumulation of POK2 at the phragmoplast midzone depends on its functional POK2 motor domain and is fine-tuned by its carboxy-terminal region that also directs POK2 to the division site. Furthermore, POK2 likely stabilizes the phragmoplast midzone via interaction with the conserved microtubule associated protein MAP65-3/PLEIADE, a well-established microtubule cross-linker. Collectively, our results suggest that dual localized POK2 plays multiple roles during plant cell division. PMID- 30002120 TI - Visual cycle proteins: Structure, function, and roles in human retinal disease. AB - Here, we seek to summarize the current understanding of the biochemical and molecular events mediated by visual cycle molecules in the eye. The structures and functions of selected visual cycle proteins and their roles in human retinal diseases are also highlighted. Genetic mutations and malfunctions of these proteins provide etiological evidence that many ocular diseases arise from anomalies of retinoid (vitamin A) metabolism and related visual processes. Genetic retinal disorders such as retinitis pigmentosa, Leber's congenital amaurosis, and Stargardt's disease are linked to structural changes in visual cycle proteins. Moreover, recent reports suggest that visual cycle proteins may also play a role in the development of diabetic retinopathy. Basic science has laid the groundwork for finding a cure for many of these blindness-causing afflictions, but much work remains. Some translational research projects have advanced to the clinical trial stage, while many others are still in progress, and more are at the ideas stage and remain yet to be tested. Some examples of these studies are discussed. Recent and future progress in our understanding of the visual cycle will inform intervention strategies to preserve human vision and prevent blindness. PMID- 30002121 TI - The unusual glycine-rich C terminus of the Acinetobacter baumannii RNA chaperone Hfq plays an important role in bacterial physiology. AB - Acinetobacter baumannii is a Gram-negative nosocomial pathogen that causes soft tissue infections in patients who spend a long time in intensive care units. This recalcitrant bacterium is very well known for developing rapid drug resistance, which is a combined outcome of its natural competence and mobile genetic elements. Successful efforts to treat these infections would be aided by additional information on the physiology of A. baumannii Toward that end, we recently reported on a small RNA (sRNA), AbsR25, in this bacterium that regulates the genes of several efflux pumps. Because sRNAs often require the RNA chaperone Hfq for assistance in binding to their cognate mRNA targets, we identified and characterized this protein in A. baumannii The homolog in A. baumannii is a large protein with an extended C terminus unlike Hfqs in other Gram-negative pathogens. The extension has a compositional bias toward glycine and, to a lower extent, phenylalanine and glutamine, suggestive of an intrinsically disordered region. We studied the importance of this glycine-rich tail using truncated versions of Hfq in biophysical assays and complementation of an hfq deletion mutant, finding that the tail was necessary for high-affinity RNA binding. Further tests implicate Hfq in important cellular processes of A. baumannii like metabolism, drug resistance, stress tolerance, and virulence. Our findings underline the importance of the glycine-rich C terminus in RNA binding, ribo-regulation, and auto-regulation of Hfq, demonstrating this hitherto overlooked protein motif to be an indispensable part of the A. baumannii Hfq. PMID- 30002119 TI - Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine. AB - Melanoma antigen genes (Mage) were first described as tumour markers. However, some of Mage are also expressed in healthy cells where their functions remain poorly understood. Here, we describe an unexpected role for one of these genes, Maged1, in the control of behaviours related to drug addiction. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP) and drug self administration. Electrophysiological experiments in brain slices and conditional knockout mice demonstrate that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex (PFC) and the amygdala, but not in dopaminergic or striatal and other GABAergic neurons, is necessary for cocaine-mediated behavioural sensitization, and its expression in the PFC is also required for cocaine-induced extracellular dopamine (DA) release in the nucleus accumbens (NAc). This work identifies Maged1 as a critical molecule involved in cellular processes and behaviours related to addiction. PMID- 30002122 TI - Streptococcal inhibitor of complement (SIC) modulates fibrinolysis and enhances bacterial survival within fibrin clots. AB - Some strains of the bacterial pathogen Streptococcus pyogenes secrete protein SIC (streptococcal inhibitor of complement), including strains of the clinically relevant M1 serotype. SIC neutralizes the effect of a number of antimicrobial proteins/peptides and interferes with the function of the host complement system. Previous studies have shown that some S. pyogenes proteins bind and modulate coagulation and fibrinolysis factors, raising the possibility that SIC also may interfere with the activity of these factors. Here we show that SIC interacts with both human thrombin and plasminogen, key components of coagulation and fibrinolysis. We found that during clot formation, SIC binds fibrin through its central region and that SIC inhibits fibrinolysis by interacting with plasminogen. Flow cytometry results indicated that SIC and plasminogen bind simultaneously to S. pyogenes bacteria, and fluorescence microscopy revealed co localization of the two proteins at the bacterial surface. As a consequence, SIC expressing bacteria entrapped in clots inhibit fibrinolysis, leading to delayed bacterial escape from the clots as compared with mutant bacteria lacking SIC. Moreover, within the clots SIC-expressing bacteria were protected against killing. In an animal model of subcutaneous infection, SIC-expressing bacteria exhibited a delayed systemic spread. These results demonstrate that the bacterial protein SIC interferes with coagulation and fibrinolysis and thereby enhances bacterial survival, a finding that has significant implications for S. pyogenes virulence. PMID- 30002124 TI - Interim PET-directed therapy in limited stage Hodgkin lymphoma initially treated with ABVD. PMID- 30002123 TI - The endoplasmic reticulum-resident collagen chaperone Hsp47 interacts with and promotes the secretion of decorin, fibromodulin, and lumican. AB - The build-up of diversified and tissue-specific assemblies of extracellular matrix (ECM) proteins depends on secreted and cell surface-located molecular arrays that coordinate ECM proteins into discrete designs. The family of small leucine-rich proteins (SLRPs) associates with and dictates the structure of fibrillar collagens, which form the backbone of most ECM types. However, whether SLRPs form complexes with proteins other than collagens is unclear. Here, we demonstrate that heat shock protein 47 (Hsp47), a well-established endoplasmic reticulum-resident collagen chaperone, also binds the SLRPs decorin, lumican, and fibromodulin with affinities comparable with that in the Hsp47-type I collagen interaction. Furthermore, we show that a lack of Hsp47 inhibits the cellular secretion of decorin and lumican. Our results expand the understanding of the concerted molecular interactions that control the secretion and organization of a functional collagenous ECM. PMID- 30002126 TI - N-linked glycosylation modulates the immunogenicity of recombinant human factor VIII in hemophilia A mice. AB - Immune responses to factor VIII remain the greatest complication in the treatment of severe hemophilia A. Recent epidemiological evidence has highlighted that recombinant factor VIII produced in baby hamster kidney cells is more immunogenic than factor VIII produced in Chinese hamster ovary cells. Glycosylation differences have been hypothesized to influence the immunogenicity of these synthetic concentrates. In two hemophilia A mouse models, baby hamster kidney cell-derived factor VIII elicited a stronger immune response compared to Chinese hamster ovary cell-derived factor VIII. Furthermore, factor VIII produced in baby hamster kidney cells exhibited accelerated clearance from circulation independent of von Willebrand factor. Lectin and mass spectrometry analysis of total N-linked glycans revealed differences in high-mannose glycans, sialylation, and the occupancy of glycan sites. Factor VIII desialylation did not influence binding to murine splenocytes or dendritic cells, nor surface co-stimulatory molecule expression. We did, however, observe increased levels of immunoglobulin M specific to baby hamster kidney-derived factor VIII in naive hemophilia A mice. De-N-glycosylation enhanced immunoglobulin M binding, suggesting that N-glycan occupancy masks epitopes. Elevated levels of immunoglobulin M and immunoglobulin G specific to baby hamster kidney-derived factor VIII were also observed in healthy individuals, and de-N-glycosylation increased immunoglobulin G binding. Collectively, our data suggest that factor VIII produced in baby hamster kidney cells is more immunogenic than that produced in Chinese hamster ovary cells, and that incomplete occupancy of N-linked glycosylation sites leads to the formation of immunoglobulin M- and immunoglobulin G-factor VIII immune complexes that contribute to the enhanced clearance and immunogenicity in these mouse models of hemophilia A. PMID- 30002125 TI - The SLC40A1 R178Q mutation is a recurrent cause of hemochromatosis and is associated with a novel pathogenic mechanism. AB - Hemochromatosis type 4 is one of the most common causes of primary iron overload, after HFE-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense mutations in SLC40A1 This gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous missense mutations in SLC40A1 are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare SLC40A1 variations are fortuitously observed in patients with a secondary cause of hyperferritinemia. Structure/function analysis is the most effective way of establishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We present the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevated serum ferritin concentrations and normal to low transferrin saturation levels. In vitro experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mislocalization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformational changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of function mutations and that the study of "gating residues" is necessary in order to fully understand the action mechanism of FPN1. PMID- 30002127 TI - Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells. AB - A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein alpha levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein alpha, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein alpha and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase. PMID- 30002129 TI - Differential expression of Obek controls ploidy in the Drosophila blood-brain barrier. AB - During development, tissue growth is mediated by either cell proliferation or cell growth, coupled with polyploidy. Both strategies are employed by the cell types that make up the Drosophila blood-brain barrier. During larval growth, the perineurial glia proliferate, whereas the subperineurial glia expand enormously and become polyploid. Here, we show that the level of ploidy in the subperineurial glia is controlled by the N-terminal asparagine amidohydrolase homolog Obek, and high Obek levels are required to limit replication. In contrast, perineurial glia express moderate levels of Obek, and increased Obek expression blocks their proliferation. Interestingly, other dividing cells are not affected by alteration of Obek expression. In glia, Obek counteracts fibroblast growth factor and Hippo signaling to differentially affect cell growth and number. We propose a mechanism by which growth signals are integrated differentially in a glia-specific manner through different levels of Obek protein to adjust cell proliferation versus endoreplication in the blood-brain barrier. PMID- 30002128 TI - Molecular analysis of enthesopathy in a mouse model of hypophosphatemic rickets. AB - The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH. PMID- 30002130 TI - Histone deacetylase activity has an essential role in establishing and maintaining the vertebrate neural crest. AB - The neural crest, a progenitor population that drove vertebrate evolution, retains the broad developmental potential of the blastula cells it is derived from, even as neighboring cells undergo lineage restriction. The mechanisms that enable these cells to preserve their developmental potential remain poorly understood. Here, we explore the role of histone deacetylase (HDAC) activity in this process in Xenopus We show that HDAC activity is essential for the formation of neural crest, as well as for proper patterning of the early ectoderm. The requirement for HDAC activity initiates in naive blastula cells; HDAC inhibition causes loss of pluripotency gene expression and blocks the ability of blastula stem cells to contribute to lineages of the three embryonic germ layers. We find that pluripotent naive blastula cells and neural crest cells are both characterized by low levels of histone acetylation, and show that increasing HDAC1 levels enhance the ability of blastula cells to be reprogrammed to a neural crest state. Together, these findings elucidate a previously uncharacterized role for HDAC activity in establishing the neural crest stem cell state. PMID- 30002131 TI - Direct control of somatic stem cell proliferation factors by the Drosophila testis stem cell niche. AB - Niches have traditionally been characterised as signalling microenvironments that allow stem cells to maintain their fate. This definition implicitly assumes that the various niche signals are integrated towards a binary fate decision between stemness and differentiation. However, observations in multiple systems have demonstrated that stem cell properties, such as proliferation and self-renewal, can be uncoupled at the level of niche signalling input, which is incompatible with this simplified view. We have studied the role of the transcriptional regulator Zfh1, a shared target of the Hedgehog and Jak/Stat niche signalling pathways, in the somatic stem cells of the Drosophila testis. We found that Zfh1 binds and downregulates salvador and kibra, two tumour suppressor genes of the Hippo/Wts/Yki pathway, thereby restricting Yki activation and proliferation to the Zfh1+ stem cells. These observations provide an unbroken link from niche signal input to an individual aspect of stem cell behaviour that does not, at any step, involve a fate decision. We discuss the relevance of these findings for an overall concept of stemness and niche function. PMID- 30002133 TI - Liver Glutamate Dehydrogenase Controls Whole-Body Energy Partitioning Through Amino Acid-Derived Gluconeogenesis and Ammonia Homeostasis. AB - Ammonia detoxification and gluconeogenesis are major hepatic functions mutually connected through amino acid metabolism. The liver is rich in glutamate dehydrogenase (GDH) that catalyzes the reversible oxidative deamination of glutamate to alpha-ketoglutarate and ammonia, thus bridging amino acid-to-glucose pathways. Here we generated inducible liver-specific GDH-knockout mice (HepGlud1 /- ) to explore the role of hepatic GDH on metabolic homeostasis. Investigation of nitrogen metabolism revealed altered ammonia homeostasis in HepGlud1-/- mice characterized by increased circulating ammonia associated with reduced detoxification process into urea. The abrogation of hepatic GDH also modified energy homeostasis. In the fasting state, HepGlud1-/- mice could barely produce glucose in response to alanine due to impaired liver gluconeogenesis. Compared with control mice, lipid consumption in HepGlud1-/- mice was favored over carbohydrates as a compensatory energy fuel. The changes in energy partitioning induced by the lack of liver GDH modified the circadian rhythm of food intake. Overall, this study demonstrates the central role of hepatic GDH as a major regulator for the maintenance of ammonia and whole-body energy homeostasis. PMID- 30002132 TI - Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo. AB - Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l-NG-nitro-l arginine methyl ester (l-NAME) enhanced the rate of TIE by ~30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM. PMID- 30002135 TI - Opposing effects of intracellular versus extracellular adenine nucleotides on autophagy: implications for beta-cell function. AB - AMPK-mTORC1 signaling senses nutrient availability, thereby regulating autophagy. Surprisingly, we found that, in beta-cells, the AMPK activator 5-amino-4 imidazolecarboxamide ribofuranoside (AICAR) inhibited, rather than stimulated, autophagy. AICAR is an intermediate in the generation of inosine monophosphate, with subsequent conversion to other purine nucleotides. Adenosine regulated autophagy in a concentration-dependent manner: at high concentrations, it mimicked the AICAR effect on autophagy, whereas at low concentrations it stimulated autophagy through its cognate A1 receptor. Adenosine regulation of autophagy was independent of AMPK or mTORC1 activity. Adenosine kinase (ADK) is the principal enzyme for metabolic adenosine clearance. ADK knockdown and pharmacological inhibition of the enzyme markedly stimulated autophagy in an adenosine A1 receptor-dependent manner. High-concentration adenosine increased insulin secretion in a manner sensitive to treatment with the autophagy inducer Tat-beclin1, and inhibition of autophagy augmented secretion. In conclusion, high concentrations of AICAR or adenosine inhibit autophagy, whereas physiological concentrations of adenosine or inhibition of adenosine clearance by ADK stimulate autophagy via the adenosine receptor. Adenosine might thus be an autocrine regulator of autophagy, independent of AMPK-mTORC1 signaling. Adenosine regulates insulin secretion, in part, through modulation of autophagy. PMID- 30002137 TI - FGFR2-activating mutations disrupt cell polarity to potentiate migration and invasion in endometrial cancer cell models. AB - Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer. However, little is known about how these FGFR2 mutations contribute to endometrial cancer metastasis. Here, we report that expression of the activating mutations FGFR2N550K and FGFR2Y376C in an endometrial cancer cell model induce Golgi fragmentation, and loss of polarity and directional migration. In mutant FGFR2-expressing cells, this was associated with an inability to polarise intracellular pools of FGFR2 towards the front of migrating cells. Such polarization defects were exacerbated in three-dimensional culture, where FGFR2 mutant cells were unable to form well organised acini, instead undergoing exogenous ligand-independent invasion. Our findings uncover collective cell polarity and invasion as common targets of disease-associated FGFR2 mutations that lead to poor outcome in endometrial cancer patients. PMID- 30002138 TI - Rectal Levothyroxine for the Treatment of Hypothyroidism: A Case Study. AB - Transient hypothyroidism can present itself as clinically asymptomatic or with few symptoms. Early treatment with levothyroxine (L-T4) prevents complications related to this disorder. We report a case of a male infant with concomitant short bowel syndrome and transient hypothyroidism treated with rectal L-T4. A 4 month-and-10-day-old boy with previous gastroschisis underwent multiple surgical approaches for small bowel resection and developed short bowel syndrome. We suspected hypothyroidism because of jaundice (direct bilirubin up to 59 mg/dL), the absence of evacuation, oral diet intolerance, and intestinal dysmotility. Because of a thyrotropin level of 34.45 MUIU/mL and a free thyroxine level of 0.64 ng/dL, the diagnosis was confirmed. Because fasting was demanding, we started the patient on rectal diluted L-T4. After 4 weeks, the patient had spontaneous peristalsis, improvement of jaundice (direct bilirubin: 4.6 mg/dL), and normalized free thyroxine and thyrotropin values. In the present case, the patient was diagnosed with hypothyroidism and was on absolute fasting. An alternative route of drug administration was warranted. We empirically prescribed rectal diluted L-T4 when intravenous and suppository L-T4 were not available. This method was proven to be safe and effective in improving the patient's clinical and biochemical status. Rectal L-T4 is a possible alternative route of administration to treat hypothyroidism in patients who are unable to take the medication orally. PMID- 30002134 TI - miR-30a Remodels Subcutaneous Adipose Tissue Inflammation to Improve Insulin Sensitivity in Obesity. AB - Chronic inflammation accompanies obesity and limits subcutaneous white adipose tissue (WAT) expandability, accelerating the development of insulin resistance and type 2 diabetes mellitus. MicroRNAs (miRNAs) influence expression of many metabolic genes in fat cells, but physiological roles in WAT remain poorly characterized. Here, we report that expression of the miRNA miR-30a in subcutaneous WAT corresponds with insulin sensitivity in obese mice and humans. To examine the hypothesis that restoration of miR-30a expression in WAT improves insulin sensitivity, we injected adenovirus (Adv) expressing miR-30a into the subcutaneous fat pad of diabetic mice. Exogenous miR-30a expression in the subcutaneous WAT depot of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. High-throughput proteomic profiling and RNA-Seq suggested that miR-30a targets the transcription factor STAT1 to limit the actions of the proinflammatory cytokine interferon-gamma (IFN-gamma) that would otherwise restrict WAT expansion and decrease insulin sensitivity. We further demonstrated that miR-30a opposes the actions of IFN-gamma, suggesting an important role for miR-30a in defending adipocytes against proinflammatory cytokines that reduce peripheral insulin sensitivity. Together, our data identify a critical molecular signaling axis, elements of which are involved in uncoupling obesity from metabolic dysfunction. PMID- 30002136 TI - Primary cilia are necessary for Prx1-expressing cells to contribute to postnatal skeletogenesis. AB - Although Prx1 (also known as PRRX1)-expressing cells and their primary cilia are critical for embryonic development, they have yet to be studied in the context of postnatal skeletogenesis owing to the lethality of mouse models. A tamoxifen inducible Prx1 model has been developed, and we determined that expression directed by this promoter is highly restricted to the cambium layers in the periosteum and perichondrium after birth. To determine the postnatal role of these cambium layer osteochondroprogenitors (CLOPs) and their primary cilia, we developed models to track the fate of CLOPs (Prx1CreER-GFP;Rosa26tdTomato) and selectively disrupt their cilia (Prx1CreER-GFP;Ift88fl/fl). Our tracking studies revealed that CLOPs populate cortical and trabecular bone, the growth plate and secondary ossification centers during the normal program of postnatal skeletogenesis. Furthermore, animals lacking CLOP cilia exhibit stunted limb growth due to disruptions in endochondral and intramembranous ossification. Histological examination indicates that growth is stunted due to limited differentiation, proliferation and/or abnormal hypertrophic differentiation in the growth plate. Collectively, our results suggest that CLOPs are programmed to rapidly populate distant tissues and produce bone via a primary cilium-mediated mechanism in the postnatal skeleton. PMID- 30002139 TI - Placental Abruption and Child Mortality. AB - BACKGROUND AND OBJECTIVES: Placental abruption causes asphyxia and leads to high perinatal mortality. Our objective was to study the overall mortality and causes of death among children born after placental abruption. METHODS: Data on children born from singleton pregnancies complicated by placental abruption between 1987 and 2005 were collected from the Finnish Medical Birth Register, the Hospital Discharge Register, and the Cause-of-Death Register. A reference group consisted of children born from pregnancies without placental abruption. After excluding stillbirths, the final study sample comprised 3888 children born after placental abruption (index children) and 12 530 referent children. The main outcome measure was overall mortality. RESULTS: By the end of 2013, there were 280 deaths among the index children and 107 deaths among the referent children. Compared with the referent children, the overall mortality among the index children was significantly increased (hazard ratio: 8.70; 95% confidence interval 6.96-10.90). During the neonatal period (0-27 days) the mortality was nearly 15-fold (14.8; 10.9-20.0), birth-related asphyxia being the leading cause of death (108; 34 341). The mortality remained high during days 28 to 365 (10.3; 4.83-21.8) and beyond 365 days (1.70; 1.03-2.79). Furthermore, the overall mortality was increased among the index children born at 32 to 36 + 6 gestational weeks (2.77; 1.54-4.98) and at >=37 weeks (4.98; 3.54-6.99) and among children with a birth weight of 2500 g or more (5.94; 4.33-8.14). CONCLUSIONS: The impact of abruption on offspring mortality extends far beyond the perinatal period. This is mainly due to birth-related asphyxia and prematurity-related consequences. PMID- 30002141 TI - From Cardiologist to Patient.... PMID- 30002140 TI - Adapting and Evaluating a Health System Intervention From Kaiser Permanente to Improve Hypertension Management and Control in a Large Network of Safety-Net Clinics. AB - BACKGROUND: Nearly half of Americans with diagnosed hypertension have uncontrolled blood pressure (BP) while some integrated healthcare systems, such as Kaiser Permanente Northern California, have achieved control rates upwards 90%. METHODS AND RESULTS: We adapted Kaiser Permanente's evidence-based treatment protocols in a racially and ethnically diverse population at 12 safety-net clinics in the San Francisco Health Network. The intervention consisted of 4 elements: a hypertension registry, a simplified treatment intensification protocol that included fixed-dose combination medications containing diuretics, standardized BP measurement protocol, and BP check visits led by registered nurse and pharmacist staff. The study population comprised patients with hypertension who made >=1 primary care visits within the past 24 months (n=15 917) and had a recorded BP measurement within the past 12 months. We conducted a postintervention time series analysis from August 2014 to August 2016 to assess the effect of the intervention on BP control for 24 months for the pilot site and for 15 months for 11 other San Francisco Health Network clinics combined. Secondary outcomes were changes in use of guideline-recommended medication prescribing. Rates of BP control increased at the pilot site (68%-74%; P<0.01) and the 11 other San Francisco Health Network clinic sites (69%-74%; P<0.01). Statistically significant improvements in BP control rates (P<0.01) at the 11 San Francisco Health Network clinic sites occurred in all racial and ethnic groups (blacks, 60%-66%; whites, 69%-75%; Latinos, 67%-72%; Asians, 78%-82%). Use of fixed-dose combination medications increased from 10% to 13% (P<0.01), and the percentage of angiotensin-converting enzyme inhibitor prescriptions dispensed in combination with a thiazide diuretic increased from 36% to 40% (P<0.01). CONCLUSIONS: Evidence-based system approaches to improving BP control can be implemented in safety-net settings and could play a pivotal role in achieving improved population BP control and reducing hypertension disparities. PMID- 30002142 TI - How do policymakers interpret and implement the principle of equivalence with regard to prison health? A qualitative study among key policymakers in England. AB - BACKGROUND: The principle of equivalence in prison health has been established for nearly four decades. It seeks to ensure that prisoners have access to the same level of healthcare as members of society at large, which is entrenched within the international legal framework and England's national health policies. AIMS: This study examined how key policymakers interpret and implement the principle of equivalence in English prisons. It also identified opportunities and threats associated with the application of the principle. METHODS: In total, 30 policymakers took part in this research. These participants engaged in policymaking activities and occupied positions of authority in the prison field. RESULTS: Despite the policymakers' consensus on the importance of the equivalence principle, there was a varying degree of understanding regarding what constitutes 'equivalence'. Participants described how the security culture impedes prisoners' access to healthcare services. Additionally, the increasing size and complexity of the prison population, coupled with a diminishing level of resources, reduce the level of care being provided in prisons and thus compromise implementation of equivalence in English prisons. CONCLUSIONS: Inconsistent interpretation of equivalence, the prevailing security drive, increasing numbers and health complexities of prisoners and fiscal austerity threaten the implementation of equivalence in English prisons. This research calls for new guidance on how to interpret and implement equivalence, along with measures to educate prison governors and staff on the prison rehabilitation value, ensure greater investment in prison health and consider alternatives to imprisonment to future-proof the principle of equivalence in the English prison system. PMID- 30002143 TI - The need for donor consent in mitochondrial replacement. AB - Mitochondrial replacement therapy (MRT) requires oocytes of women whose mitochondrial DNA will be transmitted to resultant children. These techniques are scientifically, ethically and socially controversial; it is likely that some women who donate their oocytes for general in vitro fertilisation usage would nevertheless oppose their genetic material being used in MRT. The possibility of oocytes being used in MRT is therefore relevant to oocyte donation and should be included in the consent process when applicable. In present circumstances (especially because MRT is still an emerging technique), specific consent should be obtained. However, once MRT becomes more routine, such consent could be incorporated into the general consent process for oocyte donation. The reported lack of proper consent for MRT from the oocyte donor in the first baby born via the technique is an ethical failing and should be corrected in any future practice of MRT. PMID- 30002144 TI - Oncogene-specific T cells fail to eradicate lymphoma-initiating B cells in mice. AB - To date, little is known about the interaction between (pre-)malignant B cells and T cells. We generated transgenic mice that allow B cell-specific induction of the oncogene SV40 large T-antigen (TAg) to analyze the role of oncogene-specific T cells during sporadic B-cell lymphoma development. Constitutive TAg expression in CD19-Cre * LoxP-Tag mice resulted in TAg-tolerant CD8+ T cells and development of B-cell lymphomas. In contrast, CD19-CreERT2 * LoxP-Tag mice retained TAg competent CD8+ T cells at time of oncogene induction and TAg expression in few B cells of adult mice resulted in exceptionally rare lymphoma formation late in life. Increased lymphoma incidence in the absence of TAg-specific T cells suggested T cell-mediated inhibition of lymphoma progression. However, TAg initiated B cells were not eliminated by T cells and detected long term. Our results demonstrate a failure of the immune system to eradicate lymphoma initiating B cells, retaining the risk of lymphoma development. PMID- 30002145 TI - Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. AB - Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti cardiolipin, and anti-beta2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272. PMID- 30002146 TI - Speaking up about care concerns in the ICU: patient and family experiences, attitudes and perceived barriers. AB - BACKGROUND: Little is known about patient/family comfort voicing care concerns in real time, especially in the intensive care unit (ICU) where stakes are high and time is compressed. Experts advocate patient and family engagement in safety, which will require that patients/families be able to voice concerns. Data on patient/family attitudes and experiences regarding speaking up are sparse, and mostly include reporting events retrospectively, rather than pre-emptively, to try to prevent harm. We aimed to (1) assess patient/family comfort speaking up about common ICU concerns; (2) identify patient/family-perceived barriers to speaking up; and (3) explore factors associated with patient/family comfort speaking up. METHODS: In collaboration with patients/families, we developed a survey to evaluate speaking up attitudes and behaviours. We surveyed current ICU families in person at an urban US academic medical centre, supplemented with a larger national internet sample of individuals with prior ICU experience. RESULTS: 105/125 (84%) of current families and 1050 internet panel participants with ICU history completed the surveys. Among the current ICU families, 50%-70% expressed hesitancy to voice concerns about possible mistakes, mismatched care goals, confusing/conflicting information and inadequate hand hygiene. Results among prior ICU participants were similar. Half of all respondents reported at least one barrier to voicing concerns, most commonly not wanting to be a 'troublemaker', 'team is too busy' or 'I don't know how'. Older, female participants and those with personal or family employment in healthcare were more likely to report comfort speaking up. CONCLUSION: Speaking up may be challenging for ICU patients/families. Patient/family education about how to speak up and assurance that raising concerns will not create 'trouble' may help promote open discussions about care concerns and possible errors in the ICU. PMID- 30002148 TI - Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo. AB - Background and Purpose- This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging. Methods- In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers 18F-GE180 and 68Ga-Pentixafor and evaluated by histopathology. In addition, 68Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS. Results- Distinct patterns of upregulation of TSPO (18F-GE180 uptake) and CXCR4 (68Ga-Pentixafor uptake) were identified in carotid plaque by autoradiography. The spatial distribution was associated with specific histological hallmarks that are established features of high-risk plaque: TSPO upregulation correlated with activated macrophages infiltration, whereas CXCR4 upregulation also corresponded to areas of intraplaque hemorrhage. 68Ga Pentixafor uptake was significantly higher in plaques of symptomatic compared with asymptomatic CS. Clinical positron emission tomography revealed marked 68Ga Pentixafor uptake in carotid plaque of a patient with high-grade CS. Conclusions- Clinical imaging of molecular signatures of high-risk atherosclerotic plaque is feasible and may become a promising diagnostic tool for comprehensive characterization of carotid disease. This methodology provides a platform for future studies targeting carotid plaque. PMID- 30002147 TI - Clinical Prediction Rules to Classify Types of Stroke at Prehospital Stage. AB - Background and Purpose- Endovascular therapy is effective against acute cerebral large vessel occlusion (LVO). However, many patients do not receive such interventions because of the lack of timely identification of the type of stroke. If the types of stroke (any stroke, LVO, intracranial hemorrhage [ICH], and subarachnoid hemorrhage [SAH]) were to be predicted at the prehospital stage, better access to appropriate interventions would be possible. Japan Urgent Stroke Triage (JUST) score was clinical prediction rule to classify suspected patients of acute stroke into different types at the prehospital stage. Methods- We obtained information for signs and symptoms and medical history of consecutive suspected patients of acute stroke at prehospital stage from paramedics and final diagnosis from the receiving hospital. We constructed derivation cohort in the historical multicenter cohort study from June 2015 to March 2016 and validation cohort in the prospective multicenter cohort study from August 2016 to July 2017. The derivation and the validation cohorts included 1229 and 1007 patients, respectively. We constructed multivariate logistic regression models with 21 variables to develop clinical prediction rules, which distinguish between different types of stroke: any stroke, LVO, ICH, and SAH. Results- Among the 1229 patients (median age, 72 years; 55% men) in the derivation cohort, 533 stroke, 104 LVO, 169 ICH, and 57 SAH cases were observed. The developed rules showed that the areas under the receiver operating curves were 0.88 for any stroke, 0.92 for LVO, 0.84 for ICH, and 0.89 for SAH. The validation cohort of 1007 patients (median age, 75 years; 56% men) showed that the areas under the curves of any stroke, LVO, ICH, and SAH were 0.80, 0.85, 0.77, and 0.94, respectively. Conclusions- These clinical prediction rules can help paramedics classify the suspected patients of stroke into any stroke, LVO, ICH, and SAH groups with excellent accuracy. PMID- 30002150 TI - How to Organize a Journal Club for Fellows and Residents. PMID- 30002149 TI - Stereotactic Radiosurgery for Pediatric Versus Adult Brain Arteriovenous Malformations. AB - Background and Purpose- The aim of this international, multicenter, retrospective matched cohort study is to directly compare the outcomes after stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVM) in pediatric versus adult patients. Methods- We performed a retrospective review of patients with AVM who underwent SRS at 8 institutions participating in the International Gamma Knife Research Foundation from 1987 to 2014. Patients were categorized into pediatric (<18 years of age) and adult (>=18 years of age) cohorts and matched in a 1:1 ratio using propensity scores. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation induced changes. Results- From a total of 2191 patients who were eligible for inclusion in the overall study cohort, 315 were selected for each of the matched cohorts. There were no significant differences between matched pediatric versus adult cohorts with respect to the rates of favorable outcome (59% versus 58%; P=0.936), AVM obliteration (62% versus 63%; P=0.934), post-SRS hemorrhage (9% versus 7%; P=0.298), radiological radiation-induced changes (26% versus 26%; P=0.837), symptomatic radiation-induced changes (7% versus 9%; P=0.383), or permanent radiation-induced changes (2% versus 3%; P=0.589). The all-cause mortality rate was significantly lower in the matched pediatric cohort (3% versus 10%; P=0.003). Conclusions- The outcomes after SRS for comparable AVMs in pediatric versus adult patients were not found to be appreciably different. SRS remains a reasonable treatment option for appropriately selected pediatric patients with AVM, who harbor a high cumulative lifetime hemorrhage risk. Age seems to be a poor predictor of AVM outcomes after SRS. PMID- 30002151 TI - Admission Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker of Outcomes in Large Vessel Occlusion Strokes. AB - Background and Purpose- The purpose of this study is to evaluate the relationship between neutrophil-to-lymphocyte ratio (NLR) at admission with safety and efficacy outcomes in acute stroke patients with large vessel occlusion after mechanical thrombectomy. Methods- Consecutive large vessel occlusion patients treated with mechanical thrombectomy during a 4-year period were evaluated. Outcome measures included symptomatic intracranial hemorrhage, 3-month mortality, successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b/3), and 3-month functional independence (modified Rankin Scale scores of 0-2). Results- A total of 293 large vessel occlusion patients underwent mechanical thrombectomy (median admission NLR, 3.5; interquartile range [IQR], 1.7-6.8). In initial univariable analyses, higher median admission NLR values were documented in patients with symptomatic intracranial hemorrhage (8.5; IQR, 4.7-11.3) versus (3.9; IQR, 1.9-6.5); P<0.001 and individuals who were dead at 3-months (5.4; IQR, 2.8-9.6) versus (4.0; IQR, 1.8-6.4); P=0.004. Lower NLR values were recorded in patients with 3-month functional independence (3.7; IQR, 1.7-6.5) versus (4.3; IQR, 2.6-8.3); P=0.039. After adjustment for potential confounders, a 1-point increase in NLR was independently associated with higher odds of symptomatic intracranial hemorrhage (odds ratio, 1.11; 95% CI, 1.03-1.20; P=0.006) and 3 month mortality (odds ratio, 1.08; 95% CI, 1.01-1.16; P=0.014). Conclusions- Higher admission NLR is an independent predictor of symptomatic intracranial hemorrhage and 3-month mortality in large vessel occlusion patients treated with mechanical thrombectomy, and it may identify a target group for testing adjunctive anti-inflammatory therapies. PMID- 30002153 TI - Acute presentation of a partially obstructing laryngeal tumour: adjuvant agents to gaseous induction of anaesthesia. AB - We present the case of a 53-year-old man who attended our emergency department with stridor. He had recently undergone investigation for possible glottic cancer. We discuss the airway management of such a case. We believe this to be the first description of propofol target controlled infusion and clonidine to supplement a sevoflurane gas induction, in order to obtund response to intubation while maintaining spontaneous ventilation. We also consider how airway interventions may impact prognosis and need to be considered. PMID- 30002155 TI - T-wave alternans: a harbinger for malignant ventricular arrhythmias. PMID- 30002154 TI - Neonatal facial palsy, a case series: is CPAP the culprit? AB - We report a case series of three idiopathic unilateral facial nerve palsies in neonates with no identified risk factors. Neuroimaging done was normal. All the neonates had complete spontaneous recovery within a month, with no residual deficits. As per our knowledge, there are very few case reports of facial palsy in a neonate reported in literature and are often labelled as idiopathic. PMID- 30002156 TI - Circulating Tumor Microparticles Promote Lung Metastasis by Reprogramming Inflammatory and Mechanical Niches via a Macrophage-Dependent Pathway. AB - Despite the frequency of lung metastasis and its associated mortality, the mechanisms behind metastatic tumor cell survival and colonization in the lungs remain elusive. Here, we show that tumor cell-released microparticles (T-MPs) from the primary tumor site play a critical role in the metastatic process. The T MPs remodeled the lung parenchyma via a macrophage-dependent pathway to create an altered inflammatory and mechanical response to tumor cell invasion. Mechanistically, we show that circulating T-MPs readily enter the lung parenchyma where they are taken up by local macrophages and induce CCL2 production. CCL2 recruits CD11b+Ly6Chigh inflammatory monocytes to the lungs where they mature into F4/80+CD11b+Ly6C- macrophages that not only produce IL6 but also trigger fibrin deposition. IL6 and the deposited fibrin facilitate the survival and growth of tumor-repopulating cells in the lungs by providing chemical and mechanical signals, respectively, thus setting the stage for lung metastasis. These data illustrate that T-MPs reprogram the lung microenvironment promoting metastasis. Cancer Immunol Res; 6(9); 1046-56. (c)2018 AACR. PMID- 30002152 TI - Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. AB - Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ~250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6*10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5*10-8) partially independent of known common signal ( PEA(conditional)=1.4*10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9*10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8*10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH. PMID- 30002157 TI - Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort. AB - The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan-Meier techniques. We found that 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-year OS to 14.1% from 7.4% preapproval (P < 0.001). Postapproval, the proportion of MBM patients who received CBI rose from 10.5% in 2011 to 34.0% in 2015 (P < 0.001). Initial CBI in MBM patients displayed an improved median and 4-year OS of 12.4 months (compared with 5.2 months; P < 0.001) and 28.1% (compared with 11.1%), respectively. These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-year OS of 56.4 months (compared with 7.7 months; P < 0.001) and 51.5% (compared with 16.9%), respectively. Using a large national cohort composed of a "real-life" MBM treatment population, we demonstrated the dramatic OS improvements associated with novel checkpoint blockade immunotherapies. Cancer Immunol Res; 6(9); 1039 45. (c)2018 AACR. PMID- 30002158 TI - A common pattern of DNase I footprinting throughout the human mtDNA unveils clues for a chromatin-like organization. AB - Human mitochondrial DNA (mtDNA) is believed to lack chromatin and histones. Instead, it is coated solely by the transcription factor TFAM. We asked whether mtDNA packaging is more regulated than once thought. To address this, we analyzed DNase-seq experiments in 324 human cell types and found, for the first time, a pattern of 29 mtDNA Genomic footprinting (mt-DGF) sites shared by ~90% of the samples. Their syntenic conservation in mouse DNase-seq experiments reflect selective constraints. Colocalization with known mtDNA regulatory elements, with G-quadruplex structures, in TFAM-poor sites (in HeLa cells) and with transcription pausing sites, suggest a functional regulatory role for such mt DGFs. Altered mt-DGF pattern in interleukin 3-treated CD34+ cells, certain tissue differences, and significant prevalence change in fetal versus nonfetal samples, offer first clues to their physiological importance. Taken together, human mtDNA has a conserved protein-DNA organization, which is likely involved in mtDNA regulation. PMID- 30002163 TI - We must collaborate for a better future. PMID- 30002164 TI - Brexit: medicines talks hitting 'a brick wall'. PMID- 30002166 TI - 130 years of Recording veterinary knowledge. PMID- 30002162 TI - Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors. AB - Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion channel activator motif. Because these compounds block action potential generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold. PMID- 30002159 TI - Plant 24-nt reproductive phasiRNAs from intramolecular duplex mRNAs in diverse monocots. AB - In grasses, two pathways that generate diverse and numerous 21-nt (premeiotic) and 24-nt (meiotic) phased siRNAs are highly enriched in anthers, the male reproductive organs. These "phasiRNAs" are analogous to mammalian piRNAs, yet their functions and evolutionary origins remain largely unknown. The 24-nt meiotic phasiRNAs have only been described in grasses, wherein their biogenesis is dependent on a specialized Dicer (DCL5). To assess how evolution gave rise to this pathway, we examined reproductive phasiRNA pathways in nongrass monocots: garden asparagus, daylily, and lily. The common ancestors of these species diverged approximately 115-117 million years ago (MYA). We found that premeiotic 21-nt and meiotic 24-nt phasiRNAs were abundant in all three species and displayed spatial localization and temporal dynamics similar to grasses. The miR2275-triggered pathway was also present, yielding 24-nt reproductive phasiRNAs, and thus originated more than 117 MYA. In asparagus, unlike in grasses, these siRNAs are largely derived from inverted repeats (IRs); analyses in lily identified thousands of precursor loci, and many were also predicted to form foldback substrates for Dicer processing. Additionally, reproductive phasiRNAs were present in female reproductive organs and thus may function in both male and female germinal development. These data describe several distinct mechanisms of production for 24-nt meiotic phasiRNAs and provide new insights into the evolution of reproductive phasiRNA pathways in monocots. PMID- 30002170 TI - Lyme disease cases on the rise in the UK. AB - Georgina Mills explains how more work needs to be done on Lyme disease, in both people and animals. PMID- 30002173 TI - One Health: Doctors and vets working together for antibiotic stewardship. AB - Doctors and the farming industry are often blamed for overuse of antibiotics that spurs the growing problem of antimicrobial resistance. Ingrid Torjesen reports from an expert discussion jointly hosted by Vet Record and The BMJ to identify ways to tackle it. PMID- 30002174 TI - Inadequate feeding and grazing leads to illthrift and death in cattle and sheep. PMID- 30002175 TI - Mastitis diagnoses in Scotland in 2017. AB - Mastitis bacteriology plays a crucial role in understanding the epidemiology of mastitis in a herd. Understanding which bacteria are present, and the antibiotics to which they are sensitive, allows targeted preventive and control measures to be implemented. PMID- 30002176 TI - Musings on the future direction of One Health, William Hunting and tuberculosis, while listening to blackbirds sing. PMID- 30002177 TI - Making critically important antimicrobials a priority in practice. PMID- 30002178 TI - Who are you, and why are you here? PMID- 30002180 TI - The role of a good receptionist. PMID- 30002181 TI - Reviewing processes for road traffic fatalities. PMID- 30002182 TI - Seeing it from a horse's point of view. PMID- 30002183 TI - Annual review of pharmacovigilance. PMID- 30002186 TI - Are TV vets good or bad for the profession? PMID- 30002193 TI - Tumor Suppressor Activity of Selenbp1, a Direct Nkx2-1 Target, in Lung Adenocarcinoma. AB - The Nkx2-1 transcription factor promotes differentiation of lung epithelial lineages and suppresses malignant progression of lung adenocarcinoma. However, targets of Nkx2-1 that limit tumor growth and progression remain incompletely understood. Here, direct Nkx2-1 targets are identified whose expression correlates with Nkx2-1 activity in human lung adenocarcinoma. Selenium-binding protein 1 (Selenbp1), an Nkx2-1 effector that limits phenotypes associated with lung cancer growth and metastasis, was investigated further. Loss- and gain-of function approaches demonstrate that Nkx2-1 is required and sufficient for Selenbp1 expression in lung adenocarcinoma cells. Interestingly, Selenbp1 knockdown also reduced Nkx2-1 expression and Selenbp1 stabilized Nkx2-1 protein levels in a heterologous system, suggesting that these genes function in a positive feedback loop. Selenbp1 inhibits clonal growth and migration and suppresses growth of metastases in an in vivo transplant model. Genetic inactivation of Selenbp1, using CRISPR/Cas9, also enhanced primary tumor growth in autochthonous lung adenocarcinoma mouse models. Collectively, these data demonstrate that Selenbp1 is a direct target of Nkx2-1, which inhibits lung adenocarcinoma growth in vivo Implications: Selenbp1 is an important suppressor of lung tumor growth that functions in a positive feedback loop with Nkx2-1, and whose loss is associated with worse patient outcome. Mol Cancer Res; 16(11); 1737 49. (c)2018 AACR. PMID- 30002191 TI - ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties. AB - Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5' fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 5' partner is present. There is little data addressing how the 5' partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKI). On the basis of the hypothesis that the 5' partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated. Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC50s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5-10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 5' fusion partner plays an important biological role that affects sensitivity to ALK TKIs.Implications: This study shows that the 5' ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies. Mol Cancer Res; 16(11); 1724-36. (c)2018 AACR. PMID- 30002195 TI - Seven days in medicine: 4-10 July 2018. PMID- 30002192 TI - Mitotic Gene Bookmarking: An Epigenetic Program to Maintain Normal and Cancer Phenotypes. AB - Reconfiguration of nuclear structure and function during mitosis presents a significant challenge to resume the next cell cycle in the progeny cells without compromising structural and functional identity of the cells. Equally important is the requirement for cancer cells to retain the transformed phenotype, that is, unrestricted proliferative potential, suppression of cell phenotype, and activation of oncogenic pathways. Mitotic gene bookmarking retention of key regulatory proteins that include sequence-specific transcription factors, chromatin-modifying factors, and components of RNA Pol (RNAP) I and II regulatory machineries at gene loci on mitotic chromosomes plays key roles in coordinate control of cell phenotype, growth, and proliferation postmitotically. There is growing recognition that three distinct protein types, mechanistically, play obligatory roles in mitotic gene bookmarking: (i) Retention of phenotypic transcription factors on mitotic chromosomes is essential to sustain lineage commitment; (ii) Select chromatin modifiers and posttranslational histone modifications/variants retain competency of mitotic chromatin for gene reactivation as cells exit mitosis; and (iii) Functional components of RNAP I and II transcription complexes (e.g., UBF and TBP, respectively) are retained on genes poised for reactivation immediately following mitosis. Importantly, recent findings have identified oncogenes that are associated with target genes on mitotic chromosomes in cancer cells. The current review proposes that mitotic gene bookmarking is an extensively utilized epigenetic mechanism for stringent control of proliferation and identity in normal cells and hypothesizes that bookmarking plays a pivotal role in maintenance of tumor phenotypes, that is, unrestricted proliferation and compromised control of differentiation. Mol Cancer Res; 16(11); 1617-24. (c)2018 AACR. PMID- 30002194 TI - Clusterin, a Novel DEC1 Target, Modulates DNA Damage-Mediated Cell Death. AB - Differentiated embryonic chondrocyte expressed gene 1 (DEC1, also known as Sharp2/Stra13/BHLHE40) is a basic helix-loop-helix transcription factor that plays an important role in circadian rhythms, cell proliferation, apoptosis, cellular senescence, hypoxia response, and epithelial-to-mesenchymal transition of tumor cells. Secretory clusterin (sCLU) is a cytoprotective protein that guards against genotoxic stresses. Here, clusterin (CLU) was identified as a novel target gene of DEC1 and suppresses DNA damage-induced cell death in tumor cells. Mechanistically, based on chromatin immunoprecipitation and luciferase assays, DEC1 binds to and activates the promoter of the CLU gene. DEC1 and DNA damaging agents induce sCLU expression, whereas DEC1 knockdown decreases the expression of sCLU upon DNA damage. Moreover, the data demonstrate that DEC1 inhibits, whereas sCLU knockdown enhances, DNA damage-induced cell death in MCF7 breast cancer cells. Given that DEC1 and sCLU are frequently overexpressed in breast cancers, these data provide mechanistic insight into DEC1 as a prosurvival factor by upregulating sCLU to reduce the DNA damage-induced apoptotic response. Together, this study reveals sCLU as a novel target of DEC1 which modulates the sensitivity of the DNA damage response.Implications: DEC1 and sCLU are frequently overexpressed in breast cancer, and targeting the sCLU-mediated cytoprotective signaling pathway may be a novel therapeutic approach. Mol Cancer Res; 16(11); 1641-51. (c)2018 AACR. PMID- 30002196 TI - Poor Glycemic Control Is Associated With Increased Extracellular Volume Fraction in Diabetes. AB - OBJECTIVE: We assessed whether poor glycemic control is associated with an increase in myocardial fibrosis among adults with diabetes. RESEARCH DESIGN AND METHODS: We studied 47 adults with type 2 diabetes and stratified them into three groups according to their hemoglobin A1c (HbA1c) level: <6.5% (group 1; n = 12), 6.5-7.5% (group 2; n = 20), and >7.5% (group 3; n = 15). Left ventricular (LV) mass was assessed using cardiac MRI. The extracellular volume fraction (ECVF), an index of myocardial fibrosis, was measured by using myocardial T1 mapping before and after the administration of a gadolinium-based contrast agent. RESULTS: Mean HbA1c was 5.84 +/- 0.16%, 6.89 +/- 0.14%, and 8.57 +/- 0.2% in groups 1, 2, and 3, respectively. LV mass was not significantly different between the groups. The myocardial ECVF was significantly greater in groups 2 (mean 27.6% [95% CI 24.8 30.3]) and 3 (27.6% [24.4-30.8]) than in group 1 (21.1% [17.5-24.7]; P = 0.015). After adjusting for age, sex, BMI, blood pressure, and estimated glomerular filtration rate, the myocardial ECVF was significantly greater in groups 2 (27.4% [24.4-30.4]) and 3 (28% [24.5-31.5]) than in group 1 (20.9% [17.1-24.6]; P = 0.0156, ANCOVA). CONCLUSIONS: An increased myocardial ECVF, suggesting myocardial fibrosis, is independently associated with poor glycemic control among adults with diabetes. Further research should assess whether tight glycemic control can revert fibrosis to healthy myocardium or ameliorate it and its adverse clinical consequences. PMID- 30002197 TI - Performance of Cardiovascular Disease Risk Scores in People Diagnosed With Type 2 Diabetes: External Validation Using Data From the National Scottish Diabetes Register. AB - OBJECTIVE: To evaluate the performance of five cardiovascular disease (CVD) risk scores developed in diabetes populations and compare their performance to QRISK2. RESEARCH DESIGN AND METHODS: A cohort of people diagnosed with type 2 diabetes between 2004 and 2016 was identified from the Scottish national diabetes register. CVD events were identified using linked hospital and death records. Five-year risk of CVD was estimated using each of QRISK2, ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation), Cardiovascular Health Study (CHS), New Zealand Diabetes Cohort Study (NZ DCS), Fremantle Diabetes Study, and Swedish National Diabetes Register (NDR) risk scores. Discrimination and calibration were assessed using the Harrell C statistic and calibration plots, respectively. RESULTS: The external validation cohort consisted of 181,399 people with type 2 diabetes and no history of CVD. There were 14,081 incident CVD events within 5 years of follow-up. The 5-year observed risk of CVD was 9.7% (95% CI 9.6, 9.9). C statistics varied between 0.66 and 0.67 for all risk scores. QRISK2 overestimated risk, classifying 87% to be at high risk for developing CVD within 5 years; ADVANCE underestimated risk, and the Swedish NDR risk score calibrated well to observed risk. CONCLUSIONS: None of the risk scores performed well among people with newly diagnosed type 2 diabetes. Using these risk scores to predict 5-year CVD risk in this population may not be appropriate. PMID- 30002198 TI - Effects of High Blood Pressure on Cardiovascular Disease Events Among Chinese Adults With Different Glucose Metabolism. AB - OBJECTIVE: To investigate cardiovascular disease (CVD) risks caused by blood pressure (BP) of 130-139/80-89 mmHg among Chinese adults with different glucose metabolism. RESEARCH DESIGN AND METHODS: A prospective population-based cohort of 2,132 adults in Shanghai was established in 2002, and CVD information was collected during 10.9 years of follow-up. After assessing the association between BP categories and incident CVD, we analyzed the risk for CVD by blood glucose categories and BP categories combined by using multiple Cox regression analysis among 1,419 participants at follow-up. RESULTS: The corresponding incidence of CVD per 1,000 person-years for the BP <130/80 mmHg, 130-139/80-89 mmHg, and >=140/90 mmHg or treated groups were 3.0, 6.0, and 13.9, respectively. After adjusting for age, sex, and other factors, BP >=140/90 mmHg was significantly associated with a higher CVD risk in general (hazard ratio 2.68 [95% CI 1.36 5.25]) and in various blood glucose categories (normoglycemia 2.59, prediabetes 3.03, diabetes mellitus [DM] 4.98). However, BP of 130-139/80-89 mmHg was significantly associated with a higher CVD risk in an estimated baseline 10-year atherosclerotic CVD (ASCVD) risk >=10% (3.82 [1.42-9.78]) or DM (3.54 [1.05 11.88]) but not in the general population or for a baseline 10-year ASCVD risk <10%, normoglycemia, or prediabetes. CONCLUSIONS: BP of 130-139/80-89 mmHg may result in a significantly higher CVD risk in Chinese adults with an estimated 10 year ASCVD risk >=10% or DM but not in those with normoglycemia or prediabetes. PMID- 30002200 TI - Differences Between Randomized Clinical Trial Patients and Real-World Initiators of the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide. PMID- 30002201 TI - Bullous Pemphigoid and Dipeptidyl Peptidase 4 Inhibitors: A Disproportionality Analysis Based on the Japanese Adverse Drug Event Report Database. PMID- 30002205 TI - Superficial siderosis misdiagnosed as idiopathic bilateral neurosensorial deafness. AB - Superficial siderosis (SS) is a rare condition resulting from different sources of bleeding into the subpial space. The most common symptoms are: hypoacusia, ataxia, incontinence, dementia and parkinsonism. Since several neurodegenerative disorders may present with same clinical features, SS is often misdiagnosed. Here we present a case of SS misdiagnosed as idiopathic bilateral neurosensorial deafness. PMID- 30002203 TI - Proteomic Analysis of NCK1/2 Adaptors Uncovers Paralog-specific Interactions That Reveal a New Role for NCK2 in Cell Abscission During Cytokinesis. AB - Signals from cell surface receptors are often relayed via adaptor proteins. NCK1 and NCK2 are Src-Homology (SH) 2 and 3 domain adaptors that regulate processes requiring a remodeling of the actin cytoskeleton. Evidence from gene inactivation in mouse suggests that NCK1 and NCK2 are functionally redundant, although recent reports support the idea of unique functions for NCK1 and NCK2. We sought to examine this question further by delineating NCK1- and NCK2-specific signaling networks. We used both affinity purification-mass spectrometry and BioID proximity labeling to identify NCK1/2 signaling networks comprised of 98 proteins. Strikingly, we found 30 proteins restricted to NCK1 and 28 proteins specifically associated with NCK2, suggesting differences in their function. We report that Nck2 -/-, but not Nck1 -/- mouse embryo fibroblasts (MEFs) are multinucleated and display extended protrusions reminiscent of intercellular bridges, which correlate with an extended time spent in cytokinesis as well as a failure of a significant proportion of cells to complete abscission. Our data also show that the midbody of NCK2-deficient cells is not only increased in length, but also altered in composition, as judged by the mislocalization of AURKB, PLK1 and ECT2. Finally, we show that NCK2 function during cytokinesis requires its SH2 domain. Taken together, our data delineate the first high confidence interactome for NCK1/2 adaptors and highlight several proteins specifically associated with either protein. Thus, contrary to what is generally accepted, we demonstrate that NCK1 and NCK2 are not completely redundant, and shed light on a previously uncharacterized function for the NCK2 adaptor protein in cell division. PMID- 30002206 TI - Multiple intestinal perforations due to blister pill pack ingestion. AB - A 72-year-old woman with morbid obesity and history of psychosis attended the emergency room due to abdominal pain. CT scan revealed a mesenteric infiltration surrounding a thickened wall bowel agglomeration; inside, a dense 2 cm foreign body with no pneumoperitoneum or peritoneal effusion. Surgery revealed four contained bowel perforations due to a blister pill pack inside the ileum; consequently, a 30 cm bowel resection was performed. Ingestion was restarted on day 2, a superficial wound infection was evacuated on day 4 and the patient was discharged 6 days after surgery. Foreign body ingestion is relatively common in paediatric patients. Adult cases are usually related to vision problems, intellectual disability and psychiatric or cognitive disorders. Mostly, no consequences are reported, but some cases (<1%) can lead to complications such as perforations or gastrointestinal (GI) bleeding. Endoscopic extraction may be considered when placed in the upper GI tract, but surgery remains imperative if perforation is established. PMID- 30002202 TI - Biochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study. AB - OBJECTIVE: To investigate the relationship of osteocalcin (OC), a marker of bone formation, and C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone resorption, with incident diabetes in older women. RESEARCH DESIGN AND METHODS: The analysis included 1,455 female participants from the population based Cardiovascular Health Study (CHS) (mean [SD] age 74.6 [5.0] years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regression. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models. RESULTS: OC and CTX were strongly correlated (r = 0.80). In cross-sectional analyses, significant or near significant inverse associations with HOMA-IR were observed for continuous levels of OC (beta = -0.12 per SD increment; P = 0.004) and CTX (beta = -0.08 per SD; P = 0.051) after full adjustment for demographic, lifestyle, and clinical covariates. During a median follow-up of 11.5 years, 196 cases of incident diabetes occurred. After full adjustment, both biomarkers exhibited inverse associations with incident diabetes (OC: hazard ratio 0.85 per SD [95% CI 0.71 1.02; P = 0.075]; CTX: 0.82 per SD [0.69-0.98; P = 0.031]), associations that were comparable in magnitude and approached or achieved statistical significance. CONCLUSIONS: In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders. PMID- 30002204 TI - Integrated Analysis of Quantitative Proteome and Transcriptional Profiles Reveals the Dynamic Function of Maternally Expressed Proteins After Parthenogenetic Activation of Buffalo Oocyte. AB - Maternal-effect genes are especially critical for early embryonic development after fertilization and until massive activation of the embryonic genome occurs. By applying a tandem mass tag (TMT)-labeled quantitative proteomics combined with RNA sequencing approach, the proteome of the buffalo was quantitatively analyzed during parthenogenesis of mature oocytes and the two-cell stage embryo. Of 1908 quantified proteins, 123 differed significantly. The transcriptome was analyzed eight stages (GV, MII, 2-cell, 4-cell, 8-cell, 16-cell, morula, blastocyst) of Buffalo using the RNA sequencing approach, and a total of 3567 unique genes were identified to be differently expressed between all consecutive stages of pre implantation development. Validation of proteomics results (TUBB3, CTNNA1, CDH3, MAP2K1), which are involved in tight junction and gap junction, revealing that the maternal expression of the proteins possibly plays a role in the formation of cellular junctions firstly after parthenogenetic activation. Correlation and hierarchical analyses of transcriptional profiles and the expression of NPM2 and NLRP5 mRNA of buffalo in vitro developed oocytes and parthenogenetic embryos indicated that the "maternal-to-zygotic transition" (MZT) process might exist in the model of parthenogenesis, which is similar to a normally fertilized embryo, and may occur between the 8-cell to 16-cell stage. These data provide a rich resource for further studies on maternal proteins and genes and are conducive to improving nuclear transfer technology. PMID- 30002207 TI - Squamous cell carcinoma arising in hypertrophic lichen planus. AB - Hypertrophic lichen planus (HLP) is a chronic T-cell-mediated inflammatory disease characterised by pruritic hypertrophic or verrucous plaques on the lower limbs. We report a case of an 87-year-old woman with a 12-year history of HLP on both lower legs presenting with malignant transformation of one lesion into a squamous cell carcinoma (SCC). Malignancy developing in cutaneous lichen planus is rare, with less than 50 cases reported in the literature. This case highlights the need to be aware of suspicious changes in long-standing HLP to allow early detection of a developing SCC. PMID- 30002208 TI - Uterine artery pseudoaneurysm with an anastomotic feeding vessel requiring repeat embolisation. AB - Uterine artery pseudoaneurysm (UAP) is a rare cause of delayed postpartum haemorrhage. Early diagnosis and endovascular management are effective in treating this condition. We present the case of a 36-year-old gravida 3, para 2 woman with delayed postpartum haemorrhage and endometritis following a spontaneous vaginal delivery. Ultrasound and catheter angiogram demonstrated a UAP arising from the distal aspect of the left uterine artery. Significant bleed persisted despite selective bilateral uterine artery embolisation. A repeat angiogram confirmed complete occlusion of bilateral uterine arteries, but abdominal aortogram demonstrated that the left ovarian artery was now feeding the pseudoaneurysm. A repeat embolisation procedure was performed to occlude the left ovarian artery. The patient was discharged the following day. Selective arterial embolisation is effective in the management of UAP. Persistent bleeding despite embolisation should raise the suspicion of anastomotic vascular supply and may require repeat embolisation. PMID- 30002209 TI - Metastatic Merkel-cell carcinoma: the dawn of a new era. AB - Merkel-cell carcinoma (MCC) is a rare but aggressive cutaneous malignancy arising most often in sun-exposed Caucasians who are immunosuppressed or the elderly. Patients with metastatic disease treated with chemotherapy have a median progression-free survival of just 3 months. This report describes a 58-year-old man with a background history of psoriasis treated with immunosuppressive therapy and subsequently diagnosed with metastatic MCC. Chemotherapy produced a partial response. Then, a novel immunotherapy agent, pembrolizumab, induced a complete response maintained for at least 19 months. Quality of life was unaffected, and toxicity from immunotherapy was minimal. At the time of writing, there was no clinical or radiological evidence of recurrence and treatment is ongoing. PMID- 30002210 TI - Combination therapy for systemic sclerosis-associated pneumatosis intestinalis. AB - We present a case of a patient with pneumatosis intestinalis and pneumoperitoneum secondary to gastrointestinal systemic sclerosis, who presented following recurrent accident and emergency attendances with abdominal pain. Pneumatosis intestinalis is a rare complication of systemic sclerosis; management approaches focus largely on exclusion of life-threatening surgical pathologies and subsequent symptom control. To date, there are still no established gold-standard treatment strategy and no large-scale trial data to support a specific management strategy. We describe a case of successful medical management with a combination of antimicrobial, elemental diet and high-flow inhalation oxygen therapy, with supporting evidence of CT image confirming resolution. This case therefore contributes to the literature, being the first to report both symptomatic and radiological improvement following combination therapy without the need for surgical intervention. PMID- 30002212 TI - Small bowel perforation by toothpick. AB - Toothpick ingestion is a rare but potentially fatal condition which may cause bowel perforation and rare complications if it migrates out of the gastrointestinal tract. This case report describes a delayed presentation of toothpick-induced small bowel injury leading to abdominal wall abscess and spondylodiscitis. A 51-year-old man was admitted twice with fever and loin pain, but repeated non-contrast CT was reported to be unremarkable. However, 5 months later, he presented with a left lower quadrant abdominal wall abscess and back pain. An updated CT showed a linear hyperdensity which was already present in previous scans, causing small bowel perforation, abdominal wall abscess and spondylodiscitis. Emergency laparotomy identified a toothpick causing small bowel perforation. The abdominal wall abscess was incised and drained, and small bowel was repaired. PMID- 30002211 TI - Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers. AB - A 65-year-old man with treatment-resistant psoriatic arthritis, hypertension, dyslipidaemia and benign prostatic hyperplasia (BPH) presented with herpes simplex virus (HSV) oral ulcers and a recent 15 lb weight loss due to reduced consumption. Five weeks previously, his methotrexate was tapered and he had begun taking azathioprine. The patient's thiopurine S-methyltransferase (TPMT) activity level was normal prior to starting azathioprine. He was found to have pancytopenia with normal folate levels and azathioprine was discontinued. His pancytopenia worsened, with a nadir 8 days after stopping azathioprine, before returning to normal levels. His oral ulcers improved and he was able to tolerate solid food. This case illustrates that decreased TPMT activity is not the only risk factor for pancytopenia as an adverse reaction to azathioprine. Furthermore, HSV stomatitis may be the presenting symptom of pancytopenia. The timeline of improvement in cell counts illustrated in this patient has implications for the management of suspected azathioprine-induced pancytopenia. PMID- 30002213 TI - Secondary spindle cell sarcoma following external beam radiotherapy for prostate cancer: a rare but devastating complication. AB - We report a case of rapidly growing sarcoma that resulted in mortality only 6 years after radiotherapy for low-grade prostate cancer.At the age of 69 years and a prostate-specific antigen (PSA) that had risen to 9.0 ug/L, transrectal ultrasound-guided biopsy of the prostate found a single core of Gleason 3+3 disease involving 4 mm of a 10 mm core. The patient declined active surveillance and completed 78 Gy of external beam radiotherapy over 39 fractions to a prostate volume of 46 mL.His PSA nadir was 0.62 ug/L 1-year postradiation; however, in April 2017, his PSA began to rise satisfying the definition of biochemical recurrence. He underwent cystoscopy, biopsy favoured an undifferentiated pleomorphic sarcoma. Restaging scans (CT/bone scan) were completed showing no metastasis, and repeat MRI showed rapid growth of the lesion in 3 months.He underwent palliative pelvic exenteration, however, 1 month later presented with large volume tumour recurrence and was subsequently palliated and died. PMID- 30002214 TI - Vesicovaginal fistula and vesicocutaneous fistula in a patient having pelvic ectopic kidney with pyonephrosis: a unique therapeutic challenge. AB - Patients with ectopic kidney require special considerations in their management due to the anatomic characteristics predisposing the kidney to obstruction and related complications. Pelvic ectopic kidneys have the added disadvantage of being confined in the bony pelvis giving less manoeuvrability during surgery of that unit. Vesicovaginal fistulas are usually managed surgically and careful surgical dissection has to be carried out because the highest success rates are usually seen at the first operation. It is rare to find a combination of such challenging diseases in a single patient. We present the case of a young woman who developed iatrogenic vesicovaginal and vesicocutaneous fistulae during an attempt to surgically manage a pyonephrotic ectopic pelvic kidney. PMID- 30002215 TI - Neutropaenia and splenomegaly without arthritis: think rheumatoid arthritis. AB - Felty syndrome(FS) is an uncommon, but severe, extra-articular manifestation of rheumatoid arthritis (RA). It occurs in patients with longstanding RA. It is extremely rare for RA to present as FS or develop after initially presenting as neutropaenia and splenomegaly. We describe a case of 47-year-old woman who was diagnosed simultaneously with FS and possible RA after testing positive for anticyclic citrullinated peptide antibody, but a negative rheumatoid factor. She had an excellent response to methotrexate. We review the existing literature of such cases and emphasise the importance of serological testing for RA in patients presenting with neutropaenia and splenomegaly, even in the absence of joint symptoms or prior diagnosis of RA. PMID- 30002216 TI - A challenging case of primary amenorrhoea. AB - The differential diagnosis of a girl presenting with primary amenorrhoea includes numerous conditions. Often, patients of 46XY disorder of sex development (DSD) are reared as girl and present with primary amenorrhoea. Their further evaluation to reach the final diagnosis is often a great challenge. In this article, we report a challenging case of 46XY DSD presented with primary amenorrhoea. Patient had spontaneous breast development which initially confused the diagnosis to complete androgen insensitivity syndrome. However, low testosterone suggested against this possibility and further evaluation revealed hormonal findings consistent with 17alpha hydroxylase/17,20 lyase (CYP17A1) deficiency. Patient had 46XY karyotype and in consistence with hormonal findings patient was found to have a likely pathogenic homozygous c.1345C>T (p.Arg449Cys) variation in exon 8 of CYP17A1. PMID- 30002217 TI - Giant pituitary incidentaloma. PMID- 30002219 TI - Acute upper gastrointestinal bleeding in a patient with malignant melanoma. PMID- 30002220 TI - The 40th anniversary of human IVF: time to celebrate and time to reflect. PMID- 30002218 TI - Visible-free cholesterol crystal emboli adjacent to microinfarcts in myocardial capillaries and arterioles on H&E-stained frozen sections of an autopsied patient. AB - The number of released free cholesterol crystal emboli (fCCE) and their role during percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) have not been documented yet. Furthermore, fCCE manifesting in the coronary lumen following plaque rupture has been historically overlooked owing to the standard tissue preparation for light microscopy which uses ethanol as a dehydrating agent that can dissolve fCCE, leaving behind empty tissue. In this case report, we evaluated fCCE released during PCI for ACS and their relationship with myocardial injury and coronary artery obstruction on the H&E-stained sections by using polarised light microscopy. To our knowledge, there has been no mention of the visibility of fCCE on H&E-stained frozen polarised sections before. PMID- 30002221 TI - Single-Cell Sequencing the Glomerulus, Unraveling the Molecular Programs of Glomerular Filtration, One Cell at a Time. PMID- 30002223 TI - Correction: Concussion, dementia and CTE: are we getting it very wrong? PMID- 30002222 TI - The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes. AB - BACKGROUND: We previously reported that mutations in the anillin (ANLN) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. METHODS: We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLNR431C and ANLNG618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN (ANLNWT ) or ANLNR431C . RESULTS: Experiments in anln-deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLNR431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLNR431C -expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLNR431C -expressing podocytes. Inhibition of mTOR, GSK-3beta, Rac1, or calcineurin ameliorated the effects of ANLNR431C . Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. CONCLUSIONS: The ANLNR431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes. PMID- 30002224 TI - Risks and Benefits of Direct Oral Anticoagulants across the Spectrum of GFR among Incident and Prevalent Patients with Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVES: All randomized trials of direct oral anticoagulants in atrial fibrillation excluded patients with severe kidney disease. The safety and effectiveness of direct oral anticoagulants across the range of eGFR in real world settings is unknown. Our objective is to quantify the risk of bleeding and benefit of ischemic stroke prevention for direct oral anticoagulants compared with warfarin in patients with atrial fibrillation with and without CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We created a propensity score-matched cohort of 3206 patients with atrial fibrillation and direct oral anticoagulant use and 3206 patients with atrial fibrillation using warfarin from October of 2010 to February of 2017 in an electronic health record (Geisinger Health System). The risks of bleeding and ischemic stroke were compared between direct oral anticoagulant and warfarin users using Cox proportional hazards regression, stratified by eGFR (>=60 and <60 ml/min per 1.73 m2). RESULTS: The mean (SD) age of the 6412 participants was 72 (12) years, 47% were women, and average eGFR was 69 (21) ml/min per 1.73 m2. There were 1181 bleeding events and 466 ischemic strokes over 7391 person-years of follow-up. Compared with warfarin use, the hazard ratios (HRs) (95% confidence interval [95% CI]) of bleeding associated with direct oral anticoagulant use were 1.01 (0.88 to 1.17) and 1.23 (1.02 to 1.48) for those with eGFR>=60 and eGFR<60 ml/min per 1.73 m2, respectively (P interaction=0.10). There was no difference between direct oral anticoagulant and warfarin users in the risk of ischemic stroke: HRs (95% CI) of 0.94 (0.74 to 1.18) and 1.02 (0.76 to 1.37) for those with eGFR>=60 and eGFR<60 ml/min per 1.73 m2, respectively (P-interaction=0.70). Similar findings were observed with individual drugs. CONCLUSIONS: In a large health care system, patients with eGFR<60 ml/min per 1.73 m2 who took direct oral anticoagulants for atrial fibrillation had slightly higher risk of bleeding compared with those on warfarin, but similar benefits from prevention of ischemic stroke. PMID- 30002225 TI - Comment on "Designing river flows to improve food security futures in the Lower Mekong Basin". AB - Sabo et al (Research Articles, 8 December 2017, p. 1270) use sophisticated analyses of flow and fishery data from the Lower Mekong Basin to design a "good" hydrograph that, if implemented by planned hydropower dams, would increase the catch by a factor of 3.7. However, the hydrograph is not implementable, and, if it were, it would devastate the fishery. Further, the analyses are questionable. PMID- 30002227 TI - Response to Comments on "Designing river flows to improve food security futures in the Lower Mekong Basin". AB - Sabo et al presented an empirically derived algorithm defining the socioecological response of the Tonle Sap Dai fishery in the Cambodian Mekong to basin-scale variation in hydrologic flow regime. Williams suggests that the analysis leading to the algorithm is flawed because of the large distance between the gauge used to measure water levels (hydrology) and the site of harvest for the fishery. Halls and Moyle argue that Sabo et al's findings are well known and contend that the algorithm is not a comprehensive assessment of sustainability. We argue that Williams' critique stems from a misunderstanding about our analysis; further clarification of the analysis is provided. We regret not citing more of the work indicated by Halls and Moyle, yet we note that our empirical analysis provides additional new insights into Mekong flow-fishery relationships. PMID- 30002228 TI - Comment on "Designing river flows to improve food security futures in the Lower Mekong Basin". AB - The designer flow regime proposed by Sabo et al (Research Articles, 8 December 2017, p. 1270) to support fisheries in the Lower Mekong Basin fails to account for important ecological, political, and economic dimensions. In doing so, they indicate that dam impacts can be easily mitigated. Such an action would serve to increase risks to food and livelihood futures in the basin. PMID- 30002229 TI - Spain's good news. PMID- 30002230 TI - News at a glance. PMID- 30002231 TI - Ice reveals a messenger from a blazing galaxy. PMID- 30002232 TI - China announces new flotilla of space science missions. PMID- 30002234 TI - A 'gene drive' makes its debut in mammals. PMID- 30002233 TI - Digital chemical test impresses. PMID- 30002236 TI - Liquid sunshine. PMID- 30002237 TI - When persistence doesn't pay. PMID- 30002235 TI - Molecular 'barcodes' reveal lost whale hunts. PMID- 30002238 TI - Many roads to convergence. PMID- 30002239 TI - Femtosecond structural photobiology. PMID- 30002240 TI - Double trouble at the beginning of life. PMID- 30002242 TI - Perovskite ferroelectrics go metal free. PMID- 30002241 TI - Eradication genomics-lessons for parasite control. PMID- 30002243 TI - Jens Christian Skou (1918-2018). PMID- 30002244 TI - Citizen science, public policy. PMID- 30002245 TI - Brazil naturalizes non-native species. PMID- 30002247 TI - Funding agencies can prevent harassment. PMID- 30002246 TI - Free satellite data key to conservation. PMID- 30002249 TI - Metal-free three-dimensional perovskite ferroelectrics. AB - Inorganic perovskite ferroelectrics are widely used in nonvolatile memory elements, capacitors, and sensors because of their excellent ferroelectric and other properties. Organic ferroelectrics are desirable for their mechanical flexibility, low weight, environmentally friendly processing, and low processing temperatures. Although almost a century has passed since the first ferroelectric, Rochelle salt, was discovered, examples of highly desirable organic perovskite ferroelectrics are lacking. We found a family of metal-free organic perovskite ferroelectrics with the characteristic three-dimensional structure, among which MDABCO (N-methyl-N'-diazabicyclo[2.2.2]octonium)-ammonium triiodide has a spontaneous polarization of 22 microcoulombs per square centimeter [close to that of barium titanate (BTO)], a high phase transition temperature of 448 kelvins (above that of BTO), and eight possible polarization directions. These attributes make it attractive for use in flexible devices, soft robotics, biomedical devices, and other applications. PMID- 30002251 TI - Deconstructive fluorination of cyclic amines by carbon-carbon cleavage. AB - Deconstructive functionalizations involving scission of carbon-carbon double bonds are well established. In contrast, unstrained C(sp3)-C(sp3) bond cleavage and functionalization have less precedent. Here we report the use of deconstructive fluorination to access mono- and difluorinated amine derivatives by C(sp3)-C(sp3) bond cleavage in saturated nitrogen heterocycles such as piperidines and pyrrolidines. Silver-mediated ring-opening fluorination using Selectfluor highlights a strategy for cyclic amine functionalization and late stage skeletal diversification, establishing cyclic amines as synthons for amino alkyl radicals and providing synthetic routes to valuable building blocks. PMID- 30002250 TI - Phase transitions in a programmable quantum spin glass simulator. AB - Understanding magnetic phases in quantum mechanical systems is one of the essential goals in condensed matter physics, and the advent of prototype quantum simulation hardware has provided new tools for experimentally probing such systems. We report on the experimental realization of a quantum simulation of interacting Ising spins on three-dimensional cubic lattices up to dimensions 8 * 8 * 8 on a D-Wave processor (D-Wave Systems, Burnaby, Canada). The ability to control and read out the state of individual spins provides direct access to several order parameters, which we used to determine the lattice's magnetic phases as well as critical disorder and one of its universal exponents. By tuning the degree of disorder and effective transverse magnetic field, we observed phase transitions between a paramagnetic, an antiferromagnetic, and a spin-glass phase. PMID- 30002252 TI - Sensitivity to "sunk costs" in mice, rats, and humans. AB - Sunk costs are irrecoverable investments that should not influence decisions, because decisions should be made on the basis of expected future consequences. Both human and nonhuman animals can show sensitivity to sunk costs, but reports from across species are inconsistent. In a temporal context, a sensitivity to sunk costs arises when an individual resists ending an activity, even if it seems unproductive, because of the time already invested. In two parallel foraging tasks that we designed, we found that mice, rats, and humans show similar sensitivities to sunk costs in their decision-making. Unexpectedly, sensitivity to time invested accrued only after an initial decision had been made. These findings suggest that sensitivity to temporal sunk costs lies in a vulnerability distinct from deliberation processes and that this distinction is present across species. PMID- 30002255 TI - Heed the call to change. PMID- 30002254 TI - Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryos. AB - At the beginning of mammalian life, the genetic material from each parent meets when the fertilized egg divides. It was previously thought that a single microtubule spindle is responsible for spatially combining the two genomes and then segregating them to create the two-cell embryo. We used light-sheet microscopy to show that two bipolar spindles form in the zygote and then independently congress the maternal and paternal genomes. These two spindles aligned their poles before anaphase but kept the parental genomes apart during the first cleavage. This spindle assembly mechanism provides a potential rationale for erroneous divisions into more than two blastomeric nuclei observed in mammalian zygotes and reveals the mechanism behind the observation that parental genomes occupy separate nuclear compartments in the two-cell embryo. PMID- 30002253 TI - Ethylene-gibberellin signaling underlies adaptation of rice to periodic flooding. AB - Most plants do poorly when flooded. Certain rice varieties, known as deepwater rice, survive periodic flooding and consequent oxygen deficiency by activating internode growth of stems to keep above the water. Here, we identify the gibberellin biosynthesis gene, SD1 (SEMIDWARF1), whose loss-of-function allele catapulted the rice Green Revolution, as being responsible for submergence induced internode elongation. When submerged, plants carrying the deepwater rice specific SD1 haplotype amplify a signaling relay in which the SD1 gene is transcriptionally activated by an ethylene-responsive transcription factor, OsEIL1a. The SD1 protein directs increased synthesis of gibberellins, largely GA4, which promote internode elongation. Evolutionary analysis shows that the deepwater rice-specific haplotype was derived from standing variation in wild rice and selected for deepwater rice cultivation in Bangladesh. PMID- 30002248 TI - Neutrino emission from the direction of the blazar TXS 0506+056 prior to the IceCube-170922A alert. AB - A high-energy neutrino event detected by IceCube on 22 September 2017 was coincident in direction and time with a gamma-ray flare from the blazar TXS 0506+056. Prompted by this association, we investigated 9.5 years of IceCube neutrino observations to search for excess emission at the position of the blazar. We found an excess of high-energy neutrino events, with respect to atmospheric backgrounds, at that position between September 2014 and March 2015. Allowing for time-variable flux, this constitutes 3.5sigma evidence for neutrino emission from the direction of TXS 0506+056, independent of and prior to the 2017 flaring episode. This suggests that blazars are identifiable sources of the high energy astrophysical neutrino flux. PMID- 30002256 TI - Identification of ASYNAPTIC4, a Component of the Meiotic Chromosome Axis. AB - During the leptotene stage of prophase I of meiosis, chromatids become organized into a linear looped array via a protein axis that forms along the loop bases. Establishment of the axis is essential for the subsequent synapsis of the homologous chromosome pairs and the progression of recombination to form genetic crossovers. Here, we describe ASYNAPTIC4 (ASY4), a meiotic axis protein in Arabidopsis (Arabidopsis thaliana). ASY4 is a small coiled-coil protein that exhibits limited sequence similarity with the carboxyl-terminal region of the axis protein ASY3. We used enhanced yellow fluorescent protein-tagged ASY4 to show that ASY4 localizes to the chromosome axis throughout prophase I. Bimolecular fluorescence complementation revealed that ASY4 interacts with ASY1 and ASY3, and yeast two-hybrid analysis confirmed a direct interaction between ASY4 and ASY3. Mutants lacking full-length ASY4 exhibited defective axis formation and were unable to complete synapsis. Although the initiation of recombination appeared to be unaffected in the asy4 mutant, the number of crossovers was reduced significantly, and crossovers tended to group in the distal parts of the chromosomes. We conclude that ASY4 is required for normal axis and crossover formation. Furthermore, our data suggest that ASY3/ASY4 are the functional homologs of the mammalian SYCP2/SYCP3 axial components. PMID- 30002257 TI - OsATX1 Interacts with Heavy Metal P1B-Type ATPases and Affects Copper Transport and Distribution. AB - Copper (Cu) is an essential micronutrient for plant growth. However, the molecular mechanisms underlying Cu trafficking and distribution to different organs in rice (Oryza sativa) are poorly understood. Here, we report the function and role of Antioxidant Protein1 (OsATX1), a Cu chaperone in rice. Knocking out OsATX1 resulted in increased Cu concentrations in roots, whereas OsATX1 overexpression reduced root Cu concentrations but increased Cu accumulation in the shoots. At the reproductive stage, the concentrations of Cu in developing tissues, including panicles, upper nodes and internodes, younger leaf blades, and leaf sheaths of the main tiller, were increased significantly in OsATX1 overexpressing plants and decreased in osatx1 mutants compared with the wild type. The osatx1 mutants also showed a higher Cu concentration in older leaves. Yeast two-hybrid and bimolecular fluorescence complementation assays showed that OsATX1 interacts with the rice heavy metal P1B-ATPases HMA4, HMA5, HMA6, and HMA9. These results suggest that OsATX1 may function to deliver Cu to heavy metal P1B-ATPases for Cu trafficking and distribution in order to maintain Cu homeostasis in different rice tissues. In addition, heterologous expression of OsATX1 in the yeast (Saccharomyces cerevisiae) cadmium-sensitive mutant Deltaycf1 increased the tolerance to Cu and cadmium by decreasing their respective concentrations in the transformed yeast cells. Taken together, our results indicate that OsATX1 plays an important role in facilitating root-to-shoot Cu translocation and the redistribution of Cu from old leaves to developing tissues and seeds in rice. PMID- 30002258 TI - MAP KINASE PHOSPHATASE1 Controls Cell Fate Transition during Stomatal Development. AB - Stomata on the plant epidermis control gas and water exchange and are formed by MAPK-dependent processes. Although the contribution of MAP KINASE3 (MPK3) and MPK6 (MPK3/MPK6) to the control of stomatal patterning and differentiation in Arabidopsis (Arabidopsis thaliana) has been examined extensively, how they are inactivated and regulate distinct stages of stomatal development is unknown. Here, we identify a dual-specificity phosphatase, MAP KINASE PHOSPHATASE1 (MKP1), which promotes stomatal cell fate transition by controlling MAPK activation at the early stage of stomatal development. Loss of function of MKP1 creates clusters of small cells that fail to differentiate into stomata, resulting in the formation of patches of pavement cells. We show that MKP1 acts downstream of YODA (a MAPK kinase kinase) but upstream of MPK3/MPK6 in the stomatal signaling pathway and that MKP1 deficiency causes stomatal signal-induced MAPK hyperactivation in vivo. By expressing MKP1 in the three discrete cell types of stomatal lineage, we further identified that MKP1-mediated deactivation of MAPKs in early stomatal precursor cells directs cell fate transition leading to stomatal differentiation. Together, our data reveal the important role of MKP1 in controlling MAPK signaling specificity and cell fate decision during stomatal development. PMID- 30002260 TI - Effect of Eu doping concentration on fluorescence and magnetic resonance imaging properties of Gd2O3:Eu3+ nanoparticles used as dual-modal contrast agent. AB - Europium-doped gadolinium oxide (Gd2O3:Eu3+) nanoparticles (NPs) with favorable properties for use in fluorescence imaging (FI) and magnetic resonance imaging (MRI) dual-modal contrast agent has attracted intense attention in biomedical applications. However, limited information is available on balancing FI and MRI by adjusting doping concentrations. In this study, Gd2O3:Eu3+ NPs with various Eu3+ doping concentrations were prepared by the facile and general technique of laser ablation in liquid (LAL). The influence of Eu3+-doping concentration on fluorescence properties and longitudinal relaxivity were investigated. The optimum Eu3+-doping concentration with both high fluorescence properties and longitudinal relaxivity was determined to be 5%. The characterization of the structure, morphology, and composition shows that these NPs possess good crystallinity and excellent dispersibility. These results show that Gd2O3:Eu3+ NPs prepared by LAL are promising candidates for highly efficient FI and MRI dual modal contrast agents. PMID- 30002226 TI - Multimessenger observations of a flaring blazar coincident with high-energy neutrino IceCube-170922A. AB - Previous detections of individual astrophysical sources of neutrinos are limited to the Sun and the supernova 1987A, whereas the origins of the diffuse flux of high-energy cosmic neutrinos remain unidentified. On 22 September 2017, we detected a high-energy neutrino, IceCube-170922A, with an energy of ~290 tera electron volts. Its arrival direction was consistent with the location of a known gamma-ray blazar, TXS 0506+056, observed to be in a flaring state. An extensive multiwavelength campaign followed, ranging from radio frequencies to gamma-rays. These observations characterize the variability and energetics of the blazar and include the detection of TXS 0506+056 in very-high-energy gamma-rays. This observation of a neutrino in spatial coincidence with a gamma-ray-emitting blazar during an active phase suggests that blazars may be a source of high-energy neutrinos. PMID- 30002261 TI - GFP fluorescence: A few lesser-known nuggets that make it work. AB - Use of Green Fluorescent Protein (GFP) as a marker has revolutionized biological research in the last few decades. In this brief commentary, we reflect upon the success story of GFP and highlight a few lesser-known facets about GFP that add up to its usefulness. PMID- 30002262 TI - A novel fluorescence microscopic approach to quantitatively analyse protein induced membrane remodelling. AB - Membrane remodelling or the bending and rupture of the lipid bilayer occurs during diverse cellular processes such as cell division, synaptic transmission, vesicular transport, organelle biogenesis and sporulation. These activities are brought about by the localized change in membrane curvature, which in turn causes lipid-packing stress, of a planar lipid bilayer by proteins. For instance, vesicular transport processes are typically characterized by the cooperative recruitment of proteins that induce budding of a planar membrane and catalyse fission of the necks of membrane buds to release vesicles. The analysis of such membrane remodelling reactions has traditionally been restricted to electron microscopy-based approaches or force spectroscopic analysis of membrane tethers pulled from liposome-based model membrane systems. Our recent work has demonstrated the facile creation of tubular model membrane systems of supported membrane tubes (SMrTs), which mimic late-stage intermediates of typical vesicular transport reactions. This review addresses the nature of such an assay system and a fluorescence-intensity-based analysis of changes in tube dimensions that is indicative of the membrane remodelling capacity of proteins. PMID- 30002259 TI - Coordination of Chloroplast Development through the Action of the GNC and GLK Transcription Factor Families. AB - Fundamental questions regarding how chloroplasts develop from proplastids remain poorly understood despite their central importance to plant life. Two families of nuclear transcription factors, the GATA NITRATE-INDUCIBLE CARBON-METABOLISM INVOLVED (GNC) and GOLDEN TWO-LIKE (GLK) families, have been implicated in directly and positively regulating chloroplast development. Here, we determined the degree of functional overlap between the two transcription factor families in Arabidopsis (Arabidopsis thaliana), characterizing their ability to regulate chloroplast biogenesis both alone and in concert. We determined the DNA-binding motifs for GNC and GLK2 using protein-binding microarrays; the enrichment of these motifs in transcriptome datasets indicates that GNC and GLK2 are repressors and activators of gene expression, respectively. ChIP-seq analysis of GNC identified PHYTOCHROME INTERACTING FACTOR and brassinosteroid activity genes as targets whose repression by GNC facilitates chloroplast biogenesis. In addition, GNC targets and represses genes involved in ERECTA signaling and thereby facilitates stomatal development. Our results define key regulatory features of the GNC and GLK transcription factor families that contribute to the control of chloroplast biogenesis and photosynthetic activity, including areas of independence and cross talk. PMID- 30002264 TI - Single-molecule photobleaching: Instrumentation and applications. AB - Single-molecule photobleaching (smPB) technique is a powerful tool for characterizing molecular assemblies. It can provide a direct measure of the number of monomers constituting a given oligomeric particle and generate the oligomer size distribution in a specimen. A major current application of this technique is in understanding protein aggregation, which is linked to many incurable diseases. Quantitative measurement of the size distribution of an aggregating protein in a physiological solution remains a difficult task, since techniques such as dynamic light scattering or fluorescence correlation spectroscopy (FCS) can provide an average size, but cannot accurately resolve the underlying size distribution. Here we describe the smPB method as implemented on a home-built total internal reflection fluorescence microscope (TIRF). We first describe the construction of a TIRF microscope, and then demonstrate the power of smPB by characterizing a solution of Amylin (hIAPP) oligomers, a 37-residue peptide whose aggregation is associated with Type II diabetes. We compare our results with FCS data obtained from the same specimen, and discuss the advantages and disadvantages of the two techniques. PMID- 30002263 TI - Fluorescence microscopy applied to intracellular transport by microtubule motors. AB - Long-distance transport of many organelles inside eukaryotic cells is driven by the dynein and kinesin motors on microtubule filaments. More than 30 years since the discovery of these motors, unanswered questions include motor- organelle selectivity, structural determinants of processivity, collective behaviour of motors and track selection within the complex cytoskeletal architecture, to name a few. Fluorescence microscopy has been invaluable in addressing some of these questions. Here we present a review of some efforts to understand these sub microscopic machines using fluorescence. PMID- 30002265 TI - Studying backbone torsional dynamics of intrinsically disordered proteins using fluorescence depolarization kinetics. AB - Intrinsically disordered proteins (IDPs) do not autonomously adopt a stable unique 3D structure and exist as an ensemble of rapidly interconverting structures. They are characterized by significant conformational plasticity and are associated with several biological functions and dysfunctions. The rapid conformational fluctuation is governed by the backbone segmental dynamics arising due to the dihedral angle fluctuation on the Ramachandran phi- psi conformational space. We discovered that the intrinsic backbone torsional mobility can be monitored by a sensitive fluorescence readout, namely fluorescence depolarization kinetics, of tryptophan in an archetypal IDP such as alpha-synuclein. This methodology allows us to map the site-specific torsional mobility in the dihedral space within picosecond-nanosecond time range at a low protein concentration under the native condition. The characteristic timescale of ~1.4 ns, independent of residue position, represents collective torsional dynamics of dihedral angles (phi and psi) of several residues from tryptophan and is independent of overall global tumbling of the protein. We believe that fluorescence depolarization kinetics methodology will find broad application to study both short-range and long-range correlated motions, internal friction, binding-induced folding, disorder-to-order transition, misfolding and aggregation of IDPs. PMID- 30002266 TI - Fluorescence-based approaches for monitoring membrane receptor oligomerization. AB - Membrane protein structures are highly under-represented relative to water soluble protein structures in the protein databank. This is especially the case because membrane proteins represent more than 30% of proteins encoded in the human genome yet contribute to less than 10% of currently known structures (Torres et al. in Trends Biol Sci 28:137-144, 2003). Obtaining high-resolution structures of membrane proteins by traditional methods such as NMR and x-ray crystallography is challenging, because membrane proteins are difficult to solubilise, purify and crystallize. Consequently, development of methods to examine protein structure in situ is highly desirable. Fluorescence is highly sensitive to protein structure and dynamics (Lakowicz in Principles of fluorescence spectroscopy, Springer, New York, 2007). This is mainly because of the time a fluorescence probe molecule spends in the excited state. Judicious choice and placement of fluorescent molecule(s) within a protein(s) enables the experimentalist to obtain information at a specific site(s) in the protein (complex) of interest. Moreover, the inherent multi-dimensional nature of fluorescence signals across wavelength, orientation, space and time enables the design of experiments that give direct information on protein structure and dynamics in a biological setting. The purpose of this review is to introduce the reader to approaches to determine oligomeric state or quaternary structure at the cell membrane surface with the ultimate goal of linking the oligomeric state to the biological function. In the first section, we present a brief overview of available methods for determining oligomeric state and compare their advantages and disadvantages. In the second section, we highlight some of the methods developed in our laboratory to address contemporary questions in membrane protein oligomerization. In the third section, we outline our approach to determine the link between protein oligomerization and biological activity. PMID- 30002268 TI - Ultrafast dynamics-driven biomolecular recognition where fast activities dictate slow events. AB - In general, biological macromolecules require significant dynamical freedom to carry out their different functions, including signal transduction, metabolism, catalysis and gene regulation. Effectors (ligands, DNA and external milieu, etc) are considered to function in a purely dynamical manner by selectively stabilizing a specific dynamical state, thereby regulating biological function. In particular, proteins in presence of these effectors can exist in several dynamical states with distinct binding or enzymatic activity. Here, we have reviewed the efficacy of ultrafast fluorescence spectroscopy to monitor the dynamical flexibility of various proteins in presence of different effectors leading to their biological activity. Recent studies demonstrate the potency of a combined approach involving picosecond-resolved Forster resonance energy transfer, polarisation-gated fluorescence and time-dependent stokes shift for the exploration of ultrafast dynamics in biomolecular recognition of various protein molecules. The allosteric protein-protein recognition following differential protein-DNA interaction is shown to be a consequence of some ultrafast segmental motions at the C-terminal of Gal repressor protein dimer with DNA operator sequences OE and OI. Differential ultrafast dynamics at the C-terminal of lambda repressor protein with two different operator DNA sequences for the protein protein interaction with different strengths is also reviewed. We have also systemically briefed the study on the role of ultrafast dynamics of water molecules on the functionality of enzyme proteins alpha-chymotrypsin and deoxyribonuclease I. The studies on the essential ultrafast dynamics at the active site of the enzyme alpha-chymotrypsin by using an anthraniloyl fluorescent extrinsic probe covalently attached to the serine-195 residue for the enzymatic activity at homeothermic condition has also been reviewed. Finally, we have highlighted the evidence that a photoinduced dynamical event dictates the molecular recognition of a photochromic ligand, dihydroindolizine with the serine protease alpha-chymotrypsin and with a liposome (L-a-phosphatidylcholine). PMID- 30002267 TI - Applications of STED fluorescence nanoscopy in unravelling nanoscale structure and dynamics of biological systems. AB - Fluorescence microscopy, especially confocal microscopy, has revolutionized the field of biological imaging. Breaking the optical diffraction barrier of conventional light microscopy, through the advent of super-resolution microscopy, has ushered in the potential for a second revolution through unprecedented insight into nanoscale structure and dynamics in biological systems. Stimulated emission depletion (STED) microscopy is one such super-resolution microscopy technique which provides real-time enhanced-resolution imaging capabilities. In addition, it can be easily integrated with well-established fluorescence-based techniques such as fluorescence correlation spectroscopy (FCS) in order to capture the structure of cellular membranes at the nanoscale with high temporal resolution. In this review, we discuss the theory of STED and different modalities of operation in order to achieve the best resolution. Various applications of this technique in cell imaging, especially that of neuronal cell imaging, are discussed as well as examples of application of STED imaging in unravelling structure formation on biological membranes. Finally, we have discussed examples from some of our recent studies on nanoscale structure and dynamics of lipids in model membranes, due to interaction with proteins, as revealed by combination of STED and FCS techniques. PMID- 30002269 TI - Dynamics of water and ions around DNA: What is so special about them? AB - Water around biomolecules is special for behaving strangely - both in terms of structure and dynamics, while ions are found to control various interactions in biomolecules such as DNA, proteins and lipids. The questions that how water and ions around these biomolecules behave in terms of their structure and dynamics, and how they affect the biomolecular functions have triggered tremendous research activities worldwide. Such activities not only unfolded important static and dynamic properties of water and ions around these biomolecules, but also provoked heated debate regarding their explanation and role in biological functions. DNA, being negatively charged, interacts strongly with the surrounding dipolar water and positively charged counterions, leading to complex electrostatic coupling of water and ions with the DNA. Recent timeresolved fluorescence Stokes shift experiments and related computer simulation studies from our and other laboratories have unfolded some unique dynamic characteristics of water and ions near different structures of DNA. These results are discussed here to showcase the specialty of water and ion dynamics around DNA. PMID- 30002271 TI - Fluorescence techniques in developmental biology. AB - Advanced fluorescence techniques, commonly known as the F-techniques, measure the kinetics and the interactions of biomolecules with high sensitivity and spatiotemporal resolution. Applications of the F-techniques, which were initially limited to cells, were further extended to study in vivo protein organization and dynamics in whole organisms. The integration of F-techniques with multi-photon microscopy and light-sheet microscopy widened their applications in the field of developmental biology. It became possible to penetrate the thick tissues of living organisms and obtain good signal-to-noise ratio with reduced photo-induced toxicity. In this review, we discuss the principle and the applications of the three most commonly used F-techniques in developmental biology: Fluorescence Recovery After Photo-bleaching (FRAP), Fo rster Resonance Energy Transfer (FRET), and Fluorescence Correlation and Cross-Correlation Spectroscopy (FCS and FCCS). PMID- 30002199 TI - A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. AB - OBJECTIVE: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals. RESEARCH DESIGN AND METHODS: We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables. RESULTS: Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002). CONCLUSIONS: The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives. PMID- 30002272 TI - Fluorescence spectroscopy for revealing mechanisms in biology: Strengths and pitfalls. AB - This article describes the basic principles of steady-state and time-resolved fluorescence. The formal equivalence of the two methodologies is described first, followed by the extra advantages of time-resolved methods in revealing population heterogeneity in complex systems encountered in biology. Several examples from the author's work are described in support of the above contention. Finally, several misinterpretations and pitfalls in the interpretation of fluorescence data and their remedy are described. PMID- 30002273 TI - Evaluation of a Tool to Measure Pharmacists' Readiness to Manage Intimate Partner Violence. AB - Intimate partner violence (IPV) is a public health problem that demands a comprehensive health care response. Provider education and training is needed for the entire health care team, including pharmacists, to competently care for IPV impacted patients. Standardized assessments are needed to determine need for training and to evaluate the effectiveness of IPV training initiatives. The Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS) has previously been validated for physicians. This study adapted and evaluated the PREMIS instrument for use with pharmacists to assess knowledge, attitudes, behaviors, and intentions related to IPV and IPV screening. A total of 144 surveys from community pharmacists were analyzed. Pharmacists had low levels of IPV knowledge. Exploratory factor analysis revealed a five-factor structure: workplace and self-efficacy, preparation, legal requirements, alcohol and drugs, and constraints. This instrument can be utilized to guide the development and implementation of IPV-related training initiatives for pharmacists. PMID- 30002270 TI - Single-molecule fluorescence imaging: Generating insights into molecular interactions in virology. AB - Single-molecule fluorescence methods remain a challenging yet information-rich set of techniques that allow one to probe the dynamics, stoichiometry and conformation of biomolecules one molecule at a time. Viruses are small (nanometers) in size, can achieve cellular infections with a small number of virions and their lifecycle is inherently heterogeneous with a large number of structural and functional intermediates. Single-molecule measurements that reveal the complete distribution of properties rather than the average can hence reveal new insights into virus infections and biology that are inaccessible otherwise. This article highlights some of the methods and recent applications of single molecule fluorescence in the field of virology. Here, we have focused on new findings in virus-cell interaction, virus cell entry and transport, viral membrane fusion, genome release, replication, translation, assembly, genome packaging, egress and interaction with host immune proteins that underline the advantage of single-molecule approach to the question at hand. Finally, we discuss the challenges, outlook and potential areas for improvement and future use of single-molecule fluorescence that could further aid our understanding of viruses. PMID- 30002274 TI - Below versus above Ground Plant Sources of Abscisic Acid (ABA) at the Heart of Tropical Forest Response to Warming. AB - Warming surface temperatures and increasing frequency and duration of widespread droughts threaten the health of natural forests and agricultural crops. High temperatures (HT) and intense droughts can lead to the excessive plant water loss and the accumulation of reactive oxygen species (ROS) resulting in extensive physical and oxidative damage to sensitive plant components including photosynthetic membranes. ROS signaling is tightly integrated with signaling mechanisms of the potent phytohormone abscisic acid (ABA), which stimulates stomatal closure leading to a reduction in transpiration and net photosynthesis, alters hydraulic conductivities, and activates defense gene expression including antioxidant systems. While generally assumed to be produced in roots and transported to shoots following drought stress, recent evidence suggests that a large fraction of plant ABA is produced in leaves via the isoprenoid pathway. Thus, through stomatal regulation and stress signaling which alters water and carbon fluxes, we highlight the fact that ABA lies at the heart of the Carbon Water-ROS Nexus of plant response to HT and drought stress. We discuss the current state of knowledge of ABA biosynthesis, transport, and degradation and the role of ABA and other isoprenoids in the oxidative stress response. We discuss potential variations in ABA production and stomatal sensitivity among different plant functional types including isohydric/anisohydric and pioneer/climax tree species. We describe experiments that would demonstrate the possibility of a direct energetic and carbon link between leaf ABA biosynthesis and photosynthesis, and discuss the potential for a positive feedback between leaf warming and enhanced ABA production together with reduced stomatal conductance and transpiration. Finally, we propose a new modeling framework to capture these interactions. We conclude by discussing the importance of ABA in diverse tropical ecosystems through increases in the thermotolerance of photosynthesis to drought and heat stress, and the global importance of these mechanisms to carbon and water cycling under climate change scenarios. PMID- 30002277 TI - Radar Detection of Fluctuating Targets under Heavy-Tailed Clutter Using Track Before-Detect. AB - This paper considers the detection of fluctuating targets in heavy-tailed clutter through the use of dynamic programming based on track-before-detect (DP-TBD) in radar systems. The clutter is modeled in terms of K-distribution, which can be widely used to describe non-Gaussian clutter received from high-resolution radars and radars working at small grazing angles. Swerling type 1 is considered to describe the target fluctuation between scans. Conventional TBD techniques suffer from significant performance loss in heavy-tailed environments due to the more frequent occurrences of target-like outliers. In this paper, we resort to a DP TBD algorithm based on prior information, which can enhance the detection performance by using the environment and target fluctuating information during the integration process of TBD. Under non-Gaussian background, the expressions of the likelihood ratio merit function for Swerling type 1 targets are derived first. However, the closed-form of the merit function is difficult to obtain. In order to reduce the complexity of evaluating the merit function and the computational load, an efficient approximation method as well as a two-stage detection approach is proposed and used in the integration process. Finally, several numerical simulations of the new strategy and the comparisons are presented to verify that the proposed algorithm can improve the detection performance, especially for fluctuating targets in heavy-tailed clutter. PMID- 30002279 TI - Gold Nanoparticles for Targeting Varlitinib to Human Pancreatic Cancer Cells. AB - Colloidal gold nanoparticles are targeting probes to improve varlitinib delivery into cancer cells. The nanoconjugates were designed by the bioconjugation of pegylated gold nanoparticles with varlitinib via carbodiimide-mediated cross linking and characterized by infrared and X-ray photoelectron spectroscopy. The drug release response shows an initial delay and a complete drug release after 72 h is detected. In vitro experiments with MIA PaCa-2 cells corroborate that PEGAuNPsVarl conjugates increase the varlitinib toxic effect at very low concentrations (IC50 = 80 nM) if compared with varlitinib alone (IC50 = 259 nM). Our results acknowledge a decrease of drug side effects in normal cells and an enhancement of drug efficacy against to the pancreatic cancer cells reported. PMID- 30002276 TI - Pattern of Response to Bronchial Challenge with Histamine in Patients with Non Atopic Cough-Variant and Classic Asthma. AB - BACKGROUND: The aim of this study was to establish whether non-atopic patients with cough variant asthma (CVA) have different pattern of response to direct bronchoconstrictors than non-atopic patients with classic asthma (CA). METHOD: A total of 170 patients of both sexes with stable CVA and CA were screened for the study and 153 were included. Patients with proven atopy were not included and 17 patients with worsening of their condition or with verified bronchial obstruction during screening were excluded. All included patients performed spirometry and underwent a bronchial challenge with histamine according to long-standing protocol in our laboratory. RESULTS: Significantly higher frequency of bronchial hyper-responsiveness (BHR) was found in patients with CA than in patients with CVA (63.9% vs. 44.9%, respectively; p < 0.05). Sensitivity was significantly lower in patients with CVA (p < 0.05), while no significant difference was found in maximal response and responsiveness. Only patients with positive challenge tests were included in the analysis. CONCLUSION: Adult non-atopic patients with CVA and CA have a pattern of response to non-specific bronchial stimuli similar to atopic patients with same conditions, with the exception of similar maximal response, which may reflect the efficacy of previous treatment. We believe that further studies are needed to clarify the mechanisms involved in airway response to non-specific stimuli in CVA and CA, especially in non-atopic patients. Further studies should also clarify whether this response pattern has any implications on clinical presentation or on treatment options. PMID- 30002275 TI - Analysis of the Literature and Patents on Solid Dispersions from 1980 to 2015. AB - Background: Solid dispersions are an effective formulation technique to improve the solubility, dissolution rate, and bioavailability of water-insoluble drugs for oral delivery. In the last 15 years, increased attention was focused on this technology. There were 23 marketed drugs prepared by solid dispersion techniques. Objective: This study aimed to report the big picture of solid dispersion research from 1980 to 2015. Method: Scientific knowledge mapping tools were used for the qualitative and the quantitative analysis of patents and literature from the time and space dimensions. Results: Western Europe and North America were the major research areas in this field with frequent international cooperation. Moreover, there was a close collaboration between universities and industries, while research collaboration in Asia mainly existed between universities. The model drugs, main excipients, preparation technologies, characterization approaches and the mechanism involved in the formulation of solid dispersions were analyzed via the keyword burst and co-citation cluster techniques. Integrated experimental, theoretical and computational tools were useful techniques for in silico formulation design of the solid dispersions. Conclusions: Our research provided the qualitative and the quantitative analysis of patents and literature of solid dispersions in the last three decades. PMID- 30002280 TI - Applications of Nanosheets in Frontier Cellular Research. AB - Several types of nanosheets, such as graphene oxide (GO) nanosheet, molybdenum disulfide (MoS2) and poly(l-lactic acid) (PLLA) nanosheets, have been developed and applied in vitro in cellular research over the past decade. Scientists have used nanosheet properties, such as ease of modification and flexibility, to develop new cell/protein sensing/imaging techniques and achieve regulation of specific cell functions. This review is divided into three main parts based on the application being examined: nanosheets as a substrate, nanosheets as a sensitive surface, and nanosheets in regenerative medicine. Furthermore, the applications of nanosheets are discussed, with two subsections in each section, based on their effects on cells and molecules. Finally, the application prospects of nanosheets in cellular research are summarized. PMID- 30002281 TI - Olive Oil Nutraceuticals in the Prevention and Management of Diabetes: From Molecules to Lifestyle. AB - Lifestyle is the primary prevention of diabetes, especially type-2 diabetes (T2D). Nutritional intake of olive oil (OO), the key Mediterranean diet component has been associated with the prevention and management of many chronic diseases including T2D. Several OO bioactive compounds such as monounsaturated fatty acids, and key biophenols including hydroxytyrosol and oleuropein, have been associated with preventing inflammation and cytokine-induced oxidative damage, glucose lowering, reducing carbohydrate absorption, and increasing insulin sensitivity and related gene expression. However, research into the interaction of OO nutraceuticals with lifestyle components, especially physical activity, is lacking. Promising postprandial effects have been reported when OO or other similar monounsaturated fatty acids were the main dietary fat compared with other diets. Animal studies have shown a potential anabolic effect of oleuropein. Such effects could be further potentiated via exercise, especially strength training, which is an essential exercise prescription for individuals with T2D. There is also an evidence from in vitro, animal, and limited human studies for a dual preventative role of OO biophenols in diabetes and cancer, especially that they share similar risk factors. Putative antioxidative and anti-inflammatory mechanisms and associated gene expressions resulting from OO biophenols have produced paradoxical results, making suggested inferences from dual prevention T2D and cancer outcomes difficult. Well-designed human interventions and clinical trials are needed to decipher such a potential dual anticancer and antidiabetic effects of OO nutraceuticals. Exercise combined with OO consumption, individually or as part of a healthy diet is likely to induce reciprocal action for T2D prevention outcomes. PMID- 30002278 TI - Resveratrol Chemosensitizes TNF-beta-Induced Survival of 5-FU-Treated Colorectal Cancer Cells. AB - Objective: Resveratrol, a safe and multitargeted natural agent, has been linked with inhibition of survival and invasion of tumor cells. Tumor Necrosis Factor beta (TNF-beta) (Lymphotoxin alpha) is known as an inflammatory cytokine, however, the underlying mechanisms for its pro-carcinogenic effects and whether resveratrol can suppress these effects in the tumor microenvironment are poorly understood. Methods: We investigated whether resveratrol modulates the effects of 5-Fluorouracil (5-FU) and TNF-beta on the malignant potential of human colorectal cancer (CRC) cells (HCT116) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R) in 3D-alginate tumor microenvironment. Results: CRC cells cultured in alginate were able to migrate from alginate and the numbers of migrated cells were significantly increased in the presence of TNF-beta, similar to TNF-alpha, and dramatically decreased by resveratrol. We found that TNF-beta promoted chemoresistance in CRC cells to 5-FU compared to control cultures and resveratrol chemosensitizes TNF-beta-induced increased capacity for survival and invasion of HCT116 and HCT116R cells to 5-FU. Furthermore, TNF-beta induced a more pronounced cancer stem cell-like (CSC) phenotype (CD133, CD44, ALDH1) and resveratrol suppressed formation of CSC cells in two different CRC cells and this was accompanied with a significant increase in apoptosis (caspase-3). It is noteworthy that resveratrol strongly suppressed TNF-beta-induced activation of tumor-promoting factors (NF-kappaB, MMP-9, CXCR4) and epithelial-to-mesenchymal transition-factors (increased vimentin and slug, decreased E-cadherin) in CRC cells. Conclusion: Our results clearly demonstrate for the first time that resveratrol modulates the TNF-beta signaling pathway, induces apoptosis, suppresses NF-kappaB activation, epithelial-to-mesenchymal-transition (EMT), CSCs formation and chemosensitizes CRC cells to 5-FU in a tumor microenvironment. PMID- 30002283 TI - Effect of C/N Ratio on the Removal of Nitrogen and Microbial Characteristics in the Water Saturated Denitrifying Section of a Two-Stage Constructed Rapid Infiltration System. AB - The aim of this study was to improve the removal of nitrogen pollutants from artificial sewage by a modeled two-stage constructed rapid infiltration (CRI) system. The C/N ratio of the second stage influent was elevated by addition of glucose. When the C/N ratio was increased to 5, the mean removal efficiency of total nitrogen (TN) reached up to 75.4%. Under this condition, the number of denitrifying bacteria in the permanently submerged denitrifying section (the second stage) was 22 times higher than that in the control experiment without added glucose. Elevation of the C/N ratio resulted in lower concentrations of nitrate and TN in the second stage effluent, without impairment of chemical oxygen demand removal. The concentration of nitrate and TN in effluent decreased as the abundance of denitrifying bacteria increased. Moreover, the bacterial biofilms that had formed in the sand of the second stage container were analyzed. The secretion of extracellular polymeric substances, a major constituent of biofilms, was enhanced as a result of the elevated C/N ratio, which lead to the improved protection of the bacteria and enhanced the removal of pollutants. PMID- 30002282 TI - Graphene-Based Raman Spectroscopy for pH Sensing of X-rays Exposed and Unexposed Culture Media and Cells. AB - Graphene provides a unique way of sensing the local pH level of substances on the micrometric scale, with important implications for the monitoring of cellular metabolic activities where proton excretion could occur. Accordingly, an innovative biosensing approach for the quantification of the pH value of biological fluids, to be used also with small amounts of fluids, was realized and tested. It is based on the use of micro-Raman spectroscopy to detect the modifications of the graphene doping level induced by the contact of the graphene with the selected fluids. The approach was preliminarily tested on aqueous solutions of known pH values. It was then used to quantify the pH values of cell culture media directly exposed to different doses of X-ray radiation and to media exposed to X-ray-irradiated cells. The Raman response of cells placed on graphene layers was also examined. PMID- 30002284 TI - Impact of Veteran Status and Timing of PTSD Diagnosis on Criminal Justice Outcomes. AB - Previous research has demonstrated that jurors show a bias towards treatment for veterans with post-traumatic stress disorder (PTSD). The present research examines this bias when jurors are faced with cases of potential malingering, in which the defendant's claim of PTSD is a perceived attempt to escape legal punishments. Trial vignettes, in which veteran status and PTSD diagnosis timing were manipulated, were used to explore this phenomenon. It was found that veterans who received their diagnosis after being arrested were found guilty more often, and were diverted to treatment less often, than those who were diagnosed before an arrest. This has critical implications for mental healthcare in that it is crucial to properly diagnose and treat people before they find themselves in court. Further, the negative outcomes in court demonstrate one of the severe social impacts of untreated or late-diagnosed PTSD. PMID- 30002287 TI - Change of Petals' Color and Chemical Components in Oenothera Flowers during Senescence. AB - Oenothera flower petals change color during senescence. When in full bloom, the flowers of O. tetraptera are white and those of O. laciniata and O. stricta are yellow. However, the colors change to pink and orange, respectively, when the petals fade. We analyzed the flavonoid components in these petals as a function of senescence using HPLC-DAD and LC-MS. In all three species, cyanidin 3 glucoside (Cy3G) was found in faded petals. The content of Cy3G increased in senescence. In full bloom (0 h), no Cy3G was detected in any of the petals. However, after 12 h, the content of Cy3G in O. tetraptera was 0.97 umol/g fresh weight (FW) and the content of Cy3G in O. laciniata was 1.82 umol/g FW. Together with anthocyanins, major flavonoid components in petals were identified. Quercitrin was detected in the petals of O. tetraptera and isosalipurposide was found in the petals of O. laciniata and O. stricta. The content of quercitrin did not change during senescence, but the content of isosalipurposide in O. laciniata increased from 3.4 umol/g FW at 0 h to 4.8 umol/g FW at 12 h. The color change in all three Oenothera flowers was confirmed to be due to the de novo biosynthesis of Cy3G. PMID- 30002285 TI - Allyl Isothiocyanate Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mouse by Enhancing Tight Junction and Mucin Expression. AB - Inflammatory bowel disease (IBD) is characterized by chronic or recurrent inflammation of the gastrointestinal tract. Even though the current strategies to treat IBD include anti-inflammatory drugs and immune modulators, these treatments have side-effects. New strategies are, therefore, required to overcome the limitations of the therapies. In this study, we investigated the anti-colitic effects of allyl isothiocyanate (AITC), which is an active ingredient present in Wasabia japonica. The DSS-induced colitis model in the mouse was used to mimic human IBD and we observed that AITC treatment ameliorated the severity of colitis. We further studied the mechanism involved to ameliorate the colitis. To investigate the involvement of AITC on the intestinal barrier function, the effect on the intercellular tight junction was evaluated in the Caco-2 cell line while mucin expression was assessed in the LS174T cell line. AITC positively regulated tight junction proteins and mucin 2 (MUC2) against DSS-induced damage or depletion. Our data of in vivo studies were also consistent with the in vitro results. Furthermore, we observed that MUC2 increased by AITC is dependent on ERK signaling. In conclusion, we propose that AITC can be considered as a new strategy for treating IBD by modulating tight junction proteins and mucin. PMID- 30002286 TI - Phosphokinome Analysis of Barth Syndrome Lymphoblasts Identify Novel Targets in the Pathophysiology of the Disease. AB - Barth Syndrome (BTHS) is a rare X-linked genetic disease in which the specific biochemical deficit is a reduction in the mitochondrial phospholipid cardiolipin (CL) as a result of a mutation in the CL transacylase tafazzin. We compared the phosphokinome profile in Epstein-Barr-virus-transformed lymphoblasts prepared from a BTHS patient with that of an age-matched control individual. As expected, mass spectrometry analysis revealed a significant (>90%) reduction in CL in BTHS lymphoblasts compared to controls. In addition, increased oxidized phosphatidylcholine (oxPC) and phosphatidylethanolamine (PE) levels were observed in BTHS lymphoblasts compared to control. Given the broad shifts in metabolism associated with BTHS, we hypothesized that marked differences in posttranslational modifications such as phosphorylation would be present in the lymphoblast cells of a BTHS patient. Phosphokinome analysis revealed striking differences in the phosphorylation levels of phosphoproteins in BTHS lymphoblasts compared to control cells. Some phosphorylated proteins, for example, adenosine monophosphate kinase, have been previously validated as bonafide modified phosphorylation targets observed in tafazzin deficiency or under conditions of reduced cellular CL. Thus, we report multiple novel phosphokinome targets in BTHS lymphoblasts and hypothesize that alteration in the phosphokinome profile may provide insight into the pathophysiology of BTHS and potential therapeutic targets. PMID- 30002288 TI - A Miniature Binocular Endoscope with Local Feature Matching and Stereo Matching for 3D Measurement and 3D Reconstruction. AB - As the traditional single camera endoscope can only provide clear images without 3D measurement and 3D reconstruction, a miniature binocular endoscope based on the principle of binocular stereoscopic vision to implement 3D measurement and 3D reconstruction in tight and restricted spaces is presented. In order to realize the exact matching of points of interest in the left and right images, a novel construction method of the weighted orthogonal-symmetric local binary pattern (WOS-LBP) descriptor is presented. Then a stereo matching algorithm based on Gaussian-weighted AD-Census transform and improved cross-based adaptive regions is studied to realize 3D reconstruction for real scenes. In the algorithm, we adjust determination criterions of adaptive regions for edge and discontinuous areas in particular and as well extract mismatched pixels caused by occlusion through image entropy and region-growing algorithm. This paper develops a binocular endoscope with an external diameter of 3.17 mm and the above algorithms are applied in it. The endoscope contains two CMOS cameras and four fiber optics for illumination. Three conclusions are drawn from experiments: (1) the proposed descriptor has good rotation invariance, distinctiveness and robustness to light change as well as noises; (2) the proposed stereo matching algorithm has a mean relative error of 8.48% for Middlebury standard pairs of images and compared with several classical stereo matching algorithms, our algorithm performs better in edge and discontinuous areas; (3) the mean relative error of length measurement is 3.22%, and the endoscope can be utilized to measure and reconstruct real scenes effectively. PMID- 30002290 TI - Using Deep Learning and Low-Cost RGB and Thermal Cameras to Detect Pedestrians in Aerial Images Captured by Multirotor UAV. AB - The use of Unmanned Aerial Vehicles (UAV) has been increasing over the last few years in many sorts of applications due mainly to the decreasing cost of this technology. One can see the use of the UAV in several civilian applications such as surveillance and search and rescue. Automatic detection of pedestrians in aerial images is a challenging task. The computing vision system must deal with many sources of variability in the aerial images captured with the UAV, e.g., low resolution images of pedestrians, images captured at distinct angles due to the degrees of freedom that a UAV can move, the camera platform possibly experiencing some instability while the UAV flies, among others. In this work, we created and evaluated different implementations of Pattern Recognition Systems (PRS) aiming at the automatic detection of pedestrians in aerial images captured with multirotor UAV. The main goal is to assess the feasibility and suitability of distinct PRS implementations running on top of low-cost computing platforms, e.g., single-board computers such as the Raspberry Pi or regular laptops without a GPU. For that, we used four machine learning techniques in the feature extraction and classification steps, namely Haar cascade, LBP cascade, HOG + SVM and Convolutional Neural Networks (CNN). In order to improve the system performance (especially the processing time) and also to decrease the rate of false alarms, we applied the Saliency Map (SM) and Thermal Image Processing (TIP) within the segmentation and detection steps of the PRS. The classification results show the CNN to be the best technique with 99.7% accuracy, followed by HOG + SVM with 92.3%. In situations of partial occlusion, the CNN showed 71.1% sensitivity, which can be considered a good result in comparison with the current state-of-the-art, since part of the original image data is missing. As demonstrated in the experiments, by combining TIP with CNN, the PRS can process more than two frames per second (fps), whereas the PRS that combines TIP with HOG + SVM was able to process 100 fps. It is important to mention that our experiments show that a trade-off analysis must be performed during the design of a pedestrian detection PRS. The faster implementations lead to a decrease in the PRS accuracy. For instance, by using HOG + SVM with TIP, the PRS presented the best performance results, but the obtained accuracy was 35 percentage points lower than the CNN. The obtained results indicate that the best detection technique (i.e., the CNN) requires more computational resources to decrease the PRS computation time. Therefore, this work shows and discusses the pros/cons of each technique and trade-off situations, and hence, one can use such an analysis to improve and tailor the design of a PRS to detect pedestrians in aerial images. PMID- 30002289 TI - Asperuloside and Asperulosidic Acid Exert an Anti-Inflammatory Effect via Suppression of the NF-kappaB and MAPK Signaling Pathways in LPS-Induced RAW 264.7 Macrophages. AB - Hedyotis diffusa is a folk herb that is used for treating inflammation-related diseases in Asia. Previous studies have found that iridoids in H. diffusa play an important role in its anti-inflammatory activity. This study aimed to investigate the anti-inflammatory effect and potential mechanism of five iridoids (asperuloside (ASP), asperulosidic acid (ASPA), desacetyl asperulosidic acid (DAA), scandoside methyl ester (SME), and E-6-O-p-coumaroyl scandoside methyl ester (CSME)) that are presented in H. diffusa using lipopolysaccharide (LPS) induced RAW 264.7 cells. ASP and ASPA significantly decreased the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF alpha), and interleukin-6 (IL-6) in parallel with the inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha, and IL-6 mRNA expression in LPS-induced RAW 264.7 cells. ASP treatment suppressed the phosphorylation of the inhibitors of nuclear factor-kappaB alpha (IkappaB-alpha), p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). The inhibitory effect of ASPA was similar to that of ASP, except for p38 phosphorylation. In summary, the anti-inflammatory effects of ASP and ASPA are related to the inhibition of inflammatory cytokines and mediators via suppression of the NF-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways, which provides scientific evidence for the potential application of H. diffusa. PMID- 30002291 TI - The Occurrence of 275 Rare Diseases and 47 Rare Disease Groups in Italy. Results from the National Registry of Rare Diseases. AB - Knowledge of rare diseases (RD) is often scattered among many data collections and registries of patient cohorts. Therefore, assessing the burden of RD in the general population, developing appropriate policies and planning services for the care of RD patients is difficult. This study aimed at providing a systematic picture of RD occurrence in a population as big as 60 million. Data of diagnoses were certified and collected by a network of 247 specialized centres covering the whole Italian territory. Data received (about 200,000 records) were validated according to formal criteria and, where necessary, corrected by the data sources. Data of age at onset and sex distribution are given for about 400 diseases. Incidence and/or birth prevalence are given for 275 diseases and 47 disease groups, which, altogether, comprise a substantial part of the known rare diseases. Data quality, internal consistency, and external validity of the database have also been assessed and ways to limit the impact of some discrepancies were devised. The information provided by RNMR, cutting across such a wide range of RD, represents a unique coherent basis allowing the prioritization of relevant public health measures and research activities. PMID- 30002292 TI - Application of Low-Cost Me-N-C (Me = Fe or Co) Electrocatalysts Derived from EDTA in Direct Methanol Fuel Cells (DMFCs). AB - Co-N-C and Fe-N-C electrocatalysts have been prepared by mixing Fe or Co precursors, ethylene diamine tetra acetic acid (EDTA) as a nitrogen source, and an oxidized carbon. These materials were thermally treated at 800 degrees C or 1000 degrees C under nitrogen flow to produce four samples, named CoNC8, CoNC10, FeNC8, and FeNC10. They have been physicochemically characterized by X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). Direct methanol fuel cell (DMFC) analyses have been carried out to investigate the performance of the nonprecious cathode catalysts, using a low amount of Pt (0.7 mg/cm2) at the anode side. It appears that FeNC8 is the best performing low cost cathode catalyst in terms of higher oxygen reduction reaction activity and methanol tolerance. PMID- 30002294 TI - Electrodeposition of p-Type Sb2Te3 Films and Micro-Pillar Arrays in a Multi Channel Glass Template. AB - Antimony telluride (Sb2Te3)-based two-dimensional films and micro-pillar arrays are fabricated by electrochemical deposition from electrolytes containing SbO+ and HTeO2+ on Si wafer-based Pt electrode and multi-channel glass templates, respectively. The results indicate that the addition of tartaric acid increases the solubility of SbO+ in acidic solution. The compositions of deposits depend on the electrolyte concentration, and the micro morphologies rely on the reduction potential. Regarding the electrolyte containing 8 mM of SbO+ and 12 mM of HTeO2+, the grain size increases and the density of films decreases as the deposition potential shifts from -100 mV to -400 mV. Sb2Te3 film with nominal composition and dense morphology can be obtained by using a deposition potential of -300 mV. However, this condition is not suitable for the deposition of Sb2Te3 micro-pillar arrays on the multi-channel glass templates because of its drastic concentration polarization. Nevertheless, it is found that the pulsed voltage deposition is an effective way to solve this problem. A deposition potential of -280 mV and a dissolve potential of 500 mV were selected, and the deposition of micro-pillars in a large aspect ratio and at high density can be realized. The deposition technology can be further applied in the fabrication of micro-TEGs with large output voltage and power. PMID- 30002293 TI - Detection of the Potential Inactivation of Tetrodotoxin by Lactic Acid Bacterial Exopolysaccharide. AB - Screening for compounds that can neutralize the toxicity of tetrodotoxin (TTX) or reduce its negative effects is necessary. Our study tested the TTX detoxification capacity of exopolysaccharide (EPS) extracted from lactic acid bacteria. EPS of Leuconostoc mesenteroides N3 isolated from the Vung Tau sea (Vietnam), Lactobacillus plantarum PN05, and Lactobacillus rhamnosus PN04 were used in the study. To more completely evaluate the importance of EPS in detoxification, EPS samples of Leuconostoc mesenteroides N3, Lactobacillus plantarum PN05 and Lactobacillus rhamnosus PN04 were also tested. The majority of EPS of these bacteria contained glucose; this was observed using thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analysis. As observed with FTIR analysis, only EPS of Lactobacillus plantarum PN05 contained methyl groups. The results indicated that detoxification of TTX in mice could be obtained at an optimal dose of 248 ug EPS from Leuconostoc mesenteroides incubated with 54 ug cuprous oxide for 40 min or 148 ug EPS Lactobacillus rhamnosus incubated with 55 ug cuprous oxide for 40 min, while EPS from Lactobacillus plantarum showed TTX detoxification capacity without cuprous oxide combination. Consequently, EPS from Lactobacillus plantarum PN05 can be used in TTX prevention. This is the first report on the importance of lactic acid bacteria in TTX detoxification. PMID- 30002295 TI - Large-Scale Fabrication of Ultrasensitive and Uniform Surface-Enhanced Raman Scattering Substrates for the Trace Detection of Pesticides. AB - Technology transfer from laboratory into practical application needs to meet the demands of economic viability and operational simplicity. This paper reports a simple and convenient strategy to fabricate large-scale and ultrasensitive surface-enhanced Raman scattering (SERS) substrates. In this strategy, no toxic chemicals or sophisticated instruments are required to fabricate the SERS substrates. On one hand, Ag nanoparticles (NPs) with relatively uniform size were synthesized using the modified Tollens method, which employs an ultra-low concentration of Ag+ and excessive amounts of glucose as a reducing agent. On the other hand, when a drop of the colloidal Ag NPs dries on a horizontal solid surface, the droplet becomes ropy, turns into a layered structure under gravity, and hardens. During evaporation, capillary flow was burdened by viscidity resistance from the ropy glucose solution. Thus, the coffee-ring effect is eliminated, leading to a uniform deposition of Ag NPs. With this method, flat Ag NPs-based SERS active films were formed in array-well plates defined by hole shaped polydimethylsiloxane (PDMS) structures bonded on glass substrates, which were made for convenient detection. The strong SERS activity of these substrates allowed us to reach detection limits down to 10-14 M of Rhodamine 6 G and 10-10 M of thiram (pesticide). PMID- 30002296 TI - Effects of High Frequency Acceleration Device on Aligner Treatment-A Pilot Study. AB - Evaluation of the effect of a high frequency acceleration device (HFA) on clear aligner exchange intervals and treatment time required to achieve prescribed tooth movements. Sixteen subjects with similar Class I malocclusions, <=5 mm crowding, and treated with aligner orthodontic therapy (Invisalign) were divided into two groups. Group 1 (experimental; n = 8) underwent aligner treatment in conjunction with daily use of the HFA device and exchanged aligners every five days. Group 2 (controls; n = 8) underwent aligner treatment without use of the device and exchanged aligners every 14 days according to the manufacturer's recommended interval. All subjects were treated by one investigator, and results total number of aligners used, and number of refinements required-were evaluated by both prior to final mobile retention (Vivera) scan. A significant decrease in both treatment time and number of aligners required to complete treatment was observed by HFA subjects vs. controls. In addition, no refinements were required by HFA subjects, whereas six of eight control subjects required one or more refinements. The results of the present preliminary report showed that the use of the HFA device in conjunction with aligner orthodontic treatment resulted in a significant decrease in the length of treatment. Moreover, the number of patients requiring refining treatment was significantly lower. PMID- 30002297 TI - Quinazolinone-Amino Acid Hybrids as Dual Inhibitors of EGFR Kinase and Tubulin Polymerization. AB - Some fluoroquinazolinones (A-H) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA MBA-231. New derivative G (IC50 = 0.44 +/- 0.01 uM) showed antitumor activity, better than that of the reference drug erlotinib (IC50 = 1.14 +/- 0.04 uM) against MCF-7. New derivative E (IC50 = 0.43 +/- 0.02 uM) showed higher activity than the reference drug erlotinib (IC50 = 2.55 +/- 0.19 uM) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening. PMID- 30002299 TI - Mapping Forest Structure Using UAS inside Flight Capabilities. AB - We evaluated two unmanned aerial systems (UASs), namely the DJI Phantom 4 Pro and DJI Mavic Pro, for 3D forest structure mapping of the forest stand interior with the use of close-range photogrammetry techniques. Assisted flights were performed within two research plots established in mature pure Norway spruce (Picea abies (L.) H. Karst.) and European beech (Fagus sylvatica L.) forest stands. Geotagged images were used to produce georeferenced 3D point clouds representing tree stem surfaces. With a flight height of 8 m above the ground, the stems were precisely modeled up to a height of 10 m, which represents a considerably larger portion of the stem when compared with terrestrial close-range photogrammetry. Accuracy of the point clouds was evaluated by comparing field-measured tree diameters at breast height (DBH) with diameter estimates derived from the point cloud using four different fitting methods, including the bounding circle, convex hull, least squares circle, and least squares ellipse methods. The accuracy of DBH estimation varied with the UAS model and the diameter fitting method utilized. With the Phantom 4 Pro and the least squares ellipse method to estimate diameter, the mean error of diameter estimates was -1.17 cm (-3.14%) and 0.27 cm (0.69%) for spruce and beech stands, respectively. PMID- 30002298 TI - Understanding the Role of Anti-PEG Antibodies in the Complement Activation by Doxil in Vitro. AB - Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety. PMID- 30002301 TI - Salt-Mediated Au-Cu Nanofoam and Au-Cu-Pd Porous Macrobeam Synthesis. AB - Multi-metallic and alloy nanomaterials enable a broad range of catalytic applications with high surface area and tuning reaction specificity through the variation of metal composition. The ability to synthesize these materials as three-dimensional nanostructures enables control of surface area, pore size and mass transfer properties, electronic conductivity, and ultimately device integration. Au-Cu nanomaterials offer tunable optical and catalytic properties at reduced material cost. The synthesis methods for Au-Cu nanostructures, especially three-dimensional materials, has been limited. Here, we present Au-Cu nanofoams and Au-Cu-Pd macrobeams synthesized from salt precursors. Salt precursors formed from the precipitation of square planar ions resulted in short- and long-range ordered crystals that, when reduced in solution, form nanofoams or macrobeams that can be dried or pressed into freestanding monoliths or films. Metal composition was determined with X-ray diffraction and energy dispersive X ray spectroscopy. Nitrogen gas adsorption indicated an Au-Cu nanofoam specific surface area of 19.4 m2/g. Specific capacitance determined with electrochemical impedance spectroscopy was 46.0 F/g and 52.5 F/g for Au-Cu nanofoams and Au-Cu-Pd macrobeams, respectively. The use of salt precursors is envisioned as a synthesis route to numerous metal and multi-metallic nanostructures for catalytic, energy storage, and sensing applications. PMID- 30002300 TI - The Mechanism of Melatonin and Its Receptor MT2 Involved in the Development of Bovine Granulosa Cells. AB - Ovarian granulosa cells (GCs) are a critical approach to investigate the mechanism of gene regulation during folliculogenesis. The objective of this study was to investigate the role of MT2 in bovine GCs, and assess whether MT2 silencing affected GCs response to melatonin. We found that MT2 silencing significantly decreased the secretion of progesterone and estradiol, and increased the concentration of inhibin B and activin B. To further reveal the regulatory mechanism of MT2 silencing on steroids synthesis, it was found that the expression of CYP19A1 and CYP11A1 enzymes (steroid hormone synthesis) were down-regulated, while genes related to hormonal synthesis (StAR, RUNX2, INHA and INHBB) were up-regulated without affecting the expression of INHBA, suggesting that MT2 silencing may regulate hormone abundance. Furthermore, MT2 silencing significantly increased the expression of TGFBR3 and BMP6, and decreased the expression of LHR and DNMT1A without significant difference in the expression of FSHR and EGFR. In addition, MT2 silencing didn't affect the effect of melatonin on increasing the expression of DNMT1A, EGFR, INHBA and LHR, and progesterone level, or decreasing INHA, TGFBR3 and StAR expression, and production of inhibin B. Moreover, MT2 silencing could disrupt the role of melatonin in decreasing the FSHR, INHBB and BMP6 expression, and activin B secretion. In conclusion, these results reveal that melatonin and MT2 are essential regulator of bovine GCs function by modulating reproduction-related genes expression, hormones secretion and other regulators of folliculogenesis. PMID- 30002302 TI - Process for a Reactive Monomer Alignment Layer for Liquid Crystals Formed on an Azodye Sublayer. AB - In this work, the detailed studies of surface polymerization stabilizing liquid crystal formed on an azodye sublayer are presented. The surface localized stabilization is obtained by free-radical polymerization of a dilute solution of a bi-functional reactive monomer (RM) in a liquid crystal (LC) solvent. To optimize the process for surface localized stabilization, we investigate the effects of several process parameters including RM concentration in LC hosts, the types of materials (either RM or LC), the photo-initiator (PI) concentration, ultra-violet (UV) polymerization intensity, and the UV curing temperature. The quality of surface localized stabilization is characterized and/or evaluated by optical microscopy, electro-optical behavior (transmission/voltage curve), the life test, and photo-bleaching. Our results show that, by carefully selecting materials, formulating mixtures, and controlling the polymerizing variables, the RM polymerization can be realized either at the surface or through the bulk. Overall, the combination of surface localized stabilization and photo-alignment offers an elegant and dynamic solution for controlling the alignment for LC, which could play a profound role in almost all liquid crystal optical devices. PMID- 30002303 TI - The C-Type Lectin Domain Gene Family in Aedes aegypti and Their Role in Arbovirus Infection. AB - Several medically important flaviviruses that are transmitted by mosquitoes have been shown to bind to the C-type lectin fold that is present in either vertebrate or invertebrate proteins. While in some cases this interaction is part of a neutralizing anti-viral immune response, many reports have implicated this as critical for successful virus entry. Despite the establishment of mosquito C-type lectin domain containing proteins (CTLDcps) as known host factors in assisting the infectious process for flaviviruses, little is known about the structural characteristics of these proteins and their relationships to each other. In this report, we describe the manual annotation and structural characterization of 52 Aedes aegypti CTLDcps. Using existing RNAseq data, we establish that these genes can be subdivided into two classes: those highly conserved with expression primarily in development (embryo/early larvae) and those with no clear orthologs with expression primarily in late larvae/pupae or adults. The latter group contained all CTLDcps that are regulated by the Toll/Imd immune pathways, all known microbiome-regulating CTLDcps, and almost all CTLDcps that are implicated as flavivirus host factors in A. aegypti. Finally, we attempt to synthesize results from multiple conflicting gene expression profiling experiments in terms of how flavivirus infection changes steady-state levels of mRNA encoding CTLDcps. PMID- 30002304 TI - Acute Effects of High-Intensity Interval and Moderate-Intensity Continuous Exercise on GLP-1, Appetite and Energy Intake in Obese Men: A Crossover Trial. AB - This study investigated the effect of high-intensity interval (HIIE) and moderate intensity continuous exercise (MICE) on glucagon-like peptide 1 (GLP-1), appetite and energy intake (EI) in obese men. In a randomized crossover trial, 12 participants (28.4 +/- 2.6 years, 35.5 +/- 4.5 kg/m2, 39.8 +/- 2.2% body fat) performed: (I) Control (CON, no exercise); (II) MICE (20 min, 70% of maximal heart rate) and (III) HIIE (10 * 1 min at 90% of maximal heart rate with 1 min recovery). GLP-1 and appetite were assessed at: (I) PRE: pre-exercise; (II) POST: immediately post-exercise; (III) POST-1 h: 1 h post-exercise. EI was assessed after an ad libitum meal offered 1 h post-exercise and over 24 h. There was a significant time * condition interaction for GLP-1 (p = 0.035). Higher GLP-1 levels in MICE vs. CON (p = 0.024) and a trend for HIIE vs. CON (p = 0.069) POST 1h was found. Hunger was reduced immediately post-HIIE compared to CON (p < 0.01), but was not sustained POST-1 h (p > 0.05). EI did not differ between the sessions 1 h post-exercise or over 24H (p > 0.05). In summary, although MICE increased GLP-1 levels POST-1h and HIIE induced a transient reduction in hunger, both exercise protocols did not impact EI in obese men. PMID- 30002305 TI - Health Effects of Air Pollution in China. AB - Background Rapid economic and social development in China has resulted in severe air pollution and consequent adverse impacts on society. The health effects of air pollution have been widely studied. Methods Using information from the China Health and Retirement Longitudinal Study (CHARLS) database, we established a hierarchical linear model combining pollution and socioeconomic and psychosocial variables to examine the effects of air pollution on public health in China. Local air pollution was characterized in multiple dimensions. Results The relationship of health to its determinants greatly differed between Eastern and Central/Western China. Higher education, higher income level, better life satisfaction, and long-term marriage were significantly associated with better health status among Chinese. In addition, regional healthcare resources were positively associated with the health of residents. As indicated by the hierarchical model with health as dependent variable, in Central/Western China, longest duration of good air quality in spring/summer was positively associated with health (estimated coefficient = 0.067, standard error = 0.026), while the mean Air Quality Index (AQI) in autumn/winter was inversely associated with health (estimated coefficient = -0.082, standard error = 0.031). Good air quality in the current study is defined as daily average AQI less than 35. Conclusions Duration (in days) of acceptable air quality was particularly important for improving public health. Future policies should target increased duration of good air quality while managing air pollution by controlling or decreasing severe air pollution. PMID- 30002307 TI - Effect of a Positive Photo Appreciation Program on Depressive Mood in Older Adults: A Pilot Randomized Controlled Trial. AB - Safer and more effective programs are required to cope with an increasing number of older people with depression. Hence, we developed the Positive Photo Appreciation (PPA) program. A three-month pilot randomized controlled trial was conducted with healthy Japanese individuals aged 65-84 years, assigned to a PPA group (n = 28) or Photo Correspondence Education (PCE) (control group) (n = 27). We used the Center for Epidemiologic Studies Depression Scale (CES-D) score as the primary outcome measure. Secondary outcome measures, among others, were cognitive function and positive emotion. Data collected at baseline and post intervention were analyzed using a linear mixed-effect model. Over 80% of the participants in the PPA group completed and were satisfied with the program. Compared with the PCE group, the CES-D score in the PPA group significantly improved (main effect of group: t = -4.30, p < 0.001; interaction effect of group by time: t = 4.39, p < 0.001), with an effect size of d = 1.23. Additionally, a positive significant interaction effect of group by time was found in the Positive and Negative Affect Schedule (t = -2.33, p = 0.024). The PPA program might be promising for mitigating depressive mood in older adults. PMID- 30002306 TI - Slight pH Fluctuations in the Gold Nanoparticle Synthesis Process Influence the Performance of the Citrate Reduction Method. AB - Gold nanoparticles (AuNPs) are currently under intense investigation for biomedical and biotechnology applications, thanks to their ease in preparation, stability, biocompatibility, multiple surface functionalities, and size-dependent optical properties. The most commonly used method for AuNP synthesis in aqueous solution is the reduction of tetrachloroauric acid (HAuCl4) with trisodium citrate. We have observed variations in the pH and in the concentration of the gold colloidal suspension synthesized under standard conditions, verifying a reduction in the reaction yield by around 46% from pH 5.3 (2.4 nM) to pH 4.7 (1.29 nM). Citrate-capped AuNPs were characterized by UV-visible spectroscopy, TEM, EDS, and zeta-potential measurements, revealing a linear correlation between pH and the concentration of the generated AuNPs. This result can be attributed to the adverse effect of protons both on citrate oxidation and on citrate adsorption onto the gold surface, which is required to form the stabilization layer. Overall, this study provides insight into the effect of the pH over the synthesis performance of the method, which would be of particular interest from the point of view of large-scale manufacturing processes. PMID- 30002308 TI - Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials. AB - BACKGROUND: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with standard chemotherapies. This review assesses the evidence for safety and clinical effectiveness of intravenous (IV) ascorbate in treating various types of cancer. METHODS: Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to determine if they met inclusion criteria, and then summarized using a narrative approach. RESULTS: A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or standard of care (chemotherapy). That trial reported an 8.75 month increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm. CONCLUSION: Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer. PMID- 30002309 TI - Ranking of Production Animal Welfare and Ethics Issues in Australia and New Zealand by Veterinary Students. AB - The importance of animal welfare and ethics (AWE) within the veterinary education should reflect community concerns and expectations about AWE, and the professional demands of veterinary accreditation on the first day of practice (or 'Day One' competences). Currently, much interest and debate surrounds the treatment of production animals, particularly around live export. To explore the attitudes to AWE of veterinary students in Australia and New Zealand, a survey was undertaken to (i) understand what students consider important AWE topics for initial production animal competence; and (ii) ascertain how these priorities correlated with gender, area of intended practice and stage-of-study. The results from 575 veterinary students showed that all students ranked strategies to address painful husbandry procedures as the most important issues on their first day in production animal practice. Additionally, it was found that the importance students assigned to an understanding of human-animal interactions declined as they progressed through the veterinary course. In contrast, the importance of an understanding of euthanasia issues for production animals increased for male students as they progressed through the course, and remained consistently high in females. Females also gave higher ranking to the importance of understanding production animal stress associated with transport, and ranked strategies to address painful husbandry procedures more important than did males. These findings should help the development of AWE teaching resources that address students' attitudes and competence and that can be delivered when students are most receptive. PMID- 30002310 TI - Aspirin is Involved in the Cell Cycle Arrest, Apoptosis, Cell Migration, and Invasion of Oral Squamous Cell Carcinoma. AB - Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. In China, its 5-year survival rate is roughly 50%, owing to acquired chemotherapeutic resistance and metastasis of the disease. Accumulating evidence demonstrates that aspirin (ASA) acts as a preventive or therapeutic agent in multiple cancers; however, anti-tumor activities induced by aspirin are unclear in OSCC. To investigate the possible role of aspirin in OSCC development, we first employed bioinformatics to analyze the anti-OSCC effects of aspirin. We performed a genetic oncology (GO) enrichment analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and the protein protein interaction (PPI) network analysis by Cytoscape for differentially expressed genes (DEGs). We also evaluated the potential effects of aspirin on cell proliferation, invasion, migration, and apoptosis in two well-characterized OSCC cell lines (TCA8113 and CAL27). The bioinformatic results revealed that aspirin could inhibit proliferation by blocking the cell cycle, and could reduce migration and invasion via the PI3K-Akt and focal adhesion pathways. We found that ASA could downregulate the OSCC cell proliferation colony formation, invasion, and migration, as well as upregulate apoptosis. Furthermore, we found that ASA suppressed the activation of the focal adhesion kinase (FAK) and the phosphorylation of Akt, NF-kappaB, and STAT3. Overall, our data suggested that ASA may be developed as a chemopreventive agent to effectively treat OSCC. PMID- 30002311 TI - Simultaneous Determination of Chrysin and Tectochrysin from Alpinia oxyphylla Fruits by UPLC-MS/MS and Its Application to a Comparative Pharmacokinetic Study in Normal and Dementia Rats. AB - A simple and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) coupled with a one-step liquid-liquid extraction method has been developed and validated for the simultaneous determination of two flavonoids (chrysin, tectochrysin) from Alpinia oxyphylla fruits extract in rat plasma. Plasma samples were extracted with diethyl ether and separated on an ACQUITY UPLC BEH C18 column (100 mm * 2.1 mm, 1.7 MUm) using gradient elution consisting of 0.1% formic acid in water (A) and methanol (B). The multiple reaction monitoring (MRM) mode with electrospray ionization in the positive ion mode was used for detection. The linear range was 0.1 ng/mL to 50 ng/mL for chrysin and tectochrysin, respectively. The accuracy (relative error, RE%) ranged from -8.8% to 7.5% and the intra-day and inter-day precision were within 15% and had a mean extraction recovery rate of 80.3% to 86.7%. The validated method was applied to a comparative pharmacokinetic study after oral administration of Alpinia oxyphylla fruit ethanol extract between normal rats and dementia rats. The area under the curve (AUC) and peak plasma concentration (Cmax) of the two constituents were remarkably increased in dementia rats than in normal rats. PMID- 30002312 TI - Giant Self-Kerr Nonlinearity in the Metal Nanoparticles-Graphene Nanodisks Quantum Dots Hybrid Systems Under Low-Intensity Light Irradiance. AB - Hybrid nanocomposites can provide a promising platform for integrated optics. Optical nonlinearity can significantly widen the range of applications of such structures. In the present paper, a theoretical investigation is carried out by solving the density matrix equations derived for a metal nanoparticles-graphene nanodisks-quantum dots hybrid system interacting with weak probe and strong control fields, in the steady state. We derive analytical expressions for linear and third-order nonlinear susceptibilities of the probe field. A giant self-Kerr nonlinear index of refraction is obtained in the optical region with relatively low light intensity. The optical absorption spectrum of the system demonstrates electromagnetically induced transparency and amplification without population inversion in the linear optical response arising from the negative real part of the polarizabilities for the plasmonic components at the energy of the localized surface plasmon resonance of the graphene nanodisks induced by the probe field. We find that the self-Kerr nonlinear optical properties of the system can be controlled by the geometrical features of the system, the size of metal nanoparticles and the strength of the control field. The controllable self-Kerr nonlinearities of hybrid nanocomposites can be employed in many interesting applications of modern integrated optics devices allowing for high nonlinearity with relatively low light intensity. PMID- 30002313 TI - A Reverse Genetics System for Zika Virus Based on a Simple Molecular Cloning Strategy. AB - The Zika virus (ZIKV) has recently attracted major research interest as infection was unexpectedly associated with neurological manifestations in developing foetuses and with Guillain-Barre syndrome in infected adults. Understanding the underlying molecular mechanisms requires reverse genetic systems, which allow manipulation of infectious cDNA clones at will. In the case of flaviviruses, to which ZIKV belongs, several reports have indicated that the construction of full length cDNA clones is difficult due to toxicity during plasmid amplification in Escherichia coli. Toxicity of flaviviral cDNAs has been linked to the activity of cryptic prokaryotic promoters within the region encoding the structural proteins leading to spurious transcription and expression of toxic viral proteins. Here, we employ an approach based on in silico prediction and mutational silencing of putative promoters to generate full-length cDNA clones of the historical MR766 strain and the contemporary French Polynesian strain H/PF/2013 of ZIKV. While for both strains construction of full-length cDNA clones has failed in the past, we show that our approach generates cDNA clones that are stable on single bacterial plasmids and give rise to infectious viruses with properties similar to those generated by other more complex assembly strategies. Further, we generate luciferase and fluorescent reporter viruses as well as sub-genomic replicons that are fully functional and suitable for various research and drug screening applications. Taken together, this study confirms that in silico prediction and silencing of cryptic prokaryotic promoters is an efficient strategy to generate full-length cDNA clones of flaviviruses and reports novel tools that will facilitate research on ZIKV biology and development of antiviral strategies. PMID- 30002315 TI - High Accuracy Open-Type Current Sensor with a Differential Planar Hall Resistive Sensor. AB - In this paper, we propose a high accuracy open-type current sensor with a differential Planar Hall Resistive (PHR) sensor. Conventional open-type current sensors with magnetic sensors are usually vulnerable to interference from an external magnetic field. To reduce the effect of an unintended magnetic field, the proposed design uses a differential structure with PHR. The differential structure provides robust performance to unwanted magnetic flux and increased magnetic sensitivity. In addition, instead of conventional Hall sensors with a magnetic concentrator, a newly developed PHR with high sensitivity is employed to sense horizontal magnetic fields. The PHR sensor and read-out integrated circuit (IC) are integrated through a post-Complementary metal-oxide-semiconductor (CMOS) process using multi-chip packaging. The current sensor is designed to measure a 1 A current level. The measured performance of the designed current sensor has a 16 kHz bandwidth and a current nonlinearity of under +/-0.5%. PMID- 30002314 TI - Transcription of IVIAT and Virulence Genes in Photobacterium damselae Subsp. piscicida Infecting Solea senegalensis. AB - Photobacterium damselae subsp. piscicida (Phdp) is responsible for disease outbreaks in marine aquaculture worldwide. Solea senegalensis, a valuable fish species for aquaculture in the south of Europe, is frequently affected by this pathogen. It is well established that bacteria respond to environmental signals and, in the case of pathogens, this ability may determine the outcome of their interaction with the host. Determination of gene expression under in vivo conditions constitutes a valuable tool in the assessment of microbial pathogenesis. Considering that different hosts may represent different environments for the pathogen, expression of Phdp virulence and in vivo induced antigen (IVIAT) genes during S. senegalensis infection has been determined in the present work. Increased transcription of genes encoding proteins involved in iron acquisition (Irp1, Irp2, HutB and HutD), oxidative stress defence (AhpC and Sod), adhesion (PDP_0080), toxins (AIP56) and metabolism (Impdh, Shmt and AlaRS) were detected in Phdp infecting S. senegalensis head kidney or liver. The highest increases corresponded to genes involved in survival under iron limiting conditions and oxidative stress, indicating their essential role during infection of sole. Results obtained give insight into Phdp virulence strategies and contribute to the identification of promising targets for the control of photobacteriosis. PMID- 30002316 TI - Improving the Catalytic Performance of Keggin [PW12O40]3- for Oxidative Desulfurization: Ionic Liquids versus SBA-15 Composite. AB - Different methodologies were used to increase the oxidative desulfurization efficiency of the Keggin phosphotungstate [PW12O40]3- (PW12). One possibility was to replace the acid proton by three different ionic liquid cations, forming the novel hybrid polyoxometalates: [BMIM]3PW12 (BMIM as 1-butyl-3-methylimidazolium), [BPy]3PW12 (BPy as 1-butylpyridinium) and [HDPy]3PW12 (HDPy as hexadecylpyridinium. These hybrid Keggin compounds showed high oxidative desulfurization efficiency in the presence of [BMIM]PF6 solvent, achieving complete desulfurization of multicomponent model diesel (2000 ppm of S) after only 1 h, using a low excess of oxidant (H2O2/S = 8) at 70 degrees C. However, their stability and activity showed some weakness in continuous reused oxidative desulfurization cycles. An improvement of stability in continuous reused cycles was reached by the immobilization of the Keggin polyanion in a strategic positively-charged functionalized-SBA-15 support. The PW12@TM-SBA-15 composite (TM is the trimethylammonium functional group) presented similar oxidative desulfurization efficiency to the homogeneous IL-PW12 compounds, having the advantage of a high recycling capability in continuous cycles, increasing its activity from the first to the consecutive cycles. Therefore, the oxidative desulfurization system catalyzed by the Keggin-type composite has high performance under sustainable operational conditions, avoids waste production during recycling and allows catalyst recovery. PMID- 30002317 TI - A Software-Defined Networking Framework to Provide Dynamic QoS Management in IEEE 802.11 Networks. AB - In this paper, the concept of SDN (Software Defined Networking) is extended to be applied to wireless networks. Traditionally, in a wired SDN environment, the OpenFlow protocol is the communication protocol used to configure the flow table of forwarding elements (i.e., switches and Access Points). However, although in IEEE 802.11 networks there is no concept of forwarding, the SDN paradigm could also be applied to set up the wireless network dynamically, in order to improve the performance. In this case, not only the network elements, that is the Access Points, but also the mobile elements should configure their link and physical layers parameters following the guidelines of a centralized SDN controller. In particular, we propose a mechanism called DEDCA (Dynamic Enhanced Distributed Channel Access) to manage the channel access in wireless networks, and a framework that enables its implementation in 802.11-based wireless networks using SDN technology. The key aspect of this alternative solution is the control over the contention window size of the wireless terminals. Thus, an adequate response to dynamic and short-term Quality of Service (QoS) requirements can be offered to services running on these networks. DEDCA mechanism relies upon the use of a scalar parameter called gain. The mathematical model which has allowed us to obtain this parameter is presented and evaluated in this paper. Finally, the usefulness of the proposed solutions have been evaluated by means of their implementation in an example case. PMID- 30002318 TI - Improvement of Eco-Efficiency in China: A Comparison of Mandatory and Hybrid Environmental Policy Instruments. AB - China's environmental problems have long been criticized. The Communist Party of China (CPC) and the government have increasingly paid attention to developing environmental protection and included the construction of an ecological civilization in the "Five-in-One" development strategy. The improvement of regional eco-efficiency is an important way to realize the coordinated development of the entire society, and environmental policy instruments are a powerful means to enhance regional eco-efficiency. This paper categorizes environmental policy instruments into mandatory, hybrid, and voluntary types. Based on panel data from 31 provinces in China from 2005 to 2015, the paper discusses the impact of environmental policy instruments on regional eco efficiency and the means of the impact. The research shows that (1) mandatory and hybrid environmental policy instruments play a significant role in promoting regional eco-efficiency, while the role of voluntary instruments is not significant in promoting regional eco-efficiency; (2) hybrid and mandatory environmental policy instruments have negative interactions; and (3) the level of economic development will positively affect the role of hybrid environmental policy instruments in promoting regional eco-efficiency but negatively affect the role of mandatory instruments in promoting regional efficiency. PMID- 30002319 TI - Smart Environmental Monitoring and Assessment Technologies (SEMAT)-A New Paradigm for Low-Cost, Remote Aquatic Environmental Monitoring. AB - Expense and the logistical difficulties with deploying scientific monitoring equipment are the biggest limitations to undertaking large scale monitoring of aquatic environments. The Smart Environmental Monitoring and Assessment Technologies (SEMAT) project is aimed at addressing this problem by creating an open standard for low-cost, near real-time, remote aquatic environmental monitoring systems. This paper presents the latest refinement of the SEMAT system in-line with the evolution of existing technologies, inexpensive sensors and environmental monitoring expectations. We provide a systems analysis and design of the SEMAT remote monitoring units and the back-end data management system. The system's value is augmented through a unique e-waste recycling and repurposing model which engages/educates the community in the production of the SEMAT units using social enterprise. SEMAT serves as an open standard for the community to innovate around to further the state of play with low-cost environmental monitoring. The latest SEMAT units have been trialled in a peri-urban lake setting and the results demonstrate the system's capabilities to provide ongoing data in near real-time to validate an environmental model of the study site. PMID- 30002320 TI - Ag-Coated Cellulose Fibers as Surface-Enhanced Raman Scattering Substrates for Adsorptive Detection of Malachite Green. AB - Surface-enhanced Raman scattering (SERS) is a sensitive technique for the detection of low concentration analytes. In this study, we used cellulose fibers (CF) as the templates for the loading of silver nanoparticles (Ag NPs), and the obtained CF-Ag was applied in the detection of R6G and Malachite Green (MG) by surface-enhanced Raman scattering. The adsorption technique was employed in the sample preparation, and the optimal detecting status was identified in the dynamic range (sample status ranging from wet to dry) for different concentration of analytes. In comparison to Ag NPs, CF-Ag showed enhanced performance for adsorptive detection of Malachite Green, and the limit of detection was 5 * 10-12 M. PMID- 30002321 TI - In-Depth Aroma and Sensory Profiling of Unfamiliar Table-Grape Cultivars. AB - We present an in-depth analysis of aroma profiles and sensory attributes, employing solid-phase microextraction gas chromatography/mass spectrometry (SPME GC-MS) to identify the key compounds driving consumer preference in 19 unfamiliar cultivars. In combination with popular cultivars, we identified a total of 100 compounds in all table grapes, of which 26 key volatiles were correlated with consumer liking. Based on this relationship, five aroma combinations (AC) were formulated, wherein 33 compounds contributed to aroma intensity, and thus, were viewed as active volatiles. The fruity, floral, and sweet aromas were further divided into secondary aromatic series, of which the apple, citrus, orange, rose, geranium, violet, and honey aromas constituted the predominant series in unfamiliar cultivars. Xiangyue and Heikuixiang emerged as the preferred table grapes according to our analysis. By comparison, the popular cultivars showed relatively fewer volatiles, but their contents were much greater than the large number of volatiles identified in the unfamiliar cultivars. PMID- 30002322 TI - Cloacal and Ocular Microbiota of the Endangered Australian Northern Quoll. AB - The Australian northern quoll is an important predatory marsupial carnivore that is currently endangered due to inappropriate fire regimes, predation, and the spread of invasive cane toads. The microbiota of Australian marsupials has not been extensively studied, but is thought to play a role in their health. This study provides an initial characterization of the cloacal microbiota of the northern quoll, as well as other marsupials including possums and kangaroos which were opportunistically sampled. The northern quoll cloaca microbiota was dominated by Enterococcus and Lactobacillus and had a relatively high proportion of members of the Proteobacteria phylum, which has been observed in other carnivorous marsupials. The diversity and structure of the microbiota was not influenced by presence of Chlamydiales which are intracellular bacteria and potential pathogens. The microbiota of the other marsupials was quite varied, which may be related to their health status. Characterization of the northern quoll microbiota will help to better understand the biology of this endangered animal. PMID- 30002323 TI - A Vegetarian Diet Is a Major Determinant of Gut Microbiota Composition in Early Pregnancy. AB - The composition of the gut microbiota can be influenced by dietary composition. In pregnancy, the maternal gut microbiome has associations with maternal and infant metabolic status. There is little known regarding the impact of a vegetarian diet in pregnancy on maternal gut microbiota. This study explored the gut microbiota profile in women who were vegetarian or omnivorous in early gestation. Women were selected from participants in the Study of PRobiotics IN Gestational diabetes (SPRING) randomised controlled trial. Nine women identified as vegetarians were matched to omnivorous women in a 1:2 ratio. Microbiota analyses were performed using 16S rRNA gene amplicon sequencing and analysed using the Quantitative Insights Into Microbial Ecology (QIIME) and Calypso software tools. There was no difference in alpha diversity, but beta diversity was slightly reduced in vegetarians. There were differences seen in the relative abundance of several genera in those on a vegetarian diet, specifically a reduction in Collinsella, Holdemania, and increases in the relative abundances of Roseburia and Lachnospiraceae. In this sub-analysis of gut microbiota from women in early pregnancy, a vegetarian as compared to omnivorous diet, was associated with a different gut microbiome, with features suggesting alterations in fermentation end products from a mixed acid fermentation towards more acetate/butyrate. PMID- 30002325 TI - Study of the Effect of Curing Residual Stress on the Bonding Strength of the Single Lap Joint Using a High-Temperature Phosphate Adhesive. AB - High-temperature phosphate adhesives are widely used in the aerospace and nuclear power industries. However, complex residual stresses can result when the curing temperature parameters are unreasonable due to the brittleness of the adhesive. To reveal the curing temperature mechanism affecting the bonding strength of the phosphate adhesives, several curing temperature curves (CT-1~6) were designed for the single lap joint (SLJ) using phosphate adhesive. The residual stress helped to reveal the relationship between the curing temperature parameters and the bonding performance. In this process, the residual stress of the silicon carbide joint was measured using micro-Raman spectroscopy, and the tensile strength of the joint was tested. A cohesive zone model (CZM) was established with Abaqus(r) to verify the results, and the numerical results from the model agreed well with the experimental values. The residual stress and adhesive strength were obviously affected by curing temperature. The reasonable curing temperature curves have the benefits of reducing the residual stress and improving the bonding strength. PMID- 30002324 TI - Interconnected PolymerS TeChnology (IPSTiC): An Effective Approach for the Modulation of 5alpha-Reductase Activity in Hair Loss Conditions. AB - Hair loss represents a condition that adversely affects the social life of patients. The most common cause is androgenetic alopecia (AGA), which is a genetically determined progressive hair-loss condition involving 5alpha reductase. In this study, a novel anti-baldness agent based on Interconnected PolymerS TeChnology (IPSTiC), which is an effective strategy for the delivery of bioactive molecules, was developed. This product (IPSTiC patch hair) is based on a polymeric blend consisting of high molecular weight hyaluronic acid and soybean proteins and is able to improve efficacy and stability of bioactive ingredients such as Origanum vulgare leaf extract, Camellia Sinensis leaf extract, and Capsicum Annuum fruit extract. The efficacy of the developed anti-baldness agent was investigated by performing several tests including NO radical and 5alpha reductase inhibition assays, stability studies under different conditions, and in vitro diffusion studies using Franz cells. The biocompatibility of IPSTiC patch hair was also evaluated by in vitro analysis of the pro-sensitising potential and EPISKIN model. The obtained results confirmed both the efficacy and safety of IPSTiC patch hair supporting the potential use of this product in the topical treatment of AGA. PMID- 30002326 TI - Strong Dependence of Surface Enhanced Raman Scattering on Structure of Graphene Oxide Film. AB - Graphene and its derivatives have been demonstrated to be good surface-enhanced Raman scattering (SERS) substrates. However, the literature offers some contrasting views on the SERS effect of graphene-based materials. Thus, understanding the mechanism of the SERS enhancement of graphene is essential for exploring its application as a SERS substrate. In this study, graphene oxide (GO) and chemically reduced graphene oxide (CRGO) films with different morphologies and structures were prepared and applied as SERS substrates to detect Raman dye molecules. The observed enhancement factors can be as large as 10~103. The mechanism of SERS enhancement is discussed. It is shown that the SERS effect was independent of the adsorption of dye molecules and the surface morphologies of graphene-based films. Raman shifts are observed and are almost the same on different graphene-based films, indicating the existence of charge transfer between dye molecules and substrates. The Raman enhancement factors and sensitivities of dye molecules on different films are consistently within the IG/ID ratios of graphene-based substrates, indicating that the dramatically enhanced Raman spectra on graphene-based films are strongly dependent on the average size of sp2 carbon domain. PMID- 30002327 TI - Tackling the Consumption of High Sugar Products among Children and Adolescents in the Pacific Islands: Implications for Future Research. AB - The Pacific Islands are experiencing an obesity epidemic with a rate of overweight and obesity as high as 80% among adults in some Pacific Island nations. Children and adolescents in the region are also affected by overweight and obesity, which is alarming due to the increased likelihood of remaining overweight as an adult. Research supports an association between poor diet and an increased risk of obesity and development of non-communicable diseases (NCDs). Excess consumption of free sugars is associated with poorer overall diet quality and increased risk of weight gain, chronic inflammation and dental caries. Traditional diets in the Pacific Islands are being supplemented with processed, high-sugar foods and beverages; thus, there is a clear need for effective interventions promoting positive dietary behaviors in the region. School and community based interventions offer an opportunity to promote positive behavior change among children and adolescents. This review aims to evaluate interventions targeting the consumption of high-sugar products in this population in the Pacific Islands. PMID- 30002328 TI - Portable Force Plates: A Viable and Practical Alternative to Rapidly and Accurately Monitor Elite Sprint Performance. AB - This study aimed to examine the associations between a series of mechanical variables automatically generated by a portable force plate (PFP) and the actual performance of professional sprinters over a 150 m course. To test these correlations, 12 top-level sprinters performed vertical jumps (squat and countermovement jumps; SJ and CMJ, respectively), a 60 m sprint test, and a 150 m sprint test. Pearson product-moment coefficient of correlation and multiple regression analyses were used to determine the relationships between the sprinting velocities and vertical jump outputs. The SJ parameters were moderately to near perfectly associated with the different sprint distances, and the SJ height presented the highest correlation scores (r = 0.90 with velocities over 10 and 20-m). The correlation coefficients between the CMJ outcomes and sprint results varied between moderate and very large (from 0.38 to 0.88). Finally, the coefficients of determination (R2) ranged from 0.71 to 0.85 for the different multiple regressions involving PFP automatic measures. The PFP can provide practitioners with quick and accurate information regarding competitive athletes. Due to the strong correlations observed, coaches are encouraged to frequently adjust and tailor the training strategies of their sprinters, using practical and timesaving PFP measurements. PMID- 30002329 TI - Trends in Neisseria gonorrhoeae Antimicrobial Resistance over a Ten-Year Surveillance Period, Johannesburg, South Africa, 2008-2017. AB - BACKGROUND: In South Africa, sexually transmitted infections (STIs) are managed through a syndromic approach at primary healthcare centres (PHCs). Neisseria gonorrhoeae is the predominant cause of male urethritis syndrome. We describe antimicrobial resistance patterns and trends in Neisseria gonorrhoeae during a ten-year surveillance period at a large PHC in Johannesburg. METHODS: Neisseria gonorrhoeae was cultured from genital discharge swab specimens obtained from consenting adult patients presenting at the Alexandra Health Centre in Johannesburg between 2008 and 2017. Isolates were tested for antimicrobial susceptibility by EtestTM (cefixime, ceftriaxone, ciprofloxacin) or agar dilution (penicillin, tetracycline, azithromycin). RESULTS: During the period of surveillance, high-level resistance prevalence increased from 30% to 51% for penicillin (p-value for trend < 0.001), 75% to 83% for tetracycline (p-value for trend = 0.008), and 25% to 69% for ciprofloxacin (p-value for trend < 0.001). Analysis did not reveal high-level resistance to spectinomycin or a minimum inhibitory concentration (MIC) creep for extended-spectrum cephalosporins, and the prevalence of intermediate-resistance to azithromycin was less than 5%. CONCLUSIONS: High prevalence resistance to penicillin, tetracycline, and ciprofloxacin in N. gonorrhoeae obviates their use in future national treatment algorithms for genital discharge. It is essential to continue monitoring for emerging resistance to currently recommended antimicrobial therapy in this rapidly evolving pathogen. PMID- 30002331 TI - Adsorption Heat Storage: State-of-the-Art and Future Perspectives. AB - Thermal energy storage (TES) is a key technology to enhance the efficiency of energy systems as well as to increase the share of renewable energies. In this context, the present paper reports a literature review of the recent advancement in the field of adsorption TES systems. After an initial introduction concerning different heat storage technologies, the working principle of the adsorption TES is explained and compared to other technologies. Subsequently, promising features and critical issues at a material, component and system level are deeply analyzed and the ongoing activities to make this technology ready for marketing are introduced. PMID- 30002332 TI - Mechanical Response and Shear-Induced Initiation Properties of PTFE/Al/MoO3 Reactive Composites. AB - Polytetrafluoroethylene/aluminum/molybdenum oxide (PTFE/Al/MoO3) reactive composites of a volume ratio of 60:16:24 were studied in this research. Quasi static compression, dynamic compression and drop-weight experiments were performed to explore the mechanical response and the shear-induced initiation properties of the composites. Mesoscale images of the specimens after sintering demonstrate that PTFE, Al and MoO3 powders were evenly mixed and no chemical reaction occurred after the materials were stirred, pressed and sintered. The yield stress and compressive strength of PTFE/Al/MoO3 specimens are sensitive to strain rate within the range of 10-3~3 * 103 s-1, and the yield stress shows a bilinear dependence on the logarithm values of strain rate. The established Johnson-Cook constitutive model based on the experimental data can describe the mechanical response of PTFE/Al/MoO3 material well. Drop-weight tests show that the PTFE/Al/MoO3 specimens can react violently when impacted, with the characteristic drop height (H50) calculated as 51.57 cm. The recovered specimens show that the reaction started from the outer edge of the specimen with the largest shear force and the most concentrated shear deformation, indicating a shear-induced initiation mechanism. The reaction products of PTFE/Al/MoO3 specimens were AlF3, Al2O3, Mo and C, demonstrating that redox reaction occurred between PTFE and Al, and between Al and MoO3. PMID- 30002334 TI - Consistent Semantic Annotation of Outdoor Datasets via 2D/3D Label Transfer. AB - The advance of scene understanding methods based on machine learning relies on the availability of large ground truth datasets, which are essential for their training and evaluation. Construction of such datasets with imagery from real sensor data however typically requires much manual annotation of semantic regions in the data, delivered by substantial human labour. To speed up this process, we propose a framework for semantic annotation of scenes captured by moving camera(s), e.g., mounted on a vehicle or robot. It makes use of an available 3D model of the traversed scene to project segmented 3D objects into each camera frame to obtain an initial annotation of the associated 2D image, which is followed by manual refinement by the user. The refined annotation can be transferred to the next consecutive frame using optical flow estimation. We have evaluated the efficiency of the proposed framework during the production of a labelled outdoor dataset. The analysis of annotation times shows that up to 43% less effort is required on average, and the consistency of the labelling is also improved. PMID- 30002333 TI - Recent Progress in Metal-Based Nanoparticles Mediated Photodynamic Therapy. AB - Photodynamic therapy (PDT) is able to non-invasively treat and diagnose various cancers and nonmalignant diseases by combining light, oxygen, and photosensitizers (PSs). However, the application of PDT is hindered by poor water solubility and limited light-penetration depth of the currently available photosensitizers (PSs). Water solubility of PSs is crucial for designing pharmaceutical formulation and administration routes. Wavelength of light source at visible range normally has therapeutic depth less than 1 mm. In this review, focus is on the recent research progress of metal-based nanoparticles being applied in PDT. The potential toxicity of these nanoscales and future directions are further discussed. PMID- 30002330 TI - A Current Overview of the Biological and Cellular Effects of Nanosilver. AB - Nanosilver plays an important role in nanoscience and nanotechnology, and is becoming increasingly used for applications in nanomedicine. Nanosilver ranges from 1 to 100 nanometers in diameter. Smaller particles more readily enter cells and interact with the cellular components. The exposure dose, particle size, coating, and aggregation state of the nanosilver, as well as the cell type or organism on which it is tested, are all large determining factors on the effect and potential toxicity of nanosilver. A high exposure dose to nanosilver alters the cellular stress responses and initiates cascades of signalling that can eventually trigger organelle autophagy and apoptosis. This review summarizes the current knowledge of the effects of nanosilver on cellular metabolic function and response to stress. Both the causative effects of nanosilver on oxidative stress, endoplasmic reticulum stress, and hypoxic stress-as well as the effects of nanosilver on the responses to such stresses-are outlined. The interactions and effects of nanosilver on cellular uptake, oxidative stress (reactive oxygen species), inflammation, hypoxic response, mitochondrial function, endoplasmic reticulum (ER) function and the unfolded protein response, autophagy and apoptosis, angiogenesis, epigenetics, genotoxicity, and cancer development and tumorigenesis-as well as other pathway alterations-are examined in this review. PMID- 30002335 TI - Gender Differences in Psychological Well-Being and Health Problems among European Health Professionals: Analysis of Psychological Basic Needs and Job Satisfaction. AB - Background: The aim was to examine the mediating role of basic psychological needs and job satisfaction in the relationship between the gender effect on health problems and psychological well-being for health professionals in Europe in 2015. Methods: Two multiple partial mediation analyses were conducted in order to test the partial mediation of both basic needs and job satisfaction, with gender as the independent variable and health problems or well-being, respectively, as the dependent variables, with a sample of health professionals. Results: Women reported lower psychological well-being and more health problems than men. The total effect of gender on both well-being and health problems was found to be significant. Regarding multiple mediation analyses: (a) the effect of gender on well-being was fully mediated by global basic need satisfaction and job satisfaction, such that gender did not present a significant direct effect and (b) the effect of gender on health problems was partially mediated by global basic need satisfaction and job satisfaction, such that the direct effect remained significant. Conclusions: The fulfillment of basic needs for autonomy, competence, and relatedness, as postulated within self-determination theory, was hypothesized to play a mediating role in the relationship between gender and well being. Since significant gender differences in basic need satisfaction were observed, such a mediator should be controlled in order to achieve a significant relationship between gender and well-being when basic needs comes into play. The current study adds to the research emphasizing the need for satisfaction as a promising mechanism underlying for female health professionals' well-being. PMID- 30002337 TI - Ensemble Consensus-Guided Unsupervised Feature Selection to Identify Huntington's Disease-Associated Genes. AB - Due to the complexity of the pathological mechanisms of neurodegenerative diseases, traditional differentially-expressed gene selection methods cannot detect disease-associated genes accurately. Recent studies have shown that consensus-guided unsupervised feature selection (CGUFS) performs well in feature selection for identifying disease-associated genes. Since the random initialization of the feature selection matrix in CGUFS results in instability of the final disease-associated gene set, for the purposes of this study we proposed an ensemble method based on CGUFS-namely, ensemble consensus-guided unsupervised feature selection (ECGUFS) in order to further improve the accuracy of disease associated genes and the stability of feature gene sets. We also proposed a bagging integration strategy to integrate the results of CGUFS. Lastly, we conducted experiments with Huntington's disease RNA sequencing (RNA-Seq) data and obtained the final feature gene set, where we detected 287 disease-associated genes. Enrichment analysis on these genes has shown that postsynaptic density and the postsynaptic membrane, synapse, and cell junction are all affected during the disease's progression. However, ECGUFS greatly improved the accuracy of disease associated gene prediction and the stability of the disease-associated gene set. We conducted a classification of samples with labels based on the linear support vector machine with 10-fold cross-validation. The average accuracy is 0.9, which suggests the effectiveness of the feature gene set. PMID- 30002336 TI - A Decellularized Porcine Xenograft-Derived Bone Scaffold for Clinical Use as a Bone Graft Substitute: A Critical Evaluation of Processing and Structure. AB - BACKGROUND: Bone grafts are used in approximately one half of all musculoskeletal surgeries. Autograft bone is the historic gold standard but is limited in supply and its harvest imparts significant morbidity to the patient. Alternative sources of bone graft include allografts, synthetics and, less commonly, xenografts which are taken from animal species. Xenografts are available in unlimited supply from healthy animal donors with controlled biology, avoiding the risk of human disease transmission, and may satisfy current demand for bone graft products. METHODS: In the current study, cancellous bone was harvested from porcine femurs and subjected to a novel decellularization protocol to derive a bone scaffold. RESULTS: The scaffold was devoid of donor cellular material on histology and DNA sampling (p < 0.01). Microarchitectural properties important for osteoconductive potential were preserved after decellularization as shown by high resolution imaging modalities. Proteomics data demonstrated similar profiles when comparing the porcine bone scaffold against commercially available human demineralized bone matrix approved for clinical use. CONCLUSION: We are unaware of any porcine derived bone graft products currently used in orthopaedic surgery practice. Results from the current study suggest that porcine-derived bone scaffolds warrant further consideration to serve as a potential bone graft substitute. PMID- 30002338 TI - Process Evaluation of an eHealth Intervention Implemented into General Practice: General Practitioners' and Patients' Views. AB - (1) Background: It has been shown that online interventions can be enhanced by providing additional support; accordingly, we developed an implementation plan for the use of an eHealth intervention targeting physical activity and healthy nutrition in collaboration with general practitioners (GPs). In this study, GPs and patients evaluated the actual implementation; (2) Methods: Two hundred and thirty two patients completed the feasibility questionnaire regarding the implementation of "MyPlan 1.0" in general practice. Individual interviews were conducted with 15 GPs who implemented "MyPlan 1.0" into their daily work flow; (3) Results: The majority of the patients indicated that general practice was an appropriate setting to implement the online intervention. However, patients were not personally addressed by GPs and advice/action plans were not discussed with the GPs. The GPs indicated that this problem was caused by the severe time restrictions in general practice. GPs also seemed to select those patients who they believed to be able to use (e.g., highly educated patients) and to benefit from the intervention (e.g., patients with overweight); (4) Conclusions: Although GPs were involved in the development of the online intervention and its implementation plan, the programme was not used in general practice as intended. PMID- 30002340 TI - The Growing Threat of Gonococcal Blindness. AB - Antibiotic-resistant gonorrhea is now a reality, as well as the consequences of untreatable infections. Gonococcal eye infections result in blindness if not properly treated; they accounted for the vast majority of infections in children in homes for the blind in the pre-antibiotic era. Neisseria gonorrhoeae infects the eyes of infants born to mothers with gonorrhea and can also infect the eyes of adults. Changes in sexual practices may account for the rise in adult gonococcal eye infections, although some cases seem to have occurred with no associated genital infection. As gonorrhea becomes increasingly difficult to treat, the consequences for the treatment of gonococcal blindness must be considered as well. Monocaprin was shown to be effective in rapidly killing N. gonorrhoeae, and is non-irritating in ocular models. Repeated passage in sub lethal monocaprin induces neither resistance in gonococci nor genomic mutations that are suggestive of resistance. Here, we show that 1 mM monocaprin kills 100% of N. gonorrhoeae in 2 min, and is equally effective against N. meningitidis, a rare cause of ophthalmia neonatorum that is potentially lethal. Monocaprin at 1 mM also completely kills Staphylococcus aureus after 60 min, and 25 mM kills 80% of Pseudomonas aeruginosa after 360 min. Previously, 1 mM monocaprin was shown to eliminate Chlamydia trachomatis in 5 min. Monocaprin is, therefore, a promising active ingredient in the treatment and prophylaxis of keratitis, especially considering the growing threat of gonococcal blindness due to antimicrobial resistance. PMID- 30002341 TI - Morin as a Preservative for Delaying Senescence of Banana. AB - Banana is a climacteric fruit with desirable palatability and high nutritional value. It ripens rapidly accompanied with metabolite changes during postharvest storage. In this work, morin was applied to treat banana to delay senescence. Nuclear magnetic resonance (NMR) spectroscopy was used to monitor the changes of metabolite composition and levels in banana. The results showed that morin significantly delayed the changes of color and firmness. 1D and 2D NMR spectra reflected that the levels and composition of metabolites were changed with the senescence initiation. The principal component analysis revealed that the first principal components responsible for banana senescence were carbohydrates, amino acids, lipids and phenolics. Morin treatment delayed the transformation of starch to glucose, fructose and sucrose, accelerated the accumulations of alanine and gamma-Amino-butyrate (GABA), postponed the generations of valine and l-aspartic acid, suppressed the degradation of saponin a. It indicated that morin was effective in delaying banana senescence. PMID- 30002339 TI - Serving Size and Nutrition Labelling: Implications for Nutrition Information and Nutrition Claims on Packaged Foods. AB - The presentation of nutrition information on a serving size basis is a strategy that has been adopted by several countries to promote healthy eating. Variation in serving size, however, can alter the nutritional values reported on food labels and compromise the food choices made by the population. This narrative review aimed to discuss (1) current nutrition labelling legislation regarding serving size and (2) the implications of declared serving size for nutrition information available on packaged foods. Most countries with mandatory food labelling require that serving size be presented on food labels, but variation in this information is generally allowed. Studies have reported a lack of standardisation among serving sizes of similar products which may compromise the usability of nutrition information. Moreover, studies indicate that food companies may be varying serving sizes as a marketing strategy to stimulate sales by reporting lower values of certain nutrients or lower energy values on nutrition information labels. There is a need to define the best format for presenting serving size on food labels in order to provide clear and easily comprehensible nutrition information to the consumer. PMID- 30002343 TI - Carbonate Apatite Containing Statin Enhances Bone Formation in Healing Incisal Extraction Sockets in Rats. AB - The purpose of this study was to evaluate the feasibility of using apatite blocks fabricated by a dissolution-precipitation reaction of preset gypsum, with or without statin, to enhance bone formation during socket healing after tooth extraction. Preset gypsum blocks were immersed in a Na3PO4 aqueous solution to make hydroxyapatite (HA) low crystalline and HA containing statin (HAFS), or in a mixed solution of Na2HPO4 and NaHCO3 to make carbonate apatite (CO) and CO containing statin (COFS). The right mandibular incisors of four-week-old male Wistar rats were extracted and the sockets were filled with one of the bone substitutes or left untreated as a control (C). The animals were sacrificed at two and four weeks. Areas in the healing socket were evaluated by micro-computed tomography (micro-CT) and histological analyses. The bone volume, trabecular thickness, and trabecular separation were greatest in the COFS group, followed by the CO, HAFS, HA, and C groups. The bone mineral density of the COFS group was greater than that of the other groups when evaluated in the vertical plane. The results of this study suggest that COFS not only allowed, but also promoted, bone healing in the socket. This finding could be applicable for alveolar bone preservation after tooth extraction. PMID- 30002344 TI - Risk Assessment and Mapping of Hand, Foot, and Mouth Disease at the County Level in Mainland China Using Spatiotemporal Zero-Inflated Bayesian Hierarchical Models. AB - Hand, foot, and mouth disease (HFMD) is a worldwide infectious disease, prominent in China. China's HFMD data are sparse with a large number of observed zeros across locations and over time. However, no previous studies have considered such a zero-inflated problem on HFMD's spatiotemporal risk analysis and mapping, not to mention for the entire Mainland China at county level. Monthly county-level HFMD cases data combined with related climate and socioeconomic variables were collected. We developed four models, including spatiotemporal Poisson, negative binomial, zero-inflated Poisson (ZIP), and zero-inflated negative binomial (ZINB) models under the Bayesian hierarchical modeling framework to explore disease spatiotemporal patterns. The results showed that the spatiotemporal ZINB model performed best. Both climate and socioeconomic variables were identified as significant risk factors for increasing HFMD incidence. The relative risk (RR) of HFMD at the local scale showed nonlinear temporal trends and was considerably spatially clustered in Mainland China. The first complete county-level spatiotemporal relative risk maps of HFMD were generated by this study. The new findings provide great potential for national county-level HFMD prevention and control, and the improved spatiotemporal zero-inflated model offers new insights for epidemic data with the zero-inflated problem in environmental epidemiology and public health. PMID- 30002342 TI - Celiac Disease and Liver Disorders: From Putative Pathogenesis to Clinical Implications. AB - Immunologically mediated liver diseases belong to the common extraintestinal manifestations of celiac disease. We have reviewed the current literature that addresses the association between celiac disease and liver disorders. We searched relevant articles on MEDLINE/PubMed up to 15 June 2018. The objective of the article is to provide a comprehensive and up-to-date review on the latest hypotheses explaining the pathogenetic relationship between celiac disease and liver injury. Besides the involvement of gut-liver axis, tissue transglutaminase antibodies, and impairment of intestinal barrier, we integrate the latest achievements made in elucidation of the role of gut microbiota in celiac disease and liver disorders, that has not yet been sufficiently discussed in the literature in this context. The further objective is to provide a complete clinical overview on the types of liver diseases frequently found in celiac disease. In conclusion, the review highlights the clinical implication, recommend a rational approach for managing elevated transaminases in celiac patients, and underscore the importance of screening for celiac disease in patients with associated liver disease. PMID- 30002345 TI - Targeted Approaches for In Situ Gut Microbiome Manipulation. AB - Microbial communities and their collective genomes form the gut microbiome, of which bacteria are the major contributor. Through their secreted metabolites, bacteria interact with the host, influencing human health and physiology. Perturbation of the microbiota and metabolome has been associated with various diseases and metabolic conditions. As knowledge on fundamental host-microbiome interactions and genetic engineering tools becomes readily available, targeted manipulation of the gut microbiome for therapeutic applications gains favourable attention. Manipulation of the gut microbiome can be achieved by altering the microbiota population and composition, or by modifying the functional metabolic activity of the microbiome to promote health and restore the microbiome balance. In this article, we review current works that demonstrate various strategies employed to manipulate the gut microbiome in situ to various degrees of precision. PMID- 30002346 TI - Post-Exercise Whole Body Cryotherapy (-140 degrees C) Increases Energy Intake in Athletes. AB - PURPOSE: The purpose of the present study was to investigate the effect of whole body cryotherapy (WBC) treatment after exercise on appetite regulation and energy intake. METHODS: Twelve male athletes participated in two trials on different days. In both trials, participants performed high-intensity intermittent exercise. After 10 min following the completion of the exercise, they were exposed to a 3-min WBC treatment (-140 degrees C, WBC trial) or underwent a rest period (CON trial). Blood samples were collected to assess plasma acylated ghrelin, serum leptin, and other metabolic hormone concentrations. Respiratory gas parameters, skin temperature, and ratings of subjective variables were also measured after exercise. At 30 min post-exercise, energy and macronutrient intake were evaluated during an ad libitum buffet meal test. RESULTS: Although appetite regulating hormones (acylated ghrelin and leptin) significantly changed with exercise (p = 0.047 for acylated ghrelin and p < 0.001 for leptin), no significant differences were observed between the trials. Energy intake during the buffet meal test was significantly higher in the WBC trial (1371 +/- 481 kcal) than the CON trial (1106 +/- 452 kcal, p = 0.007). CONCLUSION: Cold exposure using WBC following strenuous exercise increased energy intake in male athletes. PMID- 30002348 TI - Biosensing System for Concentration Quantification of Magnetically Labeled E. coli in Water Samples. AB - Bacterial contamination of water sources (e.g., lakes, rivers and springs) from waterborne bacteria is a crucial water safety issue and its prevention is of the utmost significance since it threatens the health and well-being of wildlife, livestock, and human populations and can lead to serious illness and even death. Rapid and multiplexed measurement of such waterborne pathogens is vital and the challenge is to instantly detect in these liquid samples different types of pathogens with high sensitivity and specificity. In this work, we propose a biosensing system in which the bacteria are labelled with streptavidin coated magnetic markers (MPs-magnetic particles) forming compounds (MLBs-magnetically labelled bacteria). Video microscopy in combination with a particle tracking software are used for their detection and quantification. When the liquid containing the MLBs is introduced into the developed, microfluidic platform, the MLBs are accelerated towards the outlet by means of a magnetic field gradient generated by integrated microconductors, which are sequentially switched ON and OFF by a microcontroller. The velocities of the MLBs and that of reference MPs, suspended in the same liquid in a parallel reference microfluidic channel, are calculated and compared in real time by a digital camera mounted on a conventional optical microscope in combination with a particle trajectory tracking software. The MLBs will be slower than the reference MPs due to the enhanced Stokes' drag force exerted on them, resulting from their greater volume and altered hydrodynamic shape. The results of the investigation showed that the parameters obtained from this method emerged as reliable predictors for E. coli concentrations. PMID- 30002347 TI - Lactobacillus paracasei PS23 Delays Progression of Age-Related Cognitive Decline in Senescence Accelerated Mouse Prone 8 (SAMP8) Mice. AB - Probiotic supplements are potential therapeutic agents for age-related disorders due to their antioxidant and anti-inflammatory properties. However, the effect of probiotics on age-related brain dysfunction remains unclear. To investigate the effects of Lactobacillus paracasei PS23 (LPPS23) on the progression of age related cognitive decline, male and female senescence-accelerated mouse prone 8 (SAMP8) mice were divided into two groups (n = 6 each): the control and PS23 groups. From the age of 16 weeks, these groups were given saline and LPPS23, respectively, because SAMP8 mice start aging rapidly after four months of age. After 12 weeks of treatment, we evaluated the effect of LPPS23 by analyzing their appearance, behavior, neural monoamines, anti-oxidative enzymes, and inflammatory cytokines. The PS23 group showed lower scores of senescence and less serious anxiety-like behaviors and memory impairment compared to the control group. The control mice also showed lower levels of neural monoamines in the striatum, hippocampus, and serum. Moreover, LPPS23 induced the anti-oxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). Higher levels of tumor necrosis factor (TNF)-alpha and monocyte chemotactic protein-1 (MCP1) and lower levels of interleukin (IL)-10 indicated that LPPS23 modulated the inflammation. Our results suggest that LPPS23 supplements could delay age-related cognitive decline, possibly by preventing oxidation and inflammation and modulating gut-brain axis communication. PMID- 30002350 TI - A Review of PZT Patches Applications in Submerged Systems. AB - Submerged systems are found in many engineering, biological, and medicinal applications. For such systems, due to the particular environmental conditions and working medium, the research on the mechanical and structural properties at every scale (from macroscopic to nanoscopic), and the control of the system dynamics and induced effects become very difficult tasks. For such purposes in submerged systems, piezoelectric patches (PZTp), which are light, small and economic, have been proved to be a very good solution. PZTp have been recently used as sensors/actuators for applications such as modal analysis, active sound and vibration control, energy harvesting and atomic force microscopes in submerged systems. As a consequence, in these applications, newly developed transducers based on PZTp have become the most used ones, which has improved the state of the art and methods used in these fields. This review paper carefully analyzes and summarizes these applications particularized to submerged structures and shows the most relevant results and findings, which have been obtained thanks to the use of PZTp. PMID- 30002349 TI - New Insights in Anti-Angiogenesis in Multiple Myeloma. AB - Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. This article summarizes the more recent literature data concerning the employment of anti-angiogenic therapeutic agents actually used in preclinical models and clinical settings for the treatment of multiple myeloma. PMID- 30002351 TI - Establishment of a New Zealand White Rabbit Model for Lethal Toxin (LT) Challenge and Efficacy of Monoclonal Antibody 5E11 in the LT-Challenged Rabbit Model. AB - Anthrax caused by Bacillus anthracis is a lethal infectious disease, especially when inhaled, and the mortality rate approaches 100% without treatment. The anthrax antitoxin monoclonal antibody (MAb) 5E11 is a humanized antibody that targets the anthrax protective antigen (PA). The efficacy of 5E11 needs proper animal models. However, anthrax spores are extremely dangerous, so experiments must be conducted under Biosafety Level 3 conditions. Considering the critical effects of lethal toxin (LT) on hosts during infection, we report the establishment of a LT-challenged rabbit model, which caused 100% mortality with a dose of 2 mg PA + 1 mg LF, while a 4 mg PA + 2 mg LF challenge could limit death to within three days. Then, we evaluated 5E11 efficacy against LT. A prophylactic study showed that the i.v. administration of 40 mg/kg 5E11 four days before lethal dose LT challenge could lead to 100% survival. In therapeutic studies, the i.v. administration of 40 mg/kg 5E11 10 min after lethal dose LT challenge could provide complete protection. Overall, we developed a new LT-challenged rabbit model, and our results indicate that 5E11 shows potential for the clinical application in anthrax treatment. PMID- 30002353 TI - Strategy for Determining the Stochastic Distance Characteristics of the 2D Laser Scanner Z + F Profiler 9012A with Special Focus on the Close Range. AB - Kinematic laser scanning with moving platforms has been used for the acquisition of 3D point clouds of our environment for many years. A main application of these mobile systems is the acquisition of the infrastructure, e.g., the road surface and buildings. Regarding this, the distance between laser scanner and object is often notably shorter than 20 m. In the close range, however, divergent incident laser light can lead to a deterioration of the precision of laser scanner distance measurements. In the light of this, we analyze the distance precision of the 2D laser scanner Z + F Profiler 9012A, purpose-built for kinematic applications, in the range of up to 20 m. In accordance with previous studies, a clear dependency between scan rate, intensity of the backscattered laser light and distance precision is evident, which is used to derive intensity-based stochastic models for the sensor. For this purpose, a new approach for 2D laser scanners is proposed that is based on the static scanning of surfaces with different backscatter. The approach is beneficial because the 2D laser scanner is operated in its normal measurement mode, no sophisticated equipment is required and no model assumptions for the scanned surface are made. The analysis reveals a lower precision in the range below 5 m caused by a decreased intensity. However, the Z + F Profiler 9012A is equipped with a special hardware-based close range optimization partially compensating for this. Our investigations show that this optimization works best at a distance of about 2 m. Although increased noise remains a critical factor in the close range, the derived stochastic models are also valid below 5 m. PMID- 30002352 TI - Acoustic Radiation Force Based Ultrasound Elasticity Imaging for Biomedical Applications. AB - Pathological changes in biological tissue are related to the changes in mechanical properties of biological tissue. Conventional medical screening tools such as ultrasound, magnetic resonance imaging or computed tomography have failed to produce the elastic properties of biological tissues directly. Ultrasound elasticity imaging (UEI) has been proposed as a promising imaging tool to map the elastic parameters of soft tissues for the clinical diagnosis of various diseases include prostate, liver, breast, and thyroid gland. Existing UEI-based approaches can be classified into three groups: internal physiologic excitation, external excitation, and acoustic radiation force (ARF) excitation methods. Among these methods, ARF has become one of the most popular techniques for the clinical diagnosis and treatment of disease. This paper provides comprehensive information on the recently developed ARF-based UEI techniques and instruments for biomedical applications. The mechanical properties of soft tissue, ARF and displacement estimation methods, working principle and implementation instruments for each ARF based UEI method are discussed. PMID- 30002354 TI - Estimation of Human Body Vital Signs Based on 60 GHz Doppler Radar Using a Bound Constrained Optimization Algorithm. AB - In this study, a bound-constrained optimization algorithm is applied for estimating physiological data (pulse and breathing rate) of human body using 60 GHz Doppler radar, by detecting displacements induced by breathing and the heartbeat of a human subject. The influence of mutual phasing between the two movements is analyzed in a theoretical framework and the application of optimization algorithms is proved to be able to accurately detect both breathing and heartbeat rates, despite intermodulation effects between them. Different optimization procedures are compared and shown to be more robust to receiver noise and artifacts of random body motion than a direct spectrum analysis. In case of a large-scale constrained bound, a parallel optimization procedure executed in subranges is proposed to realize accurate detection in a reduced span of time. PMID- 30002356 TI - Associations between Participation in a Ranger Program and Health and Wellbeing Outcomes among Aboriginal and Torres Strait Islander People in Central Australia: A Proof of Concept Study. AB - Culture can be viewed as an integral part of Aboriginal and Torres Strait Islander health and wellbeing. This study explores the association between caring for country, through participation in a Ranger program, and wellbeing. We analyzed cross-sectional data collected in Central Australia in 2017, comparing health and wellbeing (life satisfaction, general health, psychological wellbeing and family wellbeing) among Aboriginal and Torres Strait Islander peoples employed as Rangers (n = 43) versus not employed as Rangers (n = 160). We tested if any differences in outcomes were explained by differences in key demographic or health factors. Ranger participation was significantly associated with very high life satisfaction (PR = 1.69, 95% CI: 1.29, 2.20) and high family wellbeing (PR = 1.47, 95% CI: 1.13, 1.90); associations remained significant after individual adjustment for education, income, employment, health risk factors and health conditions. The magnitude and direction of associations were similar for very good general health, but results were not significant. We did not identify an association between Ranger participation and psychological wellbeing. While based on a small sample, these findings support the assertion that participation in the Ranger program is associated with positive health and wellbeing outcomes. This supports the continuation of cultural participation and practice through the Ranger program and has implications for funding, program and policy development. PMID- 30002355 TI - SunGold Kiwifruit Supplementation of Individuals with Prediabetes Alters Gut Microbiota and Improves Vitamin C Status, Anthropometric and Clinical Markers. AB - Kiwifruit are a nutrient dense food and an excellent source of vitamin C. Supplementation of the diet with kiwifruit enhances plasma vitamin C status and epidemiological studies have shown an association between vitamin C status and reduced insulin resistance and improved blood glucose control. In vitro experiments suggest that eating kiwifruit might induce changes to microbiota composition and function; however, human studies to confirm these findings are lacking. The aim of this study was to investigate the effect of consuming two SunGold kiwifruit per day over 12 weeks on vitamin C status, clinical and anthropometric measures and faecal microbiota composition in people with prediabetes. This pilot intervention trial compared baseline measurements with those following the intervention. Participants completed a physical activity questionnaire and a three-day estimated food diary at baseline and on completion of the trial. Venous blood samples were collected at each study visit (baseline, 6, 12 weeks) for determination of glycaemic indices, plasma vitamin C concentrations, hormones, lipid profiles and high-sensitivity C-reactive protein. Participants provided a faecal sample at each study visit. DNA was extracted from the faecal samples and a region of the 16S ribosomal RNA gene was amplified and sequenced to determine faecal microbiota composition. When week 12 measures were compared to baseline, results showed a significant increase in plasma vitamin C (14 umol/L, p < 0.001). There was a significant reduction in both diastolic (4 mmHg, p = 0.029) and systolic (6 mmHg, p = 0.003) blood pressure and a significant reduction in waist circumference (3.1 cm, p = 0.001) and waist-to-hip ratio (0.01, p = 0.032). Results also showed a decrease in HbA1c (1 mmol/mol, p = 0.005) and an increase in fasting glucose (0.1 mmol/L, p = 0.046), however, these changes were small and were not clinically significant. Analysis of faecal microbiota composition showed an increase in the relative abundance of as yet uncultivated and therefore uncharacterised members of the bacterial family Coriobacteriaceae. Novel bacteriological investigations of Coriobacteriaceae are required to explain their functional relationship to kiwifruit polysaccharides and polyphenols. PMID- 30002358 TI - Real-Time Early Warning System Design for Pluvial Flash Floods-A Review. AB - Pluvial flash floods in urban areas are becoming increasingly frequent due to climate change and human actions, negatively impacting the life, work, production and infrastructure of a population. Pluvial flooding occurs when intense rainfall overflows the limits of urban drainage and water accumulation causes hazardous flash floods. Although flash floods are hard to predict given their rapid formation, Early Warning Systems (EWS) are used to minimize casualties. We performed a systematic review to define the basic structure of an EWS for rain flash floods. The structure of the review is as follows: first, Section 2 describes the most important factors that affect the intensity of pluvial flash floods during rainfall events. Section 3 defines the key elements and actors involved in an effective EWS. Section 4 reviews different EWS architectures for pluvial flash floods implemented worldwide. It was identified that the reviewed projects did not follow guidelines to design early warning systems, neglecting important aspects that must be taken into account in their implementation. Therefore, this manuscript proposes a basic structure for an effective EWS for pluvial flash floods that guarantees the forecasting process and alerts dissemination during rainfall events. PMID- 30002357 TI - Hepatoprotective Principles and Other Chemical Constituents from the Mycelium of Phellinus linteus. AB - In the dimethylnitrosamine (DMN)-induced hepatic fibrosis Wistar rat model, the mycelium extract of Phellinus linteus (PLE) (20 mg/Kg) displayed significant protection against hepatic fibrosis. The present investigation characterized eleven new ionone derivatives, phellinulins D-N (4-14), from the P. linteus mycelium extract and the relative stereochemical structures were constructed according to the spectroscopic and spectrometric analytical results. Some purified compounds were examined for their inhibitory effects on activated rat hepatic stellate cells (HSCs) and several isolates did exhibit significant protection. The results indicated that the mycelium of P. linteus could be explored as a hepatoprotective drug or healthy food candidate in the near future. PMID- 30002360 TI - A Case of Herpes Simplex Virus Type 1 (HSV-1) Encephalitis as a Possible Complication of Cosmetic Nasal Dermal Filler Injection. AB - BACKGROUND Dermal fillers are increasingly used for medical and aesthetic purposes in clinical practice. Common complications following filler injections include bruising, itching, infections, allergic reactions, and tissue necrosis. This case is the first report of Herpes simplex virus type 1 (HSV-1) encephalitis as a possible complication of dermal filler injection. CASE REPORT A 27-year-old woman with no past medical history presented with altered mental state, headaches, and seizures. She had a nasal dermal filler injection for aesthetic purpose five weeks before her acute presentation. A diagnosis of HSV-1 encephalitis was made based on brain imaging with computed tomography and magnetic resonance imaging (MRI) findings that showed bilateral frontotemporal lobe hyperintensity. Analysis of her cerebrospinal fluid (CSF) confirmed the presence of HSV-1 DNA. Despite anti-viral treatment with acyclovir, she developed postencephalitic syndrome. CONCLUSIONS This case report highlights the possibility that among the complications of the use of cosmetic dermal fillers, the transmission of HSV-1 and the development of HSV-1 encephalitis should be recognized. PMID- 30002359 TI - Molecular Characterization of Divergent Closterovirus Isolates Infecting Ribes Species. AB - Five isolates of a new member of the family Closteroviridae, tentatively named blackcurrant leafroll-associated virus 1 (BcLRaV-1), were identified in the currant. The 17-kb-long genome codes for 10 putative proteins. The replication associated polyprotein has several functional domains, including papain-like proteases, methyltransferase, Zemlya, helicase, and RNA-dependent RNA polymerase. Additional open reading frames code for a small protein predicted to integrate into the host cell wall, a heat-shock protein 70 homolog, a heat-shock protein 90 homolog, two coat proteins, and three proteins of unknown functions. Phylogenetic analysis showed that BcLRaV-1 is related to members of the genus Closterovirus, whereas recombination analysis provided evidence of intraspecies recombination. PMID- 30002362 TI - Evaluation of Graft Effluent High Mobility Group Box-1 (HMGB-1) for Prediction of Outcome After Liver Transplantation. AB - BACKGROUND Pre-transplant assessment of the graft for liver transplantation is crucial. Based on experimental data, this study was designed to assess both nuclear high mobility group box-1 (HMGB-1) protein and arginine-specific proteolytic activity (ASPA) in the graft effluent. MATERIAL AND METHODS In a non interventional trial, both HMGB-1 and ASPA were measured in the effluent of 30 liver grafts after cold storage before transplantation. Values of HMGB-1 and ASPA levels were compared with established prognostic parameters such as the donor risk index, balance of risk score, and Donor-Model for End-Stage Liver Disease. RESULTS The early allograft dysfunction (EAD) was best predicted by recipient age (p=0.026) and HMGB-1 (p=0.031). HMGB -1 thresholds indicated the likelihood for initial non-function (1608 ng/ml, p=0.004) and EAD (580 ng/ml, p=0.017). The multivariate binary regression analysis showed a 21-fold higher (95% CI: 1.6 284.5, p=0.022) risk for EAD in cases with levels exceeding 580 ng/ml. The ASPA was lower in cases of initial non-function (p=0.028) but did not correlate with the rate of EAD (p=0.4). CONCLUSIONS This study demonstrates the feasibility of HMGB-1 detection in the graft effluent after cold storage. Along with conventional prognostic scores, it may be helpful to predict the early fate of a graft in human liver transplantation. PMID- 30002361 TI - Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine 5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas. AB - BACKGROUND Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas. MATERIAL AND METHODS We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs. RESULTS Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high methylation status persisted after adjusting for clinicopathological features. CONCLUSIONS Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma. PMID- 30002363 TI - Yellow fever in the diagnostics laboratory. AB - Yellow fever (YF) remains a public health issue in endemic areas despite the availability of a safe and effective vaccine. In 2015-2016, urban outbreaks of YF were declared in Angola and the Democratic Republic of Congo, and a sylvatic outbreak has been ongoing in Brazil since December 2016. Of great concern is the risk of urban transmission cycles taking hold in Brazil and the possible spread to countries with susceptible populations and competent vectors. Vaccination remains the cornerstone of an outbreak response, but a low vaccine stockpile has forced a sparing-dose strategy, which has thus far been implemented in affected African countries and now in Brazil. Accurate laboratory confirmation of cases is critical for efficient outbreak control. A dearth of validated commercial assays for YF, however, and the shortcomings of serological methods make it challenging to implement YF diagnostics outside of reference laboratories. We examine the advantages and drawbacks of existing assays to identify the barriers to timely and efficient laboratory diagnosis. We stress the need to develop new diagnostic tools to meet current challenges in the fight against YF. PMID- 30002364 TI - Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system. AB - While protein ubiquitination was long believed to be a truly eukaryotic feature, recently sequenced genomes revealed complete ubiquitin (Ub) modification operons in archaea. Here, we present the structural and mechanistic characterization of an archaeal Rpn11 deubiquitinase from Caldiarchaeum subterraneum, CsRpn11, and its role in the processing of CsUb precursor and ubiquitinated proteins. CsRpn11 activity is affected by the catalytic metal ion type, small molecule inhibitors, sequence characteristics at the cleavage site, and the folding state of CsUb conjugated proteins. Comparison of CsRpn11 and CsRpn11-CsUb crystal structures reveals a crucial conformational switch in the CsRpn11 Ins-1 site, which positions CsUb for catalysis. The presence of this transition in a primordial soluble Rpn11 thus predates the evolution of eukaryotic Rpn11 immobilized in the proteasomal lid. Complementing phylogenetic studies, which designate CsRpn11 and CsUb as close homologs of the respective eukaryotic proteins, our results provide experimental support for an archaeal origin of protein ubiquitination. PMID- 30002365 TI - Predicting marsh vulnerability to sea-level rise using Holocene relative sea level data. AB - Tidal marshes rank among Earth's vulnerable ecosystems, which will retreat if future rates of relative sea-level rise (RSLR) exceed marshes' ability to accrete vertically. Here, we assess the limits to marsh vulnerability by analyzing >780 Holocene reconstructions of tidal marsh evolution in Great Britain. These reconstructions include both transgressive (tidal marsh retreat) and regressive (tidal marsh expansion) contacts. The probability of a marsh retreat was conditional upon Holocene rates of RSLR, which varied between -7.7 and 15.2 mm/yr. Holocene records indicate that marshes are nine times more likely to retreat than expand when RSLR rates are >=7.1 mm/yr. Coupling estimated probabilities of marsh retreat with projections of future RSLR suggests a major risk of tidal marsh loss in the twenty-first century. All of Great Britain has a >80% probability of a marsh retreat under Representative Concentration Pathway (RCP) 8.5 by 2100, with areas of southern and eastern England achieving this probability by 2040. PMID- 30002367 TI - Attosecond coherent control of free-electron wave functions using semi-infinite light fields. AB - Light-electron interaction is the seminal ingredient in free-electron lasers and dynamical investigation of matter. Pushing the coherent control of electrons by light to the attosecond timescale and below would enable unprecedented applications in quantum circuits and exploration of electronic motions and nuclear phenomena. Here we demonstrate attosecond coherent manipulation of a free electron wave function, and show that it can be pushed down to the zeptosecond regime. We make a relativistic single-electron wavepacket interact in free-space with a semi-infinite light field generated by two light pulses reflected from a mirror and delayed by fractions of the optical cycle. The amplitude and phase of the resulting electron-state coherent oscillations are mapped in energy-momentum space via momentum-resolved ultrafast electron spectroscopy. The experimental results are in full agreement with our analytical theory, which predicts access to the zeptosecond timescale by adopting semi-infinite X-ray pulses. PMID- 30002366 TI - Network-based approach to prediction and population-based validation of in silico drug repurposing. AB - Here we identify hundreds of new drug-disease associations for over 900 FDA approved drugs by quantifying the network proximity of disease genes and drug targets in the human (protein-protein) interactome. We select four network predicted associations to test their causal relationship using large healthcare databases with over 220 million patients and state-of-the-art pharmacoepidemiologic analyses. Using propensity score matching, two of four network-based predictions are validated in patient-level data: carbamazepine is associated with an increased risk of coronary artery disease (CAD) [hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.12-2.18], and hydroxychloroquine is associated with a decreased risk of CAD (HR 0.76, 95% CI 0.59-0.97). In vitro experiments show that hydroxychloroquine attenuates pro-inflammatory cytokine mediated activation in human aortic endothelial cells, supporting mechanistically its potential beneficial effect in CAD. In summary, we demonstrate that a unique integration of protein-protein interaction network proximity and large-scale patient-level longitudinal data complemented by mechanistic in vitro studies can facilitate drug repurposing. PMID- 30002369 TI - A molecular neuromorphic network device consisting of single-walled carbon nanotubes complexed with polyoxometalate. AB - In contrast to AI hardware, neuromorphic hardware is based on neuroscience, wherein constructing both spiking neurons and their dense and complex networks is essential to obtain intelligent abilities. However, the integration density of present neuromorphic devices is much less than that of human brains. In this report, we present molecular neuromorphic devices, composed of a dynamic and extremely dense network of single-walled carbon nanotubes (SWNTs) complexed with polyoxometalate (POM). We show experimentally that the SWNT/POM network generates spontaneous spikes and noise. We propose electron-cascading models of the network consisting of heterogeneous molecular junctions that yields results in good agreement with the experimental results. Rudimentary learning ability of the network is illustrated by introducing reservoir computing, which utilises spiking dynamics and a certain degree of network complexity. These results indicate the possibility that complex functional networks can be constructed using molecular devices, and contribute to the development of neuromorphic devices. PMID- 30002368 TI - Two-dimensional semiconductors in the regime of strong light-matter coupling. AB - The optical properties of transition metal dichalcogenide monolayers are widely dominated by excitons, Coulomb-bound electron-hole pairs. These quasi-particles exhibit giant oscillator strength and give rise to narrow-band, well-pronounced optical transitions, which can be brought into resonance with electromagnetic fields in microcavities and plasmonic nanostructures. Due to the atomic thinness and robustness of the monolayers, their integration in van der Waals heterostructures provides unique opportunities for engineering strong light matter coupling. We review first results in this emerging field and outline future opportunities and challenges. PMID- 30002370 TI - The origin and adaptive evolution of domesticated populations of yeast from Far East Asia. AB - The yeast Saccharomyces cerevisiae has been an essential component of human civilization because of its long global history of use in food and beverage fermentation. However, the diversity and evolutionary history of the domesticated populations of the yeast remain elusive. We show here that China/Far East Asia is likely the center of origin of the domesticated populations of the species. The domesticated populations form two major groups associated with solid- and liquid state fermentation and appear to have originated from heterozygous ancestors, which were likely formed by outcrossing between diverse wild isolates primitively for adaptation to maltose-rich niches. We found consistent gene expansion and contraction in the whole domesticated population, as well as lineage-specific genome variations leading to adaptation to different environments. We show a nearly panoramic view of the diversity and life history of S. cerevisiae and provide new insights into the origin and evolution of the species. PMID- 30002371 TI - Lineage marker synchrony in hematopoietic genealogies refutes the PU.1/GATA1 toggle switch paradigm. AB - Molecular regulation of cell fate decisions underlies health and disease. To identify molecules that are active or regulated during a decision, and not before or after, the decision time point is crucial. However, cell fate markers are usually delayed and the time of decision therefore unknown. Fortunately, dividing cells induce temporal correlations in their progeny, which allow for retrospective inference of the decision time point. We present a computational method to infer decision time points from correlated marker signals in genealogies and apply it to differentiating hematopoietic stem cells. We find that myeloid lineage decisions happen generations before lineage marker onsets. Inferred decision time points are in agreement with data from colony assay experiments. The levels of the myeloid transcription factor PU.1 do not change during, but long after the predicted lineage decision event, indicating that the PU.1/GATA1 toggle switch paradigm cannot explain the initiation of early myeloid lineage choice. PMID- 30002373 TI - Vibrio spp. infections. PMID- 30002372 TI - Ratiometric nanothermometer in vivo based on triplet sensitized upconversion. AB - Temperature is an essential factor that counts for living systems where complicated vital activities are usually temperature dependent. In vivo temperature mapping based on non-contact optical approach will be beneficial for revealing the physiological phenomena behind with minimized influence to the organism. Herein, a highly thermal-sensitive upconversion system based on triplet triplet annihilation (TTA) mechanism is pioneered to indicate body temperature variation sensitively over the physiological temperature range. The temperature insensitive NaYF4: Nd nanophosphors with NIR emission was incorporated into the temperature-responsive TTA-upconversion system to serve as an internal calibration unit. Consequently, a ratiometric thermometer capable of accurately monitoring the temperature changes in vivo was developed with high thermal sensitivity (~7.1% K-1) and resolution (~0.1 K). PMID- 30002374 TI - Collapse and rescue of cooperation in evolving dynamic networks. AB - The evolutionary dynamics of social traits depend crucially on the social structure of a population. The effects of social structure on social behaviors are well-studied, but relatively little is known about how social structure itself coevolves with social traits. Here, I study such coevolution with a simple yet realistic model of within-group social structure where social connections are either inherited from a parent or made randomly. I show that cooperation evolves when individuals make few random connections, but the presence of cooperation selects for increased rates of random connections, which leads to its collapse. Inherent costs of social connections can prevent this negative feedback, but these costs can negate some or all of the aggregate benefits of cooperation. Exogenously maintained social inheritance can mitigate the latter problem and allow cooperation to increase the average fitness of a population. These results illustrate how coevolutionary dynamics can constrain the long-term persistence of cooperation. PMID- 30002375 TI - Domino-like multi-emissions across red and near infrared from solid-state 2-/2,6 aryl substituted BODIPY dyes. AB - Considerable achievements on multiple emission capabilities and tunable wavelengths have been obtained in inorganic luminescent materials. However, the development of organic counterparts remains a grand challenge. Herein we report a series of 2-/2,6-aryl substituted boron-dipyrromethene dyes with wide-range and multi-fluorescence emissions across red and near infrared in their aggregation states. Experimental data of X-ray diffraction, UV-vis absorption, and room temperature fluorescence spectra have proved the multiple excitation and easy adjustable emission features in aggregated boron-dipyrromethene dyes. Temperature dependent and time-resolved fluorescence studies have indicated a successive energy transfer from high to step-wisely lower-located energy levels that correspond to different excitation states of aggregates. Consistent quantum chemical calculation results have proposed possible aggregation modes of boron dipyrromethene dyes to further support the above-described scenario. Thus, this study greatly enriches the fundamental recognition of conventional boron dipyrromethene dyes by illustrating the relationships between multiple emission behaviors and the aggregation states of boron-dipyrromethene molecules. PMID- 30002376 TI - Anomalous mechanical behavior of nanocrystalline binary alloys under extreme conditions. AB - Fundamentally, material flow stress increases exponentially at deformation rates exceeding, typically, ~103 s-1, resulting in brittle failure. The origin of such behavior derives from the dislocation motion causing non-Arrhenius deformation at higher strain rates due to drag forces from phonon interactions. Here, we discover that this assumption is prevented from manifesting when microstructural length is stabilized at an extremely fine size (nanoscale regime). This divergent strain-rate-insensitive behavior is attributed to a unique microstructure that alters the average dislocation velocity, and distance traveled, preventing/delaying dislocation interaction with phonons until higher strain rates than observed in known systems; thus enabling constant flow-stress response even at extreme conditions. Previously, these extreme loading conditions were unattainable in nanocrystalline materials due to thermal and mechanical instability of their microstructures; thus, these anomalies have never been observed in any other material. Finally, the unique stability leads to high temperature strength maintained up to 80% of the melting point (~1356 K). PMID- 30002378 TI - Self-assembly of metal-organic polyhedra into supramolecular polymers with intrinsic microporosity. AB - Designed porosity in coordination materials often relies on highly ordered crystalline networks, which provide stability upon solvent removal. However, the requirement for crystallinity often impedes control of higher degrees of morphological versatility, or materials processing. Herein, we describe a supramolecular approach to the synthesis of amorphous polymer materials with controlled microporosity. The strategy entails the use of robust metal-organic polyhedra (MOPs) as porous monomers in the supramolecular polymerization reaction. Detailed analysis of the reaction mechanism of the MOPs with imidazole based linkers revealed the polymerization to consist of three separate stages: nucleation, elongation, and cross-linking. By controlling the self-assembly pathways, we successfully tuned the resulting macroscopic form of the polymers, from spherical colloidal particles to colloidal gels with hierarchical porosity. The resulting materials display distinct microporous properties arising from the internal cavity of the MOPs. This synthetic approach could lead to the fabrication of soft, flexible materials with permanent porosity. PMID- 30002379 TI - A comparison of hydrological and topological watersheds. AB - We introduce the hydrological watershed, a watershed where water can penetrate the soil, and compare it with the topological watershed for a two-dimensional landscape. For this purpose, we measure the fractal dimension of the hydrological watershed for different penetration depths and different grid sizes. Through finite size scaling, we find that the fractal dimension is 1.31 +/- 0.02 which is significantly higher than the fractal dimension of the topological watershed. This indicates that the hydrological watershed belongs to a new universality class. We also find that, as opposed to the topological watershed, the hydrodynamic watershed can exhibit disconnected islands. PMID- 30002377 TI - Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR. AB - 53BP1 performs essential functions in DNA double-strand break (DSB) repair and it was recently reported that Tudor interacting repair regulator (TIRR) negatively regulates 53BP1 during DSB repair. Here, we present the crystal structure of the 53BP1 tandem Tudor domain (TTD) in complex with TIRR. Our results show that three loops from TIRR interact with 53BP1 TTD and mask the methylated lysine-binding pocket in TTD. Thus, TIRR competes with histone H4K20 methylation for 53BP1 binding. We map key interaction residues in 53BP1 TTD and TIRR, whose mutation abolishes complex formation. Moreover, TIRR suppresses the relocation of 53BP1 to DNA lesions and 53BP1-dependent DNA damage repair. Finally, despite the high sequence homology between TIRR and NUDT16, NUDT16 does not directly interact with 53BP1 due to the absence of key residues required for binding. Taken together, our study provides insights into the molecular mechanism underlying TIRR-mediated suppression of 53BP1-dependent DNA damage repair. PMID- 30002380 TI - Effect of Transportation on Cultured Limbal Epithelial Sheets for Worldwide Treatment of Limbal Stem Cell Deficiency. AB - Limbal stem cell deficiency can be treated with transplantation of cultured human limbal epithelial cells (LEC). It can be advantageous to produce LEC in centralized labs and thereafter ship them to eye clinics. The present study used transport simulations of LEC to determine if vigorous shaking during transport altered the viability, morphology and phenotype during a 4 day-long storage of LEC with a previously described serum-free storage method. Inserts with LEC cultured on amniotic membranes were sutured to caps inside air-tight containers with generous amounts of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)-buffered minimal essential medium (MEM). The containers were distributed among the following testing conditions: 6 hours with full containers, 36 hours with full containers, 36 hours with container three quarters full of medium, and 36 hours with container full of medium containing a shear-protecting agent (Pluronic-F68). Compared to stored, but non-transported controls, no statistically significant changes in viability and immunohistochemical staining were observed. The epithelial sheets remained intact. However, an air-liquid interface in the containers reduced the number of desmosomes and hemi-desmosomes compared to the controls. In conclusion, cultured LEC sheets appear to endure vigorous shaking for at least 36 hours if the container is full. PMID- 30002381 TI - Evolutionary significance of antiparasite, antipredator and learning phenotypes of avian nest defence. AB - Avian nest defence, which is expected to serve both antiparasite and antipredator functions, may benefit or be detrimental to birds, although selective forces that potentially operate on nest defence have not been quantified as a whole. Together with fitness values, we analysed two traits of nest defence, intensity and plasticity, in two distantly related passerine species, yellow warbler (Setophaga petechia) in North America and reed warbler (Acrocephalus scirpaceus) in Europe, both favourite host species for brood parasites. Breeders that escaped parasitism were the most vocal among reed warblers, whereas there was no specific defence phenotype that predicted prevention of parasitism in yellow warblers. Breeders that escaped nest predation were, in both species, those with the most distractive response at the first exposure to a nest-threatening event, such as the experimental predation or parasitism simulated at the nest. However, increasing defence intensity benefited yellow warblers but was detrimental to reed warblers, because intense defence responses attracted predators. Adaptiveness of nest defence was revealed by nest defence phenotypes when examined in concert with the seasonal fitness (i.e. measures of reproductive success). Results revealed selective forces favoured yellow warblers with strong defence phenotypes. Opposite forces were instead revealed among reed warblers whose favoured phenotypes were strong, yet less flexible, defenders. PMID- 30002383 TI - Structural basis for cross-reactivity and conformation fluctuation of the major beech pollen allergen Fag s 1. AB - Fag s 1 is a member of the Pathogen Related protein family 10 (PR-10) and can elicit cross-reaction with IgE antibodies produced against the birch pollen allergen Bet v 1. The Nuclear Magnetic Resonance (NMR) structure of Fag s 1 is presented along with its dynamic properties. It shares 66% identity with Bet v 1 and exhibits the expected three alpha-helices and seven beta-sheets arranged as a semi-beta barrel and exposing the residues mapped as the Bet v 1 IgE epitope. The structural dynamics of Fag s 1 were monitored on the fast and intermediate timescales, using relaxation rates. The complex dynamics of Fag s 1 are closely related to the internal cavity, and they modulate IgE and ligand binding. PMID- 30002382 TI - Characterization of a ripening-related transcription factor FcNAC1 from Fragaria chiloensis fruit. AB - Fragaria chiloensis is a strawberry endemic from Chile with attractive white-pink fruit, pleasant aroma and taste. However, this fruit has a limited post-harvest period due to fast softening. Several transcription factors (TFs) are involved in the regulation of fruit ripening, and members of the NAC family have been implicated in cell wall remodeling. FcNAC1 was isolated from F. chiloensis fruit, coding a protein of 332 amino acid residues and displaying a characteristic NAC domain at the N terminus. FcNAC1 protein showed nuclear localization. An increase in transcript level was observed during ripening. A sequence of 1488 bp of FcNAC1 promoter was obtained. In silico analysis identified cis elements able to respond to some hormones and Secondary wall NAC binding elements (SNBE), and responding to auxin and ABA. A structural model of FcNAC1 provided evidence for interaction with DNA sequences containing SNBE, while a dual luciferase assay confirmed the transcriptional activation by FcNAC1 of the promoter of FcPL, a gene involved in cell wall remodeling in F. chiloensis fruit. The results suggest the participation of FcNAC1 during ripening development of strawberry fruit, by regulating pectin metabolism during softening. PMID- 30002384 TI - Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines. AB - Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter individual variability in rivaroxaban plasma concentrations. PMID- 30002385 TI - Wnt4 is significantly upregulated during the early phases of cisplatin-induced acute kidney injury. AB - Wnt4 is a secreted growth factor associated with renal tubulogenesis. Our previous studies identified that renal and urinary Wnt4 are upregulated following ischemia-reperfusion injury in mice, but the roles of Wnt4 in other forms of acute kidney injury (AKI) remain unclear. Here, we investigated the changes in Wnt4 expression using a cisplatin-induced AKI model. We found that renal and urinary Wnt4 expression increased as early as 12 hours, peaked at day 4 following cisplatin-induced AKI and was closely correlated with histopathological alterations. By contrast, the serum creatinine level was significantly elevated until day 3, indicating that Wnt4 is more sensitive to early tubular injury than serum creatinine. In addition, renal Wnt4 was co-stained with aquaporin-1 and thiazide-sensitive NaCl cotransporter, suggesting that Wnt4 can detect both proximal and distal tubular injuries. These data were further confirmed in a clinical study. Increased urinary Wnt4 expression was detected earlier than serum creatinine and eGFR in patients with contrast-induced AKI after vascular intervention. This study is the first to demonstrate that increased expression of renal and urinary Wnt4 can be detected earlier than serum creatinine after drug induced AKI. In particular, urinary Wnt4 can potentially serve as a noninvasive biomarker for monitoring patients with tubular injury. PMID- 30002386 TI - Microemulsion formulation of a new biopesticide to control the diamondback moth (Lepidoptera: Plutellidae). AB - This study was designed to develop a microemulsion formulation of norcantharidin for the control of the diamondback moth (DBM), Plutella xylostella (Linnaeus), a notorious pest of brassica crops worldwide. The oil phase was screened and selected based on norcantharidin solubility while the surfactants were selected on the basis of their efficiency to form microemulsion. Optimized batches were selected using pseudo ternary phase diagrams. The microemulsion system were stabilized using mixtures composed of norcantharidin, surfactants (Tx13 and Tw80), and cosurfactant (ethanol). Its physicochemical characteristics were also demonstrated to have a higher cloud point than 72 degrees C as well as good thermodynamic and dilution stability. In additon, a subsequent insecticidal bioassay indicated that the acute LC50 for norcantharidin microemulsion to P. xylostella was estimated to be 12.477 mg/L (11.58-13.41, 95% CL). Our results provide an environment-friendly promising alternative to control P. xylostella and possibly contribute to ameliorating any pesticide resistance in P. xylostella. PMID- 30002387 TI - Monocarboxylate transporter-1 promotes osteoblast differentiation via suppression of p53, a negative regulator of osteoblast differentiation. AB - Monocarboxylate transporter-1 (MCT-1) is a transmembrane transporter for monocarboxylates including lactate and pyruvate. Silencing Mct1 by its small interfering RNA (siRNA) suppressed the expression of marker genes for osteoblast differentiation, namely, Tnap, Runx2, and Sp7, induced by BMP-2 in mouse myoblastic C2C12 cells. Mct1 siRNA also suppressed alkaline phosphatase activity, as well as expressions of Tnap and Bglap mRNAs in mouse primary osteoblasts. On the other hand, Mct1 siRNA did not have effects on the Smad1/5 or ERK/JNK pathways in BMP-2-stimulated C2C12 cells, while it up-regulated the mRNA expression of p53 (Trp53) as well as nuclear accumulation of p53 in C2C12 cells in a BMP-2-independent manner. Suppression of osteoblastic differentiation by Mct1 siRNA in C2C12 cells was abolished by co-transfection of Trp53 siRNA. Together, these results suggest that MCT-1 functions as a positive regulator of osteoblast differentiation via suppression of p53. PMID- 30002388 TI - Tunable double-Weyl Fermion semimetal state in the SrSi2 materials class. AB - We discuss first-principles topological electronic structure of noncentrosymmetric SrSi2 materials class based on the hybrid exchange-correlation functional. Topological phase diagram of SrSi2 is mapped out as a function of the lattice constant with focus on the semimetal order. A tunable double-Weyl Fermion state in Sr1-xCaxSi2 and Sr1-xBaxSi2 alloys is identified. Ca doping in SrSi2 is shown to yield a double-Weyl semimetal with a large Fermi arc length, while Ba doping leads to a transition from the topological semimetal to a gapped insulator state. Our study indicates that SrSi2 materials family could provide an interesting platform for accessing the unique topological properties of Weyl semimetals. PMID- 30002389 TI - Novel Interplay Between Smad1 and Smad3 Phosphorylation via AGE Regulates the Progression of Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. We previously found that Smad1 plays a critical role in the development of DN both in vitro and in vivo. However, functional interaction between Smad1 and Smad3 signaling in DN is unclear. Here, we addressed the molecular interplay between Smad1 and Smad3 signaling under a diabetic condition by using Smad3-knockout diabetic mice. Extracellular matrix (ECM) protein overexpression and Smad1 activation were observed in the glomeruli of db/db mice but were suppressed in the glomeruli of Smad3+/-; db/db mice. Smad3 activation enhanced the phosphorylation of Smad1 C-terminal domain but decreased the phosphorylation of linker domain, thus regulating Smad1 activation in advanced glycation end product-treated mesangial cells (MCs). However, forced phosphorylation of the Smad1 linker domain did not affect Smad3 activation in MCs. Phosphorylation of the Smad1 linker domain increased in Smad3+/-; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression. PMID- 30002390 TI - Resting-state fMRI study on drug-naive patients of essential tremor with and without head tremor. AB - This study used resting-state functional MRI (r-fMRI) to evaluate intrinsic brain activity in drug-naive patients with essential tremor (ET) with and without head tremor. We enrolled 20 patients with ET with hand and head tremor (h-ET), 27 patients with ET without head tremor (a-ET), and 27 healthy controls (HCs). All participants underwent r-fMRI scans on a 3-T MR system. The amplitude of low frequency fluctuation (ALFF) of blood oxygen level-dependent signals was used to characterize regional cerebral function. We identified increased ALFF value in the bilateral posterior lobe of cerebellum in the h-ET patients relative to a-ET and HCs and demonstrated that h-ET is related to abnormalities in the cerebello cortical areas, while the a-ET is related to abnormalities in the thalamo cortical areas. In addition, we observed the ALFF abnormality in the cerebellum (left cerebellum VIII and right cerebellum VI) correlated with the tremor score in h-ET patients and abnormal ALFF in the left precentral gyrus correlated with the age at onset and disease duration in h-ET patients. These findings may be helpful for facilitating further understanding of the potential mechanisms underlying different subtypes of ET. PMID- 30002391 TI - Effects of gadolinium on cardiac mechanosensitivity in whole isolated swine hearts. AB - Mechanical stimulation can elicit electrical activation of the heart. This mechanosensitivity can start life-threatening arrhythmias (commotio cordis) or terminate them (precordial thump). Mechanosensitivity may also be involved in arrhythmogenesis in other settings. Stretch-activated ion channels (SACs) are thought to be important in mechanosensitivity and a number of agents that block them have been identified. Such agents could potentially be used as tools in experimental investigation of mechanosensitivity. However, studies using them in intact-heart preparations have yielded inconsistent results. In the present study, we used isolated, perfused hearts from 25-35 kg pigs and a computer controlled device that repeatably delivered focal mechanical stimuli. The concentration-dependent ability of the SAC blocker gadolinium to suppress mechanical activation was assessed by the success rate of mechanical stimulation and by the delay between successful mechanical stimulation and electrical activation. In six hearts, perfusate was recirculated. In an additional six hearts, perfusate was not recirculated to prevent gadolinium from forming complexes with metabolic waste and possibly precipitating. Gadolinium did not suppress mechanically-induced activation. Although gadolinium has been shown to be an effective SAC blocker in isolated cells, using it to probe the role of mechanical stimulation in whole heart preparations should be done with great caution. PMID- 30002393 TI - Comparison of Image-Guided Intensity-Modulated Radiotherapy and Low-dose Rate Brachytherapy with or without External Beam Radiotherapy in Patients with Localized Prostate Cancer. AB - To compare the outcome of low-dose rate brachytherapy (LDR-BT) and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer, we examined 488 LDR-BT and 269 IG-IMRT patients. IG-IMRT treated older and advanced disease with more hormonal therapy than LDR-BT, which excluded T3b-T4 tumor and initial PSA > 50 ng/ml. The actuarial five-year biochemical failure-free survival rate was 88.7% and 96.7% (p = 0.0003) in IG-IMRT and LDR-BT, respectively; it was 88.2% (85.1% for IG-IMRT and 94.9% for LDR-BT, p = 0.0578) for the high-risk group, 95.2% (91.6% and 97.0%, p = 0.3361) for the intermediate IG-IMRT and 96.8% (95.7% and 97%, p = 0.8625) for the low-risk group. Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. IPTW showed a statistically significant difference between LDR-BT and IG-IMRT in high risk (p = 0.0009) and high risk excluding T3 4/initial PSA > 50 ng/ml group (p = 0.0073). IG-IMRT showed more gastrointestinal toxicity (p = 0.0023) and less genitourinary toxicity (p < 0.0001) than LDR-BT. LDR-BT and IG-IMRT showed equivocal outcome in low- and intermediate-risk groups. For selected high-risk patients, LDR-BT showed more potential to improve PSA control rate than IG-IMRT. PMID- 30002394 TI - Wavelength-shifting properties of luminescence nanoparticles for high energy particle detection and specific physics process observation. AB - Ultraviolet (UV) photon detection is becoming increasingly important in the quest to understand the fundamental building blocks of our universe. Basic properties of neutrinos and Dark Matter are currently being explored through interactions with noble elements. In response to interactions with fundamental particles, these elements emit scintillation photons in the UV range. However, most available detectors have poor response in the UV so it is typically necessary to shift UV to a wavelength, matching the sensitivity of the viable detectors. We report on development of UV-enhanced photosensors using wavelength-shifting properties of nanoparticles. Several nanoparticle coatings were tested for absorption of UV light with subsequent emission in the visible wavelength for high energy particle detection. ZnS:Mn,Eu, ZnS:Mn, CuCy (Copper Cysteamine) and CdTe nanoparticles all exhibited enhanced detection for wavelengths in the range 200-320 nm in several different tests, while ZnS:Ag and CdS nanoparticle showed little or no enhancement in that range. In addition, various LaF3:Ce nanoparticle concentrations in approximately constant thickness of 2,5-diphenyloxazole (PPO)/polystyrene bases were also tested to optimize the nanoparticle concentration for the best outcome. Our studies indicated that ZnS:Mn,Eu, ZnS:Mn, Cu-Cy, CdTe and LaF3:Ce nanoparticles show potential for light detection from fundamental particle interactions. PMID- 30002392 TI - The tomato subtilase family includes several cell death-related proteinases with caspase specificity. AB - Phytaspases are Asp-specific subtilisin-like plant proteases that have been likened to animal caspases with respect to their regulatory function in programmed cell death (PCD). We identified twelve putative phytaspase genes in tomato that differed widely in expression level and tissue-specific expression patterns. Most phytaspase genes are tandemly arranged on tomato chromosomes one, four, and eight, and many belong to taxon-specific clades, e.g. the P69 clade in the nightshade family, suggesting that these genes evolved by gene duplication after speciation. Five tomato phytaspases (SlPhyts) were expressed in N. benthamiana and purified to homogeneity. Substrate specificity was analyzed in a proteomics assay and with a panel of fluorogenic peptide substrates. Similar to animal caspases, SlPhyts recognized an extended sequence motif including Asp at the cleavage site. Clear differences in cleavage site preference were observed implying different substrates in vivo and, consequently, different physiological functions. A caspase-like function in PCD was confirmed for five of the seven tested phytaspases. Cell death was triggered by ectopic expression of SlPhyts 2, 3, 4, 5, 6 in tomato leaves by agro-infiltration, as well as in stably transformed transgenic tomato plants. SlPhyts 3, 4, and 5 were found to contribute to cell death under oxidative stress conditions. PMID- 30002395 TI - Effect of unloading brace treatment on pain and function in patients with symptomatic knee osteoarthritis: the ROTOR randomized clinical trial. AB - Evidence is still inconclusive for the benefits of bracing in patients with knee osteoarthritis. To assess the effect of REBEL RELIEVER unloading knee brace in conservative treatment of knee osteoarthritis, a randomized controlled trial was conducted in 67 patients with symptomatic medial knee osteoarthritis, who randomly received 6-week treatment with either REBEL RELIVER unloading knee brace + usual care (Brace group, N = 32) or usual care alone (Control group, N = 35). Primary outcome was the global last 24h-pain relief (100-mm visual analogic scale [VAS]) at 6 weeks. Secondary endpoints included pain on motion (100-mm VAS), function (Lequesne index), safety and observance. At 6 weeks, mean [SD] last 24h pain decreased significantly more in Brace group versus Control group (-41.35 [3.37] vs -15.37 [3.23], difference -25.98, 95% CI -41.64 to -10.33, P < 0.0001). Higher mean [SD] pain on motion decrease (-51.91 [3.49] vs -19.91 [3.34], difference -32.01, 95% CI -48.21 to -15.80, P < 0.0001) and better improvement of Lequesne index score (-5.8 [0.5] vs -2.3 [0.5], difference -3.5, 95% CI -5.0 to 2.0, P < 0.0001) were observed in Brace group. Safety and observance to the brace were excellent. The additive clinical benefit of wearing REBEL RELIEVER unloading knee brace was demonstrated in knee osteoarthritis patients. PMID- 30002396 TI - First data of Neandertal bird and carnivore exploitation in the Cantabrian Region (Axlor; Barandiaran excavations; Dima, Biscay, Northern Iberian Peninsula). AB - Neandertals were top predators who basically relied on middle- to large-sized ungulates for dietary purposes, but there is growing evidence that supports their consumption of plants, leporids, tortoises, marine resources, carnivores and birds. The Iberian Peninsula has provided the most abundant record of bird exploitation for meat in Europe, starting in the Middle Pleistocene. However, the bird and carnivore exploitation record was hitherto limited to the Mediterranean area of the Iberian Peninsula. Here we present the first evidence of bird and carnivore exploitation by Neandertals in the Cantabrian region. We have found cut marks in two golden eagles, one raven, one wolf and one lynx remain from the Mousterian levels of Axlor. The obtaining of meat was likely the primary purpose of the cut-marks on the golden eagle and lynx remains. Corvids, raptors, felids and canids in Axlor could have likely acted as commensals of the Neandertals, scavenging upon the carcasses left behind by these hunter-gatherers. This could have brought them closer to Neandertal groups who could have preyed upon them. These new results provide additional information on their dietary scope and indicate a more complex interaction between Neandertals and their environment. PMID- 30002397 TI - DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. AB - Recent studies have investigated the epigenetic effects of environmental exposure to chemicals on human health. The associations of DNA methylation, environmental exposure and human diseases have been widely demonstrated. However, the use of gene methylation patterns as a predictive biomarker for exposure to environmental toxicants is relatively poorly understood. Here, we focused on low-molecular weight saturated aliphatic aldehydes (LSAAs), which are important environmental risk factors in humans as major indoor air pollutants. Based on DNA methylation profiling in gene promoter regions, we analysed DNA methylation profiles following exposure of A549 cells to seven LSAAs (propanal, butanal, pentanal, hexanal, heptanal, octanal, and nonanal) to identify LSAA-characterized methylated sites and target genes, as well as to investigate whether exposure to LSAAs contributes to inducing of pulmonary toxicity. Additionally, by integrating DNA methylation and mRNA expression profile analyses, we identified core anti correlated target genes. Gene ontology analysis of these target genes revealed several key biological processes. These findings suggest that alterations in DNA methylation by exposure to LSAAs provide novel epigenetic biomarkers for risk assessments. This DNA methylation-mRNA approach also reveals potential new mechanistic insights into the epigenetic actions of pulmonary toxicity. PMID- 30002398 TI - Antitumor and immunomodulatory activities of total flavonoids extract from persimmon leaves in H22 liver tumor-bearing mice. AB - Persimmon (Diospyros kaki L.) leaves are commonly used in Asia as tea infusion and as an agent in traditional medicine. The present study aims to explore the antitumor and immunomodulatory effects of total flavonoids extract from persimmon leaves (PLF) in H22 liver tumor-bearing mice. We found that the PLF showed significant inhibition on the liver tumor growth in mice with a tumor inhibition rate of up to 49.35%. In contrast to the severe side effects of cyclophosphamide (CTX), the PLF exhibited anti-cachexia effect and showed no alternation in the body weight and food intake in mice. Moreover, compared with the vehicle control and CTX group, the PLF significantly enhanced the thymus and spleen indices, level of serum interleukin-18 (IL-18), monocyte/macrophage phagocytosis, level of serum hemolysin, and activity of natural killer (NK) cells. This study demonstrated that the PLF could effectively inhibit liver tumor growth in vivo via enhancement of the immune function in mice, and it displayed the potential to be a safe and effective anticancer agent or functional immune-enhancing agent. PMID- 30002399 TI - Imaging through scattering medium by adaptive non-linear digital processing. AB - Scattering media have always posed obstacles for imaging through them. In this study, we propose a single exposure, spatially incoherent and interferenceless method capable of imaging multi-plane objects through scattering media using only a single lens and a digital camera. A point object and a resolution chart are precisely placed at the same axial location, and light scattered from them is focused onto an image sensor using a spherical lens. For both cases, intensity patterns are recorded under identical conditions using only a single camera shot. The final image is obtained by an adaptive non-linear cross-correlation between the response functions of the point object and of the resolution chart. The clear and sharp reconstructed image demonstrates the validity of the method. PMID- 30002400 TI - Distinct Aqueous Humour Cytokine Profiles of Patients with Pachychoroid Neovasculopathy and Neovascular Age-related Macular Degeneration. AB - This study investigated the pathophysiological features of pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD) by analysing and comparing cytokine profiles in aqueous humour (AH) collected from 18 PNV, 18 nAMD and 11 control patients. Responses to intravitreal injection of aflibercept were also analysed in the PNV and nAMD groups. In the PNV group, vascular endothelial growth factor (VEGF)-A was significantly lower than in the nAMD group (p = 0.03) but was almost identical to that in the control group (p = 0.86). The nAMD group showed positive correlations between interleukin (IL)-6 and IL-8 (r = 0.78, p < 0.001), IL-6 and monocyte chemoattractant protein (MCP)-1 (r = 0.68, p = 0.002) and IL-8 and MCP-1 (r = 0.68, p = 0.002). In the nAMD group, eyes with dry maculae one month after the first aflibercept injection showed significantly lower VEGF-A and placental growth factor (PlGF) at baseline than those with wet maculae (p = 0.02 for both). However, there was no significant difference between dry and wet maculae in the PNV group. The results suggest that angiogenic factors and proinflammatory cytokines may play the distinct roles in the pathogenesis of PNV and nAMD. PMID- 30002401 TI - Preliminary study of Cell Wall Structure and its Mechanical Properties of C3H and HCT RNAi Transgenic Poplar Sapling. AB - This research focused on the cell wall structure and its mechanical properties of down-regulated Coumaroyl shikimate 3-hydroxylase (C3H) transgenic poplar and down regulated hydroxycinnamoyl CoA: shikimate hydroxycinnamoyl transferase (HCT) transgenic poplar (Populus alba * P. glandulosa cv '84 k'). The wood samples with respect to microstructure, the longitudinal elastic modulus (MOE) and hardness of wood fiber secondary cell wall were investigated. The results show that the lignin contents in the two transgenic poplar woods were lower than non-modified wood. The C3H transgenic poplar and HCT transgenic poplar have more than 18.5% and 16.1% cellulose crystalline regions than non-modified poplar respectively. The diameter of the fiber cell and the vessel element of transgenic poplars are smaller. Double radial vessel cell wall thicknesses of both transgenic poplars were smaller than non-modified poplar. Cell wall ratios for the transgenic poplar were higher than non-modified poplar and cell wall density was significantly lower in both C3H and HCT transgenic poplar. The cell wall MOEs of C3H and HCT transgenic poplar was 5.8% and 7.0% higher than non-modified poplar. HCT can be more effective than C3H to modify the trees by considerably increasing mechanical properties of the cell wall. PMID- 30002403 TI - Systematic RNA-interference in primary human monocyte-derived macrophages: A high throughput platform to study foam cell formation. AB - Macrophage-derived foam cells are key regulators of atherogenesis. They accumulate in atherosclerotic plaques and support inflammatory processes by producing cytokines and chemokines. Identifying factors that regulate macrophage lipid uptake may reveal therapeutic targets for coronary artery disease (CAD). Here, we establish a high-throughput screening workflow to systematically identify genes that impact the uptake of DiI-labeled low-density lipoprotein (LDL) into monocyte-derived primary human macrophages. For this, monocytes isolated from peripheral blood were seeded onto 384-well plates, solid-phase transfected with siRNAs, differentiated in vitro into macrophages, and LDL-uptake per cell was measured by automated microscopy and quantitative image analysis. We applied this workflow to study how silencing of 89 genes impacts LDL-uptake into cells from 16 patients with CAD and 16 age-matched controls. Silencing of four novel genes (APOC1, CMTM6, FABP4, WBP5) reduced macrophage LDL-uptake. Additionally, knockdown of the chemokine receptor CXCR4 reduced LDL-uptake, most likely through a G-protein coupled mechanism that involves the CXCR4 ligand macrophage-induced factor (MIF), but is independent of CXCL12. We introduce a high-throughput strategy to systematically study gene function directly in primary CAD-patient cells. Our results propose a function for the MIF/CXCR4 signaling pathway, as well as several novel candidate genes impacting lipid uptake into human macrophages. PMID- 30002402 TI - IDPpi: Protein-Protein Interaction Analyses of Human Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) are characterized by the lack of a fixed tertiary structure and are involved in the regulation of key biological processes via binding to multiple protein partners. IDPs are malleable, adapting to structurally different partners, and this flexibility stems from features encoded in the primary structure. The assumption that universal sequence information will facilitate coverage of the sparse zones of the human interactome motivated us to explore the possibility of predicting protein-protein interactions (PPIs) that involve IDPs based on sequence characteristics. We developed a method that relies on features of the interacting and non-interacting protein pairs and utilizes machine learning to classify and predict IDP PPIs. Consideration of both sequence determinants specific for conformational organizations and the multiplicity of IDP interactions in the training phase ensured a reliable approach that is superior to current state-of-the-art methods. By applying a strict evaluation procedure, we confirm that our method predicts interactions of the IDP of interest even on the proteome-scale. This service is provided as a web tool to expedite the discovery of new interactions and IDP functions with enhanced efficiency. PMID- 30002404 TI - Reference values for white blood-cell-based inflammatory markers in the Rotterdam Study: a population-based prospective cohort study. AB - Novel prognostic inflammatory markers of cancer survival and cardiovascular disease are; the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic immune-inflammation index (SII). As normal values for these markers are unknown, our objective was to obtain reference values in the general population. We obtained data from a population-based prospective cohort study of individuals aged 45 years and over between 2002 and 2014. Absolute blood counts were used to calculate the NLR, PLR and SII. All inflammatory indices followed a log-normal distribution. We calculated the mean and 95% reference intervals in an unselected population. Furthermore we studied whether the inflammatory markers differed between age categories and gender. In total 8,711 participants (57.1% female; mean age 65.9 years, standard deviation 10.5 years) were included. Mean values and corresponding 95% reference intervals for the NLR were: 1.76 (0.83-3.92), for PLR: 120 (61-239) and for SII: 459 (189 1168). The inflammatory markers increased with age. The PLR and SII were higher in females, whilst the NLR was higher in males. In conclusion, we provided reference values for new inflammatory markers. All increase with age and vary with gender. This provides context that allows for proper interpretation of their potential value in future clinical practice and research. PMID- 30002405 TI - Sexual ancestors generated an obligate asexual and globally dispersed clone within the model diatom species Thalassiosira pseudonana. AB - Sexual reproduction roots the eukaryotic tree of life, although its loss occurs across diverse taxa. Asexual reproduction and clonal lineages persist in these taxa despite theoretical arguments suggesting that individual clones should be evolutionarily short-lived due to limited phenotypic diversity. Here, we present quantitative evidence that an obligate asexual lineage emerged from a sexual population of the marine diatom Thalassiosira pseudonana and rapidly expanded throughout the world's oceans. Whole genome comparisons identified two lineages with characteristics expected of sexually reproducing strains in Hardy-Weinberg equilibrium. A third lineage displays genomic signatures for the functional loss of sexual reproduction followed by a recent global colonization by a single ancestral genotype. Extant members of this lineage are genetically differentiated and phenotypically plastic, potentially allowing for rapid adaptation when they are challenged by natural selection. Such mechanisms may be expected to generate new clones within marginal populations of additional unicellular species, facilitating the exploration and colonization of novel environments, aided by exponential growth and ease of dispersal. PMID- 30002406 TI - Motor neuron development in zebrafish is altered by brief (5-hr) exposures to THC (?9-tetrahydrocannabinol) or CBD (cannabidiol) during gastrulation. AB - Marijuana is one of the most commonly used illicit recreational drugs and is widely used for medicinal purposes. The psychoactive ingredient in marijuana is ?9-tetrahydrocannabinol (?9-THC), whereas the major non-psychoactive ingredient is cannabidiol (CBD). Here, we exposed zebrafish embryos to ?9-THC or CBD for 5 hours during the critical stage of development known as gastrulation. Embryos were allowed to develop normally and were examined at 2 and 5 days post fertilization. THC and CBD treated embryos exhibited reduced heart rates, axial malformations and shorter trunks. Cannabinoid treatment altered synaptic activity at neuromuscular junctions (NMJs), and fluorescent labelling of primary and secondary motor neurons indicated a change in branching patterns and a reduction in the number of axonal branches in the trunk musculature. Furthermore, there were alterations in the alpha-bungarotoxin labelling of nicotinic acetylcholine receptors at NMJs. Locomotion studies show that larvae exposed to THC or CBD during gastrulation exhibited drastic reductions in the number of C-start escape responses to sound stimuli, but not to touch stimuli. Together these findings indicate that zebrafish embryos exposed to ?9-THC or CBD during the brief but critical period of gastrulation exhibited alterations in heart rate, motor neuronal morphology, synaptic activity at the NMJ and locomotor responses to sound. PMID- 30002408 TI - Locally Gated SnS2/hBN Thin Film Transistors with a Broadband Photoresponse. AB - Next-generation flexible and transparent electronics demand newer materials with superior characteristics. Tin dichalcogenides, Sn(S,Se)2, are layered crystal materials that show promise for implementation in flexible electronics and optoelectronics. They have band gap energies that are dependent on their atomic layer number and selenium content. A variety of studies has focused in particular on tin disulfide (SnS2) channel transistors with conventional silicon substrates. However, the effort of interchanging the gate dielectric by utilizing high quality hexagonal boron nitride (hBN) still remains. In this work, the hBN coupled SnS2 thin film transistors are demonstrated with bottom-gated device configuration. The electrical transport characteristics of the SnS2 channel transistor present a high current on/off ratio, reaching as high as 105 and a ten fold enhancement in subthreshold swing compared to a high-kappa dielectric covered device. We also demonstrate the spectral photoresponsivity from ultraviolet to infrared in a multi-layered SnS2 phototransistor. The device architecture is suitable to promote diverse studied on flexible and transparent thin film transistors for further applications. PMID- 30002407 TI - Facile one-step synthesis of TiO2/Ag/SnO2 ternary heterostructures with enhanced visible light photocatalytic activity. AB - Novel TiO2/Ag/SnO2 composites were successfully prepared by a facile one-step reduction approach using stannous chloride as both SnO2 precursor and reducing agent. The Ag nanoparticles with sizes of 2.04-3.94 nm were located on TiO2 matrix and immobilized by the surrounded SnO2. The resulted TiO2/Ag/SnO2 nanocomposites were used as photocatalyst for photodegradation of methylene blue under visible light. The experimental results demonstrated that the visible light photocatalytic activity of the TiO2/Ag/SnO2 was significantly enhanced in comparison with the individual TiO2 or the binary composite (TiO2/Ag or TiO2/SnO2) and the degradation rate was up to about 9.5 times that of commercial TiO2. The photocatalytic activity of the TiO2/Ag/SnO2 composites could be well controlled by simply tuning the dosages of Ag precursor and the optimized activity of the composites was obtained when the dosage of Ag precursor was 2%. Moreover, the TiO2/Ag/SnO2 photocatalyst exhibited high stability for degradation of methylene blue even after four successive cycles. PMID- 30002409 TI - Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation. AB - Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulated by a balance of costimulatory signaling (mediated by the costimulatory receptor CD28 on T cells) and coinhibitory signaling (mediated by the coinhibitory ligands CD80 and PD-L1 and -2 on Antigen-Presenting Cells). Here, we found that ACs specifically upregulated the coinhibitory ligand CD80 on macrophages. Conversely, ACs did not exhibit a robust regulation of the other coinhibitory ligands on macrophages or the costimulatory receptor CD28 on T cells. We show that the robust positive regulation of CD80 by ACs requires phagocytosis of ACs by macrophages. We also demonstrate that CD80 modulation by dead cells is a specific effect of ACs, but not necrotic cells (which stimulate immune responses). These results indicate that ACs modulate the coinhibitory pathway of T cell activation via CD80, and suggest a role for CD80 in suppressing T cell responses by ACs. Understanding a mechanism of regulating adaptive immune responses to ACs, which harbor an abundance of self-antigens, may advance our understanding of mechanisms of regulating autoimmunity and facilitate future therapy development for autoimmune disorders. PMID- 30002410 TI - Authentication of Garcinia fruits and food supplements using DNA barcoding and NMR spectroscopy. AB - Garcinia L. (Clusiaceae) fruits are a rich source of (-)-hydroxycitric acid, and this has gained considerable attention as an anti-obesity agent and a popular weight loss food supplement. In this study, we assessed adulteration of morphologically similar samples of Garcinia using DNA barcoding, and used NMR to quantify the content of (-)-hydroxycitric acid and (-)-hydroxycitric acid lactone in raw herbal drugs and Garcinia food supplements. DNA barcoding revealed that mostly G. gummi-gutta (previously known as G. cambogia) and G. indica were traded in Indian herbal markets, and there was no adulteration. The content of (-) hydroxycitric acid and (-)-hydroxycitric acid lactone in the two species varied from 1.7% to 16.3%, and 3.5% to 20.7% respectively. Analysis of ten Garcinia food supplements revealed a large variation in the content of (-)-hydroxycitric acid, from 29 mg (4.6%) to 289 mg (50.6%) content per capsule or tablet. Only one product contained quantifiable amounts of (-)-hydroxycitric acid lactone. Furthermore the study demonstrates that DNA barcoding and NMR could be effectively used as a regulatory tool to authenticate Garcinia fruit rinds and food supplements. PMID- 30002411 TI - Distinct Brain Areas involved in Anger versus Punishment during Social Interactions. AB - Although anger and aggression can have wide-ranging consequences for social interactions, there is sparse knowledge as to which brain activations underlie the feelings of anger and the regulation of related punishment behaviors. To address these issues, we studied brain activity while participants played an economic interaction paradigm called Inequality Game (IG). The current study confirms that the IG elicits anger through the competitive behavior of an unfair (versus fair) other and promotes punishment behavior. Critically, when participants see the face of the unfair other, self-reported anger is parametrically related to activations in temporal areas and amygdala - regions typically associated with mentalizing and emotion processing, respectively. During anger provocation, activations in the dorsolateral prefrontal cortex, an area important for regulating emotions, predicted the inhibition of later punishment behavior. When participants subsequently engaged in behavioral decisions for the unfair versus fair other, increased activations were observed in regions involved in behavioral adjustment and social cognition, comprising posterior cingulate cortex, temporal cortex, and precuneus. These data point to a distinction of brain activations related to angry feelings and the control of subsequent behavioral choices. Furthermore, they show a contribution of prefrontal control mechanisms during anger provocation to the inhibition of later punishment. PMID- 30002412 TI - RGN-259 (thymosin beta4) improves clinically important dry eye efficacies in comparison with prescription drugs in a dry eye model. AB - This study evaluated the clinical activity of RGN-259 (thymosin beta4) in comparison with cyclosporine A (CsA), diquafosol (DQS), and lifitegrast (LFA) in a murine model of dry eye. The model was NOD.B10-H2b mice in a 30-40% humidified environment together with daily scopolamine hydrobromide injections for 10 days. After desiccation stress, all drugs were evaluated after 10 treatment days. RGN 259 increased tear production similar to that in the DQS- and LFA-treated mice while CsA was inactive. RGN-259 improved corneal smoothness and decreased fluorescein staining similar to that of LFA group while CsA and DQS were inactive. Corneal epithelial detachment was reduced by RGN-259, and DQS and LFA showed similar activity but the CsA was inactive. RGN-259 increased conjunctival goblet cells and mucin production comparable to that seen with CsA, while DQS and LFA were inactive. RGN-259 reduced the over-expression of inflammatory factors comparable to that with CsA and LFA, while DQS was inactive. RGN-259 increased mucin production comparable to that observed with CsA, while DQS and LFA were inactive. In conclusion, RGN-259 promoted recovery of mucins and goblet cells, improved corneal integrity, and reduced inflammation in a dry eye mouse model and was equal to or more effective than prescription treatments. PMID- 30002413 TI - Neural signatures of different behavioral types in fairness norm compliance. AB - Fairness norm compliance is critical in any society. However, norm compliant behavior is very heterogeneous. Some people are reliably fair (voluntary compliers). Some are fair to avoid sanctions (sanction-based compliers), and some are reliably unfair (non-compliers). These types play divergent roles in society. However, they remain poorly understood. Here, we combined neural measures (resting electroencephalography and event-related potentials) and economic paradigms to better understand these types. We found that voluntary compliers are characterized by higher baseline activation in the right temporo-parietal junction, suggesting better social cognition capacity compared to sanction-based compliers and non-compliers. The latter two types are differentiated by (a) baseline activation in the dorso-lateral prefrontal cortex, a brain area known to be involved in self-control processes, and (b) event-related potentials in a classic self-control task. Both results suggest that sanction-based compliers have better self-control capacity than non-compliers. These findings improve our understanding of fairness norm compliance. Broadly, our findings suggest that established training techniques that boost self-control might help non-compliers adhere to fairness norms. PMID- 30002414 TI - Whole genome sequencing and phylogenetic analysis of strains of the agent of Lyme disease Borrelia burgdorferi from Canadian emergence zones. AB - Lyme disease is emerging in southern Canada due to range expansion of the tick vector, followed by invasion of the agent of Lyme disease Borrelia burgdorferi sensu stricto. Strain diversity, as determined by Multi Locus Sequence Typing, occurs in this zone of emergence, and this may have its origins in adaptation to ecological niches, and have phenotypic consequences for pathogenicity and serological test performance. Sixty-four unique strains were cultured from ticks collected in southern Canada and the genomes sequenced using the Illumina MiSeq platform. A maximum likelihood phylogenetic tree of the chromosome revealed two large clades with multiple subclades. Consistent with previous studies on this species, the clades were not geographically defined, and some Canadian strains were highly divergent from previously sequenced US strains. There was evidence for recombination in the chromosome but this did not affect the phylogeny. Analysis of chromosomal genes indicated that these are under intense purifying selection. Phylogenies of the accessory genome and chromosome were congruent. Therefore strain differences identified in the phylogeny of chromosomal genes likely act as a proxy for genetic determinants of phenotypic differences amongst strains that are harboured in the accessory genome. Further studies on health implications of strain diversity are needed. PMID- 30002415 TI - O-GlcNAcylation of FoxO1 mediates nucleoside diphosphate kinase B deficiency induced endothelial damage. AB - Nucleoside diphosphate kinase B (NDPK-B) acts as a protective factor in the retinal vasculature. NDPK-B deficiency leads to retinal vasoregression mimicking diabetic retinopathy (DR). Angiopoetin 2 (Ang-2), an initiator of retinal vasoregression in DR, is upregulated in NDPK-B deficient retinas and in NDPK-B depleted endothelial cells (ECs) in vitro. We therefore investigated the importance of Ang-2 in NDPK-B deficient retinas and characterized the mechanisms of Ang-2 upregulation upon NDPK-B depletion in cultured ECs. The crucial role of retinal Ang-2 in the initiation of vasoregression was verified by crossing NDPK-B deficient with Ang-2 haplodeficient mice. On the molecular level, FoxO1, a transcription factor regulating Ang-2, was upregulated in NDPK-B depleted ECs. Knockdown of FoxO1 abolished the elevation of Ang-2 induced by NDPK-B depletion. Furthermore O-GlcNAcylated FoxO1 was found preferentially in the nucleus. An increased O-GlcNAcylation of FoxO1 was revealed upon NDPK-B depletion. In accordance, the inhibition of protein O-GlcNAcylation normalized NDPK-B depletion induced Ang-2 upregulation. In summary, we demonstrated that the upregulation of Ang-2 upon NDPK-B deficiency is driven by O-GlcNAcylation of FoxO1. Our data provide evidence for a central role of protein O-GlcNAcylation in NDPK-B associated vascular damage and point to the hexosamine pathway as an important target in retinal vasoregression. PMID- 30002416 TI - Targeting a Reticulocyte Binding Protein and Duffy Binding Protein to Inhibit Reticulocyte Invasion by Plasmodium vivax. AB - Plasmodium vivax merozoite invasion is restricted to Duffy positive reticulocytes. Merozoite interaction with the Duffy antigen is mediated by the P. vivax Duffy binding protein (PvDBP). The receptor-binding domain of PvDBP maps to an N-terminal cysteine-rich region referred to as region II (PvDBPII). In addition, a family of P. vivax reticulocyte binding proteins (PvRBPs) mediates interactions with reticulocyte receptors. The receptor binding domain of P. vivax reticulocyte binding protein 1a (PvRBP1a) maps to a 30 kD region (PvRBP1a30). Antibodies raised against recombinant PvRBP1a30 and PvDBPII recognize the native P. vivax antigens and inhibit their binding to host receptors. Rabbit IgG purified from sera raised against PvRBP1a30 and PvDBPII were tested individually and in combination for inhibition of reticulocyte invasion by P. vivax field isolates. While anti-PvDBPII rabbit IgG inhibits invasion, anti-PvRBP1a30 rabbit IgG does not show significant invasion inhibitory activity. Combining antibodies against PvDBPII and PvRBP1a30 also does not increase invasion inhibitory activity. These studies suggest that although PvRBP1a mediates reticulocyte invasion by P. vivax merozoites, it may not be useful to include PvRBP1a30 in a blood stage vaccine for P. vivax malaria. In contrast, these studies validate PvDBPII as a promising blood stage vaccine candidate for P. vivax malaria. PMID- 30002417 TI - Thermal conductivity of amorphous SiO2 thin film: A molecular dynamics study. AB - Amorphous SiO2 (a-SiO2) thin films are widely used in integrated circuits (ICs) due to their excellent thermal stability and insulation properties. In this paper, the thermal conductivity of a-SiO2 thin film was systematically investigated using non-equilibrium molecular dynamics (NEMD) simulations. In addition to the size effect and the temperature effect for thermal conductivity of a-SiO2 thin films, the effect of defects induced thermal conductivity tuning was also examined. It was found that the thermal conductivity of a-SiO2 thin films is insensitive to the temperature from -55 degrees C to 150 degrees C. Nevertheless, in the range of the thickness in this work, the thermal conductivity of the crystalline SiO2 (c-SiO2) thin films conforms to the T-alpha with the exponent range from -0.12 to -0.37, and the thinner films are less sensitive to temperature. Meanwhile, the thermal conductivity of a-SiO2 with thickness beyond 4.26 nm has no significant size effect, which is consistent with the experimental results. Compared with c-SiO2 thin film, the thermal conductivity of a-SiO2 is less sensitive to defects. Particularly, the effect of spherical void defects on the thermal conductivity of a-SiO2 is followed by Coherent Potential model, which is helpful for the design of low-K material based porous a-SiO2 thin film in microelectronics. PMID- 30002418 TI - Oblique convergence and strain partitioning in the outer deformation front of NE Himalaya. AB - Himalayan-Tibetan orogeny has considered as a natural black box in the context of geodynamic evolution and tectonic complexity. The eastward extrusion model of Tibetan crust contradicts with the oblique convergence model in the NE-Himalaya (Bhutan/Arunachal region), where the overall convergence rate accommodated in the Himalaya is about 20-25% less than that in the neighbouring central Himalaya and Eastern Himalayan syntaxis (EHS). We propose that instead of partitioning in the backarc, the NE-Himalaya has developed an active sliver along the Assam Brahmaputra valley in the outer deformation front, in order to accommodate the deficiency in long-term plate convergence between Himalaya and southern Tibet. We argue that the strong eastward extrusion of Tibetan crust along NE-Himalaya is the main driving force for the unusual development of the Assam-Brahmaputra sliver. This new hypothesis can explain active convergence along EHS, low convergence and subdued topography in Bhutan and Arunachal Himalaya, kinematic and space-problem of Indo-Burmese wedge, and finally solves the contradiction between Tibetan extrusion and oblique convergence model of the HimalayanTibetan orogeny. PMID- 30002420 TI - Acoustic Complexity of vocal fish communities: a field and controlled validation. AB - The Acoustic Complexity Index (ACI) is increasingly applied to the study of biodiversity in aquatic habitats. However, it remains unknown which types of acoustic information are highlighted by this index in underwater environments. This study explored the robustness of the ACI to fine variations in fish sound abundance (i.e. number of sounds) and sound diversity (i.e. number of sound types) in field recordings and controlled experiments. The ACI was found to be sensitive to variations in both sound abundance and sound diversity, making it difficult to discern between these variables. Furthermore, the ACI was strongly dependent on the settings used for its calculation (i.e. frequency and temporal resolution of the ACI algorithm, amplitude filter). Care should thus be taken when comparing ACI absolute values between studies, or between sites with site specific characteristics (e.g. species diversity, fish vocal community composition). As the use of ecoacoustic indices presents a promising tool for the monitoring of vulnerable environments, methodological validations like those presented in this paper are of paramount importance in understanding which biologically important information can be gathered by applying acoustic indices to Passive Acoustic Monitoring data. PMID- 30002421 TI - Vibrio spp. infections. AB - Vibrio is a genus of ubiquitous bacteria found in a wide variety of aquatic and marine habitats; of the >100 described Vibrio spp., ~12 cause infections in humans. Vibrio cholerae can cause cholera, a severe diarrhoeal disease that can be quickly fatal if untreated and is typically transmitted via contaminated water and person-to-person contact. Non-cholera Vibrio spp. (for example, Vibrio parahaemolyticus, Vibrio alginolyticus and Vibrio vulnificus) cause vibriosis - infections normally acquired through exposure to sea water or through consumption of raw or undercooked contaminated seafood. Non-cholera bacteria can lead to several clinical manifestations, most commonly mild, self-limiting gastroenteritis, with the exception of V. vulnificus, an opportunistic pathogen with a high mortality that causes wound infections that can rapidly lead to septicaemia. Treatment for Vibrio spp. infection largely depends on the causative pathogen: for example, rehydration therapy for V. cholerae infection and debridement of infected tissues for V. vulnificus-associated wound infections, with antibiotic therapy for severe cholera and systemic infections. Although cholera is preventable and effective oral cholera vaccines are available, outbreaks can be triggered by natural or man-made events that contaminate drinking water or compromise access to safe water and sanitation. The incidence of vibriosis is rising, perhaps owing in part to the spread of Vibrio spp. favoured by climate change and rising sea water temperature. PMID- 30002419 TI - Increasing isoflurane dose reduces homotopic correlation and functional segregation of brain networks in mice as revealed by resting-state fMRI. AB - Effects of anesthetics on brain functional networks are not fully understood. In this work, we investigated functional brain networks derived from resting-state fMRI data obtained under different doses of isoflurane in mice using stationary and dynamic functional connectivity (dFC) analysis. Stationary network analysis using FSL Nets revealed a modular structure of functional networks, which could be segregated into a lateral cortical, an associative cortical network, elements of the prefrontal network, a subcortical network, and a thalamic network. Increasing isoflurane dose led to a loss of functional connectivity between the bilateral cortical regions. In addition, dFC analysis revealed a dominance of dynamic functional states (dFS) exhibiting modular structure in mice anesthetized with a low dose of isoflurane, while at high isoflurane levels dFS showing widespread unstructured correlation displayed highest weights. This indicates that spatial segregation across brain functional networks is lost with increasing dose of the anesthetic drug used. To what extent this indicates a state of deep anesthesia remains to be shown. Combining the results of stationary and dynamic FC analysis indicates that increasing isoflurane levels leads to loss of modular network organization, which includes loss of the strong bilateral interactions between homotopic brain areas. PMID- 30002422 TI - Enhancing the systems productivity and water use efficiency through coordinated soil water sharing and compensation in strip-intercropping. AB - In arid areas, water shortage is threating agricultural sustainability, and strip intercropping may serve as a strategy to alleviate the challenge. Here we show that strip-intercropping enhances the spatial distributions of soil water across the 0-110 cm rooting zones, improves the coordination of soil water sharing during the co-growth period, and provides compensatory effect for available soil water. In a three-year (2009-2011) experiment, shorter-season pea (Pisum sativum L.) was sown in alternate strips with longer-season maize (Zea mays L.) without or with an artificially-inserted root barrier (a solid plastic sheet) between the strips. The intercropped pea used soil water mostly in the top 20-cm layers, whereas maize plants were able to absorb water from deeper-layers of the neighboring pea strips. After pea harvest, the intercropped maize obtained compensatory soil water from the pea strips. The pea-maize intercropping without the root barrier increased grain yield by 25% and enhanced water use efficiency by 24% compared with the intercropping with the root barrier. The improvement in crop yield and water use efficiency was partly attributable to the coordinated soil water sharing between the inter-strips and the compensatory effect from the early-maturing pea to the late-maturing maize. PMID- 30002423 TI - Hypothermia ameliorates blast-related lifespan reduction of C. elegans. AB - Blast-related mild traumatic brain injury induces significant long-term health issues, yet treatment procedures remain underdeveloped. Therapeutic hypothermia has been postulated as a potentially effective therapy. In a Caenorhabditis elegans model, we demonstrate a dose-dependent reduction in lifespan following exposure to blast-like shock waves. Using polyvinyl alcohol, we show that cavitation is a key injurious factor in the damaging shock wave component. Short and long lifespan C. elegans mutants demonstrated the interaction of genetic and environmental longevity-determining factors. Hypothermia reduced the long term effect of shock wave exposure. Thus, we present an effective C. elegans model of long term effects of blast-related mild traumatic brain injury, as well as evidence of the merit of therapeutic hypothermia as a therapy option following blast exposure. PMID- 30002424 TI - Variation in fluoroquinolone pharmacodynamic parameter values among isolates of two bacterial pathogens of bovine respiratory disease. AB - To design an antimicrobial treatment regimen for a bacterial disease, data on the drug pharmacodynamics (PD) against selected drug-susceptible strains of the pathogen are used. The regimen is applied across such strains in the field, assuming the PD parameter values remain the same. We used time-kill experiments and PD modeling to investigate the fluoroquinolone enrofloxacin PD against different isolates of two bovine respiratory disease pathogens: four Mannheimia haemolytica and three Pasteurella multocida isolates. The models were fitted as mixed-effects non-linear regression; the fixed-effects PD parameter values were estimated after accounting for random variation among experimental replicates. There was both inter- and intra- bacterial species variability in the PD parameters Hill-coefficient and Emax (maximal decline of bacterial growth rate), with more variable PD responses among M. haemolytica than among P. multocida isolates. Moreover, the Hill-coefficient was correlated to the isolate's maximal population growth rate in the absence of antimicrobial exposure (a.k.a. specific growth rate; Spearman's rho = 0.98, p-value = 0.003, n = 6 isolates excluding one outlier). Thus, the strain's properties such as growth potential may impact its PD responses. This variability can have clinical implications. Modifying the treatment regimen depending on phenotypic properties of the pathogen strain causing disease may be a precision medicine approach. PMID- 30002425 TI - Plant-expressed bacteriophage lysins control pathogenic strains of Clostridium perfringens. AB - The anaerobic spore-forming bacterium Clostridium perfringens is a source of one of the most common food-borne illnesses in the United States and Europe. The costs associated with disease management are high and interventions are limited; therefore, effective and safe antimicrobials are needed to control food contamination by C. perfringens. A viable solution to this problem could be bacteriophage lysins used as food additives or food processing aids. Such antimicrobials could be produced cost-effectively and in ample supply in green plants. By using edible plant species as production hosts the need for expensive product purification can be reduced or obviated. We describe the first successful expression in plants of C. perfringens-specific bacteriophage lysins. We demonstrate that six lysins belonging to two different families (N-acetylmuramoyl L-alanine amidase and glycosyl hydrolase 25) are active against a panel of enteropathogenic C. perfringens strains under salinity and acidity conditions relevant to food preparation environments. We also demonstrate that plant expressed lysins prevent multiplication of C. perfringens on cooked meat matrices far better than nisin, the only currently approved bacteriocin food preservative to control this pathogen. PMID- 30002426 TI - Generation of multiparametric MRI maps by using Gd-labelled- RBCs reveals phenotypes and stages of murine prostate cancer. AB - Prostate Cancer (PCa) is the second most common and fifth cause of cancer-related mortality in males in Western Countries. The development of innovative tools for an early, more precise and noninvasive diagnosis is a medical need. Vascular volume (Vv) and hypoxia are two of the most important tumor hallmarks. Herein, they have been assessed in TRAMP mice by using MRI. Their quantification has been carried out by injecting autologous Red Blood Cells (RBCs), ex vivo labelled with Gd-HPDO3A or Gd-DOTP complexes, respectively. Gd-labelled-RBCs are stably confined in the intravascular space, also in presence of a very leaky tumor endothelium, thus representing efficient probes for vascular space analysis. Vv enhancement and hypoxia onset have been demonstrated to be present at early stages of PCa and their expression largely increases with tumor development. Moreover, also Diffusion weighted MRI and Amide Proton Transfer MRI have been herein applied to characterize PCa. The herein applied multiparametric MRI (mpMRI) analysis allows a detailed in vivo characterization of PCa, in which each histotype and cancer stage displays a specific MRI pattern. This provides an unprecedented opportunity to feature prostate tumor, making possible a non invasive, precise and early diagnosis, which could direct treatments towards a more personalized medicine. PMID- 30002427 TI - Investigating molecular interactions between oxidized neuroglobin and cytochrome c. AB - The formation of a complex between neuroglobin (Ngb) and cytochrome c (Cyt c) has an important biological role in preventing apoptosis. Binding of Ngb to Cyt c alone is sufficient to block the caspase 9 activation by ferric Cyt c that is released during ischemic insults. Therefore, a detailed information on the Ngb Cyt c interactions is important for understanding apoptosis. However, the exact nature of the interactions between oxidized human neuroglobin (hNgb) and Cyt c is not well understood. In this work, we used a combination of computational modeling and surface plasmon resonance experiments to obtain and characterize the complex formation between oxidized hNgb and Cyt c. We identified important residues involved in the complex formation, including K72 in Cyt c, which is otherwise known to interact with the apoptotic protease-activation factor-1. Our computational results, together with an optimized structure of the hNgb-Cyt c complex, provide unique insights into how the hNgb-Cyt c complex can abate the apoptotic cascade without an hNgb-Cyt c redox reaction. PMID- 30002428 TI - Quantum phase transition in a realistic double-quantum-dot system. AB - Observing quantum phase transitions in mesoscopic systems is a daunting task, thwarted by the difficulty of experimentally varying the magnetic interactions, the typical driving force behind these phase transitions. Here we demonstrate that in realistic coupled double-dot systems, the level energy difference between the two dots, which can be easily tuned experimentally, can drive the system through a phase transition, when its value crosses the difference between the intra- and inter-dot Coulomb repulsion. Using the numerical renormalization group and the semi-analytic slave-boson mean-field theory, we study the nature of this phase transition, and demonstrate, by mapping the Hamiltonian into an even-odd basis, that indeed the competition between the dot level energy difference and the difference in repulsion energies governs the sign and magnitude of the effective magnetic interaction. The observational consequences of this transition are discussed. PMID- 30002429 TI - Iron chelation increases the tolerance of Escherichia coli to hyper-replication stress. AB - In Escherichia coli, an increase in the frequency of chromosome replication is lethal. In order to identify compounds that affect chromosome replication, we screened for molecules capable of restoring the viability of hyper-replicating cells. We made use of two E. coli strains that over-initiate DNA replication by keeping the DnaA initiator protein in its active ATP bound state. While viable under anaerobic growth or when grown on poor media, these strains become inviable when grown in rich media. Extracts from actinomycetes strains were screened, leading to the identification of deferoxamine (DFO) as the active compound in one of them. We show that DFO does not affect chromosomal replication initiation and suggest that it was identified due to its ability to chelate cellular iron. This limits the formation of reactive oxygen species, reduce oxidative DNA damage and promote processivity of DNA replication. We argue that the benzazepine derivate (+/-)-6-Chloro-PB hydrobromide acts in a similar manner. PMID- 30002430 TI - Angelica gigas Nakai and Decursin Downregulate Myc Expression to Promote Cell Death in B-cell Lymphoma. AB - Angelica gigas Nakai (AGN) is an oriental traditional medicine to treat anemia, dysmenorrhea, and migraine. However, its anti-lymphoma effect is yet to be tested. Here, we demonstrated that AGN and its major component decursin target Myc to suppress lymphomagenesis in vitro and in vivo. AGN inhibited cell viability in multiple B lymphoma cells, while sparing normal splenocytes and bone marrow cells. Increased cleaved PARP level and caspase 3/7 activity and the repression of survival-promoting AKT/mTOR and MAPK pathways downstream of BCR, were responsible for the pro-apoptotic effects of AGN. We found that Myc, a prominent downstream target of these signaling pathways, contributes to AGN induced cell death. Moreover, co-treatment with AGN and a Myc inhibitor, JQ1 or 10058-F4 yielded synergistic cytotoxic activities against cancer cells with markedly reduced Myc expression. AGN downregulated Myc expression and suppressed tumorigenesis in EMU-myc transgenic mice. The proapoptotic activities of AGN were recapitulated by decursin, indicating that the anti-tumor effect of AGN was mainly caused by decursin. These findings suggest that AGN and decursin possess potent anti-lymphoma activity, and combination therapies with AGN/decursin and a Myc inhibitor to target Myc more efficiently could be a valuable avenue to explore in the treatment of B-cell lymphoma. PMID- 30002431 TI - An account of solvent accessibility in protein-RNA recognition. AB - Protein-RNA recognition often induces conformational changes in binding partners. Consequently, the solvent accessible surface area (SASA) buried in contact estimated from the co-crystal structures may differ from that calculated using their unbound forms. To evaluate the change in accessibility upon binding, we compare SASA of 126 protein-RNA complexes between bound and unbound forms. We observe, in majority of cases the interface of both the binding partners gain accessibility upon binding, which is often associated with either large domain movements or secondary structural transitions in RNA-binding proteins (RBPs), and binding-induced conformational changes in RNAs. At the non-interface region, majority of RNAs lose accessibility upon binding, however, no such preference is observed for RBPs. Side chains of RBPs have major contribution in change in accessibility. In case of flexible binding, we find a moderate correlation between the binding free energy and change in accessibility at the interface. Finally, we introduce a parameter, the ratio of gain to loss of accessibility upon binding, which can be used to identify the native solution among the flexible docking models. Our findings provide fundamental insights into the relationship between flexibility and solvent accessibility, and advance our understanding on binding induced folding in protein-RNA recognition. PMID- 30002432 TI - Risk factors for breakthrough vitreous hemorrhage after intravitreal anti-VEGF injection in age-related macular degeneration with submacular hemorrhage. AB - To investigate the risk factors for breakthrough vitreous hemorrhage (VH) after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection in age related macular degeneration (AMD) accompanied by submacular hemorrhage (SMH). We retrospectively reviewed the medical records of patients diagnosed with AMD combined with SMH, and enrolled 31 patients. We formed an age- and sex-matched control group of patients with submacular hemorrhage who did not develop breakthrough VH after intravitreal injection during 6 month follow-up. The mean patient age was 70.8 +/- 10.3 years in the breakthrough VH group. Of the 31 patients, 8 were diagnosed with choroidal neovascularization (CNV), 22 with polypoidal choroidal vasculopathy (PCV), and 1 with retinal angiomatous proliferation (RAP). PCV was associated with a significantly higher incidence of VH (odds ratio, 35.01; p = 0.001). The size of the SMH was 22.7 +/- 12.4 disc areas (DAs) in the breakthrough VH group and 5.4 +/- 6.9 DAs in the control group, and was thus significantly related to the development of VH (p < 0.001). The risk of VH was significantly higher in those taking anticoagulants (p = 0.014). There was no significant difference between the types of anti-VEGF agents. When taking anticoagulant medications, a SMH of large diameter, and PCV subtype were risk factors for breakthrough VH after anti-VEGF injection. PMID- 30002434 TI - Both air-sea components are crucial for El Nino forecast from boreal spring. AB - The spring predictability barrier severely limits our ability to forecast the El Nino-Southern Oscillation (ENSO) from and across the boreal spring. Our observational analysis shows that the spring predictability barrier (SPB) can be largely reduced when information from both the ocean and atmosphere are effectively taken into account during the boreal spring. The correlation coefficient between the predicted and observed sea surface temperature anomalies over the equatorial central-eastern Pacific determined by a simple quaternary linear regression model is >0.81 for the period 1980-2016. The frame structure of the ENSO evolution is mostly controlled by variations in the oceanic heat content along the equatorial Pacific and the zonal wind stress over the tropical western Pacific during the boreal spring. These results indicate that to predict ENSO events with a long lead time, i.e., largely reducing the SPB, variations in both the ocean and atmosphere during the boreal spring should be well predicted first. While the oceanic information is mainly located in the equatorial Pacific and well characterized by the delayed oscillator and recharging oscillator models, variations in the atmosphere may contain information beyond this area and are more difficult to deal with. PMID- 30002433 TI - Association Between Left Renal Vein Entrapment and Varicocele Recurrence: A Cohort Study in 3042 Patients. AB - The recurrence rates after varicocelectomy vary from 0.9% to 32.2%, especially for patients with the left renal vein entrapment (LRVE). This study aims to study the association between LRVE and varicocele recurrence, and to find the risk factors of LRVE. With the design of a cohort study, we included 3042 varicocele patients who would undergo modified inguinal microscope-assisted varicocelectomy (MHMV). 858 (28.21%) patients with LRVE were as the study group, and 2184 (71.79%) patients without LRVE were as the control group. Compared with the control group, BMI was lower (p < 0.001) in study group. Totally, 18 patients had recurrence after surgery, so the recurrence rate was 0.59%. Seventeen patients (1.98%) in study group and 1 patients (0.05%) in control group had recurrence, and significant statistical difference was found between the two groups (p < 0.001). The risk ratio of LRVE for varicocele recurrence is 43.27. In conclusion, the recurrence rate of our MHMV is the lowest (0.59%). There is association between LRVE and varicocele recurrence, and varicocele patients with LRVE have higher probability of recurrence rate after varicocelectomy. BMI could be a risk factor of LRVE. Thus, for varicocele patients, especially those with lower BMI, attentions should be payed to LRVE. PMID- 30002435 TI - Senescent tumor cells building three-dimensional tumor clusters. AB - Cellular senescence, a permanent cell-cycle arrest, is a common yet intriguing phenomenon, in which its beneficial significance for biological organisms has only begun to be explored. Among others, senescent cells are able to transform tissue structures around them. Tumor cells, whose hallmark is their ability to proliferate indefinitely, are not free from the phenomenon. Here, we report a remarkable observation where senescent cells in a dense mono-layer of breast cancer colony act as aggregating centers for non-senescent cells in their vicinity. Consequently, the senescent cells actively form localized 3D cell clusters in a confluent 2D tumor layer. The biophysical mechanism underpinning the surprising phenomenon primarily involves mitotic cell-rounding, dynamic and differential cell attachments, and cellular chemotaxis. By incorporating these few biophysical factors, we were able to recapitulate the experimental observation via a cellular Potts Model. PMID- 30002436 TI - Can we establish a hierarchy among trastuzumab biosimilar candidates? AB - The European patent for intravenous trastuzumab lapsed in 2017, and this stimulated research into a number of trastuzumab biosimilars. Quality assessment of their development and clinical results might enable establishment of a clinical hierarchy of these agents. This editorial will underline the key points for consideration when determining such an evaluation. PMID- 30002437 TI - Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer. AB - BACKGROUND: This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: Patients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20 MUg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20 MUg/ml was above the prespecified non-inferiority margin of - 12.5%. RESULTS: For PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20 MUg/ml; the lower limit of the 95% confidence interval (- 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (- 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%. CONCLUSIONS: PF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy. PMID- 30002438 TI - Meta-proteomics of rumen microbiota indicates niche compartmentalisation and functional dominance in a limited number of metabolic pathways between abundant bacteria. AB - The rumen is a complex ecosystem. It is the primary site for microbial fermentation of ingested feed allowing conversion of a low nutritional feed source into high quality meat and milk products. However, digestive inefficiencies lead to production of high amounts of environmental pollutants; methane and nitrogenous waste. These inefficiencies could be overcome by development of forages which better match the requirements of the rumen microbial population. Although challenging, the application of meta-proteomics has potential for a more complete understanding of the rumen ecosystem than sequencing approaches alone. Here, we have implemented a meta-proteomic approach to determine the association between taxonomies of microbial sources of the most abundant proteins in the rumens of forage-fed dairy cows, with taxonomic abundances typical of those previously described by metagenomics. Reproducible proteome profiles were generated from rumen samples. The most highly abundant taxonomic phyla in the proteome were Bacteriodetes, Firmicutes and Proteobacteria, which corresponded with the most abundant taxonomic phyla determined from 16S rRNA studies. Meta-proteome data indicated differentiation between metabolic pathways of the most abundant phyla, which is in agreement with the concept of diversified niches within the rumen microbiota. PMID- 30002439 TI - Mechanisms and Signaling Associated with LPDBD Plasma Mediated Growth Improvement in Wheat. AB - This study investigates the effect and mechanisms of low pressure dielectric barrier discharge (LPDBD) produced with Ar/O2 and Ar/Air technique causing biological stimulation leading to improved germination and growth in wheat. Both plasma treatments caused rougher and chapped seed surface along with noticeable improvement in seed germination in wheat. Beside this, seed H2O2 concentration significantly increased compared to controls subjected to Ar/O2 and Ar/Air while this phenomenon was more pronounced due to Ar/Air plasma. Analysis of plants grown from the plasma treated seeds showed significant improvement in shoot characteristics, iron concentration, total soluble protein and sugar concentration in comparison with the controls more efficiently due to Ar/O2 plasma than that of Ar/Air. Further, none of the plasma treatments caused membrane damage or cell death in root and shoot of wheat. Interestingly, Ar/O2 treated plants showed a significant increase (2-fold) of H2O2 compared to controls in both root and shoot, while Ar/Air plasma caused no changes in H2O2. This phenomenon was supported by the biochemical and molecular evidence of SOD, APX and CAT in wheat plants. Plants derived from Ar/O2 treated seeds demonstrated a significant increase in SOD activity and TaSOD expression in roots of wheat, while APX and CAT activities along with TaCAT and TaAPX expression showed no significant changes. In contrast, Ar/Air plasma caused a significant increase only in APX activity in the shoot. This suggests that Ar/O2 plasma caused a slight induction in H2O2 accumulation without triggering the H2O2 scavengers (APX and CAT) and thus, efficiency affect growth and development in wheat plants. Further, grafting of control and Ar/O2 treated plants showed a significant increase in shoot biomass and H2O2 concentration in grafts having Ar/O2 rootstock regardless of the type scion attached to it. It indicates that signal driving Ar/O2 plasma mediated growth improvement in wheat is possibly originated in roots. Taken together, this paper delivers new insight into the mechanistic basis for growth improvement by LPDBD technique. PMID- 30002440 TI - Multipronged activity of combinatorial miR-143 and miR-506 inhibits Lung Cancer cell cycle progression and angiogenesis in vitro. AB - Lung cancer (LC) is the leading cause of cancer-related deaths. Downregulation of CDK1, 4 and 6, key regulators of cell cycle progression, correlates with decreased LC cell proliferation. Enforced expression of miRNAs (miRs) is a promising approach to regulate genes. Here, we study the combinatorial treatment of miR-143 and miR-506 to target the CDK1, 4/6 genes, respectively. We analyzed the differential expression of CDK genes by qPCR, and western blot, and evaluated changes in the cell cycle distribution upon combinatorial treatment. We used an antibody microarray analysis to evaluate protein expression, focusing on the cell cycle pathway, and performed RNA-sequencing for pathway analysis. The combinatorial miR treatment significantly downregulated CDK1, 4 and 6 expression, and induced a shift of the cell cycle populations, indicating a G1 and G2 cell cycle block. The two miRs induces strong cytotoxic activity, with potential synergism, and a significant Caspase 3/7 activation. We identified a strong inhibition of tube formation in the presence or absence VEGF in an in vitro angiogenesis model. Together with the pathways analysis of the RNA-sequencing data, our findings establish the combinatorial miR transfection as a viable strategy for lung cancer treatment that merits further investigation. PMID- 30002441 TI - Voxel size and gray level normalization of CT radiomic features in lung cancer. AB - Radiomic features are potential imaging biomarkers for therapy response assessment in oncology. However, the robustness of features with respect to imaging parameters is not well established. Previously identified potential imaging biomarkers were found to be intrinsically dependent on voxel size and number of gray levels (GLs) in a recent texture phantom investigation. Here, we validate the voxel size and GL in-phantom normalizations in lung tumors. Eighteen patients with non-small cell lung cancer of varying tumor volumes were analyzed. To compare with patient data, phantom scans were acquired on eight different scanners. Twenty four previously identified features were extracted from lung tumors. The Spearman rank (rs) and interclass correlation coefficient (ICC) were used as metrics. Eight out of 10 features showed high (rs > 0.9) and low (rs < 0.5) correlations with number of voxels before and after normalizations, respectively. Likewise, texture features were unstable (ICC < 0.6) and highly stable (ICC > 0.8) before and after GL normalizations, respectively. We conclude that voxel size and GL normalizations derived from a texture phantom study also apply to lung tumors. This study highlights the importance and utility of investigating the robustness of radiomic features with respect to CT imaging parameters in radiomic phantoms. PMID- 30002442 TI - Enhancement of chondrogenesis of adipose-derived stem cells in HA-PNIPAAm-CL hydrogel for cartilage regeneration in rabbits. AB - Injectable thermoresponsive hydrogels have the advantages of effective cell delivery and minimal invasion for tissue engineering applications. In this study, we investigated the chondroinductive potential of newly developed hyaluronic acid (HA)-modified thermoresponsive poly(N-isopropylacrylamide) (HA-PNIPAAm-CL) hydrogels on enhancing rabbit ADSC (rADSC) chondrogenesis in vitro and in the synovial cavity of rabbit. The HA-mixed PNIPAAm (HA-PNIPAAm-CP) and HA-cross linked PNIPAAm (HA-PNIPAAm-CL) were fabricated using physical interaction and chemical cross-linking methods, respectively. The in vitro results showed that, compared to unmodified PNIPAAm, both HA-modified hydrogels significantly increased cell viability, chondrogenic marker gene (aggrecan and type II collagen) expression and sulfide glycosaminoglycan (sGAG) formation in embedded rADSCs. However, HA-PNIPAAm-CL showed the highest rADSC viability and chondrogenesis. The chondrogenic effects of HA-modified hydrogels on rADSCs were confirmed in vivo by the intraarticular injection of hydrogel-embedded rADSC constructs into rabbit synovial cavities for 3 weeks and tracing with CM-DiI labeling. Neocartilage formation in the hydrogels was determined by histomorphological staining of GAG and type II collagen. In vivo injected rADSC/HA-PNIPAAm-CL constructs showed more hyaline cartilage formation than that of rADSC/HA-PNIPAAm-CP and rADSC/PNIPAAm constructs in the synovial cavity of rabbit. These results suggest that the HA-PNIPAAm-CL provides a suitable microenvironment to enhance ADSC chondrogenesis for articular cartilage tissue engineering applications. PMID- 30002443 TI - LINC01638 lncRNA activates MTDH-Twist1 signaling by preventing SPOP-mediated c Myc degradation in triple-negative breast cancer. AB - Breast cancer is a heterogeneous disease, and triple-negative breast cancer (TNBC) continues to be a serious health problem. The potential involvement of lncRNAs in TNBC progression remains unexplored. Here, we demonstrated that LINC01638 is highly expressed in TNBC tissues and cells. LINC01638 maintains the mesenchymal traits of TNBC cells, including an enriched epithelial-mesenchymal transition (EMT) signature and cancer stem cell-like state. LINC01638 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. LINC01638 overexpression predicts a poor outcome of breast cancer patients. Mechanistically, LINC01638 interacts with c-Myc to prevent SPOP-mediated c-Myc ubiquitination and degradation. C-Myc transcriptionally enhances MTDH (metadherin) expression and subsequently activates Twist1 expression to induce EMT. Our findings describe LINC01638-mediated signal transduction and highlight the crucial role of LINC01638 in TNBC progression. PMID- 30002446 TI - Negligible contribution of M2634V substitution to ZIKV pathogenesis in AG6 mice revealed by a bacterial promoter activity reduced infectious clone. AB - ZIKV has emerged as a significant human pathogene for the severe neurological complications, including Guillain-Barre(GBS) syndrome in adults and a variety of fetal abnormalities such as microcephaly. A stable and efficient infectious clone of Brazilian ZIKV isolate is required to study pathogenesis of epidemic ZIKV and virus evolution impact on it. Here we successfully constructed infectious cDNA clone on an early Brazilian isolate by eliminating the activity of predicted bacterial promoter in 1-3000 nt of ZIKV genome, leading to a stable infectious cDNA clone (pZL1). pZL1 derived virus could infect different cell lines and cause lethal effect to AG6 mice. We further investigated the role of a recent emerged substitution in NS5 (M2634V). We found that a reverse mutation (V2634M) caused negligible effect on the ZIKV viral genome replication and infectious progeny production in multiple cell culture systems. Additionally, this mutation did not alter the pathogenesis feature and virulence of ZIKV in AG6 mice. In summary, our results present another robust infectious ZIKV clone from Brazilian isolate and provide evidences to support that M2634V single mutation did not alter virus life cycle in cell culture and pathogenesis in AG6 mouse model. PMID- 30002445 TI - Single-pot glycoprotein biosynthesis using a cell-free transcription-translation system enriched with glycosylation machinery. AB - The emerging discipline of bacterial glycoengineering has made it possible to produce designer glycans and glycoconjugates for use as vaccines and therapeutics. Unfortunately, cell-based production of homogeneous glycoproteins remains a significant challenge due to cell viability constraints and the inability to control glycosylation components at precise ratios in vivo. To address these challenges, we describe a novel cell-free glycoprotein synthesis (CFGpS) technology that seamlessly integrates protein biosynthesis with asparagine-linked protein glycosylation. This technology leverages a glyco optimized Escherichia coli strain to source cell extracts that are selectively enriched with glycosylation components, including oligosaccharyltransferases (OSTs) and lipid-linked oligosaccharides (LLOs). The resulting extracts enable a one-pot reaction scheme for efficient and site-specific glycosylation of target proteins. The CFGpS platform is highly modular, allowing the use of multiple distinct OSTs and structurally diverse LLOs. As such, we anticipate CFGpS will facilitate fundamental understanding in glycoscience and make possible applications in on demand biomanufacturing of glycoproteins. PMID- 30002447 TI - Transdermal optical imaging revealed different spatiotemporal patterns of facial cardiovascular activities. AB - Human cardiovascular activities are important indicators of a variety of physiological and psychological activities in human neuroscience research. The present proof-of-concept study aimed to reveal the spatiotemporal patterns of cardiovascular activities from the dynamic changes in hemoglobin concentrations in the face. We first recorded the dynamics of facial transdermal blood flow using a digital video camera and the Electrocardiography (ECG) signals using an ECG system simultaneously. Then we decomposed the video imaging data extracted from different sub-regions of a face into independent components using group independent component analysis (group ICA). Finally, the ICA components that included cardiovascular activities were identified by correlating their magnitude spectrum to those obtained from the ECG. We found that cardiovascular activities were associated with five independent components reflecting different spatiotemporal dynamics of facial blood flow changes. The strongest strengths of these ICA components were observed in the bilateral forehead, the left chin, and the left cheek, respectively. Our findings suggest that the cardiovascular activities presented different dynamic properties within different facial sub regions, respectively. More broadly, the present findings point to the potential of the transdermal optical imaging technology as a new neuroscience methodology to study human physiology and psychology, noninvasively and remotely in a contactless manner. PMID- 30002449 TI - Apoptosis inhibitor of macrophage and diabetic kidney disease. PMID- 30002444 TI - Epithelial-mesenchymal-transition-inducing transcription factors: new targets for tackling chemoresistance in cancer? AB - Chemoresistance remains a major complication of cancer treatments. Recent data provide strong evidence that chemoresistance is linked to epithelial-mesenchymal transition (EMT), a latent developmental process, which is re-activated during cancer progression. EMT involves transcriptional reprogramming and is driven by specific EMT transcription factors (EMT-TFs). In this review, we provide support for the idea that EMT-TFs contribute to the development of resistance against cancer therapy and discuss how EMT-TFs might be targeted to advance novel therapeutic approaches to the treatment of cancer. PMID- 30002448 TI - Anti-inflammatory and hepatoprotective effects of exopolysaccharides isolated from Pleurotus geesteranus on alcohol-induced liver injury. AB - The present work investigated the hepatoprotective role of exopolysaccharides (EPS) isolated from the mushroom Pleurotus geesteranus with respect to alcohol induced liver injury in mice. Based on a physico-chemical analysis, the EPS produced by Pleurotus geesteranus was identified as a heteropolysaccharide with alpha-glycosidic bond. The results revealed that prophylactic application of the EPS reduces detrimental alcoholic effects on the liver. This observation was followed by decreased levels of total cholesterol, triglycerides, CYP2E1 and pro inflammatory mediators (TNF-alpha, IL-6, IL-1beta, COX-2, NO and iNOS) in the liver homogenates, suggesting that the EPS exhibits anti-inflammatory and hepatoprotective effects. Moreover, the increased activity of hepatic enzymes (superoxide dismutase, glutathione peroxidase and catalase) and reduced lipid peroxidation status indicated that the antioxidative effect of the EPS contributes to alleviation of liver injury. Therefore, this study reports that the EPS produced by Pleurotus geesteranus could be considered a potential natural drug or functional food supplement for the prevention of liver damage. PMID- 30002450 TI - Failure of a T cell regulator: CD6 contributes to the aggravation of autoimmune inflammation. PMID- 30002451 TI - Emerging predictors of the response to the blockade of immune checkpoints in cancer therapy. AB - Checkpoint blockade-based immunotherapy offers new options and powerful weapons for the treatment of cancer, but its efficacy varies greatly among different types of cancer and across individual patients. Thus, the development of the right tools that can be used to identify patients who could benefit from this therapy is of utmost importance in order to maximize the therapeutic benefit, minimize risk of toxicities, and guide combination approaches. Multiple predictors have emerged that are based on checkpoint receptor ligand expression, tumor mutational burden, neoantigen and microsatellite instability, tumor infiltrating immune cells, and peripheral blood biomarkers. In this review, we discuss the current state and progress of predictors as aids in checkpoint blockade-based immunotherapy in cancer. PMID- 30002452 TI - Decoding unconstrained arm movements in primates using high-density electrocorticography signals for brain-machine interface use. AB - Motor deficit is among the most debilitating aspects of injury to the central nervous system. Despite ongoing progress in brain-machine interface (BMI) development and in the functional electrical stimulation of muscles and nerves, little is understood about how neural signals in the brain may be used to potentially control movement in one's own unconstrained paralyzed limb. We recorded from high-density electrocorticography (ECoG) electrode arrays in the ventral premotor cortex (PMv) of a rhesus macaque and used real-time motion tracking techniques to correlate spatial-temporal changes in neural activity with arm movements made towards objects in three-dimensional space at millisecond precision. We found that neural activity from a small number of electrodes within the PMv can be used to accurately predict reach-return movement onset and directionality. Also, whereas higher gamma frequency field activity was more predictive about movement direction during performance, mid-band (beta and low gamma) activity was more predictive of movement prior to onset. We speculate these dual spatiotemporal signals may be used to optimize both planning and execution of movement during natural reaching, with prospective relevance to the future development of neural prosthetics aimed at restoring motor control over one's own paralyzed limb. PMID- 30002453 TI - Ectopic expression of a Brassica rapa AINTEGUMENTA gene (BrANT-1) increases organ size and stomatal density in Arabidopsis. AB - The AINTEGUMENTA-like (AIL) family plays a central role in regulating the growth and development of organs in many plants. However, little is known about the characteristics and functions of the AIL family in Chinese cabbage (Brassica rapa L. ssp. pekinensis). In this study, a genome-wide analysis was performed to identify the members of the AIL family in Chinese cabbage. We identified three ANT genes and six ANT-like genes of Chinese cabbage, most of which were differentially expressed in different organs or tissues. Furthermore, compared with the wild-type line, the size of different organs in the 35S-BrANT-1 line was significantly increased by promoting cell proliferation. Meanwhile, over expression of BrANT-1 also increases the stomatal number and delays the leaf senescence. Transcriptome analyses revealed that a set of cell proliferation and stoma development genes were up-regulated, while the senescence-associated genes were down-regulated, suggesting these genes may be involved in BrANT-1 regulated processes for controlling organ size, stomatal density and leaf senescence. In summary, this study offers important insights into the characteristics and functions of the ANT genes in Chinese cabbage, and provides a promising strategy to improve yield or head size in Chinese cabbage breeding programs. PMID- 30002455 TI - Author Correction: Induction of micronuclei by four cytostatic compounds in human hematopoietic stem cells and human lymphoblastoid TK6 cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30002454 TI - Agulhas Current properties shape microbial community diversity and potential functionality. AB - Understanding the impact of oceanographic features on marine microbial ecosystems remains a major ecological endeavour. Here we assess microbial diversity, community structure and functional capacity along the Agulhas Current system and the Subtropical Front in the South Indian Ocean (SIO). Samples collected from the epipelagic, oxygen minimum and bathypelagic zones were analysed by 16S rRNA gene amplicon and metagenomic sequencing. In contrast to previous studies, we found high taxonomic richness in surface and deep water samples, but generally low richness for OMZ communities. Beta-diversity analysis revealed significant dissimilarity between the three water depths. Most microbial communities were dominated by marine Gammaproteobacteria, with strikingly low levels of picocyanobacteria. Community composition was strongly influenced by specific environmental factors including depth, salinity, and the availability of both oxygen and light. Carbon, nitrogen and sulfur cycling capacity in the SIO was linked to several autotrophic and copiotrophic Alphaproteobacteria and Gammaproteobacteria. Taken together, our data suggest that the environmental conditions in the Agulhas Current system, particularly depth-related parameters, substantially influence microbial community structure. In addition, the capacity for biogeochemical cycling of nitrogen and sulfur is linked primarily to the dominant Gammaproteobacteria taxa, whereas ecologically rare taxa drive carbon cycling. PMID- 30002456 TI - 3D surface morphology imaging of opaque microstructures via light-field microscopy. AB - Observing dynamic micro-scale phenomena occurring at millisecond time scales, such as organism activity, micron particle flows, or any opaque object observation, requires volumetric microscopy techniques able to achieve high data acquisition rates while maintaining contrast so that measurement of fine micro scale features is possible. In realizing this purpose, the light-field (LF) technique has already been used on three-dimensional (3D) scene capturing and even for microscopic visualizations. In studying the ability and feasibility of 3D surface morphology reconstruction via LF microscopy, we adopted a lab-made LF microscope and integrated a four-dimensional Fourier slice algorithm and a Markov random field propagation algorithm. Furthermore, for numerical comparison and quantized analysis, the Tenengrad function was utilized to calculate the average contrast of the region of interest. Reflective US Air Force targets and 3D photolithography-made micro-scaffolds coated with 50 nm nickel thin films were adopted for system alignment and calibration. The experimental results demonstrate that the developed LF microscope with the signal processing algorithms can observe the 3D surface morphology of opaque microstructures with one snapshot, and has been preliminary applied to Brownian motion observation with 30 Hz volumetric image rate. PMID- 30002458 TI - Microbiota alters behaviour. PMID- 30002459 TI - New role for indoleamine 2,3-dioxygenase. PMID- 30002457 TI - Predicting global tuna vulnerabilities with spatial, economic, biological and climatic considerations. AB - Overfishing impacts the three pillars of sustainability: social, ecological and economic. Tuna represent a significant part of the global seafood market with an annual value exceeding USD$42B and are vulnerable to overfishing. Our understanding of how social and economic drivers contribute to overexploitation is not well developed. We address this problem by integrating social, ecological and economic indicators to help predict changes in exploitation status, namely fishing mortality relative to the level that would support the maximum sustainable yield (F/FMSY). To do this we examined F/FMSY for 23 stocks exploited by more than 80 states across the world's oceans. Low-HDI countries were most at risk of overexploitation of the tuna stocks we examined and increases in economic and social development were not always associated with improved stock status. In the short-term frozen price was a dominant predictor of F/FMSY providing a positive link between the market dynamics and the quantity of fish landed. Given the dependence on seafood in low-income regions, improved measures to safeguard against fisheries overexploitation in the face of global change and uncertainty are needed. PMID- 30002460 TI - Functional brain networks reveal the existence of cognitive reserve and the interplay between network topology and dynamics. AB - We investigated how the organization of functional brain networks was related to cognitive reserve (CR) during a memory task in healthy aging. We obtained the magnetoencephalographic functional networks of 20 elders with a high or low CR level to analyse the differences at network features. We reported a negative correlation between synchronization of the whole network and CR, and observed differences both at the node and at the network level in: the average shortest path and the network outreach. Individuals with high CR required functional networks with lower links to successfully carry out the memory task. These results may indicate that those individuals with low CR level exhibited a dual pattern of compensation and network impairment, since their functioning was more energetically costly to perform the task as the high CR group. Additionally, we evaluated how the dynamical properties of the different brain regions were correlated to the network parameters obtaining that entropy was positively correlated with the strength and clustering coefficient, while complexity behaved conversely. Consequently, highly connected nodes of the functional networks showed a more stochastic and less complex signal. We consider that network approach may be a relevant tool to better understand brain functioning in aging. PMID- 30002461 TI - Relationship between Systemic Vascular Characteristics and Retinal Nerve Fiber Layer Loss in Patients with Type 2 Diabetes. AB - Retinal nerve fiber layer (RNFL) loss in diabetic patients is especially common regardless of diabetic retinopathy (DR). The correlations between nonglaucomatous RNFL loss and systemic characteristics in diabetic patients have aroused interests in many aspects. 167 subjects with type 2 diabetes who underwent evaluation for arterial stiffness and cardiovascular autonomic function using heart rate variability (HRV) were included in this study. Arterial stiffness was measured using cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI). Multivariate regression analysis was performed to determine factors influencing the presence of RNFL loss according to age. Factors determining the superior location of diabetic RNFL loss were also investigated. CAVI were worse in patients with RNFL loss, especially in those with old age (>=50 yrs) (p = 0.037). Influential factor of RNFL defect in old group was ABI (p = 0.007). However, in young group (<50 yrs), HRV parameter (low-frequency/high-frequency ratio) determined the presence of RNFL loss (p = 0.040). Significant determinants of superior RNFL defect in old subjects were CAVI and ABI (p = 0.032 and p = 0.024). For young diabetic patients, autonomic dysfunction may have relationship with RNFL loss, but as patients get older, arterial stiffness could aggravate vascular autoregulation and diabetic RNFL loss. RNFL loss in diabetes may be correlated with systemic vascular conditions. PMID- 30002463 TI - Jaw-dropping new surgical approach. PMID- 30002462 TI - Physical Activity as a Determinant of Successful Aging over Ten Years. AB - We aimed to examine the temporal association between physical activity and successful aging. The analyses involved 1,584 adults aged 49 + years living west of Sydney (Australia), who did not have cancer, coronary artery disease and stroke at baseline and who were followed over 10 years. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week. Successful aging status was determined through interviewer-administered questionnaire and was classified as the absence of: depressive symptoms, disability, cognitive impairment, respiratory symptoms and systemic conditions (e.g. cancer, coronary artery disease). 249 (15.7%) participants (mean age 59.9 +/- 6.1) had aged successfully 10 years later. After multivariable adjustment; older adults in the highest level of total physical activity (>=5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (<1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging, odds ratio, OR, 2.08 (95% confidence intervals, CI, 1.12-3.88). Older adults who engaged in high levels of total physical activity, well above the current recommended minimum level had a greater likelihood of aging successfully 10 years later. PMID- 30002464 TI - Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis. AB - The trafficking of leukocytes from their site of production in the bone marrow through the circulation and into peripheral tissues is a highly coordinated and tightly regulated process in healthy individuals. Lymphocytes are long-lived cells that visit many lymphoid and peripheral tissues over their lifetime and can even recirculate back to the bone marrow, whereas granulocytes and monocytes are not thought to recirculate so widely. Using rheumatoid arthritis (RA) as an example, this Review explores the migratory journey of leukocytes during the establishment and resolution of disease - from the blood, through the lymphoid tissues and into peripheral sites such as the lungs and the gut before their entry into the synovium. This Review explores our current understanding of differences in the molecular processes that regulate leukocyte trafficking at different phases of disease and in different stromal compartments, which could help to explain the disease heterogeneity seen in patients with RA. Expanding our knowledge of these processes will open new avenues in the clinical management of RA, paving the way for personalized medicine that is founded on the pathological molecular signature of each patient, which varies according to their phase of disease or disease subtype. PMID- 30002466 TI - Current Management of Hepatic Encephalopathy. AB - Hepatic encephalopathy is a state of brain dysfunction resulting from decompensation of cirrhosis. The mortality and morbidity associated with the overt form of hepatic encephalopathy are high, and even the covert form associates with poor outcomes and poor quality of life. We know that the dysfunction is not just an acute insult to the brain but rather results in long standing cognitive issues that get worse with each episode of HE. Hence, there is an urgency to accurately diagnose these conditions, start appropriate therapy, and to maintain remission. Currently, we have two mainstay pharmacological treatment options (lactulose and rifaximin), but the narrative is evolving with new therapies under trial. Microbiome manipulation resulting in a favorable change to the gut microbiota seems to be a promising new area of therapy. PMID- 30002465 TI - Author Correction: Multidisciplinary study of the secondary immune response in grandparents re-exposed to chickenpox. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30002467 TI - Current Concept of Autoimmune Pancreatitis and IgG4-related Disease. PMID- 30002469 TI - Anisotropic transverse magnetoresistance and Fermi surface in TaSb2. AB - TaSb2 has been predicted theoretically to be a weak topological insulator. Whereas, the earlier magnetotransport experiment has established it as a topological semimetal. In the previous works, the Shubnikov-de Haas oscillation has been analyzed to probe the Fermi surface, with magnetic field along a particular crystallographic axis only. By employing a sample rotator, we reveal highly anisotropic transverse magnetoresistance by rotating the magnetic field along different crystallographic directions. To probe the anisotropy in the Fermi surface, we have performed magnetization measurements and detected strong de Haas van Alphen (dHvA) oscillations for the magnetic field applied along a and b axes as well as perpendicular to ab plane of the crystals. Three Fermi pockets have been identified by analyzing the dHvA oscillations. With the application of magnetic field along different crystal directions, the cross-sectional areas of the Fermi pockets have been found significantly different, i.e., the Fermi pockets are highly anisotropic in nature. Three-band fitting of electrical and Hall conductivity reveals two high mobility electron pockets and one low mobility hole pocket. The angular variation of transverse magnetoresistance has been qualitatively explained using the results of dHvA oscillations and three-band analysis. PMID- 30002470 TI - Science under siege: behind the scenes at Trump's troubled environment agency. PMID- 30002471 TI - Multi-level magma plumbing at Agung and Batur volcanoes increases risk of hazardous eruptions. AB - The island of Bali in Indonesia is home to two active stratovolcanoes, Agung and Batur, but relatively little is known of their underlying magma plumbing systems. Here we define magma storage depths and isotopic evolution of the 1963 and 1974 eruptions using mineral-melt equilibrium thermobarometry and oxygen and helium isotopes in mineral separates. Olivine crystallised from a primitive magma and has average delta18O values of 4.80/00. Clinopyroxene records magma storage at the crust-mantle boundary, and displays mantle-like isotope values for Helium (8.62 RA) and delta18O (5.0-5.80/00). Plagioclase reveals crystallisation in upper crustal storage reservoirs and shows delta18O values of 5.5-6.40/00. Our new thermobarometry and isotope data thus corroborate earlier seismic and InSAR studies that inferred upper crustal magma storage in the region. This type of multi-level plumbing architecture could drive replenishing magma to rapid volatile saturation, thus increasing the likelihood of explosive eruptions and the consequent hazard potential for the population of Bali. PMID- 30002468 TI - Relation of Prenatal Air Pollutant and Nutritional Exposures with Biomarkers of Allergic Disease in Adolescence. AB - Prenatal exposures may be critical for immune system development, with consequences for allergic disease susceptibility. We examined associations of prenatal exposures (nutrient intakes and air pollutants) with allergic disease biomarkers in adolescence. We used data from 857 mother-child pairs in Project Viva, a Massachusetts-based pre-birth cohort. Outcomes of interest at follow-up (median age 12.9 years) were fractional exhaled nitric oxide (FeNO) and total serum IgE. We applied Bayesian Kernel Machine Regression analyses to estimate multivariate exposure-response functions, allowing for exposure interactions. Exposures were expressed as z-scores of log-transformed data and we report effects in % change in FeNO or IgE z-score per increase in exposure from the 25th to 75th percentile. FeNO levels were lower with higher intakes of prenatal vitamin D (-16.15%, 95% CI: -20.38 to -2.88%), folate from foods (-3.86%, 95% CI: -8.33 to 0.83%) and n-3 PUFAs (-9.21%, 95% CI -16.81 to -0.92%). Prenatal air pollutants were associated with higher FeNO and IgE, with the strongest associations detected for PM2.5 with IgE (25.6% increase, 95% CI 9.34% to 44.29%). We identified a potential synergistic interaction (p = 0.02) between vitamin E (food + supplements) and PM2.5; this exposure combination was associated with further increases in FeNO levels. PMID- 30002472 TI - Blocking of BDNF-TrkB signaling inhibits the promotion effect of neurological function recovery after treadmill training in rats with spinal cord injury. AB - STUDY DESIGN: Experimental study. OBJECTIVES: To investigate the role of BDNF TrkB signaling that promotes the recovery of neurological function in rats with incomplete spinal cord injury (SCI) after treadmill training (TT). SETTING: Rehabilitation Medicine Center of the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. METHODS: Forty rats were divided into five groups: (i) Sham; (ii) SCI and phosphate-buffered saline (PBS) (SCI/PBS); (iii) SCI-TT/PBS; (iv) SCI/TrkB-IgG; and (v) SCI-TT/TrkB-IgG. The intrathecal catheter and T10 contusion SCI model was established. At 7-day post SCI, the BDNF-TrkB signaling was blocked by TrkB-IgG. Exercise began at 8th day after SCI and continued for 4 weeks. The BBB scale and motor-evoked potential (MEP) were used for the evaluation of the locomotor functions. The BDNF/TrkB, PSD-95, SYP synthesis, and neuroprotective effect was determined by western blot, Nissl, or immunohistochemistry staining. RESULTS: The expression of BDNF and TrkB in the SCI-TT/PBS group was 1.46 +/- 0.09 and 1.70 +/- 0.22, respectively, higher than that in SCI/PBS group (0.51 +/- 0.04 and 0.76 +/- 0.07, respectively), relative to the Sham group. The BBB scores in the Sham, SCI/PBS, SCI-TT/PBS, SCI/TrkB-IgG, and SCI-TT/TrkB-IgG groups were 21.00 +/- 0.00, 7.63 +/- 0.74, 12.13 +/- 1.36, 7.88 +/- 0.64, and 8.75 +/- 0.88, respectively. The percentages of MEP responders/non-responders were 100, 0, 75, 0, and 50%. The MEP latencies in Sham, SCI-TT/PBS, and SCI-TT/TrkB-IgG groups were 6.65 +/- 0.19, 13.32 +/- 2.95, and 19.55 +/- 4.55 ms, respectively. The number of NeuN+ neurons, the cell body area of motor neurons, PSD-95, and SYP expression in the SCI-TT/PBS group was significantly higher than that in the SCI/PBS, SCI/TrkB-IgG, and SCI-TT/TrkB-IgG groups. CONCLUSION: The BDNF-TrkB signaling is a critical pathway in exercise training that promotes the recovery of neurological function in rats with incomplete SCI. PMID- 30002473 TI - High speed error correction for continuous-variable quantum key distribution with multi-edge type LDPC code. AB - Error correction is a significant step in postprocessing of continuous-variable quantum key distribution system, which is used to make two distant legitimate parties share identical corrected keys. We propose an experiment demonstration of high speed error correction with multi-edge type low-density parity check (MET LDPC) codes based on graphic processing unit (GPU). GPU supports to calculate the messages of MET-LDPC codes simultaneously and decode multiple codewords in parallel. We optimize the memory structure of parity check matrix and the belief propagation decoding algorithm to reduce computational complexity. Our results show that GPU-based decoding algorithm greatly improves the error correction speed. For the three typical code rate, i.e., 0.1, 0.05 and 0.02, when the block length is 106 and the iteration number are 100, 150 and 200, the average error correction speed can be respectively achieved to 30.39 Mbits/s (over three times faster than previous demonstrations), 21.23 Mbits/s and 16.41 Mbits/s with 64 codewords decoding in parallel, which supports high-speed real-time continuous variable quantum key distribution system. PMID- 30002475 TI - Transient localized surface plasmon induced by femtosecond interband excitation in gold nanoparticles. AB - Localized surface plasmon resonance (LSPR) is essentially a collective oscillation of free electrons in nanostructured metals. Interband excitation may also produce conduction-band electrons above the Fermi level. However, a question here is whether these excited electrons can take part in plasmonic oscillation. To answer this question, femtosecond pump-probe measurements on gold nanoparticles were performed using interband excitation, where the pump pulse produced a large amount of electrons in the sp-conduction band and left holes in the d-band. Probing by transient absorption spectroscopy, we resolved an induced LSPR feature located at a red-shifted spectrum. This feature cannot be observed for a pumping photon energy lower than the threshold for interband transition. The commonly observed red-shift or broadening of LSPR spectrum due to electron electron and electron-phonon scattering under strong optical excitation can be ruled out for understanding this feature by a comparison between the plasmonic dynamics at a pump above and below the interband-transition threshold. In particular, a "holding" time of about 1 ps was resolved for the interband excitation-induced electrons to relax to the LSPR oscillation. PMID- 30002476 TI - Inherited pancreatic cancer risk. PMID- 30002474 TI - Microalgal Microscale Model for Microalgal Growth Inhibition Evaluation of Marine Natural Products. AB - Marine organisms especially sessile invertebrates, such as soft corals, gorgonians and sponges, can survive in the competitive environment mainly relying on their second metabolites with chemoecological effects including allelopathy and algal growth inhibition. It is well known that the microscale models are urgently needed in marine chemoecology assessment to evaluate the algal growth inhibition activity of trace quantity natural products. In this work, a microalgal growth inhibition model was established for microalgal inhibition evaluation of marine natural products with 96-well microplate by automatic fluorescence observation using microplate reader. Subsequently, this model was applied to bioassay-guided isolation and preliminary bioactivity screening of the secondary metabolites from soft corals, gorgonians, sponges and their symbiotic microbes collected from the South China Sea. As a result, fifteen compounds (1 15) were found to exhibit microalgal growth inhibition activities against at least one of marine microalgae, Karenia mikimotoi, Isochrysis galbana, and Heterosigma akashiwo. Specifically, altersolanol C (13) demonstrated potent activity against K. mikimotoi with the 96h-EC50 value of 1.16 ug/mL, more than four times stronger than that of the positive control K2Cr2O7. It was suggested that the microalgal growth inhibition microscale model is suitable for bioassay guided isolation and preliminary bioactivity screening of marine natural products. PMID- 30002477 TI - Differences between microhabitat and broad-scale patterns of niche evolution in terrestrial salamanders. AB - The extent to which closely related species share similar niches remains highly debated. Ecological niches are increasingly analysed by combining distribution records with broad-scale climatic variables, but interactions between species and their environment often occur at fine scales. The idea that macroscale analyses correctly represent fine-scale processes relies on the assumption that average climatic variables are meaningful predictors of processes determining species persistence, but tests of this hypothesis are scarce. We compared broad- and fine scale (microhabitat) approaches by analyzing the niches of European plethodontid salamanders. Both the microhabitat and the macroecological approaches identified niche differences among species, but the correspondence between micro- and macroecological niches was weak. When exploring niche evolution, the macroecological approach suggested a close relationship between niche and phylogenetic history, but this relationship did not emerge in fine-scale analyses. The apparent pattern of niche evolution emerging in broad-scale analyses likely was the by-product of related species having closely adjacent ranges. The environment actually experienced by most of animals is more heterogeneous than what is apparent from macro-scale predictors, and a better combination between macroecological and fine-grained data may be a key to obtain robust ecological generalizations. PMID- 30002479 TI - Every step of the way: integrins in cancer progression and metastasis. AB - Cell adhesion to the extracellular matrix is fundamental to tissue integrity and human health. Integrins are the main cellular adhesion receptors that through multifaceted roles as signalling molecules, mechanotransducers and key components of the cell migration machinery are implicated in nearly every step of cancer progression from primary tumour development to metastasis. Altered integrin expression is frequently detected in tumours, where integrins have roles in supporting oncogenic growth factor receptor (GFR) signalling and GFR-dependent cancer cell migration and invasion. In addition, integrins determine colonization of metastatic sites and facilitate anchorage-independent survival of circulating tumour cells. Investigations describing integrin engagement with a growing number of versatile cell surface molecules, including channels, receptors and secreted proteins, continue to lead to the identification of novel tumour-promoting pathways. Integrin-mediated sensing, stiffening and remodelling of the tumour stroma are key steps in cancer progression supporting invasion, acquisition of cancer stem cell characteristics and drug resistance. Given the complexity of integrins and their adaptable and sometimes antagonistic roles in cancer cells and the tumour microenvironment, therapeutic targeting of these receptors has been a challenge. However, novel approaches to target integrins and antagonism of specific integrin subunits in stringently stratified patient cohorts are emerging as potential ways forward. PMID- 30002478 TI - A protonic biotransducer controlling mitochondrial ATP synthesis. AB - In nature, protons (H+) play an important role in biological activities such as in mitochondrial ATP synthesis, which is driven by a H+ gradient across the inner membrane, or in the activation of acid sensing ion channels in neuron cells. Bioprotonic devices directly interface with the H+ concentration (pH) to facilitate engineered interactions with these biochemical processes. Here we develop a H+ biotransducer that changes the pH in a mitochondrial matrix by controlling the flow of H+ between a conductive polymer of sulfonated polyaniline and solution. We have successfully modulated the rate of ATP synthesis in mitochondria by altering the solution pH. Our H+ biotransducer provides a new way to monitor and modulate pH dependent biological functions at the interface between the electronic devices and biological materials. PMID- 30002480 TI - Calibrating the Extended Huckel Method to Quantitatively Screen the Electronic Properties of Materials. AB - The extended Huckel (eH) tight-binding method has historically been prized for its computational ease and intuitive chemical clarity. However, its lack of quantitative predictiveness has prevented the eH method from being used as a tool for rapidly screening materials for desired electronic properties. In this work, we demonstrate that when eH input parameters are calibrated using density functional theory (DFT) calculations of carefully chosen sets of simple crystals, the eH parameters retain most of their quantitative accuracy when transferred to more complex, structurally related phases. Using solar-energy-relevant semiconductors and insulators in the Sr-Ti-O family as a case study, we show that calibrated eH parameters can match the features of DFT band structures within about two tenths of an eV, at a tiny fraction of the computational cost of DFT. PMID- 30002481 TI - Dual-therapy stent shows promise. PMID- 30002482 TI - Socially-mediated arousal and contagion within domestic chick broods. AB - Emotional contagion - an underpinning valenced feature of empathy - is made up of simpler, potentially dissociable social processes which can include socially mediated arousal and behavioural/physiological contagion. Previous studies of emotional contagion have often conflated these processes rather than examining their independent contribution to empathic response. We measured socially mediated arousal and contagion in 9-week old domestic chicks (n = 19 broods), who were unrelated but raised together from hatching. Pairs of observer chicks were exposed to two conditions in a counterbalanced order: air puff to conspecifics (AP) (during which an air puff was applied to three conspecifics at 30 s intervals) and control with noise of air puff (C) (during which the air puff was directed away from the apparatus at 30 s intervals). Behaviour and surface eye temperature of subjects and observers were measured throughout a 10-min pre treatment and 10-min treatment period. Subjects and observers responded to AP with increased freezing, and reduced preening and ground pecking. Subjects and observers also showed reduced surface eye temperature - indicative of stress induced hyperthermia. Subject-Observer behaviour was highly correlated within broods during both C and AP conditions, but with higher overall synchrony during AP. We demonstrate the co-occurrence of socially-mediated behavioural and physiological arousal and contagion; component features of emotional contagion. PMID- 30002483 TI - Low-density lipoprotein (LDL)-dependent uptake of Gram-positive lipoteichoic acid and Gram-negative lipopolysaccharide occurs through LDL receptor. AB - Lipoteichoic acid (LTA) and lipopolysaccharide (LPS) are bacterial lipids that stimulate pro-inflammatory cytokine production, thereby exacerbating sepsis pathophysiology. Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates uptake of cholesterol by downregulating hepatic lipoprotein receptors, including low-density lipoprotein (LDL) receptor (LDLR) and possibly LDLR-related protein-1 (LRP1). PCSK9 also negatively regulates Gram-negative LPS uptake by hepatocytes, however this mechanism is not completely characterized and mechanisms of Gram-positive LTA uptake are unknown. Therefore, our objective was to elucidate the mechanisms through which PCSK9 regulates uptake of LTA and LPS by investigating the roles of lipoproteins and lipoprotein receptors. Here we show that plasma PCSK9 concentrations increase transiently over time in septic and non-septic critically ill patients, with highly similar profiles over 14 days. Using flow cytometry, we demonstrate that PCSK9 negatively regulates LDLR mediated uptake of LTA and LPS by HepG2 hepatocytes through an LDL-dependent mechanism, whereas LRP1 and high-density lipoprotein do not contribute to this uptake pathway. Bacterial lipid uptake by hepatocytes was not associated with cytokine production or hepatocellular injury. In conclusion, our study characterizes an LDL-dependent and LDLR-mediated bacterial lipid uptake pathway regulated by PCSK9, and provides evidence in support of PCSK9 inhibition as a potential therapeutic strategy for sepsis. PMID- 30002484 TI - Intergenerational Sex-Specific Transmission of Maternal Social Experience. AB - The social environment is a major determinant of individual stress response and lifetime health. The present study shows that (1) social enrichment has a significant impact on neuroplasticity and behaviour particularly in females; and (2) social enrichment in females can be transmitted to their unexposed female descendants. Two generations (F0 and F1) of male and female rats raised in standard and social housing conditions were examined for neurohormonal and molecular alterations along with changes in four behavioural modalities. In addition to higher cortical neuronal density and cortical thickness, social experience in mothers reduced hypothalamic-pituitary-adrenal (HPA) axis activity in F0 rats and their F1 non-social housing offspring. Only F0 social mothers and their F1 non-social daughters displayed improved novelty-seeking exploratory behaviour and reduced anxiety-related behaviour whereas their motor and cognitive performance remained unchanged. Also, cortical and mRNA measurements in the F1 generation were affected by social experience intergenerationally via the female lineage (mother-to-daughter). These findings indicate that social experience promotes cortical neuroplasticity, neurohormonal and behavioural outcomes, and these changes can be transmitted to the F1 non-social offspring in a sexually dimorphic manner. Thus, a socially stimulating environment may form new biobehavioural phenotypes not only in exposed individuals, but also in their intergenerationally programmed descendants. PMID- 30002485 TI - Clinical outcomes in Caucasian patients with polypoidal choroidal vasculopathy. AB - PURPOSE: To describe treatment outcomes in a cohort of Caucasian patients with polypoidal choroidal vasculopathy (PCV). METHODS: Clinical charts from 48 eyes of 45 Caucasian patients with PCV were retrospectively reviewed. All cases were diagnosed with indocyanine green angiography. Best corrected visual acuity (BCVA) and optical coherence tomography (OCT) imaging were analyzed at baseline and final follow-up. RESULTS: Eyes were treated with a combination of verteporfin photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) (n = 24), or PDT monotherapy (n = 9), or anti-VEGF monotherapy (n = 8), or no treatment (n = 7). Aflibercept was the anti-VEGF agent in 30 out of 32 eyes. Sixteen out of 24 eyes in the combination treatment group received initial PDT at diagnosis. All treatments led to stabilization of BCVA at final visit with a trend for better visual acuity in the anti-VEGF monotherapy group. There was a substantial reduction in central retinal thickness associated with resolution of subfoveal fluid and improvement in retinal pigment epithelial detachment in all treatment groups. BCVA and OCT findings remained stable in eyes which received no treatment. The use of PDT was associated with 0.5 fewer intravitreal injections per annum, which was not statistically significant. CONCLUSIONS: In the largest series of Caucasian patients with PCV presented to date, anti-VEGF monotherapy, PDT, or their combination preserved visual acuity and improved subfoveal exudative changes. Combination treatment was not superior to anti-VEGF monotherapy. PMID- 30002486 TI - Incidence, causes and risk factors for 30-day readmission after radical gastrectomy for gastric cancer: a retrospective study of 2,023 patients. AB - The aim of this retrospective study was to investigate the incidence of, causes and risk factors for readmission to hospital <=30 days after discharge of patients who underwent radical gastrectomy for gastric cancer. A total of 2,023 patients underwent radical gastrectomy operations from November 2010 to July 2017 in our hospital. Of these, 60 patients (3.0%) were readmitted within 30 days after their original discharge. The median time span between the index discharge and readmission was 14 days and the median time for readmission was 8 days. The main reasons for readmission were intestinal obstruction (n = 10, 16.7%), intra abdominal fluid collection (n = 9, 15.0%), abdominal pain (n = 7, 11.7%), nutritional difficulty (n = 4, 6.7%) and anastomotic leakage (n = 4, 6.7%). Five patients (8.3%) required intensive care and 4 patients (6.7%) died from sudden cardiac arrest, gastrointestinal bleeding, sepsis or multiple organ dysfunctions. Multivariate analysis revealed that post-operative complications (Odds Ratio = 5.116, 95% confidence interval: 2.885-9.073, P < 0.001) was the only independent risk factor for readmission. Thus, appropriate strategies on discharge and close follow-ups for these high-risk patients should be drawn up in order to enhance significantly their quality of care. PMID- 30002488 TI - Wnt signaling pathways in myocardial infarction and the therapeutic effects of Wnt pathway inhibitors. AB - Myocardial infarction (MI) is one of the most serious health threats, resulting in huge physical and economic burdens worldwide. Wnt signaling pathways play an important role in developmental processes such as tissue patterning, cell differentiation and cell division. Appropriate regulation of the activities of Wnt signaling pathways is also important for heart development and healing in post-MI heart. Moreover, Wnt pathway inhibitors have been identified as novel antitumor drugs and applied in ongoing clinical trials. This research progress has generated increasing interests for investigating the effects of Wnt pathway inhibitors on MI healing. In this short review, we summarize the roles of Wnt signaling pathways in post-MI heart and the therapeutic effects of Wnt pathway inhibitors on MI, and discuss the underlying mechanisms of Wnt pathway inhibitors in cardiac repairing. PMID- 30002489 TI - Integrating endocannabinoid signaling in the regulation of anxiety and depression. AB - Brain endogenous cannabinoid (eCB) signaling seems to harmonize appropriate behavioral responses, which are essential for the organism's long-term viability and homeostasis. Dysregulation of eCB signaling contributes to negative emotional states and increased stress responses. An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression. This review focuses on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefits in neuropsychiatric disease and on the future research direction of neural circuit modulation. PMID- 30002490 TI - Sevoflurane postconditioning protects against myocardial ischemia/reperfusion injury by restoring autophagic flux via an NO-dependent mechanism. AB - Volatile anesthetics improve postischemic cardiac function and reduce infarction even when administered for only a brief time at the onset of reperfusion. A recent study showed that sevoflurane postconditioning (SPC) attenuated myocardial reperfusion injury, but the underlying mechanisms remain unclear. In this study, we examined the effects of sevoflurane on nitric oxide (NO) release and autophagic flux during the myocardial ischemia/reperfusion (I/R) injury in rats in vivo and ex vivo. Male rats were subjected to 30 min ischemia and 2 h reperfusion in the presence or absence of sevoflurane (1.0 minimum alveolar concentration) during the first 15 min of reperfusion. We found that SPC significantly improved hemodynamic performance after reperfusion, alleviated postischemic myocardial infarction, reduced nicotinamide adenine dinucleotide content loss, and cytochrome c release in heart tissues. Furthermore, SPC significantly increased the phosphorylation of endothelial nitric oxide synthase (NOS) and neuronal nitric oxide synthase, and elevated myocardial NOS activity and NO production. All these effects were abolished by treatment with an NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v.). We also observed myocardial I/R-induced accumulation of autophagosomes in heart tissues, as evidenced by increased ratios of microtubule-associated protein 1 light chain 3 II/I, up-regulation of Beclin 1 and P62, and reduced lysosome-associated membrane protein-2 expression. SPC significantly attenuated I/R-impaired autophagic flux, which were blocked by L-NAME. Moreover, pretreatment with the autophagic flux blocker chloroquine (10 mg/kg, i.p.) increased autophagosome accumulation in SPC-treated heart following I/R and blocked SPC-induced cardioprotection. The same results were also observed in a rat model of myocardial I/R injury ex vivo, suggesting that SPC protects rat hearts against myocardial reperfusion injury by restoring I/R-impaired autophagic flux via an NO dependent mechanism. PMID- 30002487 TI - Exposure to Polycyclic Aromatic Hydrocarbons Leads to Non-monotonic Modulation of DNA and RNA (hydroxy)methylation in a Rat Model. AB - Besides genetic modifications, rapidly growing evidence has linked environmental pollutants with epigenetic variations. To date, only a few studies have been performed on DNA methylation changes of polycyclic aromatic hydrocarbons (PAH), which showed contradictory results. These discrepancies might be partially explained by differences in used agents. Generally in in vitro studies, a single compound is used, while in humans environmental studies, multi-residue exposure is investigated. The present study aimed to study epigenetic alterations induced by multi-residue exposure to PAH. Female Long Evans rats were exposed to a mixture of 16 US-EPA priority PAH, 3 times per week over a 90-day period. The livers were used to assess the (hydroxy)methylation status of genomic DNA/RNA, together with reduced and oxidized forms of glutathione. The results of this study demonstrate that a multi-residue exposure to PAH affects glutathione status, DNA (hydroxy)methylation, and RNA (hydroxy)methylation, together with DNA PAH-adducts formation. In addition, a non-monotonic response relationship was demonstrated between PAH concentration, the levels of glutathione and DNA (hydroxy)methylation levels at environmental relevant doses. This hormetic response gives a novel insight concerning the toxicity of environmental pollutants such as PAH and the biological response that may be different depending on the level of exposure. PMID- 30002491 TI - Perivascular adipose tissue dysfunction aggravates adventitial remodeling in obese mini pigs via NLRP3 inflammasome/IL-1 signaling pathway. AB - Perivascular adipose tissue (PVAT), a special type of adipose tissue, closely surrounds vascular adventitia and produces numerous bioactive substances to maintain vascular homeostasis. PVAT dysfunction has a crucial role in regulating vascular remodeling, but the exact mechanisms remain unclear. In this study, we investigated whether and how obesity-induced PVAT dysfunction affected adventitia remodeling in early vascular injury stages. Mini pigs were fed a high sugar and fat diet for 6 months to induce metabolic syndrome and obesity. In the mini pigs, left carotid vascular injury was then generated using balloon dilation. Compared with normal mini pigs, obese mini pigs displayed significantly enhanced vascular injury-induced adventitial responses, evidenced by adventitia fibroblast (AF) proliferation and differentiation, and adventitia fibrosis, as well as exacerbated PVAT dysfunction characterized by increased accumulation of resident macrophages, particularly the M1 pro-inflammatory phenotype, increased expression of leptin and decreased expression of adiponectin, and production of pro inflammatory cytokines interleukin (IL)-1beta and IL-18. Primary AFs cultured in PVAT-conditioned medium from obese mini pigs also showed significantly increased proliferation and differentiation. We further revealed that activated nod-like receptor protein 3 (NLRP3) inflammasome and its downstream products, i.e., IL-1 family members such as IL-1beta and IL-18 were upregulated in the PVAT of obese mini pigs; PVAT dysfunction was also demonstrated in preadipocytes treated with palmitic acid. Finally, we showed that pretreatment with IL-1 receptor (IL-1R) antagonist or IL-1R knockdown blocked AF proliferation and differentiation in AFs cultured in PVAT-conditioned medium. These results demonstrate that obesity induced PVAT dysfunction aggravates adventitial remodeling after early vascular injury with elevated AF proliferation and differentiation via activating the NLRP3/IL-1 signaling pathway. PMID- 30002492 TI - Thymopentin-loaded phospholipid-based phase separation gel with long-lasting immunomodulatory effects: in vitro and in vivo studies. AB - Thymopentin (TP5) is an effective immunomodulatory agent for autoimmune disease that has been used clinically for decades. However, its application is greatly limited by its extremely short half-life in vivo, poor membrane permeability and extensive metabolism in gastrointestinal tract, resulting in repeated injection and poor patient compliance. In the present study, we developed a TP5-loaded, phospholipid-based phase separation gel (PPSG) to achieve sustained drug release profile and long-lasting therapeutic effects. We firstly demonstrated the physiochemical characteristics of PPSG before and after phase transition by examining the viscosity and morphology change caused by the phase transition. Moreover, the PPSG exerted a low cytotoxicity in L929 cells and HUVECs, suggesting the biocompatibility of PPSG. A month-long drug release profile of TP5 PPSG was observed both in vitro and in vivo, revealing its sustained and controlled drug release property. Most importantly, in cyclophosphamide-induced immunosuppressive rats, a single dose of TP5 PPSG (15 mg/kg, sc) injected could normalize their T-SOD levels and CD4+/CD8+ ratio; such an immunoregulatory effect was comparable to that produced by repeated injection of TP5 solution (0.6 mg/kg per day, sc) for 14 consecutive days. Thus, TP5 PPSG has a great potential for sustained delivery of TP5 in clinical use because of its simple manufacture process, good biocompatibility and long-lasting immunomodulatory efficacy, which could greatly improve patient compliance. PMID- 30002493 TI - CB1 receptor activation induces intracellular Ca2+ mobilization and 2 arachidonoylglycerol release in rodent spinal cord astrocytes. AB - Accumulating evidence supports the role of astrocytes in endocannabinoid mediated modulation of neural activity. It has been reported that some astrocytes express the cannabinoid type 1 receptor (CB1-R), the activation of which is leading to Ca2+ mobilization from internal stores and a consecutive release of glutamate. It has also been documented that astrocytes have the potential to produce the endocannabinoid 2-arachidonoylglycerol, one of the best known CB1-R agonist. However, no relationship between CB1-R activation and 2-arachidonoylglycerol production has ever been demonstrated. Here we show that rat spinal astrocytes co express CB1-Rs and the 2-arachidonoylglycerol synthesizing enzyme, diacylglycerol lipase-alpha in close vicinity to each other. We also demonstrate that activation of CB1-Rs induces a substantial elevation of intracellular Ca2+ concentration in astrocytes. Finally, we provide evidence that the evoked Ca2+ transients lead to the production of 2-arachidonoylglycerol in cultured astrocytes. The results provide evidence for a novel cannabinoid induced endocannabinoid release mechanism in astrocytes which broadens the bidirectional signaling repertoire between astrocytes and neurons. PMID- 30002495 TI - Allocation of forest biomass across broad precipitation gradients in China's forests. AB - Forests act as major sinks for atmospheric CO2. An understanding of the relationship between forest biomass allocation and precipitation gradients is needed to estimate the impacts of changes in precipitation on carbon stores. Biomass patterns depend on tree size or age, making it unclear whether biomass allocation is limited by tree age at regional scales. Using a dataset of ten typical forest types spanning a large age scale, we evaluated forest biomass allocation-precipitation correlations with the aim of testing whether biomass allocation patterns vary systematically in response to altered precipitation. With increasing mean annual precipitation, a significant quadratic increase occurred in <=30 yr and >60 yr groups in stem biomass, >60 yr group in branch biomass, and >60 yr groups in leaf biomass; and a significant cubic increase occurred in 30-60 yr and all age forest groups in stem biomass, <=30 yr, 30-60 yr and all age forest groups in branch biomass, <=30 yr and all age forest groups in leaf biomass, and in each group in root biomass, indicating that organ biomass is strongly limited by precipitation. Thus, forest biomass responds predictably to changes in mean annual precipitation. The results suggest that forest organ biomass-precipitation relationships hold across independent datasets that encompass a broad climatic range and forest age. PMID- 30002494 TI - Cerebrovascular Injury After Serial Exposure to Chronic Stress and Abstinence from Methamphetamine Self-Administration. AB - Cerebrovascular damage caused by either exposure to stress or the widely abused drug, methamphetamine (Meth) is known but stress and drug abuse frequently occur in tandem that may impact their individual cerebrovascular effects. This study examined their co-morbid cerebrovascular effects during abstinence from self administered Meth after the exposure to chronic unpredictable stress (CUS). Exposure to CUS prior to unrestricted Meth self-administration had no effect on Meth intake in rats; however, the pro-inflammatory mediator cyclooxygenase-2 (COX 2) and the breakdown of cell-matrix adhesion protein beta-dystroglycan in isolated cerebral cortical capillaries were increased after 3 days of abstinence and persisted for 7 days. These changes preceded decreases in occludin, a key structural protein component of the blood-brain barrier. The decrease in occludin was blocked by the COX-2 specific inhibitor nimesulide treatment during abstinence from Meth. The changes in COX-2, beta-dystroglycan, and occludin were only evident following the serial exposure to stress and Meth but not after either one alone. These results suggest that stress and voluntary Meth intake can synergize and disrupt cerebrovasculature in a time-dependent manner during abstinence from chronic stress and Meth. Furthermore, COX-2 inhibition may be a viable pharmacological intervention to block vascular changes after Meth exposure. PMID- 30002496 TI - Memory Beliefs Drive the Memory Bias on Value-based Decisions. AB - For many value-based decisions, people need to retrieve relevant information from their memory. In our previous work, we have shown that memory biases decisions in the sense that better-memorized choice options are preferred, even if these options are comparatively unattractive. However, the cognitive mechanisms that drive this memory bias remain unclear. In the current pre-registered study, we tested the hypothesis that the memory bias arises because people believe they remember better options more often than worse options. Specifically, we predicted a positive correlation between the memory bias on value-based decisions and the belief in value-dependent memory performance. This prediction was confirmed. Additional exploratory analyses revealed that memory performance was indeed higher for more attractive options, indicating that letting decisions be influenced by memory can be an adaptive strategy. However, the memory bias persisted after correcting for this effect, suggesting that it is not simply an artifact of unequal memory performance. Our results highlight a critical influence of beliefs on behavior and add to an emerging understanding of the role of memory in shaping value-based decisions. PMID- 30002498 TI - The energetic behaviour of the human foot across a range of running speeds. AB - The human foot contains passive elastic tissues that have spring-like qualities, storing and returning mechanical energy and other tissues that behave as dampers, dissipating energy. Additionally the intrinsic and extrinsic foot muscles have the capacity to act as dampers and motors, dissipating and generating mechanical energy. It remains unknown as to how the contribution of all passive and active tissues combine to produce the overall energetic function of the foot during running. Therefore, the aim of this study was to determine if the foot behaves globally as an active spring-damper during running. Fourteen participants ran on a force-instrumented treadmill at 2.2 ms-1, 3.3 ms-1 and 4.4 ms-1, while foot segment motion was collected simultaneously with kinetic measurements. A unified deformable segment model was applied to quantify the instantaneous power of the foot segment during ground contact and mechanical work was calculated by integrating the foot power data. At all running speeds, the foot absorbed energy from early stance through to mid-stance and subsequently returned/generated a proportion of this energy in late stance. The magnitude of negative work performed increased with running speed, while the magnitude of positive work remained relatively constant across all running speeds. The proportion of energy dissipated relative to that absorbed (foot dissipation-ratio) was always greater than zero and increased with running speed, suggesting that the foot behaves as a viscous spring-damper. PMID- 30002500 TI - Before progressing from "exomes" to "genomes"... don't forget splicing variants. PMID- 30002499 TI - Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants. AB - The majority of multi-exon genes undergo alternative splicing to produce different mRNA transcripts and this may occur in a tissue-specific manner. Assessment of mRNA transcripts isolated from blood samples may sometimes be unhelpful in determining the affect on function of putative splice-site variants affecting kidney-specific mRNA transcripts. Here we present data demonstrating the power of using human urine-derived renal epithelial cells (hUREC) as a source of kidney RNA. We report clinical and molecular genetic data from three affected cases from two families all with end-stage renal disease by 15 years of age. In both families, heterozygous variants which are predicted to effect function in NPHP3 were found on one allele, in combination with a synonymous SNV (c.2154C>T; p.Phe718=), 18 base pairs from the exon-intron boundary within exon 15 of NPHP3. The only mRNA transcript amplified from wild-type whole blood showed complete splicing out of exon 15. Urine samples obtained from control subjects and the father of family 2, who carried the synonymous SNV variant, were therefore used to culture hUREC and allowed us to obtain kidney-specific mRNA. Control kidney mRNA showed retention of exon 15, while the mRNA from the patient's father confirmed evidence of a heterozygous alternate splicing of exon 15 of NPHP3. Analysis of RNA derived from hUREC allows for a comparison of kidney-specific and whole-blood RNA transcripts and for assessment of the effect on function of putative splice variants leading to end-stage kidney disease. PMID- 30002497 TI - Myelin Measurement: Comparison Between Simultaneous Tissue Relaxometry, Magnetization Transfer Saturation Index, and T1w/T2w Ratio Methods. AB - Magnetization transfer (MT) imaging has been widely used for estimating myelin content in the brain. Recently, two other approaches, namely simultaneous tissue relaxometry of R1 and R2 relaxation rates and proton density (SyMRI) and the ratio of T1-weighted to T2-weighted images (T1w/T2w ratio), were also proposed as methods for measuring myelin. SyMRI and MT imaging have been reported to correlate well with actual myelin by histology. However, for T1w/T2w ratio, such evidence is limited. In 20 healthy adults, we examined the correlation between these three methods, using MT saturation index (MTsat) for MT imaging. After calibration, white matter (WM) to gray matter (GM) contrast was the highest for SyMRI among these three metrics. Even though SyMRI and MTsat showed strong correlation in the WM (r = 0.72), only weak correlation was found between T1w/T2w and SyMRI (r = 0.45) or MTsat (r = 0.38) (correlation coefficients significantly different from each other, with p values < 0.001). In subcortical and cortical GM, these measurements showed moderate to strong correlations to each other (r = 0.54 to 0.78). In conclusion, the high correlation between SyMRI and MTsat indicates that both methods are similarly suited to measure myelin in the WM, whereas T1w/T2w ratio may be less optimal. PMID- 30002501 TI - Magnetization reversal and interlayer exchange coupling in ferromagnetic metal/semiconductor Fe/GaMnAs hybrid bilayers. AB - We report a detailed study of magnetization reversal in Fe/GaMnAs bilayers carried out by magnetotransport measurements. Specifically, we have used planar Hall resistance (PHR), which is highly sensitive to the direction of magnetization, and is therefore ideally suited for tracking magnetization as it reorients between successive easy axes in the two magnetic layers during reversal. These reorientations take place separately in the two magnetic layers, resulting in a series of different magnetization alignments (parallel or orthogonal) during reversal, providing a series of stable PHR states. Our results indicate that the magnetic anisotropy of the structure is dominated by cubic symmetry of both layers, showing two in-plane easy axes, but with significantly different energy barriers between the easy orientations. Importantly, a careful analysis of the PHR results has also revealed the presence of strong ferromagnetic interlayer exchange coupling (IEC) between the two magnetic layers, indicating that although magnetization reorients separately in each layer, this process is not independent, since the behavior of one layer is influenced by its adjacent magnetic neighbor. The ability to design and realize multiple PHR states, as observed in this investigation, shows promise for engineering Fe/GaMnAs bilayer structures for multinary magnetic memory devices and related multinary logic elements. PMID- 30002502 TI - Effective Resistivity in Collisionless Magnetic Reconnection. AB - An effective resistivity relevant to collisionless magnetic reconnection (MR) in plasma is presented. It is based on the argument that pitch angle scattering of electrons in the small electron diffusion region around the X line can lead to an effective, resistivity in collisionless plasma. The effective resistivity so obtained is in the form of a power law of the local plasma and magnetic field parameters. Its validity is confirmed by direct collisionless particle-in-cell (PIC) simulation. The result agrees very well with the resistivity (obtained from available data) of a large number of environments susceptible to MR: from the intergalactic and interstellar to solar and terrestrial to laboratory fusion plasmas. The scaling law can readily be incorporated into existing collisional magnetohydrodynamic simulation codes to investigate collisionless MR, as well as serve as a guide to ab initio theoretical investigations of the collisionless MR process. PMID- 30002503 TI - Comprehensive analysis of competitive endogenous RNAs network associated with head and neck squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) can regulate gene expression directly or indirectly through interacting with microRNAs (miRNAs). However, the role of differentially expressed mRNAs, lncRNAs and miRNAs, and especially their related competitive endogenous RNAs (ceRNA) network in head and neck squamous cell carcinoma (HNSCC), is not fully comprehended. In this paper, the lncRNA, miRNA, and mRNA expression profiles of 546 HNSCC patients, including 502 tumor and 44 adjacent non-tumor tissues, from The Cancer Genome Atlas (TCGA) were analyzed. 82 miRNAs, 1197 mRNAs and 1041 lncRNAs were found to be differentially expressed in HNSCC samples (fold change >= 2; P < 0.01). Further bioinformatics analysis was performed to construct a lncRNA-miRNA-mRNA ceRNA network of HNSCC, which includes 8 miRNAs, 71 lncRNAs and 16 mRNAs. Through survival analysis based on the expression profiles of RNAs in the ceRNA network, we detected 1 mRNA, 1 miRNA and 13 lncRNA to have a significant impact on the overall survival of HNSCC patients (P < 0.05). Finally, some lncRNAs, which are more important for survival, were also predicted. Our research provides data to further understand the molecular mechanisms implicated in HNSCC. PMID- 30002505 TI - Multidrug efflux pumps: structure, function and regulation. AB - Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities. PMID- 30002504 TI - Stochastic processes govern invasion success in microbial communities when the invader is phylogenetically close to resident bacteria. AB - Despite recent efforts in identifying the determinants of invasion in microbial communities, experimental observations across different ecosystems are inconclusive. While relationships between resident community diversity and invasion success are often noted, community diversity says little about community assembly processes. Community assembly processes may provide a more inclusive framework to explain-and potentially prevent or facilitate-invasion. Here we let replicate nitrite-oxidizing bacterial guilds assemble under different conditions from a natural source community and study their compositional patterns to infer the relative importance of the assembly processes. Then, an invader strain from that same guild was introduced at one of three propagule pressures. We found no significant correlation between community diversity and invasion success. Instead, we observed that the effect of selection on invasion success was surpassed by the effect of drift, as inferred from the substantial influence of propagule pressure on invasion success. This dominance of drift can probably be generalized to other invasion cases with high phylogenetic similarity between invader and resident community members. In these situations, our results suggest that attempting to modulate the invasibility of a community by altering its diversity is futile because stochastic processes determine the invasion outcome. Increasing or reducing propagule pressure is then deemed the most efficient avenue to enhance or limit invasion success. PMID- 30002506 TI - Avoiding hot-spots in Microwave-assisted Pd/C catalysed reactions by using the biomass derived solvent gamma-Valerolactone. AB - Herein, we report the use of gamma-valerolactone as a new biomass-derived reaction medium for microwave assisted organic synthesis. The interaction of this solvent with microwaves and its heating profile under microwave irradiation has been fully characterized for the first time, demonstrating its stability and the applicability in microwave assisted Pd/C catalysed reactions avoiding the arcing phenomena frequently observed in these conditions. The use of gamma-valerolactone demonstrated to be compatible with aliphatic and aromatic amines in the hydrogen transfer Pd/C mediated synthesis of benzimidazoles. PMID- 30002507 TI - Outburst floods provide erodability estimates consistent with long-term landscape evolution. AB - Most current models for the landscape evolution over geological timescales are based on semi-empirical laws that consider riverbed incision proportional to rock erodability (dependent on lithology) and to the work performed by water flow (stream power). However, the erodability values obtained from these models are entangled with poorly known conditions of past climate and streamflow. Here we use the erosion reported for 82 outburst floods triggered by overtopping lakes as a way to estimate the outlet erodability. This avoids the common assumptions regarding past hydrology because water discharge from overtopping floods is often well constrained from geomorphological evidence along the spillway. This novel methodology yields values of erodability that show a quantitative relation to lithology similar to previous river erosion analyses, expanding the range of hydrological and temporal scales of fluvial incision models and suggesting some consistency between the mathematical formulations of long-term and catastrophic erosional mechanisms. Our results also clarify conditions leading to the runaway erosion responsible for outburst floods triggered by overtopping lakes. PMID- 30002509 TI - On the nature and use of models in network neuroscience. AB - Network theory provides an intuitively appealing framework for studying relationships among interconnected brain mechanisms and their relevance to behaviour. As the space of its applications grows, so does the diversity of meanings of the term network model. This diversity can cause confusion, complicate efforts to assess model validity and efficacy, and hamper interdisciplinary collaboration. In this Review, we examine the field of network neuroscience, focusing on organizing principles that can help overcome these challenges. First, we describe the fundamental goals in constructing network models. Second, we review the most common forms of network models, which can be described parsimoniously along the following three primary dimensions: from data representations to first-principles theory; from biophysical realism to functional phenomenology; and from elementary descriptions to coarse-grained approximations. Third, we draw on biology, philosophy and other disciplines to establish validation principles for these models. We close with a discussion of opportunities to bridge model types and point to exciting frontiers for future pursuits. PMID- 30002508 TI - Performance of Biochip system in detecting drug resistant and multidrug-resistant tuberculosis using sputum collected from multiple clinical settings in Zhejiang, China. AB - The objective of the present study was to conduct a multicentre, prospective evaluation of the diagnostic performance of the Biochip system for the detection of drug-resistant tuberculosis using smear-positive sputum specimens. This prospective study evaluated the diagnostic performance of this new platform for drug resistant and multidrug-resistant tuberculosis (MDR-TB) using 1491 smear positive sputum specimens collected from multiple clinical settings. Using conventional culture-based culturing and drug-susceptibility testing as reference standards, the biochip system had a sensitivity of 86.08% and a specificity of 97.7% for rifampicin (RIF) detection, in detecting isoniazid (INH) resistance, it had a sensitivity of 79.36% and a specificity of 98.71%. With respect to MDR-TB detection, the sensitivity was 78.01% and the specificity was 98.86%. The performance only varies among different sites for RIF resistance, and there are no other statistically difference in diagnostic performance for other variables considered. The Biochip system shows favourable sensitivity and specificity for RIF and INH resistance, along with MDR-TB detection, directly using clinical smear-positive sputum samples. It is an alternative to conventional drug susceptibility testing (DST) for detecting drug resistance or MDR-TB and is a method worth expanding to clinical settings in China. PMID- 30002510 TI - Prediction of Congou Black Tea Fermentation Quality Indices from Color Features Using Non-Linear Regression Methods. AB - Fermentation is the key process to produce the special color of congou black tea. The machine vision technology is applied to detect the color space changes of black tea's color in RGB, Lab and HSV, and to find out its relevance to black tea's fermentation quality. And then the color feature parameter is used as input to establish physicochemical indexes (TFs, TRs, and TBs) and sensory features' linear and non-linear quantitative evaluation model. Results reveal that color features are significantly correlated to quality indices. Compared with the other two color models (RGB and HSV), CIE Lab model can better reflect the dynamic variation features of quality indices and foliage color information of black tea. The predictability of non-linear models (RF and SVM) is superior to PLS linear model, while RF model presents a slight advantage over the classic SVM model since RF model can better represent the quantitative analytical relationship between image information and quality indices. This research has proved that computer image color features and non-linear method can be used to quantitatively evaluate the changes of quality indices (e.g. sensory quality) and the pigment during black tea's fermentation. Besides, the test is simple, fast, and nondestructive. PMID- 30002511 TI - Antimicrobial resistance: Antimicrobial prescribing: the work continues... PMID- 30002512 TI - Public perception: Dental imaging? PMID- 30002513 TI - Teeth Team trustee awarded MBE. PMID- 30002514 TI - Groundbreaking implant care and maintenance solutions. PMID- 30002515 TI - New classification of periodontal and peri-implant diseases and conditions. PMID- 30002516 TI - Dates for the diary. PMID- 30002519 TI - What has aviation got to do with dentistry? PMID- 30002518 TI - Reports indicate Government ready to extend HPV vaccination to boys. PMID- 30002520 TI - Oral health - where do we go from here? PMID- 30002517 TI - Tooth whitening for the under-18-year-old patient. AB - Following changes in the EU regulations, it became legal for bleaching to be undertaken by dentists and their trained team. However, restrictions remained on bleaching for patients under the age of 18. A revised position statement by the General Dental Council (GDC) determined that bleaching could be undertaken on these patients if it was wholly for the purpose of treating or preventing disease. The purpose of this paper is to discuss the safety, efficacy, indications and techniques for under-18 bleaching. PMID- 30002522 TI - New microbiome-balancing toothpaste launches in the UK. PMID- 30002521 TI - Antibiotic resistance and antibiotic prescribing by dentists in England 2007 2016. AB - The early prescribers of penicillin realised that antibiotics should be used wisely and as an adjunct to traditional surgical provision. They predicted that inappropriate use would increase sensitisation to the drug. National Health Service dentists prescribed almost 10% of antibiotics issued in NHS general practice in 2016 and an audit shows that many of these may have been prescribed inappropriately. One of the causes of antimicrobial resistance is over prescription of the drugs. This paper recalls the recommendations of some early users of penicillin, reports on the current prescription patterns of dentists in England, describes the mechanism of acquisition of anti-microbial resistance and discusses dentists' role in attempting to reduce the problem. PMID- 30002523 TI - Chief Dental Officer for Scotland to step down from role. PMID- 30002524 TI - Call out to dentists and DCPs! PMID- 30002525 TI - Culture independent characterisation of the microbiome of the healthy pulp. AB - Detectable bacterial DNA found in all pulp samples in this study. PMID- 30002526 TI - More than just a long-lasting post. PMID- 30002528 TI - Mick Horton: 'Empathy for your patients is the most important trait a GDP needs'. PMID- 30002527 TI - Dental education: Should dental schools consider a curriculum change? PMID- 30002529 TI - Restorative dentistry: Cronlays? PMID- 30002530 TI - Do dental students have acceptable working posture? PMID- 30002531 TI - Lifeworks college students become Well Connected dental ambassadors. PMID- 30002532 TI - Tooth fairy payments continue to rise. PMID- 30002533 TI - Help prevent biofilm build-up. PMID- 30002535 TI - Implants with outstanding primary stability. PMID- 30002534 TI - Caries and periodontitis: contesting the conventional wisdom of their aetiology. AB - The search for individual microorganisms that predict oral diseases may be fruitless. PMID- 30002537 TI - Dental recruitment: Acute shortage of clinicians. PMID- 30002536 TI - A 2-year clinical evaluation of stainless steel crowns and composite resin restorations in primary molars under general anaesthesia in China's Guangdong province. PMID- 30002538 TI - Intelligent implant system. PMID- 30002539 TI - Pharmacology: Paracetamol prescribing. PMID- 30002540 TI - Water fluoridation confirmed to prevent dental decay in US children and adolescents. PMID- 30002542 TI - Share your experiences of working in general dental and specialist practices. PMID- 30002543 TI - Effects of chlorhexidene gluconate oral care on hospital mortality: a hospital wide, observational cohort study. AB - Increased risk of death in low risk hospitalised patients. PMID- 30002544 TI - Better care needed for adults in care homes. PMID- 30002546 TI - Connecting the mouth and body in 21st century healthcare. PMID- 30002545 TI - Celebrity endorsements: are they worth the money? PMID- 30002547 TI - Think supplier, think member. PMID- 30002548 TI - Teach the young, teach everyone. PMID- 30002549 TI - Edgar Cowperthwaite. PMID- 30002550 TI - Richard Pennington. PMID- 30002551 TI - General dental practices with and without a dental therapist: a survey of appointment activities and patient satisfaction with their care. PMID- 30002552 TI - Oral surgery: Perio disease and flap reconstruction failure. PMID- 30002555 TI - Major expansion for Yorkshire dental group. PMID- 30002553 TI - New electronic referral system for dentistry in Wales. PMID- 30002556 TI - Honours and awards. PMID- 30002557 TI - Orthodontics: Orthodontics vs orthodontiya. PMID- 30002558 TI - The birthday party. PMID- 30002560 TI - Switchable plasmonic routers controlled by external magnetic fields by using magneto-plasmonic waveguides. AB - We analytically and numerically investigate magneto-plasmons in metal films surrounded by a ferromagnetic dielectric. In such waveguide using a metal film with a thickness exceeding the Skin depth, an external magnetic field in the transverse direction can induce a significant spatial asymmetry of mode distribution. Superposition of the odd and the even asymmetric modes over a distance leads to a concentration of the energy on one interface which is switched to the other interface by the magnetic field reversal. The requested magnitude of magnetization is exponentially reduced with the increase of the metal film thickness. Based on this phenomenon, we propose a waveguide-integrated magnetically controlled switchable plasmonic routers with 99-%-high contrast within the optical bandwidth of tens of THz. This configuration can also operate as a magneto-plasmonic modulator. PMID- 30002561 TI - Multi-spectral optical imaging of the spatiotemporal dynamics of ionospheric intermittent turbulence. AB - Equatorial plasma depletions have significant impact on radio wave propagation in the upper atmosphere, causing rapid fluctuations in the power of radio signals used in telecommunication and GPS navigation, thus playing a crucial role in space weather impacts. Complex structuring and self-organization of equatorial plasma depletions involving bifurcation, connection, disconnection and reconnection are the signatures of nonlinear evolution of interchange instability and secondary instabilities, responsible for the generation of coherent structures and turbulence in the ionosphere. The aims of this paper are three fold: (1) to report the first optical imaging of reconnection of equatorial plasma depletions in the South Atlantic Magnetic Anomaly, (2) to investigate the optical imaging of equatorial ionospheric intermittent turbulence, and (3) to compare nonlinear characteristics of optical imaging of equatorial plasma depletions for two different altitudes at same times. We show that the degree of spatiotemporal complexity of ionospheric intermittent turbulence can be quantified by nonlinear studies of optical images, confirming the duality of amplitude-phase synchronization in multiscale interactions. By decomposing the analyses into North-South and East-West directions we show that the degree of non Gaussianity, intermittency and multifractality is stronger in the North-South direction, confirming the anisotropic nature of the interchange instability. In particular, by using simultaneous observation of multi-spectral all-sky emissions from two different heights we show that the degree of non-Gaussianity and intermittency in the bottomside F-region ionosphere is stronger than the peak F region ionosphere. Our results are confirmed by two sets of observations on the nights of 28 September 2002 and 9 November 2002. PMID- 30002559 TI - Genetic variation of SORBS1 gene is associated with glucose homeostasis and age at onset of diabetes: A SAPPHIRe Cohort Study. AB - The SORBS1 gene plays an important role in insulin signaling. We aimed to examine whether common single-nucleotide polymorphisms (SNPs) of SORBS1 are associated with prevalence and incidence of diabetes, age at onset of diabetes, and the related traits of glucose homeostasis. A total of 1135 siblings from 492 ethnic Chinese families were recruited at baseline, and 630 were followed up for 5.19 +/ 0.96 years. Nine SNPs including rs7081076, rs2281939, rs3818540, rs2274490, rs61739184, rs726176, rs2296966, rs17849148, and rs3193970 were genotyped and examined. To deal with correlated data of subjects within the same families, the generalized estimating equations approach was applied throughout all association analyses. The GG genotype of rs2281939 was associated with a higher risk of diabetes at baseline, an earlier onset of diabetes, and higher steady-state plasma glucose levels in the modified insulin suppression test. The minor allele T of rs2296966 was associated with higher prevalence and incidence of diabetes, an earlier onset of diabetes, and higher 2-h glucose during oral glucose tolerance test. These two SNPs revealed independent associations with age of diabetes onset as well as risk of diabetes at baseline. These findings supported that SORBS1 gene participates in the pathogenesis of diabetes. PMID- 30002562 TI - Classification system of the tibiofibular syndesmosis blood supply and its clinical relevance. AB - Due to the lack of anatomical studies concerning complexity of the tibiofibular syndesmosis blood supply, density of blood vessels with further organization of syndesmotic vascular variations is presented in clinically relevant classification system. The material for the study was obtained from cadaveric dissections. We dissected 50 human ankles observing different types of arterial blood supply. Our classification system is based on the vascular variations of the anterior aspect of tibiofibular syndesmosis and corresponds with vascular density. According to our study the mean vascular density of tibiofibular syndesmosis is relatively low (4.4%) and depends on the type of blood supply. The highest density was observed among ankles with complete vasculature and the lowest when lateral anterior malleolar artery was absent (5.8% vs. 3.5%, respectively). Awareness of various types of tibiofibular syndesmosis arterial blood supply is essential for orthopedic surgeons who operate in the ankle region and radiologists for the anatomic evaluation of this area. Knowledge about possible variations along with relatively low density of vessels may contribute to modification of treatment approach by the increase of the recommended time of syndesmotic screw stabilization in order to prevent healing complications. PMID- 30002563 TI - Making Stream Restoration More Sustainable: A Geomorphically, Ecologically, and Socioeconomically Principled Approach to Bridge the Practice with the Science. AB - Despite large advances in the state of the science of stream ecology and river mechanics, the practitioner-driven field of stream restoration remains plagued by narrowly focused projects that sometimes even fail to improve aquatic habitat or geomorphic stability-two nearly universal project goals. The intent of this article is to provide an accessible framework that bridges that gap between the current state of practice and a more geomorphically robust and ecologically holistic foundation that also provides better accounting of socioeconomic factors in support of more sustainable stream restoration outcomes. It points to several more comprehensive design references and presents some simple strategies that could be used to protect against common failure mechanisms of ubiquitous design approaches (i.e., regional curves, Rosgen planform, and grade control). From the simple structure design to the watershed-scale restoration program, this may be a first step toward a more geomorphically principled, ecologically holistic, and socioeconomically sustainable field. PMID- 30002564 TI - [A facile method for producing selenocysteine-containing proteins]. PMID- 30002565 TI - Passive remote sensing of aerosol layer height using near-UV multi-angle polarization measurements. AB - We demonstrate that multi-angle polarization measurements in the near-UV and blue part of the spectrum are very well suited for passive remote sensing of aerosol layer height. For this purpose we use simulated measurements with different set ups (different wavelength ranges, with and without polarization, different polarimetric accuracies) as well as airborne measurements from the Research Scanning Polarimeter (RSP) obtained over the continental USA. We find good agreement of the retrieved aerosol layer height from RSP with measurements from the Cloud Physics Lidar (CPL) showing a mean absolute difference of less than 1 km. Furthermore, we found that the information on aerosol layer height is provided for large part by the multi-angle polarization measurements with high accuracy rather than the multi-angle intensity measurements. The information on aerosol layer height is significantly decreased when the shortest RSP wavelength (410 nm) is excluded from the retrieval and is virtually absent when 550 nm is used as shortest wavelength. PMID- 30002568 TI - The Association Between Shelter Rules and Psychosocial Outcomes Among Homeless Youth Residing in Family Shelters. AB - Despite growing numbers of homeless youth living in shelters with caregivers, little research has explored the impact of the shelter environment on emotional well-being. As such, this study assesses the relationship between shelter rules and two psychosocial outcomes among youth in New York City family shelters. Additionally, the direct effect of trauma and the moderating effect of difficulty following shelter rules on psychosocial outcomes was assessed. Youth with difficulty following shelter rules reported significantly more depressive symptoms, but less substance use. Trauma was found to be associated with increased depression and substance use. Difficulty following shelter rules was found to moderate the association between trauma and substance use. Recommendations for future interventions and the creation of shelter policies are discussed. PMID- 30002567 TI - Climate-induced mortality of Siberian pine and fir in the Lake Baikal Watershed, Siberia. AB - Siberian pine (Pinus sibirica) and fir (Abies sibirica) (so called "dark needle conifers", DNC) showed decreased radial growth increment within the Lake Baikal watershed since the 1980s with increasing mortality recorded since the year 2000. Tree ring width was strongly correlated with vapor pressure deficit, aridity and root zone moisture. Water stress from droughts made trees more susceptible to insect attacks causing mortality in about 10% of DNC stands within the Lake Baikal watershed. Within Siberia DNC mortality increased in the southern part of the DNC range. Biogeographically, tree mortality was located within the DNC - forest-steppes transition. Tree mortality was significantly correlated with drought and soil moisture anomalies. Within the interior of the DNC range mortality occurred within relief features with high water stress risk (i.e., steep convex south facing slopes with shallow well-drained soils). In general, DNC mortality in Siberia was induced by increased aridity and severe drought (inciting factors) in synergy with biotic attacks (contributing factor). In future climate scenarios with predicted increase in aridity DNC could be eliminated from the southern part of its current range and will be replaced by drought-resistant conifers and broadleaf species (e.g., Larix sibirica, Pinus silvestris, and Betula pubescence). PMID- 30002569 TI - Preoperative Computerized Tomographic Assessment of Regional Lymph Node and Extramural Vascular Invasion in Colonic Cancer. AB - Objective: There have been recent attempts to transfer well-established principles of rectal cancer management to colonic cancer, thereby offering neoadjuvant chemotherapy to high-risk patients at least in the trial settings. Traditionally, postoperative chemotherapy is offered to patients with colonic tumors that metastasize into regional lymph nodes and have features of extramural vascular invasion (EMVI). If the same criteria are used for the selection of patients with colonic cancer for neoadjuvant chemotherapy, then their accurate preoperative detection becomes of paramount importance. The aim of the study was to establish the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the computerized tomographic (CT) assessment of lymph node involvement and EMVI in colonic cancer. Materials and Methods: This retrospective study included 53 consecutive adult patients (35 males and 18 females; median age, 72 years) who had complete preoperative CT staging of colonic cancer followed by its surgical resection during a 12-month period from January 1, 2012, to December 31, 2012. Patients with rectal and colonic tumors presenting as an emergency who did not have complete preoperative CT imaging were excluded. Preoperative CT findings on regional lymph node status and EMVI were compared with the final histopathological staging of resected specimens calculating sensitivity, specificity, PPV, and NPV of the test. Results: In predicting regional lymph node metastases, CT scan had a sensitivity of 85% and a specificity of 24%. PPV was calculated as 63% and NPV as 50%. In predicting EMVI, it had a sensitivity of 69% and a specificity of 49%. PPV was 37% and NPV was 78%. Conclusion: Preoperative CT scan does not allow an accurate detection of regional lymph node metastases and EMVI and has a tendency to overstage colonic cancer. PMID- 30002566 TI - A dynamic threshold model for terminal investment. AB - Although reproductive strategies can be influenced by a variety of intrinsic and extrinsic factors, life history theory provides a rigorous framework for explaining variation in reproductive effort. The terminal investment hypothesis proposes that a decreased expectation of future reproduction (as might arise from a mortality threat) should precipitate increased investment in current reproduction. Terminal investment has been widely studied, and a variety of intrinsic and extrinsic cues that elicit such a response have been identified across an array of taxa. Although terminal investment is often treated as a static strategy, the level at which a cue of decreased future reproduction is sufficient to trigger increased current reproductive effort (i.e., the terminal investment threshold) may depend on context, including the internal state of the organism or its current external environment, independent of the cue that triggers a shift in reproductive investment. Here, we review empirical studies that address the terminal investment hypothesis, exploring both the intrinsic and extrinsic factors that mediate its expression. Based on these studies, we propose a novel framework within which to view the strategy of terminal investment, incorporating factors that influence an individual's residual reproductive value beyond a terminal investment trigger - the dynamic terminal investment threshold. PMID- 30002570 TI - Analysis of Intravenous Urography Findings in a Tertiary Reference Center. AB - Objective: To analyze intravenous urography (IVU) findings in a tertiary reference center. Materials and Methods: A retrospective, observational study was conducted in a tertiary reference center. The radiology reports of 1,470 patients subjected to IVU in the period from January 2008 to December 2012 were retrieved from the tertiary reference center databases. Patients' demographic characteristics, type of care (inpatient or outpatient), and IVU radiologic findings were reviewed and analyzed. Results: Of 1470 patients, approximately two thirds were males. The mean age of the patients was 39.12+/-14.80 years (range: 2 95). Most of them were inpatients (92.9%; 1365/1470). The IVU findings were abnormal in 68.8% (1012/1470) of patients. Urinary tract calculi were the most frequent type of calculi observed among patients (36.8%; 541/1470), and the kidney was the most frequently affected organ by calculi (66.5%; 541/814). Hydronephrosis was the second most frequent finding, being observed in 29.7% (436/1470) of patients. Conclusion: The presence urinary tract calculi was the most frequent IVU finding, revealing that urolithiasis could be the main indication for IVU. PMID- 30002571 TI - Sexual Dysfunction Is Associated with Depression and Anxiety in Patients with Predialytic Chronic Kidney Disease. AB - Objective: We aimed to determine the prevalence of sexual dysfunction and clarify the relationship between sexual dysfunction and depressive mood state, drugs, and disease activities in patients with predialytic chronic kidney disease (CKD). Materials and Methods: In total, 150 patients with CKD who had an estimated glomerular filtration rate of 15-60 mL/min were included; 65 healthy controls were selected. A detailed medical and sexual medical history was taken from individuals in the control and patient groups by applying the Golombok-Rust Inventory of Sexual Satisfaction and Hospital Anxiety and Depression Scale. Results: Sexual frequency (p=0.027), impotence (p<0.001), and premature ejaculation scores (p<0.001) in male patients and sexual frequency (p=0.004), communication (p=0.004),, satisfaction (p<0.001), avoidance (p=0.008), orgasmic dysfunction (p<0.001), sensuality (p=0.002), and total sexual dysfunction scores (p<0.001) in female patients with CKD were found to be higher compared with the control group. In female patients, the depression scores of patients with stage 3 CKD were found to be higher than those of patients with stage 4 CKD (p=0.028). The avoidance scores of male patients with depression (p=0.006) were high. In contrast, the communication score of female patients with depression was high (p=0.004). It has been detected that the factors that affect the sexual dysfunction score of patients with CKD in males are age (p=0.006), hypertension (p=0.008), anxiety (p=0.003), and depression (p=0.002) and those in female patients are age (p=0.034), anxiety (p<0.001), and depression (p=0.001). Conclusion: Patients with predialytic CKD substantially have sexual dysfunction. The most important factors that affect sexual dysfunction are age, hypertension, anxiety, and depression. PMID- 30002572 TI - The Role of Ionic Homeostasis in Cisplatin-Induced Neurotoxicity: A Preliminary Study. AB - Objective: The aim of the present study was to investigate the role of ionic homeostasis in cisplatin (cisdiamminedichloroplatinum (II), CDDP)-induced neurotoxicity. CDDP is a severely neurotoxic antineoplastic agent that causes neuronal excitotoxicity. According to some studies, calcium influx increases, whereas potassium efflux decreases neuronal death. Nimodipine and glibenclamide were used to analyze the role of ionic flows in CDDP-induced neurotoxicity in rat primary cerebellar granule cell (CGC) culture. Materials and Methods: CGC culture was prepared from the cerebella of Sprague Dawley 5-day-old pups. The submaximal concentration of CDDP was determined and then given with 1, 10, or 50 uM of drugs into culture. Neurotoxicity was investigated using the MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) assay. One way analysis of variance, Kruskal-Wallis H test, and Tukey test were applied for statistical analysis. Results: CDDP induced neurotoxicity in a concentration dependent manner. Neither nimodipine nor glibenclamide was able to protect CGCs against CDDP neurotoxicity. Conclusion: By blocking L-type voltage-gated calcium channels, nimodipine did not prevent CDDP neurotoxicity in CGCs. Ca2+ influx via these channels seemed to be insufficient to cause a change in CDDP-induced neurotoxicity. Similarly, glibenclamide failed to prevent CDDP neurotoxicity. Further studies are needed to elucidate the mechanisms of these preliminary results. PMID- 30002573 TI - Association Between the Subtypes of Stroke and the Various Risk Factors of Cerebrovascular Accidents: A Cross-Sectional Study. AB - Objective: Stroke is a common heterogeneous disease classified into two subtypes: ischemic and hemorrhagic. Many risk factors have been associated with stroke, and the most well-known is hypertension. Although the relation between stroke and these risk factors has been emphasized before, there is inconclusive evidence about the relation between the different risk factors and the subtypes of stroke. The present study aims to fill this gap. Materials and Methods: In the present retrospective, cross-sectional study, 827 patients with diagnosed stroke were included. Demographic data and the acquired risk factors were determined using pre-designed questionnaires. Statistical analysis was conducted using chi-square test, Student t-test, and Pearson correlation coefficient. Results: Among the included 827 patients, 432 (52.2%) were men and 395 (47.8%) were women. The mean+/-standard deviation of age was 68.41+/-12.46 y in men and 67.89+/-11.85 y in women, respectively, and the difference was not significant. Of all the patients, 672 had ischemic strokes and 155 had hemorrhagic strokes. The most common risk factor in the patients was hypertension with a prevalence of 66.7%. Of all the risk factors, only hypertension, atrial fibrillation (AF), age, and a positive family history were significantly related to a subtype of stroke. Conclusion: Knowing that the prevalence of hypertension, AF, age, and positive family history are significantly different between the two subtypes, the patients having these risk factors can be entered into more specified public health measures, which puts more emphasis on the subtype that they are more prone to. PMID- 30002574 TI - Computed Tomography-Based Diagnosis of Gastric Vein Invasion in Patients with Gastric Cancer. AB - Objective: The objective of this study was to demonstrate computed tomography (CT)-based diagnosis of venous invasion in patients with gastric cancer and its prognostic value. Materials and Methods: Medical records and CT examinations of 530 patients with gastric cancer diagnosed after biopsy from February 2003 to December 2015 were included in this retrospective study. An imaging-based diagnosis of venous invasion was established when one of the following criteria were satisfied: 1) tumoral enhancement in the lumen of the vein, 2) tumor protruding through the course of a vein, and 3) distention of the vein due to extension of the gastric tumor. CT-based diagnosis of gastric vein invasion was established in 11/530 patients. Results: Histopathological examination revealed poorly differentiated gastric adenocarcinoma (n=10) and neuroendocrine carcinoma (n=1). The median survival of the patients after the initial CT was 153.5 (range: 6-1275) days. Tumor invasion was observed at the aberrant left gastric vein (n=2), right gastroepiploic and superior mesenteric vein (n=2), gastric vein (n=4), and short gastric vein (n=3). Two of the three patients with short gastric vein invasion died 6 and 7 days after the initial CT, respectively. Conclusion: All draining veins of the stomach can be invaded by gastric cancer; CT can enable diagnosis that may be important for prognosis and surgical planning. The presence of short gastric vein invasion detected by CT may be associated with poor prognosis. PMID- 30002575 TI - Evaluation of the Relationship between Carcinoembryonic Antigen and TNM Stage in Colorectal Cancer. AB - Objective: We aimed to examine the relationship between carcinoembryonic antigen (CEA) levels in the preoperative period and TNM (T: primary tumor, N: lymph node, M: distant metastasis or metastasis) staging in patients with colorectal cancer in our region. Materials and Methods: In the present study, 752 cases diagnosed with colorectal cancer between January 1992 and December 2010 we analyzed retrospectively. Results: Data of 752 patients diagnosed with colorectal cancer between 1992 and 2010 were evaluated; of the 752 patients, 427 (56.8%) were males and 325 (43.2%) were females with the mean age of 56.8+/-14.9 years. CEA levels of 316 cases were measured; 52.2% of the samples were within normal limits. Cases with CEA <=5 ng/mL were majorly in Stage III, whereas those with CEA >5 ng/mL were predominantly in Stage IV. The TNM stage, tumor diameter, and differentiation levels were defined, and no statistically significant relationship was detected between these parameters and CEA levels. Conclusion: While the CEA levels of 52.2% of participating cases were within normal limits, there was no statistically significant relationship between the CEA levels and differentiation level of tumor, tumor diameter, and TNM staging. According to the data, CEA levels may be within normal limits in the majority of patients with colorectal cancer. Therefore, normal levels of CEA will not rule out colorectal cancer diagnosis, and it can be concluded that these patients should be investigated in detail. PMID- 30002576 TI - Frequency and Significance of Perforating Venous Insufficiency in Patients with Chronic Venous Insufficiency of Lower Extremity. AB - Objective: The aim of this study was to reveal the frequency and impact of perforating venous insufficiency (PVI) in chronic venous insufficiency (CVI) of lower extremity (LE). Materials and Methods: Between 2012 and 2017, a total of 1154 patients [781 females (67.68%) and 373 males (32.32%), 228 (19.76%) unilateral and 926 (80.24%) bilateral LE] were examined using Doppler ultrasound (US). A total of 2080 venous systems of LEs [31.4% male (n=653) and 68.6% female (n=1427); 1056 left LEs (50.77%) and 1024 right LEs (49.23%)] were examined. All patients had symptoms of venous insufficiency (VI). Results: PVI was revealed in 27.5% (n=571) of LEs. Varicose veins (VVs) related with perforating vein (PV) were revealed in 44.7% of LEs (n=929). PVI was observed in 50.91% of patients with chronic deep venous thrombosis (DVT), 64.41% with deep venous insufficiency (DVI), 59.81% with great saphenous vein (GSV) insufficiency, 68.49% with small saphenous vein (SSV) insufficiency, 58.65% with accessory GSV insufficiency, and 58.77% with PV associated with VVs. There was a statistically significant relationship between PVI and chronic DVT, DVI, GSV, SSV, and accessory GSV insufficiency (p<0.001). A significant relationship was observed between the increase in PV diameter and the presence of PVI (p<0.001). Conclusion: PVI is quite common in combined VI, and PV evaluation should be a part of LE venous system examination. PMID- 30002577 TI - The Role of GnRH Analogues in Improving Outcome in Women Undergoing Superovulation and Intrauterine Insemination after Surgical Correction of Mild Endometriosis: A Randomized Controlled Trial. AB - Objective: Treatment with laparoscopic surgery, gonadotropin-releasing hormone analog (GnRHa) therapy, superovulation (SO), and intrauterine insemination (IUI) have individual benefits in improving fertility outcomes in women with endometriosis. The aim of the study was to evaluate the role of GnRHa in improving outcome in women undergoing SO and IUI after surgical correction of mild endometriosis. Materials and Methods: This was a randomized controlled trial conducted in the Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India, over a period of 2 years and 6 months. Ninety women who were diagnosed with mild endometriosis on laparoscopy using the revised American Society for Reproductive Medicine criteria were included in the study. The patients in the study group (n=45) received a single dose of 3.75 mg GnRHa subcutaneously within 48 h of the surgery, and those in the control group (n=45) did not receive GnRHa. Thereafter, patients in both arms received SO and IUI from the next menstrual cycle. Four patients in the study group and three patients in the control group were lost to follow-up before the first cycle of ovulation induction. Primary outcomes measured in our study were live birth rates and clinical pregnancy rate. Secondary outcome measures were number of follicles >18 mm, endometrial thickness, dose and days of gonadotropin stimulation. Results: Baseline characteristics, such as age and body mass index, were comparable in both groups. The SO and IUI cycles were comparable between the two groups with regard to the secondary outcome parameters. Pregnancy rate in the first cycle was 17.1% in the study group and 19.1% in the control group (p=0.81). The overall pregnancy rate was similar in both groups (study group=21.9%, control group=23.8%; p=1). As no patient had miscarriage or any other complication during pregnancy, live birth rate was similar to the clinical pregnancy rate. Conclusion: Adding GnRHa for the suppression of mild endometriosis has shown no significant improvement in the surgical management of women undergoing SO and IUI. PMID- 30002578 TI - Effect of Nausea and Vomiting on Anxiety and Depression Levels in Early Pregnancy. AB - Objective: Nausea and vomiting of pregnancy (NVP) have been reported to be associated with distinct physiological responses to psychosocial stress. In this study, we aimed to evaluate the impact of nausea and vomiting on anxiety and depression during pregnancy. Materials and Methods: Eighty-three pregnant women with nausea and vomiting and 83 healthy pregnant women were included. All participants completed the demography- and pregnancy-related questionnaire, including Rhodes Index of Nausea and Vomiting, Beck Anxiety Inventory (BAI), and Edinburgh Postnatal Depression Scale (EPDS). Results: The median BAI and EPDS levels were 13 (min-max: 0-43) and 7 (min-max: 0-20) for the study group and 4 (min-max: 0-26) and 4 (min-max: 0-16) for control group, respectively. A univariate analysis revealed a statistically significant increase in terms of BAI levels (p<0.001) between the groups, but no significant difference was observed in terms of EPDS. In a logistic regression analysis, both anxiety (p=0.018) and depression (p=0.022) were found to be affected by NVP. The BAI levels of the NVP group correlated with the severity of NVP. Conclusion: According to the results of the present study, women with severe NVP experienced a higher level of anxiety and depression, which necessitates an extra awareness from healthcare professionals in order to be able to contribute effectively. PMID- 30002579 TI - Effects of Nonsteroidal Anti-Inflammatory Drugs at the Molecular Level. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti inflammatory, analgesic, and antipyretic effects. NSAIDs generally work by blocking the production of prostaglandins (PGs) through the inhibition of two cyclooxygenase enzymes. PGs are key factors in many cellular processes, such as gastrointestinal cytoprotection, hemostasis and thrombosis, inflammation, renal hemodynamics, turnover of cartilage, and angiogenesis. Interest has grown in the various effects of NSAIDs during the last decade. Epidemiological studies have revealed the reduced risk of several cancer types and neurodegenerative diseases by prolonged use of NSAIDs. Recent advances in the understanding of the cellular and molecular mechanisms of NSAIDs will accelerate the processes of discovery and clinical implementation. This review summarizes the molecular mechanisms of NSAIDs on the body systems. PMID- 30002580 TI - Suture Granuloma 14 Years Following Partial Thyroidectomy Masquerading as Tuberculosis af The Sinus Tract. AB - Suture granuloma rarely occurs after thyroid surgery using non-absorbable sutures. We report the case of a 63-year-old female with a chronic discharging sinus in the anterior neck region. She had a history of subtotal thyroidectomy at the age of 45. The sinus had been excised and was reported as granulomatous lesions suggestive of tuberculosis. She was treated with anti-tuberculous medications, but unfortunately, she developed side effects. Histopathological slides were re-evaluated, which showed evidence of foreign material under polarized light; hence, the diagnosis was revised to suture granuloma. In conclusion, although sinus tract discharges are commonly attributed to tuberculosis, physicians should consider suture granuloma if they encounter a patient who has undergone a surgical procedure in the past. PMID- 30002581 TI - Exogenous Lipoid Pneumonia due to Chronic Inhalation of Oily Product Used as a Lubricant of Tracheotomy Cannula. AB - Exogenous lipoid pneumonia (ELP) is caused by the inhalation of vaporized oily products. Long-term exposure can result in chronic disease, whereas acute form usually results from massive aspiration of fatty substances. It has an incidence of 1.0%-2.5%. In case of symptomatic patients, the clinical presentation mainly includes acute or chronic respiratory symptoms such as dyspnea, fever, cough and less frequently chest pain, hemoptysis, or weight loss. Radiological findings are often aspecific or misinterpreted, and ELP is sometimes misdiagnosed as a malignancy of the lungs. Patient history and radiological findings can lead to a suspicion of ELP, but histological microscopic findings of intra-alveolar lipid and lipid-laden macrophages are required to confirm the diagnosis The mainstay of treatment consists of avoiding ongoing exposure and providing supportive care as repeated whole-lung lavage, corticosteroids, and/or immunoglobulins. Surgery is reserved for cases of high suspicion of cancer or serious clinical impact (as recurrent infections). Prognosis is benign, even if it has been reported cases of progression to severe respiratory failure, cor pulmonale, superinfection, and association with lung cancer. Here, we describe a case of ELP due to chronic inhalation of oily product (Vaseline) used as a lubricant of tracheotomy cannula. PMID- 30002582 TI - Myasthenia Gravis Attack after Oral Risperidone Treatment: A Case Report. AB - Myasthenia gravis (MG) is an autoimmune disease, which can be triggered by anticholinergic agents. The 6-year-old female patient was admitted to the outpatient clinic. She was had been previously diagnosed with comorbid attention deficit hyperactivity disorder and conduct disorder and was receiving short acting methylphenidate and risperidone, as recommended by a child psychiatrist. However, after using the drugs, she stated that she was overly tired during the day and that her eyelids drooped. Hence, the current treatment was stopped. She was hospitalized with a prediagnosis of ocular type MG and pyridostigmine (90 mg/day) treatment was started. The patient recovered and subsequently the treatment was stopped. Since psychiatric symptoms of the patient resurfaced, long acting methylphenidate treatment was initiated. During this treatment, the symptoms of MG did not return. The Naranjo's scale of adverse drug reaction probability was completed. Consequently, there may be an association between risperidone and MG. PMID- 30002584 TI - A Rare Presentation of Anterior Mediastinal Teratoma Mimicking Valvular Heart Disease with A Systolic Murmur. AB - Extrinsic pulmonary artery stenosis caused by anterior mediastinum teratoma presenting with an ejection systolic murmur is a rare phenomenon. Till date, 15 cases have been reported (inclusive of this case) in the English literatures. Herein we report a 20 year old female with extrinsic pulmonary artery stenosis because of compression by an anterior mediastinal teratoma with a loud ejection systolic murmur. The case report aims to highlight the awareness of such rare presentation of anterior mediastinal teratomas that may mimic congenital valvular heart diseases among clinicians. PMID- 30002583 TI - Selective Arterial Embolization of Giant Renal Angiomyolipoma Associated with Tuberous Sclerosis Complex Using Particular and Liquid Embolic Agents. AB - Renal angiomyolipoma (AML) is a benign hamartomatous tumor that is sometimes associated with the tuberous sclerosis complex. We report a 23-year-old man who presented with acute abdominal pain and hematuria. Computed tomography (CT) revealed large heterogeneous right renal mass of 17*13*13-cm diameter, consistent with AML, and acute and subacute hemorrhages. Digital subtraction angiography revealed massive tumor vascularization and multiple aneurysms associated with right renal artery branches. First, polyvinyl alcohol particles were used for the selective embolization of AML. Then, N-butyl cyanoacrylate (glue) mixed with lipiodol in a 1:3 ratio was injected for the permanent embolization of AML. CT scan revealed 59% reduction in size at 5 months after embolization. This case illustrates the selective embolization of giant renal AML with the combination of particular and liquid embolic agents with a significant reduction in size during the follow-up period. PMID- 30002585 TI - Hydronephrosis due to a Migrated Intrauterine Device into the Ureter: A Very Rare Case. AB - Intrauterine device (IUD) insertion is a long-acting and one of the most effective modes of reversible contraception. Complications that most commonly arise following IUD insertion are failed insertion, pain, vasovagal reactions, infection, menstrual abnormalities, and expulsion. In this paper, we present the case of a woman who experienced hydronephrosis due to the migration of IUD into the ureter after 30 years of insertion. To the best of our knowledge, this is the third such case reported in the literature. PMID- 30002586 TI - An Unusual Headache: Red Ear Syndrome. PMID- 30002587 TI - "Malignant" Chronic Constrictive Pericarditis. PMID- 30002588 TI - ZooKeys anniversary: 10 years of leadership toward open-access publishing of zoological data and establishment at Pensoft of like-minded sister journals across the biodiversity spectrum. PMID- 30002589 TI - Red Sea Opisthobranchia 5: new species and new records of chromodorids from the Red Sea (Heterobranchia, Nudibranchia, Chromodorididae). AB - This is the fifth publication describing species of sea slug heterobranchs, originally based on collections from the Red Sea by the author on four expeditions carried out in 1983 and 1990, with the addition of specimens subsequently collected by underwater photographers who were stimulated by the book "Sea Slugs of the Red Sea". So much material has been amassed that only the new species and new Red Sea records of chromodorids are described in this paper, with an appendix listing specimens of previously recorded species. Three new species are described in detail and illustrated, belonging to three different genera: Doriprismatica kyanomarginatasp. n., Glossodoris kahlbrockisp. n., and Goniobranchus pseudodecorussp. n. One western Pacific species is recorded for the first time in the Red Sea, Goniobranchus collingwoodi (Rudman, 1987). The nomenclature of Verconia sudanica is discussed and stabilised. PMID- 30002590 TI - A late Pleistocene gastropod fauna from the northern Caspian Sea with implications for Pontocaspian gastropod taxonomy. AB - The present paper details a very diverse non-marine gastropod fauna retrieved from Caspian Pleistocene deposits along the Volga River north of Astrakhan (Russia). During time of deposition (early Late Pleistocene, late Khazarian regional substage), the area was situated in shallow water of the greatly expanded Caspian Sea. The fauna contains 24 species, of which 16 are endemic to the Pontocaspian region and 15 to the Caspian Sea. The majority of the species (13) belongs to the Pyrgulinae (Hydrobiidae), a group famous for its huge morphological variability in the Pontocaspian region. The phenotypic diversity has led to an inflation of genus and species names in the literature. New concepts are proposed for many of the genera and species found in the present material, with implications for the systematics and taxonomy of the entire Pontocaspian gastropod fauna. Laevicaspia vinarskiisp. n. is described as a new species. This contribution is considered a first step in revising the Pontocaspian gastropod fauna. PMID- 30002591 TI - Ancient home or in exile? The easternmost species of genus Starengovia Snegovaya, 2010 found in China (Opiliones, Nemastomatidae, Nemastomatinae). AB - Starengovia quadrituberculatasp. n. is described and illustrated based on male and female specimens collected in Yunnan Province, China. The new species is distinct from the two other congeners, S. kirgizica Snegovaya, 2010 and S. ivanloebli Martens, 2017, in having two pairs of low submedian tubercles on abdominal areae III and IV; distal margin of the lateral foliate wing-like structures of the penis situated close to the glans base, the short rod-like stylus, the form and position of spines on the stylus of the penis, anvil-shaped tubercles mainly on front margin of prosoma. The occurrence of Starengovia in Yunnan, the second nemastomatine species in China, creates a huge distributional gap of roughly 2700 km distance to its closest neighbor S. ivanloebli in Northwest Pakistan. The historical relations of Chinese nemastomatines are discussed. PMID- 30002592 TI - Sinodraconarius gen. n., a new genus of Coelotinae spiders from Southwest China (Araneae, Agelenidae). AB - A new genus of the subfamily Coelotinae F.O. Pickard-Cambridge, 1893, Sinodraconariusgen. n., with four new species, S. cawarongensissp. n. (??), S. muruoensissp. n. (??), S. sangjiuensissp. n. (??, type species), S. yuisp. n. (??) and S. patellabifidus (Wang, 2003) comb. n., ex. Draconarius Ovtchinnikov, 1999 is described. The genus is restricted to Southwest China. Sinodraconariusgen. n. is most similar to Draconarius but can be distinguished by the shape of the copulatory organs. The DNA barcodes of all species were documented for future use. PMID- 30002594 TI - Two new species of Brusqeulia Razowski & Becker, 2000 from the Neotropics, with comments on the systematic position of the genus in relation to the Apolychrosis Amsel, 1962 group of genera (Lepidoptera, Tortricidae, Cochylini). AB - Two new species of the neotropical genus Brusqeulia Razowski & Becker, 2000, are described and illustrated: B. yunkensis Perez Santa-Rita & Baixeras, sp. n. from Bolivia and B. araguensis Perez Sant-Rita & Baixeras, sp. n. from Venezuela. The systematic position and diagnostic characters of the genus are reviewed, resulting in the synonymy of Pinhaisania Razowski & Becker, 2000, with Brusqeulia, and the combination B. crispula (Razowski & Becker, 2000), comb. n. New characters of the female genitalia are discussed. PMID- 30002593 TI - Systematics of the ant genus Proceratium Roger (Hymenoptera, Formicidae, Proceratiinae) in China - with descriptions of three new species based on micro CT enhanced next-generation-morphology. AB - The genus Proceratium Roger, 1863 contains cryptic, subterranean ants that are seldom sampled and rare in natural history collections. Furthermore, most Proceratium specimens are extremely hairy and, due to their enlarged and curved gaster, often mounted suboptimally. As a consequence, the poorly observable physical characteristics of the material and its scarcity result in a rather challenging alpha taxonomy of this group. In this study, the taxonomy of the Chinese Proceratium fauna is reviewed and updated by combining examinations of traditional light microscopy with x-ray microtomography (micro-CT). Based on micro-CT scans of seven out of eight species, virtual 3D surface models were generated that permit in-depth comparative analyses of specimen morphology in order to overcome the difficulties to examine physical material of Proceratium. Eight Chinese species are recognized, of which three are newly described: Proceratium bruelheidei Staab, Xu & Hita Garcia, sp. n. and P. kepingmaisp. n. belong to the P. itoi clade and have been collected in the subtropical forests of southeast China, whereas P. shoheisp. n. belongs to the P. stictum clade and it is only known from a tropical forest of Yunnan Province. Proceratium nujiangense Xu, 2006 syn. n. is proposed as a junior synonym of P. zhaoi Xu, 2000. These taxonomic acts raise the number of known Chinese Proceratium species to eight. In order to integrate the new species into the existing taxonomic system and to facilitate identifications, an illustrated key to the worker caste of all Chinese species is provided, supplemented by species accounts with high-resolution montage images and still images of volume renderings of 3D models based on micro CT. Moreover, cybertype datasets are provided for the new species, as well as digital datasets for the remaining species that include the raw micro-CT scan data, 3D surface models, 3D rotation videos, and all light photography and micro CT still images. These datasets are available online (Dryad, Staab et al. 2018, http://dx.doi.org/10.5061/dryad.h6j0g4p). PMID- 30002595 TI - A new species of Kurixalus from western Yunnan, China (Anura, Rhacophoridae). AB - A new species of the genus Kurixalus (Anura: Rhacophoridae) is described from western Yunnan, China. Genetically the new species, Kurixalus yangisp. n., is closer to Kurixalus naso than to other known congeners. Morphologically the new species is distinguished from all other known congeners by a combination of the following characters: smaller ratios of head, snout, limbs, IND, and UEW to body size; male body size larger than 30 mm; curved canthus rostralis; weak nuptial pad; brown dorsal color; absence of large dark spots on surface of upper-middle abdomen; presence of vomerine teeth; gold brown iris; single internal vocal sac; serrated dermal fringes along outer edge of limbs; granular throat and chest; rudimentary web between fingers; and presence of supernumerary tubercles and outer metacarpal tubercle. PMID- 30002596 TI - Carnivore distribution across habitats in a central-European landscape: a camera trap study. AB - Quantitative data on local variation in patterns of occurrence of common carnivore species, such as the red fox, European badger, or martens in central Europe are largely missing. We conducted a study focusing on carnivore ecology and distribution in a cultural landscape with the use of modern technology. We placed 73 automated infra-red camera traps into four different habitats differing in water availability and canopy cover (mixed forest, wetland, shrubby grassland and floodplain forest) in the Polabi region near Prague, Czech Republic. Each habitat was represented by three or four spatially isolated sites within which the camera traps were distributed. During the year of the study, we recorded nine carnivore species, including the non-native golden jackal. Habitats with the highest numbers of records pooled across all species were wetland (1279) and shrubby grassland (1014); fewer records were made in mixed (876) and floodplain forest (734). Habitat had a significant effect on the number of records of badger and marten, and a marginally significant effect on fox. In terms of seasonal dynamics, there were significant differences in the distribution of records among seasons in fox, marginally significant in least weasel, and the occurrence among seasons did not differ for badger and marten. In the summer, fox and marten were more active than expected by chance during the day, while the pattern was opposite in winter when they were more active during the night. Our findings on habitat preferences and circadian and seasonal activity provided the first quantitative data on patterns whose existence was assumed on the basis of conventional wisdom. Our study demonstrates the potential of a long-term monitoring approach based on infra-red camera traps. Generally, the rather frequent occurrence of recorded species indicates that most carnivore species are thriving in current central-European landscapes characterized by human-driven disturbances and urbanization. PMID- 30002597 TI - The medicinal plants of Myanmar. AB - A comprehensive compilation is provided of the medicinal plants of the Southeast Asian country of Myanmar (formerly Burma). This contribution, containing 123 families, 367 genera, and 472 species, was compiled from earlier treatments, monographs, books, and pamphlets, with some medicinal uses and preparations translated from Burmese to English. The entry for each species includes the Latin binomial, author(s), common Myanmar and English names, range, medicinal uses and preparations, and additional notes. Of the 472 species, 63 or 13% of them have been assessed for conservation status and are listed in the IUCN Red List of Threatened Species (IUCN 2017). Two species are listed as Extinct in the Wild, four as Threatened (two Endangered, two Vulnerable), two as Near Threatened, 48 Least Concerned, and seven Data Deficient. Botanic gardens worldwide hold 444 species (94%) within their living collections, while 28 species (6%) are not found any botanic garden. Preserving the traditional knowledge of Myanmar healers contributes to Target 13 of the Global Strategy for Plant Conservation. PMID- 30002598 TI - Complement C5a Alters the Membrane Potential of Neutrophils during Hemorrhagic Shock. AB - Background: Polymorphonuclear granulocytes (PMN) play a crucial role in host defense. Physiologically, exposure of PMN to the complement activation product C5a results in a protective response against pathogens, whereas in the case of systemic inflammation, excessive C5a substantially impairs neutrophil functions. To further elucidate the inability of PMN to properly respond to C5a, this study investigates the role of the cellular membrane potential of PMN in response to C5a. Methods: Electrophysiological changes in cellular and mitochondrial membrane potential and intracellular pH of PMN from human healthy volunteers were determined by flow cytometry after exposure to C5a. Furthermore, PMN from male Bretoncelles-Meishan-Willebrand cross-bred pigs before and three hours after severe hemorrhagic shock were analyzed for their electrophysiological response. Results: PMN showed a significant dose- and time-dependent depolarization in response to C5a with a strong response after one minute. The chemotactic peptide fMLP also evoked a significant shift in the membrane potential of PMN. Acidification of the cellular microenvironment significantly enhanced depolarization of PMN. In a clinically relevant model of porcine hemorrhagic shock, the C5a-induced changes in membrane potential of PMN were markedly diminished compared to healthy littermates. Overall, these membrane potential changes may contribute to PMN dysfunction in an inflammatory environment. PMID- 30002600 TI - Surgical patients' perspectives on nurses' education on post-operative care and follow up in Northern Ghana. AB - Background: The purpose of the study was to explore surgical patients' experiences of discharge planning and home care in the Northern part of Ghana. Methods: The study was conducted at a referral hospital located at the Northern part of Ghana. A qualitative explorative descriptive design was adopted for the study. Purposive sampling technique was used to recruit participants. Data was saturated with 15 participants aged between 23 and 65 years. All the interviews were audio-taped and transcribed verbatim. Data analysis was done using the processes of content analysis. Results: Nurses educated surgical patients on discharge to avoid smoking, alcohol drinking, chewing cola nuts and strenuous exercise to promote healing and prevent complications. Patients were educated to keep their wound dry and clean. Patients were advised to eat nutritious food, vegetables and fruits and take their medications as prescribed. They were to report drug effects and come to the hospital for follow-up visits. Patients were urged to come for daily wound dressing at the outpatient department. On the contrary, some nurses did not educate patients on signs of wound healing or infection. Some nurses were rude to the patients during wound dressing. Nurses did not visit patients at home when they were discharged from the hospital. Conclusions: The study showed that although nurses were able to educate discharged patients on how to manage their health at home, there is the need to improve communication and attitude to enhance care. PMID- 30002601 TI - hERG1 channel expression associates with molecular subtypes and prognosis in breast cancer. AB - Background: Breast cancer (BC) is the most frequent malignancy among females worldwide. Despite several efforts and improvements in early diagnosis and treatment, there are still tumors characterized by an aggressive behavior due to unfavorable biology, thus quite difficult to treat. In this view, searching for novel potential biomarkers is mandatory. Among them, in the recent years data have been gathered addressing ion channel as important players in oncology. Methods: A retrospective pilot study was performed on 40 BC samples by means of immunohistochemistry in order to evaluate hERG1 potassium channels expression in BC. Results: We provide evidence that hERG1 is expressed in all the BC samples analyzed. hERG1 expression was significantly associated with molecular subtype with the highest expression in Luminal A and the lowest in basal-like tumors (p = 0.001), tumor grading (the highest hERG1 expression in well-moderate differentiated tumors, p = 0.020), estrogen receptors (high hERG1 expression in ER-positive samples, p = 0.008) and Ki67 proliferative index (high hERG1 scoring in samples with low proliferative index, p = 0.038). Also, a p value close to significance was noticed for the association between hERG1 and HER2 expression (p = 0.079). At the survival analysis, patients with high hERG1 expression turned out to have a longer progression-free survival, although statistical significance was not reached (p = 0.195). The same trend was observed analyzing local relapse free-survival (LRFS) and metastases-free survival (MFS): patients with higher hERG1 scoring had longer LRFS and MFS (p = 0.124 and p = 0.071, respectively). Conclusions: The results of this pilot study provide the first evidence that the hERG1 protein is expressed in primary BC, and its expression associates with molecular subtype. hERG1 apparently behaves as a protective factor, since it contributes to identify a subset of patients with better outcome. Overall, these data suggest that hERG1 might be an additional tool for the management of BC, nevertheless further investigations are warranted to better clarify hERG1 role and clinical usefulness in BC. PMID- 30002602 TI - TROP2 methylation and expression in tamoxifen-resistant breast cancer. AB - Background: The DNA methyltransferase 1 inhibitor, 5-Aza-2'-deoxycytidine (5-Aza dC) is a potential treatment for breast cancer. However, not all breast tumors will respond similarly to treatment with 5-Aza-dC, and little is known regarding the response of hormone-resistant breast cancers to 5-Aza-dC. Methods: We demonstrate that 5-Aza-dC-treatment has a stronger effect on an estrogen receptor negative, Tamoxifen-selected cell line, TMX2-28, than on the estrogen receptor positive, MCF7, parental cell line. Using data obtained from the HM450 Methylation Bead Chip, pyrosequencing, and RT-qPCR, we identified a panel of genes that are silenced by promoter methylation in TMX2-28 and re-expressed after treatment with 5-Aza-dC. Results: One of the genes identified, tumor associated calcium signal transducer 2 (TACSTD2), is altered by DNA methylation, and there is evidence that in some cancers decreased expression may result in greater proliferation. Analysis of DNA methylation of TACSTD2 and protein expression of its product, trophoblast antigen protein 2 (TROP2), was extended to a panel of primary (n = 34) and recurrent (n = 34) breast tumors. Stratifying tumors by both recurrence and ER status showed no significant relationship between TROP2 levels and TACSTD2 methylation. Knocking down TACSTD2 expression in MCF7 increased proliferation however; re-expressing TACSTD2 in TMX2-28 did not inhibit proliferation, indicating that TACSTD2 re-expression alone was insufficient to explain the decreased proliferation observed after treatment with 5-Aza-dC. Conclusions: These results illustrate the complexity of the TROP2 signaling network. However, TROP2 may be a valid therapeutic target for some cancers. Further studies are needed to identify biomarkers that indicate how TROP2 signaling affects tumor growth and whether targeting TROP2 would be beneficial to the patient. PMID- 30002599 TI - A Profibrotic Phenotype in Naive and in Fibrotic Lung Myofibroblasts Is Governed by Modulations in Thy-1 Expression and Activation. AB - Lung fibrosis is characterized by abnormal accumulation of Thy-deficient fibroblasts in the interstitium of the alveolar space. We have previously shown in bleomycin-treated chimeric Thy1-deficient mice with wild-type lymphocytes that Thy1-deficient fibroblasts accumulate and promote fibrosis and an "inflammation free" environment. Here, we aimed to identify the critical effects of Thy1, or the absence of Thy1, in lung myofibroblast profibrotic functions, particularly proliferation and collagen deposition. Using specific Thy1 siRNA in Thy1-positive cells, Thy1 knockout cells, Thy1 cDNA expression vector in Thy1-deficient cells, and Thy1 cross-linking, we evaluated cell proliferation (assessed by cell mass and BrdU uptake), differentiation (using immunofluorescence), and collagen deposition (using Sircol assay). We found that myofibroblast Thy1 cross-linking and genetic manipulation modulate cell proliferation and expression of Fgf (fibroblast growth factor) and Angtl (angiotensin) receptors (using qPCR) that are involved in myofibroblast proliferation, differentiation, and collagen deposition. In conclusion, lung myofibroblast downregulation of Thy1 expression is critical to increase proliferation, differentiation, and collagen deposition. PMID- 30002603 TI - CDA gene silencing regulated the proliferation and apoptosis of chronic myeloid leukemia K562 cells. AB - Background: As a disease of hematopoietic stem cell, chronic myeloid leukemia (CML) possesses unique biological and clinical features. However, the biologic mechanism underlying its development remains poorly understood. Thus, the objective of the present study is to discuss the effect of cytidine deaminase (CDA) gene silencing on the apoptosis and proliferation of CML K562 cells. Methods: CDA mRNA expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzymatic activity of CDA was measured by a nuclide liquid scintillation method. RT-qPCR and Western blot analysis were used to detect CDA mRNA and protein expression. Cell proliferation, apoptosis and cell cycle were measured by CCK-8 assay and flow cytometry. The expression of proteins relevant to cell proliferation, apoptosis and cell cycle was measured by Western blot analysis. Tumor xenografts were implanted in nude mice to verify the effect of CDA silencing on tumor growth in vivo. Results: CML and AL patients showed increased mRNA expression and enzymatic activity of CDA. Compared with the blank group, the mRNA and protein expression of CDA in the shRNA-1 and shRNA-2 groups decreased significantly. As a result, the proliferation of K562 cells was inhibited after CDA silencing and the cells were mainly arrested in S and G2 phases, while the apoptosis rate of these cells was increased. In addition, CDA gene silencing in K562 cells led to down-regulated p-ERK1/2, t-AKT, p-AKT and BCL 2 expression and up-regulated expression of P21, Bax, cleaved caspase-3/total caspase-3 and cleaved PARP/total PARP. Finally, CDA gene silencing inhibited tumor growth. Conclusion: Our study demonstrated that CDA gene silencing could inhibit CML cell proliferation and induce cell apoptosis. Therefore, CDA gene silencing may become an effective target for the treatment of leukemia. PMID- 30002604 TI - Vasodilator-stimulated phosphoprotein (VASP), a novel target of miR-4455, promotes gastric cancer cell proliferation, migration, and invasion, through activating the PI3K/AKT signaling pathway. AB - Background: MicroRNAs (miRNAs) are small non-coding RNAs which play important roles in the carcinogenesis of gastric cancer (GC). Expression profiling of miRNAs in paired gastric cancer and adjacent normal gastric tissues has demonstrated that miR-4455 is down-regulated in gastric cancer tissues, but its functional role in the carcinogenesis of GC had not previously been investigated. Aims: The purpose of this study was to investigate the functional and biological mechanisms of miR-4455 in the progression of GC, in vitro. Methods: Expression of miR-4455 was compared in human GC tissue samples and paired adjacent normal tissue samples. The in vitro effects of miR-4455 expression in MGC-803 cells on their proliferation, invasion, and migration were assessed by MTT assays and 5 bromo-2'-deoxyuridine staining, matrigel-invasion analysis and wound healing assays. Bioinformatics analysis (using PicTar, target scan and miRBase target) was used to identify potential targets for miR-4455, and the luciferase reporter assay, qRT-PCR and Western-blotting analyses were used to confirm VASP as the target of miR-4455. In addition, the effects of downregulation of VASP on the activation of PI3K/AKT signaling pathway were measured using Western-blot analysis. Results: The expression of miR-4455 was markedly down-regulated in gastric cancer tissues vs. adjacent normal tissues, and miR-4455 expression inhibited the proliferation, invasion and migration of MGC-803 GC cells in vitro. Luciferase reporter assays revealed that miR-4455 inhibited VASP expression by targeting the 3'-UTR sequence of VASP. Furthermore, silencing of VASP markedly inhibited the activation of the PI3K/AKT signaling pathway. Conclusion: Our results suggest that miR-4455 functions as a tumor suppressor in gastric cancer, by targeting VASP leading to activation of the PI3K/AKT signaling pathway and the inhibition of VASP mediated proliferation, migration and invasion of gastric cancer cells. PMID- 30002607 TI - The Security of Laboratory Information and Data on Patients. PMID- 30002606 TI - Contextualization of Survey Data: What Do We Gain and Does It Matter? AB - Survey research designs that integrate contextual data have become more prevalent in recent decades, presumably to enable a more refined focus on the person as the unit of analysis and a greater emphasis on interindividual differences due to social forces and contextual conditions. This article reviews varied approaches to contextualizing survey data and examines the value of linking two data sources to respondent information: interviewer ratings and neighborhood information (measured via census tracts). The utility of an integrative approach is illustrated with data from the Health and Retirement Study. The results reveal modest gains by using a contextualized approach but also demonstrate that neglecting contextual factors may lead to misdirected substantive conclusions, especially for older racial and ethnic minorities. To enhance the ecological validity of survey data, investigators should select theoretically-meaningful contextual data for specific research questions and consider cross-level interactions. PMID- 30002609 TI - Guidelines to Subcontracting Clinical Laboratory Examinations a Proposal of the Catalan Association for Clinical Laboratory Sciences. AB - Clinical laboratories, acting as subcontractors, do not always supply information on the quality of their examination procedures and results. Thus, its selection by a contracting organization is often based only in economical criteria. This article gives some guidelines to subcontractors on how to describe its quality characteristics in order to be appropriately contracted. PMID- 30002608 TI - New Biochemical Serum Markers of Boneturnover in Renal Osteodystrophy. AB - Renal osteodystrophy is a multifactorial disorder of bone remodelling that develops in patients with chronic renal failure. During the last few years numerous biochemical markers of bone turnover have been proposed for the non invasive diagnosis of renal osteodystrophy. Several enzymes and matrix proteins produced by osteoblasts and osteoclasts, including collagen type I degradation products, have been recognized as circulating biochemical markers of both bone formation and bone resorption process. The aim of this article was to present and estimate the clinical utility of new serum markers of bone metabolism like bone specific alkaline phosphatase (bAP), procollagen type I extension peptides (PICP/PINP), osteocalcin (Oc), tartrate-resistant acid phosphatase (TRAP), procollagen type I crosslinked carboxyterminal telopeptide (ICTP), pyridinoline (PYR), deoxypyridinoline (DPD), C- or N-terminal telopeptides of type I collagen (CTx, NTx) and other potential markers in diagnosis of renal osteodystrophy in patients with chronic renal failure. PMID- 30002605 TI - Focus on the agents most frequently responsible for perioperative anaphylaxis. AB - Adverse reactions (ARs) to drugs administered during general anesthesia may be very severe and life-threatening, with a mortality rate ranging from 3 to 9%. The adverse reactions to drugs may be IgE and non-IgE-mediated. Neuromuscular blocking agents (NMBA) represent the first cause of perioperative reactions during general anesthesia followed by latex, antibiotics, hypnotic agents, opioids, colloids, dyes and antiseptics (chlorhexidine). All these substances (i.e. NMBA, anesthetics, antibiotics, latex devices) may cause severe systemic non-IgE-mediated reactions or fatal anaphylactic events even in the absence of any evident risk factor in the patient's anamnesis. For this reason, in order to minimize perioperative anaphylactic reactions, it is important to have rapid, specific, sensitive in vitro diagnostic tests able to confirm the clinical diagnosis of acute anaphylaxis. PMID- 30002610 TI - Clinical Case Presentation - Fabry's Disease. PMID- 30002611 TI - Interpretation in Clinical Biochemistry: An External Quality Assurance Scheme. PMID- 30002612 TI - Ethics and Bioethics in Europe. PMID- 30002613 TI - Information from Laboratory Data. Interpretation of Serial Measurements. PMID- 30002614 TI - Asiatic Acid Prevents Oxidative Stress and Apoptosis by Inhibiting the Translocation of alpha-Synuclein Into Mitochondria. AB - The association of alpha-synuclein (alpha-syn) with mitochondria occurs through interaction with mitochondrial complex I. Defects in this protein have been linked to the pathogenesis of Parkinson disease (PD). Overexpression of alpha synuclein in cells has been suggested to cause elevations in mitochondrial oxidant radicals and structural and functional abnormalities in mitochondria. Asiatic acid (AA), a triterpenoid, is an antioxidant that is used for depression, and we have shown that pretreatment with AA can prevent PD-like damage, but its therapeutic effects in PD and mechanism remain unknown. In this study, we found that 0.5-2 mg AA/100 g diet significantly improves climbing ability in drosophila and extends their life-span-effects that we attributed to its antioxidant properties. AA also protected mitochondria against oxidative stress and apoptosis in a rotenone-induced cellular model. In an isolated mitochondria model, AA attenuated the decline in mitochondrial membrane potential that was induced by alpha-syn. Consequently, AA maintained membrane integrity and ATP production. Finally, we demonstrated that AA protects by blocking the translocation of alpha syn into mitochondria. Our results suggest that mitochondria are crucial in PD and that AA is an excellent candidate for the prevention and therapy of this disease. PMID- 30002615 TI - Evaluation of Switch and Continuous Navigation Paradigms to Command a Brain Controlled Wheelchair. AB - A brain-computer interface (BCI) is a technology allowing patients with severe motor dysfunctions to use their electroencephalographic signals to create a communication channel to control devices. The objective of this paper is to study the feasibility of continuous and switch control modes for a brain-controlled wheelchair (BCW) using sensorimotor rhythms (SMR) modulated through a right-hand motor imagery task. Previous studies, which used a continuous navigation control with SMR, have reported the difficulty of maintaining the motor imagery task for a long time, especially for the forward command. The switch control has been presented as a proposal that may help to solve this issue since this task is only used temporary for either disabling or enabling the movement. Regarding the methodology, 10 of 15 able-bodied users, who had overcome the criterion of 30% error rate in the calibration phase, controlled the BCW using both paradigms. The navigation tasks consisted of a straight path divided in five sections: in three of them the users had to move forward, and in the other two the users had to maintain their position. To assess user performance in the device management, a usability approach was adopted, measuring the factors of effectiveness, efficiency, and satisfaction. Then, variables related to the time employed and commands selected by the user or parameters related to the confusion matrix were applied. In addition, the scores in NASA-TLX and two ad hoc questionnaires were considered to discuss the user experience controlling the wheelchair. Despite the results showed that the best system for a specific user relies on his/her abilities and preferences, the switch control mode obtained better accuracy (0.59 +/- 0.17 for continuous and 0.72 +/- 0.05 for switch). Furthermore, the switch paradigm can be recommended for the advance sections as with it users could complete the advance sections in less time (42.2 +/- 28.7 s for continuous and 15.47 +/- 3.43 s for switch), while the continuous mode seems to be better at keeping the wheelchair stopped (42.45 +/- 16.01 s for continuous and 24.35 +/- 10.94 s for switch). PMID- 30002616 TI - Yeast as a Model to Unravel Mechanisms Behind FUS Toxicity in Amyotrophic Lateral Sclerosis. AB - Fused in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein predominantly localized in the cell nucleus. However, FUS has been shown to accumulate and form aggregates in the cytoplasm when mislocalized there due to mutations. These FUS protein aggregates are known as pathological hallmarks in a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) cases. In this review, we discussed recent research developments on elucidating the molecular mechanisms behind FUS protein aggregation and toxicity. We mainly focus on studies using the budding yeast (Saccharomyces cerevisiae) as a model system, especially on results acquired from yeast genome-wide screens addressing FUS aggregation and toxicity. Human homologs of the FUS toxicity suppressors, identified from these studies, indicate a strong relevance and correlation to a human disease model. By using yeast as a FUS cytotoxicity model these studies provided valuable clues on potential novel targets for therapeutic intervention in ALS. PMID- 30002618 TI - Apoptosis of Endothelial Cells Contributes to Brain Vessel Pruning of Zebrafish During Development. AB - During development, immature blood vessel networks remodel to form a simplified and efficient vasculature to meet the demand for oxygen and nutrients, and this remodeling process is mainly achieved via the pruning of existing vessels. It has already known that the migration of vascular endothelial cells (ECs) is one of the mechanisms underlying vessel pruning. However, the role of EC apoptosis in vessel pruning remains under debate, especially in the brain. Here, we reported that EC apoptosis makes a significant contribution to vessel pruning in the brain of larval zebrafish. Using in vivo long-term time-lapse confocal imaging of the brain vasculature in zebrafish larvae, we found that EC apoptosis was always accompanied with brain vessel pruning and about 15% of vessel pruning events were resulted from EC apoptosis. In comparison with brain vessels undergoing EC migration-associated pruning, EC apoptosis-accompanied pruned vessels were longer and showed higher probability that the nuclei of neighboring vessels' ECs occupied their both ends. Furthermore, we found that microglia were responsible for the clearance of apoptotic ECs accompanying vessel pruning, though microglia themselves were dispensable for the occurrence of vessel pruning. Thus, our study demonstrates that EC apoptosis contributes to vessel pruning in the brain during development in a microglial cell-independent manner. PMID- 30002617 TI - The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. AB - Orexins, also known as hypocretins, are two neuropeptides secreted from orexin containing neurons, mainly in the lateral hypothalamus (LH). Orexins orchestrate their effects by binding and activating two G-protein-coupled receptors (GPCRs), orexin receptor type 1 (OX1R) and type 2 (OX2R). Orexin/receptor pathways play vital regulatory roles in many physiological processes, especially feeding behavior, sleep-wake rhythm, reward and addiction and energy balance. Furthermore several reports showed that orexin/receptor pathways are involved in pathological processes of neurological diseases such as narcolepsy, depression, ischemic stroke, drug addiction and Alzheimer's disease (AD). This review article summarizes the expression patterns, physiological functions and potential molecular mechanisms of the orexin/receptor system in neurological diseases, providing an overall framework for considering these pathways from the standpoints of basic research and clinical treatment of neurological diseases. PMID- 30002621 TI - Commentary: Augmentation of Fear Extinction by Transcranial Direct Current Stimulation (tDCS). PMID- 30002620 TI - Glucocerebrosidase Mutations and Synucleinopathies. Potential Role of Sterylglucosides and Relevance of Studying Both GBA1 and GBA2 Genes. AB - Gaucher's disease (GD) is the most prevalent lysosomal storage disorder. GD is caused by homozygous mutations of the GBA1 gene, which codes for beta glucocerebrosidase (GCase). Although GD primarily affects peripheral tissues, the presence of neurological symptoms has been reported in several GD subtypes. GBA1 mutations have recently deserved increased attention upon the demonstration that both homo- and heterozygous GBA1 mutations represent the most important genetic risk factor for the appearance of synucleinopathies like Parkinson's disease (PD) and dementia with Lewy bodies (LBD). Although reduced GCase activity leads to alpha-synuclein aggregation, the mechanisms sustaining a role for GCase in alpha synuclein homeostasis still remain largely unknown. Furthermore, the role to be played by impairment in the physiological function of endoplasmic reticulum, mitochondria and other subcellular membranous components is currently under investigation. Here we focus on the impact of GCase loss-of-function that impact on the levels of sterylglucosides, molecules that are known to trigger a PD related synucleinopathy upon administration in rats. Moreover, the concurrence of another gene also coding for an enzyme with GCase activity (GBA2 gene) should also be taken into consideration, bearing in mind that in addition to a hydrolytic function, both GCases also share transglycosylation as a second catalytic activity. Accordingly, sterylglycoside levels should also be considered to further assess their impact on the neurodegenerative process. In this regard and besides GBA1 genotyping-we suggest that screening for GBA2 mutations should be considered, together with analytical measurements of cholesterol glycosides in body fluids, as biomarkers for both PD risk and disease progression. PMID- 30002622 TI - Deficits in Burrowing Behaviors Are Associated With Mouse Models of Neuropathic but Not Inflammatory Pain or Migraine. AB - Burrowing, or the removal of material from an enclosed tube, is emerging as a prominent means of testing changes in a voluntary behavior in rodent models of various pain states. Here, we report no significant differences between male and female mice in terms of burrowing performance, in a substantially shorter time frame than previous reports. We found that the color of the burrow tube affects the variability of burrowing performance when tested in a lit room, suggesting that light aversion is at least a partial driver of this behavior. Spared nerve injury (SNI; as a model of neuropathy) impairs burrowing performance and correlates with enhanced mechanical sensitivity as assessed by von Frey filaments, as well as being pharmacologically reversed by an analgesic, gabapentin. Loss of the SNI-induced burrowing deficit was observed with daily testing post-surgery, but not when the testing interval was increased to 5 days, suggesting a confounding effect of daily repeat testing in this paradigm. Intraplantar complete Freund's adjuvant (as a model of inflammatory pain) and systemic nitroglycerin (as a model of migraine-like symptoms) administration did not induce any burrowing deficit, indicating that assessment of burrowing behavior may not be universally suitable for the detection of behavioral changes across all rodent pain models. PMID- 30002619 TI - Synaptic Vesicle Endocytosis in Different Model Systems. AB - Neurotransmission in complex animals depends on a choir of functionally distinct synapses releasing neurotransmitters in a highly coordinated manner. During synaptic signaling, vesicles fuse with the plasma membrane to release their contents. The rate of vesicle fusion is high and can exceed the rate at which synaptic vesicles can be re-supplied by distant sources. Thus, local compensatory endocytosis is needed to replenish the synaptic vesicle pools. Over the last four decades, various experimental methods and model systems have been used to study the cellular and molecular mechanisms underlying synaptic vesicle cycle. Clathrin mediated endocytosis is thought to be the predominant mechanism for synaptic vesicle recycling. However, recent studies suggest significant contribution from other modes of endocytosis, including fast compensatory endocytosis, activity dependent bulk endocytosis, ultrafast endocytosis, as well as kiss-and-run. Currently, it is not clear whether a universal model of vesicle recycling exist for all types of synapses. It is possible that each synapse type employs a particular mode of endocytosis. Alternatively, multiple modes of endocytosis operate at the same synapse, and the synapse toggles between different modes depending on its activity level. Here we compile review and research articles based on well-characterized model systems: frog neuromuscular junctions, C. elegans neuromuscular junctions, Drosophila neuromuscular junctions, lamprey reticulospinal giant axons, goldfish retinal ribbon synapses, the calyx of Held, and rodent hippocampal synapses. We will compare these systems in terms of their known modes and kinetics of synaptic vesicle endocytosis, as well as the underlying molecular machineries. We will also provide the future development of this field. PMID- 30002624 TI - Measuring Mindfulness: A Psychophysiological Approach. AB - Mindfulness-based interventions have proved effective in reducing various clinical symptoms and in improving general mental health and well-being. The investigation of the mechanisms of therapeutic change needs methods for assessment of mindfulness. Existing self-report measures have, however, been strongly criticized on various grounds, including distortion of the original concept, response bias, and other. We propose a psychophysiological method for the assessment of the mindfulness learned through time-limited mindfulness-based therapy by people who undergo meditation training for the first time. We use the individual pre-post-therapy changes (dERPi) in the event-related brain potentials (ERPs) recorded in a passive meditation task as a measure of increased mindfulness. dERPi is computed through multivariate assessment of individual participant's ERPs. We tested the proposed method in a group of about 70 recurrently depressed participants, randomly assigned in 1.7:1 ratio to mindfulness-based cognitive therapy (MBCT) or cognitive therapy (CT). The therapy outcome was measured by the long-term change (dDS) relative to baseline in the depression symptoms (DS) assessed weekly, for 60 weeks, by an online self-report questionnaire. We found a strong, highly significant, negative correlation (r = 0.55) between dERPi (mean = 0.4) and dDS (mean = -0.7) in the MBCT group. Compared to this result, the relationship between dDS and the other (self-report) measures of mindfulness we used was substantially weaker and not significant. So was also the relationship between dERPi and dDS in the CT group. The interpretation of dERPi as a measure of increased mindfulness was further supported by positive correlations between dERPi and the other measures of mindfulness. In this study, we also replicated a previous result, namely, the increase (dLCNV) of the late contingent negative variation (LCNV) of the ERP in the MBCT group, but not in the control group (in this case, CT). We interpreted dLCNV as a measure of increased meditative concentration. The relationship between dLCNV and dDS was, however, very week, which suggests that concentration might be relatively unimportant for the therapeutic effect of mindfulness. The proposed psychophysiological method could become an important component of a "mindfulness test battery" together with self-report questionnaires and other newly developed instruments. PMID- 30002625 TI - PPARbeta/delta Agonist GW501516 Inhibits Tumorigenicity of Undifferentiated Nasopharyngeal Carcinoma in C666-1 Cells by Promoting Apoptosis. AB - Activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) had been linked to inhibition on the proliferation and apoptosis in a few cancer cell lines. However, limited data exists regarding the role of PPARbeta/delta in nasopharyngeal carcinoma (NPC). This study was undertaken to determine the effect of PPARbeta/delta on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the human NPC cell lines. Gene and protein expression of PPARbeta/delta were reduced specifically in the poor- and un-differentiated NPC cell lines as compared with the control NP-69 cells. Ligand activation of PPARbeta/delta by GW501516, a specific PPARbeta/delta selective agonist, inhibited cell proliferation and colony formation strikingly, and induced a G2/M phase arrest in the EBV positive undifferentiated NPC C666-1 cells relative to the control cells. Moreover, GW501516 induced C666-1 cell apoptosis in a caspase and BAX dependent manner. In accordance with the in vitro result, GW501516 significantly suppressed the ectopic NPC xenograft tumorigenicity that derived from the C666-1 NPC cells in BALB/c nu/nu mice. This effect is greatly associated with its inhibition on the gene and protein expression of integrin linked kinase (ILK) through activation of the AMPKalpha-dependent signaling pathways. Collectively, we showed that PPARbeta/delta expression is in reverse correlation with the degree of differentiation in the NPC cell lines, and revealed the anti-tumorigenic effects of GW501516 in NPC cells by activation of AMPKalpha. This study suggested that PPARbeta/delta targeting molecules may be useful for the poor-, and particularly un-differentiated NPC chemoprevention. PMID- 30002623 TI - Feature Extraction and Classification Methods for Hybrid fNIRS-EEG Brain-Computer Interfaces. AB - In this study, a brain-computer interface (BCI) framework for hybrid functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) for locked-in syndrome (LIS) patients is investigated. Brain tasks, channel selection methods, and feature extraction and classification algorithms available in the literature are reviewed. First, we categorize various types of patients with cognitive and motor impairments to assess the suitability of BCI for each of them. The prefrontal cortex is identified as a suitable brain region for imaging. Second, the brain activity that contributes to the generation of hemodynamic signals is reviewed. Mental arithmetic and word formation tasks are found to be suitable for use with LIS patients. Third, since a specific targeted brain region is needed for BCI, methods for determining the region of interest are reviewed. The combination of a bundled-optode configuration and threshold-integrated vector phase analysis turns out to be a promising solution. Fourth, the usable fNIRS features and EEG features are reviewed. For hybrid BCI, a combination of the signal peak and mean fNIRS signals and the highest band powers of EEG signals is promising. For classification, linear discriminant analysis has been most widely used. However, further research on vector phase analysis as a classifier for multiple commands is desirable. Overall, proper brain region identification and proper selection of features will improve classification accuracy. In conclusion, five future research issues are identified, and a new BCI scheme, including brain therapy for LIS patients and using the framework of hybrid fNIRS-EEG BCI, is provided. PMID- 30002627 TI - Supplemented Use of Pre-, Pro-, and Synbiotics in Severe Acute Pancreatitis: An Updated Systematic Review and Meta-Analysis of 13 Randomized Controlled Trials. AB - Introduction: The role of pre-, pro-, and synbiotics supplemented to standard enteral nutrition in severe acute pancreatitis (SAP) remains unclear. We performed this updated meta-analysis to determine the value of pre-, pro- and synbiotics supplemented to standard enteral nutrition in predicted SAP. Methods: A systematic search in PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases was performed. Eligible studies were randomized controlled trials (RCTs) that compared the effects of pre-, pro-, and synbiotics supplemented to standard enteral nutrition with control regime in predicted SAP patients. Risk ratio (RR) and mean difference (MD) with 95% confidence interval (95% CI) were used to express the estimates of dichotomous and continuous data respectively. Results: 13 RCTs comprising an aggregate total of 950 patients were eventually enrolled. Pooled results suggested that supplemented use of pre-, pro- and synbiotics effectively shorten the length of hospital stay in Chinese SAP cohorts (6 RCTs, MD = -5.57, 95% CI = -8.21 to -2.93, P < 0.001); however significant differences with regard to remaining clinical outcomes were not detected for all patients. Further analysis based on category of interventions including pre-, pro- and synbiotics also confirmed the findings to be reliable. Conclusions: Supplemented use of pre-, pro and synbiotics reduced the length of hospital stay in Chinese SAP cohorts. And thus, we concluded that pre-, pro- and synbiotics supplemented to standard enteral nutrition may be a potential option for the treatment of SAP patients. However, we also suggest designing further studies with large-scale and rigorous methods of addressing data to establish the effects and safety of supplemented use of pre-, pro- and synbiotics for SAP patients due to the presence of limitations. PMID- 30002626 TI - Rhus coriaria L. (Sumac) Evokes Endothelium-Dependent Vasorelaxation of Rat Aorta: Involvement of the cAMP and cGMP Pathways. AB - Rhus coriaria L. (sumac) is widely used in traditional remedies and cuisine of countries of the Mediterranean as well as Central and South-West Asia. Administration of sumac to experimental models and patients with diverse pathological conditions generates multi-faceted propitious effects, including the quality as a vasodilator. Together, the effects are concertedly channeled toward cardiovasobolic protection. However, there is paucity of data on the mechanism of action for sumac's vasodilatory effect, an attribute which is considered to be advantageous for unhealthy circulatory system. Accordingly, we sought to determine the mechanisms by which sumac elicits its vasorelaxatory effects. We deciphered the signaling networks by application of a range of pharmacological inhibitors, biochemical assays and including the quantification of cyclic nucleotide monophosphates. Herein, we provide evidence that an ethanolic extract of sumac fruit, dose-dependently, relaxes rat isolated aorta. The mechanistic effect is achieved via stimulation of multiple transducers namely PI3-K/Akt, eNOS, NO, guanylyl cyclase, cGMP, and PKG. Interestingly, the arachidonic acid pathway (cyclooxygenases), adenylyl cyclase/cAMP and ATP-dependent potassium channels appear to partake in this sumac-orchestrated attenuation of vascular tone. Clearly, our data support the favorable potential cardio-vasculoprotective action of sumac. PMID- 30002628 TI - Screening of Combinatorial Quality Markers for Natural Products by Metabolomics Coupled With Chemometrics. A Case Study on Pollen Typhae. AB - Natural products, especially for traditional Chinese medicines (TCMs), are of great importance to cure diseases. Yet it was hard to screen the influential quality markers for monitoring the quality. A simple and comprehensive strategy was developed and validated to screen for the combinatorial quality markers for precise quality evaluation and discrimination of natural products. In this study, Pollen Typhae (PT) and it's processed products carbonized PT were selected as the representative case. Firstly, metabolomics data of 49 batches crude PT and carbonized PT was obtained by ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). Then, metabolomics approaches were performed to screen for the potential markers that lead to the quality difference. Finally, chemometric methods were used to validate the accuracy of combinatorial quality markers. Thus, 42 compounds were identified from PT, 5 markers (isorhamnetin-3-O-(2G-alpha-L-rhamnosyl) rutinoside, isorhamnetin-3-O-neohesperidoside, astragalin, kaempferol and umbelliferone) were successfully screened, identified, quantified and regarded as combinatorial quality markers for precise quality evaluation of crude and carbonized PT. It was demonstrated that the established comprehensively strategy provide an efficient tool for precise quality evaluation of natural products from the whole. PMID- 30002629 TI - A Critical Review of Consumer Wearables, Mobile Applications, and Equipment for Providing Biofeedback, Monitoring Stress, and Sleep in Physically Active Populations. AB - The commercial market for technologies to monitor and improve personal health and sports performance is ever expanding. A wide range of smart watches, bands, garments, and patches with embedded sensors, small portable devices and mobile applications now exist to record and provide users with feedback on many different physical performance variables. These variables include cardiorespiratory function, movement patterns, sweat analysis, tissue oxygenation, sleep, emotional state, and changes in cognitive function following concussion. In this review, we have summarized the features and evaluated the characteristics of a cross-section of technologies for health and sports performance according to what the technology is claimed to do, whether it has been validated and is reliable, and if it is suitable for general consumer use. Consumers who are choosing new technology should consider whether it (1) produces desirable (or non-desirable) outcomes, (2) has been developed based on real-world need, and (3) has been tested and proven effective in applied studies in different settings. Among the technologies included in this review, more than half have not been validated through independent research. Only 5% of the technologies have been formally validated. Around 10% of technologies have been developed for and used in research. The value of such technologies for consumer use is debatable, however, because they may require extra time to set up and interpret the data they produce. Looking to the future, the rapidly expanding market of health and sports performance technology has much to offer consumers. To create a competitive advantage, companies producing health and performance technologies should consult with consumers to identify real-world need, and invest in research to prove the effectiveness of their products. To get the best value, consumers should carefully select such products, not only based on their personal needs, but also according to the strength of supporting evidence and effectiveness of the products. PMID- 30002630 TI - Long-Term Chronic Intermittent Hypobaric Hypoxia Induces Glucose Transporter (GLUT4) Translocation Through AMP-Activated Protein Kinase (AMPK) in the Soleus Muscle in Lean Rats. AB - Background: In chronic hypoxia (CH) and short-term chronic intermittent hypoxia (CIH) exposure, glycemia and insulin levels decrease and insulin sensitivity increases, which can be explained by changes in glucose transport at skeletal muscles involving GLUT1, GLUT4, Akt, and AMPK, as well as GLUT4 translocation to cell membranes. However, during long-term CIH, there is no information regarding whether these changes occur similarly or differently than in other types of hypoxia exposure. This study evaluated the levels of AMPK and Akt and the location of GLUT4 in the soleus muscles of lean rats exposed to long-term CIH, CH, and normoxia (NX) and compared the findings. Methods: Thirty male adult rats were randomly assigned to three groups: a NX (760 Torr) group (n = 10), a CIH group (2 days hypoxia/2 days NX; n = 10) and a CH group (n = 10). Rats were exposed to hypoxia for 30 days in a hypobaric chamber set at 428 Torr (4,600 m). Feeding (10 g daily) and fasting times were accurately controlled. Measurements included food intake (every 4 days), weight, hematocrit, hemoglobin, glycemia, serum insulin (by ELISA), and insulin sensitivity at days 0 and 30. GLUT1, GLUT4, AMPK levels and Akt activation in rat soleus muscles were determined by western blot. GLUT4 translocation was measured with confocal microscopy at day 30. Results: (1) Weight loss and increases in hematocrit and hemoglobin were found in both hypoxic groups (p < 0.05). (2) A moderate decrease in glycemia and plasma insulin was found. (3) Insulin sensitivity was greater in the CIH group (p < 0.05). (4) There were no changes in GLUT1, GLUT4 levels or in Akt activation. (5) The level of activated AMPK was increased only in the CIH group (p < 0.05). (6) Increased GLUT4 translocation to the plasma membrane of soleus muscle cells was observed in the CIH group (p < 0.05). Conclusion: In lean rats experiencing long term CIH, glycemia and insulin levels decrease and insulin sensitivity increases. Interestingly, there is no increase of GLUT1 or GLUT4 levels or in Akt activation. Therefore, cellular regulation of glucose seems to primarily involve GLUT4 translocation to the cell membrane in response to hypoxia-mediated AMPK activation. PMID- 30002633 TI - A Comparison of Three Empirical Reliability Estimates for Computerized Adaptive Testing (CAT) Using a Medical Licensing Examination. AB - Arithmetic mean, Harmonic mean, and Jensen equality were applied to marginalize observed standard errors (OSEs) to estimate CAT reliability. Based on different marginalization method, three empirical CAT reliabilities were compared with true reliabilities. Results showed that three empirical CAT reliabilities were underestimated compared to true reliability in short test length (<40), whereas the magnitude of CAT reliabilities was followed by Jensen equality, Harmonic mean, and Arithmetic mean when mean of ability population distribution is zero. Specifically, Jensen equality overestimated true reliability when the number of items is over 40 and mean ability population distribution is zero. However, Jensen equality was recommended for computing reliability estimates because it was closer to true reliability even if small numbers of items was administered regardless of the mean of ability population distribution, and it can be computed easily by using a single test information value at theta = 0. Although CAT is efficient and accurate compared to a fixed-form test, a small fixed number of items is not recommended as a CAT termination criterion for 2PLM, specifically for 3PLM, to maintain high reliability estimates. PMID- 30002631 TI - Cyclic Stretch Negatively Regulates IL-1beta Secretion Through the Inhibition of NLRP3 Inflammasome Activation by Attenuating the AMP Kinase Pathway. AB - Macrophages are immune cells of hematopoietic origin that play diverse roles in host defenses and tissue homeostasis. In mechanical microenvironments, macrophages receive mechanical signals that regulate various cellular functions. However, the mechanisms by which mechanical signals influence the phenotype and function of macrophages in the process of inflammation have not yet been elucidated in detail. We herein examined the effects of cyclic stretch (CS) on NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation in J774.1, a murine macrophage cell line, and mouse primary bone marrow-derived macrophages. We showed that cyclic stretch inhibited adenosine triphosphate (ATP)-stimulated interleukin (IL)-1beta secretion in lipopolysaccharide (LPS)-primed macrophages using ELISA and Western blot analyses. Cyclic stretch did not affect the degradation of the Inhibitor of kappaB or the nuclear translocation/transcriptional activity of nuclear factor (NF)-kappaB, suggesting that cyclic stretch-mediated inhibition was independent of the NF-kappaB signaling pathway. Consistent with these results, cyclic stretch did not affect the LPS-induced expression of inflammasome components, such as pro-IL-1beta and NLRP3, which is known to require the activation of NF-kappaB signaling. We showed that the cyclic stretch-mediated inhibition of IL-1beta secretion was caused by the suppression of caspase-1 activity. The addition of compound C, a specific inhibitor of adenosine monophosphate-activated protein kinase (AMPK), to LPS primed macrophages inhibited IL-1beta secretion as well as caspase-1 activation, suggesting that AMPK signaling is involved in ATP-triggered IL-1beta secretion. Furthermore, the phosphorylation of AMPK induced by ATP in LPS-primed macrophages was significantly suppressed by cyclic stretch, indicating that cyclic stretch negatively regulates IL-1beta secretion through the inhibition of caspase-1 activity by attenuating the AMPK pathway. Our results suggest that mechanical stress functions to maintain homeostasis through the prevention of excessive inflammasome activation in macrophages in mechanical microenvironments. PMID- 30002632 TI - Validation and Factor Analysis of the Japanese Version of the Highs Scale in Perinatal Women. AB - Background: The Highs scale has been developed to evaluate hypomanic symptoms in the first postpartum week. However, it has not been elucidated whether this scale is also applicable to pregnant women. To address this issue, we confirmed the factor structure, reliability, and validity of the Japanese version of the Highs scale for pregnant and postpartum women. Methods: 418 women provided effective responses to both the Highs scale and the Edinburgh Postnatal Depression Scale (EPDS) during early pregnancy (before week 25), late pregnancy (around week 36), at 5 days and at 1 month after delivery. Subjects were randomly divided into two groups, and exploratory and confirmatory factor analyses were performed for each group. Cronbach's alpha was calculated and the correlation of the Highs scale with EPDS was analyzed. The correlation between the subscales was analyzed at four time points, and the correlation of subscales between the four time points was confirmed. Results: This scale was found to have the two-factor structure with elation and agitation subscales. The two subscales had reasonable internal consistency at all time points (Cronbach's alpha range: Factor 1, 0.696-0.758; Factor 2, 0.553-0.694). The overall scale had reasonable internal consistency at all time points (Cronbach's alpha range: 0.672-0.738). Based on the correlation analysis of the two subscales and EPDS, discriminative and convergent validity were indicated at all time points, confirming the construct validity of the Highs scale. Subscale scores showed a significant correlation with EPDS at all time points (r = 0.388, 0.384, 0.498, and 0.442, p < 0.01). Conclusions: The Japanese version of the Highs scale is reliable and valid, and can be applied for evaluating the hypomanic symptoms during pregnancy and postpartum period. PMID- 30002635 TI - When the Sad Past Is Left: The Mental Metaphors Between Time, Valence, and Space. AB - A mental metaphor is a strategy that consists of completing the representation of a concept with structural components of a correlating concept. Three issues were addressed here to deepen our understanding of this mechanism: the use of mental metaphors between abstract concepts, the simultaneous activation of multiple mental metaphors and the importance of the focus of attention on the relevant dimensions of a mental metaphor. In two experiments, participants made temporal or valence judgments (with their left or right hand) on verbs with a negative or positive meaning and conjugated in the past or future form, allowing for the simultaneous activation of the "time is space", "valence is space," and "time is valence" mental metaphors. Left-past/right-future and left-negative/right positive congruency effects were found, and these effects were greater in the temporal and valence judgment tasks, respectively, demonstrating the importance of attentional cuing. Simultaneously, a congruency effect between the abstract concepts of time and valence (past-negative/future-positive) was observed, revealing that a mental metaphor can occur between abstract concepts and that multiple metaphors can be processed simultaneously. These results are discussed in terms of different theories within the field of mental metaphors. PMID- 30002634 TI - Weight Fluctuation and Diet Concern Negatively Affect Food-Related Life Satisfaction in Chilean Male and Female Adolescents. AB - Problematic eating behaviors and obesity are frequent problems encountered during adolescence that may potentially result in psychological, social and physical consequences that may interfere with adolescent development and well-being. The present study evaluates the relationship between satisfaction with food-related life and satisfaction with family life, and their relationship with life satisfaction in male and female adolescents. We explored the relationships between both subscales of the Revised Restraint Scale (RRS), Diet Concern (DC) and Weight Fluctuation (WF) and adolescent life satisfaction as well as satisfaction with food-related life and family life. We also explored the moderating role of socioeconomic status (SES). A questionnaire was applied to a non-probabilistic sample of 470 adolescents (mean age 13.2 years, 52.3% female) in Chile, including the RRS, Satisfaction with Life Scale (SWLS), Satisfaction with Food-related Life (SWL-Food) scale and Satisfaction with Family Life (SWL Family) scale. Using structural equation modeling, we found that adolescent life satisfaction was related to satisfaction with family life and food-related life in both genders. In male adolescents, a negative relationship was identified between WF and food-related life satisfaction. In contrast, a negative relationship was identified in female adolescents between DC and food-related life satisfaction. DC and WF were not directly related to life satisfaction or to satisfaction with family life in either gender. SES was found to moderate the relationship between food-related life satisfaction and life satisfaction and the relationship between WF and food-related life satisfaction in female adolescents. These findings suggest that reducing DC in female adolescents and reducing WF in male adolescents and female adolescents from higher SES may improve their food related life satisfaction. PMID- 30002636 TI - Causal Illusions in the Service of Political Attitudes in Spain and the United Kingdom. AB - The causal illusion is a cognitive bias that results in the perception of causality where there is no supporting evidence. We show that people selectively exhibit the bias, especially in those situations where it favors their current worldview as revealed by their political orientation. In our two experiments (one conducted in Spain and one conducted in the United Kingdom), participants who self-positioned themselves on the ideological left formed the illusion that a left-wing ruling party was more successful in improving city indicators than a right-wing party, while participants on the ideological right tended to show the opposite pattern. In sum, despite the fact that the same information was presented to all participants, people developed the causal illusion bias selectively, providing very different interpretations that aligned with their previous attitudes. This result occurs in situations where participants inspect the relationship between the government's actions and positive outcomes (improving city indicators) but not when the outcomes are negative (worsening city indicators). PMID- 30002637 TI - Peer Victimization and Aggressive Behavior Among Chinese Adolescents: Delinquent Peer Affiliation as a Mediator and Parental Knowledge as a Moderator. AB - Grounded in social network theory and a risk-buffering model, this study examined whether delinquent peer affiliation mediated the association between peer victimization and adolescent aggressive behavior and whether this mediating process was moderated by parental knowledge. A total of 4,209 Chinese adolescents (48.47% male, Mage = 13.68) completed questionnaires on peer victimization, parental knowledge, delinquent peer affiliation, and adolescent aggressive behavior. Path analyses showed that delinquent peer affiliation partially mediated the relationship between peer victimization and aggressive behavior. Moreover, parental knowledge had a protective effect of buffering the adverse influence of peer victimization on aggressive behavior. This indirect link was stronger for adolescents with low parental knowledge than for those with high parental knowledge. This finding highlights delinquent peer affiliation as a potential link between peer victimization and aggressive behavior and provides an effective intervention for addressing the adverse effects of peer victimization. PMID- 30002638 TI - Cross-Cultural Analysis of Volition: Action Orientation Is Associated With Less Anxious Motive Enactment and Greater Well-Being in Germany, New Zealand, and Bangladesh. AB - Background: People differ in action vs. state orientation, that is, in the capacity for volitional action control. Prior research has shown that people who are action-rather than state-oriented are better able to perceive and satisfy own motives (e.g., affiliation, achievement, power), which translates into greater psychological well-being (Baumann et al., 2005; Baumann and Quirin, 2006). However, most of the extant literature has been limited to samples from European countries or the US. To address this shortcoming, the present paper investigated the associations between action vs. state orientation, psychological well-being, and anxious style of motive enactment among samples in Germany, New Zealand, and Bangladesh (combined N = 862). Methods: To examine the consistency of our results across countries, a multi-group structural equation model (SEM) was used to examine the associations between action orientation, anxious motive enactment, and well-being. Subsequent mediation analyses assessed whether anxious motive enactment mediated the relationship between action orientation and well-being across each of the three samples. Results: Across all three cultural groups, action orientation was associated with less anxious motive enactment and higher well-being. Moreover, mediation analyses revealed significant indirect paths from action orientation through less anxious motive enactment to well-being that were similar across the three samples. Conclusions: These findings suggest that individual differences in action vs. state orientation have a similar psychological meaning across Western and non-Western cultures. PMID- 30002639 TI - Moral Judgement in Early Bilinguals: Language Dominance Influences Responses to Moral Dilemmas. AB - The Foreign-Language effect (FLe) on morality describes how late bilinguals make different decisions on moral judgements, when presented in either their native or foreign language. However the relevance of this phenomenon to early bilinguals, where a language's "nativeness" is less distinct, is unknown. This study aims to verify the effect of early bilinguals' languages on their moral decisions and examine how language experience may influence these decisions. Eighty-six early English-Chinese bilinguals were asked to perform a moral dilemmas task consisting of personal and impersonal dilemmas, in either English or Mandarin Chinese. Information on language experience factors were also collected from the participants. Findings suggest that early bilinguals do show evidence of a language effect on their moral decisions, which is dependent on how dominant they are in the language. Particularly, the more dominant participants were in their tested language, the larger the difference between their personal and impersonal dilemma response choice. In light of these findings, the study discusses the need to re-examine how we conceptualize the FLe phenomenon and its implications on bilinguals' moral judgement. It also addresses the importance of treating bilingualism as multidimensional, rather than a unitary variable. PMID- 30002640 TI - A Mental Odd-Even Continuum Account: Some Numbers May Be "More Odd" Than Others and Some Numbers May Be "More Even" Than Others. AB - Numerical categories such as parity, i.e., being odd or even, have frequently been shown to influence how particular numbers are processed. Mathematically, number parity is defined categorically. So far, cognitive, and psychological accounts have followed the mathematical definition and defined parity as a categorical psychological representation as well. In this manuscript, we wish to test the alternative account that cognitively, parity is represented in a more gradual manner such that some numbers are represented as "more odd" or "more even" than other odd or even numbers, respectively. Specifically, parity processing might be influenced by more specific properties such as whether a number is a prime, a square number, a power of 2, part of a multiplication table, divisible by 4 or by 5, and many others. We suggest that these properties can influence the psychologically represented parity of a number, making it more or less prototypical for odd- or evenness. In the present study, we tested the influence of these numerical properties in a bimanual parity judgment task with auditorily presented two-digit numbers. Additionally, we further investigated the interaction of these numerical properties with linguistic factors in three language groups (English, German, and Polish). Results show significant effects on reaction times of the congruity of parity status between decade and unit digits, even if numerical magnitude and word frequency are controlled. We also observed other effects of the above specific numerical properties, such as multiplication attributes, which facilitated or interfered with the speed of parity judgment. Based on these effects of specific numerical properties we proposed and elaborated a parity continuum account. However, our cross-lingual study also suggests that parity representation and/or access seem to depend on the linguistic properties of the respective language or education and culture. Overall, the results suggest that the "perceived" parity is not the same as objective parity, and some numbers are more prototypical exemplars of their categories. PMID- 30002641 TI - Angels and Demons: The Effect of Ethical Leadership on Machiavellian Employees' Work Behaviors. AB - Machiavellians can be characterized as goal-driven people who are willing to use all possible means to achieve their ends, and employees scoring high on Machiavellianism are thus predisposed to engage in unethical and organizationally undesirable behaviors. We propose that leadership can help to manage such employees in a way that reduces undesirable and increases desirable behaviors. Studies on the effects of leadership styles on Machiavellian employees are scarce. Here we investigate the relationship of ethical leadership with prosocial (helping colleagues or affiliative OCB) and antisocial work behavior (knowledge hiding and emotional manipulation) for employees who are higher or lower in Machiavellianism. The effect of an ethical leadership style on employees predisposed to engage in unethical behaviors has not been investigated so far. In a cross-sectional multi-source survey study among a sample of 159 unique leader follower dyads, we find interaction effects between leadership and employee Machiavellianism for prosocial and antisocial work behavior. As expected, employee Machiavellianism comes with reduced helping behavior and increased knowledge hiding and emotional manipulation, but only when ethical leadership is low. Under highly ethical leaders, such increases in organizationally undesirable behaviors of Machiavellian employees do not occur. While the cross-sectional design precludes conclusions about the direction of causality, findings of our study suggest to further explore (and from a practical perspective to invest in) ethical leadership as a potential remedy for undesirable behavior of Machiavellian employees. PMID- 30002642 TI - Contributions of Neuropsychology to the Study of Ancient Literature. AB - The present work introduces the neuropsychological paradigm as a new approach to studying ancient literature. In the first part of the article, an epistemological framework for the proper use of neuropsychology in relation to ancient literature is presented. The article then discusses neuropsychological methods of studying different human experiences and dimensions already addressed by ancient literatures. The experiences of human encounters with gods among ancient cultures are first considered, through the contributions of Julian Jaynes and Eric R. Dodds. The concepts of right and left in the Bible, and that of soul are then discussed. Ecstatic experience in Paul of Tarsus is also presented, with a particular focus on glossolalia. Neuroscientific differences between mindful and unitive meditative practices are then described referring to ancient Buddhist literature, and finally a brief description of dreams in ancient Greek literature is proposed. Neuropsychology variously enables a more profound understanding of themes characterizing human experiences that ancient literature has already explored; these investigations prove that the collaboration of neuroscience and humanistic studies can return fruitful and interesting results. PMID- 30002643 TI - Why We Should Study Multimodal Language. PMID- 30002644 TI - Perioptic Cerebrospinal Fluid Dynamics in Idiopathic Intracranial Hypertension. AB - Purpose: To examine the cerebrospinal fluid (CSF) dynamics along the entire optic nerve in patients with idiopathic intracranial hypertension (IIH) and papilledema by computed tomographic (CT) cisternography. Methods: Retrospective analysis of CT cisternographies in 16 patients with a history of IIH and papilledema (14 females and 2 males, mean age: 49 +/- 16 years). Contrast loaded CSF (CLCSF) was measured in Hounsfield Units (HU) at three defined regions of interest (ROI) along the optic nerve (orbital optic nerve portion: bulbar and mid-orbital segment, intracranial optic nerve portion) and additionally in the basal cistern. The density measurements in ROI 1, ROI 2, and ROI 3 consist of measurements of the optic nerve complex: optic nerve sheath, CLCSF filled SAS and optic nerve tissue. As controls served a group of patients (mean age: 60 +/- 19 years) without elevated intracranial pressure and without papilledema. Results: In IIH patients the mean CLCSF density in the bulbar segment measured 65 +/- 53 HU on the right and 63 +/- 35 HU on the left side, in the mid-orbital segment 68 +/- 37 HU right and 60 +/- 21 HU left. In the intracranial optic nerve portion 303 +/- 137 HU right and 323 +/- 169 HU left and in the basal cistern 623 +/- 188 HU. Within the optic nerve the difference of CLCSF density showed a highly statistical difference (p < 0.001) between the intracranial optic nerve portion and the mid-orbital segment. CLCSF density was statistically significantly (p < 0.001) reduced in both intraorbital optic nerve segments in patients with IIH compared to controls. Conclusions: The current study demonstrates reduced CLCSF density within the orbital optic nerve segments in patients with IIH and papilledema compared to 12 controls without elevated intracranial pressure and without papilledema. Impaired CSF dynamics could be involved in the pathophysiology of optic nerve damage in PE in IIH. PMID- 30002646 TI - Prep1, A Homeodomain Transcription Factor Involved in Glucose and Lipid Metabolism. AB - The three-amino acid loop extension (TALE) homeodomain proteins are a family of transcription factor including the mammalian Pbx, MEIS and Prep proteins. TALE proteins can bind other transcription factors such as Pdx-1 and play an important role in the regulation of glucose metabolism. Experiments performed in mutant mice have shown that while the single Pbx1 or Pdx-1 knockout mice feature pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia, the trans-heterozygous Pbx1+/-Pdx1+/- mice develop age-dependent overt diabetes mellitus. In contrast, Prep1 plays a different role with respect to these proteins. Indeed, Prep1 hypomorphic mice, expressing low levels of protein, feature pancreatic islet hypoplasia accompanied by hypoinsulinemia similar to Pbx1 or Pdx1. Nevertheless, these animals show increased insulin sensitivity in skeletal muscle, liver and adipose tissue accompanied by protection from streptozotocin-induced diabetes. In addition, Prep1 hypomorphic mice feature reduced triglyceride synthesis and do not develop steatohepatitis after a methionine and coline deficient diet. In this review we have underlined how important metabolic functions are controlled by TALE proteins, in particular by Prep1, leading to hypothesis that its suppression might represent beneficial effect in the care of metabolic diseases. PMID- 30002645 TI - Generalizability of High Frequency Oscillation Evaluations in the Ripple Band. AB - Objective: We examined the interrater reliability and generalizability of high frequency oscillation (HFO) visual evaluations in the ripple (80-250 Hz) band, and established a framework for the transition of HFO analysis to routine clinical care. We were interested in the interrater reliability or epoch generalizability to describe how similar the evaluations were between reviewers, and in the reviewer generalizability to represent the consistency of the internal threshold each individual reviewer. Methods: We studied 41 adult epilepsy patients (mean age: 35.6 years) who underwent intracranial electroencephalography. A morphology detector was designed and used to detect candidate HFO events, lower-threshold events, and distractor events. These events were subsequently presented to six expert reviewers, who visually evaluated events for the presence of HFOs. Generalizability theory was used to characterize the epoch generalizability (interrater reliability) and reviewer generalizability (internal threshold consistency) of visual evaluations, as well as to project the numbers of epochs, reviewers, and datasets required to achieve strong generalizability (threshold of 0.8). Results: The reviewer generalizability was almost perfect (0.983), indicating there were sufficient evaluations to determine the internal threshold of each reviewer. However, the interrater reliability for 6 reviewers (0.588) and pairwise interrater reliability (0.322) were both poor, indicating that the agreement of 6 reviewers is insufficient to reliably establish the presence or absence of individual HFOs. Strong interrater reliability (>=0.8) was projected as requiring a minimum of 17 reviewers, while strong reviewer generalizability could be achieved with <30 epoch evaluations per reviewer. Significance: This study reaffirms the poor reliability of using small numbers of reviewers to identify HFOs, and projects the number of reviewers required to overcome this limitation. It also provides a set of tools which may be used for training reviewers, tracking changes to interrater reliability, and for constructing a benchmark set of epochs that can serve as a generalizable gold standard, against which other HFO detection algorithms may be compared. This study represents an important step toward the reconciliation of important but discordant findings from HFO studies undertaken with different sets of HFOs, and ultimately toward transitioning HFO analysis into a meaningful part of the clinical epilepsy workup. PMID- 30002647 TI - Cryopreservation of Ovarian Tissue: Opportunities Beyond Fertility Preservation and a Positive View Into the Future. AB - In current years, ovarian tissue cryopreservation (OTC) and transplantation is gaining ground as a successful method of preserving fertility in young women with primarily cancer diseases, hereby giving them a chance of becoming biological mothers later on. However, OTC preserves more than just the reproductive potential; it restores the ovarian endocrine function and thus the entire female reproductive cycle with natural levels of essential hormones. In a female population with an increased prevalence in the loss of ovarian function due to induced primary ovarian insufficiency (POI) and aging, there is now, a need to develop new treatments and provide new opportunities to utilize the enormous surplus of follicles that most females are born with and overcome major health issues associated with the lack of ovarian hormones. Cell/tissue-based hormone replacement therapy (cHRT) by the use of stored ovarian tissue could be one such option comprising both induction of puberty in prepubertal POI girls, treatment of POI and premature menopause, and as primary prevention at the onset of menopause. In the current review, we explore known and entirely new applications for the potential utilization of OTC including cHRT, social freezing, culture of immature oocytes, and a modern ovarian resection for women with polycystic ovaries, and discuss the indications hereof. PMID- 30002648 TI - Tetracycline and Sulfonamide Antibiotic Resistance Genes in Soils From Nebraska Organic Farming Operations. AB - There is widespread agreement that agricultural antibiotic resistance should be reduced, however, it is unclear from the available literature what an appropriate target for reduction would be. Organic farms provide a unique opportunity to disentangle questions of agricultural antibiotic drug use from questions of antibiotic resistance in the soil. In this study, soil was collected from 12 certified organic farms in Nebraska, evaluated for the presence of tetracycline and sulfonamide resistance genes (n = 15 targets), and correlated to soil physical, chemical, and biological parameters. Tetracycline and sulfonamide antibiotic resistance genes (ARGs) were found in soils from all 12 farms, and 182 of the 196 soil samples (93%). The most frequently detected gene was tetG (55% of samples), followed by tet(Q) (49%), tet(S) (46%), tet(X) (30%), and tetA(P) (29%). Soil was collected from two depths. No differences in ARGs were observed based on soil depth. Positive correlations were noted between ARG presence and soil electrical conductivity, and concentrations of Ca, Na, and Mehlich-3 phosphorus. Data from this study point to possible relationships between selected soil properties and individual tetracycline resistance genes, including tet(O) which is a common target for environmental samples. We compared organic farm results to previously published data from prairie soils and found significant differences in detection frequency for 12 genes, eight of which were more commonly detected in prairie soils. Of interest, when tetracycline ARG results were sorted by gene mechanism, the efflux genes were generally present in higher frequency in the prairie soils, while the ribosomal protection and enzymatic genes were more frequently detected in organic farm soils, suggesting a possible ecological role for specific tetracycline resistance mechanisms. By comparing soil from organic farms with prairie soils, we can start to determine baseline effects of low-chemical input agricultural production practices on multiple measures of resistance. PMID- 30002649 TI - Detection and Characterization of Salmonella Serotypes in the Production Chain of Two Pig Farms in Buenos Aires Province, Argentina. AB - The aim of the present study was to determine the prevalence of Salmonella in the pork production chain and to characterize Salmonella isolates. From 764 samples, 35 (4.6%) were positive for Salmonella spp., as determined by biochemical tests and the presence of the invA gene. From these, 2.6, 2.0, 8.8, and 8.0% corresponded to samples collected from farms, slaughterhouses, boning rooms and retail markets, respectively. Salmonella strains were classified into five serotypes and distributed as follows: S. Typhimurium in the pork production chain, S. Kentucky in farms and slaughterhouses, S. Brandenburg in slaughterhouses, S. Livingstone in farms and S. Agona in boning rooms and retail markets. Interestingly, the antimicrobial susceptibility testing indicated that all 35 Salmonella spp.-positive isolates were resistant to at least one antimicrobial agent, and 30 were multidrug-resistant (MDR) and resistant to different classes of antibiotics. The enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) analysis showed clonal relatedness among strains isolated from farms, boning rooms and retail markets. The presence of antibiotic-resistant Salmonella in food poses a potential health hazard to consumers. PMID- 30002650 TI - Investigation of Citrinin and Pigment Biosynthesis Mechanisms in Monascus purpureus by Transcriptomic Analysis. AB - Monascus purpureus YY-1 is widely used in food colorant production in China. Our previous study clearly illustrated the whole-genome data for YY-1 and provided useful insight into evolutionary research and industrial applications. However, the presence of citrinin, which has nephrotoxic, hepatotoxic, and carcinogenic activities, has attracted attention to the safety of Monascus products. In an effort to reduce the harmful effects of citrinin in Monascus-related products, a random mutant of M. purpureus YY-1 with low citrinin production (designated as "winter") was obtained in this study. To analyze the biosynthesis and regulation mechanisms of pigment and citrinin, a transcriptomic analysis of the M. purpureus YY-1 and winter strains was performed. Comparative transcriptomic analysis reveals pksCT, the essential gene for citrinin synthesis, showed a low expression level in M. purpureus YY-1 and winter, which suggested there might be isoenzymes in M. purpureus YY-1 that were responsible for the citrinin synthesis during evolution. In addition, changes in transcription factor expression may also influence the network regulating the citrinin synthesis pathway in M. purpureus. Moreover, the yields of pigments produced by the winter mutant were significantly increased. Repressing the central carbon metabolism and improving the acetyl-CoA pool can contribute to a high pigment yield, and enhanced NADPH regeneration can also lead to the metabolic flux of pigment production in M. purpureus. Investigations into the biosynthesis and regulation of citrinin and pigment production in M. purpureus will enhance our knowledge of the mechanisms behind the biosynthesis of fungal secondary metabolites. PMID- 30002651 TI - Development of a Method to Monitor Gene Expression in Single Bacterial Cells During the Interaction With Plants and Use to Study the Expression of the Type III Secretion System in Single Cells of Dickeya dadantii in Potato. AB - Dickeya dadantii is a bacterial plant pathogen that causes soft rot disease on a wide range of host plants. The type III secretion system (T3SS) is an important virulence factor in D. dadantii. Expression of the T3SS is induced in the plant apoplast or in hrp-inducing minimal medium (hrp-MM), and is repressed in nutrient rich media. Despite the understanding of induction conditions, how individual cells in a clonal bacterial population respond to these conditions and modulate T3SS expression is not well understood. In our previous study, we reported that in a clonal population, only a small proportion of bacteria highly expressed T3SS genes while the majority of the population did not express T3SS genes under hrp MM condition. In this study, we developed a method that enabled in situ observation and quantification of gene expression in single bacterial cells in planta. Using this technique, we observed that the expression of the T3SS genes hrpA and hrpN is restricted to a small proportion of D. dadantii cells during the infection of potato. We also report that the expression of T3SS genes is higher at early stages of infection compared to later stages. This expression modulation is achieved through adjusting the ratio of T3SS ON and T3SS OFF cells and the expression intensity of T3SS ON cells. Our findings not only shed light into how bacteria use a bi-stable gene expression manner to modulate an important virulence factor, but also provide a useful tool to study gene expression in individual bacterial cells in planta. PMID- 30002652 TI - Adding a C-terminal Cysteine (CTC) Can Enhance the Bactericidal Activity of Three Different Antimicrobial Peptides. AB - The emergence of antibiotic-resistant bacteria has threatened our health worldwide. There is an urgent need for novel antibiotics. Previously, we identified a novel 37-mer antimicrobial peptide (AMP), HBcARD, with broad spectrum antimicrobial activity. Here, we improved the efficacy of HBcARD, by re engineering the peptide, including the addition of a new cysteine to its C terminus (CTC). The new 28-mer derivative, D-150-177C, contains all D-form arginines, in addition to a C-terminal cycteine. This peptide can kill antibiotic resistant clinical isolates of Gram-negative bacteria, and is more potent than the parental HBcARD peptide in a mouse sepsis model. In another lung infection mouse model, D-150-177C showed protection efficacy against colistin-resistant Acinetobacter baumannii. Unlike colistin, we observed no acute toxicity of D-150 177C in vivo. Interestingly, we found that CTC modification could enhance the antibacterial activity of several other AMPs, such as buforinII and lysin. The potential application and mechanism of this CTC method as a general approach to improving drug efficacy, warrants further investigation in the future. PMID- 30002653 TI - Selective Regulation of Cytoskeletal Dynamics and Filopodia Formation by Teleost Leukocyte Immune-Type Receptors Differentially Contributes to Target Capture During the Phagocytic Process. AB - Phagocytosis evolved from a fundamental nutrient acquisition mechanism in primitive unicellular amoeboids, into a dynamic and complex component of innate immunity in multicellular organisms. To better understand the cellular mechanisms contributing to phagocytic processes across vertebrates, our research has focused on characterizing the involvement of innate immune proteins originally identified in channel catfish (Ictalurus punctatus) called leukocyte immune-type receptors (IpLITRs). These unique teleost proteins share basic structural as well as distant phylogenetic relationships with several immunoregulatory proteins within the mammalian immunoglobulin superfamily. In the present study, we use a combination of live-cell confocal imaging and high-resolution scanning electron microscopy to further examine the classical immunoreceptor tyrosine-based activation motif (ITAM)-dependent phagocytic pathway mediated by the chimeric construct IpLITR 2.6b/IpFcRgamma-L and the functionally diverse immunoreceptor tyrosine-based inhibitory motif-containing receptor IpLITR 1.1b. Results demonstrate that IpLITR 1.1b-expressing cells can uniquely generate actin-dense filopodia-like protrusions during the early stages of extracellular target interactions. In addition, we observed that these structures retract after contacting extracellular targets to secure captured microspheres on the cell surface. This activity was often followed by the generation of robust secondary waves of actin polymerization leading to the formation of stabilized phagocytic cups. At depressed temperatures of 27 degrees C, IpLITR 2.6b/IpFcRgamma-L mediated phagocytosis was completely blocked, whereas IpLITR 1.1b-expressing cells continued to generate dynamic actin-dense filopodia at this lower temperature. Overall, these results provide new support for the hypothesis that IpLITR 1.1b, but not IpLITR 2.6b/IpFcRgamma-L, directly triggers filopodia formation when expressed in representative myeloid cells. This also offers new information regarding the directed ability of immunoregulatory receptor-types to initiate dynamic membrane structures and provides insights into an alternative ITAM-independent target capture pathway that is functionally distinct from the classical phagocytic pathways. PMID- 30002654 TI - Meta-Analysis of Autoimmune Regulator-Regulated Genes in Human and Murine Models: A Novel Human Model Provides Insights on the Role of Autoimmune Regulator in Regulating STAT1 and STAT1-Regulated Genes. AB - Autoimmune regulator (AIRE) regulates promiscuous expression of tissue-restricted antigens in medullary epithelial cells (mTEC) of the thymus. To understand the diverse effects of AIRE, it is crucial to elucidate the molecular mechanisms underlying the process of AIRE-regulated gene expression. In this study, we generated a recombinant AIRE expression variant of the TEC 1A3 human cell line, TEC 1A3 AIREhi, to determine genes targeted by AIRE, and using microarray analysis, we identified 482 genes showing significant differential expression (P < 0.05; false discovery rate <5%), with 353 upregulated and 129 downregulated by AIRE expression. Microarray data were validated by quantitative PCR, confirming the differential expression of 12 known AIRE-regulated genes. Comparison of AIRE dependent differential expression in our cell line model with murine datasets identified 447 conserved genes with a number of transcription regulatory interactions, forming several key nodes, including STAT1, which had over 30 interactions with other AIRE-regulated genes. As STAT1 mutations cause dominant chronic mucocutaneous candidiasis and decreased STAT1 levels in monocytes of autoimmune polyglandular syndrome 1 (APS-1) patients, it was important to further characterize AIRE-STAT1 interactions. TEC 1A3AIREhi were treated with the STAT1 phosphorylation inhibitors fludarabine and LLL3 showed that phosphorylated STAT1 (p-STAT1) was not responsible for any of the observed differential expression. Moreover, treatment of TEC 1A3 AIREhi with STAT1 shRNA did not induce any significant variation in the expression of unphosphorylated STAT1 (U-STAT1) downstream genes, suggesting that these genes were directly regulated by AIRE but not via U-STAT1. The novel model system we have developed provides potential opportunities for further analysis of the pathogenesis of (APS-1) and the wider roles of the AIRE gene. PMID- 30002655 TI - Latent Membrane Protein 1 of Epstein-Barr Virus Promotes RIG-I Degradation Mediated by Proteasome Pathway. AB - RIG-I signaling is critical to host innate immune response against RNA virus infection, and also can be activated against many kinds of cancer. Oncogene LMP1 of Epstein-Barr virus (EBV) contributes to various tumors progress. In this study, we have provided strong evidence that LMP1 inhibits Sendai virus mediated type I interferon production and downregulates RIG-I signaling pathway by promotion RIG-I degradation dependent on proteasome. Nineteen kinds of E3 ligase are identified by IP-MS as LMP1-interactors, they are candidate E3s, which are possibly recruited by LMP1 to mediate RIG-I degradation. CHIP is among these E3s, which has been reported to lead RIG-I degradation. Notably, we find C666-1, an EBV-positive nasopharyngeal carcinoma cell line, expresses low level of RIG-I, even treated with IFN-alpha, RIG-I expression could not be induced. This evidence indicates that EBV employs a unique strategy to evade RIG-I mediated immune responses. PMID- 30002657 TI - Hepatitis C Vaccines, Antibodies, and T Cells. AB - The development of vaccines that protect against persistent hepatitis C virus (HCV) infection remain a public health priority. The broad use of highly effective direct-acting antivirals (DAAs) is unlikely to achieve HCV elimination without vaccines that can limit viral transmission. Two vaccines targeting either the antibody or the T cell response are currently in preclinical or clinical trials. Next-generation vaccines will likely involve a combination of these two strategies. This review summarizes the state of knowledge about the immune protective role of HCV-specific antibodies and T cells and the current vaccine strategies. In addition, it discusses the potential efficacy of vaccination in DAA-cured individuals. Finally, it summarizes the challenges to vaccine development and the collaborative efforts required to overcome them. PMID- 30002658 TI - Apoptotic Cell-Derived Extracellular Vesicles: More Than Just Debris. AB - The many functions of extracellular vesicles (EVs) like exosomes and microvesicles released from healthy cells have been well characterized, particularly in relation to their roles in immune modulation. Apoptotic bodies, a major class of EV released as a product of apoptotic cell disassembly, and other types of EVs released from dying cells are also becoming recognized as key players in this emerging field. There is now increasing evidence to suggest that EVs produced during apoptosis have important immune regulatory roles, a concept relevant across different disease settings including autoimmunity, cancer, and infection. Therefore, this review focuses on how the formation of EVs during apoptosis could be a key mechanism of immune modulation by dying cells. PMID- 30002656 TI - Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment-A Review From the Melanoma Perspective and Beyond. AB - Background: Immune checkpoint inhibition (ICI) with anti-CTLA-4 and/or anti-PD-1 antibodies is standard treatment for metastatic melanoma. Anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for treatment of several other advanced malignancies, including non-small-cell lung cancer (NSCLC); renal cell, and urothelial carcinoma; head and neck cancer; gastric, hepatocellular, and Merkel cell carcinoma; and classical Hodgkin lymphoma. In some of these malignancies approval was based on the detection of biomarkers such as PD-L1 expression or high microsatellite instability. Methods: We review the current status of prognostic and predictive biomarkers used in ICI for melanoma and other malignancies. We include clinical, tissue, blood, and stool biomarkers, as well as imaging biomarkers. Results: Several biomarkers have been studied in ICI for metastatic melanoma. In clinical practice, pre-treatment tumor burden measured by means of imaging and serum lactate dehydrogenase level is already being used to estimate the likelihood of effective ICI treatment. In peripheral blood, the number of different immune cell types, such as lymphocytes, neutrophils, and eosinophils, as well as different soluble factors, have been correlated with clinical outcome. For intra-tumoral biomarkers, expression of the PD-1 ligand PD L1 has been found to be of some predictive value for anti-PD-1-directed therapy for NSCLC and melanoma. A high mutational load, particularly when accompanied by neoantigens, seems to facilitate immune response and correlates with patient survival for all entities treated by use of ICI. Tumor microenvironment also seems to be of major importance. Interestingly, even the gut microbiome has been found to correlate with response to ICI, most likely through immuno-stimulatory effects of distinct bacteria. New imaging biomarkers, e.g., for PET, and magnetic resonance imaging are also being investigated, and results suggest they will make early prediction of patient response possible. Conclusion: Several promising results are available regarding possible biomarkers for response to ICI, which need to be validated in large clinical trials. A better understanding of how ICI works will enable the development of biomarkers that can predict the response of individual patients. PMID- 30002659 TI - Vectorized Delivery of Alpha-GalactosylCeramide and Tumor Antigen on Filamentous Bacteriophage fd Induces Protective Immunity by Enhancing Tumor-Specific T Cell Response. AB - We have exploited the properties of filamentous bacteriophage fd to deliver immunologically active lipids together with antigenic peptides. Filamentous bacteriophages resemble for size, capability to be permeable to blood vessels, and high density antigen expression, a nature-made nanoparticle. In addition, their major coat protein pVIII, which is arranged to form a tubular shield surrounding the phage genome, has a high content of hydrophobic residues promoting lipid association. We conjugated bacteriophages to alpha GalactosylCeramide (alpha-GalCer), a lipid antigen-stimulating invariant natural killer T (iNKT) cells and capable of inducing their anti-tumoral activities. We found that bacteriophage fd/alpha-GalCer conjugates could repeatedly stimulate iNKT cells in vitro and in vivo, without inducing iNKT anergy. Moreover, co delivery of alpha-GalCer and a MHC class I restricted tumor-associated antigenic determinant to antigen-presenting cells via bacteriophages strongly boosted adaptive CD8+ T cell response and efficiently delayed tumor progression. Co delivery of a tumor antigen and iNKT-stimulatory lipid on the surface of filamentous bacteriophages is a novel approach to potentiate adaptive anti-cancer immune responses, overcoming the current limitations in the use of free alpha GalCer and may represent an attractive alternative to existing delivery methods, opening the path to a potential translational usage of this safe, inexpensive, and versatile tool. PMID- 30002660 TI - Arguing for Adaptive Clinical Trials in Sepsis. AB - Sepsis is life-threatening organ dysfunction due to dysregulated response to infection. Patients with sepsis exhibit wide heterogeneity stemming from genetic, molecular, and clinical factors as well as differences in pathogens, creating challenges for the development of effective treatments. Several gaps in knowledge also contribute: (i) biomarkers that identify patients likely to benefit from specific treatments are unknown; (ii) therapeutic dose and duration is often poorly understood; and (iii) short-term mortality, a common outcome measure, is frequently criticized for being insensitive. To date, the majority of sepsis trials use traditional design features, and have largely failed to identify new treatments with incremental benefit over standard of care. Traditional trials are also frequently conducted as part of a drug evaluation process that is segmented into several phases, each requiring separate trials, with a long time delay from inception through design and execution to incorporation of results into clinical practice. By contrast, adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of the trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs. Adoption of new treatments in clinical practice can be accelerated if these trials are incorporated in electronic health records as part of a learning health system. In this review, we discuss challenges in the evaluation of treatments for sepsis, and explore potential benefits and weaknesses of recent advances in adaptive trial methodologies to address these challenges. PMID- 30002661 TI - Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System. AB - The purpose of this study was to elucidate the mechanism of action of baricitinib on Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, which involves in human innate and adaptive immune system. The effects of baricitinib were evaluated using human monocyte-derived dendritic cells (MoDCs), plasmacytoid dendritic cells (pDCs), B cells, and T cells. Baricitinib concentration-dependently suppressed the expression of CD80/CD86 on MoDCs and the production of type-I interferon (IFN) by pDCs. Baricitinib also suppressed the differentiation of human B cells into plasmablasts by B cell receptor and type-I IFN stimuli and inhibited the production of interleukin (IL)-6 from B cells. Human CD4+ T cells proliferated after T cell receptor stimulation with anti-CD3 and anti-CD28 antibody; however, such proliferation was suppressed by baricitinib in a concentration-dependent manner. In addition, baricitinib inhibited Th1 differentiation after IL-12 stimulation and Th17 differentiation by TGF-beta1, IL 6, IL-1beta, and IL-23 stimulation. Tofacitinib showed similar effects in these experiments. In naive CD4+ T cells, IFN-alpha and IFN-gamma induced phosphorylation of STAT1, which was inhibited by baricitinib and tofacitinib. Furthermore, IL-6-induced phosphorylation of STAT1 and STAT3 was also inhibited by JAK inhibitors. In conclusion, the results indicated that baricitinib suppresses the differentiation of plasmablasts, Th1 and Th17 cells, as well as innate immunity, such as the T cell stimulatory capacity of dendritic cells. Thus, JAK inhibitors can be potentially clinically effective not only in rheumatoid arthritis but other immune-related diseases. PMID- 30002662 TI - Enhanced Lipid Production in Chlamydomonas reinhardtii by Co-culturing With Azotobacter chroococcum. AB - The green algae, Chlamydomonas reinhardtii, is one of the model species used to study lipid production, although research has focused on nitrogen-deficient cultures, that inhibit the development of biomass by C. reinhardtii and limit lipid production. In this study, Azotobacter chroococcum was added to the algal culture to improve lipid accumulation and productivity of C. reinhardtii. The maximum lipid content and production of C. reinhardtii in the co-culture were 65.85% and 387.76 mg/L, respectively, which were 2.3 and 5.9 times the control's levels of 29.11% and 65.99 mg/L, respectively. The maximum lipid productivity of C. reinhardtii in the co-culture was 141.86 mg/(L.day), which was 19.4 times the control's levels of 7.33 mg/(L.day). These increases were attributed to the enhanced growth and biomass and the change in the activity of enzymes related to lipid regulation (ACCase, DGAT, and PDAT). Compared to the conventional strategy of nitrogen deprivation, A. chroococcum added to the culture of C. reinhardtii resulted in higher lipid accumulation and activity, greater efficiency in the conversion of proteins to lipids, higher biomass, and increased growth of C. reinhardtii. Therefore, using A. chroococcum to improve the growth and biomass of C. reinhardtii is an efficient, rapid, and economically viable strategy for enhancing lipid production in C. reinhardtii. PMID- 30002663 TI - Comparative Genomics, Whole-Genome Re-sequencing and Expression Profile Analysis of Nucleobase:Cation Symporter 2 (NCS2) Genes in Maize. AB - Nucleobase:cation symporter 2 (NCS2) proteins are important for the transport of free nucleobases, participating in diverse plant growth and developmental processes, as well as response to abiotic stress. To date, a comprehensive analysis of the NCS2 gene family has not been performed in maize. In this study, we conducted a comparative genomics analysis of NCS2 genes in 28 plant species, ranging from aquatic algae to land plants, concentrating mainly on maize. Gene duplication events contributed to the expansion of NCS2 genes from lower aquatic plants to higher angiosperms, and whole-genome/segmental and single-gene duplication events were responsible for the expansion of the maize NCS2 gene family. Phylogenetic construction showed three NCS2 subfamilies, I, II, and III. According to homology-based relationships, members of subfamily I are NCS2/AzgA like genes, whereas those in subfamilies II and III are NCS2/NATs. Moreover, subfamily I exhibited ancient origins. A motif compositional analysis showed that one symbolic motif (motif 4) of the NCS2/NAT genes was absent in subfamily I. In maize, three NCS2/AzgA-like and 21 NCS2/NAT genes were identified, and purifying selection influenced the duplication of maize NCS2 genes. Additionally, a population genetic analysis of NCS2 genes revealed that ZmNCS2-21 showed the greatest diversity between the 78 inbred and 22 wild surveyed maize populations. An expression profile analysis using transcriptome data and quantitative real time PCR revealed that NCS2 genes in maize are involved in diverse developmental processes and responses to abiotic stresses, including abscisic acid, salt (NaCl), polyethylene glycol, and low (4 degrees C) and high (42 degrees C) temperatures. ZmNCS2 genes with relatively close relationships had similar expression patterns, strongly indicating functional redundancy. Finally, ZmNCS2 16 and ZmNCS2-23 localize in the plasma membrane, which confirmed their predicted membrane structures. These results provide a foundation for future studies regarding the functions of ZmNCS2 proteins, particularly those with potentially important roles in plant responses to abiotic stresses. PMID- 30002664 TI - A Novel and Convenient Method for Early Warning of Algal Cell Density by Chlorophyll Fluorescence Parameters and Its Application in a Highland Lake. AB - The occurrence of algal blooms in drinking water sources and recreational water bodies have been increasing and causing severe environmental problems worldwide, particularly when blooms dominated by Microcystis spp. Bloom prediction and early warning mechanisms are becoming increasingly important for preventing harmful algal blooms in freshwater ecosystems. Chlorophyll fluorescence parameters (CFpars) have been widely used to evaluate growth scope and photosynthetic efficiency of phytoplankton. According to our 2-year monthly monitor datasets in Lake Erhai, a simple but convenient method was established to predict Microcystis blooms and algal cell densities based on a CFpar representing maximal photochemical quantum yield of Photosystems II (PSII) of algae. Generalized linear mixed models, used to identify the key factors related to the phytoplankton biomass in Lake Erhai, showed significant correlations between Chl a concentration and both the light attenuation coefficient and water temperature. We fitted seasonal trends of CFpars (Fv/Fm and DeltaF/Fm') and algal cell densities into the trigonometric regression to predict their seasonal variations and the autocorrelation function was applied to calculate the time lag between them. We found that the time lag only existed between Fv/Fm from blue channel and algal cell densities even both Fv/Fm and DeltaF/Fm' show the significant non linear dynamics relationships with algal cell densities. The peak values of total algal cell density, cyanobacteria density and Microcystis density followed the foregoing peak value of Fv/Fm from blue channel with a time lagged around 40 days. Therefore, we could predict the possibilities of Microcystis bloom and estimate the algal cell densities in Lake Erhai ahead of 40 days based on the trends of Fv/Fm values from blue channel. The results from our study implies that the corresponding critical thresholds between Fv/Fm value and bloom occurrence, which might give new insight into prediction of cyanobacteria blooms and provide a convenient and efficient way for establishment of early warning of cyanobacteria bloom in eutrophic aquatic ecosystems. PMID- 30002666 TI - Endophytic Bacillus and Pseudomonas spp. Modulate Apple Shoot Growth, Cellular Redox Balance, and Protein Expression Under in Vitro Conditions. AB - Interactions between host plants and endophytic microorganisms play an important role in plant responses to pathogens and environmental stresses and have potential applications for plant stress management under in vitro conditions. We assessed the effect of endophytic bacteria on the growth and proliferation of domestic apple cv. Gala shoots in vitro. Further, a model apple cell suspension system was used to examine molecular events and protein expression patterns at an early stage of plant-endophyte interaction. Among the seven strains used in the study, Bacillus spp. strains Da_1, Da_4, and Da_5 and the Pseudomonas fluorescens strain Ga_1 promoted shoot growth and auxiliary shoot proliferation. In contrast, Bacillus sp. strain Oa_4, P. fluorescens strain Ga_3 and P. orientalis strain G_12 inhibited shoot development. In the cell suspension, the effects of the association between endophytic bacteria and plant cells were specific to each strain. Modulation of the cellular redox balance was monitored in the apple cells using a 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe, and strain specific effects were observed that correlated with the in vitro shoot development results. Proteomic analysis revealed differences in protein expressions in apple cells co-cultivated with different Bacillus spp. strains that had contrasting effects on cellular redox balance and shoot development. The Bacillus sp. strain Da_4, which enhanced shoot development and oxidation of H2DCFDA, induced differential expression of proteins that are mainly involved in the defense response and regulation of oxidative stress. Meanwhile, treatment with Bacillus sp. strain Oa_4 led to strong upregulation of PLAT1, HSC70-1 and several other proteins involved in protein metabolism and cell development. Taken together, the results suggest that different cell signaling and response events at the early stage of the plant-endophyte interaction may be important for strain dependent regulation of cellular redox balance and development of shoot phenotype. PMID- 30002668 TI - Potential of Wheat Straw, Spruce Sawdust, and Lignin as High Organic Carbon Soil Amendments to Improve Agricultural Nitrogen Retention Capacity: An Incubation Study. AB - Plants like winter wheat are known for their insufficient N uptake between sowing and the following growing season. Especially after N-rich crops like oilseed rape or field bean, nitrogen retention of the available soil N can be poor, and the risk of contamination of the hydrosphere with nitrate (NO3-) and the atmosphere with nitrous oxide (N2O) is high. Therefore, novel strategies are needed to preserve these unused N resources for subsequent agricultural production. High organic carbon soil amendments (HCA) like wheat straw promote microbial N immobilization by stimulating microbes to take up N from soil. In order to test the suitability of different HCA for immobilization of excess N, we conducted a laboratory incubation experiment with soil columns, each containing 8 kg of sandy loam of an agricultural Ap horizon. We created a scenario with high soil mineral N content by adding 150 kg NH4+-N ha-1 to soil that received either wheat straw, spruce sawdust or lignin at a rate of 4.5 t C ha-1, or no HCA as control. Wheat straw turned out to be suitable for fast immobilization of excess N in the form of microbial biomass N (up to 42 kg N ha-1), followed by sawdust. However, under the experimental conditions this effect weakened over a few weeks, finally ranging between 8 and 15 kg N ha-1 immobilized in microbial biomass in the spruce sawdust and wheat straw treatment, respectively. Pure lignin did not stimulate microbial N immobilization. We also revealed that N immobilization by the remaining straw and sawdust HCA material in the soil had a greater importance for storage of excess N (on average 24 kg N ha-1) than microbial N immobilization over the 4 months. N fertilization and HCA influenced the abundance of ammonia oxidizing bacteria and archaea as the key players for nitrification, as well as the abundance of denitrifiers. Soil with spruce sawdust emitted more N2O compared to soil with wheat straw, which in relation released more CO2, resulting in a comparable overall global warming potential. However, this was counterbalanced by advantages like N immobilization and mitigation of potential NO3- losses. PMID- 30002665 TI - Wild Relatives of Maize, Rice, Cotton, and Soybean: Treasure Troves for Tolerance to Biotic and Abiotic Stresses. AB - Global food demand is expected to nearly double by 2050 due to an increase in the world's population. The Green Revolution has played a key role in the past century by increasing agricultural productivity worldwide, however, limited availability and continued depletion of natural resources such as arable land and water will continue to pose a serious challenge for global food security in the coming decades. High yielding varieties with proven tolerance to biotic and abiotic stresses, superior nutritional profiles, and the ability to adapt to the changing environment are needed for continued agricultural sustainability. The narrow genetic base of modern cultivars is becoming a major bottleneck for crop improvement efforts and, therefore, the use of crop wild relatives (CWRs) is a promising approach to enhance genetic diversity of cultivated crops. This article provides a review of the efforts to date on the exploration of CWRs as a source of tolerance to multiple biotic and abiotic stresses in four global crops of importance; maize, rice, cotton, and soybean. In addition to the overview of the repertoire and geographical spread of CWRs in each of the respective crops, we have provided a comprehensive discussion on the morphological and/or genetic basis of the traits along with some examples, when available, of the research in the transfer of traits from CWRs to cultivated varieties. The emergence of modern molecular and genomic technologies has not only accelerated the pace of dissecting the genetics underlying the traits found in CWRs, but also enabled rapid and efficient trait transfer and genome manipulation. The potential and promise of these technologies has also been highlighted in this review. PMID- 30002667 TI - Mass Spectrometry Based Imaging of Labile Glucosides in Plants. AB - Mass spectrometry based imaging is a powerful tool to investigate the spatial distribution of a broad range of metabolites across a variety of sample types. The recent developments in instrumentation and computing capabilities have increased the mass range, sensitivity and resolution and rendered sample preparation the limiting step for further improvements. Sample preparation involves sectioning and mounting followed by selection and application of matrix. In plant tissues, labile small molecules and specialized metabolites are subject to degradation upon mechanical disruption of plant tissues. In this study, the benefits of cryo-sectioning, stabilization of fragile tissues and optimal application of the matrix to improve the results from MALDI mass spectrometry imaging (MSI) is investigated with hydroxynitrile glucosides as the main experimental system. Denatured albumin proved an excellent agent for stabilizing fragile tissues such as Lotus japonicus leaves. In stem cross sections of Manihot esculenta, maintaining the samples frozen throughout the sectioning process and preparation of the samples by freeze drying enhanced the obtained signal intensity by twofold to fourfold. Deposition of the matrix by sublimation improved the spatial information obtained compared to spray. The imaging demonstrated that the cyanogenic glucosides (CNglcs) were localized in the vascular tissues in old stems of M. esculenta and in the periderm and vascular tissues of tubers. In MALDI mass spectrometry, the imaged compounds are solely identified by their m/z ratio. L. japonicus MG20 and the mutant cyd1 that is devoid of hydroxynitrile glucosides were used as negative controls to verify the assignment of the observed masses to linamarin, lotaustralin, and linamarin acid. PMID- 30002670 TI - Editorial: Plant-Microbe-Insect Interaction: Source for Bio-fertilizers, Bio medicines and Agent Research. PMID- 30002669 TI - Speciation Success of Polyploid Plants Closely Relates to the Regulation of Meiotic Recombination. AB - Polyploidization is a widespread phenomenon, especially in flowering plants that have all undergone at least one event of whole genome duplication during their evolutionary history. Consequently, a large range of plants, including many of the world's crops, combines more than two sets of chromosomes originating from the same (autopolyploids) or related species (allopolyploids). Depending on the polyploid formation pathway, different patterns of recombination will be promoted, conditioning the level of heterozygosity. A polyploid population harboring a high level of heterozygosity will produce more genetically diverse progenies. Some of these individuals may show a better adaptability to different ecological niches, increasing their chance for successful establishment through natural selection. Another condition for young polyploids to survive corresponds to the formation of well-balanced gametes, assuring a sufficient level of fertility. In this review, we discuss the consequences of polyploid formation pathways, meiotic behavior and recombination regulation on the speciation success and maintenance of polyploid species. PMID- 30002671 TI - Sample Size for Successful Genome-Wide Association Study of Major Depressive Disorder. AB - Major depressive disorder (MDD) is a complex, heritable psychiatric disorder. Advanced statistical genetics for genome-wide association studies (GWASs) have suggested that the heritability of MDD is largely explained by common single nucleotide polymorphisms (SNPs). However, until recently, there has been little success in identifying MDD-associated SNPs. Here, based on an empirical Bayes estimation of a semi-parametric hierarchical mixture model using summary statistics from GWASs, we show that MDD has a distinctive polygenic architecture consisting of a relatively small number of risk variants (~17%), e.g., compared to schizophrenia (~42%). In addition, these risk variants were estimated to have very small effects (genotypic odds ratio <= 1.04 under the additive model). Based on the estimated architecture, the required sample size for detecting significant SNPs in a future GWAS was predicted to be exceptionally large. It is noteworthy that the number of genome-wide significant MDD-associated SNPs would rapidly increase when collecting 50,000 or more MDD-cases (and the same number of controls); it can reach as much as 100 SNPs out of nearly independent (linkage disequilibrium pruned) 100,000 SNPs for ~120,000 MDD-cases. PMID- 30002672 TI - Altered Intrinsic Coupling between Functional Connectivity Density and Amplitude of Low-Frequency Fluctuation in Mild Cognitive Impairment with Depressive Symptoms. AB - Neuroimaging studies have demonstrated that major depressive disorder increases the risk of dementia in older individuals with mild cognitive impairment. We used resting-state functional magnetic resonance imaging to explore the intrinsic coupling patterns between the amplitude and synchronisation of low-frequency brain fluctuations using the amplitude of low-frequency fluctuations (ALFF) and the functional connectivity density (FCD) in 16 patients who had mild cognitive impairment with depressive symptoms (D-MCI) (mean age: 69.6 +/- 6.2 years) and 18 patients with nondepressed mild cognitive impairment (nD-MCI) (mean age: 72.1 +/- 9.7 years). Coupling was quantified as the correlations between the ALFF values and their associated FCDs. The results showed that the ALFF values in the D-MCI group were higher in the left medial prefrontal cortex (mPFC) and lower in the right precentral gyrus (preCG), and the FCD values were higher in the left medial temporal gyrus (MTG) than those in the nD-MCI group. Further, correlation analyses demonstrated that, in the D-MCI group, the mPFC was negatively correlated with the MTG. These findings may relate to the characteristics of mood disorders in patients with MCI, and they offer further insight into the neuropathophysiology of MCI with depressive symptoms. PMID- 30002673 TI - Acoustical Enrichment during Early Development Improves Response Reliability in the Adult Auditory Cortex of the Rat. AB - It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns. PMID- 30002675 TI - Is Oral Omega-3 Effective in Reducing Mucocutaneous Side Effects of Isotretinoin in Patients with Acne Vulgaris? AB - Background. Acne vulgaris is an inflammatory disease of pilosebaceous units which may cause permanent dyspigmentation and/or scars if not treated. Isotretinoin is recommended in the treatment of recalcitrant or severe acne, but it is associated with common adverse effects that frequently result in patients incompliance and discontinuation of the drug. The present study was designed to assess the efficacy of oral omega-3 in decreasing the adverse effects of isotretinoin. Materials and Methods. In this randomized double-blind clinical trial, a total of 118 patients with moderate or severe acne were randomly divided into two (case and control) groups. The control group was treated with isotretinoin 0.5 mg/kg, and the case group was treated with the same dose of isotretinoin combined with oral omega-3 (1 g/day). The treatment was lasted for 16 weeks and mucocutaneous side effects of isotretinoin were recorded and compared between the two groups in weeks 4, 8, 12, and 16. Results. Cheilitis (at weeks 4, 8, and 12), xerosis, dryness of nose at all weeks, and dryness of eyes (at week 4) were less frequent in the group that received isotretinoin combined with oral omega-3 compared to the group that received isotretinoin alone. Conclusion. Administration of oral omega-3 in acne patients who are receiving isotretinoin decreases the mucocutaneous side effects of isotretinoin. This trial is registered with IRCT201306238241N2. PMID- 30002676 TI - Knowledge and Perception of Falls among Community Dwelling Elderly: A Study from Southern Sri Lanka. AB - The knowledge and perception of falls facilitate a better pathway to improve the health status among the elderly. Knowledge and perception of falls among community dwelling elderly were assessed in 300 participants (175 females) aged 65 years and above using an interviewer-administered questionnaire. Mean (SD) age of the participants was 73.0 (6.7) years. Majority (72%) knew some biological factors, and 60% knew environmental and behavioral factors which increase the risk of falls. Among 300 participants, 18% had poor, 61% had average, and 21% had good knowledge on falls. The mean (SD) knowledge was 48.14 (19.13). The most frequent (49%) information source was television. Significant associations were found between age (p = 0.002) and educational status (p < 0.001) with level of knowledge regarding falls. Individuals, 25.4% with good knowledge, 32.2% with average knowledge, and 51.9% with poor knowledge, had experienced falls during the previous 12 months (p = 0.007). Regarding perception of falls, 20.3% (n = 61) had negative perception and 79.7% (n = 239) had positive perception. Significant associations were found between gender (p = 0.01), age (p = 0.04), and level of education (p < 0.001) with perception of falls. This study revealed that the community dwelling elders had average knowledge and positive perception regarding falls and preventive measures, emphasizing the importance of falls prevention awareness programs. PMID- 30002674 TI - Testing rTMS-Induced Neuroplasticity: A Single Case Study of Focal Hand Dystonia. AB - Focal hand dystonia in musicians is a neurological motor disorder in which aberrant plasticity is caused by excessive repetitive use. This work's purposes were to induce plasticity changes in a dystonic musician through five daily thirty-minute sessions of 1 Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left M1 by using neuronavigated stimulation and to reliably measure the effect of these changes. To this aim, the relationship between neuroplasticity changes and motor recovery was investigated using fine-grained kinematic analysis. Our results suggest a statistically significant improvement in motor coordination both in a task resembling the dystonic-inducing symptoms and in a reach-to-grasp task. This single case study supports the safe and effective use of noninvasive brain stimulation in neurologic patients and highlights the importance of evaluating outcomes in measurable ways. This issue is a key aspect to focus on to classify the clinical expression of dystonia. These preliminary results promote the adoption of kinematic analysis as a valuable diagnostic tool. PMID- 30002677 TI - Investigation of Geriatric Patients with Abdominal Pain Admitted to Emergency Department. AB - Introduction: The aim of this study is to detect the possible reasons of abdominal pain in the patients aged 65 and older admitted to emergency department (ED) with complaint of abdominal pain which is not related to trauma, to determine the length of hospitalization of old (65-75 age) and elderly (aged 75 and older) patients, and to define the hospitalization and mortality rates. Material and Methods: In the study, 336 patients were included. Groups were compared in respect to gender, internal or surgical prediagnoses, complaints accompanying abdominal pain, vital findings, comorbidities, requested consultations, hospitalizing service, waiting time in the ED and in the hospital, and treatment methods. Results: Of the patients, 48.2% were male, and 51.8% were female. While 52.4% of the patients were in 65-74 age group, 47.6% of them were aged 75 years and above. An internal disease was detected in 76.8% of the patients as an origin of abdominal pain. Most common prediagnoses were biliary diseases and diseases related to biliary tract followed by nonspecific abdominal pain, abdominal pain secondary to malignity, ileus, and acute gastroenteritis, respectively. The most frequent finding accompanying abdominal pain was vomiting. The most frequent chronic disease accompanying abdominal pain was hypertension in both age groups. We observed that 75.9% of the patients required consultation. We detected that 48.8% of the patients with abdominal pain were hospitalized and they were hospitalized mostly by gastroenterology ward (24.8%). Surgical treatments were applied to the 17.6% of the patients with abdominal pain. Conclusion: Clinical findings become indistinct by age, and differential diagnosis of abdominal pain gets more difficult in geriatric patients. Therefore, physicians should consider age related physiological changes in order to distinguish geriatric patients admitted to emergency service with abdominal pain from pathological cases requiring immediate surgical operation. PMID- 30002678 TI - The Role of Uron and Chlorobenzene Derivatives, as Potential Endocrine Disrupting Compounds, in the Secretion of ACTH and PRL. AB - Uron herbicides polluting the environment represent a serious concern for environmental health and may be regarded as endocrine-disrupting compounds (EDCs), which influence the regulation of human homeostasis. We aimed to investigate the effect of EDC urons (phenuron: PU, monuron: MU, and diuron: DU) and chlorobenzenes on the basal release of the adrenocorticotropic hormone (ACTH), which is a part of the adenohypophysis-adrenocortical axis. Hormone secretion in the presence of EDC was studied in two cell types: normal adenohypophysis cells (AdH) and cells of prolactinomas (PRLOMA). PRLOMA was induced in female Wistar rats by subcutaneously injecting them with estrone acetate for 6 months. AdH and PRLOMA were separated from treated and untreated experimental animals, dissociated enzymatically and mechanically in order to create monolayer cell cultures, which served as an experimental in vitro model. We investigated the effects of ED agents separately and in combination on ACTH and prolactin (PRL) release through the hypophyseal-adrenal axis. Hormone determination was carried out by the luminescent immunoassay and the radioimmunoassay methods. Our results showed that (1) uron agents separately did not change ACTH and PRL release in AdH culture; (2) ACTH secretion in arginine vasopressin- (AVP-) activated AdH cells was significantly increased by EDC treatment; (3) ED agents increased the basal hormone release (ACTH, PRL) in PRLOMA cells; and (4) EDC exposure increased ACTH release in AVP-activated PRLOMA cells. We conclude that the herbicides PU, MU, and DU carry EDC effects and show human toxicity potential. PMID- 30002680 TI - Hepatic Abscess in a Returning Traveler with Crohn's Disease: Differentiating Amebic from Pyogenic Liver Abscess. AB - Liver abscess is a rare but serious complication of Crohn's disease. Patients with Crohn's disease are at risk for pyogenic liver abscesses due to immunosuppressive therapy, fistulous disease, and intraabdominal abscesses. Inflammatory bowel disease patients are also known to have a greater prevalence of amebiasis compared to the rest of the population; however, a higher incidence of amebic liver abscess has not been reported. We describe a case of a liver abscess in a patient with Crohn's disease that was initially presumed pyogenic but later determined to be amebic in origin. Epidemiology, clinical presentation, diagnosis, and treatment of amebic and pyogenic liver abscesses are discussed. PMID- 30002679 TI - Plasminogen Activator Inhibitor-1 Level Correlates with Lipoprotein Subfractions in Obese Nondiabetic Subjects. AB - Background: The elevated level of plasminogen activator inhibitor-1 (PAI-1) in obese subjects with metabolic syndrome and in patients with type 2 diabetes is well established. The association of plasma PAI-1 and lipid metabolism is still unclear. The aim of the present study was to determine the relationship between plasma PAI-1 levels and the distribution of lipoprotein subfractions in obese and lean nondiabetic individuals. Subjects and Methods: We enrolled fifty nondiabetic obese patients and thirty-two healthy volunteers. Lipoprotein subfractions were detected with Lipoprint System. Plasma PAI-1, tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), and myeloperoxidase (MPO) concentrations were determined with enzyme-linked immunosorbent assay (ELISA), while serum paraoxonase-1 (PON1) activities were measured by spectrophotometry. Results: The TNF-alpha, IL-6, oxidized low-density lipoprotein (oxLDL), and MPO levels were found to be significantly higher, while PON1 paraoxonase and arylesterase activities were nonsignificantly lower in the obese patients. Strong significant negative correlations were found between plasma PAI-1 concentration and mean LDL size, as well as between PAI-1 concentrations and the levels of the large and intermediate high-density lipoprotein (HDL) subfractions. In multiple regression analysis, PAI-1 was predicted by waist circumference and intermediate HDL subfraction. Conclusion: The significant correlations between PAI-1 levels and lipoprotein subfractions indicate the link between PAI-1 and lipid metabolism in obesity. PMID- 30002681 TI - The Epidemiology of Human Immunodeficiency Virus (HIV) and Syphilis in Ghana: A Five-Year Single Urban Site Parallel Population-Based Analysis vis-a-vis the Sentinel Survey. AB - The study was aimed at comparing the estimation of the burden and trends (2012 2016) of Human Immunodeficiency Virus (HIV) and Syphilis infections by the national Sentinel Survey vis-a-vis the use of population-based studies at a single urban site (Municipal Hospital) in Ho, the Volta Region of Ghana. Using blood donors as a proxy of the asymptomatic adult population, a retrospective analysis of secondary data on HIV and Syphilis testing was conducted using Ho Municipal Hospital's archives comprising 4,180 prospective blood donors. Published reports from the National Sentinel Survey for the Ho Sentinel Site comprising 2,452 pregnant women from 2012 to 2016 were used. The cumulative prevalence of HIV and Syphilis infections in the population-based survey was 4.78% and 2.58% while the epidemiology was estimated at 2.75% and 0.24% by the Sentinel Survey for the five-year under review. The new HIV and Syphilis infections were 3.78% and 2.46% in the population-based survey compared to 2.64% and 0.23% in the Sentinel Survey. Gender cumulative prevalence and the yearly trend was found to be higher in the general population compared to the pregnant women. The use of pregnant women to estimate the HIV and Syphilis epidemiology might not be representative of the general population. PMID- 30002682 TI - DSPP-MMP20 gene silencing downregulates cancer stem cell markers in human oral cancer cells. AB - Background: Recent findings indicate that dentin sialophosphoprotein (DSPP) and matrix metalloproteinase (MMP) 20 interact in oral squamous cell carcinoma (OSCC). The objective of this study was to determine the effects of DSPP/MMP20 gene silencing on oral cancer stem cell (OCSC) markers. Methods: The expression of well-established OCSC markers: ABCG2; ALDH1; CD133; CD44; BMI1; LGR4, and Podoplanin in DSPP/MMP20-silenced OSCC cell line, OSC2, and controls were assayed by western blot (WB), and flow cytometry techniques. The sensitivity of OSC2 cells to cisplatin following DSPP/MMP20 silencing was also determined. Results: DSPP/MMP20 silencing resulted in downregulation of OCSC markers, more profoundly ABCG2 (84%) and CD44 (81%), following double silencing. Furthermore, while treatment of parent (pre-silenced) OSC2 cells with cisplatin resulted in upregulation of OCSC markers, DSPP/MMP20-silenced OSC2 cells similarly treated resulted in profound downregulation of OCSC markers (72 to 94% at 50 MUM of cisplatin), and a marked reduction in the proportion of ABCG2 and ALDH1 positive cells (~ 1%). Conclusions: We conclude that the downregulation of OCSC markers may signal a reduction in OCSC population following MMP20/DSPP silencing in OSCC cells, while also increasing their sensitivity to cisplatin. Thus, our findings suggest a potential role for DSPP and MMP20 in sustaining OCSC population in OSCCs, possibly, through mechanism(s) that alter OCSC sensitivity to treatment with chemotherapeutic agents such as cisplatin. PMID- 30002684 TI - Regular follow-up visits reduce the risk for asthma exacerbation requiring admission in Korean adults with asthma. AB - Background: Asthma requires regular follow-up visits and sustained medication use. Although several studies have reported the importance of adherence to medication and compliance with the treatment, none to date have reported the importance of regular follow-up visits. We investigated the effects of regular clinical visits on asthma exacerbation. Methods: We used claims data in the national medical insurance review system provided by the Health Insurance Review and Assessment Service of Korea. We included subjects aged >= 15 years with a diagnosis of asthma, and who were prescribed asthma-related medication, from July 2013 to June 2014. Regular visitors (frequent visitors) were defined as subjects who visited the hospital for follow-up of asthma three or more times per year. Results: Among 729,343 subjects, 496,560 (68.1%) were classified as regular visitors. Old age, male sex, lack of medical aid insurance, attendance of a tertiary hospital, a high Charlson comorbidity index, and a history of admission for exacerbated asthma in the previous year were significant determining factors for regular visitor status. When we adjusted for all these factors, frequent visitors showed a lower risk of asthma exacerbation requiring general ward admission (odds ratio [OR] 0.48; 95% confidence interval [CI] 0.47-0.50; P < 0.001), emergency room admission (OR 0.83; 95% CI 0.79-0.86; P < 0.001), and intensive care unit admission (OR 0.49; 95% CI 0.44-0.54; P < 0.001) than infrequent visitors. Conclusions: Regular clinical visits are significantly associated with a reduced risk of asthma exacerbation requiring hospital admission in Korean adults with asthma. PMID- 30002683 TI - Laminopathies: what can humans learn from fruit flies. AB - Lamin proteins are type V intermediate filament proteins (IFs) located inside the cell nucleus. They are evolutionarily conserved and have similar domain organization and properties to cytoplasmic IFs. Lamins provide a skeletal network for chromatin, the nuclear envelope, nuclear pore complexes and the entire nucleus. They are also responsible for proper connections between the karyoskeleton and structural elements in the cytoplasm: actin and the microtubule and cytoplasmic IF networks. Lamins affect transcription and splicing either directly or indirectly. Translocation of active genes into the close proximity of nuclear lamina is thought to result in their transcriptional silencing. Mutations in genes coding for lamins and interacting proteins in humans result in various genetic disorders, called laminopathies. Human genes coding for A-type lamin (LMNA) are the most frequently mutated. The resulting phenotypes include muscle, cardiac, neuronal, lipodystrophic and metabolic pathologies, early aging phenotypes, and combined complex phenotypes. The Drosophila melanogaster genome codes for lamin B-type (lamin Dm), lamin A-type (lamin C), and for LEM-domain proteins, BAF, LINC-complex proteins and all typical nuclear proteins. The fruit fly system is simpler than the vertebrate one since in flies there is only single lamin B-type and single lamin A-type protein, as opposed to the complex system of B- and A-type lamins in Danio, Xenopus and Mus musculus. This offers a unique opportunity to study laminopathies. Applying genetic tools based on Gal4 and in vitro nuclear assembly system to the fruit fly model may successfully advance knowledge of laminopathies. Here, we review studies of the laminopathies in the fly model system. PMID- 30002685 TI - Frequency of CD4+ and CD8+ T cells in Iranian chronic rhinosinusitis patients. AB - Background: Chronic Rhinosinusitis (CRS) is a persistent inflammatory disease affecting paranasal sinuses. CRS is categorized into two distinct subgroups defined as CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Although several immune cells are involved in the CRS pathogenesis, the role of T cells is not fully understood. The objective of the present study was to evaluate the frequency of CD4+ and CD8+ T cells and macrophages in the sinonasal mucosa of CRS patients, as well as to investigate the specific transcription factors for Th1, Th2, Th17, and Treg cells. Methods: In this study, 15 healthy controls, 12 CRSsNP, and 23 CRSwNP patients participated. CD4+, CD8+, and CD68+ cells were investigated in the sinonasal tissues using immunohistochemistry. The expression of transcription factors related to Th subsets (T-bet, GATA3, Ror-gammat, and FoxP3) was evaluated using real-time PCR. Furthermore, CRSwNP patients were defined as eosinophilic when eosinophils consisted of more than 10% of total inflammatory cells. The Kruskal-Wallis, Mann-Whitney, and Spearman tests were used in statistical analyses. Results: The median (range) age of the studied groups was: 32 (14-67) for CRSwNP, 28 (10-43) for CRSsNP, and 27 (17-44) for controls. The number of eosinophils in CRSwNP patients was higher than two other groups, whereas neutrophils were elevated in both CRSwNP and CRSsNP groups in comparison to controls. The frequency of CD4+ and CD8+ T cells, macrophages, and total inflammatory cells were significantly increased in CRSwNP and CRSsNP patients compared with controls. The mRNA expression of GATA3 was increased in CRSwNP patients while mRNA expression of Ror-gammat was elevated in CRSsNP patients. No significant difference was observed in T-bet mRNA expression among three groups. Both CRSwNP and CRSsNP patients showed decreased FoxP3 mRNA expression in comparison to controls. Conclusion: The frequency of CD4+ and CD8+ T cells was elevated in CRS patients. In addition, we demonstrated Th2 dominance in CRSwNP patients and Th17 dominance in CRSsNP patients, implicating different mechanisms may underlie the disease. Better CRS classification and targeted therapeutic strategies may be achievable by determining the pattern of infiltrating inflammatory cells. Therefore, further experimental investigations on T cells are needed. PMID- 30002686 TI - Effect of magnesium supplements on serum C-reactive protein: a systematic review and meta-analysis. AB - Introduction: The aim of the study was to undertake a systematic review and meta analysis of prospective studies to determine the effect of magnesium (Mg) supplementation on C-reactive protein (CRP). Design: Systematic review and meta analysis of randomised controlled trials (RCTs). Material and methods: Data sources: PubMed-Medline, Web of Science, Cochrane Database, and Google Scholar databases were searched (up until December 2016). Eligibility criteria: Randomized controlled trials evaluating the impact of Mg supplementation on CRP. We used random effects models meta-analysis for quantitative data synthesis. For sensitivity analysis was used the leave-one-out method. Heterogeneity was quantitatively assessed using the I2 index. Main outcome: Level of CRP after Mg supplementation. Results: From a total of 96 entries identified via searches, eight studies were included in the final selection. The meta-analysis indicated a significant reduction in serum CRP concentrations following Mg supplementation (weighted mean difference (WMD) -1.33 mg/l; 95% CI: -2.63 to -0.02, heterogeneity p < 0.123; I2 = 29.1%). The WMD for interleukin 6 was -0.16 pg/dl (95% CI: -3.52 to 3.26, heterogeneity p = 0.802; I2 = 2.3%), and 0.61 mg/dl (95% CI: -2.72 to 1.48, p = 0.182, heterogeneity p = 0.742; I2 = 6.1%) for fasting blood glucose. These findings were robust in sensitivity analyses. Random-effects meta regression revealed that changes in serum CRP levels were independent of the dosage of Mg supplementation (slope: -0.004; 95% CI: -0.03, 0.02; p = 0.720) or duration of follow-up (slope: -0.06; 95% CI: -0.37, 0.24; p = 0.681). Conclusions: This meta-analysis suggests that Mg supplementation significantly reduces serum CRP level. RCTs with a larger sample size and a longer follow-up period should be considered for future investigations to give an unequivocal answer. PMID- 30002688 TI - Apelin/APJ axis improves angiotensin II-induced endothelial cell senescence through AMPK/SIRT1 signaling pathway. AB - Introduction: Previous studies have shown that endothelial cell senescence is involved in cardiovascular diseases such as cardiac fibrosis, atherosclerosis and heart failure. Accumulating evidence indicates that apelin exerts protective effects on ageing-related endothelial dysfunction. In this study, we aim to investigate the role of the apelin/APJ axis in angiotensin II (AngII)-induced endothelium senescence and its associated mechanisms. Material and methods: Senescence-related beta-gal activity assay and western blot were used to evaluate human umbilical vein endothelial cell (HUVEC) senescence. In addition, DCFH-DA staining was carried out to detect the generation of reactive oxygen species (ROS). A validated, high-sensitivity real-time quantitative telomeric repeat amplification protocol (RQ-TRAP) was applied to determine telomerase activity in HUVECs, and a CCK-8 assay was employed to measure cellular viability. Results: AngII induced an increase in SA-beta-Gal-positive cells and upregulation on expression of P21 and PAI-1 compared to the control group (p < 0.05), while apelin against this process (p < 0.05). The protective effects were attenuated when APJ, AMPK and SIRT1 expression was knocked down (p < 0.05). Furthermore, apelin reduced AngII-induced ROS generation and enhanced telomerase activity in HUVECs (p < 0.05), which contributed to increased HUVEC viability as assessed by the CCK-8 assay (p < 0.05). Conclusions: The apelin/APJ axis improved AngII induced HUVEC senescence via the AMPK/SIRT1 signaling pathway, and the underlying mechanisms might be associated with reduced ROS production and enhanced telomerase activity. PMID- 30002687 TI - Descriptive epidemiology: prevalence, incidence, sociodemographic factors, socioeconomic domains, and quality of life of epilepsy: an update and systematic review. AB - Introduction: The purpose of this study was to investigate the contributions of quality of life (QOL), sociodemographic factors (age, sex, etc.), residential areas, general attitudes toward epilepsy, socioeconomic domains, prevalence and incidence in epileptic patients from Iran. Material and methods: A systematic literature search was conducted, including database searches in PubMed, Medline, Embase, ScienceDirect, Scopus, ISC, Health, Web of Science, and the Cochrane Library Database of relevant articles, personal files and systematic reviews to identify studies examining risk factors in epilepsy. Results: This review article shows that certain socio-demographic and socio-economic factors, geographic variation in epidemiologic patterns of epilepsy as well as clinical factors may be crucial in determining QOL in epilepsy patients and provides further evidence supporting the validity of the scale in QOL based on consideration of different target groups in different areas. Conclusions: Prevalence of epilepsy appears to be correlated with socioeconomic status in the lower socioeconomic groups. Also demographic characteristics, socio-economic factors and clinical presentation are linked to different QOL of these patients among nations. The educational program has a beneficial effect on self-management behaviors in patients with epilepsy. More work needs to be done to improve tools that help to evaluate efficiently the health-related quality of life of people with epilepsy. PMID- 30002690 TI - miR-181b inhibits chemoresistance in cisplatin-resistant H446 small cell lung cancer cells by targeting Bcl-2. AB - Introduction: MicroRNAs (miRNAs) are a group of small non-coding RNAs that affect multiple aspects of tumor biology including chemo resistance. miR-181b has been reported to modulate multidrug resistance in non-small cell lung cancer cells. This study was undertaken to determine the role of miR-181b in chemo resistance of small cell lung cancer cells. Material and methods: This study was undertaken to determine the role of miR-181b in chemoresistance of small cell lung cancer cells with use of qRt-PCR, WB, bioinformatics analysis, and double luciferase reporter system. Results: Our data showed that miR-181b was significantly downregulated in cisplatin-resistant H446 small cell lung cancer cells, compared to parental cells, compared to parental cells. Ectopic expression of miR-181b inhibited cell proliferation and invasion in cisplatin-resistant H446 cells (p = 0.023). Moreover, overexpression of miR-181b increased the susceptibility of cisplatin-resistant H446 cells to cisplatin. Mechanistic investigations demonstrated that miR-181b inhibited B-cell lymphoma-2 (Bcl-2) expression by binding to the 3'-untranslated region. Overexpression of Bcl-2 reversed miR-181b mediated chemo sensitization, which is accompanied by a reduced apoptotic response. Conclusions: Taken together, this work demonstrated that miR-181b might have the ability to overcome chemo resistance of small cell lung cancer cells, and restoration of this miRNA may represent a potential therapeutic strategy for improving chemo sensitivity in small cell lung cancer. PMID- 30002689 TI - MicroRNA-135b-5p prevents oxygen-glucose deprivation and reoxygenation-induced neuronal injury through regulation of the GSK-3beta/Nrf2/ARE signaling pathway. AB - Introduction: MicroRNAs (miRNAs) are emerging as critical regulators in the pathological process of cerebral ischemia/reperfusion injury. miRNAs play an important role in regulating neuronal survival. miR-135b-5p has been reported as an important miRNA in regulating cell apoptosis. However, the role of miR-135b-5p in regulating neuronal survival remains poorly understood. Here, we aimed to investigate the role of miR-135b-5p in cerebral ischemia/ reperfusion using an in vitro model of oxygen-glucose deprivation and reoxygenation-(OGD/R) induced neuron injury. Material and methods: miRNA, mRNA and protein expression was detected by real-time quantitative polymerase chain reaction and Western blot. Cell viability was detected by cell counting kit-8 and lactate dehydrogenase assays. Cell apoptosis was detected by caspase-3 activity assay. Oxidative stress was determined using commercial kits. The target of miR-135b-5p was confirmed by dual-luciferase reporter assay. Results: We found that miR-135b-5p expression was significantly decreased in hippocampal neurons receiving OGD/R treatment. Overexpression of miR-135b-5p markedly alleviated OGD/R-induced cell injury and oxidative stress, whereas suppression of miR-135b-5p showed the opposite effects. We observed that miR-135b-5p directly targeted the 3'-untranslated region of glycogen synthase kinase-3beta (GSK-3beta). We found that miR-135b-5p negatively regulates the expression of GSK-3beta in hippocampal neurons. Moreover, miR-135b 5p overexpression promotes activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling. However, the restoration of GSK-3beta expression significantly reversed the protective effects of miR-135b-5p overexpression. Conclusions: Overall, our results suggest that miR 135b-5p protects neurons against OGD/R-induced injury through downregulation of GSK-3beta and promotion of the Nrf2/ARE signaling pathway-mediated antioxidant responses. PMID- 30002691 TI - Expression of UCA1 and MALAT1 long-chain non-coding RNAs in esophageal squamous cell carcinoma tissues is predictive of patient prognosis. AB - Introduction: The long non-coding RNAs (lncRNAs) urothelial cancer associated 1 (UCA1) and metastasis associated lung adenocarcinoma transcript 1 (MALAT1) are known to impact cancer cell regulation. The aim of the present study was to determine the relationship between the expression of these lncRNAs in esophageal squamous cell carcinoma (ESCC) tissues and disease prognosis. Material and methods: The expression of UCA1 and MALAT1 lncRNAs was assessed in ESCC and adjacent carcinoma tissues (5 cm away from the tumor) and evaluated in relation to overall survival (OS) and disease-free survival (DFS) of patients. This prospective study included 100 ESCC patients who were admitted to the First Hospital of Yulin City between January 2007 and January 2014. Results: The expression levels of UCA1 and MALAT1 lncRNAs in ESCC tissues were significantly higher than those in adjacent carcinoma tissues, and there were statistically significant differences in TNM staging between the patients with high lncRNA expression and low lncRNA expression. The OS and DFS of patients with high UCA1 and MALAT1 lncRNA expression levels were significantly shorter than those with low expression levels. Furthermore, the OS and DFS of ESCC patients appeared to be correlated with TNM staging. Conclusions: These results imply that the up regulation of UCA1 and MALAT1 lncRNAs in ESCC tissues can impact the degree of tumor progression and is predictive of postoperative survival. Therefore, the expression levels of these lncRNAs can be used as measurement indexes to determine the prognosis of ESCC patients. PMID- 30002692 TI - Response to an oral fat load and effects on lipid profile, glycemia and high sensitivity C-reactive protein after soybean extract consumption. AB - Introduction: The aim of this study was to evaluate the response in terms of lipid profile, glycemia and high-sensitivity C-reactive protein after an oral fat load (OFL) with a non-dairy cheese cream containing fermented soybean extract soy, compared to a dairy cheese. Material and methods: One hundred twenty-four healthy subjects underwent an OFL performed using a mixture containing non-dairy cheese cream, containing 75% fermented soybean extract (Valsoia Lo spalmabile), or a dairy cheese cream. Results: During the OFL, total cholesterol and triglycerides at 6 h were lower with non-dairy cheese cream containing fermented soybean compared to dairy cheese cream. The value of low-density lipoprotein cholesterol recorded at 6 h with the active treatment was lower than the one recorded at the same time with the dairy cheese cream. A decrease of high-density lipoprotein cholesterol (HDL-C) was recorded with the dairy cheese cream, but not with the active treatment; moreover, the HDL-C value recorded with the active treatment was higher than the one observed with the dairy cheese cream. There was an increase of high-sensitivity C-reactive protein (hs-CRP) at 3, 6, and 9 h compared to 0 h with the dairy cheese cream, but not with the active treatment. The hs-CRP value observed with the active treatment was lower than the one observed with the dairy cheese cream. Conclusions: A non-dairy cheese cream, containing 75% fermented soybean extract, caused a minor increase of lipid profile and of hs-CRP during OFL compared to a dairy cheese cream in healthy subjects. PMID- 30002693 TI - Variability of metabolic risk factors associated with prehypertension in males and females: a cross-sectional study in China. AB - Introduction: Prehypertension is highly prevalent. However, very few studies have evaluated the association of various metabolic risk factors in those with prehypertension and, more importantly, possible differences based on gender. Material and methods: Data of clinical characteristics were collected from 3891 subjects. Risk factors were analyzed by multiple logistic regression analysis. The areas under receiver operating characteristic curves were compared to assess the discriminatory value of metabolic parameters for predicting prehypertension. Results: The incidence of prehypertension was 55.9% (66.9% of men, 41.1% of women). Prehypertensives showed clusters of metabolic associations including changes in the levels of plasma high-density lipoprotein cholesterol (OR = 1.550), triglycerides (OR = 1.141) and fasting blood glucose (OR = 1.320) after adjusting for age, sex, body mass index and smoking. The metabolic associations also showed differences based on gender. For instance, higher total cholesterol (OR = 1.602) was the most evident risk factor in men with prehypertension, while higher triglycerides (OR = 1.314) and lower high-density lipoprotein cholesterol (OR = 1.729) were the main risk factors in women. Conclusions: Our study suggests that risk associations of prehypertension show gender differences. These results emphasize the importance of health education, active management of blood pressure and timely and effective treatment of abnormal lipid profile in subjects with prehypertension. PMID- 30002695 TI - Angiopoietin-like protein 2 and angiopoietin-like protein 6 levels in patients with nonalcoholic fatty liver disease. AB - Introduction: The aim of the current study was to examine the difference between patients detected with nonalcoholic fatty liver disease (NAFLD) and healthy subjects in terms of serum angiopoietin-like protein (ANGPTL) 2 and ANGPTL6 levels and to evaluate the correlation between ANGPTL2 and ANGPTL6 levels and liver enzyme levels, fasting glucose, lipid levels, and steatosis degree on ultrasonography (USG). Material and methods: A total of 159 participants were included in the study. The participants were divided into 3 groups depending on the steatosis degree on USG and serum alanine aminotransferase (ALT) levels: the NAFLD group with increased ALT, the NAFLD group with normal ALT, and the healthy control group. The groups were compared in terms of biochemical and ultrasonographic findings, insulin resistance, metabolic syndrome (MetS), and anthropometric parameters. Results: There was no significant difference between NAFLD patients and healthy subjects with respect to serum ANGPTL2 and ANGPTL6 levels (p > 0.05). ANGPTL2 levels did not correlate with serum, biochemical, or ultrasonographic findings, or anthropometric parameters (p > 0.05). A positive correlation was found between serum ANGPTL6 levels and fasting blood glucose, ALT, alkaline phosphatase, gamma-glutamyl transpeptidase, fasting insulin, and HOMA-IR levels. Conclusions: While our findings suggest no relationship between serum ANGPTL2 and ANGPTL6 levels and NAFLD, ANGPTL6 levels may be related to metabolic and biochemical parameters. The effects of ANGPTL2 and ANGPTL6 in the pathogenesis of NAFLD should be investigated further. PMID- 30002696 TI - Fluoroscopy integrating technology in a 3D mapping system during ablation of atrial arrhythmias: first experiences. AB - Introduction: Ablation of the cavotricuspid isthmus (CTI) in patients with atrial flutter (AFL) and pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) are both common therapies. As the demand for ablative treatments rises, total radiation exposure times of staff increase concomitantly. Here, we report on our first experiences with a new fluoroscopy integrating system (FIS) integrated into a current 3D mapping system (3DMS). Material and methods: The study population consisted of 59 consecutive patients who underwent PVI or CTI ablation (26 and 33 patients with and without FIS respectively). Total procedure time (PT), fluoroscopy exposure time (FT) and dose-area product (DAP) were monitored. Results: All procedures were successfully completed without major complications. Employing FIS in the PVI group, FT and DAP were both significantly reduced after completing a short learning curve of 6 cases (respectively 361.6 +/ 181 s vs. 530.3 +/-156.7 s, p = 0.039; 801.9 +/-439.15 cGycm2 vs. 1495 +/-435.2 cGycm2, p = 0.002). Mean PT was not significantly affected (121 +/-26.7 min vs. 135.6 +/-23.2 min, p = 0.21). The same holds true for CTI ablation: FT (99.29 +/ 51.4 s vs. 153.9 +/-76.6 s, p = 0.022) and DAP (269 +/-128.7 cGycm2 vs. 524.3 +/ 288.4 cGycm2, p = 0.002) were significantly reduced, leaving PT not significantly affected (29.5 +/-10 min vs. 35.2 +/-16.3 min, p = 0.23). Conclusions: The introduction of the new FIS with a current 3DMS results in a significant reduction of both the total FT and DAP without affecting PT. The initial learning curve for adopting this method is considerably short. PMID- 30002694 TI - Standardised tomato extract as an alternative to acetylsalicylic acid in patients with primary hypertension and high cardiovascular risk - a randomised, controlled trial. AB - Introduction: Cardiovascular (CV) diseases remain a leading global cause of death. It has been proven that the use of acetylsalicylic acid (ASA) in secondary prevention reduces the CV risk, while the benefits of ASA in primary prevention have recently been debated. The aim of the study was to compare the antiplatelet effect of standardised tomato extract (STE) and ASA in hypertensive patients with high CV risk. Material and methods: The study involved high-risk patients with arterial hypertension (AH) randomly assigned to one of two groups: group 1 included 33 patients receiving ASA and group 2 included 32 patients receiving STE. The platelet aggregation was determined using the VerifyNow analyser. Results: After 4 weeks of ASA treatment in group 1, a statistically significant reduction in aspirin reaction units (ARU) was observed (p < 0.001). However, the obese subgroup using ASA (n = 18) did not reveal a significant decrease in ARU (p > 0.05). After 4 weeks of STE treatment in the obese subgroup (n = 14), significant declines in ARU by 8.6% (95% CI: -19.5 to -1.7%; p < 0.05) and in P2Y12 reaction units (PRU) by 7.5% (95% CI: -17.6 to 1.8%; p < 0.05) were observed. Conclusions: The antiplatelet effect of STE in hypertensive patients may be weight dependent. The group with AH and obesity might have potentially benefitted from STE treatment. PMID- 30002697 TI - Non-invasive evaluation of cardiac index by impedance cardiography in patients undergoing percutaneous nephrolithotomy. AB - Introduction: Percutaneous nephrolithotomy (PNL) is an endoscopic treatment of renal lithiasis. It is usually two-staged: it begins in the lithotomy position for ureteral catheter placement and retrograde pyelography, and subsequently an optimal renal access is obtained in the prone position. Some patients under epidural anesthesia do not tolerate the prone position and the PNL cannot be continued. This may be related to changes occurring within the circulatory system. The aim of this prospective randomized double-blind study was to evaluate the changes of the cardiac index (CI) during PNL. Material and methods: In a group of 50 patients, with ASA physical status grade 1-2, epidural anesthesia with either 0.2% ropivacaine or 0.25% bupivacaine was performed and then the CI was evaluated by impedance cardiography. Results: Forty-five patients were included in the analysis; all tolerated the PNL well. After turning prone, a decrease in the CI was always recorded, a maximum after 10-15 min - 22.58 +/ 11.47%. There was significant variability of recorded values. The average CI dropped from 2.96 +/-0.42 l/min/m2 to 2.28 +/-0.39 l/min/m2. In 7 patients the decrease in the CI was greater than 35%. No correlation was observed with the arterial blood pressure or the heart rate. The decrease in the CI occurred irrespective of the type of local anesthetic used (p = 0.91). Conclusions: A decrease in the CI was observed in every case, and it should be taken into consideration during qualification for PNL in the prone position. PMID- 30002698 TI - Dialysis vintage stratified comparison of body composition, hydration and nutritional state in peritoneal dialysis and hemodialysis patients. AB - Introduction: Body mass decomposition and hydration state imbalances affect patients on maintenance dialysis. We compared body composition, hydration and nutritional state of patients on peritoneal dialysis (PD) and hemodialysis (HD) based on dialysis vintage (DV). Material and methods: Three hundred and fifty nine prevalent patients on HD (n = 301) and PD (n = 58) were divided into 3 subgroups depending on DV: < 2 years HD (n = 41) and PD (n = 28), 2-4 years HD (n = 111) and PD (n = 17), > 4 years HD (n = 149) and PD (n = 13). Bioimpedance analysis delivered data including overhydration (OH), Lean (LTM) and adipose lipids mass (FAT). Other measurements included daily diuresis (DD), subjective global assessment (SGA) and serum albumin (alb), C-reactive protein (CRP) and total cholesterol (TChol), and hemoglobin (Hb). Results: Dialysis vintage < 2 years. Hemodialysis patients were older (65.5 +/-18.5 vs. 50.9 +/-17.1; p < 0.01) with a higher mortality (28 vs. 1; p < 0.01) and OH (8.0 +/-4.3 vs. 1.6 +/-3.1; p < 0.001). Hemoglobin (10.6 +/-1.5 vs. 11.8 +/-1.7; p < 0.05), TChol (180.2 +/ 47.0 vs. 211.7 +/-46.3; p < 0.05), DD (871 +/-729 vs. 1695 +/-960; p < 0.001) and LTM (46.5 +/-12.9 vs. 53.8 +/-14.4; p < 0.05) were lower on HD. Dialysis vintage 2-4 years: when compared to PD, HD patients had higher OH (11.7 +/-5.9 vs. 2.1 +/ 3.2; p < 0.001) and lower Hb (10.8 +/-1.5 vs. 11.9 +/-1.4; p < 0.01). Dialysis vintage > 4 years: compared to PD, HD patients had higher LTM (44.3 +/-11.7 vs. 38.6 +/-7.9; p < 0.05) and lower FAT (34.4 +/-11.1 vs. 42.8 +/-6.4; p < 0.01). Conclusions: Dialysis patients' body composition depends on dialysis modality and DV. Dialysis vintage < 2 years is associated with better hydration, nutritional state, and survival in PD patients, but longer DV reduces these benefits. Dialysis vintage > 4 years associated with similar hydration and mortality in both PD and HD while body composition was better on HD. PMID- 30002699 TI - Corneal integrity and thickness of central fovea after phacoemulsification surgery in diabetic and nondiabetic cataract patients. AB - Introduction: Here we intended to investigate the changes in corneal endothelial cells and foveal thickness after phacoemulsification surgery on the eyes of diabetic and non-diabetic cataract patients. Material and methods: A total of 120 cataract patients who were scheduled for phacoemulsification surgery and intraocular lens implantation were recruited and divided into 2 categories according to the diagnosis of diabetes mellitus. Changes in integrity, endothelial cell density (ECD), coefficient of variation (CV), percentage of hexagonal cells (PHC), central corneal thickness (CCT), and central foveal thickness (CFT) were all recorded at preoperative day 1 and postoperative day 3, 1 week, 1 month, 3 months and 6 months. Results: None of the recorded variables showed any difference between the nondiabetic and diabetic groups before surgery (p > 0.05). During the postoperative 6 months, ECD and PHC decreased and CV increased in both groups (all ptime < 0.05), whereas CCT and CFT fluctuated in both groups significantly (both ptime < 0.05), with their individual peaks at postoperative 1 week in the diabetic group. The groups differed significantly in ECD, PHC, and CV at each time point postoperatively (all pgroup < 0.05). Furthermore, the diabetic group had improved CFT during the postoperative 1 month and higher CCT during the 6 months postoperatively than the nondiabetic group (all pgroup < 0.05). The time and group interactions were significant for ECD, CV, PHC, CCT and CFT (all pgroup * time < 0.05). Conclusions: The diabetic group had more changes in corneal endothelial cells and foveal thickness than the nondiabetic group postoperatively. PMID- 30002700 TI - Surgical outcome and clinicopathological characteristics of emergency presentation elective cases of colorectal cancer. AB - Introduction: The aim of this study was to evaluate the significance of clinicopathological characteristics of colorectal cancer patients undergoing emergency and elective surgery. Material and methods: In total, 116 tumors from patients treated surgically for colorectal cancer at four hospitals in Tehran between 2008 and 2013 were analyzed in the current study. Results: Our findings revealed that the emergency cases were significantly more likely to have an advanced TNM stage (p = 0.027) and histologic grade (p = 0.01) compared with the elective patients. Furthermore, the nature of surgery was significantly associated with vascular and perineural invasion (p = 0.021; p = 0.001). We also evaluated the association of gender, age, and tumor location with the nature of surgical presentation. However, no association was found between these parameters and the nature of surgery. Emergency was also correlated with greater length of hospital stay and higher rate of admission to the intensive care unit. The mortality rate was 20% in emergency cases, while patients with elective surgery had 5.63% perioperative mortality (p = 0.001). The emergency patients had a higher rate of mortality. Conclusions: Our data indicated that colorectal cancer patients undergoing emergency surgery showed an advanced stage. The emergency patients had a higher rate of mortality than elective cases. PMID- 30002701 TI - Do the European League Against Rheumatism (EULAR) Sjogren's syndrome outcome measures correlate with impaired quality of life, fatigue, anxiety and depression in primary Sjogren's syndrome? AB - Introduction: The aim of the study was to investigate whether there is a relationship between the European League Against Rheumatism (EULAR) outcome measures and quality of life (QoL), fatigue, anxiety and depression in patients with pSS and to define determinants which could affect quality of life. Material and methods: The study included 105 pSS patients and 72 age/sex-matched healthy controls (HCs). Cross-sectional clinical data were collected, including the Hospital Anxiety and Depression Scale (HADS), the Multidimensional Assessment of Fatigue (MAF) scale, the Short Form (SF-36), EULAR Sjogren's syndrome disease activity index (ESSDAI) and EULAR Sjogren's syndrome patient reported index (ESSPRI). Results: The SF-36 scores were significantly lower and anxiety, depression and fatigue scores were significantly higher in the pSS group than in the control group (all p-value < 0.05). ESSDAI was negatively correlated with SF 36 scores and positively with MAF. ESSPRI was negatively correlated with SF-36 scores except for the mental health subdimension, and a positive correlation was determined with MAF, HADS-A and HADS-D. Multiple linear regression analysis revealed that HADS-A, HADS-D, MAF, ESSPRI and ESSDAI were associated with most SF 36 subscales. Conclusions: The results of this study provide further evidence supporting the use of ESSDAI and ESSPRI in daily practice. Quality of life was diminished in patients with pSS and was associated with different symptoms. This should be taken into account when managing patients with pSS. PMID- 30002702 TI - Pregnancy as a predictor of deviations from the recommended diagnostic pathway in women with suspected pulmonary embolism: ZATPOL registry data. AB - Introduction: Pulmonary embolism (PE) is a leading cause of mortality in pregnancy and a great diagnostic challenge. Deviations from the recommended diagnostic pathway in suspected PE contribute to greater mortality in the general population. The deviations from the guidelines of the European Society of Cardiology (ESC) for diagnosis of PE were analyzed, with particular emphasis on pregnant women with suspected PE. Material and methods: ZATPOL is a prospective national registry including data of all patients with suspected PE admitted to 86 Polish cardiology departments between January 2007 and September 2008. We analyzed diagnostic pathways used in all 2015 patients (mean age: 67 +/-15 years, 60% women) with suspected PE. Detailed analysis included diagnostic pathways used in 12 pregnant patients and 85 non-pregnant women in childbearing age. Results: Pregnancy was the strongest predictor of deviations from the recommended diagnostic pathway in the whole study group (HR = 4.0, 95% CI: 1.28-12.5, p = 0.02). Pregnant patients did not differ significantly from non-pregnant women in most risk factors and symptoms of PE, and diagnostic tests used in this condition. Deviations from the recommended diagnostic pathway were found in 7 (58%) and 36 (42%) pregnant and non-pregnant women, respectively (p = 0.297), and the preliminary diagnosis of PE was eventually confirmed in 42% and 67% of the patients, respectively (p = 0.086). Conclusions: Despite the lack of significant differences in PE symptomatology in pregnant and non-pregnant women, pregnancy seems to be the strongest predictor of deviations from the diagnostic pathway recommended in PE by the ESC. Further studies are required to evaluate the adherence to current guidelines in pregnant women. PMID- 30002703 TI - Could first- and second-trimester biochemical markers for Down syndrome have a role in predicting intrahepatic cholestasis of pregnancy? AB - Introduction: The aim of this study is to compare first- and second-trimester Down syndrome biochemical screening markers in intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies. Material and methods: This observational case-control study was conducted at Health Sciences University Zeynep Kamil Maternity and Children's Health Training and Research Hospital and the Department of Obstetrics and Gynecology at Erciyes University Medical Faculty during 2016 2017. The study included 165 patients, and consisted of 62 women who had been diagnosed with ICP (the ICP-diagnosed group) and 103 healthy pregnant women (the control group). First-trimester free beta-human chorionic gonadotropin (beta hCG), pregnancy-associated plasma protein-A (PAPP-A) and second-trimester total beta-hCG, estriol (E3), alpha-fetoprotein (AFP), and inhibin A levels were compared between the two groups. Results: The mean patient age was 28.67 +/-5.96 years, with no significant difference between the groups (p > 0.05). Average PAPP A levels were significantly lower in the ICP-diagnosed group (p < 0.001). When the cut-off value for PAPP-A was taken as <= 0.93 multiple of median (MoM), the sensitivity and specificity values for ICP were 73.8% and 56.3%, respectively (95% CI, AUC +/- SE: 0.663 +/-0.042). Conclusions: The decrease in PAPP-A MoM value indicates an increase in the risk of developing ICP, while changes in other markers were not sufficient to predict ICP. PMID- 30002704 TI - Comparison of ovarian responsiveness tests with outcome of assisted reproductive technology - a retrospective analysis. AB - Introduction: This study aims to compare the association between the most commonly used ovarian responsiveness markers - age, anti-Mullerian hormone levels (AMH), antral follicle count (AFC), ovarian sensitivity index (OSI), and ovarian response prediction index (ORPI) - and ovarian responsiveness to gonadotropin stimulation in assisted reproductive technology (ART) cycles. Material and methods: Patients who underwent intracytoplasmic sperm injection treatment using either a gonadotropin releasing hormone (GnRH) antagonist or agonist protocol were enrolled in the study. Data of the patients were abstracted from the hospital's database. Tests were compared for total number of retrieved oocytes, metaphase II (MII) oocytes, embryos, good quality embryos on day 1 and day 3, and ongoing pregnancies per cycle. Results: The OSI was the ovarian response test that had the strongest relationship with the ART outcomes. The level of association between the ovarian response tests and poor ovarian response data was (in descending order): OSI, ORPI, AFC, AMH, and age (AUCOSI = 0.976, AUCORPI = 0.905, AUCAFC = 0.899, AUCAMH = 0.864, AUCage = 0.617). The overall association between OSI and poor ovarian response was significantly higher than the other parameters (p1 = 0.0023, p2 = 0.0014, p3 = 0.0001, p4 <= 0.0001). In patients with high ovarian response data, OSI had the highest association, followed by AFC and ORPI age (AUCOSI = 0.984, AUCAFC = 0.907, AUCORPI = 0.887). There was no statistically significant difference among the tests for the data of patients with ongoing pregnancies. Conclusions: In this study, which is the first study comparing the five most frequently used ovarian responsiveness markers and the second study signifying the role of OSI in an antagonist protocol, OSI was found to be more convenient to calculate, and it could be superior to other ovarian responsiveness markers for poor and high ovarian responses on cycles with agonist or antagonist protocols. PMID- 30002705 TI - Dual therapy based on raltegravir and boosted protease inhibitors - the experience of Polish centers. AB - Introduction: The aim of the study was to present the experience of Polish centers regarding dual therapy based on the integrase inhibitor raltegravir (RAL) and ritonavir-boosted protease inhibitors (PI/r) for treating treatment-naive and -experienced HIV-infected patients. Material and methods: The paper concerns a retrospective multicenter study. The medical databases of six main Polish HIV centers from January 2009 to December 2014 were analyzed for the use of combined antiretroviral treatment consisting of RAL + PI/r. This study included 126 HIV infected patients receiving RAL + PI/r therapy, of whom 17 patients were treatment-naive and 109 patients were treatment-experienced. Results: In treatment-experienced patients, the most common reasons for the introduction of a RAL + PI/r regimen were virologic failure and impaired renal function (45 of 109 patients). In the treatment-naive group kidney disease was the cause of the RAL + PI/r regimen in 3 of 17 participants. In treatment-experienced patients, 80% of individuals still were on RAL + PI/r treatment after 12 months, 65% after 24 months and 53% of subjects after 60 months. In both groups, the simplification of the antiretroviral regimen was the most common reason for discontinuation of RAL + PI/r based therapy. Conclusions: In antiretroviral-experienced patients the dual therapy based on RAL + PI/s is safe and effective. In antiretroviral-naive patients the RAL + PI/r regimen is rarely used in Poland. PMID- 30002706 TI - Additional data from clinical examination on site significantly but marginally improve predictive accuracy of the Revised Trauma Score for major complications during Helicopter Emergency Medical Service missions. AB - Introduction: The Revised Trauma Score (RTS) accurately identifies trauma patients at high risk of adverse events or death. Less is known about its usefulness in the general population and non-trauma recipients of Helicopter Emergency Medical Service (HEMS). The RTS is a simple tool and omits a lot of other data obtained during clinical evaluation. The aim was to assess the role of the RTS to identify patients at risk of major complications (death, cardiopulmonary resuscitation, defibrillation, intubation) in the general population of HEMS patients. Clinical factors beyond the RTS were analyzed to identify additional prognostic factors for predicting major complications. Material and methods: A retrospective analysis of medical records of adult patients routinely collected during HEMS missions in the years 2011-2014 was performed. Results: The analysis included 19 554 HEMS missions. Patients were 55 +/-20 years old and 68% were male. The most common indication for HEMS was diseases of the circulatory system - 41%. Major complications occurred in 2072 (10.6%) cases. In the general population of HEMS patients, the RTS accurately identified individuals at risk of major complications at a cut-off value of 10.5 and area under the curve (AUC) of 93.5%. In multivariate analysis, additional clinical data derived from clinical examination (ECG; skin, pupil and breathing examination) significantly but marginally improved the accuracy of RTS assessment: AUC 95.6% (p < 0.001 for the difference). Conclusions: The Revised Trauma Score accurately identifies individuals at risk of major complications during HEMS missions regardless of the indication. Additional clinical data significantly but marginally improved the accuracy of RTS in the general population of HEMS patients. PMID- 30002707 TI - Effectiveness of median nerve neural mobilization versus oral ibuprofen treatment in subjects who suffer from cervicobrachial pain: a randomized clinical trial. AB - Introduction: Oral ibuprofen (OI) and median nerve neural mobilization (MNNM) are first line treatments for patients who suffer cervicobrachial pain (CP). OI may produce side effects which are not tolerated by all subjects who suffer CP, whereas MNNM has no known side effects. Therefore, the aim of this study was to assess the effectiveness of both treatments (OI vs. MNNM) in CP. Material and methods: This investigation was a blinded parallel randomized clinical trial (NCT02593721). Sixty-two participants diagnosed with CP were recruited and randomly assigned to 2 groups (n = 31), which received MNNM or 1200 mg/day OI treatment for 6 weeks. The numeric rating scale for pain intensity was the primary outcome. The cervical rotation range of motion (CROM) and the upper limb function were the secondary outcomes. Results: The results showed that OI treatment (eta2 = 0.612-0.755) was clearly superior to MNNM (eta2 = 0.816-0.821) in all assessments (p < 0.05) except for the CROM device results, which were equivalent to those of the MNNM group (p > 0.05). Three subjects were discharged because of OI side effects. Conclusions: Oral ibuprofen may be superior to MNNM for pain reduction and upper limb function increase of subjects with CP. Nevertheless, both treatments were effective. Median nerve neural mobilization may be considered an effective non-pharmaceutical treatment option in subjects with CP. Regarding OI adverse effects, our findings challenge the role of pharmacologic versus manual therapy as possible treatments that may improve pain intensity and upper limb functionality in subjects with CP. PMID- 30002708 TI - Validation of the Polish version of the Critical Care Pain Observation Tool (CPOT) to assess pain intensity in adult, intubated intensive care unit patients: the POL-CPOT study. AB - Introduction: Pain in the critically ill affects nearly 50% of patients. In patients unable to self-report pain, behavioural scales are used. The aim of this study was to validate the Polish version of the Critical Care Pain Observation Tool (CPOT). Material and methods: The prospective observational cohort study included patients observed during non-nociceptive and nociceptive procedures, at rest, during the intervention, and 15 min after each intervention. Assessments included self-report by patients and CPOT assessment carried out by two blinded observers. Results: A total of 71 patients were included in the study (mean age: 66 years), predominantly males (50/71, 70%), mean APACHE II score 26.04 +/-10.56. Results showed an excellent inter-rater correlation (ICC) between raters (ICC scores > 0.97). Self-report NRS (numeric rating scale) scores were available from 58/71 patients (82%). Patients' self-reported pain and CPOT showed a very strong correlation (Spearman's R > 0.85, p < 0.0001). The CPOT has high diagnostic value for detection of presence of patients' self-reported pain (ROC AUC = 0.938 for rater A and 0.951 for rater B, p < 0.0001). CPOT score >= 2 is an optimal cut-off to detect pain during a nociceptive procedure. A significantly higher mean CPOT score during a nociceptive procedure as compared to a non-nociceptive procedure or at rest was found (p < 0.0001). Conclusions: This study shows that the Polish version of the CPOT can be used to assess pain in critically ill patients with no hypnotic, opioid-based analgo-sedation. Polish CPOT scores correlated well with patients' self-reported presence of pain and showed excellent inter-rater reliability. This makes the Polish version of the CPOT a reliable pain assessment tool. PMID- 30002711 TI - Pretreatment with obestatin inhibits the development of acetic acid-induced colitis in rats. AB - Introduction: Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies have shown that obestatin exhibits some protective and therapeutic effects in the pancreas and stomach. The aim of this study was to examine the effect of pretreatment with obestatin on the development of acetic acid-induced colitis. Material and methods: Studies were performed on Wistar rats. Before induction of colitis, rats were treated intraperitoneally with saline or obestatin, administered twice at a dose of 4, 8 or 16 nmol/kg/dose. The first dose of saline or obestatin was administered 8 h before the induction of colitis, the second one 7 h after the first dose. Colitis was induced by enema with 1 ml of 4% acetic acid solution. The severity of colitis was assessed 1 or 24 h after administration of enema. Results: Pretreatment with obestatin administered at a dose of 8 or 16 nmol/kg/dose significantly reduced the area of mucosal damage evoked by enema with acetic acid (p < 0.05). This effect was accompanied by an improvement of mucosal blood flow and DNA synthesis in the colon. Moreover, obestatin administered at a dose of 8 or 16 nmol/kg/dose significantly reduced mucosal concentration of IL-1beta and activity of myeloperoxidase (p < 0.05). Conclusions: Pretreatment with obestatin exhibited a protective effect in the colon, leading to a reduction of colonic damage in acetic acid-induced colitis. This effect was associated with an improvement of mucosal blood flow, an increase in mucosal cell proliferation, and a decrease in local inflammation. PMID- 30002709 TI - Biomarkers, myocardial fibrosis and co-morbidities in heart failure with preserved ejection fraction: an overview. AB - The prevalence of heart failure with preserved ejection fraction (HFpEF) is steadily increasing. Its diagnosis remains difficult and controversial and relies mostly on non-invasive echocardiographic detection of left ventricular diastolic dysfunction and elevated filling pressures. The large phenotypic heterogeneity of HFpEF from pathophysiologic al underpinnings to clinical manifestations presents a major obstacle to the development of new therapies targeted towards specific HF phenotypes. Recent studies suggest that natriuretic peptides have the potential to improve the diagnosis of early HFpEF, but they still have significant limitations, and the cut-off points for diagnosis and prognosis in HFpEF remain open to debate. The purpose of this review is to present potential targets of intervention in patients with HFpEF, starting with myocardial fibrosis and methods of its detection. In addition, co-morbidities are discussed as a means to treat HFpEF according to cut-points of biomarkers that are different from usual. Biomarkers and approaches to co-morbidities may be able to tailor therapies according to patients' pathophysiological needs. Recently, soluble source of tumorigenicity 2 (sST2), growth differentiation factor 15 (GDF-15), galectin-3, and other cardiac markers have emerged, but evidence from large cohorts is still lacking. Furthermore, the field of miRNA is a very promising area of research, and further exploration of miRNA may offer diagnostic and prognostic applications and insight into the pathology, pointing to new phenotype-specific therapeutic targets. PMID- 30002710 TI - 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. AB - Cell culture is a widely used in vitro tool for improving our understanding of cell biology, tissue morphology, and mechanisms of diseases, drug action, protein production and the development of tissue engineering. Most research regarding cancer biology is based on experiments using two-dimensional (2D) cell cultures in vitro. However, 2D cultures have many limitations, such as the disturbance of interactions between the cellular and extracellular environments, changes in cell morphology, polarity, and method of division. These disadvantages led to the creation of models which are more closely able to mimic conditions in vivo. One such method is three-dimensional culture (3D). Optimisation of the culture conditions may allow for a better understanding of cancer biology and facilitate the study of biomarkers and targeting therapies. In this review, we compare 2D and 3D cultures in vitro as well as different versions of 3D cultures. PMID- 30002714 TI - Intracerebral hemorrhage in a patient with tuberous sclerosis complex. PMID- 30002712 TI - Therapeutic and immunological interventions in primary biliary cholangitis: from mouse models to humans. PMID- 30002713 TI - Comorbidities on kidney transplantation waiting list relative to the status of the potential recipient. PMID- 30002715 TI - Regorafenib in hepatocellular carcinoma: latest evidence and clinical implications. AB - Over the past ten years, sorafenib, a multikinase inhibitor, has been the only systemic agent approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Whereas only recently lenvatinib was shown to be noninferior to sorafenib, in terms of survival, all other agents previously tested failed to prove noninferiority (or superiority) when compared with sorafenib. Similarly, in a second-line setting, most investigational drugs have failed to provide better survival outcomes than placebo. However, in 2016, data from the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Overall, side-effects were in line with the known safety profile of regorafenib. More recently, the survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with cabozantinib in the frame of the phase 3 CELESTIAL trial. As HCC seems to be an attractive target for immunotherapy, a phase 1/2 trial reported promising efficacy signals from nivolumab, and results of a larger phase 3 trial with another checkpoint inhibitor, namely, pembrolizumab, are still pending. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and immunotherapy that will likely change the treatment scenario of HCC. PMID- 30002716 TI - Expression of Concern on "Modes of Antiviral Action of Chemical Portions and Constituents from Woad Root Extract against Influenza Virus A FM1". PMID- 30002717 TI - Ingestion of Exopolymers from Aureobasidium pullulans Reduces the Duration of Cold and Flu Symptoms: A Randomized, Placebo-Controlled Intervention Study. AB - Aim: The objective of the study was to assess the efficacy of exopolymers from Aureobasidium pullulans (EAP) on the incidence of colds and flu in healthy adults. Methods: We conducted a randomized, double-blind, placebo-controlled study at the onset of the influenza season. A total of 76 subjects (30-70 years of age) were recruited from the general population. The subjects were instructed to take one capsule per day of either EAP or a placebo for a period of 8 weeks. The duration of cold and flu symptoms, a primary variable in assessing effectiveness, and serum cytokine levels as well as WBC counts as secondary variables were also evaluated. Results: EAP was associated with a statistically significant decrease in the duration of cold and flu symptoms, a primary variable in assessing effectiveness. Although cold and flu symptom levels were not significantly different at a significance level of 5%, the cold and flu symptom levels of the EAP group were less severe compared to the placebo group. No statistically significant changes of serum cytokine levels as well as WBC counts were observed. Conclusion: The results showed that EAP is a useful pharmaceutical and functional food material for preventing and treating colds and flu. PMID- 30002718 TI - A Pilot Study on Characteristics of Metabolomics and Lipidomics according to Sasang Constitution. AB - Although classification of an individual's Sasang constitution is a key step in the prescription of traditional Korean medicine, the classifying process is complex and not objective. Identification of metabolic-based biomarkers could allow the development of a reliable and sensitive classification technique and even therapeutic management. Our pilot study investigated whether metabolites in plasma are characteristic of Sasang constitutions. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolic analysis was conducted against 15 Soyangin (SY), 15 Taeeumin (TE), and 18 Soeumin (SE) individuals, as classified according to the Questionnaire for Sasang Constitution Classification II (QSCC II) and specialist diagnosis. Metabolomics data showed that the TE group was significantly separated from the SY and SE groups. Nine canonical pathways related to constitution; phenylalanine metabolism, aminoacyl-tRNA, tyrosine, and tryptophan biosynthesis were activated in the TE group as compared with the other groups. Similar to the results of the metabolomics analysis, the TE group was also significantly separated from the other two groups by lipidomic analysis. On the other hand, the intensity of lipid metabolites was higher in the SY group than in the other groups. Our findings suggest that the combined analysis of metabolomics and lipidomics can provide useful information for characteristics of Sasang constitutions. PMID- 30002719 TI - Correction to: Effect of a short-term dietary supplementation with phytosterols, red yeast rice or both on lipid pattern in moderately hypercholesterolemic subjects: a three-arm, double-blind, randomized clinical trial. AB - [This corrects the article DOI: 10.1186/s12986-017-0214-2.]. PMID- 30002721 TI - Understanding mental health difficulties and associated psychosocial outcomes in adolescents in the HIV clinic at Kenyatta National Hospital, Kenya. AB - Background: Globally adolescents continue to have an upward trend in HIV incidence and AIDS-related mortality. The interplay between the rapid physical growth, sexual maturation, and enormous albeit slow-evolving cognitive and psychological changes in adolescence may partly explain this trend. Our main purpose was to highlight key psychosocial characteristics of HIV-infected adolescents and explore if these characteristics are associated with depression symptoms. Methods: From August to December 2016 after obtaining informed consent, adolescents living with HIV at Kenyatta National Hospital were interviewed using the Home environment, Education and Employment, Activity, Sexuality, Suicide and depression traits (HEADSS) tool combined with the Patient Health Questionnaire (PHQ-9) to elucidate which key symptoms of depression and link with psychosocial characteristics mapped on HEADSS. In order to determine which psychosocial characteristics were linked with risk of depression, the traits of adolescents who were symptomatic were compared to those who were not using univariate and multivariate regression analysis. Results: All the 270 adolescents offered participation in the study accepted to enroll. The aged 10-19 years were recruited and mean age was 14.75 and 53.7% (n = 145) were males. Overall, 269 (99.9%) were still in school and 52.6% of the adolescents had symptoms of depression. The independent predictors of depression were being of ages 15-19 years [OR = 2.34 (95% CI 1.36, 4.04) P < 0.02], ever repeating classes [OR = 1.74 (95% CI 1.0-3.05) P = 0.05], ever being sent away from school due to lack of school fees [OR = 1.71 (95% CI 1.0-2.91) P = 0.05], and non-adherence to medication [OR = 1.84 (95% CI 1.08-3.14) P = 0.03. Missing of meals due to food insecurity was associated with an important trend towards increased risk of depression [OR = 2.42 (CI 0.96-6.14) P = 0.06]. Conclusion: One in two of the adolescents interviewed had depression symptoms which were significantly associated with lack of school fees, missing meals, non-adherence to medication, and substance abuse. PMID- 30002720 TI - The relationship between sleep duration and obesity risk among school students: a cross-sectional study in Zhejiang, China. AB - Background: Obesity has been identified as a major risk factor for a large number of chronic diseases. Understanding factors related to adolescent obesity is critical for prevention of chronic diseases. The associations between sleep duration and obesity among adolescents in the existing literature are controversial. Our study was designed to determine the prevalence of short sleep duration, and assess the association of sleep duration and obesity, among middle and high school students in Zhejiang, China. Methods: 18,403 Students in 442 schools were recruited and surveyed using an anonymous, self-administered questionnaires. Weighted multivariable logistic regression models were used for data analyses. Results: The mean (SD) age of the students was 15.9 (1.8) years. 49.7% of students were girls. The mean (SD) height and weight were 166.2 (8.5) cm and 54.6 (11.1) kg, respectively. The overall prevalence of obesity and overweight were 3.4% (95% CI: 3.0-3.8) and 7.8% (95% CI: 7.4-8.3), respectively. The overall prevalence of short sleep duration among students was 66.0% (95% CI: 63.8-68.1), higher among girls than boys (69.8% vs. 62.1%) (P < 0.0001). The figures for middle school, academic high school, and vocational high school were 59.0, 82.4 and 59.7%, respectively (P < 0.0001). As compared with girls who sleep 8 h per day (reference), the odds ratios (95% CI) of obesity for girls who sleep < 7 h, 7 h, 9 h and >= 10 h were 1.97 (1.15-3.38), 1.90 (1.18-3.04), 1.38 (0.86 2.20) and 2.12 (1.22-3.67) respectively, after adjustment for socio-demographic status, lifestyle factors, and mental health. The corresponding figures among boys were 1.45 (0.97-2.16), 1.13 (0.81-1.57), 1.25 (0.89-1.74), and 1.12 (0.81 1.54), respectively. Conclusions: Insufficient sleep is prevalent among students in Zhejiang China. A U-shaped relationship was found between sleep duration and obesity risk among girls, with the lowest risk among those who slept for 8 h, but not among boys. Adequate sleep duration may be an important component of obesity prevention initiatives among adolescents. PMID- 30002722 TI - Factors associated with delayed initiation of breastfeeding: a cross-sectional study in South Sudan. AB - Background: The global breastfeeding recommendation states that all infants should be put to the breast within one hour of birth, which is defined as timely initiation or early initiation of breastfeeding. Early initiation of breastfeeding is associated with reduced risk in infant illness and death. Understanding the determinants of delay in initiation of breastfeeding might spur health staff and policy makers to foster timely breastfeeding. We assessed the prevalence and determinants of delay in initiation of breastfeeding among mothers in Juba Teaching Hospital. Methods: The present study enrolled 806 mother-infant pairs within 24 hrs of birth in Juba Teaching Hospital in 2017. The mothers were interviewed about the time of initiation of breastfeeding, sociodemographic and birth characteristics. The independent variables associated with delay in initiation of breastfeeding were identified using multivariable logistic regression analysis. Results: In the current study, 52% (418/806) of the mothers initiated breastfeeding later than one hour after birth. Birth by Caesarean section (Adjusted Odds Ratio [AOR] 41; 95% Confidence Interval [CI] 12.21, 138), discarding of colostrum (AOR 9.89; 95% CI 4.14, 23.62), unmarried mothers (AOR 3.76; 95% CI 1.53, 9.24), exposure to infant formula advertisement (AOR 1.82; 95% CI 1.09, 3.02) and no house ownership (AOR 1.52; 95% CI 1.11, 2.09) were independent factors associated with delay in initiation of breastfeeding. Conclusion: We found that more than half of the mothers delayed the initiation of breastfeeding. Therefore, we recommend training on best breastfeeding practices and counselling skills for health staff in Juba Teaching Hospital. Policy dialogue, with the relevant ministries and departments on the promotion and protection of early initiation of breastfeeding is crucial. PMID- 30002724 TI - Correction to: Bayesian functional regression as an alternative statistical analysis of high-throughput phenotyping data of modern agriculture. AB - [This corrects the article DOI: 10.1186/s13007-018-0314-7.]. PMID- 30002723 TI - In vivo monitoring of plant small GTPase activation using a Forster resonance energy transfer biosensor. AB - Background: Small GTPases act as molecular switches that regulate various plant responses such as disease resistance, pollen tube growth, root hair development, cell wall patterning and hormone responses. Thus, to monitor their activation status within plant cells is believed to be the key step in understanding their roles. Results: We have established a plant version of a Forster resonance energy transfer (FRET) probe called Ras and interacting protein chimeric unit (Raichu) that can successfully monitor activation of the rice small GTPase OsRac1 during various defence responses in cells. Here, we describe the protocol for visualizing spatiotemporal activity of plant Rac/ROP GTPase in living plant cells, transfection of rice protoplasts with Raichu-OsRac1 and acquisition of FRET images. Conclusions: Our protocol should be adaptable for monitoring activation for other plant small GTPases and protein-protein interactions for other FRET sensors in various plant cells. PMID- 30002725 TI - Mobile Personal Health Monitoring for Automated Classification of Electrocardiogram Signals in Elderly. AB - Mobile electrocardiogram (ECG) monitoring is an emerging area that has received increasing attention in recent years, but still real-life validation for elderly residing in low and middle-income countries is scarce. We developed a wearable ECG monitor that is integrated with a self-designed wireless sensor for ECG signal acquisition. It is used with a native purposely designed smartphone application, based on machine learning techniques, for automated classification of captured ECG beats from aged people. When tested on 100 older adults, the monitoring system discriminated normal and abnormal ECG signals with a high degree of accuracy (97%), sensitivity (100%), and specificity (96.6%). With further verification, the system could be useful for detecting cardiac abnormalities in the home environment and contribute to prevention, early diagnosis, and effective treatment of cardiovascular diseases, while keeping costs down and increasing access to healthcare services for older persons. PMID- 30002726 TI - Siegesbeckia pubescens Makino inhibits Pam3CSK4-induced inflammation in RAW 264.7 macrophages through suppressing TLR1/TLR2-mediated NF-kappaB activation. AB - Background: Siegesbeckia pubescens Makino (SP) is one of the important plant origins for the anti-inflammatory Chinese herbal medicine of Siegesbeckiae Herba. The current investigations indicated that the anti-inflammatory effects of SP were associated with the toll-like receptors (TLRs)-mediated nuclear factor kappaB (NF-kappaB) and the mitogen-activated protein kinase (MAPK) signaling pathways. Methods: Raw 264.7 macrophages were pretreated with the 50% ethanol extract of SP (SPE, 50-200 ug/mL) and then co-treated with Pam3CSK4 (200 ng/mL) for another 12 h. The inhibitory effect of SPE on Pam3CSK4-stimulated NO release and post-inflammatory cytokines secretions were determined using Griess reagent and Elisa kits, respectively. The influence of SPE on NF-kappaB and MAPKs signaling relevant proteins was measured by Western blotting analysis, while the intracellular nitric oxide (NO) generation and NF-kappaB/p65 nuclear translocation were determined using Leica TCS SP8 laser scanning confocal microscope. Moreover, the effect of SPE on luciferase reporter gene in NF-kappaB luc DNA transfected raw 264.7 cells was determined using the Dual-Glo luciferase assay system kit. Results: SPE dose-dependently (50-200 ug/mL) attenuated Pam3CSK4-induced NO release, post-inflammatory cytokines (IL-6, TNF-alpha and MCP 1) secretions and intracellular NO generation in raw 264.7 cells. Biologically, SPE suppressed Pam3CSK4-induced expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phosphorylation of NF-kappaB/p65 and IkappaBalpha, but did not significantly show effect on the proteins involved in MAPKs signaling (p38, ERK and JNK). The results were further confirmed by NF kappaB-luc reporter gene assay and p65 nuclear translocation assay. Conclusions: In conclusion, SPE ameliorated Pam3CSK4-induced inflammation in raw 264.7 cells through suppressing TLR 1/2-mediated NF-kappaB activation. PMID- 30002727 TI - Small and light arms violence reduction as a public health measure: the case of Libya. AB - The conflict environment in Libya is characterized by continued pervasive insecurity amidst the widespread availability of small arms and light weapons (SALW). After the First Civil War, armed brigades took the law into their own hands and the resulting violence terminated a short-lived post-conflict period that has relapsed into a Second Civil War. The Libyan government has struggled to assert authority over armed groups and these brigades, refusing to disarm have contributed directly the initiation of a second conflict; some are motivated by self-defense, status, criminality, vindication or political aims. Once, a bastion of public health in the Middle East and North Africa (MENA), the country now faces a substantial and unprecedented challenge: to rebuild a devastated health system amidst the burden of armed violence and the proliferation of small and light weapons (SALW) especially firearms of various kinds. The health system in Libya is compromised; healthcare professionals have little time to record or document such cases given the immediate clinical needs of the patient. This corresponding decreased capacity to deal with an increasing demand on services caused by SALW-related morbidity compounds the challenge of data collection and indicates that external support and advocacy are required. A public health strategy towards effective SALW armed violence reduction and injury prevention requires the interdisciplinary advocacy of practitioners across the fields of justice, security, development, health and education. Through surveillance of firearms and injuries in the post-conflict environment we can better evaluate and respond to the burden of armed violence in Libya. In order to reduce armed a reconceptualisation of arms reduction campaigns must occur. Notable emerging evidence recommends the inclusion of community-based interventions and development programs which address local motivations for firearms ownership alongside improved international coordination. This renewed approach holds importance for recovery, development and securing the transition to peace. The high prevalence of firearm ownership, weak institutions, nascent security forces, porous borders, inadequate weapons stockpiles, combined with high military spending, compounds public weaponisation as a health crisis for the entire MENA region. PMID- 30002728 TI - Iterative cycle of widely targeted metabolic profiling for the improvement of 1 butanol titer and productivity in Synechococcus elongatus. AB - Background: Metabolomics is the comprehensive study of metabolites that can demonstrate the downstream effects of gene and protein regulation, arguably representing the closest correlation with phenotypic features. Hence, metabolomics-driven approach offers an effective way to facilitate strain improvement. Previously, targeted metabolomics on the 1-butanol-producing cyanobacterial strain Synechococcus elongatus BUOHSE has revealed the reduction step from butanoyl-CoA to butanal, catalyzed by CoA-acylating propionaldehyde dehydrogenase (PduP), as a rate-limiting step in the CoA-dependent pathway. Moreover, an increase in acetyl-CoA synthesis rate was also observed in this strain, by which the increased rate of release of CoA from butanoyl-CoA was used to enhance formation of acetyl-CoA to feed into the pathway. Results: In the present study, a new strain (DC7) with an improved activity of PduP enzyme, was constructed using BUOHSE as the background strain. DC7 showed a 33% increase in 1 butanol production compared to BUOHSE. For a deeper understanding of the metabolic state of DC7, widely targeted metabolomics approach using ion-pair reversed-phase LC/MS was performed. Results showed a decreased level of butanoyl CoA and an increased level of acetyl-CoA in DC7 compared to BUOHSE. This served as an indication that the previous bottleneck has been solved and free CoA regeneration increased upon the improvement of the PduP enzyme. In order to utilize the enhanced levels of acetyl-CoA in DC7 for 1-butanol production, overexpression of acetyl-CoA carboxylase (ACCase) in DC7 was performed by inserting the gene encoding an ACCase subunit from Yarrowia lipolytica into the aldA site. The resulting strain, named DC11, was able to reach a production titer of 418.7 mg/L in 6 days, compared to DC7 that approached a similar titer in 12 days. A maximum productivity of 117 mg/L/day was achieved between days 4 and 5 in DC11. Conclusions: In this study, the iterative cycle of genetic modification based on insights from metabolomics successfully resulted in the highest reported 1-butanol productivity for engineered Synechococcus elongatus PCC 7942. PMID- 30002730 TI - Nitrogen and phosphorus removal from anaerobically digested wastewater by microalgae cultured in a novel membrane photobioreactor. AB - Background: With the further development of anaerobic digestion, an increasing output of anaerobically digested wastewater (ADW), which typically contained high concentrations of ammonium, phosphate, and suspended solids, was inevitable. Microalgae cultivation offered a potential waste-to-value strategy to reduce the high nutrient content in ADW and obtain high value-added microalgae. However, ADW generally contained a mass of pollutants (suspended solids, competitors, etc.), which could inhibit microalgae growth and even result in microalgae death by limiting light utilization. Thus, it is highly imperative to solve the problem by a novel modified photobioreactor for further practical applications. Results: Four microalgae species, Scenedesmus dimorphus, Scenedesmus quadricauda, Chlorella sorokiniana, and Chlorella vulgaris ESP-6, were cultivated in the membrane photobioreactor (MPBR) fed with ADW to investigate the efficiency of ammonia and phosphorus removal. The results showed that C. sorokiniana had the best performance for the removal of ammonia and phosphorus from ADW. The highest amount of C. sorokiniana biomass was 1.15 g/L, and the removal efficiency of phosphate (66.2%) peaked at an ammonia concentration of 128.5 mg/L after 9 days' incubation. Moreover, the MPBR with 0.1 MUm membrane pore size had the best ammonia and phosphate removal efficiencies (43.9 and 64.9%) at an ammonia concentration of 128.5 mg/L during 9 days' incubation. Finally, the continuous multi-batch cultivation of C. sorokiniana was performed for 45 days in MPBR, and higher removal ammonia amount (18.1 mg/day) and proteins content (45.6%) were obtained than those (14.5 mg/day and 37.4%) in an normal photobioreactor. Conclusion: In this study, a novel MPBR not only eliminated the inhibitory effects of suspended solid and microorganisms, but also maintained a high microalgae concentration to obtain a high amount of ammonia and phosphate removal. The research provided a theoretical foundation for the practical application of MPBRs in various wastewater treatment schemes without pretreatment by algae, which could be used as biofuels or protein feed. PMID- 30002729 TI - An iterative computational design approach to increase the thermal endurance of a mesophilic enzyme. AB - Background: Strategies for maximizing the microbial production of bio-based chemicals and fuels include eliminating branched points to streamline metabolic pathways. While this is often achieved by removing key enzymes, the introduction of nonnative enzymes can provide metabolic shortcuts, bypassing branched points to decrease the production of undesired side-products. Pyruvate decarboxylase (PDC) can provide such a shortcut in industrially promising thermophilic organisms; yet to date, this enzyme has not been found in any thermophilic organism. Incorporating nonnative enzymes into host organisms can be challenging in cases such as this, where the enzyme has evolved in a very different environment from that of the host. Results: In this study, we use computational protein design to engineer the Zymomonas mobilis PDC to resist thermal denaturation at the growth temperature of a thermophilic host. We generate thirteen PDC variants using the Rosetta protein design software. We measure thermal stability of the wild-type PDC and PDC variants using circular dichroism. We then measure and compare enzyme endurance for wild-type PDC with the PDC variants at an elevated temperature of 60 degrees C (thermal endurance) using differential interference contrast imaging. Conclusions: We find that increases in melting temperature (Tm) do not directly correlate with increases in thermal endurance at 60 degrees C. We also do not find evidence that any individual mutation or design approach is the major contributor to the most thermostable PDC variant. Rather, remarkable cooperativity among sixteen thermostabilizing mutations is key to rationally designing a PDC with significantly enhanced thermal endurance. These results suggest a generalizable iterative computational protein design approach to improve thermal stability and endurance of target enzymes. PMID- 30002731 TI - Effect of perchlorate and thiocyanate exposure on thyroid function of pregnant women from South-West England: a cohort study. AB - Background: Iodine is important for thyroid hormone synthesis, and iodine deficiency in pregnancy may impair fetal neurological development. As perchlorate and thiocyanate inhibit sodium-iodide symporter reducing the transport of iodine from circulation into the thyroid follicular cells, environmental exposure to these substances in pregnancy may impair maternal thyroid hormone synthesis. We aimed to explore the impact of perchlorate and thiocyanate exposure on thyroid status in a cohort of pregnant mothers from South West England. Methods: Urine samples were obtained from 308 women participating in a study of breech presentation in late pregnancy. They had no known thyroid disease and a singleton pregnancy at 36-38 weeks gestation. Samples were analysed for urinary concentrations of iodine (UIC), perchlorate (UPC) and thiocyanate (UTC). Blood samples were taken for free T4 (FT4), thyrotropin (TSH) and thyroid peroxidase antibodies (TPO-Ab). Baseline data included age, parity, smoking status, ethnicity and BMI at booking. Following delivery, data on offspring's sex, gestational age at birth and birthweight were collected. Results: Participants had a mean (SD) age 31 (5) years, median (IQR) BMI 24.4 (22.0, 28.3) kg/m2, 42% were primiparous, 10% were smokers, and 96% were Caucasian. Median UIC was 88 MUg/l, and 174/308 (57%) women had UIC < 100 MUg/l. Log transformed UPC negatively correlated with FT4, but not with TSH, in the whole cohort (r = - 0.12, p = 0.03) and in the subgroup of women with UIC < 100 MUg/l (r = - 0.15, p = 0.04). Regression analysis with the potential confounders (TPO-Ab status, UIC and UTC) identified UPC to be negatively associated with FT4 (p = 0.01). There was no correlation between UTC and FT4 or TSH. Maternal UPC or UTC was not associated with offspring birthweight. Conclusion: Environmental perchlorate exposure is negatively associated with circulating FT4 levels in third trimester pregnant women. This may have an adverse impact on neurocognitive development of the fetus. PMID- 30002733 TI - Gut colonization with vancomycin-resistant Enterococcus and risk for subsequent enteric infection. AB - Background: Gut colonization with vancomycin-resistant Enterococcus (VRE) is associated with poor outcomes. This study evaluated the impact of VRE colonization on subsequent acquisition of enteric pathogens. Methods: We performed a retrospective cohort study of adults admitted to an ICU from 2012 to 2017 who were screened for VRE colonization and subsequently underwent stool testing with a gastrointestinal pathogen PCR panel (GI PCR) with or without PCR testing for Clostridium difficile. Our primary outcome was the presence of any enteric pathogen. Cox proportional hazards modeling was used to adjust for factors associated with enteric infection. Results: Of 761 patients who underwent VRE screening and subsequent GI PCR, 131 (17%) were colonized with VRE. Patients with VRE colonization were less likely to test positive on GI PCR compared to patients without VRE (9.2% vs 18%, p = 0.01); specifically for E. coli species (p = 0.03) and viral (p = 0.04) enteric infections. In 716 patients who underwent C. difficile testing, there was a trend towards more C. difficile infections in patients colonized with VRE (15% vs 10%, p = 0.11). On multivariable analysis, patients with VRE had a decreased risk of a positive GI PCR (aHR 0.47, 95% CI 0.25-0.88, p = 0.02) but not C. difficile infection, effects which persisted during 5 years of follow-up. Among positive tests, there was a greater proportion of C. difficile with VRE (57% vs 28%, p < 0.01). Conclusions: VRE colonization was associated with a decreased risk of subsequent non-C. difficile enteric infection. VRE domination of the gut microbiome may protect against acquisition of common enteric pathogens. PMID- 30002732 TI - Big issues for small feet: developmental, biomechanical and clinical narratives on children's footwear. AB - The effects of footwear on the development of children's feet has been debated for many years and recent work from the developmental and biomechanical literature has challenged long-held views about footwear and the impact on foot development. This narrative review draws upon existing studies from developmental, biomechanical and clinical literature to explore the effects of footwear on the development of the foot. The emerging findings from this support the need for progress in [children's] footwear science and advance understanding of the interaction between the foot and shoe. Ensuring clear and credible messages inform practice requires a progressive evidence base but this remains big issue in children's footwear research. PMID- 30002734 TI - Association of adiponectin with cognitive function precedes overt diabetes in the Brazilian Longitudinal Study of Adult Health: ELSA. AB - Background: Adiponectin is an insulin-sensitizer adipocytokine endowed with neuroprotective actions. Whether adiponectin regulates neuronal functioning toward delaying cognitive decline independently of the glucose metabolism disturbance has been poorly explored. This study evaluated if the performance in cognitive tests was associated with adiponectin levels prior the development of type 2 diabetes in middle-aged individuals. Methods: A sample of 938 non-diabetic participants of ELSA had their cognitive function assessed by the CERAD delayed word recall test, the verbal fluency test and the trail making test. Stepwise multiple linear regression using forward selection had the response to cognitive tests as the dependent variable and adiponectin as the independent variable of main interest, adjusted for glucose tolerance status and confounders. Results: Mean age was 45.7 +/- 4.9 years, 54.5% were women, 43.0% had high education level, 59.3% weight excess and 70.0% prediabetes. In crude model, only the delayed recall memory was associated with adiponectin levels. In an initial regression model, delayed recall memory remained independently associated with adiponectin levels and prediabetes. After complete adjustments, adiponectin but not prediabetes maintained independently associated with delayed recall memory (beta 0.067; 95% CI 0.006-0.234; p = 0.040). On the other hand, learning memory showed to be associated with prediabetes (beta 0.71 95% CI 0.17; 1.24; p = 0.009) but not with adiponectin. Conclusions: The association of memory with adiponectin in middle-aged individuals, prior overt diabetes, suggests that this adipocytokine could anticipate cognitive impairmentrho detection, when preventive strategies could be more effectively implemented. The usefulness of adiponectin to identify increased risk for cognitive dysfunction before advanced age needs to be prospectively investigated in ELSA cohort. PMID- 30002736 TI - Drosophila parasitoid wasps bears a distinct DNA transposon profile. AB - Background: The majority of Eukaryotic genomes are composed of a small portion of stable (non-mobile) genes and a large fraction of parasitic mobile elements such as transposable elements and endogenous viruses: the Mobilome. Such important component of many genomes are normally underscored in genomic analysis and detailed characterized mobilomes only exists for model species. In this study, we used a combination of de novo and homology approaches to characterize the Mobilome of two non-model parasitoid wasp species. Results: The different methodologies employed for TE characterization recovered TEs with different features as TE consensus number and size. Moreover, some TEs were detected only by one or few methodologies. RepeatExplorer and dnaPipeTE estimated a low TE content of 5.86 and 4.57% for Braconidae wasp and 5.22% and 7.42% for L. boulardi species, respectively. Both mobilomes are composed by a miscellaneous of ancient and recent elements. Braconidae wasps presented a large diversity of Maverick/Polintons Class II TEs while other TE superfamilies were more equally diverse in both species. Phylogenetic analysis of reconstructed elements showed that vertical transfer is the main mode of transmission. Conclusion: Different methodologies should be used complementarity in order to achieve better mobilome characterization. Both wasps genomes have one of the lower mobilome estimates among all Hymenoptera genomes studied so far and presented a higher proportion of Class II than Class I TEs. The large majority of superfamilies analyzed phylogenetically showed that the elements are being inherited by vertical transfer. Overall, we achieved a deep characterization of the mobilome in two non model parasitoid wasps improving our understanding of their evolution. PMID- 30002737 TI - Correction to: Plasma fatty acid levels and gene expression related to lipid metabolism in peripheral blood mononuclear cells: a cross-sectional study in healthy subjects. AB - [This corrects the article DOI: 10.1186/s12263-018-0600-z.]. PMID- 30002738 TI - Exploring the cellular network of metabolic flexibility in the adipose tissue. AB - Background: Metabolic flexibility is the ability of cells to change substrates for energy production based on the nutrient availability and energy requirement. It has been shown that metabolic flexibility is impaired in obesity and chronic diseases such as type 2 diabetes mellitus, cardiovascular diseases, and metabolic syndrome, although, whether it is a cause or an effect of these conditions remains to be elucidated. Main body: In this paper, we have reviewed the literature on metabolic flexibility and curated pathways and processes resulting in a network resource to investigate the interplay between these processes in the subcutaneous adipose tissue. The adipose tissue has been shown to be responsible, not only for energy storage but also for maintaining energy homeostasis through oxidation of glucose and fatty acids. We highlight the role of pyruvate dehydrogenase complex-pyruvate dehydrogenase kinase (PDC-PDK) interaction as a regulatory switch which is primarily responsible for changing substrates in energy metabolism from glucose to fatty acids and back. Baseline gene expression of the subcutaneous adipose tissue, along with a publicly available obesity data set, are visualised on the cellular network of metabolic flexibility to highlight the genes that are expressed and which are differentially affected in obesity. Conclusion: We have constructed an abstracted network covering glucose and fatty acid oxidation, as well as the PDC-PDK regulatory switch. In addition, we have shown how the network can be used for data visualisation and as a resource for follow-up studies. PMID- 30002739 TI - Metabolic transition of milk triacylglycerol synthesis in response to varying levels of palmitate in porcine mammary epithelial cells. AB - Background: Milk in mammals is a key source of lipids for offspring, providing both critical energy and essential fatty acids. For lactating sows, palmitic acid is one of the most abundant fatty acids in milk, providing 10~12% of the suckling pig total dietary energy supply. However, the effects of exogenous palmitic acid on milk fat synthesis in sow mammary glands are not well-known. In this study, we investigated the effects of palmitic acid on lipogenic genes in porcine mammary epithelial cells (pMECs) to explore the role of exogenous palmitic acid in mediating milk triacylglycerols (TAG) synthesis. Methods: Porcine mammary epithelial cells were cultured for 24 h in the presence of different concentrations of palmitate (0, 25, 50, 100, 200, 400, and 600 MUM). The effect of palmitate on cell viability was tested via MTT assay. Intracellular lipid accumulation was measured through Oil Red O staining, and TAG levels were quantified by enzymatic colorimetric methods. Expression of genes and proteins involved in milk fat biosynthesis were assayed with quantitative real-time polymerase chain reaction (qPCR) and Western blotting, respectively. Results: Incubation with palmitate promoted cellular lipid synthesis in a dose-dependent manner, as reflected by the increased TAG content and enhanced formation of cytosolic lipid droplets. The increased lipid synthesis by palmitate was probably attributable to the upregulated mRNA expression of genes associated with milk fat biosynthesis, including long-chain fatty acid uptake (LPL, CD36), intracellular activation and transport (ACSL3, FABP3), TAG synthesis (GPAM, AGPAT6, DGAT1), lipid droplet formation (PLIN2), and regulation of transcription (PPARgamma). Western blot analysis of CD36 and DGAT1 proteins confirmed the increased lipid synthesis with increasing incubation of palmitate. However, the genes involved in fatty acid de novo synthesis (ACACA, FASN), fatty acid desaturation (SCD), and regulation of transcription (SREBP1, INSIG1) were inversely affected by incubation with increasing concentrations of palmitate. Western blot analysis of ACACA protein confirmed this decrease associated with increasing levels of palmitate. Conclusions: Results from this study suggest that palmitate stimulated the cytosolic TAG accumulation in pMECs, probably by promoting lipogenic genes and proteins that are involved in lipid synthesis. However, addition of palmitate decreased the fatty acid de novo synthesis in pMECs. PMID- 30002742 TI - Predicting and Understanding Cancer Response to Treatment. PMID- 30002740 TI - Identification and validation of SRY-box containing gene family member SOX30 methylation as a prognostic and predictive biomarker in myeloid malignancies. AB - Background: Methylation-associated SOX family genes have been proved to be involved in multiple essential processes during carcinogenesis and act as potential biomarkers for cancer diagnosis, staging, prediction of prognosis, and monitoring of response to therapy. Herein, we revealed SOX30 methylation and its clinical implication in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Results: In the discovery stage, we identified that SOX30 methylation, a frequent event in AML, was negatively associated with SOX30 expression and correlated with overall survival (OS) and leukemia-free survival (LFS) in cytogenetically normal AML among SOX family members from The Cancer Genome Atlas (TCGA) datasets. In the validation stage, we verified that SOX30 methylation level was significantly higher in AML even in MDS-derived AML compared to controls, whereas SOX30 hypermethylation was not a frequent event in MDS. SOX30 methylation was inversely correlated with SOX30 expression in AML patients. Survival analysis showed that SOX30 hypermethylation was negatively associated with complete remission (CR), OS, and LFS in AML, where it only affected LFS in MDS. Notably, among MDS/AML paired patients, SOX30 methylation level was significantly increased in AML stage than in MDS stage. In addition, SOX30 methylation was found to be significantly decreased in AML achieved CR when compared to diagnosis time and markedly increased in relapsed AML when compared to the CR population. Conclusions: Our findings revealed that SOX30 methylation was associated with disease progression in MDS and acted as an independent prognostic and predictive biomarker in AML. PMID- 30002741 TI - Incidence and Comorbidity of Dementia with Lewy Bodies: A Population-Based Cohort Study. AB - Background and Aims: Dementia with Lewy bodies (DLB) is the third most common form of dementia. Epidemiological studies of DLB in Taiwan are scarce. In this study, we estimated the incidence of DLB and comorbidity in the population of Taiwan. Methods: Data were obtained from the Taiwan National Health Insurance Research Database (NHIRD). DLB patients between 2000 and 2013 were enrolled in assessments of incidence and comorbidity. Results: The incidence of DLB was shown to be 7.10 per 100,000 person-years (95% CI = 6.63-7.59), which increased with age. The average age at diagnosis was 76.3, and this was higher for males than for females. The comorbidity rates of hypertension and hyperlipidemia in DLB patients were higher in females than in males. Conclusions: Epidemiologic data from large-scale retrospective studies is crucial to the prevention of DLB. PMID- 30002735 TI - L1 retrotransposition in the soma: a field jumping ahead. AB - Retrotransposons are transposable elements (TEs) capable of "jumping" in germ, embryonic and tumor cells and, as is now clearly established, in the neuronal lineage. Mosaic TE insertions form part of a broader landscape of somatic genome variation and hold significant potential to generate phenotypic diversity, in the brain and elsewhere. At present, the LINE-1 (L1) retrotransposon family appears to be the most active autonomous TE in most mammals, based on experimental data obtained from disease-causing L1 mutations, engineered L1 reporter systems tested in cultured cells and transgenic rodents, and single-cell genomic analyses. However, the biological consequences of almost all somatic L1 insertions identified thus far remain unknown. In this review, we briefly summarize the current state-of-the-art in the field, including estimates of L1 retrotransposition rate in neurons. We bring forward the hypothesis that an extensive subset of retrotransposition-competent L1s may be de-repressed and mobile in the soma but largely inactive in the germline. We discuss recent reports of non-canonical L1-associated sequence variants in the brain and propose that the elevated L1 DNA content reported in several neurological disorders may predominantly comprise accumulated, unintegrated L1 nucleic acids, rather than somatic L1 insertions. Finally, we consider the main objectives and obstacles going forward in elucidating the biological impact of somatic retrotransposition. PMID- 30002743 TI - Enhanced expression of IL-34 in an inflammatory cyst of the submandibular gland: a case report. AB - Background: Cysts of the salivary glands are common lesions that occur in the context of various etiologies. Although the diagnostic importance of cysts in salivary gland diseases has been well studied, molecular mechanisms that control the related pathological process remain largely unknown. IL-34 is a novel cytokine that was discovered recently as a tissue-specific ligand of colony stimulating factor-1 receptor. Since its discovery, accumulating evidence has revealed emerging roles of IL-34 in various pathological conditions and has been suggested to correlate remarkably with inflammation. In this study, we report a medical case of an inflammatory cyst within the submandibular gland, through which evaluating the possible involvement of IL-34 in salivary gland disorders. Case presentation: A 37-year-old male patient suffered from a sudden swelling in the right submandibular region, started initially small and had gradually increased in size to reach 3-4 cm in 1 week, accompanied by pain and local fever. Ultrasonography and MRI imaging revealed the existence of a well-defined cystic lesion with sharp borders measuring 39.8 mm * 19.7 mm within the right submandibular gland. The cyst was removed surgically, and the diagnostic decision was determined based on histopathological observations as an inflammatory cyst in the submandibular gland. Sections were generated from different regions of the surgically resected inflammatory cyst and used to examine IL-34 expression by immunohistochemistry compared to normal salivary gland tissues. Immunohistochemical staining showed enhanced expression of IL-34 in the ductal epithelial cells and endothelial cells of blood vessels, with a tendency to be accompanied with high infiltration of immune cells, which suggests a possible involvement of IL-34 in the pathogenesis of salivary gland inflammation. Conclusions: In this report, we introduce interesting findings of enhanced IL-34 expression in a case of an inflamed submandibular gland. Our findings emphasize the pathological roles of IL-34 as an inflammation amplifier and angiogenic enhancer in inflammatory conditions, such as in salivary gland disorders. PMID- 30002744 TI - Is the laparoscopic approach for rectal cancer superior to open surgery? A systematic review and meta-analysis on short-term surgical outcomes. AB - Introduction: Over the past years the incidence of colorectal cancers has increased worldwide. Currently it is the most common gastrointestinal malignancy worldwide. The laparoscopic approach has become the gold standard for surgical treatment. However, a recently published meta-analysis showed no difference in short- and long-term oncological outcomes of laparoscopy for treating rectal cancer. Aim: To assess current literature on short-term outcomes of rectal cancer treatment using laparoscopic surgery in comparison to the open approach. Material and methods: We performed a systematic review and meta-analysis according to the PRISMA guidelines. The primary outcomes of interest were morbidity and short-term complications. Results: We identified 4,328 potential references. In the end we included 13 randomized controlled trials (RCTs). We did not find any significant differences in terms of morbidity, haemorrhage, ureter injury, anastomotic leakage, mortality, intra-abdominal abscess or postoperative ileus. We found significant differences in the rate of surgical site infections, operative time, blood loss, length of hospital stay and time to first bowel movement. Conclusions: This systematic review based on available RCTs confirms that laparoscopic rectal cancer surgery is associated with short-term outcomes comparable to the open approach. Moreover, in some aspects it provides better results (e.g. functional postoperative recovery, lower rate of surgical site infections (SSIs)). The quality of evidence is high; therefore in our opinion it is very unlikely that future trials will alter these results, and for this reason the laparoscopic approach can be considered the gold standard for the treatment of the majority of patients. PMID- 30002745 TI - Risk factors for prolonged hospitalization in patients undergoing laparoscopic adrenalectomy. AB - Introduction: Even though laparoscopic adrenalectomy is currently a standard, there are important variations between different centres in short-term treatment results such as length of hospital stay (LOS) or morbidity. Aim: To determine the factors affecting LOS in patients after laparoscopic transperitoneal lateral adrenalectomy (LTA). Material and methods: The study enrolled 453 patients (173 men and 280 women, mean age 57 years) who underwent LTA between 2009 and 2017. Discharge from hospital after more than median hospital stay was considered as prolonged LOS. We evaluated factors that potentially may influence LOS (primary length of stay after surgery, excluding readmissions). Logistic regression models were used in univariate and corrected multivariate analyses, in order to identify the factors related to prolonged LOS. Results: The median LOS after LTA in the studied group was 2 days. One hundred seventy-five (38.5%) patients required prolonged hospitalization. Univariate logistic regression showed that the following factors were related to prolonged LOS: presence of any comorbidity, cardiovascular disease, intraoperative complications, postoperative complications, day of the week of operation (surgery on Thursday or Friday), intraoperative blood loss, need for transfusion, hormonal activity, postoperative drainage, ASA (III-IV) and histological type - pheochromocytoma. Multivariate logistic regression showed that only complications (OR = 3.86; 95% CI: 1.84 8.04), day of the week of operation (Thursday or Friday) (OR = 4.85; 95% CI: 3.04 7.73), need for drainage (OR = 3.63; 95% CI: 1.55-8.52), and histological type - pheochromocytoma (OR = 2.48; 95% CI: 1.35-4.54) prolonged LOS. Conclusions: Prolonged length of hospital stay following laparoscopic transperitoneal lateral adrenalectomy is strongly associated with the presence of postoperative complications, day of the week of operation (Thursday or Friday), need for drainage, and histological type - pheochromocytoma. PMID- 30002746 TI - Spinal/epidural block as an alternative to general anesthesia for laparoscopic appendectomy: a prospective randomized clinical study. AB - Introduction: Laparoscopic appendectomy (LA) has been generally performed under general anesthesia. Laparoscopic appendectomy is rarely performed under regional anesthesia because of pneumoperitoneum-related problems. Aim: To compare spinal/epidural anesthesia (SEA) and general anesthesia (GA) during LA with respect to perioperative and postoperative adverse events and postoperative pain. Material and methods: Fifty patients, aged 18-65, who underwent LA, were randomly allocated to two groups: the GA (n = 25) and SEA (n = 25) groups. Perioperative and postoperative adverse events, postoperative pain level, and patient satisfaction were compared between the groups. Results: None of the patients needed conversion to an open procedure or conversion from SEA to GA. In the SEA group we encountered shoulder pain in 6 (24%) patients, abdominal discomfort/pain in 4 (16%) patients, anxiety in 4 (16%) patients, and hypotension in 2 (8%) patients intraoperatively. Also, post-spinal headache was observed in 5 (20%) patients in the SEA group. Postoperative right shoulder pain was significantly higher in the GA group compared to the SEA group (32% vs. 8%; p = 0.037). In the SEA group the incidence of urinary retention and in the GA group the incidence of postoperative nausea and vomiting (PONV) were higher, but these differences were not statistically significant. The postoperative surgical pain level was significantly lower in the SEA group (p < 0.001). Conclusions: Spinal/epidural anesthesia is effective and safe in ASA I healthy patients undergoing LA. Less postoperative pain, PONV and shoulder pain are the advantages of SEA compared to GA. PMID- 30002747 TI - Laparoscopic splenectomy for immune thrombocytopenia in patients with a very low platelet count. AB - Introduction: Laparoscopic splenectomy (LS) is the gold standard in treating immune thrombocytopenia (ITP). However, there are still some problems in decision making when considering LS in patients with a very low platelet count (PLT). Aim: To evaluate safety outcomes of LS in patients with severe ITP and very low PLT in comparison to those with higher PLT. Material and methods: We retrospectively analyzed consecutive patients who underwent LS in a single institution between April 1998 and December 2017. Perioperative care was based on an algorithm developed at our department which takes into consideration the patient's PLT level. Patients were divided into 2 groups depending on the PLT level (cut-off point 50,000/mm3). Results: The mean operative time in the low PLT group and high PLT group was 90 +/-42.1 min and 95 +/-45 min, respectively (p = 0.59). Intraoperative blood loss was 144 +/-226.1 ml in the low PLT group and 83 +/ 161.24 ml in the high PLT group (p = 0.23). Complications occurred in 5 (9.09%) patients in the low PLT group and 16 (11.51%) in the high PLT group (p = 0.67). There were no conversions in the group with lower PLT, while 2 patients in the group with higher PLT had to be converted to open surgery (p = 0.38). Patients with low PLT preoperatively more often required perioperative platelet transfusions (13 vs. 1, p < 0.001). Conclusions: Laparoscopic splenectomy is safe and feasible treatment in patients with ITP regardless of the PLT level. Still, patients with critical ITP and marginally low PLT require special awareness. PMID- 30002749 TI - Safety and efficacy of oesophageal stenting with simultaneous percutaneous endoscopic gastrostomy as a supplementary feeding route in unresectable proximal oesophageal cancer. AB - Introduction: Proximally located oesophageal cancer poses an especially difficult problem in terms of restoration of patency and the stenting procedure. Supplementary percutaneous endoscopic gastrostomy (PEG) may be useful in these patients. Aim: To assess the safety of the stenting procedure in the proximal oesophagus in patients with unresectable upper oesophageal cancer, performed simultaneously with PEG insertion. Material and methods: Patients with obstructing upper oesophageal tumours were scheduled for an oesophageal stenting procedure and simultaneous PEG insertion. Degree of dysphagia, body weight loss, daily energy requirement, body mass index and performance status before and after the stenting procedure as well as complications were assessed. Results: Forty five patients aged 19-88 years were included in the study. Six of them had a fistula to the trachea and underwent stenting of the oesophagus or both the oesophagus and the airway. The technical success rate was 100%. Following the procedure all patients were able to swallow fluids and semi-liquids, and PEG was used as the primary feeding route. Body mass index increased from 20.4 to 21.1 (p = 0.0001), body weight gain improved from -10.1 to +2.0 kg and metabolic requirements improved (p = 0.0001). Also, the Karnofsky score improved significantly (56.7 vs. 65.1, p = 0.0001). Mean survival time was 133 days (range: 36-378). Conclusions: Stenting of the proximal oesophagus with simultaneous PEG is a safe procedure, allowing the patients to resume oral intake of liquids whilst improving nutritional status and general performance, with an acceptable rate of complications. PMID- 30002748 TI - Indications and benefits of intraoperative esophagogastroduodenoscopy. AB - Introduction: Intraoperative esophagogastroduodenoscopy (IOG) is a diagnostic and therapeutic method for a variety of special conditions in upper gastrointestinal (UGI) pathology. The indication remains individual due to insufficient evidence and limited training of surgeons in digestive endoscopy. Aim: To evaluate the indications, benefits and risks of IOG. Material and methods: A single-center retrospective study of 110 consecutive IOGs in 104 patients was performed. The preoperative plan, the timing of IOG, preoperative evaluation, intraoperative finding, localization of the pathology, type of the procedure, change of expected therapy and complications were assessed. Results: The cohort comprised 29 esophageal tumors, 5 tumors of the cardia, 36 gastric tumors, gastrointestinal bleeding (8), esophageal diverticula (3), perforations (3), GERD (5), mediastinal pathology (3), fistula (4), assessment of nutrition (10), duodenal adenoma (2), ulcer disease, esophageal stenosis and gastric volvulus. The indication for IOG was established preoperatively in 79% and intraoperatively in 21%. The lesion was localized in 96.4%. The therapy was altered to a wider resection (11), smaller resection (5), localization and surgical therapy of bleeding (8) or allowed minimally invasive surgery (25). A total of 3 postoperative complications included gastric perforation and positivity of resection line (following EMR/ESD) and recurrent bleeding. The 30-day mortality reached 3.6% without a specific cause in IOG. Conclusions: The IOG is a complementary method in the diagnosis and treatment of UGI pathology. It enables minimally invasive finalization of the procedures and individualization of the therapy. PMID- 30002750 TI - Clinical predictors of malignancy in patients diagnosed with atypical ductal hyperplasia on vacuum-assisted core needle biopsy. AB - Introduction: Atypical ductal hyperplasia (ADH) is a benign lesion, which due to the risk of coexisting cancer is classified as a lesion of uncertain malignant potential. Aim: To identify clinical predictors of cancer underestimation in patients with ADH diagnosed after vacuum-assisted breast biopsy (VABB). Material and methods: Between 2001 and 2016, a total of 3804 vacuum-assisted core needle biopsies were performed at the First Chair of General Surgery of the Jagiellonian University Medical College in Krakow, including 2907 ultrasound (US)-guided biopsies and 897 digital stereotactic procedures. Seventy-six women were diagnosed with ADH and 72 of them underwent subsequent surgical excision. Demographic factors, medical history, family history, clinical symptoms, type and size of lesion determined in imaging scans, size of biopsy needle, and presence of coexisting lesions in VABB specimens were analysed as potential predictors of malignancy underestimation. Results: Underestimation of breast carcinoma occurred in 21 (29.2%) patients. The upgrade rate was significantly higher only in patients with a lesion visible both in mammography (MMG) and US examinations and combined BIRADS-5. Conclusions: Vacuum-assisted core needle biopsy is a minimally invasive technique used in diagnosing ADH. As the risk of breast malignancy underestimation is relatively high, open surgical biopsy remains the recommended procedure, especially in patients with lesions detected both in mammography and US examination. As we could not identify the factors that preclude cancer underestimation, all the women diagnosed with ADH should be informed about the risk of cancer underestimation. PMID- 30002751 TI - Impact of anxiety on sedative medication dosage in patients undergoing esophagogastroduodenoscopy. AB - Introduction: Esophagogastroduodenoscopy (EGD) is a diagnostic method used in the investigation of upper gastrointestinal system diseases. A high level of anxiety of patients who undergo EGD increases the duration of the procedure and the sedation and analgesic requirements. Sedation is used to increase patient comfort and tolerance by reducing the anxiety and pain associated with endoscopic procedures. Aim: In this study, the effect of anxiety scores on medication doses was investigated in patients who underwent EGD under sedation. Material and methods: A psychiatrist, an endoscopist and an anesthesiologist conducted a prospective observational study blindly to investigate the effect of pre procedural (before EGD) anxiety level on medication doses for sedation. Patients were divided into two groups, with and without additional medication doses. Results: The study included 210 consecutive patients who underwent EGD under sedation. The average STAI-S score was 40.28 and the average STAI-T score was 40.18. There was no relationship between anxiety scores and gender (p = 0.058, p = 0.869). Statistically significant results were obtained for anxiety scores with additional sedation dosing (p < 0.05). It was observed that an additional dose of medication was affected by age, body mass index and anxiety scores (p < 0.005). Patients who were young, had a low body mass index and had high anxiety scores had significantly higher additional dose requirements. Conclusions: The medications used for sedation during EGD may be inadequate or an additional dose of medication may be needed for patients who have higher anxiety scores, younger age, and lower body mass index. PMID- 30002752 TI - Study of the prevalence of gastroesophageal reflux symptoms and the role of each in relation to the GERD Impact Scale, based on a population of patients admitted for laparoscopic surgery compared to a control group. AB - Introduction: Gastroesophageal reflux disease (GERD), demonstrated to impair quality of life (QoL), appears to show significant variation in its prevalence. Estimation of the prevalence is difficult. When defined as at least weekly heartburn and/or acid regurgitation, the prevalence reported in Asia is 2.5 27.6%, in Europe 23.7% and in the US 28.8%. Aim: The study evaluates the prevalence of GERD symptoms in the assessment of the GERD Impact Scale (GERD-IS) in two age groups of patients. Material and methods: Evaluation of the prevalence of GERD symptoms with the GERD Impact Scale survey in two groups of patients: younger and older. A total of 2,649 surveys were rated. Statistical analysis was performed using the data analysis software system Statistica version 10.0 and Microsoft Excel. Results: According to this study the symptoms of GERD included in GERD-IS in northern Poland vary from 0.9-2.4% as daily sensations to 18.9 40.5% occurring sometimes. Individuals with hiatal hernia (HH) were significantly older than those without HH. HH was significantly more frequent in males than females. Conclusions: Estimation of the prevalence of GERD is difficult, because the medications are widely available and people use them without any consultation. They do not recognize the symptoms as a disease whose treatment can also be surgical. Our analysis shows that the prevalence of symptoms of GERD in northern Poland is as high as 5%. Hence further investigation should be performed and people's awareness should be raised. PMID- 30002753 TI - Radiofrequency ablation of small renal masses in comorbid patients. AB - Introduction: Over the recent years, the progress in imaging techniques has led to increased detection of small renal masses (SRMs), including in elderly and high-risk patients. Partial nephrectomy (nephron-sparing surgery - NSS), the current standard of care in T1a kidney tumours, has some limitations in patients who are poor candidates for surgery, as it is associated with potential perioperative complications and possible renal function loss. Radiofrequency ablation (RFA), a minimally invasive method that can be performed percutaneously, is an option in such cases. Aim: To present our experience in treatment of SRMs using RFA in comorbid patients. Material and methods: In the years 2006-2012, 103 percutaneous, ultrasound-guided RFA procedures were performed in the Oncology Centre in Bydgoszcz in patients with an ASA score >= 3. Abdominal computed tomography and tumour biopsy were performed before the procedure. The average follow-up time was 46 months. Results: The 1, 3 and 5-year overall survival rates were respectively 97%, 90% and 75%, while cancer-specific survival was 100%. No Clavien-Dindo grade >= 3 complications were observed. Conclusions: Radiofrequency ablation performed percutaneously is a minimally invasive treatment and may be applied in patients who are, due to comorbidities, poor candidates for surgery. In comorbid patients, where other causes of death play an important role, the application of a minimally invasive treatment method with satisfactory oncological effectiveness is justified. PMID- 30002754 TI - Uniportal versus multiport video-assisted thoracoscopic surgery for anatomical lung resections: a glance at a dilemma. AB - Introduction: As the number of operations performed by videothoracoscopy is increasing, there is also a tendency to decrease the number of port incisions. Apart from the reduced number of surgical incisions, there are a few reports and systematic reviews that demonstrate some potential advantages of the uniportal video-assisted thoracoscopic surgery, but the impact of the reduced incisions in the clinical setting still remains uncertain. Aim: To compare uniportal video assisted thoracoscopic surgery to multiport video-assisted thoracoscopic surgery for anatomical lung resections in patients with malignant and benign lung diseases. Material and methods: From August 2010 to April 2016, a total of 102 patients with malignant and benign lung diseases underwent videothoracoscopic lobar and sublobar lung resections in our department. Comorbidities, tumor stage, tumor localization, mortality, operative time, pain visual analogue scale, length of hospital stay, perioperative blood loss, duration and amount of postoperative drainage and air leak, number of harvested lymph nodes and complication rates were analyzed. Results: No significant difference was found in the duration of chest tube drainage, pain visual analogue scale score, length of hospital stay, perioperative blood loss, amount of postoperative drainage, number of harvested lymph nodes or complication rate. There was no surgical mortality in either of the two groups. However, operative time was shorter (189 min vs. 256 min, p < 0.005) in the multiport group than in the uniportal group. Conclusions: Compared with the uniportal approach, the multiport approach is associated with a significantly shorter operative time in our study. PMID- 30002755 TI - Study on the effect of nano-hydroxyapatite on bone repair of athletes. AB - Introduction: Minimally invasive surgery is a widely used method for bone repair. Nano-hydroxyapatite (n-HA) is a non-toxic and harmless bone repair material. Aim: To study the repair effect of n-HA/PA66 on the lumbar vertebrae injury of basketball players. Material and methods: Firstly, the n-HA/PA66 material was prepared and its properties were studied. Then, the n-HA/PA66 material was used in a rabbit vertebral replacement experiment to study its bone coverage, fiber coverage and bone density. Afterwards, the material was used in vertebral injury treatment of basketball players to study its bone repairing effect. Results: It was found that the fiber coverage of artificial vertebral bodies of n-HA/PA66 material tended to decrease with the increase of replacement time but no significant difference was found in the fiber coverage at different times (p > 0.05); the longer the replacement time, the greater the bone coverage, with statistically significant differences (p < 0.05); as the replacement time increased, the density and osteogenic volume increased; the Japanese Orthopaedic Association (JOA) scoring both 3 months and 6 months after surgery was greater than that immediately after surgery, with a significant difference (p < 0.05); the difference of angle of Cobb showed a decreasing trend with the increase of replacement time, and there was a significant difference (p < 0.05); follow-up results showed that the subjects had no rejection reaction. Conclusions: N-HA material played an important role in basketball players' bone repair treatment and is worth being promoted for application. PMID- 30002756 TI - Balloon-expandable stent angioplasty in the treatment of vertebral artery stenosis in the V2 segment. AB - Introduction: Vertebral artery stenosis is a major cause of posterior circulation ischemia in the elderly. There is not a clear consensus on the optimal therapeutic approach for symptomatic extracranial vertebral artery stenosis. Aim: To evaluate the feasibility and efficacy of balloon-expandable stent angioplasty in the treatment of vertebral artery stenosis in the V2 segment. Material and methods: Five patients with vertebral artery stenosis (V2 segment) and treatment of percutaneous transluminal stenting from July 2009 to June 2014 were retrospectively evaluated. All patients underwent color Doppler, transcranial color Doppler (TCD), CT angiography (CTA) and cerebral digital subtraction angiography (DSA) preoperatively. Whether there was osseous oppression was determined according to neck computed tomography (CT) and CTA. After the surgery, angiography was performed to determine if there was infarction or bleeding in the intracranial vertebral artery, basilar artery and posterior cerebral artery. The surgical parameters, residual stenosis, complications, etc. were recorded and evaluated. The patients were followed up accordingly. Results: Five patients (3 males, 2 females; average age of 66 +/-4.2, range of 54-75) were enrolled in the study. Balloon-expandable stents were successfully implanted in the 5 patients. The mean residual stenosis after the balloon-expandable stenting (preoperative: average, 87.0 +/-6.6%, range: 75-93%) was 12.6 +/-7.8% (range: 5-25%). The clinical symptoms disappeared or receded. No serious complications occurred. Conclusions: The balloon-expandable stent angioplasty seemed to be feasible and efficacious in treating vertebral artery stenosis in the V2 segment. Further study with a large sample size is needed. PMID- 30002757 TI - Treatment of high- and intermediate-risk pulmonary embolism using the AngioJet percutaneous mechanical thrombectomy system in patients with contraindications for thrombolytic treatment - a pilot study. AB - Introduction: Intravenous thrombolysis is the treatment of choice in patients presenting with high- and intermediate-risk pulmonary embolism. The role of percutaneous mechanical pulmonary thrombectomy (PMPT) is not fully established, although selected patients can be managed with this method. Aim: This open-label single-centre prospective pilot study was aimed at assessing the feasibility of PMPT for the treatment of severe pulmonary embolism in a Polish hospital. We also evaluated the safety and efficacy of such management. Material and methods: We managed 7 patients, aged 52.7 +/-16.6 years, presenting with high- and intermediate-risk pulmonary embolism (4 patients with class 5 and one patient with class 4 of the Pulmonary Embolism Severity Index), with occlusion of at least 2 lobar arteries and contraindications for thrombolysis. Percutaneous mechanical pulmonary thrombectomy was performed using the AngioJet system. Results: It was possible to introduce the thrombectomy system to the pulmonary arteries in all patients. The procedure was successful in 6 patients (technical success rate: 85.7%). Two (28.6%) patients died during the hospital stay, one patient with unsuccessful thrombectomy and the other due to pneumonia. In all survivors control echocardiography demonstrated normalised function of the right ventricle. Also, dyspnoea disappeared and blood gas parameters normalised. There was no recurrent thromboembolism during 3-14 months of follow-up. Conclusions: In the Polish setting, in selected patients, management of high- and intermediate risk pulmonary embolism with PMPT is technically feasible. Such treatment is relatively safe and effective. It can be an alternative to standard management, especially in patients with contraindications for fibrinolysis or surgical embolectomy. PMID- 30002758 TI - Short-term outcomes of endovascular repair of abdominal aortic aneurysm, including ruptured cases. AB - Introduction: Endovascular aneurysm repair as a minimally invasive alternative has become a commonly used surgical method for treating patients with abdominal aortic aneurysm (AAA). Aim: To analyze short-term outcomes of endovascular treatment of AAA patients, including ruptured cases. Material and methods: From 2010 to 2015, 247 patients with AAA were treated using the endovascular aneurysm repair technique. A short-term analysis was conducted - up to 30 days after surgery. It included 236 patients with planned surgery and 11 operated on in emergency mode, due to ruptured AAA. Results: Rates of short-term mortality and re-interventions among patients undergoing planned surgery were 2.5% and 4.2%, respectively. Surgical complications occurred in 18 (7.6%) patients, with the most common being thrombosis and blockage of the stent graft (2.5%). Systemic complications were found in 19 (8%) planned cases, with the most common being arrhythmias (1.7%). In patients with ruptured AAA, short-term mortality was 36.4%, while re-interventions were performed in 3 (27.3%) patients. Rates of surgical and systemic complications for ruptured AAA were 45.4% and 72.7%, respectively. Conclusions: The AAA patients undergoing endovascular aneurysm repair showed relatively low short-term mortality. However, larger groups of patients with ruptured AAA are required in order to assess the outcomes in this sub-population. PMID- 30002759 TI - Analysis of the management and risk factors for complications of esophageal foreign body impaction of jujube pits in adults. AB - Introduction: Foreign body impaction is a common emergency in the field of otolaryngology. The prevalence of a jujube pit as an esophageal foreign body has increased in the Jiaodong Peninsula. However, reports on this are scarce. Aim: To investigate the methods for diagnosing and treating esophageal foreign body impaction of a jujube pit and to determine the risk factors for complications. Material and methods: We conducted a retrospective review of the medical records of patients who were diagnosed with esophageal impaction of a jujube pit. Demographic, clinical, radiological, and endoscopic data were collected and analyzed. Results: Neither plain radiography nor esophagogram provided enough information on the surrounding issues and complications. The rate of secondary radiological examination was 51.61% for the patients who did not undergo prior computed tomography. The success rate of rigid esophagoscopy was 95.45%; 18 of these patients (27.27%) had previously undergone flexible esophagoscopy without foreign body removal. Logistic regression showed that the time from ingestion to presentation and the jujube pit size were independent risk factors for complications. Conclusions: Computed tomography without contrast material is the preferred diagnostic method for adults with esophageal jujube pit impaction, and rigid esophagoscopy can be used for therapy even though the first flexible esophagoscopy failed. Large diameter of the jujube pit constituting the esophageal foreign body (>= 25 mm) and long duration between pit ingestion and presentation (> 12 h) were associated with increased complications in the patients in this study. PMID- 30002760 TI - Intrahepatic cholangiocarcinoma in an obese patient qualified for laparoscopic bariatric surgery - a case study. AB - Intrahepatic cholangiocarcinoma is a rare type of biliary tract malignancy, seldom found resectable at diagnosis, the 5-year survival rate depending on the possibility of complete surgical excision. In most cases it is only accidentally found in the early stage. The report presents a case of a 58-year-old obese male patient qualified for laparoscopic Roux-en-Y gastric bypass. During general inspection of the abdominal cavity, a tumor of 10 mm in diameter was found in the second hepatic segment and resected. Final pathology results showed low-grade intrahepatic cholangiocarcinoma without vascular invasion, with positive margins of incision (R1), classified as stage I. The abdominal computed tomography scan showed no evidence of metastatic disease. Two months later the patient underwent a laparoscopic partial hepatectomy. Pathological investigation showed focal bile duct hamartoma with no signs of malignancy. No adjuvant therapy was administered and no recurrence has been found to date. PMID- 30002761 TI - Laparoscopic management of abdominal pseudocyst following ventriculoperitoneal shunt implantation in hydrocephalus. AB - Abdominal pseudocyst (AP) is quite a rare complication after ventriculoperitoneal shunting (VPS) for the treatment of hydrocephalus. Laparoscopy is an alternative method to open surgery with well-known advantages. There are not many reports of using laparoscopy to treat this condition and existing algorithms are based on small groups of patients; thus every case would give an additional insight into the treatment of this complication. A 37-year-old male patient with a history of VPS presented with headache, nausea and upper abdominal pain. Computed tomography of the abdominal cavity revealed a cyst in the left upper quadrant. After the ultrasound-guided percutaneous drainage the patient was qualified for laparoscopy. The cyst was removed laparoscopically under guidance of laparoscopic ultrasound. The patient recovered uneventfully with very good general and cosmetic results. In the follow-up period of 3 months we have not observed any abdominal or general health problems. PMID- 30002762 TI - Transumbilical single-incision laparoscopic-assisted technique for removal of ileocecal foreign body. AB - The aim of this paper is to present the case of a 40-year-old man who accidentally ingested a piece of metal. The patient complained of having intermittent right lower quadrant abdominal pain for 2 days. An abdominal X-ray was performed, and a piece of metal was found in the right lower quadrant of the abdomen. There was no gas in the abdominal cavity. Surgical treatment was therefore needed. Single-incision laparoscopic surgery (SILS) was attempted with conventional laparoscopic instruments. The foreign body was identified around the ileocecal region, an enterostomy was made and the foreign body was successfully removed. Subsequently, the incised ileocecal was wall sutured. The time for this surgery was 1 h with little bleeding. The patient made a quick recovery with a good cosmetic outcome. Based on this case, the use of SILS-assisted technique in the removal of an ileocecal foreign body proves to be safe and feasible. PMID- 30002763 TI - Thoracoscopic approach in the treatment of ectopic thymic parathyroid adenoma. AB - Primary hyperparathyroidism is overproduction of parathyroid hormone, causing hypercalcemia. Parathyroid adenomas have been found to be the etiology for 80% of cases of primary hyperparathyroidism, while almost a quarter of them are ectopic. We present a case of ectopic thymic parathyroid adenoma, treated by the thoracoscopic approach. Preoperative computed tomogram and technetium-99 sestamibi imaging showed an adenoma, located in the front mid-mediastinum, approximately 8 * 10 mm in size. Resection of the tumor was indicated according to the persistent hypercalcemia after unsuccessful surgical treatment performed 3 years ago. It was decided to perform a parathyroidectomy during thoracoscopy. The diagnosis of parathyroid adenoma was established on postoperative histopathology staining. The patient was discharged from hospital 5 days after the surgery. We found this minimally invasive operation to be an effective and well-tolerated treatment option, determined by the experience of the surgeon. PMID- 30002764 TI - Mechanical intestinal obstruction caused by displacement of a stomach balloon - case report. AB - Methods of treating obesity in selected cases include endoscopically performed procedures, among them endoscopically placed intragastric balloons. It is a method associated with a low complication rate, traditionally reserved to treat the most obese patients. Balloon rupture or deflation and its migration into the small bowel is one of the possible complications. In some cases, the balloon moves through the digestive tract without side effects. When the balloon's displacement in the intestine is impossible, gastrointestinal obstruction occurs. We report a case of a patient with a mechanical obstruction of the gastrointestinal tract caused by asymptomatic balloon rupture and its migration into the jejunum. PMID- 30002765 TI - The influence of antibiotics and dietary components on gut microbiota. AB - The gut microbiota acts as a real organ. It exerts important metabolic functions, and regulates the inflammatory response by stimulating the immune system. Gut microbial imbalance (dysbiosis) has been linked to important human diseases and inflammation-related disorders. The symbiotic interactions between resident microorganisms and the gastrointestinal tract significantly contribute to maintaining gut homeostasis. The present review summarizes our knowledge regarding the impact of different antibiotics causing such long-term consequences as decreased microbial diversity, modulation of the Bacteroidetes/Firmicutes ratio, Clostridium difficile overgrowth, and increased expansion of the opportunistic pathogens Salmonella typhimurium, Escherichia spp., and Klebsiella spp. Also, food additives, such as emulsifiers and artificial sweeteners, which are meant to reduce the risk of obesity and diabetes, may actually increase the risk of diseases due to microbial alterations. On the other hand, dietary components such as polyphenols, omega-3 acids or curcumin may positively affect gut microbiota composition. PMID- 30002766 TI - Effectiveness of Helicobacter pylori eradication established on the basis of examination of antibiotic resistance of the bacteria. AB - Introduction: The treatment of Helicobacter pylori (HP) tends to be empirical despite a high number of failures (over 20%). The efficacy of eradication therapies is declining, reaching in some countries 60%, which correlates inversely with the growing drug resistance of the bacteria. Aim: Given the frequent inefficacy of the hitherto proposed treatment schemes for HP infection, an attempt was made to assess the efficacy of a therapy based on the antibiotic resistance of the cultured bacteria, and to analyse factors with possible contribution to the inefficacy of HP eradication treatment. Material and methods: The study covered patients from one region of Central Poland in the years 2005 2015. The total material for bacteriological assessment was collected from 154 patients who had previously been subject to HP eradication treatment at least two times, including 80 women and 74 men, reporting subsequently to the Clinic. Results: The efficacy of the antibiogram-based treatment was merely 65.62%. A low, but slightly higher than expected, resistance to amoxicillin (3.48%) and tetracycline (2.27%), as well as to clarithromycin (27.27%) and metronidazole (70.69%), was established. Conclusions: In Polish patients resistance to clarithromycin and metronidazole of HP is high and becoming increasingly resistant; however, we found low bacterial resistance to tetracycline. PMID- 30002767 TI - Applying protective rectal tube in intestinal anastomosis. AB - Introduction: Colorectal resection is used for various diseases, including neoplasms (benign and malignant) and inflammatory bowel disorders. Leakage is one of the complications that increase mortality and morbidity in patients. The beneficial effects of a rectal tube in reducing anastomosis leak are controversial. Ileostomy as diverting stool may reduce risk of anastomosis leak. Aim: To evaluate the results of rectal tube application to reduce leakage in low pelvic anastomosis. Material and methods: In a prospective cohort study, 53 patients who were candidates for low anterior resection, extended low anterior resection, and ileal pouch-anal anastomosis, were enrolled in this study. After anastomosis, a large bore Foley was inserted transanally and put in the proximal of the anastomotic site, after fixation; we left it at least for 5 days then removed it if there was any sign of leakage. Results: In this research, 53 patients were studied; 30 (56.6%) were male and 23 (43%) were female. Among 32 (60%) patients who underwent total proctocolectomy and ileal pouch anal anastomosis, 24 (45%) had ulcerative colitis and 8 (15%) had familial adenomatous polyposis disorder. Among 21 (40%) patients who had rectal cancer, 8 (15%) cases had low anterior resection (LAR) and 13 (25%) underwent extended LAR. Seventeen (32%) patients used ileostomy and 36 (67.9%) patients used a rectal tube. Anastomotic leak occurred in 6 (11%) patients; all of them had ileostomy. No leakage or complication appeared in rectal tube cases. The difference was statistically significant (p < 0.001). Conclusions: The results of our study suggest that using a rectal tube instead of protective ileostomy may reduce anastomosis leak in the lower pelvis by reducing intraluminal pressure to effect and lower tension at the anastomosis site in low pelvic intestinal anastomosis. PMID- 30002768 TI - Quality of life and depression in patients with irritable bowel syndrome. AB - Introduction: While irritable bowel syndrome (IBS) is not life-threatening for most, it has enormous influence on quality of life (QOL) and mental health. Aim: To evaluate the association between QOL and depressive symptoms in IBS patients. Material and methods: A total of 87 patients and 56 healthy subjects were enrolled consecutively. All participants were asked to complete self-administered questionnaires: an IBS-specific quality of life (IBS-QOL) questionnaire and the Beck Depression Inventory questionnaire (BDI). Results: Mean BDI score was higher in IBS group than in controls. IBS-QOL score was significantly lower in IBS patients compared to the control group, in all IBS-QOL domains: dysphoria (DY), interference with activity (IN), body image (BI), health worry (HW), food avoidance (FA), social relation (SR), and sexual (SX) and relationship (RL) issues. QOL DY, IN, and BI scores and overall score were significantly lower in women with IBS compared to men. We found that BDI score was significantly negatively correlated with IBS-QOL score in the domain of DY, IN, HW, FA, SR, and RL scores and overall QOL score. We also found a negative correlation between older age and health worry. RL and IN QOL scores represented the highest correlation with BDI score. Conclusions: Irritable bowel syndrome is connected with impaired patient quality of life and high prevalence of depression with high correlation rate of both parameter scores. Assessment of depression and QOL should be provided during patient visits in outpatients clinics. PMID- 30002770 TI - Expression of chosen cell cycle and proliferation markers in pancreatic intraepithelial neoplasia. AB - Introduction: Pancreatic ductal adenocarcinoma is one of the most aggressive tumours that develops from precursor lesions, most frequently including pancreatic intraepithelial neoplasia (PanIN). Deregulation of the cell cycle, responsible for uncontrolled cell proliferation, is an important phenomenon in the development of this cancer. Aim: To evaluate the cell cycle and the expression of proliferation markers, namely Ki67, PCNA, and cyclin D1 in pancreatic intraepithelial neoplasia at its different stages of progression. Material and methods: The study group consisted of 70 patients with different pancreatic diseases (pancreatic ductal adenocarcinoma, pancreatitis, and pancreatic cysts), who also had pancreatic intraepithelial neoplasia. Expression of Ki67, PCNA, and Cyclin D1 was analysed immunohistochemically using appropriate antibodies. Results: Statistically significant differences were demonstrated in Ki67, PCNA, and Cyclin D1 expression between normal pancreatic ducts and various stages of PanIN (p < 0.001). Expression of these proteins increased from normal pancreas to PanIN 1, 2, and 3. Expression of these proteins was higher in stages PanIN 1, 2, and 3 compared to normal pancreas. The expression of Ki67, PCNA, and cyclin D1 was associated with age (p < 0.001), Ki67 and PCNA with sex (p < 0.001), and PCNA with the type of primary disease (p = 0.031). Simultaneously, a directly proportional relationship was established between the expression of all proteins examined (p < 0.001). Conclusions: An increase in the expression of Ki67, PCNA, and cyclin D1 suggests that these proteins may enhance epithelial cell proliferation and may influence the development of pancreatic intraepithelial neoplasia. Moreover, immunohistochemical assessment of Ki67, PCNA, and cyclin D1 expression may be helpful in the differential diagnosis of PanIN. PMID- 30002769 TI - Assessment of risk factors affecting mortality in patients with colorectal cancer. AB - Introduction: The most important risk factors for colorectal cancer are age, high ASA score, anemia, low albumin, tumor stage, histopathological properties, tumor's relationship with adjacent tissues, positivity of surgical borders and timing of the surgical procedure. Aim: To determine possible risk factors for mortality in patients undergoing colorectal cancer surgery. Material and methods: The medical records of 101 consecutive patients who underwent colorectal cancer surgery at the Department of Surgery, Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey between January 2008 and November 2015 were retrospectively reviewed. The patients were divided into two groups: surviving (n = 76) and deceased (n = 25) groups. The groups were compared in terms of several demographic, clinical, biochemical, and histopathological parameters. In addition, risk factors for mortality were analyzed with multivariate analysis. SPSS 22.2, PAST 3, and MedCalc 14 software packages were used for statistical analyses. Results: The surviving and deceased groups significantly differed with respect to age (p = 0.001), hemoglobin (p = 0.001), lymph node positivity (p = 0.009), positive lymph node/total lymph node ratio (p = 0.012), thrombocyte count (p = 0.047), lymphovascular invasion (p = 0.028), urgency of admission (emergency/elective) (p = 0.036), and postoperative carcinoembryonic antigen (CEA) level (p = 0.002). A receiver operating characteristics curve was drawn to determine the cut-off values of various parameters including age (63), hemoglobin (12.8), node positivity (3), positive/total lymph node ratio (0.435) and thrombocyte count (308), with age (p < 0.001), hemoglobin (p < 0.001), node positivity (p = 0.025) and positive/total lymph node ratio (p = 0.024) being significantly different. A multivariate analysis revealed that age (p = 0.049), hemoglobin (p = 0.045), and positive/total lymph node ratio (p = 0.025) were independent risk factors for mortality. Conclusions: This study shows that older age, lower hemoglobin level, and high positive/total lymph node ratio were independent risk factors for mortality among colorectal cancer patients. PMID- 30002771 TI - Frequency of overweight/obesity among a group of children with celiac disease in Iran. AB - Introduction: A small number of overweight and obese children with celiac disease (CD) has been reported. Aim: To estimate the prevalence of obesity, underweight and normal weight in a group of Iranian pediatric patients. Material and methods: In a retrospective study from 2007 to 2015, 225 children less than 18 years old with biopsy-proven CD were enrolled. Data collected included demographic characteristics, clinical presentation, antibody titers and severity of small bowel mucosal damage. Body mass index (BMI) profile of subjects was calculated based on the age and gender percentile at presentation. Results: The mean +/- standard deviation (SD) for age was 7.4 +/-3.8 and 62% of patients were female. Fifty-four percent of patients presented with a normal BMI, 43% were underweight, and the remaining patients (3.5%) were overweight/obese. The mean age of underweight and normal weight patients was higher than that of obese/overweight patients. Mean +/- SD of TTG titer was higher in overweight/obese and normal weight children compared to underweight subjects. The majority of patients (195/225) had severe enteropathy compatible with Marsh III on duodenal biopsy. Most of the children had gastrointestinal (GI) and extra-intestinal manifestations on presentation. There was no association between severity of histological disease and BMI for age. Five out of eight cases in the obese/overweight group had an index case with CD in their family. Conclusions: This study highlights the importance of considering celiac disease in children regardless of their BMI. Failure to diagnose CD in children leads to unnecessary diagnostic delays and long-term adverse health consequences. PMID- 30002772 TI - Cystic fluid neutrophil gelatinase-associated lipocalin (NGAL) concentration in differential diagnosis of pancreatic cystic lesions: a new factor enters the scene? AB - Introduction: Neutrophil gelatinase-associated lipocalin - 25 kDa peptide - is at present one of the most fascinating and unrecognised proteins implicated in the process of tumour development. Precise assessment of pancreatic cystic lesions is crucial for selecting available treatment options, such as conservative therapy or surgical resection. Aim: To determine the utility of NGAL concentration in cyst fluid obtained by endoscopic ultrasound (EUS) with EUS-guided fine-needle aspiration (EUS-FNA) to distinguish neoplastic pancreatic cysts from pseudocysts. Material and methods: Twenty-two patients underwent EUS and FNA of a pancreatic cystic lesion; 9 of these patients underwent surgical resection, providing a histologic diagnosis of the cystic lesion. Furthermore, the final diagnosis was based on cyst fluid cytology, cyst fluid tumour markers (CEA, CA 72-4, CA 19-9), and medical history. Patients were divided in two groups: cystic neoplasms and inflammatory cysts (pseudocysts). Results: The final diagnosis was pseudocyst in 7 patients, serous cystadenoma in 4, mucinous cystadenoma in 3, intraductal papillary mucinous neoplasms in 6 patients, and cystic form of pancreatic adenocarcinoma in 2. Cyst fluid analysis of these patients showed that median cyst fluid NGAL for the cystic neoplasm group (211 ng/ml; n = 15) was significantly lower (p = 0.02) than the inflammatory cystic group (4689 ng/ml; n = 7). Correlation analysis showed that only fluid CA 72-4 was positively related to NGAL (r = 0.8, p < 0.01). Conclusions: In this single-centre study, pancreatic cyst fluid NGAL concentration appeared to be useful in distinguishing neoplastic pancreatic cysts from pseudocysts. Larger studies are recommended to evaluate this role further. PMID- 30002773 TI - Endoscopic drainage combined with percutaneous drainage in treatment of walled off pancreatic necrosis - a single-center experience. AB - Introduction: In last three decades we have been observing development of minimally invasive walled-off pancreatic necrosis (WOPN) treatment techniques. The choice of access to the necrosis and technique of treatment depends not only on the position and spread of necrosis, but in the first place on the experience of the medical center. Aim: To assess the effectiveness and safety of combined endoscopic and percutaneous drainage of WOPN. Material and methods: We performed a retrospective analysis of 64 consecutive patients with symptomatic WOPN, who underwent endoscopic treatment in our department between 2011 and 2013. Results: Additional percutaneous drainage was executed during endoscopic treatment in 20/64 (31.25%) patients. Complications of treatment occurred in 4/20 (20%) patients. Complications of treatment occurred in 4/20 (20%) patients. All these complications were related to endoscopic treatment. No complications related to percutaneous drainage were noted. There were no deaths. Therapeutic success was achieved in all 20 patients. No patients required surgery. The average time of endoscopic drainage was 41.4 (11-173) days. The mean number of endoscopic procedures was 4.2 (2-12). The average time of percutaneous drainage was 11.3 (5 20) days. The medium time of follow-up was 54 (48-64) months. During the observation the recurrence of WOPN was noted in 2/20 (10%) patients. Long-term success of combined drainage was achieved in 18/20 (90%) patients. Conclusions: In selected patients with symptomatic WOPN combined endoscopic and percutaneous drainage enables a high success rate with a low procedure-related complication rate. PMID- 30002774 TI - Peculiarities of diagnostics of billiary hypertension in patients with complicated forms of chronic pancreatitis. AB - Introduction: The morbidity of chronic pancreatitis (CP) remains at a high level. In cases of CP, prepapillary stenosis of the common bile duct (CBD) complicates the course of disease in 30-60% of patients. Aim: To improve the detection of biliary hypertension (BH) in patients with complicated forms of CP by increasing the accuracy of preoperative and intraoperative diagnostics using modern diagnostic methods. Material and methods: We analysed the results of surgical treatment of 573 patients with complicated forms of CP. In 163 (28.5%) patients, CP was complicated by BH. The method of intraoperative monitoring of biliary pressure (IOM BP) was developed and introduced for intraoperative control and determination of the adequacy of intervention regarding biliary decompression. Results: Mechanical jaundice was diagnosed by clinical methods in 101 (61.9%) CP patients with BH, and by laboratory methods in 108 (66.2%) patients. Such methods as magnetic resonance cholangiopancreatography (95.6%), endoscopic retrograde cholangiopancreatography (93.7%), and computed tomography (93.8%) proved to have the highest sensitivity for the diagnostics of BH in cases of CP. Conclusions: The application of an integrated approach with extensive use of modern non invasive preoperative methods of assessment allowed an approximation of the reliability of preoperative diagnostics of BH in CP patients to 95.6%. The use of the IOM BP method enables us to increase the sensitivity of intraoperative diagnostics of BH to 97.3% and choose the method of surgical intervention, which significantly reduces the risk of BH recurrence in the distant postoperative period by 15.1% (chi2 = 4.22, p = 0.04). PMID- 30002776 TI - Intraductal pancreatic stent fragmentation in patients with walled-off pancreatic necrosis and pancreatic duct disruption. PMID- 30002775 TI - Comparison between different first-line therapy protocols in eradicating Helicobacter pylori in a region with high clarithromycin resistance. AB - Introduction: Helicobacter pylori infection is encountered in more than 50% of the world population. A high rate of clarithromycin resistance is observed among Helicobacter pylori strains in some regions because clarithromycin is a drug commonly used for the treatment of other infections. Aim: To identify an efficient eradication protocol for patients infected with H. pylori and to suggest an alternative first-line therapy particularly in countries with high clarithromycin resistance. Material and methods: Patients (18-75 years old) having dyspeptic complaints in a 1-year period and diagnosed with H. pylori infection by gastric biopsy were included and randomised to three groups, each receiving different sequential eradication therapy (LAM-B: lansoprazole, amoxicillin, metronidazole, bismuth: LAM-T: lansoprazole, amoxicillin, metronidazole, tetracycline; LAM-BT: lansoprazole, amoxicillin, metronidazole, bismuth, tetracycline). Eradication was evaluated via urea breath test. Results: This study included 166 patients (mean age: 40 +/-12 years; female, 68.7%) with H. pylori infection. Among them, 50 (30.1%) were in the LAM-B group, 59 (35.5%) were in the LAM-T group, and 57 (34.3%) were in the LAM-BT group. The non steroidal anti-inflammatory drug use was the lowest in the LAM-BT group. Eradication rates were over 80% and similar in each group, with the highest rate in the LAM-BT group (93%). Adverse event rate was the highest in the LAM-T group. Helicobacter pylori eradication was achieved in 143 (86.1%) patients. Conclusions: The combination regimens without clarithromycin achieved an eradication rate over 80% in all groups. Knowing and monitoring the regional antibiotic resistance rates is important for successful treatment of H. pylori infections. PMID- 30002777 TI - The role of endoscopic ultrasonography in transmural drainage/debridement of walled-off pancreatic necrosis. PMID- 30002778 TI - Carcinoma of gastro-oesophageal junction in a pregnant woman. PMID- 30002779 TI - Poor Science; Poorly Trained Scientists; Poor Policies: Major Deterrents to the War on Cancer. AB - Although the availability of funding has been described as the major limitation on advances in cancer, the progress in the war on cancer has been deterred mainly by poor science, poorly trained scientists, and poor NIH policies. This is the result of NIH policies of its extreme focus on molecular biology (genomics, molecular genetics, molecular biology) identification of the molecular factors and pathways; which are required for the acceptability of treatment and preventive protocols. As such, this has influenced virtually all agencies that provide grants for medical research to adopt the NIH policies. This has impacted the funding of the research as well as the focus of the training of scientists. Directors of NCI Dr. Varmus (also Nobel Prize awardee) and Dr. Zerhouni had addressed this issue; and they rejected the necessity of molecular biology studies and information. NIH should return to the holistic physiological/pathophysiological approach to studies of cancer issues. This would provide the best approach for winning the war on cancer. PMID- 30002780 TI - Circumaortic right renal vein with multiple vascular anomalies. AB - Circumaortic right renal vein is an extremely rare finding and to our knowledge only 1 case has been reported in the literature so far. Its rareness, in contrast to left renal vein anomalies, is thought to be due to a relatively simple embryologic development of right renal vein compared with left renal vein. On the other hand, association of Circumaortic right renal vein with inferior vena cava agenesis and aortic coarctation is an extremely rare occurrence. Our aim is to introduce a case of Circumaortic right renal vein in a 3-month-old child with inferior vena cava agenesis and aortic coarctation. Discussion on the underlying embryology of Circumaortic right renal vein, its clinical importance and the association with other vascular anomalies, will be on our focus as well. Precise understanding of renal vein anomalies is important when planning retroperitoneal surgery or interventional vascular procedures. Awareness of such anomaly implies crucial knowledge for radiologists who should include it in the medical reports to aid future patient's management. PMID- 30002781 TI - Lymphangiomatosis in a 14-year-old female presenting with chylothorax and multiple cystic lesions. AB - Lymphangiomatosis is a rare congenital disease; diagnosis is made in the first 2 decades and affects almost all body parts. Imaging findings play an important role in the diagnosis. We present a case of a patient with lymphangiomatosis whose diagnosis was made solely with imaging findings; we also include a small review of the topic. PMID- 30002782 TI - IUD embedment in the fallopian tube: An unexpected location for a translocated IUD. AB - Intrauterine devices (IUDs) are the most common form of contraceptive used worldwide. The imaging features of IUDs and their potential complications are crucial to recognize in order to determine adequate positioning and ultimately function of the IUD. Herein, we report a rare case of a copper IUD embedded in the left fallopian tube that required surgical removal. Only a few such cases have been reported in the literature to date. PMID- 30002783 TI - Unexpected endometrial metastasis of a primary lung adenocarcinoma. AB - Following diagnosis of primary malignancies, subsequent workup includes evaluation for metastasis. Each malignancy, both location and histologic features, have statistically common and less common metastatic patterns. Metastatic lung adenocarcinoma typically involves lymph nodes, liver, brain, and bone. Very rarely can it involve the reproductive tract. Specifically, in females, multiple reported cases include ovarian metastasis. Even rarer, endometrial metastasis, such as this case report, has been reported. Even with usual staging utility of PET/CT, common things remain common; knowledge of common metastatic patterns can bias overall interpretation. This case is a reminder that despite our tendencies to focus on frequent patterns, even the rarest of metastatic patterns are still possible. PMID- 30002784 TI - Acute upper gastrointestinal hemorrhage from a pseudoaneurysm of an unusual superior polar artery of the spleen. AB - Splenic artery (SA) aneurysm and pseudoaneurysm are rare pathologies and uncommon causes of massive upper gastrointestinal (GI) bleeding. They represent the third most common intra-abdominal aneurysms. Variations in the origin of SA are relatively common and asymptomatic. However, the presence of an accessory SA that is symptomatic is quite atypical. In this report, we describe the case of a 73 year-old female who presented with massive upper GI bleeding caused by a pseudoaneurysm of a superior polar artery with an unusual anatomic origin. The patient was successfully treated endovascularly with transarterial coil embolization. Early diagnosis and interventional management are crucial for patient's survival; hence, it must be kept in mind as possible etiology of life threatening GI bleeding to reduce morbidity and mortality. PMID- 30002785 TI - Avulsion fracture of the tibial eminence in an adult with a unique mechanism of injury. AB - Tibial eminence avulsion fractures are not infrequent in the pediatric population; however, they are rare in the adult population. These injuries typically occur in skeletally immature patients between the ages of 8 and 14 years. We report the unique clinical history, imaging findings, and operative results of a 48-year-old female who presented with severe knee pain. Imaging findings revealed an anterior tibial eminence fracture with an intact anterior cruciate ligament tendon attached to the avulsed fragment. The patient underwent knee arthroscopy, with direct repair of the tibial eminence fracture. PMID- 30002786 TI - Bilateral emphysematous pyelonephritis cured by antibiotics alone in a black African woman. AB - A 78-year-old black woman with a 10-year history of diabetes mellitus was admitted to the intensive care unit. Upon admission, she presented with chills, nausea, and left flank pain. The presence of hyperglycemia (fasting blood glucose, 19.7 mmol/L) and an altered consciousness required immediate treatment with insulin analog. Laboratory investigations and enhanced computed tomography scan led to the diagnosis of bilateral emphysematous pyelonephritis (EPN). The patient responded well to conservative treatment with antibiotics, and was finally discharged after 22 days when the computed tomography scan showed resolution of all the pockets of air. This case and associated literature review of 25 previously reported cases of bilateral EPN show the changing trend of EPN management from emergency nephrectomy toward conservative treatment with potent antibiotics and/or percutaneous drainage, and has been associated with higher survival rates compared to emergency nephrectomy. PMID- 30002787 TI - Insufficiency fractures: A rare cause of foot and ankle pain in three patients with rheumatoid arthritis. AB - Insufficiency fractures are recognized but rare complications in patients with longstanding rheumatoid arthritis. Such fractures are typically solitary and are rarely seen to affect the foot and ankle. We describe 3 women with longstanding rheumatoid arthritis, treated with one, or a combination of, corticosteroids, DMARDs and anti-TNF, presenting with foot and ankle pain with no prior history of trauma. MRIs showed rare multiple florid insufficiency fractures of the foot and ankle, in 2 cases bilaterally, which were managed conservatively. These cases highlight the importance of considering insufficiency fractures in similar patients presenting with foot and ankle pain. Radiographs may fail to demonstrate these lesions, delaying diagnosis, and worsening patient outcome, therefore in such cases MRI is a valuable modality. PMID- 30002788 TI - Cytoprotective Roles of a Novel Compound, MHY-1684, against Hyperglycemia-Induced Oxidative Stress and Mitochondrial Dysfunction in Human Cardiac Progenitor Cells. AB - Diabetic cardiomyopathy (DCM) is tightly linked to heart disorders and dysfunction or death of the cardiomyocytes including resident cardiac progenitor cells (CPCs) in diabetic patients. In order to restore loss of function of resident or transplanted CPCs, much research has focused on novel therapeutic strategies including the discovery of novel function-modulating factors such as reactive oxygen species (ROS) scavengers. Here, we developed and defined a novel antioxidant, MHY-1684, for enhancing the angiogenic potential of CPCs against ROS related DCM. Short-term treatment with MHY-1684 restored ROS-induced CPC cell death. Importantly, MHY-1684 decreased hyperglycemia-induced mitochondrial ROS generation and attenuated hyperglycemia-induced mitochondrial fragmentation. We observed that the activation process of both Drp1 (phosphorylation at the site of Ser616) and Fis-1 is drastically attenuated when exposed to high concentrations of D-glucose with MHY-1684. Interestingly, phosphorylation of Drp1 at the site of Ser637, which is an inhibitory signal for mitochondrial fusion, is restored by MHY-1684 treatment, suggesting that this antioxidant may affect the activation and inhibition of mitochondrial dynamics-related signaling and mitochondrial function in response to ROS stress. In conclusion, our finding of the novel compound, MHY-1684, as an ROS scavenger, might provide an effective therapeutic strategy for CPC-based therapy against diabetic cardiomyopathy. PMID- 30002789 TI - Protein Sequences Recapitulate Genetic Code Evolution. AB - Several hypotheses predict ranks of amino acid assignments to genetic code's codons. Analyses here show that average positions of amino acid species in proteins correspond to assignment ranks, in particular as predicted by Juke's neutral mutation hypothesis for codon assignments. In all tested protein groups, including co- and post-translationally folding proteins, 'recent' amino acids are on average closer to gene 5' extremities than 'ancient' ones. Analyses of pairwise residue contact energies matrices suggest that early amino acids stereochemically selected late ones that stablilize residue interactions within protein cores, presumably producing 5'-late-to-3'-early amino acid protein sequence gradients. The gradient might reduce protein misfolding, also after mutations, extending principles of neutral mutations to protein folding. Presumably, in self-perpetuating and self-correcting systems like the genetic code, initial conditions produce similarities between evolution of the process (the genetic code) and 'ontogeny' of resulting structures (here proteins), producing apparent teleonomy between process and product. PMID- 30002792 TI - Clonal T-cell Large Granular Lymphocytic Disorders Manifesting in Patients with HIV-1 Infection: Case Series and Review of the Literature. AB - We report five patients with human immunodeficiency virus-1/acquired immunodeficiency syndrome (HIV-1/AIDS) who developed T-cell large granular lymphocytic proliferation (T-LGLP) or leukemia (T-LGLL). None of the patients fulfilled criteria for diagnosis of diffuse infiltrative lymphocyte syndrome (DILS) or HIV-associated CD8+ lymphocytosis syndrome at the time of diagnosis of LGL. The immunophenotype of malignant T-cells was identical in three patients with co-expression of CD3, CD8, CD57, and T-cell receptor (TCR) alpha/beta. Three out of five patients were also diagnosed with clonal disorders of B-cell origin including diffuse large B-cell lymphoma, Burkitt's lymphoma, and monoclonal gammopathy of undetermined significance (MGUS). Two patients developed cytopenias due to T-LGLL prompting initiation of therapy. Our study suggests that chronic viral infection with HIV can contribute to the evolution of T-LGLP. Clinical and laboratory characteristics of T-LGLP associated with HIV-1/AIDS resemble those of immunocompetent patients. PMID- 30002790 TI - Taxonomy and evolution of Aspergillus, Penicillium and Talaromyces in the omics era - Past, present and future. AB - Aspergillus, Penicillium and Talaromyces are diverse, phenotypically polythetic genera encompassing species important to the environment, economy, biotechnology and medicine, causing significant social impacts. Taxonomic studies on these fungi are essential since they could provide invaluable information on their evolutionary relationships and define criteria for species recognition. With the advancement of various biological, biochemical and computational technologies, different approaches have been adopted for the taxonomy of Aspergillus, Penicillium and Talaromyces; for example, from traditional morphotyping, phenotyping to chemotyping (e.g. lipotyping, proteotypingand metabolotyping) and then mitogenotyping and/or phylotyping. Since different taxonomic approaches focus on different sets of characters of the organisms, various classification and identification schemes would result. In view of this, the consolidated species concept, which takes into account different types of characters, is recently accepted for taxonomic purposes and, together with the lately implemented 'One Fungus - One Name' policy, is expected to bring a more stable taxonomy for Aspergillus, Penicillium and Talaromyces, which could facilitate their evolutionary studies. The most significant taxonomic change for the three genera was the transfer of Penicillium subgenus Biverticillium to Talaromyces (e.g. the medically important thermally dimorphic 'P. marneffei' endemic in Southeast Asia is now named T. marneffei), leaving both Penicillium and Talaromyces as monophyletic genera. Several distantly related Aspergillus-like fungi were also segregated from Aspergillus, making this genus, containing members of both sexual and asexual morphs, monophyletic as well. In the current omics era, application of various state-of-the-art omics technologies is likely to provide comprehensive information on the evolution of Aspergillus, Penicillium and Talaromyces and a stable taxonomy will hopefully be achieved. PMID- 30002793 TI - Very Early Development and Recognition of Coronary Involvement in a Febrile Infant with Typical Signs of Kawasaki Disease. AB - Kawasaki disease (KD) is an acute, self-limited, inflammatory disease affecting medium-sized arteries and particularly the coronary arteries in about 25% of untreated cases. KD is a clinical diagnosis based on the presence of >=5 days of fever and the presence of >=4 of the 5 principal clinical criteria. We described, for the first time to our knowledge, a case of a very early development (on day 1) of typical KD with transient coronary involvement, diagnosed on day 2 of disease and treated with aspirin and steroids on day 3, with complete resolution of clinical signs and coronary involvement. PMID- 30002794 TI - Oral Nutritional Supplementation in Children Treated for Cancer in Low- and Middle-Income Countries Is Feasible and Effective: the Experience of the Children's Hospital Manuel De Jesus Rivera "La Mascota" in Nicaragua. AB - Children with cancer are particularly vulnerable to malnutrition, which can affect their tolerance of chemotherapy and outcome. In Nicaragua approximately two-thirds of children diagnosed with cancer present with under-nutrition. A nutritional program for children with cancer has been developed at "La Mascota" Hospital. Results of this oral nutritional intervention including difficulties, benefits, and relevance for children treated for cancer in low- and middle-income countries are here reported and discussed. PMID- 30002795 TI - Infections in Myelodysplastic Syndrome in Relation to Stage and Therapy. AB - Infections remain a significant problem in myelodysplastic syndromes (MDS) in treated as well in non-treated patients and assume a particular complexity. The susceptibility to infections is due, in the absence of intensive chemotherapies, mainly to functional defects in the myeloid lineage with or without neutropenia. Furthermore, MDS includes a heterogeneous group of patients with very different prognosis, therapy and risk factors regarding survival and infections. You should distinguish risk factors related to the disease, like as neutrophils function impairment, neutropenia, unfavorable cytogenetics and bone marrow insufficiency; factors related to the patient, like as age and comorbidities, and factors related to the therapy. When the patients with MDS are submitted to intensive chemotherapy with and without hematopoietic stem cell transplantation (HSCT), they have a risk factor for infection very similar to that of patients with acute myeloid leukemia (AML), and mostly related to neutropenia. Patients with MDS treated with supportive therapy only or with demethylating agent or lenalidomide or immunosuppressive drugs should have a tailored approach. Most of the infections in MDS originate from bacteria, and the main risk factors are represented by neutropenia, thrombocytopenia, and unfavorable cytogenetics. Thus, it is reasonable to give antibacterial prophylaxis to patients who start the therapy with demethylating agents with a number of neutrophils <500 * 109/L, or with thrombocytopenia and unfavorable cytogenetics. The antifungal prophylaxis is not considered cost/benefit adequate and should be taken into consideration only when there is an antecedent fungal infection or presence of filamentous fungi in the surveillance cultures. Subjects submitted to immunosuppression with ATG+CSA have a high rate of infections, and when severely neutropenic should ideally be nursed in isolation, should be given prophylactic antibiotics and antifungals, regular mouth care including an antiseptic mouthwash. PMID- 30002796 TI - Disseminated Histoplasmosis as AIDS-presentation. Case Report and Comprehensive Review of Current Literature. AB - Progressive disseminated histoplasmosis (PDH) is an AIDS-defining illness with a high lethality rate if not promptly treated. The wide range of its possible clinical manifestations represents the main barrier to diagnosis in non-endemic countries. Here we present a case of PDH with haemophagocytic syndrome in a newly diagnosed HIV patient and a comprehensive review of disseminated histoplasmosis focused on epidemiology, clinical features, diagnostic tools and treatment options in HIV-infected patients. PMID- 30002797 TI - Impact of Multiplex PCR in Reducing the Risk of Residual Transfusion-Transmitted Human Immunodeficiency and Hepatitis B and C Viruses in Burkina Faso. AB - Background and Objective: The improved performance of serological tests has significantly reduced the risk of human immunodeficiency and hepatitis B and C viruses transmission by blood transfusion, but there is a persistence of residual risk. The objective of this study was to evaluate the impact of multiplex PCR in reducing the risk of residual transmission of these viruses in seronegative blood donors in Burkina Faso. Methods: This cross-sectional study was conducted from March to September 2017. The serological tests were performed on sera using ARCHITECTSRi1000 (Abbot diagnosis, USA). Detection of viral nucleic acids was performed by multiplex PCR on mini-pools of seronegative plasma for HBV, HCV and HIV using SaCycler-96 Real Time PCR v.7.3 (Sacace Biotechnologies). Multiplex PCR positive samples from these mini-pools were then individually tested by the same method. Results: A total of 989 donors aged 17 to 65 were included in the present study. "Repeat donors" accounted for 44.79% (443/989). Seroprevalences for HIV, HBV, and HCV were 2.53% (25/989), 7.28% (72/989) and 2.73% (27/989), respectively. Of the 14 co-infections detected, HBV/HCV was the most common with 0.71% (7/989) of cases. Of 808 donations tested by multiplex PCR, 4.70% (38/808) were positive for HBV while no donation was positive for HIV or HCV. Conclusion: Our study showed a high residual risk of HBV transmission through blood transfusion. Due to the high prevalence of blood-borne infections in Burkina Faso, we recommend the addition of multiplex PCR to serologic tests for optimal blood donation screening. PMID- 30002791 TI - Lung Cancer Therapy Targeting Histone Methylation: Opportunities and Challenges. AB - Lung cancer is one of the most common malignancies. In spite of the progress made in past decades, further studies to improve current therapy for lung cancer are required. Dynamically controlled by methyltransferases and demethylases, methylation of lysine and arginine residues on histone proteins regulates chromatin organization and thereby gene transcription. Aberrant alterations of histone methylation have been demonstrated to be associated with the progress of multiple cancers including lung cancer. Inhibitors of methyltransferases and demethylases have exhibited anti-tumor activities in lung cancer, and multiple lead candidates are under clinical trials. Here, we summarize how histone methylation functions in lung cancer, highlighting most recent progresses in small molecular inhibitors for lung cancer treatment. PMID- 30002798 TI - Prevalence of beta-Thalassemia Mutations among Northeastern Iranian Population and their Impacts on Hematological Indices and Application of Prenatal Diagnosis, a Seven-Years Study. AB - Background and Objective: beta-thalassemia results from a diverse range of mutations inside the hemoglobin subunit beta (HBB) gene. In a study of beta thalassemia carriers and some of their at-risk fetuses in the Khorasan province of Iran, we aimed to recognize the most common mutations in the region. We also investigated a possible link between these mutations and some of the relevant hematological indices. Methods: Amplification-refractory mutation system-PCR (ARMS-PCR) was used to detect the typical HBB mutations among 1593 individuals, suspected of having a mutated HBB allele from March/2011 to January/2018. Sanger sequencing of HBB had been performed, where ARMS-PCR was uninformative. In some cases, reverse dot blot was utilized. Analysis of variance was used to compare parametric variables. Results: Among 1273 beta-thalassemia carriers, the prevalence of the mutations were reported as follows: IVS-I-5 (42.03%), IVS-II-1 (11.23%), codons 8/9 (4.79%), codon 44 (4.56%), codon 15 (3.53%), Los Angeles (2.91%), codon 5 (2.75%), IVS-I-110 (2.51%), -88 (2.20%) and other mutations were less than 2% of all of the reported mutations. 644 conceptions were subjected to prenatal diagnosis, using chorionic villus sampling. 118 cases were reported as normal. 352 cases were detected as carriers. 174 cases were diagnosed as affected. There was a significant difference in mean corpuscular volume and hemoglobin A2 levels between the nine most commonly reported mutation types (p<0.001). Conclusion: This study makes a reliable guide for beta-thalassemia diagnosis in the region. The possibility of a correlation between HBB mutations and hematological indices opens a gate of future investigations. PMID- 30002799 TI - Successful Management of Kaposiform Hemangioendothelioma with Long-Term Sirolimus Treatment: a Case Report and Review of the Literature. AB - Background: Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumour of the infancy and the first decade of life. It is locally aggressive and potentially life threatening when associated with consumptive coagulopathy, known as Kasabach-Merritt syndrome (KMS). No consensus or guideline for the therapy has been reached because of the lack of prospective trials, and the different standard care suggestions are based on retrospective case series. Case report: We report the case of a 9-month-old male with KHE and KMS in which the initial response, obtained with prednisone and vincristine, was subsequently consolidated and strengthened by long-term treatment with sirolimus, a mTOR inhibitor. A summary of the published data is presented as well. Conclusions: The inhibition of mTOR pathway represents the most important therapeutic innovation introduced in the last few years for KHE. Our case shows the effectiveness and good tolerance of long-term therapy with sirolimus. PMID- 30002800 TI - Evaluation of Polymyxin B Susceptibility Profile and Detection of Drug Resistance Genes among Acinetobacter Baumannii Clinical Isolates in Tehran, Iran during 2015 2016. AB - Acinetobacter baumannii is an important opportunistic pathogen, responsible for approximately 10% of all gram-negative nosocomial infection. The aim of this study was to determine aminoglycoside and quinolone resistance genes and their antimicrobial susceptibility profile in the clinically A. baumannii. In this cross-sectional study, a total of 100 nonduplicative A. baumannii isolates were collected from different clinical samples. Antimicrobial susceptibility test was performed by disk diffusion method. QnrA, anrB, qnrS, aac(3)-IIa, and aac(6')-Ib genes were identified using PCR method. The results of antibiotic susceptibility test showed that polymyxin B was the most effective antimicrobial against A. baumannii. 97%, 95% and 82% of isolates were resistant to cefepime, ceftriaxone, and amikacin, respectively. The molecular distribution of aac(3)-IIa, aac(6')-Ib, and qnrA genes were 45%, 50%, and 50% of isolates, respectively. However, qnrB and qnrS genes could not be detected in any strain. This study showed that polymyxin B was the best drug against A. baumannii clinical isolates. This data is also valid for polymyxin E (colistin), which is mostly used in clinics. There is a high level of resistance genes among clinical A. baumannii isolates. This high prevalence rate highlights the necessity for the development of rapid diagnostic assays and continuous monitoring of antibiotic resistance. PMID- 30002801 TI - Acute Promyelocytic Leukemia in Children: A Single Centre Experience from Turkey. AB - Background and objectives: Acute promyelocytic leukemia (APL), is a distinct subtype of acute myeloid leukemia (AML) characterized by a tendency to hemorrhage and excellent response to all-trans retinoic acid (ATRA). In this retrospective study, we aimed to determine the incidence, clinical symptoms, toxicities, and outcome of children with APL in our center. Methods: We retrospectively reviewed the medical records of children (age < 18 years) diagnosed with APL in our pediatric hematology department between January 2006-December 2016. Results: Pediatric APL represents 20.5% of AML cases in this cohort. Most of the cases presented as classical M3, albeit hypogranular variant was described in 12% of the cohort. Patients with hypogranular variant APL were differed from classical APL by co-expression of CD2 and CD34. About 3/4 of APL patients had hemorrhagic findings at admission or the induction treatment. Severe bleeding manifested as intracranial hemorrhage was present in three patients and intracranial arterial thrombosis was present in one. Six patients showed side effects of ATRA such as pseudotumor cerebri, differentiation syndrome resulting in dilated cardiomyopathy, and pulmonary infiltrates. Five-year overall survival (OS) and early death rate were found to be 82.5% and 12% respectively. Conclusions: A high frequency (20.5%) of APL was noted among children with AML in this single-center study. The overall mortality rate was 17.5%. Since the induction death rate was 12% and life-threatening bleeding was the primary problem, awareness and urgent treatment are critical factors to reduce early losses. PMID- 30002802 TI - Thrombocytopenia in Patients with Myelodysplastic Syndromes: Still an Unsolved Problem. AB - The myelodysplastic syndromes (MDS) are a group of clonal bone marrow (BM) stem cell disorders, characterized by ineffective hematopoiesis, peripheral cytopenias, and hematologic cellular dysfunction, as well as potential transformation to acute leukemia. Thrombocytopenia is common in MDS and is associated with bleeding complications, occasionally life-threatening. Low platelet count (PLT), as well declining PLT also serves as a prognostic marker. Understanding thrombopoiesis led to the cloning of thrombopoietin, resulting in the development of platelet stimulating agents, thrombomimetics, romiplostim and eltrombopag. Both agents have been shown to increase PLT, decrease the need for platelet transfusions and reduce the number of bleeding episodes, with a reasonable tolerance. They are already approved for immune thrombocytopenia and thrombocytopenia related to liver disease. Romiplostim and eltrombopag have proven efficacy in lower- and higher-risk MDS with thrombocytopenia, as monotherapy, as well as a part of a combination, either with lenalidomide, and mainly combined with hypomethylating agents. However, safety concerns have been raised: while several trials have been completed with no evidence of disease progression, others have been early terminated due to an increased number of BM blasts and possible leukemic transformation in treated-patients. The jury is still out regarding this safety concern, although recent publications are more encouraging. PMID- 30002803 TI - Study on Tripping Risks in Fast Walking through Cadence-Controlled Gait Analysis. AB - Fast walking is a common exercise for most people to promote health. However, a higher cadence due to fast walking on ordinary or uneven ground raises the risk of tripping. To investigate the tripping issue, research to observe the gait in fast walking is needed. To explore the relationship between fast gait and the risk of tripping, a gait recording system with a specific synchronization mechanism was developed in this work. The system can acquire gait signals from wearable sensors and action cameras at different cadences. Meanwhile, algorithms for gait cycle segmentation and characteristic extraction were proposed for analyzing a fast gait. In the gait analysis, the correlations of low, moderate, and high cadence in cueing and no cueing gaits were computed, and two results were obtained. First, the higher the cadence is, the larger the motion strength in the terminal foot swing will be and the smaller the motion strength at the starting foot swing. Second, the decreased distance of foot clearance becomes more conspicuous as the cadence increased, especially if one is walking more than 120 beats. The results indicate that fast walking with bigger strides and lower cadence is the best way to maintain safety in moving over ordinary ground. PMID- 30002805 TI - Successful use of adipose-derived mesenchymal stem cells to correct a male breast affected by Poland Syndrome: a case report. AB - Poland syndrome is a rare congenital anomaly in which affected persons are born with missing or underdeveloped muscles on one side of the body. In this case study we present the case of a 28-year-old male with absence of all middle phalanges of the right hand and other rare anomalies, who underwent reconstruction with a new method that combines a mixture of adipose-derived mesenchymal stem cells and fat transfer. The patient's restoration of the pectoralis area was aesthetically successful with no complications and remained unchanged even after 3.5 years. The proposed method represents an interesting reconstructive approach for treating Poland's syndrome deformities. PMID- 30002806 TI - Repair of gastrocutaneous fistula utilizing thickened fluids: application of Poiseuille's Law to fistula healing. AB - Enterocutaneous fistulas are a rare occurrence after placement of a PEG tube. The key risk factor for their development is the time the PEG tube is in situ, giving time for the fistula tract to mature. Enterocutaneous fistulae are traditionally treated with parenteral nutrition or surgical management. We present a case of a 69-year-old woman who underwent surgical closure of an enterocutaneous fistula with a fibrin plug. The fistula recurred on post-operative Day 5, and the patient was placed on thickened fluids to increase the viscosity of the fluid exiting the fistula tract. This approach decreased the output and lead to subsequent closure of the fistula by outpatient follow up at 4 weeks. This case demonstrates an application of Poiseuille's law to closure of fistula tracts. PMID- 30002807 TI - Erratum: Triple thrombophilic simultaneous mutations in patients after bariatric surgery: is there a role for screening in the Eastern Mediterranean? AB - [This corrects the article DOI: 10.1093/jscr/rjy135.][This corrects the article DOI: 10.1093/jscr/rjy135.]. PMID- 30002804 TI - Event-related potential (ERP) correlates of face processing in verbal children with autism spectrum disorders (ASD) and their first-degree relatives: a family study. AB - Background: Inherited abnormalities of perception, recognition, and attention to faces have been implicated in the etiology of autism spectrum disorders (ASD) including abnormal components of event-related brain potentials (ERP) elicited by faces. Methods: We examined familial aggregation of face processing ERP abnormalities previously implicated in ASD in 49 verbal individuals with ASD, 36 unaffected siblings (US), 18 unaffected fathers (UF), and 53 unrelated controls (UC). The ASD, US, and UC groups ranged in age from 12 to 21 years, the UF group ranged in age from 30 to 56 years. ERP responses to images of upright and inverted faces and houses were analyzed under disparate EEG reference schemes. Results: Face-sensitive features of N170 and P1 were readily observed in all groups. Differences between ASD and control groups depended upon the EEG reference scheme. Notably, the superiority of face over object for N170 latency was attenuated in ASD subjects, but not their relatives; this occurred exclusively with the average reference. The difference in N170 amplitude between inverted and upright faces was reduced in both ASD and US groups relative to UC, but this effect was significant only with the vertex reference. Furthermore, similar group differences were observed for both inverted faces and inverted houses, suggesting a lack of face specificity for the attenuation of the N170 inversion effect in ASD. Conclusion: The present findings refine understanding of face processing ERPs in ASD. These data provide only modest evidence for highly selective ASD-sensitive ERP features, and underscore the sensitivity of these biomarkers to ERP reference scheme. These schemes have varied across published studies and must be accounted for in future studies of the relationship between these commonly acquired ERP characteristics, genotype, and ASD. PMID- 30002808 TI - Modelling Trends of Climatic Variability and Malaria in Ghana Using Vector Autoregression. AB - Malaria is considered endemic in over hundred countries across the globe. Many cases of malaria and deaths due to malaria occur in Sub-Saharan Africa. The disease is of great public health concern since it affects people of all age groups more especially pregnant women and children because of their vulnerability. This study sought to use vector autoregression (VAR) models to model the impact of climatic variability on malaria. Monthly climatic data (rainfall, maximum temperature, and relative humidity) from 2010 to 2015 were obtained from the Ghana Meteorological Agency while data on malaria for the same period were obtained from the Ghana Health Service. Results of the Granger and instantaneous causality tests led to a conclusion that malaria is influenced by all three climatic variables. The impulse response analyses indicated that the highest positive effect of maximum temperature, relative humidity, and rainfall on malaria is observed in the months of September, March, and October, respectively. The decomposition of forecast variance indicates varying degree of malaria dependence on the climatic variables, with as high as 12.65% of the variability in the trend of malaria which has been explained by past innovations in maximum temperature alone. This is quite significant and therefore, policy makers should not ignore temperature when formulating policies to address malaria. PMID- 30002809 TI - Tenosynovial giant cell tumor: case report of a patient effectively treated with pexidartinib (PLX3397) and review of the literature. AB - Background: Tenosynovial giant cell tumors (TGCTs) or giant cell tumors of tendon sheath are neoplasms that arise in the synovium. They can be categorized as nodular (localized) or diffuse type (D-TGCT). Historically, surgery has been the mainstay of therapy, but diffuse type disease recurs at a high rate and treatment often requires increasingly morbid procedures. Elucidation of the importance of the colony-stimulating factor (CSF1)/CSF1 receptor (CSF1R) pathway in the pathogenesis of this disease has created significant interest in targeting this pathway as a novel TGCT treatment approach. Pexidartinib, a selective tyrosine kinase inhibitor against CSF1R, showed an 83% disease control rate (52% with partial response and 31% with stable disease) in a recent phase 1 study of patients with TGCT. Case presentation: We present an illustrative example of a TGCT patient who would have required a morbid operation who derived considerable clinical benefit from pexidartinib treatment. Her tumor volume decreased by 48% after 4 months of treatment, and 55 months after starting treatment the patient exhibits continued disease stability with minimal clinical symptoms, and significant improvement in functional status. Conclusions: This case illustrates the effectiveness of systemic therapy in controlling a disease associated with high surgical morbidity. This approach may be especially useful in the treatment of extra-articular disease which often invades neurovascular bundles; as the effectiveness in metastatic disease is still unknown. In the future, systemic treatment for TGCT may be appropriate for the neoadjuvant setting to decrease disease burden prior to surgery with the aim of decreasing recurrence rates. However, properly designed prospective studies will need to be carried out to answer these questions. PMID- 30002812 TI - Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder? AB - Background: Spontaneous cervical artery dissections more often manifest in young people and have been associated with catastrophic consequences. Some indeterminate risk factors have been identified, making the diagnosis of developing dissections quite difficult. Fluoroquinolone antibiotics have been recognized for their degradative effects on connective tissue. Recent studies have implicated fluoroquinolones in the genesis of aortic artery aneurysms. It is the purpose of this paper to provide reasoning for a testable hypothesis of whether fluoroquinolones constitute a risk factor associated with cervical artery dissections. Methods: A PubMed search was conducted to investigate whether cervical artery dissection has been associated with fluoroquinolone use. An assessment of risk factors was made of hereditary connective tissue disorders, infection, and seasonal predisposition related to cervical artery dissection. These factors were considered in conjunction with reports of connective tissue toxicity associated with fluoroquinolone medications. Results: It appears that no reported cases of cervical artery dissection have previously been correlated with fluoroquinolone use. Heritable connective tissue disorders, infection, seasonal predisposition and condition latencies are associated with fluoroquinolone medications. Several recent articles have implicated fluoroquinolones with aortic dissections and aneurysm. Conclusion: A causal relationship of fluoroquinolone antibiotics to cervical artery dissection is plausible. The suppositions developed in this paper are insufficient to suggest that fluoroquinolones currently represent an established risk factor in the development of cervical artery dissections. Fluoroquinolones may indeed be a novel and previously unrecognized cause of cervical artery dissections. PMID- 30002813 TI - Correction to: Thoracic index in adults with asthma: a study of validity and reliability. AB - [This corrects the article DOI: 10.1186/s12998-018-0187-x.]. PMID- 30002810 TI - Mutant huntingtin induces iron overload via up-regulating IRP1 in Huntington's disease. AB - Background: Iron accumulation in basal ganglia accompanies neuronal loss in Huntington's disease (HD) patients and mouse disease models. Disruption of HD brain iron homeostasis occurs before the onset of clinical signs. Therefore, investigating the mechanism of iron accumulation is essential to understanding its role in disease pathogenesis. Methods: N171-82Q HD transgenic mice brain iron was detected by using Diaminobenzidine-enhanced Perls' stain. Iron homeostatic proteins including iron response protein 1 (IRP1), transferrin (Tf), ferritin and transferrin receptor (TfR) were determined by using western blotting and immunohistochemistry, and their relative expression levels of RNA were measured by RT-PCR in both N171-82Q HD transgenic mice and HEK293 cells expressing N terminal of huntingtin. Results: Iron was increased in striatum and cortex of N171-82Q HD transgenic mice. Analysis of iron homeostatic proteins revealed increased expression of IRP1, Tf, ferritin and TfR in N171-82Q mice striatum and cortex. The same results were obtained in HEK293 cells expressing N-terminal of mutant huntingtin containing 160 CAG repeats. Conclusion: We conclude that mutant huntingtin may cause abnormal iron homeostatic pathways by increasing IRP1 expression in Huntington's disease, suggesting potential therapeutic target. PMID- 30002811 TI - Severity of allergic rhinitis impacts sleep and anxiety: results from a large Spanish cohort. AB - Background: Allergic rhinitis (AR) is a highly prevalent disease that generates high social and health care costs and also has a significant effect on quality of life and quality of sleep. It has also been related to some psychological disorders like anxiety or depression. Objective: To evaluate anxiety, depression, and quality of sleep and life alteration in a group of patients with perennial AR compared to a group of seasonal AR patients. Methods: Six-hundred seventy adults (> 18 years) with perennial and seasonal AR were recruited consecutively in 47 centers in Spain. Individuals were grouped in "Perennial" and "Seasonal" according to the seasonality of their symptoms. Anxiety, depression, sleep quality and health related quality of life were evaluated using the Hospital Anxiety and Depression Scale, Medical Outcomes Study Sleep Scale (MOS Sleep Scale) and the Health-related quality of life questionnaire ESPRINT-15, respectively. Both groups of patients were evaluated in and out of the pollen season. Results: AR symptoms are related to worse quality of life and more anxiety and depression symptoms. Indeed, symptom severity also correlates with worse outcomes (quality of life, sleep and depression/anxiety) regardless allergen seasonality. Symptoms severity, compared with seasonality and persistence, is the most important factor related with more anxiety and depression and poor sleep. However, symptoms severity, persistence and seasonality are independently affecting the quality of life in patients with AR. Conclusions: Although AR symptoms have a great impact on depression and anxiety symptoms, quality of life and quality of sleep in all AR patients, as expected, individuals with more severe AR seem to suffer more intensely their effects. PMID- 30002814 TI - Recent advances in understanding inherited disorders of keratinization. AB - The ichthyoses are a heterogeneous group of skin diseases characterized by localized or generalized scaling or both. Other common manifestations include palmoplantar keratoderma, erythroderma, recurrent infections, and hypohidrosis. Abnormal barrier function is a cardinal feature of the ichthyoses, which results in compensatory hyperproliferation and transepidermal water loss. Barrier function is maintained primarily by the stratum corneum, which is composed of cornified cells surrounded by a corneocyte lipid envelope and intercellular lipid layers. The lipid components are composed primarily of ceramides. Human genetics has advanced our understanding of the role of the epidermal lipid barrier, and a series of discoveries in animals and humans revealed mutations in novel genes causing disorders of keratinization. Recently, next-generation sequencing has further expanded our knowledge, identifying novel mutations that disrupt the ceramide pathway and result in disorders of keratinization. This review focuses on new findings in ichthyoses caused by mutations involving lipid synthesis or function or both. PMID- 30002815 TI - One Environmental Health: an emerging perspective in toxicology. AB - The One Environmental Health research approach, a subspecialty of the One Health initiative, focuses on toxic chemicals. Distinct disciplines work together to give a holistic perspective of a health concern through discrete disciplines, including, but not limited to, public health and the medical and veterinary sciences. In this article, we illustrate the concept of One Environmental Health with two case studies. One case study focuses on alligators and contributions to the field of endocrine disruption. The other case study focuses on whales and contributions to understanding carcinogenic metals. Both studies illustrate how the health of sentinel organisms has the potential to inform about the health of humans and the ecosystem. PMID- 30002818 TI - Dopamine synergizes with caffeine to increase the heart rate of Daphnia. AB - Dopamine is a key neurotransmitter, and is widely used as a central nervous system (CNS) agent. Dopamine plays an important role in humans, including a major role in reward and motivation behaviour. Several addictive drugs are well known to increase neuronal dopamine activity. We selected Daphnia, an important model organism, to investigate the effect(s) of selected CNS agents on heart rate. Dopamine's effects on Daphnia's heart has not been previously reported. Caffeine is a well-known and widely consumed stimulant. Ethanol is well known for its effects on both neurological and physiological processes in mammals. We tested the effect of dopamine on the heart rate of Daphnia, and compared its effect with caffeine and ethanol alone and in combination. Both caffeine and dopamine were found to instantly increase the heart rate of Daphnia in a dose dependent manner. Interestingly, caffeine synergized with dopamine to increase Daphnia's heart rate. As ethanol decreased the heart rate of Daphnia and dopamine increased the heart rate of Daphnia, we wanted to test the effect of these molecules in combination . Indeed, Dopamine was able to restore the ethanol induced decrease in the heart rate of Daphnia. Effects of these CNS agents on Daphnia can possibly be correlated with similar effects in the case of mammals. PMID- 30002819 TI - iSEE: Interactive SummarizedExperiment Explorer. AB - Data exploration is critical to the comprehension of large biological data sets generated by high-throughput assays such as sequencing. However, most existing tools for interactive visualisation are limited to specific assays or analyses. Here, we present the iSEE (Interactive SummarizedExperiment Explorer) software package, which provides a general visual interface for exploring data in a SummarizedExperiment object. iSEE is directly compatible with many existing R/Bioconductor packages for analysing high-throughput biological data, and provides useful features such as simultaneous examination of (meta)data and analysis results, dynamic linking between plots and code tracking for reproducibility. We demonstrate the utility and flexibility of iSEE by applying it to explore a range of real transcriptomics and proteomics data sets. PMID- 30002817 TI - Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts. AB - Hepatic fibrosis is characterized by the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying noxious trigger, tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. Genetic disorders, chronic viral infection, alcohol abuse, autoimmune attacks, metabolic disorders, cholestasis, alterations in bile acid composition or concentration, venous obstruction, and parasite infections are well-established factors that predispose one to hepatic fibrosis. In addition, excess fat and other lipotoxic mediators provoking endoplasmic reticulum stress, alteration of mitochondrial function, oxidative stress, and modifications in the microbiota are associated with non-alcoholic fatty liver disease and, subsequently, the initiation and progression of hepatic fibrosis. Multidisciplinary panels of experts have developed practice guidelines, including recommendations of preferred therapeutic approaches to a specific cause of hepatic disease, stage of fibrosis, or occurring co-morbidities associated with ongoing loss of hepatic function. Here, we summarize the factors leading to liver fibrosis and the current concepts in anti-fibrotic therapies. PMID- 30002816 TI - State of the art of the Fontan strategy for treatment of univentricular heart disease. AB - In patients with a functionally univentricular heart, the Fontan strategy achieves separation of the systemic and pulmonary circulation and reduction of ventricular volume overload. Contemporary modifications of surgical techniques have significantly improved survival. However, the resulting Fontan physiology is associated with high morbidity. In this review, we discuss the state of the art of the Fontan strategy by assessing survival and risk factors for mortality. Complications of the Fontan circulation, such as cardiac arrhythmia, thromboembolism, and protein-losing enteropathy, are discussed. Common surgical and catheter-based interventions following Fontan completion are outlined. We describe functional status measurements such as quality of life and developmental outcomes in the contemporary Fontan patient. The current role of drug therapy in the Fontan patient is explored. Furthermore, we assess the current use and outcomes of mechanical circulatory support in the Fontan circulation and novel surgical innovations. Despite large improvements in outcomes for contemporary Fontan patients, a large burden of disease exists in this patient population. Continued efforts to improve outcomes are warranted. Several remaining challenges in the Fontan field are outlined. PMID- 30002820 TI - Alcohol-based surgical hand preparation: translating scientific evidence into clinical practice. AB - Background: Although alcohol-based surgical hand preparation offers potential advantages over the traditional surgical scrubbing technique, implementing it may be challenging due to resistance of surgeons in changing their practice. We aimed to implement alcohol-based surgical hand preparation in the hospital setting evaluating the impact of that on the quality and duration of the procedure, as well as on the prevention of surgical site infections. Methods: A quasi experimental study conducted at a tertiary-care university hospital from April 01 to November 01, 2017. Participants were cardiac and orthopedic surgical teams (n = 56) and patients operated by them (n = 231). Intervention consisted of making alcohol-based handrub available in the operating room, convincing and training surgical teams for using it, promoting direct observation of surgical hand preparation, and providing aggregated feedback on the quality of the preparation. The primary study outcome was the quality of the surgical hand preparation, inferred by the compliance with each one of the steps predicted in the World Health Organization (WHO) technique, evaluated through direct observation. Secondary study outcome was the patient's individual probability of developing surgical site infection in both study periods. We used the Wilcoxon for paired samples and McNemar's test to assess the primary study outcome and we build a logistic regression model to assess the secondary outcome. Results: We observed 534 surgical hand preparation events. Among 33 participants with full data available for both study periods, we observed full compliance with all the steps predicted in the WHO technique in 0.03% (1/33) of them in the pre-intervention period and in 36.36% (12/33) of them in the intervention period (OR:12.0, 95% CI: 2. 4-59.2, p = 0.002). Compared to the pre-intervention period, the intervention reduced the duration of the preparation (4.8 min vs 2.7 min, respectively; p < 0.001). The individual risk of developing a surgical site infection did not significantly change between the pre-intervention and the intervention phase (Adjusted RR = 0.66; 95% CI 0. 16-2.70, p = 0.563). Conclusion: Our results demonstrate that, when compared to the traditional surgical scrub, alcohol-based surgical hand preparation improves the quality and reduces the duration of the preparation, being at least equally effective for the prevention of surgical site infections. PMID- 30002821 TI - Variability in contact precautions to control the nosocomial spread of multi-drug resistant organisms in the endemic setting: a multinational cross-sectional survey. AB - Background: Definitions and practices regarding use of contact precautions and isolation to prevent the spread of gram-positive and gram-negative multidrug resistant organisms (MDRO) are not uniform. Methods: We conducted an on-site survey during the European Congress on Clinical Microbiology and Infectious Diseases 2014 to assess specific details on contact precaution and implementation barriers. Results: Attendants from 32 European (EU) and 24 non-EU countries participated (n = 213). In EU-respondents adherence to contact precautions and isolation was high for Methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacteriaceae, and MDR A. baumannii (84.7, 85.7, and 80%, respectively) whereas only 68% of EU-respondents considered any contact precaution measures for extended-spectrum-beta-lactamase (ESBL) producing non-E. coli. Between 30 and 45% of all EU and non-EU respondents did not require health care workers (HCW) to wear gowns and gloves at all times when entering the room of a patient in contact isolation. Between 10 and 20% of respondents did not consider any rooming specifications or isolation for gram-positive MDRO and up to 30% of respondents abstain from such interventions in gram-negative MDRO, especially non-E. coli ESBL. Understaffing and lack of sufficient isolation rooms were the most commonly encountered barriers amongst EU and non-EU respondents. Conclusion: The effectiveness of contact precautions and isolation is difficult to assess due to great variation in components of the specific measures and mixed levels of implementation. The lack of uniform positive effects of contact isolation to prevent transmission may be explained by the variability of interpretation of this term. Indications for contact isolation require a global definition and further sound studies. PMID- 30002822 TI - Over-diagnosis for preoperative T staging of colorectal cancer - A case series. AB - Introduction: Recent progressive imaging technology such as multiplanar reconstruction on computed tomography (CT) and colonoscopy has made preoperative T staging of colorectal cancer (CRC) more accurate. Nevertheless, it is still difficult to make a correct diagnosis in some cases. The aim of this case study was to investigate the accuracy of T staging diagnosis in patients with CRC who underwent curative operations and to identify the causes of preoperative over diagnosis. Method: Medical charts of 1013 colorectal cancer patients who underwent a curative operation in the University of Tokyo Hospital between January 2011 and December 2016 were analyzed retrospectively. We defined a two level or more difference between clinical and pathological T stages as over diagnosis or under-diagnosis. Results: Nine patients were over-diagnosed in T stage preoperatively. The rate of over-diagnosis was 0.9%. At least three main factors for over-diagnosis were identified: close-to-circumferential or obstructive lesion; a rough appearance in the adipose tissues around the tumor on CT; and a tumor with a depressed structure. Conclusions: Clinical T stage is overestimated with a marked difference from pathological T stage in approximately 1% of CRC patients. Further progress in diagnostic modalities is required for more accurate staging. PMID- 30002823 TI - Vanek's tumor as an unusual cause of ileo-ileal intessuception - A unique case report. AB - Background and aim: Vanek's tumor is a rare solitary lesion that is non neoplastic, and arises from the submucosa of the gut. The most commonly affected sites are the stomach and the ileum [1]. IFP causing intestinal obstruction is uncommon and that ileo-ileal intussusception has been reported in the literature rarely. We present a case of an ileo-ileal intessuception in a patient who presented with acute on chronic pain abdomen and anorexia. CT abdomen & pelvis revealed a 46 * 36 mm intraluminal mass in the left iliac fossa causing ileo ileal intussusception. Case presentation: A 60 years old gentleman was brought to the A&E with a history of intestinal obstruction. He was examined and admitted to the surgical unit. CBC revealed unique feature of reactive thrombocytosis apart from a low hemoglobin and a raised TLC. His CT scan demonstrated findings of ileo ileal intussusception. After an informed written consent, patient underwent an exploratory laparotomy and had resection and anastomosis of the bowel. Histopathology of the specimen revealed findings compatible with IFP. Patient made an uneventful recovery post-operatively and was sent home in the next few days. On follow-up, the patient was doing well and had no complaints of abdominal pain or anorexia. Conclusion: Vanek's tumor although a rare entity, should be considered in each case of acute abdomen and physicians and surgeons need to have a high degree of suspicion in such cases. Moreover, IFP can cause reactive thrombocytosis that gets resolved after a post-operative period of 6-8 weeks. PMID- 30002824 TI - Asymmetric bilateral traumatic hip dislocation: A case report. AB - Introduction: Traumatic hip dislocation is a severe injury with the potential for significant morbidity and mortality. Bilateral hip dislocation is rare representing 1.25% of all hip dislocations. Presentation of the case: A 19-year old male had a high-speed motor vehicle accident. After stabilizing the patient, it was noticed that the position of the right lower limb was in adduction and internal rotation while the left was in external rotation and abduction. Pelvis x ray showed right superior posterior and left anterior inferior hip dislocations. Closed reduction was performed within 3 hours from the trauma for both sides. The post reduction CT scan showed adequate reduction of both hips with no associated fractures. During his three-year follow-up, he never had any complaints and the clinical examination and radiographs did not reveal any abnormalities. Discussion: Early reduction of hip dislocations minimizes the risk of osteonecrosis of the femoral head. The current recommendations state that a hip dislocation must be reduced within 6 hours. Conclusion: This is a rare case of bilateral asymmetric hip dislocations with no concomitant fractures. It is important to reduce hip dislocation within 6 hours from the time of injury to prevent osteonecrosis of the femoral head. PMID- 30002825 TI - Black soldier fly defatted meal as a dietary protein source for broiler chickens: Effects on growth performance, blood traits, gut morphology and histological features. AB - Background: The present study has evaluated the effects of different inclusion levels of a partially defatted black soldier fly (Hermetia illucens L.; HI) larva meal on the growth performance, blood parameters and gut morphology of broiler chickens. A total of 256 male broiler chickens (Ross 308) were reared from d 1 to d 35 and assigned to 4 dietary treatments (8 replicates/treatment and 8 birds/replicate). HI larva meal was included at increasing levels (0, 5%, 10% and 15%; HI0, HI5, HI10 and HI15, respectively) in isonitrogenous and isoenergetic diets formulated for 3 feeding phases: starter (1-10 d), growing (10-24 d) and finisher (24-35 d). Two birds per pen were slaughtered at d 35 and morphometric investigations and histopathological alterations were performed. Results: The live weight (LW) showed linear and quadratic responses to increasing HI larva meal (maximum for HI10 group). Average daily gain (ADG) showed a linear and quadratic responses to HI meal (maximum for HI10 group) during starter and growing periods. A linear decrease was observed for ADG during the finisher period. The daily feed intake (DFI) showed a linear and quadratic effect during the starter period (maximum for HI10 group). Linear and quadratic responses were observed for the feed conversion ratio (FCR) in the growing period and for the whole period of the experiment. The FCR showed a linear response in the finisher period (maximum for HI15). No significant effects were observed for the blood and serum parameters, except for the phosphorus concentration, which showed linear and quadratic responses as well as glutathione peroxidase (GPx) activity, the latter of which showed a linear response. The HI15 birds showed a lower villus height, a higher crypt depth and a lower villus height-to-crypt depth ratio than the other groups. Conclusions: Increasing levels of dietary HI meal inclusion in male broiler chickens may improve the LW and DFI during the starter period, but may also negatively affect the FCR and gut morphology, thus suggesting that low levels may be more suitable. However, no significant effects on the haematochemical parameters or histological findings were observed in relation to HI meal utilization. PMID- 30002827 TI - Migration as an adaptive response to ethnic nationalism in Russia. AB - In this paper, I argue that migration responses to push factors can differ along ethnic lines. To arrive at migration as an adaptive response in which minorities engage, two processes are necessary. First, an individual making the decision to migrate must interpret ethnic tensions as a threat to her life chances, and she must evaluate her future prospects in this ethnically charged framework. Second, the option of migration must be a viable one. That is, an individual must consider them self the plausible target of the threat of diminishing life chances, conclude that an adaptive response is required, and determine that the benefits of migrating outweigh the costs. In order to explain these processes, the relational theory of ethnic politics (Hale 2008) and demographic theories of migration are employed. To test this hypothesis, an event history model is estimated using regional, household, and individual-level data from Russian censuses and the Russia Longitudinal Monitoring Survey. The relationship between out-migration and regional nationalist vote share is examined as well as regional hate crimes. The findings suggest that political push factors affect minority groups differently from the ethnic majority, supporting the hypothesis that the success of ethno nationalist politics in a region signals vulnerability to ethnic minorities, influencing migration decisions. PMID- 30002826 TI - Inflammation-induced DNA methylation of DNA polymerase gamma alters the metabolic profile of colon tumors. AB - Background: Inflammation, metabolism, and epigenetic modulation are highly interconnected processes that can be altered during tumorigenesis. However, because of the complexity of these interactions, direct cause and effect during tumorigenesis have been difficult to prove. Previously, using a murine model of inflammation-induced colon tumorigenesis, we determined that the promoter of the catalytic subunit of DNA polymerase gamma (Polg) is DNA hypermethylated and silenced in inflammation-induced tumors, but not in non-inflammation-induced (mock) tumors, suggesting that inflammation can induce silencing of Polg through promoting DNA methylation during tumorigenesis. Polg is the only mitochondrial DNA polymerase and mutations in Polg cause mitochondrial diseases in humans. Because of the role of mitochondria in metabolism, we hypothesized that silencing of Polg in inflammation-induced tumors would result in these tumors having altered metabolism in comparison to mock tumors. Methods: Inflammation-induced and mock colon tumors and colon epithelium from a mouse model of inflammation induced colon tumorigenesis were assayed for alterations in Polg expression, mitochondria, and metabolism. Organoids derived from these tissues were used to study the direct effect of loss of Polg on mitochondria and metabolism. Results: We demonstrate that inflammation-induced tumors with reduced Polg expression have decreased mitochondrial DNA content and numbers of mitochondria compared to normal epithelium or mock tumors. Tumoroids derived from mock and inflammation induced tumors retained key characteristics of the original tumors. Inflammation induced tumoroids had increased glucose uptake and lactate secretion relative to mock tumoroids. shRNA-mediated knockdown of Polg in mock tumoroids reduced mtDNA content, increased glucose uptake and lactate secretion, and made the tumoroids more resistant to oxidative stress. Conclusions: These results suggest that inflammation-induced DNA methylation and silencing of Polg plays an important role in the tumorigenesis process by resulting in reduced mitochondria levels and altered metabolism. An enhanced understanding of how metabolism is altered in and drives inflammation-induced tumorigenesis will provide potential therapeutic targets. PMID- 30002828 TI - Endoplasmic reticulum and oxidative stress in immunopathology: understanding the crosstalk between cellular stress and inflammation. PMID- 30002830 TI - Domestic dilemma: when cultivated plants lose their wild side. PMID- 30002829 TI - Self-reported quantity, compulsiveness and motives of exercise in patients with eating disorders and healthy controls: differences and similarities. AB - Background: Compulsive exercise (CE) is a frequent symptom in patients with eating disorders (EDs). It includes, in addition to quantitatively excessive exercise behaviour, a driven aspect and specific motives of exercise. CE is generally associated with worse therapy outcomes. The aims of the study were to compare self-reported quantity of exercise, compulsiveness of exercise as well as motives for exercise between patients with anorexia nervosa (AN), bulimia nervosa (BN) and healthy controls (HC). Additionally, we wanted to explore predictors of compulsive exercise (CE) in each group. Methods: We investigated 335 female participants (n = 226 inpatients, n = 109 HC) and assessed self-reported quantity of exercise, compulsiveness of exercise (Compulsive Exercise Test), motives for exercise (Exercise Motivations Inventory-2), ED symptoms (Eating Disorder Inventory-2), obsessive-compulsiveness (Obsessive-Compulsive Inventory-Revised), general psychopathology (Brief Symptom Inventory-18) and depression (Beck Depression Inventory-2). Results: Both patients with AN and BN exercised significantly more hours per week and showed significantly higher CE than HC; no differences were found between patients with AN and BN. Patients with EDs and HC also partly varied in motives for exercise. Specific motives were enjoyment, challenge, recognition and weight management in patients with EDs in contrast to ill-health avoidance and affiliation in HC. Patients with AN and BN only differed in regard to exercise for appearance reasons in which patients with BN scored higher. The most relevant predictor of CE across groups was exercise for weight and shape reasons. Conclusions: Exercise behaviours and motives differ between patients with EDs and HC. CE was pronounced in both patients with AN and BN. Therefore, future research should focus not only on CE in patients with AN, but also on CE in patients with BN. Similarities in CE in patients with AN and BN support a transdiagnostic approach during the development of interventions specifically targeting CE in patients with EDs. PMID- 30002831 TI - Testicular microlithiasis and testicular tumor: a review of the literature. AB - Introduction: There are numerous scientific publications on testicular microlithiasis (TML) detected during ultrasound (US) examination. We wished to update the data. Methods: PubMed was used to identify original articles published between 1998 and May 2017 describing the association between TML and testicular tumor. Studies were only included if TML was diagnosed by US. Studies were then classified into subgroups according to the following criteria: asymptomatic, symptomatic, infertility, cryptorchidism, family or personal history of testicular cancer, and "no given reason for US". A Z-Test was used to identify differences within these subgroups. In addition, we identified prospective cohorts of TML patients. Numbers, duration of follow-up, and occurrence of the "testicular tumor" event were recorded for each of them. Results: One hundred and seventy-five articles were identified, 40 of which were included. Our review has not showed a clear evidence that cryptorchidism associated with TML is a risk factor for testicular tumor. However, there seems to be a correlation between infertility associated with TML and a higher tumor risk. There were not enough studies to confirm a relationship between family or personal history associated with TML and the tumor risk. There was also a correlation with a higher tumor risk for symptomatic associated with TML and "no given reason for US" plus TML groups. However, these groups are assumed to contain bias and caution must be taken regarding conclusions. Regarding the prospective cohort studies, 16 testicular tumors appeared in the follow-up of patients with TML, 13 patients had risk factors. Conclusion: In cases of TML incidental finding by US with the presence of risk factors (personal history of testicular cancer, testicular atrophy, infertility, cryptorchidism) a consultation with a specialist should be considered. In the absence of risk factors, the occurrence of testicular cancer in patients with TML is similar to the risk of the general population. PMID- 30002832 TI - Effectiveness of step-down versus outpatient dialectical behaviour therapy for patients with severe levels of borderline personality disorder: a pragmatic randomized controlled trial. AB - Background: Step-down dialectical behaviour therapy (DBT) is a treatment consisting of 3 months of residential DBT plus 6 months of outpatient DBT. The program was specifically developed for people suffering from severe borderline personality disorder (BPD). The present study examines the effectiveness and cost effectiveness of step-down DBT compared to 12 months of regular, outpatient DBT. Methods: Eighty-four participants reporting high levels of BPD-symptoms (mean age 26 years, 95% female) were randomly assigned to step-down versus standard DBT. Measurements were conducted at baseline and after 3, 6, 9 and 12 months. The Lifetime Parasuicide Count and BPD Severity Index (BPDSI) were used to assess suicidal behaviour, non-suicidal self-injury (NSSI) and borderline severity. Costs per Quality Adjusted Life Year (QALY) were calculated using data from the EQ-5D-3L and the Treatment Inventory Cost in Psychiatric Patients (TIC-P). Results: In step-down DBT, 95% of patients started the program, compared to 45% of patients in outpatient DBT. The probability of suicidal behaviour did not change significantly over 12 months. The probability of NSSI decreased significantly in step-down DBT, but not in outpatient DBT. BPDSI decreased significantly in both groups, with the improvement leveling off at the end of treatment. While step-down DBT was more effective in increasing quality of life, it also cost significantly more. The extra costs per gained QALY exceeded the ?80,000 threshold that is considered acceptable for severely ill patients in the Netherlands. Conclusions: A pragmatic randomized controlled trial in the Netherlands showed that 9 months of step-down DBT is an effective treatment for people suffering from severe levels of BPD. However, step-down DBT is not more effective than 12 months of outpatient DBT, nor is it more cost-effective. These findings should be considered tentative because of high noncompliance with the treatment assignment in outpatient DBT. Furthermore, the long-term effectiveness of step-down DBT, and moderators of treatment response, remain to be evaluated. Trial registration: www.clinicaltrials.govNCT01904227. Registered 22 July 2013 (retrospectively registered). PMID- 30002833 TI - Serial change of C1 inhibitor in patients with sepsis: a prospective observational study. AB - Background: C1 inhibitor (C1-INH), which belongs to the superfamily of serine protease inhibitors, regulates the complement system and also the plasma kallikrein-kinin, fibrinolytic, and coagulation systems. The biologic activities of C1-INH can be divided into the regulation of vascular permeability and anti inflammatory functions. The objective of this study was to clarify the serial change of C1-INH in patients with sepsis and evaluate the relationship with the shock severity. Methods: This was a single-center, prospective, observational study. We serially examined C1-INH activity values (normal range 70-130%) in patients with sepsis admitted into the intensive care unit of the Trauma and Acute Critical Care Center at Osaka University Hospital (Osaka, Japan) during the period between January 2014 and August 2015. We defined "refractory shock" as septic shock unresponsive to conventional therapy such as adequate fluid resuscitation and vasopressor therapy to maintain hemodynamics. Results: Serial changes of C1-INH were evaluated in 40 patients with sepsis (30 men, 10 women; 30 survivors, 10 non-survivors; mean age, 70 +/- 13.5 years). We divided the patients into three groups: non-shock group (n = 14), non-refractory shock group (n = 13), and refractory shock group (n = 13: 3 survivors, 10 non-survivors). In the non-shock group, C1-INH was 107.3 +/- 26.5% on admission and 104.2 +/- 22.3% on day 1, and it increased thereafter to 128.1 +/- 26.4% on day 3, 138.3 +/- 21.2% on day 7, and 140.3 +/- 12.5% on day 14 (p < 0.0001). In the non-refractory shock group, C1-INH was 113.9 +/- 19.2% on admission, 120.2 +/- 23.0% on day 1, 135.7 +/- 19.9% on day 3, 138.8 +/- 17.2% on day 7, and 137.7 +/- 10.7% on day 14 (p < 0.0001). In the refractory shock group, C1-INH was 96.7 +/- 15.9% on admission, 88.9 +/- 22.3% on day 1, 119.8 +/- 39.6% on day 3, 144.4 +/- 21.1% on day 7, and 140.5 +/- 24.5% on day 14 (p < 0.0001). The difference between these three groups was statistically significant (p < 0.0001). C1-INH in non-survivors did not increase significantly during their clinical course (p = 0.0690). Conclusions: In refractory shock patients with sepsis, the values of C1-INH activity were lower (especially in non-survivors) on admission and day 1 as compared with non-shock and non-refractory shock patients. PMID- 30002834 TI - An unusual cause of adrenal insufficiency and bilateral adrenal masses. AB - : Primary adrenal insufficiency secondary to syphilis is extremely rare, with only five cases being reported in the literature. We report a case of adrenal insufficiency as a manifestation of Treponema pallidum infection (tertiary syphilis). A 69-year-old, previously fit and well Caucasian male was found to have adrenal insufficiency after being admitted with weight loss, anorexia and postural dizziness resulting in a fall. Biochemical testing showed hyponatraemia, hyperkalaemia, and an inadequate response to Synacthen testing, with a peak cortisol level of 302 nmol/L after administration of 250 ug Synacthen. Abdominal imaging revealed bilateral adrenal hyperplasia with inguinal and retroperitoneal lymphadenopathy. He was started on hydrocortisone replacement; however, it was not until he re-attended ophthalmology with a red eye and visual loss 1 month later, that further work-up revealed the diagnosis of tertiary syphilis. Following a course of penicillin, repeat imaging 5 months later showed resolution of the abnormal radiological appearances. However, adrenal function has not recovered and 3 years following initial presentation, the patient remains on both glucocorticoid and mineralocorticoid replacement. In conclusion, this case highlights the importance of considering syphilis as a potential differential diagnosis in patients presenting with adrenal insufficiency and bilateral adrenal masses, given the recent re-emergence of this condition. The relative ease of treating infectious causes of adrenal lesions makes accurate and timely diagnosis crucial. Learning points: Infectious causes, including syphilis, should be excluded before considering adrenalectomy or biopsy for any patient presenting with an adrenal mass.It is important to perform a full infection screen including tests for human immunodeficiency virus, other blood-borne viruses and concurrent sexually transmitted diseases in patients presenting with bilateral adrenal hyperplasia with primary adrenal insufficiency.Awareness of syphilis as a potential differential diagnosis is important, as it not only has a wide range of clinical presentations, but its prevalence has been increasing in recent times. PMID- 30002835 TI - Macroprolactinoma causing VI, X, XII cranial nerve palsies nearly 30 years after initial treatment. AB - : A 48-year-old man was diagnosed with a large macroprolactinoma in 1982 treated with surgery, adjuvant radiotherapy and bromocriptine. Normal prolactin was achieved in 2005 but in 2009 it started rising. Pituitary MRIs in 2009, 2012, 2014 and 2015 were reported as showing empty pituitary fossa. Prolactin continued to increase (despite increasing bromocriptine dose). Trialling cabergoline had no effect (prolactin 191,380 mU/L). In January 2016, he presented with right facial weakness and CT head was reported as showing no acute intracranial abnormality. In late 2016, he was referred to ENT with hoarse voice; left hypoglossal and recurrent laryngeal nerve palsies were found. At this point, prolactin was 534,176 mU/L. Just before further endocrine review, he had a fall and CT head showed a basal skull mass invading the left petrous temporal bone. Pituitary MRI revealed a large enhancing mass within the sella infiltrating the clivus, extending into the left petrous apex and occipital condyle with involvement of the left Meckel's cave, internal acoustic meatus, jugular foramen and hypoglossal canal. At that time, left abducens nerve palsy was also present. CT thorax/abdomen/pelvis excluded malignancy. Review of previous images suggested that this lesion had started becoming evident below the fossa in pituitary MRI of 2015. Temozolomide was initiated. After eight cycles, there is significant tumour reduction with prolactin 1565 mU/L and cranial nerve deficits have remained stable. Prolactinomas can manifest aggressive behaviour even decades after initial treatment highlighting the unpredictable clinical course they can demonstrate and the need for careful imaging review. Learning points: Aggressive behaviour of prolactinomas can manifest even decades after first treatment highlighting the unpredictable clinical course these tumours can demonstrate.Escape from control of hyperprolactinaemia in the absence of sellar adenomatous tissue requires careful and systematic search for the anatomical localisation of the lesion responsible for the prolactin excess.Temozolomide is a valuable agent in the therapeutic armamentarium for aggressive/invasive prolactinomas, particularly if they are not amenable to other treatment modalities. PMID- 30002836 TI - Hematological profile of pregnant women at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. AB - Background: In pregnancy, hematological changes occur in order to meet the demands of the developing fetus and placenta, with major alterations in blood volume. Abnormal hematological profile affects pregnancy and its outcome. This study aimed to assess hematological profiles of pregnant women at a tertiary care teaching hospital. Method: This cross sectional study was conducted among 284 consecutive pregnant women at St. Paul's Hospital Millennium Medical College. Socio-demographic characteristics were collected using pre-tested structured questionnaire. About 4 ml of venous blood was collected from each participant for hematological parameters analysis using Cell-Dyn1800 (Abbott Laboratories Diagnostics Division, USA) and peripheral blood film review. Result: There were differences in mean hematological parameters between trimesters: specifically differences in mean values of WBC (1stand 3rd), Hb(1stand2nd and 1st& 3rd), HCT (1stand2nd), RDW (1stand2nd and 1stand3rd), neutrophil and lymphocyte (1stand 2nd and 1stand3rd, for both) were statistically significant (p < 0.05). The prevalence rates of anemia and thrombocytopenia were 11.62 and 7.7%, respectively and were dominantly of mild type. On the bases of blood picture, we classified anemia's of pregnancy as microcytic hypochromic (51.5%), normocytic hypochromic (27.3%), normocytic normochromic (18.2%), and dimorphic (3%). Conclusion: Significant changes in selected hematological parameters between trimesters, and an anemia and thrombocytopenia of mild type were documented in this study. The commonest morphologic features were mostly characteristic features of iron deficiency anemia. These warrant the need for monitoring hematological parameters of pregnant women at any stage of the pregnancy to avoid adverse outcomes. PMID- 30002837 TI - Symmetry breaking by enzyme-catalyzed epoxide hydrolysis. AB - Janfalk Carlsson et al. [IUCrJ (2018), 5, 269-282] describe studies on factors determining selective ring opening of methylstyrene oxide stereoisomers by the epoxide hydrolase StEH1. The stereo-differentiating step is selective hydrolysis of an alkylated intermediate formed by reaction of the epoxide with an aspartyl residue. PMID- 30002838 TI - Identification of ions in experimental electrostatic potential maps. AB - Cryo-electron microscopy (cryo-EM) directly images the distribution of electrostatic potential (ESP) within macromolecules, and thus can provide much more information about atomic charge than X-ray crystallography. The electron scattering length of an isolated ion is quite different from that of the corresponding neutral atom. The difference is very large at small scattering angles where the effects of electron distributions are largest, but becomes smaller at high scattering angles where nuclear charge determines outcomes. For this reason, in cryo-EM maps that have been solved at resolutions lower than ~2.5 A, peaks corresponding to anions will always be less prominent than those of cations, and may even be negative. Furthermore, if a map of this kind is smeared computationally after the fact, which reduces its effective resolution, anion peaks will diminish in size, cation peaks will grow and peaks that represent uncharged atoms will remain about the same. These effects can be used to determine the sign of the charges carried by the ions associated with a macromolecule and even estimate their magnitudes. The ESP value for a cation in a cation-anion pair is smaller than the value of the cation in isolation, but the ESP value for the anion in the ionic pair is greater than the value of the anion in isolation. The experimental range of ESP values for Mg2+ relative to that of the closest C1' atom is found to be between 0.57 and 1.27. PMID- 30002839 TI - Using cryo-electron microscopy maps for X-ray structure determination. AB - X-ray crystallography and cryo-electron microscopy (cryo-EM) are complementary techniques for structure determination. Crystallography usually reveals more detailed information, while cryo-EM is an extremely useful technique for studying large-sized macromolecules. As the gap between the resolution of crystallography and cryo-EM data narrows, the cryo-EM map of a macromolecule could serve as an initial model to solve the phase problem of crystal diffraction for high resolution structure determination. FSEARCH is a procedure to utilize the low resolution molecular shape for crystallographic phasing. The IPCAS (Iterative Protein Crystal structure Automatic Solution) pipeline is an automatic direct methods-aided dual-space iterative phasing and model-building procedure. When only an electron-density map is available as the starting point, IPCAS is capable of generating a completed model from the phases of the input map automatically, without the requirement of an initial model. In this study, a hybrid method integrating X-ray crystallography with cryo-EM to help with structure determination is presented. With a cryo-EM map as the starting point, the workflow of the method involves three steps. (1) Cryo-EM map replacement: FSEARCH is utilized to find the correct translation and orientation of the cryo-EM map in the crystallographic unit cell and generates the initial low-resolution map. (2) Phase extension: the phases calculated from the correctly placed cryo-EM map are extended to high-resolution X-ray data by non-crystallographic symmetry averaging with phenix.resolve. (3) Model building: IPCAS is used to generate an initial model using the phase-extended map and perform model completion by iteration. Four cases (the lowest cryo-EM map resolution being 6.9 A) have been tested for the general applicability of the hybrid method, and almost complete models have been generated for all test cases with reasonable Rwork/Rfree. The hybrid method therefore provides an automated tool for X-ray structure determination using a cryo-EM map as the starting point. PMID- 30002840 TI - Dummy-atom modelling of stacked and helical nanostructures from solution scattering data. AB - The availability of dummy-atom modelling programs to determine the shape of monodisperse globular particles from small-angle solution scattering data has led to outstanding scientific advances. However, there is no equivalent procedure that allows modelling of stacked, seemingly endless structures, such as helical systems. This work presents a bead-modelling algorithm that reconstructs the structural motif of helical and rod-like systems. The algorithm is based on a 'projection scheme': by exploiting the recurrent nature of stacked systems, such as helices, the full structure is reduced to a single building-block motif. This building block is fitted by allowing random dummy-atom movements without an underlying grid. The proposed method is verified using a variety of analytical models, and examples are presented of successful shape reconstruction from experimental data sets. To make the algorithm available to the scientific community, it is implemented in a graphical computer program that encourages user interaction during the fitting process and also includes an option for shape reconstruction of globular particles. PMID- 30002841 TI - Direct shape determination of intermediates in evolving macromolecular solutions from small-angle scattering data. AB - Many important biological processes like amyloid formation, viral assembly etc. can be monitored in vitro. Small-angle X-ray scattering (SAXS) is one of the most effective techniques to structurally characterize these processes in solution. For monodisperse systems and some oligomeric mixtures, low-resolution shapes can be determined ab initio from the SAXS data, but for evolving systems, such analysis is hampered by the presence of multiple species and no direct reconstruction procedures are available. The authors consider a frequently occurring case where the scattering from the initial and final states of the process are known but there exists a major (unknown) intermediate component. A method is presented to directly reconstruct the low-resolution shape of this transient component together with its volume fractions from multiple scattering patterns recorded from an evolving system. The method is implemented in the computer program DAMMIX freely available to academic users and its effectiveness is illustrated in several synthetic and experimental examples. PMID- 30002842 TI - Model-free reconstruction of magnetic correlations in frustrated magnets. AB - Frustrated magnetic systems exhibit extraordinary physical properties, but quantification of their magnetic correlations poses a serious challenge to experiment and theory. Current insight into frustrated magnetic correlations relies on modelling techniques such as reverse Monte-Carlo methods, which require knowledge about the exact ordered atomic structure. Here, we present a method for direct reconstruction of magnetic correlations in frustrated magnets by three dimensional difference pair distribution function analysis of neutron total scattering data. The methodology is applied to the disordered frustrated magnet bixbyite, (Mn1-x Fe x )2O3, which reveals nearest-neighbor antiferromagnetic correlations for the metal sites up to a range of approximately 15 A. Importantly, this technique allows for magnetic correlations to be determined directly from the experimental data without any assumption about the atomic structure. PMID- 30002843 TI - Monoclinic distortion, polarization rotation and piezoelectricity in the ferroelectric Na0.5Bi0.5TiO3. AB - The relationship between crystal structure and physical properties in the ferroelectric Na0.5Bi0.5TiO3 (NBT) has been of interest for the last two decades. Originally, the average structure was held to be of rhombohedral (R3c) symmetry with a fixed polarization direction. This has undergone a series of revisions, however, based on high-resolution X-ray diffraction, total neutron scattering, and optical and electron microscopy. The recent experimental findings suggest that the true average symmetry is monoclinic (space group Cc), which allows for a rotatable spontaneous polarization. Neither polarization rotation nor its potentially important real role in enhanced piezoelectricity is well understood. The present work describes an in situ investigation of the average monoclinic distortion in NBT by time-resolved single-crystal X-ray diffraction under external electric fields. The study presents a high-resolution inspection of the characteristic diffraction features of the monoclinic distortion - splitting of specific Bragg reflections - and their changes under a cyclic electric field. The results favour a model in which there is direct coupling between the shear monoclinic strain and the polarization rotation. This suggests that the angle of polarization rotation under a sub-coercive electric field could be 30 degrees or more. PMID- 30002844 TI - Towards a practical implementation of X-ray ghost imaging with synchrotron light. AB - An experimental procedure for transmission X-ray ghost imaging using synchrotron light is presented. Hard X-rays from an undulator were divided by a beamsplitter to produce two copies of a speckled incident beam. Both beams were simultaneously measured on an indirect pixellated detector and the intensity correlation between the two copies was used to retrieve the ghost image of samples placed in one of the two beams, without measuring the samples directly. Aiming at future practical uses of X-ray ghost imaging, the authors discuss details regarding data acquisition, image reconstruction strategies and measure the point-spread function of the ghost-imaging system. This approach may become relevant for applications of ghost imaging with X-ray sources such as undulators in storage rings, free-electron lasers and lower-coherence laboratory facilities. PMID- 30002845 TI - Chlamydia protein Pgp3 studied at high resolution in a new crystal form. AB - The protein Pgp3 is implicated in the sexually transmitted disease chlamydia and comprises an extended complex arrangement of a C-terminal domain (CTD) and an N terminal domain (NTD) linked by a triple-helix coiled coil (THCC). Here, the X ray crystal structure of Pgp3 from an LGV1 strain is reported at the highest X ray diffraction resolution obtained to date for the full protein. The protein was crystallized using a high concentration of potassium bromide, which resulted in a new crystal form with relatively low solvent content that diffracted to a resolution of 1.98 A. The three-dimensional structure of this new crystal form is described and compared with those of other crystal forms, and the potassium bromide binding sites and the relevance to chlamydia isolates from around the globe are described. The crystal packing is apparently driven by the CTDs. Since the threefold axes of the THCC and NTD are not collinear with the threefold axis of a CTD, this naturally leads to disorder in the THCC and the portion of the NTD that does not directly interact with the CTD via crystal packing. The key avenue to resolving these oddities in the crystal structure analysis was a complete new analysis in space group P1 and determining the space group as P212121. This space group assignment was that originally determined from the diffraction pattern but was perhaps complicated by translational noncrystallographic symmetry. This crystal structure of a three-domain multi-macromolecular complex with two misaligned threefold axes was a unique challenge and has not been encountered before. It is suggested that a specific intermolecular interaction, possibly of functional significance in receptor binding in chlamydia, might allow the design of a new chemotherapeutic agent against chlamydia. PMID- 30002847 TI - Sr2Pt8-x As: a layered incommensurately modulated metal with saturated resistivity. AB - The high-pressure synthesis and incommensurately modulated structure are reported for the new compound Sr2Pt8-x As, with x = 0.715 (5). The structure consists of Sr2Pt3As layers alternating with Pt-only corrugated grids. Ab initio calculations predict a metallic character with a dominant role of the Pt d electrons. The electrical resistivity (rho) and Seebeck coefficient confirm the metallic character, but surprisingly, rho showed a near-flat temperature dependence. This observation fits the description of the Mooij correlation for electrical resistivity in disordered metals, originally developed for statistically distributed point defects. The discussed material has a long-range crystallographic order, but the high concentration of Pt vacancies, incommensurately ordered, strongly influences the electronic conduction properties. This result extends the range of validity of the Mooij correlation to long-range ordered incommensurately modulated vacancies. Motivated by the layered structure, the resistivity anisotropy was measured in a focused-ion-beam micro fabricated well oriented single crystal. A low resistivity anisotropy indicates that the layers are electrically coupled and conduction channels along different directions are intermixed. PMID- 30002846 TI - Protonated nucleobases are not fully ionized in their chloride salt crystals and form metastable base pairs further stabilized by the surrounding anions. AB - This paper presents experimental charge-density studies of cytosinium chloride, adeninium chloride hemihydrate and guaninium dichloride crystals based on ultra high-resolution X-ray diffraction data and extensive theoretical calculations. The results confirm that the cohesive energies of the studied systems are dominated by contributions from intermolecular electrostatic interactions, as expected for ionic crystals. Electrostatic interaction energies (Ees) usually constitute 95% of the total interaction energy. The Ees energies in this study were several times larger in absolute value when compared, for example, with dimers of neutral nucleobases. However, they were not as large as some theoretical calculations have predicted. This was because the molecules appeared not to be fully ionized in the studied crystals. Apart from charge transfer from chlorine to the protonated nucleobases, small but visible charge redistribution within the nucleobase cations was observed. Some dimers of singly protonated bases in the studied crystals, namely a cytosinium-cytosinium trans sugar/sugar edge pair and an adeninium-adeninium trans Hoogsteen/Hoogsteen edge pair, exhibited attractive interactions (negative values of Ees) or unusually low repulsion despite identical molecular charges. The pairs are metastable as a result of strong hydrogen bonding between bases which overcompensates the overall cation-cation repulsion, the latter being weakened due to charge transfer and molecular charge-density polarization. PMID- 30002848 TI - Structural characterization of free-state and product-state Mycobacterium tuberculosis methionyl-tRNA synthetase reveals an induced-fit ligand-recognition mechanism. AB - Mycobacterium tuberculosis (MTB) caused 10.4 million cases of tuberculosis and 1.7 million deaths in 2016. The incidence of multidrug-resistant and extensively drug-resistant MTB is becoming an increasing threat to public health and the development of novel anti-MTB drugs is urgently needed. Methionyl-tRNA synthetase (MetRS) is considered to be a valuable drug target. However, structural characterization of M. tuberculosis MetRS (MtMetRS) was lacking for decades, thus hampering drug design. Here, two high-resolution crystal structures of MtMetRS are reported: the free-state structure (apo form; 1.9 A resolution) and a structure with the intermediate product methionyl-adenylate (Met-AMP) bound (2.4 A resolution). It was found that free-state MtMetRS adopts a previously unseen conformation that has never been observed in other MetRS homologues. The pockets for methionine and AMP are not formed in free-state MtMetRS, suggesting that it is in a nonproductive conformation. Combining these findings suggests that MtMetRS employs an induced-fit mechanism in ligand binding. By comparison with the structure of human cytosolic MetRS, additional pockets specific to MtMetRS that could be used for anti-MTB drug design were located. PMID- 30002849 TI - Structural flexibility of halogen bonds showed in a single-crystal-to-single crystal [2+2] photodimerization. AB - Halogen bonds have emerged as noncovalent forces that govern the assembly of molecules in organic solids with a degree of reliability akin to hydrogen bonds. Although the structure-directing roles of halogen bonds are often compared to hydrogen bonds, general knowledge concerning the fundamental structural behavior of halogen bonds has had limited opportunity to develop. Following an investigation of solid-state reactions involving organic syntheses and the development of photoresponsive materials, this work demonstrates the ability of the components of intermolecular N?I halogen bonding - a 'workhorse' interaction for the crystal engineer - to support a single-crystal-to-single-crystal [2+2] photodimerization. A comparison is provided of the geometric changes experienced by the halogen-bonded components in the single-crystal reaction to the current crystal landscape of N?I halogen bonds, as derived from the Cambridge Structural Database. Specifically, a linear-to-bent type of deformation of the halogen bonded components was observed, which is expected to support the development of functional halogen-bonded materials containing molecules that can undergo movements in close-packed crystal environments. PMID- 30002850 TI - Exploiting superspace to clarify vacancy and Al/Si ordering in mullite. AB - Synchrotron single-crystal X-ray diffraction has revealed diffuse scattering alongside sharp satellite reflections for different samples of mullite (Al4+2x Si2-2x O10-x ). Structural models have been developed in (3+1)-dimensional superspace that account for vacancy ordering and Al/Si ordering based on harmonic modulation functions. A constraint scheme is presented which explains the crystal chemical relationships between the split sites of the average structure. The modulation amplitudes of the refinements differ significantly by a factor of ~3, which is explained in terms of different degrees of ordering, i.e. vacancies follow the same ordering principle in all samples but to different extents. A new approach is applied for the first time to determine Al/Si ordering by combining density functional theory with the modulated volumes of the tetrahedra. The presence of Si-Si diclusters indicates that the mineral classification of mullite needs to be reviewed. A description of the crystal structure of mullite must consider both the chemical composition and the degree of ordering. This is of particular importance for applications such as advanced ceramics, because the physical properties depend on the intrinsic structure of mullite. PMID- 30002851 TI - Identification of a tyrosine switch in copper-haem nitrite reductases. AB - There are few cases where tyrosine has been shown to be involved in catalysis or the control of catalysis despite its ability to carry out chemistry at much higher potentials (1 V versus NHE). Here, it is shown that a tyrosine that blocks the hydrophobic substrate-entry channel in copper-haem nitrite reductases can be activated like a switch by the treatment of crystals of Ralstonia pickettii nitrite reductase (RpNiR) with nitric oxide (NO) (-0.8 +/- 0.2 V). Treatment with NO results in an opening of the channel originating from the rotation of Tyr323 away from AspCAT97. Remarkably, the structure of a catalytic copper-deficient enzyme also shows Tyr323 in the closed position despite the absence of type 2 copper (T2Cu), clearly demonstrating that the status of Tyr323 is not controlled by T2Cu or its redox chemistry. It is also shown that the activation by NO is not through binding to haem. It is proposed that activation of the Tyr323 switch is controlled by NO through proton abstraction from tyrosine and the formation of HNO. The insight gained here for the use of tyrosine as a switch in catalysis has wider implications for catalysis in biology. PMID- 30002852 TI - Comment on the article 'Protein crystal lattices are dynamic assemblies: the role of conformational entropy in the protein condensed phase'. AB - A comment is given on Dimova & Devedjiev [IUCrJ (2018), 5, 130-140]. PMID- 30002853 TI - Erratum: Grazing-incidence small-angle X-ray scattering (GISAXS) on small periodic targets using large beams. Erratum. AB - [This corrects the article DOI: 10.1107/S2052252517006297.]. PMID- 30002854 TI - Article 2: Longitudinal study assessing the one-year effects of supervision performance assessment and recognition strategy (SPARS) to improve medicines management in Uganda health facilities. AB - Background: In late 2010, Uganda introduced a supervision, performance assessment, and recognition strategy (SPARS) to improve staff capacity in medicines management in government and private not-for-profit health facilities. This paper assesses the impact of SPARS in health facilities during their first year of supervision. Methods: SPARS uses health workers trained as Medicines Management Supervisors (MMS) to supervise health facilities and address issues identified through indicatorbased performance assessment in five domains: stock management, storage management, ordering and reporting, prescribing quality, and dispensing quality. We used routine data generated during SPARS visits to 1222 health facilities to evaluate performance changes during the first year of supervision as well as the time until achieving an adequate score in this period. We also explored variables related to facilities, MMS, and intensity of implementation as predictors of performance improvement and time until achieving an adequate score. Results: Health facilities received an average of 3.4 MMS visits during the first year of supervision, with an average of 88 days between visits; each MMS implemented a median of 28 visits per year. Overall SPARS scores (maximum of 25) improved by 2.3 points (22.3%) per visit from a mean baseline score of 10.3. The adjusted improvement in overall SPARS score was significantly higher in primary health care facilities (2.36) versus higher-level health facilities and hospitals (2.15) (p = 0.001). The incremental improvement was highest at visit 2, with decreasing but continuing positive gains in subsequent visits. The adjusted mean incremental improvement per visit was highest in the prescribing quality domain, followed by dispensing quality, ordering and reporting, stock management, and storage management. Adjusted improvement in SPARS scores varied by region, year of implementation, and facility ownership. After one year of SPARS, 22% of facilities achieved an adequate score of 18.75 (75% of maximum score). Conclusions: SPARS was effective in building health facility capacity in medicines management, with a median overall improvement of almost 70% during the first year. The greatest improvements occurred in prescribing quality and at lower levels of care, although the highest level of performance was achieved in storage management. We recommend broad dissemination of the SPARS approach in all Ugandan health facilities as well as in other countries seeking a practical strategy to improve medicines management performance. PMID- 30002855 TI - Association between cadmium and anti-Mullerian hormone in premenopausal women at particular ages. AB - Background: Anti-Mullerian hormone (AMH) in women is secreted by granulosa cells of antral follicles. AMH appears to be a very stable marker for ovarian function. It may be used to diagnosis cases of premature ovarian failure, polycystic ovary syndrome (PCOS), and ovarian tumors. It has been suggested that cadmium exposure can reduce female fecundity. The purpose of this study was to investigate whether environmental exposure to cadmium was associated with alterations in AMH with regards to age. Methods: In a cross-sectional study, the data of premenopausal women living in Seoul, ranging from 30 to 45 of age was collected. The study included a total of 283 women who completed serum AMH and whole blood cadmium assessments. Linear regression analyses were used in order to examine the association between cadmium and AMH. Given that age was the strongest confounder in both cadmium and AMH concentrations, we stratified subjects by 5 years old and analyzed their data. Results: Geometric mean concentrations of blood cadmium and AMH were 0.97 MUg/L and 3.02 ng/ml, respectively. Total association between cadmium and AMH was statistically significant (adjusted coefficient = - 0.34 (0.15), p = 0.02). After stratification, the only age group with a negative association between cadmium and AMH were the women raging between 30 and 35 years (adjusted coefficient = - 0.43 (0.18), p = 0.01). Conclusions: The results of this study suggest that environmental exposure to cadmium may alter the AMH level of premenopausal women, depending on their age group. PMID- 30002856 TI - Adverse effect of long work hours on incident diabetes in 7065 Ontario workers followed for 12 years. AB - Objective: According to the International Diabetes Federation, the most important challenge for prevention is now to identify social and environmental modifiable risk factors of diabetes. In this regard, long work hours have recently been linked with diabetes, but more high-quality prospective studies are needed. We evaluated the relationship between long work hours and the incidence of diabetes among 7065 workers over a 12-year period in Ontario, Canada. Research design and methods: Data from Ontario respondents (35-74 years of age) to the 2003 Canadian Community Health Survey were prospectively linked to the Ontario Health Insurance Plan database for physician services and the Canadian Institute for Health Information Discharge Abstract Database for hospital admissions. Our sample consisted of actively employed participants with no previous diagnoses of diabetes. Cox proportional hazard regression models were then performed to evaluate the relationship between long work hours (>=45 hours per week) and the incidence of diabetes. Results: Long work hours did not increase the risk of developing diabetes among men. However, among women, those usually working 45 hours or more per week had a significantly higher risk of diabetes than women working between 35 and 40 hours per week (HR: 1.63 (95% CI 1.04 to 2.57)). The effect was slightly attenuated when adjusted for the potentially mediating factors which are smoking, leisure time physical activity, alcohol consumption and body mass index. Conclusion: Working 45 hours or more per week was associated with an increased incidence of diabetes among women, but not men. Identifying modifiable risk factors such as long work hours is of major importance to improve prevention strategies and orient policy making. PMID- 30002857 TI - Increased risk of hospital-acquired foot ulcers in people with diabetes: large prospective study and implications for practice. AB - Aims: Diabetes increases the risk of costly and potentially preventable hospital acquired pressure ulceration. Given that peripheral arterial disease and neuropathy, important risk factors for foot ulceration, are more common in people with diabetes, their risk of hospital-acquired foot ulceration (HAFU) in particular may be even greater. This study aims to determine this risk. Methods: Using data collected over 2 years from all admissions to the Ipswich Hospital NHS Trust, we conducted a prospective multilevel regression analysis of the risk of HAFU in 5043 admissions of people with diabetes versus 23 599 without diabetes. Patients over 50 years who developed HAFU at least 48 hours after admission were included in analyses. Progressive adjustment for important risk factors and subgroup analyses were conducted to compare patients with and without diabetes. Results: There were significant differences between patients with and without diabetes among a range of covariates including sex, Comorbidity Score, and length of stay (p value <0.001). After progressive adjustment for age, sex, and other risk factors, there persisted a significant increase risk of HAFU in people with diabetes (OR 2.24; 95% CI 1.80 to 2.69). There were no substantial differences between clinically relevant subgroups. Conclusions: These analyses demonstrate at least a twofold increase in the risk of HAFU in patients with diabetes and suggest further work should focus on specific processes to detect those inpatients with diabetes at increased risk, in whom preventative measures may reduce the prevalence of this costly complication. PMID- 30002859 TI - Correction: Physicians' real-world experience with IDegLira: results of a European survey. AB - [This corrects the article DOI: 10.1136/bmjdrc-2018-000531.]. PMID- 30002858 TI - Derivation and external validation of a clinical version of the German Diabetes Risk Score (GDRS) including measures of HbA1c. AB - Objective: The German Diabetes Risk Score (GDRS) is a diabetes prediction model which only includes non-invasively measured risk factors. The aim of this study was to extend the original GDRS by hemoglobin A1c (HbA1c) and validate this clinical GDRS in the nationwide German National Health Interview and Examination Survey 1998 (GNHIES98) cohort. Research design and methods: Extension of the GDRS was based on the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study with baseline assessment conducted between 1994 and 1998 (N=27 548, main age range 35-65 years). Cox regression was applied with the original GDRS and HbA1c as independent variables. The extended model was evaluated by discrimination (C-index (95% CI)), calibration (calibration plots and expected to observed (E:O) ratios (95% CI)), and reclassification (net reclassification improvement, NRI (95% CI)). For validation, data from the GNHIES98 cohort with baseline assessment conducted between 1997 and 1999 were used (N=3717, age range 18-79 years). Missing data were handled with multiple imputation. Results: After 5 years of follow-up 593 incident cases of type 2 diabetes occurred in EPIC-Potsdam and 86 in the GNHIES98 cohort. In EPIC-Potsdam, the C-index for the clinical GDRS was 0.87 (0.81 to 0.92) and the overall NRI was 0.26 (0.21 to 0.30), with a stronger improvement among cases compared with non cases (NRIcases: 0.24 (0.19 to 0.28); NRInon-cases: 0.02 (0.01 to 0.02)). Almost perfect calibration was observed with a slight tendency toward overestimation, which was also reflected by an E:O ratio of 1.07 (0.99 to 1.16). In the GNHIES98 cohort, discrimination was excellent with a C-index of 0.91 (0.88 to 0.94). After recalibration, the calibration plot showed underestimation of diabetes risk in the highest risk group, while the E:O ratio indicated overall perfect calibration (1.02 (0.83 to 1.26)). Conclusions: The clinical GDRS provides the opportunity to apply the original GDRS as a first step in risk assessment, which can then be extended in clinical practice with HbA1c whenever it was measured. PMID- 30002860 TI - Prevalence and associated factors of overweight/ obesity among children and adolescents in Ethiopia: a systematic review and meta-analysis. AB - Background: Overweight and obesity can be defined as excessive and abnormal fat depositions in our body. They have become one of the emerging and serious public health concerns of the twenty-first century in low income countries like Ethiopia. Hence, the aim of this study was to determine the pooled prevalence and review associated risk factors of overweight/obesity among children and adolescents in Ethiopia. Method: The articles were identified through explicit and reproducible electronic search of reputable databases (PubMed, Google scholar, Science Direct, EMBASE, Cochrane library), and the hand search of reference lists of previous prevalence studies to retrieve more related articles. The 18 studies were selected based on a comprehensive list of inclusion and exclusion criteria. Data were extracted using a standardized and pre-tested data extraction checklist, and the analysis was done using STATA 14 statistical software. To assess heterogeneity, the Cochrane Q test statistic and I2 tests were used. Since the included studies exhibited considerable heterogeneity, a random effect model was used to estimate the pooled prevalence of overweight/obesity. Moreover, the risk factors of overweight/obesity were reviewed. Results: The combined pooled prevalence of overweight and obesity among children and adolescents in Ethiopia was 11.30% (95% CI: 8.71, 13.88%). Also, the separate pooled prevalence of overweight and obesity were 8.92 and 2.39%, respectively. Subgroup analysis revealed that the highest overweight/obesity prevalence among children and adolescents was observed in Addis Ababa, 11.94 (95% CI: 9.39, 14.50). Female gender of the children: 3.23 (95% CI 2.03,5.13), high family socioeconomic status: 3.16 (95% CI 1.87,5.34), learning in private school: 3.22 (95% CI 2.36,4.40), physical inactivity: 3.36 (95% CI 1.68,6.72), sweet nutriments preference: 2.78 (95% CI 1.97,3.93) and less use of fruits/vegetables: 1.39 (95% CI 1.10,1.75) have shown a positive association with the development of overweight/obesity among children and adolescents. Conclusion: The pooled prevalence of overweight/obesity among children and adolescents in Ethiopia is substantially high, and has become an emerging nutrition linked problem. Female gender, high family socioeconomic status, learning in private school, physical inactivity, sweet nutriments preference and less use of fruits/vegetables were found to be significantly associated with overweight/obesity. PMID- 30002861 TI - Onconeural antigen spreading in paraneoplastic neurological disease due to small cell lung cancer. AB - Cellular and humoral immunity towards distinct onconeural antigens is the hallmark of paraneoplastic neurological diseases (PNDs). Stable formation of immunoglobulin (Ig) G antibodies to particular onconeural antigens occurs in the majority of cases, whereas persistent coexistence of antibodies specific for multiple onconeural antigens is a relatively rare phenomenon of certain malignant tumors like small cell lung cancer (SCLC). We here describe onconeural antigen spreading in a 70-year-old Caucasian male with PND due to SCLC. Onconeural antigen spreading may be promoted by two mutually non-exclusive mechanisms: (i) a switch of antigen expression pattern of the underlying tumor tissue as a result of a mutagenic process caused by the cancer itself and (ii) a self-propagated paraneoplastic immune response with persistent neuronal destruction, liberation, processing and presentation of intracellular neural antigens. This illustrates a potential dissociation between peripheral anti-tumoral immunity and central anti neural immunity during the course of PND. PMID- 30002862 TI - Novel variants in COL4A4 and COL4A5 are rare causes of FSGS in two unrelated families. AB - We report two female patients with focal segmental glomerulosclerosis and chronic kidney disease. The first patient was found to have a heterozygous, de novo, pathogenic variant in COL4A5 (c.141+1G>A, IVS2+1G>A), which is associated with Alport syndrome. The second patient was found to have a heterozygous, likely pathogenic variant in COL4A4 (c.2842G>T). Both these variants in COL4A5 and COL4A4 are novel, and they were detected using whole exome sequencing and gene panel testing, respectively. Additionally, we discuss the complexities of diagnosis in such cases and the benefits of using the abovementioned diagnostic approaches. PMID- 30002863 TI - Real-world effectiveness of sofosbuvir plus ribavirin for chronic hepatitis C genotype 2 in Asia: a systematic review and meta-analysis. AB - Background: Sofosbuvir plus ribavirin (SOF+RBV) for 12 weeks is the standard treatment for chronic hepatitis C (CHC) genotype 2 (GT2) in most of Asia despite availability of new CHC medications. SOF-RBV real-world effectiveness has only been reported in small and/or single-centre studies. Our goal was to determine the real-world effectiveness of 12-week SOF+RBV therapy for CHC GT2 in Asia. Methods: A systematic search on PubMed and Embase was conducted through 30 June 2017. We identified full articles and conference proceedings of at least 10 adult patients with CHC GT2 treated with SOF+RBV for 12 weeks under real-world setting in Asia. Results: A total of 2208 patients from 13 studies were included. The pooled sustained virological response 12 weeks after the end of treatment (SVR12) was 95.8% (95% CI 94.6% to 96.9%) with non-significant heterogeneity (I2=34.4%). Anaemia (27.9%) was the most common adverse event (AE), with serious AEs in 2.0% and only 0.7% discontinued therapy prematurely. In subgroup analyses, patients with cirrhosis had 8.7% lower SVR12 than non-cirrhotic patients (P<0.0001), and treatment-experienced patients had 7.2% lower SVR12 than treatment-naive patients (P=0.0002). Cirrhotic treatment-experienced patients had the lowest SVR12 at 84.5%. There were no significant differences in pooled SVR12 among patient subgroups: RBV dose reduction versus no dose reduction (P=0.30); hepatocellular carcinoma (HCC) versus no HCC (P=0.10); GT 2a versus 2b (P=0.86); and <65 vs >=65 years of age (P=0.20). Conclusions: SOF+RBV for 12 weeks was safe and effective for patients with CHC GT2 in Asia, although those with cirrhosis and prior treatment failure had a lower pooled SVR12 rate. Trial registration number: CRD42017067928. PMID- 30002865 TI - Spectrum of practice in the routine management of cervical dystonia with abobotulinumtoxinA: findings from three prospective open-label observational studies. AB - Background: Cervical dystonia is a heterogeneous disorder with several possible presentations, for which first-line therapy is often botulinum toxin (BoNT). In routine clinical practice the success of each BoNT injection is dependent on several variables, including individual presentation and injection technique. Large multicenter, observational studies provide important information on individualized administration strategies that cannot be otherwise ascertained from controlled clinical trials. In this meta-analysis of patient level data, we aimed to evaluate the clinical characteristics of patients with cervical dystonia undergoing routine treatment with botulinum toxin, specifically abobotulinumtoxinA. We also aimed to characterize current abobotulinumtoxinA injection techniques and parameters and to explore international differences in patient presentation and treatment. Methods: This was a meta-analysis of baseline data from three prospective, international, multicenter, observational studies (NCT01314365, NCT00833196 and NCT01753349) of botulinum toxin treatment for the routine management of adult cervical dystonia. Results: Data presented illustrate the significant heterogeneity of CD presentation in routine practice. Most subjects presented with a complex pattern of dystonic movements and the majority had additional components of shoulder elevation, tremor and/or jerk. Dosing was generally in accordance with that recommended in the abobotulinumtoxinA prescribing information, although the range of dosing also indicates that injections are tailored to individual presentation. Sub-group analyses at the country level revealed distinct differences in injection practice. Conclusions: This meta-analysis is based on the largest dataset of subjects with cervical dystonia studied to date. The heterogeneity revealed in our baseline findings support the need to develop consistent, practical and comprehensive best practice guidelines. PMID- 30002866 TI - Determinants of choice of skilled antenatal care service providers in Ghana: analysis of demographic and health survey. AB - Background: The International Safe Motherhood initiative provides a focus for programmes and research to improve maternal health in low - income countries. Antenatal care is one of the key pillars of the initiative. This study sought to examine the association between background characteristics and choice of skilled providers of antenatal care services in Ghana. Methods: The study used data from the six rounds of the Ghana Demographic and Health Survey (GDHS). Binary logistic regression models were applied to analyse the data. Results: Results show that the proportion of women who received antenatal care (ANC) services from skilled providers improved over the period. Also, women with secondary education (OR = 1.42, CI = 1.07-1.88), richest wealth status (OR = 5.10, CI = 2.28-11.85) were more likely to utilise antenatal care services from skilled providers. Whereas women from rural areas (OR = 0.55, CI = 0.41-0.74), with four births or more (OR = 0.55, CI = 0.36-0.85) and from the northern ethnic group were less likely to utilise antenatal care services from skilled providers. Conclusion: Choice of skilled providers of antenatal care services were predicted by some predisposing factors including education, ethnicity, and ecological zone. Also enabling factors such as wealth status, residence and the need for care factor, parity predicted choice of skilled providers of antenatal care services. Women with secondary or higher education, those within richer and richest wealth status, those from forest zone are more likely to utilise the services of skilled providers during their antenatal care visits. Whereas women from rural areas, those with four births or more and those with the northern ethnic group were more likely to utilise ANC service from unskilled providers. The Ghana Health Service and Ministry of Health should encourage women in rural areas to utilise antenatal care services from skilled providers through social and behaviour change communication campaigns. PMID- 30002867 TI - Effectiveness of scheduled postoperative intravenous acetaminophen for colon cancer surgery pain. AB - Background: Clinical cases are often observed when patients are in need of repeated use of analgesic infusion to manage pain after colon cancer surgery. This paper investigates analgesic frequency as well as safety of postoperative intravenous (IV) acetaminophen in colon cancer surgery where epidural anesthesia is used. Methods: Among patients who received epidural anesthesia during colon cancer surgery, one group of twenty eight (28) patients received acetaminophen while another group of patients (30) did not receive it. The groups were analyzed from the surgery day to two days after for the postoperative occurrence and frequency of liver dysfunction in relation to analgesic usage. Results: The patient group with acetaminophen infusion significantly reduced the amount of analgesic medication compared to the group without the treatment (p = 0.008). Furthermore there was a significantly larger number of patients in the group receiving acetaminophen treatment with the baseline increase of alanine aminotransferase (p = 0.043). In most of the cases, however, the rate of the increase is mild and the patients did not need medication and subsequently recovered quickly. Conclusions: Scheduled IV infusion of acetaminophen after colon cancer surgey is concluded an effective method of pain control and alleviation of postoperative discomfort from the surgery day to two days after the surgery. PMID- 30002864 TI - Golimumab induction and maintenance for moderate to severe ulcerative colitis: results from GO-COLITIS (Golimumab: a Phase 4, UK, open label, single arm study on its utilization and impact in ulcerative Colitis). AB - Objective: GO-COLITIS aimed to measure the effectiveness of subcutaneous golimumab in tumour necrosis factor-alpha antagonist-naive patients with moderate to severe ulcerative colitis (UC) despite conventional treatment. Design: GO COLITIS was an open label, single arm, phase 4 study with a pragmatic design which reflected UK clinical practice. Adult patients were eligible if diagnosed with UC >=3 months, partial Mayo score (PMS) 4-9. Patients received subcutaneous golimumab induction (200 mg initially and 100 mg at week 2) followed at week 6 by 50 mg or 100 mg (depending on weight) every 4 weeks until week 54 with a 12-week follow-up. Efficacy was measured by PMS at baseline, week 6, 30, 54 and 66. Health-related quality of life (HRQoL; Inflammatory Bowel Disease Questionnaire (IBDQ) and EuroQol Group 5 Dimensions Health Questionnaire (EQ-5D)) was assessed at baseline, week 6 and week 54. All safety adverse events (AEs) were recorded. Results: 207 patients were enrolled and 205 received golimumab (full analysis set (FAS)205). At week 6, 68.8% (95% CI 62.0% to 75.1%) and 38.5% (95% CI 31.8% to 45.6%) of patients were in response and remission, respectively, using PMS. At the end of the induction phase, 140/141 patients in clinical response continued into the maintenance phase (Maintenance FAS). Sustained clinical response through week 54 was achieved in 51/205 (24.9%) of the FAS205 population and 51/140 (36.4%) of the Maintenance FAS population. Statistically significant improvements from baseline to week 6 were observed for the IBDQ total score and for each IBDQ domain score (bowel symptoms, emotional function, systemic symptoms and social function), as well as the EQ-5D index score and associated visual analogue scale score (p<0.0001). Improvement of HRQoL was sustained through week 54. Serious AEs leading to treatment discontinuation occurred in 8.8% of patients. Conclusion: In this study measuring patient-reported outcomes in patients with moderate to severe UC, golimumab induced and maintained response as measured by PMS and significantly improved quality of life measures. Trial registration number: NCT02092285; 2013-004583-56. PMID- 30002868 TI - Evolutionary conservation of the antimicrobial function of mucus: a first defence against infection. AB - Mucus layers often provide a unique and multi-functional hydrogel interface between the epithelial cells of organisms and their external environment. Mucus has exceptional properties including elasticity, changeable rheology and an ability to self-repair by re-annealing, and is therefore an ideal medium for trapping and immobilising pathogens and serving as a barrier to microbial infection. The ability to produce a functional surface mucosa was an important evolutionary step, which evolved first in the Cnidaria, which includes corals, and the Ctenophora. This allowed the exclusion of non-commensal microbes and the subsequent development of the mucus-lined digestive cavity seen in higher metazoans. The fundamental architecture of the constituent glycoprotein mucins is also evolutionarily conserved. Although an understanding of the biochemical interactions between bacteria and the mucus layer are important to the goal of developing new antimicrobial strategies, they remain relatively poorly understood. This review summarises the physicochemical properties and evolutionary importance of mucus, which make it so successful in the prevention of bacterial infection. In addition, the strategies developed by bacteria to counteract the mucus layer are also explored. PMID- 30002869 TI - Supporting prescribing in Irish primary care: protocol for a non-randomised pilot study of a general practice pharmacist (GPP) intervention to optimise prescribing in primary care. AB - Background: Prescribing for patients taking multiple medicines (i.e. polypharmacy) is challenging for general practitioners (GPs). Limited evidence suggests that the integration of pharmacists into the general practice team could improve the management of these patients. The aim of this study is to develop and test an intervention involving pharmacists, working within GP practices, to optimise prescribing in Ireland, which has a mixed public and private primary healthcare system. Methods: This non-randomised pilot study will use a mixed methods approach. Four general practices will be purposively sampled and recruited. A pharmacist will join the practice team for 6 months. They will participate in the management of repeat prescribing and undertake medication reviews (which will address high-risk prescribing and potentially inappropriate prescribing, deprescribing and cost-effective and generic prescribing) with adult patients. Pharmacists will also provide prescribing advice regarding the use of preferred drugs, undertake clinical audits, join practice team meetings and facilitate practice-based education. Throughout the 6-month intervention period, anonymised practice-level medication (e.g. medication changes) and cost data will be collected. A nested Patient Reported Outcome Measure (PROM) study will be undertaken during months 4 and 5 of the 6-month intervention period to explore the impact of the intervention in older adults (aged >= 65 years). For this, a sub-set of 50 patients aged >= 65 years with significant polypharmacy (>= 10 repeat medicines) will be recruited from each practice and invited to a medication review with the pharmacist. PROMs and healthcare utilisation data will be collected using patient questionnaires, and a 6-week follow-up review conducted. Acceptability of the intervention will be explored using pre- and post intervention semi-structured interviews with key stakeholders. Quantitative and qualitative data analysis will be undertaken and an economic evaluation conducted. Discussion: This non-randomised pilot study will provide evidence regarding the feasibility and potential effectiveness of general practice-based pharmacists in Ireland and provide data on whether a randomised controlled trial of this intervention is indicated. It will also provide a deeper understanding as to how a pharmacist working as part of the general practice team will affect organisational processes and professional relationships in a mixed public and private primary healthcare system. PMID- 30002871 TI - Use of effective family planning methods and frequency of sex among HIV-infected and HIV-uninfected African women. AB - Background: Frequency of sex, contraceptive use and HIV infection are key determinants of fertility. Use of an effective family planning (EFP) method (injectable, oral, intra-uterine contraceptive device (IUCD), or Norplant) potentially eliminates women's concerns of unintended pregnancy. We report the association between EFP and frequency of sex among HIV-infected and HIV uninfected non-pregnant African women. Methods: Prospective fertility intentions study nested within a phase 3 randomized double-masked placebo-controlled trial (2003-2005) to treat genital tract infections in HIV-infected and HIV-uninfected non-pregnant women. Enrollment of study participants was stratified by HIV infection status. Data on demographics, family planning and sexual history were obtained at baseline and at 3, 6, 9 and 12 months. Chi square and Wilcoxon Rank Sum tests were used to compare categorical and continuous variables, respectively. Generalized Estimating Equations method was used to estimate relative risk (RR) of frequent sex (>= 2 acts/week) among users of different EFP methods (injectable, oral, implant or intra-uterine contraceptive device). Results: After adjusting for age, current health status, and fertility intentions, EFP use was significantly associated with frequent sex among HIV infected women (RR 1.32; 95% Confidence Interval [CI] 1.14-1.52); this association was not statistically significant among HIV-uninfected women (RR 1.10; 95% CI 0.96-1.24). Fertility intentions among HIV-infected, and education among HIV-uninfected womenwere independent predictors of sex frequency. Conclusion: These data suggest that the association between EFP use and frequency of sex among women varies by HIV infection status. Service-delivery of diverse EFP methods should be integrated within HIV counseling, testing and treatment facilities. Trial registration: Registration number NCT00140764 under the clinicaltrials.gov, first Posted: September 1, 2005, last Update Posted: August 10, 2011. PMID- 30002870 TI - Eutectic mixture of local anaesthetics (EMLA(r)) as a primary dressing on painful chronic leg ulcers: a pilot randomised controlled trial. AB - Background: The physical, occupational, social and psychological impact of chronic leg ulcers (CLUs) on an individual is considerable. Wound-related pain (WRP), the most common symptom, is frequently reported as moderate to severe and mostly occurs at dressing change. WRP pain may not be alleviated by oral analgesics alone. Persistent poorly controlled leg ulcer pain can negatively impact wound healing and health-related quality of life (HRQoL). Methods: A pilot, parallel group, non-blinded, randomised controlled trial was conducted in six procedure clinics located in a public community nursing service in New South Wales, Australia to evaluate eutectic mixture of local anaesthetics (EMLA(r)) on painful CLUs when used as a primary dressing. The primary objective was to assess feasibility by using pre-determined criteria: at least 80% recruitment rate, 80% retention rate and 80% adherence to the study protocol. Key eligibility criteria were that participants had a painful CLU no larger than 100 cm2, a numerical rating scale (NRS) wound-related pain intensity score equal to or greater than 4, low to moderate exudate, no contraindications to EMLA(r) and capacity to consent. One hundred and seven patients with painful CLUs were screened for eligibility; 56% (n = 60) were eligible and consented to participate in the study. Participants were randomly assigned to the intervention (n = 30) or control (n = 30) groups. The intervention group received a measured dose of the topical anaesthetic EMLA(r) 5% cream daily as a primary dressing for 4 weeks followed by usual wound management for a further 8 weeks. The control group received usual wound management. Participants and investigators were not blinded to the treatment. WRP was measured at every dressing change. Wound healing and HRQoL were measured at baseline, 4 and 12 weeks. Results: Recruitment rate was lower than expected which likely meant patients were missed. Study retention rate was 90% (n = 54). Intervention fidelity was impacted by availability of resources and patient factors such as increased WRP. Conclusion: This study identified that a larger randomised controlled trial investigating EMLA(r) applied as a primary dressing on painful chronic leg ulcers is feasible with modifications to the study protocol. Trial registration: Australian New Zealand Clinical Trials Register: Registered 16 December, 2009. PMID- 30002872 TI - Genetic editing and interrogation with Cpf1 and caged truncated pre-tRNA-like crRNA in mammalian cells. AB - Cpf1, an RNA-guided DNA endonuclease that belongs to a new class II CRISPR system, has recently been harnessed for genome editing. Herein, we report an RNase-resistant caged truncated pre-tRNA-like crRNA (catRNA) that confers precise and efficient gene editing with the Lachnospiraceae bacterium Cpf1 (LbCpf1) and enables the reprogramming of catalytically dead LbCpf1 (dCpf1) lacking DNA endonuclease activity into a transcriptional modulator. Specific gene knock-outs and knock-ins were increased 3.2-fold and 4.3-fold, respectively, with catRNA compared to that induced by conventional crRNA. A much higher augmentation of gene disruption (up to 37-fold) was observed when electroporation was used. We report herein that catRNA enables efficient gene activation with dCpf1 activators. Our study reveals the potential of catRNA and a versatile application of the CRISPR/Cpf1 system, establishing a simple approach for selective gene perturbation in mammalian cells. PMID- 30002873 TI - Quantitative integration of epigenomic variation and transcription factor binding using MAmotif toolkit identifies an important role of IRF2 as transcription activator at gene promoters. PMID- 30002874 TI - Using qualitative research perspectives to inform patient engagement in research. AB - Plain English summary: In Canada, and internationally, there is an increased demand for patient engagement in health care research. Patients are being involved throughout the research process in a variety of roles that extend beyond the traditional passive participant role. These practices, referred to collectively as 'patient engagement', have raised questions about how to engage patients in the research process. Specifically, researchers have noted a lack of theory underpinning patient engagement and are looking for guidance on how to select patients and engage patients throughout the research process. In this commentary, we draw on qualitative research perspectives to generate theoretical and methodological ideas that novice or experienced researchers can apply to facilitate patient engagement in research. Abstract: Despite the recent advancements in patient engagement in health care research, there is limited research evidence regarding the best strategies for developing and supporting research partnerships with patients and caregivers. Three particular outstanding concerns that have been reported in the literature and that we will explore in this commentary are: (i) the lack of theoretical underpinning to inform the practice of patient engagement in research; (ii) the lack of knowledge regarding how to select patients to engage in research; and (iii) the lack of clear guidance about the best methods for engaging patients in research. We draw on qualitative research perspectives to reflect on these three areas of concern and propose insights into the theory and methods that we believe are useful for engaging patients in research. PMID- 30002875 TI - Inverting the patient involvement paradigm: defining patient led research. AB - Plain English Summary: Patients usually understand their disease and lifestyle needs better than many medical professionals. They also have important ideas about what research would be most beneficial to their lives, especially on how to manage symptoms in a way that improves daily quality of life. In the UK, the National Institute for Health Research has recognised the value of patient insight, and now requires researchers with public funding to involve patients and the public throughout the research process. There are many opportunities for involvement, but these generally focus on improving study design to ensure the trial is acceptable to participants. Some programmes work towards setting research priorities as important to patients, public members, and medical experts, but due to the complexity and cost involved in running clinical trials, the majority of research originates with the pharmaceutical industry or academic institutions. There is a clear mismatch between research ideas that patients prioritise (quality of life), and those actually investigated (drug development).The Patient Led Research Hub (PLRH) is a new initiative hosted by the Cambridge Clinical Trials Unit. The PLRH supports research ideas as proposed by patient organisations, providing resources and expertise in research design and delivery. The PLRH aims to co-produce any technically feasible project, regardless of disease or symptom focus. The proposing patient group maintains ownership of the project with an active role in study management. This method of research has proven to produce credible research studies that are of direct relevance to patients. Abstract: Patient and Public Involvement has become an indispensable and expected component of healthcare research in the United Kingdom, largely driven by the National Institute of Health Research and other research funders. Opportunities for patients to become involved in research abound, and many organisations now have dedicated 'public involvement' teams. However, its value is often questioned amidst criticism of tokenism and the recognition that a mismatch persists between patient priorities and funded research. Although patients are frequently consulted, evidence that their involvement influences the research agenda remains limited. We propose a novel model that allows patients and the public not only to propose research questions, but to design, initiate and deliver their own research with all the necessary support from research professionals. We demonstrate the feasibility and utility of this approach in reporting the establishment, experiences and progress of the Patient Led Research Hub. Using this resource, patient organisations are now able to initiate and conduct rigorous clinical research unfettered by the constraints of academic or economic agendas. PMID- 30002877 TI - Crystal structure, electrochemical and spectroscopic investigation of mer-tris-[2 (1H-imidazol-2-yl-kappaN3)pyrimidine-kappaN1]ruthenium(II) bis-(hexa-fluorido phosphate) trihydrate. AB - The crystal structure of the title compound, [Ru(C7H6N4)3](PF6)2.3H2O, a novel RuII complex with the bidentate ligand 2-(1H-imidazol-2-yl)pyrimidine, comprises a complex cation in the meridional form exclusively, with a distorted octa-hedral geometry about the ruthenium(II) cation. The Ru-N bonds involving imidazole N atoms are comparatively shorter than the Ru-N bonds from pyrimidine because of the stronger basicity of the imidazole moiety. The three-dimensional hydrogen bonded network involves all species in the lattice with water mol-ecules inter acting with both counter-ions and NH hydrogen atoms from the complex. The supra molecular structure of the crystal also shows that two units of the complex bind strongly through a mutual N-H?N bond. The electronic absorption spectrum of the complex displays an asymmetric band at 421 nm, which might point to the presence of two metal-to-ligand charge-transfer (MLCT) bands. Electrochemical measurements show a quasi-reversible peak referring to the RuIII/RuII reduction at 0.87 V versus Ag/AgCl. PMID- 30002876 TI - Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. AB - Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011-August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34-0.48, I2 = 44%) and WES (0.36, 95% CI 0.33-0.40, I2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08 0.12, I2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I2 = 13% and I2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I2 = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62 2.56, I2 = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38-0.45, I2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27-0.31, I2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I2 = 22% and I2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17-0.40, I2 = 54%) and WES (0.17, 95% CI 0.12-0.24, I2 = 76%) were higher than CMA (0.06, 95% CI 0.05-0.07, I2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases. PMID- 30002878 TI - Crystal structure determination, Hirshfeld surface analysis and energy frameworks of 6-phenyl-sulfonyl-6H-thieno[3,2-c]carbazole. AB - In the title compound, C20H13NO2S2, the carbazole ring system forms a dihedral angle of 89.08 (1) degrees with the sulfonyl-substituted phenyl ring. Intra molecular C-H?O hydrogen bonds involving the sulfone O atoms and the carbazole moiety result in two S(6) rings. In the crystal, mol-ecules are linked via pairs of C-H?O hydrogen bonds forming inversion dimers with an R22(12) graph-set motif. Analysis of the Hirshfeld surfaces and two-dimensional fingerprint plots was used to explore the distribution of weak inter-molecular inter-actions in the crystal structure. PMID- 30002879 TI - A new crystal form and anti-microbial activity of (E)-1-[3-(2-hy-droxy-benzyl idene-amino)-phen-yl]ethanone. AB - The title Schiff base compound, C15H13NO2, crystallizes in a new crystal form in the space group P212121, which is different from the monoclinic P21/n space group reported previously [De et al. (2009 ?). Indian J. Chem. Sect. B, 48, 595-598]. An intra-molecular O-H?N hydrogen bond occurs between the hy-droxy and azomethine moieties. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds into supra-molecular chains propagating along the b-axis direction with a C(8) graph set motif. The contribution of these two contacts in Hirshfeld surface area are around 19 and 21%, respectively. The title compound was screened for its anti bacterial activity against two gram-negative (Escherichia coli and Salmonella typhimurium) and one gram-positive (Staphyloccus aureus) bacteria. The results of this study reveal that this Schiff base shows good activity against only one bacterium, i.e. Salmonella typhimurium. PMID- 30002880 TI - Two tris-(3,5-disubstituted phen-yl)phosphines and their isostructural PV oxides. AB - The crystal structures of tris-(3,5-di-methyl-phen-yl)phosphine (C24H27P), (I), tris-(3,5-di-methyl-phen-yl)phosphine oxide (C24H27OP), (II), tris-(4-meth-oxy 3,5-di-methyl-phen-yl)phosphine (C27H33O3P), (III), and tris-(4-meth-oxy-3,5-di methyl-phen-yl)phosphine oxide (C27H33O4P), (IV), are reported. The strucure of (III) has been described before [Romain et al. (2000 ?). Organometallics, 19, 2047-2050], but it is rereported here on the basis of modern area-detector data and to facilitate comparison with the other structures reported here. Compounds (I) and (II) crystallize isostructurally in P21/c. Similarly, (III) and (IV) crystallize isostructurally in Pbca. The conformations of (I) and (II) in the solid state deviate strongly from helical, whereas those of (III) and (IV) are found to be closer to an ideal threefold rotational symmetry. The pyramidality indices, ?(C-P-C), are 305.35 (16), 317.23 (15), 307.2 (4) and 318.67 (18) degrees for (I), (II), (III) and (IV), respectively. Each is found to be more pyramidal than Ph3P or Ph3PO. Hybrid DFT calculations incorporating terms for dispersion provide evidence that the causes of the increased pyramidality, despite the 3,5-dimethyl group substitution, include dispersion inter-actions. The calculated ?(C-P-C) values are 304.8 degrees for both (I) and (III) and 317.4 degrees for both (II) and (IV), with no difference arising from the substitution at ring position 4. PMID- 30002881 TI - Racemic mefloquinium chloro-difluoro-acetate: crystal structure and Hirshfeld surface analysis. AB - In the racemic title mol-ecular salt, C17H17F6N2O+.C2ClF2O3- (systematic name: 2 {[2,8-bis-(tri-fluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidin-1-ium chloro-difluoro-acetate), the cation, which is protonated at the piperidine N atom, has the shape of the letter, L, with the piperidin-1-ium group being approximately orthogonal to the quinolinyl residue [the Cq-Cm-Cm-Na (q = quinolinyl; m = methine; a = ammonium) torsion angle is 177.79 (18) degrees ]. An intra-molecular, charge-assisted ammonium-N-H?O(hydrox-yl) hydrogen bond ensures the hy-droxy-O and ammonium-N atoms lie to the same side of the mol-ecule [Oh-Cm Cm-Na (h = hydrox-yl) = -59.7 (2) degrees ]. In the crystal, charge-assisted hydroxyl-O-H?O-(carboxyl-ate) and ammonium-N+-H?O-(carboxyl-ate) hydrogen bonds generate a supra-molecular chain along [010]; the chain is consolidated by C-H?O inter-actions. Links between chains to form supra-molecular layers are of the type C-Cl?pi(quinolinyl-C6) and the layers thus formed stack along the a-axis direction without directional inter-actions between them. The analysis of the calculated Hirshfeld surface points to the dominance of F?H contacts to the surface (40.8%) with significant contributions from F?F (10.5%) and C?F (7.0%) contacts. PMID- 30002882 TI - Crystal structure of 1-ethyl-3-(2-oxo-1,3-di-thiol-4-yl)quinoxalin-2(1H)-one. AB - The title compound I, C13H10N2O2S2, crystallizes in the monoclinic space group C2/c with eight mol-ecules in the unit cell. Excluding for the ethyl substituent, the mol-ecule of I adopts a nearly coplanar conformation (r.m.s. deviations is 0.058 A), which is supported by the intra-molecular C-H?O hydrogen-bonding inter action between the two ring systems [C?O = 2.859 (3) A]. In the crystal, the mol ecules form dimeric associates via two bifurcated C-H?O hydrogen-bonding inter actions between an ene hydrogen atom and a carbonyl functional group of an adjacent mol-ecule [C?O = 3.133 (3) A] and vice versa. The crystal structure is further stabilized by a three-dimensional network of weak hydrogen bonds between one mol-ecule and six adjacent mol-ecules as well as offset pi-pi stacking. The combination of the quinoxaline 2(1H)-one moiety with the di-thio-carbonate moiety extends the aromaticity of the quinoxaline scaffold towards the substituent as well as influencing the pi-system of the quinoxaline. The title compound is the direct precursor for a di-thiol-ene ligand mimicking the natural cofactor ligand molybdopterin. PMID- 30002883 TI - Spontaneous enanti-omorphism in poly-phased alkaline salts of tris (oxalato)ferrate(III): crystal structure of cubic NaRb5[Fe(C2O4)3]2. AB - We show here that the phenomenon of spontaneous resolution of enanti-omers occurs during the crystallization of the sodium and rubidium double salts of the transition metal complex tris-(oxalato)ferrate(III), namely sodium penta-rubidium bis-[tris-(oxalato)ferrate(III)], NaRb5[Fe(C2O4)3]2. One enanti-omer of the salt crystallizes in the cubic space group P4332 with Z = 4 and a Flack absolute structure parameter x = -0.01 (1) and its chiral counterpart in the space group P4132 with x = -0.00 (1). All metal ions are at crystallographic special positions: the iron(III) ion is on a threefold axis, coordinated by three oxalate dianions in a propeller-like conformation. One of the two independent rubidium ions is on a twofold axis in an eightfold coordination with neighbouring oxalate oxygen atoms, and the other one on a threefold axis in a sixfold RbO6 coordination. The sodium ion is at a site of D3 point group symmetry in a trigonal-anti-prismatic NaO6 coordination. PMID- 30002884 TI - Crystal structure of (E)-N'-[1-(4-amino-phen-yl)ethyl-idene]-2-hy-droxy-5-iodo benzohydrazide methanol monosolvate. AB - In the title compound, C15H14IN3O2.CH3OH, two aromatic rings are linked by an N substituted hydrazide function. The dihedral angle between the aromatic rings is 10.53 (8) degrees . The stereochemistry about the imine function is E. The methanol mol-ecule forms an O-H?O hydrogen bond to the hydrazide O atom. In the crystal, chains of mol-ecules running along the c-axis direction are formed by O H?O hydrogen bonds. Adjacent chains are linked through N-H?O hydrogen bonds and pi-pi stacking inter-actions. The inter-molecular inter-actions in the crystal packing were investigated using Hirshfeld surface analysis, which indicated that the most significant contacts are H?H (38.2%), followed by C?H/H?C (20.6%), O?H/H?O (11.1%) and I?H/H?I (9.7%). PMID- 30002885 TI - Crystal structure of diethyl {2,2,2-tri-chloro-1-[2-(1,3-dioxo-2,3-di-hydro-1H isoindol-2-yl)-4-methyl-pentanamido]-eth-yl}phospho-nate. AB - In the title phospho-rylated compound, C20H26Cl3N2O6P, the phthalimide unit is essentially planar (r.m.s. deviation = 0.0129 A) and the O atoms of this unit deviate from the mean plane by 0.080 (3) and 0.041 (3) A. In the crystal, pairs of mol-ecules are linked by N-H?O and weak C-H?O hydrogen bonds involving the same acceptor atom, forming inversion dimers. In addition, pi-pi stacking inter actions between the phthalimide groups, with a centroid-centroid distance of 3.7736 (13) A, and further weak C-H?O hydrogen bonds connect the inversion dimers into columns along [01]. PMID- 30002886 TI - Crystal structures of sodium-, lithium-, and ammonium 4,5-di-hydroxy-benzene-1,3 di-sulfonate (tiron) hydrates. AB - The solid-state structures of the Na+, Li+, and NH4+ salts of the 4,5-di-hydroxy benzene-1,3-di-sulfonate (tiron) dianion are reported, namely disodium 4,5-di hydroxy-benzene-1,3-di-sulfonate, 2Na+.C6H4O8S22-, MU-4,5-di-hydroxy-benzene-1,3 di-sulfonato-bis-[aqua-lithium(I)] hemihydrate, [Li2(C6H4O8S2)(H2O)2].0.5H2O, and di-ammonium 4,5-di-hydroxy-benzene-1,3-di-sulfonate monohydrate, 2NH4+.C6H4O8S22 .H2O. Inter-molecular inter-actions vary with the size of the cation, and the asymmetric unit cell, and the macromolecular features are also affected. The sodium in Na2(tiron) is coordinated in a distorted octa-hedral environment through the sulfonate oxygen and hydroxyl oxygen donors on tiron, as well as an inter-stitial water mol-ecule. Lithium, with its smaller ionic radius, is coordinated in a distorted tetra-hedral environment by sulfonic and phenolic O atoms, as well as water in Li2(tiron). The surrounding tiron anions coordinating to sodium or lithium in Na2(tiron) and Li2(tiron), respectively, result in a three-dimensional network held together by the coordinate bonds to the alkali metal cations. The formation of such a three-dimensional network for tiron salts is relatively rare and has not been observed with monovalent cations. Finally, (NH4)2(tiron) exhibits extensive hydrogen-bonding arrays between NH4+ and the surrounding tiron anions and inter-stitial water mol-ecules. This series of structures may be valuable for understanding charge transfer in a putative solid state fuel cell utilizing tiron. PMID- 30002887 TI - Crystal structure and Hirshfeld surface analysis of (Z)-4-(4-hy-droxy-benzyl idene)-3-methyl-isoxazol-5(4H)-one. AB - The title compound, C11H9NO3, contains an isoxazole and a hy-droxy-benzyl-idene ring, which are inclined to each another by 3.18 (8) degrees . There is an intra molecular C-H?O contact forming an S(7) ring. In the crystal, mol-ecules stack head-to-tail in columns along the b-axis direction, linked by offset pi-pi inter actions [inter-centroid distances of 3.676 (1) and 3.723 (1) A]. The columns are linked by O-H?O and O-H?N hydrogen bonds, forming layers parallel to the ab plane. The layers are linked by C-H?O hydrogen bonds, forming a supra-molecular three-dimensional framework. An analysis of the Hirshfeld surfaces points to the importance of the O-H?O and O-H?N hydrogen bonding in the packing mechanism of the crystal structure. PMID- 30002888 TI - Crystal structure and Hirshfeld surface analysis of 3-octyl-4-oxo-2,6-bis-(3,4,5 tri-meth-oxy-phen-yl)piperidinium chloride. AB - The title compound, C31H46NO7+.Cl-, was synthesized by a one-pot Mannich condensation reaction. In the mol-ecule, the piperidinone ring adopts a chair conformation, and the trimeth-oxy-substituted benzene rings and octyl chain are arranged equatorially. In the crystal, centrosymmetric dimers are linked into layers parallel to (011) by N-H?Cl and C-H?Cl hydrogen bonds. A Hirshfeld surface analysis indicates that the most important contributions for the crystal packing are O?H (20.5%) inter-actions followed by C?H (7.8%), Cl?H (5.5%), C?C (1.2%), C?O (0.5%) and Cl?O (0.4%) inter-actions. PMID- 30002889 TI - Crystal structure and Hirshfeld surface analysis of (2E)-3-(3-chloro-phen-yl)-1 (3,4-di-meth-oxy-phen-yl)prop-2-en-1-one. AB - In title compound, C17H15ClO3, the dihedral angle between the benzene and chloro phenyl rings is 18.46 (7) degrees . In the crystal, mol-ecules are linked by C H?O hydrogen contacts, enclosing an R22(14) ring motif, and by a further C-H?O hydrogen contact, forming a two-dimensional supra-molecular structure extending along the direction parallel to the ac plane. Hirshfeld surface analysis shows that van der Waals inter-actions constitute the major contribution to the inter molecular inter-actions, with H?H contacts accounting for 36.2% of the surface. PMID- 30002890 TI - Crystal structure and Hirshfeld surface analysis and energy frameworks of 1-(2,4 di-methyl-phen-yl)-4-(4-meth-oxy-phen-yl)naphthalene. AB - In the title compound, C25H22O, the two rings of the naphthalene system are inclined to each other by 3.06 (15) degrees . The mean plane of the naphthalene ring system makes a dihedral angle of 65.24 (12) degrees with the di-methyl phenyl ring and 55.82 (12) degrees with the meth-oxy-phenyl ring. The di-methyl phenyl ring is inclined to the meth-oxy-phenyl ring by 59.28 (14) degrees . In the crystal, adjacent mol-ecules are linked via C-H?pi inter-actions, forming chains along [100]. Using Hirshfeld surface and two-dimensional fingerprint plots, the presence of short inter-molecular inter-actions in the crystal structure were analysed. The inter-molecular inter-action energies were also calculated and their distribution over the crystal structure was visualized graphically using energy frameworks. PMID- 30002891 TI - Crystal structure and Hirshfeld surface analysis of 2,4-di-amino-6-methyl-1,3,5 triazin-1-ium tri-chloro-acetate monohydrate. AB - The asymmetric unit of the title mol-ecular salt, C4H8N5+.C2Cl3O2-.H2O, coomprises a 2,4-di-amino-6-methyl-1,3,5-triazin-1-ium cation, a tri-chloro acetate anion and a water mol-ecule of solvation. The protonated N atom of the cation forms a hydrogen bond with a carboxyl O atom of the anion, which also acts as a hydrogen-atom acceptor with the water mol-ecule. The cations form centrosymmetric dimeric units through R22(8) N-H?N bond pairs and are extended into zigzag chains along the c-axis direction, also through similar cyclic R22(8) dual N-H?N hydrogen-bonding inter-actions. The water mol-ecule acts as a dual acceptor forming N-H?O hydrogen bonds between the amine groups of the cations, forming cyclic R23(8) motifs. The second H atom of the water mol-ecule also acts as a donor in an O-H?O hydrogen bond with the second carboxyl O atom, linking the chains along the b-axis direction. These interactions give rise to an overall three-dimensional supra-molecular structure. A Hirshfeld surface analysis was employed in order to study the inter-molecular inter-actions. PMID- 30002892 TI - Crystal structure, Hirshfeld surface analysis and energy framework calculation of the first oxoanion salt containing 1,3-cyclo-hexa-nebis(methyl-ammonium): [3-(aza niumylmeth-yl)cyclo-hex-yl]methanaminium dinitrate. AB - The title salt, C8H20N22+.2NO3-, was obtained by a reaction between 1,3-cyclohexa nebis(methyl-amine) and nitric acid. The cyclo-hexane ring of the organic cation is in a chair conformation with the methyl-ammonium substituents in the equatorial positions and the two terminal ammonium groups in a trans conformation. In the crystal, mixed cation-anion layers lying parallel to the (010) plane are formed through N-H?O hydrogen-bonding inter-actions; these layers are formed by infinite undulating chains running parallel to the [001] direction. The overall inter-molecular inter-actions involved in the structure were qu-anti fied and fully described by Hirshfeld surface analysis. In addition, energy framework calculations were used to analyse and visualize the three-dimensional topology of the crystal packing. The electrostatic energy framework is dominant over the dispersion energy framework. PMID- 30002893 TI - Reinvestigation of the crystal structure of Ca2Ce8(SiO4)6O2 apatite by Rietveld refinement. AB - Ca2Ln8(SiO4)6O2 apatites with Ln = La, Ce, Pr, Nd, Sm, Eu, Gd and Tb crystallize in space group P63/m. The crystal structure of apatite-type Ca2Ce8(SiO4)6O2 [dicalcium octa-cerium hexa-kis-(silicate) dioxide], which has been synthesized by calcination, was refined from powder X-ray diffraction data using the Rietveld method. A database survey shows that contrary to the previously published Ca2Ce8(SiO4)6O2 structure [Skakle et al. (2000 ?). Powder Diffr.15, 234-238], the cell volume of the structure reported here is consistent with those of other Ln apatites. PMID- 30002894 TI - Crystal structure and theoretical study of (2E)-1-[4-hy-droxy-3-(morpholin-4 ylmeth-yl)phen-yl]-3-(thio-phen-2-yl)prop-2-en-1-one. AB - In the title compound, C18H19NO3S, the morpholine ring adopts a chair conformation. The thio-phene ring forms dihedral angles of 26.04 (9) and 74.07 (10) degrees with the benzene ring and the mean plane of the morpholine ring, respectively. The mol-ecular conformation is stabilized by an O-H?N hydrogen bond. In the crystal, mol-ecules are connected through C-H?O hydrogen bonds, forming wave-like layers parallel to the ab plane, which are further linked into a three-dimensional network by C-H?pi inter-actions involving the benzene rings and the methyl-ene H atoms of the morpholine rings. PMID- 30002895 TI - Crystal structures of (aceto-nitrile-kappaN)tris-(pyridine-4-thio-amide kappaN)bis-(thio-cyanate-kappaN)cobalt(II) aceto-nitrile disolvate and tetra-kis (pyridine-4-thio-amide-kappaN)bis-(thio-cyanate-kappaN)nickel(II) methanol penta solvate. AB - Reaction of Co(NCS)2 or Ni(NCS)2 with pyridine-4-thio-amide in different solvents led to the formation of two compounds with composition [Co(NCS)2(C2H3N)(C6H6N2S)3].2CH3CN (1) and [Ni(NCS)2(C6H6N2S)4].5CH3OH (2), respectively. The asymmetric unit of compound 1 consists of one cobalt(II) cation, two thio-cyanate anions, three pyridine-4-thio-amide ligands, one coordinating and two solvate aceto-nitrile mol-ecules. One of the two aceto nitrile solvate mol-ecules is disordered over two sets of sites in a 0.62:0.38 ratio. The asymmetric unit of compound 2 comprises of one nickel(II) cation, two thio-cyanate anions, four N-bonding pyridine-4-thio-amide ligands and five methanol solvate mol-ecules. In compound 1, the cobalt(II) cations are octa hedrally coordinated into discrete complexes by two terminal N-bonding thio cyanate anions, the N atoms of three pyridine-4-thio-amide ligands and one aceto nitrile mol-ecule. Additional aceto-nitrile solvate mol-ecules are located between the complexes,. The complexes and solvate mol-ecules are linked via inter molecular hydrogen bonding into a three-dimensional framework. In compound 2, the nickel(II) cations are likewise octa-hedrally coordinated by two terminal N bonded thio-cyanate anions and four N-bonding pyridine-4-thio-amide ligands into discrete complexes. From their arrangement cavities are formed, in which the methanol solvate mol-ecules are located. Again, the complexes and solvate mol ecules are linked into a three-dimensional framework by inter-molecular hydrogen bonding. PMID- 30002896 TI - Crystal structure of (2,2'-bi-pyridine-kappa2N,N')-trans-bis-(tert-butyl-dimethyl sil-yloxy)-cis-dioxidomolybdenum(VI). AB - In the title compound, [( t BuSiMe2O)2MoO2(2,2'-bi-pyridine)] or [Mo(C6H15OSi)2O2(C10H8N2)], the MoVI atom has a distorted octa-hedral environment with the sil-oxy substituents occupying the trans positions. The complex contains a rare (R3SiO)2MO2 (M = Mo, W) structural motif and was formed in a reaction between sodium molybdate and tert-butyl-dimethyl-silyl chloride in the presence of 2,2-bi-pyridine. In the crystal, neighbouring mol-ecules are linked by C H?O=Mo hydrogen bonds, forming chains propagating along the a-axis direction. PMID- 30002897 TI - Crystal structure of (E)-2-(tert-butyl-amino)-4-(tert-butyl-imino)-naphthalen 1(4H)-one. AB - The title compound, C18H24N2O, is the first example of a naphtho-quinone imine derivative isolated in the 4-imine/2-amine tautomeric form having bulky alkyl substituents at the N atoms. The mol-ecular conformation is stabilized by an intra-molecular hydrogen bond between the amine and a carbonyl group and by London attraction between the two tert-butyl groups. Only van der Waals inter actions were identified in the crystal packing. PMID- 30002898 TI - Crystal structure of homodinuclear platinum complex containing a metal-metal bond bridged by hydride and phosphide ligands. AB - In the title compound, MU-di-phenyl-phosphido-MU-hydrido-bis-[bromido-(tri-phenyl phosphane-kappaP)platinum(II)] diethyl ether monosolvate, [Pt2Br2(C12H10P)H(C18H15P)2].C4H10O or [Pt2(MU-H)(MU-PPh2)Br2(PPh3)2].(C2H5)2O, the PtII atoms are coordinated in a distorted square-planar arrangement, with one hydrido and one phosphido ligand bridging in a trans position. In the lattice, C H?.O and C-H?pi interactions are present. This complex has a total number of 32 electrons, 16 electrons for each PtII atom. One of the Br atoms is disordered over two positions in a 0.92:0.08 ratio. PMID- 30002899 TI - Structure of copper(II) complexes grown from ionic liquids - 1-ethyl-3-methyl imidazolium acetate or chloride. AB - Crystals of four new copper(II) complexes have been grown from copper(II) acetate/chloride-1-ethyl-3-methyl-imidazolium acetate/chloride-water systems and characterized by X-ray analysis. The first complex, bis-(1-ethyl-3-methyl imidazolium) tetra-MU-acetato-bis[chloridocuprate(II)], [Emim]2[Cu2(C2H3O2)4Cl2] (1) (Emim is 1-ethyl-3-methyl-imidazolium, C6H11N2), contains [Cu2(C2H3O2)4Cl2]2- coordination anions with a paddle-wheel structure and ionic liquid cations. Two of the synthesized complexes are one-dimensional polymers, namely catena-poly[1 ethyl-3-methyl-imidazolium [[tetra-MU-acetato-dicuprate(II)]-MU-chlorido] monohydrate], {[Emim][Cu2(C2H3O2)4Cl].H2O} n (2), and catena-poly[1-ethyl-3 methyl-imidazolium [[tetra-MU-acetato-dicuprate(II)]-MU-acetato]], {[Emim][Cu2(C2H3O2)5]} n (3). In these compounds, the Cu2(C2H3O2)4 units with a paddle-wheel structure are connected to each other through chloride (in 2) or acetate (in 3) anions to form parallel chains, between which cations of ionic liquid are situated. The last compound, bis-(1-ethyl-3-methyl-imidazolium) tetra MU-acetato-bis[aquacopper(II)] tetra-MU-acetato-bis[acetatocuprate(II)] dihydrate, [Emim]2[Cu2(C2H3O2)4(H2O)2][Cu2(C2H3O2)6].2H2O (4), contains two different binuclear coordination units (neutral and anionic), connected through hydrogen bonds between water mol-ecules and acetate ions. PMID- 30002901 TI - Crystal structure and Hirshfeld surface analysis of 4-[4-(1H-benzo[d]imidazol-2 yl)phen-oxy]phthalo-nitrile monohydrate. AB - In the title compound, C21H12N4O.H2O, the five-membered ring is essentially planar with a maximum deviation of 0.004 (2) A. An N-H?O hydrogen bond connects the organic and water mol-ecules. In the crystal, O-H?N hydrogen bonds link mol ecules into a two-dimensional network parallel to (100). Hirshfeld surface analyses and two-dimensional fingerprint plots were used to qu-antify the inter molecular inter-actions present in the crystal, indicating that the most important contributions for the crystal packing are from H?H (28.7%), C?H/H?C (27.1%), N?H/H?N (26.4%), C?N/N?C (6.1%), O?H/H?O (3.7%) and C?C (6.0%) inter actions. PMID- 30002900 TI - M4Au12Ag32(p-MBA)30 (M = Na, Cs) bimetallic monolayer-protected clusters: synthesis and structure. AB - Crystals of M4Au12Ag32(p-MBA)30 bimetallic monolayer-protected clusters (MPCs), where p-MBA is p-mercapto-benzoic acid and M+ is a counter-cation (M = Na, Cs) have been grown and their structure determined. The mol-ecular structure of triacontakis[(4-carboxylatophenyl)sulfanido]dodecagolddotriacontasilver, Au12Ag32(C7H5O2S)30 or C210H150Ag32Au12O60S30, exhib-its point group symmetry at 100 K. The overall diameter of the MPC is approximately 28 A, while the diameter of the Au12Ag20 metallic core is 9 A. The structure displays ligand bundling and inter-molecular hydrogen bonding, which gives rise to a framework structure with 52% solvent-filled void space. The positions of the M+ cations and the DMF solvent mol-ecules within the void space of the crystal could not be determined. Three out of the five crystallographically independent ligands in the asymmetric unit cell are disordered over two sets of sites. Comparisons are made to the all silver M4Ag44(p-MBA)30 MPCs and to expectations based on density functional theory. PMID- 30002902 TI - Crystal structure of cis-[1,2-bis-(di-phenyl-phosphan-yl)ethene-kappa2P,P']di chlorido-platinum(II) chloro-form disolvate: a new polymorph. AB - The title compound, [PtCl2(C26H22P2)].2CHCl3 (I), is the third monoclinic polymorph of this platinum(II) complex involving the bidentate ligand cis-1,2-bis (di-phenyl-phosphan-yl)ethyl-ene (cis-dppe) [for the others, see: Oberhauser et al. (1998a ?). Inorg. Chim. Acta, 274, 143-154, and Oberhauser et al. (1995 ?). Inorg. Chim. Acta, 238, 35-43]. The structure of compound (I) was solved in the space group P21/c, with one complex mol-ecule in the asymmetric unit along with two solvate chloro-form mol-ecules. The PtII atom is ligated by two P and two Cl atoms in the equatorial plane and has a perfect square-planar coordination sphere. In the crystal, the complex mol-ecule is linked to the chloro-form solvate mol-ecules by C-H?Cl hydrogen bonds and face-on C-Cl?pi inter-actions. There are also weak offset pi-pi inter-actions present [inter-centroid distances are 3.770 (6) and 4.096 (6) A], linking the mol-ecules to form supra-molecular sheets that lie in the bc plane. PMID- 30002903 TI - Crystal structure and Hirshfeld surface analysis of N-[(2-hy-droxy-naphthalen-1 yl)(3-methyl-phen-yl)meth-yl]acetamide. AB - The title compound, C20H19NO2, is of inter-est as a precursor to biologically active substituted quinolines and related compounds. This compound crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. The dihedral angles between mean planes of the methyl-phenyl ring and the naphthalene ring system are 78.32 (6) and 84.70 (6) degrees in mol-ecules A and B, respectively. In the crystal, the anti-ferroelectric packing of mol-ecules A and B is of an ABBAABB type along the b-axis direction. The crystal structure features N-H?O, O H?O and weak C-H?O hydrogen bonds, which link the mol-ecules into infinite chains propagating along the b-axis direction. PMID- 30002904 TI - Crystal structures of the triple perovskites Ba2K2Te2O9 and Ba2KNaTe2O9, and redetermination of the double perovskite Ba2CaTeO6. AB - Single crystals of Ba2K2Te2O9 (dibarium dipotassium nona-oxidoditellurate), (I), Ba2KNaTe2O9 (dibarium potassium sodium nona-oxidoditellurate), (II), and Ba2CaTeO6 (dibarium calcium hexa-oxidotellurate), (III), were obtained from KNO3/KI or KNO3/NaNO3 flux syntheses in platinum crucibles for (I) and (II), or porcelain crucibles for (III). (I) and (II) are isotypic and are members of triple perovskites with general formula A2[12co]A'[12co]B2[6o]B'[6o]O9. They crystallize in the 6H-BaTiO3 structure family in space-group type P63/mmc, with the A, A', B and B' sites being occupied by K, Ba, Te and a second Ba in (I), and in (II) by mixed-occupied (Ba/K), Ba, Te and Na sites, respectively. (III) adopts the A2[12co]B'[6o]B''[6o]O6 double perovskite structure in space-group type Fmm, with Ba, Ca and Te located on the A, B' and B'' sites, respectively. The current refinement of (III) is based on single-crystal X-ray data. It confirms the previous refinement from X-ray powder diffraction data [Fu et al. (2008). J. Solid State Chem.181, 2523-2529], but with higher precision. PMID- 30002905 TI - Ge0.57Ti0.43O2: a new high-pressure material with rutile-type crystal structure. AB - Single crystals of a GeO2-TiO2 solid solution with the corresponding composition Ge0.57Ti0.43O2 (germanium titanium tetra-oxide) were obtained by devitrification of germania-titania glass at high pressure and temperature. The new compound crystallizes in the rutile structure type (space group P42/mnm), where Ge and Ti share the same position M (site symmetry m.mm), with occupancy values of 0.57 (3) and 0.43 (3), respectively, and one O-atom position (m.2m). The M site is in a sixfold O-atom coordination and, as in the original TiO2 rutile structure, an elongation of the O-M-O bonds along the c-axis direction of the coordination polyhedron and deviation of the angles from 90 degrees lead to a decrease in the coordination symmetry from octa-hedral to tetra-gonal. The Ge and Ti atoms are fully disordered in the structure, which indicates that the rutile structure is surprisingly pliant given the differing sizes of the two cations. PMID- 30002906 TI - Crystal structure of 2-[2-(pyridin-3-yl)diazen-1-yl]aniline. AB - The crystal structure of the title compound, C11H10N4, comprises mol-ecules in a trans conformation for which all the atoms are located in general positions. The six-membered rings are coplanar and this arrangement might be stabilized by intra molecular N-H?N hydrogen bonding. In the crystal, the mol-ecules are linked into helical chains parallel to the b axis via N-H?N hydrogen bonding. The mol-ecular packing shows a herringbone-like pattern along the a axis. Comparison of the X ray powder diffraction with that calculated from single crystal data proves that a pure crystalline phase was obtained and UV-Vis measurements reveal that only the trans isomer is present. PMID- 30002907 TI - Crystal structure of the tetra-meth-yl(pheneth-yl)cyclo-penta dienylmolybdenumtricarbonyl dimer. AB - The structure of the dimer bis-{tricarbon-yl[eta5-tetra-meth-yl(pheneth-yl)cyclo penta-dien-yl]molybdenum}(Mo-Mo), [Mo2(C17H21)2(CO)6], at 102 K has triclinic (P ) symmetry. The reaction between tetra-meth-yl(pheneth-yl)cyclo-penta-diene and molybdenum hexa-carbonyl in refluxing xylenes for 18 h led to a 56% yield of the dimer as a red solid. The asymmetric unit of the structure is the tetra-meth yl(pheneth-yl)cyclo-penta-dienylmolybdenumtricarbonyl moiety and the entire dimeric mol-ecule is generated by inversion symmetry. The Mo-Mo bond length is 3.2773 (3) A, a value slightly above the mean value for all [CpMo(CO)3]2 compounds listed in the CSD and slightly below the mean for [Cp*Mo(CO)3]2 complexes. PMID- 30002908 TI - Crystal structure and Hirshfeld surface analysis of ethane-1,2-diaminium 3-[2 (1,3-dioxo-1,3-di-phenyl-propan-2-yl-idene)hydrazin-yl]-5-nitro-2-oxido-benzene sulfonate dihydrate. AB - In the anion of the title hydrated salt, C2H10N22+.C21H13N3O8S2-.2H2O, the planes of the phenyl rings and the benzene ring of the 5-nitro-2-oxido-benzene-sulfonate group are inclined to one another by 44.42 (11), 56.87 (11) and 77.70 (12) degrees . In the crystal, the anions are linked to the cations and the water mol ecules by N-H?O and O-H?O hydrogen bonds, forming a three-dimensional network. Furthermore, there are face-to-face pi-pi stacking inter-actions between the centroids of one phenyl ring and the benzene ring of the 5-nitro-2-oxido-benzene sulfonate group [centroid-centroid distance = 3.8382 (13) A and slippage = 1.841 A]. A Hirshfeld surface analysis was conducted to verify the contributions of the different inter-molecular inter-actions. PMID- 30002909 TI - Synthesis, crystal structure and Hirshfeld surface analysis of tetra-aqua-bis (isonicotinamide-kappaN1)cobalt(II) succinate. AB - The reaction of CoCl2 with succinic acid and isonicotinamide in basic solution produces the title complex [Co(C6H6N2O)2(H2O)4](C4H4O4). The cobalt(II) ion of the complex cation and the succinate anion are each located on an inversion centre. The CoII ion is octa-hedrally coordinated by four O atoms of water mol ecules and two N atoms of isonicotinamide mol-ecules. The two ions are linked via Owater-H?Osuccinate hydrogen bonds, forming chains propagating along [001]. In the crystal, these hydrogen-bonded chains are linked into a three-dimensional framework by further O-H?O hydrogen bonds and N-H?O hydrogen bonds. The framework is reinforced by C-H?O hydrogen bonds. Hirshfeld surface analysis and two dimensional fingerprint plots have been used to analyse the inter-molecular inter actions present in the crystal. PMID- 30002910 TI - Crystal structure and Hirshfeld surface analysis of a pyridiniminium bromide salt: 1-[2-(adamantan-1-yl)-2-oxoeth-yl]pyridin-4-iminium bromide. AB - In the cation of the title salt, C17H23N2O+.Br-, the adamantyl moiety and the pyridiniminium ring are inclined to the ketone bridge by torsion angles of -78.1 (2) (C-C-C=O) and 58.3 (2) degrees (C-C-N-C), respectively, and the ketone bridge has a C-C-C-N torsion angle of 174.80 (15) degrees . In the crystal, the cations are connected into chains parallel to the c axis by C-H?O hydrogen bonds. The chains are further linked into layers parallel to the bc plane by N-H?Br and C-H?Br hydrogen bonds, C-H?pi inter-actions and pi-pi stacking inter-actions [centroid-to-centroid distance = 3.5657 (11) A]. A Hirshfeld surface analysis, which comprises the dnorm surface, electrostatic potential map and two dimensional fingerprint plots, was carried out to verify the contribution of the various inter-molecular inter-actions. PMID- 30002911 TI - Crystal structure and Hirshfeld surface analysis of 3,3',3''-[(1,3,5-triazine 2,4,6-tri-yl)tris-(-oxy)]tris-(5,5-di-methyl-cyclo-hex-2-en-1-one). AB - The three cyclo-hexenone rings of the title compound, C27H33N3O6, adopt slightly distorted envelope conformations, with the C atom bearing two methyl groups as the flap atom in each case. These cyclo-hexenone mean planes form dihedral angles of 87.41 (11), 70.73 (11) and 70.47 (11) degrees with the 1,3,5-triazine ring, while the dihedral angle between the cyclo-hexenone mean planes are 57.52 (12), 23.75 (12) and 53.21 (12) degrees . In the crystal, mol-ecules are linked via C H?O hydrogen bonds, forming a three-dimensional network. PMID- 30002912 TI - Idiopathic full thickness macular hole in a 10-year-old girl. AB - Background: Macular holes in children are generally associated with trauma. Case presentation: We report the first case of an idiopathic full thickness macular hole in a 10-year-old girl. 23-gauge transconjunctival pars plana vitrectomy, induction of a posterior vitreous detachment, ILM blue-assisted internal limiting membrane peel, fluid-air exchange and air-26% sulfur hexafluoride (SF6) exchange was performed with subsequent macular hole closure. Conclusion: This is the first reported case of an idiopathic full thickness macular hole in a child. Treatment with pars plana vitrectomy with peeling of the ILM resulted in significant anatomic and functional improvement. PMID- 30002913 TI - Erratum: Author Correction: Concerns on a new therapy for severe heart failure using cell sheets with skeletal muscle or myocardial cells from iPS cells in Japan. AB - [This corrects the article DOI: 10.1038/s41536-018-0047-2.]. PMID- 30002914 TI - High mortality from pyogenic vertebral osteomyelitis: a retrospective cohort study. AB - Study design: Retrospective cohort study. Objective: In this pilot study, we aimed to assess the incidence, diagnostic strategies, treatment regimens, and outcomes of pyogenic vertebral osteomyelitis (PVO), in a non-urban, Northern European population during 1 year. Setting: Region Zealand, Denmark. Methods: All patients admitted to a hospital in Region Zealand during 2013 and subsequently discharged with a diagnosis of PVO or discitis were eligible for screening. Discharge diagnosis codes were obtained from a central register and patients were identified with unique identification numbers from the Danish Civil Registration System. Results: Forty-one consecutive patients were included. Patients presented with back pain (78%), fever (76%), elevated C-reactive protein levels (95%), and bacteremia (76%). Nine patients (22%) were treated empirically, as no bacterial etiology was isolated from blood culture or biopsy. The median duration of antibiotic treatment was 92 days, and we report an in-hospital mortality of 15%. Conclusions: This study supports previous findings of increasing incidence of PVO. In addition, we found a high rate of bacteremia and a high mortality in this single year cohort. Treatment regimens were heterogeneous and prolonged, due to delayed diagnosis and various or unknown microbial etiology. The study suggests that back pain, fever, and increased C-reactive protein levels are frequent in patients with PVO, and efforts should be made on securing early diagnosis and microbial etiology. Further studies of predictors of different clinical outcomes are warranted. Treatment of culture-negative cases and clinical value of bone biopsies are of special interest. PMID- 30002915 TI - International Spinal Cord Injury Lower Urinary Tract Function Basic Data Set (version 2.0). AB - Study design: Revision, review, and presentation of the International Spinal Cord Injury (SCI) Lower Urinary Tract (LUT) Function Basic Data Set (version 2.0). Objectives: Describe the revision and review and present the data set. Setting: International. Methods: The first version of the data set was revised according to new knowledge and suggestions. The review included International SCI Data Sets Committee, American Spinal Injury Association (ASIA) board, International Spinal Cord Society (ISCoS) executive and scientific committees, major organizations, and interested individuals. The data set was also on ASIA and ISCoS websites. All replies were answered and appropriate adjustments made. Finally, the data set was endorsed by ASIA board, and ISCoS executive and scientific committees. Results: Among revisions are adoptions of new terminology by the International Continence Society. For most variables, advice for collection of information from pediatric patients stated. For the variable 'Bladder emptying', is in the data collection form to the response category 'Normal voiding' expanded. 'Sacral Anterior Root Stimulator' is deleted as response category. For the variable 'Any involuntary urine leakage (incontinence) within the last 4 weeks' 'last 4 weeks' has replaced 'last 3 months'. The response categories have been adjusted to: 'Daily', 'Once or more per week (but not daily)', 'Less than once per week', 'Never', 'Not applicable' and 'Unknown'. For the variable 'Any drugs for the urinary tract within the last four weeks' 'last four weeks' has replaced 'last year'. Conclusions: The International SCI LUT Function Basic Data Set (version 2.0) with its complete syllabus is available from http://www.iscos.org.uk/international-sci data-sets. PMID- 30002916 TI - Misdiagnosis of posterior sequestered lumbar disc herniation: report of three cases and review of the literature. AB - Introduction: Posterior migration of sequestered disc is an extremely rare event that mimics more common spinal lesions as spinal tumors, making difficult its preoperative diagnosis and appropriate management. We retrospectively reviewed all lumbar disc herniations treated by surgery at our institution from 2006 to 2016 to identify cases with posterior sequestered disc fragments and possible misdiagnosis for other spinal lesions. Complementarily, a literature review of misdiagnosed cases of posterior migrated discs was undertaken. Case report: Three posterior sequestered lumbar disc cases (one intradural), were found among the 1153 reviewed surgeries. Two of them, presenting with progressive neurological deficit, were respectively misdiagnosed as pseudotumoral lesion and meningioma/neurogenic tumor on MRI. After intraoperative diagnosis and emergent resection, histology confirmed intervertebral disc tissue. The remaining case had an accurate preoperative diagnosis and after an initial conservative management finally underwent surgery because of refractory pain. Full recovery was achieved months after surgical treatment in all cases. Discussion: Non-tumoral lesions are the most frequent misdiagnosis of posterior sequestered lumbar disc described in the literature. Early surgical treatment is the standard management due to high incidence of cauda equine syndrome (CES); however, spontaneous regression of posterior sequestered lumbar disc herniations has been recently reported. In conclusion low incidence and similar clinical and radiological features with other more common posterior spinal lesions like hematomas, synovial cyst or abscess turns posterior sequestered disc herniations a diagnosis challenge. Despite high incidence of CES, an initial conservative management should be evaluated in selected patients without neurological deficit and well-controlled pain. PMID- 30002917 TI - Antibody targeting of a specific region of Pfs47 blocks Plasmodium falciparum malaria transmission. AB - Transmission-blocking vaccines are based on eliciting antibody responses in the vertebrate host that disrupt parasite development in the mosquito vector and prevent malaria transmission. The surface protein Pfs47 is present in Plasmodium falciparum gametocytes and female gametes. The potential of Pfs47 as a vaccine target was evaluated. Soluble full-length recombinant protein, consisting of three domains, was expressed in E. coli as a thioredoxin fusion (T-Pfs47). The protein was immunogenic, and polyclonal and monoclonal antibodies (mAb) were obtained, but they did not confer transmission blocking activity (TBA). All fourteen mAb targeted either domains 1 or 3, but not domain 2 (D2), and immune reactivity to D2 was also very low in polyclonal mouse IgG after T-Pfs47 immunization. Disruption of the predicted disulfide bond in D2, by replacing cysteines for alanines (C230A and C260A), allowed expression of recombinant D2 protein in E. coli. A combination of mAbs targeting D2, and deletion proteins from this domain, allowed us to map a central 52 amino acid (aa) region where antibody binding confers strong TBA (78-99%). This 52 aa antigen is immunogenic and well conserved, with only seven haplotypes world-wide that share 96-98% identity. Neither human complement nor the mosquito complement-like system are required for the observed TBA. A dramatic reduction in ookinete numbers and ookinete-specific transcripts was observed, suggesting that the antibodies are interacting with female gametocytes and preventing fertilization. PMID- 30002919 TI - Correction: Measuring progress towards Sustainable Development Goal 3.8 on universal health coverage in Kenya. AB - [This corrects the article DOI: 10.1136/bmjgh-2018-000904.][This corrects the article DOI: 10.1136/bmjgh-2018-000904.]. PMID- 30002918 TI - Status of Nordic research on simulation-based learning in healthcare: an integrative review. AB - Background: Based on common geography, sociopolitics, epidemiology, and healthcare services, the Nordic countries could benefit from increased collaboration and uniformity in the development of simulation-based learning (SBL). To date, only a limited overview exists on the Nordic research literature on SBL and its progress in healthcare education. Therefore, the aim of this study is to fill that gap and suggest directions for future research. Methods: An integrative review design was used. A search was conducted for relevant research published during the period spanning from 1966 to June 2016. Thirty-seven studies met the inclusion criteria. All included studies were appraised for quality and were analyzed using thematic analysis. Results: The Nordic research literature on SBL in healthcare revealed that Finland has published the greatest number of qualitative studies, and only Sweden and Norway have published randomized control trials. The studies included interprofessional or uniprofessional teams of healthcare professionals and students. An assessment of the research design revealed that most studies used a qualitative or a descriptive design. The five themes that emerged from the thematic analysis comprised technical skills, non technical skills, user experience, educational aspects, and patient safety. Conclusion: This review has identified the research relating to the progress of SBL in the Nordic countries. Most Nordic research on SBL employs a qualitative or a descriptive design. Shortcomings in simulation research in the Nordic countries include a lack of well-designed randomized control trials or robust evidence that supports simulation as an effective educational method. In addition, there is also a shortage of studies focusing on patient safety, the primary care setting, or a combination of specialized and primary care settings. Suggested directions for future research include strengthening the design and methodology of SBL studies, incorporating a cross-country comparison of studies using simulation in the Nordic countries, and studies combining specialized and primary care settings. PMID- 30002921 TI - Accountability mechanisms and the value of relationships: experiences of front line managers at subnational level in Kenya and South Africa. AB - Resource constraints, value for money debates and concerns about provider behaviour have placed accountability 'front and centre stage' in health system improvement initiatives and policy prescriptions. There are a myriad of accountability relationships within health systems, all of which can be transformed by decentralisation of health system decision-making from national to subnational level. Many potential benefits of decentralisation depend critically on the accountability processes and practices of front-line health facility providers and managers, who play a central role in policy implementation at province, county, district and facility levels. However, few studies have examined these responsibilities and practices in detail, including their implications for service delivery. In this paper we contribute to filling this gap through presenting data drawn from broader ongoing research collaborations between researchers and health managers in Kenya and South Africa. These collaborations are aimed at understanding and strengthening day-to-day micropractices of health system governance, including accountability processes. We illuminate the multiple directions and forms of accountability operating at the subnational level across three sites. Through detailed illustrative examples we highlight some of the unintended consequences of bureaucratic forms of accountability, the importance of relational elements in enabling effective bureaucratic accountability, and the ways in which front-line managers can sometimes creatively draw upon one set of accountability requirements to challenge another set to meet their goals. Overall, we argue that interpersonal interactions are key to appropriate functioning of many accountability mechanisms, and that policies and interventions supportive of positive relationships should complement target-based and/or audit-style mechanisms to achieve their intended effects. Where this is done systematically and across key elements and actors of the health system, this offers potential to build everyday health system resilience. PMID- 30002920 TI - Risk factors and risk factor cascades for communicable disease outbreaks in complex humanitarian emergencies: a qualitative systematic review. AB - Background: Communicable diseases are a major concern during complex humanitarian emergencies (CHEs). Descriptions of risk factors for outbreaks are often non specific and not easily generalisable to similar situations. This review attempts to capture relevant evidence and explore whether it is possible to better generalise the role of risk factors and risk factor cascades these factors may form. Methods: A systematic search of the key databases and websites was conducted. Search terms included terms for CHEs (United Nations Office for the Coordination of Humanitarian Affairs definition) and terms for communicable diseases. Due to the types of evidence found, a thematic synthesis was conducted. Results: 26 articles met inclusion criteria. Key risk factors include crowded conditions, forced displacement, poor quality shelter, poor water, sanitation and hygiene, lack of healthcare facilities and lack of adequate surveillance. Most identified risk factors do not relate to specific diseases, or are specific to a group of diseases such as diarrhoeal diseases and not to a particular disease within that group. Risk factors are often listed in general terms but are poorly evidenced, not contextualised and not considered with respect to interaction effects in individual publications. The high level of the inter-relatedness of risk factors became evident, demonstrating risk factor cascades that are triggered by individual risk factors or clusters of risk factors. Conclusions: CHEs pose a significant threat to public health. More rigorous research on the risk of disease outbreaks in CHEs is needed, from a practitioner and from an academic point of view. PMID- 30002922 TI - Delivery of Immunomodulatory Microparticles in a Murine Model of Rotator Cuff Tear. AB - Full thickness rotator cuff tears (RCT) and the associated muscle degeneration that results due to this injury presents a significant clinical burden. The prevention or recovery from this degeneration requires the synchronized behavior of many cells that participate in regeneration. Strategies that tune the inflammatory cascade that is initiated after injury serves as a powerful way to influence tissue repair. Here, we use the local, sustained delivery of the immunomodulatory small molecule FTY720 to examine whether the recruitment of pro regenerative myeloid cells affects the healing outcome. We find that PLGA microparticles have an atrophic effect on the muscle that is ameliorated with the release of FTY720. However, the inability of FTY720 delivery to induce pro regenerative monocyte and macrophage recruitment and our findings demonstrating enrichment of CD4+ T cells suggest that effects of this small molecule are context dependent and that the underlying mechanisms behind this RCT associated muscle degeneration require further studies. PMID- 30002923 TI - How Universal Is the Relationship between Remotely Sensed Vegetation Indices and Crop Leaf Area Index? A Global Assessment. AB - Leaf Area Index (LAI) is a key variable that bridges remote sensing observations to the quantification of agroecosystem processes. In this study, we assessed the universality of the relationships between crop LAI and remotely sensed Vegetation Indices (VIs). We first compiled a global dataset of 1459 in situ quality controlled crop LAI measurements and collected Landsat satellite images to derive five different VIs including Simple Ratio (SR), Normalized Difference Vegetation Index (NDVI), two versions of the Enhanced Vegetation Index (EVI and EVI2), and Green Chlorophyll Index (CIGreen). Based on this dataset, we developed global LAI VI relationships for each crop type and VI using symbolic regression and Theil Sen (TS) robust estimator. Results suggest that the global LAI-VI relationships are statistically significant, crop-specific, and mostly non-linear. These relationships explain more than half of the total variance in ground LAI observations (R2 >0.5), and provide LAI estimates with RMSE below 1.2 m2/m2. Among the five VIs, EVI/EVI2 are the most effective, and the crop-specific LAI EVI and LAI-EVI2 relationships constructed by TS, are robust when tested by three independent validation datasets of varied spatial scales. While the heterogeneity of agricultural landscapes leads to a diverse set of local LAI-VI relationships, the relationships provided here represent global universality on an average basis, allowing the generation of large-scale spatial-explicit LAI maps. This study contributes to the operationalization of large-area crop modeling and, by extension, has relevance to both fundamental and applied agroecosystem research. PMID- 30002924 TI - Psychological Aspects and Depression in Patients with Symptomatic Keratoconus. AB - Purpose: To assess the psychological status of keratoconus sufferers and to determine the relationship between depression and visual impairment in this group of patients. Methods: Fifty-six patients with keratoconus and forty-seven age- and gender-matched healthy control subjects were retroprospectively analyzed. Every participant underwent a complete ophthalmological examination. Keratoconus diagnosis was confirmed with corneal topography and tomography. Zung Depression Inventory Questionnaire and Patient Health Questionnaire-9 (PHQ-9) were completed by everyone. Results: Visual acuity (logMAR 0.53 +/-0.30 versus 0.11 +/- 0.16), PHQ-9 score (10.20 +/- 4.00 versus 5.40 +/- 5.01), and Zung score (46.52 +/- 8.70 versus 38.53 +/- 8.41) showed a statistically significant difference between keratoconus patients and healthy controls (p < 0.001 for all). Worse visual acuity was strongly correlated with older individuals (rho = 0.339, p=0.011) and higher PHQ-9 (rho = 0.765, p < 0.001) and Zung score (rho = 0.672, p < 0.001). Conclusion: Depressive disorders appear to be directly associated with keratoconus, both in frequency and intensity. Worse visual acuity and older age could be identified as predictive factors for their emotional status. Moreover, the disease itself could be recognized as an independent risk factor for depression development, underlying the need for close monitoring and supportive management. To the best of our knowledge, our study is the first in the literature to elaborate the association between keratoconus and depression, by assessing two different questionnaires simultaneously. PMID- 30002925 TI - Blood Pressure and Its Association with Gender, Body Mass Index, Smoking, and Family History among University Students. AB - Hypertension is one of the major risk factors associated with cardiovascular diseases. In this study, we will assess the frequency of hypertension among healthy university students and its association with gender, body mass index, smoking, and family history of both hypertension and cardiovascular diseases. We screened healthy university students ranging from 18 to 26 years of age. For each participant, we performed blood pressure measurements using a previously validated device and obtained demographic data, body mass index (BMI), smoking status, and family history of both hypertension and cardiovascular diseases. Out of the total number of 505 participants included in this study, 35.2% have blood pressure between 130/80 and 139/89, and 13.5% have blood pressure of more than 140/90. We found significant gender differences in both systolic pressure (p = 0.003) with mean difference = 18.08 mmHg (CI: 16.13 to 19.9) and diastolic pressure (p = 0.011) with mean difference = 3.6 mmHg (CI: 2.06 to 5.14), higher in males than in females. Upon comparing the mean difference in both systolic and diastolic blood pressure with BMI, we found significant differences in both systolic (p < 0.001) and diastolic (p = 0.002) blood pressure. We also found that smokers have significantly (p = 0.025) higher systolic blood pressure (mean difference = 4.2 mmHg, CI: 3.2 mmHg to 8.8 mmHg), but no significant difference for diastolic blood pressure (p = 0.386), compared to nonsmokers. First-degree family history of both hypertension and cardiovascular diseases affected systolic but not diastolic blood pressure. Taking into account the adverse short- and long term effect of hypertension, we recommend adopting an awareness program highlighting the importance of screening blood pressure in young adolescent populations, keeping in mind that both high BMI and smoking are important modifiable factors. PMID- 30002926 TI - Epidemiology of Hypertensive State among Chinese Migrants: Effects of Unaffordable Medical Care. AB - Hypertension is a major risk factor for heart disease and stroke. Affordability of medical care affects hypertension prevention, treatment, and control, but limited information is available for Chinese migrants with hypertensive state. Using Longitudinal Survey on Rural Urban Migration in China 2009 data, 2468 Chinese migrants reported hypertensive status. On the basis of comparison between medical payment and job income, participants were categorized as unaffordable and affordable. Thus, unaffordable expenses and unaffordable services were defined based on a public available survey. The descriptive statistics showed that 24.96% were at risk of prehypertension and mild-moderate-severe hypertension among 2468 Chinese migrants from 15 cities. Small part of the sample was not affordable to pay medical expenses and services. There were significant differences of hypertensive states between gender, marital status, regular smoker, and economic unaffordability. Multiple logistic regressions indicated that economic unaffordability had associations with abnormal weight, poor health assessment, and unhealthy hypertensive status. The alarming results may necessitate targeted interventions, even among people with good health status. PMID- 30002927 TI - A Shorter Circular Stapler Height at the Gastrojejunostomy during a Roux-En-Y Gastric Bypass Results in Less Strictures and Bleeding Complications. AB - The laparoscopic Roux-en-Y gastric bypass (LRYGB) is prone to a number of complications, most notably at the gastrojejunostomy (GJ) staple line. The circular stapler technique is a common method used to create the GJ anastomosis. Although recent studies have shown a decreased rate of anastomotic strictures with shorter stapler heights, the optimal circular stapler height to use remains controversial. We therefore completed a retrospective cohort study within the Alberta Provincial Bariatric Program (APBP) to compare outcomes between the 3.5 mm and 4.8 mm stapler heights. We identified 215 patients who had a LRYGB done between the years 2015 and 2017. 143 patients had the GJ constructed with a 3.5 mm circular stapler height, with the remaining 72 patients having the GJ fashioned with a 4.8 mm stapler height. The rate of anastomotic stricturing was lower in the 3.5 mm stapler group compared to the other cohort (3.5 versus 13.9%, resp., p=0.008). Likewise, the overall rate of bleeding complications was lower in the 3.5 mm stapler group compared to the 4.8 mm group (6.3 versus 15.3%, resp., p=0.04). The rate of anastomotic stricturing and postoperative bleeding is lower with the use of a 3.5 mm circular stapler compared to a 4.8 mm circular stapler when forming the GJ. PMID- 30002928 TI - Biosynthesis of the Essential Fatty Acid Oxidation Cofactor Carnitine Is Stimulated in Heart and Liver after a Single Bout of Exercise in Mice. AB - We determined whether one single bout of exercise stimulates carnitine biosynthesis and carnitine uptake in liver and heart. Free carnitine (FC) in plasma was assayed using acetyltransferase and [14C]acetyl-CoA in Swiss Webster mice after 1 hour of moderate-intensity treadmill running or 4 hours and 8 hours into recovery. Liver and heart were removed under the same conditions for measurement of carnitine biosynthesis enzymes (liver butyrobetaine hydroxylase, gamma-BBH; heart trimethyllysine dioxygenase, TMLD), organic cation transporter-2 (OCTN2, carnitine transporter), and liver peroxisome proliferator-activated receptor-alpha (PPARalpha, transcription factor for gamma-BBH and OCTN2 synthesis). In exercised mice, FC levels in plasma decreased while heart and liver OCTN2 protein expressed increased, reflecting active uptake of FC. During recovery, the rise in FC to control levels was associated with increased liver gamma-BBH expression. Protein expression of PPARalpha was stimulated in liver after exercise and during recovery. Interestingly, heart TMLD protein was also detected after exercise. Acute exercise stimulates carnitine uptake in liver and heart. The rapid return of FC levels in plasma after exercise indicates carnitine biosynthesis by liver is stimulated to establish carnitine homeostasis. Our results suggest that exercise may benefit patients with carnitine deficiency syndromes. PMID- 30002929 TI - Neuropsychiatric Involvement in Juvenile-Onset Systemic Lupus Erythematosus. AB - Objective: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by multisystem involvement, including the nervous system. In the present study, we aimed to assess neuropsychiatric manifestations in juvenile onset systemic lupus erythematosus (JSLE) in Iran. Methods: One hundred and forty six pediatric onset patients with SLE who had registered in our pediatric rheumatology database were evaluated prospectively and cross sectionally within 2013-2015. Data including sex, age, age at the time of diagnosis, age at the time of study, physical examination, laboratory review, and neuropsychiatric inventory were extracted from this database. Classification of neuropsychiatric JSLE was according to the 1999 American College of Rheumatology (ACR) neuropsychiatric manifestations of SLE case definitions. Result: A total number of 41 patients with neuropsychiatric symptoms were selected. The patients' average age was 12.2 years. The most common neuropsychiatric symptoms were seizures, migraine, and depression. The mean age at the onset of symptoms was 10.2 +/- 3 years. Mean follow-up period was 57+/-34 (range: 12-120) months. From 41 SLE patients, 18 (43.9) presented symptoms at the time of diagnosis. In thirteen (31.7%) patients, neurological symptoms were developed more than 1 year after SLE diagnosis. Headache was the most common feature (13%), followed by seizure (9.5%) and chorea (3.4%). Other neurological manifestations included cranial nerve involvement (0.7%), loss of consciousness (2.7%), and impaired deep tendon reflex neuropathy (2.5%). The least common neuropsychiatric JSLE manifestation was aseptic meningitis seen in only one patient (0.7%). Conclusion: The presence of headache, mood disorders, psychosis, depression, and other neuropsychological manifestations in a patient with JSLE should prompt investigations into diagnosis of the primary nervous system involvement in order to reduce mortality and morbidity. PMID- 30002930 TI - Can Chaotic Analysis of Electroencephalogram Aid the Diagnosis of Encephalopathy? AB - Chaotic analysis is a relatively novel area in the study of physiological signals. Chaotic features of electroencephalogram have been analyzed in various disease states like epilepsy, Alzheimer's disease, sleep disorders, and depression. All these diseases have primary involvement of the brain. Our study examines the chaotic parameters in metabolic encephalopathy, where the brain functions are involved secondary to a metabolic disturbance. Our analysis clearly showed significant lower values for chaotic parameters, correlation dimension, and largest Lyapunov exponent for EEG in patients with metabolic encephalopathy compared to normal EEG. The chaotic features of EEG have been shown in previous studies to be an indicator of the complexity of brain dynamics. The smaller values of chaotic features for encephalopathy suggest that normal complexity of brain function is reduced in encephalopathy. To the best knowledge of the authors, no similar work has been reported on metabolic encephalopathy. This finding may be useful to understand the neurobiological phenomena in encephalopathy. These chaotic features are then utilized as feature sets for Support Vector Machine classifier to identify cases of encephalopathy from normal healthy subjects yielding high values of accuracy. Thus, we infer that chaotic measures are EEG parameters sensitive to functional alterations of the brain, caused by encephalopathy. PMID- 30002932 TI - Severely Circumferentially Calcified Neointima as a New Cause of Undilatable In Stent Restenosis. AB - A 74-year old man presented recurrent angina pectoris due to in-stent restenosis (ISR) with severely calcified neointima. In-stent neoatherosclerosis (NA) is associated with late stent failure, and NA with calcified neointima occurs in some cases. Because the presence of neointimal calcification could lead to underexpansion of newly implanted stent for ISR, a scoring balloon was selected for predilatation to obtain maximum extrusion of the neointimal plaque and subsequently, an everolimus-eluting stent was implanted. However, moderate stenosis remained on coronary angiography, and optical coherence tomography (OCT) revealed underexpansion of the newly implanted stent because an attempt at balloon dilatation of neointimal calcification failed. Although OCT can clearly discriminate stent struts from neointimal calcification, we did not perform OCT assessment between scoring balloon and stenting. It is highly recommended to confirm whether the lesion is adequately treated by balloon angioplasty before stenting in cases with calcified ISR. PMID- 30002931 TI - Magnesium Supplementation and Blood Pressure in Pregnancy: A Double-Blind Randomized Multicenter Study. AB - Objective: To investigate the effect of magnesium (Mg) supplementation in healthy pregnant women for prevention of blood pressure increase. Secondary outcomes were comparison of biomarkers for hypertensive disorders and labour and fetal outcomes between the groups. Methods: Two hundred nulliparous healthy pregnant women were double-blind randomized to receive Mg daily or placebo. Results: There were no differences in blood pressure increase. However, among the Mg-treated women, there was a significant negative correlation between increase in blood levels of magnesium and increase in systolic blood pressure (p = 0.042). Magnesium supplementation seems to be safe for both mother and infant. Conclusion: Magnesium supplementation in healthy first-time pregnant women is not to be recommended for prevention of blood pressure increase. Supplementation in risk pregnancies needs to be further investigated. The study is listed on the ISRCTN registry with study ID 13890849. PMID- 30002933 TI - Approach and Treatment of Giant Luminal Unicystic Ameloblastoma. AB - Unicystic ameloblastoma is an odontogenic tumor that affects mainly young patients and usually involves the posterior region of the mandible. In this article, we report on the case a 12-year-old girl presenting with an 8-month history of facial swelling in her lower right quadrant. Radiographic examination revealed a unilocular radiolucent lesion extending from the body of the mandible through to the angle and ascending ramus. An incisional biopsy was performed, and a diagnosis of luminal unicystic ameloblastoma was made based on clinicopathological features. The lesion was treated in two stages, namely, an initial conservative approach via decompression and subsequent excision. The patient has been followed up for 6 months without clinical and radiographic evidence of recurrence. In conclusion, conservative timely intervention combined with a conservative surgical approach has proven efficacious in the treatment of ameloblastoma in this young patient. PMID- 30002935 TI - Orbital Pseudotumor as an Extrahepatic Complication of Chronic HCV Infection. AB - We present a patient who was admitted for eye swelling, pain, and discharge, with CT orbits with contrast demonstrating inflammation and enlargement of the lacrimal glands and surrounding tissue. He was found to have an HCV infection for unknown duration upon further investigation. All other workup (autoimmune, rheumatic, and infectious) was unrevealing. The patient was diagnosed with orbital pseudotumor as an extrahepatic complication of chronic HCV infection, and he was managed with prednisone which dramatically decreased his eye swelling and pain. Steroid treatment may serve as a bridge to suppress symptoms of extrahepatic manifestations, especially in ocular cases, while HCV-infected patients await treatment to eradicate their HCV infection. PMID- 30002934 TI - Successful Management of Teeth with Different Types of Endodontic-Periodontal Lesions. AB - Endodontic-periodontal diseases often present great challenges to the clinician in their diagnosis, management, and prognosis. Understanding the disease process through cause-and-effect relationships between the pulp and supporting periodontal tissues with the aid of rational classifications leads to successful treatment outcomes. In this report, we present several treatment modalities in patients with different endodontic-periodontal lesions. A modification to the new endodontic-periodontic classification, Al-Fouzan's classification, was also added. The first case was classified as retrograde periodontal disease (i.e., primary endodontic lesion with drainage through the periodontal ligament). The second case was diagnosed as an iatrogenic periodontal lesion caused by root perforation. The third case was diagnosed as an iatrogenic periodontal lesion caused by tooth trauma due to orthodontic treatment. The first two cases were managed with a nonsurgical approach, whereas the third case was managed with nonsurgical and surgical approaches. All patients showed complete healing of soft and hard tissue lesions. A thorough understanding of the disease history and the patient's signs and symptoms, complete examination with full investigation, and the use of a systematic step-by-step approach in the management of such challenging endodontic-periodontal lesions with regular recall visits were very useful and successful. PMID- 30002936 TI - Immunosuppression with Antitumour Necrosis Factor Therapy Leading to Strongyloides Hyperinfection Syndrome. AB - Strongyloides stercoralis is an endemic parasitic infection that can remain asymptomatic for years, but it can cause death in immunosuppressed individuals. Here, we present a case of Strongyloides hyperinfection in a 75-year-old male secondary to sepsis and chronic immunosuppression due to TNF-alpha inhibitors. Despite aggressive treatment including broad-spectrum antibiotics and antihelminths, his respiratory failure worsened and he died after palliative extubation. S. stercoralis infection remains a diagnostic challenge. Presentation with Strongyloides is often nonspecific, and eosinophilia is absent in hyperinfection. Diagnosis can be delayed, especially in low-prevalence areas where suspicion is low. Strongyloides should be considered in the differential diagnosis in the presence of risk factors including immunosuppressive therapy, and a travel history should be carefully obtained. Patients with recurrent enterobacterial sepsis or respiratory failure with diffuse infiltrates in the setting of eosinophilia should undergo testing for Strongyloides. A multidisciplinary approach can result in earlier diagnosis and favorable outcomes. PMID- 30002937 TI - Acute Ascending Flaccid Paralysis Secondary to Multiple Trigger Factor Induced Hyperkalemia. AB - Background: Acute flaccid paralysis is an uncommon, but potentially life threatening, sequel of severe hyperkalemia. Reported primary aetiologies include renal failure, Addison's disease, potassium sparing diuretics, potassium supplements, and dietary excess. Coconut water, when consumed in excess, has been reported to cause severe hyperkalemia. We report the case of acute ascending flaccid paralysis secondary to hyperkalemia induced by multiple trigger factors king coconut water, renal failure, diabetes, metabolic acidosis, and potassium sparing diuretics. Case Presentation: A 78-year-old man presented with acute ascending type flaccid paralysis over five-hour duration and subsequently developed preterminal cardiac arrhythmias secondary to severe hyperkalemia (serum potassium: 7.02 mEq/L). He was on Losartan and Spironolactone for ischemic heart disease. Dietary history revealed excessive intake of king coconut water (Cocos nucifera) over past one week. Electrocardiogram returned to normal rhythm and serum potassium was 6.1 mEq/L within 2 hours of institution of emergency management for life threatening hyperkalemia. Neurological symptoms completely recovered within twenty-four hours without the need for dialysis. Electromyogram three days after the initial presentation revealed normal findings. Conclusions: The report describes a rare case of secondary hyperkalemic flaccid paralysis induced by multiple trigger factors. It is important that patients with risk factors for hyperkalemia are educated regarding avoiding excess dietary potassium. Regular follow-up of these patients is mandatory with review of medication related side effects and serum electrolytes. PMID- 30002938 TI - Arthroscopic Management and Radiographic Interpretation of an Everted Bony Bankart Lesion. AB - Soft tissue injuries are prevalent after traumatic anterior shoulder dislocation. However, bony fractures, often referred to as bony Bankart injuries, are less common. The authors describe the case of a 16-year-old male who displayed a bony Bankart with a unique, everted presentation. The patient presented with left shoulder pain, restricted range of motion, and crepitus. Two weeks prior to physical examination, he sustained a traumatic anterior glenohumeral dislocation after a bicycle accident, which reduced spontaneously. Plain film imaging revealed a bony fragment off the anterior glenoid. Upon critical examination of magnetic resonance imaging axial cuts, the bony fragment was found to be flipped. Intraoperatively, this orientation was confirmed. The fragment was reduced and stabilized in an anatomic position using a double row technique with the capsule then advanced over the top of the fragment using three additional anchors. Imaging four months postoperatively revealed an anatomical reduction of the fragment. To the authors' knowledge, this is the first reported case of bony fragment eversion following traumatic anterior shoulder dislocation. Although the incidence of everted bony fragments following traumatic dislocation is unknown, such a situation presents unique challenges to the orthopedic surgeon. The authors discuss potential eversion mechanisms, fragment identification by imaging, surgical indications, and operative techniques. PMID- 30002941 TI - A Case Report of Pulmonary Exacerbation after Initiation of Lumacaftor/Ivacaftor Therapy in a CF Female with Complicated Lung Disease. AB - Novel targeted treatments for Cystic Fibrosis give rise to new hope for an ever growing number of CF patients with various mutations. However, very little evidence and guidelines exist to steer clinical decisions regarding patients whose illness takes an unexpected course. In such cases, the benefits and risks of discontinuing these treatments must be carefully and individually weighed, since their long-term effects remain mainly uncharted territory. In this report we document the case of a homozygous F508del CF patient with severe lung disease who presented with a pulmonary exacerbation shortly after the beginning of treatment with lumacaftor/ivacaftor and the complicated initial phase of therapy, which was followed by significant improvements. PMID- 30002939 TI - An Inguinal Perivascular Epithelioid Cell Tumor Metastatic to the Orbit. AB - Malignant PEComas are rare mesenchymal neoplasms. These tumors harbor distinct myomelanocytic phenotype. The PEComa family of tumors includes lymphangioleiomyomatosis, angiomyolipoma, clear cell sugar tumor of the lung, and myomelanocytic tumor of the falciparum ligament/ligamentum teres. PEComas have no known normal cell counterpart. Majority of PEComas are benign and occur predominantly in the middle-age women. These tumors are commonly encountered in the uterus. Herein, we report a 20-year-old woman with a left inguinal mass metastatic to orbit, brain, lumbar spine, and skin at presentation. To our knowledge, this is the first case of metastatic PEComa to the orbit. This is the third case of primary PEComa of the inguinal area. PMID- 30002940 TI - Low-Dose Fluoxetine in Four Children with Autistic Spectrum Disorder Improves Self-Injurious Behavior, ADHD-Like Symptoms, and Irritability. AB - Autism Spectrum Disorder (ASD) is defined by the copresence of two core symptoms: alteration in social communication and repetitive behaviors and/or restricted interests. In ASD children and adults, irritability, self-injurious behavior (SIB), and Attention Deficit and Hyperactivity Disorders- (ADHD-) like symptoms are regularly observed. In these situations, pharmacological treatments are sometimes used. Selective Serotonin Reuptake Inhibitors- (SSRI-) based treatments have been the subject of several publications: case reports and controlled studies, both of which demonstrate efficacy on the symptoms mentioned above, even if no consensus has been reached concerning their usage. In this article four clinical cases of children diagnosed with ASD and who also present ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors or irritability and impulsivity treated with low doses of fluoxetine are presented. PMID- 30002942 TI - Inadvertent Traumatic Fracture of Central Venous Catheter during Procurement, Transmitted Through Solid Organ Transplant. AB - Central venous catheters play a pivotal role in the perioperative support of critically ill patients. They are used for administration of fluids, vasopressors, blood products, and various medications; however, their use may be associated with serious complications, such as catheter fracture and embolization. While most data on catheter fracture embolization consist of isolated case reports, only a few studies have examined patients with central venous catheter embolism. We report a traumatic inadvertent transection of central venous catheter that migrated through a donor transplanted liver and was found to be lodged in the recipient's right ventricle. The catheter was retrieved under fluoroscopy using a trilobed snare device. PMID- 30002943 TI - Antidiarrheal and Antioxidant Activities of Methanol Extract of Bryophyllum pinnatum Leaf Harvested from South-Eastern Nigeria in Mice. AB - Bryophyllum pinnatum belongs to the family Crassulaceae and it is commonly used in the ethnomedical practices. This study investigated the antidiarrheal and antioxidant properties of methanol extract of Bryophyllum pinnatum leaf harvested from South-Eastern Nigeria in mice. Cold maceration method in 80% methanol was adopted in the extract preparation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays were used to evaluate the antioxidant property while castor oil-induced diarrhea, small intestinal transit, and enteropooling models were used for the antidiarrheal investigation. The effects of the extract (50, 100, and 200 mg/kg) were compared to distilled water (10 ml/kg) and loperamide (5 mg/kg). The extract produced concentration dependent increase in antioxidant effect in both DPPH and FRAP assay. The extract caused a significant (p < 0.05) reduction in mean stool output, percentage of wet stools, small intestinal transit, and intestinal fluid accumulation in the treated mice when compared to the distilled water treated mice. The study validates the use of Bryophyllum pinnatum in the ethnomedical management of diarrhea. PMID- 30002944 TI - Fecal Incontinence after Posterior Sagittal Anorectoplasty for Anorectal Malformation: A Single-Center Study. AB - Background: Fecal incontinence is one of the worst functional complications of posterior sagittal anorectoplasty for treatment of anorectal malformation. Objectives: In this study, we aimed to identify the prevalence of fecal incontinence in patients with the diagnosis of high or low anorectal malformation who underwent three-stage posterior sagittal anorectoplasty surgery in our center. Patients and Methods: Children with the diagnosis of anorectal malformation who underwent posterior sagittal anorectoplasty at the Department of Pediatric Surgery of Besat Hospital, Hamadan University of Medical Sciences, Iran, from 2012 to 2016 were enrolled in the study. Parents or guardians were recruited and asked to fill the study questionnaire including the Templeton and Ditesheim Scoring System to assess the status of fecal continence of the patients. Results: Thirty-four patients including 10 (29.4%) males were enrolled in the study. High type of anorectal malformation was diagnosed in 23 (67.6%) patients. The overall mean scores of fecal continence were 4.57 +/- 0.84 (range 1.5-5) after a mean follow-up time of 50.7 (range 22.5-69.8) months. Good fecal continence was observed in 91.3% of patients with low type compared to 72.8% of patients with high type of anorectal malformation; however, the difference was not significant (P=0.13). Conclusion: Posterior sagittal anorectoplasty surgery in patients with anorectal malformation may result in acceptable fecal continence. PMID- 30002946 TI - Social autopsy for maternal and perinatal deaths in Bangladesh: a tool for community dialog and decision making. AB - Bangladesh has an established comprehensive death review system for tracking and reviewing maternal and perinatal deaths. This death review system, established in 2010, was initially known as the "Maternal and Perinatal Death Review (MPDR) System." One of the key interventions of the MPDR system, social autopsy (SA), is generally undertaken following a maternal or perinatal death notification. Social autopsy is managed at the community level by government field health workers. The main purpose of SA is to enable community discussion and create awareness of the preventable causes of maternal or neonatal deaths. Through these conversations, it is hoped to reduce future maternal and neonatal deaths. During the scaling up of the system in Bangladesh in 2016, the Ministry of Health and Family Welfare (MoH&FW) included social autopsy as a useful intervention in reviewing death at the community level and named it "Maternal and Perinatal Death Surveillance and Response" (MPDSR). The new MPDSR tool is currently being administered for the the 2017 to 2021 period under the National Health and Nutrition Population Sector Program (HPNSP). This paper seeks to review the experiences of the social autopsy tool, from the initial MPDR system to the current MPDSR system and its role in reducing maternal and neonatal deaths in Bangladesh. PMID- 30002947 TI - Validation of Miniaturized Particulate-Matter Real-Time Samplers for Characterizing Personal Polycyclic Aromatic Hydrocarbon Exposure. AB - This study validates the analysis of polycyclic aromatic hydrocarbons (PAHs) in microgram levels of particulate matter (PM) collected on filters by two low-flow rate, real-time monitors, microPEMTM and microAeth(r). Particle-associated PAHs were analyzed by a coupling of a gas chromatograph to a sensitive, atmospheric pressure laser ionization-mass spectrometer. Air particulate samples were collected over the course of one or two days in the living room of a fourth-floor apartment in New York City. Three types of samplers, the two aforementioned personal samplers and a high-flow rate pump (4 liters per minute), were operated side by side, and three samples of each type were collected during each sampling period. Intrasampler agreement as measured by relative standard deviation (RSD) was within 1% to 18%. After background subtraction, total PAH measured by all three sampler types had good agreement (R=0.99). This ability to accurately characterize personal PAH exposure in archived filters collected by these real time samplers could provide additional important PAH exposure information that can benefit many environmental health studies using these monitors. PMID- 30002945 TI - Dietary fat-associated osteoarthritic chondrocytes gain resistance to lipotoxicity through PKCK2/STAMP2/FSP27. AB - Free fatty acids (FFAs), which are elevated with metabolic syndrome, are considered the principal offender exerting lipotoxicity. Few previous studies have reported a causal relationship between FFAs and osteoarthritis pathogenesis. However, the molecular mechanism by which FFAs exert lipotoxicity and induce osteoarthritis remains largely unknown. We here observed that oleate at the usual clinical range does not exert lipotoxicity while oleate at high pathological ranges exerted lipotoxicity through apoptosis in articular chondrocytes. By investigating the differential effect of oleate at toxic and nontoxic concentrations, we revealed that lipid droplet (LD) accumulation confers articular chondrocytes, the resistance to lipotoxicity. Using high fat diet induced osteoarthritis models and articular chondrocytes treated with oleate alone or oleate plus palmitate, we demonstrated that articular chondrocytes gain resistance to lipotoxicity through protein kinase casein kinase 2 (PKCK2)-six transmembrane protein of prostate 2 (STAMP2)-and fat-specific protein 27 (FSP27) mediated LD accumulation. We further observed that the exertion of FFAs-induced lipotoxicity was correlated with the increased concentration of cellular FFAs freed from LDs, whether FFAs are saturated or not. In conclusion, PKCK2/STAMP2/FSP27-mediated sequestration of FFAs in LD rescues osteoarthritic chondrocytes. PKCK2/STAMP2/FSP27 should be considered for interventions against metabolic OA. PMID- 30002948 TI - Are patients with high-risk polycythemia vera receiving cytoreductive medications? A retrospective analysis of real-world data. AB - Background: Patients with polycythemia vera (PV) have a higher mortality risk compared with the general population, primarily driven by cardiovascular disease, thrombotic events (TEs), and hematologic transformations. The goal of risk adapted therapy in PV is prevention of TEs. Current treatment recommendations indicate that high-risk patients (aged >= 60 years and/or with history of TEs) should be managed with cytoreductive medications, phlebotomy, and low-dose aspirin. This noninterventional study was conducted to describe real-world cytoreductive medication treatment in adult patients with PV, stratified by risk, in the United States. Methods: This retrospective analysis used claims data from the Truven Health MarketScan(r) database. Inclusion criteria were >= 2 nondiagnostic claims for PV >= 30 days apart, age >= 18 years, continuous enrollment during the preindex period (January 1 to December 31, 2012), and continuous enrollment or death during the postindex period (January 1, 2013, to December 31, 2014). Assessments included patient demographics, clinical characteristics, and treatment with cytoreductive medications. Results: A total of 2856 patients were identified for this analysis, including 1823 with high-risk PV and 1033 with low-risk PV. Mean (SD) age was 62.5 (13.5) years, and 65.9% of patients were male. Preindex comorbid conditions of interest were more common in high-risk than low-risk patients, including hypertension (65.0% vs 43.1%), type 2 diabetes (21.7% vs 10.1%), and congestive heart failure (6.6% vs 0.6%). Among patients who received preindex cytoreductive therapy, the most commonly used medications in high-risk (n = 666) and low-risk (n = 160) patients were hydroxyurea (94.7 and 87.5%, respectively), anagrelide (7.4 and 11.9%), and interferon (1.7 and 4.4%). Among patients who initiated cytoreductive therapy postindex, the most commonly used medications in high-risk (n = 100) and low-risk (n = 35) patients were hydroxyurea (97.0 and 91.4%, respectively), anagrelide (4.0 and 2.9%), and interferon (2.0 and 8.6%). Overall, 42.0% of high-risk and 18.9% of low-risk patients received cytoreductive medication during the preindex or postindex periods. Conclusions: Despite consistent guideline recommendations for cytoreductive therapy in patients with high-risk PV, this analysis revealed that only a minority of these patients received cytoreductive medication. A notable proportion of high-risk patients with PV would likely benefit from a revised treatment plan that aligns with current guidelines. PMID- 30002949 TI - High-Performance Virtual Reality Volume Rendering of Original Optical Coherence Tomography Point-Cloud Data Enhanced With Real-Time Ray Casting. AB - Purpose: Feasibility testing of a novel volume renders technology to display optical coherence tomography data (OCT) in a virtual reality (VR) environment. Methods: A VR program was written in C++/OpenGL to import and display volumetric OCT data in real time with 180 frames per second using a high-end computer and a tethered head-mounted display. Following exposure, participants completed a Simulator Sickness Questionnaire (SSQ) to assess for nausea, disorientation, and oculomotor disturbances. A user evaluation study of this software was conducted to explore the potential utility of this application. Results: Fifty-seven subjects completed the user testing (34 males and 23 females). Mean age was 48.5 years (range, 21-77 years). Mean acquired work experience of the 35 ophthalmologists (61.40%) included in the group was 15.46 years (range, 1-37 years). Twenty-nine participants were VR-naive. The SSQ showed a mean total score of 5.8 (SD = 9.44) indicating that the system was well tolerated and produced minimal side effects. No difference was reported between VR-naive participants and experienced users. Overall, immersed subjects reported an enjoyable VR-OCT presence effect. Conclusions: A usable and satisfying VR imaging technique was developed to display and interact with original OCT data. Translational Relevance: An advanced high-end VR image display method was successfully developed to provide new views and interactions in an ultra high-speed projected digital scenery using point-cloud OCT data. This represents the next generation of OCT image display technology and a new tool for patient engagement, medical education, professional training, and telecommunications. PMID- 30002950 TI - Optical Detection of Macular Pigment Formation in Premature Infants. AB - Purpose: To demonstrate the presence of macular pigment in the retina of premature infants, and to examine its changes with age. Methods: The participants included 40 premature infants. Infants who had received laser photocoagulation for retinopathy of prematurity were excluded. Macular pigment optical density (MPOD) was measured by fundus reflectometry using RetCam3, a digital fundus camera. The reflection imaging was performed for ROP screening. The imaging time points were from a post menstrual age (PMA) of 29 weeks 0 days to 46 weeks 5 days. Results: The MPOD levels could be obtained from 39 premature infants. The levels at the first measurement ranged from 0 to 0.18 (mean 0.076, SD 0.044). The earliest time, when a nonvanishing MPOD level was obtained, was at a PMA of 33 weeks and 2 days, and that level was 0.05. The initial examination MPOD levels showed a moderate correlation with age (R2 = 0.32, P < 0.00017). The mean MPOD levels measured each week during the follow-up period showed a very strong correlation with age (R2 = 0.91, P < 0.0001). A regression line of MPOD = 0.0069 * age - 0.1783 was derived, where age is counted in PMA days. Conclusions: The MPOD levels of premature infants were for the first time measured in living eyes. Macular pigment increased linearly with age. Translational Relevance: Macular pigment increased with the development of macular morphology. This result suggested the importance of nutritional management of infants and mothers during perinatal period. PMID- 30002951 TI - The largest European theropod dinosaurs: remains of a gigantic megalosaurid and giant theropod tracks from the Kimmeridgian of Asturias, Spain. AB - The Kimmeridgian Vega, Terenes and Lastres formations of Asturias have yielded a rich vertebrate fauna, represented by both abundant tracks and osteological remains. However, skeletal remains of theropod dinosaurs are rare, and the diversity of theropod tracks has only partially been documented in the literature. Here we describe the only non-dental osteological theropod remain recovered so far, an isolated anterior caudal vertebra, as well as the largest theropod tracks found. The caudal vertebra can be shown to represent a megalosaurine megalosaurid and represents the largest theropod skeletal remain described from Europe so far. The tracks are also amongst the largest theropod footprints reported from any setting and can be assigned to two different morphotypes, one being characterized by its robustness and a weak mesaxony, and the other characterized by a strong mesaxony, representing a more gracile trackmaker. We discuss the recently proposed distinction between robust and gracile large to giant theropod tracks and their possible trackmakers during the Late Jurassic-Berriasian. In the absence of complete pedal skeletons of most basal tetanurans, the identity of the maker of Jurassic giant theropod tracks is difficult to establish. However, the notable robustness of megalosaurine megalosaurids fits well with the described robust morphotypes, whereas more slender large theropod tracks might have been made by a variety of basal tetanurans, including allosaurids, metriocanthosaurids or afrovenatorine megalosaurids, or even exceptionally large ceratosaurs. Concerning osteological remains of large theropods from the Late Jurassic of Europe, megalosaurids seem to be more abundant than previously recognized and occur in basically all Jurassic deposits where theropod remains have been found, whereas allosauroids seem to be represented by allosaurids in Western Europe and metriacanthosaurids in more eastern areas. Short-term fluctuations in sea level might have allowed exchange of large theropods between the islands that constituted Europe during the Late Jurassic. PMID- 30002953 TI - Automatic analysis of treadmill running to estimate times to fatigue and exhaustion in rodents. AB - Introduction: The determination of fatigue and exhaustion in experimental animals is complicated by the subjective nature of the measurement. Typically, it requires an observer to watch exercising animals, e.g. rats running on the treadmill, and to identify the time of the event. In this study, we hypothesized that automatic analysis of the time-averaged position of a rat on a treadmill could be an objective way for estimating times to fatigue and exhaustion. To test this hypothesis, we compared these times measured by a human observer to the results of an automated video tracking system. Methods: Rats, previously familiarized to running on the treadmill, ran at a fixed speed with zero incline, until exhaustion. The experiments were performed at either room temperature (24 degrees C) or in a hot environment (32 degrees C). Each experiment was video recorded. A trained observer estimated the times to fatigue and exhaustion. Then, video tracking software was used to determine the position of the animals on the treadmill belt. The times to fatigue and exhaustion were determined, based on the position on the treadmill using predefined criteria. Results: Manual scores and the average position on the treadmill had significant correlation. Both the observer and the automated video tracking determined that exercise in a hot environment, compared with the exercise at room temperature, results in shorter times to exhaustion and fatigue. Also, estimates of times made by the observer and the automated video tracking were not statistically different from each other. Discussion: A similarity between the estimates of times to fatigue and exhaustion made by the observer and the automated technique suggests that video tracking of rodents running on a treadmill can be used to determine both parameters in experimental studies. Video tracking technique allows for a more objective measure and would allow for an increased performance in experimentation. The Supplemental information to this manuscript contains an Excel file, which includes the code in Virtual Basic with freeware license, to process and visualize running data and automatically estimate the times to fatigue and exhaustion. Instructions for the software are also included. PMID- 30002952 TI - Variable retention harvesting influences belowground plant-fungal interactions of Nothofagus pumilio seedlings in forests of southern Patagonia. AB - Background: The post-harvest recovery and sustained productivity of Nothofagus pumilio forests in Tierra del Fuego may be affected by the abundance and composition of ectomycorrhizal fungi (EMF). Timber harvesting alters EMF community structure in many managed forests, but the impacts of harvesting can vary with the management strategy. The implementation of variable retention (VR) management can maintain, increase, or decrease the diversity of many species, but the effects of VR on EMF in the forests of southern Patagonia have not been studied, nor has the role of EMF in the regeneration process of these forests. Methods: We evaluated the effects of VR management on the EMF community associated with N. pumilio seedlings. We quantified the abundance, composition, and diversity of EMF across aggregate (AR) and dispersed (DR) retention sites within VR managed areas, and compared them to primary forest (PF) unmanaged stands. EMF assemblage and taxonomic identities were determined by ITS-rDNA sequencing of individual root tips sampled from 280 seedlings across three landscape replicates. To better understand seedling performance, we tested the relationships between EMF colonization, EMF taxonomic composition, seedling biomass, and VR treatment. Results: The majority of EMF taxa were Basidiomycota belonging to the families Cortinariaceae (n = 29), Inocybaceae (n = 16), and Thelephoraceae (n = 8), which was in agreement with other studies of EMF diversity in Nothofagus forests. EMF richness and colonization was reduced in DR compared to AR and PF. Furthermore, EMF community composition was similar between AR and PF, but differed from the composition in DR. EMF community composition was correlated with seedling biomass and soil moisture. The presence of Peziza depressa was associated with higher seedling biomass and greater soil moisture, while Inocybe fibrillosibrunnea and Cortinarius amoenus were associated with reduced seedling biomass and lower soil moisture. Seedling biomass was more strongly related to retention type than EMF colonization, richness, or composition. Discussion: Our results demonstrate reduced EMF attributes and altered composition in VR treatments relative to PF stands, with stronger impacts in DR compared to AR. This suggests that VR has the potential to improve the conservation status of managed stands by supporting native EMF in AR. Our results also demonstrate the complex linkages between retention treatments, fungal community composition, and tree growth at individual and stand scales. PMID- 30002954 TI - Nitrogen addition increases the contents of glomalin-related soil protein and soil organic carbon but retains aggregate stability in a Pinus tabulaeformis forest. AB - Background: Glomalin-related soil protein (GRSP) and soil organic carbon (SOC) contribute to the formation and stability of soil aggregates, but the mechanism by which global atmospheric nitrogen (N) deposition changes soil aggregate stability by altering the distribution of GRSP and SOC in different aggregate fractions remains unknown. Methods: We used a gradient N addition (0-9 g N m-2 y 1) in Pinus tabulaeformis forest for two years in northeast China and then examined the changes in SOC contents, total GRSP (T-GRSP), and easily extractable GRSP (EE-GRSP) contents in three soil aggregate fractions (macro-aggregate: >250 MUm, micro-aggregate: 250-53 MUm, and fine material: <53 MUm) and their relationship with aggregate stability. Results: (1) The soil was dominated by macro-aggregates. Short term N addition had no significant effect on mean weight diameter (MWD) and geometric mean diameter (GMD). (2) GRSP varied among aggregate fractions, and N addition had different effects on the distribution of GRSP in aggregate fractions. The EE-GRSP content in the macro-aggregates increased initially and then decreased with increasing N addition levels, having a peak value of 0.480 mg g-1 at 6 g N m-2 y-1. The micro-aggregates had the lowest EE GRSP content (0.148 mg g-1) at 6 g N m-2 y-1. Furthermore, the T-GRSP content significantly increased in the aggregate fractions with the N addition levels. (3) The macro-aggregate had the highest SOC content, followed by the micro aggregate and the fine material had the lowest SOC content. N addition significantly increased the SOC content in all the aggregate fractions. (4) GRSP and SOC contents were not significantly correlated with MWD. Conclusion: Glomalin related soil protein and SOC contents increased by N addition, but this increase did not enhance aggregate stability in short term, and the improvement of stability might depend on binding agents and incubation time. PMID- 30002955 TI - Responses of an oyster host (Crassostrea virginica) and its protozoan parasite (Perkinsus marinus) to increasing air temperature. AB - Background: Changes in climate are predicted to influence parasite and pathogen infection patterns in terrestrial and marine environments. Increases in temperature in particular may greatly alter biological processes, such as host parasite interactions. For example, parasites could differentially benefit from increased reproduction and transmission or hosts could benefit from elevated immune responses that may mediate or even eliminate infections. In the southeastern United States, the Eastern oyster, Crassostrea virginica, is infected by the lethal protozoan parasite, Perkinsus marinus. Under field conditions, intertidal (air-exposed) oysters have been found to have significantly higher P. marinus infection intensity and marginally higher infection prevalence than subtidal (submerged) oysters. During summer, air temperatures are much warmer than water and this exposure of intertidal oysters to higher temperatures is a suggested mechanism for increased infection intensity. Methods: We simulated intertidal exposure using controlled laboratory experiments to determine how host traits (survival and immune response) and parasite infection intensity will respond to elevated air temperature ranging from 27 degrees C to 53 degrees C during emersion at low tide. In Georgia, where our work was conducted, the average summer water temperature is 29 degrees C and the average maximum high air temperature in July is 33 degrees C (though oysters have been shown to survive at much higher air temperatures). Results: Host survival declined as temperature increased, with a definitive drop-off between 39-43 degrees C. Negative effects of air temperature on host immune response (phagocytic activity) were detectable only at extremely high temperatures (47-50 degrees C) when hosts were suffering acute mortality. Parasite infection intensity peaked at 35 degrees C. Discussion: Our results suggest that an increase in average summer air temperature to 35 degrees C or higher could affect oyster survival directly through temperature-related impacts in the short-term and indirectly through increased P. marinus infection intensity over the long-term. PMID- 30002956 TI - Genetic analysis of water loss of excised leaves associated with drought tolerance in wheat. AB - Background: Wheat is widely affected by drought. Low excised-leaf water loss (ELWL) has frequently been associated with improved grain yield under drought. This study dissected the genetic control of ELWL in wheat, associated physiological, morphological and anatomical leaf traits, and compared these with yield QTLs. Methods: Ninety-four hexaploid wheat (Triticum aestivum L.) doubled haploids, mapped with over 700 markers, were tested for three years for ELWL from detached leaf 4 of glasshouse-grown plants. In one experiment, stomata per unit area and leaf thickness parameters from leaf cross-sections were measured. QTLs were identified using QTLCartographer. Results: ELWL was significantly negatively correlated with leaf length, width, area and thickness. Major QTLs for ELWL during 0-3 h and 3-6 h were coincident across trials on 3A, 3B, 4B, 5B, 5D, 6B, 7A, 7B, 7D and frequently coincident (inversely) with leaf size QTLs. Yield in other trials was sometimes associated with ELWL and leaf size phenotypically and genotypically, but more frequently under non-droughted than droughted conditions. QTL coincidence showed only ELWL to be associated with drought/control yield ratio. Discussion: Our results demonstrated that measures of ELWL and leaf size were equally effective predictors of yield, and both were more useful for selecting under favourable than stressed conditions. PMID- 30002957 TI - Recombination between T-DNA insertions to cause chromosomal deletions in Arabidopsis is a rare phenomenon. AB - We previously described the identification of a chromosomal deletion in Arabidopsis thaliana that resulted in the elimination of genomic DNA between two T-DNA insertions located ca. 25 kilobases apart on chromosome IV. The mechanism responsible for this deletion appears to have been recombination between the closely spaced T-DNA elements located in trans in a parent plant. In our original study, we observed one such deletion event after screening ca. 2,000 seedlings using a polymerase chain reaction (PCR) assay. Because a method for precisely deleting a selected region of the Arabidopsis genome would have significant value as a research tool, we were interested in determining the frequency with which this type of T-DNA-directed deletion occurs. To do this we designed a genetic screen that would allow us to phenotypically screen for deletions caused by recombination between T-DNA inserts. This screen involved crossing T-DNA single mutant lines in order to produce F1 plants in which the two T-DNA insertions flanked a FUSCA (FUS) locus present in the genome. Loss-of-function mutations of FUS genes cause a distinctive developmental phenotype that can be easily scored visually in young seedlings. We used T-DNA lines flanking FUS2, FUS6, FUS7, and FUS11 for this study. Recombination between the T-DNAs in an F1 parent should result in deletion of the FUS gene located between the T-DNAs. Because the deletion would be heterozygous in the F2 generation, we screened the F3 progeny of pooled F2 individuals to search for the fus loss-of-function phenotype. Using this strategy we were able to evaluate a total of 28,314 meioses for evidence of deletions caused by recombination between the T-DNA inserts. No seedlings displaying the fus phenotype were recovered, suggesting that deletions caused by recombination between T-DNA inserts are relatively rare events and may not be a useful tools for genome engineering in Arabidopsis. PMID- 30002958 TI - Spatial changes in zooplankton communities in a strong human-mediated river ecosystem. AB - River damming causes a decrease in water current velocity which leads to an increase in richness and abundance of organisms atypical for running waters. Zooplankton is a representative example of such organisms. The influx of zooplankton from carp ponds is an additional factor that increases richness and abundance of zooplankton in rivers. We hypothesized that zooplankton dispersing from the carp ponds colonize the impoundments in river and the richness of zooplankton increase in impoundments by development of new species, not observed in the upstream. The zooplankton was collected monthly from April to September of 2013 and 2014. Sampling sites were located in the Barycz river (in the lotic sections and in the dam impoundments), as well as in its tributaries, which are the outlets of carp ponds. The most changes in zooplankton richness and abundance were observed at sites located within the dam impoundments, especially in relation to the lower values of the current velocity. Since the abundance of pelagic rotifers, cladocerans and copepods in the carp pond outlets was similar to that at lower sites in the Barycz, the influence of the carp pond outlets on the abundance in the dam and lotic sections was significant. The river itself in its impounded sections provides advantageous conditions for retention and colonization by a high abundance of zooplankton dispersing from the carp ponds, and for the development of species not occurred in the upstream, which, in turn, increases richness. PMID- 30002959 TI - Effects of estrogens and antiestrogens on gonadal sex differentiation and embryonic development in the domestic fowl (Gallus gallus domesticus). AB - Since it is known that environmental contaminants have the potential to cause endocrine disorders in humans and animals, there is an urgent need for in vivo tests to assess possible effects of these endocrine disrupting chemicals (EDCs). Although there is no standardized guideline, the avian embryo has proven to be particularly promising as it responds sensitively to a number of EDCs preferentially impacting the reproductive axis. In the present study we examined the effects of in ovo exposure to fulvestrant and tamoxifen as antiestrogenic model compounds and co-exposure to both substances and the potent estrogen 17alpha-ethinylestradiol (EE2) regarding sex differentiation and embryonic development of the domestic fowl (Gallus gallus domesticus). The substances were injected into the yolk of fertilized eggs on embryonic day 1. On embryonic day 19 sex genotype and phenotype were determined, followed by gross morphological and histological examination of the gonads. Sole EE2-treatment (20 ng/g egg) particularly affected male gonads and resulted in an increased formation of female-like gonadal cortex tissue and a reduction of seminiferous tubules. In ovo exposure to tamoxifen (0.1/1/10 ug/g egg) strongly impaired the differentiation of female gonads, led to a significant size reduction of the left ovary and induced malformations of the ovarian cortex, while fulvestrant (0.1/1/10 ug/g egg) did not affect sexual differentiation. However, both antiestrogens were able to antagonize the feminizing effects of EE2in genetic males when administered simultaneously. Since both estrogens and antiestrogens induce concentration dependent morphological alterations of the sex organs, the chick embryo can be regarded as a promising model for the identification of chemicals with estrogenic and antiestrogenic activity. PMID- 30002961 TI - Nitrous oxide variability at sub-kilometre resolution in the Atlantic sector of the Southern Ocean. AB - The Southern Ocean is an important region for global nitrous oxide (N2O) cycling. The contribution of different source and sink mechanisms is, however, not very well constrained due to a scarcity of seawater data from the area. Here we present high-resolution surface N2O measurements from the Atlantic sector of the Southern Ocean, taking advantage of a relatively new underway setup allowing for collection of data during transit across mesoscale features such as frontal systems and eddies. Covering a range of different environments and biogeochemical settings, N2O saturations and sea-to-air fluxes were highly variable: Saturations ranged from 96.5% at the sea ice edge in the Weddell Sea to 126.1% across the Polar Frontal Zone during transit to South Georgia. Negative sea-to-air fluxes (N2O uptake) of up to -1.3 umol m-2 d-1 were observed in the Subantarctic Zone and highest positive fluxes (N2O emission) of 14.5 umol m-2 d-1 in Stromness Bay, coastal South Georgia. Although N2O saturations were high in areas of high productivity, no correlation between saturations and chlorophyll a (as a proxy for productivity) was observed. Nevertheless, there is a clear effect of islands and shallow bathymetry on N2O production as inferred from supersaturations. PMID- 30002962 TI - Who bears the cost of forest conservation? AB - Background: While the importance of conserving ecosystems for sustainable development is widely recognized, it is increasingly evident that despite delivering global benefits, conservation often comes at local cost. Protected areas funded by multilateral lenders have explicit commitments to ensure that those negatively affected are adequately compensated. We make the first comparison of the magnitude and distribution of the local costs of a protected area with the magnitude and distribution of the compensation provided under the World Bank social safeguard policies (Performance Standard 5). Methods: In the Ankeniheny-Zahamena Corridor (a new protected area and REDD+ pilot project in eastern Madagascar), we used choice experiments to estimate local opportunity costs (n = 453) which we annualized using a range of conservative assumptions concerning discount rates. Detailed surveys covering farm inputs and outputs as well as off-farm income (n = 102) allowed us to explore these opportunity costs as a proportion of local incomes. Intensive review of publically available documents provided estimates of the number of households that received safeguard compensation and the amount spent per household. We carried out a contingent valuation exercise with beneficiaries of this compensation two years after the micro-development projects were implemented (n = 62) to estimate their value as perceived by beneficiaries. Results: Conservation restrictions result in very significant costs to forest communities. The median net present value of the opportunity cost across households in all sites was US$2,375. When annualized, these costs represent 27-84% of total annual income for median-income households; significantly higher proportionally for poorer households. Although some households have received compensation, we conservatively estimate that more than 50% of eligible households (3,020 households) have not. Given the magnitude of compensation (based both on amount spent and valuation by recipients two years after the compensation was distributed) relative to costs, we argue that no one was fully compensated. Achieving full compensation will require an order of magnitude more than was spent but we suggest that this should be affordable given the global value of forest conservation. Discussion: By analyzing in unprecedented depth both the local costs of conservation, and the compensation distributed under donor policies, we demonstrate that despite well-intentioned policies, some of the poorest people on the planet are still bearing the cost of forest conservation. Unless significant extra funding is provided by the global beneficiaries of conservation, donors' social safeguarding requirements will not be met, and forest conservation in developing countries will jeopardize, rather than contribute to, sustainable development goals. PMID- 30002960 TI - Novel inflammatory cell infiltration scoring system to investigate healthy and footrot affected ovine interdigital skin. AB - Ovine footrot is a degenerative disease of sheep feet leading to the separation of hoof-horn from the underlying skin and lameness. This study quantitatively examined histological features of the ovine interdigital skin as well as their relationship with pro-inflammatory cytokine (IL-1beta) and virulent Dichelobacter nodosus in footrot. From 55 healthy and 30 footrot ovine feet, parallel biopsies (one fixed for histology) were collected post-slaughter and analysed for lesions and histopathological analysis using haematoxylin and eosin and Periodic Acid Schiff. Histological lesions were similar in both conditions while inflammatory scores mirror IL-1beta expression levels. Increased inflammatory score corresponded with high virulent D. nodosus load and was significant (p < 0.0001) in footrot feet with an inflammatory score of 3 compared to scores 1 and 2. In addition, in contrast to healthy tissues, localisation of eubacterial load extended beyond follicular depths in footrot samples. The novel inflammatory cell infiltration scoring system in this study may be used to grade inflammatory response in the ovine feet and demonstrated an association between severity of inflammatory response and increased virulent D. nodosus load. PMID- 30002963 TI - Fabrication of calixarene-grafted bio-polymeric magnetic composites for magnetic solid phase extraction of non-steroidal anti-inflammatory drugs in water samples. AB - Calixarene framework functionalized bio-polymeric magnetic composites (MSp-TDI calix) were synthesized and utilized as magnetic solid-phase extraction (MSPE) sorbent for the extraction of non-steroidal anti-inflammatory drugs (NSAIDs), namely indoprofen (INP), ketoprofen (KTP), ibuprofen (IBP) and fenoprofen (FNP), from environmental water samples. MSp-TDI-calix was characterized by FT-IR, XRD, FESEM, EDX, VSM and BET analysis, and the results were compared with Sp-TDI and Sp-TDI-calix. To maximize the extraction performance of MSp-TDI-calix decisive MSPE affective parameters such as sorbent amount, extraction time, sample volume, type of organic eluent, volume of organic eluent, desorption time and pH were comprehensively optimized prior to HPLC-DAD determination. The analytical validity of the proposed MSPE method was evaluated under optimized conditions and the following figures of merit were acquired: linearity with good determination coefficient (R2 >= 0.991) over the concentration range of 0.5-500 ug/L, limits of detection (LODs) ranged from 0.06-0.26 ug/L and limits of quantitation (LOQ) between 0.20-0.89 ug/L. Excellent reproducibility and repeatability under harsh environment with inter-day and intra-day relative standard deviations were obtained in the range of 2.5-3.2% and 2.4-3.9% respectively. The proposed method was successfully applied for analysis of NSAIDs in tap water, drinking water and river water with recovery efficiency ranging from 88.1-115.8% with %RSD of 1.6 4.6%. PMID- 30002964 TI - Honey reduces the metastatic characteristics of prostate cancer cell lines by promoting a loss of adhesion. AB - Honey has been shown to have a range of therapeutic effects in humans, with anti inflammatory and anti-bacterial effects among those previously characterised. Here, we examine the possibility of New Zealand thyme, manuka and honeydew honeys, and their major sugar and phenolic components, reducing the development of metastatic cancer. Their activity was examined in vitro, in PC3 and DU145 prostate cancer cell lines, through measuring the compounds' effects on the metastatic characteristics of migration, invasion and adhesion. First, the phenolic compounds gallic acid, caffeic acid, quercetin, kaempferol and chrysin were quantified in the honeys using high performance liquid chromatography, and found in nanomolar concentrations. In a Boyden chamber-based migration assay, non toxic concentrations of thyme and honeydew honeys reduced cell migration by 20%, and all phenolic compounds except caffeic acid also lowered migration, although a mixture of only the sugars found in honey had no effect. All of the honeys, phenolics and the sugar-only mixture reduced invasive movement of cells through extracellular matrix by up to 75%. Most notably, each of the three honeys and the sugar-only mixture reduced cell adhesion to collagen I by 90%. With the exception of quercetin, phenolic compounds did not reduce adhesion. Therefore, honey and its sugar and phenolic components can lower the metastatic properties of cancer cells, and may do this by preventing effective cell adhesion to the extracellular matrix. The sugars and phenol compounds of honey are much more effective in combination than individually. PMID- 30002966 TI - Peptide presentation by HLA-DQ molecules is associated with the development of immune tolerance. AB - HLA class II proteins are important elements of human adaptive immune recognition and are associated with numerous infectious and immune-mediated diseases. These highly variable molecules can be classified into DP, DQ and DR groups. It has been proposed that in contrast with DP and DR, epitope binding by DQ variants rather results in immune tolerance. However, the pieces of evidence are limited and controversial. We found that DQ molecules bind more human epitopes than DR. Pathogen-associated epitopes bound by DQ molecules are more similar to human proteins than the ones bound by DR. Accordingly, DQ molecules bind epitopes of significantly different pathogen species. Moreover, the binding of autoimmunity associated epitopes by DQ confers protection from autoimmune diseases. Our results suggest a special role of HLA-DQ in immune homeostasis and help to better understand the association of HLA molecules with infectious and autoimmune diseases. PMID- 30002965 TI - Genetic polymorphisms and forensic efficiency of 19 X-chromosomal STR loci for Xinjiang Mongolian population. AB - Aim: X-chromosomal short tandem repeat (X-STR) loci are playing an increasingly important role in some complex kinship cases in recent years. To investigate the forensic efficiency of X-STRs of Mongolian minority group from Xinjiang Uygur Autonomous Region, China, and further depict the genetic relationship among Xinjiang Mongolians and other populations, 267 blood samples from unrelated healthy Xinjiang Mongolians were amplified by an AGCU X-19 STR kit. Results: No deviations for all 19 X-STR loci were observed from the Hardy-Weinberg equilibrium after Bonferroni correction (p > 0.0026) in female samples. The most frequent allele was allele 10 at locus DXS10164 with the frequency 0.5663. The polymorphism information content values of the 19 X-STR loci were more than 0.5 with the highest polymorphism at the locus DXS10135. The cumulative power of discrimination were 0.99999999999999999999988761005481 in females and 0.999999999999903 in males, respectively; and the cumulative mean exclusion chances were 0.9999999969738068321121 in duos and 0.999999999998952 in trios, respectively. The seven linkage groups were extremely informative, with all the haplotype diversities greater than 0.9487. No linkage disequilibrium was observed for a significance level of 0.00029 (p = 0.05/171) after Bonferroni correction. The DA distances, multidimensional scaling plot and phylogenetic tree based on the 11 overlapping X-STR loci all presented that the Xinjiang Mongolian population was genetically different from other Asian populations, including the Mongolian population from Inner Mongolia Autonomous Region, China. Conclusion: This study indicated that the 19 X-STR multiplex PCR system was of high utility value for both forensic practices and population genetic research in Xinjiang Mongolian group. PMID- 30002967 TI - Levels of DNA cytosine methylation in the Drosophila genome. AB - Insects provide an accessible system to study the contribution of DNA methylation to complex epigenetic phenotypes created to regulate gene expression, chromatin states, imprinting and dosage compensation. The members of genus Drosophila have been used as a model system to study aspects of biology like development, behaviour and genetics. Despite the popularity of Drosophila melanogaster as a genetic and epigenetic model organism, DNA methylation studies are limited due to low levels of genomic 5-methylcytosine. Our study employs a sensitive liquid chromatography-mass spectrometry (LCMS) based method to quantify the levels of 5 methylcytosine from the genomic DNA in different members of the genus Drosophila. Our results reveal that, despite being phylogenetically related, there is a marked variation in the levels of 5-methylcytosine between the genomes of the members of genus Drosophila. Also, there is a change in the genomic levels of 5 methylcytosine through each life cycle stage of holometabolous development in D. melanogaster. PMID- 30002968 TI - Hummingbird migration and flowering synchrony in the temperate forests of northwestern Mexico. AB - Background: Many species of birds are morphologically and physiologically adapted for migration. Migratory movements of birds can range from thousands of kilometers, such as when birds migrate from wintering to breeding sites in summer, to several kilometers, such as when birds migrate among habitats in a single mountain system. The main factor that influences bird migration is the seasonal fluctuation of food resources; climate, predation, competition for resources and endogenous programming are also important factors. Hummingbirds are highly dependent on nectar, so their migration is likely correlated with the blooming of plant species. The ecological implications of altitudinal migration in the mountains of North America as well as the latitudinal migration of Selasphorus rufus through Mexico are still poorly understood. To explore these issues, over three non-consecutive years, we evaluated interannual variation in the phenologies of a latitudinal migrant (S. rufus) and an altitudinal migrant (Amazilia beryllina) and their visited plants. Methods: We assessed the relationship between two migratory hummingbirds and flower abundance in 20 fixed radius plots (25 m radius). All available flowers were counted along transects (40 * 5 m) inside each fixed-radius plot. Sampling was performed every 10 days from November 12 through February 20 of 2010-2011, 2013-2014 and 2015-2016, resulting in a total of 11 samples of each plot per period. Phenological variation and the relationships among hummingbird abundance, flower abundance and vegetation type were evaluated using a generalized additive mixed model. Results: S. rufus abundance was related to sampling time in the first and third periods; this relationship was not significant in the second period. A. beryllina abundance was related with the sampling time over all three periods. The abundance of S. rufus hummingbirds was significantly related to the number of Salvia iodantha flowers. The abundance of A. beryllina hummingbirds was related to the number of S. iodantha and Cestrum thyrsoideum flowers and the total number of flowers. We found a non-significant correlation between S. rufus and A. beryllina abundance and vegetation types. Conclusion: Contrary to expectations, the long-distance migration of S. rufus was not consistent over the sampling periods. The migration of S. rufus through the study region may be altered by changes in climate, as has occurred with other species of migratory birds. In the present study, the migration of S. rufus was correlated with the blooming of S. iodantha. In comparison, the altitudinal migrant A. beryllina responded to the availability of floral resources but was not associated with a particular plant. The migration of this latter species in the area probably depends on multiple factors, including climatic and demographic factors, but is particularly dependent on the supply of floral resources and competition for these resources. PMID- 30002969 TI - Testing accuracy in 2D and 3D geometric morphometric methods for cut mark identification and classification. AB - The analysis of bone surface modifications (BSMs) is a prominent part of paleoanthropological studies, namely taphonomic research. Behavioral interpretations of the fossil record hinge strongly upon correct assessment of BSMs. With the significant impact of microscopic analysis to the study of BSMs, multiple authors have discussed the reliability of these technological improvements for gaining resolution in BSM discrimination. While a certain optimism is present, some important questions are ignored and others overemphasized without appropriate empirical support. This specifically affects the study of cut marks. A diversity of geometric morphometric approaches applied to the study of cut marks have resulted in the coexistence (and competition) of different 2D and 3D methods. The present work builds upon the foundation of experiments presented by Mate-Gonzalez et al. (2015), Courtenay et al. (2017) and Otarola-Castillo et al. (2018) to contrast for the first time 2D and 3D methods in their resolution of cut mark interpretation and classification. The results presented here show that both approaches are equally valid and that the use of sophisticated 3D methods do not contribute to an improvement in accuracy. PMID- 30002970 TI - Enriched environment prevents oxidative stress in zebrafish submitted to unpredictable chronic stress. AB - Background: The enriched environment (EE) is a laboratory housing model that emerged from efforts to minimize the impact of environmental conditions on laboratory animals. Recently, we showed that EE promoted positive effects on behavior and cortisol levels in zebrafish submitted to the unpredictable chronic stress (UCS) protocol. Here, we expanded the characterization of the effects of UCS protocol by assessing parameters of oxidative status in the zebrafish brain and reveal that EE protects against the oxidative stress induced by chronic stress. Methods: Zebrafish were exposed to EE (21 or 28 days) or standard housing conditions and subjected to the UCS protocol for seven days. Oxidative stress parameters (lipid peroxidation (TBARS), reactive oxygen species (ROS) levels, non protein thiol (NPSH) and total thiol (SH) levels, superoxide dismutase (SOD) and catalase (CAT) activities were measured in brain homogenate. Results: Our results revealed that UCS increased lipid peroxidation and ROS levels, while decreased NPSH levels and SOD activity, suggesting oxidative damage. EE for 28 days prevented all changes induced by the UCS protocol, and EE for 21 days prevented the alterations on NPSH levels, lipid peroxidation and ROS levels. Both EE for 21 or 28 days increased CAT activity. Discussion: Our findings reinforce the idea that EE exerts neuromodulatory effects in the zebrafish brain. EE promoted positive effects as it helped maintain the redox homeostasis, which may reduce the susceptibility to stress and its oxidative impact. PMID- 30002971 TI - Influence of elevated CO2 on development and food utilization of armyworm Mythimna separata fed on transgenic Bt maize infected by nitrogen-fixing bacteria. AB - Background: Bt crops will face a new ecological risk of reduced effectiveness against target-insect pests owing to the general decrease in exogenous-toxin content in Bt crops grown under elevated carbon dioxide (CO2). The method chosen to deal with this issue may affect the sustainability of transgenic crops as an effective pest management tool, especially under future atmospheric CO2 level raising. Methods: In this study, rhizobacterias, as being one potential biological regulator to enhance nitrogen utilization efficiency of crops, was selected and the effects of Bt maize (Line IE09S034 with Cry1Ie vs. its parental line of non-Bt maize Xianyu 335) infected by Azospirillum brasilense (AB) and Azotobacter chroococcum (AC) on the development and food utilization of the target Mythimna separate under ambient and double-ambient CO2 in open-top chambers from 2016 to 2017. Results: The results indicated that rhizobacteria infection significantly increased the larval life-span, pupal duration, relative consumption rate and approximate digestibility of M. separata, and significantly decreased the pupation rate, pupal weight, adult longevity, fecundity, relative growth rate, efficiency of conversion of digested food and efficiency of conversion of ingested food of M. separata fed on Bt maize, while here were opposite trends in development and food utilization of M. separata fed on non-Bt maize infected with AB and AC compared with the control buffer in 2016 and 2017 regardless of CO2 level. Discussion: Simultaneously, elevated CO2 and Bt maize both had negative influence on the development and food utilization of M. separata. Presumably, CO2 concentration arising in future significantly can increase their intake of food and harm to maize crop; however, Bt maize infected with rhizobacterias can reduce the field hazards from M. separata and the application of rhizobacteria infection can enhance the resistance of Bt maize against target lepidoptera pests especially under elevated CO2. PMID- 30002972 TI - Motor self-regulation in goats (Capra aegagrus hircus) in a detour-reaching task. AB - Motor self-regulation is the ability to inhibit a prepotent response to a salient cue in favour of a more appropriate response. Motor self-regulation is an important component of the processes that interact to generate effective inhibitory control of behaviour, and is theorized to be a prerequisite of complex cognitive abilities in humans and other animals. In a large comparative study using the cylinder task, motor self-regulation was studied in 36 different species, mostly birds and primates. To broaden the range of species to comprehensively evaluate this phenomenon, motor self-regulation was studied in the domestic goat, which is a social ungulate species and moderate food specialist. Using the cylinder task, goats were first trained to perform a detour reaching response to retrieve a reward from an opaque cylinder. Subsequently, an otherwise identical transparent cylinder was substituted for the opaque cylinder over 10 test trials. The goats' ability to resist approaching the visible reward directly by touching the cylinder and to retain the trained detour-reaching response was measured. The results indicated that goats showed motor self regulation at a level comparable to or better than that of many of the bird and mammal species tested to date. However, the individual reaction patterns revealed large intra- and inter-individual variability regarding motor self-regulation. An improvement across trials was observed only in latency to make contact with the reward; no improvement in the proportion of accurate trials was observed. A short, distinct pointing gesture by the experimenter during baiting did not have any impact on the side of the cylinder to which the goats detoured. In half of goats, individual side biases were observed when detouring to the side of the cylinder, but there was no bias at the population level for either the left or right side. The results underline the need for a detailed examination of individual performance and additional measures to achieve a complete understanding of animal performance in motor self-regulation tasks. PMID- 30002973 TI - Local and relaxed clocks: the best of both worlds. AB - Time-resolved phylogenetic methods use information about the time of sample collection to estimate the rate of evolution. Originally, the models used to estimate evolutionary rates were quite simple, assuming that all lineages evolve at the same rate, an assumption commonly known as the molecular clock. Richer and more complex models have since been introduced to capture the phenomenon of substitution rate variation among lineages. Two well known model extensions are the local clock, wherein all lineages in a clade share a common substitution rate, and the uncorrelated relaxed clock, wherein the substitution rate on each lineage is independent from other lineages while being constrained to fit some parametric distribution. We introduce a further model extension, called the flexible local clock (FLC), which provides a flexible framework to combine relaxed clock models with local clock models. We evaluate the flexible local clock on simulated and real datasets and show that it provides substantially improved fit to an influenza dataset. An implementation of the model is available for download from https://www.github.com/4ment/flc. PMID- 30002974 TI - Stream acidification and reduced aquatic prey availability are associated with dietary shifts in an obligate riparian Neotropical migratory songbird. AB - Streams and their surrounding riparian habitats are linked by reciprocal exchanges of insect prey essential to both aquatic and terrestrial consumers. Aquatic insects comprise a large proportion of total prey in riparian habitats and are opportunistically exploited by terrestrial insectivores; however, several species of songbirds are known to preferentially target aquatic prey via specialized foraging strategies. For these songbirds, reduced availability of aquatic insects via stream acidification may result in compensatory changes in provisioning during the nesting period, thereby influencing both adult and nestling diet composition. In this study, we used DNA metabarcoding to test the hypothesis that an obligate riparian Neotropical migratory songbird, the Louisiana Waterthrush (Parkesia motacilla), expands its diet to compensate for the loss of preferred aquatic prey taxa (primarily pollution-sensitive Ephemeroptera, Plecoptera, and Trichoptera) as a result of stream acidification. Our results revealed that both adult and nestling waterthrush exhibited an increase in dietary richness and niche breadth resulting from the consumption of terrestrial prey taxa in acidified riparian habitats. In contrast, compensatory dietary shifts were not observed in syntopic Neotropical migrant species known to primarily provision terrestrial prey taxa. In addition to providing support for our hypothesis that waterthrush compensate for stream acidification and aquatic prey limitations by expanding their diet, our findings highlight the vulnerability of Louisiana Waterthrush to anthropogenic disturbances that compromise stream quality or reduce the availability of pollution-sensitive aquatic insects. PMID- 30002975 TI - Combining motor imagery with action observation training does not lead to a greater autonomic nervous system response than motor imagery alone during simple and functional movements: a randomized controlled trial. AB - Both motor imagery (MI) and action observation (AO) trigger the activation of the neurocognitive mechanisms that underlie the planning and execution of voluntary movements in a manner that resembles how the action is performed in a real way. The main objective of the present study was to compare the autonomic nervous system (ANS) response in an isolated MI group compared to a combined MI + AO group. The mental tasks were based on two simple movements that are recorded in the revised movement imagery questionnaire in third-person perspective. The secondary objective of the study was to test if there was any relationship between the ANS variables and the ability to generate mental motor imagery, the mental chronometry and the level of physical activity. The main outcomes that were measured were heart rate, respiratory rate and electrodermal activity. A Biopac MP150 system, a measurement device of autonomic changes, was used for the quantification and evaluation of autonomic variables. Forty five asymptomatic subjects were selected and randomized in three groups: isolated MI, MI + AO and control group (CG). In regards to the activation of the sympathetic nervous system (SNS), no differences were observed between MI and MI + AO groups (p > .05), although some differences were found between both groups when compared to the CG (p < .05). Additionally, even though no associations were reported between the ANS variables and the ability to generate mental motor imagery, moderate strong positive associations were found in mental chronometry and the level of physical activity. Our results suggest that MI and MI + AO, lead to an activation of the SNS, although there are no significant differences between the two groups. Based on results obtained, we suggest that tasks of low complexity, providing a visual input through the AO does not facilitates their subsequent motor imagination. A higher level of physical activity as well as a longer time to perform mental task, seem to be associated with a greater increase in the ANS response. PMID- 30002977 TI - The cranial endocast of the Upper Devonian dipnoan 'Chirodipterus' australis. AB - One of the first endocasts of a dipnoan (lungfish) to be realised was that of the Upper Devonian taxon Chirodipterus australis. This early interpretation was based on observations of the shape of the cranial cavity alone and was not based on a natural cast or 'steinkern' nor from serial sectioning. The validity of this reconstruction is therefore questionable and continued reference to and use of this interpretation in analyses of sarcopterygian cranial evolution runs the risk of propagation of error. Here we present a new detailed anatomical description of the endocast of 'Chirodipterus' australis from the Upper Devonian Gogo Formation of Western Australia, known for exceptional 3D preservation which enables fine scale scrutiny of endocranial anatomy. We show that it exhibits a suite of characters more typical of Lower and Middle Devonian dipnoan taxa. Notably, the small utricular recess is unexpected for a taxon of this age, whereas the ventral expansion of the telencephalon is more typical of more derived taxa. The presence of such 'primitive' characters in 'C.' australis supports its relatively basal position as demonstrated in the most recent phylogenies of Devonian Dipnoi. PMID- 30002976 TI - Fossil eggshell cuticle elucidates dinosaur nesting ecology. AB - The cuticle layer consisting mainly of lipids and hydroxyapatite (HAp) atop the mineralized avian eggshell is a protective structure that prevents the egg from dehydration and microbial invasions. Previous ornithological studies have revealed that the cuticle layer is also involved in modulating the reflectance of eggshells in addition to pigments (protoporphyrin and biliverdin). Thus, the cuticle layer represents a crucial trait that delivers ecological signals. While present in most modern birds, direct evidence for cuticle preservation in stem birds and non-avian dinosaurs is yet missing. Here we present the first direct and chemical evidence for the preservation of the cuticle layer on dinosaur eggshells. We analyze several theropod eggshells from various localities, including oviraptorid Macroolithus yaotunensis eggshells from the Late Cretaceous deposits of Henan, Jiangxi, and Guangdong in China and alvarezsaurid Triprismatoolithus eggshell from the Two Medicine Formation of Montana, United States, with the scanning electron microscope (SEM), electron probe micro analysis (EPMA), and Raman spectroscopy (RS). The elemental analysis with EPMA shows high concentration of phosphorus at the boundary between the eggshell and sediment, representing the hydroxyapatitic cuticle layer (HAp). Depletion of phosphorus in sediment excludes the allochthonous origin of the phosphorus in these eggshells. The chemometric analysis of Raman spectra collected from fossil and extant eggs provides further supportive evidence for the cuticle preservation in oviraptorid and probable alvarezsaurid eggshells. In accordance with our previous discovery of pigments preserved in Cretaceous oviraptorid dinosaur eggshells, we validate the cuticle preservation on dinosaur eggshells through deep time and offer a yet unexplored resource for chemical studies targeting the evolution of dinosaur nesting ecology. Our study also suggests that the cuticle structure can be traced far back to maniraptoran dinosaurs and enhance their reproductive success in a warm and mesic habitat such as Montana and southern China during the Late Cretaceous. PMID- 30002978 TI - Study of community-living Alzheimer's patients' adherence to the Mediterranean diet and risks of malnutrition at different disease stages. AB - Background: Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by deficits in episodic memory. It is the most common form of dementia and affects 50-70% of patients with cognitive impairments over the age of 65. Elderly people are particularly susceptible to malnutrition and that risk is even higher in patients with AD. This study assessed the nutritional status of patients with AD at different stages of AD and explored how that status correlated with cognitive, functional and behavioural variables and caregiver overburden. The characteristics of the diet and the degree of adherence to the Mediterranean diet were also analysed. Methods: This was a cross-sectional study that was representative of the general population and it was carried out in the Unit of Cognitive Disorders, Lleida, Spain. The participants were 111 subjects with AD who were aged 65 and over and still living at home. The subjects' nutritional status was assessed using the Mini Nutritional Assessment (MNA) and Controlling Nutritional Status system. The monthly food intake was estimated using the short Food Frequency Questionnaire and adherence to the Mediterranean diet was evaluated using the Mediterranean Diet Score. The Mini Mental State Examination (MMSE), Global Deterioration Scale, Neuropsychiatric Inventory (NPI) and Zarit Burden Interview (ZBI) were also used. Results: We found that 68% of the subjects presented with a risk of malnutrition and 19% were malnourished according to the MNA scale. Patients ate a higher quantity of meat and dairy products than recommended and fewer products from the remaining healthier food groups. Of the 111 subjects, 73% showed low adherence to the Mediterranean diet and 27% showed moderate adherence. There was a partial correlation between nutritional status and the MMSE when the data were adjusted for age and sex (r = 0, 318; p = 0.001) and inverse correlations were found for functional status (r = - 0.283; p = 0.004) and the NPI (r = - 0.409; p = 0.000) and ZBI scales (r = - 0.433; p = 0.000) when they were adjusted using the same variables. The ZBI scale (OR 1.08, 95% CI [1.01-1.15]) showed an increase in the risk of malnutrition in the multivariate analysis. Discussion: Alterations in nutritional status were more common during the advanced stages of AD and were also associated with behavioural changes and caregiver overburden. Low adherence to traditional healthy diets in Mediterranean countries and food intake profiles should be considered when managing patients with AD. Other countries can use the results to examine diets in people with AD that are high in meat and dairy and low in healthy food groups like fruit and vegetables. PMID- 30002980 TI - Beetles in bamboo forests: community structure in a heterogeneous landscape of southwestern Amazonia. AB - Amazonian bamboo forests dominated by large woody bamboo plants in the genus Guadua cover approximately 180,000 km2 and represent a key resource for many organisms. In southwestern Amazonia, native bamboo forests differ in structure, biodiversity, and growth dynamics from other forest types in the region. However, with the exception of a few species in which habitat specialization or a strong habitat association has been demonstrated, little is known about how bamboo forests influence animal community structure. In an effort to understand more about the animal assemblages associated with Amazonian bamboo forests, we characterized the structure of ground-dwelling beetle assemblages living in bamboo forests and adjacent terra firme forests in a lowland rainforest site in Peru. We conducted intensive pitfall trap surveys in 13 bamboo habitat patches and 13 adjacent terra firme habitat patches to determine if there were differences in the abundance and richness of beetle species in these two habitat types. Additionally, given that southwestern Amazonia experiences distinct dry and wet seasons, we conducted our study during the dry and wet season of one year to account for differences in seasonality. We found a distinct beetle assemblage associated with each forest type, and identified a set of dominant species that significantly contributed to the distinctness in beetle community structure between bamboo and terra firme forest. The terra firme forest had a greater number of rare species than the bamboo forest. Several beetle species exhibited a strong association with the bamboo forest, including a large species of Scarabaeidae that appears to be specializing on bamboo. We also found marked differences in beetle assemblages between dry and wet seasons. Our results support the prediction that beetle community structure in bamboo forest differs from that of terra firme in terms of species richness, abundance, and composition. Bamboo-associated animal communities require more exploration and study, and must be included in regional conservation plans seeking to protect entire animal communities in southwestern Amazonia. PMID- 30002979 TI - An online survey of personal mosquito-repellent strategies. AB - Background: Mosquito repellents can be an effective method for personal protection against mosquito bites that are a nuisance and carry the risk of transmission of mosquito-borne pathogens like plasmodia, dengue virus, chikungunya virus, and Zika virus. A multitude of commercially available products are currently on the market, some of them highly effective while others have low or no efficacy. Many home remedies of unknown efficacy are also widely used. Methods: We conducted a survey study to determine what kind of mosquito repellents and other mosquito control strategies people use. Our online survey was focused on unconventional methods and was answered by 5,209 participants. Results: The majority of participants resided in the United States, were female (67%), had higher education (81% had a university degree), and were 18 to 37 years old (50%). The most commonly used repellent was DEET spray (48%), followed closely by citronella candles (43%) and 'natural' repellent sprays (36%). We collected a plethora of home remedies and other strategies people use that warrant further research into their effectiveness. Discussion: Our study lays the foundation for future research in alternative, unconventional methods to repel mosquitoes that may be culturally acceptable and accessible for people. PMID- 30002982 TI - Revisiting historical beech and oak forests in Indiana using a GIS method to recover information from bar charts. AB - Historical GIS involves applying GIS to historical research. Using a unique method, I recovered historical tree survey information stored in bar chart figures of a 1956 publication. I converted PDF files to TIF files, which is a format for a GIS layer. I then employed GIS tools to measure lengths of each bar in the TIF file and used a regression (R2 = 97%) to convert bar lengths to numerical values of tree composition. I joined this information to a spatial GIS layer of Indiana, USA. To validate results, I compared predictions against an independent dataset and written summaries. I determined that historically (circa 1799 to 1846) in Indiana, oaks were 27% of all trees, beech was 25%, hickories and sugar maple were 7% each, and ash was 4.5%. Beech forests dominated (i.e., >24% of all trees) 44% of 8.9 million ha (i.e., where data were available in Indiana), oak forests dominated 29%, beech and oak forests dominated 4.5%, and oak savannas were in 6% of Indiana, resulting in beech and/or oak dominance in 84% of the state. This method may be valuable to reclaim information available in published figures, when associated raw data are not available. PMID- 30002981 TI - Trabecular bone patterning in the hominoid distal femur. AB - Background: In addition to external bone shape and cortical bone thickness and distribution, the distribution and orientation of internal trabecular bone across individuals and species has yielded important functional information on how bone adapts in response to load. In particular, trabecular bone analysis has played a key role in studies of human and nonhuman primate locomotion and has shown that species with different locomotor repertoires display distinct trabecular architecture in various regions of the skeleton. In this study, we analyse trabecular structure throughout the distal femur of extant hominoids and test for differences due to locomotor loading regime. Methods: Micro-computed tomography scans of Homo sapiens (n = 11), Pan troglodytes (n = 18), Gorilla gorilla (n = 14) and Pongo sp. (n = 7) were used to investigate trabecular structure throughout the distal epiphysis of the femur. We predicted that bone volume fraction (BV/TV) in the medial and lateral condyles in Homo would be distally concentrated and more anisotropic due to a habitual extended knee posture at the point of peak ground reaction force during bipedal locomotion, whereas great apes would show more posteriorly concentrated BV/TV and greater isotropy due to a flexed knee posture and more variable hindlimb use during locomotion. Results: Results indicate some significant differences between taxa, with the most prominent being higher BV/TV in the posterosuperior region of the condyles in Pan and higher BV/TV and anisotropy in the posteroinferior region in Homo. Furthermore, trabecular number, spacing and thickness differ significantly, mainly separating Gorilla from the other apes. Discussion: The trabecular architecture of the distal femur holds a functional signal linked to habitual behaviour; however, there was more similarity across taxa and greater intraspecific variability than expected. Specifically, there was a large degree of overlap in trabecular structure across the sample, and Homo was not as distinct as predicted. Nonetheless, this study offers a comparative sample of trabecular structure in the hominoid distal femur and can contribute to future studies of locomotion in extinct taxa. PMID- 30002983 TI - Effects of size and microclimate on whole-tree water use and hydraulic regulation in Schima superba trees. AB - Background: Plant-water relations have been of significant concern in forestry and ecology studies in recent years, yet studies investigating the annual differences in the characteristics of inter-class water consumption in trees are scarce. Methods: We classified 15 trees from a Schima superba plantation in subtropical South China into four ranks using diameter at breast height (DBH). The inter-class and whole-tree water use were compared based on three parameters: sap flux density, whole-tree transpiration and canopy transpiration over two years. Inter-class hydraulic parameters, such as leaf water potential, stomatal conductance, hydraulic conductance, and canopy conductance were also compared. Results: (1) Mean water consumption of the plantation was 287.6 mm over a year, 165.9 mm in the wet season, and 121.7 mm in the dry season. Annual mean daily water use was 0.79 mm d-1, with a maximum of 1.39 mm d-1. (2) Isohydrodynamic behavior were found in S. superba. (3) Transpiration was regulated via both hydraulic conductance and stoma; however, there was an annual difference in which predominantly regulated transpiration. Discussion: This study quantified annual and seasonal water use of a S. superba plantation and revealed the coordinated effect of stoma and hydraulic conductance on transpiration. These results provide information for large-scale afforestation and future water management. PMID- 30002984 TI - AnnotationBustR: an R package to extract subsequences from GenBank annotations. AB - Background: DNA sequences are pivotal for a wide array of research in biology. Large sequence databases, like GenBank, provide an amazing resource to utilize DNA sequences for large scale analyses. However, many sequence records on GenBank contain more than one gene or are portions of genomes. Inconsistencies in the way genes are annotated and the numerous synonyms a single gene may be listed under provide major challenges for extracting large numbers of subsequences for comparative analysis across taxa. At present, there is no easy way to extract portions from many GenBank accessions based on annotations where gene names may vary extensively. Results: The R package AnnotationBustR allows users to extract sequences based on GenBank annotations through the ACNUC retrieval system given search terms of gene synonyms and accession numbers. AnnotationBustR extracts subsequences of interest and then writes them to a FASTA file for users to employ in their research endeavors. Conclusion: FASTA files of extracted subsequences and accession tables generated by AnnotationBustR allow users to quickly find and extract subsequences from GenBank accessions. These sequences can then be incorporated in various analyses, like the construction of phylogenies to test a wide range of ecological and evolutionary hypotheses. PMID- 30002985 TI - Identification of hub genes and potential molecular mechanisms in gastric cancer by integrated bioinformatics analysis. AB - Objective: Gastric cancer (GC) is the fourth most common cause of cancer-related deaths in the world. In the current study, we aim to identify the hub genes and uncover the molecular mechanisms of GC. Methods: The expression profiles of the genes and the miRNAs were extracted from the Gene Expression Omnibus database. The identification of the differentially expressed genes (DEGs), including miRNAs, was performed by the GEO2R. Database for Annotation, Visualization and Integrated Discovery was used to perform GO and KEGG pathway enrichment analysis. The protein-protein interaction (PPI) network and miRNA-gene network were constructed using Cytoscape software. The hub genes were identified by the Molecular Complex Detection (MCODE) plugin, the CytoHubba plugin and miRNA-gene network. Then, the identified genes were verified by Kaplan-Meier plotter database and quantitative real-time PCR (qRT-PCR) in GC tissue samples. Results: A total of three mRNA expression profiles (GSE13911, GSE79973 and GSE19826) were downloaded from the Gene Expression Omnibus (GEO) database, including 69, 20 and 27cases separately. A total of 120 overlapped upregulated genes and 246 downregulated genes were identified. The majority of the DEGs were enriched in extracellular matrix organization, collagen catabolic process, collagen fibril organization and cell adhesion. In addition, three KEGG pathways were significantly enriched, including ECM-receptor interaction, protein digestion and absorption, and the focal adhesion pathways. In the PPI network, five significant modules were detected, while the genes in the modules were mainly involved in the ECM-receptor interaction and focal adhesion pathways. By combining the results of MCODE, CytoHubba and miRNA-gene network, a total of six hub genes including COL1A2, COL1A1, COL4A1, COL5A2, THBS2 and ITGA5 were chosen. The Kaplan-Meier plotter database confirmed that higher expression levels of these genes were related to lower overall survival, except for COL5A2. Experimental validation showed that the rest of the five genes had the same expression trend as predicted. Conclusion: In conclusion, COL1A2, COL1A1, COL4A1, THBS2 and ITGA5 may be potential biomarkers and therapeutic targets for GC. Moreover, ECM-receptor interaction and focal adhesion pathways play significant roles in the progression of GC. PMID- 30002986 TI - High expression of SLC26A6 in the kidney may contribute to renal calcification via an SLC26A6-dependent mechanism. AB - Background: Solute-linked carrier 26 gene family 6 (SLC26A6), which is mainly expressed in intestines and kidneys, is a multifunctional anion transporter crucial in the transport of oxalate anions. This study aimed to investigate the role of kidney SLC26A6 in urolithiasis. Methods: Patients were divided into two groups: stone formers and nonstone formers. Samples were collected from patients following nephrectomy. Lentivirus with Slc26a6 (lentivirus-Slc26a6) sequence and lentivirus with siRNA-Slc26a6 (lentivirus-siRNA-Slc26a6) sequence were transfected into rats' kidneys respectively and Slc26a6 expression was detected using Western blot and immunohistochemical analyses. After administering ethylene glycol, oxalate concentration and prevalence of stone formation between the transgenic and control groups were measured using 24-h urine analysis and Von Kossa staining, respectively. Results: Immunohistochemical and Western blot analyses indicated that stone formers had a significantly higher level of expression of SLC26A6 in the kidney compared with the control group. After lentivirus infection, the urinary oxalate concentration and rate of stone formation in lentivirus-Slc26a6-tranfected rats increased remarkably, while lentivirus-siRNA-Slc26a6-transfected rats showed few crystals. Conclusion: The results showed that high expression levels of renal SLC26A6 may account for kidney stone formation. Downregulating the expression of SLC26A6 in the kidney may be a potential therapeutic target to prevent or treat urolithiasis. PMID- 30002987 TI - New insights into chasmosaurine (Dinosauria: Ceratopsidae) skulls from the Upper Cretaceous (Campanian) of Alberta, and an update on the distribution of accessory frill fenestrae in Chasmosaurinae. AB - Chasmosaurine ceratopsids are well documented from the Upper Cretaceous (Campanian) Dinosaur Park Formation (DPF) of southern Alberta and Saskatchewan, and include Chasmosaurus belli, Chasmosaurus russelli, Mercuriceratops gemini, Vagaceratops irvinensis, and material possibly referable to Spiclypeus shipporum. In this study, we describe three recently prepared chasmosaurine skulls (CMN 8802, CMN 34829, and TMP 2011.053.0046) from the DPF, and age-equivalent sediments, of Alberta. CMN 8802 and CMN 34829 are both referred to Chasmosaurus sp. based on the size and shape of the preserved parietal fenestrae. TMP 2011.053.0046 is referred to Vagaceratops sp. based on the position and orientation of its preserved epiparietals. Each skull is characterized by the presence of an accessory fenestra in either the squamosal (CMN 8802 and TMP 2011.053.0046) or parietal (CMN 34829). Such fenestrae are common occurrences in chasmosaurine squamosals, but are rare in the parietal portion of the frill. The origin of the fenestrae in these three specimens is unknown, but they do not appear to exhibit evidence of pathology, as has been previously interpreted for the accessory fenestrae in most other chasmosaurine frills. These three skulls contribute to a better understanding of the morphological variation, and geographic and stratigraphic distribution, of chasmosaurines within the DPF and age-equivalent sediments in Western Canada. PMID- 30002988 TI - Age of onset of cannabis use and decision making under uncertainty. AB - Objective: Cannabis, like other substances, negatively affects health, inducing respiratory problems and mental and cognitive alterations. Memory and learning disorders, as well as executive dysfunctions, are also neuropsychological disorders associated to cannabis use. Recent evidence reveals that cannabis use during adolescence may disrupt the normal development of the brain. This study is aimed to analyze possible differences between early-onset and late-onset cannabis consumers. Method: We used a task based on a card game with four decks and different programs of gains/losses. A total of 72 subjects (19 women; 53 men) participated in the study; they were selected through a purposive sampling and divided into three groups: early-onset consumers, late-onset consumers, and control (non-consumers). The task used was the "Cartas" program (computerized version based on the Iowa Gambling Task (IGT)), with two versions: direct and inverse. The computational model "Prospect Valence Learning" (PVL) was applied in order to describe the decision according to four characteristics: utility, loss aversion, recency, and consistency. Results: The results evidence worst performance in the IGT in the early-onset consumers as compared to late-onset consumers and control. Differences between groups were also found in the PVL computational model parameters, since the process of decision making of the early onset consumers was more influenced by the magnitude of the gains-losses, and more determined by short-term results without loss aversion. Conclusions: Early onset cannabis use may involve decision-making problems, and therefore intervention programs are necessary in order to reduce the prevalence and delay the onset of cannabis use among teenagers. PMID- 30002990 TI - Evaluation of the estimate bias magnitude of the Rao's quadratic diversity index. AB - Rao's quadratic diversity index is one of the most widely applied diversity indices in functional and phylogenetic ecology. The standard way of computing Rao's quadratic diversity index for an ecological assemblage with a group of species with varying abundances is to sum the functional or phylogenetic distances between a pair of species in the assemblage, weighted by their relative abundances. Here, using both theoretically derived and observed empirical datasets, we show that this standard calculation routine in practical applications will statistically underestimate the true value, and the bias magnitude is derived accordingly. The underestimation will become worse when the studied ecological community contains more species or the pairwise species distance is large. For species abundance data measured using the number of individuals, we suggest calculating the unbiased Rao's quadratic diversity index. PMID- 30002991 TI - Xenoposeidon is the earliest known rebbachisaurid sauropod dinosaur. AB - Xenoposeidon proneneukos is a sauropod dinosaur from the Early Cretaceous Hastings Group of England. It is represented by a single partial dorsal vertebra, NHMUK PV R2095, which consists of the centrum and the base of a tall neural arch. Despite its fragmentary nature, it is recognisably distinct from all other sauropods, and is here diagnosed with five unique characters. One character previously considered unique is here recognised as shared with the rebbachisaurid diplodocoid Rebbachisaurus garasbae from the mid-Cretaceous of Morocco: an 'M' shaped arrangement of laminae on the lateral face of the neural arch. Following the more completely preserved R. garasbae, these laminae are now interpreted as ACPL and lateral CPRL, which intersect anteriorly; and PCDL and CPOL, which intersect posteriorly. Similar arrangements are also seen in some other rebbachisaurid specimens (though not all, possibly due to serial variation), but never in non-rebbachisaurid sauropods. Xenoposeidon is therefore referred to Rebbachisauridae. Due to its inferred elevated parapophysis, the holotype vertebra is considered a mid-posterior dorsal despite its elongate centrum. Since Xenoposeidon is from the Berriasian-Valanginian (earliest Cretaceous) Ashdown Formation of the Wealden Supergroup of southern England, it is the earliest known rebbachisaurid by some 10 million years. Electronic 3D models were invaluable in determining Xenoposeidon's true affinities: descriptions of complex bones such as sauropod vertebrae should always provide them where possible. PMID- 30002989 TI - Distribution and ecological segregation on regional and microgeographic scales of the diploid Centaurea aspera L., the tetraploid C. seridis L., and their triploid hybrids (Compositae). AB - Although polyploidy is considered a ubiquitous process in plants, the establishment of new polyploid species may be hindered by ecological competition with parental diploid taxa. In such cases, the adaptive processes that result in the ecological divergence of diploids and polyploids can lead to their co existence. In contrast, non-adaptive processes can lead to the co-existence of diploids and polyploids or to differentiated distributions, particularly when the minority cytotype disadvantage effect comes into play. Although large-scale studies of cytotype distributions have been widely conducted, the segregation of sympatric cytotypes on fine scales has been poorly studied. We analysed the spatial distribution and ecological requirements of the tetraploid Centaurea seridis and the diploid Centaurea aspera in east Spain on a large scale, and also microspatially in contact zones where both species hybridise and give rise to sterile triploid hybrids. On the fine scale, the position of each Centaurea individual was recorded along with soil parameters, accompanying species cover and plant richness. On the east Spanish coast, a slight latitudinal gradient was found. Tetraploid C. seridis individuals were located northerly and diploid C. aspera individuals southerly. Tetraploids were found only in the habitats with strong anthropogenic disturbance. In disturbed locations with well-developed semi fixed or fixed dunes, diploids and tetraploids could co-exist and hybridise. However, on a fine scale, although taxa were spatially segregated in contact zones, they were not ecologically differentiated. This finding suggests the existence of non-adaptive processes that have led to their co-existence. Triploid hybrids were closer to diploid allogamous mothers (C. aspera) than to tetraploid autogamous fathers (C. seridis). This may result in a better ability to compete for space in the tetraploid minor cytotype, which might facilitate its long-term persistence. PMID- 30002992 TI - Potential biocontrol efficacy of Trichoderma atroviride with cellulase expression regulator ace1 gene knock-out. AB - The biocontrol function of the repressor of cellulase expression I (ACE1) in Trichoderma atroviride was verified through constructing Deltaace1 mutant strain by Agrobacterium tumefaciens-mediated transformation. The activities of cell wall degrading enzymes (cellulase, xylanase, chitinase, beta-1,3-glucanase, and protease) in the supernatant of Deltaace1 mutant strain were distinctly higher than those of control strain, followed with the elevation of related genes transcript levels. Besides, the Deltaace1 mutant resulted in an elevating transcript level of xyr1, but no obvious change in the expression of cre1, which suggested that ACE1 was negative regulator of the xyr1 transcription, but not involved in cre1 transcription. On core polyketide synthases of four biosynthesis gene clusters for antibiotic secondary metabolites, only the transcription levels of encoding genes Try83179/TryH and Aza79482/AzaJ in Deltaace1 mutant strain were significantly higher than that in wild-type during antagonizing with pathogenic fungi Fusarium oxysporum and Rhizoctonia solani (with the inhibition rate of 30.7 and 19.8%, respectively). The biocontrol function of Deltaace1 mutant strain was remarkably enhanced. The results indicated that ACE1, indeed, acted as a repressor for cell wall-degrading enzymes and PKSs expression in T. atroviride, and the Deltaace1 mutant strain effectively made related enzymes activities improved with potential enhancement of biocontrol potency. PMID- 30002993 TI - Methionine attenuates the intensity of rheumatoid arthritis by downregulating NF kappaB and iNOS expression in neonatal rats. AB - The present study investigated the anti-arthritic effects of methionine in neonatal rats. Rats were divided into four groups, with six rats in each group. The rats were administered methionine (150- or 300-mg/kg body weight) orally for 45 consecutive days. The expression levels of catalase, superoxide dismutase (SOD), reduced glutathione (GSH), lipid peroxidation, glutathione peroxidase (Gpx), prostaglandin E2 (PGE2), matrix metalloproteinase-3, uric acid, nitric oxide (NO), ceruloplasmin, inducible nitric oxide synthase (iNOS), and nuclear factor (NF)-kappaB were determined in rheumatoid arthritis-induced neonatal rats. The levels of SOD, catalase, Gpx, and GSH were substantially reduced in control rats, while the levels of other parameters were increased in control neonatal rats. However, methionine supplementation significantly increased (more than 40%) the levels of SOD, catalase, Gpx, and GSH in neonatal rats. The levels of lipid peroxidation, uric acid, ceruloplasmin, NO, and PGE2 were significantly reduced following methionine supplementation. Furthermore, NF-kappaB mRNA expression was substantially reduced up to 51.7% in the 300-mg/kg methionine group, whereas the mRNA expression of iNOS was reduced up to 43.5% in the 300-mg/kg methionine group. NF-kappaB protein expression was substantially reduced up to 45.8% in the 300-mg/kg methionine group, whereas the protein expression of iNOS was reduced up to 45.4% in the 300-mg/kg methionine group. Taken together, these data suggest that methionine supplementation was effective against rheumatoid arthritis. PMID- 30002994 TI - Soil bacterial diversity under conservation agriculture-based cereal systems in Indo-Gangetic Plains. AB - In Indo-Gangetic plains (IGP) of India, natural resources (soil, water, and environment) are degrading under the conventional-till (CT)-based management practices in rice-wheat cropping system. A long-term field experiment was conducted to understand the soil bacterial diversity and abundance under different sets of management scenarios (Sc). The study comprised of four scenarios, namely, -Sc.I CT-based rice-wheat system (farmers' practice); Sc.II, partial conservation agriculture (CA) based in which rice is under CT-wheat and mungbean under zero-tillage (ZT); Sc.III, full CA-based in which rice-wheat mungbean are under ZT and Sc.IV, where maize-wheat-mungbean are under ZT. These scenarios varied in cropping system, tillage, and crop residue management practices. Using Illumina MiSeq sequencing technology, the variable regions V3-V4 of 16S rRNA were sequenced and the obtained reads were analyzed to study the diversity patterns in the scenarios. Results showed the presence of 53 bacterial phyla across scenarios. The predominant phyla in all scenarios were Proteobacteria, Acidobacteria, Actinobacteria, and Bacteroidetes which accounted for more than 70% of the identified phyla. However, the rice-based systems (Sc.I, Sc.II, and Sc.III) were dominated by phylum Proteobacteria; however, maize-based system (Sc.IV) was dominated by Acidobacteria. The class DA052 and Acidobacteriia of Acidobacteria and Bacteroidetes of Bacteroidia were exceptionally higher in Sc.IV. Shannon diversity index was 8.8% higher in Sc.I, 7.5% in Sc.II, and 2.7% in Sc.III compared to Sc.IV. The findings revealed that soil bacterial diversity and abundance are influenced by agricultural management practices as bacterial diversity under full CA-based management systems (Sc.III and Sc.IV) was lower when compared to farmer's practice (Sc.I) and partial CA (Sc.II) scenarios. PMID- 30002995 TI - Enhancement of quality retention of Grifola frondosa fruiting bodies by erythorbic acid treatment. AB - In this paper, the effects of erythorbic acid (EA) treatment with different concentrations on the quality of Grifola frondosa fruiting bodies stored at 4 degrees C for 27 days were studied by determining the changes in moisture content, weight loss, browning, electrolyte leakage, malondialdehyde (MDA), and nutritional compounds. The activities of polyphenoloxidase (PPO), cellulase and other antioxidant enzymes including superoxide dismutase (SOD), catalase, and peroxidase (POD) were also measured. Results showed that 0.1% EA-treated G. frondosa fruiting body maintained lower weight loss (< 6.0%, w/w), electrolyte leakage (< 45.8%), MDA (< 4.17 umol kg-1), and higher moisture content (> 90.7%, w/w). Lower activities of PPO (< 72.64 * 103 U kg-1) and cellulase (< 189.86 * 103 U kg-1) in 0.1% EA-treated samples were observed compared with the other treatments. As a stereoisomer of ascorbic acid (AA), EA also could enhance SOD and POD activities of G. frondosa fruiting bodies. Our findings were the first time to evaluate the effect of EA on maintaining quality in G. frondosa fruiting bodies, and proved that low concentrations of EA (especially 0.1% EA, w/v) treatments were beneficial to preserve G. frondosa fruiting body with even higher efficiency than AA treatment. This study paved a foundation for the enhancement of quality retention of G. frondosa fruiting bodies. PMID- 30002996 TI - Development of PCR-based molecular marker for screening of disease-suppressive composts against Fusarium wilt of tomato (Solanum lycopersicum L.). AB - The present study was carried out to develop a PCR-based molecular marker suitable for screening of disease-suppressive composts against Fusarium wilt of tomato. An effective uncultured bacterial community was screened from our previous study on investigation of microbial communities in composts for their potential for biocontrol of Fusarium wilt. Based on available sequence information (Accession no. HQ388491) of selective community, PCR-based molecular markers were designed and tested for their specificity in different compost sample. To confirm specificity of designed marker, real-time reverse transcription-PCR (qRT-PCR) analysis was performed. Selective marker efficacy was further tested for different set of composts and results were cross-verified by conducting bioassay of same composts against Fusarium wilt in tomato crop. Results showed that out of two designed set of primers (i.e., PAC1F/PAC1R and PAC4F/PAC4R), primer set PAC4F/PAC4R resulted in successful amplification of 199 bp in highly disease-suppressive compost (i.e., CPP); however, no/below detection level amplification was observed in non-suppressive compost (JC). qRT-PCR analysis confirmed the specificity of selective marker by representing single peak in melting curve. A clear difference was observed in relative population of selective community in different set of composts. It was observed maximum in the most effective compost, i.e., CPP followed by other disease-suppressive composts. Cross-examination of results with bioassay confirmed that composts with presence of selective bacterial community having no/very less disease incidence of Fusarium. It is clearly evident from the study that such kind of molecular markers can be developed and used in future research focusing on compost-based disease suppression. PMID- 30002997 TI - Selection and evaluation of microorganisms for biodegradation of agricultural plastic film. AB - Three Bacillus amyloliquefaciens isolates (HK1, GSDM02, and GSDM15) were tested for effectiveness in biodegradation of plastic films. Isolates were screened by plate on carbon-free medium and by using the clear-zone formation test. Their biodegradation ability was analyzed based on: film weight reduction, pH change of the fluid medium, a soil microbial biomass carbon test, scanning electron microscopy (SEM), and Fourier transform infrared spectrometry (FTIR). Polyvinyl alcohol (PVA) clear-zone and film weight reduction results revealed that the strain with a bigger clear-zone had a better biodegradation effect, that PVA can be evenly distributed in the medium, and that PVA can be a substitution for polyethylene in screening the biodegradation of strains. SEM and FTIR revealed that HK1 can tear the film apart and make surface chemical changes within 30 days. HK1 exhibited a better biodegradation effect in all tests, indicating its potential for helping solve the plastic pollution problems. PMID- 30002998 TI - Plants in traditional medicine with special reference to Cyperus rotundus L.: a review. AB - The nutgrass, Cyperus rotundus L. (Family: Cyperaceae), is a colonial, perennial herb considered to have originated in India 2000 years ago and widely used in Ayurveda to treat several ailments. In addition to its prehistoric uses, it is used in several systems of medicine for treating variety of diseases. The synergistic actions of the Cyperus' compounds have added advantage over that of a single constituent. In the past decade, numerous studies proved analgesic, anti allergic, anti-arthritic, anti-candida, anti-cariogenic, anti-convulsant, anti diarrheal, anti-emetic, anti-helminthic, anti-histamine, anti-hyperglycemic, anti hypertensive, anti-inflammatory, anti-malarial, anti-obesity, antioxidant, anti platelet, anti-pyretic, anti-ulcer, anti-viral, cardioprotective, cytoprotective, cytotoxic, gastroprotective, hepatoprotective, neuroprotective, ovicidal, and larvicidal, wound healing and inhibition of brain Na+ K+ ATPase activities of C. rotundus and its chemical constituents. However, the exact the mechanism of action is not very clear and requires further evaluation. These properties strongly suggest an extensive use of C. rotundus for clinical applications. In this review, we attempted to provide information about the pharmacological effects of Cyperus and its proposed mechanisms of actions. PMID- 30002999 TI - Metabolic engineering of E. coli for the production of O-succinyl-l-homoserine with high yield. AB - O-succinyl-l-homoserine (OSH) is a promising platform chemical for the production of C4 chemicals with huge market potential which can be produced by fermentation from glucose. To construct a strain capable of producing OSH with high yield, the metJ (encodes transcriptional repressor) and metI (encodes a subunit of dl methionine transporter) were deleted in Escherichia coli W3110 to obtain a strain E. coli ?JI. Then, overexpression of metL (encodes bifunctional aspartate kinase/homoserine dehydrogenase II) and inactivation of metB (encodes cystathionine gamma-synthase) were implemented in one step, and the OSH titer of the resulting strain E. coli ?JIB* TrcmetL was dramatically increased to 7.30 g/L. The feedback regulation was further relieved by progressively overexpressing metAfbr (encodes homoserine O-succinyltransferase), yjeH (encodes l-methionine exporter), and thrAfbr (encodes bifunctional aspartate kinase/homoserine dehydrogenase I) to increase the metabolic flux from aspartate to OSH. The 100% rationally designed strain E. coli ?JIB* TrcmetL/pTrc-metAfbr -Trc-thrAfbr -yjeH produced 9.31 g/L OSH from 20 g/L glucose (0.466 g/g glucose) in batch fermentation, which represents the highest OSH yield from glucose reported to date. The culture profiles of the newly constructed strains were recorded to investigate their productive properties. The effects of l-methionine addition on the fermentation process of the optimal strain were also studied. Our results demonstrate that tuning the expression level of metL, inactivation of metB, and attenuation of feedback resistance of the crucial enzymes in the biosynthetic pathway are the key factors that impact the OSH production in E. coli. PMID- 30003001 TI - Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents. AB - Invited for this month's cover picture is the group of Professor Peter Nilsson at the Department of Physics, Chemistry and Biology at Linkoping University (Sweden). The cover picture shows a fluoro-glycoporphyrin that selectively targets cancer cells. The selectivity towards cancer cells are afforded due to proper functionalization of the porphyrin scaffold with specific carbohydrates, and the cancer cells can be visualized because of the intrinsic fluorescence from the porphyrin. The molecule also exhibits properties for photodynamic therapy and the incorporation of fluorine, in the form of 2-fluoro-2-deoxy glucose (FDG), offers the possibility to apply these compounds as 18F positron emission tomography (PET) tracers. Thus, fluoro-glycoporphyrins display multimodal properties and can be employed as theranostic agents targeting cancer cells. Read the full text of their Full Paper at https://doi.org/10.1002/open.201800020. PMID- 30003000 TI - Identification of miRNAs and their targets in regulating tuberous root development in radish using small RNA and degradome analyses. AB - High-throughput small RNA sequencing and degradome analysis were used in this study to thoroughly investigate the role of miRNA-mediated regulatory network in tuberous root development of radish. Samples from the early seedling stage (RE) and the cortex splitting stage (RL) were used for the construction of six small RNA libraries and one degradome library. A total of 518 known and 976 novel miRNAs were identified, of which, 338 known and 18 novel miRNAs were expressed in all six libraries, respectively. A total of 52 known and 57 novel miRNAs were identified to be significantly differentially expressed between RE and RL, and 195 mRNAs were verified to be the targets of 194 miRNAs by degradome sequencing. According to the degradome analysis, 11 differentially expressed miRNAs had miRNA mRNA targets, and 13 targets were identified for these 11 miRNAs. Of the 13 miRNA mRNA targets, 4 genes (RSG11079.t1, RSG11844.t1, RSG16775.t1, and RSG42419.t1) were involved in hormone-mediated signaling pathway, 2 gens (RSG11079.t1 and RSG16775.t1) were related to post-embryonic root development, and 1 gene (RSG23799.t1) was involved in anatomical structure morphogenesis, according to the GO function analysis for biological process. Target Genes participated in these processes are important candidates for further studies. This study provides valuable information for a better understanding of the molecular mechanisms involved in radish tuberous root formation and development. PMID- 30003002 TI - Exploring the Interactions of Oxygen with Defective ZnO. AB - Exploring the interactions of oxygen with defective oxide is of importance to understand the microscopic process and performance of ZnO-based oxygen sensors. The interactions of environmental oxygen with vacuum-annealed defective ZnO have been studied by electrical methods, vacuum Fourier transform infrared spectroscopy, and in situ adsorption experiments. It was found that the vacuum annealed defective ZnO exhibits varied electrical response at different temperatures, which, by vacuum IR investigation, was ascribed to the subtle balance between formation of oxygen vacancies and their interactions with environmental oxygen. Further studies showed that two microscopic steps including surface adsorption and bulk diffusion were dominating the interactions between defective ZnO and environmental oxygen, and the corresponding apparent activation energies were estimated to be 0.093 and 0.67 eV through in situ adsorption experiments. The quite low activation barrier of oxygen adsorption on the defective ZnO was proposed to be responsible for the extreme high sensitivity of ZnO-based oxygen sensors. PMID- 30003003 TI - Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents. AB - Small molecules with modalities for a variety of imaging techniques as well as therapeutic activity are essential, as such molecules render opportunities to simultaneously conduct diagnosis and targeted therapy, so called theranostics. In this regard, glycoporphyrins have proven useful as theranostic agents towards cancer, as well as noncancerous conditions. Herein, the synthesis and characterization of heterobifunctional glycoconjugated porphyrins with two different sugar moieties, a common monosaccharide at three sites, and a 2-fluoro 2-deoxy glucose (FDG) moiety at the fourth site are presented. The fluoro glycoconjugated porphyrins exhibit properties for multimodal imaging and photodynamic therapy, as well as specificity towards cancer cells. We foresee that our findings might aid in the chemical design of heterobifunctional glycoconjugated porphyrins that could be utilized as theranostic agents. PMID- 30003004 TI - Partial Substitution of Potassium with Sodium in the K2Ti2(PO4)3 Langbeinite-Type Framework: Synthesis and Crystalline Structure of K1.75Na0.25Ti2(PO4)3. AB - The interaction of TiN with Na2O-K2O-P2O5 melts was investigated at (Na+K)/P molar ratios of 0.9, 1.0, and 1.2 and at Na/K molar ratios of 1.0 and 2.0. Interactions in the system led to the loss of nitrogen and the partial loss of phosphorus and resulted in the formation of KTiP2O7 and langbeinite-type K2-x Na x Ti2(PO4)3 (x=0.22-0.26) solid solutions over the temperature range of 1173 to 1053 K. The phase compositions of the obtained samples were determined by using X ray diffraction (including Rietveld refinement), scanning electron microscopy (using energy-dispersive X-ray spectroscopy and element mapping), FTIR spectroscopy, and thermogravimetric analysis/differential thermal analysis. K1.75Na0.25Ti2(PO4)3 was characterized by single-crystal X-ray diffraction [P213 space group, a=9.851(5) A]. The 3D framework is built up by TiO6 octahedra and PO4 tetrahedra sharing all the oxygen vertices with the formation of cavities occupied by K(Na) cations. Only one of the two crystallographically inequivalent potassium sites is partially substituted by sodium, and this was confirmed by calculating the bond-valence sum. The thermodynamic stability of K1.75Na0.25Ti2(PO4)3 crystals and the preferable occupation sites of NaK cationic substitutions were investigated by DFT-based electronic structure calculations performed by the plane-wave pseudopotential method. PMID- 30003005 TI - Understanding the Molecular Structure of the Sialic Acid-Phenylboronic Acid Complex by using a Combined NMR Spectroscopy and DFT Study: Toward Sialic Acid Detection at Cell Membranes. AB - The origin of the unusually high stability of the sialic acid (SA) and phenylboronic acid (PBA) complex was investigated by a combined nuclear magnetic resonance (NMR) spectroscopy and density functional theory (DFT) study. SA is a glycan-terminating monosaccharide, and its importance as a clinical target has long been recognized. Inspired by the fact that the binding properties of SA-PBA complexation are anomalously high relative to those of typical monosaccharides, great effort has been made to build a clinical platform with the use of PBA as a SA-selective receptor. Although a number of applications have been reported in recent years, the ability of PBA to recognize SA-terminating surface glycans selectively is still unclear, because high-affinity SA-PBA complexation might not occur in a physiological environment. In particular, different forms of SA (alpha and beta-pyranose) were not considered in detail. To answer this question, the combined NMR spectroscopy/DFT study revealed that the advantageous binding properties of the SA-PBA complex arise from ester bonding involving the alpha carboxylate moieties (C1 and C2) of beta-SA but not alpha-SA. Moreover, the facts that the C2 atom is blocked by a glycoside bond in a physiological environment and that alpha-SA basically exists on membrane-bound glycans in a physiological environment lead to the conclusion that PBA cannot selectively recognize the SA unit to discriminate specific types of cells. Our results have a significant impact on the field of SA-based cell recognition. PMID- 30003006 TI - Direct Access by Mechanochemistry or Sonochemistry to Protonated Merocyanines: Components of a Four-State Molecular Switch. AB - Direct access to the protonated merocyanine forms of two substituted spiropyrans by mechanosynthesis or sonochemistry was explored. The compounds were formed by the condensation reaction of the methyleneindolium iodide salt with salicylaldehyde derivatives. X-ray crystallography, 1H NMR spectroscopy, ab initio geometry optimization, and absorption spectroscopy were combined to provide a better understanding of the four-state molecular switch system in which the newly synthesized protonated merocyanines were found to play a central role. The results of this study suggest that the stability of the protonated merocyanines requires acidic conditions, as treatment with base led to the corresponding unprotonated merocyanines, which in turn spontaneously converted into photochromic closed spiropyrans. PMID- 30003007 TI - Transformation and Stability of N-Nitrodiethanolamine Dinitrate Nitration Liquid System under Thermal and Mechanical Stimulation. AB - To obtain a deeper understanding of the process involved in the synthesis of N nitrodiethanolamine dinitrate (DINA), in this work we carried out systematic studies on the transformation and stability of the N-nitration liquid and DINA. The thermal decomposition processes and dynamic characteristics for both the N nitration liquid and DINA were carried out by thermal analysis methods and the mechanism for the decrease of stability of the N-nitration liquid was proposed according to experimental results. Mechanical stimulation of the N-nitration liquid and DINA were also studied by friction and impact sensitivity testing. The experimental results showed that the N-nitration liquid is highly sensitive to temperature and can decompose easily when the reaction temperature increases. However, mechanical sensitivity of the N-nitration was demonstrated to be much lower than that of DINA. Therefore, precise thermal control is the key factor to ensure safety during the preparation of DINA. PMID- 30003008 TI - Exploring host and geographical shifts in transmission of haemosporidians in a Palaearctic passerine wintering in India. AB - This is the first molecular study of avian haemosporidia diversity in wintering populations of the Blyth's Reed Warbler (Acrocephalus dumetorum) in India that explores the extent of host and geographical shifts in transmission areas. In 156 birds, six Haemoproteus lineages (37.8%; 95% CI 30.41-45.82%) and one Plasmodium lineage (1.9%; 95% CI 0.053-5.6%) were recovered. Of these, two Haemoproteus lineages (ACDUM1 and ACDUM5) were detected in resident Himalayan birds, albeit in low frequency with absence of gametocytes in the blood suggesting no transmission from breeding to wintering quarters. In addition, there was no host sharing of local parasite lineages with the wintering populations. PMID- 30003009 TI - How low can we go? The implications of low bacterial load in respiratory microbiota studies. AB - Background: Culture-independent sequencing methods are increasingly used to investigate the microbiota associated with human mucosal surfaces, including sites that have low bacterial load in healthy individuals (e.g. the lungs). Standard microbiota methods developed for analysis of high bacterial load specimens (e.g. stool) may require modification when bacterial load is low, as background contamination derived from sterile laboratory reagents and kits can dominate sequence data when few bacteria are present. Main body: Bacterial load in respiratory specimens may vary depending on the specimen type, specimen volume, the anatomic site sampled and clinical parameters. This review discusses methodological issues inherent to analysis of low bacterial load specimens and recommends strategies for successful respiratory microbiota studies. The range of methods currently used to process DNA from low bacterial load specimens, and the strategies used to identify and exclude background contamination are also discussed. Conclusion: Microbiota studies that include low bacterial load specimens require additional tests to ensure that background contamination does not bias the results or interpretation. Several methods are currently used to analyse the microbiota in low bacterial load respiratory specimens; however, there is scant literature comparing the effectiveness and biases of different methods. Further research is needed to define optimal methods for analysing the microbiota in low bacterial load specimens. PMID- 30003010 TI - Erythrocyte Senescence in a Model of Rat Displaying Hutchinson-Gilford Progeria Syndrome. AB - Background: Increased oxidative stress is a major cause of aging and age-related diseases. Erythrocytes serve as good model for aging studies. Dihydrotachysterol is known to induce premature aging feature in rats mimicking Hutchinson-Gilford progeria syndrome. Aim: In the present study, attempts have been made to explore the differential response of young and senescent erythrocytes separated by density gradient centrifugation from accelerated senescence model of rats mimicking Hutchinson-Gilford progeria syndrome and naturally aged rats. Methods: The erythrocytes of naturally aged and progeroid rats were separated into distinct, young and old cells on the basis of their differential densities. The parameters of oxidative stress and membrane transport systems were studied. Discussion and Conclusion: Our study provides evidence that organismal aging negatively affects oxidative stress markers and membrane transport systems in both young and old erythrocytes. This study further substantiates that the changes in progeria model of rats resemble natural aging in terms of erythrocyte senescence. PMID- 30003011 TI - Practice-, Provider-, and Patient-level interventions to improve preventive care: Development of the P3 Model. AB - For adequate provision of preventive services, there is an interplay between activities at the healthcare practice, healthcare provider, and patient levels of the clinical encounter. Commonly used health promotion and behavior theoretical models address some of these three levels, but none fully account for all three. Building off of key components of many existing theoretical models, including the Health Belief Model, Theory of Planned Behavior/Theory of Reasoned Action, Social Cognitive Theory, Social Ecological Model, and the Systems Model of Clinical Preventive Care, we describe the development of the P3 (Practice-, Provider-, and Patient-level) Model for preventive care interventions. The P3 Model accounts for all three levels of the clinical encounter, and the factors that impact these levels, concurrently. This yields a model for preventive care that is applicable and adaptable to different settings, and that provides a framework for the development, implementation, and evaluation of preventive care promotion interventions. The applicability of the P3 Model is shown through two exemplar preventive care programs - immunization and colorectal cancer screening. The P3 Model allows interventions to be developed and evaluated in a modular approach, to allow more practical refinement and optimization of the intervention. PMID- 30003012 TI - Hepatitis A virus immunity and vaccination among at-risk persons receiving HIV medical care. AB - United States guidelines recommend hepatitis A virus (HAV) vaccination for persons living with HIV (PLWH) who are at increased risk for HAV infection, including men who have sex with men (MSM) and persons who inject drugs (PWID). However, nationally representative estimates of vaccine coverage and immunity for this population are lacking. We used medical record and interview data from the 2009-2012 cycles of the Medical Monitoring Project, a nationally representative surveillance system of PLWH receiving HIV medical care in the United States, to estimate the prevalence of HAV immunity, defined as receipt of at least one dose of vaccine or laboratory documentation of anti-HAV antibodies, among 8695 MSM and PWID. Among HAV-nonimmune PLWH, we then examined factors associated with HAV vaccination during the 12-month retrospective observation period using Rao-Scott chi-square tests. Among MSM and PWID receiving HIV medical care, 64% had evidence of HAV immunity. Among those who were nonimmune, 10% were vaccinated during the 12-month retrospective observation period. Factors associated with vaccination during follow-up included younger age (i.e., 18-29 years), self-reported black non-Hispanic race/ethnicity, having detectable HIV RNA, and having been diagnosed with HIV within the past 5 years. Over one third of MSM and PWID receiving HIV medical care during 2009-2012 cycles were not immune to HAV. This analysis suggests that a sizeable proportion of at risk MSM and PWID receiving HIV medical care do not receive HAV vaccination, which is currently recommended. PMID- 30003013 TI - Assessing hearing and cognition challenges in consumer processing of televised risk information: Validation of self-reported measures using performance indicators. AB - Public health researchers face important challenges if they wish to include measures of hearing or cognitive ability in risk communication studies. We sought validity evidence for self-report measures of hearing and cognitive ability by comparing those measures to performance-based measures and risk information recall. We measured hearing ability (with audiologist-assisted assessment and self report), cognitive ability (with an established performance task and self report), and reactions to direct-to-consumer prescription drug promotion with adults 18 and older (n = 1064) in North Carolina, USA, in 2017. We found moderate correspondence between self-reported hearing loss and audiologist-assessed hearing loss. Both measures also showed a small negative association with recall of presented risk information. Cognitive ability results suggested less substantial correspondence between self report and performance task and the measures differed in predicting risk recall. Our results suggested a moderately efficient measure for hearing ability for research on risk information exposure and retention, and yet also suggested the need for caution regarding future use of self-reported cognitive ability as a substitute for a performance-based measure. PMID- 30003015 TI - Association of behavioral health factors and social determinants of health with high and persistently high healthcare costs. AB - A high proportion of U.S. health care costs are attributable to a relatively small proportion of patients. Understanding behavioral and social factors that predict initial and persistent high costs for these "high utilizers" is critical for health policy-makers. This prospective observational study was conducted at Kaiser Permanente Northern California (KPNC), an integrated healthcare delivery system with 4.1 million members. A stratified random sample of high-cost vs. non high-cost adult KPNC members matched by age, gender, race/ethnicity, type of health insurance, and medical severity (N = 378) was interviewed between 3/14/2013 and 3/20/2014. Data on health care costs and clinical diagnoses between 1/1/2008 and 12/31/2012 were derived from the electronic health record (EHR). Social-economic status, depression symptoms, adverse childhood experiences (ACEs), interpersonal violence, financial stressors, neighborhood environment, transportation access, and patient activation and engagement were obtained through telephone interviews. Initial and subsequent high-cost status were defined as being classified in top 20% cost levels over 1/1/2009-12/31/2011 and 1/1/2012-12/31/2012, respectively. Psychiatric diagnosis (OR 2.55, 95% CI 1.52 4.29, p < 0.001), financial stressors (OR 1.97, 95% CI 1.19-3.26, p = 0.009), and ACEs (OR 1.10, 95% CI 1.00-1.20, p = 0.051) predicted initial high-cost status. ACEs alone predicted persistent high-cost status in the subsequent year (OR 1.12, 95% CI 1.00-1.25, p = 0.050). Non-medical factors such as psychiatric problems, financial stressors and adverse childhood experiences contribute significantly to the likelihood of high medical utilization and cost. Efforts to predict and reduce high utilization must include measuring and potentially addressing these factors. PMID- 30003014 TI - Using community-based participatory research to develop healthy retail strategies in Native American-owned convenience stores: The THRIVE study. AB - In rural Native American communities, access to healthy foods is limited and diet related disparities are significant. Tribally owned and operated convenience stores, small food stores that sell ready-to-eat foods and snacks primarily high in fat and sugar, serve as the primary and, in some areas, the only food stores. The Tribal Health and Resilience in Vulnerable Environments or "THRIVE" study, implemented between 2013 and 2018, is the first healthy retail intervention study implemented in tribally owned and operated convenience stores. THRIVE aims to increase vegetable and fruit intake among Native Americans living within the Chickasaw and Choctaw Nation of Oklahoma. The study comprises three phases: 1) formative research assessing tribal community food environments and associated health outcomes; 2) intervention development to assess convenience stores and tailor healthy retail product, pricing, promotion, and placement strategies; and 3) intervention implementation and evaluation. In this paper we share the participatory research process employed by our tribal-university partnership to develop this healthy retail intervention within the unique contexts of tribal convenience stores. We summarize our methods to engage tribal leaders across diverse health, government, and commerce sectors and adapt and localize intervention strategies that test the ability of tribal nations to increase fruit and vegetable purchasing and consumption among tribal members. Study processes will assist in developing a literature base for policy and environmental strategies that intervene broadly to improve Native community food environments and eliminate diet-related disparities among Native Americans. PMID- 30003016 TI - Symptoms of depression in young adulthood is associated with unfavorable clinical and behavioral cardiovascular disease risk factors. AB - Depression in young adults is a growing concern to public health. This study aims to investigate if depression status in young adults is related to clinical and behavioral cardiovascular disease (CVD) risk factors. Cross-sectional data from a population-based sample of young Danish adults participating in the European Youth Heart Study 2009-2010 were used to examine this (n = 644, mean age 24.3 years 47% male). Measures of cardiorespiratory fitness (CRF), body composition, blood pressure, fasting levels of high and low density lipids (HDL, LDL), insulin, and glucose were obtained. Symptoms of depression were obtained using the Major Depression Inventory scale. Information on sleep disorders; drinking and smoking habits were obtained by questionnaires. Associations of depression with CVD risk factors were examined using logistic and linear regression adjusted for age and sex. Prevalence of mild-moderate-severe depression was 8.7% (5.6% males, 11.5% females). Significant sex differences were found in the association between several CVD risk factors and depression status. Women with depression had higher odds of overweight (OR = 2.2, 95%CI: 1.01-4.0), abdominal adiposity (OR = 2.5, 95%CI: 1.2-4.8), low CRF (OR = 2.5, 95%CI: 1.2-5.5), insulin resistance (OR = 2.3, 95%CI: 1.1-4.6), low HDL (OR = 2.0, 95%CI: 1.01-4.1) and high LDL (OR = 2.2, 95%CI: 1.04-4.5) compared to women without depression. Men with depression had significantly increased odds of having high blood pressure and being smokers compared to men without depression (OR: 3.1, 95%CI: 1.1-8.8 and OR: 3.0, 95%CI: 1.1-8.4, respectively). Depression symptoms in young adulthood were related to unfavorable clinical- and behavioral CVD risk factors, particularly in women. PMID- 30003017 TI - Fitting a square peg into a round hole: Perceptions of Appalachian physicians on the incorporation of chronic disease prevention into their practice. AB - This study used a focus group in August 2017 (n = 9) to explore the perceptions of rural physicians to a state request to incorporate diabetes prevention screening into their West Virginia medical practice. Analysis of the data revealed that the participants did not think private physicians were equipped to incorporate diabetes prevention programming into their practice. Three categories emerged from the data analysis to explain the reasoning of the health practitioners on the incorporation of pre-diabetes screening and management into their practice.*The practice of medicine*Prevention is a mismatch*Social determinants of health In the end, the study revealed that a request for physicians to identify and refer at risk patients to a diabetes prevention program is problematic due to conceptual and structural issues. Based on the findings it does not appear at this time that private physicians in rural settings can incorporate diabetes prevention into their existing practice. To address conceptual and structural barriers the invitation to rural physicians must: 1) present evidence on how physicians may be effective in a diabetes management team; 2) include a model that demonstrates a limited, specific role and duties for the physician within a team setting; and last, 3) integrate physicians into an existing community-based network of social and human service providers set up to provide diabetes prevention services. PMID- 30003020 TI - Anticoagulation in Behcet related intrathoracic vasculitis. AB - Behcet disease is a rare multisystem condition associated with HLA-B51 positivity that commonly afflicts individuals of Turkish or Middle Eastern descent, less than 10% of whom have pulmonary involvement. Behcet-related pulmonary vasculitis is an uncommon and heterogeneous group of conditions, often with associated pulmonary artery thrombus formation. These microthrombi can result in a misdiagnosis of acute pulmonary embolism. Anticoagulation therapy can be difficult, as blood thinners increase the risk of pulmonary hemorrhage without affording the same benefits as in pulmonary embolism management. We present two cases of pulmonary vasculitis in the context of Behcet's syndrome, one in a Native American man with associated superior vena cava syndrome and pericarditis, with an increased risk of hemorrhagic pericardial effusion, and the other in an African American man with acute hypoxic respiratory failure with an increased risk of alveolar hemorrhage. We describe their management and the balancing act surrounding anticoagulation therapy in Behcet-related pulmonary vasculitis. PMID- 30003019 TI - Schwannoma arising in a lymph node mimicking metastatic pulmonary carcinoma. AB - Schwannomas commonly arise in the torso, extremities, and mediastinum. However, no interlobar lymph node (#11i) lesions have ever been reported. This is a thought-provoking case, because it involved a schwannoma arising in a lymph node mimicking metastatic pulmonary carcinoma. A 72-year-old man was diagnosed with primary pulmonary carcinoma, and 18F-fluorodeoxyglucose (FDG) positron emission tomography demonstrated high FDG uptake in the primary lesion and in #11i, which suggested metastasis (clinical stage IIA). A right lower lobectomy with lymph node dissection was performed. Fortunately, the enlarged #11i was a schwannoma and not metastasis. The take-home message is "a patient with multiple neuromatosis tends to have schwannomas throughout the body". PMID- 30003021 TI - Pulmonary hyalinising granuloma: A rare cause of multiple lung nodules in lung cancer clinic. AB - Here we report a case of Pulmonary Hyalinising Granuloma (PHG) presenting with mild to moderate FDG positive nodules in an individual with a high risk of cancer. We explore the considerations in interpreting imaging findings and assess the benefits and risks of undertaking invasive investigations such as tissue biopsy. We highlight the importance of reaching an accurate diagnosis of this benign condition on our patients and their future outlook. PMID- 30003022 TI - A case of pulmonary siderosis misdiagnosed as pneumonia. AB - We report first case of pulmonary siderosis appearing as a consolidation upon radiological examination and being misdiagnosed as pneumonia. A 59-year-old man visited our hospital with a cough and sputum that had persisted for more than a month. He had undergone chest computed tomography (CT) after abnormal findings on chest X-ray at other hospitals. Based on the chest CT results, he was diagnosed with pneumonia. He was then administered antibiotics for 3 weeks, but there was no improvement. We identified the patient's occupational history first, and then performed bronchoalveolar lavage and chest CT-guided transthoracic lung biopsy. The obtained specimen showed alveolar, macrophage-containing, Prussian blue positive iron particles. Based on the results, we diagnose/d the patient with pulmonary siderosis. We advised him to discontinue his job. He is currently undergoing observation, and has not shown any special symptoms. PMID- 30003023 TI - Respiratory distress in a 2-month-old infant: Is the primary cause cardiac, pulmonary or both? AB - A 2-month-old female with worsening cough, respiratory distress and an abnormal chest X-ray was referred to our institution for further evaluation of suspected scimitar syndrome. She was found to have normal pulmonary venous drainage with a large patent ductus arteriosus and severe pulmonary arterial hypertension. Chest CT was suggestive of interstitial lung disease. Wedge lung biopsy revealed alveolar simplification and patchy pulmonary interstitial glycogenosis. A definitive diagnosis of Filamin A deficiency was made with genetic studies. The patient is currently showing clinical improvement on systemic glucocorticoid therapy. PMID- 30003024 TI - Deep accidental hypothermia accompanied with cardiac arrest after alcohol and drug poisoning treated with extracorporeal life support. AB - Deep accidental hypothermia is an unusual clinical entity in developed countries. We report a case of a 30 year old male Caucasian patient with accidental severe hypothermia who was transferred to the emergency department of our hospital after prolonged exposure in the urban city's night environment cold as a result of alcohol and drugs abuse. The patient was found unconscious in the first early hours from onlookers. The time that the patient remained unconscious is unknown. During the transfer to the hospital because of cardiac arrest cardiopulmonary resuscitation began. In the emergency department an extracorporeal life support system (ECLS) was implanted under cardiopulmonary resuscitation in order to achieve hemodynamic stabilization and rapid and safe rewarming. The patient's rewarming lasted 6 hours. The patient was extubated the next day. PMID- 30003025 TI - Cortical thickness analysis in operculo-insular epilepsy. AB - Background: In temporal lobe epilepsy (TLE), advanced neuroimaging techniques reveal anomalies extending beyond the temporal lobe such as thinning of fronto central cortices. Operculo-insular epilepsy (OIE) is an under-recognized and poorly characterized condition with the potential of mimicking TLE. In this work, we investigated insular and extra-insular cortical thickness (CT) changes in OIE. Methods: All participants (14 patients with refractory OIE, 9 age- and sex matched patients with refractory TLE and 26 healthy controls) underwent a T1 weighted acquisition on a 3 T MRI. Anatomical images were processed with Advanced Normalization Tools. Between-group analysis of CT was performed using a two-sided t-test (threshold of p < 0.05 after correction for multiple comparisons; cut-off threshold of 250 voxels) between (i) patients with OIE vs TLE, and (ii) patients with OIE vs healthy controls. Results: Significant widespread thinning was observed in OIE patients as compared with healthy controls mainly in the ipsilateral insula, peri-rolandic region, orbito-frontal area, mesiotemporal structures and lateral temporal neocortex. Contralateral cortical shrinkage followed a similar albeit milder and less diffuse pattern.The CT of OIE patients was equal or reduced relative to the TLE group for every cortical region analyzed. Thinning was observed diffusely in OIE patients, predominantly inboth insulae and the ipsilateral occipito-temporal area. Conclusion: Our results reveal structural anomalies extending beyond the operculo-insular area in OIE. PMID- 30003026 TI - Evaluation of methods for volumetric analysis of pediatric brain data: The childmetrix pipeline versus adult-based approaches. AB - Pediatric brain volumetric analysis based on Magnetic Resonance Imaging (MRI) is of particular interest in order to understand the typical brain development and to characterize neurodevelopmental disorders at an early age. However, it has been shown that the results can be biased due to head motion, inherent to pediatric data, and due to the use of methods based on adult brain data that are not able to accurately model the anatomical disparity of pediatric brains. To overcome these issues, we proposed childmetrix, a tool developed for the analysis of pediatric neuroimaging data that uses an age-specific atlas and a probabilistic model-based approach in order to segment the gray matter (GM) and white matter (WM). The tool was extensively validated on 55 scans of children between 5 and 6 years old (including 13 children with developmental dyslexia) and 10 pairs of test-retest scans of children between 6 and 8 years old and compared with two state-of-the-art methods using an adult atlas, namely icobrain (applying a probabilistic model-based segmentation) and Freesurfer (applying a surface model-based segmentation). The results obtained with childmetrix showed a better reproducibility of GM and WM segmentations and a better robustness to head motion in the estimation of GM volume compared to Freesurfer. Evaluated on two subjects, childmetrix showed good accuracy with 82-84% overlap with manual segmentation for both GM and WM, thereby outperforming the adult-based methods (icobrain and Freesurfer), especially for the subject with poor quality data. We also demonstrated that the adult-based methods needed double the number of subjects to detect significant morphological differences between dyslexics and typical readers. Once further developed and validated, we believe that childmetrix would provide appropriate and reliable measures for the examination of children's brain. PMID- 30003027 TI - Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network. AB - Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state. Method: seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction -10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC). Results: In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4). Conclusion: Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms. PMID- 30003028 TI - Temporal lobe epilepsy lateralization using retrospective cerebral blood volume MRI. AB - Steady-state cerebral blood volume (CBV) is tightly coupled to regional cerebral metabolism, and CBV imaging is a variant of MRI that has proven useful in mapping brain dysfunction. CBV derived from exogenous contrast-enhanced MRI can generate sub-millimeter functional maps. Higher resolution helps to more accurately interrogate smaller cortical regions, such as functionally distinct regions of the hippocampus. Many MRIs have fortuitously adequate sequences required for CBV mapping. However, these scans vary substantially in acquisition parameters. Here, we determined whether previously acquired contrast-enhanced MRI scans ordered in patients with unilateral temporal lobe epilepsy can be used to generate hippocampal CBV. We used intrinsic reference regions to correct for intensity scaling on a research CBV dataset to identify white matter as a robust marker for scaling correction. Next, we tested the technique on a sample of unilateral focal epilepsy patients using clinical MRI scans. We find evidence suggestive of significant hypometabolism in the ipsilateral-hippocampus of unilateral TLE subjects. We also highlight the subiculum as a potential driver of this effect. This study introduces a technique that allows CBV maps to be generated retrospectively from clinical scans, potentially with broad application for mapping dysfunction throughout the brain. PMID- 30003029 TI - Abnormal dynamic functional connectivity between speech and auditory areas in schizophrenia patients with auditory hallucinations. AB - Purpose: Auditory hallucinations (AH), typically hearing voices, are a core symptom in schizophrenia. They may result from deficits in dynamic functional connectivity (FC) between cortical regions supporting speech production and language perception that interfere with the ability to recognize self-generated speech as not coming from external sources. We tested this hypothesis by investigating dynamic connectivity between the frontal cortex region related to language production and the temporal cortex region related to auditory processing. Methods: Resting-state fMRI scans were acquired from 18 schizophrenia patients with AH (AH+), 17 schizophrenia patients without AH (AH-) and 22 healthy controls. A multiband sequence with TR = 427 ms was adopted to provide relatively high temporal resolution data for characterizing dynamic FC. Analysis focused on connectivity between speech production and language comprehension areas, eloquent language cortex in the left hemisphere. Two frequency bands of brain oscillatory activity were evaluated (0.01-0.027 Hz, 0.027-0.08 Hz) in which differential alterations that have been previously linked to schizophrenia. Conventional static FC maps of these seeds were also calculated. Results: Dynamic connectivity analysis indicated that AH+ patients showed not only less temporal variability but transient lower strength in connectivity between speech and auditory areas than healthy controls, while AH- patients not. These findings were restricted to 0.027-0.08 Hz activity. In static connectivity analysis, no significant differences were observed in connectivity between speech production and language comprehension areas in either frequency band. Conclusions: Reduced temporal variability and connectivity strength between key regions of eloquent language cortex may represent a mechanism for AH in schizophrenia. PMID- 30003030 TI - Identifying preclinical vascular dementia in symptomatic small vessel disease using MRI. AB - Sporadic cerebral small vessel disease is an important cause of vascular dementia, a syndrome of cognitive impairment together with vascular brain damage. At post-mortem pure vascular dementia is rare, with evidence of co-existing Alzheimer's disease pathology in 95% of cases. This work used MRI to characterize structural abnormalities during the preclinical phase of vascular dementia in symptomatic small vessel disease. 121 subjects were recruited into the St George's Cognition and Neuroimaging in Stroke study and followed up longitudinally for five years. Over this period 22 individuals converted to dementia. Using voxel-based morphometry, we found structural abnormalities present at baseline in those with preclinical dementia, with reduced grey matter density in the left striatum and hippocampus, and more white matter hyperintensities in the frontal white-matter. The lacunar data revealed that some of these abnormalities may be due to lesions within the striatum and centrum semiovale. Using support vector machines, future dementia could be best predicted using hippocampal and striatal Jacobian determinant data, achieving a balanced classification accuracy of 73%. Using cluster ward linkage we identified four anatomical subtypes. Successful predictions were restricted to groups with lower levels of vascular damage. The subgroup that could not be predicted were younger, further from conversion, had the highest levels of vascular damage, with milder cognitive impairment at baseline but more rapid deterioration in processing speed and executive function, consistent with a primary vascular dementia. In contrast, the remaining groups had decreasing levels of vascular damage and increasing memory impairment consistent with progressively more Alzheimer's-like pathology. Voxel-wise rates of hippocampal atrophy supported these distinctions, with the vascular group closely resembling the non-dementing cohort, whereas the Alzheimer's like group demonstrated global hippocampal atrophy. This work reveals distinct anatomical endophenotypes in preclinical vascular dementia, forming a spectrum between vascular and Alzheimer's like pathology. The latter group can be identified using baseline MRI, with 73% converting within 5 years. It was not possible to predict the vascular dominant dementia subgroup, however 19% of negative predictions with high levels of vascular disease would ultimately develop dementia. It may be that techniques more sensitive to white matter damage, such as diffusion weighted imaging, may prove more useful for this vascular dominant subgroup in the future. This work provides a way to accurately stratify patients using a baseline MRI scan, and has utility in future clinical trials designed to slow or prevent the onset of dementia in these high-risk cohorts. PMID- 30003031 TI - Regional cortical perfusion on arterial spin labeling MRI in dementia with Lewy bodies: Associations with clinical severity, glucose metabolism and tau PET. AB - Visually preserved metabolism in posterior cingulate cortex relative to hypometabolism in precuneus and cuneus, the cingulate island sign, is a feature of dementia with Lewy bodies (DLB) on FDG-PET. Lower cingulate island sign ratio (posterior cingulate cortex/cuneus+precuneus; FDG-CISr) values have been associated with a higher Braak neurofibrillary tangle stage in autopsied DLB. Using voxel-wise analysis, we assessed the patterns of regional cortical perfusion and metabolism, and using an atlas-based approach, we measured perfusion cingulate island sign ratio on arterial spin labeling MRI (ASL-CISr), and its associations with FDG-CISr, uptake on tau-PET and clinical severity in DLB. Our study sample (n = 114) included clinically probable DLB patients (n = 19), age-matched patients with probable Alzheimer's disease dementia (AD; n = 19) and matched controls (n = 76) who underwent MRI with 3-dimensional pseudo continuous arterial spin labeling, 18F-FDG-PET and 18F-AV-1451 tau PET. Patterns of cortical perfusion and metabolism were derived from quantitative maps using Statistical Parametric Mapping. DLB patients showed hypoperfusion on ASL-MRI in precuneus, cuneus and posterior parieto-occipital cortices, compared to controls, and relatively spared posterior cingulate gyrus, similar to pattern of hypometabolism on FDG-PET. DLB patients had higher ASL-CISr and FDG-CISr than AD patients (p <0.001). ASL-CISr correlated with FDG-CISr in DLB patients (r = 0.67; p =0.002). Accuracy of distinguishing DLB from AD patients was 0.80 for ASL-CISr and 0.91 for FDG-CISr. Lower ASL-CISr was moderately associated with a higher composite medial temporal AV-1451 uptake (r = -0.50; p =0.03) in DLB. Lower perfusion in precuneus and cuneus was associated with worse global clinical scores. In summary, the pattern of cortical hypoperfusion on ASL-MRI is similar to hypometabolism on FDG-PET, and respective cingulate island sign ratios correlate with each other in DLB. Non-invasive and radiotracer-free ASL-MRI may be further developed as a tool for the screening and diagnostic evaluation of DLB patients in a variety of clinical settings where FDG-PET is not accessible. PMID- 30003032 TI - Test-retest variability of resting-state networks in healthy aging and prodromal Alzheimer's disease. AB - In recent years, changes in resting-state networks (RSN), identified by functional magnetic resonance imaging (fMRI), have gained increasing attention as potential biomarkers and trackers of neurological disorders such as Alzheimer's disease (AD). Intersession reliability of RSN is fundamental to this approach. In this study, we investigated the test-retest reliability of three memory related RSN (i.e., the default mode, salience, and executive control network) in 15 young, 15 healthy seniors (HS), and 15 subjects affected by mild cognitive impairment (MCI) with positive biomarkers suggestive of incipient AD (6 females each). FMRI was conducted on three separate occasions. Independent Component Analysis decomposed the resting-state data into RSNs. Comparisons of variation in functional connectivity between groups were made applying different thresholds in an explorative approach. Intersession test-retest reliability was evaluated by intraclass correlation coefficient (ICC) comparisons. To assess the effect of gray matter volume loss, motion, cerebrospinal fluid based biomarkers and the time gap between sessions on intersession variation, the former four were correlated separately with the latter. Data showed that i) young subjects ICCs (relative to HS/MCI-subjects) had higher intersession reliability, ii) stringent statistical thresholds need to be applied to prevent false-positives, iii) both HS and MCI-subjects (relative to young) showed significantly more clusters of intersession variation in all three RSN, iv) while intersession variation was highly correlated with head motion, it was also correlated with biomarkers (especially phospho-tau), the time gap between sessions and local GMV. Results indicate that time gaps between sessions should be kept constant and that head motion must be taken into account when using RSN to assess aging and neurodegeneration. In patients with prodromal AD, re-test reliability may be increased by accouting for overall disease burden by including biomarkers of neuronal injury (especially phospho-tau) in statistical analyses. Local atrophy however, does not seem to play a major role in regards to reliability, but should be used as covariate depending on the research question. PMID- 30003033 TI - The cumulative effect of small vessel disease lesions is reflected in structural brain networks of memory clinic patients. AB - Background and purpose: Mechanisms underlying cognitive impairment in patients with small vessel disease (SVD) are still unknown. We hypothesized that cognition is affected by the cumulative effect of multiple SVD-related lesions on brain connectivity. We therefore assessed the relationship between the total SVD burden on MRI, global brain network efficiency, and cognition in memory clinic patients with vascular brain injury. Methods: 173 patients from the memory clinic of the University Medical Center Utrecht underwent a 3 T brain MRI scan (including diffusion MRI sequences) and neuropsychological testing. MRI markers for SVD were rated and compiled in a previously developed total SVD score. Structural brain networks were reconstructed using fiber tractography followed by graph theoretical analysis. The relationship between total SVD burden score, global network efficiency and cognition was assessed using multiple linear regression analyses. Results: Each point increase on the SVD burden score was associated with 0.260 [-0.404 - -0.117] SD units decrease of global brain network efficiency (p < .001). Global network efficiency was associated with information processing speed (standardized B = -0.210, p = .004) and attention and executive functioning (B = 0.164, p = .042), and mediated the relationship between SVD burden and information processing speed (p = .027) but not with executive functioning (p = .12). Conclusion: Global network efficiency is sensitive to the cumulative effect of multiple manifestations of SVD on brain connectivity. Global network efficiency may therefore serve as a useful marker for functionally relevant SVD related brain injury in clinical trials. PMID- 30003034 TI - Alterations to task positive and task negative networks during executive functioning in Mild Cognitive Impairment. AB - Poor executive functioning increases risk of decline in Mild Cognitive Impairment (MCI). Executive functioning can be conceptualized within the framework of working memory. While some components are responsible for maintaining representations in working memory, the central executive is involved in the manipulation of information and creation of new representations. We aimed to examine the neural correlates of these components of working memory using a maintenance working memory and visuospatial reasoning task. Twenty-five patients with amnestic MCI and 19 elderly controls (EC) completed functional MRI during reasoning and maintenance working memory tasks. In MCI, maintenance working memory was associated with hypoactivation of right frontoparietal regions and hyperactivation of left prefrontal cortex, coupled with attenuation of default mode network (DMN) relative to EC. During reasoning, MCI showed hypoactivation of parietal regions, coupled with attenuation of anterior DMN and increased deactivation of posterior DMN relative to EC. Comparing the reasoning task to the maintenance working memory task yields the central executive. In MCI, the central executive showed hypoactivation of right parietal lobe and increased deactivation of posterior DMN compared to EC. Consistent with prior work on executive functioning, MCI show different neural circuitry during visuospatial reasoning, including changes to both task positive frontoparietal regions, as well as to deactivation patterns within the DMN. Both hyperactivation of task positive networks and increased deactivation of DMN may be compensatory. PMID- 30003035 TI - Brain activation during the expectations of sensory experience for cutaneous electrical stimulation. AB - The brain actively interprets sensory inputs by integrating top-down and bottom up information. Humans can make inferences on somatosensation based on prior experiences and expectations even without the actual stimulation. We used functional magnetic resonance imaging to investigate the neural substrates of the expectations of the sensory experience of cutaneous electrical stimulation on acupoint without actual stimuli. This study included 22 participants who wore sticker-type electrodes attached on three different acupoints on different body regions: CV17 (chest), CV23 (chin), and left PC6 (arm). Participants evaluated de qi sensations after they expected electrical stimulation on those points in random order without actual stimulation. All stimuli were presented with corresponding visual information of the stimulation sites. The control condition included the same visual information but outside the body. The expectations of cutaneous electrical stimuli without actual stimulation on three acupoints resulted in greater de qi sensation compared to the control condition. Cognitive components of cutaneous electrical stimulation exhibited greater brain activation in the anterior insula, pre-supplementary motor area, and secondary somatosensory area. The expectations of acupuncture stimulation exhibited a distinct experience of somatosensation as well as brain activations in insula and pre-supplementary motor area. Our findings suggest that the sensory experience of the pseudo cutaneous stimulation may be derived from the predictive role of the salience network in monitoring internal and external body states. PMID- 30003036 TI - Predicting seizure outcome of vagus nerve stimulation using MEG-based network topology. AB - Vagus nerve stimulation (VNS) is a low-risk surgical option for patients with drug resistant epilepsy, although it is impossible to predict which patients may respond to VNS treatment. Resting-state magnetoencephalography (rs-MEG) connectivity analysis has been increasingly utilized to investigate the impact of epilepsy on brain networks and identify alteration of these networks after different treatments; however, there is no study to date utilizing this modality to predict the efficacy of VNS treatment. We investigated whether the rs-MEG network topology before VNS implantation can be used to predict efficacy of VNS treatment. Twenty-three patients with epilepsy who had MEG before VNS implantation were included in this study. We also included 89 healthy control subjects from the Human Connectome Project. Using the phase-locking value in the theta, alpha, and beta frequency bands as a measure of rs-MEG functional connectivity, we calculated three global graph measures: modularity, transitivity, and characteristic path length (CPL). Our results revealed that the rs-MEG graph measures were significantly heritable and had an overall good test retest reliability, and thus these measures may be used as potential biomarkers of the network topology. We found that the modularity and transitivity in VNS responders were significantly larger and smaller, respectively, than those observed in VNS non-responders. We also observed that the modularity and transitivity in three frequency bands and CPL in delta and beta bands were significantly different in controls than those found in responders or non responders, although the values of the graph measures in controls were closer to those of responders than non-responders. We used the modularity and transitivity as input features of a naive Bayes classifier, and achieved an accuracy of 87% in classification of non-responders, responders, and controls. The results of this study revealed that MEG-based graph measures are reliable biomarkers, and that these measures may be used to predict seizure outcome of VNS treatment. PMID- 30003037 TI - Altered cortical functional network in major depressive disorder: A resting-state electroencephalogram study. AB - Background: Electroencephalogram (EEG)-based brain network analysis is a useful biological correlate reflecting brain function. Sensor-level network analysis might be contaminated by volume conduction and does not explain regional brain characteristics. Source-level network analysis could be a useful alternative. We analyzed EEG-based source-level network in major depressive disorder (MDD). Method: Resting-state EEG was recorded in 87 MDD and 58 healthy controls, and cortical source signals were estimated. Network measures were calculated: global indices (strength, clustering coefficient (CC), path length (PL), and efficiency) and nodal indices (eigenvector centrality and nodal CC) in six frequency. Correlation analyses were performed between network indices and symptom scales. Results: At the global level, MDD showed decreased strength, CC in theta and alpha bands, and efficiency in alpha band, while enhanced PL in alpha band. At nodal level, eigenvector centrality of alpha band showed region dependent changes in MDD. Nodal CCs of alpha band were reduced in MDD and were negatively correlated with depression and anxiety scales. Conclusion: Disturbances in EEG based brain network indices might reflect altered emotional processing in MDD. These source-level network indices might provide useful biomarkers to understand regional brain pathology in MDD. PMID- 30003038 TI - It takes two to pantomime: Communication meets motor cognition. AB - For over a century, pantomime of tool use has been employed to diagnose limb apraxia, a disorder of motor cognition primarily induced by left brain damage. While research consistently implicates damage to a left fronto-temporo-parietal network in limb apraxia, findings are inconsistent regarding the impact of damage to anterior versus posterior nodes within this network on pantomime. Complicating matters is the fact that tool use pantomime can be affected and evaluated at multiple levels. For instance, the production of tool use gestures requires the consideration of semantic characteristics (e.g. how to communicate the action intention) as well as motor features (e.g. forming grip and movement). Together, these factors may contribute substantially to apparent discrepancies in previously reported findings regarding neural correlates of tool use pantomime. In the current study, 67 stroke patients with unilateral left-brain damage performed a classic pantomime task. In order to analyze different error characteristics, we evaluated the proper use of grip and movement for each pantomime. For certain objects, healthy subjects may use body parts as representative for the object, e.g. use of the fingers to indicate scissors blades. To specify the pathological use of body parts as the object (BPO) we only assessed pantomime items that were not prone to this response in healthy participants. We performed modern voxel-based lesion analyses on MRI or CT data to determine associations between brain injury and the frequency of the specific types of pantomime errors. Our results support a model in which anterior and posterior nodes of the left fronto-temporo-parietal network contribute differentially to pantomime of tool use. More precisely, damage in the inferior frontal cortex reaching to the temporal pole is associated with an increased frequency of BPO errors, whereas damage to the inferior parietal lobe is predominantly linked to an increased frequency of movement and/or grip errors. Our work suggests that the validity of attempts to specify the neural correlates of limb apraxia based on tool use pantomime depends on differentiating the specific types of errors committed. We conclude that successful tool use pantomime involves dissociable functions with communicative aspects represented in more anterior (rather ventral) regions and motor-cognitive aspects in more posterior (rather dorsal) nodes of a left fronto-temporo-parietal network. PMID- 30003039 TI - Neurophysiological correlates of the attention training technique: A component study. AB - In the current study, we investigate the neuronal correlates of the Attention Training Technique (ATT), a psychotherapeutic intervention used in metacognitive therapy to enhance flexible cognitive control and ameliorate rumination. We adapted the ATT in a neuroscientific attention paradigm in order to investigate the effects of its components: selective attention, attention switching and divided attention in comparison to a control task. Functional near-infrared spectroscopy was used to measure changes in blood oxygenation of fronto-lateral and parietal cortical areas. Furthermore, subjects rated their task performance, effort and attention drifts in each task condition. We observed increased blood oxygenation in the right inferior frontal gyrus, right dorsolateral prefrontal cortex and superior parietal lobule during the ATT conditions in comparison to the control condition. Additionally, subjective effort was associated with blood oxygenation in the right inferior prefrontal cortex. Our results are consistent with the theoretical underpinnings of the ATT suggesting that the ATT's mechanism of change lies in the training of areas of the cognitive control network and dorsal attention network. Aberrant functioning of both networks has been shown to be related to depression and rumination. PMID- 30003040 TI - Optoacoustic signal excitation with a tone-burst of short pulses. PMID- 30003041 TI - Vascular branching point counts using photoacoustic imaging in the superficial layer of the breast: A potential biomarker for breast cancer. AB - This study aimed to identify the characteristics of the vascular network in the superficial subcutaneous layer of the breast and to analyze differences between breasts with cancer and contralateral unaffected breasts using vessel branching points (VBPs) detected by three-dimensional photoacoustic imaging with a hemispherical detector array. In 22 patients with unilateral breast cancer, the average VBP counts to a depth of 7 mm below the skin surface were significantly greater in breasts with cancer than in the contralateral unaffected breasts (p < 0.01). The ratio of the VBP count in the breasts with cancer to that in the contralateral breasts was significantly increased in patients with a high histologic grade (p = 0.03), those with estrogen receptor-negative disease (p < 0.01), and those with highly proliferative disease (p < 0.01). These preliminary findings indicate that a higher number of VBPs in the superficial subcutaneous layer of the breast might be a biomarker for primary breast cancer. PMID- 30003043 TI - Recurrent retroperitoneal soft tissue sarcoma showing drastic reduction after pazopanib administration accompanied by severe liver dysfunction. AB - Pazopanib is an orally bioavailable tyrosine kinase inhibitor anticancer drug approved worldwide for the treatment of metastatic renal cell carcinoma and advanced soft tissue sarcoma. Here we report the case of a patient whose recurrent retroperitoneal soft tissue sarcoma showed a drastic reduction immediately after pazopanib administration accompanied by severe liver dysfunction. His liver function was restored conservatively by giving him hepatoprotectors and having him stop taking pazopanib. The recurrent tumor disappeared but by 4 months later had regrown. PMID- 30003042 TI - AhR signaling pathways and regulatory functions. AB - Animals and humans are exposed each day to a multitude of chemicals in the air, water and food. They have developed a battery of enzymes and transporters that facilitate the biotransformation and elimination of these compounds. Moreover, a majority of these enzymes and transporters are inducible due to the activation of xenobiotic receptors which act as transcription factors for the regulation of their target genes (such as xenobiotic metabolizing enzymes, see below S4 for the AhR). These receptors include several members of the nuclear/steroid receptor family (CAR for Constitutive Androstane Receptor, PXR for Pregnane X Receptor) but also the Aryl hydrocarbon Receptor or AhR, a member of the bHLH-PAS family (basic Helix-Loop-Helix - Period/ARNT/Single minded). In addition to the regulation of xenobiotic metabolism, numerous alternative functions have been characterized for the AhR since its discovery. These alternative functions will be described in this review along with its endogenous functions as revealed by experiments performed on knock-out animals. PMID- 30003044 TI - Crohn's disease patient serum changes protein expression in a human mesenchymal stem cell model in a linear relationship to patients' disease stage and to bone mineral density. AB - Background: Crohn's disease (CD) is associated with a higher prevalence of osteoporosis, a complication that is recognized as a significant cause of morbidity. Its pathogenesis is controversial, but the activity of CD is one contributing factor. Methods: We stimulated SCP-1 cells (mesenchymal stem cell line) under osteogenic conditions with serum from adult patients with CD in the symptomatic phase (SP) and in remission (R) and with control sera. Concentrations of IL-6, IL-1 beta, and TNF alpha in the sera were measured. Patients were classified as normal or osteopenic/osteoporotic based on bone mineral density (BMD) T-score measurements. After 14 days in culture, protein expression and gene ontology (GO) annotation analysis was performed. Results: Cytokine concentrations (IL-6, IL-1 beta, TNF alpha) varied within sera groups. None of the cytokines were significantly increased in the symptomatic phase compared to remission. Protein analysis revealed 17 proteins regulated by the SP versus R phase sera of disease. A linear relationship between CDAI (Crohn's disease activity index) and normalized protein expression of APOA1 and 2, TTR, CDKAL1 and TUBB6 could be determined. Eleven proteins were found to be differentially regulated comparing osteoporosis-positive and osteoporosis-negative sera. Gene annotation and further analysis identified these genes as part of heme and erythrocyte metabolism, as well as involved in hypoxia and in endocytosis. A significant linear relationship between bone mineral density and normalized protein expression could be determined for proteins FABP3 and TTR. Conclusion: Our explorative results confirm our hypothesis that factors in serum from patients with CD change the protein expression pattern of human immortalized osteoblast like cells. We suggest, that these short time changes indeed influence factors of bone metabolism. PMID- 30003045 TI - Assessment of metal levels in foodstuffs from the Region of Valencia (Spain). AB - Concentrations of lead, mercury, cadmium, arsenic, tin, copper and chromium were measured in a study carried out in 2010-2011. A total of 8100 food samples were collected and composite samples for 12 food groups were analysed for metal concentration levels. Metal levels were, in general, below the maximum levels set by the current European legislation. The fish group presented the highest Cd, Hg and As levels, whereas sweeteners and condiments group was the most contaminated food group by Pb, Cr and Sn and the meat group had the highest concentrations of Cu. The results of this study are generally similar to or lower than those observed in other studies conducted in other countries, except in the case of Hg, for which high values were obtained, mainly in swordfish. In addition, this survey confirms a decreasing tendency when compared with other studies carried out in Spain. PMID- 30003046 TI - Assessment of rabbit spermatozoa characteristics after amygdalin and apricot seeds exposure in vivo. AB - This study evaluates rabbit spermatozoa motility parameters after in vivo administration of amygdalin and apricot seeds during a 28-day period. Apricot seeds are potentially useful in human nutrition and amygdalin is the major cyanogenic glycoside present therein. The rabbits were randomly divided into the five groups (Ctrl-Control, P1, P2, P3, P4) with 4 males in each group. Control group received no amygdalin/apricot seeds while the experimental groups P1 and P2 received a daily intramuscular injection of amygdalin at a dose 0.6 and 3.0 mg/kg b.w. respectively during 28 days. P3 and P4 received a daily dose 60 and 300 mg/kg b.w. of crushed apricot seeds mixed with feed during 28 days, respectively. CASA system was used to evaluate for motility, progressive motility, curvilinear velocity, amplitude of lateral head displacement and beat cross frequency. Intramuscular application of amygdalin resulted in a significant time- and dose dependent decrease of spermatozoa motility as well as progressive motility. On the other hand, oral consumption of apricot seeds had no significant effect either on the rabbit spermatozoa motility or progressive motility over the entire course of the study. The analysis of the other motion characteristics revealed a similar trend depicting a continuous, time- and dose-dependent decrease of all parameters following intramuscular AMG administration, with significant differences particularly for the dose 3.0 mg AMG/kg b.w. On the other hand, oral administration of apricot seeds had no significant impact on spermatozoa motility parameters. The present study suggests that short-term intramuscular application of amygdalin decreased rabbit spermatozoa motility in vivo. Whereas, consumption of apricot seeds did not induce any change in rabbit spermatozoa in vivo. Our findings suggest dose-dependent negative effect of pure amygdalin, but not apricot seeds on the rabbit spermatozoa parameters. PMID- 30003047 TI - Immunosuppressant drug tacrolimus induced mitochondrial nephrotoxicity, modified PCNA and Bcl-2 expression attenuated by Ocimum basilicum L. in CD1 mice. AB - Tacrolimus (TAC) is used sporadically as an immunosuppressive agent for organ transplantation, but its clinical used is limited due to its marked nephrotoxicity. Ocimum basilicum L. (Lamiaceae) (OB) had been shown to possess antioxidant, anti-inflammatory and nephroprotective activity, and effective at improving renal inflammation and glomerular. In our study, we aim to evaluate the efficacy of the OB against TAC-induced mitochondrial nephrotoxicity in CD1 mice. Mice were randomly divided into four groups. Group 1 (control group); administered orally with normal saline (1 mL/kg) for two weeks; Group 2 (OB extract treated-group) (500 mg/kg b.wt) gavaged once/day for two weeks; Group 3 (TAC-treated group) (3 mg/kg b.wt, administered ip once a day for two weeks); and Group 4; (TAC plus OB extract treated-group). Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. The OB extract was high in phenolic content (50.3 mg/g of gallic acid equivalent), total flavonoids (14.5 mg/g CE equivalent). The potential antioxidant efficacy of the extract (IC50) was 24.5 MUg/mL. OB pretreatment significantly improved the TAC-induced changes in biochemical markers of nephrotoxicity for instance blood urea nitrogen (BUN), creatinine, total protein, and albumin (P < 0.01, when compared with TAC treated group). Also, it significantly restored the increase activities of TBARS, protein carbonyl (PC) (P < 0.001, when compared to healthy control group) and decreased activities of nonprotein thiol (NP-SH) levels, Mn-superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx) antioxidants of mitochondria. The nephroprotective efficacy of the OB leaves extract was further evident by histopathological analysis together with the PCNA-ir and Bcl2. The upshot of the present study revealed that the OB possessed significant antioxidant and nephroprotective activity and had a preventive effect on the biochemical alterations and histological changes in TAC-treated mice. PMID- 30003048 TI - Toxicological safety evaluation of freeze-dried Protaetia brevitarsis larva powder. AB - White-spotted flower chafer (Protaetia brevitarsis) is an edible insect and its larva was used as a traditional Asian medicine. It's a promising material as a novel food source because of its nutritional components. In this study, as part of the preclinical toxicity program, we evaluated the toxicity of freeze-dried P. brevitarsis larva powder to develop a novel food material. In a single-dose oral toxicity study in rats, there were no changes in mortality, clinical observations, and body weight in rats administered 5000 mg/kg P. brevitarsis larva powder. In a 13-week oral repeated dose toxicity study in rats, there were no adverse effects or changes in mortality, clinical observations, body weight, food consumption, ophthalmology, clinical pathology, necropsy, organ weight, and histopathology at doses of 300, 1000, and 3000 mg/kg/day. In identification of allergic reactions, P. brevitarsis larva powder induced no increases of serum immunoglobulin E and histamine concentrations over 13 weeks of oral administration in rats. In a genotoxicity assessment, P. brevitarsis larva powder didn't provoke bacterial reverse mutations, chromosomal aberrations, and micronucleated reticulocytes. Therefore, freeze-dried P. brevitarsis larva powder shows no evidence of toxic and mutagenic changes under the experimental conditions of the present in vitro and in vivo studies. PMID- 30003049 TI - Wavelet regression: An approach for undertaking multi-time scale analyses of hydro-climate relationships. AB - Previous studies showed that hydro-climate processes are stochastic and complex systems, and it is difficult to discover the hidden patterns in the and non stationary data and thoroughly understand the hydro-climate relationships. For the purpose to show multi-time scale responses of a hydrological variable to climate change, we developed an integrated approach by combining wavelet analysis and regression method, which is called wavelet regression (WR). The customization and the advantage of this approach over the existing methods are presented below: *The patterns in the data series of a hydrological variable and its related climatic factors are revealed by the wavelet analysis at different time scales.*The hydro-climate relationship of each pattern is revealed by the regression method based on the results of wavelet analysis.*The advantage of this approach over the existing methods is that the approach provides a routing to discover the hidden patterns in the stochastic and non-stationary data and quantitatively describe the hydro-climate relationships at different time scales. PMID- 30003050 TI - Methodology for soil respirometric assays: Step by step and guidelines to measure fluxes of trace gases using microcosms. AB - This methodology is proposed to measure the fluxes of trace gases among microcosms and the atmosphere. As microcosm respiration we include both aerobic and anaerobic respiration, which may results in CO2, CH4, NO, N2O, N2, H2S and H2 fluxes. Its applicability includes the assessment of products biodegradability and toxicity, the effect of treatments and products on greenhouse gases fluxes, and the mineralization of organic fertilizers. A step by step procedure; the complementary parameters and good practices that might be taken into account to perform a microcosm experiment; and the tools nowadays available that could be useful in this respirometric methodology are presented. We included a spreadsheet with calculus examples. Samples were taken at 1; 30; 60 and 90 min after closing the microcosms to determine the gases fluxes. The dilution effect was negligible, as we present. Besides CO2, we have successfully quantified the fluxes of CH4 and N2O from the microcosms in a broad range of concentrations. This method is useful in technical and scientific studies, for instances to test new products and improve the understanding of microbial processes, respectively. *Simple materials are required to set up the microcosm.*Examples of (pre) treatments are given regarding water availability, fertilizer doses, pH adjustment and nutrients amendments.*The method was suitable to directly measure multiple trace gases fluxes, either produced or consumed during microcosm respiration. PMID- 30003051 TI - A novel method for rapid and sensitive metagenomic activity screening. AB - Direct cloning of metagenomes has proven to be a powerful tool for the exploration of the diverse sequence space of a microbial community leading to gene discovery and biocatalyst development. The key to such approach is the development of rapid, sensitive, and reliable functional screening of libraries. The majority of library screen have relied on the use of agar plates in petri dishes incorporating the target enzyme substrate for activity detection of positive clones (Iqbal et al. [1], Knietsch et al. [2], Popovic et al. [3]). In this article, a novel method is described consisting of: (1) formulation and application of substrate gel microtiter assay plates, (2) screening of libraries of clones in split pools in the wells of the assay plate, and (3) progressive enrichment and isolation of individual positive clones. The method has been successfully used in the rapid discovery of novel genes and enzymes from rumen microbial metagenome with high efficacy. *Novel substrate gel assay plates for activity screening with localized and intensified signals.*Rapid and complete screening of library clones in split pools.*Progressive enrichment scheme as a refining step for isolating target gene. PMID- 30003052 TI - Immobilization and stabilization of alcohol dehydrogenase on polyvinyl alcohol fibre. AB - A polyvinyl alcohol (PVA) fibrous carrier has been chemically modified for the immobilization of yeast alcohol dehydrogenase (ADH) with an aim to increase its stability over a wide pH range, prolong its activity upon storage, and enhance its reusability. The strategy for immobilization involved functionalization of the fibrous carrier with chloropropinoyl chloride followed by amination with ethylenediamine. Tethering of the ADH enzyme to the PVA scaffold was achieved with glutaraldehyde. The activity profile of the immobilized enzyme was compared to soluble enzyme as a function of pH, temperature and reusability. The immobilization of ADH on PVA fibrous carrier shifted the optimal reaction pH from 7 to 9, and improved the thermostability at 60 degrees C. Furthermore, the immobilized enzyme retained 60% of its original activity after eight cycles of reuse. These results demonstrate that PVA based textiles can serve as a flexible, reusable carrier for enzyme immobilization. PMID- 30003054 TI - Reader's Forum. PMID- 30003053 TI - Molecular cloning and characteristics analysis of Pmtgfbr1 from Pinctada fucata martensii. AB - Pinctada fucata martensii is cultured for pearl production. Growth improvement has received considerable research interest. Transforming growth factor beta type I receptor (TbetaR-I), which is involved in signals transmission of transforming growth factor beta (TGF-beta), participates in cell proliferation and growth. In this study, we characterized a Tgfbr1 gene which encoded TbetaR-I from P. fucata martensii (Pmtgfbr1). Pmtgfbr1 cDNA contains an open reading frame of 1569 bp and encodes a polypeptide of 522 amino acids (aa). Pmtgfbr1 possesses a typical TbetaR-I structure (extracellular receptor ligand domain, transmembrane domain, and cytoplasmic tyrosine kinase catalytic domain). Pmtgfbr1 is expressed in all the studied tissues and exhibited the highest expression level in the adductor muscle. Moreover, Pmtgfbr1 exhibited the lower expression level in the larger group (L) than that in the smaller group (S) and is negatively correlated with growth traits (P < 0.01). Our results indicated that Pmtgfbr1 is a candidate functional gene associated with growth traits. PMID- 30003055 TI - Trend of health care utilization of cleft lip and/or palate in Korea during 2007 2016. AB - Objective: This study is performed to investigate the trend of health care (HC) utilization among cleft lip and/or palate (CL/P) during 2007-2016 by using data from the Korean National Health Insurance Service (KNHIS). Methods: The KNHIS data were reorganized to count a specific patient only once for a specific year. Cleft type (cleft lip [CL], cleft palate [CP], and cleft lip and palate [CLP]), sex, and age at HC utilization were investigated. The study period was divided into the first half (2007-2011) and the last half (2012-2016). The utilization number and rate per 1,000 population were calculated for the total population and for new-born patients. Independent t-test and one-way analysis of variance were used for statistical analyses. Results: The total CL/P population (n = 48,707) comprised 19.2% CLP, 35.5% CL, and 45.3% CP (CLP < CL < CP; p < 0.001). Their HC utilization rate increased from 0.066 in 2007 to 0.118 in 2016. The new-born patient population (n = 7,617) comprised 18.6% CLP, 30.4% CL, and 51.0% CP (CLP < CL < CP; p < 0.001). Their HC utilization rate increased from 1.12 in 2007 to 1.74 in 2016. An examination of the utilization number and rate among new-born patients revealed CP exhibited a female-dominant pattern (all p < 0.01), while CL and CLP exhibited a male-dominant pattern (all p < 0.01). However, utilization number showed no difference by sex and cleft type between 2007-2011 and 2012 2016. Conclusions: These results might serve as a guideline for HC utilization among patients with CL/P. PMID- 30003056 TI - Comparison of treatment effects between four premolar extraction and total arch distalization using the modified C-palatal plate. AB - Objective: The purpose of this study was to compare the skeletal, dental, and soft-tissue treatment effects of nonextraction therapy using the modified C palatal plate (MCPP) to those of premolar extraction (PE) treatment in adult patients with Class II malocclusion. Methods: Pretreatment and posttreatment lateral cephalographs of 40 adult patients with Class II malocclusion were retrospectively analyzed. The MCPP group comprised 20 patients treated with total arch distalization of the maxillary arch while the PE group comprised 20 patients treated with four PE. Fifty-eight linear and angular measurements were analyzed to assess the changes before and after treatment. Descriptive statistics, paired t-test, and multivariate analysis of variance were performed to evaluate the treatment effects within and between the two groups. Results: The MCPP group presented 3.4 mm of retraction, 1.0 mm of extrusion, and 7.3 degrees lingual inclination of the maxillary central incisor. In comparison, the PE group displayed greater amount of maxillary central incisor retraction and retroclination, mandibular incisor retraction, and upper lip retraction (5.3 mm, 14.8 degrees , 5.1 mm, and 2.0 mm, respectively; p < 0.001 for all). In addition, the MCPP group showed 4.0 mm of distalization and 1.3 mm of intrusion with 2.9 degrees distal tipping of the maxillary first molars. Conclusions: These findings suggest the MCPP is an effective distalization appliance in the maxillary arch. The amount of incisor retraction, however, was significantly higher in the PE group. Therefore, four PE may be recommended when greater improvement of incisor position and soft-tissue profile is required. PMID- 30003057 TI - The effect of occlusogingival placement of clinical bracket points on the adaptation of a straight wire to the lingual arch form. AB - Objective: The aim of this study is to compare the adaptation of a straight wire between brackets positioned at the mid-lingual surface and those placed gingivally by using a three-dimensional simulation software. Methods: This cross sectional study was performed using OrthoAid, an in-house software. The subjects were 36 adolescents with normal Class I occlusion. For each dental cast, two bracket positioning approaches, namely the middle and gingival, were examined. In the middle group, the reference points were placed on the mid-lingual surface of each tooth, while in the gingival group, the reference points were positioned lingually on the anterior teeth. A 4th degree polynomial was adopted, and the in plane and off-plane root mean squares (RMSs) of the distances between the reference points and the fitted polynomial curve were calculated using the software. Statistical analysis was performed using the paired-samples t-test (alpha = 0.05). Results: The mean in-plane RMS of the polynomial curve to the bracket distance in the gingival group was significantly lower than that in the middle group (p < 0.001). The off-plane RMS was higher in the gingivally positioned brackets in the maxilla than in the middle group (p < 0.001). However, the off-plane RMS in mandible was not statistically significantly different between the two groups (p = 0.274). Conclusions: The results demonstrated that the gingival placement of lingual brackets on the anterior teeth could decrease the distance between a tooth and the straight wire. PMID- 30003058 TI - Effects of different primers on indirect orthodontic bonding: Shear bond strength, color change, and enamel roughness. AB - Objective: We aimed to perform in-vitro evaluation to compare 1) shear bond strength (SBS), adhesive remnant index (ARI), and color change between self etched and acid-etched primers; 2) the SBS, ARI and color change between direct and indirect bonding; and 3) the enamel roughness (ER) between 12-blade bur and aluminum oxide polisher debonding methods. Methods: Seventy bovine incisors were distributed in seven groups: control (no bonding), direct (DTBX), and 5 indirect bonding (ITBX, IZ350, ISONDHI, ISEP, and ITBXp). Transbond XT Primer was used in the DTBX, ITBX, and ITBXp groups, flow resin Z350 in the IZ350 group, Sondhi in the ISONDHI group, and SEP primer in the ISEP group. SBS, ARI, and ER were evaluated. The adhesive remnant was removed using a low-speed tungsten bur in all groups except the ITBXp, in which an aluminum oxide polisher was used. After coffee staining, color evaluations were performed using a spectrophotometer immediately after staining and prior to bonding. Results: ISONDHI and ISEP showed significantly lower SBS (p < 0.01). DTBX had a greater number of teeth with all the adhesive on the enamel (70%), compared with the indirect bonding groups (0 30%). The ER in the ITBX and ITBXp groups was found to be greater because of both clean-up techniques used. Conclusions: Direct and indirect bonding have similar results and all the primers used show satisfactory adhesion strength. Use of burs and polishers increases the ER, but polishers ensure greater integrity of the initial roughness. Resin tags do not change the color of the teeth. PMID- 30003059 TI - Effect of caspases and RANKL induced by heavy force in orthodontic root resorption. AB - Objective: Orthodontic root resorption (ORR) due to orthodontic tooth movement is a difficult treatment-related adverse event. Caspases are important effector molecules for apoptosis. At present, little is known about the mechanisms underlying ORR and apoptosis in the cementum. The aim of the present in vivo study was to investigate the expression of tartrate-resistant acid phosphatase (TRAP), caspase 3, caspase 8, and receptor activator of nuclear factor kappa-B ligand (RANKL) in the cementum in response to a heavy or an optimum orthodontic force. Methods: The maxillary molars of male Wistar rats were subjected to an orthodontic force of 10 g or 50 g using a closed coil spring. The rats were sacrificed each experimental period on days 1, 3, 5, and 7 after orthodontic force application. And the rats were subjected to histopathological and immunohistochemical analyses. Results: On day 7 for the 50-g group, hematoxylin and eosin staining revealed numerous root resorption lacunae with odontoclasts on the root, while immunohistochemistry showed increased TRAP- and RANKL-positive cells. Caspase 3- and caspase 8-positive cells were increased on the cementum surfaces in the 50-g group on days 3 and 5. Moreover, the number of caspase 3- and caspase 8-positive cells and RANKL-positive cells was significantly higher in the 50-g group than in the 10-g group. Conclusions: In our rat model, ORR occurred after apoptosis was induced in the cementum by a heavy orthodontic force. These findings suggest that apoptosis of cementoblasts is involved in ORR. PMID- 30003060 TI - Clinical application of an intraoral scanner for serial evaluation of orthodontic tooth movement: A preliminary study. AB - The aim of this study was to test the clinical application of an intraoral scanner for serial evaluation of orthodontic tooth movement. The maxillary dentitions of eight patients with fixed orthodontic appliances were scanned using an intraoral scanner at the beginning of treatment (T0), and at 1 month (T1), 2 months (T2), 3 months (T3), and 4 months (T4) after T0. The serial digital models were superimposed on the palatal surface as a reference area, and the linear and angular changes of the central incisors, canines, and first molars were evaluated. The intraclass correlation coefficient and method errors showed that this method was clinically acceptable. Various types of orthodontic tooth movements, including minute movements, could be observed every month. The intraoral scanner and digital superimposition technique enabled the serial evaluation of orthodontic tooth movement without taking serial impressions and/or acquiring radiographs. PMID- 30003061 TI - Resistance to sliding in orthodontics: misconception or method error? A systematic review and a proposal of a test protocol. AB - Resistance to sliding (RS) between the bracket, wire, and ligature has been largely debated in orthodontics. Despite the extensive number of published studies, the lack of discussion of the methods used has led to little understanding of this phenomenon. The aim of this study was to discuss variables affecting RS in orthodontics and to suggest an operative protocol. The search included PubMed(c), Medline(c), and the Cochrane Library(c). References of full text articles were manually analyzed. English-language articles published between January 2007 and January 2017 that performed an in vitro analysis of RS between the bracket, wire, and ligature were included. Study methods were analyzed based on the study design, description of materials, and experimental setup, and a protocol to standardize the testing methods was proposed. From 404 articles identified from the database search and 242 records selected from published references, 101 were eligible for the qualitative analysis, and six for the quantitative synthesis. One or more experimental parameters were incompatible and a meta-analysis was not performed. Major factors regarding the study design, materials, and experimental setup were not clearly described by most studies. The normal force, that is the force perpendicular to the sliding of the wire and one of the most relevant variable in RS, was not considered by most studies. Different variables were introduced, often acting as confounding factors. A protocol was suggested to standardize testing procedures and enhance the understanding of in vitro findings. PMID- 30003062 TI - Testing of a Tool for Prostate Cancer Screening Discussions in Primary Care. AB - Background: As prostate cancer (PCa) screening decisions often occur in outpatient primary care, a brief tool to help the PCa screening conversation in busy clinic settings is needed. Methods: A previously created 9-item tool to aid PCa screening discussions was tested in five diverse primary care clinics. Fifteen providers were recruited to use the tool for 4 weeks, and the tool was revised based upon feedback. The providers then used the tool with a convenience sample of patients during routine clinic visits. Pre- and post-visit surveys were administered to assess patients' knowledge of the option to be screened for PCa and of specific factors to consider in the decision. McNemar's and Stuart-Maxwell tests were used to compare pre-and post-survey responses. Results: 14 of 15 providers completed feedback surveys and had positive responses to the tool. All 15 providers then tested the tool on 95 men aged 40-69 at the five clinics with 2 10 patients each. The proportion of patients who strongly agreed that they had the option to choose to screen for PCa increased from 57 to 72% (p = 0.018) from the pre- to post-survey, that there are factors in the personal or family history that may affect PCa risk from 34 to 47% (p = 0.012), and that their opinions about possible side effects of treatment for PCa should be considered in the decision from 47 to 61% (p = 0.009). Conclusion: A brief conversation tool for the PCa screening discussion was well received in busy primary-care settings and improved patients' knowledge about the screening decision. PMID- 30003064 TI - The family Raphitomidae (Mollusca: Gastropoda: Conoidea) in the Greek Seas with the description of two new species. AB - Background: The Raphitomidae family in the Mediterranean Sea is under revision. Accordingly, new data are of taxonomic and comparative relevance. In this study, new material from the Hellenic Seas is presented. Results: The Raphitomidae fauna of Greece was collected and investigated during the period from October 2008 to February 2018. Thirty-five (35) species were identified and their status was compared with existing checklists and other collections. This effort revealed two new Raphitoma species, and one new record for the Mediterranean Sea. Also from the present collection, four species are new records for the East Mediterranean, 10 for the Hellenic fauna and six are reported for second time. The main identification characteristics and baseline ecological information are given and discussed. Conclusions: By this report, the Hellenic Raphitomidae biodiversity is enriched by 10 new records, out of which, two are new species, one is new record for the Mediterranean Sea, and four for the East basin. PMID- 30003063 TI - Understanding the Virulence of Staphylococcus pseudintermedius: A Major Role of Pore-Forming Toxins. AB - Staphylococcus pseudintermedius is responsible for severe and necrotizing infections in humans and dogs. Contrary to S. aureus, the pathophysiological mechanisms involved in this virulence are incompletely understood. We previously showed the intracellular cytotoxicity induced after internalization of S. pseudintermedius. Herein, we aimed to identify the virulence factors responsible for this cytotoxic activity. After addition of filtered S. pseudintermedius supernatants in culture cell media, MG63 cells, used as representative of non professional phagocytic cells (NPPc), released a high level of LDH, indicating that the cytotoxicity was mainly mediated by secreted factors. Accordingly, we focused our attention on S. pseudintermedius toxins. In silico analysis found the presence of two PSMs (delta-toxin and PSMepsilon) as well as Luk-I leukotoxin, the presence of which was confirmed by PCR in all clinical strains tested (n = 17). Recombinant Luk-I leukotoxin had no cytotoxic activity on NPPc but the ectopic expression of the CXCR2 receptor in U937 cells conferred cytotoxity to Luk-I. This is in agreement with the lack of Luk-I effect on NPPc and the previous report of Luk-I cytoxic activity on immune cells. Contrary to Luk-I, synthetic delta-toxin and PSMepsilon had a strong cytotoxic activity on NPPc. The secretion of delta-toxin and PSMepsilon at cytotoxic concentrations by S. pseudintermedius in culture supernatant was confirmed by HPLC-MS. In addition, the supplementation of such supernatants with human serum, known to inhibit PSM, induced a complete abolition of cytotoxicity which indicates that PSMs are the key players in the cytotoxic phenotype of NPPc. The results suggest that the severity of S. pseudintermedius infections is, at least in part, explained by a combined action of Luk-I that specifically targets immune cells expressing the CXCR2 receptor, and PSMs that disrupt cell membranes whatever the cell types. The present study strengthens the key role of PSMs in virulence of the different species belonging to Staphylococcus genus. PMID- 30003065 TI - Anti-proliferative Effect of 15,16-Dihydrotanshinone I Through Cell Cycle Arrest and the Regulation of AMP-activated Protein Kinase/Akt/mTOR and Mitogen-activated Protein Kinase Signaling Pathway in Human Hepatocellular Carcinoma Cells. AB - Background: 15,16-dihydrotanshinone I (DHTS) is a natural abietane diterpenoid that is mainly found in the roots of Salvia miltiorrhiza Bunge (Labiatae). DHTS exhibits a potential anti-proliferative effect in various human cancer cells. However, the mechanisms of action of DHTS as an anti-cancer agent have not been fully elucidated. Therefore, the present study investigated the anti-cancer effect of DHTS in terms of cell cycle regulation and the regulation of the AMP activated protein kinase (AMPK)/Akt/mTOR signaling pathway in SK-HEP-1 human hepatocellular carcinoma cells. Methods: The anti-proliferative effects of DHTS were evaluated by the sulforhodamine B assay in SK-HEP-1 cells. Cell cycle distribution was analyzed by flow cytometry. The elucidation of mechanisms of action such as the AMPK/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathway was assessed by Western blot analysis. Results: DHTS showed a significant anti-proliferative activity against SK-HEP-1 cells. DHTS induced cell cycle arrest in the G0/G1 phase, which was mediated by downregulation of cyclin D1, cyclin A, cyclin E, CDK4, CDK2, c-Myc and p-Rb expression and with increased expression of the CDK inhibitor p21. DHTS also activated the AMPK signaling. In addition, DHTS downregulated the Akt/mTOR and MAPK signaling pathways. Conclusions: Our results suggest that the anti-proliferative activity of DHTS might be associated with the induction of G0/G1 phase cell cycle arrest and regulation of AMPK/Akt/mTOR and MAPK signaling pathways in SK-HEP-1 cells. PMID- 30003066 TI - Comparative Analysis of Ileal and Cecal Microbiota in Aged Rats. AB - Background: Gut microbiota contributes to intestinal and immune homeostasis through host-microbiota interactions. Distribution of the gut microbiota differs according to the location in the gastrointestinal tract. Although the microbiota properties change with age, evidence for the regional difference of gut microbiota has been restricted to the young. The aim of this study is to compare the gut microbiota between terminal ileum and cecum of old rats. Methods: We analyzed gut microbiome of luminal contents from ileum and cecum of 74-week-old and 2-year-old rats (corresponding to 60-year and 80-year-old of human age) by metagenome sequencing of 16S rRNA. Results: Inter-individual variation (beta diversity) of microbiota was higher in ileum than in cecum. Conversely, alpha diversity of microbiota composition was higher in cecum than in ileum. Lactobacillaceae were more abundant in ileum compared to cecum while Ruminococcaceae and Lachnospiraceae were more enriched in cecum. The proportions of Deltaproteobacteria were increased in cecal microbiota of 2-year-old rats compared to 74-week-old rats. Conclusions: Major regional distinctions of microbiota between ileum and cecum of old rats appear consistent with those of young rats. Age-related alterations of gut microbiota in old rats seem to occur in minor compositions. PMID- 30003067 TI - Oral Health of Korean Patients With Head and Neck Cancer. AB - Background: Association between periodontitis and of head and neck carcinoma was suggested. In the present study, we evaluated the oral health status of patients with head and neck carcinoma and analyzed the relationship between cancer characteristics and oral health. Methods: Oral health of 40 patients with head and neck carcinoma was examined. Decayed teeth, missing teeth, plaque index, gingival index, and probing depth were measured. Cancer type and site were recorded based on the patients' medical records. Results: The average age of participants was 60.10 +/- 8.99 years, and 35 of participants were male. The decay or missing teeth index was 5.43 +/- 5.57, and the plaque index, gingival index, and probing depth were 1.37 +/- 1.03, 1.57 +/- 0.84, and 4.13 +/- 1.45, respectively. These indexes showed no significant difference according to the type or site of cancer (P > 0.05). Conclusions: This study showed that there was no correlation between oral health parameters and characteristics of head and neck carcinoma. PMID- 30003068 TI - Characterization of JAK2 V617F (1849 G > T) Mutation in Cervical Cancer Related to Human Papillomavirus and Sexually Transmitted Infections. AB - Background: Human papillomavirus (HPV) genotypes that infect the genital tract play a main etiologic role in cervical cancer progression. Other environmental factors, such as sexually transmitted diseases and the host genetic pattern, contribute to infection persistence of the uterus and cervical epithelium in sustaining their malignancy. The Janus kinase 2 is a non-receptor tyrosine kinase in cell signaling process of tumor genesis. In the present study, JAK2 V167F mutation was distinguished in women with sexually transmitted infections, such as Herpes simplex virus 2, Chlamydia trachomatis and Mycoplasma genitalium and cervical cancer. Methods: This case-control survey was performed on 195 liquid based cytology of women specimens. Fifty, 98, and 47 samples were from women with known cervical cancer, HPV positive and HPV negative, respectively. Single nucleotide polymorphism analysis, sexually transmitted infections detection and HPV genotyping were carried out using approved PCR- RFLP, in-house multiplex TaqMan Real Time PCR and the reverse dot blot hybridization assay. Results: HPVs 6, 16, 18, 11, 31, and 51 were the most common genotypes. The prevalence rate of multiple HPV genotypes was 46.0% to 10.1%. Analysis of JAK2 V617F (1849 G > T) showed that prevalence of mutation was GG (65.1%), GA (34.9%), and TT (0%), respectively. There were no statistically significant differences between this mutation and variables of population survey (P >= 0.05). Conclusions: The molecular epidemiology study on the genetic polymorphisms, i.e., JAK2 V617F and other single nucleotide polymorphisms as a diagnostic tool is necessary for cancer screening and prophylactic programs. PMID- 30003069 TI - Mechanical Alteration Associated With Chemotherapeutic Resistance of Breast Cancer Cells. AB - Background: The mechanical deformability of cancer cells has attracted particular attention as an emerging biomarker for the prediction of anti-cancer drug sensitivity. Nevertheless, it has not been possible to establish a general rubric for the identification of drug susceptibility in breast cancer cells from a mechanical perspective. In the present study, we investigated the mechanical alteration associated with resistance to adjuvant therapy in breast cancer cells. Methods: We performed an 'atomic force microscopy (AFM)-based nanomechanical study' on 'drug-sensitive (MCF-7)' and 'drug-resistant (MCF-7/ADR)' breast cancer cells. We also conducted cell viability tests to evaluate the difference in doxorubicin responsiveness between two breast cancer cell lines. We carried out a wound closure experiment to investigate the motility changes associated with chemotherapeutic resistance. To elucidate the changes in molecular alteration that accompany chemotherapeutic resistance, we investigated the expression of vinculin and integrin-linked kinase-1-which are proteins involved in substrate adhesion and the actin cytoskeleton-using Western blotting analysis. Results: A MTT assay confirmed that the dose-dependent efficacy of doxorubicin was reduced in MCF-7/ADR cells compared to that in MCF-7 cells. The wound assay revealed enhanced two-dimensional motility in the MCF-7/ADR cells. The AFM mechanical assay showed evidence that the drug-resistant breast cancer cells exhibited a significant decrease in mechanical deformability compared to their drug-sensitive counterparts. The mechanical alteration in the MCF-7/ADR cells was accompanied by upregulated vinculin expression. Conclusions: The obtained results manifestly showed that the altered mechanical signatures-including mechanical deformability and motility-were closely related with drug resistance in the breast cancer cells. We believe that this investigation has improved our understanding of the chemotherapeutic susceptibility of breast cancer cells. PMID- 30003070 TI - The Impact of Implant Location on Breast Cancer Characteristics in Previously Augmented Patients: A Systematic Literature Analysis. AB - Background: There is a paucity of data comparing the oncologic properties of breast cancer among patients previously having undergone breast augmentation in either the subglandular or subpectoral planes. The objective of the present systematic review was to evaluate whether implant location influenced the characteristics of breast tumors in previously augmented women. Methods: A systematic literature search was performed to identify relevant articles reporting tumor characteristics in augmented patients. The search included published articles in three electronic databases; Ovid MEDLINE, EMBASE, and PubMed. Comparative studies (subglandular vs. subpectoral) were included. Results: Analysis of data pooled from the included studies showed that subglandular implants had a higher frequency of tumors between 2 to 5 cm (26.5% vs. 9.9%, P = 0.0130). Subglandular implants also had a higher frequency of stage 2 tumors (42.9% vs. 23.7%, P = 0.0308). There was no significant difference in lymphovascular invasion between the 2 groups. These results of this systematic review suggest that the prognosis of patients undergoing augmentation is unaffected by implant location (subpectoral vs. subglandular). Conclusions: With the absence of large randomized controlled trials, our study provides surgeons with an evidence-based reference to improve informed consent with regards to implant placement. PMID- 30003071 TI - Leucrose, a Sucrose Isomer, Suppresses Hepatic Fat Accumulation by Regulating Hepatic Lipogenesis and Fat Oxidation in High-fat Diet-induced Obese Mice. AB - Obesity is currently one of the most serious public health problems and it can lead to numerous metabolic diseases. Leucrose, d-glucopyranosyl-alpha-(1-5)-d fructopyranose, is an isoform of sucrose and it is naturally found in pollen and honey. The aim of this study was to investigate the effect of leucrose on metabolic changes induced by a high-fat diet (HFD) that lead to obesity. C57BL/6 mice were fed a 60% HFD or a HFD with 25% (L25) or 50% (L50) of its total sucrose content replaced with leucrose for 12 weeks. Leucrose supplementation improved fasting blood glucose levels and hepatic triglyceride content. In addition, leucrose supplementation reduced mRNA levels of lipogenesis-related genes, including peroxisome proliferator-activated receptor gamma, sterol regulatory element binding protein 1C, and fatty acid synthase in HFD mice. Conversely, mRNA levels of beta oxidation-related genes, such as carnitine palmitoyltransferase 1A and acyl CoA oxidase, returned to control levels with leucrose supplementation. Taken together, these results demonstrated the therapeutic potential of leucrose to prevent metabolic abnormalities by mediating regulation of plasma glucose level and hepatic triglyceride accumulation. PMID- 30003072 TI - Erratum: Identification of Epithelial-Mesenchymal Transition-related Target Genes Induced by the Mutation of Smad3 Linker Phosphorylation. AB - [This corrects the article on p. 1 in vol. 23, PMID: 29629343.]. PMID- 30003074 TI - Oenin and Quercetin Copigmentation: Highlights From Density Functional Theory. AB - Making use of anthocyanin copigmentation, it is possible to effectively improve color quality and stability of red wines and other foods. This can be done by selecting strong copigments, but a 1-fold experimental screening usually entails a high cost and a low efficiency. The aim of this work is to show how a theoretical model based on density functional theory can be useful for an accurate and rapid prediction of copigmentation ability of a copigment. The present study, concerning the copigmentation between oenin and quercetin under the framework of implicit solvent, indicates that, in these conditions, the intermolecular hydrogen bonds play an important role in the system stabilization. The dispersion interaction slightly affects the structure, energies and UV-Vis spectral properties of the copigmentation complex. PMID- 30003073 TI - Zebrafish as a Model for Drug Screening in Genetic Kidney Diseases. AB - Genetic disorders account for a wide range of renal diseases emerging during childhood and adolescence. Due to the utilization of modern biochemical and biomedical techniques, the number of identified disease-associated genes is increasing rapidly. Modeling of congenital human disease in animals is key to our understanding of the biological mechanism underlying pathological processes and thus developing novel potential treatment options. The zebrafish (Danio rerio) has been established as a versatile small vertebrate organism that is widely used for studying human inherited diseases. Genetic accessibility in combination with elegant experimental methods in zebrafish permit modeling of human genetic diseases and dissecting the perturbation of underlying cellular networks and physiological processes. Beyond its utility for genetic analysis and pathophysiological and mechanistic studies, zebrafish embryos, and larvae are amenable for phenotypic screening approaches employing high-content and high throughput experiments using automated microscopy. This includes large-scale chemical screening experiments using genetic models for searching for disease modulating compounds. Phenotype-based approaches of drug discovery have been successfully performed in diverse zebrafish-based screening applications with various phenotypic readouts. As a result, these can lead to the identification of candidate substances that are further examined in preclinical and clinical trials. In this review, we discuss zebrafish models for inherited kidney disease as well as requirements and considerations for the technical realization of drug screening experiments in zebrafish. PMID- 30003076 TI - QM Cluster or QM/MM in Computational Enzymology: The Test Case of LigW Decarboxylase. AB - The catalytic mechanism of the decarboxylation of 5-carboxyvanillate by LigW producing vanillic acid has been studied by using QM cluster and hybrid QM/MM methodologies. In the QM cluster model, the environment of a small QM model is treated with a bulky potential while two QM/MM models studies include partial and full protein with and without explicitly treated water solvent. The studied reaction involves two sequential steps: the protonation of the carbon of the 5 carboxy-vanillate substrate and the decarboxylation of the intermediate from which results deprotonated vanillic acid as product. The structures and energetics obtained by using three structural models and two density functionals are quite consistent to each other. This indicates that the small QM cluster model of the presently considered enzymatic reaction is appropriate enough and the reaction is mainly influenced by the active site. PMID- 30003077 TI - The Anisotropic Thermal Expansion of Non-linear Optical Crystal BaAlBO3F2 Below Room Temperature. AB - Thermal expansion is a crucial factor for the performance of laser devices, since the induced thermal stress by laser irradiation would strongly affect the optical beam quality. For BaAlBO3F2 (BABF), a good non-linear optical (NLO) crystal, due to the highly anisotropic thermal expansion its practical applications are strongly affected by the "tearing" stress with the presence of local overheating area around the laser spot. Recently, the strategy to place the optical crystals in low-temperature environment to alleviate the influence of the thermal effect has been proposed. In order to understand the prospect of BABF for this application, in this work, we investigated its thermal expansion behavior below room temperature. The variable-temperature XRD showed that the ratio of thermal expansion coefficient between along c- and along a(b)- axis is high as 4.5:1 in BABF. The Raman spectrum combined with first-principles phonon analysis revealed that this high thermal expansion anisotropy mainly ascribe to progressive stimulation of the respective vibration phonon modes related with the thermal expansion along a(b)- and c-axis. The good NLO performance in BABF can be kept below room temperature. The work presented in this paper provides an in-depth sight into the thermal expansion behavior in BABF, which, we believe, would has significant implication to the manipulation in atomic scale on the thermal expansion of the materials adopted in strong-field optical facility. PMID- 30003079 TI - A Plasma Biochemical Analysis of Acute Lead Poisoning in a Rat Model by Chemometrics-Based Fourier Transform Infrared Spectroscopy: An Exploratory Study. AB - In this work, we explored to use chemometrics-based Fourier transform infrared (FTIR) spectroscopy to investigate the plasma biochemical changes due to acute lead poisoning (ALP) in a rat model. We first collected the FTIR spectra of the plasma samples from the rats with and without suffering from ALP. We then performed the chemometric analysis of these FTIR spectra using principal component analysis (PCA) and partial least squares discriminant analysis (PLS DA). We found that the chemometrics-based FTIR spectroscopy can discriminate the rats with and without ALP. Further analysis on the PLS-DA regression coefficient revealed that the spectral changes, in particular, corresponding to the biochemical changes of proteins in the plasma may be used as potential spectral biomarkers for the diagnostics of lead poisoning. Our work demonstrates the potential of chemometrics-based FTIR spectroscopy as a promising tool for the biochemical analysis of plasma that could consequently enable an objective, convenient and non-destructive diagnostics of lead poisoning. To the best of our knowledge, this work is the first application of chemometrics-based FTIR spectroscopy in the diagnostics of lead poisoning. PMID- 30003075 TI - P2RX7 Purinoceptor as a Therapeutic Target-The Second Coming? AB - The P2RX7 receptor is a unique member of a family of extracellular ATP (eATP) gated ion channels expressed in immune cells, where its activation triggers the inflammatory cascade. Therefore, P2RX7 has been long investigated as a target in the treatment of infectious and inflammatory diseases. Subsequently, P2RX7 signaling has been documented in other physiological and pathological processes including pain, CNS and psychiatric disorders and cancer. As a result, a range of P2RX7 antagonists have been developed and trialed. Interestingly, the recent crystallization of mammalian and chicken receptors revealed that most widely-used antagonists may bind a unique allosteric site. The availability of crystal structures allows rational design of improved antagonists and modeling of binding sites of the known or presumed inhibitors. However, several unanswered questions limit the cogent development of P2RX7 therapies. Firstly, this receptor functions as an ion channel, but its chronic stimulation by high eATP causes opening of the non-selective large pore (LP), which can trigger cell death. Not only the molecular mechanism of LP opening is still not fully understood but its function(s) are also unclear. Furthermore, how can tumor cells take advantage of P2RX7 for growth and spread and yet survive overexpression of potentially cytotoxic LP in the eATP-rich environment? The recent discovery of the feedback loop, wherein the LP-evoked release of active MMP-2 triggers the receptor cleavage, provided one explanation. Another mechanism might be that of cancer cells expressing a structurally altered P2RX7 receptor, devoid of the LP function. Exploiting such mechanisms should lead to the development of new, less toxic anticancer treatments. Notably, targeted inhibition of P2RX7 is crucial as its global blockade reduces the immune and inflammatory responses, which have important anti-tumor effects in some types of malignancies. Therefore, another novel approach is the synthesis of tissue/cell specific P2RX7 antagonists. Progress has been aided by the development of p2rx7 knockout mice and new conditional knock-in and knock-out models are being created. In this review, we seek to summarize the recent advances in our understanding of molecular mechanisms of receptor activation and inhibition, which cause its re-emergence as an important therapeutic target. We also highlight the key difficulties affecting this development. PMID- 30003078 TI - A Fluorescent Sensor Array Based on Heteroatomic Macrocyclic Fluorophores for the Detection of Polluting Species in Natural Water Samples. AB - The development of a novel all-solid-state optical sensor array based on heteroatomic macrocyclic fluorophores (diaza-crown ether, metallocorrole and pyridinophans) for the photographic analysis of liquid media, is presented. The sensitivity of the new optical system toward a number of different species (cations: Li+, K+, Na+, NH4+ , Mg2+, Ca2+, Co2+, Cu2+, Zn2+, Cd2+, Pb2+ and anions: NO2- , NO3- , Cl-, Br-, HCO3- ) was evaluated both in single selective sensor mode and in multisensory arrangement. The satisfactory PLS1 regression models between sensor array optical response and analyte concentration were obtained for Cd2+, Cu2+, Zn2+, and NO2- ions in all the range of tested concentrations. Among these species the highest attention was focused onto detection of cadmium and nitrite ions, for which the detection limits, DL, estimated by 3sigma method were found 0.0013 mg/L and 0.21 mg/L respectively, and these values are lower than the corresponding WHO guideline values of 0.003 mg/L (Cd2+) and 2 mg/L ( NO2- ). The suitability of the developed sensors implemented with familiar devices for signal acquisition (Light Emitting Diode, LED, as light source and a digital camera as a signal detector), and chemometric methods for data treatment to perform fast and low-cost monitoring of species under interest, in real samples of environmental importance, is demonstrated. PMID- 30003081 TI - Apoptosis Is a Demanding Selective Tool During the Development of Fetal Male Germ Cells. AB - Apoptosis is widely known to play a major role on diseases related to male infertility. Diseases of the male genital tract as defective spermatogenesis, decreased sperm motility, sperm DNA fragmentation, testicular torsion, varicocele and immunological infertility are strongly related to apoptotic cell death. Apoptosis must not be considered only as a fail on germ cell physiology or a secondary effect of certain pathologies and exogenous hazardous agents. Apoptosis orchestrates correct function and development of the male germ cell from the early embryonic stages of gonadal differentiation to the fertilization. In this review we have tried to address a reading frame of the main knowledge about apoptosis in male germ cell development. Focussing on mechanisms concerning cellular apoptosis, which are independent of exogenous stimuli, we aimed to highlight that apoptosis is a selective instrument that guarantees the delivery of genetic message to offspring. PMID- 30003080 TI - Designed Surface Topographies Control ICAM-1 Expression in Tonsil-Derived Human Stromal Cells. AB - Fibroblastic reticular cells (FRCs), the T-cell zone stromal cell subtype in the lymph nodes, create a scaffold for adhesion and migration of immune cells, thus allowing them to communicate. Although known to be important for the initiation of immune responses, studies about FRCs and their interactions have been impeded because FRCs are limited in availability and lose their function upon culture expansion. To circumvent these limitations, stromal cell precursors can be mechanotranduced to form mature FRCs. Here, we used a library of designed surface topographies to trigger FRC differentiation from tonsil-derived stromal cells (TSCs). Undifferentiated TSCs were seeded on a TopoChip containing 2176 different topographies in culture medium without differentiation factors, then monitored cell morphology and the levels of ICAM-1, a marker of FRC differentiation. We identified 112 and 72 surfaces that upregulated and downregulated, respectively, ICAM-1 expression. By monitoring cell morphology, and expression of the FRC differentiation marker ICAM-1 via image analysis and machine learning, we discovered correlations between ICAM-1 expression, cell shape and design of surface topographies and confirmed our findings by using flow cytometry. Our findings confirmed that TSCs are mechano-responsive cells and identified particular topographies that can be used to improve FRC differentiation protocols. PMID- 30003082 TI - Roles of PLODs in Collagen Synthesis and Cancer Progression. AB - Collagen is the major component of extracellular matrix. Collagen cross-link and deposition depend on lysyl hydroxylation, which is catalyzed by procollagen lysine, 2-oxoglutarate 5-dioxygenase (PLOD). Aberrant lysyl hydroxylation and collagen cross-link contributes to the progression of many collagen-related diseases, such as fibrosis and cancer. Three lysyl hydroxylases (LH1, LH2, and LH3) are identified, encoded by PLOD1, PLOD2, and PLOD3 genes. Expression of PLODs is regulated by multiple cytokines, transcription factors and microRNAs. Dysregulation of PLODs promotes cancer progression and metastasis, suggesting that targeting PLODs is potential strategy for cancer treatment. Here, we summarize the recent progress in the investigation of function and regulation of PLODs in normal tissue development and disease progression, especially in cancer. PMID- 30003083 TI - Personality Research in Mammalian Farm Animals: Concepts, Measures, and Relationship to Welfare. AB - Measuring and understanding personality in animals is a rising scientific field. Much research has been conducted to assess distinctive individual differences in behavior in a large number of species in the past few decades, and increasing numbers of studies include farm animals. Nevertheless, the terminology and definitions used in this broad scientific field are often confusing because different concepts and methods are used to explain often synonymously applied terms, such as personality, temperament and coping style. In the present review we give a comprehensive overview of the concepts and terms currently used in animal personality research and critically reveal how they are defined and what they measure. First, we shortly introduce concepts describing human personality and how these concepts are used to explain animal personality. Second, we present which concepts, methods and measures are applied in farm animal personality research and show that the terminology used seems to be somehow species-related. Finally, we discuss some findings on the possible impact of personality on the welfare of farm animals. The assessment of personality in farm animals is of growing scientific and practical interest. Differences in theoretical frameworks and methodological approaches may also entail the diverse use of the different concepts between basic and applied research approaches. We conclude that more consistency is needed in using different theoretical concepts, terms and measures, especially in farm animal personality research. The terms coping style and temperament, which are used in different ways, should not be examined as independent concepts, but rather should be considered as different aspects of the whole personality concept. Farm animal personality should be increasingly considered for the improvement of animal housing, management, breeding and welfare. PMID- 30003084 TI - Using High Performance Thin Layer Chromatography-Densitometry to Study the Influence of the Prion [RNQ+] and Its Determinant Prion Protein Rnq1 on Yeast Lipid Profiles. AB - The baker's yeast Saccharomyces cerevisiae harbors multiple prions that allow for the creation of heterogeneity within otherwise clonal cell populations. However, in many cases, the consequences of prion infection are entirely unclear. Predictions of prion-induced changes in cell physiology are complicated by pleotropic effects, and detection is often limited to relatively insensitive cell growth assays that may obscure many physiological changes. We previously showed that silica gel high performance thin-layer chromatography-densitometry (HPTLC) can be used to empirically determine prion-induced changes in lipid content in yeast. Here, we conduct pair-wise quantifications of the relative levels of free sterols, free fatty acids, and triacylglycerols [petroleum ether-diethyl ether glacial acetic acid (80:20:1, v/v/v) mobile phase and phosphomolybdic acid (PMA) detection reagent]; steryl esters, methyl esters, and squalene [hexane-petroleum ether-diethyl ether-glacial acetic acid (50:20:5:1, v/v/v/v) and PMA]; and phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol (chloroform-diethyl ether-acetic acid (65:25:4.5, v/v/v) and cupric sulfate phosphoric acid) in otherwise clonal prion-infected ([RNQ+]) and prion-free ([rnq ]) cells in both stationary- and logarithmic-growth phases. We detected multiple statistically significant differences between prion-infected and prion-free cells that varied by growth phase, confirming our pr evious observations that prions exert distinct influences on cell physiology between stationary- and log-phase growth. We also found significant differences between cells expressing or lacking the Rnq1 protein which forms the [RNQ+] prion, providing new clues to the as yet unresolved normal biological function of this prion-forming protein. This investigation further emphasizes the utility of HPTLC-densitometry to empirically determine the effects of prions and other presumed innocuous gene deletions on lipid content in yeast, and we expect that additional analyses will continue to resolve the physiological effects of prion infection. PMID- 30003086 TI - Isolation of a Reassortant H1N2 Swine Flu Strain of Type "Swine-Human-Avian" and Its Genetic Variability Analysis. AB - We isolated an influenza strain named A/Swine/Fujian/F1/2010 (H1N2) from a pig suspected to be infected with swine flu. The results of electron microscopy, hemagglutination (HA) assay, hemagglutination inhibition (HI) assay, and whole genome sequencing analysis suggest that it was a reassortant virus of swine (H1N1 subtype), human (H3N2 subtype), and avian influenza viruses. To further study the genetic evolution of A/Swine/Fujian/F1/2010 (H1N2), we cloned its whole genome fragments using RT-PCR and performed phylogenetic analysis on the eight genes. As a result, the nucleotide sequences of HA, NA, PB1, PA, PB2, NP, M, and NS gene are similar to those of A/Swine/Shanghai/1/2007(H1N2) with identity of 98.9%, 98.9%, 99.0%, 98.6%, 99.0%, 98.9%, 99.3%, and 99.3%, respectively. Similar to A/Swine/Shanghai/1/2007(H1N2), we inferred that the HA, NP, M, and NS gene fragments of A/Swine/Fujian/F1/2010 (H1N2) strain were derived from classical swine influenza H3N2 subtype, NA and PB1 were derived from human swine influenza H3N2 subtype, and PB2 and PA genes were derived from avian influenza virus. This further validates the role of swine as a "mixer" for influenza viruses. PMID- 30003085 TI - Nonredundant, Highly Connected MicroRNAs Control Functionality in Breast Cancer Networks. AB - Alterations to transcriptional regulation are an important factor in breast cancer. Noncoding RNA, such as microRNA (miR), have very influential roles in the transcriptional regulation of genes. Transcriptional regulation can be successfully modeled and analyzed using complex network theory. Particularly, interactions between two distinct classes of biological elements, such as miR and genes, can be approached through the bipartite network formalism. Based on bipartite network properties, it is possible to identify highly influential miRs in the network, such as those that have a large number of connections indicating regulation of a large set of genes. Some miRs in a network are nonredundant, which indicates that they are solely responsible of the regulation of a particular set of genes, which in turn may be associated to a particular biological process. We hypothesize that highly influential, nonredundant miRs, which we call Commodore miRs (Cdre-miRs), have an important role on the control of biological functions through transcriptional networks. In this work, we analyze the regulation of gene expression by miRs in healthy and cancerous breast tissue using bipartite miR-gene networks inferred from the Cancer Genome Atlas (TCGA) expression data. We observe differences in the degree, clustering coefficient and redundancy distributions for miRs and genes in the network, indicating differences in the way that these elements interact with each other. Furthermore, we identify a small set of five Cdre-miRs in the breast cancer network: miR-190b, miR-let7i, miR-292-b, miR-511, and miR-141. The neighborhood of genes controlled by each of these miRs is involved in particular biological functions such as dynein structure-associated processes, immune response, angiogenesis, cytokine activity, and cell motility. We propose that these Cdre miRs are important control elements of biological functions deregulated in breast cancer. PMID- 30003087 TI - Selected Enzyme Inhibitory Effects of Euphorbia characias Extracts. AB - Extracts of aerial part of Euphorbia characias were examined to check potential inhibitors for three selected enzymes involved in several metabolic disorders. Water and ethanol extracts from leaves and flowers showed in vitro inhibitory activity toward alpha-amylase, alpha-glucosidase, and xanthine oxidase. IC50 values were calculated for all the extracts and the ethanolic extracts were found to exert the best effect. In particular, for the alpha-glucosidase activity, the extracts resulted to be 100-fold more active than the standard inhibitor. The inhibition mode was investigated by Lineweaver-Burk plot analysis. E. characias extracts display different inhibition behaviors toward the three enzymes acting as uncompetitive, noncompetitive, and mixed-type inhibitors. Moreover, ethanolic extracts of E. characias showed no cytotoxic activity and exhibited antioxidant capacity in a cellular model. The LC-DAD metabolic profile was also performed and it showed that leaves and flowers extracts contain high levels of quercetin derivatives. The results suggest that E. characias could be a promising source of natural inhibitors of the enzymes involved in carbohydrate uptake disorders and oxidative stress. PMID- 30003088 TI - Genetic Polymorphism Study on Aedes albopictus of Different Geographical Regions Based on DNA Barcoding. AB - Aedes albopictus is a very important vector for pathogens of many infectious diseases including dengue fever. In this study, we explored the genetic polymorphism of Aedes albopictus strains in different geographical regions using DNA barcoding of mitochondrial COI (MT-COI) gene. We collected MT-COI sequence of 106 Aedes albopictus mosquitos from 6 provinces in China including Fujian, Guangdong, Hainan, Yunnan, and Taiwan. The length of the sequences is 709bp with the content of A+T (67.7%) greater than that of G+C (32.3%). We identified mutations in 90 (13.68%) loci, of which 57 (63.33%) are transitions, 28 (31.11%) are transversions, and 5 (5.56%) are hypervariable loci. In addition, we obtained 42 haplotypes, 4 (9.52%) of which are shared among different populations. The haplotype diversity of Aedes albopictus is 0.882 and nucleotide diversity is 0.01017. Moreover, the pedigree network diagram shows that most haplotypes are under parallel evolution, suggesting a local expansion of Aedes albopictus in history. Finally, the Neighbor-Joining tree of MT-COI haplotypes reveals a certain correlation between haplotype clusters and geographical distribution, and there are differences among Aedes albopictus in different geographical regions. In conclusion, DNA barcoding of MT-COI gene is an effective method to study the genetic structure of Aedes albopictus. PMID- 30003090 TI - Assessment the Bond Strength of Ceramic Brackets to CAD/CAM Nanoceramic Composite and Interpenetrating Network Composite after Different Surface Treatments. AB - Adult orthodontics may confront problems related to the bonding performance of orthodontic brackets to new generation restorative materials used for crown or laminate restorations. The aim of the present study was to investigate the shear bond strength of ceramic brackets to two new generation CAD/CAM interpenetrating network composite and nanoceramic composite after different surface treatments. Er,Cr:YSGG Laser, hydrofluoric acid (9%), sandblasting (50 MUm Al2O3), and silane were applied to the surfaces of 120 CAD/CAM specimens with 2 mm thickness and then ceramic brackets were bonded to the treated surfaces of the specimens. Bond strength was evaluated using the shear bond strength test. According to the results, CAD/CAM block types and surface treatment methods have significant effects on shear bond strength. The lowest bond strength values were found in the specimens treated with silane (3.35 +/- 2.09 MPa) and highest values were found in the specimens treated with sandblast (8.92 +/- 2.77 MPa). Sandblasting and hydrofluoric acid surface treatment led to the most durable bonds for the two types of CAD/CAM blocks in the present study. In conclusion, different surface treatments affect the shear bond strength of ceramic brackets to CAD/CAM interpenetrating network composite and nanoceramic composite. Among the evaluated treatments, sandblasting and hydrofluoric acid application resulted in sufficient bonding strength to ceramic brackets for both of the CAD/CAM materials. PMID- 30003089 TI - Advantages of Graphene Biosensors for Human Stem Cell Therapy Potency Assays. AB - Regenerative medicine is challenged by the need to conform to rigorous guidelines for establishing safe and effective development and translation of stem cell based therapies. Counteracting widespread concerns regarding unproven cell therapies, stringent cell-based assays seek not only to avoid harm but also to enhance quality and efficacy. Potency indicates that the cells are functionally fit for purpose before they are administered to the patient. It is a paramount quantitative critical quality attribute serving as a decisive release criterion. Given a broad range of stem cell types and therapeutic contexts the potency assay often comprises one of the most demanding hurdles for release of a cell therapy medicinal product. With need for improved biomarker assessment and expedited measurement, recent advances in graphene-based biosensors suggest that they are poised to be valuable platforms for accelerating potency assay development. Among several potential advantages, they offer versatility for sensitive measurement of a broad range of potential biomarker types, cell biocompatibility for direct measurement, and small sample sufficiency, plus ease of use and point-of-care applicability. PMID- 30003091 TI - First Report of Seroprevalence and Risk Factors of Neospora caninum Infection in Tibetan Sheep in China. AB - Neospora caninum is an intracellular protozoan parasite which can cause abortion and stillbirth in ruminants. However, there is no information on Tibetan sheep N. caninum infection in China. A total of 2187 serum samples were collected from Tibetan sheep in the major production areas of Luqu, Maqu, and Tianzhu in Gansu province, and Nyingchi in southeast Tibet, China. All samples were analyzed for the presence of antibodies to N. caninum using a competitive-inhibition enzyme linked immunoassay. Of the 2187 serum samples, 184 (8.4%, 95% CI 7.3-9.6) were tested N. caninum seropositive. The N. caninum seroprevalence ranged from 4.4% (95% CI 1.4-7.4) to 11.3% (95% CI 8.2-14.4) among different regions, seasons, ages, and pregnancies, and there was no statistical significance among those groups (P > 0.05). Seroprevalence in male (10.8% 69/638) (95% CI 8.4-13.2) was significantly higher than in female (7.4% 115/1549) (OR =1.51, 95% CI 6.1-8.7) (P < 0.01). To our knowledge, this is the first report of N. caninum seroprevalence in Tibetan sheep in China, which provides baseline data for the prevention and control of N. caninum infection in Tibetan sheep. PMID- 30003093 TI - A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome. AB - Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology. PMID- 30003092 TI - Use of Quantitative Morphological and Functional Features for Assessment of Axillary Lymph Node in Breast Dynamic Contrast-Enhanced Magnetic Resonance Imaging. AB - Background: Axillary lymph-node assessment is considered one of the most important prognostic factors concerning breast cancer survival. Objective: We investigated the discriminative power of morphological and functional features in assessing the axillary lymph node. Methods: We retrospectively analysed data from 52 consecutive patients who undergone DCE-MRI and were diagnosed with primary breast carcinoma: 94 lymph nodes were identified. Per each lymph node, we extracted morphological features: circularity, compactness, convexity, curvature, elongation, diameter, eccentricity, irregularity, radial length, entropy, rectangularity, roughness, smoothness, sphericity, spiculation, surface, and volume. Moreover, we extracted functional features: time to peak (TTP), maximum signal difference (MSD), wash-in intercept (WII), wash-out intercept (WOI), wash in slope (WIS), wash-out slope (WOS), area under gadolinium curve (AUGC), area under wash-in (AUWI), and area under wash-out (AUWO). Selection of important features in predicting metastasis has been done by means of receiver operating characteristic (ROC) analysis. Performance of linear discriminant analysis was analysed. Results: All morphological features but circularity showed a significant difference between median values of metastatic lymph nodes group and nonmetastatic lymph nodes group. All dynamic parameters except for MSD and WOS showed a statistically significant difference between median values of metastatic lymph nodes group and nonmetastatic lymph nodes group. Best results for discrimination of metastatic and nonmetastatic lymph nodes were obtained by AUGC (accuracy 75.8%), WIS (accuracy 71.0%), WOS (accuracy 71.0%), and AUCWO (accuracy 72.6%) for dynamic features and by compactness (accuracy 82.3%), curvature (accuracy 71.0%), radial length (accuracy 71.0%), roughness (accuracy 74.2%), smoothness (accuracy 77.2%), and speculation (accuracy 72.6%) for morphological features. Linear combination of all morphological and/or of all dynamic features did not increase accuracy in metastatic lymph nodes discrimination. Conclusions: Compactness as morphological feature and area under time-intensity curve as dynamic feature were the best parameters in identifying metastatic lymph nodes on breast MRI. PMID- 30003094 TI - The Transcription Factor ATF4 Promotes Expression of Cell Stress Genes and Cardiomyocyte Death in a Cellular Model of Atrial Fibrillation. AB - Introduction: Cardiomyocyte remodelling in atrial fibrillation (AF) has been associated with both oxidative stress and endoplasmic reticulum (ER) stress and is accompanied by a complex transcriptional regulation. Here, we investigated the role the oxidative stress and ER stress responsive bZIP transcription factor ATF4 plays in atrial cardiomyocyte viability and AF induced gene expression. Methods: HL-1 cardiomyocytes were subjected to rapid field stimulation. Forced expression of ATF4 was achieved by adenoviral gene transfer. Using global gene expression analysis and chromatin immunoprecipitation, ATF4 dependent transcriptional regulation was studied, and tissue specimen of AF patients was analysed by immunohistochemistry. Results: Oxidative stress and ER stress caused a significant reduction in cardiomyocyte viability and were associated with an induction of ATF4. Accordingly, ATF4 was also induced by rapid field stimulation mimicking AF. Forced expression of wild type ATF4 promoted cardiomyocyte death. ATF4 was demonstrated to bind to the promoters of several cell stress genes and to induce the expression of a number of ATF4 dependent stress responsive genes. Moreover, immunohistochemical analyses showed that ATF4 is expressed in the nuclei of cardiomyocytes of tissue specimen obtained from AF patients. Conclusion: ATF4 is expressed in human atrial cardiomyocytes and is induced in response to different types of cell stress. High rate electrical field stimulation seems to result in ATF4 induction, and forced expression of ATF4 reduces cardiomyocyte viability. PMID- 30003095 TI - Magnetic Resonance Imaging Findings in the Muscle Tissue of Patients with Limb Girdle Muscular Dystrophy Type 2I Harboring the Founder Mutation c.545A>G in the FKRP Gene. AB - Limb girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy that is rare in Asia and is caused by mutations in the fukutin related protein gene (FKRP). The aim of this study was to determine if there are any characteristic features of muscle on magnetic resonance imaging (MRI) in patients with LGMD2I harboring the founder mutation c.545A>G in FKRP. Using MRI, we delineated changes in the thigh muscles of ten patients with genetically confirmed LGMD2I. The majority of muscle biopsy specimens showed reduced glycosylation of alpha-dystroglycan, decreased expression of laminin alpha2, and a dystrophic pattern. In our cohort, the muscles with the most severe fatty infiltration were adductor magnus and vastus intermedius, whereas the rectus femoris, sartorius, and gracilis muscles were relatively spared. In seven patients, we identified a concentric fatty infiltration pattern that was most pronounced in the vastus intermedius and vastus medialis muscles around the distal femoral diaphysis. In this disease, the initial fatty infiltration of the posterior thigh muscles gradually progresses anteriorly regardless of the founder mutation in FKRP. Muscle tissue in patients with LGMD2I who have the founder mutation c.545A>G in FKRP shows a distinctive concentric pattern of fatty infiltration and edema on MRI. PMID- 30003096 TI - Risk Factors Related to Peripherally Inserted Central Venous Catheter Nonselective Removal in Neonates. AB - We aimed to investigate the incidence and risk factors associated with nonselective removal of peripherally inserted central venous catheter (PICC) in neonates. In this prospective cohort study, neonates who underwent PICC placement at neonatal intensive care units (NICUs) in China from October 2012 to November 2015 were included. The patient demographics, catheter characteristics, catheter duration, PICC insertion site, indication for PICC insertion, infuscate composition, PICC tip location, and catheter complications were recorded in a computerized database. Risk factors for nonselective removal were analyzed. A total of 497 PICCs were placed in 496 neonates. Nonselective removal occurred in 9.3% of PICCs during 10,540 catheter-days (4.6 nonselective removals per 1,000 catheter-days). These included occlusion (3%), infection (1.4%), leakage (2.0%), phlebitis (0.6%), displacement (1%), pleural effusion(0.6%), and breaks (0.6%). Noncentral tip position was independently associated with an increased risk of nonselective removal (odds ratio 2.621; 95% confidence interval, 1.258-5.461) after adjusting for gestational age, sex, birth weight, and PICC dwell time. No significant differences in the rate of complications occurred between silastic and polyurethane PICC or different insertion sites. Noncentral PICC tip position was the only independent risk factor for nonselective removal of PICC. PMID- 30003097 TI - Could the Combined Administration of Bone Antiresorptive Drug, Taxanes, and Corticosteroids Worsen Medication Related Osteonecrosis of the Jaws in Cancer Patients? AB - The study presents a report of 58 metastatic cancer patients who developed osteonecrosis of the jaws after being treated with zoledronic acid and taxanes, plus corticosteroids. A retrospective analysis of data registered in the archives of two Italian osteonecrosis of the jaws treatment centers, who are based at the University of Messina and at the University of Palermo, was performed in order to study, in these patients, demographic data and characteristics such as frequency of cancer location, lines of therapy, frequency of cancer drugs, presence/absence of oral trigger, number, location, and stage of jaw osteonecrosis. It was found that the majority of patients developed advanced stages of osteonecrosis, frequently complicated with infection. It was hypothesized that the concurrent administration of chemotherapeutic agents could be eventually considered as a factor able to allow a faster worsening of the clinical manifestation through the exacerbation of soft tissue defects, due to chemotherapy drugs. PMID- 30003098 TI - Renal Tubular Complement 3 Deposition in Children with Primary Nephrotic Syndrome. AB - Background: This study aimed to investigate the clinical significance of complement 3 (C3) deposition in renal tubules of children with primary nephrotic syndrome (PNS). Methods: The clinical and pathological characteristics of PNS were retrospectively reviewed in 99 PNS pediatric patients, who were divided into the C3 deposition and the non-C3 deposition groups. Results: A total of 39 patients (39.39%) had renal tubule C3 deposition. In the C3 deposition group, the ratios of urine N-acetylglucosaminidase/creatinine (UNAG/Cr), urine beta2 microglobulin/creatinine (Ubeta2MG/Cr), and urine transferrin/creatinine (UTRF/Cr) were significantly higher than those of the non-C3 deposition group. The patients of the C3 deposition group had lower serum total protein and albumin, higher cholesterol and D-dimer (DD), lower proportion of CD3+CD8+ cells, and higher proportion of CD19+CD23+ cells. The number of the patients with interstitial fibrosis, renal cell vacuolar degeneration, renal tubular immunoglobulin deposition, and severe tubulointerstitial injury in the C3 deposition group was higher than that of the non-C3 deposition group. The C3 deposition intensity was positively correlated with the number of recurrences. Conclusion: PNS pediatric patients with C3 deposition in renal tubules have more severe disease condition, tubulointerstitial injury, and recurrence suggesting a worse long-term prognosis. PMID- 30003099 TI - Comparison of Outcomes between Two Methods to Extract Stone Fragments during Flexible Ureteroscopic Lithotripsy. AB - Objectives: To retrospectively compare the operative and clinical outcomes of flexible ureteroscopic lithotripsy (fURSL) with stone extraction performed either by a surgeon (SE) who manipulates the retrieval basket or by having the surgical assistant (AE) manipulate the retrieval basket with the aim of clarifying which method provides a greater stone-free postoperative status. Methods: The study group consisted of patients who underwent fURSL with SE or AE at our institution between April 2015 and December 2016. Demographic, clinical, stone, and operative variables were compared between the two groups. Multivariate logistic regression was used to identify risk factors associated with a stone-free and non-stone-free status postoperatively. Results: Our analysis included 196 cases of renal stones treated using fURSL, with 109 who underwent AE and 87 who underwent SE. The rate of stone-free status was higher for the SE group (90.8%) than for the AE group (61.5%; P < 0.001). The method of extraction was identified as an independent predictor of stone-free status (P < 0.001, odds ratio (SE compared to AE), 9.133, 95% confidence interval, 3.736-22.322). Conclusion: The stone-free rate is improved by having the surgeon perform the stone extraction as part of the fURSL procedure. PMID- 30003100 TI - Altered DNA Methylation of Long Noncoding RNA uc.167 Inhibits Cell Differentiation in Heart Development. AB - In previous studies, we have demonstrated the function of uc.167 in the heart development. DNA methylation plays a crucial role in regulating the expression of developmental genes during embryonic development. In this study, the methylomic landscape was investigated in order to identify the DNA methylation alterations. Methylated DNA immunoprecipitation (MeDIP) was performed to examine the differences in methylation status of overexpressed uc.167 in P19 cells. GO and KEGG pathway analyses of differentially methylated genes were also conducted. We found that the distribution of differentially methylated regions (DMRs) peaks in different components of genome was mainly located in intergenic regions and intron. The biological process associated with uc.167 was focal adhesion and Rap1 signaling pathway. MEF2C was significantly decreased in uc.167 overexpressed group, suggesting that uc.167 may influence the P19 differentiation through MEF2C reduction. Taken together, our findings revealed that the effect of uc.167 on P19 differentiation may be attributed to the altered methylation of specific genes. PMID- 30003101 TI - Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast. AB - Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA), and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthracyclines use can be limited by serious side effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin. HOM6 is required for synthesis of threonine and interruption of the pathway leads to accumulation of the threonine intermediate L-aspartate semialdehyde. This intermediate may synergize with doxorubicin to kill the cell. In fact, deleting HOM3 in the first step, preventing the pathway to reach the HOM6 step, rescues the sensitivity of the hom6 strain to doxorubicin. Using several S. cerevisiae strains (wild type, hom6, hom3, hom3hom6, ydj1, siz1, and msh2), we determined their sensitivity to aldehydes and to their combination with doxorubicin, cisplatin, and etoposide. Combination of formaldehyde and doxorubicin was most effective at reducing cell survival by 31-fold-39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This effect was dose dependent on doxorubicin. Cotreatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. The hom6 mutant also showed sensitivity to menadione with a 2.5-fold reduction in cell survival. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline based therapy. PMID- 30003103 TI - Khat Induced Toxicity: Role on Its Modulating Effects on Inflammation and Oxidative Stability. AB - Long-term khat (Catha edulis Forsk.) chewing has negative effects on human body. Khat constituents appear to be capable of disturbing the delicate equilibrium between damaging and protective mechanisms of a cell that is essential for optimal activity, thereby producing oxidative damage. Therefore, the current study was designed to understand the role of khat on cell toxicity, oxidative stability, and inflammation. Khat was extracted using 60% methanol and assessed calorimetrically for its phenolic and flavonoid contents. 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging, oxygen radical absorbance capacity (ORAC), and ferric reducing/antioxidant power (FRAP) assays were used to assess the antioxidant properties. Lipopolysaccharide and interferon gamma induced murine monocytic macrophages cell line (RAW 264.7) were used to assess khat effects on cellular inflammation, oxidative stability, and viability. Khat possesses high content of polyphenols and flavonoids. The results showed a strong potency of antioxidants in DPPH, ORAC, and FRAP assays. Khat decreases the production of the proinflammatory nitric oxide and induces cytotoxicity and reactive oxygen species inhibition. Heavy khat consumption induced-toxicity and symptoms are probably due the harmful effects of its polyphenolic contents. PMID- 30003102 TI - A Multicenter, Randomized, Controlled Trial of Electroacupuncture for Perimenopause Women with Mild-Moderate Depression. AB - Objective: Up to 62% of perimenopausal women have depression symptoms. However, there is no efficacy treatment. The aim of this study is to compare the clinical efficacy and safety of EA therapy and escitalopram on perimenopause women with mild-moderate depressive symptom. Method: A multicenter, randomized, positive controlled clinical trial was conducted at 6 hospitals in China. 242 perimenopause women with mild-moderate depressive symptom were recruited and randomly assigned to receive 36 sessions of EA treatment or escitalopram treatment. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HAMD-17). The secondary outcome measures include menopause-specific quality of life (MENQOL) and serum sexual hormones which include estrogen, follicle-stimulating hormone, and luteinizing hormone. Results: 221 (91.3%) completed the study, including 116 in the EA group and 105 in the escitalopram group. The baseline levels of demographic and outcome measurements were similar in the two groups. In the intervention period, there was no difference between two groups. However, in the follow-up, both HAMD-17 and MENQOL were significantly decreased, and at week 24 the mean differences were -2.23 and -8.97, respectively. There were no significant differences in the change of serum sexual hormones between the two groups. No serious adverse events occurred. Conclusion: EA treatment is effective and safe in relieving depression symptom and improving the quality of life in the perimenopausal depression. Further research is needed to understand long-term efficacy and explore the mechanism of this intervention. This study is registered with ClinicalTrials.gov NCT02423694. PMID- 30003104 TI - Clinical and Epidemiological Status of Leptospirosis in a Tropical Caribbean Area of Colombia. AB - Objective: To describe and analyze the clinical and epidemiological status in 28 confirmed cases of human leptospirosis at the main public hospital of Cordoba. Methods: Between 2012 and 2013, we conducted an active surveillance at the main hospital of Cordoba to establish the etiologic diagnosis of the undifferentiated tropical febrile illness (UTFI) cases. UTFI is defined as a fever without an infection focus in the initial physical examination or in basic laboratory tests. Patients in acute phase were accompanied by prodromal symptoms, including myalgia, arthralgia, headache, asthenia, chills, icterus, dyspnea, abdominal pain, rash, and nausea. Samples were collected on admission and at discharge. Clinical and epidemiological data were collected for each patient. Microscopic agglutination test (MAT) was performed. Results: The 28 leptospirosis cases presented the following gender distribution: male (n=24) and female (n=4). The duration of hospitalization was 10.39 days. The main symptoms and clinical manifestations were fever, headache and nausea, vomiting, and abdominal pain, all of which occurred in up to 60% of patients. Of the 28 cases studied, 4 were fatal. The most frequent infecting serogroups were Ballum and Canicola. Conclusion: Leptospirosis is a common cause of undifferentiated tropical febrile illness in Colombia; it is important to establish ongoing and accurate surveillance for acute febrile illness to facilitate the detection of cases of leptospirosis. PMID- 30003105 TI - Human MLL-AF9 Overexpression Induces Aberrant Hematopoietic Expansion in Zebrafish. AB - The 11q23 of the mixed lineage leukemia 1 (MLL1) gene plays a crucial role in early embryonic development and hematopoiesis. The MLL-AF9 fusion gene, resulting from chromosomal translocation, often leads to acute myeloid leukemia with poor prognosis. Here, we generated a zebrafish model expressing the human MLL-AF9 fusion gene. Microinjection of human MLL-AF9 mRNA into zebrafish embryos resulted in enhanced hematopoiesis and the activation of downstream genes such as meis1 and hox cluster genes. Embryonic MLL-AF9 expression upregulated HSPC and myeloid lineage markers. Doxorubicin and MI-2 (a menin inhibitor) treatments significantly restored normal hematopoiesis in MLL-AF9-expressing animals. This study provides insight into the role of MLL-AF9 in zebrafish hematopoiesis and establishes a robust and efficient in vivo model for high-throughput drug screening. PMID- 30003106 TI - Lysophosphatidic Acid Analogue rather than Lysophosphatidic Acid Promoted the Bone Formation In Vivo. AB - Lysophosphatidic acid (LPA), a bioactive lipid molecule, has recently emerged as physiological and pathophysiological regulator in skeletal biology. Here we evaluate the effects of LPA on bone formation in vivo in murine femoral critical defect model. Primary femoral osteoblasts were isolated and treated with osteogenic induction conditional media supplemented with 20 MUM LPA or LPA analogue. Mineralized nodules were visualized by Alizarin Red S staining. Forty five C57BL/6 mice underwent unilateral osteotomy. The femoral osteotomy gap was filled with porous scaffolds of degradable chitosan/beta-tricalcium phosphate containing PBS, LPA, or LPA analogue. 2, 5, and 10 weeks after surgery, mice were sacrificed and femurs were harvested and prepared for Micro-Computed Tomography (Micro-CT) and histological analysis. Alizarin Red S staining showed that LPA and LPA analogue significantly enhanced the mineral deposition in osteoblasts. Micro CT 3D reconstruction images and HE staining revealed that significantly more newly formed bone in osteotomy was treated with LPA analogue when compared to control and LPA group, which was verified by histological analysis and biomechanical characterization testing. In summary, our study demonstrated that although LPA promotes mineralized matrix formation in vitro, the locally administrated LPA was not effective in promoting bone formation in vivo. And bone formation was enhanced by LPA analogue, administrated locally in vivo. LPA analogue was a potent stimulating factor for bone formation in vivo due to its excellent stability. PMID- 30003107 TI - Clinical and Etiological Aspects of Gynecomastia in Adult Males: A Multicenter Study. AB - Objectives: To evaluate the characteristics of presentation, biochemical profile, and etiology of gynecomastia in adults. Methods: Medical records of 237 men aged 18-85 years with gynecomastia were evaluated. Results: Highest prevalence of gynecomastia was observed between 21 and 30 years (n = 74; 31.2%). The most common presenting complaints were aesthetic concerns (62.8%) and breast pain (51.2%). 25.3% of the subjects had a history of pubertal gynecomastia. 56.5% had bilateral gynecomastia. 39.9% were overweight and 22.8% were obese. The etiology could not be identified in 45.1% of the cases; the most frequent identified causes were anabolic steroids consumption (13.9%), hypogonadism (11.1%), and use of pharmaceutical drugs (7.8%). Patients with bilateral gynecomastia had a longer history of disease, higher BMI, and lower testosterone levels. Conclusions: Patients with gynecomastia presented more often with aesthetic concerns and secondarily with breast pain. The most frequent final diagnosis was idiopathic gynecomastia, whereas the most frequent identified etiologies were anabolic steroids consumption, hypogonadism, and use of pharmaceutical drugs. Despite the low frequency of etiologies such as thyroid dysfunction or adrenal carcinoma, we emphasize the importance of a thorough assessment of the patient, as gynecomastia may be the tip of the iceberg for the diagnosis of treatable diseases. PMID- 30003108 TI - Elastic Tubing Resistance Training and Autonomic Modulation in Subjects with Chronic Obstructive Pulmonary Disease. AB - This study addresses evidence concerning elastic tubing resistance training (ET) on autonomic modulation in patients with chronic obstructive pulmonary disease (COPD). Autonomic dysfunction is common in COPD and contributes to the development of arrhythmias and sudden death. Along with autonomic dysfunction, muscle dysfunction is related to functional limitations and prognosis of the disease. This study investigated the effects of ET on autonomic modulation, muscle strength, and walking distance in COPD. Subjects were divided into two groups, ET (n = 20; 66,5 +/- 8,9 y; 25,5 +/- 3,5 kg/m2; FEV1/FVC: 50,3 +/- 11,0) and conventional training (n = 19; 66,0 +/- 6,9; 27,1 +/- 4,3; FEV1/FVC: 55,05 +/ 9,56). Both groups undertook 24 sessions for 60 minutes, 3 times in a week. The significance level was p <= 0,05. Autonomic modulation was evaluated using heart rate variability in the time (rMSSD, ms) and frequency domain (HF, ms). Strength for upper and lower limbs was measured using dynamometry and walking distance was measured using a 6-minute walking test. There were no significant differences in the outcomes between groups. There was an increment to rMSSD [(16,7 +/- 11,0 versus 20,8 +/- 14,9) versus (14,2 +/- 10,0 versus 17,4 +/- 12,1)], HF [(141,9 +/ 191,3 versus 234,9 +/- 335,7) versus (94,1 +/- 123,5 versus 177,6 +/- 275,5)], shoulder abduction [(50,1 +/- 19,6 versus 56,9 +/- 20,4) versus (50,5 +/- 19,0 versus 56,9 +/- 19,3)], knee flexion [(101,9 +/- 34,0 versus 116,8 +/- 43,3) versus (98,6 +/- 21,5 versus 115,1 +/- 30,8)], and walking test [(433,0 +/- 84,8 versus 468,9 +/- 90,8) versus (397,4 +/- 99,8 versus 426,3 +/- 101,6)] after training for ET and conventional training, respectively. In conclusion, ET improves autonomic modulation in COPD with additional benefits for strength and cardiorespiratory capacity similar to conventional training. PMID- 30003109 TI - miR-30 Family: A Promising Regulator in Development and Disease. AB - MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate posttranscriptional expression of target genes. Accumulating evidences have demonstrated that the miR-30 family, as a member of microRNAs, played a crucial regulating role in the development of tissues and organs and the pathogenesis of clinical diseases, which indicated that it may be a promising regulator in development and disease. This review aims to clarify the current progress on the regulating role of miR-30 family in tissues and organs development and related disease and highlight their research prospective in the future. PMID- 30003110 TI - The Antidiabetic Agent Sodium Tungstate Induces Abnormal Glycogen Accumulation in Renal Proximal Tubules from Diabetic IRS2-Knockout Mice. AB - The kidney is an insulin-sensitive organ involved in glucose homeostasis. One major effect of insulin is to induce glycogen storage in the liver and muscle. However, no significant glycogen stores are detected in normal kidneys, but diabetic subjects present a characteristic renal histopathological feature resulting from extensive glycogen deposition mostly in nonproximal tubules. The mechanism of renal glycogen accumulation is yet poorly understood. Here, we studied in situ glycogen accumulation in the kidney from diabetic IRS2-knockout mice and the effect of the insulin-mimetic agent sodium tungstate (NaW). IRS2 knockout mice displayed hyperglycemia and hyperinsulinemia. NaW only normalized glycemia. There was no evident morphological difference between kidneys from untreated wild-type (WT), NaW-treated WT, and untreated IRS2-knockout mice. However, NaW-treated IRS2-knockout mice showed tubular alterations resembling clear cells in the cortex, but not in the outer medulla, that were correlated with glycogen accumulation. Immunohistochemical detection of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, mostly expressed by renal proximal tubules, showed that altered tubules were of proximal origin. Our preliminary study suggests that IRS2 differentially regulates glycogen accumulation in renal tubules and that NaW treatment in the context of IRS2 ablation induces abnormal glycogen accumulation in cortical proximal tubules. PMID- 30003111 TI - CD4+CD25highCD127low/-FoxP3+ Regulatory T Cell Subpopulations in the Bone Marrow and Peripheral Blood of Children with ALL: Brief Report. AB - CD4+CD25highCD127low/-FoxP3+ regulatory T cells (Tregs) are currently under extensive investigation in childhood acute lymphoblastic leukemia (ALL) and in other human cancers. Usually, Treg cells maintain the immune cell homeostasis. This small subset of T cells has been, in fact, considered to be involved in the pathogenesis of autoimmune diseases and progression of acute and chronic leukemias. However, whether Treg dysregulation in CLL and ALL plays a key role or it rather represents a simple epiphenomenon is still a matter of debate. Treg cells have been proposed as a prognostic indicator of the clinical course of the disease and might also be used for targeted immune therapy. Our study revealed statistically higher percentage of Treg cells in the bone marrow than in peripheral blood in the group of 42 children with acute lymphoblastic leukemia. By analyzing Treg subpopulations, it was shown that only memory Tregs in contact with leukemic antigens showed statistically significant differences. We noticed a low negative correlation between Treg cells in the bone marrow and the percentage of blasts (R = -0.36) as well as a moderate correlation between Treg cells in the bone marrow and Hb level (R = +0.41) in peripheral blood before therapy. The number of peripheral blood blasts on day 8th correlates negatively (R = -0.36) with Tregs. Furthermore, statistical analysis revealed low negative correlation between the number of Tregs in the bone marrow and the minimal residual disease measured on day 15th, the percentage of blasts in the bone marrow and leukocytosis after 15 days of chemotherapy. These results indicate the influence of Tregs on the final therapeutic effect. PMID- 30003112 TI - Lower FOXP3 mRNA Expression in First-Trimester Decidual Tissue from Uncomplicated Term Pregnancies with a Male Fetus. AB - Pregnancies with a male fetus are associated with higher risks of pregnancy complications through maladaptation of the maternal immune system. The pathophysiology of this phenomenon is unknown. A possible pathway could be a fetal sex-dependent maternal immune response, since males have a Y chromosome encoding specific allogenic proteins, possibly contributing to a different response and higher complication risks. To analyze whether fetal sex affects mRNA expression of maternal immune genes in early pregnancy, real-time PCR quantification was performed in the decidual tissue from primigravid pregnancies (n = 20) between 10 and 12 weeks with uncomplicated term outcomes. Early pregnancy decidual mRNA expression of the regulatory T-cell marker, FOXP3, was sixfold lower (p < 0.01) in pregnancies with a male fetus compared to pregnancies with a female fetus. Additionally, mRNA expression of IFNgamma was sixfold (p < 0.05) lower in pregnancies with a male fetus. The present data imply maternal immunologic differences between pregnancies with male and female fetuses which could be involved in different pregnancy pathophysiologic outcomes. Moreover, this study indicates that researchers in reproductive immunology should always consider fetal sex bias. PMID- 30003113 TI - PD-L1 Expression and CD8+ T Cell Infiltration Predict a Favorable Prognosis in Advanced Gastric Cancer. AB - Advanced gastric cancer (AGC) has high morbidity and mortality in East Asia, and it is urgent to explore new treatments to improve patient prognosis. Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have exhibited remarkable activity in clinical trials and were approved by the FDA for clinical therapy in several types of tumors. Here, we evaluated PD-L1 expression and T cell infiltration in AGC. Positive tumor PD-L1 expression was detected in 171 AGCs (33.60%) out of 509 AGCs. PD-L1 expression was positively correlated with CD8+ T cell infiltration. Then, PD-L1 and CD8A mRNA expression was analyzed using gastric cancer data from the TCGA database, confirming a positive correlation. Patient survival was assessed according to PD-L1 status and the T cell infiltration density. PD-L1 expression and a high density of CD8+ T cells in AGCs were associated with improved prognosis, whereas no significant difference was noted between PD-1 and CD3 expression. In contrast, a high density of FOXP3+ T cells in AGCs indicated a poor prognosis. Multivariate Cox regression analysis revealed that CD8+ T cell density acts as an independent predictor of overall survival (OS) in AGC patients. Taken together, this study further highlights targets for immune checkpoint-based therapy in AGC. PMID- 30003114 TI - Hei-Gu-Teng Zhuifenghuoluo Granule Modulates IL-12 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a type of chronic systemic inflammatory disease; it has a very complicated pathogenesis, and multiple pathological changes are implicated. Traditional Chinese medicine (TCM) like Tripterygium wilfordii Hook. F. or Sinomenium acutum (Thunb.) Rehd et Wils. has been extensively used for centuries in the treatment of arthritic diseases and been reported effective for relieving the severity of RA. Hei-Gu-Teng Zhuifenghuoluo granule (HGT) which contains Periploca forrestii Schltr., Sinomenium acutum (Thunb.) Rehd et Wils., and Lysimachia paridiformis Franch. var. stenophylla Franch. was a representative natural rattan herb formula for the treatment of RA in China, but the mechanism has not been elucidated. This study aimed at exploring the mechanism of HGT on RA using the bioinformatics analysis with in vivo and in vitro experiment validation. The potential action mechanism was first investigated by bioinformatics analysis via Ingenuity Pathway Analysis (IPA) software. After that, we use experimental validation such as collagen-induced arthritis (CIA) mice model in vivo and U937 cell model in vitro. The bioinformatics results suggested that HGT may have anti-inflammatory characteristic on RA and IL-12 signaling pathway could be the potential key trigger. In vivo experiments demonstrated that HGT ameliorated the symptoms in CIA mice and decreased the production of inflammatory cytokines in both mice ankle joints and serum. Furthermore, HGT effectively inhibited the activation of IL-12R and STAT4 on IL 12 signaling pathway. In vitro experiments showed that HGT inhibited the production of IL-12R and STAT4 induced by IL-12 in lipopolysaccharide- (LPS-) stimulated U937 cells. Moreover, IL-12R knockdown was able to interfere with the inhibition effects of HGT on the production of these cytokines. Our results confirmed the anti-inflammatory property of HGT, which was attributed to its inhibition on IL-12 signaling pathway. PMID- 30003115 TI - Electrically stimulated cell migration and its contribution to wound healing. AB - Naturally occurring electric fields are known to be morphogenetic cues and associated with growth and healing throughout mammalian and amphibian animals and the plant kingdom. Electricity in animals was discovered in the eighteenth century. Electric fields activate multiple cellular signaling pathways such as PI3K/PTEN, the membrane channel of KCNJ15/Kir4.2 and intracellular polyamines. These pathways are involved in the sensing of physiological electric fields, directional cell migration (galvanotaxis, also known as electrotaxis), and possibly other cellular responses. Importantly, electric fields provide a dominant and over-riding signal that directs cell migration. Electrical stimulation could be a promising therapeutic method in promoting wound healing and activating regeneration of chronic and non-healing wounds. This review provides an update of the physiological role of electric fields, its cellular and molecular mechanisms, its potential therapeutic value, and questions that still await answers. PMID- 30003118 TI - Development of Methods for the Selective Measurement of the Single Amino Acid Exchange Variant Coagulation Factor IX Padua. AB - The description of hyper-functional factor IX (FIX) Padua triggered the development of BAX 335, an AAV8-based hemophilia B gene therapy vector designed to compensate for low FIX protein expression levels by expressing the FIX Padua variant, thereby reducing the exposure to viral vector. The presence of inactive FIX protein at baseline hindered conventional FIX:Ag ELISA from contributing to a more profound understanding of clinical data from the BAX 335 Phase 1/2 study (ClinicalTrials.gov: NCT01687608). By applying phage display technology, a Fab2 mini-antibody selectively binding to FIX Padua was developed and used to establish a FIX Padua-specific ELISA. The assay adequately performed, utilizing human and monkey plasma samples, and enabled the selective quantification of FIX Padua protein in human plasma samples from the BAX 335 trial. The mini-antibody also allowed the development of a chromogenic FIX Padua-specific activity assay, which adequately performed in human and mouse plasma. Collectively, the isolated FIX Padua-specific mini-antibody enabled the development of transgene-product specific assays, which should improve the monitoring of hemophilia B gene therapies. The approach applied here for FIX Padua could be leveraged to develop variant-specific activity assays for other therapies where highly active enzymes are instrumental in achieving therapeutic levels of the transgene product. PMID- 30003116 TI - Long scan depth optical coherence tomography on imaging accommodation: impact of enhanced axial resolution, signal-to-noise ratio and speed. AB - Background: Spectral domain optical coherence tomography (SD-OCT) was a useful tool to study accommodation in human eye, but the maximum image depth is limited due to the decreased signal-to-noise ratio (SNR). In this study, improving optical resolutions, speeds and the SNR were achieved by custom built SD-OCT, and the evaluation of the impact of the improvement during accommodation was investigated. Methods: Three systems with different spectrometer designs, including two Charge Coupled Device (CCD) cameras and one Complementary Metal Oxide-Semiconductor Transistor (CMOS) camera, were tested. We measured the point spread functions of a mirror at different positions to obtain the axial resolution and the SNR of three OCT systems powered with a light source with a 50 nm bandwidth, centered at a wavelength of 840 nm. Two normal subjects, aged 26 and 47, respectively, and one 75-year-old patient with an intraocular lens implanted were imaged. Results: The results indicated that spectrometers using cameras with 4096 camera pixels optimized the axial resolutions, due to the use of the full spectrum provided by the light source. The CCD camera system with 4096 pixels had the highest SNR and the best image quality. The system with the CMOS camera with 4096 pixels had the highest speed but had a compromised SNR compared to the CCD camera with 4096 pixels. Conclusions: Using these three OCT systems, we imaged the anterior segment of the human eye before and after accommodation, which showed similar results among the different systems. The system using the CMOS camera with an ultra-long scan depth, high resolution and high scan speed exhibited the best overall performance and therefore was recommended for imaging real-time accommodation. PMID- 30003117 TI - Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis. AB - Variants in the PLPP3 gene encoding for lipid phosphate phosphohydrolase 3 have been associated with susceptibility to atherosclerosis independently of classical risk factors. PLPP3 inactivates lysophosphatidic acid (LPA), a pro-inflammatory, pro-thrombotic product of phospholipase activity. Here we performed the first exploratory analysis of PLPP3, LPA, and LPA receptors (LPARs 1-6) in human atherosclerosis. PLPP3 transcript and protein were repressed when comparing plaques versus normal arteries and plaques from symptomatic versus asymptomatic patients, and they were negatively associated with risk of adverse cardiovascular events. PLPP3 localized to macrophages, smooth muscle, and endothelial cells (ECs) in plaques. LPAR 2, 5, and especially 6 showed increased expression in plaques, with LPAR6 localized in ECs and positively correlated to PLPP3. Utilizing in situ mass spectrometry imaging, LPA and its precursors were found in the plaque fibrous cap, co-localizing with PLPP3 and LPAR6. In vitro, PLPP3 silencing in ECs under LPA stimulation resulted in increased expression of adhesion molecules and cytokines. LPAR6 silencing inhibited LPA-induced cell activation, but not when PLPP3 was silenced simultaneously. Our results show that repression of PLPP3 plays a key role in atherosclerosis by promoting EC activation. Altogether, the PLPP3 pathway represents a suitable target for investigations into novel therapeutic approaches to ameliorate atherosclerosis. PMID- 30003119 TI - Medicinal versus Recreational Cannabis Use among Returning Veterans. AB - Background: Although increasing rates of cannabis use and cannabis use disorder (CUD) are well-documented among veterans, little is known about their use of cannabis specifically for medicinal purposes. The present study characterizes such use and compares veterans reporting cannabis use for medicinal (n = 66) versus recreational (n = 77) purposes on (a) sociodemographic factors, (b) psychiatric disorders (posttraumatic stress disorder [PTSD], major depressive disorder [MDD], and CUD), (c) other substance use, (d) reasons for cannabis use and cannabis-related problems, and (e) physical and mental health. Methods: Participants were veterans deployed post 9/11/2001 recruited from a Veterans Health Administration (VHA) facility (N = 143; mean [SD] age = 30.0 [6.6]; mean [SD] deployments = 1.7 [1.1]) who reported past-year cannabis use. Results: The most frequently endorsed conditions for medicinal cannabis (MC) use were anxiety/stress, PTSD, pain, depression, and insomnia. In logistic regression analyses adjusted for frequency of cannabis use, MC users were significantly more likely (OR = 3.16) to meet criteria for PTSD than recreational cannabis (RC) users. Relative to RC users, MC users reported significantly greater motivation for using cannabis to cope with sleep disturbance as well as significantly poorer sleep quality and worse physical health. Conclusions: Veterans who use cannabis for medicinal purposes differ significantly in sleep, physical and mental health functioning than veterans who use cannabis for recreational purposes. PTSD and sleep problems may be especially relevant issues to address in screening and providing clinical care to returning veterans who are using cannabis for medicinal purposes. PMID- 30003120 TI - Cytokine-specific Neurograms in the Sensory Vagus Nerve. AB - The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body's metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1beta (IL-1beta). Importantly, the afferent vagus neurograms generated by TNF exposure are abolished in double knockout mice lacking TNF receptors 1 and 2 (TNF-R1/2KO), whereas IL-1beta-specific neurograms are eliminated in knockout mice lacking IL-1beta receptor (IL-1RKO). Conversely, TNF neurograms are preserved in IL-1RKO mice, and IL-1beta neurograms are unchanged in TNF-R1/2KO mice. Analysis of the temporal dynamics and power spectral characteristics of afferent vagus neurograms for TNF and IL-1beta reveals cytokine-selective signals. The nodose ganglion contains the cell bodies of the sensory neurons whose axons run through the vagus nerve. The nodose neurons express receptors for TNF and IL-1beta, and we show that exposing them to TNF and IL-1beta significantly stimulates their calcium uptake. Together these results indicate that afferent vagus signals in response to cytokines provide a basic model of nervous system sensing of immune responses. PMID- 30003121 TI - Bones in human CYP26B1 deficiency and rats with hypervitaminosis A phenocopy Vegfa overexpression. AB - Angulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity. PMID- 30003122 TI - Effects of high fat or high sucrose diet on behavioral-response to social defeat stress in mice. AB - Stress increases risk for psychopathology, and diet may moderate the impact of stress on mental health. A "Western" diet has been linked to psychopathology in humans; animal studies also show that diet can influence negative valence behavior in the presence or absence of stress, but findings are inconsistent. Contradictions in existing studies may result from differences in macronutrient content of diets and presence of metabolic syndrome. The present study exposed mice to 10 days of high fat or high sucrose diet concurrent with social defeat stress exposure and examined negative valence behavior at acute (30 days) time points after stress/diet exposure. Predictably, stress increased negative valence behavior in the social interaction, open field, elevated zero maze, and tail suspension tests at the acute time point. While most stress-induced behaviors normalized after the 30-day recovery period, social avoidance was still highly significant for stress-exposed mice, supporting the hypothesis that avoidance of a trauma-related cue persists beyond non-specific anxiety-like behaviors. Supporting the hypothesis that an unhealthy diet contributes to psychopathology, non-stressed mice fed high fat or high sucrose diets spent less time exploring the center of the open field. This effect was no longer present after a 30-day recovery. Intriguingly, mice previously fed either high fat or high sucrose diets exhibited increased rearing behavior in the elevated zero maze 30 days post stress and diet exposure. This finding could be evidence that short-term diet administration can initiate a long-term increase in risk-assessment behavior. PMID- 30003125 TI - Iceberg hemangioma: A segmental cutaneous lesion marking extensive extracutanous involvement. PMID- 30003126 TI - Malignant degeneration of diffuse intertriginous flat warts in a patient with AIDS. PMID- 30003124 TI - E47 Governs the MYC-CDKN1B/p27KIP1-RB Network to Growth Arrest PDA Cells Independent of CDKN2A/p16INK4A and Wild-Type p53. AB - Background & Aims: Oncogenic mutations in KRAS, coupled with inactivation of p53, CDKN2A/p16INK4A, and SMAD4, drive progression of pancreatic ductal adenocarcinoma (PDA). Overexpression of MYC and deregulation of retinoblastoma (RB) further promote cell proliferation and make identifying a means to therapeutically alter cell-cycle control pathways in PDA a significant challenge. We previously showed that the basic helix-loop-helix transcription factor E47 induced stable growth arrest in PDA cells in vitro and in vivo. Here, we identified molecular mechanisms that underlie E47-induced growth arrest in low-passage, patient derived primary and established PDA cell lines. Methods: RNA sequencing was used to profile E47-dependent transcriptomes in 5 PDA cell lines. Gene Ontology analysis identified cell-cycle control as the most altered pathway. Small interfering RNA/short hairpin RNA knockdown, small-molecule inhibitors, and viral expression were used to examine the function of E47-dependent genes in cell-cycle arrest. Cell morphology, expression of molecular markers, and senescence associated beta-galactosidase activity assays identified cellular senescence. Results: E47 uniformly inhibited PDA cell-cycle progression by decreasing expression of MYC, increasing the level of CDKN1B/p27KIP1, and restoring RB tumor suppressor function. The molecular mechanisms by which E47 elicited these changes included altering both RNA transcript levels and protein stability of MYC and CDKN1B/p27KIP1. At the cellular level, E47 elicited a senescence-like phenotype characterized by increased senescence-associated beta-galactosidase activity and altered expression of senescence markers. Conclusions: E47 governs a highly conserved network of cell-cycle control genes, including MYC, CDKN1B/p27KIP1, and RB, which can induce a senescence-like program in PDA cells that lack CDKN2A/p16INK4A and wild-type p53. RNA sequencing data are available at the National Center for Biotechnology Information GEO at https://www.ncbi.nlm.nih.gov/geo/; accession number: GSE100327. PMID- 30003123 TI - Enteropathogenic Escherichia coli EspH-Mediated Rho GTPase Inhibition Results in Desmosomal Perturbations. AB - Background & Aims: The diarrheagenic pathogen, enteropathogenic Escherichia coli (EPEC), uses a type III secretion system to deliver effector molecules into intestinal epithelial cells (IECs). While exploring the basis for the lateral membrane separation of EPEC-infected IECs, we observed infection-induced loss of the desmosomal cadherin desmoglein-2 (DSG2). We sought to identify the molecule(s) involved in, and delineate the mechanisms and consequences of, EPEC induced DSG2 loss. Methods: DSG2 abundance and localization was monitored via immunoblotting and immunofluorescence, respectively. Junctional perturbations were visualized by electron microscopy, and cell-cell adhesion was assessed using dispase assays. EspH alanine-scan mutants as well as pharmacologic agents were used to evaluate impacts on desmosomal alterations. EPEC-mediated DSG2 loss, and its impact on bacterial colonization in vivo, was assessed using a murine model. Results: The secreted virulence protein EspH mediates EPEC-induced DSG2 degradation, and contributes to desmosomal perturbation, loss of cell junction integrity, and barrier disruption in infected IECs. EspH sequesters Rho guanine nucleotide exchange factors and inhibits Rho guanosine triphosphatase signaling; EspH mutants impaired for Rho guanine nucleotide exchange factor interaction failed to inhibit RhoA or deplete DSG2. Cytotoxic necrotizing factor 1, which locks Rho guanosine triphosphatase in the active state, jasplakinolide, a molecule that promotes actin polymerization, and the lysosomal inhibitor bafilomycin A, respectively, rescued infected cells from EPEC-induced DSG2 loss. Wild-type EPEC, but not an espH-deficient strain, colonizes mouse intestines robustly, widens paracellular junctions, and induces DSG2 re-localization in vivo. Conclusions: Our studies define the mechanism and consequences of EPEC induced desmosomal alterations in IECs. These perturbations contribute to the colonization and virulence of EPEC, and likely related pathogens. PMID- 30003127 TI - Use of reflectance confocal microscopy to diagnose occult basal cell carcinoma: 2 case reports. PMID- 30003129 TI - Nivolumab-induced systemic vasculitis. PMID- 30003128 TI - A novel AIRE gene mutation in a patient with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy revealed by alopecia areata. PMID- 30003130 TI - Lipoid proteinosis: Unfamiliar skin findings delay diagnosis. PMID- 30003131 TI - Use of the 532-nm Q-switched neodymium-doped yttrium aluminum garnet laser for the treatment of recalcitrant repigmentation in vitiligo. PMID- 30003132 TI - Nevus anemicus: An island of sparing in the setting of drug-induced hypersensitivity. PMID- 30003133 TI - Prolonged intubation after robotic-assisted hysterectomy for endometrial cancer: Case reports. AB - *Experienced prolonged intubation after robotic hysterectomy for endometrial cancer*Risk triad: Trendelenburg position, high pneumo-pressure, and excess hydration*Recognition of the risk triad is key to avoiding airway complications in robotic surgery.*Introduction of a 5-step method to prevent airway complications in robotic surgery. PMID- 30003134 TI - Immigrant health trajectories in historical context: Insights from European immigrant childhood mortality in 1910. AB - Recent studies of immigrant health have focused on an apparent paradox in which some new immigrants arrive healthier than expected but exhibit poorer health outcomes with duration of residence. Although a variety of explanations have been put forth for this epidemiological pattern, questions remain about the socio historical generalizability of the empirical findings and accompanying theoretical explanations. By examining childhood mortality patterns of European immigrants to the United States in the early 20th century, this study tests hypotheses from current immigrant health literature in a previous era of immigration. In contrast with post-1965 immigrant groups, European arrivals did not have better outcomes than their U.S.-born white counterparts. Rather, their rates corresponded to a "middle tier" status in between U.S.-born black and white populations. Analysis of post-migration trajectories returned mixed results that similarly differ from contemporary patterns. Many new immigrant groups had higher rates of excess childhood mortality than their U.S-born counterparts, but outcomes appear to have improved with duration of residence or among the second generation. These findings suggest socio-historical variation in the context of reception may act as a "fundamental cause" of immigrant health and mortality outcomes. PMID- 30003135 TI - Exercise addiction is associated with emotional distress in injured and non injured regular exercisers. AB - Introduction: Exercise addiction is characterized by the use of physical activity to cope with emotions and mood, while sports injuries can lead to psychological distress such as depression and anxiety. The aim of the present study was to investigate the association between risk of exercise addiction and psychological distress, and whether this association was modified by injury status. Methods: A cross-sectional study with injured and non-injured recreational exercisers (n = 1083). Using the Exercise Addiction Inventory participants were classified into the following groups: High risk of exercise addiction (HREA) with musculoskeletal injury (n = 44); HREA without musculoskeletal injury (n = 31); Low risk of addiction (LREA) with injury (n = 563); LREA without injury (n = 445). The outcomes were depression using the Major Depression Inventory, and emotional stress using the Perceived Stress Scale. Data were analyzed using binomial regression analysis with prevalence proportion difference (PPD) as measure of association. Results: Compared with LREA-exercisers, more HREA exercisers were depressed (PPD = 13% points [95%CI 3.6; 22.4]) or experienced emotional stress (PPD = 26.2% points [95%CI 14.5; 37.8]). Amongst injured exercisers, more HREA exercisers had depression (PPDHREA-injured = 15.9% points [95%CI 2.5; 29.3]) compared with LREA-exercisers. Conclusions: Recreational exercisers with high risk of exercise addiction reported more symptoms of depression and emotional stress, and this relationship seemed exacerbated in the presence of musculoskeletal injury. Psychological assessment and counseling may be useful supplements to somatic injury interventions for addressing emotional distress. PMID- 30003136 TI - Examining co-patterns of depression and alcohol misuse in emerging adults following university graduation. AB - Depression and alcohol use disorders are highly comorbid. Typically, alcohol use peaks in emerging adulthood (e.g., during university), and many people also develop depression at this time. Self-medication theory predicts that depressed emerging adults drink to reduce negative emotions. While research shows that depression predicts alcohol use and related problems in undergraduates, far less is known about the continuity of this association after university. Most emerging adults "mature out" of heavy drinking; however, some do not and go on to develop an alcohol use disorder. Depressed emerging adults may continue to drink heavily to cope with the stressful (e.g., remaining unemployed) transition out of university. Accordingly, using parallel process latent class growth modelling, we aimed to distinguish high- from low-risk groups of individuals based on joint patterns of depression and alcohol misuse following university graduation. Participants (N = 123) completed self-reports at three-month intervals for the year post-graduation. Results supported four classes: class 1: low stable depression and low decreasing alcohol misuse (n = 52), class 2: moderate stable depression and moderate stable alcohol misuse (n = 35), class 3: high stable depression and low stable alcohol misuse (n = 29), and class 4: high stable depression and high stable alcohol misuse (n = 8). Our findings show that the co development of depression and alcohol misuse after university is not uniform. Most emerging adults in our sample continued to struggle with significant depressive symptoms after university, though only two classes continued to drink at moderate (class 2) and high (class 4) risk levels. PMID- 30003137 TI - Apraxia profiles-A single cognitive marker to discriminate all variants of frontotemporal lobar degeneration and Alzheimer's disease. AB - Introduction: Apraxia is common in neurodegenerative dementias but underrepresented in clinical workup for differential diagnoses. Methods: Praxis profiles were assessed with the Dementia Apraxia Test in 93 patients with early stages of biologically supported Alzheimer's disease or frontotemporal lobar degeneration: semantic primary-progressive aphasia, nonfluent primary-progressive aphasia, and behavioral variant frontotemporal dementia. Associations with core cognitive deficits of the dementia subtypes (i.e., visuospatial, sociocognitive, and semantic-linguistic) were explored. Results: Patients showed significant apraxia compared with healthy controls but also disease-specific praxis-profiles. Using only the Dementia Apraxia Test, all four dementia subtypes could be correctly discriminated in 64.4% of cases, and in 78.2% when only distinguishing Alzheimer's disease versus frontotemporal lobar degeneration. Praxis-profiles showed consistent associations with core cognitive impairments of the different dementia subtypes. Discussion: The Dementia Apraxia Test is a valid, time efficient and versatile cognitive marker to delineate variants of frontotemporal lobar degeneration and Alzheimer's disease in clinical routine, facilitating differential diagnoses of dementia subtypes in early disease stages. PMID- 30003139 TI - Prevalence and Genotypes of Parvovirus B19 Among HIV Positive Children in Ibadan, Oyo State, Nigeria. AB - Human Parvovirus B19 (B19V) is a global infection with over 50% of infected children residing in sub-Saharan Africa. It causes persistent anaemia under immuno-compromised states such as HIV infection, thereby complicating the course of HIV infection. This study was therefore designed to determine the prevalence and genotypes of B19V among HIV positive children. Blood specimens were collected from HIV positive children and genomic DNA extracted and assayed for the presence of Parvovirus B19 DNA using polymerase chain reaction and the product detected by gel electrophoresis. Amplicons for positive PCR were purified and sequenced for genotype analysis. For the purpose of comparison (differences in the sequences of the NS1/VP1u region), nine HIV negative children were enrolled in this study. Two (1.3%) of the 158 HIV infected children were positive for Parvovirus B19 DNA. Analysis of the results showed a low prevalence of Parvovirus B19 among HIV positive children but a significant relationship was established between Parvovirus B19 infection and the severity of anaemia (p=0.015). Phylogenetic analysis of the sequence data showed that all the B19 virus isolates detected in this study were genotype 1. This study therefore has been able to give an insight to the prevalence and circulating genotypes of Parvovirus B19 among HIV infected children and also establishing a relationship between anaemia and parvovirus B19 infection. PMID- 30003138 TI - Underdiagnosis of mild cognitive impairment: A consequence of ignoring practice effects. AB - Introduction: Longitudinal testing is necessary to accurately measure cognitive change. However, repeated testing is susceptible to practice effects, which may obscure true cognitive decline and delay detection of mild cognitive impairment (MCI). Methods: We retested 995 late-middle-aged men in a ~6-year follow-up of the Vietnam Era Twin Study of Aging. In addition, 170 age-matched replacements were tested for the first time at study wave 2. Group differences were used to calculate practice effects after controlling for attrition effects. MCI diagnoses were generated from practice-adjusted scores. Results: There were significant practice effects on most cognitive domains. Conversion to MCI doubled after correcting for practice effects, from 4.5% to 9%. Importantly, practice effects were present although there were declines in uncorrected scores. Discussion: Accounting for practice effects is critical to early detection of MCI. Declines, when lower than expected, can still indicate practice effects. Replacement participants are needed for accurately assessing disease progression. PMID- 30003142 TI - Erratum for Grieneisen and Blekhman, "Crowdsourcing Our National Gut". AB - [This corrects the article DOI: 10.1128/mSystems.00060-18.]. PMID- 30003140 TI - Prevalence of Parkinson's disease across North America. AB - Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged >=45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged >=45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood. PMID- 30003143 TI - Critical Assessment of Metagenome Interpretation Enters the Second Round. PMID- 30003141 TI - Erratum: Author Correction: Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study. AB - [This corrects the article DOI: 10.1038/npjbcancer.2016.17.]. PMID- 30003144 TI - The Current and Future State of Department of Defense (DoD) Microbiome Research: a Summary of the Inaugural DoD Tri-Service Microbiome Consortium Informational Meeting. AB - The Tri-Service Microbiome Consortium (TSMC) was recently established to enhance collaboration, coordination, and communication of microbiome research among Department of Defense (DoD) organizations. The TSMC aims to serve as a forum for sharing information related to DoD microbiome research, policy, and applications, to monitor global advances relevant to human health and performance, to identify priority objectives, and to facilitate Tri-Service (Army, Navy, and Air Force) collaborative research. The inaugural TSMC workshop held on 10 to 11 May 2017 brought together almost 100 attendees from across the DoD and several key DoD partners. The meeting outcomes informed attendees of the scope of current DoD microbiome research efforts and identified knowledge gaps, collaborative/leveraging opportunities, research barriers/challenges, and future directions. This report details meeting presentations and discussions with special emphasis on Tri-Service labs' current research activities. PMID- 30003145 TI - Simultaneous monitoring of transcription and translation in mammalian cell-free expression in bulk and in cell-sized droplets. AB - Transcription and translation are two critical processes during eukaryotic gene expression that regulate cellular activities. The development of mammalian cell free expression (CFE) systems provides a platform for studying these two critical processes in vitro for bottom-up synthetic biology applications such as construction of an artificial cell. Moreover, real-time monitoring of the dynamics of synthesized mRNA and protein is key to characterize and optimize gene circuits before implementing in living cells or in artificial cells. However, there are few tools for measurement of mRNA and protein dynamics in mammalian CFE systems. Here, we developed a locked nucleic acid (LNA) probe for monitoring transcription in a HeLa-based CFE system in real-time. By using this LNA probe in conjunction with a fluorescent reporter protein, we were able to simultaneously monitor mRNA and protein dynamics in bulk reactions and cell-sized single emulsion droplets. We found rapid production of mRNA transcripts that decreased over time as protein production ensued in bulk reactions. Our results also showed that transcription in cell-sized droplets has different dynamics compared to the transcription in bulk reactions. The use of this LNA probe in conjunction with fluorescent proteins in HeLa-based mammalian CFE system provides a versatile in vitro platform for studying mRNA dynamics for bottom-up synthetic biology applications. PMID- 30003147 TI - Effective anti-cancer property of Pouteria sapota leaf on breast cancer cell lines. AB - Natural products are vital in drug discovery and the search for anticancer agents has been significant importance to the researchers for a long time. In the present study, aqueous leaf extract of Pouteria sapota (P.sapota) was evaluated for its cytotoxic activity. The leaf extract was preliminarily screened for antioxidant activity using DPPH method for Radical Scavenging Activity, Hydrogen Peroxide Scavenging Activity and Reducing Power Activity. Further, the aqueous leaf extract was screened for cytotoxic activity against breast cancer cell lines (MCF-7) in vitro. The results of the study showed that aqueous extract of the P.sapota leaf was rich in phytochemicals, antioxidant activity and showed a significant anti-cancer activity against tested MCF-7 cell lines. The present study was designed to evaluate the anticancer potential of P.sapota leaf. The antioxidants present in P.sapota have strong cytotoxic activity suggests that it can be considered for anti-cancer treatment. PMID- 30003146 TI - When Adults Don't Exercise: Behavioral Strategies to Increase Physical Activity in Sedentary Middle-Aged and Older Adults. AB - Physical activity is one of the most promising nonpharmacological, noninvasive, and cost-effective methods of health-promotion, yet statistics show that only a small percentage of middle-aged and older adults engage in the recommended amount of regular exercise. This state of affairs is less likely due to a lack of knowledge about the benefits of exercise than to failures of motivation and self regulatory mechanisms. Many types of intervention programs target exercise in later life, but they typically do not achieve sustained behavior change, and there has been very little increase in the exercise rate in the population over the last decade. The goal of this paper is to consider the use of effective low cost motivational and behavioral strategies for increasing physical activity, which could have far-reaching benefits at the individual and population levels. We present a multicomponent framework to guide development of behavior change interventions to increase and maintain physical activity among sedentary adults and others at risk for health problems. This involves a personalized approach to motivation and behavior change, which includes social support, goal setting, and positive affect coupled with cognitive restructuring of negative and self defeating attitudes and misconceptions. These strategies can lead to increases in exercise self-efficacy and control beliefs as well as self- management skills such as self-regulation and action planning, which in turn are expected to lead to long-term increases in activity. These changes in activity frequency and intensity can ultimately lead to improvements in physical and psychological well being among middle-aged and older adults, including those from underserved, vulnerable populations. Even a modest increase in physical activity can have a significant impact on health and quality of life. Recommendations for future interventions include a focus on ways to achieve personalized approaches, broad outreach, and maintenance of behavior changes. PMID- 30003148 TI - SMART (stroke-like migraine attacks after radiation therapy) syndrome responded to steroid pulse therapy: Report of a case and review of the literature. AB - This report presents a case of stroke-like migraine attacks after radiation therapy (SMART) syndrome in a 31-year-old man in whom symptoms and radiological findings resolved with steroid pulsed therapy and reviews the literatures with special emphasis on the use of steroids against SMART syndrome. The patient had a past history of left temporal anaplastic astrocytoma and was treated with surgery followed by local 72 Gy radiation therapy and chemotherapy using Nimustine Hydrochloride. Four years after the surgery, he was suffering from subacute progressing symptoms of headache, right hemianopia, right hemiparesis and aphasia from 2 to 4 days before admission to our hospital. At first he was diagnosed as symptomatic epilepsy but after extensive examination, the final diagnosis was SMART syndrome. His symptoms soon improved with steroid pulse therapy. In the literature, steroid pulse therapy is not necessarily a standard of care for SMART syndrome, but it seemed to decrease the need of biopsy. As the lesions of SMART syndrome require differential diagnosis from recurrences, biopsy was performed in some cases. However, lack of benefit and possible detriment is reported with biopsy of SMART lesions. Through this experience we suggest that steroid pulse therapy may provide speedy recovery from symptoms, and it should be considered before other invasive investigations or treatments. PMID- 30003149 TI - CBCT and MRT imaging in patients clinically diagnosed with temporomandibular joint arthralgia. AB - Objectives: To compare cone beam computed tomography (CBCT) and magnetic resonance tomography (MRT) in patients with temporomandibular joint (TMJ) arthralgia in respect of the evaluation of bony structures, and to correlate joint space distances measured in CBCT with the morphology and the position of the disc visualized in MRT. Materials & methods: 26 temporomandibular joints (TMJs) in 13 patients clinically diagnosed with TMJ arthralgia were examined by both CBCT and MRT. All images were evaluated by use of a form. The results were compared in regard of conformability of the diagnoses of osseous structures established by each imaging method. Anterior, superior and posterior joint space distances measured in CBCT-images were related to disc morphology and position visualized in MRT. Results: Conformability of CBCT and MRT in the evaluation of bony TMJ structures ranged from 69.3 to 96.6 %. Osseous alterations such as erosions, osteophytes and cysts detected by CBCT could partly not be discerned by MRT. The correlation of joint space distances with disc morphology (biconcave or not biconcave) was not statistically significant. The correlation of joint space distances and disc position was statistically significant only for the superior joint distance. Conclusion: CBCT outclasses MRT in the visualization of osseous alterations, which are diacritic in the differentiation of simple arthralgia from osteoarthritis. Therefore, CBCT imaging is appropriate in patients clinically diagnosed with TMJ arthralgia.Superior joint space distance not being the highest joint space in sagittal CBCT indicates an anterior disc displacement.For the visualization of structural changes or displacement of the disc frequently associated with osseous changes, MRT is the optimal tool. Thus, the combination of the two imaging methods allows a comprehensive diagnosis in TMJ arthralgia patients. PMID- 30003152 TI - First-rotation growth and stand structure dynamics of tree species in organic and conventional short-rotation agroforestry systems. AB - Short-rotation agroforestry systems can potentially maintain agricultural production and promote conservation of soil and biodiversity, especially if grown organically. Hereby, species-specific stand growth determines woody biomass yield and influences management decisions like planting density and harvest requirements. Studies of longer-term growth dynamics in Southern Germany are scarce and none analyzed differences between conventional and organic systems. In this study, four tree species (black alder, black locust, poplar clone Max 3, and willow clone Inger) were planted in an alley-cropping configuration in Southern Germany, grown under organic and conventional systems, and monitored from 2009 to 2012. Growth was assessed with stem base diameter, height, aboveground woody biomass, sprouting, and survival. The tree species did not show a uniform ranking in biometric variables and biomass over time. Four-year mean annual biomass increment (MAI) ranged from 7 to 10 t ha-1 a-1, with poplar and locust having the highest growth rates. Willow had the lowest MAI, as it had a low diameter growth paired with a low wood density, but it developed the highest number of shoots because of increased sprouting in the last year. Size inequality and skewness of the dominant stems increased for all species throughout the years suggesting asymmetric competition. Size inequality as well as mortality was greatest for black locust. Furthermore this was the only species, which developed a right skewed SBD distribution and the highest diameter size range. Size inequality was smallest for poplar and willow, with no or only minimal mortality. Alder was inbetween. For black locust and alder no difference in growth traits between organic and conventional systems appeared after four years. Organic poplar and willow stands performed better than conventional ones after the second year, leaving unclear whether this can be attributed to management or site effect. PMID- 30003150 TI - Suppression of T cells by mesenchymal and cardiac progenitor cells is partly mediated via extracellular vesicles. AB - Adverse remodeling after myocardial infarction (MI) is strongly influenced by T cells. Stem cell therapy after MI, using mesenchymal stem cells (MSC) or cardiomyocyte progenitor cells (CMPC), improved cardiac function, despite low cell retention and limited differentiation. As MSC secrete many factors affecting T cell proliferation and function, we hypothesized the immune response could be affected as one of the targets of stem cell therapy. Therefore, we studied the immunosuppressive properties of human BM-MSC and CMPC and their extracellular vesicles (EVs) in co-culture with activated T cells. Proliferation of T cells, measured by carboxyfluorescein succinimidyl ester dilution, was significantly reduced in the presence of BM-MSC and CMPC. The inflammatory cytokine panel of the T cells in co-culture, measured by Luminex assay, changed, with strong downregulation of IFN-gamma and TNF-alpha. The effect on proliferation was observed in both direct cell contact and transwell co-culture systems. Transfer of conditioned medium to unrelated T cells abrogated proliferation in these cells. EVs isolated from the conditioned medium of BM-MSC and CMPC prevented T cell proliferation in a dose-dependent fashion. Progenitor cells presence induces up- and downregulation of multiple previously unreported pathways in T cells. In conclusion, both BM-MSC and CMPC have a strong capacity for in vitro immunosuppression. This effect is mediated by paracrine factors, such as extracellular vesicles. Besides proliferation, many additional pathways are influenced by both BM-MSC and CMPC. PMID- 30003153 TI - Comparative genomic analysis of eutherian adiponectin genes. AB - The present study proposed updated and standardized classification and nomenclature of eutherian adiponectin genes implicated in regulation of systemic metabolism and inflammation and activation of classical complement pathway. The revisions of comprehensive adiponectin gene data sets used eutherian comparative genomic analysis protocol and public reference genomic sequence assemblies. Among 438 potential coding sequences, the tests of reliability of eutherian public genomic sequences annotated most comprehensive curated third-party data gene data set of eutherian adiponectin genes that included 211 complete coding sequences. There were 18 major gene clusters of eutherian adiponectin genes described, one of which included evidence of differential gene expansions. For example, the present analysis initially described human ADIF2 and ADIR genes. Finally, the tests of protein molecular evolution using relative synonymous codon usage statistics confirmed protein primary structure similarities between eutherian adiponectins and tumor necrosis factor ligands. PMID- 30003154 TI - Integrating species-centric and geomorphic-centric views of interior least tern and piping plover habitat selection. AB - The Federally endangered interior least tern (Sterna antillarum athalassos) and threatened piping plover (Charadrius melodus) nest on emergent sandbars in several braided rivers in the USA. Previous habitat selection and geomorphic investigations identified a relationship between channel width and nesting incidence. Species-centric analyses indicate selection for the widest available channels whereas geomorphic-centric analyses indicate the probability of species occurrence was higher in narrow channels that better supported suitable sandbar habitat. Given the disparate conclusions from each of these perspectives, we examined species use in relation to channel-width metrics across segments of the Platte, Niobrara, and Loup Rivers from both perspectives. We found the probability of nesting incidence increased with increased maximum unvegetated channel width in all river segments. However, maximum unvegetated width decreased with increased total channel width once total width exceeded 300 m in the central Platte River and 500 m in all other river segments as did the probability that the channel was free of permanently-vegetated islands. Channels within the Lower Platte, Loup and Niobrara River systems with total widths of 500-800 m appear to be both wide enough to have a high probability of nesting incidence and narrow enough to be free of vegetated islands. Actions that affect channels with total, bank-to-bank widths of <500 m and >800 m would likely have a small influence on species use while actions that change the width characteristics of 500-800 m channels could have a strong negative or positive influence on species use. Integrating species- and geomorphic-centric views into a single analysis provided a fuller picture of the relationship between species use and channel-width metrics. PMID- 30003151 TI - Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations. AB - Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient with regional recurrence, and implanted in the anterior gastric wall of nude mice. The GIST PDOX mice were randomized into 3 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration [p.o.], daily, for 3 weeks); G3, S. typhimurium A1-R group (intravenous [i.v.] injection, weekly, for 3 weeks). All mice from each group were sacrificed on day 22. Relative tumor volume was estimated by laparotomy on day 0 and day 22. Body weight of the mouse was evaluated 2 times per week. We found that S. typhimurium A1-R significantly reduced tumor growth in contrast to the untreated group (P = 0.001). In addition, we found that S. typhimurium A1-R was more effective compared to imatinib (P = 0.013). Furthermore, Imatinib was not significantly effective compared to the control group (P = 0.462). These results indicate that S. typhimurium A1-R may be new effective therapy for imatinib-resistant GIST and therefore a good candidate for clinical development of this disease. PMID- 30003155 TI - Guided bone regeneration with polypropylene barrier in rabbit's calvaria: A preliminary experimental study. AB - Objectives: This study aimed to evaluate the bone formation process in experimental defects created on rabbit calvarial, in which one of the bone defects was covered by the impermeable membrane before suturing the skin flap, while the other was closed only by the cutaneous flap. The experimental holes were filled only by the blood clot. Material and methods: Sixteen New Zealand female rabbits weighing between 3.5 and 4 kg were used. Two experimental bone defects were made in the rabbit calvarial. The holes were filled only with the blood clot and one of them was covered with an impermeable polypropylene membrane. A histological analysis was made at 21 and 42 days following the surgery. Histological evaluation consisted of the following: 1. inflammatory process; 2. Bone repair; 3. Bone remodeling; 4. Presence of osteoid matrix and mineralization, and 5. Formation of hematopoietic tissue. Each characteristic was analyzed semi quantitatively. Results: There was a statistical difference between the test and the control group at 21 days of healing in the following items: presence of cementation line (p = 0.012), presence of osteoid tissue (p = 0.012), and trabecular bone tissue development and mineralization (p = 0.012). A greater amount of lamellar bone tissue (mature) was also observed in the test group compared to the control group. Conclusion: The semiquantitative analysis showed that at 21 days there was a superiority of the repair process in the test group; at 42 days there was no significant difference in bone formation between the two groups; and that the polypropylene membrane is feasible to be used in GBR. Clinical significance: The impermeable polypropylene barrier is feasible for use in the guided bone regeneration technique. It can be used only on the blood clot, without the need for grafting, and can be easily removed a few days after surgery. These results are unprecedented. PMID- 30003156 TI - How gaze time on screen impacts the efficacy of visual instructions. AB - This article explores whether GTS (gaze time on screen) can be useful as an engagement measure in the screen mediated learning context. Research that exemplifies ways of measuring engagement in the on-line education context usually does not address engagement metrics and engagement evaluation methods that are unique to the diverse contemporary instructional media landscape. Nevertheless, unambiguous construct definitions of engagement and standardized engagement evaluation methods are needed to leverage instructional media's efficacy. By analyzing the results from a mixed methods eye-tracking study of fifty-seven participants evaluating their visual and assembly performance levels in relation to three visual, procedural instructions that are versions of the same procedural instruction, we found that the mean GTS-values in each group were rather similar. However, the original GTS-values outputted from the ET-computer were not entirely correct and needed to be manually checked and cross validated. Thus, GTS appears not to be a reliable, universally applicable automatic engagement measure in screen-based instructional efforts. Still, we could establish that the overall performance of learners was somewhat negatively impacted by lower than mean GTS scores, when checking the performance levels of the entire group (N = 57). When checking the stimuli groups individually (N = 17, 20, 20), the structural diagram group's assembly time durations were positively influenced by higher than mean GTS-scores. PMID- 30003157 TI - Antitumour, acute toxicity and molecular modeling studies of 4-(pyridin-4-yl)-6 (thiophen-2-yl) pyrimidin-2(1H)-one against Ehrlich ascites carcinoma and sarcoma 180. AB - In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1H) one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 MUM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (EAT, solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile since all 51 computed physicochemical parameters fall within the recommended range for 95% of known drugs. The current study provides insight for further investigation of the antitumour potential of the molecule. PMID- 30003158 TI - Study of diatom assemblages in Sundarbans mangrove water based on light microscopy and rbcL gene sequencing. AB - Sundarbans, the world's largest mangrove deltaic region, is one of the most productive ecosystems in tropical and subtropical latitudes and also serve as a nursery ground for rich coastal fisheries. In this study, we highlighted diatom assemblages from the Indian part of Sundarbans Biosphere Reserve (SBR) area for the first time based on light microscopy and rbcL gene sequencing and phylogeny. In total, 15 diatom species (11 centric forms and 4 pennate forms) were documented using light microscopy, and 3 major clades of diatoms were detected in rbcL phylogeny. Out of 15 diatom species, 7 were the first record from Sundarbans mangrove water. One of the species, Thalassiosira ferelineata Hasle and Fryxell, was reported for the first time in an Asian mangrove ecosystem based on light microscopy. Our study suggests the importance of establishing cultures and their polyphasic taxonomy are the future necessity to create an authenticated diatom database from mangrove water, which is still overlooked globally. PMID- 30003159 TI - Characterising shoot and root system trait variability and contribution to genotypic variability in juvenile cassava (Manihot esculenta Crantz) plants. AB - The development of cassava genotypes with root system traits that increase soil resource acquisition could increase yields on infertile soils but there are relatively few work that has quantified cassava root system architecture (RSA). We used an easily adaptable and inexpensive protocol to: (i) measure genotypic variation for RSA and shoot traits of a range of cassava genotypes; and (ii) identify candidate variables that contribute the largest share of variance. Cassava genotypes were grown in soil-filled pots, maintained at 70% field capacity. Shoot and RSA traits were measured on plants grown up to 30, 45 and 60 days. Multivariate analysis was used to determine major traits contributing to variation. The study showed that cassava roots are adventitious in origin consisting of a main root axis and orders of lateral roots, and therefore the historically used term "fibrous roots" are redundant currently not contributing to clarity. There were significant differences (P < 0.05) for traits evaluated. The highest relative root growth rate occurred over the first 30 days and ranged from 0.39 to 0.48 cm day-1. Root fresh weight was significantly correlated with other traits, including root length (r = 0.79), leaf area (r = 0.72), number of lower nodal roots (r = 0.60), indicating that direct selection based on these traits might be sufficient to improve root biomass. Up to the first six principal components explained over 80% of the total variation among the genotypes for the traits measured at 30, 45 and 60 days. Leaf area, root diameter and branching density-related traits were the most important traits contributing to variation. Selection of cassava genotypes based on shoot and root biomass, root diameter and branching density at juvenile growth stage could be successful predictors of nutrient and water-use efficiency in the field. Further studies are required to relate studied juvenile cassava root traits with the performance of field-grown mature plant with regard to drought, nutrient-use efficiency and yield. PMID- 30003160 TI - Autoradiographic analysis of internal plutonium radiation exposure in Nagasaki atomic bomb victims. AB - Background: Radiation doses received by Hiroshima and Nagasaki atomic bomb survivors has been evaluated from data related only to external exposure because there was no reliable evidence for internal exposure in atomic bomb victims. However, we assumed that the contribution of internal exposure cannot be ruled out. Methods: Autoradiography was carried out with the 70-year old paraffin embedded specimens taken from Nagasaki atomic bomb victims who died within 5 months after the bombing. After exposure to photo emulsion for 6 months alpha tracks were revealed in the specimens. We confirmed the alpha-tracks were emitted from deposited plutonium (Pu) in reference to the track length of the 8.787 MeV alpha-particle of thorium series from Polonium-212. Radioactivity concentration of Pu was obtained by counting alpha-tracks. The absorbed dose of each cell nucleus penetrated by an alpha-particle was estimated by calculating the absorbed energy from the particle. Results: Using old paraffin embedded sections processed about 70 years ago, we demonstrated for the first time that conditions in the aftermath of the bombing led to internal exposure to alpha-particles emitted from Pu, the fissile material of the Nagasaki atomic bomb. Dose rate of internal exposure was higher in the victims exposed outdoors than those indoors. Radioactivity concentration was relatively uniform among organs examined in a victim. Conclusion: Pu was deposited in the bodies of the Nagasaki A-bomb victims presumably via various routes. Organ dose from Pu of the Nagasaki A-bomb victims studied was during their surviving period, which is lower compared with external exposure. However, the impact to the individual cell nucleus by a single alpha particle might not be negligible, It would be meaningful; to analyze the relationship of the impact of internal exposure at the cellular level and organ dose. The 70-year old pathological specimens utilized in our study are an invaluable source for understanding internal radiation exposure and are crucial in elucidating experimentally unreproducible phenomena. PMID- 30003162 TI - Identification and characterization of microRNAs from the tube foot in the sea urchin Strongylocentrotus intermedius. AB - MicroRNAs (miRNAs) play critical roles in regulating many bio-processes of eukaryotes. The sea urchin Strongylocentrotus intermedius (an important fishery resource) is of great economic importance in Japan, North Korea, Russia, and China. In the current study, miRNAs of tube foot in S. intermedius were firstly identified and characterized. Data in this study can provide more genomic information for the further understanding of the complex regulation network in sea urchins and present a new way for monitoring the health status of cultured sea urchins. PMID- 30003161 TI - Single cell expression analysis of primate-specific retroviruses-derived HPAT lincRNAs in viable human blastocysts identifies embryonic cells co-expressing genetic markers of multiple lineages. AB - Chromosome instability and aneuploidies occur very frequently in human embryos, impairing proper embryogenesis and leading to cell cycle arrest, loss of cell viability, and developmental failures in 50-80% of cleavage-stage embryos. This high frequency of cellular extinction events represents a significant experimental obstacle challenging analyses of individual cells isolated from human preimplantation embryos. We carried out single cell expression profiling of 241 individual cells recovered from 32 human embryos during the early and late stages of viable human blastocyst (VHB) differentiation. Classification of embryonic cells was performed solely based on expression patterns of human pluripotency-associated transcripts (HPAT), which represent a family of primate specific transposable element-derived lincRNAs highly expressed in human embryonic stem cells and regulating nuclear reprogramming and pluripotency induction. We then validated our findings by analyzing transcriptomes of 1,708 individual cells recovered from more than 100 human embryos and 259 mouse cells from more than 40 mouse embryos at different stages of preimplantation embryogenesis. HPAT's expression-guided spatiotemporal reconstruction of human embryonic development inferred from single-cell expression analysis of VHB differentiation enabled identification of telomerase-positive embryonic cells co expressing key pluripotency regulatory genes and genetic markers of three major lineages. Follow-up validation analyses confirmed the emergence in human embryos prior to lineage segregation of telomerase-positive cells co-expressing genetic markers of multiple lineages. Observations reported in this contribution support the hypothesis of a developmental pathway of creation embryonic lineages and extraembryonic tissues from telomerase-positive pre-lineage cells manifesting multi-lineage precursor phenotype. PMID- 30003163 TI - Automated analysis of images for molecular quantification in immunohistochemistry. AB - The quantification of the expression of different molecules is a key question in both basic and applied sciences. While protein quantification through molecular techniques leads to the loss of spatial information and resolution, immunohistochemistry is usually associated with time-consuming image analysis and human bias. In addition, the scarce automatic software analysis is often proprietary and expensive and relies on a fixed threshold binarization. Here we describe and share a set of macros ready for automated fluorescence analysis of large batches of fixed tissue samples using FIJI/ImageJ. The quantification of the molecules of interest are based on an automatic threshold analysis of immunofluorescence images to automatically identify the top brightest structures of each image. These macros measure several parameters commonly quantified in basic neuroscience research, such as neuropil density and fluorescence intensity of synaptic puncta, perisomatic innervation and col-localization of different molecules and analysis of the neurochemical phenotype of neuronal subpopulations. In addition, these same macro functions can be easily modified to improve similar analysis of fluorescent probes in human biopsies for diagnostic purposes based on the expression patterns of several molecules. PMID- 30003164 TI - Hypothalamic gene expression changes in F1 California mice (Peromyscus californicus) parents developmentally exposed to bisphenol A or ethinyl estradiol. AB - Bisphenol A (BPA) is a pervasive industrial chemical used in many common household items. To examine how early exposure to BPA and ethinyl estradiol (EE, estrogen in birth control pill) might affect biparental care, effects of these chemicals in male and female California mice (Peromyscus californicus), who are monogamous and biparental, were examined. California mice exposed during pre- and peri-natal life to BPA at an environmentally relevant concentration or EE show later disrupted biparental behaviors. The hypothalamus is an important brain region for regulating parental behaviors. Thus, it was hypothesized compromised biparental care might be partially due to hypothalamic gene alterations. To address this question, brains from F1 parenting female and male California mice from controls, BPA- and EE-exposed groups were collected at postnatal day (PND) 2, and RNA was isolated from hypothalamic micropunches. Gene expression was examined in this brain region for genes affected by BPA exposure and attributed to governing parental care in rodents and humans. BPA-exposed California mice showed increased hypothalamic expression of Kiss1, Esr1 and Esr2 relative to AIN control and EE-exposed parents in the case of Esr2. Notably, current studies represent the first report to show that early exposure to BPA can induce longstanding effects on hypothalamic gene expression in parenting male and female rodents. Absence of such hypothalamic gene expression changes in EE-exposed parents indicates early BPA exposure may induce later transcriptomic effects through estrogen receptor-independent pathways. BPA-driven changes in hypothalamic function of California mice might contribute to decreased biparental investment, which could result in F2 multigenerational effects. PMID- 30003165 TI - The impact of Staphylococcus aureus genomic variation on clinical phenotype of children with acute hematogenous osteomyelitis. AB - Background: Children with acute hematogenous osteomyelitis (AHO) have a broad spectrum of illness ranging from mild to severe. The purpose of this study is to evaluate the impact of genomic variation of Staphylococcus aureus on clinical phenotype of affected children and determine which virulence genes correlate with severity of illness. Methods: De novo whole genome sequencing was conducted for a strain of Community Acquired Methicillin Resistant Staphylococcus aureus (CA MRSA), using PacBio Hierarchical Genome Assembly Process (HGAP) from 6 Single Molecule Real Time (SMRT) Cells, as a reference for DNA library assembly of 71 Staphylococcus aureus isolates from children with AHO. Virulence gene annotation was based on exhaustive literature review and genomic data in NCBI for Staphylococcus aureus. Clinical phenotype was assessed using a validated severity score. Kruskal-Wallis rank sum test determined association between clinical severity and virulence gene presence using False Discovery Rate (FDR), significance <0.01. Results: PacBio produced an assembled genome of 2,898,306 bp and 2054 Open Reading Frames (ORFs). Annotation confirmed 201 virulence genes. Statistical analysis of gene presence by clinical severity found 40 genes significantly associated with severity of illness (FDR <=0.009). MRSA isolates encoded a significantly greater number of virulence genes than did MSSA (p < 0.0001). Phylogenetic analysis by maximum likelihood (PAML) demonstrated the relatedness of genomic distance to clinical phenotype. Conclusions: The Staphylococcus aureus genome contains virulence genes which are significantly associated with severity of illness in children with osteomyelitis. This study introduces a novel reference strain and detailed annotation of Staphylococcus aureus virulence genes. While this study does not address bacterial gene expression, a platform is created for future transcriptome investigations to elucidate the complex mechanisms involved in childhood osteomyelitis. PMID- 30003166 TI - Unraveling the in vitro antitumor activity of Vismia baccifera against HepG2: role of hydrogen peroxide. AB - Currently natural products derived from plants are receiving huge attention because of their antitumor activities. In previous work we reported that an aqueous leaf extract of Vismia baccifera induced toxicity in HepG2. The present study focuses on the mechanisms of the cytotoxic actions induced by the extract. Results showed that V. baccifera was innocuous in non-transformed human HH4 hepatocytes. In HepG2 it caused deregulation of antioxidant status (increasing superoxide dismutase expression and decreasing glutathione levels and glutathione peroxidase activity) and accumulation of reactive oxygen species, particularly hydrogen peroxide. The extract induced a) cell cycle arrest at G2/M phase, b) phosphorylation of ATM (protein kinase ataxia-telangiectasia mutated) and gammaH2AX (gamma-histone family 2A variant), c) caspase-3 activation, and e) deregulation of the Bax/Bcl family, increasing pro-apoptotic proteins. ATM did not seem to be involved in gammaH2AX activation. Co-incubation with catalase prevented the alterations elicited by V. baccifera in HepG2. Taking together, these results indicate that hydrogen peroxide mediates the HepG2 cytotoxic response and provide evidence for more in-depth studies of the signaling involved. PMID- 30003167 TI - Short and long arm cast and pain after discharge in children who underwent reduction of distal forearm fracture in the Emergency Department: A study protocol for a randomized comparative effectiveness study. AB - Distal forearm fracture is the most common fracture in childhood. Patients with this type of injury suffer from meaningful pain after Emergency Department (ED) discharge. Previous studies demonstrated that short arm (below-the-elbow) casts perform as well as long arm (above-the-elbow) casts for maintaining the reduction of distal forearm fractures, with a similar rate of complications. Consequently, short casts are the commonly used method of immobilization after closed reduction of a distal forearm fractures in children older than 4 years. However, short casts carry a potential disadvantage; since they cannot prevent supination in a wrist that is held in pronation, and vice versa, their use might be associated with pain. We initiated this study to examine the effect of the type of casting on post discharge pain. We will conduct an open-label randomized, controlled trial comparing short cast immobilization with long cast immobilization in children who had a reduction of distal forearm fracture in the ED. Our hypothesis is that children with distal forearm fractures who are treated with a long cast, experience less pain during the first 48 h after ED discharge than children who are treated with a short cast. PMID- 30003168 TI - A review of strategies used to retain participants in clinical research during an infectious disease outbreak: The PREVAIL I Ebola vaccine trial experience. AB - Introduction: This article describes a retrospective review of participant follow up and retention strategies in the Partnership for Research on the Ebola Virus in Liberia (PREVAIL) I Vaccine Trial. It illustrates and analyzes strategies used to retain participants in an emergency clinical research response vaccine trial conducted during the 2014 Ebola outbreak in Liberia. Methods: An anecdotal review of participant retention strategies developed and employed during the PREVAIL I vaccine trial. Results: Though other factors likely contributed to the high retention rate of trial participants, the unique PREVAIL I follow-up process described resulted in an exceptionally high participant retention rate (97.8%) through 12 months of follow-up, increased the ability to obtain meaningful trial results, and provided a platform through which to respond to social issues in an emergency clinical research response setting. Conclusion: Successful strategies were developed and employed in the PREVAIL I vaccine trial that resulted in extraordinarily high participant retention and follow-up rates during an infectious disease outbreak. This review illustrates that employing host country social mobilization concepts within a modified clinical research management framework is highly correlated to elevated rates of retention and minimal loss to follow-up. These strategies also contributed to increased data quality and enhanced adherence to protocol requirements. The increased ability to respond to social issues such as stigma, job retention and relationship conflicts was an additional and significant benefit of this follow-up methodology. PMID- 30003170 TI - Seamless phase IIa/IIb adaptive design with the same primary endpoint for proof of concept and dose finding. AB - This paper considers combining a proof of concept (POC) study and a dose finding (DF) study where the POC and the DF share the same primary endpoint. An example based on real study conditions shows that compared to a conventional design the proposed adaptive design tests more active doses, with a smaller sample size and a shorter overall duration leading to a budget saving of 30% in study operations. PMID- 30003169 TI - The impact of probiotics' administration on glycemic control, body composition, gut microbiome, mitochondria, and other hormonal signals in adolescents with prediabetes - A randomized, controlled trial study protocol. AB - Background: Recent studies have demonstrated that a significant proportion of adolescents exhibit abdominal obesity in early-middle adolescence, and impaired glucose metabolism. Dysregulation of glucose metabolism is aggravated by the existing osteosarcopenia not only in obese but also in overweight youth. Biochemical inflammation, derived from glucose metabolism dysregulation, in combination with increased stress levels lead to the accumulation of reactive oxygen species, also known as ROS, which seem to afflict the integrity of the gastrointestinal wall, gut mucosa, and commensal, intestinal gut microflora. The current scientific protocol aims to assess the administration of probiotics in prediabetic adolescents in relation with their glycemic control, body composition, and intestinal microbiome. Methods/Design: This is a study protocol of a two-armed RCT, that recruits adolescents with prediabetes, who will receive either a 4-month, life-style intervention, or a life-style intervention along with a probiotic supplement. The primary outcome is the differences in gut microbiome synthesis, body composition analysis parameters, and concentrations of hormones, before and after the intervention. Discussion: This study aims to halt the progression of obesity and diabetes and aspires to contribute new evidence for upgraded treatment of obesity and diabetes. Trial registration: Australian New Zealand Clinical Trial Registry (ACTRN12615000470594). PMID- 30003171 TI - Impact of informed consent content and length on recruitment of older adults into a community based primary prevention trial. AB - Aims: To compare recruitment, refusal and randomisation rates of older adults into a general practice-based clinical trial with two versions (varied format, content and language) of the Participant Information and Consent Form (PICF). Methods: This prospective PICF study was conducted within the STAREE (STAtins in Reducing Events in the Elderly) clinical trial. Participants phone screened between October 2015 to February 2016 formed Group 1 and were mailed the extended PICF version and participants phone screened between October 2016 to February 2017 formed Group 2 and were mailed the shortened PICF version. Participants who attended a subsequent baseline screening visit were guided through a comprehensive informed consent process. Results: During the screening phase of the trial, the likelihood of refusing trial participation was lower in Group 2 compared to Group 1 equating to an overall 23% reduction in risk (RR 0.77, P = 0.005, 95% CI 0.62-0.95). Group 2 had a 6.4% higher randomisation rate compared with Group 1 (65.3% versus 58.9% respectively) but this difference was not statistically significant. Factors associated with trial participation were male gender, age between 70 and 75 years and living alone (all p < .0.05). Conclusions: Whilst avoiding lengthy and complex PICF documents may assist with initial trial engagement, it needs to be supplemented with other strategies to support ongoing trial interest to randomisation and beyond. Participants refused trial participation throughout the screening phase indicating that the PICF was only one factor among several affecting an individual's decision to participate in this clinical trial. PMID- 30003172 TI - Researchers' experiences with and perceptions of returning results to participants: Study protocol. AB - Background: Health research participants want to receive the results from research studies in which they have participated, and health research funding agencies encourage the returning of results to research participants. However, researchers rarely return results to research participants. This study protocol aims to fill the significant gap in knowledge that exists regarding experiences, perceptions, and challenges health researchers have with returning results to research participants. Design: The study will use a mixed-methods concurrent triangulation design that will collect qualitative and quantitative data in one simultaneous phase to allow researchers to utilize each type of data to corroborate the findings from the other. The research team developed a mixed methods survey to assess the experiences, perceptions, and challenges health researchers have with returning results to research participants. Method: The survey includes both quantitative and qualitative (open-ended) questions and will be implemented online and will take approximately 10-15 min for respondents to complete. The survey is divided into four topics areas, which include respondents': 1) general opinion of returning results to participants in health research studies, 2) experiences with a specific study in which they did not return results to participants, 3) perceptions of specific challenges they face in returning results to participants, and 4) demographic characteristics and professional background information. Summary: The study to be conducted will address knowledge gaps related to researchers' experiences, perceptions, and challenges with returning research results. The study is an important step toward pragmatic solutions that can improve researchers' ability to return results to participants. PMID- 30003174 TI - Submacular sclerosing capillary hemangioblastoma. AB - Purpose: To report a case of submacular cystic lesion that turned out to be a sclerosing capillary hemangioblastoma. The retinal capillary hemangioblastoma may arise as a part of von Hippel-Lindau syndrome 1 however, they may occur as an isolated entity 2, but submacular capillary hemangioblastoma has never been reported. Observations: A case of a 56-year-old female who presented with a right yellow submacular lesion. The mass was excised via pars-plana vitrectomy and histopathological assessment revealed a submacular sclerosing capillary hemangioblastoma. Conclusion: and importance: The capillary hemangioblastoma is a benign vascular tumor that may arise submacularly and is not necessarily associated with von Hippel-Lindau disease. It is difficult to be differentiated clinically from other submacular lesions but the possibility should be considered. PMID- 30003173 TI - Main changes in European Clinical Trials Regulation (No 536/2014). AB - The new Regulation (EU) No. 536/2014 for clinical trials of medicinal products for human is part of a European regulatory framework in which the European Commission has wished to give a strong impetus to scientific research and industrial progress. It is a new regulation that fills a series of regulatory gaps in the Clinical Trials through the creation of a uniform framework for the authorization of clinical trials by all interested Member States with a single assessment of the results. The Regulation thus facilitates cross-border cooperation to make the clinical tests wider and encourage the development of special treatments, for example for rare diseases, but above all streamlines the rules on clinical trials across European Union (EU), introducing simplified rules for experimentation so-called 'low level of intervention', on which much has been discussed and still arouses concern, providing for authorized medicines or used off-label in the presence of scientific evidence published on efficacy and safety and to benefit from they will be mainly the pediatric and oncological therapeutic areas. The applications and any communication will be submitted paperlessly via a new electronic EU portal. The complex processing procedures and shorter time limits are to be stressed in comparison to the previously valid regulations. This is a major challenge for all stakeholders, but on the other hand it should contribute to the future role of the EU in the development of innovative medicines. PMID- 30003175 TI - Spontaneous retinal-choroidal anastomosis in a case of branch retinal vein occlusion. AB - Purpose: To report a case of a patient affected by branch retinal vein occlusion (BRVO) showing a possible spontaneous retinal-choroidal anastomosis (RCA) at the level of the fovea. Observations: A 72 years old male patient with diagnosis of BRVO of left eye (LE) one year before came to our observation for a follow-up visit.The patient underwent a complete ophthalmologic examination, including fluorescein angiography, structural optical coherence tomography (OCT), OCT Angiography (OCT-A). Interestingly, OCT-A revealed the presence of blood flow suggestive of single collateral vessel descending from the deep capillary plexus up to and possibly below a hyperreflective subfoveal deposit. Conclusions and importance: We hypothesize that it can represent a RCA, starting from retinal capillaries and reaching the choriocapillary and choroidal vessels in order to allow a vascular shunt between the 2 circulations and thus a new passage for the blood flow. A similar condition is represented by laser-induced RCA for the treatment of non-ischemic central retinal vein occlusion in order to establish a new passage for the blood flow. PMID- 30003176 TI - Corneal infiltration and xanthoma formation in mycosis fungoides. AB - Purpose: To report a case of corneal infiltration and xanthoma formation in mycosis fungoides (cutaneous T-cell lymphoma). Observations: A middle aged Japanese man with mycosis fungoides (MF) involving the face was referred to Ophthalmology for evaluation of unilateral, painless conjunctival injection. Biopsy of the conjunctiva revealed a malignant T cell population consistent with MF tumor invasion. Years later, he returned following several episodes of infectious keratitis with a painless, yellow, rapidly forming mass in the left eye over two weeks. Corneal biopsy showed foamy histiocytes and positive staining for CD68, and a diagnosis of corneal xanthoma was made. Conclusions and importance: Severe ocular surface disease can rarely occur in MF by direct invasion of tumor cells. Corneal infiltration and xanthoma development may be avoidable by careful monitoring for infectious keratitis in patients with conjunctival involvement, as in our case. PMID- 30003177 TI - Conservative management of penetrating ocular trauma caused by a nail gun. AB - Purpose: To report the conservative management of a penetrating ocular trauma caused by a nail gun with a six-month follow up. Observations: A 21 year-old healthy female suffered an ocular penetrating trauma with a nail gun. She presented with a metallic foreign body that partially entered her left eye through the nasal sclera via pars plana, 3 mm posterior to the limbus, but did not reach the retina. Surgical removal of the foreign body and closure of the scleral wound, without vitrectomy, was performed 16 h after the injury. Intravitreal prophylactic antibiotic was administered. Retinal atrophy developed in the areas that had commotio retinae at presentation, but no further complications were observed. Conclusions: and Importance: Pars plana vitrectomy may not be necessary in all penetrating ocular traumas with intraocular foreign body, as long as the foreign body is accessible from the exterior of the eye and there are no other conditions (such as vitreous hemorrhage, retinal detachment, endophthalmitis, etc) that are an indication for vitrectomy. PMID- 30003178 TI - Therapeutic neovascularization promoted by injectable hydrogels. AB - The aim of therapeutic neovascularization is to repair ischemic tissues via formation of new blood vessels by delivery of angiogenic growth factors, stem cells or expansion of pre-existing cells. For efficient neovascularization, controlled release of growth factors is particularly necessary since bolus injection of molecules generally lead to a poor outcome due to inadequate retention within the injured site. In this regard, injectable hydrogels, made of natural, synthetic or hybrid biomaterials, have become a promising solution for efficient delivery of angiogenic factors or stem and progenitor cells for in situ tissue repair, regeneration and neovascularization. This review article will broadly discuss the state-of-the-art in the development of injectable hydrogels from natural and synthetic precursors, and their applications in ischemic tissue repair and wound healing. We will cover a wide range of in vitro and in vivo studies in testing the functionalities of the engineered injectable hydrogels in promoting tissue repair and neovascularization. We will also discuss some of the injectable hydrogels that exhibit self-healing properties by promoting neovascularization without the presence of angiogenic factors. PMID- 30003180 TI - Antibiofilm peptides against biofilms on titanium and hydroxyapatite surfaces. AB - Biofilms are the main challenges in the treatment of common oral diseases such as caries, gingival and endodontic infection and periimplantitis. Oral plaque is the origin of microbes colonizing in the form of biofilms on hydroxyapatite (tooth) and titanium (dental implant) surfaces. In this study, hydroxyapatite (HA) and titanium (Ti) disks were introduced, and their surface morphology was both qualitatively and quantitatively analyzed by a scanning electron microscope (SEM) and atomic force microscope (AFM). The average roughness of Ti disks (77.6 +/- 18.3 nm) was less than that of HA (146.1 +/- 38.5 nm) (p < 0.05). Oral multispecies biofilms which were cultured on Ti and HA disks for 6 h and three weeks were visualized by SEM. We investigated the ability of two new antibiofilm peptides, DJK-5 and 1018, to induce killing of bacteria in oral multispecies biofilms on Ti and HA disks. A 6-h treatment by DJK-5 and 1018 (2 or 10 MUg/mL) significantly reduced biomass of the multispecies biofilms on both Ti and HA disks. DJK-5 was able to kill more bacteria (40.4-75.9%) than 1018 (30.4-67.0%) on both surfaces (p < 0.05). DJK-5 also led to a more effective killing of microbes after a 3-min treatment of 3-day-old and 3-week-old biofilms on Ti and HA surfaces, compared to peptide 1018 and chlorhexidine (p < 0.05). No significant difference was found in the amount of biofilm killing between Ti and HA surfaces. Both peptide DJK-5 and 1018 may potentially be used as effective antibiofilm agents in clinical dentistry. PMID- 30003179 TI - Bioactive hydrogels for bone regeneration. AB - Bone self-healing is limited and generally requires external intervention to augment bone repair and regeneration. While traditional methods for repairing bone defects such as autografts, allografts, and xenografts have been widely used, they all have corresponding disadvantages, thus limiting their clinical use. Despite the development of a variety of biomaterials, including metal implants, calcium phosphate cements (CPC), hydroxyapatite, etc., the desired therapeutic effect is not fully achieved. Currently, polymeric scaffolds, particularly hydrogels, are of interest and their unique configurations and tunable physicochemical properties have been extensively studied. This review will focus on the applications of various cutting-edge bioactive hydrogels systems in bone regeneration, as well as their advantages and limitations. We will examine the composition and defects of the bone, discuss the current biomaterials for bone regeneration, and classify recently developed polymeric materials for hydrogel synthesis. We will also elaborate on the properties of desirable hydrogels as well as the fabrication techniques and different delivery strategies. Finally, the existing challenges, considerations, and the future prospective of hydrogels in bone regeneration will be outlined. PMID- 30003182 TI - General relativistic magnetohydrodynamics simulations of prompt-collapse neutron star mergers: The absence of jets. AB - Inspiraling and merging binary neutron stars are not only important source of gravitational waves, but also promising candidates for coincident electromagnetic counterparts. These systems are thought to be progenitors of short gamma-ray bursts (sGRBs). We have shown previously that binary neutron star mergers that undergo delayed collapse to a black hole surrounded by a weighty magnetized accretion disk can drive magnetically powered jets. We now perform magnetohydrodynamic simulations in full general relativity of binary neutron stars mergers that undergo prompt collapse to explore the possibility of jet formation from black hole-light accretion disk remnants. We find that after t - tBH ~26(MNS/1.8 M?) ms (MNS is the ADM mass) following prompt black hole formation, there is no evidence of mass outflow or magnetic field collimation. The rapid formation of the black hole following merger prevents magnetic energy from approaching force-free values above the magnetic poles, which is required for the launching of a jet by the usual Blandford-Znajek mechanism. Detection of gravitational waves in coincidence with sGRBs may provide constraints on the nuclear equation of state (EOS): the fate of an NSNS merger-delayed or prompt collapse, and hence the appearance or nonappearance of an sGRB-depends on a critical value of the total mass of the binary, and this value is sensitive to the EOS. PMID- 30003181 TI - Multimodality quantitative assessments of myocardial perfusion using dynamic contrast enhanced magnetic resonance and 15O-labelled water positron emission tomography imaging. AB - Kinetic modelling of myocardial perfusion imaging data allows the absolute quantification of myocardial blood flow (MBF) and can improve the diagnosis and clinical assessment of coronary artery disease (CAD). Positron emission tomography (PET) imaging is considered the reference standard technique for absolute quantification, whilst oxygen-15 (15O)-water has been extensively implemented for MBF quantification. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has also been used for MBF quantification and showed comparable diagnostic performance against (15O)-water PET studies. We investigated for the first time the diagnostic performance of two different PET MBF analysis softwares PMOD and Carimas, for obstructive CAD detection against invasive clinical standard methods in 20 patients with known or suspected CAD. Fermi and distributed parameter modelling-derived MBF quantification from DCE-MRI was also compared against (15O)-water PET, in a subgroup of 6 patients. The sensitivity and specificity for PMOD was significantly superior for obstructive CAD detection in both per vessel (0.83, 0.90) and per patient (0.86, 0.75) analysis, against Carimas (0.75, 0.65), (0.81, 0.70), respectively. We showed strong, significant correlations between MR and PET MBF quantifications (r=0.83-0.92). However, DP and PMOD analysis demonstrated comparable and higher haemodynamic differences between obstructive versus (no, minor or non)-obstructive CAD, against Fermi and Carimas analysis. Our MR method assessments against the optimum PET reference standard technique for perfusion analysis showed promising results in per segment level and can support further multi-modality assessments in larger patient cohorts. Further MR against PET assessments may help to determine their comparative diagnostic performance for obstructive CAD detection. PMID- 30003183 TI - GW170817, general relativistic magnetohydrodynamic simulations, and the neutron star maximum mass. AB - Recent numerical simulations in general relativistic magnetohydrodynamics (GRMHD) provide useful constraints for the interpretation of the GW170817 discovery. Combining the observed data with these simulations leads to a bound on the maximum mass of a cold, spherical neutron star (the TOV limit): Mmaxsph?2.74/beta , where beta is the ratio of the maximum mass of a uniformly rotating neutron star (the supramassive limit) over the maximum mass of a nonrotating star. Causality arguments allow beta to be as high as 1.27, while most realistic candidate equations of state predict beta to be closer to 1.2, yielding Mmaxsph in the range 2.16-2.28M?. A minimal set of assumptions based on these simulations distinguishes this analysis from previous ones, but leads a to similar estimate. There are caveats, however, and they are enumerated and discussed. The caveats can be removed by further simulations and analysis to firm up the basic argument. PMID- 30003185 TI - Novichok agents: a historical, current, and toxicological perspective. AB - The Novichok, or "newcomer" class of nerve agents are lesser characterized, weaponized organophosphate agents. The use of known Novichok agents in warfare is banned under the Chemical Weapons Convention of 1997. Novichok agents are considered more potent than VX gas and can be applied in unitary and binary forms. Like other nerve agents, Novichok agents irreversibly bind acetylcholinesterase and produce a cholinergic toxidrome. Uniquely, these agents are thought to also target neurons in the peripheral nervous system. Delayed treatment or massive exposure may therefore cause a debilitating neuropathy. The recent 2018 assassination attempt of Russian dissident Sergei Skripal and his daughter Yulia in the United Kingdom highlights the importance of recognizing the potential lethal effects of these nerve agents. Treatment of Novichok agent poisoning is similar to management of other nerve agents. Given increasing worldwide incidents attributed to chemical weapons such as Novichok agents, clinicians should know how to rapidly recognize symptoms of acute poisoning and administer life-saving antidotal therapy, when indicated. PMID- 30003186 TI - Advances in cancer immunotherapy for gastroenterological malignancy. PMID- 30003184 TI - Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board. AB - Purpose: Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. Methods: A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. Results: One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. Conclusion: The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy. PMID- 30003187 TI - Implementation of genomic medicine for gastrointestinal tumors. AB - Genomic medicine is an approach to take advantage of genomic data in medical practice and health care. The advancement of sequencing technologies has enabled the determination of individual genomes as well as the genome in neoplasms. In the field of human cancer, understanding genomic alterations in tumors and variations associated with drug responses has paved the way towards the development of new drugs and personalized medicine. International collaborations of cancer genome analyses have accumulated a huge body of information about somatic mutations, and identified new driver mutations and pathways in a wide range of cancers. In particular, a growing body of evidence has shown that information about mutations in neoplasms helps to assess the efficacy and resistance of anti-cancer drugs. Information about germline mutations associated with hereditary cancer has been shown to benefit patients by enabling early detection of their tumors and disease-specific treatment, as well as reducing the risk for those at risk. To promote personalized medicine in a more cost-effective and personalized way, further inter-institutional, nationwide, and international collaboration is needed. This article summarizes the background and current situation of genomic medicine in the field of gastrointestinal tumors to help physicians and medical coworkers by assisting their better understanding of genomic medicine and strengthening their confidence of its clinical use. PMID- 30003188 TI - Recent advancements in esophageal cancer treatment in Japan. AB - The 11th edition of the Japanese Classification of Esophageal Cancer (EC) was published in 2017. Some correction was made in the depth of tumor invasion to be consistent with the TNM classification by the Union for International Cancer Control (UICC). With regard to surgery, short-term safety and long-term effectiveness under thoracotomy/video-assisted thoracoscopic surgery are expected to be proven by the Japan Clinical Oncology Group (JCOG)1409 study. Results of nutritional management and countermeasures for adverse events not only during the perioperative period but also during EC chemotherapy were reported. From now on, the pursuit of low invasiveness and radicality is desired. Esophageal surgery is also expected to be safe at all institutions. To determine the optimal modality of preoperative treatment and a novel chemo(radio)therapy regimen for patients with distant metastasis, the results of the ongoing JCOG1109 and 0807 studies are being released. The effect of the addition of molecular targeted drugs on chemotherapy and concurrent chemoradiation has not yet improved overall survival. Immune checkpoint inhibitor drugs could offer a potential new treatment approach for patients with treatment-refractory advanced squamous cell carcinoma (SCC). The Cancer Genome Atlas Research Network reported the results of a comprehensive genome analysis and molecular analysis of SCC and adenocarcinoma of the esophagus. Further differentiation of SCC and adenocarcinoma by molecular characterization analysis may be useful for the development of clinical trials and targeted drug therapies as precision medicine. The era of ultimate minimally invasive surgery and personalized treatment has begun. Large, prospective studies will be required to confirm the value of these advancements. PMID- 30003189 TI - p53 molecular approach to diagnosis and treatment of esophageal squamous cell carcinoma. AB - We reviewed our research concerning p53 molecules in esophageal squamous cell carcinoma by focusing on the p53 molecular diagnosis and treatment of esophageal squamous cell carcinoma. First, we developed diagnostic tools to analyze serum p53 autoantibodies to detect esophageal squamous cell carcinoma. Positive rate was around 25% to 30% in all patients and around 20% even in stage I patients. Presence of serum p53 antibodies was significantly associated with overexpression of p53 protein in tumor cells. Seropositive patients were more likely than seronegative patients to be resistant to chemotherapy. Monitoring of the titer of serum p53 autoantibodies was useful in predicting patients at high risk of recurrence and/or treatment response. Second, using Ad5CMV-p53 for 10 patients with advanced esophageal squamous cell carcinoma, we carried out a phase I/II study of adenoviral-mediated p53 gene therapy. Although no complete response was observed, local tumor was stabilized in nine patients. No serious adverse events related to Ad5CMV-p53 were observed in these patients. One patient survived for over 5 years after the start of p53 gene therapy. Intratumoral injection of Ad5CMV-p53 is therefore safe, feasible, and biologically active when given in multiple doses to patients with esophageal squamous cell carcinoma. Our observations from these clinical studies indicate that p53 is a useful molecular target both in the diagnosis and in the treatment of esophageal squamous cell carcinoma. PMID- 30003190 TI - Immunotherapy for pancreatic cancer: Barriers and breakthroughs. AB - Immunotherapy is a rapidly growing field and represents a paradigm shift in the treatment of malignancies as it offers a new therapeutic approach beyond surgery, conventional chemotherapy, and radiation treatment. Targeting immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 and programmed death 1/programmed death ligand 1 has had immense clinical success resulting in sustained treatment response for a subset of patients with certain malignancies such as melanoma, non-small-cell lung cancer, urothelial carcinoma, squamous cell carcinoma of the head and neck, renal cell cancer, hepatocellular cancer, and metastatic colorectal cancer. Importantly, there has been limited success in the use of immunotherapy in the treatment of pancreatic cancer. Investigation into the complex tumor microenvironment of pancreatic cancer that is composed of immune cells, stromal cells, and extracellular matrix proteins has begun to shed light on important attributes of this microenvironment that act as barriers to the effective use of immunotherapy. In this review, we will discuss the progress that has been made in treating pancreatic cancer with immunotherapy, the barriers that have limited treatment success, and breakthroughs with combination treatments that hold promise for the future. PMID- 30003191 TI - Recent trends (2016-2017) in the treatment of inflammatory bowel disease. AB - Prevalence of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease has dramatically increased in Asian countries in the last three decades. In this period, many new medical therapies were introduced for the treatment of IBD, such as immunosuppressants, anti-tumor necrosis factor agents, leukocyte apheresis, anti-integrin antibody, and so on, which have contributed to induce remission and to reduce complications in IBD. As for surgical techniques for Crohn's disease, a stapled functional end-to-end anastomosis and conventional end to-end anastomosis have similar perianastomotic recurrence rate and reoperation rate. Prospective randomized controlled studies which compare Kono-S anastomosis and stapled side-to-side anastomosis are ongoing. Variant two-stage ileal pouch anal anastomosis (IPAA) and transanal IPAA are new concepts for surgical treatment of ulcerative colitis. Various endoscopic procedures, such as balloon dilation for stenosis or stricture, endoscopic fistulotomy, injection of filling agents, and clipping for fistulas or perforations will be new options in the treatment of Crohn's disease. Adverse effects of preoperative treatments on postoperative complications should also be taken into account to improve surgical outcomes in IBD patients. PMID- 30003193 TI - Surgical management of hilar cholangiocarcinoma at Memorial Sloan Kettering Cancer Center. AB - Hilar cholangiocarcinoma, which represents approximately 60% of biliary tract malignancies, is increasing in incidence and presents an ongoing challenge for patients and hepatobiliary surgeons. Although the majority of patients present with advanced disease, the remaining minority of patients are best treated with surgical resection or transplant. Transplant is typically reserved for locally unresectable tumors often in the setting of underlying hepatic dysfunction and will not be discussed herein. This review, therefore, focuses on oncological resection and the strategies implemented for the treatment of hilar cholangiocarcinoma at a quaternary referral center, including preoperative considerations such as patient selection and optimization of the future liver remnant, nuances to the operative approach for these tumors such as resection under low central venous pressure and management of the bile duct, as well as postoperative management. PMID- 30003194 TI - Is high serum programmed death ligand 1 level a risk factor for poor survival in patients with gastric cancer? AB - Background and Aim: Although the clinicopathological significance of the expression of programmed death ligand 1(PD-L1) in various cancer tissues has been reported, serum PD-L1 level has not been evaluated in patients with surgically treated gastric cancer. Therefore, we evaluated the clinicopathological characteristics and prognostic significance of preoperative serum PD-L1 levels in patients with gastric cancer. Patients and Methods: Serum samples were obtained before surgery from 152 patients with gastric cancer, including 75 patients with stage I, 31 with stage II, 23 with stage III, and 23 with stage IV gastric cancer. The samples were analyzed using enzyme-linked immunosorbent assay to detect soluble PD-L1. Using the median serum PD-L1 level of 50 pg/mL, patients were divided into two groups, namely high serum and low serum PD-L1 level groups. Clinicopathological characteristics and prognosis were compared between these two groups using univariate and multivariate analysis. Results: Serum PD-L1 level was significantly associated with older age, positive cancer antigen 19-9 (CA19-9), C reactive protein levels, and albumin levels but not with tumor stage. Patients in the high serum PD-L1 group showed significantly worse overall survival and recurrence-free survival than those in the low serum PD-L1 group (P < .05). Multivariate analysis showed that high serum PD-L1 level was an independent risk factor for poor overall survival (P = .02). Conclusion: High serum PD-L1 level was a prognostic factor for reduced overall survival in patients with surgically treated gastric cancer. PMID- 30003192 TI - Current status of immunotherapy against gastrointestinal cancers and its biomarkers: Perspective for precision immunotherapy. AB - Immunotherapy has shown encouraging results for some types of tumor. Although enormous efforts have been made toward the development of specific immunotherapeutic strategies against gastrointestinal cancers, such as adoptive T cell transfer, peptide vaccines, or dendritic cell vaccines, the efficacy of immunotherapies prior to the introduction of immune checkpoint inhibitors was not substantial. This article reviews immunotherapy for gastrointestinal malignancies, including cell therapy, peptide vaccine, and immune checkpoint inhibitors, and attempts to resolve the immunosuppressive conditions surrounding the tumor microenvironment, and to construct novel combination immunotherapies beyond immune checkpoint inhibitors. PMID- 30003196 TI - Comparing Survival After Recurrent vs De Novo Stage IV Advanced Breast, Lung, and Colorectal Cancer. AB - The treatments provided to and survival of patients with recurrent vs de novo stage IV advanced breast, lung, and colorectal cancer may differ but have not been well studied. Using population-based data from the Cancer Research Network for 4510 patients with advanced breast, lung, or colorectal cancer, we matched recurrent/de novo patients on demographic factors. We found longer survival for recurrent vs de novo lung cancer (182 matched pairs); no significant difference for colorectal cancer (332 matched pairs); and shorter survival for recurrent vs de novo breast cancer (219 matched pairs). Compared with recurrent cases, chemotherapy use and radiation therapy use were more common among de novo cases. Differences in treatment and survival between recurrent and de novo advanced cancer patients could inform prognostic estimates and clinical trial design. PMID- 30003195 TI - Obesity and recurrence-free survival in patients with hepatocellular carcinoma after achieving sustained virological response to interferon therapy for chronic hepatitis C. AB - Aim: Some patients who achieve a sustained virological response (SVR) to interferon (IFN) treatment for chronic hepatitis C prior to hepatic resection for hepatocellular carcinoma (HCC) experience postoperative recurrence. This study investigated the relationship between obesity and postoperative HCC recurrence in SVR patients. Methods: Fifty-nine patients who had achieved SVR before hepatic resection were evaluated. Patients had a solitary tumor <=5 cm in diameter or <=3 lesions each <=3 cm in size with no macroscopic vascular invasion (Milan criteria). Patient characteristics potentially associated with recurrence risk were investigated. Results: Three-, 5-, and 7-year recurrence-free survival after surgery were 65%, 44%, and 41%, respectively. Univariate analysis showed that obesity (P < .01), hypertension (P = .038), and non-anatomical resection (P = .022) were significantly associated with a lower recurrence-free survival rate. In a multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval [CI] 1.3-6.1; P < .01) and non-anatomical resection (hazard ratio, 2.7; 95% CI 1.1-6.2; P = .025) were independently associated with postoperative recurrence. Three-, 5-, and 7-year overall survival rates after surgery were 100%, 80%, and 64% in obese patients and 100%, 92%, and 82% in non-obese patients, respectively (P = .014). However, other variables showed no significant difference in the overall survival rate. Conclusions: Obesity and non-anatomical resection were independent risk factors for HCC recurrence after hepatic resection and successful IFN therapy. Obesity is an important clinical problem to consider to improve postoperative outcomes in such patients. PMID- 30003197 TI - Any-k: Anytime Top-k Tree Pattern Retrieval in Labeled Graphs. AB - Many problems in areas as diverse as recommendation systems, social network analysis, semantic search, and distributed root cause analysis can be modeled as pattern search on labeled graphs (also called "heterogeneous information networks" or HINs). Given a large graph and a query pattern with node and edge label constraints, a fundamental challenge is to find the top-k matches according to a ranking function over edge and node weights. For users, it is difficult to select value k. We therefore propose the novel notion of an any-k ranking algorithm: for a given time budget, return as many of the top-ranked results as possible. Then, given additional time, produce the next lower-ranked results quickly as well. It can be stopped anytime, but may have to continue until all results are returned. This paper focuses on acyclic patterns over arbitrary labeled graphs. We are interested in practical algorithms that effectively exploit (1) properties of heterogeneous networks, in particular selective constraints on labels, and (2) that the users often explore only a fraction of the top-ranked results. Our solution, KARPET, carefully integrates aggressive pruning that leverages the acyclic nature of the query, and incremental guided search. It enables us to prove strong non-trivial time and space guarantees, which is generally considered very hard for this type of graph search problem. Through experimental studies we show that KARPET achieves running times in the order of milliseconds for tree patterns on large networks with millions of nodes and edges. PMID- 30003198 TI - Electrochemical N2 fixation to NH3 under ambient conditions: Mo2N nanorod as a highly efficient and selective catalyst. AB - A highly attractive, but still a key challenge, is the development of earth abundant electrocatalysts for efficient NH3 electrosynthesis via the N2 reduction reaction (NRR). In this communication, we report the development of a Mo2N nanorod as a highly efficient and selective NRR electrocatalyst for artificial N2 fixation in acidic electrolytes under ambient conditions. In 0.1 M HCl, this catalyst achieved a high Faradaic efficiency of 4.5% with a NH3 yield of 78.4 MUg h-1 mgcat.-1 at -0.3 V vs. a reversible hydrogen electrode, thus outperforming most reported NRR electrocatalysts under ambient conditions and some under harsh conditions. Density functional theory calculations revealed that the free energy barrier of the potential determining step of NRR on MoO2 decreases dramatically after nitrogenization. PMID- 30003199 TI - DNA logic assembly powered by a triplex-helix molecular switch for extracellular pH imaging. AB - We demonstrate a strategy for pH-programmable self-assembly of DNA nanostructures by taking advantage of the pH dependence of reverse Hoogsteen interactions for a triplex-helix molecular switch. This strategy is successfully applied to the construction of molecular logic gates and imaging of extracellular pH. PMID- 30003200 TI - Exquisite sensitivity of the ligand field to solvation and donor polarisability in coordinatively saturated lanthanide complexes. AB - Crystallographic, emission and NMR studies of a series of C3-symmetric, nine coordinate substituted pyridyl triazacyclononane Yb(iii) and Eu(iii) complexes reveal the impact of local solvation and ligand dipolar polarisability on ligand field strength, leading to dramatic variations in pseudocontact NMR shifts and emission spectral profiles, giving new guidance for responsive NMR and spectral probe design. PMID- 30003201 TI - Three-dimensional layered double hydroxide membranes: fabrication technique, growth mechanism, and enhanced photocatalytic activity. AB - Novel three-dimensional ZnAl-LDH/AAO and NiAl-LDH/AAO membranes using porous anodic aluminum oxide (AAO) templates as a substrate and an Al3+ source were successfully fabricated via a simple precipitant-free in situ growth technique. These membranes with uniform layered double hydroxide (LDH) plates on the outer and inner surfaces exhibit enhanced activities in photocatalysis. PMID- 30003202 TI - Anion-enhanced solvophobic effects in organic solvent. AB - The influence of salts on the solvophobic interactions of two non-polar surfaces in organic solvent was examined using a series of molecular balances. Specific anion effects were observed that followed the Hofmeister series and enhanced the solvophobic effect up to two-fold. PMID- 30003203 TI - Infrared photodissociation spectroscopy of cold cationic trimethylamine complexes. AB - Cryogenic ion-trap infrared photodissociation spectroscopy combined with a dielectric barrier discharge source was constructed to establish the general trends in the stepwise growth motif of trimethylamine (TMA)n+ complexes. The results showed a strong preference for the formation of a stable charge-shared NN type (TMA)2+ ion core over the proton-transferred CHN type ion core, evidencing that the source condition has a remarkable effect on the kinetic stability of isomers. A maximum of four TMA molecules are located perpendicularly to the NN axis of the charge-shared (TMA)2+ ion core. In the n = 7 and 8 clusters, the subsequent two TMA molecules are located at each end of the NN axis of the (TMA)2+ ion core, completing the first coordination shell. Starting at n = 9, the additional TMA molecules form a second solvation shell, and the cluster spectra show similarities to the solution phase spectrum of aqueous TMA. PMID- 30003204 TI - Syntheses, crystal-solution structures and magnetic properties of a series of decanuclear heterometallic [LnCoCo] (Ln = Eu, Gd, Tb, Dy) clusters. AB - Four unprecedented decanuclear heterometallic [Ln2CoII4CoIII4] clusters based on a diethanolamine ligand (H2dea), namely [Eu2CoII4CoIII4(dea)8(HCOO)4(OH)2(Cl)2(CH3OH)2]Cl2.4CH3OH.2H2O (1), [Gd2CoII4CoIII4(dea)8(HCOO)4(OH)2(Cl)2(CH3OH)2]Cl2.4CH3OH.2H2O (2), [Tb2CoII4CoIII4(dea)8(HCOO)4(OH)2(Cl)2(CH3OH)2]Cl2.2CH3OH.4H2O (3) and [Dy2CoII4CoIII4(dea)8(HCOO)4(OH)2(Cl)2(CH3OH)2]Cl2.2CH3OH.4H2O (4) were synthesized through a facile solution method. Single-crystal X-ray diffraction analyses reveal that complexes 1-4 consist of a [Ln2CoII4CoIII4] core, which is constructed by bridging a quasi-double cuboidal [Ln2CoII2CoIII2] core with two [CoIICoIII] units. Electrospray ionization mass spectrometry (ESI-MS) using methanol solution reveals that complexes 1-4 are stable in the solution, and the clusters undergo three different substitution reactions (Cl- replaced by OH-, OH- replaced by CH3O- and HCOO- replaced by OH-/CH3O-) at the same time in the ionization state. Magnetic susceptibilities reveal ferromagnetic couplings within complexes 3 and 4, and the magnetocaloric effect (MCE) for 2 was also evaluated and the maximum entropy change (-DeltaSm) value reaches 16.3 J kg-1 K-1 at about 3 K and 5 T. PMID- 30003205 TI - Structural insight into the catalytic mechanism of a cis-epoxysuccinate hydrolase producing enantiomerically pure d(-)-tartaric acid. AB - Crystal structure determination and mutagenesis analysis of a cis-epoxysuccinate hydrolase which produces enantiomerically pure d(-)-tartaric acids revealed a zinc ion and essential residues in the stereoselective mechanism for the catalytic reaction of the small mirror symmetric substrate. PMID- 30003206 TI - Geoff Cloke at 65: a pioneer in organometallic chemistry. AB - Professor Geoff Cloke FRS celebrates his 65th birthday in 2018. In a career spanning four decades, his research endeavours have accounted for some of the most innovative synthetic chemistry of the modern era, with his many publications describing truly exceptional compounds and experimental methods that portray a unique chemical imagination. In addition to his scientific accomplishments, Cloke can be particularly proud of his successful mentoring, a level of dedication that propelled many students and post-docs on to become research leaders in their own right. In compiling this collection of some of his research articles, a small cross-section of his friends, colleagues and collaborators, wish to pay tribute to his modesty, compassion and generous personality. PMID- 30003208 TI - Bismuth oxysulfide film electrodes with giant incident photon-to-current conversion efficiency: the dynamics of properties with deposition time. AB - It was demonstrated in our previous work that the photoelectrochemical (PEC) reduction processes occur with a giant incident photon-to-current conversion efficiency (IPCE ? 100%) at bismuth oxysulfide (BOS) semiconductor films in aqueous solutions containing acceptors of photoelectrons ([Fe(CN)6]3-). The anomalously high IPCE was related to the photoconductivity of the semiconductor. In this work, we analyze the dynamics of the chemical and phase composition of BOS films with variation of their deposition time, as well as the dependence of photocurrent on the film thickness and wavelength of the incident light. We demonstrate that in the case of illumination with a short-wavelength light (lambda = 465 nm), the photocurrent is reduced down to a complete disappearance with an increase in the film thickness in the range of 0.3-1.3 MUm, and for a fixed thickness of the bismuth oxysulfide film, the photocurrent decreases with the reduction of the wavelength indicating that photogeneration of the charge carriers over the entire thickness of the film is necessary for the giant IPCE effect. Using the light induced transient grating (LITG) method, the lifetime of the charge carriers (tau) was determined in the range of 25-80 ps depending on the film thickness, whereas the diffusion coefficient (D) does not exceed 1 cm2 s 1 meaning that the charge transport across the films is determined only by drift. PMID- 30003209 TI - Electrospinning of in situ crosslinked recombinant human collagen peptide/chitosan nanofibers for wound healing. AB - Electrospun collagen nanofibers are effective for wound healing; however, many problems, such as the tedious preparation process, weak strength and poor structure integration, limit further applications. In this study, recombinant human collagen (RHC) peptides and a simple one-step crosslinking strategy were used to prepare RHC/chitosan nanofibers. With the nonpathogenic, water-soluble RHC and a mild electrospinning solvent, in situ crosslinked nanofibers (S-CN) not only simplified the preparation procedure but also maintained a more integrated morphology. Compared with the immersed crosslinked nanofibers (I-CN), S-CN showed better performance in moisture retention, degradation and mechanical strength tests. In vitro cell proliferation, morphology and RT-PCR studies confirmed that fibroblasts presented better activities on nanofibers crosslinked in situ. Importantly, after treating with the nanofibers, rapid epidermidalization and angiogenesis were observed in an SD rat scalding model. All these data suggest that electrospun RHC/chitosan nanofibers crosslinked in situ are an ideal candidate that can be used for wound healing applications. PMID- 30003210 TI - CO2-Switchable-hydrophilicity membrane (CO2-SHM) triggered by electric potential: faster switching time along with efficient oil/water separation. AB - We report a membrane that can be reversibly switched between a hydrophilic state and a hydrophobic state simply by alternately bubbling CO2 into and passing electric potential (EP) through a solution in contact with the membrane. The prepared membrane could be effectively used for oil/water separation. PMID- 30003211 TI - Visible-light circular dichroism of colourless chiral organic compounds enabled by interfacial charge-transfer transitions. AB - We report the visible-light circular dichroism (CD) of colourless organic compounds based on interfacial charge-transfer (ICT) transitions with TiO2 nanoparticles. We employed three kinds of colourless chiral compounds, l-ascorbic acid, d-ascorbic acid, and l-noradrenaline. These compounds showed a broad ICT band in the visible region between 400 and 600 nm upon their chemisorption on TiO2 nanoparticles. l-Ascorbic acid and l-noradrenaline adsorbed on the TiO2 nanoparticles showed positive and negative CD signals in the visible region, respectively. d-Ascorbic acid, which is the enantiomer of l-ascorbic acid, exhibited positive CD signals in the visible region, but different g factors (Deltaepsilon/epsilon) from those of TiO2-l-ascorbic acid, well reflecting the different chirality of the substituent group. The visible-light CD based on ICT transitions enables selective visible-light CD sensing and imaging of colourless chiral biomolecules even if coexisting with other colourless chiral compounds such as proteins and DNA. Furthermore, the molecular dependence of the g factor allows us to identify chiral molecules. PMID- 30003212 TI - Catalysis and photocatalysis by metal organic frameworks. AB - Metal organic frameworks (MOFs) are a class of porous crystalline materials that feature a series of unique properties, such as large surface area and porosity, high content of transition metals, and possibility to be designed and modified after synthesis, that make these solids especially suitable as heterogeneous catalysts. The active sites can be coordinatively unsaturated metal ions, substituents at the organic linkers or guest species located inside the pores. The defects on the structure also create these open sites. The present review summarizes the current state of the art in the use of MOFs as solid catalysts according to the type of site, making special emphasis on the more recent strategies to increase the population of these active sites and tuning their activity, either by adapting the synthesis conditions or by post-synthetic modification. This review highlights those reports illustrating the synergy derived from the presence of more than one of these types of sites, leading to activation of a substrate by more than one site or to the simultaneous activation of different substrates by complementary sites. This synergy is frequently the main reason for the higher catalytic activity of MOFs compared to homogeneous catalysts or other alternative solid materials. Besides dark reactions, this review also summarizes the use of MOFs as photocatalysts emphasizing the uniqueness of these materials regarding adaptation of the linkers as light absorbers and metal exchange at the nodes to enhance photoinduced electron transfer, in comparison with conventional inorganic photocatalysts. This versatility and flexibility that is offered by MOFs to optimize their visible light photocatalytic activity explains the current interest in exploiting these materials for novel photocatalytic reactions, including hydrogen evolution and photocatalytic CO2 reduction. PMID- 30003207 TI - The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research. AB - Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields. PMID- 30003213 TI - Pollen-like ZIF-8 colloidosomes via emulsion templating and etching. AB - We report a one-pot emulsion-templating strategy for the preparation of ZIF-8 microcapsules both in the presence and absence of surfactants. Capsule diameter is tuneable in the range 1-10 MUm, and they can be post-synthetically etched with excess imidazole to form hierarchical architectures resembling Oleaceae pollen grains. PMID- 30003214 TI - Squaryl group modified phosphoglycolipid analogs as potential modulators of GPR55. AB - Lysophosphatidyl glucoside (LPGlc) is a structurally unique glycolipid that acts as a guidance cue for extending axons during central nervous system development by activating the class A G protein coupled receptor (GPR) 55 of spinal cord sensory axons. GPR55 not only plays an important role during development, but is also implicated in many disease states, rendering molecules that target GPR55 of widespread interest. In this study, we developed synthetic access to a novel class of LPGlc analogues featuring a squaryl diamide group as surrogate for the phosphodiester. We report the facile synthesis of a series of LPGlc analogues, their GPR dependent biological activity and a systematic analysis of the structure-activity relationship in regards to GPR55 modulation. The lead compound featuring identical configuration at all stereocenters compared to natural LPGlc exhibits an activity to repel axons of dorsal root ganglion (DGR) nociceptive neurons. PMID- 30003215 TI - Association of Symptoms and Clinical Findings With Anticipated Outcomes in Patients With Recurrent Head and Neck Cancer. AB - Importance: Despite advances in treatment over the last decades, recurrent head and neck cancer continues to have a poor prognosis. Prognostic accuracy may help in patient counseling. Objective: To explore whether symptoms and clinical variables can predict prognosis in the setting of recurrent head and neck cancer. Design, Setting, and Participants: In this retrospective cohort study, patients treated for head and neck cancer with curative intent at Siteman Cancer Center in St Louis, Missouri (a tertiary cancer center) between January 1, 2007, and December 31, 2014, were reviewed. The dates of data analysis were October 2016 to June 2017. Patients who developed a recurrent cancer were included, with 196 patients meeting inclusion criteria. Main Outcomes and Measures: Symptoms and clinical findings at presentation of recurrence were recorded. Sequential sequestration and conjunctive consolidation (2 multivariable techniques) were used to create a composite staging system to predict 1-year overall survival (OS). Results: Among 196 patients (mean [SD] age, 61 [11] years; 166 [84.7%] of white race/ethnicity; 76.5% male), 1-year OS was 58.2% (114 of 196 patients). Time to recurrence, symptom severity stage, and rTNM stage were consolidated into a 3-category Clinical Severity Staging System, with 1-year OS rates of 90.2% (95% CI, 82.7%-97.6%) for the 61 patients classified as A, 58.1% (95% CI, 47.7%-68.6%) for the 86 patients classified as B, and 18.4% (95% CI, 7.5%-29.2%) for the 49 patients classified as C. The discriminative power of the new composite staging was better than that of the American Joint Committee on Cancer classification (C = 0.79 vs C = 0.66). Conclusions and Relevance: These findings suggest that clinical variables are associated with anticipated outcomes in patients with recurrent head and neck cancer. PMID- 30003217 TI - Sociodemographic Characteristics and Treatment Response Among Aging Adults With Voice Disorders in the United States. AB - Importance: Aging adults face unique barriers to care and have unique health care needs with a high prevalence of chronic conditions. A high proportion of individuals in this group have voice disorders, in part due to age-related changes in laryngeal anatomy and physiologic features. These disorders contribute significantly to health care costs and remain poorly understood. Objective: To describe sociodemographic characteristics and response to treatment among aging adults with voice disorders. Design, Setting, and Participants: A cross-sectional study using the 2012 National Health Interview Survey was used to evaluate adults who reported voice disorders in the past 12 months. Self-reported demographics and data regarding health care visits for voice disorders were analyzed. Statistical analysis was conducted from March 1, 2017, to February 1, 2018. Main Outcomes and Measures: Self-reported voice disorders, whether or not treatment was sought, which types of professionals were seen for treatment, and whether or not the voice disorder improved after treatment. Results: Among 41.7 million adults in the United States 65 years or older, 4.20 million (10.1%; 2 683 199 women and 1 514 909 men; mean [SE] age, 74.5 [0.3] years) reported having voice disorders. Of those with voice disorders, 10.0% (95% CI, 8.3%-11.7%) sought treatment. Of individuals seeking treatment, 22.1% (95% CI, 7.9%-36.3%) saw an otolaryngologist and 24.3% (95% CI, 10.6%-38.0%) saw a speech language pathologist. By controlling for race/ethnicity, income, sex, and geography, it was found that men were less likely than women to report voice disorders (36.1% [95% CI, 31.7%-40.5%] vs 63.9% [95% CI, 59.5%-68.3%]; odds ratio, 0.70; 95% CI, 0.57-0.86). Race/ethnicity, income, and geography were not significantly associated with the likelihood that an individual 65 years or older reported voice disorders. A greater percentage of elderly adults seeking treatment than not seeking treatment reported improvement in symptoms (32.4%; 95% CI, 17.9% 47.0% vs 15.6%; 95% CI, 10.4%-20.8%). Among adults treated for a voice disorder, a lower proportion of adults 65 years or older reported improvement in symptoms with treatment compared with adults younger than 65 years (32.4%; 95% CI, 17.9% 47.0% vs 56.0%; 95% CI, 42.5%-69.6%). Conclusions and Relevance: A small percentage of older adults with voice disorders seek treatment; even fewer are treated by an otolaryngologist or a speech language pathologist. A greater percentage of those who undergo treatment experienced symptomatic improvement compared with those who did not undergo treatment. These trends highlight the need for greater access to and awareness of services available to older adults with voice disorders. PMID- 30003216 TI - Development of Modified Screening Criteria for Retinopathy of Prematurity: Primary Results From the Postnatal Growth and Retinopathy of Prematurity Study. AB - Importance: Current retinopathy of prematurity (ROP) guidelines, which are based on studies of high-risk infants and expert opinion, have low specificity for disease requiring treatment. Postnatal weight gain-based models improve specificity but have been limited by complexity and small development cohorts, which results in model overfitting and resultant decreased sensitivity in validation studies. Objective: To develop a birth weight (BW), gestational age (GA), and weight gain (WG) prediction model using data from a broad-risk cohort of premature infants. Design, Setting, and Participants: The Postnatal Growth and ROP Study was a retrospective multicenter cohort study conducted in 29 hospitals in the United States and Canada from 2006 to 2012 that included 7483 premature infants at risk for ROP with a known ROP outcome. A hybrid modeling approach was used that combined BW/GA criteria, weight comparison with expected growth from infants without ROP, multiple growth-interval assessments, consideration of nonphysiological WG, and user-friendly screening criteria. Numerous BW/GA levels, postnatal age periods, time intervals, and WG percentile thresholds were evaluated to identify the most robust parameters. Main Outcome and Measures: Sensitivity for Early Treatment of ROP Study type 1 ROP and potential reduction in infants who require examinations. Results: Of 7483 infants, the median (SD) BW was 1099 (359) g, the median GA was 28 weeks (range, 22-35), 3575 (47.8%) were female, 3615 (48.4%) were white, 2310 (30.9%) were black, 233 (3.1%) were Asian, 93 (1.2%) were Pacific Islander, and 40 (0.5%) were American Indian/Alaskan Native. Infants who met any of 6 criteria would undergo examinations: (1) a GA of younger than 28 weeks; (2) a BW of less than 1051 g; a WG of less than 120 g, 180 g, or 170 g during ages 10 to 19, 20 to 29, or 30 to 39 days, respectively; or hydrocephalus. These criteria predicted 459 of 459 (100%) type 1 (sensitivity, 100%; 95% CI, 99.2%-100%), 524 of 524 (100%) treated, and 466 of 472 (98.7%) type 2 cases while reducing the number of infants who required examinations by 2269 (30.3%). Conclusions and Relevance: This cohort study, broadly representative of infants who are undergoing ROP examinations, provides evidence-based screening criteria. With validation, the Postnatal Growth and ROP Study criteria could be incorporated into ROP screening guidelines to reduce the number of infants who require examinations in North America. PMID- 30003219 TI - Error in End Matter. PMID- 30003218 TI - The Role of Migraine in Hearing and Balance Symptoms. PMID- 30003220 TI - Indications and Outcomes of Single-Pedicle vs 2-Pedicle Thigh Free Flaps in Head and Neck Reconstruction. AB - Importance: Flap choice and design are crucial to the success of free flap reconstruction of the head and neck. These are dependent on donor and recipient site characteristics. Objective: To demonstrate indications and outcomes of a single-pedicle anterolateral thigh flap (standard ALT flap) vs a thigh free flap with 2 pedicles in head and neck reconstruction. Design, Setting, and Participants: A retrospective case series of consecutive patients treated in a tertiary academic care center between October 2011 and June 2017 by a single reconstructive microsurgeon was carried out. Eighty-one patients underwent reconstruction of a cutaneous and/or mucosal defect of the head and neck. Patients with a composite mandibular defect who received both a fibular flap and a thigh flap were excluded. Those with less than 6 months of follow-up were excluded. Main Outcomes and Measures: Patient characteristics and clinical variables, including age, sex, primary diagnosis/indication for reconstruction, type of flap, dimensions of flap, and number of perforators in the flap, were collected. Optimal cutoff values to quantitate the differences in length and width between the standard ALT and 2-pedicle thigh flaps were determined using receiver operating characteristic (ROC) curve analysis and the Youden Index. The types of flap were compared to determine any difference in flap complications including flap loss, venous congestion, and poor wound healing. Results: Of the 81 patients (mean [SD] age, 58.2 [15.9] years; 62 [76.5%] men), 57 and 18 patients were reconstructed with a standard ALT flap and a thigh flap with 2 pedicles, respectively. Six patients underwent multiple simultaneous thigh (MST) flaps. Defect size (width >=12 cm, standard ALT: 95% CI, 7.6-9.7; thigh flap with 2 pedicles: 95% CI, 7.0-17.4; P = .02; length >=17 cm, standard ALT: 95% CI, 11.9 15.2; thigh flap with 2 pedicles: 95% CI, 13.6-30.0; P = .001), the presence of divergent mucosal defects, and through-and-through oral cavity/pharyngeal defects were associated with the use of 2 pedicles. Within groups of thigh flaps with 2 pedicles and MST flaps, there were no flap complications (ie, partial loss, venous congestion, or wound healing issues from poor perfusion). Conclusions and Relevance: Harvesting a thigh flap with 2 pedicles has the potential to reduce flap complications and should be considered for divergent and wide or long defects. Width and length measurements respectively of 12 cm and 17 cm are reasonable numbers to initially consider when deciding whether to include a second pedicle. Level of Evidence: 3. PMID- 30003221 TI - Suspicious Eyelid Lesion. PMID- 30003222 TI - Self-reported Eyeglass Use by US Medicare Beneficiaries Aged 65 Years or Older. AB - Importance: Medicare benefits do not include coverage for eyeglasses except after cataract surgery. Understanding the implications of a change to this policy would require knowing the number of Medicare beneficiaries who use eyeglasses, but no recent estimates are available. Objective: To estimate the number of older adults with Medicare who use eyeglasses. Design, Setting, Participants: This cross sectional study used data from the 2015 US National Health and Aging Trends Study. Nationally representative data from 7497 respondents were reviewed and sample weights were applied so that the data represented 43.9 million Medicare beneficiaries aged 65 years or older. The estimates were based on the following 4 groupings of beneficiaries: (1) number who used eyeglasses for distance vision correction and had distance vision impairment, (2) number who did not use eyeglasses for distance vision correction and had distance vision impairment, (3) number who used eyeglasses for near vision correction and had near vision impairment, and (4) number who did not use eyeglasses for near vision correction and had near vision impairment. The prevalence of self-reported use of glasses was estimated using the results of this survey and the Medicare enrollment file. Data were analyzed from July 12, 2017, to November 30, 2017. Main Outcomes and Measures: Self-reported use of eyeglasses or contact lenses. Results: Of the estimated 43.9 million Medicare beneficiaries aged 65 years or older in 2015, approximately 40.5 million (92.4%; 95% CI, 91.6%-93.1%) reported using eyeglasses for either distance or near vision correction. Differences in sociodemographics were observed between those who reported using eyeglasses. Individuals who were older, were nonwhite, had lower educational levels, were less affluent, and had prior cataract surgery were significantly less likely to use eyeglasses. Approximately 27 million beneficiaries (61.7%; 95% CI, 60.3%-63.1%) used eyeglasses for distance vision correction, and approximately 37.2 million beneficiaries (84.8%; 95% CI, 83.8%-85.8%) used eyeglasses for near vision correction. Conclusions and Relevance: Potential sociodemographic disparities in eyeglass use by age, race/ethnicity, educational level, and income were identified. This finding suggests that innovative public policy solutions are needed to address these disparities among the large number of Medicare beneficiaries who use eyeglasses. PMID- 30003223 TI - Error in Key Points. PMID- 30003224 TI - Improving Access-but Not Outcomes-With Iris Optical Coherence Tomography Angiography. PMID- 30003225 TI - Optic Nerve Swelling in a Patient With Cancer. PMID- 30003226 TI - Association of Tinnitus and Other Cochlear Disorders With a History of Migraines. AB - Importance: A headache is a symptom of a migraine, but not all patients with migraine have headaches. It is still unclear whether a migraine might increase the risk of cochlear disorders, even though a migraine does not occur concurrently with cochlear disorders. Objective: To investigate the risk of cochlear disorders for patients with a history of migraines. Design, Setting, and Participants: This study used claims data from the Taiwan Longitudinal Health Insurance Database 2005 to identify 1056 patients with migraines diagnosed between January 1, 1996, and December 31, 2012. A total of 4224 controls were also identified from the same database based on propensity score matching. Statistical analysis was performed from January 23, 1996, to December 28, 2012. Main Outcomes and Measures: The incidence rate of cochlear disorders (tinnitus, sensorineural hearing impairment, and/or sudden deafness) was compared between the cohorts by use of the Kaplan-Meier method. The Cox proportional hazards regression model was also used to examine the association of cochlear disorders with migraines. Results: Of the 1056 patients with migraines, 672 were women and 384 were men, and the mean (SD) age was 36.7 (15.3) years. Compared with the nonmigraine cohort, the crude hazard ratio for cochlear disorders in the migraine cohort was 2.83 (95% CI, 2.01-3.99), and the adjusted hazard ratio was 2.71 (95% CI, 1.86-3.93). The incidence rates of cochlear disorders were 81.4 (95% CI, 81.1 81.8) per 1 million person-years for the migraine cohort and 29.4 (95% CI, 29.2 29.7) per 1 million person-years for the nonmigraine cohort. The cumulative incidence of cochlear disorders in the migraine cohort (12.2%) was significantly higher than that in the matched nonmigraine cohort (5.5%). Subgroup analysis showed that, compared with the nonmigraine cohort, the adjusted hazard ratios in the migraine cohort were 3.30 (95% CI, 2.17-5.00) for tinnitus, 1.03 (95% CI, 0.17-6.41) for sensorineural hearing impairment, and 1.22 (95% CI, 0.53-2.83) for sudden deafness. Conclusions and Relevance: In this population-based study, the risk of cochlear disorders, especially for tinnitus, was found to be significantly higher among patients with a history of migraines. This finding may support the presence and/or concept of "cochlear migraine." PMID- 30003227 TI - Association of Change in Iris Vessel Density in Optical Coherence Tomography Angiography With Anterior Segment Ischemia After Strabismus Surgery. AB - Importance: Anterior segment ischemia (ASI) is a rare but potentially serious complication of strabismus surgery. Indocyanine green angiography and fluorescein angiography have been used to reveal iris-filling defects for clinicians considering a patient's risk of ASI. However, both are limited by invasive and time-consuming nature and potential adverse effects. Recently, optic coherence tomography angiography (OCT-A) has been introduced and used to image iris vasculature in individuals without abnormalities. Objective: To determine the use of iris OCT-A for patients undergoing strabismus surgery and who are at risk for ASI. Design, Setting, and Participants: This prospective case series study took place in an academic center. Adults undergoing strabismus surgery on at least 1 vertical muscle were prospectively recruited. The study took place from June to November 2017, and analysis began in January 2018. Interventions: Indocyanine green angiography and OCT-A of the iris preoperatively and 1 day postoperatively. Main Outcomes and Measures: A masked examiner evaluated all images and determined whether any filling defects were present qualitatively (lack of perfusion) and quantitatively (for OCT-A using internal software to calculate vessel density). Results: Ten eyes of 9 individuals (mean [SD] age, 63 [11] years) were included. Two individuals (22.2%) identified as Hispanic, and 7 (77.8%) identified as white. There were 6 women (66.7%). The mean preoperative vessel density (percentage of the area occupied by vessels) averaged for all quadrants decreased from 57% preoperatively to 55% postoperatively (mean difference, 2%; 95% CI, 0.4% 4.2%; P = .05). When comparing quadrants adjacent to operated muscles, the mean vessel density decreased from 56% to 53% (mean difference, 2.6%; 95% CI, 0.17% 4.8%; P = .02). In addition, OCT-A detected vascular filling defects in the quadrant adjacent to the operated muscle on the patients in whom they were present (n = 1, inferior rectus recession). Conclusions and Relevance: In this preliminary study, OCT-A determined iris vessel filling defects when present. In addition, OCT-A gives qualitative vessel density values that can be compared preoperatively and postoperatively although the clinical relevance of small differences is not known. While only 10 eyes were evaluated, and as such generalizability of these findings cannot be determined, the results suggest that OCT-A may be a useful tool in the evaluation of patients undergoing strabismus surgery to determine whether a patient is at risk to develop ASI. PMID- 30003228 TI - Beyond Primary Tumor Location and RAS/BRAF Mutational Status as Prognostic Factor in Stage III Colon Cancer-Reply. PMID- 30003229 TI - Optimal Multimodal Treatment for Desmoplastic Small Round Cell Tumors-Reply. PMID- 30003231 TI - Conditional Survival as a Pragmatic Resource for Cancer Survivors and Health Care Professionals. PMID- 30003230 TI - Optimal Multimodal Treatment for Desmoplastic Small Round Cell Tumors. PMID- 30003232 TI - The Role of Lexical Status and Individual Differences for Perceptual Learning in Younger and Older Adults. AB - Purpose: This study examined whether older adults remain perceptually flexible when presented with ambiguities in speech in the absence of lexically disambiguating information. We expected older adults to show less perceptual learning when top-down information was not available. We also investigated whether individual differences in executive function predicted perceptual learning in older and younger adults. Method: Younger (n = 31) and older adults (n = 27) completed 2 perceptual learning tasks composed of a pretest, exposure, and posttest phase. Both learning tasks exposed participants to clear and ambiguous speech tokens, but crucially, the lexically guided learning task provided disambiguating lexical information whereas the distributional learning task did not. Participants also performed several cognitive tasks to investigate individual differences in working memory, vocabulary, and attention-switching control. Results: We found that perceptual learning is maintained in older adults, but that learning may be stronger in contexts where top-down information is available. Receptive vocabulary scores predicted learning across both age groups and in both learning tasks. Conclusions: Implicit learning is maintained with age across different learning conditions but remains stronger when lexically biasing information is available. We find that receptive vocabulary is relevant for learning in both types of learning tasks, suggesting the importance of vocabulary knowledge for adapting to ambiguities in speech. PMID- 30003234 TI - Management of Relapsed and Refractory Hodgkin Lymphoma in 2018. PMID- 30003235 TI - Causes of Death and Conditional Survival Estimates of Medium- and Long-term Survivors of Pancreatic Adenocarcinoma. PMID- 30003233 TI - Association of Second Allogeneic Hematopoietic Cell Transplant vs Donor Lymphocyte Infusion With Overall Survival in Patients With Acute Myeloid Leukemia Relapse. AB - Importance: The optimal treatment approach to patients with acute myeloid leukemia (AML) who relapse after an allogeneic hematopoietic cell transplant (allo-HCT) remains elusive. No randomized clinical trial comparing survival outcomes of a second allo-HCT (allo-HCT2) vs donor lymphocyte infusion (DLI) has been conducted to date. Objective: To compare overall survival (OS) after an allo HCT2 or DLI in relapsed AML after a first allo-HCT. Design, Setting, and Participants: A retrospective registry study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation involving 418 adults who received an allo-HCT2 (n = 137) or DLI (n = 281) for postallograft relapsed AML. Analysis was assessed on the principle of intent-to-first received intervention. The data were collected from November 21, 2015, to May 15, 2017, and analysis was performed June 1, 2017. Main Outcomes and Measures: Number of patients with relapsed AML who are alive after 2 years and 5 years from receiving an allo-HCT2 or DLI. Results: Of the 418 patients, 228 (54.5%) were men; mean age was 46.2 years (interquartile range, 36.5-56.9 years). There was no apparent difference in OS whether an allo-HCT2 or DLI was prescribed (2-year OS with allo HCT2, 26%; 5-year OS with allo-HCT2, 19%; 2-year OS with DLI, 25%; 5-year OS with DLI, 15%; P = .86). Overall survival was better if either of these procedures was offered when the patient was in complete remission (hazard ratio, 0.55; 95% CI, 0.41-0.74; P < .001). Conversely, OS was low for patients relapsing within less than 6 months after an allo-HCT1, regardless of the treatment prescribed (5-year OS: allo-HCT2, 9%; 95% CI, 1%-17% vs DLI, 4%; 95% CI, 1%-8%; P = .86). Conclusion and Relevance: Heterogeneity of the patient-, disease-, and treatment-related characteristics limit the ability to recommend one approach over another. Findings of this study highlight that best outcomes seem to be achieved in patients relapsing 6 or more months from an allo-HCT1 or those in complete remission at the time of either allo-HCT2 or DLI. PMID- 30003236 TI - Direct Primary Care: One Step Forward, Two Steps Back. PMID- 30003237 TI - Surgeon Attitudes Toward the Omission of Axillary Dissection in Early Breast Cancer. AB - Importance: The American College of Surgeons Oncology Group (ACOSOG) Z0011 study demonstrated the safety of sentinel node biopsy alone in clinically node-negative women with metastases in 1 or 2 sentinel nodes treated with breast conservation. Little is known about surgeon perspectives regarding when axillary lymph node dissection (ALND) can be omitted. Objectives: To determine surgeon acceptance of ACOSOG Z0011 findings, identify characteristics associated with acceptance of ACOSOG Z0011 results, and examine the association between acceptance of the Society of Surgical Oncology and American Society for Radiation Oncology negative margin of no ink on tumor and surgeon preference for ALND. Design, Setting, and Participants: A survey was sent to 488 surgeons treating a population-based sample of women with early-stage breast cancer (N = 5080). The study was conducted from July 1, 2013, to August 31, 2015. Main Outcomes and Measures: Surgeons were categorized as having low, intermediate, or high propensity for ALND according to the outer quartiles of ALND scale distribution. A multivariable linear regression model was used to confirm independent associations. Results: Of the 488 surgeons invited to participate, 376 (77.0%) responded and 359 provided complete information regarding propensity for ALND derived from 5 clinical scenarios. Mean surgeon age was 53.7 (range, 31-80) years; 277 (73.7%) were male; 142 (37.8%) treated 20 or fewer breast cancers annually and 108 (28.7%) treated more than 50. One hundred seventy-five (49.0%) recommended ALND for 1 macrometastasis. Of low-propensity surgeons who recommended ALND, only 1 (1.1%) approved ALND for any nodal metastases compared with 69 (38.6%) and 85 (95.5%) of selective and high-propensity surgeons (P < .001), respectively. In multivariable analysis, lower ALND propensity was significantly associated with higher breast cancer volume (21-50: -0.19; 95% CI, -0.39 to 0.02; >51: -0.48; 95% CI, -0.71 to 0.24; P < .001), recommendation of a minimal margin width (1-5 mm: -0.10; 95% CI, -0.43 to 0.22; no ink on tumor: -0.53; 95% CI, -0.82 to -0.24; P < .001), participation in a multidisciplinary tumor board (1%-9%: -0.25; 95% CI, -0.55 to 0.05; >9%: -0.37; 95% CI, -0.63 to -0.11; P = .02), and Los Angeles Surveillance, Epidemiology, and End Results site (-0.18; 95% CI, -0.35 to -0.01; P = .04). Conclusions and Relevance: This study shows substantial variation in surgeon acceptance of more limited surgery for breast cancer, which is associated with higher breast cancer volume and multidisciplinary interactions, suggesting the potential for overtreatment of many patients and the need for education targeting lower-volume breast surgeons. PMID- 30003239 TI - Beyond Primary Tumor Location and RAS/BRAF Mutational Status as Prognostic Factor in Stage III Colon Cancer. PMID- 30003240 TI - Delayed Adoption of Evidence-Based Breast Cancer Surgical Practices: History Repeats Itself. PMID- 30003241 TI - Amelanotic and Pigmented Uveal Melanoma. PMID- 30003242 TI - Reversible Peripapillary Vascular Loop Change. PMID- 30003243 TI - Active IgGkappa Multiple Myeloma Presenting With Crystalline Keratopathy. PMID- 30003238 TI - Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins. AB - Importance: There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. Objective: To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. Design, Setting, and Participants: Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). Main Outcomes and Measures: Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver operating characteristics curve [AUC], sensitivity, and specificity). Results: In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. Conclusions and Relevance: This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening. PMID- 30003244 TI - Retinal Oxalosis in End-stage Renal Disease. PMID- 30003247 TI - Compressibility and Anisotropy of the Ventricular Myocardium: Experimental Analysis and Microstructural Modeling. AB - While the anisotropic behavior of the complex composite myocardial tissue has been well characterized in recent years, the compressibility of the tissue has not been rigorously investigated to date. In the first part of this study, we present experimental evidence that passive-excised porcine myocardium exhibits volume change. Under tensile loading of a cylindrical specimen, a volume change of 4.1+/-1.95% is observed at a peak stretch of 1.3. Confined compression experiments also demonstrate significant volume change in the tissue (loading applied up to a volumetric strain of 10%). In order to simulate the multiaxial passive behavior of the myocardium, a nonlinear volumetric hyperelastic component is combined with the well-established Holzapfel-Ogden anisotropic hyperelastic component for myocardium fibers. This framework is shown to describe the experimentally observed behavior of porcine and human tissues under shear and biaxial loading conditions. In the second part of the study, a representative volumetric element (RVE) of myocardium tissue is constructed to parse the contribution of the tissue vasculature to observed volume change under confined compression loading. Simulations of the myocardium microstructure suggest that the vasculature cannot fully account for the experimentally measured volume change. Additionally, the RVE is subjected to six modes of shear loading to investigate the influence of microscale fiber alignment and dispersion on tissue scale mechanical behavior. PMID- 30003248 TI - A Low-Cost Mechanical Stretching Device for Uniaxial Strain of Cells: A Platform for Pedagogy in Mechanobiology. AB - Mechanical cues including stretch, compression, and shear stress play a critical role in regulating the behavior of many cell types, particularly those that experience substantial mechanical stress within tissues. Devices that impart mechanical stimulation to cells in vitro have been instrumental in helping to develop a better understanding of how cells respond to mechanical forces. However, these devices often have constraints, such as cost and limited functional capabilities, that restrict their use in research or educational environments. Here, we describe a low-cost method to fabricate a uniaxial cell stretcher that would enable widespread use and facilitate engineering design and mechanobiology education for undergraduate students. The device is capable of producing consistent and reliable strain profiles through the use of a servomotor, gear, and gear rack system. The servomotor can be programmed to output various waveforms at specific frequencies and stretch amplitudes by controlling the degree of rotation, speed, and acceleration of the servogear. In addition, the stretchable membranes are easy to fabricate and can be customized, allowing for greater flexibility in culture well size. We used the custom-built stretching device to uniaxially strain macrophages and cardiomyocytes, and found that both cell types displayed functional and cell shape changes that were consistent with the previous studies using commercially available systems. Overall, this uniaxial cell stretcher provides a more cost-effective alternative to study the effects of mechanical stretch on cells, and can therefore, be widely used in research and educational environments to broaden the study and pedagogy of cell mechanobiology. PMID- 30003249 TI - A Methodology for Individual-Specific Modeling of Rat Optic Nerve Head Biomechanics in Glaucoma. AB - Glaucoma is the leading cause of irreversible blindness and involves the death of retinal ganglion cells (RGCs). Although biomechanics likely contributes to axonal injury within the optic nerve head (ONH), leading to RGC death, the pathways by which this occurs are not well understood. While rat models of glaucoma are well suited for mechanistic studies, the anatomy of the rat ONH is different from the human, and the resulting differences in biomechanics have not been characterized. The aim of this study is to describe a methodology for building individual specific finite element (FE) models of rat ONHs. This method was used to build three rat ONH FE models and compute the biomechanical environment within these ONHs. Initial results show that rat ONH strains are larger and more asymmetric than those seen in human ONH modeling studies. This method provides a framework for building additional models of normotensive and glaucomatous rat ONHs. Comparing model strain patterns with patterns of cellular response seen in studies using rat glaucoma models will help us to learn more about the link between biomechanics and glaucomatous cell death, which in turn may drive the development of novel therapies for glaucoma. PMID- 30003252 TI - Comparison of Heat Transfer Enhancement Between Magnetic and Gold Nanoparticles During HIFU Sonication. AB - Long procedure times and collateral damage remain challenges in high-intensity focused ultrasound (HIFU) medical procedures. Magnetic nanoparticles (mNPs) and gold nanoparticles (gNPs) have the potential to reduce the acoustic intensity and/or exposure time required in these procedures. In this research, we investigated relative advantages of using gNPs and mNPs during HIFU thermal ablation procedures. Tissue-mimicking phantoms containing embedded thermocouples (TCs) and physiologically acceptable concentrations (0.0625% and 0.125%) of gNPs were sonicated at acoustic powers of 5.2 W, 9.2 W, and 14.5 W, for 30 s. It was observed that when the concentration of gNPs was doubled from 0.0625% to 0.125%, the temperature rise increased by 80% for a power of 5.2 W. For a fixed concentration (0.0625%), the energy absorption was 1.7 times greater for mNPs than gNPs for a power of 5.2 W. Also, for the power of 14.5 W, the sonication time required to generate a lesion volume of 50 mm3 decreased by 1.4 times using mNPs, compared with gNPs, at a concentration of 0.0625%. We conclude that mNPs are more likely than gNPs to produce a thermal enhancement in HIFU ablation procedures. PMID- 30003250 TI - Repeated High Rate Facet Capsular Stretch at Strains That are Below the Pain Threshold Induces Pain and Spinal Inflammation With Decreased Ligament Strength in the Rat. AB - Repeated loading of ligamentous tissues during repetitive occupational and physical tasks even within physiological ranges of motion has been implicated in the development of pain and joint instability. The pathophysiological mechanisms of pain after repetitive joint loading are not understood. Within the cervical spine, excessive stretch of the facet joint and its capsular ligament has been implicated in the development of pain. Although a single facet joint distraction (FJD) at magnitudes simulating physiologic strains is insufficient to induce pain, it is unknown whether repeated stretching of the facet joint and ligament may produce pain. This study evaluated if repeated loading of the facet at physiologic nonpainful strains alters the capsular ligament's mechanical response and induces pain. Male rats underwent either two subthreshold facet joint distractions (STFJDs) or sham surgeries each separated by 2 days. Pain was measured before the procedure and for 7 days; capsular mechanics were measured during each distraction and under tension at tissue failure. Spinal glial activation was also assessed to probe potential pathophysiologic mechanisms responsible for pain. Capsular displacement significantly increased (p = 0.019) and capsular stiffness decreased (p = 0.008) during the second distraction compared to the first. Pain was also induced after the second distraction and was sustained at day 7 (p < 0.048). Repeated loading weakened the capsular ligament with lower vertebral displacement (p = 0.041) and peak force (p = 0.014) at tissue rupture. Spinal glial activation was also induced after repeated loading. Together, these mechanical, physiological, and neurological findings demonstrate that repeated loading of the facet joint even within physiologic ranges of motion can be sufficient to induce pain, spinal inflammation, and alter capsular mechanics similar to a more injurious loading exposure. PMID- 30003251 TI - Multiscale Computational Analysis of Right Ventricular Mechanoenergetics. AB - Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO. PMID- 30003254 TI - Using Hands-On Physical Computing Projects to Teach Computer Programming to Biomedical Engineering Students. AB - Rapid advancements in the multidisciplinary field of biomedical engineering (BME) require competitive engineers with skill sets in a broad range of subjects including biology, physiology, mechanics, circuits, and programming. Accordingly, such a need should be reflected in the training of BME students. Among those skills, computer programming is an essential tool that is used in a wide variety of applications. In this paper, we have provided our experience in incorporating project-based learning, a promising approach in active learning, for teaching computer programming to BME students. We describe a low-cost method for using physical, hands-on computing that directly relates to BME. Additionally, we detail our efforts to teach multiple programming languages in one semester and provide a detailed analysis of the outcomes. We also provide basic materials for other instructors to adapt to fit their own needs. PMID- 30003253 TI - Regional Quantification of Brain Tissue Strain Using Displacement-Encoding With Stimulated Echoes Magnetic Resonance Imaging. AB - Intrinsic cardiac-induced deformation of brain tissue is thought to be important in the pathophysiology of various neurological disorders. In this study, we evaluated the feasibility of utilizing displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging (MRI) to quantify two-dimensional (2D) neural tissue strain using cardiac-driven brain pulsations. We examined eight adult healthy volunteers with an electrocardiogram-gated spiral DENSE sequence performed at the midsagittal plane on a 3 Tesla MRI scanner. Displacement, pixel wise trajectories, and principal strains were determined in seven regions of interest (ROI): the brain stem, cerebellum, corpus callosum, and four cerebral lobes. Quantification of small neural tissue motion and strain along with their spatial and temporal variations in different brain regions was found to be feasible using DENSE. The medial and inferior brain structures (brain stem, cerebellum, and corpus callosum) had significantly larger motion and strain compared to structures located more peripherally. The brain stem had the largest peak mean displacement (PMD) (187 +/- 50 MUm, mean +/- SD). The largest mean principal strains in compression and extension were observed in the brain stem (0.38 +/- 0.08%) and the corpus callosum (0.37 +/- 0.08%), respectively. Measured values in percent strain were altered by as much as 0.1 between repeated scans. This study showed that DENSE can quantify regional variations in brain tissue motion and strain and has the potential to be utilized as a tool to evaluate the changes in brain tissue dynamics resulting from alterations in biomechanical stresses and tissue properties. PMID- 30003255 TI - Bad to the Bone: Multifaceted Enrichment of Open-Ended Biomechanics Class Projects. AB - Equipping engineering students for career success requires more than technical proficiency; mindset and contextual interpretation also matter. Entrepreneurial mindset learning (EML) is one framework that faculty can use to systematically enrich course projects to encourage development of these important career skills. We present the thought process behind enriching two biomechanics class projects to foster both the entrepreneurial mindset and the technical proficiency in undergraduate engineering students. One project required students to analyze a court case surrounding vertebral fracture in an elderly woman diagnosed one year after a fall in an elevator. In addition to technical analysis, students had to make a recommendation about the likelihood that the injury occurred due to the fall, and contextualize the results within economic and societal terms-how much should the plaintiff sue for and how could such injuries be prevented through design and regulation? The second project asked students to evaluate cervine cancellous bone as a suitable laboratory model for biomechanics research. In addition to technical analysis, students considered the value of cervine vertebrae as a laboratory model within the context of societal and economic benefits of ex vivo animal models, including the relevant policy and regulatory issues. In both projects, implemented at different institutions with similar student demographics, students performed well and enjoyed the "real-world" nature of the projects, despite their frustrations with the open-ended nature of the questions posed. These and other similar projects can be further enhanced to foster the entrepreneurial mindset in undergraduate engineering students without undue burden on the instructor. PMID- 30003257 TI - Implementation of a Biomedical Engineering Research Experience for African American High School Students at a Tier One Research University. PMID- 30003256 TI - Modeling Skeletal Muscle Stress and Intramuscular Pressure: A Whole Muscle Active Passive Approach. AB - Clinical treatments of skeletal muscle weakness are hindered by a lack of an approach to evaluate individual muscle force. Intramuscular pressure (IMP) has shown a correlation to muscle force in vivo, but patient to patient and muscle to muscle variability results in difficulty of utilizing IMP to estimate muscle force. The goal of this work was to develop a finite element model of whole skeletal muscle that can predict IMP under passive and active conditions to further investigate the mechanisms of IMP variability. A previously validated hypervisco-poroelastic constitutive approach was modified to incorporate muscle activation through an inhomogeneous geometry. Model parameters were optimized to fit model stress to experimental data, and the resulting model fluid pressurization data were utilized for validation. Model fitting was excellent (root-mean-square error or RMSE <1.5 kPa for passive and active conditions), and IMP predictive capability was strong for both passive (RMSE 3.5 mmHg) and active (RMSE 10 mmHg at in vivo lengths) conditions. Additionally, model fluid pressure was affected by length under isometric conditions, as increases in stretch yielded decreases in fluid pressurization following a contraction, resulting from counteracting Poisson effects. Model pressure also varied spatially, with the highest gradients located near aponeuroses. These findings may explain variability of in vivo IMP measurements in the clinic, and thus help reduce this variability in future studies. Further development of this model to include isotonic contractions and muscle weakness would greatly benefit this work. PMID- 30003258 TI - Improving Biomedical Engineering Education Through Continuity in Adaptive, Experiential, and Interdisciplinary Learning Environments. AB - This study reports our experience of developing a series of biomedical engineering (BME) courses having active and experiential learning components in an interdisciplinary learning environment. In the first course, BME465: biomechanics, students were immersed in a simulation laboratory setting involving mannequins that are currently used for teaching in the School of Nursing. Each team identified possible technological challenges directly related to the biomechanics of the mannequin and presented an improvement overcoming the challenge. This approach of exposing engineering students to a problem in a clinical learning environment enhanced the adaptive and experiential learning capabilities of the course. In the following semester, through BME448: medical devices, engineering students were partnered with nursing students and exposed to simulation scenarios and real-world clinical settings. They were required to identify three unmet needs in the real-world clinical settings and propose a viable engineering solution. This approach helped BME students to understand and employ real-world applications of engineering principles in problem solving while being exposed to an interdisciplinary collaborative environment. A final step was for engineering students to execute their proposed solution from either BME465 or BME448 courses by undertaking it as their capstone senior design project (ENGR401 402). Overall, the inclusion of clinical immersions in interdisciplinary teams in a series of courses not only allowed the integration of active and experiential learning in continuity but also offered engineers more practice of their profession, adaptive expertise, and an understanding of roles and expertise of other professionals involved in enhancement of healthcare and patient safety. PMID- 30003259 TI - The Effect of Pentagalloyl Glucose on the Wall Mechanics and Inflammatory Activity of Rat Abdominal Aortic Aneurysms. PMID- 30003261 TI - Balancing Academic Rigor and Creative Thinking: A Transformational Approach to Teaching Senior Design. AB - Innovation arises from creativity. "Thinking outside the box" has long been seen as a necessary precursor to innovation and invention in engineering. However, creativity is rarely part of traditional engineering curricula. In 2015, our group began to explore integrating theater-based creativity methods into bioengineering capstone design. Evaluation of student outcomes was encouraging, so we continued to develop the course in 2016 and 2017. As we worked to refine the pedagogical process, we discovered tensions (real or perceived) between providing academic rigor and allowing students to embrace their creativity; for instance, we experienced some resistance from engineering faculty and students toward adopting methods they viewed as "artsy" or lacking academic rigor. Here, we discuss the tensions we observed offer potential ways to mitigate such tensions and begin to consider how to expand on our successes. PMID- 30003260 TI - Anthropomorphic Model of Intrathecal Cerebrospinal Fluid Dynamics Within the Spinal Subarachnoid Space: Spinal Cord Nerve Roots Increase Steady-Streaming. AB - Cerebrospinal fluid (CSF) dynamics are thought to play a vital role in central nervous system (CNS) physiology. The objective of this study was to investigate the impact of spinal cord (SC) nerve roots (NR) on CSF dynamics. A subject specific computational fluid dynamics (CFD) model of the complete spinal subarachnoid space (SSS) with and without anatomically realistic NR and nonuniform moving dura wall deformation was constructed. This CFD model allowed detailed investigation of the impact of NR on CSF velocities that is not possible in vivo using magnetic resonance imaging (MRI) or other noninvasive imaging methods. Results showed that NR altered CSF dynamics in terms of velocity field, steady-streaming, and vortical structures. Vortices occurred in the cervical spine around NR during CSF flow reversal. The magnitude of steady-streaming CSF flow increased with NR, in particular within the cervical spine. This increase was located axially upstream and downstream of NR due to the interface of adjacent vortices that formed around NR. PMID- 30003263 TI - Incorrect Email Address for Corresponding Author. PMID- 30003262 TI - A Surface-to-Surface Finite Element Algorithm for Large Deformation Frictional Contact in febio. AB - This study formulates a finite element algorithm for frictional contact of solid materials, accommodating finite deformation and sliding. The algorithm uses a penalty method regularized with an augmented Lagrangian scheme to enforce contact constraints in a nonmortar surface-to-surface approach. Use of a novel kinematical approach to contact detection and enforcement of frictional constraints allows solution of complex problems previously requiring mortar methods or contact smoothing algorithms. Patch tests are satisfied to a high degree of accuracy with a single-pass penalty method, ensuring formulation errors do not affect the solution. The accuracy of the implementation is verified with Hertzian contact, and illustrations demonstrating the ability to handle large deformations and sliding are presented and validated against prior literature. A biomechanically relevant example addressing finger friction during grasping demonstrates the utility of the proposed algorithm. The algorithm is implemented in the open source software febio, and the source code is made available to the general public. PMID- 30003266 TI - Perception of the role of physical and rehabilitation medicine among physiotherapy students. AB - OBJECTIVE: To determine how the role of physical and rehabilitation medicine specialists in healthcare is perceived by physiotherapy students. DESIGN: Cross sectional observational study. SUBJECTS: A total of 677 physiotherapy students and 519 final year medical students at the largest university-level educational institutions in Warsaw, Poland. METHODS: Questionnaire about knowledge of the role of physical and rehabilitation medicine specialists in the healthcare system. RESULTS: The definition of physical and rehabilitation medicine specialists was known to 32.9% of medical students and 19.9% of physiotherapy students. Misconceptions most frequently resulted from an inability to distinguish physical and rehabilitation medicine from physiotherapy. The leading role of physical and rehabilitation medicine specialists in team management of persons with disabilities was identified by 25.4-55.5% of medical and 5.8-9.0% of physiotherapy students. DISCUSSION: Inadequate perception of the role of physical and rehabilitation medicine specialists in healthcare may result from recent changes in the management of rehabilitation services, tendencies towards professional independence among health professionals, and insufficient formative education. CONCLUSION: Perception of the role of physical and rehabilitation medicine specialists in healthcare was found to be inadequate among physiotherapy students. Changes in health professional education are warranted to maintain an effective patient-centred collaborative practice. Further research is needed at national and international levels to address the mutual perception of competencies and roles among students of health professions. PMID- 30003267 TI - Relationship between fatigue after acquired brain injury and depression, injury localization and aetiology: An explorative study in a rehabilitation setting. AB - OBJECTIVE: Fatigue after acquired brain injury may be related to the subcortico frontal attention network. Depression is also strongly related to fatigue. This study investigates whether injury localization, diagnosis and depression are related to self-rated mental fatigue in patients with an acquired brain injury. DESIGN: Retrospective cross-sectional cohort study. SUBJECTS: Sixty-one patients diagnosed with stroke, subarachnoidal haemorrhage, traumatic brain injury, or brain tumour were included in the study. METHODS: Patients who underwent a multidisciplinary team assessment during September 2011 to June 2012, and who were assessed with the Mental Fatigue Scale, were included in the study. RESULTS: A significantly higher number of patients with posterior and non-specific lesions experienced fatigue compared with those with subcortical/frontal injuries. Fewer stroke patients experienced fatigue compared with the other patient groups. How ever, after logistic regression, only depression remained as an explanatory variable for self-rated fatigue. Nevertheless, although all patients with depression were fatigued, not all fatigued patients were depressed. CONCLUSION: Although depression explains a high degree of fatigue after an acquired brain injury, mental fatigue after brain injury should be viewed as a condition partly separate from depression. Future extensive comparative studies are required, preferably including neuropsychological measures. PMID- 30003268 TI - Feasibility of a wearable soft-robotic glove to support impaired hand function in stroke patients. AB - OBJECTIVE: To investigate the feasibility of a wear-able, soft-robotic glove system developed to combine assistive support in daily life with performing therapeutic exercises on a computer at home (the HandinMind system). DESIGN: Feasibility study. PATIENTS: Five chronic stroke patients with limitations in activities of daily living due to impaired hand function. METHODS: Participants performed a usability test and several functional tasks with the HandinMind system across 2 sessions. Feasibility was measured using the System Usability Scale (SUS), Intrinsic Motivation Inventory (IMI) and performance times of the functional tasks. RESULTS: User acceptance measured by the SUS and IMI was scored high. The median SUS scores of sessions 1 and 2 were 80.0 (interquartile range (IQR) 70.0-88.8) and 77.5 (IQR 75.0-87.5), respectively, and the median IMI score was 6.3 points out of 7 points (IQR 6.2-6.3). Functional task performance was initially slower with the HandinMind glove compared with performance without the glove, but improved up to the level of performance without the glove across no more than 3 repetitions. CONCLUSION: Chronic stroke patients with impaired hand function were positive about the feasibility of the first prototype of the HandinMind system. How-ever, performance and ease of use of the system should be improved further in future development phases. PMID- 30003269 TI - Associations between self and informant ratings of executive functioning and driver behaviour following acquired brain injury. AB - OBJECTIVES: To investigate self and informant ratings of everyday executive functions and their correlation with driving behaviour after acquired brain injury. METHODS: A 1-year follow-up study of 24 adults with stroke and 10 adults with traumatic brain injury deemed fit to drive after a multidisciplinary driving assessment. Baseline measures included neuropsychological tests and self and informant reports of everyday executive function (Behavior Rating of Executive Function; BRIEF-A). Follow-up measurements were the Swedish Driver Behaviour Questionnaire (DBQ) and Sunnaas Driving Pattern Questionnaire (SDPQ). RESULTS: Patients' ratings on the BRIEF-A were significantly associated with the DBQ at follow-up, whereas informants' ratings were not. Neither patients' nor informants' reports were associated with accident involvement or the use of compensatory driving strategies. No significant associations were found between level of awareness and driving parameters. CONCLUSION: Patients' reports of everyday executive functioning were more strongly associated with driving behaviour than were informants' reports. Future studies are warranted to explore how informant and patient reports can contribute to distinguishing safe from unsafe drivers among patient groups with impaired awareness of deficits. PMID- 30003271 TI - Introduction to the special section on kidney transplantation. PMID- 30003272 TI - Computed tomography prediction of pancreatic extracorporeal shock wave lithotripsy outcomes could be improved. PMID- 30003273 TI - Multimodality imaging and clinicopathologic assessment of abdominal wall endometriosis: knocking down the enigma. AB - PURPOSE: To review the clinical, multimodality imaging, and pathologic characteristics of abdominal wall endometriosis (AWE), the most common type of extra-pelvic endometriosis. METHODS: 116 women with histopathologically confirmed extragenital endometriosis diagnosed between 2/2014 and 6/2017 were evaluated retrospectively. Of these, 26 (22.4%) were found to have AWE and 18/26 met inclusion criteria for imaging. Available imaging studies were re-reviewed by two expert radiologists. Data regarding clinical features, histopathologic findings, and management were collected through medical record review. RESULTS: 21 pathology-proven AWE deposits were identified by imaging in 18 women [mean age at diagnosis of 38.5 years (range 31-48)]. Prior C-section was present in 15/18 (83.3%) and pelvic endometriosis in 3/18 (16.7%) patients. Patients presented with abdominal pain in 14/18 (77.8%) cases, which was cyclical in 8/14; palpable mass in 12/18 (66.7%); fluid discharge in 2/18 (11.1%); and local skin discoloration in 2/18 (11.1%). Of the 21 lesions, 15 were evaluated with US, 10 with CT, and 5 with MRI. Mean lesion dimensions were 2.5 * 2.2 * 2.6 cm, and deposits were predominantly located at midline or left hemiabdomen [22/30 (73.3%)], were either stellate [15/30 (50%)] or round [15/30 (50%)] in shape, had ill-defined margins [21/30 (70%)], were heterogenous in appearance [27/30 (90%)], and involved both deep and superficial abdominal wall layers [17/30 (56.7%)]. On US, lesions were mainly isoechoic/hyperechoic [7/15 (46.7%)], and scarcely vascular [8/15 (53.3%)] with a peripheral vascular pattern [8/13 (61.5%)]. On CT, AWEs were hypervascular and homogeneous [8/10 (80%)], superiorly located to scar tissue, and on MRI lesions appeared hyperintense [4/5 (80%)] to muscle with T2 cystic and T1 hemorrhagic foci [4/5 (80%)]. In 23/27 (85.1%) original reports, there was at least one known mass prior to imaging; AWE was correctly diagnosed in only 7/23 (30.4%) cases. In those with no prior knowledge of a mass, the lesion was detected in 3/4 (75%), but AWE was only diagnosed in a single case. Median time between onset of symptoms and histopathology was 24.41 moths (IQR 15.18-47.33). CONCLUSIONS: AWE is a challenging clinical entity frequently diagnosed with a significant delay and easily misinterpreted despite multimodality imaging. Familiarity with its radiologic features holds the potential for positively impacting diagnosis. PMID- 30003274 TI - Calyceal crescents (of Dunbar and Nogrady). PMID- 30003270 TI - Targeting epigenetics using synthetic lethality in precision medicine. AB - Technological breakthroughs in genomics have had a significant impact on clinical therapy for human diseases, allowing us to use patient genetic differences to guide medical care. The "synthetic lethal approach" leverages on cancer-specific genetic rewiring to deliver a therapeutic regimen that preferentially targets malignant cells while sparing normal cells. The utility of this system is evident in several recent studies, particularly in poor prognosis cancers with loss-of function mutations that become "treatable" when two otherwise discrete and unrelated genes are targeted simultaneously. This review focuses on the chemotherapeutic targeting of epigenetic alterations in cancer cells and consolidates a network that outlines the interplay between epigenetic and genetic regulators in DNA damage repair. This network consists of numerous synergistically acting relationships that are druggable, even in recalcitrant triple-negative breast cancer. This collective knowledge points to the dawn of a new era of personalized medicine. PMID- 30003275 TI - Neuropsychiatric manifestations among HIV-1 infected African patients receiving efavirenz-based cART with or without tuberculosis treatment containing rifampicin. AB - PURPOSE: Efavirenz-based combination antiretroviral therapy (cART) is associated with neuropsychiatric adverse events. We investigated the time to onset, duration, clinical implications, impact of pharmacogenetic variations, and anti tuberculosis co-treatment on efavirenz-associated neuropsychiatric manifestations. METHODS: Prospective cohort study of cART naive HIV patients with or without tuberculosis (HIV-TB) co-infection treated with efavirenz-based cART. Rifampicin-based anti-tuberculosis therapy was initiated 4 weeks prior to efavirenz-based cART in HIV-TB patients. Data on demographic, clinical, laboratory, and a 29-item questionnaire on neuropsychiatric manifestations were collected for 16 weeks after cART initiation. Genotyping for CYP2B6, CYP3A5, SLCO1B1, and ABCB1 and quantification of efavirenz plasma concentration were done on the 4th and 16th week. RESULTS: Data from 458 patients (243 HIV-only and 215 HIV-TB) were analyzed. Overall incidence of neuropsychiatric manifestations was 57.6% being higher in HIV-only (66.7%) compared to HIV-TB patients (47.4%) (p < 0.01). HIV-only patients were more symptomatic, with proportionately higher grades of manifestations compared to HIV-TB patients. Median time to manifestations was 1 week after cART initiation in HIV-only and 6 weeks after anti-TB (i.e., 2 weeks after cART initiation) in HIV-TB patients. HIV-only patients had significantly higher efavirenz plasma concentrations at 4 weeks after cART compared to HIV-TB patients. No association of sex or genotype was seen in relation to neuropsychiatric manifestations. Risk for neuropsychiatric manifestations was three times more in HIV-only patients compared to HIV-TB (p < 0.01). CONCLUSIONS: Incidence of neuropsychiatric manifestations during early initiation of efavirenz-based cART is high in Tanzanian HIV patients. Risk of neuropsychiatric manifestations is lower in HIV patients co-treated with rifampicin containing anti-TB compared to those treated with efavirenz-based cART only. PMID- 30003276 TI - Subterranean Desert Rodents (Genus Ctenomys) Create Soil Patches Enriched in Root Endophytic Fungal Propagules. AB - Subterranean rodents are considered major soil engineers, as they can locally modify soil properties by their burrowing activities. In this study, the effect of a subterranean rodent of the genus Ctenomys on soil properties and root endophytic fungal propagules in a shrub desert of northwest Argentina was examined. Our main goal was to include among root endophytic fungi not only arbuscular mycorrhiza but also the dark septate endophytes. We compared the abundance of fungal propagules as well as several microbiological and physicochemical parameters between soils from burrows and those from the surrounding landscape. Our results show that food haulage, the deposition of excretions, and soil mixing by rodents' burrowing promote soil patchiness by (1) the enrichment in both types of root endophytic fungal propagules; (2) the increase in organic matter and nutrients; and (3) changes in soil edaphic properties including moisture, field capacity, and texture. These patches may play a critical role as a source of soil heterogeneity in desert ecosystems, where burrows constructed in interpatches of bare soil can act, once abandoned, as "islands of fertility," promoting the establishment of plants in an otherwise hostile environment. PMID- 30003277 TI - Nonoccupational Exposure of Agricultural Area Residents to Pesticides: Pesticide Accumulation and Evaluation of Genotoxicity. AB - Although many studies related the toxic effects of pesticides on agricultural workers, little research has been done about agricultural area residents. The purpose of this work was to monitor the presence of pesticides, as well as their genotoxic and cytotoxic potential, in humans with blood samples collected from control and intensive agricultural areas in the Thrace region. Pesticide accumulations were determined by LC-MS/MS. Cytotoxicity and genotoxicity were analyzed by comet assay, and the effect of pesticide accumulation on oxidative stress, DNA repair, and molecular chaperone response were analyzed by qRT-PCR assays in the human blood samples. The agricultural area residents had a significantly higher concentration of pesticides than those in the control area at all three sampling times, and the total pesticide amounts were 4.3 and 10 times significantly higher in blood sampled in the pesticide use period (August 2015 and 2016, respectively) than in the nonuse period (November 2015). The results showed that the pesticide level in blood during the use period led to oxidative stress, DNA damage (mean comet length and % tail DNA), and unfolded/misfolded protein response. Particularly, in pesticide use season, difference between these parameters was found statistically significant with comparison to control. Our results indicate that individuals residing around a monoculture rice farming area comprise an at-risk group as a result of increased genotoxicity evidenced in human blood. We suggest that biological monitoring efforts should be used to control nonoccupational exposures to pesticides and thus safeguard the health of agricultural area residents. PMID- 30003278 TI - Second opinions in orthopedic oncology imaging: can fellowship training reduce clinically significant discrepancies? AB - OBJECTIVE: To determine factors that lead to significant discrepancies in second opinion consultation of orthopedic oncology patients, and particularly if musculoskeletal fellowship training can decrease clinically significant discrepancies. METHODS: A PACS database was queried for secondary reads on outside cross-sectional imaging studies, as requested by orthopedic oncology from 2014 to 2017. Comparison of original and secondary reports was performed using a published seven-point scale that defines clinically significant discrepancies. An online search was performed for each original radiologist to record if a fellowship in musculoskeletal imaging was completed. Additionally, years of post residency experience, number of Medicare part B patients billed per year (marker of practice volume), and average hierarchical condition category for each radiologist (marker of practice complexity) was recorded. RESULTS: A total of 571 patients met the inclusion criteria, with 184 cases initially interpreted by an outside fellowship trained musculoskeletal (MSK) radiologist and 387 cases initially interpreted by a non-MSK trained radiologist. The rate of clinically significant discrepancy was 9.2% when initially interpreted by MSK radiologists compared with 27.9% when initially performed by non-MSK radiologists (p < 0.05). After adjustment by both patient characteristics and radiologist characteristics, the likelihood of clinically significant discrepancies was greater for initial interpretations by non-MSK radiologists compared with MSK radiologists (OR = 1.36; 95% CI = 1.23-2.49). CONCLUSION: In orthopedic oncology patients, the rate of clinically significant discrepancies was significantly higher when initially interpreted by non-MSK radiologists compared with MSK radiologists. The lower rate of clinically significant discrepancies demonstrates that subspecialty training may direct more appropriate diagnosis and treatment. PMID- 30003280 TI - [Embrace the new technology?! : Telematics infrastructure is coming]. PMID- 30003279 TI - Point vs. traditional method evaluation of hallux valgus: interreader reliability and intermethod performance using X-ray and MRI. AB - BACKGROUND: The two most widely used measurements for diagnosing and assessing the severity of hallux valgus are the hallux valgus angle (HVA) and the intermetatarsal angle (IMA). Traditionally, these have been measured by using the midaxial lines approximating the axis of each bone. A new simpler point method has been recently suggested for measuring these angles by connecting points along the medial corners of each bone. Interreader reliability of these measurements on X-ray and MRI as well as intermethod and intermodality differences have not been assessed. METHODS: A series of 56 consecutive patients between 18 and 100 years old with no history of foot trauma or orthopedic hardware in their feet were included. All had AP and lateral X-rays and MRI performed on the same foot between April 27, 2015 and March 9, 2016. Two readers measured HVA and IMA using both the traditional midaxial and new point methods. ICC correlations were obtained. RESULTS: The interreader reliability for HVA was similar on point method (0.92) and traditional method (0.94). For the IMA, the ICC was 0.77 on point method versus 0.76 on traditional method. The intermodality agreement (between X-ray and MRI) was higher for HVA (ICC = 0.85, 0.88) as compared to IMA (0.58, 0.74), respectively on both methods. The mean difference between the methods was larger on traditional method = 5.5 for HVA and 2.5 degrees for IMA. CONCLUSIONS: HVA is more reliable than IMA on both methods and modalities and a significant difference exists between the magnitudes of values obtained using the two methods. LEVEL OF CLINICAL EVIDENCE: 3. PMID- 30003281 TI - [Urogister and Uroscience : A combination of a supported, automatic cancer registry and health care research]. AB - The Professional Association of German Urologists (BvDU e. V) and Deutsches Institut fur Facharztliche Versorgungsforschung GmbH (DIFA) jointly develop the online portals urogister.de and uroscience.de. Urogister.de allows all German urologists to perform the obligatory communication with the regional cancer registry in a unified manner. The parties' goal is to minimize the daily effort in the doctors' practices. This is achieved mainly through software that is able to read, analyze, and communicate the existing data in the local documentation software of the practice. This software will find and use all data that can be used to complete the cancer registry's required forms. As an additional benefit, the physician can take part in a comprehensive medical outcomes research project that builds on the data that is used during the urogister process, i. e., the complete content of the practice's medical data base plus the additional data from the cancer registry communication. These data will be rendered anonymous and centrally stored, under the regular control and supervision of BvDU. Uroscience.de, the second online solution, builds on this anonymous database. Its main function is to offer urologists the possibility to take part in projects of medical outcomes research. This research will be organized by DIFA, and the projects are offered to interested parties from the scientific domain, from the professional associations, and from industry partners searching for specific insight into real world medical treatment. In all such projects, the urologists/BvDU have the supervision and final say. PMID- 30003282 TI - Ionic Liquids as Stabilization and Refolding Additives and Solvents for Proteins. AB - This chapter focuses on recent advances in the use of ionic liquids as additives and solvents in protein applications. The solvent properties of ionic liquids can be tuned by the appropriate selection of cation and anion. The effects of different kinds of ionic liquids on protein stability and refolding behavior have been investigated and reported. The ionic liquid properties affect the intermolecular interactions of proteins, inducing different formations and folding behavior. These effects also vary with the concentration of ionic liquids. Although many of the associated mechanisms are not completely clear, some of this behavior may be attributed to the kosmotropicity of the ions and their Hofmeister effects. Graphical Abstract. PMID- 30003284 TI - Validation of the Polish version of the Pelvic Floor Distress Inventory. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to develop a Polish language version of the short form of the Pelvic Floor Distress Inventory (PFDI 20) and to validate it in a sample of Polish-speaking women with pelvic floor disorders (PFDs). METHODS: The PFDI-20 was initially translated in a stepwise fashion as guided by the International Urogynecological Association (IUGA) Translation Protocol. After initial forward translation from English to Polish, a community review process consisting of cognitive interviews and confirmation via back translation was performed. The final Polish version of the PFDI-20 was administered to Polish-speaking patients presenting with PFDs at university-based urogynecology clinics in Poland and the United States, along with a Polish version of the King's Health Questionnaire (KHQ). Internal consistency and criterion validity were assessed. Test-retest reliability was assessed in 100 patients after 2 weeks. RESULTS: A total of 254 women with PFDs enrolled in this multicenter study. Complete data from 44 Polish-speaking women in the United States and 200 women in Poland were analyzed. Participants had a mean age of 60.3 +/- 11.2 years and mean body mass index (BMI) 27.6 +/- 4.7. Internal consistency as measured by Cronbach's alpha was good (0.89). Criterion validity was adequate between responses on the KHQ and PFDI-20 with Pearson correlations in particular domains (0.27-0.50, P < 0.05). Excellent test-retest reliability was demonstrated by intraclass correlation using a two-way mixed-effects model with absolute agreement (0.87). CONCLUSIONS: The Polish version of the PFDI is a reliable tool for evaluating pelvic floor symptoms in Polish-speaking women with PFDs. PMID- 30003283 TI - Diffusion-weighted breast imaging. AB - Magnetic resonance imaging (MRI) of the breast represents one of the most sensitive imaging modalities in breast cancer detection. Diffusion-weighted imaging (DWI) is a sequence variation introduced as a complementary MRI technique that relies on mapping the diffusion process of water molecules thereby providing additional information about the underlying tissue. Since water diffusion is more restricted in most malignant tumors than in benign ones owing to the higher cellularity of the rapidly proliferating neoplasia, DWI has the potential to contribute to the identification and characterization of suspicious breast lesions. Thus, DWI might increase the diagnostic accuracy of breast MRI and its clinical value. Future applications including optimized DWI sequences, technical developments in MR devices, and the application of radiomics/artificial intelligence algorithms may expand the potential of DWI in breast imaging beyond its current supplementary role. PMID- 30003285 TI - [Action plan of the Federal Ministry of Health for improvement of medication safety in Germany : An inventory]. AB - In 2008, the Federal Ministry of Health launched an action plan for the improvement of medication safety. The action plan includes measures to prevent medication errors. Implementation of the action plan is supported by national associations of all professional groups involved in the medication process as well as patient associations. The major importance of medication safety has been recognised not only by scientists and researchers but also by political decision makers. More efforts are clearly needed to translate the findings gleaned from the action plans into binding regulations to secure their nationwide implementation and, in the process, the further material improvement of medication safety. Irrespective of any such regulations-which is for the legislator or regulator to take-the fact remains that the greatest contributions towards this goal must come not only from the medical and nursing professionals in their daily clinical practice but also, and even to a far greater extent than has been the case so far, from the patients themselves. PMID- 30003286 TI - Transportal central femoral tunnel placement has a significantly higher revision rate than transtibial AM femoral tunnel placement in hamstring ACL reconstruction. AB - PURPOSE: It is proposed that central femoral ACL graft placement better controls rotational stability. This study evaluates the consequence of changing the femoral tunnel position from the AM position drilled transtibially to the central position drilled transportally. The difference in ACL graft failure is reported. METHODS: This prospective consecutive patient single surgeon study compares the revision rates of 1016 transtibial hamstring ACL reconstructions followed for 6 15 years with 464 transportal hamstring ACL reconstructions followed for 2-6 years. Sex, age, graft size, time to surgery, meniscal repair and meniscectomy data were evaluated as contributing factors for ACL graft failure to enable a multivariate analysis. To adjust for the variable follow-up a multivariate hazard ratio, failure per 100 graft years and Kaplan-Meier survivorship was determined. RESULTS: With transtibial ACLR 52/1016 failed (5.1%). With transportal ACLR 32/464 failed (6.9%). Significant differences between transportal and transtibial ACLR were seen for graft diameter, time to surgery, medial meniscal repair rates and meniscal tissue remaining after meniscectomy. Adjusting for these the multivariate hazard ratio was 2.3 times higher in the transportal group (p = 0.001). Central tunnel placement resulted in a significantly 3.5 times higher revision rate compared to an anteromedial tunnel placement per 100 graft years (p = 0.001). Five year survival was 980/1016 (96.5%) for transtibial versus 119/131 (90.5%) for transportal. Transportal ACLR also showed a significantly higher earlier failure rate with 20/32 (61%) of the transportal failing in the first year compared with 14/52 (27%) for transtibial. (p = 0.001.) CONCLUSION: Transportal central femoral tunnel ACLR has a higher failure rate and earlier failure than transtibial AM femoral tunnel ACLR. LEVEL OF EVIDENCE: Level II prospective comparative study. PMID- 30003288 TI - Epicardial adipose tissue: good or bad for cardiac function? PMID- 30003287 TI - Effects of antiepileptic drugs on lipogenic gene regulation and hyperlipidemia risk in Taiwan: a nationwide population-based cohort study and supporting in vitro studies. AB - To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population based cohort study with data obtained from the National Health Insurance Research Database of Taiwan. The effects of AEDs on lipogenic gene expression were also examined in vitro. We identified 3617 cases involving patients, whose epilepsy was newly diagnosed between 2000 and 2011, and selected a comparison cohort comprising 14,468 patients without epilepsy. The Cox proportional hazards model was used to evaluate the association between epilepsy, AED use, and hyperlipidemia. The incidence rate of hyperlipidemia was higher in the epilepsy cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 1.21 [95% confidence interval (CI): 1.06-1.38] after adjusting for comorbidities and medications. Epilepsy patients not taking AEDs had a higher risk of hyperlipidemia (aHR 1.65; 95% CI 1.35-2.03). Among AEDs, only valproate treatment showed a higher risk of hyperlipidemia (aHR 1.53; 95% CI 1.01-2.33), although the dose-dependent effect did not reach statistical significance. In vitro studies with two hepatic cell lines showed that valproate may exert its effects by activating the liver X receptor alpha (LXRalpha) signaling pathway, inducing the expression of lipogenesis-related genes and increasing cellular lipid contents. In silico calculations concluded that valproate can bind stably with the ligand binding domain of LXRalpha. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXRalpha activation. Predicting the 'off-target' effects of valproate may prove valuable in developing antiepileptic agents with fewer adverse reactions. Monitoring blood lipid levels throughout the course of treatment is recommended. PMID- 30003289 TI - Matrix-free laser desorption ionization mass spectrometry as a functional tool for the analysis and differentiation of complex phenolic mixtures in propolis: a new approach to quality control. AB - Matrix-free laser desorption ionization (LDI) is a rapid and versatile technique for the ionization of small, UV-light-absorbing molecules. Indeed, many natural products such as polyphenols exhibit inherent LDI properties, potentially facilitating their detection from highly complex samples such as crude extracts. With this in mind, the present work thoroughly evaluated the potential of LDI as an analytical tool for the chemical profiling and differentiation of propolis samples obtained from different global regions. Propolis is a complex bee product containing, among others, significant amounts of phenolic constituents that may show LDI effects. The present work will demonstrate that LDI not only provides reproducible and highly specific fingerprint spectra for each of the tested samples, it further allows their clear differentiation by principal compound analysis (PCA). Contrary to classical analytical approaches such as LC- or GC-MS, LDI does not require time-consuming sample preparation and method optimization procedures. Thus, the technique represents a most interesting analytical tool and potent supplement to classic LC-MS for quality control of herbal pharmaceuticals and dietary supplements. Present results clearly support this approach and further suggest the use of LDI as a versatile tool for the automated analysis of large sample batches on an industrial scale. Graphical abstract ?. PMID- 30003290 TI - Correction to: Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes. AB - In the original version of this article, PCR fragments and digestion product sizes for the VRN-B2 and VRN-D2 markers were not accurate. The corrected sizes are detailed below. PMID- 30003293 TI - Portuguese Neuroradiology Society (Sociedade Portuguesa de Neurorradiologia - SPNR) XIII Annual Congress, May 31st to June 6th, 2017. PMID- 30003292 TI - Phase II study of accelerated Linac-based SBRT in five consecutive fractions for localized prostate cancer. AB - AIM: The goal was to evaluate feasibility, side effects and biochemical no evidence of disease (bNED) after stereotactic body radiation therapy (SBRT) delivered on 5 consecutive days for localized prostate cancer (PC). METHODS: The study was approved by the ethical committee and started in March 2014. Inclusion criteria were age <=85 years, WHO performance status <=2, histologically proven adenocarcinoma, low-intermediate risk, no previous surgery (except transurethral resection of the prostate), and a pre-SBRT International Prostatic Symptoms Score of 0-7. The radiotherapy regimen consisted of 35 Gy for low-risk and 37.5 Gy for intermediate-risk PC in 5 consecutive fractions. RESULTS: At the time of the analysis, 52 patients were recruited to the study (median age 73 years, range 55 83 years; median follow-up 34 months, range 12-49 months; 34 patients low-risk and 18 intermediate risk). The median initial prostate-specific antigen (PSA) was 5.9 ng/ml (range 1.8-15.7). Acute genitourinary (GU) toxicity was G0 (grade 0) 36/52 (69%), G1 11/52 (21%), G2 5/52 (10%), while acute rectal (GI) toxicity was G0 43/52 (83%), G1 8/52 (15%), G2 1/52 (2%). No acute toxicity >=G3 was recorded. At the time of analysis late GU and GI toxicities were as follows: GU-G0 43/52 (83%), GU-G1 7/52 (13%), GU-G2 2/52 (4%); GI-G0 48/52 (92%), GI-G1 2/52 (4%), GI G2 2/52 (4%). No late toxicities >=G3 were recorded. bNED was 98%. One patient with intermediate PC had distant progression. CONCLUSIONS: Accelerated SBRT for low-intermediate PC is feasible and well tolerated with comparable oncological outcome as described for other series with the same RT technique but treatment delivery on every other day. Longer follow-up is needed to the assess late toxicity profile and long-term clinical outcome. PMID- 30003295 TI - How do reaching and walking costs affect movement path selection? AB - Although reaching and walking are commonly coordinated, their coordination has been little studied. We investigated decision-making related to reaching and walking in connection with a recently discovered phenomenon called pre crastination-the tendency to expend extra effort in the service of hastening goal or sub-goal completion. In the earlier studies where pre-crastination was discovered, participants decided which of two buckets to carry to the end of a walkway, picking the bucket they thought was easier. Surprisingly, the majority of participants chose to carry the bucket that was closer to the start position, which meant that the bucket they chose had to be carried farther than the bucket they did not choose. Here we inquired into participants' sensitivity to reaching effort and walking effort by varying how far participants had to reach to pick up a bucket, how heavy the bucket was, and how far participants had to walk with the bucket they chose. We found that participants were willing to lean and reach far to pick up an empty bucket that was a shorter walk from the start position. However, as reaching costs and carrying costs increased, participants prioritized shorter reaches over shorter walking distances. The results show that although pre-crastination is a robust tendency, there are limits to the kinds of costs people are willing to incur to complete sub-goals as soon as possible. PMID- 30003291 TI - Epigenetic regulation of Toll-like receptors and its roles in type 1 diabetes. AB - The immune system can be divided into adaptive immunity and innate immunity. Adaptive immunity has been confirmed to be involved in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, the role of innate immunity in T1D has only been studied recently. T1D is caused by selective autoimmune destruction of pancreatic islet beta cells. A series of studies have suggested that TLRs play a critical role in the pathogenesis of T1D. Aberrant TLR signaling will change immune homeostasis and result in immunopathological conditions such as endotoxin shock and autoimmune responses. Thus, TLR signaling pathways are supposed to be strictly and finely regulated. Epigenetics has recently been proven to be a new regulator of TLR expression. DNA methylation, histone modification, and microRNAs are the three main epigenetic modifications. This review will mainly focus on these epigenetic mechanisms of regulation of TLRs and the role of TLRs in the pathogenesis of T1D. PMID- 30003296 TI - Everyone loves an underdog: metabolic engineering of the xylose oxidative pathway in recombinant microorganisms. AB - The D-xylose oxidative pathway (XOP) has recently been employed in several recombinant microorganisms for growth or for the production of several valuable compounds. The XOP is initiated by D-xylose oxidation to D-xylonolactone, which is then hydrolyzed into D-xylonic acid. D-Xylonic acid is then dehydrated to form 2-keto-3-deoxy-D-xylonic acid, which may be further dehydrated then oxidized into alpha-ketoglutarate or undergo aldol cleavage to form pyruvate and glycolaldehyde. This review introduces a brief discussion about XOP and its discovery in bacteria and archaea, such as Caulobacter crescentus and Haloferax volcanii. Furthermore, the current advances in the metabolic engineering of recombinant strains employing the XOP are discussed. This includes utilization of XOP for the production of diols, triols, and short-chain organic acids in Escherichia coli, Saccharomyces cerevisiae, and Corynebacterium glutamicum. Improving the D-xylose uptake, growth yields, and product titer through several metabolic engineering techniques bring some of these recombinant strains close to industrial viability. However, more developments are still needed to optimize the XOP pathway in the host strains, particularly in the minimization of by-product formation. PMID- 30003297 TI - Preoperative Coronary Anatomy Assessment with Echocardiography and Morbidity After Arterial Switch Operation of Transposition of the Great Arteries. AB - In transposition of the great arteries (TGA), certain coronary patterns have been associated with major adverse events early after the arterial switch operation (ASO). We sought to determine the impact of preoperative echocardiographic (ECHO) diagnosis on the intra- and postoperative morbidity. All patients with TGA born between June 2001 and June 2017 and who underwent ASO were reviewed. Data on presumed coronary anatomy (CA) preoperatively were obtained from the preoperative ECHO report. Intraoperative CA was categorized according to Yacoub classification. Major postoperative morbidity included at least one of the following: delayed sternal closure (DSC), prolonged (> 72 h) mechanical ventilation, reintubation, peritoneal dialysis (PD), ECMO, reoperation, and readmission within 30 days after surgery. 240 patients with median age of 5 days (range 1-614) and mean weight at surgery was 3.6 kg (1.8-8.4) were included. Preoperative ECHO assessment of CA was available in 228 patients. Intraoperatively, 181 patients (75%) were found to have type A, 25 patients had type B or C or intramural (B-C-IM; 10%), and 34 patients had type D or E (D-E; 14%). Patients with types B, C, and intramural coronary (B-C-IM) had increased risk for delayed sternum closure (9/25 vs. 20/181 in type A and 8/34 in type D-E; p = 0.04), peritoneal dialysis (4/25 vs. 8/181 and 1/34; p = 0.04), and ECMO (2/25 vs. 1/131 and 1/34; p = 0.02). Within the B-C-IM group, preoperative ECHO raised suspicion of type A in 13 patients (i.e., incorrect diagnosis, ID; 52%), whereas non-A CA was suspected in 12 patients (i.e., correct diagnosis, CD; 48%). With the exception of reoperation, which was seen only in the ID subgroup (4/12 vs. 0/10 in the CD subgroup; p = 0.04), the intraoperative (cardiopulmonary bypass time and cross-clamp time) and postoperative morbidity indices were comparable in both ID and CD subgroups (p > 0.1). Although there is a significant risk for early postoperative morbidity in TGA patients with single, interarterial, and intramural CA, there seems to be relatively limited influence of preoperative ECHO assessment of coronary anatomy on this morbidity burden. PMID- 30003298 TI - Evaluation of Early Left Ventricular Dysfunction in Patients with Duchenne Muscular Dystrophy Using Two-Dimensional Speckle Tracking Echocardiography and Tissue Doppler Imaging. AB - Although progressive cardiac dysfunction is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), their cardiac function measured by conventional echocardiography has been generally interpreted as normal at a young age. We aimed to determine whether two-dimensional speckle tracking echocardiography (STE) or tissue Doppler imaging (TDI) could be used for early identification and detection of cardiac dysfunction in young patients with DMD. Thirteen pediatric patients (mean age, 9.69 +/- 2.2 years) with DMD and 26 age matched healthy children (mean age, 9.65 +/- 2.2 years) were included in the study. All patients were examined via conventional echocardiography, TDI, and STE. Standard echocardiographic measurements of left ventricular (LV) systolic and diastolic function were obtained. Myocardial velocities including peak systolic and early- and late-diastolic myocardial velocities were calculated in longitudinal direction in the interventricular septum, using TDI. Speckle tracking analyses were performed by acquiring apical four-, three-, and two chamber views with the highest possible frame rates. Conventional parameters were similar between the two groups, but heart rates were higher in patients with DMD than in controls. The results of LV diastolic function evaluated using TDI showed that annular peak velocity during early diastole (e'; 10.9 +/- 1.7 vs. 14.6 +/- 1.7 cm/s), e'/a' ratio (2.0 +/- 0.5 vs. 3.0 +/- 0.5), E/e' ratio (9.4 +/- 1.4 vs. 7.3 +/- 0.8), and myocardial performance index (0.46 +/- 0.05 vs. 0.36 +/- 0.06) of the mitral septal annulus among patients with DMD differed significantly from those of healthy children. A significant decrease in global longitudinal systolic strain was found in patients with DMD (- 16.6 +/- 3.7 vs. - 21.2 +/- 2.1), with a marked decrease in the LV basal inferolateral and basal inferior walls. In young patients with DMD who have global normal systolic function, reductions in systolic deformation parameters as well as reduced early diastolic myocardial velocities can be detected particularly in the basal inferolateral LV walls. The prognostic significance of these findings warrants further longitudinal follow up. PMID- 30003299 TI - The modulatory role of accumbens and hippocampus D2 receptors in anxiety and memory. AB - The present study investigated the role of dopamine D2 receptors (D2Rs) of the dorsal hippocampus (DH) and the nucleus accumbens (NAc) and the effect of their dopaminergic activities on anxiety-like behavior and aversive learning using a test-retest elevated plus-maze (EPM) paradigm in male Wistar rats. Guide cannulae were implanted to allow microinjection of D2R agonist quinpirole or antagonist sulpiride. The pre-test intra-NAc microinjection of quinpirole (0.0625-0.25 MUg/rat) or sulpiride (0.125-0.5 MUg/rat) increased the percentage of time spent in the open arms (%OAT) of EPM, suggesting an anxiolytic-like effect. However, an increase in open-arm avoidance was observed in the control rats when retested in the EPM, suggesting aversive information storage. Furthermore, a similar result was obtained in the quinpirole-treated rats. In contrast, the sulpiride-treated rats failed to demonstrate further open-arm avoidance, thus proposing an aversive learning deficit. The intra-DH microinjection of drugs alone induced an anxiolytic-like effect and learning deficit. The quinpirole (0.125 MUg/rat) injected into each site had no effect on the response induced by sulpiride injected into another site. Finally, a subthreshold dose of quinpirole in both sites did not alter the %OAT; on the contrary, it preserved the aversive memory. The sulpiride induced an anxiolytic-like effect and a learning deficit. Our data suggests that the involvement of D2Rs in the interactions of DH-NAc dopaminergic system helps regulate anxiety-related behavior and EPM-associative memory. PMID- 30003301 TI - Venovenous ECMO cannulation in a patient with a pre-existing IVC filter. PMID- 30003300 TI - AUC measurements of diffusion coefficients of monoclonal antibodies in the presence of human serum proteins. AB - The goal of this work is to develop a preclinical method for quantitative hydrodynamic and thermodynamic analysis of therapeutic proteins in crowded environments like human serum. The method utilizes tracer amounts of fluorescently labeled monoclonal antibodies and the Aviv AU-FDS optical system. We have performed sedimentation velocity experiments as a function of mAb, human serum albumin and human IgG concentration to extract self- and cross-term hydrodynamic nonideality effects. SV measurements are consistently complicated by weak mAb-mAb and mAb-IgG interactions (Wright et al. in Anal Biochem 550:72-83, 2018). In an attempt to explore different approaches we have investigated measurements of diffusion coefficients by traditional synthetic boundary experiments. Here we present a new technique incorporated into SEDANAL that can globally analyze the full time course of synthetic boundary experiments. This approach also utilizes F-mAb against a high concentration of unlabeled carrier protein (HSA or IgG). In principle both diffusion and sedimentation coefficient information can be extracted including hydrodynamic and thermodynamic nonideality. The method can be performed at a traditional low speed (5-7K rpm) or at high speeds. The high speed method can also be used to measure D and s for small molecules like fluorescein (often contaminants of F-HSA and F-mAb). The advantage of synthetic boundary over the standard sedimentation velocity method is that it allows for higher precision determination of diffusion coefficients. The concentration dependence of D can be corrected for hydrodynamic nonideality effects by plotting D * (1 + kijcj) vs total carrier concentration. The slope of the fitted data allows an alternate approach to determine self- and cross-term thermodynamic nonideality. This method can also explore cross-term diffusion coefficient effects. These results are compared to dynamic light scattering approaches which are limited to kD determinations for solutions of pure protein. PMID- 30003302 TI - MAP of 65: target of the past? PMID- 30003303 TI - Increased risk of death and readmission after hospital discharge of critically ill patients in a developing country: a retrospective multicenter cohort study. AB - PURPOSE: To describe long-term mortality and hospital readmissions of patients admitted to Brazilian intensive care units (ICU). METHODS: Retrospective cohort study of adult patients admitted to Brazilian hospitals affiliated to the Public Healthcare System from 10 state capitals. ICU patients were paired to non-ICU patients by frequency matching (ratio 1:2), according to postal code and admission semester. Hospitalization records were linked through deterministic linkage to national mortality data. Primary outcome was mortality up to 1 year. Other outcomes were mortality and readmissions at 30 and 90 days and 3 years. Multiple Cox regressions were used adjusting for age, sex, cancer diagnosis, type of hospital, and surgical status. RESULTS: We included 324,594 patients (108,302 ICU and 216,292 non-ICU). ICU patients had increased hospital length of stay [9 (5-17) vs. 3 (1-6) days, p < 0.001] and mortality (18.5 vs. 3.6%, p < 0.001) versus non-ICU patients. One year after discharge, ICU patients were more frequently readmitted to hospital (25.4 vs. 17.4%, p < 0.001) and to ICU (31.4 vs. 7.3%, p < 0.001) than controls. Mortality up to 1 year was also higher for ICU patients (14.3 vs. 3.9%, p < 0.001). A significant interaction between surgical status and mortality was found, with adjusted hazard ratios (HRs) up to 1 year of 2.7 [95% confidence interval (CI) 2.5-2.9] for surgical patients, and 3.4 (95%CI 3.3-3.5) for medical patients. The risk for death and readmission diminished over time up to 3 years. CONCLUSIONS: In a public healthcare system of a developing country, ICU patients have excessive long-term mortality and frequent readmissions. The ICU burden tended to reduce over time after hospital discharge. PMID- 30003305 TI - Breech presentation is associated with lower bone mass and area: findings from the Southampton Women's Survey. AB - : We compared bone outcomes in children with breech and cephalic presentation at delivery. Neonatal whole-body bone mineral content (BMC) and area were lower in children with breech presentation. At 4 years, no differences in whole-body or spine measures were found, but hip BMC and area were lower after breech presentation. INTRODUCTION: Breech presentation is associated with altered joint shape and hip dysplasias, but effects on bone mineral content (BMC), area (BA) and density (BMD) are unknown. METHODS: In the prospective Southampton Women's Survey mother-offspring cohort, whole-body bone outcomes were measured using dual energy X-ray absorptiometry (DXA) in 1430 offspring, as neonates (mean age 6 days, n = 965, 39 with a breech presentation at birth) and/or at age 4.1 years (n = 999, 39 breech). Hip and spine bone outcomes were also measured at age 4 years. RESULTS: Neonates with breech presentation had 4.2 g lower whole-body BMC (95% CI -7.4 to - 0.9 g, P = 0.012) and 5.9 cm2 lower BA (- 10.8 to - 1.0 cm2, P = 0.019), but BMD was similar between groups (mean difference - 0.007, - 0.016 to 0.002 g/cm2, P = 0.146) adjusting for sex, maternal smoking, gestational diabetes, mode of delivery, social class, parity, ethnicity, age at scan, birthweight, gestational age and crown-heel length. There were no associations between breech presentation and whole-body outcomes at age 4 years, but, in similarly adjusted models, regional DXA (not available in infants) showed that breech presentation was associated with lower hip BMC (- 0.51, - 0.98 to - 0.04 g, P = 0.034) and BA (- 0.67, - 1.28 to - 0.07 cm2, P = 0.03) but not with BMD (- 0.009, - 0.029 to 0.012 g, P = 0.408), or spine outcomes. CONCLUSIONS: These results suggest that breech presentation is associated with lower neonatal whole body BMC and BA, which may relate to altered prenatal loading in babies occupying a breech position; these differences did not persist into later childhood. Modest differences in 4-year hip BMC and BA require further investigation. PMID- 30003304 TI - Assessing predictive accuracy for outcomes of ventilator-associated events in an international cohort: the EUVAE study. AB - PURPOSE: To analyze the impact on patient outcome of ventilator-associated events (VAEs) as defined by the Centers for Disease Control and Prevention (CDC) in 2008, 2013, and the correlation with ventilator-associated pneumonia (VAP) or tracheobronchitis (VAT). METHODS: This was a prospective, observational, multicenter, international study conducted at 13 intensive care units (ICUs); thirty consecutive adults mechanically ventilated for >= 48 h per site were eligible, with daily follow-up being recorded in a collaborative web database; VAEs were assessed using the 2013 CDC classification and its 2015 update. RESULTS: A total of 2856 ventilator days in 244 patients were analyzed, identifying 33 VAP and 51 VAT episodes; 30-day ICU mortality was significantly higher (42.8 vs. 19.6%, p < 0.007) in patients with VAP than in those with VAT. According to the 2013 CDC definitions, 117 VAEs were identified: 113 (96%) were infection-related ventilator-associated complication-plus (IVAC-plus), while possible ventilator-associated pneumonia (PVAP) was found in 64 (56.6%) of them. VAE increased the number of ventilator days and prolonged ICU and hospital LOS (by 5, 11, and 12 days, respectively), with a trend towards increased 30-day mortality (43 vs 28%, p = 0.06). Most episodes (26, 55%) classified as IVAC-plus without PVAP criteria were due to atelectasis. PVAP significantly increased (p < 0.05) ventilator days as well as ICU and hospital LOS (by 10.5, 14, and 13 days, respectively). Only 24 (72.7%) of VAP and 15 (29.4%) of VAT episodes met IVAC plus criteria. CONCLUSIONS: Respiratory infections (mainly VAT) were the most common complication. VAE algorithms only identified events with surrogates of severe oxygenation deterioration. As a consequence, IVAC definitions missed one fourth of the episodes of VAP and three fourths of the episodes of VAT. Identifying VAT (often missed by IVAC-plus criteria) is important, as VAP and VAT have different impacts on mortality. PMID- 30003306 TI - Attenuation of cocaine seeking in rats via enhancement of infralimbic cortical activity using stable step-function opsins. AB - RATIONALE: The infralimbic cortex (IL) and its downstream projection target the nucleus accumbens shell (NAshell) mediate the active suppression of cocaine seeking behavior. Although an optogenetic approach would be beneficial for stimulating the IL and its efferents to study their role during reinstatement of cocaine seeking, the use of channelrhodopsin introduces significant difficulties, as optimal stimulation parameters are not known. OBJECTIVES: The present experiments utilized a stable step-function opsin (SSFO) to potentiate endogenous activity in the IL and in IL terminals in the NAshell during cocaine-seeking tests to determine how these manipulations affect cocaine-seeking behaviors. METHODS: Rats first underwent 6-h access cocaine self-administration followed by 21-27 days in the homecage. Rats then underwent cue-induced and cocaine-primed drug-seeking tests during which the optogenetic manipulation was given. The same rats then underwent extinction training, followed by cue-induced and cocaine primed reinstatements. RESULTS: Potentiation of endogenous IL activity did not significantly alter cue-induced or cocaine-primed drug seeking following the homecage period. However, following extinction training, enhancement of endogenous IL activity attenuated cue-induced reinstatement by 35% and cocaine primed reinstatement by 53%. Stimulation of IL terminals in the NAshell did not consistently alter cocaine-seeking behavior. CONCLUSION: These results suggest the utility of an SSFO-based approach for enhancing activity in a structure without driving specific patterns of neuronal firing. However, the utility of an SSFO-based approach for axon terminal stimulation remains unclear. Moreover, these results suggest that the ability of the IL to reduce cocaine seeking depends, at least in part, on rats first having undergone extinction training. PMID- 30003307 TI - Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank. AB - AIMS/HYPOTHESIS: Coronary artery disease (CAD) is a common complication among individuals with diabetes. A better understanding of the genetic background of CAD in this population has the potential to suggest novel molecular targets for screening, risk assessment and drug development. METHODS: We performed a genome wide association study of CAD in 15,666 unrelated individuals (3,968 CAD cases and 11,698 controls) of white British ancestry with diabetes at inclusion in the UK Biobank study. Our results were compared with results from participants without diabetes. RESULTS: We found genome-wide significant evidence for association with CAD at the previously well-established LPA locus (lead variant: rs74617384; OR 1.38 [95% CI 1.26, 1.51], p = 3.2 * 10-12) and at 9p21 (lead variant: rs10811652; OR 1.19 [95% CI 1.13, 1.26], p = 6.0 * 10-11). Moreover, other variants previously associated with CAD showed similar effects in the participants with and without diabetes, indicating that the genetic architecture of CAD is largely the same. CONCLUSIONS/INTERPRETATION: Our results indicate large similarities between the genetic architecture of CAD in participants with and without diabetes. Larger studies are needed to establish whether there are important diabetes-specific CAD loci. PMID- 30003308 TI - The chicken or the egg? Does glycaemic control predict cognitive function or the other way around? AB - The association between type 2 diabetes and cognitive dysfunction is well established. Prevention of the development of type 2 diabetes and its complications, as well as cognitive dysfunction and dementia, are leading goals in these fields. Deciphering the causality direction of the interplay between type 2 diabetes and cognitive dysfunction, and understanding the timeline of disease progression, are crucial for developing efficient prevention strategies. The prevailing perception is that type 2 diabetes leads to cognitive dysfunction and dementia. There is substantial evidence showing that accelerated cognitive decline in type 2 diabetes starts in midlife (mean age 40-60 years) and that it may even begin at the prediabetes stage. However, in this issue of Diabetologia, Altschul et al (doi: https://doi.org/10.1007/s00125-018-4645-8 ) show evidence for the reverse causality hypothesis, i.e. that lower cognitive function precedes poor glycaemic control. They found that cognitive function at early adolescence (age 11 years) predicts both HbA1c levels and cognitive function at age 70 years. Moreover, they found that lower cognitive function at age 70 is associated with an increase in HbA1c from age 70 to 79 years. Based on these findings, future studies should explore whether developing prevention strategies that target young adolescents with lower cognitive function will result in prevention of type 2 diabetes, breaking the vicious cycle of type 2 diabetes and cognitive dysfunction. PMID- 30003309 TI - Activation of insulin receptors and IGF-1 receptors in COLO-205 colon cancer xenografts by insulin and insulin analogue X10 does not enhance growth under normo- or hypoglycaemic conditions. AB - AIMS/HYPOTHESIS: Recent studies with normal rats and mouse allograft models have reported that insulin and insulin analogues do not activate the IGF-1 receptor in vivo, and that this characteristic therefore cannot be responsible for the increased incidence of mammary tumours observed for the insulin analogue X10 in chronic toxicity studies with Sprague Dawley rats. This is in clear contrast to reports of insulin and insulin analogues in vitro. Clarification of this is important for understanding the mechanisms behind possible growth-promoting effects of insulin analogues, and will have implications for the development of novel insulin analogues. METHODS: We established a xenograft model in BALB/c nude mice with the human colon cancer cell line COLO-205, which expresses human insulin and IGF-1 receptors, and explored the acute and chronic effects of treatment with supra-pharmacological doses of human insulin, insulin analogue X10 and human IGF-1. With a novel antibody, acute IGF-1 receptor activation was also examined in various tissues from normal rats treated with human insulin, insulin analogue X10 or human IGF-1. Finally, the effects of pharmacologically relevant doses of human insulin and insulin analogue X10 on receptor activation and growth of COLO-205 xenograft were explored in BALB/c nude mice with alloxan-induced hyperglycaemia. RESULTS: In normal rats and in BALB/c nude mice bearing a COLO 205 cell xenograft, treatment with supra-pharmacological doses of human insulin, insulin analogue X10 or human IGF-1 resulted in activation of insulin receptors as well as IGF-1 receptors. Treatment of diabetic nude mice with pharmacologically relevant doses of human insulin or insulin analogue X10, which decreased blood glucose from hyperglycaemic levels to the normoglycaemic range, did not increase IGF-1 receptor activation. Furthermore, repeated treatment with supra-pharmacological as well as pharmacological doses of human insulin or insulin analogue X10 did not influence the growth of COLO-205 xenografts. CONCLUSIONS/INTERPRETATION: This study demonstrates that activation of IGF-1 receptors in cancer cells by insulin and insulin analogues cannot be considered as a purely in vitro phenomenon. It does occur in vivo in animal models, although only after treatment with supra-pharmacological doses. Furthermore, treatment with insulin or insulin analogue X10 did not influence the growth of COLO-205 xenografts under normo- or hypoglycaemic conditions. Further studies are needed before a conclusion can be reached on whether IGF-1 receptor activation by insulin analogues correlates with increased growth in vivo. PMID- 30003310 TI - Time course of panic disorder and posttraumatic stress disorder onsets. AB - PURPOSE: Posttraumatic stress disorder (PTSD) often co-occurs with panic disorder (PD), with some etiological models positing a causal role of panic reactivity in PTSD onset; however, data addressing the temporal ordering of these conditions are lacking. The aim of this study was to examine the bi-directional associations between PD and PTSD in a nationally representative, epidemiologic sample of trauma-exposed adults. METHODS: Participants were community-dwelling adults (62.6% women; Mage = 48.9, SD 16.3) with lifetime DSM-IV PTSD criterion A trauma exposure drawn from the 2001/2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and re-interviewed in 2004/5 (N = 12,467). Cox discrete-time proportional hazards models with time-varying covariates were used to investigate the bi-directional associations between lifetime PD and PTSD, accounting for demographic characteristics, trauma load, and lifetime history of major depression, generalized anxiety disorder, and social anxiety disorder. RESULTS: PD was significantly associated with subsequent onset of PTSD (HR 1.210, 95%CI = 1.207-1.214, p < .001), and PTSD was significantly associated with onset of PD (HR 1.601, 95% CI 1.597-1.604, p < .001). The association between PTSD and subsequent PD was stronger in magnitude than that between PD and subsequent PTSD (Z = - 275.21, p < .01). Men evidenced stronger associations between PD and PTSD compared to women. CONCLUSIONS: Results were consistent with a bidirectional pathway of risk, whereby PD significantly increased risk for the development of PTSD, and PTSD significantly increased risk for PD. Given the association between PTSD and subsequent PD, particularly among men, clinicians may consider supplementing PTSD treatment with panic-specific interventions, such as interoceptive exposure, to prevent or treat this disabling comorbidity. PMID- 30003311 TI - Prevalence rates, reporting, and psychosocial correlates of stalking victimization: results from a three-sample cross-sectional study. AB - PURPOSE: Public health and criminal justice stalking victimization data collection efforts are plagued by subjective definitions and lack of known psychosocial correlates. The present study assesses the question of stalking victimization prevalence among three groups. Psychosocial risk and protective factors associated with stalking victimization experiences were assessed. METHODS: Archival data (n = 2159) were drawn from a three-sample (i.e., U.S. nationwide sexual diversity special interest group, college student, and general population adult) cross-sectional survey of victimization, sexuality, and health. RESULTS: The range of endorsement of stalking-related victimization experiences was 13.0-47.9%. Reported perpetrators were both commonly known and unknown persons to the victim. Participants disclosed the victimization primarily to nobody or a family member/friend. Bivariate correlates of stalking victimization were female gender, Associates/Bachelor-level education, bisexual or other sexual orientation minority status, hypertension, diabetes, older age, higher weekly drug use, elevated trait aggression, higher cognitive reappraisal skills, lower rape myth acceptance, and elevated psychiatric symptoms. Logistic regression results showed the strongest factors in identifying elevated stalking victimization risk were: older age, elevated aggression, higher cognitive reappraisal skills, lesser low self-control, increased symptoms of suicidality and PTSD re-experiencing, and female and other gender minority status. CONCLUSIONS: Behavioral approaches to epidemiological and criminal justice stalking victimization are recommended. Victimization under reporting to healthcare and legal professionals were observed. Further research and prevention programming is needed to capitalize on data concerning personality and coping skills, sexual diversity, and trauma-related psychiatric symptoms. PMID- 30003312 TI - Transcriptome analysis of Cd-treated switchgrass root revealed novel transcripts and the importance of HSF/HSP network in switchgrass Cd tolerance. AB - KEY MESSAGE: Transcriptome analysis of Cd-treated switchgrass roots not only revealed novel switchgrass transcripts and gene structures but also highlighted the indispensable role of HSF/HSP network in switchgrass Cd tolerance. Switchgrass (Panicum virgatum L.), a C4 perennial tall grass, can be used for revegetation of Cd-contaminated soil. In the present study, a comparative transcriptome analysis of Cd-treated switchgrass roots was conducted. The result revealed a total of 462 novel transcripts and refined gene structures of 2337 transcripts. KEGG pathway and Gene Ontology analyses of the differentially expressed genes (DEGs) suggested that activation of redox homeostasis and oxidation-related metabolic processes were the primary response to Cd stress in switchgrass roots. In particular, 21 out of 23 differentially expressed shock transcription factor genes (HSFs), and 22 out of 23 differentially expressed heat shock protein genes (HSPs) had increased expression levels after Cd treatment. Furthermore, over-expressing one HSP-encoding gene in Arabidopsis significantly improved plant Cd tolerance. The result highlighted the activation of the redox homeostasis and the involvement of the HSF/HSP network in re-establishing normal protein conformation and thus cellular homeostasis in switchgrass upon Cd stress. These DEGs, especially those of the HSF/HSP network, could be used as candidate genes for further functional studies toward improved plant Cd tolerance in switchgrass and related species. PMID- 30003313 TI - Pharmacokinetics of ferric pyrophosphate citrate administered via dialysate and intravenously to pediatric patients on chronic hemodialysis. AB - BACKGROUND: Iron deficiency is a common cause of anemia in pediatric patients with hemodialysis-dependent chronic kidney disease (CKD-5HD). Ferric pyrophosphate citrate (FPC, Triferic(r)) donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Administration of FPC via dialysate or intravenously (IV) may provide a suitable therapeutic option to current IV iron preparations for these patients. METHODS: The pharmacokinetics and safety of FPC administered via dialysate and IV to patients aged < 6 years (n = 3), 6 to < 12 years (n = 4), and 12 to <18 years (n = 15) were investigated in a multicenter, open-label, two-period, single-dose study. FPC (0.07 mg iron/kg) was infused IV into the venous blood return line during hemodialysis session no. 1. FPC iron was added to bicarbonate concentrate to deliver 2 MUM (110 MUg/L) iron via dialysate during hemodialysis session no. 2. RESULTS: Mean serum total iron concentrations peaked 3 to 4 h after administration via dialysate and 2 to 4 h after IV administration and returned to baseline by 10 h after the start of hemodialysis for both routes. Iron exposure was greater after administration via dialysate than after IV administration. The absolute amount of absorbed iron after administration via dialysate roughly doubled with increasing age, but the weight-normalized amount of absorbed iron was relatively constant across age groups (~ 0.06-0.10 mg/kg). FPC was well tolerated in the small number of patients studied. CONCLUSIONS: FPC iron can be administered to pediatric patients with CKD-5HD via dialysate or by the IV route. Further study of FPC administered to maintain hemoglobin concentration is indicated. PMID- 30003314 TI - Beyond playing games: nephrologist vs machine in pediatric dialysis prescribing. AB - In a recent article in Pediatric Nephrology, Olivier Niel and colleagues applied an artificial intelligence algorithm to a clinical problem that continues to challenge experienced pediatric nephrologists: optimizing the target weight of children on dialysis. They compared blood pressure, antihypertensive medication and intradialytic symptoms in children whose target weight was prescribed firstly by a nephrologist, then subsequently using a machine learning algorithm. Improvements in all outcome measures are reported. Their innovative approach to tackling this important clinical problem appears promising. In this editorial, we discuss the strengths and weaknesses of their study and consider to what extent machine learning strategies are suited to optimizing pediatric dialysis outcomes. PMID- 30003315 TI - The prognostic value of multiorgan metastases in patients with non-small cell lung cancer and its variants: a SEER-based study. AB - PURPOSE: This study aimed to investigate the prognostic value of different organs metastases in patients with non-small cell lung cancer (NSCLC) and its most common subtypes. METHODS: We identified 45,423 NSCLC cases (25,129 men and 20,294 women) between 2010 and 2013 with distant metastases, with complete clinical information obtained from the surveillance, epidemiology, and end results (SEER) database. RESULTS: Bone and liver were the most and the least common metastatic sites with rates of 37.1 and 16.8%, respectively. The mortality rates associated with bone, brain, liver, lung metastases, and multiorgan metastases (MOM) were 73.2, 72.7, 78.3, 65.4, and 77.5%, respectively. Kaplan-Meier analyses demonstrated that patients with MOM and liver metastasis had the worst survival. Compared with NSCLC cases with other organ metastasis, but without the four organs metastasis, hazard ratios (HRs) for lung, bone, brain, and liver metastases, and MOM were 0.906 (95% CI 0.866-0.947), 1.276 (95% CI 1.225-1.330), 1.318 (95% CI 1.260-1.379), 1.481 (95% CI 1.388-1.580), and 1.647 (95% CI 1.587 1.709), respectively. Similar results were obtained for adenocarcinoma (AD) cases. CONCLUSIONS: The mortality risk is highest with MOM and liver metastasis followed by bone, brain, other organ, and lung metastases in NSCLC and AD which is the most common variant for NSCLC. These results will be helpful for pre treatment evaluation regarding the prognosis of NSCLC patients. PMID- 30003317 TI - Langerhans cell histiocytosis associated with classical Hodgkin lymphoma contains BRAF V600E mutation. PMID- 30003316 TI - Imaging prediction of isocitrate dehydrogenase (IDH) mutation in patients with glioma: a systemic review and meta-analysis. AB - OBJECTIVES: To evaluate the imaging features of isocitrate dehydrogenase (IDH) mutant glioma and to assess the diagnostic performance of magnetic resonance imaging (MRI) for prediction of IDH mutation in patients with glioma. METHODS: A systematic search of Ovid-MEDLINE and EMBASE up to 10 October 2017 was conducted to find relevant studies. The search terms combined synonyms for 'glioma', 'IDH mutation' and 'MRI'. Studies evaluating the imaging features of IDH mutant glioma and the diagnostic performance of MRI for prediction of IDH mutation in patients with glioma were selected. The pooled summary estimates of sensitivity and specificity and their 95% confidence intervals (CIs) were calculated using a bivariate random-effects model. The results of multiple subgroup analyses are reported. RESULTS: Twenty-eight original articles in a total of 2,146 patients with glioma were included. IDH mutant glioma showed frontal lobe predominance, less contrast enhancement, well-defined border, high apparent diffusion coefficient (ADC) value and low relative cerebral blood volume (rCBV) value. For the meta-analysis that included 18 original articles, the summary sensitivity was 86% (95% CI, 79%-91%) and the summary specificity was 87% (95% CI, 78-92%). In a subgroup analysis, the summary sensitivity of 2-hydroxyglutarate magnetic resonance spectroscopy (MRS) [96% (95% CI, 91-100%)] was higher than the summary sensitivities of other imaging modalities. CONCLUSIONS: IDH mutant glioma consistently demonstrated less aggressive imaging features than IDH wild-type glioma. Despite the variety of different MRI techniques used, MRI showed the potential to non-invasively predict IDH mutation in patients with glioma. 2 Hydroxyglutarate MRS shows higher pooled sensitivity than other imaging modalities. KEY POINTS: * IDH mutant glioma showed frontal lobe predominance, less contrast enhancement, well-defined border, high ADC value, and low rCBV value. * The diagnostic performance of MRI for prediction of IDH mutation in patients with glioma is within a clinically acceptable range, the summary sensitivity was 86% (95% CI, 79-91%) and the summary specificity was 87% (95% CI, 78-92%). * In a subgroup analysis, the summary sensitivity of 2-hydroxyglutarate MRS [96% (95% CI, 91-100%)] was higher than the summary sensitivities of other imaging modalities. PMID- 30003318 TI - Comparison of argatroban and fondaparinux for the management of patients with isolated heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a serious complication of the administration of heparin and its derivatives. Non-heparin anticoagulants such as argatroban and fondaparinux are widely used in the management of HIT to compare the effectiveness of argatroban and fondaparinux in the resolution of thrombocytopenia and to compare clinical outcomes in patients with isolated HIT. A retrospective cohort analysis was performed at King Abdulaziz Medical City (KAMC) on patients diagnosed with isolated HIT between 31 Jan, 2014 and 30 June, 2017. Demographics data, non-heparin anticoagulants, related laboratory results, and clinical outcomes were retrieved and analysed. The cohort comprised a total of 95 adult patients who received either argatroban (56 patients) or fondaparinux (39 patients) for isolated HIT. The median age and sex distribution were similar in both argatroban and fondaparinux groups. The mean (+ SD) time (in days) for the resolution of thrombocytopenia was 3.5 (+/- 1.8) for patients who received argatroban and 3.7 (+/- 1.7) for patients administered fondaparinux (p = 0.843). Thromboembolic events occurred in five patients (8.9%) administered argatroban and in three patients (7.7%) administered fondaparinux (p = 0.382). There was no significant difference in the rates of bleeding or death (p = 0.829); however, the small number of cases limits our ability to draw conclusions about these outcomes. In this retrospective study, fondaparinux and argatroban were similarly effective in resolving thrombocytopenia, preventing further thromboembolic events, and maintaining safety in patients with confirmed HIT. To confirm this observation, larger prospective studies are needed. PMID- 30003319 TI - [Novel molecular mechanisms in the pathophysiology of psoriatic arthritis]. AB - The complex pathogenesis of psoriatic arthritis (PsA) is still only partially understood; however, recently a greatly improved understanding of this disease has been achieved, especially with respect to the inflammatory processes of the entheses. Thus, the clinical aspects of enthesitis increasingly differentiate PsA from other autoimmune diseases and sharpen the unique pathological clinical picture of PsA. Better pathophysiological understanding and the development of different biomarker approaches will bolster early detection of PsA. Therefore, the successful early recognition of PsA and more reliable identification of psoriasis patients at risk might be possible in the near future. PMID- 30003321 TI - Interactions among myeloid regulatory cells in cancer. AB - Mounting evidence has accumulated on the critical role of the different myeloid cells in the regulation of the cancerous process, and in particular in the modulation of the immune reaction to cancer. Myeloid cells are a major component of host cells infiltrating tumors, interacting with each other, with tumor cells and other stromal cells, and demonstrating a prominent plasticity. We describe here various myeloid regulatory cells (MRCs) in mice and human as well as their relevant therapeutic targets. We first address the role of the monocytes and macrophages that can contribute to angiogenesis, immunosuppression and metastatic dissemination. Next, we discuss the differential role of neutrophil subsets in tumor development, enhancing the dual and sometimes contradicting role of these cells. A heterogeneous population of immature myeloid cells, MDSCs, was shown to be generated and accumulated during tumor progression as well as to be an important player in cancer-related immune suppression. Lastly, we discuss the role of myeloid DCs, which can either contribute to effective anti-tumor responses or play a more regulatory role. We believe that MRCs play a critical role in cancer-related immune regulation and suggest that future anti-cancer therapies will focus on these abundant cells. PMID- 30003320 TI - Making ends meet: targeted integration of DNA fragments by genome editing. AB - Targeted insertion of large pieces of DNA is an important goal of genetic engineering. However, this goal has been elusive since classical methods for homology-directed repair are inefficient and often not feasible in many systems. Recent advances are described here that enable site-specific genomic insertion of relatively large DNA with much improved efficiency. Using the preferred repair pathway in the cell of nonhomologous end-joining, DNA of up to several kb could be introduced with remarkably good precision by the methods of HITI and ObLiGaRe with an efficiency up to 30-40%. Recent advances utilizing homology-directed repair (methods of PITCh; short homology arms including ssODN; 2H2OP) have significantly increased the efficiency for DNA insertion, often to 40-50% or even more depending on the method and length of DNA. The remaining challenges of integration precision and off-target site insertions are summarized. Overall, current advances provide major steps forward for site-specific insertion of large DNA into genomes from a broad range of cells and organisms. PMID- 30003322 TI - CD34+ circulating cells display signs of immune activation in patients with acute coronary syndrome. AB - Bone marrow-derived endothelial progenitor cells (EPC) are released into the peripheral blood in situations of vascular repair/angiogenesis. Regulation of vascular repair and angiogenesis by EPC depends not only on the number of circulating EPC but also on their functionality. As endothelial cells can act as antigen-presenting cells in coronary artery disease (CAD), we postulated that EPC can be immune activated here as well. CD34+-EPC were isolated from peripheral blood of patients with ST-elevation myocardial infarction (STEMI, n = 12), non STEMI/unstable angina (UA, n = 15), and stable CAD (SA, n = 18). Expression of HLA-DR, adhesion and costimulatory molecules by isolated CD34+-EPC were compared with levels in healthy controls (n = 18). There were no significant differences in VCAM-1 and CD80 expression by peripheral circulating CD34+-EPC between the four groups, yet expression of CD86 was highest in UA (p < 0.05). ICAM-1 expression was lowest in SA (p < 0.01). CD34+-EPC constitutively expressed HLA-DR across all groups. Of note, patients pretreated with HMG-CoA reductase inhibitors exhibited lower expression of VCAM-1 by CD34+-EPC throughout all patient groups; furthermore, statins significantly limited ex vivo-induced upregulation of ICAM-1 by TNF-alpha. To the best of our knowledge, this is the first study to examine the expression of immune markers in peripheral circulating CD34+-EPC ex vivo. We demonstrate that CD34+-EPC display different patterns of adhesion and costimulatory molecules in various states of CAD. Expression levels were affected by pretreatment with statins. Hence, immune activity of peripheral circulating CD34+ cells might play a pathophysiologic role in evolution of CAD. PMID- 30003323 TI - Renal cell cancer after kidney transplantation. AB - PURPOSE: This study aims to identify modifiable risk factors for de novo renal cell carcinoma (RCC) after kidney transplantation in a matched-pair approach matching for unmodifiable factors. PATIENTS AND METHODS: One thousand six hundred fifty-five adults who underwent kidney transplantation in the period 1 January 2000 to 31 December 2012 were analyzed. Patients with RCC after kidney transplantation were matched in a 1:2 ratio with those without RCC using the indication for transplantation, age at transplantation (+/- 10 years), recipient sex (male/female), number of received transplants, living organ donor transplantation (yes/no), and time of follow-up in days as matching criteria. The paired t test was used to compare continuous variables and the Cochran-Mantel Haenszel test for categorical variables. Multivariable conditional logistic regression modeling was used to identify independent risk factors for RCC. RESULTS: In matched-pair analysis, a total number of 26 incident cases with RCC after kidney transplantation could be matched. Post-transplant RCC was significantly associated with longer durations of pre-transplant hemodialysis (p = 0.007) and post-transplant immunosuppression with cyclosporine (p = 0.029) and/or mycophenolate mofetil (p = 0.020) and with larger proportions of post transplant time on mycophenolate mofetil (p = 0.046) and/or prednisolone medication (p = 0.042). Multivariable conditional logistic regression modeling revealed a significant risk increasing multiplicative factor interaction between the duration of pre-transplant dialysis (years) and the time of prednisolone usage (percent/100). Cyclosporine A usage and mycophenolate mofetil usage were also revealed as independent, significant risk factors for RCC development. CONCLUSIONS: Longer pre-transplant dialysis, cyclosporine-based protocols and/or intensified immunosuppression with additional mycophenolate mofetil, and larger proportions of time of prednisolone treatment during follow-up increase de novo RCC risk. PMID- 30003324 TI - Comparative short-term effectiveness of ibuprofen gel and cream phonophoresis in patients with knee osteoarthritis. AB - The objective of the present study was to compare the effectiveness of gel and cream ibuprofen phonophoresis in patients with knee osteoarthritis. A single blinded, randomized, comparative design was applied. Patients diagnosed with knee osteoarthritis according to the American College of Rheumatology criteria were included in the study. After obtaining written informed consent, patients were randomized into ibuprofen gel and cream phonophoresis groups. Each patient was treated five sessions per week for 2 weeks (ten sessions). Main outcome measures were 100 mm visual analogue scale (VAS) for pain and the disease-specific questionnaire; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Sixty-one knee osteoarthritis patients with a mean age of 57.9 +/- 9.7 years were included in the study. Baseline VAS and WOMAC scores were similar between gel (n = 30) and cream (n = 31) phonophoresis groups (p > 0.05 for both). Following the treatment, both groups showed improvement compared to baseline measures including VAS pain and WOMAC scores. In the gel phonophoresis group, the improvement in VAS score was higher than that observed in the cream phonophoresis group (p < 0.001). Similarly, the improvement in WOMAC total score was also higher in the gel phonophoresis group (p < 0.001). Ibuprofen phonophoresis is clinically effective in patients with knee osteoarthritis. Phonophoresis using the gel form of ibuprofen is associated with more clinical improvement than that using the cream form of the same molecule. PMID- 30003325 TI - Incidentally detected pancreatic neuroendocrine microadenoma with lymph node metastasis. AB - Pancreatic neuroendocrine microadenomas (NEMAs) are non-functioning neuroendocrine tumors < 0.5 cm with a low proliferation rate and are considered benign. We report on a pancreatic NEMA with lymph node metastasis. A male in his 70s had pylorus-preserving pancreaticoduodenectomy for a distal bile duct carcinoma, which was a 2.1 cm well-differentiated-infiltrating adenocarcinoma with invasion limited to the bile duct wall. An incidental separate 0.4 cm well differentiated NEMA was found in the pancreatic head with metastatic well differentiated neuroendocrine tumor in one peripancreatic lymph node. Both neuroendocrine tumors in the pancreatic head and in the lymph node were composed of nests of uniform neoplastic cells with a fine chromatin pattern. The Ki-67 labeling index of NEMA was 0.85%. The neoplastic neuroendocrine cells in both the pancreas and node were diffusely positive for synaptophysin, chromogranin, and insulin. Therefore, this unusual case provides an exception to the current classification system which regards NEMAs as benign lesions. PMID- 30003326 TI - Ethylene Vinyl Alcohol Copolymer as First Hemostatic Liquid Embolic Agent for Non variceal Upper Gastrointestinal Bleeding Patients: Pros and Cons. PMID- 30003327 TI - Ventriculosubgaleal shunting-a comprehensive review and over two-decade surgical experience. AB - INTRODUCTION: The subgaleal space is the fibroareolar layer found between the galea aponeurotica and the periosteum of the scalp. Due to its elastic and absorptive capabilities, the subgaleal space can be used as a shunt to drain excess cerebrospinal fluid from the ventricles. A subgaleal shunt consists of a shunt tube with one end in the lateral ventricles while the other end is inserted into the subgaleal space of the scalp. This will allow for the collection and absorption of excess cerebrospinal fluid. Indications for ventriculosubgaleal shunting (VSG) include acute head trauma, subdural hematoma, and malignancies. DISCUSSION: VSG shunt is particularly advantageous for premature infants suffering from post-hemorrhagic hydrocephalus due to their inability to tolerate long-term management such as a ventriculoperitoneal shunt. Complications include infection and shunt blockage. In comparison with other short-term treatments of hydrocephalus, the VSG exhibits significant advantages in the drainage of excess cerebrospinal fluid. VSG shunt is associated with lower infection rates than other external ventricular drain due to the closed system of CSF drainage and lack of external tubes. CONCLUSION: This review discusses the advantages and disadvantages of the VSG shunt, as well as our personal experience with the procedure. PMID- 30003328 TI - Raman spectroscopy for medulloblastoma. AB - PURPOSE: The aim of the study is to use Raman spectroscopy to analyze the biochemical composition of medulloblastoma and normal tissues from the safety margin of the CNS and to find specific Raman biomarkers capable of differentiating between tumorous and normal tissues. METHODS: The tissue samples consisted of medulloblastoma (grade IV) (n = 11). The tissues from the negative margins were used as normal controls. Raman images were generated by a confocal Raman microscope-WITec alpha 300 RSA. RESULTS: Raman vibrational signatures can predict which tissue has tumorous biochemistry and can identify medulloblastoma. The Raman technique makes use of the fact that tumors contain large amounts of protein and far less lipids (fatty compounds), while healthy tissue is rich in both. CONCLUSION: The ability of Raman spectroscopy and imaging to detect medulloblastoma tumors fills the niche in diagnostics. These powerful analytical techniques are capable of monitoring tissue morphology and biochemistry. Our results demonstrate that RS can be used to discriminate between normal and medulloblastoma tissues. PMID- 30003329 TI - GDF9-beta promotes folliculogenesis in sheep ovarian transplantation onto the chick embryo chorioallantoic membrane (CAM) in cryopreservation programs. AB - PURPOSE: Ovarian tissue (OT) cryopreservation is a treatment option for fertility preservation among young cancer patients. However, the procedure may involve a reduction in the GDF9-beta expression and a delay in follicular growth after thawing and transplantation. The aim of this study was to evaluate whether supplementation of GDF9-beta can compensate the reduction of this factor during the cryopresevation process and promote folliculogenesis after transplantation of thawed sheep ovarian tissue. METHODS: Sheep OT was cryopreserved using two methods of vitrification and slow freezing. Fresh and thawed OTs were then transplanted onto chick embryo chorioallantoic membrane (CAM) and then divided into two groups based on the addition of GDF9-beta to the grafted tissue. After 5 days of culture, both histological and immunohistological (Ki-67) assessments were performed to evaluate follicular structure, development, and proliferation. The fibrotic and necrotic areas were measured using MICROVISIBLE software. RESULTS: Folliculogenesis took place in all culture groups, but was significantly improved only in the +GDF9-beta cultured group. Also, better follicular structure was preserved in the aforementioned group (p < 0.05). When GDF9-beta was supplemented to the culture medium, more neovascularization (p < 0.05) and better transplantation (p > 0.05) was observed. Furthermore, the areas of fibrosis and necrosis were lower in this group rather than the controls. Follicular proliferative activity was significantly higher only in the slow freezing +GDF9 beta cultured group. CONCLUSIONS: GDF9-beta, as a stimulatory factor, not only promoted the folliculogenesis in the fresh ovarian transplant, but also compensated for its reduction during the cryopreservation process. PMID- 30003330 TI - Reliability of sonoelastography in predicting pediatric cervical lymph node malignancy. AB - PURPOSE: Controversy exists as regards the best non-invasive diagnostic tool for pediatric cervical lymphadenopathy. The current work aimed to evaluate the reliability, sensitivity, specificity, and accuracy of sonoelastography in diagnosing benign and/or malignant pediatric cervical lymphadenopathy. METHODS: Prospective study took place over a period of 4 years from January 2013 to December 2016. A total of 177 lymph nodes (LNs) in 128 children with an age ranging from 11 months to 12 years were recruited in this study. Patients were 77 males and 51 females with a ratio of 3:2. All patients underwent a thorough history taking and clinical examination of the neck focusing on the cervical lymph nodes. After that, a B-mode sonography, Color Doppler ultrasound, and Sonoelastography were performed. Elastographic patterns of 1-5 were evaluated, whereas patterns of 3-5 (firm to hard) were suspected to have a malignant nature. Sonographic-guided aspiration cytology took place in 107 lymph nodes and excisional biopsy in 102 lymph nodes, whereas 13 lymph nodes responded adequately to conservative treatment. They proved to be benign reactive hyperplasia. RESULTS: The majority of LNs (87%) were of the malignant type that showed an elastographic pattern of 3-5. The same patterns were observed in only 6 (3.4%) of the benign LNs. Sonoelastography showed a sensitivity of 85.9%, specificity of 100%, PPV of 100%, NPV of 75.96%, and overall accuracy of 90.23% in distinguishing benign from malignant lymph nodes. Using the B-Mode ultrasound, an abnormal hilum was seen in 75%. The accuracy of color Doppler US reached 82.7%. CONCLUSIONS: Sonoelastography may be superior to other US modalities in elucidating different cervical lymph node biopsy helping to distinguish benign from malignant lesions. This may replace the lymph node biopsies in the future. Moreover, its use in the follow-up of patients with cervical malignancies may reduce the number of future biopsies. Further studies with more patients may be needed for a better assessment of results. PMID- 30003331 TI - Morphological and molecular characterisation of Eimeria vison-like oocysts (Apicomplexa:Eimeriidae) in farmed mink (Neovison vison) in Denmark. AB - A survey was conducted on 30 Danish mink farms from April to October 2016 to determine the prevalence and species of Eimeria in Danish farmed mink. In total, 2.6% of mink faecal samples (108/4140) were positive for Eimeria vison-like oocysts by microscopy, with 24.8% (78/315) of mink being positive at least once during the study period. Morphological analysis of sporulated oocysts (n = 20) identified Eimeria vison-like oocysts measuring 21.0 * 13.8 MUm with a length/width (L/W) ratio of 1.5. Phylogenetic analysis of 18S rRNA sequences (1221 bp) from three positive mink indicated that Eimeria vison-like shared the highest genetic similarity to Eimeria sp. ex Apodemus agrarius from a Striped field mouse (A. agrarius) from the Czech Republic (99.6%). Analysis of a shorter region of 18S (531 bp) revealed that the E. vison-like genotype sequences grouped in the same clade and shared 97.7% similarity with E. furonis. At the cytochrome c oxidase subunit I (COI) locus, mink-derived sequences were not available from GenBank and phylogenetic analysis placed the novel E. vison-like in a clade with E. cf. ictidea (99.4% similarity) from a black footed ferret (Mustela nigripes) from Canada. PMID- 30003332 TI - Postprandial metabolic responses to ingestion of bovine glycomacropeptide compared to a whey protein isolate in prediabetic volunteers. AB - PURPOSE: Whey protein was shown to reduce blood glucose responses in humans and various other positive effects have been attributed to this protein. In contrast, studies using glycomacropeptide (GMP) as part of the whey fraction of bovine milk are rare. We, therefore, studied the postprandial responses to GMP administration in humans with impaired glucose tolerance compared to the effects of pure whey protein in a random design. METHODS: Fifteen prediabetic volunteers received on different occasions one of three test drinks containing 50 g of maltodextrin19 (MD19) alone or in combination with either 50 g GMP or 50 g whey protein isolate (WPI). Blood was collected over 4 h with analysis of blood glucose and hormones, gastric emptying rate as well as plasma amino- and fatty acids, beta hydroxybutyrate and acylcarnitines. RESULTS: The WPI drink reduced the AUC of venous blood glucose compared to the MD19 drink in the prediabetic group by 11% (p = 0.0018) whereas GMP reduced the AUC by 18% (p < 0.0001), significantly different to the WPI drink (p = 0.0384). The reduction in blood glucose after the GMP drink was accompanied by a significantly lower AUC of insulin (- 34%) than for the WPI drink. Levels of C-peptide and of glucose insulinotropic polypeptide (GIP) were highly increased after the WPI drink over the MD19 control drink but remained in essence unaffected by the GMP. CONCLUSION: GMP reduced the glycemic response more potently than whey protein, whereas insulin output was less affected making GMP an interesting protein to control postprandial glucose responses. PMID- 30003333 TI - Gomphocarpus mosaic virus, a distinctive member of the genus Potyvirus. AB - Plants of the species Gomphocarpus physocarpus, commonly known as balloon plant or swan plant, exhibiting virus-like symptoms of mosaic, mottle and crinkling were observed and collected in the southwestern part of Taiwan in 2015. Electron microscopic examination showed the presence of virus-like flexuous-rod particles. Potyvirus pinwheel-shape and laminated inclusion bodies were observed in the preparations of ultrathin sections of diseased leaves. The complete genome sequence of the potyvirus of balloon plant was determined. It is 9998 nucleotides in length, excluding the 3'-terminal poly(A) tail. It contains two open reading frames encoding a polyprotein of 3196 amino acids and a PIPO protein of 89 amino acids. The polyprotein gene shares 52.8-68.4% nucleotide sequence identity and 40.2-75.8% amino acid sequence identity with other potyviruses tested. Molecular analysis indicates that the virus is most closely related to but distinct from keunjorong mosaic virus (KjMV). The virus causing mosaic, mottle and crinkling on Gomphocarpus plants (gomphocarpus mosaic virus, GoMV) likely belongs to a new species of the genus Potyvirus. PMID- 30003334 TI - Microbial biomarkers for immune checkpoint blockade therapy against cancer. AB - Three major standard treatments, i.e., surgery, chemotherapy, and radiotherapy, were traditionally applied to the treatment of cancer and saved many patients. Meanwhile, clinical studies as well as basic research of immunotherapy are being actively conducted for intractable or advanced malignancies that cannot be cured by the conventional standard treatments. Remarkable therapeutic efficacies have been recently reported in clinical trials on some cancer types, and immunotherapy is now being recognized as the "fourth" standard therapy against cancer. In particular, immune checkpoint inhibitor therapy (ICI) has demonstrated the effectiveness of immunotherapy through large-scale randomized clinical trials, leading to the paradigm-shift in cancer treatment. Immune checkpoint molecules transduce co-inhibitory signals to immunocompetent cells including T cells, and crucially contribute to the formation of an immunosuppressive microenvironment in tumor tissues, which intrinsically confers the treatment resistance. Programmed death-1 (PD-1, CD279) is one of the typical immune checkpoint molecules. Anti tumor therapies targeting PD-1 and its ligands had been developed and approved in many countries, and various studies utilizing clinical specimens are currently progressing. In this review, we provide an overview of the biomarkers based on the analysis of enteric microbiota that correlate with the clinical efficacy/inefficacy of PD-1-based therapy. PMID- 30003336 TI - Comparison of sustained-release and rapid-release beta-alanine formulations on changes in skeletal muscle carnosine and histidine content and isometric performance following a muscle-damaging protocol. AB - beta-alanine supplementation increases muscle carnosine content and improves anaerobic exercise performance by enhancing intracellular buffering capacity. beta-alanine ingestion in its traditional rapid-release formulation (RR) is associated with the symptoms of paresthesia. A sustained-release formulation (SR) of beta-alanine has been shown to circumvent paresthesia and extend the period of supply to muscle for carnosine synthesis. The purpose of this investigation was to compare 28 days of SR and RR formulations of beta-alanine (6 g day-1) on changes in carnosine content of the vastus lateralis and muscle fatigue. Thirty nine recreationally active men and women were assigned to one of the three groups: SR, RR, or placebo (PLA). Participants supplementing with SR and RR formulations increased muscle carnosine content by 50.1% (3.87 mmol kg-1ww) and 37.9% (2.62 mmol kg-1ww), respectively. The change in muscle carnosine content in participants consuming SR was significantly different (p = 0.010) from those consuming PLA, but no significant difference was noted between RR and PLA (p = 0.077). Although participants ingesting SR experienced a 16.4% greater increase in muscle carnosine than RR, fatigue during maximal voluntary isometric contractions was significantly attenuated in both SR and RR compared to PLA (p = 0.002 and 0.024, respectively). Symptoms of paresthesia were significantly more frequent in RR compared to SR, the latter of which did not differ from PLA. Results of this study demonstrated that only participants consuming the SR formulation experienced a significant increase in muscle carnosine. Differences in the muscle carnosine response between these formulations may have practical significance for athletic populations in which small changes may have important implications on performance. PMID- 30003335 TI - Effects of single and combined metformin and L-citrulline supplementation on L arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications. AB - The L-arginine/nitric oxide synthase (NOS) pathway is considered to be altered in muscular dystrophy such as Becker muscular dystrophy (BMD). We investigated two pharmacological options aimed to increase nitric oxide (NO) synthesis in 20 male BMD patients (age range 21-44 years): (1) supplementation with L-citrulline (3 * 5 g/d), the precursor of L-arginine which is the substrate of neuronal NO synthase (nNOS); and (2) treatment with the antidiabetic drug metformin (3 * 500 mg/d) which activates nNOS in human skeletal muscle. We also investigated the combined use of L-citrulline (3 * 5 g/d) and metformin (3 * 500 mg/d). Before and after treatment, we measured in serum and urine samples the concentration of amino acids and metabolites of L-arginine-related pathways and the oxidative stress biomarker malondialdehyde (MDA). Compared to healthy subjects, BMD patients have altered NOS, arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) pathways. Metformin treatment resulted in concentration decrease of arginine and MDA in serum, and of homoarginine (hArg) and guanidinoacetate (GAA) in serum and urine. L-Citrulline supplementation resulted in considerable increase of the concentrations of amino acids and creatinine in the serum, and in their urinary excretion rates. Combined use of metformin and L-citrulline attenuated the effects obtained from their single administrations. Metformin, L-citrulline or their combination did not alter serum nitrite and nitrate concentrations and their urinary excretion rates. In conclusion, metformin or L-citrulline supplementation to BMD patients results in remarkable antidromic changes of the AGAT and GAMT pathways. In combination, metformin and L-citrulline at the doses used in the present study seem to abolish the biochemical effects of the single drugs in slight favor of L-citrulline. PMID- 30003337 TI - Locally adapted Brazilian ewes with different coat colors maintain homeothermy during the year in an equatorial semiarid environment. AB - The present paper aimed to show the thermoregulatory responses of locally adapted Morada Nova sheep with different coat colors that were exposed to direct solar radiation in an equatorial semiarid region. Animals were classified into four groups according to the coat color as follows: (1) dark red, (2) intermediate red, (3) light red, and (4) white coats. Forty Morada Nova ewes were observed in for 7 consecutive months. The experimental variables measured were rectal temperature (RT), skin surface temperature (ST), respiratory rate (RR), skin surface evaporation (CE), respiratory evaporation (RE), and heat exchange by convection (HC) and radiation (R). Data were collected from 1100 to 1400 h after the animals were exposed to 30 min direct sunlight. The results showed that all groups maintained homeothermy. The RR was higher in the animals of groups 1 to 3, which also showed higher values for ST when compared to the white-coated animals. Sensible heat exchange mechanisms were not important for heat loss, and R was a significant source of heat gain from the environment for the animals. Groups 1, 2, and 3 used RR more intensely than group 4 (P value = 0.001); however, CE was higher for the white-coated animals. It was concluded that Morada Nova sheep are well adapted to the semiarid environment, regardless of coat color. PMID- 30003338 TI - Unchanged risk of frost exposure for subalpine and alpine plants after snowmelt in Switzerland despite climate warming. AB - The length of the snow-free season is a key factor regulating plant phenology and shaping plant community composition in cold regions. While global warming has significantly advanced the time of snowmelt and the growth period at all elevations in the Swiss Alps, it remains unclear if it has altered the likelihood of frost risk for alpine plants. Here, we analyzed the influence of the snowmelt timing on the risk of frost exposure for subalpine and alpine plants shortly after snowmelt, i.e., during their most vulnerable period to frost at the beginning of their growth period. Furthermore, we tested whether recent climate warming has changed the risk of exposure of plants to frost after snowmelt. We analyzed snow and air temperature data in the Swiss Alps using six weather stations covering the period 1970-2016 and 77 weather stations covering the period 1998-2016, spanning elevations from 1418 to 2950 m asl. When analyzed across all years within each station, our results showed strong negative relationships between the time of snowmelt and the frequency and intensity of frost during the most vulnerable period to frost for subalpine and alpine plants, indicating a higher frost risk damage for plants during years with earlier snowmelt. However, over the last 46 years, the time of snowmelt and the last spring frost date have advanced at similar rates, so that the frequency and intensity of frost during the vulnerable period for plants remained unchanged. PMID- 30003339 TI - Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition. AB - Hydroxypyridinethiones (HOPTOs) are strong ligands for metal ions and potentially useful pharmacophores for inhibiting metalloenzymes relevant to human disease. However, HOPTOs have been sparingly used in drug discovery efforts due, in part, to concerns that this scaffold will act as a promiscuous, non-selective metalloenzyme inhibitor, as well as possess poor pharmacokinetics (PK), which may undermine drug candidates containing this functional group. To advance HOPTOs as a useful pharmacophore for metalloenzyme inhibitors, a library of 22 HOPTO isostere compounds has been synthesized and investigated. This library demonstrates that it is possible to maintain the core metal-binding pharmacophore (MBP) while generating diversity in structure, electronics, and PK properties. This HOPTO library has been screened against a set of four different metalloenzymes, demonstrating that while the same metal-binding donor atoms are maintained, there is a wide range of activity between metalloenzyme targets. Overall, this work shows that HOPTO isosteres are useful MBPs and valuable scaffolds for metalloenzyme inhibitors. PMID- 30003340 TI - Treatment of distal radius fractures with locking plates: an update. AB - Internal fixation with volar locking plates has revolutionized the treatment of distal radius fractures. Manufacturers have introduced plate designs that closely follow the anatomy of the distal radius. However, use of volar plates has also led to the emergence of new types of complications. While the use of monoaxial or polyaxial locking screws and of minimally invasive techniques (arthroscopy, preservation of pronator quadratus) increases the cost of the surgical procedure, it results in a tangible benefit for patients, allowing them to move their wrist almost immediately after surgery and to quickly regain their autonomy. We reviewed the literature to analyze the level of proof. PMID- 30003341 TI - Disparities in health-related quality of life in women undergoing treatment for advanced ovarian cancer: the role of individual-level and contextual social determinants. AB - PURPOSE: Social determinants may influence health-related quality of life (HRQOL) among women with ovarian cancer, potentially creating disparities in clinical outcomes. We investigated the relationship between HRQOL and social determinants of health, including travel distance to access cancer care and health insurance type, among women participating in a randomized trial of primary adjuvant treatment for advanced ovarian cancer. METHODS: The Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire captured HRQOL (physical well being, functional well-being, ovarian-specific, and trial outcome index [TOI]) prior to chemotherapy (baseline), during the trial, and 84 weeks after initiation of chemotherapy for women with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. We constructed bivariate and multivariable linear mixed effects models examining the associations of social determinants of health (individual-level and contextual factors) with HRQOL scores at 84 weeks, clustering participants (n = 993) within treatment centers, and Census regions and controlling for baseline HRQOL. RESULTS: Most individual-level (race, age, cancer stage, adverse events) and contextual (travel distance to treatment center, community socioeconomic status) factors were not statistically significantly associated with HRQOL. Compared to participants with private health insurance, other participants had lower mean HRQOL (physical well-being: public insurance, - 1.00 (standard error[SE] = 0.49) points, uninsured, - 1.93 (SE = 0.63) points; functional well-being: public, - 1.29 (SE = 0.59), uninsured, - 1.98 (SE = 0.76); ovarian cancer-specific: public, - 1.60 (SE = 0.59), uninsured, - 1.66 (SE = 0.75); TOI: public, - 3.81 (SE = 1.46), uninsured, - 5.51 (SE = 1.86); all p < .05). CONCLUSIONS: Private health insurance was associated with improved HRQOL at the completion of treatment for advanced stage ovarian cancer. Implications of health insurance on HRQOL should be further investigated, particularly among women with ovarian cancer who receive standard of care treatment. PMID- 30003342 TI - Injectable platelet rich fibrin: cell content, morphological, and protein characterization. AB - OBJECTIVES: The aim of the present study was to evaluate the blood cell content, morphological aspects, gene expression of type I collagen, and release of growth factors on an injectable platelet rich fibrin (i-PRF). MATERIALS AND METHODS: Blood samples were collected from 15 volunteers to prepare i-PRF samples. Peripheral blood was used as a control group. Blood clot and i-PRF samples were cultured for 10 days. The supernatant of the samples was collected for ELISA immunoassay quantification of PDGF and VEGF growth factors over periods of 1, 8, 24, 72, and 240 h. I-PRF and blood clot samples were biologically characterized using histological and immunohistochemistry analysis for IL-10, osteocalcin, and TGF-beta. Scanning electron microscopy (SEM) was used to inspect the fibrin network and distribution of blood platelets and leukocytes. Reverse transcriptase polymerase chain reaction (RT-PCR) method was used to evaluate gene expression for type I collagen. RESULTS: A higher concentration of platelets and lymphocytes was recorded in i-PRF than in peripheral blood (p < 0.05). The release of VEGF was higher in blood clot samples (1933 +/- 704) than that for i-PRF (852 +/- 376; p < 0.001). Immunohistochemistry showed upregulation of TGF-B, IL-10, and osteocalcin in the i-PRF group. RT-PCR showed increased type I collagen gene expression in i-PRF (p < 0.05). SEM images revealed agglomeration of platelets in some regions, while a fibrin networking was noticeable in the entire i-PRF sample. CONCLUSIONS: Injectable platelet rich fibrin becomes a good approach for soft and mineralized tissue healing considering the formation of a three dimensional fibrin network embedding platelets, leukocytes, type I collagen, osteocalcin, and growth factors. Indeed, the injectable platelet rich fibrin can be indicated in several medical applications regarding bioactivity, simplied technique, and flowable mixing with other biomaterials. CLINICAL RELEVANCE: Morphological, cell, and protein characterization of platelet rich fibrin provides a better understanding of the clinical effects and improvement of clinical guidelines for several medical applications. Once well physicochemical and biologically characterized, the use of an injectable platelet rich fibrin can be extended to other applications in the field of orthopedics, periodontics, and implant dentistry on the repairing process of both soft and mineralized tissues. PMID- 30003343 TI - Verification of water environment monitoring network representativeness under estuary backwater effects. AB - The multi-functional weirs constructed as part of the Four Major River Restoration Project in Korea are operated for water level management and may have a backwater effect in estuaries. If the main channel of the Nakdong River flows backward and affects the estuary water, the water quality in the estuaries may not be representative of the tributary water quality. In this study, we confirmed the representativeness of the existing water quality monitoring networks using spatiotemporally disperse electrical conductivity observations, self-organizing maps (SOMs) for monthly pattern analysis, and the LOcally WEighted Scatter plot Smoother (LOWESS) technique for trend analysis. The results show that the Namgang 4-1 site, which is located in the Nam River estuary, is not affected by the Nakdong River, while the Baekcheon (Sunwongyo) site in the Baekcheon estuary is always affected by the Nakdong River. Therefore, it is necessary to relocate the existing monitoring network or establish a new monitoring network for locations affected by mainstream backflow, as is seen in Baekcheon (Sunwongyo). The methods proposed in this study, including spatiotemporally diverse electrical conductivity measurement, dimensionless fluctuation values, SOMs, and LOWESS, can be used to verify the representativeness of water quality measurement networks in other regions. PMID- 30003345 TI - Outcome of endoscopic small-bore naso-jejunal tube stenting in early postoperative jejunal limb obstruction after gastrectomy. AB - BACKGROUND: Early postoperative jejunal limb obstruction is a rare complication following gastric surgery with jejunal reconstruction. The condition is mainly attributed to kinking of the jejunal limbs, gastrojejunal or jejunojejunal anastomosis. There has been currently limited information regarding the safety and efficacy of endoscopic treatment in patients with early postoperative jejunal obstruction. We aimed to investigate outcome of endoscopic small-bore naso jejunal (N-J) tube stenting across the obstructed segment in patients with uncomplicated early postoperative partial jejunal limb obstruction. METHODS: All patients diagnosed of jejunal limb obstruction within 8 weeks after gastric related surgery were reviewed. Patients with malignant obstruction, complete closed loop obstruction, sepsis, instability, intestinal strangulation, or perforation were excluded. All patients underwent endoscopic dekinking and stenting for 2 weeks with an N-J tube using 16-French single lumen plastic nasogastric tube across the obstruction segment after failed conservative therapy. Successful N-J tube placement across the obstruction point was confirmed by contrast study. Complications, technical, and clinical success were evaluated. RESULTS: Twenty-one patients met the criteria. The primary operations were 7 partial gastrectomies with Billroth-II reconstruction, 7 total or partial gastrectomies with Roux-en-Y reconstruction and 4 Whipple's operations, 2 bypass procedures, and 1 proximal gastrectomy. Most common site of obstruction was jejunojejunal anastomosis and gastrojejunal anastomosis following Roux-en-Y and Billroth-II reconstruction, respectively. Endoscopic N-J tube placement was technically successful in 20 out of 21 patients (95%). One patient had aspirated pneumonia. There was no procedure-related mortality. After N-J tube removal, clinical success was demonstrated in 19 out of 20 patients (95%) at the median duration of 6 months. One patient underwent reoperation due to repeated tube dislodgement. CONCLUSIONS: Endoscopic stenting with a 16-F naso-jejunal tube across the angulated segment is safe and effective for treatment of patients with uncomplicated early postoperative partial jejunal limb obstruction following gastric surgery with jejunal reconstruction. PMID- 30003346 TI - De novo gastroesophageal reflux disease after sleeve gastrectomy: role of preoperative silent reflux. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become the most frequently performed bariatric procedure to date. However, LSG is known to worsen pre operative and result in de novo gastroesophageal reflux disease (GERD). Pre operative evaluation reveals a high percentage of silent GERD of so far unknown influence on post-operative GERD. METHODS: Prospective data of patients undergoing primary LSG between 01/2012 and 12/2015 were evaluated. Pre-operative GERD-specific evaluation consisted of validated questionnaires, upper endoscopy, 24 h-pH-manometry, and esophagograms. Patients were followed-up with questionnaires every 6 months, upper endoscopies after 1 year and 24 h-pH-metry after 2 years. Silent GERD was defined as esophagitis grade > B and/or abnormal esophageal acid exposure in absence of symptoms. LSG was performed over a 32F bougie, hiatal hernias > 1 cm were addressed with posterior hiatoplasty. Excluded were patients with hiatal hernias > 4 cm, patients with incorrect anatomy (stenosis, fundus too large) and conversion to RYGB for early leaks. RESULTS: 222 patients were included. Mean follow-up was 32 +/- 16 months, mean preoperative body mass index 49.6 +/- 7.2 kg/m2. 116 patients (52%) presented with post operative GERD-symptoms, of which 85 (73%) had de novo symptoms. Of those, 48 (of 85, 56%) had no preoperative GERD and 37 (of 85, 44%) silent GERD. 57 patients (26%) had neither pre- nor post-operative GERD, 7 (3%) had silent pre-operative and no postop GERD, and in 19 patients (9%) GERD was cured with LSG. 31 patients (14%) stayed symptomatic. Of 56 patients (25%) with pre-operative silent GERD, 37 (of 54, 66%) became symptomatic. CONCLUSION: LSG leads to a considerable rate of post-operative GERD. De novo-GERD consist of around half of pre-operative silent GERD and completely de novo-GERD. Most patients with pre-operative silent GERD became symptomatic. PMID- 30003347 TI - Roux-en-Y gastric bypass as a salvage procedure in complicated patients with failed fundoplication(s). AB - BACKGROUND: In symptomatic patients after failed fundoplication, reoperation is considered. In complex or obese patients, Roux-en Y gastric bypass (RYGB) may be the best operation. We sought to characterize the outcomes of patients with failed fundoplication to undergo salvage RYGB, and to compare these outcomes to patients undergoing reoperative fundoplication. METHODS: A prospectively maintained database was queried for procedures performed at a single institution from 2011 to 2017. GERD health-related quality of life (HRQL) surveys were administered at defined intervals. RESULTS: Thirty-six patients underwent salvage RYGB and 84 patients underwent reoperative fundoplication. The RYGB cohort had a higher BMI (35.5 +/- 6.8 vs. 28.7 +/- 5.3, p < 0.01), more gastroparesis (52.8% vs. 9.5%, p < 0.01), more esophagitis (42.9% vs. 20.2%, p = 0.01), and more prior fundoplications (1.9 vs. 1.2, p < 0.01). The incidence of gastroparesis and esophagitis was directly related to the number of failed fundoplications (p < 0.05). Operative times were longer with RYGB (332.7 +/- 131.5 vs. 200.0 +/- 67.6 min, p < 0.01) as was length of stay (4.3 +/- 3.4 vs. 2.8 +/- 1.5 days, p = 0.02), incidence of Clavien-Dindo complications >= Grade 3 (19.4% vs. 4.8%, p = 0.01), 30-day reoperation (11.1% vs. 1.2%, p = 0.01), and 30-day readmission (32.4% vs. 11.9%, p < 0.01). In five patients with three or more prior fundoplication attempts, an esophagojejunostomy was necessary. If these patients are excluded, there was no difference for RYGB with gastrojejunostomy compared to reoperative fundoplication for complications, reoperations, or readmissions. GERD HRQL scores were similar prior to surgery in both cohorts and improved significantly and to a similar degree on long-term follow-up. CONCLUSIONS: In a complex cohort of patients with high rates of obesity and numerous failed previous fundoplication attempts, conversion to RYGB results in good symptomatic outcomes. Patients with three or more previous fundoplication attempts are more likely to require esophagojejunostomy. Complication rates in this subset of patients appear to be quite high. PMID- 30003348 TI - Autologous blood, a novel agent for preoperative colonic localization: a safety and efficacy comparison study. AB - BACKGROUND: Preoperative localization is essential for minimally invasive colorectal surgery. However, conventional endoscopic tattooing agents such as India ink have safety issues. The availability of new endoscopic markers such as non-India-ink-based agent is limited. We assessed the efficacy and safety of preoperative endoscopic tattooing using autologous blood in colorectal surgery. METHODS: From February 2016, all patients who required localization of a target lesion before colorectal surgery underwent endoscopic tattooing using autologous blood, and the outcomes were collected prospectively. As a comparison, we retrospectively reviewed the medical records of a further 51 consecutive patients who underwent endoscopic tattooing using India ink before February 2016. A total of 102 patients who underwent endoscopic tattooing using either India ink or autologous blood were included in this study. The primary outcomes were the visibility of the tattooing in the peritoneal cavity and related adverse events. RESULTS: Endoscopic tattoos produced using India ink were visible in 49 (96.1%) patients, and tattoos created using autologous blood were visible in 47 (92.2%) patients. In the autologous blood group, the tattoo could not be identified in four patients due to excessive peritoneal fat, bleeding tendency, congenital anomaly, and suboptimal tattooing. Seven (13.7%) patients in the India ink group and three (5.9%) patients in the autologous blood group experienced endoscopic tattooing-related adverse events. CONCLUSIONS: Autologous blood is a feasible and safe tattooing agent for preoperative endoscopic localization of colorectal lesions within maximal interval of 5 days. PMID- 30003349 TI - A minimally invasive approach for peritonectomy procedures and hyperthermic intraperitoneal chemotherapy (HIPEC) in limited peritoneal carcinomatosis: The American Society of Peritoneal Surface Malignancies (ASPSM) multi-institution analysis. AB - BACKGROUND: Minimally invasive surgery is playing an increasing role in the treatment of patients with gastrointestinal and gynaecological malignancies as the data show reduced morbidity, faster recovery and similar oncological outcome when compared to open procedures. MATERIALS AND METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) conducted a retrospective study to analyse peritonectomy procedures and HIPEC done via the laparoscopic route. A database with standard clinical and pathological parameters was set up and distributed amongst ASPSM members. Rate of relapse, morbidity and mortality were the primary endpoints of the study. RESULTS: A total of 90 patients from 7 centres around the world were identified. Sixty percent were female. Mean age was 50 years. Peritoneal carcinomatosis from appendiceal origin was the most common diagnosis in a 64.9% of patients and colon origin was diagnosed in 16.5% of patients. Mean peritoneal cancer index (PCI) was 4.1 (0-10). Forty-one percent of patients had a bowel resection. Mean operative time was 4.7 h (2.5-8). All patients had a complete cytoreduction and HIPEC. Grade 3 and 4 morbidity was 3.0 and 6.5%, respectively. The most common reason for re-operation was an internal hernia in 2 out of 5 cases. Operative mortality and re-admission rates were 0 and 5%, respectively. Mean hospital stay was 7.4 days (1-18). At a mean follow-up of 31.6 months, 15/90 patients have a disease relapse but loco-regional relapse was identified in only five patients. CONCLUSIONS: Analysis of these data suggests that minimally invasive approach for peritonectomy procedures and HIPEC is feasible, safe and should be considered as part of the armamentarium for highly selected patients with peritoneal surface malignancies with limited tumour burden, defined as PCI of 10 or less and borderline tumours as low-grade pseudomyxoma and benign multicystic mesothelioma. PMID- 30003350 TI - Safety of laparoscopic hepatectomy in patients with hepatocellular carcinoma and portal hypertension: interim analysis of an open prospective study. AB - BACKGROUND: The laparoscopic approach might increase the number of cirrhotic patients with hepatocellular carcinoma (HCC) indicated for liver resection, otherwise contraindicated due to portal hypertension. The goal of this study was to confirm the safety of laparoscopic liver resection (LLR) in patients with portal hypertension. METHODS: This prospective, single-center, open study (ClinicalTrials.gov ID: NCT02145013) included all consecutive cirrhotic patients who underwent LLR for HCC from 2014 to 2017. Short-term outcomes were compared between patients with and without clinically significant portal hypertension (CSPH, defined by hepatic venous pressure gradient >= 10 mmHg). RESULTS: The study population included 45 patients, comprising 27 patients (60%) in the no CSPH group and 18 patients (40%) in the CSPH group. All planned procedures could be performed. The two groups did not differ in the extent of resection, transfusion, duration of clamping, and need for conversion. Overall, the 90-day mortality and severe morbidity rates were nil. Moderate morbidity was significantly higher in the CSPH group (39 vs. 4%, p = 0.01); however, the two groups did not differ in the rate of unresolved liver decompensation. Intensive care unit and hospital stays were significantly longer in the CSPH group. At 2 years, overall survival was 77% in the no CSPH group and 100% in the CSPH group (p = 0.17), and recurrence-free survival was 55% in the no CSPH group and 79% in the CSPH group (p = 0.10). CONCLUSION: LLR is safe in BCLC 0-A patients with CSPH, with no mortality and good short-term outcomes. Re-evaluation of the BCLC guidelines is needed. PMID- 30003344 TI - Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine. AB - The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously "leaky" BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents. Future success in therapeutics for brain metastases must take into account the adequate delivery of "active, free drug" to the target, and may include combinations of targeted drugs that are appropriate to address each individual patient's tumor type. This review discusses some issues that are pertinent to precision medicine for brain metastases, using specific examples of tumor types that have a high incidence of brain metastases. PMID- 30003351 TI - Predicting venous thromboembolism following laparoscopic bariatric surgery: development of the BariClot tool using the MBSAQIP database. AB - BACKGROUND: Bariatric surgery is an effective treatment for severe obesity; however, postoperative venous thromboembolism (VTE) remains a leading cause of morbidity and mortality. The objective of this study is to develop a tool to stratify individuals undergoing laparoscopic bariatric surgery according to their 30-day VTE risk. METHODS: This is a retrospective cohort study of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. This registry collects data specific for metabolic or bariatric surgery with 30-day outcomes from 791 centers. Individuals undergoing primary laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) were included. Characteristics associated with 30-day VTE were identified using univariate and multivariable analyses. A predictive model, BariClot, was derived from a randomly-generated derivation cohort using a forward selection algorithm. BariClot's robustness was tested against a validation cohort of subjects not included in the derivation cohort. The calibration and discrimination of two previously published VTE risk tools were assessed in the MBSAQIP population and compared to BariClot. RESULTS: A total of 274,221 patients underwent LRYGB or LSG. Overall, 1106 (0.4%) patients developed VTE, 452 (0.2%) developed pulmonary embolism, and 43 (0.02%) died due to VTE. VTE was the most commonly identified cause of 30-day mortality. A prediction model to assess for risk of VTE, BariClot, was derived and validated. BariClot consists of history of VTE, operative time, race, and functional status. It stratifies individuals into very high (> 2%), high (1-2%), medium (0.3-1%), and low risk groups (< 0.3%). This model accurately predicted events in the validation cohort and outperformed previously published scoring systems. CONCLUSIONS: BariClot is a predictive tool that stratifies individuals undergoing bariatric surgery based on 30-day VTE risk. Stratifying low- and high-risk populations for VTE allows for informed clinical decision-making and potentially enables further research on customized prophylactic measures for low- and high-risk populations. PMID- 30003353 TI - Neutron reflectivity measurements at the oil/water interface for the study of stimuli-responsive emulsions?. AB - Stable stimuli-responsive emulsions between oil and water are formed with an amphiphilic block copolymer bearing polystyrene (PS) and poly(dimethylaminoethyl methacrylate) (PDMAEMA) moieties. Different kinds of emulsions like direct, multiple or inverse ones are reproducibly formed as a function of chemical parameters such as p H and salt concentration. To test the correlation between the different nature of the emulsion and the conformation of the polymer chain at the interface, neutron reflectometry at the oil/water interface was carried out. An original sample cell was built and the procedure to get reliable results with it on the FIGARO reflectometer at the Institut Laue-Langevin is described. Results show that for direct emulsions, the copolymer is much more extended on the water side than on the oil side. In the case where multiple emulsions are stabilized, the conformation is strongly modified and is compatible with a more equilibrated extension of the chain on both sides. The inverse case shows that the extension in oil is stronger than in water. These results are discussed in term of polymer brushes (charged or neutral) extension with respect to salt addition and hydrophobic interactions. PMID- 30003354 TI - The Economics of Infectious Disease, Trade and Pandemic Risk. PMID- 30003352 TI - Chronic and intermittent administration of systemic nitroglycerin in the rat induces an increase in the gene expression of CGRP in central areas: potential contribution to pain processing. AB - BACKGROUND: Calcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular system and it is likely related to migraine chronification. Here, we investigated the role of CGRP in an animal model that mimics the chronic migraine condition via repeated and intermittent nitroglycerin (NTG) administration. We also evaluated the modulatory effect of topiramate on this experimental paradigm. Male Sprague-Dawley rats were injected with NTG (5 mg/kg, i.p.) or vehicle, every 2 days over a 9-day period (5 total injections). A group of animals was injected with topiramate (30 mg/kg, i.p.) or saline every day for 9 days. Twenty-four hours after the last administration of NTG or vehicle, animals underwent tail flick test and orofacial Von Frey test. Rats were subsequently sacrificed to evaluate c-Fos and CGRP gene expression in medulla-pons region, cervical spinal cord and trigeminal ganglia. RESULTS: NTG administration induced spinal hyperalgesia and orofacial allodynia, together with a significant increase in the expression of CGRP and c-Fos genes in trigeminal ganglia and central areas. Topiramate treatment prevented NTG-induced changes by reversing NTG-induced hyperalgesia and allodynia, and inhibiting CGRP and c-Fos gene expression in all areas evaluated. CONCLUSIONS: These findings point to the role of CGRP in the processes underlying migraine chronification and suggest a possible interaction with gamma-aminobutyrate (GABA) and glutamate transmission to induce/maintain central sensitization and to contribute to the dysregulation of descending pain system involved in chronic migraine. PMID- 30003355 TI - Frequencies of human leukocyte antigen alleles and haplotypes among Japanese patients with age-related macular degeneration. AB - PURPOSE: Stem cell therapy is a potential treatment for retinal disorders. We are currently exploring treating HLA matched patients of age-related macular degeneration (AMD) by using allogenic retinal pigment epithelium cells derived from induced pluripotent stem cells (iPS-RPE) from human leukocyte antigen (HLA) homozygote donors. The purpose of this study was to investigate the frequency of HLA class I and II alleles and haplotypes in Japanese patients with AMD. STUDY DESIGN: Cross-sectional observation clinical study. METHODS: A total of 138 consecutive patients diagnosed with neovascular AMD (mean age, 76.0 +/- 7.8 years, 105 men) and 300 controls were included in the study. The frequencies of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 alleles were determined using illumina MiSeq platform. Frequencies of HLA alleles at six loci in patients with AMD were compared with those of the controls. RESULTS: The alleles with the highest prevalence at each locus were A*24:02 (29.7%), B*52:01 (15.5%), C*12:02 (16.1%), DRB1*09:01 (19.1%), DQB1*06:01 (23.2%), and DPB1* 05:01 (40.5%). There were no significant associations between the HLA alleles and AMD. The most common haplotype was A*24:02-B*52:01-C*12:02-DRB1*15:02-DQB1*06:01-DPB1*09:01, with a 9.8% genetic frequency among all haplotypes, detected in 18.8% of the patients. CONCLUSION: The genotype of HLA in patients with AMD was not different from that in the Japanese control population. Thus, therapy with iPS-RPEof the most frequent HLA haplotype could be a feasible alternative for AMD in a wider population. PMID- 30003356 TI - Telomere length as a modifier of age-at-onset in Huntington disease: a two-sample Mendelian randomization study. PMID- 30003357 TI - Cognitive and fatigue side effects of anti-epileptic drugs: an analysis of phase III add-on trials. AB - We aimed to investigate the terms used to refer to cognitive and fatigue related side effects and their prevalence in phase III add-on clinical trials of anti epileptic drugs (AEDs). We extracted data from publicly available FDA documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). The odds ratio of developing the side effects was calculated for each drug load, and the presence of a dose-response effect was also assessed. We found that the cognitive terms used across trials were very variable, and data on discontinuation rates were limited. Placebo rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Keeping in mind the variable placebo rates and terminology, the majority of AEDs exhibited a clear dose response effect and significant odds ratios at high doses except brivaracetam and zonisamide for the cognitive side effects and tiagabine, topiramate, and zonisamide for the fatigue side effects. Due to their clinical relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Given the clear dose response effect, physicians should consider aiming for lower drug loads and adjusting doses to improve tolerability. PMID- 30003359 TI - ERAS programs in elderly patients: is there a limit? PMID- 30003358 TI - Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies. AB - OBJECTIVE: The aim of this study was to describe specificities of patients with NMDA receptor antibody (NMDAR-Ab) encephalitis associated with a malignant tumor. METHODS: Retrospective observational study of 252 patients with NMDAR-Ab encephalitis of the French Paraneoplastic Neurological Syndrome Reference Center. Patients were classified in three groups: (1) non-malignant ovarian teratomas, (2) malignant ovarian teratomas (immature), and (3) other malignant tumors. RESULTS: Sixty patients (23.8%) had an associated tumor and 15 (6%) were malignant. No particular neurological symptom was observed in these patients. Ovarian teratomas were the most frequent (51 cases) with 6 of them immature (11.8% of teratomas). Nine patients (3.6%) developed other malignant tumors (3 small cell lung carcinomas, 1 uterine adenocarcinoma, 1 prostate adenocarcinoma, 1 Hodgkin lymphoma, 1 pineal dysgerminoma, 1 neuroblastoma and 1 pancreatic neuroendocrine tumor). Among patients with a cancer other than teratoma, 6/9 were elderly patients (median age 65 years, representing 30% of elderly patients with such encephalitis) compared to a median age of 26 years in adult patients included herein. The clinical course was similar in the three groups, other than a higher death rate among patients with malignant tumors (86 versus 2%; p < 0.001) mainly due to tumor progression (5/7 deaths). CONCLUSION: Immature ovarian teratomas represent 11.8% of all teratomas in patients with NDMAR-Ab encephalitis. The other malignant tumors are mainly observed in elderly patients. The presence of a malignant tumor does not impact the neurological presentation but is directly associated with a higher risk of death. PMID- 30003360 TI - Timing of surgery in ulcerative colitis in the biologic therapy era-the patient's perspective. AB - BACKGROUND: There is no general consensus regarding the ideal timing of surgery in patients with refractory ulcerative colitis (UC). Decision-making and timing of restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is influenced by treating physicians and patients themselves. The aim of this study was to determine whether or not patients would have preferred the operation to be performed earlier, at the same time, or at a later point of time and to determine the reasons for their preference. METHODS: Clinical data of 193 patients with UC who have undergone IPAA were documented in a prospective database at our institution between 2004 and 2015. From this database, 190 patients were identified and a standardized custom-made questionnaire was mailed for follow-up survey. Patients who did not respond were called by telephone and encouraged to complete the questionnaire. RESULTS: One hundred nine questionnaires were eligible for analysis (57.4%). Average time between diagnosis and surgery was 11.2 +/- 10.8 years (mean +/- SD). Indications for surgery were refractory disease (70.6%), colitis-associated colorectal cancer (11.0%), high-grade dysplasia or stenosis (11.9%), and septic complications of UC (6.4%); 39 of 77 patients (50.6%) with refractory UC reported to have preferred their operation to be carried out earlier as it was actually performed (16.8 +/- 11.9 months). Refractory course of the disease was identified as a predictor for a retrospectively desired earlier surgical approach (p = 0.014). CONCLUSION: A substantial proportion of patients felt that they should have undergone surgery earlier than actually performed. It appears that timing of the decision to undergo surgery is suboptimal. This situation may be improved by earlier surgical consultation in the course of the disease. PMID- 30003362 TI - Obstetric risk factors for early-onset anal incontinence. AB - PURPOSE: The aim of the study was to identify primiparous pregnant women with a higher risk for early anal incontinence (AI) after labour. METHODS: In the retrospective case control study, 133 primiparous women were questioned using the Wexner scoring system, and possible obstetric anal sphincter injuries (OASIS) were assessed using endoanal ultrasonography (EUS) 6-12 weeks after the labour. Obstetric characteristics (possible risk factors) for AI were collected from the maternal medical records. The univariate and multiple regression of maternal, neonatal and labour risk factors were calculated. Cut-off values were set to divide women into groups with higher and lower risk for AI. RESULTS: The data of 30 primiparous women with and 103 without AI were analysed. Univariate logistic regression of obstetrics characteristics showed that stimulation of labour (RO [95% CI] 3.31 [1.07, 10.28]) and neonatal head circumference (RO [95% CI] 1.36 [1.03, 1.78]) are both associated with AI. With a neonatal head circumference of 34 cm or more (cut-off value), probability for AI was 33%, while below that value, it was just 2%. The incidence of AI was not significantly different between women with surgically repaired OASIS and women without anal sphincter injury. CONCLUSION: The findings can assist in the identification of pregnant women at higher risk of AI. The women at higher risk of AI should be given special attention during the labour and specific rehabilitation after the labour. PMID- 30003361 TI - Increased risk of periodontitis among patients with Crohn's disease: a population based matched-cohort study. AB - BACKGROUND: Periodontitis is a frequently cited extraintestinal manifestation of Crohn's disease (CD). Despite a plethora of investigations and a recent meta analysis linking CD and periodontitis, no study has estimated the risk of periodontitis among CD patients with respect to a comparison group nor has any investigation analyzed the effect of CD-specific medications on the risk of periodontitis. The present cohort study compared CD patients and matched subjects without a history of inflammatory bowel disease (IBD) to estimate the effect of CD and CD-specific pharmaceutical prescriptions on the risk of developing periodontitis by leveraging a population-based dataset in Taiwan. METHODS: We sourced 6657 CD patients and 26,628 comparison subjects without a history of IBD from the Taiwan National Health Insurance Database. Cox proportional hazards regressions were used to estimate the risk of subsequent periodontitis by CD status and pharmaceutical prescription during the follow-up period. RESULTS: After adjusting for socioeconomic status (SES), urbanicity, selected medical co morbidities, and CD-specific pharmaceutical prescriptions, the hazard ratio (HR) for subsequent periodontitis among patients with CD was 1.36 (95% CI = 1.25-1.48) that of comparison subjects. There was not a significant difference in risk between genders or across ages. Steroids (95% CI = 0.66-0.77) appeared to confer a protective effect and Aspirin, Plavix, and Licodin were marginally protective (95% CI = 0.76-0.95). CONCLUSION: This is the first study to report an increased HR for subsequent periodontitis among CD patients when compared to matched comparison subjects without IBD. The protective effect of some pharmaceuticals may suggest that treatment of CD protects against periodontitis. PMID- 30003363 TI - Indistinguishable T2/T3-N0 rectal cancer on rectal magnetic resonance imaging: comparison of surgery-first and neoadjuvant chemoradiation therapy-first strategies. AB - PURPOSE: We compared the treatment outcome between surgery-first and neoadjuvant chemoradiation therapy (nCRT)-first strategies in patients with indistinguishable T2/T3-N0 rectal cancer on rectal magnetic resonance imaging (MRI). METHODS: Our institutional review board approved this retrospective study, and informed consent was waived. Among 1910 patients who underwent rectal MRI between 2008 and 2012, 79 patients (mean age, 59.4 years, 49 men and 30 women) who had indistinguishable T2/T3-N0 rectal cancer on rectal MRI were included. Local recurrence-free survival (LRFS), recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were compared between the two groups. Treatment-related complications were evaluated. RESULTS: Among 79 patients, 51 were treated by surgery first and 28 were treated by nCRT first. In comparison of survival of the surgery- and nCRT-first groups at 5 years, the LRFS rate was 95.6 and 96.3%, RFS rate was 91.0 and 92.4%, OS rate was 93.7 and 92.6%, and DSS rate was 98.0 and 92.6%, respectively. LRFS, RFS, OS, and DSS showed no significant difference between the two groups (p = 0.862, 0.677, 0.953, and 0.479). The complication rate was not significantly different between the groups (20.0% for surgery-first group vs. 10.7% for nCRT-first group, p = 0.357). CONCLUSION: Treatment outcomes were not significantly different between surgery-first and nCRT-first strategies for indistinguishable T2/T3-N0 rectal cancer on rectal MRI. PMID- 30003364 TI - Recent insights into the microbial catabolism of aryloxyphenoxy-propionate herbicides: microbial resources, metabolic pathways and catabolic enzymes. AB - Aryloxyphenoxy-propionate herbicides (AOPPs) are widely used to control annual and perennial grasses in broadleaf crop fields and are frequently detected as contaminants in the environment. Due to the serious environmental toxicity of AOPPs, there is considerable concern regarding their biodegradation and environmental behaviors. Microbial catabolism is considered as the most effective method for the degradation of AOPPs in the environment. This review presents an overview of the recent findings on the microbial catabolism of various AOPPs, including fluazifop-P-butyl, cyhalofop-butyl, diclofop-methyl, fenoxaprop-P ethyl, metamifop, haloxyfop-P-methyl and quizalofop-P-ethyl. It highlights the microbial resources that are able to catabolize these AOPPs and the metabolic pathways and catabolic enzymes involved in their degradation and mineralization. Furthermore, the application of AOPPs-degrading strains to eliminate AOPPs contaminated environments and future research hotspots in biodegradation of AOPPs by microorganisms are also discussed. PMID- 30003365 TI - Long-term effects of iron deficiency in patients with heart failure with or without anemia: the RAID-HF follow-up study. AB - INTRODUCTION: Iron deficiency (ID) has been recognized as a relevant comorbidity in heart failure with reduced ejection fraction (HFrEF); however, study data have shown that diagnostic and therapeutic efforts on ID are primarily performed in patients with anemia. METHODS: The RAID-HF registry investigated consecutive patients with ID and HFrEF in 11 heart centers in Germany and Switzerland. The present analysis focuses on 1-year follow-up data in patients with versus without anemia. RESULTS: In 505 patients with HFrEF and ID and 418 patients with HFrEF without ID 1-year follow-up was performed. Patients with ID had a higher long term mortality compared to those without ID (19.5% vs. 13.7%, p = 0.02) and reported a lower quality of life. Only a minority of patients with ID (9.3%) received iron supplementation during long-term course, just 4.7% intravenously. Anemia was associated with an elevated mortality whereas ID versus no ID did not predict mortality in anemic patients (log-rank p = 0.78). However, in patients without anemia ID versus no ID predicted mortality (log-rank p = 0.002). In the adjusted analysis a significant interaction remained, with ID being a significant predictor of 1-year mortality in patients without anemia (HR 2.15, 95% CI 1.12 3.78), but not in anemic patients (HR 0.99, 95% CI 0.65-1.49). CONCLUSIONS: RAID HF demonstrates the impact of ID on long-term mortality and quality of life in patients with HFrEF and reveals an underuse of iron supplementation in current clinical practice. Particularly in patients without anemia the diagnosis of ID is of clinical relevance to identify patients at higher mortality risk. PMID- 30003366 TI - Transcatheter valve-in-valve implantation (VinV-TAVR) for failed surgical aortic bioprosthetic valves. AB - OBJECTIVE: We sought to investigate the procedural and hemodynamic outcome after valve-in-valve transcatheter aortic valve replacement (VinV-TAVR) for different surgical (SBV) and transcatheter (TAVR) bioprosthetic valves. METHODS AND RESULTS: 223 patients (76 +/- 11years, STS-Score 8.3 +/- 10.1) suffering from SBV failure treated with VinV-TAVR were enrolled at 6 centers across Germany. At time of the intervention, the majority of patients were in NYHA-class >= III (88%, n = 180). Failure mode of the SBVs was either stenosis, regurgitation (AR) or a combination of both in 85 (38%), 76 (34%) and 62 (28%) patients, respectively. 138 (62%) patients were treated with first generation TAVR valves (Edwards Sapien XT or CoreValve). Second generation valves were implanted in 85 (38%) patients (Sapien 3, Medtronic CoreValve Evolut, SJM-Portico, JenaValve). VinV-TAVR was associated with high procedural success rate, conversion to surgery was necessary in 3 (2%) patients. After VinV-TAVR procedure, 4 (2%) patients suffered from >= moderate AR. In 6 (3%) patients a second valve was implanted due to mispositioning of the first valve and subsequent severe paravalvular AR. Coronary obstruction was observed in 4 (2%) patients. Major bleeding and cerebrovascular complications (according to VARC) were reported in 3 (1%) and 4 (2%) patients at 30 days. Post-interventionally, 44/178 (25%) patients evidenced a mean pressure gradient (mPG) >= 20 mmHg. Residual stenosis was not associated with increased mortality (HR 0.39; 95% CI 0.13-1.22; p = 0.11). CONCLUSION: In VinV-TAVR for SBV failure is a safe procedure resulting in hemodynamic improvement in the majority of patients. Residual stenosis is a common finding which can be observed in 1/4 of patients undergoing VinV-TAVR. However, this condition is not associated with increased 1-year-mortality. PMID- 30003367 TI - The influence of induced mood on music preference. AB - The purpose of this study was to clarify the impact of different self-centered moods on music preference without listening to music. Participants' affective state (sad vs. happy vs. neutral) were experimentally manipulated through the mood induction procedure, and then their preferences for music were ascertained through self-reports. To understand participants' internal motivations for their choices, we also asked them to indicate how appropriate he/she felt it would be to select the different music types as well as why they made such choices. Results suggested that participants in a sad mood were inclined to listen to sad (and slow) music, those in a happy mood preferred to listen to happy (and fast) music, and those in a neutral mood did not consistently prefer to listen to neutral music. In addition, participants were averse to sad music when they were in a happy or neutral mood; while they showed no aversion to happy music when they were in a sad mood. In conclusion, individuals select valence-consistent music when they are in an autobiographical memory-induced mood state. PMID- 30003368 TI - Correction to: Changes in the bee fauna of a German botanical garden between 1997 and 2017, attributable to climate warming, not other parameters. AB - The same is included here. PMID- 30003369 TI - Host plant iridoid glycosides mediate herbivore interactions with natural enemies. AB - Many insect herbivores are dietary specialists capable of sequestering the secondary metabolites produced by their host plants. These defensive compounds have important but complex implications for tritrophic interactions between plants, herbivores, and natural enemies. The sequestration of host plant secondary metabolites defends herbivores from attack by generalist predators, but may also compromise the immune response, making insect herbivores more vulnerable to parasitism. Here, we investigate the role of plant secondary metabolites in mediating interactions between a specialist herbivore and its natural enemies. The host plants are two Penstemon species, Penstemon glaber and Penstemon virgatus, which are chemically defended by iridoid glycosides (IGs). First, we examined how Penstemon iridoid glycoside content influences the sequestration of IGs by a specialist herbivore, Euphydryas anicia. Then, we performed ant bioassays to assess how host plant species influences larval susceptibility to predators and phenoloxidase assays to assess the immunocompetence and potential vulnerability to parasitoids and pathogens. We found that the concentration of IGs sequestered by E. anicia larvae varied with host plant diet. Larvae reared on P. glaber sequestered more IGs than larvae reared on P. virgatus. Yet, ant predators found larvae unpalatable regardless of host plant diet and were also repelled by sugar solutions containing isolated IGs. However, E. anicia larvae reared on P. glaber showed higher levels of phenoloxidase activity than larvae reared on P. virgatus. Our results suggest that the sequestration of some secondary metabolites can effectively protect herbivores from predation, yet may also increase vulnerability to parasitism via decreased immunocompetence. PMID- 30003370 TI - Landscape variation in canopy nitrogen and carbon assimilation in a temperate mixed forest. AB - Canopy nitrogen (N) is a key factor regulating carbon cycling in forest ecosystems through linkages among foliar N and photosynthesis, decomposition, and N cycling. This analysis examined landscape variation in canopy nitrogen and carbon assimilation in a temperate mixed forest surrounding Harvard Forest in central Massachusetts, USA by integration of canopy nitrogen mapping with ecosystem modeling, and spatial data from soils, stand characteristics and disturbance history. Canopy %N was mapped using high spectral resolution remote sensing from NASA's AVIRIS (Airborne Visible/Infrared Imaging Spectrometer) instrument and linked to an ecosystem model, PnET-II, to estimate gross primary productivity (GPP). Predicted GPP was validated with estimates derived from eddy covariance towers. Estimated canopy %N ranged from 0.5 to 2.9% with a mean of 1.75% across the study region. Predicted GPP ranged from 797 to 1622 g C m-2 year 1 with a mean of 1324 g C m-2 year-1. The prediction that spatial patterns in forest growth are associated with spatial patterns in estimated canopy %N was supported by a strong, positive relationship between field-measured canopy %N and aboveground net primary production. Estimated canopy %N and GPP were related to forest composition, land-use history, and soil drainage. At the landscape scale, PnET-II GPP was compared with predicted GPP from the BigFoot project and from NASA's MODIS (Moderate Resolution Imaging Spectroradiometer) data products. Estimated canopy %N explained much of the difference between MODIS GPP and PnET II GPP, suggesting that global MODIS GPP estimates may be improved if broad-scale estimates of foliar N were available. PMID- 30003371 TI - Assimilation and discrimination of hydrogen isotopes in a terrestrial mammal. AB - Stable isotope analysis has revolutionized the way ecologists study animal resource use from the individual to the community level. Recent interest has emerged in using hydrogen isotopes (2H/1H) as ecological tracers, because they integrate information from both abiotic and biotic processes. A better physiological understanding of how animals assimilate hydrogen and use it to synthesize tissues is needed to further refine this tool and broaden its use in animal ecology. We conducted a controlled-feeding experiment using laboratory mice (Mus musculus) in which we varied the hydrogen isotope (delta2H) values of water and the proportions of dietary protein and carbohydrates among nine experimental treatments. For each tissue, we calculated the percent of hydrogen derived from water and the percent hydrogen derived from dietary protein versus carbohydrates using linear relationships and isotope mixing models based on accompanying carbon isotope (delta13C) data. The net discrimination (?2HNet) between mice tissues and potential water and dietary sources of hydrogen differed among tissues. ?2HNet was positively correlated with dietary protein content in red blood cells (RBC) and muscle, but negatively correlated in liver and plasma. We also report the first estimates for hydrogen isotope discrimination factors (?2H) for different sources of hydrogen (?2HWater, ?2HProtein, and ?2HCarbs) available for tissue synthesis. This research provides a foundation for understanding how diet quality (e.g., protein content) influences hydrogen isotope assimilation and discrimination in different tissues of a terrestrial mammal, which is a first step towards using delta2H as a tracer of resource use in free-ranging mammals. PMID- 30003372 TI - Allele-specific methylation contributed by CpG-SNP is associated with regulation of ALOX5AP gene expression in ischemic stroke. AB - Previous studies have shown that CpG-SNPs might have influence on gene function via allele-specific DNA methylation (ASM). However, association study between DNA methylation and the promoter CpG-SNPs in ALOX5AP gene with IS has not been reported. The present study aims to explore the relationship among CpG-SNPs, methylation levels, and messenger RNA (mRNA) expression levels of ALOX5AP gene. Firstly, we made a two-stage association study to identify a potential associated CpG-SNP (rs4073259) by SNaPshot genotyping approach (P = 0.015, OR = 0.672, 95% CI 0.487-0.927; P = 0.035, OR = 0.809, 95% CI 0.664-0.985, respectively). In addition, the methylation levels of 17 CpG sites located in the promoter of ALOX5AP were tested by MethylTarget sequencing. The methylation level of GG genotype carriers is significantly higher than those with the AG and AA genotypes (P < 0.05). And the GG genotype carriers with higher DNA methylation levels have a decreased mRNA expression levels of ALOX5AP (P < 0.05). Finally, we found that the G allele with higher methylation level has got a lower transcription activity than the A allele by luciferase assay (P = 0.000).The study provided evidence that IS-associated CpG-SNP rs4073259 may affect the expression level of ALOX5AP through allele-specific methylation and consequently the phenotype of the disease. PMID- 30003373 TI - Update on the ICUD-SIU consultation on multi-parametric magnetic resonance imaging in localised prostate cancer. AB - INTRODUCTION: Prostate cancer (PCa) imaging is a rapidly evolving field. Dramatic improvements in prostate MRI during the last decade will probably change the accuracy of diagnosis. This chapter reviews recent current evidence about MRI diagnostic performance and impact on PCa management. MATERIALS AND METHODS: The International Consultation on Urological Diseases nominated a committee to review the literature on prostate MRI. A search of the PubMed database was conducted to identify articles focussed on MP-MRI detection and staging protocols, reporting and scoring systems, the role of MP-MRI in diagnosing PCa prior to biopsy, in active surveillance, in focal therapy and in detecting local recurrence after treatment. RESULTS: Differences in opinion were reported in the use of the strength of magnets [1.5 Tesla (T) vs. 3T] and coils. More agreement was found regarding the choice of pulse sequences; diffusion-weighted MRI (DW-MRI), dynamic contrast-enhanced MRI (DCE MRI), and/or MR spectroscopy imaging (MRSI) are recommended in addition to conventional T2-weighted anatomical sequences. In 2015, the Prostate Imaging Reporting and Data System (PI-RADS version 2) was described to standardize image acquisition and interpretation. MP-MRI improves detection of clinically significant PCa (csPCa) in the repeat biopsy setting or before the confirmatory biopsy in patients considering active surveillance. It is useful to guide focal treatment and to detect local recurrences after treatment. Its role in biopsy-naive patients or during the course of active surveillance remains debated. CONCLUSION: MP-MRI is increasingly used to improve detection of csPCa and for the selection of a suitable therapeutic approach. PMID- 30003375 TI - The utility of PET-based imaging for prostate cancer biochemical recurrence: a systematic review and meta-analysis. AB - INTRODUCTION: Conventional imaging modalities have been poor in characterizing the true extent of disease in men with biochemical recurrence following primary treatment for prostate cancer. Functional imaging with positron emission tomography (PET) has shown promise of being a superior imaging modality. We conducted a systematic review and meta-analysis to define the diagnostic accuracy of PET/CT using 11C-choline, 18F-FACBC, or 68Ga-PSMA in detecting recurrent prostate cancer. METHODS: We searched multiple databases in line with the preferred reporting items for systematic review and meta-analysis (PRISMA) statement to define the diagnostic accuracy of 11C-choline, 18F-FACBC, or 68Ga PSMA PET/CT. Only studies secondarily staging participants with biochemical recurrence and those with an appropriate reference standard (pathology, further imaging, and/or clinical response) were eligible for analysis. RESULTS: Twenty one studies with 3202 participants met the inclusion criteria. Of these, 11C choline, 18F-FACBC, and 68Ga-PSMA were the tracer investigated in 16, 5, and 1 studies, respectively. The summary sensitivity for each tracer was 80.9% (95% CI 70.4-88.3%), 79.7% (95% CI 51.9-93.4%), and 76.4% (95% CI 68.3-82.9%), respectively. The corresponding summary specificity was 84.1% (95% CI 70.2 92.2%), 61.9% (95% CI 41.1-79.0%), and 99.8% (95% CI 97.5-100%), respectively. Detection rates ranged between 58.6 and 82.8%. All included studies were judged to be at high risk of bias primarily due to study limitations pertaining to the reference standard. CONCLUSION: There is a lack of high-quality data to verify the accuracy of PET-based imaging using 11C-choline, 18F-FACBC, or 68Ga-PSMA. The early results are encouraging that these techniques are superior to conventional imaging modalities, which would allow salvage therapies to be optimized. PMID- 30003374 TI - Unintended consequences of decreased PSA-based prostate cancer screening. AB - BACKGROUND: In May 2012, the US Preventive Services Task Force issued a grade D recommendation against PSA-based prostate cancer screening. Epidemiologists have concerns that an unintended consequence is a problematic increase in high-risk disease and subsequent prostate cancer-specific mortality. MATERIALS AND METHODS: To assess the effect of decreased PSA screening on the presentation of high-risk prostate cancer post-radical prostatectomy (RP). Nine high-volume referral centers throughout the United States (n = 19,602) from October 2008 through September 2016 were assessed and absolute number of men presenting with GS >= 8, seminal vesicle and lymph node invasion were compared with propensity score matching. RESULTS: Compared to the 4-year average pre-(Oct. 2008-Sept. 2012) versus post-(Oct. 2012-Sept. 2016) recommendation, a 22.6% reduction in surgical volume and increases in median PSA (5.1-5.8 ng/mL) and mean age (60.8-62.0 years) were observed. The proportion of low-grade GS 3 + 3 cancers decreased significantly (30.2-17.1%) while high-grade GS 8 + cancers increased (8.4-13.5%). There was a 24% increase in absolute numbers of GS 8+ cancers. One-year biochemical recurrence rose from 6.2 to 17.5%. To discern whether increases in high-risk disease were due to referral patterns, propensity score matching was performed. Forest plots of odds ratios adjusted for age and PSA showed significant increases in pathologic stage, grade, and lymph node involvement. CONCLUSIONS: All centers experienced consistent decreases of low-grade disease and absolute increases in intermediate and high-risk cancer. For any given age and PSA, propensity matching demonstrates more aggressive disease in the post recommendation era. PMID- 30003377 TI - Letter to the Editor regarding the article "A contemporary lower pole approach for complete staghorn calculi: outcomes and efficacy". PMID- 30003378 TI - Treatment of thermophilic hydrolysis reactor effluent with ceramic microfiltration membranes. AB - For an undisturbed operation of two-stage high-pressure fermentation up to 100 bar, a particle-free hydrolysate appears to be necessary. This is even more important if the second stage, i.e., the methane reactor, is designed as fixed bed. Here, we present the potential of microfiltration membranes as separation unit after the first stage, which is the hydrolysis. The study included the selection of membrane material, membrane performance investigations, and long term-behavior during the filtration period. In a series of experiments, the optimum type of membrane material and the mode of operation [either crossflow (CF) or submerged (S)] were determined. Ceramic membranes proved to be the better option to treat the process stream due to their chemical and temperature resistance. The crossflow filtration achieved a sustainable flux of up to 33 L/(m2 h), while long-term experiments with the submerged membranes confirmed a critical flux of 7 L/(m2 h). Comparative analyses of hydrolysate and permeate showed that the rejected chemical oxygen demand (COD) as well as total organic carbon (TOC) fraction and thereby the loss of organic carbon in the permeate does not reduce the methane yield. PMID- 30003379 TI - Modeling the dynamic performance of full-scale anaerobic primary sludge digester using Anaerobic Digestion Model No. 1 (ADM1). AB - Anaerobic digestion is one of the most commonly accepted processes applied for the stabilization and treatment of primary sludge generated in municipal wastewater treatment plants enabling energy recovery via biogas production. Understanding and optimizing anaerobic sludge digesters play a key role in sustainability of wastewater treatment plants. Mathematical modeling of biological treatment systems provides several advantages such as better understanding of biochemical processes, interrelations of different biomass types, and impact of environmental conditions on the treatment plant performance. This research presents the modeling of a full-scale anaerobic sludge digester by implementing Anaerobic Digestion Model No. 1 with a limited number of monitored parameters. Model calibration was carried out using a long-term data set. The accuracy of the optimized parameter sets was assessed against measured data obtained from the full-scale sludge digester. The model could predict the methane flow and effluent chemical oxygen demand concentration in good agreement with the measured data. Therefore, the validated model can be used to predict full-scale sludge digester performance under dynamic loadings, and to optimize methane production at different operation conditions. PMID- 30003376 TI - Special considerations in the urological management of the older spinal cord injury patient. AB - PURPOSE: This paper reports the key findings of Committee 8 of the Joint SIU-ICUD Consultation on Urologic Management of the Spinal Cord Injured Patient and address issues pertaining to the older person with a SCI and the time-related changes relevant to their urological, gastrointestinal and functional management. METHODS: A literature review using the Pubmed and Ovid search engines was performed examining pertinent literature regarding SCI in the older patient. RESULTS: There is a rising incidence of both traumatic and non-traumatic spinal cord injury (SCI) in older people and improvements in healthcare and nutrition mean patients with SCI are living longer. Outcomes after a SCI in the older person are a sum of the effects of injury and its management compounded by specific effects of ageing and the emergence of unrelated comorbidities. Changes in health, comorbidities, cognition and dexterity with ageing have an impact on function and are important considerations in the management of the older patient with SCI. Treatment decisions are thus increasingly complex due to the need to take into account these changes and accompanying polypharmacy. For the person living with a SCI, changes in circumstances (social and financial) have an impact on quality of life and influence management and support strategies. CONCLUSIONS: Older patients with SCI face additional challenges both in the acute setting and with ageing. Clinicians should take into account comorbid conditions, mental health, physical function, cognition and social support in making management decisions. With the global ageing population, health services planning will need to allow for increase in resources required to care for older patients with SCI. PMID- 30003380 TI - High-throughput optimization of the chemically defined synthetic medium for the production of erythromycin A. AB - Erythromycin A is an important antibiotic. A chemically defined synthetic medium for erythromycin production was systematically optimized in this study. A high throughput method was employed to reduce the number of components and optimize the concentration of each component. After two round single composition deletion experiment, only 19 components were remained in the medium, and then the concentration of each component was optimized through PB experiment. The optimal medium from the PB experiment was further optimized according to the nitrogen and phosphate metabolic consumption in 5 L bioreactor. It was observed that among the 8 amino acids concluded in the media, 4 amino acids were first consumed, when they are almost depleted, the other 4 amino acids were initiated their consumption afterwards in 5 L bioreactor. The decrease of phosphate concentration would increase qglc and qery. However, when phosphate concentration was too low, the production of erythromycin was hindered. The positive correlation between intracellular metabolite pools and Yery/glc indicated that low phosphate concentration in the medium can promote cell metabolism especially secondary metabolism during the stationary phase; however, if it was too low (5 mmol/L), the cell metabolism and secondary metabolism would both slow down. The erythromycin titer in the optimized medium (medium V) reached 1380 mg/L, which was 17 times higher than the previously used synthetic medium in our lab. The optimized medium can facilitate the metabolomics study or metabolic flux analysis of the erythromycin fermentation process, which laid a solid foundation for further study of erythromycin fermentation process. PMID- 30003381 TI - Analysis of oxygen uptake efficiency parameters in young people with cystic fibrosis. AB - PURPOSE: This study characterised oxygen uptake efficiency (OUE) in children with mild-to-moderate cystic fibrosis (CF). Specifically, it investigated (1) the utility of OUE parameters as potential submaximal surrogates of peak oxygen uptake ([Formula: see text]), and (2) the relationship between OUE and disease severity. METHODS: Cardiopulmonary exercise test (CPET) data were collated from 72 children [36 CF, 36 age- and sex-matched controls (CON)], with OUE assessed as its highest 90-s average (plateau; OUEP), the gas exchange threshold (OUEGET) and respiratory compensation point (OUERCP). Pearson's correlation coefficients, independent t tests and factorial ANOVAs assessed differences between groups and the use of OUE measures as surrogates for [Formula: see text]. RESULTS: A significant (p < 0.05) reduction in allometrically scaled [Formula: see text] and all OUE parameters was found in CF. Significant (p < 0.05) correlations between measurements of OUE and allometrically scaled [Formula: see text], were observed in CF (r = 0.49-0.52) and CON (r = 0.46-0.52). Furthermore, measures of OUE were significantly (p < 0.05) correlated with pulmonary function (FEV1%predicted) in CF (r = 0.38-0.46), but not CON (r = -0.20-0.14). OUEP was able to differentiate between different aerobic fitness tertiles in CON but not CF. CONCLUSIONS: OUE parameters were reduced in CF, but were not a suitable surrogate for [Formula: see text]. Clinical teams should, where possible, continue to utilise maximal CPET parameters to measure aerobic fitness in children and adolescents with CF. Future research should assess the prognostic utility of OUEP as it does appear sensitive to disease status and severity. PMID- 30003382 TI - Effects of repeated long-duration water immersions on skeletal muscle performance in well-trained male divers. AB - PURPOSE: The objective of this study was to examine the effects of repeated long duration water immersions (WI)s at 1.35 atmospheres absolute (ATA) on neuromuscular performance in load bearing and non-load bearing muscle groups. METHODS: During a dive week (DW), fifteen well-trained male divers completed five consecutive 6-h resting dives with 18-h surface intervals while breathing compressed air at 1.35 ATA. Skeletal muscle performance assessments occurred immediately before and after each WI, and 24 and 72 h after the final WI. Exercise assessments included maximum voluntary isometric contraction (MVIC), maximal isokinetic (IK) contraction, maximum handgrip strength (MHG). Surface electromyography measured neuromuscular activation of the quadriceps, biceps brachii (BB), and brachioradialis. RESULTS: MVIC torque of knee extensors and BB decreased by 6% (p = 0.001) and 2% (p = 0.014), respectively, by WI 3. Maximal IK torque of knee extensors increased by 11 and 5% post-WI on WIs 3 and 5 (p < 0.001) with greater neuromuscular activation post-WI than pre-WI (p < 0.001). Maximum IK elbow flexion torque did not change throughout the DW with BB neuromuscular activation greater post-WI than pre-WI (p < 0.001). MHG force output was 4% greater post-WI than pre-WI (p < 0.001) with increased brachioradialis activation through 72-h post-WI (p < 0.001). All muscle performance metrics returned baseline levels by 72-h post-WI. CONCLUSION: Our findings indicate that repeated WIs caused noticeable decrements in neuromuscular activation and performance of load bearing muscles on WI 3 while full recovery was observed by 72-h post-WI. PMID- 30003383 TI - PiggyBac transposon-mediated mutagenesis and application in yeast Komagataella phaffii. AB - OBJECTIVE: Around one-fourth of the Komagataella phaffii genes encode hypothetical proteins with unknown functions. However, lack of powerful tools for genetic screening in K. phaffii significantly limits the functional analysis of these unknown genes. Transposon mutagenesis has been utilized as an insertional mutagenesis tool in many other organisms and would be extremely valuable if it could be applied in K. phaffii. RESULTS: In this study, we investigated in K. phaffii the transposition activity and efficiency of piggyBac (PB) transposon, a DNA transposon from the cabbage looper moth Trichoplusia ni through the integrated-plasmid system. We also designed a binary-plasmid system which could generate stable mutants. Finally we evaluated the quality of this mutagenesis system by a simple screening for functional genes involved in K. phaffii carbon catabolite repression. CONCLUSIONS: Our results demonstrate that PB-mediated mutagenesis could be a feasible and useful tool for functional gene screening in K. phaffii. PMID- 30003384 TI - Correction to: Mandibular response after rapid maxillary expansion in class II growing patients: a pilot randomized controlled trial. AB - In the publication of this article (1) there is an error in the Methods section. PMID- 30003385 TI - Outcome of thyroid ultrasound screening in FAP patients with a normal baseline exam. AB - Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome associated with a substantial lifetime risk for colorectal cancer. The leading extra-colonic causes of cancer in FAP include duodenal and thyroid cancer (TC). Recent guidelines recommend annual thyroid ultrasound (TUS) screening beginning in the teenage years but the evidence to support the interval particularly in FAP patients with a normal baseline ultrasound is lacking. TUS results from FAP patients enrolled in a thyroid screening program from 2006 to 2016 and who had at least 2 TUS were reviewed. TUS findings were classified as normal, low (LR) or high risk (HR) for TC based on nodule characteristics as determined by American Thyroid Association (ATA) guidelines. We assessed the incidence of TC in patient with normal baseline TUS and factors associated with TC. 264 FAP patients were included. Baseline TUS was normal in 167, LR in 74, and HR in 24 patients. Patients were observed for a mean 4.8 years and underwent an average of 3 TUS. Patients with normal baseline TUS did not develop TC during the course of follow up of 5.1 years. TC developed in 6 patients (2.3%) all with baseline nodules; 5 in the LR group and 1 in the HR group. Factors associated with development of TC were presence of baseline nodule(s) and female sex. The development of TC in FAP patients in a TUS screening program with short term follow up is low and no FAP patient with a normal baseline TUS developed TC during observation. Annual TUS in patients with a normal baseline TUS may not be needed. Extending the screening interval to 2 years may be reasonable until nodules are detected. PMID- 30003386 TI - beta-Blockers Improve Presinusoidal Portal Hypertension. AB - BACKGROUND: Presinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas beta-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown. AIMS: To evaluate the hemodynamic effect of beta-blockers in non cirrhotic patients with presinusoidal portal hypertension. METHODS: We measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off beta-blocker treatment (random sequence). RESULTS: The beta-blockers reduced the gradient from a mean off treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%). CONCLUSIONS: beta-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic beta-blockage in patients with presinusoidal portal hypertension. PMID- 30003387 TI - Normal Rectal Filling Sensations in Patients with an Enlarged Rectum. AB - BACKGROUND: Increased rectal volume is believed to be associated with diminished rectal sensation, i.e., rectal hyposensitivity. AIMS: To demonstrate that patients with increased rectal volumes do not automatically have diminished rectal filling sensations. METHODS: We, retrospectively, observed 100 adult patients with defecation problems, and 44 healthy controls who had undergone anorectal function tests. Using the balloon retention test, we analyzed the distribution of rectal volumes and pressures at different rectal filling sensation levels. RESULTS: We found variance in the distribution of rectal volumes at all levels, while rectal pressures showed a normal distribution. We found no correlation between rectal volumes and pressures (constant sensation, r = 0.140, P = 0.163, urge sensation, r = - 0.090, P = 0.375, and maximum tolerable volumes, r = - 0.091, P = 0.366), or when taking age and sex into account. The findings for the patient group were congruent with those for the control group. CONCLUSIONS: Participants with increased rectal volumes do not experience increased rectal pressures at any sensation level. This finding, combined with the knowledge that rectal pressure triggers rectal filling sensation, indicates that rectal filling sensations in patients with increased rectal volumes are not diminished. Therefore, "rectal hyposensitivity" should be reserved for patients with increased rectal pressure thresholds, and not for "abnormally" increased rectal volume thresholds. PMID- 30003389 TI - Association of Induced Hyperhomocysteinemia with Alzheimer's Disease-Like Neurodegeneration in Rat Cortical Neurons After Global Ischemia-Reperfusion Injury. AB - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that results in massive hippocampal and neocortical neuronal loss leading to dementia and eventual death. The exact cause of Alzheimer's disease is not fully explored, although a number of risk factors have been recognized, including high plasma concentration of homocysteine (Hcy). Hyperhomocysteinemia (hHcy) is considered a strong, independent risk factor for stroke and dementia. However, the molecular background underlying these mechanisms linked with hHcy and ischemic stroke is not fully understood. Paper describes rat model of global forebrain ischemia combined with the experimentally induced hHcy. Global ischemia reperfusion injury (IRI) was developed by 4-vessels occlusion lasting for 15 min followed by reperfusion period of 72 h. hHcy was induced by subcutaneous injection of 0.45 umol/g of Hcy in duration of 14 days. The results showed remarkable neural cell death induced by hHcy in the brain cortex and neurodegeneration is further aggravated by global IRI. We demonstrated degeneration of cortical neurons, alterations in number and morphology of tissue astrocytes and dysregulation of oxidative balance with increased membrane protein oxidation. Complementary to, an immunohistochemical analysis of tau protein and beta-amyloid peptide showed that combination of hHcy with the IRI might lead to the progression of AD-like pathological features. Conclusively, these findings suggest that combination of risk factor hHcy with IRI aggravates neurodegeneration processes and leads to development of AD-like pathology in cerebral cortex. PMID- 30003388 TI - NCAM Mimetic Peptides: Potential Therapeutic Target for Neurological Disorders. AB - The neural cell adhesion molecule (NCAM) plays a pivotal role in the development and maintenance of the nervous system via homophilic (NCAM-NCAM) and heterophilic (NCAM-other molecules) interactions. Many synthetic peptides have been engineered to mimic these interactions and induce NCAM-downstream signaling pathways. Such NCAM mimetics have displayed neuritogenic and neuroprotective properties, as well as synaptic modulation in vitro and in vivo. Furthermore, they have been used successfully in preclinical studies to treat neurological disorders including stroke, traumatic brain injury and Alzheimer's disease. This review focuses on recent progress in the development of NCAM mimetic peptides, in particular, on establishing C3, plannexin, and FGL as therapeutic candidates for neurological disorders. PMID- 30003390 TI - TNF-alpha G/A308 polymorphism association with nasal polyposis in North part of Iran. AB - Nasal Polyposis (NP) is a complex multi-factorial disease; associated with several environmental, genetic and inflammatory factors. TNF-alpha is one of the major pro-inflammatory cytokines involved in NP pathogenesis. Some of the polymorphisms of this gene affect its expression. Therefore, the aim of this study was to evaluate the polymorphism of TNF-alpha G/A308 gene and its association with nasal polyposis in north part of Iran. In this case-control study, 60 patients with NP and 75 healthy individuals referred to Guilan University hospital were evaluated. After DNA extraction, RFLP-PCR was used to determine polymorphism. Chi-square test was used to compare the frequency distribution of genotype and alleles of TNF-alpha gene with NP. The frequency of genotype G/G, A/A and G/A in the NP group was 46.7, 10.0 and 43.3%, and in the control group was 65.3, 5.3 and 29.3%, respectively. There was a statistically significant difference between genotype G/G in two groups (P = 0.006, OR 2.58, CI 1.27-5.23). In addition, the frequency of allele A in patients and controls was 31.7 and 20%, respectively; and this difference was statistically significant (p = 0.02). The findings of this study demonstrated that polymorphism in TNF-alpha gene might be a risk factor for NP in north part of Iran and the minor frequency of G308A allele in the current study is slightly more than other major populations. However, more investigations with high number of population are necessary in future. PMID- 30003391 TI - Differential expression of cyclooxygenase-2 and cyclin D1 in salivary gland tumors. AB - PURPOSE: Salivary gland tumors are complex and have a great histomorphological diversity; more than 30 histological subtypes are currently described and the study of proteins that help understand and differentiate these tumors is essential. We aimed to analyze the immunoexpression of cyclooxygenase-2 (COX-2) and cyclin D1 proteins in pleomorphic adenomas (PA), mucoepidermoid carcinomas (MEC) and adenoid cystic carcinomas (AdCC) of salivary glands. METHODS: A total of 38 PA, 12 AdCC and 12 MEC underwent immunohistochemical study by the polymeric biotin-free technique. Immunopositive cells were analyzed semi-quantitatively. For statistical analysis, a significance level was set at p <= 0.05. RESULTS: Overall, these tumors were more prevalent in women (n = 37). The mean age of these patients was 58-year-old and the parotid gland was the most affected anatomic site (n = 33). All cases of AdCC and MEC showed immunopositivity to cyclin D1; however, 39.5% of the PAs were negative (p < 0.001). Regarding COX-2 immunoexpression, we observed that all cases of CME were positive, whereas 60.5% of the PA and 75% of the CAC analyzed were completely negative (p = 0.042). CONCLUSIONS: The overexpression of COX-2, observed only in MEC, emphasizes that salivary gland tumors have different profiles. Cyclin D1 is more immunoexpressed in malignant tumors. Together, these immunohistochemical findings may be useful in differentiating the studied tumors. PMID- 30003392 TI - What is a normal pharynx? A videofluoroscopic study of anatomy in older adults. AB - PURPOSE: Structural and functional pharyngeal changes occur with age. How these affect swallowing in healthy older adults is not well defined. This study presents quantitative pharyngeal anatomic features in healthy adults using videofluoroscopic study of swallowing (VFSS). This will help our understanding of the normal changes in swallowing that occur with age and illustrate what may constitute normal variation compared with abnormal swallow function. METHODS: 138 mixed gender adults with no history of dysphagia were recruited and underwent a standardized VFSS protocol. Parameters including age, BMI, and gender were correlated with the presence of a cricopharyngeal bar, spinal changes and pharyngeal wall thickness at rest. RESULTS: 46% of participants had notable spinal changes. 8% of participants demonstrated cricopharyngeal bars and 12% of subjects revealed osteophytes. Age positively correlated with the presence of a cricopharyngeal bar (rs = 0.281, p < 0.001) and presence of osteophytes (rs = 0.334, p < 0.001). The incidence of cricopharyngeal bars in adults over 70 years old was 16%. CONCLUSIONS: A significant number of healthy adults with no swallowing complaints have variant pharyngeal anatomic findings such as cervical vertebral osteophytes and cricopharyngeal bars. This must be taken into account when assessing patients with dysphagia complaints to avoid misattribution of symptoms to these potentially asymptomatic variants. This ensures correct recommendations are made regarding management including diet modification, compensatory strategies, and surgical intervention. PMID- 30003394 TI - Towards treatment personalisation in triple negative breast cancer: role of platinum-based neoadjuvant chemotherapy. PMID- 30003393 TI - The clinical relevance of serum vascular endothelial growth factor (VEGF) in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer. AB - PURPOSE: VEGF is one of the most important angiogenesis-stimulating cytokines and has been previously shown to be overexpressed in several solid cancers. The aim of the present study was to assess the clinical relevance of serum VEGF (sVEGF) in a large cohort of metastatic breast cancer patients and to explore the relationship between sVEGF and other blood-based biomarkers. METHODS: Two hundred fifty-three patients with metastatic breast cancer were enrolled in this prospective, multicentre study. Blood samples were collected before start of first-line or later-line treatment. sVEGF was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch and other biomarkers (EGFR, HER2, RAS p21, TIMP1, CAIX) by ELISA. RESULTS: Levels of sVEGF were determined in all patients, with a median concentration of 231 pg/ml. After a median follow-up of 19 months, median overall survival (OS) was 10.2 months in patients with sVEGF levels above the upper quartile (i.e. 367 pg/ml), while median OS has not been reached in patients with sVEGF < 367 pg/ml (p < 0.001). Median progression-free survival (PFS) was 4.8 months for patients with sVEGF >= 367 pg/ml versus 9.1 months with sVEGF levels < 367 pg/ml (p < 0.001). Patients with sVEGF levels >= 367 pg/ml and >= 5 CTCs had the shortest OS, while those with sVEGF < 367 pg/ml and non-elevated CTCs had the longest OS. CTCs, grading, line of therapy and RAS p21 were independent predictors of OS. sVEGF, line of therapy and CTCs were independent predictors of PFS in the multivariate analysis. CONCLUSIONS: Metastatic breast cancer patients with elevated levels of sVEGF have significantly worse clinical outcome. This finding supports the biological role of VEGF in breast cancer. TRIAL REGISTRATION: Current Controlled Trials ISRCTN59722891 (DETECT). PMID- 30003395 TI - Factors associated with long-term survival in central nervous system metastases. AB - BACKGROUND: Cancer is a leading cause of death worldwide; central nervous system metastases (CNSm) are amongst the most common complications of cancer and are associated with high morbidity and mortality. The aim of the study was to associate clinic and oncologic characteristics with the possibility of survival for >= 1 year. MATERIALS AND METHODS: A prospective cohort in two referral centers recollected clinical and oncologic data from patients diagnosed with CNSm. Chronic metastases were defined as those patients that survived for >= 12 months after the diagnosis of CNSm. RESULTS: Of 613 patients with CNSm, 554 had solid tumors as the primary cancer and were included; 405 (73%) were women, the most common primary cancer site were breast, lung and urologic. Chronic CNSm were found in 260 (47%) and were compared to those who did not. After multivariate logistic regression analysis, variables associated with good prognosis (living > 12 months) were: female sex (HR 0.55), single CNSm (HR 0.39), diagnosis of CNSm during initial extension studies or during presentation of cancer (HR 0.43), and occipital location (HR 0.62). CONCLUSIONS: Long-term survival in patients with CNSm remains a topic of debate; their bad prognosis could be changing towards improvement. Clinical findings are typically overlooked in CNSm reports and prognostic scales. After our findings, we propose to include them in forthcoming studies to aid prognostic considerations. Factors associated with prolonged survival found in our study include female gender, timing of CNSm diagnosis, occipital lobe location, and single CNSm. PMID- 30003396 TI - Dimensions and subtypes of oppositionality and their relation to comorbidity and psychosocial characteristics. AB - The symptoms of oppositional defiant disorder (ODD), or oppositionality, seem to constitute a three-dimensional structure of angry/irritable, vindictiveness and argumentative behavior dimensions. Also, subjects with oppositionality are characterized by different comorbidity and longitudinal trajectories, suggesting that they could be divided into subtypes. This study is the first to examine the dimensions and subtypes of oppositionality in Nordic children. Study participants included 3435 children aged 7-10 years from the Danish National Birth Cohort. Information was collected using the Development and Well-Being Assessment (DAWBA) online version. A three-factor ODD model was identified. The angry/irritable dimension was associated with emotional problems and disorders, fewer social skills and fewer personal positive attributes. The argumentative behavior dimension was associated with hyperactivity/conduct problems, reduced social skills and positive attributes. The vindictiveness dimension was associated with externalizing, internalizing and prosocial problems. Four ODD subtypes were identified. The subtypes with many or mainly angry/irritable symptoms were characterized by comorbid psychopathology, increased functional impairment and psychosocial problems. Children with ODD had fewer positive attributes, more friendship/school problems and higher functional impairment than children with emotional disorders and control group children. Oppositionality consists of three dimensions differently associated with comorbidity and psychosocial characteristics, and the same pattern is seen for the four ODD subtypes identified in this study. Children with ODD experience more adversities and functional impairment than children with emotional disorders. Our results indicate that treatment of children with ODD would improve from extended knowledge on individual ODD dimensions and subtypes and the related child psychosocial characteristics. PMID- 30003397 TI - Bullying: peer-to-peer maltreatment with severe consequences for child and adolescent mental health. PMID- 30003398 TI - Returning to school after a terror attack: a longitudinal study of school functioning and health in terror-exposed youth. AB - Terrorist attacks and mass shootings often involve youth. Knowledge is needed on how this may impact their health and functioning. This study investigates perceived academic performance and school wellbeing in 237 terror-exposed survivors of the Utoya youth camp attack according to their sociodemographic characteristics, health and mental health service (MHS) utilization. Semi structured interviews were conducted after 4-5 and 14-15 months. The year following the attack, 143 (61%) survivors reported impaired academic performance and 66 (29%) impaired school wellbeing. Female survivors more often reported impaired performance. Non-Norwegian origin, being financially disadvantaged and less social support were associated with impaired wellbeing. Sleep problems, posttraumatic stress, anxiety/depression, somatic symptoms, and lower life satisfaction were associated with both impaired performance and impaired wellbeing. Survivors who had received MHS were more likely to report impaired or improved academic performance and school wellbeing. Higher age and posttraumatic stress reactions were associated with impaired academic performance after multivariate logistic regression adjustments for gender, somatic symptoms and social support. When additionally adjusting for impaired school wellbeing, age and impaired wellbeing were associated with impaired performance. Only posttraumatic stress reactions were associated with impaired wellbeing after similar adjustments. Non-Norwegian origin and being financially disadvantaged were not significantly associated with impaired wellbeing after adjusting for posttraumatic stress reactions, age and gender. Our findings demonstrate how a terrorist attack can considerably deteriorate young survivors' performance and wellbeing at school, which is associated with poorer health. Consequently, it is important to provide appropriate school support, and coordinate MHS with follow up at school. PMID- 30003399 TI - Computer-aided design of magnetic dummy molecularly imprinted polymers for solid phase extraction of ten phthalates from food prior to their determination by GC MS/MS. AB - Magnetic dummy molecularly imprinted polymers (MDMIPs) were prepared by combining the surface imprinting technique with computer simulation for selective recognition of phthalate esters (PAEs). A computational study based on the density functional theory was performed to evaluate the template-monomer geometry and interaction energy in the prepolymerization mixture. The MDMIPs were characterized by transmission electron microscopy, scanning electron microscopy, vibrating sample magnetometry, X-ray diffraction, and Fourier transform infrared spectroscopy. They exhibited (a) high saturation magnetization of 53.14 emu g-1 (leading to fast separation), and (b) large adsorption capacity, fast binding kinetics, and high selectivity for PAEs. Subsequently, a molecularly imprinted solid-phase extraction procedure followed by GC-MS was established for selective extraction and determination of 10 PAEs in food samples. Under the optimal experimental conditions, the response (peak area) was linear in the 0.5-100 ng mL 1 concentration range. The limits of detection ranged from 0.15 to 1.64 ng g-1. The method was applied to the determination of PAEs in spiked real samples. The recoveries for 10 PAEs from various foods were in the range of 73.7%-98.1%, with relative standard deviations of 1.7%-10.2%. Graphical abstract Magnetic dummy molecularly imprinted polymers (MDMIPs) were prepared and successfully were applied as a special sorbent for the selective recognition and fast enrichment of 10 PAEs from different complex matrix. PMID- 30003400 TI - A novel fused convolutional neural network for biomedical image classification. AB - With the advent of biomedical imaging technology, the number of captured and stored biomedical images is rapidly increasing day by day in hospitals, imaging laboratories and biomedical institutions. Therefore, more robust biomedical image analysis technology is needed to meet the requirement of the diagnosis and classification of various kinds of diseases using biomedical images. However, the current biomedical image classification methods and general non-biomedical image classifiers cannot extract more compact biomedical image features or capture the tiny differences between similar images with different types of diseases from the same category. In this paper, we propose a novel fused convolutional neural network to develop a more accurate and highly efficient classifier for biomedical images, which combines shallow layer features and deep layer features from the proposed deep neural network architecture. In the analysis, it was observed that the shallow layers provided more detailed local features, which could distinguish different diseases in the same category, while the deep layers could convey more high-level semantic information used to classify the diseases among the various categories. A detailed comparison of our approach with traditional classification algorithms and popular deep classifiers across several public biomedical image datasets showed the superior performance of our proposed method for biomedical image classification. In addition, we also evaluated the performance of our method in modality classification of medical images using the ImageCLEFmed dataset. Graphical abstract The graphical abstract shows the fused, deep convolutional neural network architecture proposed for biomedical image classification. In the architecture, we can clearly see the feature-fusing process going from shallow layers and the deep layers. PMID- 30003402 TI - Gender identity development in the shadow of socialization: a grounded theory approach. AB - Gender identity is one of the basic forms of identity which has a key role in the mental health during adolescence. The present study was conducted to determine the process of gender identity development among Iranian female adolescents. In this grounded theory study, semi-structured interviews were conducted with 55 purposefully and theoretical selected participants including 30 female adolescents and 25 key informants who lived in urban society of Isfahan, Iran, in 2016-2018. Data were analyzed using Strauss and Corbin's mode of analysis (2008), through constant comparative method, applying levels of open, axial, and selective coding with MAXQDA software. Development of gender identity in the shadow of socialization was presented as the core category extracted from the data in this study. Female adolescents would use "sexual self-expression during puberty," "attachment to parents and peers," "tendency towards the opposite sex," and "effort for social acceptance" as the main strategies in the development of gender identity until achieving "stabilized gender identity." "Girls' communicational skills" and "parents' empowerment" were the causal conditions in this process. "Gender differences" and "sociocultural texture of the society" were the contextual conditions and the influence of "peers" and "media" was the interventional conditions in the development of gender identity in female adolescents. Improving girls' communicational skills, empowering parents for managing their interactions with their daughters, adjusting gender roles in the society, and creating appropriate content by the media could have an important role in helping female adolescents achieving stabilized gender identity. PMID- 30003403 TI - ECRG4: a new potential target in precision medicine. AB - Given the rapid development in precision medicine, tremendous efforts have been devoted to discovering new biomarkers for disease diagnosis and treatment. Esophageal cancer-related gene-4 (ECRG4), which is initially known as a new candidate tumor suppressor gene, is emerging as a sentinel molecule for gauging tissue homeostasis. ECRG4 is unique in its cytokine-like functional pattern and epigenetically-regulated gene expression pattern. The gene can be released from the cell membrane upon activation and detected in liquid biopsy, thus offering considerable potential in precision medicine. This review provides an updated summary on the biology of ECRG4, with emphasis on its important roles in cancer diagnosis and therapy. The future perspectives of ECRG4 as a potential molecular marker in precision medicine are also discussed in detail. PMID- 30003401 TI - Unsaturated Cuticular Hydrocarbon Components of the Sex Pheromone of Eggplant Fruit Borer, Leucinodes orbonalis Guenee (Lepidoptera: Crambidae). AB - Leucinodes orbonalis is one of the most damaging insect pests affecting eggplant in the Mekong Delta of Vietnam. While (E)-11-hexadecenyl acetate (E11-16:OAc) and its alcohol, (E)-11-hexadecenol (E11-16:OH), have been identified as major and minor sex pheromone components, respectively, few males were attracted to a blend of these compounds in Vietnamese fields. In order to utilize synthetic pheromone of L. orbonalis as a tool for sustainable pest management programs, we reexamined the pheromone of this species in order to search for other minor components. Gas chromatography-electroantennogram detection and gas chromatography/mass spectrometry analyses of abdominal tip extract revealed the presence of two electroantennogram-active compounds, E11-16:OAc and (3Z,6Z,9Z)-3,6,9 tricosatriene (Z3,Z6,Z9-23:H) in a ratio of 100:2. An extract of the abdomen and thorax showed an additional electroantennogram-active component, (3Z,6Z,9Z)-3,6,9 docosatriene (Z3,Z6,Z9-22:H), with the three compounds (E11-16:OAc, Z3,Z6,Z9-23:H and Z3,Z6,Z9-22:H) being present in a ratio of 100:45:1, indicating that the trienes were mainly present on the cuticular surface. In the field, traps baited with E11-16:OAc and the C23 triene, in a mix of 10:1, caught more male moths than traps baited with the acetate alone. A field evaluation of other polyunsaturated hydrocarbons showed that the C22 triene found in body extract also increased catches when added to the acetate, but no other hydrocarbons did. In contrast, to other studies with this moth, the addition of E11-16:OH to E11-16:OAc plus the C22 or C23 triene, resulted in decreased trap catches. PMID- 30003404 TI - The Protective Effects of Terpinen-4-ol on LPS-Induced Acute Lung Injury via Activating PPAR-gamma. AB - Terpinen-4-ol, the major constituent of tea tree oil, has been reported to have anti-inflammatory effect. However, whether terpinen-4-ol could attenuate LPS induced inflammation in lung tissues remains unclear. In the present study, we aimed to investigate the protective effects of terpinen-4-ol on LPS-induced acute lung injury (ALI) in mice. Terpinen-4-ol could inhibit LPS-induced ALI as confirmed by the decreased lung histopathological changes, MPO activity, and lung W/D ratio caused by terpinen-4-ol. The production of TNF-alpha and IL-1beta in the BALF was suppressed by the treatment of terpinen-4-ol. Western blot analysis showed that terpinen-4-ol significantly attenuated LPS-induced phosphorylation of IkappaBalpha and NF-kappaB p65. Furthermore, the expression of PPAR-gamma was dose-dependently upregulated by the treatment of terpinen-4-ol. In conclusion, the results of this study indicated that terpinen-4-ol inhibited LPS-induced ALI via activating PPAR-gamma, which subsequently attenuated LPS-induced NF-kappaB activation and inflammatory response. PMID- 30003405 TI - The In Vitro Impact of Glycyrrhizic Acid on CD4+ T Lymphocytes through OX40 Receptor in the Patients with Allergic Rhinitis. AB - Glycyrrhizic acid (GA), the major bioactive component of glycyrrhiza, possesses anti-inflammatory, anti-allergic, and immunomodulatory activities. This study aimed to investigate the in vitro anti-allergic effect of GA through the OX40 receptor in patients with allergic rhinitis. Purified naive CD4+ T cells of patients with allergic rhinitis (n = 12) were activated with anti-CD3/anti-CD28 with and without anti-OX40 agonist mAbs and then treated with 50, 100, and 200 MUM GA and 0.1 MUM dexamethasone. Cells were incubated (72 h) to measure cell proliferation. Expression of OX40 in anti-OX40 mAb stimulated CD4+ T cells was evaluated by flow cytometry. mRNA expression of the OX40 receptor and T-bet, GATA 3, and forkhead box P3 (FoxP3) transcriptional factors were measured by a quantitative polymerase chain reaction. The levels of interleukin (IL)-4, IL-10, and interferon-gamma (IFN-gamma) were also measured. GA inhibited significantly the augmented T cell proliferation induced with anti-OX40 mAb. Protein and gene expression of OX40 was also decreased significantly. Dexamethasone and GA inhibited T-bet and GATA-3 genes expression, but this inhibition was only significant for GATA-3. In contrast, enhanced gene expression of FoxP3 was seen using 200 MUM GA and dexamethasone. The levels of IL-4, IL-10, and IFN-gamma decreased after treatment with both dexamethasone and GA, but the ratio of IFN gamma/IL-4 (Th1/Th2 balance) increased significantly due to 200 MUM GA treatment. This study suggests that GA may have a therapeutic effect on allergic rhinitis, partly by modulation of the Th1/Th2 balance through suppression of OX40 and increasing the activity of regulatory T cells. PMID- 30003406 TI - Presenting a new method to improve the detection of micro-seismic events. AB - Seismic events such as earthquakes are one of the most important issues in the field of geology. Meanwhile, less attention has been paid to micro-seismic events, despite the high number of earthquakes. Earthquakes, regardless of their size, affect human life; therefore, their detection and management is considered an important issue. For this purpose, experts developed seismic arrays as a system of linked seismometers. These systems equipped with sensors and seismographs are able to receive a range of waves from the earth, which are then sent to the central seismic station for analysis. So far, many tools and methods have been devised to analyze seismic data. However, the dominant method in most seismic mechanisms is trigger function, based on STA/LTA (short-time-average through long-time-average trigger). These mechanisms have considerable threshold in terms of earthquake range, so many micro-events are ignored as noise. Generally, in this field of geology, computer science techniques have been used to detect and classify these events. Statistical methods such as kurtosis, variance, and skewness can be applied to understand the changes in the signal curves of geophones in a seismic event, thereby helping in the initial detection of fuzzy features. According to the last 3 years' reports of global data mining agencies such as Rexer, KDnugget, and Gartner, Rapid Miner is one of the most popular tools for data mining in recent years. Furthermore, these institutions considered artificial neural networks, especially multilayer perceptron (MLP) and base radial function (RBF), to be among the most successful algorithms for detection and classification of stream data. In this research, the recorded data from several seismic experiments has been classified by a hybrid model. Hence, the present study was aimed to enhance the authenticity of data based on the application of effective variables. This was undertaken through use of a fuzzy method and an integrated neural network algorithm, involving MLP perceptron and radial network of RBF in the form of a collective learning system, in order to identify seismic events on a small scale. Based on the results, in comparison to basic methods, the proposed method significantly improved using the actual error and root-mean-square error (RMSE) criteria. PMID- 30003407 TI - Safety and feasibility of outpatient robot-assisted radical prostatectomy. AB - Since its inception, robot-assisted radical prostatectomy (RARP) has developed into a familiar surgical modality with improved perioperative outcomes including decreased hospital stay for localized prostate cancer patients. Experience with outpatient RARP has been reported as early as 2010. In this study, we evaluate the safety and feasibility of outpatient RARP by comparing perioperative outcomes between patients undergoing outpatient RARP to patients discharged on the day following surgery. This is a single-institution retrospective cohort study. Patients with localized disease who underwent RARP without pelvic lymph node dissection from September 2017 to January 2018 were included. T tests and Chi squared analysis were used to compare demographic and perioperative characteristics of patients who were discharged on the same day of surgery (outpatient RARP) to patients discharged on the day after surgery (inpatient RARP). Of the 51 patients included in the study, 26 underwent outpatient RARP while 25 underwent inpatient RARP. There was no significant difference in mean age (61.4 vs 65.8 years, p = 0.05), BMI (27.1 vs 28.3 kg/m2, p = 0.35), ethnicity, tobacco use (8 vs 15%, p = 0.41), PSA (8.7 vs 8.4 ng/dL, p = 0.77), biopsy Gleason score distribution, prostate size (51.8 vs 57.7 cc, p = 0.26) or preoperative hemoglobin (14.3 vs 13.4 g/dL, p = 0.06), respectively. There was no significant difference between operative time (95.3 vs 101 min, p = 0.16), EBL (52.8 vs 66.5 cc, p = 0.08), postoperative change in hemoglobin (- 1 vs - 1.1 g/dL, p = 0.62), pathologic stage distribution or complication rate (4 vs 8%, p = 0.58) between patients who underwent outpatient vs inpatient RARP, respectively. Outpatient RARP offers similar or improved perioperative outcomes when compared to inpatient RARP. We advocate outpatient RARP as a safe and feasible alternative to inpatient RARP for appropriately selected prostate cancer patients. Furthermore, we introduce an outpatient model that can be applied to other institutions seeking to implement outpatient RARP. PMID- 30003408 TI - New insight into GABAergic neurons in the hypothalamic feeding regulation. AB - Several lines of study have suggested that GABA in the hypothalamic feeding center plays a role in promoting food intake. Recent studies revealed that not only NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) that co-express GABA but also other GABAergic neurons act as an orexigenic. Here, we review the progress of studies on hypothalamic GABAergic neurons distributed in ARC, dorsomedial hypothalamus (DMH), and lateral hypothalamus (LH). Three advanced technologies have been applied and greatly contributed to the recent progress. Optogenetic (and chemogenetic) approaches map input and output pathways of particular subpopulations of GABAergic neurons. In vivo Ca2+ imaging using GRIN lens and GCaMP can correlate the activity of GABAergic neuron subpopulations with feeding behavior. Single-cell RNA-seq approach clarifies precise transcriptional profiles of GABAergic neuron subpopulations. These approaches have shown diversity of GABAergic neurons and the subpopulation-dependent role in feeding regulation. PMID- 30003409 TI - Microencapsulated Lactobacillus plantarum LAB12 Showed No Sign of Acute or Sub chronic Toxicity In Vivo. AB - Lactic acid bacteria (LAB) with probiotic properties are useful options for prophylactic and therapeutic applications against gastrointestinal diseases. The safety of probiotics should, however, be verified before incorporation into food or drinks. The present study had encapsulated Lactobacillus plantarum LAB12 within microcapsules that could withstand extremely high temperature (up to 100 degrees C) during pelletisation. The microencapsulated LAB12 were then tested for their acute (single dosing) and sub-chronic (a 90-day feeding) toxicity. For acute toxicity study, six male Sprague-Dawley rats were being administered with a single dose of freeze-dried microencapsulated LAB12 at 11 log CFU/kg BW through oral gavage. No clear treatment-related effects were observed after 14 days. For sub-chronic toxicity study, rodents were randomly divided into four groups (6 rats/sex/group) and treated with 0, 8, 9 and 10 log CFU/kg BW of microencapsulated LAB12 in pellet form. No mortality or treatment-related findings were observed in terms of clinical body weight, water intake, or food consumption. No treatment-related adverse effects were observed in blood and tissue samples. The no-observed-adverse-effect-level (NOAEL) for microencapsulated LAB12 was 2.5 * 1010 CFU/kg BW for both genders. These results imply that LAB12 are likely non-pathogenic and non-toxic. PMID- 30003411 TI - Official definitions for undesirable medical events : Are they correctly applied in medicine? AB - BACKGROUND: In Austria, elaborate definitions exist for the undesirable medical events side effect, adverse event, complication and medical malpractice. We aimed at investigating whether the official definitions for the abovementioned terms can be understood by a sample population representing a cross-section of the Austrian population. METHODS: In this study 1021 Austrian citizens were interviewed. Demographic parameters (age, gender, occupation, level of education, monthly income, number of inhabitants at place of residence) were assessed. Participants were told the official definitions for complication, side effect, adverse event and medical malpractice and asked to select the correct definition for "complication". The impact of sample characteristics on the ability to identify the correct definition was investigated. RESULTS: Of the participants 315 (31%) identified the correct definition of a complication. Almost the same number (n = 302, 30%; chi2 for single samples: p = 0.087) falsely selected the definition for side effect. Significantly fewer (both p < 0.001) chose the definitions for adverse event (n = 220, 22%) and medical malpractice (n = 155, 15%). Only the respective state of origin showed significant influence on the probability of choosing the correct definition out of the four. The probability was highest in Vorarlberg (0.400) and lowest in Upper Austria (0.216, p < 0.001). CONCLUSION: For the majority the present official definitions for undesirable medical events are too complex to understand. Simple definitions for undesirable medical events should be included into patient education. PMID- 30003410 TI - Importance of amino acids Leu135 and Tyr236 for the interaction between EhCFIm25 and RNA: a molecular dynamics simulation study. AB - The CFIm25 subunit of the heterotetrameric cleavage factor Im (CFIm) is a critical factor in the formation of the poly(A) tail at mRNA 3' end, regulating the recruitment of polyadenylation factors, poly(A) site selection, and cleavage/polyadenylation reactions. We previously reported the homologous protein (EhCFIm25) in Entamoeba histolytica, the protozoan causing human amoebiasis, and showed the relevance of conserved Leu135 and Tyr236 residues for RNA binding. We also identified the GUUG sequence as the recognition site of EhCFIm25. To understand the interactions network that allows the EhCFIm25 to maintain its three-dimensional structure and function, here we performed molecular dynamics simulations of wild-type (WT) and mutant proteins, alone or interacting with the GUUG molecule. Our results indicated that in the presence of the GUUG sequence, WT converged more quickly to lower RMSD values in comparison with mutant proteins. However, RMSF values showed that movements of amino acids of WT and EhCFIm25*L135 T were almost identical, interacting or not with the GUUG molecule. Interestingly, EhCFIm25*L135 T, which is the only mutant with a slight RNA binding activity experimentally, presents the same stabilization of bend structures and alpha helices as WT, notably in the C-terminus. Moreover, WT and EhCFIm25*L135 T presented almost the same number of contacts that mainly involve lysine residues interacting with the G4 nucleotide. Overall, our data proposed a clear description of the structural and mechanistic data that govern the RNA binding capacity of EhCFIm25. PMID- 30003413 TI - Subpopulation Structure of IFNgamma-Producing T Lymphocytes in Patients with Pulmonary Tuberculosis. AB - The study of subpopulation structure of IFNgamma-producing T cells in patients with pulmonary tuberculosis revealed a decrease in the number of CD3+ IFNgamma+ cells against the background of significantly increased IFNgamma secretion in vitro irrespective of the clinical form of the disease and drug sensitivity of M. tuberculosis, most strongly expressed in case of the disseminated tuberculosis. In patients with infiltrative drug-sensitive and drug-resistant pulmonary tuberculosis, increased number of Th1/Th17 lymphocytes (CD4+ IFNgamma+IL-17A+) and, conversely, decreased number of blood gammadeltaT cells was detected. PMID- 30003414 TI - Generation of Highly Specific Proteolytic Biocatalysts by Screening Technologies. AB - We propose a yeast display-based system for screening of proteolytic enzyme libraries that utilizes substrate protein adsorbed on the yeast cell surface and containing a desired cleavage sequence. Specific cleavage of the substrate protein releases its biotin-binding center. The cells carrying the target proteinase can be selected by cytofluorometry due to interaction with biotinylated fluorescent protein. Using human enterokinase light chain as the model proteinase we showed that the proposed screening system highly effectively selects the proteolytic enzymes with preset specificity. PMID- 30003415 TI - Effect of Erythrocyte Density on Blood Clot Properties in Healthy Individuals and in Patients with Hemophilia A. AB - We measured specific volume and hematocrit of blood clots prepared from the whole blood of patients with hemophilia A and healthy male volunteers. It was shown that in the hematocrit range of 43.5-52.5%, specific volume of the blood clot in hemophilia patients with low level of factor VIII (1-4%) was higher than in volunteers. After injection of factor VIII, specific volume of blood clots in hemophilia patients decreased. Hematocrit of the blood clots derived from the whole blood linearly depended on the mean erythrocyte density in both volunteers (r=-0.74, p=0.01) and patients with factor VIII level of 1-4% (r=-0.95, p<0.0001). The increase in the mean erythrocyte density led to a decrease in blood clot hematocrit. The curve describing blood clot hematocrit as a function of the mean erythrocyte density in hemophilia patients was lower than in healthy volunteers. The increase in factor VIII level was associated with an increase in blood clot hematocrit. The results showed that blood clot hematocrit depends on the mean erythrocyte density, and therefore, hematocrit of the blood clot can be changed by modulating the properties of erythrocyte population. PMID- 30003416 TI - Expression of New Recombinant IgG-Binding Polypeptides and Analysis of Their Capacity to Bind Human IgG. AB - Protein G is present in group G streptococcus strain (G4223); the IgG-binding part of this protein contains three IgG-binding domains and binds human IgG with very high activity. We obtained two recombinant polypeptides G4223 and G14223 with high IgG-binding activity. Polypeptide G14223 consisting of three IgG binding domains and W region has higher molecular weight and is characterized by higher affinity for IgG than polypeptide G4223 consisting of only three IgG binding domains. It was shown that polypeptide affinity depends on its structure and size. PMID- 30003417 TI - Proliferative and Apoptotic Activity of Bone Marrow Monocyte Lineage Cells in the Offspring of Female Rats with Chronic Toxic Liver Injury. AB - We analyzed proliferative and apoptotic activity of bone marrow monocyte lineage cells in the offspring of mothers with experimental toxic injury to the liver. Rat pups were examined at different times of ontogeny. Inhibition of proliferative activity and increase in apoptotic activity in bone marrow monocyte cells of experimental rat pups in comparison with intact ones were found. PMID- 30003418 TI - Effects of Glycolipid Rhodococcus Biosurfactant on Innate and Adaptive Immunity Parameters In Vivo. AB - The glycolipid biosurfactant complex from actinobacterium Rhodococcus ruber IEGM 231 inhibits the innate and adaptive immunity parameters after intraperitoneal and intramuscular injection. Marked suppression of antibody production, bactericidal potential, and production of proinflammatory cytokines by peritoneal macrophages, detected in vivo, do not agree with the previously detected immunostimulatory activity of biosurfactants towards the immunocompetent cell cultures; this fact indicates an important role of the cell environment in the formation of immune response under the effect of bacterial glycolipids. PMID- 30003419 TI - Association of 3111T/C Polymorphism of the Clock Gene with Circadian Rhythm of Melatonin in Menopausal Women with Insomnia. AB - We carried out a comparative analysis of circadian rhythms of melatonin secretion in Caucasian menopausal women with and without insomnia depending on the 3111T/C polymorphism of the Clock gene. Melatonin levels was measured in the saliva 4 times a day (06.00-07.00, 12.00-13.00, 18.00-19.00, and 23.00-00.00 h). Carriers of the TT genotype with insomnia demonstrated significantly higher level of melatonin in the early morning hours compared to the carriers of the minor allele C (12.60+/-7.58 and 8.98+/-8.62 pg/ml, respectively, p=0.023). In the control group, no statistically significant differences were revealed. The carriers of the TT genotype with sleep disorders have higher morning melatonin level compared to control group women (12.60+/-7.58 and 5.48+/-4.74 pg/ml, respectively, p=0.005) and low nocturnal melatonin level (6.42+/-4.97 and 12.52+/-10.40 pg/ml, respectively, p=0.039). PMID- 30003412 TI - Medication-overuse headache: a widely recognized entity amidst ongoing debate. AB - Medication overuse in primary headache disorders is a worldwide phenomenon and has a role in the chronification of headache disorders. The burden of disease on individuals and societies is significant due to high costs and comorbidities. In the Third Edition of the International Classification of Headache Disorders, medication-overuse headache is recognized as a separate secondary entity next to mostly primary headache disorders, although many clinicians see the disease as a sole complication of primary headache disorders. In this review, we explore the historical background of medication-overuse headache, its epidemiology, phenomenology, pathophysiology and treatment options. The review explores relevant unanswered questions and summarizes the current debates in medication overuse headache. PMID- 30003420 TI - Dihydroquercetin and Fucoidin Inhibit the Increase of Angiotensin-Converting Enzyme Activity in the Rat Aorta after Irradiation. AB - The time course of angiotensin-converting enzyme activity in the rat aorta after fractionated exposure to ionizing radiation and the effects of dihydroquercetin and fucoidin on this parameter were studied. Male Wistar rats were exposed to single or repeated (fractionated) X-ray radiation in a dose of 2.5 Gy at 200 kV. Activity of angiotensin-converting enzyme in aorta segments was evaluated 2 h after the last exposure by hydrolysis of hippuryl-histidineleucin substrate. Enzyme activity in the rat aorta was higher than normally after all the studied doses of fractionated exposure (2.5 Gy per fraction) with the maximum effect after the total dose of 7.5 Gy (3 fractions). Fucoidin, a blocker of endothelium receptors realizing the leukocyte adhesion to the endothelium, and flavonoid dihydroquercetin inhibiting expression of adhesion molecules in the endothelium abolished the increase in activity of angiotensinconverting enzyme in the rat aorta after single exposure; moreover, dihydroquercetin reduced significantly the effect of fractionated exposure. These data indicate that leukocyte adhesion to the endothelium is an important factor contributing to the increase of angiotensin-converting enzyme activity in the aorta. PMID- 30003421 TI - Moricizine (Ethmozine) Can Break Electrical Coupling between Rat Right Atrial Working Cardiomyocytes In Vitro. AB - A previously popular antiarrhythmic drug moricizine (ethmozine) is known for its blocking action on the fast sodium channels in cardiomyocytes. Its effects were examined only in isolated cardiomyocytes or in vivo. Here, the effect of moricizine (10 MUM) was examined in vitro on perfused right atrial preparation, where it completely reproduced all the previously observed phenomena and disturbed electrical coupling between the working cardiomyocytes in 35.3+/-3.4 min, which arrested generation of action potentials. During washing, the cardiomyocytes restored rhythmic firing in 34.1+/-3.7 min. Inhibition of firing in the working atrial cardiomyocytes was not accompanied by suppression of rhythmic activity in the pacemaker cells of sinoatrial node as attested by rhythmic miniature spikes in the records of resting (diastolic) potential of these cardiomyocytes. Thus, moricizine disturbed conduction between the working atrial cardiomyocytes without affecting the pacemaker activity. PMID- 30003422 TI - Peculiarities of Osteogenesis by Periosteal Cells after Experimental Ectopic Transplantation. AB - We carried out a comparative study of the features of osteogenesis from the progenitor osteogenic periosteal cells in rabbit and human. At the initial stages, high osteogenic potential of both human and rabbit periosteal cells was observed. However, at the later stages, the cell response favors resorption of the new bone tissue formed from periosteal cells in rabbits, but does not affect the bone tissue formed from human progenitor osteogenic periosteal cells. These functional characteristics of rabbit periosteal cells should be considered when planning the experiment. PMID- 30003423 TI - Directed Change in TNFalpha Specificity to Create DR5 Antagonists. AB - Death receptor 5 (DR5) is a promising target for antitumor therapy due to its high expression on different tumor cells. Resistance of various tumor cells against TRAIL, a natural ligand for the death receptors, reduces its therapeutic potential and prompts the search for novel agonists at these receptors. Previous screening across the combinatorial peptide library yielded a peptide sequence KVVLTHR that specifically binds DR5. Incorporation of this sequence into TNFalpha resulted in binding DR5 with mutant protein TNFalpha-mut and appearance of cytotoxicity against lymphoma cells. PMID- 30003424 TI - Method for Studies of Orientation and Exploratory Behavior in Humans. Effects of Emotional Stress. AB - We developed a new experimental model for studies of orientation and exploratory behavior in humans. This method allows analysis of variants of orientation and exploratory behavior in humans, including risky behavior, and cognitive and individual typological parameters. The model allows distinguishing examinees with high and low orientation and exploratory activity, which helps to determine their psychoemotional status. Surprisingly, individuals in emotional strain demonstrated longer orientation and exploratory behavior. This allows them to achieve the results more rapidly during purposeful behavior under similar conditions. This model provides the tool for evaluation of the electrophysiological, autonomic, and biochemical mechanisms of orientation and exploratory behavior of humans. PMID- 30003425 TI - Evaluation of the therapeutic effect of micro-plasma radio frequency on hypertrophic scars in rabbit ears. AB - To evaluate the therapeutic effect of micro-plasma radio frequency on hypertrophic scars in rabbit ears to provide an experimental basis and theoretical foundation for the treatment of hypertrophic scars. Hypertrophic scars were established on the ventral surface of the ears of six New Zealand white rabbits. Left and right ears were randomly divided into two groups: experimental group treated with micro-plasma radio frequency and control group with no treatment. H&E staining and CD34 labeling of microvessels were performed to analyze ear specimens, and immunohistochemical staining was conducted to detect IL-8 and MCP-1 in the scars. Compared with the control group, scar tissue in the experimental group was improved by color and texture. H&E-stained collagen fiber bundles were more organized after treatment as assessed by optical microscopy. The number of microvessels in the experimental group was decreased compared with that in the control group. Microvascular density was significantly reduced in the experimental group compared with the control group (27.16 +/- 5.64 and 48.75 +/- 8.25 mm2, respectively; P < 0.01). The mean optical densities of IL 8 and MCP-1 were significantly reduced in the experimental group compared with the control group (IL-8 0.016 +/- 0.011 and 0.078 +/- 0.023, respectively; MCP-1 0.018 +/- 0.016 and 0.054 +/- 0.038, respectively; both P < 0.01). The micro plasma radio-frequency technique has a therapeutic effect on hypertrophic scars in rabbit ears. PMID- 30003426 TI - Effects of Nd:YAG low-level laser irradiation on cultured human osteoblasts migration and ATP production: in vitro study. AB - Low-level laser therapy has become one of the fastest growing fields of medicine in recent years. Many in vivo and in vitro studies have shown that laser irradiation activates a range of cellular processes in a variety of cell types and can promote tissue repair. However, few in vitro experiments have evaluated the effects of laser irradiation on cells in real time. The purpose of this study was to examine the effects of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on the migration of cultured human osteoblasts. A dedicated 96 well plate was used, and confluent cultures of the human osteoblast-like cell line, Saos-2, were injured with a wound maker. The wounded cells were then exposed to the Nd:YAG laser (wavelength of 1064 nm) for 60 s at 0.3 W (10 pps, 30 mJ). The total energy density was about 10.34 J/cm2. Images of the wounds were automatically acquired inside the CO2 incubator by the IncuCyte ZOOMTM software. In addition, after laser irradiation, the production of adenosine triphosphate (ATP) was measured using the CellTiter-GloTM Luminescent Cell Viability Assay. Migration of cells from the border of the original scratch zone was accelerated by laser irradiation. In addition, compared with the control group, significant enhancement of ATP production was observed in the irradiated group. The present study showed that Nd:YAG laser irradiation (wavelength of 1064 nm, 0.3 W, 10 pps, 30 mJ, 10.34 J/cm2, irradiation time 60 s) may contribute to the regeneration of bone tissues owing to enhanced osteoblast cell migration. PMID- 30003427 TI - Er:YAG laser application in caries removal and cavity preparation in children: a meta-analysis. AB - The aim of this meta-analysis was to systematically evaluate the applications of Er:YAG lasers for the removal of caries and cavity preparation in children. The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was conducted with data extracted from seven relevant randomized controlled trials (RCTs) published from 1997 to July 2017. The data heterogeneity of each study was assessed by a Q test. We used the heterogeneity results to calculate the standard mean difference (SMD) or relative risk (RR) and 95% confidence interval (95%CI) using STATA version 10.0. The publication bias was evaluated using Begger's test. There were seven randomized controlled trials included in this study. The analysis results indicate that compared to the conventional mechanical method, more time was needed for Er:YAG laser treatment (SMD 1.945, 95%CI 0.942 to 2.948). However, the pain reported by patients was reduced with Er:YAG laser treatment (SMD - 1.013, 95%CI - 1.892 to - 0.196). There were no significant differences between the groups in the complete retention rate (RR 1.021, 95%CI 0.963 to 1.114), the marginal discoloration (RR 1.638, 95% CI 0.240 to 11.986) and the marginal adaptation (RR 1.480, 95%CI 0.257 to 8.515). In conclusion, our data indicate that the time required for Er:YAG laser treatment was longer than that for the conventional mechanical method, but there was less pain associated with the Er:YAG laser treatment. There were no significant differences in the complete retention rate, marginal discoloration, and marginal adaptation between the two groups. PMID- 30003428 TI - Pharmacokinetic Factors to Consider in the Selection of Antiseizure Drugs for Older Patients with Epilepsy. AB - The incidence of epilepsy is highest in the older adult age group. Seizures in older adults can be more difficult to diagnose because their presentation is often subtle and can easily be mistaken for other conditions. Fortunately, new onset epilepsy in the older adult is often pharmaco-responsive, with as many as 80-85% of patients achieving remission, often with monotherapy at modest doses. Many physiological and pathological changes occur with aging that can alter the pharmacokinetics of antiseizure drugs (ASDs). For the majority of the old- and new-generation ASDs, a decrease in dose may be needed to maintain concentrations equivalent to those found in young adults. The risk of drug interactions with ASDs is substantial, as polypharmacy is common. The first-generation ASDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) have the potential to interact with many drugs, but many newer ASDs either do not have significant interactions or are selective inhibitors and inducers of specific hepatic enzymes. The differences in adverse effects between younger and older adults are not just due to dosing and pharmacokinetics. Older adults are more susceptible to the gait, balance, and cognitive effects of ASDs. Overall, the improved tolerability and decreased drug interaction potential of the newer-generation ASDs, such as lamotrigine and levetiracetam, have demonstrated their superiority in the treatment of seizures in older adults and, as such, are clearly favored for new-onset epilepsy in older adults. PMID- 30003429 TI - Cost-Effectiveness Analysis of a Physician-Implemented Medication Screening Tool in Older Hospitalised Patients in Ireland. AB - BACKGROUND: A recent randomised controlled trial conducted in an Irish University teaching hospital that evaluated a physician-implemented medication screening tool, demonstrated positive outcomes in terms of a reduction in incident adverse drug reactions. OBJECTIVE: The present study objective was to evaluate the cost effectiveness of physicians applying this screening tool to older hospitalised patients compared with usual hospital care in the context of the earlier randomised controlled trial. METHOD: We used a cost-effectiveness analysis alongside a conventional outcome analysis in a cluster randomised controlled trial. Patients in the intervention arm (n = 360) received a multifactorial intervention consisting of medicines reconciliation, communication with patients' senior medical team, and generation of a pharmaceutical care plan in addition to usual medical and pharmaceutical care. Control arm patients (n = 372) received usual medical and pharmaceutical care only. Incremental cost effectiveness was examined in terms of costs to the healthcare system and an outcome measure of adverse drug reactions during inpatient hospital stay. Uncertainty in the analysis was explored using a cost-effectiveness acceptability curve. RESULTS: On average, the intervention arm was more costly but was also more effective. Compared with usual care (control), the intervention was associated with a non statistically significant increase of ?877 (95% confidence interval - ?1807, ?3561) in the mean healthcare cost, and a statistically significant decrease of - 0.164 (95% confidence interval - 0.257, - 0.070) in the mean number of adverse drug reaction events per patient. The associated incremental cost-effectiveness ratio per adverse drug reaction averted was ?5358. The probability of the intervention being cost effective at threshold values of ?0, ?5000 and ?10,000 was 0.236, 0.455 and 0.680, respectively. CONCLUSION: Based on the evidence presented, this physician-led intervention is not likely to be cost effective compared with usual hospital care. To inform future healthcare policy decisions in this field, more economic analyses of structured medication reviews by other healthcare professionals and by computerised clinical decision support software need to be conducted. PMID- 30003430 TI - Transplantation of Human-Induced Pluripotent Stem Cell-Derived Neural Precursors into Early-Stage Zebrafish Embryos. AB - Induced pluripotent stem cells (iPS cells) generated from somatic cells through reprogramming hold great promises for regenerative medicine. However, how reprogrammed cells survive, behave in vivo, and interact with host cells after transplantation still remains to be addressed. There is a significant need for animal models that allow in vivo tracking of transplanted cells in real time. In this regard, the zebrafish, a tropical freshwater fish, provides significant advantage as it is optically transparent and can be imaged in high resolution using confocal microscopy. The principal goal of this study was to optimize the protocol for successful short-term and immunosuppression-free transplantation of human iPS cell-derived neural progenitor cells into zebrafish and to test their ability to differentiate in this animal model. To address this aim, we isolated human iPS cell-derived neural progenitor cells from human fibroblasts and grafted them into (a) early (blastocyst)-stage wild-type AB zebrafish embryos or (b) 3 day-old Tg(gfap:GFP) zebrafish embryos (intracranial injection). We found that transplanted human neuronal progenitor cells can be effectively grafted and that they differentiate and survive in zebrafish for more than 2 weeks, validating the model as an ideal platform for in vivo screening experiments. We conclude that zebrafish provides an excellent model for studying iPS cell-derived cells in vivo. PMID- 30003431 TI - A comparison of the antioxidant activities and biomonitoring of heavy metals by pollen in the urban environments. AB - Pollen is one of the most valuable nutrients due to its content and antioxidant activity. In this study, its botanic origin, total phenol content (TPC), total flavonoid content (TFC), the hydrogen peroxide scavenging activity (HPSA) (in terms of SC50), ferric reducing antioxidant power capacity (FRAP), 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging activity (in terms of SC50), metal chelating activity (MCA) (%), and heavy metal content were examined to determine the quality of pollen that has been collected from seven different cities of Turkey. According to the melissopalynological analysis, the botanic origin of samples is six uni-flora and one multiflora. The TPC, TFC, HPSA, FRAP, DPPH, and MCA were found between 1360.70-2981.34 mg GAE/100 g, 74.23-111.74 mg CAE/100 g, 25.56-30.28 MUg/mL, 71.92-73.86%, 52.26-53.27 MUg/mL, and 43.97-65.21%, respectively. When obtained results compared to the standards (Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT) and alpha-Tocopherol (TOC)), pollen samples showed the effective antioxidant properties with respect to HPSA, FRAP, and DPPH radical scavenging activity. In addition, it was observed that honey samples were being contaminated with most of the metals to some extent (Al, Cr, Mn, Fe, Ni, Cu, Zn, B, As, Te, U), while some heavy metals (Co, Cd, V, Ga, and Ag) were never determined in all samples. However, Pb was determined only in sample 2 and sample 4, Mo in sample 1 and sample 2. According to meteorological parameters, samples 3, 4, and 5 were distinguished from the other samples. Finally, the data indicate that pollen could be affected by environmental pollutions. PMID- 30003432 TI - Transforming Growth Factor Beta (TFG-beta) Concentration Isoforms are Diminished in Acute Coronary Syndrome. AB - Acute coronary syndrome (ACS) is the leading cause of death in elderly patients worldwide. Due its participation in apoptosis, fibrosis, and angiogenesis, transforming growth factor-beta (TGF-beta) isoforms had been categorized as risk factors for cardiovascular diseases. However, due their contradictory activities, a cardioprotective role has been suggested. The aim was to measure the plasma levels of TGF-beta1, 2, and 3 proteins in patients with ACS. This was a case control study including 225 subjects. The three activated isoforms were measured in serum using the Bio-Plex Pro TGF-beta assay by means of magnetic beads; the fluorescence intensity of reporter signal was read in a Bio-Plex Magpix instrument. We observed a significant reduction of the three activated isoforms of TGF-beta in patients with ACS. The three TGF-beta isoforms were positively correlated with each other in moderate-to-strong manner. TGFbeta-2 was inversely correlated with glucose and low-density lipoprotein (LDL)-cholesterol, whereas TGF-beta3 was inversely correlated with the serum cholesterol concentration. The production of TGF-beta1, TGF-beta2, and TGF-beta3 are decreased in the serum of patients with ACS. Further follow-up controlled studies with a larger sample size are needed, in order to test whether TGF-beta isoforms could be useful as biomarkers that complement the diagnosis of ACS. PMID- 30003433 TI - Potential strain-dependent mechanisms defining matrix alignment in healing tendons. AB - Tendon mechanical function after injury and healing is largely determined by its underlying collagen structure, which in turn is dependent on the degree of mechanical loading experienced during healing. Experimental studies have shown seemingly conflicting outcomes: although collagen content steadily increases with increasing loads, collagen alignment peaks at an intermediate load. Herein, we explored potential collagen remodeling mechanisms that could give rise to this structural divergence in response to strain. We adapted an established agent based model of collagen remodeling in order to simulate various strain-dependent cell and collagen interactions that govern long-term collagen content and fiber alignment. Our simulation results show two collagen remodeling mechanisms that give rise to divergent collagen content and alignment in healing tendons: (1) strain-induced collagen fiber damage in concert with increased rates of deposition at higher strains, or (2) strain-dependent rates of enzymatic degradation. These model predictions identify critical future experiments needed to isolate each mechanism's specific contribution to the structure of healing tendons. PMID- 30003434 TI - Active contraction of cardiac cells: a reduced model for sarcomere dynamics with cooperative interactions. AB - We propose a reduced ODE model for the mechanical activation of cardiac myofilaments, which is based on explicit spatial representation of nearest neighbour interactions. Our model is derived from the cooperative Markov Chain model of Washio et al. (Cell Mol Bioeng 5(1):113-126, 2012), under the assumption of conditional independence of specific sets of events. This physically motivated assumption allows to drastically reduce the number of degrees of freedom, thus resulting in a significantly large computational saving. Indeed, the original Markov Chain model involves a huge number of degrees of freedom (order of [Formula: see text]) and is solved by means of the Monte Carlo method, which notoriously reaches statistical convergence in a slow fashion. With our reduced model, instead, numerical simulations can be carried out by solving a system of ODEs, reducing the computational time by more than 10, 000 times. Moreover, the reduced model is accurate with respect to the original Markov Chain model. We show that the reduced model is capable of reproducing physiological steady-state force-calcium and force-length relationships with the observed asymmetry in apparent cooperativity near the calcium level producing half activation. Finally, we also report good qualitative and quantitative agreement with experimental measurements under dynamic conditions. PMID- 30003436 TI - Angiogenic capacity in pre-eclampsia and uncomplicated pregnancy estimated by assay of angiogenic proteins and an in vitro vasculogenesis/angiogenesis test. AB - OBJECTIVE: The purpose of the study was to determine the angiogenic capacity of sera in early and late pregnancy and in umbilical blood serum after childbirth, and to define how angiogenic properties assessed in a functional in vitro test are related to individual angiogenic proteins in six women with pre-eclampsia and in six healthy pregnant controls. METHODS: Maternal first and third trimester serum samples, and umbilical blood samples after childbirth, were tested in an in vitro human adipose stromal cell-human umbilical vein endothelial cell (hASC HUVEC) vasculogenesis/angiogenesis assay. The angiogenic properties of the samples were measured by quantifying tubule formation. Concentrations of total placental growth factor (PlGF), total vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) were determined by immunoassay. RESULTS: First-trimester maternal sera of both groups had a stimulatory effect on angiogenesis in vitro and levels of angiogenic proteins did not differ between the groups. Third-trimester maternal sera in the pre-eclampsia group had an inhibitory effect on tubule formation, while those from normal pregnancies remained stimulatory. Compared with the first trimester there was a significant change in the concentrations of angiogenic proteins toward an anti-angiogenic state in pre-eclampsia. Umbilical blood serum exhibited strong anti-angiogenic effects without a significant difference between groups. CONCLUSIONS: Third-trimester serum of pre-eclamptic patients is anti-angiogenic. This phenomenon is not yet present in the first trimester. Umbilical blood serum shows inhibitory effects on angiogenesis after normal as well as pre-eclamptic pregnancy. PMID- 30003435 TI - The Future of Precision Medicine: Potential Impacts for Health Technology Assessment. AB - OBJECTIVE: Precision medicine allows healthcare interventions to be tailored to groups of patients based on their disease susceptibility, diagnostic or prognostic information, or treatment response. We analysed what developments are expected in precision medicine over the next decade and considered the implications for health technology assessment (HTA) agencies. METHODS: We performed a pragmatic literature search to account for the large size and wide scope of the precision medicine literature. We refined and enriched these results with a series of expert interviews up to 1 h in length, including representatives from HTA agencies, research councils and researchers designed to cover a wide spectrum of precision medicine applications and research. RESULTS: We identified 31 relevant papers and interviewed 13 experts. We found that three types of precision medicine are expected to emerge in clinical practice: complex algorithms, digital health applications and 'omics'-based tests. These are expected to impact upon each stage of the HTA process, from scoping and modelling through to decision-making and review. The complex and uncertain treatment pathways associated with patient stratification and fast-paced technological innovation are central to these effects. DISCUSSION: Innovation in precision medicine promises substantial benefits but will change the way in which some health services are delivered and evaluated. The shelf life of guidance may decrease, structural uncertainty may increase and new equity considerations will emerge. As biomarker discovery accelerates and artificial intelligence-based technologies emerge, refinements to the methods and processes of evidence assessments will help to adapt and maintain the objective of investing in healthcare that is value for money. PMID- 30003437 TI - American Political-Party Affiliation as a Predictor of Usage of an Adultery Website. AB - The more politically conservative Americans are, the more restrictive their sexual attitudes are. A natural follow-up question is how this difference in attitudes relates to actual behavior. But self-reports of sexual behavior may be compromised by a social desirability bias that is influenced by the very sexual attitudes at issue. We employed a non-self-reported measure of sexual behavior: usage of the adultery-focused dating website Ashley Madison. Linking an August 2015 leak of user data from Ashley Madison to 2012 voter registration rolls from five U.S. states, we found 80,000 matches between 200,000 Ashley Madison user accounts and 50 million voters. According to simple rates in the sample, and also to predictively validated regression models controlling for state, gender, and age, we found that Democrats were least likely to use Ashley Madison, Libertarians were most likely, and Republicans, Greens, and unaffiliated voters were in between. Our results provide support for theories arguing that people with stricter sexual attitudes are paradoxically more likely to engage in deviant sexual behavior. PMID- 30003438 TI - Sexual Arousal and Implicit and Explicit Determinants of Condom Use Intentions. AB - Being sexually aroused may be an important risk factor contributing to sexual decision making. Dual-process cognitive models, such as the reflective-impulsive model of Strack and Deutsch (2004), could be used to explain the effect of sexual arousal on intentions to use a condom. In this study, we investigated whether explicit and implicit attitudes toward condom use can predict intentions to use a condom when participants are sexually aroused and not aroused. In a within subjects experimental design, male participants (N = 27) watched both a neutral and an erotic movie clip in counterbalanced order. After each clip, participants completed a questionnaire assessing their intentions to use a condom and explicit condom attitudes, followed by a wanting Implicit Association Test (IAT; Greenwald et al., 2003) and a liking IAT to assess their implicit attitudes to unsafe sex. In concordance with the reflective-impulsive model, we found that when participants were not sexually aroused, their intentions to use a condom were solely predicted by their explicit attitudes. However, when they were sexually aroused, intentions to use a condom were predicted by both explicit and implicit attitudes toward condom use. PMID- 30003439 TI - Correction to: Attitudes of physicians from 10 European countries on adherence and how treatment modalities in ABSSSI affect adherence: results from a Delphi survey. AB - In the originally published article, the name of the last author was not correct. The name is Paolo Antonio Grossi, which is correctly shown above. PMID- 30003440 TI - Evaluating the diagnostic and prognostic value of lone anti-Sm for autoimmune diseases using Euroimmun line immunoassays. AB - To investigate the value of lone anti-Smith antibody (anti-Sm) using Euroimmun line immunoassay (LIA) in a Chinese population. One thousand two hundred eight of 39,766 patients who were analyzed for anti-Sm had positive anti-Sm, and were divided into true group (having both positive Sm and nRNP/Sm bands) and lone group (only having Sm band without nRNP/Sm band). The proportions of clinical diagnosis of autoimmune diseases (AIDs), non-autoimmune diseases (NAIDs), concentration of C3, C4, and rheumatoid factor (RF), positive rate of autoantibodies of antinuclear antibody (ANA) profile, and titer of anti-Sm and ANA in systemic lupus erythematosus (SLE) patients were analyzed. Lone anti-Sm was evident in 271/1208 (22.42%) of all positive cases. One hundred seventy-five of them had definitive diagnoses with AIDs being the most prominent (69.71%, 122/175). Compared to the true group, SLE patients in the lone group showed significantly lower ANA and anti-Sm titers (both P < 0.001). There was no difference in frequency of other autoantibodies or C3, C4, and RF levels of SLE patients between the two groups. In NAIDs patients, lone anti-Sm indicates less incidence of kidney injury than true anti-Sm (P = 0.05). Lone anti-Sm has great diagnostic value in AIDs, especially SLE. Lone anti-Sm has relationship with mild kidney impairment. Positive anti-Sm patients with no clinical findings or SLE diagnosis should be submitted to new testing to identify changes in anti-Sm, because turning of lone anti-Sm to true anti-Sm indicates evolving kidney injury. PMID- 30003441 TI - Non-steroidal anti-inflammatory drug induces luteinized unruptured follicle syndrome in young female juvenile idiopathic arthritis patients. AB - To assess prospectively luteinized unruptured follicle (LUF) syndrome in juvenile idiopathic arthritis (JIA) patients with and without non-steroidal anti inflammatory drugs (NSAIDs) and healthy controls. Twenty-three adolescent and young adult female JIA patients (ILAR criteria) and 11 female healthy subjects were studied by pelvic ultrasound monitoring for follicular development and ovulation in one menstrual cycle. LUF syndrome was prospectively investigated by pelvic ultrasound with a dominant ovarian follicle without signs of follicular rupture, with elevation of serum progesterone in the luteal phase of the menstrual cycle and luteinizing hormone (LH) detected in the urine. Comparison between JIA patients with (n = 8) vs. without NSAIDs (n = 15) and healthy controls (n = 11) revealed that LUF syndrome was significantly higher in the former group (2 (25%) vs. 0% vs. 0%, p = 0.049). These two patients with LUF syndrome had normal menstrual cycles without reduced ovarian reserve, and they were under naproxen 500 mg bid during the menstrual cycle. Disease duration was comparable in JIA with and without NSAIDs [19.8 (4.4-25) vs. 13 (3.1-33) years, p = 0.232]. Further comparison between JIA patients with and without NSAIDs and healthy controls showed similar mean anti-Mullerian hormone levels (p = 0.909), estradiol (p = 0.436), FSH (p = 0.662), LH (p = 0.686), and mean antral follicle count (p = 0.240) and ovarian volume (p = 0.363). No differences were evidenced in three groups regarding Caucasian race, body mass index, duration, and length of menstrual cycles (p > 0.05). This is the first study to identify that JIA patients have a high frequency of LUF without impaired ovarian reserve. Future prospective studies are necessary to determine if chronic/continuous use of NSAIDs in JIA will have an impact in these patients' fertility. PMID- 30003442 TI - Assessing the causal association between smoking behavior and risk of gout using a Mendelian randomization study. AB - This study aimed to examine whether smoking behavior is causally related to gout. Summary statistics of publicly available data from genome-wide association studies (GWAS) of smoking behavior (n = 85,997) served as the exposure dataset, while meta-analysis results of 14 studies including 2115 cases and 67,259 controls of European descent served as the outcome dataset. The data were subjected to two-sample Mendelian randomization (MR) analysis using the inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. Five single-nucleotide polymorphisms (SNPs) from GWAS of smoking behavior were selected as instrumental variables (IVs) to improve inference: CHRNA3 (rs1051730), PDE1C (rs215614), CYP2A6 (rs4105144), CHRNB3 (rs6474412), and CYP2B6 (rs7260329). The IVW data did not support a causal association between smoking behavior and gout (beta = - 0.035, SE = 0.036, p = 0.333). MR-Egger regression indicated that directional pleiotropy did not bias the result (intercept = 0.021; p = 0.560). MR-Egger analysis revealed no causal association between smoking behavior and gout (beta = - 0.074, SE = 0.070, p = 0.366). The weighted median approach did not support a causal association between smoking behavior and gout (beta = - 0.043, SE = 0.040, p = 0.279). Cochran's Q test indicated no evidence of heterogeneity between IV estimates based on individual variants. The results of "leave one out" analysis demonstrated that no single SNP drove the IVW point estimate. MR estimates using IVW, weighted median, and MR-Egger analysis were consistent and did not support a causal inverse association between smoking behavior and gout. PMID- 30003443 TI - Effect of Inhalation Flow Rate on Mass-Based Plume Geometry of Commercially Available Suspension pMDIs. AB - Although high-speed laser imaging is the current standard to characterize the plume angle of suspension-based pressurized metered dose inhalers (pMDIs), this method is limited by the inability to identify the drug content in a droplet and simulate inhalation flow. The Plume Induction Port Evaluator (PIPE) is a modified induction port for cascade impactors that allows for the calculation of the angle of a plume based on direct drug mass quantification rather than indirect droplet illumination under airflow conditions. The objective of this study was to investigate the use of the PIPE apparatus to evaluate the effect of airflow on the Mass Median Plume Angle (MMPA) of commercially available suspension-based pMDIs (Ventolin(r) HFA, ProAir(r) HFA, and Proventil(r) HFA). Deposition patterns within PIPE were log-normally distributed allowing for the calculation of the MMPA for the three suspension products. Mass-based plume angles were significantly smaller (narrower angle) when inhalation airflow was used compared to no flow conditions (reduction of MMPA was 8, 16, and 13% for Ventolin(r) HFA, ProAir(r) HFA, and Proventil(r) HFA, respectively). Additionally, new parameters for characterizing plume geometry were calculated (MMPA ex-actuator and plume orientation). Mass-based plume angles of the suspension-based pMDI formulations were highly reproducible and demonstrated the effect of inhalation flow rate. These results suggest that plume geometry tests should be evaluated under flow conditions which is not possible using current methodologies. Graphical Abstract ?. PMID- 30003444 TI - Insulin-dependent, glucose transporter 1 mediated glucose uptake and tube formation in the human placental first trimester trophoblast cells. AB - During early gestation, hypoxic condition is critically maintained by optimal glucose metabolism and transporter activities. Glucose is readily available energy nutrient required for placentation. However, limited data are available on glucose uptake and its transporters during first trimester placentation processes. To this end, effects of glucose and the roles of glucose transporters (GLUTs) were investigated during hypoxia on trophoblast migration and placental angiogenesis processes using early gestation-derived trophoblast cells, HTR8/SVneo, and first trimester human placental explant tissues. Exogenously added glucose (25 mM) significantly increased tube formation (in vitro angiogenesis) in HTR8/SVneo cells with concomitant activation of AKT-PI3K pathway and increased expression of vascular cell adhesion molecule 1 (VCAM1) compared with those in the presence of 11 mM glucose. Cobalt chloride (CoCl2)-induced hypoxia also significantly increased glucose uptake and GLUT1 expression along with tube formation and migration of HTR8/SVneo cells. During hypoxia, addition of glucose further stimulated HIF1alpha expression than by hypoxia alone. Cytochalasin B (cyt-B) inhibited the glucose uptake both in the presence of 11 mM and 25 mM glucose. Insulin (1 ng/ml) stimulated GLUT1 expression and tube formation and up-regulated the expression of VEGFR2 in HTR8/SVneo cells. Insulin and glucose-stimulated tube formation was inhibited by cyt-B but had no effect on hypoxia-induced tube formation. Silencing of GLUT1 inhibited the glucose and insulin-stimulated tube formation as well as glucose uptake. However, fatty acid stimulated tube formation was not affected in GLUT1 knockdown cells. All these data suggest that glucose uptake, glucose-stimulated tube formation, and insulin stimulated glucose uptake of the first trimester trophoblast cells, HTR8/SVneo, are mediated in part via GLUT1. PMID- 30003445 TI - On the historical significance of Beijerinck and his contagium vivum fluidum for modern virology. AB - This paper considers the foundational role of the contagium vivum fluidum-first proposed by the Dutch microbiologist Martinus Beijerinck in 1898-in the history of virology, particularly in shaping the modern virus concept, defined in the 1950s. Investigating the cause of mosaic disease of tobacco, previously shown to be an invisible and filterable entity, Beijerinck concluded that it was neither particulate like the bacteria implicated in certain infectious diseases, nor soluble like the toxins and enzymes responsible for symptoms in others. He offered a completely new explanation, proposing that the agent was a "living infectious fluid" whose reproduction was intimately linked to that of its host cell. Difficult to test at the time, the contagium vivum fluidum languished in obscurity for more than three decades. Subsequent advances in technologies prompted virus researchers of the 1930s and 1940s-the first to separate themselves from bacteriologists-to revive the idea. They found in it both the seeds for their emerging virus concept and a way to bring hitherto opposing thought styles about the nature of viruses and life together in consensus. Thus, they resurrected Beijerinck as the founding father, and contagium vivum fluidum as the core concept of their discipline. PMID- 30003446 TI - Detection of needle tract implantation and peritoneal seeding after radiofrequency ablation using intraoperative near-infrared fluorescence system for recurrent hepatocellular carcinoma: a case report. AB - BACKGROUND: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is already fully established worldwide. Needle tract implantation and peritoneal seeding occasionally occur by RFA, and the prognosis of these cases is thought to be poor. In this study, intraoperative real-time near-infrared fluorescence (NIRF) system by indocyanine green (ICG) incidentally detected both needle tract implantation and peritoneal seeding. As the utility of this system for identification of implanted and disseminated lesions after RFA for HCC has not been widely reported, we report a case of successful detection by real-time ICG NIRF imaging and subsequent resection. CASE PRESENTATION: A 76-year-old man originally underwent medial sectionectomy for HCC in 2009. When repeated intrahepatic recurrence occurred, he underwent RFA and transcatheter arterial chemoembolization (TACE) for recurrent HCC twice at segment III and once at segment IV. In 2013, the second hepatectomy for recurrent HCC at segment VIII was performed. In 2016, he had recurrent HCC at segment III around a previous RFA and TACE scar; therefore, left lateral sectionectomy was planned. ICG-NIRF system was used to observe a main intrahepatic metastasis at segment III and to search for other tumors in the remnant liver. Although there was no signal on the surface of the remnant liver, tiny signals were observed in the abdominal wall and greater omentum. These tumors were on the needle tract of the previous RFA; both lesions, therefore, were resected. These tumors were pathologically proven to be HCC metastases. The patient has had no recurrence 14 months after the last hepatectomy. CONCLUSIONS: ICG-NIRF system might be helpful in the detection of not only intrahepatic lesions but also needle tract implantations or peritoneal seeding. RFA should be avoided in patients with high risk of needle tract implantation and peritoneal seeding. PMID- 30003447 TI - Influence of various medium environment to in vitro human T cell culture. AB - Nowadays, adoptive T cell immunotherapy is emerging as a novel and potent treatment for cancer. To prepare enough effective T cells for treatment use, their rapid expansion is favorable. Our study compared 6 commonly used cultural media for human T cells, including serum-containing media and serum-free media, namely RPMI 1640, IMDM, Gibco OpTmizer CTS T Cell Expansion SFM, Gibco AIM-V Medium CTS, LONZA X-VIVO 15, and StemSpan SFEM with or without Dynabeads Human T Activator CD3/CD28, on in vitro T cell expansion, apoptosis, and immune phenotype. Our study results suggest that serum-free media provide better proliferation environment for T cells. Among the 3 serum-free media, we identify OpTmizer and AIM-V as better T cell culture environments compared with X-VIVO as T cells are proved to have higher viability in the first two media. Besides, we found that in vitro human T cells keep relatively resting status among non CD3/CD28 groups, since they have weak proliferation and apoptosis abilities. The phenotypes of T cells in different cultural environments over time indicate T cells maturation during culture duration. These results provide a firm foundation of adoptive T cell immunotherapy. PMID- 30003448 TI - Distribution and assessment of mercury (Hg) in surface sediments of Futian mangrove forest, China. AB - To investigate the distribution of mercury (Hg) in Futian mangrove wetland, surface sediments from land to sea were collected, including Kandelia obovata, Avicennia marina, Sonneratia caseolaris, and mud flat. The ecological risks of Hg in sediments were also assessed. The results showed that mangrove forests acidified sediments and promoted the accumulation of salinity and organic matter in sediments. Hg concentrations in both mangrove forests (154.7-218.4 ng g-1) and mud flat sediments (226.3-251.9 ng g-1) surpassed the background level (71.0 ng g 1). Furthermore, Hg concentrations in sediments decreased gradually from sea to land at all depth. From the bottom to the top layer sediment, Hg concentration decreased gradually in the sediments near land, while it kept vertically stable in the coastal area, indicating its pollution may mainly come from the coastal area rather than the land to some extent. Although the mean values of geo accumulation indexes revealed uncontaminated to moderately contaminated levels, the mean values of potential ecological risk coefficients revealed considerable ecological risk of Hg to the environment, deserving further attention. PMID- 30003449 TI - Inhibitory effects against alpha-glucosidase and alpha-amylase of the flavonoids rich extract from Scutellaria baicalensis shoots and interpretation of structure activity relationship of its eight flavonoids by a refined assign-score method. AB - A flavonoids-rich extract of Scutellaria baicalensis shoots and its eight high content flavonoids were investigated for their inhibitory effects against alpha glucosidase and alpha-amylase. Results show that abilities of the extract in inhibiting the two enzymes were obviously higher than those of acarbose. Moreover, inhibitory abilities of all the eight individual flavonoids against the two enzymes show exactly a same order (i.e., apigenin > baicalein > scutellarin > chrysin > apigenin-7-O-glucuronide > baicalin > chrysin-7-O-glucuronide > isocarthamidin-7-O-glucuronide), and their structure-activity relationship could be well-interpretated by the refined assign-score method. Furthermore, based on the inhibitory abilities and their contents in the extract, it was found that the eight flavonoids made predominant contributions, among which baicalein and scutellarin played roles as preliminary contributors, to overall inhibitory effects of the extract against the two enzymes. Beyond these, contributions of the eight flavonoids to the overall enzyme inhibitory activity were compared with those to the overall antioxidant activity characterized in our recent study, and it could be inferred that within the basic flavonoid structure the hydroxyl on C 4' of ring B was more effective than that on C-6 of ring A in enzyme inhibitory activities while they behaved inversely in antioxidant activities; scutellarin and apigenin contributed more to the overall enzyme inhibitory activity, and baicalin and scutellarin, to the overall antioxidant activity of the extract; and flavonoids of the extract, apart from directly inhibiting enzymes, might also be conducive to curing type 2 diabetes via scavenging various free radicals caused by increased oxidative stresses. PMID- 30003450 TI - Results from the American Society of Breast Surgeons Oncoplastic Surgery Committee 2017 Survey: Current Practice and Future Directions. AB - INTRODUCTION: Oncoplastic surgery is emerging as a validated, safe, patient centric approach to breast cancer surgery in the United States. The American Society of Breast Surgeons Oncoplastic Surgery Committee (ASBrS-OSC) conducted a survey to assess the scope of practice and level of interest in oncoplastic surgery among its members. Furthermore, the group sought to identify barriers to incorporating oncoplastic skills in a surgeon's practice. METHODS: A 10-question survey was administered in March 2017 to the entire ASBrS membership using an online format. Three solicitations were sent. Unique identifiers allowed a single response. RESULTS: Of the 2655 surveys sent out, 708 members responded. Nearly all (99%) respondents had at least some interest in oncoplastic surgery. The current rates of performing nipple-sparing mastectomy, adjacent tissue transfer, and breast reduction with lumpectomy were 80, 60, and 51%, respectively. A minority of respondents reported independently performing breast reductions/mammaplasties (19%) or contralateral symmetrization (10%). Barriers to learning oncoplastic surgery included surgeon's time and access to oncoplastic educational material/courses. Most respondents felt that training courses and videos may allow them to better incorporate oncoplastic techniques in their practices. CONCLUSIONS: The interest in oncoplastic surgery among U.S. surgeons is significant, yet there are barriers to incorporate these surgical techniques into a breast surgeon's practice. As professional organizations provide access to effective training and enduring educational resources, breast surgeons will be enabled to develop their oncoplastic skill set and safely offer these techniques to their patients. PMID- 30003451 TI - Development of Patient-Derived Gastric Cancer Organoids from Endoscopic Biopsies and Surgical Tissues. AB - BACKGROUND: Organoids are three-dimensional in vitro models of human disease developed from benign and malignant gastrointestinal tissues with tremendous potential for personalized medicine applications. We sought to determine whether gastric cancer patient-derived organoids (PDOs) could be safely established from endoscopic biopsies for rapid drug screening. METHODS: Patients underwent esophagogastroduodenoscopy (EGD) for surveillance or staging and had additional forceps biopsies taken for PDO creation. Cancer tissues from operative specimens were also used to create PDOs. To address potential tumor heterogeneity, we performed low-coverage whole-genome sequencing of endoscopic-derived PDOs with paired surgical PDOs and whole-tumor lysates. The stability of genomic alterations in endoscopic organoids was assessed by next-generation sequencing and nested polymerase chain reaction (PCR) assay. The feasibility and potential accuracy of drug sensitivity screening with endoscopic-derived PDOs were also evaluated. RESULTS: Gastric cancer PDOs (n = 15) were successfully established from EGD forceps biopsies (n = 8) and surgical tissues (n = 7) from five patients with gastric adenocarcinoma. Low-coverage whole-genomic profiling of paired EGD and surgical PDOs along with whole-tumor lysates demonstrated absence of tumor heterogeneity. Nested PCR assay identified similar KRAS alterations in primary tumor and paired organoids. Drug sensitivity testing of endoscopic-derived PDOs displayed standard dose-response curves to current gastric cancer cytotoxic therapies. CONCLUSIONS: Our study results demonstrate the feasibility of developing gastric cancer PDOs from EGD biopsies. These results also indicate that endoscopic-derived PDOs are accurate surrogates of the primary tumor and have the potential for drug sensitivity screening and personalized medicine applications. PMID- 30003452 TI - The Impact of Hospital Neoadjuvant Therapy Utilization on Survival Outcomes for Pancreatic Cancer. AB - BACKGROUND: Many surgeons advocate the use of neoadjuvant treatment for resectable pancreatic cancer, however little is known about variation in the utilization of neoadjuvant therapy (NAT) at the hospital level. METHODS: The National Cancer Data Base was used to identify patients undergoing resection for pancreatic cancer between 2006 and 2014 at high-volume centers. Hospitals were grouped by NAT utilization using standard deviations (SD) from the mean as follows: high neoadjuvant utilizers (> 2 SDs above the mean, > 40% of patients receiving NAT); medium-high (1-2 SDs, 27-40%), medium (0-1 SD, 14-26%); or low (- 1.1 to 0 SDs, < 14%). Overall survival (OS) was compared across NAT utilization groups. RESULTS: Among 107 high-volume centers, 20,119 patients underwent resection. The proportion of patients receiving NAT varied widely among hospitals, ranging from 0 to 74%, with only five centers using NAT in > 40% of patients. These five hospitals had the longest median OS at 28.9 months, compared with 21.1 months for low neoadjuvant utilizers (p < 0.001). On multivariable analysis, high and medium-high NAT utilization predicted improved OS, with a hazard ratio (HR) of 0.68 (95% confidence interval [CI] 0.56-0.83, p < 0.001) and 0.80 (95% CI 0.68-0.95, p = 0.010), respectively, compared with low utilizers. After excluding patients who underwent NAT, there remained an association of improved OS with high NAT utilization (HR 0.74, 95% CI 0.60-0.93, p = 0.009). CONCLUSION: High-volume hospitals that more commonly utilize NAT demonstrated longer survival for all patients treated at those centers. In addition to altering patient selection for surgery, high neoadjuvant utilization may be a marker of institutional factors that contribute to improved outcomes. PMID- 30003453 TI - The Complexity and Fractal Geometry of Nuclear Medicine Images. AB - Irregularity in shape and behavior is the main feature of every anatomical system, including human organs, tissues, cells, and sub-cellular entities. It has been shown that this property cannot be quantified by means of the classical Euclidean geometry, which is only able to describe regular geometrical objects. In contrast, fractal geometry has been widely applied in several scientific fields. This rapid growth has also produced substantial insights in the biomedical imaging. Consequently, particular attention has been given to the identification of pathognomonic patterns of "shape" in anatomical entities and their changes from natural to pathological states. Despite the advantages of fractal mathematics and several studies demonstrating its applicability to oncological research, many researchers and clinicians remain unaware of its potential. Therefore, this review aims to summarize the complexity and fractal geometry of nuclear medicine images. PMID- 30003454 TI - Sonographic early findings in a case of bladder schistosomiasis. AB - Urinary schistosomiasis is a tropical infection with a high endemicity in the developing countries and is included in the list of "Neglected Tropical Diseases". It is caused by a parasitic worm, Schistosoma haematobium, and it has come into the spotlight as a major cause of urogenital disease. Furthermore, it is linked to bladder cancer and it is a predisposing factor for HIV/AIDS. In this case, we describe a bladder schistosomal disease in a young African boy with persistent macroscopic hematuria and its ultrasound diagnostic bladder imaging. PMID- 30003455 TI - Identification of molecular features necessary for selective inhibition of B cell lymphoma proteins using machine learning techniques. AB - Selective inhibition of Bcl-2 and Bcl-xL proteins due to their dual inhibition toxicity plays an important role in treatment of cancer and chemotherapy effectiveness; therefore, in the last decade, discovery of selective inhibitors for Bcl-2 and Bcl-xL proteins has become a significant and important research topic. The present contribution paves the way for characterization of molecular features which induce selectivity for inhibition of Bcl-2 and Bcl-xL. In this line, a total of 1534 molecules related to inhibition of Bcl-2 and Bcl-xL proteins were collected from Binding Database. A diverse set of molecular descriptors was calculated for each molecule, and the best subset of descriptors were selected using variable importance in projection (VIP) approach. The molecules were classified according to their therapeutic targets (Bcl-2/Bcl-xL) and activities. Partial least square-discriminate analysis (PLS-DA) and supervised Kohonen network (SKN) models were utilized to relate the molecular structures of chemicals to their activities and selectivities. According to the VIP-selected descriptors physicochemical properties, such as polarity number, number of branches, size and cyclicity of the molecule, flexibility, functional counts and constitutional descriptors, all affect the activities of Bcl-2 and Bcl xL inhibitors. The performances of PLS-DA and SKN methods were evaluated based on statistical parameters derived from the confusion matrices. The models were validated using tenfold cross-validation and an external test set. The best statistical results were obtained by implementing the SKN model. The classification rates range from 93.5 to 79.1% for the training and validation procedure for the optimized SKN models. The high values of the obtained classification rates demonstrate that the information provided in this work would be useful to design new drugs with selective inhibitory activities toward Bcl-2 or Bcl-xL proteins for more effective treatment of cancer. PMID- 30003456 TI - A facile solvent-free three-component domino synthesis of novel 2,4-diaryl-5,6 dihydrobenzo[j][1,7]phenanthrolines. AB - A simple, efficient and green procedure for the synthesis of novel 2,4-diaryl-5,6 dihydrobenzo[j][1,7]phenanthrolines has been developed via a Krohnke-type one-pot three-component reaction of 2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones and (2-aryl-2-oxoethyl)pyridinium bromides in the presence of excess ammonium acetate in good yields under solvent-free conditions. Good functional group tolerance, high substrate scope and no column purification are the practical advantages of this methodology. PMID- 30003458 TI - Multiple treatment lines and prognosis in metastatic colorectal cancer patients. AB - The proportion of patients with metastatic colorectal cancer (mCRC) receiving second or further lines of treatment has not been widely studied. To shed light on this issue, we retrospectively analysed the treatments administered for metastatic disease, and investigated prognostic factors after a diagnosis of metastases, in a consecutive cohort of mCRC patients. Three hundred forty-six mCRC patients were enrolled: 173 were stage II or III (metachronous group), and 173 stage IV (synchronous group) at diagnosis. Survival was calculated between the date of metastatic disease and the date of death or last follow-up. Patients with synchronous lesions more frequently had multiple disease sites, peritoneal carcinomatosis and massive liver deposits, whereas significantly more patients with metachronous lesions developed lung metastases as the sole disease site. 97.4% patients received at least one, 62.4% two, 41.9% three and 23.7% four treatment lines. Patients with metachronous metastases more frequently underwent surgery of metastases in first-line treatment (48.5 versus 24.8%), and more of them were progression-free at the time of the analysis (44 versus 34.9%). At univariate analysis, age > 70 years, multiple disease sites and peritoneal carcinomatosis were associated with significantly decreased survival, whereas surgery of metastases and isolated lung metastases predicted better survival. At multivariate analysis, only peritoneal carcinomatosis and surgery of metastases independently affected survival. The percentage of patients who received an active treatment decreased going from first- to fourth-line treatment. However, the proportion of patients who received efficacious treatment in advanced line remained high. Surgery of metastases was the most important prognostic factors. PMID- 30003459 TI - Publicly Available Internet Content as a HIV/STI Prevention Intervention for Urban Youth. AB - Sexual and racial minority adolescents and young adults account for the most substantial number of new HIV infections in the United States. Numerous publicly available websites and YouTube videos contain HIV/STI prevention information that is culturally tailored to racial and ethnic minorities, and gay and bisexual youth. However, the effect of this easily accessible Internet content on adolescent and young adult HIV/STI related knowledge, attitudes and behaviors is unknown. We assembled a HIV/STI Internet intervention from publicly available online sources, including YouTube and privately and publicly hosted websites. We tested the preliminary efficacy of this internet intervention by means of a randomized controlled pilot study with 60 diverse adolescents and young adults recruited in Providence, RI (mean age 18.6 years, 62% male, 52% Black/African American, 36% Hispanic, 47% non-heterosexual). Youth who received links to publicly accessible online prevention content by email had a significant improvement in HIV self-efficacy (p < .05) and a significant reduction in unprotected vaginal or anal sex (12.5 vs. 47.6%, AOR = 7.77, p < .05), as compared to a control group who did not receive the internet content by email. If these preliminary findings can be confirmed by future research, free online content could be inexpensively distributed to at risk youth in underserved communities and could hold promise as an inexpensive method of HIV/STI prevention. PMID- 30003461 TI - Pain exposure physical therapy in complex regional pain syndrome: promising enough to warrant further investigation. PMID- 30003460 TI - The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy: a systematic review. AB - PURPOSE: Electroanatomic mapping (EAM) has been utilized as a modality to improve the sensitivity of endomyocardial biopsy (EMB). We sought to systematically review published medical literature on the efficacy and safety of EAM-guided EMB. METHODS: We searched Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central, Scopus, and Web of Science for studies where EAM was used for EMB. Data abstracted included demographics, indications, final diagnoses, histology findings, and technical details of biopsy extraction. Test characteristics including sensitivity (Se), specificity (Sp), and area under curve (AUC) were calculated on a per-patient and per-biopsy level. RESULTS: Seventeen studies (9 case series, 8 case reports) were included in this systematic review. EAM-guided EMB was performed in 148 patients and results of 207 individual biopsies were available for analysis. The most common indications for EAM-guided EMB were suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), myocarditis, and cardiac sarcoidosis (CS). The pooled sensitivity and specificity for EAM guided EMB for the diagnosis of cardiomyopathies (ARVC, myocarditis, CS, and other specific diagnoses) were 92 and 58% on per-biopsy analysis and 100 and 39% on per-patient analysis. Among the individual components of abnormal EGMs, abnormal unipolar EGM had the best AUC on per-biopsy (0.81, 95% CI 0.68-0.90) and per-patient analysis (0.84, 95% CI 0.68-0.92). EAM-guided EMB appears safe. Adverse events included 1 hemopericardium, 2 minimal asymptomatic pericardial effusions, and 1 femoral hematoma. CONCLUSIONS: EAM-guided EMB is a safe and efficacious method and might improve test characteristics over conventional fluoroscopy-guided biopsy. PMID- 30003462 TI - In reply: Pain exposure physical therapy in complex regional pain syndrome: promising enough to warrant further investigation. PMID- 30003463 TI - Diagnostic performance of CT for pediatric patients with suspected appendicitis in various clinical settings: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the diagnostic performance of CT for pediatric patients with suspected appendicitis in various clinical settings and the proportion of acute appendicitis on final diagnosis among equivocal CT findings. METHODS: MEDLINE and EMBASE databases were searched until October 21, 2017, for studies investigating diagnostic performance of CT for acute appendicitis in pediatric patients confirmed by histopathologic findings and/or clinical follow-up. Pooled estimates of sensitivity and specificity were calculated using a hierarchical logistic regression modeling. The proportion of true appendicitis among patients with inconclusive CT results was obtained using fixed and random effects meta analyses. RESULTS: Twenty-two articles with 3396 patients were included. The pooled sensitivity and specificity were 95% (95% CI, 93-97%) and 94% (95% CI, 90 96%), respectively, and the area under the hierarchical summary receiver operating characteristic (HSROC) curve was 0.98 (95% CI, 0.96-0.99). Subgroup analyses revealed a comparable diagnostic performance in the low-dose CT group (sensitivity, 97%; specificity, 96%) and the unenhanced group (sensitivity, 95%; specificity, 95%). Other subgroups (publication year, study design, enrolled population, true appendicitis proportion, CT channel number, and slice thickness) also showed good diagnostic performance. Six studies reporting the true appendicitis proportion among patients with equivocal CT findings had pooled proportion of 17% (95% CI, 9-29%). CONCLUSIONS: CT showed good performance for suspected appendicitis in pediatric patients under various clinical settings, including in cases with dose reduction or absence of IV contrast. The prevalence of true appendicitis among patients with equivocal appendicitis results on CTs was not low; therefore, clinical attention should not be disregarded in this population. PMID- 30003465 TI - Terminalia bellirica (Gaertn.) Roxb fruit exerts anti-inflammatory effect via regulating arachidonic acid pathway and pro-inflammatory cytokines in lipopolysaccharide-induced RAW 264.7 macrophages. AB - Terminalia bellirica (Gaertn.) Roxb. (Family: Combretaceae), known as Bhibhitaki in Sanskrit and locally known as Behera in India, has been used for centuries in Ayurveda, a universal system of medicine in India. The dried fruit of T. bellirica is used for the treatment of several disorders. The present study aims to explore the anti-inflammatory effects of aqueous acetone extracts isolated from T. bellirica (AATB) in RAW 264.7 cell lines. The AATB was prepared from the fruits of T. bellirica. Different concentrations of AATB (6.25-100 MUg/ml) were used for MTT assay. The anti-inflammatory effect of AATB was evaluated by using different assays such as total cyclooxygenase (COX), 5-lipoxygenase (5-LOX) activity, nitrate and reactive oxygen species (ROS) production. The mRNA level expression of COX-2, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were studied in LPS stimulated RAW 264.7 cells. AATB treatment significantly diminished the elevated levels of inflammatory markers. Moreover, AATB downregulated the mRNA level expression of TNF-alpha, IL-6 and COX-2 genes. The result of our study suggest the use of AATB and is able to reduce inflammatory conditions associated with various diseases. PMID- 30003464 TI - Molecular characterization of bmyC gene of the mosquito pupicidal bacteria, Bacillus amyloliquefaciens (VCRC B483) and in silico analysis of bacillomycin D synthetase C protein. AB - A strain of Bacillus amyloliquefaciens (VCRC B483) exhibiting mosquito pupicidal, keratinase and antimicrobial activities was isolated from mangrove forest ecosystem of Andaman and Nicobar Islands. Molecular characterization of the strain showed the presence of lipopeptide encoding bmyC gene. Phylogenetic tree based on protein sequence of this gene exhibited homology with mycosubtilin synthetase of Bacilus atropheus and Iturin synthetase of Bacillus subtilis and B. amyloliquefaciens. This is the first report on the evolutionary conservation of amino acids concerned with the function and structure of bmyC protein of B. amyloliquefaciens. The presence of valine at the 1197th position in our strain was found to be unique and different from the existing strains of B. subtilis and B. amyloliquefaciens. Molecular modelling studies revealed significant changes in the structure of epimerization domain of the bmyC protein with A1197V variation. Crude metabolite of this strain exhibited antifungal activity against Fusarium sp. and Carvularia sp. PMID- 30003467 TI - Correction to: Nonacog Beta Pegol: A Review in Haemophilia B. AB - The article Nonacog Beta Pegol: A Review in Haemophilia B, written by Yahiya Y. Syed, was originally published Online First without open access. After publication in volume 77, issue 18, pages 2003-2012 Novo Nordisk A/S requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Novo Nordisk A/S. The article is forthwith distributed under the terms of the Creative Commons Attribution NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. PMID- 30003466 TI - Assessment of the Risk of Rhabdomyolysis and Myopathy During Concomitant Treatment with Ticagrelor and Statins. AB - The introduction of ticagrelor, one of the first directly-acting oral antiplatelet drugs, provided new possibilities in the prevention of thrombotic events in patients with acute coronary syndromes (ACS). Current guidelines recommend ticagrelor in dual antiplatelet therapy with aspirin over clopidogrel for prevention of stent thrombosis in patients with ACS. Moreover, in the management of ACS, lipid-lowering treatment with high-intensity statin therapy is advised for secondary prevention of cardiovascular events over the long term. Despite the apparent advantages of combined antiplatelet and lipid-lowering treatments, a possible interaction between statins and ticagrelor may lead to myopathy and rhabdomyolysis. In this review, relevant information was gathered on the ticagrelor-statin interaction that might lead to this life-threatening condition. This review focuses on the most widely used statins-simvastatin, atorvastatin, and rosuvastatin. Possible mechanisms of this interaction are discussed, including CYP3A4 isoenzymes, organic anion transporter polypeptide (OATPs), P-glycoprotein and glucuronidation. PubMed database was searched for relevant case reports and all data gathered from the introduction of ticagrelor to March 2018 are presented and discussed. In summary, co-administration of statins and ticagrelor was found to be relatively safe in routinely prescribed doses. However, caution should be exercised, especially in elder populations. PMID- 30003469 TI - Rare case of a gallbladder neuroendocrine carcinoma. AB - There are no neuroectodermal cells in the gallbladder mucosa. Therefore, gallbladder neuroendocrine carcinoma (NEC) is extremely rare and has a poor prognosis. We report a case of a Japanese man in his 60s with this disease. The patient visited a family doctor for epigastralgia. Blood tests showed no abnormalities, including tumor markers, such as CEA and CA19-9. Abdominal ultrasonography (US) showed a low-echoic mass, 39 * 30 mm, with clear boundaries to the liver from the fundus of the gallbladder. Contrast-enhanced computed tomography showed that the tumor was enhanced early and washed out. Diffusion weighted MRI showed a high signal. We suspected liver invasion of gallbladder cancer and performed a cholecystectomy, S4 and S5 hepatectomy, and lymphadenectomy. The resected whitish tumor was 29 * 22 mm. The tumor cells had honeycomb growth to the liver from the gallbladder. Tumor cells were poorly differentiated, and there was no stricture of the gland duct. Immunostaining showed that the tumor cells were positive for CD56, chromogranin A and synaptophysin, and about 30% were positive for Ki-67. Our diagnosis was gallbladder NEC with liver invasion. Although most malignant gallbladder tumors are adenocarcinomas, this case indicates that gallbladder NEC should be considered as a differential diagnosis of gallbladder tumor. PMID- 30003468 TI - Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking. AB - Modulating protein interaction pathways may lead to the cure of many diseases. Known protein-protein inhibitors bind to large pockets on the protein-protein interface. Such large pockets are detected also in the protein-protein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation. The conformational change on the protein interface upon binding to the other protein results in a pocket employed by the ligand when it binds to that interface. This proof-of-concept study suggests that rather than using computational pocket-opening procedures, one can opt for an experimentally determined structure of the target co-crystallized protein-protein complex as a starting point for drug design. PMID- 30003470 TI - Constitutive expression of antimicrobial peptide PR-39 in transgenic mice significantly enhances resistance to bacterial infection and promotes growth. AB - Use of huge amounts of antibiotics in farm animal production has promoted the prevalence of antibiotic-resistant bacteria, which poses a serious threat to public health. Therefore, alternative approaches are needed to reduce or replace antibiotic usage in the food animal industry. PR-39 is a pig-derived proline-rich antimicrobial peptide that has a broad spectrum of antibacterial activity and a low propensity for development of resistance by microorganisms. To test whether ubiquitous expression of PR-39 in transgenic (TG) mice can increase resistance against bacterial infection, we generated TG mice that ubiquitously express a pig derived antimicrobial peptide PR-39 and analyzed their growth and resistance to infection of the highly pathogenic Actinobacillus pleuropneumoniae (APP) isolated from swine. The growth performance was significantly increased in TG mice compared with their wild-type (WT) littermates. After the APP challenge, TG mice exhibited a significantly higher survival rate and significantly lower tissue bacterial load than WT littermates. Furthermore, the tissue lesion severity that resulted from APP infection was milder in TG mice than that in their WT littermates. This study provides a good foundation for the development of PR-39 expressing TG animals, which could reduce the use of antibiotics in the farm animal industry. PMID- 30003473 TI - Half Sandwich Rhodium(III) and Iridium(III) Complexes as Cytotoxic and Metallonuclease Agents. AB - Half sandwich complexes of the type [(eta5-C5Me5)M(L1-3)Cl]Cl.2H2O were synthesized using [{(eta5-C5Me5)M(MU-Cl)Cl}2], where M = Rh(III)/Ir(III) and L1-3 = pyrimidine-based ligands. The complexes were characterized by spectral analysis. DNA interaction studies by absorption titration and hydrodynamic measurement and suggest intercalative mode of binding of complexes with CT-DNA. The molecular docking study also supports intercalation of the complexes between the stacks of nucleotide base pairs. The gel electrophoresis assay demonstrated the ability of the complexes to interact and cleave plasmid DNA. Minimum inhibitory concentrations (MIC) of the complexes were investigated by the microdilution broth method. The cytotoxic properties of the metal complexes were evaluated using brine shrimp lethality bioassay. PMID- 30003472 TI - Amino Acid Supplementations Enhance the Stress Resistance and Fermentation Performance of Lager Yeast During High Gravity Fermentation. AB - The effects of different wort gravity or ethanol concentration in initial wort on the fermentation performance of lager yeast and assimilation of free amino acids (FAAs) were studied. Results showed that compared with high wort gravity (24 degrees P), high ethanol concentration (10%, v/v) decreased yeast growth, cell viability, and wort fermentability significantly. The assimilation of FAAs was changed dramatically by high ethanol toxicity, and positive correlations between the assimilation amounts of 10 FAAs (Asp, Ser, Gly, Arg, Tyr, Val, Met, Lys, Ile, and Leu) and fermentation performance (cell viability, fermentability, and ethanol production) were identified, especially for Arg and Lys exhibiting extremely significant positive correlations. Furthermore, confirmatory testing was carried out by supplementing 24 degrees P worts with 10 FAAs of 0.5, 1, and 2 times of their standard concentrations, respectively. Results exhibited that 10 FAA supplementations improved physiological characteristics and fermentation performance of lager yeast significantly, especially for 1 times FAA supplementation increasing wort fermentability and ethanol yield by 6 and 17%, respectively, and upregulated the expression level of HSP12 and increased more intracellular trehalose accumulation in yeast cells, indicating that stronger protective function was stimulated in yeast cells. Therefore, it was suggested that these 10 FAAs could regulate yeast cells to adapt to high gravity environmental stresses. PMID- 30003471 TI - Heparan sulfate S-domains and extracellular sulfatases (Sulfs): their possible roles in protein aggregation diseases. AB - Highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, consist of repeated trisulfated disaccharide units [iduronic acid (2S) glucosamine (NS, 6S)-]. The expression of HS S-domains at the cell surface is determined by two mechanisms: tightly regulated biosynthetic machinery and enzymatic remodeling by extracellular endoglucosamine 6-sulfatases, Sulf-1 and Sulf-2. Intracellular or extracellular deposits of misfolded and aggregated proteins are characteristic of protein aggregation diseases. Although proteins can aggregate alone, deposits of protein aggregates in vivo contain a number of proteinaceous and non-protein components. HS S-domains are one non-protein component of these aggregated deposits. HS S-domains are considered to be critical for signal transduction of several growth factors and several disease conditions, such as tumor progression, but their roles in protein aggregation diseases are not yet fully understood. This review summarizes the current understanding of the possible roles of HS S-domains and Sulfs in the formation and cytotoxicity of protein aggregates. PMID- 30003474 TI - Lack of Diagnosis of Pneumoperitoneum in Perforated Duodenal Ulcer After RYGB: a Short Case Series and Review of the Literature. AB - Perforated duodenal ulcer following RYGB is an unusual clinical situation that may be a diagnostic challenge. Only 23 cases have previously been reported. We present five cases. The hallmark of visceral perforation, namely pneumoperitoneum, was not seen in three of the four cases that underwent cross sectional imaging. This is perhaps due to the altered anatomy of the RYGB that excludes air from the duodenum. Our cases had more free fluid than expected. The bariatric surgeon should not wait for free intraperitoneal air to suspect duodenal perforation after RYGB. PMID- 30003475 TI - [A career in elderly care medicine; an option for today's medical student? : Medical students' interest in elderly care medicine]. AB - BACKGROUND: Due to the rise of older patients with multi-morbidity, we need more elderly care physicians. However, not all available training slots for the elderly care medicine specialty have been fully utilized in recent years. To assess medical student interest in this specialty as well as potential causes for this interest we explored the interest of medical students in the profession of elderly care physician, as well their perception of this profession, both in the 'old curriculum' and in a 'new curriculum', where the new curriculum had a mandatory elderly care medicine clerkship and more competency-related learning. METHOD: At VUmc 120 final year medical students were asked to complete a questionnaire in 2014 about professional preferences and professional characteristics. The same questionnaire had been presented five years earlier, in 2009, to 150 medical students at the end of their final year. RESULTS: The response rates were 100% and 85% respectively. Of the students in the new curriculum 16,7% considered a career in elderly care medicine. This percentage was 9,4% for students in the old curriculum (p = 0,087). The characteristics of the profession that appealed most to the students, but were not considered applicable to elderly care medicine were: diagnostics skills, acute complaints, visible results. The professional characteristics that students found to be very much applicable to this specialty, but less attractive for their future profession were: psychosocial, chronic and terminal conditions. DISCUSSION: We observe a trend that students in the new curriculum are more interested in the profession of elderly care physician, even though this interest remains limited. We recommend that the basic medical training, both in the bachelor phase and in a mandatory elderly care medicine clerkship, focus more on demonstrating that the characteristics students find appealing in the medical profession are indeed present in this speciality. Also, the basic training should concentrate more on guidance and treatment of patients with chronic and terminal conditions. PMID- 30003476 TI - Interventions to Promote Healthy Eating, Physical Activity and Smoking in Low Income Groups: a Systematic Review with Meta-Analysis of Behavior Change Techniques and Delivery/Context. AB - PURPOSE: Healthy eating, physical activity and smoking interventions for low income groups may have small, positive effects. Identifying effective intervention components could guide intervention development. This study investigated which content and delivery components of interventions were associated with increased healthy behavior in randomised controlled trials (RCTs) for low-income adults. METHOD: Data from a review showing intervention effects in 35 RCTs containing 45 interventions with 17,000 participants were analysed to assess associations with behavior change techniques (BCTs) and delivery/context components from the template for intervention description and replication (TIDieR) checklist. The associations of 46 BCTs and 14 delivery/context components with behavior change (measures of healthy eating, physical activity and smoking cessation) were examined using random effects subgroup meta-analyses. Synergistic effects of components were examined using classification and regression trees (meta-CART) analyses based on both fixed and random effects assumptions. RESULTS: For healthy eating, self-monitoring, delivery through personal contact, and targeting multiple behaviors were associated with increased effectiveness. Providing feedback, information about emotional consequences, or using prompts and cues were associated with reduced effectiveness. In synergistic analyses, interventions were most effective without feedback, or with self monitoring excluding feedback. More effective physical activity interventions included behavioral practice/rehearsal or instruction, focussed solely on physical activity or took place in home/community settings. Information about antecedents was associated with reduced effectiveness. In synergistic analyses, interventions were most effective in home/community settings with instruction. No associations were identified for smoking. CONCLUSION: This study identified BCTs and delivery/context components, individually and synergistically, linked to increased and reduced effectiveness of healthy eating and physical activity interventions. The identified components should be subject to further experimental study to help inform the development effective behavior change interventions for low-income groups to reduce health inequalities. PMID- 30003478 TI - Capsule Commentary on Christian et al.'s "Measuring the Health of an Invisible Population: Lessons from the Colorado Transgender Health Survey". PMID- 30003477 TI - Testing an Online, Theory-Based Intervention to Reduce Pre-drinking Alcohol Consumption and Alcohol-Related Harm in Undergraduates: a Randomized Controlled Trial. AB - PURPOSE: The present study tested the efficacy of a theory-based online intervention comprising motivational (autonomy support) and volitional (implementation intention) components to reduce pre-drinking alcohol consumption and alcohol-related harm. METHOD: Undergraduate students (N = 202) completed self report measures of constructs from psychological theories, pre-drinking alcohol consumption, and alcohol-related harm at baseline and were randomly assigned to one of four intervention conditions in a 2 (autonomy support: present/absent) * 2 (implementation intention: present/absent) design. Participants completed follow up measures of all variables at 4 weeks post-intervention. All participants received national guidelines on alcohol consumption and an e-mail summary of intervention content at its conclusion. Participants also received weekly SMS messages in the 4-week post-intervention period restating content relevant to their intervention condition. RESULTS: Neither statistically significant main effect for either the autonomy support or implementation intention intervention components nor an interaction effect was found on the outcome measures. However, statistically significant reductions in pre-drinking alcohol consumption and alcohol-related harm were observed across all groups at follow-up, when compared to baseline. CONCLUSION: Reductions in outcome measures were likely related to elements common to each condition (i.e., provision of national guidelines, assessment of outcome measures, e-mail summary, and SMS messages), rather than motivational and volitional components. PMID- 30003479 TI - Post-intervention Durability of Alcohol Care Management: 1-Year Follow-up of a Randomized Controlled Trial. PMID- 30003480 TI - A Summary Report from the Research Partnership on Women in Science Careers. AB - BACKGROUND: In response to the landmark report "Beyond Bias and Barriers: Fulfilling the Potential of Women in Academic Science and Engineering," the NIH Office of Research on Women's Health issued a request for applications that funded 14 R01 grants to investigate causal factors to career success for women in STEM. Following completion of the 4-year grants, the grant PIs formed a grassroots collaborative, the Research Partnership on Women in Science Careers. OBJECTIVE: To summarize the work of the Research Partnership, which resulted in over 100 publications. METHODS: We developed six themes to organize the publications, with a "Best Practices" for each theme at the end of each section: Barriers to Career Advancement; Mentoring, Coaching, and Sponsorship; Career Flexibility and Work-Life Balance; Pathways to Leadership; Compensation Equity; and Advocating for Change and Stakeholder Engagement. RESULTS: Women still contend with sexual harassment, stereotype threat, a disproportionate burden of family responsibilities, a lack of parity in compensation and resource allocation, and implicit bias. Strategies to address these barriers using the Bronfenbrenner ecological model at the individual, interpersonal, institutional, academic community, and policy levels include effective mentoring and coaching, having a strong publication record, addressing prescriptive gender norms, positive counter-stereotype imaging, career development training, networking, and external career programs such as the AAMC Early and Mid-Career Programs and Executive Leadership in Academic Medicine (ELAM). CONCLUSIONS: Cultural transformation is needed to address the barriers to career advancement for women. Implementing the best practices noted of the work of the Research Partnership can help to achieve this goal. PMID- 30003481 TI - Social Incentives and Gamification to Promote Weight Loss: The LOSE IT Randomized, Controlled Trial. AB - BACKGROUND: Social networks influence obesity patterns, but interventions to leverage social incentives to promote weight loss have not been well evaluated. OBJECTIVE: To test the effectiveness of gamification interventions designed using insights from behavioral economics to enhance social incentives to promote weight loss. DESIGN: The Leveraging Our Social Experiences and Incentives Trial (LOSE IT) was a 36-week randomized, controlled trial with a 24-week intervention and 12 week follow-up. PARTICIPANTS: One hundred and ninety-six obese adults (body mass index >= 30) comprising 98 two-person teams. INTERVENTIONS: All participants received a wireless weight scale, used smartphones to track daily step counts, formed two-person teams with a family member or friend, and selected a weight loss goal. Teams were randomly assigned to control or one of two gamification interventions for 36 weeks that used points and levels to enhance collaborative social incentives. One of the gamification arms also had weight and step data shared regularly with each participant's primary care physician (PCP). MAIN OUTCOME MEASURES: The primary outcome was weight loss at 24 weeks. Secondary outcomes included weight loss at 36 weeks. KEY RESULTS: At 24 weeks, participants lost significant weight from baseline in the control arm (mean: - 3.9 lbs; 95% CI: - 6.1 to - 1.7; P < 0.001), the gamification arm (mean: - 6.6 lbs; 95% CI: - 9.4 to - 3.9; P < 0.001), and the gamification arm with PCP data sharing (mean: - 4.8 lbs; 95% CI: - 7.4 to - 2.3; P < 0.001). At 36 weeks, weight loss from baseline remained significant in the control arm (mean: - 3.5 lbs; 95% CI: - 6.1 to - 0.8; P = 0.01), the gamification arm (mean: - 6.3 lbs; 95% CI: - 9.2 to - 3.3; P < 0.001), and the gamification arm with PCP data sharing (mean: - 5.2 lbs; 95% CI: - 8.5 to - 2.0; P < 0.01). However, in the main adjusted model, there were no significant differences in weight loss between each of the intervention arms and control at either 12, 24, or 36 weeks. CONCLUSIONS: Using digital health devices to track behavior with a partner led to significant weight loss through 36 weeks, but the gamification interventions were not effective at promoting weight loss when compared to control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: 02564445. PMID- 30003483 TI - Design of natural elements in open spaces of cities with a Mediterranean climate, conditions for comfort and urban ecology. AB - More than half the world's population lives in cities that were designed with a complete disregard for nature. Then, it is vital that nature should be present in these spaces to provide ecological support for urban areas. Natural elements that are in these spaces should be designed with people's comfort in mind. This research explores the application of the PET and UTCI biometeorological comfort indices in urban microspaces, where the general environmental parameters of the city are not valid and each space must be measured individually. The research looked into the influence of the design of natural elements on improving comfort. The results show that in the children's playing spaces, the absence of thermal comfort and considerable thermal stress were detected in summer. This effect is more easily seen in the PET values. The benefits to comfort of having double layers of vegetation in the gardens have also been shown. The micro-droplets of water from the jets in the fountains are carried by the breeze and modify the human-biometeorological conditions around the fountains and reduce thermal stress. This improvement needs an appropriate design of the fountains and an awareness of the breeze patterns in these spaces. PMID- 30003482 TI - Exogenous silicon alters ascorbate-glutathione cycle in two salt-stressed indica rice cultivars (MTU 1010 and Nonabokra). AB - Silicon is widely available in soil and is known to mitigate both biotic and abiotic stress in plants. Very low doses of silicon are becoming increasingly essential in rice for biofortification and preventing water loss. Soil salinity is a matter of grave concern in various parts of the world, and silicon is a suitable candidate to mitigate salinity-induced stress of important plants in affected areas. The present study investigates the protective capability of exogenously applied silicon in ameliorating NaCl-induced toxicity in two rice (Oryza sativa L.) cultivars, the salt-sensitive MTU 1010, and salt-tolerant Nonabokra. Rice seedlings were treated with three doses of NaCl (25, 50, and 100 mM), initially alone and subsequently in combination with 2 mM sodium silicate (Na2SiO3, 9H2O). After 21 days, these plants were examined to determine levels of reduced glutathione, ascorbic acid, cysteine, and activities of different enzymes involved in the ascorbate-glutathione cycle, viz., glutathione reductase (GR), ascorbate peroxidase (APX), glutathione peroxidase (GPx), and glutathione S transferase (GST). Though ROS levels increased in both the cultivars with increasing NaCl concentrations, cv. MTU 1010 accumulated comparatively higher amounts. A differential response of NaCl-induced toxicity on the two cultivars was observed with respect to the various enzymatic and non-enzymatic antioxidants. APX and GST activities, as well as, cysteine contents, increased concomitantly with salt concentrations, whereas GR activity declined at increasing salt concentrations, in both cultivars. Activity of GPx increased in cv. Nonabokra but declined in cv. MTU 1010, under similar NaCl concentrations. Reduced glutathione (GSH) contents decreased in both cultivars, whereas ascorbate contents declined in only the sensitive cultivar. Application of silicon, along with NaCl, in the test seedlings of both the cultivars, reduced ROS accumulation and boosted antioxidant defense mechanism, through enhancing ascorbate and GSH levels, and activities of ascorbate-glutathione cycle enzymes as well. However, amelioration of salt-induced damages in the sensitive cv. MTU 1010 was more pronounced upon silicon administration, than the tolerant cv. Nonabokra. Thus, cv. MTU 1010 was found to be more responsive to applied silicon. Hence, this study was instrumental in realizing a successful strategy in silicon-mediated amelioration of salinity stress in plants. PMID- 30003484 TI - Origins and discrimination between local and regional atmospheric pollution in Haiphong (Vietnam), based on metal(loid) concentrations and lead isotopic ratios in PM10. AB - Southeast Asia is a hotspot of anthropogenic emissions where episodes of recurrent and prolonged atmospheric pollution can lead to the formation of large haze events, giving rise to wide plumes which spread over adjacent oceans and neighbouring countries. Trace metal concentrations and Pb isotopic ratios in atmospheric particulate matter < 10 MUm (PM10) were used to track the origins and the transport pathways of atmospheric pollutants. This approach was used for fortnightly PM10 collections over a complete annual cycle in Haiphong, northern Vietnam. Distinct seasonal patterns were observed for the trace metal concentration in PM10, with a maximum during the Northeast (NE) monsoon and a minimum during the Southeast (SE) monsoon. Some elements (As, Cd, Mn) were found in excess according to the World Health Organization guidelines. Coal combustion was highlighted with enrichment factors of As, Cd, Se, and Sb, but these inputs were outdistanced by other anthropogenic activities. V/Ni and Cu/Sb ratios were found to be markers of oil combustion, while Pb/Cd and Zn/Pb ratios were found to be markers of industrial activities. Pb isotopic composition in PM10 revealed an important contribution of soil dusts (45-60%). In PM10, the Pb fraction due to oil combustion was correlated with dominant airflow pathways (31% during the north-easterlies and 20% during the south-easterlies), and the Pb fraction resulting from industrial emissions was stable (around 28%) throughout the year. During the SE monsoon, Pb inputs were mainly attributed to resuspension of local soil dusts (about 90%), and during the NE monsoon, the increase of Pb inPM10 was due to the mixing of local and regional inputs. PMID- 30003486 TI - Impact of ozonation and biologically enhanced activated carbon filtration on the composition of micropollutants in drinking water. AB - A pilot-scale drinking water treatment process for Songhua River, including conventional treatment (coagulation-settlement and rapid sand filtration), ozonation, biological enhanced activated carbon (BEAC) filtration, and chlorination disinfection, was carried out in this study. To investigate the impact of ozonation and BEAC filtration on removing the composition of micropollutants in drinking water, we detected the micropollutant composition from each stage of the treatment process by non-targeted analysis using a GC-MS technique and compared the results between effluents of single BEAC and O3-BEAC processes. Aromatic compounds and esters could be abated efficiently during single BEAC filtration via biodegradation and adsorption; however, possible metabolic products (i.e., alkenes) were formed by biodegradation. Comparatively, O3-BEAC process could reduce micropollutants much more significantly than single BEAC process especially for aromatic compounds including substituted benzenes and polycyclic aromatic hydrocarbons (PAHs) without the formation of metabolic products through the coupling effect of oxidation, biodegradation, and adsorption, suggesting that ozonation improved the removal potential of micropollutants in the BEAC process. In addition, conventional and novel chlorinated disinfection by-products were also measured during post-chlorination. PMID- 30003485 TI - Soil sustainable utilization technology: mechanism of flavonols in resistance process of heavy metal. AB - The soil ecosystem is critical for agricultural production, affecting many aspects of human health. Soil has more unknown biodiversity and edaphic parameters than any other ecosystem especially when polluted. Metagenomics and metatranscriptomics were applied to research on toxicological characteristics of Pb and resistance mechanism of flavonols. Rhizosphere microorganisms-plants system, a unified system closely related to soil environment was taken as research object. Results emphasize gene expression changes in different test groups. Gene ontology enrichment and eggNOG showed that Pb has a toxic effect on gene and protein function which concentrated on ATPase and ATP-dependent activity. Differentially expressed genes in the flavonols group indicated that flavonols regulate amino acid transport and other transportation process related to Pb stress. Kegg analysis represents that Pb interferences energy production process via not only the upstream like glycolysis and tricarboxylic acid (TCA) circle but also oxidative phosphorylation process, which can also produce reactive oxygen species and impact the eliminating process. Flavonols have shown the ability in alleviating toxic effect of Pb and improving the resistance of plants. Flavonols can recover the electronic transmission and other process in TCA and oxidative phosphorylation via ascorbic acid-glutathione metabolism. Flavonols activated antioxidative process and non-specific immunity via vitamins B2-B6 metabolism. PMID- 30003488 TI - Cyanobacteria and microcystins in Koka reservoir (Ethiopia). AB - The composition and abundance of cyanobacteria and their toxins, microcystins (MCs), and cylindrospermopsins (CYN) were investigated using samples collected at monthly intervals from the Amudde side of Koka Reservoir from May 2013 to April 2014. Cyanobacteria were the most abundant and persistent phytoplankton taxa with Microcystis and Cylindrospermopsis species alternately dominating the phytoplankton community of the reservoir and accounting for up to 84.3 and 11.9% of total cyanobacterial abundance, respectively. Analyses of cyanotoxins in filtered samples by HPLC-DAD and LC-MS/MS identified and quantified five variants of MCs (MC-LR, MC-YR, MC-RR, MC-dmLR, and MC-LA) in all samples, with their total concentrations ranging from 1.86 to 28.3 MUg L-1 and from 1.71 to 33 MUg L-1, respectively. Despite the presence and occasional abundance of Cylindrospermopsis sp., cylindrospermopsin was not detected. Redundancy analysis (RDA) showed that the environmental variables explained 82.7% of the total variance in cyanobacterial abundance and microcystin concentration. The presence of considerably high levels of MCs almost throughout the year represents a serious threat to public health and life of domestic and wild animals. PMID- 30003489 TI - Heavy metal contamination in "chemicalized' green revolution banana fields in southern India. AB - The present report is a general assessment of the level of nutrient and toxic heavy metals as an impact of "chemicalized" cultivation practices for decades in banana fields in the three south Indian states, Kerala, Karnataka, and Tamilnadu. The major objective was to critically analyze the status of metallic content in green revolution fields, where chemical fertilizers or plant protective chemicals remain the major source of heavy metal contaminants. Since soil series being a soil taxonomic category that includes slightly variant soils of similar origin and common parent materials, the 286 field samples of the broad south Indian region were further grouped into composite samples representing 47 different soil series for limiting the sample analysis. The quantitative assessment of ten metals done in these soils using the Atomic Absorption Spectrophotometer included Ca, Mg, Mn, Zn, Fe, Cu, Pb, Ni, Cr, and Co. The amount of Cu observed in many fields was higher than all the previous reports of the same in the "chemicalized" fields. Similarly, the amount of Co observed in 25 fields was above its threshold levels expected for normal soils. The amount of Pb observed in all the soils appeared quite normal. The amount of Ni observed in 14 soil series was higher than its threshold levels for normal soils, except in 4 soil series, where its amount exceeded the upper limit of contamination. Cr was detected in all the samples, but found higher than its threshold level in 31 soil series. Significant positive correlations were observed between the amounts of different metals in the study. PCA results indicated that variables were correlated to four principal components, and 74.36% of the total variance was justified. PMID- 30003487 TI - Vitamin E alleviates phoxim-induced toxic effects on intestinal oxidative stress, barrier function, and morphological changes in rats. AB - Phoxim is an organic phosphorus pesticide that remains easily in the environment, such as human food and animal feed. The objective of this study was to explore the effect of vitamin E on phoxim-induced oxidative stress in the intestinal tissues of Sprague-Dawley (SD) rats. Forty-eight Sprague-Dawley rats were randomly assigned to a control group and three treatment groups: treatment group 1 (phoxim: 20 mg/kg.BW), treatment group 2 (phoxim: 180 mg/kg.BW), and treatment 3 (vitamin E + phoxim: 200 mg/kg.BW + 180 mg/kg.BW). Phoxim was given by gavage administration once a day for 28 days. The results showed that phoxim significantly reduced jejunum villus height in rats (P < 0.05), and decreased the mRNA expression of junction protein genes of rats, including Occlidin and Claudin 4 (P < 0.05). Phoxim reduced GSH content and T-AOC level in the intestinal mucosa (P < 0.05). The mRNA expression levels of oxidative stress-related genes (Nrf2 and GPx2) were decreased. The mRNA expression of SOD was significantly increased. In addition, phoxim increased the level of interleukin-6 (IL-6) in jejunum mucosa and significantly reduced the level of IL-8 in ileum mucosas, while significantly increased TNF-alpha secretion. The mRNA expression levels of IL-1beta, IL-6, and IL-8 were significantly decreased, and mRNA expression of TNF-alpha was significantly increased (P < 0.05). Phoxim also increased the DNA expression of total cecal bacteria and Escherichia coli, inhibited the DNA expression of Lactobacillus and destroyed the intestinal barrier. Two hundred milligrams per kilogram BW vitamin E reduced the effect of phoxim on intestinal structure, alleviated the oxidative stress in intestinal tissue, and decreased the level of TNF-alpha. The mRNA expressions of antioxidative stress genes (SOD and GPx2) were significantly increased. The DNA expression level of Lactobacillus was significantly increased. In conclusion, vitamin E helped reduce the toxicity of organophosphate pesticides, such as phoxim on rat intestinal tissue. PMID- 30003490 TI - Native vertebral osteomyelitis in aged patients: distinctive features. An observational cohort study. AB - PURPOSE: To describe the demographic, clinical, and microbiological profile of native vertebral osteomyelitis (NVO) in aged patients as compared to that of younger patients, to identify differences that could motivate changes in clinical management. METHODS: Retrospective, observational cohort study (1990-2015) including all adult patients with microbiologically confirmed NVO divided into 2 groups: aged (>= 65 years) vs younger (18-64 years). RESULTS: 247 patients included, 138 aged and 109 younger. Relative to younger patients, the aged had higher rates of healthcare-related infection (40.6 vs 25.7%, p = 0.014), previous known heart valve disease (29.7 vs 9.2%, p < 0.001), and concomitant infective endocarditis (38.4 vs 20.2%, p = 0.002). The groups showed similar rates of symptomatic spinal cord compression (14.5 vs 11.9%, p = 0.556) and paraspinal abscesses (62.3 vs 68.8%, p = 0.288) at presentation. There was a trend to lower spine surgery rates in the aged (11.6 vs 17.4%, p = 0.192). On univariate analysis, Staphylococcus aureus infection was associated with higher in-hospital mortality in aged (29%, OR 4.3, 95% CI 1.61-11.45). In-hospital mortality was higher among the aged (14.5 vs 6.4%, p = 0.044) as well as relapse rate due to treatment failure (3.4 vs 1%, p = 0.377). CONCLUSIONS: The findings underscore the importance of preventing healthcare-related infection and maintaining high clinical suspicion of infective endocarditis in aged NVO patients to implement proper management. S. aureus infection had a poorer prognosis in this population. As compared to younger patients, spinal surgery rates were slightly lower and overall prognosis poorer in the aged, despite similar rates of symptomatic spinal cord compression and abscesses at presentation. PMID- 30003492 TI - Two Sessions of Radiotherapy Were Successful in Treating Gastric Cancer with Bleeding. PMID- 30003493 TI - Alpha-fetoprotein Secreting Neuroendocrine Carcinoma of the Liver: a Case Report and Literature Review. PMID- 30003491 TI - Gut-origin sepsis in the critically ill patient: pathophysiology and treatment. AB - INTRODUCTION: Gut permeability is increased in critically ill patients, and associated with the development of the systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). The pathogenetic link(s) and potential therapies are an area of intense research over the last decades. METHODS: We thoroughly reviewed the literature on gut-origin sepsis and MODS in critically ill patients, with emphasis on the implicated pathophysiological mechanisms and therapeutic interventions. FINDINGS: Intestinal barrier failure leading to systemic bacterial translocation associated with MODS was the predominant pathophysiological theory for several years. However, clinical studies with critically ill patients failed to provide the evidence of systemic spread of gut-derived bacteria and/or their products as a cause of MODS. Newer experimental data highlight the role of the mesenteric lymph as a carrier of gut derived danger-associated molecular patterns (DAMPs) to the lung and the systemic circulation. These substances are recognized by pattern recognition receptor bearing cells in diverse tissues and promote proinflammatory pathways and the development MODS. Therefore, the gut becomes a pivotal proinflammatory organ, driving the systemic inflammatory response through DAMPs release in mesenteric lymph, without the need for systemic bacterial translocation. CONCLUSIONS: There is an emerging need for application of sensitive non-invasive and easily measured biomarkers of early intestinal injury (e.g., citrulline, intestinal fatty acid protein, and zonulin) in our everyday clinical practice, guiding the early pharmacological intervention in critically ill patients to restore or prevent intestinal injury and improve their outcomes. PMID- 30003494 TI - Laparoscopic Liver Resection in a Case of Asymptomatic Elderly Patient with Caroli Syndrome. PMID- 30003495 TI - The Neutrophil-Lymphocyte Ratio Is an Independent Prognostic Factor for Overall Survival in Hispanic Patients with Gastric Adenocarcinoma. AB - INTRODUCTION: High values of neutrophil-lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) are related with poor prognosis in patients with gastric cancer. However, this association has been rarely assessed in Hispanic populations that show important clinicopathological differences to Asian and Caucasian patients. In this study, we determined the prognostic value of these biomarkers in Hispanic patients from Costa Rica. MATERIALS AND METHODS: We retrieved data regarding pre-treatment NLR and PLR, as well as clinical variables from medical records of 381 consecutive gastric cancer patients treated in four major hospitals in Costa Rica between 2009 and 2012. Univariate and multiple Cox regression analyses were performed to assess the value of NLR and PLR as predictors of overall survival (OS) and disease-free survival (DFS). The best cutoff point was based on the maximization of the Log-rank test. RESULTS: Median follow-up was 13.21 months. In univariate analysis, a NLR >= 5 was associated with reduced DFS (hazard ratio (HR) 2.31; 95% confidence interval (CI) 1.78-3.00; p < 0.001) and poor OS (HR 2.24; 95% CI 1.72-2.92; p < 0.001). Similarly, a PLR >= 350 was associated with worse DFS (HR 2.28; 95% CI 1.70-3.06; p < 0.001) and poor OS (HR 2.33; 95% CI 1.73-3.13; p < 0.001). After adjustment for potential confounders, multivariate analysis revealed that only the NLR >= 5 was independently associated with worse DFS (HR 1.97; 95% CI 1.44-2.47) and OS (HR 1.59; 95%CI 1.15-2.28). CONCLUSIONS: NLR >= 5 was independently associated with worse OS and DFS in Hispanic patients with gastric cancer. PMID- 30003496 TI - Evaluating the mycostimulation potential of select carbon amendments for the degradation of a model PAH by an ascomycete strain enriched from a superfund site. AB - Although ecological flexibility has been well documented in fungi, it remains unclear how this flexibility can be exploited for pollutant degradation, especially in the Ascomycota phylum. In this work, we assess three mycostimulation amendments for their ability to induce degradation in Trichoderma harzanium, a model fungus previously isolated from a Superfund site contaminated with polycyclic aromatic hydrocarbons. The amendments used in the present study were selected based on the documented ecological roles of ascomycetes. Chitin was selected to simulate the parasitic ecological role while cellulose and wood were selected to mimic bulk soil and wood saprobic conditions, respectively. Each amendment was tested in liquid basal medium in 0.1 and 1% (w/v) suspensions. Both chitin and cellulose amendments were shown to promote anthracene degradation in T. harzanium with the 0.1% chitin amendment resulting in over 90% removal of anthracene. None of the targets monitored for gene expression were found to be upregulated suggesting alternate pathways may be used in T. harzanium. Overall, our data suggest that mycostimulation amendments can be improved by understanding the ecological roles of indigenous fungi. However, further research is needed to better estimate specific amendment requirements for a broader group of target fungi and follow up studies are needed to determine whether the trends observed herein translate to more realistic soil systems. PMID- 30003497 TI - Targeting the IL-23/IL-17 Pathway in Psoriasis: the Search for the Good, the Bad and the Ugly. AB - New promising treatments have been developed for psoriasis that target different parts of the interleukin (IL)-23/IL-17 pathway. This approach is believed to be more disease specific, and sparing the T helper 1 pathway might prevent serious long-term adverse events. Moreover, superior Psoriasis Area and Severity Index improvements are observed, which has redefined treatment goals in psoriasis. The new molecules can be divided into different categories, according to the target: blocking agents can target the upstream cytokine IL-23 or the downstream IL-17. In the latter, a variety of targets exist, such as the ligands IL-17A and IL-17F, or a combination thereof, or a subunit of the receptor, IL-17RA. Each target seems to have its own set of advantages and pitfalls, which will impact the treatment decision in clinical practice. In this review, we summarize the current knowledge on the different inhibitors of the IL-23/IL-17 pathway. Furthermore, we briefly discuss the role of IL-17 in other diseases and comorbidities. Finally, we discuss how comprehensive knowledge is needed for the prescribing physician in order to make the most appropriate therapeutic choice for each individual patient. PMID- 30003499 TI - Gastrointestinal Manifestations of Hypereosinophilic Syndromes and Mast Cell Disorders: a Comprehensive Review. AB - Hypereosinophilic syndrome and mastocytosis are relatively rare proliferative diseases encountered in the general population. However, allergists frequently consider these disorders in the differential of patients presenting with gastrointestinal, pulmonary, cutaneous, and allergic symptoms. Gastrointestinal symptoms are some of the most frequent and/or debilitating aspects of both disease states and in many cases lead to poor quality of life and functional limitation for the patient. They are the third most common clinical manifestation in hypereosinophilic syndrome and have been found to be the most distressful aspect of the disorder in those with systemic mastocytosis. Both eosinophils and mast cells play integral parts in normal gut physiology, but when and how exactly their effector functionality translates into clinically significant disease remains unclear, and the available literature regarding their pathophysiology remains sparse. Eosinophils and mast cells even, in fact, may not necessarily function in isolation from each other but can participate in bidirectional crosstalk. Both are affected by similar mediators and can also influence one another in a paracrine fashion. Their interactions include both production of soluble mediators for specific eosinophil and mast cell receptors (for example, eosinophil recruitment and activation by mast cells releasing histamine and eotaxin) as well as direct physical contact. The mechanistic relationship between clonal forms of hypereosinophilia and systemic mastocytosis has also been explored. The nature of gastrointestinal symptomatology in the setting of both hypereosinophilic syndrome and mast cell disease is frequently manifold, heterogeneous, and the lack of better targeted therapy makes diagnosis and management challenging, especially when faced with a substantial differential. Currently, the management of these gastrointestinal symptoms relies on the treatment of the overall disease process. In hypereosinophilia patients, systemic corticosteroids are mainstay, although steroid-sparing agents such as hydroxyurea, IFN-alpha, methotrexate, cyclosporine, imatinib, and mepolizumab have been utilized with varying success. In mastocytosis patients, anti-mediator therapy with antihistamines and mast cell stabilization with cromolyn sodium can be considered treatments of choice, followed by other therapies yet to be thoroughly studied, including the role of the low-histamine diet, corticosteroids, and treatment of associated IBS symptoms. Given that both eosinophils and mast cells may have joint pathophysiologic roles, they have the potential to be a combined target for therapeutic intervention in disease states exhibiting eosinophil or mast cell involvement. PMID- 30003500 TI - Large Vessel Vasospasm Is Not Associated with Cerebral Cortical Hypoperfusion in a Murine Model of Subarachnoid Hemorrhage. AB - Clinical studies on subarachnoid hemorrhage (SAH) have shown discrepancies between large vessel vasospasm, cerebral perfusion, and clinical outcome. We set out to analyze the contribution of large vessel vasospasm to impaired cerebral perfusion and neurological impairment in a murine model of SAH. SAH was induced in C57BL/6 mice by endovascular filament perforation. Vasospasm was analyzed with microcomputed tomography, cortical perfusion by laser SPECKLE contrast imaging, and functional impairment with a quantitative neuroscore. SAH animals developed large vessel vasospasm, as shown by significantly lower vessel volumes of a 2.5 mm segment of the left middle cerebral artery (MCA) (SAH 5.6 +/- 0.6 nL, sham 8.3 +/- 0.5 nL, p < 0.01). Induction of SAH significantly reduced cerebral perfusion of the corresponding left MCA territory compared to values before SAH, which only recovered partly (SAH vs. sham, 15 min 35.7 +/- 3.1 vs. 101.4 +/- 10.2%, p < 0.01; 3 h, 85.0 +/- 8.6 vs. 121.9 +/- 13.4, p < 0.05; 24 h, 75.3 +/- 4.6 vs. 110.6 +/- 11.4%, p < 0.01; 72 h, 81.8 +/- 4.8 vs. 108.5 +/- 14.5%, n.s.). MCA vessel volume did not correlate significantly with MCA perfusion after 72 h (r = 0.34, p = 0.25). Perfusion correlated moderately with neuroscore (24 h: r = - 0.58, p < 0.05; 72 h: r = - 0.44, p = 0.14). There was no significant correlation between vessel volume and neuroscore after 72 h (r = - 0.21, p = 0.50). In the murine SAH model, cerebral hypoperfusion occurs independently of large vessel vasospasm. Neurological outcome is associated with cortical hypoperfusion rather than large vessel vasospasm. PMID- 30003501 TI - Development of an Educational Program for Non-Professional Soccer Coaches in Charge of Community-Based Soccer in Men with Prostate Cancer: a Qualitative Study. AB - BACKGROUND: While clinical trials have demonstrated the benefits of structured exercise for prostate cancer survivors, few attempts have been made to investigate and implement sustainable community-based exercise programs supporting adoption of long-term physical activity behavior. Against this background, the aims of this study was to explore the perspectives of experts and stakeholders on the development of a training course and intervention manual used to support the delivery of community-based soccer training in men with prostate cancer (the FC Prostate Community [FCPC] trial). METHODS: A two-step qualitative design including triangulation of methods, data sources, and researchers. Step 1 comprised key informant interviews with clinical and scientific experts (n = 4). Step 2 included stakeholder focus group interviews with nurses (n = 5), non professional soccer coaches and club representatives (n = 5), and prostate cancer survivors (n = 7). RESULTS: Four themes emerged from the analysis of the key informant interviews: The Coach's Qualifications, Structure of the Training, Prevention of Injuries, and A Non-Patient Environment, which informed development of the training course and intervention manual. The stakeholders added the importance of clarifying the Responsibility of the Coach, the value of Positive Competition, and Social Inclusion of the prostate cancer survivors in the club. Based on these results, we present the final templates for the training course and intervention manual. CONCLUSIONS: No general set of rules or safety measures to promote or optimize the delivery of community-based exercise in cancer survivors is recommended. However, the general principles related to the necessary clarification of the coach's responsibility in relation to the prevention and management of injuries and participant adherence through a non patient environment may be transferable to the training and education of other groups of lay persons in charge of delivering exercise interventions to other clinical subpopulations in a non-hospital setting. PMID- 30003502 TI - Label-Free Assessment of Collagenase Digestion on Bovine Pericardium Properties by Fluorescence Lifetime Imaging. AB - The extracellular matrix architecture of bovine pericardium (BP) has distinct biochemical and biomechanical properties that make it a useful biomaterial in the field of regenerative medicine. Collagen represents the dominant structural protein of BP and is therefore intimately associated with the properties of this biomaterial. Enzymatic degradation of collagen molecules is critical for extracellular matrix turnover, remodeling and ultimately tissue regeneration. We present a quantitative, label-free and non-destructive method for monitoring changes in biochemical and biomechanical properties of BP during tissue degradation, based on multi-spectral fluorescence lifetime imaging (ms-FLIm). Strong correlations of fluorescence intensity ratio and average fluorescence lifetime were identified with collagen content, Young's Modulus and Ultimate tensile strength during collagenase degradation, indicating the potential of optically monitoring collagen degradation using ms-FLIm. The obtained results demonstrate the value of ms-FLIm to assess the quality of biomaterials in situ for applications in regenerative medicine. PMID- 30003498 TI - Pharmacokinetics and Drug Interaction of Antiepileptic Drugs in Children and Adolescents. AB - Selecting the most appropriate antiepileptic drug (AED) or combination of drugs for each patient and identifying the most suitable therapeutic regimen for their needs is increasingly challenging, especially among pediatric populations. In fact, the pharmacokinetics of several drugs vary widely in children with epilepsy because of age-related factors, which can influence the absorption, distribution, metabolism, and elimination of the pharmacological agent. In addition, individual factors, such as seizure type, associated comorbidities, individual pharmacokinetics, and potential drug interactions, may contribute to large fluctuations in serum drug concentrations and, therefore, clinical response. Therapeutic drug concentration monitoring (TDM) is an essential tool to deal with this complexity, enabling the definition of individual therapeutic concentrations and adaptive control of dosing to minimize drug interactions and prevent loss of efficacy or toxicity. Moreover, pharmacokinetic/pharmacodynamic modelling integrated with dashboard systems have recently been tested in antiepileptic therapy, although more clinical trials are required to support their use in clinical practice. We review the mechanism of action, pharmacokinetics, drug-drug interactions, and safety/tolerability profiles of the main AEDs currently used in children and adolescents, paying particular regard to issues of relevance when treating this patient population. Indications for TDM are provided for each AED as useful support to the clinical management of pediatric patients with epilepsy by optimizing pharmacological therapy. PMID- 30003503 TI - Biomimetic Placenta-Fetus Model Demonstrating Maternal-Fetal Transmission and Fetal Neural Toxicity of Zika Virus. AB - Recent global epidemics of viral infection such as Zika virus (ZIKV) and associated birth defects from maternal-fetal viral transmission highlights the critical unmet need for experimental models that adequately recapitulates the biology of the human maternal-fetal interface and downstream fetal development. Herein, we report an in vitro biomimetic placenta-fetus model of the maternal fetal interface and downstream fetal cells. Using a tissue engineering approach, we built a 3D model incorporating placental trophoblast and endothelial cells into an extracellular matrix environment and validated formation of the maternal fetal interface. We utilized this model to study ZIKV exposure to the placenta and neural progenitor cells. Our results indicated ZIKV infects both trophoblast and endothelial cells, leading to a higher viral load exposed to fetal cells downstream of the barrier. Viral inhibition by chloroquine reduced the amount of virus both in the placenta and transmitted to fetal cells. A sustained downstream neural cell viability in contrast to significantly reduced viability in an acellular model indicates that the placenta sequesters ZIKV consistent with clinical observations. These findings suggest that the placenta can modulate ZIKV exposure-induced fetal damage. Moreover, such tissue models can enable rigorous assessment of potential therapeutics for maternal-fetal medicine. PMID- 30003504 TI - Sex Differences in 2-DOF Human Ankle Stiffness in Relaxed and Contracted Muscles. AB - Ankle stiffness has been known as one of the most important components contributing to the maintenance of lower body stability during postural balance and locomotion. It has been repeatedly shown that women have lower stability and increased risk of injury when compared to men participating in similar sports activities, yet sex differences in neuromuscular control of the ankle, including the modulation of ankle stiffness, and their contribution to stability remain unknown. To identify sex differences in human ankle stiffness, this study quantified multi-dimensional ankle stiffness in 20 young, healthy men and 20 young, healthy women over a range of ankle muscle contractions, from relaxed to 20% of maximum voluntary co-contraction of ankle muscles. A wearable ankle robot and a system identification method were used to reliably quantify ankle stiffness in a 2-dimensional space spanning the sagittal plane and the frontal plane. In all muscle activation levels, significant sex differences in ankle stiffness were identified in both the sagittal and frontal planes. In the given experimental conditions, ankle stiffness in males was higher than females up to 15.1 and 8.3 Nm/rad in the sagittal plane and the frontal plane, respectively. In addition, sex differences in the spatial structure of ankle stiffness were investigated by quantifying three parameters defining the stiffness ellipse of the ankle: area, aspect ratio, and orientation. In all muscle activation levels, a significant sex difference was identified in the area of stiffness ellipse as expected from the sex difference in the sagittal and frontal planes. However, no statistical sex difference was observed in the aspect ratio and orientation, which would be due to little differences in major anatomical configurations of the ankle joint between sexes. This study, in combination with future studies investigating sex differences during dynamic tasks (e.g. postural balance and locomotion) would serve as a basis to develop a risk assessment tool and sex-specific training programs for efficient ankle injury prevention or rehabilitation. PMID- 30003505 TI - Jaw clonus and opercular syndrome in ALS: a rare and interesting finding. PMID- 30003506 TI - Composite Risk for HIV: A New Approach Towards Integrating Biomedical and Behavioral Strategies in Couples-Based HIV Prevention Research. AB - A substantial number of new HIV infections among gay, bisexual, and other men who have sex with men and transgender women occurs in the context of primary partnerships. Given the diversity of risk reduction needs and various approaches available for reducing risk within couples, condomless sex is no longer the gold standard HIV outcome. We present a novel, comprehensive, and flexible Composite Risk for HIV (CR-HIV) approach for integrating evolving biomedical and behavioral HIV prevention strategies into couples-based HIV prevention intervention and survey research. We provide illustrative examples of the utility of the CR-HIV approach based on couples' HIV status. PMID- 30003507 TI - Understanding HIV Risk Behaviors Among Young Men in South Africa: A Syndemic Approach. AB - Young men in South Africa experience several adverse socio-structural and psychosocial factors that may contribute HIV risk behaviors. This study applied a syndemic framework to explore whether these syndemic factors are interconnected and work in synergy to increase HIV risk behaviors. Five syndemic factors were assessed including: binge drinking, polydrug use, depressive symptoms, violence and food insecurity on two HIV risk behaviors: multiple sex partners and transactional sex. Participants were (N = 1233) young men aged 18-29 years from a township in Cape Town, South Africa. Bivariate logistic regression analysis demonstrated that many of the syndemic factors were related to one another. Pairwise interactions (on an additive scale) among the syndemic factors revealed significant positive interactions between binge drinking and violence on greater odds of reporting multiple sex partners (aOR = 5.10, 95% CI 3.10, 8.29; p = < .001) compared to reporting neither factor. Also, food insecurity and violence (aOR = 2.89, 95% CI 1.63, 5.11; p = < .001) as well as food insecurity and polydrug use (aOR = 2.73, 95% CI 1.54, 4.84; p = < .001) were significantly associated with greater odds of transactional sex compared to reporting neither factor. Our findings highlight a synergistic relationship between some adverse socio-structural and psychosocial factors on HIV risk behaviors. HIV prevention programs that address multiple syndemic factors simultaneously may achieve greater impact on HIV risk reduction. PMID- 30003509 TI - Neuroimmune Impacts of Early-Life Stress on Development and Psychopathology. AB - Maltreatment and trauma in childhood, termed early-life stress (ELS), has long term effects on the immune system. ELS impacts immune signaling at the time of exposure but also disrupts the developmental trajectory of certain immunological processes, both in the periphery and in the brain. One consequence of these early alterations is a heightened immune response to stressors later in life. However, chronic and sustained inflammatory response can also lead to excitotoxicity and prevent typical brain development. In this chapter, we discuss current progress toward understanding the contribution of neuroimmune signaling to ELS attributable dysfunction or maladaptation with a focus on postnatal experiences. To do so we first present an operational definition of ELS. Then, we offer a brief overview of the immune system and neuroimmune development, followed by a section discussing the interaction between immunity, childhood trauma, and mental disorders in humans. We present evidence from animal models about immune alterations after ELS and discuss the ways in which ELS-induced immune changes ultimately affect brain and behavior, as well as the importance of individual differences and future directions in this field. Taken together, we submit that when encountered with ELS, some core brain circuits could develop differently via various mechanisms involving dysfunctional immune reprograming. However, given the remarkable plasticity of both the brain and the immune system, many of the deleterious effects of ELS may be mitigated with interventions that account for sex and target neuroimmune interactions over the lifespan. PMID- 30003508 TI - Historical records under the genetic evidence: "Chiriguano" tribe genesis as a test case. AB - Historical records suggest that Chiriguano tribe is the result of a genetic admixture event. The process involved the arrival of Guarani tribesmen descending from Amazonian region of Brazil along with groups of Arawak origin that inhabited the foothill plains of Bolivia. Later they arrived in Argentina at the beginning of the twentieth century. Aiming to test the historical records, we analysed a set of 46 samples collected at San Ramon de la Nueva Oran, Province of Salta, Argentina. A wide set of uni- and biparentally transmitted genetic markers were analysed, including 23 autosomal STRs; 46 AIM-DIPs and 24 AIM-SNPs all located at diverse autosomal chromosome locations; 23 Y-STRs and the entire mtDNA D-Loop sequence. Ancestry informative markers allowed for the detection of a strong Native American component in the genomes (> 94%), while all mtDNA haplotypes showed Native American characteristic motives, and 93% of Y-haplotypes belonged to the Q1a3a Y-haplogroup. The analysis of mitochondrial haplotypes and Y chromosome, although they did not match other populations, revealed a relationship between the Chiriguano and other groups of Guarani and Arawak origin inhabiting Brazil and Bolivia, confirming, at least in part, the historical records describing the origins of Chiriguano tribal settlements in northwestern Argentina. PMID- 30003510 TI - Why Regulators Lost Track and Control of Pesticide Risks: Lessons From the Case of Glyphosate-Based Herbicides and Genetically Engineered-Crop Technology. AB - PURPOSE OF REVIEW: The approval of genetically engineered (GE) crops in the late 1990s triggered dramatic changes in corn, soybean, and cotton pest management systems, as well as complex, novel regulatory challenges. Lessons learned are reviewed and solutions described. RECENT FINDINGS: Government-imposed resistance management provisions can work and adapt to changing circumstances, but within the private sector, pressures to gain and hold market share have thus far trumped the widely recognized need for resistance management. Risks arising from the use of formulated pesticides often exceed by a wide margin those in regulatory risk assessments based on data derived from studies on nearly 100% pure active ingredients. Innovative policy changes are needed in four problem areas: excessive faith in the accuracy of pre-market risk assessments and regulatory thresholds; post-approval monitoring of actual impacts; risk arising from formulated pesticides, rather than just pure active ingredient; challenges inherent in assessing and mitigating the combined impacts of all GE traits and associated pesticides on agroecosystems, as opposed to each trait or pesticide alone; and, tools to deal with failing pest management systems. PMID- 30003511 TI - Physical and mental health inequalities among aging lesbian, gay, and bisexual Canadians: cross-sectional results from the Canadian Longitudinal Study on Aging (CLSA). AB - OBJECTIVE: International estimates suggest the presence of health inequalities among older sexual minorities (i.e., individuals who identify as lesbian, gay, or bisexual and are 65 years old or above). In this study, we investigated the presence of health inequalities among aging lesbian and bisexual females, as well as aging gay and bisexual males in Canada. METHODS: We used baseline data from the Canadian Longitudinal Study on Aging (CLSA) Tracking and Comprehensive cohorts to cross-sectionally compare self-reported physical and mental health indicators by sex and sexual orientation. Within our analysis sample of 51,208 Canadians 45 years old and over, 2% (n = 1057) of respondents identified as lesbian, gay, or bisexual. RESULTS: Compared to heterosexual female peers, lesbian and bisexual females had greater odds of heavy drinking (AOR = 1.8, 95% CI = 1.3-2.4) and being a former smoker (AOR = 1.5, 95% CI = 1.2-1.9). Gay and bisexual males had greater odds of reporting a diagnosis of cancer (AOR = 1.5, 95% CI = 1.0-1.9) and currently smoking (AOR = 1.5, 95% CI = 1.1-2.0), compared to heterosexual males. Female and male sexual minorities had greater odds of reporting mood disorders (including depression) and anxiety disorders relative to heterosexual peers of the same sex. CONCLUSION: These findings highlight the importance of considering both sex and sexual orientation when developing approaches to support the physical and mental health of a diverse aging population in Canada. PMID- 30003512 TI - How war, drought, and dam management impact water supply in the Tigris and Euphrates Rivers. AB - The fast-paced conflicts in the Middle East can disrupt management and supply of water, particularly on dams and barrages along the Tigris and Euphrates rivers that have experienced threats or changes in sovereignty. Water supply is also under pressure from upstream water management, drought, and structural decline. In this research, we used a satellite-based algorithm, the normalized difference water index (NDWI), to monitor changes in the extent of surface reservoirs (1985 present). We compared the timeline of reservoir fluctuations with the timeline of events related to conflicts, droughts, and dam management. Our results show that the most sudden changes in water supply occurred during events related to conflict, but conflict was not often a cause of the greatest absolute changes to reservoir area. Though not as precise as on-the-ground information, satellite data can give insights to water supply when conflict has disrupted the flow of information or restricted on-the-ground data collection. PMID- 30003514 TI - Clinical comparison of Kedo-S paediatric rotary files vs manual instrumentation for root canal preparation in primary molars: a double blinded randomised clinical trial. AB - AIM: This was to compare and evaluate the instrumentation time and quality of obturation between paediatric rotary file (Kedo-S) and manual instrumentation techniques in primary molars. METHODS: A double blinded randomised control trial was performed that included mandibular primary molars in children of age 4-7 years with pulp necrosis. Sixty primary mandibular molars were randomly divided into two groups: 30 were instrumented with paediatric rotary files Kedo-S (experimental group) and 30 with hand K-files (control group). During the preparation of the primary root canals the instrumentation time was recorded in seconds. The quality of obturation was recorded as optimal, under filled or over filled using immediate post-operative radiographs. The instrumentation time and quality of obturation were analysed using independent t-test and Chi-square test. RESULTS: Mean instrumentation time with paediatric rotary files Kedo-S (78.53 s) was significantly less than K-files (95.46 s) (p < 0.05). There was a significant improvement in the quality of obturation (p < 0.05) with paediatric rotary files (Kedo-S). CONCLUSION: Clinical use of paediatric rotary files Kedo-S was effective during root canal preparation of primary teeth with reduction in instrumentation time and better quality of obturation. PMID- 30003513 TI - Real-Life Evidence for Tedizolid Phosphate in the Treatment of Cellulitis and Wound Infections: A Case Series. AB - INTRODUCTION: Tedizolid phosphate 200 mg, once daily for 6 days, has recently been approved for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) in several countries; however, clinical experience in real-life settings is currently limited. Here, we report on the use of tedizolid with an extended treatment duration for complex and severe ABSSSIs in real-world clinical settings. METHODS: Two patients with cellulitis and two patients with surgical site infection (SSI), aged 26-60 years, were treated with tedizolid phosphate 200 mg, intravenous/oral (IV/PO) or IV only, once daily at four different institutions. RESULTS: Two morbidly obese patients had non necrotizing, non-purulent severe cellulitis, which were complicated by sepsis or systemic inflammatory response syndrome plus myositis. One female patient failed on first-line empiric therapy with IV cefalotin, clindamycin and imipenem (3-4 days), and was switched to IV/PO tedizolid (7 + 5 days). One male patient received IV clindamycin plus IV/PO tedizolid (5 + 5 days), but clindamycin was discontinued on Day 3 due to an adverse event. For both patients, clinical signs and symptoms improved within 72 h, and laboratory results were normalized by Days 7 and 8, respectively. Two other patients (one obese, diabetic female with chronic hepatitis and chronic obstructive pulmonary disease) had complicated SSIs occurring 10 days after hernia repair with mesh or 3 months after spinal fusion surgery with metal implant. First patient with previous methicillin-resistant Staphylococcus aureus (MRSA) bacteremia received a 7-day tedizolid IV course empirically. The second patient with culture-confirmed MRSA infection received a 14-day IV course. Both patients responded within 72 h, and local and systemic signs normalized by end of treatment. There were no reports of thrombocytopenia. CONCLUSION: Tedizolid phosphate 200 mg for 7-14 days was a favored treatment option for patients with severe/complex ABSSSIs, and was effective following previous treatment failure or in late-onset infections. FUNDING: Editorial assistance and the article processing charges were funded by Bayer AG, Berlin, Germany. PMID- 30003515 TI - Absence of Stress Response in Dorsal Raphe Nucleus in Modulator of Apoptosis 1 Deficient Mice. AB - Modulator of apoptosis 1 (MOAP-1) is a Bcl-2-associated X Protein (BAX) associating protein that plays an important role in regulating apoptosis. It is highly enriched in the brain but its function in this organ remains unknown. Studies on BAX-/- mice suggested that disruption of programmed cell death may lead to abnormal emotional states. We thus hypothesize that MOAP-1-/- mice may also display stress-related behavioral differences and perhaps involved in stress responses in the brain and investigated if a depression-like trait exists in MOAP 1-/- mice, and if so, whether it is age related, and how it relates to central serotonergic stress response in the dorsal raphe nucleus. Young MOAP-1-/- mice exhibit depression-like behavior, in the form of increased immobility time when compared to age-matched wild-type mice in the forced swimming test, which is abolished by acute treatment of fluoxetine. This is supported by data from the tail suspension and sucrose preference tests. Repeated forced swimming stress causes an up-regulation of tryptophan hydroxylase 2 (TPH2) and a down-regulation of brain-derived neurotrophic factor (BDNF) in the dorsal raphe nucleus (DRN) in young wild-type (WT) control mice. In contrast, TPH2 up-regulation was not observed in aged WT mice. Interestingly, such a stress response appears absent in both young and aged MOAP-1-/- mice. Aged MOAP-1-/- and WT mice also have similar immobility times on the forced swimming test. These data suggest that MOAP-1 is required in the regulation of stress response in the DRN. Crosstalk between BDNF and 5-HT appears to play an important role in this stress response. PMID- 30003516 TI - Impairment of Axonal Transport in Diabetes: Focus on the Putative Mechanisms Underlying Peripheral and Central Neuropathies. AB - Diabetes mellitus is a chronic disease with numerous complications that severely impact on the quality of life of patients. Different neuropathies may arise as complications associated with the nervous system, both peripherally and at the central level. The mechanisms behind these neuronal complications are far from being clarified, but axonal transport impairment, a vital process for neuronal physiology, has been described in the context of experimental diabetes. Alterations in neuronal cytoskeleton and motor proteins, deficits in ATP supply or neuroinflammation, as processes that disturb the effective transport of cargoes along the axon, were reported as putative causes of axonal impairment, ultimately leading to axonal degeneration. The main goal of the present review is to reunite the main studies in the literature exploring diabetes-induced alterations likely involved in axonal transport deficits, and call the attention for the uttermost importance of further exploring the field. Understanding the mechanisms underlying neuronal deficits in diabetes is crucial for the development of new therapeutic strategies to prevent neuronal degeneration in diabetes and related neuropathies. PMID- 30003517 TI - Abeta Oligomer Elimination Restores Cognition in Transgenic Alzheimer's Mice with Full-blown Pathology. AB - Oligomers of the amyloid-beta (Abeta) protein are suspected to be responsible for the development and progression of Alzheimer's disease. Thus, the development of compounds that are able to eliminate already formed toxic Abeta oligomers is very desirable. Here, we describe the in vivo efficacy of the compound RD2, which was developed to directly and specifically eliminate toxic Abeta oligomers. In a truly therapeutic, rather than a preventive study, oral treatment with RD2 was able to reverse cognitive deficits and significantly reduce Abeta pathology in old-aged transgenic Alzheimer's Disease mice with full-blown pathology and behavioral deficits. For the first time, we demonstrate the in vivo target engagement of RD2 by showing a significant reduction of Abeta oligomers in the brains of RD2-treated mice compared to placebo-treated mice. The correlation of Abeta elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice support the hypothesis that Abeta oligomers are relevant not only for disease development and progression, but also offer a promising target for the causal treatment of Alzheimer's disease. PMID- 30003518 TI - Evaluation of Training Program for the Maternal and Child Health Workforce at Tulane University. AB - Objectives Despite significant investments in Maternal and Child Health (MCH), the United States still lags behind other countries in key MCH indicators. A well trained workforce is needed to improve MCH. The Division of MCH Workforce Development of HRSA's Maternal and Child Health Bureau provides funding to schools of Public Health to support Centers of Excellence in MCH, which is focused on preparing the next generation of MCH leaders through specialized training and mentorship. One such center, the Tulane Center of Excellence in MCH (CEMCH), is housed at the Tulane University School of Public Health and Tropical Medicine. This study evaluated the perceived effectiveness and acceptability of the CEMCH leadership training program. Methods A mixed-methods approach was used, consisting of semi-structured interviews and quantitative surveys which were analyzed through inductive methods based in grounded theory and non-parametric methods respectively. Results Results indicated an overall high level of program satisfaction by all stakeholders. Mentorship and personal attention emerged as an important benefit for both former and current Scholars. The opportunity to gain real-world understanding of MCH work through program activities was an added benefit, although these activities also presented the most challenges. Community stakeholders generally did not view the program as providing immediate organizational benefit, but recognized the distal benefit of contributing to a well-trained MCH workforce. Conclusions for Practice These results will be used to inform other MCH training programs and strengthen Tulane's CEMCH. A well trained MCH workforce is essential to improving MCH, and high-quality training its foundation. PMID- 30003519 TI - Encouraging Parenting Behaviors That Promote Early Childhood Development Among Caregivers From Low-Income Urban Communities: A Randomized Static Group Comparison Trial of a Primary Care-Based Parenting Program. AB - Objectives Encouraging key parenting behaviors in early infancy may help decrease income-related developmental disparities. In this study we assessed whether a brief, primary care-based program (Sit Down and Play; SDP) could be successful in impacting key parenting behaviors that promote early childhood development. Methods An ethnically diverse group of predominantly low-income caregivers of children 2-6 months of age were enrolled, interviewed, and randomized to intervention (n = 20) or control (n = 20) groups. Intervention families received SDP at recruitment and the subsequent well-child visit. Control families were provided handouts regarding developmental milestones. One month after the second well-child visit, all families were reinterviewed (n = 34; 85% retention rate). Using open-ended questions and standardized measures (i.e., StimQ), parents were asked about parenting behaviors central to children's development: (1) participation in cognitively stimulating activities, (2) provision of learning materials, and (3) the quality of parent-child verbal interactions. Potential impact on perceived parenting confidence was also explored utilizing The Parenting Sense of Competence Scale. Analyses were conducted using chi square tests and analysis of variance. Results A significant main effect of time, and as hypothesized, an interaction between time and condition emerged that favored SDP on play behaviors (p = 0.03). Post-intervention, SDP families had significantly higher levels of interactional activities between a parent and child that promote cognitive development (p = 0.02). Conclusions for Practice Results appear promising for an accessible, low-intensity program delivered in the primary care setting. Further studies to determine the effectiveness of SDP on parenting behaviors and subsequent developmental outcomes are warranted. PMID- 30003520 TI - Body Image Dissatisfaction, Obesity and Their Associations with Breastfeeding in Mexican Women, a Cross-Sectional Study. AB - Introduction In Mexico the breastfeeding rate is low and the obesity rate is high. Body image concerns, particularly prevalent in obese women, are associated with low breastfeeding rate; however, this association has never been examined in Mexican women. To fill this need, we examined the association between body image dissatisfaction (BID) and breastfeeding across levels of maternal weight status in Mexican women. Methods A cross-sectional study was used, utilizing data from the Mexican National Health and Nutrition Survey (ENSANUT) for 2012. The breastfeeding (Never or breastfed less than 30 days, Still breastfeeding, Ever breastfed) of the last child (age <= 3 years), BID (Stunkard Figure Rating Scale), anthropometric (Body Mass Index, BMI), and associated characteristics were collected. Weighted-multinomial logistic regression models were utilized to examine the adjusted association between BID and breastfeeding and the effect modification of maternal weight status. Results Overall, 2422 women aged 20-49 years met the eligibility criteria. Of these, 247 (10.8%) had never breastfed or breastfed less than 30 days, 826 (32%) were still breastfeeding, and 1349 (57.2%) had breastfed. A total of 38.2% were overweight (25 <= BMI < 30 kg m2) and 26.2% were obese (BMI >= 30 kg m2). In the adjusted model, while stratifying by maternal weight status levels, a greater BID was associated with a lower odds of sill breastfeeding (OR 0.58, 95% CI 0.45-0.75) and having breastfed (OR 0.65, 95% CI 0.50-0.83) only among women with BMI >= 30 kg m2. Discussion The results highlight the potential relationship between body image concerns and breastfeeding in Mexican women with obesity. However, the causality of such relationship needs further investigation, ideally using a longitudinal study design. PMID- 30003521 TI - Effect of Maternal Vitamin B12 Supplementation on Cognitive Outcomes in South Indian Children: A Randomized Controlled Clinical Trial. AB - Objectives To examine the effects of oral maternal vitamin B12 supplementation during pregnancy and early lactation on cognitive development in children. Method We studied 218 children born to mothers enrolled in a placebo-controlled, randomized trial of vitamin B12 supplementation during pregnancy through 6 weeks post-partum. Cognitive functions were assessed at 30 months using the Bayley Scales of Infant Development- 3rd edition (BSID III). The association of maternal sociodemographic characteristics, maternal biochemical status during pregnancy, birth weight and home environment with each sub-domain of BSID-III was examined using linear regression analysis. Separate multiple linear regression analyses for each of the BSID-III sub-domains with maternal trimester specific nutritional biomarker status was conducted. Results Children of mothers who received oral vitamin B12 supplementation had significantly higher scores on expressive language compared to children of mothers who received placebo (beta = 0.14, P = 0.03). Children of mothers with elevated serum total homocysteine (tHcy) in the second and third trimesters of pregnancy had significantly lower scores on expressive language (beta = - 0.18, P = 0.03 and beta = - 0.19, P = 0.02, respectively) and gross motor domains (beta = - 0.23, P = 0.008 and beta = - 0.30, P = 0.001, respectively) of BSID-III adjusted for treatment arm and multiple confounders, compared with children whose mothers did not have elevated tHcy. Conclusions for practice Maternal B12 supplementation during pregnancy was associated with higher expressive language scores in children at 30 months. Elevated maternal tHcy levels during pregnancy had negative associations with expressive language and gross motor domains of BSID-III. Larger trials of maternal B12 supplementation are needed to confirm these findings. PMID- 30003522 TI - Acculturation and Breastfeeding Among Hispanic American Women: A Systematic Review. AB - Introduction Hispanic immigrants are more likely to breastfeed than are Hispanics born in the US, in part due to their acculturation. This paper aims to systematically review the existing literature on the association between acculturation and Hispanics' breastfeeding behaviors. Methods The systematic search used major databases such as Medline and PubMed, and it followed the PRISMA checklist. The scientific quality of the studies was rated using the Quality Assessment Tool for Quantitative Studies. Results We identified 1943 potential citations, of which 18 studies met the eligibility criteria. Overall, while 13 studies suggested that high-acculturated Hispanics were less likely to breastfeed compared with low-acculturated, five studies did not find significant evidence of such an association. Moreover, 12 studies used a static measure or a linear scale, which is not optimal; only three studies utilized bi/multidimensional scales to assess acculturation. Intention to breastfeed was examined in six studies, but the results were inconsistent. Breastfeeding initiation was examined in 11 studies, and two out of eight studies that examined breastfeeding duration, specifically analyzed exclusive breastfeeding at 6 months. Discussion Our results agree with the general hypothesis that higher acculturation is inversely related to breastfeeding rates, independently of income. Researchers used different methodologies to study acculturation and breastfeeding practices, limiting our ability to reach more detailed conclusions. Owing to the lack of a standard methodology for measuring acculturation, future studies should utilize bi/multidimensional scales when studying breastfeeding, in particular, in relation to breastfeeding intention and exclusive breastfeeding at 6 months; preferably according to Hispanic subgroups. PMID- 30003523 TI - Milk yield did not decrease in large herds of high-producing Holstein cows in semi-arid climate of Mexico. AB - This study aimed to determine the trends in milk production, fertility, temperature-humidity index (THI), and herd size in dairy herds from the Laguna region in northern Mexico. Records of 16 dairy herds of Holstein cows from January 2002 to December 2016 were used. Milk production was categorized in low and high levels. Milk production and fertility were analyzed using generalized equation estimation procedures by a model of repeated measures that included the effect of year, month, and productive level, an interaction for month * productive level, and herd effect was nested in productive level. For THI, a generalized linear model that included the effects of year and month was used. Dairy herds with high levels of milk production yielded more milk than those with low levels (P < 0.001). Milk production in 2002 and 2016 was 27.4 +/- 0.6 and 32.3 +/- 0.7 L/cow/day, respectively. Fertility fluctuated throughout the study. Dairy herds with high levels of milk production recorded higher fertility than those with low levels (P < 0.001). From October to April, THI was < 70, whereas it was > 73 from May to September, indicating that cows were in heat stress (20 h/day). The median herd size was 995 and 2569 cows in 2002 and 2016, respectively. In conclusion, in large herds, milk production increased over the years of study, whereas fertility showed a wave cycle; nonetheless, when THI was > 73, both milk production and fertility decreased. PMID- 30003524 TI - Tuberculosis in dromedary camels slaughtered in Nigeria: a documentation of lesions at postmortem. AB - In comparison with other livestock, tuberculosis (TB) in camels has not been extensively studied in Nigeria. Camels in the hands of Nigerian pastoralists share the livestock ecosystem and are increasingly becoming an important component of the sector. This study was designed to investigate the occurrence of TB lesions and animal-level risk of infection in slaughtered camel carcasses in one of the public abattoirs in Nigeria, from June to August 2016. A total of 212 camel carcasses comprising 82.5% (175/212) males and 17.5% (37/212) females were examined for tuberculous lesions. Of the carcasses examined, 33.5% (71/212) had TB lesions. The occurrence of lesions was most significantly associated with poor body condition (OR = 0.249; CI 0.134-0.454 [p < 0.001]). Distribution among anatomical sites of macroscopic lesions in the infected camels revealed three different pathological patterns as pulmonary (n = 51), abdominal (n = 11), and disseminated (n = 9) forms. Higher prevalence of gross TB lesions in camel carcasses highlights eminent threats to both animal and public health, pointing to an already existing risk of intra- and inter-species transmission of infection. PMID- 30003525 TI - Milk production and composition, food consumption, and energy balance of postpartum crossbred Holstein-Gir dairy cows fed two diets of different energy levels. AB - The objective of this study was to evaluate the production, consumption, and energy balance parameters of primiparous 3/4 and 7/8 Holstein * Gir (HG) dairy cows fed two diets of differing energy levels during the postpartum period. At the beginning of the study, 28 days prepartum, the average weight of both genetic groups was 498 +/- 12 kg and body condition score (BCS) was 3.5 +/- 0.05. At the end of the study, 61 days postpartum, the 3/4 HG cows had higher weight and body condition scores than the 7/8 HG (456 +/- 8 and 429 +/- 8 kg and 3.13 +/- 0.03 and 2.94 +/- 0.03 BCS for 3/4 HG and 7/8 HG, respectively). Milk from cows fed the high-energy diet had higher percentages of fat, protein, lactose, and total dry extract than cows fed the low-energy diet. Cows fed the high-energy diet had higher net energy intake (95.3 +/- 1.9 vs. 88.1 +/- 2.1 MJ/day) and higher energy balance (3.64 +/- 2.13 vs - 6.02 +/- 2.30 MJ/day). The 3/4 HG cows displayed higher energy for maintenance (33.1 +/- 0.4 MJ/day) than the 7/8 HG (31.5 +/- 0.5 MJ /day). In conclusion, although the primiparous 3/4 HG were heavier than the 7/8 HG and had a higher body condition score, no differences in milk produced up to 60 days postpartum were observed. The higher energy diet during the postpartum period increased energy balance, resulting in higher production of milk fat, protein, and lactose. PMID- 30003526 TI - Economic analysis of dairy farming in Bangladesh. AB - A study was conducted to analyze the dairy farming sector of Bangladesh from an economic viewpoint. Primary data was collected from smallholder dairy farms using survey questionnaires. A Cobb-Douglas production function and multiple regression models were estimated to analyze farm milk productivity and gross margin of the dairy farms. Surveyed dairy farms owned on an average 3.07 milking cows comprising 0.37 indigenous and 2.70 crossbred cows. Average milk productivity was 7.80 liter per cow per day, in which indigenous cow milk productivity was 1.9 1iter per day and crossbred cow milk productivity was 6.48 liter per cow per day. The study found that average daily milk production of small, medium, and large dairy farms were 5.45, 32.50, and 59.83 liter, respectively. Average monthly revenue and cost of milk production were US$ 79 and US$ 21 per cow, resulting in the average net return of US$ 58 per cow per month. Both quantitative estimation and t test results indicated a positive and statistically significant relationship between farm size and milk productivity and gross margin. The study findings also indicate that crossbred cows are providing higher economic benefits to the dairy farmers compared to the indigenous breeds. Despite being smallholder and subsistence, dairy farming shows potential for increasing returns to scale, and hence, there is a scope for further growth of the sector. PMID- 30003527 TI - Emergence of co-existence of blaNDM with rmtC and qnrB genes in clinical carbapenem-resistant Klebsiella pneumoniae isolates in burning center from southeast of Iran. AB - Dissemination of carbapenemase-producing Klebsiella pneumoniae along with 16S rRNA methyltransferase (16S-RMTase) has been caused as a great concern for healthcare settings. The aim of this study was to investigate the prevalence of resistance genes among K. pneumoniae isolates. During October 2015 to February 2016, 30 non-duplicative K. pneumoniae strains were isolated from clinical specimens in a burn center in Kerman, Iran. Antibiotic susceptibility tests of isolates, carbapenemase, extended-spectrum beta-lactamases (ESBLs) and AmpC beta lactamase-producing isolates were determined by phenotypic methods. The beta lactamase, oqxA/B efflux pumps, qnr A, B, S, 16S-RMTase (rmt A, B, and C), and mcr-1 resistance genes were determined by PCR. Enterobacterial repetitive intergenic consensus (ERIC)-PCR was used for molecular typing. According to our findings, tigecycline has been shown the most active agent against K. pneumoniae isolates. Antibiotic resistance genes, blaTEM-1, blaSHV-12, blaCTX-M-15, blaCTX-M 2, blaNDM-1, blaFOX, blaMOX, blaEBC, blaACC, blaCIT, rmtC, qnrB, qnrS, oqxA, and oqxB, were detected in 11 (36.7%), 13 (43.3%), 11 (36.6%), 5 (16.6%), 9 (30%), 1 (3.3%), 1 (3.3%), 1 (3.3%), 1 (3.3%), 2 (6.7%), 1 (3.3%), 9 (30%), 2 (6.7%), 18 (60%), and 13 (43.3%) of isolates, respectively. The blaNDM-1 with rmtC was simultaneously observed in one isolate. ERIC-PCR results revealed 25 distinct patterns in eight clusters (A-H) and five singletons. This study highlights the high prevalence of blaNDM and emergence of rmtC among carbapenem-resistant K. pneumoniae. The resistance genes are often co-located on the conjugative plasmids, so it might be the reason of the rapid spread of them. The prevalence of multidrug-resistant K. pneumoniae isolates limits the available treatment options and presents tremendous challenges to public health. PMID- 30003529 TI - An Evaluation of the Information Sources of Cancer Patients' Relatives. A Prospective Survey. AB - Patients followed up with a cancer diagnosis must be well-informed about cancer to be able to cope with it. Besides, informing the relatives of the cancer patients who are also experiencing the same process about the diagnosis and follow-up period of cancer is highly important. In the current study, it was aimed to evaluate the information sources about cancer which are referred to by relatives of cancer patients. Three hundred ninety-one cancer patient relatives were included in medical oncology clinic between May 1 and June 30, 2015. A questionnaire was applied to the participants, comprising 12 questions to elicit demographic information and 11 questions about the information sources to which they referred. The study included 183 female and 208 male participants with a mean age of 47.9 +/- 13.6 years. While the oncologists were the primary information sources referred to by 87%, the Internet was the second most preferred information source by 72%. The websites most frequently referred were the official websites (70%), the websites of oncology associations (53%), and social networks and forums (32%). The primary factors affecting the Internet preference were age, education level, income level, and place of residence. The Internet was the second most referred information source about cancer by family caregivers following oncologists. Therefore, it is of crucial importance that physicians inform patients and their relatives comprehensively as well as guiding them to correct and reliable information sources. PMID- 30003528 TI - Inter-arm Systolic Blood Pressure Difference in Physically Active, Adult Subjects. AB - INTRODUCTION: Increased inter-arm systolic blood pressure difference (DeltaPsys) has been associated with cardiovascular (CV) disease in elderly patients with CV risk factors. However, its significance in healthy subjects is unclear. AIM: To determine the relationship between DeltaPsys, the individual level of physical activity and the global CV risk in apparently healthy adults. METHODS: Systolic blood pressure was measured in both arms in 400 subjects aged 46.5 +/- 12.2 years, using a simultaneous oscillometric device (WatchBP Office, Microlife, Widnau, Switzerland). In the subjects with DeltaPsys >= 10 mmHg (Cases n = 20) and in a Control group (20 subjects without DeltaPsys >= 10 mmHg), another simultaneous measurement was repeated during a second visit. The physical activity level was assessed via the International Physical Activity Questionnaire Short Form (IPAQ-SF), the ankle brachial pressure index (ABPI) with a photoplethysmographic method (Angioflow-Microlab, Padova, Italy) and the CV risk via the Framingham Risk Score (FRS). RESULTS: The prevalence of DeltaPsys >= 10 mmHg in the whole population was 5% (95% CI 3.24-8.01%). Cases and Controls were comparable in gender, age, and BMI. DeltaPsys >= 10 mmHg was only confirmed in 17.6% of the Cases. No statistically significant differences were found between groups for IPAQ-SF, ABPI, or FRS. CONCLUSIONS: The prevalence of DeltaPsys >= 10 mmHg in this population was only slightly lower than what observed in older, hypertensive or diabetic patients. Cases and Controls did not differ in physical activity level, ankle brachial pressure index and CV risk. However, low test retest reliability might limit the use of DeltaPsys as a reliable marker for CV screening in this population. PMID- 30003530 TI - CalliSpheres(r) drug-eluting beads (DEB) transarterial chemoembolization (TACE) is equally efficient and safe in liver cancer patients with different times of previous conventional TACE treatments: a result from CTILC study. AB - PURPOSE: To assess the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) in liver cancer patients with different times of previous conventional transarterial chemoembolization (cTACE) treatments. METHODS: 367 liver cancer patients about to receive DEB-TACE treatment were enrolled in this prospective cohort study. All patients were divided into no previous cTACE group (NPC group), 1-2 times previous cTACE group (PC group) and triple or above previous cTACE group (TPC group) according to the times of previous cTACE treatments. RESULTS: There was no difference in complete response (CR) (P = 0.671) and objective response rate (ORR) (P = 0.062) among three groups. Additionally, no difference in overall survival (OS) among groups (P = 0.899) was found. As to liver function, most liver function indexes were deteriorative at 1 week after DEB-TACE operation, but returned to baseline at 1-3 months after DEB-TACE operation in all three groups, while percentage of abnormal total bile acid (TBA) patients was higher in TPC group than NPC and PC groups at 1-3 month post-DEB-TACE (P = 0.018). As for safety profiles, the incidence of pain during DEB-TACE operation was lower in TPC group compared to NPC and PC groups (P = 0.005), while no difference of other adverse events was found during and 1 month post-DEB-TACE treatment among three groups. CONCLUSION: DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous cTACE treatments. PMID- 30003531 TI - Molecular biomarkers for prognosis of gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. However, the development of molecular markers, especially circulating biomarkers, remains largely undone for the prognosis of GIST. We discussed the clinical-pathological characteristics of GIST and identified potential biomarkers for guidance of therapy and prognosis of GIST. Around 90% of GISTs contain mutations in KIT or PDGFRA and the remaining 10% of GISTs are wild type. Recent studies have indicated that various DNAs and miRNAs could serve as potential biomarkers for prognosis of GIST, including KIT, PDGFRA, other DNAs (such as BRAF, SDH, SETD2 and ROR2), and microRNAs (miRNAs). The pressing need and challenges in the development of circulating prognostic biomarkers for GIST are also discussed. Although challenges remain, DNAs and miRNAs are promising circulating biomarkers for surveillance and prognosis of GIST. Advances in clarification of aberrant molecular alterations may open new avenues for exploration of reliable and robust biomarkers to improve the management of GIST. PMID- 30003533 TI - Impact of Race on Immunization Status in Long-Term Care Facilities. AB - OBJECTIVES: This study examined the relationship between resident race and immunization status in long-term care facilities (LTCFs). Race was captured at the resident and the facility racial composition level. DESIGN: Thirty-six long term care facilities varying in racial composition and size were selected for site visits. SETTING: LTCFs were urban and rural, CMS certified, and non-hospital administered. MEASUREMENTS: Chart abstraction was used to determine race, immunization, and refusal status for the 2010-2011 flu season (influenza 1), the 2011-2012 flu season (influenza 2), and the pneumococcal pneumonia vaccine for all residents over 65 years old. RESULTS: Thirty-five LTCFs submitted sufficient data for inclusion, and 2570 resident records were reviewed. Overall immunization rates were 70.5% for influenza 1, 74.1% for influenza 2, and 65.6% for pneumococcal pneumonia. Random effects logistic regression indicated that as the percent of Black residents increased, the immunization rate significantly decreased (immunization 1, p < 0.018, immunization 2, p < 0.002, pneumococcal pneumonia, p = 0.0059), independent of the effect of resident race which had less of an impact on rates. CONCLUSIONS: This study found considerable LTCF variation and racial disparities in immunization rates. Compared to Blacks, Whites were vaccinated at higher rates regardless of the LTCF racial composition. Facilities with a greater proportion of Black residents had lower immunization rates than those with primarily White residents. Facility racial mix is a stronger predictor of influenza immunization than resident race. Black residents had significantly higher vaccination refusal rates than White residents for immunization 2. Further studies examining LTCF-level factors that affect racial disparities in immunizations in LTCFs are needed. PMID- 30003532 TI - Solid Cell Nests Within a Parathyroid Gland-Report of an Exceptional Case. AB - The ultimobranchial body (UBB) denotes the cellular mass originating from the fourth branchial pouch, which migrates from the neural crest and infolds within the middle and upper poles of the thyroid lobes, thereby establishing the presence of calcitonin-secreting parafollicular C cells. In various numbers, UBB remnants (entitled "solid cell nests", or SCNs) are found in thyroid glands examined histologically. However, despite the close embryological relation between the UBB and the superior parathyroid glands, intraparathyroidal SCNs have to our knowledge not been previously reported. Here, we describe a patient presenting with a papillary thyroid carcinoma with central and lateral lymph node metastases. Upon postoperative analysis, an unintentionally removed parathyroid gland was observed adjacent to the superior aspect of the right thyroid lobe. Within a 0.6 * 0.5-mm area of the parathyroid gland, solid nests composed of epithelial cells with oval and slightly elongated nuclei were seen. The cells were positive for p40, p63, and GATA3, but negative for PTH. The final diagnosis was a SCN entrapped within the parathyroid gland. Empirically, we have not previously observed SCNs within the parathyroid glands. To our knowledge, our finding thus constitutes a very unusual histological manifestation, and could indicate an underlying aberrancy during embryogenesis given the close anatomical relationship between the UBB and the superior parathyroid glands. PMID- 30003535 TI - Egos has a reduced capacity to predicts GBS prognosis in Northeast Brazil. AB - OBJECTIVE: The Erasmus Guillain Barre Outcome Score (EGOS) is a prognostic model that predicts the chance of being able to walk independently at 6 months after Guillain Barre syndrome (GBS). This study was conducted aiming to determine the validity of EGOS in a Brazilian population. MATERIAL AND METHODS: Data collected from GBS patients in Rio Grande do Norte, Brazil, were used to determine the validity of EGOS. GBS disability score was assessed in the second week of disease and at 6 months. RESULTS: A total of 206 subjects were studied. The Brazilian patients were younger, with a more severe clinical presentation, with higher percentage of cranial nerve involvement and upper respiratory infection. There was no difference relative to sex or presence of anti-gangliosides antibodies. The demyelinating variant was more common (73.9%). However, only 24% of the Brazilians with EGOS 5.5-7 were not able to walk after 6 months, compared to 52% to European Group. Nine patients (3.8%) presented nodopathies, of these four had an EGOS >5, but only one of the latter group was unable to walk after 6 months of GBS. CONCLUSIONS: Erasmus Guillain Barre Outcome Score was not a good predictor for the ability to walk after 6 months of GBS in Rio Grande do Norte, Brazil. Differences could be that the Brazilian GBS were younger, or alternatively, it could be due to a different infection profile or in the incidence of nodopathies. PMID- 30003536 TI - The role of the microbiome in nonhealing diabetic wounds. AB - Wound healing is a highly coordinated and complex process, and there can be devastating consequences if it is interrupted. It is believed that, in combination with host factors, microorganisms in a wound bed can not only impair wound healing but can lead to stalled, chronic wounds. It is hypothesized that the wound microbiota persists in chronic wounds as a biofilm, recalcitrant to antibiotic and mechanical intervention. Cultivation-based methods are the gold standard for identification of pathogens residing in wounds. However, these methods are biased against fastidious organisms, and do not capture the full extent of microbial diversity in chronic wounds. Thus, the link between specific microbes and impaired healing remains tenuous. This is partially because local infection and, more specifically, the formation of a biofilm, is difficult to diagnose. This has led to research efforts aimed at understanding if biofilm formation delays healing and leads to persistent and chronic infection. Circumventing challenges associated with culture-based estimations, advances in high-throughput sequencing analysis has revealed that chronic wounds are host to complex, diverse microbiomes comprising multiple species of bacteria and fungi. Here, we discuss how the use of genomic methodologies to study wound microbiomes has advanced the current understanding of infection and biofilm formation in chronic wounds. PMID- 30003534 TI - Extracting Charge and Mass Information from Highly Congested Mass Spectra Using Fourier-Domain Harmonics. AB - Native mass spectra of large, polydisperse biomolecules with repeated subunits, such as lipoprotein Nanodiscs, can often be challenging to analyze by conventional methods. The presence of tens of closely spaced, overlapping peaks in these mass spectra can make charge state, total mass, or subunit mass determinations difficult to measure by traditional methods. Recently, we introduced a Fourier Transform-based algorithm that can be used to deconvolve highly congested mass spectra for polydisperse ion populations with repeated subunits and facilitate identification of the charge states, subunit mass, charge state-specific, and total mass distributions present in the ion population. Here, we extend this method by investigating the advantages of using overtone peaks in the Fourier spectrum, particularly for mass spectra with low signal-to-noise and poor resolution. This method is illustrated for lipoprotein Nanodisc mass spectra acquired on three common platforms, including the first reported native mass spectrum of empty "large" Nanodiscs assembled with MSP1E3D1 and over 300 noncovalently associated lipids. It is shown that overtone peaks contain nearly identical stoichiometry and charge state information to fundamental peaks but can be significantly better resolved, resulting in more reliable reconstruction of charge-state-specific mass spectra and peak width characterization. We further demonstrate how these parameters can be used to improve results from Bayesian spectral fitting algorithms, such as UniDec. Graphical Abstract ?. PMID- 30003537 TI - Divergent strategies in pre- and postzygotic reproductive isolation between two closely related Dianthus species. AB - Quantifying the relative contribution of multiple isolation barriers to gene flow between recently diverged species is essential for understanding speciation processes. In parapatric populations, local adaptation is thought to be a major contributor to the evolution of reproductive isolation. However, extrinsic postzygotic barriers assessed in reciprocal transplant experiments are often neglected in empirical assessments of multiple isolation barriers. We analyzed multiple isolation barriers between two closely related species of the plant genus Dianthus, a genus characterized by the most rapid species diversification in plants reported so far. Although D. carthusianorum L. and D. sylvestris Wulf. can easily be hybridized in crossing experiments, natural hybrids are rare. We found that in parapatry, pollinator-mediated prezygotic reproductive isolation barriers are important for both D. carthusianorum (0.761) and D. sylvestris (0.468). In contrast to D. carthusianorum, high hybrid viability in D. sylvestris (-0.491) was counteracted by strong extrinsic postzygotic isolation (0.900). Our study highlights the importance of including reciprocal transplant experiments for documenting extrinsic postzygotic isolation and demonstrates clearly divergent strategies and hence asymmetric pre- and postzygotic reproductive isolation between closely related species. It also suggests that pollinator mediated and ecological isolation could have interacted in synergistic ways, further stimulating rapid speciation in Dianthus. PMID- 30003538 TI - Effect of biosurfactant extract obtained from the corn-milling industry on probiotic bacteria in drinkable yogurt. AB - BACKGROUND: Recent studies have proven that biosurfactants (BS) obtained from controlled fermentation have shown surfactant and antimicrobial properties. In this work a biosurfactant extract obtained from a raw agroindustrial stream from the corn-milling industry was introduced into a drinkable probiotic yogurt containing Lactobacillus casei. RESULTS: The effect of the biosurfactant extract on the probiotic population was determined under different biosurfactant concentration, temperature, and time conditions. This extract was able to reduce the surface tension of water by 30 mN/m and it was observed that its addition to a drinkable probiotic yogurt did not negatively affect the biomass of L. casei during incubation. It also had a positive effect on the population of L. casei, increasing the growth of the probiotic bacterium in the yogurt under optimum temperature conditions for the growth of L. casei, in the range of 30-40 degrees C. Likewise, the biosurfactant extract did not modify the homofermentative pathway of L. casei; hence no acetic acid was detected in the presence of the biosurfactant extract in the drinkable yogurt. CONCLUSION: This is the first time that a biosurfactant extract, obtained from natural sources, has been introduced into a food product like a drinkable probiotic yogurt, producing a positive effect in the growth of probiotic bacterium. (c) 2018 Society of Chemical Industry. PMID- 30003539 TI - Obesity surgery and risk of cancer. AB - BACKGROUND: Obesity increases the risk of several types of cancer. Whether bariatric surgery influences the risk of obesity-related cancer is not clear. This study aimed to uncover the risk of hormone-related (breast, endometrial and prostate), colorectal and oesophageal cancers following obesity surgery. METHODS: This national population-based cohort study used data from the Hospital Episode Statistics database in England collected between 1997 and 2012. Propensity matching on sex, age, co-morbidity and duration of follow-up was used to compare cancer risk among obese individuals undergoing bariatric surgery (gastric bypass, gastric banding or sleeve gastrectomy) and obese individuals not undergoing such surgery. Conditional logistic regression provided odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: In the study period, from a cohort of 716 960 patients diagnosed with obesity, 8794 patients who underwent bariatric surgery were matched exactly with 8794 obese patients who did not have surgery. Compared with the no-surgery group, patients who had bariatric surgery exhibited a decreased risk of hormone-related cancers (OR 0.23, 95 per cent c.i. 0.18 to 0.30). This decrease was consistent for breast (OR 0.25, 0.19 to 0.33), endometrium (OR 0.21, 0.13 to 0.35) and prostate (OR 0.37, 0.17 to 0.76) cancer. Gastric bypass resulted in the largest risk reduction for hormone-related cancers (OR 0.16, 0.11 to 0.24). Gastric bypass, but not gastric banding or sleeve gastrectomy, was associated with an increased risk of colorectal cancer (OR 2.63, 1.17 to 5.95). Longer follow-up after bariatric surgery strengthened these diverging associations. CONCLUSION: Bariatric surgery is associated with decreased risk of hormone-related cancers, whereas gastric bypass might increase the risk of colorectal cancer. PMID- 30003540 TI - Characterization of aroma, aroma-active compounds and fatty acids profiles of cv. Nizip Yaglik oils as affected by three maturity periods of olives. AB - BACKGROUND: The present study aimed to investigate how olive maturity indices (MI) (2.5, 3.5 and 4.5 MI) affect the aroma, aroma-active compounds, fatty acid profiles and color properties of cv. Nizip Yaglik olive oils. Various techniques for extracting volatiles from oil materials are available in the literature. Aroma compounds were extracted by the solvent-assisted flavor evaporation extraction method for the first time in olive oil. RESULTS: The type and number of aroma-active compounds varied according to maturity periods of olives. A total of 22, 21 and 20 different key odorants were found in aromatic extracts of samples with 2.5, 3.5 and 4.5 MI, respectively. The most potent aroma-active compounds based on flavor dilution (FD) factor values were hexanal (green) for 2.5 MI (FD: 1024) and 3.5 MI (FD: 512), as well as 1-penten-3-ol (green-leafy) for 4.5 MI (FD: 512). CONCLUSION: Overall, olive oils obtained from unripe and medium-ripe olives had stronger green and fruity odours compared to ripe olives. Principal component analysis demonstrated that oils were clearly discriminated according to their general physicochemical analysis, fatty acids, aroma profiles and key odorants. The results of the present study show that the olive maturity period has a significant influence on the quality parameters of olive oil. (c) 2018 Society of Chemical Industry. PMID- 30003541 TI - Thermal and functional characteristics of defatted bovine heart using supercritical CO2 and organic solvent. AB - BACKGROUND: Consumer demand for low-fat foods has been increasing as a result of attempts to reduce obesity and chronic diseases. Bovine heart was defatted using supercritical CO2 (SC-CO2 ) at different pressures together with solvent extraction to produce a protein-based functional ingredient for low-fat food products. Thermal and functional characteristics of control and defatted samples were compared. RESULTS: Supercritical CO2 treatment at high pressure results in more removal of fat, producing a protein-rich defatted bovine heart (DBH). The differential scanning calorimeter (DSC) thermograms and SDS-PAGE bands for SC-CO2 -treated DBHs were similar to those of the control sample, indicating high protein stability and better functionality. Hexane-treated DBH showed no major thermal peaks and very diffuse bands in SDS-PAGE, indicating denaturation of proteins during solvent extraction. No denaturation of proteins in SC-CO2 treated DBHs resulted in significantly higher water/oil absorption capacities (3320.00 and 2630.00 g kg-1 , respectively), total soluble solids (822.20 and 208.71 g kg-1 at pH 3.5 and 6.5, respectively), foaming capacities (149.37%), and emulsion activity (66.89%) than the hexane-treated DBH. CONCLUSION: Supercritical CO2 treatment of DBH led to higher thermal stability and functional properties than the control and hexane-treated DBH. Defatted bovine heart using SC-CO2 can be a functional ingredient for various low-fat and high-protein food products for health-conscious consumers. (c) 2018 Society of Chemical Industry. PMID- 30003542 TI - In vitro gastrointestinal biotransformation and characterization of a Desmodium adscendens decoction: the first step in unravelling its behaviour in the human body. AB - OBJECTIVES: The isolation and identification of the flavonoids present in a decoction of Desmodium adscendens was performed. In view of the oral use of the decoction, this work focused on the stability in gastrointestinal conditions and biotransformation by intestinal microflora in the colon of D-pinitol, vitexin and the flavonoid fraction of the decoction, as a first step in unravelling its behaviour in the human body. METHODS: The freeze-dried decoction was first subjected to column chromatography. Subsequently an enriched flavonoid fraction, was separated by repeated semi-preparative high-performance liquid chromatography (HPLC) or by HPLC-SPE. The isolated compounds were elucidated by NMR. Biotransformation experiments were carried in an in vitro gastrointestinal dialysis model. KEY FINDINGS: The major flavonoids of a decoction of D. adscendens were characterized as vicenin-2, isoschaftoside, schaftoside, 2"-O xylosylvitexin, 2"-O-pentosyl-C-hexosyl apigenin and a O-hexosyl-C-hexosyl apigenin, tentatively identified as 2"-O-glucosyl-vitexin. During their passage in the gastrointestinal dialysis model, vitexin and C-glycosides thereof were found to be stable. Only the O-glycosidic bonds of O-glycosides of vitexin or isovitexin were hydrolysed during the colonic phase. CONCLUSIONS: A D. adscendens decoction was found to be rich in vitexin and isovitexin glycosides from which vitexin and the C-glycosides thereof were found to be stable in the simulated gastrointestinal tract. PMID- 30003543 TI - Assessing the population transmission dynamics of tilapia lake virus in farmed tilapia. AB - A novel virus, tilapia lake virus (TiLV), has been identified as a key pathogen responsible for disease outbreak and mass mortality of farmed tilapia. We used a deterministic susceptible-infectious-mortality (SIM) model to derive key disease information appraised with published TiLV-induced cumulative mortality data. The relationship between tilapia mortality and TiLV exposure dosages was described by the Hill model. Furthermore, a disease control model was proposed to determine the status of controlled TiLV infection using a parsimonious control reproduction number (RC )-control line criterion. Results showed that the key disease determinants of transmission rate and basic reproduction number (R0 ) could be derived. The median R0 estimate was 2.59 in a cohabitation setting with 2.6 * 105 TCID50 fish-1 TiLV. The present RC -control model can be employed to determine whether TiLV containment is feasible in an outbreak farm by quantifying the current level of transmission. The SIM model can then be applied to predict what additional control is required to manage RC < 1. We offer valuable tools for aquaculture engineers and public health scientists the mechanistic-based assessment that allows a more rigorous evaluation of different control strategies to reduce waterborne diseases in aquaculture farming systems. PMID- 30003544 TI - Development, characterization and virus susceptibility of a continuous cell line from the caudal fin of marbled eel (Anguilla marmorata). AB - A continuous cell line consisting mostly of epithelioid cells was established from the caudal fin of marbled eels (Anguilla marmorata) and designated as marbled eel caudal fin (MECF)-1. The cells multiplied well in Leibovitz's L-15 medium containing 2% to 15% foetal bovine serum at temperatures of 20 degrees C to 35 degrees C and were subcultured for >90 passages during a 5-year period from 2012 to 2017. Transcripts of ictacalcin, keratin 13, cd146, nestin, ncam1 and myod1 were demonstrated in the cells using reverse transcription polymerase chain reaction. The results indicated that MECF-1 was composed of epidermal and mesenchyme stem and progenitor cells including myoblasts. MECF-1 was susceptible to Japanese eel herpesvirus HVA980811, marbled eel polyoma-like virus (MEPyV), aquabirnavirus MEIPNV1310 and aquareovirus CSV. By contrast, MECF-1 was noted refractory to megalocytiviruses RSIV-Ku and GSIV-K1 infection. Moreover, the cells were resistant to betanodavirus infection. In conclusion, MECF-1 derived from marbled eel is suitable for studies on anguillid viruses and interaction with host cells. PMID- 30003545 TI - Value development during adolescence: Dimensions of change and stability. AB - OBJECTIVE: Value change stability was examined in a longitudinal sample of Jewish and Arab Israeli adolescents. METHOD: Adolescents (N = 520; 55.4% girls; Mage = 13.76, SD = 0.52, at initial assessment) reported value importance at four annual evaluations. RESULTS: Adolescents increased in values' internal coherence and rank-order stability. Their value hierarchy was consistent and differentiated from the hierarchy of adults. Latent growth curve analyses indicated a similar pattern of mean-level value change for both ethnic groups: an increase in power and a decrease in tradition values; an increase in self-direction values among Jewish adolescents but not among Arab participants. Overall, the perceived importance of power, achievement, and self-direction values was more likely to increase than decrease, and the importance of conformity, tradition, security, and benevolence values was more likely to decrease than increase. Intraindividual changes in value importance followed the postulated pattern, as compatible values changed together, whereas conflicting values changed in opposite directions. CONCLUSIONS: This article suggests that values become better indicators of individual characteristics during adolescence. Adolescents increase their endorsement of self-focused values and decrease their valuation of other-focused values. They maintain the integrity of their value system despite value changes, confirming and validating value theory. PMID- 30003546 TI - Antimicrobial discovery from natural and unusual sources. AB - OBJECTIVES: Whether vertebrates/invertebrates living in polluted environments are an additional source of antimicrobials. KEY FINDINGS: Majority of antimicrobials have been discovered from prokaryotes and those which are of eukaryotic origin are derived mainly from fungal and plant sources. With this in mind, it is important to note that pests, such as cockroaches come across pathogenic bacteria routinely, yet thrive in polluted environments. Other animals, such as snakes thrive from feeding on germ-infested rodents. Logically, such species must have developed an approach to protect themselves from these pathogens, yet they have largely been ignored as a potential source of antimicrobials despite their remarkable capability to fight disease-causing organisms. SUMMARY: Animals living in polluted environments are an underutilized source for potential antimicrobials, hence it is believed that several novel bioactive molecule(s) will be identified from these sources to counter increasingly resistant bacterial infections. Further research will be necessary in the development of novel antimicrobial(s) from these unusual sources which will have huge clinical impact worldwide. PMID- 30003547 TI - Impact of cold soak duration on Cabernet Sauvignon fermentation and phenolic composition. AB - BACKGROUND: Cold soak is a prefermentative maceration technique believed to enhance grape skin extraction. Studies show variable results depending on cold soak and winemaking conditions. To investigate the effect of cold soak more fully, systematic and highly reproducible Cabernet Sauvignon fermentations with increasing cold-soak durations were performed. RESULTS: Phenolic extraction during cold soak and fermentation showed significant differences among all treatments for monitored phenolics at the end of the cold soak. At the end of alcoholic fermentation only gallic acid, (-)-epicatechin, and the flavonols were significant, and only (-)-epicatechin was significant after bottle ageing. Descriptive analysis of the bottled wines showed that the 4- and 7-day treatments were significantly higher in caramelized/vanilla/browned flavor compared to the 1 day treatment and lower levels of bitterness were observed up to 2 days of cold soak. While oligosaccharide content increased with increasing cold-soak duration, differences were not large enough to result in sensory differences. CONCLUSION: While increased cold soak duration led to differences in phenolic extraction during early fermentation, these differences did not last through to the end product. Thus, under the conditions of this study, cold-soak duration had little overall impact on Cabernet Sauvignon wine composition and style. (c) 2018 Society of Chemical Industry. PMID- 30003548 TI - Mental health symptoms during imprisonment: a longitudinal study. AB - OBJECTIVE: Mental health problems are common in prison populations. Less is known about how mental health problems develop during imprisonment. The objective was to examine the longitudinal course of mental health symptoms during imprisonment and individual factors associated with the development of these symptoms. METHOD: In a prospective cohort study, 1.664 Dutch male prisoners were questioned 3 weeks after their arrival in detention. Those still in custody were questioned again after 3, 9, and 18 months. Multilevel analyses were conducted to identify predictors of the course of mental health symptoms. RESULTS: Prisoners reported continued elevated symptom levels compared to the general population. Inmates who entered detention with pre-existing mental health problems and problematic alcohol/drugs use showed mental health improvements during detention. CONCLUSION: The high levels of prisoners' mental health problems highlight the importance of addressing mental health issues in prison. Imprisonment does not have an overall negative effect on mental health. PMID- 30003549 TI - Changes of the echocardiographic parameters in chronic heart failure patients with Ile337val, Glu23lys, and Ser1369ala polymorphisms of genes encoding the ATP sensitive potassium channels subunits in the Ukrainian population. AB - Different allelic variants of genes that encode ATP-sensitive potassium (KATP ) channels' subunits may contribute to the development of heart failure. The purpose of the work to investigate SNPs in genes that encode KATP channels in relation to echocardiographic parameters in chronic heart failure (CHF) patients. Ninety-nine people with CHF of ischemic origin with left ventricular systolic dysfunction were examined. The control group is represented by 108 clinically healthy subjects. KCNJ11 polymorphisms Ile337Val and Glu23Lys, and ABCC8 polymorphism Ser1369Ala were genotyped using polymerase chain reaction. In CHF patients, the frequency of the Ile337Val genotype was: Ile/Ile, 40.4%; Ile/Val, 45.5%; and Val/Val, 14.1%. The patients with the Val/Val genotype had left ventricular (LV) mass that was 334.15 g, which was 27.3% (P < 0.05) lower versus Ile/Val patients (425.48 g). The index of this parameter was also significantly lower (28.4%, P < 0.05). In CHF patients, the frequency of Glu23Lys and Ser1369Ala was: Glu/Glu and Ser/Ser, 43.4%; heterozygote, 44.4%; Lys/Lys and Ala/Ala, 12.2%. The patients with the Lys/Lys and Ala/Ala genotypes had a significantly lower LV mass index and LV end-diastolic volume (22.9% and 26.8%, P < 0.05) versus heterozygotes. Thus, the greatest LV mass and LV end-diastolic volume values are associated with heterozygotes, while the smallest are associated with minor homozygotes. PMID- 30003550 TI - Long-term neurocognitive functioning after electroconvulsive therapy in patients with late-life depression. AB - OBJECTIVE: There is ongoing concern about the possible negative impact of ECT on neurocognitive functioning in older patients. In this study, we aimed to characterize the long-term cognitive effects of ECT in patients with late-life depression, using an extensive neuropsychological battery. METHODS: A total of 110 patients aged 55 years and older with unipolar depression, referred for ECT were included. The neuropsychological test battery was assessed prior to ECT and 6 months after the last ECT session. RESULTS: There were no statistically significant group-level changes from baseline to 6 months post-ECT in any of the neuropsychological measurements. Individual differences in cognitive performance were detected using the Reliable Change Index. CONCLUSION: Patients with late life depression do not show deleterious cognitive effects 6 months following an ECT index course, although there are considerable differences at an individual level. Clinicians should not hesitate to prescribe ECT in older patients, as most of these patients will tolerate the treatment course and a small group will even experience a cognitive enhancement. However, clinicians should be aware that a small group of patients can experience cognitive side-effects. Further study is needed to predict which patients have a higher risk of developing cognitive side effects. PMID- 30003551 TI - Identification of transfusion-transmitted hepatitis A through postdonation information in Korea: results of an HAV lookback (2007-2012). AB - BACKGROUND AND OBJECTIVES: Despite safety measures to minimize the risk of transfusion-transmitted infections, a residual risk remains. To trace and review some such cases, we ask donors to notify the blood centre if they are diagnosed with an infection after they donate blood. MATERIALS AND METHODS: We analysed all data on postdonation cases of hepatitis A reported between 2007 and 2012. Archived specimens from these donors were tested for hepatitis A virus (HAV) using anti-HAV IgM/IgG and HAV-PCR as markers. If any of the test results were positive, we reviewed the medical records of the recipients and, if necessary, tested them for hepatitis A. RESULTS: Fifteen blood donors notified the blood centres of having been diagnosed with hepatitis A after donation. All archived samples except for one were HAV-PCR-positive and anti-HAV IgM/IgG-negative. Of the donated components, four RBCs and 14 FFPs had not been transfused to patients and were recalled. Among 26 recipients of the implicated components, fourteen were still alive when they were notified. Two patients showed clinical symptoms of hepatitis A and had positive results with anti-HAV IgM. CONCLUSION: Transfusion-transmitted hepatitis A is rare but exists. To reduce the risk, donors should be told to notify the blood centre if they are diagnosed with blood borne diseases after they donate blood. Physicians should consider the possibility of transfusion-transmitted hepatitis A if a transfused patient has hepatitis A but no history of travel or route of faecal-oral infection. PMID- 30003552 TI - Persistent regulatory T-cell response 2 years after 3 years of grass tablet SLIT: Links to reduced eosinophil counts, sIgE levels, and clinical benefit. AB - BACKGROUND: In the first 2 years of grass tablet sublingual immunotherapy treatment, we have previously demonstrated a progressive development of a regulatory T-cell response, which was preceded by an early decrease in the frequency of both IL-4+ cells and sIgE levels. A progressive increase in sIgG4 levels and FAB blockage were also found. METHODS: By monitoring immunological kinetics during 3 years of active treatment + 2 years of follow-up, we aimed to identify key immunological parameters that could explain sustained clinical benefit of grass tablet sublingual immunotherapy. RESULTS: Thirty patients completed the 5-year clinical trial protocol. Although individual responses were heterogeneous, reduction in both sIgE and circulating IL-4+ cells compared to the initial 1- to 4-month peak was maintained throughout the 3-year treatment period and for 2 years after discontinuation. Meanwhile, after a 2-year increase in sIgG4, the levels were stabilized during the third year and decreased post therapy. FAB inhibition remained significantly inhibited throughout the study compared to preimmunotherapy in 83% of patients. A sustained regulatory T-cell response, after IT cessation, occurs in two-thirds of the patients. There was a statistical association between this regulatory response, the maintenance of lower eosinophil counts during grass pollen seasons, and sIgE titers lower than before immunotherapy treatment, and the latter were significantly associated with clinical response. CONCLUSION: Our results suggest that the immunological mechanisms underlying the sustained response after 2 years of cessation of immunotherapy (3-year treatment period) are linked to the acquisition and maintenance of a regulatory T-cell response. PMID- 30003553 TI - By Myself and Liking It? Predictors of Distinct Types of Solitude Experiences in Daily Life. AB - OBJECTIVE: Solitude is a ubiquitous experience, often confused with loneliness, yet sometimes sought out in daily life. This study aimed to identify distinct types of solitude experiences from everyday affect/thought patterns and to examine how and for whom solitude is experienced positively versus negatively. METHOD: 100 community-dwelling adults aged 50-85 years (64% female, 56% East Asian, 36% European, 8% Other/Mixed heritage) and 50 students aged 18-28 years (92% female, 42% East Asian, 22% European, 36% Other/Mixed) each completed approximately 30 daily life assessments over 10 days on their current and desired social situation, thoughts, and affect. RESULTS: Multilevel latent profile analysis identified two types of everyday solitude: one characterized by negative affect and effortful thought (negative solitude experiences) and one characterized by calm and the near-absence of negative affect/effortful thought (positive solitude experiences). Individual differences in social self-efficacy and desire for solitude were associated with everyday positive solitude propensity; trait self-rumination and self-reflection were associated with everyday negative solitude propensity. CONCLUSIONS: This study provides a new framework for conceptualizing everyday solitude. It identifies specific affect/thought patterns that characterize distinct solitude experience clusters, and it links these clusters with well-established individual differences. We discuss key traits associated with thriving in solitude. This article is protected by copyright. All rights reserved. PMID- 30003554 TI - Assessment of chicken breast meat quality after freeze/thaw abuse using magnetic resonance imaging techniques. AB - BACKGROUND: Freezing/thawing meat can result in quality losses as a result of the formation, melting and reformation of ice. These changes in water state can result in alterations in texture, water holding and other key quality attributes. It was hypothesized that magnetic resonance imaging (MRI) could quantify changes in mobility and localization of water as a function of freezing/thawing, which could be correlated with quality measurements. RESULTS: Drip loss increased significantly for unbrined samples by over 100% after each freeze/thaw cycle (1.5% to 3.3% to 5.3% drip loss). Brine uptake decreased 50% after 2 cycles (from 53% to 28% mass uptake). Drip loss for brined samples increased after 2 cycles; other attributes were not significantly affected. MRI showed brined samples had less change in both proton density and T2 distributions. High-field nuclear magnetic resonance (NMR) imaging showed greater change in T2 distributions. CONCLUSION: As freeze/thaw damage increased, meat quality was reduced in both brined and unbrined chicken breasts, with more prominent changes in unbrined meat. These decreases in quality correlated with changes, albeit small, in water mobility and localization as measured by MRI. High-field NMR micro-imaging showed more dramatic changes in T2 distributions in unbrined samples. These MRI techniques are shown to be useful in the assessment of meat quality after freeze/thaw abuse. (c) 2018 Society of Chemical Industry. PMID- 30003555 TI - Treatment strategies for persistent methicillin-resistant Staphylococcus aureus bacteraemia. AB - WHAT IS KNOWN AND OBJECTIVE: Treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a long-standing challenge to health care, often complicated by metastatic infections, treatment failure and mortality. When MRSA bacteraemia persists despite adequate initial treatment, current Infectious Diseases Society of America guidelines recommend evaluation and removal of possible sources of infection. In addition, a change in therapy may be considered. The objective of this review was to explore the therapeutic options for the treatment of persistent MRSA bacteraemia. METHODS: A literature search of PubMed, MEDLINE and Google Scholar was performed using the following search terms: [methicillin-resistant Staphylococcus aureus OR MRSA] AND [bacteraemia OR bloodstream infection] AND [persistent OR persistence OR refractory OR treatment failure OR salvage] AND treatment. We evaluated relevant, adult, English language, peer-reviewed studies published between 1985 and May 2018. In vitro and animal studies were considered as supportive of in vivo data. RESULTS AND DISCUSSION: Randomized, controlled trials are lacking. However, case series and case reports support multiple treatment options including high-dose daptomycin in combination with an antistaphylococcal beta-lactam, ceftaroline, trimethoprim sulfamethoxazole (TMP-SMX) or fosfomycin; ceftaroline alone or in combination with vancomycin or TMP-SMX; linezolid alone or in combination with a carbapenem, or telavancin. WHAT IS NEW AND CONCLUSION: Given the heterogeneity of the data, a preferred regimen has not emerged. Prescribers must take into consideration recent exposure, source control, and available synergy and clinical data. Further comparative trials are needed to establish a preferred regimen and the creation of a universal treatment algorithm. PMID- 30003556 TI - Agricultural injuries among farm and non-farm children and adolescents in Alberta, Canada. AB - BACKGROUND: Understanding of the specific risk of agricultural injury sustained by different populations of children and adolescents is needed for effective safety intervention. OBJECTIVE: To compare the rates and patterns of agricultural injury incidence (fatal and non-fatal injury) between farm and non-farm children less than 18 years of age in Alberta, Canada. METHODS: A total of 115 378 children (five subgroups: two groups of farm children and three groups of non farm children) in Alberta were followed from 1999 to 2010 to examine injury incidence using the linkage of three administrative health databases. A recurrent event survival analysis using Cox proportional hazards regression was carried out. RESULTS: A total of 1 849 agricultural injury episodes (1 616 emergency department visits, 225 hospitalizations, and 8 deaths) were identified from 1999 to 2010. The age- and gender-adjusted rate (per 100 000 person years) of agricultural injury was 672.3 for rural-living farm children, 369.4 for urban living farm children, 180.2 for rural non-First Nations (FN) children, 64.4 for rural FN children, and 23.7 for urban children in descending order. CONCLUSION: Specific strategies for different children's populations to prevent agricultural injuries and to extend agricultural injury controls to non-farming populations are needed. PMID- 30003557 TI - Optimal unidirectional switch designs. AB - Stepped wedge designs and delayed start designs can all be considered as special cases of the so-called unidirectional switch design. This paper provides optimal proportions of clusters that are allocated to switch patterns in a unidirectional switch design to minimize the asymptotic variance of the treatment effect estimator. This unique optimal design applies to certain cross-sectional and longitudinal variance component models. When the intraclass correlation coefficient is zero, the optimal unidirectional switch design coincides with the classic (cluster) parallel group design. The optimal unidirectional switch design is more efficient than the optimal stepped wedge design and delayed start designs. Compared with the uniform unidirectional switch design, the efficiency gain of the optimal unidirectional switch design can be substantial, but it depends on the intraclass correlation and the cluster size. We also showed that augmenting the optimal stepped wedge design with pure control pattern is more efficient than the optimal stepped wedge design. In addition, robust minimax design for unidirectional switch design, delayed start design, and stepped wedge design are provided. PMID- 30003558 TI - Quantitative determination of armodafinil in human plasma by liquid chromatography-electrospray mass spectrometry: Application to a clinical study. AB - Armodafinil is a wake-promoting agent approved in 2007 by the US Food and Drug Administration for the treatment of excessive sleepiness. A rapid, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of armodafinil in human plasma was developed and validated. Armodafinil and internal standard (armodafinil d-10) were extracted from human plasma using protein precipitation combined with liquid-liquid extraction. This developed method only requires 50 MUL of plasma for the analysis. The chromatographic separation was performed with a Waters symmetry, C18 , 4.6 * 150 mm, 5 MUm column using formic acid, water and acetonitrile as solvent delivered at a 0.7 mL/min flow rate. The total run time of the method was 3 min. The method was validated according to regulatory guidance in terms of specificity, selectivity, linearity, matrix effect, recovery and stability. Optimized Q1/Q3 mass transitions for armodafinil and armodafinil d-10 were 274.1/167.2 (m/z) and 284.4/177.4 (m/z) respectively. The method showed linearity within the tested concentration range of 10-10,000 ng/mL. The method was successfully applied to quantify armodafinil concentrations after single oral administration of a 250 mg tablet in a clinical study conducted in healthy volunteers. Significant advantages of this method are minimal sample volume, short run time and a lower LLOQ. PMID- 30003559 TI - Sensor Fusion for Myoelectric Control Based on Deep Learning With Recurrent Convolutional Neural Networks. AB - Electromyogram (EMG) signal decoding is the essential part of myoelectric control. However, traditional machine learning methods lack the capability of learning and expressing the information contained in EMG signals, and the robustness of the myoelectric control system is not sufficient for real life applications. In this article, a novel model based on recurrent convolutional neural networks (RCNNs) is proposed for hand movement classification and tested on the noninvasive EMG dataset. The proposed model uses deep architecture, which has advantages of dealing with complex time-series data, such as EMG signals. Transfer learning is used in the training of multimodal model. The classification performance is compared with support vector machine (SVM) and convolutional neural networks (CNNs) on the same dataset. To improve the adaptability to the effect of arm movements, we fused the EMG signals and acceleration data that are the multimodal input of the model. The parameter transferring of deep neural networks is used to accelerate the training process and avoid over-fitting. The experimental results show that time domain input and 1-dimensional convolution have higher accuracy in the RCNN model. Compared with SVM and CNNs, the proposed model has higher classification accuracy. Sensor fusion can improve the model performance in the condition of arm movements. The RCNN model is a promising decoder of EMG and the sensor fusion can increase the accuracy and robustness of the myoelectric control system. PMID- 30003560 TI - Simultaneous determination of nine analytes related to the pathogenesis of diabetic encephalopathy in diabetic rat cortex and hippocampus by HPLC-FLD. AB - The determination of amino acids and monoamine with actions like neurotransmitters or modulators has become increasingly important for studying the relationship between the dysfunction of neurotransmitters and the pathogenesis of diabetic encephalopathy. Here, a high-performance liquid chromatography with fluorescence detection method was developed to simultaneously determine nine monoamines and amino acids including three excitatory neurotransmitters (aspartate, glutamate, and serotonin), four inhibitory neurotransmitters (glycine, gamma-aminobutyric acid, taurine, dopamine), a precursor of 5-HT (tryptophan) and methionine using homoserine as the internal standard. The separation was performed on a BDS column with methanol-buffer solution of 35 mmol/L sodium acetate and 5 mmol/L citric acid (pH 6.0) using a simple gradient elution. Several parameters including specificity, precision, and recovery were validated after optimization of the analytical conditions. The developed method was successfully applied to determine the cortex and the hippocampus samples from Sprague-Dawley rats. Our results showed that various neurotransmitters involved in diabetes mellitus may tend to be differentially modulated and present a different alteration tendency at different time course, which might be associated with the duration of diabetes mellitus. PMID- 30003561 TI - Effectiveness of pharmaceutical care on treatment outcomes for patients with first-time pulmonary tuberculosis in China. AB - WHAT IS KNOWN AND OBJECTIVE: In this study, the effectiveness of pharmaceutical care on treatment outcomes for patients with first-time pulmonary tuberculosis in China was assessed. METHODS: In this study, patients were randomized either to the usual care (UC) group (n = 72) where patients received routine medical and nursing care or to the pharmaceutical care (PC) group (n = 59) where patients were simultaneously provided with pharmaceutical care. The primary objectives were to evaluate whether treatment outcomes and patient adherence improved more in the PC group than in the UC group. In addition, in PC group, outcomes included the number of patient-reported pharmaceutical care issues and pharmacists' interventions. RESULTS AND DISCUSSION: As compared to the UC group, treatment success rate was improved in the PC group, but the difference was not statistically significant (71% vs 54%; P = 0.137). However, as compared to the UC group, the number of patients who attended all of the scheduled visits was higher in the PC group; the difference was statistically significant (81% vs 60%, P = 0.018). Furthermore, the number of patients who had positive test results for all of the isoniazid tests was higher in the PC group than in the UC group; the difference was also statistically significant (80% vs 50%, P = 0.002). The consumed medication rate was improved in the PC group, but no significant difference was found between the two groups. The patient-reported pharmaceutical care issues mainly included dermatological, gastrointestinal, hepatic, metabolic, sensory, central nervous system and haematological problems. On the basis of clinical examination, laboratory parameters and drug information database, the pharmacists addressed most of these pharmaceutical care issues. WHAT IS NEW AND CONCLUSION: Pharmaceutical care might improve patient adherence for patients with first-time pulmonary tuberculosis in China, and further, rigorously controlled trials are required. PMID- 30003562 TI - Synthesis, antitumor activity and pharmacokinetic study of 10-propionyloxy camptothecin in rats. AB - In the present study, a 10-position modified of camptothecin, 10-propionyloxy camptothecin (PCPT) was esterified from 10-hydroxcamptothecin (HCPT), which could metabolize to HCPT in vivo. PCPT displayed a relatively stronger antitumor activity in vitro and in vivo. Thereafter a simple, sensitive and rapid HPLC method coupled with a fluorescence detector was developed and validated for the assay of PCPT and its active metabolite HCPT in rat plasma. The method was validated for accuracy, precision, linearity, selectivity and recovery. The validated method was successfully applied to the pharmacokinetic study of PCPT in rats after intravenous administration. The results showed that PCPT could be mainly converted to HCPT in plasma with the AUC0-infinity value of 3.69 +/- 4.44 and 311.16 +/- 188.81 ng h/mL for PCPT and HCPT, respectively. PMID- 30003564 TI - Density estimation in the presence of heteroscedastic measurement error of unknown type using phase function deconvolution. AB - It is important to properly correct for measurement error when estimating density functions associated with biomedical variables. These estimators that adjust for measurement error are broadly referred to as density deconvolution estimators. While most methods in the literature assume the distribution of the measurement error to be fully known, a recently proposed method based on the empirical phase function (EPF) can deal with the situation when the measurement error distribution is unknown. The EPF density estimator has only been considered in the context of additive and homoscedastic measurement error; however, the measurement error of many biomedical variables is heteroscedastic in nature. In this paper, we developed a phase function approach for density deconvolution when the measurement error has unknown distribution and is heteroscedastic. A weighted EPF (WEPF) is proposed where the weights are used to adjust for heteroscedasticity of measurement error. The asymptotic properties of the WEPF estimator are evaluated. Simulation results show that the weighting can result in large decreases in mean integrated squared error when estimating the phase function. The estimation of the weights from replicate observations is also discussed. Finally, the construction of a deconvolution density estimator using the WEPF is compared with an existing deconvolution estimator that adjusts for heteroscedasticity but assumes the measurement error distribution to be fully known. The WEPF estimator proves to be competitive, especially when considering that it relies on minimal assumption of the distribution of measurement error. PMID- 30003563 TI - Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia. AB - BACKGROUND: In a phase 2 short-term (6 months) study of patients with congenital adrenal hyperplasia (CAH), continuous subcutaneous hydrocortisone infusion (CSHI) was found to be a safe, effective and well-tolerated method of replacing cortisol with improved disease and patient-related outcomes. OBJECTIVE: To evaluate the safety and efficacy of long-term CSHI. DESIGN: Single-centre, open-label, phase 2 extension study. PATIENTS: Five adults with classic CAH. MEASUREMENTS: Biomarkers of disease control, metabolic indices and health-related quality-of-life (HRQoL) estimates. RESULTS: Six of eight patients chose to continue on long-term CSHI therapy. Compared to baseline, eighteen months of CSHI resulted in decreased (P = 0.043) 0700-hour ACTH, 17-hydroxyprogesterone, androstenedione and progesterone; increased whole-body lean mass (P = 0.024); and improved HRQoL, especially symptoms of adrenal insufficiency (P = 0.003). Findings at six and eighteen months did not differ, and improvements achieved in androgen control, lean body mass and HRQoL after 6 months of CSHI were maintained at eighteen months. The hydrocortisone dose appeared to decrease with time [6 vs 18 months: 38.3 +/- 8.8 vs 33.6 +/- 12.2 mg/day (P = 0.062)], especially in women receiving oral contraceptives. Reduction of testicular adrenal rest and adrenal size observed at 6 months remained stable. In one patient, an adrenal adenoma continually decreased over time. Subjective improvement in hirsutism was reported. CONCLUSIONS: Long-term use of CSHI is a safe and well-tolerated treatment option in a select set of adults with classic CAH. Improvements observed short term in disease control and subjective health status continued long term. PMID- 30003565 TI - A log rank test for clustered data with informative within-cluster group size. AB - The log rank test is a popular nonparametric test for comparing survival distributions among groups. When data are organized in clusters of potentially correlated observations, adjustments can be made to account for within-cluster dependencies among observations, eg, tests derived from frailty models. Tests for clustered data can be further biased when the number of observations within each cluster and the distribution of groups within cluster are correlated with survival times, phenomena known as informative cluster size and informative within-cluster group size. In this manuscript, we develop a log rank test for clustered data that adjusts for the potentially biasing effect of informative cluster size and within-cluster group size. We provide the results of a simulation study demonstrating that our proposed test remains unbiased under cluster-based informativeness, while other candidate tests not accounting for the clustering structure do not properly maintain size. Furthermore, our test exhibits power advantages under scenarios in which traditional tests are appropriate. We demonstrate an application of our test by comparing time to functional progression between groups defined initial functional status in a spinal cord injury data set. PMID- 30003566 TI - A hybrid method for the determination of tubeimoside I in rat plasma after oral administration by LC-IT-TOF and UPLC-MS/MS. AB - Tubeimoside I (Tub) is a triterpenoid saponin isolated from Bolbostemma paniculatum[Maxim]Franquet. A sensitive and validated method was developed to determine Tub in rat plasma. This method combined the qualitative and quantitative advantages from liquid chromatography coupled with hybrid ion trap time of flight mass spectrometer (HPLC-DAD-IT-TOF-MS) and a triple quadrupole linear ion trap mass spectrometer 5500 (Qtrap 5500), owing to the narrow molecular range of Qtrap 5500 relative to the molecular weight of Tub. Initially, ion detection was achieved using negative ionization mode along with full scan on IT-TOF-MS. The detected precursor and product ions of Tub with the optimal mass parameters were determined on Qtrap 5500 by an online stepped optimization strategy and operated in negative multiple reaction monitoring mode. A simple methanol precipitation was employed with saikosaponin A as internal standard. The method was validated over the range from 20 to 2000 ng/mL with a lower limit of quantification of 20 ng/mL for Tub in plasma. The developed method was successfully applied to the pharmacokinetic study of Tub in rats following oral administration. Moreover, this method has some directive significance for the determination of other drugs whose parent ions exceeding the upper detection limit in Qtrap 5500. PMID- 30003567 TI - Time Course and Extent of Renal Function Changes in Patients Receiving Treatment for Staphylococcal Pneumonias: An Analysis Comparing Telavancin and Vancomycin from the ATTAIN Trials. AB - STUDY OBJECTIVE: Telavancin and vancomycin are both approved for treatment of hospital-acquired and ventilator-associated bacterial pneumonias caused by Staphylococcus aureus, and both agents can cause renal dysfunction. The objective of this study was to assess renal function changes by performing renal shift table analyses of telavancin- and vancomycin-treated patients in phase III trials. DESIGN: Retrospective, descriptive analysis of data from the safety population from the Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) trials. PATIENTS: A total of 1503 adults with hospital acquired or ventilator-associated bacterial pneumonia primarily caused by gram positive pathogens and who received telavancin (n = 751) or vancomycin (n = 752). MEASUREMENTS AND MAIN RESULTS: Decline or improvement in creatinine clearance (CrCl) across seven defined categories (<=30, >30-40, >40-50, >50-60, >60-70, >70 80, and >80 ml/min) was classified as negative or positive shifts, respectively. The number of categories crossed (either positive or negative) determined the grade of shift (of a potential grades 1-6, with crossing from one category to the next adjacent category defined as a grade 1 shift) at specific time points compared with baseline: day 4, day 7, and end of therapy (EOT). Approximately 77% 91.6% of patients had either no change or improvement of CrCl across all time points for both treatments. Negative shifts were consistent for telavancin (day 4, 19.3%; day 7, 19.0%; EOT, 23.0%) but increased over time for vancomycin (day 4, 8.4%; day 7, 12.3%; EOT, 19.3%). A significantly lower proportion of patients receiving vancomycin showed renal function decline on day 4 and day 7. At EOT, negative shift rates were similar between treatments (treatment difference 3.6% [95% CI -0.7 to 7.9]). At day 7 and EOT, a higher percentage of vancomycin treated patients experienced high-grade negative shifts relative to telavancin (day 7, vancomycin 2.8% vs telavancin 1.9%; EOT, vancomycin 4.7% vs telavancin 4.1%), though differences were not statistically significant. CONCLUSION: Use of shift tables revealed differences in timing of renal function changes in patients receiving telavancin and vancomycin. Telavancin-related declines in renal function were similar at day 4 and day 7, with a slight increase by EOT. This differed from vancomycin, which caused a steady increase in the percentage of patients with renal function decline over time. A significant difference in negative renal shifts between treatments occurred at day 4 and day 7 and favored vancomycin; however, the difference was minimal and not significant at EOT. PMID- 30003568 TI - Molecular bloodmeal analyses reveal that Trypanosoma cruzi-infected, native triatomine bugs often feed on humans in houses in central Brazil. AB - The identification of bloodmeal sources in triatomine bugs (Hemiptera: Reduviidae) is important in understanding vector-host associations and in measuring the risk for Chagas' disease transmission. The bloodmeal sources of triatomines infected with Trypanosoma cruzi (Trypanosomatida: Trypanosomatidae) caught in houses in central Brazil (Goias State and the Federal District) were investigated during 2012-2014. Mitochondrial cytochrome b amplicons were used to identify bloodmeals through high-resolution melting and DNA sequencing. Most bugs were found to have fed on either humans (45.7%) or chickens (43.1%). Human blood was detected in Triatoma sordida (n = 22/50 bugs), Triatoma pseudomaculata (n = 7/11 bugs), Panstrongylus megistus (n = 10/24 bugs), Panstrongylus geniculatus (n = 1/3 bugs) and Rhodnius neglectus (n = 18/28 bugs) (all: Hemiptera: Reduviidae). Sequencing identified Necromys (Rodentia: Cricetidae) mouse blood in P. geniculatus and Tropidurus (Squamata: Tropiduridae) lizard blood in T. pseudomaculata and T. sordida. These findings reveal new vector-host associations. The present results suggest frequent contact between humans and T. cruzi-infected triatomines in central Brazil and indicate that Chagas' disease transmission by native vectors is an ongoing threat. PMID- 30003569 TI - A pooling strategy to effectively use genotype data in quantitative traits genome wide association studies. AB - The goal of quantitative traits genome-wide association studies is to identify associations between a phenotypic variable, such as a vitamin level and genetic variants, often single-nucleotide polymorphisms. When funding limits the number of assays that can be performed to measure the level of the phenotypic variable, a subgroup of subjects is often randomly selected from the genotype database and the level of the phenotypic variable is then measured for each subject. Because only a proportion of the genotype data can be used, such a simple random sampling method may suffer from substantial loss of efficiency, especially when the number of assays is relative small and the frequency of the less common variant (minor allele frequency) is low. We propose a pooling strategy in which subjects in a randomly selected reference subgroup are aligned with randomly selected subjects from the remaining study subjects to form independent pools; blood samples from subjects in each pool are mixed; and the level of the phenotypic variable is measured for each pool. We demonstrate that the proposed pooling approach produces considerable gains in efficiency over the simple random sampling method for inference concerning the phenotype-genotype association, resulting in higher precision and power. The methods are illustrated using genotypic and phenotypic data from the Trinity Students Study, a quantitative genome-wide association study. PMID- 30003571 TI - Isocitrate dehydrogenase 1 mutations in melanoma frequently co-occur with NRAS mutations. AB - AIMS: Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to alpha-ketoglutarate. IDH1 mutations are associated with the accumulation of the oncometabolite D-2-hydroxyglutarate, which acts as an epigenetic modifier, and the development of multiple malignancies. METHODS AND RESULTS: From May 2013 to June 2017, 252 melanoma samples from 214 patients with advanced or distant metastatic disease were tested for somatic mutations with the 50-gene AmpliSeq version 2 Cancer Hotspot Panel. Two hundred and twenty-six samples were sequenced successfully from 206 patients with 26 samples being characterised as quantity not sufficient. Melanomas from 10 separate patients (4.9%) were positive for IDH1 R132C (nine) or R132S (one). In six cases, the tumours also had a co-existing NRAS mutation (p.Q61R, Q61L and Q61K in two patients each) (P = 0.0044), whereas three patients had BRAF non-V600E mutations (V600K, V600G and V600R). Two cases had a TP53 variant, two cases an ATM variant, one a CDKN2A variant and one had an APC variant. The patients' ages ranged from 45 to 82 years (mean = 65.3, median = 65 years) and three of 10 patients were female (M:F ratio = 2:3). Three patients were stage 3 and seven were stage 4. Two are deceased, five are alive with stable disease (four on pembrolizumab) and three have no evidence of disease. CONCLUSION: IDH mutations may define a unique subset of melanoma patients who are eligible for IDH1 targeted therapies or combined therapies, such as MEK inhibitors when there is co-existing NRAS mutations, or immunotherapy. PMID- 30003572 TI - MYB rearrangement and immunohistochemical expression in adenomyoepithelioma of the breast: a comparison with adenoid cystic carcinoma. AB - AIMS: Adenomyoepithelioma (AME) and adenoid cystic carcinoma (ACC) of the breast have been noted to occur simultaneously, raising the possibility that AME may represent a related or precursor lesion to ACC. ACC frequently harbours genetic rearrangement of the MYB gene. We sought to clarify the relationship between AME and ACC by comparing their rates of MYB expression by IHC and MYB rearrangement by FISH. METHODS AND RESULTS: IHC and FISH for MYB rearrangement were performed on paraffin-embedded sections of 11 breast ACCs, 11 non-breast ACCs and 11 breast AMEs. Using FISH, five of eight (63%) interpretable breast ACCs demonstrated MYB gene rearrangement. Nine of 11 (81%) breast ACCs demonstrated MYB expression (range = 20-95%). Of the three FISH-negative breast ACCs, two were solid variant and demonstrated strong MYB expression by IHC. Of the 10 interpretable non-breast ACCs, six showed MYB rearrangement, all of which were conventional type. Nine of these 11 (81%) cases showed MYB immunoexpression (range = 10-90%), including three solid-variant cases which were negative by FISH. No MYB rearrangements were detected by FISH in 10 interpretable AMEs. However, three of 11 cases (27%) showed weak to moderate MYB expression by IHC (range = 10-40%). CONCLUSIONS: Our results indicate that AMEs do not harbour MYB gene rearrangement. IHC for MYB may be helpful in diagnosing FISH-negative cases of ACC, particularly the diagnostically more difficult solid variants. However, weak to moderate MYB expression in a subset of AMEs highlights not only a potential diagnostic pitfall, but also shared pathophysiology with ACC worth investigating further at the genomic level. PMID- 30003570 TI - Quality evaluation for Radix Astragali based on fingerprint, indicative components selection and QAMS. AB - Radix Astragali (RA) is one of the most widely used Chinese herbs prescribed in many Chinese formulas to reinforce 'Qi' and treat vital energy deficiency. This study combined fingerprinting with quantitative analysis multi-components by a single marker (QAMS) to improve the quality control standard for RA on the basis of existing quality control methods of traditional Chinese medicinal materials. UPLC-ESI-TOF-MS technique was used to evaluate the quality of RA by fingerprinting and QAMS. Using the anti-inflammatory, anti-oxidation and anti anoxic activities to screen characteristic components of RA, the calycosin-7-O beta-d-glucoside (CG), ononin, astragaloside IV, astragaloside II, calycosin and astrageloside I significantly inhibited ear edema in mice, the calycosin and CG had good antioxidant activity and the astragaloside I had a significant anti hypoxia activity. Astragaloside I, astragaloside II, astragaloside IV, ononin, calycosin and CG had significant pharmacological actions. These components were comprehensively used as the indicative components for the quality control of RA. Astragaloside I was used as the internal standard of the relative correction factors of CG (13.45), ononin (0.51), calycosin (12.08), astragaloside IV (0.73) and astragaloside II (0.81). Astragaloside I and CG were used as internal standards of the relative correction factors of the flavonoids and saponins of ononin (1.11), calycosin (0.04), astragaloside IV (0.73) and astragaloside II (0.81). The study combined fingerprinting with QAMS to improve the quality control standard for RA. PMID- 30003574 TI - Concordance of PD-L1 expression in matched urothelial bladder cancer specimens. AB - AIMS: Programmed death ligand 1 (PD-L1) expression has predictive value for response to immune-checkpoint inhibitor treatment in urothelial cancer patients. The consistency of PD-L1 expression among different specimen types, however, is unknown. The aim of this study is to compare PD-L1 expression in matched transurethral resections of the bladder (TURB), cystectomy specimens and lymph node metastases of urothelial cancer patients. METHODS AND RESULTS: We performed PD-L1 (SP142) immunohistochemistry on whole tissue slides of 115 urothelial carcinoma patients who had undergone TURB, followed by radical cystectomy and/or pelvic lymph node dissection. The PD-L1 assay was positive if PD-L1 expression in immune cells occupied >=5% of the tumour area. PD-L1 was positive in 15 of 97 (15.5%) TURB, 17 of 98 (17.3%) cystectomies and nine of 49 (18.4%) lymph node metastases. Agreement of PD-L1 assay outcome between cystectomy and TURB (kappa = 0.34; P = 0.002) and cystectomy and lymph node metastasis (kappa = 0.35; P = 0.034) was fair; there was no agreement between TURB and lymph node metastasis (kappa = 0.045; P = 0.82). Discordance of PD-L1 outcome in matched TURB and cystectomy specimens occurred more frequently after neoadjuvant therapy (53.3% versus 25.4%; P = 0.03), and was not associated with other clinicopathological parameters. CONCLUSIONS: Urothelial bladder cancer patients showed fair agreement of PD-L1 assay outcome in cystectomies and matched TURB or lymph node specimens. PD-L1 expression was discordant more often after neoadjuvant therapy. Therefore, immune-checkpoint inhibitor studies should take into account specimen type and neoadjuvant therapy in assessing the predictive value of PD-L1 expression. PMID- 30003577 TI - Rethinking the voluntary act requirement: Implications from neuroscience and behavioral science research. AB - Criminal responsibility in the American legal system requires the presence of an actus reus-a harmful act that was committed voluntarily-and a mens rea, or guilty mind. Courts frequently consider questions surrounding mens rea but rarely question whether an act was committed voluntarily. Thus, courts presume that acts have been committed voluntarily and with an ill will; retribution, which serves the primary basis for punishment in the USA, relies on this presumption. Research in neuroscience and the behavioral sciences, however, suggests that this presumption is flawed and not sufficiently robust to justify punishment that is grounded in retribution. In this paper we discuss the presumption of voluntariness and free will inherent in the law, provide examples of how the courts have conflated actus reus and mens rea and the consequences of doing so, and the implications of neuroscience and behavioral science research for actus reus (also known as the voluntary act requirement). Finally, we propose re conceptualizing punishment within a consequentialist, empirically-based framework that does not rely on folk psychological notions about human behavior and reinvigorates the actus reus as the foundational requirement for legal responsibility. PMID- 30003573 TI - Model-based assessment of the benefits and risks of recombinant tissue plasminogen activator treatment in acute ischaemic stroke. AB - AIMS: Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to risk ratio assessment scheme as a supportive tool to optimize treatment outcome. METHODS: The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR). RESULTS: High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2-3 fold higher than with MCA stroke. CONCLUSIONS: The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity. PMID- 30003578 TI - Influence of soil porewater properties on the fate and toxicity of silver nanoparticles to Caenorhabditis elegans. AB - Engineered nanoparticles (NPs) entering the environment are subject to various transformations that in turn influence how particles are presented to, and taken up by, organisms. To understand the effect of soil properties on the toxicity of nanosilver to Caenorhabditis elegans, toxicity assays were performed in porewater extracts from natural soils with varying organic matter content and pH using 3-8 nm unfunctionalized silver (Ag 3-8Unf), 52-nm polyvinylpyrrolidone (PVP)-coated Ag NPs (Ag 52PVP), and AgNO3 as ionic Ag. Effects on NP agglomeration and stability were investigated using ultraviolet-visible (UV-vis) spectroscopy and asymmetric flow field-flow fractionation (AF4); Ag+ showed greater overall toxicity than nanosilver, with little difference between the NP types. Increasing soil organic matter content significantly decreased the toxicity of Ag 3-8Unf, whereas it increased that of AgNO3 . The toxicity of all Ag treatments significantly decreased with increasing porewater pH. Dissolution of both NPs in the porewater extracts was too low to have contributed to their observed toxic effects. The UV-vis spectroscopy revealed low levels of agglomeration/aggregation independent of soil properties for Ag 3-8Unf, whereas higher organic matter as well as low pH appeared to stabilize Ag 52PVP. Overall, both soil organic matter content and pH affected NP fate as well as toxicity to C. elegans; however, there appears to be no clear connection between the measured particle characteristics and their effect. Environ Toxicol Chem 2018;37:2609-2618. (c) 2018 SETAC. PMID- 30003579 TI - Beyond mean modelling: Bias due to misspecification of dispersion in Poisson inverse Gaussian regression. AB - In clinical trials one traditionally models the effect of treatment on the mean response. The underlying assumption is that treatment affects the response distribution through a mean location shift on a suitable scale, with other aspects of the distribution (shape/dispersion/variance) remaining the same. This work is motivated by a trial in Parkinson's disease patients in which one of the endpoints is the number of falls during a 10-week period. Inspection of the data reveals that the Poisson-inverse Gaussian (PiG) distribution is appropriate, and that the experimental treatment reduces not only the mean, but also the variability, substantially. The conventional analysis assumes a treatment effect on the mean, either adjusted or unadjusted for covariates, and a constant dispersion parameter. On our data, this analysis yields a non-significant treatment effect. However, if we model a treatment effect on both mean and dispersion parameters, both effects are highly significant. A simulation study shows that if a treatment effect exists on the dispersion and is ignored in the modelling, estimation of the treatment effect on the mean can be severely biased. We show further that if we use an orthogonal parametrization of the PiG distribution, estimates of the mean model are robust to misspecification of the dispersion model. We also discuss inferential aspects that are more difficult than anticipated in this setting. These findings have implications in the planning of statistical analyses for count data in clinical trials. PMID- 30003580 TI - Modulation of the orthostatic blood pressure response by acute nitrate consumption is dependent upon ethnic origin. AB - Orthostatic stress triggers a response to maintain cerebral perfusion and prevent syncope. Given the hypotensive effects of inorganic nitrate this response to orthostasis may be altered by acute supplementation with inorganic nitrate and modified by ethnic origin. Caucasian and SE Asian (n = 30 for both), were recruited and subjected to an 'active stand test' and brachial artery blood pressure (BP), digit blood flow and ECG were recorded. Following inorganic nitrate supplementation, (10 mg/kg body mass) the tests were repeated. For both Caucasian and SE Asians transition to standing increased diastolic pressure (DP) and heart rate (HR) (P < 0.001 for both) and by calculation increased rate pressure product (P < 0.001) and decreased pulse pressure (P < 0.01 for both) indicative of decreased ventricular filling. Nitrate supplementation decreased both DP (P < 0.001) and HR (P < 0.001). Assessment of HR variability suggested sympathetic nerve activity, was higher throughout in Caucasians (P < 0.05) coupled with higher parasympathetic tone (P < 0.01). Nitrate had no effect on cardiac autonomic nerve activity, as estimated using HR variability, for supine or standing subjects. The tachycardia and hypertension associated with orthostatic stress were preserved in both Caucasian and SE Asian subjects, however, we highlight possible differences in autonomic nervous system activity between Caucasians and SE Asians. SE Asians are resistant to the hypotensive effects of inorganic nitrate supplementation suggesting the absence of a crucial mechanism for activation of the nitrate-nitrite-nitric oxide system. PMID- 30003581 TI - ETA as a novel Kv2.1 inhibitor ameliorates beta-cell dysfunction and hyperglycaemia. AB - The Kv2.1 channel plays an important role in the regulation against pancreatic beta-cell dysfunctions. Therefore, it is regarded as a promising target for drug discovery against type 2 diabetes. In the present study, we found that the small molecule 4-ethoxy-N-{[6-(2-thienyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3 yl]methyl}aniline (ETA), a novel Kv2.1 inhibitor, may be capable of promoting glucose-stimulated insulin secretion and protecting from apoptosis in pancreatic INS-832/13 cells. The assay of ETA on type 2 diabetic mice induced by high-fat diet (HFD)/streptozocin (STZ) confirmed its potency in ameliorating glucose homeostasis. ETA administration reduced fasting blood glucose and glycated haemoglobin levels, improved oral glucose tolerance, and increased serum insulin levels in HFD/STZ mice. Mechanism study demonstrated that ETA protected INS 832/13 cells involving the regulation against protein kinase B and extracellular regulated protein kinase 1/2 signalling pathways. Our study has confirmed the underlying regulation of Kv2.1 against beta-cell function and also addressed the potential of ETA as a lead compound in the treatment of type 2 diabetes mellitus. PMID- 30003582 TI - Effect of ghrelin on the biochemical and histopathology parameters and spermatogenesis cycle following experimental varicocele in rat. AB - BACKGROUND: Varicocele is one of the major causes of infertility in men in which testicular function is progressively damaged. OBJECTIVES: This study aimed to determine the effect of ghrelin on antioxidant enzymes activity (catalase, SOD, GPx), malondialdehyde (MDA) level and spermatogenesis cycle after induction of varicocele in rat. MATERIALS AND METHODS: Twenty-one male Wistar rats were randomly divided into three groups: I-control group, II-rats with induced varicocele and injection of physiological saline and III-rats with induced varicocele and injection of ghrelin. At the end of the experiment, animals were sacrificed and their testes were removed. Antioxidant enzymes activity and MDA level were measured. Histopathological tests, Johnsen's score and sperm parameters were also evaluated. RESULTS: In varicocele group with ghrelin administration (group III), the levels of SOD (0.183 +/- 0.024), GPX (9.4250 +/- 0.103) and TAC (2.79 +/- 0.464) increased significantly (p < 0.05), while MDA (0.304 +/- 0.004) level decreased significantly (p < 0.05) compared with varicocele and normal saline group (II). There was no significant difference in the activity of catalase between group III (0.122 +/- 0.018) and group II (0.108 +/- 0.018), although ghrelin improved catalase activity in group III compared to group II. Also, in group III, there were significant increases in the Johnsen's score (7.920), sperm count (70.29 +/- 5.82) and sperm viability (87.14 +/- 5.21) compared with group II (p < 0.05). CONCLUSION: Ghrelin can improve the capacity of antioxidant enzymes to reduce the oxidative stress caused by varicocele and reduce spermatogenesis cycle. Therefore, special attention should be paid to ghrelin in studies evaluating antioxidant compounds in varicocele. PMID- 30003583 TI - Surgical treatment of peri-implantitis lesions with or without the use of a bone substitute-a randomized clinical trial. AB - AIM: To assess whether the treatment outcome differed between surgical debridement, with or without a bone substitute. MATERIALS AND METHODS: Forty-one adults with three- or four-wall peri-implant bone defects were enrolled in a 1 year RCT. Surgical debridement (control group), or in combination with a bone substitute (Endobon(r)) (test group) was performed. RESULTS: Radiographic evidence of defect fill (primary outcome) was only significant in the test group (P = 0.004). At year 1, no bleeding on probing (BOP) in the control and test groups were 7/20 (35%) and 10/21 (47.6%), respectively (chi2 = 0.67, P = 0.41). Plaque scores did not differ by study group at baseline (P = 0.31), or at year 1 (P = 0.08). Mid-buccal soft tissue recession changes did not differ by groups (P = 0.76). Successful treatment outcome (defect fill >=1.0 mm, PPD values at implant <=5 mm, no BOP, and no suppuration was identified in 1/20 (5.0%) control, and 9/21 (42.9%) test individuals (F = 7, 9, P < 0.01). Number needed to treat analysis identified an absolute risk reduction of 32.8% in benefit of the test procedure. (F = 7, 9, P < 0.01). CONCLUSIONS: Successful treatment outcome using a bone substitute was more predictable when a composite therapeutic endpoint was considered. PMID- 30003584 TI - The protective effects of Arctium lappa L. Extract on testicular injuries induced by ethanol in rats. AB - The aim of this study is to assess the antioxidant activity and also protective effects of Arctium lappa L. (AL) extract on ethanol-induced testicular injuries in rats. In addition, the total phenol and flavonoid contents of the methanolic extracts were analysed and the antioxidant activity of the extract was investigated. The studied extract possessed strong antioxidant activity (IC50 ; 0.113 +/- 0.007 mg/ml) and exhibited more active than the ascorbic acid (IC50 ; 0.142 +/- 0.002 mg/ml). The histological examinations revealed that the co administration of ethanol and AL extract inhibits the testicular injuries, alterations in superoxide dismutase (SOD) activity, and H2 O2 and malondialdehyde (MDA) levels were observed in ethanol-treated rats in comparison to the control group. The obtained results demonstrated strong pharmaceutical activities of AL and its potential capacity to be developed as a new health-care supplement against ROS-related substances. PMID- 30003585 TI - Proton pump inhibitors and Raynaud's phenomenon: is there a link? PMID- 30003586 TI - Serial evaluation of resting and exercising overground endoscopic examination results in young Thoroughbreds with no treatment intervention. AB - BACKGROUND: We hypothesised that grade/appearance for upper respiratory tract (URT) disorders identified at the first overground endoscopy (OGE) examination would vary at subsequent examinations. OBJECTIVES: To compare OGE examinations from horses evaluated on at least two occasions under similar exercise conditions without treatment intervention. STUDY DESIGN: Retrospective cohort. METHODS: Pre exercise and exercising OGE recordings from Thoroughbred horses undergoing multiple examinations under similar exercise conditions were reviewed, with the first two recordings for each horse statistically evaluated. Paired Wilcoxon signed-rank tests were used to assess differences in exercise and physiological parameters between examinations. Z-tests were used to assess the proportion of changes in URT disorder grade/appearance between examinations. A McNemar's test was used to compare the proportion of horses with each disorder at each examination. Test-retest reliability across examinations was assessed using Spearman's rho, and ordered logistic regression used to explore temporal effects on repeatability. Lattice plots were constructed to view variability in disorders over time. RESULTS: Seventy-eight horses (median age 2.4 years) with 195 resting endoscopic examinations including 72/78 horses with 179 pre-exercise and exercising OGE examinations were evaluated. Median time between examinations was 226.5 days with no differences between exercise and physiological parameters. Grades significantly varied between examinations for all disorders, and in particular for palatal instability (PI) and epiglottic grade at rest. A temporal link between examination interval and disorder grade change was identified for PI and resting arytenoid asymmetry. MAIN LIMITATIONS: OGE re-examinations within a shorter, more consistent time-frame would allow determination of intrahorse variability. The sample size was inadequate to conclusively establish temporal links between disorders and time between examinations. CONCLUSIONS: Variability for most URT abnormalities identified with OGE should be considered when making therapeutic decisions based on a single examination and may partially explain development of additional URT conditions after surgical intervention. The Summary is available in Portuguese - see Supporting Information. PMID- 30003587 TI - Multivariate multiple test procedures based on nonparametric copula estimation. AB - Multivariate multiple test procedures have received growing attention recently. This is due to the fact that data generated by modern applications typically are high-dimensional, but possess pronounced dependencies due to the technical mechanisms involved in the experiments. Hence, it is possible and often necessary to exploit these dependencies in order to achieve reasonable power. In the present paper, we express dependency structures in the most general manner, namely, by means of copula functions. One class of nonparametric copula estimators is constituted by Bernstein copulae. We extend previous statistical results regarding bivariate Bernstein copulae to the multivariate case and study their impact on multiple tests. In particular, we utilize them to derive asymptotic confidence regions for the family-wise error rate (FWER) of multiple test procedures that are empirically calibrated by making use of Bernstein copulae approximations of the dependency structure among the test statistics. This extends a similar approach by Stange et al. (2015) in the parametric case. A simulation study quantifies the gain in FWER level exhaustion and, consequently, power that can be achieved by exploiting the dependencies, in comparison with common threshold calibrations like the Bonferroni or Sidak corrections. Finally, we demonstrate an application of the proposed methodology to real-life data from insurance. PMID- 30003588 TI - Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase-5 in human monocytes. AB - Outer membrane vesicles (OMVs) are constitutively produced by Gram-negative bacteria both in vivo and in vitro. These lipid-bound structures carry a range of immunogenic components derived from the parent cell, which are transported into host target cells and activate the innate immune system. Recent advances in the field have shed light on some of the multifaceted roles of OMVs in host-pathogen interactions. In this study, we investigated the ability of OMVs from two clinically important pathogens, Pseudomonas aeruginosa and Helicobacter pylori, to activate canonical and noncanonical inflammasomes. P. aeruginosa OMVs induced inflammasome activation in mouse macrophages, as evidenced by "speck" formation, as well as the cleavage and secretion of interleukin-1beta and caspase-1. These responses were independent of AIM2 and NLRC4 canonical inflammasomes, but dependent on the noncanonical caspase-11 pathway. Moreover, P. aeruginosa OMVs alone were able to activate the inflammasome in a TLR-dependent manner, without requiring an exogenous priming signal. In contrast, H. pylori OMVs were not able to induce inflammasome activation in macrophages. Using CRISPR/Cas9 knockout THP 1 cells lacking the human caspase-11 homologs, caspase-4 and -5,we demonstrated that caspase-5 but not caspase-4 is required for inflammasome activation by P. aeruginosa OMVs in human monocytes. In contrast, free P. aeruginosa lipopolysaccharide (LPS) transfected into cells induced inflammasome responses via caspase-4. This suggests that caspase-4 and caspase-5 differentially recognize LPS depending on its physical form or route of delivery into the cell. These findings have relevance to Gram-negative infections in humans and the use of OMVs as novel vaccines. PMID- 30003589 TI - Melatonin secretion following brain midline irradiation is diminished, but not correlated with subjective sleep disturbances. AB - OBJECTIVE: Cranial irradiation for brain tumours or leukaemias has been related to cognitive, endocrine and psychosocial late effects as well as sleep disturbances and increased daytime sleepiness. Studies suggest that cranial irradiation might impact on pineal melatonin secretion. Melatonin is an important regulator in human circadian rhythms and the sleep-wake cycle. The objective of this study was to investigate melatonin secretion, subjective sleep parameters and their interplay in a cohort of cranially irradiated head and brain tumour and leukaemia survivors at least 3 years after radiotherapy. DESIGN: Cross-sectional study. PATIENTS: Thirty-eight adults. MEASUREMENTS: Melatonin secretion was evaluated by measuring its metabolite 6-sulphatoxymelatonin in collected overnight urine. Subjective sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. The Beck Depression Inventory II was used to screen for depressive symptoms because of their impact on sleep. RESULTS: Patients irradiated in the brain midline had significantly lower melatonin secretion (P = 0.008). Subjects exhibited a high prevalence of sleeping difficulties, daytime sleepiness and depression, with females and overweight subjects particularly affected. Melatonin values and subjective sleep parameters did not correlate with each other or with treatment and most patient variables. CONCLUSIONS: Our data suggest that radiation exposure to the pineal gland negatively affects melatonin secretion. This lack of pineal melatonin does not influence subjective sleep quality. As melatonin has important antioxidant and cancer-protective effects, further research is necessary to elucidate whether these patients have an increased risk of developing secondary neoplasms and other radiation late effects. PMID- 30003590 TI - Plasmonic Retrofitting of Membrane Materials: Shifting from Self-Regulation to On Command Control of Fluid Flow. AB - This work calls for a paradigm shift in order to change the operational patterns of self-regulated membranes in response to chemical signals. To this end, the fabrication of a retrofitting material is introduced aimed at developing an innovative generation of porous substrates endowed with symbiotic but fully independent sensing and actuating capabilities. This is accomplished by transferring carefully engineered plasmonic architectures onto commercial microfiltration membranes lacking of such features. The integration of these materials leads to the formation of a coating surface proficient for ultrasensitive detection and "on-command" gating. Both functionalities can be synergistically modulated by the spatial and temporal distribution of an impinging light beam offering an unprecedented control over the membrane performance in terms of permeability. The implementation of these hybrid nanocomposites in conventional polymeric porous materials holds great potential in applications ranging from intelligent fluid management to advanced filtration technologies and controlled release. PMID- 30003591 TI - A Deformable and Highly Robust Ethyl Cellulose Transparent Conductor with a Scalable Silver Nanowires Bundle Micromesh. AB - Huge challenges remain regarding the facile fabrication of neat metallic nanowires mesh for high-quality transparent conductors (TCs). Here, a scalable metallic nanowires bundle micromesh is achieved readily by a spray-assisted self assembly process, resulting in a conducting mesh with controllable ring size (4 45 um) that can be easily realized on optional polymer substrates, rendering it transferable to various deformable and transparent substrates. The resultant conductors with the embedded nanowires bundle micromesh deliver superior and customizable optoelectronic performances, and can sustain various mechanical deformations, environmental exposure, and severe washing, exhibiting feasibility for large-scale manufacturing. The silver nanowires bundle micromesh with explicit conductive paths is embedded into an ethyl cellulose (EC) transparent substrate to achieve superior optoelectronic properties endowed by a low amount of incorporated nanowires, which leads to reduced extinction cross-section as verified by optical simulation. A representative EC conductor with a low sheet resistance of 25 Omega ?-1 , ultrahigh transmittance of 97%, and low haze of 2.6% is attained, with extreme deformability (internal bending radius of 5 um) and waterproofing properties, opening up new possibilities for low-cost and scalable TCs to replace indium-tin oxide (ITO) for future flexible electronics, as demonstrated in a capacitive touch panel in this work. PMID- 30003592 TI - Some comments on "Achilles and patellar tendinopathy display opposite changes in elastic properties: A shear wave elastography study". PMID- 30003593 TI - Do insertional and mid-portion Achilles tendinopathy display different material properties? PMID- 30003594 TI - Pharmacological effects of the isomeric mixture of alpha and beta amyrin from Protium heptaphyllum: a literature review. AB - Protium heptaphyllum Aubl. belongs to the Burseraceae family. It is commonly called 'almecegueira' and is known to produce an amorphous resin which has constituents such as alpha- and beta-amyrin, taraxastan-3-oxo-20-ol and sitostenonein. The alpha- and beta-amyrin from P. heptaphyllum have pharmacological activities in several systems, such as central and peripheral nervous system, gastrointestinal tract and immunological system. In this study, our objective was to review pharmacological activities and to gather more information on the mixture of alpha- and beta-amyrin obtained from P. heptaphyllum to guide future preclinical and clinical studies using this compound. This review consisted of searches performed using scientific databases such as PubMed, SciELO, LILACS, SciFinder and Science Direct. Some uses of alpha- and beta-amyrin have been partially confirmed by previous studies demonstrating analgesic, anti-inflammatory, anticonvulsant, antidepressive, gastroprotective, hepatoprotective, antipancreatitic, anticholytic, antihyperglycemic and hypolipidemic effects. It is noteworthy that there are no alpha- and beta-amirin toxicity tests described in the literature as recommended in the international guidelines, and such tests are one of the research stages to proceed in clinical and preclinical trials if this compound was to be used. PMID- 30003595 TI - Association between vitamin D, antimicrobial peptides and urinary tract infection in infants and young children. AB - AIM: Vitamin D stimulates production of the endogenous antimicrobial peptides cathelicidin and beta-defensin-2, which are expressed in the urinary tract. We investigated vitamin D status and levels of cathelicidin and beta-defensin-2 and their association with urinary tract infection (UTI). METHODS: The study included 120 children under three years of age: 76 children with UTIs and 44 otherwise healthy children with congenital hydronephrosis. Serum 25-hydroxycholecalciferol levels were measured by direct competitive electro-chemiluminescence immunoassay, and plasma cathelicidin and beta-defensin-2 concentrations were analysed by enzyme-linked immunosorbent assay. RESULTS: We found that vitamin D insufficiency and deficiency are prevalent in young children (21%). Serum vitamin D levels negatively correlated with age and were significantly lower in girls. Levels of vitamin D positively correlated with levels of cathelicidin but not with beta defensin-2. Low concentrations of vitamin D were associated with UTIs in girls, but we did not see any correlation with the recurrence of infection at one-year follow-up. CONCLUSION: Vitamin D deficiency is common and may prove to be a risk factor for UTIs especially in girls. We hypothesise that adequate supplementation with vitamin D may become a way to prevent first-time UTIs. PMID- 30003596 TI - Identification and tracking of Addictovigilance signals in general practice: which interactions between the general practitioners and the French Addictovigilance Network? AB - Addictovigilance is a health vigilance dedicated to the survey of medicinal or illicit psychoactive substance use disorders (SUDs). France is the only European country to have a vigilance system specifically dedicated to substances with an abuse/addiction potential. The French Addictovigilance system is organized in a network of regional tertiary centres (called Abuse and Dependence Monitoring Centres, CEIP-Addictovigilance) and works in close collaboration with Regional and National health authorities. Because of the essential and unavoidable nature of their practice in the French Healthcare system, general practitioners (GPs) are key actors to identify and track Addictovigilance signals. They have been involved in several of the pharmacoepidemiological surveys implemented by the French Addictovigilance Network (FAN). Now, they increasingly participate in clinical research projects and studies. In this article, interactions between GPs and the FAN are illustrated with two examples: patients on opioid substitution treatment and patients on opioid analgesics. Collaborations between GPs and the FAN could be further potentiated. In particular, more effective communication on psychoactive SUDs including abuse/addiction is necessary to optimize the implementation of preventive measures for patients on psychoactive substances medications, and to improve the attitudes of GPs and more widely health professionals in the management of any psychoactive user suffering from SUDs. In addition, both adapted training and improved collaborative research could contribute to the optimization (safety, quality) of professional practices. PMID- 30003597 TI - 5alpha-Cyprinol sulfate: Complete NMR assignment and revision of earlier published data, including the submission of a computer-readable assignment in NMReDATA format. PMID- 30003598 TI - Marginal bone level and survival of short and standard-length implants after 3 years: An Open Multi-Center Randomized Controlled Clinical Trial. AB - OBJECTIVES: The present multi-center randomized controlled clinical trial sought to compare the marginal bone level (MBL) changes and survival of 6- and 11-mm implants. MATERIAL AND METHODS: Ninety-five patients receiving a total of 209 dental implants were enrolled. Subjects were randomly allocated to two cohorts: test (4.0 * 6 mm; N = 108) or control (4.0 * 11 mm; N = 101) implant groups. To be randomized, all edentulous sites were anatomically qualified to receive 11 mm implant. Two to three implants were placed in maxillary or mandibular posterior regions and loaded with splinted provisional restoration after 6 weeks and definitive restoration 6 months thereafter. Test and control implants were followed by clinical and radiographic examinations on an annual basis up to 3 years. RESULTS: Radiographic assessment of MBL 3 years after loading revealed the bone to be located at 0.27 mm (+/-0.40) and 0.44 mm (+/-0.74) apical to the implant platform in the test and control groups, respectively. During the 3 years of follow-up since loading, 0.04 mm (+/-0.43) MBL gain and 0.02 mm (+/-0.76) of MBL loss were observed in the 6-mm (test) and 11-mm (control) groups, respectively. The MBL's for test and control were significantly different (p = 0.000) in favor of short implants. The cumulative survival rates from placement after 3 years were 96% and 99% for the 6- and 11-mm implants, respectively, with no statistical significance. CONCLUSIONS: Reconstruction of partially edentulous posterior maxilla or mandible with 6- or 11-mm implants led to stable marginal bone level and high implant survival rate after 3 years. PMID- 30003599 TI - Hookworms Make Us Human: The Microbiome, Eco-immunology, and a Probiotic Turn in Western Health Care. AB - Historians of science have identified an ecological turn underway in immunology, driven by the mapping of the human microbiome and wider environmentalist anxieties. A figure is emerging of the human as a holobiont, composed of microbes and threatened by both microbial excess and microbial absence. Antimicrobial approaches to germ warfare are being supplemented by probiotic approaches to restoring microbial life. This article examines the political ecology of this probiotic turn in Western health care. It focuses on Necator americanus-a species of human hookworm-and its relations with immunologists. The analysis moves from a history of human disentanglement from hookworm, to contemporary anxieties about their absence. It examines the reintroduction of worms for helminthic therapy and explores emerging trajectories for probiotic health care involving the synthesis, modification, and/or restoration of worms and their salutary ecologies. The conclusion differentiates these trajectories and identifies an emerging model of "post-paleo" microbiopolitics. This article is protected by copyright. All rights reserved. PMID- 30003600 TI - One-Step Construction of N,P-Codoped Porous Carbon Sheets/CoP Hybrids with Enhanced Lithium and Potassium Storage. AB - Despite the desirable advancement in synthesizing transition-metal phosphides (TMPs)-based hybrid structures, most methods depend on foreign-template-based multistep procedures for tailoring the specific structure. Herein, a self template and recrystallization-self-assembly strategy for the one-step synthesis of core-shell-like cobalt phosphide (CoP) nanoparticles embedded into nitrogen and phosphorus codoped porous carbon sheets (CoP?NPPCS), is first proposed. Relying on the unusual coordination ability of melamine with metal ions and the cooperative hydrogen bonding of melamine and phytic acid to form a 2D network, a self-synthesized single precursor can be attained. Importantly, this approach can be easily expanded to synthesize other TMPs?NPPCS. Due to the unique compositional and structural characteristics, these CoP?NPPCSs manifest outstanding electrochemical performances as anode materials for both lithium- and potassium-ion batteries. The unusual hybrid architecture, the high specific surface area, and porous features make the CoP?NPPCS attractive for other potential applications, such as supercapacitors and electrocatalysis. PMID- 30003601 TI - Liquid extraction surface analysis nanospray electrospray ionization based lipidomics for in situ analysis of tumor cells with multidrug resistance. AB - RATIONALE: Multidrug resistance (MDR) occurs frequently and is a major challenge in tumor treatment. The lipid composition in the cell membrane and the redox balance are closely associated with the development of MDR. Liquid extraction surface analysis in combination with mass spectrometry (LESA-MS) has the characteristics of minimal sample preparation, rapid analysis, high sensitivity and high throughput, and has obtained wide applications. METHODS: LESA-MS was employed to in situ determine the lipids and other specific metabolites of intact MCF-7/ADR cells (adriamycin-resistant breast cancer cells) and its parental MCF 7/S cells grown on a glass slide. In situ atomic force microscopy was used to observe the morphology of tumor cells before and after extraction. Multivariate statistical analysis was used to investigate the potential lipid biomarkers correlated with the MDR. Moreover, the cell membrane fluidity and potential were determined. RESULTS: The changes in the level of the lipids were closely correlated with the multidrug resistance of MCF-7/S cells. Moreover, lower cell membrane fluidity and higher cell membrane potential were observed and thus demonstrated the changes in the cell membrane induced by multidrug resistance. Also, the ratios of GSH/GSSG, ATP/ADP and ATP/AMP were significantly higher in MCF-7/ADR cells relative to MCF-7/S cells. CONCLUSIONS: Lower cell membrane fluidity and higher cell membrane potential caused by the changes in lipid compositions, enhanced anti-oxidative ability and energy generation were involved in the development of the MDR. The specific alterations identified in this study may provide more information for overcoming MDR. PMID- 30003604 TI - Editor's Note. PMID- 30003602 TI - Motor skills in association with physical activity, sedentary time, body fat, and day care attendance in 5-6-year-old children-The STEPS Study. AB - PURPOSE: This study examined how motor skills are associated with physical activity (PA), sedentary time, body fat, and day care attendance among young children. Also, the motor skills of healthy weight children were compared to those who were overweight or obese. METHODS: The study population consisted of five to six years old children (n = 111; 45 boys) who participated in the longitudinal STEPS Study carried out in Southwest Finland in 2013-2014. Motor skills were measured with the Bruininks-Oseretsky test, second edition (BOT-2) including fine manual control, manual coordination, body coordination, and strength and agility. Moderate-to-vigorous intensity PA (MVPA) and sedentary time were objectively measured with hip-worn accelerometers. Body mass index (BMI) was calculated based on measured weight and height. Body fat percentage (BF%) was measured using segmental multifrequency bio impedance analysis. Day care attendance was measured with parental questionnaires. Linear regression analyses were adjusted by age, sex, and parental education. RESULTS: Day care attendance was positively associated with body coordination and strength and agility. Lower BF% in girls was associated with higher strength and agility scores. There were no associations between manual coordination or fine manual control and the explanatory variables. Objectively measured MVPA and sedentary time showed no associations with motor skills. Overweight children had significantly lower scores in all motor skill composites (P < 0.05) than healthy weight children, except in fine manual control where the association was non-significant (P = 0.202). CONCLUSIONS: Early prevention of overweight and obesity may be of importance and day care attendance may be beneficial for motor skill development. PMID- 30003603 TI - Asymmetric assortative mating and queen polyandry are linked to a supergene controlling ant social organization. AB - Nonrecombining genomic variants underlie spectacular social polymorphisms, from bird mating systems to ant social organization. Because these "social supergenes" affect multiple phenotypic traits linked to survival and reproduction, explaining their persistence remains a substantial challenge. Here, we investigate how large nonrecombining genomic variants relate to colony social organization, mating system and dispersal in the Alpine silver ant, Formica selysi. The species has colonies headed by a single queen (monogynous) and colonies headed by multiple queens (polygynous). We confirmed that a supergene with alternate haplotypes-Sm and Sp-underlies this polymorphism in social structure: Females from mature monogynous colonies had the Sm/Sm genotype, while those from polygynous colonies were Sm/Sp and Sp/Sp. Queens heading monogynous colonies were exclusively mated with Sm males. In contrast, queens heading polygynous colonies were mated with Sp males and Sm males. Sm males, which are only produced by monogynous colonies, accounted for 22.9% of the matings with queens from mature polygynous colonies. This asymmetry between social forms in the degree of assortative mating generates unidirectional male-mediated gene flow from the monogynous to the polygynous social form. Biased gene flow was confirmed by a significantly higher number of private alleles in the polygynous social form. Moreover, heterozygous queens were three times as likely as homozygous queens to be multiply mated. This study reveals that the supergene variants jointly affect social organization and multiple components of the mating system that alter the transmission of the variants and thus influence the dynamics of the system. PMID- 30003605 TI - Influence of rearing temperature on triacylglycerol storage in the pea aphid, Acyrthosiphon pisum. AB - Total fatty acids in the pea aphid reared at low temperatures increased significantly compared to that at high rearing temperatures. This change is reflected in a large increase of myristic acid, which occurs exclusively in triacylglycerols. When aphids were moved from 25 degrees C to a lower rearing temperature at 10 degrees C, saturated fatty acids accumulated over time, reaching a maximum at 16th day. When aphids were moved to 4 degrees C, a temperature below the developmental threshold, those aphids did not accumulate saturated fatty acids. Similar results were observed when aphids were exposed to sequential decrease in rearing temperature. However, both total fatty acids and myristic acid in the aphids from the treatments of sequential decreasing rearing temperature were significantly higher compared to those in the aphids from the treatments of sudden decreasing rearing temperature. This result, therefore, supports the hypothesis that cold-adapted aphids can survive under threshold temperature for a longer period of time than noncold-adapted aphids. Acetyl-CoA carboxylase activity in the aphids at 25 degrees C was twofold higher than that in the aphids at 10 degrees C, whereas fatty acid synthase activities in the aphids reared at 25 and 10 degrees C are similar. Aphids reared at 10 degrees C showed a threefold reduction in reproduction rates. This reduced production of new nymphs reduces energy demand and would allow for accumulation of energy in the form of triacylglycerols. Therefore, the increased level of saturated fatty acids in aphids reared at low temperature is probably related to lower utilization of fatty acids rather than increased rates of biosynthesis. PMID- 30003606 TI - The pentatricopeptide repeat protein EMPTY PERICARP8 is required for the splicing of three mitochondrial introns and seed development in maize. AB - Splicing of plant organellar group II introns is under accurate nuclear control that employs many nucleus-encoded protein cofactors from various families. For mitochondrial introns, only a few splicing factors have been characterized because disruption of their functions often causes embryo lethality. Here, we report the function of Empty Pericarp8 (Emp8) in the splicing of three group II introns in mitochondria, complex I biogenesis, and seed development in maize. Emp8 encodes a P subfamily pentatricopeptide repeat protein that localizes in mitochondria. The loss-of-function mutants of Emp8 are embryo lethal, showing severely arrested embryo and endosperm development in maize. The respiration rate in the emp8 mutants is reduced with substantially enhanced expression of alternative oxidases. Transcript analysis indicated that the trans-splicing of nad1 intron 4 and cis-splicing of nad4 intron 1 are abolished, and the cis splicing of nad2 intron 1 is severely impaired in the emp8 mutants. These defects consequently lead to the disassembly of mitochondrial complex I and a dramatic reduction in its activity. Together, these results suggest that Emp8 is required for the trans-splicing of nad1 intron 4 and cis-splicing of nad4 intron 1 and nad2 intron 1, which is essential to mitochondrial complex I assembly and hence to embryogenesis and endosperm development in maize. PMID- 30003607 TI - Diacylglycerol acyltransferase 1 is activated by phosphatidate and inhibited by SnRK1-catalyzed phosphorylation. AB - Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final and committed step in the Kennedy pathway for triacylglycerol (TAG) biosynthesis and, as such, elucidating its mode of regulation is critical to understand the fundamental aspects of carbon metabolism in oleaginous crops. In this study, purified Brassica napus diacylglycerol acyltransferase 1 (BnaDGAT1) in n-dodecyl-beta-d maltopyranoside micelles was lipidated to form mixed micelles and subjected to detailed biochemical analysis. The degree of mixed micelle fluidity appeared to influence acyltransferase activity. BnaDGAT1 exhibited a sigmoidal response and eventual substrate inhibition with respect to increasing concentrations of oleoyl CoA. Phosphatidate (PA) was identified as a feed-forward activator of BnaDGAT1, enabling the final enzyme in the Kennedy pathway to adjust to the incoming flow of carbon leading to TAG. In the presence of PA, the oleoyl-CoA saturation plot became more hyperbolic and desensitized to substrate inhibition indicating that PA facilitates the transition of the enzyme into the more active state. PA may also relieve possible autoinhibition of BnaDGAT1 brought about by the N-terminal regulatory domain, which was shown to interact with PA. Indeed, PA is a key effector modulating lipid homeostasis, in addition to its well recognized role in lipid signaling. BnaDGAT1 was also shown to be a substrate of the sucrose non fermenting-1-related kinase 1 (SnRK1), which catalyzed phosphorylation of the enzyme and converted it to a less active form. Thus, this known regulator of carbon metabolism directly influences TAG biosynthesis. PMID- 30003608 TI - The impact of transposable elements in adaptive evolution. AB - The growing knowledge about the influence of transposable elements (TEs) on (a) long-term genome and transcriptome evolution; (b) genomic, transcriptomic and epigenetic variation within populations; and (c) patterns of somatic genetic differences in individuals continues to spur the interest of evolutionary biologists in the role of TEs in adaptive evolution. As TEs can trigger a broad range of molecular variation in a population with potentially severe fitness and phenotypic consequences for individuals, different mechanisms evolved to keep TE activity in check, allowing for a dynamic interplay between the host, its TEs and the environment in evolution. Here, we review evidence for adaptive phenotypic changes associated with TEs and the basic molecular mechanisms by which the underlying genetic changes arise: (a) domestication, (b) exaptation, (c) host gene regulation, (d) TE-mediated formation of intronless gene copies-so-called retrogenes and (e) overall increased genome plasticity. Furthermore, we review and discuss how the stress-dependent incapacitation of defence mechanisms against the activity of TEs might facilitate adaptive responses to environmental challenges and how such mechanisms might be particularly relevant in species frequently facing novel environments, such as invasive, pathogenic or parasitic species. PMID- 30003609 TI - The interplay between experiential states in first generation schema therapy of Cluster C personality problems: A network approach. AB - We tested a theory-derived network of within-person causal relations between experiential states in schema therapy of Cluster C personality problems. The sample consisted of 35 patients with panic disorder and/or agoraphobia and DSM-IV Cluster C personality traits or disorders who participated in an inpatient programme. In a 6-week schema therapy phase, the patients had nine or 10 individual sessions and completed measures of experiential states (anger, sadness, depression, anxiety, optimism, and schema belief) before and after each session. The impact of these six states on each other and on themselves over time was examined in mixed models. Schema belief was positively related to subsequent anger and sadness, whereas optimism was negatively related to subsequent schema belief, sadness, and depression. The results suggest that one could maximize the effect of schema therapy on dysphoric feelings in patients with Cluster C personality problems through a therapeutic focus on optimism and schema belief. PMID- 30003610 TI - What is the quality of drug safety information for patients: An analysis of REMS educational materials. AB - BACKGROUND: Poor-quality patient drug information has been identified as a major cause of preventable medication errors in the United States. The US Food and Drug Administration (FDA) has the authority to require marketing authorization holders of medicinal products to implement risk evaluation and mitigation strategies (REMS) to ensure that the benefits of a drug or biological product outweigh its risks. Aside from medication guides, no research has been conducted to assess the quality of patient-targeted REMS materials, including whether, and to what extent, patients find these materials understandable and actionable. PURPOSE: To describe the readability, understandability, and actionability of patient educational materials in currently approved REMS programs, and to highlight opportunities for improving both the quality and effectiveness of these important drug safety tools. METHODS: Seventy-seven REMS programs were identified from the FDA REMS database. We excluded medication guides (MGs) from our analysis because of the fact that there is a mandatory MG template. Based on this, we identified a total of 27 (non-MG) REMS patient materials on the FDA REMS website for analysis purposes. The materials were tested for readability using the Lexile Measure, the Gunning Fog Index, and Flesch Kincaid and then assessed using the Patient Education Materials Assessment Tool for printable materials, for understandability and actionability. RESULTS: Twenty-three of 77 (30%) REMS programs used educational materials to communicate serious risks to patients, yielding a total of 27 REMS patient materials for analysis. The median readability score for these materials was at a ninth-grade reading level or higher. While most (89%) of these patient education materials met established criteria for being understandable, less than half (49%) were deemed actionable. DISCUSSION: Currently approved REMS patient materials fell short in terms of recommended reading level, and over half did not meet recommended standards for actionability. Developers of these materials should apply plain language principles when design these materials to improve their readability and to assess both understandability and actionability in order to increase the effectiveness when distributed to patients. PMID- 30003611 TI - A role for the carbohydrate-binding module (CBM) in regulatory SnRK1 subunits: the effect of maltose on SnRK1 activity. AB - SnRK1 is a protein kinase complex that is involved in several aspects of plant growth and development. There are published data indicative of a participation of SnRK1 in the regulation of the synthesis and degradation of starch, although the molecular mechanism is not known. In this work, we performed electron microscopy to explore the in vivo localization of the regulatory and catalytic subunits that constitute the SnRK1 complex. The results indicated that all the subunits are present in the chloroplast and, in particular, the SnRK1 betagamma and SnRK1 beta3 subunits are associated with starch. Furthermore, the regulatory subunits bind maltose, a relevant product of starch degradation. The kinase activity of immunoprecipitated complexes containing the betagamma regulatory subunit was positively regulated by maltose only in the complexes obtained from Arabidopsis leaves collected at dusk. Recombinant complexes with the SnRK1alpha1 catalytic subunit, SnRK1betagamma and three different beta subunits showed that maltose only had an effect on a complex formed with the beta3 subunit. Truncation of the CBM domain form SnRK1 betagamma abolished the maltose activation of the complex and the activity was significantly reduced, indicating that the CBM is a positive regulator of SnRK1. A model of the SnRK1alpha1/betagamma/beta3 complex suggests the presence of two putative maltose-binding sites, both involving ligand interactions with the betagamma subunit and the alpha subunit. PMID- 30003612 TI - Ethylene signaling is critical for synergid cell functional specification and pollen tube attraction. AB - ETHYLENE INSENSITIVE 3 (EIN3) is a key regulator of ethylene signaling, and EIN3 BINDING F-BOX1 (EBF1) and EBF2 are responsible for EIN3 degradation. Previous reports have shown that the ebf1 ebf2 double homozygous mutant cannot be identified. In this study, the genetic analysis revealed that the ebf1 ebf2 female gametophyte is defective. The pollination experiment showed that ebf1 ebf2 ovules failed to attract pollen tubes. In female gametophyte/ovule, the synergid cell is responsible for pollen tube attraction. Observation of the pEIN3::EIN3 GFP transgenic lines showed that EIN3 signal was over-accumulated at the micropylar end of ebf1 ebf2 female gametophyte. The overexpression of stabilized EIN3 in synergid cell led to the defect of pollen tube guidance. These results suggested that the over-accumulated EIN3 in ebf1 ebf2 synergid cell blocks its pollen tube attraction which leads to the failure of ebf1 ebf2 homozygous plant. We identified that EIN3 directly activated the expression of a sugar transporter, SENESCENCE-ASSOCIATED GENE29 (SAG29/SWEET15). Overexpression of SAG29 in synergid cells blocked pollen tube attraction, suggesting that SAG29 might play a role in ethylene signaling to repel pollen tube entry. Taken together, our study reveals that strict control of ethylene signaling is critical for the synergid cell function during plant reproduction. PMID- 30003613 TI - Comparative out-of-hospital mortality of long-acting opioids prescribed for non cancer pain: A retrospective cohort study. AB - PURPOSE: Despite significant growth of opioid prescriptions, only limited data are available regarding the comparative safety of long-acting opioids for chronic non-cancer pain. Recent data suggest that transdermal fentanyl and oxycodone CR may have greater toxicity than morphine SR in patients with non-cancer pain. Thus, we compared the risk of out-of-hospital deaths in patients with non-cancer pain filling prescriptions for transdermal fentanyl or oxycodone CR with that for morphine SR. METHODS: We conducted a retrospective cohort study in 50 658 patients enrolled in Tennessee Medicaid who filled prescriptions for transdermal fentanyl (n = 8717), oxycodone CR (n = 14 118), or morphine SR (n = 27 823) between 1999 and 2011. We excluded individuals with cancer or other life threatening diagnoses and used propensity scores to adjust for multiple potential confounders. The primary outcome was out-of-hospital mortality. RESULTS: During 44 385 person-years of follow-up, 689 patients died. The out-of-hospital mortality rate among all study subjects was 155/10 000 patient-years. Contrary to earlier data suggesting greater risk, mortality was not significantly different in patients filling prescriptions for transdermal fentanyl compared with morphine SR (adjusted HR = 0.96, 95% C.I.: 0.77-1.21); moreover, patients filling prescriptions for oxycodone CR had lower mortality risk compared with those filling prescriptions for morphine SR (adjusted HR = 0.79, 95% C.I. 0.66-0.95). CONCLUSION: In the study population, long-acting opioids for non-cancer pain were associated with high out-of-hospital mortality rates. We found comparable out-of hospital mortality risks associated with transdermal fentanyl and morphine SR. The risk of out-of-hospital death for oxycodone CR was lower than that for morphine SR. PMID- 30003614 TI - The multistress-induced Translocator protein (TSPO) differentially modulates storage lipids metabolism in seeds and seedlings. AB - Translocator proteins (TSPO) are conserved membrane proteins extensively studied in mammals, but their function is still unclear. Angiosperm TSPO are transiently induced by abiotic stresses in vegetative tissues. We showed previously that constitutive expression of the Arabidopsis TSPO (AtTSPO) could be detrimental to the cell. Degradation of AtTSPO requires an active autophagy pathway. We show here that genetic modifications of TSPO expression in plant and yeast cells reduce the levels of cytoplasmic lipid droplets (LD). Transgenic Arabidopsis seedlings overexpressing AtTSPO contain less LD as compared with wild type (WT). LD levels were increased in Arabidopsis AtTSPO knockout (KO) seedlings. Deletion of the Schizosaccharomyces pombe TSPO resulted in an increase in LD level in the cell. As compared with the WT, the mutant strain was more sensitive to cerulenin, an inhibitor of fatty acids and sterol biosynthesis. We found that in contrast with seedlings, overexpression of AtTSPO (OE) resulted in an up to 50% increase in seeds fatty acids as compared with WT. A time course experiment revealed that after 4 days of seed imbibition, the levels of triacylglycerol (TAG) was still higher in the OE seeds as compared with WT or KO seeds. However, the de novo synthesis of phospholipids and TAG after 24 h of imbibition was substantially reduced in OE seeds as compared with WT or KO seeds. Our findings support a plant TSPO role in energy homeostasis in a tissue-specific manner, enhancing fatty acids and LD accumulation in mature seeds and limiting LD levels in seedlings. PMID- 30003615 TI - Plastic Scintillator-Based Microfluidic Devices for Miniaturized Detection of Positron Emission Tomography Radiopharmaceuticals. AB - A miniaturized radio-HPLC detector has been developed comprising a microfluidic device fabricated from plastic scintillator in combination with a silicon photomultiplier light sensor, and tested with samples containing a positron emitting radionuclide, [18 F]fluoride. This cost-effective, small footprint analytical tool is ideal for incorporation into integrated quality control systems for the testing of positron emission tomography (PET) radiopharmaceuticals to good manufacturing practice (GMP) standards. PMID- 30003616 TI - Methyl Methacrylate HIPE Solely Stabilized by Fluorinated Di-block Copolymer for Fabrication of Highly Porous and Interconnected Polymer Monoliths. AB - Preparation of stable water-in-oil (W/O) high internal phase emulsion (HIPE) containing methyl methacrylate (MMA) monomer as oil phase is a difficult task due to the significant solubility of MMA in water. Here, for the first time a fluorinated di-block copolymer (FDBC) poly (2-dimethylamino)ethylmethacrylate-b poly (trifluoroethyl methacrylate) (PDMAEMA-b-PTFEMA) is proposed to stabilize HIPEs of MMA without the use of any co-stabilizer or thickening agent. Fluorinated segments in FDBC anchored well at oil/water interface of HIPE, offering high hydrophobicity to the partially hydrophilic MMA monomer and in turn stabilization to MMA-HIPE. By using fluorinated di-block copolymer as stabilizer, highly stable HIPEs can be obtained. In addition, highly interconnected porous monoliths were obtained after free radical polymerization, which are highly desirable materials in various practical applications including tissue engineering scaffolds, separation science, bio-engineering and so on. The as prepared MMA-HIPEs possess high thermal stability without phase separation. The textural characteristics of as-prepared composites, such as pore size and distribution, can be easily controlled by simply varying the amount of FDBC and/or dispersed phase fraction. Moreover, the influence of di-block concentration on water uptake (WU) capability of the prepared porous monoliths is explored. PMID- 30003617 TI - Validation of body mass index (BMI)-related ICD-9-CM and ICD-10-CM administrative diagnosis codes recorded in US claims data. AB - PURPOSE: To quantify the sensitivity and positive predictive value (PPV) of body mass index (BMI)-related ICD-9-CM and ICD-10-CM diagnosis codes in claims data. METHODS: De-identified electronic health record (EHR) and claims data were obtained from the Optum Integrated Claims-Clinical Database for cross-sections of commercial and Medicare Advantage health plan members age >= 20 years in 2013, 2014, and 2016. In each calendar year, health plan members' BMI as coded in the insurance claims data (error-prone measure) was compared with their BMI as recorded in the EHR (gold standard) to estimate the sensitivity and PPV of BMI related ICD-9-CM and ICD-10-CM diagnosis codes. The unit of analysis was the person-year. RESULTS: The study sample included 746 763 distinct health plan members who contributed 1 116 283 eligible person-years (median age 56 years; 57% female; 65% commercially insured and 35% with Medicare Advantage). BMI-related diagnoses were coded for 14.6%. The sensitivity of BMI-related diagnoses codes for the detection of underweight, normal weight, overweight, and obesity was 10.1%, 3.7%, 6.0%, and 25.2%, and the PPV was 49.0% for underweight, 89.6% for normal weight, 73.4% for overweight, and 92.4% for obesity, respectively. The sensitivity of BMI-related diagnosis codes was higher in the ICD-10-CM era relative to the ICD-9-CM era. CONCLUSIONS: The PPV of BMI-related diagnosis codes for normal weight, overweight, and obesity was high (>70%) but the sensitivity was low (<30%). BMI-related diagnoses were more likely to be coded in patients with class II or III obesity (BMI >=35 kg/m2 ), and in 2016 relative to 2013 or 2014. PMID- 30003618 TI - Suffering without a medical diagnosis. A critical view on the biomedical attitudes towards persons suffering from burnout and the implications for medical care. AB - The search for causal explanations in medically unexplained syndromes such as burnout has not been resolved by evidence-based medicine. A biomedical model encourages a reductionist diagnostic practice and a dualist split between physical and psychological symptoms. Therefore, diagnosing and treating these syndromes remains a challenge. Depression is a common aspect in burnout and, as a result, clinicians often diagnose burnout patients as depressed. The Norwegian government expects medical efficiency to reduce sick leaves. Medically treating depression has a documented effect. This practice may pose threats to the increasing number of individuals experiencing burnout. The clinical guidelines in evidence-based medicine mirror what counts as knowledge in medical inquiry, which in turn shapes attitudes towards individual patients. The aim of this article is 2-fold: firstly, to assess how the values that accompany the biomedical paradigm affect clinical care, and secondly, to replace the biomedical model with a genuine person-centred approach. In the study described, an existential phenomenological method was applied. Eight individuals, who experienced burnout, were included. They had been on long-term sick leave (>1 year) due to symptoms of fatigue and pain and fulfilled the criteria for Exhaustion Disorder (ICD-10, F43.8A). Their symptoms were not medically explained, and almost all the participants were labelled as depressed. Four themes emerged that described how they experienced living with burnout: "unhomelike being in the world," "the limit of diagnosis," "naked in the eyes of the public," and "a path to hopelessness." I identify 2 main problems; firstly, the mismatch between the patient's experience of his or her illness and the doctor's interpretation of the condition can lead to ineffective treatment. Secondly, the interviewees struggled to be recognized as ill. Thus, the inherent values in the biomedical paradigm might have serious implications for the medical care of patients with burnout. PMID- 30003619 TI - Developmental role of the tomato Mediator complex subunit MED18 in pollen ontogeny. AB - Pollen development is a crucial step in higher plants, which not only makes possible plant fertilization and seed formation, but also determines fruit quality and yield in crop species. Here, we reported a tomato T-DNA mutant, pollen deficient1 (pod1), characterized by an abnormal anther development and the lack of viable pollen formation, which led to the production of parthenocarpic fruits. Genomic analyses and the characterization of silencing lines proved that pod1 mutant phenotype relies on the tomato SlMED18 gene encoding the subunit 18 of Mediator multi-protein complex involved in RNA polymerase II transcription machinery. The loss of SlMED18 function delayed tapetum degeneration, which resulted in deficient microspore development and scarce production of viable pollen. A detailed histological characterization of anther development proved that changes during microgametogenesis and a significant delay in tapetum degeneration are associated with a high proportion of degenerated cells and, hence, should be responsible for the low production of functional pollen grains. Expression of pollen marker genes indicated that SlMED18 is essential for the proper transcription of a subset of genes specifically required to pollen formation and fruit development, revealing a key role of SlMED18 in male gametogenesis of tomato. Additionally, SlMED18 is able to rescue developmental abnormalities of the Arabidopsis med18 mutant, indicating that most biological functions have been conserved in both species. PMID- 30003621 TI - Orthogonal gammaPNA Dimerization Domains Empower DNA Binders with Cooperativity and Versatility Mimicking that of Transcription Factor Pairs. AB - Synthetic molecules capable of DNA binding and mimicking cooperation of transcription factor (TF) pairs have long been considered a promising tool for manipulating gene expression. Our previously reported Pip-HoGu system, a programmable DNA binder pyrrole-imidazole polyamides (PIPs) conjugated to host guest moiety, defined a general framework for mimicking cooperative TF pair-DNA interactions. Here, we supplanted the cooperation modules with left-handed (LH) gammaPNA modules: i.e., PIPs conjugated with nucleic acid-based cooperation system (Pip-NaCo). LH gammaPNA was chosen because of its bioorthogonality, sequence-specific interaction, and high binding affinity toward the partner strand. From the results of the Pip-NaCo system, cooperativity is highly comparable to the natural TF pair-DNA system, with a minimum energetics of cooperation of -3.27 kcal mol-1 . Moreover, through changing the linker conjugation site, binding mode, and the length of gammaPNAs sequence, the cooperative energetics of Pip-NaCo can be tuned independently and rationally. The current Pip-NaCo platform might also have the potential for precise manipulation of biological processes through the construction of triple to multiple heterobinding systems. PMID- 30003620 TI - Tracking the Fate of Porous Silicon Nanoparticles Delivering a Peptide Payload by Intrinsic Photoluminescence Lifetime. AB - A nanoparticle system for systemic delivery of therapeutics is described, which incorporates a means of tracking the fate of the nanocarrier and its residual drug payload in vivo by photoluminescence (PL). Porous silicon nanoparticles (PSiNPs) containing the proapoptotic antimicrobial peptide payload, D [KLAKLAK]2 , are monitored by measurement of the intrinsic PL intensity and the PL lifetime of the nanoparticles. The PL lifetime of the PSiNPs is on the order of microseconds, substantially longer than the nanosecond lifetimes typically exhibited by conventional fluorescent tags or by autofluorescence from cells and tissues; thus, emission from the nanoparticles is readily discerned in the time resolved PL spectrum. It is found that the luminescence lifetime of the PSiNP host decreases as the nanoparticle dissolves in phosphate-buffered saline solution (37 degrees C), and this correlates with the extent of release of the peptide payload. The time-resolved PL measurement allows tracking of the in vivo fate of PSiNPs injected (via tail vein) into mice. Clearance of the nanoparticles through the liver, kidneys, and lungs of the animals is observed. The luminescence lifetime of the PSiNPs decreases with increasing residence time in the mice, providing a measure of half-life for degradation of the drug nanocarriers. PMID- 30003622 TI - Ex vivo liver resection and autotransplantation with cardiopulmonary bypass for hepatoblastoma in children: A case report. AB - Some primary and secondary liver carcinomas cannot be resected using a conventional approach due to their size, location, or major vascular invasion. The aim of this study was to explore the application of ex vivo liver resection and autotransplantation for complicated HB in children. A 1.5-year-old girl with HB after repeated chemotherapy was analyzed. In this patient, tumor invasion includes the IV, V, and VIII liver segments, and thrombosis formed in the inferior vena cava and right atrium. It is difficult to obtain complete tumor resection using conventional hepatectomy. The patient was treated via ex vivo liver resection and autotransplantation, and tumor thrombus in the inferior vena cava and right atrium was removed via cardiopulmonary bypass. Operative methods and precautions were analyzed during and after the operation. The operation was completed successfully within 8 hours, and the liver's cold ischemia time was 190 minutes. The patient recuperated successfully, and the liver's function and AFP levels gradually tended to normalize 2 weeks after the operation. Ultrasonic examination revealed that the blood flow velocity of the hepatic vein, portal vein, and hepatic artery was good. The patient recovered and was discharged 3 weeks after the operation. Ex vivo liver resection and autotransplantation have great application value for complicated HB in children that is not suitable for conventional hepatic lobectomy. PMID- 30003623 TI - Recurrent oral ulcerations following heart transplant in a pediatric patient: A diagnostic dilemma. AB - Oral ulceration is a non-specific clinical finding with many potential causes. The persistence of oral ulcers in the context of a patient post-SOT is concerning for PTLD. There is growing evidence that SOT recipients may also be at higher risk of autoimmune diseases. This case report describes a pediatric patient with persistent oral ulcers after heart transplant, who underwent an extensive workup for PTLD, including repeat investigations, with a subsequent diagnosis of Behcet's disease. PMID- 30003624 TI - Time Travels: A 40-Year Journey from Drosophila's Clock Mutants to Human Circadian Disorders (Nobel Lecture). AB - Living organisms have a biological clock that helps to prepare our physiology for the fluctuations of the day. Key research to elucidate the biological mechanisms of this regular adaptation, referred to as the circadian rhythm, is described by M. W. Young in his Nobel lecture. PMID- 30003626 TI - Behavioural phenotypes: working towards translational research through research partnerships. PMID- 30003627 TI - Using randomization tests to assess treatment effects in multiple-group interrupted time series analysis. AB - RATIONALE, AIMS, AND OBJECTIVES: Interrupted time series analysis (ITSA) is a popular evaluation methodology in which a single treatment unit's outcome is studied over time and the intervention is expected to "interrupt" the level and/or trend of the outcome, subsequent to its introduction. The internal validity of this analysis is strengthened considerably if the treated unit is contrasted with a comparable control group. However, multiple-group ITSA typically has small sample sizes, and parametric methods for multiple-group ITSA require strong assumptions that are unlikely to be met, possibly resulting in misleading P values. In this paper, randomization tests are introduced as a non parametric, distribution-free option for computing exact P values. METHOD: The effect of California's Proposition 99 (passed in 1988) for reducing cigarette sales is evaluated by comparing California (CA) to Montana (MT) and Idaho (ID) the two best matched control states not exposed to any smoking reduction initiatives. Results from randomization tests are contrasted to those of interrupted time series analysis regression (ITSAREG)-a commonly used parametric approach for evaluating treatment effects in ITSA studies. RESULTS: Both approaches found ID and MT to be comparable to CA on their preintervention time series, and both approaches equally found CA to have statistically lower cigarette sales in the postintervention period (P < 0.01). CONCLUSIONS: In these data, randomization tests computed P values comparable with ITSAREG, bolstering confidence in the intervention effect. Routinely including randomization tests as a complement, or alternative, to parametric methods is therefore beneficial because randomization tests are free of assumptions regarding sample size and distribution and are extremely flexible in the choice of test statistic. PMID- 30003628 TI - The effect of psychomotor physical therapy on health-related quality of life, pain, coping, self-esteem, and social support. AB - BACKGROUND: Norwegian psychomotor physiotherapy (NPMP) is commonly applied for patients with long-lasting pain and psychological symptoms. The approach is based on a bio-psychosocial model of health and might have benefits to physical, psychological, and physical domains of health-related quality of life (HRQOL). No previous randomized controlled clinical trials have been performed to examine the effectiveness of NPMP as individual treatment. The aim was therefore to assess the effect of a 6-month intervention of NPMP on HRQOL and on pain, coping, social support, and self-esteem. METHODS: The study was a pragmatic randomized controlled trial comparing an intervention group with a control group. Participants were recruited from 36 physiotherapists specialized in NPMP, working in private practice. The intervention group received NPMP once weekly for 6 months, whereas the control group received no intervention. Measurements were performed at baseline and after 6 months. A total of 105 participants were included. HRQOL was measured by the 36-item Short Form Health Survey, SF-36. To examine the effect of the intervention, independent sample t tests were performed with the "difference in mean values," delta (=?, posttest result - baseline result). RESULTS: Significant differences between the two groups were observed in six of the eight SF-36 domains: Physical Functioning, Bodily Pain, General Health, Mental Health, Social Functioning, and Vitality. Effect size ranged from 0.9 for Vitality to 0.3 for Role Physical and Role Emotional. Furthermore, there was a significant difference between groups regarding pain and self-esteem in favour of the intervention group. The Cohen's d effect sizes of the different dimensions of HRQOL ranged from 0.3 to 0.9 with a median of 0.6. CONCLUSION: The results of this study demonstrate that 6-month intervention of NPMP increased HRQOL and self-esteem as well as reduced pain. PMID- 30003629 TI - Engaging people experiencing communication disability in stroke rehabilitation: a qualitative study. AB - BACKGROUND: Engagement is commonly considered important in stroke rehabilitation, with some arguing it is essential for positive patient outcomes. An emerging body of research indicates the practitioner influences engagement through their ways of relating, communicating and working with the patient. People experiencing communication disability may face particular challenges with engagement as a practitioner's communication and interactional patterns may limit their ability to engage. AIMS: To understand how rehabilitation practitioners worked to engage people experiencing communication disability throughout the course of rehabilitation. METHODS & PROCEDURES: A qualitative study using the Voice Centred Relational Approach. Longitudinal observational and interview data were gathered from 28 practitioners and three people experiencing communication disability in inpatient and community stroke rehabilitation services. Data were analyzed using the Listening Guide. OUTCOMES & RESULTS: Engagement was a relational practice on the part of the rehabilitation practitioner. It was underpinned by a relational philosophy and characterized by three core processes: embedding relational work throughout rehabilitation; getting to know the patient and working in ways valued by the patient; and communicating using relational dialogue and supported conversation. Practitioners wove these together with their technical, disciplinary-based work and rehabilitation tasks. CONCLUSIONS & IMPLICATIONS: Patient engagement was constructed through relationships and strongly influenced by the practitioners' way of thinking about and enacting practice, challenging the idea that engagement is solely an intrinsic patient state and behaviour. The findings raise questions about which aspects of rehabilitation work and communication are most valuable when working to engage people experiencing communication disability. Viewing engagement as a relational practice and understanding the different ways this is enacted may support practitioners to reflect on their understandings of engagement, their patient's engagement, their ways of working, and the frames and philosophies that surround and influence their practice. PMID- 30003631 TI - Work-related stress among nursing staff working in government hospitals and primary health care centres. AB - AIM: Work-related stress (WRS) in the nursing working environment is prevalent and significantly affects the performance of nurses and organizations. Poor nursing and administrative performance affects the delivery of safety and quality patient care. Thus, this study aims to compare the sources and factors of stress among nurses from hospitals and primary health care centres. METHODS: A cross sectional study was conducted in five government hospitals and four sectors of primary health care centres in Saudi Arabia. Through a survey, the Nursing Stress Scale was completed by 347 nurses from February to March 2016. RESULTS: Workload is perceived as the most common source of WRS, whereas inadequate preparation is regarded as the least. Other major sources are conflicts with physicians and nurses in primary centres and the lack of support and uncertainty concerning treatment in hospitals. The nurses' age, marital status, nationality, and job position are the significantly identified factors that contribute to stress. CONCLUSION: Overall, the sources and factors of WRS significantly vary with nurses' working environment. Hence, understanding the perception of nurses towards their working environment can be a strategic basis in modifying policies in occupational stress management. PMID- 30003632 TI - Relationships among structural empowerment, innovative behaviour, self-efficacy, and career success in nursing field in mainland China. AB - AIM: The purpose of the study is to explore the relationships among structural empowerment, innovative behaviour, self-efficacy, and career success by nurses in mainland China. METHOD: A cross-sectional study was designed, and participants were recruited from 6 tertiary hospitals in Tianjin, China. The study used an anonymous questionnaire, filled voluntarily by 460 nurses in spring 2017. Structural equation modelling analyses were conducted. RESULTS: The results reveal that innovative behaviour is positively associated with career success and self-efficacy, which, in turn, mediates the relationship between structural empowerment and career success. Structural empowerment is positively associated with innovative behaviour and career success. Self-efficacy is positively associated with career success and mediates the relationship between innovative behaviour and career success. CONCLUSION: Higher perceived structural empowerment, innovative behaviour, and self-efficacy can increase career success of Chinese nurses. PMID- 30003633 TI - Rapid shifts in distribution and high-latitude persistence of oceanographic habitat revealed using citizen science data from a climate change hotspot. AB - The environmental effects of climate change are predicted to cause distribution shifts in many marine taxa, yet data are often difficult to collect. Quantifying and monitoring species' suitable environmental habitats is a pragmatic approach for assessing changes in species distributions but is underdeveloped for quantifying climate change induced range shifts in marine systems. Specifically, habitat predictions present opportunities for quantifying spatiotemporal distribution changes while accounting for sources of natural climate variation. Here we demonstrate the utility of a marine-based habitat model parameterized using citizen science data and remotely sensed environmental covariates for quantifying shifts in oceanographic habitat suitability over 22 years for a coastal-pelagic fish species in a climate change hotspot. Our analyses account for the effects of natural intra- and interannual climate variability to reveal rapid poleward shifts in core (94.4 km/decade) and poleward edge (108.8 km/decade) oceanographic habitats. Temporal persistence of suitable oceanographic habitat at high latitudes also increased by approximately 3 months over the study period. Our approach demonstrates how marine citizen science data can be used to quantify range shifts, but necessitates shifting focus from species distributions directly, to the distribution of species' environmental habitat preferences. PMID- 30003634 TI - Smartphone-based cognitive bias modification training improves healthy food choice in obesity: A pilot study. AB - Obesity is partly driven by unhealthy food choices underpinned by cognitive biases, including approach bias (a tendency to move towards food cues) and delay discounting (a preference for immediate rewards). Cognitive training strategies aimed at modifying these biases, namely, approach-avoidance training (AAT) and episodic future thinking (EFT), may improve food choice. This pilot randomised trial examined the effect of these two trainings, delivered daily for 1 week via smartphone apps, on approach bias for healthy/unhealthy foods, delay discounting for money/food, and hypothetical food choice. Sixty overweight/obese participants (18-45 years) were randomly allocated to AAT, EFT, or control. Outcomes were measured at pretraining, posttraining, and 6-week follow-up. AAT reduced approach bias for unhealthy food and increased healthy food choice. However, EFT did not affect delay discounting or food choice. We conclude that AAT is useful for improving food choice in obesity and that smartphones are a feasible, engaging way to deliver training. PMID- 30003630 TI - Genome-wide association meta-analysis of age at first cannabis use. AB - BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20 56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2 > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders. PMID- 30003635 TI - In Situ Tracking of Organic Reactions at the Vapor/Liquid Interfaces of Ionic Liquids. AB - The molecular structures of ionic liquids at interfaces play a crucial role in determining their chemical activities in applications. In situ X-ray photoelectron spectroscopy (XPS) was used to track the evolution of X-ray irradiation-induced chemical reactions in a series of ionic liquids ([Cn mim][AuCl4 ]; n=4, 6, 8, 10) on the Si (111) single-crystal surface. Analyses of microstructure and chemical bonding based on the XPS results indicated that reactions occurred at the vapor/liquid interfaces of the ionic liquids. The time resolved XPS spectra revealed that with increasing irradiation time, the intensity of the peak corresponding to trivalent Au anion decreased for the four ionic liquids as Au was continually reduced to a lower chemical state and finally converted to gold nanoparticles. The rate and conversion of the reaction were associated with the length of the alkyl chain of the ionic liquids cation. Molecular dynamics simulations further revealed that the alkyl chain of the cation in the ionic liquids was oriented towards the vacuum environment at the vapor/liquid interface. Our results provide a real-time atomic-scale experimental evidence of organic reactions at the vapor/liquid interfaces of ionic liquids. The findings are important for understanding the roles of ionic liquids in catalysis, separation, electrochemistry, functional materials, and so on. PMID- 30003636 TI - Prophylactic recombinant thrombomodulin treatment prevents hepatic sinusoidal obstruction syndrome in high-risk pediatric patients that undergo hematopoietic stem cell transplants. AB - Hepatic SOS is a potentially life-threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high-risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post-HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI-1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS. PMID- 30003637 TI - Towards an assessment of perceived COPD exacerbation triggers: Initial development and validation of a questionnaire. AB - BACKGROUND AND OBJECTIVE: Prevention of exacerbations in chronic obstructive pulmonary disease (COPD) is important to decrease overall declines in functioning and improve quality of life. The present study sought to develop a psychometrically valid measure of perceived triggers of exacerbations in COPD patients, the COPD Exacerbation Trigger Inventory (CETI). METHODS: Participants (n = 192) were recruited through local clinics and online to complete surveys of the CETI, demographic information, disease-specific information and the COPD Assessment Test (CAT). The CETI included a free response section on patients' individual top triggers, combined with ratings of their controllability. RESULTS: Exploratory principal component analyses identified a stable 5-factor structure (33 items), from which trigger subscales for weather/climate, air pollution/irritants, exercise, infection/illness and psychological factors were formed (internal consistency Cronbach's alpha = 0.90-0.94). Trigger factors were associated with COPD functional status, exacerbation frequency and healthcare utilization. Participants found personal triggers related to dust, air pollution, smoking and physical activity to be the most easily controlled, whereas those related to psychological factors, climate, infection, respiratory symptoms and sleep to be more difficult to control. Greater perceived controllability of triggers was associated with lower CAT scores, indicating better health status and less impact of the disease on functioning. CONCLUSION: The CETI is a psychometrically valid measure of perceived exacerbation triggers in patients with COPD. Perceived triggers are associated with clinical outcomes. Assessment of trigger classes and their controllability may prove useful in both research and clinical settings with COPD patients and to further our knowledge in prevention and disease management. PMID- 30003638 TI - Chalcogen Bonding in Protein-Ligand Complexes: PDB Survey and Quantum Mechanical Calculations. AB - A chalcogen bond is a nonclassical noncovalent interaction which can stabilise small-molecule crystals as well as protein structures. Here, we systematically explore the stabilising potential of chalcogen bonding in protein-ligand complexes in the Protein Data Bank (PDB). We have found that a large fraction (23 %) of complexes with a S/Se-containing ligand feature close S/Se???O/N/S contacts. Eleven non-redundant representative potential S/Se???O chalcogen-bond motifs were selected and truncated to model systems and seven more model systems were prepared by S-to-Se substitution. These systems were then subjected to analysis by quantum chemical (QM) methods-electrostatic potential, geometry optimisation or interaction energy calculations, including solvent effects. The QM calculations indicate that chalcogen bonding does indeed play a dominant role in stabilising some of the interaction motifs studied. We thus advocate further exploration of chalcogen bonding with the aim of potential future use in structure-based drug design. PMID- 30003639 TI - What confidence should we have in GRADE? AB - RATIONALE, AIMS, AND OBJECTIVES: Confidence (or belief) that a therapy is effective is essential to practicing clinical medicine. GRADE, a popular framework for developing clinical recommendations, provides a means for assigning how much confidence one should have in a therapy's effect estimate. One's level of confidence (or "degree of belief") can also be modelled using Bayes theorem. In this paper, we look through both a GRADE and Bayesian lens to examine how one determines confidence in the effect estimate. METHODS: Philosophical examination. RESULTS: The GRADE framework uses a criteria-based method to assign a quality of evidence level. The criteria pertain mostly to considerations of methodological rigour, derived from a modified evidence-based medicine evidence hierarchy. The four levels of quality relate to the level of confidence one should have in the effect estimate. The Bayesian framework is not bound by a predetermined set of criteria. Bayes theorem shows how a rational agent adjusts confidence (ie, degree of belief) in the effect estimate on the basis of the available evidence. Such adjustments relate to the principles of incremental confirmation and evidence proportionism. Use of the Bayesian framework reveals some potential pitfalls in GRADE's criteria-based thinking on confidence that are out of step with our intuitions on evidence. CONCLUSIONS: A rational thinker uses all available evidence to formulate beliefs. The GRADE criteria seem to suggest that we discard some of that information when other, more favoured information (eg, derived from clinical trials) is available. The GRADE framework should strive to ensure that the whole evidence base is considered when determining confidence in the effect estimate. The incremental value of such evidence on determining confidence in the effect estimate should be assigned in a manner that is theoretically or empirically justified, such that confidence is proportional to the evidence, both for and against it. PMID- 30003641 TI - Hot Off the Press: A Novel Algorithm to Decrease Unnecessary Hospitalizations in Patients with Atrial Fibrillation. PMID- 30003640 TI - Estimated glomerular filtration rate after nephrectomy for Wilms tumor. AB - BACKGROUND: The aim of this study was to assess long-term residual kidney function after unilateral nephrectomy for non-syndromic Wilms tumor (NSWT). METHODS: Of the patients who underwent one-sided NSWT at Tohoku University Hospital between 1977 and 2003, nine were followed up until age >=18 years. For these nine patients, we retrospectively evaluated estimated glomerular filtration rate (eGFR) in childhood (3-10 years old), adolescence (11-17 years old) and adulthood (>=18 years). RESULTS: Mean age at the last follow up was 23.0 years. Tumor classification was as follows: stage I tumor, n = 6; stage II tumor, n = 3; mixed-type nephroblastoma, n = 8; and congenital mesoblastic nephroma, n = 1. Mean eGFR was 101.3 +/- 21.2 mL/min/1.73 m2 in childhood, 106.0 +/- 32.1 mL/min/1.73 m2 in adolescence and 100.5 +/- 20.7 mL/min/1.73 m2 in adulthood. Therefore, no significant change in eGFR was observed over the three life stages evaluated. Further, none of the patients met the diagnostic criteria for chronic kidney disease by early adulthood. CONCLUSIONS: eGFR after unilateral nephrectomy in patients with NSWT remained >=60 mL/min/1.73 m2 during the transition from childhood to early adulthood, with no development of chronic kidney disease or end-stage kidney failure. PMID- 30003642 TI - Glycaemic control and hypoglycaemia benefits with insulin glargine 300 U/mL extend to people with type 2 diabetes and mild-to-moderate renal impairment. AB - AIM: To investigate the impact of renal function on the safety and efficacy of insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100). MATERIALS AND METHODS: A meta-analysis was performed using pooled 6-month data from the EDITION 1, 2 and 3 trials (N = 2496). Eligible participants, aged >=18 years with a diagnosis of type 2 diabetes (T2DM), were randomized to receive once daily evening injections of Gla-300 or Gla-100. Pooled results were assessed by two renal function subgroups: estimated glomerular filtration rate (eGFR) <60 and >=60 mL/min/1.73 m2 . RESULTS: The decrease in glycated haemoglobin (HbA1c) after 6 months and the proportion of individuals with T2DM achieving HbA1c targets were similar in the Gla-300 and Gla-100 groups, for both renal function subgroups. There was a reduced risk of nocturnal (12:00-5:59 am) confirmed (<=3.9 mmol/L [<=70 mg/dL]) or severe hypoglycaemia with Gla-300 in both renal function subgroups (eGFR <60 mL/min/1.73 m2 : relative risk [RR] 0.76 [95% confidence interval {CI} 0.62-0.94] and eGFR >=60 mL/min/1.73 m2 : RR 0.75 [95% CI 0.67 0.85]). For confirmed (<=70 mg/dL [<=3.9 mmol/L]) or severe hypoglycaemia at any time of day (24 hours) the hypoglycaemia risk was lower with Gla-300 vs Gla-100 in both the lower (RR 0.94 [95% CI 0.86-1.03]) and higher (RR 0.90 [95% CI 0.85 0.95]) eGFR subgroups. CONCLUSIONS: Gla-300 provided similar glycaemic control to Gla-100, while indicating a reduced overall risk of confirmed (<=3.9 and <3.0 mmol/L [<=70 and <54 mg/dL]) or severe hypoglycaemia, with no significant difference between renal function subgroups. PMID- 30003643 TI - Forecasting effects of tree species reintroduction strategies on carbon stocks in a future without historical analog. AB - American chestnut (Castanea dentata) was once an important component forests in the central Appalachians (USA), but it was functionally extirpated nearly a century ago. Attempts are underway to reintroduce blight-resistant chestnut to its former range, but it is uncertain how current forest composition, climate, and atmospheric changes and disturbance regimes will interact to determine future forest dynamics and ecosystem services. The combination of novel environmental conditions (e.g. climate change), a reintroduced tree species and new disturbance regimes (e.g. exotic insect pests, fire suppression) have no analog in the past that can be used to parameterize phenomenological models. We therefore used a mechanistic approach within the LANDIS-II forest landscape model that relies on physiological first principles to project forest dynamics as the outcome of competition of tree cohorts for light and water as a function of temperature, precipitation, CO2 concentration, and life history traits. We conducted a factorial landscape simulation experiment to evaluate specific hypotheses about future forest dynamics in two study sites in the center of the former range of chestnut. Our results supported the hypotheses that climate change would favor chestnut because of its optimal temperature range and relative drought resistance, and that chestnut would be less competitive in the more mesic Appalachian Plateau province because competitors will be less stressed. The hypothesis that chestnut will increase carbon stocks was supported, although the increase was modest. Our results confirm that aggressive restoration is needed regardless of climate and soils, and that increased aggressiveness of chestnut restoration increased biomass accumulation. The hypothesis that chestnut restoration will increase both compositional and structural richness was not supported because chestnut displaced some species and age cohorts. Although chestnut restoration did not markedly enhance carbon stocks, our findings provide hope that this formerly important species can be successfully reintroduced and associated ecosystem services recovered. PMID- 30003644 TI - The effect of workload on nurses' non-observance errors in medication administration processes: A cross-sectional study. AB - AIM: This study, based on actual medical error cases involving nurses, sought to identify non-observance errors-defying the standard operating procedures-in medication administration processes, and clarify the relationship between nursing workload and such behaviours. METHODS: Based on a cross-sectional survey, non observance error cases were collected from three Japanese hospitals between January and December 2014, using self-reported data from participating nurses. Standard operating procedures and actual error content were compared to identify non-observance errors and workload. The statistical analysis was used to determine the relationship between non-observance error and workload. RESULTS: A total of 637 error cases were found in administering medication, of which 163 (25.6%) were workload-related non-observance errors. Individual analysis of the 163 cases identified seven workload issues that caused non-observance error and six categories of non-observance errors. The relationship between workload and such errors was also clarified. CONCLUSION: Our findings clarify the influence of workload on non-observance errors and may also help identify adjacent areas for specific improvements. PMID- 30003645 TI - Bacterial communities of decaying Norway spruce follow distinct slope exposure and time-dependent trajectories. AB - Deadwood decay employs a complex metabolism and provides carbon and nutrients for soils. Although being highly diverse, the contribution of the bacterial deadwood colonizing community is underexplored compared with the fungal one. Therefore, we performed an in-field mesocosm study and monitored the bacterial communities in decaying experimental Picea abies wood blocks and their underlying soil on north- and south- exposed slopes in the Italian Alps over a 2-year period. The faster deadwood decay at the south-facing slope was associated with a higher bacterial richness and a higher number of specialist operational taxonomic units (OTUs) which were more strongly correlated to environmental parameters than other bacterial community members. With progressing decay, the wood and soil bacterial communities became more similar in terms of richness, diversity and evenness and especially at the south-facing slope, they also became more similar in terms of community composition. Exposure-specific OTUs suggest wood-soil interaction. However, despite the strong influence of exposure on the soil bacterial communities, the P. abies wood blocks shared a comparably high number of OTUs with the soil irrespective of the slope. At finer taxonomic scale, we identified Pseudomonas, Microbacteria, Sphingomonas, Xanthomonas, Methylovirgula and Burkholderia as decay associated, although their functional role needs further studies. PMID- 30003646 TI - In memory of Jun-ichi Tomizawa, Professor Emeritus of the National Institute of Genetics. PMID- 30003647 TI - The influence of bioregenerative life-support system dietary structure and lifestyle on the gut microbiota: a 105-day ground-based space simulation in Lunar Palace 1. AB - Understanding the dynamics of human gut microbiota in space is crucial in maintaining astronaut health. Long-duration and deep-space manned exploration will require the in situ regeneration of resources, which would be achieved by an artificial ecosystem, such as a bioregenerative life-support system (BLSS). Potential response of human gut microbiota to particular lifestyle and dietary structure experienced in a BLSS remains unclear. Here, we report how a BLSS impacts the gut microbiota during a 105-day study that took place in the Chinese Lunar Palace 1 (LP1). The three crewmembers were provided with high-plant and high-fibre diet, and they followed a fixed schedule including extensive labour in the plant cabin. The gut microbiota composition of the three crewmembers showed convergence and similar dynamic change. Increased diversity and abundance of Lachnospira, Faecalibacterium and Blautia indicated that the LP1 dietary structure and the lifestyle may be beneficial for the maintenance of healthy gut microbiome. A stronger impact was found from the gut microbiome to the environment compared with the opposite direction, suggesting the necessity of environmental pathogen control in BLSS. PMID- 30003648 TI - Monoamine oxidase-A is a novel driver of stress-induced premature senescence through inhibition of parkin-mediated mitophagy. AB - Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age-associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase-A (MAO-A) is a relevant source of ROS in the heart through the formation of H2 O2 derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO-A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO-A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS-dependent DNA damage response, activation of cyclin-dependent kinase inhibitors p21cip , p16ink4a , and p15ink4b and typical features of senescence such as cell flattening and SA-beta-gal activity. Moreover, we observe that ROS produced by MAO-A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO-A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO-dependent oxidative stress in age-related pathologies. PMID- 30003650 TI - Methanol metabolism in the acetogenic bacterium Acetobacterium woodii. AB - Methanol derived from plant tissue is ubiquitous in anaerobic sediments and a good substrate for anaerobes growing on C1 compounds such as methanogens and acetogens. In contrast to methanogens little is known about the physiology, biochemistry and bioenergetics of methanol utilization in acetogenic bacteria. To fill this gap, we have used the model acetogen Acetobacterium woodii to study methanol metabolism using physiological and biochemical experiments paired with molecular studies and transcriptome analysis. These studies identified the genes and enzymes involved in acetogenesis from methanol and the redox carriers involved. We will present the first comprehensive model for carbon and electron flow from methanol in an acetogen and the bioenergetics of acetogenesis from methanol. PMID- 30003651 TI - Rediscovering the "Narrative" review. PMID- 30003649 TI - Resistant ammonia-oxidizing archaea endure, but adapting ammonia-oxidizing bacteria thrive in boreal lake sediments receiving nutrient-rich effluents. AB - Climate change along with anthropogenic activities changes biogeochemical conditions in lake ecosystems, modifying the sediment microbial communities. Wastewater effluents introduce nutrients and organic material but also novel microbes to lake ecosystems, simulating forthcoming increases in catchment loadings. In this work, we first used 16s rRNA gene sequencing to study how the overall sediment microbial community responds to wastewater in six boreal lakes. To examine forthcoming changes in the lake biogeochemistry, we focused on the ammonia-oxidizing archaea (AOA) and bacteria (AOB), and examined their functional and compositional community response to wastewater. Although we found the least diverse and least resistant prokaryotic communities from the most wastewater influenced sediments, the community changed fast toward the natural composition with the diminishing influence of wastewater. Each lake hosted a unique resistant AOA community, while AOB communities were adapting, responding to environmental conditions as well as receiving new members from WWTPs. In general, AOB dominated in numbers in wastewater-influenced sediments, while the ratio between AOA and AOB increased when moving toward pristine conditions. Our results suggest that although future climate-change-driven increases in nutrient loading and microbial migration might significantly disrupt lake sediment microbiomes, they can promote nitrification through adapting and abundant AOB communities. PMID- 30003652 TI - Identification of a novel PLCD1 mutation in Chinese Han pedigree with hereditary leukonychia and koilonychia. AB - BACKGROUND: Hereditary leukonychia is a rare nail dystrophy characterized by distinctive whitening of the nail plate. Mutations in the PLCD1 gene have been identified as a major causative factor in hereditary leukonychia (HL). However, few reports have analyzed the relationship between genotype and phenotype, especially in Chinese HL patients. Our study aims to explore the typical clinical features of hereditary leukonychia cases in Chinese Han pedigree and the correlations with PLCD1 gene mutation. PATIENTS AND METHODS: In this study, two Chinese patients presented with leukonychia and koilonychia. Whole-exome sequencing (WES) was performed to screen for the mutations in PLCD1 gene and other candidate genes for hereditary leukonychia. Parents with PLCD1 mutation were selected for Sanger sequencing. RESULTS: A novel heterozygote missense mutation in exon 9 of PLCD1 gene was identified in the proband and his mother. Whole-exome sequencing revealed both, the proband (III.5) and his mother (II.4) carrying c.1451A>G mutation, while other family members had a normal sequence of the PLCD1 gene. CONCLUSION: For the first time, a hereditary leukonychia case with PLCD1 mutation has been described in Chinese Han pedigree. This finding suggests the PLCD1 mutation maybe involved in hereditary leukonychia. PMID- 30003653 TI - Imaging of Enzyme Activity by Electron Paramagnetic Resonance: Concept and Experiment Using a Paramagnetic Substrate of Alkaline Phosphatase. AB - Enzyme activities are well established biomarkers of many pathologies. Imaging enzyme activity directly in vivo may help to gain insight into the pathogenesis of various diseases but remains extremely challenging. In this communication, we report the use of EPR imaging (EPRI) in combination with a specially designed paramagnetic enzymatic substrate to map alkaline phosphatase activity with a high selectivity, thereby demonstrating the potential of EPRI to map enzyme activity. PMID- 30003654 TI - Food addiction among men and women in India. AB - OBJECTIVE: This study aimed to address a cultural gap in the food addiction (FA) literature by examining FA and associated clinical features in a nonclinical group of men and women residing in India. METHOD: Participants (N = 415) were recruited from Amazon Mechanical Turk to complete an online survey about weight and eating. Participants completed self-report measures assessing FA (Yale Food Addiction Scale [YFAS]), eating-disorder psychopathology (Eating Disorder Examination-Questionnaire [EDE-Q]), health-related quality of life (Short Form Health Survey-12-item version [SF-12]), and depression (Patient Health Questionnaire-2). RESULTS: The FA symptom mean was 3.53 (SD = 1.90); 32.5% (n = 129) met FA clinical threshold on the YFAS. Groups categorized with and without FA on the YFAS did not differ significantly in sex or body mass index. YFAS scores were significantly correlated with greater frequency of binge eating, higher severity scores on all EDE-Q subscales, higher depression, and poorer functioning scores on the SF-12 (all ps < 0.05). CONCLUSIONS: FA, as conceptualized and measured by the YFAS, appears to be common among individuals residing in India. PMID- 30003655 TI - Observational research on sodium glucose co-transporter-2 inhibitors: A real breakthrough? AB - Sodium glucose co-transporter-2 inhibitors have attracted the interest of the scientific community following the results from dedicated cardiovascular outcome trials, which demonstrated remarkable reduction in all-cause mortality and other cardiovascular (CV) endpoints with empagliflozin and canagliflozin. These impressive results raised further expectations on real world data from large observational cohort studies. They were designed to address the possible existence of a class effect, and the uncertainty on whether this benefit can be extended from secondary to primary CV prevention of patients with type 2 diabetes. In this review, we collated data from existing observational studies (including the celebrated CVD-REAL cohorts) and critically appraised results and methodological issues with the aim of providing clinical insight, including unsettled aspects, and proposing a research agenda for future investigations. PMID- 30003656 TI - A Size-Reducible Nanodrug with an Aggregation-Enhanced Photodynamic Effect for Deep Chemo-Photodynamic Therapy. AB - Fluorescent dyes with multi-functionality are of great interest for photo-based cancer theranostics. However, their low singlet oxygen quantum yield impedes their potential applications for photodynamic therapy (PDT). Now, a molecular self-assembly strategy is presented for a nanodrug with a remarkably enhanced photodynamic effect based on a dye-chemodrug conjugate. The self-assembled nanodrug possesses an increased intersystem crossing rate owing to the aggregation of dye, leading to a distinct singlet oxygen quantum yield (Phi(1 O2 )). Subsequently, upon red light irradiation, the generated singlet oxygen reduces the size of the nanodrug from 90 to 10 nm, which facilitates deep tumor penetration of the nanodrug and release of chemodrug. The nanodrug achieved in situ tumor imaging and potent tumor inhibition by deep chemo-PDT. Our work verifies a facile and effective self-assembly strategy to construct nanodrugs with enhanced performance for cancer theranostics. PMID- 30003658 TI - Clinical support time: Perspective from a new FACEM. PMID- 30003657 TI - Whole-plant reddening in Silene germana is due to anthocyanin accumulation in response to visible light. AB - The phenology of anthocyanin accumulation in leaves has been widely studied in perennial plants; several hypotheses have been proposed to explain their adaptive significance. Here, we explored the photoprotection hypothesis in Silene germana, a Mediterranean annual plant with late-spring/summer flowering. We analysed the temporal patterns of anthocyanin accumulation in photosynthetic calyces, leaves and stems and throughout the reproductive season, and their relationship with flower abortion, florivory and plant mortality due to drought. In addition, the flavonoid production and the photoinhibitory response were measured in a shading experiment. The whole plant becomes red at the end of the flowering and remains red until fruiting and senescence. Calyces were redder on the side with more sun exposition. Aborted flowers showed redder calyces than those of fruiting flowers. No effect of plant redness on florivory or plant mortality was found. The shading experiment showed a positive relationship between anthocyanin accumulation and intensity of solar radiation, but plants growing in absence of UV showed similar redness than full sunlight plants. Plants growing in natural shade lack anthocyanins but produced the same amount of non-anthocyanin flavonoids. Anthocyanic and non-anthocyanic plants showed similar photochemical efficiency (Fv /Fm ) after sun exposition, but in early morning, the former showed lower Fv /Fm values. Plants growing in full sunlight produced more fruits than those of natural shade plants. Whole-plant reddening during fruiting and senescence appears to be a property of S. germana. Our results suggest that anthocyanin accumulation depends on sunlight intensity, but non-anthocyanin flavonoids are produced constitutively. PMID- 30003659 TI - Merging Art and Science-The 53rd Burgenstock Conference. AB - For the 53rd time, the Burgenstock Conference gathered some of the most gifted scientists and rising stars in organic, physical, and bioorganic chemistry. Orchestrated by Ilan Marek (President) and his successor, Veronique Gouverneur, the synergy between art and science took place in Brunnen, Switzerland, with a beatiful view over Lake Lucerne. PMID- 30003660 TI - A Self-Digitization Dielectrophoretic (SD-DEP) Chip for High-Efficiency Single Cell Capture, On-Demand Compartmentalization, and Downstream Nucleic Acid Analysis. AB - The design and fabrication of a self-digitization dielectrophoretic (SD-DEP) chip with simple components for single-cell manipulation and downstream nucleic acid analysis is presented. The device employed the traditional DEP and insulator DEP to create the local electric field that is tailored to approximately the size of single cells, enabling highly efficient single-cell capture. The multistep procedures of cell manipulation, compartmentalization, lysis, and analysis were performed in the integrated microdevice, consuming minimal reagents, minimizing contamination, decreasing lysate dilution, and increasing assay sensitivity. The platform developed here could be a promising and powerful tool in single-cell research for precise medicine. PMID- 30003661 TI - An efficient and facile green synthesis of bisindole methanes as potential Mtb FtsZ inhibitors. AB - The rising multidrug-resistant Mycobacterium tuberculosis (Mtb) strain made current anti-TB drug therapy ineffective and became a major health concern globally; hence it is crucial to develop new molecules against vital targets with a novel mechanism. Mtb Filamenting temperature sensitive protein Z (FtsZ), a tubulin homolog plays a major role in bacterial cell division, in the presence of GTP recruiting essential proteins for cell division and considered to be a potential target for drug discovery. Most of MtbFtsZ inhibitors known are of antibiotics from natural resources and suffer from cellular uptake, specificity. In the present study, we demonstrated for the first time bisindole derivatives as potential MtbFtsZ inhibitors. The synthesis of bisindole derivatives has been carried out using green synthetic approach by applying ammonium molybdate as a catalyst under Ultrasonic condition. Among the synthesized bisindole derivative, I16 and I5 showed 62.29% and 56.86% inhibition of GTPase activity of MtbFtsZ and increased the length of Mycobacterium smegmatis and Bacillus subtilis by two folds. Further compound I16 inhibited Mtb growth with a MIC of 37.5 MUg/ml. To explain these interactions, detailed Molecular docking studies have been carried out and found to be supportive to the biological activity. PMID- 30003662 TI - Reproducible Enhancement of Fluorescence by Bimetal Mediated Surface Plasmon Coupled Emission for Highly Sensitive Quantitative Diagnosis of Double-Stranded DNA. AB - Plasmonic enhancement of fluorescence from SYBR Green I conjugated with a double stranded DNA (dsDNA) amplicon is demonstrated on polymerase chain reaction (PCR) products. Theoretical computation leads to use of the bimetallic (Au 2 nm-Ag 50 nm) surface plasmons due to larger local fields (higher quality factors) than monometallic (Ag or Au) ones at both dye excitation and emission wavelengths simultaneously, optimizing fluorescence enhancement with surface plasmon coupled emission (SPCE). Two kinds of reverse Kretschmann configurations are used, which favor, in signal-to-noise ratio, a fluorescence assay that uses optically dense buffer such as blood plasma. The fluorescence enhancement (12.9 fold at maximum) with remarkably high reproducibility (coefficient of variation (CV) < 1%) is experimentally demonstrated. This facilitates credible quantitation of enhanced fluorescence, however unlikely to obtain by localized surface plasmons. The plasmon-induced optical gain of 46 dB due to SPCE-active dye molecules is also estimated. The fluorescence enhancement technologies with PCR enables LOD of the dsDNA template concentration of ~400 fg uL-1 (CV < 1%), the lowest ever reported in DNA fluorescence assay to date. SPCE also reduces photobleaching significantly. These technologies can be extended for a highly reproducible and sufficiently sensitive fluorescence assay with small volumes of analytes in multiplexed diagnostics. PMID- 30003663 TI - Environmental determinants of pyoverdine production, exploitation and competition in natural Pseudomonas communities. AB - Many bacteria rely on the secretion of siderophores to scavenge iron from the environment. Laboratory studies revealed that abiotic and biotic factors together determine how much siderophores bacteria make, and whether siderophores can be exploited by non-producing cheaters or be deployed by producers to inhibit competitors. Here, we explore whether these insights apply to natural communities, by comparing the production of the siderophore pyoverdine among 930 Pseudomonas strains from 48 soil and pond communities. We found that pH, iron content, carbon concentration and community diversity determine pyoverdine production levels, and the extent to which strains are either stimulated or inhibited by heterologous (non-self) pyoverdines. While pyoverdine non-producers occurred in both habitats, their prevalence was higher in soils. Environmental and genetic analyses suggest that non-producers can evolve as cheaters, exploiting heterologous pyoverdine, but also due to pyoverdine disuse in environments with increased iron availability. Overall, we found that environmental factors explained between-strain variation in pyoverdine production much better in soils than in ponds, presumably because high strain mixing in ponds impedes local adaption. Our study sheds light on the complexity of natural bacterial communities, and provides first insights into the multivariate nature of siderophore-based iron acquisition and competition among environmental pseudomonads. PMID- 30003664 TI - Patient- and health care-related factors associated with initiation of potentially inappropriate medication in community-dwelling older persons. AB - Potentially inappropriate medications (PIMs) in older persons are defined as medications of which the potential harms outweigh their benefits. The purpose of this study was to determine how initiation of PIMs accumulate in community dwelling persons aged 65-74 and >=75 years, and which patient- and health care related factors are associated with PIM initiation over time. Data of this study were gathered from population-based registers by a 10% random sample of persons (n = 28 497) aged >=65 years with no prior PIMs within a 2-year period preceding the index date (1 January 2002), and the study individuals were followed until 2013. The Finnish Prescription Register was linked using a personal identity code to register on inpatient care and causes of deaths and socio-economic data. In this study, 10 698 (37.5%) persons initiated PIMs during the study period. Female gender was associated with PIM initiation in 65-74-year-olds, but not in >=75 year-olds. In 65-74-year-olds, the risk of PIM initiation increased with the higher income, whereas in >=75-year-olds, the association between PIM initiation and the high income was not significant. The prescribing physician explained 9% 16% of the variation in the probability of PIM initiation. In conclusion, there were age-related differences in the factors associated with PIM initiation in relation to gender and socio-economic status. Overall, patient-related factors explained a large proportion of variation of PIM initiation, but there were also differences in PIM prescribing among physicians. However, physician-related variance of PIM initiations decreased during the 12-year follow-up. PMID- 30003665 TI - Electron Tomography Reveals the Droplet Covered Surface Structure of Nanowires Grown by Aerotaxy. AB - For the purpose of functionalizing III-V semiconductor nanowires using n-doping, Sn-doped GaAs zincblende nanowires are produced, using the growth method of Aerotaxy. The growth conditions used are such that Ga droplets, formed on the nanowire surface, increase in number and concentrations when the Sn-precursor concentration is increased. Droplet-covered wires grown with varying Sn concentrations are analyzed by transmission electron microscopy and electron tomography, which together establish the positioning of the droplets to be preferentially on {-111}B facets. These facets have the same polarity as the main wire growth direction, [-1-1-1]B. This means that the generated Ga particles can form nucleation sites for possible nanowire branch growth. The concept of azimuthal mapping is introduced as a useful tool for nanowire surface visualization and evaluation. It is demonstrated here that electron tomography is useful in revealing both the surface and internal morphologies of the nanowires, opening up for applications in the analysis of more structurally complicated systems like radially asymmetrical nanowires. The analysis also gives a further understanding of the limits of the dopants which can be used for Aerotaxy nanowires. PMID- 30003667 TI - Recent Advances toward the Rational Design of Efficient Bifunctional Air Electrodes for Rechargeable Zn-Air Batteries. AB - Large-scale application of renewable energy and rapid development of electric vehicles have brought unprecedented demand for advanced energy-storage/conversion technologies and equipment. Rechargeable zinc (Zn)-air batteries represent one of the most promising candidates because of their high energy density, safety, environmental friendliness, and low cost. The air electrode plays a key role in managing the many complex physical and chemical processes occurring on it to achieve high performance of Zn-air batteries. Herein, recent advances of air electrodes from bifunctional catalysts to architectures are summarized, and their advantages and disadvantages are discussed to underline the importance of progress in the evolution of bifunctional air electrodes. Finally, some challenges and the direction of future research are provided for the optimized design of bifunctional air electrodes to achieve high performance of rechargeable Zn-air batteries. PMID- 30003666 TI - Triglyceride-rich very low-density lipoproteins (VLDL) are independently associated with insulin secretion in a multiethnic cohort of adolescents. AB - Excess insulin secretion and hyperinsulinaemia contribute to the progression of type 2 diabetes. However, the mechanisms leading to insulin hypersecretion remain largely unknown. Based on our preliminary data, we examined whether triglycerides and very low-density lipoprotein (VLDL) are independently associated with insulin secretion, and whether ethnicity/race modulates these associations. Fasting triglycerides and VLDL were measured in a multiethnic cohort of 630 non-diabetic adolescents. Insulin secretion, beta-cell function parameters, insulin sensitivity and insulin clearance were estimated through a 3-h oral glucose tolerance test. Metabolic assessments were repeated after 2 years in 239 subjects. Triglycerides and triglyceride-rich VLDL (large and medium size fractions) were associated with both basal and glucose-stimulated insulin secretion, after adjustment for age, sex, ethnicity, BMI z-score, plasma glucose, and insulin sensitivity. Ethnicity per se had an impact on lipid profile and beta cell function, but did not modulate the effect of triglycerides/VLDL on insulin secretion. At follow-up, changes in triglyceride levels were proportional to changes in insulin secretion. These findings support the hypothesis that hypertriglyceridaemia is an important stimulus for beta-cell insulin release in young people under both fasting and fed conditions. PMID- 30003668 TI - Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA-approved inhibitors: MD study. AB - HIV-1 protease (HIV PR) is considered as one of the most attractive targets for the treatment of HIV and the impact of flap dynamics of HIV PR on the binding affinities of protease inhibitors (PIs) is a crucial ongoing research field. Recently, our research group evaluated the binding affinities of different FDA approved PIs against the South African HIV-1 subtype C (C-SA) protease (PR). The CSA-HIV PR displayed weaker binding affinity for most of the clinical PIs compared to HIV-1 B subtype for West and Central Europe, the Americas. In the current work, the flap dynamics of four different systems of HIV-1 C-SA PR complexed to FDA approved second generation PIs and its impact on binding was explored over the molecular dynamic trajectories. It was observed that the interactions of the selected drugs with the binding site residues of the protease may not be the major contributor for affinity towards PIs. Various post-MD analyses were performed, also entropic contributions, solvation free energies and hydrophobic core formation interactions were studied to assess how the flap dynamics of C-SA PR which is affected by such factors. From these contributions, large van der Waals interactions and low solvation free energies were found to be major factors for the higher activity of ATV against C-SA HIV PR. Furthermore, a comparatively stable hydrophobic core may be responsible for higher stability of the PR flaps of the ATV complex. The outcome of this study provides significant guidance to how the flap dynamics of C-SA PR is affected by various factors as a result of the binding affinity of various protease inhibitors. It will also assist with the design of potent inhibitors against C-SA HIV PR that apart from binding in the active site of PR can interacts with the flaps to prevent opening of the flaps resulting in inactivation of the protease. PMID- 30003669 TI - Sculpting Extreme Electromagnetic Field Enhancement in Free Space for Molecule Sensing. AB - A strongly confined and enhanced electromagnetic (EM) field due to gap-plasmon resonance offers a promising pathway for ultrasensitive molecular detections. However, the maximum enhanced portion of the EM field is commonly concentrated within the dielectric gap medium that is inaccessible to external substances, making it extremely challenging for achieving single-molecular level detection sensitivity. Here, a new family of plasmonic nanostructure created through a unique process using nanoimprint lithography is introduced, which enables the precise tailoring of the gap plasmons to realize the enhanced field spilling to free space. The nanostructure features arrays of physically contacted nanofinger pairs with a 2 nm tetrahedral amorphous carbon (ta-C) film as an ultrasmall dielectric gap. The high tunneling barrier offered by ta-C film due to its low electron affinity makes an ultranarrow gap and high enhancement factor possible at the same time. Additionally, its high electric permittivity leads to field redistribution and an abrupt increase across the ta-C/air boundary and thus extensive spill-out of the coupled EM field from the gap region with field enhancement in free space of over 103 . The multitude of benefits deriving from the unique nanostructure hence allows extremely high detection sensitivity at the single-molecular level to be realized as demonstrated through bianalyte surface enhanced Raman scattering measurement. PMID- 30003670 TI - Glycaemic control and mortality in older people with type 2 diabetes: The Fremantle Diabetes Study Phase II. AB - AIM: To investigate whether tight glycaemic control achieved with metformin, insulin or sulphonylurea-based pharmacotherapy increases all-cause mortality in older people with type 2 diabetes. MATERIALS AND METHODS: We conducted a prospective cohort study of individuals with known diabetes recruited between 2008 and 2011 and followed until 2016. The impact of baseline glycated haemoglobin (HbA1c) on mortality hazards was investigated in participants aged >=75 years. Proportional hazards models for time to death were constructed from the baseline clinical assessment, then the variables of interest (HbA1c, treatment category and their interactions) were entered. RESULTS: There were 367 participants (mean age 80.1 +/- 3.9 years, median [interquartile range] HbA1c 50 [45-56] mmol/mol or 6.7 [6.3-7.3]%) who were followed for a median (interquartile range) 6.7 (4.5-7.7) years, during which 40.9% of the participants died. At baseline, 60.4% were on metformin-based treatment, 35.3% on sulphonylurea-based treatment and 23.2% on treatment including insulin. Baseline HbA1c was significantly associated with mortality in a model that included interactions between HbA1c and the three treatment-based groups compared with non pharmacological treatment. The metformin treatment group had higher mortality when HbA1c levels were <48 mmol/mol (<6.5%) and the sulphonylurea and insulin treatment groups had higher mortality when HbA1c levels were <52 mmol/mol (<7.0%), with hazard ratios of 2.63 (95% confidence interval [CI] 1.39-4.97), 2.49 (95% CI 1.14-5.44) and 2.22 (95% CI 1.12-4.43), respectively. CONCLUSIONS: Tight glycaemic control may be hazardous in older people with type 2 diabetes when achieved with pharmacotherapy with metformin, and especially with insulin or sulphonylureas. These data confirm that overtreatment is likely to be an important clinical problem in this vulnerable population. PMID- 30003671 TI - Motion modelling and error compensation of a cable-driven continuum robot for applications to minimally invasive surgery. AB - BACKGROUND: The continuum robot is widely used in minimally invasive surgery (MIS) because of its flexibility, dexterity and safety. However, because of the friction in the transmission system, backlash, and shape error from nominal kinematics, the tracking accuracy of the continuum robot is low, which may damage the tissues and organs during surgery. A novel error compensation method is presented to improve control. METHODS: Considering the nonlinear friction and coupling effects, the static model of a robot is derived based on the principle of virtual work. A modified Capstan equation including bending rigidity and nonlinear friction is established to analyze the transmission characteristics of a cable-pulley system. RESULTS: The results of the experiments conducted with a continuum robot indicate the validity of the proposed compensation method. CONCLUSIONS: The established model and the proposed compensation method can be used for the cable-driven continuum robot to guarantee safety and stability in MIS. PMID- 30003672 TI - The diagnosis and management of idiosyncratic drug-induced liver injury. AB - Drug-induced liver injury (DILI) is an uncommon but important cause of liver disease that can arise after exposure to a multitude of drugs and herbal and dietary supplements. The severity of idiosyncratic DILI varies from mild serum aminotransferase elevations to the development of severe liver injury that can progress to acute liver failure resulting in death or liver transplantation within days of DILI onset. Chronic liver injury that persists for more than 6 months after DILI onset is also becoming increasingly recognized in up to 20% of DILI patients. Host demographic (age, gender, race), clinical and laboratory features at DILI onset have been associated with the severity and outcome of liver injury in DILI patients. In addition to cessation of the suspect drug, other medical interventions including the use of N-acetylcysteine and corticosteroids in selected patients have shown some clinical benefit, but additional prospective studies are needed. A number of promising diagnostic, prognostic and mechanistic serum and genetic biomarkers may help improve our understanding of the pathogenesis and treatment of idiosyncratic DILI. PMID- 30003673 TI - Proper splicing contributes to visual function in the aging Drosophila eye. AB - Changes in splicing patterns are a characteristic of the aging transcriptome; however, it is unclear whether these age-related changes in splicing facilitate the progressive functional decline that defines aging. In Drosophila, visual behavior declines with age and correlates with altered gene expression in photoreceptors, including downregulation of genes encoding splicing factors. Here, we characterized the significance of these age-regulated splicing associated genes in both splicing and visual function. To do this, we identified differential splicing events in either the entire eye or photoreceptors of young and old flies. Intriguingly, aging photoreceptors show differential splicing of a large number of visual function genes. In addition, as shown previously for aging photoreceptors, aging eyes showed increased accumulation of circular RNAs, which result from noncanonical splicing events. To test whether proper splicing was necessary for visual behavior, we knocked down age-regulated splicing factors in photoreceptors in young flies and examined phototaxis. Notably, many of the age regulated splicing factors tested were necessary for proper visual behavior. In addition, knockdown of individual splicing factors resulted in changes in both alternative splicing at age-spliced genes and increased accumulation of circular RNAs. Together, these data suggest that cumulative decreases in splicing factor expression could contribute to the differential splicing, circular RNA accumulation, and defective visual behavior observed in aging photoreceptors. PMID- 30003674 TI - Single neuron activity and c-Fos expression in the rat striatum following electrical stimulation of the peripheral vestibular system. AB - Connections between the vestibular system and the basal ganglia have been postulated since the early 20th century. However, the results of electrophysiological studies investigating neuronal responses to electrical stimulation of the vestibular system have been inconsistent. The aim of this study was to investigate the effects of electrical stimulation of the vestibular labyrinth on single neuron activity and c-Fos expression in the rat striatum. We used electrical stimulation of the vestibular labyrinth (various intensities delivered to the round window) to examine the electrophysiological response of striatal neurons and c-Fos expression. From 507 single neurons recorded (n = 20 rats), no vestibular-responsive neuron was found at 1* and 2* the nystagmus threshold; however, 6 neurons were found at 3* the threshold. These neurons were found bilaterally, with a response latency of ~50 msec from the end of the stimulus. For the c-Fos study, the number of neurons expressing c-Fos was quantified using stereological methods. Stimulation at 2* the threshold for nystagmus (n = 5 rats) resulted in a significant decrease in the number of neurons expressing c-Fos in the bilateral striatum compared to both the sham control group (n = 5) and the lower stimulus intensity group (n = 5) (P <= 0.0001 for both). The results of this study demonstrate that: (1) some single striatal neurons respond to electrical vestibular stimulation, however, these responses are circumscribed and infrequent; (2) electrical stimulation of the vestibular labyrinth results in a decrease in the number of striatal neurons expressing c Fos, in a current-dependent manner. PMID- 30003676 TI - Continuing Professional Development. PMID- 30003677 TI - Bilateral uveal melanoma: hunting for the source. PMID- 30003678 TI - Sulfur-Deficient Bismuth Sulfide/Nitrogen-Doped Carbon Nanofibers as Advanced Free-Standing Electrode for Asymmetric Supercapacitors. AB - The use of free-standing carbon-based hybrids plays a crucial role to help fulfil ever-increasing energy storage demands, but is greatly hindered by the limited number of active sites for fast charge adsorption/desorption processes. Herein, an efficient strategy is demonstrated for making defect-rich bismuth sulfides in combination with surface nitrogen-doped carbon nanofibers (dr-Bi2 S3 /S-NCNF) as flexible free-standing electrodes for asymmetric supercapacitors. The dr-Bi2 S3 /S-NCNF composite exhibits superior electrochemical performances with an enhanced specific capacitance of 466 F g-1 at a discharge current density of 1 A g-1 . The high performance of dr-Bi2 S3 /S-NCNF electrodes originates from its hierarchical structure of nitrogen-doped carbon nanofibers with well-anchored defect-rich bismuth sulfides nanostructures. As modeled by density functional theory calculation, the dr-Bi2 S3 /S-NCNF electrodes exhibit a reduced OH- adsorption energy of -3.15 eV, compared with that (-3.06 eV) of defect-free bismuth sulfides/surface nitrogen-doped carbon nanofiber (df-Bi2 S3 /S-NCNF). An asymmetric supercapacitor is further fabricated by utilizing dr-Bi2 S3 /S-NCNF hybrid as the negative electrode and S-NCNF as the positive electrode. This composite exhibits a high energy density of 22.2 Wh kg-1 at a power density of 677.3 W kg-1 . This work demonstrates a feasible strategy to construct advanced metal sulfide-based free-standing electrodes by incorporating defect-rich structures using surface engineering principles. PMID- 30003679 TI - Serum uric acid levels and decreased estimated glomerular filtration rate in patients with type 2 diabetes: A cohort study and meta-analysis. AB - BACKGROUND: Epidemiological studies suggest that elevated serum uric acid (SUA) is associated with heightened incident kidney disease in both the general population and the type 2 diabetes (T2D) cases, although the results were not entirely consistent. METHODS: We investigated prospective association between SUA levels and estimated glomerular filtration (eGFR) decline risk (eGFR <60 mL min-1 1.73 m-2 ) among 3123 T2D in the Dongfeng-Tongji cohort and further examined this association with a meta-analysis. Generalize linear model was used to assess the associations of SUA with eGFR decline in the cohort. In the meta-analysis, we used both fix-effects and random-effects models to calculate the overall effect estimate. RESULTS: During 5-year follow-up, 303 (9.7%) patients developed eGFR decline. After multiple adjustments, the relative risk (RR) (95% CI) of eGFR decline was 1.55 (1.07, 2.26) when comparing the highest with the lowest sex specific uric acid quartile. A 100 MUmol/L increment of SUA level was significantly associated with 21% increased risk of eGFR decline. The SUA-eGFR decline association was more evident in men, but not in women. In meta-analysis, the pooled RR (95% CI) was 2.33 (1.66, 3.25) for developing eGFR decline when comparing the highest with the lowest levels of uric acid. A 100 MUmol/L increment of SUA level was significantly associated with a 33% increased risk of eGFR decline. CONCLUSIONS: Our results indicate an independent and significant positive association between higher SUA and increased risk of developing eGFR decline among T2D cases. PMID- 30003680 TI - The HLA-B*46:67 allele identified in a volunteer donor for hematopoietic stem cell transplant. AB - HLA-B*46:67 differs from HLA-B*46:01:01 in codons 94, 95, and 103 in exon 3. PMID- 30003675 TI - Does urinary cytology have a role in haematuria investigations? AB - OBJECTIVES: To determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria. PATIENT AND METHODS: The DETECT I study (clinicaltrials.gov NCT02676180) recruited patients presenting with haematuria following referral to secondary case at 40 hospitals. All patients had a cystoscopy and upper tract imaging (renal bladder ultrasound [RBUS] and/ or CT urogram [CTU]). Patients, where urine cytology were performed, were sub-analysed. The reference standard for the diagnosis of bladder cancer and UTUC was histological confirmation of cancer. A positive urine cytology was defined as a urine cytology suspicious for neoplastic cells or atypical cells. RESULTS: Of the 3 556 patients recruited, urine cytology was performed in 567 (15.9%) patients from nine hospitals. Median time between positive urine cytology and endoscopic tumour resection was 27 (IQR: 21.3-33.8) days. Bladder cancer was diagnosed in 39 (6.9%) patients and UTUC in 8 (1.4%) patients. The accuracy of urinary cytology for the diagnosis of bladder cancer and UTUC was: sensitivity 43.5%, specificity 95.7%, positive predictive value (PPV) 47.6% and negative predictive value (NPV) 94.9%. A total of 21 bladder cancers and 5 UTUC were missed. Bladder cancers missed according to grade and stage were as follows: 4 (19%) were >= pT2, 2 (9.5%) were G3 pT1, 10 (47.6%) were G3/2 pTa and 5 (23.8%) were G1 pTa. High-risk cancer was confirmed in 8 (38%) patients. There was a marginal improvement in sensitivity (57.7%) for high-risk cancers. When urine cytology was combined with imaging, the diagnostic performance improved with CTU (sensitivity 90.2%, specificity 94.9%) superior to RBUS (sensitivity 66.7%, specificity 96.7%). False positive cytology results were confirmed in 22 patients, of which 12 (54.5%) had further invasive tests and 5 (22.7%) had a repeat cytology. No cancer was identified in these patients during follow-up. CONCLUSIONS: Urine cytology will miss a significant number of muscle-invasive bladder cancer and high-risk disease. Our results suggest that urine cytology should not be routinely performed as part of haematuria investigations. The role of urine cytology in select cases should be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia. PMID- 30003681 TI - Reducing seed waste and increasing value of dynamic intraoperative implantation of Pd-103 seeds in prostate brachytherapy. AB - Several nomograms exist for ordering palladium-103 seeds for permanent prostate seed implants (PSI). Excess seeds from PSIs pose additional radiation safety risks and increase the cost of care. This study compared five nomograms to clinical data from dynamic modified-peripheral intraoperative PSI to determine (a) the cause of excess seeds and (b) the optimal nomogram for our institution. Pre- and intraoperative patient data were collected for monotherapy PSIs and compiled into a clinical database. All patients were prescribed 125 Gy with dose coverage of D90% = 100% to the planning target volume (PTV) using 103 Pd seeds with mean air-kerma strength ( SK- ) of 2 U. Seeds were ordered based upon an in house nomogram as a function of preoperative prostate volume and prescription dose. Preoperative prostate volume was assessed with transrectal ultrasound. If any of the following four conditions were not met: (a) preoperative volume = intraoperative volume, (b) D90% = 100%, (c) SK-=2U , and (d) seed ordering matched the in-house nomogram, then a normalization factor was applied to the number of seeds used intraoperatively to meet all four conditions. Four published nomograms, an in-house nomogram, and the normalized number of implanted seeds for each patient were plotted against intraoperative prostate volume. Of the 226 patients, 223 had excess seeds at the completion of their PSI. On average, 25.7 +/- 9.9% of ordered seeds were not implanted. Excess seeds were separated into two categories, accounted-for excess, determined by the four normalization factors, and residual excess, assumed to be due to overordering. The upper 99.9% CI linear fit of the normalized clinical data plus a 5% "cushion" may provide a more reasonable nomogram for 103 Pd seed ordering for our institution. Nomograms customized for individual institutions may reduce seed waste, thereby reducing radiation safety risks and increasing the value of prostate brachytherapy. PMID- 30003684 TI - Reply. PMID- 30003683 TI - CCAR-1 is a negative regulator of the heat-shock response in Caenorhabditis elegans. AB - Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat-shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA-bound state of HSF1 through deacetylation of the DNA-binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell-cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF-1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR-1. This negative regulation requires the SIRT1 homolog SIR-2.1. In addition, knockdown of CCAR-1 via ccar-1 RNAi works through SIR-2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism. PMID- 30003685 TI - Genomic full-length sequence of HLA-B*15:178 was identified by full-length group specific sequencing. AB - Genomic full-length sequence of HLA-B*15:178 was identified by a group-specific sequencing approach from China. PMID- 30003686 TI - Clinical experiences and case review of angiotensin II receptor blocker-related angioedema in Korea. AB - Although angiotensin-converting enzyme inhibitor-related angioedema is well known, angiotensin II receptor blocker (ARB)-related angioedema has not been extensively studied because of its lower incidence. Therefore, ARB-related angioedema is likely to be overlooked in the clinical setting. We analysed the medical records of adults who had been prescribed ARB and diagnosed with angioedema between 2009 and 2015. All adults over the age of 18 years who were initially administered ARB between 1 January 2009 and 31 December 2015 were selected as participants in this study. To confirm whether the angioedema was actually due to the administration of ARB, we conducted a chart review. A total of 35 584 patients were prescribed ARB for the first time when visiting the Seoul St. Mary's Hospital during the study period. Twenty-four patients diagnosed with angioedema for other reasons prior to their first prescription of ARB were excluded from this study. ARB-related angioedema was suspected in six of 35 560 patients (0.02%) who were initially prescribed ARB during the study period. The manifestation of ARB-related angioedema ranged from several days (1/6 case) to several years (3/6 cases). Some patients continued taking ARB with intermittent antihistamine or steroid therapy. In such cases, angioedema symptoms improved but did not completely resolve. Its diagnosis can be delayed and the symptoms may be recurrent as symptoms improve with antihistamine use. In some cases, the same person had different reactions depending on the type of ARB. Definitively diagnosing ARB-related angioedema is difficult, and physicians often overlook angioedema without suspecting that it is an adverse effect of ARB. Close attention of physicians and improved patient education can reduce the incidence of ARB-related angioedema. PMID- 30003687 TI - Autoimmunity or Lineage-Specific Virulence as Drivers of Chikungunya Chronic Arthritis: Comment on the Article by Chang et al. PMID- 30003682 TI - Roux-en-Y gastric bypass surgery alters serum metabolites and fatty acids in patients with morbid obesity. AB - AIM: Bariatric surgery induces significant weight loss, increases insulin sensitivity, and reduces mortality, but the underlying mechanisms are not clear. It was hypothesized that Roux-en-Y gastric bypass (RYGB) surgery improves metabolic profile along with weight loss. The objective of this pilot study was to evaluate changes in serum metabolites and fatty acids (FA) at 2 weeks and 6 months after RYGB. MATERIALS AND METHODS: Serum samples were collected pre surgery, at 2 weeks and 6 months post-surgery from 20 patients undergoing RYGB surgery. Serum non-esterified free FA (NEFA) were measured. Serum metabolites and FA were measured using nuclear magnetic resonance spectroscopy and improved direct fatty acid methyl ester synthesis and the gas chromatography/mass spectrometry method, respectively, in subjects who completed follow-up at 6 months (n = 8). RESULTS: Mean (standard deviation) percent total weight loss was 6.70% (1.7) and 24.91% (6.63) at 2 weeks (n = 15) and 6 months (n = 8) post surgery, respectively. NEFA were significantly reduced at 6 months post-surgery (P = 0.001, n = 8). Serum branched chain amino acids, 2-aminobutyrate, butyrate, 2-hydroxybutyrate, 3-hydroxybutyrate, acetone, 2-methylglutarate, and 2 oxoisocaproate were significantly reduced, while serum alanine, glycine, pyruvate, and taurine were significantly elevated at 6 months post-surgery compared with pre-surgery (n = 8, P < 0.05). Also, serum FA C10:0, C13:0, C14:0, C15:0, and C18:0 increased significantly (n = 8, P < 0.05) by 6 months post surgery. CONCLUSIONS: Changes in serum metabolites and FA at 6 months post-RYGB surgery in this pilot study with limited number of participants are suggestive of metabolic improvement; larger studies are warranted for confirmation. PMID- 30003688 TI - Mood instability contributes to impulsivity, non-suicidal self-injury, and binge eating/purging in people with anxiety disorders. AB - OBJECTIVES: The purpose of this study was to determine whether mood instability in people with anxiety disorders contributes to trait impulsivity, non-suicidal self-injury, and binge eating/purging. METHODS: Data were analysed from a general population sample of 7,221 adults (Mage = 51.0 years; 56.9% female). Logistic regression analyses with effect decompositions were used to establish the associations of five anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, agoraphobia, and obsessive-compulsive disorder) with impulsivity, non-suicidal self-injury, and binge eating/purging, and then to determine the extent that adding mood instability to each model reduced these relationships. RESULTS: Participants with an anxiety disorder were more likely to report impulsivity compared to participants without an anxiety disorder (ORs = 2.40-3.92, all p < .001), but these relationships reduced by 59-78% and became non-significant when mood instability was added to the models. Participants with an anxiety disorder were also more likely to report non-suicidal self-injury (ORs = 3.86-18.9, all p < .001) and binge eating/purging (ORs = 4.05-14.9, all p < .01); adding mood instability to the models reduced these relationships by at least 30%. CONCLUSIONS: Mood instability and impulsivity are common in people with anxiety disorders. Anxiety disorders are associated with impulsivity largely because of the association between mood instability and impulsivity. Mood instability may contribute to non-suicidal self-injury and binge eating/purging in people with anxiety disorders. Treatments for mood instability in addition to standard anxiety disorder treatment may reduce impulsivity, non-suicidal self injury, and binge eating/purging in people with anxiety disorders. PRACTITIONER POINTS: Many patients with anxiety disorders experience mood instability, which is associated with impulsivity, non-suicidal self-injury, and binge eating/purging. Treating mood instability alongside anxiety may help reduce impulsivity, non-suicidal self-injury, and binge eating/purging in people with anxiety disorders. PMID- 30003689 TI - ADAM15 in Apoptosis Resistance of Synovial Fibroblasts: Converting Fas/CD95 Death Signals Into the Activation of Prosurvival Pathways by Calmodulin Recruitment. AB - OBJECTIVE: To investigate mechanisms underlying the capability of ADAM15 to transform FasL-mediated death-inducing signals into prosurvival activation of Src and focal adhesion kinase (FAK) in rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Caspase 3/7 activity and apoptosis rate were determined in RASFs and ADAM15-transfected T/C28a4 cells upon Fas/CD95 triggering using enzyme assays and annexin V staining. Phosphorylated Src and FAK were analyzed by immunoblotting. Interactions of ADAM15 and CD95 with calmodulin (CaM), Src, or FAK were analyzed by pull-downs using CaM-Sepharose and coimmunoprecipitations with specific antibodies. Protein binding assays were performed using recombinant CaM and ADAM15. Immunofluorescence was performed to investigate subcellular colocalization of ADAM15, Fas/CD95, and CaM. RESULTS: The antiapoptotic effect of ADAM15 in FasL-stimulated cells was demonstrated either by increased apoptosis of cells transfected with an ADAM15 construct lacking the cytoplasmic domain compared to cells transfected with full-length ADAM15 or by reduced apoptosis resistance of RASFs upon RNA interference silencing of ADAM15. Fas ligation triggered a Ca2+ release-activated Ca2+ /calcium release-activated calcium channel protein 1 (CRAC/Orai1) channel-dependent CaM recruitment to Fas/CD95 and ADAM15 in the cell membrane. Simultaneously, Src associated with CaM was shown to become engaged in the ADAM15 complex also containing cytoplasmic-bound FAK. Accordingly, Fas ligation in RASFs led to ADAM15-dependent phosphorylation of Src and FAK, which was associated with increased survival. Pharmacologic interference with either the CaM inhibitor trifluoperazine or the CRAC/Orai inhibitor BTP-2 simultaneously applied with FasL synergistically enhanced Fas-mediated apoptosis in RASFs. CONCLUSION: ADAM15 provides a scaffold for formation of CaM-dependent prosurvival signaling complexes upon CRAC/Orai coactivation by FasL-induced death signals and a potential therapeutic target to break apoptosis resistance in RASFs. PMID- 30003690 TI - Evaluating a wayfinding video. AB - BACKGROUND: Many occupational therapy students experience anxiety and distraction when entering a new setting at the beginning of a clinical placement. Orientation processes may provide students with the information they need to feel more comfortable in an unfamiliar clinical setting. The aim of this project was to evaluate a revised wayfinding video for first- and second-year occupational therapy students, with a particular focus on reducing anxiety. METHODS: A revised version of a wayfinding video (with a duration of 3 minutes and 40 seconds) was created by final-year occupational therapy students and then evaluated using a paper-based descriptive survey. All data were analysed using a content analysis approach. RESULTS: A total of 71 responses were received, demonstrating a response rate of 47%. The students indicated that the video addressed the main sources of pre-placement anxiety and supported their pre-existing anxiety management strategies. Anxiety-reducing features of the video included an overview and visual introduction to the facility, hearing the positive experiences of other students, the provision of placement expectations and an introduction to the student coordinators. All but two of the students indicated that they would watch the video if it were attached to their welcome pack. Many occupational therapy students experience anxiety and distraction when entering a new setting CONCLUSIONS: The revised wayfinding video addressed many of the students' anxieties about commencing placement and now forms part of a broader suite of student orientation materials. There are several limitations to the development of wayfinding videos, but they are surmountable via collaboration and investment in careful planning. PMID- 30003691 TI - Decoding the Rich Biological Properties of Noble Gases: How Well Can We Predict Noble Gas Binding to Diverse Proteins? AB - The chemically inert noble gases display a surprisingly rich spectrum of useful biological properties. Relatively little is known about the molecular mechanisms behind these effects. It is clearly not feasible to conduct large numbers of pharmacological experiments on noble gases to identify activity. Computational studies of the binding of noble gases and proteins can address this paucity of information and provide insight into mechanisms of action. We used bespoke computational grid calculations to predict the positions of energy minima in the interactions of noble gases with diverse proteins. The method was validated by quantifying how well simulations could predict binding positions in 131 diverse protein X-ray structures containing 399 Xe and Kr atoms. We found excellent agreement between calculated and experimental binding positions of noble gases. 94 % of all crystallographic xenon atoms were within 1 Xe van der Waals (vdW) diameter of a predicted binding site, and 97 % lay within 2 vdW diameters. 100 % of crystallographic krypton atoms were within 1 Kr vdW diameter of a predicted binding site. We showed the feasibility of large-scale computational screening of all ~60 000 unique structures in the Protein Data Bank. This will elucidate biochemical mechanisms by which these novel 'atomic drugs' elicit their valuable biochemical properties and identify new medical uses. PMID- 30003693 TI - Identification of a novel HLA-DQB1 allele, DQB1*06:111, by sequence-based typing in a Taiwanese individual. AB - HLA-DQB1*06:111 differs from HLA-DQB1*06:02:01 by the single nucleotide substitution resulting in one amino acid change. PMID- 30003692 TI - In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury. AB - Tissue regeneration is a highly coordinated process with sequential events including immune cell infiltration, clearance of damaged tissues, and immune supported regrowth of the tissue. Aging has a well-documented negative impact on this process globally; however, whether changes in immune cells per se are contributing to the decline in the body's ability to regenerate tissues with aging is not clearly understood. Here, we set out to characterize the dynamics of macrophage infiltration and their functional contribution to muscle regeneration by comparing young and aged animals upon acute sterile injury. Injured muscle of old mice showed markedly elevated number of macrophages, with a predominance for Ly6Chigh pro-inflammatory macrophages and a lower ratio of the Ly6Clow repair macrophages. Of interest, a recently identified repair macrophage-derived cytokine, growth differentiation factor 3 (GDF3), was markedly downregulated in injured muscle of old relative to young mice. Supplementation of recombinant GDF3 in aged mice ameliorated the inefficient regenerative response. Together, these results uncover a deficiency in the quantity and quality of infiltrating macrophages during aging and suggest that in vivo administration of GDF3 could be an effective therapeutic approach. PMID- 30003694 TI - Home blood pressure monitoring in the 21st century. AB - Home blood pressure monitoring provides multiple measurements in the usual environment of each individual, allows the detection of intermediate hypertension phenotypes (white-coat and masked hypertension), and appears to have superior prognostic value compared to the conventional office blood pressure measurements. Accumulating evidence suggests that home blood pressure monitoring improves long term hypertension control rates. Moreover, it is widely available, relatively inexpensive, and well accepted by patients. Thus, current guidelines recommend home blood pressure monitoring as an essential method for the evaluation of almost all untreated and treated patients with suspected or treated hypertension. Validated automated upper-arm cuff devices with automated storage and averaging of readings should be used. The home blood pressure monitoring schedule for 4 to 7 days with exclusion of the first day (12-24 readings) should be averaged to provide values for decision making. PMID- 30003695 TI - Guidelines for blood pressure measurement: development over 30 years. AB - In the last 2 decades, several scientific societies have published specific guidelines for blood pressure (BP) measurement, providing detailed recommendations for office, home, and ambulatory BP monitoring. These documents typically provided strong support for using out-of-office BP monitoring (ambulatory and home). More recently, several organizations recommended out-of office BP evaluation as a primary method for diagnosing hypertension and for treatment titration, with office BP regarded as a screening method. Efforts should now be directed towards making ambulatory and home BP monitoring readily available in primary care and ensuring that such measurements are obtained by following current guidelines. Moreover, it should be mandatory for all published clinical research papers on hypertension to provide details on the methodology of the BP measurement. PMID- 30003696 TI - Patterns of ambulatory blood pressure: clinical relevance and application. AB - Ambulatory blood pressure measurement (ABPM) is now recommended in all patients suspected of having hypertension. However, in practice, the mean daytime pressures are often used to make diagnostic and therapeutic decisions, and the information from abnormal patterns of blood pressure behavior is often overlooked. This paper presents daytime patterns (eg, white coat hypertension and siesta dipping), nocturnal patterns (eg, dipping, non-dipping, reverse dipping, and the morning surge), and discusses ambulatory hypotension, and abnormal patterns and indices of related hemodynamic parameters (eg, heart rate, pulse pressure, and blood pressure variability). PMID- 30003697 TI - Validation protocols for blood pressure measuring devices in the 21st century. AB - Blood pressure (BP) is a vital sign and the essential measurement for the diagnosis of hypertension. Therefore, its accurate measurement is a key element for the evaluation of many medical conditions and for the reliable diagnosis and efficient treatment of hypertension. In the last 3 decades prestigious organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on BP Monitoring, and the International Organization for Standardization (ISO), have developed protocols for clinical validation of BP measuring devices. All these initiatives aim to standardize validation procedures and establish minimum accuracy standards for BP monitors. Unfortunately, only a few of the BP measuring devices available on the market have been subjected to independent validation using one of these protocols. Recently, the AAMI, ESH, and ISO experts agreed to develop a single universally acceptable standard (AAMI/ESH/ISO), which will replace all previous protocols. This major international initiative has been undertaken to best serve the needs of patients with hypertension, a public interested in cardiovascular health, practicing physicians, scientific researchers, regulatory bodies, and manufacturers. There is an urgent need to influence regulatory authorities throughout the world to make it mandatory for all BP measuring devices to have undergone independent validation before approval for marketing. Efforts need to be intensified to improve the accuracy of BP measuring devices, further optimize the validation procedure, and ensure that objective and unbiased validation data become available. PMID- 30003698 TI - Office blood pressure measurement in the 21st century. AB - Measurement of blood pressure (BP) using the auscultatory method must follow specific rules and conditions to be reliable. Nonetheless, these requirements are often not followed in clinical practice, resulting in inaccurate BP readings. Simply replacing manual sphygmomanometers with an oscillometric device may still produce readings that are associated with a white coat effect. These limitations can be overcome by using an oscillometric sphygmomanometer that automatically records multiple readings with the patient resting quietly and alone, called automated office (AO)BP. AOBP produces office readings with a reduced white coat effect, which are also similar to the awake ambulatory BP. There is also evidence that AOBP is a better predictor of target organ damage than attended office BP. Furthermore, clinical outcome data support AOBP as having both a similar diagnostic threshold as awake ambulatory BP and a lower treatment target. Using AOBP in clinical practice simplifies recording office BP by not requiring an additional period of rest before activation of the device and by not having staff present during the actual measurements. Recent studies have reported that automatic BP measurements taken by staff in research studies with close adherence to guidelines using AOBP devices may produce similar readings to AOBP. Further research is needed to determine the best method for recording BP at systolic targets < 130 mm Hg and the relationship of office BP to ambulatory BP and home BP. PMID- 30003699 TI - Cuff challenges in blood pressure measurement. AB - The characteristics of the optimal cuff for blood pressure (BP) measurement are still the subject of much debate. The choice of the appropriate cuff in obese individuals depends not only on the arm circumference but also on its shape because a conically shaped arm makes it difficult to fit the cuff to the arm. When a large-size cylindrical cuff is used in conical arms, an overestimation of the true BP is likely to occur with BP discrepancies that may be as large as 10 mm Hg. With the advent of automatic oscillometric devices, the choice of the appropriate cuff became even more controversial because with oscillometric BP measurement the reference point is not the artery occlusion but the oscillometric peak signal. To overcome the problem of miscuffing in obese individuals, special cuffs that can accommodate a wide range of arm sizes have been designed. Using these cuffs, accurate oscillometric BP measurements can be obtained over a wide range of arm circumferences using a unique software algorithm. These wide-range cuffs coupled to oscillometric devices may represent a good option for BP measurement in very obese subjects. However, their reliability should be confirmed in larger populations and different settings. PMID- 30003700 TI - Achieving reliable blood pressure measurements in clinical practice: It's time to meet the challenge. AB - A summary of statements for blood pressure (BP) measurement in the evaluation of hypertension in the 21st century by 25 international experts is provided. The status of office, home and ambulatory BP measurement techniques are discussed. Office BP measurement, whether automated (preferred), or otherwise, should only be used as a screening measurement, and diagnostic decisions for the initiation and titration of drug treatment should be based on out-of-office measurements (ambulatory or home). The hardware and software requirements and the adaptations of BP measuring devices to record other cardiovascular functions, such as arrhythmias, and adaptations for smartphone use and for electronic transmission are discussed. Regulatory bodies are urged to make accuracy and performance assessment mandatory before marketing BP measuring devices. The legal implications of manufacturing inaccurate devices are noted. PMID- 30003701 TI - Home blood pressure telemonitoring in the 21st century. AB - Blood pressure telemonitoring (BPT) is a telehealth strategy that allows remote data transmission of blood pressure and additional information on patients' health status from their dwellings or from a community setting to the doctor's office or the hospital. There is sufficiently strong evidence from several randomized controlled trials that the regular and prolonged use of BPT combined with telecounseling and case management under the supervision of a team of healthcare professionals is associated with a significant blood pressure reduction compared with usual care, particularly in cases of patients at high risk. However, most current evidence is based on studies of relatively short duration (<12 months), and in the few studies that have investigated longer-term outcomes, no evidence of better or sustained effect could be provided. In addition, no definition of the optimal BPT-based healthcare delivery model could be derived from the studies performed so far, because of the heterogeneity of interventions, technologies, and study designs. BPT can also be provided in the context of "mobile health" (m-health) wireless solutions, together with educational support, medication reminders, and teleconsultation. When BPT is integrated in an m-health solution, it has the potential to promote patient's self-management, as a complement to the doctor's intervention, and encourage greater participation in medical decision-making. In conclusion, BPT has a potential key role in the management of patients with hypertension, since it seems to improve the quality of delivered care and allow for more effective prevention of the cardiovascular consequences of hypertension. PMID- 30003702 TI - Ambulatory blood pressure monitoring in the 21st century. AB - In clinical practice, ambulatory blood pressure monitoring (ABPM) tends to be used solely for diagnosing hypertension, especially to identify white-coat and masked hypertension. However, ABPM can provide additional information to guide the management and drug treatment of hypertension. In this brief review, the general principles governing the use of ABPM in clinical practice, such as the devices and software, recording requirements, the thresholds for the day, night and 24-hour periods and how often to repeat ABPM are summarized. The use of ABPM for diagnosing, determining the efficacy of treatment, and assessing the long term control of hypertension are discussed. PMID- 30003703 TI - The quest for accuracy of blood pressure measuring devices. AB - The accuracy of blood pressure (BP) measuring devices is fundamental to good practice and scientific research. International guidelines on BP measurement are provided for clinicians who diagnose and treat patients with hypertension, clinical researchers who conduct trials on the efficacy of BP lowering drugs and interventional strategies, epidemiologists who conduct population surveys to determine the demographic consequences of hypertension on society, and researchers who perform meta-analyses on published research to further influence the practice of medicine and the provision of resources. Although the outcomes of the endeavors of all these groups are dependent on the accuracy of BP measurements, the equipment is often of doubtful accuracy and the methodology of measurement is often poorly described and frequently not standardized. Thus, the fundamental element of hypertension evaluation has been largely ignored by both clinical practitioners and scientific researchers. Here, the authors briefly review the development of efforts to improve and validate the accuracy of BP measuring devices and highlight the deficiencies that persist. We conclude that, to protect the public from the serious consequences of inaccurate BP measurements, the following steps are required: (1) regulatory requirement for mandatory independent validation of all BP measuring devices using a universal protocol; (2) accreditation of laboratories for the performance of BP device validations; (3) online evaluation of validation studies with detection of protocol violations prior to publication of results; and (4) establishment of an independent scientific forum for the listing of accurate BP measuring devices. PMID- 30003704 TI - Blood pressure variability: clinical relevance and application. AB - Blood pressure variability is an entity that characterizes the continuous and dynamic fluctuations that occur in blood pressure levels throughout a lifetime. This phenomenon has a complex and yet not fully understood physiological background and can be evaluated over time spans ranging from seconds to years. The present paper provides a short overview of methodological aspects, clinical relevance, and potential therapeutic interventions related to the management of blood pressure variability. PMID- 30003706 TI - Accurate blood pressure measuring devices: Influencing users in the 21st century. AB - Hypertension is now recognized as a major global cause of morbidity and death. All decisions relating to the epidemiology, diagnosis, and management of hypertension are dependent on being able to measure blood pressure accurately. Scientists have developed protocols to assess the accuracy of blood pressure measuring devices, but little attention has been given to informing users which devices are accurate and inaccurate. This article identifies a recipient audience of researchers, clinicians, and scientists, the public, healthcare executives and administrators, and consumer and regulatory bodies, and discusses how best to communicate the results of device accuracy to these groups with the aim of improving the accurate measurement of blood pressure. PMID- 30003705 TI - Blood pressure measurement in special populations and circumstances. AB - According to the established validation protocols, a typical validation study of a blood pressure (BP) monitor includes general population adults with normal or elevated BP. It is recognized, however, that the automated (oscillometric) BP monitors may have different accuracy or uses in some special populations compared with adults in the general population. Thus, an automated BP monitor with proven accuracy in a general population of adults may not be accurate in a special population, and therefore separate validation is needed. Recognized special populations deserving separate validation are those for which there is theoretical, and also clinical evidence, that the accuracy of BP monitors in these groups differs from that in the general population. Young children, pregnant women (including those with preeclampsia), individuals with arm circumference >42 cm, and patients with atrial fibrillation are regarded as special populations. Adolescents, individuals older than 80 years, and patients with end-stage renal disease or diabetes mellitus have also been considered as possible special groups, but there is still inadequate evidence of altered accuracy of BP monitors in these subjects. Validation studies should be performed in special populations and evaluated separately after the BP-measuring device has successfully undergone a validation study in a general population (unless the test device is intended only for a special population). This article discusses issues relating to the measurement of BP and the diagnosis of hypertension in selected special populations, as well as in low-resource settings, where a simplified yet efficient evaluation strategy is necessary. PMID- 30003707 TI - Miniature probe for all-optical double gradient-index lenses photoacoustic microscopy. AB - A novel all-optical double gradient-index (GRIN) lens optical-resolution photoacoustic microscopy (OR-PAM), termed as DGL-PAM, is demonstrated. The miniature probe consists of a single-mode fiber and double GRIN lenses for optical focusing and a miniature fiber Fabry-Perot sensor for ultrasound detection. The new design is simple and realizes high resolution with long working distance (WD) by virtue of the double GRIN lenses. The overall size of the probe is 2.7 mm in diameter. High lateral resolution of 3.7 MUm (at 532 nm laser wavelength) and long WD of 5.5 mm are achieved. In vivo OR-PAM of mouse ear demonstrates the imaging ability of DGL-PAM. Since precise alignment of optical and acoustic foci is not needed, the proposed DGL-PAM is relatively easy to implement. It has potential to be developed as a low-cost, disposable OR-PAM probe and for endoscopic applications. The proposed double GRIN lenses for making miniature endoscopic probes can also be applied to other modalities, such as optical coherence tomography and confocal fluorescence microscopy, to enable high resolution and long WD. PMID- 30003709 TI - SLEep among diabetic patients and their GlycaEmic control (SLEDGE): A pilot observational study. AB - BACKGROUND: Recent cohort studies have proven the association between sleep deprivation and adverse glycemic control (GC). The aim of this study was to assess the prevalence of excessive daytime sleepiness (EDS), a subjective measure of sleep deprivation, among type 2 diabetic mellitus (T2DM) patients and its association with GC. METHODS: This cross-sectional study was conducted between July 2015 and June 2016 in five diabetes clinics in the district of Erode, Tamil Nadu, India. An equal number of consenting patients with T2DM was recruited consecutively from each of the centers, and EDS was measured subjectively using the Epworth sleepiness scale (ESS), whereas GC was assessed using HbA1c levels. RESULTS: In all, 126 patients were screened and 102 were found eligible for the study. The prevalence of EDS was 17.5% (95% confidence interval 10.13-24.87). The association between ESS scores and HbA1c levels was analyzed using linear regression after adjusting for age, dietary intake, inflammatory markers (erythrocyte sedimentation rate), depression (Patient Health Questionnaire-9 score) and stress (Perceived Stress Scale score): for every unit increase in the ESS score, HbA1c increased by 0.143 g/dL (P < 0.001). CONCLUSION: Subjective EDS was seen in approximately one-quarter of patients with diabetes in our population. There was a positive association between EDS and glycemic control. Screening of patients with diabetes for EDS should be part of routine diabetes management. PMID- 30003708 TI - The correlation of circulating pro-angiogenic miRNAs' expressions with disease risk, clinicopathological features, and survival profiles in gastric cancer. AB - This study aimed to explore the correlation of circulating pro-angiogenic miRNAs' expressions with risk, clinicopathological features, and survival profiles in gastric cancer (GC). Three hundred and thirty-three GC patients underwent radical resection and 117 health controls (HCs) were recruited for this study. Plasma samples were obtained from GC patients before the operation and from HCs after enrollment. Fourteen pro-angiogenic miRNAs were asseassed by quantitative polymerase chain reaction (qPCR). Disease-free survival (DFS) and overall survival (OS) of GC patients were calculated and the median follow-up duration was 36.0 months. Seven out of 14 pro-angiogenic miRNAs including let-7f, miR-17 5p, miR-18a, miR-19b-1, miR-20a, miR-210, and miR-296 were observed to be elevated in GC patients compared with HCs. MiR-18a, miR-20a, and miR-210 disclosed good predictive values of GC risk. Six pro-angiogenic miRNAs including miR-17-5p, miR-92a, miR-210, miR-20a, miR-18a, and miR-296 expressions were positively while 1 pro-angiogenic miRNA (miR-130a) was negatively correlated with tumor malignancy degree in GC patients. K-M curve disclosed that 5 pro-angiogenic miRNAs including miR-17-5p, miR-18a, miR-20a, miR-92a, and miR-210 correlated with worse DFS, while 4 pro-angiogenic miRNAs including miR-17-5p, miR-18a, miR 20a, and miR-210 associated with shorter OS. Further multivariate Cox's analysis revealed that miR-17-5p, miR-18a, miR-20a, and miR-210 were independent predictive factors for unfavorable DFS and OS. In conclusion, circulating pro angiogenic miRNAs could serve as novel noninvasive biomarkers for disease risk and malignancy degree, and miR-17-5p, miR-18a, miR-20a, and miR-210 are independent factors predicting poor prognosis in GC patients. PMID- 30003710 TI - Stratiform Protein Microtube Reactors Containing Glucose Oxidase Layer. AB - This paper describes the synthesis and catalytic activities of stratiform protein microtube reactors containing a glucose oxidase (GOD) enzyme layer. The microtubes were fabricated by layer-by-layer assembly using a microporous polycarbonate membrane with human serum albumin (HSA), poly(l-arginine) (PLA), and GOD. The GOD component was introduced into the tube wall as the innermost layer, the intermediate layer, or all internal protein layers. SEM observations revealed the formation of uniform hollow cylinders with ca. 1.17 MUm outer diameter and ca. 135 nm wall thickness. In aqueous medium, each microtube catalyzed beta-d-glucose oxidation with high efficiency. We first ascertained the enzyme parameters (Km and kcat ) of these microtube reactors. Different catalytic activities that have dependent on the GOD layer position in the cylindrical wall have been elucidated. PMID- 30003711 TI - Incomplete methylation of a germ cell tumor (Seminoma) in a Prader-Willi male. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by lack of satiety leading to morbid obesity, variable degrees of mental retardation, behavior disorders, short stature, and hypogonadism. The underlying genetic cause for PWS is an imprinting defect resulting from a lack of expression of several paternally inherited genes embedded within the 15q11.2-q13 region. Although the clinical expression of hypogonadism in PWS is variable, there are no known cases of fertility in PWS men. In this paper, we described a pure, nearly diploid seminoma in an apparently 32 year-old infertile man with PWS due to maternal uniparental disomy (UPD) on chromosome 15. The development of a germ cell tumor in this subject was an unanticipated result. The aim of this study was to explore the origin of the germ cell tumor in this PWS male patient. METHODS: To explain the origin of the germ cell tumor (seminoma) in our PWS patient we have characterized the tumor for cell morphology and tumor type by pathological examination (H&E and immuno-stainings), evaluated its karyotype by chromosomal microarray analysis and confirmed its UPD origin by haplotype analysis. In addition, DNA methylation status of the PWS- and H19- imprinting centers in wild-type and affected fibroblasts, patient derived induced pluripotent stem cells (iPSCs), and PWS seminoma were determined by bisulfite DNA colony sequencing. RESULTS: To explain the apparent contradiction between the existence of a germ cell tumor and hypogonadism we first confirmed the germ cell origin of the tumor. Next, we determined the tumor chromosomal composition, and validated the presence of a maternal UPD in all examined cell types from this patient. Finally, we characterized the maternal imprints in the PWS and H19 imprinting centers in the tumor and compared them with patient's fibroblasts and iPSCs derived from them. Unpredictably, methylation was reduced to 50% in the tumor, while preserved in the other cell types. CONCLUSION: We infer from this assay that the loss of methylation in the PWS-IC specifically in the tumor of our patient is most likely a locus-specific event resulting from imprint relaxation rather than from general resetting of the imprints throughout the genome during germ line specification. PMID- 30003712 TI - Reply. PMID- 30003714 TI - Thermal effect on dispersive infrared spectroscopic imaging of prostate cancer tissue. AB - A system that combines dispersive infrared micro-spectroscopic imaging and thermography has been developed to study the effect of thermal radiation on the infrared absorption spectra of prostate biopsy samples. The system allows the distribution of thermal signal intensity as a function of emissivity to be interpreted from the integrated absorbance obtained by spectroscopic imaging. Biochemical differences between cancer and benign areas within the specimens are identified in the spectra. Side-by-side comparison of H&E stained adjacent tissue sections with infrared images constructed before and after the removal of thermal effect showed that the latter strongly support differentiation of regions within tissues. The use of spectral bands at discrete wavelengths significantly reduced spectral acquisition time, making this technique promising as a future clinical diagnostic tool. A systemic methodology was implemented to process the data, first by k-means clustering on the second derivative spectra without a priori knowledge, followed by principal component analysis (PCA). Four distinct regions within the tissue samples were successfully classified based on the antisymmetric stretching mode of the methylene functional group. Separation between data in clusters occurs when projecting spectra on a PCA score plot on a plane made by first 2 principal components. The significance of the disparity was verified with statistical test. Regulation of signal to chopper and detector enables simultaneous acquisition of infrared and thermal images of the prostate biopsy tissues. PMID- 30003713 TI - You won't believe this old test ... that does cheap single-cell mutation detection. AB - Detecting mutations in single cells from cancer specimens is now a major area of translational research. In a recent article in this journal, Khalique et al validated an immunohistochemistry assay for ARID1A that reliably identifies loss of function mutations in single cells in tissue sections. This work exemplifies best practice for developing and orthogonally validating immunohistochemical assays to provide clearly interpretable mutational results with spatial context. PMID- 30003716 TI - Corrigendum. PMID- 30003715 TI - Need for Accurate and Consistent Definition of Chronic Chikungunya Arthritis: Comment on the Article by Chang et al. PMID- 30003717 TI - Carbon nanotubes: An alternative for platinum-based drugs delivery systems. AB - Currently, nanomedicine is approaching the research of nanomaterials that could work as drug delivery systems, to increase the efficiency, specificity and safety of drugs reducing toxicity and side effects. In this regard, carbon nanotubes have acquired great interest due to their physicochemical properties. The use of platinum-based drugs is facing some troubles in the clinic due to their side effects such as nephrotoxicity, neutropenia, neurotoxicity, among others. In addition, cases of tumors resistant to these drugs have been recently observed. The goal of this review was to analyze the reports about the use of formulations of platinum-based drugs in carbon nanotubes, to know and establish the most functional and potential conditions for its use in cancer treatment, identifying perspectives and develop areas for the improvement of these nanomaterials in the application of cancer therapy. PMID- 30003718 TI - The foundation of personalized medicine is the establishment of biobanks and their standardization. AB - The present review outlines the current information available about biobanks including: summarizing the main ethical issues encountered when integrating patient samples in research projects; emphasizing the importance of biobanks as the basis for any personalized medicine therapies in cancer with a particular focus for oral cancer, through the use of biomarkers; and providing examples of biobanks that use anonymous sample collection and labelling methodologies to help alleviate the problems of privacy, informed consent, data security as well as public trust. PMID- 30003719 TI - Photodynamic combinational therapy in cancer treatment. AB - Photodynamic therapy (PDT) has attracted widespread attention in recent years as a non-invasive and highly selective approach for cancer treatment. PDT involves the activation of a photosensitizer by an appropriate wavelength of light, generating transient levels of reactive oxygen species (ROS). However, the utilization of PDT against deep tumors has been greatly limited by insufficient luminous flux and the occurrence of peripheral tissue damage. Therefore, experts have begun to explore whether the combination of PDT with other treatments can improve its efficacy. In this review, we have collected articles about experiments (in vitro and in vivo) and clinical research on photodynamic combination therapies in recent years, roughly divided into four parts corresponding to PDT combined with chemotherapy, radiotherapy, immunotherapy and other therapies, to compare the therapeutic effects of the combination therapy and monotherapy. The results showed that photodynamic combination treatments, in general, perform better than single treatment modalities. Thus, the increased therapeutic effects, reduced side effects and coordination treatment effects of PDT are worth of further exploration. PMID- 30003720 TI - Adjuvant chemotherapy for high-risk stage II and stage III colon cancer: timing of initiation and optimal duration. AB - The benefit of adjuvant chemotherapy has been clearly proven for patients with stage III (node-positive) and highrisk stage II colon cancer and consists to eradicating micrometastases that may be present during the time of surgical resection, reducing thereby the likelihood of disease recurrence and potentially increasing the cure rates after surgery. In this review, the appropriate timing of initiation and optimal duration of adjuvant chemotherapy are discussed. Current guidelines recommend an oxaliplatinbased regimen (FOLFOX: 5-fluorouracil with oxaliplatin or CapeOx: capecitabine with oxaliplatin) instead of 5-FU/LV (5 fluorouracil/leucovorin) for 6 months. For patients with a contraindication to oxaliplatin, a fluoropyrimidine-based regimen alone is an acceptable option. It should be initiated within 6-8 weeks from the time of surgical resection. Studies on reduced duration of fluoropyrimidine-based only regimens (bolus 5-FU/LV vs 5 FU) showed no significant difference in overall (OS) and disease free survival (DFS) benefits. However, the studies showed significantly lower toxicities for protracted venous infusion (PVI) 5-FU given for shorter duration. For oxaliplatin based therapies, prospective trials failed to establish non-inferiority of 3 months compared to 6 months of oxaliplatin-based adjuvant therapy. The longterm data of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration for OS are not mature to date yet. Six months of oxaliplatin-based therapy still remain the standard of care. Decisions to shorten the duration of adjuvant oxaliplatin-based therapy should be dictated by drug tolerability, risk stratification of the disease, consideration of the value of decreased neurotoxicity at the cost of decreased DFS, and patient preference. PMID- 30003721 TI - Anticancer activity of safranal against colon carcinoma is due to induction of apoptosis and G2/M cell cycle arrest mediated by suppression of mTOR/PI3K/Akt pathway. AB - PURPOSE: Colon cancer is among the deadliest malignancies and is responsible for a significant number of deaths across the globe. The treatment options for colon cancer are limited and with lot of side effects. In this study we evaluated the potential anticancer effects of safranal against colo-205 colon cancer cells along with evaluation of its effects on apoptosis, cell cycle phase distribution, reactive oxygene species (ROS) and PI3K/AKT/m-TOR signalling pathway. METHODS: Cell viability was examined by MTT assay. Apoptosis was checked by DAPI staining, comet assay and annexin V/propidium iodide (PI) staining involving the use of fluorescence microscopy and flow cytometry. ROS, mitochondrial membrane potential (MMP) and cell cycle phase distribution were checked by flow cytometry using different fluorescent probes. Effects of safranal on the protein expression of PI3K/AKT/m-TOR were studied by western blot assay. RESULTS: The results revealed that safranal suppressed the proliferation of colo-205 cancer cells with an IC50 of 20 MUM. Furthermore, the anticancer effects of safranal were found to be due to accretion of ROS and decrease in the MMP, ultimately leading to apoptosis of colo-205 cancer cells. In addition, safranal caused increase in the expression of Bax in parallel with concomitant reduction in the expression of Bcl-2. Safranal also triggered G2/M cell cycle arrest and inhibition of PI3K/AKT/mTOR signalling pathway. CONCLUSION: In conclusion, the above results indicate that safranal could prove a potential lead molecule in the treatment of colon cancer, provided further in vivo studies are carried out. PMID- 30003722 TI - MiR-503 promotes the migration and invasion of colorectal cancer cells by regulating PDCD4. AB - PURPOSE: MicroRNAs are expressed abnormally in colorectal cancer (CRC) and could participate in its development. In this study we aimed to explore the molecular mechanisms of miR-503 in the genesis of CRC. METHODS: The relative expression of miR-503 and programmed cell death 4 (PDCD4) tumor suppressor in CRC tissues and cell lines were detected by qRT-PCR and Western blot. Cell migration and cell invasion were assessed by transwell assay. Moreover, the confirmation of the direct target of miR-503 in CRC was performed by luciferase reporter assay. RESULTS: The expression of miR-503 was increased remarkably in CRC, while PDCD4 decreased. Moreover, PDCD4 was verified as a specific target of miR-503 in CRC and it could reverse the effect of miR-503 on CRC cells. Furthermore, the abnormal expression of miR-503 played an important role in regulating of the development of CRC cells. In addition, PDCD4 protein expression and miR-503 mRNA expression were negatively correlated in CRC tissues. CONCLUSION: The inhibitory effect of miR-503 in CRC was realized by the upregulation of PDCD4, suggesting that miR-503/PDCD4 axis might play a critical role in CRC and could possibly be a therapeutic target. PMID- 30003723 TI - Antitumor effects of emodin in CACO-2 human colon carcinoma cells are mediated via apoptosis, cell cycle arrest and downregulation of PI3K/AKT signalling pathway. AB - PURPOSE: Emodin is an important constituent of Rheum emodi, an important medicinal herb. Emodin has been reported to exhibit significant pharmacological potential. Several activities such as anticancer activity have been attributed to emodin. However, the anticancer effects of emodin on colon cancer cells have not been fully studied. Therefore, the present study was designed to investigate the anticancer activity of emodin against the CACO-2 colon carcinoma cells. METHODS: The anti-proliferative activity of emodin was assessed by MTT assay. Apoptosis, and cell cycle analysis were carried out by flow cytometry using different fluorescent probes. Expression of proteins was examined by western blotting. RESULTS: The results indicated that emodin reduced the viability of CACO-2 colon cancer cells. The observed IC50 for emodin was 30 MUM at 24 hrs of incubation. Furthermore, the anticancer effects of emodin were found to be due to induction of apoptosis. Mitochondrial membrane potential (MMP) determination and Bax/Bcl-2 ratio indicated that emodin-induced apoptosis followed the mitochondrial pathway. Emodin could also trigger cell cycle arrest in CACO-2 colon carcinoma cells in a dose-dependent manner. Evaluation of the effect of emodin in PI3/AKT signalling pathway revealed that emodin could inhibit this signalling cascade indicating the potential of emodin as anticancer drug for the treatment of colon cancer. CONCLUSION: Emodin exhibited potent anticancer effects in CACO-2 human colon carcinoma cells by inducing apoptosis, cell cycle arrest and inhibition of PI3K/AKT signalling pathway. PMID- 30003724 TI - Ultrasound/CT combined with serum CEA/CA19.9 in the diagnosis and prognosis of rectal cancer. AB - PURPOSE: To explore the significance of computed tomography (CT) and transrectal ultrasonography (TRUS) combined with serum CEA and CA19.9 in the staging, diagnosis and prognosis of rectal cancer. METHODS: Fifty-six patients with rectal cancer were recruited from our oncology department. ELISA detected the expression level of CEA and CA19.9 in serum. The hemodynamic parameters of the rectal mucosa and tumor were detected by TRUS [resistance index (RI), pulse index (PI), peak systolic velocity (PSV), end-diastolic volume (EDV)]. All patients were pathologically examined to determine the disease stage and to compare the diagnostic accuracy of serum tumor markers, CT and TRUS. All patients were followed up for 24 months to assess the relationship between the combined examinations and the disease prognosis. RESULTS: CEA and CA19.9 levels were significantly different in patients with different pathological stages (p<0.05). RI and PI decreased with increasing pathological stage, while PSV and EDV were increased with increasing pathological stage. The serum CEA+CA19.9 examination showed 12 cases of misdiagnosis, with an accuracy diagnostic rate of 78.57% (447sol;56). CT examination showed 8 cases of misdiagnosis, with an accuracy diagnostic rate of 85.71% (48/56). TRUS showed 6 cases of misdiagnosis, with an accuracy diagnostic rate of 89.28% (50/56). However, only 2 cases were misdiagnosed and 96.43% (54/56) were accurate, while no statistical difference was noticed between combined detection and pathology (p<0.05). Postoperative follow-up showed significant differences in T staging at 6 months, 1 year and 2 years after operation (p<0.05). CONCLUSION: CT and TRUS combined with serum CEA and CA19.9 had great value in the diagnosis and prognosis in rectal cancer. PMID- 30003725 TI - KISS1 and KISS1R expression in primary and metastatic colorectal cancer. AB - PURPOSE: Kisspeptins are produced by the KISS1 gene and have tumor-suppressing and anti-metastatic properties. Our aim was to study the expression of KISS1 and its receptor, KISS1R, in colorectal cancer. METHODS: KISS1 and KISS1R expression was detected using immunohistochemistry in malignant tissue samples from 66 patients (34 men, 32 women) with colorectal adenocarcinoma. In total, 74 tumor samples were studied, 57 samples from primary tumors and 17 samples from liver metastases. KISS1 and KISS1R levels were associated with various clinicopathological parameters and survival data. RESULTS: KISS1 expression was higher in primary tumors with advanced stage (III or IV) and in those with infiltrated lymph nodes. KISS1R expression was higher in primary tumors with distant metastases. No significant differences were detected between primary and metastatic tumors regarding KISS1 and KISS1R levels. Furthermore, patients with high KISS1R levels had longer overall survival. CONCLUSIONS: KISS1 and KISS1R expression is higher in advanced colorectal cancers and high KISS1R levels are associated with better prognosis in colorectal cancer. PMID- 30003726 TI - miR-218 suppresses the growth of hepatocellular carcinoma by inhibiting the expression of proto-oncogene Bmi-1. AB - PURPOSE: To identify microRNAs (miRNAs) directly regulating the proto-oncogene Bmi-1 expression in the development of hepatocellular carcinoma (HCC) and to explore the underlying molecular mechanisms. METHODS: Four HCC cell lines, including HepG2, Bel7404, Huh7, and PLC5, the normal hepatocellular cell line MIHA, and 30 HCC biopsies were included in this study. Potential miRNAs, which interact with Bmi-1 and are involved in the development of HCC were identified through bioinformatic analyses. The expression of miRNA and Bmi-1 in HCC cell lines and HCC tissues was analyzed using fluorescence protein analysis, real-time quantitative PCR (RT-qPCR), and Western blotting. RESULTS: Bioinformatic analysis suggested that miR-218 is a potential miRNA regulating Bmi-1 expression. Fluorescence protein analysis, RT-qPCR, and Western blotting confirmed the direct interaction between miR-218 and Bmi-1. In addition, increased expression of Bmi-1 was detected in HCC cell lines and HCC tissues. In most HCC tissues, the expression of miR-218 was decreased and was associated with increased expression of Bmi-1. CONCLUSION: miR-p218 downregulates the expression of the proto-oncogene Bmi-1 in HCC, and it may be an effective target for the treatment of this disease. PMID- 30003727 TI - Selection of treatment modalities for hepatocellular carcinoma at stages T1 and T2: A preliminary analysis based on the Surveillance, Epidemiology, and End Results registry database. AB - PURPOSE: To explore the selection of treatment modalities for hepatocellular carcinoma (HCC) at stages T1 and/or T2 and to compare the survival of patients treated with surgery alone vs radiation therapy (RT) alone. METHODS: Surveillance, Epidemiology, and End Results (SEER) database was used to identify the patients diagnosed with HCC between 2004 and 2013. The tumor-nodemetastasis (TNM) stage was established according to the American Joint Committee on Cancer (AJCC) Staging. After age, sex, TNM stage, and tumor extension were matched, the survival was further compared between patients undergoing surgery alone vs RT alone. RESULTS: Of 11967 patients at stages T1 (n=7829) and T2 (n=4138), 10449 (87.31%) underwent surgery alone, 1241 (10.37%) RT alone, and 277 (2.32%) surgery combined with RT. Compared with those treated with RT alone and in combination with surgery, patients treated with surgery alone were younger, with smaller tumor size, higher proportion of females, single lesion, and AJCC stage I/II, and lower proportion of regional and distant lymph nodes, bone, brain, and lung invasion. Among them, 758 pairs (surgery alone and RT alone) at stage T1 and 430 pairs (surgery alone and RT alone) at stage T2 were matched. Regardless of stage T1 or T2, patients undergoing surgery alone had a significantly better cumulative survival than those undergoing RT alone (p<0.001). CONCLUSION: The treatment selection of HCC was dependent on the age, sex, tumor size, number of lesions, and extrahepatic invasion. Surgery alone should be the preferred treatment modality of HCC at stages T1 and T2. PMID- 30003728 TI - Blood sugar level affects the recurrence of hepatocellular carcinoma after laparoscopic surgery: a retrospective study. AB - PURPOSE: To investigate the effect of blood sugar level on the recurrence of hepatocellular carcinoma (HCC) after laparoscopic surgery. METHODS: The data of 177 patients with primary HCC who underwent laparoscopic radical liver resection were retrospectively analyzed. Patients were divided into the hyperglycemia group (n=56) and the control group (n=121) according to whether postoperative fasting blood sugar (FBS) was >=6.1 mmol/L. Postoperative hospitalization and blood glucose level during follow-up were observed and recurrence and relative risk factors of HCC of patients from the two groups were analyzed. The recurrence rate of HCC after one and two years were compared between the two groups, and the influencing factors of recurrence after laparoscopic surgery were analyzed by single-factor analysis. RESULTS: The recurrence rate one year after surgery in patients with hyperglycemia and the control group were 30.4 and 16.5% respectively, and the recurrence rate two years after surgery were 64.3 and 37.2%, respectively. The recurrence rate one and two years after surgery in HCC patients from the hyperglycemia group were significantly higher than those of the control group (p<0.05). Multivariate analysis showed that FBS, Child-Pugh grade B, low differentiated carcinoma and high postoperative AFP were risk factors for recurrence of HCC after laparoscopic surgery, which affected significantly the disease-free survival (DFS) of postoperative HCC (p<0.05). CONCLUSION: The recurrence rate of patients with elevated FBS after laparoscopic surgery of HCC was high during the 2 postoperative years, and FBS was high, while the Child- Pugh grade B, low grade of tumor differentiation, and postoperative AFP were risk factors affecting the recurrence rate. Monitoring high-risk patients should be strengthened to reduce the recurrence rate. PMID- 30003730 TI - Lupeol triterpene exhibits potent antitumor effects in A427 human lung carcinoma cells via mitochondrial mediated apoptosis, ROS generation, loss of mitochondrial membrane potential and downregulation of m-TOR/PI3Ksol;AKT signalling pathway. AB - PURPOSE: Lung cancer is one among the most commonly diagnosed malignancies in developed countries with highest rates of morbidity and mortality. The treatment options for lung cancer are limited and have side effects. Hence, researches are being directed at the exploration and evaluation of new molecules showing anticancer activity. In this study we investigated the anticancer effects of lupeol on the lung cancer A427 cancer cells and normal MRC-5 cells. METHODS: Growth inhibitory effects were checked by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were estimated by flow cytometry. Protein expression analysis was performed by western blotting. RESULTS: The results showed that lupeol inhibited the growth of A427 lung cancer cells as observed by MTT and colony formation assay. The antiproliferative effects were due to induction of apoptosis as indicated by DAPI and annexin V/PI staining. This was further confirmed by Bax and Bcl-2 expression. Moreover, lupeol triggered generation of ROS and decrease of MMP. Lupeol could also inhibit the mTOR/ PI3K/AKT signalling pathway. Taken together, lupeol could prove beneficial in the treatment of lung cancer. CONCLUSIONS: In brief, the present study indicated that lupeol induced potent and selective cytotoxic effects and these effects were mediated via apoptosis, ROS generation, loss of MMP and inhibition of mTOR/PI3K/AKT signalling pathway. PMID- 30003729 TI - Comparison of the effects of postoperative prophylactic transcatheter arterial chemoembolization (TACE) and transhepatic arterial infusion (TAI) after hepatectomy for primary liver cancer. AB - PURPOSE: To explore the impact of transcatheter arterial chemoembolization (TACE) and transhepatic arterial infusion (TAI) on the therapeutic effect of postoperative prophylactic hepatic artery interventional therapy after hepatectomy for primary liver cancer (PLC). METHODS: This study was conducted on 93 patients who had undergone hepatectomy for PLC and received prophylactic interventional treatment within 1 to 3 months after hepatectomy. These patients were divided into two groups: TACE (n=50) and TAI (n=43). The TACE group was treated with lipiodol-chemotherapy drug emulsion, and the TAI group received chemotherapeutics infusion only. The differences of postoperative tumor recurrence and impact on liver function were compared between the two groups. RESULTS: There were no significant differences between the two groups with regard to sex, age, liver function Child-Pugh score, preoperative tumor size, preoperative serum alpha-fetoprotein (AFP) and other factors. Clinical overall remission rates (82 vs 76%), recurrence rates (12.2 vs 16.2%) and mean hospital stay (6.31+/-1.98 vs 5.98+/-2.02 days) of the TACE group and TAI group showed no obvious differences. However, the disease-free survival (DFS) of the TACE group was remarkably higher than that of the TAI group (23.60+/-3.56 vs 16.95+/-2.67 months). Both TACE and TAI caused transient liver dysfunction, but compared with TAI, TACE resulted in more severe liver function injury. CONCLUSIONS: No significant differences between TACE and TAI groups were noticed in overall remission and recurrence rate, but TACE showed a better performance in prolonging DFS than TAI. Compared with TAI, TACE leads to more serious but transient liver dysfunction. Concerning the impact of TACE and TAI on recurrence after PLC operation, further studies are needed to reach more reliable conclusions. PMID- 30003731 TI - Effect of genistein on apoptosis of lung adenocarcinoma A549 cells and expression of apoptosis factors. AB - PURPOSE: To investigate the effect of genistein (GEN) on the apoptosis of lung adenocarcinoma cells and the expression of Bcl-2 and Bax, so as to screen effective antitumor drugs for the clinical treatment of lung adenocarcinoma. METHODS: Lung adenocarcinoma A549 cells were cultured in vitro and treated with different concentrations of GEN. The untreated cells were set as control group. MTT assay and Annexin V/PI double staining were used to analyze cell proliferation and apoptosis after GEN treatment. RT-qPCR and Western blot were used to detect the expression of Bcl-2 and Bax at mRNA and protein levels, respectively. RESULTS: Cell p roliferation a ssay s howed t hat GEN c ould inhibit the proliferation of lung adenocarcinoma cell line A549 in vitro in a dose-dependent manner. Cell apoptosis assay showed that, compared with the control group, the apoptotic rate of A549 cells was significantly increased after GEN treatment. RT-qPCR and Western blot showed that the expression levels of anti apoptotic factor Bcl-2 in A549 cells were significantly decreased at both mRNA and protein levels at 48 hrs after treatment with GEN, but the levels of pro apoptotic Bax were significantly increased at both mRNA and protein levels. CONCLUSION: GEN can inhibit the proliferation of A549 lung adenocarcinoma cells in vitro and induce their apoptosis. The antitumor activity of GEN is achieved by downregulating Bcl-2 and upregulating Bax. Therefore, GEN can be applied to the clinical treatment of lung adenocarcinoma. PMID- 30003732 TI - Clinical impact of gastric acid suppressing medication on the effectiveness of tyrosine kinase inhibitors in lung cancer patients. AB - PURPOSE: Erlotinib and gefitinib are both tyrosine kinase inhibitors (TKIs) approved for the treatment of non-small cell lung cancer (NSCLC). Although it is well known that the increase of gastric pH may decrease the solubility of TKIs, there is limited evidence about the clinical repercussion of this fact. The purpose of this study was to determine if the use of gastric acid suppressive therapy (As) concomitantly with TKIs has an adverse impact on progression-free survival (PFS) and to determine whether the type of drug used (proton pump inhibitors/PPIs or histamine-2 receptors antagonists (H2RAs) may influence it. METHODS: In this retrospective observational study included were patients treated for >=1 week with erlotinib or gefitinib from January 2012 to December 2015. Demographic, diagnostic and therapeutic variables were collected. Patients were divided into two groups (As users and non-As users). For the calculation of the PFS the Kaplan Meier and multivariate Cox regression analysis were used. RESULTS: 163 patients with mean age 70 years were included. 72.397percnt; (n=118) received TKIs and As concomitantly. The mean PFS was 84 days (95% CI, 65-101) and 221 days (95% CI, 125-429; p <0.0001) in As users and non-As users, respectively. Regarding the type of As used, no significant differences were observed. CONCLUSION: Concomitant use of As and TKIs adversely impacted the PFS outcomes in NSCLC patients regardless of the type of As used. Further studies are needed to determine the clinical impact of interactions between antiacids and antineoplastics. PMID- 30003733 TI - An observational study of apatinib mesylate in treating advanced non-small cell lung cancer with unknown driving gene(s). AB - PURPOSE: To investigate the efficacy and safety of apatinib mesylate (AM) in treating advanced non-small cell lung cancer (aNSCLC) with wild or unknown epidermal growth factor receptor (w/nEGFR). METHODS: A total of 34 w/nEGFR aNSCLC patients who failed chemotherapy from August 2015 to April 2017 were administered orally AM (425 mg/d) as primary treatment and observed their progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), as well as related adverse events. RESULTS: Efficacy was evaluable in 30 cases, with median PFS (mPFS) 3.75 months (95% CI 0.648-6.852), ORR 20%, and DCR 73.33%. The main adverse reactions included hypertension (52.94%), hand-foot syndrome (52.94%), proteinuria (44.12%), and fatigue (41.18%); no drug-related death occurred. The efficacy correlation analysis showed that Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (p=0.008) combined with chemotherapy (p=0.009) were the factors that extended PFS, and combined chemotherapy (p=0.040, HR=3.052, 95% CI 1.052- 8.858) was an independent prognostic factor. CONCLUSIONS: AM has good therapeutic efficacy in treating aNSCLC patients after chemotherapy failure. The side effects can be controlled and it is worth testing it in large-scale clinical studies. PMID- 30003734 TI - A study on the roles of Helicobacter pylori in bile reflux gastritis and gastric cancer. AB - PURPOSE: To observe the infection rates of Helicobacter pylori (HP) in bile reflux gastritis (BRG) and gastric cancer and the clinical significance of HP eradication in BRG and gastric cancer patients complicated with HP. METHODS: 248 patients diagnosed with BRG and gastric cancer via gastroscopy were enrolled in this study. HP detection and infection rates of HP were evaluated. Then, BRG and gastric cancer patients complicated with HP were randomly divided into BRG group 1, BRG group 2, gastric cancer group 1 and gastric cancer group 2. BRG group 1 and gastric cancer group 1 were treated with conventional anti-inflammatory drugs for 10 days, and BRG group 2 and gastric cancer group 2 were treated with anti-HP drugs in addition to conventional anti-inflammatory drugs. One month after drug withdrawal, the infection rates of HP in each group were evaluated, and prognostic follow-up was performed to record the post-therapy patient conditions. RESULTS: HP infection rate was 35.8% (57/159) in the BRG group and 73.0% (65/89) in the gastric cancer group, with statistically significant difference (p<0.01). In patients treated with anti-HP drugs had the HP infection rate effectively reduced. The treatment effective rates of patients with BRG and gastric cancer complicated with HP infection after eradication of HP were 82.8 and 68.8%, respectively, while those of patients with non-eradicated HP were only 46.4 and 37.5 %, respectively. The differences between the two groups were statistically significant (p<0.05). CONCLUSION: HP is directly and closely related to the occurrence of gastric diseases, HP infection rate in patients with gastric cancer is significantly higher than that in patients with BRG, and the treatment of HP can effectively improve the rehabilitation rate in patients with gastric diseases. PMID- 30003735 TI - Correlation of COX-2 and MMP-13 expressions with gastric cancer and their effects on prognosis. AB - PURPOSE: To study the expressions of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-13 (MMP-13) genes in gastric cancer, and to investigate the correlation between them and gastric cancer and their effects onprognosis. METHODS: 80 cases of tumor tissues and 40 cases of normal tumor-adjacent tissues were collected from patients with gastric cancer admitted to the Surgical Department of our hospital. The mRNA expression levels of COX-2 and MMP- 13 in tumor tissues and normal tumor-adjacent tissues were detected via real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR). The expressions of COX-2 and MMP-13 in gastric cancer tissues and normal tumor adjacent tissues were detected via immunohistochemical method. The clinical data of patients were recorded and the correlation between the COX-2 and MMP-13 expressions and the pathological parameters and prognosis of patients with gastric cancer were analyzed. RESULTS: RT-PCR results showed that the mRNA expressions of COX-2 and MMP-13 in gastric cancer tissues were significantly higher than those in normal tumor-adjacent tissues. Immunohistochemical results showed that the positive expression rates of COX-2 and MMP-13 in gastric cancer tissues were 76.25% (60/80) and 71.25% (57/80), respectively and the high expression was related to the invasion, metastasis and tumor stage. The 5-year overall survival of patients was 16.6% (13/80). Single-factor survival analysis showed that both COX-2 and MMP-13 were factors influencing the overall survival of patients with gastric cancer (p<0.01). CONCLUSION: The high expressions of COX 2 and MMP-13 are closely related to the pathological parameters of patients with gastric cancer, especially the invasion, metastasis and tumor stage. COX-2 and MMP-13 can be used as reference indexes to guide the treatment of gastric cancer and predict the disease prognosis. PMID- 30003736 TI - Perioperative blood transfusion is one of the factors that affect the prognosis of gastric cancer. AB - PURPOSE: To demonstrate the potential significance of perioperative blood transfusion on the prognosis of gastric cancer. METHODS: Data from 234 patients who were subjected to radical gastrectomy in our hospital were obtained and retrospectively analyzed. Patients' age, gender, preoperative anemia, tumor size, location, invasion depth, lymph node metastasis, TNM stage, presence or absence of blood transfusion and blood transfusion volume were observed and analyzed. RESULTS: The difference of tumor recurrence in patients whose blood transfusion volume was greater than 2U was significant (p<0.001). The tumor recurrence in patients whose blood transfusion was less than 2U was significantly shorter than in those whose transfusion volume was greater than 4U (p=0.03). The survival in the blood transfusion group was significantly lower in comparison with the nonblood transfusion group (p=0.002). The survival of transfusion group in TNM stage III and IV was significantly shorter than that in non-transfusion group (p=0.03). Statistical significance was found in survival between the transfusion group and non-transfusion group when the tumor size was less than 5 cm and greater than 5 cm (p=0.006, p=0.04, respectively). CONCLUSIONS: Perioperative transfusion is one of the factors for predicting the prognosis of postoperative gastric cancer patients, and the larger the perioperative transfusion, the shorter the tumor recurrence, the worse the prognosis. Therefore, it is of great significance reducing the intraoperative blood loss and strict controlling blood transfusion indications. PMID- 30003737 TI - Effects of probiotics combined with enteral nutrition on immune function and inflammatory response in postoperative patients with gastric cancer. AB - PURPOSE: To explore the therapeutic effect of probiotics combined with enteral nutrition (EpsilonNu) in postoperative patients with gastric cancer (GC). METHODS: 140 GC patients were enrolled in this study and randomly assigned into the test group and the control group, with 70 patients in each group. Patients in the test group were treated with probiotics combined with EpsilonNu, while those in the control group were treated with common EpsilonNu. Patients' conditions were observed for 8 days. IgG, IgA, IgM, IL-6, IL- 8, TNF-alpha, hemoglobin, albumin, pre-albumin, time to relief of abdominal distension, time to first flatus, length of hospital stay and adverse events were recorded and analyzed. RESULTS: The factors related to immune function in patients of the test group, such as IgG, IgA and IgM, were higher than those of the control group. Moreover, the improvements of inflammatory cytokines including IL-6, IL-8 and TNF-alpha in patients of the test group were better than those of the control group. However, no obvious difference was found in the nutritional status before and after treatment between the two groups (p>0.05). In the comparison of clinical symptoms, time to relief of abdominal distention and time to first flatus were both earlier in patients of the test group than in those of the control group (p=0.002, p=0.03, respectively). Additionally, the diarrhea caused by EpsilonNu was also significantly less in the test group compared with the probiotics control (p=0.03). CONCLUSIONS: Probiotics combined with EpsilonNu could improve the immune function and reduce the inflammatory response and the incidence of diarrhea in postoperative patients with gastric cancer. PMID- 30003739 TI - A miRNAs profile evolution of triple negative breast cancer cells in the presence of a possible adjuvant therapy and senescence inducer. AB - PURPOSE: Breast cancer is a highly heterogeneous disease with an increasing number of cases resistant to chemotherapy. To increase the response to therapy, different adjuvant systems are tested, like the case of deuterium-depleted water (DDW). METHODS: For this study, we selected as in vitro model the triple-negative breast cancer cell line MDA-MB-231 and we performed a series of microscopy-based functional tests (apoptosis, autophagy assays, senescence detection) and microarray evaluation of the miRNA profile in order to evaluate changes induced by cisplatin and DDW treatment at cellular and molecular level. RESULTS: Cisplatin treatment led to increased mitochondrial activity and autophagy for cells kept in DDW, compared with those in standard conditions (SC). We also observed that cells treated with DDW medium promoted senescence in a higher level than SC. The exosomal miRNAs released in cell culture revealed an altered pattern in the case of cells maintained in DDW compared to SC. CONCLUSION: DDW was proved to be non-toxic, and, when administered with cisplatin, to slightly increase the senescence of cancer cells, therefore, can be pondered as adjuvant therapeutic agent. However, future studies are needed to be done in order to further elucidate its mechanism of action. PMID- 30003738 TI - Promoter hypermethylation of p16, BRCA1 and RASSF1A genes in triple-negative breast cancer patients from Serbia. AB - PURPOSE: In order to investigate if aberrant promoter methylation of p16, BRCA1 and RASSF1A genes contributes to biological behavior of triple-negative breast cancer (TNBC), marked as the most aggressive phenotype of breast cancer, we compared the hypermethylation pattern between TNBC and ER+PR+Her2- breast cancer. METHODS: 131 patients with histologically confirmed breast cancers were included 61 TNBC and 70 ER+PR+Her2- cases. The patients were followed up for 1-87 months (median 78). DNA from tumor tissues was isolated by the salting out procedure. The methylation status was assessed by nested methylation-specific PCR after bisulfite modification of DNA. RESULTS: The frequency of p16 hypermethylated breast cancer cases was significantly higher in TNBC than in ER+PR+Her2- group (33; 54.1% vs. 20; 28.6%, p=0.00298). Co-methylated p16 and RASSF1A genes were more frequent in the TNBC than in ER+PR+Her2- group (20; 32.8% vs. 10; 14.3%, p=0.0225). The same result was observed when hypermethylated BRCA1 gene was added in the analysis: 12; 19.7% vs. 3; 4.3%, p=0.00791. Although there was significant difference in disease-free survival (DFS) and overall survival (OS) between TNBC and ER+PR+Her2- group, further analysis of co-methylation of p16 and RASSF1A (p16+RASSF1A+) showed that DFS was significantly shorter in the patients with both genes co-methylated in TNBC than in ER+PR+Her-2- group (8/20; 40% vs. 2/10; 20%, p=0.03272). CONCLUSIONS: The obtained data indicate that hypermethylated p16 and RASSF1A cell-cycle inhibitor genes might be considered as biomarkers for bad prognosis in breast cancer. Hypermethylation of these genes may influence the clinical disease course, distinguishing a particular group of TNBC patients with even more aggressive phenotype. PMID- 30003740 TI - Factors influencing participation in breast cancer opportunistic screening in Belgrade, Serbia. AB - PURPOSE: To assess the motivation and barrier factors influencing participation of women in opportunistic breast cancer screening in Belgrade, Serbia, and to detect changes in these factors over time. METHODS: A cross-sectional study has been carried out at the Institute for Oncology and Radiology of Serbia in 2009 and 2016 among women aged 40 to 69 years from Belgrade who came at the Institute for opportunistic breast cancer screening. The demographic characteristics, data regarding breast exams practices, screening motivators and barriers and sources of information on breast cancer were collected by self-administered questionnaire. RESULTS: The questionnaire was completed by 478 women in 2009 and 453 in 2016, with increase in women reporting regular mammograms or at least one previous mammogram (from 30.1% to 58.6%, p=0.000). In 2009, the most frequent motivating factors were health maintenance (36%), friend's advice, TV, cancer in the family or fear of breast cancer; in 2016, advice from gynecologist (significant increase from 10.9% to 37.7%, p=0.000), health maintenance, family cancer and fear of cancer. The most frequent reasons for not going to exams regularly were absence of breast problems, crowded doctor's offices and no family breast cancer. CONCLUSIONS: These findings provide information on motivation and barrier factors that may influence women's decision to participate in opportunistic breast cancer screening. Those factors have changed over time and the role of physicians has increased significantly. Further exploration of motivating and barrier factors and the extent of their association with actual women's behavior would be helpful for the development of interventions to improve organized and opportunistic screening participation. PMID- 30003741 TI - The expression of ANXA3 and its relationship with the occurrence and development of breast cancer. AB - PURPOSE: To investigate the expression of ANXA3 in breast cancer tissues and normal breast tissues and its relationship with the clinicopathological features. METHODS: The expression levels of ANXA3 mRNA and protein were determined by fluorescent quantitative RT-PCR and Western blot, respectively, in 81 samples from breast cancer tissues and normal breast tissues. Flow cytometry, used to detect the cell cycle, further analyzed the differences in the cell proliferation indexes between cancer and the normal tissues. In addition, the correlation between the gene and protein expression levels of ANXA3 and the cell proliferation indexes in breast cancer tissues was calculated. RESULTS: The expression levels of ANXA3 mRNA and protein were significantly higher in breast cancer tissues than in control samples. Furthermore, their expression patterns were significantly different in patients with different axillary lymph node metastasis states, with or without vascular tumor thrombus, and with different molecular classifications. The expression of ANXA3 mRNA and protein in patients with triple-negative breast cancer was significantly higher than in Luminal A and B types. However, no significant differences were detected in the expression levels in other subtypes. Compared to normal tissues, the cell proliferation indexes of breast cancer tissues were significantly higher, and presented significant positive correlations with the ANXA3 gene and protein expression levels. CONCLUSION: The expression of ANXA3 might play a crucial role in promoting the occurrence, development, and metastasis of breast cancer. It could serve as an important marker involved in the invasion and metastasis states, and the prognosis of breast cancer. PMID- 30003742 TI - The potential pathway of FOXC1 high expression in regulating the proliferation, migration, cell cycle and epithelialmesenchymal transition of basal-like breast cancer and in vivo imaging. AB - PURPOSE: To investigate the role of high forkhead box C1 (FOXC1) expression in basal-like breast cancer (BLBC) cells in vitro and in vivo, as well as its potential regulatory pathway. METHODS: Stable MDA-MB-231 cells, a type of BLBC cells, with high FOXC1 expression and luciferase (FOXC1) were established. The parental MDA-MB-231 cells with luciferase served as the control group. Proliferation, migratory capabilities and the cell cycle were evaluated. The tumorigenicity and the spontaneous pulmonary metastasis were measured in mice in vivo. In vivo imaging was also performed. Histopathology, immunohistochemical analysis and microarray processing were evaluated. Paired Student's t-test was used. RESULTS: The proliferation and migratory ability of FOXC1- MDA-MB-231 cells were enhanced significantly (p<0.05). Spontaneous pulmonary metastases were observed in 2 out of 5 mice, but no pulmonary metastases were observed in control animals. There were more FOXC1 cells in the G1 phase compared to the control (p<0.05), but there were also significant reductions of cells in the S and G2 phases (p<0.05). The CD31 and endoglin (CD105) expression in the FOXC1 tumor was higher than in the control, especially CD105 (p<0.05). The total fluorescence expression quantity of FOXC1 was higher than in the control cells (p<0.05), and the apparent diffusion coefficient (ADC) values were lower compared with the control (p<0.05). One pathway with the most gene enrichment (p38 MAPK signalling) may play a key role in regulating BLBC cell proliferation, migration, cell cycle and epithelial-mesenchymal transition (EMT) through the interaction of related critical regulatory genes (IL-6 and FOXC1). CONCLUSION: High FOXC1 enhanced the proliferation, migratory ability and EMT of BLBC cells. This function may be regulated by IL-6 and FOXC1 through the p38 MAPK signalling pathway. PMID- 30003743 TI - Marrubenol inhibits osteosarcoma cancer cell growth by inducing autophagic cell death and inhibiting cancer cell migration and invasion. AB - PURPOSE: The present study aimed at evaluating the anticancer activity of marrubenol against osteosarcoma cells along with evaluating its effects on autophagic cell death, reactive oxygen species (ROS) generation and cell migration and invasion tendency. METHODS: In this study the Saos-2 osteosarcoma cell line was used. Cell cytotoxicity effects were evaluated by MTT cell viability assay, while clonogenic assay assessed the effects on cancer cell colony formation. In vitro wound healing assay was used to evaluate the effects on cell migration. To confirm autophagy, we evaluated the expression of several autophagy-associated proteins Western blot assay along with transmission electron microscopy (TEM). RESULTS: The results indicated that the marrubenol exhibited an IC50 value of 45 MUM and exerted its cytotoxic effects in a dose-dependent manner. Moreover, it was observed that the drug inhibited colony formation and induced autophagy dose-dependently. The underlying mechanism for the induction of autophagy was found to be ROS-mediated and significant inhibition of cell migration as well as cell invasion potential of osteosarcoma cells at the IC50 was observed. CONCLUSIONS: These results strongly indicate that marrubenol may be considered as a potent drug lead molecule for the treatment and management of osteosarcoma. PMID- 30003744 TI - Pelargonidin induces antitumor effects in human osteosarcoma cells via autophagy induction, loss of mitochondrial membrane potential, G2/M cell cycle arrest and downregulation of PI3K/AKT signalling pathway. AB - PURPOSE: Osteosarcoma is the most common type of primary malignancy of bone in children and adults. The treatment options for osteosarcoma are limited and are associated with a number of drawbacks. Therefore there is an urgent need to look for more efficient options for the treatment of this disease. Flavonoids have been considered as important anticancer agents due to their efficacy and lower cytotoxicity. In the present study we evaluated the anticancer effects of pelargonidin in U2OS osteosarcoma cell line. METHODS: Cell viability was assessed by MTT assay. Reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and cell cycle analysis was done by flow cytometry. Expression of proteins was examined by western blotting. RESULTS: Pelargonidin exhibited significant anticancer effects on osteosarcoma U2OS cell line with an IC50 of 15 MUM. The anticancer effects of pelargonidin were due to induction of autophagy as evidenced from the expression of LC3-I, LC-3II and Beclin-1. Moreover, pelargonidin triggered ROSinduced reduction in MMP and triggered G2/M cell cycle arrest. In addition, pelargonidin inhibited the expression of p-PI3K and p-AKT in a concentration-dependent manner. CONCLUSIONS: Taken together, these results indicated that pelargonidin may prove a potential lead drug for the treatment of osteosarcoma. PMID- 30003745 TI - Carnosic acid regulates cell proliferation and invasion in chronic myeloid leukemia cancer cells via suppressing microRNA-708. AB - PURPOSE: Carnosic acid (CA) is an important polyphenol mainly isolated from the famous spice and the medicinal plant Rosmarinus officinalis. CA has been shown to exhibit tremendous pharmacological properties which include, but are not limited to, anticancer, antioxidant and anti-inflammatory activities. The current study was designed to evaluate the anticancer effects of CA against chronic myeloid leukemia (CML) which is one of the rare but deadly malignancies both in men and women. METHODS: CML KBM-7 cell line was used in this study. Cell viability was assessed by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining, cell cycle analysis by flow cytometry and cell invasion by Boyden chamber assay. The microRNA-780 expression was determined by quantitative RT-PCR. RESULTS: Our results indicated that CA exhibits significant anticancer activity on CML KBM-7 cells with an IC50 of 25 MUM. The anticancer activity was due to induction of apoptosis and cell cycle arrest. Moreover, it was observed that CA inhibits the proliferation and invasion of CML KBM-7 cells which could mainly be due to downregulation of microRNA- 780 expression as indicated by the quantitative RT PCR analysis. CONCLUSION: Taken together, we propose that carnosic acid could prove a potential lead compound in the treatment of CML and deserves further in vitro as well as in vivo study. PMID- 30003746 TI - Anticancer effects of Carvone in myeloma cells is mediated through the inhibition of p38 MAPK signalling pathway, apoptosis induction and inhibition of cell invasion. AB - PURPOSE: There is accumulating evidence indicating that plant-derived monoterpenes have impressive health-promoting effects, among them anticancer, antimicrobial and many other activities. Carvone is an important monoterpene with pharmacological potential. In the current study we investigated the anticancer effects of carvone in myeloma KMS-5 cells. METHODS: The cell viability was estimated by MTT assay. Apoptosis was detected by DAPI, acridine orange/ethidium bromide (AO/EB) and annexin V/propidium iodide (PI) staining. Cell cycle analysis was done by flow cytometry. Cell invasion was determined by martigel invasion assay and protein expression was checked by western blotting. RESULTS: The results of the present study indicated carvone exerts significant anticancer effects on the myeloma cancer cells in a dose-dependent manner. The IC50 of carvone was found to be 20 MUM against the myeloma KMS-5 cells. The antiproliferative effects were due to induction of apoptosis and G2/M cell cycle arrest. Moreover, carvone could inhibit the cell invasion and the expression of p P38 protein at IC50. CONCLUSIONS: In conclusion, the results indicate that carvone could prove to be an important molecule for the development of natural product-based anticancer therapy, especially against myeloma. PMID- 30003747 TI - Antiproliferative activity of Farnesol in HeLa cervical cancer cells is mediated via apoptosis induction, loss of mitochondrial membrane potential (LambdaPsim) and PI3K/Akt signalling pathway. AB - PURPOSE: Cervical cancer remains the most gruesome health problem in women worldwide as it ranks third in incidence. Despite recent developments in the treatment options of cervical cancer, the survival of patients not fit for surgical treatment rather remains poor. The main purpose of the current research was to determine the anticancer effect of farnesol in HeLa human cervical cancer cells together with studying its impact on apoptosis induction, mitochondrial membrane potential (MMP) and PI3K/Akt signalling cascade. METHODS: Cell viability was estimated by MTT assay while clonogenic assay was used to assess the effects on colony formation tendency in these cells. Fluorescence microscopy indicated apoptosis induction while flow cytometry showed the farnesol effects on the loss of MMP. RESULTS: Farnesol exerted both dose and time-dependent antiproliferative effects on cervical cancer cells with IC50 values of 33.5, 23.8 and 17.6 MUM at 24, 48 and 72 hrs time intervals, respectively. Colony formation of HeLa cells was considerably affected in a dose-dependent manner with the addition of farnesol to the cell culture. Farnesol-treated cells mostly emitted orange fluorescence indicating apoptotic cell death and this effect increased with increasing dose of the compound. Furthermore, farnesol induced considerable reduction in the number of cells with depolarized mitochondria corresponding to a reduction of MMP. With increase in the dosage of farnesol, there was a noticeable decrease in the expression levels of PI3K, p-PI3K and p-Akt proteins. CONCLUSIONS: In brief, this study showed that farnesol -a naturally occurring sesquiterpene- exerts powerful antiproliferative activity via apoptosis induction, loss of MMP and downregulation of the expression levels of PI3K, p PI3K and p-Akt proteins. PMID- 30003748 TI - Analysis of clinical effects of neoadjuvant chemotherapy in advanced epithelial ovarian cancer. AB - PURPOSE: To investigate the role and significance of neoadjuvant chemotherapy in advanced ovarian cancer. METHODS: 128 patients clinically diagnosed with stage IIC-IV advanced epithelial ovarian cancer (EOC) were randomized into neoadjuvant chemotherapy (NACT) combined with interval cytoreductive surgery (ICS) group (n=66) and primary cytoreductive surgery (PCS) group (n=62). Chemotherapy in the PCS group was administered after cytoreductive surgery. RESULTS: Age, body mass index, clinical symptoms, clinical staging, histopathological grading and histopathological type had no differences between PCS and ICS groups (p>0.05). In NACT-ICS group, the mean operation time was shorter, the bleeding was less, the rate of optimal debulking surgery was higher and the total effective rate of clinical remission was higher, compared with those in PCS group (p<0.05). No significant differences were found in the survival rate, progression-free survival (PFS) and overall survival (OS) between the two groups. CONCLUSIONS: In comparison to PCS, NACT-ICS can improve the intraoperative conditions, increase the cytoreductive rate, reduce the bleeding of operation, reduce the operation time and increase the clinical remission rate, but it has no impact on PFS and OS. PMID- 30003749 TI - Anticancer effects of Rosmarinic acid in OVCAR-3 ovarian cancer cells are mediated via induction of apoptosis, suppression of cell migration and modulation of lncRNA MALAT-1 expression. AB - PURPOSE: The main objective of the present research work was to study the anticancer properties of rosmarinic acid in OVCAR-3 human ovarian cancer cells and also to evaluate its effects on apoptosis induction, cancer cell migration and modulation of lncRNA MALAT-1 expression. METHODS: MTT assay was used to study the effects of the agent on OVCAR-3 cell viability, while inverted phase contrast microscopy and fluorescence microscopy were used to study the effects on cell morphology. Scanning electron microscopy (SEM) was used to study the effects of rosmarinic acid on cell surface morphology in OVCAR-3 cells. In vitro wound healing assay was used to study the effects on cell migration. RESULTS: Rosmarinic acid induced time-dependent and concentration- dependent cytotoxic effects in these malignant cells. The IC50 values at 48 and 72 hrs time intervals were found to be 34.6 and 25.1 MUM respectively. Rosmarinic acidtreated cells revealed significant changes in cell morphology including cellular shrinkage and cell rounding. The cells also lost attachment with the plate surface. Doses of 10, 40 and 160 MUM rosmarinic acid led to a substantial increase in bright blue fluorescence which is a signpost of chromatin condensation and DNA fragmentation. Rosmarinic acid treatment also led to a significant suppression of cell migration corresponding to 46.5% and 86.2 % cell migration inhibition at 40 and 160 MUM doses, respectively. CONCLUSION: In conclusion, the current study showed that rosmarinic acid induced potent anticancer effects in OCVAR- 3 cancer cells by inducing apoptosis, inhibiting cell migration and modulating lncRNA Malat-1 expression. PMID- 30003750 TI - Correlations of p53 expression with transvaginal color Doppler ultrasound findings of cervical cancer after radiotherapy. AB - PURPOSE: To investigate the correlations of p53 expression with transvaginal color Doppler ultrasound findings of cervical cancer after radiotherapy (RT). METHODS: A total of 78 patients with cervical cancer (stage II and III) treated in the Oncology Department of our hospital from March 2011 to September 2017 were enrolled, and another 10 normal cervical tissue specimens were taken from the Pathology Department as controls. RT was performed to the 78 enrolled patients. Morphological features of tumor tissues after RT were detected via hematoxylineosin (HE) staining, the mutant p53 protein level was detected via immunohistochemistry (IHC), and imaging signs and blood flow resistance index (RI) of cervical cancer were detected via transvaginal color Doppler ultrasound. Finally, the correlations of p53 protein with transvaginal color Doppler ultrasound findings were analyzed. RESULTS: After RT, most cervical cancer tissues showed nuclear degeneration, karyolysis, cytoplasmic keratosis (vacuolization), and regeneration and fibrosis of cancer tissues. The expression of p53 was negative in normal cervix, while there were 48 p53-positive cases (61.54%) and 30 p53-negative cases (38.46%) in patients with cervical cancer (p<0.05). No echo was detected in 2 out of 78 patients, and there were 4 cases of equal echo, 36 cases of low echo and 36 cases of high echo. Results of x2 test showed that the positive rate of p53 protein was significantly correlated with cervical space-occupying lesion and mass diameter shown in transvaginal color Doppler ultrasound (p<0.05), but it had no significant correlation with pelvic lymph node metastasis (p>0.05). The p53 protein expression level was significantly correlated with color Doppler flow imaging (CDFI) grading and RI (p<0.05). CONCLUSIONS: The p53 protein expression in cervical cancer after RT is significantly correlated with cervical space-occupying lesion and tumor size shown in transvaginal color Doppler ultrasound, CDFI grading and RI. p53 level and transvaginal color Doppler ultrasound can provide certain valuable clinical information for the treatment and monitoring of cervical cancer. PMID- 30003752 TI - Effects of human enhancer of filamentation 1 (HEF1) gene on the proliferation, invasion and metastasis of bladder cancer cells. AB - PURPOSE: To investigate the effects of human enhancer of filamentation 1 (HEF1) gene on the proliferation, invasion and metastasis of bladder cancer cells. METHODS: Three human bladder cancer cell lines (T24, EJ and BIU-87) were selected to extract total RNA at logarithmic growth phase. The relative expression level of HEF1 in these cell lines was detected by semi-quantitative reverse transcription PCR (RT-PCR), and the cell lines with relatively high expression and relatively low expression level of HEF1 cells were identified. HEF1 overexpression recombinant adenovirus was transfected into the bladder cancer cells with low expression level of HEF1, and HEF1 siRNA was transfected into the bladder cancer cells with high expression level of HEF1. MTT assay, migration assay and invasion assay were performed to detect the proliferation, migration and invasion of bladder cancer cells. RESULTS: The relative expression level of HEF1 mRNA in T24 cell line was significantly higher than that in EJ and BIU-87 cells, and BIU-87 cell line showed the lowest expression level (p<0.05). After transfection with HEF1 overexpression recombinant adenovirus, the proliferation, migration and invasion of BIU-87 cells were significantly improved (p<0.05). After siRNA silencing, the proliferation, migration and invasion of T24 cells were significantly inhibited (p<0.05). CONCLUSION: High expression level of HEF1 gene can promote the proliferation, invasion and metastasis of bladder cancer cells. PMID- 30003751 TI - LncRNA-SNHG7 regulates proliferation, apoptosis and invasion of bladder cancer cells assurance guidelines. AB - PURPOSE: The purpose of this study was to investigate the expression of long chain non-coding RNA (lncRNA) SNHG7 in bladder cancer tissues and cell lines, and to explore its impact on bladder cancer cell proliferation, apoptosis and invasion processes. METHODS: Bladder cancer tissues and near-cancer tissues were collected. The expression of lncRNA-SNHG7 in tissues and cell lines was detected by real-time PCR (RT-PCR). The expression of lncRNA-SNHG7 was downregulated by RNA interference (siRNA) as detected by RT-PCR that was used to detect the interference efficiency. CCK-8, flow cytometry and Transwell assays were used to evaluate the effect of lncRNASNHG7 on the proliferation, apoptosis and invasion capability of bladder cancer cells. The downregulation effect of lncRNA-SNHG7 on Epithelial-Mesenchymal Transition (EMT) related markers was tested by westernblot. RESULTS: lncRNA-SNHG7 was upregulated in bladder cancer cell lines. After the expression of lncRNA-SNHG7 was downregulated, the proliferation of bladder cancer cells was decreased, the apoptosis was increased, and the invasion ability of cells was decreased. The expression of E-cadherin was increased, but the expression of N-cadherin, vimentin and snail were decreased. Increased expression of lncRNASNHG7 in cancer tissues was significantly related to tumor size, metastasis and stage. CONCLUSIONS: This study showed that lncRNA -SNHG7 is overexpressed in bladder cancer tissues and cells. Downregulation of lncRNA-SNHG7 can inhibit the proliferation of bladder cancer cells and promote apoptosis, as well as inhibit cell invasion, which provides a potential molecular target for future tumor targeted therapy. PMID- 30003753 TI - MiR-384 represses tumorigenesis by regulating CDK6 and predicts prognosis of clear cell renal cell carcinoma. AB - PURPOSE: Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of renal cell carcinomas. Various microRNAs (miRs) have been reported to affect the tumorigenesis of ccRCC. However, the role of miR-384 in ccRCC is still unknown. Thus, the purpose of this study was to investigate the function of miR-384 in ccRCC. METHODS: qRT-PCR or Western blot were employed to examine the expressions of miR-384 and CDK6 in ccRCC tissues or cell lines. MTT and transwell assays were applied to measure cell proliferation and motility. The survival rate was analyzed by Kaplan-Meier method accompanied with log-rank test. Dual luciferase assay was used to verify the relationship among miR-384 and CDK6 in ccRCC cells. RESULTS: MiR-384 was downregulated in ccRCC tissues and cell lines, and its overexpression inhibited cell proliferation and motility in ccRCC. In addition, miR-384 was found to be a marker for good prognosis in ccRCC. Furthermore, CDK6 was confirmed to be directly targeted by miR-384, and upregulation of CDK6 restored the inhibitory effects of miR- 384 in ccRCC. CONCLUSION: MiR-384 repressed tumorigenesis by regulating CDK6 in ccRCC and predicted good prognosis for ccRCC. PMID- 30003754 TI - Galangin induced antitumor effects in human kidney tumor cells mediated via mitochondrial mediated apoptosis, inhibition of cell migration and invasion and targeting PI3K/ AKT/mTOR signalling pathway. AB - PURPOSE: Galangin is an important flavonoid that has been reported to be of immense pharmacological importance. It has been shown to have a number of bioactivities which range from anticancer to antimicrobial. In this study the effects of Galangin were studied on the proliferation of the A498 kidney cancer cells. METHODS: The antiproliferative effects were tested by MTT assay. Apoptosis was checked by subjecting the A498 cell to DAPI and annexin V/PI double staining. The effect on the cell migration and invasion was assessed by Boyden chamber assays. The expression of the apoptosis-related proteins was examined by western blot analysis. RESULTS: Galangin inhibited the proliferation of the kidney cancer A498 cells. The IC50 of Galangin against the A498 cancer cells was 15 MUM. The anticancer effects of Galangin were due to induction of apoptosis in the A498 cancer cells as indicated by DAPI and annexin V/PI staining. Furthermore, Galangin could increase the expression of Bax, Cyt-c and decrease the expression of Bcl-2. Galangin could also inhibit the migration and invasion of the kidney cancer cells and also suppress the expression of some of the important proteins of the PI3K/AKT/mTOR signalling pathway. CONCLUSION: In conclusion, Galangin could prove a useful new molecule in the treatment of kidney carcinoma. PMID- 30003755 TI - SChitosan-capped gold nanoparticles impair radioresistant glioblastoma stem-like cells. AB - PURPOSE: Glioblastoma is a rapidly evolving lethal disease mainly due to its highly chemo- and radioresistant glioblastoma stem cells (GSCs). Herein, we tested if chitosan-capped gold nanoparticles (Chit-GNPs) may overcome the limitations of drug concentrations by increased cell internalization in GSCs and if such GNPs could enhance the response to irradiation. METHODS: Chitosan was used for Chit-GNP synthesis as a reducing and stabilizing agent. Chit-GNPs were characterized by spectroscopy, dark field, transmission electron microscopy and zeta potential measurements. Patient-derived GSCs and human osteoblasts were treated with increasing concentrations of nanoparticles and irradiated. The uptake and cytotoxicity of Chit-GNPs were compared to that of uncoated GNPs. RESULTS: The positively-charged, 26 nm-sized, spherical Chit-GNPs, showed a huge intracellular accumulation into the cytosol, lysosomes and near the nucleus, whereas no uncoated GNPs were internalized within GSCs. Surprisingly, Chit-GNPs were highly cytotoxic for GSCs irrespective of cell irradiation, that failed to add an additional benefit when combined with Chit-GNPs/GNPs. Moreover, Chit-GNPs were selectively cytotoxic for GSCs and did not affect the normal cells, despite an increased nanoparticle internalization. CONCLUSIONS: The important Chit-GNP internalization and their selective cytotoxicity for GSCs make this compound a potential novel anticancer agent and a promising backbone for drug delivery in glioblastoma. PMID- 30003756 TI - Effects of MiR-210 on proliferation, apoptosis and invasion abilities of esophageal cancer cells. AB - PURPOSE: To investigate the effects of microRNA-210 (miRNA- 210) on the biological behaviors (proliferation and invasion) of EC109 cells of highly metastatic human esophageal cancer (EC). METHODS: The EC109 genomic DNA of human EC was used as a template to amplify the precursor sequence of miRNA-210 by polymerase chain reaction (PCR). The precursor sequence of miRNA-210 was sub cloned into the eukaryotic expression vector pcDNA3.1(-) via double digestion by BamH I and Hind III restriction enzymes. Then the pcDNA3.1 (-)-pri-miRNA-210 vector (named as p-miRNA-210) that was constructed successfully was transiently transfected into EC109 cells of human EC in vitro. Quantitative real-time PCR (qRT-PCR) was used to detect the expression level of mature miR-210. 3-(4,5 dimethyl-2-thiazolyl)-2,5- diphenyl-2-H-tetrazolium bromide (MTT) assay and scratch method were adopted to detect the proliferation and in vitro migration of EC109 cells, and flow cytometry was performed to detect the degree of cell apoptosis. RESULTS: The eukaryotic expression vector carrying miRNA- 210 was constructed successfully. Compared with that in the blank group (Mock) and the control group (P-Blank), miRNA-210 was overexpressed in the transfected EC109 cells. The cell apoptosis was significantly increased compared with that in the control group (p<0.05); the inhibition of proliferation of EC109 cells in the p miRNA-210 vector transfected group was remarkably elevated (p<0.05), and wound healing ability was also significantly increased (p<0.05). CONCLUSION: The overexpression of miRNA-210 can significantly inhibit the proliferation of EC109 cells of human EC and accelerate the migration ability and the rate of apoptosis, providing a potential strategy for the treatment of EC. PMID- 30003757 TI - A comparative study of treatment of gastrointestinal stromal tumors with laparoscopic surgery: a retrospective study. AB - PURPOSE: The purpose of this study was to analyze the clinical efficacy and complications of endoscopic submucosal dissection (ESD) and laparoscopic resection of stromal tumors, and to explore the clinical value and complications of stromal tumors treated with ESD. METHODS: 146 patients with gastric stromal tumors (GSTs) treated in our hospital from January 2012 to January 2016 were retrospectively analyzed. Patients were divided into the ESD group and the laparoscopic surgery group (LS). The operation time, postoperative recovery time of diet, postoperative exhaust time, etc were observed and analyzed. All the measurement indexes were described as mean +/- standard deviation. The t-test of two independent samples was used for the hypothesis test. Chi-square test was used for comparison of the percent data between the two groups and p<0.05 indicated significant difference. RESULTS: The postoperative diet recovery time, postoperative exhaust time, hospital stay and hospitalization cost of the ESD group were better compared with the LS group (p<0.001). There was no significant difference in operative time between the ESD and LS group (p>0.05), while the operation time in ESD group was longer than in the LS group (p<0.05). The operation time of gastric body and antrum stromal tumors was shorter than in the ESD group group (p<0.05). There were no significant differences in tumor diameter, mitotic number and Flether classification between the groups (p>0.05). No significant difference in the incidence of postoperative bleeding, incision infection and recurrence rate was noticeable between the groups (p>0.05). CONCLUSIONS: Endoscopic treatment of GSTs is safe and feasible, and may be better than laparoscopic resection. PMID- 30003758 TI - Deregulation of p53/survivin apoptotic markers correlated to PTEN expression in pterygium neoplastic cells. AB - PURPOSE: Pterygium is a distinct clinicopathological entity characterized by degenerated and neoplastic-like features. Concerning its rise on normal conjunctiva epithelia, the role of specific gene deregulations including apoptotic/anti-apoptotic factors and significant suppressor genes in signaling transduction pathways is under investigation. In the current study, we co analyzed p53, survivin and PTEN proteins in pterygia and normal conjunctiva. METHODS: Using a liquid-based cytology assay, 50 cell specimens were obtained by a smooth scraping on conjunctiva epithelia and fixed accordingly. Among them, 38 were pterygia and the remaining (n=12) normal epithelia (control group). Immunocytochemistry assays were implemented on the corresponding slides by applying ani-p53, survivin, and PTEN antibodies. Digital image analysis was performed for evaluating objectively the corresponding immunostaining intensity levels. RESULTS: The majority of the examined pterygia cases overexpressed the markers p53:22/38-57.9%, survivin:30/38-78.9%, and PTEN:25/38-65.7%. Interestingly, overall p53/PTEN co-expression was found to be statistically significant (p=0.022). CONCLUSIONS: Survivin overexpression leads to an increased anti-apoptotic activity playing a central molecular role in the pathogenesis and progression of pterygia. Furthermore, although p53 expression is observed in these lesions, its impact seems to be low compared to survivin's influence on them. Additionally, the role of PTEN in the process is potentially significant providing a suppressor balance to the p53/ survivin complex. PMID- 30003759 TI - Cancer wars: reflections of a medical oncologist from a visit to Moscow in 1987. PMID- 30003760 TI - Is it rational to extend the duration of preventive endocrine treatment in hormone receptor positive ductal carcinoma in situ? PMID- 30003763 TI - The role of radiotherapy following mastectomy and reconstruction. PMID- 30003762 TI - Are bilateral and unilateral interval breast cancers different? PMID- 30003761 TI - PD/L1 in oral squamous cell carcinoma. PMID- 30003764 TI - Are intramammary lymph node metastases significant in the staging of breast cancer? PMID- 30003765 TI - Importance of telomere length and telomerase activity in radiosensitivity. PMID- 30003766 TI - The distinguished Greek born, French ophthalmologist Photinos Panas (1832-1903) and his views on ocular cancer. AB - Photinos Panas (1832-1903) was one of the world's most important ophthalmologists in the second half of the 19th century. In his leading work entitled, Traite des maladies des yeux (Treatise of ophthalmic diseases), he made an in depth analysis of the various types of ocular cancer. His ideas on the subject were important for their tutorial character, their connection to the clinical work and very helpful for the everyday clinical practice of physicians of that time. PMID- 30003767 TI - Use of Noninvasive Imaging in Giant Cell Arteritis. AB - Giant cell arteritis (GCA) requires a prompt diagnosis to avoid significant morbidity among the elderly. An accurate diagnosis is also paramount given the side effect profile of long-term corticosteroid treatment. Temporal artery biopsy (TAB) has long remained the gold standard for the diagnosis of GCA but requires an invasive procedure that is not without risk. This article discusses the argument for and against the use of noninvasive imaging including ultrasound, magnetic resonance imaging, and positron emission tomography scanning for the diagnosis of GCA. It also provides a suggested diagnostic algorithm for when to consider noninvasive imaging versus TAB. PMID- 30003768 TI - [Isolation and Identification of a Novel Cypovirus from Daphnis nerii]. AB - In order to develop a novel effective biological insecticide for controlling oleander hawk moth, a new pathogen was isolated from naturally diseased Daphnis nerii. Based on scanning electron microscopy, full-length amplification of cDNAs (FLAC), and phylogenetic analysis of genome segments 2and 10,the virus was identified as a new type of cypovirus (Da phnis nerii cypovirus [DnCPV]). Electrophoresis analysis showed that DnCPV had a genome comprising 10double stranded RNA (dsRNA) segments, ranging from 892 to 4160bp.Using FLAC, the cDNAs from the 10 dsRNA segments of the new CPV were cloned and genome segments 2and 10 were sequenced. Sequencing results showed that segment 2 encoded RNA-dependent RNA-polymerases (RdRps) and segment 10 encoded polyhedrin. These two segments shared conserved terminal sequences of AGUCAAA and AGC at the 5'and 3'ends,respectively.These conserved terminal sequences were not consistent with any of the known CPV types.Phylogenetic analysis of the RdRp and polyhedrin indicated that this CPV was more closely related to CPV type 19 and type 5than other CPV types. Based on the unique conserved terminal sequences and the electrophoresis pattern of the new virus, we tentatively named it DnCPV Nanchang isolate: DnCPV-NC. PMID- 30003769 TI - [Advances in Avian Antiviral Innate Immune Effectors]. AB - As direct antiviral effector proteins, the innate antiviral proteins induced by pathogens and interferon can restrict intracellular viral infection at an early stage, establishing the state of the host antiviral immune response. Mx, PKR, OAS, IFITM, ZAP, and other proteins have all been shown to play important roles in the antiviral response. The host innate immune factors Mx and IFITM are both key antiviral effectors against influenza, while the antiviral mechanism of viperin remains to be completely elucidated. Research on the avian innate immune system is still at an early stage, resulting in fragmented knowledge in this area. Moreover, mechanisms of intrinsic and innate immunity in birds remain unclear. PMID- 30003770 TI - [Recent Progress and Practical Prospects for the HIV-1 Capsid Structure]. AB - The human immunodeficiency virus type 1(HIV-1)has spread globally and often exhibits antiviral resistance. Therefore, there is an ongoing need for the development of novel, highly efficient antiretroviral drugs with low toxicity. The capsid protein(CA),which is composed of an N-terminal domain(NTD)and C terminal domain(CTD),plays an important role in the process of HIV-1assembly and maturation. In recent years, the structure of capsid protein has been solved. In this article, we summarizes the spatial structure of the HIV-1capsid protein determined by X-ray crystallography, and describe the structural characteristics of the NTD-NTD,NTD-CTD and CTD-CTD interfaces. This article summarizes the antiviral approaches targeting CA and expounds a new strategy in combination with CRISPR/Cas9 gene editing technology. PMID- 30003771 TI - Correction to Catalytic Oxidation of Chlorobenzene over Mn xCe1- xO2/HZSM-5 Catalysts: A Study with Practical Implications. PMID- 30003772 TI - Ratiometric Two-Photon Fluorescent Probe for Detecting and Imaging Hypochlorite. AB - The ratiometric fluorescent probe B6S, which contains pyrene as a fluorophore and imidazoline-2-thione as a reactive site, was developed for detection of hypochlorite (OCl-). B6S displays a high specificity toward OCl- in contrast to other reactive oxygen species and reactive nitrogen species. The probe has a low detection limit and operates under biological conditions. Moreover, the low cytotoxicity of B6S enables it to be utilized effectively for OCl- imaging in living cells and tissues by using two-photon microscopy. The findings indicate that B6S has the capability of serving as a probe to explore the biological functions of OCl- in living systems. PMID- 30003773 TI - Strategies, Setbacks, and Successes in the Synthesis of (-)-Spiroleucettadine. AB - Various strategies toward the synthesis of the marine natural product (-) spiroleucettadine are described. In the original strategy, a biomimetic inspired oxidation of a 2-imidazoline scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a Baeyer-Villiger reaction was observed. The second generation approach examined oxidative dearomatization of the phenol ring system first, where a competing spirocyclization process was uncovered. Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful. Highlights of the successful synthesis include two consecutive hypervalent iodine reactions: the first formed the spirocyclic center and the second facilitated installation of an acetate group at the C-5 position to allow for subsequent introduction of the methyl amine side chain. PMID- 30003774 TI - Laser-Induced Flash-Evaporation Printing CH3NH3PbI3 Thin Films for High Performance Planar Solar Cells. AB - Organic-inorganic hybrid perovskites have been emerging as promising light harvesting materials for high-efficiency solar cells recently. Compared to solution-based methods, vapor-based deposition technologies are more suitable in preparing compact, uniform, and large-scale perovskite thin films. Here, we utilized flash-evaporation printing (FEP), a laser-induced ultrafast single source evaporation method employing a carbon nanotube evaporator, to fabricate high-quality methylammonium lead iodide perovskite thin films. Stoichiometric films with pure tetragonal perovskite phase can be achieved using a controlled methylammonium iodide to lead iodide ratio in evaporation precursors. The film crystallinity and crystal grain growth could further be promoted after postannealing. Planar solar cells (0.06 cm2) employing these perovskite films exhibit a champion power conversion efficiency (PCE) of 16.8% with insignificant hysteresis, which is among the highest reported PCEs using vapor-based deposition methods. Large-area (1 cm2) devices based on such perovskite films also achieved a stabilized PCE of 11.2%, indicating the feasibility and scalability of our FEP method in fabricating large-area perovskite films for other optoelectronic applications. PMID- 30003776 TI - Single Molecule Fluorescent Colocalization of Split Aptamers for Ultrasensitive Detection of Biomolecules. AB - Single-molecule fluorescence imaging is a promising strategy for biomolecule detection. However, the accuracy of single-molecule method is often compromised by the false-positive events at the ultralow sample levels that are caused by the nonspecific adsorption of the fluorescent labeled probe and other fluorescent impurities on the imaging surface. Here, we demonstrate an ultrasensitive single molecule detection assay based on dual-color fluorescent colocalization of spilt aptamers that was implemented to the measurement of adenosine triphosphate (ATP). The ATP aptamer was split into two fragments and labeled with green and red dye molecules, respectively. When the two probes of split aptamers were brought together by the target ATP molecule, the two colors of fluorescence of two probes were simultaneously detected through two channels and projected to the correlated locations in the two halves of image. The colocalizaiton imaging of two split apatamer probes greatly excluded the false detection of biomolecules that was usually caused by the fluorescent noise of single nonbound aptamer probes and impurities, and further improved the accuracy of measurement. The assay showed excellent selectivity and high sensitivity for ATP detection with linear range of 1 pM to 5 nM and a detection limit of 100 fM. This versatile protocol of single molecule colocalization of split apatamer can be widely applied to the ultrasensitive and highly accurate detection of many types of biomolecules in basic research and biomedical applications. PMID- 30003775 TI - Sulfur-Doped Nickel Phosphide Nanoplates Arrays: A Monolithic Electrocatalyst for Efficient Hydrogen Evolution Reactions. AB - Searching for cost-efficient electrocatalysts with high catalytic activity and stability for hydrogen generation by means of water electrolysis would make a great improvement on energy technologies field. Herein, we report high performance hydrogen evolution reaction (HER) electrocatalysts based on sulfur doped Ni5P4 nanoplate arrays grown on carbon paper (S-Ni5P4 NPA/CP). This ternary, robust, monolithic S-Ni5P4 NPA/CP exhibits remarkable performance for the HER compared to nickel phosphide and nickel sulfide catalysts. The S-Ni5P4 NPA/CP with ~6% S presents the most promising behavior for water electrolysis applications. Specifically, it shows an onset potential of 6 mV, needing overpotentials (eta) of 56 and 104 mV to attain current densities of 10 and 100 mA cm-2 with a Tafel slope of 43.6 mV dec-1. The turnover frequency of 6% S-Ni5P4 NPA/CP is about 0.11 s-1 at overpotential of 100 mV, which is ca. 10 and 40 times that of Ni5P4 NPA/CP and NiS2 NPA/CP, respectively. It also shows remarkable stability and durability in 0.5 M H2SO4 solution. The results indicate that S and P tune the electronic properties mutually and produce an active catalyst phase for the HER. Furthermore, the density functional theory calculations show that S Ni5P4 NPA/CP exhibits only 0.04 eV of hydrogen adsorption free energy(Delta GH*), which is more suitable than Pt (~-0.09 eV). We propose that the S-doping not only restrains the surface oxidation and dissolution of S-Ni5P4 NPA/CP in acid solution but also reduces the Delta GH*. We believe that our work will provide a new strategy to design transition metal phosphide composite materials for practical applications in catalysis and energy fields. PMID- 30003777 TI - Scanning Gel Electrochemical Microscopy for Topography and Electrochemical Imaging. AB - Scanning electrochemical probe techniques have been widely applied for analyzing the local electrochemical activity of surfaces and interfaces. In this work, we develop a new concept of carrying out local electrochemical measurements by localizing both the electrode and the electrolyte. This is achieved through a gel probe, which is prepared by electrodepositing chitosan-gelatin gel on a microdisk electrode. It is positioned in contact with the sample surface by shear force feedback. The preliminary results indicate that the topography of the sample can be mapped by tapping the probe and recording the coordinates at a given normalized shear force signal, while the local electrochemical activity can be retrieved from local measurements with the probe touching the sample surface. The technique is denoted as scanning gel electrochemical microscopy. As compared with existing techniques, it has a major advantage of operating in air with the electrolyte immobilized in gel. This would prevent the spreading and leakage of solution on the sample surface and may lead to field applications. PMID- 30003778 TI - Napabucasin and Related Heterocycle-Fused Naphthoquinones as STAT3 Inhibitors with Antiproliferative Activity against Cancer Cells. AB - Napabucasin (6) and its angularly anellated isomer (7), for which the synthesis is described, together with related plant-derived naphthoquinones, were evaluated in vitro against human breast cancer (MDA-MB-231) and chronic myelogenous leukemia (K562) cells. As observed for beta-lapachone (3), the active naphthoquinones all induced apoptosis in a cell-cycle-independent fashion. In contrast to the pyran-fused beta-lapachone (3), however, the most potent furan fused naphthoquinones were able to redox cycle and generate superoxide in cell based assays, which was independent of NAD(P)H:quinone oxido-reductase 1. In a homogeneous time-resolved fluorescence (HTRF) assays with MDA-MB-231 cells, both napabucasin (6) and isonapabucasin (7) were identified as targeting STAT3 phosphorylation. In addition, drug affinity responsive target stability assays were performed to validate a direct interaction of the naphthoquinones with STAT3. Isonapabucasin (7) turned out to be twice as potent against STAT3 as napabucasin (6) in the HTRF assay, with an EC50 in the submicromolar range, which was in excellent agreement with the potency of both agents to inhibit the growth of MDA-MB-231 cells. Moreover, molecular docking experiments predicted different binding modes to the STAT3 SH2 domain for the linearly anellated napabucasin (6) and its angularly anellated isomer (7). PMID- 30003779 TI - Multinuclear Cu(I) Clusters Featuring a New Triply Bridging Coordination Mode of Phosphaamidinate Ligands. AB - Phosphabenzamidine [mes-NH-C(Ph)?P-mes) (1) and phosphaformamidine (mes-NH-CH?P mes) (4) ligands have been synthesized and characterized. The conjugate bases of 1 and 4 coordinate by each bridging three Cu(I) ions, forming hexa- and tetranuclear clusters Cu6[mes-N?C(Ph)-P-mes]3Cl4Li(THF)2 (3) and Cu4[mes-N?CH-P mes]4 (5), respectively. Both clusters have been fully characterized using 1H NMR, 31P NMR, and X-ray crystallography. Complexes 3 and 5 exhibit a previously unknown coordination mode of phosphaamidinates, which are far less studied than their well-known amidinate counterparts. PMID- 30003780 TI - Bionic Fish-Scale Surface Structures Fabricated via Air/Water Interface for Flexible and Ultrasensitive Pressure Sensors. AB - In recent years, wearable and flexible sensors have attracted considerable research interest and effort owing to their broad application prospects in wearable devices, robotics, health monitoring, and so on. High-sensitivity and low-cost pressure sensors are the primary requirement in practical application. Herein, a convenient and low-cost process to fabricate a bionic fish-scale structure poly(dimethylsiloxane) (PDMS) film via air/water interfacial formation technique is presented. High-sensitivity flexible pressure sensors can be constructed by assembling conductive films of graphene nanosheets into a microstructured film. Thanks to the unique fish-scale structures of PDMS films, the prepared pressure sensor shows excellent performance with high sensitivity ( 70.86% kPa-1). In addition, our pressure sensors can detect weak signals, such as wrist pulses, respiration, and voice vibrations. Moreover, the whole process of pressure sensor preparation is cost-effective, eco-friendly, and controllable. The results indicate that the prepared pressure sensor has a profitable and efficient advantage in future applications for monitoring human physiological signals and sensing subtle touch, which may broaden its potential applications in wearable devices. PMID- 30003781 TI - Roll-to-Roll Processing of Silicon Carbide Nanoparticle-Deposited Carbon Fiber for Multifunctional Composites. AB - This work provides a proof of principle that a high volume, continuous throughput fiber coating process can be used to integrate semiconducting nanoparticles on carbon fiber surfaces to create multifunctional composites. By embedding silicon carbide nanoparticles in the fiber sizing, subsequent composite fabrication methods are used to create unidirectional fiber-reinforced composites with enhanced structural health monitoring (SHM) sensitivity and increased interlaminar strength. Additional investigations into the mechanical damping behavior of these functional composites reveal a significantly increased loss factor at the glass-transition temperature ranging from a 65 to 257% increase. Composites with both increased interlaminar strength and SHM sensitivity are produced from a variety of epoxy and silicon carbide nanoparticle concentrations. Overall, the best performing composite in terms of combined performance shows an increase of 47.5% in SHM sensitivity and 7.7% increase in interlaminar strength. This work demonstrates successful and efficient integration of nanoparticle synthesis into large-scale, structural applications. PMID- 30003783 TI - Oligo(ethylene glycol)-Functionalized Squaraine Fluorophore as a Near-Infrared Fluorescent Probe for the In Vivo Detection of Diagnostic Enzymes. AB - Squaraine dyes have excellent photostability with intensive absorption and strong fluorescence in the near-infrared (NIR) region. However, they display a strong tendency to aggregate in aqueous media because of their poor water solubility, often causing fluorescence quenching that severely limits their in vivo applications, especially for detecting or imaging diagnostic enzymes. In this work, an oligo(ethylene glycol)-functionalized squaraine fluorophore has been developed as an NIR-fluorescent probe that can detect and image the activities of a diagnostic enzyme (leucine aminopeptidase) both in vitro and in vivo. The probe shows near-infrared absorption and emission, a low detection limit (0.61 ng/mL), relatively good aqueous solubility, high selectivity, and little toxicity. In addition, the probe herein was successfully used to track endogenous leucine aminopeptidase both in vitro and in vivo with a nude-mouse model. PMID- 30003782 TI - Isolating Clusters of Light Elements in Molecular Sieves with Atom Probe Tomography. AB - Understanding the 3-D distribution and nature of active sites in heterogeneous catalysts is critical to developing structure-function relationships. However, this is difficult to achieve in microporous materials as there is little relative z-contrast between active and inactive framework elements (e.g., Al, O, P, and Si), making them difficult to differentiate with electron microscopies. We have applied atom probe tomography (APT), currently the only nanometer-scale 3-D microscopy to offer routine light element contrast, to the methanol-to hydrocarbons (MTH) catalyst SAPO-34, with Si as the active site, which may be present in the framework as either isolated Si species or clusters (islands) of Si atoms. 29Si solid-state NMR data on isotopically enriched and natural abundance materials are consistent with the presence of Si islands, and the APT results have been complemented with simulations to show the smallest detectable cluster size as a function of instrument spatial resolution and detector efficiency. We have identified significant Si-Si affinity in the materials, as well as clustering of coke deposited by the MTH reaction (13CH3OH used) and an affinity between Bronsted acid sites and coke. A comparison with simulations shows that the ultimate spatial resolution that can be attained by APT applied to molecular sieves is 0.5-1 nm. Finally, the observed 13C clusters are consistent with hydrocarbon pool mechanism intermediates that are preferentially located in regions of increased Bronsted acidity. PMID- 30003784 TI - Attractive Nonbonded Interactions Help Stabilize the Z Form of Alkenyl Anions. AB - Alkenyl anions ((-)H2C-CH?CH-Y; Y = aliphatic, aromatic, amine, ether) are often thermodynamically stable in the sterically congested Z form. This preference for Z structures is used to control regiochemistry in organometallic and Grignard reactions, allyl amine rearrangements to enamines, and allyl ether rearrangements to enol ethers. Explanations for Z stability in alkenes (Y = CH2R) typically invoke through-space attraction (Coulomb or charge transfer) between the formally anionic carbon C1 and the Y = CH2R hydrogens. However, this explanation is difficult to generalize to amines and ethers. We suggest that the orbital-driven so-called "attractive nonbonded interactions" suggested to stabilize the Z forms of 1,2-difluoroethylene and 1-substituted propenes also help stabilize Z alkenyl anions. We present electronic structure calculations and surveys of the experimental literature to show these effects' relevance for alkenyl anions. Our results suggest new approaches for regiocontrol in reactions with alkenyl anion intermediates and motivate revisiting older orbital-based theories of "attractive nonbonded interactions". PMID- 30003785 TI - Photoinduced Shape Changes of Mixed Molecular Glass Particles Containing Azobenzene-Based Photochromic Amorphous Molecular Materials Fixed in Agar Gel. AB - It has been found that mixed molecular glass particles exhibit photoinduced shape changes, elongating their shapes to form stringlike structures similar to single molecular glass particles of azobenzene-based photochromic amorphous molecular materials. Furthermore, interestingly, the addition of 15 mol % photochemically inert 4,4',4"-tris[3-methylphenyl(phenyl)amino]triphenylamine enhanced the phenomenon relative to single particles of 4-[bis(4 methylphenyl)amino]azobenzene. The present mixed systems allowed to elucidate the effects of Tg and of the apparent photochromic reactivity independently by changing the mixing ratio of suitable materials. It has been clearly demonstrated that increase in the apparent photochromic reactivity enhanced monotonically the photomechanical elongation of the particles. On the other hand, it has been found that increase in Tg was favorable for the present photoinduced elongation of the particle, whereas the effect of Tg became saturated at sufficiently high Tg values. PMID- 30003786 TI - Novel Conductive Filament Metal-Interlayer-Semiconductor Contact Structure for Ultralow Contact Resistance Achievement. AB - In the post-Moore era, it is well-known that contact resistance has been a critical issue in determining the performance of complementary metal-oxide semiconductor (CMOS) reaching physical limits. Conventional Ohmic contact techniques, however, have hindered rather than helped the development of CMOS technology reaching its limits of scaling. Here, a novel conductive filament metal-interlayer-semiconductor (CF-MIS) contact-which achieves ultralow contact resistance by generating CFs and lowering Schottky barrier height (SBH)-is investigated for potential applications in various nanodevices in lieu of conventional Ohmic contacts. This universal and innovative technique, CF-MIS contact, forming the CFs to provide a quantity of electron paths as well as tuning SBH of semiconductor is first introduced. The proposed CF-MIS contact achieves ultralow specific contact resistivity, exhibiting up to ~*700 000 reduction compared to that of the conventional metal-semiconductor contact. This study proves the viability of CF-MIS contacts for future Ohmic contact schemes and that they can easily be extended to mainstream electronic nanodevices that suffer from significant contact resistance problems. PMID- 30003787 TI - Total Synthesis of (-)-Actinophyllic Acid Enabled by a Key Dual Ir/Amine Catalyzed Allylation. AB - A synthetic strategy for the catalytic asymmetric total synthesis of (-) actinophyllic acid is described. This highly efficient and enantioselective approach allows the rapid installation of the four contiguous chiral centers (C16, C15, C20, and C19) by way of a dual Ir/amine catalytic allylation of 2 indolyl vinyl carbinol 6 and an aldol reaction of resultant chiral aldehyde 4a with 2-pyrrolidinone 5. The key indol-3-ylmethanamine moiety and 1 azabicyclo[4.2.1]nonane ring system were readily generated through a selective Mannich-like cyclization and an intramolecular N-alkylation, respectively. PMID- 30003788 TI - Complexity of Uranyl Peroxide Cluster Speciation from Alkali-Directed Oxidative Dissolution of Uranium Dioxide. AB - Solid UO2 dissolution and uranium speciation in aqueous solutions that promote formation of uranyl peroxide macroanions was examined, with a focus on the role of alkali metals. UO2 powders were dissolved in solutions containing XOH (X = Li, Na, K) and 30% H2O2. Inductively coupled plasma optical emission spectrometry (ICP-OES) measurements of solutions revealed linear trends of uranium versus alkali concentration in solutions resulting from oxidative dissolution of UO2, with X:U molar ratios of 1.0, showing that alkali availability determines the U concentrations in solution. The maximum U concentration in solution was 4.20 * 105 parts per million (ppm), which is comparable to concentrations attained by dissolving UO2 in boiling nitric acid, and was achieved by lithium hydroxide promoted dissolution. Raman spectroscopy and electrospray ionization mass spectrometry (ESI-MS) of solutions indicate that dissolution is accompanied by the formation of various uranyl peroxide cluster species, the identity of which is alkali concentration dependent, revealing remarkably complex speciation at high concentrations of base. PMID- 30003789 TI - Total Synthesis of Pericoannosin A. AB - The first total synthesis of pericoannosin A (1) containing 15 steps in the longest linear sequence with an overall yield of 5.5% is reported. The hybrid peptide-polyketide was isolated from the endophytic fungus Periconia sp. F-31 and bears a unique tricyclic core structure. The key steps are a glycolate aldol reaction and a Diels-Alder reaction utilizing an Evans auxiliary for controlling the stereochemistry. Furthermore, a late-stage equilibration was employed. PMID- 30003790 TI - Formal [7 + 2] Cycloaddition of Arynes with N-Vinyl-alpha,beta-Unsaturated Nitrones: Synthesis of Benzoxazonines and Their N-O Bond Cleavage. AB - Various benzoxazonines were synthesized through a formal [7 + 2] cycloaddition of arynes with N-vinyl-alpha,beta-unsaturated nitrones under mild conditions. Controllable N-O bond cleavage of benzoxazonines afforded polysubstituted pyrrole tethered benzopyrans and acyclic ketone-substituted phenols in moderate to good yields. Further transformations provided a facile approach to access useful building blocks with specific stereoselectivity. PMID- 30003791 TI - Bioinspired Total Synthesis of Delitschiapyrone A. AB - A bioinspired seven-step total synthesis of delitschiapyrone A was accomplished in 32% overall yield from commercially available 4-bromo-3,5-dimethoxybenzoic acid. The key step of the synthesis is an exclusively regioselective and diastereoselective reaction cascade consisting of the Diels-Alder reaction, alpha ketol rearrangement, and cyclic hemiacetalization, achieved by simply stirring a heterogeneous mixture of two Diels-Alder substrates (putative biosynthetic intermediates) and water at 35 degrees C, directly furnishing the pentacyclic natural product in 75% yield. PMID- 30003792 TI - A Case of Cutaneous Rosai-Dorfman Disease. PMID- 30003793 TI - Development of the Pediatric Social Risk Instrument Using a Structured Panel Approach. AB - BACKGROUND: Social determinants of health impact child illness. Currently, no instrument exists to identify social need during hospital admission. METHODS: Using the UCLA (University of California Los Angeles)-RAND appropriateness method, consensus was reached for an instrument to identify social need in hospitalized children. A panel of 11 experts reviewed candidate indicators through 3 rounds to reach consensus. The instrument then underwent usability testing. RESULTS: Three hundred and forty-seven indicators from the literature were sorted into 18 social risk themes. After 3 rounds, consensus was reached on 82 indicators. Six additional social risk themes were recommended by the panel, resulting in consensus for 18 additional indicators. Final refinement resulted in an instrument containing 86 indicators representing 11 social risk themes. Usability testing identified that the tool was well received by families. Final feedback was incorporated into a post-usability instrument. CONCLUSIONS: Using the UCLA-RAND appropriateness method, a new pediatric social risk instrument was created to identify social need for hospitalized children. PMID- 30003794 TI - Outreach and Reminders to Improve Human Papillomavirus Vaccination in an Integrated Primary Care System. AB - This study evaluated the impact of health system-based outreach and reminders on human papillomavirus (HPV) vaccine series initiation and completion. Parents of 10 to 12 year olds (n = 1805) were randomized to receive either (1) an outreach letter and brochure recommending HPV vaccination followed by automated HPV vaccine reminders or (2) usual care. We interviewed a subset of 50 parents to assess program acceptability. Outcomes were HPV vaccine initiation during the study period and on-time series completion. Rates of HPV vaccine initiation during the study period (July 2015 to August 2016) were similar between the intervention and control groups, but initiation within 120 days of randomization was higher in the intervention group (23.6% and 18.8%, P = .04) as was completion during the study period (10.3% vs 6.8%, P = .04). Reminders for doses 2 and 3 did not affect completion. The program was acceptable to parents. This study provides evidence that health system-based outreach and reminders can improve HPV vaccination. PMID- 30003796 TI - Two Cases of Traumatic Brachial Plexus Injury With Complete Spinal Cord Injury. AB - BACKGROUND: Traumatic brachial plexus injury (BPI) in patients with complete spinal cord injury (SCI) such as paraplegia or tetraplegia is a very rare and debilitating combined injury that can occur in high-energy traumas. Management of a BPI should be aimed at regaining strength for self-transfers and activities of daily living to restore independence. However, brachial plexus reconstruction (BPR) in this unique patient population requires considerable planning due to the combined elements of upper and lower motor neuron injuries. METHODS: We present 2 cases of traumatic complete SCI with concomitant BPI with mean follow-up of 42 months after BPR. The first patient had a left C5-7 BPI with a T2 complete SCI. The second patient sustained a left C5-8 BPI with complete SCI at C8. RESULTS: The first patient underwent BPR including free functioning muscle, intra- and extraplexal nerve transfers, and tendon transfers resulting in active elbow flexion and active elbow, finger, and thumb extension, but no recovery of shoulder function. While the second patient underwent extra-plexal nerve transfer to restore elbow flexion yet did not recover any function in the left upper extreimty. CONCLUSIONS: Because extensive upper and lower motor neuron injuries are present in these combined injuries, treatment strategies are limited. Expectations should be tempered in these patients as traditional methods to reconstruct the brachial plexus may result in less than ideal functional outcomes due to the associated upper motor neuron injury. PMID- 30003795 TI - Development and validation of a prognostic model for survival in patients treated with venoarterial extracorporeal membrane oxygenation: the PREDICT VA-ECMO score. AB - AIMS: Several scoring systems have been introduced for prognostication after initiating venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy. However, static scores offer limited guidance once VA-ECMO is implanted, although continued allocation of healthcare resources is critical. Patients requiring continued VA-ECMO support are extremely unstable, with minimal heart function and multi-organ failure in most cases. The aim of the present study was to develop and validate a dynamic prognostic model for patients treated with VA-ECMO. METHODS AND RESULTS: A derivation cohort included 205 all-comers undergoing VA ECMO implantation at a tertiary referral hospital (51% received VA-ECMO during resuscitation and 43% had severe shock). Two prediction models based on point-of care biomarkers were developed using penalised logistic regression in an elastic net approach. A validation cohort was recruited from an independent tertiary referral hospital. Comparators for the prediction of hospital survival were the SAVE score (area under the receiver operation characteristic curve (AUC) of 0.686), the SAPS score (AUC 0.679), the APACHE score (AUC 0.662) and the SOFA score (AUC 0.732) in 6-hour survivors. The 6-hour PREDICT VA-ECMO score (based on lactate, pH and standard bicarbonate concentration) outperformed the comparator scores with an AUC of 0.823. The 12-hour PREDICT VA-ECMO integrated lactate, pH and standard bicarbonate concentration at 1 hour, 6 hours and 12 hours after ECMO insertion allowed even better prognostication (AUC 0.839). Performance of the scores in the external validation cohort was good (AUCs 0.718 for the 6-hour score and 0.735 for the 12-hour score, respectively). CONCLUSION: In patients requiring VA-ECMO therapy, a dynamic score using three point-of-care biomarkers predicts hospital mortality with high reliability. Furthermore, the PREDICT scores are the first scores for extracorporeal cardiopulmonary resuscitation patients. PMID- 30003798 TI - Arts-based interventions to promote transition outcomes for young people with long-term conditions: A review. AB - Objectives To conduct a systematic review of arts-based interventions promoting transition from paediatric to adult services for young people (Note: The term young people refers to adolescents and young adults.) with long-term conditions and to explore their effectiveness. Interventions Arts-based interventions included studies of young people who were actively participating in the intervention rather than passive observers. Visual arts interventions included film/video production, time-based media, photography, animation, sculpture, audio, installation, sound recordings, painting, textiles, print, mixed media, multimedia. Arts-based interventions included creative writing, poetry, dance, choreography and storytelling. Main outcome measures We included all outcome measures relevant to transition and any chronic condition. These included: self care knowledge and skills, autonomy, continuity of care, adherence to treatment and attendance at appointments. Results Seven studies reported arts-based interventions promoting outcomes that are relevant to transition. These studies showed that arts-based interventions may influence young people with long-term conditions self-esteem, confidence and self-expression. The findings must be treated with caution as the evidence was weak with studies using qualitative measures and of poor methodological quality. Conclusions There is a need for further research of arts-based interventions for children and adolescents with long-term conditions that incorporate objective measurements or validated tools to assess outcomes relevant to the transition process. PMID- 30003797 TI - Screening for Attention-Deficit/Hyperactivity Disorder and Comorbidities in a Diverse, Urban Primary Care Setting. AB - We tested the accuracy of 2 parent-report tools, the Pediatric Symptom Checklist (PSC-35) and Child Behavior Checklist (CBCL), to identify attention deficit/hyperactivity disorder (ADHD) and distinguish complex (highly comorbid) cases in an urban, largely Latino pediatric practice. Spanish- and English speaking parents of children aged 6 to 10 years completed a PSC-35 and CBCL at well visits. Those with CBCL Attention Problems Subscale (CBCL-APS) T scores >=60 plus controls completed the diagnostic MINI-KID (Miniature International Neuropsychiatric Interview) for Children. Receiver operating characteristic (ROC) curves quantified accuracy of both scales to distinguish ADHD from non-ADHD, and complex from simple ADHD. Two hundred and nine children were screened, and 41 completed diagnostic interviews. Both the CBCL-APS and PSC Attention Scale (PSC AS) accurately identified ADHD; the CBCL-APS performed best (AUROCCBCL_APS = 0.837; AUROCPSC_AS = 0.728). The PSC Total and Internalizing Scores and the number of CBCL subscale elevations accurately distinguished complex from simple ADHD; the PSC Internalizing Score performed best (AUROCPSC_TOTAL = 0.700; AUROCPSC_INT = 0.817; AUROCCBCL_SUBS = 0.762). PMID- 30003799 TI - DSM Borderline Criterion Function Across Age-Groups: A Cross-Sectional Mixed Method Study. AB - DSM-5 ( Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) Section II criteria for borderline personality disorder (BPD) lack developmental operationalization. The aim of the current study was to evaluate whether DSM criteria operate similarly across adolescents and adults to determine if developmental adjustment for DSM criteria was needed. Three age cohorts were recruited: adolescents (ages 12-17 years; n = 484), young adults (ages 18-25 years; n = 442), and adults (ages >=26 years; n = 953). The Child Interview for DSM-IV BPD and the Structured Clinical Interview for DSM-IV Axis II disorders were administered to adolescents and adults, respectively. Item response theory methods were used to evaluate differential item (or criterion) functioning (DIF) of BPD criteria across adolescents and adults. Qualitative analyses were then used to evaluate the potential sources of DIF. Item response theory results demonstrated DIF across adolescents and adults for all DSM BPD criteria. Qualitative analyses suggested that the source of DIF was most likely due to rater/interviewer bias. Results furthermore suggested that behavioral criteria may represent the heterotypic features of BPD, while intra- and interpersonal criteria represent the homotypic features of the disorder. The article concludes with recommendations for developmentally informed guidelines for the assessment of BPD. PMID- 30003800 TI - Usability, Satisfaction, and Usefulness of an Illustrated Eczema Action Plan. AB - BACKGROUND: An eczema action plan (EAP) is an individualized tool to help caregivers and patients self-manage eczema. While novel illustrated EAPs have been developed and validated, there is limited literature examining the value of EAPs from patient and caregiver perspectives. OBJECTIVES: The objective of this study was to test the usability, satisfaction, and usefulness of our validated EAP from the perspective of patients and caregivers. METHODS: Consecutive patients from the pediatric dermatology clinic of a tertiary children's hospital from July 2016 to July 2017 were offered enrolment in a prospective survey study; informed consent was obtained from participants. The illustrated EAP was explained to the participant by a trained research assistant. Participants were sent electronic postvisit surveys using Likert scale questions via REDCap on EAP usability and satisfaction (9 items) as well as on usefulness (3 items). RESULTS: Of 233 consecutive clinic patients, 192 participants (82%) were enrolled, and 112 (58%; 85 caregivers and 22 patients) completed the postvisit surveys. Characteristics were similar between responders and nonresponders. Overall, participants rated the usability (96%), satisfaction (85%), and usefulness (78%) of the EAP positively. Education level, experience with eczema, previous dermatology consultation, and participant type (caregiver vs patient) did not significantly affect the usability or usefulness ratings. However, caregivers' overall EAP ratings were significantly higher ( P = .02) than the patients'. CONCLUSION: The caregivers and participants demonstrate that the EAP is a useful and highly usable tool. Future research should examine the effectiveness of EAP use on objective atopic dermatitis outcomes using a pragmatic clinical trial design. PMID- 30003802 TI - Review of Internal Radiocarpal Distraction Plating for Distal Radius Fracture Fixation. AB - Internal radiocarpal distraction plating is a versatile tool in the treatment of distal radius fractures that are not amenable to nonoperative treatment or operative fixation with standard volar or dorsal implants. Internal distraction plates may also be indicated in the setting of polytrauma or osteopenic bone. The plate functions as an internal fixator, using ligamentotaxis to restore length and alignment while providing relative stability for bony healing. The plate can be fixed to either the second or the third metacarpal, and anatomic and biomechanical studies have assessed the strengths and weaknesses of each strategy. This operative fixation technique leads to acceptable radiographic results and functional outcomes. Following fracture union, the plate is removed, and wrist range of motion is resumed. PMID- 30003803 TI - Selfie posting and self-esteem among young adult women: A mediation model of positive feedback and body satisfaction. AB - This study examined whether selfie-posting was positively associated with women's self-esteem and whether this association was mediated by positive feedback and body satisfaction. A sample of 442 Chinese young adult women completed questionnaires on selfie-posting, positive feedback, body satisfaction, and self esteem. Results indicated that selfie-posting was significantly and positively related to women's self-esteem. In addition, positive feedback mediated the relation between selfie-posting and women's self-esteem. Furthermore, the association between selfie-posting and self-esteem was sequentially mediated through positive feedback and body satisfaction. Findings from this study provide new insights into the relation between selfie-posting and self-esteem. PMID- 30003801 TI - Modeling of Diabetes and Its Clinical Impact. AB - Understanding all aspects of diabetes treatment is hindered by the complexity of this chronic disease and its multifaceted complications and comorbidities, including social and financial impacts. In vivo studies as well as clinical trials provided invaluable information for unraveling not only metabolic processes but also risk estimations of, for example, complications. These approaches are often time- and cost-consuming and have frequently been supported by simulation models. Simulation models provide the opportunity to investigate diabetes treatment from additional viewpoints and with alternative objectives. This review presents selected models focusing either on metabolic processes or risk estimations and financial outcomes to provide a basic insight into this complex subject. It also discusses opportunities and challenges of modeling diabetes. PMID- 30003804 TI - Trends in the "Off-Label" Use of GnRH Agonists Among Pediatric Patients in the United States. AB - BACKGROUND: Gonadotropin-releasing hormone (GnRH) agonists are FDA approved for the treatment of precocious puberty. The therapy consists of histrelin acetate (Supprelin), a surgically implanted device, or Lupron injections. In recent years, the use of these agents has been extended to include the off-label treatment of children with normally timed puberty. Trends in the off-label use of GnRH agonists in children across the U.S. have not been previously described in the literature. METHODS: We analyzed data on the use of Supprelin and Lupron reported to the Pediatric Health Information System (PHIS) from 2013 to 2016 to determine the trends in both the FDA-approved and off-label uses of these medications. RESULTS: We identified a stable cohort of 39 children's hospitals administering GnRH agonist therapies from 2013 to 2016. During this period, the annual number of children treated with these medications for precocious puberty increased modestly, from 283 to 303; meanwhile, the fraction of children receiving therapy for an off-label indication more than doubled, from 12% (39 of 322 total patients) to 29% (125 of 428 total patients). Privately insured patients were more likely to be treated for an off-label indication (13%; 119 out of 883 patients) than Medicaid patients (8%; 58 out of 706 patients; chi2[1] = 10.97, P = .00093). CONCLUSION: From 2013 to 2016, the proportion of children treated with GnRH agonists for an off-label indication notably increased. The number of children treated for precocious puberty modestly increased. Private insurance coverage was associated with higher rates of off-label use. PMID- 30003805 TI - Extra-articular Medial Impression Fracture of the Talus: A Previously Undescribed Injury. AB - BACKGROUND: Peripheral fractures of the talus are uncommon. Almost all the literature regarding talar fractures consists of central intra-articular fractures, whereas studies about peripheral talar fractures are lacking. The aim of this study is to increase awareness in diagnosing an unusual peripheral extra articular medial impression fracture of the talus. METHODS: This study includes a retrospective case series of patients with an extra-articular medial impression fracture of the talus. Patient characteristics, trauma mechanism, diagnostics, fracture characteristics, and treatment were reported. RESULTS: Eight consecutive patients with an extra-articular medial impression fracture of the talus were identified. In 80%, the trauma mechanism was a supination or inversion injury of the ankle and foot. An X-ray was obtained in all patients; in 7 (88%) patients, a computed tomography scan was done, and an additional magnetic resonance imaging was done in 3 (38%) patients. In 4 patients (50%), the correct diagnosis was missed at first presentation. The delay between injury and diagnosis was 0 to 180 days (of 36 days on average). CONCLUSION: This is the first case series to describe patients with a peripheral extra-articular medial impression fracture of the talus. Good clinical examination and judicious use of diagnostic imaging are a necessity to find the talar impression fractures in a timely manner, and treatment can be started immediately. LEVELS OF EVIDENCE: Level V. PMID- 30003806 TI - Radial Plate Fixation of Distal Radius Fracture. AB - BACKGROUND: A radial incision with radial plate fixation for distal radius fracture has historically been avoided due to its risk to the superficial branch of the radial nerve (SBRN). With careful technique, it is possible to avoid injury to the SBRN, thereby minimizing the soft tissue injury associated with other approaches. We compare subjective and objective functional outcomes of radial plate fixation surgeries that we performed with those of dorsal and volar plate fixation in current literature. METHODS: Patients at a single center who underwent radial plate fixation for an AO type A or AO type B distal radius fracture between December 2006 and December 2014 were enrolled in the study. Postoperative grip strength and 3-digit pinch strength were measured systematically in the injured and uninjured wrists. Patients also completed a Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire to assess subjective outcomes. RESULTS: Thirty-six patients met our inclusion criteria and had available medical records. Postoperative grip strength in the injured wrist was significantly lowered-68% compared with the uninjured wrist. After subgroup analysis of dominant and nondominant wrist injuries, there was no significant difference in grip strength between injured and uninjured wrists. There was no significant decrease in postoperative 3-digit pinch strength in the injured wrist-89% compared with the uninjured wrist. The mean QuickDASH score for our study participants was 20.9. CONCLUSIONS: Radial plate fixation is an effective approach for distal radius fractures. Objective and subjective outcomes are noninferior to those of a dorsal or volar approach. PMID- 30003807 TI - Challenges of Menstrual Dysfunction Screening Using the Preparticipation Physical Examination: A Pilot Study. PMID- 30003808 TI - Utilization and Impact of Social Media in Hand Surgeon Practices. AB - BACKGROUND: Social media is an effective tool to enhance reputation and brand recognition and is being used by more than 40% of patients when selecting a physician. This study aimed to evaluate the use of social media in hand surgeon practices, and to assess the impact that one's social media presence has on physician-rating website scores (PRWs). METHODS: Randomly selected hand surgeons from across the United States were identified. Sequential searches were performed using the physicians name + the respective social media platform (Facebook, LinkedIn, YouTube, Twitter, Instagram, personal website, group website). A comprehensive social media utilization index (SMI) was created for each surgeon. Utilizing descriptive statistics, we assessed the effect of social media on the PRW. RESULTS: A total of 116 board-certified hand surgeons were included in our study. The sample identified 10.3% of the population used Facebook, 1.7% used Twitter, 25.8% used YouTube, 22.4% used LinkedIn, 27.5% used a personal website, and 36.2% used a group website, 0% used Instagram. The average SMI was 1.53 +/- 1.42 (0-6). Physicians with a personal website received higher Healthgrades scores than those without one ( P < .05). Analysis of SMI demonstrated that hand surgeons with an index less than 3 received lower Healthgrades scores compared to those with an SMI above 3 ( P < .001). CONCLUSION: Hand surgeons underutilize social media platforms in their practice. A personal website is single most important social media platform to improve HealthGrades score in hand surgeons. PMID- 30003809 TI - Malaysian Parent Ratings of the Strengths and Difficulties Questionnaire: Factor Structure and Measurement Invariance Across Language Versions, Gender, Informants, and Race. AB - For a Malaysian sample, the current study used exploratory factor analysis (EFA) to determine the best model for parent ratings of the Strengths and Difficulties Questionnaire (SDQ), and then multiple-group confirmatory factor analysis (MCFA) to confirm this model, and to examine measurement invariance across different language versions (Malay and English), child's gender (boys and girls), informants (mothers and fathers), and racial groups (Malay, Chinese, and Indians). In all 1,407 Malaysian parents completed SDQ ratings of their children (age ranging from 5 to 13 years). The EFA showed most support for a two-factor model oblique model, with factors for a positive construal factor and a psychopathology factor. CFA confirmed this model, and MCFA showed full measurement invariance (configural, metric. and scalar) across the groups in the different comparisons. For all comparisons, there were equivalencies for latent mean scores. The implications of the findings for clinical and research practice involving the SDQ in Malaysia are discussed. PMID- 30003810 TI - Antioxidant effects of vitamin D on lacrimal glands against high dose radioiodine associated damage in an animal model. AB - PURPOSE: To evaluate antioxidant effects of active vitamin D (calcitriol) against high-dose radioiodine (RAI) therapy-associated damage of lacrimal gland. MATERIALS AND METHODS: Wistar albino rats were used and divided into three groups randomly (n = 12/group). The first group was appointed as the negative control group and received no RAI or medication. The second group was appointed as the positive control group that only received 3 mCi/kg (111 MBq/kg) RAI via gastric gavage and the last group was the treatment group that received 3 mCi/kg RAI via same method and calcitriol (200 ng/kg/day) via intraperitoneal administration. Seven days after RAI administration, bilateral intraorbital (IG), extraorbital (EG) and Harderian (HG) glands were removed for the evaluations of histopathologic, tissue cytokine, total oxidant status (TOS) and total antioxidant status (TAS). RESULTS: RAI led to significant increase in tissue TOS, TNF-alpha, IL-6 levels and significant decrease in IL-10 and TAS levels (p < 0.05 for each). Addition of adjunctive calcitriol reversed all these parameters significantly (p < 0.05 for each).The following histopathologic parameters were seen more frequently in positive control group than the other groups: Abnormal lobular pattern, perivascular infiltration, periductal infiltration, lipofuscin like accumulation, acinar atrophy, periductal and periacinar fibrosis in all lacrimal gland types (p < 0.05), acinar fibrosis in EG (p = 0.049), periductal fibrosis in EG and HG (p = 0.049 and 0.038, respectively), abnormal cell outlines in EG and HG (p = 0.020 and 0.011, respectively) and variation in cell size in the IG and the HG (p = 0.003 and 0.049 respectively). CONCLUSIONS: RAI caused significant oxidative stress and inflammation in lacrimal glands. Vitamin D demonstrated potent anti-inflammatory, antioxidant and radio-protective effects on lacrimal glands in histopathologic, tissue cytokine and oxidant/antioxidant level evaluations. PMID- 30003811 TI - Assessment of Pronator Quadratus Repair Integrity Using Dynamic Ultrasonography Following Volar Plate Fixation for Distal Radius Fractures. AB - BACKGROUND: Previous work evaluating the pronator quadratus (PQ) muscle following volar plate fixation (VPF) of distal radius fractures (DRF) suggests that PQ repair often fails in the postoperative period. The purpose of this investigation was to assess PQ repair integrity following VPF of DRF using dynamic musculoskeletal ultrasonography. METHODS: Twenty adult patients who underwent VPF of DRF with repair of the PQ with a minimum follow-up of 3 months underwent bilateral dynamic wrist ultrasonography. The integrity of the PQ repair, wrist range of motion (ROM) and strength, and functional outcome scores were assessed. RESULTS: Mean patient age at the time of surgery was 59 +/- 14 years, and 50% underwent VPF of their dominant wrist. Patients were evaluated at a mean 9 +/- 4 months after VPF. All patients had an intact PQ repair. The volar plate was completely covered by the PQ in 55% of patients and was associated with a larger PQ when compared to patients with an incompletely covered volar plate ( P = .026). The flexor pollicis longus tendon was in contact with the volar plate in 20% of patients, with those patients demonstrating a trend toward significantly increased wrist flexion ( P = .053). No difference in ROM, strength, or outcome scores was noted among wrists with completely or incompletely covered volar plates. CONCLUSIONS: The PQ demonstrates substantial durability after repair following VPF. Wrist ROM, strength, and functional outcomes are similar in wrists in which the volar plate is completely or incompletely covered by the repaired PQ. PMID- 30003812 TI - Short Communication: Protective Efficacy of Broadly Neutralizing Antibody PGDM1400 Against HIV-1 Challenge in Humanized Mice. AB - Broadly neutralizing antibodies (bNAbs) such as PGDM1400 show promise as prophylactic and therapeutic agents against HIV-1. Human immune system mice were passively immunized with different doses of PGDM1400 and challenged 24 h later with a high dose of HIV-1JRCSF. We found that PGDM1400 provided protection against HIV-1 challenge in a concentration dependent manner and that the protective concentration in blood was ~75-fold higher than the in vitro 50% inhibitory concentration. The results demonstrate that PGDM1400 might be a promising component of strategies to prevent HIV-1 infection and provide support for the pursuit of vaccines that induce PGDM1400-like bNAbs. PMID- 30003814 TI - Oxidative stress and atrial fibrillation: an update. AB - Atrial remodelling involves electrophysiological and structural abnormalities that promote the development and perpetuation of atrial fibrillation. Experimental and clinical data indicate that oxidative stress is implicated in the pathophysiology of atrial remodelling. The mechanistic links between atrial remodelling and oxidative stress are complex with several underlying diseases and conditions may affect these pathways. Therefore, the development of antioxidant interventions in this setting remains difficult. Besides classical antioxidant compounds, several agents with pleiotropic effects, including anti-inflammatory and antioxidant, have been tested in experimental and clinical settings with variable results. Strategies applying conventional antioxidants in specific situations such as postoperative atrial fibrillation show beneficial effects, especially the two-step regimen of antioxidants combination. Of note, there are limited data on the development of strategies that target specific sources of reactive oxygen species implicated in atrial remodelling. Lifestyle, diet, and risk factors modification is a complementary promising approach. This updated review provides a concise and critical overview of all available data regarding oxidative stress and its modulation in atrial fibrillation. Future directions on this exciting field are also discussed. PMID- 30003813 TI - Urocortin 3 Gene Transfer Increases Function of the Failing Murine Heart. AB - Peptide infusions of peptides the corticotropin releasing factor family, including urocortin 2, stresscopin, and urocortin 3 (UCn3), have favorable acute effects in clinical heart failure (HF), but their short half-lives make them unsuitable for chronic therapy. This study asked whether UCn3 gene transfer, which provides sustained elevation of plasma UCn3 levels, increases the function of the failing heart. HF was induced by transmural left ventricular (LV) cryoinjury in mice. LV function was assessed 3 weeks later by echocardiography. Those with ejection fractions (EF) <40% received intravenous saline or intravenous adeno-associated virus type-8 encoding murine UCn3 (AAV8.mUCn3; 1.9 * 1013 genome copies/kg). Five weeks after randomization, repeat echocardiography, assessment of LV function (+dP/dt, -dP/dt), and quantification of Ca2+ transients and sarcomere shortening in isolated cardiac myocytes were conducted, and assessment of LV Ca2+ handling and stress proteins was performed. Three weeks after myocardial infarction, prior to treatment, EFs were reduced (mean 31%, from 63% in sham-operated animals). Mice randomized to receive UCn3 gene transfer showed increased plasma UCn3 (from 0.1 +/- 0.01 ng/mL in the saline group to 5.6 +/- 1.1 ng/mL; n = 12 each group; p < 0.0001). Compared to mice that received saline, UCn3 gene transfer was associated with higher values for EF (p = 0.0006); LV +dP/dt (p < 0.0001), and LV -dP/dt (p < 0.0001). Cardiac myocytes from mice that received UCn3 gene transfer showed higher peak Ca2+ transients (p = 0.0005), lower time constant of cytosolic Ca2+ decline (tau, p < 0.0001), and higher rates of sarcomere shortening (+dL/dt, p = 0.03) and lengthening (-dL/dt, p = 0.04). LV samples from mice that received UCn3 gene transfer contained higher levels of SERCA2a (p = 0.0004 vs. HF) and increased amounts of phosphorylated troponin I (p = 0.04 vs. HF). UCn3 gene transfer is associated with improved Ca2+ handling and LV function in mice with HF and reduced EF. PMID- 30003815 TI - The Epidemiology of Scapholunate Advanced Collapse. AB - BACKGROUND: Scapholunate advanced collapse (SLAC) is the most common pattern of wrist arthritis. Sparse data exist regarding the SLAC wrist pattern of arthritis. This study aimed to document the epidemiology of advanced SLAC in terms of patients' sociodemographics and possible association with trauma. METHODS: Sixty one patients with severe SLAC wrist were included. Baseline sociodemographic characteristics were reviewed. To evaluate the relationship to injury, this group of cases was compared with a control group of 61 patients with first carpometacarpal osteoarthritis (CMC OA). The following data were collected for both groups: age, gender, history of traumatic injury, history of manual labor, duration of symptoms, and dominant hand involvement. Pearson chi-square tests for categorical variables and independent samples t test for continuous variables were performed to determine differences between groups. RESULTS: Patients with SLAC wrist were more likely to be male (80.3% vs 31.1%; p<0.001), have a history of a traumatic injury (69.5% vs 25.9%, P < .001), have longer symptom duration (10.3 +/- 13.3 vs 3.5 +/- 2.5 years, P = .001), be involved in a manual labor job (49.0% vs 20.0%, P = .002), and be younger (53.1 +/- 10.4 vs 58.3 +/- 9.8; P = .006) compared with patients with CMC OA. There was no difference in dominant hand involvement (49.2% vs 53.3%; P = .571) between the groups. CONCLUSIONS: This study identified the characteristics of patients with advanced SLAC wrist. Compared with a control cohort of CMC OA, patients with SLAC wrist were more likely to be male, have a history of a traumatic injury, and be younger. PMID- 30003816 TI - Accuracy of Carpal Tunnel Injection: A Prospective Evaluation of 756 Patients. AB - BACKGROUND: Corticosteroid injection into the carpal tunnel is both a diagnostic test and a therapeutic modality in the treatment of carpal tunnel syndrome. Many injection techniques are described in the literature. Improper placement of injection may result in damage to neurovascular structures in the carpal canal or decrease efficacy of the test and/or therapy. The purpose of this study is to determine if carpal tunnel injection using anatomic landmarks is reproducible and safe. A review of the senior author's injection technique is presented. METHODS: Over 8 years, there were 756 attempted placements of a 25-gauge needle into the carpal tunnel in a simulated carpal tunnel injection prior to open carpal tunnel release. The needle was inserted at the wrist crease, just ulnar to palmaris longus. Open carpal tunnel release was subsequently performed, and position of the needle was recorded. RESULTS: In 572 patients (75.7%), the needle was found to be in the carpal tunnel without penetration of contents. The needle was in the carpal tunnel but piercing the median nerve in 66 attempts (8.7%). The carpal tunnel was missed in 118 attempts (15.6%). CONCLUSIONS: This is the largest study looking at accuracy of carpal tunnel injection using anatomic landmarks. Our injection accuracy (75.7%) is less than reported in previous studies, which note 82% to 100% accuracy using the same injection technique. This may indicate that carpal tunnel injection is less reliable than previously thought. Safety of carpal tunnel injection remains an important concern. The median nerve was penetrated in 8.7% of attempts. PMID- 30003817 TI - The epigenetic modification during the induction of Foxp3 with sodium butyrate. AB - CONTEXT: CD4 + CD25+ regulatory T (Treg) lymphocytes are critical for immune homeostasis. Foxp3 (Forkhead Box protein P3) is always considered as a marker of function and identities determination of Treg cells because of special occurring in Treg cell. People who lack Treg cells or have a low expression of Foxp3 gene will suffer fatal autoimmunity. Scientists are trying to use Treg cells as a treatment for autoimmune disease, such as systemic lupus erythematosus. OBJECTIVE: Our objective was to induce Foxp3 + CD4+ T cells from naive CD4 + T cells isolated from C57 mice spleen in vitro using stimuli that include the short chain fatty acid sodium butyrate. Furthermore, to explore the relationship between Foxp3+ T cells induction and epigenetic modification, by observing the changes of Foxp3, Ezh2 (Enhancer of Zeste Homolog 2) and phosphorylated Ezh2 in the induced Treg cells. MATERIALS AND METHODS: The naive CD4+ T cells were separated from C57 mice spleen by immunomagnetic separation. Anti-CD28, anti-CD3, IL-2, TGF-beta1, and sodium butyrate were added with proper concentration to induce Foxp3 expression during 72 hours. Then, we observed the effect of GSK126 (Ezh2 inhibitor) on the induction within the same over 72 hours duration. Then, western blot and Q-PCR were used to see the changes in gene/protein expression of Foxp3, Ezh2, and phosphorylated Ezh2. RESULTS: According to our results, group 3 that received full stimulus had a significant higher level of Foxp3 and Ezh2 expression (p < .05, comparing with group 1,2) and adding 5 mM sodium butyrate to the full stimulus (group 5) increased significantly the induction of Foxp3 and Ezh2 than control group and higher concentration group (p < .05, comparing with group 3,4, 6). The gene and protein expression of Foxp3 and Ezh2 both were enhanced in group 5 (p < .05 comparing with group 3). However, phosphorylated Ezh2 decreased in group 5 (p < .05 comparing with group3). Sodium butyrate removed part inhibition of GSK126, result in Foxp3 and Ezh2 expression (p < .05, p < .01, comparing with group7). CONCLUSION: In this study, we were able to transform CD4 + T cells into CD4 + Foxp3 + T cell by using stimulus like antibodies (anti-CD28, anti-CD3) and cytokines (IL-2, TGF-beta1). Sodium butyrate contributes to CD4 + Foxp3 + T cell induction in vitro and at an optimum concentration of 5 mM. Sodium butyrate promotes expression of Ezh2 and Fxop3 of T cells in vitro; in addition, to lowering relative expression of phosphorylated Ezh2 probably be influencing some pathways like PI3K-Akt. Epigenetic modification is also thought to take essential part into the upregulation of Foxp3 from naive CD4 + Tcells. PMID- 30003818 TI - Novel treatment strategies and drugs in development for cryptosporidiosis. AB - INTRODUCTION: Cryptosporidium is a protozoan pathogen that can cause diarrheal disease in healthy and immunosuppressed individuals, worldwide. Recent studies have highlighted the impact of cryptosporidiosis on children in resource-limited countries. Nitazoxanide is the only Food and Drug Administration approved treatment, but it is not consistently effective therapy for cryptosporidiosis in the most vulnerable populations. Areas covered: This review focused on recent published studies evaluating novel drugs and new compounds for the treatment of cryptosporidiosis. Expert commentary: Combinations of approved drugs have demonstrated some activity. Broad screens have demonstrated activity against Cryptosporidium for a number of available drugs, including statins and clofazimine, and the latter has advanced into clinical trials. Cryptosporidium calcium-dependent protein kinase 1 (CDPK1) has been identified as an attractive target for treatment, and bumped kinase inhibitors have been developed which inhibit CDPK1 and are active against Cryptosporidium growth both in vitro and in vivo. Inhibition of Plasmodium lipid kinase PI(4)K8 of Cryptosporidium by KDU731 greatly reduced oocyst shedding and improved diarrhea in calves with limited effects on the human PI(4)K. Another novel potent inhibitor MMV665917 was efficacious in mouse models with cidal activity against Cryptosporidium. Additional compounds have proved active in vitro. So far, only clofazimine has entered human trials. PMID- 30003819 TI - Tourniquet Use in Wide-Awake Carpal Tunnel Release. AB - BACKGROUND: Carpal tunnel syndrome is a common cause of upper extremity discomfort. Surgical release of the median nerve can be performed under general or local anesthetic, with or without a tourniquet. Wide-awake carpal tunnel release (CTR) (local anesthesia, no sedation) is gaining popularity. Tourniquet discomfort is a reported downside. This study reviews outcomes in wide-awake CTR and compares tourniquet versus no tourniquet use. METHODS: Wide-awake, open CTRs performed from February 2013 to April 2016 were retrospectively reviewed. Patients were divided into 2 cohorts: with and without tourniquet. Demographics, comorbidities, tobacco use, operative time, estimated blood loss, complications and outcomes were compared. RESULTS: A total of 304 CTRs were performed on 246 patients. The majority of patients were male (88.5%), and the mean age was 59.9 years. One hundred patients (32.9%) were diabetic, and 92 patients (30.2%) were taking antithrombotics. Seventy-five patients (24.7%) were smokers. A forearm tourniquet was used for 90 CTRs (29.6%). Mean operative time was 24.97 minutes with a tourniquet and 21.69 minutes without. Estimated blood loss was 3.16 mL with a tourniquet and 4.25 mL without. All other analyzed outcomes were not statistically significant. CONCLUSION: Operative time was statistically longer and estimated blood loss was statistically less with tourniquet use, but these findings are not clinically significant. This suggests that local anesthetic with epinephrine is a safe and effective alternative to tourniquet use in CTR. The overall rate of complications was low, and there were no major differences in postoperative outcomes between groups. PMID- 30003820 TI - Coenzyme Q10 serves to couple mitochondrial oxidative phosphorylation and fatty acid beta-oxidation, and attenuates NLRP3 inflammasome activation. AB - Multiple acyl-CoA dehydrogenase deficiency (MADD), an autosomal recessive metabolic disorder of fatty acid metabolism, is mostly caused by mutations in the ETFA, ETFB or ETFDH genes that result in dysfunctions in electron transfer flavoprotein (ETF) or electron transfer flavoprotein-ubiquinone dehydrogenase (ETFDH). In beta-oxidation, fatty acids are processed to generate acyl-CoA, which is oxidised by flavin adenine dinucleotide and transfers an electron to ETF and, through ETFDH, to mitochondrial respiratory complex III to trigger ATP synthesis. Coenzyme Q10 (CoQ10) is believed to be a potential treatment that produces symptom relief in some MADD patients. CoQ10 acts as a key regulator linking ETFDH and mitochondrial respiratory complex III. Our aim is to investigate the effectiveness of CoQ10 in serving in the ETF/ETFDH system to improve mitochondrial function and to reduce lipotoxicity. In this study, we used lymphoblastoid cells with an ETFDH mutation from MADD patients. ETFDH dysfunction caused insufficient beta-oxidation, leading to increasing lipid droplet and lipid peroxide accumulation. In contrast, supplementation with CoQ10 significantly recovered mitochondrial function and concurrently decreased the generation of reactive oxygen species and lipid peroxides, inhibited the accumulation of lipid droplets and the formation of the NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome, and reduced interleukin-1beta release and cell death. These results clarify the causal role of CoQ10 in coupling the electron transport chain with beta-oxidation, which may promote the development of CoQ10-directed therapies for MADD patients. PMID- 30003821 TI - The protective effect of berberine against lipopolysaccharide-induced abortion by modulation of inflammatory/immune responses. AB - OBJECTIVE: Berberine is an isoquinoline derivative alkaloid with anti inflammatory activity. In this study, we investigated the protective effects of berberine in prevention of LPS-induced abortion. MATERIALS AND METHODS: On the gestation day (GD) 9.5, the pregnant mice were injected with low, medium, and high doses of berberine or with PBS. After 4 h, berberine or PBS-pretreated mice were injected with LPS. On GD 11.5, blood samples and uterine tissues were collected from treated mice and percentage of abortion and serum levels of NO, TNF-alpha, IL-10, and IL12p70 were measured by macroscopic examination and sandwich ELISA, respectively. RESULTS: Our findings show that mice injected with berberine were resistant to LPS-induced abortion. We also found that this treatment prevents the reduction of IL-10 and the enhancement of NO, TNF-alpha, and IL-12p70 in LPS-treated pregnant mice. CONCLUSIONS: Taken together, our results suggest that berberine as an anti-inflammatory agent has protective effects on LPS-induced abortion by modulation of inflammatory/immune responses. PMID- 30003823 TI - Establishing Methods to Determine Clinically Relevant Bolus and Basal Rate Delivery Accuracy of Insulin Pumps. AB - BACKGROUND: Adequate testing of delivery accuracy of insulin pumps is under discussion. Especially for patch pumps, test settings are challenging. In addition, evaluation and presentation of accuracy results in a way that is reasonable and useful for clinicians, not only for technicians, is important. METHODS: Test setups based on IEC 60601-2-24 were used and, in addition, different setups for patch pumps were compared to identify an adequate alternative for pumps without external infusion set. These setups are applicable for both bolus and basal rate accuracy testing. In addition, evaluation procedures considering clinical relevance were compiled. RESULTS: A setup for patch pumps that provides reliable results could be realized. Evaluation of basal rate accuracy data should also consider the actual clinical use of insulin pumps and thus, deviating from IEC 60601-2-24, compose the whole measurement period without excluding the first 24 hours. In addition to the presentation using trumpet curves, accuracy of 1-hour windows should be evaluated and displayed. CONCLUSIONS: This article proposes an approach on how to test, evaluate, and present bolus and basal rate accuracy of insulin pumps from a clinical perspective. PMID- 30003822 TI - Heading and unintentional head impacts have opposing associations with Patient Reported Outcomes in amateur soccer players. AB - The effects of soccer-related head impacts, beyond overt concussions, on Patient Reported Outcomes (PROs) have not been explored to date. Generalized estimating equations were employed to determine the association between soccer-related head impacts (headers in the prior 2 weeks, unintentional head impacts in the prior 2 weeks, headers in the prior 12 months and lifetime concussions) on PROs including depression, anxiety, sleep disturbance and sleep impairment. Compared to players with no unintentional head impacts in the prior 2 weeks, players with one unintentional exposure reported more symptoms of anxiety (p = 0.002) and players with 2+ exposures reported more symptoms of depression (p = 0.006) and anxiety (p < 0.001). In contrast, players in the 3rd Quartile of 12 mo. headers reported less anxiety (p = 0.001), sleep disturbance (p = 0.002) and sleep impairment (p < 0.001) compared to those in the 1st quartile. Unintentional head impacts are associated with worse PROs while more headers are paradoxically associated with better PROs. PMID- 30003824 TI - An Association Between Maternal Intimate Partner Physical Violence and a Loaded Firearm in the Home. AB - A loaded firearm in the home increases the risk of firearm-related mortality. Furthermore, firearms are often used in fatal cases of intimate partner physical violence (IPPV) during pregnancy and in the postpartum period. Young children are often caught in the crossfire. Although firearms are more prevalent in homes with IPPV compared with homes without IPPV, little is known about the relationship between a loaded firearm and maternal IPPV. The objective was to determine whether maternal IPPV in the context of additional psychosocial factors is associated with a loaded firearm in the home. We analyzed population-based survey data (2004-2011) from the Centers for Disease Control and Prevention (CDC) Pregnancy Risk Assessment Monitoring System (PRAMS) in eight states for which questions on firearms were included. Chi-square analysis of independence was used to determine differences between mothers reporting both IPPV and a loaded firearm to mothers reporting IPPV only or a loaded firearm only. Multivariable weighted logistic regression examined the association between IPPV and presence of a loaded firearm in the home (adjusting for sociodemographic and psychosocial factors). Of the 43,845 mothers in our sample, 5.3% mothers reported storing a loaded firearm in the home and 6.7% reported maternal IPPV. Among mothers reporting IPPV, 5% also reported a loaded firearm. When adjusting for sociodemographic characteristics only, maternal IPPV was significantly associated with storing a loaded firearm in the home (adjusted odds ratio [aOR] = 1.39; 95% confidence interval [CI] = [1.01, 1.91]). However, after additionally considering psychosocial factors, there was no longer a statistically significant association between maternal IPPV and storing a loaded firearm in the home (aOR = 1.31; 95% CI = [0.93, 1.84]). Contextual factors play an important role in understanding the complex relationship between maternal IPPV and the presence of a loaded firearm in the home, and maternal IPPV should be considered in efforts to promote firearm safety. PMID- 30003826 TI - The Role of Dissolved Oxygen Levels on Human Mesenchymal Stem Cell Culture Success, Regulatory Compliance, and Therapeutic Potential. AB - Most cells in the human body, including human mesenchymal stem cells (hMSCs), have evolved to survive and function in a low physiological oxygen (O2) environment. Investigators have become increasingly aware of the effects of O2 levels on hMSC biology and culture and are mimicking the natural niche of these cells in vitro to improve cell culture yields. This presents many challenges in relation to hMSC identity and function and in the maintenance of a controlled O2 environment for cell culture. The aim of this review was to discuss an "hMSC checklist" as a guide to establishing which identity and potency assays to implement when studying hMSCs. The checklist includes markers, differentiation potential, proliferation and growth, attachment and migration, genomic stability, and paracrine activity. Evidence drawn from the current literature demonstrates that low O2 environments could improve most "hMSC checklist" attributes. However, there are substantial inconsistencies around both the terminology and the equipment used in low O2 studies. Therefore, "hypoxia" as a term and as a culture condition is discussed. The biology of short-term (acute) versus long-term (chronic) hypoxia is considered, and a nascent hypothesis to explain the behavior of hMSCs in long-term hypoxia is presented. It is hoped that by establishing an ongoing discourse and driving toward a regulatory recognizable "hMSC checklist," we may be better able to provide the patient population with safe and efficacious regenerative treatments. PMID- 30003825 TI - Dihydromyricetin improves vascular hyporesponsiveness in experimental sepsis via attenuating the over-excited MaxiK and KATP channels. AB - CONTEXT: Dihydromyricetin (DMY) has oxidation resistance, anti-inflammatory and free radical scavenging capabilities. The preventive effects of DMY for vascular hyporeactivity remain unclear. OBJECTIVE: This study investigates the preventive effects of DMY in vascular hyporeactivity. MATERIALS AND METHODS: The experimental sepsis was induced by transvenous administration of lipopolysaccharide (LPS) to Sprague-Dawley (SD) rats. DMY-treated rats received daily administration of DMY, 5 MUg/kg dissolved in DMSO through the tail vein for 7 days. The invasive mean arterial pressure (MAP) of the caudal ventral artery was measured. Dose-response curves for norepinephrine (NE, doses from 10-9 to 10 6 M) were obtained in isolated thoracic aorta in a cumulative manner. The function of MaxiK and KATP channels were investigated using whole-cell patch clamp recording. The Elisa was adopted to measure the serum concentration of NO, MDA, 3-NT, IL-1beta and TNF-alpha. RESULTS: The increased MAP in septic rats induced by vasopressor agents was smaller than that in control rats. However, the % of increased MAP induced by vasopressor agents was raised by DMY injection (NE: 20.4 +/- 8.495 vs. 15.16 +/- 5.195%; AVP: 14.05 +/- 2.459 vs. 9.583 +/- 2.982%, p < 0.05). The vascular hyporesponsiveness to NE (10-6 M) in vitro. was increased by 51% in LPS + DMY group compared with that in LPS + Con group (2.74 +/- 0.81 vs. 1.82 +/- 0.92 g, p < 0.05). Charybdotoxin (a potent MaxiK channel blocker) and glibenclamide (a KATP channel blocker) pretreatment, instead of 4 aminopyridine (4-AP) and BaCl2, could diminish the DMY-induced improvement of vasoconstrictor hyporeactivity (ChTX: 73.2 +/- 11.8 vs. 71.8 +/- 13.5%; Glib: 63.1 +/- 12.5 vs. 58.1 +/- 13.7%, p > 0.05). DMY blunted the highly sensitized MaxiK and KATP channels of arterial smooth muscle cells isolated from the thoracic aorta of LPS rats. DMY decreased the serum level of NO, MDA, IL-1beta and TNF-alpha, which had increased in LPS rats. DISCUSSION AND CONCLUSIONS: Our results indicate that DMY administration ameliorated the impaired contractility of the rat aorta in experimental sepsis. Such an effect is mediated by normalization of the over-excited MaxiK and KATP, channels possibly via oxidative stress inhibition. PMID- 30003827 TI - Economic impact of severe asthma in Spain: multicentre observational longitudinal study. AB - OBJECTIVE: Estimate the economic impact of severe asthma from the Spanish social perspective through the estimation of the associated annual direct and indirect costs. METHODS: Observational, longitudinal, retrospective study carried out in 20 Spanish secondary settings (Pulmonology and Allergy Services) among patients aged >=18, diagnosed with severe asthma according to European Respiratory Society/American Thoracic Society consensus and who have not experienced an exacerbation in the previous 2 months. Asthma-related healthcare resource utilization as well as asthma-related days off work were collected over a retrospective 12-month period from medical records review (inclusion period: June to November 2016). Total costs were calculated by multiplying the natural resource units used within 1 year by the corresponding unit cost. Costs were expressed in Euros for 2018. RESULTS: A total of 303 patients were included, mean age was 54 years old and 67% were women. There were 5.7 physician visits per patient (3.3 in secondary care). The most common pharmacologic treatment was fixed dose combination of inhaled corticosteroids/long-acting beta2-adrenergic agonists (96.7%), followed by leukotriene receptor antagonists (57.1%). 134 patients (44.2%) had at least one severe asthma exacerbation (mean: 1.9 exacerbation/patient), of whom 22 patients required hospitalization, with a mean hospital stay of 10.9 days/patient. Mean sick leave due to severe asthma was 9.1 days per patient per year. Mean annual direct cost (confidence interval 95%) was ?7472/patient (?6578-8612). The cost per exacerbation was ?1410/patient. When indirect costs were added (?1082/patient [?564-1987]), the total annual mean cost rose to ?8554/patient (?7411-10199). CONCLUSIONS: Taking the social perspective, the economic impact of severe asthma in Spain was estimated to be ?8554/patient/year. PMID- 30003828 TI - Nuclear factor-kappa B activation inhibits proliferation and promotes apoptosis of vascular smooth muscle cells. AB - OBJECTIVES: To investigate the role of nuclear factor-kappa B (NF-kappaB) performed in cell proliferation and apoptosis of vascular smooth muscle cells (VSMCs), and to assess the mechanisms. METHODS: Human aorta VSMCs were divided into control, NF-kappaB inhibitor, NF-kappaB overexpression + NF-kappaB inhibitor, control vector + NF-kappaB inhibitor, NF-kappaB overexpression, and control vector groups. NF-kappaB overexpression vector was constructed and transfected into VSMCs. Proliferation of VSMCs in each group was detected by 3 (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide. Apoptosis of VSMCs was detected by flow cytometry. The expression of NF-kappaB, FasL, and hypertension-related gene (HRG-1) was measured by Western blotting. RESULTS: NF kappaB overexpression vector was constructed correctly by restriction endonuclease, and the results showed that the activation of NF-kappaB could inhibit the proliferation of VSMCs. The results of flow cytometry also confirmed that NF-kappaB overexpression promoted apoptosis of VSMCs. Mechanically, NF kappaB overexpression could up-regulate the expression of FasL and HRG-1. CONCLUSIONS: NF-kappaB overexpression promotes apoptosis and inhibits cell proliferation of VSMCs. The mechanisms might be regulated by promoting FasL and HRG-1 expression. PMID- 30003830 TI - An initial validation of a new quality of life measure for adults with intellectual disability: The Mini-MANS-LD. AB - There is an appropriate increasing focus on the need to ensure the voices of people with intellectual disability are captured as part of assessing individuals' quality of life; however, there remains a lack of a consensus on ways to achieve this. This article describes the development of a self-report measure of quality of life for people with intellectual disability, the 'Mini MANS-LD', based on the concepts of Maslow's hierarchy of needs. Following use with 33 individuals with intellectual disability, the Mini-MANS-LD was found to have acceptable psychometric properties, including moderate congruent validity and acceptable internal consistency. Administrators' feedback suggested good acceptability and feasibility, and the measure was relatively quick to administer, easy to use and acceptable to service users. Despite a small sample size, this initial study suggests that the Mini-MANS-LD may present a conceptually relevant, feasible and acceptable self-report measure of quality of life for people with intellectual disability. PMID- 30003829 TI - Prognostic factors of ulcer healing and amputation-free survival in patients with critical limb ischemia. AB - OBJECTIVE: A multidisciplinary approach is required to treat critical limb ischemia. We determined the poor prognostic factors of ischemic ulcer healing after optimal arterial revascularization, and assessed the efficacy of the medication therapy using cilostazol, which is a selective inhibitor of phosphodiesterase 3. METHODS: In this retrospective, single-center, cohort study, 129 limbs that underwent infrainguinal arterial revascularization for Rutherford class 5 critical limb ischemia were reviewed. The primary end point was the ulcer healing time after arterial revascularization. The secondary end point was the amputation-free survival rate. RESULTS: Of the 129 limbs, endovascular therapy was performed in 69 limbs, and surgical reconstructive procedures were performed in 60 limbs for initial therapy. Complete ulcer healing was achieved in 95 limbs (74%). The median ulcer healing time was 90 days. In multivariate analysis, no cilostazol use significantly inhibited ulcer healing ( p = 0.0114). A white blood cell count >10,000 ( p = 0.0185), a major defect after debridement ( p = 0.0215), and endovascular therapy ( p = 0.0308) were significant poor prognostic factors for ulcer healing. Additionally, ischemic heart disease ( p < 0.0001), albumin levels <3 g/dl ( p = 0.0016), no cilostazol use ( p = 0.0078), and a major defect after debridement ( p = 0.0208) were significant poor prognostic factors for amputation-free survival rate. CONCLUSIONS: Ulcer healing within 90 days after arterial revascularization is impaired by no cilostazol use, a white blood cell count >10,000, a major defect after debridement, and endovascular therapy. Furthermore, cilostazol improves amputation-free survival rate in patients with critical limb ischemia. PMID- 30003831 TI - People with intellectual disabilities' experiences of psychological therapy: A systematic review and meta-ethnography. AB - The effectiveness of a range of psychological models adapted for use with people with intellectual disabilities has been well documented. A number of studies have used qualitative methods to examine people with intellectual disabilities' experiences of these adapted interventions. Such research is important for identifying service users' views on the helpful and challenging aspects of psychological interventions to ensure that they meet the needs of people with intellectual disabilities. To consolidate this research, a systematic review using a meta-ethnographic approach was undertaken. A systematic search identified 16 relevant studies. These studies were reviewed, critically appraised and key themes were extracted. Five key concepts were identified: adapting to therapy, the therapeutic environment, group dynamics, the therapeutic relationship and the impact of therapy on life. The need for further consideration of power differentials within the therapeutic relationship and further adaptations to ensure accessibility of therapy for people with intellectual disabilities is discussed. PMID- 30003832 TI - Hedgehog and Wnt Signaling Pathways Regulate Tail Regeneration. AB - Urodele amphibians have a tremendous capacity for the regeneration of appendages, including limb and tail, following injury. While studies have focused on the cellular and morphological changes during appendicular regeneration, the signaling mechanisms that govern these cytoarchitectural changes during the regenerative response are unclear. In this study, we describe the essential role of hedgehog (Hh) and Wnt signaling pathways following tail amputation in the newt. Quantitative PCR studies revealed that members of both the Hh and Wnt signaling pathways, including the following: shh, ihh, ptc-1, wnt-3a, beta catenin, axin2, frizzled (frzd)-1, and frzd-2 transcripts, were induced following injury. Continuous pharmacological-mediated inhibition of Hh signaling resulted in spike-like regenerates with no evidence of tissue patterning, whereas activation of Hh signaling enhanced the regenerative process. Pharmacological mediated temporal inhibition experiments demonstrated that the Hh-mediated patterning of the regenerating tail occurs early during regeneration and Hh signals are continuously required for proliferation of the blastemal progenitors. BrdU incorporation and PCNA immunohistochemical studies demonstrated that Hh signaling regulates the cellular proliferation of the blastemal cells following amputation. Similarly, Wnt inhibition resulted in perturbed regeneration, whereas its activation promoted tail regeneration. Using an inhibitor-activator strategy, we demonstrated that the Wnt pathway is likely to be upstream of the Hh pathway and together these signaling pathways function in a coordinated manner to facilitate tail regeneration. Mechanistically, the Wnt signaling pathway activated the Hh signaling pathway that included ihh and ptc-1 during the tail regenerative process. Collectively, our results demonstrate the absolute requirement of signaling pathways that are essential in the regulation of tail regeneration. PMID- 30003834 TI - Is Attitudinal Acceptance of Violence a Risk Factor? An Analysis of Domestic Violence Against Women in Pakistan. AB - Violence against women (VAW) is a grave problem in Pakistan, and women from all socioeconomic groups are vulnerable to domestic violence in varying degrees. It is argued that patriarchal definition of gender roles may reinforce the internalized inferiority of women. So, it may not be a mere coincidence that a large number of women in Pakistan justify VAW for various reasons. The objectives of this article are threefold: (a) to identify the drivers of VAW, (b) to see if women's attitudinal acceptance of violence is causally linked with observed violence against women, and (c) to see if attitudinal acceptance of violence mediates between the socioeconomic status of women and observed violence. We used data from the Pakistan Demographic and Health Survey (PDHS) 2012-13. The sample consisted of 3,265 ever married women aged between 15 and 49 years who were interviewed for domestic violence. We used multivariate logit regression analysis to identify the drivers of VAW and used the Karlson-Holm-Breen (KHB) method for mediation analysis. We found that women's attitudinal acceptance of violence, their childhood experience of violence in their parental household, the education of both husband and wife, and some occupation types significantly predicted their experience of spousal violence. In addition, we found that women's attitudinal acceptance of violence mediated the relationships between socioeconomic factors (education and wealth status) and VAW. The significance of the study lies in the fact that it highlights the need to modify the perceptions of violence through change in educational policy. Among multiple other factors, an increase in the economic status of women is an effective hedge against the risk of spousal violence. PMID- 30003833 TI - A cost-effectiveness analysis of reslizumab in the treatment of poorly controlled eosinophilic asthma. AB - INTRODUCTION: Poorly controlled severe eosinophilic asthma is difficult and costly to manage. Reslizumab, an add-on treatment for adults with severe eosinophilic asthma, reduces the number of exacerbations and improves the quality of life (QoL). The objective of this study was to evaluate the cost-effectiveness of reslizumab. METHODS: A Markov model was used to compare the cost-effectiveness of add-on reslizumab with the standard-of-care (SOC) from the US societal perspective over a five-year time horizon. Efficacy and safety inputs for the model were based on data from two clinical trials (NCT01287039 and NCT01285323). Other model inputs, including mortality rates, costs, and utility, were estimated from literature, the Centers for Disease Control and Prevention (CDC), the US Department of Veterans Affairs (VA) and the Centers for Medicare and Medicaid Services (CMS). One-way, threshold, and probabilistic sensitivity analyses (PSA) were performed. Adherence, treatment response, and the placebo effect were evaluated in separate scenario analyses. RESULTS: The base case incremental cost effectiveness ratio (ICER) was $697 403 (2017 USD) per quality-adjusted life years (QALYs). In the PSA, reslizumab becomes cost-effective in 50% of the iterations at a willingness-to-pay (WTP) threshold of $689 000. The model is most sensitive to the QoL improvement with reslizumab treatment in the one-way and threshold analyses. The response and adherence models had lower ICERs than the base model but still above $500 000. The ICER of the placebo effect model was $29 820. CONCLUSIONS: The improvement in QoL and exacerbation rates with reslizumab are associated with high costs, making reslizumab unlikely to be cost-effective at the $200 000 WTP threshold. PMID- 30003835 TI - Left ventricular torsion rate and the relation to right ventricular function in pediatric pulmonary arterial hypertension. AB - The right ventricle and left ventricle are physically coupled through the interventricular septum. Therefore, changes in the geometry and mechanics of one ventricle can directly affect the function of the other. In treatment of pediatric pulmonary arterial hypertension, the left ventricle is often overlooked, with clinical focus primarily on improving right ventricular function. Pediatric pulmonary arterial hypertension represents a disease distinct from adult pulmonary arterial hypertension based on etiology and survival rates. We aimed to assess left ventricular torsion rate in pediatric pulmonary arterial hypertension and its role in right ventricular dysfunction. Cardiac magnetic resonance images with tissue tagging were prospectively acquired for 18 pediatric pulmonary arterial hypertension (WHO class I) patients and 17 control subjects with no known cardiopulmonary disease. The pulmonary arterial hypertension cohort underwent cardiac magnetic resonance within 48 hours of clinically indicated right heart catheterization. Using right heart catheterization data, we computed single beat estimation of right ventricular end-systolic elastance (as a measure of right ventricular contractility) and ventricular vascular coupling ratio (end systolic elastance/arterial afterload). Left ventricular torsion rate was quantified from harmonic phase analysis of tagged cardiac magnetic resonance images. Ventricular and pulmonary pressures and pulmonary vascular resistance were derived from right heart catheterization data. Right ventricular ejection fraction and interventricular septum curvature were derived from cardiac magnetic resonance. Left ventricular torsion rate was significantly reduced in pulmonary arterial hypertension patients compared to control subjects (1.40 +/- 0.61 degrees vs. 3.02 +/- 1.47 degrees , P < 0.001). A decrease in left ventricular torsion rate was significantly correlated with a decrease in right ventricular contractility (end-systolic elastance) ( r = 0.61, P = 0.007), and an increase in right ventricular systolic pressure in pulmonary arterial hypertension kids ( r = -0.54, P = 0.021). In both pulmonary arterial hypertension and control subjects, left ventricular torsion rate correlated with right ventricular ejection fraction (controls r = 0.45, P = 0.034) (pulmonary arterial hypertension r = 0.57, P = 0.032). In the pulmonary arterial hypertension group, interventricular septum curvature demonstrated a strong direct relationship with right ventricular systolic pressure ( r = 0.7, P = 0.001) and inversely with left ventricular torsion rate ( r = -0.57, P = 0.013). Left ventricular torsion rate showed a direct relationship with ventricular vascular coupling ratio ( r = 0.54, P = 0.021), and an inverse relationship with mean pulmonary arterial pressure ( r = 0.60, P = 0.008), and pulmonary vascular resistance ( r = -0.47, P = 0.049). We conclude that in pediatric pulmonary arterial hypertension, reduced right ventricular contractility is associated with decreased left ventricular torsion rate. PMID- 30003838 TI - Propofol associated Brugada - like coved type electrogardiogram in a trauma patient with a fatal outcome. PMID- 30003837 TI - Is There Any Relationship Between Body Image Perception, Eating Disorders, and Muscle Dysmorphic Disorders in Male Bodybuilders? AB - Bodybuilding has increasingly become popular between males since male body shape has become a subject of interest in the last decades. Bodybuilders have desired to gain more muscle and paid attention to their body shape. Based on this purpose, they have string rules that include restrictive eating and excessive exercise program. Recent research has demonstrated that desiring more muscular body shape exhibits eating behavior problems and body dissatisfaction issues in bodybuilders. Limited research exists on the relationship between body dissatisfaction and eating disorders in male bodybuilders. The aim of this study was to determine the relationship between body image disturbance and eating disorders in 120 male bodybuilders. The Eating Attitude Test (EAT-40) was used to determine eating disorders, the Muscle Dysmorphia Disorder Inventory was used to determine bigorexia symptoms, and Bodybuilder Image Grid-Original (BIG O) and Scaled (BIG S) forms were used to detect the factors associated with body dissatisfaction. There was a positive relationship between Eating Attitude Test and Muscle Dysmorphia Disorder Inventory total scores. Eating Attitude Test was positively correlated with both fat and muscle dissatisfaction. Our results indicated that eating disorder psychopathology is positively related to body dissatisfaction and body dysmorphic disorders in male bodybuilders. PMID- 30003836 TI - Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism. AB - Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10 day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 +/- 1.1, 41.5 +/- 0.5 and 85.1 +/- 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted. PMID- 30003839 TI - Efficacy of brief guided self-help cognitive behavioral treatment for perfectionism in reducing perinatal depression and anxiety: a randomized controlled trial. AB - Perfectionism has been proposed as a transdiagnostic process that maintains depression and anxiety through shared cognitive and behavioral processes. The purpose of this study was to investigate the efficacy of a brief, guided cognitive behavioral treatment (CBT) for perfectionism delivered via a self-help booklet in reducing perfectionism and symptoms of depression and anxiety during the antenatal period. Pregnant women in their third trimester were randomly allocated to self-help (n = 30) or waitlist control (n = 30). There were significant reductions in perfectionism and symptoms for participants who received CBT for perfectionism from pre- to post-treatment, which were maintained at 3-month follow-up, while the waitlist control group demonstrated no significant changes. Path analysis demonstrated a significant indirect effect of treatment condition on post-treatment depression and anxiety scores via perfectionism, controlling for pre-treatment scores, suggesting changes in perfectionism were associated with decreases in symptoms. The findings suggest that it would be useful for future research with larger samples to further investigate the efficacy of CBT for perfectionism for perinatal depression and anxiety. PMID- 30003841 TI - Comparative evaluation of half-maximum inhibitory concentration and cytotoxicity of silver nanoparticles and multiwalled carbon nanotubes using buffalo bull spermatozoa as a cell model. AB - There is a dearth of information regarding the safety of silver nanoparticles (Ag NPs) and multiwalled carbon nanotubes (MWCNTs) with respect to their impact on human/animal health and the environment. This study aimed to determine the half maximum inhibitory concentration (IC50) of Ag NPs and MWCNTs by employing different doses and time interval combinations in buffalo bull spermatozoa. Semen samples containing 100 million spermatozoa each were incubated with 1, 10, 25, 50, 75 and 100 ug/mL of Ag NPs and MWCNTs at 37 degrees C for 30, 60 and 120 min. Sperm viability was monitored by the MTT assay and eosin-nigrosin staining followed by estimation of IC50 values using correlation-regression analysis. Spermatozoa treated with IC50 doses of Ag NPs and MWCNTs were also assessed for different sperm functionality parameters including oxidative stress and membrane integrity. These parameters were observed to be significantly affected in treated spermatozoa compared with the controls. We concluded that both nanomaterials showed cytotoxicity, mediated principally via oxidative stress. This work has provided valuable toxicological information that will serve as a benchmark for future studies aimed at safe use of nanomaterials. PMID- 30003840 TI - Chronic co-exposure to low levels of brominated flame retardants and heavy metals induces reproductive toxicity in zebrafish. AB - Brominated flame retardants (BFRs) and heavy metals (HMs) are two main types of pollutants in electronic waste recycling sites, which are also ubiquitously detectable in environmental media and human tissues. However, the adverse health effects of exposure to the mixture of these types of pollutants are unknown. In this study, we investigated the reproductive toxicity of a mixture of decabromodiphenyl ether (BDE-209), tetrabromobisphenol A, cadmium chloride, and lead acetate (PbAc) at the environmental relevant levels. Zebrafish were waterborne and exposed to chemical mixtures for one generation. The reproductive effects were evaluated for F0 adults and F1 offspring. Chemical residues were also analyzed in the exposed adults and their eggs at the end of exposure. Our findings demonstrated that exposure to the chemical mixture for 150 days had no effect on the survival rate of zebrafish, but it decreased body length and weight in females and increased body weight and condition factor in males. The mixture exposure resulted in a female-biased sex ratio in adults and decreased sperm density and motility in males and egg production in females. For the F1 offspring, decreased fertilization, delayed hatching, and increased malformation were found in all exposure groups. In conclusion, chronic co-exposure to BFRs and HMs at the environmental relevant levels not only affected growth, sex ratio, and sperm quantity/quality and egg production in adults but also reduced the reproductive success in the offspring, implying that multi-pollutants in the environmental media may pose a public health risk to other exposed organisms or human beings. PMID- 30003842 TI - Effect of developmental lead exposure on neurogenesis and cortical neuronal morphology in Wistar rats. AB - Lead (Pb) is a neurotoxic heavy metal that largely affects the developing nervous system. The present study examined the temporal effect of perinatal Pb exposure on neurogenesis and cortical neuronal morphology. Wistar pregnant rats were exposed to 0.5% lead acetate throughout pregnancy and to postnatal day (PD) 28. Offspring were grouped as gestational day (GD) 18 and 21 and PD 7, 14, 21, and 28 in both control and experimental groups. Brain sections were processed for immunohistological staining with anti-proliferating cell nuclear antigen (PCNA) or glial fibrillary acidic protein (GFAP). Brains from 14, 21, and 28 PDs pups were processed for Golgi-Cox stain. Pb exposure significantly increased PCNA positive nuclei in the ventricular and subventricular zones of the lateral ventricle at 18 and 21 GDs. Postnatally, the Pb-treated groups showed a significant decrease in PCNA-positivity and neuron density compared to control. This reduction was associated with an increase in damaged or apoptotic cell profiles in the experimental groups. At PD 21, there was a significant increase in GFAP immunoreactivity in Pb-exposed groups compared with control. Furthermore, the total apical and basal dendritic length of pyramidal neurons in layer 2-3 of the Golgi-Cox stained sensorimotor cortex was comparable in both control and Pb exposed groups. Spine density per 10 um was significantly increased at PD 14 and 21 on the apical dendrites but not basal dendrites of Pb-treated groups. In conclusion, developmental Pb exposure in rats induces a toxic effect on neurogenesis and on cortical neurons, which may be related to cognitive disabilities observed in children exposed to lead. PMID- 30003843 TI - Stone quarrying induces organ dysfunction and oxidative stress in Meriones libycus. AB - Exposure to heavy metal-containing dust arising from stone quarrying may cause severe health problems. The aim of this study was to evaluate the impact of stone quarrying in Riyadh (Saudi Arabia) on the Libyan jird Meriones libycus. Soil samples and jirds were collected from four sites located at different distances from the quarrying area. Soil from the first (500 m away from the quarry) and second (1800 m away) sites showed a significant increase in cadmium (Cd), lead (Pb), nickel (Ni), and vanadium (V) when compared with the reference site (38,000 m away). Jirds at these sites exhibited significant increases in liver, kidney, lung, and fur levels of Cd, Pb, Ni, and V. Serum transaminases, creatinine, and malondialdehyde (MDA) levels were significantly increased in jirds, whereas reduced glutathione (GSH) levels decreased. Liver, kidney, and lung tissues of jirds, collected from the first and second sites, showed significantly increased MDA and decreased GSH levels. Additionally, animals at both sites showed altered hematological parameters and several histopathological changes in their liver, kidney, and lung. Soil and animals at the third site (7300 m away) showed no significant changes. Thus, our study showed the impact and hazardous effects of quarrying on the liver, kidney, lung, and hemogram of M. libycus. These findings can provide scientific evaluation for studying the impact of quarrying on the workers and communities living close to the studied area. PMID- 30003845 TI - Promoting mental health of students living with HIV using appreciative inquiry. AB - Living with HIV poses many challenges. This is especially true for students living with HIV (SLHIV) within a university setting. The challenges faced by SLHIV makes it difficult for them to see new possibilities in living with the virus. The purpose of the study was to describe the experiences of being a student living with HIV and being a practitioner caring for them by using Appreciative Inquiry which incorporated individual interviews. A qualitative, exploratory, descriptive and contextual research design was applied in this study. Purposeful sampling was utilised to select participants in accordance with specific criteria. Individual interviews using the 4-D model of Appreciative Inquiry, were conducted with SLHIV and practitioners caring for them. The individual interviews were transcribed verbatim and analysed into themes and categories which were verified separately by an independent coder, who is experienced in qualitative research, and further confirmed by research participants through member checking. Themes and categories derived from the data were discussed, and the findings were positioned in terms of relevant literature and the results of similar studies. The study concluded that when SLHIV and practitioners caring for them, embarked on a journey of discovering their strengths in living with HIV and dealing with SLHIV respectively, they start to see new possibilities and potential to effect change to help students manage their HIV infection more effectively. PMID- 30003844 TI - Barriers to antiretroviral therapy initiation for HIV-positive children aged 2-18 months in Swaziland. AB - Although early antiretroviral therapy (ART) reduces HIV-related mortality in children by up to 75%, almost half of HIV-positive children younger than 1 year old in Swaziland do not initiate ART. This study was conducted to identify barriers to early ART initiation among HIV-positive infants. This was a case control study among HIV-positive infants, aged 2 to 18 months, who either did not initiate ART (cases), or initiated ART (controls), during 18 months after testing. Multivariable logistic regression showed that infants who visited the clinic every month, or every 2 months, were 5.78 and 6.20 times more likely to initiate ART than those who visited less often (OR 5.78, 95% CI 1.82-18.33 and OR 6.20, 95% CI 1.30-29.60 respectively). Children who lived <=30 and 31-60 minutes from the nearest clinic were 84% and 79% less likely respectively to initiate ART (OR 0.16, 95% CI 0.03-0.78 and OR 0.21, 95% CI 0.04-0.98) compared with those who lived more than 60 minutes away. Children who received immunisation after 6 months were 22.59 times more likely to initiate ART (OR 22.59, 95% CI 7.00-21.72) than those who did not. Infants of caregivers who had excellent or good relationships with their healthcare provider were 4.32 times more likely to initiate ART (OR 4.32, 95% CI 1.01-18.59) than those of caregivers who had average or poor relationships with healthcare providers. The significant predictors of ART initiation identified in this study should be regarded as priority areas for intervention among HIV-positive women in Swaziland. PMID- 30003846 TI - "Bringing back hope": how faith-based responses to HIV and AIDS differ from secular responses. AB - This article investigates an assertion by faith-based organisations (FBO) that spirituality is the defining feature of their HIV and AIDS interventions. It is based on interviews with 24 people working on the issue of HIV and AIDS in churches or church organisations in Johannesburg, Rustenburg, Pretoria, Durban, Pietermaritzburg, and Cape Town. The article critically assesses the perceived difference between faith-based responses to HIV and AIDS and secular responses, including government programmes, in relation to the research literature on spirituality. After introducing the article, the argument begins with an exploration of the literature on churches and HIV and AIDS, outlining a gap which the article seeks to fill. The article then discusses the methods used for interviewing and analysing interview material. This is followed by religious leaders' own comments on how faith-based responses to HIV and AIDS differ from secular responses. The article concludes with a discussion which brings the literature to bear on the interview excerpts and then outlines the implications of decreased international funding for the HIV and AIDS programmes operated by the Anglican and Catholic churches, for example, a likely reduction in the accompaniment and monitoring of those who are HIV-positive. PMID- 30003847 TI - A critical participatory pedagogical approach to enabling life orientation students to develop social literacy through HIV education. AB - HIV education is an important component of the life orientation curriculum, since an intersectional understanding of HIV provides an entry point to appreciate the interrelatedness of various social injustices. Yet, our interaction with predominantly white and privileged pre-service life orientation students led us to believe that they did not perceive HIV education as something that was relevant to their personal or professional lives. Their rigid, stigmatising belief systems and "othering" attitudes prevented them from embodying the inclusive and life-enhancing values that life orientation is supposed to develop. This paper explains how we used iterative cycles of reflection and action to enable 86 student teachers of life orientation to interrogate their misconceptions about HIV education and its applicability for their professional and personal contexts. Students were able to acknowledge their prejudices and privileges, which in turn created a willingness to engage with HIV education and to embody their learning to bring about change in their daily interactions. The knowledge generated from this study indicates how a critical, participatory pedagogical approach to HIV education can develop the social literacy of students to enable them to live out the life-enhancing values that underpin the life orientation curriculum. PMID- 30003848 TI - Physical activity, social support and socio-economic status amongst persons living with HIV and AIDS: a review. AB - Physical activity can be used for the effective and comprehensive management of HIV and AIDS. Social support and socio-economic status (SES) are two factors that shape physical activity behaviours. Individuals of low SES carry a disproportionate burden of the HIV and AIDS epidemic. In addition, limited resources constitute socio-ecological barriers predisposing such individuals to physical inactivity. The purpose of this narrative review is to examine the available literature on physical activity, social support and SES and to generate recommendations for designing and implementing physical activity interventions targeting people living with HIV and AIDS (PLWHA) of low SES. The review used literature from Google, Google Scholar and PubMed on physical activity of PLWHA, social support for physical activity, and SES and physical activity. Qualitative and quantitative studies in English were included from 1970 to 2016. The results show that social support plays a major role in promoting physical activity and counteracting the barriers to PA in PLWHA of low SES. The results on the role of social support and the influence of SES are integrated to help design appropriate physical activity interventions for PLWHA of low SES. Well-designed interventions should utilise social support and be contextualised for PLWHA of low SES, whose living conditions present multiple barriers to physical activity. PMID- 30003849 TI - Provider understandings of and attitudes towards integration: Implementing an HIV and sexual and reproductive health service integration model, South Africa. AB - In South Africa, a lack of integration between sexual and reproductive health (SRH) and HIV services has led to lost opportunities in the treatment cascade. In a context of high HIV, tuberculosis (TB) and unplanned pregnancies, a model for integrating SRH and HIV services was implemented in a hospital and six feeder clinics in KwaZulu-Natal, South Africa. Changes in healthcare provider knowledge, attitudes and understandings were explored following model implementation. Baseline data were collected via focus group discussions (FGDs) and a cross sectional survey, and were used to inform the development of a model for integrating SRH and HIV services. Following the implementation of the model, an endline survey was conducted to explore any changes. Four FGDs were conducted with healthcare providers at study facilities. A total of 46 providers participated in the baseline survey, and 44 in the endline survey. Qualitative data were thematically analysed using NVivo 11, and quantitative data were descriptively analysed using SPSS 24. The understanding of integration improved by endline. Integration of services was considered important for reducing stigma and increasing access to and improving quality of care. Concerns raised were that integration would increase workload and time per client. Physical structure of facilities was not always conducive to referral or integration. Perceived benefits of integration and actual integration of services improved between baseline and endline. Enhanced understanding of integration and increased levels of reported integration over time imply that providers are more aware, suggesting that the model was effective. Provider perspectives and understandings are important for the successful integration of services. This integration model is relevant and useful to inform training and mentoring of providers, as well as to provide recommendations for policy implementation. PMID- 30003850 TI - Poverty as a barrier to antiretroviral therapy access for people living with HIV/AIDS in Kenya. AB - Understanding barriers to access to essential health services is critical for devising effective strategies to improve access and align such strategies with national health and development policy objectives. However, while considerable empirical evidence exists on correlates of HIV prevalence and populations at risk of contracting HIV, there is very little such evidence on access to antiretroviral therapy. This paper addresses this gap through a cross-sectional analysis of coverage of antiretroviral therapy and its correlates across 47 counties in Kenya. It considers health-sector and social factors, and applying instrumental variables to address error-in-variables and reverse-causality issues regarding HIV prevalence. Poverty was the most robust and - statistically and substantially - significant determinant of treatment coverage. The gap in treatment coverage between the poorest and richest counties amounted to about 40 percentage points and has not narrowed between 2012 and 2015. Health sector capacities independently played a role and exacerbated the poverty gap. For Kenya, the results suggest that policies on expanding treatment access need to be differentiated across counties to greatest effect and to align the HIV/AIDS response with national health and social policy objectives. Regarding global HIV/AIDS policies, the findings suggest a need to recognise "people left behind" owing to socio-economic and specifically poverty-related barriers to access to services. PMID- 30003851 TI - A pilot randomized controlled trial on the impact of text messaging check-ins and a web-based asthma action plan versus a written action plan on asthma exacerbations. AB - OBJECTIVE: We compared electronic asthma action plans (eAAP) supported by automated text messaging service (SMS) with written asthma action plans (AAP) on assessing acceptability and asthma control improvement. We hypothesized that the patients in eAAP group would have more improvements in their quality of life, asthma control and decreased asthma exacerbations. METHODS: Patients with physician-diagnosed asthma having at least one asthma exacerbation in the previous 12 months were recruited. Participants received individualized action plans and were randomly assigned into either the intervention (eAAP) or control (AAP) group. Intervention participants received weekly SMS, triggering assessment of asthma control and viewing their eAAP. We assessed applicability of Telehealth platform on asthma exacerbations, asthma control, and quality of life over a 12 month period. RESULTS: 106 patients were enrolled (eAAP = 52, AAP = 54). The cumulative response rate to all weekly SMS check-ins was 68.4%. Overall, 28% of patients checked into their eAAP during the intervention period. There were fewer exacerbations in the eAAP group (18%) compared to the AAP group (RR = 0.82 [95%CI 0.49, 1.36]), (P = 0.44). The mean scores for asthma control and quality of life were higher in the eAAP group compared to the AAP group by 4% (RR = 1.04 [95%CI 0.83, 1.30]), (P = 0.73) and 5.5% (RR = 1.06 [95%CI 0.87, 1.28]), (P = 0.59), respectively, but were not statistically significant. CONCLUSIONS: We demonstrated that the eAAP presented improved asthma control outcomes, but as expected the sample size was inadequate to show a significant difference, but based on this pilot study we plan a larger appropriately powered randomized controlled trial (RCT). PMID- 30003853 TI - "Micromanaging" Glioblastoma Multiforme: The Potential of MicroRNAs, Circular RNAs, and the Hippo Pathway as Novel Treatment Strategies. PMID- 30003852 TI - Association of vitamin D deficiency with an increased risk of late-onset neonatal sepsis. AB - BACKGROUND: Vitamin D deficiency in mothers and neonates is being recognised increasingly as a leading cause of many adverse health effects in the newborn infant, including sepsis. METHODS: A prospective observational study was conducted at a tertiary care Paediatric teaching hospital in northern India to assess vitamin D deficiency as a possible risk factor for late-onset sepsis (LOS) in term and late preterm neonates and also to examine the correlation between maternal and infant vitamin D levels during the neonatal period. Late-onset sepsis (LOS) was defined as the development of signs and symptoms of severe sepsis after 72 h of life and a positive sepsis screen. All term and late preterm neonates admitted with LOS between September 2015 and February 2016 who had not been previously admitted for >48 h and had not been prescribed antibiotics or vitamin D were included in the study. Matched controls were recruited from otherwise healthy neonates admitted with physiological hyperbilirubinaemia. Serum 25(OH) vitamin D was assessed in neonates in both groups and their mothers. RESULTS: A total of 421 neonates were admitted to the neonatal intensive care unit during the study period, 120 of whom satisfied the inclusion criteria, and 60 were recruited as cases. Sixty neonates were recruited as controls who were similar in gender, gestational age, age at admission and anthropometry. The study group had significantly lower mean (SD) vitamin D levels [15.37 ng/ml (10.0)] than the control group [21.37 ng/ml (9.53)] (p = 0.001). The odds ratio was 1.7 (95% CI 0.52-5.51) for LOS in vitamin D-deficient neonates. Mothers of septic neonates also had significantly lower mean (SD) vitamin D levels [17.87 (11.89)] than the mothers of non-septic neonates [23.65 ng/ml (9.55)] (p = 0.004). Maternal vitamin D levels strongly correlated to neonatal vitamin D levels in both groups. CONCLUSION: Neonates with vitamin D deficiency are at greater risk of LOS than those with sufficient vitamin D levels. PMID- 30003854 TI - Osteoarthritis - Current Insights in Pathogenesis, Diagnosis and Treatment. PMID- 30003855 TI - Interventional Cardiologist Approach to Cardiac Arrest. PMID- 30003856 TI - Preoperative albumin level serves as a predictor for postoperative pulmonary complications following elective laparoscopic gastrectomy. AB - OBJECTIVE: Postoperative pulmonary complications (PPCs) can contribute to increased mortality and prolonged hospital stay in surgical patients with gastric cancer (GC). This study aimed to investigate potential risk factors for PPCs in elderly GC patients following elective laparoscopic gastrectomy. METHODS: Eligible consecutive elderly GC patients (aged over 65 years) who were scheduled to undergo elective laparoscopic gastrectomy were enrolled in this study. The demographic, clinicopathological characteristics and laboratory variables were compared in patients with or without PPCs within postoperative 30 days. Risk factors for PPCs were analyzed by multiple logistic regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: 35 of all the 262 enrolled patients have developed PPCs with an incidence of 13.4%. Age, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), forced expiratory volume in one second/ forced vital capacity (FEV1/FVC) ratio, duration of operation, hemoglobin, albumin and C-reactive protein (CRP) were potential risk factors for PPCs by univariate analysis. The preoperative albumin level was the only independent risk factor for PPCs (OR: 1.15, 95%CI: 1.06-1.28, P=0.011) by multiple logistic regression analysis. Preoperative albumin level was a predictor for PPCs with an area under the curve (AUC) of 0.728 and a cut-off value of 33.8 mg/dl (specificity: 54.19%, sensitivity: 77.14%, P<0.001). CONCLUSIONS: Preoperative albumin level was an independent risk factor for PPCs in elderly GC patients after elective laparoscopic gastrectomy. PMID- 30003857 TI - Diagnostic Biomarkers of Epilepsy. AB - BACKGROUND: Diagnostic biomarkers of epilepsy are objectively measurable variables associated with the development of epilepsy or the propensity to generate seizures. Identification of biomarkers could be helpful for differential diagnosis and for tailored therapeutic approaches. OBJECTIVE: This review focuses on diagnostic biomarkers of epilepsy, including genetic, serological, neuroimaging and electrophysiological variables. METHODS: References were mainly identified through PubMed search until December 2017 and backtracking of references in pertinent studies. RESULTS: Several promising diagnostic biomarkers of epilepsy exist, with causative value or predicting liability to develop seizures after acquired brain injuries. Short non-coding RNAs are deregulated in serum and cerebral tissue of epilepsy subjects: these molecules are promising diagnostic biomarkers, being easy to assess and reproducible. Advanced imaging techniques may allow identification of subtle epileptogenic lesions, often with prognostic value. Novel electrophysiological biomarkers of epilepsy include perturbed cortical connectivity and excitability induced by transcranial magnetic stimulation, as well as high-frequency oscillations detected by intracranial and scalp electroencephalographic recordings. Finally, serological biomarkers may support the differential diagnosis between epileptic seizures and non-epileptic events. CONCLUSION: Ongoing research on diagnostic biomarkers of epilepsy is promising and future preclinical and clinical studies are warranted. PMID- 30003858 TI - The Drug Combination of SB202190 and SP600125 Significantly Inhibit the Growth and Metastasis of Olaparib-resistant Ovarian Cancer Cell. AB - BACKGROUND & OBJECTIVE: Many targeted ovarian cancer patients are resistant to olaparib treatment. Here we seek to understand the underlying molecular events and search for potential combinational therapeutics to surmount the intrinsic olaparib resistance in human ovarian cancer. METHODS: The cytotoxicity was determined by the MTT assay and cell viability was measured using Cell Counting Kit-8 (CCK-8). Protein expressions of ERK, P38, JNK, ERK5, LC3, N-CADHERIN, alpha SMA were determined by western blotting. The invasion capacity was evaluated by the transwell chamber. Autophagy flux was monitored by the LC3 puncta formation. The epithelial-mesenchymal transition (EMT) markers were profiled by immunoblotting detection. The in vivo tumor progression was determined by xenograft mice model. RESULTS: The olaparib-resistant cell lines were successfully generated in both SKOV3 and A2780 cells. The proliferative index was significantly higher in resistant cells in comparison with sensitive counterparts in the presence of olaparib. Both P38 and JNK were up-regulated in olaparib resistant cells. The combinational treatment with P38-specific inhibitor SB202190 and JUN-specific inhibitor SP600125 significantly suppressed cell growth and migration, which was further attributed to the induction of autophagy flux and inhibition of EMT processing. We further consolidated the anti-tumor activities of SB202190 and SP600125 in xenograft mice. CONCLUSION: Our data suggested that aberrant over-expression of P38 and JNK is causally linked to the olaparib resistance in ovarian cancer. Combination of P38 and JUN inhibitors demonstrated significant anti-tumor activity both in vitro and in vivo. Our study highlighted the potential therapeutic value of Mitogen-Activated Protein Kinase (MAPK) inhibitors in olaparib-resistant human ovarian cancer. PMID- 30003859 TI - The Role of Sensing Peptides in the Cross-talk between Microbiota and Human Cancer Cells. AB - The epithelium of the gastrointestinal tract is densely populated by complex microbial communities which exert both local and distant effects in the human body with relevant consequences on the metabolic status, immune system and overall health. A dynamic equilibrium between the many bacterial species and the host intestinal epithelium is maintained through the release of a large number of small molecules and peptides. The quorum sensing peptides are mainly secreted by Gram-positive bacteria and are able to "communicate" with human cells. Some sensing peptides have shown to promote angiogenesis, tumor cell invasion and metastasis of colon cancer as well as of breast cancer cells. On the other hand, quorum sensing cyclodipeptides produced by bacteria and fungi have shown significant antitumor activities. In this review, we summarize the available data on the pro-tumor activities of quorum sensing peptides and the anti-cancer functions of cyclodipeptides in the human malignancies. PMID- 30003860 TI - Statins: They are Really All the Same? PMID- 30003861 TI - Development of QSPR Strategy for the Solubility Prediction. AB - INTRODUCTION: QSPR modelling is one of the major computational tools used to correlate molecular characteristics with physiochemical properties of molecules. In present work, QSPR models are formed using AIC and VIF multicollinearity indicators for descriptors selection taking solubility data of Paclitaxel prodrugs. Geometry optimization of these Paclitaxel prodrugs was performed at the PM6 and AM1levels using Gaussian software. METHODS: Four descriptor groups such as 2D Autocorrelation, CATS_3D, WHIM, GETAWAY provided initial QSPR models with moderate accuracy for both the optimized geometry datasets. The descriptors from two descriptor-groups which were showing reasonable correlation (Q2) were combined to form improved models. The selection of descriptors was performed in multiple steps to determine optimal models which contain five and four descriptors for PM6 and AM1 optimized geometry datasets respectively. The R2 & Q2 values are 0.86 & 0.83 and 0.87 & 0.86 for PM6 and AM1 geometries respectively. RESULTS: The models formed shows comparable results with the earlier reported results. The proposed protocol is also implemented on Huuskonen small dataset and the final QSPR model contains only two descriptors. On this smaller dataset, the QSPR model gives the R2 and Q2 values 0.87 and 0.85, respectively which is comparable to the results of Paclitaxel prodrugs. CONCLUSION: Our approach can be applicable to different datasets and it can assist the synthesis of molecule with better solubility. These QSPR models can be implemented for predicting the aqueous solubility of unknown Paclitaxel prodrugs. PMID- 30003862 TI - Therapeutic Targeting of Chemokines and Chemokine Receptors in Multiple Sclerosis: Opportunities and Challenges. AB - BACKGROUND & OBJECTIVE: Multiple sclerosis is an autoimmune demyelinating disease of the human central nervous system with still unknown etiology. Infiltration, accumulation and activation of autoreactive T cells, macrophages and other inflammatory immune cells in the CNS are the crucial steps in MS neuropathogenesis and development. Chemokines and their receptors play the main role in the attraction of the pathogenic cells into the CNS in MS. Specific chemokines and chemokine receptors are up-regulated in the actively demyelinating lesions and cerebrospinal fluid of MS patients. Many medical studies investigated how changes in levels or activities of chemokines and their receptors are implicated in leukocyte migration into CNS and consequently causing MS. These chemokines and their receptors are under intense focus to introduce new therapeutic strategies for MS. CONCLUSION: The aim of this review is to summarize previous findings on the relationship between chemokines network and MS development. Furthermore, opportunities and challenges in the chemokine system intervention as a potential therapeutic target for the treatment of MS will be outlined. PMID- 30003863 TI - Preparation, Characterization and In Vivo Assessment of Repaglinide Nanosuspension for Oral Bioavailability Improvement. AB - AIM AND BACKGROUND: The objective of the study was to improve the bioavailability of poorly soluble repaglinide (RPG) by preparing nanosuspension with poloxamer 188 using high pressure homogenization (HPH). The recent patents on nanocrystals (US20150337006A1) facilitated selection of drug and polymer. METHODS: Suspensions containing dissimilar sized particles were prepared by ultrasonication and HPH. The prepared aqueous suspensions were lyophilized and then characterized. Further, the dried aqueous suspensions were evaluated for drug content, solubility, in vitro dissolution, oral bioavailability study and stability study. RESULTS: RPG nanoparticles size, polydispersity index (PDI) and zeta potential was found to be 280.8 +/- 15 nm, 0.279 +/- 0.04 and - 25.81 +/- 1.6mV respectively. DSC and XRD results showed that RPG particles in aqueous suspensions were present in a crystalline state; however, RPG nanoparticles exhibited decreased lattice energy due to smaller particle size. Nanoparticles prepared by HPH exhibited significant improvements in solubility and dissolution rate. Oral bioavailability was found to be enhanced by 1.93 fold in comparison with that of plain RPG. The nanosuspension was found to be stable when stored at 50C +/- 30C. CONCLUSION: The outcomes of the study revealed significant enhancement in dissolution rate and oral bioavailability of RPG due to size reduction to nano range by HPH. PMID- 30003864 TI - Antimicrobial Resistance in Mycoplasma spp. AB - Mycoplasmas are intrinsically resistant to antimicrobials targeting the cell wall (fosfomycin, glycopeptides, or beta-lactam antibiotics) and to sulfonamides, first-generation quinolones, trimethoprim, polymixins, and rifampicin. The antibiotics most frequently used to control mycoplasmal infections in animals are macrolides and tetracyclines. Lincosamides, fluoroquinolones, pleuromutilins, phenicols, and aminoglycosides can also be active. Standardization of methods used for determination of susceptibility levels is difficult since no quality control strains are available and because of species-specific growth requirements. Reduced susceptibility levels or resistances to several families of antimicrobials have been reported in field isolates of pathogenic Mycoplasma species of major veterinary interest: M. gallisepticum and M. synoviae in poultry; M. hyopneumoniae, M. hyorhinis, and M. hyosynoviae in swine; M. bovis in cattle; and M. agalactiae in small ruminants. The highest resistances are observed for macrolides, followed by tetracyclines. Most strains remain susceptible to fluoroquinolones. Pleuromutilins are the most effective antibiotics in vitro. Resistance frequencies vary according to the Mycoplasma species but also according to the countries or groups of animals from which the samples were taken. Point mutations in the target genes of different antimicrobials have been identified in resistant field isolates, in vitro selected mutants, or strains reisolated after an experimental infection followed by one or several treatments: DNA-gyrase and topoisomerase IV for fluoroquinolones; 23S rRNA for macrolides, lincosamides, pleuromutilins, and amphenicols; 16S rRNAs for tetracyclines and aminoglycosides. Further work should be carried out to determine and harmonize specific breakpoints for animal mycoplasmas so that in vitro information can be used to provide advice on selection of in vivo treatments. PMID- 30003865 TI - Genes within Genes in Bacterial Genomes. AB - Genetic coding in bacteria largely operates via the "one gene-one protein" paradigm. However, the peculiarities of the mRNA structure, the versatility of the genetic code, and the dynamic nature of translation sometimes allow organisms to deviate from the standard rules of protein encoding. Bacteria can use several unorthodox modes of translation to express more than one protein from a single mRNA cistron. One such alternative path is the use of additional translation initiation sites within the gene. Proteins whose translation is initiated at different start sites within the same reading frame will differ in their N termini but will have identical C-terminal segments. On the other hand, alternative initiation of translation in a register different from the frame dictated by the primary start codon will yield a protein whose sequence is entirely different from the one encoded in the main frame. The use of internal mRNA codons as translation start sites is controlled by the nucleotide sequence and the mRNA folding. The proteins of the alternative proteome generated via the "genes-within-genes" strategy may carry important functions. In this review, we summarize the currently known examples of bacterial genes encoding more than one protein due to the utilization of additional translation start sites and discuss the known or proposed functions of the alternative polypeptides in relation to the main protein product of the gene. We also discuss recent proteome- and genome wide approaches that will allow the discovery of novel translation initiation sites in a systematic fashion. PMID- 30003867 TI - Regulatory RNAs in Virulence and Host-Microbe Interactions. AB - Bacterial regulatory RNAs are key players in adaptation to changing environmental conditions and response to diverse cellular stresses. However, while regulatory RNAs of bacterial pathogens have been intensely studied under defined conditions in vitro, characterization of their role during the infection of eukaryotic host organisms is lagging behind. This review summarizes our current understanding of the contribution of the different classes of regulatory RNAs and RNA-binding proteins to bacterial virulence and illustrates their role in infection by reviewing the mechanisms of some prominent representatives of each class. Emerging technologies are described that bear great potential for global, unbiased studies of virulence-related RNAs in bacterial model and nonmodel pathogens in the future. The review concludes by deducing common principles of RNA-mediated gene expression control of virulence programs in different pathogens, and by defining important open questions for upcoming research in the field. PMID- 30003866 TI - Antimicrobial Resistance in Escherichia coli. AB - Multidrug resistance in Escherichia coli has become a worrying issue that is increasingly observed in human but also in veterinary medicine worldwide. E. coli is intrinsically susceptible to almost all clinically relevant antimicrobial agents, but this bacterial species has a great capacity to accumulate resistance genes, mostly through horizontal gene transfer. The most problematic mechanisms in E. coli correspond to the acquisition of genes coding for extended-spectrum beta-lactamases (conferring resistance to broad-spectrum cephalosporins), carbapenemases (conferring resistance to carbapenems), 16S rRNA methylases (conferring pan-resistance to aminoglycosides), plasmid-mediated quinolone resistance (PMQR) genes (conferring resistance to [fluoro]quinolones), and mcr genes (conferring resistance to polymyxins). Although the spread of carbapenemase genes has been mainly recognized in the human sector but poorly recognized in animals, colistin resistance in E. coli seems rather to be related to the use of colistin in veterinary medicine on a global scale. For the other resistance traits, their cross-transfer between the human and animal sectors still remains controversial even though genomic investigations indicate that extended-spectrum beta-lactamase producers encountered in animals are distinct from those affecting humans. In addition, E. coli of animal origin often also show resistances to other-mostly older-antimicrobial agents, including tetracyclines, phenicols, sulfonamides, trimethoprim, and fosfomycin. Plasmids, especially multiresistance plasmids, but also other mobile genetic elements, such as transposons and gene cassettes in class 1 and class 2 integrons, seem to play a major role in the dissemination of resistance genes. Of note, coselection and persistence of resistances to critically important antimicrobial agents in human medicine also occurs through the massive use of antimicrobial agents in veterinary medicine, such as tetracyclines or sulfonamides, as long as all those determinants are located on the same genetic elements. PMID- 30003868 TI - Sponges and Predators in the Small RNA World. AB - Most noncoding small RNAs (sRNAs) that regulate gene expression do so by base pairing with mRNAs, affecting their translation and/or stability. Regulators as evolutionarily distant as the trans-encoded sRNAs of bacteria and the microRNAs (miRNAs) of higher eukaryotes share the property of targeting short sequence segments that occur in multiple copies in bacterial and eukaryotic transcriptomes. This target promiscuity has major implications for sRNA function. On the one hand, it allows the sRNA to coordinately control several different targets and thus be at the center of regulatory networks. On the other hand, it allows the existence of target mimics or decoys that divert the sRNA/miRNA away from bona fide targets and thus serve as mechanisms to regulate the regulator. In addition, by competing for pairing with the same sRNA, bona fide targets establish a cross talk that can impact on each other's expression levels. Here we review evidence that target mimicry and competition are important components of the regulatory architecture of bacterial sRNA networks. PMID- 30003869 TI - Present and Future Surveillance of Antimicrobial Resistance in Animals: Principles and Practices. AB - There is broad consensus internationally that surveillance of the levels of antimicrobial resistance (AMR) occurring in various systems underpins strategies to address the issue. The key reasons for surveillance of resistance are to determine (i) the size of the problem, (ii) whether resistance is increasing, (iii) whether previously unknown types of resistance are emerging, (iv) whether a particular type of resistance is spreading, and (v) whether a particular type of resistance is associated with a particular outbreak. The implications of acquiring and utilizing this information need to be considered in the design of a surveillance system. AMR surveillance provides a foundation for assessing the burden of AMR and for providing the necessary evidence for developing efficient and effective control and prevention strategies. The codevelopment of AMR surveillance programs in humans and animals is essential, but there remain several key elements that make data comparisons between AMR monitoring programs, and between regions, difficult. Currently, AMR surveillance relies on uncomplicated in vitro antimicrobial susceptibility methods. However, the lack of harmonization across programs and the limitation of genetic information of AMR remain the major drawbacks of these phenotypic methods. The future of AMR surveillance is moving toward genotypic detection, and molecular analysis methods are expected to yield a wealth of information. However, the expectation that these molecular techniques will surpass phenotypic susceptibility testing in routine diagnosis and monitoring of AMR remains a distant reality, and phenotypic testing remains necessary in the detection of emerging resistant bacteria, new resistance mechanisms, and trends of AMR. PMID- 30003870 TI - Small RNA-Based Regulation of Bacterial Quorum Sensing and Biofilm Formation. AB - Quorum sensing is a vital property of bacteria that enables community-wide coordination of collective behaviors. A key example of such a behavior is biofilm formation, in which groups of bacteria invest in synthesizing a protective, joint extracellular matrix. Quorum sensing involves the production, release, and subsequent detection of extracellular signaling molecules called autoinducers. The architecture of quorum-sensing signal transduction pathways is highly variable among different species of bacteria, but frequently involves posttranscriptional regulation carried out by small regulatory RNA molecules. This review illustrates the diverse roles small trans-acting regulatory RNAs can play, from constituting a network's core to auxiliary roles in adjusting the rate of autoinducer synthesis, mediating cross talk among different parts of a network, or integrating different regulatory inputs to trigger appropriate changes in gene expression. The emphasis is on describing how the study of small RNA-based regulation in quorum sensing and biofilm formation has uncovered new general properties or expanded our understanding of bacterial riboregulation. PMID- 30003871 TI - Monitoring Antimicrobial Drug Usage in Animals: Methods and Applications. AB - Monitoring antimicrobial drug usage in animals at the national and international levels is important for identification and tracking if and how often quantities are used. This information can be used for many purposes, including raising awareness, comparing use patterns across countries, identifying trends over time, integrating with antimicrobial resistance data, conducting risk assessment, and evaluating the effectiveness of measures to manage antimicrobial usage. The goal of this article is to describe how monitoring systems for antimicrobial drug usage in animals are set up and conducted, using examples from specific countries as well as international efforts. Several key figures and variables are used to describe and evaluate antimicrobial consumption in animals, including the amount in kilograms of active ingredient, standardized units (e.g., number of defined daily dose animals, DDDAs) and number of treatments (e.g., number of used daily doses, UDDA). Data can be collected from a variety of sources including pharmaceutical sales, pharmacy dispensing, veterinary prescriptions, and farm records. In many countries, data analysis and reporting at the national level provide statistics on overall quantities used in animals, in some cases by animal species. Antimicrobial consumption data should be contrasted to the respective animal population, for example, the weight of different categories of livestock and slaughtered animals. Several countries have established antimicrobial usage monitoring systems. Most report overall sales data, but some provide usage data to the levels of animal species and production type. At the international level, several organizations (e.g., European Union, World Organization for Animal Health, World Health Organization) have initiatives to support the development of antimicrobial consumption data collection and reporting. However, these initiatives are ongoing and so far lack harmonization, which will be the biggest challenge for the future. PMID- 30003872 TI - Widespread Antisense Transcription in Prokaryotes. AB - Although bacterial genomes are usually densely protein-coding, genome-wide mapping approaches of transcriptional start sites revealed that a significant fraction of the identified promoters drive the transcription of noncoding RNAs. These can be trans-acting RNAs, mainly originating from intergenic regions and, in many studied examples, possessing regulatory functions. However, a significant fraction of these noncoding RNAs consist of natural antisense transcripts (asRNAs), which overlap other transcriptional units. Naturally occurring asRNAs were first observed to play a role in bacterial plasmid replication and in bacteriophage lambda more than 30 years ago. Today's view is that asRNAs abound in all three domains of life. There are several examples of asRNAs in bacteria with clearly defined functions. Nevertheless, many asRNAs appear to result from pervasive initiation of transcription, and some data point toward global functions of such widespread transcriptional activity, explaining why the search for a specific regulatory role is sometimes futile. In this review, we give an overview about the occurrence of antisense transcription in bacteria, highlight particular examples of functionally characterized asRNAs, and discuss recent evidence pointing at global relevance in RNA processing and transcription-coupled DNA repair. PMID- 30003875 TI - Relationships of carotenoid-related gene expression and serum cholesterol and lipoprotein levels to retina and brain lutein deposition in infant rhesus macaques following 6 months of breastfeeding or formula feeding. AB - The purpose of this study was to investigate if the enhanced bioaccumulation of lutein in retina and brain of breastfed, compared to formula-fed, infant monkeys was associated with higher levels of serum total and HDL cholesterol, apolipoproteins, or mRNA/protein expression of carotenoid-related genes. Newborn rhesus macaques were either breastfed, fed a carotenoid-supplemented formula, or fed an unsupplemented formula for 6 months (n = 8, 8, 7). Real-time qPCR and western blotting were performed in two brain regions (occipital cortex and cerebellum) and two retina regions (macular and peripheral retina). Breastfed infants had higher serum total cholesterol, HDL cholesterol, apoA-I, and apoB-100 levels than the combined formula-fed groups (P < 0.05). Breast milk or infant formulas did not alter expression of the nine genes (CD36, SCARB1, SCARB2, LDLR, STARD3, GSTP1, BCO1, BCO2, RPE65) examined except for SCARB2 in the retina and brain regions. In conclusion, dietary regimen did not impact the expression of carotenoid-related genes except for SCARB2. However, carotenoid-related genes were differentially expressed across brain and retina regions. Breastfed infants had higher serum total and HDL cholesterol, and apolipoproteins, suggesting that lipoprotein levels might be important for delivering lutein to tissues, especially the macular retina, during infancy. PMID- 30003874 TI - Telocytes role during the postnatal development of the Mongolian gerbil jejunum. AB - Telocytes are recently categorised CD34-positive interstitial cells that comprise the cells which were previously called interstitial Cajal-like cells (ICLCs). These were detected in the stroma of various organs such as the prostate, lungs, mammary glands, liver, gallbladder, and jejunum, among others. Several functions have been proposed for telocytes, such as a supportive role in smooth muscle contraction and immune function in adult organs, and tissue organisation and paracrine signalling during development, as well as others. In the jejunum, little is known about the function of telocytes in the adult organ, or is there any information about when these cells develop or if they could have an auxiliary role in the development of the jejunum. The present study employed histological, immunohistochemical and immunofluorescence techniques on histological sections of the jejunum of Mongolian gerbil pups on two different days of postnatal development of the jejunum, covering the maturation period of the organ. By immunolabelling for CD34, it was observed that telocytes are already present in the jejunum during the first week of postnatal life and exist in close association with the developing muscularis mucosae, which are therefore TGFbeta1 positive. The telocytes are still present at the end of the first month of life, and a portion of them present co-localisation with c-Kit. Fibroblast-like cells, which are exclusively c-Kit-positive, are also observed, which may indicate the presence of interstitial Cajal cells (ICCs). Finally, it can be hypothesised that a portion of the telocytes may give rise to ICCs, which are c-Kit-positive but CD34 negative. PMID- 30003876 TI - Structural and enzymatic properties of mammalian d-glutamate cyclase. AB - d-Glutamate cyclase (DGLUCY) is a unique enzyme that reversibly converts free d glutamate to 5-oxo-d-proline and H2O. Mammalian DGLUCY is highly expressed in the mitochondrial matrix in the heart, and its downregulation disrupts d-glutamate and/or 5-oxo-d-proline levels, contributing to the onset and/or exacerbation of heart failure. However, detailed characterisation of DGLUCY has not yet been performed. Herein, the structural and enzymatic properties of purified recombinant mouse DGLUCY were examined. The results revealed a dimeric oligomerisation state, and both d-glutamate-to-5-oxo-d-proline and 5-oxo-d proline-to-d-glutamate reactions were catalysed in a stereospecific manner. Catalytic activity is modulated by divalent cations and nucleotides including ATP and ADP. Interestingly, the presence of Mn2+ completely abolished the 5-oxo-d proline-to-d-glutamate reaction but stimulated the d-glutamate-to-5-oxo-d-proline reaction. The optimum pH is ~8.0, similar to that in the mitochondrial matrix, and the catalytic efficiency for d-glutamate is markedly higher than that for 5 oxo-d-proline. These findings suggest that DGLUCY functions as a metalloenzyme that degrades d-glutamate in the mitochondrial matrix in mammalian cells. The results also provide insight into the correlation between DGLUCY enzyme activity and the physiological and pathological roles of d-glutamate and 5-oxo-d-proline in cardiac function, which is of relevance to the risk of onset of heart failure. PMID- 30003877 TI - Clinical efficacy of anti-migration features in fully covered metallic stents for anastomotic biliary strictures after liver transplantation: comparison of conventional and anti-migration stents. AB - BACKGROUND AND AIMS: Anastomotic biliary strictures (ABSs) are one of the most frequent adverse events that occur after orthotopic liver transplantation (OLT). Multiple plastic stents (MPS) have been validated for this indication. More recently, fully covered self-expandable metallic stents (FCSEMSs) have been used with positive outcomes, but also have a higher rate of migration, which may limit success. Our primary objective was to compare stent migration rates observed with standard FCSEMSs (Std-FCSEMSs) and so-called anti-migration FCSEMSs (Am-FCSEMSs), which are newly designed with reversed proximal side flaps. Secondary objectives were to compare rates of stricture resolution and procedure-related morbidity. METHODS: We conducted a retrospective analysis of a subset of patients (FCSEMSs for post-OLT ABS) from 2 prospectively maintained databases of (1) OLT patients, and (2) ERCP and stent placement. Between January 2009 and January 2016, consecutive patients presenting with ABS after OLT referred to Cochin Hospital (Paris, France) for ERCP and receiving a FCSEMS were included. Exclusion criteria were any other cause of biliary stricture (ie, malignant stricture, ischemic origin), and biliary fistulae. RESULTS: One hundred twenty-five FCSEMSs (57 Am FCSEMSs, 52 type 1 Std-FCSEMSs, and 16 type 2 Std-FCSEMSs) were used in 75 patients for ABS after OLT, with a planned stent placement period of 6 months in all patients. Patient characteristics and rates of previous endoscopic treatment or timing of ABS occurrence after OLT were not different between the groups. The rate of FCSEMS complete migration was 16% (20/125), consisting of 1.7% (1/57) for Am-FCSEMSs and 28% (19/68) for type 1 and 2 Std-FCSEMSs (P < .0001). All attempted stent removals (100% of patients) were successful. First follow-up ERCP after each FCSEMS highlighted a stricture resolution rate of 78.4% (98/125), including 93% (53/57) for Am-FCSEMSs and 66.2% (45/68) for type 1 and 2 Std FCSEMSs (P < .001). After a median follow-up of 28 months after stent removal (range, 12-66 months), stricture recurrence was observed in 12.3% (range, 11% 17%) of patients treated with Am-FCSEMSs against 55.9% (range, 54%-56%) of those receiving Std-FCSEMSs (P < .0001). CONCLUSIONS: In patients with ABS after OLT, the use of Am-FCSEMSs significantly decreased the risk of stent migration, improved stricture resolution at the time of stent removal, and reduced the rate of stricture recurrence during follow-up. Endoscopic removal success and procedure-related morbidity were similar for both standard and anti-migration stents. PMID- 30003873 TI - Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these 'like-C9' brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum. PMID- 30003878 TI - Cisterno-lumbar gradient of complement fractions in geriatric patients with suspected normal pressure hydrocephalus. AB - BACKGROUND: The complement system is a functional link between the innate and adaptive immune system and present in all compartments of the body. The composition of the cerebrospinal fluid (CSF) differs between the ventricular, cisternal and lumbar space. Usually, concentrations of blood-derived CSF proteins increase from ventricular to lumbar fractions. METHODS: In 20 geriatric patients with suspected normal pressure hydrocephalus (NPH) [13 women, 7 men, age 80.5 (75/85) years; median (25th/75th percentile)] a lumbar spinal tap of 40 ml was performed, and 10 ml of serum was drawn. CSF, sequentially collected in 8 fractions of 5 ml (1st fraction: lumbar CSF; 8th fraction: cisterna magna-near CSF), was analyzed for complement protein C3, and the activation products C3a and sC5b-9 by enzyme immunoassay. RESULTS: The concentrations of the complement factors measured in fractions 1 and 8 of each individual patient were strongly correlated: C3 (Spearman's rank correlation coefficient rS = 0.75, p = 0.0002); C3a (rS = 0.93, p < 0.0001); sC5b-9 (rS = 0.64, p = 0.002). CSF complement concentrations were lower in the cistern-near fraction 8 than in the lumbar fraction 1 (C3: p = 0.005; C3a: p = 0.0009; sC5b-9: p = 0.0003, Wilcoxon signed rank test). The concentrations of complement factors in CSF were two orders of magnitude lower than those in serum. C3 levels in the lumbar CSF strongly correlated with the lumbar CSF/serum albumin concentration quotient (QAlb) as a measure of the functionability of the blood-CSF barrier and the velocity of CSF flow (rS = 0.84, p < 0.0001) suggesting diffusion of C3 from blood to CSF. The lumbar and cistern-near concentrations of C3a did not significantly correlate with QAlb (rS = 0.26) pointing to a local conversion of C3 to C3a. The lumbar concentrations of sC5b-9 moderately correlated with QAlb (rS = 0.62, p = 0.004). Plotting the CSF/serum quotient of C3 and sC5b-9 versus the QAlb revealed an approx. 50% local synthesis of C3, but a strong production of sC5b-9 in the CNS. CONCLUSIONS: The increase of the complement concentrations from cisternal to lumbar CSF and the strong correlation of C3 with QAlb suggest that (1) a substantial portion of complement C3 in CSF originates from blood and (2) the complement system is mildly activated in the CSF of NPH patients. PMID- 30003881 TI - Determination of glyphosate residues in Egyptian soil samples. AB - A sensitive linker-assisted enzyme-linked immunosorbent assay (L'ELISA) was developed for the analysis of glyphosate in Egyptian soil samples. Polyclonal glyphosate antibodies were produced from rabbits immunized with glyphosate protein conjugate. The conjugate was prepared by activating the carboxylic groups of proteins; thyroglobulin or bovine serum albumin with 1-ethyl-3- (3 diaminopropyl) carbodiimide hydrochloride and N-hydroxysulfosuccinimide followed by directly coupled to the amino group of glyphosate. The L'ELISA used succinic anhydride to derivatize glyphosate, which mimics the epitopic attachment of glyphosate to thyroglobulin. L'ELISA recognized the derivatized glyphosate with a limit of detection (LOD) of 0.8 ng g-1 and sensitivity (IC50 value) of 0.018 MUg g-1. The recovery values of the spiked soil samples with different concentrations of glyphosate were in the range of 87.4-97.2%. Good correlation was achieved between L'ELISA and conventional high-pressure liquid chromatography (HPLC) with fluorescence detection. This study demonstrated the utility and convenience of the sensitive, simple, practical and cost-effective L'ELISA method for glyphosate analysis in soil samples. Also, it is ideal for rapid screening of a large number of environmental samples. PMID- 30003879 TI - Talin is a substrate for SUMOylation in migrating cancer cells. AB - Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration. PMID- 30003882 TI - Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits. AB - BACKGROUND: Antiproliferative drugs in drug eluting stents (DES) are associated with complications due to impaired re-endothelialization. Additionally, adventitial neovascularization has been suggested to contribute to in-stent restenosis (ISR). Since Vascular Endothelial Growth Factors (VEGFs) are the key mediators of angiogenesis, we investigated feasibility and efficacy of local gene therapy for ISR utilizing soluble decoy VEGF receptors to reduce biological activity of adventitial VEGFs. METHOD: Sixty-nine adult WHHL rabbit aortas were subjected to endothelial denudation. Six weeks later catheter-mediated local intramural infusion of 1.5x10e10 pfu adenoviruses encoding soluble VEGF Receptor 1 (sVEGFR1), sVEGFR2, sVEGFR3 or control LacZ and bare metal stent implantation were performed in the same aortic segment. Marker protein expression was assessed at 6d in LacZ cohort. Immunohistochemistry, morphometrical analyses and angiography were performed at d14, d42 and d90. RESULTS: Transgene expression was localized to adventitia. All decoy receptors reduced the size of vasa-vasorum at 14d, AdsVEGFR2 animals also had reduced density of adventitial vasa-vasorum, whereas AdsVEGFR3 increased the density of vasa-vasorum. At d42, AdsVEGFR1 and AdsVEGFR2 reduced ISR (15.7 +/- 6.9% stenosis, P < 0.01 and 16.5 +/- 2.7%, P < 0.05, respectively) vs. controls (28.3 +/- 7.6%). Moreover, AdsVEGFR-3 treatment led to a non-significant trend in the reduction of adventitial lymphatics at all time points and these animals had significantly more advanced neointimal atherosclerosis at 14d and 42d vs. control animals. CONCLUSIONS: Targeting adventitial neovascularization using sVEGFR1 and sVEGFR2 is a novel strategy to reduce ISR. The therapeutic effects dissipate at late follow up following short expression profile of adenoviral vectors. However, inhibition of VEGFR3 signaling accelerates neoatherosclerosis. PMID- 30003880 TI - The multiple functions and mechanisms of osteopontin. AB - Osteopontin (OPN) is a highly phosphorylated glycophosphoprotein having acidic characteristics and rich in aspartic acid. OPN, a multifunctional protein, has important functions on cardiovascular diseases, cancer, diabetes and kidney stone diseases and in the process of inflammation, biomineralization, cell viability and wound healing. Osteopontin acts on organisms by playing a key role in secretion levels of interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-3 (IL-3), interferon-gamma (IFN-gamma), integrin alphavB3, nuclear factor kappa B (NF-kB), macrophage and T cells, regulating the osteoclast function and affecting CD44 receptors. The aim of the present review is to address majority of different functions of OPN protein which are known, suspected or suggested through the data obtained about this protein yet. PMID- 30003883 TI - Phosphene perception and pupillary responses to sinusoidal electrostimulation - For an objective measurement of retinal function. AB - The purpose was to evaluate retinal function by measuring pupillary responses to sinusoidal transcorneal electrostimulation in healthy young human subjects. This work also translates data from analogous in vitro experiments and connects it to the pupillary responses obtained in human experiments. 14 healthy human subjects participated (4 males, 10 females); for the in vitro experiments, two male healthy mouse retinas (adult wild-type C57B/6J) were used. Pupillary responses to sinusoidal transcorneal electrostimulation of varying stimulus carrier frequencies (10, 20 Hz; envelope frequency constantly kept at 1.2 Hz) and intensities (10, 20, 50 MUA) were recorded and compared with those obtained with light stimulation (1.2 Hz sinusoidal blue, red light). A strong correlation between the sinusoidal stimulation (electrical as well as light) and the pupillary sinusoidal response was found. The difference between the lag of electrical and light stimulation allowed the estimation of an intensity threshold for pupillary responses to transcorneal electrostimulation (mean +/- SD: 30 +/- 10 MUA (10 Hz); 38 +/- 10 MUA (20 Hz)). A comparison between the results of the two stimulation frequencies showed a not statistically significant smaller lag for 10 Hz (10 Hz: 633 +/- 90 ms; 20 Hz: 725 +/- 178 ms; 50 MUA intensity). Analogous in vitro experiments on murine retinas indicated a selective stimulation of photoreceptors and bipolar cells (lower frequencies) and retinal ganglion cells (higher frequencies) and lower stimulation thresholds for the retinal network with sinusoidal compared to pulsatile stimulation - emphasizing that sinusoidal waveforms are well-suited to our purposes. We demonstrate that pupillary responses to sinusoidal transcorneal electrostimulation are measurable as an objective marker in healthy young subjects, even at very low stimulus intensities. By using this unique approach, we unveil the potential for an estimation of the individual intensity threshold and a selective activation of different retinal cell types in humans by varying the stimulation frequency. This technique may have broad clinical utility as well as specific relevance in the monitoring of patients with hereditary retinal disorders, especially as implemented in study protocols for novel therapies, e.g. retinal prostheses or gene therapies. PMID- 30003884 TI - The presence of a feeder layer improves human corneal endothelial cell proliferation by altering the expression of the transcription factors Sp1 and NFI. AB - Based on the use of tissue-cultured human corneal endothelial cells (HCECs), cell therapy is a very promising avenue in the treatment of corneal endothelial pathologies such as Fuchs' dystrophy, and post-surgical corneal edema. However, once in culture, HCECs rapidly lose their phenotypic and physiological characteristics, and are therefore unsuitable for the reconstruction of a functional endothelial monolayer. Expression of NFI, a transcription factor that can either function as an activator or a repressor of gene transcription, has never been examined in endothelial cells. The present study therefore aimed to determine the impact of a non-proliferating, lethally irradiated i3T3 feeder layer on the maintenance of HCEC's morphological characteristics, and both the expression and stability of Sp1 (a strong transcriptional activator) and NFI in such cells. The typical morphology of endothelial cells was best maintained when 8 * 103/cm2 HCECs were co-cultured in the presence of 2 * 104 cells/cm2 i3T3. HCECs were found to express both Sp1 and NFI in vitro. Also, the presence of i3T3 led to higher levels of Sp1 and NFI in HCECs, with a concomitant increase in their DNA binding levels (assessed by electrophoretic mobility shift assays (EMSA)). Specifically, i3T3 increased the expression of the NFIA, NFIB and NFIC isoforms, without a noticeable increase in their mRNAs (as revealed by gene profiling on microarray). Gene profiling analysis also identified a few feeder layer-dependent, differentially regulated genes whose protein products may contribute to improving the properties of HCECs in culture. Therefore, co culturing HCECs with an i3T3 feeder layer clearly improves their morphological characteristics by maintaining stable levels of Sp1 and NFI in cell culture. PMID- 30003885 TI - Derivation of phenotypically diverse neural culture from hESC by combining adherent and dissociation methods. AB - BACKGROUND: Differentiation of human embryonic stem cells (hESCs) into distinct neural lineages has been widely studied. However, preparation of mixed yet neurochemically mature populations, for the study of neurological diseases involving mixed cell types has received less attention. NEW METHOD: We combined two commonly used differentiation methods to provide robust and reproducible cultures in which a mixture of primarily GABAergic and Glutamatergic neurons was obtained. Detailed characterisation by immunocytochemistry (ICC) and quantitative real-time PCR (qPCR) assessed the neurochemical phenotype, and the maturation state of these neurons. RESULTS: We found that once neurospheres (NSs) had attached to the culture plates, proliferation of neural stem cell was suppressed. Neuronal differentiation and synaptic development then occurred after 21 days in vitro (DIV). By 49DIV, there were large numbers of neurochemically and structurally mature neurons. The qPCR studies indicated that expression of GABAergic genes increased the most (93.3-fold increase), followed by glutamatergic (51-fold increase), along with smaller changes in expression of cholinergic (3-fold increase) and dopaminergic genes (6-fold increase), as well as a small change in glial cell marker expression (5-fold increase). COMPARISON WITH EXISTING METHOD (S): Existing methods isolate hESC-derived neural progenitors for onward differentiation to mature neurons using either migration or dissociative paradigms. These give poor survival or yield. By combining these approaches, we obtain high yields of morphologically and neurochemically mature neurons. These can be maintained in culture for extended periods. CONCLUSION: Our method provides a novel, effective and robust neural culture system with structurally and neurochemically mature cell populations and neural networks, suitable for studying a range of neurological diseases from a human perspective. PMID- 30003886 TI - New Onset Hematochezia in a Post-Transplant Patient. PMID- 30003887 TI - Enabling Precision Medicine through Integrative Network Models. AB - A key challenge in precision medicine lies in understanding molecular-level underpinnings of complex human disease. Biological networks in multicellular organisms can generate hypotheses about disease genes, pathways, and their behavior in disease-related tissues. Diverse functional genomic data, including expression, protein-protein interaction, and relevant sequence and literature information, can be utilized to build integrative networks that provide both genome-wide coverage as well as contextual specificity and accuracy. By carefully extracting the relevant signal in thousands of heterogeneous functional genomics experiments through integrative analysis, these networks model how genes work together in specific contexts to carry out cellular processes, thereby contributing to a molecular-level understanding of complex human disease and paving the way toward better therapy and drug treatment. Here, we discuss current methods to build context-specific integrative networks, focusing on tissue specific networks. We highlight applications of these networks in predicting tissue-specific molecular response, identifying candidate disease genes, and increasing power by amplifying the disease signal in quantitative genetics data. Altogether, these exciting developments enable biomedical scientists to characterize disease from pathophysiology to cellular system and, finally, to specific gene alterations-making significant strides toward the goal of precision medicine. PMID- 30003888 TI - Control of pheromone production by ovaries in Drosophila. AB - Drosophila pheromones are long chain hydrocarbons (CHCs) produced by specialized epidermal cells, the oenocytes. Here we were explored the role of ovaries in CHC regulation. We studied tudor, a grandchildless-like mutation, resulting in progeny without ovaries and three alleles of ovoD, resulting in ovarian defects depending on the strength of the allele. We show here that these mutant flies with no or abnormal ovaries have a decrease in C29 length CHC ratio, balanced by an increase in C23 and C25 length ratio; this effect is dependent on the strength of the mutation. An increase in the amount of CHCs also occurred but was not related to the strength of ovoD alleles. As ovaries are the main site of ecdysone production in females, we knocked down the receptor to ecdysone EcR in the oenocytes and obtained increased amounts of CHCs and inhibition of long chain CHC synthesis, showing that the lack of an ecdysone signal arriving into the oenocytes is responsible for these defects. We then investigated the role of follicular cells and oocyte on CHC regulation: we RNAi-knocked down the LPR receptors in the oocyte to hinder vitellogenesis without significantly modifying CHC profile. We then expressed apoptosis genes within the follicle cells or within the ovocytes and obtained less long chain and more short chain CHC levels in the former case and an enhanced CHC production in the latter case. Together, these results support the notion of an interaction between oocyte and follicular cells, which send an ecdysone signal to the oenocytes to regulate CHC synthesis. PMID- 30003890 TI - Transfection of crayfish hematopoietic tissue cells. AB - Transfection is a powerful tool useful for studying gene function. Establishing transfection methods that enable highly efficient DNA uptake has become increasingly important. The crayfish hematopoietic tissue (Hpt) cell cultures have been proven to be suitable for studies on immunity and cell differentiation in crustaceans including shrimps, but no efficient gene transfer and expression method is available for these cells. Here we report a novel and highly efficient DNA transfection system based on electroporation. This method depends on a recombinant plasmid with the promoter from white spot syndrome virus immediate early gene wsv249. This plasmid could be introduced into primary cells and efficiently express foreign genes by electroporation. By optimizing different electroporation parameters, more than 30% transfection efficiency could be achieved with the relative viability of cells around 50%. This is the first report of gene introduction to crayfish Hpt cells and will be useful for the expanding our research on crustacean immunity. PMID- 30003889 TI - Development of a primary culture system for haematopoietic tissue cells from Cherax quadricarinatus and an exploration of transfection methods. AB - Various known and unknown viral diseases can threaten crustacean aquaculture. To develop prophylactic and therapeutic strategies against viruses, crustacean cell lines are urgently needed for immunology and virology studies. However, there are currently no permanent crustacean cell lines available. In this study, we developed a new method for preparing crayfish plasma (CP) and found that CP enhanced the proliferative capacity of haematopoietic tissue (hpt) cells from Cherax quadricarinatus by an EdU (5-ethynyl-2'-deoxyuridine) assay. The optimal CP concentration for hpt cell culture and the optimal subculture method are discussed. To achieve efficient expression of a foreign gene in hpt cells cultured in vitro, different transfection methods and vectors were analysed. We found that Lipofectamine 2000 could be used to efficiently transfect a foreign vector into hpt cells and exhibited a lower level of cytotoxicity than the other methods tested, and transfection of pEGFP-N1/w249 and pDHsp70-EGFP-FLAG resulted in high EGFP expression. By transmission electron microscopy (TEM) and virus copy number analysis, we found that white spot syndrome virus (WSSV) could infect hpt cells and multiply efficiently. Our results implied that the crayfish hpt cell culture system we improved could be used as a replacement for immortal crustacean cell lines in viral infection studies. Our findings provide a solid foundation for future immortalization and gene function studies in crustacean cells. PMID- 30003892 TI - Discrimination of spatial phase: The roles of luminance distribution and attention. AB - We can easily discriminate certain phase relations in spatial patterns but not others. Phase perception has been found different in the fovea vs. periphery, and for single patterns vs. textures. Different numbers of mechanisms have been proposed to account for the regularities of phase perception. In this study, I attempt to better understand the mechanisms behind discrimination of spatial phase. In order to reveal the role of luminance cues, I use histogram matching of patterns with different phases. Possible effects of attention were studied using visual search experiments with varied stimulus set size. Simple and compound Gabor patches, broadband lines and edges, and textures composed of those patterns were used as stimuli. The experiments indicate that phase discrimination is mediated by two mechanisms. The first uses luminance differences and operates pre attentively, in parallel across the visual field. The second compares relative positions of dark and bright segments within an image, and is strictly limited by capacity of attention. PMID- 30003891 TI - Korean reading speed: Effects of print size and retinal eccentricity. AB - Evaluating the effects of print size and retinal eccentricity on reading speed is important for identifying the constraints faced by people with central-field loss. Previous work on English reading showed that 1) reading speed increases with print size until a critical print size (CPS) is reached, and then remains constant at a maximum reading speed (MRS), and 2) as eccentricity increases, MRS decreases and CPS increases. Here we extend this work to Korean, a language with more complex orthography. We recruited 6 Korean native speakers (mean age = 22) and measured their reading speed in central vision (0 degrees ) and peripheral vision (10 degrees in the lower field). 900 Korean sentences (average 8.25 words) were created with frequently-occurring beginner-level words, presented using a rapid serial visual presentation (RSVP) paradigm. Data for English reading were obtained from Chung, Mansfield & Legge, Vision Research, 1998, for comparison. MRS was similar for Korean and English at 0 degrees (713 vs. 787 wpm), but decreased faster with eccentricity for Korean. CPS was larger for Korean than for English regardless of eccentricity, but increased with eccentricity similarly for both languages. From 0 to 10 degrees , MRS decreased by a factor of 6.5 for Korean and 2.8 for English, and CPS increased by a factor of 11.7 for Korean and 10.2 for English. Korean reading speed is more affected by retinal eccentricity than English, likely due to additional within-character crowding from more complex orthography. Korean readers with central-field loss may experience more difficulty than English readers. PMID- 30003893 TI - Restricted lesions of the ventrolateral or dorsal columns of the periaqueductal gray promotes distinct effects on tonic immobility and defensive analgesia in guinea pigs. AB - Tonic immobility (TI) is an innate defensive response exhibited by prey when physical contact with a predator is prolonged and inescapable. This defensive response is able to activate analgesia mechanisms; this activation has adaptive value because, during an attack by a predator, the manifestation of recuperative behaviors can affect the appropriate behavioral defense strategy. Some studies have suggested that similar structures of the central nervous system can regulate the response of both TI and nociception. Thus, this study evaluated the effect of chemical lesion through the administration of ibotenic acid in restricted brain areas of the periaqueductal gray matter (PAG) in guinea pig on the TI response and nociception evaluated in the hot plate test before and after emission of TI. The data showed that an irreversible chemical lesion in the ventrolateral PAG reduced of the TI response as well as defensive antinociception. However, a lesion in the dorsal PAG blocked the defensive antinociception induced by TI but did not alter TI duration. In summary, one could hypothesize that the neural substrates responsible for defensive behavior and antinociception represent similar systems that are distinct in modulation. Thus, the ventrolateral PAG has been associated with the modulation of TI and the defensive antinociception induced by TI. In contrast, the integrity of the dorsal PAG should be necessary for defensive antinociception to occur but not to elicit TI behavior in guinea pigs. PMID- 30003894 TI - Assay system development to measure the concentration of sargramostim with high specificity in patients with autoimmune pulmonary alveolar proteinosis after single-dose inhalation. AB - During a clinical trial of a Saccharomyces cerviciae-derived recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), sargramostim, in patients with autoimmune pulmonary alveolar proteinosis (aPAP), we conducted a pharmacokinetic study of single-dose sargramostim inhalation. Several problems were encountered whereby sargramostim formed an immune-complex with GM-CSF autoantibodies (GMAbs) immediately after entering the body; thus, we could not measure the concentration of sargramostim using a commercial high sensitivity enzyme-linked immunosorbent assay (ELISA). Moreover, the ELISA could not discriminate inhaled sargramostim from intrinsic GM-CSF. To solve these problems, we developed a novel ELISA system with a capture antibody that is specific for sargramostim and a detection antibody capable of binding with GM-CSF. This system quantified the serum sargramostim concentration, but not E. coli-, CHO-, or HEK293T-derived human recombinant GM-CSF. Using this system, serum pharmacokinetics were estimated in five patients after inhalation of 250 MUg sargramostim, with a mean Cmax of 9.7 +/- 2.85 pg/ml at a Tmax of 2 +/- 1.22 h. PMID- 30003895 TI - Proteomic profiles by multiplex microsphere suspension array. AB - Advances in high-throughput proteomic approaches have provided substantial momentum to novel disease-biomarker discovery research and have augmented the quality of clinical studies. Applications based on multiplexed microsphere suspension array technology are making strong in-roads into the clinical diagnostic/prognostic practice. Conventional proteomic approaches are designed to discover a broad set of proteins that are associated with a specific medical condition. In comparison, multiplex microsphere immunoassays use quantitative measurements of selected set(s) of specific/particular molecular markers such as cytokines, chemokines, pathway signaling or disease-specific markers for detection, metabolic disorders, cancer, and infectious agents causing human, plant and animal diseases. This article provides a foundation to the multiplexed microsphere suspension array technology, with an emphasis on the improvements in the technology, data analysis approaches, and applications to translational and clinical research with implications for personalized and precision medicine. PMID- 30003896 TI - Self-directed exercise programmes in sedentary middle-aged individuals in good overall health; a systematic review. AB - Many chronic diseases and illnesses are caused by the lifestyle, including the physical activity habits, of an individual. As such, consistent high levels of exercise should be encouraged across the lifespan, to limit the risk of developing one of these conditions and allowing for healthy aging to occur. Exercise prescriptions that encourage high completion and adherence rates in an independent manner and improve health related outcomes should be provided to individuals. To date, no review has identified optimal prescriptions of exercise to achieve this in sedentary middle-aged adults and this is important, given the higher risk of developing illnesses in this population as they age. This review examines the effects prescriptions of self-directed (SD) exercise has on adherence and health related outcomes in sedentary middle-aged individuals in good general health currently and aims to identify the most suitable forms of planned SD exercise that can be carried out independently. A systematic search of the electronic database PubMed was conducted. Randomised controlled trials published in English between February 2007 and February 2017 examining healthy, sedentary middle-aged participants only were included. Studies were critically appraised using the PEDro scale and data were presented on standardised tables. Twenty-one articles examining different aerobic activities, combined training and non-traditional exercise prescriptions were included. This review summarised in detail the effects SD exercise interventions had on sedentary middle-aged individuals alongside the adherence to the prescriptions. SD exercise was seen to be beneficial for improving metabolic outcomes physical characteristics, cardiorespiratory fitness and functional measures. PMID- 30003897 TI - Food insecurity, comorbidity, and mobility limitations among older U.S. adults: Findings from the Health and Retirement Study and Health Care and Nutrition Study. AB - Both food insecurity and comorbidity have been identified as precursors to functional limitation in older adults, yet whether food insecurity modifies the progression from chronic disease to disability has not been assessed. We examined 5986 respondents age 50 and older drawn from the 2012-2014 Health and Retirement Study (HRS) and 2013 Health Care and Nutrition Study (HCNS). Mobility limitations reported in 2014 and change in mobility limitations from 2012 to 2014 were regressed on measures of food insecurity, number of chronic conditions, and their interaction terms using Poisson regression. Around 17.3% of the sample was identified as food insecure. In 2012, respondents reported an average of 1.9 (SD = 1.5) chronic conditions and 2.4 mobility limitations (SD = 3.0). In 2014, individuals reported an average of 2.5 (SD = 3.1) mobility limitations. Food insecurity was associated with a greater number of mobility limitations (IRR = 1.20, 95% CI: 1.11-1.29, p < .001) and more rapid increase in mobility limitations over the two-year observational period (IRR = 1.06, 95% CI: 1.00 1.11, p = .047). Food security status also modified the association between comorbidity and both mobility limitation outcomes, with the food secure exhibiting a stronger positive association between chronic conditions and mobility limitations than the food insecure. The food insecure tended to have more mobility limitations than the food secure when few chronic conditions were reported. Our results suggest that food insecurity is associated with prevalence and change in mobility limitations among older adults. PMID- 30003898 TI - Submicron Size Particles of a Murine Monoclonal Antibody Are More Immunogenic Than Soluble Oligomers or Micron Size Particles Upon Subcutaneous Administration in Mice. AB - Protein aggregates are one of the several risk factors for undesired immunogenicity of biopharmaceuticals. However, it remains unclear which features determine whether aggregates will trigger an unwanted immune response. The aim of this study was to determine the effect of aggregates' size on their relative immunogenicity. A monoclonal murine IgG1 was stressed by exposure to low pH and elevated temperature followed by stirring to obtain aggregates widely differing in size. Aggregate fractions enriched in soluble oligomers, submicron size particles and micron size particles were isolated via centrifugation or size exclusion chromatography and characterized physicochemically. The secondary and tertiary structures of aggregates were altered in a similar way for all the fractions, while no substantial chemical degradation was observed. Development of anti-drug antibodies was measured after subcutaneous administration of each enriched fraction to BALB/c mice. Among all tested fractions, the most immunogenic was the one highly enriched in submicron size particles (~100-1000 nm). Fractions composed of micron size (>1-100 MUm) particles or soluble oligomers (<100 nm) were not immunogenic under the dosing regimen studied in this work. These results show that aggregate size is an important factor for protein immunogenicity. PMID- 30003899 TI - Improvement in the efficiency of natural transformation of Haemophilus parasuis by shuttle-plasmid methylation. AB - Some Haemophilus parasuis strains display resistance to transformation with Escherichia.coli-derived plasmids. This property limits the application of genetic approaches previously developed for H. parasuis. The present study showed that natural transformation with the shuttle plasmid pS2UK led to allelic exchange in H. parasuis strains SH0165 and CF7066. Furthermore, natural transformation with pS2UK yielded allelic exchange mutants in 10 of 17 H. parasuis strains, similar to results using the suicide plasmid pK2UK. Subsequently, 17 H. parasuis strains were transformed with pS2UK by electroporation and 13 obtained the transformants harboring the complete plasmid molecules. As a result, natural transformation of homologous blank strains with the H. parasui-derived plasmids significantly improved the transformation efficiency targeted at obtaining allelic exchange mutants. In addition, shuttle plasmids pS1UG and pSHUK that carried the different homologous arm sequences also displayed the increased transformation efficiency after they were replicated in homologous H. parasuis cells. The approach described here not only improved the efficiency of natural transformation of H. parasuis, but also enlarged the range of transformable H. parasuis strains, thereby enabling application of H. parasuis specific genetic manipulation techniques in a wider range of isolates. PMID- 30003900 TI - Hypoxic preconditioning enhances cell hypoxia tolerance and correlated lncRNA and mRNA analysis. AB - AIMS: Hypoxia makes cells death but it is not always true. Short term anoxia can boost remaining cells activities and promote tissue repair. This study is to explore the effects of hypoxic preconditioning (HP) on osteoblasts and analyze the involved lncRNA and mRNA. MAIN METHODS: Human osteoblast was used. Normoxic control group (N) were cultured in normoxic culture medium (L-DMEM, 10% FBS and 1% penicillin-streptomycin) 8 h. Long-term hypoxic group (H) were cultured in 4 h hypoxic culture medium (200 MUmol/L CoCl2 and L-DMEM)/4 h normoxic culture medium. Hypoxic preconditioning group (HP) were received 3 times HP (cultured in 10 min hypoxic culture medium/10 min normoxic culture medium, which was HP 1times) and then cultured in 4 h hypoxic culture medium/4 h normoxic culture medium. Cell proliferation ability, osteonectin, transforming growth factor beta1, insulin like growth factors-1 and osteopontin were test. The lncRNA and mRNA was detected by high-throughput sequencing. p-Value < 0.05 was accepted as statistically significant. KEY FINDINGS: Cell proliferation activity: N > HP > P. Corrected osteonectin, TGF-beta1, IGF-1 and osteopontin: HP > P > N. High throughput sequencing of gene shown the expression of 4630 RNAs. Further, we identified that HP group made 239 and 160 target genes up-regulated and down regulated respectively compared with H group (p < 0.05). GO, KEGG and PPI analysis indicated relevant biological processes. SIGNIFICANCE: Hypoxic preconditioning alleviated cells anoxia tolerance and promoted cells to synthesis many cytokines. The protection mechanism involved many lncRNAs and mRNAs. PMID- 30003902 TI - Methylene blue activates the PMCA activity and cross-interacts with amyloid beta peptide, blocking Abeta-mediated PMCA inhibition. AB - The phenothiazine methylene blue (MB) is attracting increasing attention because it seems to have beneficial effects in the pathogenesis of Alzheimer's disease (AD). Among other factors, the presence of neuritic plaques of amyloid-beta peptide (Abeta) aggregates, neurofibrilar tangles of tau and perturbation of cytosolic Ca2+ are important players of the disease. It has been proposed that MB decreases the formation of neuritic plaques due to Abeta aggregation. However, the molecular mechanism underlying this effect is far from clear. In this work, we show that MB stimulates the Ca2+-ATPase activity of the plasma membrane Ca2+ ATPase (PMCA) in human tissues from AD-affected brain and age-matched controls and also from pig brain and cell cultures. In addition, MB prevents and even blocks the inhibitory effect of Abeta on PMCA activity. Functional analysis with mutants and fluorescence experiments strongly suggest that MB binds to PMCA, at the C-terminal tail, in a site located close to the last transmembrane helix and also that MB binds to the peptide. Besides, Abeta increases PMCA affinity for MB. These results point out a novel molecular basis of MB action on Abeta and PMCA as mediator of its beneficial effect on AD. PMID- 30003903 TI - Motor cognition in patients treated with subthalamic nucleus deep brain stimulation: Limits of compensatory overactivity in Parkinson's disease. AB - Recent fMRI findings revealed that impairment in a serial prediction task in patients suffering from Parkinson's disease (PD) results from hypoactivity of the SMA. Furthermore, hyperactivity of the lateral premotor cortex sustained performance after withdrawal of medication. To further explore these findings, we here examined the impact of deep brain stimulation of the subthalamic nucleus on the activity of the putamen and premotor areas while performing the serial prediction task. To this end, we measured eight male PD patients ON and OFF deep brain stimulation and eight healthy age-matched male controls using [15O] water positron emission tomography to measure regional cerebral blood flow. As expected, PD patients showed poorer performance than healthy controls while performance did not differ between OFF and ON stimulation. Hypoactivity of the putamen and hyperactivity of the left lateral premotor cortex was found in patients compared to controls. Lateral premotor hyperactivity further increased OFF compared to ON stimulation and was positively related to task performance. These results confirm that the motor loop's dysfunction has impact on cognitive processes (here: prediction of serial stimuli) in PD. Extending prior data regarding the role of the lateral premotor cortex in cognitive compensation, our results indicate that lateral premotor cortex hyperactivity, while beneficial in moderate levels of impairment, might fail to preserve performance in more severe stages of the motor loop's degeneration. PMID- 30003901 TI - The Effects of Exercise and Physical Activity on Weight Loss and Maintenance. AB - Obesity represents a major health problem in the United States and is associated with increased prevalence of cardiovascular (CV) disease risk factors. Physical activity (PA) and exercise training (ET) are associated with reduced CV risk, improved cardiometabolic risk factors, and facilitated weight loss through creating a negative energy balance. Clinicians need to counsel overweight and obese patients on how much PA/ET is needed to promote weight loss and weight loss maintenance. This will help establish realistic expectations and maximize improvements in CV risk factors. Although the minimum guidelines for aerobic PA (150 min of moderate or 75 min of vigorous physical activity per week) can improve CV health, these levels are generally inadequate for clinically significant weight loss or weight maintenance without caloric restriction. The purpose of this review is to evaluate the role of ET to promote clinically significant weight loss and promote weight maintenance. In particular, we will evaluate the likelihood of weight loss from ET programs composed of aerobic training only, resistance training only and programs that combine diet and ET. We will also explore the role of PA in promoting short-term and long-term weight maintenance. PMID- 30003904 TI - Aging-associated changes of movement-related functional connectivity in the human brain. AB - Motor performance declines with normal aging. Previous neuroimaging work revealed aging-related general increases in neural activity, especially in the prefrontal and pre-motor areas, associated with a loss of hemispheric lateralization. However, the functional mechanisms underlying these changes and their relation to aging-associated motor decline to date remain elusive. To further elucidate the neural processes underlying aging-related motor decline, we recorded EEG from younger and older subjects while they performed a finger-tapping task. As a measure of synchronization between motor areas, we computed the inter-regional phase-locking value which reflects functional connectivity between distinct neural populations. Behavioral data revealed increased movement times in older subjects. EEG data showed that phase locking in the delta-theta frequencies is a general, age-independent phenomenon underlying the execution of simple finger movements. In stark contrast, the extent of synchronization between motor areas significantly differed dependent upon age of subjects: multiple additional intra- and inter-hemispheric connections were observed in older subjects. Our data shed light upon the results of previous neuroimaging studies showing aging-related increases in neural activation. In particular, data suggest that the observed aging-dependent substantial intra- and inter-hemispheric reorganization of connectivity between the corresponding motor areas underlies the previously reported loss of lateralization in older subjects. The changes observed are likely to represent compensatory mechanisms aiming at preserved task performance in older subjects. PMID- 30003905 TI - Comparative proteomics reveals the neurotoxicity mechanism of ER stressors tunicamycin and dithiothreitol. AB - Severity or duration of endoplasmic reticulum (ER) stress leads to two different cellular events: cell survival and apoptosis. Drug-induced ER stress or neurotoxicity has been observed as one of the main side effects. However, how ER stress affects cellular signaling cascades leading to neuronal damage is still not well understood. In this study, the toxicological mechanisms of two typical ER stress inducers, tunicamycin (Tm) and dithiothreitol (DTT), were investigated by cell viability, unfolded protein response, apoptosis and proteomic responses in mouse neuro-2a cells. A large portion of differentially expressed proteins (DEPs) that participate in protein synthesis and folding were identified in the Tm treated group, indicating adaptive cellular responses like the unfolded protein response were activated, which was not the case in the DTT treated group. Interestingly, KEGG pathway analysis and validation experiments revealed that proteins involved in proteasomal degradation were down-regulated by both inducers, while proteins involved in ubiquitination were up-regulated by Tm and down-regulated by DTT. A protein responsible for delivering ubiquitinated proteins to the proteasome, the UV excision repair protein RAD23 homolog A (HR23 A), was discovered as a DEP altered by both Tm and DTT. This protein was down regulated in the Tm treated group and up-regulated in the DTT treated group, which explained the differences we observed in the ubquintination and proteasomal degradation pathways. Autophagy was activated in the Tm treated group, suggesting that it may serve as a compensatory effect to proteasomal degradation. Our work provides new insights into the neurotoxicity generated by various ER stress inducers and the underlying mechanisms. PMID- 30003906 TI - An epidemiological investigation of associated risk factors with equine influenza (H3N8) epidemic 2015-16 in Pakistan. AB - Infection with equine influenza viruses in unvaccinated population could cause large-scale morbidity leading to huge economic losses compromising equine welfare in developing countries. Here we conducted a matched case-control study to identify the potential risk factors responsible for the EI epidemic in Pakistan in the year 2015-16. Total of 197 laboratory-confirmed matched pairs of cases and controls were included in the study. A predesigned questionnaire-based epidemiological data was collected for this purpose from all the matched pairs respondents. Conditional logistic regression analysis was conducted analyzing the data. Multivariable regression analysis identified local equine density and frequency of manure removal as potential risk factors for the incidence of EI. Due to lack of vaccination, the spread of EI was favored supported by many infected equine population free movements. The first case of this epidemic was imported from Afghanistan which was considered as a source case for the epidemic. Management and biosecurity practices compliance was very low due to lack of awareness amongst the respondents. These findings agree with the previous findings in various developing countries. Strategic control of infected equines free movement and vaccination of the equine population are suggested in future to control such epidemics. PMID- 30003907 TI - Bacterial symbionts in human blood-feeding arthropods: Patterns, general mechanisms and effects of global ecological changes. AB - Due to their high impact on public health, human blood-feeding arthropods are one of the most relevant animal groups. Bacterial symbionts have been long known to play a role in the metabolism, and reproduction of these arthropod vectors. Nowadays, we have a more complete picture of their functions, acknowledging the wide influence of bacterial symbionts on processes ranging from the immune response of the arthropod host to the possible establishment of pathogens and parasites. One or two primary symbiont species have been found to co-evolve along with their host in each taxon (being ticks an exception), leading to various kinds of symbiosis, mostly mutualistic in nature. Moreover, several secondary symbiont species are shared by all arthropod groups. With respect to gut microbiota, several bacterial symbionts genera are hosted in common, indicating that these bacterial groups are prone to invade several hematophagous arthropod species feeding on humans. The main mechanisms underlying bacterium-arthropod symbiosis are discussed, highlighting that even primary symbionts elicit an immune response from the host. Bacterial groups in the gut microbiota play a key role in immune homeostasis, and in some cases symbiont bacteria could be competing directly or indirectly with pathogens and parasites. Finally, the effects climate change, great human migrations, and the increasingly frequent interactions of wild and domestic animal species are analyzed, along with their implications on microbiota alteration and their possible impacts on public health and the control of pathogens and parasites harbored in arthropod vectors of human parasites and pathogens. PMID- 30003908 TI - The mosquitoes (Diptera: Culicidae) of Hidalgo state, Mexico. AB - In order to document the species richness of mosquitoes (Diptera: Culicidae) and their distributions in the Mexican state of Hidalgo, collecting trips were conducted to all physiographic regions (Coastal Plain of North Gulf, Sierra Madre Oriental, and Neo-volcanic Axis) and subregions of the state. Additionally, mosquito specimens from Hidalgo deposited in the Collection of Arthropods of Medical Importance (CAIM) were reexamined. A total of 3225 specimens were collected and studied and an additional 69 pinned mosquitoes and 15 microscope slides in CAIM were examined. The two Culicidae subfamilies Anophelinae and Culicinae, 8 tribes, 12 genera, 24 subgenera, and 56 species were documented. Of these, 4 tribes, 7 genera, 13 subgenera, and 26 species are new records for the mosquito fauna of Hidalgo. Nine species previously recorded were not found in the collections made during this study. Taxonomic notes, new distribution records, and comments about the medical importance of the species found are included. PMID- 30003909 TI - Hybrid of dehydroergosterol and nitrogenous alternariol derivative from the fungus Pestalotiopsis uvicola. AB - A new hybrid of dehydroergosterol and nitrogenous alternariol derivative, pestauvicomorpholine A (1), and three alternariol analogues (2-4) including a new aminated one, pestauvicolactone A (2), were isolated from the fermentation product of the fungus Pestalotiopsis uvicola on rice media. Compounds 1 and 2 represent the first example of aza-alternariol and aza-alternariol-steroid derived from transamination followed by intermolecular hetero-Diels-Alder reaction. PMID- 30003910 TI - 1H NMR determination of adulteration of anabolic steroids in seized drugs. AB - Counterfeiting and adulteration of pharmaceuticals is a prevalent problem worldwide and represents a major health risk to the population, with anabolic steroids being one of the main classes of drugs consumed and obtained from dubious sources. In this work, we propose the use of the 1H NMR technique to evaluate formulations containing anabolic steroids, with analysis of 40 samples of anabolic drugs that are used in injectable and capsule forms. The samples analyzed presented the following active ingredients: testosterone propionate, testosterone phenylpropionate, testosterone isocaproate, testosterone decanoate, testosterone cypionate, testosterone undecanoate, stanozolol, drostanolone propionate, trenbolone acetate, oxymetholone, and methandrostenolone. The 1H NMR spectroscopic measurements were performed using a 600 MHz Bruker Avance III spectrometer, with deuterated chloroform (CDCl3) containing 0.1% TMS as solvent. Of the 40 samples analyzed, eight did not show the presence of the active principle stated on the label. Three types of adulteration were found in the analyzed samples: absence of the active ingredient, adulteration with other substances, and concentration values below those indicated on the label. Sildenafil citrate was found in four samples. The GC-MS technique was used to confirm the adulteration results found using 1H NMR. Quantitative determination by NMR was performed using internal standard and ERETIC 2 methods, and the results obtained were statistically the same. PMID- 30003911 TI - Testosterone enhances expression and functional activity of epithelial sodium channel (ENaC), cystic fibrosis transmembrane regulator (CFTR) and sodium hydrogen exchanger (NHE) in vas deferens of sex-steroid deficient male rats. AB - : Effects of testosterone on expression and functional activity of ENaC, CFTR and NHE in vas deferens were investigated. METHODS: Orchidectomized, adult male rats were given 125 and 250 MUg/kg/day testosterone subcutaneously, with or without flutamide and finasteride for seven consecutive days. At the end of the treatment, rats were anesthetized and vas deferens were perfused. Changes in vas deferens fluid secretion rate, pH, HCO3-, Cl- and Na+ concentrations were recorded in the presence of amiloride and Cftr inh-172. Rats were then sacrificed and vas deferens were harvested and subjected for molecular biological analysis. RESULTS: Testosterone treatment caused the fluid pH and HCO3- concentrations to decrease but secretion rate, Cl- and Na+ concentrations to increase, where upon amiloride administration, the pH and HCO3- concentration increased but Cl- and Na+ concentrations further increased. In testosterone-treated rats, administration of Cftr inh-172 caused all fluid parameters to decrease. In testosterone-treated rats co-administered with flutamide or finasteride, pH and HCO3- concentration increased but fluid secretion rate, Cl- and Na+ concentrations decreased and these parameters were not affected by amiloride or Cftr inh-172 administration. Under testosterone influence, CFTR and gamma-ENaC were highly expressed at the apical membrane while NHE-1 and 4 were highly expressed at the basolateral membrane of vas deferens epithelium. Meanwhile, NHE 2 and 3 were highly expressed at the apical membrane. CONCLUSIONS: Differential expression of ENaC, CFTR and NHE in vas deferens under testosterone influence indicated the important role of these transporters in creating optimal fluid microenvironment that is essential for preserving male fertility. PMID- 30003912 TI - A tri-enzyme co-immobilized magnetic complex: Process details, kinetics, thermodynamics and applications. AB - A tri-enzyme mixture of cellulase, pectinase and xylanase present in fermentation broth of Aspergillus niger culture was directly recovered by solvent precipitation and co-immobilized on magnetic nanoparticles (MNPs) by cross linking with glutaraldehyde. A 2:1 ratio of isopropanol:total protein in the fermentation broth gave a precipitate with maximal activity recovery of the three enzymes. The co-immobilization on MNPs was optimized at 30 mM glutaraldehyde for 3 h incubation, and 3:1 MNPs:enzyme ratio, yielding a maximum activity recovery of cellulase (80.25 +/- 1.03%), pectinase (84.76 +/- 1.71%) and xylanase (75.62 +/- 0.76%), respectively. The tri-enzyme co-immobilized MNPs were characterized by particle size analysis, FTIR, XRD, VSM and SEM studies, and showed enhanced thermal stability as evident from lower kd, higher t1/2 and D-value in the range of 55-75 degrees C. The tri-enzyme co-immobilized MNPs showed a shift in optimum temperature from 55 to 60 degrees C with improved pH tolerance along with a slender rise in kinetic constants and enhanced thermodynamic parameters. It was stable for 36 days at 5 degrees C, and retained >90% activity up to 4 cycles. The tri-enzyme co-immobilized MNPs were successfully utilized for extraction of piperine from black pepper, preparation of sugarcane cell protoplasts, and clarification of papaya juice with prominent yield and reusability vis-a-vis traditional methods. PMID- 30003913 TI - Protein kinase A-dependent insulinotropic effect of selected flavonoids. AB - In the present study, we have estimated the binding affinities of nine flavonoids with cAMP sensing protein kinase A (PKA) by molecular docking. Furthermore, their potential roles in stimulating insulin secretion in a PKA-dependent manner were evaluated in isolated islets using H-89, a PKA inhibitor. Among selected flavonoids, i.e. eriodictyol, kaempferol, hesperetin, naringin, apigenin, hesperidin, quercetin, naringenin and rutin, we found that eriodictyol, kaempferol, and naringenin speculated the best binding interactions with crucial residues in PKA binding pocket. Glucose-dependent insulin secretion was inhibited by eriodictyol, kaempferol and naringenin of 92%, 87%, and 89%, respectively in isolated islets co-incubated with H-89. In contrast, quercetin also got binding with PKA; however, showed no significant PKA-dependent insulinotropic activity in vitro. Rutin showed the least docking interactions with PKA, reflects well in vitro by exhibiting a PKA-independent mode of action. Naringin, hesperetin, hesperidin, and apigenin showed favourable docking affinities with PKA but not with the hot spot residues. Although naringin and hesperetin mimic well in vitro by showing PKA-independent mode of action, hesperidin and apigenin were still exhibited the PKA-dependent effect. The present work suggests that few of the selected flavonoids have strong potential to be used as alternative insulin secretagogues in diabetic treatment. PMID- 30003914 TI - JNK2 silencing and caspase-9 activation by hyperosmotic polymer inhibits tumor progression. AB - c-Jun N-terminal kinase 2 (JNK2) is primarily responsible for the oncogenic transformation of the transcription factor c-Jun. Expression of the proto oncogene c-Jun progresses the cell cycle from G1 to S phase, but when its expression becomes awry it leads to uncontrolled proliferation and angiogenesis. Delivering a JNK2 siRNA (siJNK2) in tumor tissue was anticipated to reverse the condition with subsequent onset of apoptosis which predominantly requires an efficient delivering system capable of penetrating through the compact tumor mass. In the present study, it was demonstrated that polymannitol-based vector (PMGT) with inherent hyperosmotic properties was able to penetrate through and deliver the siJNK2 in the subcutaneous tumor of xenograft mice. Hyperosmotic activity of polymannitol was shown to account for the enhanced therapeutic delivery both in vitro and in vivo because of the induction of cyclooxygenase-2 (COX-2) which stimulates caveolin-1 for caveolae-mediated endocytosis of the polyplexes. Further suppression of JNK2 and hence c-Jun expression led to the activation of caspase-9 to induce apoptosis and inhibition of tumor growth in xenograft mice model. The study exemplifies PMGT as an efficient vector for delivering therapeutic molecules in compact tumor tissue and suppression of JNK2 introduces a strategy to inhibit tumor progression. PMID- 30003915 TI - The inhibitory effect of saPLIgamma, a snake sourced PLA2 inhibitor on carrageenan-induced inflammation in mice. AB - SaPLIgamma is a natural phospholipase A2 (PLA2) inhibitor, isolated from Sinonatrix annularis, that has been demonstrated to protect against envenomation by other venomous snakes. As snake venom PLA2s and mammalian secretory PLA2s are similar, saPLIgamma is thought to have potential to alleviate inflammatory reactions in which PLA2s act as a key enzyme for arachidonic acid release. The aim of this study was to investigate the anti-inflammatory effects and mechanisms of action of saPLIgamma in an animal model of carrageenan-induced acute inflammation. The results indicated that saPLIgamma inhibited PLA2 subtypes extensively, especially IIA-PLA2, in a dose-dependent manner. Paw swelling in mice was reduced markedly by intraperitoneal saPLIgamma 2.5 mg/kg, and the effect was significantly better than observed with dexamethasone at the same dose. Lower neutrophil infiltration and tissue edema was observed in the paws of saPLIgamma treated mice. Additionally, carrageenan-induced cyclooxygenase-2 (COX-2) and pro inflammatory cytokines (TNFalpha and IL-1beta) were also significantly down regulated by saPLIgamma in a dose-dependent manner. These results suggested that saPLIgamma had effective anti-inflammatory effects in vivo, and these were produced by blocking mammalian IB, IIA, V and X sPLA2 subtypes. PMID- 30003916 TI - Phoneutria nigriventer venom: A pharmacological treasure. AB - In millions of years, spiders have optimized their venoms in order to assure successful prey capture and defence against predators. Spider venoms have become unique cocktails of biological active components enabling potentially interesting application for drug discovery or for agricultural purposes. The venom of Phoneutria nigriventer has been studied for over 60 years. This spider is responsible for a high number of envenomations with severe clinical manifestations in humans, which necessitates a comprehensive knowledge of its venom composition. With over 40 different neurotoxic peptides characterized so far and still many more awaiting identification, this venom is undoubtedly a pharmacological treasure. This review provides an overview of the Phoneutria nigriventer toxins known today and describes their mechanism of action at a molecular level. We critically discuss the potential of the Phoneutria nigriventer venom peptides as pharmaceutical tools or lead compounds for drug development. PMID- 30003917 TI - Exposure routes and health effects of microcystins on animals and humans: A mini review. AB - Microcystins (MCs) pollution has quickly risen in infamy and has become a major problem to public health worldwide. MCs are a group of monocyclic hepatotoxic peptides, which are produced by some bloom-forming cyanobacteria in water. More than 100 different MCs variants posing a great threat to animals and humans due to their potential carcinogenicity have been reported. To reduce MCs risks, the World Health Organization has set a provisional guideline of 1 MUg/L MCs in human's drinking water. This paper provides an overview of exposure routes of MCs into the human system and health effects on different organs after MCs exposure including the liver, intestine, brain, kidney, lung, heart and reproductive system. In addition, some evidences on human poisoning and deaths associated with MCs exposure are presented. Finally, in order to protect human life against the health threats posed by MCs, this paper also suggests some directions for future research that can advance MCs control and minimize human exposure to MCs. PMID- 30003919 TI - Hemolymph defensin from the hard tick Haemaphysalis longicornis attacks Gram positive bacteria. AB - Ticks are key vectors of some important diseases of humans and animals. Although they are carriers of disease agents, the viability and development of ticks are not harmed by the infectious agents due to their innate immunity. Antimicrobial peptides directly protect hosts against pathogenic agents such as viruses, bacteria, and parasites. Among the identified and characterized antimicrobial peptides, defensins have been considerably well studied. Defensins are commonly found among fungi, plants, invertebrates, and vertebrates. The sequence of the tick hemolymph defensin (HEdefensin) gene from the hard tick Haemaphysalis longicornis was analyzed after identification and cloning from a cDNA library. HEdefensin has a predicted molecular mass of 8.15 kDa including signal peptides and a theoretical isoelectric point of 9.48. Six cysteine residues were also identified in the amino acids. The synthetic HEdefensin peptide only showed antibacterial activity against Gram-positive bacteria such as Micrococcus luteus. A fluorescence propidium iodide exclusion assay also showed that HEdefensin increased the membrane permeability of M. luteus. Additionally, an indirect fluorescent antibody test showed that HEdefensin binds to M. luteus. These results suggested that HEdefensin strongly affects the innate immunity of ticks against Gram-positive bacteria. PMID- 30003918 TI - Cdc45/Mcm2-7/GINS complex down-regulation mediates S phase arrest in okadaic acid induced cell damage. AB - Okadaic acid (OA) is one of the most common and widespread marine toxins and causes acute gastrointestinal symptoms known as diarrheic shellfish poisoning (DSP) in humans. Although OA is not classified as a typical neurotoxin, an increasing number of studies have reported its neurotoxic effects. However, most of the available studies have focused on OA-induced inhibition of serine/threonine protein phosphatases, while the molecular mechanism of OA induced neurotoxicity remains largely unclear. To better understand the potentially toxicological profile of OA, cell cycle arrest, DNA damage and alterations in gene expression in the human neuroblastoma cell line SHSY5Y upon OA exposure were determined using flow cytometry, comet assay, and transcriptome microarray. The results showed that OA could induce cell cycle arrest at S phase and might be involved in significant DNA strand breaks. Gene expression profiling indicated that the differentially expressed genes after OA exposure were significantly enriched in the "DNA replication" and "cell cycle" pathways. Real time PCR result had further validated that down-regulation of the Cdc45/Mcm2 7/GINS complex might be the major factor regulating those alterations. These findings provide new insight into the molecular mechanisms of OA-induced neurotoxicity, and the current data may also provide a basis for future studies. PMID- 30003920 TI - Non-host larvae negatively impact persistence of the entomopathogen Beauveria bassiana in soil. AB - A better understanding of the ecology of the insect pathogenic fungus, Beauveria bassiana, in soil is needed to identify reasons behind the variable efficacy often seen after field application. A transformed strain of a candidate commercial strain of B. bassiana (F418 gfp tr3), expressing the green fluorescent protein and the hygromycin B resistance gene, was used to assess the effects of the larvae of a host insect, Tenebrio molitor L. (Coleoptera: Tenebrionidae), a non-host, Costelytra zealandica (Coleoptera: Scarabaeidae) and the absence of larvae on the persistence of F418 gfp tr3 in pasteurised and non-sterile soil over 4 months. In the presence of a T. molitor larvae, F418 gfp tr3 populations increased significantly in pasteurised and non-sterile soil; however, populations increased less in non-sterile soil than in pasteurised soil. Lower populations of F418 gfp tr3 were recovered in pasteurised soil in the presence of C. zealandica larvae than in pasteurised soil without larvae. No difference was observed between F418 gfp tr3 populations in non-sterile soil with a non-host larvae or without larvae. Accompanying studies showed that F418 gfp tr3 conidia germinated and produced appressoria on live and excised cuticle of non-host (C. zealandica) larvae but infection did not occur, leading to a net loss of viable conidia in the soil. Conidia administrated orally to C. zealandica larvae were viable on recovery from faecal samples, suggesting that ingestion of the fungus by the larvae had little impact on the viable fungal population. Soil bacterial and fungal community patterns were analysed using Single-Strand Conformation Polymorphism (SSCP) and showed a correlation between changes in F418 gfp tr3 persistence in pasteurised and non-sterile soil and changes in soil communities in the presence of a host insect, non-host insect or in the absence of insect. In pasteurised soil, non-specific germination of F418 gfp tr3 conidia on the non host larval cuticle and the presence of antagonistic bacteria introduced with the field-collected larvae are most likely responsible for the differences observed. The more complex microbial community structures in non-sterile soil could lead to fungistasis, preventing potentially antagonistic bacteria degrading conidia or inhibiting attachment and germination on the non-host larval cuticle, resulting in the observed lack of difference between non-host and no larval treatments. PMID- 30003921 TI - Mosquito-larvicidal BinA toxin displays affinity for glycoconjugates: Proposal for BinA mediated cytotoxicity. AB - Lysinibacillus sphaericus parasporal BinAB toxin displays mosquito larvicidal activity against Culex and Anopheles, but several Aedes species are refractory. Recently reported crystal structure of BinAB revealed the presence of N-terminal lectin-like domain in BinA. Hemagglutination and hemolytic activities were not observed for BinA in the present studies. We attempted to characterize carbohydrate specificity of BinA by high-throughput approaches using extrinsic fluorescence and thermofluor shift assay. A total of 34 saccharides (mono-, di- and polysaccharides, and glycoproteins) were used for initial high-throughput screening. The promising glycans were identified based on significant change in the fluorescence intensity. Surface plasmon resonance revealed differential binding of BinA with glycoproteins (fetuin, asialofetuin and thyroglobulin) and affinity for simple sugars, l-fucose and l-arabinose. In the limited carbohydrate competition assay, arabinose, fucose and fetuin inhibited BinA toxicity towards Culex larvae. This study for the first time provides direct evidence that BinA is competent to bind diverse and structurally different glycosylated proteins. This activity may be linked to its intracellular cytotoxicity, as protein N glycosylation is thought to be critical for development and survival of insect larvae. The glycoproteins do not form stable complexes with BinA, however, as observed in the pull-down assay using affinity immobilized BinA and in native PAGE analysis. As BinA displays only mild affinity with receptor polypeptide, we hypothesize that toxin-receptor specificity of BinA in Culex may be mediated by dual interaction of BinA with glycan core of GPI anchor and receptor polypeptide. The study shall be useful for refining strategies for improving larvicidal activity and for broadening target specificity of BinAB toxin. PMID- 30003922 TI - Digestive gland inclusion bodies in queen conch (Lobatus gigas) are non parasitic. AB - Unusual inclusion bodies occur within the epithelial cells of the digestive gland of queen conch, Lobatus gigas, and have previously been described as apicomplexan parasites. The aim of this study was to investigate the parasitic features of these inclusion bodies in queen conch. L. gigas from St. Kitts (Caribbean Sea) consistently (100% of n = 61) showed large numbers of ovoid to tri-bulbous dark brown inclusion bodies (15 * 30 um) within vacuolar cells. Histochemical stains demonstrated iron, melanin, and glycoprotein and/or mucopolysaccharide within the inclusion bodies. Microscopic features indicative of a host response to injury were lacking in every case, as were consistent morphological forms to indicate distinct parasitic stages. Transmission electron microscopy failed to reveal cellular organelles of parasitic organisms and DNA extractions of purified inclusion bodies did not yield sufficient concentrations for successful PCR amplification. Scanning electron microscopy with energy dispersive X-ray analysis revealed a number of elements, particularly iron, within the inclusion bodies. We conclude that the inclusion bodies are not an infectious agent, and hypothesize that they represent a storage form for iron, and potentially other elements, within a protein matrix. Similar structures have been described in the digestive glands of other invertebrates, including prosobranchs. PMID- 30003923 TI - Mathematical analysis of the role of hospitalization/isolation in controlling the spread of Zika fever. AB - The Zika virus is transmitted to humans primarily through Aedes mosquitoes and through sexual contact. It is documented that the virus can be transmitted to newborn babies from their mothers. We consider a deterministic model for the transmission dynamics of the Zika virus infectious disease that spreads in, both humans and vectors, through horizontal and vertical transmission. The total populations of both humans and mosquitoes are assumed to be constant. Our models consist of a system of eight differential equations describing the human and vector populations during the different stages of the disease. We have included the hospitalization/isolation class in our model to see the effect of the controlling strategy. We determine the expression for the basic reproductive number R0 in terms of horizontal as well as vertical disease transmission rates. An in-depth stability analysis of the model is performed, and it is consequently shown, that the model has a globally asymptotically stable disease-free equilibrium when the basic reproduction number R0 < 1. It is also shown that when R0 > 1, there exists a unique endemic equilibrium. We showed that the endemic equilibrium point is globally asymptotically stable when it exists. We were able to prove this result in a reduced model. Furthermore, we conducted an uncertainty and sensitivity analysis to recognize the impact of crucial model parameters on R0. The uncertainty analysis yields an estimated value of the basic reproductive number R0 = 1.54. Assuming infection prevalence in the population under constant control, optimal control theory is used to devise an optimal hospitalization/isolation control strategy for the model. The impact of isolation on the number of infected individuals and the accumulated cost is assessed and compared with the constant control case. PMID- 30003924 TI - Role of circulating miR-182 and miR-150 as biomarkers for cirrhosis and hepatocellular carcinoma post HCV infection in Egyptian patients. AB - In Egypt, liver diseases are exceptionally high, maintaining the highest prevalence of hepatitis C virus (HCV) worldwide, and increasing rates of hepatocellular carcinoma (HCC). Available diagnostic methods show poor performance in early diagnosis of HCC. Definite pathogenic factors contributing in the development of HCV are still lacking. MicroRNAs have been reported as promising biomarkers for cancers diagnosis and in virus-host interaction. This study was conducted to detect the role of miR-182 and miR-150 as biomarkers for development of cirrhosis and malignant transformation in HCV infected patients. The expression of miR-182 and miR-150 was evaluated using real-time quantitative PCR (qRT-PCR) in 120 subjects: 40 HCC patients, 40 hepatitis C patients (20 cirrhotic and 20 non-cirrhotic HCV genotype 4) and 40 healthy controls. In HCC, statistically significant decrease of miR-182 and miR-150 compared to non cirrhotic HCV patients (p = 0.015, p = 0.006 respectively) and of miR-150 compared to controls (p = 0.039). In cirrhotic HCV patients, significant down regulation of miR-182 and miR-150 compared to non-cirrhotic HCV (p = 0.003, p = 0.024 respectively). On the other hand, significant upregulation of miR-182 was observed in non-cirrhotic HCV compared to controls (p = 0.036). Alpha-fetoprotein (AFP) showed sensitivity 15% for HCC diagnosis at the cut-off value of 400 ng/ml, while combining AFP with miR-182 and miR-150, resulted in improving sensitivity to (90%) and diagnostic accuracy to (80%). miR-182 and miR-150 can be used as non invasive biomarkers for HCC and combination of these miRNAs and AFP markedly improve the diagnosis of HCC. Both miR-182 and miR-150 can also be used as predictive markers for detection of cirrhosis progression in HCV infected patients. PMID- 30003925 TI - An optimized high-throughput fluorescence plate reader-based RSV neutralization assay. AB - A licensed vaccine for respiratory syncytial virus (RSV) has yet to be developed, and a reliable and repeatable neutralizing assay is indispensable for vaccine development. Here, we demonstrated an optimized high-throughput RSV neutralization assay that utilizes a fluorescence plate reader (reader) as a substitute for flow cytometry to detect fluorescent signals in RSV-A2 mKate infected cells. Furthermore, this study tested the influence of virus input and infectivity on the neutralizing assay and highlighted critical factors (together with a suggested protocol) for obtaining stable data using this assay. PMID- 30003926 TI - A novel magnetic beads-based method for polioviral concentration from environmental samples. AB - Environmental surveillance (EnvS)2 is an important tool for monitoring the presence of poliovirus in endemic and poliovirus free regions. Unlike acute flaccid paralysis (AFP)3 surveillance, EnvS can monitor large populations using small numbers of samples and detect the introduction of poliovirus even before the appearance of AFP cases. Early detection and timely response can prevent the onset of poliovirus associated AFP, as was demonstrated by silent poliovirus transmission in Israel in 2013. Although EnvS is currently recommended as supplementary to AFP surveillance, it is limited to laboratories with equipment for poliovirus concentration and to regions where samples can be easily transported under temperature controlled conditions to such facilities. However the highest risk of poliovirus re-emergence is in developing countries where such conditions do not exist. We developed and evaluated an affinity purification method using antibody or poliovirus receptor (CD155) presenting bacteriophage covered magnetic beads for poliovirus concentration. This method requires only simple, inexpensive and portable equipment. Though tested only on Sabin 1 spiked sewage samples it provided better recovery than our current polyethylene glycol (PEG)4/NaCl- based concentration method. On site use of this method might facilitate EnvS in currently inaccessible remote regions by significantly reducing the volume of sample that needs to be transported back to the laboratory under temperature-controlled conditions5. PMID- 30003927 TI - Suppression of ribosomal protein RPS6KB1 by Nexrutine increases sensitivity of prostate tumors to radiation. AB - Radiation therapy (XRT) is a standard treatment for prostate cancer (PCa). Although dose escalation increases local control, toxicity hampers further escalation. Broader improvement will be possible by the addition of adjuvant therapies, which can synergize with radiation and thus improve efficacy. We have identified a natural compound (Nexrutine, Nx) that inhibits the survival and growth of PCa cells in combination with radiation. Combination studies demonstrated strong interaction between Nx and radiation both in vitro in multiple PCa cell lines and in the Transgenic adenocarcinoma of mouse prostate (TRAMP) model. Nx potentiated growth inhibitory effects of IR by down regulating ribosomal protein S6K (RPS6KB1), CyclinD1, Chk1 and HIF-1 alpha and prolonging G2/M checkpoint block. RPS6KB1 is upregulated in prostate cancers and its expression is correlated with tumor grade. Knockdown of RPS6KB1 in PCa cells increased their sensitivity toward radiation-induced survival inhibition. Overall, we provide scientific evidence (i) in support of Nx as an adjuvant in PCa patients receiving XRT (ii) suggesting that RPS6KB1 is an important player in Nx-mediated combinatorial benefits and emphasizes that RPS6KB1 is a novel target for PCa treatment. These data underscore the need to test the agent in additional preclinical models to validate these observations. PMID- 30003928 TI - Decrease in phosphorylated ERK indicates the therapeutic efficacy of a clinical PI3Kalpha-selective inhibitor CYH33 in breast cancer. AB - PI3Ks are frequently hyper-activated in breast cancer and targeting PI3Kalpha has exhibited promising but variable response in preclinical and clinical settings. CYH33 is a novel PI3Kalpha-selective inhibitor in phase I clinical trial. We investigated the efficacy of CYH33 against breast cancer and explored potential predictive biomarkers. CYH33 potently restrained tumor growth in mice bearing human breast cancer cell xenografts and in R26-Pik3caH1047R;MMTV-Cre transgenic mice. CYH33 significantly inhibited proliferation of a panel of human breast cancer cells, while diversity in sensitivity has been observed. Cells harboring activating PIK3CA mutation, amplified HER2 were more responsive to CYH33 than their counterparts. Besides, cells in HER2-enriched or luminal subtype were more sensitive to CYH33 than basal-like breast cancer. Sensitivity to CYH33 has been further revealed to be associated with induction of G1 phase arrest and simultaneous inhibition of Akt and ERK. Sensitivity of patient-derived xenograft to CYH33 was also positively correlated with decrease in phosphorylated ERK. Taken together, CYH33 is a promising PI3Kalpha inhibitor for breast cancer treatment and decrease in ERK phosphorylation may indicate its efficacy, which provides useful clues for rational design of the ongoing clinical trials. PMID- 30003929 TI - Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABAA receptor. AB - Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p FADD and other neuroplastic markers in brain. Low (5-15 mg/kg) and high (150 mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex. During the time course of KET (150 mg/kg)-induced sleep (up to 50 min) p-MEK was increased (up to +79%) and p-ERK decreased (up to -46%) indicating disruption of MEK to ERK signal. Subhypnotic KET (5-15 mg/kg) also revealed uncoupling of p-MEK (+13-81%) to p-ERK (unchanged content). KET did not alter contraregulatory MAPK mechanisms such as inactivated p-MEK1 (ERK dampening) and phosphatases MKP1/2/3 (ERK dephosphorylation). As other relevant findings, KET (5, 15 and 150 mg/kg) upregulated p-FADD in a dose-dependent manner, and for the hypnotic dose the effect paralleled the time course of sleep which resulted in increased p-FADD/FADD ratios. KET (150 mg/kg) also increased NF-kappaBeta and PSD-95 neuroplastic markers. Flumazenil (a neutral allosteric antagonist at GABAA receptor) prolonged KET sleep and blocked p-MEK upregulation, indicating the involvement of this receptor as a negative modulator. SL-327 (a MEK inhibitor) augmented KET sleep, further indicating the relevance of reduced p-ERK1/2 in KET induced hypnosis. These findings suggest that hypnotic and subhypnotic doses of KET inducing uncoupling of p-MEK to p-ERK signal and regulation of p-ERK (downregulation) and p-FADD (upregulation) may participate in the expression of some of its adverse effects (e.g. amnesia, dissociative effects). PMID- 30003931 TI - GLP-1 receptor agonists stimulate ANGPTL8 production through the PI3K/Akt pathway in a GLP-1 receptor-dependent manner. AB - The level of serum angiopoietin-like protein 8 (ANGPTL8), a novel hepatokine, is associated with obesity and type 2 diabetes mellitus (T2DM). The aims of this study were to investigate whether serum ANGPTL8 level in patients with T2DM was affected by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, and to determine whether and how GLP-1R agonists regulated ANGPTL8 production in hepatocytes. A multiple-center trial was conducted in China. Among 240 patients with T2DM enrolled in this trial, 195 patients adhered to a 16-week exenatide treatment and follow-up. Human liver cell line HepG2 cells were incubated for 24 h with either exendin-4 (a native form of exenatide) or liraglutide in the presence or absence of GLP-1R antagonist exendin (9-39) and PI3K inhibitor LY294002. Change of serum ANGPTL8 level in patients with T2DM and regulation of ANGPTL8 production by the GLP-1R agonists in HepG2 cells were evaluated. Results showed that compared with baseline, exenatide treatment significantly increased serum ANGPTL8 level, and lowered body weight, fasting blood glucose (FBG) and glycated hemoglobin A1c (HbA1c) in patients with T2DM (all P < 0.05). The exenatide treatment-mediated upregulation of serum ANGPTL8 level was not associated with the levels of its lowering effects on body weight, FBG and HbA1c stratified by the median. Moreover, exendin-4 or liraglutide dose dependently upregulated the level of ANGPTL8 expression and secretion in HepG2 cells, which was eliminated by adding exendin (9-39) and LY294002. In conclusion, GLP-1R agonists enhance ANGPTL8 production in vivo and in vitro, which is mediated via the PI3K/Akt pathway in a GLP-1R-dependent manner. PMID- 30003930 TI - 7beta-hydroxycholesterol-induced cell death, oxidative stress, and fatty acid metabolism dysfunctions attenuated with sea urchin egg oil. AB - Some oxysterols resulting either from enzymatic oxidation or autoxidation of cholesterol are associated with age-related diseases including neurodegenerative diseases. Among these oxysterols, 7beta-hydroxycholesterol (7beta-OHC) is often found at increased levels in patients. It is therefore important to identify molecules or mixtures of molecules to prevent 7beta-OHC-induced side effects. Consequently, murine oligodendrocytes (158N) were cultured in the absence or presence of 7beta-OHC (20 MUg/mL, 24 h) with or without a natural oil extracted from sea urchin (Paracentrotus lividus) eggs known for its biological activity. Firstly, the chemical composition of this oil was determined using 31P NMR and GC MS. Secondly, this oil was used to reduce 7beta-OHC-induced side effects. To this end, the oil (160 MUg/mL) was added to the culture medium of 158N cells 2 h before 7beta-OHC. The effects of 7beta-OHC with or without the oil on cell viability were studied with the MTT test. Photometric methods were used to analyze antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPx), as well as the generation of lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CDs)) and protein oxidation product (carbonylated proteins (CPs)). Gas chromatography was used to determine the fatty acid profile. With 7beta-OHC, an induction of cell death associated with oxidative stress (alteration of GPx and SOD activities) was observed; an overproduction of lipid peroxidation products (MDA and CDs) and CPs was also revealed. Sea urchin egg oil attenuated 7beta-OHC-induced cytotoxicity: 7beta-OHC induced cell death was reduced, GPx and SOD activities were normalized, and lower levels of MDA, CDs and CPs were produced. In addition, whereas a disturbed fatty acid profile was observed with 7beta-OHC, similar fatty acid profiles were found in control cells and in cells cultured with 7beta-OHC associated with sea urchin egg oil. These data demonstrate the protective activities of sea urchin egg oil against 7beta-OHC-induced side effects on 158N cells, supporting the concept that this oil may have benefits in the prevention of neurodegenerative diseases. PMID- 30003932 TI - Lactobacillus acidophilus ameliorates pain and cartilage degradation in experimental osteoarthritis. AB - Osteoarthritis (OA) is a chronic and degenerative disease that causes pain, cartilage deformation, and joint inflammation. Lactobacillus species have been used as dietary supplements to induce the production of antimicrobial and anti inflammatory factors. The goal of this study was to determine whether Lactobacillus acidophilus ameliorates monosodium iodoacetate-induced OA. L. acidophilus showed anti-nociceptive properties and protected against cartilage destruction. It also downregulated the levels of proinflammatory cytokines and increased the levels of anti-inflammatory cytokines in the joints of OA rats. L. acidophilus additionally restored the balance between anabolic and catabolic factors in chondrocytes from OA patients. These results suggest that L. acidophilus can alleviate OA-associated pain and delay the progression of the disease by inhibiting proinflammatory cytokine production and reducing cartilage damage. PMID- 30003933 TI - Lipid-associated genetic polymorphisms are associated with FBP and LDL-c levels among myocardial infarction patients in Chinese population. AB - AIMS: Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that were associated with blood lipid levels in Europeans. However, little is known about such association in the Chinese populations. The present study was to determine the association of lipid levels susceptibility loci with the risk of China myocardial infarction (MI) patients. METHODS: A total of 401 patients with MI and 409 controls were included in the study. Five SNPs (including HNF1A rs1169286 and rs2244608, C12orf43 rs2258287, LIPA rs2246833 and TRPS1 rs2293889) were selected using a tagging single nucleotide polymorphism (tSNP) strategy. The SNP genotyping work was performed using an improved multiplex ligation detection reaction (iMLDR) technique. RESULTS: The subjects with rs1169286 CT genotype in MI cases had lower FBG levels than the subjects with rs1169286 CC/TT genotypes (P = 0.002). The subjects with rs2246833 TT genotype in MI patients had higher LDL-C levels than the subjects with rs2246833 CC/CT genotypes (P = 0.006). Several SNPs interacted with sex and age to modify TC, TG, LDL-C, CRE and FBG levels, and the risk of MI (P < 0.01 for all). However, our results disclosed no association between the SNPs and susceptibility to MI (P > 0.05 for all). CONCLUSIONS: Taken together, this study provides additional evidence that functional genetic variation of the lipid related mutations can mediate atherogenic processes and the risk of MI in humans. PMID- 30003934 TI - Respiratory changes in term infants immediately after birth. AB - INTRODUCTION: Over 5% of infants worldwide receive breathing support immediately after birth. Our goal was to define references ranges for exhaled carbon dioxide (ECO2), exhaled tidal volume (VTe), and respiratory rate (RR) immediately after birth in spontaneously breathing, healthy infants born at 36 weeks' gestational age or older. METHODS: This was a single-centre, observational study at the Royal Women's Hospital in Melbourne, Australia, a busy perinatal referral centre. Immediately after the infant's head was delivered, we used a face mask to measure ECO2, VTe, and RR through the first ten minutes after birth. Respiratory measurements were repeated at one hour. RESULTS: We analysed 14,731 breaths in 101 spontaneously breathing infants, 51 born via planned caesarean section and 50 born vaginally with a median (IQR) gestational age of 391/7 weeks (383/7-395/7). It took a median of 7 (4-10) breaths until ECO2 was detected. ECO2 quickly increased to peak value of 48 mmHg (43-53) at 143 s (76-258) after birth, and decreased to post-transitional values, 31 mmHg (28-24), by 7 min. VTe increased after birth, reaching a plateau of 5.3 ml/kg (2.5-8.4) by 130 s for the remainder of the study period. Maximum VTe was 19 ml/kg (16-22) at 257 s (82-360). RR values increased slightly over time, being higher from minute five to ten as compared to the first two minutes after birth. CONCLUSIONS: This study provides reference ranges of exhaled carbon dioxide, exhaled tidal volumes, and respiratory rate for the first ten minutes after birth in term infants who transition without resuscitation. PMID- 30003935 TI - Guidelines 2017 update: response to "In mountain and rural areas all CPR providers should perform chest compressions and rescue breaths for patients in cardiac arrest" and "Pharmacotherapy during cardiac arrest - When evidence-based data failed to be implemented in clinical practice guidelines". PMID- 30003937 TI - Whole exome sequencing reveals novel NOV and DCAF13 variants in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy. AB - OBJECTIVE: We report a large new family of familial cortical myoclonic tremor with epilepsy(FCMTE) from China and identify the possible causative gene(s) for the family. METHOD: Whole exome sequencing of blood genomic DNA from 4 patients and 2 unaffected family members were performed. Detected variants and their cosegregation were confirmed by Sanger sequencing. RESULTS: We identified c.20 G > C variant in the DCAF13 gene and c.983 T > C variant in the NOV gene cosegregating in the family. There was no additional cross-over in the family to narrow to one gene. The two DCAF13 and NOV gene variants are located on 8q23.3 and 8q24.12, which is consistent with the location 8q23.3-q24.13 reported previously for a group of Japanese families. The DCAF13 variant is located in alternative transcription start site(TSS) and the function of alternative TSS is unknown. The missense NOV variant is near the C terminus in a site that is highly conserved across species. It was predicted to be deleterious on protein function. CONCLUSIONS: In this study, we identify two novel variants in the DCAF13 and NOV genes associated with FCMTE in Asian populations. The interval between two variants is 15.6Mb, which is very close to each other. Future studies of additional families with this phenotype are warranted to confirm whether it is rare bigenic or monogenic inheritance. PMID- 30003936 TI - Systematic assessment of food item preference and reinforcer effectiveness: Enhancements in training laboratory-housed rhesus macaques. AB - The use of systematic preference assessments can enhance positive reinforcement training with captive animals. We found that the multiple stimulus without replacement (MSWO) technique identified food preferences in laboratory housed rhesus macaques, with raisins and grapes being ranked higher on average than dried apricot, pasta, and green beans (Friedman Test, chi2 (4) = 35.52, p < .001). Agreement between individuals (N = 21) was moderate (Kendall's W = 0.42), and consistency across time varied among individuals (W = .03-.90). Highly preferred items identified by the MSWO assessment were subsequently found to increase subjects' engagement in a husbandry task on which they were being trained (Mann-Whitney U = 6.00, p = .002) and to improve performance on a progressive ratio schedule (Wilcoxon signed-rank test, Z = -2.17, p = .03) when compared with low preference items. The progressive ratio technique supplements other preference assessment techniques by measuring the amount of work a subject will do to gain access to an item. The use of more effective reinforcers identified through systematic assessment has the potential to increase animal performance on husbandry and research tasks and to improve animal welfare in the laboratory setting. PMID- 30003938 TI - Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation. AB - RNA binding proteins are a diverse class of proteins that regulate all aspects of RNA metabolism. Accumulating studies indicate that heterogeneous nuclear ribonucleoproteins are associated with cellular adaptations in response to drugs of abuse. We recently mapped and validated heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1) as a quantitative trait gene underlying differential behavioral sensitivity to methamphetamine. The molecular mechanisms by which hnRNP H1 alters methamphetamine behaviors are unknown but could involve pre- and/or post-synaptic changes in protein localization and function. Methamphetamine initiates post-synaptic D1 dopamine receptor signaling indirectly by binding to pre-synaptic dopamine transporters and vesicular monoamine transporters of midbrain dopaminergic neurons which triggers reverse transport and accumulation of dopamine at the synapse. Here, we examined changes in neuronal localization of hnRNP H in primary rat cortical neurons that express dopamine receptors that can be modulated by the D1 or D2 dopamine receptor agonists SKF38393 and (-)-Quinpirole HCl, respectively. Basal immunostaining of hnRNP H was localized primarily to the nucleus. D1 dopamine receptor activation induced an increase in hnRNP H nuclear immunostaining as detected by immunocytochemistry with a C-domain directed antibody containing epitope near the glycine-rich domain but not with an N-domain specific antibody. Although there was no change in hnRNP H protein in the nucleus or cytoplasm, there was a decrease in Hnrnph1 transcript following D1 receptor stimulation. Taken together, these results suggest that D1 receptor activation increases availability of the hnRNP H C-terminal epitope, which could potentially reflect changes in protein protein interactions. Thus, D1 receptor signaling could represent a key molecular post-synaptic event linking Hnrnph1 polymorphisms to drug-induced behavior. PMID- 30003939 TI - Cancer stem cells in sarcomas: Getting to the stemness core. AB - BACKGROUND: Sarcomas are rare tumors but represent the third most common malignancy in children. The cancer stem cell (CSC) paradigm is well established, and CSCs have been intensively studied in sarcomas in the past decade. SCOPE OF REVIEW: This review summarizes current knowledge on CSCs in sarcomas and provides new perspectives on the role of a deregulated stemness program in sarcomagenesis. MAJOR CONCLUSIONS: Cell surface markers have so far failed to specifically target sarcoma CSCs. Sarcomas likely arise from immature cells that undergo pathological reprogramming. Transcription factor Sox2, which is frequently upregulated in sarcomas, is directly involved in this process, and its crucial role in the acquisition and maintenance of the CSC phenotype has been demonstrated in various sarcomas. GENERAL SIGNIFICANCE: Sox2 is a core functional regulator of the stem like state and is an outstanding marker of sarcoma CSCs. Fluorescence protein based reporters of Sox2 expression might provide useful tools for subsequent studies of sarcoma CSCs. PMID- 30003940 TI - Global perspectives on the provision of diabetic retinopathy screening and treatment: Survey of health care professionals in 41 countries. AB - AIM: To assess the level of awareness and provision of screening and treatment for Diabetic Eye Disease (DED) comprising Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME) among health care professionals. METHODS: The study was conducted in two phases. The first phase consisted of a qualitative study, based on semi-structured face-to-face and telephone interviews in 8 countries. The second phase used a quantitative approach utilising online surveys in 41 countries. The survey for health care professionals comprised of 43 questions covering provider information, practice characteristics, management of adults with diabetes and specific information from ophthalmologists on screening and treatments for DR. RESULTS: There were 2329 health care professionals who participated in the online survey. More than one third of diabetes specialists surveyed reported that they did not discuss eye care with their diabetes patients. Nearly two-thirds of all health care professionals surveyed reported that they had written information about diabetes for patients available in their practice. Only one in five (22%, n = 58) primary care providers reported they had material that contained sufficient information on eye complications, and 37% (n = 252) of ophthalmologists reported that they had sufficient information on eye complications. Sixty-five percent (n = 378) of ophthalmologists reported that most of their patients presented when visual problems had already occurred. Six percent (n = 36) stated that most of their patients presented when it was already too late for effective treatment. The most substantial barriers to eye health mentioned by health care professionals responding to the survey were: a patients' lack of knowledge and/or awareness about eye complications (43%), followed by lack of importance given to eye examinations by patients (33%), and the high cost of care (32%). Ophthalmologists also reported late screening (66%), and lack of patient education materials (55%) as obstacles for improving eye health outcomes. CONCLUSION: Health care professionals need to be appropriately supported and trained so they can provide adults with diabetes with information about the risks of DR, support them in reducing their risk, and advocate for the provision of affordable DR screening and treatment as required. PMID- 30003941 TI - Type 1 diabetes impairs female fertility even before it is diagnosed. AB - AIMS: The aim of this study was to assess the fertility rate in Taiwanese women before and after a diagnosis of type 1 diabetes. The potential risk factors which may have influenced fertility were also investigated. METHODS: We conducted this retrospective, nationwide, population-based, matched cohort study using data from the Taiwan National Health Insurance Research Database. The diabetic group (n = 1191) included women with type 1 diabetes aged between 16 and 30 years in 2000. The non-diabetic group (n = 4764) was matched by sex, gender, income, and urbanization. The endpoints, including live births, abortions, and fertility, were tracked until the end of 2013. Poisson regression was used to assess incidence rate ratios (IRRs). We also analyzed the influence of autoimmune thyroid disease, diabetic ketoacidosis, diabetic complications, and daily insulin dose on the endpoints. RESULTS: The diabetic group had a lower rate of live births (IRR 0.67 [95% CI 0.62-0.73]) than the non-diabetic group, and it was even lower when combined with hyperthyroidism (IRR 0.54 [0.39-0.74]). There were also fewer live births before a diagnosis of diabetes than after a diagnosis of diabetes (IRR 0.58 [0.52-0.65] vs. 0.80 [0.71-0.90]). Diabetic ketoacidosis and a higher daily insulin dose were strongly associated with abortion. Diabetic complications significantly reduced the number of live births. CONCLUSIONS: Type 1 diabetes compromises female fertility, even before it is diagnosed. Associated hyperthyroidism further reduces fertility. Blood glucose and thyroid function surveillance in infertile females may allow for an early diagnosis of type 1 diabetes and associated thyroid disease. PMID- 30003942 TI - Exosomes and their implications in central nervous system tumor biology. AB - Exosomes are 20-100 nm cellular derived vesicles that upon discovery, were thought to be a form of cellular recycling of intracellular contents. More recently, these vesicles are under investigation for their purported significant roles in intercellular communication in both healthy and diseased states. Herein, we focus on the secretion of exosomes associated with glioblastoma, as most exosome studies on brain tumors have been performed in this tumor type. However, we included exosomes secreted from other forms of brain tumors for comparison as available. Exosomes contain intracellular content that can be transferred to other cells in the tumor or to cells of the immune system and endothelial cells. These recipient cells may subsequently take on oncogenic properties, including therapeutic resistance, cancer progression, and angiogenesis. Genetic components (DNA, RNA and miRNA) of the cell of origin may be included in the secreted exosomes. The presence of genetic material in the exosomes could serve as a biomarker for mutations in tumors, potentially leading to novel treatment strategies. In the last decade, exosomes have been identified as having a major impact on multiple aspects of medicine and tumor biology, and appear to be primed for a critical position in cancer diagnosis, prognosis, and treatment. PMID- 30003943 TI - Putting a good face on touch: Facial expression reflects the affective valence of caress-like touch across modalities. AB - Touch plays a central role in interpersonal behavior, especially in its capacity to convey-and induce- changes in affect. Previous research has established that slow, caress-like stroking over the skin elicits positive subjective affective responses, with higher ratings of "pleasantness" compared to a faster-moving touch stimulus. Ratings of pleasantness are associated with increased activity of a distinct class of nerve fibers: C-tactile (CT) afferents. Here, we used facial electromyography (EMG) to determine if touch that optimally activates CT afferents also influences facial muscle activity believed to reflect changes in affect. We found that less pleasant, fast-moving stroking (30 cm/s) elicited robustly negative facial EMG responses, as indexed by stronger contraction of the corrugator muscle. In contrast, pleasant, slow-moving stroking (3 cm/s) that optimally activates CT afferents resulted in decreased negative facial affective responses, manifested as significant corrugator relaxation compared to fast stroking. Moreover, the facial tracking of affective valence during touch was supra-modal, with similar effects during both directly-experienced touch and viewing of touch videos. The results of this EMG study imply that touch that fails to optimally activate CT afferent produces a negative affective response, whereas pleasant, caress-like touch has not only subjective but expressive correlates, reflected in net positive affective changes in facial expression. PMID- 30003944 TI - Genome-wide transcriptome profiling of the medicinal plant Zanthoxylum planispinum using a single-molecule direct RNA sequencing approach. AB - High-throughput RNA sequencing has revolutionized transcriptome-based studies of candidate genes, key pathways and gene regulation in non-model organisms. We analyzed full-length cDNA sequences in Zanthoxylum planispinum (Z. planispinum), a medicinal herb in major parts of East Asia. The full-length mRNA derived from tissues of leaf, early fruit and maturing fruit stage were sequenced using PacBio RSII platform to identify isoform transcriptome. We obtained 51,402 unigenes, with average 1781 bp per gene in 82.473 Mb gene lengths. Among 51,402, 3963 unigenes showed variety of isoform. By selection of one representative gene among each of the various isoforms, we finalized 46,306 unique gene set for this herb. We identified 76 cytochrome P450 (CYP450) and related isoforms that are of the wide diversity in the molecular function and biological process. These transcriptome data of Z. planispinum will provide a good resource to study metabolic engineering for the production of valuable medicinal drugs and phytochemicals. PMID- 30003945 TI - Fast and slow-twitching muscles are differentially affected by reduced cholinergic transmission in mice deficient for VAChT: A mouse model for congenital myasthenia. AB - Congenital myasthenic syndromes (CMS) result from reduced cholinergic transmission at neuromuscular junctions (NMJs). While the etiology of CMS varies, the disease is characterized by muscle weakness. To date, it remains unknown if CMS causes long-term and irreversible changes to skeletal muscles. In this study, we examined skeletal muscles in a mouse line with reduced expression of Vesicular Acetylcholine Transporter (VAChT, mouse line herein called VAChT-KDHOM). We examined this mouse line for several reasons. First, VAChT plays a central function in loading acetylcholine (ACh) into synaptic vesicles and releasing it at NMJs, in addition to other cholinergic nerve endings. Second, loss of function mutations in VAChT causes myasthenia in humans. Importantly, VAChT-KDHOM present with reduced ACh and muscle weakness, resembling CMS. We evaluated the morphology, fiber type (myosin heavy chain isoforms), and expression of muscle related genes in the extensor digitorum longus (EDL) and soleus muscles. This analysis revealed that while muscle fibers atrophy in the EDL, they hypertrophy in the soleus muscle of VAChT-KDHOM mice. Along with these cellular changes, skeletal muscles exhibit altered levels of markers for myogenesis (Pax-7, Myogenin, and MyoD), oxidative metabolism (PGC1-alpha and MTND1), and protein degradation (Atrogin1 and MuRF1) in VAChT-KDHOM mice. Importantly, we demonstrate that deleterious changes in skeletal muscles and motor deficits can be partially reversed following the administration of the cholinesterase inhibitor, pyridostigmine in VAChT-KDHOM mice. These findings reveal that fast and slow type muscles differentially respond to cholinergic deficits. Additionally, this study shows that the adverse effects of cholinergic transmission, as in the case of CMS, on fast and slow type skeletal muscles are reversible. PMID- 30003946 TI - Annexin A1 peptide is able to induce an anti-parasitic effect in human placental explants infected by Toxoplasma gondii. AB - This study was conducted to investigate annexin A1 (ANXA1) functions in human placental explants infected with Toxoplasma gondii (T. gondii). We examined the first and third trimester placental explants infected with T. gondii (n = 7 placentas/group) to identify the number and location of parasites, ANXA1 protein, potential involvement of formyl peptide receptors (FPR1 and FPR2), and COX-2 expressions by immunohistochemistry. Treatments with Ac2-26 mimetic peptide of ANXA1 were performed to verify the parasitism rate (beta-galactosidase assay), prostaglandin E2 levels (ELISA assay), and ANXA1, FPR1 and COX-2 expression in third trimester placentas. Placental explants of third trimester expressed less ANXA1 and were more permissive to T. gondii infection than first trimester placentas that expressed more ANXA1. Ac2-26 treatment increases endogenous ANXA1 and decreases parasitism rate, COX-2, and prostaglandin E2 levels. Altogether, these data provide further insight into the anti-parasitic and anti-inflammatory effects of ANXA1 in placentas infected with T. gondii. PMID- 30003947 TI - Audible acoustic emission data analysis for active pharmaceutical ingredient concentration prediction during tableting processes. PMID- 30003948 TI - Urinary levels of metal elements in the non-smoking general population in Italy: SIVR study 2012-2015. AB - The purpose of this study of the Italian Society of Reference Values (SIVR) was to provide the reference values for metals in the urine of the Italian general population. Thirteen sampling centres situated in the north, centre and south of Italy took part in this project. Each sampling centre selected 20 adult subjects. The sample was made up of 120 male and 140 female non-smokers or smokers who had abandoned the habit at least 5 years previously, aged between 18 and 60 years. Urine samples were obtained from the same subjects in June and again in November of the same year. During collection of these two samples, we administered an ad hoc questionnaire designed to assess factors that might influence exposure and the results of the study such as personal characteristics, occupational or extra occupational activities, dietary habits, the presence of dental fillings containing amalgam, the frequency and mode of exposure to passive smoking and exhaust gases of motor vehicles (traffic). Therefore, the urinary levels of thirteen trace elements (Be, Cd, Co, Cr, Cu, In, Mn, Ni, Pb, Pt, Sb, Tl and V) were determined by Inductively Coupled Plasma Mass Spectrometry. The concentrations obtained (95th percentile) are in MUg/L: 0.034, 0.900, 2.24, 0.600, 24.0, 0.013, 1.53, 4.44, 2.64, 0.022, 0.095, 0.759 and 0.855 for Be, Cd, Co, Cr, Cu, In, Mn, Ni, Pb, Pt, Sb, Tl and V, respectively. Further studies with a larger number of subjects are needed in order to continue the biomonitoring of the Italian general population and to monitor the modified levels over time. PMID- 30003949 TI - Relationship between transient severe motion of the liver in gadoxetic acid or iodinated contrast agent-enhanced imaging and arterial oxygen saturation and heart rate changes. AB - PURPOSE: To clarify the relationship between transient sever motion artifact in arterial phase (TSMA) and changes in peripheral capillary oxygen saturation (SpO2) and heart rate (HR) after contrast media administration during MRI or CT of the liver. METHODS: 87 patients undergoing 61 MRI examination with gadoxetic acid or 26 CT examination with iodinated contrast were included. Dynamic contrast enhanced imaging (DCEI) was obtained at four vascular phase acquisitions. Reviewers extracted the segmental data of SpO2 and HR in each phase from consecutive data in DCE-CT or DCE-MRI. In addition, reviewers scored for respiratory motion in each phase using 5-point scale. Patients with an arterial score of 4-5, and other phase scores of 1-2 were considered to be exhibiting TSMA. RESULTS: In gadoxetic acid, mean SpO2 of arterial phase was significantly lower than three other phases (P = 0.045 to P < 0.001). However, the decrease in SpO2 in arterial phase compared with other phases was <1%. Mean HR in gadoxetic acid or iodinated contrast agent was highest in the portal-phase. The incidence of TSM was 0% in patients with iodinated contrast agent and was 8.2% (5/61 patients; TSM group) in patients with gadoxetic acid, respectively. In addition, there was no significant difference in mean SpO2 of arterial phase between the TSM group (97.5% +/- 1.08%) and non-TSM group (96.4% +/- 1.85%) (P = 0.219). CONCLUSION: The slight decrease in SpO2 in arterial phase is not associated with TSMA. PMID- 30003950 TI - Identification of an acute functional cross-talk between amyloid-beta and glucocorticoid receptors at hippocampal excitatory synapses. AB - Amyloid-beta is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-beta (Abetaomicron) is now believed to represent the main Amyloid beta species affecting synapse function. Yet, the exact molecular mechanism by which Abetaomicron modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Abetaomicron generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Abeta and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Abetao (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Abetao mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Abetao-mediated LTP impairment, but not Abetao-mediated LTD induction. The necessity of neuronal GRs for Abetao-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Abeta activities at excitatory synapses. PMID- 30003951 TI - Poly-ubiquitin profile in Alzheimer disease brain. AB - Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory, reasoning and other cognitive functions. Pathologically, patients with AD are characterized by deposition of senile plaques (SPs), formed by beta-amyloid (Abeta), and neurofibrillary tangles (NTFs) that consist of aggregated hyperphosphorylated tau protein. The accumulation of insoluble protein aggregates in AD brain can be associated with an impairment of degradative systems. This current study investigated if the disturbance of protein polyubiquitination is associated with AD neurodegeneration. By using a novel proteomic approach, we found that 13 brain proteins are increasingly polyubiquitinated in AD human brain compared to age-matched controls. Moreover, the majority of the identified proteins were previously found to be oxidized in our prior proteomics, and these proteins are mainly involved in protein quality control and glucose metabolism. This is the first study showing alteration of the poly-ubiquitin profile in AD brain compared with healthy controls. Understanding the onset of the altered ubiquitin profile in AD brain may contribute to identification of key molecular regulators of cognitive decline. In AD, deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins that are not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology and cognitive decline. PMID- 30003952 TI - A meta-analysis of effectiveness of interventions to improve adherence in pregnant women receiving antiretroviral therapy in sub-Saharan Africa. AB - OBJECTIVE: We evaluated the effectiveness of interventions aimed at improving antiretroviral therapy (ART) adherence during pregnancy in sub-Saharan Africa. METHODS: For this meta-analysis, the following databases were searched: MEDLINE Complete, Embase, Global Health, CINAHL Complete, and Google Scholar. Randomized and nonrandomized studies were considered for inclusion if they involved an intervention with the intent of improving medication adherence among pregnant women taking ART in sub-Saharan Africa. Databases were searched from inception to the end of August 2017. The primary outcome assessed was adherence to ART, defined as the proportion of women adherent to treatment in the control and intervention groups. Risk ratios and random effect meta-analysis were undertaken, and heterogeneity was examined with the I2 statistic. RESULTS: The systematic search of databases yielded a total of 402 articles, of which 19 studies were selected for meta-analysis with a total of 27,974 participants. Nine types of interventions were identified in the 19 studies to improve ART adherence. The test for the subgroup differences showed that there was a statistically significant difference among the 9 subgroups of interventions, chi2 (8)=102.38; p=0.00001. Collectively, in the meta-analysis, the various intervention types made a significant impact on improving medication adherence. The overall effect estimate with 95% CI was as follows: 1.25 (95% CI=1.03, 1.52, p=0.03). The following risk ratio results for meta-analysis were obtained for the three interventions that showed significant impact on adherence; namely social support and structural support, 1.58 (95% CI=1.36, 1.84, p<0.00001); education, social support and structural support=2.60 (95% CI=1.95, 3.45, p<0.00001); and device reminder=1.13 (95% CI=1.05, 1.20, p=0.0004). The proportion of women who were adherent to ART as a result of the interventions was 59.3% compared with 22.5% in the control groups. CONCLUSION: The use of device reminder, a combination of social support and structural support, and education, social support and structural support has the potential to improve ART adherence during pregnancy. Good quality prospective observational studies and randomized control trials are needed in sub-Saharan Africa to determine the most effective interventions. PMID- 30003953 TI - Epidemiology and clinical outcomes of hepatitis delta (D) virus infection in Queensland, Australia. AB - OBJECTIVES: To investigate the epidemiology, clinical characteristics and outcomes of those with hepatitis delta virus (HDV) infection in Queensland, Australia. DESIGN: Retrospective cohort study of individuals tested for HDV between 1997 and 2016 in the public healthcare system in Queensland. RESULTS: 179 individuals recorded positive HDV serology between 1997 and 2016, with a total of 4407 individuals undergoing testing (seroprevalence 4.1%). The majority of HDV positive individuals were male and were born overseas. Those born in Africa had a higher risk ratio (RR) for HDV infection (RR, 1.55; 95% CI, 1.14-2.09); being born in Asia was associated with a relatively lower risk of HDV infection (RR, 0.36; 95% CI, 0.27-0.58). Positive hepatitis C virus (HCV) serology was significantly associated with positive HDV serology (RR, 2.98; 95% CI, 2.36 3.78). Of the HDV positive individuals born in Australia, the majority were HCV positive (69.8%). HDV positive individuals were less likely to be Hepatitis B e antigen (HBeAg) positive (RR, 0.64; 95% CI, 0.45-0.93) and recorded lower hepatitis B virus (HBV) viral loads. Positive HDV serology was associated with increased risk of liver cirrhosis (RR, 2.3; 95% CI 1.73-3.07) and liver transplantation (RR, 1.93; CI 1.31-2.85). Only 8% of HDV positive individuals underwent HDV treatment. CONCLUSIONS: In Queensland, HDV seropositivity is associated with overseas birth, particularly in Africa. HDV infection is associated with decreased HBV viraemia and more advanced liver disease. PMID- 30003955 TI - Haploidentical Transplants: An Answer to Ethical Challenges on the Use of Preimplantation Donor Selection. PMID- 30003954 TI - Surface functionalized dendrimers as controlled-release delivery nanosystems for tumor targeting. AB - Dendrimers are nano-sized and three-dimensional macromolecules with well-defined globular architecture and are widely used in various aspects such as drug and gene delivery owing to multivalent and host-guest entrapment properties. However, dendrimers like other nanomaterials have some disadvantages for example rapid clearance by reticuloendothelial system, toxicity due to interaction of amine terminated group with cell membrane, low transfection efficiency and lack of controlled release behavior, which reduce their therapeutic efficiency. To solve these problems, surface functionalization of dendrimers can be carried out. Surface functionalization not only mitigates this obstacle but also renders excessive specificity to dendrimer to improve efficiency of cancer therapy. Specific properties in cancer cell compared to normal cells such as overexpression of various receptors and difference in biological condition like pH, temperature and redox of tumor environment can be an appropriate strategy to increase site-specific targeting efficiency. Therefore, in this article we focus on numerous functionalization strategies, which are used in the modification of dendrimers through attachment of lipid, amino acid, protein/peptide, aptamer, vitamin, antibody. Moreover, increased biocompatibility, site-specific delivery based on various ligands, enhanced transfection efficiency, sustained and controlled release behavior based on stimuli responsiveness are benefits of functionalized dendrimer which we discuss in this review. Overall, these functionalized dendrimers can open a new horizon in the field of targeted drug and gene delivery. PMID- 30003956 TI - The heat shock protein 40 LeDnaJ regulates stress resistance and indole-3-acetic acid biosynthesis in Lentinula edodes. AB - DnaJ proteins, termed heat shock proteins based on their molecular weight, function as molecular chaperones that play critical roles in regulating organism growth and development as well as adaptation to the environment. However, little has been reported on their gene function in higher basidiomycetes. Here, the heat shock protein 40 (LeDnaJ) gene was cloned and characterized from Lentinula edodes. RNA interference was used to explore the function of LeDnaJ in response to heat stress and Trichoderma atroviride. Integration of the target gene into the L. edodes genome was confirmed by Southern blot analysis, and the silence efficiency of LeDnaJ was analyzed by qRT-PCR. The results revealed that LeDnaJ silence caused defects in mycelial growth and resistance to heat stress and T. atroviride, but increased the mycelial density compared with the wild type (WT) strain S606. Additionally, the IAA content showed a more than 10-fold increase in the WT after heat stress, but an about two-fold increase in the two LeDnaJ RNAi transfortants (LeDnaJ-i-6 and LeDnaJ-i-8). Previous study has shown that enhanced IAA (indole-3-acetic acid) content enhanced the thermotolerance of the heat sensitive strain YS3357. In this study, it was documented that IAA amendments could partly restore the resistance to T. atroviride and thermotolerance of the two LeDnaJ RNAi transformants. Overall, LeDnaJ is nvolved in fungal growth, T. atroviride resistance, and thermotolerance by regulating the IAA biosynthesis in L. edodes. PMID- 30003957 TI - Investigation of factors associated with the success of adult strabismus surgery from the patient's perspective. AB - PURPOSE: To explore factors that influence the success of adult strabismus surgery based on health-related quality of life (HRQOL) criteria. METHODS: The HRQOL aspect of strabismus surgery was assessed using the Adult Strabismus 20 (AS 20) questionnaire. Adult patients (>=16 years of age) undergoing strabismus surgery between 2014 and 2016 were identified using a treatment register. Pre- and postoperative AS-20 scores were calculated. HRQOL surgical success was defined as a pre- to postoperative change in AS-20 score exceeding previously published 95% limits of agreement. Any relationship between demographic factors (sex, age, and socioeconomic status), presence or absence of diplopia, type and magnitude of deviation, and change in deviation size with HRQOL success was investigated. RESULTS: A total of 87 patients were included (mean age, 47 years; 53% female). Nondiplopic patients showed significantly lower pre- and postoperative scores on the AS-20 psychosocial subscale compared to diplopic patients. Of 87 surgeries, 54 (62%) were classified as successful based on HRQOL criteria. Multiple logistic regression analysis showed only lower socioeconomic status to be significantly associated with a higher rate of HRQOL success (P = 0.04). CONCLUSIONS: Strabismic patients with a lower socioeconomic status are more likely to achieve HRQOL success following surgery. We also show that nondiplopic patients have more psychosocial concerns than those with diplopia and that this disparity persists even after strabismus surgery. PMID- 30003958 TI - Characterization and localization of primordial germ cells in Totoaba macdonaldi. AB - The totoaba, Totoaba macdonaldi, is an endangered fish of the Gulf of California with high economic and ecological potential. Therefore, our purpose was to characterize the Primordial Germ Cells (PGCs) of this Sciaenid with two objectives: (1) to provide the basis for PGCs cryopreservation to preserve the genetic resources and (2) to take the first step to know the gonadal genesis and sex differentiation of totoaba. Immunofluorescence analysis performed from 2-cell stage to 8-day after hatch (DAH) shows that Vasa protein is specific for PGCs. These cells were first observed in the peripheral and dorsal regions of the blastodisc at approximately the 50%-epiboly stage and migrated to both sides of embryo body during the development. Finally, at 7 DAH the PGCs of the hatching embryo reached the place where the gonad will be developed. Histology analysis of larvae showed a genital ridge with enclosed PGCs on the dorsal side of the peritoneum at 9 DAH, gonadal primordium growth was observed at 11 DAH as a result of the interaction between PGCs and somatic cells derived from the peritoneum. Results of qPCR showed that vasa expression was restricted to the embryonic and early larval development, highest values were observed in 2-cell and mid-blastula stage suggesting the maternal inheritance of vasa mRNA. These findings support the hypothesis of preformation in T. macdonaldi PGCs. The migration pattern of PGCs allow us to recommend the isolation and subsequent cryopreservation of these cells before 7 DAH when the embryonic and larval development is given at 21 degrees C. PMID- 30003959 TI - Early experience with intravenous sotalol in children with and without congenital heart disease. AB - BACKGROUND: Arrhythmias are common in the pediatric population. In patients unable to take oral medications or in need of acute therapy, options of intravenous (IV) antiarrhythmic medications are limited. Recently IV sotalol has become readily available, but experience in children is limited. OBJECTIVE: The purpose of this study was to describe our initial experience with the use of IV sotalol in the pediatric population. METHODS: A retrospective study of all pediatric patients receiving IV sotalol was performed. Patient demographic characteristics, presence of congenital heart disease, arrhythmia type, efficacy of IV sotalol use, and adverse effects were evaluated. RESULTS: A total of 47 patients (26 (55%) male and 24 (51%) with congenital heart disease) received IV sotalol at a median age of 2.05 years (interquartile range 0.07-10.03 years) and a median weight of 12.8 kg (interquartile range 3.8-34.2 kg), and 13 (28%) received IV sotalol in the acute postoperative setting. Supraventricular arrhythmias occurred in 40 patients (85%) and ventricular tachycardia in 7 (15%). Among 24 patients receiving IV sotalol for an active arrhythmia, acute termination was achieved in 21 (88%). Twenty-three patients received IV sotalol as maintenance therapy for recurrent arrhythmias owing to inability to take oral antiarrhythmic medications; 19 (83%) were controlled with sotalol monotherapy. No patient required discontinuation of IV sotalol secondary to adverse effects, proarrhythmia, or QT prolongation. CONCLUSION: IV sotalol is an effective antiarrhythmic option for pediatric patients and may be an excellent agent for acute termination of active arrhythmias. It was well tolerated, with no patient requiring discontinuation secondary to adverse effects. PMID- 30003960 TI - A novel method to isolate retinal and brain microvessels from individual rats: Microscopic and molecular biological characterization and application in hyperglycemic animals. AB - Alterations in the retinal microvessel (RMV) compartment occurring in systemic disease states such as diabetes may eventually contribute to blindness. To specifically address the pathophysiological role of the microvasculature we developed a new method for RMV bulk isolation from individual rats. The extraction procedure performed in the cold throughout takes less than one hour. Slight modifications enable isolation of brain microvessels (BMVs) for comparison. Microscopically, RMVs and BMVs consisted mainly of capillaries of good structural integrity. The endothelial cell/pericyte ratio was approximately 1.8 in RMVs and 2.7 in BMVs, well in agreement with data from intact vascular beds. Total RNA extracted from individual rats amounted to approximately 7 ng in RMVs, 50 ng in BMVs, and 155 ng in pial arteries (which were also isolated) with highly preserved integrity throughout. Measurements using microfluidic card methodology revealed segregation of RMVs, BMVs, and pial arteries in distinct clusters based on principal component analysis. In all three vascular compartments endothelial cell-specific markers were significantly enriched. Similarly, pericyte-specific markers displayed accumulation in RMVs, BMVs, and pial arteries, the latter probably reflecting the common ontogenetic origin of pericytes and smooth muscle cells. Isolation of RMVs, BMVs, and pial arteries from rats suffering from 8-weeks hyperglycemia yielded expression patterns of endothelial cell- and pericyte-specific marker genes largely comparable to those obtained in control rats. Our newly developed protocols allow for selective studies of RMVs from individual rats to characterize reactive pathways, in comparison with the ontogenetically closely related BMVs. Moreover, our protocols with inclusion of pial arteries enable comparative studies of the macro- and microvasculature from the same organ. PMID- 30003962 TI - Response to R. L. Nevin "Considerations in the repurposing of mefloquine for prevention and treatment of osteoporosis". PMID- 30003961 TI - Temporal evolution of Acinetobacter baumannii ST107 clone: conversion of blaOXA 143 into blaOXA-231 coupled with mobilization of ISAba1 upstream occAB1. AB - Nine carbapenem-resistant Acinetobacter baumannii isolates carrying blaOXA-231 and an ISAba1 upstream occAB1 were evaluated. They were clonally related and belonged to ST107. An OXA-143-producing A. baumannii ST107 strain (Ac-148) that did not possess ISAba1 upstream occAB1 was included in the analysis. Reduction in the expression of occAB1 and a 4-fold increase of carbapenem MICs were observed for all isolates, except for the Ac-148 strain, probably due to the presence of ISAba1 upstream occAB1 but in the same transcriptional orientation. We reported an A. baumannii ST107 clone carrying blaOXA-143 that acquired a mutation resulting into blaOXA-231 and mobilized ISAba1 upstream occAB1. PMID- 30003964 TI - Group 1B phospholipase A2 in metabolic and inflammatory disease modulation. AB - The group 1B phospholipase A2 (PLA2G1B) is a secreted phospholipase that catalyzes the hydrolytic removal of the sn-2 fatty acyl moiety from phospholipids. This enzyme is synthesized most abundantly in the pancreas and is also expressed in the lung. The first part of this review article focuses on the role of pancreatic-derived PLA2G1B in mediating lipid absorption and discusses how the PLA2G1B-derived metabolic product contributes to cardiometabolic diseases, including obesity, hyperinsulinemia, hyperlipidemia, and atherosclerosis. The anti-helminth properties of PLA2G1B will also be discussed. The second part of this review will focus on PLA2G1B expressed in the lung, and in vitro data suggest that how this enzyme may modulate lung inflammation via both hydrolytic activity-dependent and -dependent mechanisms. Finally, recent studies revealing a relationship between PLA2G1B and cancer will also be discussed. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau. PMID- 30003963 TI - Lysine acetylproteome profiling under water deficit reveals key acetylated proteins involved in wheat grain development and starch biosynthesis. AB - : Lysine acetylation is a widespread protein posttranslational modification in all organisms. However, quantitative acetylproteome characterization in response to water deficit during crop grain development remains unknown. In the study, we performed the first large-scale acetylproteome analysis of developing wheat grains under water-deficit using label-free quantitative proteome approach. In total, 716 acetylated sites corresponding to 442 acetylated proteins were identified, of which 106 acetylated sites representing 93 acetylated proteins (including 88 non-histones) showed significant changes under water-deficit. The functional classification showed that 57% and 20% of acetylated proteins were related to metabolic and cellular processes, respectively. Water-deficit caused widespread functional crosstalk between protein acetylation and other PTMs. Particularly, both acetylation and phosphorylation occurred in two key enzymes involved in starch biosynthesis, sucrose synthase (SuSy) and ADP glucose pyrophosphorylase (AGPase). Their crosstalk could play important roles in starch biosynthesis and yield formation under drought conditions. Western blot analysis combined with tandem mass spectrometry identification further verified the reliability of the acetylproteome results. Most of the acetylated proteins showed consistences between transcription and post-translation levels by quantitative real-time PCR. A putative metabolic pathway was proposed to dissect the roles of protein acetylation in regulation of drought response and defense during wheat grain development. SIGNIFICANCE: Lysine acetylation is a widespread modification in all organisms. We performed the first large-scale acetylproteome analysis of developing wheat grains under water-deficit and revealed key acetylated proteins involved in wheat grain development and starch biosynthesis. PMID- 30003965 TI - Central European Strigeidae Railliet, 1919 (Trematoda: Strigeidida): Molecular and comparative morphological analysis suggests the reclassification of Parastrigea robusta Szidat, 1928 into Strigea Abildgaard, 1790. AB - Strigeidae Railliet, 1919 are digenean parasites of birds and mammals that are characteristic by their cup-shaped forebody and bilobed holdfast organ. Despite that the family is taxonomically unsettled, particularly due to a very limited number of visible autapomorphic identification features, molecular phylogenetics have never been applied to analyze the relationships among European members of Strigeidae except for the genus Ichthyocotylurus. Here, we analyze the Strigeidae found during the examination of Czech birds performed from 1962 to 2017, and we provide comparative measurements and host spectra, including prevalence and intensity; we also provide and analyze sequences of four DNA loci of 12 of the Strigeidae species. We suggest the reclassification of Parastrigea robusta Szidat, 1928 as Strigea robusta (Szidat, 1928) Heneberg and Sitko, 2018 comb. n. The genera Strigea Abildgaard, 1790 and Parastrigea Szidat, 1928 appear paraphyletic, and morphological diagnostic features of genera within Strigeini Dubois, 1936 are invalid. The mute swan Cygnus olor hosts two Cotylurus spp., Cotylurus syrius Dubois, 1934 and a second species with molecular identification features shared in part with Cotylurus cornutus (Rudolphi, 1808) and Cotylurus gallinulae Lutz, 1928. New host records are provided for seven species. Analyses of non-European genera of the Strigeidae are needed to provide an updated key to Strigeini. PMID- 30003966 TI - Interaction between low back pain and knee pain contributes to disability level in individuals with knee osteoarthritis: a cross-sectional study. AB - OBJECTIVE: To test the hypothesis that the interaction between low back pain (LBP) and knee pain intensity contributes to the disability level of individuals with knee osteoarthritis (OA). DESIGN: Community-dwelling participants with knee OA (Kellgren/Lawrence [K/L] grade >=1) were enrolled. LBP and its severity were identified using questionnaires. Knee pain severity and disability level were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM) subscale. Multiple linear regression analyses were performed to examine the effect of the LBP-knee pain interaction, an independent variable, on disability, a dependent variable. RESULTS: A total of 260 participants (age, 48-88 years; 77.7% women) were included. Of them, 151 (58.1%) had LBP. The LBP-knee pain interaction was significantly associated with disability after the adjustment for covariates. A post-hoc subgroup analysis revealed that the relationship between knee pain intensity and disability level was higher in individuals with LBP (beta: 0.621 points; 95% confidence interval [CI]: 0.511 to 0.731 points) than in those without LBP (beta: 0.402 points; 95% CI: 0.316 to 0.487 points). CONCLUSIONS: LBP interacts with knee pain intensity and contributes to disability level in individuals with knee OA. Coexisting LBP and knee pain had a stronger impact on disability level than LBP or knee pain alone. These findings highlight the potential deteriorative effects of the LBP-knee interaction on disability. Maximal treatment effects for disability might be achieved when LBP and knee pain are targeted simultaneously, rather than separately. PMID- 30003968 TI - Severity strata for POEM, PO-SCORAD, and DLQI in US adults with atopic dermatitis. AB - BACKGROUND: Patient-Oriented Eczema Measure (POEM) is the preferred patient reported outcome (PRO) for assessing symptoms of atopic dermatitis (AD). Dermatology Life Quality Index (DLQI) is commonly used to assess the burden of skin disease. Previous severity strata were developed for POEM and DLQI in clinical cohorts, which may be biased toward more severe disease. Severity strata were not previously examined in population-based cohorts. Patient-Oriented Scoring AD (PO-SCORAD) is another commonly used PRO for assessing AD symptoms; however, severity strata are not established. OBJECTIVE: We sought to confirm previously developed strata for POEM and DLQI, and to develop strata for the PO SCORAD in a population-based cohort of adults with AD. METHODS: A cross sectional, population-based study of 8,217 adults was performed using a structured questionnaire. A diagnosis of AD was determined using modified UK Diagnostic Criteria for AD (n = 602). AD severity was assessed using self reported global AD severity (anchoring question), POEM, PO-SCORAD, and DLQI. Strata were selected using an anchoring approach based on patient-reported disease severity. RESULTS: We confirmed the existing strata for DLQI (mild = 0-5, moderate = 6-10, severe = 11-30) (kappa = 0.446). However, the preferred strata for POEM was mild = 0-7, moderate = 8-19, and severe = 20-28 (kappa = 0.409) and PO-SCORAD was mild = 1-27, moderate = 28-56, severe = 57-104 (kappa = 0.444). CONCLUSION: Existing strata for DLQI performed well in a population-based cohort of adult AD. The optimal severity strata for the POEM in our AD population varies slightly from those previously published for AD. This may suggest that different strata may be optimal in different study settings and cohorts. Finally, we proposed new strata for PO-SCORAD in adult AD. PMID- 30003967 TI - Isolated adult turtle brainstems exhibit central hypoxic chemosensitivity. AB - During hypoxia, red-eared slider turtles increase ventilation and decrease episodic breathing, but whether these responses are due to central mechanisms is not known. To test this question, isolated adult turtle brainstems were exposed to 240 min of hypoxic solution (bath PO2 = 32.6 +/- 1.2 mmHg) and spontaneous respiratory-related motor bursts (respiratory event) were recorded on hypoglossal nerve roots. During hypoxia, burst frequency increased during the first 15 min, and then decreased during the remaining 35-240 min of hypoxia. Burst amplitude was maintained for 120 min, but then decreased during the last 120 min. The number of bursts/respiratory event decreased within 30 min and remained decreased. Pretreatment with either prazosin (alpha1-adrenergic antagonist) or MDL7222 (5-HT3 antagonist) blocked the hypoxia-induced short-term increase and the longer duration decrease in burst frequency. MDL7222, but not prazosin, blocked the hypoxia-induced decrease in bursts/respiratory event. Thus, during bath hypoxia, isolated turtle brainstems continued to produce respiratory motor output, but the frequency and pattern were altered in a manner that required endogenous alpha1-adrenergic and serotonin 5-HT3 receptor activation. This is the first example of isolated reptile brainstems exhibiting central hypoxic chemosensitivity similar to other vertebrate species. PMID- 30003969 TI - Effect of polyols on the structure and aggregation of recombinant human gamma Synuclein, an intrinsically disordered protein. AB - Polyol osmolytes accumulated in cells under stress are known to promote stability in globular proteins with respect to their increasing hydroxyl groups but their effect on the structure, stability and aggregation of intrinsically disordered proteins (IDPs) is still elusive. The lack of a natively folded structure in intrinsically disordered proteins under physiological conditions results in their aggregation and fibrillation that gives rise to a number of diseases. We have investigated the effect of a series of polyols, ethylene glycol (EG), glycerol, erythritol, xylitol and sorbitol on the fibrillation pathway of recombinant human gamma-Synuclein, used as a model, for an IDP known to form fibrils that play a role in neurodegeneration and cancer. With an increase in the number of -OH groups in polyols except EG, we observe a decrease in lag time for fibrillation at equimolar concentrations, suggesting stronger preferential exclusion of polyols that promotes gamma-Syn self-association and oligomerization. The polyols act early during nucleation and their diverse effect on the rate of fibrillation suggests the role of favourable solvent-side chain interactions. With increasing OH group, polyols stabilize the natively unfolded conformation of gamma-Syn under non-fibrillating conditions and delay the structural transition to characteristic beta-sheet structure by forming an alpha-helical intermediate during fibrillation. The results, overall suggest that the effect of osmolytes on IDPs is much more complex than their effect on globular protein stability and aggregation and a fine balance between the dominant unfavourable osmolyte-peptide backbone and favourable osmolyte-charged side chain interactions would govern their stability and aggregation properties. PMID- 30003970 TI - Blastocystis infection and subtype distribution in humans, cattle, goats, and pigs in central and western Thailand. AB - Blastocystis is a common intestinal pathogen of humans and a variety of animals, with various host-specific subtypes. The aim of this study was to determine the prevalence and subtype distribution of Blastocystis in humans and domestic animals, Thailand. 113 stool samples were collected from pigs, goats, and cattle in Ayutthaya Province (AP; central Thailand) and 218 stool samples were collected from pigs, dogs, cats, chickens, and humans in Kanchanaburi Province (KP; western Thailand). Blastocystis was detected by nested PCR targeting the SSU rRNA gene. Subtypes were identified by DNA sequencing, and phylogenetic analysis was conducted. The overall prevalence of Blastocystis in animals was 76.1% (86/113) and 11.88% (12/101) in AP and KP, respectively, and the prevalence in humans was 12.82% (15/117) in KP. The prevalence of Blastocystis in the AP and KP pigs were 87.88% (29/33) and 20.37% (11/54), respectively. Blastocystis ST5 was the most abundant in pigs in both areas while Blastocystis ST10 and ST12 were most frequently found in cattle and goats. In addition, low percentage of Blastocystis ST1 and Blastocystis ST14 were found in pigs and goats, respectively. In this study, Blastocystis ST3, followed by ST2 and ST1 were predominantly found in humans. In conclusion, pigs may be a natural host of Blastocystis and this ST may be the pig-adapted ST in the studied areas, in this study. PMID- 30003971 TI - Optimal data-driven parameterization of coiled coils. AB - alpha-Helical coiled coils (CCs) represent an important, highly regular protein folding motif. To date, many thousands of CC structures have been determined experimentally. Their geometry is usually modelled by theoretical equations introduced by F. Crick that involve a predefined set of parameters. Here we have addressed the problem of efficient CC parameterization from scratch by performing a statistical evaluation of all available CC structures. The procedure is based on the principal component analysis and yields a minimal set of independent parameters that provide for the reconstruction of the complete CC structure at a required precision. The approach is successfully validated on a set of canonical parallel CC dimers. Its applications include all cases where an efficient sampling of the CC geometry is important, such as for solving the phase problem in crystallography. PMID- 30003972 TI - A drug-delivering-drug strategy for combined treatment of metastatic breast cancer. AB - Treatment of metastatic cancer continues to be a huge challenge worldwide. Notably, drug nanocrystals (Ns) in nanosuspensions clearly belong to a type of nanoparticle. Therefore, a question arose as to whether these drug particles can also be applied as carriers for drug delivery. Here, we design a novel paclitaxel (PTX) nanocrystal stabilized with complexes of matrix metalloproteinase (MMP) sensitive beta-casein/marimastat (MATT) for co-delivering MATT and PTX and combined therapy of metastatic breast cancer. The prepared Ns (200 nm) with a drug-loading of >50% were potent in treatment of metastatic cancer, which markedly inhibited MMP expression and activity and greatly blocked the lung metastasis and angiogenesis. In conclusion, employing protein-drug complexes as stabilizers, Ns with dual payloads are developed and are a promising strategy for co-delivery. Furthermore, the developed Ns can target the tumor microenvironment and cancer cells and, as a result, enable efficient treatment for breast metastatic cancer. PMID- 30003973 TI - Over-expression of SINAL7 increases biomass and drought tolerance, and also delays senescence in Arabidopsis. AB - The seven in absentia like 7 gene (At5g37890, SINAL7) from Arabidopsis thaliana encodes a RING finger protein belonging to the SINA superfamily that possesses E3 ubiquitin-ligase activity. SINAL7 has the ability to self-ubiquitinate and to mono-ubiquitinate glyceraldehyde-3-P dehydrogenase 1 (GAPC1), suggesting a role for both proteins in a hypothetical signaling pathway in Arabidopsis. In this study, the in vivo effects of SINAL7 on plant physiology were examined by over expressing SINAL7 in transgenic Arabidopsis plants. Phenotypic and gene expression analyses suggest the involvement of SINAL7 in the regulation of several vegetative parameters, essentially those that affect the aerial parts of the plants. Over-expression of SINAL7 resulted in an increase in the concentrations of hexoses and sucrose, with a concommitant increase in plant biomass, particularly in the number of rosette leaves and stem thickness. Interestingly, using the CAB1 (chlorophyll ab binding protein 1) gene as a marker revealed a delay in the onset of senescence. Transgenic plants also displayed a remarkable level of drought resistance, indicating the complexity of the response to SINAL7 over-expression. PMID- 30003974 TI - The diploid genome of the only sclerotia-forming wild-type species in the genus Pleurotus -Pleurotus tuber-regium - provides insights into the mechanism of its biomass conversion from lignocellulose substrates. AB - Pleurotus tuber-regium (Fr.) Singer, being a white-rot fungus, is widely used for food and medicine in the Asia-Pacific region. In this study, we sequenced and annotated the genome of a dikaryon P. tuber-regium wild strain to provide a better understanding of the carbohydrate-active enzymes (CAZymes) involved in the bio-conversion of lignocellulose to beta-glucan reserves in this sclerotia forming Pleurotus mushroom with reference to enzyme participated in cellulosic compound breakdown and glucan reserve biosynthesis. The present genomic data provides new insights for lignocellulose bioconversion of white-rot fungus for the genus Pleurotus. PMID- 30003975 TI - Extraction of astaxanthin from microalga Haematococcus pluvialis in red phase by using generally recognized as safe solvents and accelerated extraction. AB - Solvent Extraction was tested to extract astaxanthin from Haematococcus pluvialis in red phase (HPR), by investigating effects of solvents, extraction pressure and temperature. Astaxanthin isomers were identified and quantified in the extract. The performances of acetone and ethanol, Generally Recognized As Safe (GRAS) solvents, were explored. Negligible effect of pressure was found, while with increasing extraction temperature astaxanthin recovery increased till a maximum value, beyond which thermal degradation seemed to be greater than the positive effect of temperature on extraction. Furthermore, to maximize the extraction yield of astaxanthin, mechanical pre-treatment of HPR biomass was carried out and several extraction runs were consecutively performed. Experimental results showed that after the mechanical pre-treatment the astaxanthin recovery strongly increased while a single extraction run of 20 min was sufficient to extract more than 99% of total astaxanthin extracted. After pre-treatment, maximum recovery of about 87% was found for acetone (pressure = 100 bar; temperature = 40 degrees C; total time = 60 min). PMID- 30003976 TI - Saccade latency delays in young apolipoprotein E (APOE) epsilon 4 carriers. AB - The apolipoprotein E (APOE) epsilon 4 isoform has been associated with a significantly greater risk of developing late onset Alzheimer's disease (AD). However, the negative effects of APOE-epsilon4 allele on cognitive function vary across the lifespan: reduced memory and executive function have been found in older individuals but, paradoxically, young APOE-epsilon4 carriers perform better on cognitive tests and show higher neural efficiency. This study aimed to assess the association between APOE genotype and saccade latency using a prosaccade and antisaccade task in young individuals (N = 97, age: 17-35 years). Results showed that prosaccade latency was significantly delayed in a group of epsilon4 carriers in comparison to non-carriers, which was due to a lower rate of signal accumulation rather than a change in the criterion threshold. In contrast, there was no significant genotype difference for antisaccade latency in this young cohort. These results indicate that prosaccade latency may be useful in establishing the APOE behavioural phenotype, which could ultimately assist with distinguishing between normal and pathological aging. PMID- 30003977 TI - Low-frequency repetitive transcranial magnetic stimulation inhibits the development of methamphetamine-induced conditioned place preference. AB - The abuse of amphetamine-type stimulants (ATS) has become a global public health issue in recent years, these new-type drugs can cause addiction and serious cognitive impairment. However, there are no effective methods for the prevention and treatment of ATS addiction at present. Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive new therapeutic approach that has been used for the treatment of depression and other neuropsychiatric disorders, but whether it can be used to treat drug addiction is unclear. In the present study, we investigated the possible effects of rTMS on methamphetamine(METH)-induced conditioned place preference (CPP). High-frequency (10 Hz) and low-frequency stimulation patterns (1 Hz) were applied to test the effect of rTMS on METH-induced CPP. The results showed that low-frequency but not high-frequency rTMS could block METH-CPP, accompanied with a downregulation of gamma-aminobutyric acid type B receptor subunit 1 (GABABR1) expression in rat dorsolateral striatum. These results suggested that low-frequency rTMS could effectively inhibit the development of METH addiction and shed light on the rTMS as a potential approach for the prevention of drug addiction. PMID- 30003978 TI - Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat. AB - Activated microglia-induced neuroinflammation can stimulate the hypothalamic- pituitary-adrenal (HPA) axis to release glucocorticoids and suppress astrocyte functions, such as reducing neurotrophin production, which occur in depression. However, the balance between M1 (pro-inflammation) and M2 (anti-inflammation) microglial phenotypes and the interaction between these two glial cells are unclear in the depression. Hence, the chronic unpredictable mild stress (CUMS) induced depression model was chosen to study depression- and anxiety-like behaviors, the concentration of corticosterone and relevant hippocampal cytokines, mRNA and protein expressions of microglial and astrocyte markers. To demonstrate the role of M1 phenotype activation in depression, the effect of microglial inhibitor minocycline on these aspects was also evaluated. Six weeks after CUMS exposure, behaviors were tested. Compared to the control group, CUMS increased serum corticosterone concentration and depression-like behaviors, like anhedonia, helplessness and anxiety. Moreover, CUMS increased microglia M1 marker CD11b expression and tumor necrosis factor (TNF)-alpha, interferon (INF)-gamma, interleukin (IL)-1beta and IL-17 concentrations, but decreased the concentration of M2 cytokines, IL-4, IL-10 and IL-13. Meanwhile, CUMS inhibited the expressions of astrocyte marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrKB. Minocycline (40 mg/kg, 45 days) treatment significantly attenuated CUMS-induced behavioral abnormalities, which were associated with the suppressed M1 response, restored GFAP, BDNF and its receptor expression. In conclusion, CUMS-induced depression- and anxiety-like behavior may result from an imbalance between M1 and M2 and suppressed astrocyte function. Minocycline treatment reversed M1 response, which was associated with behavioral normalization. PMID- 30003979 TI - Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling. AB - Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can be used in combination therapy with low doses of standard drugs. Verapamil (VP) a known antihypertensive drug has been shown to enhance the activity of bis chloroethylnitrosourea (BCNU), a drug used to treat GBM. Since, TMZ has replaced BCNU as the standard GBM chemotherapy; therefore, we aimed to study in vitro interaction of VP and TMZ against GBM. Anti-proliferative and apoptotic activities were studied using MTT, TUNEL assay and DAPI staining. Synergy was assessed using combination index method. Apoptotic markers were evaluated by RT PCR, and immunocytochemistry. Both VP and TMZ significantly inhibited the growth of U87 cells in dose dependent manner. The combine effect of TMZ with VP was synergistic with a CDI value of <1. Combination of TMZ and VP increased the ratio of Bax to Bcl-2 expression and thus shifted the equilibrium of cells towards apoptosis. Our findings suggest that the synergistic growth inhibition that was observed in combination treatment group may in part relate to increase in apoptosis. The combine administration of VP and TMZ may be therapeutically exploited for the management of GBM. PMID- 30003980 TI - Delivery efficiencies of constituents of combustion-derived aerosols across the air-liquid interface during in vitro exposures. AB - In vitro aerosol exposure of epithelial cells grown at the air-liquid interface is an experimental methodology widely used in respiratory toxicology. The exposure depends to a large part on the physicochemical properties of individual aerosol constituents, as they determine the transfer kinetics from the aerosol into the cells. We characterized the transfer of 70 cigarette smoke constituents from the smoke into aqueous samples exposed in the Vitrocell(r) 24/48 aerosol exposure system. The amounts of these compounds in the applied smoke were determined by trapping whole smoke in N,N-dimethylformamide and then compared with their amounts in smoke-exposed, phosphate-buffered saline, yielding compound specific delivery efficiencies. Delivery efficiencies of different smoke constituents differed by up to five orders of magnitude, which indicates that the composition of the applied smoke is not necessarily representative for the delivered smoke. Therefore, dose metrics for in vitro exposure experiments should, if possible, be based on delivered and not applied doses. A comparison to literature on in vivo smoke retention in the respiratory tract indicated that the same applies for smoke retention in the respiratory tract. PMID- 30003981 TI - Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and meta-analysis. AB - BACKGROUND: Sonic hedgehog inhibitors (SHHis) provide an additional treatment option for basal cell carcinomas (BCCs), especially for metastatic or locally advanced BCC. However, studies have been heterogeneous and lacked direct comparisons between molecules. OBJECTIVE: To determine the efficacy and safety of the class of molecules SHHi for treating BCC and to compare them individually. METHODS: We performed a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review of studies followed by a meta analysis. RESULTS: Eighteen articles were included in our meta-analysis; 16 articles were combined for efficacy and 16 for safety. In locally advanced BCC, overall response rates (ORRs) were similar for vismodegib and sonidegib (69% vs 57%, respectively) but not complete response rates (31% vs 3%, respectively). In metastatic disease, the ORR of vismodegib was 2.7-fold higher than the ORR of sonidegib (39% vs 15%, respectively). For side effects affecting a majority of patients, prevalences for muscle spasms (67.1%), dysgeusia (54.1%), and alopecia (57.7%) were in similar proportions for sonidegib and vismodegib. Patients receiving sonidegib experienced more upper gastrointestinal distress than patients receiving vismodegib. CONCLUSION: SHHis induce a partial response to locally advanced BCC disease. Side effects are common, similar across molecules, associated with high discontinuation rates, and warrant discussion beforehand. PMID- 30003982 TI - Drug-induced phototoxicity: A systematic review. AB - BACKGROUND: Phototoxicity has been attributed to numerous oral drugs over the past 60 years. OBJECTIVE: Determine the quality of evidence supporting suspected phototoxicity from oral drugs. METHODS: The MEDLINE and EMBASE databases were searched for all studies that contain original data for drug-induced phototoxicity and were published between May 1959 and December 2016. Study quality was assessed by using a modified Grading of Recommendations, Assessment, Development and Evaluation scale. RESULTS: The review included 240 eligible studies with a total of 2466 subjects. There were 1134 cases of suspected phototoxicity associated with 129 drugs. Most associations were supported by either very low-quality or low-quality evidence (89.1% of the studies). Medications supported by stronger evidence were vemurafenib, nonsteroidal anti inflammatory drugs, and antibiotics, specifically, fluoroquinolones and tetracyclines. The most frequently reported drugs were vemurafenib, voriconazole, doxycycline, hydrochlorothiazide, amiodarone, and chlorpromazine. Photobiologic evaluation was performed in only 56 studies (23.3%), whereas challenge rechallenge was done in 10% of cases. LIMITATIONS: Only English-language publications were reviewed. Cases of phototoxicity that had been incorrectly categorized as photoallergy would not have been included. CONCLUSIONS: Most purported associations between oral drugs and phototoxicity are not supported by high-quality evidence. Despite the variable quality of data, clinicians should be aware of the possible consequences of long-term use of culprit drugs. PMID- 30003983 TI - Intralesional immunotherapy for the treatment of warts: A network meta-analysis. AB - BACKGROUND: Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging. OBJECTIVE: Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities. METHODS: We included randomized controlled trials comparing intralesional immunotherapeutic modalities to cryotherapy, placebo, or imiquimod. All outcomes were presented as odds ratios (ORs) with 95% confidence intervals. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments. RESULTS: Network meta-analysis of 17 randomized controlled trials (1676 patients) showed that PPD (purified protein derivative vaccine, OR 39.56), MMR (measles, mumps, rubella vaccine, OR 17.46) and interferon beta (OR 15.55) had the highest efficacy in terms of complete recovery at the primary site compared with placebo. Regarding complete recovery at the distant site, autoinoculation (OR 79.95), PPD (OR 42.95), and MMR (OR 15.39) were all statistically superior to placebo. According to the P-score, MMR was more effective than other modalities in reducing the recurrence rate at the same site. LIMITATIONS: Relatively small sample size in some comparisons and variability in baseline characteristics. CONCLUSION: PPD and MMR were the most effective in achieving complete primary and distant recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site compared with cryotherapy and other immunotherapeutic modalities. PMID- 30003984 TI - Comparing the eighth and the seventh editions of the American Joint Committee on Cancer staging system and the Brigham and Women's Hospital alternative staging system for cutaneous squamous cell carcinoma: Implications for clinical practice. AB - BACKGROUND: The new eighth edition of the American Joint Committee on Cancer staging system (AJCC-8) incorporates changes regarding cutaneous squamous cell carcinoma (CSCC). OBJECTIVES: We aimed to compare the AJCC-8 staging system with the previous seventh edition of the AJCC staging system (AJCC-7) and the Brigham and Women's Hospital (BWH) alternative staging system to identify their usefulness and the utility of their risk factors in defining prognostic groups in CSCC. METHODS: A series of 186 CSCCs of the head and neck were retrospectively collected. All 3 staging systems were compared from the standpoint of their ability to predict poor prognosis. Binary logistic regression models were built to determine which risk factors were most relevant. RESULTS: Poor prognosis was mainly associated with stage T2 of the AJCC-7, with stages T2b/T3 of the BWH system, and with stage T3 of the AJCC-8. The AJCC-8 and the BWH staging systems displayed overlap with each another in predicting poor prognosis, and both were superior to the AJCC-7. The new risk factors incorporated into the AJCC-8 and the poor degree of differentiation were independently associated with poor outcome. LIMITATIONS: Retrospective study and few cases with bone invasion. CONCLUSIONS: The AJCC-8 is more distinctive, monotonous, and homogeneous than the AJCC-7 and shows some overlap with the BWH system in stratification of tumors. PMID- 30003985 TI - Surgical Pearl: A Granny Sliding Knot for High Tension Closures. PMID- 30003986 TI - Mohs micrographic surgery with melanoma antigen recognized by T cells 1 (MART-1) immunostaining for atypical intraepidermal melanocytic proliferation. AB - BACKGROUND: The efficacy of Mohs micrographic surgery (MMS) for atypical intraepidermal melanocytic proliferation (AIMP) is unknown. OBJECTIVE: To ascertain the frequency of diagnostic change to melanoma (upstaging) and the frequency of local recurrence after MMS for AIMP. A secondary outcome was the frequency of subclinical spread (defined as the requirement for >1 stage of MMS to achieve tumor-free margins). METHODS: Retrospective, cross-sectional study of 223 AIMP (with 92.4% located on the head, neck, hand, foot, or pretibial leg) patients treated with MMS with melanoma antigen recognized by T cells 1 (MART-1) immunostaining. RESULTS: Upstaging to unequivocal melanoma in situ or invasive melanoma was identified in 18.8% (42/223) of all AIMP patients. The local recurrence rate was 0% (0/223) with a mean follow-up time of 2.7 years (998 days). Subclinical spread was present in 23.8% (53/223) of AIMP patients. LIMITATIONS: Single site, retrospective design, observational study, lack of objective criteria to diagnose AIMP. CONCLUSION: MMS with MART-1 immunostaining achieves excellent local control of specialty site AIMP and permits definitive removal of subclinical spread before reconstruction. The central debulking excision should be evaluated with formalin-fixed paraffin-embedded section staining, since a significant percentage of AIMP are reclassified as melanoma in situ or invasive melanoma. PMID- 30003987 TI - The ALT-70 predictive model outperforms thermal imaging for the diagnosis of lower extremity cellulitis: A prospective evaluation. AB - BACKGROUND: We previously demonstrated that dermatology consultation substantially reduces the rates of misdiagnosis of cellulitis; however, broad implementation of dermatology consultation is impractical on account of existing practice patterns and reimbursement systems. Meanwhile, efforts to improve diagnostic accuracy have culminated in point-of-care tools, including the ALT-70 predictive model for lower extremity cellulitis and thermal imaging. OBJECTIVE: To prospectively evaluate the performance of the ALT-70 predictive model and thermal imaging in diagnosing lower extremity cellulitis in a head-to-head comparison. METHODS: We collected ALT-70 and thermal imaging data from patients with presumed lower extremity cellulitis and compared classification measures and accuracy for the ALT-70 predictive model, thermal imaging, and combination testing (ALT-70 predictive model plus thermal imaging). RESULTS: We enrolled 67 patients with ALT-70 and thermal imaging data. The ALT-70 predictive model conferred the highest sensitivity (97.8%) and negative predictive value (90.9%), whereas combination testing had the highest specificity (71.4%) and positive predictive value (86.6%). The ALT-70 predictive model had improved classification measures compared with thermal imaging. Combination testing conferred a marginal benefit compared with the ALT-70 predictive model alone. LIMITATIONS: Single center design may limit generalizability. CONCLUSION: The ALT-70 predictive model outperformed thermal imaging in diagnosing lower extremity cellulitis. The accuracy of the ALT-70 predictive model was high and consistent with its performance in previously published literature. Broad implementation of the ALT 70 predictive model in clinical practice may decrease the rates of misdiagnosis of lower extremity cellulitis. PMID- 30003989 TI - Beyond JAAD October 2018: Articles of interest to dermatologists from the nondermatologic literature. PMID- 30003988 TI - Topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 phase 3 randomized controlled trials. AB - BACKGROUND: Glycopyrronium tosylate (GT) is a topical anticholinergic developed for once-daily treatment of primary axillary hyperhidrosis. OBJECTIVE: Assess the efficacy and safety of GT for primary axillary hyperhidrosis. METHODS: ATMOS-1 and ATMOS-2 were replicate randomized, double-blind, vehicle-controlled, 4-week phase 3 trials. Patients were randomized 2:1 to GT 3.75% or vehicle applied once daily to each axilla for 4 weeks. Coprimary endpoints were responder rate (>=4 point improvement from baseline) on item 2 (severity of sweating) of the Axillary Sweating Daily Diary (ASDD), which is a newly developed patient-reported outcome measure, and absolute change from baseline in axillary gravimetric sweat production at week 4. Safety evaluation included treatment-emergent adverse events. RESULTS: Pooled data, which are consistent with the individual trial results, show that significantly more GT-treated patients achieved an ASDD-Item 2 response than did those treated with vehicle (59.5% vs 27.6%), and they had reduced sweat production from baseline (-107.6 mg/5 min vs -92.1 mg/5 min) at week 4 (P < .001 for both coprimary end points). Most treatment-emergent adverse events were mild or moderate and infrequently led to discontinuation. LIMITATIONS: Short trial duration and inherent challenges in gravimetrically assessing sweat production. CONCLUSIONS: GT applied topically on a daily basis over 4 weeks reduced the severity of sweating as measured by ASDD-Item 2, reduced sweat production as measured gravimetrically, and was generally well tolerated in patients with primary axillary hyperhidrosis. PMID- 30003990 TI - Methotrexate for alopecia areata: a systematic review and meta-analysis. AB - BACKGROUND: Methotrexate has been used both as an adjunct for low-risk maintenance therapy after initiation with corticosteroids for alopecia areata (AA) and as standalone therapy in some investigations, based on a lack of definitive evidence/guidelines. OBJECTIVE: To (1) determine the efficacy and risks associated with methotrexate therapy for AA (2) determine differences efficacy of combination with corticosteroids versus standalone treatment, and (3) determine relative efficacy of methotrexate in adult versus pediatric populations. METHODS: A systematic review and meta-analysis was performed according to recommended PRISMA guidelines. RESULTS: Methotrexate has reasonable effectiveness in patients with severe AA, and that adults appear to be more responsive to methotrexate treatment compared to pediatric cases. Methotrexate in conjunction with corticosteroids result in higher good/complete response rates compared to those treated with methotrexate alone. A large proportion of recurrence rates occurred in the setting of tapering treatment. Complication rates were acceptable and similar between adults and pediatric cases. LIMITATIONS: Studies reviewed were retrospective observational studies with heterogeneity between centers in terms of dosages/protocols for methotrexate use in AA, and adjunctive treatments with a lack of data beyond one year. CONCLUSION: Methotrexate is an effective monotherapy or adjunct to corticosteroid in the treatment of severe AA. PMID- 30003991 TI - Ustekinumab treatment for neutrophilic dermatoses associated with Crohn's disease: a multicenter-retrospective study. PMID- 30003992 TI - Pigmentation of basal cell carcinoma is inversely associated with tumor aggressiveness in Asian patients. PMID- 30003993 TI - Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa. AB - BACKGROUND: Hormonal therapy is a potential treatment for hidradenitis suppurativa (HS). However, few data exist describing the efficacy of spironolactone in treatment of HS. OBJECTIVE: To assess whether spironolactone treatment improves HS disease severity and patient-reported pain. METHODS: We performed a single-center chart review of female patients with HS who were treated with spironolactone between 2000 and 2017. Primary outcome measurements included the HS Physician's Global Assessment (HS-PGA), Hurley staging, inflammatory lesion count, fistula count, and a numeric rating scale for pain. RESULTS: On average, subjects were exposed to 75 mg of spironolactone daily over a 7.1-month follow-up period. Patients achieved significant disease improvement with regard to pain (Delta-1.5 [P = .01]), inflammatory lesions (Delta-1.3 [P = .02]), and HS-PGA score (Delta-0.6 [P < .001]). As expected, no change was found for Hurley stage (Delta0 [P = .32]) or fistulas (Delta0 [P = .73]). There was no difference in improvement between subjects who received less than 75 mg of spironolactone daily (n = 25; average dose, 45 mg/d) and those who received more than 100 mg daily (n = 21; average dose, 112 mg/d). LIMITATIONS: Retrospective nature, limited sample size, and variations in severity measures documented were limiting factors. CONCLUSIONS: Management of HS with spironolactone reduces lesion count, HS-PGA score, and pain. Lower doses appear to be effective and may be an appropriate option for patients with tolerability concerns. PMID- 30003994 TI - Imaging-Based Outcomes for 24 Gy in 2 Daily Fractions for Patients with de Novo Spinal Metastases Treated With Spine Stereotactic Body Radiation Therapy (SBRT). AB - PURPOSE: We report mature outcomes for a cohort of patients with no prior radiation (de novo) to the spine treated with 24 Gy in 2 daily fractions for metastases, which represents the same stereotactic body radiation therapy (SBRT) regimen under evaluation in the current Symptom Control-24 phase 3 randomized trial (NCT02512965). METHODS AND MATERIALS: The cohort consisted of 279 de novo spinal metastases in 145 consecutive patients treated with 24 Gy in 2 SBRT fractions, identified from a prospective single-institution database. The endpoints were overall survival (OS), imaging-based local failure (LF), and cumulative risk of vertebral compression fractures (VCF). RESULTS: The median follow-up per treated metastasis was 15.0 months (range, 0.1-71.6). The 1-year and 2-year OS rates were 73.1% and 60.7%, respectively. Presence of epidural disease (P < .0001), lung (P = .0415), and renal cell (P < .0001) primary histologies and baseline diffuse metastases (P = .0034) were significant prognostic factors for OS. The 1-year and 2-year LF rates were 9.7% and 17.6%, respectively, and the median time to LF was 9.2 month (range, 0.4-31.3 months). Only the presence of epidural disease predicted for LF (P < .0001). The cumulative risk of VCF at 1 and 2 years was 8.5% and 13.8%, respectively. Lytic (P = .0143) or mixed lytic/blastic (P = .0214) lesions, spinal malalignment (P = .0121), and the dose to 90% of the planning target volume (P = .0085) were significant predictors for VCF. CONCLUSIONS: Twenty-four Gray in 2 daily fractions is safe and effective in achieving high tumor control rates for de novo spinal metastases. These outcomes will serve as a benchmark for the ongoing Symptom Control-24 randomized trial comparing 24 Gy in 2 SBRT fractions to 20 Gy delivered in 5 daily conventional fractions. PMID- 30003995 TI - Responses to the 2017 "1 Million Gray Question": ASTRO Membership's Opinions on the Most Important Research Question Facing Radiation Oncology. PMID- 30003996 TI - Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer. AB - PURPOSE: Recent data indicate consolidative radiation therapy improves progression-free survival (PFS) for patients with oligometastatic non-small cell lung cancer (NSCLC). Data on long-term outcomes are limited. METHODS AND MATERIALS: This prospective, multicenter, single-arm, phase 2 trial was initiated in 2010 and enrolled patients with oligometastatic NSCLC. Oligometastatic disease was defined as a maximum of 5 metastatic lesions for all disease sites, including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Patients achieving a partial response or stable disease after 3 to 6 cycles of platinum-based chemotherapy were treated with CRT to the primary and metastatic sites of disease, followed by observation alone. The primary endpoint was PFS, with secondary endpoints of local control, overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled between October 2010 and October 2015, and 27 were eligible for consolidative radiation therapy. The study was closed early because of slow accrual but met its primary endpoint for success, which was PFS >6 months (P < .0001). The median PFS (95% confidence interval) was 11.2 months (7.6-15.9 months), and the median OS was 28.4 months (14.5-45.8 months). Survival outcomes were not significantly different for patients with brain metastases (P = .87 for PFS; P = .12 for OS) or lymph node involvement (P = .74 for PFS; P = .86 for OS). CONCLUSIONS: For patients with oligometastatic NSCLC, chemotherapy followed by consolidative radiation therapy without maintenance chemotherapy was associated with encouraging long-term outcomes. PMID- 30003997 TI - Early Changes in Serial CBCT-Measured Parotid Gland Biomarkers Predict Chronic Xerostomia After Head and Neck Radiation Therapy. AB - PURPOSE: To determine whether serial cone beam computed tomography (CBCT) images taken during head and neck radiation therapy (HNR) can improve chronic xerostomia prediction. METHODS AND MATERIALS: In a retrospective analysis, parotid glands (PGs) were delineated on daily kV CBCT images using deformable image registration for 119 HNR patients (60 or 70 Gy in 2 Gy fractions over 6 or 7 weeks). Deformable image registration accuracy for a subset of deformed contours was quantified using the Dice similarity coefficient and mean distance to agreement in comparison with manually drawn contours. Average weekly changes in CBCT measured mean Hounsfield unit intensity and volume were calculated for each PG relative to week 1. Dose-volume histogram statistics were extracted from each plan, and interactions among dose, volume, and intensity were investigated. Univariable analysis and penalized logistic regression were used to analyze association with observer-rated xerostomia at 1 year after HNR. Models including CBCT delta imaging features were compared with clinical and dose-volume histogram only models using area under the receiver operating characteristic curve (AUC) for grade >=1 and grade >=2 xerostomia prediction. RESULTS: All patients experienced end-treatment PG volume reduction with mean (range) ipsilateral and contralateral PG shrinkage of 19.6% (0.9%-58.4%) and 17.7% (4.4%-56.3%), respectively. Midtreatment volume change was highly correlated with mean PG dose (r = -0.318, P < 1e-6). Incidence of grade >=1 and grade >=2 xerostomia was 65% and 16%, respectively. For grade >=1 xerostomia prediction, the delta-imaging model had an AUC of 0.719 (95% confidence interval [CI], 0.603-0.830), compared with 0.709 (95% CI, 0.603-0.815) for the dose/clinical model. For grade >=2 xerostomia prediction, the dose/clinical model had an AUC of 0.692 (95% CI, 0.615 0.770), and the addition of contralateral PG changes modestly improved predictive performance, with an AUC of 0.776 (0.643-0.912). CONCLUSIONS: The rate of CBCT measured PG image feature changes improves prediction over dose alone for chronic xerostomia prediction. Analysis of CBCT images acquired for treatment positioning may provide an inexpensive monitoring system to support toxicity-reducing adaptive radiation therapy. PMID- 30003998 TI - Clinical Feasibility of Single-Source Dual-spiral 4D Dual-Energy CT for Proton Treatment Planning Within the Thoracic Region. AB - PURPOSE: Single-source dual-spiral dual-energy computed tomography (DECT) provides additional patient information but is prone to motion between the 2 consecutively acquired computed tomography (CT) scans. Here, the clinical applicability of dual-spiral time-resolved DECT (4D-DECT) for proton treatment planning within the thoracic region was evaluated. METHODS AND MATERIALS: Dual spiral 4D-DECT scans of 3 patients with lung cancer were acquired. For time averaged datasets and 4 breathing phases, the geometric conformity of 80 kVp and 140 kVp 4D-DECT scans before image post-processing was assessed by normalized cross correlation (NCC). Additionally, the conformity of the corresponding DECT derived 58 keV and 79 keV pseudo-monoenergetic CT datasets after image post processing, including deformable image registration (DIR), was determined. To analyze the reliability of proton dose calculation, clinical (PlanClin) and artificial worst-case (PlanWorstCase, targeting the diaphragm) treatment plans were calculated on 140 kVp and 79 keV datasets and compared with gamma analyses (0.1% dose-difference and 1 mm distance-to-agreement criterion). The applicability of a patient-specific DECT-based prediction of stopping-power ratio (SPR) was investigated and proton range shifts compared with the clinical heuristic CT-number-to-SPR conversion were assessed. Finally, the delineation variability of an experienced radiation oncologist was quantified. RESULTS: Dual spiral 4D-DECT scans without DIR showed a high geometric conformity, with an average NCC +/- standard deviation of 98.7% +/- 1.0% when including all patient voxels or 88.2% +/- 7.8% when considering only lung. DIR improved the conformity, leading to an average NCC of 99.9% +/- 0.1% and 99.6% +/- 0.5%, respectively. PlanClin dose distributions on 140 kVp and 79 keV datasets were similar, with an average gamma passing rate of 99.9% (99.2%-100%). The worst-case evaluation still revealed high passing rates (99.3% on average, 92.4% as minimum). Clinically relevant mean range shifts of 2.2% +/- 1.2% were determined between patient specific DECT-based SPR prediction and clinical heuristic CT-number-to-SPR conversion. The intra-observer delineation variability was slightly reduced using additional DECT-derived datasets. CONCLUSIONS: The 79 keV pseudo-monoenergetic CT datasets can be consistently obtained from dual-spiral 4D-DECT and are applicable for dose calculation. Patient-specific DECT-based SPR prediction performed well and potentially reduces range uncertainty in proton therapy of patients with lung cancer. PMID- 30003999 TI - Extracellular vesicles and anti-cancer drug resistance. AB - Extracellular vesicles (EVs) including exosomes, microvesicles, oncosomes, and microparticles have been associated with communicating anti-cancer drug resistance. The in vitro, pre-clinical in vivo and patients' data linking EVs to drug-resistance (and the specific drugs involved) in breast cancer, prostate cancer, lung cancer, ovarian cancer, haematological malignancies, colorectal cancer, gastric cancer, pancreatic cancer, glioblastoma, neuroblastoma, melanoma, kidney cancer and osteosarcoma. Details of the mechanisms by which the resistance seems to be occurring (e.g. EVs transferring drug-efflux pumps from drug resistant cancer cells, EVs binding monoclonal antibodies in the peripheral circulation and so reducing their bioavailability, EVs from tumour microenvironment cells, etc.) are outlined, as are efforts to try to block such resistance. Research to date strongly supports EVs as playing a key role in drug resistance. Further studies including tailored clinical studies are now warranted to determine how best to prevent this occurring, in the interest of patients and also for economic benefit. Furthermore, efforts to exploit safe (non-cancer origin) EVs as anti-cancer drug delivery vehicles that may achieve efficacy with more limited side-effects than free drug, deserve further investigation. PMID- 30004000 TI - PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy. AB - The lung remains an attractive target for the gene therapy of monogenetic diseases such as cystic fibrosis (CF). Despite over 27 clinical trials, there are still very few gene therapy vectors that have shown any improvement in lung function; highlighting the need to develop formulations with improved gene transfer potency and the desirable physiochemical characteristics for efficacious therapy. Herein, we introduce a novel cell penetrating peptide (CPP)-based non viral vector that utilises glycosaminoglycan (GAG)-binding enhanced transduction (GET) for highly efficient gene transfer. GET peptides couple directly with DNA through electrostatic interactions to form nanoparticles (NPs). In order to adapt the GET peptide for efficient in vivo delivery, we engineered PEGylated versions of the peptide and employed a strategy to form DNA NPs with different densities of PEG coatings. We were able to identify candidate formulations (PEGylation rates >=40%) that shielded the positively charged surface of particles, maintained colloidal stability in bronchoalveolar lavage fluid (BALF) and retained gene transfer activity in human bronchial epithelial cell lines and precision cut lung slices (PCLS) in vitro. Using multiple particle tracking (MPT) technology, we demonstrated that PEG-GET complexes were able to navigate the mucus mesh and diffuse rapidly through patient CF sputum samples ex vivo. When tested in mouse lung models in vivo, PEGylated particles demonstrated superior biodistribution, improved safety profiles and efficient gene transfer of a reporter luciferase plasmid compared to non-PEGylated complexes. Furthermore, gene expression was significantly enhanced in comparison to polyethylenimine (PEI), a non-viral gene carrier that has been widely tested in pre-clinical settings. This work describes an innovative approach that combines novel GET peptides for enhanced transfection with a tuneable PEG coating for efficacious lung gene therapy. PMID- 30004001 TI - Crown therapy in young individuals with amelogenesis imperfecta: Long term follow up of a randomized controlled trial. AB - OBJECTIVES: Amelogenesis imperfecta (AI) is a rare, genetically determined defect in enamel mineralization. Several problems are associated with AI: hypersensitivity, wear, restorations requiring replacement, gingivitis, aesthetic problems, and social avoidance. We conducted a randomized controlled trial of crown therapy in young individuals with AI showing excellent results. This study reports results from a long-term-follow-up with focus on quality, longevity and adverse events. METHODS: The RCT included 27 patients (aged 11-22 years) with severe AI in need of crown therapy and used a split-mouth technique. After placing 119 Procera(r) crowns and 108 IPS e.max Press crowns following randomization, we assessed longevity, quality, adverse events, and tooth sensitivity and calculated survival rates and success rates. RESULTS: We followed the original 227 crowns for 4.3-7.4 years (mean 5.5 +/- 0.8). In all, 79% (193) crowns were followed for at least 5 years. The survival rate was 99.6% and the success rate, 94.7%; 95% of the crowns had excellent or acceptable quality. Due to suboptimal marginal integrity, 4% of the crowns required adjustment. Sensitivity problems decreased after crown therapy (p < 0.001). All adverse events occurred in patients aged 19-23 years and involved apical periodontitis (3% of teeth); all but two events were related to dental trauma in the actual tooth. CONCLUSIONS: Ceramic crown therapy in adolescents and young adults with severe forms of AI show excellent survival and success rates and longevity with few adverse events. CLINICAL SIGNIFICANCE: Ceramic crown therapy can be recommended for adolescents and young adults with severe forms of amelogenesis imperfecta. PMID- 30004003 TI - Provision of information to patients on dental implant treatment: Clinicians' perspectives on the current approaches and future strategies. AB - OBJECTIVES: To explore 1) the approaches that are adopted by clinicians to give patients information in relation to dental implant treatment during clinical consultations; 2) clinicians' reflections on their current practices of implant information provision; and 3) clinicians' suggestions to improve future implant information provision. METHODS: A qualitative study employing face-to-face semi structured interviews with eight clinicians working in UK secondary dental care. The data gathering and analysis followed the principles of qualitative thematic analysis. RESULTS: Clinicians reported that patients often hold misconceptions about dental implants, which are commonly acquired from generic information sources such as the media. This might be linked to high expectations regarding treatment outcomes and difficulties in communicating during clinical consultations. Clinicians were sometimes reluctant to voluntarily offer information about the longevity/ lifespan of implant supported restoration (ISR) and they had different opinions regarding the timing of information related to their long-term maintenance needs. Several strategies for improving the current practice of information giving in relation to dental implant treatment were suggested by clinicians. CONCLUSION: Providing accurate and timely information to patients could be challenging, although clinicians recognised the importance of doing so. As clinicians explained and debated their current approaches and reflected on their practices, they identified areas of potential improvement and ways to improve information provision related to dental implants. These were mainly focused on transforming patient care so that there is efficient co operative alliance between patients and dental care providers. Considering upgrading information provision throughout the implant treatment pathway would transform this aspect of healthcare to make it more "patient-centred" than it is currently. PMID- 30004002 TI - Decision-making of general practitioners on interventions at restorations based on bitewing radiographs. AB - OBJECTIVE: The aim of this study was to compare decision-making based on bitewing analysis of restored proximal surfaces by general dental practitioners (GDPs) with diagnossis and clinical decisions made by experts in cariology and restorative dentistry. METHODS: This practice-based study used a database of 7 general dental practices. Posterior bitewing radiographs were selected from the electronic patient files of patients, and 770 cases of proximal restored surfaces were selected. Fifty percent of the cases which lead to the restorative decision, and the other half were cases decided for monitoring by the GDPs. Three experts performed radiographic assessment. The outcome variables were agreement of diagnosis and decision of treatment. Cohen's kappa statistic was used. RESULTS: For the experts, moderate to substantial intraexaminer agreement was observed for the diagnostic criteria, and kappa values of 0.77, 0.79, and 0.88 were obtained for each expert regarding the treatment assignment. Agreement between GDPs and the majority of experts for secondary caries varied between 67 and 83%. One hundred seventy-three out of 385 cases that were treated by GDPs were decided for monitoring by the experts, while 8 cases that were decided for monitoring by the GDPs were decided for treatment. The agreement between experts and GDPs was moderate for secondary caries detection, and fair for treatment decision. CONCLUSION: The GDPs tend to have a less conservative approach regarding the decision to intervene or not concerning the reassessment of restorations, showing moderate agreement with the experts for secondary caries detection and fair agreement regarding the treatment decision. CLINICAL SIGNIFICANCE: This study highlights that GDPs tend to have a less conservative approach to the decision to intervene or not in posterior restorations, compared to experts in cariology and restorative dentistry. Efforts should be made to reduce these differences based on minimally invasive dentistry. PMID- 30004004 TI - Neurobehavioral effects of long-term maternal fructose intake in rat offspring. AB - BACKGROUND: Previous studies have indicated an association between maternal metabolic conditions and general developmental disturbances of the offspring. OBJECTIVE: We aimed to investigate the influence of long-term maternal fructose intake during gestation and lactation on neurobehavioral development of rat offspring. METHODS: Twelve female Sprague Dawley rats were received either 30% fructose enriched water (n = 6) or regular tap water (control, n = 6) for 12 weeks. Then, control and fructose-received females were caged with a fertile male, and received 30% fructose and regular chow throughout pregnancy, delivery and until offspring's weaning. On P21, forty littermates (10 male control, 10 female control, 10 male fructose and 10 female fructose) were separated and housed with ad libitum access to standard food and tap water. Following behavioral evaluations at P50, brain levels of TNF-alpha, neuregulin 1 (NRG1), glutamic acid decarboxylase 67 (GAD67), nerve growth factor (NGF), insulin-like growth factor 1 (IGF-1), and 5-hydroxyindoleacetic acid (5-HIAA) were measured. Histologically, hippocampal neuronal density and GFAP expression were assessed. RESULTS: Analysis of the behavioral tests (three-chamber social test, open field test, passive avoidance learning test and stereotypy test) revealed significant differences among the groups. Histologically, hippocampal CA1 and CA3 regions displayed significant alterations such as gliosis and neuronal cell death in fructose-exposed groups compare to controls. Biochemical measurements of the brain levels of TNF-alpha and neurodevelopmental markers showed significant differences between controls and fructose-exposed groups. CONCLUSION: These results suggest a possible link between the chronic maternal metabolic stress, such as long-term fructose intake, and neurodevelopmental disturbances in the offspring. PMID- 30004005 TI - Martin Vigorimeter assesses muscle fatigability in older adults better than the Jamar Dynamometer. AB - INTRODUCTION: Muscle fatigability can be measured based on sustained handgrip performance, but different grip strength devices exist and their relationship to frailty remains unclear. We aimed to compare muscle fatigability obtained by Martin Vigorimeter and Jamar Dynamometer in older women across levels of frailty. METHOD: 53 community-dwelling women living in Greece (63-100 y), categorized according to tertiles on the Frailty Index score (FI) as: low-frail (FI < 0.19), intermediate-frail (FI 0.19-0.36), and high-frail (FI > 0.36). Fatigue resistance (FR, time for maximal grip strength to decrease to 50% during sustained contraction) was measured with both Martin Vigorimeter and Jamar Dynamometer, and grip work (GW, reflecting the area under the time-force curve) was calculated. RESULTS: FR, when measured with the Martin Vigorimeter, was approximately double in low-frail (44.3 +/- 24.6 s) compared to high-frail participants (23.9 +/- 12.7 s, p = 0.011), whereas FR was similar across frailty groups when measured with the Jamar Dynamometer. In logistic regression models, FR (OR = 0.94 [0.90-0.99]) and GW (OR = 0.90 [0.82-0.99]) were significantly related to high frailty when measured with the Martin Vigorimeter but not when measured with Jamar Dynamometer. There is a significantly proportional difference in FR measured with both devices (R2 = 0.364, p < 0.001), highlighting that the longer the participant could sustain the FR test, the higher the difference in FR measured with both devices. CONCLUSION: Our results suggest that the Martin Vigorimeter is a more appropriate handgrip device compared with the Jamar Dynamometer to assess muscle fatigability for older women across levels of frailty. When measured with the Martin Vigorimeter, high-frail participants show twice the level of fatigability compared to low-frail, whereas no difference was observed when using the Jamar Dynamometer. Older participants might stop the FR test prematurely when using the Jamar Dynamometer, before muscle fatigue is reached, indicating that the Jamar Dynamometer is unable to identify those participants with higher levels of muscle endurance. Martin Vigorimeter assessed muscle fatigability might be a good additional marker to include in frailty tools. PMID- 30004006 TI - Age-induced diminution of free radicals by Boeravinone B in Caenorhabditis elegans. AB - Oxidative damage is accrual of molecular deterioration from reactive oxygen species (ROS) while decrease in generation of ROS is related with free radical scavenging enzymes. Boerhaavia diffusa L. (Nyctaginaceae) derived novel molecule Boeravinone B (BOB) possesses a variety of pharmacological activities, yet their anti-aging potential has not been explored. The aim of the present study was to elucidate the mechanism of BOB mediated oxidative stress resistance and lifespan extension in Caenorhabditis elegans. The results showed that the BOB significantly extends the lifespan of C. elegans with its anti-oxidative potential via reducing accumulation of reactive oxygen species (ROS). BOB was found to recover the shortened lifespan of oxidative stress prone mutants mev-1 and gas-1 (14.75 and 16.11%, respectively). Additionally, this finding supported by the reduced ROS levels seen in BOB treated worms. Further, the effective concentration of BOB (25 MUM) significantly enhanced the expressions of target genes such as superoxide dismutase (SOD-3), glutathione-S-transferase (GST-4) and heat shock protein (HSP-16.2) fused to green fluorescent protein (GFP), and it does so by modulating the stress-related signaling pathways (SEK-1) and transcription factors (SKN-1/Nrf and DAF-16/Foxo). Moreover, BOB exposure (25 MUM) caused significant changes of age-dependent biomarkers such as pharyngeal pumping, body bend, locomotor activity and lipofuscin accumulation were also showed that BOB retards the aging. Overall, the findings highlight the antioxidant supplement triggering pharmaceutical potential of BOB which may serve as a new future perspective for healthy aging or delayed onset of oxidative related diseases. PMID- 30004007 TI - When "Extraneous" Becomes "Mine". Neurophysiological Evidence of Sensorimotor Integration During Observation of Suboptimal Movement Patterns Performed by People with Multiple Sclerosis. AB - Action observation is known to enhance sensorimotor system activation, and such effect has been linked to neural priming and response facilitation mechanisms. This facilitation effect, however, has been primarily studied by focusing on high level motor proficiency, whereas evidence on the effect of observing poorly performed actions is still lacking. We then devised a study to investigate neural correlates of the observation of suboptimal motor acts as mirrored by corticospinal activation (via transcranial magnetic stimulation (TMS), Experiment 1) and by modulation of cortical oscillatory activity (via electroencephalography (EEG), Experiment 2). 40 participants were presented with four randomly reiterated videos. Videos depicted a healthy confederate, a minimally impaired multiple sclerosis (MS) patient, a mildly impaired MS patient, or a confederate trying to simulate mild motor difficulties performing a test concerning fine motor abilities. In Experiment 1 we analyzed TMS-induced motor-evoked potentials during the observation of videos. In Experiment 2 EEG data were analyzed in the frequency-domain. Analyses highlighted both increased corticospinal excitability and desynchronized alpha-beta oscillations during the observation of poorly performed motor acts performed by the mildly impaired MS patient. Further, we observed gradually increasing beta activity across videos reiterations, specifically for the minimally impaired patient's video. Reported findings corroborate the hypotheses that the action-observation network and the motor system might be involved in processes evoked in the attempt to understand and predict observed actions which do not belong to the onlookers' motor repertoire, reflecting in an increased sensorimotor activity. PMID- 30004008 TI - Detecting Concealed Information with Fused Electroencephalography and Functional Near-infrared Spectroscopy. AB - In this study, fused electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) techniques were utilized to examine the relationship between the ERP (event-related potential) component P300 and fNIRS hemodynamic signals for high-accuracy deception detection. During the performance of a modified concealed information test (CIT) task, a series of Chinese names were presented, which served as the target, irrelevant, or the probe stimuli for both the guilty and innocent groups. For participants in the guilty group, the probe stimulus was their individual name, whereas for the innocent group, the probe stimulus was one irrelevant name. In particular, data from concurrent fNIRS and ERP recordings were carefully inspected for participants from the two groups. Interestingly, we discovered that for the guilty group, the probe stimulus elicited significantly higher P300 amplitude at parietal site and also evoked significantly stronger oxyhemoglobin (HbO) concentration changes in the bilateral superior frontal gyrus and bilateral middle frontal gyrus than the irrelevant stimuli. However, this is not the case for the innocent group, in which participants exhibited no significant differences in both ERP and fNIRS measures between the probe and irrelevant stimuli. More importantly, our findings also demonstrated that the combined ERP and fNIRS feature was able to differentiate the guilty and innocent groups with enhanced sensitivity, in which AUC (the area under Receiver Operating Characteristic curve) is 0.94 for deception detection based on the combined indicator, much higher than that based on the ERP component P300 only (0.85) or HbO measure only (0.84). PMID- 30004009 TI - Global and Subnetwork Changes of the Structural Connectome in de novo Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by widespread neuropathological involvement of cortical and subcortical brain areas, which may therefore affect the structural brain network or 'connectome'. Using diffusion tensor imaging (DTI) and graph analysis we studied the structural connectome of medication-naive PD patients. DTI was acquired in 23 early-stage PD patients and 38 age, sex and education matched healthy controls. We studied global, subnetwork and local network topology using the Brainnetome atlas. At the subnetwork level we focused on the default-mode, frontoparietal, sensorimotor and attention networks. Graph measures included global efficiency, clustering coefficient and betweenness centrality. PD patients showed lower global efficiency and global clustering coefficient compared with healthy controls. This was also evident in all four subnetworks. These findings were largely replicated with the automated anatomical labeling (AAL) atlas and robust across a large range of thresholds. These results suggest that the wiring of the structural brain network of early-stage medication-naive PD patients is altered relative to healthy controls in such a way that it allows for less integration (global efficiency) and segregation (clustering coefficient) of information processing. PMID- 30004010 TI - The Impact of Perineuronal Net Digestion Using Chondroitinase ABC on the Intrinsic Physiology of Cortical Neurons. AB - Perineuronal nets (PNNs) are a form of aggregate Extracellular Matrix (ECM) in the brain. Recent evidence suggests that the postnatal deposition of PNNs may play an active role in regulating neuroplasticity and, potentially, neurological disorders. Observations of high levels of PNN expression around somas, proximal dendrites, and axon initial segments of a subtype of neurons have also led to proposals that PNNs may modulate the intrinsic properties of the neurons they ensheathe. While high levels of PNNs are postnatally expressed throughout the neocortex, it is still unclear how they impact the neuronal physiology of the many classes and subtypes of neurons that exist. In this study, we demonstrate that Chondroitinase ABC digestion of PNNs from acute cortical slices from juvenile mice (P28-35) resulted in neuron-specific impacts on intrinsic physiology. Fast spiking (FS) interneurons showed decreased input resistance, resting membrane potential (RMP), reduced action potential (AP) peaks and altered spontaneous synaptic inputs. Low-Threshold Spiking interneurons showed altered rebound depolarizations and decreased frequency of spontaneous synaptic inputs. Putative excitatory neurons; regular spiking, bursting, and doublet phenotypes did not demonstrate any alterations. Our data indicate that chABC-sensitive PNNs may specifically regulate the intrinsic and synaptic physiology of inhibitory interneurons. PMID- 30004011 TI - Species delimitation and mitogenome phylogenetics in the subterranean genus Pseudoniphargus (Crustacea: Amphipoda). AB - The amphi-Atlantic distributions exhibited by many thalassoid stygobiont (obligate subterranean) crustaceans have been explained by fragmentation by plate tectonics of ancestral shallow water marine populations. The amphipod stygobiont genus Pseudoniphargus is distributed across the Mediterranean region but also in the North Atlantic archipelagos of Bermuda, Azores, Madeira and the Canaries. We used species delimitation methods and mitogenome phylogenetic analyses to clarify the species diversity and evolutionary relationships within the genus and timing their diversification. Analyses included samples from the Iberian Peninsula, northern Morocco, the Balearic, Canarian, Azores and Madeira archipelagoes plus Bermuda. In most instances, morphological and molecular-based species delimitation analyses yielded consistent results. Notwithstanding, in a few cases either incipient speciation with no involvement of detectable morphological divergence or species crypticism were the most plausible explanations for the disagreement found between morphological and molecular species delimitations. Phylogenetic analyses based on a robust calibrated mitochondrial tree suggested that Pseudoniphargus lineages have a younger age than for other thalassoid amphipods displaying a disjunct distribution embracing both sides of the Atlantic Ocean. A major split within the family was estimated to occur at the Paleocene, when a lineage from Northern Iberian Peninsula diverged from the rest of pseudoniphargids. Species diversification in the peri-Mediterranean area was deduced to occur in early Miocene to Tortonian times, while in the Atlantic islands it started in the Pliocene. Our results show that the current distribution pattern of Pseudoniphargus resulted from a complex admix of relatively ancient vicariance events and several episodes of long- distance dispersal. PMID- 30004013 TI - Novel split luciferase-based biosensors for evaluation of vitamin D receptor ligands and their application to estimate CYP27B1 activity in living cells. AB - Recently, we successfully generated a novel detection system for vitamin D receptor (VDR) ligands in vivo and in vitro, using a split-luciferase technique called the LucN-LBD-LucC biosensor that is a chimeric fusion protein of firefly luciferase with the ligand binding domain (LBD) of VDR. In this system, the luciferase light intensity of the LucN-LBD-LucC biosensor was decreased by binding of VDR ligands. Although this system is quite useful for evaluation of VDR ligands in a short time, the sensitivity of the LucN-LBD-LucC biosensor is not high enough. In this study, LXXLL motif peptides involved in the interaction between LBD and coactivators, such as the steroid receptor coactivator-1 (SRC-1), transcriptional intermediary factor 2 (TIF2), and the vitamin D receptor interacting protein 205 (DRIP205) were each inserted between LucN and LBD of the LucN-LBD-LucC biosensor. Surprisingly, the resulting LucN-LXXLL-LBD-LucC biosensor increased the light intensity in response to natural VDR ligands. This high-sensitivity biosensor system may be a powerful tool for discovery of high affinity ligands for the mutant VDR. In addition, we have successfully estimated the activity of the wild-type and mutant CYP27B1 using the LucN-LXXLL-LBD-LucC biosensor in living cells within 90 min. PMID- 30004012 TI - Sympathetic Plexus Schwannoma of Carotid Canal: 2 Cases with Surgical Technique and Review of Literature. AB - Carotid sympathetic plexus schwannomas are rare, and only 3 cases have been reported to the best of our knowledge. We report the fourth and fifth cases and define its origin on the basis of the exact division of the plexus from which the tumor arises. The surgical approach and technique in each variety and the postoperative outcome are also described. The relationship of partial Horner syndrome with the sympathetic plexus schwannoma of the internal carotid artery is discussed in detail. PMID- 30004014 TI - Introduction to the thematic mini-review series on "Matrix biology in lung health and disease". PMID- 30004015 TI - Regulation of actin dynamics during structural plasticity of dendritic spines: Signaling messengers and actin-binding proteins. AB - Activity-dependent plasticity of synaptic structure and function plays an essential role in neuronal development and in cognitive functions including learning and memory. The formation, maintenance and modulation of dendritic spines are mainly controlled by the dynamics of actin filaments (F-actin) through interaction with various actin-binding proteins (ABPs) and postsynaptic signaling messengers. Induction of long-term potentiation (LTP) triggers a cascade of events involving Ca2+ signaling, intracellular pathways such as cAMP and cGMP, and regulation of ABPs such as CaMKII, Cofilin, Aip1, Arp2/3, alpha-actinin, Profilin and Drebrin. We review here how these ABPs modulate the rate of assembly, disassembly, stabilization and bundling of F-actin during LTP induction. We highlight the crucial role that CaMKII exerts in both functional and structural plasticity by directly coupling Ca2+ signaling with F-actin dynamics through the beta subunit. Moreover, we show how cAMP and cGMP second messengers regulate postsynaptic structural potentiation. Brain disorders such as Alzheimer's disease, schizophrenia or autism, are associated with alterations in the regulation of F-actin dynamics by these ABPs and signaling messengers. Thus, a better understanding of the molecular mechanisms controlling actin cytoskeleton can provide cues for the treatment of these disorders. PMID- 30004016 TI - Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases. AB - There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2). We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators. PMID- 30004017 TI - The polycomb group proteins functions in epithelial to mesenchymal transition in lung cancer. AB - Polycomb group proteins (PcG) play important roles in the maintenance of DNA sequencing and multi-dimensional organization of genome. The main PcG complexes are consisted of Polycomb repressive complex 1 and 2, of which the diversity is dependent upon target gene sequences and functions. The present review initially explores the mechanism-based relationship and functional roles of PcG proteins in the interplay between epithelial mesenchymal transition (EMT) and chromatin dynamics in lung cancer. PcG proteins regulate the target genes by modifying histone and chromosome conformation and influencing chromatin looping and long range interactions between topologically associating domains (TADs). PcG proteins regulate target genes expression and long-distance interactions between TADs in nucleus in the development of EMT and lung cancer. PcG plays decisive regulatory roles in epithelial differentiation and transition or signaling and activation of oncogenes, by promoting the isoforms at the transcriptional levels, to drive EMT to greater invasive ability and carcinogenesis. With the development of single cell systems biology and gene editing, PcG roles in 3D genome organization, heterogeneity, and EMT will be furthermore understood at single cell levels. PMID- 30004018 TI - The advances in CRISPR technology and 3D genome. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein (Cas) system is a prokaryotic immune system that used to resist foreign genetic factors. It rapidly becomes the hot technology in life sciences and is applies for genome editing to solve the problem of genome-derived diseases. Using CRISPR/Cas technique, the biological DNA sequence can be repaired, cut, replaced, or added. It can effectively change the human stem cells and is expected to achieve results in the treatment. Compared with ZFN and TALEN genome editing techniques, CRISPR is more effective, accurate, and convenient. The application of CRISPR technique in three dimensional (3D) genome structure makes us understand the relationship between linear DNA sequence and 3D chromatin structure. Utilizing CRISPR/Cas9 genome editing to reverse or delete CTCF binding sites, to recognize changes of topological isomerism of the genome and interactions between chromatin loops. The purpose of this review is to introduce the characteristics and classification of the current CRISPR/Cas system, multiple functions, and potential therapeutic uses, as well as to outline the effect of the technique on chromatin loops by changing CTCF sites in 3D genomes. We will also briefly describe the importance of ethical dilemmas to be faced in CRISPR applications and provide a perspective for potential CRISPR considerations. PMID- 30004019 TI - A sequence-to-sequence model-based deep learning approach for recognizing activity of daily living for senior care. AB - Ensuring the health and safety of independent-living senior citizens is a growing societal concern. Researchers have developed sensor based systems to monitor senior citizens' Activity of Daily Living (ADL), a set of daily activities that can indicate their self-caring ability. However, most ADL monitoring systems are designed for one specific sensor modality, resulting in less generalizable models that is not flexible to account variations in real-life monitoring settings. Current classic machine learning and deep learning methods do not provide a generalizable solution to recognize complex ADLs for different sensor settings. This study proposes a novel Sequence-to-Sequence model based deep-learning framework to recognize complex ADLs leveraging an activity state representation. The proposed activity state representation integrated motion and environment sensor data without labor-intense feature engineering. We evaluated our proposed framework against several state-of-the-art machine learning and deep learning benchmarks. Overall, our approach outperformed baselines in most performance metrics, accurately recognized complex ADLs from different types of sensor input. This framework can generalize to different sensor settings and provide a viable approach to understand senior citizen's daily activity patterns with smart home health monitoring systems. PMID- 30004020 TI - Modeling association detection in order to discover compounds to inhibit oral cancer. AB - In the past, algorithms exploiting varying semantics in interactions between biological objects such as genes and diseases have been used in bioinformatics to uncover latent relationships within biological datasets. In this paper, we consider the algorithm Medusa in parallel with binary classification in order to find potential compounds to inhibit oral cancer. Oral cancer affects the mouth and pharynx and has a high mortality rate due to its late discovery. Current methods of oral cancer treatment, such as chemoradiation and surgery, fail to provide better chances for survival, warranting an alternative approach. By running Medusa on a data fusion graph consisting of biological objects, we incorporate binary classification to model the algorithm's association detection to discover compounds with the potential to mitigate the effects of oral cancer. PMID- 30004021 TI - The Effect of Pain on Major Cognitive Impairment in Older Adults. AB - Older adults frequently report pain; cross-sectional studies have shown that pain is associated with worse cognitive function. However, longitudinal studies are lacking. We prospectively studied 441 participants without dementia, including 285 with pain, aged 65 years and older, enrolled in the Central Control of Mobility in Aging study, a prospective cohort study. We analyzed the longitudinal association between pain (measured with the Medical Outcomes Study pain severity scale) and major cognitive impairment (measured with the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test Delta) using Cox regression analysis adjusted for age, gender, ethnicity, and education. Over a mean follow-up of 2.75 years (standard deviation = 1.94), there was no difference in the risk of developing cognitive impairment between participants with pain and participants without pain. However, among those with pain, risk for developing major memory impairment was higher among those with high levels of pain than those with low levels of pain (adjusted hazard ratio = 3.47, 95% confidence interval = 1.42-8.46). The association with pain and incident impairments in attention or executive function was not significant. We did not find that pain is associated with incident cognitive impairment in general, but among older adults with pain, a high level of pain is associated with increased risk of developing incident memory impairment. PERSPECTIVE: Our study results suggest that high levels of pain may contribute to incident memory impairment. Further research is needed to determine whether a high level of chronic pain is a modifiable risk factor for cognitive impairment in older adults. PMID- 30004022 TI - Cerebrospinal fluid neurofilament light is associated with survival in mitochondrial disease patients. AB - We studied the biomarker patterns related to axonal injury, astrogliosis and amyloid metabolism in cerebrospinal fluid (CSF) of children and adolescents with mitochondrial encephalopathy and identified correlations with phenotype and survival outcome. Forty-six pediatric patients with genetically verified mitochondrial encephalopathy and twenty-two controls investigated at the Queen Silvia Children's Hospital, Sweden, were included. CSF lactate and neurofilament light (NF-L) were significantly increased in patients with mitochondrial encephalopathy compared to controls. Elevated CSF NF-L was associated with abnormal brain MRI and poorer survival. We suggest that CSF NF-L may be used in both clinical and research settings for monitoring the neurodegenerative process in mitochondrial disease. PMID- 30004023 TI - Magnetic targeting of smooth muscle cells in vitro using a magnetic bacterial cellulose to improve cell retention in tissue-engineering vascular grafts. AB - : Tissue-engineered vascular grafts (TEVG) use biologically-active cells with or without supporting scaffolds to achieve tissue remodeling and regrowth of injured blood vessels. However, this process may take several weeks because the high hemodynamic shear stress at the damaged site causes cellular denudation and impairs tissue regrowth. We hypothesize that a material with magnetic properties can provide the force required to speed up re-endothelization at the vascular defect by facilitating high cell density coverage, especially during the first 24 h after implantation. To test our hypothesis, we designed a magnetic bacterial cellulose (MBC) to locally target cells in vitro under a pulsatile fluid flow (0.514 dynes cm-2). This strategy can potentially increase cell homing at TEVG, without the need of blood cessation. The MBC was synthesized by an in situ precipitation method of Fe3+ and Fe2+ iron salts into bacterial cellulose (BC) pellicles to form Fe3O4 nanoparticles along the BC's fibrils, followed by the application of dextran coating to protect the embedded nanoparticles from oxidation. The iron salt concentration used in the synthesis of the MBC was tuned to balance the magnetic properties and cytocompatibility of the magnetic hydrogel. Our results showed a satisfactory MBC magnetization of up to 10 emu/g, which is above the value considered relevant for tissue engineering applications (0.05 emu/g). The MBC captured magnetically-functionalized cells under dynamic flow conditions in vitro. MBC magnetic properties and cytocompatibility indicated a dependence on the initial iron oxide nanoparticle concentration. STATEMENT OF SIGNIFICANCE: Magnetic hydrogels represent a new class of functional materials with great potential in TVEG because they offer a platform to (1) release drugs on demand, (2) speed up tissue regrowth, and (3) provide mechanical cues to cells by its deformability capabilities. Here, we showed that a magnetic hydrogel, the MBC, was able to capture and retain magnetically-functionalized smooth muscle cells under pulsatile flow conditions in vitro. A magnetic hydrogel with this feature can be used to obtain high-density cell coverage on sites that are aggressive for cell survival such as the luminal face of vascular grafts, whereas simultaneously can support the formation of a biologically-active cell layer that protects the material from restenosis and inflammation. PMID- 30004024 TI - Basic Skin Care and Topical Therapies for Atopic Dermatitis: Beyond Essential Approaches. AB - Atopic dermatitis (AD) is a recurrent and chronic skin disease characterised by dysfunction in the epithelial barrier, skin inflammation and immune dysregulation with changes in the skin microbiota and colonisation of Staphylococcus aureus being common. For this reason, the therapeutic approach to AD is complex and should be directed at restoring skin barrier function, reducing dehydration, maintaining acidic pH and avoiding superinfection and exposure to possible allergens. No curative treatment for AD currently exists. However, a series of measures are recommended to alleviate the disease and enable patients to improve their quality of life, including adequate skin hydration and restoration of the skin barrier with the use of emollients, antibacterial measures, specific approaches reducing pruritus and scratching, wet wrap applications, avoidance of typical AD triggers and topical anti-inflammatory drugs. Anti-inflammatory treatment will be, generally, recommended during the acute flares or more recently, for preventive management. Nevertheless, the selection of the pharmacologic agent, its potency, duration and the frequency of application must be in accordance with the severity of the disease, the distribution or the type of lesion. The purpose of this review is emphasising the importance of basic skin care as well as describing the current and novel topical therapies for atopic dermatitis. PMID- 30004025 TI - Implications of recent epidemiologic studies for the linear nonthreshold model and radiation protection. AB - The recently published NCRP Commentary No. 27 evaluated the new information from epidemiologic studies as to their degree of support for applying the linear nonthreshold (LNT) model of carcinogenic effects for radiation protection purposes (NCRP 2018 Implications of Recent Epidemiologic Studies for the Linear Nonthreshold Model and Radiation Protection, Commentary No. 27 (Bethesda, MD: National Council on Radiation Protection and Measurements)). The aim was to determine whether recent epidemiologic studies of low-LET radiation, particularly those at low doses and/or low dose rates (LD/LDR), broadly support the LNT model of carcinogenic risk or, on the contrary, demonstrate sufficient evidence that the LNT model is inappropriate for the purposes of radiation protection. An updated review was needed because a considerable number of reports of radiation epidemiologic studies based on new or updated data have been published since other major reviews were conducted by national and international scientific committees. The Commentary provides a critical review of the LD/LDR studies that are most directly applicable to current occupational, environmental and medical radiation exposure circumstances. This Memorandum summarises several of the more important LD/LDR studies that incorporate radiation dose responses for solid cancer and leukemia that were reviewed in Commentary No. 27. In addition, an overview is provided of radiation studies of breast and thyroid cancers, and cancer after childhood exposures. Non-cancers are briefly touched upon such as ischemic heart disease, cataracts, and heritable genetic effects. To assess the applicability and utility of the LNT model for radiation protection, the Commentary evaluated 29 epidemiologic studies or groups of studies, primarily of total solid cancer, in terms of strengths and weaknesses in their epidemiologic methods, dosimetry approaches, and statistical modelling, and the degree to which they supported a LNT model for continued use in radiation protection. Recommendations for how to make epidemiologic radiation studies more informative are outlined. The NCRP Committee recognises that the risks from LD/LDR exposures are small and uncertain. The Committee judged that the available epidemiologic data were broadly supportive of the LNT model and that at this time no alternative dose-response relationship appears more pragmatic or prudent for radiation protection purposes. PMID- 30004026 TI - Bulk scale fabrication of sodium tungsten bronze nanoparticles for applications in plasmonics. AB - In order to advance plasmon-based technologies, new materials with low damping losses and high chemical stability are needed. In this letter, we report the bulk scale fabrication of sodium tungsten bronze (Na x WO3) nanoparticles with high Na content (x <= 0.83) using a furnace-assisted method. Phase purity and morphology is confirmed with x-ray diffraction and scanning electron microscopy. Plasmon responses are characterized using spectrophotometry and spatially-resolved electron energy-loss spectroscopy (EELS) in a scanning transmission electron microscope. Experimental EELS maps of individual nanoparticles show the excitation of distinct plasmon resonances at visible and near-infrared (NIR) frequencies, and these observations are supported by boundary element method simulations. Na x WO3 is a promising alternative material for plasmonics due to its strong plasmon resonances when compared to Au, its simple nanofabrication, and low cost. In particular, their high NIR extinction makes these materials ideal for applications in solar control window coatings or plasmonic photocatalysis. PMID- 30004027 TI - Probing the mechanics of aqueous two-phase extraction using large diameter single walled carbon nanotubes. AB - We have demonstrated that large diameter (1.8 +/- 0.4 nm) carbon nanotubes (CNTs) can be separated by means of the aqueous two-phase extraction (ATPE). This rapid and convenient tool has enabled us to isolate fractions of particular CNT diameter distribution. We have shown how a range of parameters can be used to fine tune the characteristics of the isolated material. Interestingly, by varying the pH of the medium, we have suppressed the extraction of low diameter CNTs and only large diameter CNTs were obtained. A number of other factors such as selected surfactant concentration steps, temperature or amount of starting CNT material have been found to have a significant effect on the end result of the CNT differentiation. The findings have provided us with more insight regarding the underlying mechanics of ATPE for processing polydisperse CNT mixtures. PMID- 30004028 TI - Iterative spectral CT reconstruction based on low rank and average-image incorporated BM3D. AB - In a photon counting detector integrated spectral CT scanner, the received photons are counted in several energy channels to generate the corresponding projections. Since the projection in each energy channel is generated using part of the received photons, the reconstructed channel image suffers from severe noise. Therefore, image reconstruction in spectral CT is considered to be a big challenge. Because the inter-channel images are all from the same object but in different energy bins, there exists a strong correlation among these images. Moreover, it is suggested that there are similarities among various patches of CT images in the spatial domain. In this work, we propose average-image-incorporated block-matching and 3D (aiiBM3D) filtering along with low rank regularization for iterative spectral CT reconstruction. The aiiBM3D method is based on filtered 3D data arrays formed by similar 2D blocks using the mapped version of the average image obtained from linear regression. The reconstruction procedure consists of two main steps. First, the alternating direction method of multipliers is employed to solve the problem with low rank regularization where the goal is to exploit the correlation in inter-channel images. Second, our proposed BM3D-based algorithm is applied to all the channel images to make use of the redundant information in the spatial domain and inter-channel. The two steps repeat until the stopping criteria are satisfied. The proposed method is validated on numerically simulated and preclinical datasets. Our results confirm its high performance in terms of signal to noise ratio and structural preservation. PMID- 30004029 TI - Suppression of magnetoresistance in PtSe2 microflakes with antidot arrays. AB - Suppression of magnetoresistance (MR) is meaningful for sensor applications to immure magnetic fields. Herein, we report the observation of suppressed MR in PtSe2 microflakes by introducing the antidot arrays (AAs). We have compared the magnetotransport properties of PtSe2 microflakes before and after milling of AAs. The enhanced resistivity and notable MR suppression were observed while the AAs are milled in the PtSe2 microflakes. Their physical mechanism has been ascribed to the enhanced electron scattering rate due to the additional electron-antidot interactions. This work gave an example to suppress MR in materials by introducing AAs, which may be useful for sensor applications in magnetic fields. PMID- 30004030 TI - Doxorubicin/gold nanoparticles coated with liposomes for chemo-photothermal synergetic antitumor therapy. AB - Hybrid liposome/metal nanoparticles are promising candidate drug-carriers for therapy of various diseases due to their unique photothermal effect. In this study, self-crystallized gold nanoparticles (Au NPs) and doxorubicin (DOX) were co-encapsulated within liposomes (Au/DOX-Lips) by thin film hydration and gel separation technology. The surface plasmon resonance bands of drug-carriers were controllable in the near-infrared (NIR) zone. When the complex liposome/metallic hybrids were irradiated by NIR light, they displayed higher endocytosis efficiency following the fracture of liposomal membranes and the release of Au NPs. Then, the Au NPs penetrated further into deeper tumor tissue to accomplish photothermal treatment. The Au/DOX-Lips showed an excellent antitumor effect, whose inhibition rate for tumor cells was up to 78.28%. In experiments on mice bearing tumors, the Au/DOX-Lips treated mice exhibited superior tumor suppression. This novel drug system provides huge potential for biomedical application. PMID- 30004031 TI - Experimental study and mechanism analysis on the effect of substrate wettability on graphene sheets distribution morphology within uniform printing droplets. AB - Uniform graphene films and micro-patterns are the cornerstones of graphene-based printed electronics. However, disk-like reduced graphene oxide (RGO) sheets trend to concentrate at the edge of the drop because of the famous coffee-ring effect, resulting in non-uniform patterns. To understand the physics of coffee-ring formation for RGO droplets on hydrophilic substrates, we propose a mechanical model to elucidate the influence and its mechanism of substrate wettability on the solute migration behavior and solute distribution morphology of RGO droplets. Stronger coffee-ring morphology and a slower velocity transition on the PMMA can be observed as compared to that on the glass slides. An explanation based on the mechanical model is provided as the large contact angle on the PMMA leads to a small hindrance force and finally results in more significant coffee-ring morphology. Remarkably, we have revealed one underlying mechanism by which the hydrophilic substrate with better wettability will form more uniform patterns. This study can provide fundamental insights into the relationship between substrate wettability and RGO sheets distribution morphology. It might contribute to morphology regulation of RGO droplets in the DOD printing of graphene films and micro-patterns. PMID- 30004032 TI - Static and dynamic compact analytical model for junctionless nanowire transistors. AB - This paper presents a compact analytical model for the static and dynamic electrical characteristics of Junctionless Nanowire Transistors. The static drain current model formulation is derived from the 2D solution of the Poisson equation with appropriate boundary conditions and long-channel devices, leading to a continuous effective surface potential that accounts for the conduction in partial depletion and accumulation regimes. The long-channel model is modified to account for short-channel effects by using the coupled solution of 3D Laplace equation with the 2D Poisson equation. The substrate bias influence on the drain current is also included in the model formulation. The charges at the device terminals are differentiated with respect to the applied biases leading to an analytical description of the transconductances and transcapacitances. The proposed model is validated using experimental data at different bias conditions and temperatures, showing very good agreement. PMID- 30004033 TI - Laparoscopic surgery with total mesocolic excision in colon cancer. A systematic review of the literature. AB - PURPOSE: Nowadays, there is no standardization in surgical procedures for treatment of colon cancer. Since its introduction, laparoscopic surgery has gained increasing interest in colorectal surgery and it is now performed worldwide for treatment of colon cancer. Following the concept of total mesocolic excision introduced by Heald in 1988 in order to reduce local recurrence after surgical treatment of mid/low rectal tumors, the idea of complete removal of the mesocolon mesocolic envelope has been developed also for colon cancer, has evolved longtime and complete mesocolic excision has been recently adopted as the optimal approach for colon cancer. However, complete mesocolic excision, whose purpose is to remove all lymphatics and lymph nodes draining the tumor, is still discussed as far as oncologic results are concerned. Moreover, the role of laparoscopic approach for complete removal of mesocolon has to be defined. METHODS: Selection of studies. A MEDLINE-PubMed database search of the current English Literature was performed using the terms: complete mesocolic excision; high vascular ligation; splenic flexure mobilization. INCLUSION CRITERIA: The inclusion criteria were report on CME for colonic cancer with high vascular ligation; minimum number of patients included (20 patients). Two independent reviewers (CRS, IE) extracted the data. RESULTS AND CONCLUSION: In this article, an update from the Literature on results of complete mesocolic excision was undertaken and data have been discussed. The role of laparoscopic complete mesocolic excision in colon cancer patients has been focused, and it seems to be safe and feasible, it should be standardized and hypothetical oncologic advantages should be expected. KEY WORDS: Colorectal-tumor, Complete mesocolic excision, High vascular ligation, Laparoscopic colorectal surgery, Splenic flexure mobilization, Total mesocolic excision. PMID- 30004034 TI - Acellular dermal matrix for breast reconstruction after surgery for giant dermatofibrosarcoma protuberans. AB - INTRODUCTION: Dermatofibrosarcoma protuberans (DFSP) is a rare neoplasm that exceptionally can affect the breast, always originating from skin and dermis, so imposing large sacrifice of skin. Only few cases have been reported of intraparenchymal DFS. We describe a unique case of giant intraparenchymal DFS that required removal of all the gland and reconstructive surgery. CASE REPORT: A 34 years old woman presents with a quickly growing breast mass, about 12 cm, with radiological features suggestive for giant fibroadenoma or mesenchymal neoplasm. The histology showed a Dermatofibrosarcoma protuberans infiltrating the surrounding parenchyma. The need for radicalization imposed, due to the size of the tumour, a nipple sparing mastectomy. The reconstruction has been performed using a new type of Acellular Dermal Matrix (ADM) mesh to wrap the prosthesis that has been placed and fixed over the great pectoral muscle. RESULTS: The final histologic report showed that the residual parenchyma and the skin removed were free from neoplastic infiltration. The patient is free from recurrence at 24 months from the surgery and the cosmetic result is excellent. DISCUSSION AND CONCLUSIONS: The treatment of DFSP should be aimed to prevent local recurrence, that are usually located in the scar or very close to it. Large size DFS can impose even mastectomy. If skin is not compromised like in this case, a nipple sparing mastectomy is suitable and the one time reconstruction with ADM wrapping of the prosthesis and fixation over the muscle can help to spare time, avoid complications and pain medication and reach excellent cosmetic resu. KEY WORDS: Acellular Dermal Matrix (ADM) mesh, Protuberans, Breast neoplasms, Dermatofibrosarcoma, Mastectomy, Nipple sparing, reconstructive surgery. PMID- 30004035 TI - A rare case of epithelioid hemangiothelioma of the quadriceps. AB - Hemangioendotelioma is a group of rare vascular tumors with border-line behavior. They may involve internal organs, limbs, bones and soft tissue. The histological variant epitheliod hemangiothelioma is locally aggressive and has metastatic potential. We present a case of a 41-years old woman affected by epitheliod hemangiothelioma of the right quadriceps. The patient complained of localized pain in the anterior region of the right thigh, which started about 3 months earlier during physical exercise. For the increasing size of the lesion, the patient was referred to our Department. On physical examination, the lesion appeared elastic, fixed to the surrounding tissues and painful under pressure. An ultrasound examination revealed a small avascular lesion and a MRI examination showed an oval formation measuring about 18 mm in diameter of nonspecific significance. A surgical removal of the lesion was performed and diagnosis of epithelioid hemangiothelioma was achieved. A complete removal of the quadriceps muscle was then accomplished. In this paper, clinical and oncologic aspects of this rare tumor are discussed KEY WORDS: Epithelioid hemangiothelioma, Lower limbs tumor, Rare tumors. PMID- 30004036 TI - EUS-guided gastroenterostomy for afferent loop syndrome treatment stent. PMID- 30004037 TI - Polycystic ovary syndrome (PCOS) and kisspeptin - A Sri Lankan study. AB - Context: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting young women. Kisspeptins are a family of closely related peptides encoded by Kiss1 gene that controls the hypothalamic-pituitary-gonadal axis by binding to its receptor (GPR54) expressed in gonadotropin-releasing hormone (GnRH) neurons and releases GnRH. Since GnRH secretion is deregulated in PCOS, we hypothesized that dysregulated gonadotropin secretion in PCOS is reflected by kisspeptin levels. Aim: We aimed to measure serum kisspeptin levels of subjects with well-characterized PCOS versus controls and explore any correlation between kisspeptin and PCOS-related reproductive and metabolic disturbances. Materials and Methods: : Consecutive women with PCOS manifesting from adolescence (n = 55) and adult controls (n = 110) were recruited. Pre-treatment baseline clinical, anthropometry, and biochemical parameters were measured in all. Serum kisspeptin and testosterone levels were determined by enzyme-linked immunosorbent assay method. Results: : Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS (kisspeptin 4.873 nmol/L; testosterone 4.713 nmol/L) than controls (kisspeptin 4.127 nmol/L; testosterone 3.415 nmol/L; P < 0.05). Serum kisspeptin levels were positively associated with PCOS (odds ratio: 1.853; 95% confidence interval: 1.246-2.755; P = 0.002) in our studied population. Conclusion: Serum kisspeptin levels are higher in Sri Lankan women with PCOS manifesting from adolescence compared with controls regardless of body mass index. We propose serum kisspeptin concentration as a useful marker to recognize PCOS that manifests from adolescence. PMID- 30004038 TI - Peripheral arterial disease and risk of hip fracture: A systematic review and meta-analysis of cohort studies. AB - Background: Previous studies have suggested an increased risk of hip fracture among patients with peripheral arterial disease (PAD), however, the results have been inconsistent. This meta-analysis was conducted with the aim to summarize all available evidence to better characterize the risk of incident hip fracture among these patients. Materials and Methods: A comprehensive literature review was conducted using the MEDLINE and EMBASE databases through October 2017 to identify all cohort and case-control studies that compared the risk of subsequent hip fracture between patients with PAD and individuals without PAD. Effect estimates of the included studies were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Results: The systematic review process yielded six eligible cohort studies comprising 15,895 patients with PAD. There was a significant association between incident hip fracture and PAD with the pooled relative risk (RR) of 1.64 (95% CI, 1.17-2.29; I2, 80%), comparing patients with PAD and individuals without PAD. Subgroup analysis by study design revealed significant results for both prospective studies (pooled RR 1.60; 95% CI, 1.12-2.28; I2, 0%) and retrospective studies (pooled RR 1.72; 95% CI, 1.07-2.77; I2, 92%). The funnel plot is relatively asymmetric suggesting publication bias. Conclusion: This study found a significant association between PAD and hip fracture with the pooled RR of 1.64 (95% CI, 1.17-2.29) on comparing patients with PAD and individuals without PAD. Major limitations include high between-study heterogeneity, possibility of publication bias, and lack of data on the characteristics and type of hip fracture which may limit the clinical significance of the observations. PMID- 30004039 TI - Evaluation of the long-term safety and effectiveness of tadalafil once daily in Chinese men with erectile dysfunction: interim results of a multicenter, randomized, open-label trial. AB - Once-daily tadalafil administration has been well established; however, studies about tadalafil once-daily treatment in the Chinese population are lacking. In this phase 4, postmarketing study, we ascertained the long-term safety and effectiveness of tadalafil 2.5 mg and 5.0 mg once daily in Chinese men with erectile dysfunction (n = 635). The primary endpoint of the study was safety at 12 months as assessed by the proportion of patients experiencing at least one treatment-emergent adverse event (serious or nonserious). The secondary endpoints included safety and effectiveness, measured by the International Index of Erectile Function-Erectile Function (IIEF-EF) domain scores. Similar adverse events to the known safety profile of tadalafil, such as nasopharyngitis, upper respiratory tract infection, headache, and dizziness, were detected. No new cardiovascular safety concerns were observed. After 3 months of treatment, significant increases in IIEF-EF domain scores were detected for both 2.5-mg (least squares [LS] mean change: 6.3; 95% confidence interval [CI]: 5.4-7.1; P < 0.001) and 5.0-mg (LS mean change: 7.4; 95% CI: 6.8-7.9; P < 0.001) tadalafil doses, and significance was maintained up to 12 months. In addition, approximately 40% of patients regained normal erectile function (IIEF-EF >=26) following 1 year of tadalafil once-daily treatment. The findings in this study provide evidence for the extended effectiveness and tolerability of tadalafil, demonstrating no new safety concerns, in a Chinese population and make once-daily tadalafil administration a viable option for improving sexual performance and satisfaction in Chinese men with erectile dysfunction. PMID- 30004040 TI - Nanotechnology-assisted adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury: In vivo cell tracking, optimized injection dosage, and functional evaluation. AB - Stem cell therapy is a potentially promising option for erectile dysfunction; however, its risk of tumorigenicity is a clinical hurdle and the risk is positively related to the number of injected cells. Our previous study showed that nanotechnology improved adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury (CNI) by attracting cells in the corpus cavernosum. These results indicated the possibility of using a reduced dosage of ADSCs for intracavernous injection. In this exploratory study, we used lower dosage (2 * 105 cells) of ADSCs for intracavernous injection (ICI) and the nanotechnology approach. Intracavernous pressure and mean arterial pressure were measured at day 28 to assess erectile function. The low-dose ADSC therapy group showed favorable treatment effects, and nanotechnology further improved these effects. In vivo imaging of ICI cells revealed that the fluorescein signals of NanoShuttle-bound ADSCs (NanoADSCs) were much stronger than those of ADSCs at days 0, 1, and 3. Both immunofluorescence and Western blot analysis showed a significant increase in smooth muscle, endothelium, and nerve tissue in the ADSC group compared to that in the CNI group; further improvement was achieved with assisted nanotechnology. These findings demonstrate that nanotechnology can be used to further improve the effect of small dosage of ADSCs to improve erectile function. Abundant NanoADSCs remain in the corpus cavernosum in vivo for at least 3 days. The mechanism of erectile function improvement may be related to the regeneration of the smooth muscle, endothelium, and nerve tissues. PMID- 30004041 TI - Initial experience of video capsule endoscopy at a tertiary center in Saudi Arabia. AB - Background/Aim: No prior experience with video capsule endoscopy (VCE) has been published from Saudi Arabia. In this study, we aim to report the first Saudi experience with VCE. Patients and Methods: A prospective study was conducted between March 2013 and September 2017 at King Abdulaziz Medical City, Riyadh, Saudi Arabia. Eligible patients underwent VCE and their data (age, sex, indication for VCE, type of obscure gastrointestinal bleeding [OGIB: overt vs occult], VCE findings, and complications) were recorded. Approval was obtained from the institutional ethics board before the study began and all patients provided verbal and signed consent for the procedure. The procedure was performed according to the established guidelines. Results: During the study period, a total 103 VCE procedures were performed on 96 patients. Overall, 60 participants (62.5%) were male (mean age, 58.8 years; range, 25-97 years) and 36 (37.5%) were female (mean age, 52.8 years; range, 18-78 years). The most frequent indication for VCE was OGIB (n = 91, 88.35%; overt, n = 46, 50.55%; occult, n = 45, 49.45%). Other indications were suspected Crohn's disease (n = 4, 3.88%), suspected complicated celiac disease (n = 4, 3.88%), and unexplained chronic abdominal pain (n = 4, 3.88%). The VCE results were categorized as incomplete (n = 2, 1.94%), poor-quality (n = 7; 6.8%), normal (n = 39, 37.86%), and abnormal (n = 55, 53.4%). The completion rate was 98.06% (n = 101), and the overall diagnostic yield was 53.4%. Of the 55 patients with abnormal VCE results, 43 (78.2%) had small bowel (SB) abnormalities and 12 (21.8%) had abnormalities in the proximal or distal gut. The most frequent SB abnormalities were angiodysplasia (n = 22, 40.0%) and tumors (n = 7, 12.7%). Conclusion: The diagnostic yield of VCE for Saudi patients with OGIB is comparable to that reported internationally; however, data for other VCE indications, including inflammatory bowel disease, are still lacking. PMID- 30004042 TI - Real-world single-center experience with entecavir and tenofovir disoproxil fumarate in treatment-naive and experienced patients with chronic hepatitis B. AB - Background/Aim: The goal of antiviral therapy for chronic hepatitis B (CHB) is to improve survival of the patients by achieving a complete virological response (CVR). This study aimed to evaluate long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in nucleos(t)ide analog (NA)-naive and NA experienced Korean patients with CHB and to determine the incidence of cirrhosis related complications in these patients. Patients and Methods: We retrospectively reviewed medical records of all patients treated with ETV or TDF from July 2007 to January 2017. We examined CVR and analyzed the predictive factors influencing the rate of CVR and evaluated the incidences of cirrhosis-related complications. Results: The proportion of patients who achieved CVR was 94.2% in the ETV group and 91.1% in the TDF group (P = 0.358). Among patients who achieved CVR, the mean time to CVR was 13.5 +/- 14.3 months in the ETV group and 11.5 +/- 10.6 months in the TDF group (P = 0.169). Positive predictive factors for CVR included the current treatment with TDF, a low hepatitis B virus DNA level, negative hepatitis B e-antigen status, and high alanine aminotransferase level in baseline laboratory test. The annual incidence rate of HCC was 127 per 10,000 patient years (1.27% per year) in ETV group, and 85 per 10,000 patient-years (0.85% per year) in TDF group (P = 0.526). Conclusion: Both ETV and TDF therapy resulted in a high CVR, and the annual incidence rates of HCC and other cirrhosis-related complications were not significantly different between the two treatment groups. PMID- 30004043 TI - Biologic agents in inflammatory bowel disease - quality of internet website information. AB - Background/Aims: Many patients currently seek the Internet for health-related information without discerning the quality or bias of the evidence presented. Biologic agents have become the mainstay of therapy in inflammatory bowel disease (IBD), and it is important that patients have access to high-quality information when exploring the various available agents to make informed decisions about their therapy. The primary aim of this study was to evaluate the quality of patient-searched Internet websites that describe the biologic agents used as treatment options for IBD. The secondary aim was to compare the quality of patient-searched with physician-recommended websites and to evaluate any differences. Materials and Methods: The DISCERN model was used to evaluate the quality of the information content of a total of 110 websites of all the biologic agents used in the treatment of IBD from July to September 2017. The first 10 "Google search" hits meeting the inclusion criteria for each agent were included. There were four additional physician-recommended websites that were evaluated for the purpose of the secondary aim of this study. Results: The mean DISCERN score among all websites combined was 3.21 out of a 5-point scale. The highest scoring website was "ema.europa.eu" at 4.13 whereas the lowest scoring website was "https://www.fda.gov" at 1.97 for Entyvio. There was no significant difference between patient-searched and physician-recommended websites, with a mean total score of 3.21 versus 3.63, respectively (P value of 0.158). Conclusions: The combined quality of Internet web-based resources used for each drug was fairly consistent in scoring (intermediate to slightly above average). There was no significant advantage in the overall combined scores of the pooled physician recommended websites when compared with the patient-searched websites. PMID- 30004044 TI - From the Editor's desk. PMID- 30004045 TI - HER2 as a prospective novel biomarker in squamous cell carcinomas of the head and neck. PMID- 30004047 TI - Histopathological differences between primary Sjogren's syndrome and Sjogren's syndrome accompanied by scleroderma. AB - Background: Investigation of morphological differences in relation with serological variables between primary versus secondary Sjogren's syndrome associated with systemic scleroderma (Scl-SS). Materials and Methods: A total of 69 primary Sjogren's syndrome (pSS) and Scl-SS patients were grouped according to the American-European Consensus Group criteria. Serum autoantibody information was obtained from the patient records. Hematoxylin and eosin sections of the minor salivary gland biopsy were reevaluated, and the lymphocyte focus score (FS), plasma cell focus, and fibrosis rates were all evaluated. Results: There were 43 pSS and 26 Scl-SS cases. Both biopsy and autoantibody were positive in 16 pSS cases while only biopsy was positive in 25 cases and only antibody in 1 case. Both biopsy and antibody were positive in 5 Scl-SS cases while only biopsy was positive in 18 and only antibody in 3 cases. The plasma cell focus was statistically significantly higher in pSS cases (P = 0.003). No difference was seen between Sjogren' syndrome (SS) subtypes in terms of lymphocyte FS, fibrosis, and autoantibody positivity. Conclusion: We found that plasma cell focuses could be found more frequently in pSS than Scl-SS. In addition, our study reveals that the coexistence of SS and systemic scleroderma decreases the incidence of FS value >=1 compared to pSS. PMID- 30004046 TI - Human epidermal growth factor receptor 2 neu expression in head and neck squamous cell cancers and its clinicopathological correlation: Results from an Indian cancer center. AB - Background: Human epidermal growth factor receptor 2 (HER2)/neuprotooncogene (neu) is a proven molecular prognostic marker in breast, ovarian, gastric, and ovarian cancers. In head-and-neck cancers, varied expression is documented and therefore its prognostic role is debatable. Aim of the Study: To find the rate of overexpression of HER2/neu in head-and-neck cancers and to understand its prognostic role by evaluating its association with nodal stage and overall stage of the patient. Methodology: A total of 70 surgically resected cases of head-and neck cancers were evaluated for expression of HER2/neu by immunohistochemistry. Scoring was done according to the American Society of Clinical Oncologists/College of American Pathologistsguidelines for Her2/neu testing in breast cancer. Results: Of the 70 cases studied, 57 were of oral cavity and 13 were laryngeal squamous cell cancers and 14 (20%) were Her2/neu positive. On correlating the expression of HER2/neu in T1/T2 (41 cases) versus T3/T4 (27 cases), the P value was found to be 0.8273 which was statistically insignificant. Furthermore, no statistically significant difference in expression of HER2/neu was found in between node negative and node positive cases (49 vs. 19 cases, respectively), with P = 0.512. Conclusion: In the current settings, HER2/neu is not found to be a prognostic marker in head-and-neck cancers. Standard immunohistochemistry staining protocols need to be established like in breast cancers to aid uniform reporting and further evaluate the role of this important protooncogene in head-and-neck cancers. PMID- 30004048 TI - Evaluation of human epididymal secretory protein 4 expression according to the molecular subtypes (luminal A, luminal B, human epidermal growth factor receptor 2-positive, triple-negative) of breast cancer. AB - Background/Aims: Human epididymal secretory protein 4 (HE4) is originally described as an epididymis-specific protein but more recently suggested to be a putative serum tumor marker for some tumors, including breast carcinomas. In this study, we aimed to investigate the interactions between HE4 expression and molecular subtypes of breast carcinomas. Methods: HE4 expressions were studied in 242 formalin-fixed, paraffin-embedded breast carcinoma specimens and their association with different pathological and clinical parameters was evaluated. Results: Immunohistochemical (IHC) staining for HE4 was negative in 3 (1.2%) cases, weakly positive (1+) in 7 (2.9%) cases, moderately positive (2+) in 58 (24.0%) cases, and strongly positive (3+) in 174 (71.9%) cases. A correlation between IHC HE4 staining grade and molecular groups was detected (P = 0.005). Furthermore, it was found that HE4 expression was strongly associated with histological tumor grade, c-erbB2 expression, and positive fluorescence in situ hybridization test results that detect human epidermal growth factor receptor 2 (HER2)/neu amplification (P = 0.022, P = 0.014, and P = 0.011). Conclusion: This study showed that HE4 expression is associated with HER2/neu amplification in breast cancers. These results may be commented as HE4 expression rises in patients with HER2/neu amplification. As is known, HER2/neu amplification is a poor diagnostic factor in breast cancer and HE4 expression is possibly associated with poor prognosis. PMID- 30004049 TI - Detection of micrometastasis in axillary lymph nodes of breast carcinoma patients and its association with clinical outcome. AB - Context: There is heterogeneity in the clinical behavior of breast carcinoma patients with node negativity. Studies have analyzed different factors influencing the outcome in such patients. It is suggested that the presence of nodal micrometastasis can act as a tool in predicting the aggressiveness of these tumors. Aims: The aim of this study is to assess the yield of micrometastasis/isolated tumor cell (ITC) by ultrastaging the morphologically negative axillary nodes and staining them with immunohistochemistry for epithelial membrane antigen. The association of such metastasis with the clinical outcome is determined. Settings and Design: This was a retrospective analytical study. One hundred cases of node-negative breast carcinoma patients who underwent surgery along with axillary lymph node dissection were selected. Materials and Methods: The largest node from the axillary dissection was selected and subjected to ultrastaging and immunohistochemical staining (as sentinel node dissection was not a routine practice at that time), to look for occult metastasis in the form of micrometastasis or ITCs. Statistical Analysis: Occurrence of events in the form of recurrence or death was noted. Association of the parameters was analyzed using Fisher's exact test. Results: Among the 100 cases, 79 patients were followed up for a minimum period of 5 years. Two cases had micromets in one node each. These two patients were among the eight, who developed events subsequently (25%). Hence, a statistically significant association was found between the presence of micromets with events. Conclusions: There is a statistically significant association between the presence of micromets and disease recurrence. Hence, we suggest that ultrastaging of the negative axillary node (now sentinel node, as it is being routinely done) might prove effective in predicting the events/prognosis in clinically and morphologically node-negative breast carcinoma patients. PMID- 30004050 TI - A study of spectrum of pulmonary pathology and expression of thyroid transcription factor-1 during neonatal period. AB - Context: Neonatal period is the single most hazardous period of life. The major causes of neonatal death are prematurity and respiratory distress syndrome. We report a series of neonatal autopsies in our Neonatal Intensive Care Unit with special emphasis on pulmonary pathology. The spectrum of pathological changes in the lungs and thyroid transcription factor-1 (TTF-1) expression was studied in detail with reference to its spatial distribution. Aims: This study aims to analyze the causes of neonatal death with special attention to pulmonary pathology along with associated histopathological changes in lungs. We also evaluated the expression of TTF-1 at different levels of the airway. Materials and Methods: After taking consent and anthropometric measurements, autopsy was performed. Weights of all organs were taken, and histological sections were examined under hematoxylin and eosin stain. TTF-1 immunostaining was done on lung sections. Localization of TTF-1 was evaluated at the intrapulmonary level of terminal bronchioles (TBs), distal bronchioles, and alveoli. Results: We performed a series of 25 autopsies in neonates. In our series, most of the neonates were preterm (64%), had low birth weight (44%), and died within the first 7 days of life (80%). Majority (60%) of the neonates died due to pulmonary causes, followed by septicemia (24%), congenital anomalies (12%), and birth injury (4%). Among the respiratory causes, hyaline membrane disease (HMD) was diagnosed in maximum number of cases (32%), followed by pneumonia (12%) and pulmonary hemorrhage (12%). The TTF-1 expression in TBs, distal airways, and alveoli was significantly reduced or absent in cases of HMD compared to the control group. Conclusions: In this study, we observed that HMD is the most common cause of perinatal death among respiratory disorders, and in this disease, the expression of TTF-1 is significantly reduced in TBs, distal airways, and alveoli compared to the control group. PMID- 30004051 TI - Peripheral neuropathy and the role of nerve biopsy: A revisit. AB - Background: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy and in many centers, it is still a part of the diagnostic armamentarium. In this study, the histopathological spectrum of the nerve biopsies received is being revisited to analyze the various clinical and pathologic features and also to assess their relevance. Materials and Methods: Retrospective analysis of the data retrieved was done for 74 cases of nerve biopsies. Results: On the basis of the data and histopathological features, broad diagnoses were obtained in 52 cases and further categorized into biopsies being supportive for patient management (including acute and chronic axonopathies and demyelinating neuropathies) and biopsies considered essential for patient management (including vasculitic neuropathies, leprous neuropathies, hereditary neuropathies, and chronic inflammatory demyelinating neuropathies). Nine nerve biopsies did not show any abnormal histopathological features, while 13 nerve biopsies were found to be inadequate for diagnosis, both these groups were categorized as noncontributory. Conclusion: With advanced nerve conduction studies available, nerve biopsy is losing its relevance. However, in our experience, nerve biopsy did complement the clinical findings and nerve conduction studies, with which a close correlation is required to make the histopathology of nerve biopsy more relevant in terms of guiding further specific workup and management. PMID- 30004052 TI - Incidentally detected asymptomatic hepatitis C virus infection with significant fibrosis: Possible impacts on management. AB - Background and Aims: Liver biopsy may be considered in patients with hepatitis C virus (HCV) infection to assess the severity of liver injury and stage of fibrosis, thereby guiding therapeutic decisions. In addition, advanced stage also necessitates surveillance for hepatocellular carcinoma. The aim of this study was to assess whether transaminase (alanine transaminase [ALT]) levels and RNA titers correlate with the histological activity index (HAI) and fibrosis (F) stage in asymptomatic patients with incidentally detected HCV (IDHCV). Patients and Methods: Retrospective evaluation of liver biopsies was done in 113 patients with IDHCV, diagnosed during routine screening. Decision of liver biopsy was made on the basis of age, genotype, acceptable clinical, hematological, and biochemical profiles, and willingness of the patients to undergo treatment. Serum ALT levels, HCV RNA titers, and genotypes were correlated with HAI and F stage. Results: Genotyping was done in 77 of the 113 patients, of which genotype 3 was seen in 43 and genotype 1 in 25 patients. A higher fibrosis stage (Ishak's >F2) was noted in 23.8% of the biopsies. Serum ALT showed a significant correlation with the HAI score on liver biopsy (P = 0.01) but not with the stage of fibrosis (P = 0.52). HCV RNA titers did not reveal any correlation with HAI score or fibrosis stage. Conclusion: Serum transaminases and HCV RNA titers are poor predictors of disease severity and fibrosis. Since HCV shows a slow disease progression, higher stage may predict a worse prognosis irrespective of the low viral RNA load. Liver biopsy may help guide therapeutic decisions in IDHCV infection. PMID- 30004053 TI - Immunohistochemical expression profiles of MUC1 and MUC2 mucins in urothelial tumors of bladder. AB - Background: Mucins may show aberrant expression, localization, and/or glycosylation in multiple malignancies. However, information regarding expression of these mucins is mostly unknown in urothelial tumors. Aim: This study was conducted for examining the expressions of membrane associated and secreted mucin (MUC1) and a secreted gel-forming mucin (MUC2) in urothelial tumors of the urinary bladder. Subjects and Methods: Archival transurethral resection materials of 97 urothelial carcinoma cases were reexamined light microscopically and graded according to the 2004 WHO Classification. Pathological stage was given as pTa, pT1, and pT2. Demonstrative sections were recut for immunohistochemistry for MUC1 and MUC2. The results were statistically analyzed, and P < 0.05 was considered statistically significant. Results: The positivity for MUC1 and MUC2 was 89.7% and 44.3%, respectively. Independent from pathological stage of the tumor, MUC1 expression showed statistically significant correlation with tumor grade (P < 0.05). We did not find any correlation between pathological stage and MUC1 and MUC2 expression (P > 0.05). MUC1 staining pattern in papillary urothelial neoplasm of low malignant potential cases was more commonly apical and superficial (luminal cell layer only). Intermediate cells +/- basal cells or isolated cells or islands of tumor cells with cytoplasmic and/or circumferential membrane positivity for MUC1 and MUC2 were more commonly observed in both low- and high-grade carcinomas. The difference between groups in terms of MUC1 and MUC2 staining was statistically significant (P < 0.05). Conclusions: The staining patterns of both mucins are different between urothelial papillary tumors and may be used to make a differentiation, especially for low-grade papillary urothelial lesions. This difference may also be important in the carcinomatous transformation of urothelial neoplastic and preneoplastic lesions. PMID- 30004054 TI - Utility of urine reagent strips in cerebrospinal fluid analysis: An aid to bedside diagnosis of meningitis. AB - Context: The provision of initial treatment to a patient with suspected meningitis depends greatly on early recognition and rapid diagnostic evaluation of cerebrospinal fluid (CSF) leukocytes, proteins, and glucose. The diagnosis is time critical and timely intervention has an implication on the prognosis and outcome. Reasonably, sound laboratorial setups are not available in our country in the primary health-care level and, even in the settings where they are available, long waiting periods precede the availability of results. Aims: We conducted this study to emphasize the role of urine reagent strip test as a rapid diagnostic tool in CSF analysis. Settings and Design: : This is a prospective single-blinded study on 100 consecutive CSF samples received with in 1h of tap. Subjects and Methods: All the 100 samples were subjected to definitive test being CSF microscopy and biochemical analysis of proteins and sugar and index test being a semi quantitative analysis of CSF leukocytes, proteins, and sugar by urinary reagent strips. Statistical Analysis Used: The diagnostic accuracy of the reagent strip for different cutoff levels was estimated and tabulated in the form of sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio. Results: 77% of cases were in the pediatric age group and 23% cases were adults. The sensitivity and specificity for leukocytes by the strip method for >=15 cells/cumm were 89.28% and 98.61%, respectively, which increased to 100% with an increase in the counts. The reagent strip test had a sensitivity of 85.71% and a specificity of 95.65% for the protein levels >30 mg/dl which increased to 100% with an increase in protein levels. The reagent strip test for glucose was highly specific (100%) but less sensitive. Conclusions: The results indicate that urine reagent strip is instrumental in bedside CSF analysis and has a future stand in the diagnosis of meningitis. PMID- 30004055 TI - Effectiveness of the International Consensus Group criteria for manual peripheral smear review. AB - Context: The International Consensus Group for Hematology Review (ICGHR) are essentially review criteria designed to reduce the number of manual smear reviews following analysis in automated hematology analyzers (AHAs). Although AHAs are an indispensable part of the present-day clinical laboratory, manual smear reviews still play an integral role in identifying morphological abnormalities and to confirm the results of the analyzers. Aims: The aim of this study is to evaluate the efficacy of the ICGHR criteria and our laboratory criteria using the Sysmex XN-1000 for manual peripheral smear review (MSR). Study Design: A prospective cross-sectional comparative study between the two sets of criteria for MSR was performed. Material and Methods: A total of 860 whole blood samples sent over a period of 19 months for complete blood count testing to our laboratory were collected using systematic random sampling. Truth tables were prepared for each set of criteria. Tests of proportion were used to compare performance specifications between both sets of criteria. Results: Using ICGHR criteria, sensitivity was 81.58%, specificity was 84.61%, 83.38% positive predictive value, and 82.92% negative predictive value. The microscopic smear review rate was 47.56% and efficiency was 83.14%. Using our laboratory criteria, sensitivity was 98.80%, specificity was 41.40%, positive predictive value of 61.46%, and negative predictive value of 97.34%. The microscopic smear review rate was 78.14% and efficiency 69.30%. Conclusions: There was a significant reduction in the microscopic smear review rates using the ICGHR criteria compared to our laboratory criteria. The ICGHR criteria can thus be adapted to daily laboratory practice provided they are first optimized and locally validated before use. PMID- 30004057 TI - Association of JAK2V617F mutation with thrombosis in Indian patients with Philadelphia negative chronic myeloproliferative neoplasms. AB - Background: : It is still a matter of debate regarding the association of JAK2V617F mutation with thrombosis in BCR-ABL negative CMPN patients. The role of JAK2V617F mutation in increasing the thrombotic risk in CMPNs is yet unequivocal. Aims: : To clarify the contribution of JAK2V617F mutation in thrombosis in CMPN patients. Settings and Design: This retrospective study was done to evaluate role of JAK2V617F mutation in thrombosis in CMPNs. Materials and Methods: 65 CMPN patients (PV, ET and PMF) were analyzed for JAK2V617F mutation using ARMS-PCR and detailed history of thrombosis was recorded in these patients. Statistical Analysis: P values were 2 tailed, and statistical significance was set at P < 0.05. Results: : 46/65 were males and 19/65 were females [M: F: 2.4:1] with median age 46 years [range, 14-80 years]. Patients had median Hb 15.6 g/dl [range, 5.1-20.3], median TLC 10.7 * 109/l [range 2.4-216] and platelet count 360 * 109/l [range, 20-1859]. 32 were JAK2V617F positive and 33 were negative for this mutation. On comparing the prevalence of thrombosis in JAK2V617F positive patients with JAK2V617F negative patients, we observed that 20/32 (62.5%) JAK2V617F positive patients had thrombosis as compared to 16/33 (48%) in JAK2V617F negative patients (P = 0.04). We observed significant association of JAK2V617F mutation with thrombosis, however no association of this mutation with thrombosis was observed among the JAK2V617F negative patients. Conclusion: Our study suggests that JAK2V617F mutation may increase the risk of thrombosis in CMPNs. This finding could lead to risk stratification, setting up the treatment strategy in CMPNs. PMID- 30004056 TI - Platelet function tests: A 5-year audit of platelet function tests done for bleeding disorders in a tertiary care center of a developing country. AB - Introduction: The platelet function disorders remain largely undiagnosed or incompletely diagnosed in developing nations due to lack of availability of tests like lumiaggregometry, granule release assay or molecular testing. We performed a retrospective analysis of all the platelet function test (PFT) carried out in past 5 years by Light transmission aggregometery (LTA) using a panel of agonist. The indications and the test results were analyzed by two hematopathologist with the aim to look into the present diagnostic facilities or lack of it for correct diagnosis. This is essential for better management and genetic counselling. Materials and Methods: The PFT was performed both on patients and healthy unrelated age specific controls by light transmission aggregometry on Chronolog platelet aggregometer using platelet rich plasma. The panel of agonists included ADP (10MUm/l and 2.0 MUm/l), epinephrine (10.0 MUm/l), collagen (2MUg/ml), arachidonic acid (0.75 mM) and ristocetin (1.25 mg/ml & 0.25 mg/l). Results: The 5 years records of 110 cases were audited, 101 of these were tested for clinical bleeding , 35 adults and 66 children. The adults included 29 women and 6 men, 17 to 82 years of age. The children were 16 years to 3 months of age, 30 girls and 36 boys. Platelet function test abnormality was found in 31.6% (32/101) cases ,a majority remained undiagnosed of these about 21% had clinically significant bleeding.The cases diagnosed included Glanzmann Thromboasthenia-11 , von Willebrand Disease-6, Bernard Soulier'syndrome-1, storage pool disorder-6, mild defect of Epinephrine-3, isolated defect with collagen in1. Conclusion: An epidemiologically large proportion of platelet function disorders amongst people living in developing nations remain undiagnosed. This lacunae needs to be highlighted and addressed on larger scale. The options available are to increase the available armamentarium of tests or international collaboration with a specialized laboratory to aid in complete diagnosis. PMID- 30004058 TI - Bacteriological profile of ventilator-associated pneumonia in a tertiary care hospital. AB - Background: Ventilator-associated pneumonia (VAP) is the most frequent intensive care unit (ICU)-acquired infection. The etiology of VAP and their antimicrobial susceptibility pattern varies with different patient populations and types of ICUs. Materials and Methods: An observational cross-sectional study was performed over a period of 2 years in a tertiary care hospital to determine the various etiological agents causing VAP and to detect the presence of multidrug-resistant (MDR) pathogens in these VAP patients. Combination disk method, Modified Hodge test, ethylenediaminetetraacetic acid disk synergy test, and AmpC disk test were performed for the detection of extended-spectrum beta-lactamase (ESBL), carbapenemases, metallo-beta-lactamases (MBL), and AmpC beta-lactamases, respectively. Results: The prevalence of VAP was 35%. Enterobacteriaceae (66.66%) and Staphylococcus aureus (20%) were common in early-onset VAP, while nonfermenters (50%) and Enterobacteriaceae (40.61%) were predominant from late onset VAP. Nearly 60.87% of the bacterial pathogens were MDR. ESBL was produced by 21.74% of Enterobacteriaceae. AmpC beta-lactamase was positive in 35.29% nonfermenters and 26.08% Enterobacteriaceae. MBL was positive in 17.64% nonfermenters and 17.39% Enterobacteriaceae. Among the S. aureus isolates, 75% were cefoxitin resistant. Prior antibiotic therapy (P = 0.001) and hospitalization of 5 days or more (P = 0.001) were independent risk factors for VAP by MDR pathogens. polymyxin B, tigecycline, and vancomycin were the most sensitive drugs for Gram-negative and positive isolates respectively from VAP. Statistical Analysis: SPSS for Windows Version SPSS 17.0 (SPSS Inc., Chicago, IL, USA) and Chi-square with Yates correction. Conclusion: Late-onset VAP is increasingly associated with MDR pathogens. Treatment with polymyxin B, tigecycline, and vancomycin should be kept as last-line reserve drugs against most of the MDR pathogens. PMID- 30004059 TI - Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: A distinct clinicopathologic entity. AB - Objective: The objective of this study is to retrospectively evaluate follicular variant of papillary thyroid carcinoma (FVPTC) and reclassify encapsulated FVPTC as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) according to the criteria proposed by The Endocrine Pathology Society working group in 2015 to correlate with outcome. Materials and Methods: Retrospective review of case records of all patients diagnosed as carcinoma of thyroid between 2015 and 2016 was done for the histologic subtype. Gross and microscopic features on resected specimens of FVPTC were reviewed and subtyped as invasive and encapsulated based on capsular/vascular invasion; the encapsulated forms were further studied for size, number, follicular architecture, nuclear features, presence of psammoma bodies, stromal fibrosis, necrosis, mitoses, and lymph node status. Results: Out of the 383 patients with thyroid carcinomas in the study period, 349 were PTC which included 106 FVPTC. Thirty-three patients fulfilled the criteria to be labeled as NIFTP. Total thyroidectomy was performed in 8 patients and hemithyroidectomy in 25 patients. Lymph node dissection along with total thyroidectomy was done in 3 and completion thyroidectomy following hemithyroidectomy was done in 9. There were 29 single and 4 multiple lesions with size varying from 0.2 to 7 cm including 5 lesions measuring <1 cm. The involvement was confined to one lobe in 31 and both lobes in 2 specimens. Patients are on follow-up with no recurrence till date. Conclusion: Thyroid carcinomas currently diagnosed as FVPTC should be evaluated for criteria of NIFTP to avoid overtreatment as they have an indolent behavior. PMID- 30004060 TI - A 54-year-old male with diabetic nephropathy and suspected disseminated tuberculosis: Clinicopathologic correlation in a rare diagnosis. AB - Tuberculosis (TB) and Non-Hodgkins lymphoma (NHL) share similar clinical and radiological features, which make diagnosis a challenge. It is often difficult to rule out a diagnosis of extrapulmonary and/or disseminated TB because of its paucibacillary nature and difficulty in accessing the involved organs. In countries with high prevalence of TB like ours, empirical antitubercular treatment (ATT) is started, and the patient is followed up closely for response. We present a rare case of a 54-year old diabetic male who was suspected to be a case of disseminated TB but had a rapid downhill course despite ATT. A postmortem revealed features of a rare, aggressive T-cell NHL masquerading as disseminated TB. PMID- 30004062 TI - Fluoroscopy-induced chronic radiation dermatitis masquerading as morphea: A diagnostic pitfall. AB - Chronic radiodermatitis is a rare complication of fluoroscopy-guided procedures. The diagnosis of fluoroscopy-induced chronic radiation dermatitis is challenging because of its rarity, late insidious onset, and close clinicopathological resemblance to morphea. We report two cases of fluoroscopy-induced chronic radiodermatitis following cardiac procedures to highlight the clinicopathological features. The diagnosis relies on recognizing the characteristic clinical presentation of well-demarcated, rectangular- or square-shaped indurated plaque with depigmentation, telangiectasia, and ulceration located on the scapula, back, or axilla; supported by the histological identification of radiation fibroblasts in a sclerotic dermis. PMID- 30004061 TI - Idiopathic granulomatous hypophysitis: A report of an uncommon disorder. AB - Hypophysitis of the pituitary gland is a rare inflammatory disorder and broadly classified as primary and secondary hypophysitis. Primary hypophysitis is mainly of lymphocytic, granulomatous, and xanthomatous types. Among the various primary hypophysitis, granulomatous hypophysitis is rare type with an incidence of 1 in 10 million. The various forms of hypophysitis are misdiagnosed as pituitary adenoma in 40% cases. Idiopathic granulomatous hypophysitis is even rarer inflammatory disorder accounting for <1% of cases involving panhypopituitarism with headache and visual disturbances. We report idiopathic granulomatous hypophysitis in a 28-year-old female presenting with blurring of vision and headache. PMID- 30004063 TI - Mucoepidermoid carcinoma of hard palate. AB - Salivary gland tumors are clinically diverse group of neoplasms, of which pleomorphic adenoma and mucoepidermoid carcinoma (MEC) are most common benign and malignant tumors, respectively. Besides the major salivary glands, these tumors can affect the minor salivary gland tissues in the posterior part of the hard palate. Minor salivary gland tumor accounts for about 15% of all the salivary gland neoplasm, of which MEC accounts to about 35.9%. MEC appears as asymptomatic swellings and shows a variety of biological behaviors and variable natural history. This article reports a case of MEC involving the posterior part of the hard palate. The lesion was treated by wide surgical excision with a regular follow-up and no recurrence was noted. PMID- 30004064 TI - Metastatic squamous cell carcinoma in autotransplanted thyroid: A diagnostic dilemma. AB - Metastasis to the thyroid is uncommon. Mostly, they are tumors that originate in the lung or head or neck. Metastases from breast or kidney carcinomas and metastatic melanoma have also been reported. Autotransplantation of benign thyroid tissue is a surgical procedure designed to achieve normal thyroid hormonal status following surgery. Metastasis into autotransplanted thyroid tissue has not been reported earlier. We report a case of squamous cell carcinoma (SCC) metastatic to autotrasplanted thyroid diagnosed on fine-needle aspiration. Further workup revealed a primary oral cavity SCC. PMID- 30004065 TI - Duodenal neuroendocrine tumor, adenocarcinoma and gastrointestinal stromal tumor in association with neurofibromatosis type 1: An unique occurrence. AB - Mixed endocrine-nonendocrine neoplasms are rare tumors and pose challenges in diagnosis and management. Neurofibromatosis-1 (NF-1) patients are known to develop malignancies. Although neuroendocrine tumors and gastro-intestinal stromal tumors are seen in NF-1, its association with adenocarcinoma is rare. The existence of these three entities with NF-1 is extremely rare. NF1 patients presenting with symptoms suggestive of malignancies should alert the physician for a detailed clinical work up. Diagnosis of these malignancies often requires a meticulous histopathological and immunohistochemical examination. We report the first case from Indian experience. PMID- 30004066 TI - Paraganglioma with a very rare presentation. AB - Paragangliomas (PGLs) are rare tumors of neural crest origin, with a malignancy rate of approximately 10% and a 5-year survival rate of <50%. We present a case of malignant PGL arising from the porta hepatis with metastasis to the portal lymph node and bilateral ovaries. PGLs arising from the porta hepatis are very rare. As per our knowledge, only three cases of hepatic duct PGL have been reported. It is important to detect it earlier because the treatment modality and prognosis of benign and malignant PGL differs and defines the prognosis of the patient. PMID- 30004067 TI - Sclerosing pneumocytoma with metastasis to the mediastinal and regional lymph nodes. AB - Sclerosing pneumocytoma (SP) is an uncommon benign tumor, and metastasis of SP has been rarely reported. Here, we report the case of a 26-year-old woman with surgically confirmed SP. The tumor diameter was 40 mm, and metastasis to mediastinal and regional lymph nodes was observed. Immunohistochemically, both surface and round cells were positive for epithelial membrane antigen, thyroid transcription factor 1, and vimentin. Only surface cells expressed creatine kinase, carcinoembryonic antigen, napsin A, and cytokeratin 7, and only round cells expressed progesterone receptor. Ki-67 was detected in ~3% of cells, and the rate of weak positive p53 staining was 3%. Both cell types were negative for chromogranin A, synaptophysin, CD3, and CK20. Multiple metastases in a young SP patient are very rare, and potential mechanisms of metastasis may be related to epithelial-mesenchymal transformation. PMID- 30004068 TI - Collecting duct carcinoma kidney masquerading as hydatid cyst: A rare case report and review of literature. AB - Cystic renal masses pose diagnostic challenge especially when they belong to Bosniak Type II and III. Septal and nodular enhancement on computed tomography (CT) is the strongest predictor of malignant process. A unilocular cyst with a calcified rim or a multilocular cystic lesion with heterogeneity on CT goes in favor of hydatid disease. We report a case in a 65-year-old female who presented with painless hematuria, was found to have a cystic mass in the right kidney. The mass turned out to be collecting duct carcinoma after histopathological examination though imaging studies were in favor of a hydatid cyst. PMID- 30004069 TI - Kyrle's disease associated with HIV infection, diabetes, and chronic kidney disease. AB - Kyrle's disease (KD) is a rare skin pathology characterized by transepidermal elimination of abnormal keratin. The aim of this article is to report a rare case of KD associated with diabetes mellitus, chronic kidney disease, and HIV. A 51 year-old male patient complained of diarrhea for 8 months. He was submitted to HIV testing, which showed a positive result. He started antiretroviral therapy with zidovudine, lamivudine, and lopinavir. The diagnostic investigation was negative for opportunistic diseases. After 2 months, skin lesions started appearing, characterized by hyperchromic, pruritic macules and papules distributed in the trunk, back, and upper limbs. He also developed erythematous, scaly lesions in the facial region. A biopsy of the skin was performed, of which histopathological report consisted of perforating disorder, favoring a diagnosis of KD. Treatment with keratolytic soap (Actine) was started, with skin lesion improvement. In this reported case, it is possible that, in addition to diabetes and renal failure, HIV infection played an important role in the genesis of the lesions. PMID- 30004070 TI - Pulmonary alveolar proteinosis in children: An unusual presentation with significant clinical impact. AB - Pulmonary alveolar proteinosis (PAP) - an unusual diffuse lung disease characterized by alveolar accumulation of phospholipoprotein material, with a peak incidence in third to fourth decade and male predominance is also described in children. Recorded prevalence is 0.1/100,000 individuals. Major clinicopathogenetic subtypes include autoimmune (idiopathic) associated with granulocyte-macrophage colony-stimulating factor autoantibodies, secondary form, and the congenital form (associated with surfactant gene mutations). Common presenting features include dyspnea, cough, low-grade fever, inspiratory crackles, and digital clubbing. Pulmonary function shows a restrictive ventilatory defect. X-rays show bilateral patchy to extensive consolidations, and bronchial lavage yields a milky fluid. Characteristic microscopic findings on lung biopsy include filling of terminal bronchioles and alveolar spaces by deep pink granular PAS-positive material. Whole lung lavage is the safest and most effective form of treatment. We present brief profiles of two young children identified as having PAP, along with follow-up data on one of them. PMID- 30004071 TI - Superficial CD34-positive fibroblastic tumor in the forearm of a middle-aged patient: A newly described, rare soft-tissue tumor. AB - Superficial CD34-positive fibroblastic tumor is a recently described soft-tissue tumor entity. A 48 year-old-male presented with a gradually increasing soft tissue mass in his right forearm of 2 years' duration, along with multiple subcutaneous soft-tissue nodular lesions, and reminiscent of lipomas over his body. He underwent a wide excision of his forearm mass. Microscopic sections showed a circumscribed tumor in the dermis and subcutaneous fat, composed of spindle cells, inflammatory cells, including lymphocytes, plasma cells, and eosinophils, along with interspersed markedly pleomorphic giant cells containing moderate-to-abundant "glassy" cytoplasm, vesicular nuclei, exhibiting prominent nucleoli, and intranuclear pseudoinclusions. There were no significant mitotic figures, areas of hemorrhage, necrosis, or pigment histiocytes. By immunohistochemistry, the tumor cells were diffusely positive for CD34 while negative for cytokeratin (CK), pan CK (AE1/AE3), S100 protein, CD30, and CD31. MIB1/Ki-67 was low and highlighted 4%-5% tumor nuclei. Diagnosis of superficial CD34-positive fibroblastic tumor was offered. Sections from the various resection margins were free of tumor. Postresection, the patient is alive with no evidence of disease for the past 8 months. This constitutes as one of the first case reports of this rare tumor entity from our country. Its diagnostic and treatment implications are discussed herewith. PMID- 30004072 TI - Cutaneous intramuscular lipoma: A new subtype of intramuscular lipoma. AB - Intramuscular lipoma is an uncommon variant of lipoma that occurs inside muscle tissue. Pathogenesis is thought to be related to neoplastic activity of mesenchymal stem cells, but there still is not an established theory. This entity can be found in almost all areas of the body, mostly within or in connection with skeletal muscle tissue. We have encountered an atypical intramuscular lipoma located in the epidermal layer of the right thigh of an otherwise healthy 35-year old female. The superficial, protruding skin mass resembled a sebaceous nevus or skin malignancy but was histologically composed of well-defined adipocytes between a mixture of muscle fibers, corresponding with the diagnosis of intramuscular lipoma. Intramuscular lipoma of the skin has never been reported before; thus, the authors suggest the classification "cutaneous" intramuscular lipoma to describe lesions located in the dermal or epidermal layer. PMID- 30004073 TI - A rare case of hyaline cell-rich atypical chondroid syringoma with divergent differentiation. AB - Chondroid syringoma (CS) also known as mixed tumor of the skin, is a rare benign adnexal tumor accounting for < 0.098%. Epithelial cells arranged in cords and tubules set in myxoid or chondroid stroma. Differentiation such as osteoid, sebaceous or mature adipocytes can be seen rarely. Hyaline cell rich is a rare variant of CS composed of cells with eosinophilic hyaline cytoplasm and plasmacytoid features. CS can have benign, atypical and malignant variants. The term atypical mixed tumor is recommended for those tumors which have histological features of malignancy such as infiltrative margin, satellite tumor nodules and tumor necrosis but without proven metastasis. Very few case reports of hyaline cellrich benign CS have been reported in the past, but to the best of our knowledge, possibly it is the first case of atypical hyaline cellrich CS of the little finger in a 65 year-old female showing divergent differentiation. PMID- 30004074 TI - Renal-type clear cell carcinoma of prostate: A case report and review of literature. AB - We analyzed the clinicopathological features of renal-type clear cell carcinoma (RTCCC) in the prostate and its diagnosis according to the example in our hospital and review of the literature. Clinicopathological features of RTCCC in the prostate were observed in a patient from our hospital combining with a review of the literature. Microscopically, the tumor was composed of cells with abundant and translucent cytoplasm, arranged in the form of the vesicular nest or glandular structure. Therefore, it was necessary to distinguish between metastatic clear cell renal cell carcinoma and primary RTCCC in the prostate. Immunohistochemistry (IHC) of this case showed tumor cells were positive expression for cytokeratin (CKpan), low-molecular weight cytokeratin, epithelial membrane antigen, and prostate-specific antigen (PSA), P504S, prostate-specific membrane antigen and partial positive expression for vimentin and CD10. The tumor cells displayed negative expression of high molecular weight cytokeratin, cytokeratin 7 (CK7), CK34, PAX8, and renal cell carcinoma. The morphological and immunohistochemical features of this tumor were in correspondence with RTCCC of the prostate. This tumor is a rare variant of the prostate carcinomas. To the best of our knowledge, this type of extrarenal tumor has only been reported in six previous studies. Combination of histology, IHC, imaging, and serum PSA is needed to perform a suitable diagnosis. PMID- 30004075 TI - Coexisting prostate adenocarcinoma with multiple myeloma: A rare case report. AB - We report a rare case of an 83-year-old male with synchronous occurrence of prostate adenocarcinoma and multiple myeloma. He presented with lower back pain and incontinence of urine for the past 6 months. Routine hematological and biochemical investigations were performed which pointed toward prostate adenocarcinoma. Transrectal ultrasonography and magnetic resonance imaging showed prostatomegaly along with osteolytic lesions in the skull and vertebrae. Prostate biopsy was performed and adenocarcinoma was confirmed. To rule out metastatic deposits in the bone and to rule out bone marrow infiltration, bone marrow aspiration and biopsy of the patient was done, and unexpectedly, it showed multiple myeloma. The association between these two disorders is poorly understood, but some studies show that bone marrow microenvironment plays an important role. PMID- 30004076 TI - Spermatocytic seminoma with rhabdomyoblastic differentiation: Case report and review of literature. AB - Spermatocytic seminoma (SCS) is an indolent germ cell tumor of the testis. It has an excellent prognosis and orchidectomy is generally curative. Very rarely, it can be complicated by a sarcomatous transformation which is associated with a very aggressive behavior and requires adjuvant therapy. SCS with sarcomatous component is a very rare occurrence with <20 cases described in the world literature of which eight showed rhabdomyoblastic differentiation. We report a case of SCS with rhabdomyosarcomatous differentiation in a 60-year-old male along with a short review of literature. PMID- 30004077 TI - Metastasizing uterine mullerian adenosarcoma in a young female: Diagnostic enigma. AB - Uterine adenosarcomas are uncommon tumors. It is a biphasic tumor with both epithelial and mesenchymal component. The epithelial component is benign in nature, and the mesenchymal component is malignant. Metastasis is rare in adenosarcoma. We report a case of adenosarcoma with lymph nodal metastasis. A 20 year-old female presented with history of per vaginal bleeding for 1 month. Per vaginal examination revealed a fungating mass protruding through the cervical os. Ultrasonography and magnetic resonance imaging showed a large intrauterine mass. Biopsy of the mass done at an outside hospital was reported as rhabdomyosarcoma. Hence, she was given one cycle of neoadjuvant chemotherapy. Following this, she had profuse bleeding. Emergency hysterectomy with pelvic lymph nodal dissection was performed. The final histopathology was reported as adenosarcoma. One pelvic lymph node showed metastatic deposit of rhabdomyosarcomatous element. In young females presenting with polypoidal mass, uterine adenosarcoma can be considered in the differential diagnosis. PMID- 30004078 TI - Psammomatoid variant of juvenile ossifying fibroma. AB - Juvenile ossifying fibroma (JOF) is a rare benign tumor of the craniofacial bones differing from other fibro-osseous lesions in terms of early age of onset, aggressive clinical behavior, and high recurrence rate. Histopathologically, it is divided into two as trabecular JOF (TrJOF) and psammomatoid JOF (PsJOF). In PsJOF, psammoma-like spherical ossicles constitute pathognomonic histopathological images, whereas TrJOF has trabeculae of fibrillary osteoid and woven bone. Despite the histopathologic separation, both lesions have similar clinical behavior, thus the treatment procedure is also the same. Complete surgical resection is preferred for the treatment. We report a rare case of PsJOF involving the maxillary sinus and resultant facial symmetry in a 13-year-old female child. PMID- 30004079 TI - Primary follicular lymphoma of disguised as multiple miliary like lesions: A case report and review of literature. AB - Primary follicular lymphoma (PFL) of gastrointestinal tract (GIT) is rare and account for 1%-3% of non-Hodgkin lymphoma. Within the small intestine, the PFL is more common in jejunum than in the ileum. Due to low prevalence of the disease, the clinical manifestations are not well known, and diagnosis is usually delayed leading to complications. We herein report a case of PFL of GIT who presented with intestinal obstruction and unique gross morphology. Diagnosis was made by morphology and supported by immunohistochemistry. PMID- 30004080 TI - A rare case of accessory mitral valve tissue. PMID- 30004081 TI - Ectopic prostatic tissue presenting as a mucosal tumor in urinary bladder. PMID- 30004082 TI - An unusual presentation of hydatid cyst in the neck: A cytological diagnosis. PMID- 30004083 TI - Metastasizing pleomorphic adenoma of parotid presenting as a huge renal mass. PMID- 30004084 TI - An unusual intra-abdominal tumor of the gastrointestinal tract. PMID- 30004085 TI - Sertoliform endometrioid carcinoma of the ovary in a young female. PMID- 30004086 TI - Current status and way forward for National Accreditation Board for Testing and Calibration Laboratories Accreditation of Laboratories in Government Organizations. PMID- 30004087 TI - Coexistence of T-cell lymphoblastic lymphoma and acute myeloid leukemia mimicking acute lymphocytic leukemia. PMID- 30004088 TI - Remembering the genius on her birth anniversary: Professor Janet Davidson Rowley, MD (05.04.1925-17.12.2013). PMID- 30004089 TI - Klotho Inhibits Proliferation and Migration of Angiotensin II-Induced Vascular Smooth Muscle Cells (VSMCs) by Modulating NF-kappaB p65, Akt, and Extracellular Signal Regulated Kinase (ERK) Signaling Activities. AB - BACKGROUND It has been proven that phenotype shifting, from the contractile phenotype to the synthetic phenotype, of vascular smooth muscle cells (VSMCs), plays an important role in vascular diseases such as atherosclerosis, restenosis, and hypertension. Recently, accumulating evidence suggests that Klotho is associated with many cardiovascular diseases or damage. Through the estimation of the proliferation and migration of Ang II-induced VSMCs and the related intracellular signal transduction pathways, we researched the effects of Klotho on phenotype modulation in this study. MATERIAL AND METHODS A rat vascular smooth muscle cell line was grown in vitro with or without Ang II or Klotho, and cell proliferation and migration were evaluated. RESULTS The dose-dependent inhibition of Ang II-induced proliferation and migration by Klotho was shown in VSMCs. The phenotype modulation was inhibited by Klotho co-treatment; this co-treatment promoted the expression of contractile phenotype marker proteins, including SM22alpha, and also the proliferation phenotype marker protein PCNA compared with Ang II alone, which was suppressed, and activated VSMCs. Furthermore, by reducing the expression of G0/G1-specific regulatory proteins such as cyclin D1, cyclin dependent kinase (CDK) 4, cyclin E, and CDK2, cell cycle arrest was induced by Klotho at G0/G1 phase. Although Ang II strongly stimulated NF-kappaB, p65, Akt, and ERK phosphorylation, these activation events were diminished by co-treatment with Ang II and Klotho. CONCLUSIONS Phenotype modulation of Ang II-induced VSMCs and stimulation of the NF-kappaB, p65, Akt, and ERK signaling pathways were inhibited by Klotho, which suggests that Klotho may play an important role in the phenotype modulation of VSMCs. PMID- 30004090 TI - Author Correction: Metabolic engineering of Saccharomyces cerevisiae for production of very long chain fatty acid-derived chemicals. AB - This corrects the article DOI: 10.1038/ncomms15587. PMID- 30004091 TI - Publisher Correction: Feasibility and coexistence of large ecological communities. AB - This corrects the article DOI: 10.1038/ncomms14389. PMID- 30004093 TI - Author Correction: Improving 10-deacetylbaccatin III-10-beta-O-acetyltransferase catalytic fitness for Taxol production. AB - This corrects the article DOI: 10.1038/ncomms15544. PMID- 30004092 TI - Author Correction: Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. AB - This corrects the article DOI: 10.1038/ncomms16081. PMID- 30004094 TI - Response to comment on 'Protein crystal lattices are dynamic assemblies: the role of conformational entropy in the protein condensed phase'. AB - A response is given to Nespolo's comment [IUCrJ (2018), 5, https://doi.org/10.1107/S2052252518006267] about the usage of the the term 'crystal lattice' in Dimova & Devedjiev [IUCrJ (2018), 5, 130-140]. PMID- 30004095 TI - Strong light-matter interaction in tungsten disulfide nanotubes. AB - Transition metal dichalcogenide materials have recently been shown to exhibit a variety of intriguing optical and electronic phenomena. Focusing on the optical properties of semiconducting WS2 nanotubes, we show here that these nanostructures exhibit strong light-matter interaction and form exciton polaritons. Namely, these nanotubes act as quasi 1-D polaritonic nano-systems and sustain both excitonic features and cavity modes in the visible-near infrared range. This ability to confine light to subwavelength dimensions under ambient conditions is induced by the high refractive index of tungsten disulfide. Using "finite-difference time-domain" (FDTD) simulations we investigate the interactions between the excitons and the cavity mode and their effect on the extinction spectrum of these nanostructures. The results of FDTD simulations agree well with the experimental findings as well as with a phenomenological coupled oscillator model which suggests a high Rabi splitting of ~280 meV. These findings open up possibilities for developing new concepts in nanotube-based photonic devices. PMID- 30004096 TI - Potential dependent changes in the structural and dynamical properties of 1-butyl 3-methylimidazolium bis(trifluoromethanesulfonyl)imide on graphite electrodes revealed by molecular dynamics simulations. AB - An understanding of the characteristics of ionic liquid/graphite interfaces is highly important for electrochemical devices such as batteries and capacitors. In this paper, we report microscopic studies of 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BMIM-TFSI) on charged graphite electrodes using molecular dynamics simulations to reveal the two-dimensional arrangement of the ions and their dynamics at the interfaces. Analyses of surface distribution and mobility of ions revealed that the ion arrangement changes from a bilayer type to a checkerboard type with increasing applied potential. Whereas the bilayer type arrangement increases the ionic mobility parallel to the interfaces with the negative potential, the ions arranged in the checkerboard type tend to localize because of the increased lateral electrostatic interactions. Furthermore, we revealed that the inhomogeneity of ionic distribution at the positive potential propagates up to a few nanometers from the interface. PMID- 30004097 TI - Controllable formation of meso- and macropores within metal-organic framework crystals via a citric acid modulator. AB - Citric acid (CA) is introduced to modulate the synthesis of octahedral HKUST-1 (also known as Cu3(BTC)2, BTC = benzene-1,3,5-tricarboxylate) particles with hierarchical micro, meso- and/or macropores (noted as HP-HKUST-1 particles) under mild conditions. The particle size of the resultant product could be tuned from 300 nm to 2.4 MUm by varying the amount of CA added, solvents, reaction time and so on. The intrinsic microporous structure of HKUST-1 is maintained despite the strong chelation capability of CA towards Cu2+ while the larger pores' size is in the range of 30 to 100 nm. The possible formation mechanism of these octahedral HP-HKUST-1 particles is proposed on the basis of our systematic investigations. The resulting micrometer HP-HKUST-1 particle is employed to encapsulate phosphomolybdic acid hydrate (HPMo), a catalyst for the methanolysis of styrene oxide. After encapsulation, a superior catalytic activity with a high conversion rate (99.6%) is achieved when the reaction is carried out at 40 degrees C for 20 min. PMID- 30004100 TI - Force-induced structural changes in non-sulfated carrageenan based oligosaccharides - a theoretical study. AB - In this work we use the Enforced Geometry Optimization (EGO) approach to simulate force-induced structural changes in the monomer, and di- up to pentameric oligomers of neutral and non-sulfated carrageenan based oligosaccharides. Our results indicate that the monosaccharide unit sequence in the oligomeric structure determines: (i) the type(s) of the enforced conformational transition(s), and (ii) the mechanical resistance to external forces. It is a direct consequence of the different glycosidic bonding types in the examined carregeenan based oligosaccharides. PMID- 30004104 TI - Karyotypes of Brazilian non-volant small mammals (Didelphidae and Rodentia): An online tool for accessing the chromosomal diversity. AB - We have created a database system named CIPEMAB (CItogenetica dos PEquenos MAmiferos Brasileiros) to assemble images of the chromosomes of Brazilian small mammals (Rodents and Marsupials). It includes karyotype information, such as diploid number, karyotype features, idiograms, and sexual chromosomes characteristics. CIPEMAB facilitates quick sharing of information on chromosome research among cytogeneticists as well as researchers in other fields. The database contains more than 300 microscopic images, including karyotypic images obtained from 182 species of small mammals from the literature. Researchers can browse the contents of the database online (http://www.citogenetica.ufes.br). The system enables users to locate images of interest by taxa, and to display the document with detailed information on species names, authors, year of the species publication, and karyotypes pictures in different colorations. CIPEMAB has a wide range of applications, such as comparing various karyotypes of Brazilian species and identifying manuscripts of interest. PMID- 30004105 TI - Comparison of radiosensitivity response to acute and chronic gamma irradiation in colored wheat. AB - We aimed to investigate the biological responses induced by acute and chronic gamma irradiation in colored wheat seeds rich in natural antioxidants. After acute and chronic irradiation, the phenotypic effects on plant growth, germination rate, seedling height, and root length were examined, and the biochemical changes were investigated by analyzing the expression of antioxidant enzyme-related genes, antioxidant enzyme activities, and total antioxidant capacity. High dosages of chronic radiation reduced plant growth compared with the controls. Electron spin resonance measurement and 2,2-diphenyl-1 picrylhydrazyl activity analysis showed lower amount of free radicals in colored wheat seeds on chronic irradiation with low dosage of gamma rays compared to seeds subjected to acute irradiation. Expression levels of anthocyanin biosynthesis genes, antioxidant-related genes, and antioxidant enzyme activity in seeds and young leaves of seedling showed diverse effects in response to different dosages and types of gamma irradiation. This suggests that phenotype is affected by the dosage and type of gamma radiation, and the phytochemicals in colored wheat seeds involved in antioxidant activity to scavenge free radicals respond differently to irradiation types. This provides evidence that acute and chronic exposure to radiation have different effects on seeds and young leaves after germination. PMID- 30004106 TI - Could human coronavirus OC43 have co-evolved with early humans? AB - This paper reports on an investigation of the role of codon usage evolution on the suggested bovine-to-human spillover of Bovine coronavirus (BCoV), an enteric/respiratory virus of cattle, resulting in the emergence of the exclusively respiratory Human coronavirus OC43 (HCoV-OC43). Analyses based on full genomes of BCoV and HCoV-OC43 and on both human and bovine mRNAs sequences of cholecystokinin (CCK) and surfactant protein 1 A (SFTP1-A), representing the enteric and respiratory tract codon usage, respectively, have shown natural selection leading to optimization or deoptimization of viral codon usage to the human enteric and respiratory tracts depending on the virus genes under consideration. A higher correlation was found for the nucleotide distance at the 3rd nucleotide position of codons and codon usage optimization to the human respiratory tract when BCoV and HCoV-OC43 were compared. An MCC tree based on relative synonymous codon usage (RSCU) data integrating data from both viruses and hosts into a same analysis indicated three putative host/virus contact dates ranging from 1.54E8 to 2.44E5 years ago, suggesting that an ancestor coronavirus might have followed human evolution. PMID- 30004107 TI - Transcriptome sequencing and expression profiling of genes involved in the response to abiotic stress in Medicago ruthenica. AB - Medicago ruthenica is a perennial forage legume with the remarkable ability to survive under unfavorable environmental conditions. It has been identified as an excellent species of Medicago that can adapt to various environmental stresses including low temperature, drought, and salinity. To investigate its potential as a genetic resource, we performed transcriptome sequencing and analysis in M. ruthenica under abiotic stresses. We generated >120 million reads from six cDNA libraries, resulting in 79,249 unique transcripts, most of which were highly similar to transcripts from M. truncatula (44,608, 56.3%) and alfalfa (M. sativa, 48,023, 60.6%). Based on gene expression profiles, 2,721 transcripts were identified as abiotic stress responsive genes which were predicted to be mainly involved in phytohormone signaling pathways, transcriptional regulation, and ROS scavenging. These results suggest that they play critical roles in the response to abiotic stress. In summary, we identified genes in our transcriptome dataset involved in the regulation of the abiotic stress response in M. ruthenica which will provide a valuable resource for the future identification and functional analysis of candidate genes for adaption to unfavorable conditions. The genes identified here could be also useful for improving stress tolerance traits in alfalfa through molecular breeding in the future. PMID- 30004109 TI - High-grade encapsulated papillary carcinoma of the breast is clinicopathologically distinct from low/intermediate-grade neoplasms in Chinese patients. AB - Encapsulated papillary carcinoma (EPC) of the breast is typically of low-to intermediate grade (LTIG) with favorable prognosis. Rarely, high-grade (HG) EPC cases have been documented in recent years. Herein we compared the morphological, immunohistochemical, and clinical features of LTIG EPC to those of HG EPC. Of the 30 EPC patients, 25 were diagnosed as LTIG and five as HG (median age: 60 and 36 years, respectively); 80% of the HG EPCs exhibited predominantly solid architecture with prominent lymphoplasmacytic infiltrates, more crowded and thicker papillae, and greater stratification and irregular arrangement of malignant epithelial cells. Coexisting invasive components were observed in 32% and 80% of LTIG and HG cases, respectively. HG EPC was negative for hormone receptor staining. Additionally, 48% of LTIG EPC cases were moderately positive for human epidermal growth factor receptor 2 (Her-2) immunostaining (2+); among them, one case showed Her-2 gene amplification by fluorescence in situ hybridization. The basal-like markers cytokeratin 5/6 and epidermal growth factor receptor were detected in two and five HG cases, respectively. HG EPC was also characterized by a significantly high Ki-67 index (median: 85%, P<0.001). No local recurrence or distant metastasis was noted during the follow-up. HG EPC typically exhibited a solid architecture with a concurrent invasive component as well as a triple-negative and basal-like immunophenotype in young women. HG EPC might be indicative of high proliferative activity and potential aggressiveness. PMID- 30004108 TI - Test-re-test reliability of quadriceps muscle strength measures in people with more severe chronic obstructive pulmonary disease. AB - OBJECTIVE: To investigate the interday test-retest reliability of volitional and non-volitional measurements of isometric quadriceps strength using a strain-gauge in people with severe to very severe chronic obstructive pulmonary disease. DESIGN: Cross-sectional study. Volitional quadriceps measurements consisted of isometric maximal voluntary contractions. Non-volitional measurements were obtained during magnetic potentiated twitch stimulations of the femoral nerve. SETTING: Research centre laboratory. PARTICIPANTS: Twenty-four individuals with severe to very severe chronic obstructive pulmonary disease (percentage of predicted forced expiratory volume in 1 s, 37% predicted). RESULTS: Maximal voluntary contractions and potentiated twitch stimulations measures demonstrated excellent interday test-retest relative reliability (ICC 0.97 and 0.80, respectively), while absolute reliability measures were different between techniques (SEM 1.4 kg, CV 3.2%, MDC 3.9 kg vs SEM 1.5 kg, CV 12.2%, MDC 4.2 kg for maximal voluntary contractions and potentiated twitch stimulations, respectively). CONCLUSION: The results supports that maximal voluntary contraction and potentiated twitch stimulation measurements of isometric quadriceps strength are reliable in people with severe to very severe chronic obstructive pulmonary disease as evident excellent relative reliability using both techniques, although the former technique appears to have better absolute reliability. PMID- 30004110 TI - Myelodysplastic syndrome (MDS) with isolated trisomy 8: a type of MDS frequently associated with myeloproliferative features? A report by the Groupe Francophone des Myelodysplasies. AB - Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of 138 MDS patients with isolated +8, classified or reclassified as MDS (excluding MDS/myeloproliferative neoplasm). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood cell count >10 * 109 /l, myelemia (presence of circulating immature granulocytes with a predominance of more mature forms) >2%, palpable splenomegaly. Fifty-four patients (39.1%) had MP features: 28 at diagnosis, 26 were acquired during evolution. MP forms had more EZH2 (33.3% vs. 12.0% in non-MP, P = 0.047), ASXL1 (66.7% vs. 42.3%, P = 0.048) and STAG2 mutations (77.8% vs. 21.7%, P = 0.006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (P = 0.15) and 39 months (P = 0.085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 months vs. 23 months in non-MP cases, P = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more EZH2, ASXL1 and STAG2 mutations, responded poorly to HMA, and tended to have poorer survival than non-MP forms. PMID- 30004112 TI - Microdeletion of 7p12.1p13, including IKZF1, causes intellectual impairment, overgrowth, and susceptibility to leukaemia. PMID- 30004111 TI - Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples. AB - Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft-versus-host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. alpha-defensin-5 (HD5) and regenerating islet-derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre-transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced-intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP * graft source interaction term in CTN-0201 and a SNP * conditioning intensity term in CTN-0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II-IV [rs4415345 G vs. C: hazard ratio (HR) 0.58, 95% confidence interval (95% CI) 0.37-0.92, P = 0.02; rs4610776 T vs. A: HR 1.53, 95% CI 1.01-2.32, P = 0.05] in CTN-0201, but not CTN-0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function. PMID- 30004113 TI - LDL-Cholesterol Is the Only Clinically Relevant Biomarker for Atherosclerotic Cardiovascular Disease (ASCVD) Risk. PMID- 30004114 TI - Network meta-analysis of surgical management of gastro-oesophageal reflux disease in adults. AB - BACKGROUND: Proton pump inhibitors are the mainstay of treatment for gastro oesophageal reflux disease, but are associated with ongoing costs and side effects. Antireflux surgery is cost-effective and is preferred by many patients. A total (360o or Nissen) fundoplication is the traditional procedure, but other variations including partial fundoplications are also commonly performed, with the aim of achieving durable reflux control with minimal dysphagia. Many RCTs and some pairwise meta-analyses have compared some of these procedures but there is still uncertainty about which, if any, is superior. Network meta-analysis allows multiple simultaneous comparisons and robust synthesis of the available evidence in these situations. A network meta-analysis comparing all antireflux procedures was performed to identify which has the most favourable outcomes at short-term (3 12 months), medium-term (1-5 years) and long-term (10 years and more than 10 years) follow-up. METHODS: Article databases were searched systematically for all eligible RCTs. Primary outcomes were quality-of-life measures and dysphagia. Secondary outcomes included reflux symptoms, pH studies and complications. RESULTS: Fifty-one RCTs were included, involving 5357 patients and 14 different treatments. Posterior partial fundoplication ranked best in terms of reflux symptoms, and caused less dysphagia than most other interventions including Nissen fundoplication. This was consistent across all time points and outcome measures. CONCLUSION: Posterior partial fundoplication provides the best balance of long-term, durable reflux control with less dysphagia, compared with other treatments. PMID- 30004115 TI - LDL-Cholesterol Is Not the Only Clinically Relevant Biomarker for Coronary Artery Disease or Acute Coronary Syndrome. AB - Coronary artery disease (CAD) is a progressive disorder and its risk is best determined using multiple biomarkers and risk factors. Many novel biomarkers have been shown to improve cardiovascular disease risk beyond that of the traditional risk factors, including polygenic risk scores, small very low-density lipoprotein (VLDL), ApoB, triglycerides (TG), non-HDL-c, lipoprotein (a) (Lp(a)), coronary calcium scores, C-reactive protein (CRP), B-type natriuretic peptide (BNP), troponins, and many other novel biomarkers that have been measured using high throughput assays. PMID- 30004116 TI - Arthroscopic approach and intra-articular anatomy of the equine atlanto-occipital joint. AB - OBJECTIVE: To develop arthroscopic approaches to the atlanto-occipital (A-O) and describe associated arthroscopic anatomy. STUDY DESIGN: Experimental ex vivo study and clinical case report. ANIMALS: Ten equine cadaver joints and 1 clinical case. METHODS: CT arthrograms of 8 A-O joints were performed to determine the placement of an arthroscopic portal. Arthroscopy was performed via dorsal and/or ventral approaches (dorsal or ventral to the longissimus capitis tendon) in 10 cadaveric A-O joints and the A-O joint of a 2-week-old foal with septic arthritis. Accessible cartilage was debrided in 3 cadaver joints. Accessibility and risks were assessed by review of arthroscopic images, postoperative necropsy, and computed tomography (CT). RESULTS: Dorsal and ventral outpouchings of the A-O joint were identified with CT. Arthroscopy of the dorsal pouch provided access to 50% of the dorsocranial occipital condyle and 15% of the dorsocranial atlas articular surfaces. Joint distension caused displacement of the dura. Dura perforation occurred with a blind dorsal approach in 2 of 5 joints. Dura perforation did not occur after ultrasonography-guided approaches. Arthroscopic debridement of septic arthritis and osteomyelitis was successful in 1 clinical case. CONCLUSION: Approaches to the A-O joint were determined from CT examinations. The cranial aspect of the dorsal pouch of the A-O joint was accessed via arthroscopic triangulation in all horses of this study. Ultrasound guided joint access prevented perforation of vital structures, including the spinal canal. CLINICAL SIGNIFICANCE: Advanced imaging improves the diagnosis of A O joint pathology. Descriptions of arthroscopic anatomy and accessibility provide important information for surgical intervention. PMID- 30004118 TI - Prevalence of internet gaming disorder in adolescents: A meta-analysis across three decades. AB - The inclusion of "Internet gaming disorder (IGD)" in the fifth edition of Diagnostic and statistical manual of mental disorders (DSM-5) creates a possible line of research. Despite the fact that adolescents are vulnerable to IGD, studies had reported wide array of prevalence estimates in this population. The aim of this paper is to review the published studies on prevalence of IGD among adolescents. Relevant studies prior to March 2017 were identified through databases. A total of 16 studies met the inclusion criteria. The pooled prevalence of IGD among adolescents was 4.6% (95% CI = 3.4%-6.0%). Male adolescents generally reported higher prevalence rate (6.8%, 95% CI = 4.3%-9.7%) than female adolescents (1.3%, 95% CI = 0.6%-2.2%). Subgroup analyses revealed that prevalence estimates were highest when studies were conducted in: (i) 1990s; (ii) use DSM criteria for pathological gambling; (iii) examine gaming disorder; (iv) Asia; and (v) small samples (<1,000). This study confirms the alarming prevalence of IGD among adolescents, especially among males. Given the methodological deficits in past decades (such as reliance on DSM criteria for "pathological gambling," inclusion of the word "Internet," and small sample sizes), it is critical for researchers to apply a common methodology for assess this disorder. PMID- 30004117 TI - Obstruction of ventricular Ca2+ -dependent arrhythmogenicity by inositol 1,4,5 trisphosphate-triggered sarcoplasmic reticulum Ca2+ release. AB - KEY POINTS: Augmented inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R2) expression has been linked to a variety of cardiac pathologies. Although cardiac IP3 R2 function has been in the focus of research for some time, a detailed understanding of its potential role in ventricular myocyte excitation-contraction coupling under pathophysiological conditions remains elusive. The present study focuses on mechanisms of IP3 R2-mediated sarcoplasmic reticulum (SR)-Ca2+ release in ventricular excitation-contraction coupling under IP3 R2-overexpressing conditions by studying intracellular Ca2+ events. We report that, upon IP3 R2 overexpression in ventricular myocytes, IP3 -induced Ca2+ release (IP3 ICR) modulates the SR-Ca2+ content via "eventless" SR-Ca2+ release, affecting the global SR-Ca2+ leak. Thus, IP3 R2 activation could act as a SR-Ca2+ gateway mechanism to escape ominous SR-Ca2+ overload. Our approach unmasks a so far unrecognized mechanism by which "eventless" IP3 ICR plays a protective role against ventricular Ca2+ -dependent arrhythmogenicity. ABSTRACT: Augmented inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R2) function has been linked to a variety of cardiac pathologies including cardiac arrhythmias. The functional role of IP3 -induced Ca2+ release (IP3 ICR) within ventricular excitation contraction coupling (ECC) remains elusive. As part of pathophysiological cellular remodelling, IP3 R2s are overexpressed and have been repeatedly linked to enhanced Ca2+ -dependent arrhythmogenicity. In this study we test the hypothesis that an opposite scenario might be plausible in which IP3 ICR is part of an ECC protecting mechanism, resulting in a Ca2+ -dependent anti arrhythmogenic response on the cellular scale. IP3 R2 activation was triggered via endothelin-1 or IP3 -salt application in single ventricular myocytes from a cardiac-specific IP3 R type 2 overexpressing mouse model. Upon IP3 R2 overexpression, IP3 R activation reduced Ca2+ -wave occurrence (46 vs. 21.72%; P < 0.001) while its block increased SR-Ca2+ content (~29.4% 2-aminoethoxydiphenyl borate, ~16.4% xestospongin C; P < 0.001), suggesting an active role of IP3 ICR in SR-Ca2+ content regulation and anti-arrhythmogenic function. Pharmacological separation of ryanodine receptor RyR2 and IP3 R2 functions and two-dimensional Ca2+ event analysis failed to identify local IP3 ICR events (Ca2+ puffs). SR-Ca2+ leak measurements revealed that under pathophysiological conditions, "eventless" SR-Ca2+ efflux via enhanced IP3 ICR maintains the SR-Ca2+ content below Ca2+ spark threshold, preventing aberrant SR-Ca2+ release and resulting in a protective mechanism against SR-Ca2+ overload and arrhythmias. Our results support a so far unrecognized modulatory mechanism in ventricular myocytes working in an anti-arrhythmogenic fashion. PMID- 30004119 TI - Clinical efficiency and safety of Hsp90 inhibitor Novobiocin in avian tibial dyschondroplasia. AB - Tibial dyschondroplasia (TD) is a bone defect of broilers and other poultry birds that disturbs growth plate and it causes lameness. Previously we evaluated differential expression of multiple genes involved in growth plate angiogenesis and reported the safety and efficacious of medicinal plant root extracted for controlling TD. In this study, clinical and protective effect of an antibiotic Novobiocin (Hsp90 inhibitor) and expression of Hsp90 and proteoglycan aggrecan was examined. The chicks were divided into three groups; Control, thiram-induced TD, and Novobiocin injected TD. After the induction of TD, the Novobiocin was administered through intraperitoneal route to TD-affected birds until the end of the experiment. The expressions and localization of Hsp90 were evaluated by qRT PCR, immunohistochemistry (IHC) and western blot, respectively. Morphological, histological examinations, and serum biomarker levels were evaluated to assess specificity and protective effects of Novobiocin. The results showed that TD causing retarded growth, enlarged growth plate, distended chondrocytes, irregular columns of cells, decreased antioxidant capacity, reduced protein levels of proteoglycan aggrecan, and upregulated in Hsp90 expression (p < 0.05) in dyschondroplastic birds as compared with control. Novobiocin treatment restored growth plate morphology, reducing width, stimulated chondrocyte differentiation, sprouting blood vessels, corrected oxidative imbalance, decreased Hsp90 expressions and increased aggrecan level. Novobiocin treatment controlled lameness and improved growth in broiler chicken induced by thiram. In conclusion, the accumulation of the cartilage and up-regulated Hsp90 are associated with TD pathogenesis and irregular chondrocyte morphology in TD is along with reduced aggrecan levels in the growth plate. Our results indicate that Novobiocin treatment has potential to reduce TD by controlling the expression of Hsp90 in addition to improve growth and hepatic toxicity in broiler chicken. PMID- 30004120 TI - Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats. AB - Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross-over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 15.9 hr, Cmax = 21.5 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-infinity = 260 ng*hr/mL and calculated half-life = 26.8 hr. Single oral administration of mirtazapine resulted in mean Tmax = 1.1 hr, Cmax = 83.1 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-infinity = 434 ng*hr/mL and calculated half-life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 2.1 hr, Cmax = 39.6 ng/mL, AUC0 24 = 400 ng*hr/mL, AUC0-infinity = 647 ng*hr/mL and calculated half-life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats. PMID- 30004121 TI - Revisit of wall-induced lateral migration in particle electrophoresis through a straight rectangular microchannel: Effects of particle zeta potential. AB - Previous studies have reported a lateral migration in particle electrophoresis through a straight rectangular microchannel. This phenomenon arises from the inherent wall-induced electrical lift that can be exploited to focus and separate particles for microfluidic applications. Such a dielectrophoretic-like force has been recently found to vary with the buffer concentration. We demonstrate in this work that the particle zeta potential also has a significant effect on the wall induced electrical lift. We perform an experimental study of the lateral migration of equal-sized polystyrene particles with varying surface charges under identical electrokinetic flow conditions. Surprisingly, an enhanced focusing is observed for particles with a faster electrokinetic motion, which indicates a substantially larger electrical lift for particles with a smaller zeta potential. We speculate this phenomenon may be correlated with the particle surface conduction that is a strong function of particle and fluid properties. PMID- 30004122 TI - Mutation accumulation in selfing populations under fluctuating selection. AB - Selfing species are prone to extinction, possibly because highly selfing populations can suffer from a continuous accumulation of deleterious mutations, a process analogous to Muller's ratchet in asexual populations. However, current theory provides little insight into which types of genes are most likely to accumulate deleterious alleles and what environmental circumstances may accelerate genomic degradation. Here, we investigate temporal changes in the environment that cause fluctuations in the strength of purifying selection. We simulate selfing populations with genomes containing a mixture of loci experiencing constant selection and loci experiencing selection that fluctuates in strength (but not direction). Even when both types of loci experience the same average strength of selection, loci under fluctuating selection contribute disproportionately more to deleterious mutation accumulation. Moreover, the presence of loci experiencing fluctuating selection in the genome increases the deleterious fixation rate at loci under constant selection; under most realistic scenarios, this effect of linked selection can be attributed to a reduction in Ne . Fluctuating selection is particularly injurious when selective environments are strongly autocorrelated over time and when selection is concentrated into rare bouts of strong selection. These results imply that loci under fluctuating selection are likely important drivers of extinction in selfing species. PMID- 30004123 TI - Polyunsaturated fatty acids supplementation impairs anti-oxidant high-density lipoprotein function in heart failure. AB - BACKGROUND: The underlying reasons for the highly inconsistent clinical outcome data for omega-3-polyunsaturated fatty acids (n3-PUFAs) supplementation in patients with cardiac disease have not been understood yet. The aim of this prospective, randomized, double-blind, placebo controlled study was to determine the effects of oral treatment with n3-PUFAs on the anti-oxidant capacity of HDL in heart failure (HF) patients. METHODS: A total of 40 patients with advanced HF of nonischaemic origin, defined by NT-proBNP levels of >2000 pg/mL, NYHA class III or IV and a LVEF <35% who were on stable optimized medical therapy for >=3 months, were consecutively enrolled into this prospective, double-blind, placebo controlled trial and randomized in a 1:1:1 fashion to receive 1 g/day or 4 g/day of n3-PUFA, or placebo, respectively, for 12 weeks. RESULTS: After 12 weeks of treatment, the anti-oxidant function of HDL, measured by the HDL inflammatory index, was found significantly impaired in the treatment group in a dose dependent fashion with 0.67 [IQR 0.49-1.04] for placebo vs 0.71 [IQR 0.55-1.01] for 1 g/day n3-PUFA vs 0.98 [IQR 0.73-1.16] for 4 g/day n3-PUFA (P for trend = 0.018). CONCLUSION: We provide evidence for an adverse effect of n3-PUFA supplementation on anti-oxidant function of HDL in nonischaemic heart failure patients, establishing a potential mechanistic link for the controversial outcome data on n3-PUFA supplementation. PMID- 30004125 TI - Coconut Milk and Coconut Oil: Their Manufacture Associated with Protein Functionality. AB - Coconut palm (Cocos nucifera L.) is an economic plant cultivated in tropical countries, mainly in the Asian region. Coconut fruit generally consists of 51.7% kernel, 9.8% water, and 38.5% shell. Coconut milk is commonly manufactured from grated coconut meat (kernel). Basically, coconut milk is an oil-in-water emulsion, stabilized by some proteins existing in the aqueous phase. Maximization of protein functionality as an emulsifier can enhance the coconut milk stability. In addition, some stabilizers have been added to ensure the coconut milk stability. However, destabilization of emulsion in coconut milk brings about the collapse of the emulsion, from which virgin coconut oil (VCO) can be obtained. Yield, characteristics, and properties of VCO are governed by the processes used for destabilizing coconut milk. VCO is considered to be a functional oil and is rich in medium chain fatty acids with health advantages. PMID- 30004126 TI - How to quantify (the response to) sexual selection on traits. AB - Natural selection operates via fitness components like mating success, fecundity, and longevity, which can be understood as intermediaries in the causal process linking traits to fitness. In particular, sexual selection occurs when traits influence mating or fertilization success, which, in turn, influences fitness. We show how to quantify both these steps in a single path analysis, leading to better estimates of the strength of sexual selection. Our model controls for confounding variables, such as body size or condition, when estimating the relationship between mating and reproductive success. Correspondingly, we define the Bateman gradient and the Jones index using partial rather than simple regressions, which better captures how they are commonly interpreted. The model can be applied both to purely phenotypic data and to quantitative genetic parameters estimated using information on relatedness. The phenotypic approach breaks down selection differentials into a sexually selected and a "remainder" component. The quantitative genetic approach decomposes the estimated evolutionary response to selection analogously. We apply our method to analyze sexual selection in male dusky pipefish, Syngnathus floridae, and in two simulated datasets. We highlight conceptual and statistical limitations of previous path-based approaches, which can lead to substantial misestimation of sexual selection. PMID- 30004127 TI - Comparative efficacy of three antiseptics as surgical skin preparations in dogs. AB - OBJECTIVE: To compare the antimicrobial efficacy of a 2% chlorhexidine gluconate and 70% ethanol solution (CG+A) with that of F10 Skin Prep Solution (F10) and electrochemically activated water (EAW) when used as a surgical preparation in canine patients. STUDY DESIGN: Prospective randomized clinical study. SAMPLE POPULATION: One hundred sixteen dogs presented for ovariohysterectomy. METHODS: Dogs were randomly divided into 1 of the 3 antiseptic groups (CG+A, F10, EAW). Skin samples with replicating organism detection and counting plates were taken at 4 different perioperative sites and time intervals (postskin preparation, postskin antisepsis, 2 hours after the second sample, and at the end of surgery) during ovariohysterectomies performed by students. The colony forming unit (CFU) counts from each sample were quantified according to the level of bacterial contamination. Zero CFU was defined as no contamination, 1-12 CFU was defined as low contamination, and greater than 12 CFU was defined as high contamination. The 3 antiseptics were compared with respect to the level of contamination. RESULTS: There was no difference in the level of colonization between the antiseptics at the first sampling time (P = .454). However, the level of contamination for CG+A was lower compared with F10 and EAW at the second, third, and fourth sampling times (P = .001, P = .01, P = .02, respectively). CONCLUSION: CG+A was more effective at achieving a zero CFU count and low levels of contamination compared with F10 and EAW for surgical preparation in dogs undergoing ovariohysterectomy. CLINICAL SIGNIFICANCE: This study does not provide evidence to support the use of F10 and EAW instead of CG+A for the surgical skin preparation of dogs undergoing ovariohysterectomy. PMID- 30004124 TI - Central sensitization of the spino-parabrachial-amygdala pathway that outlasts a brief nociceptive stimulus. AB - KEY POINTS: Chronic pain is disabling because sufferers form negative associations between pain and activities, such as work, leading to the sufferer limiting these activities. Pain information arriving in the amygdala is responsible for forming these associations and contributes to us feeling bad when we are in pain. Ongoing injuries enhance the delivery of pain information to the amygdala. If we want to understand why chronic pain can continue without ongoing injury, it is important to know whether this facilitation continues once the injury has healed. In the present study, we show that a 2 min noxious heat stimulus, without ongoing injury, is able to enhance delivery of pain information to the amygdala for 3 days. If the noxious heat stimulus is repeated, this enhancement persists even longer. These changes may prime this information pathway so that subsequent injuries may feel even worse and the associative learning that results in pain-related avoidance may be promoted. ABSTRACT: Pain is an important defence against dangers in our environment; however, some clinical conditions produce pain that outlasts this useful role and persists even after the injury has healed. The experience of pain consists of somatosensory elements of intensity and location, negative emotional/aversive feelings and subsequent restrictions on lifestyle as a result of a learned association between certain activities and pain. The amygdala contributes negative emotional value to nociceptive sensory information and forms the association between an aversive response and the environment in which it occurs. It is able to form this association because it receives nociceptive information via the spino-parabrachio amygdaloid pathway and polymodal sensory information via cortical and thalamic inputs. Synaptic plasticity occurs at the parabrachial-amygdala synapse and other brain regions in chronic pain conditions with ongoing injury; however, very little is known about how plasticity occurs in conditions with no ongoing injury. Using immunohistochemistry, electrophysiology and behavioural assays, we show that a brief nociceptive stimulus with no ongoing injury is able to produce long lasting synaptic plasticity at the rat parabrachial-amygdala synapse. We show that this plasticity is caused by an increase in postsynaptic AMPA receptors with a transient change in the AMPA receptor subunit, similar to long-term potentiation. Furthermore, this synaptic potentiation primes the synapse so that a subsequent noxious stimulus causes prolonged potentiation of the nociceptive information flow into the amygdala. As a result, a second injury could have an increased negative emotional value and promote associative learning that results in pain-related avoidance. PMID- 30004129 TI - Harnessing the Integrated Stress Response to Counteract Metabolic Disease. PMID- 30004128 TI - Exterior-electrode electrically driven microconcentrator. AB - This study uses negative dielectrophoresis and AC electroosmosis as a driving mechanism and presents an electrically driven microconcentrator that concentrates the sample in the region exterior to the electrodes (termed as exterior-electrode electrically driven microconcentrator in this paper). The proposed microconcentrator uses a 3-D face-to-face electrode pair; the top electrode is a relatively large planar electrode, and the bottom electrode is formed with three to six long and thin electrodes connected into an open ring. The sample is brought to the vicinity of the open electrode at the bottom by electroosmotic flow; then, negative dielectrophoresis is used to push the sample away from the electrode and concentrate it in the region surrounded by the open ring electrode. Concentration using an exterior-electrode electrically driven microconcentrator offers promise for convenient use in conjunction with relevant detection systems. The results indicate that for the proposed exterior-electrode electrically driven microconcentrator, the optimal frequency is 100 kHz and the optimal voltage is 13 Vp-p . The corner concentration process at the corners of the bottom open electrodes enables the multi-corner electrodes to exhibit better concentration results than that exhibited by semicircular-shaped electrodes. The concentration performance is most favorable when the shape of the open electrode at the bottom is a five-vertex electrode, enabling a concentration enhancement factor of 55 times for a latex particle solution and 11 times for E. coli. The experimental results also demonstrate that the concentration phenomenon in this study is not induced by non-specific adsorption and can be repeated multiple times. PMID- 30004130 TI - The Microbiota-Inflammasome Hypothesis of Major Depression. AB - We propose the "microbiota-inflammasome" hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long-lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro-inflammatory pathways mediated by the Nod-like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress-induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive-like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co morbid conditions. A number of testable predictions surface from this microbiota gut-inflammasome-brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. PMID- 30004131 TI - Dispersive liquid-liquid microextraction of five chlorophenols in water samples followed by determination using capillary electrophoresis. AB - Dispersive liquid-liquid microextraction (DLLME) coupled with CE was developed for simultaneous determination of five types of chlorophenols (CPs), namely 2 chlorophenol (2-CP), 4-chlorophenol (4-CP), 2,4-dichlorophenol (2,4-DCP), 2,6 dichlorophenol (2,6-DCP), and 2,4,6-trichlorophenol (2,4,6-TCP) in water samples. Several parameters affecting DLLME and CE conditions were systematically investigated. Under the optimized DLLME-CE conditions, the five CPs were separated completely within 7.5 min and good enrichment factors were obtained of 40, 193, 102, 15, and 107 for 4-CP, 2,4,6-TCP, 2,4-DCP, 2-CP, and 2,6-DCP, respectively. Good linearity was attained in the range of 1-200 MUg/L for 2,4,6 TCP, 2,4-DCP, 2-300 MUg/L for 4-CP and 2-CP, and 1-300 MUg/L for 2,6-DCP, with correlation coefficients (r) over 0.99. The LOD (S/N = 3) and the LOQ (S/N = 10) were 0.31-0.75 MUg/L and 1.01-2.43 MUg/L, respectively. Recoveries ranging from 60.85 to 112.36% were obtained with tap, lake, and river water spiked at three concentration levels and the RSDs (for n = 3) were 1.31-11.38%. With the characteristics of simplicity, cost-saving, and environmental friendliness, the developed DLLME-CE method proved to be potentially applicable for the rapid, sensitive, and simultaneous determination of trace CPs in complicated water samples. PMID- 30004132 TI - Diagnostic accuracy of parathyroid hormone levels in washout samples of suspicious parathyroid adenomas: A single-centre retrospective cohort study. AB - INTRODUCTION: Minimally invasive surgery is an alternative surgical approach for primary hyperparathyroidism with less surgical trauma and anaesthesia complications. When combined with intraoperative measurement of parathyroid hormone (PTH), cure rates are exceeding 97%. Preoperative intact PTH determination in washout samples is really very useful when parathyroid lesions cannot be easily distinguished from thyroid lesions or sometimes lymph nodes. Herein, we aimed to report our institutional experience about parathyroid fine needle aspiration (FNA) method and suggest a cut-off ratio for this purpose. METHODS: In our clinic, we performed ultrasonography (USG)-guided parathyroid FNA procedure for 131 patients diagnosed with primary hyperparathyroidism between January 2005 and January 2016. Both cytologic evaluation and intact PTH determination were performed in washout samples. Eighty-seven of the study group also had a parathyroid scintigraphy. Both demographic features and laboratory results were all recorded. RESULTS: Median serum PTH level was 142 (113-197), while mean PTH washout level was 1824 (0-3953). When three of the localization techniques are compared with each other, FNA-PTH washout group had a better diagnostic accuracy (90.8%) when compared to cytology (7.92%) and MIBI (67.8%) groups. Both MIBI and FNA-PTH washout group had 100% positive predictive value (PPV) and 100% specificity. We found values greater than 436.5 pg/mL for FNA-PTH washout with a sensitivity of 90.3% and specificity of 88.9% (P < 0.01 and AUC 94.3 (87.8-100)) and a cut-off for FNA/serum PTH greater than 3.05 with a sensitivity of 91.2% and specificity of 89% (P = 0.02 and AUC 94.5 (88.8-100)) which implicate parathyroid lesions. CONCLUSION: According to the literature, PTH determination in washout samples has a specificity of 75%-100% and sensitivity of 70%-100%. This approach has better results than both cytology and scintigraphy in case of concomitant multinodular thyroid disease in experienced hands. Although there is not a definite cut-off for PTH levels in washout samples, we agree with the need of ratios rather than cut-offs in this issue. PMID- 30004133 TI - Dynamics of Dof domain-DNA interaction in wheat: Insights from atomistic simulations and free energy landscape. AB - DNA-binding one zinc finger protein (Dof) is a plant-specific transcription factor involved in numerous biological processes. In the current study, the plausible mechanism underlying Dof domain-DNA interaction in wheat was investigated using extensive molecular dynamics (MD) simulations analysis. We depicted that one key residue Lys29, possessing the ability to disturb the interaction between Dof domain-DNA upon substitution to Arg29. Frequent conformational changes were observed in Lys29Arg (K29R)-DNA complex during the entire MD simulation period, which significantly altered the interactions, thereby indicating the importance of Lys29 in complex stability. Principal component analysis and free energy landscape results also suggested strong affinity between wild-type Dof domain and DNA due to restricted atomic movement. Our study not only substantiates the structural and mechanistic insights of Dof transcription factor but also provides new avenues toward employment of these key amino acid residues in genetic engineering for development of abiotic stress tolerance crop plant. PMID- 30004134 TI - Meta-analysis of the effects of upstream land cover on stream recovery. AB - Unpredictable or variable ecosystem recovery from disturbance presents a challenge to conservation, particularly as the scale of human disturbance continues to increase. Theory suggests land-cover and disturbance characteristics affect recovery, but individual studies of disturbance and recovery frequently struggle to uncover generalizable patterns because of high levels of site specific variation. To understand how land-cover, disturbance type, and disturbance duration influence ecosystem recovery, we used studies documenting recovery of 50 streams to perform a global meta-analysis of stream recovery from disturbances that affect water quality (e.g., oil spill, fire, wastewater). We extracted upstream natural and urban land-cover percentages for each site and performed model selection and averaging to identify influences on recovery completeness. Most streams improved following the end of a disturbance (median 240% of disturbed condition) but did not recover fully to baseline predisturbance condition within the studied period (median study period 2 years; median recovery 60% of baseline). Scale of disturbance in time and space did not predict recovery, but sites with higher percentages of upstream natural land cover had less complete recovery relative to sites with more urban or agricultural cover, possibly due to higher baseline conditions in these streams. Our findings suggest impacts to systems with low anthropogenic stress may be more irreversible than impacts to already modified systems. We call for more long-term evaluations of ecosystem response to disturbance and the inclusion of regional references and predisturbance reference conditions for comparison. A more thorough understanding of the role of the surrounding landscape in shaping stream response to disturbance can help managers calibrate expectations for recovery and prioritize protection. PMID- 30004135 TI - Cast into doubt: Free will and the justification for punishment. AB - Criminal punishment is justified on either retributive or consequential grounds. The retributive justification is premised on a common-sense view of free will: offenders can freely choose to commit crimes and so deserve blame for their actions. The consequentialist justification, in contrast, is not necessarily premised on the free will concept, but rather justifies punishment when it is the most cost-effective way of preventing crime. Science elucidating the mechanistic causes of human behavior has thrown the notion of free will into doubt, leading some to predict a shift in public support away from retribution towards consequentialism. Past research shows that free will doubt weakens support for retribution, but less is known about its effects on support for consequentialism, or about whether these effects differ across the crime severity spectrum. In this study, we explore the effects of free will doubt on support for retribution and consequentialism in response to three different categories of crime - drug crime, property crime, and violent crime - which have been shown to evoke varying levels of emotion. We find clear inconsistencies across the crime spectrum. For high affect crime, free will doubt weakens support for retribution via blame, and increases support for consequentialism. For low affect crime, free will doubt weakens support for retribution to an even greater extent, yet also decreases support for consequentialism via blame. These findings suggest that, as science reveals the mechanistic causes of criminal behavior, support for criminal punishment will decrease, especially with respect to less serious crimes. PMID- 30004137 TI - Developmental impairments in moral competence as mitigation in capital cases. AB - In this article we propose a mitigation approach in those capital murder cases where traditional mitigation themes such as mental illness or low IQ are not present. To avoid prosecution characterization of these defendants as simply evil or antisocial personalities, we suggest reframing the issue as one of moral incompetence, based not on character defect but rather stemming from profoundly neglectful or abusive parenting. Under this reframing, defense teams would present evidence about the many antecedents of poor moral competence, its origins in neglect or abuse, its neurophysiological basis, and, most importantly, its potential for change. Evaluation in such cases would pay close attention to early childhood and family characteristics. We also recommend presentation of research findings showing how moral competence can be improved in adulthood, given appropriate guidance and support. This approach to mitigation is consistent with much of the developmental literature. But juror responses to these mitigation themes are as yet unknown. PMID- 30004136 TI - Inhibition of transcription factor SP1 produces neuroprotective effects through decreasing MAO B activity in MPTP/MPP+ Parkinson's disease models. AB - Monoamine oxidase B (MAO B) inhibitors, which inhibit dopamine decomposition by antagonizing MAO B activity, are approved and widely used for clinical treatment of Parkinson's disease (PD). Nonetheless, the mechanism of the abnormally increased MAO B activity in PD is still unclear. Previous research showed transcription factor specificity protein 1 (SP1) directly regulates MAO B activity by binding the SP1 binding sequence in MAO B promoter. In our study, we first observed that the SP1 protein level and SP1 binding activity in the MAO B promoter were increased in 1-methyl-4-phenylpyridinium (MPP+ ) neurotoxin-induced SH-SY5Y cells. Inhibition of SP1 by pretreatment with SP1 inhibitor mithramycin A (MMA) attenuated the abnormal increase in SP1 binding activity and the MAO B protein level to basal levels. Then, we investigated the neuroprotective effects of SP1 inhibition. In SH-SY5Y cell models of PD, preincubation with MMA or knockdown by SP1-specific small interfering RNA showed potent protection against MPP+ -induced apoptosis via SP1. In a male C57BL/6 mouse model of PD, MAO B activity and MPP+ concentrations in mouse brain following injection of 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) were increased, whereas the elevated MAO B activity was decreased after pre-injection of MMA. Moreover, MMA ameliorated MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and mouse behavioral impairments. Altogether, our study suggests that SP1 is a principal factor regulating increases in MAO B activity, and SP1 inhibition produces neuroprotective effects in PD models through decreases in MAO B activity, which may be a new neuroprotective therapeutic strategy for PD treatment. PMID- 30004138 TI - Differential impact of socioeconomic position across life on oral cancer risk in Kerala, India: An investigation of life-course models under a time-varying framework. AB - OBJECTIVES: The incidence of oral cancer has been rapidly increasing in India, calling for evidence contributing to a deeper understanding of its determinants. Although disadvantageous life-course socioeconomic position (SEP) is independently associated with the risk of these cancers, the explanatory mechanisms remain unclear. Possible pathways may be better understood by testing which life-course model most influences oral cancer risk. We estimated the association between life-course SEP and oral cancer risk under three life-course models: critical period, accumulation and social mobility. METHODS: We recruited incident oral cancer cases (N = 350) and controls (N = 371) frequency-matched by age and sex from two main referral hospitals in Kozhikode, Kerala, India, between 2008 and 2012. We collected information on childhood (0-16 years), early adulthood (17-30 years) and late adulthood (above 30 years) SEP and behavioural factors along the life span using interviews and a life-grid technique. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the association between life-course SEP and oral cancer risk using inverse probability weighted marginal structural models. RESULTS: Relative to an advantageous SEP in childhood and early adulthood, a disadvantageous SEP was associated with oral cancer risk [(OR = 2.76, 95% CI: 1.99, 3.81) and (OR = 1.84, 95% CI: 1.21, 2.79), respectively]. In addition, participants who were in a disadvantageous (vs advantageous) SEP during all three periods of life had an increased oral cancer risk (OR = 4.86, 95% CI: 2.61, 9.06). The childhood to early adulthood social mobility model and overall life-course trajectories indicated strong influence of exposure to disadvantageous SEP in childhood on the risk for oral cancer. CONCLUSIONS: Using novel approaches to existing methods, our study provides empirical evidence that disadvantageous childhood SEP is critical for oral cancer risk in this population from Kerala, India. PMID- 30004139 TI - Randomised clinical trial: Efficacy of strategies to provide oral hygiene activities to nursing home residents with dementia who resist mouth care. AB - OBJECTIVES: The purpose of this study was to test the efficacy of MOUTh (Managing Oral Hygiene Using Threat Reduction), a nonpharmacologic, relationship-based intervention vs. control on 2 primary outcomes for nursing home (NH) residents with dementia who resisted mouth care: (i) reduction in the occurrence and intensity of care-resistant behaviours (CRBs) and (ii) improvement in oral health. Two secondary outcomes were also examined: (i) the duration of mouth care and (ii) the completion of oral hygiene activities. BACKGROUND: Persons with dementia who exhibit CRBs are at risk for inadequate mouth care and subsequent systemic illnesses. MATERIALS AND METHODS: The study used a randomised repeated measures design. Recruitment occurred in 9 nursing homes that varied in size, ownership, reimbursement patterns and location. One hundred and one nursing home residents with dementia were randomised at the individual level to experimental (n = 55) or control groups (n = 46). One hundred participants provided data for the analyses. RESULTS: Compared to the control group, persons in the experimental group had twice the odds of allowing mouth care and completing oral hygiene activities; they also allowed longer duration of mouth care (d = 0.56), but showed only small reductions in the intensity of CRBs (d = 0.16) and small differential improvements in oral health (d = 0.18). CONCLUSION: The data suggest that this intervention facilitates mouth care among persons with dementia. The management of refusal behaviour may be a clinically more realistic approach than reducing or eradicating refusals. PMID- 30004140 TI - Capital jurors, mental illness, and the unreliability principle: Can capital jurors comprehend and account for evidence of mental illness? AB - Recent U.S. Supreme Court opinions have given rise to the question of whether persons suffering from a severe mental illness should be categorically exempt from the death penalty. This article presents a brief overview of relevant U.S. Supreme Court cases and the empirical evidence relevant to this question. We then present our findings on how actual capital jurors respond to and discuss engaging with evidence of mental illness, as drawn from in-depth interviews collected as part of the Capital Jury Project. Existing research reveals that in the controlled situation of an experiment, evidence of mental illness is associated with votes for life rather than death. Similarly, actual capital jurors in our study reported anticipating that evidence of mental illness would make them less likely to vote for death. However, those jurors who dealt with mental illness in their case appeared to be less sensitive: they describe such evidence as having been overshadowed by the brutality of the crime; as indicative of the defendant's future dangerousness; as being confusing, especially as presented by experts; and as a manipulative attempt on the part of the defendant to trick the jurors. The findings suggest that capital jurors cannot reliably comprehend and account for evidence of mental illness and thus offer a compelling reason for the Court to exempt those suffering from a mental illness from the death penalty. PMID- 30004141 TI - Comparing public concern and support for drone regulation to the current legal framework. AB - In this study we assess the extent to which the regulations governing the use of drones in the United States address the concerns held by the public they are meant to protect. In general, respondents were most supportive of those regulations that could be categorized as limiting one's exposure to an unwanted drone. The most popular policies were those that protected personal privacy, while the least popular were those that hampered drones used for public safety. The largest discrepancy was found to be respondents' preference for laws protecting personal privacy compared with the lack of regulatory constraints currently in place. Federal regulators have only begun to introduce regulations on how drones can be used in our national airspace, with additional regulations for other types and sizes of drones likely to be introduced in the future. The results of this study may be utilized by regulators and lawmakers to create a regulatory structure that effectively mitigates risk and supports the public interest. PMID- 30004142 TI - Genetic and clinical features of social cognition in 22q11.2 deletion syndrome. AB - 22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol-O methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior. PMID- 30004143 TI - Limits of monetization in protecting ecosystem services. AB - The monetary valuation of ecosystem services is gaining traction in policy and business communities. Several tools and decision-making processes have been proposed, including criteria to assess the appropriateness of using monetary valuation for biodiversity conservation outcomes. These criteria include measures such as scale, uniqueness, and threat. We used case studies of monetization projects for which the outcomes were measured to explore the limitations and application of these criteria. There was limited evidence of the effectiveness of such schemes. The majority of the schemes were established in areas where the criteria specifically excluded their use in isolation. Thus, although some aspects of monetization may be beneficial for biodiversity conservation, these schemes were not being used appropriately and require some quantitative minimum (or maximum) measurements to be applied through additional policy or governance measures to ensure biodiversity conservation outcomes. PMID- 30004144 TI - Natural variation in GmGBP1 promoter affects photoperiod control of flowering time and maturity in soybean. AB - The present study screened for polymorphisms in coding and non-coding regions of the GmGBP1 gene in 278 soybean accessions with variable maturity and growth habit characteristics under natural field conditions in three different latitudes in China. The results showed that the promoter region was highly diversified compared with the coding sequence of GmGBP1. Five polymorphisms and four haplotypes were closely related to soybean flowering time and maturity through association and linkage disequilibrium analyses. Varieties with the polymorphisms SNP_-796G, SNP_-770G, SNP_-307T, InDel_-242normal, SNP_353A, or haplotypes Hap-3 and Hap-4 showed earlier flowering time and maturity in different environments. The shorter growth period might be largely due to higher GmGBP1 expression levels in soybean that were caused by the TCT-motif with SNP_-796G in the promoter. In contrast, the lower expression level of GmGBP1 in soybean caused by RNAi interference of GmGBP1 resulted in a longer growth period under different day lengths. Furthermore, the gene interference of GmGBP1 also caused a reduction in photoperiod response sensitivity (PRS) before flowering in soybean. RNA-seq analysis on GmGBP1 underexpression in soybean showed that 94 and 30 predicted genes were significantly upregulated and downregulated, respectively. Of these, the diurnal photoperiod-specific expression pattern of three significant flowering time genes GmFT2a, GmFT5a, and GmFULc also showed constantly lower mRNA levels in GmGBP1-i soybean than in wild type, especially under short day conditions. Together, the results showed that GmGBP1 functioned as a positive regulator upstream of GmFT2a and GmFT5a to activate the expression of GmFULc to promote flowering on short days. PMID- 30004148 TI - Solitary fibrous tumor presenting on the scalp: a potential diagnostic pitfall. PMID- 30004147 TI - A novel synonymous variant in the F8 gene, p.(Leu40=)/c.120C>A, likely causes mild haemophilia A. PMID- 30004146 TI - beta-catenin regulates IRF3-mediated innate immune signalling in colorectal cancer. AB - OBJECTIVE: beta-catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage-associated molecular patterns (DAMPs) and primes the anti-tumour adaptive responses. While the function of beta-catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of beta catenin in inhibiting RIG-I-like receptor (RLR)-mediated IFN-beta signalling in colorectal cancer. MATERIALS AND METHODS: Immunohistochemical staining and western blotting were conducted to study the expression of beta-catenin, IRF3 and phospho-IRF3 (p-IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of beta-catenin on IFN beta signalling. The inhibition of beta-catenin on RLR-mediated IFN-beta signalling was further studied by real-time analyses and reporter assays in the context of lentiviral-mediated beta-catenin stably knocking down. Lastly, co immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between beta-catenin and IRF3. RESULTS: We found that high expression of beta-catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of beta-catenin increased the viral replication. Conversely knocking down of beta-catenin inhibited viral replication. Furthermore, our data demonstrated that beta-catenin could inhibit the expression of IFN-beta and interferon-stimulated gene 56 (ISG56). Mechanistically, we found that beta catenin interacted with IRF3 and blocked its nuclear translocation. CONCLUSION: Our study reveals an unprecedented role of beta-catenin in enabling innate immune evasion in CRC. PMID- 30004149 TI - Measuring emotional support in family networks: Adapting the Family Network Method for individuals with a mild intellectual disability. AB - BACKGROUND: Informal supportive networks of individuals with intellectual disability have become increasingly important. The aim of this paper is to describe how the Family Network Method - Intellectual Disability (FNM-ID) offers a way to gather the perspective of people with mild intellectual disability on their family support. METHOD: The FNM is designed to explore how individuals define their family contexts, and more specifically how they perceive existing supportive relationships in these contexts. RESULTS: By carefully piloting ways of questioning people with mild intellectual disability, systematic adaptations were made to the original FNM. Data obtained by the FNM-ID can be analysed using social network analysis. Thereby, the FNM-ID provides rich, theoretically significant information on emotional support in the family networks of individuals with mild intellectual disability. CONCLUSIONS: The FNM-ID is a useful and successfully adapted tool for other researchers and professionals to systematically explore the family support experiences of individuals with mild intellectual disability. PMID- 30004150 TI - Clinical and radiologic results after open-wedge high tibial osteotomy in haemophilic knee arthropathy with varus deformity. AB - INTRODUCTION: The previous studies have described only closed-wedge high tibial osteotomy (HTO) in haemophilic arthropathy (HA). AIM: The purpose of this study was to evaluate clinical and radiographic results after open-wedge HTO in HA with varus knee deformity. METHODS: We included 13 open-wedge HTOs in HA performed between 2005 and 2016. The mean age of patients was 28.9 years. Visual analogue scale (VAS), Western Ontario and McMaster Universities (WOMAC), and range of motion (ROM) indices were assessed. Any complications or requirements for total knee arthroplasty (TKA) were investigated. Mechanical axis (MA), minimal joint space width (mJSW) and Pettersson score were measured. Bone union rates at 3 and 6 months postoperative were evaluated. RESULTS: VAS improved from 5.1 to 2.4 (P < .001). WOMAC was 66.5 preoperatively, and 26.6 postoperatively (P < .001). Pre- and postoperative ROM did not differ significantly. There were no cases of HTO converted to TKA, but one case of HTO required TKA 152 months postoperative. No complications were observed. The MA was corrected from varus 5.1 degrees to valgus 1.2 degrees (P < .001). Pre- and postoperative mJSW did not significantly differ. Pettersson score improved from 3.84 to 2.47 (P < .001). The bone union rates at the osteotomy gap were 45.2% and 67.8% at 3 and 6 months postoperative. CONCLUSIONS: Open-wedge HTO should be considered in cases of HA with varus deformity in young haemophilic patients, even though inflammatory arthritis is not an optimal indication for this procedure. It can be an appropriate treatment with respect to the choice to postpone TKA. PMID- 30004152 TI - Corrigendum. PMID- 30004151 TI - Risk factors for cardiovascular disease in children and young adults with haemophilia. AB - INTRODUCTION: The origins of cardiovascular disease (CVD) begin in childhood. The primary objective of this cross-sectional cohort study was to determine the prevalence of cardiovascular risk factors in patients with congenital haemophilia A or B followed at Rady Children's Hospital San Diego Hemophilia and Thrombosis Treatment Center (HTC). We hypothesized that cardiovascular risk factors could be identified as part of a comprehensive clinic visit. MATERIALS AND METHODS: Standardized measurement of weight, height, waist circumference and blood pressure plus non-fasting glucose and lipid panel were performed. Participants and/or caregivers completed questionnaires about family history, medical history and lifestyle. Clinical data were abstracted from the medical record. Descriptive statistics, Student's t test, correlation, Mann-Whitney U test and chi-square test were performed to analyse the data. RESULTS: Forty-three males (mean 12 years, range 5-20 years) enrolled. High rates of overweight and obesity, (pre)hypertension and abnormal lipids were identified. Subjects with normal weight had more days of >60 minutes of physical activity compared with those with overweight or obesity (5.2 +/- 2.4 vs. 3.8 +/- 2.5 day; P = 0.07). Higher weight was correlated with higher factor consumption (cor = 0.88; P < 0.001). There was no difference in target joints based on weight category (30% in normal weight vs. 25% in overweight or obese, chi2 = 0.11, P = 0.74), which may be attributed to high rates of prophylaxis. CONCLUSIONS: Modifiable risk factors for CVD were identified as part of the study during comprehensive clinic visits. The HTC team may develop behavioural interventions to target cardiovascular risk reduction as part of the comprehensive care model. PMID- 30004153 TI - Performance of next-generation sequencing in the detection of large exon deletion in patients of haemophilia A. PMID- 30004154 TI - Desmopressin in non-severe haemophilia A: Test-response and clinical outcomes in a single Canadian centre review. AB - INTRODUCTION: Desmopressin is an effective haemostatic agent for patients with non-severe haemophilia A; however, response may differ between patients of similar severity. Responsiveness is classified based on various cut-off values for plasma levels of FVIII post-desmopressin administration. Patients may be classified differently depending on the values chosen. AIM: To classify desmopressin response in non-severe haemophilia A patients with respect to current test-response definitions. Also, to characterize relationships between test response and clinical outcome of desmopressin use. METHODS: Current desmopressin test-response definitions were obtained from the literature. We adopted peak FVIII level (at 1 hour post-administration) >=50 IU/dL and <20 IU/dL as complete and no response, respectively, thereby satisfying most reported definitions. Test-responses and clinical outcomes of use between 2007 and 2017 for adult mild/moderate haemophilia A patients were reviewed and correlated. RESULTS: All patients classified as complete responders (n = 31; peak FVIII >=50 IU/dL) and the majority of partial responders (n = 11; peak FVIII >=20 to <50 IU/dL) had good clinical outcomes after desmopressin use for a variety of bleeding episodes and procedures. Two non-responders (peak FVIII <20 IU/dL) given desmopressin for minor bleeding/procedures also had good clinical outcomes. One patient with a partial test-response (peak FVIII 23 IU/dL) required additional factor concentrate to achieve haemostasis. CONCLUSIONS: Based on our review, we suggest that the determination of desmopressin responsiveness should consider both the change in plasma FVIII levels as well as clinical outcomes associated with prior therapeutic use. PMID- 30004156 TI - Newly qualified Saudi nurses' ability to recognize the deteriorating child in hospital. AB - BACKGROUND: It is recognized that nurses' failure to recognize and respond promptly to deterioration in children's physiological status can result in increased morbidity and mortality. AIM: The aim of this study was to explore the ability of Saudi-educated, newly qualified nurses, working in paediatric wards, to recognize children's deterioration. METHODS: A pilot study was carried out to assess nurses' responses to three clinical vignettes (deteriorating child, improving child and ambiguous scenarios). The nurses' ability to make a correct identification was captured using a 'Think Aloud' approach and quantified using a visual analogue scale. RESULTS: Twenty-seven nurses in two geographical regions in Saudi Arabia participated. Only half the nurses (51.8%) correctly identified the deteriorating child vignette. Of those who could not, 37% were unsure and 11% responded incorrectly. No nurses correctly identified all three vignettes, and four nurses (15%) responded incorrectly to all vignettes. CONCLUSIONS: The recognition of the deteriorating child is complex, and even in non-stressful simulated scenarios using vignettes, many newly qualified nurses working with children failed to recognize clear signs of deterioration. A focused (culturally specific) educational intervention is being developed to target this, taking into account Saudi nurses' perceived education and training needs. RELEVANCE TO CLINICAL PRACTICE: Newly qualified nurses working in paediatric wards frequently find it difficult to identify the deteriorating child. PMID- 30004155 TI - Targeting mitochondria by anthelmintic drug atovaquone sensitizes renal cell carcinoma to chemotherapy and immunotherapy. AB - Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA-approved antibiotic but is also known as a mitochondrial inhibitor. We found that atovaquone inhibited proliferation and induced apoptosis of RCC cells. Mechanistically, atovaquone inhibits mitochondrial respiration in a concentration-dependent and time-dependent manner, via targeting mitochondrial respiratory complex III. Although increased glycolysis was observed in atovaquone-treated cells, atovaquone decreased ATP levels. As a consequence of mitochondrial respiration inhibition, reactive oxygen species levels were increased by atovaquone. The complete rescue of atovaquone's effects by an antioxidant suggests the important role of oxidative stress in the action of atovaquone in RCC. Importantly, atovaquone enhanced the in vitro and in vivo efficacy of 5-fluorouracil (5-FU) and interferon-alpha (IFN-alpha). Our preclinical findings suggest that atovaquone is a useful addition for RCC treatment. Our work also further demonstrates that RCC is more dependent on mitochondrial respiration than glycolysis. PMID- 30004158 TI - Vision for the Future. PMID- 30004159 TI - Distinguishing lupus anticoagulants from factor VIII inhibitors in haemophilic and non-haemophilic patients. AB - INTRODUCTION: Accurate diagnosis of an inhibitor, a neutralizing antibody to infused factor VIII (FVIII), is essential for appropriate management of haemophilia A (HA). Low-titre inhibitors may be difficult to diagnose due to high rates of false-positive inhibitor results in that range. Transient low-titre inhibitors and false-positive inhibitors may be due to the presence of a lupus anticoagulant (LA) or other non-specific antibodies. Fluorescence immunoassay (FLI) to detect antibodies to FVIII is a sensitive method to identify inhibitors in HA. Evaluations of antibody profiles by various groups have demonstrated that haemophilic inhibitors detected by Nijmegen-Bethesda (NBA) and chromogenic Bethesda (CBA) assays correlate with positivity for anti-FVIII immunoglobulin (Ig) G1 and G4. AIM: This study sought to determine whether FLI could distinguish false-positive FVIII inhibitor results related to LAs from clinically relevant FVIII inhibitors in HA patients. METHODS: Samples from haemophilic and non haemophilic subjects were tested for LA, specific FVIII inhibitors by NBA and CBA, and anti-FVIII immunoglobulin profiles by FLI. RESULTS: No samples from LA positive non-haemophilic subjects were positive by FLI for anti-FVIII IgG4. Conversely, 91% of NBA-positive samples from haemophilia subjects were positive for anti-FVIII IgG4. Two of 11 haemophilia subjects had samples negative for anti FVIII IgG4 and CBA, which likely represented LA rather than FVIII inhibitor presence. CONCLUSIONS: Assessment of anti-FVIII profiles along with the CBA may be useful to distinguish a clinically relevant low-titre FVIII inhibitor from a transient LA in HA patients. PMID- 30004160 TI - Successful immune tolerance in a young female with inhibitor and severe haemophilia A due to a complex genetic rearrangement. PMID- 30004161 TI - Central command in heart failure: was there effect of hemispheric lateralization in insular cortex activation? Reply. PMID- 30004162 TI - Chiral Crystal Packing Induces Enhancement of Vibrational Circular Dichroism. AB - We demonstrate that molecular vibrations with originally low or zero intensity in a vibrational circular dichroism (VCD) spectrum attain chirality in molecular crystals by coordinated motion of the atoms. Ab initio molecular dynamics simulations of anharmonic solid-state VCD spectra of l-alanine crystals reveal how coherent vibrational modes exploit the space group's chirality, leading to non-local, enhanced VCD features, most significantly in the carbonyl region of the spectrum. The VCD-enhanced signal is ascribed to a helical arrangement of the oscillators in the crystal layers. No structural irregularities need to be considered to explain the amplification, but a crucial point lies in the polarization of charge, which requires an accurate description of the electronic structure. Delivering a quantitative atomic conception of supramolecular chirality induction, our ab initio scheme is applicable well beyond molecular crystals, for example, to address VCD in proteins and related compounds. PMID- 30004163 TI - Terminal Alkyne Coupling Reactions through a Ring: Mechanistic Insights and Regiochemical Switching. AB - The mechanism and selectivity of terminal alkyne coupling reactions promoted by rhodium(I) complexes of NHC-based CNC pincer ligands have been investigated. Synthetic and kinetic experiments support E- and gem-enyne formation through a common reaction sequence involving hydrometallation and rate-determining C-C bond reductive elimination. The latter is significantly affected by the ligand topology: Employment of a macrocyclic variant enforced exclusive head-to-head coupling, contrasting the high selectivity for head-to-tail coupling observed for the corresponding acyclic pincer ligand. PMID- 30004164 TI - [Varieties and Mechanisms of Synergistic Factors Enhancing Baculovirus Infectivity]. AB - Baculoviruses are a diverse group of viruses with double-stranded circular DNA genomes. They have certain advantageous properties for biotechnology applications, including high host specificity and environmental friendliness.Baculoviruses could play more important roles in sustainable agriculture as potential microbial insecticides. However, the popularization and application of baculovirus-based insecticides were seriously restricted due to deficiencies such as low virulence and slow rates of action. The infectivity of baculoviruses can be improved by synergistic factors. The present review summarizes characteristics of seven types of synergistic factors including baculovirus enhancin, entomopoxvirus fusolin and calcofluor. The mechanisms of these seven synergistic factors were analyzed. The information presented in this review can serve as a reference to aid in the development and application of baculovirus-based insecticides. PMID- 30004165 TI - Total Synthesis and Structural Revision of the Antibiotic Tetrapeptide GE81112A. AB - The total synthesis of the naturally occurring antibiotic GE81112A, a densely functionalized tetrapeptide, is reported. Comparison of spectral data with those of the natural product and the lack of biological activity of the synthesized compound led us to revise the published configuration of the 3-hydroxypipecolic acid moiety. This hypothesis was fully validated by the synthesis of the corresponding epimer. PMID- 30004167 TI - Smart Materials. PMID- 30004166 TI - Enacting person-centredness in integrated care: A qualitative study of practice and perspectives within multidisciplinary groups in the care of older people. AB - BACKGROUND: Person-centredness is important in delivering care for long-term conditions. New models of care aim to co-ordinate care through integration of health and social care which require new ways of working, often remotely from the patient. OBJECTIVE: To describe how person-centred care is enacted within multidisciplinary groups (MDGs) created as part of a new service, integrating health and social care for older people. METHODS: We followed the implementation of eight neighbourhood MDGs, observing and interviewing staff from three MDGs at different phases of programme implementation using semi-structured topic guides. RESULTS: Thirty-four MDG meetings were observed and 32 staff interviewed. Three core themes were identified which impacted on enactment of person-centred care: the structural context of MDGs enabling person-centred care; interaction of staff and knowledge sharing during the MDG meetings; and direct staff involvement of the person outside the MDG discussion. CONCLUSIONS: This study provides new insights into attempts to enact person-centred care within a new model of service delivery. Teams did what they could to enact person-centred care in the absence of the "real" patient within MDG meetings. They were successful in delivering and co-ordinating some aspects of care (eg prompting medication reviews, referring to social worker, health improvement and arranging further multidisciplinary team meetings for complex cases). This "absence of patients" and time pressures within the MDGs led to reliance on the "virtual" record, enhanced by additional "soft" knowledge provided by staff, rather than ensuring the patient's voice was included. PMID- 30004168 TI - One-step Construction of the Shape Persistent, Chiral But Symmetrical Polyimine Macrocycles. AB - A unique combination of structural flexibility, shape persistency and functionality, makes macrocycles and molecular cages as essential molecular entities that have displayed applications that go beyond chemistry. Among macrocycles, the selectively obtained symmetrical (poly)cyclic polyimines have shown great utility in the design of molecules varied in shape and properties. The reversible and thermodynamically controlled cycloimination reaction is governed by configurational and conformational constraints imposed on the intermediate products, ensures a sufficiently high level of preorganization. The high geometrical control over the macrocycle structure has profound effect on their assembly mode. In this Account, we were interested in showing how the structure of small building blocks affects the structure of macrocyclic product and further, how influenced the association mode of the given macromolecule. The latter is of primarily importance in supramolecular and in material chemistry. PMID- 30004169 TI - Upregulation of miR-874-3p and miR-874-5p inhibits epithelial ovarian cancer malignancy via SIK2. AB - Based on miR-874 expression levels in the GSE47841 microarray, we hypothesized that the mature products of miR-874, miR-874-3p, or miR-874-5p, would inhibit epithelial ovarian cancer (EOC) cell proliferation, metastasis, and chemoresistance. We first examined miR-874-3p and miR-874-5p expression levels in primary EOC tumor tissue samples and found that they were significantly decreased. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell proliferation and transwell assays revealed that miR-874-3p and miR-874-5p significantly inhibit EOC cell proliferation, migration, and invasion. Then, using MTT and soft agar assays of paclitaxel-treated Caov3 and SKOV3 cells transfected with miR-874-3p and miR-874-5p, we found that miR-874-3p and miR-874 5p enhance EOC cell chemosensitivity. We then confirmed that serine/threonine protein kinase 2 (SIK2) was a target gene of miR-874-3p and miR-874-5p. Overall, the results of this study indicate that SIK2 expression can serve as a prognostic biomarker for EOC and that miR-874-3p and miR-874-5p have the potential to enhance clinical treatment of EOC. PMID- 30004170 TI - omega-Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase. AB - Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library of omega-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5 bis(trifluoromethyl)phenyl group and the aromatic character of the omega phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3 dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4 (1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (Ki ) of 1 19 MUm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases-monoacylglycerol lipase and fatty acid amide hydrolase-were inhibited by omega-phthalimidoalkyl aryl ureas to a lesser extent. PMID- 30004171 TI - Surgical management of haemorrhoids: an Italian survey of over 32 000 patients over 17 years. AB - AIM: The management of haemorrhoids has changed significantly in the last two decades as a result of new insights into their pathophysiology and the availability of new surgical devices. The aim of this survey was to evaluate changes in the management of haemorrhoids in Italy over the last 17 years. METHOD: An electronic database which recorded details of management relating to the severity of haemorrhoids between 2000 and 2016 was obtained from 18 of 34 colorectal surgeons who were invited to participate. RESULTS: A total of 32 458 patients were treated for haemorrhoids by 18 expert coloproctologists during a 17 year period. Patients were classified as Grade II (7542, 23.2%), Grade III(15 360, 47.3%) and Grade IV (9556, 29.4%). Grade II haemorrhoids were treated with rubber band ligation in over 90% of the cases, and patients with Grade IV had a Milligan-Morgan (MM) haemorrhoidectomy in over 90% of the cases. In Grade III, the use of stapled haemorrhoidopexy progressively decreased from 30% to 35% (between 2000 and 2007) to 5% of the cases. Meanwhile, commencing from 2006 the use of Doppler-guided haemorrhoid artery ligation (DGHAL) with mucopexy increased progressively from 6% to 24%. Over the years, the percentage of MM haemorrhoidectomy remained consistent at between 65% and 70% of the cases. CONCLUSION: Relevant changes in the surgical choice of haemorrhoid treatment have occurred in Italy over the last 17 years. MM haemorrhoidectomy remains the most frequently performed procedure for Grade III haemorrhoids. Stapled haemorrhoidopexy has become much less popular in contrast to DGHAL with mucopexy which is being performed much more frequently. PMID- 30004172 TI - The preliminary effects of laughter therapy on loneliness and death anxiety among older adults living in nursing homes: A nonrandomised pilot study. AB - OBJECTIVES: This study evaluated the preliminary effect of laughter therapy on the level of loneliness and death anxiety of older adults. METHODS: This was a quasi-experimental study with a nonequivalent control group pretest-posttest design. The study participants were older adults living in two nursing homes set up by foundations located in the capital of Turkey. A total of 50 older adults formed the intervention group (n = 20) and control group (n = 30). The intervention group received laughter therapy twice a week for 5 weeks. The control group received no intervention. Data were collected using a socio demographic form, the De Jong Gierveld Loneliness Scale (DJGLS) and the Turkish Death Anxiety Scale (TDAS). RESULTS: After laughter therapy, the DJGLS total and subscale (emotional and social loneliness) scores decreased among older adults in the intervention group (p < 0.005). While there were no significant differences for overall TDAS, death uncertainty and pain subscales scores between the intervention and control group after laughter therapy, there was a significant decrease in TDAS exposure subscale scores of the intervention group (p < 0.005). DISCUSSION: The results suggest that laughter therapy can be used to decrease levels of loneliness and death anxiety among older adults living in nursing homes. IMPLICATIONS FOR PRACTICE: Anxiety regarding death and loneliness are important issues that affect quality of life in older adults. This first pilot study demonstrates the beneficial effects of laughter therapy on loneliness and death anxiety in nursing home residents. Nurses can incorporate laughter therapy into routine programmes in nursing homes. PMID- 30004173 TI - Construction of a novel turn-on-off fluorescence sensor used for highly selective detection of thiamine via its quenching effect on o-phen-Zn2+ complex. AB - In this work, a simple and selective fluorescence sensor approach called 'turn-on off' for the determination of thiamine (TM) has been developed. As known, the o phenanthroline (o-phen) has inner fluorescence, though when reacted with zinc ions to form the o-phen-Zn2+ complex the fluorescence intensity was enhanced effectively, while upon addition of TM into the o-phen-Zn2+ complex solution, the intensity of the system was gently quenched, which was termed the 'turn-on-off' probe. Notably, the method possessed highly selective, sensitive determination for TM with a detection limit of 0.25 MUmol L-1 and the reduced fluorescence intensity was proportional to the concentration of TM in the range 0.84-80.0 MUmol L-1 . Besides, the proposed mechanism was also investigated through exploring the Fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR) spectroscopy. Furthermore, this manner was successfully applied into practical samples for TM detection with satisfactory results. PMID- 30004174 TI - Less than one-third of hip fracture patients return to their prefracture level of instrumental activities of daily living in a prospective cohort study of 480 patients. AB - AIM: A significant loss of instrumental activities of daily living (IADL) after a hip fracture has been reported. The aim of the present study was to identify specific predictors for low IADL after a hip fracture, in order to target better postoperative care for these patients. METHODS: A prospective observational cohort study of 480 hip fracture patients was carried out. IADL was measured at baseline, and after 3 and 12 months using the Groningen Activity Restriction Scale. Multivariable logistic regression analysis was carried out using age, sex, American Society of Anesthesiologists classification, prefracture living with a partner, prefracture living situation, prefracture use of walking aids, type of fracture, type of anesthesia, length of hospital stay, postoperative complications and prefracture IADL as potential predictors for low IADL after a hip fracture. The correlation between IADL, mobility and living situation, both at admission, and 3 and 12 months postoperatively, were measured. RESULTS: Three months after hip fracture treatment, 24% of patients returned to their baseline IADL level, at 12 months postoperative this was 29%. Factors associated with a larger loss in IADL after a hip fracture were older age, prefracture living with a partner, prefracture living at home, prefracture use of walking aids and longer length of hospital stay. The correlation between IADL and living situation was 0.69, and between IADL and use of walking aids was 0.80. CONCLUSIONS: A return to prefracture IADL level was low. Healthier patients have a steeper decline in postoperative IADL. Geriatr Gerontol Int 2018; 18: 1244-1248. PMID- 30004176 TI - Comparison of 48-week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor-sparing regimens: a systematic review and network meta-analysis. AB - OBJECTIVES: To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens with tenofovir alafenamide (TAF)-based combinations in HIV-1-infected adults, we performed a network meta-analysis (NMA) to provide estimates of relative efficacy for these two regimens. METHODS: A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI-sparing regimens. A Bayesian random-effect model was used to compare virological suppression rates at 48 weeks for NRTI-sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF). RESULTS: Twenty-three studies in treatment-naive patients identified by the SLR were included in the NMA, including four studies assessing NRTI-sparing regimens. In treatment-naive patients, the probability of achieving virological suppression at 48 weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI-sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r) + raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naive patients with viral load < 100 000 HIV-1 RNA copies/mL, a credible difference was found between NRTI sparing treatments and E/C/F/TAF. Studies in treatment-experienced patients were too heterogeneous to allow for an NMA. CONCLUSIONS: The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naive patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naive HIV-infected patients. PMID- 30004177 TI - The Influence of Carbosilane Nanosegregation on the Dynamics in 'de Vries-type' Liquid Crystals. AB - The mesogens QL32-6, QL33-6 and QL-34-6 contain 5-phenylpyrimidine cores and terminal nanosegregating carbosilane end groups of different lengths and are known to exhibit 'de Vries-type' properties of varying strength. We report a systematic study of the influence of the nanosegregating sublayer on the dynamics and rotational viscosities of the collective modes in the smectic A* (SmA*) and smectic C* (SmC*) phase using dielectric spectroscopy. It was found that the dynamics of the Goldstone mode corresponding to phase angle fluctuations are almost not affected while the relaxation time and rotational viscosity of the soft mode are influenced by the degree of nanosegregation. In other words, the nanosegregating sublayer does not influence the dynamics of ferroelectric switching in the SmC* phase, but is critical in inducing 'de Vries-type' properties. PMID- 30004175 TI - Glycation of the Major Milk Allergen beta-Lactoglobulin Changes Its Allergenicity by Alterations in Cellular Uptake and Degradation. AB - SCOPE: During food processing, the Maillard reaction (MR) may occur, resulting in the formation of glycated proteins. Glycated proteins are of particular importance in food allergies because glycation may influence interactions with the immune system. This study compared native and extensively glycated milk allergen beta-lactoglobulin (BLG), in their interactions with cells crucially involved in allergy. METHODS AND RESULTS: BLG was glycated in MR and characterized. Native and glycated BLG were tested in experiments of epithelial transport, uptake and degradation by DCs, T-cell cytokine responses, and basophil cell degranulation using ELISA and flow cytometry. Glycation of BLG induced partial unfolding and reduced its intestinal epithelial transfer over a Caco-2 monolayer. Uptake of glycated BLG by bone marrow-derived dendritic cells (BMDC) was increased, although both BLG forms entered BMDC via the same mechanism, receptor-mediated endocytosis. Once inside the BMDC, glycated BLG was degraded faster, which might have led to observed lower cytokine production in BMDC/CD4+ T cells coculture. Finally, glycated BLG was less efficient in induction of degranulation of BLG-specific IgE sensitized basophil cells. CONCLUSIONS: This study suggests that glycation of BLG by MR significantly alters its fate in processes involved in immunogenicity and allergenicity, pointing out the importance of food processing in food allergy. PMID- 30004178 TI - Association between asthma and migraine: A cross-sectional study of over 110 000 adolescents. AB - BACKGROUND: Epidemiological studies have reported an association between asthma and migraine, mainly in adults. OBJECTIVE: To examine the association between specialist-diagnosed asthma and migraine among adolescents. METHODS: The electronic database of a recruitment center was retrospectively searched for all 17-year-old draftees during the years 1987-2010. Diagnoses of asthma and migraine were made by certified specialists. The prevalence of migraine was compared among draftees with and without asthma. Covariate data on socio-demographics and associated medical conditions were recorded. RESULTS: A total of 113 671 adolescents were available for analysis. Asthma was diagnosed among 4.0% and migraine among 1.9%. Migraine was significantly more prevalent among adolescents with asthma [174 of the 4581 subjects (3.8%)] compared to those without asthma [1946 of the 109 090 (1.8%)] [OR = 2.17 (95% CI 1.86-2.55; P < 0.001)]. Rates of migraine among subjects with and without allergic rhinitis were 6.3% and 1.7%, respectively [OR = 4.04 (95% CI 3.58-4.56; P < 0.001)]. On multivariate analysis, there was a significant association between migraine and both asthma [OR = 1.42 (95% CI 1.19-1.68)] and allergic rhinitis [OR = 3.18 (95% CI 2.80-3.63)]. Other factors significantly associated with migraine were female gender, urban area of residence, recent immigration to Israel, having three or fewer siblings, and abnormal body mass index. CONCLUSION: Clinicians should be aware that asthma and allergic rhinitis are potential risk factors for migraine in adolescents. A combined finding of these conditions and recurrent headache is highly suggestive of migraine and warrants a different diagnosis and treatment approach from sinusitis. PMID- 30004179 TI - Nutritional intake is associated with activities of daily living and complications in older inpatients with stroke. AB - AIM: There is no consensus on energy intake in the acute stage and how it relates to improvement in activities of daily living (ADL) in geriatric stroke patients. We examined whether energy intake after admission is related to improvement in ADL and complications. METHODS: This retrospective cohort study evaluated the data from stroke inpatients at five acute care hospitals, including the mean daily energy intake during the first week after admission. Patients were categorized into two groups based on their daily energy intake; cases where the energy intake per day reached the basal energy expenditure calculated by the Harris-Benedict equation were designated as the intake energy sufficiency group. Patient characteristics were compared between groups. We assessed ADL using the Functional Independence Measure; a secondary outcome was the presence of complications. RESULTS: Of the 192 participants (mean age 79.6 +/- 7.6 years) included in the study, 131 patients were admitted for cerebral infarction, 58 for intracerebral hemorrhage and three for subarachnoid hemorrhage. Of the two groups, that with an energy sufficiency had a greater gain in total Functional Independence Measure (median 27 and 9, respectively; P = 0.001) and a lower complication rate (6.7% and 26.5%, respectively; P <= 0.001). Multivariate analyses showed that energy sufficiency was independently associated with the total Functional Independence Measure gain and complication rate. CONCLUSIONS: Energy intake during the first week after admission affected improvement of ADL and onset of complications during hospitalization in geriatric stroke inpatients. Geriatr Gerontol Int 2018; 18: 1334-1339. PMID- 30004180 TI - The role of brain biopsy in the clinical management of HIV-related focal brain lesions. AB - OBJECTIVES: Up to 20% of HIV-related focal brain lesion (FBL) diagnoses cannot be determined without invasive procedures. In such cases, brain biopsy is an important step in the evaluation algorithm. The aims of this study were to describe the clinical outcomes of patients with FBL, the proportion of diagnoses confirmed by brain biopsies and their aetiologies, and to analyse the proportion of patients in whom the biopsy motivated a change in therapeutic management. METHODS: A retrospective cohort study was performed. The data from clinical records of patients with HIV-related FBL admitted between January 2005 and December 2015 were reviewed. RESULTS: A total of 137 patients were included in the study. The median age was 39 years [interquartile range (IQR) 33-44.5 years]. The median CD4 count was 54 cells/MUL (IQR 21-124 cells/MUL). Cerebral brain biopsy was performed in 21.16% of patients (29 of 137); 68.9% of these individuals (20 of 29) were diagnosed by histology, with results of central nervous system (CNS) lymphoma in 20.6% (six of 29), progressive multifocal leucoencephalopathy in 6.8% (two of 29), toxoplasmosis in 6.8% (two of 29), tuberculoma in 6.8% (two of 29), and other diagnoses in 27.6% (eight of 29). In nine patients, the histology was nonspecific. In 75.8% of patients (22 of 29), the result of the biopsy led to a change in the therapeutic management. We did not observe higher rates of mortality related to the procedure. Overall mortality at 30 and 90 days was similar in patients who were and were not biopsied. CONCLUSIONS: In this retrospective cohort study, cerebral biopsy was associated with significant adjustments in therapeutic management for a high percentage of patients. PMID- 30004181 TI - SEPT7-mediated regulation of Ca2+ entry through Orai channels requires other septin subunits. AB - Orai channels are plasma membrane resident Ca2+ channels that allow extracellular Ca2+ uptake after depletion of ER-Ca2+ stores by a process called store-operated Ca2+ entry (SOCE). Septins of the SEPT2 subgroup act as positive regulators of SOCE in human nonexcitable cells. SEPT2 subgroup septins form the central core of hetero-hexameric or hetero-octameric complexes with SEPT6, SEPT7 and SEPT9 subgroup septins. The presence of fewer septin encoding genes coupled with ease of genetic manipulation allows for better understanding of septin subgroup function in Drosophila. Our earlier findings show that although dSEPT7 reduction does not alter Orai-mediated Ca2+ entry during SOCE, it results in constitutive activation of Orai channels in resting neurons. Here, we have investigated the role of other septin subgroup members in regulating Orai channel activation in Drosophila neurons by both cellular and functional assays. We show that dSEPT1, a SEPT2 subgroup septin can exist in a complex with dSEPT2 and dSEPT7 in the central nervous system (CNS) of Drosophila. Our findings suggest that the nature of septin filaments and heteromers obtained after reducing septins of different subgroups alters their ability to regulate Orai channel opening. The molecular mechanisms underlying this complex regulation of Orai function by septins require further cellular investigations. PMID- 30004182 TI - Prognostic significance of nomograms integrating IL-37 expression, neutrophil level, and MMR status in patients with colorectal cancer. AB - Interleukin (IL)-37 and neutrophils are considered to be involved in human cancer, but their prognostic significance in colorectal cancer (CRC) has not been elucidated. The aim of this study was to evaluate the prognostic value of IL-37 expression and neutrophil levels in CRC. We retrospectively analyzed IL-37 expression, CD66b+ neutrophil levels, and mismatch repair (MMR) status in 337 paraffin-embedded CRC specimens from the training cohort by immunohistochemistry. Their prognostic values were assessed using Kaplan-Meier curves and multivariate Cox regression models. Moreover, several risk factors were used to form nomograms to evaluate survival, and the performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. Further validation was performed in an independent cohort of 245 cases. Low IL-37 expression and high CD66b+ neutrophil levels were significantly associated with diminished disease-free survival (DFS) and overall survival (OS), and patients with MMR-deficient CRC had better clinical outcomes. Furthermore, multivariate Cox analysis identified IL-37, CD66b+ neutrophils, and MMR status as independent prognostic factors for DFS and OS. Two nomograms integrating the three markers with four clinicopathological risk factors were developed and validated for predicting DFS and OS with good calibration and discrimination (C-index: training cohort, 0.798 (95% confidence interval:0.764-0.832) and 0.828 (0.796-0.860), respectively; validation cohort, 0.739 (0.696-0.783) and 0.761 (0.715-0.808), respectively). Decision curve analysis demonstrated that the nomograms were clinically useful. Intratumoral IL-37, CD66b+ neutrophils, and MMR status were independent prognostic factors for CRC patients. Nomograms incorporating these biomarkers and clinicopathological features could be conveniently used to facilitate the individualized prediction of DFS and OS. PMID- 30004183 TI - Factors associated with dental fractures in Brazilian individuals. AB - AIM: The aim of the present study was to assess the association of sex, age, group of teeth, and type of accident (exposure) with dental fractures (outcome: enamel-dentine fracture without [EDF] or with pulp exposure [EDPF] and root fracture RF]). METHODS: In total, 1046 patients were selected. Logistic binary regression was used. RESULTS: The findings showed that EDF has less change of affecting individuals <=9 years of age than >=40 years of age (odds ratio [OR]: 0.58, 95% confidence interval [CI]: 0.35-0.95). Violence (OR: 3.07, 95% CI: 1.77 5.31), traffic accidents (OR: 1.50, 95% CI: 1.05-2.13), and sporting accidents (OR: 1.70, 95% CI: 1.19-2.44)] were associated with EDF. Regarding EDPF, the mandibular lateral incisors had a 10 times higher chance of being injured than canines and posterior teeth (OR: 10.43, 95% CI: 1.74-62.4). Those aged <=9 years (OR: 0.21, 95% CI: 0.07-0.58) and 10-19 years (OR: 0.38, 95% CI: 0.17-0.88) had a significantly lower chance of being affected by RF. CONCLUSION: EDF and RF are associated with individuals >=40 years of age; violence and traffic and sporting accidents are also associated with EDF, and mandibular incisors have a greater chance of being affected by EDPF. PMID- 30004184 TI - Biodiversity monitoring, earth observations and the ecology of scale. AB - Human activity and land-use change are dramatically altering the sizes, geographical distributions and functioning of biological populations worldwide, with tremendous consequences for human well-being. Yet our ability to measure, monitor and forecast biodiversity change - crucial to addressing it - remains limited. Biodiversity monitoring systems are being developed to improve this capacity by deriving metrics of change from an array of in situ data (e.g. field plots or species occurrence records) and Earth observations (EO; e.g. satellite or airborne imagery). However, there are few ecologically based frameworks for integrating these data into meaningful metrics of biodiversity change. Here, I describe how concepts of pattern and scale in ecology could be used to design such a framework. I review three core topics: the role of scale in measuring and modelling biodiversity patterns with EO, scale-dependent challenges linking in situ and EO data and opportunities to apply concepts of pattern and scale to EO to improve biodiversity mapping. From this analysis emerges an actionable approach for measuring, monitoring and forecasting biodiversity change, highlighting key opportunities to establish EO as the backbone of global-scale, science-driven conservation. PMID- 30004185 TI - Addressing Unmet Clinical Needs with 3D Printing Technologies. AB - Recent advances in 3D printing have enabled the creation of novel 3D constructs and devices with an unprecedented level of complexity, properties, and functionalities. In contrast to manufacturing techniques developed for mass production, 3D printing encompasses a broad class of fabrication technologies that can enable 1) the creation of highly customized and optimized 3D physical architectures from digital designs; 2) the synergistic integration of properties and functionalities of distinct classes of materials to create novel hybrid devices; and 3) a biocompatible fabrication approach that facilitates the creation and cointegration of biological constructs and systems. This progress report describes how these capabilities can potentially address a myriad of unmet clinical needs. First, the creation of 3D-printed prosthetics to regain lost functionalities by providing structural support for skeletal and tubular organs is highlighted. Second, novel drug delivery strategies aided by 3D-printed devices are described. Third, the advancement of medical research heralded by 3D printed tissue/organ-on-chips systems is discussed. Fourth, the developments of 3D-printed tissue and organ regeneration are explored. Finally, the potential for seamless integration of engineered organs with active devices by leveraging the versatility of multimaterial 3D printing is envisioned. PMID- 30004187 TI - Analog mental representation. AB - Over the past 50 years, philosophers and psychologists have perennially argued for the existence of analog mental representations of one type or another. This study critically reviews a number of these arguments as they pertain to three different types of mental representation: perceptual representations, imagery representations, and numerosity representations. Along the way, careful consideration is given to the meaning of "analog" presupposed by these arguments for analog mental representation, and to open avenues for future research. This article is categorized under: Philosophy > Foundations of Cognitive Science Philosophy > Representation Philosophy > Psychological Capacities. PMID- 30004186 TI - Adaptation to poststroke visual field loss: A systematic review. AB - AIM: To provide a systematic overview of the factors that influence how a person adapts to visual field loss following stroke. METHOD: A systematic review was undertaken (data search period 1861-2016) inclusive of systematic reviews, randomized controlled trials, controlled trials, cohort studies, observational studies, and case controlled studies. Studies including adult subjects with hemifield visual field loss, which occured as a direct consequence of stroke, were included. Search terms included a range of MESH terms as well as alternative terms relating to stroke, visual field loss, visual functions, visual perception, and adaptation. Articles were selected by two authors independently, and data were extracted by one author, being verified by the second. All included articles were assessed for risk of bias and quality using checklists appropriate to the study design. RESULTS: Forty-seven articles (2,900 participants) were included in the overall review, categorized into two sections. Section one included seventeen studies where the reviewers were able to identify a factor they considered as likely to be important for the process of adaptation to poststroke visual field loss. Section two included thirty studies detailing interventions for visual field loss that the reviewers deemed likely to have an influence on the adaptation process. There were no studies identified which specifically investigated and summarized the factors that influence how a person adapts to visual field loss following stroke. CONCLUSION: There is a substantial amount of evidence that patients can be supported to compensate and adapt to visual field loss following stroke using a range of strategies and methods. However, this systematic review highlights the fact that many unanswered questions in the area of adaptation to visual field loss remain. Further research is required on strategies and methods to improve adaptation to aid clinicians in supporting these patients along their rehabilitation journey. PMID- 30004188 TI - Association Between Knee Load and Pain: Within-Patient, Between-Knees, Case Control Study in Patients with Knee Osteoarthritis. AB - OBJECTIVE: The association between knee loading and pain in patients with knee osteoarthritis (OA) is reported to be low and of questionable importance, but may be confounded by several factors that differ between patients. We aimed to elucidate the association between dynamic knee load and pain by minimizing confounding using a within-patient, between-knees study design. METHODS: 265 patients with knees discordant for pain (530 knees) rated the pain in each knee before and after walking 6 minutes, then underwent three-dimensional gait analysis. RESULTS: The peak knee adduction moment and knee adduction impulse (proxies for medial knee loading) were associated with increased pain (odds ratio 2.43, 95% confidence interval 1.77 to 3.33; and 6.62, 3.46 to 12.7, respectively) and remained significant after controlling for radiographic disease severity. When split into quartiles, knees in the highest loading quartile had 4.7 (2.3 to 9.5; peak adduction moment) and 9.0 (4.0 to 20.1; knee adduction impulse) times greater odds of experiencing increased pain with walking compared to knees in the lowest loading quartile. CONCLUSION: When between-patient confounding is minimized, there is a strong association between medial knee load and increased knee pain during walking. This article is protected by copyright. All rights reserved. PMID- 30004189 TI - Barriers and facilitators of vigorous cardiorespiratory training in axial Spondyloarthritis: Surveys among patients, physiotherapists, rheumatologists. AB - OBJECTIVE: Vigorous cardio-respiratory training (vCRT) in patients with axial Spondyloarthritis (axSpA) is effective, safe and feasible, however not yet adopted in axSpA exercise programmes. We therefore aimed to explore the barriers and facilitators for vCRT among patients, physiotherapists (PTs) and rheumatologists. METHODS: "Stakeholder-specific surveys examined perceptions of barriers and facilitators to vCRT organized under categories identified by Grol & Wensing. Respondents chose the 3 most important barrier and facilitator categories and rated individual items on a 4-point scale. Frequencies and proportions were calculated; ratings between active and inactive patients were compared." RESULTS: Patients (n= 575, response rate 34%): the top-3 barrier categories included 'low motivation' (n=317=/59%),' unsuccessful timing in daily routine' (n=292/55%) and 'hindering disease symptoms' (n=272/51%). The top-3 facilitator categories were 'high motivation' (n=248/47%), 'good organisational conditions' (n=217/41%), 'facilitating disease symptoms' (n=209/40%). More inactive than active patients chose 'low motivation' as barrier (p=0.01). PTs (n= 40, response rate 48%): The top-3 barrier categories included 'heterogeneous group composition' (n=26/70%), 'difficult organisational conditions' (n=19/51%) and 'low motivation' (n=19/51%). The PTs' top-3 facilitator categories were 'knowledge' (n=20/54%), 'homogeneous group composition' and 'high perceived motivation' (both n=17/46%). Rheumatologists (n=73, response rate 17%; with 54 (74%) answering barrier items and 68 (93%) answering facilitator items): Strongest barriers included 'not enough information' (n=25/47%) and 'anticipated /perceived disinterest of patient (n=27/50%). Strongest facilitators included 'exercise important topic even in limited consultation time' (n=65/96%) and 'clear evidence for effectiveness of flexibility exercises' (n=62/91%). CONCLUSION: The identified facilitators and barriers will guide the development of stakeholder-specific implementation strategies. This article is protected by copyright. All rights reserved. PMID- 30004190 TI - Vasogenic cerebral edema associated with the disability in activities of daily living in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION: The aim of this study was to explore whether patients with chronic obstructive pulmonary disease (COPD) develop vasogenic cerebral edema, and whether this edema contributes to the COPD-related disability. METHODS: Eighteen stable patients with COPD and 17 matched healthy volunteers were enrolled. Apparent diffusion coefficient (ADC) values were calculated by voxel-based analysis using DTI-Studio software based on diffusion tensor imaging. COPD related disability was calculated using activities of daily living (ADL) scale. RESULTS: In patients with COPD, ADC increased in the white matter fiber tracts including the bilateral anterior cingulum and posterior corpus callosum and in the white matter fibers connecting the bilateral insular cortices, sub-lobar cortices, and pars triangularis cortices and the left rectus and olfactory gyrus. However, after further controlling for cigarette smoking, the difference in ADC values in the posterior corpus callosum between groups disappeared. Patients with COPD had significantly higher scores in ADL than that in controls. Moreover, ADL scores were positively correlated with the increased regional ADC values. CONCLUSION: Vasogenic cerebral edema occurs in patients with COPD. Cigarette smoking may be a risk factor for COPD-related vasogenic edema. Vasogenic cerebral edema may be related to the COPD-related ADL impairment. PMID- 30004193 TI - [Recent Advances in Hepatitis B Virus Antivirals]. AB - The ultimate goal of chronic hepatitis B virus(HBV)therapy is full eradication of the virus from the liver. However, this is rarely achieved with the clinically available first-line agents (entecavir and tenofovir disoproxil fumarate) due to the inability to eliminate covalently closed circular DNA(cccDNA), which persists in the nucleus of infected hepatocyte cells,and failure of the host to induce an adequate specific immune response to control the infection. Currently, the clinical treatment for chronic HBV infection mainly includes nucleos(t)ide analogues (NAs), non-NAs and immune modulatory agents; however, each agent has individual advantages and drawbacks. It is, therefore, extremely urgent to identify novel targets involved in viral replication and develop novel anti-HBV drugs. In light of the breakthroughs in cccDNA research and host immune treatments, this review aims to summarize the state of the recent HBV drug research and development to highlight future therapeutic strategies to target the virus and host immune response. PMID- 30004192 TI - Acceleration of Diabetic Wound Regeneration using an In Situ-Formed Stem-Cell Based Skin Substitute. AB - Chronic diabetic ulcers are a common complication in patients with diabetes, often leading to lower limb amputations and even mortality. Stem cells have shown promise in promoting cutaneous wound healing by modulating inflammation, angiogenesis, and re-epithelialization. However, more effective delivery and engraftment strategies are needed to prolong transplanted stem cell lifespan and their pro-healing functions in a chronic wound environment to improve skin regeneration. In this study, an injectable poly(ethylene glycol) (PEG)-gelatin based hydrogel system is examined to create a functional stem cell niche for the delivery of adipose-derived stem cells (ASCs) into diabetic wounds. Human ASCs are encapsulated into the in situ crosslinked hydrogels and cultured in a 3D topography. The encapsulated cells are well attached and spread inside the hydrogels, retaining viability, proliferation, and metabolic activity up to three weeks in vitro. Allogeneic ASCs are delivered to diabetic wounds by this hydrogel vehicle. It is found that stem cell retention is significantly improved in vivo with vehicle-mediated delivery. The ASC-hydrogel-based treatment decreases inflammatory cell infiltration, enhances neovascularization, and remarkably accelerates wound closure in diabetic mice. Together, these findings suggest this conveniently-applicable ASC-hydrogel-based skin substitute provides a promising potential for the treatment of chronic diabetic wounds. PMID- 30004191 TI - Involvement of amygdala-prefrontal dysfunction in the influence of negative emotion on the resolution of cognitive conflict in patients with schizophrenia. AB - INTRODUCTION: Patients with schizophrenia often have impaired cognition and abnormal conflict control. Conflict control is influenced by the emotional values of stimuli. This study investigated the neural basis of negative emotion interference with conflict control in schizophrenia. METHODS: Seventeen patients with schizophrenia and 20 healthy controls underwent functional magnetic resonance imaging while performing the emotional Simon task, in which positive or negative emotional pictures were located in congruent or incongruent positions. Analysis was focused on identifying brain regions with the significant interaction among group, emotion, and conflict in whole brain voxel-wise analysis, and abnormality in their functional connectivity in the patient group. RESULTS: The regions showing the targeted interaction was the right amygdala, which exhibited significantly reduced activity in the negative congruent (t = 2.168, p = 0.036) and negative incongruent (t = -3.273, p = 0.002) conditions in patients versus controls. The right amygdala also showed significantly lower connectivity with the right dorsolateral prefrontal cortex in the cognitive and emotional loading contrast (negative incongruent-positive congruent) in patients versus controls (t = -5.154, p < 0.01), but not in the cognitive-only or emotional-only loading contrast. CONCLUSIONS: These results suggest that negative emotion interferes with cognitive conflict resolution in patients with schizophrenia due to amygdala-dorsolateral prefrontal cortex disconnection. Based on these findings, interventions targeting conflict control under negative emotional influence may promote cognitive rehabilitation in patients with schizophrenia. PMID- 30004194 TI - [Analysis of Common Issues and Research Progress in Loop Mediated Isothermal Amplification]. AB - Loop mediated isothermal amplification(LAMP)technology is a newly developed isothermal amplification technology for in vitro detection of nucleic acids. Although the LAMP assay is rapid, specific, sensitive, simple and has been widely applied for rapid detection of nucleic acids, it continues to improve and develop. In this paper, we summarize approaches to addressing amplification product contamination, primer design to avoid false positives, and the development of related techniques based on LAMP technology. This paper could serve as a reference for the application of the assay at the grassroots level. PMID- 30004195 TI - [Advances in Application of Rabies Immunoglobulin]. AB - China has the second highest number of rabies cases worldwide. There are millions of category III rabies exposure cases in China every year, which are treated with rabies immunoglobulin(RIG)and the rabies vaccine. The price of RIG is relatively expensive, and the application of RIG is relatively complicated. The rate of RIG use in post exposure prophylaxis(PEP)for rabies exposure category III cases has remained low for a significant amount of time. Reducing the dosage of RIG could reduce the cost of PEP, while simplifying the use of RIG could make PEP easier. Together, these steps could improve the rate of RIG utilization in PEP. There are conflicting conclusions in studies of RIG on the immune effects of the rabies vaccine.Exploring the mechanism of action of RIG in the immune response to the rabies vaccine would help to explain the role of RIG in the immune effects mediated by the rabies vaccine. In this paper, the progress of research on the application of RIG is systematically reviewed in order to provide a reference for the formulation of new and more practical guidelines for the application of RIG. PMID- 30004196 TI - [Establishment of a Model of Infection by Enterovirus 71 in ICR Mice]. AB - We aimed to study infections in neonatal ICR mice of different ages infected with Enterovirus 71(EV-A71)through three routes of infection, and to explore the dynamic distribution and infection mechanism of EV-A71 in vivo.Three-,5-and 9-day old neonatal ICR mice were infected with an EV-A71 strain isolated from a child with severe hand, foot and mouth disease through intramuscular(IM), intraperitoneal (IP)and intracerebral (IC)injection, respectively. Consequently, blood, brain, hind-limb muscle, heart, and intestines of mice were collected at regular intervals. Changes in viral load in organs were measured using real-time polymerase chain reaction. Hematoxylin and eosin staining and immunohistochemical (IHC)analyses were undertaken to detect pathogenic and pathologic changes in infected mice.Five-day-old neonatal mice infected with EV-A71 through IM,IP or IC routes had obvious neurologic symptoms and a high mortality rate. Symptoms were alleviated slightly with increasing age of mice upon injection. However, the pathogenicity associated with IM and IP injections was more severe than that of IC injection. Also, the mortality rates of IM and IP injections were significantly higher than that of IC injection. Compared with the control group, the mean body weight(in g)of 3-day-old neonatal mice at 6days post infection(dpi)injected by IM,IP and IC routes decreased by 1.54(31.43%),1.31(15.06%)and 2.52(44.28%),respectively. Similarly, the mean body weight(in g)of 5-day-old neonatal mice at 6dpi injected by IM and IP decreased by 0.605(8.95%),0.886(15.51%),whereas that of mice injected by IC increased by 0.904(14.70%).The body weight of all infection groups was significantly lower than that of the control group(P<0.05).All 3-day-old neonatal mice infected with EV-A71 through IM,IP and IC routes died at 9dpi.Survival rates of 5-day-old neonatal mice infected through IM,IP and IC routes at 9dpi and14 dpi were 42.8%,25%,and 87.5%,and 0%,0%,and 25%,respectively.Those of 9-day-old neonatal mice at 14 dpi were 70%,69.23% and 100%,respectively.Pathologic and IHC examination showed that EV-A71 had a strong preference for infecting nervous systems and skeletal muscle, and could also lead to: viremia; necrosis of brain neurons and skeletal muscle; myocardial interstitial edema; inflammatory response of multiple organs. These data suggest that 5-day-old ICR neonatal mice injected through IM or IP routes can establish an ideal model of infection by EV-A71 in mice. PMID- 30004197 TI - [Phylogenetic Analysis of Complete VP1 Sequence of Coxsackievirus B1 in Shandong Province, China ]. AB - To investigate the molecular epidemiological characterization of coxsackieivirus B1(CV-B1),we performed VP1 sequencing on all isolates from acute flaccid paralysis (AFP) surveillance, environmental surveillance and viral meningitis specimens from 1994 to 2015.A total of 53CV-B1 strains were isolated, among which 41 strains,4strains,and 8strains were obtained from AFP surveillance, environmental surveillance and meningitis specimens, respectively. Phylogenetic analysis based on VP1 entire coding region revealed that Shandong CV-B1 strains were segregated into a major cluster alongside with other domestic strains, with no foreign strains existing in this cluster. Foreign strains composed two other exclusive branches.Shandong strains had VP1 nucleotide similarities of 84.4%to 100.0% with each other, and 77.9%to 85.0% with foreign strains. The results presented here demonstrate Chinese CV-B1 strains have great genetic divergence with foreign strains. EV associated surveillance should be reinforced to monitor possible importation of different EV transmission lineages. PMID- 30004198 TI - [Genetic Characteristics of the VP1 Region of the Coxsackie A16 Virus from Jiangsu Province, China, in 2015]. AB - The aim of this study was to analyze the genetic characteristics of the VP1 gene of coxsackievirus A16(CA16)strains isolated from Jiangsu Province, China, in 2015.The VP1 regions of 20CA16 virus strains from Jiangsu Province in 2015 were amplified, and the amplification products were sequenced. Mega 6.0and DNA Star software were applied to build the phylogenetic tree and analyze the homogeneity of nucleotides and amino acids. The sequence homologies of the nucleotides and amino acids of the VP1 gene were 88.2%~100.0%and 98.0%~100.0%among 20CA16 isolates, respectively. Comparison with the sequence of the prototype strain A G10 showed 75.3%~77.4% homologies in nucleotide sequence and90.6%~92.3%in amino acid sequences, respectively. Comparison with the sequence of the representative strain B1 showed 88.3%~98.4% homologies in nucleotide sequence and 96.3%~100.0%in amino-acid sequence, respectively. Comparison with the sequence of the representative strain B2 showed 88.4%~90.8% homologies in nucleotide sequence and 96.6%~100.0%in amino-acid sequence, respectively. Twenty CA16 isolates were subgenotype B1.One isolate was subgenotype B1a, whereas the remainder of isolates was subgenotype B1b among 20 CA16 isolates. A subgenotype B1b transmission chain was also noted. The CA16 strains isolated from Jiangsu Province in 2015 belonged to subgenotype B1.There were two evolutionary branches, whereby B1 a and B1bwere co-circulating and evolving together. The epidemic strain was subgenotype B1b. PMID- 30004199 TI - [Expression of Type-Iota Interferon Production Pathway-Related Genes Induced by Infection Due to Enterovirus 71 or Coxsackievirus A16 in Normal Human Airway Epithelial Cells]. AB - Hand, foot, and mouth disease(HFMD)is caused by mainly enterovirus 71(EV-A71)and coxsackievirus A16(CV-A16),and is a serious healthcare problem worldwide.EV-A71 infection is thought to progress readily to serious complications whereas CV-A16 infection, in general, results in mild symptoms and presents repeatedly. However, the underlying mechanisms leading to these differences are not known. We compared changes in expression of type-I interferon(IFN-I)-related genes in normal human bronchial epithelial(16HBE) cells. Gene-expression levels of TLR3,MAVS,MDA5,MyD88,IRF7,IFNalphaand IFNbetawere elevated significantly after EVA71 infection.MDA5expression was increased markedly, and that of TLR3 and IRF3was decreased obviously after CV-A16 infection, but that of MAVS,MyD88,IFNalphaand IFNbetadid not show significant differences. Viral copy number and viral titers suggested that CV-A16 replicates more efficiently than EV A71 in 16HBE.These results suggest that IFN-I production pathway-related genes in response to infection by EV-A71 and CV-A16 have notable discrepancies. Such information could shine a light on the different manifestations caused by EV-A71 and CV-A16,and the mechanism of repeat infection by CV-A16. PMID- 30004200 TI - [Genetic Characterization of Coxsackievirus A6 Strains Isolated in Ningxia Region, China, 2013~2015]. AB - To study the genetic characteristics of coxsackievirus (CV)-A6 strains isolated from hand, food and mouth(HFMD)cases in Ningxia Province, China, in 2013~2015.A total of 998 specimens identified as non-EV71,non-CVA16 enteroviruses by real time polymerase chain reaction were collected in 2013~2015and cultured using RD cells. The viral protein(VP)1gene of isolated strains was amplified by reverse transcription-polymerase chain reaction with degenerate primers and sequenced.Sequences were compared using the GenBank database by the BLAST algorithm to identify virus genotypes. All CV-A6 stains identified underwent homologous comparison and phylogenetic analyses. A total of 227 virus strains were isolated from 998 clinical specimens, and 61 stains were identified as CV A6.Homologies of nucleotides and amino acids among Ningxia CV-A6 strains were 96.1%~99.8% and 98%~100%,respectively.The nucleotide homogeneity of Ningxia CV-A6 strains with Gudla strains, and the similarity of nucleotides and amino-acid sequences with VP1 of CV-A6 were 82.0%~83.5% and 93.8%~95.7%,respectively.CVA6 was the main pathogen of HFMD apart from EV71 and CV-A16 in Ningxia Province in 2013~2015. PMID- 30004201 TI - [The Epidemiology and Etiology Characteristics of Hand-foot-mouth Disease in Chongqing, China,2014~2015]. AB - In this study, the epidemiology of Hand-foot-mouth disease(HFMD)composition of enterovirus (EV) pathogen and VP1 coding gene of Enterovirus A71(EV-A71)were analyzed in Chongqing from 2014 to 2015,to provide a scientific basis for strategies of prevention and control of HFMD in Chongqing. It is reported that there were a total of 100,176 cases of HFMD, of which 284 cases of severe,37 cases of death in Chongqing.39counties(autonomous counties)of Chongqing have reported cases, and the urbans reported incidence rate(298.83/100,000)was significantly higher than the suburbs(103.37/100,000),children 3and under 3years old accounted for 83.21%%,and 5and under 5years old accounted for 95.64%of reported cases, the big peak of epidemics of HFMD was from April to July and the small peak took shape from October to November. Severe cases(96.83%)and deaths(100%)were concentrated in the age group of 5years old and below. The severe cases were mainly in the three districts, WanZhou District, Liangping County and FuLing District, accounting for 74.65% of reported cases, and death cases were widely distributed, scattered in 17 counties.7503nucleic acid of clinical specimens of HFMD were detected, suggested that EV-A71,CV-A16,non-EV A71/CV-A16 of other EV accounted for 23.54%,33.21%,43.25% respectively,Non-EV A71/ CV-A16 of other EV became the dominant pathogen of HFMD in Chongqing, but EV A71 was still the dominant pathogen in severe and death cases. The results showed that 54 strains belonged to C4a and one strain belonged to B5 in the analyses of the VP1 sequences of 55 strains during2014-2015 in Chongqing. This study provides important epidemiological and etiological data for HFMD prevention and control strategies and reduction of severe and death caused by EV-A71 in Chongqing. PMID- 30004202 TI - [Epidemiology Characteristics and Pathogen Surveillance of Hand, Foot and Mouth Disease in Guangdong Province, China, 2008~2015]. AB - To understand the epidemiological etiology characteristics of hand, foot and mouth disease(HFMD)in Guangdong province, and to explore the risk change trend of the whole province. By using the descriptive epidemiological methods, the whole province's incidence trend, population distribution and pathogenic form of HFMD were analyzed with the HFMD surveillance data,population data and geographic information of Guangdong province from 2008 to 2015.The analysis results show: A total of 2,133,722 cases of HFMD, including 5,066 severe cases and 259 death cases were reported in Guangdong province from 2008 to 2015.All the cities of Guangdong had HFMD cases, especially the Pearl River Delta Regions, which were on high-risk areas. There were two peaks every year, with the main peak of incidence occurred in spring and summer, and the sub peak occurred in autumn.Most cases were children aged<5years old, the proportion of this group in overall infections, the severe and death cases were 90.58%,95.93%and 97.30%,respectively,while the proportion for the children less than 3years old were 77.32% and 81.85%,respectively. The incidence of this disease among men was higher than that of women. Dynamic changes were presented between different years and seasons:CV-A16 was more popular in 2009,and enterovirus that none EV-A71 and none CV-A16 were predominant strains in 2013 and 2015.Especially in 2015,the proportion of other EV ranged as high as 71.97%.Besides,EV-A71 was the absolute predominance pathogen within death cases and was important pathogen in severe cases. This study suggests that HFMD epidemiology and laboratory monitoring in Guangdong Province should be strengthened, and provides scientific data support for further improvement of HFMD prevention and control strategies in Guangdong Province. PMID- 30004203 TI - [Pathogenic Analyses of an Outbreak of Viral Encephalitis Caused by ECHO30 in Guazhou of Gansu Province, China]. AB - We used molecular-biology methods to identify the pathogens that caused an outbreak of viral encephalitis in Guazhou (Gansu province, China)during June August 2015.We also undertook molecular characterizations of these pathogens. A total of 132samples(14cerebrospinal fluid(CSF)samples;25throat swabs;66serum samples;27fecal samples)were collected from 74 patients during the outbreak of viral encephalitis. For CSF and serum samples, enzyme-linked immunosorbent assay immunoglobulin-M tests were undertaken to detect Japanese encephalitis viruses, enteroviruses, herpes simplex viruses, mumps viruses, and adenoviruses. Real-time polymerase chain reaction was done to detect enteroviruses(including coxsackievirus A16 and enterovirus 71) and the RNA of human adenoviruses. Then, viral isolation was carried out using HEp-2 and RD cells, and the entire VP1 region of positive viral isolates was amplified and sequenced. Finally, molecular characterizations of these pathogens were completed. Seventy two samples were identified as enteroviruses from 132 samples. Among them,71 were identified as echovirus(ECHO)30using enterovirus molecular typing. Japanese encephalitis viruses,herpes simplex viruses, mumps viruses, and adenoviruses were not detected.ECHO30 was isolated from 46 samples out of 29 patients.Similarities in nucleic acids among these ECHO30 isolates were 99.2%-100.0%.ECHO30 from Gansu province and other ECHO30 strains isolated in China since 2011 belonged to a same evolutionary branch.ECHO30 was the pathogen that caused the outbreak of viral encephalitis in Guazhou in 2015.ECHO30 from and Gansu province and ECHO30 isolated in China since 2011 belonged to the same evolutionary branch. PMID- 30004204 TI - [Molecular Epidemiology of Echovirus 30 in Longyan City, Fujian, China, 2011~2014]. AB - We studied the molecular epidemiology of echovirus 30 in sporadic cases of viral encephalitis in Longyan City, Fujian, China, from 2011 to 2014.Specimens of cerebrospinal fluid from patients diagnosed with viral encephalitis or infection of the central nervous system were collected. Viruses were isolated by cell culture. Identification of the echovirus 30 serotype and genetic analyses were undertaken. Amplification of virus protein(VP)-1gene sequences was done by reverse transcription-polymerase chain reaction. A total of 168 strains of enterovirus were isolated in 608 cases from 2011 to 2014,of which 60 strains were echovirus 30.The epidemic "peak" of echovirus 30 was from June to August. The age range of patients was wide, with 65% of cases under 10 years of age. Clinical manifestations were pyrexia, headache and vomiting.Cerebrospinal fluid was clear, and the number of cells and protein was increased. The epidemic strains in Longyan City from 2011 to 2014belonged to the "h" genotype, and there were two transmission chains. Compared with the viral encephalitis strains from the outbreak in Fujian Province in 2011,they were highly homologous, but a new amino acid variation of VP1 protein I 120 V was found in Longyan City strains from 2014.The viral encephalitis strains from the outbreak in Fujian Province in 2011 were present in Longyan City strains, and two transmission chains are still circulating,but there were new mutations in the virus strains from 2014.Continuous monitoring will aid:(i)early detection of viral variants that may accumulate;(ii)assessment of the risk of epidemics. PMID- 30004205 TI - [Canine Parvovirusin Diarrheal Dogs and Analyses of the Full-Length VP2 Gene of Dogs]. AB - We investigated infection by canine parvovirus and genetic variation of the VP2 gene. We collected feces samples of 50 diarrheal dogs in Sichuan Province, China. Analyses polymerase chain reaction (PCRs), agarose gel electrophoresis, and amplification of the complete sequence of canine parvovirus were done. We observed 19PCR-positive samples. Sequencing analyses of 15PCR-positive samples based on amplification of the complete VP2 gene showed all to be CPV-2a,and to be polymerized with Sichuan isolates. These results suggest that the common epidemic strain in Sichuan Province is CPV-2a,and may originate from the same strain. Compared with reference strains, there were no significant variations in canine parvovirus in Sichuan Province, China. PMID- 30004206 TI - [Development and Application of Reverse Transcription Loop-mediated Isothermal Amplification Method for Detection of Porcine Rotavirus of Swine]. AB - We wished to establish a method for rapid and sensitive detection of reverse transcription loop-mediated isothermal amplification(RT-LAMP)for the rapid and sensitive detection of porcine rotavirus (PoRV). According to the published PoRV VP7 sequences in GenBank,6specific primers were designed. According to the concentrations of foward and reverse primers, Bst DNA polymerase, Mg(2+), and dNTP, reaction conditions were optimized. Results revealed the concentration ratio of foward and reverse primers to be 200 nmol/L:2, 400 nmol (1:12), Bst DNA polymerase concentration to be 0.64U/MUL,Mg2+concentration to be 2.5mmol/L, and dNTP concentration to be 1.0mmol/L in 1hat 60C.The amplification effect achieved a "ladder" effect, with amplified bands being shown only for PoRV. RT-LAMP was specific and did not elicit a cross reaction with porcine epidemic diarrhea virus, transmissible gastroenteritis virus of pigs, or classical swine fever virus. The sensitivity of RT-LAMP was 1.0*10(2) copies/MUL. After the reaction, inspection by the naked eye revealed positive amplification products to appears as cloudy-white precipitates, and addition of SYBR Green I showed a color change. These data demonstrate that RT-LAMP is suitable for the rapid and sensitive detection of PoRV. PMID- 30004207 TI - [Effect of PLSCR1 on the Antiviral Activity of IFN against HBV in HepG2 Cells]. AB - To study the effect of interferon(IFN)against hepatitis B virus(HBV)by silencing phospholipid scramblase (PLSCR)1in HepG2 cells. siRNA specific for PLSCR1 was designed and transfected in HepG2 cells. The inhibitory effect of siRNA was determined using semi-quantitative polymerase chain reaction(PCR)and western blotting 48hpost-transfection.HepG2 cells treated with IFN were co-transfected with plasmids expressing HBV1.3and siRNA targeting PLSCR1.Total RNA of HepG2 cells was isolated and the mRNA level of PLSCR1 measured by reverse-transcription semi-quantitative PCR. The expression of HBsAg in culture supernatants was determined by enzyme-linked immunosorbent assay. Expression of PLSCR1 was inhibited by siRNA911 in HepG2cells.Compared with the control, the level of HBsAg decreased in the cell supernatants of cells transfected with HBV1.3plasmid or NC siRNA + HBV1.3plasmid.Compared with cells not treated with IFN, the level of HBsAg did not change significantly in the supernatants of cells transfected with siRNA + HBV1.3plasmid and treated with IFN. Inhibition of PLSCR1 could decrease the antiviral activity of IFN against HBV. These data suggest that PLSCR1 has an important role in the inhibition of HBV replication due to IFN. PMID- 30004208 TI - Binary Mixtures of Highly Concentrated Tetraglyme and Hydrofluoroether as a Stable and Nonflammable Electrolyte for Li-O2 Batteries. AB - Developing a long-term stable electrolyte is one of the most enormous challenges for Li-O2 batteries. Equally, the high flammability of frequently used solvents seriously weakens the electrolyte safety in Li-O2 batteries, which inevitably restricts their commercial applications. Here, a binary mixture of highly concentrated tetraglyme electrolyte (HCG4) and 1,1,2,2-tetrafluoroethyl 2,2,3,3 tetrafluoropropyl ether (TTE) was used for a novel electrolyte (HCG4/TTE) in Li O2 batteries, which exhibit good wettability, enhanced ionic conductivity, considerable nonflammability, and high electrochemical stability. Being a co solvent, TTE can contribute to increasing ionic conductivity and to improving flame retardance of the as-prepared electrolyte. The cell with this novel electrolyte displays an enhanced cycling stability, resulting from the high electrochemical stability during cycling and the formation of electrochemically stable interfaces prevents parasitic reactions occurring on the Li anode. These results presented here demonstrate a novel electrolyte with a high electrochemical stability and considerable safety for Li-O2 batteries. PMID- 30004209 TI - Exceptional Electrocatalytic Activity and Selectivity of Platinum@Nitrogen-Doped Mesoporous Carbon Nanospheres for Alcohol Oxidation. AB - Porous carbon materials have attracted considerable attention for their various applications such as catalyst supports for fuel cells. However, few studies focus on the effect of carbon pore structure on different alcohols electrooxidation. In this work, platinum@nitrogen-doped carbon nanospheres with tailored mesopores (Pt@NMCs) are fabricated and exhibit outstanding electrocatalytic activity and durability for alcohol oxidation because of the structural advantages such as adjustable mesopores, N-doped carbon, and embedded catalysts. More importantly, the pore size of NMCs (or called the size of the windows connecting the neighboring spherical cavities), which can be tuned simply by adjusting the diameter of colloidal silica nanospheres, has a great effect on the electrocatalytic activity and selectivity of Pt catalysts toward oxidation of alcohols (methanol, ethanol, and n-propanol). Accordingly, we can adopt optimal Pt@NMCs with appropriate pore size based on different requirements and applications. PMID- 30004210 TI - A Future with Ubiquitous Sensing and Intelligent Systems. AB - In this paper, we discuss the relevance of sensing and biosensing for the ongoing revolution in science and technology as a product of the merging of machine learning and Big Data into affordable technologies and accessible everyday products. Possible scenarios for the next decades are described with examples of intelligent systems for various areas, most of which will rely on ubiquitous sensing. The technological and societal challenges for developing the full potential of such intelligent systems are also addressed. PMID- 30004211 TI - Wire-Shaped Supercapacitors with Organic Electrolytes Fabricated via Layer-by Layer Assembly. AB - A wire-shaped supercapacitor (WSS) has structural advantages of high flexibility and ease of incorporation into conventional textile substrates. In this work, we report a thin reproducible WSS fabricated via layer-by-layer (LbL) assembly of multiwalled carbon nanotubes (MWCNTs), combined with an organic electrolyte of propylene carbonate (PC)-acetonitrile (ACN)-lithium perchlorate (LiClO4) poly(methyl methacrylate) (PMMA) that extends the voltage window to 1.6 V. The MWCNTs were uniformly deposited on a curved surface of a thin Au wire using an LbL assembly technique, resulting in linearly increased areal capacitance of the fabricated WSS. Vanadium oxide was coated on the LbL-assembled MWCNT electrode to induce pseudocapacitance, hence enhancing the overall capacitance of the fabricated WSS. Both the cyclic stability of the WSS and the viscosity of the electrolyte could be optimized by controlling the mixing ratio of PC to ACN. As a result, the fabricated WSS exhibits an areal capacitance of 5.23 mF cm-2 at 0.2 mA cm-2, an energy density of 1.86 MU W h cm-2, and a power density of 8.5 mW cm 2, in addition to a high cyclic stability with a 94% capacitance retention after 10 000 galvanostatic charge-discharge cycles. This work demonstrates a great potential of the fabricated scalable WSS in the application to high-performance textile electronics as an integrated energy storage device. PMID- 30004212 TI - Engineering Organelle-Specific Molecular Viscosimeters Using Aggregation-Induced Emission Luminogens for Live Cell Imaging. AB - Subcellular viscosity is essential for cell functions and may indicate its physiological status. We screen two fluorescent probes by engineering tetraphenylethene (TPE) for measuring viscosity in mitochondria and lysosomes, respectively. These two probes are only weakly emissive in nonviscous medium and the emission signals are greatly enhanced in viscous medium due to the restriction of intramolecular motion. The presence of pyridium has endowed one probe with mitochondrial specificity, while the presence of indole ring has granted the other probe with lysosome-targeting ability. Their optical properties are characterized in vitro and their applications in imaging viscosity variations in mitochondria and lysosomes are also demonstrated in living cells under different stimulated processes. In addition, an increase in both mitochondrial and lysosomal viscosity during mitophagy was revealed for the first time with our probes. To our knowledge, this is the first time that TPE is engineered to be fluorescent molecular viscosimeters that possess desirable aqueous solubility, red-shifted emission, and organelle specificity. PMID- 30004213 TI - Flexible Polyimide Nanocomposites with dc Bias Induced Excellent Dielectric Tunability and Unique Nonpercolative Negative- k toward Intrinsic Metamaterials. AB - Intrinsic metamaterials with negative- k that originated from random-structured materials have drawn increasing attention. Currently, intrinsic negative- k was mainly achieved in percolative composites by tailoring the compositions and microstructures. Herein, plasmalike negative- k was successfully achieved in multiwalled carbon nanotubes (MWCNT)/polyimide (PI) nanocomposites via applying external dc bias which exhibited excellent capability in conveniently and accurately adjusting negative- k. Mechanism analysis indicated that the localized charges at the interfaces between MWCNT and PI became delocalized after gaining energy from the dc bias, resulting in elevated concentration of delocalized charges, and hence the enhanced negative- k. Furthermore, it is surprising to observe that negative- k also appeared in multilayer nanocomposites consisting of alternating BaTiO3/PI and PI layers, in which there was no percolative conducting network. On the basis of systematic analysis, it is proposed that the unique nonpercolative negative- k resulted from the mutual competition between plasma oscillations of delocalized charges and polarizations of localized charges. Negative- k appeared once the polarizations were overwhelmed by plasma oscillations. This work demonstrated that applying dc bias is a promising way to achieve highly tailorable negative- k. Meanwhile, the observation of unique nonpercolative negative- k and the clarification of underlying mechanisms offer new insights into negative- k metamaterials, which will greatly facilitate the exploration of high-performance electromagnetic metamaterials. PMID- 30004214 TI - Microenvironmental Stiffness Regulates Dental Papilla Cell Differentiation: Implications for the Importance of Fibronectin-Paxillin-beta-Catenin Axis. AB - The mechanical stiffness of substrates is recognized to be an important physical cue in the microenvironment of local cellular residents in mammalian species due to their great capacity in regulating cell behavior. Dental papilla cells (DPCs) play an important role in the field of dental tissue engineering for their stem cell-like properties. Therefore, it is essential to provide the suitable microenvironment by combining with the physical cues of biomaterials for DPCs to carry out the function of effective tissue regeneration. However, how the substrate stiffness influences the odontogenic differentiation of DPCs is still unclear. Thus, we fabricated poly(dimethylsiloxane) substrates with varied stiffness for cell behavior. Both cell morphology and focal adhesion were shown to have significant changes in response to varied stiffness. Paxillin, an important protein adapter of focal adhesion kinase protein, was shown to interact with both ectoplasmic fibronectin and cytoplasmic beta-catenin by coimmunoprecipitation. The resultant changes of beta-catenin by varied stiffness were confirmed by immunofluorescent stain and western blotting. Further, the higher quantity nuclear translocation of beta-catenin and the less phospho-beta catenin on the stiff substrate were detected. This nuclear translocation in the stiff substrate finally led to an increased mineralization of DPCs relative to the soft substrate detected by Von Kossa and Alizarin Red stain. Taken together, this work not only points out that the substrate stiffness can regulate the odontogenic differentiation potential of DPCs via fibronectin/paxillin/beta catenin pathway but also provides significant consequence for biomechanical control of cell behavior in cell-based tooth tissue regeneration. PMID- 30004215 TI - Tuning Band Alignments and Charge-Transport Properties through MoSe2 Bridging between MoS2 and Cadmium Sulfide for Enhanced Hydrogen Production. AB - Transition-metal dichalcogenide materials play a major role in the state-of-the art innovations for energy conversion because of potential applications resulting from their unique properties. These materials additionally show inordinate potential toward the progress of hygienic power sources to deal with increasing environmental disputes at the time of skyrocketing energy demands. Herein, we report earth-abundant, few-layered, MoSe2-bridged MoS2/cadmium sulfide (CdS) nanocomposites, which reduce photogenerated electron and hole recombination by effectively separating charge carriers to achieve a high photocatalytic efficiency. Accordingly, the MoSe2-bridged MoS2/CdS system produced effective hydrogen (193 MUmol.h-1) as that of water using lactic acid as a hole scavenger with the irradiation of solar light. The presence of few-layered MoSe2 bridges in MoS2/CdS successfully separates photogenerated charge carriers, thereby enhancing the shuttling of electrons on the surface to active edge sites. To the best of our knowledge, this few-layered MoSe2-bridged MoS2/CdS system exhibits the most effective concert among altogether-reported MoS2-based CdS composites. Notably, these findings with ample prospective for the development of enormously real photocatalytic systems are due to their economically viable and extraordinary efficiency. PMID- 30004216 TI - Fe3O4-Decorated Porous Graphene Interlayer for High-Performance Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries are seriously restrained by the shuttling effect of intermediary products and their further reduction on the anode surface. Considerable researches have been devoted to overcoming these issues by introducing carbon-based materials as the sulfur host or interlayer in the Li-S systems. Herein, we constructed a multifunctional interlayer on a separator by inserting Fe3O4 nanoparticles (NPs) in a porous graphene (PG) film to immobilize polysulfides effectively. The porous structure of graphene was optimized by controlling the oxidation conditions for facilitating ion transfer. The polar Fe3O4 NPs were employed to trap sulfur species via strong chemical interaction. By exploiting the PG-Fe3O4 interlayer with optimal porous structure and component, the Li-S battery delivered a superior cycling performance and rate capability. The reversible discharge capacity could be maintained at 732 mAh g-1 after 500 cycles and 356 mAh g-1 after total 2000 cycles at 1 C with a final capacity retention of 49%. Moreover, a capacity of 589 mAh g-1 could also be maintained even at 2 C rate. PMID- 30004217 TI - Ferrodrop Dose-Optimized Digital Quantification of Biomolecules in Low-Volume Samples. AB - We present an approach to estimate the concentration of a biomolecule in a solution by sampling several nanoliter-scale volumes and determining if the volumes contain any biomolecules. In this method, varying volume fractions (nanoliter-scale) of a sample of nucleic acids are introduced to an array of uniform volume reaction wells (100 MUL), which are then fluorescently imaged to determine if signal is above a threshold after nucleic acid amplification, all without complex instrumentation. The nanoliter volumes are generated and introduced using the simple positioning of a permanent magnet, and imaging is performed with a cellphone-based fluorescence detection scheme, both methods suitable for limited-resource settings. We use the length of time a magnetic field is applied to generate a calibrated number of nanoliter ferrodrops of sample mixed with ferrofluid at a step emulsification microfluidic junction. Each dose of ferrodrops is then transferred into larger microliter scale reaction wells on chip through a simple shift of the external magnet. Nucleic acid amplification is achieved using loop-mediated isothermal amplification (LAMP). By repeating each nanoliter dosage a number of times to calculate the probability of a positive signal at each dosage, we can use a binomial probability distribution to estimate the sample nucleic acid concentration. Using this approach we demonstrate detection of lambda DNA molecules down to 25 copies per microliter. The ability to dose separate nanoliter-scale volumes of a low-volume sample across wells in this platform is suited for multiplexed assays. This platform has the potential to be applied to a range of diseases by mixing a sample with magnetic nanoparticles. PMID- 30004218 TI - Intrinsic, Cancer Cell-Selective Toxicity of Organic Photothermal Nanoagent: A Simple Formulation for Combined Photothermal Chemotherapy of Cancer. AB - Nano-agent-mediated photothermal therapy (PTT) combined with chemotherapy has been proposed as an effective strategy against cancer. However, chemotherapeutic agents often cause serious side effects. Herein, a novel PTT nanoagent (Cy5.5-MSA G250) with unanticipated intrinsic tumor-selective cytotoxicity is developed. The Cy5.5-MSA-G250 nanoparticles (NPs) are created by mixing mouse serum albumin (MSA) and coomassie brilliant blue (G250) and then conjugated with cyanine 5.5 (Cy5.5). As expected, Cy5.5-MSA-G250 NPs can efficiently kill cancer cells in vitro and in vivo by PTT. Meanwhile, we accidentally discover that Cy5.5-MSA-G250 have intrinsic specific cytotoxicity against tumor cells but not against normal cells. Moreover, the tumor-specific cytotoxicity of Cy5.5-MSA-G250 is much stronger than that of cytarabine, an FDA-approved anticancer drug. In vivo experiments also prove that Cy5.5-MSA-G250 NPs can effectively eliminate residual tumor cells and prevent metastasis. Further study indicates that selective induction of G1 cell cycle arrest and inhibition of DNA duplication in tumor cells may be the possible mechanism of the tumor cell-selective cytotoxicity of Cy5.5-MSA-G250 NPs. In addition, direct visualization, low systematic toxicity, good biodegradation, and efficient body excretion further make Cy5.5-MSA-G250 NPs attractive for in vivo applications. Taken together, Cy5.5-MSA-G250 NPs are proven to be a promising platform for combined photothermal chemotherapy. PMID- 30004219 TI - Design of Ultrasensitive Protein Biosensor Strips for Selective Detection of Aromatic Contaminants in Environmental Wastewater. AB - Phenol and its derivatives constitute a class of highly toxic xenobiotics that pollute both river and groundwater. Here, we use a highly stable enzyme-based in vitro biosensing scaffold to develop a chip-based environmental diagnostic for in situ accurate, direct detection of phenol with selectively down to 10 ppb. Mesoporous silica nanoparticles (MCM41) having a pore diameter of 6.5 nm was screened and found to be the optimal solid support for creation of a robust immobilized protein based sensor, which retains stability, enzyme activity, sensitivity, and selectivity at par with solution format. The sensor strip exhibits minimal cross reactivity in simulated wastewater, crowded with several common pollutants. Moreover, this design is competent towards detection of phenol content with 95% accuracy in real-time environmental samples collected from local surroundings, making it a viable candidate for commercialization. The enzyme has been further modified via evolution driven mutagenesis to generate an exclusive 2,3-dimethylphenol sensor with equivalent selectivity and sensitivity as the native phenol sensor. Thus, this approach can be extended to generate a battery of sensors for other priority aromatic pollutants, highlighting the versatility of the biosensor unit. This novel biosensor design presents promising potential for direct detection and can be integrated in a device format for on-site pollutant monitoring. PMID- 30004221 TI - Probabilistic Material Flow Analysis of Seven Commodity Plastics in Europe. AB - The omnipresence of plastics in our lives and their ever-increasing application range continuously raise the requirements for the monitoring of environmental and health impacts related to both plastics and their additives. We present a static probabilistic material flow analysis of seven polymers through the European and Swiss anthropospheres to provide a strong basis for exposure assessments of polymer-related impacts, which necessitates that the plastic flows from production to use and finally to waste management are well-understood. We consider seven different polymers, chosen for their popularity and application variety: low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), polystyrene (PS), expanded polystyrene (EPS), polyvinyl chloride (PVC), and polyethylene terephthalate (PET). We include synthetic textile products and consider trade flows at various stages of the life cycle, thus achieving a complete overview of the consumption for these polymers. In Europe, the order of consumption is PP > LDPE > PET > HDPE > PVC > PS > EPS. Textile products account for 42 +/- 3% of the consumption of PET and 22 +/- 4% of PP. Incineration is the major waste management method for HDPE, PS, and EPS. No significant difference between landfilling and incineration for the remaining polymers is found. The highest recycling share is found for PVC. These results can serve as a basis for a detailed assessment of exposure pathways of plastics or their additives in the environment or exposure of additives on human health. PMID- 30004220 TI - Microbial Protein Produced from Brown Seaweed and Spruce Wood as a Feed Ingredient. AB - The conversion of nonedible biomass to protein for use in feed is an attractive strategy toward improved sustainability in aquaculture. We have studied the possibility to produce protein-rich yeast Candida utilis on a medium consisting of enzymatically hydrolyzed sulphite-pulped spruce wood, mainly providing glucose, and enzymatically hydrolyzed brown seaweed, supplemented with ammonium sulfate. The results show that this blend constitutes a complete fermentation medium that enables good growth rates and cell yields. Results from a salmon feeding trial showed that the yeast can replace parts of a traditional fishmeal diet without harmful effects, although the apparent protein digestibility coefficient for the yeast was suboptimal. While further optimization of both the fermentation process and downstream processing is needed, the present proof-of concept study shows a path to the production of microbial protein based on a simple, local and sustainable fermentation medium. PMID- 30004222 TI - Influence of Different Acids on the Transport of CdSe Quantum Dots from Polymer Nanocomposites to Food Simulants. AB - We fabricated polymer nanocomposites (PNCs) from low-density polyethylene and CdSe quantum dots (QDs) and used these materials to explore potential exposure after long-term storage in different acidic media that could be encountered in food contact applications. While the low-level release of QD-associated mass into all the food simulants was observed, exposure to dilute acetic acid resulted in more than double the mass transfer compared to that which occurred during exposure to dilute hydrochloric acid at the same pH. Conversely, exposure to citric acid resulted in a suppression of QD release. Permeation experiments and confocal microscopy were used to reveal mechanistic details underlying these mass transfer phenomena. From this work, we conclude that the permeation of undissociated acid molecules into the polymer, limited by partitioning of the acids into the hydrophobic polymer, plays a larger role than pH in determining exposure to nanoparticles embedded in plastics. Although caution must be exercised when extrapolating these results to PNCs incorporating other nanofillers, these findings are significant because they undermine current thinking about the influence of pH on nanofiller release phenomena. From a regulatory standpoint, these results also support current guidance that 3% acetic acid is an acceptable acidic food simulant for PNCs fabricated from hydrophobic polymers because the other acids investigated resulted in significantly less exposure. PMID- 30004223 TI - Synthesis of Chiral cis-Cyclopropane Bearing Indole and Chromone as Potential TNFalpha Inhibitors. AB - Conformationally restricted analogues of SPD-304, the first small-molecule TNFalpha inhibitor, in which two heteroaryl groups, indole and chromone, are connected by chiral methyl- or ethyl- cis-cyclopropane, were designed. Synthesis of these molecules was achieved via Suzuki-Miyaura or Stille coupling reactions with chiral bromomethylenecyclopropane or iodovinyl- cis-cyclopropane as the substrate, both of which were prepared from chiral methylenecyclopropane as a common intermediate, constructing the heteroaryl-methyl or -ethyl- cis cyclopropane structures as key steps. This study presents an efficient synthesis of a series of chiral cis-cyclopropane conjugates with two heteroaryl groups. PMID- 30004224 TI - Spatial Distribution of Novel and Legacy Brominated Flame Retardants in Soils Surrounding Two Australian Electronic Waste Recycling Facilities. AB - Informal recycling of electronic waste (e-waste) has been shown to cause significant brominated flame retardant (BFR) contamination of surrounding soils in a number of Asian and West African countries. However, to the authors' knowledge, there have been no published studies demonstrating polybrominated diphenyl ether (PBDE) and novel brominated flame retardant (NBFR) soil contamination from regulated "formal" e-waste processing facilities in developed countries. This study reports on PBDEs (-28, -47, -99, -100, -153, -154, -183, and -209) and NBFRs (PBT, PBEB, HBB, EH-TBB, BTBPE and DBDPE) in 36 soil samples surrounding two Australian e-waste recycling plants and a further eight reference soils. Overall ?PBDE concentrations ranged 0.10-98 000 ng/g dw (median; 92 ng/g dw) and ?NBFRs ranged ND-37 000 ng/g dw (median 2.0 ng/g dw). Concentrations in soils were found to be significantly negatively associated with distance from one of the e-waste facilities for ?penta-BDEs, BDE-183, BDE-209, and ?NBFR compound groups. ANOVA tests further illustrated the potential for e-waste recycling to significantly elevate concentrations of some BFRs in soils over distances up to 900 m compared to references sites. This study provides the first evidence of soil contamination with PBDEs and NBFRs originating from formal e-waste recycling facilities in Australia, which may have implications for e-waste recycling practices throughout the world. PMID- 30004225 TI - Chemical Resolution of C, N-Unprotected alpha-Substituted beta-Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands. AB - We report the first purely chemical method for the resolution of C, N-unprotected racemic alpha-substituted beta-amino acids (beta2-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic beta2-AAs along with Ni(II) could form a pair of Ni(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure C, N unprotected beta2-AAs could be obtained by simple hydrolysis of an isolated favored Ni(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of beta2-AAs. PMID- 30004226 TI - Recent Advances in the Medicinal Chemistry of Liver X Receptors. AB - Nuclear hormone receptors represent a large family of ligand-activated transcription factors that include steroid receptors, thyroid/retinoid receptors, and orphan receptors. Among nuclear hormone receptors, the liver X receptors have emerged as very important drug targets. These receptors regulate some of the most important metabolic functions, and they were also identified as anti-inflammatory transcription factors and regulators of the immune system. The development of drugs targeting liver X receptors continues to be a challenge, but advances in our knowledge of receptor structure and function move us forward, toward achieving this goal. This review highlights the latest advances in the development of synthetic LXR modulators in the primary literature from 2013 to 2017. In this review, we place great emphasis on the structure and function of LXRs because of their essential role in the drug design process. The structure activity relationships of the most active and promising synthetic modulators are discussed. PMID- 30004228 TI - Access to Highly Enantioenriched Donepezil-like 1,4-Dihydropyridines as Promising Anti-Alzheimer Prodrug Candidates via Enantioselective Tsuji Allylation and Organocatalytic Aza-Ene-Type Domino Reactions. AB - This work aims at exploiting both the enantioselective Tsuji allylation of allyl carbonate 6 and an organocatalytic aza-ene-type domino reaction between enal 3a and beta-enaminone 4a to develop a straightforward access to all of the four possible stereoisomers of a donepezil-like 1,4-dihydropyridine 1a (er up to 99.5:0.5; overall yield up 64%), an anti-Alzheimer's prodrug candidate. This strategy was extended to the preparation of other enantioenriched 1,4 dihydropyridines 1b-i (eight examples), highlighting its potential in the development of these chiral AChE inhibitors. PMID- 30004229 TI - Testing Kinetic Identities Involving Transition-Path Properties Using Single Molecule Folding Trajectories. AB - Recent advances in single-molecule assays have allowed individual transition paths during the folding of single molecules to be observed directly. We used the transition paths of DNA hairpins having different sequences, measured with high resolution optical tweezers, to test theoretical relations between the properties of the transition paths and the folding kinetics. We showed that folding and unfolding rates were related to the average transition-path times, as expected from theory, for all hairpins studied. We also found that the probability distribution of transition-path occupancies agreed with the profile of the average velocity along the transition paths for each of the hairpins, as expected theoretically. Finally, we used the latter result to show that the committor probability recovered from the velocity profile matches the committor measured empirically. These results validate the proposed kinetic identities. PMID- 30004227 TI - Characterizing the Surface Coverage of Protein-Gold Nanoparticle Bioconjugates. AB - Functional enzyme-nanoparticle bioconjugates are increasingly important in biomedical and biotechnology applications such as drug delivery and biosensing. Optimization of the function of such bioconjugates requires careful control and characterization of their structures and activity, but current methods are inadequate for this purpose. A key shortcoming of existing approaches is the lack of an accurate method for quantitating protein content of bioconjugates for low (monolayer) surface coverages. In this study, an integrated characterization methodology for protein-gold nanoparticle (AuNP) bioconjugates is developed, with a focus on site-specific attachment and surface coverage of protein on AuNPs. Single-cysteine-containing mutants of dihydrofolate reductase are covalently attached to AuNPs with diameters of 5, 15, and 30 nm, providing a range of surface curvature. Site-specific attachment to different regions of the protein surface is investigated, including attachment to a flexible loop versus a rigid alpha helix. Characterization methods include SDS-PAGE, UV-vis spectrophotometry, dynamic light scattering, and a novel fluorescence-based method for accurate determination of low protein concentration on AuNPs. An accurate determination of both protein and AuNP concentration in conjugate samples allows for the calculation of the surface coverage. We find that surface coverage is related to the surface curvature of the AuNP, with a higher surface coverage observed for higher surface curvature. The combination of these characterization methods is important for understanding the functionality of protein-AuNP bioconjugates, particularly enzyme activity. PMID- 30004230 TI - Direct Liquid to Crystal Transition in a Quasi-Two-Dimensional Colloidal Membrane. AB - Using synchrotron-based small-angle X-ray scattering, we study rigid fd viruses assembled into isolated monolayers from mixtures with a nonabsorbing polymer, which acts as an osmotic agent. As the polymer concentration increases, we observe a direct liquid to crystal transition, without an intermediate hexatic phase, in contrast with many other similar systems, such as concentrated DNA phases or packings of surfactant micelles. We tentatively attribute this effect to the difference in stiffness. The liquid phase can be well described by a hard disk fluid, while we model the crystalline one as a hexagonal harmonic lattice and we evaluate its elastic constants. PMID- 30004231 TI - Enantioselective Synthesis of 2-Aminomethyl and 3-Amino Pyrrolidines and Piperidines through 1,2-Diamination of Aldehydes. AB - An efficient method for the synthesis of 1,2-diamines from aldehydes through proline-catalyzed asymmetric alpha-amination followed by reductive amination is reported. The products resemble those obtained through direct asymmetric diamination of terminal alkenes. The methodology is used to synthesize 2 aminomethyl and 3-amino pyrrolidines and piperidines in high yields and with a good enantioselectivity. The usefulness of the method is demonstrated through the synthesis of a 2-aminomethyl iminocyclitol. PMID- 30004232 TI - Reactions of 3,3,3-Trihalogeno-1-nitropropenes with Arenes in the Superacid CF3SO3H: Synthesis of ( Z)-3,3,3-Trihalogeno-1,2-diarylpropan-1-one Oximes and Study on the Reaction Mechanism. AB - 3,3,3-Trihalogeno-1-nitropropenes C(Hal3)CH?CH(NO2) (Hal = F, Cl, Br) in reaction with arenes in the superacid CF3SO3H (TfOH) at room temperature in 1 h afford 3,3,3-trihalogeno-1,2-diarylpropan-1-one oximes C(Hal3)CH(Ar)-C(Ar)?NOH (CHal3 oximes) in yields of 23-99%. Such CHal3-oximes having one ortho-substituent in the aryl ring exist as atropoisomers in solutions at room temperature. Several cationic intermediates of this reaction were studied by means of NMR and DFT calculations, which proves the detailed reaction mechanism of the formation of CHal3-oximes in TfOH. CHal3-oximes (for Hal = Cl, Br) with DBU in DMF at microwave or thermal activation are cyclized into 5-halogeno-3,4-diarylisoxazoles in yields of 37-59%. CHal3-oximes under the conditions of Beckmann rearrangement with PCl5 in benzene at room temperature in 24 h are turned at first into imidoyl chlorides (yields of 94-96%), which undergo transformation into the corresponding benzamides PhCONHCHPh(CHal3) on silica gel (yields of 46-47%). PMID- 30004233 TI - Cu(I)-Catalyzed Coupling and Cycloisomerization of Diazo Compounds with Terminal Yne-Alkylidenecyclopropanes: Synthesis of Functionalized Cyclopenta[ b]naphthalene Derivatives. AB - A Cu(I)-catalyzed coupling and cycloisomerization of diazo compounds with terminal yne-alkylidenecyclopropanes (ACPs) has been presented. This reaction starts from the formation of an allenic intermediate in the Cu(I)-catalyzed cross coupling reaction of a diazo compound with terminal alkyne in yne-tethered ACP and then undergoes a domino cycloisomerization of a 6pi-electrocyclization and cyclopropane ring-opening rearrangement to give functionalized cyclopenta[ b]naphthalene derivatives in moderate to excellent yields under mild conditions. PMID- 30004236 TI - Lurasidone in Children and Adolescents: Systematic Review and Case Report. AB - OBJECTIVE: To perform a systematic review of studies of lurasidone in children and/or adolescents and to present a case report aimed to add further insights into its use in clinical practice with youth. METHODS: We searched the following databases for empirical studies, of any design, focusing on the pharmacokinetics, efficacy, or safety of lurasidone in children and/or adolescents: Pubmed (Medline), OVID (PsycInfo, EMBASE+EMBASE classic, OVID Medline), Web of Knowledge, and ClinicalTrials.gov (last search January 23, 2018). RESULTS: From a pool of 301 potentially relevant references, we retained 12 pertinent studies (reported in 28 references), including 1 pharmacokinetics study, 1 double blind randomized controlled trial (RCT) for bipolar depression (BD) with 1 related interim analysis study of its extension phase and 1 related external posterior predictive check study, 1 double blind RCT for schizophrenia with 3 related interim analyses of its extension phase, 1 RCT and 1 case report for autism spectrum disorder, and 2 open-label studies focusing on a variety of disorders. Overall, these studies show that lurasidone is significantly more efficacious than placebo, with moderate effect sizes, and is well tolerated for BD and schizophrenia in youth. Published studies in youth have in general used doses up to 80 mg/day. Our case report suggests that high doses of lurasidone (148 mg/day) were well tolerated and might have contributed to substantial functional improvement in a 14-year old girl with psychosis and a previous history of anorexia nervosa, who had not responded to previous antipsychotics (olanzapine, risperidone, aripiprazole). CONCLUSIONS: There is increasing evidence that lurasidone may be moderately effective and well tolerated for the treatment of BD and psychosis in youth and may have procognitive effects. Our case report suggests that future RCTs should assess the efficacy and tolerability of high doses (>80 mg/day) of lurasidone in youth. PMID- 30004235 TI - The Piezo1 cation channel mediates uterine artery shear stress mechanotransduction and vasodilation during rat pregnancy. AB - During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and growth to maintain sufficient uteroplacental perfusion. Although we and others have shown that nitric oxide (NO) is a key mediator of these processes, the mechanisms that augment uterine artery NO signaling during gestation have not been identified. We hypothesized that Piezo1, a recently discovered cation channel, may be involved in the process of shear stress mechanotransduction, as other studies have shown that it is both mechanosensitive and linked to NO production. Surprisingly, there are no studies on Piezo1 in the uterine circulation. Our aims in the present study were to determine whether this novel channel is 1) present in uterine arteries, 2) regulated by gestation, 3) functionally relevant (able to elicit rises in intracellular Ca2+ concentration and vasodilation), and 4) linked to NO. Immunohistochemistry confirmed that Piezo1 is present in uterine arteries, primarily but not exclusively in endothelial cells. Western blot analysis showed that its protein expression was elevated during gestation. In pressurized main uterine arteries, pharmacological activation of Piezo1 by Yoda1 produced near maximal vasodilation and was associated with significant increases in intracellular Ca2+ concentration in endothelial cell sheets. Shear stress induced by intraluminal flow produced reversible vasodilations that were inhibited >50% by GsMTx-4, a Piezo1 inhibitor, and by Nomega-nitro-l-arginine methyl ester/ Nomega-nitro-l-arginine, inhibitors of NO synthase. These findings are the first to implicate a functional role for Piezo1 in the uterine circulation as a mechanosensor of endothelial shear stress. Moreover, our data demonstrate that Piezo1 activation leads to vasodilation via NO and indicate that its molecular expression is upregulated during pregnancy. NEW & NOTEWORTHY This is the first study to highlight Piezo1 in the uterine circulation. As a potentially important endothelial mechanosensor of shear stress, Piezo1 may be linked to mechanisms that support increased uteroplacental perfusion during pregnancy. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/piezo1-mechanotransduction-in-the-uterine circulation/ . PMID- 30004234 TI - Regional and temporal changes in left ventricular strain and stiffness in a porcine model of myocardial infarction. AB - The aim of the present study was to serially track how myocardial infarction (MI) impacts regional myocardial strain and mechanical properties of the left ventricle (LV) in a large animal model. Post-MI remodeling has distinct regional effects throughout the LV myocardium. Regional quantification of LV biomechanical behavior could help explain changes in global function and thus advance clinical assessment of post-MI remodeling. The present study is based on a porcine MI model to characterize LV biomechanics over 28 days post-MI via speckle-tracking echocardiography (STE). Regional myocardial strain and strain rate were recorded in the circumferential, radial, and longitudinal directions at baseline and at 3, 14, and 28 days post-MI. Regional myocardial wall stress was calculated using standard echocardiographic metrics of geometry and Doppler-derived hemodynamic measurements. Regional diastolic myocardial stiffness was calculated from the resultant stress-strain relations. Peak strain and phasic strain rates were nonuniformly reduced throughout the myocardium post-MI, whereas time to peak strain was increased to a similar degree in the MI region and border zone by 28 days post-MI. Elevations in diastolic myocardial stiffness in the MI region plateaued at 14 days post-MI, after which a significant reduction in MI regional stiffness in the longitudinal direction occurred between 14 and 28 days post-MI. Post-MI biomechanical changes in the LV myocardium were initially limited to the MI region but nonuniformly extended into the neighboring border zone and remote myocardium over 28 days post-MI. STE enabled quantification of regional and temporal differences in myocardial strain and diastolic stiffness, underscoring the potential of this technique for clinical assessment of post-MI remodeling. NEW & NOTEWORTHY For the first time, speckle-tracking echocardiography was used to serially track regional biomechanical behavior and mechanical properties postmyocardial infarction (post-MI). We found that changes initially confined to the MI region extended throughout the myocardium in a nonuniform fashion over 28 days post-MI. Speckle-tracking echocardiography-based evaluation of regional changes in left ventricular biomechanics could advance both clinical assessment of left ventricular remodeling and therapeutic strategies that target aberrant biomechanical behavior post-MI. PMID- 30004237 TI - Proteomic analysis of aortic smooth muscle cell secretions reveals an association of myosin heavy chain 11 with abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is a life-threatening disease, and no disease specific circulating biomarkers for AAA screening are currently available. We have identified a smooth muscle cell (SMC)-specific biomarker for AAA. We cultured aneurysmal tunica media that were collected from eight patients undergoing elective open-repair surgeries. Secreted proteins in culture medium were subjected to liquid chromatography/tandem mass spectrometry. Myosin heavy chain 11 (myosin-11) was identified as a SMC-specific protein in the tunica media derived secretions of all patients. We then examined myosin-11 protein concentrations by ELISA in plasma samples from patients with AAA ( n = 35) and age-matched healthy control subjects ( n = 34). Circulating myosin-11 levels were significantly higher in patients with AAA than control subjects. The area under the receiver-operating characteristic curve (AUC) of myosin-11 was 0.77, with a specificity of 65% at a sensitivity of 91%. Multivariate logistic regression analysis showed a significant association between the myosin-11 level and presence of AAA. When the myosin-11 level was combined with hypertension, it improved the prediction of AAA (AUC 0.88) more than hypertension per se. We then investigated the correlation between aortic diameter and circulating myosin-11 levels using AAA serum samples from patients undergoing endovascular aneurysm repair ( n = 20). Circulating myosin-11 levels were significantly correlated with maximum aortic diameter. Furthermore, changes in myosin-11 concentrations from the baseline 12 mo after endovascular aneurysm repair were associated with those in aortic diameter. These data suggest that circulating levels of myosin-11, which is a SMC-specific myosin isoform, may be useful as a biomarker for AAA. NEW & NOTEWORTHY Extensive studies have revealed that inflammation- or proteolysis related proteins are proposed as biomarkers for abdominal aortic aneurysm (AAA). Changes in these protein concentrations are not specific for smooth muscle, which is a major part of AAA pathologies. Hence, no disease-specific circulating markers for AAA are currently available. We found, using secretome-based proteomic analysis on human AAA tunica media, that myosin heavy chain 11 was associated with AAA. Circulating myosin heavy chain 11 may be a new tissue specific AAA marker. PMID- 30004238 TI - Not all fiber is good for you: targeting fibroblast activation to improve cardiac function in heart failure. PMID- 30004239 TI - Proteomics reveals Rictor as a noncanonical TGF-beta signaling target during aneurysm progression in Marfan mice. AB - The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-beta-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-beta activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of beta3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that beta3-integrin expression and activation modulated TGF-beta-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-beta signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide reaching findings that expression and signaling by beta3-integrin constitute a modulator of transforming growth factor-beta-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells. PMID- 30004240 TI - Massively Parallel Implementation of Sequence Alignment with Basic Local Alignment Search Tool Using Parallel Computing in Java Library. AB - Basic Local Alignment Search Tool (BLAST) is an essential algorithm that researchers use for sequence alignment analysis. The National Center for Biotechnology Information (NCBI)-BLAST application is the most popular implementation of the BLAST algorithm. It can run on a single multithreading node. However, the volume of nucleotide and protein data is fast growing, making single node insufficient. It is more and more important to develop high performance computing solutions, which could help researchers to analyze genetic data in a fast and scalable way. This article presents execution of the BLAST algorithm on high performance computing (HPC) clusters and supercomputers in a massively parallel manner using thousands of processors. The Parallel Computing in Java (PCJ) library has been used to implement the optimal splitting up of the input queries, the work distribution, and search management. It is used with the nonmodified NCBI-BLAST package, which is an additional advantage for the users. The result application-PCJ-BLAST-is responsible for reading sequence for comparison, splitting it up and starting multiple NCBI-BLAST executables. Since I/O performance could limit sequence analysis performance, the article contains an investigation of this problem. The obtained results show that using Java and PCJ library it is possible to perform sequence analysis using hundreds of nodes in parallel. We have achieved excellent performance and efficiency and we have significantly reduced the time required for sequence analysis. Our work also proved that PCJ library could be used as an effective tool for fast development of the scalable applications. PMID- 30004241 TI - Osteoporosis detection in panoramic radiographs using a deep convolutional neural network-based computer-assisted diagnosis system: a preliminary study. AB - Objectives To evaluate the diagnostic performance of a deep convolutional neural network (DCNN)-based computer-assisted diagnosis (CAD) system in the detection of osteoporosis on panoramic radiographs, through a comparison with diagnoses made by oral and maxillofacial radiologists. Methods: Oral and maxillofacial radiologists with >10 years of experience reviewed the panoramic radiographs of 1268 females {mean [+/- standard deviation (SD)] age: 52.5 +/- 22.3 years} and made a diagnosis of osteoporosis when cortical erosion of the mandibular inferior cortex was observed. Among the females, 635 had no osteoporosis [mean (+/- SD) age: 32.8 +/- SD 12.1 years] and 633 had osteoporosis (72.2 +/- 8.5 years). All panoramic radiographs were analysed using three CAD systems, single-column DCNN (SC-DCNN), single-column with data augmentation DCNN (SC-DCNN Augment) and multicolumn DCNN (MC-DCNN). Among the radiographs, 200 panoramic radiographs [mean (+/- SD) patient age: 63.9 +/- 10.7 years] were used for testing the performance of the DCNN in detecting osteoporosis in this study. The diagnostic performance of the DCNN-based CAD system was assessed by receiver operating characteristic (ROC) analysis. Results: The area under the curve (AUC) values obtained using SC-DCNN, SC-DCNN (Augment) and MC-DCNN were 0.9763, 0.9991 and 0.9987, respectively. Conclusions: The DCNN-based CAD system showed high agreement with experienced oral and maxillofacial radiologists in detecting osteoporosis. A DCNN-based CAD system could provide information to dentists for the early detection of osteoporosis, and asymptomatic patients with osteoporosis can then be referred to the appropriate medical professionals. PMID- 30004242 TI - Scalable Consistency in T-Coffee Through Apache Spark and Cassandra Database. AB - Next-generation sequencing, also known as high-throughput sequencing, has increased the volume of genetic data processed by sequencers. In the bioinformatic scientific area, highly rated multiple sequence alignment tools, such as MAFFT, ProbCons, and T-Coffee (TC), use the probabilistic consistency as a prior step to the progressive alignment stage to improve the final accuracy. However, such methods are severely limited by the memory required to store the consistency information. Big data processing and persistence techniques are used to manage and store the huge amount of information that is generated. Although these techniques have significant advantages, few biological applications have adopted them. In this article, a novel approach named big data tree-based consistency objective function for alignment evaluation (BDT-Coffee) is presented. BDT-Coffee is based on the integration of consistency information through Cassandra database in TC, previously generated by the MapReduce processing paradigm, to enable large data sets to be processed with the aim of improving the performance and scalability of the original algorithm. PMID- 30004243 TI - Mitochondria "THE" target of myocardial conditioning. AB - Several interventions such as ischemic preconditioning, remote pre /perconditioning, or postconditioning are known to decrease lethal myocardial ischemia/reperfusion injury. Whereas several signal transduction pathways become activated by such maneuvers, they all have a common endpoint, namely the mitochondria. The organelles represent an essential target of the cardioprotective strategies and the preservation of mitochondrial function is central for the reduction of ischemia/reperfusion injury. In the present review we address the role of mitochondria in the different conditioning strategies; in particular, we will focus on alterations of mitochondrial function in terms of energy production, formation of reactive oxygen species, opening of the mitochondrial permeability transition pore, and mitochondrial dynamics induced by ischemia/reperfusion. PMID- 30004245 TI - A qualitative study of health professionals' views on the holding of children for clinical procedures: Constructing a balanced approach. AB - Children undergoing clinical procedures can experience fear, uncertainty, and anxiety which can cause them to become upset and resist procedures. This study aimed to capture an international perspective of how health professionals report they would act if a child was upset and resisted a procedure. An online questionnaire, distributed through network sampling, used three vignettes to elicit qualitative open text responses from health professionals. Seven hundred and twelve professionals participated, resulting in 2072 pieces of text across the three vignettes. Many professionals reported that they would use distraction and spend time to inform and engage children in making choices about their procedure. However, most professionals indicated that if a child became uncooperative they would hold or instruct the holding of the child in order to get the procedure done 'as quickly as possible'. The findings demonstrate that professionals experience difficulty in balancing the different agendas, rights and priorities within the momentum which can build during a clinical procedure, often resulting in the child's voice and rights being undermined. A more balanced approach could be facilitated by a 'clinical pause' that would equip professionals with the time to consider children's expressed wishes and explore alternative approaches to holding. PMID- 30004244 TI - Positron Emission Tomography Imaging of Lesions pH Using 11C-Labeled Bicarbonate. AB - OBJECTIVES: As acid-base imbalance is involved in many pathological processes, the capability to image tissue pH alterations in the clinic could offer new ways to detect disease and respond to treatment. In this study, the authors show that tissue pH can be imaged in vivo with 11C-labeled bicarbonate (H11CO3-) buffer and positron emission tomography (PET). METHODS: H11CO3- was produced by on-column NaOH adsorption. Biodistribution of H11CO3- in normal mice was determined. In addition, uptake studies and inhibition experiments of H11CO3- in the S180 fibrosarcoma-bearing mice and the inflammatory mice were investigated with PET imaging. The tumor and inflammatory interstitial pH was measured by a needle pH microelectrode. RESULTS: PET imaging demonstrated the high uptake of H11CO3- in mice tumor tissues and inflammatory tissues, which showed that the average tumor or inflammatory interstitial pH was significantly lower than the surrounding tissue. Administration of sodium bicarbonate in the drinking water increased the measured tumor pH, while the uptake of H11CO3- in mice model tissues had no change. Similarly, administration with ammonium chloride (NH4Cl) decreased the pH, whereas the unchanged uptake of H11CO3- in mice model tissues was also found. However, after administration of acetazolamide, the low uptake of H11CO3- in mice model tissues was observed. CONCLUSIONS: H11CO3- solution is an endogenous bicarbonate buffer tracer that can be injected into patients without toxicity. H11CO3- PET can be used clinically to image pathological processes that are associated with acid-base imbalance, such as cancer and inflammation. PMID- 30004246 TI - Expression of APOB, ADFP and FATP1 and their correlation with fat deposition in Yunnan's top six famous chicken breeds. AB - 1. Adipose differentiation related protein (ADFP), fatty acid transport protein 1 (FATP1) and apolipoprotein B (APOB) are suspected to play an important role in determining intramuscular fat and in overall meat quality. 2. Yunnan's top six famous chicken breeds (the Daweishan Mini, Yanjin Black-bone, Chahua, Wuding, Wuliangshan Black-bone and Piao chicken) are known for the high quality of their meat, but little is known about their expression of these three genes. 3. The present study aimed to examine the ADFP, FATP1 and APOB genes in different tissues of these six breeds at different development stages. The subcutaneous fat from the back midline and front, abdominal fat, liver and muscle tissue was sampled at 28, 49, 70, 91 and 112 days. The expression of ADFP, FATP1 and APOB was measured by real-time PCR. 4. The results showed that the expression of the three genes differed depending on age, tissue types and breeds. However, the expression of the three genes correlated with fat traits. In conclusion, the expression of the ADFP, FATP1 and APOB genes is associated with the fat traits of Yunnan's top six chicken breeds. These results could help with molecular marker screening and marker-assisted breeding to improve the quality of poultry for meat production. PMID- 30004247 TI - Challenges of Increasing Childcare Center Compliance With Nutrition Guidelines: A Randomized Controlled Trial of an Intervention Providing Training, Written Menu Feedback, and Printed Resources. AB - PURPOSE: To assess the effectiveness of an intervention including training, provision of written menu feedback, and printed resources on increasing childcare compliance with nutrition guidelines. DESIGN: Parallel group randomized controlled trial. SETTING: Hunter New England region, New South Wales, Australia. PARTICIPANTS: Forty-four childcare centers that prepare and provide food on-site to children while in care. INTERVENTION: The intervention was designed using the Theoretical Domains Framework, targeted managers, and cooks and included implementation strategies that addressed identified barriers. MEASURES: Outcomes included the proportion of menus providing food servings (per child) compliant with overall nutrition guideline recommendations and each individual food group assessed via menu assessments. Cook knowledge of recommendations, intervention acceptability, adverse events, and barriers were also assessed via questionnaires with cooks and managers. ANALYSIS: Logistic regression models, adjusted for baseline values of the outcome. RESULTS: At baseline and follow-up, zero centers in the intervention and control groups were compliant with the overall menu guidelines or for the vegetable and meat food groups. Follow-up between-group differences in compliance for discretionary (33.3 vs 5, P = .18), dairy (41.7 vs 15, P = .16), breads and cereals (8.3 vs 10 P = 1.00), and fruit (16.7 vs 10, P = .48) were all nonsignificant. Relative to the control group, intervention centers showed a significantly greater increase in percentage of cooks with correct knowledge for vegetable servings (93.3 vs 36.4, P = .008). CONCLUSION: Although the application of the theoretical framework produced a broader understanding of the determinants of menu compliance, due to the complexity of guidelines, limited follow-up support, lower training uptake, and low intervention dose, the intervention was not effective in supporting the practice change required. PMID- 30004248 TI - The Impact of a Policy-Based Multicomponent Nutrition Pilot Intervention on Young Adult Employee's Diet and Health Outcomes. AB - PURPOSE: Evaluate the effect of a policy-based, multicomponent workplace diet intervention on young adult employees' diet and health. DESIGN: A 6-month, single armed pilot study with before and after assessments. SETTING: Insurance company in Belfast, Northern Ireland. PARTICIPANTS: Employees who worked at the company throughout the intervention period were included. Employees were excluded if pregnant, breast-feeding, or following a strict diet. INTERVENTION: Multicomponent diet intervention: ban of unhealthy foods brought into the premises, free fruit, education, individual advice, and further support. MEASURES: Mixed-methods approach: Diet-, health-, and work-related measures were assessed quantitatively. The campaign was evaluated quantitatively (via questionnaire) and qualitatively (via semistructured interviews). ANALYSIS: Changes in measures were analyzed using paired samples t tests. Interviews were analyzed using thematic analysis. RESULTS: Sixty (75.9%) staff completed all assessments. Males reduced their sugar intake on working days (-8.7% of total energy standard deviation [SD]: 20.1; P value <.01). Systolic blood pressure reduced in males and females (-3.3 SD: 9.9; P value <.05 and -8.0 SD: 7.7; P value <.001, respectively); 85.2% of staff strongly agreed/agreed that they appreciated the healthy eating ethos. This was supported by the qualitative analysis which furthermore suggested that the education, team support, individual advice, and free fruit were beneficial. CONCLUSION: Influencing workplace policies and offering additional dietary support could lead to meaningful changes in employees' diet and health and may change workplace culture. PMID- 30004249 TI - The Healthfulness of Food-at-Home Expenditures, the Local Food Environment, and Childhood Obesity. AB - PURPOSE: Despite the growth of food-away-from-home expenditures, food-at-home (FAH) expenditures still constitute the majority of American families' food dollars. The FAH expenditures may have important impacts on children's diets and, consequently, their weight statuses. This study examined the association between the composition of FAH expenditures and childhood overweight or obesity. DESIGN: We compiled a longitudinal data set from the 2010 to 2012 IRI Consumer Panel and its associated MedProfiler surveys. SETTING: This study took place in the United States. PARTICIPANTS: One thousand seven hundred thirty-one households across the United States, with 2645 children aged 2 to 17, were surveyed over 3 years (2010 2012). MEASURES: The binary outcome variable indicated whether a child was overweight or obese. The key predictor variable-composition of FAH expenditures was an index reflecting households' adherence to expenditure shares for 24 food categories recommended by the United States Department of Agriculture (USDA) Thrifty Food Plans. The key control variables were FAH expenditure shares from different food stores. ANALYSIS: Data were analyzed by multilevel logistic regressions that controlled for a number of individual-level and household-level characteristics. RESULTS: Higher compliance with the USDA Thrifty Food Plans was associated with lower risk of childhood overweight or obesity. Channel expenditure shares were not significantly associated with the weight outcomes. CONCLUSION: To prevent childhood obesity, the USDA Thrifty Food Plans can provide potential guidelines for households to decide the composition of their FAH expenditures. PMID- 30004250 TI - Incorporating Coexisting Chronic Illness into Decisions about Patient Selection for Lung Cancer Screening. An Official American Thoracic Society Research Statement. AB - BACKGROUND: Lung cancer screening (LCS) has the potential to reduce the risk of lung cancer death in healthy individuals, but the impact of coexisting chronic illnesses on LCS outcomes has not been well defined. Consideration of the complex relationship between baseline risk of lung cancer, treatment-related harms, and risk of death from competing causes is crucial in determining the balance of benefits and harms of LCS. OBJECTIVES: To summarize evidence, identify knowledge and research gaps, prioritize topics, and propose methods for future research on how best to incorporate comorbidities in making decisions regarding LCS. METHODS: A multidisciplinary group of international clinicians and researchers reviewed available data on the effects of comorbidities on LCS outcomes, focusing on the juxtaposition of lung cancer risk and competing risks of death, consideration of benefits and risks in patients with chronic obstructive pulmonary disease, communication of risk, and treatment of screen-detected lung cancer. RESULTS: This statement identifies gaps in knowledge regarding how comorbidities and competing causes of death impact outcomes in LCS, and we have developed questions to help guide future research efforts to better inform patient selection, education, and implementation of LCS. CONCLUSIONS: There is an urgent need for further research that can help guide clinical decision-making with patients who may not benefit from LCS owing to coexisting chronic illness. This statement establishes a research framework to address essential questions regarding how to incorporate and communicate risks of comorbidities into patient selection and decisions regarding LCS. PMID- 30004251 TI - Primary Ciliary Dyskinesia (PCD). PMID- 30004252 TI - Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. AB - Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5'-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-beta1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/glycogen synthase kinase -3beta pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3beta pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice. PMID- 30004253 TI - Influence of sucrose concentration on electric conductivity of banana pulp during ohmic heating. AB - Ohmic heating is a substitutive rapid heating method for food products. In this study, banana pulp with different concentrations of sugar is ohmically heated and the influence of sucrose concentration on electrical conductivity was investigated. The electrical conductivity, pH, total soluble solids, acidity, ascorbic acid content before and after ohmic heat treatment were also analysed. As the sucrose concentration increased, heating time at various voltage gradients 13.33, 20 and 26.66 V/cm increased, and the electrical conductivity decreased. As the voltage gradient increased, the pH and TSS of treated pulp with different sugar concentration increased followed by decrease in colour and acidity. PMID- 30004255 TI - Evaluation of jawbone morphology and bone density indices in panoramic radiographs of selective serotonin reuptake inhibitor users: a preliminary study. AB - OBJECTIVES: To assess the influence of selective serotonin reuptake inhibitor (SSRI) use on jawbone and bone mineral density by retrospective analysis of panoramic radiographs. METHODS: Radiographic and clinical records were sourced from the Division of Orthodontics and TMJD, Eastman Institute for Oral Health, University of Rochester. Randomly selected adults (20-65 years) were categorized into: "Active" (with history of SSRI use of >6 months) and a "Control" group. Panoramic indices: Klemetti index (KI), panoramic mandibular index, antegonial notching index, condylar pathology, mandibular cortical width (MCW)? and mean ramus height were recorded. Frequency-weighted Chi2 tests and multinomial regression controlling for age and gender were applied to categorical indices (KI, condylar pathology, antegonial notching index). Multivariate generalized linear modeling was applied to mean ramus height, MCW and panoramic mandibular index. Multiple regression analyses determined: (a) panoramic indices that best predicted SSRI use, and (b) independent predictors of KI category. RESULTS: 64 SSRI users and 48 Controls were assessed. SSRI users had significantly higher odds of having worse KI status than normal [mildly to moderately eroded cortex: odds ratio (OR) = 2.926, 95% CI (1.07-8.04) and severely eroded cortex: OR = 19.86, 95% CI (3.91-100.69)], more frequent flat condylar anatomy (right side: p = 0.009, left side: p < 0.001) but greater ramus height (p = 0.001) and mandibular cortical width (p = 0.032). Age, gender, SSRI use each significantly impacted KI. Only SSRI use significantly impacted condylar pathology, ramus height and MCW. KI category (OR = 1.3) was the best panoramic predictor of SSRI use. Conversely, KI category C3 was significantly predicted by SSRI use (OR = 31.2, p = 0.002), female gender (17.5, p = 0.006), and severe antegonial notching (OR = 1289, p < 0.001). CONCLUSIONS: SRRI use was significantly associated with worse panoramic morphometric indices: KI, condylar pathology, ramus height, and MCW, where KI was its strongest predictor. Worse KI was independently predicted by SSRI use. PMID- 30004256 TI - Evaluation of soft tissues simulant materials in cone beam computed tomography. AB - OBJECTIVES: To evaluate different materials in simulating soft tissues and to analyze the influence of these materials on the mean (MPIV) and standard deviation of pixel intensity values comparing them to a gold-standard in CBCT images. METHODS: Images of three piglet heads with their soft tissues intact (gold-standard) and different simulant materials were acquired: ice, modelling wax, and ballistic gelatin, with the same thickness of the original soft tissues. The pixel intensities were measured in dental, bone and soft tissues regions, in the mandible and maxilla, for all the groups. Analysis of variance, Dunnet's, Pearson's and linear regression tests were performed. RESULTS: The simulators did not significantly change the MPIV of teeth in comparison with the gold-standard (p = 0.1017). Only ice (p = 0.0156) affected the MPIV of bone. Wax (p = 0.001) and ice (p = 0.0076), but not ballistic gelatin (p = 0.5814), altered the MPIV of soft tissue regions. When assessing the influence of the location (mandible or maxilla) among the simulants, the differences were significant only for the soft tissue regions. Standard deviation was not influenced by simulants (p > 0.05), but ballistic gelatin presented the lower variability. CONCLUSIONS: The ballistic gelatin was the best soft tissue simulant since it had the lowest influence on the pixel intensity values for all regions. PMID- 30004257 TI - Maternal Support as a Predictor of Children's Sexualized Behaviors Following Childhood Sexual Abuse. AB - Although previous studies have concluded that maternal support following children's sexual abuse disclosures is an important predictor of children's symptoms, the empirical data to support this is limited. Much of the small prior literature has used measures of maternal support without adequately reported psychometric properties, which may obscure the true relationship between support and children's sexual behaviors. Further, it is unclear whether maternal support is related to children's sexual acting out in the context of known predictors of sexual behaviors. The purposes of the current study were to (1) examine the relationships between support and children's sexual behaviors and (2) determine whether support is related to sexual behaviors after controlling for known predictors among 161 treatment-seeking children (6-12 years old; M = 8.70, SD = 2.69) and their nonoffending mothers. In the bivariate analyses, emotional support was negatively related to children's sexual behaviors, whereas maternal blame/doubt was positively correlated with sexual behaviors. Nonetheless, after controlling for other predictors, emotional support predicted developmentally related sexual behaviors but not sexual abuse-specific sexual behaviors. Levels of emotional support and blame/doubt predicted children's total sexual behaviors, after accounting for identified predictors, suggesting that support may play a small role in understanding children's sexual behaviors. PMID- 30004254 TI - Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open Label Study. AB - BACKGROUND: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors. METHODS: Adolescents, 12-18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children's Depression Rating Scale-Revised (CDRS R); remission was CDRS-R score <=28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS). RESULTS: Thirteen participants (mean age 16.9 years, range 14.5-18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6 week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response. CONCLUSIONS: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose-response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use. PMID- 30004259 TI - Neurosurgical referral service using smartphone client WhatsApp: preliminary study at a tertiary referral neurosurgical unit. AB - BACKGROUND: Smartphone-based clients are being increasingly used in a medical world for individual as well as group communications. The authors report the use of WhatsApp, a common social media smartphone client for neurosurgical referral service in their Institution. They extend the use of WhatsApp application from a purely intra-departmental informal communication to a formal tertiary referral service for Neurosurgical referrals. The pros and cons of deploying such system are discussed and important concerns are highlighted. METHODS: Over a period of one year, the authors record 1412 referrals to the Neurosurgical service at a tertiary referral centre using WhatsApp application. All the data gathered through WhatsApp referrals was subsequently validated and analysed for any errors. They identify eight incidences where the system did not accurately convey the intended information. They highlight the potential issues related to data accuracy and confidentiality encountered in using such a system. OBSERVATIONS: In this preliminary study, the authors consider WhatsApp application as an important tool for Neurosurgical referrals. It is safe, cheap, reliable and user-friendly application allowing seamless transfer of data including clinical videos and scan images to the on call neurosurgical team. Loss of data quality, concerns surrounding patient confidentiality, errors caused by inter-operator variability in capturing data and default prohibition of use of such social media applications in many institutions are important disadvantages in regularly using such service. CONCLUSIONS: Smartphone-based social media clients such as WhatsApp provide a promising future for faster, reliable communication of clinical and radiological data, which can be used for on-call neurosurgical referrals. Integration with PACs applications and facial recognition may facilitate increasing use of such applications in future addressing many of the concerns that currently prohibit their universal use. PMID- 30004258 TI - Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is caused, or exacerbated by, a wide range of extracardiac conditions. Diabetes, obesity, and metabolic dysfunction are associated with a unique HFpEF phenotype, characterized by inflammation, cardiac fibrosis, and microvascular dysfunction. Development of new therapies for HFpEF is hampered by the absence of reliable animal models. The leptin-resistant db/ db mouse has been extensively studied as a model of diabetes associated cardiomyopathy; however, data on the functional and morphological alterations in db/ db hearts are conflicting. In the present study, we report a systematic characterization of the cardiac phenotype in db/ db mice, focusing on the time course of functional and histopathological alterations and on the identification of sex-specific cellular events. Although both male and female db/ db mice developed severe obesity, increased adiposity, and hyperglycemia, female mice had more impressive weight gain and exhibited a modest but significant increase in blood pressure. db/ db mice had hypertrophic ventricular remodeling and diastolic dysfunction with preserved ejection fraction; the increase in left ventricular mass was accentuated in female mice. Histological analysis showed that both male and female db/ db mice had cardiomyocyte hypertrophy and interstitial fibrosis, associated with marked thickening of the perimysial collagen, and expansion of the periarteriolar collagen network, in the absence of replacement fibrosis. In vivo and in vitro experiments showed that fibrotic changes in db/ db hearts were associated with increased collagen synthesis by cardiac fibroblasts, in the absence of periostin, alpha-smooth muscle actin, or fibroblast activation protein overexpression. Male db/ db mice exhibited microvascular rarefaction. In conclusion, the db/ db mouse model recapitulates functional and histological features of human HFpEF associated with metabolic dysfunction. Development of fibrosis in db/ db hearts, in the absence of myofibroblast conversion, suggests that metabolic dysfunction may activate an alternative profibrotic pathway associated with accentuated extracellular matrix protein synthesis. NEW & NOTEWORTHY We provide a systematic analysis of the sex specific functional and structural myocardial alterations in db/ db mice. Obese diabetic C57BL6J db/ db mice exhibit diastolic dysfunction with preserved ejection fraction, associated with cardiomyocyte hypertrophy, interstitial/perivascular fibrosis, and microvascular rarefaction, thus recapitulating aspects of human obesity-related heart failure with preserved ejection fraction. Myocardial fibrosis in db/ db mice is associated with a matrix producing fibroblast phenotype, in the absence of myofibroblast conversion, suggesting an alternative mechanism of activation. PMID- 30004260 TI - Social Justice as Epidemic Control: Two Latin American Case Studies. AB - In this article, we draw on two cases-one of the reproductive justice movements in the wake of the Latin American Zika epidemic, and one of an environmental justice movements spurred by an epidemic of chronic kidney disease among sugarcane workers-to argue for social justice as an "elastic" technology of epidemic control. In its compressed form, social justice simply refers to the fair distribution of medical goods. In its expanded form, it emphasizes the recognition and representation not just of medical problems, but of entangled histories of racial, gendered, and economic inequity. PMID- 30004262 TI - Associations Between MTR A2756G, MTRR A66G, and TCN2 C776G Polymorphisms and Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate: A Meta-Analysis. AB - OBJECTIVE: We conducted a meta-analysis to investigate the associations of methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G, and transcobalamin 2 (TCN2) C776G gene polymorphisms with nonsyndromic cleft lip with or without cleft palate (NSCL/P). MATERIALS AND METHODS: The PubMed, Web of Science, Embase, and Wiley Online Library databases and the China Biomedical Literature Service System (SinoMed) were searched for relevant articles to explore the associations between the MTR A2756G, MTRR A66G, and TCN2 C776G polymorphisms and the risk of NSCL/P. We performed overall comparisons and stratified analyses according to the ethnicity, type of NSCL/P, and Hardy Weinberg equilibrium (HWE) of the control group. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to estimate the associations of these gene polymorphisms with NSCL/P risk using fixed-effects or random-effects models incorporating five genetic models. RESULTS: Ultimately, 12 articles were included in this study. The pooled results did not reveal a significant association of the MTR A2756G polymorphism with NSCL/P risk (G vs. A: OR = 0.95, 95% CI = 0.82-1.11, p = 0.55). Similar results were observed for the MTRR A66G polymorphism (G vs. A: OR = 0.99, 95% CI = 0.82-1.18, p = 0.72) and the TCN2 C776G polymorphism (G vs. C: OR = 0.95, 95% CI = 0.86-1.06, p = 0.37). CONCLUSION: In summary, the MTR A2756G, MTRR A66G, and TCN2 C776G polymorphisms might not be associated with NSCL/P risk. PMID- 30004261 TI - Mismatch repair deficiency assessment by immunohistochemistry: for Lynch syndrome screening and beyond. AB - While mismatch repair (MMR) deficiency has been studied extensively, the assessment of MMR status in colorectal and other cancers remains highly relevant, particularly in light of recent data demonstrating that MMR deficiency is a strong predictor for treatment benefit with immune checkpoint inhibitors across multiple tumor types. In colorectal cancer, there is a growing consensus in support of routine MMR testing for Lynch syndrome screening, to inform prognosis and adjuvant chemotherapy use in early stage disease, and to predict response to immunotherapy in advanced disease. Here, we provide a review of the Ventana MMR Immunohistochemistry Panel, which was recently approved by the US FDA for use in Lynch syndrome screening. PMID- 30004263 TI - Epitope Mapping of Anti-Telomerase Reverse Transcriptase Monoclonal Antibodies. AB - Telomerase reverse transcriptase (TERT) is the main catalytic subunit of telomerase-associated protein machinery. Upregulation of TERT at the transcriptional level results in immortal cell phenotype associated with cancer. To date we have developed eight anti-TERT monoclonal antibodies (mAbs) (TMab-4, TMab-5, TMab-6, TMab-7, TMab-9, TMab-10, TMab-11, and TMab-12) by immunizing mice with synthetic peptides (302-QHHAGPPSTSRPPRPWDTPC-321) of TERT. We further characterized those epitopes using enzyme-linked immunosorbent assay, and here we discuss the critical epitope of an anti-TERT mAb, which is applicable for immunohistochemical analysis. PMID- 30004264 TI - Two-dimensional in vivo rectal dosimetry during high-dose-rate brachytherapy for cervical cancer: a phantom study. AB - BACKGROUND: The aim of the present study was to verify the dosimetric accuracy of two-dimensional (2D) in vivo rectal dosimetry using an endorectal balloon (ERB) with unfoldable EBT3 films for high-dose-rate (HDR) brachytherapy for cervical cancer. The clinical applicability of the technique was discussed. MATERIAL AND METHODS: ERB inflation makes the EBT3 films unrolled, whereas its deflation makes them rolled. Patient-specific quality assurance (pQA) tests were performed in 20 patient plans using an Ir-192 remote afterloading system and a water-filled cervical phantom with the ERB. The dose distributions measured in ERBs were compared with those of the treatment plans. RESULTS: The absolute dose profiles measured by the ERBs were in good agreement with those of treatment plans. The global gamma passing rates were 96-100% and 91-100% over 20 pQAs under the criteria of 3%/3 mm and 3%/2 mm, respectively, with a 30% low-dose threshold. Dose-volume histograms of the rectal wall were obtained from the measured dose distributions and showed small volume differences less than 2% on average from the patients' plans over the entire dose interval. The positioning error of the applicator set was detectable with high sensitivity of 12% dose area variation per mm. Additionally, the clinical applicability of the ERB was evaluated in volunteers, and none of them felt any pain when the ERB was inserted or removed. CONCLUSIONS: The 2D in vivo rectal dosimetry using the ERB with EBT3 films was effective and might be clinically applicable for HDR brachytherapy for cervical and prostate cancers to monitor treatment accuracy and consistency as well as to predict rectal toxicity. PMID- 30004265 TI - Comparison of different three dimensional-printed resorbable materials: In vitro biocompatibility, In vitro degradation rate, and cell differentiation support. AB - Biodegradable materials play a crucial role in both material and medical sciences and are frequently used as a primary commodity for implants generation. Due to their material inherent properties, they are supposed to be entirely resorbed by the patients' body after fulfilling their task as a scaffold. This makes a second intervention (e.g. for implant removal) redundant and significantly enhances a patient's post-operative life quality. At the moment, materials for resorbable and biodegradable implants (e.g. polylactic acid or poly-caprolactone polymers) are still intensively studied. They are able to provide mandatory demands such as mechanical strength and attributes needed for high-quality implants. Implants, however, not only need to be made of adequate material, but must also to be personalized in order to meet the customers' needs. Combining three dimensional printing and high-resolution imaging technologies a new age of implant production comes into sight. Three dimensional images (e.g. magnetic resonance imaging or computed tomography) of tissue defects can be utilized as digital blueprints for personalized implants. Modern additive manufacturing devices are able to use a variety of materials to fabricate custom parts within short periods of time. The combination of high-quality resorbable materials and personalized three dimensional-printing for the custom application will provide the patients with the best suitable and sustainable implants. In this study, we evaluated and compared four resorbable and three dimensional printable materials for their in vitro biocompatibility, in vitro rate of degradation, cell adherence and behavior on these materials as well as support of osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells. The tests were conducted with model constructs of 1 cm2 surface area fabricated with fused deposition modeling three dimensional-printing technology. PMID- 30004266 TI - A case of massive metoprolol and amlodipine overdose with blood concentrations and survival following extracorporeal corporeal membrane oxygenation (ECMO). PMID- 30004267 TI - Gastroesophageal Reflux Disease in Obese Patients. AB - Gastroesophageal reflux disease (GERD) and obesity coexist in many patients in the Western population. The association is not coincidental, since GERD pathophysiology is, in part, linked to obesity. Visceral adipose tissue secretes hormones, which increase the risk of GERD. Obesity increases esophageal motor disorders and higher number of transient lower esophageal sphincter relaxations. Central obesity increases abdominal-thoracic pressure gradient and disrupts the gastroesophageal junction by inducing hiatal hernia formation. Obese patients benefit from weight loss by diet to decrease GERD symptoms; however, Roux-en-Y gastric bypass surgery is associated with a higher weight loss and a decrease in GERD symptoms, and is considered the best way to treat both diseases at the same time. PMID- 30004268 TI - Cerebrolysin: a multi-target drug for recovery after stroke. AB - INTRODUCTION: Cerebrolysin is a neuropeptide preparation with neurotrophic effects and promotes recovery after brain injury. Its preclinical profile promises wide applications due to its multi-target effects. Currently, Cerebrolysin is used for treatment of cerebral ischemia and neurodegeneration. Areas covered: In stroke, earlier clinical trials with Cerebrolysin were performed mostly in mildly affected stroke populations, which usually have a favorable prognosis. Due to this selection, a floor or ceiling effect of recovery measures in the mild cases may have prevented to show a clear benefit between treatment groups. In contrast, subgroup analyses of more severely affected patients reveal a strikingly positive effect for enhanced recovery. Based on the findings from several studies, it became evident that the effect size of Cerebrolysin was increasing with stroke severity. Other controlled studies showed that Cerebrolysin can be safely used in combination with thrombolysis. More recently, Cerebrolysin has been tested not only for neuroprotection but also for its neurorecovery potential and also showed efficacy in patients with moderate to severe strokes. Expert commentary: Cerebrolysin shows a benefit mostly in moderate to severe ischemic stroke patients and an overall significant effect for functional recovery when combined with neurorehabilitation versus neurorehabilitation alone. This gives lead to the planning of a more rigorous study design in the future. PMID- 30004269 TI - Pilot Trial of an Acceptance-Based Behavioral Intervention to Promote Physical Activity Among Adolescents. AB - Prior interventions have shown limited efficacy in increasing the number of adolescents engaging in adequate physical activity (PA). Preliminary evidence suggests acceptance-based behavioral treatments (ABTs) may increase PA; however, this approach has not been tested in adolescents. This was a nonrandomized experimental pilot study that examined feasibility, acceptability, and treatment outcomes of a school-based, acceptance-based behavioral intervention for PA. Adolescents ( n = 20) with low activity received a PA tracking device and were allocated to device use only or device use plus 10-weeks of ABT. PA, cardiovascular fitness, and physiological outcomes were measured pre- and postintervention. The intervention was found to be feasible and acceptable. PA, cardiovascular fitness, and physiological outcomes improved over time in the intervention group, but not in the comparison condition. This study demonstrated feasibility, acceptability, and preliminary treatment efficacy based on effect sizes for an acceptance-based behavioral intervention to increase PA in adolescents. PMID- 30004270 TI - Preoperative Evaluation in Bariatric Surgery. AB - An adequate preoperative workup is critical for the success of bariatric surgery. A key component of the preoperative evaluation involves a comprehensive patient education about surgical outcomes and the postoperative behavioral regimen required. A complete medical evaluation should include the study of the cardiovascular, pulmonary, and gastrointestinal systems as well as a metabolic status assessment. The nutrition professional should be in charge of the nutritional assessment, preoperative weight loss efforts, and diet education regarding postoperative eating behaviors. A psychological evaluation is also needed because psychosocial factors have a significant impact on the long-term outcomes of bariatric surgery, including adherence to recommended postoperative lifestyle regimen, emotional adjustment, and weight loss outcomes. We recommend preoperative abdominal ultrasound to assess for biliary tract pathology, steatosis, fibrosis, and presence of nonalcoholic steatohepatitis. A routine preoperative esophagogastroduodenoscopy is also recommended to evaluate common gastrointestinal disorders associated with obesity. Preoperative weight loss should be strongly encouraged. PMID- 30004271 TI - Evaluation of Potential Drug-Drug Interactions With Direct Oral Anticoagulants in a Large Urban Hospital. AB - OBJECTIVE: The aim of this study is to assess patterns of potential drug-drug interactions (DDIs) with direct oral anticoagulants (DOACs) in an inpatient hospital setting. METHODS: A retrospective chart review was conducted at the Brookdale University Hospital and Medical Center (BUHMC) from January 2014 to November 2016. All adult patients admitted to the BUHMC who were treated with a DOAC for at least 3 days were screened. Among them, those who received selected interacting drugs at any time during the course of DOAC therapy were included in this study. RESULTS: This study included 165 patients with an average of 73 years (standard deviation [SD] = 12.3) and 233 cases. The most commonly used concomitant drug with a DOAC was aspirin (58%), followed by amiodarone (16%) and P2Y12 inhibitors (11%). The combined use of dual antiplatelet therapy and a DOAC was identified in 18 (6%) cases. Approximately one-third of the cases encountered were classified as the "avoidance" category. CONCLUSIONS: Despite computerized DDI alerts, potentially significant DDIs with DOACs still occur. While the present study provides insight into the current patterns of DDIs, further studies are needed to evaluate clinical outcomes of the potential DDIs with DOACs in practice. PMID- 30004272 TI - Unintentional use of the word "accident"? PMID- 30004273 TI - Metabolomics and Lipidomics Approaches in the Science of Probiotics: A Review. AB - The intestinal microflora plays important roles in the health of the host, such as nutrient processing and the modulation of intestinal immune responses. The constituents of the diet greatly affect the composition of the microbiota and its metabolites. The human intestinal microbiota is made up of around 100 trillion microbial cells encompassing at least 300 species. Consuming probiotics may lead to changes in the intestinal microflora that influence host health. Metabolomics is a powerful tool for revealing metabolic changes in biofluids, tissues, and organs of hosts induced by the consumption of probiotics, and lipidomics in particular is a technical approach that focuses on the analysis of lipids in various cells and biofluids. Metabolomics and lipidomics have been used to investigate intracellular and extracellular metabolites as well as for the nontargeted profiling and fingerprinting of metabolites. Based on metabolomics and lipidomics investigations, we reviewed the effects of consuming probiotics on metabolic profiles in controlled intestinal environments. We also discuss the associations between metabolic changes and human diseases after consuming probiotics in uncontrolled intestinal environments. In addition, we review the metabolic changes that take place within the food matrix during probiotic fermentation. PMID- 30004274 TI - Digital microfluidics comes of age: high-throughput screening to bedside diagnostic testing for genetic disorders in newborns. AB - INTRODUCTION: Digital microfluidics (DMF) is an emerging technology with the appropriate metrics for application to newborn and high-risk screening for inherited metabolic disease and other conditions that benefit from early treatment. Areas covered: This review traces the development of electrowetting based DMF technology toward the fulfillment of its promise to provide an inexpensive platform to conduct enzymatic assays and targeted biomarker assays at the bedside. The high-throughput DMF platform, referred to as SEEKER(r), was recently authorized by the United States Food and Drug Administration to screen newborns for four lysosomal storage disorders (LSDs) and is deployed in newborn screening programs in the United States. The development of reagents and methods for LSD screening and results from screening centers are reviewed. Preliminary results from a more compact DMF device, to perform disease-specific test panels from small volumes of blood, are also reviewed. Literature for this review was sourced using principal author and subject searches in PubMed. Expert commentary: Newborn screening is a vital and highly successful public health program. DMF technology adds value to the current testing platforms that will benefit apparently healthy newborns with underlying genetic disorders and infants at-risk for conditions that present with symptoms in the newborn period. PMID- 30004276 TI - Microsurgical rhizotomy for trigeminal neuralgia in MS patients: technique, patient satisfaction, and clinical outcomes. AB - OBJECTIVE Patients with multiple sclerosis (MS)-associated trigeminal neuralgia (TN) have higher recurrence and retreatment rates than non-MS patients. The optimal management strategy and role for microsurgical rhizotomy (MSR) for MS-TN remains to be determined. The aim of this study was to report time to treatment failure (TTF) and pain scores following MSR compared to percutaneous and Gamma Knife procedures. METHODS Time to treatment failure was analyzed after MSR (n = 14) versus prior procedures (n = 53) among MS-TN patients. Kaplan-Meier curves and log-rank test were utilized to compare TTF after MSR versus prior procedures using the same cohort of patients as their own control group. Subsequent analysis compared TTF after MSR to TTF after 93 other procedures among a second cohort of 18 MS-TN patients not undergoing MSR. BNI pain scores were compared between MSR and other procedures among the MS-TN cohort using a chi-square test. RESULTS TTF was significantly longer after MSR than after other procedures in the MSR cohort (median TTF 79 vs 10 months, respectively, p < 0.0001). Similarly, TTF was longer after MSR than after prior procedures in the non-MSR cohort (median TTF 79 vs 13 months, respectively, p < 0.001). MSR resulted in a higher proportion of excellent pain scores when compared to other procedures in the non-MSR cohort (77% vs 29%, p < 0.001). Probability of treatment survival was higher after MSR than after other procedures at all time points (3, 6, 12, 24, 36, and 48 months). There were no deaths or major complications after MSR. CONCLUSIONS TTF was significantly longer following MSR compared to prior procedures in MS-TN patients. Additionally, a higher proportion of patients achieved excellent BNI pain scores after MSR. PMID- 30004275 TI - Leptin and camel milk abate oxidative stress status, genotoxicity induced in valproic acid rat model of autism. AB - The aspect of treatment of autistic behaviour was investigated using valproic acid rat model of pregnant female rats. Two main groups (10 male rats/group) were treated for 6 days and then divided into six subgroups. The first group of normal rats was divided into three subgroups: (A) - control group, (B) - treated with camel milk (CAM; 2 mL/p.o) and (C) - treated with leptin (1000 ug/kg i.p) twice daily. The second group of autistic rats was randomly distributed into four subgroups as follows: (D) - positive control (autistics rats), (E) - treated with CAM, (F) - treated with a moderate dose of leptin and (G) - treated with a higher dose of leptin. Autistic behaviours of male offspring were checked by grooming and elevated pulz maze tests. Valproic acid (VPA)-induced autistic rats showed severe changes in oxidative stress markers, neurotransmitters and inflammatory cytokines, besides genotoxic manifestation of expression of tumour necrosis factor (TNF)-alpha, Bax and caspase-3. Leptin or CAM alone showed no signs of toxicity. CAM showed pronounced improvement in control rats than control itself. Leptin or CAM treatment of autistic animals showed a significant improvement of all measured parameters and genetic expression values. The improvement was pronounced in animals treated with CAM. These results suggest that CAM is a potential therapeutic candidate for autism via regulation of inflammatory and apoptotic pathways. Leptin plays an essential role in alleviation of autistic behaviour through antioxidant effects. PMID- 30004278 TI - Phenytoin versus levetiracetam as prophylaxis for postcraniotomy seizure in patients with no history of seizures: systematic review and meta-analysis. AB - OBJECTIVE De novo seizure following craniotomy (DSC) for nontraumatic pathology may adversely affect medical and neurological outcomes in patients with no history of seizures who have undergone craniotomies. Antiepileptic drugs (AEDs) are commonly used prophylactically in patients undergoing craniotomy; however, evidence supporting this practice is limited and mixed. The authors aimed to collate the available evidence on the efficacy and tolerability of levetiracetam monotherapy and compare it with that of the classic AED, phenytoin, for DSC. METHODS PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies that compared levetiracetam with phenytoin for DSC prevention. Inclusion criteria were adult patients with no history of epilepsy who underwent craniotomy with prophylactic usage of phenytoin, a comparator group with levetiracetam treatment as the main treatment difference between the two groups, and availability of data on the numbers of patients and seizures for each group. Patients with brain injury and previous seizure history were excluded. DSC occurrence and adverse drug reaction (ADR) were evaluated. Seizure occurrence was calculated using the Peto odds ratio (POR), which is the relative effect estimation method of choice for binary data with rare events. RESULTS Data from 7 studies involving 803 patients were included. The DSC occurrence rate was 1.26% (4/318) in the levetiracetam cohort and 6.60% (32/485) in the phenytoin cohort. Meta-analysis showed that levetiracetam is significantly superior to phenytoin for DSC prevention (POR 0.233, 95% confidence interval [CI] 0.117-0.462, p < 0.001). Subgroup analysis demonstrated that levetiracetam is superior to phenytoin for DSC due to all brain diseases (POR 0.129, 95% CI 0.039-0.423, p = 0.001) and tumor (POR 0.282, 95% CI 0.117-0.678, p = 0.005). ADRs in the levetiracetam group were cognitive disturbance, thrombophlebitis, irritability, lethargy, tiredness, and asthenia, whereas rash, anaphylaxis, arrhythmia, and hyponatremia were more common in the phenytoin group. The overall occurrence of ADR in the phenytoin (34/466) and levetiracetam (26/432) groups (p = 0.44) demonstrated no statistically significant difference in ADR occurrence. However, the discontinuation rate of AEDs due to ADR was 53/297 in the phenytoin group and 6/196 in the levetiracetam group (POR 0.266, 95% CI 0.137-0.518, p < 0.001). CONCLUSIONS Levetiracetam is superior to phenytoin for DSC prevention for nontraumatic pathology and has fewer serious ADRs that lead to discontinuation. Further high-quality studies that compare levetiracetam with placebo are necessary to provide evidence for establishing AED guidelines. PMID- 30004277 TI - Surgical anatomy of the superior hypophyseal artery and its relevance for endoscopic endonasal surgery. AB - OBJECTIVE The endoscopic endonasal approach has become a routine corridor to the suprasellar region. The superior hypophyseal arteries (SHAs) are intimately related to lesions in the suprasellar space, such as craniopharyngiomas and meningiomas. Here the authors investigate the surgical anatomy and variations of the SHA from the endoscopic endonasal perspective. METHODS Thirty anatomical specimens with vascular injection were used for endoscopic endonasal dissection. The number of SHAs and their origin, course, branching, anastomoses, and areas of supply were collected and analyzed. RESULTS A total of 110 SHAs arising from 60 internal carotid arteries (ICAs), or 1.83 SHAs per ICA (range 0-3), were found. The most proximal SHA always ran in the preinfundibular space and provided the major blood supply to the infundibulum, optic chiasm, and proximal optic nerve; it was defined as the primary SHA (pSHA). The more distal SHA(s), present in 78.3% of sides, ran in the retroinfundibular space and supplied the stalk and may also supply the tuber cinereum and optic tracts. In the two sides (3.3%) in which no SHA was present, the territory was covered by a pair of infundibular arteries originating from the posterior communicating artery. Two-thirds of the pSHAs originated proximal to the distal dural ring; half of these arose from the carotid cave portion of the ICA, whereas the other half originated proximal to the cave. Four branching patterns of the pSHA were recognized, with the most common pattern (41.7%) consisting of three or more branches with a tree-like pattern. Descending branches were absent in 25% of cases. Preinfundibular anastomoses between pSHAs were found in all specimens. Anastomoses between the pSHA and the secondary SHA (sSHA) or the infundibular arteries were found in 75% cases. CONCLUSIONS The first SHA almost always supplies the infundibulum, optic chiasm, and proximal optic nerve and represents the pSHA. Compromising this artery can cause a visual deficit. Unilateral injury to the pSHA is less likely to cause an endocrine deficit given the artery's abundant anastomoses. A detailed understanding of the surgical anatomy of the SHA and its many variations may help surgeons when approaching challenging lesions in the suprasellar region. PMID- 30004279 TI - Comparison of 3D intraoperative digital subtraction angiography and intraoperative indocyanine green video angiography during intracranial aneurysm surgery. AB - OBJECTIVE During the last decade, improvements in real-time, high-resolution imaging of surgically exposed cerebral vasculature have been realized with the successful introduction of intraoperative indocyanine green video angiography (ICGVA) and technical advances in intraoperative digital subtraction angiography (DSA). With the availability of 3D intraoperative DSA (3D-iDSA) in hybrid operating rooms, the present study offers a contemporary comparison for rates of accuracy and discordance. METHODS In this retrospective study of prospectively collected data, 140 consecutive patients underwent microsurgical treatment of intracranial aneurysms (IAs) in a hybrid operating room. Variables analyzed included patient demographics, aneurysm-specific characteristics, intraoperative ICGVA and 3D-iDSA findings, and the need for intraoperative clip readjustment. The authors defined the discordance rate of the two modalities as a false negative finding that necessitated clip repositioning after 3D-iDSA. RESULTS In 120 patients, ICGVA and 3D-iDSA were used to evaluate 134 IA obliterations. Of 215 clips used, 29 (14%) were repositioned intraoperatively, improving the surgical result in all 29 patients (24%). Repositioning was prompted by visual inspection and microvascular Doppler ultrasonography in 8 (28%), ICGVA in 13 (45%), and 3D-iDSA in 7 (24%) patients. Clip repositioning was needed in 7 patients (6%) based on 3D-iDSA, yielding an ICGVA accuracy rate of 94%. Five (71%) of the ICGVA-3D-iDSA discordances that prompted clip repositioning occurred at the anterior communicating artery complex. CONCLUSIONS A combination of vascular monitoring techniques most often achieved correct intraoperative interpretation of complete IA occlusion and parent artery integrity. Compared with 3D-iDSA imaging, ICGVA demonstrated high accuracy. Despite the relatively low discordance rate, iDSA was confirmed to be the gold standard. Improved imaging quality, including 3D-iDSA, supports its routine use in IA surgery, obviating the need for postoperative DSA. PMID- 30004280 TI - Longitudinal survey of cranial case log entries during neurological surgery residency training. AB - OBJECTIVE The purpose of this study was to analyze national trends in adult cranial cases performed by neurological surgery residents as logged into the Accreditation Council for Graduate Medical Education (ACGME) system. METHODS The ACGME resident case logs were retrospectively reviewed for the years 2009-2017. In these reports, the national average of cases performed by graduating residents is organized by year, type of procedure, and level of resident. These logs were analyzed in order to evaluate trends in residency experience with adult cranial procedures. The reported number of cranial procedures was compared to the ACGME neurosurgical minimum requirements for each surgical category. A linear regression analysis was conducted in order to identify changes in the average number of procedures performed by residents graduating during the study period. Additionally, a 1-sample t-test was performed to compare reported case volumes to the ACGME required minimums. RESULTS An average of 577 total cranial procedures were performed throughout residency training for each of the 1631 residents graduating between 2009 and 2017. The total caseload for graduating residents upon completion of training increased by an average of 26.59 cases each year (r2 = 0.99). Additionally, caseloads in most major procedural subspecialty categories increased; this excludes open vascular and extracranial vascular categories, which showed, respectively, a decrease and no change. The majority of cranial procedures performed throughout residency pertained to tumor (mean 158.38 operations), trauma (mean 102.17 operations), and CSF diversion (mean 76.12 operations). Cranial procedures pertaining to the subspecialties of trauma and functional neurosurgery showed the greatest rise in total procedures, increasing at 8.23 (r2 = 0.91) and 6.44 (r2 = 0.95) procedures per graduating year, respectively. CONCLUSIONS Neurosurgical residents reported increasing case volumes for most cranial procedures between 2009 and 2017. This increase was observed despite work hour limitations set forth in 2003 and 2011. Of note, an inverse relationship between open vascular and endovascular procedures was observed, with a decrease in open vascular procedures and an increase in endovascular procedures performed during the study period. When compared to the ACGME required minimums, neurosurgery residents gained much more exposure to cranial procedures than was expected. Additionally, a larger caseload throughout training suggests that residents are graduating with greater competency and experience in cranial neurosurgery. PMID- 30004281 TI - Letter to the Editor. Injury among neurosurgeons participating in organized softball. PMID- 30004282 TI - Letter to the Editor. EVD clamp trials and ventriculoperitoneal shunt insertions in patients with nontraumatic SAH. PMID- 30004283 TI - Letter to the Editor. Effect of facility costs in the treatment of neurosurgical patients using the Value Driven Outcome database. PMID- 30004285 TI - Surgical or endovascular management of ruptured intracranial aneurysms: an agreement study. AB - OBJECTIVE Ruptured intracranial aneurysms (RIAs) can be managed surgically or endovascularly. In this study, the authors aimed to measure the interobserver agreement in selecting the best management option for various patients with an RIA. METHODS The authors constructed an electronic portfolio of 42 cases of RIA in which an angiographic image along with a brief clinical vignette for each patient were displayed. Undisclosed to the responders was that the RIAs had been categorized as International Subarachnoid Aneurysm Trial (ISAT) (small, anterior circulation, non-middle cerebral artery location, n = 18) and non-ISAT (n = 22) aneurysms; the non-ISAT group also included 2 basilar apex aneurysms for which a high number of endovascular choices was expected. The portfolio was sent to 132 clinicians who manage patients with RIAs and circulated to members of an American surgical association. Judges were asked to choose between surgical and endovascular management, to indicate their level of confidence in the choice of treatment on a quantitative 0-10 scale, and to determine whether they would include the patient in a randomized trial in which both treatments are compared. Eleven clinicians were asked to respond twice at least 1 month apart. Responses were analyzed using kappa statistics. RESULTS Eighty-five clinicians (58 cerebrovascular surgeons, 21 interventional neuroradiologists, and 6 interventional neurologists) answered the questionnaire. Overall, endovascular management was chosen more frequently (n = 2136 [59.8%] of 3570 answers). The proportions of decisions to clip were significantly higher for non-ISAT (50.8%) than for ISAT (26.2%) aneurysms (p = 0.0003). Interjudge agreement was only fair (kappa 0.210, 95% CI 0.158-0.276) for all cases and judges, despite high confidence levels (mean score > 8 for all cases). Agreement was no better within subgroups of clinicians with the same specialty, years of experience, or location of practice or across capability groups (ability to clip or coil, or both). When agreement was defined as > 80% of responders choosing the same option, agreement occurred for only 7 of 40 cases, all of which were ISAT aneurysms, for which coiling was preferred. CONCLUSIONS Agreement between clinicians regarding the best management option was infrequent but centered around coiling for some ISAT aneurysms. Surgical clipping was chosen more frequently for non-ISAT aneurysms than for ISAT aneurysms. Patients with such an aneurysm might be candidates for inclusion in randomized trials. PMID- 30004284 TI - Proposal of a follow-up imaging strategy following Pipeline flow diversion treatment of intracranial aneurysms. AB - OBJECTIVE There is currently no standardized follow-up imaging strategy for intracranial aneurysms treated with the Pipeline embolization device (PED). Here, the authors use follow-up imaging data for aneurysms treated with the PED to propose a standardizable follow-up imaging strategy. METHODS A retrospective review of all patients who underwent treatment for ruptured or unruptured intracranial aneurysms with the PED between March 2013 and March 2017 at 2 major academic institutions in the US was performed. RESULTS A total of 218 patients underwent treatment for 259 aneurysms with the PED and had undergone at least 1 follow-up imaging session to assess aneurysm occlusion status. There were 235 (90.7%) anterior and 24 posterior (9.3%) circulation aneurysms. On Kaplan-Meier analysis, the cumulative incidences of aneurysm occlusion at 6, 12, 18, and 24 months were 38.2%, 77.8%, 84.2%, and 85.1%, respectively. No differences in the cumulative incidence of aneurysm occlusion according to aneurysm location (p = 0.39) or aneurysm size (p = 0.81) were observed. A trend toward a decreased cumulative incidence of aneurysm occlusion in patients 70 years or older was observed (p = 0.088). No instances of aneurysm rupture after PED treatment or aneurysm recurrence after occlusion were noted. Sixteen (6.2%) aneurysms were re treated with the PED; 11 of these had imaging follow-up data available, demonstrating occlusion in 3 (27.3%). CONCLUSIONS The authors propose a follow-up imaging strategy that incorporates 12-month digital subtraction angiography and 24-month MRA for patients younger than 70 years and single-session digital subtraction angiography at 12 months in patients 70 years or older. For recurrent or persistent aneurysms, re-treatment with the PED or use of an alternative treatment modality may be considered. PMID- 30004286 TI - Bariatric Surgery and Gastroesophageal Reflux. AB - The epidemic of morbid obesity in the United States has reached dramatic proportions. Because of the associated comorbidities and because life style changes and exercise have limited effect, bariatric surgery has been used more often during the last 10 years as it has been shown to be safe and effective in decreasing weight and resolving comorbidities. Recently many studies have focused on a potential complication of bariatric surgery, gastroesophageal reflux disease, mostly because of the increasing use of sleeve gastrectomy. This article reviews the pathophysiology of reflux in morbid obese patients, the proper work up before a bariatric operation, and the selection of the procedure based on the individual patient's characteristics. PMID- 30004287 TI - Laparoscopic Transperitoneal Radical Nephrectomy for Renal Masses with Level I and II Thrombus. AB - BACKGROUND: We aimed to report surgical and oncological outcomes of renal cell carcinoma (RCC) patients with level I and II thrombus treated with laparoscopic transperitoneal radical nephrectomy. PATIENTS AND METHODS: Medical records of 13 patients were reviewed retrospectively in a single center between 2005 and 2017. Hem-o-lok(r) clips were used to secure renal artery and renal vein, excluding 2 patients with an attached thrombus on the right side. RESULTS: Seven male and 6 female patients were treated laparoscopically, and conversion to open surgery was not required in any case. The mean age was 61.6 +/- 7.8 years (range 45 to 75 years) and the mean body mass index was 27 +/- 4.6 kg/m2 (range 18.8 to 34.5 kg/m2). Median tumor size was 9.5 * 7.3 cm (range 5 to 14 cm) and 5 patients who had preoperative metastases underwent cytoreductive nephrectomy. The mean operative time was 137.6 +/- 45.8 minutes (range 60 to 200 minutes) and blood loss was 105 +/- 34.9 mL (range 50 to 150 mL). The mean hospital stay was 4.4 +/- 3.9 days (range 1 to 15 days). Splenic capsular injury occurred in 1 patient and the vena cava was injured in another. Three patients needed blood transfusions. The mean follow-up period was 25 months (range 12 to 86 months). CONCLUSION: Laparoscopic transperitoneal radical nephrectomy can be reliable option for surgical management of RCC with level I and II thrombus in experienced centers. PMID- 30004288 TI - Expression of Luminal Progenitor Marker CD117 in the Human Breast Gland. AB - CD117 is a putative marker of luminal progenitor cells in the human breast. However, so far mapping the expression pattern of CD117 within the normal gland has not been reported. Here, we examined the anatomical distribution of CD117 expressing cells in lobular and ductal structures by immunohistochemistry. The presence of CD117-positive luminal cells could be divided into three distinct patterns: (1) contiguous, with coherent positive cells and rare negative cells interspaced; (2) patched, with a roughly equal frequency of positive and negative cells distributed focally; or (3) scattered, with few or no positive cells in the structure. Generally, a patched or scattered expression pattern was more frequent in lobules compared with ducts. Furthermore, an age-correlated increase in heterogeneity was observed. When comparing women below and above 21 years of age this heterogeneity was evident for both lobules and ducts. Although CD117 expression was generally segregated from luminal-lineage transcription factor GATA3-positive cells, some did co-express both markers. Finally, co-staining with Ki-67 revealed that a prominent part of cycling cells belonged to the CD117 positive population. Together these data demonstrate the presence of a CD117 expressing progenitor compartment with the capacity to replenish the luminal lineage of the breast gland. PMID- 30004289 TI - ABO blood type and risk of hepatocellular carcinoma: a meta-analysis. AB - BACKGROUND: ABO blood type is an invariant factor. There is a link between ABO blood type and some malignancies, such as gastric, pancreatic, and skin cancer. The role of ABO blood type in the pathogenesis of hepatocellular carcinoma (HCC) remains controversial. We performed a meta-analysis to explore the relationship between ABO blood type and risk of HCC. METHODS: Literature search was conducted among the PubMed, EMBASE, and Cochrane Library databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Seven papers were included. They included 92,847 healthy subjects, 5,463 patients with hepatitis, 294 cirrhotic patients, and 3,322 HCC patients. The proportion of blood type O was significantly lower in HCC patients than healthy subjects (OR = 0.76, 95%CI = 0.66-0.87, P < 0.0001) without any significant heterogeneity (P = 0.55, I2 = 0%). The proportions of blood types A, B, and AB were not significantly different between HCC patients and healthy subjects. The proportion of ABO blood type was not significantly different between patients with HCC and those with hepatitis or cirrhosis. CONCLUSION: HCC patients might have a lower proportion of blood type O than healthy subjects. Among the patients with chronic liver diseases, ABO blood type might not be associated with the risk of HCC. PMID- 30004290 TI - Leveraging RNA-Seq to Characterize Resistance to Brown Stem Rot and the Rbs3 Locus in Soybean. AB - Brown stem rot, caused by the fungus Phialophora gregata, reduces soybean yield by up to 38%. Although three dominant resistance loci have been identified (Rbs1 to Rbs3), the gene networks responsible for pathogen recognition and defense remain unknown. Further, identification and characterization of resistant and susceptible germplasm remains difficult. We conducted RNA-Seq of infected and mock-infected leaf, stem, and root tissues of a resistant (PI 437970, Rbs3) and susceptible (Corsoy 79) genotype. Combining historical mapping data with genotype expression differences allowed us to identify a cluster of receptor-like proteins that are candidates for the Rbs3 resistance gene. Reads mapping to the Rbs3 locus were used to identify potential novel single-nucleotide polymorphisms within candidate genes that could improve phenotyping and breeding efficiency. Comparing responses to infection revealed little overlap in differential gene expression between genotypes or tissues. Gene networks associated with defense, DNA replication, and iron homeostasis are hallmarks of resistance to P. gregata. This novel research demonstrates the utility of combining contrasting genotypes, gene expression, and classical genetic studies to characterize complex disease resistance loci. PMID- 30004291 TI - Altered nuclei-specific thalamic functional connectivity patterns in multiple sclerosis and their associations with fatigue and cognition. AB - BACKGROUND: The thalamus, affected early in multiple sclerosis (MS), is a heterogeneous composition of functionally distinct nuclei and is associated with fatigue, cognition, and other outcomes. However, most previous functional imaging studies considered the thalamus only as a whole. OBJECTIVE: To investigate MS related abnormalities in nuclei-specific thalamic functional connectivity (FC) and their associations with fatigue and cognitive outcomes. METHODS: Resting state functional magnetic resonance imaging (fMRI) was analyzed in 64 MS patients and 26 healthy controls (HC). Whole-brain FC maps for four thalamic subregions seeds were computed for each subject. FC maps were compared between groups, and group by FC interaction effects were assessed for fatigue and cognitive measures. RESULTS: MS patients had decreased FC between the left medial thalamic nuclei and left angular gyrus and reduced FC between the left posterior thalamic nuclei and left supramarginal gyrus, as well as decreased right medial thalamic nuclei connectivity with bilateral caudate/thalamus and left cerebellar areas ( p < 0.05 corrected). MS patients had increased FC between the left anterior thalamic nuclei and anterior cingulate cortex bilaterally. There were significant relationships between connectivity alterations and fatigue and cognitive measures between groups ( p < 0.05 corrected). CONCLUSION: FC alteration is nuclei specific and is differentially associated with fatigue and cognition. PMID- 30004292 TI - Reversing Antimicrobial Resistance in Multidrug-Resistant Klebsiella pneumoniae of Clinical Origin Using 1-(1-Naphthylmethyl)-Piperazine. AB - Eleven clinical Klebsiella pneumoniae fluoroquinolone-resistant isolates were tested to access the potential of adjuvant therapies to reduce antimicrobial resistance using fixed concentrations of the chemosensitizers chlorpromazine (CPZ), thioridazine (TZ), phenylalanine-arginine-beta-naphthylamide (PAbetaN), and 1-(1-naphthylmethyl)-piperazine-(NMP) with varying concentrations of antimicrobial agents nalidixic acid (NAL), ciprofloxacin (CIP), moxifloxacin (MXF), tetracycline (TET), and chloramphenicol (CHL). Ethidium bromide dye was used together with the chemosensitizers to investigate permeabilization effects. NMP was assessed for its capacity to reduce the mass of biofilm alone and in combination with CIP and MXF. Of the selected chemosensitizers, NMP exhibited the greatest capacity to reverse resistance and inhibit efflux, based on the concentrations tested. Susceptibility to antimicrobial agents including (fluoro)quinolones, TET, and CHL were found to be increased in the presence of NMP, in a concentration-dependent manner. PAbetaN also demonstrated similar effects when combined with the chemosensitizers tested. In the case of half of the isolates studied, NMP alone reduced preformed biofilm biomass. Combinations of latter along with CIP or MXF were also found to reduce the mass of preformed biofilm, in the case of only some of the bacterial isolates. The capacity of NMP to reduce antimicrobial resistance could be of relevance as a strategy to limit bacterial colonization on abiotic surfaces. PMID- 30004293 TI - Vibratory splint therapy for decreasing sleep clenching: A pilot study. AB - Objective To estimate the effect of a vibratory splint (VibS) in reducing sleep clenching (SC) and TMD pain. Methods Target sample was consecutive 19 TMD patients attending the Orofacial Pain Clinic at FFO-FOUSP. Patients used the VibS or acrylic occlusal splint (OS) as control for 14 days. Outcome variables were SC frequency and pain, assessed by a portable electromyography detector-analyzer (BiteStripTM) and 100 mm VAS, respectively. Statistical analyses were performed with two-way repeated measures ANOVA, and analysis of covariance (ANCOVA). Results VibS promoted a marked decrease, whereas acrylic OS increased SC frequency after two weeks of use. Due to a significant difference in initial VAS levels between VibS and control group, the effect of the two splints on TMD pain could not be clearly estimated. Conclusion The results suggested that VibS can potentially be used to reduce SC frequency, although further studies with larger sample size are necessary to confirm these findings. PMID- 30004294 TI - Sport-specific musculoskeletal growth and postural control in female artistic gymnasts: a 12 month cohort study. AB - Female gymnasts have been evidenced to experience sport-specific growth, of which broad shoulders and narrow hips are common characteristics. In addition to being a central component of handstand performance, postural control mechanisms, including whole-body and lumbo-pelvic stability, have been identified as risk factors for overuse spinal pathology. The study aimed to develop a fundamental understanding of musculoskeletal growth and postural control responses of female artistic gymnasts in order to extend longitudinal insights into overuse spinal pathology risk. Whole-body anthropometric measures were collected for 12 competitive female gymnasts (age at recruitment: nine to 15 years) at three time points across a 12 month period. Musculoskeletal growth was partially defined as the rate of bicristal-to-biacromial breadth ratio development, and informed shoulder- and pelvis-dominant growth sub-groups. Kinematic and kinetic indicators of postural control were determined for a total of 700 handstand trials. The shoulder-dominant (gymnastics-specific) growth group was found to have significantly greater biomechanical risk for general stability (p < 0.001) than the pelvis-dominant group. Significantly greater lumbo-pelvic risk was demonstrated for the pelvis-dominant group (p < 0.001). Extended idiosyncratic examination of proportional sport-specific growth measures alongside multi faceted risk monitoring was advocated for the effective development of future overuse pathology prevention protocols. PMID- 30004295 TI - A novel Cervical Spine Protection device for reducing neck injuries in contact sports: design concepts and preliminary in vivo testing. AB - Head and neck injuries are common in contact sports such as American football. Different mechanisms can produce such injuries, including compressive impact forces on the crown of the helmet with the neck in a flexed chin-down position. The aim of this paper was developing and testing a novel Cervical Spine Protection Device (CSPD) designed to keep the neck within its safe physiological range. The cervical spine range of motion (ROM) of ten participants was measured under four conditions: free; wearing a football gear; wearing the CSPD; and wearing the CSPD underneath the gear. The CSPD was tested in terms of passive and active restraint of head motion, and for its capability to improve endurance time of the neck extensor muscles. Wearing the CSPD resulted in a significant 40-60% reduction in ROM across the three anatomical planes, and in increased endurance of the neck extensor muscles (FREE: 114 +/- 57 s; CSPD: 214 +/- 95 s; p = 0.004). In quasi-static loading conditions the CSPD was capable of keeping the neck within its physiological range, thus it may be used to decrease the risk of severe injuries due to dangerous chin-down positions. PMID- 30004296 TI - Onset of Accelerated Muscle Deoxygenation During the 20-m Shuttle Run Test in Boys. AB - PURPOSE: This study aimed to compare the relative exercise intensity at which the onset of accelerated muscle deoxygenation occurs during the 20-m shuttle run test (20mSRT) between boys and men and to examine whether the timing of the onset of acceleration appearance is related to 20mSRT performance in boys. METHODS: Twenty four boys performed the 20mSRT, during which concentration changes in oxygenated and deoxygenated hemoglobin and myoglobin (DeltaOxy-Hb and DeltaDeoxy-Hb, respectively) in the m. vastus lateralis were monitored using a portable near infrared spectroscopy device. The boys' data were compared with those of 29 men in a previous study. RESULTS: An onset of accelerated decrease in Delta[Oxy-Hb - Deoxy-Hb] was found in 11 of the 24 boys (45.8%) and 20 of the 29 men (69.0%) and was found at a higher relative exercise intensity in the boys than in the men. The number of laps at which the onset of acceleration occurred correlated with total laps in the boys (r = .87). CONCLUSIONS: These findings demonstrate that the onset of accelerated muscle deoxygenation during the 20mSRT occurs at a higher relative exercise intensity in boys than in men. Our findings also show that the timing of the onset of acceleration appearance is associated with 20mSRT performance in boys. PMID- 30004297 TI - Contribution of passive actions to the lower limb joint moments and powers during gait: A comparison of models. AB - The lower limb passive actions representing the actions of all the passive periarticular structures have been shown to have a significant contribution to the power generation and absorption during gait. However, the respective magnitude of its different components was not established, although models of ligament moment were implemented in some musculoskeletal models. These ligament moments have shown to have an influence on the musculo-tendon forces and contact forces but the models used were never specifically evaluated, that is, compared to the passive and net joint moments. Two models of passive joint moments and three models of ligament moments were selected from the literature. Ten subjects (23-29 years old, 79.8 +/- 9.5 kg, 1.85 +/- 0.06 m) participated in the study. Each subject performed three gait cycles in a gait laboratory to acquire the kinematics and ground reaction forces and to compute the ligament, passive and net moments of the right lower limb joints. The contributions of the passive joint moments to the net joint moments were in accordance with the literature, although time shifts appeared for peaks in the hip and knee powers. Two of the models of ligament moments seemed, in fact, to represent the passive joint moments as their contributions were very similar while the third model of ligament moments seemed to represent only penalty-based joint limits. As a conclusion, this study showed that the models of ligament moments existing in the literature do not seem reliable. This study also demonstrated that the use of non subject-specific models of the passive joint moments could be a valid approach for healthy subjects. PMID- 30004298 TI - Increased Rho kinase activity in patients with heart ischemia/reperfusion. AB - BACKGROUND/AIM: Rho kinase is a downstream effector of Rho GTPase that is known to regulate various pathological processes. The aim of this study was to evaluate the regulation of Rho kinase activity in leukocytes in patients with ischemia/reperfusion (I/R) injury. PATIENTS AND METHODS: We investigated 38 patients with acute ST-segment elevation myocardial infarction (STEMI), 26 patients with atherosclerosis (AS) and 22 normal subjects. All patients underwent coronary angiography (CAG) and all STEMI patients received primary percutaneous coronary intervention (PPCI) of the left anterior descending artery (LAD) within 12 h after chest pain on-set. Blood samples for leukocyte Rho kinase activity were obtained before CAG and 3 and 24 hours after CAG/PCI. RESULTS: Rho kinase activity increased in the I/R and AS groups. Compared with the AS group, Rho kinase activity was significantly higher in peripheral blood leukocytes in STEMI/PPCI. Furthermore, there was no correlation between changes in Rho kinase activity and changes in high-sensitivity troponin I (hs-TnI) and C-reactive protein (CRP). There was a negative correlation between Rho kinase activity and IL-6. CONCLUSION: Rho kinase is involved in the pathogenesis of heart I/R injury in patients. Inhibition of Rho kinase may be an additional therapeutic intervention for the treatment of I/R. PMID- 30004299 TI - Bone mineral density and serum osteocalcin levels in patients with gout. AB - OBJECTIVE: The objective of the study is to evaluate the relation of gout with osteoporosis and serum osteocalcin (OC) levels. MATERIAL AND METHODS: Seventy five patients diagnosed with gout and 55 controls were included in the study. Comorbid conditions and drugs associated with osteoporosis were excluded. The T and Z scores from lumbar spine (L2-L4) and femur (neck, ward, trochanter, total) were determined by dual-energy X-ray absorptiometry (DXA). OC levels were measured by enzyme-linked immunosorbent assay. RESULTS: Osteoporosis according to T scores of lumbar vertebrae L2-L4 was found to be significantly higher in patients with gout compared to the control group (p = 0.02). Lumbar spine T-score was -1.6 in gout group and -1.0 in controls. OC level was 7.9 ng/mL in the gout group and 18.9 ng/mL in the control group. There was a significant difference (p < 0.001). In addition, mean OC level was 12.4 +/- 6.9 ng/mL in the patients diagnosed with osteoporosis and 17.2 +/- 10.6 ng/mL in the patients that were classified as normal and a significant difference was established between the two groups (p = 0.03). A significant negative correlation was found between OC level and body mass index, age, and age at first attack. Similarly, femoral T-score established a negative correlation with parathyroid hormone, age, age at first attack, and allopurinol dose. CONCLUSION: Serum OC level can be a useful marker in the assessment of bone turnover and clinicians should keep osteoporosis in mind in gout patients. PMID- 30004300 TI - Precision Medicine Goes Global: How to Get It Right? Four Ways to Mobilize Scientific Knowledge. AB - Globalization and knowledge mobilization (KM) are twin challenges impacting precision medicine currently. Previous KM models have been largely limited to an implementation framework whereby knowledge is imagined as a billiard ball to be simply rolled over from the laboratory to society and from developed to developing countries. This narrow and sanitized understanding of KM and science as being detached from social forces, human values, politics, and power inequities does not help to achieve robust and responsible emergence of precision medicine, not least because tailored medicines are not simple products ready to use off-the-shelf without customization in each country, local context and society. It is time to broaden the art and science of KM by rethinking knowledge as a dynamic co-product of both technology and social systems in which science is embedded. This article presents an analysis of the four possible approaches to KM available to the precision medicine community: (1) "knowledge implementation," (2) "research collaborator capacity building," (3) "collaborative entanglement" that removes the barriers between research and practice, and extends knowledge co creation activities beyond scientists by inviting publics, patients, and clinicians as researchers, and (4) "knowledge ecosystem" approach that adopts systems thinking, addressing not only technology development but also the politics of innovation, whereby power differences in scientific practice are addressed, for example, to achieve gender parity and diversity in the scientific work force. Blending of laboratory science with KM theory and practice informs robust and responsible emergence of precision medicine innovations, and helps strike the right balance between promotion and regulation of emerging technologies. PMID- 30004302 TI - Partial swing golf shots: scaled from full swing or independent technique? AB - During practice and competition, golfers are required to use submaximal effort to hit the ball a given distance, i.e., perform a partial shot. While the full golf swing has undergone extensive research, little has addressed partial shots and the biomechanical modifications golfers employ. This study investigates the biomechanical changes between full and partial swings, and determines if the partial swing is a scaled version of the full swing. Using a repeated measures design, 13 male golfers completed a minimum of 10 swings in the full and partial swing conditions, whilst club, ball, kinematic, and kinetic parameters were recorded. Large and statistically significant reductions in body motion (centre of pressure ellipse: 33.0%, p = 0.004, d = 2.26), combined with moderate reductions in lateral shift (25.5%, p = 0.004, d = 0.33) and smaller reductions in trunk rotation (arm to vertical at top of backswing: 14.1%, p = 0.002, d = 2.58) indicate golfers favour larger reductions in proximal measures, combined with diminished reductions as variables moved distally. Furthermore, the partial swing was not found to be a scaled version of the full swing implying a new approach to coaching practices might be considered. PMID- 30004301 TI - Hydromorphone-induced chorea as an atypical presentation of opioid neurotoxicity: A case report and review of the literature. AB - BACKGROUND: While opioid-induced myoclonus is well described, there are limited reports of opioid-induced chorea. Here we present the first case of chorea as a manifestation of opioid neurotoxicity due to hydromorphone. CASE PRESENTATION: A 20-year-old woman presenting with fevers and cutaneous lesions was diagnosed with hemophagocytic lymphohistiocytosis secondary to primary cutaneous lymphoma. Surgical resection of a cutaneous lesion was complicated by severe postoperative pain requiring rapid opioid dose escalation. Seven days after hydromorphone was initiated, she developed positive myoclonus, hallucinations, delirium, and involuntary, flowing movements consistent with chorea. She had no personal or family history of nervous system disorders and was not taking any medications associated with drug-induced chorea. Case management: The remainder of her neurologic examination was unremarkable. Her renal function was normal and no etiology was found on neuroimaging or laboratory workup. Hydromorphone was discontinued and pain control was achieved with fentanyl. Case outcome: The patient's neurotoxic symptoms including chorea resolved within 72 h of hydromorphone discontinuation. CONCLUSION: Further studies are needed to determine which patients have a unique sensitivity to opioids predisposing them to chorea. Clinicians should be aware that chorea may be a sign of such toxicity so that rapid corrective action can be taken. PMID- 30004303 TI - Is specialized palliative cancer care associated with use of antineoplastic treatment at the end of life? A population-based cohort study. AB - BACKGROUND: The use of chemotherapy in the last 14 days of life should be as low as possible. AIM: To study the factors related to the use of chemotherapy in the last 14 days of life and the factors related to concurrent antineoplastic treatment and specialized palliative care. DESIGN: This was a population-based cohort study. The data were collected from the Danish Register of Causes of Death, the Danish National Patient Register, and the Danish Palliative Care Database. Analyses were descriptive and multivariate logistic regression. SETTING/PARTICIPANTS: Cancer decedents between 2010 and 2013 in the Capital Region of Denmark. RESULTS: During the study period, 17,246 individuals died of cancer and 33% received specialized palliative care. In the last 14 days of life, 4.2% received chemotherapy. Younger patients and patients with hematological cancers were more likely to receive chemotherapy in the last 14 days of life. Receiving specialized palliative care was associated with a lower risk of receiving chemotherapy in the last 14 days of life-odds ratio 0.15 for hospices and 0.53 for palliative hospital units. A total of 8% of the population received concurrent antineoplastic treatment and specialized palliative care. Female gender, younger age, and breast and prostate cancer were significantly associated with this concurrent model. CONCLUSION: Overall, the incidence of antineoplastic treatment in the last 14 days of life was low compared to other studies. Patients in specialized palliative care had a reduced risk of receiving chemotherapy at the end of life. PMID- 30004304 TI - High Level of APOA1 in Blood and Maternal Fetal Interface Is Associated With Early Miscarriage. AB - Early miscarriage (EM) is one of the most devastating obstetrical complications globally affecting the quality of women's life. In the present study, we aimed to identify proteins that correlate with and could act as biomarkers for EM. We performed 2-dimensional gel electrophoresis in chorionic villi samples followed by mass spectrometry for identification of differential protein expression with EM. Proteomic studies detected a total 124 protein spots, out of which 83 spots were differentially expressed between EM and controls in chorionic villi samples. Matrix assisted laser desorbtion/ionization-time of flight (MALDI-TOF) mass spectrometry analysis revealed Apolipoprotein A1 (APOA1) to be the most upregulated protein in the EM group that was validated by Western blotting and Enzyme-linked immunosorbent assay (ELISA) . We found low but not statistically significant level of APOA1 on 21st day of menstruation in comparison to the 7th day. APOA1 level was observed to be the lowest in the first trimester. Hence, this study suggests that low APOA1 expression is critical in establishing pregnancy and elevated APOA1 expression in chorionic villi correlates with EM. Similar observation in serum samples suggests its potential as a marker for the risk of EM. PMID- 30004305 TI - ? PMID- 30004307 TI - ? PMID- 30004308 TI - ? PMID- 30004306 TI - ? PMID- 30004309 TI - ? PMID- 30004312 TI - Twenty years' experience with myelomeningocele management at a single institution: lessons learned. AB - OBJECTIVE: The authors reviewed 20 years' experience with the surgical management of open myelomeningocele in a well-defined retrospective cohort from a single large academic medical center. Their goal was to define the characteristics of a modern cohort of children with myelomeningocele to allow for evidence-based decision-making for the treatment of these patients. METHODS: After IRB approval was obtained, the authors queried an operative database maintained by the Department of Neurological Surgery at Children's Hospital of Pittsburgh for patients who underwent closure of a myelomeningocele between 1995 and 2015. They identified 153 infants, and a retrospective chart review was performed. RESULTS: Eighty-eight percent of the patients required placement of a ventriculoperitoneal shunt, and 15% of these patients acquired shunt-related infections. Eighteen percent of patients underwent Chiari malformation type II (CM-II) decompression. Sixteen percent of patients underwent a tethered cord release. Three percent of patients died within the 1st year of life. Predictors of an early demise included poor Apgar scores, large head circumference, and need for early CM-II decompression. Functional motor outcome was slightly better than predicted by anatomical level of defect. CONCLUSIONS: Myelomeningoceles represent a severe birth defect with life-threatening complications. The authors provide long-term follow-up data and insight into factors that contribute to early death. PMID- 30004313 TI - Letter to the Editor. Ligamentum nuchae as a graft material for duraplasty in patients with Chiari malformation type I. PMID- 30004311 TI - Intensive care resources required to care for critically ill children with focal intracranial infections. AB - The authors reviewed cases in which children with a focal infection inside the head (ex: a brain abscess) were cared for in their pediatric ICU to describe the frequency of complications and quantify the ICU resources needed (ex: breathing tube, blood pressure medications, and/or an intracranial pressure monitor). This information helps clarify illness severity and has identified complications that we should further investigate to improve care for these children. PMID- 30004314 TI - Using subdural strip electrodes to define functional sensory nerves and the most inferior functional portion of the conus medullaris during detethering surgeries for tethered cord syndrome: a pilot study. AB - OBJECTIVE: The aim of this study was to investigate the feasibility of using subdural strip electrodes, placed just rostral to the surgical field, to record sensory evoked potentials (SEPs) from the lumbosacral sensory nerves and define the most inferior functional portion of the conus medullaris during detethering surgery for spinal dysraphism and/or tethered cord syndrome (TCS). METHODS: Six patients, 2 boys and 4 girls, aged 0.5 to 16 years, were enrolled in this study. One patient had lipomyelomeningocele-related, 4 had myelomeningocele-related, and 1 had diastematomyelia and lipomyelomeningocele-related TCS. In addition to the routine preparations that are needed for performing functional mapping and monitoring during surgery for spinal dysraphism and TCS, the patients had a 1 * 4 strip of electrodes placed rostral to the surgical field, where it was secured by a surgeon after opening the dura. With the patient under total intravenous anesthesia, the sensory nerves and conus medullaris were stimulated with a concentric bipolar electrode over the surgical field while SEPs were recorded with the strip electrodes to identify any possible sensory roots with remaining function and the most inferior functional portion of the conus medullaris. RESULTS: The SEP amplitudes that were recorded with the subdural strip electrodes ranged from 4 to 400 MUV, and the responses to sensory nerve stimulation were frequently much larger than were those to conus stimulation. Use of the SEP recordings for sensory mapping along with the routine mapping and monitoring techniques allowed detethering to be completed such that none of the patients sustained any new functional deficit after surgery. CONCLUSIONS: Recording SEPs from the functional sensory nerves and conus medullaris through subdural strip electrodes proved to be a feasible and valuable tool during detethering surgery in young patients. This approach may help surgeons achieve maximal detethering while preserving important sensory functions, consequently retaining the patient's quality of life. PMID- 30004315 TI - A novel etiology for craniospinal hypovolemia: a case of inferior vena cava obstruction. AB - The authors report on a patient with craniospinal hypovolemia and inferior vena cava obstruction, and describe how the two conditions may be linked. This unique report further advances the emerging literature on spinal CSF venous fistulae. PMID- 30004316 TI - Letter to the Editor. Percutaneous transforaminal endoscopic discectomy versus microendoscopic discectomy. PMID- 30004317 TI - Effects of preoperative mental distress versus surgical modality, arthroplasty, or fusion on long-term outcome in patients with cervical radiculopathy. AB - OBJECTIVE: Several efforts have been made to investigate the long-term efficacy of artificial disc replacement surgery compared with that of fusion after decompression for the treatment of cervical degenerative disc disease and radiculopathy. However, research on the impact of mental distress on surgical treatment outcome has been sparse. The aim of the authors was to investigate the potential predictive value of preoperative risk factors in determining long-term outcome. METHODS: A total of 153 patients (mean age 47 years) with single- or double-level cervical degenerative disc disease and radiculopathy were randomly assigned to undergo either anterior cervical discectomy and fusion (n = 70) or artificial disc replacement (n = 83). The primary outcome was the Neck Disability Index (NDI) score, a patient-reported function score that ranges from 0% to 100%; higher scores indicate greater disability. Preoperative variables such as sex, age, smoking status, employment status, having a strenuous job, neck pain duration, arm pain duration, amount of regular exercise, Hospital Anxiety and Depression Scale (HADS) score, NDI score, whether surgery was performed on 1 or 2 levels, and allocated treatment were analyzed in multiple linear regression models with the 5-year NDI score as the outcome. RESULTS: A total of 47 (31%) patients had either a HADS anxiety or HADS depression score of 10 points or higher. High values on the preoperative HADS were a negative predictor of outcome (p = 0.009). Treatment allocation had no effect on 5-year NDI scores (p = 0.32). CONCLUSIONS: Preoperative mental distress measured with the HADS affects long term outcome in surgically treated patients with cervical radiculopathy. PMID- 30004318 TI - Information Technologies: An Augmentation to Post-Traumatic Stress Disorder Treatment Among Trauma Survivors. AB - This review article presents existing research describing how information technologies can be used to improve mental health services for trauma survivors, either by enhancing existing treatment approaches or as a stand-alone means of delivering trauma-relevant interventions. The potential ways in which technology aids in overcoming barriers to care are first addressed in terms of providing mental health treatment. The use of technologies enables shifting the locus of care from the traditional provider's office to mobile, online, and virtual environments which are less threatening for patients with post-traumatic stress disorder (PTSD), helping to overcome the core nature of the illness which includes avoidance and increased personal isolation. We then outline how different technological tools can be used for key therapeutic tasks and conclude by discussing key emergent issues that are shaping current and future use of electronic technologies as part of the continuum of care for trauma-related disorders such as PTSD. PMID- 30004319 TI - Effects of Photobiomodulation on Degranulation and Number of Mast Cells and Wound Strength in Skin Wound Healing of Streptozotocin-Induced Diabetic Rats. AB - BACKGROUND: A lack of effective treatments still exists for patients suffering from diabetes mellitus. Photobiomodulation is proved as a beneficial therapeutic modality for wounds. OBJECTIVE: The aim of this study is to examine the effect of degranulation of mast cells and total number of mast cells in the remodeling step of an ischemic model of wound healing under the influence of photobiomodulation and conditioned medium (CM) from human bone marrow-derived mesenchymal stem cells (hBM-MSCs-CM), or CM, administered alone and or in combination. MATERIALS AND METHODS: Initially, type 1 diabetes mellitus was induced in 72 male adult rats. Then, after a month, one incision was made on the back of each rat. Subsequently, the rats were divided into four groups. The first group was considered as the control (placebo) group, the second group received CM, the third group received photobiomodulation, and the fourth group received photobiomodulation+CM. On days 4, 7, and 15, samples were extracted from the wound for histological and tensiometric examinations. The total number of mast cells, including the three types of mast cells, was counted by the stereological methods. The tensiometric properties of the repairing tissue were examined. RESULTS: The administration of photobiomodulation and CM, alone or in combination, significantly increased the tensiometric properties within the healing wounds. Histologically, photobiomodulation+CM, CM, and photobiomodulation groups showed a significant decrease in the three types of mast cells and in the total number of mast cells compared with the control group on day 15. CONCLUSIONS: We conclude that photobiomodulation and CM alone and or in combination significantly accelerated the healing process in a rat with a diabetic and ischemic wound, and significantly decreased the total number of mast cells and degranulation of mast cells. We suggest that the increased number of type 2 mast cells in the control group adversely affected the tensiometric properties of wounds in this group. PMID- 30004320 TI - Review: Beef-eating quality: a European journey. AB - This paper reviews recent research into predicting the eating qualities of beef. A range of instrumental and grading approaches have been discussed, highlighting implications for the European beef industry. Studies incorporating a number of instrumental and spectroscopic techniques illustrate the potential for online systems to non-destructively measure muscle pH, colour, fat and moisture content of beef with R 2 (coefficient of determination) values >0.90. Direct predictions of eating quality (tenderness, flavour, juiciness) and fatty acid content using these methods are also discussed though success is greatly variable. R 2 values for instrumental measures of tenderness have been quoted as high as 0.85 though R 2 values for sensory tenderness values can be as low as 0.01. Discriminant analysis models can improve prediction of variables such as pH and shear force, correctly classifying beef samples into categorical groups with >90% accuracy. Prediction of beef flavour continues to challenge researchers and the industry alike, with R 2 values rarely quoted above 0.50, regardless of instrumental or statistical analysis used. Beef grading systems such as EUROP and United States Department of Agriculture systems provide carcase classification and some indication of yield. Other systems attempt to classify the whole carcase according to expected eating quality. These are being supplemented by schemes such as Meat Standards Australia (MSA), based on consumer satisfaction for individual cuts. In Australia, MSA has grown steadily since its inception generating a 10% premium for the beef industry in 2015-16 of $187 million. There is evidence that European consumers would respond to an eating quality guarantee provided it is simple and independently controlled. A European beef quality assurance system might encompass environmental and nutritional measures as well as eating quality and would need to be profitable, simple, effective and sufficiently flexible to allow companies to develop their own brands. PMID- 30004321 TI - Under-5 mortality and the contribution of congenital disorders in South Africa. PMID- 30004323 TI - How climate change can fuel listeriosis outbreaks in South Africa. PMID- 30004322 TI - Decentralised clinical training of health professionals will expand the training platform and enhance the competencies of graduates. PMID- 30004325 TI - Posthumous conception: Recent legal developments in South Africa. AB - Posthumous conception - when a deceased person's gametes are used for procreative purposes - made its debut in South African (SA) courts in NC v Aevitas Fertility Clinic. A widow was granted the right to use her deceased husband's sperm for procreation. Against the background of legislative ambiguity, this case creates legal certainty that posthumous conception is legally permissible in SA - at least where deceased persons provided written consent that their gametes can be used by their surviving spouses or life partners after their death, and where there is no controversy about such consent. PMID- 30004326 TI - Staphylococcus aureus and Escherichia coli levels on the hands of theatre staff in three hospitals in Johannesburg, South Africa, before and after handwashing. AB - BACKGROUND: Hand hygiene is a fundamental component of infection control. Hand contamination with Staphylococcus aureus and Escherichia coli may contribute to infections. OBJECTIVES: To assess the effectiveness of different handwashing methods in reducing the levels of bacterial flora, especially S. aureus and E. coli, on the hands of theatre staff. METHODS: A cross-sectional study was conducted among 70 staff in surgical theatres of three randomly chosen hospitals in Johannesburg, South Africa. Samples were taken before and after handwashing using the modified glove juice method and the fingernail press technique. Standard microbiological techniques were used to identify bacteria. Descriptive statistics and non-parametric analysis were used to compare the differences between hospitals and to determine the effects of handwashing on microbial flora and skin irritation. RESULTS: S. aureus organisms were isolated in the prewash samples of 29 (41%) and in the postwash samples of 20 (29%) workers. Of the 29 with positive prewash cultures, 19 (65.5%) showed decreased postwash counts, while 10 (34.5%) showed no change or increased counts. Four workers with a negative prewash count had a positive postwash count. No statistical differences were found between postwash counts categorised by the type of cleansing formula used and the washing technique. E. coli organisms were identified in the prewash count of the fingertip press of one worker. CONCLUSIONS: Almost half of the theatre staff carried S. aureus isolates on their hands prior to handwashing and approximately one-third after handwashing. Closer monitoring of handwashing techniques should be introduced. PMID- 30004324 TI - Prolonged paralysis in a child with organophosphate pesticide poisoning. AB - A 17-month-old boy presented to a local community health centre in Cape Town, South Africa, with severe organophosphate pesticide poisoning (OPP), necessitating the use of intravenous atropine to control cholinergic symptoms, as well as emergency intubation for ongoing respiratory distress. He required prolonged ventilatory support in the intensive care unit at his referral hospital and had subsequent delayed neurological recovery, spending 8 days in hospital.We present this case to emphasise the importance of adequate atropinisation in the management of severe OPP and to highlight the dangers of inappropriate use of suxamethonium for intubation in patients with OPP. PMID- 30004327 TI - Economic evaluation of safety-engineered devices and training in reducing needlestick injuries among healthcare workers in South Africa. AB - BACKGROUND: Healthcare workers (HCWs) are at increased risk of contracting various communicable diseases. Needlestick injuries (NSIs) are a common mechanism of exposure. Training in basic universal precautions and utilisation of safety engineered devices (SEDs) are interventions known to reduce the risk of NSI. OBJECTIVES: To assess the cost-utility of SEDs v. a training programme in universal precautions (TP) v. a combination strategy to reduce NSIs among South African HCWs. METHODS: A Markov model comparing SEDs v. a TP v. a combination strategy against current practice was developed. A hypothetical cohort of HCWs working in the SA public sector was followed from a payer's perspective for a period of 45 years, and discounted costs and benefits were assessed. Data were obtained from the National Department of Health, suppliers and published literature. One-way and probabilistic sensitivity analysis was conducted. RESULTS: Over the study time horizon, our model estimated that 2 209, 3 314 and 4 349 needlestick injuries per 1 000 HCWs could be prevented if a TP, SEDs or a combination strategy, respectively, was adopted compared with current practice. All three candidate interventions were cost-effective at a willingness to pay (WTP) of one times the gross domestic product per capita (USD6 483.90/quality adjusted life-year (QUALY) gained). SEDs as a stand-alone intervention was dominated by a combination strategy. Compared with current practice, the incremental cost-effectiveness of training was USD32.90/QALY v. USD432.32/QALY for SEDs and USD377.08/QALY for a combination strategy. Results were sensitive to the effectiveness of the interventions. Probabilistic sensitivity analysis showed that at a WTP of USD6 483.90/QALY gained, a combination strategy would be cost effective 95.4% of the time. CONCLUSIONS: A combination strategy in which both SEDs and a TP are adopted is preferred. PMID- 30004328 TI - Medical students' perspectives on euthanasia and physician-assisted suicide and their views on legalising these practices in South Africa. AB - BACKGROUND: Euthanasia/physician-assisted suicide have been a controversial and sometimes taboo topic for a long time, not only in South Africa (SA) but also internationally. A recent (SA) judicial case has seen the topic debated again. Consensus on accepting or abolishing these practices in SA has yet to be reached. All relevant role players need to be adequately engaged before policy can be informed. OBJECTIVES: To determine the views of future doctors (medical students) regarding euthanasia and physician-assisted suicide (PAS) and to ascertain their stance on its legalisation in South Africa (SA). METHODS: A paper-based, semi quantitative descriptive study design consisting of 16 questions, using convenience sampling of third- to fifth-year medical students at Stellenbosch University, was used. RESULTS: The overall response rate was 69.3% (N=277). In total, 52.7% of participants (n=146) felt that the practices of euthanasia/PAS should be legalised in SA. Responses varied depending on patient morbidities. If a patient had terminal disease with intractable suffering, 41.9% of participants would terminate the patient's life upon request. A further 36.1% of participants stated that they would have no part in ending a patient's life, while 35.0% said that they would be comfortable with providing the patient with the correct means to end their life (PAS). The majority (80.1%) of participants indicated that they would prefer a dedicated ethics committee to decide who receives euthanasia/PAS. Many factors influenced participants' responses, but differences in opinion between and within the various religious groups were particularly evident in the responses received. CONCLUSIONS: More than half the respondents in this study were open to legalising euthanasia/PAS, substantially more than in previous studies. However, only 41.9% of respondents would consider actually performing euthanasia/PAS, for certain patients. Views of other healthcare workers as well as the public are required before policy can be informed. PMID- 30004329 TI - Poor anticoagulation control in patients taking warfarin at a tertiary and district-level prothrombin clinic in Cape Town, South Africa. AB - BACKGROUND: Warfarin is the most commonly used anticoagulant for both primary and secondary prevention of thromboembolism. For anticoagulation efficacy, the international normalised ratio (INR) needs to be within the therapeutic range for at least 65% of time on warfarin. OBJECTIVES: To describe INR control in patients on long-term warfarin and identified predictors of good INR control at two dedicated warfarin follow-up clinics in Cape Town, South Africa (SA). METHODS: We reviewed clinical records of patients in care at the INR clinics at Mitchell's Plain Community Health Centre and Groote Schuur Hospital. We included patients who had been on warfarin therapy for at least 27 months and excluded patients with <6 months of INR monitoring data or a >70-day gap between INR tests in the calculation period, and if >25% of follow-up time was at an alternative site. The time in therapeutic range (TTR) over 180 days using the Rosendaal method was calculated, and we categorised INR control as good if the TTR was >=65%. We constructed a multivariate logistic regression model to identify associations with good INR control. RESULTS: We included 363 patients, with a median age of 55 years (interquartile range (IQR) 44 - 64), of whom 65.6% were women. The most common indications for warfarin were valvular heart disease (45.7%) and atrial fibrillation (25.1%). The mean TTR was 47%, with only 91/363 patients having good INR control. In a multivariate model adjusted for age, sex, clinic and target INR, patients aged >=55 years were more likely to have good INR control than younger patients (adjusted odds ratio 1.69, 95% confidence interval 1.03 - 2.79). Poorly controlled patients had more frequent INR monitoring than those with good INR control, with a median of 8 INRs (IQR 6 - 10) v. 6 INRs (IQR 5 - 8) in the 180-day period (p<0.0001). CONCLUSIONS: Only 25.1% of patients in our study achieved good INR control, despite regular INR monitoring. There is an urgent need to improve anticoagulation control of patients receiving warfarin in SA. Validated dosing algorithms are required, and access to lower warfarin dosage formulations may optimise individual dose titration. Advocacy for these formulations is advised. PMID- 30004330 TI - Phenotypic and genotypic correlation of carbapenememase-producing Enterobacteriaceae and problems experienced in routine screening. AB - BACKGROUND: The emergence and transmission of carbapenem-resistant Enterobacteriaceae (CRE) is a concern in both the clinical and public health arenas. Reliable and accurate detection of these organisms is required for patient management and infection prevention and control purposes. In the routine laboratory, phenotypic methods are utilised for identification of CRE. OBJECTIVES: To investigate the phenotypic profiles of suspected carbapenemase producing Enterobacteriaceae (CPE) isolates generated by the automated MicroScan Walkaway system making use of the Clinical and Laboratory Standards Institute (CLSI) guidelines, and correlate these with carbapenemase production by molecular methods. METHODS: Antimicrobial susceptibility testing was performed using the MicroScan Walkaway system, and the presence of six carbapenemase genes (blaNDM, blaVIM, blaIMP, blaOXA-48and variants, blaGESand blaKPC) was screened for using a multiplex real-time polymerase chain reaction. RESULTS: A total of 2 678 isolates were evaluated. Klebsiella pneumoniae accounted for 62.9% of the isolates (n=1 685), followed by Enterobacter cloacae (n=361, 13.5%). Carbapenemases accounted for 75.2% of isolates; blaOXA-48 and its variants predominated (n=978, 36.5%), followed by blaNDM (n=904, 33.8%), blaVIM (n=108, 4.0%), blaIMP (n=35, 1.3%), blaGES (n=24, 0.9%) and blaKPC (n=18, 0.7 %). CONCLUSIONS: A considerable number of isolates expressing a carbapenemase or carbapenemases (the majority of which were blaOXA-48 producing) were susceptible to third-and fourth-generation cephalosporins and carbapenems, demonstrating that confirmed carbapenemase producing isolates are not presenting as possible carriers of carbapenemases using routine diagnostic methods. Similar results were obtained when CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints were applied and are suitable for the purpose of patient management. However, since genotyping assays are costly, it is suggested that routine laboratories first perform comprehensive phenotypic screening for CPE. PMID- 30004331 TI - Is adrenal suppression in asthmatic children reversible? A case series. AB - BACKGROUND: Six hypocortisolaemic asthmatic children on steroids given at physiological doses were identified during a previous study. OBJECTIVES: To establish whether hypothalamic-pituitary-adrenal axis suppression (HPAS) could be reversed in hypocortisolaemic asthmatic children treated with steroids without sacrificing asthma control. METHODS: In this case series, treatment of six hypocortisolaemic patients was modified by introducing steroid-sparing asthma medications. Serum cortisol and repeat overnight metyrapone tests (ONMTPTs) were done until HPAS was reversed in all patients. A retrospective folder review was performed and the following data were extracted: body mass index standard deviation score (BMI SDS), adherence, daily steroid type and dose, treatment modification, serum cortisol, final ONMTPT result and time taken to achieve normalisation. RESULTS: The median serum cortisol level recovered to 311 nmol/L after 0.9 years (median). The ONMTPT normalised within 3.3 years (median). Steroid load decreased from 9.2 to 5.0 hydrocortisone equivalent mg/m2/d (medians), while asthma score improved from 1.42 to 0.85 (medians). Poor adherence was noted in two children before and four after treatment modification. BMI SDS decreased from -0.08 to -0.16 (medians). CONCLUSIONS: Hypocortisolaemia and HPAS could be reversed in asthmatic children treated with physiological doses of steroids by reducing steroid load by 40% and supplementing therapy with steroid-sparing medication. Poor adherence may have either contributed to or retarded HPA recovery. Simultaneously, asthma control improved. Confirmation by a prospective study would be ideal, but may not be feasible. PMID- 30004332 TI - Outcomes of outpatient ureteral stenting without fluoroscopy at Groote Schuur Hospital, Cape Town, South Africa. AB - BACKGROUND: Ureteral stenting is generally a theatre-based procedure that requires a multidisciplinary team and on-table imaging. Limited hospital bed numbers and theatre time in our centre in Cape Town, South Africa, have led us to explore an alternative approach. OBJECTIVES: To see whether outpatient insertion of ureteric stents under local anaesthesia without fluoroscopy was a possible and acceptable alternative to theatre-based ureteral stenting. METHODS: Ureteral stenting (double-J stents and ureteric catheters) was performed with flexible cystoscopy under local anaesthesia and chemoprophylaxis, but without fluoroscopic guidance, in an outpatient setting. Every patient had an abdominal radiograph and an ultrasound scan of the kidney after the procedure to confirm stent position. RESULTS: Three hundred and sixteen procedures (276 double-J stents and 40 ureteric catheters) were performed in 161 men and 155 women. The overall success rate for the procedures was 85.4%, independent of gender (p=0.87), age (p=0.13), type of device inserted (p=0.81) or unilateral/bilateral nature of the procedure (p=1.0). Procedures with a successful outcome were performed in a significantly (p<0.0001) shorter median time (10 minutes (interquartile range (IQR) 5 - 15)) than failed procedures (20 minutes (IQR 10 - 30)). Patients with a pain score of >5 experienced a significantly (p=0.02) greater proportion of failure (27.3%) than patients with a pain score of <=5 (12.5%). Difficulties were encountered in 23.7% of procedures, with a significantly higher proportion being registered in failed interventions compared with successful ones (82.6% v. 13.7%; p<0.0001). CONCLUSIONS: The procedure was easily mastered and technically simple, and represents savings in cost, time and human resources in our setting. PMID- 30004333 TI - Predictors of unplanned pregnancies among female students at South African Technical and Vocational Education and Training colleges: Findings from the 2014 Higher Education and Training HIV and AIDS survey. AB - BACKGROUND: Unplanned pregnancies among college/tertiary female students pose a serious public health concern in South Africa (SA) and are associated with adverse health and social outcomes that impact negatively on educational progress and future career prospects. OBJECTIVES: To examine the potential predictors of unplanned pregnancy among female students at Technical and Vocational Education and Training (TVET) colleges in SA. METHODS: This analysis used data drawn from the 2014 Higher Education and Training HIV and AIDS survey, which was a nationally representative survey of TVET college students in SA. Associations between unplanned pregnancy and the explanatory variables were assessed using bivariate analysis. Multivariate logistic regression analysis was used to identify the effect of several independent predictors of unplanned pregnancy. RESULTS: Of 1 002 female students who responded to the question on unplanned pregnancy, 74.6% reported having had an unplanned pregnancy. Predictors significantly associated with a reduced likelihood of unplanned pregnancy among female TVET students included living with a husband (odds ratio (OR) 0.28, 95% confidence interval (CI) 0.13 - 0.62; p=0.002), having two (OR 0.45, 95% CI 0.23 0.88; p=0.003) or three (OR 0.07, 95% CI 0.01 - 0.39; p=0.003) previous pregnancies, and not having had an abortion (OR 0.16, 95% CI 0.04 - 0.62; p=0.008). CONCLUSIONS: The high level of unplanned pregnancies is indicative of the state of women's reproductive health services at SA TVET colleges. The findings suggest that certain groups of female students are at increased risk of unplanned pregnancy and would benefit from targeted family planning interventions tailored to their needs. PMID- 30004334 TI - High risk of suicide among high-school learners in uMgungundlovu District, KwaZulu-Natal Province, South Africa. AB - BACKGROUND: Worldwide, suicide affects the most vulnerable populations, including adolescents and young adults. It is estimated that suicide will contribute more than 2% to the global burden of disease by 2020. Information about the prevalence of suicidal behaviour and the sociodemographic characteristics and risk factors associated with suicide in the South African (SA) rural context is important for local and national policy and contributes to global understanding of the phenomenon. OBJECTIVE: To investigate key demographic factors and behaviours associated with planning and attempting suicide among high-school learners. METHODS: In a cross-sectional study, we used stratified random sampling to select 16 schools in uMgungundlovu District, KwaZulu-Natal Province, SA. All grade 10 learners (N=1 759) at these schools completed a self-administered questionnaire (Centers for Disease Control and Prevention (CDC) Youth Risk Behavior Surveillance System). Data analysis was carried out with Stata 13 statistical software using generalised estimating equations. RESULTS: In total, 222 learners (12.6% of the 1 759) had made plans to attempt suicide during the previous 12 months, 261 (14.8%) had actually attempted suicide, and 218 attempts had resulted in the learner being treated by a doctor or nurse (12.4%). The risk of planning suicide increased with age. For male learners, being threatened with a weapon on school property (adjusted odds ratio (AOR) 3.7, 95% confidence interval (CI) 1.9 7.1; p<0.01) or bullied through Facebook or WhatsApp (AOR 3.1, 95% CI 1.5 - 7.1; p<0.01) significantly increased the likelihood of making a suicide attempt that resulted in treatment by a doctor or nurse. For female learners, engaging in risk behaviours increased this likelihood, risk factors including being physically hurt by someone they were dating (1 - 3 times AOR 3.3, 95% CI 1.9 - 5.7; p<0.01, >=4 times AOR 10.0, 95% CI 2.5 - 40.2 (p<0.01) and number of drinks consumed in the past month (AOR 2.0, 95% CI 1.4 - 3.0; p<0.01). CONCLUSIONS: The prevalence of suicide attempts among these SA learners was high and was influenced by multiple factors. Routine surveillance systems are urgently required to develop context-based interventions for male and female learners at uMgungundlovu District rural high schools. PMID- 30004335 TI - Contribution of congenital disorders to neonatal mortality in South Africa. PMID- 30004336 TI - Post-pulmonary tuberculosis complications in South Africa and a potential link with pulmonary hypertension: Premise for clinical and scientific investigations. PMID- 30004337 TI - Completing laboratory request forms diligently - when did it become optional? PMID- 30004338 TI - National coverage of reflex cryptococcal antigen screening: A milestone achievement in the care of persons with advanced HIV disease. PMID- 30004340 TI - Current strategies are inadequate to curb the rise of tobacco use in Africa. AB - Recently, there have been significant advances in the battle against tobacco use in Africa, with achievements including ratification of the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) and the passing of tobacco control legislation in several countries. Many African countries have achieved measured success, while Uganda, South Africa and Mauritius have accomplished significantly more in their efforts to curb tobacco use. Nevertheless, few African countries meet the standards of the individual WHO FCTC articles with regard to comprehensive implementation. Africa has lower rates of tobacco taxation, weaker smoke-free policies and fewer restrictions on tobacco advertising compared with other world regions. These shortcomings have enabled the tobacco industry to expand its markets on the continent by capitalising on economic growth, changing social norms and population demographics. Consequently, tobacco use is increasing in Africa, with smoking prevalence having risen 57% between 1990 and 2009 compared with western Europe, where it decreased substantially during the same period. Rapid smoking uptake in Africa has led to tobacco-related conditions emerging as increasingly important public health problems. African nations are unlikely to meet the 2025 goal of a 30% relative reduction in tobacco use, as advocated by the World Health Assembly in 2013 and identified as the 'most urgent and immediate priority' intervention to reduce non communicable diseases (NCDs). While there has been some progress, the current commitment of most African countries to the WHO FCTC has not translated into effective delivery of tobacco control policies and programmes. Strong tobacco control policies, which are among the most effective population-based strategies for NCD prevention, are needed. These include introducing higher tobacco excise taxes, stronger smoke-free policies, graphic warnings on cigarette packages, bans on tobacco advertising, promotion and sponsorship, and anti-smoking mass media campaigns. Furthermore, tobacco industry interference needs to be actively addressed by monitoring its activities and exposing misconducts, thereby changing attitudes to the industry. Technical support, capacity building and adequate financing are needed in Africa to enable countries to competently manage legal challenges to tobacco control and deal with the subversive tactics of the industry. Civil society and the media - major players in holding governments accountable for responsible stewardship - need to educate and pressurise African politicians and governments to implement and enforce effective tobacco control policies. Otherwise, if unchecked, the widespread uptake of tobacco use will be a threat not only to health but also to sustainable human development in Africa. PMID- 30004339 TI - Antimicrobial stewardship in a rural regional hospital - growing a positive culture. AB - Antimicrobial stewardship programmes have been introduced worldwide in response to the rise in antimicrobial resistance. The World Health Organization has mandated each Member State to produce a plan to address this problem. We report on the organic development of an antibiotic stewardship programme in a rural regional hospital in a resource-limited setting in South Africa. This has resulted in organisational change with increased awareness, participation, monitoring and education in antibiotic stewardship throughout the hospital. PMID- 30004341 TI - Obtaining informed consent for a sterilisation in the light of recent case law. AB - The need to obtain informed consent prior to any sterilisation is a very well established ethical and legal obligation. South African law, however, does not specifically state who is responsible for obtaining informed consent before performing a sterilisation. This has implications for the liability of a surgeon or gynaecologist in circumstances where the informed consent is defective. Due to the vagueness of the applicable law, a surgeon or gynaecologist might be held liable, even in situations where he/she did not obtain the consent and relied on a nurse or assistant to procure the relevant informed consent. This article explores the relevant statutory law and canvasses two legal cases that came before the court regarding defective informed consent and the resultant liability for damages. We also make recommendations for proposed amendments to the current law to provide further clarity. PMID- 30004342 TI - Rapunzel syndrome: A South African variety. AB - Trichobezoars are intraluminal accretions of ingested hair. Rapunzel syndrome is a rare and extreme presentation, with the trichobezoar extending into the small intestine. It is most frequently reported in children and psychiatric patients. We report a South African series of 5 patients who presented with trichobezoars. Each patient was retrospectively reviewed and analysed with regard to background, demographics, clinical presentation, diagnosis, surgical management and complications. Five female patients with a median age of 19 (range 12 - 27) years presented with clinical symptoms, including early satiety, intermittent vomiting with gastric outlet obstruction, abdominal pain and weight loss. The diagnosis was made by endoscopy, abdominal computed tomography (CT) imaging, barium meal examination or plain abdominal radiography. Two patients presented with sealed/contained gastric perforations, and 1 patient with a small-bowel perforation. All 5 bezoars, 2 of which consisted entirely of artificial hair extensions, extended into the jejunum, the longest measuring 1.4 m. All were removed by laparotomy. While trichobezoars are a rare entity, they may present with significant complications, such as obstructions and perforations. In view of the infection risk and considerable size of many of these bezoars, an open removal is probably safer than any minimally invasive attempt. PMID- 30004343 TI - Incidence of Hodgkin lymphoma in HIV-positive and HIV-negative patients at a tertiary hospital in South Africa (2005 - 2016) and comparison with other African countries. AB - BACKGROUND: Hodgkin lymphoma (HL) is the most common non-AIDS-defining cancer in HIV-positive patients. Studies on South African (SA) populations have described the prevalence as 7 - 17% of all lymphomas, 8 - 27% of head and neck lymphomas, 9% of lymph node biopsies and 4% of HIV-related malignancies. OBJECTIVES: To describe the incidence of HL at our centre between 2005 and 2016 by year, gender, HIV status, histological subclassification and bone marrow involvement, and compare these findings with similar SA and African studies. METHODS: This was a retrospective study of all incident HL cases diagnosed in the Department of Pathology, National Health Laboratory Service, Tygerberg Academic Hospital, Cape Town. Follow-up, relapsed and referral cases were excluded. A positive diagnosis of HL was confirmed by either lymph node or bone marrow biopsy and was based on morphological and immunohistochemical findings in accordance with the World Health Organization classification. RESULTS: There were 303 incident cases of HL diagnosed. The incidence increased from 2005 to 2011, with a spike in cases in 2008 and a subsequent decline overall after 2011. The highest proportion of cases was in the 25 - 49-year-old age category (51.1%). There were 77 HIV-positive patients (25.4%), of whom 53 (68.8%) had CD4+ counts <500 cells/uL. In keeping with other African studies, the main subtypes were nodular sclerosis HL (49.8%) and mixed-cellularity HL (23.1%). Bone marrow biopsy following lymph node diagnosis of HL confirmed involvement in 23.7% of patients. CONCLUSIONS: Absolute numbers of cases of HL at our centre have increased since the roll-out of antiretroviral therapy (ART) to the public sector. The recent change in policy to make ART available to all HIV-positive patients independent of CD4+ count suggests that patients will survive longer and are therefore at increased risk of developing HL. We anticipate that numbers of HL cases will increase or remain high in the coming years, and we need to prepare for this. PMID- 30004344 TI - Hepatitis C prevalence in HIV-infected heterosexual men and men who have sex with men. AB - BACKGROUND: Globally 1% of individuals are infected with hepatitis C virus (HCV). In South Africa (SA) the prevalence ranges between 0.3% and 1%, with few prospective screening data available. Similarly, local data on transmission modes of HCV are limited, but probably include parenteral routes and pre-1992 blood or blood products. The risk of heterosexual transmission of HCV is low but is increased in men who have sex with men (MSM), with co-transmission risk of both HIV and HCV. OBJECTIVES: Given few local data, we sought to better understand HCV characteristics and prevalence in two groups of HIV-infected men. METHODS: HIV positive men in the greater Cape Town metropolitan area were recruited. Sexual orientation was self-identified and demographic and other personal data were obtained via a confidential questionnaire. Participants were screened for HCV after a blood draw. Those with positive HCV tests had further HCV RNA confirmation. Risk factors associated with HCV seropositivity were determined. RESULTS: Five hundred HIV-positive men were recruited, 285 (57.0%) MSM and 215 (43.0%) non-MSM, median age 36 years (interquartile range (IQR) 20 - 64) and 37 years (IQR 21 - 56), respectively (p=NS). Overall, 3.4% (n=17) screened HCV positive, 5.6% MSM (n=16) and 0.5% non-MSM (n=1); 82.4% were viraemic for HCV RNA. In respect of genotype distribution, 50.0% were infected with genotype 1a, 14.3% with genotype 4 and 35.7% with genotype 2. In terms of risk, MSM were more likely to have used drugs (54.4% v. 30.2%; p<0.001) and to have used all five modes of drug administration (13.0% MSM v. 0.5% non-MSM for injected drugs, 36.1% v. 2.3% for inhaled, 10.0% v. 0% for rectal, 48.1% v. 28.8% for smoked and 27.4% v. 2.3% for oral). More MSM than non-MSM (46.3% v. 16.7%) reported having sex while using recreational drugs, and similarly more MSM (21.4% v. 14%) reported having sex with a sex worker (SW). Risk factors for HCV seropositivity included drug use history (odds ratio (OR) 6.28, 95% confidence interval (CI) 1.78 - 22.12; p=0.004) and in MSM, sex with an SW (OR 5.5, 95% CI 2.06 - 14.68; p=0.001) or use of recreational drugs with sex (OR 6.88, 95% CI 2.21 - 21.44; p=0.001). CONCLUSIONS: HCV prevalence in HIV-positive MSM is higher than previously appreciated or documented in SA. Risk factors include injection drug use, use of recreational drugs with sex, and sex with SWs. Targeted interventions are required to address this emerging challenge to achieve the viral hepatitis elimination ideal by 2030. PMID- 30004345 TI - A Seasonal Autoregressive Integrated Moving Average (SARIMA) forecasting model to predict monthly malaria cases in KwaZulu-Natal, South Africa. AB - BACKGROUND: South Africa (SA) in general, and KwaZulu-Natal (KZN) Province in particular, have stepped up efforts to eliminate malaria. To strengthen malaria control in KZN, a relevant malaria forecasting model is important. OBJECTIVES: To develop a forecasting model to predict malaria cases in KZN using the Seasonal Autoregressive Integrated Moving Average (SARIMA) time series approach. METHODS: The study was carried out retrospectively using a clinically confirmed monthly malaria case dataset that was split into two. The first dataset (January 2005 - December 2013) was used to construct a SARIMA model by adopting the Box-Jenkins approach, while the second dataset (January - December 2014) was used to validate the forecast generated from the best-fit model. RESULTS: Three plausible models were identified, and the SARIMA (0,1,1)(0,1,1)12 model was selected as the best fit model. This model was used to forecast malaria cases during 2014, and it was observed to fit closely with malaria cases reported in 2014. CONCLUSIONS: The SARIMA (0,1,1)(0,1,1)12 model could serve as a useful tool for modelling and forecasting monthly malaria cases in KZN. It could therefore play a key role in shaping malaria control and elimination efforts in the province. PMID- 30004346 TI - Describing key performance indicators for waiting times in emergency centres in the Western Cape Province, South Africa, between 2013 and 2014. AB - BACKGROUND: Data measured as key performance indicators (KPIs) are used internationally in emergency medicine to measure and monitor quality of care. The Department of Health in the Western Cape Province, South Africa, introduced time based KPIs for emergency centres (ECs) in 2012. OBJECTIVES: To describe the most recently processed results of the audits conducted in Western Cape ECs between 2013 and 2014. METHODS: A retrospective, descriptive study was conducted on data collected in the 6-monthly Western Cape EC triage and waiting time audits for 2013 - 2014. Time variables were analysed overall and per triage category. ECs in hospitals were compared with ECs in community health centres (CHCs). A descriptive analysis of the sample was undertaken. Proportions for categorical data are presented throughout. The continuous variable time was described using means and standard deviations. The chi2 test and Fisher's exact test were used to describe associations. The level of significance was p<0.05, with the 95% confidence interval where appropriate. RESULTS: There was no significant difference in triage acuity proportions between hospital and CHC ECs. Waiting times were longer than recommended for the South African Triage Scale, but higher acuity patients were seen faster than lower-acuity patients. Waiting times were significantly longer at hospitals than at CHCs. A red priority patient presenting to a CHC would take 6.1 times longer to reach definitive care than if the patient had presented to a hospital EC. CONCLUSIONS: The triage process appears to improve waiting times for the sickest patients, although it is protracted throughout. Acutely ill patient journeys starting at CHC ECs suggested significant delays in care. Models need to be explored that allow appropriate care at the first point of contact and rapid transfer if needed. To improve waiting times, resource allocation in the emergency care system will need to be reconsidered. PMID- 30004347 TI - Striking increase in the incidence of infective endocarditis associated with recreational drug abuse in urban South Africa. AB - BACKGROUND: We have recently noted a dramatic rise in the number of patients with infective endocarditis (IE) related to intravenous (IV) nyaope (a mixture of heroin, cocaine and antiretroviral drugs) presenting to Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa. OBJECTIVES: To document the clinical and echocardiographic characteristics of these patients. METHODS: Clinical and echocardiographic characteristics of all patients (N=68) with IE due to IV nyaope use were retrospectively extracted from hospital records (December 2014 - February 2017). RESULTS: The mean (standard deviation) age of the patients was 25.8 (4.5) years (97.1% were male). Withdrawal symptoms were noted in 25.1% of cases, fever in 58.8%, dyspnoea in 86.7% and right ventricular failure in 42.6%. Most patients were HIV-positive (76.1%), with CD4+ cell counts of <200 cells/uL in 8.8% of the total, 58.1% had hepatitis C infection, and only three were on antiretrovirals. Septic pulmonary emboli were noted in 61.8%. Blood cultures revealed Staphylococcus aureus in 61.2%, Enterococcus faecalis in 8.8% and Pseudomonas aeruginosa in 1 patient; 29.2% had sterile cultures and 8.8% polymicrobial infection. Severe right ventricular systolic dysfunction (RVS' Doppler velocity <10 cm/s) and pulmonary hypertension were noted in 19.1% and 62.2% of patients, respectively. Pericardial effusion was noted in 37.8%. The most commonly involved valve was the tricuspid (60.1%), followed by the mitral (17.2%), aortic (2.9%) and pulmonary (1 patient) valves. Combined valve lesions were noted in 19.1% of patients. Ten patients (14.7%) died. The main predictor of in-hospital mortality was S. aureus infection (odds ratio 5.0; p=0.042). CONCLUSIONS: We have documented the common clinical and echocardiographic characteristics of patients with IE secondary to IV nyaope use. IE due to IV drug use is responsible for considerable morbidity and mortality in a predominantly young male population. PMID- 30004348 TI - A multicentre, cross-sectional study investigating the prevalence of hypertensive disease in patients presenting for elective surgery in the Western Cape Province, South Africa. AB - BACKGROUND: Hypertension is common, affecting over one billion people worldwide. In sub-Saharan Africa, hypertensive disease not only affects the older population but is becoming increasingly prevalent in younger individuals. In South Africa (SA), >30% of the adult population has hypertension, making it the single most common cardiovascular risk factor and the predominant contributor to cardiovascular disease and mortality. Elevated blood pressure is the most common perioperative comorbidity encountered in non-cardiac surgical patients, with an overall prevalence of 20 - 25%, and it remains poorly controlled in low- and middle-income countries. Hypertension in the perioperative setting may adversely affect patient outcome. It therefore not only flags possible perioperative challenges to anaesthesiologists, but also identifies patients at risk of long term morbidity and mortality. OBJECTIVES: To determine the prevalence and severity of hypertension in elective adult surgical patients in the Western Cape Province, SA. RESULTS: The study population included all elective surgical patients from seven hospitals in the Western Cape during a 1-week period. Hypertension, defined as having had a previous diagnosis of hypertension or meeting the blood pressure criteria of >140/90 mmHg, was identified in 51.8% of patients during preoperative assessment. Significantly, newly diagnosed hypertension was present in 9.9% of all patients presenting for elective surgery. Although 98.1% of the known hypertensive patients were on antihypertensive therapy, 36.9% were inadequately controlled. There are numerous reasons for this, but notably 32.1% of patients admitted to forgetting to take their medication, making patient factors the most common reason for treatment non-compliance. CONCLUSIONS: The perioperative period may be an important opportunity to identify undiagnosed hypertensive patients. The perioperative encounter may have a significant public health implication in facilitating appropriate referral and treatment of patients with hypertension to decrease long-term cardiovascular complications in SA. PMID- 30004349 TI - Quality of counselling and support provided by the South African National AIDS Helpline: Content analysis of mystery client interviews. AB - BACKGROUND: Telephone helplines can facilitate referral, education and support for patients living with HIV or those concerned about the infection. The anonymity of helplines facilitates discussion of sensitive issues that are difficult to raise face to face. These services could support the expansion of HIV self-testing. However, maintaining quality and standardising messages in rapidly evolving fields such as HIV is challenging. OBJECTIVES: To evaluate the quality of the South African (SA) National AIDS Helpline. METHODS: Mystery clients posing as members of the public made 200 calls to the service in 2014. They presented several scenarios, including having received HIV-positive results from a doctor's secretary or through self-testing. Following the call, 'clients' completed a semistructured questionnaire on the information received and the caller-counsellor interaction. RESULTS: Calls were answered within a median of 5 seconds (interquartile range 2 - 14). Conversations took place in 8 of the 11 SA official languages, though mainly in English. Overall, 75% of callers felt that with the information they received they could locate a nearby clinic for further services. Counsellors expressed appropriate levels of concern about inadequate counselling that callers had received and confidentiality breaches in some scenarios. Eight counsellors incorrectly mentioned the need for a waiting period to confirm a positive result. Consistent with policy, almost all said that being foreign would not affect HIV treatment access. About 90% explained the need for CD4+ testing and antiretroviral therapy, but only 78% discussed HIV prevention. Counsellors were mostly empathetic (83%), though some adopted a neutral tone (10%) or were brusque (6%) or unhelpful (2%). CONCLUSIONS: Overall, helpline counsellors were proficient at providing information about local clinics, HIV testing and steps needed for initiating ART. Dissatisfaction with the caller counsellor interactions, instances of incorrect information and the relatively low attention accorded to HIV prevention are worrying, however. Training for both refreshing and updating knowledge, and supervision and monitoring of calls, could target these areas. PMID- 30004350 TI - Intellectual disability in South Africa: Addressing a crisis in mental health services. PMID- 30004351 TI - Medicolegal storm threatening maternal and child healthcare services. PMID- 30004352 TI - Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. PMID- 30004353 TI - Intellectual disability in the Esidimeni tragedy: Silent deaths. PMID- 30004354 TI - The Life Esidimeni tragedy: The courts are also to blame. PMID- 30004355 TI - The Life Esidimeni tragedy: Some ethical transgressions. PMID- 30004356 TI - Regulating the South African sport supplement industry: 'Whey' overdue. AB - The South African sport supplement industry has experienced rapid growth in recent years. Despite the massive market demand, this industry remains poorly regulated. From raw ingredient contamination to label compliance discrepancies, the sport supplement industry is an area of growing concern and warrants further public debate. PMID- 30004357 TI - Medical device regulation in South Africa: The Medicines and Related Substances Amendment Act 14 of 2015. AB - The Medicines and Related Substances Amendment Act, 14 of 2015, has brought significant changes in the regulation of medical devices in South Africa. The highlights include the establishment of a regulatory authority, the South African Health Products Regulatory Agency, the introduction of a tier-based licensing and registration system, and restriction of bonusing and sampling in the sale of medical devices. The enactment of the new regulations is a positive development for the South African medical device industry. However, the impact of the regulations will depend on implementation. Conditions that will support the success of the regulations include creating a critical mass of skilled personnel and measures that ensure timely registration. South Africa can learn from the experiences and practices of other countries that have introduced medical device regulations in recent years. PMID- 30004358 TI - Maternal near-miss audit in the Metro West maternity service, Cape Town, South Africa: A retrospective observational study. AB - BACKGROUND: A maternal near-miss is defined as a life-threatening pregnancy related complication where the woman survives. The World Health Organization (WHO) has produced a tool for identifying near-misses according to criteria that include the occurrence of a severe maternal complication together with organ dysfunction and/or specified critical interventions. Maternal deaths have been audited in the public sector Metro West maternity service in Cape Town, South Africa, for many years, but there has been no monitoring of near-misses. OBJECTIVES: To measure the near-miss ratio (NMR), maternal mortality ratio (MMR) and mortality index (MI), and to investigate the near-miss cases. METHODS: A retrospective observational study conducted during 6 months in 2014 identified and analysed all near-miss cases and maternal deaths in Metro West, using the WHO criteria. RESULTS: From a total of 19 222 live births, 112 near-misses and 13 maternal deaths were identified. The MMR was 67.6 per 100 000 live births and the NMR 5.83 per 1 000 live births. The maternal near-miss/maternal death ratio was 8.6:1 and the MI 10.4%. The major causes of near-miss were hypertension (n=50, 44.6%), haemorrhage (n=38, 33.9%) and puerperal sepsis (n=13, 11.6%). The first two conditions both had very low MIs (1.9% and 0%, respectively), whereas the figure for puerperal sepsis was 18.9%. Less common near-miss causes were medical/surgical conditions (n=7, 6.3%), non-pregnancy-related infections (n=2, 1.8%) and acute collapse (n=2, 1.8%), with higher MIs (33.3%, 66.7% and 33.3%, respectively). Critical interventions included massive blood transfusion (34.8%), ventilation (40.2%) and hysterectomy (30.4%). Considering health system factors, 63 near-misses (56.3%) initially occurred at a primary care facility, and the patients were all referred to the tertiary hospital; 38 (33.9%) occurred at a secondary hospital, and 11 (9.8%) at the tertiary hospital. Analysis of avoidable factors identified lack of antenatal clinic attendance (11.6%), inter-facility transport problems (6.3%) and health provider-related factors (25.9% at the primary level of care, 38.2% at secondary level and 7.1% at tertiary level). CONCLUSIONS: The NMR and MMR for Metro West were lower than in other developing countries, but higher than in high-income countries. The MI was low for direct obstetric conditions (hypertension, haemorrhage and puerperal sepsis), reflecting good quality of care and referral mechanisms for these conditions. The MIs for non-pregnancy-related infections, medical/surgical conditions and acute collapse were higher, suggesting that medical problems need more focused attention. PMID- 30004359 TI - Mental illness in the Western Cape Province, South Africa: A review of the burden of disease and healthcare interventions. AB - Neuropsychiatric disorders were ranked third as contributors to disability adjusted life-years in South Africa (SA). Despite this high morbidity, mental health is often overlooked on the public health agenda. This article reviews evidence on the burden of mental illness in the Western Cape Province of SA, as well as current provincial interventions to decrease the burden of mental illness. Available evidence supports the need for improved integration of mental health services in primary healthcare and strengthening of community services. Challenges include a lack of capacity due to staff shortages and inadequate availability and allocation of resources. Evidence from large epidemiological studies to quantify the burden of disease as well as cost-effectiveness studies of interventions are required to successfully plan and implement interventions. Similar reviews may provide a national overview of mental health issues as well as allow improvement through better understanding of research and best practices in various provinces. PMID- 30004360 TI - A longitudinal perspective on violence in the lives of South African children from the Birth to Twenty Plus cohort study in Johannesburg-Soweto. AB - BACKGROUND: Violence against children is a significant cause of personal suffering and long-term ill health, poor psychological adjustment, and a range of social difficulties, including adverse effects intergenerationally. OBJECTIVES: Using a large corpus of longitudinal data collected in the Birth to Twenty Plus cohort, to give an overview of exposure to and experience of violence, as well as perpetration of violence, across childhood, reported contemporaneously by several informants. This overcomes limitations of retrospectively recalled information collected from one person at one point in time. METHODS: We identified 280 data points relating to exposure to and perpetration of violence in 14 of the 21 waves of data collection from birth to 22 years of age. Data were classified into four developmental stages (preschool, primary school years, adolescence and young adulthood) and seven categories (exposure to violence in the community, home and school; exposure to peer violence; being a victim of violence, excluding sexual violence; sexual violence; and perpetration of violence). Both descriptive and inferential statistics were employed to analyse the data. RESULTS: Over the past two decades, only 1% of the sample had not been exposed to or experienced violence in their home, school and/or community. Two-thirds of children of schoolgoing age were reported as having been exposed to community violence, and more than half of all children to violence in their home. Reports of sexual violence increased from 10% among primary school-aged children to ~30% among adolescents and young adults. Over the course of their lives, ~40% of children were reported as having been exposed to or being victims of five or six of the categories of violence coded in this analysis. High levels of violence perpetration were reported across childhood. Age and gender differences in exposure to and experience and perpetration of violence were evident, and all categories of violence were more prevalent among poorer and more disadvantaged groups. CONCLUSIONS: Very high levels of violence were reported in all the settings of urban South African children's lives: home, community, school, among peers and in their intimate relationships. Children and youth were also reported to perpetrate high levels of violence. The personal and social costs of violence are very high, resulting in major public health problems due to its avoidable effects on short- and long-term mental and physical health and social adjustment, and intergenerationally. PMID- 30004361 TI - Ethnopharmacological use of potassium permanganate in South African traditional medicine. AB - BACKGROUND: Potassium permanganate (KMnO4), which is widely available, is often used by traditional health practitioners (THPs) in South Africa (SA) without taking its potentially harmful properties into account. The crystalline KMnO4 salt is sold at traditional medicine markets and shops throughout SA. However, to date, traditional uses of KMnO4 remain undocumented. OBJECTIVE: To describe KMnO4 use by THPs in KwaZulu-Natal, SA. METHODS: This sub-study is part of a larger study investigating substances used in SA traditional medicine that are collectively known as imikhando in isiZulu - literally translated as 'ore'. THPs (N=201) were interviewed in the local language (isiZulu) by trained interviewers. Information on the reasons for using/not using KMnO4, the source of information on its use and modes of administration were collected. RESULTS: KMnO4 was used as a constituent of traditional medicine by 158 (79%) THPs. Their knowledge of KMnO4 use was acquired predominantly from fellow THPs (n=134; 85%). Reasons for use included skin rash or wounds (n=99, 63%) and to treat aches, pains and swelling (n=74; 47%). The main modes of administration were in the bath (n=94; 60%), orally (n=67; 42%) and in herbal compresses (n=66; 42%). The principal reason of the 43 THPs for not administering KMnO4 was not knowing how to use it (n=29; 71%). CONCLUSIONS: This study has identified traditional medicine users at risk of manganese toxicity owing to commonly used sociocultural practices. In particular, reports of oral ingestion and use in enemas are cause for concern. This public health issue needs regulatory measures and education programmes to enlighten the population against possible harm caused by KMnO4 exposure. PMID- 30004362 TI - A needs-based approach to equitable allocation of district primary healthcare expenditure in North West Province, South Africa. AB - BACKGROUND: Inequity in resource allocation and expenditure exists in the South African (SA) health system at provincial and district level. Needs-based resource allocation has been utilised in developed and developing countries to promote equity. OBJECTIVES: To assess current spending patterns on primary healthcare (PHC)-level care at district level, and ultimately to promote equity in district PHC spending using a needs-based resource allocation approach in North West Province, SA. METHODS: Data on PHC expenditure in 2013/14 were derived from the Vulindlela system. Data on key indicators of need for health services in each district were collated from various sources published online. Alternative needs based formulae were calculated, and sensitivity analyses were conducted to assess the impact of key assumptions. RESULTS: The analysis produced four possible needs based formulae. The districts of Bojanala and Dr Kenneth Kaunda in North West are relatively under-resourced, while Ngaka Moderi Molema and Dr Ruth Segomotsi Mompati are relatively over-resourced. The results suggest that, in moving towards each district's equity target, a relative redistribution of resources should be undertaken over several years, preferably in the context of an annual increase in the real overall provincial PHC health budget, to avoid any absolute budget cuts for relatively over-resourced districts. CONCLUSIONS: Inequity in PHC expenditure exists between the districts of North West. A needs-based resource allocation approach can promote equity across districts. Any formula selected by the Department of Health will need to be refined over time as more up-to-date and accurate data become available. It is recommended that for the initial phase the formula be based on population size, which will need to be updated at regular intervals. The same would apply to other indicators of need selected for the formula. Important areas for refining the formula over time are: (i) estimating the differential cost of providing care in rural v. urban areas, as assumptions were used in this study; and (ii) identifying a more comprehensive burden of disease indicator for which data are available at district level in the province. PMID- 30004363 TI - A retrospective time trend study of firearm and non-firearm homicide in Cape Town from 1994 to 2013. AB - BACKGROUND: Gunshot injuries from interpersonal violence are a major cause of mortality. In South Africa (SA), the Firearms Control Act of 2000 sought to address firearm violence by removing illegally owned firearms from circulation, stricter regulation of legally owned firearms, and stricter licensing requirements. Over the last few years, varied implementation of the Act and police corruption have increased firearm availability. OBJECTIVES: To investigate whether changes in firearm availability in SA were associated with changes in firearm homicide rates. METHODS: This was a retrospective time trend study (1994 2013) using postmortem data. Time trends of firearm and non-firearm homicide rates were analysed with generalised linear models. Distinct time periods for temporal trends were assigned based on a priori assumptions regarding changes in the availability of firearms. RESULTS: Firearm and non-firearm homicide rates adjusted for age, sex and race exhibited different temporal trends. Non-firearm homicide rates either decreased or remained stable over the entire period. Firearm homicide increased at 13% annually from 1994 through 2000, and decreased by 15% from 2003 through 2006, corresponding with changes in firearm availability in 2001, 2003, 2007 and 2011. A 21% annual increase in firearm homicide after 2010 coincided with police fast-tracking new firearm licence applications. Cape Town's coloured population experienced a significantly greater increase than other population groups following additional exposure to illegal firearms from 2007. CONCLUSIONS: The strong association between firearm availability and homicide, and the reversal of a decreasing firearm homicide trend during a period of lax enforcement, provide further support for the association between reduced firearm homicide and stricter regulation. PMID- 30004364 TI - An audit of ingested and aspirated foreign bodies in children at a university hospital in South Africa: The Pietermaritzburg experience. AB - BACKGROUND: The ingestion or aspiration of foreign bodies (FBs) by children is a common problem around the world. Our centre in Pietermaritzburg, South Africa, has a dedicated paediatric surgical service, and all patients with an ingested or aspirated FB are managed under the direct care of a paediatric surgeon. OBJECTIVES: To review our centre's experience with this problem by means of a retrospective audit and use the data to develop and refine appropriate local management guidelines. METHODS: Grey's Hospital has a hybrid electronic medical registry (HEMR) that captures patient data on admission, after a procedure and on discharge. The HEMR was reviewed and all patients with an appropriate International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) code indicating an ingested or aspirated FB were identified and retrieved for review. RESULTS: A total of 105 cases of FB ingestion or aspiration in children <12 years of age from January 2012 to December 2014 were identified from the HEMR. The patients' ages ranged from 4 months to 10 years (mean 3 years and 6 months), and 59.0% (n=62) were male and 41.0% (n=43) female. A total of 107 FBs were removed (two patients each had two coins removed). The commonest FBs were coins (n=77, 71.9%), followed by batteries (n=6, 5.6%), plastic toys (n=5, 4.7%), buttons (n=5, 4.7%), screws/washers (n=3, 2.8%), seeds (n=2, 1.9%), needles (n=2, 1.9%), bones (n=2, 1.9%), a marble (n=1, 0.9%), a rubber eraser (n=1, 0.9%), a curtain hook (n=1, 0.9%), a nail (n=1, 0.9%) and a wood speck (n=1, 0.9%). Of the FBs, 67 (62.6%) were in the oesophagus, 17 (15.9%) in the respiratory system, 14 (13%) in the intestine and 9 (8.4%) in the oral cavity. The average time from ingestion/aspiration to presentation was <48 hours. Of the FBs, 67 (62.6%) were removed via rigid oesophagoscopy and 13 (12.1%) via rigid bronchoscopy, 13 (12.1%) were passed rectally, and 9 (8.4%) were removed via grasping forceps in the oral cavity, 4 (3.7%) via thoracotomy and 1 (0.9%) via emergency laparotomy. A total of 15 complications included mucosal ulceration/slough (n=6, 40.0%), oesophageal perforation (n=3, 20.0%), aspiration pneumonia (n=3, 20.0%), and tracheal perforation, lung collapse and contact bleed (n=1 each, 6.7%). No patient presented in respiratory distress or needed emergency airway management, and there were no deaths. CONCLUSIONS: The development of a dedicated paediatric surgery service and the implementation of management protocols have resulted in excellent outcomes for this problem. PMID- 30004365 TI - Surgical skills deficiencies and needs of rural general practitioners in South Africa. AB - BACKGROUND: At present, much of the global surgical workforce consists of non specialist physicians (general practitioners (GPs)) whose only formal surgical training was in medical school as an undergraduate. However, there is widespread concern that GPs do not have the skills necessary to deliver essential surgical care in a rural setting. This requires that a specific training programme be developed to train rural GPs in essential surgical skills for rural settings. OBJECTIVES: To perform a critical analysis to determine essential surgical skills required by GPs in rural South Africa, with the intention of developing the content of an accredited continuing professional development (CPD) learning programme to address needs identified. METHODS: This was a descriptive study in which a desk-top review analysis and a questionnaire survey were used to obtain both qualitative and quantitative data on essential skills required for rural surgical practice. RESULTS: Of 300 GPs, 102 (34.0%) completed the questionnaire. Some of the skills listed as essential for rural surgical practice were removal of foreign objects not in the visual axis (90.0%), packing of epistaxis (93.0%), haematoma drainage (78.3%) and wound debridement and suturing (96.0%). The study also identified the outcomes and essential content of a proposed CPD programme to provide GPs in the rural setting with the required surgical skills. CONCLUSIONS: Enhancing skills of GPs in essential surgical techniques and procedures through an accredited CPD short learning programme will ensure that adequate and comprehensive essential surgical care is provided to people living in rural communities. PMID- 30004366 TI - An assessment of the isoniazid preventive therapy programme for children in a busy primary healthcare clinic in Nelson Mandela Bay Health District, Eastern Cape Province, South Africa. AB - BACKGROUND: Tuberculosis (TB) is a significant contributor to the international and national burden of disease. Global estimates suggest that there were 10.4 million new cases of TB in 2015. Children accounted for ~10% of these cases, although in South Africa (SA) this figure is thought to be higher. Despite clear evidence that isoniazid preventive therapy (IPT) can reduce the risk of progression from TB infection to disease in TB contacts, IPT has been poorly implemented in SA national TB control programmes. OBJECTIVES: To determine current practices regarding the identification and management of child contacts (<5 years of age) at a primary care clinic in the Nelson Mandela Bay Health District, Eastern Cape Province, SA. METHODS: A cross-sectional descriptive study was conducted using a retrospective record review of infectious TB index patients aged >=15 years. Folders of index patients with bacteriologically confirmed pulmonary TB, who started TB treatment between 21 October 2011 and 28 February 2014, were included. A sample size of 246 child contacts was required to obtain adequate power. A 95% confidence interval (CI) was used to determine statistically significant results. RESULTS: Index patient records (N=491) were assessed and 261 child contacts identified. In a high percentage of index patient folders (87.5%; n=430), contacts were documented, although only 0.53 child contacts were identified per index patient. Of the 261 child contacts identified, 184 (70.5%) were screened for TB, 2 started TB treatment and 108/184 (58.7%) started IPT. For the remaining 74 (40.2%) children, there was no documentation of further management. Only 4 (3.7%) children completed the 24-week IPT course. Male patients reported fewer child contacts (chi2 =7.31; p=0.01; odds ratio (OR) 0.6; 95% CI 0.42 - 0.86) and were less likely to bring contacts for screening (chi2=8.98; p=0.003; OR 0.41; 95% CI 0.24 - 0.72). Retreatment index patients were also less likely to bring contacts for screening (chi2=6.37; p=0.01; OR 0.45; 95% CI 0.25 - 0.81) and those who were screened were less likely to initiate IPT (chi2=4.05; p=0.04; OR 0.54; 95% CI 0.3 - 0.95). CONCLUSION: Despite contacts being well documented, child contacts were poorly identified. The fall out of children at each step from identification to IPT completion was unacceptably high. Contacts of male patients and retreatment index patients were at greater risk of poor management. Recommendations to improve IPT delivery at national and local level include a review of the national IPT guidelines, considering the relative success of shorter courses of TB prophylaxis, the use of standardised IPT stationery, staff training and the involvement of community health workers in contact management. PMID- 30004367 TI - The effect of different forms of heparin on point-of-care blood gas analysis. AB - BACKGROUND: Point-of-care blood gas analysis plays an integral role in the management of critically ill and injured patients presenting to the emergency department (ED). While the use of specially manufactured syringes containing electrolyte-balanced dried heparin is recommended when processing these specimens, alternatives including manually self-prepared syringes washed with liquid heparin or heparin vacutainers are still often used. OBJECTIVES: To assess the effect of two concentrations of liquid heparin and the use of heparin vacutainers on the reliability of blood gas analysis results compared with the recommended standard of dried heparin syringes in the ED setting. METHODS: Blood samples were drawn from 54 patients attending a tertiary-level hospital ED. Individual samples were distributed equally among each of four different collection devices: a dried heparin syringe, self-prepared syringes washed separately with 1 000 IU/mL and 5 000 IU/mL liquid heparin, and a heparin vacutainer. Results obtained from the standard dried heparin syringes were compared with those from the other three methods. RESULTS: For both the liquid heparin cohorts, partial pressure of carbon dioxide (pCO2), potassium (K+), sodium (Na+), ionised calcium (iCa2+) and haemoglobin had >20% of results falling beyond the total allowable error. iCa2+ and K+ results were most affected in the 5 000 IU/mL cohort and iCa2+ and Na+ in the 1 000 IU/ml cohort. pCO2, pH and iCa2+ were the most significantly affected in the heparin vacutainer cohort. CONCLUSIONS: Use of liquid heparin can result in significant negative bias in the majority of blood gas analytes, especially electrolytes. Heparin vacutainer use can result in unacceptable variations in the respiratory analytes. While standard dried heparin syringes may not always be available, it is of vital importance that practitioners be aware of these biases and limitations when using substitutes. PMID- 30004368 TI - High positive computed tomography yields in the emergency department might not be a positive finding. AB - BACKGROUND: There is growing pressure to reduce unnecessary computed tomography (CT) imaging requests that the radiology department receives from the emergency department (ED); however, information on acceptable usage rates and diagnostic yields remains scanty. OBJECTIVES: To describe the indications, clinical categories and positive yield rates of patients receiving CT scans in the ED. METHODS: A retrospective record review was done of all patients who received CT scans at an urban, adult academic ED during a 4-month period. Primary outcomes were to establish CT scan usage and positive yield rates. Other outcomes included analysis of indications, demographics and anatomical areas scanned. RESULTS: Scans (n=1 010) were analysed. The median age of patients was 36 (range 4 - 93) years. Male patients received 64.3% of all scans, as well as 75.7% of the scans performed for trauma. The majority of the scans were for trauma patients. However, non-trauma patients had a higher positive yield; the non-trauma positive yield rate was 61.8% compared with the trauma positive yield rate of 47.1% (p<0.001). The majority of scans performed were of the head (58%) and neck (20%), with lowest positive yield rates of 48.9% and 17%, respectively. The overall CT scan usage rate was 4.6% and overall positive rate 53.8%. CONCLUSION: A negative CT scan does not necessarily mean that the test was not indicated. Higher positive yield rates may reflect insufficient use of CT scanning by the ED. Local guidelines should be established to ensure judicious and effective clinical use of CT scans. PMID- 30004369 TI - Estimating the burden of cervical disease among HIV-infected women accessing screening services in South Africa: A model-based analysis. AB - BACKGROUND: Cervical cancer remains the second most common cancer among women worldwide, with much of the global burden occurring in low- and middle-income countries. HIV-infected women are at increased risk of human papillomavirus infection, preinvasive cervical disease and invasive cervical cancer (ICC). Funded through the United States President's Emergency Plan for AIDS Relief (PEPFAR) and working in collaboration with the South African (SA) Department of Health, our team supports cervical screening integrated within public sector HIV clinics in SA. OBJECTIVES: To estimate the burden of cervical disease among HIV infected women accessing screening services supported through our programme. METHODS: We constructed conditional probability models to estimate the burden of grade 1 and grades 2/3 cervical intraepithelial lesions (CIN1 and CIN2/3) and ICC among two cohorts: one consisting of 3 190 HIV-infected women for whom only cytology results were available for analysis, and another consisting of 75 358 HIV-infected women for whom neither cytology nor histology results were available. Parameter estimates for the models were derived from routinely collected programmatic data and published clinical trials. RESULTS: Between January 2009 and November 2015, 75 358 HIV-infected women underwent Pap smear screening in public sector clinics supported by our cervical cancer prevention programme. Based on modelling analysis, we estimate that 46 123 cases of CIN1 (range 45 500 - 49 608), 13 598 cases of CIN2/3 (range 12 749 - 14 828), and 104 cases of ICC (range 61 - 186) occurred in this population. CONCLUSIONS: Our findings highlight the magnitude of cervical disease among HIV-infected women in SA. PMID- 30004370 TI - Restaurant smoking sections in South Africa and the perceived impact of the proposed smoke-free laws: Evidence from a nationally representative survey. AB - BACKGROUND: The South African Minister of Health announced in 2016 that he intends to introduce tobacco control legislation that will prohibit smoking in restaurants. This will substantially strengthen the Tobacco Products Control Act (1993, as amended), which currently allows restaurants to have a dedicated, enclosed indoor smoking area. OBJECTIVES: To analyse current smoking policies of restaurants, whether and how these policies have changed over the past decade, and restaurateurs' attitudes to the proposed legislative changes. METHODS: From a population of nearly 12 000 restaurants, derived from four websites, we sampled 2 000 restaurants, stratifying by province and type (independent v. chain) and disproportionately sampling small strata to ensure meaningful analysis. We successfully surveyed 741 restaurants, mostly by phone. We also surveyed 60 franchisors from a population of 82 franchisors. RESULTS: Of the restaurants sampled, 44% were 100% smoke-free, 44% had smoking sections outside, 11% had smoking sections inside, and 1% allowed smoking anywhere. Smoking areas were more common in independent restaurants (62%) than franchised restaurants (43%). Of the restaurants with a smoking section, 33% reported that the smoking sections were busier than the non-smoking sections. Twenty-three percent of restaurants had made changes to their smoking policies in the past 10 years, mostly removing or reducing the size of the smoking sections. Customer requests (39%), compliance with the law (35%) and cost and revenue pressures (14%) were the main reasons for changing smoking policies. Of the restaurant respondents 91% supported the current legislation, while 63% supported the proposed legislative changes; 68% of respondents who were aware of the proposed legislation supported it, compared with 58% of respondents who were not aware of the proposed legislation. CONCLUSIONS: In contrast to the vehement opposition to the 1999 legislation, which resulted in restaurants going partially smoke-free in 2001, there was limited opposition from restaurants to the proposed legislative changes that would make restaurants 100% smoke-free. Support for the proposed legislation will probably increase as the restaurant industry and the public are made more aware of the proposed legislative changes, although public opinion is vulnerable to tobacco industry-led campaigns. PMID- 30004371 TI - How well do we understand calcium and vitamin D? PMID- 30004372 TI - S aureus bacteremia: TEE and infectious disease consultation. PMID- 30004373 TI - Critical care medicine: An ongoing journey. PMID- 30004374 TI - What inpatient treatments do we have for acute intractable migraine? PMID- 30004375 TI - When does S aureus bacteremia require transesophageal echocardiography? PMID- 30004376 TI - What should I address at follow-up of patients who survive critical illness? PMID- 30004378 TI - Navigating travel with diabetes. AB - As the number of people who travel continues to increase, so too will the number of travelers with diabetes. This increase will come with new and more frequent requests for medical travel advice. This article equips clinicians with the tools to address patient concerns about travel and to empower patients to be prepared for emergency situations both abroad and at home. This includes encouraging patients to obtain a travel letter, bring enough supplies for the trip, and have a plan to manage time-zone changes. PMID- 30004379 TI - Optimizing calcium and vitamin D intake through diet and supplements. AB - Calcium, a key component of bone, is obtained through diet or supplements, or both, and vitamin D is necessary for normal calcium absorption. Controversy exists as to the efficacy and even the safety of calcium. Our opinion, backed by studies and guidelines, is that adequate amounts of calcium are a must for patients concerned about bone health, and cardiovascular safety is not a concern. PMID- 30004377 TI - 'Dry drowning' and other myths. AB - Drowning is a common and often preventable cause of death, especially in children. The mass media often propagate misinformation about "dry" and "secondary" drowning, diverting attention from appropriate efforts to prevent drowning and rescue and treat those who do drown. PMID- 30004380 TI - Cardiac rehabilitation: A class 1 recommendation. AB - Cardiac rehabilitation, consisting of prescribed exercise and counseling for risk modification, has proven benefits for patients with cardiovascular disease. Nevertheless, rates of referral and use remain low. Efforts to increase program referral and participation are ongoing. PMID- 30004381 TI - Renal disease and the surgical patient: Minimizing the impact. AB - Chronic kidney disease (CKD) is common in patients scheduled for surgery and increases the risk of postoperative acute kidney injury, major adverse cardiac events, and death. Acute kidney injury is a common complication of cardiac and noncardiac surgery and negatively affects both short- and long-term outcomes. If we can detect underlying CKD and other risk factors for acute kidney injury before surgery, we may in theory be able to give preventive therapies and improve perioperative outcomes. PMID- 30004383 TI - Osmotic demyelination syndrome due to hyperosmolar hyperglycemia. PMID- 30004382 TI - Wolff-Parkinson-White pattern unmasked by severe musculoskeletal pain. PMID- 30004384 TI - Cryo-EM structure of the polycystin 2-l1 ion channel. AB - We report the near atomic resolution (3.3 A) of the human polycystic kidney disease 2-like 1 (polycystin 2-l1) ion channel. Encoded by PKD2L1, polycystin 2 l1 is a calcium and monovalent cation-permeant ion channel in primary cilia and plasma membranes. The related primary cilium-specific polycystin-2 protein, encoded by PKD2, shares a high degree of sequence similarity, yet has distinct permeability characteristics. Here we show that these differences are reflected in the architecture of polycystin 2-l1. PMID- 30004387 TI - Presetting conductive pathway induced the switching uniformity evolution of a SiNx:H resistive switching memory. AB - Si-based resistive random access memory (RRAM) devices at the nanoscale with high uniformity have great potential applications in the future. We demonstrate that the uniformity evolution of the a-SiNx:H RRAM at the low resistance state (LRS) and the high resistance state (HRS) can be clearly monitored by presetting a Si dangling bond (Si-DB) conductive pathway through thermal energy. It is found that the increased magnitude of uniformity for the LRS and the HRS are determined by the number of preset Si-DBs, which can be controlled by tuning thermal energy. As for LRS, the Si-DBs produced under the electric field along with the preset Si-DB conductive pathways form the main conductive pathway. Theoretical calculation of current-voltage (I-V) curves indicates that the Si-DB conductive pathways obey the trap-assisted tunneling model. In the HRS, the preset Si-DBs induced by thermal energy are the unique source of the conductive pathway. The transmission mechanism involves a trap-to-trap process by the hopping of electrons under a low electric field, Poole-Frenkel emission in the main region under the medium electric field and Fowler-Nordheim tunneling under the high electric field. Our discovery of the uniformity evolution for a-SiNx:H RRAM device through presetting the Si-DB conductive pathway provides new insight into the resistive switching mechanism of next generation Si-based RRAM devices. PMID- 30004388 TI - Bioprinting of mineralized constructs utilizing multichannel plotting of a self setting calcium phosphate cement and a cell-laden bioink. AB - Due to their characteristic resemblance of the mineral component of bone, calcium phosphates are widely accepted as optimal bone substitute materials. Recent research focused on the development of pasty calcium phosphate cement (CPC) formulations, which can be fabricated into various shapes by low-temperature extrusion-based additive manufacturing, namely 3D plotting. While it could be demonstrated that sensitive substances like growth factors can be integrated in such printed CPC scaffolds without impairment of their biological activity live cells cannot be suspended in CPC as they may not be functional when enclosed in a solid and stiff matrix. In contrast, 3D bioprinting of soft cell-laden hydrogels (bioinks) enables the fabrication of constructs with spatially defined cell distribution, which has the potential to overcome problems of conventional cell seeding techniques-but such objects lack mechanical stability. Herein, we combine 3D plotting of CPC and bioprinting of a cell-laden bioink for the first time. As model bioink, an alginate-methylcellulose blend (alg/mc) was used, previously developed by us. Firstly, a fabrication regime was established, enabling optimal setting of CPC and cell survival inside the bioink. As the cells are exposed to the chemical changes of CPC precursors during setting, we studied the compatibility of the complex system of CPC and cell-laden alg/mc for a combined extrusion process and characterized the cellular behavior of encapsulated human mesenchymal stroma cells within the bioink at the interface and in direct vicinity to the CPC. Furthermore, biphasic scaffolds were mechanically characterized and a model for osteochondral tissue grafts is proposed. The manuscript discusses possible impacts of the CPC setting reaction on cells within the bioink and illustrates the advantages of CPC in bioprinting as alternative to the commonly used thermoplasts for bone tissue engineering. PMID- 30004385 TI - Lipoate-binding proteins and specific lipoate-protein ligases in microbial sulfur oxidation reveal an atpyical role for an old cofactor. AB - Many Bacteria and Archaea employ the heterodisulfide reductase (Hdr)-like sulfur oxidation pathway. The relevant genes are inevitably associated with genes encoding lipoate-binding proteins (LbpA). Here, deletion of the gene identified LbpA as an essential component of the Hdr-like sulfur-oxidizing system in the Alphaproteobacterium Hyphomicrobium denitrificans. Thus, a biological function was established for the universally conserved cofactor lipoate that is markedly different from its canonical roles in central metabolism. LbpAs likely function as sulfur-binding entities presenting substrate to different catalytic sites of the Hdr-like complex, similar to the substrate-channeling function of lipoate in carbon-metabolizing multienzyme complexes, for example pyruvate dehydrogenase. LbpAs serve a specific function in sulfur oxidation, cannot functionally replace the related GcvH protein in Bacillus subtilis and are not modified by the canonical E. coli and B. subtilis lipoyl attachment machineries. Instead, LplA like lipoate-protein ligases encoded in or in immediate vicinity of hdr-lpbA gene clusters act specifically on these proteins. PMID- 30004389 TI - Co3Fe7/nitrogen-doped graphene nanoribbons as bi-functional electrocatalyst for oxygen reduction and oxygen evolution. AB - In this work, we report a one-pot solvothermal strategy to synthesize Co3Fe7 incorporated graphene nanoribbons (Co3Fe7). An improved bi-functional electrocatalytic activity over the traditional electrocatalysts is exhibited by the Co3Fe7/nitrogen-doped graphene nanoribbon (NGNR) composite. For instance, this composite Co3Fe7/NGNRs depicted a lower overpotential of 350 mV than NGNRs (380 mV) and IrO2 (450 mV) to sustain 10 mA cm-2 for an oxygen evolution reaction in 1.0 M KOH. Furthermore, during an oxygen reduction reaction, the catalyst exhibited a four-electron pathway and it is interesting to note that its electrocatalytic behavior is on a par with commercial Pt/C. The enhancement in the electrochemical performance can be attributed to the synergistic effect that stems from the electrocatalytically active nitrogen atoms and metal alloy nanoparticles distributed uniformly over the graphene matrix. This unique composition of electrocatalyst is extremely beneficial for practical applications in fuel cells and metal-air batteries due to its high stability and sustained electrochemical activity. PMID- 30004390 TI - Chitosan/poly(ethylene glycol)/hyaluronic acid biocompatible patches obtained by electrospraying. AB - Electrospray is a promising technique to scale-up production of microparticles and nanoparticles. In this study, electrospraying was used in order to produce candidate biopatches (CPH) by using chitosan, poly(ethylene glycol) (PEG) and hyaluronic acid (HA). Four different ratios of polymer blend compositions (CPH1, CPH2, CPH3 and CPH4) were tested by dissolving in 2% acetic acid solution (Ac.A.). The HA amount in each blend was kept the same to designate the optimum surface with different chitosan/PEG ratios for electrospray process. Fourier transform infrared (FTIR) microscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM) studies showed that obtained patches had highly adhesive surfaces with the aid of heterogeneously distributed micro- and nano particles. Additionally, video images of FTIR microscopy and AFM images proved that all surfaces have similar heterogeneity except CPH2. The most homogenous surface was obtained by CPH3. Patches were directly subjected to antibacterial tests against ten different types of gram positive and gram negative bacteria using disc diffusion assay (Kirby-Bauer method). Extraordinarily there was no antibacterial property of patches coated with microparticles. Finally, biocompatibility studies were performed by using mouse fibroblast L929 cell lines (ATTC number CCL-1) to test cell adhesion and proliferation properties of the patches. Results of 72 h viability tests proved the electrospray of ternary blends had displayed good biocompatibility; in particular, CPH3 had the highest cell viability. PMID- 30004386 TI - SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion. AB - The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect, characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP-mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target. PMID- 30004392 TI - A Cross-sectional Study to Compare Hepatitis B Immunity in HIV-infected and HIV uninfected Kenyan Children After Primary Hepatitis B Immunization. AB - To evaluate protective antibody levels against hepatitis B surface antigen in HIV infected and HIV-uninfected Kenyan children, this study enrolled 531 children. In the HIV-infected group, only 18.3% had protective hepatitis B surface antigen compared with 74.4% in the HIV-uninfected group (P < 0.0001). Perhaps HIV infected children should be immunized differently. PMID- 30004391 TI - Molecular Detection of Human Astrovirus in Children With Gastroenteritis, Northern Italy. AB - BACKGROUND: Human astroviruses have increasingly been identified and are important agents of diarrheal disease, especially in infants and young children. This article presents the real-time polymerase chain reaction TaqMan assay for the detection and quantification of human astrovirus for clinical fecal samples collected from hospitalized children with acute gastroenteritis in Piedmont (northern Italy) from December 2014 to November 2015. METHODS: A total of 159 fecal specimens from hospitalized children with acute gastroenteritis, previously screened for rotavirus, adenovirus, norovirus, human parechovirus, salivirus and sapovirus, were tested for human astrovirus. RESULTS: The most commonly detected virus was norovirus GII (33.8%), followed by rotavirus (21.3%), sapovirus (10.9%), human parechovirus (8%), norovirus GI (6.7%), adenovirus (1%) and salivirus (0.52%). A total of 30 of 159 (18.87%) episodes of acute gastroenteritis were associated with human astrovirus genomic detection. CONCLUSIONS: Our data showed that the detection rate of astrovirus in diarrheal children (18.87%) was higher than observed in other countries, where they were reported in diarrheal children in 10.3%-0.8% of patients and a mean incidence worldwide of 11%. Our data showed that the detection rate of astrovirus in pediatric gastroenteritis was greater than previously reported in Italy. PMID- 30004393 TI - Clinical Significance of Interleukin-6 in the Diagnosis of Sepsis and Discriminating Sepsis Induced by Gram-negative Bacteria. AB - BACKGROUND: To discuss the clinical significance of interleukin (IL)-6 in the differential diagnosis of sepsis and its capability of differentiating the sepsis induced by Gram-negative bacteria from that induced by Gram-positive bacteria. METHODS: A total of 379 children with sepsis were involved in this study to form the case group, and their C-reactive protein (CRP), procalcitonin (PCT) and IL-6 levels before antibiotics and after recovery were checked. Receiver operating characteristic curve was applied to evaluate the significance of CRP, PCT and IL 6 in the differential diagnosis of sepsis and their capability of differentiating the sepsis induced by Gram-negative bacteria from that induced by Gram-positive bacteria. RESULTS: When these 3 indicators were applied to the differential diagnosis of sepsis, the area under the curve (AUC) of IL-6, PCT and CRP was 0.881, 0.877 and 0.754, respectively. The combination of IL-6 and PCT presented highest diagnostic efficiency. CRP, PCT and IL-6 levels in children with sepsis induced by Gram-negative bacteria were significantly higher than those in children with sepsis induced by Gram-positive bacteria. CONCLUSIONS: CRP, IL-6 and PCT are applicable to the differential diagnosis of sepsis and differentiating the sepsis induced by Gram-negative bacteria from Gram-positive bacteria. Appropriate combinations of these indicators are capable of increasing differential diagnosis efficiency. These indicators can be used as markers of antibiotics usage, but whether they can be used as markers to withdraw antibiotics is still needed to be observed. PMID- 30004394 TI - Vision Loss in an 8-Year-Old Immunocompetent Boy with Cryptococcal Meningitis. AB - Cryptococcal meningitis is an opportunistic fungal infection commonly seen in immunocompromised individuals. Information on cryptococcal meningitis is scarce in immunocompetent children. The authors report an 8-year-old immunocompetent boy with cryptococcal meningitis and bilateral vision loss. The role of repeated therapeutic lumbar puncture in the management of raised intracranial pressure in cryptococcal meningitis is discussed. PMID- 30004395 TI - Comparison of Ground-Based PM2.5 and PM10 Concentrations in China, India, and the U.S. AB - Urbanization and industrialization have spurred air pollution, making it a global problem. An understanding of the spatiotemporal characteristics of PM2.5 and PM10 concentrations (particulate matter with an aerodynamic diameter of less than 2.5 MUm and 10 MUm, respectively) is necessary to mitigate air pollution. We compared the characteristics of PM2.5 and PM10 concentrations and their trends of China, India, and the U.S. from 2014 to 2017. Particulate matter levels were lowest in the U.S., while China showed higher concentrations, and India showed the highest. Interestingly, significant declines in PM2.5 and PM10 concentrations were found in some of the most polluted regions in China as well as the U.S. No comparable decline was observed in India. A strong seasonal trend was observed in China and India, with the highest values occurring in winter and the lowest in summer. The opposite trend was noted for the U.S. PM2.5 was highly correlated with PM10 for both China and India, but the correlation was poor for the U.S. With regard to reducing particulate matter pollutant concentrations, developing countries can learn from the experiences of developed nations and benefit by establishing and implementing joint regional air pollution control programs. PMID- 30004396 TI - Microstructural Differences in Response of Thermoresistant (Ceramic) and Standard (Granite) Concretes on Heating. Studies Using SEM and Nonstandard Approaches to Microtomography and Mercury Intrusion Porosimetry Data. AB - The microstructure of concretes containing ceramic sanitary ware waste and granite aggregates was studied using scanning electron microscopy, mercury intrusion porosimetry and computer microtomography, before and after cyclic heating of the concretes to 1000 degrees C. All methods showed an increase in porosities in the concretes after heating. The proposed new approach to microtomography data analysis detected a much higher increase in the number of cracks in granite than in ceramic concrete after heating. This new approach to combining mercury intrusion and microtomography data showed that heating led to the narrowing of throats connecting smaller pore voids and a broadening of throats connecting larger pore voids, in both concretes. PMID- 30004397 TI - Conditions and Dynamics That Impact Maternal Health Literacy among High Risk Prenatal-Interconceptional Women. AB - The purpose of the study was to describe conditions and dynamics in the lives of high-risk, low-income, Southern United States prenatal-interconceptional women (n = 37) in a home visiting program that promoted maternal health literacy progression. In the Life Course Health Development (LCHD) Model, conditions were risk and protective factors that impacted health. Dynamics drove the complex, epigenetic relationships between risk and protective factors. Maternal health literacy promotion helped participants address conditions and dynamics to create positive life changes. This research was a retrospective, mixed methods study of women's service records documenting care from prenatal admission to 24 months post-delivery. The Life Skills Progression Instrument (LSP) was scored to measure maternal health literacy progression. Ethnographic content analysis of visit notes triangulated with quantitative data enabled specificity of critical data elements. Subsequently, a complementary focus group was conducted with the Registered Nurse Case Managers (RNCM). Severe social conditions included devastating poverty, low educational achievement, transient housing, unstable relationships, incarceration, lack of continuous health insurance, and shortage of health care providers. Dynamics included severe psycho-social stressors, domestic violence, lack of employment, low income, low self-esteem and self expectations, and social/family restraints upon women's intended positive changes. An important protective factor was the consistent, stable, evidence informed relationship with the RNCM. Findings from the focus group discussion supported content analysis results. PMID- 30004399 TI - Double-Dosing and Other Dangers with Non-Prescription Medicines: Pharmacists' Views and Experiences. AB - The aim of this paper was to explore pharmacists' views on reclassifications from pharmacy-only to general sales and their experiences with the supply of these medicines, in addition to pharmacists' views on the reclassification of the shingles vaccine and sildenafil to be available through 'accredited' pharmacists. New Zealand community pharmacists were surveyed in 2013 with a written questionnaire of six Likert-style or open-ended questions sent to Pharmacy Guild member pharmacies. The analysis involved descriptive statistics. Responses were received from 246 pharmacies. Two thirds of pharmacists supported the reclassification of the shingles vaccine and sildenafil, although 14% disagreed with the sildenafil reclassification. Over 90% of pharmacists disagreed with the reclassification of paracetamol and ibuprofen liquids, omeprazole, naproxen, and oxymetazoline from pharmacy-only medicine to general sales. This opinion was strongest for omeprazole. With liquid paracetamol and ibuprofen, pharmacists described consumer confusion with dosing, and particularly potentially doubling up on liquid analgesics/antipyretics including using both prescription and non prescription variants. Many reported giving safety advice frequently. Anti inflammatories and omeprazole were also subject to potential double-dosing, as well as requests by consumers with contraindications, precautions, and drug interactions, and for inappropriate indications. Pharmacists described various interventions, including some that were potentially life-saving. Pharmacy availability of medicines provides the potential for intervention that would not happen in a general sales environment. PMID- 30004398 TI - Interaction of Viral Capsid-Derived Virus-Like Particles (VLPs) with the Innate Immune System. AB - Virus-like particles (VLPs) derived from viral nucleocapsids are an important class of nanoparticles. The structure, uniformity, stability, and function of these VLPs have attracted scientists in utilizing them as a unique tool in various applications in biomedical fields. Their interaction with the innate immune system is of major importance for the adaptive immune response they induce. The innate immune cells and molecules recognize and interact with VLPs on the basis of two major characteristics: size and surface geometry. This review discusses the interaction of viral capsid-derived VLPs with the innate immune system. PMID- 30004400 TI - Evaluation of an In Situ Hardening beta-Tricalcium Phosphate Graft Material for Alveolar Ridge Preservation. A Histomorphometric Animal Study in Pigs. AB - The purpose of this study was to investigate the effectiveness of a resorbable alloplastic in situ hardening bone grafting material for alveolar ridge preservation in a swine model. Seven Landrace pigs were used. In each animal, the maxillary left and right deciduous second molars were extracted, and extraction sites were either grafted with a resorbable alloplastic in situ hardening bone substitute, composed of beta-tricalcium phosphate (beta-TCP) granules coated with poly(lactic-co-glycolic) acid (PLGA), or left unfilled to heal spontaneously. Animals were euthanized after 12 weeks, and the bone tissue was analyzed histologically and histomorphometrically. Linear changes of ridge width were also clinically measured and analyzed. Pronounced bone regeneration was found in both experimental and control sites, with no statistically significant differences. At the experimental sites, most of the alloplastic grafting material was resorbed and remnants of the graft particles were severely decreased in size. Moreover, experimental sites showed, in a statistically nonsignificant way, less mean horizontal dimensional reduction of the alveolar ridge (7.69%) compared to the control sites (8.86%). In conclusion, the beta-TCP/PLGA biomaterial performed well as a biocompatible resorbable in situ hardening bone substitute when placed in intact extraction sockets in this animal model. PMID- 30004401 TI - Magnolol Inhibits Osteoclast Differentiation via Suppression of RANKL Expression. AB - Magnolol, a compound from the traditional Korean herb Magnolia sp., has been exhaustively investigated as a therapeutic agent against several diseases including systemic and local inflammation. We examined the effects of magnolol on osteoclastic differentiation associated with inflammation. Magnolol markedly reduced interleukin (IL)-1-induced osteoclast formation in co-cultures of murine osteoblasts and bone marrow cells, whereas it had no effect on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast formation in bone marrow macrophage cultures. In osteoblasts, magnolol markedly inhibited both the up-regulation of RANKL expression and the production of prostaglandin E2 (PGE2) in response to IL-1 treatment. Addition of exogenous PGE2 reversed the inhibitory effects of magnolol on IL-1-induced RANKL expression in osteoblasts and osteoclast formation in co-cultures. Magnolol inhibited IL-1-induced PGE2 production, at least in part by suppressing cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that magnolol inhibits IL-1-induced RANKL expression in osteoblasts through suppression of COX-2 expression and PGE2 production, resulting in inhibition of osteoclast differentiation in co-cultures. PMID- 30004403 TI - A Cross-Sectional Study of Smoking Behaviors and Attitudes of Parents in Pediatric Primary Care Settings. AB - Environmental tobacco smoke (ETS) exposure is considered an important public health issue in pediatric population. In this study, we aimed to investigate parents' knowledge on side effects of passive smoking and counseling for parental smoking among pediatricians and family practitioners. Participants were biological parents of pediatric patients up to the age of 18 years old who attended Pediatric Hospital of Medical University of Warsaw. The questionnaire included 28 questions and queries on environmental tobacco smoke in children's environment. Medical students identified potential subjects and handed out previously created questionnaires. In total, 506 parents of children aged 0-18 years old were interviewed; 41% (207/506) of parents were smokers, 23% (114/506) were asked about ETS exposure by their pediatricians and 41% (205/506) by family physicians during routine visits. Only a minority of the respondents confirmed having "no smoking" policy in their car 31% (157/506) or in their households 24% (121/506). All parents believed that passive smoking could cause at least one harmful effect: most common were more frequent respiratory infections (43%), asthma (40%), and low birth weight (37%). Among smoking parents, 38% (78/207) has tried to quit smoking for their child's health sake; 63% (131/207) of smokers have never been asked to quit smoking by their doctor. Parents' understanding of passive smoking among children differs from current medical knowledge. Rates of screening and counseling for parental smoking in pediatric and family practices are still unsatisfactory. PMID- 30004402 TI - The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer. AB - There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years. PMID- 30004404 TI - Plasmonic Sensor Based on Interaction between Silver Nanoparticles and Ni2+ or Co2+ in Water. AB - Silver nanoparticles capped with 3-mercapto-1propanesulfonic acid sodium salt (AgNPs-3MPS), able to interact with Ni2+ or Co2+, have been prepared to detect these heavy metal ions in water. This system works as an optical sensor and it is based on the change of the intensity and shape of optical absorption peak due to the surface plasmon resonance (SPR) when the AgNPs-3MPS are in presence of metals ions in a water solution. We obtain a specific sensitivity to Ni2+ and Co2+ up to 500 ppb (part per billion). For a concentration of 1 ppm (part per million), the change in the optical absorption is strong enough to produce a colorimetric effect on the solution, easily visible with the naked eye. In addition to the UV VIS characterizations, morphological and dimensional studies were carried out by transmission electron microscopy (TEM). Moreover, the systems were investigated by means of dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and high-resolution X-ray photoelectron spectroscopy (HR-XPS). On the basis of the results, the mechanism responsible for the AgNPs-3MPS interaction with Ni2+ and Co2+ (in the range of 0.5-2.0 ppm) looks like based on the coordination compounds formation. PMID- 30004406 TI - A Simplified Analysis Method for the Piezo Jet Dispenser with a Diamond Amplifier. AB - Diamond amplifiers have been widely applied in Nano actuators and Robots. In order to study the dynamic characteristics of the diamond amplifier system which is used in the piezo jet dispenser, it is simplified as a spring-mass-damper system. The dynamic characteristics of the jet dispenser system are analyzed with the simplified method. The characteristics are also tested. The results agree with the simulation, which proves the method is feasible. It will provide a simplified and intuitive representation of the movement of the amplifier, and also provide reliable simulation and experimental platforms for jet dispensing analysis. PMID- 30004405 TI - Exploring Harms Experienced by Children Aged 7 to 11 Using Ambulance Attendance Data: A 6-Year Comparison with Adolescents Aged 12-17. AB - Many population data sources do not routinely collect data of children under 12, despite research showing that mental health, self-injurious behaviour, and substance ingestion can have severe consequences in this age group. We used 6 years (January 2012 to December 2017) of ambulance attendance data from the Australian state of Victoria to characterise mental health, self-injurious behaviour, and substance ingestion in children aged 7-11. We compared this group to older children aged 12-17. We found that in comparison to those aged 12-17 (n = 26,778), a smaller number of children aged 7-11 years (n = 1558) were experiencing serious harms, with mental health symptomology the most common harmful outcome. Self-injurious behaviour significantly increased in both age groups throughout the study period. For mental health, self-injurious behaviour and substance ingestion in the 7-11 age group, males were significantly over represented. These aged 7-11 were more likely to ingest pharmaceuticals, rather than alcohol or illicit substances, and suicidal ideation was the most common self-injurious behaviour in this age group. Our study suggests that data collection needs to occur specifically in the 7-11 age group, and importantly, services and interventions to improve mental health and wellbeing will need to be specifically designed and targeted at this age group. PMID- 30004408 TI - Combining New Non-Nucleoside Reverse Transcriptase Inhibitors (RTIs) with AZT Results in Strong Synergism against Multi-RTI-Resistant HIV-1 Strains. AB - Reverse transcriptase inhibitors (RTIs), including nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs), are critical antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection. Emergence of multi-RTI resistance calls for the development of more potent therapeutics or regimens against RTI-resistant strains. Here, we demonstrated that combining azidothymidine (AZT) with a new NNRTIs under development, diarylpyridine (DAPA) 2e, diarylanilin (DAAN)-14h, or DAAN-15h, resulted in strong synergism against infection by divergent HIV-1 strains, including those resistant to NRTIs and NNRTIs, suggesting the potential for developing these novel NNRTIs as salvage therapy for HIV/acquired immune deficiency syndrome (AIDS) patients. PMID- 30004407 TI - Importance of Full-Collapse Vesicle Exocytosis for Synaptic Fatigue-Resistance at Rat Fast and Slow Muscle Neuromuscular Junctions. AB - Neurotransmitter release during trains of activity usually involves two vesicle pools (readily releasable pool, or RRP, and reserve pool, or RP) and two exocytosis mechanisms ("full-collapse" and "kiss-and-run"). However, synaptic terminals are adapted to differing patterns of use and the relationship of these factors to enabling terminals to adapt to differing transmitter release demands is not clear. We have therefore tested their contribution to a terminal's ability to maintain release, or synaptic fatiguability in motor terminals innervating fast-twitch (fatiguable), and postural slow-twitch (fatigue-resistant) muscles. We used electrophysiological recording of neurotransmission and fluorescent dye markers of vesicle recycling to compare the effects of kinase inhibitors of varying myosin light chain kinase (MLCK) selectivity (staurosporine, wortmannin, LY294002 & ML-9) on vesicle pools, exocytosis mechanisms, and sustained neurotransmitter release, using postural-type activity train (20 Hz for 10 min) in these muscles. In both muscles, a small, rapidly depleted vesicle pool (the RRP) was inhibitor insensitive, continuing to release FM1-43, which is a marker of full-collapse exocytosis. MLCK-inhibiting kinases blocked all remaining FM1-43 loss from labelled vesicles. However, FM2-10 release only slowed, indicating continuing kiss-and-run exocytosis. Despite this, kinase inhibitors did not affect transmitter release fatiguability under normal conditions. However, augmenting release in high Ca2+ entirely blocked the synaptic fatigue-resistance of terminals in slow-twitch muscles. Thus, full-collapse exocytosis from most vesicles (the RP) is not essential for maintaining release during a single prolonged train. However, it becomes critical in fatigue-resistant terminals during high vesicle demand. PMID- 30004409 TI - Pleiotropic Immune Functions of Chemokine Receptor 6 in Health and Disease. AB - C-C chemoattractant cytokine (chemokine) receptor 6 (CCR6) and its exclusive binding molecule CCL20 is an extremely important chemokine receptor-ligand pair which controls cell migration and immune induction during inflammatory disease. Not many scientific studies have been undertaken to study its immune mechanisms in detail, but its unique contribution to steady state cell chemotaxis in upholding immune tolerance and regulating immune homeostasis during inflammation is evident in multiple systems in the human body, including skin, liver, lung, kidney, brain, eye, joints, gonads and the gut. The role of CCR6 is constitutively expressed as a series of much debilitating severe inflammatory and autoimmune diseases, Human Immunodeficiency Virus (HIV) and cancer metastasis. CD4+ T cells, the central organizers of adaptive immunity, are stringently mobilized by the CCR6/CCL20 axis also induced by cytokines and a host of other factors in a carefully executed immune modulation scenario, to bring about a delicate balance between inflammation inducing TH17 cells and regulatory Treg cells. Although the exact immune regulatory role is not elucidated as yet, the CCR6/CCL20 axis is implicated as a front runner which determines the polarization of TH17 and regulatory Treg cells, upon which depends the resolution or progression of many debilitating disorders. This review therefore aims at emphasizing the pleiotropic significance of the chemokines CCR6 and CCL20 in immunologic function in multiple organ systems, thereby hoping to accentuate its value in future therapeutic modalities. PMID- 30004410 TI - The Immunity Gap Challenge: Protection against a Recent Florida Clade 2 Equine Influenza Strain. AB - Vaccination is one of the most effective tools for limiting the impact of equine influenza (EI). The humoral immunity established following a primary vaccination course can decrease significantly between the second (V2) and third immunisations (V3), leaving some horses insufficiently protected for several weeks. This so called "immunity gap" poses a challenge to all EI vaccines. During this period, the EI infection of vaccinated animals may be followed by marked clinical signs and virus shedding. However, several EI vaccines have been shown to stimulate equine influenza virus (EIV)-specific cell-mediated immunity, which is likely to play a role in protection against EIV infection and/or mitigate the clinical and virological signs of EI. Reducing the interval between V2 and V3 has been shown to be counterproductive to longer-term immunity. Further research is needed to define and address the "immunity gap" in horses. This study aimed to measure the level of protection induced by a whole inactivated, ISCOMatrix adjuvanted, EI and tetanus vaccine (Equilis Prequenza-Te) when challenged during the immunity gap (i.e., immediately before the recommended boost immunisation, more than 5 months after V2) using infection with a recent heterologous Florida Clade 2 (FC2) equine influenza virus (EIV) strain. This vaccine was tested in a Welsh mountain pony model. A group of seven ponies was vaccinated twice, 4 weeks apart. The protective antibody response was measured and ponies were challenged, along with 5 unvaccinated control ponies, by experimental infection with the FC2 A/eq/Northamptonshire/1/13 EIV strain, 158 days (around 5.2 months) after V2 and their clinical signs and virus shedding were monitored. EI serology was measured by single radial haemolysis (SRH) and haemagglutination inhibition (HI). Clinical signs and virus shedding (measured by qRT-PCR and hen's egg titration) were compared with controls. All vaccinates had detectable, low SRH antibody titres and most had detectable, low HI titres. Significant clinical and virological protection was observed in vaccinates (p < 0.05), supporting the good performance of this vaccine against a recent EIV strain. In this study, the impact of the immunity gap in ponies was limited after primary vaccination with this whole inactivated, ISCOMatrix adjuvanted EI and tetanus vaccine (Equilis Prequenza-Te) when infected several months after V2 with a recent FC2 strain, which is representative of EIV circulating in the EU. PMID- 30004411 TI - A New Benzophenone C-Glucoside and Other Constituents of Pseuduvaria fragrans and Their alpha-Glucosidase Inhibitory Activity. AB - Phytochemical investigations of the leaves and stems of Pseuduvaria fragrans led to the isolation of a new benzophenone C-glucoside named pseuduvarioside (1), together with six known compounds including (-)-guaiol (2), (+)-isocorydine (3), cyathocaline (4), isoursoline (5), N-trans-coumaroyltyramine (6), and N-trans feruloyltyramine (7). Their structures were characterized by NMR spectroscopy and mass spectrometry. All of the isolates were evaluated for inhibitory activity against the enzyme alpha-glucosidase. N-trans-coumaroyltyramine and N-trans feruloyltyramine showed higher activity than the drug acarbose. Kinetic studies revealed that both tyramine-derived amides were uncompetitive inhibitors of the enzyme. PMID- 30004412 TI - Oxygen Consumption Rate Analysis of Mitochondrial Dysfunction Caused by Bacillus cereus Cereulide in Caco-2 and HepG2 Cells. AB - The emetic syndrome of Bacillus cereus is a food intoxication caused by cereulide (CER) and manifested by emesis, nausea and in most severe cases with liver failure. While acute effects have been studied in the aftermath of food intoxication, an exposure to low doses of cereulide might cause unnoticed damages to the intestines and liver. The toxicity which relies on the mitochondrial dysfunction was assessed on Caco-2 and HepG2 cells after exposure of one, three and ten days to a range of low doses of cereulide. Oxygen consumption rate analyses were used to study the impact of low doses of CER on the bioenergetics functions of undifferentiated Caco-2 and HepG2 cells using Seahorse XF extracellular flux analyzer. Both Caco-2 and HepG2 cells experienced measurable mitochondrial impairment after prolonged exposure of 10 days to 0.25 nM of cereulide. Observed mitochondrial dysfunction was greatly reflected in reduction of maximal cell respiration. At 0.50 nM CER, mitochondrial respiration was almost completely shut down, especially in HepG2 cells. These results corresponded with a severe reduction in the amount of cells and an altered morphology, observed by microscopic examination of the cells. Accurate and robust quantification of basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration allowed better understanding of the effects of cereulide in underlying respiratory malfunctions in low-dose exposure. PMID- 30004413 TI - Influence of Clitoria ternatea Flower Extract on the In Vitro Enzymatic Digestibility of Starch and Its Application in Bread. AB - This study aimed to assess the effect of the Clitoria ternatea L. flower extract (CTE), on the inhibition of pancreatic alpha-amylase, in vitro starch hydrolysis, and predicted the glycemic index of different type of flours including potato, cassava, rice, corn, wheat, and glutinous rice flour. The application in a bakery product prepared from flour and CTE was also determined. The results demonstrated that the 1% and 2% (w/v) CTE inhibited the pancreatic alpha-amylase activity by using all flours as a substrate. Moreover, 0.5%, 1%, and 2% (w/v) CTE showed a significant reduction in the glucose release, hydrolysis index (HI), and predicted glycemic index (pGI) of flour. In glutinous rice flour, 1% and 2% (w/v) CTE had a significantly lower level of rapidly digestible starch (RDS) and slowly digestible starch (SDS) with a concomitant higher level of undigested starch. The statistical analysis demonstrated strong positive significant correlations between the percentage of CTE and the undigested starch of wheat and cassava. The addition of 5%, 10%, and 20% (w/w) CTE significantly reduced the rate of starch digestion of the wheat bread. The pGI of bread incorporated with 5% CTE (w/w) was significantly lower than that of the control bread. Our findings suggest that CTE could reduce the starch digestibility, the HI, and pGI of flour through the inhibition of carbohydrate digestive enzymes. Taken together, CTE may be a potent ingredient for the reduced glycemic index of flours. PMID- 30004414 TI - Comparison of Three Modelling Approaches for Predicting Deoxynivalenol Contamination in Winter Wheat. AB - Forecasting models for mycotoxins in cereal grains during cultivation are useful for pre-harvest and post-harvest mycotoxin management. Some of such models for deoxynivalenol (DON) in wheat, using two different modelling techniques, have been published. This study aimed to compare and cross-validate three different modelling approaches for predicting DON in winter wheat using data from the Netherlands as a case study. To this end, a published empirical model was updated with a new mixed effect logistic regression method. A mechanistic model for wheat in Italy was adapted to the Dutch situation. A new Bayesian network model was developed to predict DON in wheat. In developing the three models, the same dataset was used, including agronomic and weather data, as well as DON concentrations of individual samples in the Netherlands over the years 2001-2013 (625 records). Similar data from 2015 and 2016 (86 records) were used for external independent validation. The results showed that all three modelling approaches provided good accuracy in predicting DON in wheat in the Netherlands. The empirical model showed the highest accuracy (88%). However, this model is highly location and data-dependent, and can only be run if all of the input data are available. The mechanistic model provided 80% accuracy. This model is easier to implement in new areas given similar mycotoxin-producing fungal populations. The Bayesian network model provided 86% accuracy. Compared with the other two models, this model is easier to implement when input data are incomplete. In future research, the three modelling approaches could be integrated to even better support decision-making in mycotoxin management. PMID- 30004415 TI - A Visual Cortex-Inspired Imaging-Sensor Architecture and Its Application in Real Time Processing. AB - For robots equipped with an advanced computer vision-based system, object recognition has stringent real-time requirements. When the environment becomes complicated and keeps changing, existing works (e.g., template-matching strategy and machine-learning strategy) are computationally expensive, compromising object recognition performance and even stability. In order to detect objects accurately, it is necessary to build an efficient imaging sensor architecture as the neural architecture. Inspired by the neural mechanism of primary visual cortex, this paper presents an efficient three-layer architecture and proposes an approach of constraint propagation examination to efficiently extract and process information (linear contour). Through applying this architecture in the preprocessing phase to extract lines, the running time of object detection is decreased dramatically because not only are all lines represented as very simple vectors, but also the number of lines is very limited. In terms of the second measure of improving efficiency, we apply a shape-based recognition method because it does not need any high-dimensional feature descriptor, long-term training, or time-expensive preprocessing. The final results perform well. It is proved that detection performance is good. The brain is the result of natural optimization, so we conclude that a visual cortex-inspired imaging sensor architecture can greatly improve the efficiency of information processing. PMID- 30004416 TI - The Olive Biophenols Oleuropein and Hydroxytyrosol Selectively Reduce Proliferation, Influence the Cell Cycle, and Induce Apoptosis in Pancreatic Cancer Cells. AB - Current chemotherapy drugs for pancreatic cancer only offer an increase in survival of up to six months. Additionally, they are highly toxic to normal tissues, drastically affecting the quality of life of patients. Therefore, the search for novel agents, which induce apoptosis in cancer cells while displaying limited toxicity towards normal cells, is paramount. The olive biophenols, oleuropein, hydroxytyrosol and tyrosol, have displayed cytotoxicity towards cancer cells without affecting non-tumorigenic cells in cancers of the breast and prostate. However, their activity in pancreatic cancer has not been investigated. Therefore, the aim of this study was to determine the anti-pancreatic cancer potential of oleuropein, hydroxytyrosol and tyrosol. Pancreatic cancer cells (MIA PaCa-2, BxPC-3, and CFPAC-1) and non-tumorigenic pancreas cells (HPDE) were treated with oleuropein, hydroxytyrosol and tyrosol to determine their effect on cell viability. Oleuropein displayed selective toxicity towards MIA PaCa-2 cells and hydroxytyrosol towards MIA PaCa-2 and HPDE cells. Subsequent analysis of Bcl 2 family proteins and caspase 3/7 activation determined that oleuropein and hydroxytyrosol induced apoptosis in MIA PaCa-2 cells, while oleuropein displayed a protective effect on HPDE cells. Gene expression analysis revealed putative mechanisms of action, which suggested that c-Jun and c-Fos are involved in oleuropein and hydroxytyrosol induced apoptosis of MIA PaCa-2 cells. PMID- 30004417 TI - Using Stigmergy to Distinguish Event-Specific Topics in Social Discussions. AB - In settings wherein discussion topics are not statically assigned, such as in microblogs, a need exists for identifying and separating topics of a given event. We approach the problem by using a novel type of similarity, calculated between the major terms used in posts. The occurrences of such terms are periodically sampled from the posts stream. The generated temporal series are processed by using marker-based stigmergy, i.e., a biologically-inspired mechanism performing scalar and temporal information aggregation. More precisely, each sample of the series generates a functional structure, called mark, associated with some concentration. The concentrations disperse in a scalar space and evaporate over time. Multiple deposits, when samples are close in terms of instants of time and values, aggregate in a trail and then persist longer than an isolated mark. To measure similarity between time series, the Jaccard's similarity coefficient between trails is calculated. Discussion topics are generated by such similarity measure in a clustering process using Self-Organizing Maps, and are represented via a colored term cloud. Structural parameters are correctly tuned via an adaptation mechanism based on Differential Evolution. Experiments are completed for a real-world scenario, and the resulting similarity is compared with Dynamic Time Warping (DTW) similarity. PMID- 30004419 TI - Survey on Nursing Home Caregivers' Basic Knowledge of Oral Health Management: Dental Terminology. AB - With the increasing numbers of the elderly requiring care in Japan, the management of their oral health care will require cooperation between medical and dental professionals, and we need to transfer dental knowledge from dental professionals to caregivers. With the help of a questionnaire, we examined 181 caregivers' depth of understanding regarding 20 typical dental terms with a view to improving the educational instruction provided to them. It was found that except for "clasp", popular dental terms have largely been accepted. The differences in their degrees of understanding could be owing to the lack of systematic education for caregivers. PMID- 30004418 TI - Bergamottin Suppresses Metastasis of Lung Cancer Cells through Abrogation of Diverse Oncogenic Signaling Cascades and Epithelial-to-Mesenchymal Transition. AB - Bergamottin (BGM) is a naturally occurring furanocoumarin and is known to inhibit the growth of tumor cells. However, there is no available evidence that BGM has an inhibitory effect on cancer metastasis, specifically on the epithelial-to mesenchymal transition (EMT) process in the malignant cells. Here we aimed to evaluate the antimetastatic potential of BGM in human lung adenocarcinoma cells. Our results demonstrate that BGM can block EMT, and observed inhibition was accompanied by downregulation of fibronectin, vimentin, N-cadherin, twist and snail expression, and upregulation of occludin and E-cadherin. Interestingly, transforming growth factor-beta (TGF-beta)-induced upregulation of fibronectin, vimentin, N-cadherin, twist and snail, and downregulation of occludin and E cadherin, were abrogated by BGM treatment. Moreover, the treatment of BGM repressed TGF-beta-induced cell invasive potential. BGM treatment also inhibited multiple oncogenic cascades such as PI3K/Akt/mTOR. Overall, the results demonstrate the potential antimetastatic activity of BGM against lung cancer cells. PMID- 30004420 TI - Dense RGB-D SLAM with Multiple Cameras. AB - A multi-camera dense RGB-D SLAM (simultaneous localization and mapping) system has the potential both to speed up scene reconstruction and to improve localization accuracy, thanks to multiple mounted sensors and an enlarged effective field of view. To effectively tap the potential of the system, two issues must be understood: first, how to calibrate the system where sensors usually shares small or no common field of view to maximally increase the effective field of view; second, how to fuse the location information from different sensors. In this work, a three-Kinect system is reported. For system calibration, two kinds of calibration methods are proposed, one is suitable for system with inertial measurement unit (IMU) using an improved hand-eye calibration method, the other for pure visual SLAM without any other auxiliary sensors. In the RGB-D SLAM stage, we extend and improve a state-of-art single RGB D SLAM method to multi-camera system. We track the multiple cameras' poses independently and select the one with the pose minimal-error as the reference pose at each moment to correct other cameras' poses. To optimize the initial estimated pose, we improve the deformation graph by adding an attribute of device number to distinguish surfels built by different cameras and do deformations according to the device number. We verify the accuracy of our extrinsic calibration methods in the experiment section and show the satisfactory reconstructed models by our multi-camera dense RGB-D SLAM. The RMSE (root-mean square error) of the lengths measured in our reconstructed mode is 1.55 cm (similar to the state-of-art single camera RGB-D SLAM systems). PMID- 30004421 TI - Light Chain Diversity among the Botulinum Neurotoxins. AB - Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A-G). The Centers for Disease Control classifies BoNTs as 'Category A' select agents and are the most lethal protein toxins for humans. Recently, BoNT-like proteins have also been identified in several non-clostridia. BoNTs are di-chain proteins comprised of an N-terminal zinc metalloprotease Light Chain (LC) and a C-terminal Heavy Chain (HC) which includes the translocation and receptor binding domains. The two chains are held together by a disulfide bond. The LC cleaves Soluble N ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The cleavage of SNAREs inhibits the fusion of synaptic vesicles to the cell membrane and the subsequent release of acetylcholine, which results in flaccid paralysis. The LC controls the catalytic properties and the duration of BoNT action. This review discusses the mechanism for LC catalysis, LC translocation, and the basis for the duration of LC action. Understanding these properties of the LC may expand the applications of BoNT as human therapies. PMID- 30004422 TI - ABA Receptor Subfamily III Enhances Abscisic Acid Sensitivity and Improves the Drought Tolerance of Arabidopsis. AB - The phytohormone abscisic acid (ABA) regulates plant growth, the developmental process, and abiotic stresses. ABA signaling is induced in response to mediate plant acclimation to environmental challenges, including high salinity and drought. The ABA-binding receptors (RCAR/PYR1/PYL), composing of 14 members, are the core components of the ABA-signaling pathway. Here, we observed that the three subfamilies within the RCARs showed different expression patterns at the basal and exogenous ABA levels. Subsequently, we generated transgenic plants overexpressing subfamily III, RCAR11-RCAR14, respectively. The transgenic plants showed increased ABA sensitivity in seed germination and post-germination seedling establishment and root length. Further studies revealed that the overexpressing subfamily III transgenic plants enhanced drought resistance, increased water-use efficiency, and accelerated stress-responsive gene expression compared with the wild-type plants. These findings confirm that the subfamily III plays a key role in ABA-mediated developmental processes and, more importantly, is involved in drought tolerance in the ABA-dependent pathway. PMID- 30004424 TI - A Kind of Joint Routing and Resource Allocation Scheme Based on Prioritized Memories-Deep Q Network for Cognitive Radio Ad Hoc Networks. AB - Cognitive Radio (CR) is a promising technology to overcome spectrum scarcity, which currently faces lots of unsolved problems. One of the critical challenges for setting up such systems is how to coordinate multiple protocol layers such as routing and spectrum access in a partially observable environment. In this paper, a deep reinforcement learning approach is adopted for solving above problem. Firstly, for the purpose of compressing huge action space in the cross-layer design problem, a novel concept named responsibility rating is introduced to help decide the transmission power of every Secondary User (SU). In order to deal with problem of dimension curse while reducing replay memory, the Prioritized Memories Deep Q-Network (PM-DQN) is proposed. Furthermore, PM-DQN is applied to solve the joint routing and resource allocation problem in cognitive radio ad hoc network for minimizing the transmission delay and power consumption. Simulation results illustrates that our proposed algorithm can reduce the end-to-end delay, packet loss ratio and estimation error while achieving higher energy efficiency compared with traditional algorithm. PMID- 30004423 TI - Therapeutic Opportunities of Targeting Histone Deacetylase Isoforms to Eradicate Cancer Stem Cells. AB - Cancer stem cells (CSCs), or tumor-initiating cells, are a small subset of cancer cells with the capacity for self-renewal and differentiation, which have been shown to drive tumor initiation, progression, and metastasis in many types of cancer. Moreover, therapeutic regimens, such as cisplatin and radiation were reported to induce the enrichment of CSCs, thereby conferring chemoresistance on cancer cells. Therefore, therapeutic targeting of CSCs represents a clinical challenge that needs to be addressed to improve patient outcome. In this context, the effectiveness of pan or class-I histone deacetylase (HDAC) inhibitors in suppressing the CSC population is especially noteworthy in light of the new paradigm of combination therapy. Evidence suggests that this anti-CSC activity is associated with the ability of HDAC inhibitors to target multiple signaling pathways at different molecular levels. Beyond chromatin remodeling via histone acetylation, HDAC inhibitors can also block key signaling pathways pertinent to CSC maintenance. Especially noteworthy is the ability of different HDAC isoforms to regulate the protein stability and/or activity of a series of epithelial mesenchymal transition (EMT)-inducing transcription factors, including HIF 1alpha, Stat3, Notch1, beta-catenin, NF-kappaB, and c-Jun, each of which plays a critical role in regulating CSCs. From the translational perspective, these mechanistic links constitute a rationale to develop isoform-selective HDAC inhibitors as anti-CSC agents. Thus, this review aims to provide an overview on the roles of HDAC isoforms in maintaining CSC homeostasis via distinct signaling pathways independent of histone acetylation. PMID- 30004425 TI - Signs, Fines and Compliance Officers: A Systematic Review of Strategies for Enforcing Smoke-Free Policy. AB - Background. Smoke-free environment policies limit or eliminate the use of smoke producing tobacco in designated areas thereby reducing second hand smoke. Enforcement is perceived as critical to the successful adoption of a smoke-free policy. However, there is limited guidance available regarding effective enforcement strategies. A systematic review was conducted to examine the effectiveness of enforcement strategies at increasing compliance with and enforcement of smoke-free policies; and to determine circumstances other than enforcement strategies that are associated with compliance with smoke-free policies. Design. Medline, Medline in Process, The Cochrane Library, Embase, PsycInfo and CINAHL databases were searched using MeSH and keywords for relevant studies published between January 1980 and August 2017. A narrative synthesis and methodological quality assessment of included studies was undertaken. Results. Policy promotion and awareness-raising activities, signage, enforcement officers, and penalties for violations were the enforcement strategies most frequently cited as being associated with successful policy enforcement. Additionally, awareness of the laws, non-smoking management and lower staff smoking rates, and membership of a network guiding the policy enforcement contributed to higher compliance with smoke-free policies. Conclusions. There is weak evidence of the effectiveness of strategies associated with compliance with smoke-free policies. Given the evidence base is weak, well-designed trials utilizing appropriate evaluation designs are needed. Overall enforcement strategies associated with total smoke-free bans resulted in higher levels of compliance than strategies for policies that had only partial smoke-free bans. PMID- 30004426 TI - Simultaneous Preparation of Salidroside and p-Tyrosol from Rhodiola crenulata by DIAION HP-20 Macroporous Resin Chromatography Combined with Silica Gel Chromatography. AB - The Rhodiola species have a long history of utilization in traditional medicine and have been considered as a source of adaptation to environmental challenges; salidroside and p-tyrosol are the major responsible compounds. Here we propose a novel UPLC-guided two-step method consisting of a DIAION HP-20 adsorption and silica gel column chromatographies, which can simultaneously prepare high purities of salidroside and p-tyrosol with noticeable yields from the rhizome of Rhodiola crenulata. Results demonstrated that DIAION HP-20 could successfully remove all impurities except crenulatin during a gradient elution with 5-20% ethanol, which could achieve an optimal purification of salidroside and p-tyrosol with increasing rates of 29.19% and 33.44%, respectively. Furthermore, chloroform was selected as an ideal solvent for separating p-tyrosol with salidroside, and thus crenulatin was subsequently applied in the silica gel chromatography, and the separation of salidroside with crenulatin could be achieved using silica gel chromatography with a mixture of chloroform and methanol at a volume ratio of 4:1. High purity rates of 94.17% and 97.29% and overall yields of 39.09% and 43.73% for salidroside and p-tyrosol were simultaneously achieved. Our method provides a new way to simultaneously obtain salidroside and p-tyrosol from R. Crenulata, as well as other related plant species. PMID- 30004427 TI - A3, a Scorpion Venom Derived Peptide Analogue with Potent Antimicrobial and Potential Antibiofilm Activity against Clinical Isolates of Multi-Drug Resistant Gram Positive Bacteria. AB - Current research in the field of antimicrobials is focused on developing novel antimicrobial agents to counteract the huge dilemma that the human population is mainly facing in regards to the rise of bacterial resistance and biofilm infections. Host defense peptides (HDPs) are a promising group of molecules for antimicrobial development as they display several attractive features suitable for antimicrobial activity, including their broad spectrum of activity and potency against bacteria. AamAP1 is a novel HDP that belongs to the venom of the North African scorpion Androctonus amoeruxi. In vitro antimicrobial assays revealed that the peptide displays moderate activity against Gram-positive and Gram-negative bacteria. Additionally, the peptide proved to be highly hemolytic and displayed significantly high toxicity against mammalian cells. In our study, a novel synthetic peptide analogue named A3 was synthetically modified from AamAP1 in order to enhance its activity and toxicity profile. The design strategy depended on modifying the amino acid sequence of AamAP1 in order to alter its net positive charge, percentage helicity and modify other parameters that are involved theoretically in HDPs activity. Accordingly, A3 was evaluated for its in vitro antimicrobial and anti-biofilm activity individually and in combination with four different types of conventional antibiotics against clinical isolates of multi-drug resistant (MDR) Gram-positive bacteria. A3 was also evaluated for its cytotoxicity against mammalian cells. A3 managed to selectively inhibit the growth of a wide range of resistant strains of Gram-positive bacteria. Our results also showed that combining A3 with conventional antibiotics caused a synergistic antimicrobial behavior that resulted in decreasing the MIC value for A3 peptide as low as 0.125 uM. At the concentrations needed to inhibit bacterial growth, A3 displayed minimal mammalian cell toxicity. In conclusion, A3 exhibits enhanced activity and selectivity when compared with the parent natural scorpion venom peptide. The combination of A3 with conventional antibiotics could provide researchers in the antimicrobial drug development field with a potential alternative for conventional antibiotics against MDR bacteria. PMID- 30004430 TI - Editorial for Special Issue "Microorganisms for Environmental and Industrial Applications". AB - Microorganisms play an essential role in the biogeochemical cycling of elements, and thereforethey hold potential for various environmental and industrial applications[...]. PMID- 30004429 TI - A Comparative Study of Four Kinds of Adaptive Decomposition Algorithms and Their Applications. AB - The adaptive decomposition algorithm is a powerful tool for signal analysis, because it can decompose signals into several narrow-band components, which is advantageous to quantitatively evaluate signal characteristics. In this paper, we present a comparative study of four kinds of adaptive decomposition algorithms, including some algorithms deriving from empirical mode decomposition (EMD), empirical wavelet transform (EWT), variational mode decomposition (VMD) and Vold Kalman filter order tracking (VKF_OT). Their principles, advantages and disadvantages, and improvements and applications to signal analyses in dynamic analysis of mechanical system and machinery fault diagnosis are showed. Examples are provided to illustrate important influence performance factors and improvements of these algorithms. Finally, we summarize applicable scopes, inapplicable scopes and some further works of these methods in respect of precise filters and rough filters. It is hoped that the paper can provide a valuable reference for application and improvement of these methods in signal processing. PMID- 30004428 TI - Transcriptomic Analysis of the Candidate Genes Related to Aroma Formation in Osmanthus fragrans. AB - Osmanthus fragrans, or "RiXiangGui", is an ornamental, woody, evergreen plant that is cultivated widely because it blooms recurrently and emits a strong fragrance. Recently, the germplasm resources, classification, and aroma compositions of O. fragrans have been investigated. However, the molecular mechanisms of the floral scent formation and regulation have remained largely unknown. To obtain a global perspective on the molecular mechanism of the aroma formation during blooming, nine RNA Sequencing (RNA-Seq) libraries were constructed from three flowering stages: The initial, full, and final flowering stage. In short, a total of 523,961,310 high-quality clean reads were assembled into 136,611unigenes, with an average sequence length of 792 bp. About 47.43% of the unigenes (64,795) could be annotated in the NCBI non-redundant protein database. A number of candidate genes were identified in the terpenoid metabolic pathways and 1327 transcription factors (TFs), which showed differential expression patterns among the floral scent formation stages, were also identified, especially OfMYB1, OfMYB6, OfWRKY1, and OfWRKY3, which could play critical roles in the floral scent formation. These results indicated that the floral scent formation of O. fragrans was a very complex process which involved a large number of TFs. This study provides reliable resources for further studies of the O.fragrans floral scent formation. PMID- 30004431 TI - Descriptive Epidemiology of Uruguayan Adults' Leisure Time Physical Activity. AB - Policymakers rely on information for describing and monitoring levels of physical activity among the population. However, in Uruguay there is no research presenting physical activity practices nationwide. The present study aims to describe the leisure time physical activity levels and their unequal distribution among Uruguayan adults. Data from the 2014 Uruguayan National Health Survey (n = 3543 adults aged > 15 years) were analysed. Physical activity was measured by questionnaire, with participants reporting the number of days and time spent doing physical activity during leisure time in a typical week. Only 25.1% of the participants met the international recommendations for physical activity. Males were twice as active as females in early adulthood in terms of time. The absolute socioeconomic gap between the poorest and wealthiest income quintiles was around 20 percentage points, and participants with the highest physical activity levels were within the wealthiest and highest-educational levels. A low proportion of the population met the proxy of the international recommendations for physical activity. Important socioeconomic inequalities have been found in physical activity practices and must be considered in public health interventions. PMID- 30004432 TI - Exogenous Melatonin Improves Tolerance to Water Deficit by Promoting Cuticle Formation in Tomato Plants. AB - The plant cuticle, composed of cutin and waxes, is a hydrophobic layer coating the aerial organs of terrestrial plants and playing a critical role in limiting water loss. While melatonin has been recently demonstrated to be involved in responses to drought stress in plants, its relationship with cuticle formation is not known. In the present work, we report the effects of melatonin on the formation of cuticle in tomato leaves subjected to water deficit. Preliminary analysis by light microscope showed that tomato leaves pretreated with exogenous melatonin might have thicker cutin than tomato leaves without melatonin pretreatment under water deficit condition. Chemical characterization showed that exogenous application of melatonin increased the level of cuticular waxes in tomato leaves under water deficit. Consistent with the change in cuticular waxes was the increased abundance of wax-associated gene transcripts. Further, assessment of water loss and chlorophyll leaching in tomato leaves revealed the association of cuticle deposition with reduced leaf permeability, which is important in restricting water loss in water deficit-stressed tomato plants. These results suggest a role for melatonin in regulating leaf cuticle formation and non-stomatal water loss in leaves. PMID- 30004434 TI - Cecropin A Modulates Tight Junction-Related Protein Expression and Enhances the Barrier Function of Porcine Intestinal Epithelial Cells by Suppressing the MEK/ERK Pathway. AB - Inflammatory bowel disease (IBD) in humans and animals is associated with bacterial infection and intestinal barrier dysfunction. Cecropin A, an antimicrobial peptide, has antibacterial activity against pathogenic bacteria. However, the effect of cecropin A on intestinal barrier function and its related mechanisms is still unclear. Here, we used porcine jejunum epithelial cells (IPEC J2) as a model to investigate the effect and mechanism of cecropin A on intestinal barrier function. We found that cecropin A reduced Escherichia coli (E. coli) adherence to IPEC-J2 cells and downregulated mRNA expression of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL 8). Furthermore, cecropin A elevated the transepithelial electrical resistance (TER) value while reducing the paracellular permeability of the IPEC-J2 cell monolayer barrier. Finally, by using Western blotting, immunofluorescence and pathway-specific antagonists, we demonstrated that cecropin A increased ZO-1, claudin-1 and occludin protein expression and regulated membrane distribution and F-actin polymerization by increasing CDX2 expression. We conclude that cecropin A enhances porcine intestinal epithelial cell barrier function by downregulating the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We suggest that cecropin A has the potential to replace antibiotics in the treatment of IBD due to its antibacterial activity on gram negative bacteria and its enhancement effect on intestinal barrier function. PMID- 30004433 TI - Immune Profiling of Cancer Patients Treated with Immunotherapy: Advances and Challenges. AB - The recent advances in immunotherapy and the availability of novel drugs to target the tumor microenvironment have dramatically changed the paradigm of cancer treatment. Nevertheless, a significant proportion of cancer patients are unresponsive or develop resistance to these treatments. With the aim to increase the clinical efficacy of immunotherapy, combinations of agents and standard therapies with complementary actions have been developed mostly on an empirical base, since their mechanisms of actions are not yet fully dissected. The characterization of immune responsiveness and its monitoring along with the treatment of cancer patients with immunotherapy can provide insights into the mechanisms of action of these therapeutic regimens and contribute to the optimization of patients' stratification and of combination strategies and to the prediction of treatment-related toxicities. Thus far, none of the immunomonitoring strategies has been validated for routine clinical practice. Moreover, it is becoming clear that the genomic and molecular make-up of tumors and of the infiltrating immune system represent important determinants of the clinical responses to immunotherapy. This review provides an overview of different approaches for the immune profiling of cancer patients and discusses their advantages and limitations. Recent advances in genomic-based assays and in the identification of host genomic relationships with immune responses represent promising approaches to identify molecular determinants and biomarkers to improve the clinical efficacy of cancer immunotherapy. PMID- 30004435 TI - Marine Skeletons: Towards Hard Tissue Repair and Regeneration. AB - Musculoskeletal disorders in the elderly have significantly increased due to the increase in an ageing population. The treatment of these diseases necessitates surgical procedures, including total joint replacements such as hip and knee joints. Over the years a number of treatment options have been specifically established which are either permanent or use temporary natural materials such as marine skeletons that possess unique architectural structure and chemical composition for the repair and regeneration of bone tissue. This review paper will give an overview of presently used materials and marine structures for hard tissue repair and regeneration, drugs of marine origin and other marine products which show potential for musculoskeletal treatment. PMID- 30004436 TI - Spectral Characterization and Molecular Dynamics Simulation of Pesticides Based on Terahertz Time-Domain Spectra Analyses and Density Functional Theory (DFT) Calculations. AB - This work provides the experimental and theoretical fundamentals for detecting the molecular fingerprints of six kinds of pesticides by using terahertz (THz) time-domain spectroscopy (THz-TDS). The spectra of absorption coefficient and refractive index of the pesticides, chlorpyrifos, fipronil, carbofuran, dimethoate, methomyl, and thidiazuron are obtained in frequencies of 0.1-3.5 THz. To accurately describe the THz spectral characteristics of pesticides, the wavelet threshold de-noising (WTD) method with db 5 wavelet fucntion, 5-layer decomposition, and soft-threshold de-noising was used to eliminate the spectral noise. The spectral baseline correction (SBC) method based on asymmetric least squares smoothing was used to remove the baseline drift. Spectral results show that chlorpyrifo had three characteristic absorption peaks at 1.47, 1.93, and 2.73 THz. Fipronil showed three peaks at 0.76, 1.23, and 2.31 THz. Carbofuran showed two peaks at 2.72 and 3.06 THz. Dimethoate showed three peaks at 1.05, 1.89, and 2.92 THz. Methomyl showed five peaks at 1.01, 1.65, 1.91, 2.72, and 3.20 THz. Thidiazuron showed four peaks at 0.99, 1.57, 2.17, and 2.66 THz. The density functional theory (DFT) of B3LYP/6-31G+(d,p) was applied to simulate the molecular dynamics for peak analyzing of the pesticides based on isolated molecules. The theoretical spectra are in good agreement with the experimental spectra processed by WTD + SBC, which implies the validity of WTD + SBC spectral processing methods and the accuracy of DFT spectral peak analysis. These results support that the combination of THz-TDS and DFT is an effective tool for pesticide fingerprint analysis and the molecular dynamics simulations. PMID- 30004438 TI - Using Natural Biomacromolecules for Adsorptive and Enzymatic Removal of Aniline Blue from Water. AB - The present study investigated the adsorptive and enzymatic removal of aniline blue dye (AB) from aqueous solution using waxy riceprocessing waste (RW), peanut shell (PS), microbial waste of Aspergillus niger (MW) as low cost adsorbents, and laccase (Lac) as a biocatalyst. Commercial activated carbon (AC) was also employed to compare the adsorption performance with the three adsorbents. Dye removal was examined under various parameters in batch experiments. It was found that dye removal by RW and Lac was 89-94% noticeably better than that by MW and PS (20-70%). In any cases, AC produced the highest dye removal among the tested materials. The kinetics, isotherms, and thermodynamics were then analyzed to elucidate the adsorption process by the four adsorbents. The pseudo-second order kinetic was superior to the pseudo first order kinetic model in describing adsorption for all adsorbents. The Langmuir model fitted the adsorption process very well, indicating monolayer coverage of dyes on a solid surface. A thermodynamic analysis of enthalpy (DeltaH degrees ), entropy (DeltaS degrees ), and Gibbs free energy (DeltaG degrees ) classified the adsorption as a nonspontaneous and endothermic process. The results reveal diverse natural materials (e.g., processing waste RW) as novel substitutes for traditional activated carbon, as well as laccase as a green catalyst for the treatment of dye wastewater. PMID- 30004439 TI - Correction: Cizkova, D., et al. Localized Intrathecal Delivery of Mesenchymal Stromal Cells Conditioned Media Improves Functional Recovery in A Rat Model of Contusive Spinal Cord Injury. Int. J. Mol. Sci. 2018, 19, 870. PMID- 30004437 TI - Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients. AB - The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg IFNalpha-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication. PMID- 30004440 TI - Geometric Accuracy Evaluation of High-Resolution Satellite Images Based on Xianning Test Field. AB - The evaluation of geometric accuracy of high-resolution satellite images (HRSIs) has been increasingly recognized in recent years. The traditional approach is to verify each satellite individually. It is difficult to directly compare the difference in their accuracy. In order to evaluate geometric accuracy for multiple satellite images based on the same ground control benchmark, a reliable test field in Xianning (China) was utilized for geometric accuracy validation of HRSIs. Our research team has obtained multiple HRSIs in the Xianning test field, such as SPOT-6, Pleaides, ALOS, ZY-3 and TH-1. In addition, ground control points (GCPs) were acquired with GPS by field surveying, which were used to select the significant feature area on the images. We assess the orientation accuracy of the HRSIs with the single image and stereo models. Within this study, the geometrical performance of multiple HRSIs was analyzed in detail, and the results of orientation are shown and discussed. As a result, it is feasible and necessary to establish such a geometric verification field to evaluate the geometric quality of multiple HRSIs. PMID- 30004441 TI - Lime Pretreatment of Miscanthus: Impact on BMP and Batch Dry Co-Digestion with Cattle Manure. AB - In Europe, the agricultural biogas sector is currently undergoing fast developments, and cattle manure constitutes an important feedstock. Batch dry digester processes with leachate recirculation prove to be particularly interesting for small-scale plants. However, their startup being relatively slow, the process could be facilitated by co-digestion with energy crops. In this study, Miscanthus xgiganteus was chosen for its high biomass yields and low input requirements. The carbohydrate accessibility of this lignocellulosic biomass is limited but may be improved with alkali pretreatment. The efficiency of lime (CaO) pretreatment with low water addition on the biochemical methane potential (BMP) of miscanthus was investigated through two experimental designs (CaO concentrations ranged between 2.5 and 17.5% and pretreatment lasted 1, 3, or 5 days). The pretreated miscanthus was then co-digested with cattle manure in dry leach bed reactors. CaO pretreatments led to a 14-37% improvement of miscanthus BMP, and a 67-227% increase in the first-order kinetics constant; a high contact time was shown to favor methane production. According to these results and to industrial requirements, miscanthus was pretreated with 5 and 10% CaO for 5 days, then co-digested with manure in dry leach bed reactors. Nevertheless, the promising results of the BMP tests were not validated. This could be related to the high water absorption capacity of miscanthus. PMID- 30004442 TI - A Self-Assembled ZnII-NdIII Heterohexanuclear Dimer Based on a Hexadentate N2O4 Type Ligand and Terephthalic Acid: Synthesis, Structure, and Fluorescence Properties. AB - A self-assembled ZnII-NdIII heterohexanuclear coordination compound [Zn4Nd2(L)4(bdc)2].2NO3 based on a hexadentate Salamo-like chelating ligand (H2L = 1,2-bis(3-methoxysalicylideneaminooxy)ethane]) and H2bdc (H2bdc = terephthalic acid) has been synthesized and characterized by elemental analyses, IR and UV/Vis spectra, and X-ray crystallography. Two crystallographically equivalent [Zn2Nd(L)2] moieties lie in the inversion center linked by two (bdc)2- ligands leading to a heterohexanuclear dimer in which the carboxylato group bridges the ZnII and NdIII atoms. The heteropolynuclear 3d-4f coordination compound includes four ZnII atoms, two NdIII atoms, four completely deprotonated (L)2- units, two fully deprotonated (bdc)2- units, and two crystalling nitrate ions. All of the ZnII atoms in the ZnII-NdIII coordination compound possess trigonal bipyramidal geometries and the NdIII atoms possess distorted bicapped square antiprism coordination arrangements. In addition, the fluorescence properties of the ligand and the ZnII-NdIII coordination compound were investigated. PMID- 30004443 TI - Simultaneous Determination of Five Cytochrome P450 Probe Substrates and Their Metabolites and Organic Anion Transporting Polypeptide Probe Substrate in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry. AB - A rapid and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (P450) probe substrates and their phase I metabolites in human plasma was developed. The OATP1B1 (pitavastatin) and five P450 probe substrates, caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) and their metabolites were extracted from human plasma (50 uL) using methanol. Analytes were separated on a C18 column followed by selected reaction monitoring detection using MS/MS. All analytes were separated simultaneously within a 9 min run time. The developed method was fully validated over the expected clinical concentration range for all analytes tested. The intra- and inter-day precisions for all analytes were lower than 11.3% and 8.82%, respectively, and accuracy was 88.5-117.3% and 96.1-109.2%, respectively. The lower limit of quantitation was 0.05 ng/mL for dextromethorphan, dextrorphan, midazolam, and 1'-hydroxymidazolam; 0.5 ng/mL for losartan, EXP-3174, omeprazole, 5'-hydroxyomeprazole, and pitavastatin; and 5 ng/mL for caffeine and paraxanthine. The method was successfully used in a pharmacokinetic study in healthy subjects after oral doses of five P450 and OATP1B1 probes. This analytical method provides a simple, sensitive, and accurate tool for the determination of OATP1B1 and five major P450 activities in vivo drug interaction studies. PMID- 30004444 TI - Molecular Modeling for Structural Insights Concerning the Activation Mechanisms of F1174L and R1275Q Mutations on Anaplastic Lymphoma Kinase. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in various cancers. In its basal state, the structure of ALK is in an autoinhibitory form stabilized by its A-loop, which runs from the N-lobe to the C-lobe of the kinase. Specifically, the A-loop adopts an inhibitory pose with its proximal A loop helix (alphaAL-helix) to anchor the alphaC-helix orientation in an inactive form in the N-lobe; the distal portion of the A-loop is packed against the C-lobe to block the peptide substrate from binding. Upon phosphorylation of the first A loop tyrosine (Y1278), the alphaAL-helix unfolds; the distal A-loop detaches from the C-lobe and reveals the P+1 pocket that accommodates the residues immediately after their phosphorylation, and ALK is activated accordingly. Recently, two neuroblastoma mutants, F1174L and R1275Q, have been determined to cause ALK activation without phosphorylation on Y1278. Notably, F1174 is located on the C terminus of the alphaC-helix and away from the A-loop, whereas R1275 sits on the alphaAL-helix. In this molecular modeling study, we investigated the structural impacts of F1174L and R1275Q that lead to the gain-of-function event. Wild-type ALK and ALK with phosphorylated Y1278 were also modeled for comparison. Our modeling suggests that the replacement of F1174 with a smaller residue, namely leucine, moves the alphaC-helix and alphaAL-helix into closer contact and further distorts the distal portion of the A-loop. In wild-type ALK, R1275 assumes the dual role of maintaining the alphaAL-helix-alphaC-helix interaction in an inactive form and securing alphaAL-helix conformation through the D1276-R1275 interaction. Accordingly, mutating R1275 to a glutamine reorients the alphaC helix to an active form and deforms the entire A-loop. In both F1174L and R1275Q mutants, the A-loop rearranges itself to expose the P+1 pocket, and kinase activity resumes. PMID- 30004446 TI - Retail Stores Policies for Marketing of Lobsters in Sardinia (Italy) as Influenced by Different Practices Related to Animal Welfare and Product Quality. AB - The aim of the present study was to evaluate the marketing policies of lobsters as influenced by different practices related to product quality in seven supermarkets located in Italy. Retailers were divided in two categories: large scale and medium scale. The two groups were compared to screen for differences and to assess differences in score distribution attributed to different practices related to product quality. Our results showed no statistical differences (p > 0.05) between the two categories. Lobsters were often marketed alive on ice and/or stocked for long periods in supermarket aquariums, highlighting the need to improve the specific European regulations on health, welfare, and quality at the market stage. Retail shop managers should be encouraged to develop better practices and policies in terms of marketing of lobsters. This will help in keeping the animals in good health and improve product quality at the marketing stages. PMID- 30004448 TI - Characterization of the Use of Low Frequency Ultrasonic Guided Waves to Detect Fouling Deposition in Pipelines. AB - The accumulation of fouling within a structure is a well-known and costly problem across many industries. The build-up is dependent on the environmental conditions surrounding the fouled structure. Many attempts have been made to detect fouling accumulation in critical engineering structures and to optimize the application of power ultrasonic fouling removal procedures, i.e., flow monitoring, ultrasonic guided waves and thermal imaging. In recent years, the use of ultrasonic guided waves has been identified as a promising technology to detect fouling deposition/growth. This technology also has the capability to assess structural health; an added value to the industry. The use of ultrasonic guided waves for structural health monitoring is established but fouling detection using ultrasonic guided waves is still in its infancy. The present study focuses on the characterization of fouling detection using ultrasonic guided waves. A 6.2-m long 6-inch schedule 40 carbon steel pipe has been used to study the effect of (Calcite) fouling on ultrasonic guided wave propagation within the structure. Parameters considered include frequency selection, number of cycles and dispersion at incremental fouling thickness. According to the studied conditions, a 0.5 dB/m drop in signal amplitude occurs for a fouling deposition of 1 mm. The findings demonstrate the potential to detect fouling build-up in lengthy pipes and to quantify its thickness by the reduction in amplitude found from further numerical investigation. This variable can be exploited to optimize the power ultrasonic fouling removal procedure. PMID- 30004447 TI - SEGF: A Novel Method for Gene Fusion Detection from Single-End Next-Generation Sequencing Data. AB - With the development and application of next-generation sequencing (NGS) and target capture technology, the demand for an effective analysis method to accurately detect gene fusion from high-throughput data is growing. Hence, we developed a novel fusion gene analyzing method called single-end gene fusion (SEGF) by starting with single-end DNA-seq data. This approach takes raw sequencing data as input, and integrates the commonly used alignment approach basic local alignment search tool (BLAST) and short oligonucleotide analysis package (SOAP) with stringent passing filters to achieve successful fusion gene detection. To evaluate SEGF, we compared it with four other fusion gene discovery analysis methods by analyzing sequencing results of 23 standard DNA samples and DNA extracted from 286 lung cancer formalin fixed paraffin embedded (FFPE) samples. The results generated by SEGF indicated that it not only detected the fusion genes from standard samples and clinical samples, but also had the highest accuracy and sensitivity among the five compared methods. In addition, SEGF was capable of detecting complex gene fusion types from single-end NGS sequencing data compared with other methods. By using SEGF to acquire gene fusion information at DNA level, more useful information can be retrieved from the DNA panel or other DNA sequencing methods without generating RNA sequencing information to benefit clinical diagnosis or medication instruction. It was a timely and cost-effective measure with regard to research or diagnosis. Considering all the above, SEGF is a straightforward method without manipulating complicated arguments, providing a useful approach for the precise detection of gene fusion variation. PMID- 30004445 TI - Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction. AB - This review focuses on the biological action of the compounds from the group of substituted 1,3,4-thiadiazines on stress response and myocardial infarction. The aim of this review is to propose the possible mechanisms of action of 1,3,4 thiadiazines and offer prospectives in the development of new derivatives as therapeutic agents. It is known, that compounds that have biological effects similar to those used as antidepressants can down-regulate the secretion of proinflammatory cytokines, up-regulate the release of anti-inflammatory ones and affect cell recruitment, which allows them to be considered immunomodulators as well. The results of pharmacological evaluation, in silico studies, and in vivo experiments of several compounds from the group of substituted 1,3,4-thiadiazines with antidepressant properties are presented. It is proposed that the cardioprotective effects of substituted 1,3,4-thiadiazines might be explained by the peculiarities of their multi-target action: the ability of the compounds to interact with various types of receptors and transporters of dopaminergic, serotonergic and acetylcholinergic systems and to block the kinase signal pathway PI3K-AKT. The described effects of substituted 1,3,4-thiadiazines suggest that it is necessary to search for a new agents for limiting the peripheral inflammatory/ischemic damage through the entral mechanisms of stress reaction and modifying pro-inflammatory cytokine signaling pathways in the brain. PMID- 30004450 TI - Initial Alignment Algorithm Based on the DMCS Method in Single-Axis RSINS with Large Azimuth Misalignment Angles for Submarines. AB - Since the inertial sensor error has been modulated effectively by the Rotation Modulation Technique (RMT), the Rotation Strapdown Inertial Navigation System (RSINS) has been widely used for submarines in order to satisfy the requirement of high-accuracy and long working duration. The performance of the initial alignment is main factor affecting the accuracy of the Strapdown Inertial Navigation System (SINS). The traditional initial alignment algorithm based on the compass method has bad performance when the misalignment angle is large, which will make the submarine SINS fail to launch properly in a complex operating environment. Since the RSINS uses the mathematical platform to calculate the navigation information, it allows multiple algorithms to run simultaneously, and different algorithms do not interact with each other. Thus, to improve the alignment accuracy, an initial alignment algorithm based on the Dual Mathematical Calculation System (DMCS) is proposed; moreover, to solve the problem of large azimuth misalignment angle, an improved DMCS-based alignment algorithm is also presented in this paper. Both simulations and experiments showed that the novel algorithm can effectively improve the initial alignment performance under the large misalignment angle environment, enhancing the environmental suitability of the RSINS. PMID- 30004449 TI - Association between the General Practitioner Workforce Crisis and Premature Mortality in Hungary: Cross-Sectional Evaluation of Health Insurance Data from 2006 to 2014. AB - The workforce crisis of primary care is reflected in the increasing number of general medical practices (GMP) with vacant general practitioner (GP) positions, and the GPs' ageing. Our study aimed to describe the association between this crisis and premature mortality. Age-sex-standardized mortality for 18-64 years old adults was calculated for all Hungarian GMPs annually in the period from 2006 to 2014. The relationship of premature mortality with GPs' age and vacant GP positions was evaluated by standardized linear regression controlled for list size, urbanization, geographical location, clients' education, and type of the GMP. The clients' education was the strongest protective factor (beta = -0175; p < 0.001), followed by urban residence (beta = -0.149; p < 0.001), and bigger list size (beta1601-2000 = -0.054; p < 0.001; beta2001-X = -0.096; p < 0.001). The geographical localization also significantly influenced the risk. Although GMPs with a GP aged older than 65 years (beta = 0; p = 0.995) did not affect the risk, GP vacancy was associated with higher risk (beta = 0.010; p = 0.033), although the corresponding number of attributable cases was 23.54 over 9 years. The vacant GP position is associated with a significant but hardly detectable increased risk of premature mortality without considerable public health importance. Nevertheless, employment of GPs aged more than 65 does not impose premature mortality risk elevation. PMID- 30004451 TI - Glycoside Mimics from Glycosylamines: Recent Progress. AB - Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases and glycosyltransferases, as well as for their use as pharmacological chaperones. As they provide ready access to these important glycoside mimics, we have reviewed the most significant glycosylamine-based methodologies developed to date, with a special emphasis on the literature reported after 2006. The groups of substrates covered include N-alkyl- and N-benzyl-glycosylamines, N-glycosylhydroxylamines, N (alkoxycarbonyl)-, and N-tert-butanesulfinyl-glycosylamines. PMID- 30004452 TI - Comparative Metabolic Profiling of Green and Purple Pakchoi (Brassica Rapa Subsp. Chinensis). AB - Pakchoi (Brassica rapa subsp. chinensis) is cultivated for its nutritional value, particularly with regard to vitamins, minerals and dietary fibers. However, limited metabolic information is available on the phyto-nutritional traits of pakchoi. Our GC-TOF MS analysis showed that green pakchoi has higher contents of carbon metabolism-associated metabolites such as sugars, sugar derivatives and inositol, while purple pakchoi has higher levels of nitrogen metabolism associated metabolites such as amino acids and amino acid derivatives. To compare the content and composition of secondary metabolites in green and purple pakchoi, we analyzed phenylpropanoid-derived compounds and anthocyanins in mature leaves using an HPLC-UV system. This analysis identified 9 phenylpropanoid-derived compounds and 12 anthocyanins in the mature leaves of green and purple pakchoi. The level of rutin was significantly higher in purple pakchoi compared with green pakchoi, consistent with the expression of phenylpropanoid biosynthetic genes in the two pakchoi cultivars. The data obtained from this comprehensive metabolic profiling would be helpful to improve our understanding of the nutritional values of pakchoi cultivars as food sources. PMID- 30004453 TI - Transcriptional Activation of Human GD3 Synthase (hST8Sia I) Gene in Curcumin Induced Autophagy in A549 Human Lung Carcinoma Cells. AB - Curcumin, a natural polyphenolic compound isolated from the plant Curcuma longa, is known to induce autophagy in various cancer cells, including lung cancer. In the present study, we also confirmed by LC3 immunofluorescence and immunoblotting analyses that curcumin triggers autophagy in the human lung adenocarcinoma A549 cell line. In parallel with autophagy induction, the gene expression of human GD3 synthase (hST8Sia I) responsible for ganglioside GD3 synthesis was markedly elevated in response to curcumin in the A549 cells. To investigate the transcriptional activation of hST8Sia I associated with the autophagy formation in curcumin-treated A549 cells, functional characterization of the 5'-flanking region of the hST8Sia I gene was carried out using the luciferase reporter assay system. Deletion analysis demonstrated that the -1146 to -646 region, which includes the putative c-Ets-1, CREB, AP-1, and NF-kappaB binding sites, functions as the curcumin-responsive promoter of hST8Sia I in A549 cells. The site-directed mutagenesis and chromatin immunoprecipitation assay demonstrated that the NF kappaB binding site at -731 to -722 was indispensable for the curcumin-induced hST8Sia I gene expression in A549 cells. Moreover, the transcriptional activation of hST8Sia I by the curcumin A549 cells was strongly inhibited by compound C, an inhibitor of AMP-activated protein kinase (AMPK). These results suggest that curcumin controls hST8Sia I gene expression via AMPK signal pathway in A549 cells. PMID- 30004454 TI - The ABC Transporter Components HgdB and HgdC are Important for Glycolipid Layer Composition and Function of Heterocysts in Anabaena sp. PCC 7120. AB - Anabaena sp. PCC 7120 is a filamentous cyanobacterium able to fix atmospheric nitrogen in semi-regularly spaced heterocysts. For correct heterocyst function, a special cell envelope consisting of a glycolipid layer and a polysaccharide layer is essential. We investigated the role of the genes hgdB and hgdC, encoding domains of a putative ABC transporter, in heterocyst maturation. We investigated the subcellular localization of the fusion protein HgdC-GFP and followed the differential expression of the hgdB and hgdC genes during heterocyst maturation. Using a single recombination approach, we created a mutant in hgdB gene and studied its phenotype by microscopy and analytical chromatography. Although heterocysts are formed in the mutant, the structure of the glycolipid layer is aberrant and also contains an atypical ratio of the two major glycolipids. As shown by a pull-down assay, HgdB interacts with the outer membrane protein TolC, which indicates a function as a type 1 secretion system. We show that the hgdB hgdC genes are essential for the creation of micro-oxic conditions by influencing the correct composition of the glycolipid layer for heterocyst function. Our observations confirm the significance of the hgdB-hgdC gene cluster and shed light on a novel mode of regulation of heterocyst envelope formation. PMID- 30004455 TI - Characteristics of Particulate Matter and Volatile Organic Compound Emissions from the Combustion of Waste Vinyl. AB - Vinyl samples were burned in a controlled environment to determine the characteristics of particulate matter (PM) and volatile organic compound (VOC) emissions during the combustion process. Open burning of plastic or vinyl products poses several environmental and health risks in developed and developing countries, due to the release of high concentrations of harmful pollutants. The production of fine and ultrafine particles was significant. At a heat flux of 25 kW/m2, the production of PM of 0.35 MUm in size was highest at 63.0 MUg/m3. In comparison, at fluxes of 35 and 50 kW/m2, the production of PM of 0.45 MUm in size was highest with values of 67.8 and 87.7 MUg/m3, respectively. Benzene, acetone, and other toxic compounds were also identified in the analyses. PMID- 30004456 TI - Garcinol Enhances TRAIL-Induced Apoptotic Cell Death through Up-Regulation of DR5 and Down-Regulation of c-FLIP Expression. AB - Garcinol is a polyisoprenylated benzophenone derived from the Garcinia indica fruit that possess potential therapeutic effects such as inhibition of inflammation and tumor expansion. Here, we investigated whether garcinol induces TRAIL sensitization in renal carcinoma cells. Single treatment with garcinol or TRAIL did not effect on apoptosis. However, combined treatment with garcinol plus TRAIL significantly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung carcinoma (A549), and hepatoma (SK-Hep1) cells. In contrast, garcinol plus TRAIL did not alter cell viability in normal cells. Garcinol plus TRAIL induced up-regulation of DR5 and down-regulation of c-FLIP expression at post translational levels. Furthermore, knock-down of DR5 by siRNA and ectopic expression of c-FLIP blocked apoptotic cell death induced by garcinol plus TRAIL. Overall, our study provides evidence that garcinol can be exploited as a potential TRAIL sensitizer. PMID- 30004457 TI - Low-Cost Electronic Tagging System for Bee Monitoring. AB - This paper introduces both a hardware and a software system designed to allow low cost electronic monitoring of social insects using RFID tags. Data formats for individual insect identification and their associated experiment are proposed to facilitate data sharing from experiments conducted with this system. The antennas' configuration and their duty cycle ensure a high degree of detection rates. Other advantages and limitations of this system are discussed in detail in the paper. PMID- 30004459 TI - Vibration Analysis of Vacancy Defected Graphene Sheets by Monte Carlo Based Finite Element Method. AB - The stochastic distributed placement of vacancy defects has evident effects on graphene mechanical property, which is a crucial and challenged issue in the field of nanomaterial. Different from the molecular dynamic theory and continuum mechanics theory, the Monte Carlo based finite element method (MC-FEM) was proposed and performed to simulate vibration behavior of vacancy defected graphene. Based on the Monte Carlo simulation, the difficulties in random distributed location of vacancy defects were well overcome. The beam element was chosen to represent the exact atomic lattice of the graphene. The results of MC FEM have a satisfied agreement with that in the reported references. The natural frequencies in the certain vibration mode were captured to observe the mechanical property of vacancy defected graphene sheets. The discussion about the parameters corresponding with geometry and material property was accomplished by probability theory and mathematical statistics. PMID- 30004460 TI - Application Options of the Sustainable Child Development Index (SCDI)-Assessing the Status of Sustainable Development and Establishing Social Impact Pathways. AB - The needs of children and their vulnerability to diseases, violence and poverty are different from those of adults. The Sustainable Child Development Index (SCDI) was thus developed in previous work to evaluate the status of sustainable development for countries with a focus on children and triple-bottom-line thinking. This study proposes application options to put the SCDI into practice. The SCDI can be performed similarly to existing development indices, for comparing and tracing the performance of sustainable development on different geographic levels and between population groups. In addition, the SCDI can be integrated into existing social sustainability assessment approaches (e.g., Social Life Cycle Assessment and Social Organizational Life Cycle Assessment) and databases (e.g., The Social Hotspots Database) to take children into account and enhance impact assessment of social sustainability assessment approaches. As an exemplification, this study demonstrates the application of the SCDI framework to support the development of social impact pathways. Due to the importance of tertiary education in reducing poverty, a preliminary social impact pathway addressing completion of tertiary education was established. By putting the SCDI into practice, the SCDI can support decision making in child as well as sustainable development policies. PMID- 30004463 TI - Managing Pervasive Sensing Campaigns via an Experimentation-as-a-Service Platform for Smart Cities. AB - The adoption of technologies like the IoT in urban environments, together with the intensive use of smartphones, is driving transformation towards smart cities. Under this perspective, Experimentation-as-a-Service within OrganiCity aims to create an experimental facility with technologies, services, and applications that simplify innovation within urban ecosystems. We discuss here tools that facilitate experimentation, implementing ways to organize, execute, and administer experimentation campaigns in a smart city context. We discuss the benefits of our framework, presenting some preliminary results. This is the first time such tools are paired with large-scale smart city infrastructures, enabling both city-scale experimentation and cross-site experimentation. PMID- 30004458 TI - Effect of the Strawberry Genotype, Cultivation and Processing on the Fra a 1 Allergen Content. AB - Birch pollen allergic patients show cross-reactivity to vegetables and fruits, including strawberries (Fragaria * ananassa). The objective of this study was to quantify the level of the Fra a 1 protein, a Bet v 1-homologous protein in strawberry fruits by a newly developed ELISA, and determine the effect of genotype, cultivation and food processing on the allergen amount. An indirect competitive ELISA using a specific polyclonal anti-Fra a 1.02 antibody was established and revealed high variability in Fra a 1 levels within 20 different genotypes ranging from 0.67 to 3.97 ug/g fresh weight. Mature fruits of red-, white- and yellow-fruited strawberry cultivars showed similar Fra a 1 concentrations. Compared to fresh strawberries, oven and solar-dried fruits contained slightly lower levels due to thermal treatment during processing. SDS PAGE and Western blot analysis demonstrated degradation of recombinant Fra a 1.02 after prolonged (>10 min) thermal treatment at 99 degrees C. In conclusion, the genotype strongly determined the Fra a 1 quantity in strawberries and the color of the mature fruits does not relate to the amount of the PR10-protein. Cultivation conditions (organic and conventional farming) do not affect the Fra a 1 level, and seasonal effects were minor. PMID- 30004465 TI - Distribution of Chemical Species in the Water-Soil-Plant (Carya illinoiensis) System near a Mineralization Area in Chihuahua, Mexico-Health Risk Implications. AB - The aim of this study was to quantify major and trace elements in the water, soil, and plants (Carya illionensis) in an agricultural area; and to determine the health risks associated with the walnuts ingestion by calculating the risk quotient. Samples of water, soil, tree leaves, and walnuts were collected; in total, 135 samples were analyzed. Physicochemical parameters were obtained in irrigation water and soil samples. Elemental measurements were performed in an ICP, -OES and -MS. In addition, the distribution coefficient (soil-water), transfer factor (soil-plant), and hazard quotient were evaluated. In the irrigation water, As, Cr, and Pb, showed concentrations above the maximum allowable limits. Likewise, high concentrations of As, Cr, Pb, and Sb were found in tree leave samples, indicating a possible tendency of hyperaccumulation of those elements. Furthermore, Cr concentrations in walnuts were high by far than the reference value (FAO/WHO). A possible competition between chemical congeners were detected from transfer factors. Although, Sb concentrations in walnuts were also high, and no legislation for it in fruits exists. The hazard risk quotient for Sb did indicate a potential health risk. Finally, it is important to consider that the health risk increases when exposure through consumption takes place over a prolonged period of time, even in low concentrations. PMID- 30004462 TI - Local Food Environments, Suburban Development, and BMI: A Mixed Methods Study. AB - More than half the world's population now live in urban settlements. Worldwide, cities are expanding at their fringe to accommodate population growth. Low density residential development, urban sprawl, and car dependency are common, contributing to physical inactivity and obesity. However, urban design and planning can modify urban form and enhance health by improving access to healthy food, public transport, and services. This study used a sequential mixed methods approach to investigate associations between food outlet access and body mass index (BMI) across urban-growth and established areas of Melbourne, Australia, and identify factors that influence local food environments. Population survey data for 3141 adults were analyzed to examine associations, and 27 interviews with government, non-government, and private sector stakeholders were conducted to contextualize results. Fast food density was positively associated with BMI in established areas and negatively associated in urban-growth areas. Interrelated challenges of car dependency, poor public transport, and low-density development hampered healthy food access. This study showed how patterns of suburban development influence local food environments and health outcomes in an urbanized city context and provides insights for other rapidly growing cities. More nuanced understandings of the differential effect of food environments within cities have potential to guide intra-city planning for improving health and reducing inequities. PMID- 30004461 TI - Heart Rate and Heart Rate Variability during Sleep in Family Dogs (Canis familiaris). Moderate Effect of Pre-Sleep Emotions. AB - The domestic dog (Canis familiaris) has been shown to both excel in recognising human emotions and produce emotion-related vocalisations and postures that humans can easily recognise. However, little is known about the effect of emotional experiences on subsequent sleep physiology, a set of phenomena heavily interrelated with emotions in the case of humans. The present paper examines heart rate (HR) and heart rate variability (HRV) during dogs' sleep, measures that are influenced by both positive and negative emotions in awake dogs. In Study I, descriptive HR and HRV data is provided on N = 12 dogs about the different sleep stages (wake, drowsiness, non-rapid eye movement (non-REM), REM; scoring based on electroencephalogram (EEG) data). We conclude that wakefulness is characterised by higher HR and lower HRV compared to all sleep stages. Furthermore, drowsiness is characterised by higher HR and lower HRV than non-REM and REM, but only if the electrocardiogram (ECG) samples are taken from the first occurrence of a given sleep stage, not when the longest periods of each sleep stage are analysed. Non-REM and REM sleep were not found to be different from each other in either HR or HRV parameters. In Study II, sleep HR and HRV measures are compared in N = 16 dogs after a positive versus negative social interaction (within-subject design). The positive social interaction consisted of petting and ball play, while the negative social interaction was a mixture of separation, threatening approach and still face test. Results are consistent with the two dimensional emotion hypothesis in that following the intense positive interaction more elevated HR and decreased HRV is found compared to the mildly negative (lower intensity) interaction. However, although this trend can be observed in all sleep stages except for REM, the results only reach significance in the wake stage. In sum, the present findings suggest that HR and HRV are possible to measure during dogs' sleep, and can potentially be used to study the effect of emotions not only during but also after such interactions. PMID- 30004466 TI - A 20-Questions-Based Binary Spelling Interface for Communication Systems. AB - Brain computer interfaces (BCIs) enables people with motor impairments to communicate using their brain signals by selecting letters and words from a screen. However, these spellers do not work for people in a complete locked-in state (CLIS). For these patients, a near infrared spectroscopy-based BCI has been developed, allowing them to reply to "yes"/"no" questions with a classification accuracy of 70%. Because of the non-optimal accuracy, a usual character-based speller for selecting letters or words cannot be used. In this paper, a novel spelling interface based on the popular 20-questions-game has been presented, which will allow patients to communicate using only "yes"/"no" answers, even in the presence of poor classification accuracy. The communication system is based on an artificial neural network (ANN) that estimates a statement thought by the patient asking less than 20 questions. The ANN has been tested in a web-based version with healthy participants and in offline simulations. Both results indicate that the proposed system can estimate a patient's imagined sentence with an accuracy that varies from 40%, in the case of a "yes"/"no" classification accuracy of 70%, and up to 100% in the best case. These results show that the proposed spelling interface could allow patients in CLIS to express their own thoughts, instead of only answer to "yes"/"no" questions. PMID- 30004468 TI - Spatio-Temporal Optimization of Perishable Goods' Shelf Life by a Pro-Active WSN Based Architecture. AB - The waste in the perishable goods supply-chain has prompted many global organizations (e.g., FAO and WHO), to develop the Hazard Analysis and Critical Control Points (HACCP) protocol that ensures a high degree of food quality, minimizing the losses in all the stages of the farm-to-fork chain. It has been proven that good warehouse management practices improve the average life of perishable goods. The advances in wireless sensors network (WSN) technology offers the possibility of a "smart" storage organization. In this paper, a low cost reprogrammable WSN-based architecture for functional warehouse management is proposed. The management is based on the continuous monitoring of environmental parameters (i.e., temperature, light exposure and relative humidity), and on their combination to extract a spatial real-time prediction of the product shelf life. For each product, the quality decay is computed by using a 1st order kinetic Arrhenius model to the whole storage site area. It strives to identify, in a way compatible with the other products' shelf lives, the position within the warehouse that maximizes the food expiration date. The shelf life computing and the "first-expired first-out" logistic problem are entrusted to a Raspberry Pi based central unit, which manages a set of automated pallet transporters for the displacement of products, according to the computed shelf lives. The management unit supports several commercial light/temperature/humidity sensor solutions, implementing ZigBee, Bluetooth and HTTP-request interfaces. A proof of concept of the presented pro-active WSN-based architecture is also shown. Comparing the proposed monitoring system for the storage of e.g., agricultural products, with a typical one, the experimental results show an improvement of the expected expiration date of about 1.2 +/- 0.5 days, for each pallet, when placed in a non refrigerated environment. In order to stress the versatility of the WSN solution, a section is dedicated to the implemented system user interfaces that highlight detecting critical situations and allow timely automatic or human interventions, minimizing the latter. PMID- 30004467 TI - Predictors of Hypertension in Mauritians with Normotension and Prehypertension at Baseline: A Cohort Study. AB - Information on the predictors of future hypertension in Mauritians with prehypertension is scant. The aim of this study was to analyze the 5-year and 11 year risk of hypertension and its predictors in people with normotension and prehypertension at baseline in Mauritius in 1987. This was a retrospective cohort study of 883 men and 1194 women of Mauritian Indian and Mauritian Creole ethnicity, aged 25-74 years old, free of hypertension at baseline in 1987 with follow-up examinations in 1992 and 1998 using the same methodology. The main outcome was 5- and 11-year risk of hypertension. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated. The 5-year risk of hypertension was 5.4-times higher in people with prehypertension compared with normotensive individuals at baseline. The corresponding odds for prehypertensive people at baseline regarding 11-year hypertension risk was 3.39 (95% CI 2.67 4.29) in the adjusted logistic regression models. Being of Creole ethnicity (OR 1.42; 95% CI 1.09-1.86) increased the 11-year odds of hypertension compared with the Indian population. It is of importance to screen for people with prehypertension and implement strategies to reduce their systolic blood pressure levels to the recommended levels of 120/80 mmHg. Special attention needs to be given to Mauritians of Creole ethnicity. PMID- 30004464 TI - Host-Pathogen Interactions Mediated by MDR Transporters in Fungi: As Pleiotropic as it Gets! AB - Fungal infections caused by Candida, Aspergillus, and Cryptococcus species are an increasing problem worldwide, associated with very high mortality rates. The successful prevalence of these human pathogens is due to their ability to thrive in stressful host niche colonization sites, to tolerate host immune system induced stress, and to resist antifungal drugs. This review focuses on the key role played by multidrug resistance (MDR) transporters, belonging to the ATP binding cassette (ABC), and the major facilitator superfamilies (MFS), in mediating fungal resistance to pathogenesis-related stresses. These clearly include the extrusion of antifungal drugs, with C. albicans CDR1 and MDR1 genes, and corresponding homologs in other fungal pathogens, playing a key role in this phenomenon. More recently, however, clues on the transcriptional regulation and physiological roles of MDR transporters, including the transport of lipids, ions, and small metabolites, have emerged, linking these transporters to important pathogenesis features, such as resistance to host niche environments, biofilm formation, immune system evasion, and virulence. The wider view of the activity of MDR transporters provided in this review highlights their relevance beyond drug resistance and the need to develop therapeutic strategies that successfully face the challenges posed by the pleiotropic nature of these transporters. PMID- 30004472 TI - All-fiber frequency-resolved optical gating pulse characterization from chalcogenide glass. AB - We report, to the best of our knowledge, the first all-fiber frequency-resolved optical gating device from nonlinear processing in chalcogenide glass. The strong four-wave mixing efficiency of an 11 cm long chalcogenide microwire enables a high sensitivity characterization of pulses in the 2 MUm wavelength band. The amplitude and phase of chirped and unchirped picosecond pulses are accurately characterized with a high sensitivity of 0.16 mW2. PMID- 30004469 TI - Gastrointestinal Parasites in Shelter Dogs: Occurrence, Pathology, Treatment and Risk to Shelter Workers. AB - Dogs entering shelters can carry gastrointestinal parasites that may pose serious risks to other animals, shelter staff and visitors. Shelters provide an environment that could facilitate the spread of parasitic infections between animals. Nematodes and protozoa that transmit through ingestion or skin penetration are major enteric parasites of concern in shelter settings. Ancylostoma spp., Uncinaria stenocephala, Toxocara canis, Toxascaris leonina, Trichuris vulpis and Dipylidium caninum are the major helminths while Giardia, Cryptosporidium, Isospora spp. and Sarcocystis spp. are the most prevalent protozoan parasites in shelter dogs. The prevalence of gastrointestinal parasites in shelter dogs is typically higher than in owned dogs. A range of cost-effective drugs is available for prevention and control of helminths in shelters, notably fenbendazole, pyrantel, oxantel, and praziquantel. Parasiticide options for protozoan parasites are often cost-prohibitive or limited by a lack of veterinary registration for use in dogs. Environmental control measures reliant upon hygiene and facility management are therefore a mainstay for control and prevention of protozoan parasites in shelters. This philosophy should also extend to helminth control, as integrated parasite control strategies can allow anthelmintics to be used more sparingly and judiciously. The purpose of this article is to comprehensively review the current knowledge on the prevalence of gastrointestinal parasites most commonly found in dogs in shelters, canvass recommended treatment programs in shelter dogs, and to explore the likelihood that parasiticide resistance might emerge in a shelter environment. PMID- 30004471 TI - Authors response on Klebsiella pneumoniae, producer of carbapenemases. PMID- 30004470 TI - MicroRNA-106a-5p Inhibited C2C12 Myogenesis via Targeting PIK3R1 and Modulating the PI3K/AKT Signaling. AB - The microRNA (miR)-17 family is widely expressed in mammalian tissues and play important roles in various physiological and pathological processes. Here, the functions of miR-106a-5p, a member of miR-17 family, were explored during myogenic differentiation in C2C12 cell line. First, miR-106a-5p was found to be relatively lower expressed in two-month skeletal muscle tissues and gradually decreased upon myogenic stimuli. Forced expression of miR-106a-5p significantly reduced the differentiation index, fusion index as well as the expression of myogenic markers (MyoD, MyoG, MyHC, Myomixer, Myomarker). Meanwhile, the levels of phosphorylated AKT were reduced by overexpression of miR-106a-5p, and administration of insulin-like growth factor 1 (IGF1), a booster of myogenic differentiation, could recover all the inhibitory effects above of miR-106a-5p. Furthermore, miR-106a-5p was elevated in aged muscles and dexamethasone (DEX) treated myotubes, and up-regulation of miR-106a-5p significantly reduced the diameters of myotubes accompanied with increased levels of muscular atrophy genes and decreased PI3K/AKT activities. Finally, miR-106a-5p was demonstrated to directly bind to the 3'-UTR of PIK3R1, thus, repress the PI3K/AKT signaling. PMID- 30004473 TI - Plasmonic slow light device using superfocusing on a bow-tied metallic waveguide. AB - We demonstrate a plasmonic slow light device using super focusing on a bow-tied metallic waveguide that can be fabricated using complementary metal-oxide semiconductor compatible processes. By solving the characteristic equation of a bow-tied metallic waveguide, we confirmed that the group indices increased as the waveguide width decreased and that they could attain over 11.0 in the telecommunication wavelength band. Additionally, we experimentally confirmed using an autocorrelation measurement system in which the pulse width of the bow tied metallic waveguide was 8.0 fs longer than that of a ridged metallic waveguide. Therefore, the proposed device will contribute to the realization of all-plasmonic memories and amplifiers. PMID- 30004474 TI - Dynamic computer-generated nonlinear optical holograms in a non-collinear second harmonic generation process. AB - The nonlinear holography technique is a powerful tool for all-optical switching and manipulation of an arbitrary harmonic wave. The common method of realizing such nonlinear holography is by configuring the structure of nonlinear photonic crystals. However, it is a challenge to dynamically tune the harmonic wave pattern. To overcome the long-term existing non-dynamic property of such nonlinear holographs, we realize dynamic computer-generated nonlinear optical holograms in the non-collinear second-harmonic (SH) generation process in which only one infrared beam is modulated. Arbitrary patterns in both fundamental frequency and second-harmonic wavebands can be generated at the same time. This Letter offers a flexible and dynamic method for arbitrary nonlinear wavefront shaping technology. PMID- 30004475 TI - "Tailoring axial intensity of laser beams with a heart-shaped hole," by Wang et al.: comment. AB - Some comments about the recently published Optics Letters paper "Tailoring axial intensity of laser beams with a heart-shaped hole," by Wang et al., Opt. Lett.42, 4921 (2017)OPLEDP0146-959210.1364/OL.42.004921, are provided. PMID- 30004476 TI - High-extinction-ratio directional-coupler-type polarization beam splitter with a bridged silicon wire waveguide. AB - We demonstrate an integrated polarization beam splitter (PBS) of a simple and compact device geometry with high polarization extinction ratios (PERs). A silicon PBS based on a three-waveguide directional coupler is numerically simulated for optimum device parameters, and fabricated experimentally. The measured PER values of the fabricated PBSs are 40.74 dB and 39.01 dB for transverse electric and transverse magnetic modes, respectively, and their corresponding insertion losses are 0.35 dB on average for a coupler length of about 29.4 MUm. PMID- 30004477 TI - Common-path surface plasmon interferometer with radial polarization. AB - We present a common-path surface plasmon interferometer with radial polarization. We show how the V(z) effect, the output of the microscope versus defocus z, can be derived utilizing a radially polarized illumination and a virtual annulus. The measurement of the V(z) effect gives a strong signature of the surface plasmon propagation, which is functionally related to the material properties. We discuss the advantages of using radial polarization compared to linear polarization. PMID- 30004478 TI - Quantum features in the orthogonality of optical modes for structured and plane wave light. AB - A fundamental photon creation-annihilation commutation relation underpins the familiar quantum formulation of optics. However, an internal inconsistency becomes apparent in the pursuit of structured light applications. This requires the relationship between operator commutation and mode orthogonality to be recast in a form ensuring full consistency with the precepts of quantum theory. A suitable reformulation, shown to register correctly an intrinsic quantum uncertainty in the associated interactions, has special relevance to optical vortex physics-particularly with regard to information content-through its connection to the degrees of freedom in the associated radiation modes. PMID- 30004479 TI - Launching phase-controlled surface plasmons on Babinet metasurfaces. AB - Surface plasmons are electromagnetic modes bounded at the metal-dielectric interfaces, which have numerous applications due to the strong field enhancement effect. Therefore, controlling surface plasmons is in high demand for modern photonics and plasmonics. In this Letter, we propose a kind of metasurface for launching surface plasmons with a controlled phase based on the Babinet principle. The phase control is achieved by arranging C-shaped apertures on a metal surface that exhibits highly efficient electric dipole resonance. By properly designing the spatial separation and orientation of the aperture resonators, an arbitrary phase profile is achieved that allows anomalous (directional and focusing/diverging) surface plasmon launching and manipulation of the wavefront. PMID- 30004480 TI - Adjacent-resonance etalon cancellation in ring-down spectroscopy. AB - Adjacent-resonance etalon cancellation provides a means of significantly reducing both systematic and random errors introduced in cavity ring-down spectroscopy by unwanted etalons. By stretching the ring-down cavity symmetrically about its center point and collecting two data sets at cavity lengths separated by lambda/2, two fringing components offset in phase by 180 deg are obtained. When these two data sets are averaged, oscillations in effective mirror reflectivities due to fringing are dramatically reduced. The technique is demonstrated in a 12 cm monolithic ring-down spectrometer. Long-term time constant measurements show a decrease in noise-equivalent absorption and an increase in maximum effective averaging time due to a reduction in noise coupled in by etalons; trace water spectra demonstrate how removing the systematic fringing components eases absorption peak identification. PMID- 30004481 TI - Optical sensing and detection in turbid water using multidimensional integral imaging. AB - We present an approach for optical sensing and detection in turbid water using multidimensional spatial-temporal domain integral imaging and dedicated signal processing algorithms. An optical signal is encoded using pseudorandom sequences, and an image sensor array is used to capture elemental image video sequences of light propagating through turbid water. Using the captured information, multidimensional image reconstruction followed by multi-dimensional correlation to detect the source signal is performed. We experimentally demonstrate scenarios in which turbidity causes conventional signal detection to fail, while our proposed multidimensional approach enables successful detection under the same turbidity conditions. Statistical analysis is provided to support the experimental results. To the best of our knowledge, this is the first report of using multidimensional integral imaging signal detection in turbid water conditions. PMID- 30004482 TI - Sparse representation-based demosaicing method for microgrid polarimeter imagery. AB - To address the key image interpolation issue in microgrid polarimeters, we propose a machine learning model based on sparse representation. The sparsity and non-local self-similarity priors are used as regularization terms to enhance the stability of an interpolation model. Moreover, to make the best of the correlation among different polarization orientations, patches of different polarization channels are joined to learn adaptive sub-dictionary. Synthetic and real images are used to evaluate the interpolated performance. The experimental results demonstrate that our proposed method achieves state-of-the-art results in terms of quantitative measures and visual quality. PMID- 30004483 TI - Two-dimensional combination of eight ultrashort pulsed beams using a diffractive optic pair. AB - We demonstrate, to the best of our knowledge, the first two-dimensional diffractive beam combination for ultrashort pulses-a highly scalable technique capable of using a diffractive optic pair to combine large arrays of ultrashort pulsed beams. A square array of eight 120 fs pulsed beams from eight fiber outputs is coherently combined into one beam using the diffractive combiner. The experimental results show that the combined pulse preserves the input pulse width and shape, and the combining efficiency is measured to be close to the limit of the manufactured diffractive optic. An analysis shows that the combining loss due to uncompensated temporal and spatial dispersions is negligible. PMID- 30004484 TI - Optical visualization of a fluid flow via the temperature controlling method. AB - In this Letter, a visualization method of a fluid flow through temperature control is proposed. The proposed method enables us to visualize an invisible fluid flow by controlling the temperature so that its visibility can be easily adjusted. Such ability of adjusting appearance is effective for visualizing the phenomena consisting of multiple physical processes. In order to verify the validity of the proposed method, the measurement experiment of visualization of both flow and sound in air using parallel phase-shifting interferometry, which is a similar condition to the previous research [Opt. Lett.43, 991 (2018)OPLEDP0146 959210.1364/OL.43.000991], was conducted. PMID- 30004485 TI - Achromatic linear retarder with tunable retardance. AB - We present a universal design and proof-of-concept of a tunable linear retarder of uniform wavelength response in a broad spectral range. It consists of two half wave retarders (HWR) between two quarter-wave retarders (QWRs), where the uniform retardance can be tuned continuously by simply rotating one of the HWRs. A proof of-concept of this design is built by using commercially available Fresnel rhomb retarders that provide retardation with almost wavelength uniformity in the visible and near infrared from 450 to 1550 nm. The design is universal, since other achromatic QWRs and HWRs could also be employed. The system is experimentally demonstrated to control the state of polarization of a supercontinuum laser. PMID- 30004486 TI - Controllable structural tailoring for enhanced luminescence in highly Er3+-doped germanosilicate glasses. AB - Higher concentrations of rare earth (RE) ions in glass materials would be favorable for the output of single-frequency fiber lasers. In this Letter, we adjusted the topological structure of glass networks through controlling the numbers of non-bridging oxygens (NBOs) and bridging oxygens (BOs) by tuning the composition of the glasses, hence increasing the RE doping concentration of germanosilicate glasses. The increased flexibility of the glass networks favors the distribution of clusters of RE ions to decrease fluorescence quenching, which was validated by both our experimental and theoretical results. To the best of our knowledge, for the first time, a highly Er3+-doped (up to 7 mol. %) heavy metal oxide glass was fabricated without quenching by tuning the components of the glass. In addition, we have demonstrated an approach to enhance the fluorescence properties of heavily RE-doped glass materials by tailoring network topology. PMID- 30004487 TI - Ultrafast smoothing scheme for improving illumination uniformities of laser quads. AB - The beam smoothing technology, smoothing by spectral dispersion, plays an important role in improving the illumination uniformities of the lasers in inertial confinement fusion facilities. However, due to the limitations of the modulation frequency of the electro-optic modulator, the uniformity of the lasers approaches an asymptotic value after tens of picoseconds that are much longer than the response time of laser plasma instabilities. To the best of our knowledge, this is the first time that an ultrafast smoothing approach for improving the uniformity of a laser quad in both radial and azimuthal directions in the picosecond scale was proposed. Among the four individual beams in a quad, two of them were smoothed by independent ultrafast focal zooming, and the rest were transformed into Laguerre-Gaussian (LG) beams that carry same topological charges with opposite signs. The focal spots of these two LG beams were coherent superposed, and their intensity distributions rotated rapidly in a period of several picoseconds. As a result of the focal zooming and rotation, an ultrafast and significant improvement of the uniformity of a laser quad was achieved. PMID- 30004488 TI - Fast photorefractive response in polymeric composites enabled by the control of chromophore free volume. AB - The molecular orientation of a chromophore importantly affects the electro-optic characteristics of polymeric photorefractive composites. We designed methyl, ethyl, and isopropyl derivatives of 4-piperidinobenzylidene-malononitrile (PDCST) with the aim of enhancing molecular orientation properties, and investigated the effects of alkyl substitution on the electro-optic properties and response times of polymeric photorefractive composites. The three alkyl-substituted PDCSTs showed enhanced electro-optic responses and photorefractive grating buildup rates. PMID- 30004489 TI - Improvement of the strain measurable range of an OFDR based on local similar characteristics of a Rayleigh scattering spectrum. AB - The decrease of overlap between the reference spectrum and measurement spectrum (ReS and MeS) is found to limit the strain measurable range of the optical frequency domain reflectometer (OFDR) and signal-to-noise ratio (SNR) of cross correlation results. In this Letter, the local similar characteristics of Rayleigh scattering (RS) fingerprint spectrum are discovered and, thus, an improved OFDR based on local similarity of RS spectrum is proposed to ensure the feasibility of the OFDR during measuring a large distribution strain with a high spatial resolution. The normalized length and location of the local spectrum are optimized to obtain a high spectral similarity between the ReS and MeS and achieve a robust suppression on cross-correlation fake peaks and multi-peaks. By this method, four times enhancement of similarity is experimentally achieved, compared to conventional OFDR methods when the measured distribution strain varies from 0 to 3000 MUepsilon with a 3 mm long fiber gauge. The experimental results verify that it effectively avoids influences of fake peaks and multi peaks. The advantages of this method are a large strain measurable range, robust performance, a high SNR, and applicability with current OFDR systems. PMID- 30004490 TI - Inverse prism based on temporal discontinuity and spatial dispersion. AB - We introduce the concept of the inverse prism as the dual of the conventional prism and deduce from this duality an implementation of it based on temporal discontinuity and spatial dispersion provided by anisotropy. Moreover, we show that this inverse prism exhibits the following three unique properties: chromatic refraction birefringence, ordinary monochromatic and extraordinary polychromatic temporal refraction, and linear-to-Lissajous polarization transformation. PMID- 30004491 TI - Simple and efficient nonlinear polarization evolution mode-locked fiber laser by three-dimensionally manipulating a polarization beam splitter. AB - A simple and efficient femtosecond nonlinear polarization evolution (NPE) mode locked laser is presented. Different from conventional NPE fiber lasers, the polarization beam splitter (PBS) is three-dimensionally manipulated to achieve polarization control and state selection in our NPE laser. The polarizer, half wave plate, and quarter-wave plate from conventional NPE fiber lasers are replaced by this PBS. Thus, the configuration and the system gain of our proposed laser are simply and efficiently improved. As a result, transfer efficiency of 24.17% is experimentally demonstrated. In addition, measured self-started pulses with average power of 49 mW and center wavelength of 1584 nm are generated with single-pulse energy of 1.51 nJ. PMID- 30004492 TI - High-efficiency and thermally stable far-red-emitting NaLaMgWO6:Mn4+ phosphorsfor indoor plant growth light-emitting diodes. AB - In this Letter, we report a novel NaLaMgWO6:Mn4+ double-perovskite phosphor. Under the excitation at 342 nm, this phosphor showed a high-efficiency far-red emission at approximately 700 nm with internal quantum efficiency of up to 60%. Moreover, it exhibited a high thermal stability; the emission intensity at 423 k was approximately 57% of that at room temperature. Finally, a prototype light emitting diode (LED) device was fabricated using the combination of a NaLaMgWO6:Mn4+ far-red-emitting phosphor and 365-nm LED chip. PMID- 30004494 TI - Efficient entanglement generation between exciton-polaritons using shortcuts to adiabaticity. AB - We use shortcuts to adiabaticity, a method introduced to speed up adiabatic quantum dynamics, for the efficient generation of entanglement between exciton polaritons in coupled semiconductor microcavities. A substantial improvement is achieved, compared to a recently proposed method that essentially enhances the nonlinearity of the system. Our method takes advantage of a time-dependent nonlinearity, which can become larger than the Josephson coupling between the cavities, while the conventional method is restricted to a constant nonlinearity lower than the coupling. The suggested procedure is expected to also find application in other research areas in optics, where nonlinear interacting bosons are encountered. PMID- 30004493 TI - Line-tunable Er:GGAG laser. AB - In this Letter, for the first time, to the best of our knowledge, a pulse and CW laser based on an Er-doped Gd3Ga2.7Al2.3O12 (Er:GGAG) active medium emitting laser radiation at 2.8 MUm are presented. With the longitudinal diode pumping, the maximal output energy of 4.9 mJ and slope efficiency of 13.5% in the pulse regime were reached. Using the birefringent MgF2 plate, the line tunability of Er:GGAG at several spectral bands of 2800-2822 nm, 2829-2891 nm, and 2917-2942 nm were obtained. PMID- 30004495 TI - Fluorescent nanodiamonds for luminescent thermometry in the biological transparency window. AB - Fluorescent nanodiamonds (FNDs) have attracted recent interest for biological applications owing to their biocompatibility and photostability (absence of photoblinking and bleaching). For optical thermometry, nitrogen-vacancy (NV) color centers and silicon-vacancy color centers in diamonds have demonstrated potential, where the NV has the highest sensitivity. However, NV is often excited with green light, which can cause heating and photodamage to tissues, as well as autofluorescence that decreases sensitivity. To overcome these limitations, we report temperature sensing using NV centers excited by deep red light (660 nm), plus another color center that can be excited with NIR light; the nickel (Ni) complex. The NV center measures temperature using diamond lattice expansion while the Ni complex measures temperature using phonon sideband strength. PMID- 30004497 TI - Polarization-insensitive hot-electron infrared photodetection by double Schottky junction and multilayer grating. AB - Infrared photodetection based on hot electrons is drawing increasing interest due to the capabilities of below-bandgap detection, high tunability of working wavelength, compact size, and room-temperature operation. However, conventional hot-electron photodetectors are mostly based on surface plasmons with a strong polarization preference. In this Letter, we propose a multilayer grating double junction hot-electron photodetector by introducing an ultrathin Au layer sandwiched between two Au-Si-Au cavities. The multilayer grating system allows the excitation of the guided-mode resonance that shows a weak reliance on the incident polarization and, therefore, realizes the polarization-insensitive optical absorption up to 98%. The special multilayer design facilitates hot electron generation in the ultrathin Au layers with high carrier transport efficiency, as well as enabling the formation of a double Schottky junction, which doubles the carrier emission probability. The optical and electrical benefits ensure a polarization-independent photoresponsivity ~1 mA/W at the wavelength of 1470 nm. PMID- 30004496 TI - High-temperature stable and sterilizable waveguide Bragg grating in planar cyclo olefin copolymer. AB - In this Letter, we demonstrate a high-temperature stable polymer planar waveguide Bragg grating based on cyclo-olefin copolymers. The high glass transition temperature of the polymer material amounting to 178 degrees C, in conjunction with a high-temperature stable UV-curable adhesive used to connect the polymer sensor to a standard single-mode fiber, enables temperature readings of up to 160 degrees C while exhibiting a temperature sensitivity of -7.3 pm/ degrees C. The reflected power of the Bragg wavelength remains constant up to a temperature of 130 degrees C before declining at higher temperatures with an overall reduction of 2.5 dB at 160 degrees C. However, decreasing temperature results in a complete recovery of the peak power, facilitating steam pressure sterilization (129 degrees C, 0.17 MPa) of the polymer planar waveguide Bragg grating. PMID- 30004498 TI - Resonance in modulation instability from non-instantaneous nonlinearities. AB - To explore resonance phenomena in the nonlinear region, we show by experimental measurements and theoretical analyses that resonance happens in modulation instability from non-instantaneous nonlinearities in photorefractive crystals. With a temporally periodic modulation in the external bias voltage, corresponding to a modulation in the nonlinear strength, an enhancement in the visibility of MI at resonant frequency is reported through spontaneous optical pattern formations. Theoretical curves obtained from a nonlinear non-instantaneous Schrodinger equation give good agreement to experimental data. PMID- 30004499 TI - Reconstruction of structured laser beams through a multimode fiber based on digital optical phase conjugation. AB - The digital optical phase conjugation (DOPC) technique is being actively developed for optical focusing and imaging through or inside complex media. Due to its time-reversal nature, DOPC has been exploited to regenerate different intensity targets. However, whether the targets with three-dimensional information through complex media could be recovered has not been experimentally demonstrated, to the best of our knowledge. Here, we present a method to regenerate structured laser beams based on DOPC. Although only the phase of the original scattered wave is time reversed, the reconstruction of a quasi-Bessel beam and vortex beams through a multimode fiber (MMF) is demonstrated. The regenerated quasi-Bessel beam shows the features of sub-diffraction focusing and a longer depth of field with respect to a Gaussian beam. Moreover, the reconstruction of vortex beams shows the fidelity of DOPC both in amplitude and phase, which is demonstrated for the first time, to the best of our knowledge. We also prove that the reconstruction results of DOPC through the MMF are indeed phase conjugate to the original targets. We expect that these results could be useful in super-resolution imaging and optical micromanipulation through complex media, and further pave the way for achieving three-dimensional imaging based on DOPC. PMID- 30004500 TI - High-resolution slow-light fiber Bragg grating temperature sensor with phase sensitive detection. AB - This Letter reports a slow-light fiber Bragg grating (FBG) temperature sensor with a record temperature resolution of ~0.3 m degrees C/?Hz, a drift of only ~1 m degrees C over the typical duration of a measurement (~30 s), and negligible self-heating. This sensor is particularly useful for applications requiring the detection of very small temperature changes, such as radiation-balanced lasers and the measurement of small absorptive losses using calorimetry. The sensor performance is demonstrated by measuring the heat generated in a pumped Yb-doped fiber. The sensor is also used to measure the slow-light FBG's very weak internal absorption loss (0.02 m-1), which is found to be only ~2% of the total loss. PMID- 30004501 TI - Three-dimensionally structured voxels for volumetric display. AB - A three-dimensional (3D) volumetric display has been the goal of the display research field for many years. However, volumetric displays capable of rendering multicolor and updatable graphics that users can view with the naked eye are still a challenge. Here, we show a new volumetric display using three dimensionally structured fluorescent voxels. The fluorescent voxels were generated by two-photon excitation with a femtosecond laser. To realize colorization, volumetric graphics were spatially rendered on a fluorescent screen in which structured voxels having different luminescent colors were arranged in each layer. The color of the fluorescent voxels was changed by a holographic color switching method using computer-generated holograms displayed on a liquid crystal spatial light modulator. Because this display employed RGB fluorescent voxels that are accessed optically, it has a number of advantages, such as being observable with the naked eye, and being capable of multicolor rendering and refreshable graphics. This technology will open up a wide range of applications in 3D displays, augmented reality, and computer graphics. PMID- 30004502 TI - Graded-index solitons in multimode fibers. AB - We investigate stability of optical solitons in graded-index (GRIN) fibers by solving an effective nonlinear Schrodinger equation that includes spatial self imaging effects through a length-dependent nonlinear parameter. We show that this equation can be reduced to the standard NLS equation for optical pulses whose dispersion length is much longer than the self-imaging period of the GRIN fiber. Numerical simulations are used to reveal that fundamental GRIN solitons as short as 100 fs can form and remain stable over distances exceeding 1 km. Higher-order solitons can also form, but they propagate stably over shorter distances. We also discuss the impact of third-order dispersion on a GRIN soliton. PMID- 30004503 TI - Few-layer TiSe2 as a saturable absorber for nanosecond pulse generation in 2.95 MUm bulk laser. AB - 1T-phase titanium diselenide (1T-TiSe2), a model two-dimensional (2D) transition metal dichalcogenide, has attracted much attention due to its intriguing electrical and optical properties. In this work, a 1T-TiSe2-based high-quality large-area saturable absorber (SA) (1T-TiSe2-SA) was successfully fabricated with the liquid-phase exfoliation method. With the as-prepared 1T-TiSe2-SA, a stable, passively Q-switched laser operating at 2.95 MUm was first realized. Under an absorbed pump power of 3.35 W, the maximum average output power was 130 mW with a slope efficiency of 5%. A pulse width of 160.5 ns was obtained, which is the shortest among 3.0 MUm passively Q-switched lasers ever achieved with 2D materials as SAs, to the best of our knowledge. The results indicate that 1T TiSe2 is a promising alternative as a nonlinear optical modulator for short-pulse laser generation near the 3.0 MUm mid-infrared region. PMID- 30004505 TI - Controlling attosecond transient absorption with tunable, non-commensurate light fields. AB - We demonstrate a transient absorption scheme that uses a fixed-spectrum attosecond pulse train in conjunction with a tunable probe laser to access a wide range of nonlinear light-atom interactions. We exhibit control over the time dependent Autler-Townes splitting of the 1s4p absorption line in helium, and study its evolution from a resonant doublet to a light-induced sideband with changing probe wavelength. The non-commensurate probe also allows for the background-free study of two-infrared-photon emission processes in a collinear geometry. Using this capability, we observe two different emission pathways with non-trivial delay dependencies, one prompt and the other delayed. We identify the nonlinear processes underlying these emissions by comparing the experimental results to calculations based on the time-dependent Schrodinger equation. PMID- 30004504 TI - 1.34 MUm VECSEL mode-locked with a GaSb-based SESAM. AB - Mode locking of a 1.34 MUm vertical external cavity surface emitting laser is demonstrated using a GaSb-based semiconductor saturable absorber mirror (SESAM). The SESAM includes six AlGaSb quantum wells (QWs) with an absorption edge at ~1.37 MUm. The proposed approach has two key benefits: the QWs can be grown lattice matched, and only a small number of Bragg reflector layers is required to provide high reflectivity. Pump-probe measurements also reveal that the AlGaSb/GaSb structure exhibits an intrinsically fast absorption recovery on a picosecond timescale. The mode-locked laser pulse train had a fundamental repetition rate of 1.03 GHz, a pulse duration of ~5 ps, and a peak power of ~1.67 W. The demonstration paves the way for exploiting GaSb-based SESAMs for mode locking in the 1.3-2 MUm wavelength range, which is not sufficiently addressed by GaAs and InP material systems. PMID- 30004506 TI - Maintaining broadband gain in a Nd3+/Yb3+co-doped silica fiber amplifier via dual laser pumping. AB - We report a 30 cm long Nd3+/Yb3+ co-doped silica glass fiber amplifier with well maintained broadband gain through simultaneous dual-laser pumping at 808 and 975 nm. By controlling the ratio of the pump power at 975 (P975) and 808 nm (P808), the emission band of Yb3+/Nd3+ and the energy transfer efficiency of Nd3+->Yb3+ can be well controlled; thus, a tunable broadband and flat gain in the range of 1036-1080 nm are obtained. The theoretical calculation of the energy transfer efficiency of Nd3+->Yb3+ with dual-laser pumping of 808 and 975 nm explains well the mechanism of broadband and flat gain formation in the Nd3+/Yb3+ co-doped fiber. PMID- 30004507 TI - Single-shot quantitative phase microscopy based on color-multiplexed Fourier ptychography. AB - We present a single-shot quantitative phase imaging (QPI) method based on color multiplexed Fourier ptychographic microscopy (FPM). Three light-emitting diode (LED) elements with respective R/G/B channels in a programmable LED array illuminate the specimen simultaneously, providing triangle oblique illuminations matching the numerical aperture of the objective precisely. A color image sensor records the light transmitted through the specimen, and three monochromatic intensity images at each color channel are then separated and utilized to recover the phase of the specimen. After one-step deconvolution based on the phase contrast transfer function, the obtained initial phase map is further refined by the FPM-based iterative recovery algorithm to overcome pixel-aliasing and improve the phase recovery accuracy. The high-speed, high-throughput QPI capabilities of the proposed approach are demonstrated by imaging HeLa cells mitosis in vitro, achieving a half-pitch resolution of 388 nm across a wide field of view of 1.33 mm2 at camera-limited frame rates (50 fps). PMID- 30004508 TI - 115 W fiber laser with an all solid-structure and a large-mode-area multicore fiber. AB - We investigate mode-area scaling by means of supermode operation in an all-solid multicore fiber. To obtain a large-mode area (LMA), we designed and fabricated an active double-clad multicore fiber, where each ytterbium-doped core is 19 MUm in diameter and has a numerical aperture of 0.067, comparable to the core of the largest available commercial LMA fibers. The six large cores are stacked tightly in a ring structure to enable phase locking of the core fields and supermode operation. The fiber laser performance was investigated in a linear laser cavity with an external Talbot resonator for mode selection. The highest output power achieved was 115 W with an overall 61% slope efficiency corresponding to the pump power. The measured M2 was 1.43 for the central lobe with nearly 70% of the total power. PMID- 30004509 TI - Endoscopic diffraction phase microscopy. AB - In this Letter, we present, to our knowledge, the first endoscopic diffraction phase microscopy (eDPM) system. This instrument consists of a gradient-index-lens based endoscope probe followed by a DPM module, which enables single-shot phase imaging at a single-cell-level resolution. Using the phase information provided by eDPM, we show that the geometric aberrations associated with the endoscope can be reduced by digitally applying a spectral phase filter to the raw data. The filter function is a linear combination of polynomials with weighting optimized to improve resolution. We validate the principle of the proposed method using reflective semiconductor samples and blood cells. This research extends the current scope of quantitative phase imaging applications, and proves its potential for future in vivo studies. PMID- 30004510 TI - All-fiber laser with simultaneous Tm3+ passive Q-switched and Ho3+ gain-switched operation. AB - We experimentally demonstrate simultaneous Tm3+ passive Q-switched (PQS) and Ho3+ gain-switched laser operations at 1888.8 and 2021.2 nm, respectively, in a single cavity all-fiber laser. The PQS operation of the Tm3+ laser is based on the use of a high-concentration holmium-doped fiber as a fiber saturable absorber. Then the Tm3+ laser emission is used as a pulsed pump source to achieve Ho3+ gain switched pulses. A high birefringence fiber optical loop mirror used as a spectral filter allows the tuning of both Tm3+ and Ho3+ laser emissions. PMID- 30004511 TI - Generation of 1 kHz, 2.3 mJ, 88 fs, 2.5 MUm pulses from a Cr2+:ZnSe chirped pulse amplifier. AB - We demonstrate the generation of 2.3 mJ, 88 fs, 2.5 MUm laser pulses at 1 kHz repetition rate from a three-stage chirped pulse amplifier employing Cr2+:ZnSe crystals as the active gain media. 5 MUJ seed of the amplifier is obtained via intrapulse difference frequency generation in a bismuth triborate (BIBO) crystal from spectrally broadened Ti:Sapphire amplifier output. A multi-pass amplifier followed by two single-pass amplifiers pumped by Q-switched Ho:YAG lasers boost the pulse energy to 6.5 mJ, yielding 2.3 mJ, 88 fs pulses upon pulse compression. Our results show the highest peak power at 2.5 MUm with 1 kHz repetition rate. Such a laser will be a powerful source for studying strong-field physics and extending high-harmonic generation towards the keV region. PMID- 30004512 TI - Radiation-induced reversible thermal effect in Er3+/Yb3+-codoped silica fibers. AB - We observed an induced thermal effect in Er3+/Yb3+-codoped silicate fibers (EYDFs) after gamma radiation. It is further found that the induced thermal effect is reversible under room temperature. This is the first report, to the best of our knowledge, on such a radiation-induced reversible thermal effect on EYDFs. This phenomenon, ascribed to radiation effect on EYDFs, can be used to design a novel fiber-optic temperature sensor with tailored properties. PMID- 30004513 TI - Relativistic coupling of phase and amplitude noise in optical interferometry. AB - Extraneous motion of optical elements in an interferometer leads to excess noise. Typically, fluctuations in the effective path length lead to phase noise, while beam pointing fluctuations lead to apparent amplitude noise. For a transmissive optic moving along the optical axis, neither effect should exist. However, relativity of motion suggests that, even in this case, small corrections of order v/c (v the velocity of the optic) give rise to phase and amplitude noise on the light. Here we calculate the effect of this relativistic mechanism of noise coupling and discuss when such an effect would limit the sensitivity of optical interferometers. PMID- 30004515 TI - DC-free on-axis holographic display using a phase-only spatial light modulator. AB - A DC-noise-free on-axis holographic display scheme using a phase-only spatial light modulator (SLM) is proposed. The origin of DC noise in the on-axis holographic display using a phase-only SLM is analyzed, and a DC noise rejection filter is optimized for a phase-only SLM is designed. A novel two-step iterative Fourier transform algorithm for the optimal synthesis of a phase-only computer generated hologram using the proposed scheme is devised. The proposed scheme and algorithm are validated with numerical simulations and experiments. PMID- 30004514 TI - Directional scattering from particles under evanescent wave illumination: the role of reactive power. AB - Study of photonic spin-orbital interactions, which involves control of the propagation and spatial distributions of light via its polarization, is not only important at the fundamental level but also has significant implications for functional photonic applications that require active tuning of directional light propagation. Many of the experimental demonstrations have been attributed to the spin-momentum locking characteristic of evanescent waves. In this Letter, we show another property of evanescent waves: the polarization-dependent direction of the imaginary part of the Poynting vector, i.e., reactive power. Based on this property, we propose a simple and robust way to tune the directional far-field scattering from nanoparticles near a surface under evanescent wave illumination by controlling its polarization and direction of the incident light. PMID- 30004516 TI - Monolithic integration of III-nitride voltage-controlled light emitters with dual wavelength photodiodes by selective-area epitaxy. AB - We report for the first time on-chip integration of III-nitride voltage controlled light emitters with visible and ultraviolet (UV) photodiodes (PDs). InGaN/GaN and AlGaN/GaN heterostructures were grown in specific regions by selective-area epitaxy, allowing monolithic integration of versatile devices including visible light emitting diodes (LEDs), visible-light PDs, AlGaN/GaN high electron mobility transistors (HEMTs), and UV-light Schottky barrier (SB) PDs. A serial connection between the LED and HEMT through the epitaxial layers enables a three-terminal voltage-controlled light emitter (HEMT-LED), efficiently converting voltage-controlled signals into visible-light signals that can be coupled into an adjacent visible-light PD generating electrical signals. While the integrated blue HEMT-LED and PD transmits signals carried by visible light, the visible-blind SB-PD on a chip receives external UV light control signals with negligible interference from the on-chip visible-light source. This integration scheme can be extended to open an avenue for developing a variety of applications, such as smart lighting, on-chip optical interconnect, optical wireless communication, and opto-isolators. PMID- 30004517 TI - Femtosecond laser inscribed straight waveguide in no-core fiber for in-line Mach Zehnder interferometer construction. AB - A new fiber in-line Mach-Zehnder interferometer based on a straight waveguide along the central axis of the no-core fiber sandwiched between single mode fibers is fabricated by a femtosecond laser. The device can be used for high temperature sensing with a sensitivity of -278.86 pm/ degrees C and for bending sensing with a sensitivity of 0.28 nm/m-1. The high mechanical strength, simple fabrication, and precisely controlled free spectral range make the device attractive for potential applications in high temperature monitoring. PMID- 30004518 TI - Femtosecond laser microprinting of a polymer fiber Bragg grating for high sensitivity temperature measurements. AB - We demonstrate the microprinting of a novel suspended polymer fiber Bragg grating for high-sensitivity temperature measurements. The proposed sensor was developed using a femtosecond laser-induced multiphoton polymerization technique. The grating was cured in a single-groove silica tube spliced between two single-mode fibers. Its transmission spectrum, mode field, and temperature response were thoroughly investigated. A sensitivity of -220 pm/ degrees C was achieved over a temperature range of 24 degrees C to 40 degrees C, which is meaningful in biosensing applications. This all-in-fiber polymer Bragg grating exhibits high temperature sensitivity, excellent mechanical strength, and ultrahigh integration. As such, a temperature sensing element of this type would be a beneficial tool for biological measurements. PMID- 30004519 TI - Fast demodulated white-light interferometry-based fiber-optic Fabry-Perot cantilever microphone. AB - We demonstrate a highly sensitive and stable fiber-optic Fabry-Perot cantilever microphone based on fast demodulated white-light interferometry. The cavity length of the low-finesse Fabry-Perot interferometry is absolutely measured by realizing a high-speed demodulation method utilizing a full spectrum, with the advantages of both high resolution and large dynamic range. An acoustic test demonstrates high sensitivities and linear responsivities at frequencies below 2 kHz. The pressure responsivity and the noise-limited minimum detectable acoustic pressure level are measured to be 211.2 nm/Pa and 5 MUPa/Hz1/2, respectively, at the frequency of 1 kHz. Comparative experimental results show that the signal-to noise ratio is over 10 times higher than a reference condenser microphone. PMID- 30004520 TI - Scintillation index reducing based on wide-spectral mode-locking fiber laser carriers in a simulated atmospheric turbulent channel. AB - We report on a communication link demonstration in a 1 km simulated atmospheric turbulent channel with a wide-spectral mode-locking fiber laser. Wide-spectral beams are part of the supercontinuum, which is generated from pumping a dispersion-shifted fiber by an active mode-locked fiber laser. In addition, the propagation effects of wide-spectral beams were investigated experimentally in a simulated atmosphere channel. The characteristics of bit error rate and eye pattern before and after turbulence were analyzed, respectively. The experimental results showed that the sensitivity of the whole link reaches -40 dBm. The scintillation index of free-space optical communication between wide-spectral partially coherent and narrow-spectral coherent beams was compared, which indicates that the wide-spectral partially coherent optical communication link is more resistant to atmospheric turbulence. We experimentally verified that the scintillation index of wide-spectral carriers is dependent on coherent degree rather than spectral width. PMID- 30004521 TI - 3D photoacoustic imaging using Hadamard-bias encoding with a crossed electrode relaxor array. AB - A novel 3D photoacoustic imaging technique is experimentally demonstrated using a 64*64 element bias-sensitive crossed-electrode relaxor array. This technique allows for large 2D arrays to receive across all elements while using minimal channel counts. Hadamard-bias patterns are applied to column electrodes while signals are measured from row electrodes. Photoacoustic signals are measured from a crossed-wire phantom in an intralipid scattering medium. The Hadamard-bias encoded imaging scheme showed a signal-to-noise (SNR) of 25.3 dB, while the single-column biasing strategy (or identity-matrix-bias pattern) showed a SNR of 8.8 dB. PMID- 30004522 TI - Coherence lattices in surface plasmon polariton fields. AB - We explore electromagnetic coherence lattices in planar polychromatic surface plasmon polariton (SPP) fields. When the SPP constituents are uncorrelated-and thus do not interfere-coherence lattices arise from statistical similarity of the random SPP electromagnetic field. As the SPP correlations become stronger, the coherence lattices fade away, but the lattice structure reemerges in the spectral density of the field. The polarization states of the structured SPP lattice fields are also investigated. Controllable plasmonic coherence and spectral density lattices can find applications in nanophotonics, such as nanoparticle manipulation. PMID- 30004523 TI - Compact broadband low-loss taper for coupling to a silicon nitride photonic wire. AB - We demonstrate an ultra-compact waveguide taper on a silicon nitride platform. The proposed taper provides a coupling efficiency of 95% at a length of 19.5 MUm in comparison to the standard linear taper of length 50 MUm, which connects a 10 MUm wide waveguide to a 1 MUm wide photonic wire. The taper has a spectral response >75% spanning over 800 nm and resilience to fabrication variations; +/ 200 nm change in taper and end waveguide width varies transmission by <5%. We experimentally demonstrate taper insertion loss of <0.1 dB/transition for a taper as short as 19.5 MUm, and reduce the footprint of the photonic device by 50.8% compared to the standard adiabatic taper. To the best of our knowledge, the proposed taper is the shortest waveguide taper ever reported in silicon nitride. PMID- 30004524 TI - Experimental three-party quantum random number generator based on dimension witness violation and weak measurement. AB - Random number generation is an important task in modern science. A variety of quantum random number generation protocols have been proposed and realized. These protocols, however, are all based on two parties. Based on the weak measurement technique, we propose and realize a quantum random number generator among three observers. The violation of a double classical dimension witness based on the determinant value is first observed in experiment. With the heralding single photon source, our experimental setup attains the independent assumption and the dimension assumption, which means our setup is semi-device-independent (DI). This Letter sheds new light on generating DI-type random number among multi-user and it has potential application prospect on the quantum cryptography and quantum random number in network environment. PMID- 30004525 TI - Hybrid dual-comb interferometer with easily established mutual coherence and a very high refresh rate. AB - In this Letter, we propose a hybrid dual-comb interferometer (DCI) with a free running mode-locked laser and an electro-optic frequency comb. The mutual coherence of this DCI is achieved by using an injection locking technique without any complicated phase-locking loops or post data processing algorithms. The proposed architecture is validated by resolving more than 10,000 comb lines of 250 MHz spacing with a refresh rate of 500 kHz. This combination of two kinds of optical frequency comb sources is suitable for wideband spectroscopic applications, where moderate spectral resolutions as well as high refresh rates are necessary. PMID- 30004526 TI - Effect of linear polarizers on the behavior of partially coherent and partially polarized highly focused fields. AB - In this Letter, we describe the behavior of partially coherent, partially polarized focused vector beams after passing a linear polarizer placed at the focal plane of a high numerical aperture microscope lens. In particular, we develop a mathematical framework for such beams that helps the understanding of the performance of polarizers when interact with non-paraxial beams. The features of the focused field after the polarizer are numerically evaluated for some illustrative examples. PMID- 30004527 TI - Phase unwrapping in dual-wavelength digital holographic microscopy with total variation regularization. AB - A two-step dual-wavelength phase imaging method with total variation (TV) regularization in digital holographic microscopy (DHM) is presented. The rough height map is first denoised with TV regularization, and then it is used as a guiding map for accurate phase unwrapping. By combining the principle of dual wavelength interferometry and TV regularization, the problem of phase unwrapping is converted into a minimization problem that can be efficiently solved with the Split Bregman algorithm. The proposed algorithm allows a synthetic wavelength that can be arbitrarily large in principle to a single wavelength, while the accuracy of the phase map can achieve the same level in single-wavelength DHM. Moreover, the unwrapping method is robust to the change of weighting parameters. Comparative topographic measurements of a sample with abrupt steps are illustrated, and the results verified the effectiveness of the method. PMID- 30004528 TI - Laser-controlled adaptive optics for beam quality improvements in a multi-pass thin-disk amplifier. AB - We devise a laser-controlled adaptive optical element that operates intracavity under high-intensity radiation. This element substitutes a conventional mechanically deformable mirror and is free of critical heat-sensitive components and electronics. The deformation mechanism is based on the projection of a continuous-wave control laser onto a specially designed mirror. Mounted to a water-cooled heat sink, the mirror can handle laser radiation beyond 3 MW/cm2. The properties of the adaptive optical element, including the maximum correctable wavefront pitch of 800 nm, are discussed. The successful implementation in a multi-pass thin-disk amplifier is presented. An improvement of the beam quality by a factor of three is achieved. We identify measures to enhance the performance of the adaptive optics towards efficient operation in a high-power laser system. PMID- 30004529 TI - 946 nm Nd:YAG laser with cavity dumping. AB - An end-pumped Nd:YAG 946 nm laser with pulse duration of 1.6 ns, output energy of 2.5 mJ, and pulse repetition rate of 50 Hz is described. Such a combination of the parameters achieved has become possible due to the implementation of the cavity-dumping mode. PMID- 30004530 TI - Sub-10 nm particle trapping enabled by a plasmonic dark mode. AB - We demonstrate that a highly localized plasmonic dark mode with radial symmetry, termed quadrupole-bonded radial breathing mode, can be used for optically trapping the dielectric nanoparticles. In particular, the annular potential well produced by this dark mode shows a sufficiently large depth to stably trap the 5 nm particles under a relatively low optical power. Our results address the quest for precisely trapping sub-10 nm particles with high yield and pave the way for placing sub-10 nm particles conforming to a specific geometric pattern. PMID- 30004531 TI - Double inverse nanotapers for efficient light coupling to integrated photonic devices. AB - Efficient light coupling to integrated photonic devices is of key importance to a wide variety of applications. "Inverse nanotapers" are widely used, in which the waveguide width is reduced to match an incident mode. Here, we demonstrate novel "double inverse" tapers, in which we reduce both the waveguide height and width. We demonstrate >45% chip-through coupling efficiency for both the transverse electric and transverse magnetic polarizations in Si3N4 tapers of >500 nm width, in comparison to regular inverse tapers that necessitate <100 nm width. The double inverse tapers show polarization-independent coupling and allow the fabrication using photolithography, relevant for applications at near-infrared and visible wavelengths, e.g., supercontinuum and soliton microcomb generation. PMID- 30004532 TI - Weak plasmon-exciton coupling between monolayer molybdenum disulfide and aluminum disks. AB - Manipulation of the photoluminescence (PL) of monolayer (ML) molybdenum disulfide (MoS2) with metallic plasmonic nanostructures has attracted much more attention for potential applications in optoelectronic devices. However, due to the limitation of resonance wavelength and oxidation properties, gold and silver are not the best selections for manipulating PL of MoS2. Here, we employ aluminum (Al) disks to tune the PL of ML MoS2. We have found that PL enhancement reaches the maximum when plasmonic resonances of Al disks overlap with the absorption peaks of ML MoS2. Near-field simulations show that PL enhancement is due to weak plasmon-exciton coupling. PMID- 30004533 TI - Subwavelength engineering and asymmetry: two efficient tools for sub-nanometer bandwidth silicon Bragg filters. AB - Bragg filters stand as key building blocks of the silicon-on-insulator (SOI) photonics platform, allowing the implementation of advanced on-chip signal manipulation. However, achieving narrowband Bragg filters with large rejection levels is often hindered by fabrication constraints and imperfections. Here, we show that the combination of single-side corrugation asymmetry and subwavelength engineering provides a narrowband response with large corrugations, overcoming minimum feature size constraints of conventional Si Bragg filters. We comprehensively study the impact of the corrugation asymmetry in conventional and subwavelength single-etched SOI Bragg filters, showing their potential for bandwidth reduction. Finally, we experimentally demonstrate novel subwavelength geometry based on shifted corrugation teeth, achieving null-to-null bandwidths and rejections of 0.8 nm and 40 dB for the symmetric configuration and 0.6 nm and 15 dB for the asymmetric case. PMID- 30004534 TI - Low dark-current and high-photodetectivity transparent organic ultraviolet photodetector by using polymer-modified ZnO as the electron transfer layer. AB - In this Letter, a transparent organic photodetector (OPD) with a property of ultraviolet sensitivity is demonstrated by using an inverted architecture. A conjugated polymer of ploy [(9,9-bis(3'-(N,N-dimethylamino)propyl)-2,7-fluorene) alt-2,7-(9,9-dioctyl)fluorene)] is introduced to modify the energy level and morphology between ZnO and organic optoelectronic material. As a result, at a wavelength of 350 nm and a bias of -1 V, the photodetectivity of 1012 Jones from both sides of the transparent device is obtained with a working area of 1 cm2. Moreover, an optical simulation is applied to analyze the optical electric field distribution inside the OPD. PMID- 30004535 TI - Facile way to obtain multiple interface modes in a photonic crystal heterostructure. AB - A very facile way to obtain multiple interface modes in a one-dimensional photonic crystal heterostructure is proposed in this Letter. We found that the interface modes can be generated by introducing the interfaces, and the number of interface modes equals the number of introduced interfaces. All these interface modes originating from a different geometric Zak phase can create two band branches governed by the two different interfaces. We further find that the two band branches can be renormalized into one band branch with discrete energy levels in the form of sinusoidal function. We believe that these findings can be used to provide direct guidance for practical application and can also make the estimation of practical samples more convenient. PMID- 30004536 TI - Photoelectron holography and forward scattering in atomic ionization by elliptically polarized laser pulses. AB - We report on the scaling of the photoelectron holography with the laser ellipticity in strong-field atomic ionization. We find that the spacing of the holographic fringe gradually decreases with increasing of the ellipticity. In terms of the strong-field approximation, the scaling of the fringe spacing with the laser ellipticity is explained by the effect of the initial transverse momenta at the tunnel exit. With increasing of the laser ellipticity, a ridge structure arising from forward scattering electrons is observed in the low-energy region of the electron momentum distribution. An analytic formula is obtained that demarcates the phase diagram for the observation of the holographic pattern and ridge structure in elliptically polarized laser fields. PMID- 30004537 TI - Optical trapping with planar silicon metalenses. AB - Contactless manipulation of micron-scale objects in a microfluidic environment is a key ingredient for a range of applications in the biosciences, including sorting, guiding, and analysis of cells and bacteria. Optical forces are powerful for this purpose but, typically, require bulky focusing elements to achieve the appropriate optical field gradients. To this end, realizing the focusing optics in a planar format would be very attractive and conducive to the integration of such microscale devices, either individually or as arrays. Here we report on, to the best of our knowledge, the first experimental demonstration of optical trapping using planar silicon metalenses illuminated with a collimated laser beam. The structures consist of high-contrast gratings with a locally varying period and duty cycle. They are designed to mimic parabolic reflectors with a numerical aperture of 0.56 at a vacuum wavelength of 1064 nm. We achieve both two and three-dimensional trapping in water, with the latter realized by omitting the central Fresnel zones. This Letter highlights the versatility of such lithographically defined metastructures for exerting optical forces without the need for traditional optical elements. PMID- 30004539 TI - Breast cancer subtype specific biochemical responses to radiation. AB - External beam radiotherapy is a common form of treatment for breast cancer. Among patients and across different breast cancer subtypes, the response to radiation is heterogeneous. Radiation-induced biochemical changes were examined by Raman spectroscopy using cell lines that represent a spectrum of human breast cancer. Principal component analysis (PCA) and partial least squares discriminant analysis (PLSDA) revealed unique Raman spectral features in the HER2 and Ki67 subtype. The changes in Raman spectral profiles to different doses of radiation (0-50 Gy) included variations in the levels of proteins, lipids, nucleic acids and glycogen. Importantly, the differences in radiation-induced changes on the normal breast epithelial cell line MCF10A could be discriminated within and across the various breast tumor cell lines. These results demonstrate a novel approach to uncover differences between breast cancer cell subtypes and surrounding normal tissues by their biochemical variations in response to radiation. PMID- 30004540 TI - A squaramide-based metal-organic framework as a luminescent sensor for the detection of lactose in aqueous solution and in milk. AB - A novel squaramide-containing metal-organic framework (MOF) has been designed and synthesized, which represents the first example of the luminescence selective detection of lactose over other monosaccharides and disaccharides. It was also used for the quantitative determination of lactose in milk. PMID- 30004541 TI - Exploring the interactions between model proteins and Pd(ii) or Pt(ii) compounds bearing charged N,N-pyridylbenzimidazole bidentate ligands by X-ray crystallography. AB - Pd(ii) and Pt(ii) compounds bearing N,N-pyridylbenzimidazole derivatives with an alkylated sulfonate or phosphonium side chain are able to bind the model protein lysozyme both covalently and non-covalently as an entire compound or as a product of a hydrolysis reaction. The interactions with the protein and the origin of the different behaviors of these complexes were unknown hitherto. Here, we present four crystal structures of their adducts with lysozyme. Pt- and Pd-containing fragments bind the protein with different stoichiometries close to the side chains of His15, Asp87, Asp101 and Asn77. The compounds bearing a phosphonium side chain degrade during the reaction with lysozyme. Data show the origin of the non-covalent mode of binding of Pd and Pt compounds bearing a sulfonate side chain, which drives the recognition process by forming a series of H-bonds and coulombic interactions with positively charged residue side chains. In a separate experiment, the structure of the adduct that is formed when the Pd(ii) compound containing an alkylated sulfonate group reacts with ribonuclease A was also determined. In this structure, the sulfonate-Pd(ii) complex binds the side chain of His105 on the surface of the protein and the side chain of the catalytically important His119 residue. Altogether, our data provide a structural basis for understanding the behavior of the analyzed Pd(ii)- and Pt(ii)-based cisplatin analogues in their reactions with proteins and show the first structural characterization of an adduct comprising a cisplatin analogue that is non covalently bound to a protein. The results suggest that functionalization of a ligand system with a sulfonate group can significantly alter the protein-binding activity and thus the overall pharmacological profile of Pd(ii)- and Pt(ii)-based drugs. PMID- 30004542 TI - Real-time in situ dynamic sub-surface imaging of multi-component electrodeposited films using event mode neutron reflectivity. AB - Exquisite control of the electrodeposition of metal films and coatings is critical to a number of high technology and manufacturing industries, delivering functionality as diverse as anti-corrosion and anti-wear coatings, electronic device interconnects and energy storage. The frequent involvement of more than one metal motivates the capability to control, maintain and monitor spatial disposition of the component metals, whether as multilayers, alloys or composites. Here we investigate the deposition, evolution and dissolution of single and two-component metal layers involving Ag, Cu, and Sn on Au substrates immersed in the deep eutectic solvent (DES) Ethaline. During galvanostatically controlled stripping of the metals from two-component systems the potential signature in simultaneous thickness electrochemical potential (STEP) measurements provides identification of the dissolving metal; coulometric assay of deposition efficiency is an additional outcome. When combined with quartz crystal microbalance (QCM) frequency responses, the mass change : charge ratio provides oxidation state data; this is significant for Cu in the high chloride environment provided by Ethaline. The spatial distribution (solvent penetration and external roughness) of multiple components in bilayer systems is provided by specular neutron reflectivity (NR). Significantly, the use of the recently established event mode capability shortens the observational timescale of the NR measurements by an order of magnitude, permitting dynamic in situ observations on practically useful timescales. Ag,Cu bilayers of both spatial configurations give identical STEP signatures indicating that, despite the extremely low layer porosity, thermodynamic constraints (rather than spatial accessibility) dictate reactivity; thus, surprisingly, Cu dissolves first in both instances. Sn penetrates the Au electrode on the timescale of deposition; this can be prevented by interposing a layer of either Ag or Cu. PMID- 30004543 TI - Development of a flow injection analytical system for short chain amide determination based on a tubular bioreactor and an ammonium sensor. AB - Pseudomonas aeruginosa (P. aeruginosa) possesses intracellular amidase activity, which catalyses the hydrolysis of short aliphatic amides producing NH4+, and has already been used along with an ammonium ion selective electrode for amide quantification. However, the incorporation of a biological membrane turned to be a challenging process and either the final arrangement was prone to amidase losses or the recovery of the sensor coating after the interaction took too long. In this article a flow injection system with an ammonium acoustic wave sensor is proposed, and after testing several different arrangements for the biological element, the ultimate choice consisted of the immobilization of a P. aeruginosa cell-free extract in the inner wall of a tubular glass reactor, which resulted in a reliable analytical system. Response times less than one minute and complete recovery in less than two minutes assured conveniently fast analysis. The analytical system, as long as the column was properly stored in HEPES buffer containing 2 mM beta-mercaptoethanol and 1 mM benzamidine and refrigerated when not in use, could be used at least for 20 working days, along a period of one month, maintaining the initial sensitivity. PMID- 30004544 TI - A novel electrochemical aptamer-antibody sandwich assay for the detection of tau 381 in human serum. AB - Tau protein plays a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the assay to detect low concentrations of tau protein is a great challenge for the early diagnosis of AD. We will outline a novel aptamer-antibody sandwich assay based on an electrochemical biosensor for the detection of tau-381 in human serum. To improve the detection sensitivity, the aptamer-antibody sandwich assay for the detection of tau-381 was developed by using a tau antibody (anti-tau) and an aptamer specific to tau-381 as the recognition element and cysteamine-stabilized gold nanoparticles (AuNPs) for signal amplification. Differential pulse voltammetry (DPV) was employed to record the signal response of tau-381 with different concentrations. The tau-381 concentration ranged from 0.5 pM to 100 pM. The responses of DPV measurements showed excellent results in this dynamic range. This simple, rapid, highly sensitive and specific assay gave a low limit of detection (LOD) of 0.42 pM for tau-381. The feasibility and reliability of the assay were verified by testing tau-381 in human serum from patients with AD. Thus, this method could prove valuable in diagnosing AD within the early stages of the disease. PMID- 30004545 TI - Synthesis and properties of heterobimetallic rhodium complexes featuring LiI, CuI or ZnII as a Lewis acidic metalloligand. AB - A series of [(PMP)Rh(CO)Cl]n+ complexes was synthesised and the impact of the metalloligands CuI, LiI and ZnII on the CO stretching band was analysed. PMID- 30004546 TI - Evaluation of topologically distinct constrained antimicrobial peptides with broad-spectrum antimicrobial activity. AB - Antimicrobial peptides (AMPs) are short cationic peptides with a high affinity for membranes and emerged as a promising therapeutic approach with potential for treating infectious diseases. Chemical stabilization of short peptides proved to be a successful approach for enhancing their bio-physical properties. Herein, we designed and synthesized a panel of conformationally constrained antimicrobial peptides with either alpha-helical or beta-hairpin conformation using templating strategies. These synthetic short constrained peptides possess different topological distributions of hydrophobic and hydrophilic residues and displayed distinct antimicrobial activity. Notably, the conformationally constrained alpha helical peptides displayed a faster internalization into the bacteria cells compared to their beta-hairpin analogues. These synthetic short constrained peptides showed killing effects on a broad spectrum of microorganisms mainly through pore formation and membrane damage which provided a potentially promising skeleton for the next generation of stabilized antimicrobial peptides. PMID- 30004547 TI - Up-conversion luminescence, thermometry, and optical heating properties of Er3+- and Yb3+-doped K2LaNb5O15 submicro-particles synthesized by a simple molten salt method. AB - A series of Er3+- and Yb3+-doped K2LaNb5O15 (KLN:xEr3+/Yb3+) up-conversion (UC) submicro-particles have been synthesized for the first time by a simple and low cost molten salt (MS) approach. X-ray diffraction (XRD) was performed to analyze the phase and structure, and the prepared KLN:xEr3+/Yb3+ samples exhibited a single phase tetragonal tungsten bronze (TTB) structure. The morphologies were characterized by scanning electron microscopy (SEM), and submicro-rod-like particles were obtained for all samples. Under 980 nm excitation, KLN:xEr3+/Yb3+ emitted bright green and weak red emissions which arose from the intra-4f transitions of Er3+ ions. The UC emission intensities and RR/G (the intensity ratio between red and green emissions) were disclosed to be tightly dependent on the Yb3+ ion concentration, and the involved UC luminescence mechanism was studied. Meanwhile, the slope of log I-log P plots displayed an evident reduction with a Ts (sintering temperature) increase, which was ascribed to the saturation effect coming from the competition between UC processes and linear decay. Furthermore, temperature-dependent UC behavior and temperature sensing properties of KLN:xEr3+/Yb3+ were probed based on the fluorescence intensity ratio (FIR) technique of UC green emission. The maximum sensor sensitivity (S) of KLN:0.04Er3+/Yb3+ (Ts = 900 degrees C) and KLN:0.16Er3+/Yb3+ (Ts = 900 degrees C) was determined to be as high as 10.90 * 10-3 and 12.27 * 10-3 K-1, respectively. We also showed that the particle size has an evident influence on S, which can be qualitatively interpreted by J-O theory. Thermal-cycling measurements were conducted at different temperatures, and good reliability and repeatability were confirmed. In addition, an obvious optical heating effect was also realized and the variation of temperature induced with a laser was about 32 K. These results reveal that KLN:xEr3+/Yb3+ submicroparticles with high sensor sensitivity and an obvious laser-induced thermal effect are suitable for future optical thermometers and optical heaters. PMID- 30004549 TI - ortho-Phenyl dialkylphosphonium sulfonate compounds: two rotamers in equilibrium. AB - Two known and two new ortho-phenyl phosphonium-sulfonate compounds have been synthesized and analyzed in solution and in the solid state. When the phosphonium moiety bears alkyl substituents, two rotamers are in equilibrium in solution. These two rotamers have been entirely characterized and are shown to differ by the spatial arrangement of the phosphonium proton relative to the sulfonate moiety. The phosphonium proton chemical shift and the 1JPH coupling constant are characteristic values for each rotamer. The kinetic and thermodynamic constants have been determined by means of NMR and DFT studies. PMID- 30004548 TI - Ruthenium-indolizinone complexes as a new class of metalated heterocyclic compounds: insight into unconventional alkyne activation pathways, revelation of unexpected electronic properties and exploration of medicinal application. AB - The two series of ruthenium-indolizinone complexes prepared by Ru-mediated cyclization of pyridine-tethered alkynes represent the first examples of metalated indolizinone complexes. Joint experimental-theoretical investigation suggests an unconventional 5-endo-dig cyclization pathway as their formation mechanism. They also exhibit moderate cytotoxicity against several human cancer cell lines. PMID- 30004550 TI - Modular synthesis of (E)-cinnamaldehydes directly from allylarenes via a metal free DDQ-mediated oxidative process. AB - An efficient synthesis of (E)-cinnamaldehydes by a metal-free DDQ-mediated oxidative transformation of allylarenes was developed. The protocol provides a practical method to prepare diverse (E)-cinnamaldehydes with broad functional group tolerance in good to excellent yields, including easy access to natural products randainal and geranyloxy sinapyl aldehyde from plant extracts. Finally, the mechanism of a single-electron transfer process was proposed. PMID- 30004551 TI - Chiral metamaterials via Moire stacking. AB - Chiral metamaterials have attracted strong interest due to their versatile capabilities in spin-dependent light manipulation. Benefiting from advancements in nanofabrication and mechanistic understanding of chiroptical effects, chiral metamaterials have shown potential in a variety of applications including circular polarizers, chiral sensors, and chiroptical detectors. Recently, chiral metamaterials made by moire stacking, superimposing two or more periodic patterns with different lattice constants or relative spatial displacement, have shown promise for chiroptical applications. The moire chiral metamaterials (MCMs) take advantage of lattice-dependent chirality, giving cost-effective fabrication, flexible tunability, and reconfigurability superior to conventional chiral metamaterials. This feature article focuses on recent progress of MCMs. We discuss optical mechanisms, structural design, fabrication, and applications of the MCMs. We conclude with our perspectives on the future opportunities for the MCMs. PMID- 30004552 TI - Two-step activity-based protein profiling of diacylglycerol lipase. AB - Diacylglycerol lipases (DAGL) produce the endocannabinoid 2-arachidonoylglycerol, a key modulator of neurotransmitter release. Chemical tools that visualize endogenous DAGL activity are desired. Here, we report the design, synthesis and application of a triazole urea probe for DAGL equipped with a norbornene as a biorthogonal handle. The activity and selectivity of the probe was assessed with activity-based protein profiling. This probe was potent against endogenous DAGLalpha (IC50 = 5 nM) and it was successfully applied as a two-step activity based probe for labeling of DAGLalpha using an inverse electron-demand Diels Alder ligation in living cells. PMID- 30004553 TI - The gut microbiota urolithin metabotypes revisited: the human metabolism of ellagic acid is mainly determined by aging. AB - Understanding individuals' response to dietary bioactives is crucial for personalized nutrition. We report here for the first time in a Caucasian cohort (5-90 years, n = 839) that aging is the main factor that determines the gut microbiota involved in the ellagic acid-ellagitannin metabolism (urolithin metabotypes), with potential consequences for human health. PMID- 30004554 TI - Comparison of total curative effect between total hip arthroplasty and hip arthrodesis in treating coxotuberculosis. AB - OBJECTIVE: The purpose of this study was to investigate the clinical effect of total hip arthroplasty (THA) and hip arthrodesis (HA) in treating coxotuberculosis. PATIENTS AND METHODS: 40 patients with coxotuberculosis treated in the Orthopedic Department in our hospital from February 2011 to February 2016 were retrospectively analyzed. Comparison of total curative effect between THA and HA in treating coxotuberculosis was analyzed. The operation time, intraoperative blood loss, postoperative drainage volume, visual analogue scale (VAS) score, Harris hip function score (HHS), erythrocyte sedimentation rate (ESR), C reactive protein, postoperative hip pain time (PHPT), postoperative start walking time(PSWT), postoperative start weight bearing time(PSWBT) and postoperative complications were observed and compared. RESULTS: All patients successfully underwent successful THA or HA without major complications. The operation time, intraoperative blood loss and postoperative drainage volume in patients who underwent HA were better than those of patients who underwent THA (p<0.001, p=0.010, p<0.001, respectively). During the postoperative evaluation, VAS, HHS, ESR, CRP in patients who underwent THA were better than those of patients who underwent HA, and the differences were statistically significant. About the recovery, PHPT, PSWT, PSWBT in patients who underwent THA were shorter than those in patients who underwent HA (p=0.021, p=0.044, p<0.001, respectively). There was no fracture, infection, dislocation, neurological or vascular complications in THA group. No patient had subsidence, loosening or heterotopic ossification. 1 patient in HA group had a fracture of the steel plate, and 1 patient had delayed union in HA group. CONCLUSIONS: THA is an effective treatment for advanced tuberculous arthritis. THA is superior to HA in the treatment of coxotuberculosis. PMID- 30004555 TI - Comparison between a novel human cortical bone screw and bioabsorbable interference screw for graft fixation of ACL reconstruction. AB - OBJECTIVE: To compare the mechanical behavior of a novel bioabsorbable cortical interference screw (BCIS) with bioabsorbable interference screw (BIS; Polylactate hydroxyapatite) used for anterior cruciate ligament (ACL) reconstruction in femoral and tibial fixation with doubled Achilles tendon graft in vitro. PATIENTS AND METHODS: 30 paired goat knee specimens were harvested from 15 male sheep aged 18 months. All soft tissues were stripped from the bones of 20 paired specimens, and the last 10 paired specimens were stripped all soft tissues besides ACL (femur-ACL-tibia complex). The Achilles tendon was harvested as graft for ACL reconstruction. The specimens were divided into several groups: BCIS femoral fixation (group A, n=10), BIS femoral fixation (group B, n=10), BCIS tibial fixation (group C, n=10), BIS tibial fixation (group D, n=10), Group E is femur ACL-tibia complex (n=10). Cyclic loading test was performed from 50 to 250 N at 1 Hz for 1000 cycles and followed by a load-to-failure test at 25 mm/sec. A paired t-test was used to compare the biomechanical properties of group A, B, E and group C, D, E. RESULTS: No fixation structures failed during the cyclic phase. Cyclic displacement for group B was superior to group A, and showed statistically significant difference after 30, 100, 500, 1000 cycles. Group E got minimum cyclic displacements compared with group A and group B, and showed statistically significant difference after 500, 1000 cycles compared with group A. Cyclic displacement for group D was superior to group C, and showed statistically significant difference after 100, 500, 1000 cycles. Group E got minimum cyclic displacements compared with group C and group D, and showed statistically significant difference after 500,1000 cycles compared with group C. Regarding MFL, group A was superior to group B (572.10+/-111.12 N vs. 413.96+/-34.56 N, p=0.118), group E was superior to group A (599.74+/-85.45N vs. 572.10+/-111.12 N, p=0.992), and group C was superior to group D (802.88+/-240.07 N vs. 415.63+/ 51.9 N, p<0.001), group C was superior to group E (802.88+/-240.07 N vs. 599.74+/ 85.45 N, p=0.024). Regarding YL, group A was superior to group B (521.57+/-93.96 N vs. 366.99+/-44.66 N, p=0.109), group E was superior to group A (565.37+/-66.05 N vs. 521.57+/-93.96 N, p=0.952), and group C was superior to group D (735.63+/ 242.91 N vs. 394.49+/-31.90 N, p<0.001), group C was superior to group E (735.63+/-242.91 N vs. 565.37+/-66.05 N, p=0.063). Regarding stiffness, group A was superior to group B (157.36+/-34.31 N/mm vs. 91.98+/-25.57 N/mm, p=0.001), group E was superior to group A (181.35+/-25.42 N vs. 157.36+/-34.31 N/mm, p=0.529), and group C was superior to group D (175.28+/-43.19 N/mm vs. 128.24+/ 18.92 N/mm, p=0.032), group E was superior to group C (181.35+/-25.42 N/mm vs. 175.28+/-43.19 N/mm, p=0.995). CONCLUSIONS: In vitro, this experimental study suggested the biomechanical properties of novel bioabsorbable cortical interference screw (BCIS) were superior to bioabsorbable interference screw (BIS) used for femoral and tibial anterior cruciate ligament (ACL) reconstruction in a goat knee model. PMID- 30004556 TI - A comparative study of proximal femoral locking compress plate, proximal femoral nail antirotation and dynamic hip screw in intertrochanteric fractures. AB - OBJECTIVE: We aimed to compare the clinical efficacy of three different internal fixation methods, i.e. proximal femoral locking compress plate (PF-LCP), proximal femoral nail antirotation (PFNA) and dynamic hip screw (DHS) system in intertrochanteric femur fracture. PATIENTS AND METHODS: We selected a total of 150 patients with Intertrochanteric femur fracture who were admitted to this hospital between January 2015 and December 2016 for treatment, and those patients were divided into three groups according to the difference in treatment methods, i.e., Group A (n=50), Group B (n=50) and Group C (n=50). For patients in Group A, they received the PF-LCP treatment, patients in Group B received PFNA treatment while those in Group C received DHS treatment; ultimately, clinical efficacy was compared among three groups. RESULTS: In Group B, the efficacy was superior to those in Group A and C in terms of comparison of surgical duration, bleeding amount, time point of callus formation, healing time of fracture and length of stay (LOS) in hospital (p<0.05); after operation, the prevalence rate of complication in Group B was significantly lower than those in Group A and Group C (p<0.05); in comparison of preoperative Harris score among three groups, the different had no statistical significance (p>0.05). The Harris scores in Group B at the 1st, 3rd, and 6th month after operation were all significantly higher than those in Group A and C (p<0.05). CONCLUSIONS: Compared with PF-LCP and DHS, PFDA can better fix the intertrochanteric femur fracture with little effect on blood circulation at the fracture end and slight damage to sclerotin, thereby accelerating the recovery of hip joint function without any increase in prevalence of complications. Therefore, PFDA has a promising clinical efficacy and safety, which is worthy of being promoted in clinical practice. PMID- 30004557 TI - Research on correlation between GALNT3 gene and osteoporosis. AB - OBJECTIVE: The aim of this study was to explore the correlation between GALNT3 gene and osteoporosis. PATIENTS AND METHODS: In this study, 184 cases of osteoporosis that were treated at our hospital from 2013 to 2014 were selected as research subjects in the observation group. In addition, 84 healthy people were selected as the control group from 2013 to 2014. The bone mineral density of the observation and control groups were detected by x-rays and the expression levels and differences of mRNA of the GALNT3 gene and protein in their body was detected using fluorescence quantitative polymerase chain reaction (qPCR), enzyme-linked immunoassay, and Western blotting. RESULTS: X-ray results suggest that when compared to the healthy group, bone mineral density of patients in the observation group was significantly lower than that of research subjects in the control group, with significant differences. The fluorescence qPCR results suggest that the expression levels of mRNA of the GALNT3 gene in patients with osteoporosis were significantly lower than that in the healthy group (p<0.05). Enzyme-linked immunosorbent assay (ELISA) results suggest that the expression levels of the GALNT3 gene in patients with osteoporosis (1.26+/-0.32) MUg/L was significantly lower than that in the healthy group (12.41+/-0.28) MUg/L, with significant differences (p<0.05). The Western blotting results agreed with the ELISA results. We also found in our research that the bone mineral density of patients with osteoporosis significantly correlated with the expression levels of the GALNT3 gene (r=0.95). CONCLUSIONS: Therefore, the GALNT3 gene significantly correlated with osteoporosis and the low expression of GALNT3 gene can promote the occurrence and deterioration of osteoporosis. PMID- 30004558 TI - Research on the correlation between the polymorphism of the back-2 gene and osteoarthritis. AB - OBJECTIVE: The objective of the present study was to investigate the correlation between polymorphisms of the back-2 gene and osteoarthritis. PATIENTS AND METHODS: We enrolled 76 patients with osteoarthritis who were admitted to our hospital between February 2014 and February 2015 for treatment as the observation group, and 46 healthy subjects as the control group. The analysis of back-2 gene polymorphisms (rs28502) was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). mRNA expression of the different genotypes was measured with reverse transcriptase-polymerase chain reaction (RT PCR), and the protein expression of back-2 of different genotypes was measured with enzyme-linked immunosorbent assay (ELISA) and Western blotting. RESULTS: At locus 173 of the back-2 gene, there were a total of three genotypes, i.e. CC, CT, and TT. The frequencies of these genotypes in healthy subjects and osteoarthritis patients were 9.5%, 82.2%, 8.3% and 47.4%, 7.5%, 45.1%, respectively. There was a significant difference (p<0.05). However, the frequency of C/T in healthy older subjects and osteoarthritis patients was 50.6%, 49.4%, 51.15%, 48.85%, respectively, and there was no significant difference (p>0.05). RT-PCR showed no significant difference in mRNA expressions of the back-2 gene between the control group and observation group (p>0.05), although ELISA indicated that the protein expression of back-2 (12.3+/-0.36 MUg/L) in osteoarthritis patients was significantly higher than in healthy subjects (1.52+/-0.18 MUg/L) (p<0.05). Moreover, Western blotting analysis indicated that the protein expression of back 2 in osteoarthritis patients was significantly higher than in healthy subjects. CONCLUSIONS: Genetic polymorphisms of back-2 are associated with the metabolic syndrome in older people, i.e. older people with the CC or TT genotypes may be at high risk for metabolic syndrome. PMID- 30004559 TI - Impact of knee varus and valgus deformity on alignment in lower extremities after total knee arthroplasty (TKA). AB - OBJECTIVE: To investigate the impact of knee varus and valgus in varying degrees on the alignment in lower extremities of patients who received the total knee arthroplasty (TKA). PATIENTS AND METHODS: We retrospectively analyzed the condition of varus and valgus deformity in full-length X-ray films of double lower extremities in weight-bearing position of 120 patients before and after they firstly received the TKA between March 2012 and May 2014 to discover the impact of knee varus and valgus in varying degrees on the alignment in lower extremities of patients who received the total knee arthroplasty (TKA). 120 patients were divided into three groups by the pre-operative hip-knee-ankle angle (HKA), the HKAs of three groups were compared after operation, and linear regression analysis was conducted to identify the correlation between pre- and post-operative HKAs. In addition, comparison between the pre- and post-operative lean of arms and legs (LMAL) was carried out to explore the variations before and after operation as well as the differences in the average variations among three groups. RESULTS: The differences were statistically significant in comparison of the pre- and post-operative HKAs and medial proximal tibia angles (MPTA) of all affected extremities (p<0.05), but no statistically significant difference was shown in comparison between the pre- and post-operative knee physical valgus angles (KPVA) (p>0.05). The post-operative lengths of 86.57% of affected extremities (116/134) were longer than those before operation with statistically significant differences (p<0.05). However, no statistically significant difference was identified in comparison between the pre- and post-operative lengths of extremities that did not receive any operation (p>0.05). The ratios of HKAs between -3 degrees and 3 degrees in normal group, mild-deformity group and severe-deformity group were respectively 90.48%, 81.25%, and 34.69% with a statistically significant difference (p<0.05). Besides, the scatter plot revealed that there was a linear regression relation between pre- and post-operative HKAs (F=51.197, p<0.05). There were statistically significant differences in comparisons of the pre-operative KPVA and MPTAs among three groups (p<0.05). CONCLUSIONS: Severe knee varus and valgus deformity can increase the deviation of alignment in lower extremities after TKA, and most of LMALs after TKA are longer than those before TKA, and the most significant extension is identified in severe varus and valgus deformity. PMID- 30004560 TI - Comparison of percutaneous balloon dilation kyphoplasty and percutaneous vertebroplasty in treatment for thoracolumbar vertebral compression fractures. AB - OBJECTIVE: Osteoporotic vertebral compression fractures (OVCFs) are common diseases in elderly patients and can cause serious thoracolumbar compression fractures. For patients with such fractures, conservative treatment, nail-stick fixation, percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) can be selected as treatment methods. In this study, we aimed to compare the clinical efficacy of PKP and PVP in the treatment of osteoporotic thoracolumbar vertebral compression fractures. PATIENTS AND METHODS: One hundred and sixty-one patients with single-stage osteoporotic vertebral compression fracture in thoracolumbar were enrolled and divided into two groups, percutaneous balloon kyphoplasty (PKP group) and percutaneous vertebroplasty (PVP group). The subjects were selected from patients who were once treated in our hospital from January 2012 to December 2015. There were 91 cases in PKP group and 70 cases in PVP group. The hospitalization time, operation-related index (including blood loss, bone cement injection, surgical time and number of intraoperative fluoroscopy), bedrest time, visual analog pain score (VAS), Cobb's angle, vertebral anterior height, Oswestry Disability Index (ODI) dysfunction index and quality of life score were compared to evaluate the clinical effects of the two treatment methods. RESULTS: There were significant differences in hospitalization time, operation-related index (including blood loss, bone cement injection, operation time, number of intraoperative fluoroscopies) and bed rest time between the two groups. Compared with the patients in PVP group, patients of PKP group had less hospital stay (p<0.001), less time in bed (p<0.05) and less intraoperative blood loss (p<0.05). In addition, the number of times we used intraoperative fluoroscopy was significantly different between the two groups (p<0.001). However, the operation time of PKP group was longer than that of PVP group, and the amount of intraoperative cement injection was more than that of PVP group (p<0.05). After treatment, VAS scores in both groups were dramatically decreased, of which the scores in PKP group were markedly lower than that in PVP group and the difference was statistically significant (p<0.05). The changes of Cobb's angle, the height of anterior vertebral body and ODI scores in PKP group were noticeably better than PVP group (p<0.05). There were 5 cases occurring intraoperative cement leakage in PKP group and 12 cases in PVP group, indicating that the former is relatively better (p<0.001). However, no significant difference was found between the two groups in the occurrence of secondary vertebral fractures at 1 month, 3 months, 6 months and 12 months after treatment (p>0.05). CONCLUSIONS: The clinical effects of both PKP and PVP in the treatment of osteoporotic vertebral compression fractures are good, of which the reductive and analgesic effect of PKP is superior to that of PVP and the former has less leakage of cement, higher safety and fewer complications. PMID- 30004561 TI - Therapeutic effect of transforaminal endoscopic spine system in the treatment of prolapse of lumbar intervertebral disc. AB - OBJECTIVE: To investigate the clinical efficacy and safety of transforaminal endoscopic spine system (TESSYS) in treating the prolapse of lumbar intervertebral disc. PATIENTS AND METHODS: 462 patients with prolapse of lumbar intervertebral disc who were treated in our hospital from June 2012 to May 2016 were enrolled. All patients were randomly divided into 2 groups: the study group (n=231) and the control group (n=231). Patients in the study group received TESSYS, while those in the control group received conventional surgical treatment with posterior approach. Venous blood was collected before the surgery and 6 h, 12 h, 24 h, and 48 h after surgery. C reactive protein (CRP), interleukin-6 (IL 6), creatine phosphokinase (CPK) and white blood cell (WBC) in each patient were measured. The operation time, intraoperative blood loss, length of stay, postoperative ambulation time and complications were compared between the two groups. Clinical efficacy before and after surgery (1st day, 1st month, 3rd month, and 6th month after surgery) was evaluated according to visual analogue scale (VAS), Oswestry disability index (ODI) and modified MacNab criteria. RESULTS: The operation time, intraoperative blood loss, length of stay, postoperative ambulation time and complications of patients in the study group were less than those of the control group (p<0.05). There were no significant differences in VAS score and ODI score on the 1st day before surgery, 1st day, 1st, 3rd, and 6th month after surgery (p>0.05). According to the improved MacNab standard, the excellent and good rate was 87.88% in the study group and 84.85% in the control group, the difference was not statistically significant (p>0.05). There were no significant differences in CRP, IL-6, CPK and WBC between the two groups before surgery (p>0.05). Postoperative levels of CRP, IL-6, CPK, and WBC in study group were better than those in control group, the differences were statistically significant (p<0.05). CONCLUSIONS: TESSYS has the advantages of less bleeding, less traumatic reactions, fewer complications, rapid postoperative recovery, and exact short-term effect in treatment for prolapse of lumbar intervertebral disc. PMID- 30004562 TI - Comparative study between mini-open TLIF via Wiltse's approach and conventional open TLIF in lumbar degenerative diseases. AB - OBJECTIVE: To compare the clinical effects, operation safety and radiation exposure of mini-open TLIF via Wiltse's approach (MOTLIF) and conventional open TLIF (COTLIF) in the treatment of single-segment lumbar degenerative disease via the prospective control study. PATIENTS AND METHODS: A total of 77 patients were enrolled from November 2012 to July 2014, including 42 patients in the mini-open group (MOTLIF) and 35 patients in the COTLIF group. Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) scores before operation, operation time, intraoperative blood loss, postoperative drainage volume, blood transfusion rates, postoperative bedridden time, postoperative hospital stays, intraoperative fluoroscopic time, levels of serum creatine phosphokinase (CPK) before operation, 3 days and 1 week after operation, VAS scores before operation, 3 days and 1 week after operation, and ODI and VAS scores in the last follow-up between the two groups were compared. RESULTS: There were significant differences between the two groups in the operation time, intraoperative blood loss, postoperative drainage, blood transfusion rates, postoperative bedridden time, postoperative hospital stays and intraoperative fluoroscopic time; all indicators in MOTLIF group were superior to those in COTLIF group (p<0.05). There were no significant differences between the two groups in levels of serum CPK before operation and 1 week after operation (p>0.05). However, 3 days after operation, the level of serum CPK in COTLIF group was increased more significantly than that in MOTLIF group (647.4+/ 178.6 vs. 467.4+/-189.4). There were no differences between the two groups in ODI and VAS scores before operation; ODI score in MOTLIF group in the last follow-up was significantly superior to that in COTLIF group (p>0.05). And VAS scores at 3 days and 1 week after operation and the last follow-up in MOTLIF group were superior to those in COTLIF group (p<0.05). CONCLUSIONS: Compared with the conventional open TLIF, mini-open TLIF via Wiltse's approach using the self designed operating apparatus is characterized by the convenient operation, small trauma and quick recovery after operation. At the same time, the radiation exposure is lower and long-term follow-up effect is superior. Its short-term and long-term effects in the treatment of lower lumbar degenerative disease are also superior. PMID- 30004563 TI - Biomechanical strength impact of lateral wall breach on spinal pedicle screw fixation. AB - OBJECTIVE: The purpose of our study was to make a comparison between the fixation strength of optimum placed pedicle screw (OS) and re-directionally accurate placed pedicle screw (RS) after lateral pedicle breach. PATIENTS AND METHODS: A total of 30 fresh lumbar vertebrae (L1-5) were gained from 6 male or female pigs weighing about 100 kg, which were divided into 2 groups according to different ways of pedicle screws placement: OS group (n=30) and RS group (n=30). MTS machine was employed to detect the screw loosening and axial pullout. We examined seating torque, screw-loosening force, the maximal torque and post-loosening axial pullout in each pedicle screw. RESULTS: Maximal insertion torque of OS was (111.6+/-8.4) N*cm and RS was (79.0+/-6.3) N*cm, which indicated a significant difference (Z=3.012, p=0.003). Seating torque of OS and RS were (85.9+/-5.6) N*cm and (60.3+/-4.8) N*cm separately, and the difference was statistically significant (Z=2.799, p=0.006). Screw loosening force of OS and RS were (75.9+/ 7.0) N and (52.4+/-6.3) N respectively, and the difference was statistically significant (Z=2.652, p=0.003). Post-loosening axial pullout force of OS and RS were (328.5+/-11.3) N and (269.1+/-9.6) N separately, demonstrating that the difference was statistically significant (Z=2.865, p=0.004). CONCLUSIONS: RS placement is an alternative for remediation following a lateral wall breach evidenced by significantly decreased seating torque, screw loosening force, the maximal torque and post-loosening axial pullout compared with OS. PMID- 30004564 TI - Efficacy and safety of minimal pedicle screw fixation for thoracolumbar fractures: a meta-analysis. AB - OBJECTIVE: Minimal and open pedicle screw fixation procedures have been widely used in the treatment of thoracolumbar fractures. However, the efficacy and safety of these approaches remain unclear. This meta-analysis was conducted to evaluate perioperative, functional and radiological outcomes of percutaneous versus open pedicle screw fixation for thoracolumbar fractures. MATERIALS AND METHODS: To obtain relevant literature, a systematic search was performed using the MEDLINE, EMBASE, and Cochrane databases. The Cowley criteria were used to evaluate the risk of bias for the included studies. A database that included patient demographic information and perioperative outcomes was established. Summary odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were estimated. Analyses were performed for the two subgroups of Chinese studies and studies from other nations. Publication bias was assessed using the funnel plot method. RESULTS: Eleven comparative observational studies that satisfied our inclusion criteria were identified via a literature search in the MEDLINE, EMBASE, and Cochrane databases. Relative to the open approach, the minimal approach was associated with less blood loss (WMD=-218.10, 95% CI: -266.31 to -169.88, p<0.00001) and shorter operative time (WMD=-15.31, 95% CI: -24.73 to -5.88, p=0.001). Evidence indicated that a significant difference was observed between Chinese studies and other studies with respect to blood loss (p=0.02). We also found that the minimal approach was associated with a lower postoperative visual analog scale (VAS) score (WMD = -1.06, 95% CI: -1.32 to -0.8, p<0.00001) and less correction loss (WMD=-0.59, 95% CI: -1.16 to 0.02, p=0.04) than the traditional open approach. No significant difference between these approaches was found with respect to complication rate (OR 0.78, 95% CI: 0.39 to 1.55, p=0.48). CONCLUSIONS: The evidence indicated that the minimal approach had better functional and radiological outcomes than the open approach. Neither approach was superior with respect to complication rate. Relative to the open approach, the minimal approach might be associated with decreased operative time, less blood loss and a shorter hospital stay. PMID- 30004565 TI - Postoperative functional exercise for patients who underwent percutaneous transforaminal endoscopic discectomy for lumbar disc herniation. AB - OBJECTIVE: To explore the effects of postoperative functional exercise on patients who underwent percutaneous transforaminal endoscopic discectomy for lumbar disc herniation. PATIENTS AND METHODS: From January to May 2011, patients who had a lumbar disc herniation and then underwent percutaneous transforaminal endoscopic discectomy were divided randomly into two groups: the intervention group (n=46) and the control group (n=46). The intervention group conducted early functional exercises of passive and autonomic activities after their operations, while the control group conducted routine functional exercises after their operations. Short-term and long-term curative effects and quality of life were compared; risk factors that might affect the rehabilitation effects on the patients were analyzed using logistic regression. RESULTS: The lumbar curvature, lumbar lordosis index and sacral inclination angle of the intervention group were better than that those same spinal stability factors in the control group six months after their operations (p<0.05). Scores for residual lumbocrural pain, straight leg raising, muscle strength (skin) sensory, nerve reflex and lumbar function of patients in the intervention group were better than those scores of the control group (p<0.05). The scores for physiological function, emotional function, activity and social function, mental health and quality of life of the intervention group were better than those of the control group (p<0.05). After 1 year of follow-up, the total effective rate for the intervention group was 82.6%, significantly higher than the control group, which had a total effective rate of 71.7% (p<0.05). After 3 years of follow-up, the score for the intervention group was 97.8%, significantly higher than the control group, which had an overall average score of 89.1% (p<0.05). Logistic regression analysis showed that the type of disc herniation, whether patients abided by their doctors' advice during treatment and protected their lumbar vertebra during treatment, and their age were all influential factors on patient rehabilitation. CONCLUSIONS: Early functional exercises of passive and autonomic activities can improve the postoperative quality of life of patients with lumbar disc herniation and provides a basis for inclusion in postoperative treatment of lumbar disc herniation. Importance should be placed on factors, such as postoperative exercise, that can improve the curative effect of rehabilitation. PMID- 30004566 TI - Correlation between the methylation of LIVIN gene and the pathogenesis of bone tumor. AB - OBJECTIVE: We investigated the correlation between the methylation of LIVIN gene and the pathogenesis of bone tumor at the molecular level, in order to improve the treatment method and enhance the cure rate of bone tumor. PATIENTS AND METHODS: The expression level of Livin protein was detected using Western blot analysis, and its expressions in control group and patients were detected by immunohistochemistry. The methylation frequency of LIVIN gene was calculated by direct sequencing. Finally, the prognosis of treatment was investigated by follow up. RESULTS: The experiment found that Livin protein was not expressed in normal cells, while its expression rate was about 71.4% in 112 patients. The methylation frequency of LIVIN gene was gradually decreased with the increase of clinical stage, and had no significant relationship with age and sex. The prognosis experiment indicated that the lower the methylation frequency of LIVIN gene was, the shorter the survival time would be. CONCLUSIONS: The methylation of LIVIN gene was closely related to the pathogenesis of bone tumor, which may be one of the important factors to induce the formation of a bone tumor. In addition, the methylation frequency of LIVIN gene could be used as a biomarker for the prognosis of bone tumor treatment. PMID- 30004567 TI - MiR-204 promotes fracture healing via enhancing cell viability of osteoblasts. AB - OBJECTIVE: To investigate the effects and related mechanisms of miR-204 on fracture healing. MATERIALS AND METHODS: Mouse osteoblastic cell line MC3T3-E1 was used in our experiment. Three groups were established to investigate the potential function between miR-204 and osteoblastic cells: miR-NC group (negative control), miR-204 mimics group (MC3T3-E1 cells transfected with miR-204 mimics) and miR-204 mimics + inhibitor group (MC3T3-E1 cells transfected with miR-204 mimics and inhibitor). After incubation, cell viability, activity of caspase-3, and migration ability of MC3T3-E1 cells, were measured. Further, the expression levels of Runt-related transcription factor 2 (RUNX2) and Osterix (OSX) were detected and analyzed. RESULTS: Compared with miR-NC group, the cell viability and migration ability of MC3T3-E1 cells were enhanced while the activity of caspase-3 was respectively mitigated. Besides, the expression level of RUNX2 and OSX was increased by treatment of miR-204 mimics. However, these variations of the indicators were reversed by the intervention using miR-204 inhibitor. CONCLUSIONS: We revealed the promotion effect of miR-204 on fracture healing, indicating that miR-204 could be a potential therapeutic target for the treatment of a fracture. PMID- 30004569 TI - Greater trochanter of the femur (GTF) vs. proximal femoral nail anti-rotation (PFNA) for unstable intertrochanteric femoral fracture. AB - OBJECTIVE: We aim to compare the effects of stem type prosthesis implantation of the greater trochanter of the femur (GTF) and proximal femur nail anti-rotation (PFNA) for treatment of unstable intertrochanteric femoral fracture. PATIENTS AND METHODS: We retrospectively analyzed 108 patients with unstable intertrochanteric femoral fracture, including 61 cases who underwent GTF treatment and 47 cases who underwent PFNA treatment. We compared the operative time, blood loss, clinical healing and bone healing time, partial weight bearing and full weight bearing time, Harris hip score, rate of complications and rate of adverse reactions of implantation materials. RESULTS: Comparing the two groups in terms of operative time and blood loss, the differences were not statistically significant (p>0.05). The clinical and bone healing time in the GTF group were shorter than those in the PFNA group and the differences were statistically significant (p<0.05). The partial and full-weight bearing times in the GTF group were significantly shorter than those in the PFNA group. The Harris scores, one and six months after surgery, were higher than those in the PFNA group and by comparing the scores after 12 and 18 months, the differences were not statistically significant (p>0.05). The rate of complications and rate of adverse reactions of implantation material in the GTF group were lower than those in the PFNA group and the differences were statistically significant (p<0.05). CONCLUSIONS: GTF implantation is more advantageous in functional improvement and in reducing complications compared with PFNA for the treatment of unstable intertrochanteric femoral fracture. PMID- 30004568 TI - CT measurement and analysis of the target vertebral body in elderly patients with uncompressed osteoporotic thoracolumbar fractures. AB - OBJECTIVE: To evaluate the feasibility of determining the target vertebral body (TV) of uncompressed elderly osteoporotic thoracolumbar fractures through measuring Hounsfield unit (HU) value. PATIENTS AND METHODS: Elderly patients with osteoporotic thoracolumbar fractures aged above 65 years old hospitalized from 2015 to 2016 were retrospectively analyzed. The cases whose TV could not be determined by computed tomography (CT) imaging but confirmed by magnetic resonance imaging (MRI) were selected. The mean HU values of the trabecular bone regions of TV and adjacent vertebral body in the multi-detector CT (MDCT) sagittal three-dimensional reconstructed image were measured and compared. At the same time, 60 thoracolumbar adjacent vertebral bodies without fractures were selected from 20 people, and the mean HU value of the trabecular bone region of each vertebra in the MDCT sagittal three-dimensional reconstructed image was measured and compared. RESULTS: There were correlations among the mean HU values of 60 thoracolumbar adjacent vertebral bodies in the 20 people without fractures, and there were no differences in the correlations between middle vertebral body (MV) and upper vertebral body (UV) and between MV and lower vertebral body (LV) compared with the correlation between UV and LV. In the 31 fracture cases, the mean HU values had correlations among TV, UV and LV, there was no difference in the comparison of correlations between TV and UV and between TV and LV, but the correlations between TV and UV and between TV and LV had differences compared with the correlation between UV and LV. CONCLUSIONS: The mean HU value of TV of uncompressed elderly osteoporotic thoracolumbar fractures is increased abnormally compared with that of the adjacent vertebral body, and it is feasible to determine the TV of uncompressed osteoporotic thoracolumbar fractures according to the mean HU value. PMID- 30004570 TI - PFNA vs. DHS helical blade for elderly patients with osteoporotic femoral intertrochanteric fractures. AB - OBJECTIVE: This study sought to compare the effects of proximal femoral nail anti rotation (PFNA) and dynamic hip screw (DHS) helical blade treatments in patients with osteoporotic femoral intertrochanteric fractures. PATIENTS AND METHODS: Eighty elderly osteoporosis patients with femoral intertrochanteric fracture complications admitted to the hospital between January 2013 and December 2014 were selected and divided into control (n=40) and observation (n=40) groups. The control group received DHS internal fixation while the observation group received PFNA treatment. Patients were followed up for 18 months, during which pre- and post-operative duration, Harris hip joint function scale, pain, bone mineral density and calcitonin level, 10 meter walking speed, five-fold-sit-to-stand test time, fracture healing and weight bearing time, and related complications were compared between groups. RESULTS: Operational duration, hemorrhaging and drainage volume were all decreased in the observational group relative to the control group (p<0.05). Pre-operative Harris hip joint function scale scores were not significantly different between the two groups, but were superior in the observation group post-operation (p<0.05). A similar trend was observed for pain degree, bone mineral density and calcitonin levels, 10-meter walking speed, five fold-sit-to-stand test time, and fracture and weight healing time (p<0.05). Complication incidence, such as coxa vara, loose nail, bone nonunion, delayed union of fracture, femoral head necrosis and deep venous thrombosis, etc., in the observation group was significantly lower than in the control group (p<0.05). CONCLUSIONS: PFNA is characterized by minimal invasiveness, shorter time of operation, and accelerated post-operative recovery during the treatment of osteoporotic intertrochanteric fractures, and effectively improved patient bone density post-operatively, thus further promoting joint function recovery and reducing complication incidence. PMID- 30004571 TI - Parent training interventions for parents with intellectual disability. AB - BACKGROUND: Research suggests that the number of intellectually disabled people with children is increasing. Intellectual disabilities do not inevitably cause parenting difficulties, but it may impact on an individual's capacity to parent a child effectively. Children of parents with intellectual disabilities may be at increased risk of neglectful care, which could lead to health, developmental and behavioural problems, or increased risk of intellectual disability. Compared with other parents, those with intellectual disabilities are more likely to be involved in care proceedings. OBJECTIVES: To assess the effectiveness of parent training interventions for parents with intellectual disabilities designed to support parenting, parent-child relations, safe parenting or family environments, or to develop parenting skills. SEARCH METHODS: In July 2017, we searched CENTRAL, Ovid MEDLINE, Embase, CINAHL and six other databases as well as two trials registers. We also searched reference lists of included studies and contacted experts in the field to identify additional ongoing and unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing parent training interventions for parents with intellectual disabilities with treatment as usual or a control group. DATA COLLECTION AND ANALYSIS: We used standardised Cochrane methods. MAIN RESULTS: As of July 2017, we identified four trials with 192 participants that met the review inclusion criteria. Participating parents were mostly mothers (seven fathers were included in two studies), and children's ages ranged from one month to six years and five months.One study was conducted in Australia, one in Canada, one in the Netherlands, and one in the USA. Each studied a different intervention and considered different outcomes. Three interventions were delivered at home, and one in a community venue (e.g. a church). Interventions varied in duration from seven weeks to 12 months. They included a range of practical childcare skills, home safety and developing parents' ability to respond sensitively to their children. Parents in the comparison groups included in the review received treatment as usual and most of these received the index intervention after the study was complete.One study was funded by the Ontario Mental Health Foundation and the Ontario Ministry of Community and Social Services Research Grants Program; one by the Alabama Development Disabilities Council; one by the Best Practice Parenting Education Initiative of the Commonwealth Department of Family and Community Services and the New South Wales Aging and Disability Department; and one by ZonMw, The Netherlands Organisation for Health Research and Development.It was not possible for us to conduct a meta-analysis. The GRADE quality assessment varied from very low to moderate across the studies.Primary outcomesNo study reported on the 'attainment of specific parenting skill targets'.'Safe home practices' and 'understanding of child health': one study (30 parents, very low-quality evidence) reported some improvements in parents' knowledge of life-threatening emergencies, ability to recognise dangers, and identify precautions, in favour of the intervention group. It also found limited, very low-quality evidence that parent training improved parents' ability to understand child health, implement precautions, use medicines safely, recognise child illness and symptoms, and seek medical advice (i.e. visit the doctor). Another study (22 mothers, very low-quality evidence) reported improved attainment of skills related to childcare and safety, in favour of the intervention group.Secondary outcomes'Parent-child interaction': one study (40 mothers, very low-quality evidence) reported improved maternal-child interaction following parent training at 12 months follow-up. Another study (83 mothers, 2 fathers, moderate-quality evidence) reported that inclusion in the intervention group led to a steeper decline in parenting stress related to the child compared to the control group.'Parents' retention of child': one study (22 participants; very low-quality evidence) reported that before joining the programme nine of 11 (82%) families with a previous child had had the child removed from their care by child protection authorities due to maternal maltreatment, compared with only four of 22 (19%) families after participating in the programme (only one of these four mothers had also had a previous child removed).No study reported data on: 'return to independent care of child' or 'lifting of child-related court order'. AUTHORS' CONCLUSIONS: There is some very low-quality evidence that some parents, mainly mothers, with intellectual disabilities are able to provide adequate parenting if they are given appropriate training and support to learn the parenting skills they need. However, there are few studies exploring how interventions might work, for whom and in what circumstances. In particular, there have been few studies that include fathers with intellectual disabilities, or that explore the views of parents themselves.There is a need for larger RCTs of parenting interventions, with longer follow-up, before conclusions can be drawn about the effectiveness of parent training for this group of parents. PMID- 30004573 TI - Multiple robust estimation of marginal structural mean models for unconstrained outcomes. AB - We consider estimation, from longitudinal observational data, of the parameters of marginal structural mean models for unconstrained outcomes. Current proposals include inverse probability of treatment weighted and double robust (DR) estimators. A difficulty with DR estimation is that it requires postulating a sequence of models, one for the each mean of the counterfactual outcome given covariate and treatment history up to each exposure time point. Most natural models for such means are often incompatible. Robins et al., () proposed a parameterization of the likelihood which implies compatible parametric models for such means. Their parameterization has not been exploited to construct DR estimators and one goal of this article is to fill this gap. More importantly, exploiting this parameterization we propose a multiple robust (MR) estimator that confers even more protection against model misspecification than DR estimators. Our methods are easy to implement as they are based on the iterative fit of a sequence of weighted regressions. PMID- 30004572 TI - Antiplatelet and anticoagulant agents for primary prevention of thrombosis in individuals with antiphospholipid antibodies. AB - BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid (aPL) antibodies that have prothrombotic activity. Antiphospholipid antibodies are associated with an increased risk of pregnancy complications (recurrent miscarriage, premature birth, intrauterine growth retardation) and thrombotic events (both arterial and venous). The most common thrombotic events include brain ischaemia (stroke or transient ischaemic attack) and deep vein thrombosis. To diagnose APS, the presence of aPL antibodies in two measurements and at least one thrombotic event or pregnancy complication are required. It is unclear if people with positive aPL antibodies but without any previous thrombotic events should receive primary antithrombotic prophylaxis. OBJECTIVES: To assess the effects of antiplatelet or anticoagulant agents versus placebo or no intervention or other intervention on the development of thrombosis in people with aPL antibodies who have not had a thrombotic event. We did not address obstetric outcomes in this review as these have been thoroughly addressed by other Cochrane Reviews. SEARCH METHODS: We searched the Cochrane Vascular Specialised Register (4 December 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (last search 29 November 2017), MEDLINE Ovid, Embase Ovid, CINAHL, and AMED (searched 4 December 2017), and trials registries (searched 29 November 2017). We also checked reference lists of included studies, systematic reviews, and practice guidelines, and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any antiplatelet or anticoagulant agents, or their combinations, at any dose and mode of delivery with placebo, no intervention, or other intervention. We also included RCTs that compared antiplatelet or anticoagulant agents with each other or that compared two different doses of the same drug. We included studies performed in people of any age and with no history of thrombosis (as defined by APS Sapporo classification criteria or updated Sydney classification criteria), but with aPL antibodies confirmed on at last two separate measurements. The studies included both pregnant women who tested positive for aPL antibodies and had a history of recurrent obstetric complications, as well as non-pregnancy related cases with positive screening for antibodies, in accordance with the criteria mentioned above. DATA COLLECTION AND ANALYSIS: Pairs of authors independently selected studies for inclusion, extracted data, and assessed the risk of bias for the included studies and quality of evidence using GRADE. Any discrepancies were resolved through discussion or by consulting a third review author when necessary. In addition, one review author checked all the extracted numerical data. MAIN RESULTS: We included nine studies involving 1044 randomised participants. The studies took place in several countries and had different funding sources. No study was at low risk of bias in all domains. We classified all included studies as at unclear or high risk of bias in two or more domains. Seven included studies focused mainly on obstetric outcomes. One study included non-pregnancy-related cases, and one study included both pregnancy-related cases and other patients with positive results for aPL antibodies. The remaining studies concerned women with aPL antibodies and a history of pregnancy failure. Four studies compared anticoagulant with or without acetylsalicylic acid (ASA) versus ASA only and observed no clear difference in thrombosis risk (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.25 to 3.77; 4 studies; 493 participants; low-quality evidence). No major bleeding was reported, but minor bleeding risk (nasal bleeding, menorrhagia) was higher in the anticoagulant with ASA group as compared with ASA alone in one study (RR 22.45, 95% CI 1.34 to 374.81; 1 study; 164 participants; low-quality evidence). In one study ASA was compared with placebo, and there were no clear differences in thrombosis (RR 5.21, 95% CI 0.63 to 42.97; 1 study; 98 participants; low-quality evidence) or minor bleeding risk between the groups (RR 3.13, 95% CI 0.34 to 29.01; 1 study; 98 participants; low-quality evidence), and no major bleeding was observed. Two studies compared ASA with low molecular weight heparin (LMWH) versus placebo or intravenous immunoglobulin (IVIG), and no thrombotic events were observed in any of the groups. Moreover, there were no clear differences in the risk of bleeding requiring transfusion (RR 9.0, 95% CI 0.49 to 164.76; 1 study; 180 participants; moderate-quality evidence) or postpartum bleeding (RR 1.30, 95% CI 0.60 to 2.81; 1 study; 180 participants; moderate-quality evidence) between the groups. Two studies compared ASA with high-dose LMWH versus ASA with low-dose LMWF or unfractionated heparin (UFH); no thrombotic events or major bleeding was reported. Mortality and quality of life data were not reported for any of the comparisons. AUTHORS' CONCLUSIONS: There is insufficient evidence to demonstrate benefit or harm of using anticoagulants with or without ASA versus ASA alone in people with aPL antibodies and a history of recurrent pregnancy loss and with no such history; ASA versus placebo in people with aPL antibodies; and ASA with LMWH versus placebo or IVIG, and ASA with high-dose LMWH versus ASA with low-dose LMWH or UFH, in women with aPL antibodies and a history of recurrent pregnancy loss, for the primary prevention of thrombotic events. In a mixed population of people with a history of previous pregnancy loss and without such a history treated with anticoagulant combined with ASA, the incidence of minor bleeding (nasal bleeding, menorrhagia) was increased when compared with ASA alone. Studies that are adequately powered and that focus mainly on thrombotic events are needed to draw any firm conclusions on the primary prevention of thrombotic events in people with antiphospholipid antibodies. PMID- 30004574 TI - A useful design utilizing the information fraction in a group sequential clinical trial with censored survival data. AB - Lan and DeMets () proposed the alpha spending function for group sequential trials to permit the use of unspecified frequencies and timings of interim analyses in the trial design. Regarding a trial with censored time to endpoint, Lan and DeMets () later defined information time at an interim analysis in a maximum duration trial. To compare two survival curves utilizing such a design, information times for group sequential logrank and Wilcoxon-type statistics have been developed by assuming that the survival time follows an exponential distribution or a Weibull distribution without considering the censoring distribution. To better address the practical concerns inherent in clinical trials with survival endpoints, we present a new approach to adequately design a group sequential trial using the Harrington-Fleming () test based on our proposed information fractions by assuming the censoring distribution depends on the patient's accrual time according to various entry distributions and by extending the underlying survival distribution to the generalized gamma distribution. We also determine associated sample sizes, expected number of events and expected stopping time. Two phase III trials of non-small-cell lung cancer originally designed using fixed-sample tests are utilized to illustrate the potential advantages of using a group sequential design with the proposed approach. This enhanced method facilitates the design and analysis of group sequential clinical trials studying survival endpoints by increasing implemental flexibility. PMID- 30004575 TI - Double robust estimation for multiple unordered treatments and clustered observations: Evaluating drug-eluting coronary artery stents. AB - Postmarket comparative effectiveness and safety analyses of therapeutic treatments typically involve large observational cohorts. We propose double robust machine learning estimation techniques for implantable medical device evaluations where there are more than two unordered treatments and patients are clustered in hospitals. This flexible approach also accommodates high-dimensional covariates drawn from clinical databases. The Massachusetts Data Analysis Center percutaneous coronary intervention cohort is used to assess the composite outcome of 10 drug-eluting stents among adults implanted with at least one drug-eluting stent in Massachusetts. We find remarkable discrimination between stents. A simulation study designed to mimic this coronary intervention cohort is also presented and produced similar results. PMID- 30004576 TI - Expression profile of the STAND protein Nwd1 in the developing and mature mouse central nervous system. AB - The orchestrated events required during brain development, as well as the maintenance of adult neuronal plasticity, highly depend on the accurate responses of neuronal cells to various cellular stress or environmental stimuli. Recent studies have defined a previously unrecognized, broad class of multidomain proteins, designated as signal transduction ATPases with numerous domains (STAND), which comprises a large number of proteins, including the apoptotic peptidase activating factor 1 (Apaf1) and nucleotide-binding oligomerization domain-like receptors (NLRs), central players in cell death and innate immune responses, respectively. Although the involvement of STANDs in the central nervous system (CNS) has been postulated in terms of neuronal development and function, it remains largely unclear. Here, we identified Nwd1 (NACHT and WD repeat domain-containing protein 1), as a novel STAND protein, expressed in neural stem/progenitor cells (NSPCs). Structurally, Nwd1 was most analogous to the apoptosis regulator Apaf1, also involved in mitosis and axonal outgrowth regulation in the CNS. Using a specific antibody, we show that, during the embryonic and postnatal period, Nwd1 is expressed in nestin-positive NSPCs in vivo and in vitro, while postnatally it is found in terminally differentiated neurons and blood vessels. At the subcellular level, we demonstrate that Nwd1 is preferentially located in the cytosolic compartment of cultured NSPCs, partially overlapping with cytochrome c. These observations imply that Nwd1 might be involved in the neuronal lineage as a new STAND gene, including having a pro apoptotic or nonapoptotic role, similar to Apaf1. PMID- 30004577 TI - Comparative effectiveness of mailed reminders with and without fecal immunochemical tests for Medicaid beneficiaries at a large county health department: A randomized controlled trial. AB - BACKGROUND: Colorectal cancer (CRC) screening is effective but underused. Screening rates are lower among Medicaid beneficiaries versus other insured populations. No studies have examined mailed fecal immunochemical testing (FIT) based outreach programs for Medicaid beneficiaries. METHODS: In a patient-level randomized controlled trial, a mailed CRC screening reminder plus FIT, sent from an urban health department to Medicaid beneficiaries, was compared with the same reminder without FIT. The reminder group could request FIT. Completed FIT kits were processed by the health department laboratory. Respondents were notified of normal results by mail. Abnormal results were given via phone by a patient navigator who provided counselling and assistance with follow-up care. The primary outcome was FIT return. RESULTS: In all, 2144 beneficiaries at average CRC risk were identified, and there was no evidence of screening with Medicaid claims data. To the reminder+FIT group, 1071 were randomized, and 1073 were randomized to the reminder group; 307 (28.7%) in the reminder+FIT group and 347 (32.3%) in the reminder group were unreachable or ineligible (previous screening). The FIT return rate was significantly higher in the reminder+FIT group than the reminder group (21.1% vs 12.3%; difference, 8.8%; 95% confidence interval, 3.7%-13.9%; P < .01). Eighteen individuals (7.2%) who completed FIT tests had abnormal results, and 15 were eligible for follow-up colonoscopy; 66.7% (n = 10) completed follow-up colonoscopy. CONCLUSIONS: A health department-based, mailed FIT program targeting Medicaid beneficiaries was feasible. Including a FIT kit resulted in greater screening completion than a reminder letter alone. Further research is needed to understand the comparative cost-effectiveness of these interventions. PMID- 30004578 TI - Three- to Four-Year-Old Children Rapidly Adapt Their Predictions and Use Them to Learn Novel Word Meanings. AB - Adults create and update predictions about what speakers will say next. This study asks whether prediction can drive language acquisition, by testing whether 3- to 4-year-old children (n = 45) adapt to recent information when learning novel words. The study used a syntactic context which can precede both nouns and verbs to manipulate children's predictions about what syntactic category will follow. Children for whom the syntactic context predicted verbs were more likely to infer that a novel word appearing in this context referred to an action, than children for whom it predicted nouns. This suggests that children make rapid changes to their predictions, and use this information to learn novel information, supporting the role of prediction in language acquisition. PMID- 30004579 TI - Models of synaptotagmin-1 to trigger Ca2+ -dependent vesicle fusion. AB - Vesicles in neurons and neuroendocrine cells store neurotransmitters and peptide hormones, which are released by vesicle fusion in response to Ca2+ -evoking stimuli. Synaptotagmin-1 (Syt1), a Ca2+ sensor, mediates ultrafast exocytosis in neurons and neuroendocrine cells. After vesicle docking, Syt1 has two main groups of binding partners: anionic phospholipids and the SNARE (soluble N ethylmaleimide-sensitive factor attachment protein receptors) complex. The molecular mechanisms by which Syt1 triggers vesicle fusion remain controversial. This Review introduces and summarizes six molecular models of Syt1: (a) Syt1 triggers SNARE unclamping by displacing complexin, (b) Syt1 clamps SNARE zippering, (c) Syt1 causes membrane curvature, (d) membrane bridging by Syt1, (e) Syt1 is a vesicle-plasma membrane distance regulator, and (f) Syt1 undergoes circular oligomerization. We discuss important conditions to test Syt1 activity in vitro and attempt to illustrate the possible roles of Syt1. PMID- 30004580 TI - IFN-gamma stimulates CpG-induced IL-10 production in B cells via p38 and JNK signalling pathways. AB - The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-gamma, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-gamma on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-gamma inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-gamma on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-gamma profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-gamma and CpG. Our data may represent a novel immunoregulatory role of IFN-gamma in B cells after triggering of TLR9, by stimulating IL-10 production. PMID- 30004582 TI - Neonatal Extracorporeal Life Support: A Review of Nutrition Considerations. AB - Critically ill neonates who require extracorporeal life support have particular nutrition needs. These infants require prescription of aggressive, early nutrition support by knowledge providers. Understanding the unique metabolic demands and nutrition requirements of these fragile patients is paramount, particularly if additional therapies such as aggressive diuretic regimens or continuous renal replacement therapy are used concurrently. Although the American Society for Parenteral and Enteral Nutrition has published guidelines for this population, a review of each nutrition component is warranted because few studies exist specific to this population. Long-term complications in survivors of neonatal extracorporeal life support, particularly in patients with select diagnoses such as congenital diaphragmatic hernia, can be significant and must be recognized and anticipated. This review focuses on recognizing the nutrition needs of neonatal patients requiring extracorporeal life support, appraising the available data to guide selection of an appropriate mode of nutrition delivery, and describing the anticipated long-term nutrition implications of extracorporeal life support provision during the neonatal period. PMID- 30004581 TI - Stereological analysis of the rhesus monkey entorhinal cortex. AB - The entorhinal cortex is a prominent structure of the medial temporal lobe, which plays a pivotal role in the interaction between the neocortex and the hippocampal formation in support of declarative and spatial memory functions. We implemented design-based stereological techniques to provide estimates of neuron numbers, neuronal soma size, and volume of different layers and subdivisions of the entorhinal cortex in adult rhesus monkeys (Macaca mulatta; 5-9 years of age). These data corroborate the structural differences between different subdivisions of the entorhinal cortex, which were shown in previous connectional and cytoarchitectonic studies. In particular, differences in the number of neurons contributing to distinct afferent and efferent hippocampal pathways suggest not only that different types of information may be more or less segregated between caudal and rostral subdivisions, but also, and perhaps most importantly, that the nature of the interaction between the entorhinal cortex and the rest of the hippocampal formation may vary between different subdivisions. We compare our quantitative data in monkeys with previously published stereological data for the rat and human, in order to provide a perspective on the relative development and structural organization of the main subdivisions of the entorhinal cortex in two model organisms widely used to decipher the basic functional principles of the human medial temporal lobe memory system. Altogether, these data provide fundamental information on the number of functional units that comprise the entorhinal-hippocampal circuits and should be considered in order to build realistic models of the medial temporal lobe memory system. PMID- 30004583 TI - Effects of tumor necrosis factor-alpha, interleukin-23 and interleukin-17A inhibitors on bodyweight and body mass index in patients with psoriasis. AB - Treatment with tumor necrosis factor-alpha inhibitors has been reported to cause weight gain in patients with psoriasis; however, limited information is available in terms of the effects of interleukin (IL)-23 and IL-17A inhibitors on bodyweight (BW) in patients with psoriasis. This study aimed to investigate the effects of infliximab, ustekinumab and secukinumab on BW and body mass index (BMI) in patients with psoriasis. We retrospectively examined changes in BW and BMI among patients treated with these biologics at our hospital. At baseline, no significant differences in BW and BMI were observed among the patients treated with infliximab (n = 18), ustekinumab (n = 30) or secukinumab (n = 20). After 7 months of the therapy, significant increases in mean BW (from 71.4 to 74.3 kg) and mean BMI (from 24.7 to 25.7) were observed in the patients treated with infliximab, whereas no significant changes were observed in those treated with ustekinumab (BW, from 70.3 to 70.1 kg; BMI, from 25.4 to 25.3) or secukinumab (BW, from 69.0 to 68.9 kg; BMI, from 25.2 to 25.2). There were no differences in the proportion of the patients who showed 75% or more improvement in the Psoriasis Area and Severity Index among the three groups. These results suggest that infliximab increases BW in the patients with psoriasis, whereas ustekinumab and secukinumab do not affect the BW in these patients. PMID- 30004584 TI - Analysis of gonadotrophin-releasing hormone-1 and kisspeptin neuronal systems in the nonphotoregulated seasonally breeding eastern rock elephant-shrew (Elephantulus myurus). AB - Of the 18 sub-Saharan elephant-shrew species, only eastern rock elephant-shrews reproduce seasonally throughout their distribution, a process seemingly independent of photoperiod. The present study characterizes gonadal status and location/intensity of gonadotrophin-releasing hormone-1 (GnRH-1) and kisspeptin immunoreactivities in this polyovulating species in the breeding and nonbreeding seasons. GnRH-1-immunoreactive (ir) cell bodies are predominantly in the medial septum, diagonal band, and medial preoptic area; processes are generally sparse except in the external median eminence. Kisspeptin-ir cell bodies are detected only within the arcuate nucleus; the density of processes is generally low, except in the septohypothalamic nucleus, ventromedial bed nucleus of the stria terminalis, arcuate nucleus, and internal and external median eminence. Kisspeptin-ir processes are negligible at locations containing GnRH-1-ir cell bodies. The external median eminence is the only site with conspicuously overlapping distributions of the respective immunoreactivities and, accordingly, a putative site for kisspeptin's regulation of GnRH-1 release in this species. In the nonbreeding season in males, there is an increase in the rostral population of GnRH-1-ir cell bodies and density of GnRH-1-ir processes in the median eminence. In both sexes, the breeding season is associated with increased kisspeptin-ir process density in the rostral periventricular area of the third ventricle and arcuate nucleus; at the latter site, this is positively correlated with gonadal mass. Cross-species comparisons lead us to hypothesize differential mechanisms within these peptidergic systems: that increased GnRH-1 immunoreactivity during the nonbreeding season reflects increased accumulation with reduced release; that increased kisspeptin immunoreactivity during the breeding season reflects increased synthesis with increased release. PMID- 30004585 TI - Coexistence of X-linked ichthyosis and Nagashima-type palmoplantar keratosis: A case report. PMID- 30004586 TI - Protein-protein interactions as antibiotic targets: A medicinal chemistry perspective. AB - There are 27 small molecule protein-protein interaction (PPI) modulators in Phase I, II, and III clinical trials targeting cancer, viruses, autoimmune disorders, and as immune suppression agents. Targeting PPIs as an antibiotic drug discovery strategy remains in relative infancy by comparison. However, a number of molecules are in development which target PPI within the replisome, divisome, transcriptome, and translatome are showing significant promise at the medicinal chemistry stage of drug development. Hence, the success of future PPI agents as antibiotics will build upon the techniques and design strategies of these molecules. PMID- 30004588 TI - Dental safety net capacity: An innovative use of existing data to measure dentists' clinical engagement in state Medicaid programs. AB - BACKGROUND: The demand for dentists available for state Medicaid populations has long outpaced the supply of such providers. To help understand the workforce dynamics, this study sought to develop a novel approach to measuring dentists' relative contribution to the dental safety net and, using this new measurement, identify demographic and practice characteristics predictive of dentists' willingness to participate in Indiana's Medicaid program. METHODS: We examined Medicaid claims data for 1,023 Indiana dentists. We fit generalized ordered logistic regression models to measure dentists' level of clinical engagement with Medicaid. Using a partial proportional odds specification model, we estimated proportional adjusted odds ratios for covariates and separate estimates for each contrast of nonproportional covariates. RESULTS: Though 75% of Medicaid-enrolled dentists were active providers, only 27% of them had 800 or more claims during fiscal year 2015. As has been shown in previous studies, our findings from the proportional odds model reinforced certain demographic and practice characteristics to be predictive of dentists' participation in state Medicaid programs. CONCLUSIONS: In addition to confirming predictive factors for Medicaid enrollment, this study validated the clinical engagement measure as a reliable method to assess the level of Medicaid participation. Prior studies have been limited by self-reported data and variations in Medicaid claims reporting. PRACTICAL IMPLICATIONS: Our findings have implications for state Medicaid policymakers by enabling access to data regarding dental providers' level of participation in Medicaid in addition to identifying factors predictive of such participation. This information will inform Medicaid program plans and provider recruitment efforts. PMID- 30004587 TI - Long-term histological changes in the macaque primary visual cortex and the lateral geniculate nucleus after monocular deprivation produced by early restricted retinal lesions and diffuser induced form deprivation. AB - Ocular dominance (OD) plasticity has been extensively studied in various mammalian species. While robust OD shifts are typically observed after monocular eyelid suture, relatively poor OD plasticity is observed for early eye removal or after tetrodotoxin (TTX) injections in mice. Hence, abnormal binocular signal interactions in the visual cortex may play a critical role in eliciting OD plasticity. Here, we examined the histochemical changes in the lateral geniculate nucleus (LGN) and the striate cortex (V1) in macaque monkeys that experienced two different monocular sensory deprivations in the same eye beginning at 3 weeks of age: restricted laser lesions in macular or peripheral retina and form deprivation induced by wearing a diffuser lens during the critical period. The monkeys were subsequently reared for 5 years under a normal visual environment. In the LGN, atrophy of neurons and a dramatic increase of GFAP expression were observed in the lesion projection zones (LPZs). In V1, although no obvious shift of the LPZ border was found, the ocular dominance columns (ODCs) for the lesioned eye shrunk and those for the intact eye expanded over the entirety of V1. This ODC size change was larger in the area outside the LPZ and in the region inside the LPZ near the border compared to that in the LPZ center. These developmental changes may reflect abnormal binocular interactions in V1 during early infancy. Our observations provide insights into the nature of degenerative and plastic changes in the LGN and V1 following early chronic monocular sensory deprivations. PMID- 30004590 TI - GABA immunostaining in the central complex of dicondylian insects. AB - The central complex is a group of midline-crossing neuropils in the insect brain involved in head direction coding, sky compass navigation, and spatial visual memory. To compare the neuroarchitecture and neurochemistry of the central complex in insects that differ in locomotion, ways of orientation, time of activity (diurnal, nocturnal), and evolutionary history, we studied the distribution of gamma-aminobutyric acid (GABA) immunostaining in the central complex of 29 species, ranging from Zygentoma to Diptera. In all species, the lower division of the central body was densely innervated by GABA-immunoreactive tangential neurons. These neurons had additional arborizations in the bulb, a distinct region of synaptic complexes in the lateral complex, and somata in a cell cluster mediodorsally to the antennal lobe. Differences in the appearance of GABA immunostaining in the lower division of the central body corresponded to differences in neuropil architecture, such as transformation of the lower division into a toroid in certain Diptera and Heteroptera. In nearly all species two additional systems of tangential neuron of the upper division of the central body were GABA-immunoreactive. One of these systems diffusely invaded a superior layer, while the second system showed fan-like projections in an inferior layer. Sparse immunostaining in the protocerebral bridge was detected in cockroaches, a cricket, and two hemipteran species. The data show that three systems of GABA immunoreactive tangential neurons of the central body are highly conserved and suggest that the layered organization of the upper division of the central body is, likewise, largely maintained from basal to advanced species. PMID- 30004589 TI - Cerebellar modules in the olivo-cortico-nuclear loop demarcated by pcdh10 expression in the adult mouse. AB - Topographic connection between corresponding compartments of the cerebellar cortex, cerebellar nuclei, and inferior olive form parallel modules, which are essential for the cerebellar function. Compared to the striped cortical compartmentalization which are labeled by molecular markers, such as aldolase C (Aldoc) or zebrin II, the presumed corresponding organization of the cerebellar nuclei and inferior olivary nucleus has not been much clarified. We focused on the expression pattern of pcdh10 gene coding cell adhesion molecule protocadherin 10 (Pcdh10) in adult mice. In the cortex, pcdh10 was strongly expressed in (a) Aldoc-positive vermal stripes a+//2+ in lobules VI-VII, (b) paravermal narrow stripes c+, d+, 4b+, 5a+ in crus I and neighboring lobules, and (c) paravermal stripes 4+//5+ across all lobules from lobule III to paraflocculus. In the cerebellar nuclei, pcdh10 was expressed strongly in the caudal part of the medial nucleus and the lateral part of the posterior interposed nucleus which project less to the medulla or to the red nucleus than to other metencephalic, mesencephalic, and diencephalic areas. In the inferior olive, pcdh10 was expressed strongly in the rostral and medioventrocaudal parts of the medial accessory olive which has connection with the mesencephalic areas rather than the spinal cord. Olivocerebellar and corticonuclear axonal labeling confirmed that the three cortical pcdh10-positive areas were topographically connected to the nuclear and olivary pcdh10-positive areas, demonstrating their coincidence with modular structures in the olivo-cortico-nuclear loop. We speculate that some of these modules are functionally involved in various nonsomatosensorimotor tasks via their afferent and efferent connections. PMID- 30004591 TI - Patients with urticaria are at a higher risk of anaphylaxis: A nationwide population-based retrospective cohort study in Taiwan. AB - The clinical features of urticaria and anaphylaxis are similar, and they share common causal immune-mediated pathways. We aimed to investigate the risk of anaphylaxis among patients with urticaria. A 12-year population-based retrospective cohort study was conducted. Investigated subjects were identified from the Taiwan National Health Insurance Research Database by the International Classification of Disease, Ninth Revision, Clinical Modification. We included 126 031 subjects with newly diagnosed urticaria and 252 062 matched controls between 2000 and 2013. Risk of anaphylaxis among patients with urticaria was calculated by calculating adjusted hazards ratios (HR) after matching for confounding comorbidities. Urticaria was more common in women than it was in men (58% vs 42%), with a peak onset age of 20-40 years. The number of comorbidities including asthma, allergic rhinitis, herpes zoster, hepatitis B and C, rheumatoid arthritis and gout were higher in patients with urticaria than that in age- and sex-matched controls. The crude HR for anaphylaxis among urticaria subjects was 2.883 (95% confidence interval [CI], 2.787-2.982; P < 0.001). After adjustment for potential confounders which have been proposed to increase the risk of anaphylaxis, patients with urticaria were found to be at a significantly high risk of anaphylaxis with an adjusted HR of 2.529 (95% CI, 2.442-2.619; P < 0.001). We conclude that the incidence rate of anaphylaxis is significantly high in patients with urticaria in Taiwan. PMID- 30004592 TI - Smoking in pregnancy and bed sharing, a fatal combination. PMID- 30004593 TI - Serum interleukin-34 levels in patients with systemic sclerosis: Clinical association with interstitial lung disease. AB - Interleukin (IL)-34 is a hematopoietic cytokine promoting proliferation and differentiation of macrophages. Because abnormal activation of macrophages is involved in the development of systemic sclerosis (SSc), we investigated serum IL 34 levels in patients with SSc. Serum IL-34 levels were significantly increased in diffuse cutaneous SSc compared with limited cutaneous SSc and healthy controls, while there were no significant differences between limited cutaneous SSc and healthy controls. In addition, SSc patients with increased serum IL-34 levels more often had interstitial lung disease (ILD) than those with normal levels. Moreover, in SSc patients, serum IL-34 levels negatively correlated with the percentage of predicted vital capacity, while they positively correlated with ground-glass opacity score and fibrotic score on chest computed tomography. Collectively, increased serum IL-34 levels were associated with greater frequency and severity of ILD in SSc patients. Serum IL-34 levels may be a useful serological marker for SSc-associated ILD. PMID- 30004594 TI - Effect of Home Enteral Nutrition on Diabetes and Its Management. AB - BACKGROUND: Diabetes mellitus (DM) is estimated to affect 9% of Americans and is associated with significant morbidity, mortality, and increased healthcare costs. METHODS: A retrospective review of a home enteral nutrition (HEN) database of patients seen between March 1, 2004, and April 31, 2014, at our institution was conducted to identify HEN patients who had a diagnosis of DM or were diagnosed within the acute period (4 months) of starting HEN therapy. RESULTS: 174 (3.7%) of 4682 patients in the HEN program had DM. HEN was provided through a gastrostomy tube in 82 patients and through a jejunostomy tube in 92 patients. At 3 months, data were available for 42 gastrostomy patients; 44% had a change in DM management, with 60% undergoing a change to insulin. Similarly, 34 patients with jejunostomy had data available, with 41% undergoing change in medication and 93% being changed to insulin therapy. For patients with available glycated hemogloblin values, at 3 months the gastrostomy patients noted a decrease of 0.5% (7.3% +/- 1.1% to 6.8% +/- 0.7%, not significant) and the jejunostomy patients noted a decrease of 0.4% (6.9% +/- 0.9% to 6.5% +/- 1.1%, P = .06). CONCLUSIONS: Overall, our results suggest that closer follow-up and laboratory assessment are necessary for management of HEN patients with DM. In those with data available, glycemic control can be maintained in patients receiving HEN with appropriate adjustment of DM management and focus on ensuring that patients are not overfed. PMID- 30004595 TI - Accidental allergic reactions in food allergy: Causes related to products and patient's management. PMID- 30004596 TI - SrP3 N5 NH: A Framework-Type Imidonitridophosphate Featuring Structure-Directing Hydrogen Bonds. AB - Nitridophosphates and imidonitridophosphates show intriguing structural diversity, including unprecedented structure types. Highly condensed strontium imidonitridophosphate SrP3 N5 NH has been synthesized at 8 GPa and 1100 degrees C using a high-pressure high-temperature approach starting from stoichiometric amounts of Sr(N3 )2 , P3 N5 and NH4 Cl. Herein, NH4 Cl was used as a hydrogen source and as a precursor for in situ formation of SrCl2 , which acts as mineralizer and facilitates growth of single-crystals with a diameter of <=30 MUm. SrP3 N5 NH (P21 /c (no. 14), a=5.01774(2), b=8.16912(4), c=12.70193(5) A, beta=101.7848(3) degrees , Z=4) adopts an unprecedented network structure, represented by the point symbol (3.4.5.6.72 )(3.4.5.72 .8)(3.6.73 .8). This unique three nodal P/N(H) network is stabilized by moderately strong hydrogen bonds causing a structure-directing effect, which has not yet been reported for imidonitridophosphates. PMID- 30004597 TI - The clinical effects of l-arginine and asymmetric dimethylarginine: implications for treatment in secondary Raynaud's phenomenon. AB - Secondary Raynaud's phenomenon (RP) is often the sentinel clinical finding in systemic sclerosis and may precede systemic disease by several years. Altered nitric oxide metabolism plays a critical role in both fibrosis and severe secondary RP phenotypes in these patients. Increased flux through inducible nitric oxide synthase (iNOS) drives cutaneous fibrosis. Failure of flux through endothelial nitric oxide synthase (eNOS) contributes to increased vasoconstriction and decreased vasorelaxation. The underproduction of nitric oxide by eNOS is in part due to increased levels of asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase. The inhibitory effects of increased ADMA levels may be counteracted increasing serum l-arginine, which is often an effective treatment strategy in these patients. As such, l-arginine-based therapies should be considered in managing secondary RP, particularly given their favourable safety and tolerability profile. While there is no established dosing regimen, studies of oral l-arginine in secondary RP suggest that divided dosing may begin at 1-2 g/day and may be titrated up to 10 g/day. Conversely, primary RP is not associated with increased ADMA production which likely accounts for the failure of l-arginine trials to show benefit in primary RP. PMID- 30004599 TI - Lysozyme, a new allergen in donkey's milk. PMID- 30004598 TI - Combined use of eDNA metabarcoding and video surveillance for the assessment of fish biodiversity. AB - Monitoring communities of fish is important for the management and sustainability of fisheries and marine ecosystems. Baited remote underwater video systems (BRUVs) are among the most effective nondestructive techniques for sampling bony fishes and elasmobranchs (sharks, rays, and skates). However, BRUVs sample visually conspicuous biota; hence, some taxa are undersampled or not recorded at all. We compared the diversity of fishes characterized using BRUVs with diversity detected via environmental DNA (eDNA) metabarcoding. We sampled seawater and captured BRUVs imagery at 48 locales that included reef and seagrass beds inside and outside a marine reserve (Jurien Bay in Western Australia). Eighty-two fish genera from 13 orders were detected, and the community of fishes described using eDNA and BRUVs combined yielded >30% more generic richness than when either method was used alone. Rather than detecting a homogenous genetic signature, the eDNA assemblages mirrored the BRUVs' spatial explicitness; differentiation of taxa between seagrass and reef was clear despite the relatively small geographical scale of the study site (~35 km2 ). Taxa that were not sampled by one approach, due to limitations and biases intrinsic to the method, were often detected with the other. Therefore, using BRUVs and eDNA in concert provides a more holistic view of vertebrate marine communities across habitats. Both methods are noninvasive, which enhances their potential for widespread implementation in the surveillance of marine ecosystems. PMID- 30004600 TI - Neutral, Cationic and Hydride-substituted Siloxygermylenes. AB - The introduction of the labile trimethylsiloxy group to GeII centers in the presence of an N-heterocyclic carbene donor is reported. The new complex IPr?GeCl(OSiMe3 ) (IPr=[(HCNDipp)2 C:]; Dipp=2,6-iPr2 C6 H3 ) was readily converted into the structurally unique GeII siloxy(hydrido)germylene IPr?GeH(OSiMe3 )?BH3 by treatment with lithium borohydride. Additionally, the reactive siloxygermylene cation [IPr?Ge(OSiMe3 )]+ was synthesized and clean oxidative addition of CH2 Cl2 was demonstrated. The two-coordinate [IPr?Ge(OSiMe3 )]+ cation also promoted the catalytic hydroborylation of sterically hindered ketones under mild conditions, with enhanced reactivity stemming from an open coordination site at Ge. PMID- 30004601 TI - Adipose-Derived Stem Cells of Blind Mole Rat Spalax Exhibit Reduced Homing Ability: Molecular Mechanisms and Potential Role in Cancer Suppression. AB - Adipose-derived stem cells (ADSCs) are recruited by cancer cells from the adjacent tissue, and they become an integral part of the tumor microenvironment. Here, we report that ADSCs from the long-living, tumor-resistant blind mole rat, Spalax, have a low ability to migrate toward cancer cells compared with cells from its Rattus counterpart. Tracking 5-ethynyl-2'-deoxyuridine (EdU)-labeled ADSCs, introduced to tumor-bearing nude mice, toward the xenografts, we found that rat ADSCs intensively migrated and penetrated the tumors, whereas only a few Spalax ADSCs reached the tumors. Moreover, rat ADSCs, but not Spalax ADSCs, acquired endothelial-like phenotype and incorporated in the intratumoral reticular structure resembling a vasculature. Likewise, endothelial-like cells differentiated from Spalax and rat ADSCs could form capillary-like structures; however, the tube densities were higher in rat-derived cells. Using time-lapse microscopy, in vitro wound-healing, and transwell migration assays, we demonstrated the impaired motility and low polarization ability of Spalax ADSCs. To assess whether the phosphorylated status of myosin light chain (MLC) is involved in the decreased motility of Spalax ADSCs, we inhibited MLC phosphorylation by blocking of Rho-kinase (ROCK). Inhibition of ROCK resulted in the suppression of MLC phosphorylation, acquisition of actin polarization, and activation of motility and migration of Spalax ADSCs. We propose that reduced ADSCs migration to cancer and poor intratumoral angiogenesis play a role in Spalax's cancer resistance. Learning more about the molecular strategy of noncancerous cells in Spalax to resist oncogenic stimuli and maintain a nonpermissive tumor milieu may lead us to developing new cancer-preventive strategy in humans. Stem Cells 2018;36:1630-1642. PMID- 30004602 TI - Intrinsic connectivity network dynamics in PTSD during amygdala downregulation using real-time fMRI neurofeedback: A preliminary analysis. AB - Posttraumatic stress disorder (PTSD) has been associated with a disturbance in neural intrinsic connectivity networks (ICN), including the central executive network (CEN), default mode network (DMN), and salience network (SN). Here, we conducted a preliminary investigation examining potential changes in ICN recruitment as a function of real-time fMRI neurofeedback (rt-fMRI-NFB) during symptom provocation where we targeted the downregulation of neural response within the amygdala-a key region-of-interest in PTSD neuropathophysiology. Patients with PTSD (n = 14) completed three sessions of rt-fMRI-NFB with the following conditions: (a) regulate: decrease activation in the amygdala while processing personalized trauma words; (b) view: process trauma words while not attempting to regulate the amygdala; and (c) neutral: process neutral words. We found that recruitment of the left CEN increased over neurofeedback runs during the regulate condition, a finding supported by increased dlPFC activation during the regulate as compared to the view condition. In contrast, DMN task-negative recruitment was stable during neurofeedback runs, albeit was the highest during view conditions and increased (normalized) during rest periods. Critically, SN recruitment was high for both the regulate and the view conditions, a finding potentially indicative of CEN modality switching, adaptive learning, and increasing threat/defense processing in PTSD. In conclusion, this study provides provocative, preliminary evidence that downregulation of the amygdala using rt fMRI-NFB in PTSD is associated with dynamic changes in ICN, an effect similar to those observed using EEG modalities of neurofeedback. PMID- 30004603 TI - Multimodal cortical and hippocampal prediction of episodic-memory plasticity in young and older adults. AB - Episodic memory can be trained in both early and late adulthood, but there is considerable variation in cognitive improvement across individuals. Which brain characteristics make some individuals benefit more than others? We used a multimodal approach to investigate whether volumetric magnetic resonance imaging (MRI) and resting-state functional MRI characteristics of the cortex and hippocampus, brain regions involved in episodic-memory function, were predictive of cognitive improvement after memory training. We hypothesized that these brain characteristics would differentially predict memory improvement in young and older adults, given the vulnerability of cortical regions as well as the hippocampus to healthy aging. Following structural and resting-state activity magnetic resonance scans, 50 young and 76 older participants completed 10 weeks of strategic episodic-memory training. Both age groups improved their memory performance, but the young adults more so than the older. Vertex-wise analyses of cortical volume showed no significant relation to memory benefit. When analyzing the two age groups separately, hippocampal volume was predictive of memory improvement in the group of older participants only. In this age group, the lower resting-state activity of the hippocampus was also predictive of memory improvement. Both volumetric and resting-state characteristics of the hippocampus explained unique variance of the improvement in the older participants suggesting that a multimodal imaging approach is valuable for the understanding of mechanisms underlying memory plasticity in aging. PMID- 30004604 TI - Structure-function multi-scale connectomics reveals a major role of the fronto striato-thalamic circuit in brain aging. AB - Physiological aging affects brain structure and function impacting morphology, connectivity, and performance. However, whether some brain connectivity metrics might reflect the age of an individual is still unclear. Here, we collected brain images from healthy participants (N = 155) ranging from 10 to 80 years to build functional (resting state) and structural (tractography) connectivity matrices, both data sets combined to obtain different connectivity features. We then calculated the brain connectome age-an age estimator resulting from a multi-scale methodology applied to the structure-function connectome, and compared it to the chronological age (ChA). Our results were twofold. First, we found that aging widely affects the connectivity of multiple structures, such as anterior cingulate and medial prefrontal cortices, basal ganglia, thalamus, insula, cingulum, hippocampus, parahippocampus, occipital cortex, fusiform, precuneus, and temporal pole. Second, we found that the connectivity between basal ganglia and thalamus to frontal areas, also known as the fronto-striato-thalamic (FST) circuit, makes the major contribution to age estimation. In conclusion, our results highlight the key role played by the FST circuit in the process of healthy aging. Notably, the same methodology can be generally applied to identify the structural-functional connectivity patterns correlating to other biomarkers than ChA. PMID- 30004605 TI - Repurposing the Cord Blood Bank for Haplobanking of HLA-Homozygous iPSCs and Their Usefulness to Multiple Populations. AB - Although autologous induced pluripotent stem cells (iPSCs) can potentially be useful for treating patients without immune rejection, in reality it will be extremely expensive and labor-intensive to make iPSCs to realize personalized medicine. An alternative approach is to make use of human leukocyte antigen (HLA) haplotype homozygous donors to provide HLA matched iPSC products to significant numbers of patients. To establish a haplobank of iPSCs, we repurposed the cord blood bank by screening ~4,200 high resolution HLA typed cord blood samples, and selected those homozygous for the 10 most frequent HLA-A,-B,-DRB1 haplotypes in the Korean population. Following the generation of 10 iPSC lines, we conducted a comprehensive characterization, including morphology, expression of pluripotent markers and cell surface antigens, three-germ layer formation, vector clearance, mycoplasma/microbiological/viral contamination, endotoxin, and short tandem repeat (STR) assays. Various genomic analyses using microarray and comparative genomic hybridization (aCGH)-based single nucleotide polymorphism (SNP) and copy number variation (CNV) were also conducted. These 10 HLA-homozygous iPSC lines match 41.07% of the Korean population. Comparative analysis of HLA population data shows that they are also of use in other Asian populations, such as Japan, with some limited utility in ethnically diverse populations, such as the UK. Taken together, the generation of the 10 most frequent Korean HLA-homozygous iPSC lines serves as a useful pointer for the development of optimal methods for iPSC generation and quality control and indicates the benefits and limitations of collaborative HLA driven selection of donors for future stocking of worldwide iPSC haplobanks. Stem Cells 2018;36:1552-1566. PMID- 30004606 TI - The Adaptive Remodeling of Stem Cell Niche in Stimulated Bone Marrow Counteracts the Leukemic Niche. AB - Accumulating studies have shown the cellular nature of hematopoietic stem cell (HSC) niche in bone marrow (BM) and their degenerative changes under leukemic conditions. However, the dynamic adaptation of niche cells to changes in physiological stimulatory signals remains largely uncharacterized. Here, we have established a niche stimulation model induced by 5-fluorouracil. This model reveals a rapid and reversible conversion of mesenchymal cells into niche-like stromal cells, which exhibit a platelet-derived growth factor receptor-alpha+ /leptin receptor+ (PL) phenotype. These cells selectively induce the niche signaling molecule, Jagged-1, but not CXCL12, to initiate a stimulation-induced regeneration of HSCs in a Jagged-1 dependent manner. Conversion of mesenchymal cells into niche-like cells occurred independently of mitotic activation. The conversion was accompanied by the acquisition of primitive mesenchymal cell characteristics, including the rapid induction of stage specific embryonic antigen-3 and the acquisition of clonogenic potential. The stimulation-induced remodeling of the BM niche resulted in a positive stimulatory effect on the regeneration of normal HSC, but exerted inhibitory effects on leukemic cells, leading to a competitive advantage for normal HSCs in the BM niche and prolonged survival of mice engrafted with leukemic cells. Thus, the reactive conversion of mesenchymal stroma into niche-like cells reveals the adaptive changes of the BM microenvironment to stimuli, and provides insight on the remodeling of niche toward pronormal/antileukemic microenvironment, which can counteract the progressive proleukemic changes driven by the leukemic niche. Our study raises the potential for antileukemic niche targeting therapy. Stem Cells 2018;36:1617 1629. PMID- 30004607 TI - Myeloid Disease Mutations of Splicing Factor SRSF2 Cause G2-M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells. AB - Myeloid malignancies, including myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia, are characterized by abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). Reports on analysis of bone marrow samples from patients have revealed a high incidence of mutations in splicing factors in early stem and progenitor cell clones, but the mechanisms underlying transformation of HSPCs harboring these mutations remain unknown. Using ex vivo cultures of primary human CD34+ cells as a model, we find that mutations in splicing factors SRSF2 and U2AF1 exert distinct effects on proliferation and differentiation of HSPCs. SRSF2 mutations cause a dramatic inhibition of proliferation via a G2-M phase arrest and induction of apoptosis. U2AF1 mutations, conversely, do not significantly affect proliferation. Mutations in both SRSF2 and U2AF1 cause abnormal differentiation by skewing granulo monocytic differentiation toward monocytes but elicit diverse effects on megakaryo-erythroid differentiation. The SRSF2 mutations skew differentiation toward megakaryocytes whereas U2AF1 mutations cause an increase in the erythroid cell populations. These distinct functional consequences indicate that SRSF2 and U2AF1 mutations have cell context-specific effects and that the generation of myeloid disease phenotype by mutations in the genes coding these two proteins likely involves different intracellular mechanisms. Stem Cells 2018;36:1663-1675. PMID- 30004608 TI - Reproductive isolation between Salvia elegans and S. fulgens, two hummingbird pollinated sympatric sages. AB - The integrity of species in sympatric contact sites is dependent on the existence of reproductive isolating mechanisms, which restrict gene flow between them. However, we know little about the mechanisms that enable the coexistence of species with similar floral morphologies. Here, we evaluated several reproductive isolation barriers between Salvia elegans and S. fulgens, two sympatric sages with a similar ornithophilous floral syndrome, offering nectar as the main reward. Over 3 years, we evaluated broad-scale geographic isolation, floral phenologies and floral visitors as pre-pollination barriers, and fruit set, seed number and seed germination as post-pollination barriers. We found considerable geographic isolation and significant altitudinal differences between the two sages. The flowering period of both sages always overlapped extensively during the 3 years of this study, but hummingbirds were highly specific, visiting one or the other Salvia species and showing aggressive territorial behaviour. Interspecific experimental crosses revealed that hybrid seeds might be formed although strong asymmetric barriers were found depending on the species acting as the maternal donor. Despite the low level of flowering asynchrony, reproductive isolation was remarkably high in the two sages. Geographic isolation and pollinator fidelity were the main factors responsible for maintaining species integrity. Despite an extensive review, we found very few studies quantifying the efficiency of isolation barriers in Neotropical plants or even the importance of hummingbirds as pollinators. PMID- 30004609 TI - Delivery of sevoflurane using a neonatal ventilator. AB - BACKGROUND: Most anesthetic ventilators are designed to cope with a wide range of patient sizes and may lack precision at the lowest end of the minute volume scale. Neonatal intensive care ventilators on the other hand are designed specifically for this patient group, but are not able to deliver volatile anesthesia. AIMS: We aimed to adapt the neonatal ventilator currently in use in our institution to deliver sevoflurane by incorporating a vaporizer and a scavenging system. METHODS: We used a Diamedica draw-over vaporizer incorporated into the ventilator circuit and a custom designed open interface scavenging system. A number of safety measures are described to ensure that this equipment is correctly inserted into the circuit. RESULTS: Bench testing revealed that the vaporizer output is linear and stable within the circuit flow range 4-8 L/min in all modes except high frequency oscillation where concentrations are not predictable. The scavenging system was found to be effective and did not affect volumes, pressures or waveforms when ventilating a test lung over a wide range of flows and pressures. This remained the case over the full range of scavenger flow adjustment. CONCLUSION: The addition of a Diamedica vaporizer to a Fabian neonatal ventilator was shown in bench testing to provide stable, linear vapor concentrations without compromise of ventilator function. The system should not be used in high frequency oscillation mode because concentrations will exceed those expected and will not maintain a linear relationship with the vaporizer setting. PMID- 30004610 TI - Acute idiopathic optic neuritis: not always benign. AB - BACKGROUND AND PURPOSE: Few recent data are available concerning idiopathic optic neuritis (ON). We aimed to describe a large cohort of patients with idiopathic ON. We compared this cohort with patients with ON related to myelin oligodendrocyte glycoprotein (MOG) or ON related to aquaporin-4 (AQP4) antibodies. METHODS: This was a monocentric retrospective observational study. Inclusion criteria for idiopathic ON were as follows: age >= 16 years, follow-up of at least 2 years, negative for antibodies against MOG and AQP4 immunoglobulin G, and no magnetic resonance imaging (MRI) lesions suggestive of demyelination (two brain MRI scans, one at baseline and one during follow-up, and one spinal cord MRI scan). RESULTS: Among 23 patients with idiopathic ON (female, 82.6%; median age, 36 years; median follow-up time, 41.4 months), 56.5% had recurrent ON (median time to a second ON episode, 6 months). The final visual acuity in this group (median, 0; mean, 0.43; range, 0-3) was similar to that in the AQP4 group (n = 18; P-value after Bonferroni correction = 0.936) but worse than that in the MOG group (n = 25; P-value after Bonferroni correction = 0.019). At the last evaluation, visual acuity levels were <=0.5 and <0.2, respectively, in 36.8% and 21% of the idiopathic ON group, 58.3% and 26.7% of the AQP4 group, and 0% and 0% of the MOG group. CONCLUSION: The recovery of visual acuity among patients with idiopathic ON was poor, similar to that observed in the AQP4 group. PMID- 30004611 TI - Deficits in emotion recognition are associated with depressive symptoms in youth with disruptive mood dysregulation disorder. AB - BACKGROUND: Although severe irritability is a predictor of future depression according to recent meta-analytic evidence, other mechanisms for this developmental transition remain unclear. In this study, we test whether deficits in emotion recognition may partially explain this specific association in youth with severe irritability, defined as disruptive mood dysregulation disorder (DMDD). METHODS: Participants aged 8-20 years (M = 13.3, SD = 2.8) included youth with DMDD, split by low depressive (DMDD/LD; n = 52) and high depressive (DMDD/HD; n = 25) symptoms, and healthy controls (HC; n = 39). A standardized computer task assessed emotion recognition of faces and voices of adults and children expressing happiness, fear, sadness, and anger. A Group (3) * Emotion (4) * Actor (2) * Modality (2) repeated measures analysis of covariance examined the number of errors and misidentification of emotions. Linear regression was then used to assess whether deficits in emotion recognition were predictive of depressive symptoms at a 1 year follow-up. RESULTS: DMDD/HD youth were more likely to interpret happy stimuli as angry and fearful compared to DMDD/LD (happy as angry: p = 0.018; happy as fearful: p = 0.008) and HC (happy as angry: p = 0.014; happy as fearful: p = 0.024). In youth with DMDD, the misidentification of happy stimuli as fearful was associated with higher depressive symptoms at follow up (beta = 0.43, p = 0.017), independent of baseline depressive and irritability symptoms. CONCLUSIONS: Deficits in emotion recognition are associated, cross sectionally and longitudinally, with depressive symptoms in youth with severe irritability. Future studies should examine the neural correlates that contribute to these associations. PMID- 30004612 TI - Human-Induced Pluripotent Stem Cells Generate Light Responsive Retinal Organoids with Variable and Nutrient-Dependent Efficiency. AB - The availability of in vitro models of the human retina in which to perform pharmacological and toxicological studies is an urgent and unmet need. An essential step for developing in vitro models of human retina is the ability to generate laminated, physiologically functional, and light-responsive retinal organoids from renewable and patient specific sources. We investigated five different human-induced pluripotent stem cell (iPSC) lines and showed a significant variability in their efficiency to generate retinal organoids. Despite this variability, by month 5 of differentiation, all iPSC-derived retinal organoids were able to generate light responses, albeit immature, comparable to the earliest light responses recorded from the neonatal mouse retina, close to the period of eye opening. All iPSC-derived retinal organoids exhibited at this time a well-formed outer nuclear like layer containing photoreceptors with inner segments, connecting cilium, and outer like segments. The differentiation process was highly dependent on seeding cell density and nutrient availability determined by factorial experimental design. We adopted the differentiation protocol to a multiwell plate format, which enhanced generation of retinal organoids with retinal-pigmented epithelium (RPE) and improved ganglion cell development and the response to physiological stimuli. We tested the response of iPSC-derived retinal organoids to Moxifloxacin and showed that similarly to in vivo adult mouse retina, the primary affected cell types were photoreceptors. Together our data indicate that light responsive retinal organoids derived from carefully selected and differentiation efficient iPSC lines can be generated at the scale needed for pharmacology and drug screening purposes. Stem Cells 2018;36:1535-1551. PMID- 30004613 TI - Long-term outcomes from prophylactic or episodic treatment of haemophilia A: A systematic review. AB - INTRODUCTION: Evaluating treatment success in patients with haemophilia A (HA) remains a vigorous debate, especially concerning the interpretation of results from clinical and observational research. The benefits of short-term prophylaxis are well established, but long-term outcomes, particularly related to humanistic and economic burden, are not as well understood. AIM: We conducted a systematic literature review to evaluate the association of episodic or prophylactic bleed control with long-term clinical, humanistic and economic outcomes. METHODS: Studies published in English between 1 January 2006 and 15 December 2016 were included. Participants had HA (with or without inhibitors), received prophylactic or episodic treatment and had at least 4 years of treatment or follow-up. Results were analysed qualitatively with descriptive findings. RESULTS: A total of 2091 records were screened, resulting in 19 studies from 20 publications for inclusion. Most studies included children (84%), were limited to patients with severe disease (74%) and were conducted in Europe or North America (89%). Ten studies (53%) included patients with inhibitors. Median study follow-up ranged from 5 to 19 years. Long-term bleeding and haemarthrosis outcomes were consistently better for patients receiving prophylaxis, who also required fewer hospitalizations or surgeries. Health-related quality of life, functionality and productivity were generally more favourable in patients receiving prophylaxis. Quantitative comparisons were not feasible due to the lack of consistency in endpoint collection and reporting among studies. CONCLUSION: This systematic review confirmed that the benefits of prophylactic treatment on short-term outcomes translate to broader long-term clinical, humanistic and economic benefits. Better harmonization of data collection and outcome assessments across both registries and clinical studies is needed to allow for effective comparisons across studies and across data sources. PMID- 30004614 TI - Work of breathing for cuffed and uncuffed pediatric endotracheal tubes in an in vitro lung model setting. AB - BACKGROUND: Over the last decade, cuffed endotracheal tubes are increasingly used in pediatric anesthesia and also in pediatric intensive care. However, the smaller inner diameter of cuffed endotracheal tubes and, implicitly, the increased endotracheal tube resistance is still a matter of debate. AIMS: This in vitro study investigated work of breathing and inspiratory airway pressures in cuffed and uncuffed endotracheal tubes and the impact of pressure support ventilation and automatic tube compensation. METHODS: In 5 simulated neonatal and pediatric lung models, the Active Servo Lung 5000 and an intensive care ventilator were used to quantify the differences in work of breathing under spontaneous breathing (with and without pressure support ventilation and automatic tube compensation) between cuffed and uncuffed endotracheal tubes. Additionally, differences in inspiratory airway pressures, measured either proximal or distal of the endotracheal tube, between cuffed and uncuffed endotracheal tubes under mechanical ventilation were investigated. RESULTS: Work of breathing was overall 10.27% [95% confidence interval 9.01-11.94] higher with cuffed than with uncuffed endotracheal tubes and was dramatically reduced by 34.19% [95% confidence interval 31.61-35.25] with the application of pressure support. Automatic tube compensation almost diminished work of breathing differences between the 2 endotracheal tube types in nearly all pediatric lung models. Peak inspiratory and mean airway pressures measured at the proximal endotracheal tube end revealed significantly higher values in cuffed than in uncuffed endotracheal tubes. However, these differences measured at the distal end of the endotracheal tube became minimal. CONCLUSION: This in vitro study confirmed significant differences in work of breathing and inspiratory pressures between cuffed and uncuffed endotracheal tubes. Work of breathing, however, is almost neutralized by pressure support ventilation with automatic tube compensation and distal inspiratory airway pressures that, from a clinical perspective, are not significantly increased. PMID- 30004615 TI - The effect of xenon-augmented sevoflurane anesthesia on intraoperative hemodynamics and early postoperative neurocognitive function in children undergoing cardiac catheterization: A randomized controlled pilot trial. AB - BACKGROUND: In adults, xenon has only minimal hemodynamic side effects when compared with other anesthetics. Moreover, in preclinical experiments, xenon has been demonstrated to possess cardio- and neuroprotective properties. Altogether, the favorable hemodynamic profile combined with its potential for organ protection could render xenon an attractive option for anesthesia in children with cardiovascular compromise. AIMS: The aim of this study was to explore safety and feasibility of sevoflurane-augmented xenon anesthesia in school-aged children and to assess early postoperative neurocognitive effects of xenon-sevoflurane and sevoflurane anesthesia when compared to a control group that did not have anesthesia. METHODS: Forty children aged 4-12 years, suffering from congenital heart disease, undergoing diagnostic or interventional cardiac catheterization were randomized to either xenon-augmented sevoflurane anesthesia or sevoflurane alone. Safety was assessed by the incidence of intraprocedural hemodynamic instability and feasibility by anesthetic depth and respiratory profile. In addition, neurocognitive performance was assessed preoperatively, 2 hours after discharge from PACU and at 24 hours after anesthesia using the Amsterdam Neuropsychological Tasks system. A healthy control group of 22 age- and gender matched children not exposed to anesthesia underwent an identical neurocognitive test battery, at comparable time intervals. RESULTS: Overall hemodynamics did not differ between groups. Xenon-sevoflurane anesthesia resulted in decreased intraoperative ephedrine requirements (median [IQR]) (0.00 mg/kg [0.00-0.00] vs 0.00 mg/kg [0.00-0.01], P = 0.047). Only neurocognitive tests in the domain of alertness were significantly impaired 2 hours postoperatively in both anesthesia groups in comparison with the control group (alertness variability: P = 0.02, odds ratio 5.8), but recovered at 24 hours. For working memory, inhibition, cognitive flexibility, and motor coordination tasks, no significant interaction effects of anesthesia were found in the early postoperative period. CONCLUSION: In this pilot trial, xenon-augmented sevoflurane anesthesia in school-aged children was feasible, and associated with decreased ephedrine requirements. All children exposed to anesthesia showed impaired neurocognitive performance in the immediate postoperative period when compared to control children; however, without significant differences between both treatment groups. PMID- 30004616 TI - Fms-Like Tyrosine Kinase 3-Ligand Contributes to the Development and Function of the Subpopulation of CD8alpha+ Plasmacytoid Precursor Dendritic Cells in CD8+ /TCR- Facilitating Cells. AB - Facilitating cells (FC) are a CD8+ TCR- bone marrow subpopulation that enhance engraftment of purified hematopoietic stem cells (HSC) and induce antigen specific CD4+ CD25+ FoxP3+ regulatory T cell (Treg) in vivo. The major subpopulation in FC resembles plasmacytoid precursor dendritic cells (p-preDC) both phenotypically and functionally. Here, we report that the number of FC was significantly reduced in Fms-like tyrosine kinase 3-ligand-knockout (Flt3-L-KO) mice. Specifically, there was a selective decrease in the B220+ CD11c+ CD11b- p preDC FC subpopulation. The p-preDC FC subpopulation in FC total is restored after Flt3-L administration to Flt3-L-KO mice. FC from Flt3-L-KO donors exhibit impaired facilitation of allogeneic HSC engraftment in ablatively conditioned mice (B6 -> NOD) as well as in mice conditioned with reduced intensity conditioning (B6 -> BALB/c). In addition, the number of CD4+ CD25+ Foxp3+ Treg from Flt3-L-KO mice is significantly decreased. This was associated with the expression of chemokine receptor CXCR3+ or CCR5+ on Treg. Treg from the spleen of Flt3-L-KO mice showed impaired facilitation of engraftment of allogeneic HSC compared to wild-type Treg. Flt3-L treatment significantly expanded Treg, and restored their facilitating function. These results suggest that Flt3-L is an important growth factor in the development and homeostasis of p-preDC FC and in the role of FC inducing generation of Treg. Flt3-L provides potent immunoregulatory properties that may be clinically useful to improve tolerance induction and enhance the function of allogeneic cell therapies. Stem Cells 2018;36:1567-1577. PMID- 30004618 TI - Factors associated with successful pregnancy in women of late reproductive age with uterine fibroids who undergo embryo cryopreservation before surgery. AB - AIM: The objective of this study is to determine the factors associated with successful pregnancy in women of late reproductive age with uterine fibroids who undergo embryo cryopreservation before surgery (ECBS). METHODS: Patients who underwent in vitro fertilization treatment with controlled ovarian stimulation from November 2010 to January 2017 in our university hospital were included. Twenty-two patients older than 35 years of age at the first visit with cavity distorting uterine fibroids underwent ECBS, a three-step therapeutic approach consisting of oocyte pick-up, myomectomy and embryo transfer (ET), which are performed in this order. We retrospectively calculated the pregnancy rate and determined the factors associated with successful pregnancy. RESULTS: The mean age at ET of the patients who underwent ECBS was 40.9 years, with a pregnancy rate per ET of 36.8% (21/57). Of 22 patients, 10 (45.5%) successfully continued pregnancy beyond 12 weeks of gestation (ongoing pregnancy). An ongoing pregnancy was observed only among the patients with more than three frozen embryos. The ongoing pregnancy rates of patients with <=five fibroids and <=5 cm in the maximal diameter were significantly higher compared to the respective remaining group (90.0% vs 14.3% and 87.5% vs 33.3%). CONCLUSION: ECBS is an effective strategy for infertile women of late reproductive age with cavity-distorting uterine fibroids, especially when it is applied to the patients who can freeze at least three embryos before myomectomy, with five or less fibroids smaller than 5 cm in the maximal diameter. PMID- 30004617 TI - The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom. AB - INTRODUCTION: Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure. AIM: To investigate the immunogenicity of ReFacto AF post licensure in a real-world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs). METHODS: The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01 IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors. RESULTS: One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t <= 50) = 0.33, [95% CI: 0.25-0.43]), of which 15 (P(t <= 50) = 0.16, [95% CI: 0.10-0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7-16) EDs. Inhibitors were significantly associated with high-risk mutations and non-significantly associated with non white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High-titre inhibitors were significantly associated with a family history of inhibitors. CONCLUSION: Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low- and high-titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom. PMID- 30004619 TI - Validation of the Haemophilia & Exercise Project-Test-Questionnaire (HEP-Test-Q) An instrument for the assessment of subjective physical functioning in children with haemophilia. AB - INTRODUCTION: Contemporary haemophilia management recommends sport and physical activity in children with haemophilia. Assessment of subjective physical functioning requires standardized and validated instruments. AIMS: To adapt and psychometrically test the adult Haemophilia & Exercise Project-Test-Questionnaire (HEP-Test-Q) for children (aged 6-17 years). METHODS: In discussion rounds with children, single items of the adult HEP-Test-Q were reformulated to make them understandable without changing the item concept. The validation of the child adapted version in children with haemophilia (n = 228) included pre-testing with feasibility testing, cognitive interviewing (n = 34), pilot-testing of the revised version in the EIS Study (n = 67) and field-testing in the SO-FIT Study (n = 127). RESULTS: Pre-testing revealed a completion time of 8.2 +/- 4.1 minutes and children liked the instrument. Cognitive interviews demonstrated that most items were easy to understand; 9 items were reformulated. Pilot-testing demonstrated good psychometric characteristics in terms of reliability (alpha = .94 Total Score) and validity. Convergent validity testing showed moderate correlations with the Haemo-QoL (r = -.491), but low correlations with the Petrini Score (r = -.293). Known groups' validity revealed significant differences in clinical subgroups; chronic pain (P < .002) and target joints (P < .021). Field-testing confirmed psychometric characteristics; Cronbach's alpha ranged from alpha = .80 ("endurance") to alpha = .94 (Total Score). The child adapted HEP-Test-Q showed moderate correlations with the PedHAL (r = .634, P < .0001) and the Haemo-QoL SF (r = -.575, P < .0001). Known groups' validity testing proved that the HEP-Test-Q could discriminate between clinical subgroups. CONCLUSION: The child-adapted HEP-Test-Q is a short, practical and acceptable instrument for the assessment of subjective physical functioning. Outcomes can be compared to adults because item concepts are identical to the adult version. PMID- 30004621 TI - Comment on: Interpreting data on inhibitor development from previously untreated patient studies, beware of premature conclusions. PMID- 30004620 TI - Emotional distress in haemophilia: Factors associated with the presence of anxiety and depression symptoms among adults. AB - INTRODUCTION: Haemophilia is related to several clinical and psychosocial challenges that have been associated with increased emotional distress. These may impact on disease adjustment and health outcomes, reinforcing the attention given to psychosocial health of people with haemophilia (PWH), in the scope of optimal comprehensive care. AIM: To identify potentially modifiable factors associated with the presence of anxiety and depression symptoms among adult PWH. METHODS: This was a cross-sectional observational study examining socio-demographic, clinical and psychosocial variables among 102 patients with haemophilia A or B who participated on a mail survey of haemophilia in Portugal. RESULTS: People with haemophilia revealing higher anxiety and depression symptoms were more likely to have had, in the previous year, more urgent hospital visits due to haemophilia, more bleeding episodes, more affected joints and pain, as well as worst levels of perceived functionality and quality of life. After controlling for demographic (age and education) and clinical (haemophilia severity and joint deterioration) variables in multivariate hierarchical logistic regression analyses, professional status (OR = 4.646, P = .004; OR = 3.333, P = .029) and pain interference (OR = 1.397, P = .011; OR = .1.347, P = .037) were significantly associated with both anxiety and depression symptoms. Additionally, physical activity (OR = 0.302, P = .024) and the perception of consequences underlying haemophilia (OR = 1.600, P = .012) also emerged as key factors significantly associated with depression symptoms. CONCLUSION: Current findings increased knowledge on factors associated with anxiety and depression among PWH. These highlight potential intervention targets, which are amenable to change through evidence-based tailored interventions aiming to decrease emotional distress, promote well-being and improving haemophilia-related health outcomes among these patients. PMID- 30004622 TI - Haemophilia clinical care and research needs: Assessing priorities. PMID- 30004623 TI - (P,C) Cyclometalated Gold(III) Complexes: Highly Active Catalysts for the Hydroarylation of Alkynes. AB - The first catalytic application of well-defined (P,C) cyclometalated gold(III) complexes is reported. The bench-stable bis(trifluoroacetyl) complexes 2 a,b perform very well in the intermolecular hydroarylation of alkynes. The reaction is broad in scope, it proceeds within few hours at 25 degrees C at catalytic loadings of 0.1-5 mol %. The electron-rich arene adds across the C=C bond with complete regio- and stereo-selectivity. The significance of well-defined gold(III) complexes and ligand design are highlighted in a powerful but challenging catalytic transformation. PMID- 30004624 TI - Effects of remifentanil maintenance during recovery on emergence delirium in children with sevoflurane anesthesia. AB - BACKGROUND: Emergence delirium is a common complication of sevoflurane anesthesia in children. AIMS: We examined the effects of maintaining remifentanil infusion during the recovery period on the incidence of emergence delirium in preschool age children undergoing strabismus surgery under sevoflurane anesthesia. METHODS: Eighty children (aged 3-7 years) were randomly assigned to either the control group (group C; intraoperative remifentanil infusion) or the intervention group (group R; intraoperative remifentanil infusion followed by remifentanil maintenance during the recovery phase). Intraoperative remifentanil infusion (0.2 MUg/kg/min) was discontinued upon surgery completion in the group C, and was maintained until the discharge criteria were met at a dose of 0.05 MUg/kg/min in the group R. The incidence of emergence delirium was assessed using a five-point agitation scale and the Pediatric Anesthesia Emergence Delirium scale after arrival in the postanesthesia care unit. Postoperative pain was assessed using the Children's Hospital of Eastern Ontario Pain Scale. RESULTS: The incidence of emergence delirium according to the five-point agitation scale (scores >= 4) was lower in the group R (33.3%) compared to the group C (68.3%) (odds ratio 0.206; 95% CI 0.080 to 0.531; P = 0.002). Similar results were obtained using the Pediatric Anesthesia Emergence Delirium scale (scores > 12), with an incidence of 5.1% in the group R and 34.0% in the control group (odds ratio 0.104; 95% CI 0.022 to 0.497; P = 0.001). The Children's Hospital of Eastern Ontario Pain Scale scores and occurrence of postoperative adverse events including laryngospasm, desaturation, nausea, and vomiting were similar between the two groups. CONCLUSION: Maintaining a low dose of remifentanil (0.05 MUg/kg/min) throughout the recovery phase attenuated the incidence of emergence delirium in children undergoing strabismus surgery under sevoflurane anesthesia. PMID- 30004625 TI - Recombinant activated factor VII in approved indications: Update on safety. PMID- 30004626 TI - Role of hepatoma-derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma. AB - Although identified as a growth factor, the mechanism by which hepatoma-derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA-sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF-induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP-1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P- to A-type, resulting in inability to induce SREBP-1-mediated gene transcription. The type of PWWP domain affects the recruitment of the C-terminal binding protein-1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1-mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC. PMID- 30004629 TI - What is the significance of non-specific pleuritis? A trick question. AB - Non-specific pleuritis (NSP) is defined as fibrinous or inflammatory pleuritis which cannot be attributed to a specific benign or malignant etiology. It can be diagnosed in biopsies in up to 30% of cases of exudative pleuritis after thoracoscopy, with a mean of 19.2%. In 66 out of 469 (14.2%) patients in combined series, a malignant pleural disease (mostly mesothelioma) was found during a follow-up of at least 21 months. Most likely, a follow-up time of 12 months is sufficient, although the current routine is a follow-up of 2 years. Because of a benign course in 85% of patients with NSP, a repeated invasive procedure after thoracoscopy is only indicated in a limited group of patients. The most important indications for a repeated pleural biopsy are persistent chest pain, recurrent pleural effusion, radiologic findings suggestive for malignant pleural disease. PMID- 30004627 TI - A mouse model engineered to conditionally express the progesterone receptor-B isoform. AB - Using a Rosa26 gene targeting strategy in mouse embryonic stem cells, we have generated a new transgenic mouse (Pgr-B LSL ), which is designed to conditionally express the epitope-tagged mouse progesterone receptor-B (PGR-B) isoform when crossed with a specific cre driver mouse. To functionally validate this transgenic mouse, we crossed the Pgr-B LSL mouse with the MMTV-CREA transgenic mouse to create the MMTV-CREA/Pgr-B LSL bigenic (termed PR-B:OE to denote PGR-B overexpressor). As expected, transgene-derived PGR-B protein was specifically targeted to the virgin mammary gland epithelium. At a functional level, the PR B:OE bigenic exhibited abnormal mammary morphogenesis-dilated epithelial ducts, precocious alveologenesis and lateral side-branching, along with a prominent proliferative signature-that resulted in pregnant PR-B:OE mice unable to exhibit mammary gland terminal differentiation at parturition. Because of this developmental failure, the PR-B:OE mammary gland was incapable of producing milk resulting in early neonatal death of otherwise healthy litters. This first line of analysis demonstrates the utility of the Pgr-B LSL mouse to examine the role of the PGR-B isoform in different physiologic and pathophysiologic systems that are responsive to progesterone. PMID- 30004630 TI - Ingestion of an Inulin-Enriched Pork Sausage Product Positively Modulates the Gut Microbiome and Metabolome of Healthy Rats. AB - SCOPE: Processed meat intake is associated with a potential increased colorectal cancer (CRC) risk. In contrast, dietary fiber consumption has been found to lower CRC risk, possibly via mechanisms involving the gut microbiota (GM) and its metabolites. This study investigates the effect of inulin enrichment of a common pork sausage product on GM composition and activity in healthy rats. METHODS AND RESULTS: Thirty Sprague-Dawley rats are fed a diet based on either an inulin enriched sausage (n = 12), a corresponding control sausage without enrichment (n = 12), or a standard chow diet (n = 6) during a 4 week intervention. NMR-based metabolomics analyses are conducted on fecal and plasma samples, and GM composition is determined using 16S rRNA gene amplicon sequencing. Pronounced effects of diets on GM composition and activity are found. Rats fed the inulin enriched sausages have increased levels of short chain fatty acids (SCFAs) in the fecal and plasma metabolome and increased fecal levels of Bifidobacterium spp. as compared to rats fed sausages without enrichment. CONCLUSION: Inulin enrichment of a meat product resembles general effects seen upon dietary fiber consumption and corroborates that healthier processed meats can be developed through strategic inclusion of dietary fiber ingredients. PMID- 30004631 TI - Continuous, Spontaneous, and Directional Water Transport in the Trilayered Fibrous Membranes for Functional Moisture Wicking Textiles. AB - Directional water transport is a predominant part of functional textiles used for continuous sweat release in daily life. However, it has remained a great challenge to design such textiles which ensure continuous directional water transport and superior prevention of water penetration in the reverse direction. Here, a scalable strategy is reported to create trilayered fibrous membranes with progressive wettability by introducing a transfer layer, which can guide the directional water transport continuously and spontaneously, thus preventing the skin from being rewetted. The resulting trilayered fibrous membranes exhibit a high one-way transport index R (1021%) and a desired breakthrough pressure (16.1 cm H2 O) in the reverse direction, indicating an ultrahigh directional water transport capacity. Moreover, on the basis of water transport behavior, a plausible mechanism is proposed to provide insight into the integrative and cooperative driving forces at the interfaces of trilayered hydrophobic/transfer/superhydrophilic fibrous membranes. The successful synthesis of such fascinating materials would be valuable for the design of functional textiles with directional water transport properties for personal drying applications. PMID- 30004628 TI - TGFbeta1 regulates HGF-induced cell migration and hepatocyte growth factor receptor MET expression via C-ets-1 and miR-128-3p in basal-like breast cancer. AB - Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFbeta signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal-like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal-like breast cancer cell lines, as well as in triple negative breast cancer tumor tissues, compared to other subtypes. Using real-time cell analysis technology, we demonstrated that TGFbeta1 triggered hepatocyte growth factor (HGF)-induced and MET-dependent migration in vitro. Bioinformatic analysis predicted that TGFbeta1 induces expression of C-ets-1 as a candidate transcription factor regulating MET expression. Indeed, TGFbeta1-induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR-128-3p and that this miRNA is negatively regulated by TGFbeta1. Overexpression of miR-128-3p reduced MET expression and abrogated HGF-induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFbeta1 regulates HGF-induced and MET-mediated cell migration, through positive regulation of C-ets 1 and negative regulation of miR-128-3p expression in basal-like breast cancer cell lines and in triple-negative breast cancer tissue. PMID- 30004632 TI - Reviewing Mechanistic Peptidomics in Body Fluids Focusing on Proteases. AB - The comprehension of how protease networks sculpt proteomes might help to disclose the functional annotation of the peptidome in health and disease. Envisioning to add new insights on the protease networks involved in the regulation of body fluid peptidomes, the authors apply Proteasix software to predict the proteases involved in the generation of the naturally occurring peptides present in six of the most studied human body fluids. Peptidome data is collected from the databases and from experimental studies. The analysis highlights 132 putative proteases from four families with the predominance of serine proteases and metalloproteases. From these, 49 proteases seem to be common to all fluids and are mostly associated to extracellular matrix organization as well as protein/peptide hormone processing. Data analysis also emphasizes: i) the similarity between plasma and CSF protease profiles; ii) that saliva and tears share proteases involved in the generation of peptides with antimicrobial activity; iii) that urine is the body fluid with the highest number of unique putative proteases, precluding an easy tracing of proteolytic events in this case. Taken together, the analysis emphasizes the intricate modus operandi of proteases, challenged by the interconnected pathways and amplification cascades in which they are involved. PMID- 30004634 TI - The language of abortion: time to terminate TOP: FOR: Mandating TOP reduces research visibility and engenders stigma. PMID- 30004633 TI - Australian students' perspective on interventional radiology education: A prospective cross-institutional study. AB - INTRODUCTION: As interventional radiology (IR) adopts an increasingly pivotal role within therapeutic medicine, it is essential that medical students gain exposure to IR so as future doctors, they can fulfil the growing demand for interventional radiologists (IRs) and make appropriate referrals to IRs. Nonetheless, several international studies have reported no or little representation of IR in medical schools. Our study aims to assess the current awareness, exposure, knowledge and attitudes about IR among Australian medical students, so as to provide preliminary data on whether IR teaching in Australian medical schools needs improvement. METHODS: A prospective cross-sectional study was conducted via web-based and in-person distribution of a voluntary, anonymous questionnaire. RESULTS: A total of 237 complete responses were received from approximately 1400 clinical-based students (17% response rate); 38% of respondents had never witnessed an IR procedure, 39% witnessed 1-2 and the remainder, 3-5. Few students reported adequate teaching or knowledge in IR (7% and 5% respectively). Of the 32% of the students considering a career in IR, males predominated (25% of females vs. 59% of males, OR = 0.48, 95%, CI = 0.27 0.83, P = 0.008). Most students agree that IR should be in the university curriculum (59%) and is key to improving healthcare (74%). Senior students were more likely to report adequate teaching (P < 0.001) and believe that IR teaching is important (P = 0.001). CONCLUSIONS: Australian medical students have a strong appreciation for IR despite having suboptimal teaching, exposure and knowledge in IR. In order to complement and sustain the rapid uptake of IR techniques in modern medicine, university curricula require a greater focus on IR. PMID- 30004635 TI - When the balloon goes up. PMID- 30004636 TI - Twin-to-twin-transfusion syndrome: from amniodrainage to laser. PMID- 30004638 TI - The language of abortion: time to terminate TOP : AGAINST: 'Termination of pregnancy' is less likely than 'abortion' to be misunderstood or cause distress. PMID- 30004637 TI - Author's reply re: Postpartum venous thromboembolism prophylaxis: harm versus benefit. PMID- 30004639 TI - Re: Postpartum venous thromboembolism prophylaxis: harm versus benefit. PMID- 30004640 TI - Author's reply re: Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence-based lens. PMID- 30004641 TI - We should stop using incorrect Latin to describe parity and use plain English instead. PMID- 30004644 TI - Uterine anomalies - Latin anatomy reigns. PMID- 30004643 TI - Re: Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence based lens: Postpartum thromboprophylaxis is cost-effective using the Swedish thromboprophylaxis algorithm. PMID- 30004645 TI - Wooden spoons and thromboprophylaxis in obstetrics. PMID- 30004646 TI - Septins in kidney: A territory little explored. AB - Septins are a conserved family of GTP-binding proteins that assemble into cytoskeletal filaments to function in a highly sophisticated and physiologically regulated manner. Originally septins were discovered in the budding yeast as membrane-associated filaments that affect cell polarity and cytokinesis. In the last decades, much progress has been made in understanding the biochemical properties and cell biological functions of septins. In line with this, mammalian septins have been shown to be involved in various cellular processes, including regulation of cell polarity, cytoskeletal organization, vesicle trafficking, ciliogenesis, and cell-pathogen interactions. A growing number of studies have shown that septins play important roles in tissue and organ development and physiology; yet, little is known about their role in the kidney. In the following review, we discuss the structure and functions of septins in general and summarize the evidence for their presence and roles in the kidney. PMID- 30004648 TI - [Molecular Epidemiology of Astrovirus Infection Among Hospitalized Infants in Kunming City, China, 2013~2014]. AB - We investigated the infection and molecular-epidemiologic characteristics of human astrovirus (HAstV) of hospitalized infants in Kunming City from the year 2013 to 2014.Infection and genotype of HAstV of 63 samples of diarrheal feces and 42 controls were analyzed by reverse transcription-polymerase chain reaction(RT PCR).The complete genome sequence of a HAstV strain was amplified and sequenced. The positive rate of HAstV in 63 feces samples was 41.27%(26/63).The main circulating genotype of HAstV was HAstV1.Only 1sample was positive for HAstV in 42controls(2.38%).A complete genome sequence of the HAstV strain was identified as HAstV1 by phylogenetic analyses. These data provide an important theoretical basis for the control of viral diarrhea in infants in Kunming City. PMID- 30004647 TI - Exploiting the Thiobarbituric Acid Scaffold for Antibacterial Activity. AB - Thiobarbituric acid (TBA) has been considered a privileged structure for developing antimicrobial agents. Diversity was obtained at positions N and at C5 through acylation, Schiff base formation, Knoevenagel condensation, and thioamide and enamine formation. The present work describes the synthesis of small libraries based on the TBA moiety and above-mentioned reactions. Preliminary antimicrobial activity screening of the prepared compounds against selected bacteria (both Gram-positive and -negative) showed the best results for the Boc Phe-TBA derivative. These results could be useful for designing and building libraries based on other amino acids with distinct protecting groups. PMID- 30004649 TI - [Whole Genome Sequencing and Phylogenetic Analyses of Sub-genotype A1 of the Human Metapneumovirus Detected in an Infant with Pneumonia]. AB - The human metapneumovirus (HMPV) is an important pathogen in respiratory-tract infections in children. We undertook genomic sequence analyses and described the genetic characteristics of an uncommon sub-genotype, the HMPV A1 strain, and provide useful data for further studies. The HMPV A1(BJ-1610)strain was identified from a nasopharyngeal aspirate collected from a 3-month-old female with bronchopneumonia. Gene fragments of BJ-1610 were amplified by reverse transcription-polymerase chain reaction(RT-PCR)and assembled by DNAStar software. Sequence alignment for BJ-1610 and other HMPV reference strains with four known genotypes available in the GenBank database was conducted by DNAStar. Phylogenetic trees were created using MEGA 6.06 software. The whole genome of BJ 1610 was 13406nt in length (GenBank accession number:KU821121).Compared with HMPV reference strains,BJ-1610 shared the highest similarities with HMPV/AUS/150229278/2003/A(KC562226)from Australia, which was classified into sub genotype A1.The nucleotide identity of the full genome between BJ-1610 and KC562226was 98.4%.N,P,F,M2-2and L genes had great similarity with KC562226 compared with other reference strains, whereas SH and G genes shared higher similarities with other strains of sub-genotype A1.Phylogenetic analyses of the whole genome showed that BJ-1610 was clustered into sub-genotype A1 and was close to KC562226.The N,P,M,F,M2-1,M2-2and L genes of BJ-1610 showed the same genetic features as the whole genome, whereas the variable genes SH and G were closest to KC403980.The F protein of BJ-1610 showed high genetic conservation. The length of the SH protein of BJ-1610 changed from 552 bp to 567 bp due to mutations in the stop codon. The amino-acid mutations on protein G led to a decrease in the number of N-glycosylation sites. As an infrequently circulating genotype, sequence analyses of the whole genome of a HMPV A1strain(BJ-1610)will promote further studies on its epidemiology and pathogenicity, and aid the development of vaccines and antiviral drugs. PMID- 30004650 TI - [The Effect of Influenza Type B Inter-lineage Reassortment on the Growth Characteristics of Influenza]. AB - This study aims to research the effect of inter-lineage reassortment of type B influenza virus on its biological characteristics. The representative strains isolated in 2013~2015were selected, which included wild type viruses and inter lineage reassortment viruses. We tested the growth curve of each virus based on the value of TCID50 at different time point. And further detected the Km value of virus to analysis the activity of neuraminidase of each virus. The growth curve of viruses in 2013 and 2014reached peak 48 hours after infection, maintained at high level until 72 hours, then the virus titer declined gradually, however the virus isolated in 2015 reached peak 24 hours after infection. The reassortment strain B/Fujian Tongan/1565/2013 has the similar growth characteristics with the wild type virus on the same year. Meanwhile the growth curve of other inter lineage viruses in 2014 and 2015is lower than that of wild type viruses. We determined neuraminidase kinetic constants of all viruses. The reassortment strain B/Fujian Tongan/1565/2013 has the strongest affinity of neuraminidase. The results of 2014~2015virus suggest that the stronger affinity of neuraminidase of virus the better growth characteristics of virus. But the virus in 2013 is lack of such relationship between the growth characteristics and activity of neuraminidase. The neuraminidase activity and growth characteristics of inter lineage reassortments due to surface protein gene exchange is not consistent, suggesting internal virus protein might have affected the growth characteristics of the viruses2013-2015,and pending further study. PMID- 30004651 TI - [Influence of Synonymous Codon Bias on the RNA Secondary Structure in Influenza-A Viruses]. AB - Influenza-A viruses were selected as samples. Then, the relationship between synonymous codon bias and mRNA secondary structures was analyzed. Our data will provide a theoretical basis for further research on the synonymous codon and RNA properties of the influenza-A virus. Information on the nucleic-acid sequence of all influenza-A viruses in the National Center for Biotechnology Information was collected. The secondary structure of each nucleic-acid sequence was predicted. Then, the loop structure, stem structure, and free replicating energy of RNA were calculated. Based on this information, the specific flexibility of RNA was worked out. Simultaneously, the synonymous codon bias in each nucleic-acid sequence was counted. A database on the RNA secondary structure of the influenza-A virus was set up. Then, the relationship between the synonymous codon bias and the content of loop structure, stem structure, and flexibility were analyzed.Codon usage of 50% of amino acids was correlated significantly with the content of stem structure or the content of loop structure.Also,60% of amino acids were correlated significantly with average unit folding free energy. In addition, codon usage of 50% of amino acids was correlated significantly with the specific flexibility of RNA. For codons that were correlated significantly with stem structure and loop structure, the correlation between their usage with two types of structural content was completely contrary .Also, the correlation between specific flexibility with synonymous codon bias was better than that observed for other parameters. These results suggest that synonymous codon usage bias has important influences on RNA secondary structure. PMID- 30004652 TI - [Isolation and Identification of the Nam Dinh Virus from Mosquitoes on the China Laos-Myanmar Border]. AB - Three strains of an insect nidovirus, the Nam Dinh virus (NDiV), isolated in Yunnan Province, China, have been identified. Aedes albopictus C6/36 cells were used to isolate NDiV from mosquitoes collected in Yunnan Province in 2012.Culture supernatants with a positive cytopathic effect were harvested for virus identification by sequence-independent single primer amplification. Transmission electron microscopy revealed virion structure to be spherical with a diameter of 60~80nm.Reverse transcription-polymerase chain reaction was applied to amplify sequences of RNA-dependent RNA-polymerase (RdRp), HEL1(superfamily 1helicase)and spike protein. The amino-acid sequences of three isolates from Yunnan Province showed>98% homology with NDiV strains. Phylogenetic analyses showed that these three isolates, along with NDiV, could be classified into the family Mesoniviridae. PMID- 30004653 TI - [Preparation and Preliminary Application of a Virus Library for the Neutralizing Activity of a Monoclonal Antibody Against the Rabies Virus]. AB - To establish a method for measurement of the neutralizing activity of a monoclonal antibody against the rabies virus. Twenty-four rabies street virus positive samples were isolated by the mouse inoculation test. Isolated rabies street viruses were cultured and the virus titer tested in N2A cells. We established a rabies street virus bank with viruses that could adapt to the growth of N2A cells with a high titer. Then repeatability was evaluated after three detections of the TRN006 monoclonal antibody. Of the 24 positive samples,15 strains of the virus could adapt to N2A cells and form fluorescent foci in cells.Finally,10 strains with a high titer were selected for the rabies street virus bank, which covered nine Provinces of China and four Chinese lineages. Three lineages were used for the neutralization test for the monoclonal antibody, and the Student's t-test showed that it had good repeatability. PMID- 30004654 TI - [Advances in the Role of Stem Memory T Cells in HIV-1 Infection]. AB - Stem memory T cells represent the earliest and long-lasting memory T cells. They display stem cell-like properties of self-renewal and multipotency. Tscm cells have shown their antitumor effect; the role of Tscm cells has sparked interest in anti-HIV fields recently. In this review, we will introduce the characteristics of Tscm cells, the importance of CD4(+) Tscm cells in HIV-1latent reservoir, and the antiviral activity of CD8(+) Tscm cells. Understanding the properties of Tscm cells and their potential role in antiHIV-1,will help us to explore the possibility of Tscm to be used as, or targeted by, vaccines or immunotherapies for HIV-1treatment,thereby providing new strategies for prevention, control and functional cure of HIV-1. PMID- 30004655 TI - [Research Progress in Virus Infection Altering Cellular Glucose Metabolism]. AB - Viruses "hijack" cellular metabolism to complete their proliferation. Glucose is an important source of energy and carbon in the synthesis of precursor molecules in host cells, and its metabolism is regulated dramatically during virus infection. Here, we reviewed the mechanism of virus infection that alters glucose transport, expression of glucose metabolism-related genes (glycolysis, pentose phosphate pathway, gluconeogenesis) in cells, as well as islet cells and insulin receptors. It provides references for study of virus-altering cellular glucose metabolism. PMID- 30004656 TI - [Progress in the Development of Animal Models Supporting Human Adenovirus Infection]. AB - Human adenoviruses cause respiratory diseases, conjunctivitis, gastroenteritis and even severe pneumonia. Specific antiviral drugs and vaccines are still unavailable. Animal models that support adenovirus infection and pathogenesis are critical for the study of these viruses and the development of prophylactic and therapeutic strategies. However, the receptors of some human adenoviruses have not yet been identified, most human respiratory adenoviruses cannot infect rodents, and human adenoviruses cannot replicate in rodents due to host restrictions.These factors hamper the establishment of animal models that support adenovirus pathogenesis. In this review, we discuss recent advances in research into human adenovirus receptors, host range restriction factors and animal models, and provide insights for the development of animal models supporting adenovirus infection or/and pathogenesis. PMID- 30004657 TI - [Research Advances in VP16 of the Herpes Virus]. AB - Viral protein(VP)16is an important tegument protein of the herpes virus. It is involved in early transcription activation of viral genes as well as virion assembly and release in host cells.VP16 of some herpes viruses have deubiquitinating protease activity and can help the virus counteract the host immune response. In this review, we explain the function and complex interactions between VP16 and other proteins based of the structural characteristics of VP16.This summary provides a reference for further research of maturation of the herpes virus as well as interactions between VP16 and other proteins. PMID- 30004658 TI - [Current Status of Middle East Respiratory Syndrome Vaccines]. AB - Middle East respiratory syndrome is a kind of respiratory disease Caused by Middle East respiratory syndrome Coronavirus. Now the disease has spread to 27 countries around the world, more than 1806 people infected and more than 600 people were killed, and four countries have reported cases of camel infection MERS. Prevention of the disease are very important measures to research and development related to the vaccine. In order to have more resources into the development of safe and effective vaccine, this article summarizes the current some candidate vaccine of MERS research progress for the prevention and treatment of the disease that could trigger a global public health security problems ahead. PMID- 30004659 TI - [Immune Effects and Mechanisms of HIV-specific Antibodies Against Viral Infection]. AB - Broadly neutralizing antibodies (bNAbs) have demonstrated a protective role from experimental challenge in non-human primates and humanized mouse models. Recently, bNAbs 3BNC117 and VRC01were assessed in a phase-I clinical trial, and were shown to lower plasma viremia in human immunodeficiency virus(HIV)-1 infected individuals not receiving antiretroviral therapy. However, induction of these types of antibodies by vaccination iS extremely difficult. Moreover, the 31% protection observed in the RV144 vaccine trial in the absence of detectable bNAbs in blood samples suggested the important role of additional inhibitory functions of the antibodies that control infection and replication of HIV. Increasing evidence suggests that immunoglobulin-G Fcgamma receptor-mediated inhibition of antibodies present at the mucosal site may have a protective role against mucosal transmission of HIV. Dendritic cells and macrophages express such Fc receptors on their surface, and may have a decisive role in early mucosal transmission because they have been proposed to be the first HIV target at the mucosal site. Therefore, new vaccination strategies involving induction of such non-neutralizing inhibitory antibodies and other antiviral functions, in addition to bNAbs, should be developed. PMID- 30004660 TI - Flexible Polymer-Carbon Nanotube Composite with High-Response Stability for Wearable Thermal Imaging. AB - In this work, we report a wearable thermal detector based on poly(vinyl alcohol) and carbon nanotube (CNT) composite via photo-thermoelectric effect. Passive room temperature human body thermal imaging is demonstrated with optimum detectivity up to 4.9 * 106 cm Hz1/2 W-1. Highly stable photoresponse (variation < 4%) is obtained under a bending radius down to 3.5 mm. We also found that the detector photoresponse is influenced by the composite channel length because of Seebeck effect. This flexible, self-powered, and sensitive detector opens up opportunities for wearable thermal imaging and real-time health monitoring. PMID- 30004661 TI - Direct Assembly of Large Area Nanoparticle Arrays. AB - A major goal of nanotechnology is the assembly of nanoscale building blocks into functional optical, electrical, or chemical devices. Many of these applications depend on an ability to optically or electrically address single nanoparticles. However, positioning large numbers of single nanocrystals with nanometer precision on a substrate for integration into solid-state devices remains a fundamental roadblock. Here, we report fast, scalable assembly of thousands of single nanoparticles using electrophoretic deposition. We demonstrate that gold nanospheres down to 30 nm in size and gold nanorods <100 nm in length can be assembled into predefined patterns on transparent conductive substrates within a few seconds. We find that rod orientation can be preserved during deposition. As proof of high fidelity scale-up, we have created centimeter scale patterns comprising more than 1 million gold nanorods. PMID- 30004662 TI - Sputtering-Enabled Intracellular X-ray Photoelectron Spectroscopy: A Versatile Method To Analyze the Biological Fate of Metal Nanoparticles. AB - The investigation of the toxicological profile and biomedical potential of nanoparticles (NPs) requires a deep understanding of their intracellular fate. Various techniques are usually employed to characterize NPs upon cellular internalization, including high-resolution optical and electron microscopies. Here, we show a versatile method, named sputtering-enabled intracellular X-ray photoelectron spectroscopy, proving that it is able to provide valuable information about the behavior of metallic NPs in culture media as well as within cells, directly measuring their internalization, stability/degradation, and oxidation state, without any preparative steps. The technique can also provide nanoscale vertical resolution along with semiquantitative information about the cellular internalization of the metallic species. The proposed approach is easy to-use and can become a standard technique in nanotoxicology/nanomedicine and in the rational design of metallic NPs. Two model cases were investigated: silver nanoparticles (AgNPs) and platinum nanoparticles (PtNPs) with the same size and coating. We observed that, after 48 h incubation, intracellular AgNPs were almost completely dissolved, forming nanoclusters as well as AgO, AgS, and AgCl complexes. On the other hand, PtNPs were resistant to the harsh endolysosomal environment, and only some surface oxidation was detected after 48 h. PMID- 30004664 TI - A Self-Contained Chemiluminescent Lateral Flow Assay for Point-of-Care Testing. AB - Immunoassays whose readouts rely on chemiluminescence are increasingly useful for a broad range of analytical applications, but they are rarely made into point-of care (POC) format because of the complex reagents required (some reagents have to be stored in low temperatures, and some reagents have to be freshly made right before the assay). This study reports a self-contained chemiluminescent lateral flow assay (CLFA), which prestores all necessary reagents. This CLFA contains three parts: the normal lateral flow assay (LFA) strip, the chemiluminescence substrate pad, and the polycarbonate (PC) holder. On the LFA strip, we simultaneously labeled horseradish peroxidase (HRP) and antibody on the gold nanoparticles (AuNPs) for the conjugate pad. For the substrate pad, we used sodium perborate as the oxidant and lyophilized the chemiluminescence substrate on the glass fiber, which allows long-term storage. After the transfer of substrate from the substrate pad to the nitrocellulose (NC) membrane, we captured the chemiluminescence signal for the quantification of the targets. The HRP on the AuNPs can amplify the chemiluminescence signal efficiently. We used this CLFA system to detect both macromolecules and small molecules successfully. This self contained and easily processable device is exceedingly appropriate for rapid detection and is a convenient platform for POC testing. PMID- 30004663 TI - Boron-Doped Graphene Nanoribbons: Electronic Structure and Raman Fingerprint. AB - We investigate the electronic and vibrational properties of bottom-up synthesized aligned armchair graphene nanoribbons of N = 7 carbon atoms width periodically doped by substitutional boron atoms (B-7AGNRs). Using angle-resolved photoemission spectroscopy and density functional theory calculations, we find that the dopant-derived valence and conduction band states are notably hybridized with electronic states of Au substrate and spread in energy. The interaction with the substrate leaves the bands with pure carbon character rather unperturbed. This results in an identical effective mass of ~0.2 m0 for the next-highest valence band compared with pristine 7AGNRs. We probe the phonons of B-7AGNRs by ultrahigh-vacuum (UHV) Raman spectroscopy and reveal the existence of characteristic splitting and red shifts in Raman modes due to the presence of substitutional boron atoms. Comparing the Raman spectra for three visible lasers (red, green, and blue), we find that interaction with gold suppresses the Raman signal from B-7AGNRs and the energy of the green laser (2.33 eV) is closer to the resonant E22 transition. The hybridized electronic structure of the B-7AGNR-Au interface is expected to improve electrical characteristics of contacts between graphene nanoribbon and Au. The Raman fingerprint allows the easy identification of B-7AGNRs, which is particularly useful for device fabrication. PMID- 30004665 TI - NiS1.03 Hollow Spheres and Cages as Superhigh Rate Capacity and Stable Anode Materials for Half/Full Sodium-Ion Batteries. AB - Nickle sulfides as promising anode materials for sodium-ion batteries have attracted tremendous attention owing to their large specific capacity and good electrical conductivity. However, the relative large volume changes during the sodiation/desodiation process usually result in a fast capacity decay, poor cycling stability, and sluggish electrode kinetics which hinder their practical applications. Herein, NiS1.03 porous hollow spheres (NiS1.03 PHSs) and porous NiS1.03 hollow cages (NiS1.03 PHCs) with high yield are designed and selectively fabricated via a simple solvothermal and subsequent annealing approach. The obtained NiS1.03 PHSs display long-term cycling stability (127 mAh g-1 after 6000 cycles at 8 A g-1) and excellent rate performance (605 mAh g-1 at 1 A g-1 and 175 mAh g-1 at 15 A g-1). NiS1.03 PHCs also show high rate capability and outstanding cycling stability. In addition, the analyses results of in situ and ex situ XRD patterns and HRTEM images reveal the reversible Na-ion conversion mechanism of NiS1.03. It is also worth noting that the NiS1.03 PHSs//FeFe(CN)6 full cell is successfully assembled and exhibits an initial reversible capacity of 460 mAh g-1 at 0.5 A g-1, which further evidence that NiS1.03 is a kind of prospective anode material for SIBs. PMID- 30004666 TI - Radiation and Heat Improve the Delivery and Efficacy of Nanotherapeutics by Modulating Intratumoral Fluid Dynamics. AB - Nanomedicine drug delivery systems are capable of transporting significant payloads to solid tumors. However, only a modest increase in antitumor efficacy relative to the standard of care has been observed. In this study, we demonstrate that a single dose of radiation or mild hyperthermia can substantially improve tumor uptake and distribution of nanotherapeutics, resulting in improved treatment efficacy. The delivery of nanomedicine was driven by a reduction in interstitial fluid pressure (IFP) and small perturbation of steady-state fluid flow. The transient effects on fluid dynamics in tumors with high IFP was also shown to dominate over immune cell endocytic capacity, another mechanism suspected of improving drug delivery. Furthermore, we demonstrate the specificity of this mechanism by showing that delivery of nanotherapeutics to low IFP tumors with high leukocyte infiltration does not benefit from pretreatment with radiation or heat. These results demonstrate that focusing on small perturbations to steady-state fluid dynamics, rather than large sustained effects or uncertain immune cell recruitment strategies, can impart a vulnerability to tumors with high IFP and enhance nanotherapeutic drug delivery and treatment efficacy. PMID- 30004667 TI - High-Voltage Flexible Microsupercapacitors Based on Laser-Induced Graphene. AB - High-voltage energy-storage devices are quite commonly needed for robots and dielectric elastomers. This paper presents a flexible high-voltage microsupercapacitor (MSC) with a planar in-series architecture for the first time based on laser-induced graphene. The high-voltage devices are capable of supplying output voltages ranging from a few to thousands of volts. The measured capacitances for the 1, 3, and 6 V MSCs were 60.5, 20.7, and 10.0 MUF, respectively, under an applied current of 1.0 MUA. After the 5000-cycle charge discharge test, the 6 V MSC retained about 97.8% of the initial capacitance. It also was recorded that the all-solid-state 209 V MSC could achieve a high capacitance of 0.43 MUF at a low applied current of 0.2 MUA and a capacitance of 0.18 MUF even at a high applied current of 5.0 MUA. We further demonstrate the robust function of our flexible high-voltage MSCs by using them to power a piezoresistive microsensor (6 V) and a walking robot (>2000 V). Considering the simple, direct, and cost-effective fabrication method of our laser-fabricated flexible high-voltage MSCs, this work paves the way and lays the foundation for high-voltage energy-storage devices. PMID- 30004668 TI - One-Pot Synthesis of Highly Stable CsPbBr3@SiO2 Core-Shell Nanoparticles. AB - The practical applications of CsPbX3 nanocrystals (NCs) have been limited by their poor stability. Although much effort has been devoted to making core-shell nanostructures to enhance the stability of CsPbX3 NCs, it is still very difficult to coat CsPbX3 NCs with another material on a single-particle level. In this work, we report a facile one-pot approach to synthesize CsPbBr3@SiO2 core-shell nanoparticles (NPs), in which each core-shell NP has only one CsPbBr3 NC. The formation process has been carefully monitored. It has been found that the formation rates, determined by reaction temperature, precursor species, pH value, etc., of both CsPbBr3 and SiO2 are critical for the successful preparation of core-shell NPs. Thanks to the protection of SiO2 shell, the product shows much higher long-term stability in humid air and enhanced stability against ultrasonication treatment in water than that of naked CsPbBr3 NCs. This work not only provides a robust method for the preparation of core-shell nanostructures but also sheds some light on the stabilization and applications of CsPbX3 NCs. PMID- 30004670 TI - Chemoproteomics-Enabled Covalent Ligand Screening Reveals ALDH3A1 as a Lung Cancer Therapy Target. AB - Chemical genetics is a powerful approach for identifying therapeutically active small molecules, but identifying the mechanisms of action underlying hit compounds remains challenging. Chemoproteomic platforms have arisen to tackle this challenge and enable rapid mechanistic deconvolution of small-molecule screening hits. Here, we have screened a cysteine-reactive covalent ligand library to identify hit compounds that impair cell survival and proliferation in nonsmall cell lung carcinoma cells, but not in primary human bronchial epithelial cells. Through this screen, we identified a covalent ligand hit, DKM 3-42, which impaired both in situ and in vivo lung cancer pathogenicity. We used activity based protein profiling to discover that the primary target of DKM 3-42 was the catalytic cysteine in aldehyde dehydrogenase 3A1 (ALDH3A1). We performed further chemoproteomics-enabled covalent ligand screening directly against ALDH3A1, and identified a more potent and selective lead covalent ligand, EN40, which inhibits ALDH3A1 activity and impairs lung cancer pathogenicity. We show here that ALDH3A1 represents a potentially novel therapeutic target for lung cancers that express ALDH3A1 and put forth two selective ALDH3A1 inhibitors. Overall, we show the utility of combining chemical genetics screening of covalent ligand libraries with chemoproteomic approaches to rapidly identify anticancer leads and targets. PMID- 30004671 TI - Conformal BiVO4-Layer/WO3-Nanoplate-Array Heterojunction Photoanode Modified with Cobalt Phosphate Cocatalyst for Significantly Enhanced Photoelectrochemical Performances. AB - Constructing semiconductor heterojunctions via surface/interface engineering is an effective way to enhance the charge carrier separation/transport ability and thus the photoelectrochemical (PEC) properties of a photoelectrode. Herein, we report a conformal BiVO4-layer/WO3-nanoplate-array heterojunction photoanode modified with cobalt phosphate (Co-Pi) as oxygen evolution cocatalyst (OEC) for significant enhancement in PEC performances. The BiVO4/WO3 nanocomposite is fabricated by coating a thin conformal BiVO4 layer on the surface of presynthesized WO3 nanoplate arrays (NPAs) via stepwise spin-coating, and the decoration of Co-Pi OEC is realized by photoassisted electrodeposition method. The optimized Co-Pi@BiVO4/WO3 heterojunction photoanode shows a maximum photocurrent of 1.8 mA/cm2 at 1.23 V vs RHE in a phosphate buffer electrolyte under an AM1.5G solar simulator, which is 5 and 12 times higher than those of bare WO3 and BiVO4 photoanode, respectively. Measurements of UV-vis absorption spectra, electrochemical impedance spectra (EIS) and photoluminescence (PL) spectra reveal that the enhanced PEC performances can be attributed to the increased charge carrier separation/transport benefited from the type II nature of BiVO4/WO3 heterojunction and the promoted water oxidation kinetics and photostability owing to the decoration of Co-Pi cocatalyst. PMID- 30004669 TI - Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage. AB - A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including (i) activating/inhibiting cell pathways synergistically, (ii) avoiding tumorigenesis, and (iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N fragment osteopontin mimic, and lipopeptide phosphatase tension homologue inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-d-aspartic acid induced RGC death, a single intravitreal administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs led to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome. PMID- 30004672 TI - Shotgun Lipidomics Combined with Laser Capture Microdissection: A Tool To Analyze Histological Zones in Cryosections of Tissues. AB - Shotgun analysis provides a quantitative snapshot of the lipidome composition of cells, tissues, or model organisms; however, it does not elucidate the spatial distribution of lipids. Here we demonstrate that shotgun analysis could quantify low-picomole amounts of lipids isolated by laser capture microdissection (LCM) of hundred micrometer-sized histological zones visualized at the cryosections of tissues. We identified metabolically distinct periportal (pp) and pericentral (pc) zones by immunostaining of 20 MUm thick cryosections of a healthy mouse liver. LCM was used to ablate, catapult, and collect the tissue material from 10 to 20 individual zones covering a total area of 0.3-0.5 mm2 and containing ca. 500 cells. Top-down shotgun profiling relying upon computational stitching of 61 targeted selective ion monitoring ( t-SIM) spectra quantified more than 200 lipid species from 17 lipid classes including glycero- and glycerophospholipids, sphingolipids, cholesterol esters, and cholesterol. Shotgun LCM revealed the overall commonality of the full lipidome composition of pp and pc zones along with significant ( p < 0.001) difference in the relative abundance of 13 lipid species. Follow-up proteomics analyses of pellets recovered from an aqueous phase saved after the lipid extraction identified 13 known and 7 new protein markers exclusively present in pp or in pc zones and independently validated the specificity of their visualization, isolation, and histological assignment. PMID- 30004673 TI - Top-down Approach to Produce Protein Functionalized and Highly Thermally Stable Cellulose Fibrils. AB - Protein-functionalized cellulose fibrils, having various amounts of covalently bonded proteins at their surface, were successfully extracted from the tunic of Pyura chilensis tunicates using successive alkaline extractions. Pure cellulose fibrils were also obtained by further bleaching and were used as reference material. Extraction yields of protein-functionalized cellulose fibrils were within the range of 62-76% by weight based on the dry initial tunic powder. Fourier-transform infrared and Raman spectroscopy confirmed the preservation of residual protein at the surface of cellulose fibrils, which was then quantified by X-ray photoelectron spectroscopy. The protein-functionalized cellulose fibrils were found to have relatively high crystallinity and their cellulose I crystalline structure was preserved upon applying alkaline treatments. The extracted cellulosic materials were found to be constituted of fibrils having a ribbon-like morphology with widths ranging from ~30 nm up to ~400 nm. These protein-functionalized cellulose fibrils were found to have outstanding thermal stability with one of them having onset and peak degradation temperatures of ~350 and 374 degrees C, respectively. These values were found to be 24 and 41 degrees C higher than for bleached cellulose. PMID- 30004674 TI - Molecular Determinants of Substrate Specificity in Human Insulin-Degrading Enzyme. AB - Insulin-degrading enzyme (IDE) is a 110 kDa chambered zinc metalloendopeptidase that degrades insulin, amyloid beta, and other intermediate-sized aggregation prone peptides that adopt beta-structures. Structural studies of IDE in complex with multiple physiological substrates have suggested a role for hydrophobic and aromatic residues of the IDE active site in substrate binding and catalysis. Here, we examine functional requirements for conserved hydrophobic and aromatic IDE active site residues that are positioned within 4.5 A of IDE-bound insulin B chain and amyloid beta peptides in the reported crystal structures for the respective enzyme-substrate complexes. Charge, size, hydrophobicity, aromaticity, and other functional group requirements for substrate binding IDE active site residues were examined through mutational analysis of the recombinant human enzyme and enzyme kinetic studies conducted using native and fluorogenic derivatives of human insulin and amyloid beta peptides. A functional requirement for IDE active site residues F115, A140, F141, Y150, W199, F202, F820, and Y831 was established, and specific contributions of residue charge, size, and hydrophobicity to substrate binding, specificity, and proteolysis were demonstrated. IDE mutant alleles that exhibited enhanced or diminished proteolytic activity toward insulin or amyloid beta peptides and derivative substrates were identified. PMID- 30004676 TI - Challenges in the Analysis of Novel Flame Retardants in Indoor Dust: Results of the INTERFLAB 2 Interlaboratory Evaluation. AB - The Interlaboratory Study of Novel Flame Retardants (INTERFLAB 2) was conducted by 20 laboratories in 12 countries to test the precision and accuracy of the analysis of 24 "novel" flame retardants (NFRs). Laboratories analyzed NFRs in injection-ready test mixtures, in extracts of residential dust, and in residential dust to evaluate the influence of dust handling and extraction. For test mixtures, mean reported concentrations of PBT, PBEB, EH-TBB, TBBPA, TBDP TAZTO, TBOEP, alpha-TBCO, beta-DBE-DBCH, and total HBCDD differed by >25% relative to reference values. Coefficients of variation were higher in dusts/dust extracts than in test mixtures. Concentrations among laboratories ranged over 3-4 orders of magnitude for HBB, TBP-DBPE, TBP-AE, and TDCIPP in dust extracts and dusts. Most laboratories produced repeatable dust concentrations, but differences reported in the literature among laboratories of <70% could be due to analytical variability, and the attribution of such differences to other causes should be made with caution. Most variations in accuracy and precision were introduced by matrix effects and/or sample processing, rather than instrumental analysis. We recommend recovery correction to improve accuracy. There is a need to improve analytical methods and to validate methods on complex matrices such as standard reference materials for dust or spiked matrices. PMID- 30004675 TI - Open and Closed Form of Maltose Binding Protein in Its Native and Molten Globule State As Studied by Electron Paramagnetic Resonance Spectroscopy. AB - An intensively investigated intermediate state of protein folding is the molten globule (MG) state, which contains secondary but hardly any tertiary structure. In previous work, we have determined the distances between interacting spins within maltose binding protein (MBP) in its native state using continuous wave and double electron-electron resonance (DEER) electron paramagnetic resonance (EPR) spectroscopy. Seven double mutants had been employed to investigate the structure within the two domains of MBP. DEER data nicely corroborated the previously available X-ray data. Even in its MG state, MBP is known to still bind its ligand maltose. We therefore hypothesized that there must be a defined structure around the binding pocket of MBP already in the absence of tertiary structure. Here we have investigated the functional and structural difference between native and MG state in the open and closed form with a new set of MBP mutants. In these, the spin-label positions were placed near the active site. Binding of its ligands leads to a conformational change from open to closed state, where the two domains are more closely together. The complete set of MBP mutants was analyzed at pH 3.2 (MG) and pH 7.4 (native state) using double quantum coherence EPR. The values were compared with theoretical predictions of distances between the labels in biradicals constructed by molecular modeling from the crystal structures of MBP in open and closed form and were found to be in excellent agreement. Measurements show a defined structure around the binding pocket of MBP in MG, which explains maltose binding. A new and important finding is that in both states ligand-free MBP can be found in open and closed form, while ligand-bound MBP appears only in closed form because of maltose binding. PMID- 30004677 TI - Ammonia Monooxygenase-Mediated Cometabolic Biotransformation and Hydroxylamine Mediated Abiotic Transformation of Micropollutants in an AOB/NOB Coculture. AB - Biotransformation of various micropollutants (MPs) has been found to be positively correlated with nitrification in activated sludge communities. To further elucidate the roles played by ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), we investigated the biotransformation capabilities of an NOB pure culture ( Nitrobacter sp.) and an AOB ( Nitrosomonas europaea)/NOB ( Nitrobacter sp.) coculture for 15 MPs, whose biotransformation was reported previously to be associated with nitrification. The NOB pure culture did not biotransform any investigated MP, whereas the AOB/NOB coculture was capable of biotransforming six MPs (i.e., asulam, bezafibrate, fenhexamid, furosemide, indomethacin, and rufinamide). Transformation products (TPs) were identified, and tentative structures were proposed. Inhibition studies with octyne, an ammonia monooxygenase (AMO) inhibitor, suggested that AMO was the responsible enzyme for MP transformation that occurred cometabolically. For the first time, hydroxylamine, a key intermediate of all aerobic ammonia oxidizers, was found to react with several MPs at concentrations typically occurring in AOB batch cultures. All of these MPs were also biotransformed by the AOB/NOB coculture. Moreover, the same asulam TPs were detected in both biotransformation and hydroxylamine-treated abiotic transformation experiments, whereas rufinamide TPs formed from biological transformation were not detected during hydroxylamine mediated abiotic transformation, which was consistent with the inability of rufinamide abiotic transformation by hydroxylamine. Thus, in addition to cometabolism likely carried out by AMO, an abiotic transformation route indirectly mediated by AMO might also contribute to MP biotransformation by AOB. PMID- 30004678 TI - Mechanistic Role of Two-State Reactivity in a Molecular MoS2 Edge-Site Analogue for Hydrogen Evolution Electrocatalysis. AB - We report a first-principles quantum chemical study of the mechanistic pathways for the hydrogen evolution reaction (HER) by the molecular electrocatalyst [(PY5Me2)Mo(S2)]2+. By determining the relative thermodynamics of many possible species, we propose a mechanism fully consistent with all experimental observations. We also show the presence of two close-lying spin surfaces with the high spin state having a slightly less favorable reactivity profile than the low spin state. The energy of the high spin state is related to the ease of reduction of the S2 moiety and can be disrupted by interaction between S2 and a Lewis base. From this understanding, an explanation for the nearly 400 000-fold increase in turnover frequency on Hg drop electrode compared to glassy carbon is demonstrated. A next-generation catalyst based on the same motif has been designed to stabilize the more reactive low spin state and improve catalytic function without the need of Hg. Calculations indicate that this new species would have greatly improved HER reactivity and operate at a similar overpotential as the original system. PMID- 30004679 TI - Robustness of a Reconstituted Escherichia coli Protein Translation System Analyzed by Computational Modeling. AB - Robustness against environmental changes is one of the major features of biological systems, but its origin is not well understood. We recently constructed a large-scale computational model of an Escherichia coli-based reconstituted in vitro translation system that enumerates all protein synthesis processes in detail. Our model synthesizes a formyl-Met-Gly-Gly tripeptide (MGG peptide) from 27 initial molecular components through 968 biochemical reactions. Among the 968 kinetic parameters, 483 are nonzero parameters, and the simulator was used to determine how perturbations of 483 individual reactions affect the complex reaction network. We found that even when the kinetic parameter was changed from 100- to 0.01-fold, 94% of the changes hardly affected the two indicators of reaction dynamics in MGG peptide synthesis, which represent the yield of the MGG peptide and the initial lag-time of the peptide synthesis. Moreover, none of the indicators increased proportionally to these changes: e.g., a 100-fold increase in the kinetic parameter increased the yield by only 2.2-fold at most, indicating the insensitivity of the reaction network to perturbation. Robustness and insensitivity are likely to be a common feature of large-scale biological reaction networks. PMID- 30004681 TI - Fluorescent Sulfonate-Based Inorganic-Organic Hybrid Nanoparticles for Staining and Imaging. AB - Sulfonate-based inorganic-organic hybrid nanoparticles (IOH-NPs) with the general saline composition [Gd(OH)]2+n/2[ Rdye(SO3) n] n- showing optical absorption and emission in the blue to red spectral regime are presented for the first time. All IOH-NPs are prepared via straightforward aqueous synthesis and instantaneously result in colloidally highly stable suspensions with mean particle diameters of 40-50 nm and high zeta potentials (-20 to -40 mV at pH 7.0). Specifically, the IOH-NPs comprise [Gd(OH)]2+2[CSB]4-, [Gd(OH)]2+2[DB71]4-, [Gd(OH)]2+[NFR]2-, [Gd(OH)]2+[AR97]2-, and [Gd(OH)]2+2[EB]4- showing blue, orange, red, and infrared absorption and emission ([CSB]: Chicago Sky Blue; [DB71]: Direct Blue 71; [NFR]: Nuclear Fast Red; [AR97]: Acid Red 97; [EB]: Evans Blue). The novel IOH-NPs are characterized by electron microscopy, dynamic light scattering, infrared spectroscopy, energy-dispersive X-ray analysis, thermogravimetry, elemental analysis, and fluorescence spectroscopy. In vitro studies based on HeLa and HUVEC cells were exemplarily performed with [Gd(OH)]2+2[EB]4- IOH-NPs and show intense fluorescence and only moderate toxicity at concentrations of 1 to 10 MUg/mL. Based on aqueous synthesis, good colloidal stability, absence of severely toxic metals (e.g., Cd2+, Pb2+), use of molecular dyes that are already known for staining in cell biology and histology, extremely high dye load per nanoparticle (70-80 wt %), and blue to red absorption and fluorescence, the sulfonate-based IOH-NPs can be highly interesting for staining, fluorescence microscopy, and optical imaging. PMID- 30004680 TI - A Multifunctional Lanthanide Carbonate Cluster Based Metal-Organic Framework Exhibits High Proton Transport and Magnetic Entropy Change. AB - A novel multifunctional, three-dimensional (3D) lanthanide carbonate cluster based metal-organic framework (MOF) with the general formula {[Gd2(CO3)(ox)2(H2O)2].3H2O} n (1) has been synthesized via self-assembly of gadolinium (Gd) carbonate and oxalate under hydrothermal conditions. Single crystal X-ray diffraction reveals that the compound 1 consists of the Gd carbonate cluster with oxalic acid ligands, which form a 3D framework structure with an ordered one-dimensional (1D) pore channel along the a-axis. The coordination water molecules of Gd3+ ions point to the interior of the pore and form a 1D hydrogen bond pathway with oxygen atoms in adjacent oxalic acid that is stable at high temperature (up to 150 degrees C). The compound 1 features multiple hydrogen-bonding walls and good thermal stabilities, and shows the highest proton conductivity of 1.98 * 10-3 S cm-1 at T = 150 degrees C and in room air without additional humidity. Magnetic investigations of compound 1 demonstrate that weak antiferromagnetic couplings between adjacent Gd3+ ions bring about large cryogenic magnetocaloric effects. Remarkably, the maximum entropy change (-Delta Sm) of compound 1 reaches 58.5 J kg-1 K-1 at 2 K for a moderate field change (Delta H = 7 T). Moreover, the isomorphous MOFs: {[Ln2(CO3)(ox)2(H2O)2].3H2O} n (Ln3+ = Ce3+(2), Pr3+(3), Nd3+(4), Tb3+(5)) also are structurally and functionally characterized, and compounds 2-5 exhibit proton conductivity above 10-3 S cm-1 in room air and without additional humidity. PMID- 30004682 TI - Reactive, Self-Cleaning Ultrafiltration Membrane Functionalized with Iron Oxychloride Nanocatalysts. AB - Self-cleaning, antifouling ultrafiltration membranes are critically needed to mitigate organic fouling in water and wastewater treatment. In this study, we fabricated a novel polyvinylidene fluoride (PVDF) composite ultrafiltration membrane coated with FeOCl nanocatalysts (FeOCl/PVDF) via a facile, scalable thermal-treatment method, for the synergetic separation and degradation of organic pollutants. The structure, composition, and morphology of the FeOCl/PVDF membrane were extensively characterized. Results showed that the as-prepared FeOCl/PVDF membrane was uniformly covered with FeOCl nanoparticles with an average diameter of 1-5 nm, which greatly enhanced membrane hydrophilicity. The catalytic self-cleaning and antifouling properties of the FeOCl/PVDF membrane were evaluated in the presence of H2O2 at neutral pH. Using a facile H2O2 cleaning process, we showed that the FeOCl/PVDF membrane can achieve an excellent water flux recovery rate of ~100%, following organic fouling with a model organic foulant (bovine serum albumin). Moreover, the in situ catalytic production of active hydroxyl radicals by the FeOCl/PVDF membrane was elucidated by electron spin resonance (ESR) and UV analysis. The catalytic performance of the FeOCl/PVDF membrane was further demonstrated by the complete degradation of bisphenol A when H2O2 was dosed in the feed solution at neutral pH. Our results demonstrate the promise of utilizing this novel membrane for the treatment of waters with complex organic pollutants. PMID- 30004683 TI - Influence of Particle Physical State on the Uptake of Medium-Sized Organic Molecules. AB - The uptake of medium-sized levoglucosan and 2,4-dinitrophenol to organic particles produced by alpha-pinene ozonolysis and to ammonium sulfate particles was studied from 10% to >95% relative humidity (RH). For aqueous sulfate particles, the water-normalized gas-particle partitioning coefficient of levoglucosan decreased from (1.0 +/- 0.1) * 10-3 to (0.2 +/- 0.1) * 10-3 (ng MUg 1)particle/(ng m-3)gas from 40% to >95% RH, suggestive of a salting-in mechanism between levoglucosan and ionic ammonium sulfate solutions. For the organic particles, the levoglucosan partitioning coefficient increased from 10% to 40% RH and became invariant at (2.0 +/- 0.4) * 10-3 (ng MUg-1)/(ng m-3) above 40% RH. A kinetic limitation on uptake below 40% RH was implied, compared to a thermodynamic regime above 40% RH. The estimated diffusivity was 10-19+/-0.05 m2 s-1 at 40% RH. By comparison, the uptake of 2,4-dinitrophenol onto the organic particles was below detection limit, implying an upper limit on the partitioning coefficient of 6.8 * 10-6 (ng MUg-1)/(ng m-3) at 80% RH. The results highlight that the molecular uptake of gases onto particles can be regulated by both kinetic and thermodynamic factors, either of which can limit the uptake of medium sized organic molecules by atmospherically relevant particles. PMID- 30004684 TI - K2ZnGe3S8: A Congruent-Melting Infrared Nonlinear-Optical Material with a Large Band Gap. AB - K2ZnGe3S8 belonging to the noncentrosymmetric space group P21 of the monoclinic system was discovered via a solid-state method. It possesses two-dimensional [ZnGe3S8]2- layers, with alkali-metal cations K+ located between the layers. On the basis of UV-vis-near-IR diffuse-reflectance spectrometry, the band gap of K2ZnGe3S8 is 3.36(2) eV. According to powder second-harmonic-generation (SHG) measurements, the SHG response of K2ZnGe3S8 is about 0.9 times that of AgGaS2 at the particle size range of 20-41 MUm. Experimental results demonstrate that K2ZnGe3S8 keeps a good balance between a large band gap (3.36 eV) and a moderate SHG response. Moreover, according to the differential scanning calorimetry measurements, K2ZnGe3S8 melts congruently at around 1023 K and recrystallizes at about 963 K. Therefore, it is possible to obtain bulk single crystals via the Bridgman-Stockbarger method. The first-principles calculations indicate that the optical properties of K2ZnGe3S8 are dominantly determined by the [GeS4] tetrahedra as well as a small contribution from the [ZnS4] tetrahedra. PMID- 30004686 TI - Interplay of Through-Bond Hyperfine and Substituent Effects on the NMR Chemical Shifts in Ru(III) Complexes. AB - The links between the molecular structure and nuclear magnetic resonance (NMR) parameters of paramagnetic transition-metal complexes are still relatively unexplored. This applies particularly to the contact term of the hyperfine contribution to the NMR chemical shift. We report combining experimental NMR with relativistic density functional theory (DFT) to study a series of Ru(III) complexes with 2-substituted beta-diketones. A series of complexes with systematically varied substituents was synthesized and analyzed using 1H and 13C NMR spectroscopy. The NMR spectra recorded at several temperatures were used to construct Curie plots and estimate the temperature-independent (orbital) and temperature-dependent (hyperfine) contributions to the NMR shift. Relativistic DFT calculations of electron paramagnetic resonance and NMR parameters were performed to interpret the experimental observations. The effects of individual factors such as basis set, density functional, exact-exchange admixture, and relativity are analyzed and discussed. Based on the calibration study in this work, the fully relativistic Dirac-Kohn-Sham (DKS) method, the GIAO approach (orbital shift), the PBE0 functional with the triple-zeta valence basis sets, and the polarizable continuum model for describing solvent effects were selected to calculate the NMR parameters. The hyperfine contribution to the total paramagnetic NMR (pNMR) chemical shift is shown to be governed by the Fermi contact (FC) term, and the substituent effect (H vs Br) on the through-bond FC shifts is analyzed, interpreted, and discussed in terms of spin-density distribution, atomic spin populations, and molecular-orbital theory. In contrast to the closed-shell systems of Rh(III), the presence of a single unpaired electron in the open-shell Ru(III) analogs significantly alters the NMR resonances of the ligand atoms distant from the metal center in synergy with the substituent effect. PMID- 30004687 TI - Ternary Mixed-Metal Cd4GeS6: Remarkable Nonlinear-Optical Properties Based on a Tetrahedral-Stacking Framework. AB - Noncentrosymmetric (NCS) mixed-metal chalcogenides have attracted significant attention lately because of their structural multiplicities, strong second harmonic-generation (SHG) efficiencies ( d ij) and large laser-induced damage thresholds (LIDTs), which make them promising nonlinear-optical (NLO) materials in mid- and far-IR (MFIR) applications. In this work, a ternary mixed-metal material, Cd4GeS6, has been synthesized by reacting CdS with GeS2 via a solid state method at 1273 K. It exhibits a unique tetrahedral-stacking NCS framework structure consisting of two types of [Cd2S7] asymmetric groups and dispersed GeS4 tetrahedra. Remarkably, Cd4GeS6 shows type-I phase-matching ability and achieves a desired balance between strong d ij (about 1.1AgGaS2) and large LIDT (about 3.6AgGaS2), demonstrating that this material satisfies the essential requirements as a promising MFIR NLO candidate. Moreover, theoretical calculations were performed for a better understanding of the structure-property relationships. PMID- 30004685 TI - Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase kappa. AB - Specialized DNA damage-bypass Y-family DNA polymerases contribute to cancer prevention by providing cellular tolerance to DNA damage that can lead to mutations and contribute to cancer progression by increasing genomic instability. Y-family polymerases can also bypass DNA adducts caused by chemotherapy agents. One of the four human Y-family DNA polymerases, DNA polymerase (pol) kappa, has been shown to be specific for bypass of minor groove adducts and inhibited by major groove adducts. In addition, mutations in the gene encoding pol kappa are associated with different types of cancers as well as with chemotherapy responses. We characterized nine variants of pol kappa whose identity was inferred from cancer-associated single nucleotide polymorphisms for polymerization activity on undamaged and damaged DNA, their abilities to extend from mismatched or damaged base pairs at primer termini, and overall stability and dynamics. We find that these pol kappa variants generally fall into three categories: similar activity to wild-type (WT) pol kappa (L21F, I39T, P169T, F192C, and E292K), more active than WT pol kappa (S423R), and less active than pol kappa (R219I, R298H, and Y432S). Of these, only pol kappa variants R298H and Y432S had markedly reduced thermal stability. Molecular dynamics (MD) simulations with undamaged DNA revealed that the active variant F192C and more active variant S423R with either correct or incorrect incoming nucleotide mimic WT pol kappa with the correct incoming nucleotide, whereas the less active variants R219I, R298H, and Y432S with the correct incoming nucleotide mimic WT pol kappa with the incorrect incoming nucleotide. Thus, the observations from MD simulations suggest a possible explanation for the observed experimental results that pol kappa adopts specific active and inactive conformations that depend on both the protein variant and the identity of the DNA adduct. PMID- 30004688 TI - Assessing Human Health PM2.5 and Ozone Impacts from U.S. Oil and Natural Gas Sector Emissions in 2025. AB - Incomplete information regarding emissions from oil and natural gas production has historically made it challenging to characterize the air quality or air pollution-related health impacts for this sector in the United States. Using an emissions inventory for the oil and natural gas sector that reflects information regarding the level and distribution of PM2.5 and ozone precursor emissions, we simulate annual mean PM2.5 and summer season average daily 8 h maximum ozone concentrations with the Comprehensive Air-Quality Model with extensions (CAMx). We quantify the incidence and economic value of PM2.5 and ozone health related effects using the environmental Benefits Mapping and Analysis Program (BenMAP). We find that ambient concentrations of PM2.5 and ozone, and associated health impacts, are highest in a handful of states including Colorado, Pennsylvania, Texas and West Virginia. On a per-ton basis, the benefits of reducing PM2.5 precursor emissions from this sector vary by pollutant species, and range from between $6,300 and $320,000, while the value of reducing ozone precursors ranges from $500 to $8,200 in the year 2025 (2015$). PMID- 30004689 TI - Characterization of the Interaction between Arginine Methyltransferase Hmt1 and Its Substrate Npl3: Use of Multiple Cross-Linkers, Mass Spectrometric Approaches, and Software Platforms. AB - This study investigated the enzyme-substrate interaction between Saccharomyces cerevisiae arginine methyltransferase Hmt1p and nucleolar protein Npl3p, using chemical cross linking/mass spectrometry (XL/MS). We show that XL/MS can capture transient interprotein interactions that occur during the process of methylation, involving a disordered region in Npl3p with tandem SRGG repeats, and we confirm that Hmt1p and Npl3p exist as homomultimers. Additionally, the study investigated the interdependencies between variables of an XL/MS experiment that lead to the identification of identical or different cross-linked peptides. We report that there are substantial benefits, in terms of biologically relevant cross-links identified, that result from the use of two mass-spectrometry-cleavable cross linkers [disuccinimido sulfoxide (DSSO) and disuccinimido dibutyric urea (DSBU)], two fragmentation approaches [collision-induced dissociation and electron transfer dissociation (CID+ETD)] and stepped high-energy collision dissociation (HCD)], and two programs (MeroX and XlinkX). We also show that there are specific combinations of XL/MS methods that are more successful than others for the two proteins investigated here; these are explored in detail in the text. Data are available via ProteomeXchange with identifier PXD008348. PMID- 30004691 TI - Dydrogesterone Causes Male Bias and Accelerates Sperm Maturation in Zebrafish ( Danio rerio). AB - Synthetic progestins are widely used in human and veterinary medicine. They can enter aquatic environments mainly via wastewater discharge and agricultural runoff, thus affecting fish populations in receiving waters. Here, we investigated the chronic effects of dydrogesterone (DDG) on zebrafish from 21 to 140 days post-fertilization (dpf) at 3.39, 33.1, and 329 ng L-1. The results showed that the male ratio increased with the exposure concentration, and after 120 days of exposure to 329 ng L-1, 98% of the fish were males. The DDG exposure during sex differentiation significantly increased the transcription of dmrt1 (1.83-fold) and apoptosis-related genes but suppressed the transcription of cyp19a1a (3.16-fold). Histological analysis showed that the exposure to DDG at 329 ng L-1 caused 61.5% of mature spermatocytes in males, while the exposure to DDG at 33.1 ng L-1 resulted in 14.7% of atretic follicles in females. Microarray analysis identified spermatogenesis-related gene ontology (endothelial barrier and immune response) in the testes at all concentrations. Genes from phagosome, lysosome, and sphingolipid metabolism pathways were enriched and could be responsible for sperm maturation. The findings from this study demonstrate that DDG in the aquatic environment can cause male bias and accelerate sperm maturation in zebrafish, resulting in potential high ecological risks to fish populations. PMID- 30004690 TI - An Open Library of Human Kinase Domain Constructs for Automated Bacterial Expression. AB - Kinases play a critical role in cellular signaling and are dysregulated in a number of diseases, such as cancer, diabetes, and neurodegeneration. Therapeutics targeting kinases currently account for roughly 50% of cancer drug discovery efforts. The ability to explore human kinase biochemistry and biophysics in the laboratory is essential to designing selective inhibitors and studying drug resistance. Bacterial expression systems are superior to insect or mammalian cells in terms of simplicity and cost effectiveness but have historically struggled with human kinase expression. Following the discovery that phosphatase coexpression produced high yields of Src and Abl kinase domains in bacteria, we have generated a library of 52 His-tagged human kinase domain constructs that express above 2 MUg/mL of culture in an automated bacterial expression system utilizing phosphatase coexpression (YopH for Tyr kinases and lambda for Ser/Thr kinases). Here, we report a structural bioinformatics approach to identifying kinase domain constructs previously expressed in bacteria and likely to express well in our protocol, experiments demonstrating our simple construct selection strategy selects constructs with good expression yields in a test of 84 potential kinase domain boundaries for Abl, and yields from a high-throughput expression screen of 96 human kinase constructs. Using a fluorescence-based thermostability assay and a fluorescent ATP-competitive inhibitor, we show that the highest expressing kinases are folded and have well-formed ATP binding sites. We also demonstrate that these constructs can enable characterization of clinical mutations by expressing a panel of 48 Src and 46 Abl mutations. The wild-type kinase construct library is available publicly via Addgene. PMID- 30004692 TI - Photoaffinity Cross-Linking and Unnatural Amino Acid Mutagenesis Reveal Insights into Calcitonin Gene-Related Peptide Binding to the Calcitonin Receptor-like Receptor/Receptor Activity-Modifying Protein 1 (CLR/RAMP1) Complex. AB - Calcitonin gene-related peptide (CGRP) binds to the complex of the calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein 1 (RAMP1). How CGRP interacts with the transmembrane domain (including the extracellular loops) of this family B receptor remains unclear. In this study, a photoaffinity cross-linker, p-azido l-phenylalanine (azF), was incorporated into CLR, chiefly in the second extracellular loop (ECL2) using genetic code expansion and unnatural amino acid mutagenesis. The method was optimized to ensure efficient photolysis of azF residues near the transmembrane bundle of the receptor. A CGRP analogue modified with fluorescein at position 15 was used for detection of ultraviolet-induced cross-linking. The methodology was verified by confirming the known contacts of CGRP to the extracellular domain of CLR. Within ECL2, the chief contacts were I284 on the loop itself and L291, at the top of the fifth transmembrane helix (TM5). Minor contacts were noted along the lip of ECL2 between S286 and L290 and also with M223 in TM3 and F349 in TM6. Full length molecular models of the bound receptor complex suggest that CGRP sits at the top of the TM bundle, with Thr6 of the peptide making contacts with L291 and H295. I284 is likely to contact Leu12 and Ala13 of CGRP, and Leu16 of CGRP is at the ECL/extracellular domain boundary of CLR. The reduced potency, Emax, and affinity of [Leu16Ala]-human alpha CGRP are consistent with this model. Contacts between Thr6 of CGRP and H295 may be particularly important for receptor activation. PMID- 30004694 TI - Real Gentile Statistical Systems: N-Annulenes. AB - Gentile statistics, which is famous for its advantages in dealing with composite particle systems, is a kind of fractional statistics. Lately, researchers are concentrating on finding real systems that obey Gentile statistics. Five years ago, we discovered that the cyclic hydrocarbon polyenes called N-annulenes in the Huckel model had certain correspondence with Gentile oscillators. According to their rotation and dihedral symmetry, these two systems had the same energy levels and partition functions. In this paper, we give further discussions. We discuss the transformations of wave functions between N-annulenes and Gentile oscillators, the creation and annihilation operators in site pictures of N annulenes, the coherent state, and the mathematical proofs of the intermediate commutation relations of operators. All of our works prove that N-annulenes in the Huckel model are real Gentile statistical systems and offer a new algebraic method to deal with the problems of electron-electron and electron-phonon interactions. PMID- 30004693 TI - Effects of Disease-Causing Mutations on the Conformation of Human Apolipoprotein A-I in Model Lipoproteins. AB - Plasma high-density lipoproteins (HDLs) are protein-lipid nanoparticles that transport lipids and protect against atherosclerosis. Human apolipoprotein A-I (apoA-I) is the principal HDL protein whose mutations can cause either aberrant lipid metabolism or amyloid disease. Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) was used to study the apoA-I conformation in model discoidal lipoproteins similar in size to large plasma HDL. We examined how point mutations associated with hereditary amyloidosis (F71Y and L170P) or atherosclerosis (L159R) influence the local apoA-I conformation in model lipoproteins. Unlike other apoA-I forms, the large particles showed minimal conformational heterogeneity, suggesting a fully extended protein conformation. Mutation-induced structural perturbations in lipid-bound protein were attenuated compared to the free protein and indicated close coupling between the two belt-forming apoA-I molecules. These perturbations propagated to distant lipoprotein sites, either increasing or decreasing their protection. This HDX MS study of large model HDL, compared with previous studies of smaller particles, ascertained that apoA-I's central region helps accommodate the protein conformation to lipoproteins of various sizes. This study also reveals that the effects of mutations on lipoprotein conformational dynamics are much weaker than those in a lipid-free protein. Interestingly, the mutation-induced perturbations propagate to distant sites nearly 10 nm away and alter their protection in ways that cannot be predicted from the lipoprotein structure and stability. We propose that long range mutational effects are mediated by both protein and lipid and can influence lipoprotein functionality. PMID- 30004696 TI - Exploiting Fluorescence Spectroscopy To Identify Magnetic Ionic Liquids Suitable for the Isolation of Oligonucleotides. AB - Magnetic ionic liquids (MILs), which incorporate paramagnetic ions, promise to minimize manual user intervention, decrease extraction times, and facilitate rapid recovery of the analyte-enriched extraction solvent. If, however, fluorescence is employed in the downstream analysis of an analyte tagged with a fluorophore, the paramagnetic ion may quench fluorescence by introducing new nonradiative processes. Thus, it is necessary to employ a paramagnetic ion that offers a compromise between possessing a high magnetic moment and not introducing new nonradiative channels. Mn(II), Fe(III), Co(II), and Ni(II) are considered in combination with phosphonium cations and anionic ligands based upon halides or hexafluoroacetylacetonate. Among the possibilities examined, MILs containing Mn(II) provide the best alternative for a model system involving DNA. PMID- 30004695 TI - The Design, Synthesis, and Characterizations of Spore Germination Inhibitors Effective against an Epidemic Strain of Clostridium difficile. AB - Clostridium difficile infections (CDI), particularly those caused by the BI/NAP1/027 epidemic strains, are challenging to treat. One method to address this disease is to prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified cholic amide m-sulfonic acid, CamSA, as an inhibitor of spore germination. However, CamSA is inactive against the hypervirulent strain R20291. To circumvent this problem, a series of cholic acid amides were synthesized and tested against R20291. The best compound in the series was the simple phenyl amide analogue which possessed an IC50 value of 1.8 MUM, more than 225 times as potent as the natural germination inhibitor, chenodeoxycholate. This is the most potent inhibitor of C. difficile spore germination described to date. QSAR and molecular modeling analysis demonstrated that increases in hydrophobicity and decreases in partial charge or polar surface area were correlated with increases in potency. PMID- 30004697 TI - Design and Synthesis of Tubulin and Histone Deacetylase Inhibitor Based on iso Combretastatin A-4. AB - Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1 diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity. PMID- 30004698 TI - Formulation of Small Test Sets Using Large Test Sets for Efficient Assessment of Quantum Chemistry Methods. AB - In the present study, we have examined in detail literature data of deviations for a wide range of (mainly) DFT methods for the extensive MGCDB82 set (~4400 data points) of main-group thermochemical quantities. We use the data and standard statistical techniques (lasso regularization and forward selection) to devise the MG8 model for linearly combining assessment results of a collection of small data sets to accurately estimate the MAD of MGCDB82. The MG8 model contains a total of 64 data points representing noncovalent interactions, isomerization energies, thermochemical properties, and barrier heights. It is thus well suited for rapid evaluation of new quantum chemistry procedures. We propose that a value of ~4 kJ mol-1 for an estimated MAD by the MG8 model (EMADMG8) to be an initial indicator of a highly robust quantum chemistry method, with large deviations occurring mainly for properties (such as heats of formation) that are known to be difficult to accurately compute. For methods with larger EMADs, we emphasize the importance of more thorough testing, as these methods are likely to have a larger number of outliers, and it may be less trivial to anticipate circumstances under which large deviations occur. In relation to this aspect, we have applied the same generally applicable statistical techniques to further formulate small-data set models for assessing the accuracy for some properties that are not covered by MG8 nor by MGCDB82. They include the MOR13 model for metal-organic reactions, the SBG5 model for semiconductor band gaps, and MB13 for stress-testing methods with artificial species. PMID- 30004699 TI - Correction to NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on Trypanosoma cruzi and Human Enzymes. PMID- 30004700 TI - Degradation of Sulfur Mustard on KF/Al2O3: The Role of Organic Solvents and Active Species. AB - Solvent effects on the ability of KF/Al2O3 supports to degrade the warfare agent sulfur mustard (HD) were explored. RP-KF/Al2O3 possessing hydroxide ions and ECUF/KF/Al2O3 holding fluoride ions were examined. Reactions on RP-KF/Al2O3 containing 10 wt % of organic solvents were faster than those on ECUF/KF/Al2O3. Additionally, RP-KF/Al2O3 led to elimination products, while ECUF/KF/Al2O3 mainly led to substitution derivatives. Enlarging the solvent amounts to 90 wt % resulted in decreased reaction rates. The significance of solvent identity/amount and active species is discussed. PMID- 30004701 TI - Correction to Synthesis of 2-acylindoles via Ag- and Cu-Catalyzed anti-Michael Hydroamination of beta-(2-Aminophenyl)-alpha,beta-ynones: Experimental Results and DFT Calculations. PMID- 30004702 TI - Reactions of N-Heterocyclic Carbene Boranes with 5-Diazo-2,2-dimethyl-1,3-dioxane 4,6-dione: Synthesis of Mono- and Bis-hydrazonyl NHC-Boranes. AB - N-Heterocyclic carbene boranes (NHC-boranes) react with 5-diazo-2,2-dimethyl-1,3 dioxane-4,6-dione at 40 degrees C in dichloromethane to provide NHC-boryl hydrazone derivatives of 2,2-dimethyl-1,3-dioxane-4,6-dione. These hydrazones disproportionate to bis-hydrazones on treatment with diiodine in dichloromethane at room temperature. The mono- and bis-hydrazones are yellow solids that are stable to chromatography and storage. PMID- 30004703 TI - Water Sculpts the Distinctive Shapes and Dynamics of the Tumor-Associated Carbohydrate Tn Antigens: Implications for Their Molecular Recognition. AB - The tumor-associated carbohydrate Tn antigens include two variants, alphaGalNAc- O-Thr and alphaGalNAc- O-Ser. In solution, they exhibit dissimilar shapes and dynamics and bind differently to the same protein receptor. Here, we demonstrate experimentally and theoretically that their conformational preferences in the gas phase are highly similar, revealing the essential role of water. We propose that water molecules prompt the rotation around the glycosidic linkage in the threonine derivative, shielding its hydrophobic methyl group and allowing an optimal solvation of the polar region of the antigen. The unusual arrangement of alphaGalNAc- O-Thr features a water molecule bound into a "pocket" between the sugar and the threonine. This mechanism is supported by trapping, for the first time, such localized water in the crystal structures of an antibody bound to two glycopeptides that comprise fluorinated Tn antigens in their structure. According to several reported X-ray structures, installing oxygenated amino acids in specific regions of the receptor capable of displacing the bridging water molecule to the bulk-solvent may facilitate the molecular recognition of the Tn antigen with threonine. Overall, our data also explain how water fine-tunes the 3D structure features of similar molecules, which in turn are behind their distinct biological activities. PMID- 30004705 TI - Xeno Nucleic Acid Nanosensors for Enhanced Stability Against Ion-Induced Perturbations. AB - The omnipresence of salts in biofluids creates a pervasive challenge in designing sensors suitable for in vivo applications. Fluctuations in ion concentrations have been shown to affect the sensitivity and selectivity of optical sensors based on single-walled carbon nanotubes wrapped with single-stranded DNA (ssDNA SWCNTs). We herein observe fluorescence wavelength shifting for ssDNA-SWCNT-based optical sensors in the presence of divalent cations at concentrations above 3.5 mM. In contrast, no shifting was observed for concentrations up to 350 mM for sensors bioengineered with increased rigidity using xeno nucleic acids (XNAs). Transient fluorescence measurements reveal distinct optical transitions for ssDNA and XNA-based wrappings during ion-induced conformation changes, with XNA-based sensors showing increased permanence in conformational and signal stability. This demonstration introduces synthetic biology as a complementary means for enhancing nanotube optoelectronic behavior, unlocking previously unexplored possibilities for developing nanobioengineered sensors with augmented capabilities. PMID- 30004704 TI - Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315. AB - IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive alpha,beta-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design. PMID- 30004706 TI - Selective Synthesis of Diaryl Sulfoxides and m-Arylthio Sulfones from Arylsulfinic Acids and Arenes via BF3-Promoted C-S Bond Formation. AB - A novel and efficient method for selective synthesis of diaryl sulfoxides and m arylthio sulfones has been achieved from readily available arylsulfinic acids and arenes via an unusual sulfinyl cation, providing a range of structurally diverse products in good to excellent yields under mild conditions. Notably, mechanistic investigations suggested m-arylthio sulfones were generated from diaryl sulfoxides and sulfinyl cation by a sequence of redox reaction and electrophilic aromatic substitution process. PMID- 30004707 TI - Gold(III)-Catalyzed Regioselective Oxidation/Cycloisomerization of Diynes: An Approach to Fused Furan Derivatives. AB - The first gold(III)-catalyzed regioselective oxidation/cycloisomerization of diynes 1 with pyridine N-oxide as the oxidant was developed, providing a range of synthetically valuable and useful fused furan derivatives 3 in moderate to good yields. Control experiments and the confirmation structure of minor products 5 suggest that this chemistry was a concerted gold(III)-catalyzed oxidation/SN2' type addition/cyclization process via a beta-gold vinyloxypyridinium intermediate and a putative vinyl cation intermediate. PMID- 30004708 TI - An Alternative Approach to Estimate Solute Concentration: Exploiting the Information Embedded in the Solid Phase. AB - The solute concentration in crystallization processes is generally estimated by observing properties of the liquid phase. Here, a novel method for online estimation of the change in the solute concentration caused by seeded batch crystallization or dissolution of a population of crystals in suspension is presented. The method is based on multiprojection imaging to track variations in the total solid volume of the population, thus enabling inference of the solute concentration through the mass conservation constraint. The solute concentration estimates obtained in this way are validated by using them to measure the solubilities of beta l-glutamic acid and vanillin in water within certain temperature ranges and comparing them to literature data. The presented method shows promise in estimating the solute concentration reliably under circumstances where employing conventional techniques is challenging. PMID- 30004709 TI - Unraveling Photodimerization of Cyclohexasilane from Molecular Dynamics Studies. AB - Photoinduced reactions of a pair of cyclohexasilane (CHS) monomers are explored by time-dependent excited-state molecular dynamics (TDESMD) calculations. In TDESMD trajectories, one observes vivid reaction events including dimerization and fragmentation. A general reaction pathway is identified as (i) ring-opening formation of a dimer, (ii) rearrangement induced by bond breaking, and (iii) decomposition through the elimination of small fragments. The identified pathway supports the chemistry proposed for the fabrication of silicon-based materials using CHS as a precursor. In addition, we find dimers have smaller HOMO-LUMO gaps and exhibit a red shift and line-width broadening in the computed photoluminescence spectra compared with a pair of CHS monomers. PMID- 30004710 TI - Parallel Approaches for the Functionalization of Thietes: alpha-Metalation versus C-H Activation. AB - For the first time, an approach to 3,4-disubstituted thietes was developed through two complementary paths. While the first one relies on alpha-metalation, the second is based on direct C-H functionalization. A new library of sophisticated sulfur-containing four-membered rings is described, paving the way to new bioactive analogues and small heterocycle incorporation. PMID- 30004711 TI - A Highly Regio- and Stereoselective Syntheses of alpha-Halo Enamides, Vinyl Thioethers, and Vinyl Ethers with Aqueous Hydrogen Halide in Two-Phase Systems. AB - A metal-free regio- and stereoselective method is achieved for the preparation of ( E)-configured alpha-halo enamides, vinyl thioethers, and vinyl ethers using aqueous HX (X = F, Cl, Br, I), which features high functional group compatibility and regio- and stereoselectivity, mild conditions, high efficiency, and rapid transformation. Additionally, the isomers could be yielded readily from the ( E) configured alpha-halo enamides via photocatalysis or under Sonogashira coupling conditions. PMID- 30004712 TI - Three-Dimensional Composition and Electric Potential Mapping of III-V Core Multishell Nanowires by Correlative STEM and Holographic Tomography. AB - The nondestructive characterization of nanoscale devices, such as those based on semiconductor nanowires, in terms of functional potentials is crucial for correlating device properties with their morphological/materials features, as well as for precisely tuning and optimizing their growth process. Electron holographic tomography (EHT) has been used in the past to reconstruct the total potential distribution in three-dimension but hitherto lacked a quantitative approach to separate potential variations due to chemical composition changes (mean inner potential, MIP) and space charges. In this Letter, we combine and correlate EHT and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) tomography on an individual ?111? oriented GaAs-AlGaAs core-multishell nanowire (NW). We obtain excellent agreement between both methods in terms of the determined Al concentration within the AlGaAs shell, as well as thickness variations of the few nanometer thin GaAs shell acting as quantum well tube. Subtracting the MIP determined from the STEM tomogram, enables us to observe functional potentials at the NW surfaces and at the Au-NW interface, both ascribed to surface/interface pinning of the semiconductor Fermi level. PMID- 30004713 TI - Correction to [2.2.2]- to [3.2.1]-Bicycle Skeletal Rearrangement Approach to the Gibberellin Family of Natural Products. PMID- 30004714 TI - Effects of Spreading Conditions on the Aggregation Behavior of a Symmetric Diblock Copolymer Polystyrene- block-poly(methyl methacrylate) at the Air/Water Interface. AB - Langmuir monolayers and Langmuir-Blodgett (LB) films of a symmetric diblock copolymer polystyrene- block-poly(methyl methacrylate) (PS- b-PMMA) were characterized by the film balance technique and tapping mode atomic force microscopy, respectively. Effects of both the spreading solution concentration and the surface concentration on the aggregation behavior of PS- b-PMMA at the air/water interface and the morphologies of its LB films were studied in detail. When the monolayers spread in different concentrations (<=0.50 mg/mL), all their initial morphologies exhibit tiny circular micelles because of the long hydrophilic PMMA block in the copolymer. The initial tiny circular micelles form spontaneously and then aggregate into small ones upon compression, which can further coalesce into rodlike aggregates or large micelles depending on the spreading concentrations. The LB films of PS- b-PMMA usually exhibit various mixed structures of rodlike aggregates and circular micelles, which can further transform into labyrinth patterns under some special spreading conditions. Besides spreading concentration and volume, we discover that the detailed spreading process should also be responsible for the initial and final morphologies of the LB films. Furthermore, the LB films prepared under different spreading conditions can be regarded as in the equilibrium or nonequilibrium structures because of the kinetic effect difference resulting from the different PS chain entanglement degrees. PMID- 30004715 TI - Microscale-Resolution Thermal Mapping Using a Flexible Platform of Patterned Quantum Sensors. AB - Temperature sensors with micro- and nanoscale spatial resolution have long been explored for their potential to investigate the details of physical systems at an unprecedented scale. In particular, the rapid miniaturization of transistor technology, with its associated steep boost in power density, calls for sensors that accurately monitor heating distributions. Here, we report on a simple and scalable fabrication approach, based on directed self-assembly and transfer printing techniques, to constructing arrays of nanodiamonds containing temperature-sensitive fluorescent spin defects. The nanoparticles are embedded within a low-thermal-conductivity matrix that allows for repeated use on a wide range of systems with minimal spurious effects. Additionally, we demonstrate access to a wide spectrum of array parameters ranging from sparser single particle arrays, with the potential for quantum computing applications, to denser devices with 98 +/- 0.8% yield and stronger photoluminescence signals, ideal for temperature measurements. With these, we experimentally reconstruct the temperature map of an operating coplanar waveguide to confirm the accuracy of these platforms. PMID- 30004716 TI - Self-Adapted Floquet Dynamics of Ultracold Bosons in a Cavity. AB - Floquet dynamics of a quantum system subject to periodic modulations of system parameters provides a powerful tool for engineering new quantum matter with exotic properties. While system dynamics is significantly altered, the periodic modulation itself is usually induced externally and independent of Floquet dynamics. Here we propose a new type of Floquet physics for a Bose-Einstein condensate (BEC) subject to a shaken lattice generated inside a cavity, where the shaken lattice and atomic Floquet bands are mutually dependent, resulting in self adapted Floquet dynamics. In particular, the shaken lattice induces Floquet quasienergy bands for the BEC, whose backaction leads to a self-adapted dynamical normal-superradiant phase transition for the shaken lattice. Such self-adapted Floquet dynamics shows two surprising and unique features: (i) The normal superradiant phase transition possesses a hysteresis even without atom interactions. (ii) The dynamical atom-cavity steady state could exist at free energy maxima. The atom interactions strongly affect the phase transition of the BEC from zero to finite momenta. Our results provide a powerful platform for exploring self-adapted Floquet physics, which may open an avenue for engineering novel quantum materials. PMID- 30004717 TI - Active Atoms and Interstitials in Two-Dimensional Colloidal Crystals. AB - We study experimentally and numerically the motion of a self-phoretic active particle in two-dimensional loosely packed colloidal crystals at fluid interfaces. Two scenarios emerge depending on the interactions between the active particle and the lattice: the active particle either navigates throughout the crystal as an interstitial or is part of the lattice and behaves as an active atom. Active interstitials undergo a run-and-tumble-like motion, with the passive colloids of the crystal acting as tumbling sites. Instead, active atoms exhibit an intermittent motion, stemming from the interplay between the periodic potential landscape of the passive crystal and the particle's self-propulsion. Our results constitute the first step towards the realization of non-close-packed crystalline phases with internal activity. PMID- 30004718 TI - Measuring the Winding Number in a Large-Scale Chiral Quantum Walk. AB - We report the experimental measurement of the winding number in an unitary chiral quantum walk. Fundamentally, the spin-orbit coupling in discrete time quantum walks is implemented via a birefringent crystal collinearly cut based on a time multiplexing scheme. Our protocol is compact and avoids extra loss, making it suitable for realizing genuine single-photon quantum walks at a large scale. By adopting a heralded single photon as the walker and with a high time resolution technology in single-photon detection, we carry out a 50-step Hadamard discrete time quantum walk with high fidelity up to 0.948+/-0.007. Particularly, we can reconstruct the complete wave function of the walker that starts the walk in a single lattice site through the local tomography of each site. Through a Fourier transform, the wave function in quasimomentum space can be obtained. With this ability, we propose and report a method to reconstruct the eigenvectors of the system Hamiltonian in quasimomentum space and directly read out the winding numbers in different topological phases (trivial and nontrivial) in the presence of chiral symmetry. By introducing nonequivalent time frames, we show that whole topological phases in a periodically driven system can also be characterized by two different winding numbers. Our method can also be extended to the high winding number situation. PMID- 30004720 TI - Control of Harmonic Generation by the Time Delay Between Two-Color, Bicircular Few-Cycle Mid-IR Laser Pulses. AB - We study control of high-order harmonic generation (HHG) driven by time-delayed, few-cycle omega and 2omega counterrotating mid-IR pulses. Our numerical and analytical study shows that the time delay between the two-color pulses allows control of the harmonic positions, both those allowed by angular momentum conservation and those seemingly forbidden by it. Moreover, the helicity of any particular harmonic is tunable from left to right circular without changing the driving pulse helicity. The highest HHG yield occurs for a time delay comparable to the fundamental period T=2pi/omega. PMID- 30004719 TI - Femtosecond X-Ray Diffraction Studies of the Reversal of the Microstructural Effects of Plastic Deformation during Shock Release of Tantalum. AB - We have used femtosecond x-ray diffraction to study laser-shocked fiber-textured polycrystalline tantalum targets as the 37-253 GPa shock waves break out from the free surface. We extract the time and depth-dependent strain profiles within the Ta target as the rarefaction wave travels back into the bulk of the sample. In agreement with molecular dynamics simulations, the lattice rotation and the twins that are formed under shock compression are observed to be almost fully eliminated by the rarefaction process. PMID- 30004721 TI - Silicon-Based Optical Mirror Coatings for Ultrahigh Precision Metrology and Sensing. AB - Thermal noise of highly reflective mirror coatings is a major limit to the sensitivity of many precision laser experiments with strict requirements such as low optical absorption. Here, we investigate amorphous silicon and silicon nitride as an alternative to the currently used combination of coating materials, silica, and tantala. We demonstrate an improvement by a factor of ~55 with respect to the lowest so far reported optical absorption of amorphous silicon at near-infrared wavelengths. This reduction was achieved via a combination of heat treatment, final operation at low temperature, and a wavelength of 2 MUm instead of the more commonly used 1550 nm. Our silicon-based coating offers a factor of 12 thermal noise reduction compared to the performance possible with silica and tantala at 20 K. In gravitational-wave detectors, a noise reduction by a factor of 12 corresponds to an increase in the average detection rate by three orders of magnitude (~12^{3}). PMID- 30004722 TI - Solvation in Space-time: Pretransition Effects in Trajectory Space. AB - We demonstrate pretransition effects in space-time in trajectories of systems in which the dynamics displays a first-order phase transition between distinct dynamical phases. These effects are analogous to those observed for thermodynamic first-order phase transitions, most notably the hydrophobic effect in water. Considering the (infinite temperature) East model as an elementary example, we study the properties of "space-time solvation" by examining trajectories where finite space-time regions are conditioned to be inactive in an otherwise active phase. We find that solvating an inactive region of space-time within an active trajectory shows two regimes in the dynamical equivalent of solvation free energy: an "entropic" small solute regime in which uncorrelated fluctuations are sufficient to evacuate activity from the solute, and an "energetic" large solute regime which involves the formation of a solute-induced inactive domain with an associated active-inactive interface bearing a dynamical interfacial tension. We also show that as a result of this dynamical interfacial tension there is a dynamical analog of the hydrophobic collapse that drives the assembly of large hydrophobes in water. We discuss the general relevance of these results to the properties of dynamical fluctuations in systems with slow collective relaxation such as glass formers. PMID- 30004723 TI - Parity-Controlled 2pi Josephson Effect Mediated by Majorana Kramers Pairs. AB - We study a time-reversal-invariant topological superconductor island hosting spatially separated Majorana Kramers pairs, with weak tunnel couplings to two s wave superconducting leads. When the topological superconductor island is in the Coulomb blockade regime, we predict that a Josephson current flows between the two leads due to a nonlocal transfer of Cooper pairs mediated by the Majorana Kramers pairs. Interestingly, we find that the sign of the Josephson current is controlled by the joint parity of all four Majorana bound states on the island. Consequently, this parity-controlled Josephson effect can be used for qubit readout in Majorana-based quantum computing. PMID- 30004724 TI - 18-Qubit Entanglement with Six Photons' Three Degrees of Freedom. AB - Full control of multiple degrees of freedom of multiple particles represents a fundamental ability for quantum information processing. We experimentally demonstrate an 18-qubit Greenberger-Horne-Zeilinger entanglement by simultaneous exploiting three different degrees of freedom of six photons, including their paths, polarization, and orbital angular momentum. We develop high-stability interferometers for reversible quantum logic operations between the photons' different degrees of freedom with precision and efficiencies close to unity, enabling simultaneous readout of 2^{18}=262 144 outcome combinations of the 18 qubit state. A state fidelity of 0.708+/-0.016 is measured, confirming the genuine entanglement of all 18 qubits. PMID- 30004726 TI - Maximal Randomness Generation from Steering Inequality Violations Using Qudits. AB - We consider the generation of randomness based upon the observed violation of an Einstein-Podolsky-Rosen (EPR) steering inequality, known as one-sided device independent randomness generation. We show that in the simplest scenario involving only two parties and two measurements for the uncharacterised party with d outcomes-that there exist EPR steering inequalities whose maximal violation certifies maximal randomness generation, equal to log(d) bits. We further show that all pure partially entangled full-Schmidt-rank states in all dimensions can achieve maximal violation of these inequalities, and thus lead to maximal randomness generation in the one-sided device-independent setting. More generally, the amount of randomness that can be generated is given by a semidefinite program, which we use to study the behavior for nonmaximal violations of the inequalities. PMID- 30004727 TI - Distinguishing Coherent and Thermal Photon Noise in a Circuit Quantum Electrodynamical System. AB - In the cavity-QED architecture, photon number fluctuations from residual cavity photons cause qubit dephasing due to the ac Stark effect. These unwanted photons originate from a variety of sources, such as thermal radiation, leftover measurement photons, and cross talk. Using a capacitively shunted flux qubit coupled to a transmission line cavity, we demonstrate a method that identifies and distinguishes coherent and thermal photons based on noise-spectral reconstruction from time-domain spin-locking relaxometry. Using these measurements, we attribute the limiting dephasing source in our system to thermal photons rather than coherent photons. By improving the cryogenic attenuation on lines leading to the cavity, we successfully suppress residual thermal photons and achieve T_{1}-limited spin-echo decay time. The spin-locking noise spectroscopy technique allows broad frequency access and readily applies to other qubit modalities for identifying general asymmetric nonclassical noise spectra. PMID- 30004728 TI - Geometry of Wave Propagation on Active Deformable Surfaces. AB - Fundamental biological and biomimetic processes, from tissue morphogenesis to soft robotics, rely on the propagation of chemical and mechanical surface waves to signal and coordinate active force generation. The complex interplay between surface geometry and contraction wave dynamics remains poorly understood, but it will be essential for the future design of chemically driven soft robots and active materials. Here, we couple prototypical chemical wave and reaction diffusion models to non-Euclidean shell mechanics to identify and characterize generic features of chemomechanical wave propagation on active deformable surfaces. Our theoretical framework is validated against recent data from contractile wave measurements on ascidian and starfish oocytes, producing good quantitative agreement in both cases. The theory is then applied to illustrate how geometry and preexisting discrete symmetries can be utilized to focus active elastic surface waves. We highlight the practical potential of chemomechanical coupling by demonstrating spontaneous wave-induced locomotion of elastic shells of various geometries. Altogether, our results show how geometry, elasticity, and chemical signaling can be harnessed to construct dynamically adaptable, autonomously moving mechanical surface waveguides. PMID- 30004729 TI - Geometric Frustration and Solid-Solid Transitions in Model 2D Tissue. AB - We study the mechanical behavior of two-dimensional cellular tissues by formulating the continuum limit of discrete vertex models based on an energy that penalizes departures from a target area A_{0} and a target perimeter P_{0} for the component cells of the tissue. As the dimensionless target shape index s_{0}=(P_{0}/sqrt[A_{0}]) is varied, we find a transition from a soft elastic regime for a compatible target perimeter and area to a stiffer nonlinear elastic regime frustrated by geometric incompatibility. We show that the ground state in the soft regime has a family of degenerate solutions associated with zero modes for the target area and perimeter. The onset of geometric incompatibility at a critical s_{0}^{c} lifts this degeneracy. The resultant energy gap leads to a nonlinear elastic response distinct from that obtained in classical elasticity models. We draw an analogy between cellular tissues and anelastic deformations in solids. PMID- 30004730 TI - Role of Synaptic Stochasticity in Training Low-Precision Neural Networks. AB - Stochasticity and limited precision of synaptic weights in neural network models are key aspects of both biological and hardware modeling of learning processes. Here we show that a neural network model with stochastic binary weights naturally gives prominence to exponentially rare dense regions of solutions with a number of desirable properties such as robustness and good generalization performance, while typical solutions are isolated and hard to find. Binary solutions of the standard perceptron problem are obtained from a simple gradient descent procedure on a set of real values parametrizing a probability distribution over the binary synapses. Both analytical and numerical results are presented. An algorithmic extension that allows to train discrete deep neural networks is also investigated. PMID- 30004731 TI - Atomic-Scale Measurement of Flexoelectric Polarization at SrTiO_{3} Dislocations. AB - Owing to the broken translational symmetry at dislocations, a strain gradient naturally exists around the dislocation cores and can significantly influence the electrical and mechanical properties. We use aberration corrected scanning transmission electron microscopy to directly measure the flexoelectric polarization (~28 MUC cm^{-2}) at dislocation cores in SrTiO_{3}. The polarization charges can interact with the nonstoichiometric dislocation cores and thus impact the electrical activities. Our findings can help us to understand the properties of dislocations in perovskite, providing new insights into the design of new devices via defect engineering such as bicrystal fabrication and thin film growth. PMID- 30004732 TI - Vector Effective Field Theories from Soft Limits. AB - We present a bottom-up construction of vector effective field theories using the infrared structure of scattering amplitudes. Our results employ two distinct probes of soft kinematics: multiple soft limits and single soft limits after dimensional reduction applicable in four and general dimensions, respectively. Both approaches uniquely specify the Born-Infeld (BI) model as the only theory of vectors completely fixed by certain infrared conditions which generalize the Adler zero for pions. These soft properties imply new recursion relations for on shell scattering amplitudes in BI theory and suggest the existence of a wider class of vector effective field theories. PMID- 30004733 TI - Revealing the Behavior of Photons in a Birefringent Interferometer. AB - The interferometer is one of the most important devices for revealing the nature of light and for precision optical metrology. Although many experiments were performed for probing photon behavior in various configurations, a complete study of photon behavior in a birefringent interferometer has not been performed, to our knowledge. By using an environmental turbulence immune Mach-Zehnder interferometer, we observe tunable photonic beatings by rotating a birefringent crystal versus the temperature of the crystal for both the single photon and two photons. Furthermore, the two-photon interference fringes beat 2 times faster than the single-photon interference fringes. This beating effect is used to determine the thermal dispersion coefficients of the two principal refractive axes with a single measurement: the two-photon interference shows superresolution and high sensitivity. Obvious differences between two-photon and single-photon interference are also revealed in unbalanced situations. In addition, the influence of the photon bandwidth on the beating behaviors that come from polarization-dependent decoherence is also investigated. Our findings will be important for better understanding the behavior of two-photon interference in a birefringent interferometer and for precision optical metrology with quantum enhancement. PMID- 30004734 TI - Efficient Quantum Measurement Engines. AB - We propose quantum engines powered entirely by a position-resolving measurement performed on a quantum particle. These engines produce work by moving the quantum particle against a force. Unlike classical information-driven engines (e.g., Maxwell's demon), the energy is not extracted from a thermal hot source but directly from the observation process via a partial wave-function collapse of the particle. We present results for the work done and the efficiency for different values of the engine parameters. Feedback is required for optimal performance. We find that unit efficiency can be approached when one measurement outcome prepares the initial state of the next engine cycle, while the other outcomes leave the original state nearly unchanged. PMID- 30004735 TI - Role of Kinetic Instability in Runaway-Electron Avalanches and Elevated Critical Electric Fields. AB - The effects of kinetic whistler wave instabilities on the runaway-electron (RE) avalanche is investigated. With parameters from experiments at the DIII-D National Fusion Facility, we show that RE scattering from excited whistler waves can explain several poorly understood experimental results. We find an enhancement of the RE avalanche for low density and high electric field, but for high density and low electric field the scattering can suppress the avalanche and raise the threshold electric field, bringing the present model much closer to observations. The excitation of kinetic instabilities and the scattering of resonant electrons are calculated self-consistently using a quasilinear model and local approximation. We also explain the observed fast growth of electron cyclotron emission signals and excitation of very low-frequency whistler modes observed in the quiescent RE experiments at DIII-D tokamak. Simulations using ITER parameters show that by controlling the background thermal plasma density and temperature, the plasma waves can also be excited spontaneously in tokamak disruptions and the avalanche generation of runaway electrons may be suppressed. PMID- 30004736 TI - High Spin-Flip Efficiency at 255 GeV for Polarized Protons in a Ring With Two Full Siberian Snakes. AB - In polarized proton collision experiments, it is highly advantageous to flip the spin of each bunch of protons during the stores to reduce the systematic errors. Experiments done at energies less than 2 GeV have demonstrated a spin-flip efficiency over 99%. At high energy colliders with Siberian snakes, a single magnet spin flipper does not work because of the large spin tune spread and the generation of multiple, overlapping resonances. A more sophisticated spin flipper, constructed of nine-dipole magnets, was used to flip the spin in the BNL Relativistic Heavy Ion Collider. A special optics choice was also used to make the spin tune spread very small. A 97% spin-flip efficiency was measured at both 24 and 255 GeV. These results show that efficient spin flipping can be achieved at high energies using a nine-magnet spin flipper. PMID- 30004738 TI - Extreme Ultraviolet Beam Enhancement by Relativistic Surface Plasmons. AB - The emission of high-order harmonics in the extreme ultraviolet range from the interaction of a short, intense laser pulse with a grating target is investigated experimentally. When resonantly exciting a surface plasmon, both the intensity and the highest order observed for the harmonic emission along the grating surface increase with respect to a flat target. Harmonics are obtained when a suitable density gradient is preformed at the target surface, demonstrating the possibility to manipulate the grating profile on a nanometric scale without preventing the surface plasmon excitation. In support of this, the harmonic emission is spatiotemporally correlated to the acceleration of multi-MeV electron bunches along the grating surface. Particle-in-cell simulations reproduce the experimental results and give insight on the mechanism of high harmonic generation in the presence of surface plasmons. PMID- 30004737 TI - Aging Rate of Spin Glasses from Simulations Matches Experiments. AB - Experiments on spin glasses can now make precise measurements of the exponent z(T) governing the growth of glassy domains, while our computational capabilities allow us to make quantitative predictions for experimental scales. However, experimental and numerical values for z(T) have differed. We use new simulations on the Janus II computer to resolve this discrepancy, finding a time-dependent z(T,t_{w}), which leads to the experimental value through mild extrapolations. Furthermore, theoretical insight is gained by studying a crossover between the T=T_{c} and T=0 fixed points. PMID- 30004741 TI - Dynamically Heterogeneous Relaxation of Entangled Polymer Chains. AB - Stress relaxation following deformation of an entangled polymeric liquid is thought to be affected by transient reforming of chain entanglements. In this work, we use single molecule techniques to study the relaxation of individual polymers in the transition regime from unentangled to entangled solutions. Our results reveal the emergence of dynamic heterogeneity underlying polymer relaxation behavior, including distinct molecular subpopulations described by a single-mode and a double-mode exponential relaxation process. The slower double mode timescale tau_{d,2} is consistent with a characteristic reptation time, whereas the single-mode timescale tau_{s} and the fast double-mode timescale tau_{d,1} are attributed to local regions of transient disentanglement due to deformation. PMID- 30004740 TI - Water-Compression Gating of Nanopore Transport. AB - Electric field-driven motion of biomolecules is a process essential to many analytics methods, in particular, to nanopore sensing, where a transient reduction of nanopore ionic current indicates the passage of a biomolecule through the nanopore. However, before any molecule can be examined by a nanopore, the molecule must first enter the nanopore from the solution. Previously, the rate of capture by a nanopore was found to increase with the strength of the applied electric field. Here, we theoretically show that, in the case of narrow pores in graphene membranes, increasing the strength of the electric field can not only decrease the rate of capture, but also repel biomolecules from the nanopore. As the strong electric field polarizes water near and within the nanopore, the high gradient of the field also produces a strong dielectrophoretic force that compresses the water. The pressure difference caused by the sharp water density gradient produces a hydrostatic force that repels DNA or proteins from the nanopore, preventing, in certain conditions, their capture. We show that such local compression of fluid can regulate the transport of biomolecules through nanoscale passages in the absence of physical gates and sort proteins according to their phosphorylated states. PMID- 30004742 TI - Pressure-Induced Sublattice Disordering in SnO_{2}: Invasive Selective Percolation. AB - SnO_{2} powders and single crystal have been studied under high pressure using Raman spectroscopy and ab initio simulations. The pressure-induced changes are shown to drastically depend on the form of the samples. The single crystal exhibits phase transitions as reported in the literature, whereas powder samples show a disordering of the oxygen sublattice in the first steps of compression. This behavior is proposed to be related to the defect density, an interpretation supported by ab initio simulations. The link between the defect density and an amorphouslike Raman signal is discussed in terms of the invasive percolation of the anionic sublattice. The resistance of the cationic sublattice to the disorder propagation is discussed in terms of cation close packing. This result on SnO_{2} may be extended to other systems and questions a "traditional" crystallographic description based on polyhedra packing, as a decoupling between both sublattices is observed. PMID- 30004743 TI - Soft-Photon Corrections to B[over -]->Dtau^{-}nu[over -]_{tau} Relative to B[over -]->DMU^{-}nu[over -]_{MU}. AB - We evaluate long-distance electromagnetic (QED) contributions to B[over -]^{0} >D^{+}tau^{-}nu[over -]_{tau} and B^{-}->D^{0}tau^{-}nu[over -]_{tau} relative to B[over -]^{0}->D^{+}MU^{-}nu[over -]_{MU} and B^{-}->D^{0}MU^{-}nu[over -]_{MU}, respectively, in the standard model. We point out that the QED corrections to the ratios R(D^{+}) and R(D^{0}) are not negligible, contrary to the expectation that radiative corrections are almost canceled out in the ratio of the two branching fractions. The reason is that long-distance QED corrections depend on the masses and relative velocities of the daughter particles. We find that theoretical predictions for R(D^{+})^{tau/MU} and R(D^{0})^{tau/MU} can be amplified by ~4% and ~3%, respectively, for the soft-photon energy cut in the range 20-40 MeV. PMID- 30004744 TI - New Constraints on Radii and Tidal Deformabilities of Neutron Stars from GW170817. AB - We explore in a parameterized manner a very large range of physically plausible equations of state (EOSs) for compact stars for matter that is either purely hadronic or that exhibits a phase transition. In particular, we produce two classes of EOSs with and without phase transitions, each containing one million EOSs. We then impose constraints on the maximum mass (M<2.16 M_{?}) and on the dimensionless tidal deformability (Lambda[over ~]<800) deduced from GW170817, together with recent suggestions of lower limits on Lambda[over ~]. Exploiting more than 10^{9} equilibrium models for each class of EOSs, we produce distribution functions of all the stellar properties and determine, among other quantities, the radius that is statistically most probable for any value of the stellar mass. In this way, we deduce that the radius of a purely hadronic neutron star with a representative mass of 1.4 M_{?} is constrained to be 12.00375, again at a 2sigma level. On the other hand, because EOSs with a phase transition allow for very compact stars on the so called "twin-star" branch, small radii are possible with such EOSs although not probable, i.e., 8.5335.5 at a 3sigma level. Finally, since these EOSs exhibit upper limits on Lambda[over ~], the detection of a binary with a total mass of 3.4 M_{?} and Lambda[over ~]_{1.7}>461 can rule out twin-star solutions. PMID- 30004746 TI - Externally Controlled Magnetism and Band Gap in Twisted Bilayer Graphene. AB - We theoretically study the effects of electron-electron interaction in twisted bilayer graphene in a transverse dc electric field. When the twist angle is not very small, the electronic spectrum of the bilayer consists of four Dirac cones inherited from each graphene layer. An applied bias voltage leads to the appearance of two holelike and two electronlike Fermi surface sheets with perfect nesting among electron and hole components. Such a band structure is unstable with respect to the exciton band-gap opening due to the screened Coulomb interaction. The exciton order parameter is accompanied by spin-density-wave order. The gap depends on the twist angle and can be varied by a bias voltage. This result correlates well with recent transport measurements [J.-B. Liu et al., Sci. Rep. 5, 15285 (2015)SRCEC32045-232210.1038/srep15285]. Our proposal allows the coexistence of (i) an externally controlled semiconducting gap and (ii) a nontrivial multicomponent magnetic order. This is interesting for both fundamental research and applications. PMID- 30004739 TI - Extended Measurement of the Cosmic-Ray Electron and Positron Spectrum from 11 GeV to 4.8 TeV with the Calorimetric Electron Telescope on the International Space Station. AB - Extended results on the cosmic-ray electron + positron spectrum from 11 GeV to 4.8 TeV are presented based on observations with the Calorimetric Electron Telescope (CALET) on the International Space Station utilizing the data up to November 2017. The analysis uses the full detector acceptance at high energies, approximately doubling the statistics compared to the previous result. CALET is an all-calorimetric instrument with a total thickness of 30 X_{0} at normal incidence and fine imaging capability, designed to achieve large proton rejection and excellent energy resolution well into the TeV energy region. The observed energy spectrum in the region below 1 TeV shows good agreement with Alpha Magnetic Spectrometer (AMS-02) data. In the energy region below ~300 GeV, CALET's spectral index is found to be consistent with the AMS-02, Fermi Large Area Telescope (Fermi-LAT), and Dark Matter Particle Explorer (DAMPE), while from 300 to 600 GeV the spectrum is significantly softer than the spectra from the latter two experiments. The absolute flux of CALET is consistent with other experiments at around a few tens of GeV. However, it is lower than those of DAMPE and Fermi-LAT with the difference increasing up to several hundred GeV. The observed energy spectrum above ~1 TeV suggests a flux suppression consistent within the errors with the results of DAMPE, while CALET does not observe any significant evidence for a narrow spectral feature in the energy region around 1.4 TeV. Our measured all-electron flux, including statistical errors and a detailed breakdown of the systematic errors, is tabulated in the Supplemental Material in order to allow more refined spectral analyses based on our data. PMID- 30004745 TI - Unexpected Intermediate State Photoinduced in the Metal-Insulator Transition of Submicrometer Phase-Separated Manganites. AB - At ultrafast timescales, the initial and final states of a first-order metal insulator transition often coexist forming clusters of the two phases. Here, we report an unexpected third long-lived intermediate state emerging at the photoinduced first-order metal-insulator transition of La_{0.325}Pr_{0.3}Ca_{0.375}MnO_{3}, known to display submicrometer length-scale phase separation. Using magnetic force microscopy and time-dependent magneto optical Kerr effect, we determined that the third state is a nanoscale mixture of the competing ferromagnetic metallic and charge-ordered insulating phases, with its own physical properties. This discovery bridges the two different families of colossal magnetoresistant manganites known experimentally and shows for the first time that the associated states predicted by theory can coexist in a single sample. PMID- 30004747 TI - Dispersion-Based Fresh-Slice Scheme for Free-Electron Lasers. AB - The fresh-slice technique improved the performance of several self-amplified spontaneous emission free-electron laser schemes by granting selective control on the temporal lasing slice without spoiling the other electron bunch slices. So far, the implementation has required a special insertion device to create the beam yaw, called a dechirper. We demonstrate a novel scheme to enable fresh-slice operation based on electron energy chirp and orbit dispersion that can be implemented at any free-electron laser facility without additional hardware. PMID- 30004748 TI - What Spatial Geometries do (2+1)-Dimensional Quantum Field Theory Vacua Prefer? AB - We consider relativistic (2+1)-dimensional quantum field theories (QFTs) on a product of time with a two-space and study the vacuum free energy as a functional of the temperature and spatial geometry. We focus on free scalar and Dirac fields on arbitrary perturbations of flat space, finding that the free energy difference from flat space is finite and always negative to leading order in the perturbation. Thus, free (2+1)-dimensional QFTs appear to always energetically favor a crumpled space on all scales; this is true both as a purely quantum effect at zero temperature and as a purely thermal effect at high temperature. Importantly, we show that this quantum effect is non-negligible for the relativistic Dirac degrees of freedom on monolayer graphene even at room temperature, so we argue that this vacuum energy effect should be included for a proper analysis of the equilibrium configuration of graphene or similar materials. PMID- 30004750 TI - Twinning and Dislocation Evolution during Shock Compression and Release of Single Crystals: Real-Time X-Ray Diffraction. AB - Determining the temporal evolution of twinning and/or dislocation slip, in real time (nanoseconds), in single crystals subjected to plane shock wave loading is a long-standing scientific need. Noncubic crystals pose special challenges because they have many competing slip and twinning systems. Here, we report on time resolved, in situ, synchrotron Laue x-ray diffraction measurements during shock compression and release of magnesium single crystals that are subjected to compression along the c axis. Significant twinning was observed directly during stress release following shock compression; during compression, only dislocation slip was observed. Our measurements unambiguously distinguish between twinning and dislocation slip on nanosecond timescales in a shocked hexagonal-close-packed metal. PMID- 30004749 TI - Erratum: Ultrafast Spin-State Dynamics in Transition-Metal Complexes Triggered by Soft-X-Ray Light [Phys. Rev. Lett. 118, 023001 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.023001. PMID- 30004751 TI - Ray Systems in Granular Cratering. AB - In classical experiments of granular cratering, a ball dropped on an evened-out bed of grains ends up within a crater surrounded by a uniform blanket of ejecta. In this Letter, we show that the uniform blanket of ejecta changes to a ray system, or set of radial streaks of ejecta, where the surface of the granular bed includes undulations, a factor that has not been addressed to date. By carrying out numerous experiments and computational simulations thereof, we ascertain that the number of rays in a ray system ?D/lambda, where D is the diameter of the ball and lambda is the wavelength of the undulations. Further, we show that the ejecta in a ray system originates in a narrow annulus of diameter D with the center at the site of impact. Our findings may help shed light on the enigmatic ray systems that ring many impact craters on the Moon and other planetary bodies. PMID- 30004752 TI - Blood Crystal: Emergent Order of Red Blood Cells Under Wall-Confined Shear Flow. AB - Driven or active suspensions can display fascinating collective behavior, where coherent motions or structures arise on a scale much larger than that of the constituent particles. Here, we report numerical simulations and an analytical model revealing that deformable particles and, in particular, red blood cells (RBCs) assemble into regular patterns in a confined shear flow. The pattern wavelength concurs well with our experimental observations. The order is of a pure hydrodynamic and inertialess origin, and it emerges from a subtle interplay between (i) hydrodynamic repulsion by the bounding walls that drives deformable cells towards the channel midplane and (ii) intercellular hydrodynamic interactions that can be attractive or repulsive depending on cell-cell separation. Various crystal-like structures arise depending on the RBC concentration and confinement. Hardened RBCs in experiments and rigid particles in simulations remain disordered under the same conditions where deformable RBCs form regular patterns, highlighting the intimate link between particle deformability and the emergence of order. PMID- 30004753 TI - Strong-Field Fourier Transform Vibrational Spectroscopy of D_{2}^{+} Using Few Cycle Near-Infrared Laser Pulses. AB - The photoionization of D_{2} and dissociation of the resultant D_{2}^{+} are monitored by pump-probe measurements using intense near-infrared few-cycle laser pulses. The yields of D_{2}^{+} and D^{+} recorded up to the pump-probe delay time of 527 ps exhibit oscillatory structures reflecting the motion of the created vibrational wave packet of D_{2}^{+}, and the Fourier transform of the data in time domain reveals the vibrational level separations with uncertainties of 0.0002-0.0097 cm^{-1}, showing a potential application of the strong-field pump-probe measurements to high-resolution spectroscopy of molecular ions. PMID- 30004754 TI - Delayed Onset of Nonthermal Melting in Single-Crystal Silicon Pumped with Hard X Rays. AB - In this work, we monitor the onset of nonthermal melting in single-crystal silicon by implementing an x-ray pump-x-ray probe scheme. Using the ultrashort pulses provided by the Linac Coherent Light Source (SLAC) and a custom-built split-and-delay line for hard x rays, we achieve the temporal resolution needed to detect the onset of the transition. Our data show no loss of long-range order up to 150+/-40 fs from photoabsorption, which we interpret as the time needed for the electronic system to equilibrate at or above the critical nonthermal melting temperature. Once such equilibration is reached, the loss of long-range atomic order proceeds inertially and is completed within 315+/-40 fs from photoabsorption. PMID- 30004756 TI - Crack Initiation in Viscoelastic Materials. AB - In viscoelastic materials, individually short-lived bonds collectively result in a mechanical resistance which is long lived but finite as, ultimately, cracks appear. Here, we provide a microscopic mechanism by which a critical crack length emerges from the nonlinear local bond dynamics. Because of this emerging length scale, macroscopic viscoelastic materials fracture in a fundamentally different manner from microscopically small systems considered in previous models. We provide and numerically verify analytical equations for the dependence of the critical crack length on the bond kinetics and applied stress. PMID- 30004755 TI - Precision Mass Measurements on Neutron-Rich Rare-Earth Isotopes at JYFLTRAP: Reduced Neutron Pairing and Implications for r-Process Calculations. AB - The rare-earth peak in the r-process abundance pattern depends sensitively on both the astrophysical conditions and subtle changes in nuclear structure in the region. This work takes an important step towards elucidating the nuclear structure and reducing the uncertainties in r-process calculations via precise atomic mass measurements at the JYFLTRAP double Penning trap. ^{158}Nd, ^{160}Pm, ^{162}Sm, and ^{164-166}Gd have been measured for the first time, and the precisions for ^{156}Nd, ^{158}Pm, ^{162,163}Eu, ^{163}Gd, and ^{164}Tb have been improved considerably. Nuclear structure has been probed via two-neutron separation energies S_{2n} and neutron pairing energy metrics D_{n}. The data do not support the existence of a subshell closure at N=100. Neutron pairing has been found to be weaker than predicted by theoretical mass models. The impact on the calculated r-process abundances has been studied. Substantial changes resulting in a smoother abundance distribution and a better agreement with the solar r-process abundances are observed. PMID- 30004757 TI - Observation of Out-of-Plane Spin Texture in a SrTiO_{3}(111) Two-Dimensional Electron Gas. AB - We explore the second order bilinear magnetoelectric resistance (BMER) effect in the d-electron-based two-dimensional electron gas (2DEG) at the SrTiO_{3}(111) surface. We find evidence of a spin-split band structure with the archetypal spin momentum locking of the Rashba effect for the in-plane component. Under an out-of plane magnetic field, we find a BMER signal that breaks the sixfold symmetry of the electronic dispersion, which is a fingerprint for the presence of a momentum dependent out-of-plane spin component. Relativistic electronic structure calculations reproduce this spin texture and indicate that the out-of-plane component is a ubiquitous property of oxide 2DEGs arising from strong crystal field effects. We further show that the BMER response of the SrTiO_{3}(111) 2DEG is tunable and unexpectedly large. PMID- 30004758 TI - Universal Quantum Magnetometry with Spin States at Equilibrium. AB - We address metrological protocols for the estimation of the intensity and the orientation of a magnetic field, and show that quantum-enhanced precision may be achieved by probing the field with an arbitrary spin at thermal equilibrium. A general expression is derived for the ultimate achievable precision, as given by the quantum Fisher information. The optimal observable is shown to correspond to the spin projection along a temperature-dependent direction, and allows a maximally precise parameter estimation also through ensemble measurements. Finally, we prove the robustness of our scheme against deviations of the measured spin projection from optimality. PMID- 30004759 TI - Spin Accumulation and Dynamics in Inversion-Symmetric van der Waals Crystals. AB - Inversion-symmetric materials are forbidden to show an overall spin texture in their band structure in the presence of time-reversal symmetry. However, in van der Waals materials which lack inversion symmetry within a single layer, it has been proposed that a layer-dependent spin texture can arise leading to a coupled spin-layer degree of freedom. Here we use time-resolved Kerr rotation in inversion-symmetric WSe_{2} and MoSe_{2} bulk crystals to study this spin-layer polarization and unveil its dynamics. Our measurements show that the spin-layer relaxation time in WSe_{2} is limited by phonon scattering at high temperatures and that the interlayer hopping can be tuned by a small in-plane magnetic field at low temperatures, enhancing the relaxation rates. We find a significantly lower lifetime for MoSe_{2} which agrees with theoretical expectations of a spin layer polarization stabilized by the larger spin-orbit coupling in WSe_{2}. PMID- 30004760 TI - Flow-Induced Surface Charge Heterogeneity in Electrokinetics due to Stern-Layer Conductance Coupled to Reaction Kinetics. AB - We theoretically study the electrokinetic problem of a pressure-induced liquid flow through a narrow long channel with charged walls, going beyond the classical Helmholtz-Schmolukowski picture by considering the surprisingly strong combined effect of (i) Stern-layer conductance and (ii) dynamic charge-regulating rather than fixed surface charges. We find that the water flow induces, apart from the well-known streaming potential, also a strongly heterogeneous surface charge and zeta potential on chemically homogeneous channel walls. Moreover, we identify a novel steady state with a nontrivial 3D electric flux with 2D surface charges acting as sources and sinks. For a pulsed pressure drop our findings also provide a first-principles explanation for ill-understood experiments on the effect of flow on interfacial chemistry [D. Lis et al., Science 344, 1138 (2014)SCIEAS0036 807510.1126/science.1253793]. PMID- 30004761 TI - Exact Hydrodynamic Description of Active Lattice Gases. AB - We introduce lattice gas models of active matter systems whose coarse-grained "hydrodynamic" description can be derived exactly. We illustrate our approach by considering two systems exhibiting two of the most studied collective behaviors in active matter: the motility-induced phase separation and the transition to collective motion. In both cases, we derive coupled partial differential equations describing the dynamics of the local density and polarization fields and show how they quantitatively predict the emerging properties of the macroscopic lattice gases. PMID- 30004762 TI - Salt-induced Long-to-Short Range Orientational Transition in Water. AB - We report the long-range orientational organization of water using polarization resolved second harmonic scattering operated in a right-angle configuration. A transition is observed between the neat water orientational organization involving an azimuthal molecular orientation distribution towards a radial molecular orientation distribution when salt is added. These two orientational phases are quantitatively described using a molecular model of the second harmonic scattering response. It is observed that the long-range correlation present in the neat water phase abruptly disappears and is replaced by a shorter range correlation centered around the ions as the salt concentration is increased. PMID- 30004763 TI - Quantum Hall Effect with Composites of Magnetic Flux Tubes and Charged Particles. AB - Composites formed from charged particles and magnetic flux tubes, proposed by Wilczek, are one model for anyons-particles obeying fractional statistics. Here we propose a scheme for realizing charged flux tubes, in which a charged object with an intrinsic magnetic dipole moment is placed between two semi-infinite blocks of a high-permeability (MU_{r}) material, and the images of the magnetic moment create an effective flux tube. We show that the scheme can lead to a realization of Wilczek's anyons, when a two-dimensional electron system, which exhibits the integer quantum Hall effect, is sandwiched between two blocks of the high-MU_{r} material with a temporally fast response (in the cyclotron and Larmor frequency range). The signature of Wilczek's anyons is a slight shift of the resistivity at the plateau of the IQHE. Thus, the quest for high-MU_{r} materials at high frequencies, which is underway in the field of metamaterials, and the quest for anyons, are here found to be on the same avenue. PMID- 30004764 TI - Solving the Hierarchy Problem Discretely. AB - We present a new solution to the hierarchy problem utilizing nonlinearly realized discrete symmetries. The cancellations occur due to a discrete symmetry that is realized as a shift symmetry on the scalar and as an exchange symmetry on the particles with which the scalar interacts. We show how this mechanism can be used to solve the little hierarchy problem as well as give rise to light axions. PMID- 30004765 TI - Odd and Even Modes of Neutron Spin Resonance in the Bilayer Iron-Based Superconductor CaKFe_{4}As_{4}. AB - We report an inelastic neutron scattering study on the spin resonance in the bilayer iron-based superconductor CaKFe_{4}As_{4}. In contrast to its quasi-two dimensional electron structure, three strongly L-dependent modes of spin resonance are found below T_{c}=35 K. The mode energies are below and linearly scale with the total superconducting gaps summed on the nesting hole and electron pockets, essentially in agreement with the results in cuprate and heavy fermion superconductors. This observation supports the sign-reversed Cooper pairing mechanism under multiple pairing channels and resolves the long-standing puzzles concerning the broadening and dispersive spin resonance peak in iron pnictides. More importantly, the triple resonant modes can be classified into odd and even symmetries with respect to the distance of Fe-Fe planes within the Fe-As bilayer unit. Thus, our results closely resemble those in the bilayer cuprates with nondegenerate spin excitations, suggesting that these two high-T_{c} superconducting families share a common nature. PMID- 30004766 TI - Volcano Transition in a Solvable Model of Frustrated Oscillators. AB - In 1992, a puzzling transition was discovered in simulations of randomly coupled limit-cycle oscillators. This so-called volcano transition has resisted analysis ever since. It was originally conjectured to mark the emergence of an oscillator glass, but here we show it need not. We introduce and solve a simpler model with a qualitatively identical volcano transition and find that its supercritical state is not glassy. We discuss the implications for the original model and suggest experimental systems in which a volcano transition and oscillator glass may appear. PMID- 30004767 TI - Radial Acceleration Relation of LambdaCDM Satellite Galaxies. AB - The radial acceleration measured in bright galaxies tightly correlates with that generated by the observed distribution of baryons, a phenomenon known as the radial acceleration relation (RAR). Dwarf spheroidal satellite galaxies have been recently found to depart from the extrapolation of the RAR measured for more massive objects but with a substantially larger scatter. If confirmed by new data, this result provides a powerful test of the theory of gravity at low accelerations that requires robust theoretical predictions. By using high resolution hydrodynamical simulations, we show that, within the standard model of cosmology (LambdaCDM), satellite galaxies are expected to follow the same RAR as brighter systems but with a much larger scatter which does not correlate with the physical properties of the galaxies. In the simulations, the RAR evolves mildly with redshift. Moreover, the acceleration due to the gravitational field of the host has no effect on the RAR. This is in contrast with the external field effect in modified Newtonian dynamics (MOND) which causes galaxies in strong external fields to deviate from the RAR. This difference between LambdaCDM and MOND offers a possible way to discriminate between them. PMID- 30004768 TI - First Evidence of Purely Extreme-Ultraviolet Four-Wave Mixing. AB - The extension of nonlinear optical techniques to the extreme-ultraviolet (EUV), soft and hard x-ray regime represents one of the open challenges of modern science since it would combine chemical specificity with background-free detection and ultrafast time resolution. We report on the first observation of a four-wave-mixing (FWM) response from solid-state samples stimulated exclusively by EUV pulses. The all-EUV FWM signal was generated by the diffraction of high order harmonics of the FERMI free-electron laser (FEL) from the standing wave resulting from the interference of two crossed FEL pulses at the fundamental wavelength. From the intensity of the FWM signal, we are able to extract the first-ever estimate of an effective value of ~6*10^{-24} m^{2} V^{-2} for the third-order nonlinear susceptibility in the EUV regime. This proof of principle experiment represents a significant advance in the field of nonlinear optics and sets the starting point for a manifold of techniques, including frequency and phase-resolved FWM methods, that are unprecedented in this photon-energy regime. PMID- 30004769 TI - High-Power Femtosecond Soft X Rays from Fresh-Slice Multistage Free-Electron Lasers. AB - We demonstrate a novel multistage amplification scheme for self-amplified spontaneous-emission free electron lasers for the production of few femtosecond pulses with very high power in the soft x-ray regime. The scheme uses the fresh slice technique to produce an x-ray pulse on the bunch tail, subsequently amplified in downstream undulator sections by fresh electrons. With three-stages amplification, x-ray pulses with an energy of hundreds of microjoules are produced in few femtoseconds. For single-spike spectra x-ray pulses the pulse power is increased more than an order of magnitude compared to other techniques in the same wavelength range. PMID- 30004770 TI - Dynamics of Noisy Oscillator Populations beyond the Ott-Antonsen Ansatz. AB - We develop an approach for the description of the dynamics of large populations of phase oscillators based on "circular cumulants" instead of the Kuramoto-Daido order parameters. In the thermodynamic limit, these variables yield a simple representation of the Ott-Antonsen invariant solution [E. Ott and T. M. Antonsen, Chaos 18, 037113 (2008)CHAOEH1054-150010.1063/1.2930766] and appear appropriate for constructing perturbation theory on top of the Ott-Antonsen ansatz. We employ this approach to study the impact of small intrinsic noise on the dynamics. As a result, a closed system of equations for the two leading cumulants, describing the dynamics of noisy ensembles, is derived. We exemplify the general theory by presenting the effect of noise on the Kuramoto system and on a chimera state in two symmetrically coupled populations. PMID- 30004771 TI - Superconductivity in FeSe: The Role of Nematic Order. AB - Bulk FeSe is a special iron-based material in which superconductivity emerges inside a well-developed nematic phase. We present a microscopic model for this nematic superconducting state, which takes into account the mixing between s-wave and d-wave pairing channels and the changes in the orbital spectral weight promoted by the sign-changing nematic order parameter. We show that nematicity only weakly affects T_{c}, but gives rise to cos2theta variation of the pairing gap on the hole pocket, whose magnitude and size agrees with angle resolved photoemission spectroscopy and STM data. We further show that nematicity increases the weight of the d_{xz} orbital on the hole pocket, and increases (reduces) the weight of the d_{xy} orbital on the Y (X) electron pocket. PMID- 30004772 TI - Dynamic Control of the Coupling between Dark and Bright Excitons with Vibrational Strain. AB - We numerically and experimentally investigate strain-induced coupling between dark and bright excitons and its dynamic control using a gallium arsenide (GaAs) micromechanical resonator. Uniaxial strain induced by the mechanical resonance efficiently detunes the exciton energies and modulates the coupling strength via the deformation potential in GaAs. This allows optical access to the long-lived dark states without using any external electromagnetic field. This field-free approach could be expanded to a wide range of solid-state materials, leading to on-chip excitonic memories and circuits based on micromechanical resonators. PMID- 30004773 TI - Topology of Disconnected Elementary Band Representations. AB - Elementary band representations are the fundamental building blocks of atomic limit band structures. They have the defining property that at partial filling they cannot be both gapped and trivial. Here, we give two examples-one each in a symmorphic and a nonsymmorphic space group-of elementary band representations realized with an energy gap. In doing so, we explicitly construct a counterexample to a claim by Michel and Zak that single-valued elementary band representations in nonsymmorphic space groups with time-reversal symmetry are connected. For each example, we construct a topological invariant to explicitly demonstrate that the valence bands are nontrivial. We discover a new topological invariant: a movable but unremovable Dirac cone in the "Wilson Hamiltonian" and a bent-Z_{2} index. PMID- 30004774 TI - Experimental Demonstration of Shaken-Lattice Interferometry. AB - We experimentally demonstrate a shaken-lattice interferometer. Atoms are trapped in the ground Bloch state of a red-detuned optical lattice. Using a closed-loop optimization protocol based on the dcrab algorithm, we phase-modulate (shake) the lattice to transform the atom momentum state. In this way, we implement an atom beam splitter and build five interferometers of varying interrogation times T_{I}. The sensitivity of shaken-lattice interferometry is shown to scale as T_{I}^{2}, consistent with simulation (2C. A. Weidner, H. Yu, R. Kosloff, and D. Z. Anderson, Phys. Rev. A 95, 043624 (2017).PLRAAN2469 992610.1103/PhysRevA.95.043624). Finally, we show that we can measure the sign of an applied signal and optimize the interferometer in the presence of a bias signal. PMID- 30004775 TI - Compact Object Mergers Driven by Gas Fallback. AB - Recently, several gravitational wave detections have shown evidence for compact object mergers. However, the astrophysical origin of merging binaries is not well understood. Stellar binaries are typically at much larger separations than what is needed for the binaries to merge due to gravitational wave emission, which leads to the so-called final AU problem. In this Letter we propose a new channel for mergers of compact object binaries which solves the final AU problem. We examine the binary evolution following gas expansion due to a weak failed supernova explosion, neutrino mass loss, core disturbance, or envelope instability. In such situations the binary is possibly hardened by ambient gas. We investigate the evolution of the binary system after a shock has propagated by performing smoothed particle hydrodynamics simulations. We find that significant binary hardening occurs when the gas mass bound to the binary exceeds that of the compact objects. This mechanism represents a new possibility for the pathway to mergers for gravitational wave events. PMID- 30004777 TI - Effect of Magnetization on the Tunneling Anomaly in Compressible Quantum Hall States. AB - Tunneling of electrons into a two-dimensional electron system is known to exhibit an anomaly at low bias, in which the tunneling conductance vanishes due to a many body interaction effect. Recent experiments have measured this anomaly between two copies of the half-filled Landau level as a function of in-plane magnetic field, and they suggest that increasing spin polarization drives a deeper suppression of tunneling. Here, we present a theory of the tunneling anomaly between two copies of the partially spin-polarized Halperin-Lee-Read state, and we show that the conventional description of the tunneling anomaly, based on the Coulomb self-energy of the injected charge packet, is inconsistent with the experimental observation. We propose that the experiment is operating in a different regime, not previously considered, in which the charge-spreading action is determined by the compressibility of the composite fermions. PMID- 30004776 TI - Precision Mass Measurements of Neutron-Rich Neodymium and Samarium Isotopes and Their Role in Understanding Rare-Earth Peak Formation. AB - The Canadian Penning Trap mass spectrometer at the Californium Rare Isotope Breeder Upgrade (CARIBU) facility was used to measure the masses of eight neutron rich isotopes of Nd and Sm. These measurements are the first to push into the region of nuclear masses relevant to the formation of the rare-earth abundance peak at A~165 by the rapid neutron-capture process. We compare our results with theoretical predictions obtained from "reverse engineering" the mass surface that best reproduces the observed solar abundances in this region through a Markov chain Monte Carlo technique. Our measured masses are consistent with the reverse engineering predictions for a neutron star merger wind scenario. PMID- 30004725 TI - Amplitude Analysis of the Decay B[over -]^{0}->K_{S}^{0}pi^{+}pi^{-} and First Observation of the CP Asymmetry in B[over -]^{0}->K^{*}(892)^{-}pi^{+}. AB - The time-integrated untagged Dalitz plot of the three-body hadronic charmless decay B[over -]^{0}->K_{S}^{0}pi^{+}pi^{-} is studied using a pp collision data sample recorded with the LHCb detector, corresponding to an integrated luminosity of 3.0 fb^{-1}. The decay amplitude is described with an isobar model. Relative contributions of the isobar amplitudes to the B[over -]^{0}->K_{S}^{0}pi^{+}pi^{ } decay branching fraction and CP asymmetries of the flavor-specific amplitudes are measured. The CP asymmetry between the conjugate B[over -]^{0}->K^{*}(892)^{ }pi^{+} and B^{0}->K^{*}(892)^{+}pi^{-} decay rates is determined to be -0.308+/ 0.062. PMID- 30004778 TI - Astrophobic Axions. AB - We propose a class of axion models with generation-dependent Peccei-Quinn charges for the known fermions that allow one to suppress the axion couplings to nucleons and electrons. Astrophysical limits are thus relaxed, allowing for axion masses up to O(0.1) eV. The axion-photon coupling remains instead sizable, so that next generation helioscopes will be able to probe this scenario. Astrophobia unavoidably implies flavor-violating axion couplings so that experimental limits on flavor-violating processes can provide complementary probes. The astrophobic axion can be a viable dark matter candidate in the heavy mass window and can also account for anomalous energy loss in stars. PMID- 30004779 TI - Stability Analysis of an Array of Magnets: When Will It Jump? AB - A bidimensional array of magnets whose magnetic moments share the same vertical orientation, and lying on a planar surface, can be gradually compacted. As the density reaches a threshold, the assembly becomes unstable, and the magnets violently pop out of plane. In this Letter, we investigate experimentally and theoretically the maximum packing fraction (or density) of a bidimensional planar assembly of identical cylindrical magnets. We show that the instability can be attributed to local fluctuations of the altitude of the magnets on the planar surface. The maximum density is theoretically predicted assuming dipolar interactions between the magnets and is in excellent agreement with experimental results using a variety of cylindrical magnets. PMID- 30004780 TI - Spin-Isomer Conversion of Water at Room Temperature and Quantum-Rotor-Induced Nuclear Polarization in the Water-Endofullerene H_{2}O@C_{60}. AB - Water exists in two forms, para and ortho, that have nuclear spin states with different symmetries. Here we report the conversion of fullerene-encapsulated para water to ortho water. The enrichment of para water at low temperatures is monitored via changes in the electrical polarizability of the material. Upon rapid dissolution of the material in toluene the excess para water converts to ortho water. In H_{2}^{16}O@C_{60} the conversion leads to a slow increase in the NMR signal. In H_{2}^{17}O@C_{60} the conversion gives rise to weak signal enhancements attributed to quantum-rotor-induced nuclear spin polarization. The time constants for the para-to-ortho conversion of fullerene-encapsulated water in ambient temperature solution are estimated as 30+/-4 s for the ^{16}O isotopolog of water, and 16+/-3 s for the ^{17}O isotopolog. PMID- 30004782 TI - Hydrodynamics of Diffusion in Lipid Membrane Simulations. AB - By performing molecular dynamics simulations with up to 132 million coarse grained particles in half-micron sized boxes, we show that hydrodynamics quantitatively explains the finite-size effects on diffusion of lipids, proteins, and carbon nanotubes in membranes. The resulting Oseen correction allows us to extract infinite-system diffusion coefficients and membrane surface viscosities from membrane simulations despite the logarithmic divergence of apparent diffusivities with increasing box width. The hydrodynamic theory of diffusion applies also to membranes with asymmetric leaflets and embedded proteins, and to a complex plasma-membrane mimetic. PMID- 30004783 TI - Negative Hydration Expansion in ZrW_{2}O_{8}: Microscopic Mechanism, Spaghetti Dynamics, and Negative Thermal Expansion. AB - We use a combination of x-ray diffraction, total scattering, and quantum mechanical calculations to determine the mechanism responsible for hydration driven contraction in ZrW_{2}O_{8}. The inclusion of H_{2}O molecules within the ZrW_{2}O_{8} network drives the concerted formation of new W?O bonds to give one dimensional (?W?O?)_{n} strings. The topology of the ZrW_{2}O_{8} network is such that there is no unique choice for the string trajectories: the same local changes in coordination can propagate with a large number of different periodicities. Consequently, ZrW_{2}O_{8}.H_{2}O is heavily disordered, with each configuration of strings forming a dense aperiodic "spaghetti." This new connectivity contracts the unit cell via large shifts in the Zr and W atom positions. Fluctuations of the undistorted parent structure towards this spaghetti phase emerge as the key negative thermal expansion (NTE) phonon modes in ZrW_{2}O_{8} itself. The large relative density of NTE phonon modes in ZrW_{2}O_{8} actually reflects the degeneracy of volume-contracting spaghetti excitations, itself a function of the particular topology of this remarkable material. PMID- 30004781 TI - Precision Measurement of the First Ionization Potential of Nobelium. AB - One of the most important atomic properties governing an element's chemical behavior is the energy required to remove its least-bound electron, referred to as the first ionization potential. For the heaviest elements, this fundamental quantity is strongly influenced by relativistic effects which lead to unique chemical properties. Laser spectroscopy on an atom-at-a-time scale was developed and applied to probe the optical spectrum of neutral nobelium near the ionization threshold. The first ionization potential of nobelium is determined here with a very high precision from the convergence of measured Rydberg series to be 6.626 21+/-0.000 05 eV. This work provides a stringent benchmark for state-of-the-art many-body atomic modeling that considers relativistic and quantum electrodynamic effects and paves the way for high-precision measurements of atomic properties of elements only available from heavy-ion accelerator facilities. PMID- 30004784 TI - ISBER 2018 Annual Meeting Summary and a Look Ahead. PMID- 30004785 TI - Integrity testing of a smooth surface resin sealant around orthodontic brackets using a new Fluorescence-aided Identification Technique (FIT). AB - OBJECTIVE:: To investigate the integrity of a fluorescing resin-based sealant placed around orthodontic brackets using the Fluorescence-aided Identification Technique (FIT). MATERIALS AND METHODS:: Standard brackets were bonded to the buccal surfaces of 17 extracted sound permanent premolar crowns sealed with ProSeal(r). Specimens were thermocycled (20,000 cycles, 5-55 degrees C), and toothbrushing was simulated using an electric toothbrush and artificial aqueous toothpaste slurry. Changes in the sealed area were measured after one, two, three, and four alternating thermocycling-brushing cycles simulating 2 years of wear. Digital images were captured applying FIT (405 nm) using a digital camera equipped stereomicroscope. ImageJ was used to measure sealant integrity and loss. RESULTS:: There was a time-dependent decrease in sealed areas by between 21% and 100% (mean 54%). The sealant lost its integrity immediately after the first cycle, and unfilled areas were observed in all samples. CONCLUSIONS:: The analyzed sealant lost its integrity over time. Using the proposed FIT, sealed surfaces were easily verified and quantified. PMID- 30004786 TI - Three-dimensional assessment of the middle cranial fossa and central skull base following Herbst appliance treatment. AB - OBJECTIVES:: The purpose of this three-dimensional (3D) study was to assess retrospectively the middle cranial fossa and central skull base of patients treated with the Herbst appliance (HA). MATERIALS AND METHODS:: 3D surface virtual models of 40 Class II, division 1 malocclusion patients were generated from cone-beam computed tomography (CBCT) acquired before treatment (T0) and after 8 months of HA treatment (T1). T0 and T1 3D models were superimposed volumetrically at the anterior cranial fossa. Twenty subjects who had been treated with the Herbst appliance (HAG) were compared to 20 subjects who were not treated orthopedically. The latter group served as a comparison control group (CG). Quantitative assessments of the location and directional changes were made with linear and angular measurements between anatomical landmarks. Qualitative assessments of the spatial behavior of the middle cranial fossa and central skull base relative to the anterior cranial fossa were displayed graphically for visualization with color maps and semitransparent overlays. Non-parametric tests were performed to compare the between the HAG and CG. RESULTS:: Point-to-point linear measurements and skeletal rotation (pitch, roll, and yaw) changes were very small along the observational period and were not significantly different between HAG and CG. Visual analysis of color maps and overlays confirmed that no changes in the cranial base were associated with HA. CONCLUSIONS:: HA therapy did not produce clinically significant changes in the middle cranial fossa and central skull base. PMID- 30004787 TI - Prognostic value of interim fluorodeoxyglucose and fluorothymidine PET/CT in diffuse large B-cell lymphoma. AB - OBJECTIVE:: To examine the prognostic value of fluorodeoxyglucose (FDG) and fluorothymidine (FLT) interim positron emission tomography/CT (PET/CT) for diffuse large B-cell lymphoma (DLBCL). METHODS:: 44 patients with newly diagnosed DLBCL underwent both fluorine 18 FDG (18F-FDG) and 18F-FLT PET/CT scans at baseline and after two cycles of a rituximab-containing chemotherapy regimen. Maximum standard uptake values (SUVmax) and changes in SUV (DeltaSUV) were calculated for both tracers for the predominant lesion of each patient, for prediction of progression-free survival (PFS) and overall survival (OS). RESULTS:: The median follow-up period was 71 months. Receiver operating characteristic (ROC) analysis indicated that the best DeltaSUV cut-off values for FDG (DeltaSUVFDG) and FLT (DeltaSUVFLT) were 79 and 76%, respectively. A DeltaSUVFLT cut-off of 76% had the highest significance for prediction of PFS (p = 0.003) and OS (p = 0009), with sensitivity, specificity, and accuracy of 80.0, 85.7, and 81.8% respectively in response assessment. CONCLUSION:: Interim FLT PET/CT had higher specificity and accuracy than standard FDG PET/CT-based interpretation. ADVANCES IN KNOWLEDGE:: This study demonstrated that interim FLT PET/CT had higher accuracy than standardized FDG-based interpretation for therapeutic response assessment in DLBCL. FLT had the advantage of potentially reducing false positive of interim FDG PET/CT. PMID- 30004789 TI - Maximizing the Utility of Archival Formalin-Fixed Paraffin-Embedded Blocks for Nucleic Acid Analysis. PMID- 30004788 TI - CT angiography prior to TAVI procedure using third-generation scanner with wide volume coverage: feasibility, renal safety and diagnostic accuracy for coronary tree. AB - OBJECTIVE:: To evaluate feasibility, image quality and accuracy of a reduced contrast volume protocol for pre-procedural CT imaging in transcatheter aortic valve implantation (TAVI) using a third generation wide array CT scanner. METHODS:: 115 consecutive patients (51F, mean age 82.5 +/- 6.2 y, mean BMI 26.7 +/- 3.6) referred for TAVI were examined with wide-array CT scanner with a combined scan protocol and a total amount of 50 ml contrast agent. A 4-point visual scale (4-1) was used to assess image quality . Contrast attenuation values (HU) and contrast-to-noise ratio (CNR) were measured at the level of the aortic root, ascending/descending aorta, subrenal aorta and at the level of right and left common femoral arteries. Coronary tree was assessed and compared with invasive coronary angiography (ICA). Aortic annulus measurements were compared with final procedural results. Patients creatinine was monitored at the baseline and 72 h after procedure. RESULTS:: Median quality score value was >3. Mean CNR at the level of the aortic root, ascending/descending aorta, subrenal aorta and at the level of right and left common femoral arteries were 14.8 +/- 2.3, 15.7 +/ 1.7, 14.9 +/- 3.1, 15.8 +/- 4.7, 20.3 +/- 9.9, 20.8 +/- 6.9 respectively. Only 1 patient had moderate paravalvular regurgitation. In comparison with ICA for coronary assessment CTA showed in a segment based analysis sensitivity, specificity, negative predictive value, positive predictive value and accuracy of 97, 85, 99,62 and 88% respectively. Mean creatinine before CT and 72 h after procedure were 1.21 +/- 0.52 and1.22 +/- 0.49 mg dl-1. Mean DLP was 442.4 +/- 21.2 mGy/cm. CONCLUSION:: CT with low contrast volume is feasible and clinically useful, allowing precise pre-procedural TAVI planning with accurate assessment of coronary tree. ADVANCES IN KNOWLEDGE:: third generation CT scanner with whole heart coverage allows examinations for assessment of aorta and coronary arteries in TAVI planning using low dose of contrast medium maintaining good quality and high diagnostic accuracy. PMID- 30004790 TI - Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients. AB - INTRODUCTION: Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with significant morbidity and mortality. Although available anti-CMV therapies may be effective for the prevention of CMV, they are plagued by unacceptable toxicities that prohibit their use in the post-transplant period. Recently studied CMV-active agents, such as maribavir and brincidofovir, failed to reduce the incidence of CMV infection in HCT recipients. Letermovir represents the first agent in the non-nucleoside 3,4 dihydro-quinazoline class of CMV viral terminase complex inhibitors, with activity solely against CMV. The positive results from the recently published Phase III study of letermovir for prevention of CMV infection in CMV-seropositive allo-HCT recipients led to its approval as a prophylactic agent for CMV in multiple countries. Areas covered: In this review, we will evaluate this novel agent with a focus on letermovir mechanism of action, pharmacokinetics and metabolism, clinical efficacy, and safety and toxicities. Expert commentary: With the introduction of letermovir, prevention of CMV infection in allo-HCT recipients may shift considerably, from a predominantly preemptive strategy to one that utilizes this novel therapy for prophylaxis. PMID- 30004792 TI - Cancer immunology and radiobiology: Oliver Scott's struggle for the perfect tumour model in translational research. AB - Oliver Scott is best known for his research into the role of tumour hypoxia in radiation oncology. Yet no less important were Oliver's activities in the development of concepts and methods for performing translational research on the effect of ionising radiation on tumour in experimental animals, stressing the importance of using strictly inbred animals for transplantation of tumours which had arisen in exactly the identical mouse strain. Otherwise residual immunity would lead to uncontrollable bias in the results of cure experiments, invalidating conclusions. These pioneering views are no less valid in today's cancer research. PMID- 30004793 TI - On the determination of planning target margins due to motion for mice lung tumours using a four-dimensional MOBY phantom. AB - OBJECTIVE: This work aims to analyse the effect of respiratory motion on optimal irradiation margins for murine lung tumour models. Methods: Four-dimensional mathematical phantoms with different lung tumour locations affected by respiratory motion were created. Two extreme breathing curves were adopted and divided into time-points. Each time-point was loaded in a treatment planning system and Monte Carlo (MC) dose calculations were performed for a 360 degrees arc plan. A time-resolved dose was derived, considering the gantry rotation and the breathing motion. Radiotherapy metrics were derived to assess the final treatment plans. An interpolation function was investigated to reduce calculation cost. Results: The effect of respiratory motion on the treatment plan quality is strongly dependent on the breathing pattern and the tumour position. Tumours located closer to the diaphragm required a compromise between tumour conformity and healthy tissue damage. A recipe, which considers collimator size, was proposed to derive tumour margins and spare the organs at risk (OARs) by respecting constraints on user-defined metrics. Conclusion: It is recommended to add a target margin, especially on sites where movement is substantial. A simple recipe to derive tumour margins was developed. Advances in knowledge: This work is a first step towards a standard planning target volume concept in pre-clinical radiotherapy. PMID- 30004791 TI - MRI adipose tissue and muscle composition analysis-a review of automation techniques. AB - MRI is becoming more frequently used in studies involving measurements of adipose tissue and volume and composition of skeletal muscles. The large amount of data generated by MRI calls for automated analysis methods. This review article presents a summary of automated and semi-automated techniques published between 2013 and 2017. Technical aspects and clinical applications for MRI-based adipose tissue and muscle composition analysis are discussed based on recently published studies. The conclusion is that very few clinical studies have used highly automated analysis methods, despite the rapidly increasing use of MRI for body composition analysis. Possible reasons for this are that the availability of highly automated methods has been limited for non-imaging experts, and also that there is a limited number of studies investigating the reproducibility of automated methods for MRI-based body composition analysis. PMID- 30004794 TI - Dosimetric influence of pitch in patient positioning for radiotherapy of long treatment volumes; the usefulness of six degree of freedom couch. AB - OBJECTIVE:: Pitch, the rotation around the transversal axis of the patient during radiotherapy has little impact on the dose distribution of small spherical treatment volumes; however it might affect treatment of long volumes requiring a correction with a six degree of freedom couch. METHODS:: We included 10 patients each with nasopharyngeal carcinoma (NPC) and esophageal cancer, treated with volumetric modulated arc therapy. Pitch was simulated by tilting the planning CT in ventral and dorsal direction by +/- 1.5 degrees and +/- 3 degrees . Verification plans were calculated on the tilted datasets and were compared to the original plan and the dose constraints of the organs at risk (OAR). RESULTS:: The deviation in dose to the planning target volume is increasing with the degree of pitch with mean changes of up to 2% for NPC and 1% for esophageal cancer. The most affected OAR in NPC patients are brainstem (max. dose +6.0%) and spinal cord (max. dose +10.0%) when tilted by 3 degrees dorsally and lenses (max. dose +3.3%), oral mucosa (mean dose +2.6%) and parotid glands (mean dose +4.3%) when tilted by 3 degrees ventrally. For esophageal cancer patients, there was no significant change in dose to any OAR. Whereas for esophageal cancer, all tilted treatment plans were still clinically acceptable regarding OAR, 5 NPC plans would no longer be acceptable with a pitch of 1.5 degrees ventral (N = 1), 3 degrees ventral (N = 2) and 3 degrees dorsal (N = 2). CONCLUSION:: Planning target volume coverage in both tumor entities was only slightly affected, but pitch errors could be relevant for OAR in NPC patients. ADVANCES IN KNOWLEDGE:: A correction with a six degree of freedom couch is recommended for NPC patients with a pitch mismatch of more than 1.5 degrees to avoid exceeded doses to the OAR. PMID- 30004795 TI - MicroRNA-31-5p enhances the Warburg effect via targeting FIH. AB - The enhanced expression of miR-31 has been observed in many human malignancies including lung cancer, and this microRNA regulates several aspects of oncogenesis. However, the role of miR-31-5p in energy metabolism remains elusive. Here, we confirm that H1299 and A549 cells, 2 lung cancer cell lines, relay on aerobic glycolysis as main source of ATP. Inhibition of miR-31-5p leads to decreased glycolysis and ATP production, while miR-31-5p overexpression increases them. Hypoxia inducible factor 1 (HIF-1) up-regulates the expression of glycolytic enzymes, and the HIF-1alpha inhibitor (FIH) inhibits HIF-1 activity. Because FIH is a direct target of miR-31-5p, inhibition of miR-31-5p results in enhanced FIH expression and suppression of HIF-1 signaling, while overexpression of miR-31-5p has the opposite effects. Via this mechanism, miR-31-5p up-regulates aerobic glycolytic genes and maintains energy homeostasis. To further validate the mechanism of miR-31-5p in glycolysis regulation, we show that overexpression or knockdown of FIH rescued the effects of miR-31-5p or miR-31-5p inhibitor on HIF activation and its target gene expression, respectively. Finally, by means of an A549 cell xenograft mouse model, we demonstrate that the miR-31-5p promotes cell proliferation via enhancing glycolysis. In summary, this study reveals that miR-31-5p promotes the Warburg effect via direct targeting of FIH.-Zhu, B., Cao, X., Zhang, W., Pan, G., Yi, Q., Zhong, W., Yan, D. MicroRNA-31-5p enhances the Warburg effect via targeting FIH. PMID- 30004796 TI - Ectopic expression of recipient CD47 inhibits mouse macrophage-mediated immune rejection against human stem cell transplants. AB - Like conventional transplants, immunosuppression is required to facilitate survival and function of human embryonic stem cell (hESC) derivatives after implantation into xenogeneic recipients. We have previously reported that T cells alone are sufficient to reject allogeneic murine ESC derivatives; and strategies that inhibit T-cell activation, including coreceptor and costimulation blockade, prevent hESC derivatives from being rejected. This study aimed to investigate, in addition to T cells, whether macrophages contribute to transplant rejection of hESC xenografts with nonobese diabetic (NOD)/SCID mice that lack functional T and B cells but have macrophages. We show that acute rejection against hESC-derived endothelial cells (hESC-ECs) was mediated, to some degree, by infiltrating macrophages that phagocytosed them. Transgenic expression of murine CD47 on cell surface of hESC-ECs mitigates macrophage-mediated phagocytosis and improves their survival after transplantation. Our results highlight that innate immune cells, such as macrophages, can reject hESC derivatives, raising concern against the use of NOD/SCID as transplant recipients for testing in vivo function of hESC-derived tissues. Augmenting CD47 signaling promotes survival and function of hESC derivatives after xenogeneic transplantation.-Leung, C. S., Li, J., Xu, F., Wong, A. S. L., Lui, K. O. Ectopic expression of recipient CD47 inhibits mouse macrophage-mediated immune rejection against human stem cell transplants. PMID- 30004797 TI - Pharmacological management of hypertension in the elderly and frail populations. AB - INTRODUCTION: Cardiovascular disease is a leading cause of mortality in the elderly. Hypertension is an important modifiable risk factor that contributes to cardiovascular morbidity and mortality. The prevalence of hypertension is known to increase with age, and hypertension has been associated with an increase in risk for cardiovascular disease in the elderly. There is a wealth of evidence that supports aggressive control of blood pressure to lower cardiovascular risk in the general population. However, there are limited data to guide management of hypertension in the elderly and frail patient subgroups. These subgroups are inadequately treated due to lack of clarity regarding blood pressure thresholds, treatment targets, comorbidities, frailty, drug interactions from polypharmacy, and high cost of care. Areas covered: We review the current evidence behind the definition, goals, and treatments for hypertension in the elderly and frail and outline a strategy that can be used to guide antihypertensive pharmacotherapy in this population. Expert commentary: Lower blood pressure to < 130/80 mm Hg in elderly patients if tolerated and promote use of combination therapy if the blood pressure is > 20/10 mm Hg over the goal blood pressure. Antihypertensive treatment regimens must be tailored to each individual based on their comorbidities, risk for adverse effects, and potential drug interactions ( Figure 1 ). PMID- 30004798 TI - Under Pressure: Examining Social Conformity With Computer and Robot Groups. AB - OBJECTIVE:: The authors investigate whether nonhuman agents, such as computers or robots, produce a social conformity effect in human operators and examine to what extent potential conformist behavior varies as a function of the human-likeness of the group members and the type of task that has to be performed. BACKGROUND:: People conform due to normative and/or informational motivations in human-human interactions, and conformist behavior is modulated by factors related to the individual as well as factors associated with the group, context, and culture. Studies have yet to examine whether nonhuman agents also induce social conformity. METHOD:: Participants were assigned to a computer, robot, or human group and completed both a social and analytical task with the respective group. RESULTS:: Conformity measures (percentage of times participants answered in line with agents on critical trials) subjected to a 3 * 2 mixed ANOVA showed significantly higher conformity rates for the analytical versus the social task as well as a modulation of conformity depending of the perceived agent-task fit. CONCLUSION:: Findings indicate that nonhuman agents were able to exert a social conformity effect, which was modulated further by the perceived match between agent and task type. Participants conformed to comparable degrees with agents during the analytical task but conformed significantly more strongly on the social task as the group's human-likeness increased. APPLICATION:: Results suggest that users may react differently to the influence of nonhuman agent groups with the potential for variability in conformity depending on the domain of the task. PMID- 30004799 TI - The Role of Inflammatory Cytokines in Creating T Cell Exhaustion in Cancer. AB - Secreted inflammatory cytokines are considered as critical mediators in the tumor microenvironment. Cancer cells play a significant role in the differentiation of effector T cells to exhausted T cells through mediator production. Effector T cells that undergo tumor microenvironment become terminally differentiated into exhausted T cells. These changes create an opportunity for tumorigenesis and invasion of cancer cells. Despite having some characteristics of effector T cells, the exhausted T cells lose their antitumor properties. In this article, the phenotypes and function of exhausted T cells were reviewed and the expression pattern of inflammatory cytokines in tumor tissues and peripheral blood of cancer patients were described. Additionally, the effects of inflammatory cytokines on intracellular factors and signals of T lymphocyte cells were explained. In conclusion, the authors referred to probable approaches that could be used to improve the antitumor activity of T cells and intervention into T cell exhaustion. PMID- 30004800 TI - Transplantation in highly sensitized patients: challenges and recommendations. AB - INTRODUCTION: Highly sensitized patients awaiting a kidney transplant accrue on the transplant waiting list. The breadth of HLA antibodies in this subpopulation of patients precludes receiving a compatible organ offer through regular allocation within an acceptable time-frame. Areas covered: Several alternative options to receive a transplant exist for these patients, including additional priority in regular allocation, special programs based on allocation through acceptable antigens, kidney paired donation programs, desensitization protocols, or a combination of the latter two. In this review, these options and their outcomes are discussed as well as some possibilities to further enhance transplantation of this disadvantaged group of patients. Expert commentary: For highly sensitized patients, special attention is required, for which several strategies may apply. A step-wise approach may be the optimal strategy to facilitate successful transplantation of highly sensitized patients. PMID- 30004801 TI - Pleasure and Risk: A Qualitative Study of Sexual Behaviors Among Chinese Methamphetamine Users. AB - In China, the number of methamphetamine (meth) users has increased dramatically in recent years. This issue has caused researchers to consider the association of meth use with public health concerns, such as the spread of sexually transmitted infections (STIs). Despite the potential outcomes of meth use, qualitative research has not as yet explored Chinese meth users' sexual experiences and feelings associated with meth use. To contribute to the literature, this study employed semistructured interviews to collect data from 19 female and 16 male Chinese meth users (mean age = 31) who were predominantly heterosexual and were recruited from seven compulsory drug treatment institutions in Eastern China. Most participants had completed nine or fewer years of education. Gender similarities and differences were observed in the participants' pursuits of sexual pleasure while using meth. Meth use can enhance the likelihood of high risk sexual behaviors in both genders and therefore increases the number of public health issues. Men largely dominated the discussion of unprotected sex, while women reported transactional sex in their interviews. Based on research findings, we suggest policymakers strengthen safer-sex educational programs. Policymakers should also enhance prevention methods targeting meth use among women who may engage in transactional sex. PMID- 30004804 TI - Computed tomography in paediatric heart disease. AB - Cardiovascular CT (CCT) is an important imaging modality in congenital and acquired paediatric heart disease. Technological advances have resulted in marked improvements in spatial and temporal resolution of CCT with a concomitant increase in speed of data acquisition and a decrease in radiation dose. This has elevated CCT from being sparingly used to an essential diagnostic tool in the daily multimodality imaging practice alongside echocardiography, cardiovascular MR and invasive angiography. The application of CCT in paediatric congenital and acquired heart disease can be both technically and diagnostically challenging. This review highlights important considerations for current state of the art CCT across the spectrum of heart disease encountered in children. PMID- 30004802 TI - Expression of miRNA-143 in Pancreatic Cancer and Its Clinical Significance. AB - OBJECTIVE: To analyze the expression of micro-RNA 143 (miRNA-143) in the patients with pancreatic cancer and to explore the influence of overexpression of miRNA 143 on pancreatic cancer cells. METHODS: Twenty-five patients with pancreatic cancer that received treatment in their hospital were included in this study. Pancreatic cancer tissues of the patients were surgically removed, and cancer adjacent tissues were taken for control. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expressions of miRNA 143 and its target gene Kirsten rat sarcoma (KRAS) in pancreatic cancer tissues and cancer-adjacent tissues. Western blot test was conducted to detect the expression of KRAS in pancreatic cancer tissues. Clinicopathologic data of patients were recorded in detail, and the analysis on the correlation of these data with the expression of miRNA-143 in pancreatic cancer tissues was conducted. Pancreatic cancer cell line (PANC-1) was transfected with plasmid for overexpression of miRNA-143, and the influences of miRNA-143 on the apoptosis, migration ability, and invasion ability of the cells were verified by flow cytometry, cell scratch experiment, and Transwell experiment. RESULTS: The results of semiquantitative RT-PCR showed that there were significantly lower expression of miRNA-143 (p < 0.01) and remarkably higher expressions of KRAS gene and KRAS protein (p < 0.01) in pancreatic cancer tissues compared with cancer adjacent tissues. The expression of miRNA-143 had no correlation with the patient's age and gender, but was closely related to the tumor size, clinical staging, and metastasis of lymph nodes. The detection with flow cytometry showed that cell apoptosis was significantly increased by overexpression of miRNA-143 in PANC-1 (p < 0.01). The result of cell scratch experiment indicated that the migration ability of PANC-1 was reduced significantly by overexpression of miRNA 143 (p < 0.01) and that of Transwell experiment manifested that the invasion ability of PANC-1 was decreased significantly by overexpression of miRNA-143 (p < 0.01). CONCLUSION: The expression of miRNA-143 in pancreatic cancer tissues is significantly decreased. MiRNA-143 can promote cell apoptosis and regulate the process of pancreatic cancer by inhibiting the migration and invasion of pancreatic cancer cells. PMID- 30004803 TI - Nuclear and Optical Bimodal Imaging Probes Using Sequential Assembly: A Perspective. AB - New, targeted imaging tracers enable improved diagnosis, staging, and planning of treatment of disease and represent an important step toward personalized medicine applications. The combination of radioisotopes for nuclear imaging with fluorophores for fluorescence imaging provides the possibility to noninvasively assess disease burden in a patient using positron emission tomography/single photon emission computed tomography, followed by fluorescence imaging-assisted surgical intervention in close succession. Probes enabling imaging with both modalities pose a design, synthesis, and pharmacokinetics challenge. In this study, the authors strive to summarize recent efforts toward optimized, discrete, bimodal probes as well as a perspective on future directions of this burgeoning subfield of targeted imaging probe development. PMID- 30004805 TI - Budd-Chiari syndrome: imaging review. AB - Budd-Chiari syndrome (BCS), also known as hepatic venous outflow tract obstruction includes a group of conditions characterized by obstruction to the outflow of blood from the liver secondary to involvement of one or more hepatic veins (HVs), inferior vena cava (IVC) or the right atrium. There are a number of conditions that lead to BCS-ranging from hypercoagulable states to malignancies. In up to 25% patients, no underlying disorder is identified. Diagnosis of BCS is based on a combination of clinical and imaging features. A major part of the literature in BCS has been devoted to interventions; however, a detailed description of various imaging manifestations of BCS is lacking. In this review, we highlight the importance of various imaging modalities in the diagnosis of BCS. PMID- 30004806 TI - Imaging of anomalous pulmonary venous connections by multidetector CT angiography using third-generation dual source CT scanner. AB - Abnormal embryological development of the pulmonary veins can manifest as either partial or total anomalous drainage into the systemic venous circulation. Echocardiography does not provide adequate information in all cases as the optimal visualization of anomalous structures is limited by the availability of acoustic window; also it is highly operator dependent. However, multidetector CT angiography, with its multiplanar reformatting and volume rendering techniques, offers precise information about the three-dimensional anatomy and spatial relationships of the cardiovascular structures. With advent of dual source CT scanners and use of advanced dose reduction techniques, this information can be obtained in a short time with minimal radiation dose. In this pictorial essay, we present the multidetector CT imaging findings of the spectrum of total and partial anomalous pulmonary venous connections, using a third-generation dual source CT scanner. PMID- 30004807 TI - A UK survey exploring the assistant practitioner role across diagnostic imaging: current practice, relationships and challenges to progression. AB - OBJECTIVE:: Skill mix has been established as one method of maintaining imaging service delivery, with vertical and horizontal substitution of roles and tasks. Assistant practitioners (APs) have been undertaking limited imaging practice for almost two decades, but there remains a paucity of evidence related to the impact of their roles. METHODS:: This article reports on an electronic survey of individual APs within the NHS in the UK to explore utilisation, role scope and aspirations. RESULTS:: Responses were analysed from APs (n = 193) employed in 97 different organisations across the UK. The majority work in general radiography or mammography, with very few responses from other imaging modalities. Training routes varied across modalities, with most achieving Band 4 under Agenda for Change on completion of education. Limitations on practice vary between organisations and modalities, with many reporting blurring of the radiographer-AP boundary. Many aspire to continue their training to achieve registrant radiographer status, although there were clear frustrations from respondents over the lack of overt career prospects. CONCLUSION:: Integration of the role into imaging department practice does not appear to be universal or consistent and further research is required to examine the optimal skill mix composition. ADVANCES IN KNOWLEDGE:: Skill mix implementation is inconsistent across modalities and geography in the UK. Opportunities for further workforce utilisation and expansion are evident. PMID- 30004808 TI - High resolution isotropic diffusion imaging in post-mortem neonates: a feasibility study. AB - OBJECTIVE:: To investigate the potential of advanced diffusion weighted imaging (DWI) in post-mortem MRI (PMMR) at 3T. METHODS:: We acquired PMMR brain and body imaging in 12 neonates, mean gestational age 33.4 weeks (range 29-37 weeks) at 3T and 1.5T. Head and body diffusion imaging at 1.5T consisted of bipolar diffusion encoding and single-shot spin-echo echo-planar imaging (SE-EPI) for acquisition (echo time (TE) 96 ms; repetition time (TR) 2700 ms; voxel size 1.8 x 1.8 mm in plane with slice thickness 5 mm; b-values of 500 and 1000 s/mm2 applied in three orthogonal directions; total acquisition time 2:12). A whole-body 3T diffusion imaging protocol using monopolar diffusion encoding and simultaneous multislice EPI acquisition with gradients applied in 12 uniformly distributed directions was obtained (TE 53.4 ms; TR 5600 ms; 1.8 mm isotropic; multiband factor 2; b-values of 250, 750, 1250 and 1750 s/mm2; acquisition time 2:09 for a single b-value). RESULTS:: There was significant improvement in image quality in multiband, multislice diffusion PMMR protocol. On visual assessment of image quality, 1.5T DWI scored poorly (mean 2.4 SD +/- 0.47), and all 3T b-values individually scored significantly higher (p < 0.001) apart from b = 250 s/mm2 which was not significantly different. CONCLUSION:: Recent advances in diffusion sequences and hardware utilising higher field strengths and gradient performance allows whole body diffusion PMMR imaging at high resolution with improved image quality compared to the current clinical approach. ADVANCES IN KNOWLEDGE:: We have demonstrated feasibility of a multislice, multiband quantitative diffusion imaging sequence in the perinatal post-mortem setting. This will allow more detailed and quantitative clinical PMMR investigations using diffusion MRI in the future. PMID- 30004809 TI - Hypothermia elongates the contraction-relaxation cycle in explanted human failing heart decreasing the time for ventricular filling during diastole. AB - Targeted temperature management is part of the standardized treatment for patients in cardiac arrest. Hypothermia decreases cerebral oxygen consumption and induces bradycardia; thus, increasing the heart rate may be considered to maintain cardiac output. We hypothesized that increasing heart rate during hypothermia would impair diastolic function. Human left ventricular trabeculae obtained from explanted hearts of patients with terminal heart failure were stimulated at 0.5 Hz, and contraction-relaxation cycles were recorded. Maximal developed force (Fmax), maximal rate of development of force [(dF/d t)max], time to peak force (TPF), time to 80% relaxation (TR80), and relaxation time (RT = TR80 - TPF) were measured at 37, 33, 31, and 29 degrees C. At these temperatures, stimulation frequency was increased from 0.5 to 1.0 and to 1.5 Hz. At 1.5 Hz, concentration-response curves for the beta-adrenergic receptor (beta-AR) agonist isoproterenol were performed. Fmax, TPF, and RT increased when temperature was lowered, whereas (dF/d t)max decreased. At all temperatures, increasing stimulation frequency increased Fmax and (dF/d t)max, whereas TPF and RT decreased. At 31 and 29 degrees C, resting tension increased at 1.5 Hz, which was ameliorated by beta-AR stimulation. At all temperatures, maximal beta-AR stimulation increased Fmax, (dF/d t)max, and maximal systolic force, whereas resting tension decreased progressively with lowering temperature. beta-AR stimulation reduced TPF and RT to the same extent at all temperatures, despite the more elongated contraction-relaxation cycle at lower temperatures. Diastolic dysfunction during hypothermia results from an elongation of the contraction relaxation cycle, which decreases the time for ventricular filling. Hypothermic bradycardia protects the heart from diastolic dysfunction and increasing the heart rate during hypothermia should be avoided. NEW & NOTEWORTHY Decreasing temperature increases the duration of the contraction-relaxation cycle in the human ventricular myocardium, significantly reducing the time for ventricular filling during diastole. During hypothermia, increasing heart rate further reduces the time for ventricular filling and in some situations increases resting tension further impairing diastolic function. Modest beta-adrenergic receptor stimulation can ameliorate these potentially detrimental changes during diastole while improving contractile force generation during targeted temperature management. PMID- 30004810 TI - Role of the Heart in Blood Pressure Lowering During Chronic Baroreflex Activation: Insight from an in Silico Analysis. AB - Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insight into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine, and increases in plasma atrial natriuretic peptide, providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to sustained depression of cardiac function and increased secretion of atrial natriuretic peptide. Increased atrial natriuretic peptide and suppression of renal sympathetic nerve activity both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of renal sympathetic nerve activity was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and atrial natriuretic peptide secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. PMID- 30004811 TI - Noninvasive wave intensity analysis predicts functional worsening in children with pulmonary arterial hypertension. AB - The purpose of the present study was to characterize pulmonary vascular stiffness using wave intensity analysis (WIA) in children with pulmonary arterial hypertension (PAH), compare the WIA indexes with catheterization- and MRI-derived hemodynamics, and assess the prognostic ability of WIA-derived biomarkers to predict the functional worsening. WIA was performed in children with PAH ( n = 40) and healthy control subjects ( n = 15) from phase-contrast MRI-derived flow and area waveforms in the main pulmonary artery (MPA). From comprehensive WIA spectra, we collected and compared with healthy control subjects forward compression waves (FCW), backward compression waves (BCW), forward decompression waves (FDW), and wave propagation speed ( c-MPA). There was no difference in the magnitude of FCW between PAH and control groups (88 vs. 108 mm5.s-1.ml-1, P = 0.239). The magnitude of BCW was increased in patients with PAH (32 vs. 5 mm5.s 1.ml-1, P < 0.001). There was no difference in magnitude of indexed FDW (32 vs. 28 mm5.s-1.ml-1, P = 0.856). c-MPA was increased in patients with PAH (3.2 vs. 1.6 m/s, P < 0.001). BCW and FCW correlated with mean pulmonary arterial pressure, right ventricular volumes, and ejection fraction. Elevated indexed BCW [heart rate (HR) = 2.91, confidence interval (CI): 1.18-7.55, P = 0.019], reduced indexed FDW (HR = 0.34, CI: 0.11-0.90, P = 0.030), and increased c-MPA (HR = 3.67, CI: 1.47-10.20, P = 0.004) were strongly associated with functional worsening of disease severity. Our results suggest that noninvasively derived biomarkers of pulmonary vascular resistance and stiffness may be helpful for determining prognosis and monitoring disease progression in children with PAH. NEW & NOTEWORTHY Wave intensity analysis (WIA) studies are lacking in children with pulmonary arterial hypertension (PAH) partially because WIA, which is necessary to assess vascular stiffness, requires an invasive pressure-derived waveform along with simultaneous flow measurements. We analyzed vascular stiffness using WIA in children with PAH who underwent phase-contrast MRI and observed significant differences in WIA indexes between patients with PAH and control subjects. Furthermore, WIA indexes were predictive of functional worsening and were associated with standard catheterization measures. PMID- 30004813 TI - Chaperonomics in leptospirosis. AB - INTRODUCTION: Knowledge of the function of molecular chaperones is required for a better understanding of cellular proteostasis. Nevertheless, such information is currently dispersed as most of previous studies investigated chaperones on a single-angle basis. Recently, a new subdiscipline of chaperonology, namely 'chaperonomics' (defined as 'systematic analysis of chaperone genes, transcripts, proteins, or their interaction networks using omics technologies'), has been emerging to better understand biological, physiological, and pathological roles of chaperones. Areas covered: This review provides broad overviews of bacterial chaperones, heat shock proteins (HSPs), and leptospirosis, and then focuses on recent progress of chaperonomics applied to define roles of HSPs in various pathogenic and saprophytic leptospiral species and serovars. Expert commentary: Comprehensive analysis of leptospiral chaperones/HSPs using a chaperonomics approach holds great promise for better understanding of functional roles of chaperones/HSPs in bacterial survival and disease pathogenesis. Moreover, this new approach may also lead to further development of chaperones/HSPs-based diagnostics and/or vaccine discovery for leptospirosis. PMID- 30004814 TI - Sleeve Gastrectomy: Surgical Tips. AB - The vertical sleeve gastrectomy is a bariatric procedure that was originally described as the initial step in the biliopancreatic diversion. It demonstrated effectiveness in weight loss as a single procedure, and the laparoscopic vertical sleeve gastrectomy, as a stand-alone procedure, is now the most commonly performed bariatric surgery worldwide. Due to its relative technical ease and long-term data that have established its durability in treating obesity and its related comorbid conditions, the sleeve gastrectomy has grown in popularity among patients and surgeons. While there are variations in the technical aspects of performing a laparoscopic sleeve gastrectomy, key steps must be undertaken to produce safe and effective outcomes. This article reviews the indications for bariatric surgery, patient selection, surgical technique and tips, perioperative care and complications after sleeve gastrectomy. PMID- 30004815 TI - Sex Differences in Efficacy and Toxicity of Systemic Treatments: An Undervalued Issue in the Era of Precision Oncology. PMID- 30004816 TI - Gallotannin Improves the Photoaged-Related Proteins by Extracellular Signal Regulated Kinases/c-Jun N-Terminal Kinases Signaling Pathway in Human Epidermal Keratinocyte Cells. AB - Tannins are a type of polyphenols found in several fruits such as grapes and berries, and nuts such as aronias and acorns. Both hydrolyzable tannins and condensed tannins are referred to as tannins. Among the hydrolyzable tannins, gallotannin has a strong antioxidative property and is known to protect the skin by inhibiting the precursors of elastolytic enzymes. However, its mechanism of protection against ultraviolet B (UVB) damage in human fibroblasts and keratinocytes has not yet been elucidated. In this study, we investigate the antioxidant and antiaging effect of gallotannin on UVB-irradiated human cells by studying its effect on extracellular signal-regulated kinases/c-Jun N-terminal kinases (EKRs/JNKs) signaling related to cell growth and differentiation/stress apoptosis. The results showed that gallotannin improved collagen synthesis, reduced metalloproteinase-1 (MMP-1) expression in a dose-dependent manner, and downregulated MMP-1 levels through the ERK/JNK signaling pathway in UVB irradiated human cells. Gallotannin also increased glutathione but did not increase transforming growth factor beta 1, which induces fibrosis. We propose that gallotannin is a novel agent for protection against UVB, and acts as an antiaging agent that can be used in food, pharmaceuticals, and cosmetics. PMID- 30004818 TI - Effects of in home high dose accelerometer-based feedback on perceived and actual use in participants chronic post-stroke. AB - PURPOSE: To explore the effects of home-based high dose accelerometer-based feedback on (1) perception of paretic upper extremity (UE) use; (2) actual amount of use (AOU); and (3) capability. The secondary purpose was to characterize paretic UE use in the home setting. MATERIALS AND METHODS: Prospective experimental pre/post design (trial reg: NCT02995213). Eight participants chronic post-stroke (57.03 +/- 6.64 y.o.) wore bilateral wrist accelerometers for 3 weeks during which seven sessions of accelerometer-based feedback were administered in the home. Accelerometer data (overall use, unimanual use, bimanual use, paretic/nonparetic use ratio, different intensities of use) were collected at all follow-up visits; clinical outcomes/questionnaires were collected at baseline, mid-study, and post-intervention. RESULTS: After receiving high dose accelerometer-based feedback, participants had significant perceived gains in how much (p = 0.017) and how well (p = 0.050) they used the paretic UE. However, there were no significant group changes in actual paretic UE AOU or capability. CONCLUSIONS: In home high dose accelerometer-based feedback increased perceived paretic UE use and overall awareness of paretic UE use. Perception of use may serve as a first step to promote the behavioral change necessary to encourage actual paretic UE use, potentially decreasing the maladaptive effects of learned nonuse on participation. PMID- 30004817 TI - Mechanobehavior and Ontogenesis of the Temporomandibular Joint. AB - Craniofacial secondary cartilages of the mandibular condyle and temporomandibular joint (TMJ) eminence grow in response to the local mechanical environment. The intervening TMJ disc distributes normal loads over the cartilage surfaces and provides lubrication. A better understanding of the mechanical environment and its effects on growth, development, and degeneration of the TMJ may improve treatments aimed at modifying jaw growth and preventing or reversing degenerative joint disease (DJD). This review highlights data recorded in human subjects and from computer modeling that elucidate the role of mechanics in TMJ ontogeny. Presented data provide an approximation of the age-related changes in jaw-loading behaviors and TMJ contact mechanics. The cells of the mandibular condyle, eminence, and disc respond to the mechanical environment associated with behaviors and ultimately determine the TMJ components' mature morphologies and susceptibility to precocious development of DJD compared to postcranial joints. The TMJ disc may be especially prone to degenerative change due to its avascularity and steep oxygen and glucose gradients consequent to high cell density and rate of nutrient consumption, as well as low solute diffusivities. The combined effects of strain-related hypoxia and limited glucose concentrations dramatically affect synthesis of the extracellular matrix (ECM), which limit repair capabilities. Magnitude and frequency of jaw loading influence this localized in situ environment, including stem and fibrocartilage cell chemistry, as well as the rate of ECM mechanical fatigue. Key in vivo measurements to characterize the mechanical environment include the concentration of work input to articulating tissues, known as energy density, and the percentage of time that muscles are used to load the jaws out of a total recording time, known as duty factor. Combining these measurements into a mechanobehavioral score and linking these to results of computer models of strain-regulated biochemical events may elucidate the mechanisms responsible for growth, maintenance, and deterioration of TMJ tissues. PMID- 30004819 TI - Colonized Silence: Confronting the Colonial Link in Rural Alaska Native Survivors' Non-Disclosure of Child Sexual Abuse. AB - Though there is evidence linking the history of colonialism and oppression of Indigenous people to the high rates of rape and child sexual abuse experienced by this population today, it is less understood how colonial processes, past and present, condition the decision to disclose or report victimization. Drawing on a survivorship storytelling study of rural Alaska Native survivors of child sexual abuse, this paper underscores the importance of centering colonialism in understanding the culture of silence surrounding sexual victimization among Indigenous people. Results show that reasons for non-disclosure are quite embedded within larger social, historical and political themes of colonialism, oppression, and marginalization. Implications for policy and praxes are discussed, as well as a broader mandate of social change to remove barriers to disclosure. PMID- 30004820 TI - Epstein-Barr Virus-Infected Plasma Cells Infiltrate Erosive Oral Lichen Planus. AB - Epstein-Barr virus (EBV), in addition to its transforming properties, contributes to the pathogenesis of several inflammatory diseases. Here, we investigated its involvement in oral lichen planus (OLP), a common autoimmune-like disease of unknown etiopathogenesis that can display a malignant potential. EBV-infected cells (EBV+ cells) were sought in a large series of clinically representative OLPs ( n = 99) through in situ hybridization to detect small noncoding EBV encoded RNAs. Overall, our results demonstrated that EBV was commonly found in OLP (74%), with significantly higher frequency (83%) in the erosive form than in the reticular/keratinized type mild form (58%). Strikingly, many erosive OLPs were massively infiltrated by large numbers of EBV+ cells, which could represent a large part of the inflammatory infiltrate. Moreover, the number of EBV+ cells in each OLP section significantly correlated with local inflammatory parameters (OLP activity, infiltrate depth, infiltrate density), suggesting a direct relationship between EBV infection and inflammatory status. Finally, we characterized the nature of the infiltrated EBV+ cells by performing detailed immunohistochemistry profiles ( n = 21). Surprisingly, nearly all EBV+ cells detected in OLP lesions were CD138+ plasma cells (PCs) and more rarely CD20+ B cells. The presence of EBV+ PCs in erosive OLP was associated with profound changes in cytokine expression profile; notably, the expression of key inflammatory factors, such as IL1-beta and IL8, were specifically increased in OLP heavily infiltrated with EBV+ PCs. Moreover, electron microscopy-based experiments showed that EBV+ PCs actively produced EBV viral particles, suggesting possible amplification of EBV infection within the lesion. Our study thus brings conclusive evidence showing that OLP is commonly infiltrated with EBV+ PCs, adding a further puzzling element to OLP pathogenesis, given that PCs are now considered to be major regulatory immune cells involved in several autoimmune diseases (ClinicalTrials.gov NCT02276573). PMID- 30004821 TI - Metabolic Effects of Bariatric Surgery. AB - The number of obese people in the world has risen significantly over the past three decades. Obesity is associated with severe health comorbidities and metabolic disorders such as diabetes, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. Even with aggressive pharmacotherapy, obese patients will have substantial poor health outcomes. Bariatric surgery has been used more often during the last 10 years as it has been shown to be safe and effective in decreasing weight. The term "metabolic surgery" has recently emerged from the recognition that the effects of surgery on comorbidities extended beyond weight loss. Most patients suffering from metabolic disorders will obtain significant improvements after surgery. PMID- 30004822 TI - Using Cryo-EM to Investigate Bacterial Secretion Systems. AB - Bacterial secretion systems are responsible for releasing macromolecules to the extracellular milieu or directly into other cells. These membrane complexes are associated with pathogenicity and bacterial fitness. Understanding of these large assemblies has exponentially increased in the last few years thanks to electron microscopy. In fact, a revolution in this field has led to breakthroughs in characterizing the structures of secretion systems and other macromolecular machineries so as to obtain high-resolution images of complexes that could not be crystallized. In this review, we give a brief overview of structural advancements in the understanding of secretion systems, focusing in particular on cryo electron microscopy, whether tomography or single-particle analysis. We describe how such techniques have contributed to knowledge of the mechanism of macromolecule secretion in bacteria and the impact they will have in the future. PMID- 30004823 TI - Refractory Neutropenia Secondary to Dual Immune Checkpoint Inhibitors That Required Second-Line Immunosuppression. PMID- 30004824 TI - Strategies for Successful Survivorship Care Plan Implementation: Results From a Qualitative Study. AB - INTRODUCTION: Care for US cancer survivors is often fragmented, contributing to poor health outcomes. Care and outcomes may improve when survivors and follow-up care providers receive survivorship care plans (SCPs), written documents containing information regarding cancer diagnosis, treatment, surveillance plans, and health promotion. However, implementing SCPs is challenging. As such, we sought to identify strategies for successfully implementing SCPs. METHODS: We measured SCP implementation using performance data from cancer programs participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative, an oncologist-led quality assessment and improvement program. We used semistructured interviews with cancer program employees (eg, physicians) to identify strategies for successfully implementing SCPs by comparing approaches in cancer programs that, according to Quality Oncology Practice Initiative performance indicators, developed and delivered SCPs to a relatively small proportion of eligible survivors and their follow-up care providers (ie, low performers; n = 6 participants in five programs) with approaches among programs with better performance (ie, moderate performers; n = 15 participants in nine programs). RESULTS: Ten of 14 cancer programs developed SCPs for >= 50% of eligible survivors; two of 14 delivered SCPs to any survivors; and eight of 14 delivered SCPs to >= 25% of follow-up care providers. We found that moderate performers proactively addressed SCP requirements, leveraged requirements to improve survivorship care, set internal targets, automated implementation, had active leaders and champions, and tasked appropriate employees with SCP implementation. CONCLUSION: SCP implementation remains challenging. We identified strategies for successfully implementing SCPs. Future research should examine how cancer programs have achieved these strategies; findings could contribute to an understanding of the changes needed to implement comprehensive survivorship care. PMID- 30004825 TI - Myocarditis With Radiotherapy and Immunotherapy in Multiple Myeloma. PMID- 30004826 TI - Heading Through a Crowd. AB - The ability to navigate through crowds of moving people accurately, efficiently, and without causing collisions is essential for our day-to-day lives. Vision provides key information about one's own self-motion as well as the motions of other people in the crowd. These two types of information (optic flow and biological motion) have each been investigated extensively; however, surprisingly little research has been dedicated to investigating how they are processed when presented concurrently. Here, we showed that patterns of biological motion have a negative impact on visual-heading estimation when people within the crowd move their limbs but do not move through the scene. Conversely, limb motion facilitates heading estimation when walkers move independently through the scene. Interestingly, this facilitation occurs for crowds containing both regular and perturbed depictions of humans, suggesting that it is likely caused by low-level motion cues inherent in the biological motion of other people. PMID- 30004827 TI - The Impact of Simulator Size on Forces Generated in the Performance of a Defined Intracorporeal Suturing Task: A Pilot Study. AB - BACKGROUND: In pediatric minimal access surgery, the operative domain may vary from that of an adult to that of a neonate. This study aimed to quantify the impact of decreased operative domain on forces generated in the performance of a defined intracorporeal suturing task. METHODS: One hundred five participants performed a defined intracorporeal suturing task in small and large simulators. Time to task completion and force analysis parameters (FAPs = total, maximum, and mean forces in X, Y, and Z axes) were measured. Expertise level was assigned based on the number of laparoscopic cases. Outcomes were analyzed using paired sample t-tests, P value of <.05. RESULTS: Time to task completion varied significantly for experts between adult and pediatric simulators but not for intermediates or novices. Total, maximum, and mean forces in the X ("side to side") axis were significantly greater in the larger laparoscopic simulator for all levels of expertise. In the Y axis ("in and out" movement) and Z axis ("up and down" movement), total and mean forces were higher in the adult simulator regardless of the level of expertise. Differences in maximum force between the adult and pediatric simulators in the Z axis ("up and down" movement) varied significantly for novices and intermediates but not for experts. CONCLUSION: Forces were greater, particularly in the side-to-side plane, in the larger simulator for participants of all levels in the performance of this defined intracorporeal suturing task. Further analysis will determine the reasons for and implications of the increased force parameters in the simulator of larger domain. PMID- 30004828 TI - Helping to prevent hepatitis B in family setting, by educating women to vaccinate before marriage. AB - Hepatitis B (HB) is one of the major public health problems and a major cause of liver cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to evaluate the effect of a model-based educational intervention on preventive health behavior of hepatitis B vaccination among women who were going to get married (pending marriage women). Seventy pending marriage women were selected from martial counseling centers. The participants' knowledge, health beliefs model (HBM) constructs, and intention to receive HB vaccination were collected using a questionnaire based on HBM. The questionnaire was based on the Likert type scale with the score range of 1 to 5. An educational intervention was carried out based on pretest results. The baseline and follow-up level of the variables was statistically significant within the case group. The mean score of the variables in the two groups showed a statistically significant difference in favor of the case group. Our study showed a positive effect of educational intervention on the participants' knowledge, HBM constructs, and intention to receive HB vaccination, indicating that educational intervention based on HBM could be used as an appropriate tool to improve preventive behavior of HB vaccination. PMID- 30004829 TI - beta-Lactam and Fluoroquinolone-Resistant Enterobacteriaceae Recovered from the Environment of Human and Veterinary Tertiary Care Hospitals. AB - The dissemination of Enterobacteriaceae expressing resistance to clinically important antibiotics such as extended-spectrum cephalosporins (ESC), carbapenems, and fluoroquinolones is of critical concern to both human and veterinary medicine. In healthcare facilities, the movement of patients, personnel, and equipment provides an opportunity for Enterobacteriaceae carrying antibiotic resistance genes to disseminate in the hospital environment where they pose a threat to patients, staff, and hospital visitors. We collected environmental samples using electrostatic cloths to estimate the frequency of resistant Enterobacteriaceae contamination on human and veterinary hospital surfaces. Samples were enriched in nutrient broth modified with antibiotics to provide specific selection pressure to select for bacteria expressing AmpC beta lactamase (blaCMY), extended-spectrum beta-lactamase (ESBL, blaCTX-M), carbapenemase, quinolone, and fluoroquinolone-resistant phenotypes. A total of 31 contact surfaces were sampled at each of five visits to two human hospitals. In addition, 34 surfaces were sampled at each of three visits to a veterinary hospital serving both farm animal and companion animal patients. Isolates expressing the blaCMY phenotype were recovered from 0.6%, 100%, and 18.2% of human hospitals, veterinary farm animal, and veterinary companion animal hospital surfaces, respectively. Isolates expressing the blaCTX-M phenotype were recovered from 0.6%, 55%, and 16.7% of human hospitals, farm animal, and companion animal veterinary hospital surfaces, respectively. Carbapenemase-producing Enterobacteriaceae (CPE) were detected from 1.3% of human hospital surfaces, but none were recovered from the veterinary hospital. Fluoroquinolone resistance was detected in 0.6%, 5.0%, and 37.9% of human hospitals, farm animal, and companion animal veterinary hospital surfaces, respectively. Our results indicate that ESC and fluoroquinolone-resistant Enterobacteriaceae can contaminate surfaces in both human and veterinary medical settings, with higher prevalence observed in veterinary hospitals, although the recovery of CPE from human hospital environments is concerning. Hospital medical trolleys or carts may serve as fomites for the dissemination of clinically relevant resistant bacteria. PMID- 30004831 TI - Educational Intervention Enhances Clinician Awareness of Christian, Jewish, and Islamic Teachings around End-of-Life Care. AB - BACKGROUND: Patients' religious and spiritual values impact their goals and perception of illness, especially at the end of life (EOL). According to the Joint Commission, identifying spiritual beliefs may improve cultural competency and patient-centered care. However, clinicians may be uncomfortable discussing spirituality and unaware of basic religious teachings. OBJECTIVES: To assess clinician understanding and knowledge of key Christian, Jewish, and Islamic teachings around EOL care before and after a one-hour educational intervention through video podcast. DESIGN: After literature review and consultation with religious leaders, a pre- and post-test (10 questions per religion plus demographic questions) to assess knowledge of Christian, Jewish, and Islamic teachings and an educational video podcast were developed. The pretest was administered to healthcare providers, followed by a one-hour educational intervention through a video podcast. Next, a post-test was administered. SUBJECTS: Seventy-three healthcare providers participated in this study. MEASUREMENTS: Differences between pretest and post-test scores were analyzed employing paired t-test tests using SPSS software. RESULTS: The median score on the pretest was Christian: 6 [2-9], Jewish: 6 [4-10], and Islamic: 6 [2-8]. After the educational intervention, the median Christian, Jewish, and Islamic scores improved to 8 [4-10], 9 [6-10], and 10 [3-10], respectively (p < 0.0001). Additionally, the total pretest median score improved from 17 [10-24] to 27 [16 30]. CONCLUSIONS: A one-hour educational intervention through video podcast significantly improved understanding of Christian, Jewish, and Islamic teachings around EOL care. The video podcast enabled easy distribution of the educational session to multiple facilities and providers. Additional research is needed to determine the longitudinal outcomes and impact on patient outcomes of this intervention. PMID- 30004830 TI - Oral Anti-Vascular Endothelial Growth Factor Drugs and Ocular Adverse Events. AB - PURPOSE: To evaluate possible associations between oral anti-vascular endothelial growth factor (VEGF) drugs and ocular side effects. METHODS: Spontaneous reports were collected and evaluated by the National Registry of Drug-Induced Ocular Side Effects on the three oral anti-VEGF drugs (pazopanib, sorafenib, and sunitinib) for possible ocular side effects. RESULTS: Reported side effects include blurred or decreased vision (389 cases); periocular or eyelid edema (273 cases); superficial anterior segment toxicity (270 cases); conjunctival, retinal, or vitreous bleeding (77 cases); retinal detachments (RDs) or retinal tears (RTs) (75 cases); extraocular muscle disorders, including ptosis (51 cases); discoloration of eyelashes (36 cases); retinal arterial or venous occlusions (26 cases); optic nerve disorders, including papilledema and ischemic optic neuropathy (21 cases); uveitis (10 cases); and macular edema (7 cases). Spontaneous reports of possible RD or RT have been associated with pazopanib (31 RDs and 12 RTs), sunitinib (24 RDs and 0 RT), and sorafenib (7 RDs and 2 RTs). CONCLUSIONS: Oral anti-VEGF drugs can cause superficial anterior segment side effects. Pazopanib has been reported to be possibly linked to RDs and RTs. This study suggests that sorafenib and sunitinib are suspected as well. RDs were seldom differentiated into rhegmatogenous retinal detachments (RRDs) or non-RRDs. The association of oral anti-VEGF drugs with RRD and RT are unclassified although this suggests a "signal" requiring further study. The association of oral anti VEGF drugs with serous retinal detachments, while rare, is plausible. Patients on this class of drugs should be instructed to seek immediate ophthalmic consultation if retinal symptoms occur. PMID- 30004832 TI - Baculovirus Entry and Egress from Insect Cells. AB - Baculoviruses are large DNA viruses of insects that are highly pathogenic in many hosts. In the infection cycle, baculoviruses produce two types of virions. These virion phenotypes are physically and functionally distinct, and each serves a critical role in the biology of the virus. One phenotype, the occlusion-derived virus (ODV), is occluded within a crystallized protein that facilitates oral infection of the host. A large complex of at least nine ODV envelope proteins called per os infectivity factors are critically important for ODV infection of insect midgut epithelial cells. Viral egress from midgut cells is by budding to produce a second virus phenotype, the budded virus (BV). BV binds, enters, and replicates in most other tissues of the host insect. Cell recognition and entry by BV are mediated by a single major envelope glycoprotein: GP64 in some baculoviruses and F in others. Entry and egress by the two virion phenotypes occur by dramatically different mechanisms and reflect a life cycle in which ODV is specifically adapted for oral infection while BV mediates dissemination of the infection within the animal. PMID- 30004833 TI - Color Perception: Objects, Constancy, and Categories. AB - Color has been scientifically investigated by linking color appearance to colorimetric measurements of the light that enters the eye. However, the main purpose of color perception is not to determine the properties of incident light, but to aid the visual perception of objects and materials in our environment. We review the state of the art on object colors, color constancy, and color categories to gain insight into the functional aspects of color perception. The common ground between these areas of research is that color appearance is tightly linked to the identification of objects and materials and the communication across observers. In conclusion, we argue that research should focus on how color processing is adapted to the surface properties of objects in the natural environment in order to bridge the gap between the known early stages of color perception and the subjective appearance of color. PMID- 30004834 TI - A Systematic Review of How Young People Live with Inherited Disease: What Can We Learn for Li-Fraumeni Syndrome? AB - PURPOSE: Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition caused by germline TP53 mutations, confers significant cancer risks for young people (15-39 years). Yet evidence of how individuals experience this condition and the psychosocial implications are lacking. Therefore, this systematic review assessed the psychosocial implications of living with, or at risk of, an autosomal dominant condition as a young person, to draw evidence that may be analogous for young people with LFS. METHODS: We conducted a systematic search for studies published in peer-reviewed journals using Medline, CINAHL, PsycINFO, and Embase databases. Findings were synthesized and are reported thematically. RESULTS: We screened 352 articles and identified 39 studies, representing the perspectives of 765 young people. Most studies addressed hereditary breast and ovarian cancer (n = 22) and used qualitative methodologies (n = 35). Only one LFS study was identified, highlighting the distinct lack of psychosocial research describing experiences of young people with LFS. Translatable evidence showed that familial factors strongly influenced young people's experiences of genetic testing and their mutation status. Major adverse reactions to genetic test results were rare, although young people with a gene mutation experienced various psychosocial concerns at key developmental milestones, including family planning, developing romantic relationships, and making risk management decisions. CONCLUSION: Young people undergoing genetic testing for inherited disease require individualized support and recognition of previous lived experiences. We recommend that longitudinal care be made available to young people with inherited disease as they reach developmental milestones that intersect with risk management, risk perception, and family formation. PMID- 30004835 TI - Association of HLA-DRB1 and -DQB1 alleles with type 1 (autoimmune) diabetes in African Arabs: systematic review and meta-analysis. AB - : Several studies confirmed the association of HLA-DRB1 and -DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Arabs. This is a systematic review and meta-analysis aimed at comprehensively evaluating this association with T1D, using molecular HLA data. Relevant studies were identified through systemic search of Medline/PubMed, Cochrane, Science Direct, ResearchGate, and EMBASE databases. Statistical analysis was carried out using RevMan, and Comprehensive Meta-analysis programs. Given the heterogeneity of African Arabs, we also performed subgroup analysis according to ethnicity. Analysis of sensitivity, heterogeneity, and publication bias were performed to validate the outcome of the findings. This meta-analysis included 862 T1DM cases, along with 1,390 normoglycemic control, and comprised ten comparisons. Our study indicates that DRB1*03 (OR = 2.86), DRB1*04 (OR = 2.78), and DQB1*02 (OR = 2.29), are positively associated with increased risk of T1DM, while DRB1*07 (OR = 0.48), DRB1*11 (OR = 0.20), DRB1*13 (OR = 0.47), DRB1*15 (OR = 0.30), DQB1*05 (OR = 0.39), and DQB1*06 (OR = 0.27) were negatively associated with T1D, suggesting a protective role against T1D. This meta-analysis was characterized by low heterogeneity, sensitivity, and publication bias, indicating the robustness and reliability of the results. BACKGROUND: Several studies confirmed the association of HLA-DRB1 and -DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Arabs. This is a systematic review and meta analysis aimed at comprehensively evaluating this association with T1D, using molecular HLA data. METHODS: Relevant studies were identified through systemic search of Medline/PubMed, Cochrane, Science Direct, ResearchGate, and EMBASE databases. Statistical analysis was carried out using Revman, and Comprehensive Meta-analysis programs. Given the heterogeneity of African Arabs, we also performed subgroup analysis according to ethnicity. Analysis of sensitivity, heterogeneity, and pub!lication bias were performed to validate the outcome of the findings. This meta-analysis included 862 T1DM cases, along with 1,390 normoglycemic control, and comprised ten comparisons. RESULTS: Our study indicates that DRB1*03 (OR = 2.86), DRB1*04 (OR = 2.78), and DQB1*02 (OR = 2.29), are positively associated with increased risk of T1DM, while DRB1*07 (OR = 0.48), DRB1*11 (OR = 0.20), DRB1*13 (OR = 0.47), DRB1*15 (OR = 0.30), DQB1*05 (OR = 0.39), and DQB1*06 (OR = 0.27) were negatively associated with T1D, suggesting a protective role against T1D. CONCLUSION: This meta-analysis was characterized by low heterogeneity, sensitivity, and publication bias, indicating the robustness and reliability of the results. PMID- 30004837 TI - Transcript profile distinguishes variability in human myogenic progenitor cell expansion capacity. AB - Primary human muscle progenitor cells (hMPCs) are commonly used to understand skeletal muscle biology, including the regenerative process. Variability from unknown origin in hMPC expansion capacity occurs independently of disease, age, or sex of the donor. We sought to determine the transcript profile that distinguishes hMPC cultures with greater expansion capacity and to identify biological underpinnings of these transcriptome profile differences. Sorted (CD56+/CD29+) hMPC cultures were clustered by unbiased, K-means cluster analysis into FAST and SLOW based on growth parameters (saturation density and population doubling time). FAST had greater expansion capacity indicated by significantly reduced population doubling time (-60%) and greater saturation density (+200%), nuclei area under the curve (AUC, +250%), and confluence AUC (+120%). Additionally, FAST had fewer % dead cells AUC (-44%, P < 0.05). RNA sequencing was conducted on RNA extracted during the expansion phase. Principal component analysis distinguished FAST and SLOW based on the transcript profiles. There were 2,205 differentially expressed genes (DEgenes) between FAST and SLOW (q value <= 0.05); 362 DEgenes met a more stringent cut-off (q value <= 0.001 and 2.0 fold change). DEgene enrichment suggested FAST (vs. SLOW) had promotion of the cell cycle, reduced apoptosis and cellular senescence, and enhanced DNA replication. Novel (RABL6, IRGM1, and AREG) and known (FOXM1, CDKN1A, Rb) genes emerged as regulators of identified functional pathways. Collectively the data suggest that variation in hMPC expansion capacity occurs independently of age and sex and is driven, in part, by intrinsic mechanisms that support the cell cycle. PMID- 30004836 TI - Serum Amyloid A as an Early Marker of Infectious Complications after Laparoscopic Surgery for Colorectal Cancer. AB - BACKGROUND: Our aim was to evaluate the usefulness of serum amyloid A (SAA) measurements in comparison with C-reactive protein (CRP) in the early prediction of infectious complications among patients undergoing laparoscopic surgery for colorectal cancer Methods: Consecutive patients undergoing laparoscopic resection for colorectal cancer were analyzed prospectively. All subjects had the Enhanced Recovery After Surgery protocol implemented. Blood samples were taken from all patients and SAA and CRP were measured on the day of surgery and on the three consecutive post-operative days (PODs). Patients were divided into two groups (Group 1 without complications, Group 2 with complications), and these groups were compared. RESULTS: The study included 81 patients (61 in Group 1 and 20 in Group 2). Starting from POD2, significant differences between the groups were observed for both SAA and CRP. On POD2, the median CRP values were 116.7 mg/L and 256.9 mg/L in Groups 1 and 2, respectively (p = 0.00002). On POD3, the median SAA concentration was 445 mg/L in Group 1 and 1,412 mg/L in Group 2 (p = 0.00003). The CRP concentrations were 80.2 mg/L and 247.1 mg/L in Groups 1 and 2, respectively (p = 0.00001). A receiver operating characteristic (ROC) curve analysis showed that measurements of POD3 had the highest specificity and sensitivity with no significant differences between CRP and SAA (on POD3 for SAA sensitivity 83.3% and specificity 94%; for CRP: sensitivity 88% and specificity 86%). CONCLUSION: Measurements of SAA are useful in predicting infectious complications even on the early post-operative days. It has characteristics similar to CRP, and its best values are reached on POD3. PMID- 30004838 TI - Persistent pulmonary hypertension alters the epigenetic characteristics of endothelial nitric oxide synthase gene in pulmonary artery endothelial cells in a fetal lamb model. AB - Decreased expression of endothelial nitric oxide synthase (eNOS), a key mediator of perinatal transition, characterizes persistent pulmonary hypertension of the newborn (PPHN) in neonates and a fetal lamb model; the mechanisms are unclear. We investigated whether increased DNA CpG methylation at the eNOS promoter in estrogen response elements (EREs) and altered histone code together contribute to decreased eNOS expression in PPHN. We isolated pulmonary artery endothelial cells (PAEC) from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction from 128 to 136 days gestation or gestation-matched twin controls. We measured right ventricular systolic pressure (RVSP) and Fulton index and determined eNOS expression in PAEC in control and PPHN lambs. We determined DNA CpG methylation by pyrosequencing and activity of ten eleven translocase demethylases (TET) by colorimetric assay. We quantified the occupancy of transcription factors, specificity protein 1 (Sp1), and estrogen receptors and density of four histone marks around Sp1 binding sites by chromatin immunoprecipitation (ChIP) assays. Fetal lambs with PPHN developed increased RVSP and Fulton index. Levels of eNOS mRNA and protein were decreased in PAEC from PPHN lambs. PPHN significantly increased the DNA CpG methylation in eNOS promoter and decreased TET activity in PAEC. PPHN decreased Sp1 occupancy and density of the active mark, lysine 12 acetylation of histone 4, and increased density of the repression mark, lysine 9 trimethylation of histone 3 around Sp1 binding sites in eNOS promoter. These results suggest that epigenetic modifications are primed to decrease Sp1 binding at the eNOS gene promoter in PPHN. PMID- 30004840 TI - Lipids and Women's Health: Recent Updates and Implications for Practice. AB - The obstetrician/gynecologist frequently serves as the primary care physician for women. Specialty-specific guidelines vary in screening recommendations for lipid disorders; women's health practitioners often follow recommendations to screen at age 45 in the absence of other risk factors. However, 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommend screening at age 21 to capture those at risk of cardiovascular disease and allow for early intervention with lifestyle and, in the most severe cases, evidence-based statins. We discuss the care of women who primarily benefit from screening: those with familial hypercholesterolemia (FH), those with the metabolic syndrome (MetS) or polycystic ovary syndrome, and those with hypertriglyceridemia. Those with FH have elevated low-density lipoprotein cholesterol from birth and a propensity for premature coronary heart disease. Early recognition of FH can allow risk-reducing interventions, as well as identification of additional affected relatives. Early detection of metabolic variables, such as in the MetS and hypertriglyceridemia, can lead to an enhanced focus on physical activity and heart-healthy diet. Finally, we discuss a practical approach to lipid management and review concerns regarding drug safety. Our objective is to provide a current overview of cardiovascular risk factor optimization that women's health practitioners can use in identifying and/or treating patients at risk for cardiovascular disease and diabetes. PMID- 30004841 TI - Unlocking Human Brain Metabolism by Genome-Scale and Multiomics Metabolic Models: Relevance for Neurology Research, Health, and Disease. AB - Neurology research and clinical practice are transforming toward postgenomics integrative biology. One such example is the study of human brain metabolism that is highly sophisticated due to reactions occurring in and between the astrocytes and neurons. Because of the inherent difficulty of performing experimental studies in human brain, metabolic network modeling has grown in importance to decipher the contribution of brain metabolite kinetics to human health and disease. Multiomics system science-driven metabolic models, using genome-scale and transcriptomics Big Data, offer the promise of new insights on metabolic networks in human brain. Added to this, the availability of omics technologies in both developed and developing world, neurology research, and clinical practice ought to be repositioned with a view to systems medicine. In this expert analysis, we present a critical and in-depth overview of the basic tenets of human brain metabolism, together with the most recent metabolic modeling strategies and computational studies of brain in health and neurological diseases. Human genome-scale metabolic models developed in a both global and brain-specific manner and multiomics synthesis of knowledge are highlighted in particular. We conclude by underscoring the value of multiomics modeling for metabolic diseases and computational investigations of the brain networks, with a view to unlocking the pathophysiology of Alzheimer's disease, Parkinson's disease, migraine, stroke, epilepsy, and multiple sclerosis, among other neurological disorders of importance for global health. PMID- 30004839 TI - R213G polymorphism in SOD3 protects against bleomycin-induced inflammation and attenuates induction of proinflammatory pathways. AB - Extracellular superoxide dismutase (EC-SOD), one of three mammalian SOD isoforms, is the sole extracellular enzymatic defense against superoxide. A known human single nucleotide polymorphism (SNP) in the matrix-binding domain of EC-SOD characterized by an arginine-to-glycine substitution at position 213 (R213G) redistributes EC-SOD from the matrix into extracellular fluids. We previously reported that knock-in mice harboring the human R213G SNP (R213G mice) exhibited enhanced resolution of inflammation with subsequent protection against fibrosis following bleomycin treatment compared with wild-type (WT) littermates. Herein we set out to determine the underlying pathways with RNA-Seq analysis of WT and R213G lungs 7 days post-PBS and bleomycin. RNA-Seq analysis uncovered significant differential gene expression changes induced in WT and R213G strains in response to bleomycin. Ingenuity Pathways Analysis was used to predict differentially regulated up- and downstream processes based on transcriptional changes. Most prominent was the induction of inflammatory and immune responses in WT mice, which were suppressed in the R213G mice. Specifically, PKC signaling in T lymphocytes, IL-6, and NFKappaB signaling were opposed in WT mice when compared with R213G. Several upstream regulators such as IFNgamma, IRF3, and IKBKG were implicated in the divergent responses between WT and R213G mice. Our data suggest that the redistributed EC-SOD due to the R213G SNP attenuates the dysregulated inflammatory responses observed in WT mice. We speculate that redistributed EC SOD protects against dysregulated alveolar inflammation via reprogramming of recruited immune cells toward a proresolving state. PMID- 30004842 TI - Toward Precision Nutrition: Commercial Infant Formulas and Human Milk Compared for Stereospecific Distribution of Fatty Acids Using Metabolomics. AB - Precision nutrition and nutrimetabolomics are emerging omics technology applications in public health. In this context, the infant formula (IF) is a manufactured foodstuff that aims to match the composition of human milk (HM), especially the lipid profile. The IF manufacturers have achieved relative success in matching the predominant fatty acid (FAs) profiles, but the stereospecific structures of the triacylglycerides in HM require deeper analyses with system sciences. We employed NMR-based metabolomics to compare the lipid profiles of 12 commercial IF samples and 10 HM samples. Additionally, vegetables, fish, and microalgae oil as raw materials in IFs were also investigated to understand the lipid profile of IFs. We found that IF has significantly less saturated fatty acids (SFA), higher unsaturated FAs, and similar polyunsaturated fatty acid (PUFA) content, compared with HM. However, the main difference was the stereospecific distribution of FAs: HM samples were associated with a high content of SFAs in the sn-2 position (26.03% +/- 2.93%) and PUFAs in the sn-1,3 position (15.35% +/- 3.94%). The IF had the opposite distribution, with SFAs esterified mainly in the sn-1,3 position (33.07 +/- 4.93%) and PUFAs in the sn-2 position (9.57% +/- 7.05%). Consequently, the hydrolysis of HM results in SFA mainly as sn-2-monoacylglycerides, which are well absorbed. In contrast, the hydrolysis of the IF provided SFA, mainly as free FAs, which tend to bind calcium and form insoluble calcium soaps in the intestine. Taken together, these observations can inform optimal design of infant formulas with a view to precision nutrition. PMID- 30004844 TI - Genetic Susceptibility for Cervical Cancer in African Populations: What Are the Host Genetic Drivers? AB - Human papillomavirus (HPV) is an essential but not a sufficient cervical cancer etiological factor. Cancer promoters, such as host genetic mutations, significantly modulate therapeutic responses and susceptibility. In cervical cancer, of interest have been viral clearing genes and HPV oncoprotein targets, for which conflicting data have been reported among different populations. This expert analysis evaluates cervical cancer genetic susceptibility biomarkers studied in African populations. Notably, the past decade has seen Africa as a hotbed of biomarker and precision medicine innovations, thus potentially informing worldwide biomarker development strategies. We conducted a critical literature search in PubMed/MEDLINE, Google Scholar, and Scopus databases for case-control studies reporting on cervical cancer genetic polymorphisms among Africans. We found that seven African countries conducted cervical cancer molecular epidemiology studies in one of Casp8, p53, CCR2, FASL, HLA, IL10, TGF beta, and TNF-alpha genes. This analysis reveals a remarkable gap in cervical cancer molecular epidemiology among Africans, whereas cervical cancer continues to disproportionately have an impact on African populations. Genome-wide association, whole exome- and whole-genome sequencing studies confirmed the contribution of candidate genes in cervical cancer. With such advances and omics technologies, the role of genetic susceptibility biomarkers can be exploited to develop novel interventions to improve current screening, diagnostic and prognostic methods worldwide. Exploring these genetic variations is crucial because African populations are genetically diverse and some variants or their combined effects are yet to be discovered and translated into tangible clinical applications. Thus, translational medicine and flourishing system sciences in Africa warrant further emphasis in the coming decade. PMID- 30004843 TI - Type 2 Diabetes Mellitus: Integrative Analysis of Multiomics Data for Biomarker Discovery. AB - Increased fasting plasma glucose (FPG) is an independent risk factor for type 2 diabetes mellitus (T2DM). The development of systems biology technologies for integration of multiomics data is crucial for predicting increased FPG levels. In this case-control study, immunoglobulin (Ig) G glycosylation profiling and genome wide association analyses were performed on 511 participants, and among them 76 had increased FPG (aged 47.6 +/- 6.14 years), and 435 had decreased or fluctuant FPG (aged 47.9 +/- 6.08 years). We identified nine single nucleotide polymorphisms (SNPs) in five genes (RPL7AP27, SNX30, SLC39A12, BACE2, and IGFL2) that were significantly associated with increased FPG (odds ratios 1.937-2.393). Moreover, of the 24 glycan peaks (GPs), GPs 3, 8, and 11 presented positive trends with increased FPG levels, whereas GPs 4 and 14 presented negative trends. A significant improvement of predictive power was observed when adding 24 IgG GPs to 9 SNPs with the area under the curve increased from 0.75 to 0.81. This report shows that the combination of candidate SNPs with IgG glycomics offers biomarker potentials for T2DM. The substantial predictive power obtained from integrating genomics and glycomics biomarkers suggests the feasibility of applying such multiomics strategies to enable predictive, preventive, and personalized medicine for T2DM. PMID- 30004846 TI - New Targets for Parkinson's Disease: Adhesion G Protein-Coupled Receptor B1 is Downregulated by AMP-Activated Protein Kinase Activation. AB - While progressive dopaminergic neurodegeneration is responsible for the cardinal motor defects in Parkinson's disease (PD), new diagnostics and therapeutic targets are necessary to effectively address this major global health burden. We evaluated whether the adhesion G protein-coupled receptor B1 (ADGRB1, formerly BAI1, brain-specific angiogenesis inhibitor 1) might contribute to dopaminergic neuronal loss. We used bioinformatic analyses, as well as in vitro and in vivo PD models. We report in this study that ADGRB1 is decreased in PD and that the ADGRB1 level is specifically decreased in dopaminergic neurons in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In primary mouse mesencephalic neurons and human neuroblastoma cell lines, 1-methyl 4-phenylpyridinium (MPP+), a toxic metabolite of MPTP, suppressed the expression of ADGRB1. Moreover, we applied a network generation tool, Ingenuity Pathway Analysis(r), with the transcriptomics dataset to extend the upstream regulatory pathway of ADGRB1 expression. AMP-activated protein kinase (AMPK) was predicted as a regulator, and consequently, 5-aminoimidazole-4-carboxamide ribonucleotide, a specific activator of AMPK, reduced the ADGRB1 protein level. Finally, ADGRB1 overexpression decreased nuclear condensation induced by MPP+ treatment. Taken together, we observed that decreased ADGRB1 by activation of AMPK induced neuronal cell death in MPTP/MPP+-mediated PD models, suggesting that ADGRB1 might potentially play a survival role in the neurodegenerative pathway of PD. These data offer new insights into dopaminergic cell death with therapeutic implications for neurodegenerative disorders. PMID- 30004845 TI - A Systems Biology Approach to Understanding the Pathophysiology of High-Grade Serous Ovarian Cancer: Focus on Iron and Fatty Acid Metabolism. AB - Ovarian cancer (OVC) is the most lethal of the gynecological malignancies, with diagnosis often occurring during advanced stages of the disease. Moreover, a majority of cases become refractory to chemotherapeutic approaches. Therefore, it is important to improve our understanding of the molecular dependencies underlying the disease to identify novel diagnostic and precision therapeutics for OVC. Cancer cells are known to sequester iron, which can potentiate cancer progression through mechanisms that have not yet been completely elucidated. We developed an algorithm to identify novel links between iron and pathways implicated in high-grade serous ovarian cancer (HGSOC), the most common and deadliest subtype of OVC, using microarray gene expression data from both clinical sources and an experimental model. Using our approach, we identified several links between fatty acid (FA) and iron metabolism, and subsequently developed a network for iron involvement in FA metabolism in HGSOC. FA import and synthesis pathways are upregulated in HGSOC and other cancers, but a link between these processes and iron-related genes has not yet been identified. We used the network to derive hypotheses of specific mechanisms by which iron and iron related genes impact and interact with FA metabolic pathways to promote tumorigenesis. These results suggest a novel mechanism by which iron sequestration by cancer cells can potentiate cancer progression, and may provide novel targets for use in diagnosis and/or treatment of HGSOC. PMID- 30004847 TI - Prefrontal Modulation of Visual Processing and Sustained Attention in Aging, a tDCS-EEG Coregistration Approach. AB - The ability to sustain attention is integral to healthy cognition in aging. The right PFC (rPFC) is critical for maintaining high levels of attentional focus. Whether plasticity of this region can be harnessed to support sustained attention in older adults is unknown. We used transcranial direct current stimulation to increase cortical excitability of the rPFC, while monitoring behavioral and electrophysiological markers of sustained attention in older adults with suboptimal sustained attention capacity. During rPFC transcranial direct current stimulation, fewer lapses of attention occurred and electroencephalography signals of frontal engagement and early visual attention were enhanced. To further verify these results, we repeated the experiment in an independent cohort of cognitively typical older adults using a different sustained attention paradigm. Again, prefrontal stimulation was associated with fewer attentional lapses. These experiments suggest the rPFC can be manipulated in later years to increase top-down modulation over early sensory processing and improve sustained attention performance. This holds valuable information for the development of neurorehabilitation protocols to ameliorate age-related deficits in this capacity. PMID- 30004849 TI - Neural Encoding of Attended Continuous Speech under Different Types of Interference. AB - We examined how attention modulates the neural encoding of continuous speech under different types of interference. In an EEG experiment, participants attended to a narrative in English while ignoring a competing stream in the other ear. Four different types of interference were presented to the unattended ear: a different English narrative, a narrative in a language unknown to the listener (Spanish), a well-matched nonlinguistic acoustic interference (Musical Rain), and no interference. Neural encoding of attended and unattended signals was assessed by calculating cross-correlations between their respective envelopes and the EEG recordings. Findings revealed more robust neural encoding for the attended envelopes compared with the ignored ones. Critically, however, the type of the interfering stream significantly modulated this process, with the fully intelligible distractor (English) causing the strongest encoding of both attended and unattended streams and latest dissociation between them and nonintelligible distractors causing weaker encoding and early dissociation between attended and unattended streams. The results were consistent over the time course of the spoken narrative. These findings suggest that attended and unattended information can be differentiated at different depths of processing analysis, with the locus of selective attention determined by the nature of the competing stream. They provide strong support to flexible accounts of auditory selective attention. PMID- 30004848 TI - Learning Naturalistic Temporal Structure in the Posterior Medial Network. AB - The posterior medial network is at the apex of a temporal integration hierarchy in the brain, integrating information over many seconds of viewing intact, but not scrambled, movies. This has been interpreted as an effect of temporal structure. Such structure in movies depends on preexisting event schemas, but temporal structure can also arise de novo from learning. Here, we examined the relative role of schema-consistent temporal structure and arbitrary but consistent temporal structure on the human posterior medial network. We tested whether, with repeated viewing, the network becomes engaged by scrambled movies with temporal structure. Replicating prior studies, activity in posterior medial regions was immediately locked to stimulus structure upon exposure to intact, but not scrambled, movies. However, for temporally structured scrambled movies, functional coupling within the network increased across stimulus repetitions, rising to the level of intact movies. Thus, temporal structure is a key determinant of network dynamics and function in the posterior medial network. PMID- 30004850 TI - Replay of Stimulus-specific Temporal Patterns during Associative Memory Formation. AB - Forming a memory often entails the association of recent experience with present events. This recent experience is usually an information-rich and dynamic representation of the world around us. We here show that associating a static cue with a previously shown dynamic stimulus yields a detectable, dynamic representation of this stimulus. We further implicate this representation in the decrease of low-frequency power (~4-30 Hz) in the ongoing EEG, which is a well known correlate of successful memory formation. The reappearance of content specific patterns in desynchronizing brain oscillations was observed in two sensory domains, that is, in a visual condition and in an auditory condition. Together with previous results, these data suggest a mechanism that generalizes across domains and processes, in which the decrease in oscillatory power allows for the dynamic representation of information in ongoing brain oscillations. PMID- 30004851 TI - The Scope of Planning Serial Actions during Typing. AB - Human activities consisting of multiple component actions require the generation of ordered sequences. This study investigated the scope of response planning in highly serial task, typing, by means of ERPs indexing motor response preparation. Specifically, we compared motor-related ERPs yielded by words typed using a single hand against words that had all keystrokes typed with a single hand, except for a deviant one, typed with the opposite hand. The deviant keystroke occurred either early in the typed sequence, corresponding to the second or third letters, or late, corresponding to the penultimate or last letter. Motor-related ERPs detected before response onset were affected only by deviant keystrokes located at the beginning of the sequence, whereas deviant keystrokes located at the end yielded ERPs that were undistinguishable from unimanual responses. These results impose some constraints on the notion of parallel processing of component actions. PMID- 30004852 TI - Attentional Fluctuations Influence the Neural Fidelity and Connectivity of Stimulus Representations. AB - Attention is thought to facilitate both the representation of task-relevant features and the communication of these representations across large-scale brain networks. However, attention is not "all or none," but rather it fluctuates between stable/accurate (in-the-zone) and variable/error-prone (out-of-the-zone) states. Here we ask how different attentional states relate to the neural processing and transmission of task-relevant information. Specifically, during in the-zone periods: (1) Do neural representations of task stimuli have greater fidelity? (2) Is there increased communication of this stimulus information across large-scale brain networks? Finally, (3) can the influence of performance contingent reward be differentiated from zone-based fluctuations? To address these questions, we used fMRI and representational similarity analysis during a visual sustained attention task (the gradCPT). Participants ( n = 16) viewed a series of city or mountain scenes, responding to cities (90% of trials) and withholding to mountains (10%). Representational similarity matrices, reflecting the similarity structure of the city exemplars ( n = 10), were computed from visual, attentional, and default mode networks. Representational fidelity (RF) and representational connectivity (RC) were quantified as the interparticipant reliability of representational similarity matrices within (RF) and across (RC) brain networks. We found that being in the zone was characterized by increased RF in visual networks and increasing RC between visual and attentional networks. Conversely, reward only increased the RC between the attentional and default mode networks. These results diverge with analogous analyses using functional connectivity, suggesting that RC and functional connectivity in tandem better characterize how different mental states modulate the flow of information throughout the brain. PMID- 30004853 TI - Nurture Project International: Lactation Work in Crisis. PMID- 30004855 TI - JHL News. PMID- 30004856 TI - Cost of Doing Nothing Now: We Will Pay the Price Later. PMID- 30004857 TI - Avelumab: A Novel Anti-PD-L1 Agent in the Treatment of Merkel Cell Carcinoma and Urothelial Cell Carcinoma. AB - Long-term treatment in the setting of metastatic Merkel cell carcinoma (MCC) and urothelial carcinoma (UC) has shown that current first-line chemotherapeutic agents are losing effectiveness and that there are limited treatment options available outside of radiation therapy and surgical interventions. The use of immunotherapeutic agents such as monoclonal antibodies has been considered a promising alternative for cancers that progress despite treatment with radiation therapy, surgery, and/or chemotherapeutic agents. Cancer cells escape immune surveillance by interrupting immune checkpoint pathways, resulting in dysregulation of T-cell function and so preventing its antitumor effects. In early 2017, avelumab (BAVENCIO(r)), a PD-L1-blocking monoclonal antibody agent, was approved for the treatment of metastatic MCC and UC. Trials that evaluated avelumab for the treatment of metastatic MCC and UC were the JAVELIN Merkel 200 Trial and the JAVELIN Solid Tumor trial, respectively. Efficacy results for both trials showed positive overall response rate (ORR) and progression-free survival rate (PFS). A strong safety profile was also established for avelumab. This review provides a brief introduction to checkpoint inhibitors and focuses on the recently approved PD-L1 inhibitor, avelumab. PMID- 30004858 TI - Cellular Components and Mechanisms of Oral Tolerance Induction. AB - Oral tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the oral route. Multiple mechanisms of tolerance are induced by oral-fed antigens, but induction of regulatory CD4 T-cells expressing the transcription factor Foxp3 and the membrane-bound TGF-beta stands out as the major players in oral tolerance. Oral antigen administration suppresses several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes, but also nonautoimmune inflammatory conditions such as asthma, atherosclerosis, graft rejection, allergy, and stroke. However, human trials have produced mixed results, and a great deal remains to be learned about the mechanisms of oral tolerance before it can be successfully applied to people. In this review, we highlight the cellular components involved in oral tolerance induction. A deep knowledge of these intricate cell interactions will pave the way for a successful application of antigen tolerance to treat autoimmune and nonautoimmune inflammatory diseases. PMID- 30004859 TI - Connection between gammadelta T-cell- and Adenosine- Mediated Immune Regulation in the Pathogenesis of Experimental Autoimmune Uveitis. AB - Regulatory effects of gammadelta T-cells on immune responses have been studied for years. We have investigated the regulatory effect of gammadelta T-cells on Th1 and Th17 autoimmune responses, and have studied molecular and cellular mechanisms by which gammadelta T-cells enhance or inhibit immune responses, exploiting a well-characterized murine model of experimental autoimmune uveitis (EAU). Our results show that (1) aberrant gammadelta T-cell activation is an important pathogenic event in EAU; (2) gammadelta T-cells have a unique regulatory effect on Th17 autoimmune responses, which is shaped by the activation status of gammadelta T-cells; and (3) gammadelta-mediated immunoregulation is closely linked with the extracellular adenosine metabolism. Reciprocal interactions between gammadelta T-cells and extracellular adenosine partially determine the development of EAU. PMID- 30004860 TI - Roles of Steroid Receptor Coactivator 3 in Host Defense Against Bacterial Pathogens. AB - Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors such as the estrogen receptor and the androgen receptor and several other transcription factors to enhance their effects on target gene expression. SRC-3 plays important roles in many developmental, physiological, and pathologic events, including body growth, mammary gland development, energy homeostasis, inflammatory regulation, and cancer initiation and progression. SRC-3 has been suggested to be involved in host defense against bacterial pathogens. In this review, we summarize the roles of SRC-3 in host defense against peritoneal and enteric bacterial infection and discuss the potential clinical implications. PMID- 30004861 TI - Evaluating the Resources and Need for a Lung Cancer Screening Pilot Program in Maryland. PMID- 30004863 TI - Gap difference in navigated TKA: a measure of the imbalanced flexion-extension gap. AB - INTRODUCTION: The success of Total Knee Arthroplasty (TKA) hinges on balanced flexion-extension gaps. This paper aims to evaluate the correlation between imbalanced gaps and clinical outcomes, and hence help quantify the imbalanced gap in navigation-assisted total knee arthroplasty. METHODS: We studied 195 knees with an average follow-up of two years. Flexion-extension gaps were obtained from computer calculation upon cementation of implants in both flexion (90 degrees ) and extension. The gap difference (GD) was defined as the measured difference between the gaps in flexion and extension. RESULTS: At 2 years after surgery, the mean ROM in the balanced group, with GD less than or equal to 2 mm, was 115.1 degrees +/- 16.6 degrees and the mean ROM in the imbalanced group was 116.7 degrees +/- 12.1 degrees . This was not statistically significant with p-value 0.589. Balanced flexion-extension gaps also did not show significant difference in terms of mechanical alignment, with 0.29 +/- 0.89 in the balanced group at 2 years, and 0.65 +/- 1.51 in the imbalanced group with p-value 0.123. Balanced gaps however, were associated with improved outcomes in terms of physical functioning, bodily pain, social functioning, Oxford and Knee scores at 6 months and improved social functioning scores at 2 years. CONCLUSIONS: Computer navigation is a useful tool for assessing the gap balance in TKA. Balanced flexion-extension gaps, with gap differences of less than or equal to 2 mm, is associated with improved clinical outcomes at 6 months. PMID- 30004864 TI - Removal of broken reamer stuck into femoral shaft in implanting PFNA: a case report. AB - Femoral intertrochanteric fracture is very common in elderly population. The usual treatment for these patients is intra-extramedullary fixation. In normal situations, expand medullary cavity is needed, in order to implant various intramedullary implants. On rare occasion, which will in turn lead to the reamer is stuck into the medullary cavity of femoral shaft. Open or closed technique for moving of the broken nails had been reported before. We firstly report a novel technique by using handy tool which included in orthopaedic instrument set to remove the broken reamer stuck into femoral cavity when implanting a PFNA. PMID- 30004862 TI - Management Practices to Build Evidence-Based Decision-Making Capacity for Chronic Disease Prevention in Georgia: A Case Study. AB - BACKGROUND: Research shows that training can improve skills needed for evidence based decision making, but less is known about instituting organizational supports to build capacity for evidence-based chronic disease prevention. COMMUNITY CONTEXT: The objectives of this case study were to assess facilitators and challenges of applying management practices to support evidence-based decision making in chronic disease prevention programs in the public health system in Georgia through key informant interviews and quantitatively test for changes in perceived management practices and skills through a pre-post survey. METHODS: Leadership of the chronic disease prevention section hosted a multiday training, provided regular supplemental training, restructured the section and staff meetings, led and oversaw technical assistance with partners, instituted transparent performance-based contracting, and made other changes. A 65-item online survey measured perceived importance of skills and the availability of skilled staff, organizational supports, and use of research evidence at baseline (2014) and in 2016 (after training). A structured interview guide asked about management practices, context, internal and external facilitators and barriers, and recommendations. CAPACITY-BUILDING ACTIVITIES AND SURVEY FINDINGS: Seventy four staff members and partners completed both surveys (70.5% response). Eleven participants also completed a 1-hour telephone interview. Interview participants deemed leadership support and implementation of multiple concurrent management practices key facilitators to increase capacity. Main challenges included competing priorities, lack of political will, and receipt of requests counter to evidence-based approaches. At posttest, health department staff had significantly reduced gaps in skills overall (10-item sum) and in 4 of 10 individual skills, and increased use of research evidence to justify interventions. Use of research evidence for evaluation, but not skills, increased among partners. INTERPRETATION: The commitment of leaders with authority to establish multiple management practices to help staff members learn and apply evidence-based decision-making processes is key to increased use of evidence-based chronic disease prevention to improve population health. PMID- 30004866 TI - Design, Fabrication and Evaluation of A Parylene Thin Film Electrode Array for Cochlear Implants. AB - OBJECTIVE: To improve the existing manually-assembled cochlear implant electrode arrays, a thin film electrode array (TFEA) was micro-fabricated to have a maximum electrode density of 15 sites along an 8-mm length, with each site having a 75 1.8-MUm (diameter - height) disk electrode. METHODS: The micro-fabrication method adopted a sequence of photoresist transferring, lift-off, two-step oxygen plasma etching, and fuming nitric acid release to reduce lift-off complexity, protect the metal layer, and increase the release efficiency. RESULTS: Systematic in vitro characterization showed that the TFEA's bending stiffness was 6.40 10 NMUm near the base and 1.26 10 NMUm near the apex. On average, the TFEA electrode produced an impedance of 16 kMU and a maximum current limit of 800 MUA, measured with a 1-kHz sinusoidal current using monopolar stimulation in saline. A TFEA prototype was implanted in a cat cochlea to obtain in vivo measurements of electrically-evoked auditory brainstem and inferior colliculus responses to monopolar stimulation with 41-MUs/phase, biphasic pulses. Both physiological responses produced a threshold of ~300 MUA and a dynamic range of 58 dB above the threshold. Comparing with existing electrode arrays, the present TFEA had 104 times less bending stiffness, 97% less electrode area, and comparable physiological thresholds. CONCLUSION: Using a simplified structure and stable fabrication method, the present TEFA produced physical and physiological performance comparable to existing commercial devices. SIGNIFICANCE: The present TFEA and micro-fabrication method represent a step closer towards an automated process replacing the labor-intensive and expensive manual assembly of electrode arrays in most neural prostheses including the cochlear implant. PMID- 30004865 TI - Single stage en bloc resection of a recurrent metastatic osteosarcoma of the pediatric lumbar spine through multiple exposures - a novel approach. AB - To obtain a wide resection and safe margins in recurrent spine osteosarcoma, the surgical approach can include - posterior only, combined posterior and anterior, and combined posterior and anterior with a return to posterior in multiple stages. In our case, we used a novel approach of multiple extensile exposures circumferentially in a single stage with a single surgical prep. We present the case of a 9-year-old female with a history of metastatic osteosarcoma, who previously underwent an attempted en bloc resection with an L3 corpectomy and left below knee amputation. At 1 year follow-up, she developed a recurrent solitary spine lesion at the previous surgical resection site. An additional attempt at complete surgical resection was performed with a complex en bloc L2, L3, L4 corpectomy with removal of deep spinal implants and anterior and posterior spinal fusion with instrumentation and revision decompressive laminectomy. The patient had a good functional outcome without neurological deficits, except those resulting from resection of involved lumbar nerve roots. At last follow-up of 5 months, there was no local recurrence or distant metastasis. This approach for revision resection of recurrent spinal osteosarcoma can be performed successfully with clean margins in a safe manner. PMID- 30004867 TI - In vivo impedance characterization of cortical recording electrodes shows dependence on electrode location and size. AB - OBJECTIVE: Neural prostheses are improving the quality of life for those suffering from neurological impairments. Electrocorticography electrodes located in subdural, epidural and intravascular positions, show promise as long-term neural prostheses. However, chronic implantation affects the electrochemical environments of these arrays. METHODS: In the present work, the effect of electrode location on the electrochemical properties of the interface was compared. The impedances of the electrode arrays were measured using electrochemical impedance spectroscopy in vitro in saline and in vivo four-weeks post-implantation. RESULTS: There was not a significant effect of electrode location (subdural, intravascular or epidural) on the impedance magnitude and the effect of the electrode size on impedance magnitude was frequency dependent. There was a frequency dependent, statistically significant effect of electrode location and electrode size on the phase angles of the three arrays. The subdural and epidural arrays showed phase shifts closer to -90 degrees indicating the capacitive nature of the interface in these locations. The impact of placing electrodes within a blood vessel and adjacent to the blood vessel wall was most obvious when looking at the phase responses at frequencies below 10 kHz. CONCLUSION: Our results show that intravascular electrodes, like those in subdural and epidural positions, show electrical properties that are suitable for recording. These results provide support for the use of intravascular arrays in clinically relevant neural prostheses and diagnostic devices. SIGNIFICANCE: We show, for the first time, a comparison of the electrochemical impedance spectra of the epidural, intravascular and subdural array locations. PMID- 30004868 TI - Robust Heartbeat Detection from Multimodal Data via CNN-based Generalizable Information Fusion. AB - OBJECTIVE: Heartbeat detection remains central to cardiac disease diagnosis and management, and is traditionally performed based on electrocardiogram (ECG). To improve robustness and accuracy of detection, especially, in certain critical care scenarios, the use of additional physiological signals such as arterial blood pressure (BP) has recently been suggested. There, estimation of heartbeat location requires information fusion from multiple signals. However, reported efforts in this direction often obtain multimodal estimates somewhat indirectly, by voting among separately obtained signal-specific intermediate estimates. In contrast, we propose to directly fuse information from multiple signals without requiring intermediate estimates, and thence estimate heartbeat location in a robust manner. METHOD: We propose as a heartbeat detector, a convolutional neural network (CNN) that learns fused features from multiple physiological signals. This method eliminates the need for hand-picked signal-specific features and ad hoc fusion schemes. Further, being data-driven, the same algorithm learns suitable features from arbitrary set of signals. RESULTS: Using ECG and BP signals of PhysioNet 2014 Challenge database, we obtained a score of 94%. Further, using two ECG channels of MITBIH arrhythmia database, we scored 99.92%. Both those scores compare favorably with previously reported database-specific results. Also, our detector achieved high accuracy in a variety of clinical conditions. CONCLUSION: The proposed CNN-based information fusion (CIF) algorithm is generalizable, robust and efficient in detecting heartbeat location from multiple signals. SIGNIFICANCE: In medical signal monitoring systems, our technique would accurately estimate heartbeat locations even when only a subset of channels are reliable. PMID- 30004869 TI - Capacitive ECG Monitoring in Cardiac Patients during Simulated Driving. AB - OBJECTIVE: This study aims to compare the informative value of a capacitively coupled electrocardiogram (cECG) to a conventional galvanic reference ECG (rECG) in patients after a major cardiac event under simulated driving conditions. Addressed research questions are the comparison and coherence of cECG and rECG by means of the signal quality, the artifact rate, the rate of assessable data for differential diagnosis, the visibility of characteristic ECG structures in cECG, the precision of ECG time intervals and heart rate (in particular, despite possible waveform deformations due to the cardiac preconditions). METHODS: In a clinical trial, cECG and rECG data were recorded from 10 patients after a major cardiac event. The cECG and rECG data were blindly evaluated by two cardiologists with regard to signal quality, artifacts, assessable data for differential diagnosis, visibility of ECG structures and ECG time intervals. The results were statistically compared. RESULTS: The cECG presented with more artifacts, an inferior signal quality and less assessable data. However, when the data were assessable, determination of the ECG interval lengths was coherent to the one obtained from the rECG. CONCLUSION: When the signal quality is sufficient, the cECG yields the same informative value as the rECG. SIGNIFICANCE: For certain scenarios, cECG might replace rECG systems. Hence, it is an important research question whether a similar amount of information can be obtained using a cECG system. PMID- 30004870 TI - Visual Dynamics: Stochastic Future Generation via Layered Cross Convolutional Networks. AB - We study the problem of synthesizing a number of likely future frames from a single input image. In contrast to traditional methods that have tackled this problem in a deterministic or non-parametric way, we propose to model future frames in a probabilistic manner. Our probabilistic model makes it possible for us to sample and synthesize many possible future frames from a single input image. To synthesize realistic movement of objects, we propose a novel network structure, namely a Cross Convolutional Network; this network encodes image and motion information as feature maps and convolutional kernels, respectively. In experiments, our model performs well on synthetic data, such as 2D shapes and animated game sprites, and on real-world video frames. We present analyses of the learned network representations, showing it is implicitly learning a compact encoding of object appearance and motion. We also demonstrate a few of its applications, including visual analogy-making and video extrapolation. PMID- 30004871 TI - Image Deblurring with a Class-Specific Prior. AB - A fundamental problem in image deblurring is to reliably recover distinct spatial frequencies that have been suppressed by the blur kernel. To tackle this issue, existing image deblurring techniques often rely on generic image priors such as the sparsity of salient features including image gradients and edges. However, these priors only help recover part of the frequency spectrum, such as the frequencies near the high-end. To this end, we pose the following specific questions: (i) Does any image class information offer an advantage over existing generic priors for image quality restoration (ii) If a class-specific prior exists, how should it be encoded into a deblurring framework to recover attenuated image frequencies Throughout this work, we devise a class-specific prior based on the band-pass filter responses and incorporate it into a deblurring strategy. More specifically, we show that the subspace of band-pass filtered images and their intensity distributions serve as useful priors for recovering image frequencies that are difficult to recover by generic image priors. We demonstrate that our image deblurring framework, when equipped with the above priors, significantly outperforms many state-of-the-art methods using generic image priors or class-specific exemplars. PMID- 30004872 TI - 3D perfusion imaging using principal curvature detection rendering. AB - Three-dimensional contrast-enhanced ultrasound (CEUS) imaging presents a clear advantage over its 2D counterpart in detecting and characterizing suspicious lesions as it properly surveys the inherent heterogeneity of tumours. However, 3D CEUS is also slow compared to 2D CEUS and tends to undersample the microbubble wash-in. This makes it difficult to resolve the feeding vessels, an important oncogenic marker, from the background perfusion cloud. Contrast-enhanced Doppler is helpful in isolating this conduit flow, but requires too many pulses in conventional line-by-line beamforming design. Recent breakthroughs in plane-wave imaging have greatly accelerated the volumetric imaging frame rate, but volumetric Doppler angiography still remains challenging when considering realtime limitations on the Doppler ensemble length. In this work, we demonstrate the feasibility of volumetric CEUS angiography subjected to real-time imaging constraints. Namely, we show how principal curvature detection can significantly improve 3D rendering of relatively noisy ultrasound angiograms without degrading the spatial resolution while subjected to a reasonable Doppler ensemble size. Singular Value Decomposition is also shown to be capable of identifying the quasi stationary capillary perfusion. PMID- 30004873 TI - Dual-Wavelength Good-Bad-Cavity Laser System for Cavity-Stabilized Active Optical Clock. AB - Active optical clocks (AOCs) have the intrinsic suppression of the influence of the cavity's noise on the output frequency, giving rise to the potentially ultranarrow linewidth. To break the cavity's thermal noise limitation by taking full advantage of the AOC's principle, as well as to achieve a long-term instability, we propose a scheme of cavity-stabilized active optical clock. The system consists of two key procedures. The dual-wavelength (DW) output signals share the same cavity and work in the good- and the bad-cavity regime, respectively. Then, the good-cavity signal is locked to a reference cavity by the Pound-Drever-Hall (PDH) technique to stabilize the main-cavity length. By doing this, the main-cavity's noise is expected to be reduced to the thermal noise floor of the reference cavity. Hence, the frequency stability of the bad-cavity signal will break this noise floor due to the suppression of the cavity-pulling effect. Experimentally, we realize the DW good-bad-cavity laser system by taking the Nd:YAG 1064 nm and Cs 1470 nm transitions as the good- and bad-cavity gain medium. The power and linewidth characteristics of the DW output are studied. Limitation factors of the clock frequency as well as the feasibility of the PDH cavity stabilization are analyzed. PMID- 30004874 TI - On Combination of Hadamard-Encoded Multipulses and Multiplane Wave Transmission in Contrast-Enhanced Ultrasound Imaging. AB - Contrast-enhanced ultrasound (CEUS) imaging has great potential for use in many new ultrasound clinical applications. We recently proposed a novel CEUS imaging sequence, Hadamard-encoded multipulses (HEM), to improve the signal-to-noise ratio (SNR) and the contrast-to-tissue ratio (CTR) as compared to other classic CEUS methods. HEM increases microbubble responses by using longer coded transmit pulses and the fast polarity change between coded pulses. In this study, we propose to combine the HEM pulse with multiplane wave (MW) imaging technique to further improve CEUS imaging SNR and contrast-to-noise ratio. During MW-HEM transmissions, the microbubbles undergo multiple fast pulse polarity changes, leading to significantly improved microbubble nonlinear responses, and thus further enhanced SNR and CTR as compared to HEM alone or other CEUS sequences. This improvement may facilitate more robust CEUS imaging for deep abdominal organs and the heart. PMID- 30004875 TI - Long-Term Behavior of the DORIS Oscillator Under Radiation: The Jason-2 Case. AB - This paper discusses the issues of radiation exposure that especially occur on the Doppler Orbitography and Radiopositioning Integrated on Satellite (DORIS) ultrastable oscillator (USO) that has been placed on the Jason-2 oceanography mission as the reference clock. We have studied the frequency response of the Jason-2 USO (launched in June 2008, at 66 degrees of inclination and 1336 km of altitude) over 8.5 years. This is the only mission that provides different sources of data, internal and external, which permit a precise description of the oscillator behavior using several assumptions. While the ICARE-NG instrument provided continuous measurement of the electron and the proton fluxes, the Time Transfer by Laser Link (T2L2) experiment demonstrated its ability to monitor the "reading" of the oscillator at a level of a few parts in 10-13 with respect to a ground network of laser stations equipped with atomic clocks. From these inputs, and also environmental parameters such as the orbit, the attitude law of the platform, and the temperature of the oscillator, we have developed a complete physical model of the DORIS USO that fits the data at less than slightly below the threshold of 10-12 that limits the use of the DORIS data in current space geodesy analyses. In this way, the model also makes it possible to provide an assessment of the new Jason-3 USO to radiation effects after the satellite launch in January 2016. PMID- 30004876 TI - Photo Realistic Image Completion via Dense Correspondence. AB - In this paper, we propose an image completion algorithm based on dense correspondence between the input image and an exemplar image retrieved from the Internet. Contrary to traditional methods which register two images according to sparse correspondence, in this paper, we propose a hierarchical PatchMatch method that progressively estimates a dense correspondence, which is able to capture small deformations between images. The estimated dense correspondence has usually large occlusion areas that correspond to the regions to be completed. A nearest neighbor field (NNF) interpolation algorithm interpolates a smooth and accurate NNF over the occluded region. Given the calculated NNF, the correct image content from the exemplar image is transferred to the input image. Finally, as there could be a color difference between the completed content and the input image, a color correction algorithm is applied to remove the visual artifacts. Numerical results show that our proposed image completion method can achieve photo realistic image completion results. PMID- 30004877 TI - The Influence of Label Design on Search Performance and Noticeability in Wide Field of View Augmented Reality Displays. AB - In Augmented Reality (AR), search performance for outdoor tasks is an important metric for evaluating the success of a large number of AR applications. Users must be able to find content quickly, labels and indicators must not be invasive but still clearly noticeable, and the user interface should maximize search performance in a variety of conditions. To address these issues, we have set up a series of experiments to test the influence of virtual characteristics such as color, size, and leader lines on the performance of search tasks and noticeability in both real and simulated environments. The first experiment showed that limited FOV will severe-ly limit search performance, but that appropriate placement of labels and leaders within the periphery can alleviate this problem without interfering with walking or decreasing user comfort. In the second experiment, we found that different types of motion are more no-ticeable in optical versus video see-through displays, but that blue coloration is most noticeable in both. Results can aid in designing more effective view management techniques, especially for wider field of view display. PMID- 30004878 TI - HapTable: An Interactive Tabletop Providing Online Haptic Feedback for Touch Gestures. AB - We present HapTable; a multi-modal interactive tabletop that allows users to interact with digital images and objects through natural touch gestures, and receive visual and haptic feedback accordingly. In our system, hand pose is registered by an infrared camera and hand gestures are classified using a Support Vector Machine (SVM) classifier. To display a rich set of haptic effects for both static and dynamic gestures, we integrated electromechanical and electrostatic actuation techniques effectively on tabletop surface of HapTable, which is a surface capacitive touch screen. We attached four piezo patches to the edges of tabletop to display vibrotactile feedback for static gestures. For this purpose, the vibration response of the tabletop, in the form of frequency response functions (FRFs), was obtained by a laser Doppler vibrometer for 84 grid points on its surface. Using these FRFs, it is possible to display localized vibrotactile feedback on the surface for static gestures. For dynamic gestures, we utilize the electrostatic actuation technique to modulate the frictional forces between finger skin and tabletop surface by applying voltage to its conductive layer. To our knowledge, this hybrid haptic technology is one of a kind and has not been implemented or tested on a tabletop. It opens up new avenues for gesture-based haptic interaction not only on tabletop surfaces but also on touch surfaces used in mobile devices with potential applications in data visualization, user interfaces, games, entertainment, and education. Here, we present two examples of such applications, one for static and one for dynamic gestures, along with detailed user studies. In the first one, user detects the direction of a virtual flow, such as that of wind or water, by putting their hand on the tabletop surface and feeling a vibrotactile stimulus traveling underneath it. In the second example, user rotates a virtual knob on the tabletop surface to select an item from a menu while feeling the knob's detents and resistance to rotation in the form of frictional haptic feedback. PMID- 30004879 TI - Modeling and Simulation of a Lower Extremity Powered Exoskeleton. AB - Lower extremity powered exoskeletons (LEPEs) allow people with spinal cord injury (SCI) to stand and walk. However, the majority of LEPEs walk slowly and users can become fatigued from overuse of forearm crutches, suggesting LEPE design can be enhanced. Virtual prototyping is a cost-effective way of improving design; therefore, this research developed and validated two models that simulate walking with the Bionik Laboratories' ARKE exoskeleton attached to a human musculoskeletal model. The first model was driven by kinematic data from 30 able bodied participants walking at realistic slow walking speeds (0.2-0.8 m/s) and accurately predicted ground reaction forces (GRF) for all speeds. The second model added upper limb crutches and was driven by 3-D-marker data from five SCI participants walking with ARKE. Vertical GRF had the strongest correlations (>0.90) and root-mean-square error (RMSE) and mediolateral center of pressure trajectory had the weakest (<0.35), for both models. Strong correlations and small RMSE between predicted and measured GRFs support the use of these models for optimizing LEPE joint mechanics and improving LEPE design. PMID- 30004880 TI - A Novel Multisensory Stimulation and Data Capture System (MADCAP) for Investigating Sensory Trajectories in Infancy. AB - Sensory processing differences, including responses to auditory, visual, and tactile stimuli, are ideal targets for early detection of neurodevelopmental risks, such as autism spectrum disorder. However, most existing studies focus on the audiovisual paradigm and ignore the sense of touch. In this paper, we present a multisensory delivery system that can deliver audio, visual, and tactile stimuli in a controlled manner and capture peripheral physiological, eye gaze, and electroencephalographic response data. The novelty of the system is the ability to provide affective touch. In particular, we have developed a tactile stimulation device that delivers tactile stimuli to infants with precisely controlled brush stroking speed and force on the skin. A usability study of 10 3 20 month-old infants was conducted to investigate the tolerability and feasibility of the system. Results have shown that the system is well tolerated by infants and all the data were collected robustly. This paper paves the way for future studies charting the sensory response trajectories in infancy. PMID- 30004881 TI - Detection of Bladder Contractions From the Activity of the External Urethral Sphincter in Rats Using Sparse Regression. AB - Bladder overactivity and incontinence and dysfunction can be mitigated by electrical stimulation of the pudendal nerve applied at the onset of a bladder contraction. Thus, it is important to predict accurately both bladder pressure and the onset of bladder contractions. We propose a novel method for prediction of bladder pressure using a time-dependent spectrogram representation of external urethral sphincter electromyographic (EUS EMG) activity and a least absolute shrinkage and selection operator regression model. There was a statistically significant improvement in prediction of bladder pressure compared with methods based on the firing rate of EUS EMG activity. This approach enabled prediction of the onset of bladder contractions with 91% specificity and 96% sensitivity and may be suitable for closed-loop control of bladder continence. PMID- 30004882 TI - EEG-Based Lower-Limb Movement Onset Decoding: Continuous Classification and Asynchronous Detection. AB - Brain-machine interfaces have been used to incorporate the user intention to trigger robotic devices by decoding movement onset from electroencephalography. Active neural participation is crucial to promote brain plasticity thus to enhance the opportunity of motor recovery. This paper presents the decoding of lower-limb movement-related cortical potentials with continuous classification and asynchronous detection. We executed experiments in a customized gait trainer, where 10 healthy subjects performed self-initiated ankle plantar flexion. We further analyzed the features, evaluated the impact of the limb side, and compared the proposed framework with other typical decoding methods. No significant differences were observed between the left and right legs in terms of neural signatures of movement and classification performance. We obtained a higher true positive rate, lower false positives, and comparable latencies with respect to the existing online detection methods. This paper demonstrates the feasibility of the proposed framework to build a closed-loop gait trainer. Potential applications include gait training neurorehabilitation in clinical trials. PMID- 30004883 TI - A Promising Method for Calculating True Steady-State Metabolite Concentrations in Large-Scale Metabolic Reaction Network Models. AB - The calculation of steady-state metabolite concentrations in metabolic reaction network models is the first step in the sensitivity analy-sis of a metabolic reaction system described by differential equations. However, this calculation becomes very difficult when the number of differential equations is more than 100. In the present study, therefore, we investigated a calculation procedure for obtaining true steady-state metabolite concentrations both efficiently and accurately even in large-scale network models. For convenience, a linear pathway model composed of a simple Michaelis-Menten rate law and two TCA cycle models were used as case studies. The calculation procedure is as follows: first solve the differential equations by a numerical method for solving initial-value problems until the upper several digits of the calculated values stabilize, and then use these values as initial guesses for a root-finding technique. An intensive investigation indicates that the S-system technique, finding roots in logarithmic space and providing a broader convergence region, is superior to the Newton-Raphson technique, and the algorithm using the S-system technique successfully provides true steady-state values with machine accuracy even with 1500 differential equations. The complex-step method is also shown to contribute to shorten-ing the calculation time and enhancing the accuracy. The program code has been deposited to https://github.com/BioprocessdesignLab/Steadystateconc. PMID- 30004884 TI - Protecting Privacy and Security of Genomic Data in i2b2 with Homomorphic Encryption and Differential Privacy. AB - Re-use of patients' health records can provide tremendous benefits for clinical research. Yet, when researchers need to access sensitive/identifying data, such as genomic data, in order to compile cohorts of well-characterized patients for specific studies, privacy and security concerns represent major obstacles that make such a procedure extremely difficult if not impossible. In this paper, we address the challenge of designing and deploying in a real operational setting an efficient privacy-preserving explorer for genetic cohorts. Our solution is built on top of the i2b2 (Informatics for Integrating Biology and the Bedside) framework and leverages cutting-edge privacy-enhancing technologies such as homomorphic encryption and differential privacy. Solutions involving homomorphic encryption are often believed to be costly and immature for use in operational environments. Here, we show that, for specific applications, homomorphic encryption is actually a very efficient enabler. Indeed, our solution outperforms prior work by enabling a researcher to securely compute simple statistics on more than 3,000 encrypted genetic variants simultaneously for a cohort of 5,000 individuals in less than 5 seconds with commodity hardware. To the best of our knowledge, our privacy-preserving solution is the first to also be successfully deployed and tested in a operation setting (Lausanne University Hospital). PMID- 30004885 TI - On Sharing Intentions, and Personal and Interdependent Privacy Considerations for Genetic Data: A Vignette Study. AB - Genetics and genetic data have been the subject of recent scholarly work, with significant attention paid towards understanding consent practices for the acquisition and usage of genetic data as well as genetic data security. Attitudes and perceptions concerning the trustworthiness of governmental institutions receiving test-taker data have been explored, with varied findings, but no robust models or deterministic relationships have been established that account for these differences. These results also do not explore in detail the perceptions regarding other types of organizations (e.g., private corporations). Further, considerations of privacy interdependence arising from blood relative relationships have been absent from the conversation regarding the sharing of genetic data. This paper reports the results from a factorial vignette survey study in which we investigate how variables of ethnicity, age, genetic markers, and association of data with the individual's name affect the likelihood of sharing data with different types of organizations. We also investigate elements of personal and interdependent privacy concerns. We document the significant role these factors have in the decision to share or not share genetic data. We support our findings with a series of regression analyses. PMID- 30004886 TI - Comparison of INDEL Calling Tools with Simulation Data and Real Short-Read Data. AB - Insertions and deletions (INDELs) comprise a significant proportion of human genetic variation, and recent papers have revealed that many human diseases may be attributable to INDELs. With the development of next-generation sequencing (NGS) technology, many statistical/computational tools have been developed for calling INDELs. However, there are differences among those tools, and comparisons among them have been limited. In order to better understand these inter-tool differences, five popular and publicly available INDEL calling tools - GATK HaplotypeCaller, Platypus, VarScan2, Scalpel, and GotCloud - were evaluated using simulation data, 1000 Genomes Project data, and family-based sequencing data. The accuracy of INDEL calling by each tool was mainly evaluated by concordance rates. Family-based sequencing data, which consisted of 49 individuals from 8 Korean families, were used to calculate Mendelian error rates. Our comparison results show that GATK HaplotypeCaller usually performs the best and that joint calling with Platypus can lead to additional improvements in accuracy. The result of this study provides important information regarding future directions for the variant detection and the algorithms development. PMID- 30004887 TI - Cohort Harmonization and Integrative Analysis from a Biomedical Engineering Perspective. AB - In this review the critical parts and milestones for data harmonization, from the biomedical engineering perspective, are outlined. The need for data sharing between heterogeneous sources pave the way for cohort harmonization; thus, fostering data integration and interdisciplinary research. Unmet needs in chronic as well as in other diseases, can be addressed based on the integration of patient health records and the sharing of information of the clinical picture and outcome. The stratification of patients, the determination of various clinical and outcome features and the identification of novel biomarkers for the different phenotypes of the disease characterize the impact of cohort harmonization in patient-centered clinical research and in precision medicine. Subsequently, the establishment of matching techniques and ontologies for the creation of data schemas are also presented. The exploitation of web technologies and data collection tools support the opportunities to achieve new levels of integration and interoperability. Ethical and legal issues which arise when sharing and harmonizing individual-level data are discussed in order to evaluate the harmonization potential. Use cases that shape and test the harmonization approach are explicitly analyzed along with their significant results on their research objectives. Finally, future trends and directions are discussed and critically reviewed towards a roadmap in cohort harmonization for clinical medicine. PMID- 30004888 TI - Effect of Cutaneous Feedback on the Perceived Hardness of a Virtual Object. AB - We investigate the effect of adding cutaneous cues to kinesthetic feedback on the perception of a virtual object's hardness. A cutaneous haptic interface is designed to deliver hardness information to a user's fingertip along with a force feedback interface, and the corresponding rendering strategy is implemented. Two sets of experiments are conducted to evaluate the proposed approach for hardness perception using one-finger touch and two-finger grasp. Experimental results indicate that the addition of cutaneous feedback can make the virtual surface feel significantly harder than the nominal stiffness delivered by force-feedback alone. In addition, the perceived hardness is significantly affected by the rate of hardness rendered with a cutaneous interface for the nominal stiffness and 0.5 N/mm. For two-finger grip, the effect of a virtual object's thickness has a significant effect on the perceived hardness measured in stiffness. When the perceived hardness is converted to Young's modulus, the effect of thickness is insignificant. PMID- 30004889 TI - A pneumatic tactile ring for instantaneous sensory feedback in laparoscopic tumor localization. AB - We aim to achieve intraoperative localization of an early-stage gastric tumor that cannot be visually detected during laparoscopic surgery. In this study, we developed and evaluated a pneumatic tactile ring, which is a clinically applicable tactile device to provide instantaneous feedback from a tactile sensor directly manipulated by a surgeon. It was designed to be worn on the finger of the manipulating hand and to present pressure to the finger pad. It is lightweight, cost-effective, disposable, and sterilizable. We also developed a compact pneumatic drive unit to control the pressure and investigated its fundamental performance. The bandwidth of the pressure control was at least 1.3 Hz with a controllable range of up to 79.7 kPa. Moreover, a psychophysical experiment was performed to obtain the Weber ratio of the pressure and evaluate the effectiveness of the instantaneous tactile feedback of the sensor output through the tactile ring. The Weber ratio was 0.40 at the reference pressure of 22.7 kPa. The provided tactile feedback significantly reduced the absolute localization error and increased participants' confidence in their answers. It was shown that the tactile feedback through the ring is effective in laparoscopic tumor localization. PMID- 30004890 TI - Tactile Masking by Electrovibration. AB - Future touch screen applications will include multiple tactile stimuli displayed simultaneously or consecutively to single finger or multiple fingers. These applications should be designed by considering human tactile masking mechanism since it is known that presenting one stimulus may interfere with the perception of the other. In this study, we investigate the effect of masking on tactile perception of electrovibration displayed on touch screens. Through conducting psychophysical experiments with nine subjects, we measured the masked thresholds of sinusoidal electrovibration bursts (125 Hz) under two masking conditions: simultaneous and pedestal. The masking stimuli were noise bursts, applied at five different sensation levels varying from 2 to 22 dB SL, also presented by electrovibration. For each subject, the detection thresholds were elevated as linear functions of masking levels for both masking types. We observed that the masking effectiveness was larger with pedestal masking than simultaneous masking. Moreover, in order to investigate the effect of tactile masking on our haptic perception of edge sharpness, we compared the perceived sharpness of edges separating two textured regions displayed with and without various masking stimuli. Our results suggest that sharpness perception depends on the local contrast between background and foreground stimuli, which varies as a function of masking amplitude and activation levels of frequency-dependent psychophysical channels. PMID- 30004891 TI - Toward Haptic Communication: Tactile Alphabets Based on Fingertip Skin Stretch. AB - This paper studies the possibility to convey information using tactile stimulation on fingertips. We designed and evaluated three tactile alphabets which are rendered by stretching the skin of the index's fingertip: (1) a Morse like alphabet, (2) a symbolic alphabet using two successive dashes, and (3) a display of Roman letters based on the Unistrokes alphabet. All three alphabets (26 letters each) were evaluated through a user study in terms of recognition rate, intuitiveness and learning. Participants were able to perceive and recognize the letters with very good results (80%-97% recognition rates). Tactile alphabets with representations closer to Roman alphabet seem easier to learn. Taken together, our results pave the way to novel kinds of information communication using tactile modality. PMID- 30004892 TI - Dendritic Neuron Model With Effective Learning Algorithms for Classification, Approximation, and Prediction. AB - An artificial neural network (ANN) that mimics the information processing mechanisms and procedures of neurons in human brains has achieved a great success in many fields, e.g., classification, prediction, and control. However, traditional ANNs suffer from many problems, such as the hard understanding problem, the slow and difficult training problems, and the difficulty to scale them up. These problems motivate us to develop a new dendritic neuron model (DNM) by considering the nonlinearity of synapses, not only for a better understanding of a biological neuronal system, but also for providing a more useful method for solving practical problems. To achieve its better performance for solving problems, six learning algorithms including biogeography-based optimization, particle swarm optimization, genetic algorithm, ant colony optimization, evolutionary strategy, and population-based incremental learning are for the first time used to train it. The best combination of its user-defined parameters has been systemically investigated by using the Taguchi's experimental design method. The experiments on 14 different problems involving classification, approximation, and prediction are conducted by using a multilayer perceptron and the proposed DNM. The results suggest that the proposed learning algorithms are effective and promising for training DNM and thus make DNM more powerful in solving classification, approximation, and prediction problems. PMID- 30004893 TI - An Optical Fiber Based Data-Driven Method for Human Skin Temperature 3-D Mapping. AB - Human skin temperature mapping provides abundant information of physiological conditions of human body, which provides supplementary or alternative indicators for disease monitoring or diagnosis. The existing models of temperature mapping or temperature field distribution of human skin are generally established by finite element method. Due to the complexity of biological systems, it is challenging to achieve high accuracy mathematical models of temperature field of human skin. The goal of this study is to establish human skin temperature 3D mapping platform by integrating optical fibers and improved GA-BP neural network. The proposed data-driven method is capable of acquiring entire human skin temperature 3D mapping by simply measuring a few points on human skin. Multiple experiments were conducted to validate the proposed method on different areas of human skin in different ambient environments. In each experiment setting, the measured data and the model output data were compared. The results show that the mean absolute error (MAE) among all the validation experiments is 0.11 degrees C, which is lower than that in the state of the art using physical modeling for skin temperature prediction and more close to clinical accuracy. Also the proposed approach is accurate and reliable, which may provide a platform technology for human skin temperature mapping that can be used in both medical and scientific studies as well as home monitoring. PMID- 30004894 TI - An Improved Skin Lesion Matching Scheme in Total Body Photography. AB - Total body photography is used for early detection of malignant melanoma, primarily as a means of temporal skin surface monitoring. In prior work, we presented a scanner with a set of algorithms to map and detect changes in pigmented skin lesions, thus demonstrating that it is possible to fully automate the process of total body image acquisition and processing. The key procedure in these algorithms is skin lesion matching which determines whether two images depict the same real lesion. In this paper, we aim to improve it with respect to false positive and negative outcomes. To this end, we developed two novel methods: one based on successive rigid transformations of 3-D point clouds and one based on non-rigid coordinate plane deformations in regions of interest around the lesions. In both approaches, we applied a robust outlier rejection procedure based on progressive graph matching. Using the scanner's images, we created a ground truth dataset tailored to diversify false positive match scenarios. The algorithms were evaluated according to their precision and recall values, and the results demonstrated the superiority of the second approach in all the tests. In the complete inter-positional matching experiment, it reached a precision and recall as high as 99.92% and 81.65% respectively, showing a significant improvement over our original method. PMID- 30004895 TI - Dynamic quantification of migrainous thermal facial patterns - A Pilot Study. AB - This article documents thermophysiological patterns associated with migraine episodes, where the inner canthi and supraorbital temperatures drop significantly compared to normal conditions. These drops are likely due to vasoconstriction of the ophthalmic arteries under the inner canthi and sympathetic activation of the eccrine glands in the supraorbital region, respectively. The patterns were observed on eight migraine patients and meticulously quantified using advance computational methods, capable of delineating small anatomical structures in thermal imagery and tracking them automatically over time. These methods open the way for monitoring migraine episodes in non-clinical environments, where the patient maintains directional attention, such as his/her computer at home or at work. This is a development with the potential to significantly expand the operational envelope of migraine studies. PMID- 30004896 TI - Latent-Smoothness Nonrigid Structure From Motion by Revisiting Multilinear Factorization. AB - How to implement an effective factorization for nonrigid structure from motion (NRSFM) has attracted much attention in recent years. A straightforward factorization scheme is to multilinearly solve NRSFM in an alternating manner, where each of the unknown variables in NRSFM is updated by fixing the others at each iteration. However, recent works show that most existing multilinear factorization (MLF) methods achieve poorer performances than some state-of-the art sequential factorization methods. In this paper, we reinvestigate the MLF scheme for improving factorization accuracy, and first propose an MLF method with the only low-rank prior for NRSFM in the presence of missing data. Then, for further improving the performances of such MLF methods, a latent ''smoothness'' characteristic on unknown 3-D deformable shapes is investigated, which is independent of temporal relations among deformable shapes. Accordingly, a latent smoothness prior for solving NRSFM is derived from the latent smoothness characteristic, and it is able to effectively recover 3-D deformable shapes from unordered data, which is hard for the traditional temporal-smoothness prior to handle. Finally, a regularized factorization method is proposed by integrating MLF with the explored latent-smoothness prior for further pursuing better performances. Extensive experimental results show the effectiveness of our methods in comparison to eight existing multilinear/sequential methods. PMID- 30004897 TI - Adaptive Multiobjective Differential Evolution With Reference Axis Vicinity Mechanism. AB - Due to the simple but effective search framework, differential evolution (DE) has achieved successful applications in multiobjective optimization problems. However, most of the previous research on the multiobjective DE (MODE) focused on the design of control strategies of parameters and mutation operators for a given population at each generation, and ignored that the given population might have a bad distribution in the objective space. Therefore, this paper proposes a new variant of MODE in which a reference axis vicinity mechanism (RAVM) is developed to restore the good distribution of the given population and maintain its convergence before the evolution (i.e., mutation, crossover, and selection) starts at each generation. Besides the RAVM, a hybrid control strategy of parameters and mutation operators is also presented to accelerate convergence by integrating both randomness and guided information derived from solutions generated during the search process. Computational results on four series of benchmark problems illustrate that the proposed MODE with the RAVM and hybrid control strategy is competitive or even superior to some state-of-the-art multiobjective evolutionary algorithms in the literature. PMID- 30004899 TI - Clothing Landmark Detection Using Deep Networks With Prior of Key Point Associations. AB - This paper considers a problem of landmark point detection in clothes, which is important and valuable for clothing industry. A novel method for landmark localization has been proposed, which is based on a deep end-to-end architecture using prior of key point associations. With the estimated landmark points as input, a deep network has been proposed to predict clothing categories and attributes. A systematic design of the proposed detecting system is implemented by using deep learning techniques and a large-scale clothes dataset containing 145,000 upper-body clothing images with landmark annotations. Experimental results indicate that clothing categories and attributes can be well classified by using the detected landmark points, which are associated with regions of interest in clothes (e.g., the sleeves and the collars) and share robust learning representation property with respect to large variances of human poses, nonfrontal views, or occlusion. A comprehensive performance evaluation over two newly released datasets is carried out in this paper, showing that the proposed system with deep architecture for clothing landmark detection outperforms the state-of-the-art techniques. PMID- 30004898 TI - Hinfinity Consensus for Linear Heterogeneous Discrete-Time Multiagent Systems With Output Feedback Control. AB - This paper studies the Hinfinity consensus problem for linear heterogeneous discrete-time multiagent systems (MASs). For a special kind of nonlinear matrix inequality, a novel method is provided to make these inequalities turn into some equivalent conditions that can be solved by utilizing the LMI toolbox. According to this method, a necessary and sufficient condition of Hinfinity consensus for linear heterogeneous discrete-time MAS with output feedback control scheme and a corresponding iterative algorithm are proposed, respectively. Moreover, by employing these results, a necessary and sufficient condition that makes a general linear system with one kind of constrained controller achieve Hinfinity control is provided. Finally, two numerical examples are given to illustrate the validity of our schemes. PMID- 30004900 TI - Effects of high-dose, intravenous lipid emulsion on laboratory tests in humans: a randomized, placebo-controlled, double-blind, clinical crossover trial. AB - Background Intravenous lipid emulsion (ILE) is used to treat drug poisonings. The resultant hyperlipemia may affect laboratory tests but the consequences are poorly characterized. In a clinical trial we therefore investigated the effects of ILE on laboratory tests analyzed on common analytical platforms (Roche(r) cobas 8000 and SYSMEX(r) flow-cytometry). Methods Ten healthy participants each completed 4 trial days (two with ILE and two with placebo). ILE (5.25 mL/kg) was administered from 12.5 to 30 min from baseline. At 0, 30 and 60 min, blood samples were drawn for measurement of 20 analytes. We investigated the effects of ILE on analyte levels and frequencies of exceedance of predefined analyzer hemolysis (H) or lipemia (L)-index cut-offs and test-specific reference change values (RCVs) on ILE-days. If the results were blocked due to exceedance of index values, we manually extracted the results. Results Sixteen out of 20 tests were blocked because H- or L-index cut-offs were exceeded on ILE-days. Differences in analyte levels between ILE- and placebo-days above the RCV were observed for aspartate aminotransferase, total calcium, lactate dehydrogenase (LDH), sodium and neutrophils. Mean values outside the normal range after ILE were observed for LDH (219 U/L), sodium (135.3 mmol/L) and total calcium (2.1 mmol/L). Conclusions ILE-infusion caused report failure of nearly all laboratory tests performed on a cobas 8000-platform, but it was possible to manually retrieve the results. For most test results - particularly alkaline phosphatase, bilirubin, phosphate and carbamide - the consequences of ILE were marginal, and the effects of ILE were reduced at the 60-min timepoint. PMID- 30004901 TI - Estimated GFR-specific 99th percentiles for high-sensitive cardiac troponin T based on the adjusted analytical change limit (adjACL) in hospitalized patients. PMID- 30004903 TI - On the question of non-medical cognitive enhancers among in-school adolescents: prevalence, predictors and potential health-related harms. AB - Little is known about the use of non-medical cognitive enhancers (NCEs) in the general population, and even less among youth. The study utilises a nationally representative, cross-sectional survey of adolescents attending high schools to provide a comprehensive overview of NCEs and to assess risk factors such as socio demographics, schooling, mental health and related substance use among French adolescents. A total of 6692 students attending high school (secondary schools) answered an anonymous questionnaire collecting information on demographics, health, psychoactive substance uses (neuroleptics, tobacco, alcohol, cannabis, illicit substances) and patterns of sociability. The use of cognitive enhancers appears to be an underestimated phenomenon among youth. Prevalence of use is heavily gender-influenced, with females twice as likely to use NCEs than males. More than daily school commitments, the use of cognitive enhancers is related to the proximity of the national secondary education examination. Moreover, mental health, use of prescribed anxiolytics and other psychoactive substances are significantly independently associated with the use of cognitive enhancers, particularly among females. The unregulated use of cognitive enhancers is a predictor of potential mental frailty and a substance-based response to stressful events, a behaviour likely to persist during adulthood. The study underpins the lack of contextual and comparable data. Systematic monitoring of younger students in neighbouring countries is required to develop reliable prevention programmes. PMID- 30004902 TI - Joint EFLM-COLABIOCLI Recommendation for venous blood sampling. AB - This document provides a joint recommendation for venous blood sampling of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for Preanalytical Phase (WG-PRE) and Latin American Working Group for Preanalytical Phase (WG-PRE-LATAM) of the Latin America Confederation of Clinical Biochemistry (COLABIOCLI). It offers guidance on the requirements for ensuring that blood collection is a safe and patient-centered procedure and provides practical guidance on how to successfully overcome potential barriers and obstacles to its widespread implementation. The target audience for this recommendation are healthcare staff members directly involved in blood collection. This recommendation applies to the use of a closed blood collection system and does not provide guidance for the blood collection with an open needle and syringe and catheter collections. Moreover, this document neither addresses patient consent, test ordering, sample handling and transport nor collection from children and unconscious patients. The recommended procedure is based on the best available evidence. Each step was graded using a system that scores the quality of the evidence and the strength of the recommendation. The process of grading was done at several face-to-face meetings involving the same mixture of stakeholders stated previously. The main parts of this recommendation are: 1) Pre sampling procedures, 2) Sampling procedure, 3) Post-sampling procedures and 4) Implementation. A first draft of the recommendation was circulated to EFLM members for public consultation. WG-PRE-LATAM was also invited to comment the document. A revised version has been sent for voting on to all EFLM and COLABIOCLI members and has been officially endorsed by 33/40 EFLM and 21/21 COLABIOCLI members. We encourage professionals throughout Europe and Latin America to adopt and implement this recommendation to improve the quality of blood collection practices and increase patient and workers safety. PMID- 30004904 TI - CE: Original Research: Pain in Nonverbal Children with Medical Complexity: A Two Year Retrospective Study. AB - : : Purpose: Children with medical complexity experience frequent pain. But it can be challenging to recognize unexpected behaviors as pain related, especially in the absence of self-report. Often these children undergo extensive workups aimed at diagnosing the sources of pain. This study had three objectives: to describe the signs and symptoms parents of nonverbal children with medical complexity found worrisome, to describe the sources of pain in these children, and to describe nursing pain assessment practices in this population. DESIGN AND METHODS: Retrospective chart review was used to identify the initial presenting symptoms, sources of pain, and nursing documentation for 46 children with medical complexity who were admitted with a chief concern of pain to a 395-bed pediatric teaching hospital in the northeastern United States. RESULTS: Irritability, pain, feeding intolerance, and "not acting like herself [or himself]" were common parent-reported symptoms that prompted further evaluation. On average, five diagnostic studies were taken to identify a source of pain, and four specialty services were consulted during the admission. Nursing assessments of pain were documented approximately every three hours; the mean pain intensity score documented was 1.1 out of 10. The discharge diagnoses included infection (including urinary tract infection), seizures, constipation, chronic pain, failure to thrive, dehydration, and subdural hematoma. CONCLUSIONS: The discharge diagnoses covered a wide range. A systematic approach to pain evaluation could help to ensure that the diagnostic process is both thorough and efficient. Common childhood ailments such as constipation or urinary tract infection, as well as other causes, must be considered when diagnosing pain in this population. Practice implications include consulting parents regarding changes in a child's behavior. PMID- 30004905 TI - CE: A Review of the Revised Sepsis Care Bundles. AB - : Sepsis is an extreme response to infection that can cause tissue damage, organ failure, and death if not treated promptly and appropriately. Each year in the United States, sepsis affects more than 1.5 million people and kills roughly 250,000. Prompt recognition and treatment of sepsis are essential to saving lives, and nurses play a critical role in the early detection of sepsis, as they are often first to recognize the signs and symptoms of infection. Here, the authors review recent revisions to the sepsis care bundles and discuss screening and assessment tools nurses can use to identify sepsis in the ICU, in the ED, on the medical-surgical unit, and outside the hospital. PMID- 30004906 TI - Evolution in clinical presentation of inflammatory bowel disease over time at diagnosis: a multicenter cohort study. AB - INTRODUCTION: Delayed diagnosis of inflammatory bowel disease (IBD) has become a major issue, particularly in terms of the presence of nonspecific and heterogeneous clinical signs. This study aimed to identify changes over time in the epidemiological characteristics and clinical presentation of IBD in a French cohort. PATIENTS AND METHODS: Sociodemographic data from patients at three French hospitals (age, sex, country of origin, smoking habits) and characteristics of IBD [diagnostic delay, phenotype, location, first symptoms, first test suggesting diagnosis (endoscopy, imaging examination)] were collected in a computerized database (Focus_MICI). Four diagnostic time periods were assessed: <2000, 2000 2004, 2005-2009, and >2009. RESULTS: Among the 926 patients analyzed, 638 (<2000, n=181; 2000-2004, n=104; 2005-2009, n=147; >2009, n=206) had Crohn's disease (CD) and 288 (<2000, n=54; 2000-2004, n=39; 2005-2009, n=80; >2009, n=115) had ulcerative colitis (UC). For CD, statistically significant differences over time were observed for (a) the first revealing disease symptom [more frequent abdominal pain vs. chronic diarrhea (P<0.001)], (b) first investigation suggestive of diagnosis [more frequent computed tomography vs. colonoscopy (P<0.001)], and (c) CD behavior [more frequent inflammatory vs. stricturing/penetrating forms (P<0.001)]. No significant differences over time were observed for UC variables. CONCLUSION: In this large multicenter cohort study clinical diagnostic presentation of CD has changed over time. By contrast, there were no changes in the UC clinical presentation. PMID- 30004907 TI - Breakdown of Neural Function under Isoflurane Anesthesia: In Vivo, Multineuronal Imaging in Caenorhabditis elegans. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Previous work on the action of volatile anesthetics has focused at either the molecular level or bulk neuronal measurement such as electroencephalography or functional magnetic resonance imaging. There is a distinct gulf in resolution at the level of cellular signaling within neuronal systems. The authors hypothesize that anesthesia is caused by induced dyssynchrony in cellular signaling rather than suppression of individual neuron activity. METHODS: Employing confocal microscopy and Caenorhabditis elegans expressing the calcium-sensitive fluorophore GCaMP6s in specific command neurons, the authors measure neuronal activity noninvasively and in parallel within the behavioral circuit controlling forward and reverse crawling. The authors compare neuronal dynamics and coordination in a total of 31 animals under atmospheres of 0, 4, and 8% isoflurane. RESULTS: When not anesthetized, the interneurons controlling forward or reverse crawling occupy two possible states, with the activity of the "reversal" neurons AVA, AVD, AVE, and RIM strongly intercorrelated, and the "forward" neuron AVB anticorrelated. With exposure to 4% isoflurane and onset of physical quiescence, neuron activity wanders rapidly and erratically through indeterminate states. Neuron dynamics shift toward higher frequencies, and neuron pair correlations within the system are reduced. At 8% isoflurane, physical quiescence continues as neuronal signals show diminished amplitude with little correlation between neurons. Neuronal activity was further studied using statistical tools from information theory to quantify the type of disruption caused by isoflurane. Neuronal signals become noisier and more disordered, as measured by an increase in the randomness of their activity (Shannon entropy). The coordination of the system, measured by whether information exhibited in one neuron is also exhibited in other neurons (multiinformation), decreases significantly at 4% isoflurane (P = 0.00015) and 8% isoflurane (P = 0.0028). CONCLUSIONS: The onset of anesthesia corresponds with high-frequency randomization of individual neuron activity coupled with induced dyssynchrony and loss of coordination between neurons that disrupts functional signaling. PMID- 30004909 TI - Retroperitoneal lymph node dissection in the setting of elevated markers. AB - PURPOSE OF REVIEW: The management of residual tumor masses in patients with metastatic germ cell tumor and persistently elevated tumor marker levels after first- and second-line chemotherapy usually excludes surgical resection. The lack of benefit of salvage chemotherapy in patients with persistently elevated markers implies a degree of chemotherapy resistance. However, previous studies demonstrated therapeutic efficacy for a surgical approach in these very particular patients. Therefore, we evaluated pre and postoperative factors, which help to identify suitable candidates, who could potentially benefit from tumor resection. RECENT FINDINGS: Preoperative parameters, which predict favorable outcomes, include good prognosis according to the International Germ Cell Cancer Collaborative group, a high preoperative level of alpha-fetoprotein in contrast to a high level of beta-HCG, stable or decreasing preoperative tumor markers and teratomatous elements in the initial testicular tumor. Retroperitoneal and mediastinal lymph nodes as target lesions are predictive for good long-term outcome due to the higher chance of complete tumor resection. Teratoma or necrosis in the resected residual tissue and postoperative marker normalization additionally represent a favorable prognosis. SUMMARY: Even in advanced chemorefractory germ cell tumor patients with elevated tumor markers the disease remains curative with radical surgery as a salvage option, if a complete resection can be achieved. Thus, a surgical approach should always be considered in the management of selected patients to avoid unnecessary salvage chemotherapy. PMID- 30004910 TI - Acute Respiratory Distress in the Operating Room and Prone Ventilation: A Case Report. AB - There have been many advances in the management of acute respiratory distress syndrome, a condition which Bellani et al, in the LUNG SAFE trial (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure), found represents up to 10.4% of intensive care unit admissions and 23.4% of patients requiring mechanical ventilation, with an unadjusted intensive care unit and hospital mortality of 35.3% and 40%, respectively. Studies have shown that prone positioning can improve oxygenation in patients who are mechanically ventilated for acute respiratory distress syndrome. This case report describes an example in which intraoperative prone positioning improved oxygenation in a patient after aspiration of gastric contents on induction of general anesthesia. PMID- 30004911 TI - Unexpected Color Flow Signal in the Ventricular Septum of a Patient Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery. PMID- 30004908 TI - Update on epidemiologic considerations and treatment trends in testicular cancer. AB - PURPOSE OF REVIEW: We aim to give an overview of the epidemiology and treatment trends of testicular germ cell tumors (TGCTs), with an emphasis on recent trends. RECENT FINDINGS: The incidence of TGCT appears to be increasing, particularly in developed countries, although the reasons are not well understood. There is evidence of racial differences in predisposition to TGCT, with white men having highest risk and men of African or Asian descent having lower risk. In the United States, the incidence of TGCT among Hispanics appears to be rising most quickly. A recent genomic analysis indicates there is no highly penetrant major TGCT susceptibility gene. Incorporation of multidisciplinary care has led to excellent long-term cure rates; however, access to care and insurance remains barriers in young men. Recent treatment trends have centered on maximizing oncologic outcomes while minimizing long-term morbidity. SUMMARY: Emerging population-level data provide critical insight into the evolving demographics of TGCT, which may allow for elucidation of biologic and environmental determinants of TGCT. Further, identification of socioeconomic barriers to excellent clinical outcomes will allow for targeted interventions to patients with unique demographic and socioeconomic considerations. Treatment trend analyses suggest that the field is moving toward minimizing treatment-related morbidity. PMID- 30004912 TI - Profound Bradycardia and Cardiac Arrest After Sugammadex Administration in a Previously Healthy Patient: A Case Report. AB - We report the case of a 60-year-old man who underwent open radical prostatectomy for prostate adenocarcinoma. He had no known cardiac disease or symptoms other than controlled hypertension and remote history of cocaine use. The patient was given sugammadex for reversal of neuromuscular blockade and, within 1 minute, developed severe, drug-resistant bradycardia followed by pulseless electrical activity arrest. Advanced cardiac life support was initiated and continued for 15 minutes before the return of spontaneous circulation. Subsequent cardiac workup showed no abnormalities. We believe the cause of arrest was sugammadex, considering the time of administration, the absence of cardiac disease, and stable operative course. PMID- 30004913 TI - Magnetoencephalographic Recordings in Infants: A Retrospective Analysis of Seizure-Focus Yield and Postsurgical Outcomes. AB - PURPOSE: Magnetoencephalography (MEG) is often incorporated into the presurgical work-up of children with pharmacoresistant epilepsy. There is growing literature on its role in improving selection for epilepsy surgery, particularly when brain MRI is "non-lesional" or in patients with recurrence or intractable seizures after epilepsy surgery. There are, however, no reports on the extrapolation of its role in the presurgical decision-making process of infants. METHODS: We performed a retrospective analysis of infants who underwent MEG over a 10-year period at our center for presurgical work-up. We reviewed medical records to ascertain seizure history, work-up procedures including brain MRI and scalp EEG, and in the case of surgery, intracranial recordings, operative notes, and follow up outcomes. RESULTS: We identified 31 infants (<2 years of age) who underwent MEG recordings. Despite EEG interictal readings showing patterns of generalized dysfunction in 80%, MEG was able to pinpoint the foci of epileptic activity in 45%. In the MRI-negative group, 44% had focal lateralized interictal spikes on MEG. The sensitivity of MEG to detect interictal epileptiform activity was 90%, and its ability to provide additional information was 28%. Among 18 infants who had surgery, 13 became seizure free at follow-up. The percentage of infants with a focal spike volume on MEG studies and a seizure-free outcome was 66%. CONCLUSIONS: MEG recordings in infants were found to be as sensitive for identifying seizure focus as other age groups, also supplying additional information to the decision-making process and validating its role in the presurgical work-up of infants with intractable epilepsy. PMID- 30004914 TI - Quadratus Lumborum Block Versus Perioperative Intravenous Lidocaine for Postoperative Pain Control in Patients Undergoing Laparoscopic Colorectal Surgery: A Prospective, Randomized, Double-blind Controlled Clinical Trial. AB - OBJECTIVE: To investigate the comparative analgesic efficacy of systemic lidocaine and quadratus lumborum (QL) block in laparoscopic colorectal surgery. BACKGROUND: Although epidural analgesia is the standard to control pain in patients undergoing open colorectal surgery, optimal analgesic management in laparoscopic surgery is less well-defined. There is need for effective and efficient alternatives to epidural analgesia for pain management in patients undergoing laparoscopic colorectal surgery. METHODS: A total of 125 patients undergoing laparoscopic colorectal surgery were included in this randomized, double-blind controlled clinical trial. Patients randomly received an intravenous infusion with placebo plus a QL-block with placebo, a QL-block with ropivacaine 0.25% plus intravenous placebo, or intravenous lidocaine plus a QL-block with placebo. Postoperatively, all patients received patient-controlled intravenous anesthesia (PCIA) with morphine. Primary outcome parameter was the opioid consumption during the first 24 hours postoperatively. Secondary endpoints included severity of postoperative pain, time to return of intestinal function, incidence of postoperative nausea and vomiting, and length of hospital stay. RESULTS: The QL-block was not superior to systemic lidocaine for the reduction of morphine requirements in the first 24 hours postoperatively {QL-group: 37.5 (28.4) mg [mean (standard deviation)] vs lidocaine group: 40.2 (25) mg, P = 0.15}. For the majority of secondary outcome parameters, no significant differences were found between the groups. Morphine consumption in the postanesthesia care unit, the number of PCIA-boli demanded by the patient, and the number of PCIA-boli delivered by the PCIA-pump during the first 24 hours postoperatively were lower in the placebo group. CONCLUSIONS: In our trial, the QL-block did not provide superior postoperative analgesia when compared to systemic lidocaine in laparoscopic colorectal surgery. TRIAL REGISTRATION: Eudra CT: 2014-001499-73; 31/7/2014. PMID- 30004916 TI - No Clinical Benefit of Intramuscular Delivery of Bone Marrow-derived Mononuclear Cells in Nonreconstructable Peripheral Arterial Disease: Results of a Phase-III Randomized-controlled Trial. AB - BACKGROUND AND AIMS: Prospects for no-option, end-stage peripheral artery disease (PAD) patients remain poor. Although results from open and semiblinded studies fuel hope for cell-based strategies in no-option patients, so far conclusions from the available placebo-controlled studies are not supportive. With the intention to end the remaining controversy with regard to cell therapy for PAD we conducted a confirmatory, double-blinded randomized placebo-controlled phase 3 trial. STUDY DESIGN: This randomized controlled trial was registered (NCT00539266). Inclusion criteria included stable or progressive disabling PAD, no imminent need for amputation, absent accepted options for revascularization. Diabetic disease was an exclusion criterion. Bone marrow (500-700 mL) was harvested and bone marrow-derived mononuclear cells were concentrated to 40 mL. Concentrated cells or placebo (diluted blood) were intramuscularly injected at 40 locations of the calf muscle. RESULTS: Fifty-four patients (mean (sd) age 58.2 (14.2) yrs, 58% males) were randomized. Twenty-eight patients received BM-MNCs, 26 placebo. Baseline criteria were similar in the 2 groups. No significant differences were observed for the primary (number of amputations, (pain free) walking distance) and secondary outcome parameters (ankle brachial index, pain scores, quality of life (SF-36)). DISCUSSION: This fully blinded replication trial of autologous BM-MNC fails to confirm a benefit for cell therapy in no option PAD patients, consequently BM-MNC therapy should not be offered as a clinical treatment. Apparent contrasting conclusions from open and controlled studies underscore the importance of a controlled trial design in evaluating cell based interventions in PAD. PMID- 30004915 TI - The RESTORE Randomized Controlled Trial: Impact of a Multidisciplinary Rehabilitative Program on Cardiorespiratory Fitness in Esophagogastric cancer Survivorship. AB - OBJECTIVE: The Rehabilitation Strategies in Esophagogastric cancer (RESTORE) randomized controlled trial evaluated the efficacy of a 12-week multidisciplinary program to increase the cardiorespiratory fitness and health-related quality of life (HRQOL) of esophagogastric cancer survivors. BACKGROUND: Patients following treatment for esophagogastric cancer are at risk of physical deconditioning, nutritional compromise, and sarcopenia. Accordingly, compelling rationale exists to target these impairments in recovery. METHODS: Disease-free patients treated for esophagogastric cancer were randomized to either usual care or the 12-week RESTORE program (exercise training, dietary counseling, and multidisciplinary education). The primary outcome was cardiopulmonary exercise testing (VO2peak). Secondary outcomes included body composition (bioimpedance analysis), and HRQOL (EORTC-QLQ-C30). Outcomes were assessed at baseline (T0), postintervention (T1), and at 3-month follow-up (T2). RESULTS: Twenty-two participants were randomized to the control group [mean (standard deviation) age 64.14 (10.46) yr, body mass index 25.67 (4.83) kg/m, time postsurgery 33.68 (19.56) mo], and 21 to the intervention group [age 67.19(7.49) yr, body mass index 25.69(4.02) kg/m, time postsurgery 23.52(15.23) mo]. Mean adherence to prescribed exercise sessions were 94(12)% (supervised) and 78(27)% (unsupervised). Correcting for baseline VO2peak, the intervention arm had significantly higher VO2peak at both T1, 22.20 (4.35) versus 21.41 (4.49) mL . min . kg, P < 0.001, and T2, 21.75 (4.27) versus 20.74 (4.65) mL . min . kg, P = 0.001, compared with the control group. Correcting for baseline values, no changes in body composition or HRQOL were observed. CONCLUSIONS: The RESTORE program significantly improved cardiorespiratory fitness of disease-free patients after esophagogastric cancer surgery, without compromise to body composition. This randomized controlled trial provides proof of principle for rehabilitation programs in esophagogastric cancer. CLINICAL TRIAL REGISTRATION NUMBER: NCT03314311. PMID- 30004917 TI - Postoperative Acute Pancreatitis Following Pancreaticoduodenectomy: A Determinant of Fistula Potentially Driven by the Intraoperative Fluid Management. AB - OBJECTIVE: The aim of the study is to characterize postoperative acute pancreatitis (POAP). SUMMARY BACKGROUND DATA: A standardized definition of POAP after pancreaticoduodenectomy (PD) has been recently proposed, but specific studies are lacking. METHODS: The patients were extracted from the prospective database of The Pancreas Institute of Verona. POAP was defined as an elevation of the serum pancreatic amylase levels above the upper limit of normal (52 U/L) on postoperative day (POD) 0 or 1. The endpoints included defining the incidence and predictors of POAP and investigating the association of POAP with postoperative pancreatic fistula (POPF). RESULTS: The study population consisted of 292 patients who underwent PD. The POAP and POPF rates were 55.8% and 22.3%, respectively. POAP was an independent predictor of POPF (OR 3.8), with a 92% sensitivity and 53.7% specificity (AUC 0.79). Preoperative exocrine insufficiency (OR 0.39), neoadjuvant therapy (OR 0.29) additional resection of the pancreatic stump margin (OR 0.25), soft pancreatic texture (OR 4.38), and Main Pancreatic Duct (MPD) diameter <=3 mm (OR 2.86) were independent predictors of POAP. In high risk patients, an intraoperative fluid administration of <=3 ml/kg/h was associated with an increased incidence of POAP (24.6 vs. 0%, P = 0.04) and POPF (27.6 vs. 11.4%, P = 0.05). CONCLUSION: This study represents the first clinical application of the only available definition of POAP as a specific complication of pancreatic surgery. POAP is associated with an increased occurrence of POPF and overall morbidity and could potentially be avoided through a specific intraoperative fluid regimen in high-risk pancreas. PMID- 30004918 TI - IdeS (Imlifidase): A Novel Agent That Cleaves Human IgG and Permits Successful Kidney Transplantation Across High-strength Donor-specific Antibody. AB - OBJECTIVES: The presence of a donor-specific positive crossmatch has been considered to be a contraindication to kidney transplantation because of the risk of hyperacute rejection. Desensitization is the process of removing hazardous preformed donor-specific antibody (DSA) in order to safely proceed with transplant. Traditionally, this involves plasmapheresis and intravenous immune globulin treatments that occur over days to weeks, and has been feasible when there is a living donor and the date of the transplant is known, allowing time for pre-emptive treatments. For sensitized patients without a living donor, transplantation has been historically difficult. SUMMARY OF BACKGROUND DATA: IdeS (imlifidase) is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG. METHODS: Here we present our single-center's experience with 7 highly sensitized (cPRA98-100%) kidney transplant candidates who had DSA resulting in positive crossmatches with their donors (5 deceased, 2 living) who received IdeS within 24 hours prior to transplant. RESULTS: All pre-IdeS crossmatches were positive and would have been prohibitive for transplantation. All crossmatches became negative post-IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and antibody-mediated rejection, which responded to standard of care therapies. Three patients had delayed graft function, which ultimately resolved. No serious adverse events were associated with IdeS. All patients have functioning renal allografts at a median follow-up of 235 days. CONCLUSION: IdeS may represent a groundbreaking new method of desensitization for patients who otherwise might have no hope for receiving a lifesaving transplant. PMID- 30004919 TI - More Frequent Surveillance Following Lung Cancer Resection Is Not Associated With Improved Survival: A Nationally Representative Cohort Study. AB - OBJECTIVE: To evaluate whether an association exists between the intensity of surveillance following surgical resection for non-small cell lung cancer (NSCLC) and survival. BACKGROUND: Surveillance guidelines following surgical resection of NSCLC vary widely and are based on expert opinion and limited evidence. METHODS: A Special Study of the National Cancer Database randomly selected stage I to III NSCLC patients for data reabstraction. For patients diagnosed between 2006 and 2007 and followed for 5 years through 2012, registrars documented all postsurgical imaging with indication (routine surveillance, new symptoms), recurrence, new primary cancers, and survival, with 5-year follow-up. Patients were placed into surveillance groups according to existing guidelines (3-month, 6 month, annual). Overall survival and survival after recurrence were analyzed using Cox Proportional Hazards Models. RESULTS: A total of 4463 patients were surveilled with computed tomography scans; these patients were grouped based on time from surgery to first surveillance. Groups were similar with respect to age, sex, comorbidities, surgical procedure, and histology. Higher-stage patients received more surveillance. More frequent surveillance was not associated with longer risk-adjusted overall survival [hazard ratio for 6-month: 1.16 (0.99, 1.36) and annual: 1.06 (0.86-1.31) vs 3-month; P value 0.14]. More frequent imaging was also not associated with postrecurrence survival [hazard ratio: 1.02/month since imaging (0.99-1.04); P value 0.43]. CONCLUSIONS: These nationally representative data provide evidence that more frequent postsurgical surveillance is not associated with improved survival. As the number of lung cancer survivors increases over the next decade, surveillance is an increasingly important major health care concern and expenditure. PMID- 30004920 TI - Per-oral Pyloromyotomy (POP) for Medically Refractory Gastroparesis: Short Term Results From the First 100 Patients at a High Volume Center. AB - OBJECTIVE: For patients with gastroparesis, temporary pyloric disruption has been shown to improve symptoms and gastric emptying. Per-oral pyloromyotomy (POP) is an innovative endoscopic procedure to divide the pylorus from within a submucosal tunnel, as a corollary to surgical pyloromyotomy. Here we evaluate subjective and objective outcomes 12-weeks after POP at a high volume center. METHODS: The first 100 consecutive patients undergoing POP were included, with procedure dates between January 2016 and October 2017. Patients were evaluated using the Gastroparesis Cardinal Symptom Index (GCSI), and 4-hour solid-phase scintigraphic gastric emptying studies (GES) prior to procedure and at 90 days post-POP RESULTS:: The study cohort was 85% female with a mean age of 45.0 +/- 14.6 years. Gastroparesis etiologies were divided among idiopathic (56%), diabetic (21%), postsurgical (19%), and other in 4%. There were 67% of the patients who had previous endoscopic or surgical interventions for gastroparesis. Most POP procedures were performed in the operating room (97%) and were completed in an average of 33 minutes. Ten patients incurred complications (10%), which included 1 diagnostic laparoscopy and 2 cases of gastrointestinal bleeding. Overall GCSI improved from a preoperative mean of 3.82 +/- 0.86 to 2.54 +/- 1.2 (P < 0.001). The improvement in each GCSI subscore was also highly statistically significant. Among the patients with postoperative GES available, 78% had objectively better 4 hour emptying with a mean improvement in retention by 23.6% (P < 0.001). This included 57% of patients with normal gastric emptying post-POP. CONCLUSION: For patients with medically refractory gastroparesis, POP results in both subjective and objective improvement in the majority of patients. Prior intervention does not obviate POP as a therapeutic option. POP should be included along the treatment algorithm for patients with gastroparesis as an organ-sparing procedure. PMID- 30004921 TI - Global Surgery: Effective Involvement of US Academic Surgery: Report of the American Surgical Association Working Group on Global Surgery. AB - : There is an unacceptably high burden of death and disability from conditions that are treatable by surgery, worldwide and especially in low- and middle-income countries (LMICs). The major actions to improve this situation need to be taken by the surgical communities, institutions, and governments of the LMICs. The US surgical community, including the US academic surgical community, has, however, important roles to play in addressing this problem. The American Surgical Association convened a Working Group to address how US academic surgery can most effectively decrease the burden from surgically treatable conditions in LMICs. The Working Group believes that the task will be most successful (1) if the epidemiologic pattern in a given country is taken into account by focusing on those surgically treatable conditions with the highest burdens; (2) if emphasis is placed on those surgical services that are most cost-effective and most feasible to scale up; and (3) if efforts are harmonized with local priorities and with existing global initiatives, such as the World Health Assembly with its 2015 resolution on essential surgery. This consensus statement gives recommendations on how to achieve those goals through the tools of academic surgery: clinical care, training and capacity building, research, and advocacy. Through all of these, the ethical principles of maximally and transparently engaging with and deferring to the interests and needs of local surgeons and their patients are of paramount importance. Notable benefits accrue to US surgeons, trainees, and institutions that engage in global surgical activities. PMID- 30004922 TI - Timing of Carotid Endarterectomy After Stroke: Retrospective Review of Prospectively Collected National Database. AB - OBJECTIVE: Our objective was to identify the postoperative risk associated with different timing intervals of repair. BACKGROUND: Timing of carotid intervention in poststroke patients is widely debated with the scales balanced between increased periprocedural risk and recurrent neurologic event. National database reviews show increased risk to patients treated within the first 2 days of a neurologic event compared to those treated after 6 days. METHODS: Utilizing Vascular Quality Initiative data, all carotid interventions performed on stroke patients between the years 2012 and 2017 were queried. Patients were then stratified based on the timing of surgery from their stroke (<48 hours, 3-7 days, 8-14 days, >15 days). Major outcomes included postoperative stroke, death, and myocardial infarction. RESULTS: A total of 8404 patients were included being predominantly men (5281, 62.8%), with an average age of 69 (+/-10). Patients treated at greater than 8 days showed significantly less risk of postoperative combined stroke/death and postoperative stroke. There were no significant differences in postoperative stroke or death between the 8 to 14 and greater than 15 days groups.Multivariate regression analysis showed that delayed timing of surgery between 3 and 7 days was protective for postoperative stroke/death (P = 0.003) and any postoperative complication (P = 0.028). Delaying surgery to more than 8 days after stroke was protective for postoperative stroke/death (P < 0.001), postoperative stroke (P < 0.001), and any postoperative complication (P < 0.001). CONCLUSIONS: Carotid revascularization should occur no sooner than 48 hours after index stroke event. Surgeons should strive to operate between 8 and 14 days to protect against postoperative stroke/death. PMID- 30004923 TI - Ensuring Equity, Diversity, and Inclusion in Academic Surgery: An American Surgical Association White Paper. AB - OBJECTIVE: The leadership of the American Surgical Association (ASA) appointed a Task Force to objectively address issues related to equity, diversity, and inclusion with the discipline of academic surgery. SUMMARY OF BACKGROUND DATA: Surgeons and the discipline of surgery, particularly academic surgery, have a tradition of leadership both in medicine and society. Currently, we are being challenged to harness our innate curiosity, hard work, and perseverance to address the historically significant deficiencies within our field in the areas of diversity, equity, and inclusion. METHODS: The ASA leadership requested members to volunteer to serve on a Task Force to comprehensively address equity, diversity, and inclusion in academic surgery. Nine work groups reviewed the current literature, performed primary qualitative interviews, and distilled available guidelines and published primary source materials. A work product was created and published on the ASA Website and made available to the public. The full work product was summarized into this White Paper. RESULTS: The ASA has produced a handbook entitled: Ensuring Equity, Diversity, and Inclusion in Academic Surgery, which identifies issues and challenges, and develops a set of solutions and benchmarks to aid the academic surgical community in achieving these goals. CONCLUSION: Surgery must identify areas for improvement and work iteratively to address and correct past deficiencies. This requires honest and ongoing identification and correction of implicit and explicit biases. Increasing diversity in our departments, residencies, and universities will improve patient care, enhance productivity, augment community connections, and achieve our most fundamental ambition-doing good for our patients. PMID- 30004924 TI - Results of a Prospective, Multicenter Initiative Aimed at Developing Opioid prescribing Guidelines After Surgery. AB - OBJECTIVE: The aim of this study was to conduct a prospective, multicenter survey of patients regarding postoperative opioid use to inform development of standardized, evidence-based, procedure-specific opioid prescribing guidelines. SUMMARY OF BACKGROUND DATA: Previous work has shown significant variation in the amount of opioids prescribed after elective procedures, calling for optimization of prescribing. METHODS: Adults (n = 3412) undergoing 25 elective procedures were identified prospectively from 3 academic centers (March 2017 to January 2018) to complete a 29-question telephone interview survey 21 to 35 days post-discharge (n = 688 not contacted, n = 107 refused). Discharge opioids were converted into Morphine Milligram Equivalents (MMEs). RESULTS: Of the 2486 patients who completed the survey, 91.2% received opioids at discharge [median 225 (interquartile range, IQR 125 to 381) MME]. A median of 43 (0 to 184) MMEs were consumed after discharge with 77.3% of patients having leftover opioids at the time of the survey. In total, 61.5% of prescribed opioids were unused; 31.4% of patients used no opioids, and 52.6% required <50 MME. Overall, 90.6% of patients were satisfied with their postdischarge pain control. While 28.3% reported being prescribed too many opioids, 9.0% felt they were not prescribed enough. Only 9.6% of patients disposed of remaining opioids. Of the 2068 opioid-naive respondents (83.2%), 33.6% consumed no opioids (range 5.2% to 80.0% by procedure) and 57.0% (65.7% nonorthopedic) consumed <50 MME. Utilization data and predictors of low/high opioid consumption informed development of postoperative prescribing guidelines. CONCLUSION: A large proportion of postoperative patients reported using no or few opioids following discharge. Guidelines were developed to minimize opioid prescribing and identify patients requiring low doses or additional multimodal pain control. PMID- 30004925 TI - An Academic Relative Value Unit System for Incentivizing the Academic Productivity of Surgery Faculty Members. AB - OBJECTIVE: The objective of this study was to evaluate a new academic relative value unit (aRVU) scoring system linked to faculty compensation and analyze its association with overall departmental academic productivity. SUMMARY BACKGROUND DATA: Faculty are often not incentivized or financially compensated for educational and research activities crucial to the academic mission. METHODS: We launched an online, self-reporting aRVU system in 2015 to document and incentivize the academic productivity of our faculty. The system captured 65 specific weighted scores in 5 major categories of research, education, innovation, academic service, and peer review activities. The aRVU scores were rank-aggregated annually, and bonuses were distributed to faculty members in 3 tiers: top 10%, top third, and top half. We compared pre-aRVU (academic year 2015) to post-aRVU (academic year 2017) departmental achievement metrics. RESULTS: Since 2015, annual aRVU bonuses totaling $493,900 were awarded to 59 faculty members (58% of eligible department faculty). Implementing aRVUs was associated with significant increases in several key departmental academic achievement metrics: presentations (579 to 862; P = 0.02; 49% increase), publications (390 to 446; P = 0.02; 14%), total research funding ($4.6 M to $8.4 M; P < 0.001; 83%), NIH funding ($0.6 M to $3.4 M; P < 0.001; 467%), industry sponsored clinical trials (8 to 23; P = 0.002; 188%), academic society committee positions (226 to 298; P < 0.001; 32%), and editorial leadership positions (50 to 74; P = 0.01; 48%). CONCLUSIONS: Implementing an aRVU system was associated with increases in departmental academic productivity. Although other factors undoubtedly contributed to these increases, an aRVU program may represent an important mechanism for tracking and rewarding academic productivity in surgery departments. PMID- 30004926 TI - Hyperthyroidism is Underdiagnosed and Undertreated in 3336 Patients: An Opportunity for Improvement and Intervention. AB - OBJECTIVE: The aim of this study was to determine the prevalence of undiagnosed and untreated hyperthyroidism among patients with suppressed thyroid-stimulating hormone (TSH). BACKGROUND: Hyperthyroidism can significantly diminish patient quality of life and increase the financial burden on patients and health systems. We hypothesized that many patients with hyperthyroidism remain undiagnosed because physicians fail to recognize and evaluate suppressed TSH as the first indication of disease. METHODS: We reviewed administrative data on 174011 patients with TSH measured at a tertiary referral center between 2011 and 2017 to identify individuals with hyperthyroidism (TSH <0.05 mU/L) and their subsequent outcomes: evaluation (measurement of T4, T3, radioactive iodine (RAI) uptake scan, thyroid-stimulating immunoglobulin, thyroid peroxidase antibodies) diagnosis, referral and treatment. We used Kaplan-Meier methods and multivariable time-related parametric hazard modeling to measure our outcomes. RESULTS: We found 3336 patients with hyperthyroidism. The mean age of our cohort was 52 +/- 17 years, with 79% females and 59% whites. Only 1088 patients (33%) received any appropriate evaluation and hyperthyroidism remained undiagnosed in 37% of patients who had the appropriate workup. Among those diagnosed with hyperthyroidism, only 21% were referred for surgery and 34% received RAI. Predictors for hyperthyroidism diagnosis include lower TSH (0.01u/L), younger age, African-American race, private commercial insurance, being seen in an outpatient setting, absence of medical comorbidities, presentation with ophthalmopathy, or weight loss. CONCLUSIONS: Hyperthyroidism is frequently unrecognized and untreated, which can lead to adverse outcomes and increased costs. Improved systems for detection and treatment of hyperthyroidism are needed to address this gap in care. PMID- 30004927 TI - Validity of the Novel Taiwan Lymphoscintigraphy Staging and Correlation of Cheng Lymphedema Grading for Unilateral Extremity Lymphedema. AB - OBJECTIVE: The aim was to validate the new Taiwan Lymphoscintigraphy Staging, correlate it with Cheng Lymphedema Grading (CLG) and evaluate the treatment outcomes of unilateral extremity lymphedema. BACKGROUND: No consensus has been reached for diagnosis and staging for patients with lymphedema among medical specialties. METHODS: We included 285 patients with unilateral extremity lymphedema using lymphoscintigraphy. Lymphoscintigraphy was correlated to clinical symptoms and signs, and classified into normal lymphatic drainage, partial obstruction, and total obstruction. Inter- and intraobserver reliability of Taiwan Lymphoscintigraphy Staging, correlation between Taiwan Lymphoscintigraphy Staging and clinical findings were conducted. Patients were categorized in "surgical" (n = 154) or "nonsurgical" (n = 131) groups for outcome evaluation. RESULTS: Lymphoscintigraphy found 11 patients (3.9%) with normal lymphatic drainage, 128 (44.9%) with partial obstruction, and 146 (51.2%) with total obstruction. Taiwan Lymphoscintigraphy Staging showed high interobserver agreement [intraclass correlation coefficient: 0.89 (95% confidence interval, 0.82-0.94)], and significantly correlated to computed tomography volumetric difference (r = 0.66, P < 0.001) and CLG [intraclass correlation coefficient: 0.79 (95% confidence interval 0.72-0.84)]. At a mean follow-up of 31.2 +/- 2.9 months, significant improvement in the circumferential difference (from 23.9% +/- 17.6% to 14.6% +/- 11.1%; P = 0.03) with a mean circumferential reduction rate of 40.4% +/- 4.5% was found in surgical group. At a mean follow-up of 26.6 +/- 8.7 months, the nonsurgical group had increase of mean circumferential difference from 24.0% +/- 17.2% to 25.3% +/- 19.0% (P = 0.09), with a mean circumferential reduction rate was -1.9% +/- 13.0%. CONCLUSIONS: The Taiwan Lymphoscintigraphy Staging is a reliable diagnostic tool, correlated with clinical findings and CLG, aiding in the selection of the appropriate treatment to achieve favorable long term outcomes in unilateral extremity lymphedema. PMID- 30004928 TI - Impact of the Affordable Care Act (ACA) Medicaid Expansion on Cancer Admissions and Surgeries. AB - OBJECTIVE: This study aims to evaluate the trends in cancer (CA) admissions and surgeries after the Affordable Care Act (ACA) Medicaid expansion. METHODS: This is a retrospective study using HCUP-SID analyzing inpatient CA (pancreas, esophagus, lung, bladder, breast, colorectal, prostate, and gastric) admissions and surgeries pre- (2010-2013) and post- (2014) Medicaid expansion. Surgery was defined as observed resection rate per 100 cancer admissions. Nonexpansion (FL) and expansion states (IA, MD, and NY) were compared. A generalized linear model with a Poisson distribution and logistic regression was used with incidence rate ratios (IRR) and difference-in-differences (DID). RESULTS: There were 317, 858 patients in our sample which included those with private insurance, Medicaid, or no insurance. Pancreas, breast, colorectal, prostate, and gastric CA admissions significantly increased in expansion states but decreased in nonexpansion states. (IRR 1.12, 1.14, 1.11, 1.34, 1.23; P < .05) Lung and colorectal CA surgeries (IRR 1.30, 1.25; P < .05) increased, while breast CA surgeries (IRR 1.25; P < .05) decreased less in expansion states. Government subsidized, or self-pay patients had greater odds of undergoing lung, bladder, and colorectal CA surgery (OR 0.45 vs 0.33; 0.60 vs 0.48; 0.47 vs 0.39; P < .05) in expansion states after reform. CONCLUSIONS: In states that expanded Medicaid coverage under the ACA, the rate of surgeries for colorectal and lung CA increased significantly, while breast CA surgeries decreased less. Parenthetically, these cancers are subject to population screening programs. We conclude that expanding insurance coverage results in enhanced access to cancer surgery. PMID- 30004930 TI - Experience of Airway Management Training Program for Low- and Middle-Income Countries. PMID- 30004929 TI - Insurance Status Biases Trauma-system Utilization and Appropriate Interfacility Transfer: National and Longitudinal Results of Adult, Pediatric, and Older Adult Patients. AB - OBJECTIVE: To identify the association between insurance status and the probability of emergency department admission versus transfer for patients with major injuries (Injury Severity Score >15) and other complex trauma likely to require higher-level trauma center (TC) care across the spectrum of TC care. BACKGROUND: Trauma systems were developed to facilitate direct transport and transfer of patients with major/complex traumatic injuries to designated TCs. Emerging literature suggests that uninsured patients are more likely to be transferred. METHODS: Nationally weighted Nationwide Emergency Department Sample (2010-2014) and longitudinal California State Inpatient Databases/State Emergency Department Databases (2009-2011) data identified adult (18-64 yr), pediatric (<=17 yr), and older adult (>=65 yr) trauma patients. Risk-adjusted multilevel (mixed-effects) logistic regression determined differences in the relative odds of direct admission versus transfer and outcome measures based on initial level of TC presentation. RESULTS: In all 3 age groups, insured patients were more likely to be admitted [eg, nontrauma center (NTC) private vs uninsured odds ratio (95% confidence interval): adult 1.54 (1.40-1.70), pediatric 1.95(1.45-2.61)]. The trend persisted within levels III and II TCs (eg, level II private vs uninsured adult 1.83 (1.30-2.57)] and among other forms of trauma likely to require transfer. At the state level, among transferred NTC patients, 28.5% (adult), 34.1% (pediatric), and 39.5% (older adult) of patients with major injuries were not transferred to level I/II TCs. An additional 44.3% (adult), 50.9% (pediatric), and 57.6% (older adult) of all NTC patients were never transferred. Directly admitted patients experienced higher morbidity [adult: 19.6% vs 8.2%, odds ratio (95% confidence interval):2.74 (2.17-3.46)] and mortality [3.3% vs 1.8%, 1.85 (1.13-3.04)]. CONCLUSIONS: Insured patients with significant injuries initially evaluated at NTCs and level III/II TCs were less likely to be transferred. Such a finding appears to result in less optimal trauma care for better-insured patients and questions the success of transfer-guideline implementation. PMID- 30004931 TI - Virtual Reality Analgesia in Labor: The VRAIL Pilot Study-A Preliminary Randomized Controlled Trial Suggesting Benefit of Immersive Virtual Reality Analgesia in Unmedicated Laboring Women. AB - This pilot study investigated the use of virtual reality (VR) in laboring women. Twenty-seven women were observed for equivalent time during unmedicated contractions in the first stage of labor both with and without VR (order balanced and randomized). Numeric rating scale scores were collected after both study conditions. Significant decreases in sensory pain -1.5 (95% CI, -0.8 to -2.2), affective pain -2.5 (95% CI, -1.6 to -3.3), cognitive pain -3.1 (95% CI, -2.4 to 3.8), and anxiety -1.5 (95% CI, -0.8 to -2.3) were observed during VR. Results suggest that VR is a potentially effective technique for improving pain and anxiety during labor. PMID- 30004932 TI - In Response. PMID- 30004933 TI - Frequency of Operative Anesthesia Care After Traumatic Injury. AB - BACKGROUND: Virtually all anesthesiologists care for patients who sustain traumatic injuries; however, the frequency with which operative anesthesia care is provided to this specific patient population is unclear. We sought to better understand the degree to which anesthesia providers participate in operative trauma care and how this differs by trauma center designation (levels I-V), using data from a comprehensive, regional database-the Washington State Trauma Registry (WSTR). We also sought to specifically assess operative anesthesia care frequency vis a vis the American College of Surgeons guidelines for continuous anesthesiology coverage for Level II trauma center accreditation. METHODS: We conducted a retrospective analysis measuring the frequency of operative anesthesia care among patients enrolled in the WSTR. Univariate comparisons were made between trauma patients who had surgery during their admission and those who did not (medical management only). In addition, clinical factors associated with surgical intervention were measured. We also measured the average times from hospital admission to surgery and compared these times across trauma centers, grouped level I, II, and III-V. RESULTS: From 2004 to 2014, there were approximately 176,000 encounters meeting WSTR inclusion criteria. Approximately 60% of these trauma encounters included exposure to operative anesthesia during the admission. Among all surgical procedures during the trauma admission, approximately 33% occurred within a level I trauma center, 23% occurred within a level II trauma center, and 44% occurred in a trauma center with a III, IV, or V designation. The predominant procedure category during a trauma admission was orthopedic. The presence of hypotension on admission (P < .01), increasing injury severity score (P < .01) and higher emergency department Glasgow Coma Score (P < .01) were all associated with surgical intervention during the trauma hospitalization, after adjustment for potential confounders. In level I trauma centers, for general surgical procedures, the median time to surgery was 2.5 hours; in level II trauma centers, the median time was 1.7 hours. CONCLUSIONS: This study highlights the frequent role anesthesiologists play in caring for patients who sustain traumatic injuries, in trauma centers levels I-V. In level II trauma centers, in-house anesthesiology coverage might have benefit for those patients requiring surgery within 1 hour, whereas the former American College of Surgeons requirement of 30-minute response time for out-of-hospital anesthesiology coverage is likely sufficient to provide satisfactory care to patients requiring surgery within 3 hours. Whether the increased cost of such in house anesthesiology coverage at level II trauma centers is justified by its clinical benefit remains an unanswered question. PMID- 30004934 TI - A Systematic Review Evaluating Neuraxial Morphine and Diamorphine-Associated Respiratory Depression After Cesarean Delivery. AB - The prevalence of neuraxial opioid-induced clinically significant respiratory depression (CSRD) after cesarean delivery is unknown. We sought to review reported cases of author-reported respiratory depression (ARD) to calculate CSRD prevalence. A 6-database literature search was performed to identify ARD secondary to neuraxial morphine or diamorphine, in parturients undergoing cesarean delivery. "Highest" (definite and probable/possible) and "lowest" (definite) prevalences of CSRD were calculated. Secondary outcomes included: (1) prevalence of CSRD associated with contemporary doses of neuraxial opioid, (2) prevalence of ARD as defined by each study's own criteria, (3) case reports of ARD, and (4) reports of ARD reported by the Anesthesia Closed Claims Project database between 1990 and 2016. We identified 78 articles with 18,455 parturients receiving neuraxial morphine or diamorphine for cesarean delivery. The highest and lowest prevalences of CSRD with all doses of neuraxial opioids were 8.67 per 10,000 (95% CI, 4.20-15.16) and 5.96 per 10,000 (95% CI, 2.23-11.28), respectively. The highest and lowest prevalences of CSRD with the use of clinically relevant doses of neuraxial morphine ranged between 1.63 per 10,000 (95% CI, 0.62-8.77) and 1.08 per 10,000 (95% CI, 0.24-7.22), respectively. The prevalence of ARD as defined by each individual paper was 61 per 10,000 (95% CI, 51-74). One published case report of ARD met our inclusion criteria, and there were no cases of ARD from the Closed Claims database analysis. These results indicate that the prevalence of CSRD due to neuraxial morphine or diamorphine in the obstetric population is low. PMID- 30004935 TI - Diagnosis of Multiple Primary Intestinal-Type Adenocarcinoma in the Lung by 18F FDG PET/CT. AB - A 74-year-old man with multiple soft tissue lesions in the lung, which were suspected to be metastatic neoplasms, underwent F-FDG PET/CT scan to detect primary malignancy. The images demonstrated that the lung and 2 retroperitoneal lymph nodes were the only affected organ or tissues with suspected primary lung neoplasms. Multiple intestinal-type adenocarcinoma was eventually diagnosed by CT guided transthoracic needle aspiration biopsy. PMID- 30004936 TI - 18F-FDOPA PET/CT of Nonfunctioning Paraganglioma of the Gastroepiploic Pedicle. AB - We report the case of a 54-year-old woman with a nonfunctioning paraganglioma arising from the gastroepiploic pedicle demonstrated by F-FDOPA PET/CT. Because gastroepiploic arcade can be assimilated to the gastric mesentery, this tumor has been classified as a mesenteric paraganglioma (PGL). Neural crest cells are a multipotent population of cells characterized by effective migratory properties potentially explaining PGL atypical localization as in the mesentery. Mesenteric PGLs are often nonfunctioning and can mimic gastric, colic, or pancreatic primary tumor because of their anatomical boundaries, making more difficult the diagnosis on preoperative imaging. PMID- 30004937 TI - 68Ga-Labeled Prostate-Specific Membrane Antigen Uptake in Pheochromocytoma: An Incidental Finding in PET/CT Scan. AB - We report a case of adenocarcinoma prostate treated previously with radical prostatectomy and hormonal therapy who underwent Ga-labeled prostate-specific membrane antigen PET/CT for recurrence evaluation. In addition to radiotracer uptake in the prostate bed, unusual intense prostate-specific membrane antigen uptake was also noted in the left adrenal gland. With a clinical suspicion of pheochromocytoma, Ga-DOTANOC PET/CT was done, which revealed tracer-avid left adrenal lesion. PMID- 30004938 TI - Intense FDG Uptake in the Muscles Due to Severe Vomiting. AB - A 22-year-old woman with acute lymphoblastic leukemia underwent FDG PET/CT to evaluate possible extramedullary disease. The patient experienced severe nausea and vomiting due to ongoing chemotherapy. The image demonstrated increased FDG uptake in multiple muscle groups, including intercostal, bilateral external oblique, internal oblique, transverse abdominal muscles, and psoas major. One week after the patient stopped vomiting, a repeated PET/CT showed much less muscle uptake. PMID- 30004939 TI - 18F-PBR06 Versus 11C-PBR28 PET for Assessing White Matter Translocator Protein Binding in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: F-PBR06 and C-PBR28 are second-generation PET radioligands targeting the 18-kd translocator protein to assess microglial activation. We directly compared F-PBR06 and C-PBR28 for detecting brain translocator protein binding in multiple sclerosis (MS). METHODS: Six patients with MS (4 women; mean age +/- SD, 32.1 +/- 4.9 [range, 23.5-37.4 years]; Expanded Disability Status Scale score 2.3 +/- 1.2 [range, 1.0-4.0]) underwent brain PET with both ligands, along with 3-T MRI. MRI was coregistered to the summed 60- to 90-minute PET images. SUV ratios (SUVRs), derived by normalization to global brain radioactivity, were obtained for whole-brain white matter (WM), supratentorial WM, normal-appearing WM (NAWM), and T2 (fluid-attenuated inversion recovery) hyperintense and T1 hypointense MS WM lesions. The highest mean SUVR for the fluid-attenuated inversion-recovery lesional slices was defined as SUVRmax. RESULTS: F-PBR06 and C-PBR28 were moderately intercorrelated for whole brain WM SUVR (r = 0.83, P = 0.04) and supratentorial WM SUVR (r = 0.81, P = 0.05) but not for SUVRs of NAWM, T1 lesions, T2 lesions, or SUVRmax. Both tracers demonstrated that SUVR was higher in NAWM than in T1 and T2 lesions (all P < 0.05). F-PBR06 (but not C-PBR28) demonstrated a higher SUVR in T1 versus T2 lesions (0.85 +/- 0.07 vs 0.78 +/- 0.03, P = 0.03). F-PBR06-derived (but not C PBR28) SUVRmax correlated with both Expanded Disability Status Scale score (r = 0.82, P = 0.04) and timed 25-ft walking speed (r = 0.89, P = 0.01). CONCLUSIONS: Our preliminary results suggest an association between microglial activation and physical disability in MS. Microglial detection in lesions was not interchangeable between the tracers, with a higher clinical relevance suggested for F-PBR06. PMID- 30004940 TI - The Role of SPECT/CT of Foot and Ankle in the Evaluation of Heel Pain. AB - Heel pain is a common symptom in foot and ankle disorders. Typical heel pain can be assessed according to the patient's history and the location of pain. In some atypical inconclusive cases, bone SPECT/CT is the upcoming imaging modality for the detection of causes of heel pain. We present the case of 57-year-old man with atypical heel pain, plantar and Achilles spurs. SPECT/CT images demonstrated increased bony activity in arthritis of midfoot, not plantar and Achilles spurs. It suggests potential role of SPECT/CT in the evaluation and management of heel pain by showing hidden pathology of foot and ankle. PMID- 30004942 TI - Benchtop von Willebrand Factor Testing: Comparison of Commercially Available Ventricular Assist Devices and Evaluation of Variables for a Standardized Test Method. AB - Gastrointestinal bleeding occurs in 20-30% of patients receiving ventricular assist devices (VADs) due, in part, to acquired von Willebrand syndrome. We examined factors to optimize a benchtop method to quantify changes in von Willebrand Factor (VWF) multimer distribution and function in VADs, then applied them to evaluate commercially available devices. Human plasma was circulated through flow loops with VADs. Several experimental conditions were examined, including temperature, viscosity, and enzyme inhibition. Samples were analyzed for VWF collagen-binding activity (VWF:CB) and VWF antigen level. von Willebrand Factor multimer profiles were quantified using gel electrophoresis, near-infrared in-gel visualization, and densitometric analysis. The VWF:CB/antigen ratio in the HeartMate II, CentriMag, and HVAD exhibited average decreases of 46%, 44%, and 36% from baseline after 360 minutes of operation. High molecular weight (hVWF) multimer loss occurred within 30 minutes, although the Levacor and control loop profiles were unchanged. Varying temperature and viscosity altered hVWF degradation rate, but not the final results. Inhibition of ADAMTS13 can potentially distinguish mechanoenzymatic cleavage of VWF from mechanical degradation. We developed a repeatable benchtop method to evaluate VWF compatibility of VADs similar to hemolysis testing that can be adopted for preclinical VAD evaluation. PMID- 30004941 TI - FDG PET/CT of Metabolic Myopathy With Posttreatment Follow-up. AB - A 38-year-old woman presented with extreme fatigue and multiple lung nodules. She was referred for a PET/CT, which demonstrated multiple FDG-avid pulmonary nodules and lymph nodes with intense uptake within multiple muscle groups predominantly involving the paraspinal muscles and muscles of mastication. Histopathology of a paraspinal muscle biopsy revealed increased skeletal muscle lipid stores and increased mitochondria with normal morphology. This abnormality is seen in metabolic myopathy due to a disorder of fatty acid oxidation. Transbronchial biopsy showed no evidence of sarcoidosis. The patient was commenced on carnitine and riboflavin supplementation, and a follow-up PET/CT was performed. PMID- 30004943 TI - Echo-Guided Insertion of a Dual-Lumen Cannula for Venovenous Extracorporeal Membrane Oxygenation. AB - We provide a step-by-step description of the insertion of a dual-lumen cannula, for venovenous extracorporeal membrane oxygenation support and how a close monitoring by combined transthoracic and transesophageal techniques ensures a safe procedure and can promptly detect complications. PMID- 30004944 TI - Optimal Methods to Secure Extracorporeal Membrane Oxygenation Bicaval Dual-Lumen Cannulae: What Works? AB - Ambulation while on extracorporeal membrane oxygenation (ECMO) is critical to facilitate native pulmonary recovery for patients with acute respiratory failure and is a prerequisite for listing for lung transplantation to achieve optimal outcomes. The development of a bicaval dual-lumen cannula capable of providing venovenous (VV) ECMO support via the internal jugular vein has greatly facilitated ambulation and rehabilitation programs. But cannula dislodgement is a serious concern with ambulation and rehabilitation, especially when minor cannula migration can significantly impact VV-ECMO flow. We review an optimal technique to secure dual-lumen cannula to facilitate early mobility, ambulation, and rehabilitation and prevent ECMO cannula dislodgement. PMID- 30004945 TI - Role of Cardiac Resynchronization Therapy in Patients with Left Ventricular Assist Support. PMID- 30004946 TI - Exclusive enteral nutrition in pediatric inflammatory bowel disease. AB - PURPOSE OF REVIEW: Nutritional interventions play a central role in the treatment and management of inflammatory bowel disease (IBD) in children. Although malnutrition is a common presenting sign of IBD, nutritional interventions have focused not only on correction of the malnourished state but also on treatment of the primary disease. RECENT FINDINGS: Exclusive enteral nutrition (EEN) has been the primary therapy utilized in pediatric IBD specifically, Crohn's disease. This intervention provides total calories from formula meeting complete macronutrient and micronutrient needs for a patient. EEN has been shown to improve growth and correct micronutrient deficiencies as well as improve comorbid conditions like osteopenia and anemia. EEN has also been shown to be equally as efficacious as steroids in inducing remission with better mucosal healing. SUMMARY: EEN is a primary therapy in IBD. Both the North American and European Societies of Pediatric Gastroenterology, Hepatology and Nutrition consider EEN as first line therapy for inducing remission in Crohn's disease. PMID- 30004947 TI - Feeding tubes in children. AB - PURPOSE OF REVIEW: A practical guide to different feeding tubes available for nutritional support in children, focused on indications, placement methods and complications. RECENT FINDINGS: Enteral nutritional support refers to the delivery of nutrition into the gastrointestinal tract distal to the oesophagus. Different feeding tubes are available for exclusive or supplemental nutritional support in children who are unable to independently sustain their own growth, nutritional and hydration status. Gastric feeding is the first choice; however, jejunal feeding provides a good alternative route in the presence of contraindications or intolerance. Feeding tubes can be short or long term: nasogastric and nasojejunal tubes provide short-term nutrition support, gastrostomy and jejunostomy tubes, long-term enteral feeding. The latter are established surgically through the formation of a stoma, an artificial connection between gastric or jejunal lumen and the abdominal wall, performed either endoscopically (percutaneous endoscopic gastrostomy, percutaneous endoscopic gastrojejunostomy) or surgically (gastrostomy, direct jejunostomy). Awareness of different available options, technical considerations and potential risks will inform the decision-making process for an individual patient to ensure the correct balance between adequate enteral nutritional and unnecessary morbidity. SUMMARY: Successful administration of nutrition support requires knowledge of the correct indication, route and specific functional details of the appropriate feeding tube. PMID- 30004948 TI - The Effect of Problematic Internet Use, Social Appearance Anxiety, and Social Media Use on Nursing Students' Nomophobia Levels. AB - This study examined the effect of problematic Internet use, social appearance anxiety, and social media use on nursing students' nomophobia levels. This study was conducted with 755 undergraduate nursing students. Sociodemographic data were evaluated using percentages and means. The effect of problematic Internet use, social appearance anxiety, and social media use on nomophobia levels was assessed by simple linear regression analysis. The mean age of participants was 21.4 +/- 1.3; 82.5% were female, and 59.7% (n = 450) had adequate incomes. According to the regression analysis, nomophobia levels have a strong, positive, and significant relationship with the variables of problematic Internet use (beta = .39, P < .000), social appearance anxiety (beta = .27, P < .001), and social media dependency (beta = .28, P < .001). Examining the correlation between nursing students' problematic Internet use, social appearance anxiety, and social media use levels, nomophobia levels had a positively moderate relationship with problematic Internet use (r = 0.259, P < .001), social appearance anxiety (r = 0.320, P < .001), and social media use levels (r = 0.433, P < .001). There is a direct correlation between nomophobia levels and the variables of problematic Internet use, social appearance anxiety, and social media use. PMID- 30004949 TI - How deep is your lesion? Extreme guideliner V3 intubation through RIMA graft to treat a distal left anterior descending artery stenosis. PMID- 30004951 TI - Did ultrasound fulfill the promise of safety in regional anesthesia? AB - PURPOSE OF REVIEW: Ultrasound guidance has become the accepted standard of practice for peripheral regional anesthesia. Despite evidence supporting the efficacy of ultrasound-guided regional anesthesia, its impact on patient safety has been less clear. RECENT FINDINGS: Evidence has been consistent that ultrasound guidance reduces the incidence of vascular injury, local anesthetic systemic toxicity, pneumothorax and phrenic nerve block. Within the limited global scope of the epidemiology and etiologic complexity of perioperative (including block-related) peripheral nerve injury, there has not been consistent evidence that ultrasound guidance is associated with a reduced incidence of nerve injury. However, a recently published retrospective cohort study has demonstrated that the incidence of short-term nerve injury was decreased with ultrasound guidance compared with nerve stimulation. Ultrasound has led to development of novel blocks, approaches and refinement of existing ones, which may contribute to patient safety. SUMMARY: Ultrasound has revolutionized the way we approach regional anesthesia and contributed to patient safety. It is important to note that patient safety does not hinge on one single technology. Patient safety in regional anesthesia relies on a well trained practitioner to pay meticulous attention to indication, block and patient selection, anatomy, pharmacology, equipment and technique. PMID- 30004950 TI - Management of cardiopulmonary disease in patients with systemic sclerosis: cardiorheumatology clinic and patient care standardization proposal. PMID- 30004952 TI - Traumatic brain injured patients: primum non nocere. AB - PURPOSE OF REVIEW: Traumatic brain injury (TBI) remains an unfortunately common disease with potentially devastating consequences for patients and their families. However, it is important to remember that it is a spectrum of disease and thus, a one 'treatment fits all' approach is not appropriate to achieve optimal outcomes. This review aims to inform readers about recent updates in prehospital and neurocritical care management of patients with TBI. RECENT FINDINGS: Prehospital care teams which include a physician may reduce mortality. The commonly held value of SBP more than 90 in TBI is now being challenged. There is increasing evidence that patients do better if managed in specialized neurocritical care or trauma ICU. Repeating computed tomography brain 12 h after initial scan may be of benefit. Elderly patients with TBI appear not to want an operation if it might leave them cognitively impaired. SUMMARY: Prehospital and neuro ICU management of TBI patients can significantly improve patient outcome. However, it is important to also consider whether these patients would actually want to be treated particularly in the elderly population. PMID- 30004954 TI - New blocks for the same old joints. AB - PURPOSE OF REVIEW: New block techniques are being constantly developed or old techniques modified to improve outcomes after surgery. This review discusses the reasons why new block techniques need to be developed to match the needs of contemporary anesthetic practice. RECENT FINDINGS: New block techniques have been developed for joint surgeries of both upper and lower extremities. New upper extremity blocks focus on decreasing the risk of complications like diaphragmatic paresis and improving the quality of blocks. Techniques for lower extremity surgeries are being performed distally, closer to the joints, to minimize weakness of the extremity. A review of the available evidence for these techniques is undertaken to get an understanding of the indications and limitations of these techniques. SUMMARY: Future studies need to be undertaken to further refine these techniques and produce evidence of support for analgesic efficacy, safety, and reliability. PMID- 30004953 TI - Stratification of neuropathic pain patients: the road to mechanism-based therapy? AB - PURPOSE OF REVIEW: It has been demonstrated that within one pain entity, patients may report highly heterogenic sensory signs and symptoms. Although mechanism might differ fundamentally between those patients, yet the treatment recommendations are uniform throughout all phenotypes. Therefore, the introduction of new stratification tools could pave the way to an individualized pain treatment. RECENT FINDINGS: In the past, retrospective stratifications of patients successfully identified responders to certain pharmacological treatments. This indicated predictive validity and reliability of this classification tool in those patient subgroups. Further on, these observations have been confirmed in prospective studies. SUMMARY: This review focusses on recent achievements in neuropathic pain and suggests a promising implementation of an individualized pharmacological therapy in the future. PMID- 30004955 TI - Regional anesthesia by nonanesthesiologists. AB - PURPOSE OF REVIEW: As the evidence supporting the notion that regional anesthesia improves patient outcomes grows, utilization of regional anesthesia techniques has similarly increased. Best care should not be restricted by the background of care providers, however, the evidence replicating benefits of regional anesthesia when it is delivered by nonanesthesiologists is unclear. In this review, the provision of regional anesthesia by nonanesthesiologists is discussed so that readers can come to their own conclusions. RECENT FINDINGS: Regional anesthesia procedures are performed by nonanesthesiology physicians such as emergency physicians, critical care specialists, and surgeons. Patients benefit from the provision of regional anesthesia by these groups, but inconsistencies exist in training, service provision, and collaboration between these specialties and anesthesiologists. Nonphysician anesthesia providers also provide regional anesthesia. There are limited data on outcomes or benefits of this nonphysician provided service, but consideration of team-based care and alternative models of care based upon geographical need is worthwhile. SUMMARY: The provision of regional anesthesia requires the accumulation of a suitable knowledge, skills, and behaviors that can be taught. Whilst it may not be appropriate for all techniques to be performed by all individuals, the possession of these competencies with the appropriate training and quality assurance means that more patients may ultimately benefit from the provision of regional anesthesia services. PMID- 30004956 TI - Neuroanesthesiology: building the path to superior clinical care through research and education. PMID- 30004957 TI - Effect of the Meibomian Gland Squeezer for Treatment of Meibomian Gland Dysfunction. AB - PURPOSE: To investigate the effect of the meibomian gland squeezer for treatment of meibomian gland dysfunction (MGD). METHODS: Seventy patients (140 eyes) with MGD were randomly divided into 2 groups: 36 patients who were treated by the meibomian gland squeezer as the treatment group and 34 patients were selected as the control group. Patients were evaluated at baseline, and 2-week and 1-month visits for subjective symptoms, objective signs and pain assessments, including ocular symptom scores, Ocular Surface Disease Index, tear breakup time, corneal fluorescein staining, Schirmer scores with no anesthetic (Schirmer I test), meibum quality, meibum expressibility, and Numeric Rating Scale-11. RESULTS: Sixty-five patients were followed in the study, and mean (+/-SD) age was 57.0 (+/ 12.6) years. Compared with baseline, the 2 groups had varying degrees of improvement in ocular symptom scores and Ocular Surface Disease Index at the 2 week and 1-month visits; there was a statistically significant difference between groups (P < 0.001). At the 1-month visit, the treatment group showed a greater improvement in the breakup time (3.8 +/- 1.6 vs. 1.8 +/- 1.0 seconds, P < 0.001), corneal fluorescein staining (-2.1 +/- 2.13 vs. -0.9 +/- 1.3, P = 0.03), Schirmer I test (5.3 +/- 2.9 vs. 2.3 +/- 2.8 mm, P < 0.001), meibum quality (-7.5 +/- 2.9 vs. -5.3 +/- 2.4, P = 0.004), and meibum expressibility (-1.2 +/- 0.8 vs. -0.7 +/ 0.4, P = 0.007). In the treatment group, the mean (+/-SD) of total pain scores was 2.4 +/- 1.0, which indicated that mild pain was still predominant under topical anesthesia. CONCLUSIONS: The meibomian gland squeezer may be safe, effective, and helpful for treatment of MGD and may offer an attractive treatment option for some patients with MGD, although it can cause mild pain or discomfort. PMID- 30004958 TI - Infectious Keratitis After Ocular Surface Stem Cell Transplantation. AB - PURPOSE: To describe the rate, clinical/microbiological characteristics, and outcomes of infectious keratitis in eyes with limbal stem cell deficiency after ocular surface stem cell transplantation (OSST). METHODS: In this retrospective chart review of 278 eyes that underwent OSST between January 2006 and December 2016, eyes treated for previous infectious keratitis (bacterial, fungal, or viral) were included. Demographics, risk factors, course, microbiological characteristics, and outcomes were assessed. RESULTS: A total of 52 eyes (18.7%) of 48 patients (28 men and 20 women) developed 75 episodes (culture-proven or presumed) of infectious keratitis (range 1-4 episodes) with mean follow-up of 5.3 +/- 3.6 years after OSST. The most common limbal stem cell deficiency etiologies included chemical/thermal (27 episodes), Stevens-Johnson syndrome (19 episodes), aniridia (8 episodes), and mucous membrane pemphigoid (8 episodes). There were 44 (58.7%) bacterial keratitis episodes, 24 (32%) fungal keratitis episodes, and 7 (9.3%) HSV keratitis episodes. Gram-positive bacteria (79%) and Candida species (73%) were the most common bacterial and fungal pathogens. Before infection, 33% had an epithelial defect, 69% had a bandage contact lens, 91% were on systemic immunosuppression, and 25% recently had undergone ocular surgery (<3 months). Although 75% resolved with antimicrobial treatment, 25% required a therapeutic keratoplasty (TPK; 2 cases needed multiple TPK). CONCLUSIONS: Despite successful OSST surgery, infectious keratitis is relatively common, and aggressive medical/surgical therapy is warranted. Prophylactic topical antibiotics and a cicatrizing conjunctivitis diagnosis may account for the high proportion of fungal keratitis in this population. PMID- 30004959 TI - Short Axial Length and Iris Damage Are Associated With Iris Posterior Synechiae After Descemet Membrane Endothelial Keratoplasty in Asian Eyes. AB - PURPOSE: To evaluate the frequency and severity of iris posterior synechiae after Descemet membrane endothelial keratoplasty (DMEK) and to investigate possible causes of iris posterior synechiae. METHODS: Twenty-three eyes were investigated in 20 Asian patients who underwent DMEK 1 month after phacoemulsification and intraocular lens implantation surgery. A preexisting iris damage score was defined by iris damage and classified into 5 grades. Six months after DMEK, the iris posterior synechiae severity score was evaluated based on the extent of posterior synechiae, according to every 45 degrees of the pupillary rim (posterior synechiae score, 0-8). Correlations were analyzed between the posterior synechiae score and preexisting factors (preexisting iris damage score, axial length [AXL], anterior chamber depth, and anterior chamber volume, both before and after cataract surgery). RESULTS: Iris posterior synechiae appeared in 20 of 23 eyes (87.0%). Best spectacle-corrected visual acuity significantly improved at 6 months after DMEK (P < 0.001). Endothelial cell density was 1596 +/ 530 cells/mm (P < 0.001); loss of cell density was 37.8 +/- 19.9% at 6 months. Single regression analysis showed that the onset of iris posterior synechiae was correlated with the preexisting iris damage score (P = 0.006, r = 0.55), AXL (P < 0.001, r = -0.71), anterior chamber depth (P < 0.001, r = -0.70), and anterior chamber volume before cataract surgery (P < 0.001, r = -0.79). CONCLUSIONS: Iris posterior synechiae after DMEK frequently appeared in Asian eyes with shorter AXLs or a damaged iris. PMID- 30004960 TI - Just What Do We Know About Corneal Collagen Turnover? PMID- 30004961 TI - "Eye Dropping"-A Case Report of Transconjunctival Lysergic Acid Diethylamide Drug Abuse. AB - PURPOSE: To report a case of bilateral toxic corneal and conjunctival epitheliopathy secondary to administration of filter paper impregnated with lysergic acid diethylamide (LSD) in the inferior conjunctival fornices. METHODS: This is a single case report of an 18-year-old man who presented to the emergency department with acute, bilateral eye pain and redness of 24 hours. The patient admitted to placing folded strips of blotting paper impregnated with LSD into the inferior fornices of his eyes the previous night. RESULTS: The patient was found to have localized bilateral corneal and conjunctival abrasions with underlying subconjunctival hemorrhage. Conjunctival abrasion was "kissing," involving the bulbar and palpebral conjunctiva, corresponding to the presumed location of the filter paper. There was no corneal stromal opacification. He was lost to follow up within 1 week of initial presentation but stated that his symptoms improved. CONCLUSIONS: To the best of our knowledge, this is the first reported case of bilateral hemorrhagic conjunctival abrasion and corneal abrasion secondary to LSD. "Kissing" conjunctival lesions, which have been previously reported with heroin use, should raise suspicion for drug abuse. PMID- 30004962 TI - Multicenter Study of Intense Pulsed Light Therapy for Patients With Refractory Meibomian Gland Dysfunction. AB - PURPOSE: To evaluate the efficacy of intense pulsed light (IPL) therapy combined with meibomian gland expression (MGX) for refractory meibomian gland dysfunction (MGD) in a prospective study conducted at 3 sites in Japan. METHODS: Patients with refractory obstructive MGD were enrolled and underwent 4 to 8 IPL-MGX treatment sessions at 3-week intervals. Clinical assessment included the Standard Patient Evaluation of Eye Dryness questionnaire; noninvasive breakup time of the tear film and interferometric fringe pattern as determined by tear interferometry; lid margin abnormalities, fluorescein breakup time of the tear film, corneal and conjunctival fluorescein staining (CFS), and meibum grade as evaluated with a slit-lamp microscope; meibomian gland morphology (meiboscore); and tear production as measured by the Schirmer test without anesthesia. RESULTS: Sixty-two eyes of 31 patients (17 women, 14 men; mean age +/- SD, 47.6 +/- 16.8 years) were enrolled. The Standard Patient Evaluation of Eye Dryness score (P < 0.001), noninvasive breakup time (P < 0.001), and interferometric fringe pattern (P < 0.001) were significantly improved after therapy, with 74% of eyes showing a change in the interferometric fringe pattern from 1 characteristic of lipid deficiency to the normal condition. Meibum grade, lid margin abnormality scores, fluorescein breakup time, and CFS were also significantly improved (P < 0.001, P < 0.001, P < 0.001, and P = 0.002, respectively) after treatment, whereas the meiboscore and Schirmer test value remained unchanged. CONCLUSIONS: IPL-MGX ameliorated symptoms and improved the condition of the tear film in patients with refractory MGD and is therefore a promising treatment option for this disorder. PMID- 30004964 TI - Pimavanserin for Psychotic Symptoms in People With Parkinsonism: A Second Chart Review. AB - INTRODUCTION: Pimavanserin (Pim) is a 5HT2A inverse agonist that is the only Food and Drug Administration-approved treatment for Parkinson disease (PD) psychosis. The published open-label experience is limited. METHODS: This report is a chart review of all patients who were started on the drugs since the one earlier report on 15 patients. All patients were included, whether or not they completed 6 weeks of treatment, the time required for maximum benefit found in the published phase 3 trial. RESULTS: Twenty-six patients are reported. Three patients had dementia with Lewy bodies; one had an atypical parkinsonism; 22 had PD, including one with schizophrenia and neuroleptic exacerbated, dopamine transporter scan-positive idiopathic PD; and another had PD complicated by strokes. Six stopped before 6 weeks due to adverse effects, including 1 with worsened psychosis. Eighteen completed at least 6 weeks of treatment. Of these, 3 stopped due to lack of efficacy and 3 due to worsened psychosis. Twelve found it helpful. Of the 18 who took Pim for at least 6 weeks, 12 improved and continue to take it. CONCLUSIONS: Almost 50% of parkinsonian patients with psychotic symptoms found Pim to be a useful medication, which they continue to take. Reasons for intolerance varied and were thought to be unrelated to the drug. PMID- 30004965 TI - What Matters Most When Considering Noninvasive Ventilation for Patients With Do Not-Intubate or Comfort-Measures-Only Orders? PMID- 30004963 TI - Effect of Cataract Surgery on the Refractive Index of the Cornea Estimated by Optical Pachymetry. AB - PURPOSE: To noninvasively estimate the refractive index (RI) of the central cornea along the antero-posterior direction before and after routine phacoemulsification. METHODS: Using 2 setups for a standard optical pachymeter, the ratio of observed optical section widths (OSWs) is a function of the RI. Thus, the corneal RI could be estimated using a calibration equating OSW ratios with known RI values. The OSW was measured by 2 observers for 1) normal subjects for estimating interoperator errors and effects of sex and age on the RI and 2) before and after patients underwent routine phacoemulsification. RESULTS: First, the average interoperator difference (DeltaRI) was +0.0005 (SD = +/-0.0044, 95% confidence limit, -0.0002 to +0.0012). The root mean square difference between measurements obtained by the observers was 0.0032. There was a significant correlation between the DeltaRI and the mean of each pair of measured values (r = -0.172, n = 153, P = 0.003). The mean RI (+/-SD) was 1.435 (+/-0.005, n = 82) for females and 1.429 (+/-0.005, n = 71) for males. There was no significant between sex difference or association between the RI and age (mean age, +/-SD, and range, 44.31, 20.38, and 19-88 years, respectively). Second, the difference (y) between the preoperative (x) and postoperative RI was, y = 0.844x - 1.203 (r = 0.694, n = 31, P <= 0.001) according to observer 1 and according to observer 2, y = 0.755x - 1.108 (r = 0.681, n = 31, P <= 0.001). CONCLUSIONS: The RI of the human cornea along the antero-posterior axis can be estimated using a modified application of traditional optical pachymetry. The average values for the corneal RI were higher compared with those reported in previous reports. The change in the RI after phacoemulsification could be predicted from the preoperative value. PMID- 30004966 TI - Making the Medicine Go Down: Salt or Sugar? PMID- 30004967 TI - Glucose Monitoring in the ICU: What Is Really Needed? PMID- 30004969 TI - Body Composition After Critical Illness: Fat in All the Wrong Places? PMID- 30004968 TI - Trends for Palliative Care Use in the Prolonged Mechanically Ventilated Patient: Are We Moving Toward a Proactive Approach? PMID- 30004970 TI - Sepsis Redefined...Again. PMID- 30004971 TI - Sepsis-The "Gift" That Keeps on Giving, Regardless of Age. PMID- 30004972 TI - Improving Evidence-Based Medical Care in Developing Countries. PMID- 30004973 TI - Blue Light Illuminates a Novel Sepsis Treatment. PMID- 30004976 TI - The authors reply. PMID- 30004974 TI - The Potential Role of Steroid-Induced Cerebral Vasospasm in the Pathogenesis of Delayed Cerebral Injury in Bacterial Meningitis. PMID- 30004975 TI - When Simply Informing May Not Suffice. PMID- 30004977 TI - Fluid Responsiveness: Goal-Directed Care or Resuscitative Guide to Salt Water Drowning? PMID- 30004978 TI - The authors reply. PMID- 30004979 TI - Is the Tail Wagging the Dog in Sepsis? PMID- 30004980 TI - The authors reply. PMID- 30004981 TI - Uncertainty in Diagnosis Leads to Underestimates of Performance. PMID- 30004982 TI - The authors reply. PMID- 30004983 TI - Prevent Thrombus Formation: What We Are Doing. PMID- 30004984 TI - The authors reply. PMID- 30004985 TI - How Would You Evaluate the Quality of Uncontrolled Studies in a Meta-Analysis? PMID- 30004987 TI - Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II: Erratum. PMID- 30004986 TI - The authors reply. PMID- 30004988 TI - Real-world performance and utility of a noninvasive gene expression assay to evaluate melanoma risk in pigmented lesions. AB - About 3 million surgical pigmented skin lesion biopsies are performed each year in the USA alone to diagnose fewer than 200 000 new cases of invasive melanoma and melanoma in situ using the current standard of care that includes visual assessment and histopathology. A recently described noninvasive adhesive patch based gene expression rule-out test [pigmented lesion assay (PLA)] may be helpful in identifying high-risk pigmented skin lesions to aid with surgical biopsy decisions. The main objective of this utility study was to determine the real world clinical performance of PLA use and assess how the PLA changes physician behavior in an observational cohort analysis of 381 patients assessed with the PLA. All (100%) of 51 PLA(+) test results were clinically managed with surgical biopsy. Of these, 19 (37%) were melanomas, corresponding to a number needed to biopsy of 2.7 and a biopsy ratio of 1.7. All melanomas were histopathologically classified as melanoma in situ or stage 1. Nearly all (99%) of 330 PLA(-) test results were clinically managed with surveillance. None of the three follow-up biopsies performed in the following 3-6 months, were diagnosed as melanoma histopathologically. The estimated sensitivity and specificity of the PLA from these data sets are 95 and 91%, respectively. Overall, 93% of PLA results positive for both LINC00518 and PRAME were diagnosed histopathologically as melanoma. PRAME-only and LINC00518-only lesions were melanomas histopathologically in 50 and 7%, respectively. The PLA alters clinical management of pigmented lesions and shows high clinical performance. The likelihood of positive histopathologic diagnosis of melanoma is higher in PLA results that are positive for both LINC00518 and PRAME. PMID- 30004989 TI - Compromised vitamin D receptor signalling in malignant melanoma is associated with tumour progression and mitogen-activated protein kinase activity. AB - The aims of this study were to investigate, in cutaneous malignant melanoma (MM), the integrity of nuclear vitamin D receptor (VDR) signalling, as implied by VDR subcellular location; to investigate the relationship between VDR and tumour progression and the inhibitory effect on VDR by mitogen-activated protein kinase (MAPK) overactivity. Archived tissue from 34 benign melanocytic naevi, 149 MMs and 44 matched metastases were stained by immunohistochemistry for VDR and a subset of primary MMs were stained for phosphorylated-extracellular signal regulated kinase as a marker of MAPK activity. MM cell lines were investigated to show the subcellular location of VDR and cell viability in response to ligand+/ MAPK inhibitor. Benign melanocytic naevi showed mainly a strong nuclear VDR staining in contrast to MM where decreased nuclear and emergent cytoplasmic VDRs were associated with malignant progression in terms of dermal invasion and metastasis. MMs that retained exclusive nuclear VDR at the tumour base did not metastasize, a potentially important prognostic indicator. Decreased nuclear VDR correlated with increased cytoplasmic staining, suggesting the failure of nuclear entry as a primary cause of defective VDR signalling in MM. The histological subset analysis and MM cell line studies confirmed the inhibitory effect of MAPK activity on VDR signalling, but the pattern of VDR subcellular localization suggested failure of VDR nuclear entry as a primary effect of MAPK activity rather than direct inhibition of VDR-regulated transcription. Furthermore, high MAPK activity in tumours expressing cytoplasmic VDR was associated with worsened prognosis. PMID- 30004990 TI - Unclassifiable interstitial lung disease: from phenotyping to possible treatments. AB - PURPOSE OF REVIEW: Accurate diagnosis of interstitial lung diseases (ILDs) can be challenging, and a substantial percentage of ILD patients remain unclassifiable even after thorough assessment by an experienced multidisciplinary team. In this review, we summarize the recent literature on the definition, prevalence, diagnosis, treatment, and prognosis of unclassifiable ILD, and also discuss important current issues and provide future perspectives on the classification of ILD. RECENT FINDINGS: Approximately 12% of patients with ILD are considered unclassifiable, with large variability across previous studies that is in part secondary to inconsistent definitions of unclassifiable ILD and other ILD subtypes. A recent International Working Group suggested that unclassifiable ILD should be defined by the absence of a leading diagnosis that is considered more likely than not after multidisciplinary discussion of all available information. Clinical features and outcomes of unclassifiable ILD are intermediate between idiopathic pulmonary fibrosis and nonidiopathic pulmonary fibrosis ILD cohorts, and choices for pharmacotherapy should be considered on a case-by-case basis. SUMMARY: Recent studies have provided additional data on the clinical features and prognosis of unclassifiable ILD, but also highlight the many uncertainties that still exist in ILD diagnosis and classification. New tools are needed to more accurately characterize patients with unclassifiable ILD. PMID- 30004991 TI - Why do people die from pulmonary sarcoidosis? AB - PURPOSE OF REVIEW: In sarcoidosis, the design and validation of an appropriate risk stratification strategy is hampered by the considerable variability in initial presentation, disease evolution, and outcome. Although spontaneous resolution of the disease is described in a large proportion of patients, approximately 20-30% would present with chronic or progressive lung disease that has been associated with morbidity and mortality. Higher morbidity and mortality can be related to both the disease severity and extent as well as its treatments. We review the utility of integration of clinical, pathological, and radiological features of pulmonary sarcoidosis to detect pulmonary sarcoidosis patient at risk of developing severe, fibrotic lung disease. RECENT FINDINGS: Recently published studies suggested a mortality rate of 11-14 per 1000 person-years. Demographic characteristics such as age, sex, and race may play a role but conflicting evidence are reported depending on the origin of the population. To date, there are no tools that can reliably predict the exact group of pulmonary sarcoidosis patients to progress to fibrosis. Imaging contributes significantly to the diagnosis and management of patients with sarcoidosis as it can provide useful information regarding the discrimination between reversible and irreversible disease, the extent of the parenchymal damage and the presence of possible complications. Symptoms and lung function tests are the rest of the key determinants and their change over time should be considered. SUMMARY: This review concentrates on the definition of advanced pulmonary sarcoidosis and determinants of mortality in the pulmonary sarcoidosis group of patients. PMID- 30004992 TI - Risk stratification in pulmonary arterial hypertension. AB - PURPOSE OF REVIEW: Periodic risk stratification is recommended for patients with pulmonary arterial hypertension (PAH). The purpose of this article is to review the available risk stratification tools in PAH. RECENT FINDINGS: Validated tools, such as the REVEAL (Registry to Evaluate Early And Long-term PAH Disease Management) score or European Society of Cardiology/European Respiratory Society (ESC/ERS) risk assessment table incorporate clinical, exercise, imaging, and hemodynamic variables to obtain a multidimensional estimate of prognosis. Recent studies from REVEAL and European registries have further validated these tools and improved our understanding of prognostic factors in PAH. Serial risk assessment over time, especially after treatment initiation or modification, provides more useful information than at a single time point, with changes in risk profiles being particularly informative. A brief, simplified approach includes counting the number of ESC/ERS low-risk criteria achieved, with 3 or 4 low-risk criteria associated with an excellent prognosis. When a more precise estimation of risk is desired, the REVEAL score can delineate five risk groups with 1-year survival rates between 97.3% (low risk) and 50.2% (very high risk). SUMMARY: The REVEAL and ESC/ERS risk table are useful, validated, multidimensional risk stratification tools that should be periodically applied to patients with PAH in practice. PMID- 30004993 TI - Multisystemic manifestations of sarcoidosis and comorbidities. PMID- 30004994 TI - Relationship between cerebral microbleeds location and cognitive impairment in patients with ischemic cerebrovascular disease. AB - Cerebral microbleeds (CMBs) have been identified as an important manifestation and diagnostic marker of cerebrovascular disease, but there are also some controversies about the impact of CMBs on cognition. The current cross-sectional study aimed to clarify the relationship between CMBs and cognitive impairment in patients with ischemic cerebrovascular disease. One hundred and fifty patients with lacunar infarction or transient ischemic attack were screened, and all of them were scanned by brain MRI. In the end, 125 patients who were divided into a CMBs group and a non-CMBs group were selected and completed the cognitive tests. Cognitive Function Assessment was performed using the Montreal Cognitive Assessment scale. Images of CMBs were assessed using a susceptibility-weighted imaging measure. Associations between cognitive function and the location of CMBs were determined. There was no significant difference in the demographic and clinical features between the two groups of patients. Compared with participants with no CMBs, the CMBs group showed a greater impairment in cognitive parameters and specifically in performance on three cognitive domains: visual space and executive function, memory, and abstract thinking. Basal ganglia-thalamic was associated with memory and visual space and executive function. Relationships between cortical-subcortical and abstract thinking became significant. Furthermore, the mixed region was related to memory, abstract thinking, and visual space and executive function. In summary, patients with CMBs had a greater impairment in cognitive parameters in ischemic cerebrovascular disease and CMBs location was associated with different cognitive parameters, adding to our understanding of the cognitive effects of CMBs in cerebrovascular disease. PMID- 30004995 TI - Mapping an innovative future: Pioneering the healing organization. PMID- 30004997 TI - A NOVEL CASE SERIES OF NMNAT1-ASSOCIATED EARLY-ONSET RETINAL DYSTROPHY: EXTENDING THE PHENOTYPIC SPECTRUM. AB - PURPOSE: To report two siblings with NMNAT1-associated retinopathy presenting with a later onset and milder phenotype than previously described. METHODS: Retrospective case series of two siblings. The authors describe two cases of early-onset retinal dystrophy caused by disease-causing NMNAT1 variants. Visual acuity, clinical examination, and retinal imaging including color fundus photography, spectral domain optical coherence tomography, and fundus autofluorescence were performed. Both cases underwent full-field and pattern electroretinography incorporating the International standards. RESULTS: Two siblings were found to harbor the variants c.53A>G, p.(Asn18Ser) and c.769G>A, p.(Glu257Lys) in NMNAT1 after retinal dystrophy panel gene testing. Both had good visual acuity until the ages of 6 and 11 years, respectively, with subsequent gradual worsening into their twenties. At the ages of 10 and 16 years, respectively, electroretinograms indicated generalized rod and cone system dysfunction of moderate severity, with pattern electroretinography evidence of severe macular involvement. Repeat testing at the ages of 26 and 33 years revealed only mild worsening of rod photoreceptor function in both. CONCLUSION: NMNAT1-associated retinopathy has previously only been described as a typical form of Leber congenital amaurosis, with poor visual acuity from birth associated with nystagmus, characteristic macular atrophy, and intraretinal pigmentation from birth. Here, we present two siblings with a novel, later onset, and far milder phenotype. We suggest that this may be due to the two missense NMNAT1 variants resulting in milder reduction of NMNAT1 enzymatic activity. These cases extend the phenotypic spectrum associated with NMNAT1 and further highlight the clinical heterogeneity associated with inherited retinal diseases. PMID- 30004996 TI - Relationship Between Advanced Maternal Age and Timing of First Developmental Evaluation in Children with Autism. AB - OBJECTIVE: Mothers of advanced maternal age (AMA) at childbirth (age >=35 years) may have different perceptions of autism spectrum disorder (ASD) risk, independent of sociodemographic factors, that may affect ASD identification. We aimed to estimate associations between AMA and both age of a child's first evaluation noting developmental concerns and time from first evaluation to first ASD diagnosis. METHODS: We used data for 8-year-olds identified with ASD in the 2008 to 2012 Autism and Developmental Disabilities Monitoring Network. We estimated differences in age at first evaluation noting developmental concerns and time to first ASD diagnosis by AMA using quantile and Cox regression. RESULTS: Of 10,358 children with ASD, 19.7% had mothers of AMA. AMA was associated with higher educational attainment and previous live births compared with younger mothers. In unadjusted analyses, AMA was associated with earlier first evaluation noting developmental concerns (median 37 vs 40 mo) and patterns in time to first evaluation (hazard ratio: 1.12, 95% confidence interval: 1.06 1.18). Associations between AMA and evaluation timing diminished and were no longer significant after adjustment for socioeconomic and demographic characteristics. Children's intellectual disability did not modify associations between AMA and timing of evaluations. CONCLUSION: Advanced maternal age is a sociodemographic factor associated with younger age of first evaluation noting developmental concerns in children with ASD, but AMA was not independently associated likely, because it is a consequence or cofactor of maternal education and other sociodemographic characteristics. AMA may be a demographic factor to consider when aiming to screen and evaluate children at risk for ASD. PMID- 30004998 TI - MOSAICISM AS A PROPOSED MECHANISM FOR ASYMMETRIC RETINAL TESSELLATIONS. AB - BACKGROUND/PURPOSE: Report a case of markedly asymmetric retinal tessellations and propose mosaicism as a mechanism. METHODS AND RESULTS: A 59-year-old pseudophakic woman presented with uncorrected 20/20 vision and was found to have markedly different retinal tessellation appearances in both eyes. The axial lengths were 25.66 mm and 25.88 mm in the right and left eyes, respectively, and no significant asymmetrical choroidal thinning was seen on optical coherence tomography or optical coherence tomography angiography. Fluorescein angiogram showed significant hyperfluorescence, representing the underlying choroid, which correlated with the tessellation patterns in the left eye. She had no other ocular or systemic findings such as stripes or whorled skin. CONCLUSION: This is the first reported case of markedly asymmetric retinal tessellation patterns that are not due to asymmetric axial myopia or choroidal thinning. We propose that mosaicism is a possible mechanism causing this finding. PMID- 30004999 TI - Aquaporin-4 Serostatus and Visual Outcomes in Clinically Isolated Acute Optic Neuritis. AB - BACKGROUND: Aquaporin-4 antibodies (AQP4-Ab) are associated with neuromyelitis optica spectrum disorder (NMOSD) and typically this disorder has a poor visual prognosis as a result of optic neuritis (ON). Our aim was to report the clinical features at onset and final visual outcomes at 6 months of patients with ON who were positive for AQP4-Ab vs. those who were negative for AQP4-Ab. METHODS: Retrospective cohort study. AQP4-Ab were tested by indirect immunofluorescence in 57 patients with a first episode of ON. All patients initially were referred for consideration of multiple sclerosis ON (MSON), NMOSD, or any other inflammatory central nervous system disorder during follow-up (41.31 +/- 24.32 months). Our patients were diagnosed as having NMOSD, MSON, chronic relapsing inflammatory ON, and single isolated ON. Risk factors associated with visual outcomes of ON patients were assessed through an ordinal regression model. RESULTS: Positive AQP4-Ab were associated with male sex (P = 0.02), earlier age of onset (P = 0.01), and myelitis relapses (P = 0.04). Seronegative group had fewer recurrences of ON than the seropositive group (35% vs 58%, P = 0.14). Patients that were positive for AQP4-Ab did not have worse visual acuity at baseline and after 6 months. However, poor visual acuity during first attack was associated with a worse visual acuity at 6 months (odds ratio = 2.28, 95% CI [1.58-3.28], P = 0.03). CONCLUSIONS: At 6 months, positive AQP4-Ab vs negative AQP4-Ab patients no evidence of poorer visual acuity. Lower visual acuity at baseline was associated with poor visual recovery at 6 months. PMID- 30005000 TI - Clinical Approach to Community-acquired Pneumonia. AB - Community-acquired pneumonia (CAP) remains a major health problem worldwide. The incidence of pneumonia increases with both age and the presence of specific risk factors, which lead to increased health care costs. However, although there is some controversy over the observed trend in CAP mortality over recent decades, it is clear that mortality in CAP patients who require intensive care unit care remains high. The increase in antibiotic resistance is an important global health problem that needs to be addressed, especially for pneumococcus the most frequent pathogen of CAP. The prudent use of current antibiotics will help to limit the spread of antibiotic resistant clones of pneumococcus. Pneumococcal and influenza vaccinations remain the primary strategy for the prevention of CAP, especially in an at-risk population. This article reviews CAP, with a focus on epidemiology, diagnosis, prognostic factors, microbial etiology, therapy, complications, and prevention. PMID- 30005001 TI - Examining Factors Related to Health-Related Quality of Life in People With Parkinson's Disease. AB - PURPOSE: Parkinson's disease (PD) results in a range of dysfunctions and disabilities as it progresses to later stages. All these not only affect a patient's physical well-being but also emotional, social, and spiritual well being. To tailor interventions that can address these concerns, this study aimed to examine the impacts of PD on their health-related quality of life (HRQOL). DESIGN: A cross-sectional study with 123 PD patients. METHODS: Measures included the following: Hospital Anxiety and Depression Scale, Unified PD Rating Scale Motor Examination, Hoehn and Yahr Stage, PD Questionnaire-8. Associating factors of HRQOL was examined using stepwise linear regression. FINDINGS: Psychological distress and functional impairment are significantly associated with the HRQOL of the PD population. Psychological distress is associated most to the variance of HRQOL (42.4%). CONCLUSION: Considering that PD is chronic, rehabilitation programs should be applied to address not just functional but also psychosocial needs of PD patients. CLINICAL RELEVANCE: Early recognition and management of psychological distress in PD patients is indispensable to promote their HRQOL. PMID- 30005002 TI - A NOVEL SCLERAL DEPRESSOR FOR USE IN VITRECTOMY SURGERY. PMID- 30005004 TI - FULL DIAGNOSTIC VITRECTOMY WITH POSTERIOR VITREOUS DETACHMENT INDUCTION FOR THE DIAGNOSIS OF VITRITIS DUE TO UNCERTAIN ETIOLOGY. AB - PURPOSE: To report on the diagnostic outcomes and safety of full diagnostic vitrectomy (FDV) with surgical posterior vitreous detachment induction for diagnosing vitritis of uncertain etiology. METHODS: Forty-nine patients underwent primary FDV using the cassette washings for histopathological analysis. In addition, an undiluted core vitreous sample was obtained for microbial analysis in suspected infective cases. Cases were retrospectively given a diagnosis of inflammatory, infective, or neoplastic based on the results at final follow-up and the outcome of primary FDV categorized as diagnostic or nondiagnostic. The success of FDV was evaluated in relation to the final diagnosis. The need for additional intraocular biopsies and intraoperative or postoperative complications was also recorded. RESULTS: Full diagnostic vitrectomy was diagnostic in 26/49 cases (53%) and nondiagnostic in 23 (47%). The diagnostic success rate was greatest in neoplastic (16/20, 80%) and infective cases (9/13, 69%). Seven cases (14%) required additional biopsies to establish the diagnosis, and in 15/49 cases (31%), no cause of vitritis was identified. Intraoperative retinal breaks occurred in 3/49 cases (6%) and retinal detachment in 1/49 cases (2%). Three of 49 cases (6%) developed transiently elevated intraocular pressure postoperatively. CONCLUSION: Full diagnostic vitrectomy in combination with an undiluted core vitreous biopsy for suspected infections is safe and effective at securing a diagnosis in vitritis, particularly in cases of neoplasia. PMID- 30005003 TI - Reversal of Retinal Vascular Leakage and Arrest of Progressive Retinal Nonperfusion With Monthly Anti-Vascular Endothelial Growth Factor Therapy for Proliferative Diabetic Retinopathy. PMID- 30005005 TI - The time is now: closing the pediatric treatment gap and building resilience among female sex workers and their children. AB - : Motherhood is common among female sex workers (FSWs) and many have at least one biological child. Preventable mother-to-child transmission of HIV can occur given poor uptake of contraception coupled with high rates of unintended pregnancies among FSWs. Globally, there are 2.1 million children living with HIV, and antiretroviral treatment coverage is dismally low at 43%. Without timely diagnosis and treatment, half of all children born with HIV will die by the age of 2 years. By integrating services for key populations and their children, prevention of mother-to-child transmission of HIV uptake among FSW mothers and early infant diagnosis can improve and therefore reduce transmission of HIV. This field note addresses the needs of FSWs and their children, and advocates for programs to develop and scale up comprehensive, integrated, stigma-free services for this vulnerable population. Sensitive, confidential, child-friendly, tailored services that protect FSWs while addressing their children are essential to saving these young lives and breaking the transmission cycle of the virus. By siloing programs that neglect children of FSWs, we are missing opportunities and existing entry points to take an innovative, holistic, family approach to care, support, and treatment services that could improve outcomes. Given the high prevalence of HIV in FSWs and other stigmatizing factors which affect access to services, children of FSWs can no longer afford to be left behind and the time is now to prioritize them in current and future HIV programming. PMID- 30005006 TI - Modelling interaction between HIV-1 Nef and calnexin. AB - BACKGROUND: HIV-associated atherosclerosis is a major comorbidity due, in part, to systemic effects of the virus on cholesterol metabolism. HIV protein Nef plays an important role in this pathology by impairing maturation of the main cellular cholesterol transporter ATP-Binding Cassette (ABCA) 1. ABCA1 maturation critically depends on calnexin, an integral endoplasmic reticulum membrane chaperone, and Nef binds to the cytoplasmic domain of calnexin and impairs interaction of calnexin with ABCA1. Overarching goal of the present study was to model Nef-calnexin interaction interface, and identify small molecule compounds potentially inhibiting this interaction. METHODS: Molecular dynamics was utilized to build structure model of calnexin cytoplasmic domain, followed by global docking combined with application of QASDOM software developed by us for efficient analysis of receptor-ligand complexes. Structure-based virtual screening was performed for all sites identified by docking. A soluble analogue of a compound from the screening results list was tested for ability to down regulate ABCA1. RESULTS: We identified major interaction sites in calnexin and reciprocal sites in Nef. Virtual screening yielded a number of small-molecule compounds potentially blocking a calnexin site. Interestingly, one of the compounds, NSC13987, was previously identified by us as an inhibitor targeting a Nef site. An analogue of NSC13987, AMS-55, potently reversed the negative effect of Nef on ABCA1 abundance. CONCLUSIONS: We have modelled Nef-calnexin interaction, predicted small molecule compounds that can potentially inhibit this interaction, and experimentally tested one of these compounds, confirming its effectiveness. These findings provide a platform for searching for new therapeutic agents to treat HIV-associated comorbidities. PMID- 30005007 TI - Persistent central nervous system immune activation following more than 10 years of effective HIV antiretroviral treatment. AB - OBJECTIVE: Low-grade immune activation is common in people living with HIV (PLHIV), despite long-term viral suppression by antiretroviral therapy (ART). The clinical significance of this activation remains unclear. The aim of this study was to examine residual intrathecal immune activation in relation to signs of neuronal injury and neurocognitive impairment in PLHIV who had been virally suppressed on ART for more than 10 years. DESIGN/METHODS: Twenty neuroasymptomatic PLHIV on suppressive ART for a median of 13.2 years were retrospectively identified from the longitudinal prospective Gothenburg HIV cerebrospinal fluid (CSF) study. HIV-RNA, neopterin, and neurofilament light protein (NFL) levels were measured in paired plasma and CSF samples. Pretreatment samples were available for 14 patients. Cognitive function was assessed by CogState at follow-up. RESULTS: CSF neopterin decreased from a median (IQR) of 17.8 (10.6-29.7) to 6.1 (4.6-8.0) nmol/l during treatment (P < 0.001). In 11 out of 20 participants (55%), CSF neopterin levels were above the upper normal reference limit (5.8 nmol/l) at follow-up. Age-adjusted CSF NFL decreased to within-normal levels from a median of (IQR) 1179 (557-2707) to 415 (292-610) ng/l (P < 0.001). No significant correlations were found between CSF neopterin and CSF NFL or neurocognitive performance. CONCLUSION: Although CSF neopterin decreased significantly, more than 50% of the patients had CSF concentrations above the upper normal reference value despite more than 10 years of suppressive ART. We found no correlation between CSF neopterin, CSF NFL or neurocognitive performance at follow-up, indicating that low-grade immune activation during suppressive ART may be clinically benign. PMID- 30005008 TI - HIV DNA levels and decay in a cohort of 111 long-term virally suppressed patients. AB - BACKGROUND AND METHOD: We examined specimens from 111 HIV-infected participants virally suppressed on ART for a minimum of 5 years who had donated serial peripheral blood mononuclear cell (PBMC) specimens to the University of Washington/Fred Hutch Center for AIDS Research (CFAR) Specimen Repository. We determined the HIV proviral copy number per million PBMCs, corrected for CD4 cell count, in 477 specimens collected after a minimum of 5 years of follow-up and up to 15.5 years of clinical viral suppression. Generalized estimating equation regression was used to examine the association between the reservoir size and time, age at study entry, antiretroviral regimen, and risk factors for HIV acquisition. RESULTS AND CONCLUSION: We found that the inter-participant baseline HIV DNA level varied widely between 0.01 and 4.8 pol-copies per microgram genomic DNA and per CD4 cell number/micoliter; the HIV DNA level declined with time (half life was estimated at 12 years, 95% confidence interval of 6.2-240 years); the HIV DNA level was lower for those who achieved viral suppression at a younger age; and the HIV DNA level was not affected by the specific antiretroviral regimen used to achieve and maintain suppression. PMID- 30005009 TI - Determinants of high-grade anal intraepithelial lesions in HIV-positive MSM. AB - OBJECTIVE: To assess determinants for histologically proven high-grade anal intraepithelial lesions (hHSIL) in HIV-positive men who have sex with men (MSM), a population at high-risk of HPV-related anal cancer. DESIGN: APACHES is a prospective study of anal HPV and related-lesions in 513 HIV-positive MSM aged at least 35 years in six centres across France. METHODS: At baseline, participants underwent high-resolution anoscopy (HRA) with biopsy of suspicious lesions, preceded by anal swabs for liquid-based cytology, p16/Ki67 immunostaining, and HPV DNA. hHSIL diagnosis was established by histopathological review panel consensus, and determinants assessed by logistic regression. RESULTS: Baseline hHSIL prevalence was 10.4% and did not differ significantly by age, sexual behaviour or HIV/immunodeficiency markers. hHSIL prevalence was significantly elevated in participants who smoked (ORadj = 2.6, 95% CI 1.3-5.5) or who, in concurrent anal swabs, had ASCUS/LSIL (3.6, 95% CI 1.4-9.3) or ASC-H/HSIL (22.2, 95% CI 6.8-72.6) cytologic abnormalities, p16/Ki67 dual positivity (3.4, 95% CI 1.5-7.5), or non-HPV16 HR (13.0, 95% CI 1.7-102), but most notably, HPV16 (46.3, 95% CI 6.1-355) infection. Previous diagnosis of low-grade (2.3, 95% CI 1.0-5.4) or high-grade (3.8, 95% CI 1.5-9.9) anal lesion also conveyed higher hHSIL risk. After controlling for patient-specific determinants, there remained significant centre-specific effects, most clearly in higher risk groups (HPV16-positive participants: 31.3% hHSIL in centres A-D versus 5.1% in centres E and F, P < 0.01). CONCLUSION: Anal cytology and HPV16 infection are potentially useful determinants of hHSIL risk in HIV-positive MSM, but HIV/immunodeficiency-related variables appear not to be. Controlling for patient-specific hHSIL determinants highlights variability in HRA practice across diverse clinical settings and the need for better standardization of this difficult procedure. PMID- 30005010 TI - Gender and alcohol use: influences on HIV care continuum in a national cohort of patients with HIV. AB - OBJECTIVES: To investigate whether gender is associated with three recommended stages of the HIV care continuum and whether gender modifies known associations between level of alcohol use and HIV care among US veterans. DESIGN: Retrospective cohort. METHODS: Veterans Aging Cohort Study data were used to identify Veterans Health Administration (VA) patients with HIV and AUDIT-C alcohol screening from 1 February 2008 to 30 September 2014. Modified Poisson regression models estimated the relative risk and predicted prevalences of engagement in HIV care (documented CD4 cells/MUl or viral load copies/ml lab values), ART treatment (at least one prescription), and viral suppression (HIV RNA <500 copies/ml) in the year following AUDIT-C (1) for women compared to men, and (2) for each level of alcohol use compared to nondrinking among women and among men. A multiplicative interaction between gender and alcohol use was tested. RESULTS: Among 33 224 patients, women (n = 971) were less likely than men (n = 32 253) to receive HIV care (P values <0.001). Respective predicted prevalences for women and men were 71.9% (95% CI 69.1-74.7%) and 77.9% (77.5 78.4%) for engagement, 60.0% (57.0-73.14%) and 73.8% (73.4-74.3%) for ART treatment, and 46.4% (43.3-49.6%) and 55.8% (55.3-56.3%) for viral suppression. Although the interaction between gender and alcohol use was not statistically significant, stratified analyses suggested worse outcomes for women than men at higher levels of alcohol use. CONCLUSION: In this large national cohort, women were less likely than men to be engaged in HIV medical care, prescribed ART, and virally suppressed. Interventions to improve HIV care for women are needed at all levels of alcohol use. PMID- 30005011 TI - HIV RNA persists in rectal tissue despite rapid plasma virologic suppression with dolutegravir-based therapy. AB - OBJECTIVES: Despite plasma virologic suppression with antiretroviral therapy (ART), HIV persists in gut tissue. The objectives of this study were to compare plasma and rectal tissue HIV RNA dynamics and to assess relationships with dolutegravir (DTG) plasma and tissue concentrations. DESIGN: A longitudinal cohort study of HIV-infected treatment-naive individuals initiating DTG-based ART was conducted over 12 weeks with plasma and rectal tissue sampling (Clinicaltrials.gov:NCT02924389). METHODS: HIV RNA and DTG concentrations were quantified in plasma and rectal tissue samples collected pre-ART (baseline) and post-ART at weeks 2, 6, and 12 using Abbott Real-Time HIV-1 assays and high performance liquid chromatography tandem mass spectroscopy, respectively. Relationships between rectal tissue RNA and DTG concentrations were modeled using binary logistic regression, controlling for repeated measures. RESULTS: Twelve participants were enrolled: six (50.0%) women, nine (75.0%) black, median age 42.0 years (Q1 31.2, Q3 52.0). All attained plasma virologic suppression by week 6. 11 of 12 (91.7%) had detectable rectal tissue HIV RNA at baseline, and only three of 11 (27.3%) achieved rectal tissue virologic suppression at any time point. Compared with rectal tissue nonsuppressors, three of three (100.0%) of rectal tissue suppressors were women, had higher BMI, 35.9 kg/m (range 24.9-38.5) versus 20.6 (17.7-29.9), P = 0.05, and lower baseline log plasma HIV RNA: 3.7 copies/ml (range 3.6-4.4) versus 4.7 (3.8-5.4), P = 0.02. No significant relationships between rectal tissue RNA suppression and DTG concentrations were seen. CONCLUSION: Rectal tissue HIV RNA persisted in most participants and was not predicted by DTG concentrations. Impact of host factors, particularly sex, on tissue HIV viral dynamics warrants further exploration. PMID- 30005013 TI - Weight gain of HIV-exposed, uninfected children born before and after introduction of the 'Option B+' programme in Malawi. AB - OBJECTIVE: To compare birth weight and weight gain in HIV-exposed, uninfected (HEU) infants up to 24 months old, who enrolled in the Malawian national HIV care clinic (HCC) programme either before or after Option B+ (OB+) was implemented. DESIGN, SETTING AND PARTICIPANTS: HIV-exposed infants enrol in the HCC programme as soon as possible after birth and are followed up to at least 24 months old. This analysis includes HEU infants with recorded birth weight, date of birth, gender and at least one follow-up weight measurement from 21 health facilities in central and southern Malawi (January 2010-December 2014). Weight-for-age z scores (WAZ) were derived and compared by birth period using linear regression at birth and mixed effects models for postnatal weight gain up to 24 months old. RESULTS: Of 6845 HEU infants included in this study, 88.5% were born after OB+. The proportion of infants exposed in utero to combination antiretroviral therapy (ART) significantly increased after OB+ was implemented, and infants were exposed to ART for a longer time. There was no significant difference in WAZ at birth (P = 0.654) among HEU infants by birth period, but postnatal weight gain was faster among HEU infants born in the Option B+ period than infants born pre-Option B+. CONCLUSION: Birth weight was not affected by longer exposure to ART during pregnancy after OB+ was introduced, when weight gain in HEU infants was faster, possibly because their mothers were in better health. PMID- 30005014 TI - Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts. AB - INTRODUCTION: HIV-tuberculosis (TB) co-infection remains an important cause of mortality in sub-Saharan Africa. Clinical trials have reported early (within 2 weeks of TB therapy) antiretroviral therapy (ART) reduces mortality among HIV-TB co-infected research participants with low CD4 cell counts, but this has not been consistently observed. We aimed to evaluate the current WHO recommendations for ART in HIV-TB co-infected patients on mortality in routine clinical settings. METHODS: We compared two cohorts before (2008-2010) and after (2012-2013) policy change on ART timing after TB and examined the effectiveness of early versus delayed ART on mortality in HIV-TB co-infected participants with CD4 cell count 100 cells/MUl or less. We used inverse probability censoring-weighted Cox models on baseline characteristics to balance the study arms and generated hazard ratios for mortality. RESULTS: Of 356 participants with CD4 cell counts 100 cells/MUl or less, 180 were in the delayed ART cohorts whereas 176 were in the early ART cohorts. Their median age (32.5 versus 32 years) and baseline CD4 cell counts (26.5 versus 26 cells/MUl) respectively were similar. There was no difference in mortality rates of both cohorts. The risk of death increased in participants with a positive Cryptococcal antigen (CrAg) test in both the early ART cohort (aHR = 2.6, 95% CI 1.0-6.8; P = 0.045) and the delayed ART cohort (aHR = 4.2, 95% CI 1.9 9.0; P < 0.001 CONCLUSION:: Early ART in patients with HIV-TB co-infection was not associated with reduced risk of mortality in routine care. Asymptomatic Cryptococcal antigenaemia increased the risk of mortality in both cohorts. PMID- 30005015 TI - Daily or on demand oral TDF/FTC for HIV pre-exposure prophylaxis: experience from an hospital-based clinic in France. AB - BACKGROUND: On Demand oral TDF/FTC has been approved for pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM) in France following the results of clinical studies but data are limited on real-world experience. DESIGN: A single center, open-label, prospective cohort study that recruited people at high risk of HIV infection in Paris. METHODS: Subjects were enrolled in a single hospital based outpatient clinic and were proposed to start PrEP with daily or on demand TDF/FTC. At baseline and every 3 months thereafter subjects were tested for HIV and creatinine plasma levels and data on sexual behavior, other sexually transmitted infections (STIs), and tolerability were collected. RESULTS: From November 10, 2015 to April 30, 2017, 1069 subjects were screened and 1049 (98.1%) started PrEP. Median age was 36 years, 99.4% were MSM with a median number of partners of 10, and 793 (75.6%) opted for on demand PrEP. Over 486 person-years (PY) of follow-up, 4 HIV-infection were diagnosed in poorly or non-adherent subjects (incidence: 0.82/100 PY). Rate of condomless sex at last intercourse increased from 53.3% at baseline to 79% at month 12 (p < 10) but increase in bacterial STI rates was modest (14.6% at baseline vs 19.2% at month 12, (p < 10). Most adverse events were gastrointestinal and did not lead to PrEP discontinuation. CONCLUSIONS: Most PrEP users were high risk MSM and opted for on demand PrEP. PrEP use was associated with a low HIV incidence and a high rate of condomless sex with a modest increase in bacterial STIs. PMID- 30005012 TI - Brain vascular intima vulnerability among HIV-positive and negative individuals. AB - OBJECTIVE: To test whether HIV is associated with brain large artery vulnerable intima. DESIGN: Cross-sectional study of autopsied HIV-positive (HIV+) cases sex and age-matched to HIV-negative (HIV-) controls. METHODS: Brain large arteries from 302 autopsied cases (50% HIV+) were evaluated morphometrically for the presence of atherosclerosis, size of necrotic core, and fibrous cap thickness. Intima vulnerability was measured as intima elastolytic score [0-5, based on intimal metalloproteinases (MMP)-2, MMP-3, and MMP-9, and tissue inhibitor for MMP-1 and MMP-2 staining], intima inflammatory score (0-3, based on intimal presence of CD3 and CD68 cells and TNF-alpha staining), neoangiogenesis (factor VIII staining), and apoptosis (caspase 3 staining). Hierarchical generalized linear models were used to obtain the beta estimates and their 95% confidence intervals, adjusting for demographics and vascular risk factors. RESULTS: The prevalence of atherosclerosis did not differ by HIV status. Necrotic cores filled larger proportions of the intima in HIV+ individuals with CD4 cell count above 200 cells/MUl at death compared to HIV- controls (adjusted B = 11.6%, P = 0.04). HIV+ individuals had greater elastolytic scores (adjusted B = 0.34, P = 0.02), especially those with less than 200 CD4 cells/MUl at death (adjusted B = 0.41, P = 0.01). Intima inflammation, neoangiogenesis, and apoptosis were not different among HIV+ cases versus HIV- controls. CONCLUSION: Individuals with HIV and CD4 cell count at least 200 cells/MUl at death had relatively larger necrotic cores, whereas those with HIV and CD4 cell count below 200 cells/MUl at death had evidence of increased connective tissue remodeling in the intima. These findings suggest an increased potential for endothelial erosion, thrombosis, and plaque rupture that may relate to higher risk for vascular events. PMID- 30005016 TI - Interleukin 21 (IL-21)/microRNA-29 (miR-29) axis is associated with natural resistance to HIV-1 infection. AB - BACKGROUND: Interleukin-21 (IL-21) modulates HIV-1 infection through the elicitation of different antiviral mechanisms, including Th17 lineage commitment and induction of microRNA (miR)-29, a miRNA endowed with anti-HIV activity. As miR-29 expression is significantly increased in HIV-1-exposed seronegative individuals (HESN), we investigated the role of miR-29/IL21 axis in the natural control of HIV-1 infection. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from 15 Italian sexually exposed HESN and 15 HIV-unexposed healthy controls were in-vitro infected with an R5-tropic HIV-1Ba-L strain. Seven days post HIV-1 infection we evaluated: 1) p24 production (ELISA); 2) CD4/IL-21 and CD4/IL-17 T lymphocytes (FACS); 3) IL-17 concentration in supernatants (ELISA); and 4) IL-6, IL-17, IL-21, and miR-29a,b,c expression by CD4 T lymphocytes as well as perforin and granzyme by peripheral blood mononuclear cells (qPCR). The same analyses were performed on the 15 HIV-positive partners. RESULTS: At baseline IL-6 expression alone was increased in HESN compared to healthy controls. Seven days after in-vitro HIV-1 infection, nevertheless, differences emerged. Thus, CD4/IL21 and CD4/IL17 T lymphocytes, as well as IL-21 and IL-17 expression and production were significantly augmented in HESN compared to healthy controls. Interestingly, IL-21 upregulation correlated with a significantly increased expression of miR-29a,b,c and a reduced susceptibility to in-vitro HIV-1 infection in HESN alone. No differences were observed in perforin and granzyme expression. CONCLUSION: The IL-21/miR-29 axis is upregulated by HIV 1 infection in HESN suggesting its involvement in the natural resistance to HIV-1 infection in HESN. Approaches that exogenously increase IL-21 production or prompt preexisting cellular IL-21 reservoir could confine the magnitude of the initial HIV-1 infection. PMID- 30005018 TI - Beyond binary retention in HIV care: predictors of the dynamic processes of patient engagement, disengagement, and re-entry into care in a US clinical cohort. AB - OBJECTIVES: Studies examining engagement in HIV care often capture cross sectional patient status to estimate retention and identify predictors of attrition, which ignore longitudinal patient care-seeking behaviors. We describe the cyclical nature of (dis)engagement and re-entry into HIV care using the state transition framework. DESIGN: We represent the dynamic patterns of patient care retention using five states: engaged in care, missed one, two, three, or more expected visits, and deceased. Then we describe various care-seeking behaviors in terms of transitioning from one state to another (e.g. from disengaged to engaged). This analysis includes 31 009 patients enrolled in the Center for AIDS Research Network of Integrated Systems (CNICS) in the United States from 1996 to 2014. METHOD: Multistate models for longitudinal data were used to identify barriers to retention and subgroups at higher risk of falling out of care. RESULTS: The initial 2 years following primary engagement in care were a crucial time for improving retention. Patients who had not initiated antiretroviral therapy, with lower CD4 cell counts, higher viral load, or not having an AIDS defining illness were less likely to be retained in care. CONCLUSION: Beyond the individual patient characteristics typically used to characterize retention in HIV care, we identified specific periods of time and points in the care continuum associated with elevated risk of transitioning out of care. Our findings can contribute to evidence-based recommendations to enhance long-term retention in CNICS. This approach can also be applied to other cohort data to identify retention strategies tailored to each population. PMID- 30005019 TI - Similar tenofovir hair concentrations in men and women after directly-observed: dosing of TDF/FTC: implications for PrEP adherence monitoring. AB - OBJECTIVES: Women likely require higher adherence than men to pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for similar efficacy. Pharmacologic metrics of adherence predict efficacy better than self-report, but expected drug levels (adherence benchmarks) must be established using directly-observed therapy. We sought to evaluate whether tenofovir hair concentrations differ between women and men receiving directly observed TDF/FTC. METHODS: We assessed tenofovir hair concentrations in HIV uninfected volunteers randomized to receive 100%, 67%, or 33% of daily dosing of TDF/FTC for 12 weeks (DOT-DBS, NCT02022657). Hair samples were collected at dosing weeks 4, 8, and 12 and weeks 3 and 6 during a 12-week washout. Tenofovir concentrations in the proximal 1.5 centimeters of hair (representing ~6 weeks of exposure) were analyzed using liquid chromatography/tandem mass spectrometry. Linear regression was used to model tenofovir hair concentrations in terms of sex, doses over the prior 6 weeks, and number of days since last dose. RESULTS: A total of 264 hair samples were analyzed from 23 female and 24 male participants. Female participants had similar tenofovir hair concentrations to males (estimated fold-difference 0.92, 95% CI 0.75-1.13, p = 0.43). The estimated fold-difference in tenofovir levels for female versus male participants did not appreciably change when age (0.93, CI 0.76-1.15), weight (0.89, CI 0.71-1.11), or race/ethnicity (0.95, CI 0.77-1.17) were added to the model. CONCLUSIONS: Women and men have similar adherence benchmarks for tenofovir in hair samples. As pharmacokinetic metrics are increasingly used for PrEP monitoring, these findings provide guidance for assessing adherence via hair concentrations. PMID- 30005017 TI - Variation in cell-associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator brain-and-muscle-ARNT-like-1. AB - OBJECTIVE(S): To determine whether variation in cell-associated unspliced (CA-US) HIV RNA in HIV-infected individuals on antiretroviral therapy (ART) has a circadian basis. METHODS: Prospective observational study of HIV-infected individuals on ART. Blood was collected on three occasions and CA-US HIV RNA and mRNA of the circadian-locomotor-output-cycles-kaput (CLOCK)-associated genes quantified by real time PCR. CLOCK-associated proteins were over-expressed in a cell line stably transfected with an HIV long-terminal repeat (LTR) luciferase reporter. RESULTS: Using a mixed effects model, there was a significant increase in log-CA-US RNA at the third visit compared with the first visit (effect size of 0.619 with standard error (SE) of 0.098, P < 0.001) and an independent effect of time of blood draw (effect size 0.051 (SE 0.025), P = 0.040). The CLOCK associated gene, brain-and-muscle-ARNT-like-1 (BMAL-1) had a significant relationship with log CA-US HIV RNA (effect size 8.508 (SE 3.777), P = 0.028) and also with time (P = 0.045). Over expression of BMAL-1 and CLOCK in a cell line stably transfected with an HIV-LTR luciferase reporter resulted in an increase in luciferase expression and this was reduced following mutation of the second E-box in the HIV-LTR. CONCLUSION: The basal level of HIV transcription on ART can vary significantly and is modulated by the circadian regulator BMAL-1, amongst other factors. PMID- 30005020 TI - Implementation of a point mutation assay for HIV drug resistance testing in Kenya. AB - OBJECTIVES: An increasing prevalence of HIV pretreatment drug resistance (PDR) has been observed in Africa, which could decrease the effectiveness of antiretroviral therapy (ART) programs. We describe our experiences, the costs and challenges of implementing an oligonucleotide ligation assay (OLA) for management of PDR in Nairobi, Kenya. DESIGN: An observational report of the implementation of OLA in a Kenyan laboratory for a randomized clinical trial evaluating whether onsite use of OLA in individuals initiating ART would decrease rates of virologic failure. METHODS: Compared detection of mutations and proportion of mutants in participants' viral quasispecies by OLA in Kenya vs. Seattle. Reviewed records of laboratory workflow and performance of OLA. Calculated the costs of laboratory set-up and of performing the OLA based on equipment purchase receipts and supplies and labor utilization, respectively. RESULTS: OLA was performed on 492 trial participants. Weekly batch-testing of median of seven (range: 2-13) specimens provided test results to Kenyan clinicians within 10-14 days of sample collection at a cost of US$ 42 per person tested. Cost of laboratory setup was US$ 32 594. Challenges included an unreliable local supply chain for reagents and the need for an experienced molecular biologist to supervise OLA performance. CONCLUSION: OLA was successfully implemented in a Kenyan research laboratory. Cost was twice that projected because of fewer than predicted specimens per batch because of slow enrollment. OLA is a potential simple, low-cost method for PDR testing in resource-limited settings (RLS). Ongoing work to develop a simplified kit could improve future implementation of OLA in RLS. PMID- 30005021 TI - Associations of human gene EPB41L3 DNA methylation and cervical intraepithelial neoplasia in women living with HIV-1 in Africa. AB - OBJECTIVES: To evaluate associations of DNA methylation of the human tumour suppressor gene EPB41L3 with high-grade cervical intraepithelial neoplasia (CIN2+) and HIV-related factors among women living with HIV-1 (WLHIV) in Burkina Faso and South Africa. DESIGN: Case-control study of WLHIV aged 25-50 with histology-determined CIN2+ (cases, N = 152) and <=CIN1 (controls, N = 210). METHODS: EPB41L3 methylation was measured by pyrosequencing of bisulphite converted DNA from exfoliated cervical specimens at baseline and 16 months later. Median methylation levels were compared across CIN grades using the Mann-Whitney test and Cuzick test for trend. EPB41L3 methylation levels were dichotomized into 'high' and 'low' using the 66.7 percentile point of the distribution in the controls. Associations of EPB41L3 methylation with HIV-related factors were estimated by logistic regression. RESULTS: Among 94 WLHIV in Burkina Faso and 268 in South Africa, median methylation levels at baseline for EPB41L3 increased with increasing CIN grade in both countries (P-trend <0.001).'High' methylation was more frequent among women with a longer time since HIV diagnosis in Burkina Faso [>5 years vs. <=5 years; adjusted odds ratio (aOR) = 4.15, 95% CI 1.09-15.83, adjusted for age, CD4 count, high-risk HPV and CIN status], with low CD4 count in both countries (CD4 <=200 vs. >=350 cells/MUl: aOR = 7.14, 95% CI 1.44-35.37 in Burkina Faso; aOR = 2.55, 95% CI 1.07-6.07 in South Africa), and with prolonged ART use in South Africa (ART >2 years vs. ART-naive: aOR = 2.40, 95% CI: 1.23 4.69). CONCLUSION: Methylation of EPB41L3 DNA is elevated among WLHIV with CIN2+ and independently associated with lower CD4 count and ART use. PMID- 30005023 TI - No evidence of increased risk of thyroid dysfunction in well treated people living with HIV. AB - OBJECTIVES: Possible effects of HIV on thyroid function in the modern combination antiretroviral therapy (cART) era are largely unknown. We aimed to investigate the prevalence and associated risk factors of thyroid dysfunction in well treated people living with HIV (PLWH) and matched uninfected controls and to examine whether HIV is independently associated with thyroid dysfunction. DESIGN AND METHODS: Thyroid-stimulating hormone (TSH), free thyroxine, total thyroxine, and free triiodothyronine were measured in 826 PLWH from the Copenhagen co-morbidity in HIV infection (COCOMO) Study and in 2503 matched uninfected controls, and medical treatment for hypothyroidism or hyperthyroidism was recorded. Multinomial logistic regression adjusting for known risk factor was used to examine the association between HIV and thyroid dysfunction and multivariate linear regression to study the association between HIV and serum TSH concentrations. RESULTS: The PLWH were generally well treated, with 95% having undetectable viral replication. Among PLWH and controls 31 (3.8%) and 114 (4.6%) had hypothyroidism, and 7 (0.8%) and 21 (0.8%) had hyperthyroidism, respectively. In adjusted analyses, we found no significant associations between HIV and hypothyroidism OR 0.8 [95% confidence interval (CI) 0.6-1.3], P = 0.40 or between HIV and hyperthyroidism OR 1.1 (95% CI 0.5-2.5), P = 0.91. Furthermore, serum TSH concentration was unrelated to HIV status (P = 0.6). CONCLUSION: There was no difference in the prevalence of hyperthyroidism or hypothyroidism in well treated PLWH compared with uninfected controls. HIV status was not associated with thyroid dysfunction or serum TSH concentration. PMID- 30005022 TI - Low levels of HIV-1 envelope-mediated fusion are associated with long-term survival of an infected CCR5-/- patient. AB - OBJECTIVES: This study investigated whether Env-mediated fusion levels of R5X4 viruses are associated with long-term survival of an infected CCR5-/- patient. DESIGN: Four R5X4 Envs were cloned from each of two infected homosexual individuals (DR and C2) homozygous for the CCR5Delta32 allele. DR is a long-term survivor chronically infected with HIV-1 and his Envs were cloned 12 years after testing HIV-infected, whereas C2 Envs were isolated 1 year after primary infection. METHODS: The current study sequenced the gp41 subunits and created hybrid Envs that contained exchanged gp41 subunits or V3 loops. The Env-mediated fusion activity of Envs was examined in cell fusion and virus infection assays. RESULTS: Sequence analysis indicated novel polymorphisms in the gp41 subunits of C2 and DR, and revealed sequence homology between DR and certain long-term nonprogressors. The DR Envs consistently showed lower Env-mediated fusion, smaller size, and delayed onset of syncytia formation. Envs containing swapped gp41 regions resulted in the transfer of most of the fusion phenotype and in the shift of the inhibition concentration 50 (IC50) of the inhibitory T20 peptide. In contrast, Envs with swapped V3 domains resulted in the partial transfer of the fusion phenotype and no significant change in the IC50 of T20. CONCLUSIONS: Env sequence polymorphisms identified two distinct fusion phenotypes isolated from infected CCR5-/- patients. Swapping experiments confirmed DR's low fusion phenotype. Env-mediated fusion is a critical factor among others contributing to long-term survival. PMID- 30005024 TI - Biomarker P16 predicts progression risk of anal low-grade squamous intraepithelial lesions. AB - OBJECTIVES: The aim of this study was to determine whether biomarker P16 predicts progression risk for anal low-grade squamous intraepithelial lesions (LSILs). DESIGN: A retrospective study. METHODS: One hundred and nine HIV-infected and 18 HIV-uninfected patients with biopsy-proven anal LSIL at initial screening underwent surveillance high-resolution anoscopy and biopsy within 2 years of diagnosis. P16 immunohistochemistry was performed on index lesions and evaluated using a semi-quantitative scoring system. The association of predictors and lesional outcomes (progression, persistence or regression) was analysed using ordinal logistic regression models. A subset of p16-positive LSILs was tested for high-risk human papillomavirus (HR-HPV) DNA using real-time PCR. RESULTS: Upon follow-up, 46 (36%) LSILs progressed to high-grade squamous intraepithelial lesion (HSIL), 50 (40%) persisted as LSIL and 31 (24%) regressed to benign mucosa (median 16 months, range 5-24 months). Age, sex, race, history of condylomata, CD4 T-cell count and HIV plasma viral load were similar regardless of clinical outcome. P16 immunoreactivity of index lesion was classified as block-positive (n = 36), focal-positive (n = 49) or negative (n = 42). Sixty-four percent of block positive lesions progressed, as opposed to 35% of focal-positive and 14% of negative lesions (P < 0.001). HR-HPV DNA was detected in 90% of p16 block positive lesions vs. 55% of focal-positive lesions. In unadjusted analyses, positive p16, HIV and former smoker status were significantly associated with lesional persistence and progression. P16 remained the only significant predictor in an adjusted model. CONCLUSION: Biomarker p16 is the strongest predictor for anal LSIL-to-HSIL progression, outperforming other risk factors. To enhance the overall effectiveness of surveillance, we propose using p16 immunohistochemistry to help stratify patients at high vs. low risk of progression. PMID- 30005025 TI - Comparison of short messaging service self-reported adherence with other adherence measures in a demonstration project of HIV preexposure prophylaxis in Kenya and Uganda. AB - OBJECTIVE: Short messaging service (SMS) can collect adherence data on a frequent basis and is relatively anonymous, and therefore could potentially reduce recall and social desirability biases prevalent in other self-reported measures. METHODS: We compared SMS self-reported adherence with three self-reported adherence questions (rating of ability to adhere, frequency of doses taken, percentage of doses taken) and two objective adherence measures [electronic adherence monitoring (EAM) and plasma tenofovir levels] using data from HIV uninfected members of serodiscordant couples enrolled in a preexposure prophylaxis demonstration project in Kenya and Uganda. RESULTS: Of 373 enrolled participants, 256 (69%) were male and median age at enrolment was 29 years (26, 35). Fifty-two percent were from Kenya and median education at enrolment was 10 years (7,12). Overall, median adherence was 90, 75, 85, 94 and 79%, respectively, for self-report by SMS, rating, frequency, percentage and EAM adherence. Spearman's correlation coefficient between SMS and interviewer-administered self reported measures was 0.18 for rating and frequency, 0.22 for percentage and 0.14 for EAM (all P < 0.001). The estimated difference in average adherence between SMS and self-reported rating, frequency, percentage adherence and EAM was 8.1 (P < 0.001), 0.3 (P = 0.81), -5.2 (P < 0.001) and 9.5 (P < 0.001), respectively. Area under the receiver-operating curve assessing the ability of SMS self-report to discriminate between detectable and undetectable tenofovir was 0.51. CONCLUSION: Our study found low correlation between SMS self-report and other self-reported and objective adherence measures and did not discriminate between detectable and undetectable plasma tenofovir levels. Future use of SMS self report should explore alternative means for reducing potential biases. PMID- 30005026 TI - Clinical characteristics and risk of hypertension needing treatment in young patients with systolic hypertension identified with ambulatory monitoring. AB - OBJECTIVE: The clinical significance of isolated systolic hypertension (ISH) in youth is controversial. One main confounding factor is the strong white-coat effect often observed in ISH patients. The aim of this study was to investigate the risk of hypertension needing pharmacological treatment in ISH identified with ambulatory 24-h blood pressure (24-h BP). METHODS: We examined 1206, 18-45-year old participants from the Hypertension and Ambulatory Recording VEnetia STudy. Based on 24-h BP, 269 participants were normotensive, 209 had ISH, 277 had isolated diastolic hypertension, and 451 had systolic-diastolic hypertension. The predictive role of ISH for incident hypertension was evaluated in Cox survival analyses, adjusting for risk factors and confounders. RESULTS: ISH participants were more frequently young men active in sports, with lower heart rate and cholesterol. During a 6.9-year follow-up, 61.1% of participants developed hypertension. ISH participants had a nonsignificant increase in risk of hypertension compared with normotensive (reference group). In contrast, participants with diastolic hypertension (1.44; 1.13-1.85) or systolic-diastolic hypertension (2.04; 1.59-2.64) had a significant increase in risk. When the ISH participants were divided according to whether 24-h mean BP was normal (<97 mmHg) or high, ISH patients with normal mean BP had no increase in risk (1.01; 0.73 1.40), whereas those with high mean BP had a significant increase in risk (1.70; 1.16-2.49). CONCLUSION: These data obtained with ambulatory BP monitoring show that in ISH people younger than 45 years, only mean BP is a predictor of future hypertension needing treatment, whereas the ISH status per se does not necessarily imply an increase in risk. PMID- 30005027 TI - Salt intake among Iranian population: the first national report on salt intake in Iran. AB - OBJECTIVE: In Iran, there has been no national report on salt intake based on laboratory measurements so far. Therefore, this study was conducted to measure salt intake among Iranian population at the national level. METHODS: In stepwise approach to conduct a surveillance survey 2016, 18 624 Iranian adults (25 years old and above), as a representative sample of Iranian adult population at national and subnational levels, underwent urine sodium measurement and were included in this study. The participants were recruited through a systematic random sampling from 30 provinces of Iran. For each individual, through a computer-assisted interview, a questionnaire on lifestyle risk factors was completed, all anthropometric indices were measured, and data on sodium of spot urine sample for all individuals and 24-h urine sample for a subsample were collected. To estimate the 24-h salt intake, common equations were used. RESULTS: In total, 97.66% of the population consumed at least 5 g of salt per day. In addition, in 41.20% of the population, the level of salt intake was at least two times higher than the level recommended by the WHO for adults. The mean of salt intake among Iranian population was 9.52 g/day (95% confidence interval: 9.48 9.56). CONCLUSION: The study showed that the consumption of salt among the Iranian population is higher than the level recommended by WHO. To reduce salt intake, it is necessary to adopt a combination of nationwide policies such as food reformulation and food labelling. PMID- 30005028 TI - Blood pressure elevation response to radiofrequency energy delivery: one novel predictive marker to long-term success of renal denervation. AB - BACKGROUND: Previous studies showed that radiofrequency energy delivery of the renal artery could induce an immediate and substantial blood pressure (BP) elevation response, which might be indicative of the increase in central sympathetic nervous activity. OBJECTIVE: The current study was to investigate whether the presence of BP-elevation response to radiofrequency energy delivery can serve as a surrogate to predict BP reduction following renal artery sympathetic denervation (RDN). METHOD: Data were collected on 67 patients undergoing RDN for drug-resistant hypertension. The BP-elevation response to radiofrequency application was defined as elevation of SBP by at least 10 mmHg during radiofrequency energy delivery. The extent of BP reduction at 1, 3, 6, 12 months after RDN were analyzed. Multivariable linear regression analysis of baseline and procedural characteristics was performed to identify the determinants of BP reduction after RDN. RESULTS: Ten patients (14.9%) were classified as nonresponders to radiofrequency delivery and showed significantly lower BP reduction compared with responders. The SBP reductions of radiofrequency delivery responders vs. nonresponders were 31.2 +/- 8.6 vs. 11.4 +/- 8.6 mmHg, 36.3 +/- 10.0 vs. 14.6 +/- 10.6 mmHg, 39.9 +/- 9.9 vs. 15.2 +/- 8.8 mmHg, and 40.0 +/- 8.7/13.5 +/- 5.8 mmHg (P < 0.001 for all) at 1, 3, 6, and 12 months, respectively. On multiple linear regression analysis, higher baseline office SBP, the presence of BP-elevation response to radiofrequency energy delivery, and especially larger number of BP-elevation response points, were independent predictors of SBP reduction at 6-month and 12-month follow-up. CONCLUSION: Baseline SBP and BP-elevation response during radiofrequency ablation, as well as larger positive response points to radiofrequency energy delivery could be an effective intraprocedural predictive markers to long-term procedural success of RDN. PMID- 30005029 TI - The link between elevated long-term resting heart rate and SBP variability for all-cause mortality. AB - BACKGROUND: Resting heart rate (RHR) and SBP are important risk markers for all cause mortality. However, the link between increased RHR and SBP for all causes of death remained unclear. We investigated the link between an increased visit-to visit variation of RHR and SBP for risk of all-cause mortality in the general population. METHODS: We examined long-term visit-to-visit variation of RHR and blood pressure among 46 751 residents of Tangshan city, China (mean age: 52.58 +/ 11.64 years; 78% men). Cox proportional hazard model was used to estimate the hazard ratios and 95% confidence interval (CI) adjusting for clinical characteristics assessed at the last examination (2010-2011). RESULTS: A total of 1667 deaths were recorded over 4.97 +/- 0.69 years follow-up. A rise in 1 SD of heart rate (4 bpm) was associated with an increased risk of death among the participants in third and fourth quartile of SBP-SD in the subgroups of general population [hazard ratio (95% CI) = 1.10 (1.03-1.67) and 1.16 (1.03-1.30), respectively], men [hazard ratio (95% CI) = 1.10 (1.02-1.17) and 1.16 (1.03 1.30), respectively], and participants under 65 years of age [hazard ratio (95% CI) = 1.16 (1.02-1.33) and 1.20 (1.03-1.39), respectively]. Similarly, 1-SD increase of SBP (7 mmHg) was associated with an increased risk of death among the participants in the highest quartiles of RHR-SD in the subgroups of the general population, men, and under 65 years of age. CONCLUSION: An elevated long-term SBP variability combined with an increased RHR variability or vice versa may amplify the risk of all-cause mortality in general population, as well as in men and middle-age group. PMID- 30005031 TI - Early Phacoemulsification After Acute Angle Closure in Patients With Coexisting Cataract. AB - PURPOSE: The purpose of this study is to evaluate the effect of early phacoemulsification on the management of acute angle closure glaucoma in patients with coexisting cataract after initial treatment with medical therapy and laser peripheral iridotomy. PATIENTS AND METHODS: This study involved a retrospective analysis of patients presenting to the Maastricht University Medical Center+ with acute angle closure and coexisting cataract between 2005 and 2015. Patients were included after initial treatment with a standard protocol comprising topical and systemic medical therapy and laser peripheral iridotomy. Patients underwent small incision phacoemulsification with intraocular lens implantation into the capsular bag by experienced surgeons within 3 months of the acute angle closure episode. The effect on intraocular pressure, number of glaucoma medications, visual acuity, and complications was assessed. RESULTS: A total 35 patients were included in the study (mean age, 71+/-10 y; 20% male; mean refractive error, +1.6+/-1.8 diopters). The mean duration between acute angle closure episode and phacoemulsification was 37+/-22 days. There were no complications. Intraocular pressure decreased in all patients from 17.0+/-8.2 mm Hg to 13.2+/-3.9 mm Hg after 3 months (P=0.008), whereas the mean number of glaucoma medications decreased from 2.9+/-1.1 to 0.7+/-0.9 (P<0.001), with 56% of patients discontinuing all medications. Visual acuity improved from 0.9+/-0.9 logMAR to 0.2+/-0.3 logMAR (P<0.001). CONCLUSIONS: Early phacoemulsification with intraocular lens implantation results in a reduced intraocular pressure and number of glaucoma medications after an acute angle closure glaucoma crisis in patients with coexisting cataract. Although surgery may be challenging, the results are promising, with significant improvement in visual acuity in most patients. PMID- 30005030 TI - Procedural and anatomical predictors of renal denervation efficacy using two radiofrequency renal denervation catheters in a porcine model. AB - INTRODUCTION: Several renal denervation (RDN) systems are currently under investigation for treatment of hypertension by ablation of renal sympathetic nerves. The procedural efficacy of devices, however, is variable and incompletely understood. This study aimed at investigating procedural and anatomical predictors of RDN efficacy by comparing two radiofrequency catheter systems in a porcine model. METHODS: Domestic swine were assigned into two treatment groups (n = 10) and one sham group (n = 3). Bilateral RDN in main and in branch segments of renal arteries was performed using two different multielectrode catheter systems [Symplicity Spyral (SPY) and IberisBloom (IBB)]. After 7 days, measurement of norepinephrine (NEPI) tissue concentrations and histological analyses have been performed. RESULTS: Renal NEPI tissue concentration following RDN was significantly reduced when compared with Sham (SPY: -95 +/- 3% vs. Sham, P < 0.001; IBB: -88 +/- 11% vs. Sham, P < 0.001). Histological evaluation showed comparable lesion depth and lesion area (lesion depth: SPY-main 6.26 +/- 1.62 mm vs. SPY-branch 3.49 +/- 1.11 mm; IBB-main 5.93 +/- 1.88 mm vs. IBB-branch: 3.26 +/- 1.26 mm, P < 0.001; lesion area: SPY-main 43.5 +/- 29.5 mm vs. SYP-branch 45.0 +/- 38.0 mm; IBB-main 52.3 +/- 34.8 mm vs. IBB-branch 44.0 +/- 42.6 mm, P = 0.77; intergroup SPY vs. IBB, P = 0.73). Histological investigations documented a significant correlation between number of ablations per millimeter length of renal artery and reduction in NEPI tissue concentration. CONCLUSION: The two devices under investigation demonstrated similar histopathological lesion characteristics and similar reduction of renal NEPI levels. An increase in number of ablations per millmeter length of renal artery resulted in improved efficacy and reduced variability in treatment effects. PMID- 30005034 TI - What's New in Shock, August 2018? PMID- 30005033 TI - Macular Vessel Density and Ganglion Cell/Inner Plexiform Layer Thickness and Their Combinational Index Using Artificial Intelligence. AB - PURPOSE: To evaluate the relationship between macular vessel density and ganglion cell to inner plexiform layer thickness (GCIPLT) and to compare their diagnostic performance. We attempted to develop a new combined parameter using an artificial neural network. METHODS: A total of 173 subjects: 100 for the test and 73 for neural net training. The test group consisted of 32 healthy, 33 early, and 35 advanced glaucoma subjects. Macular GCIPLT and vessel density were measured using Spectralis optical coherence tomography and Topcon swept-source optical coherence tomography, respectively. Various regression models were used to investigate the relationships between macular vessel density and GCIPLT. A multilayer neural network with one hidden layer was used to determine a single combined parameter. To compare diagnostic performance, we used the area under the receiver operating characteristic curve (AUROC). RESULTS: Correlation analyses in all subjects showed a significant correlation between macular vessel density and GCIPLT in all sectors (r=0.27 to 0.56; all Ps<=0.006). The fitness of linear, quadratic, and exponential regression models showed clinically negligible differences (Akaike's information criterion=714.6, 713.8, and 713.3, respectively) and were almost linear. In differentiating normal and early glaucoma, the diagnostic power of macular GCIPLT (AUROC=0.67 to 0.81) was much better than that of macular vessel density (AUROC=0.50 to 0.60). However, when vessel density information was incorporated into GCIPLT using the neural network, the combined parameter (AUROC=0.87) showed significantly enhanced diagnostic performance than all sectors of macular vessel density and GCIPLT (all Ps<=0.043). CONCLUSIONS: Macular vessel density was significantly decreased in glaucoma patients and showed an almost linear correlation with macular GCIPLT. The diagnostic performance of macular vessel density was much lower than that of macular GCIPLT. However, when incorporated into macular GCIPLT using an artificial neural network, the combined parameter showed better performance than macular GCIPLT alone. PMID- 30005032 TI - A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study. AB - PURPOSE: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. METHODS: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length, and intraocular pressure. We further repeated analyses stratified into age tertiles. RESULTS: In total, 5433 participants with HRT data and 3699 participants with GDxVCC data were included. Each "C" allele of rs33912345 was associated with a smaller rim area (-0.030 mm [95% CI -0.040, -0.020]; P=5.4*10), a larger VCDR (0.025 [95% CI 0.017, 0.033]; P=3.3*10) and a thinner RNFL (-0.39 MUm [95% CI -0.62, -0.15]; P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. CONCLUSIONS: The protein-coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma associated optic nerve head traits in Europeans. PMID- 30005035 TI - Temporal and Spatial Changes of MU-Opioid Receptors in the Brain, Spinal Cord and Dorsal Root Ganglion in a Rat Lumbar Disc Herniation Model. AB - STUDY DESIGN: Controlled, interventional, animal study. OBJECTIVE: To investigate the spatial and temporal changes of MU-opioid receptor (MOR) expression in a rat lumbar disc herniation (LDH) model. SUMMARY OF BACKGROUND DATA: MORs widely express in the peripheral and central nervous systems, and opioid drugs produce an analgesic effect through their activation. However, the efficacy of opioid drugs is sometimes inadequate in several pathological conditions of pain. MORs in the brain as well as the spinal cord (SC) and dorsal root ganglion (DRG) are thought to be associated with pain-related behavior, but the underlying mechanisms are not completely understood. METHODS: In all, 91 adult female Sprague-Dawley rats were used. Autologous nucleus pulposus (NP) was applied onto the left L5 DRG in the NP group rats. Rats were divided into two surgical groups, the NP and the sham group. The von Frey test of left hind paw was performed before surgery, and 2, 7, 14, 21 and 28 days after surgery. Immunohistochemistry and immunoblotting in the DRG, SC, Caudate putamen, nucleus accumbens (NAc) and periaqueductal grey matter were performed before surgery, and 2, 7, 14, 21 and 28 days after surgery. RESULTS: The thresholds in the NP group were significantly lower than those in the sham group from day 2 onwards. At days 7 and 14, MOR expression in the injured-side SC and DRG were significantly lower than those in the sham group. At day 21, MOR in the NAc was significantly decreased compared to that in the sham group. CONCLUSION: Changes of MOR expression in the NAc, SC and DRG were associated with pain-related behavior. This result might show the underling pathogenesis of the resistance to MOR agonists in the patient with LDH. LEVEL OF EVIDENCE: N/A. PMID- 30005036 TI - The Natural Course of Compensatory Lumbar Curves in Non-operated Patients with Thoracic Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A retrospective, long-term follow-up study. OBJECTIVE: We investigated the natural course of compensatory lumbar curves in patients with primary thoracic adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: The natural course of compensatory lumbar curves in primary thoracic AIS remains unknown. METHODS: Inclusion criteria were right-sided primary thoracic AIS >=30 degrees with a Lenke's lumbar modifier of A or B at skeletal maturity and >=30 years of age at the time of the survey. Fifty-one patients (mean age, 40.2 years) returned for a follow-up evaluation (follow-up rate, 34.2%). Patients were classified into 3 groups based on the lumbar modifier and direction of L4 tilt (AR, n = 11; AL, n = 18; and B, n = 22). At the time of the survey, 42 patients underwent radiological examinations and 37 underwent lumbar magnetic resonance imaging. Quality of life questionnaires were completed in all patients and in a 1:1 matched control group (no history of scoliosis). RESULTS: The thoracic curves had significantly progressed in all patient groups, while the compensatory lumbar curve progressed only in the B group. The C7 translation and L4 tilt shifted to the right in the AR and AL groups, but did not change in the B group. As a result, the L4 tilt (median, 11 degrees ) and C7 translation (18.6 mm) tended to be the greatest in the AR group. The incidences of Modic changes at L4/5 discs and >=3 cm on the visual analogue scale for low back pain were significantly higher in the AR group (77.8% and 54.5%, respectively) compared to that in the other groups. CONCLUSIONS: The natural course of compensatory lumbar curves is dependent on the lumbar modifier and direction of L4 tilt. Adolescent patients with right-sided primary thoracic AIS (>=30 degrees ) with L4 tilted to the right should be considered for periodic follow-ups into adulthood. LEVEL OF EVIDENCE: 4. PMID- 30005038 TI - Evaluating the Cross-Cultural Adaptation, Reliability and Validity of the Persian Versions of the Copenhagen Neck Function Disability Scale and Neck Bournemouth Questionnaire. AB - STUDY DESIGN: A cross sectional study OBJECTIVE.: to evaluate cross-cultural adaptation and psychometric properties of the Copenhagen Neck Function Disability Scale (CNFDS) and Neck Bournemouth Questionnaire (NBQ) in patients with chronic nonspecific neck pain. SUMMARY OF BACKGROUND DATA: CNFDS and NBQ are among the most popular scales to investigate aspects of life in patients with chronic neck pain. To date, the Persian versions of these scales have not been validated. METHODS: Following the translation process, the questionnaires were given to 106 patients with chronic nonspecific neck pain. To evaluate reliability, Cronbach's alpha and test-retest reliability were evaluated. To investigate construct validity, the Neck Disability Index (NDI) and Neck Pain Disability Scale (NPDS) were used. Internal consistency of the scales was evaluated with exploratory factor analysis. RESULTS: No missing data were observed for the NBQ, and missing data affected 0% to 3% of the CNFDS items. There were no floor or ceiling effects. Cronbach's alpha was 0.92 for the CNFDS and 0.95 for the NBQ. Test retest reliability was estimated as 0.86 for the CNFDS and 0.91 for the NBQ. The CNFDS correlated very well with the NDI pain subscale, and the NPDS. The NBQ correlated very well with the NPDS and NDI, and correlated well with the CNFDS and its subscales. Exploratory factor analysis detected three dimensions for the CNFDS and confirmed unidimensionality of the NBQ. CONCLUSIONS: The Persian versions of the CNFDS and NBQ have acceptable validity and reliability for use with Persian-speaking patients with chronic nonspecific neck pain. LEVEL OF EVIDENCE: 2. PMID- 30005037 TI - Development of a Modified Cervical Deformity Frailty Index: A Streamlined Clinical Tool for Preoperative Risk Stratification. AB - STUDY DESIGN: Retrospective review OBJECTIVE.: Develop a simplified frailty index for CD patients SUMMARY OF BACKGROUND DATA.: To improve preoperative risk stratification for surgical cervical deformity (CD) patients, a CD frailty index (CD-FI) incorporating 40 health deficits was developed. While novel, the CD-FI is clinically impractical due to the large number of factors needed for its calculation. To increase clinical utility, a simpler, modified CD-FI (mCD-FI) is necessary. METHODS: CD patients (C2-C7 Cobb>10 degrees , CL>10 degrees , cSVA>4 cm, or CBVA>25 degrees ) >18yr with preoperative CD-FI component factors. Pearson bivariate correlation assessed relationships between component deficits of the CD FI and overall CD-FI score. Top deficits contributing to CD-FI score were included in multiple stepwise regression models. Deficits from model with largest R were dichotomized, and the mean score of all deficits calculated, resulting in mCD-FI score from 0 to 1. Patients were stratified by mCD-FI: Not Frail (NF, <0.3), Frail (0.3-0.5), Severely Frail (SF, >0.5). Means comparison tests established correlations between frailty category and clinical outcomes. RESULTS: Included: 121 CD patients (61 +/- 11yr, 60%F). Multiple stepwise regression models identified 15 deficits as responsible for 86% of the variation in CD-FI; these factors were used to construct the mCD-FI. Overall, mean mCD-FI was 0.31 +/ 0.14. Breakdown of patients by mCD-FI category: NF: 47.9%, Frail: 46.3%, SF: 5.8%. Compared to NF and Frail, SF patients had the longest inpatient hospital stays (P = 0.042), as well as greater baseline neck pain (P = 0.033), inferior NDI scores (P<0.001) and inferior EQ-5D scores (P < 0.001). Frail patients had higher odds of superficial infection (OR:1.1[1.0-1.2]), and SF patients had increased odds of mortality (OR:8.3[1.3-53.9]). CONCLUSIONS: Increased frailty, assessed by mCD-FI, correlated with increased length of stay, neck pain, and decreased health-related quality of life. Frail patients were at greater risk for infection, and severely frail patients had greater odds of mortality. This relationship between frailty and clinical outcomes suggests that mCD-FI offers clinical utility as a preoperative risk stratification tool. LEVEL OF EVIDENCE: 3. PMID- 30005039 TI - Assessing Variability in In-Hospital Complication Rates Between Surgical Services for Patients Undergoing Posterior Cervical Decompression and Fusion. AB - STUDY DESIGN: A retrospective study was performed including all patients that underwent posterior cervical decompression and fusion (PCDF) by an orthopedic or neurological surgeon at a single institution between January 1, 2006 and November 30, 2016, and all patients that underwent PCDF by a spine surgeon in the NSQIP database between 2007 and 2015. In-hospital complications were compared between surgical specialties. OBJECTIVE: The goal of this study was to determine if in hospital complication rates differ significantly between surgical services for PCDF patients. SUMMARY OF BACKGROUND DATA: Orthopedic and neurological surgeons commonly perform PCDF, and differences in surgical opinion and management have been cited between these two specialties in recent literature. This represents a variable that should be evaluated. METHODS: Cases were preliminarily identified by CPT code and confirmed using the ICD-9 code 81.03 or ICD-10 code M43.22. Cases were separated based on if the primary surgeon was an orthopedic surgeon or a neurological surgeon. The primary outcome variable was in-hospital complication rates; cohorts were compared using bivariate and multivariate analysis. RESULTS: A total of 1,221 patients at a single institution and 11,116 patients within the NSQIP database underwent PCDF. Patients in the orthopedic surgery service had a higher proportion of bleeding requiring transfusion in both the institutional sample (14.5% vs. 9.08%, p = 0.003) and national sample (11.16% vs. 6.18%, p < .0001). In the national sample, orthopedic surgeons were 1.66 times as likely to encounter an in-hospital complication than neurological surgeons (95% CI: 1.44 - 1.91, p < 0.0001). CONCLUSION: When examining a large institutional sample and an even larger national sample, this study found that orthopedic surgeons were more likely to encounter perioperative bleeding requiring transfusion than neurological surgeons. When in-hospital complications were considered as a whole, in the national sample, orthopedic surgeons are more likely to encounter in hospital complications than neurological surgeons when performing PCDF. LEVEL OF EVIDENCE: 3. PMID- 30005040 TI - Solitary Plasmacytoma of Bone of the Spine: Results From Surveillance, Epidemiology, and End Results (SEER) Registry. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To determine the prognostic indicators in patients with solitary plasmacytoma of bone (SPB) of the spine. SUMMARY OF BACKGROUND DATA: Population-level estimates for prognosis among patients with SPB of the spine are still lacking. Sociodemographic and clinical predictors of outcome have not been well characterized. METHODS: The Surveillance, Epidemiology, and End Results Registry was used to identify all patients with SPB of the spine from 1995 through 2014. Associated population data were used to determine annual incidence and limited-duration prevalence. Overall survival (OS) estimates were obtained using the Kaplan-Meier method and compared across groups using log-rank test. A Cox regression model was used for multivariate analysis of survival. Logistic regression was performed to identify predictors of the progression to multiple myeloma (MM). RESULTS: The incidence and prevalence of the disease increased during the study period. Spinal SPB most commonly affected older people (>50) with a male preponderance. The median OS wer 74.0 months. The 5-year and 10-year survival rates for these patients were 56.1% and 36.7%, respectively. On multivariable analyses, older age and surgery without radiotherapy were correlated with poor survival of patients with spinal SPB. The 3-year probability of progression to MM was 10.1%. Patients aged >70 years were associated with progression to MM. There was no significant association between the methods of surgical resection (radical or local/partial) and OS or progression to MM. CONCLUSION: The findings of this study provide population based estimates of the incidence, prevalence and prognosis for patients with SPB of the spine. This analysis indicated that the only identifiable prognostic indicators were older age and surgery without radiotherapy. Moreover, the methods of surgical resection didn't influence the OS or progression to MM. LEVEL OF EVIDENCE: 4. PMID- 30005041 TI - Ponte Osteotomies Increase the Risk of Neuromonitoring Alerts in Adolescent Idiopathic Scoliosis Correction Surgery. AB - STUDY DESIGN: Observational cohort study of prospective database registry. OBJECTIVE: To determine the incidence of neurological complications in AIS patients undergoing surgical treatment with PO. SUMMARY OF BACKGROUND DATA: Despite the widespread use of Ponte Osteotomies (PO) in adolescent idiopathic scoliosis (AIS) correction, outcomes and complications in patients treated with this technique have not been well characterized. METHODS: A multicenter prospective registry of patients undergoing surgical correction of AIS was queried at 2-year follow up for patient demographics, surgical data, deformity characteristics and peri-operative complications. A neurological complication was defined as perioperative nerve root or spinal cord injury as identified by the surgeon. Patients were divided into those that underwent peri-apical PO and those without, and further stratified by Lenke curve classification into 3 groups (I types 1 & 2, II- types 3, 4, 6, and III-type 5). Patients with- and without neurological complications were compared with respect to baseline demographics, surgical variables, curve types, fusion construct types (screws vs. hybrid), curve magnitude (coronal and sagittal Cobb), apical vertebral translation, and coronal- deformity angular ratios (C-DAR). RESULTS: Of 2210 patients included in the study, 1611 underwent PO. Peri-operative neurological complications occurred in 7 patients, with 6 in the PO group (0.37%) and 1 in non-PO group (0.17%) though this was not a statistically significant risk factor for peri-operative neurological injury (p = 0.45). Neuromonitoring alerts were recorded in 168 patients (7.6%: 9.3% PO group; 4.2% no-PO group (p < 0.001). Multivariate logistic regression analysis found PO and curve magnitude to be independent risk factors for intra-operative neuromonitoring alerts (p < 0.01). CONCLUSIONS: PO and curve magnitude were independent risk factors for intra-operative neuromonitoring alerts in surgical AIS correction. The effect of Ponte osteotomy on neurological complications remains unknown due to the low incidence of these complications. LEVEL OF EVIDENCE: 3. PMID- 30005042 TI - Readmissions, Length of Stay and Mortality After Primary Surgery for Adult Spinal Deformity: A Ten-Year Danish Nationwide Cohort Study. AB - STUDY DESIGN: Cohort study. OBJECTIVE: To report outcome after primary surgery for Adult Spinal Deformity (ASD), and assess risk factors for extended length of stay (extLOS) and increased 90-day readmission. SUMMARY OF BACKGROUND DATA: Complications after ASD surgery have been reported in 20-50% of patients. Few studies have focused on detailed information concerning postoperative morbidity. METHODS: Patients >18 years undergoing primary instrumented surgery for ASD in Denmark in the period 2006-2016 were included. Patients were identified in the Danish National Patient Registry (DNPR) using procedure codes for instrumented spine surgery combined with diagnosis of spinal deformity. Information on length of stay (LOS), readmissions, and mortality were retrieved from the DNPR. Medical records were reviewed for causes of extLOS (LOS >10 days) and readmission within 90 days after surgery. Charlson Comorbidity Index (CCI) was calculated for all patients based on DNPR. RESULTS: We included 892 patients. Median LOS was 8 days (interquartile range (IQR) 7 - 11). A total of, 175 (28.0%) patients had extLOS; 75% due to "medically" related complications. Most common medically related reason (>50%) for extLOS was pain/mobilization difficulties. The 90-days readmission risk was 13.8%; 73.2% of readmissions were "medically" related, primarily opioid related side effects (18.2%) and pain/mobilization issues (15.2%); 31.8% of readmissions were "surgically" related and 16.7% of patients required revision surgery. 90-days mortality was 0.9%. Age groups 61-70 years, >70 years, CCI score 1-2 and CCI score >=3 were associated with increased risk of extLOS (Odds Ratio (OR) = 1.79, 2.01, 1.81 and 2.49 respectively). Age group >70 years and CCI score 1-2 were associated with increased risk of readmission (OR = 2.21 and 1.83). CONCLUSIONS: Increasing age and comorbidity were associated with increased risk extLOS and readmission. Pain/mobilization difficulties were the most common postoperative complications. A future focus on early mobilization and pain management may improve outcome of ASD patients. LEVEL OF EVIDENCE: 3. PMID- 30005043 TI - Comparative Analysis of Utilization of Epidural Procedures in Managing Chronic Pain in the Medicare Population: Pre and Post Affordable Care Act. AB - STUDY DESIGN: A retrospective cohort study of utilization patterns of epidural injections. OBJECTIVE: The aim of this study was to assess patterns of utilization and variables of in chronic spinal pain in the fee-for-service (FFS) Medicare population, with a comparative analysis of pre- and post-Affordable Care Act (ACA) data from 2000 to 2009 and 2009 to 2016. SUMMARY OF BACKGROUND DATA: Over the years, utilization of interventional pain management techniques, specifically epidural injections have increased creating concern over costs and public health policy. METHODS: The master data from the Centers for Medicare & Medicaid Services (CMS) physician/supplier procedure summary from 2000 to 2016 was utilized to assess utilization patterns. The descriptive analysis of the database analysis was performed using guidance from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). Multiple variables were analyzed based on the procedures, specialties, and geography. RESULTS: Caudal and lumbar interlaminar epidural injections decreased 25% from 2009 to 2016 with an annual decrease of 4% in contrast to lumbosacral transforaminal epidural injection episodes, increasing at an annual rate of 0.3%. In contrast, lumbar interlaminar epidural injections increased 2.4% annually, while transforaminal episodes increased 23% from 2000 to 2009. The ratio of interlaminar epidural injections to transforaminal epidural injection episodes has changed from 7 in 2000 to 1 in 2016, whereas ratio of services changed from 5 to 0.7. From 2009 to 2016, cervical/thoracic interlaminar epidural injections episodes increased at an annual rate of 0.5%, with a decrease of 2.3% for transforaminal epidural injections. CONCLUSION: Comparative analysis of the utilization of epidural injections from 2000 to 2009 and 2009 to 2016 showed vast differences with overall significant decreases in utilization, specifically for lumbar interlaminar and caudal epidural injections, with a continued, though greatly slowed increase of lumbosacral transforaminal epidural injections. LEVEL OF EVIDENCE: 3. PMID- 30005044 TI - Revised Cardiac Risk Index as a Predictor for Myocardial Infarction and Cardiac Arrest Following Posterior Lumbar Decompression. AB - STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To determine the ability of Revised Cardiac Risk Index (RCRI) to predict adverse cardiac events following posterior lumbar decompression (PLD). SUMMARY OF BACKGROUND DATA: PLD is an increasingly common procedure used to treat a variety of degenerative spinal conditions. The RCRI is used to predict risk for cardiac events following non-cardiac surgery. There is a paucity of literature that directly addresses the relationship between RCRI and outcomes following PLD, specifically, the discriminative ability of the RCRI to predict adverse post operative cardiac events. METHODS: ACS-NSQIP was utilized to identify patients undergoing PLD from 2006-2014. 52,066 patients met inclusion criteria. Multivariate and ROC analysis was utilized to identify associations between RCRI and postoperative complications. RESULTS: Membership in the RCRI=1 cohort was a predictor for myocardial infarction (MI) (OR = 3.3, P = 0.002) and cardiac arrest requiring CPR (OR = 3.4, P = 0.013). Membership in the RCRI = 2 cohort was a predictor for MI (OR = 5.9, P = 0.001) and cardiac arrest requiring CPR (OR = 12.5), Membership in the RCRI = 3 cohort was a predictor for MI (OR = 24.9) and cardiac arrest requiring CPR (OR = 26.9, P = 0.006). RCRI had a good discriminative ability to predict both MI (AUC = 0.876) and cardiac arrest requiring CPR (AUC = 0.855). The RCRI had a better discriminative ability to predict these outcomes that did ASA status, which had discriminative abilities of "fair" (AUC = 0.799) and "poor" (AUC = 0.674), respectively. P < 0.001 unless otherwise specified. CONCLUSIONS: RCRI was predictive of cardiac events following PLD, and RCRI had a better discriminative ability to predict MI and cardiac arrest requiring CPR and than did ASA status. Consideration of the RCRI as a component of preoperative surgical risk stratification can minimize patient morbidity and mortality. Studies such as this can allow for implementation of guidelines that better estimate the preoperative risk profile of surgical patients. LEVEL OF EVIDENCE: 3. PMID- 30005045 TI - Lancet Series: The "Magnum Opus" Regarding the Evidence on Low Back Pain. PMID- 30005046 TI - Dose Reduction Protocol for Full Spine X-ray Examination Using Copper Filters in Patients With Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Prospective case series. OBJECTIVE: To assess a new protocol for full spine X-ray using copper (Cu) filters to reduce radiation exposure in patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Radiation exposure is associated with an increased risk of cancer development in children. To reduce the radiation exposure without compromising the image quality using existing radiographic equipment, a new computed radiography protocol was optimized using a variety of heavy metal filters. METHODS: Study 1: Whole spine radiographs were obtained using a human body phantom, and radiation doses without and with 0.1-, 0.2-, and 0.3-mm thick Cu filters were compared. Study 2: Patients with AIS who underwent posterior fusion were radiographically evaluated at follow ups; the X-ray protocols with or without the use of 0.2-mm Cu filters were alternated between consecutive follow-ups. The image quality was independently evaluated using six points in the anterior-posterior (AP) view and seven in the lateral [left-right (LR)] view by three spine surgeons using a three-point grading system. RESULTS: Study 1: The surface doses while obtaining nonfiltered X rays in AP and LR views were 0.31 and 0.93 mGy, respectively, whereas those with 0.1-, 0.2-, and 0.3-mm Cu filters were 0.16 and 0.52, 0.11 and 0.36, and 0.08and 0.27 mGy, respectively.Study 2: In patients with AIS, the percentage of grade 3 scores (both endplates were identifiable) on AP-view images was 85% with nonfiltered X-rays and 75% with the filtered X-rays. However, there were no significant differences between the two protocols. On LR images, the frequency of grade 3 scores was significantly lower at Th2 and Th12 on filtered images than on nonfiltered ones. CONCLUSIONS: Whole spine radiographs using 0.2-mm Cu filters in patients with AIS could reduce radiation exposure more than 60% while preserving the image quality. LEVEL OF EVIDENCE: 4. PMID- 30005047 TI - Pedicle Screw Designs in Spinal Surgery: is There a Difference? A Biomechanical Study on Primary and Revision Pull-out Strength. AB - STUDY DESIGN: An experimental lab based biomechanical study. OBJECTIVE: The objective of this study was to evaluate, in a synthetic bone model, the difference in primary and revision pull-out strength using pedicle screws of different thread designs. SUMMARY OF BACKGROUND DATA: Over the past few decades, there has been a growing interest in optimising the screw pull-out strength using various screw designs (single-thread, mixed-thread, dual-thread). While primary pull-out strength has been studied previously, little is known about revision pull-out strength of different pedicle screws. METHODS: The pull-out strengths of three different pedicle screw designs (single-thread, mixed-thread, dual-thread) were tested in standardised polyurethane foam in three sequences.Sequence 1: A 6.5 mm screw was inserted into the foam block and the primary pull-out strength measured.Sequence 2: A 6.5 mm screw was inserted, removed, and then reinserted into the same foam block. The revision pull-out strength was then measuredSequence 3: A 6.5 mm screw was inserted, removed and a 7.5 mm screw of the same thread design was reinserted. The revision pull-out strength was then measured. RESULTS: The primary pull-out strength was similar across screw designs, although dual-thread screws showed higher primary pull-out strength (2628.8 N) compared to single-thread screws (2184.4 N, p < 0.05). For revision pull-out strength, the mixed-thread screws had significant reduction in revision pull-out strength of 18.6% (1890.2 N, p = 0.0173). Revision with a larger diameter screw improved the pull-out strength back to baseline. Single and dual thread screws showed no significant reduction in revision pull-out strength. CONCLUSIONS: The dual threaded screws provided the strongest primary pull-out strength for spinal fixation. The mixed thread screws however, had the poorest revision pull-out strength, decreasing by 18.6% compared to other screw designs. In cases where mixed threaded screws have to be revised (at the index or revision surgery), Surgeons should consider the use of larger diameter screws to improve the pull-out strength. LEVEL OF EVIDENCE: 5. PMID- 30005048 TI - Expectations for Postoperative Improvement in Health-Related Quality of Life in Young Patients With Lumbosacral Spondylolisthesis: A Prospective Cohort Study. AB - STUDY DESIGN: Prospective multicenter study of the changes in SRS-22 scores for 78 patients younger than 25 years old surgically treated for lumbosacral spondylolisthesis OBJECTIVE.: Report the change of health-related quality of life (HRQOL) in patients younger than 25 years after surgical treatment of lumbosacral spondylolisthesis. SUMMARY OF BACKGROUND DATA: There is a paucity of data with regard to the influence of surgical treatment on the HRQOL of patients with lumbosacral spondylolisthesis. Large prospective studies are needed to clearly define the benefits of surgery in the young patient population. METHODS: A prospective multicenter cohort of 78 patients younger than 25 years (14.8 +/- 2.9, range: 7.9-23.6 yr) undergoing posterior fusion for lumbosacral spondylolisthesis were enrolled. There were 17 patients with low-grade (<50%) and 61 with high-grade (>=50%) slips. SRS-22 scores calculated before surgery and after 2 years of follow-up were compared for all patients using two-tailed paired t tests. Subanalyses for low- and high-grade patients were done using two-tailed Wilcoxon signed ranked and paired t tests, respectively. The level of significance was set at 0.05. RESULTS: HRQOL was significantly improved 2 years after surgery for all domains and for the total score of the SRS-22 questionnaire. The individual total score was improved in 66 patients (85%), and 52 patients (67%) improved by at least 0.5 point. All domains and the total score of the SRS-22 questionnaire were significantly improved for high-grade patients, whereas only pain, function, and total score were improved for low-grade patients. CONCLUSION: This is the largest study comparing the HRQOL before and after surgery in young patients with low- and high-grade lumbosacral spondylolisthesis. HRQOL significantly improves after surgery for the majority of patients, especially for high-grade patients. This study helps clinicians to better counsel patients with regard to the benefits of surgery for lumbosacral spondylolisthesis. LEVEL OF EVIDENCE: 2. PMID- 30005049 TI - Does Systemic Administration of Parathyroid Hormone after Non-instrumented Spinal Fusion Surgery Improve Fusion Rates and Fusion Mass in Elderly Patients Compared to Placebo in Patients With Degenerative Lumbar Spondylolisthesis? AB - STUDY DESIGN: Prospective, randomized double-blinded placebo-controlled clinical trial. OBJECTIVE: To evaluate if 90-day subcutaneous injections with 20 MUg teriparatide increases the volume and quality of the fusion mass compared to placebo based on 12 month postop fine cut CT-scans. The secondary objective is to evaluate if PTH increases fusion rates compared to placebo. SUMMARY OF BACKGROUND DATA: Few studies have investigated the effects of PTH on fusion in patients undergoing spinal arthrodesis. Early studies showed a more robust fusion mass with PTH after spinal fusion surgery. But the efficiency of PTH on non instrumented spinal fusion surgery remains unclear. METHODS: Patients with degenerative spondylolisthesis scheduled for non-instrumented posterolateral fusion were randomized to receive 90-day subcutaneous injections with 20 MUg teriparatide (N = 41) or placebo (N = 46) in a 1:1 fashion. Fusion volume and quality was evaluated using 12 month postoperative fine cut CT scans. RESULTS: The two groups were comparable in terms of age, gender and numbers of levels operated. PTH treatment was well tolerated but provided no additional benefit versus placebo. Fusion rates, the mean volume and robustness of the fusion mass were similar between the PTH and placebo groups. CONCLUSIONS: 90-day subcutaneous administration of 20 MUg teriparatide did not increase fusion volume or improve the quality of the fusion mass in elderly patients compared to placebo after non instrumented spinal fusion surgery for degenerative spondylolisthesis. LEVEL OF EVIDENCE: 1. PMID- 30005050 TI - Perioperative Catheter Use as a Risk Factor for Surgical Site Infection After Cervical Surgery: An Analysis of 39,893 Patients. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To demonstrate the relationship between perioperative use of catheters and the incidence of surgical site infection (SSI) after cervical spine surgery, after adjusting for patient's age, severity of comorbidity, surgical approach, and use of instrumentation. SUMMARY OF BACKGROUND DATA: Although the association between SSI and the use of arterial catheters (ACs) or central venous catheters (CVCs) is established in cardiac surgery, the relation in the cervical spine was not well elucidated. METHODS: A private insurance database was analyzed. The incidence of SSI within 1 month postoperatively and the crude odds ratio (cOR) and 95% confidence interval (95% CI) were calculated based on the use of catheters. Subsequently, logistic regression analysis was performed to identify independent factors for SSI. Independent variables of the regression analysis included Charlson comorbidity index with the score of age, the use of CVC, the use of AC, surgical approach (anterior or posterior), and instrumentation (fusion or decompression alone). RESULTS: A total of 39,893 patients received cervical surgery between 2007 and 2015. Of these, 1.6% patients experienced an SSI. The incidence of SSI in patients treated with and without AC was 3.2% and 1.3%, respectively (cOR 2.44, 95% CI: 2.05-2.99, P < 0.001). Likewise, incidence of SSI in patients with and without CVC was 5.8% and 1.5%, respectively (cOR 2.61, 95% CI: 2.97-5.55, P < 0.001). Multivariate logistic regression analysis demonstrated that the adjusted OR was 1.66 in CVC use (95% CI: 1.08-2.46, P = 0.016), whereas the AC use was not significant variable (P = 0.086). CONCLUSION: The use of CVC can be a potential risk factor for SSI regardless of age, severity of comorbidity, surgical approach, or presence of instrumentation. Although the essential benefits of catheters are undisputed, our data can bring up the surgeon's attention to appropriate management of the CVC. LEVEL OF EVIDENCE: 3. PMID- 30005051 TI - Fuchs Endothelial Corneal Dystrophy: Update on Pathogenesis and Future Directions. AB - Fuchs endothelial corneal dystrophy (FECD) is the most common indication for corneal transplantation in the United States, accounting 36% of the almost 47,000 transplants performed in 2016. Although the surgical management of FECD has undergone a revolution over the past 20 years, its pathogenesis remains elusive, with multiple putative disease pathways and an ever increasing number of candidate genes thought to play a role. This review will summarize the recent advancements in our understanding of the biology of FECD, including potential parallels with neurodegenerative disease like amyotrophic lateral sclerosis and will highlight prospects for future treatment advances.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30005052 TI - A Study of Corneal Biomechanics in Delayed-Onset Mustard Gas Keratopathy Compared to Cases With Corneal Scarring and Normal Corneas. AB - PURPOSE: This study compares the corneal biomechanical properties, as measured with Corvis ST, in three groups of cases with delayed-onset mustard gas keratopathy (DMGK), chronic corneal scarring (CCS), and those with normal corneas. METHODS: Forty-five eyes were enrolled in the DMGK, CCS, and normal groups (15 eyes each). All patients were examined with the slitlamp and Corvis ST. Extracted corneal biomechanical parameters included first and second applanation time (AT1, AT2), first and second applanation length (AL1, AL2), first and second applanation velocity (AV1, AV2), deformation amplitude (DA), highest concavity time, peak distance, highest concavity radius (HCR), central corneal thickness, corrected intraocular pressure (IOP), and noncorrected IOP. RESULTS: The mean age of the participants in the DMGK, CCS, and normal groups was 49.20+/-5.16, 60.40+/-22.92, and 44.60+/-8.32 years, respectively. Comparison between DMGK and CCS groups showed significant differences in AT1, AT2, corrected IOP, and noncorrected IOP. There were also significant differences in AT1, AT2, HCR, DA, and noncorrected IOP between the DMGK and normal groups. None of the parameters were significantly different between the CCS and normal groups. CONCLUSION: There seems to be reduced corneal rigidity and stiffness in cases exposed to mustard gas, which causes the cornea in the DMGK group to become applanated more easily and take longer to rebound compared with the other two groups. Also, IOP was lower than normal in the DMGK group, and thus, misdiagnosis of glaucoma is likely for these patients. PMID- 30005053 TI - Pentacam Accuracy in Discriminating Keratoconus From Normal Corneas: A Diagnostic Evaluation Study. AB - OBJECTIVES: This study aims to determine the diagnostic ability of Pentacam indices for keratoconus and identifying the best index for differentiating diseased from normal cases. METHOD: In this study, 150 keratoconus patients and 150 refractive surgery candidates with a definitive diagnosis of normal healthy corneas were enrolled. Initially, the placido disk topography imaging was performed. The keratoconus and normal corneas were defined based on placido disk topographic data from Rabinowitz-McDonnell. After complete eye examinations for all participants, they underwent Pentacam imaging, and corneal surface topographic indices were extracted. Multiple logistic regression was used to determine the best indices for differentiating diseased from healthy corneas, and the receiver operating curve was calculated to determine the diagnostic capability of each index. RESULTS: Among the studied indices, the keratoconus index (KI), index of vertical asymmetry (IVA), thinnest point (TP), and maximum keratometry (Kmax) were found capable of detecting keratoconus. Among these, IVA was the best index, with an area under curve (AUC) of 95.24%. The best cutoff point for IVA was 0.20 MUm, and its sensitivity and specificity were 87.50% and 96.30%, respectively. Comparison of the AUC of different indices showed that only TP and IVA significantly differed (P=0.002). The combination of KI, IVA, Kmax, and TP indices leads to correct detection in 78% of cases. CONCLUSION: Measuring corneal topographic indices using Pentacam can be helpful in the diagnosis of keratoconus. According to the results of this study, IVA is the best diagnostic index for keratoconus. However, it is recommended to use a combination of Pentacam indices for more accurate differentiation of keratoconus from normal cases. PMID- 30005054 TI - Corneal Higher-Order Aberrations in Eyes With Corneal Scar After Traumatic Perforation. AB - OBJECTIVES: To evaluate corneal higher-order aberrations (HOAs) in eyes with corneal scar after traumatic perforation and their correlation with visual acuity. METHODS: This retrospective consecutive case study included 40 eyes of 40 consecutive patients (mean age, 39.2+/-21.6 years), treated for traumatic corneal perforation at Tokyo Dental College, and 18 normal control eyes. Higher-order aberrations of anterior and posterior corneal surfaces and total cornea were analyzed by swept-source optical coherence tomography. Correlations between corneal HOAs and visual acuity were analyzed. RESULTS: Higher-order aberrations within 4-mm diameter were significantly larger in eyes with corneal perforation (anterior surface, 0.51+/-0.54 MUm; posterior surface, 0.20+/-0.14; and total cornea, 0.52+/-0.50) as compared to normal controls (0.10+/-0.02, 0.02+/-0.01, and 0.09+/-0.02, respectively; all P<0.001). Higher-order aberrations within 6-mm diameter were significantly larger in eyes with corneal perforation (anterior surface, 1.15+/-1.31; posterior surface, 0.31+/-0.23; and total cornea, 1.09+/ 1.28) as compared to normal controls (0.21+/-0.06, 0.06+/-0.01, and 0.19+/-0.06, respectively; all P<0.001). The most common topography pattern observed was the minimal change pattern (37.5%), followed by asymmetric pattern (30.0%). Visual acuity significantly correlated with corneal HOAs (anterior surface: R=0.646, P<0.001; posterior surface: R=0.400, P=0.033; and total cornea: R=0.614, P<0.001). CONCLUSIONS: Corneal scar after traumatic perforations not only induces corneal opacity, but also increases corneal HOAs, which indicates a direct effect on visual acuity. PMID- 30005055 TI - Anterior Corneal Curvature and Aberration Changes After Scleral Lens Wear in Keratoconus Patients With and Without Ring Segments. AB - OBJECTIVE: To evaluate changes in the anterior corneal curvature and aberrometry after scleral contact lens wear in keratoconus (KC) subjects with and without intracorneal ring segments (ICRS). METHODS: Twenty-six subjects diagnosed with keratoconus were selected to participate in the study. Subjects were divided into 2 groups, those with ICRS (KC-ICRS group) and those without ICRS (KC group). Subjects were instructed to wear 16.5-mm scleral lenses for 8 hours. Topographic and aberrometric parameters were evaluated before lens wear and immediately after lens removal. Anterior corneal curvature was evaluated at corneal diameters of 2, 4, 6, and 8 mm, and corneal aberrations were measured at 4-, 6-, and 8-mm pupil diameters. RESULTS: The mean age of subjects was 36.95+/-8.95 years. In KC group, there was a statistically significant flattening of the central corneal curvature, from 6.98 to 7.09 mm (P<0.05). No changes were found in the central corneal curvature in the KC-ICRS group. The KC group showed anterior corneal curvature flattening, mainly in the nasal quadrant. The KC-ICRS group showed flattening primarily in the inferior hemisphere. In the KC group, spherical aberration for 6-mm pupil increased significantly. In the KC-ICRS group, changes in aberrations were significant for high-order root mean square at 4- and 6-mm pupil diameters (P<0.05), for oblique astigmatism for 4 mm and 6 mm, and for vertical coma for 4-mm pupil (P<0.05). CONCLUSION: Short-term scleral lens wear showed flattening of the anterior corneal surface in all subjects. In the KC group, the flattening was more pronounced in the nasal quadrant while changes were more pronounced inferiorly in KC-ICRS group. PMID- 30005056 TI - Conjunctival Impression Cytology and Tear-Film Changes in Patients With Inflammatory Bowel Disease. AB - PURPOSE: To evaluate the ocular surface changes and tear-film functions in patients with inflammatory bowel disease (IBD). METHODS: The IBD group included 57 patients, and the control group included 29 healthy individuals. The Schirmer I test, tear breakup time (TBUT), corneal and conjunctiva fluorescent staining, and conjunctival impression cytology tests were performed to both groups. RESULTS: The rate of dry eye was 56.1% and 10.3% in the IBD and control groups, respectively, as assessed by the Schirmer I test (P<0.001). The rate of dry eye was 52.6% and 20.8% in the IBD and control groups, respectively through TBUT (P=0.004). The Ocular Surface Disease Index scores of the IBD group (15.25+/ 7.31) were significantly higher than the control group (11.75+/-7.33) (P=0.039). According to the Oxford scheme, mild-to-moderate staining was 54.4% in the IBD group and 6.9% in the control group (P<0.001). Nelson Staging System showed that 69% of the IBD group had stage 2 or 3 impression cytology, whereas none of the control group had stage 2 or 3 impression cytology (P<0.001). Using the Schirmer I test, the rate of dry eye was 55.8% of the patients with IBD receiving 5 aminosalicylic acid (5-ASA) and 61.5% of the patients with IBD receiving both 5 ASA and azathioprine (P=0.485). CONCLUSIONS: Our study results showed that dry eye was 3 times higher in the IBD group than the control group. But, the duration of disease seems not to have effect on dry eye. PMID- 30005057 TI - Effort, Discomfort, Group III/IV Afferents, Bioenergetics, and Motor Unit Recruitment. PMID- 30005058 TI - Response. PMID- 30005059 TI - Three Weeks of Overload Training Increases Resting Muscle Sympathetic Activity Corrigendum. PMID- 30005060 TI - Lysophosphatidic Acid Promotes Expression and Activation of Matrix Metalloproteinase 9 (MMP9) in THP-1 Cells via Toll-Like Receptor 4/Nuclear Factor kappaB (TLR4/NF-kappaB) Signaling Pathway. AB - BACKGROUND Lysophosphatidic acid (LPA) is an active compound of oxidized low density lipoprotein that serves as an endogenous TLR4 ligand. Ligand activation of TLR4 activates nuclear factor-kappaB (NF-kappaB) and the transcription of NF kappaB-regulated inflammatory cytokines, which are involved in the development of atherosclerosis. MMP9 is a member of the MMP family and can affect plaque stability. However, the mechanism responsible for the effect of LPA on the expression and activation of MMP9 has not been fully elucidated. In the present study we examined the effect of LPA on MMP9 expression and activity in THP-1 cells and the involvement of Toll-like receptor 4/nuclear factor-kappaB (TLR4/NF kappaB) signaling pathway in this effect. MATERIAL AND METHODS Human THP-1 cells were treated with 0-10 MUM LPA for 4 h, or treated with 1 MUM LPA for 0-8 h, and were then transfected with TLR4-specific siRNA or treated with 20 MUg/ml cafestol acid phenethyl ester (CAPE, an NF-kappaB inhibitor). MMP9 mRNA and protein levels were measured by quantitative RT-PCR and Western blot analysis, respectively, and MMP9 activity was measured by zymography. RESULTS LPA upregulated MMP9 mRNA and protein levels and MMP9 activity in THP-1 cells in both concentration- and time dependent manners. Transfection of cells with TLR4-siRNA-2 or treatment with CAPE significantly inhibited the upregulated MMP9 expression and activation. This inhibition was further enhanced by combining the TLR4-siRNA-2 transfection and CAPE pretreatment. CONCLUSIONS LPA can promote MMP9 expression and enhance MMP9 activity in THP-1 cells, in part via the TLR4/NF-kB signaling pathway. PMID- 30005061 TI - Species in ecosystems and all that jazz. AB - Ecosystem ecologists explore how different kinds of species fit together to drive ecosystem processes such as nutrient cycling and productivity. This research is motivated by theories that assume that the suite of traits that characterize a species' form determines its function, that these traits have become fixed over evolutionary time, and that ensuing ecosystem process are not resilient to environmental change. Here, I explore new research that re-evaluates this theory. Recent results suggest that functional traits are malleable, enabling species to rapidly respond and adapt to each other as environmental conditions change with predictable effects on ecosystem processes. These basic research findings suggest that species adaptations may impart in ecosystems an inherent capacity to weather environmental changes, thereby offering deeper understanding about which biological attributes protect ecological functions and which are needed to restore damaged ecosystems. PMID- 30005062 TI - Highly diverged novel subunit composition of apicomplexan F-type ATP synthase identified from Toxoplasma gondii. AB - The mitochondrial F-type ATP synthase, a multisubunit nanomotor, is critical for maintaining cellular ATP levels. In T. gondii and other apicomplexan parasites, many subunit components necessary for proper assembly and functioning of this enzyme appear to be missing. Here, we report the identification of 20 novel subunits of T. gondii F-type ATP synthase from mass spectrometry analysis of partially purified monomeric (approximately 600 kDa) and dimeric (>1 MDa) forms of the enzyme. Despite extreme sequence diversification, key FO subunits a, b, and d can be identified from conserved structural features. Orthologs for these proteins are restricted to apicomplexan, chromerid, and dinoflagellate species. Interestingly, their absence in ciliates indicates a major diversion, with respect to subunit composition of this enzyme, within the alveolate clade. Discovery of these highly diversified novel components of the apicomplexan F-type ATP synthase complex could facilitate the development of novel antiparasitic agents. Structural and functional characterization of this unusual enzyme complex will advance our fundamental understanding of energy metabolism in apicomplexan species. PMID- 30005063 TI - Metabolic fingerprint of insulin resistance in human polymorphonuclear leucocytes. AB - The present study was aimed at determining the metabolic profile of PMNs in obese subjects, and to explore its potential relationship with insulin resistance (IR). To achieve this goal, a pilot clinical study was performed using PMNs from 17 patients with obesity and IR, and 17 lean controls without IR, which was validated in an additional smaller cohort (consisting of 10 patients and 10 controls). PMNs were isolated from peripheral blood and nuclear magnetic resonance was used to perform the metabolomic analysis. A total of 48 metabolites were quantified. The main metabolic change found in PMNs was a significant increase in 2-aminoisobutyric acid with a direct correlation with HOMA-IR (p<0.001), BMI (p<0.000001) and waist circumference (p<0.000001). By contrast, a decrease of 3-hydroxyisovalerate was observed with an inverse correlation with HOMA-IR (p = 0.001), BMI (p = 0.001) and waist circumference (p = 0.0001). Notably, the metabolic profile in plasma was different than that obtained in PMNs. In summary, our results suggest that the change in 3-hydroxyisovalerate and 2-aminoisobutyric is the key metabolic fingerprint in PMNs of obese subjects with IR. In addition, our methodology could be an easy and reliable tool for monitoring the effect of treatments in the setting of precision medicine. PMID- 30005064 TI - Comparative analysis of the male inflorescence transcriptome profiles of an ms22 mutant of maize. AB - In modern agricultural production, maize is the most successful crop utilizing heterosis. 712C-ms22 is an important male sterile material in maize. In this study, we performed transcriptome sequencing analysis of the V10 stage of male inflorescence. Through this analysis, 27.63 million raw reads were obtained, and trimming of the raw data revealed 26.63 million clean reads, with an average match rate of 94.64%. Using Tophat software, we matched these clean reads to the maize reference genome. The abundance of 39,622 genes was measured, and 35,399 genes remained after filtering out the non-expressed genes across all the samples. These genes were classified into 19 categories by clusters of orthologous groups of protein annotation. Transcriptome sequencing analysis of the male sterile and fertile 712C-ms22 maize revealed some key DEGs that may be related to metabolic pathways. qRT-PCR analysis validated the gene expression patterns identified by RNA-seq. This analysis revealed some of the essential genes responsible for pollen development and for pollen tube elongation. Our findings provide useful markers of male sterility and new insights into the global mechanisms mediating male sterility in maize. PMID- 30005065 TI - Impact of primary care provider density on detection and diagnosis of cutaneous melanoma. AB - INTRODUCTION: Early diagnosis of cutaneous melanoma is critical in preventing melanoma-associated deaths, but the role of primary care providers (PCPs) in diagnosing melanoma is underexplored. We aimed to explore the association of PCP density with melanoma incidence and mortality. METHODS: All cases of cutaneous melanoma diagnosed in the United States from 2008-2012 and reported in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed in 2016. County-level primary care physician density was obtained from the Area Health Resources File (AHRF). We conducted multivariate linear regression using 1) average annual melanoma incidence or 2) average annual melanoma mortality by county as primary outcomes, adjusting for demographic confounders and dermatologist density. Cox proportional hazard regression was conducted using individual outcome data from SEER with the same covariates. RESULTS: Across 611 counties, 167,305 cases of melanoma were analyzed. Per 100,000 people, an additional 10 PCPs per county was associated with 1.62 additional cases of melanoma per year (95% CI 1.06-2.18, p<0.001). This increased incidence occurred disproportionally in early-stage melanoma (Stage 0: 0.69 cases (0.38-1.00), p<0.001; Stage I: 0.63 cases (0.37-0.89), p<0.001; Stage II: 0.11 cases (0.03 0.19), p = 0.005). There was no statistically significant association between PCP density and incidence of stage III or IV melanoma, or with melanoma-specific mortality. Survival analysis demonstrated elimination of 5-year post-diagnosis mortality risk in medically underserved counties after adjusting for stage. CONCLUSIONS: Higher densities of PCPs may be linked to increased diagnosis of early-stage melanoma without corresponding decreases in late-stage diagnoses or melanoma-associated mortality. PMID- 30005066 TI - Human papillomavirus (HPV) prevalence and associated risk factors in women from Curacao. AB - BACKGROUND: In the Caribbean region, a notable difference in HPV-prevalence and genotypes distribution between the islands is observed. Recently we found in Curacao a low incidence of HPV16 and 18 in cervical cancer compared to the standard world population. We aimed to determine HPV-prevalence, HPV-genotype distribution and associated risk-factors in women from Curacao. METHODS: 5000 women aged 25-65 years were randomly selected from the national Population Register. HPV was detected by means of GP5+/6+PCR EIA and GP 5+/6+amplimers from HPV-positive samples were genotyped with a reverse hybridisation assay. We also collected personal data and data on risk-factors. RESULTS: 1075 women were enrolled in the study. Overall HPV-prevalence was 19.7%. Most frequent genotypes were HPV16 (2.3%), 35 (2.1%) and 52 (1.8%). Twenty-seven women detected with abnormal cytology (i.e.>=ASC-US) were referred for biopsy. In women with normal cytology (n = 1048), HPV-prevalence was 17.9% and the most common high-risk HPV (hrHPV)-types were HPV35 (2.0%), 18 (1.8%), 16 (1.5%) and 52 (1.5%). The highest HPV-prevalence (32.8%) was found in the age-group: 25-34 (n = 247). HPV positive women started sex at a younger age (p = 0.032). CONCLUSIONS: HPV-prevalence in the overall population is high and HPV16 was the most common genotype followed by 35 and 18. In women with normal cytology HPV35 is the most common genotype followed by HPV18, 52 and 16. The high HPV-prevalence (32.8%) in women of 25-34 years argue for introduction of cervical cancer prevention strategies. HPV-type distribution found in Curacao should be taken into account when considering the choice for prophylactic vaccination. PMID- 30005067 TI - Dietary diversity of 6- to 59-month-old children in rural areas of Moramanga and Morondava districts, Madagascar. AB - BACKGROUND: A dietary imbalance or a disregard for the nutritional needs of children during early childhood can affect their growth. From the age of six months, breast milk is no longer able to meet the energy and micronutrient needs of children; the consumption of adequate complementary foods is therefore essential. Various indicators have been used to assess the quality of children's diets, and the dietary diversity score is a good indicator of children's diets. The objective of this study was to describe the dietary practices of children in rural areas of Moramanga and Morondava, Madagascar, and to identify the determinants of low dietary diversity to prioritize nutritional interventions. METHODS: We collected dietary data in 2014 on children aged 6-59 months in a study on the determinants of chronic malnutrition using the 24-hour recall method. Data on the characteristics of households and mothers were also collected. We carried out bivariate and multivariate analyses to identify the determinants of low dietary diversity scores for children. RESULTS: We included 1824 children: 893 from Moramanga and 931 from Morondava. Approximately 42.1% [95% CI: 39.0-45.4] of the children from Moramanga and 47.6% [95% CI: 44.4-50.8] of those from Morondava had a poorly diversified diet, consisting mainly of foods rich in carbohydrates and poor in meat products. Poor maternal education was associated with a high likelihood of having a non-varied diet in both study areas; the adjusted odds ratios were 2.2 [95% CI: 1.3-3.8] and 4.0 [95% CI: 2.5 6.4] for children from mothers with lower education levels for Moramanga and Morondava, respectively. For children recruited in Morondava, having low household socioeconomic status (adjusted OR: 1.8, 95% CI: 1.2-2.8) and belonging to a household without livestock was associated with a low dietary diversity score (adjusted OR: 1.8, 95% CI 1.2-2.7). CONCLUSION: Our results show the need to improve girls' education, adapt nutrition education programs for mothers based on their level of education, and strengthen poverty reduction programs. PMID- 30005068 TI - How does nonsyndromic craniosynostosis affect on bone width of nasal cavity in children? - Computed tomography study. AB - Craniosynostosis is caused by premature fusion of one or more cranial sutures, restricting skull, brain and face growth. Nonsyndromic craniosynostosis could disturb the proportions of face. Although morphometric diameters of nasal cavity in healthy children are already known, they have not been established yet in children with nonsyndromic craniosynostosis. The aim our study was to check whether diameters of bone structures of nasal cavity in children with nonsyndromic craniosynostosis measured in CT are within normal range. 249 children aged 0-36 months (96 with clinical diagnosis of nonsyndromic craniosynostosis and 153 in control group) were included into the study. The following diameters were measured on head CT scans: anterior bony width (ABW), bony choanal aperture width (BCAW), right and left posterior bony width (between bone sidewall and nasal cavity septum-RPBW and LPBW). The study group has been divided into 4 categories, depending on child's age. The dimensions measured between bone structures of nasal cavity were statistically significantly lower in comparison to the control group. They did not depend on the sex for ABW, nor on age in groups 7-12 months and < 2 years for BCAW, RPBW and LPBW. The measured dimensions increased with age. In children with nonsyndromic craniosynostosis the diameter of pyriform aperture and bony choanal aperture were lower than in controls, what may be described as fronto-orbital anomalies. Morphometric measurements of anthropometric indicators on CT scans could be used as standards in the clinical identification of craniosynostosis type and may help in planning surgical procedures, particularly in the facial skeleton in children. PMID- 30005069 TI - 3D kidney segmentation from abdominal diffusion MRI using an appearance-guided deformable boundary. AB - A new technique for more accurate automatic segmentation of the kidney from its surrounding abdominal structures in diffusion-weighted magnetic resonance imaging (DW-MRI) is presented. This approach combines a new 3D probabilistic shape model of the kidney with a first-order appearance model and fourth-order spatial model of the diffusion-weighted signal intensity to guide the evolution of a 3D geometric deformable model. The probabilistic shape model was built from labeled training datasets to produce a spatially variant, independent random field of region labels. A Markov-Gibbs random field spatial model with up to fourth-order interactions was adequate to capture the inhomogeneity of renal tissues in the DW MRI signal. A new analytical approach estimated the Gibbs potentials directly from the DW-MRI data to be segmented, in order that the segmentation procedure would be fully automatic. Finally, to better distinguish the kidney object from the surrounding tissues, marginal gray level distributions inside and outside of the deformable boundary were modeled with adaptive linear combinations of discrete Gaussians (first-order appearance model). The approach was tested on a cohort of 64 DW-MRI datasets with b-values ranging from 50 to 1000 s/mm2. The performance of the presented approach was evaluated using leave-one-subject-out cross validation and compared against three other well-known segmentation methods applied to the same DW-MRI data using the following evaluation metrics: 1) the Dice similarity coefficient (DSC); 2) the 95-percentile modified Hausdorff distance (MHD); and 3) the percentage kidney volume difference (PKVD). High performance of the new approach was confirmed by the high DSC (0.95+/-0.01), low MHD (3.9+/-0.76) mm, and low PKVD (9.5+/-2.2)% relative to manual segmentation by an MR expert (a board certified radiologist). PMID- 30005070 TI - Fetal Huanjiang mini-pigs exhibit differences in nutrient composition according to body weight and gestational period. AB - Low birth weight may negatively affect energy storage and nutrient metabolism, and impair fetal growth and development. We analyzed effects of body weight (BW) and gestational period on nutrient composition in fetal Huanjiang mini-pigs. Fetuses with the lowest BW (LBW), middle BW (MBW), and highest BW (HBW) were collected at days 45, 75, and 110 of gestation. Crude protein (CP), crude fat, amino acid (AA), and fatty acid (FA) concentrations were determined. The BW gain, carcass weight, fat percentage, and uterus weight of sows increased as gestation progressed, as did litter weight, average individual fetal weight, fetal body weight, and dry matter (DM). The concentrations of Ala, Arg, crude fat, Gly, Pro, Tyr, C14:0, C16:0, C16:1, C18:1n9c, C18:2n6c, C18:3n3, C18:3n6, C20:0, C20:3n6, saturated FA (SFA), and monounsaturated FA (MUFA) increased significantly as gestation progressed. The percentage of skeleton, and the ratio of the liver, lung, and stomach to BW decreased as gestation progressed. There were also significant reductions in the concentrations of CP, Asp, Glu, His, Ile, Leu, Lys, Phe, Ser, Thr, essential AA (EAA), acidic AA, C17:0, C20:4n6, C22:6n3, unsaturated FA (UFA), polyunsaturated FA (PUFA), n-3PUFA, n-6PUFA as gestation progressed, and reductions in EAA/total AA (TAA), PUFA/SFA, and n-3/n-6 PUFA. The LBW fetuses exhibited the lowest BW and crude fat, C14:0, C16:1, C17:0, C18:2n6c, and MUFA concentrations at days 75 and 110 of gestation. They also exhibited lower Tyr concentration at day 45 of gestation and lower Glu concentration at day 75 of gestation than HBW fetuses. These findings suggest that LBW fetuses exhibit lower amounts of crude fat and several FAs during mid-gestation and late gestation, which may in turn affect adaptability, growth, and development. PMID- 30005071 TI - Sequence features governing aggregation or degradation of prion-like proteins. AB - Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer's Disease, Huntington's Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prions, which generally result from self-propagating protein aggregates, must therefore evade or outcompete these quality control systems in order to form and propagate in a cellular context. We developed a genetic screen in yeast that allowed us to explore the sequence features that promote degradation versus aggregation of a model glutamine/asparagine (Q/N)-rich prion domain from the yeast prion protein, Sup35, and two model glycine (G)-rich prion-like domains from the human proteins hnRNPA1 and hnRNPA2. Unexpectedly, we found that aggregation propensity and degradation propensity could be uncoupled in multiple ways. First, only a subset of classically aggregation-promoting amino acids elicited a strong degradation response in the G-rich prion-like domains. Specifically, large aliphatic residues enhanced degradation of the prion-like domains, whereas aromatic residues promoted prion aggregation without enhancing degradation. Second, the degradation promoting effect of aliphatic residues was suppressed in the context of the Q/N rich prion domain, and instead led to a dose-dependent increase in the frequency of spontaneous prion formation. Degradation suppression correlated with Q/N content of the surrounding prion domain, potentially indicating an underappreciated activity for these residues in yeast prion domains. Collectively, these results provide key insights into how certain aggregation prone proteins may evade protein quality control degradation systems. PMID- 30005072 TI - Are stronger memories forgotten more slowly? No evidence that memory strength influences the rate of forgetting. AB - Information stored in visual short-term memory is used ubiquitously in daily life; however, it is forgotten rapidly within seconds. When more items are to be remembered, they are forgotten faster, potentially suggesting that stronger memories are forgotten less rapidly. Here we tested this prediction with three experiments that assessed the influence of memory strength on the rate of forgetting of visual information without manipulating the number of items. Forgetting rate was assessed by comparing the accuracy of reports in a delayed estimation task following relatively short and long retention intervals. In the first experiment, we compared the forgetting rate of items that were directly fixated, to items that were not. In Experiments 2 and 3 we manipulated memory strength by extending the exposure time of one item in the memory array. As expected, direct fixation and longer exposure led to better accuracy of reports, reflecting stronger memory. However, in all three experiments, we did not find evidence that increased memory strength moderated the forgetting rate. PMID- 30005074 TI - miRAW: A deep learning-based approach to predict microRNA targets by analyzing whole microRNA transcripts. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to partially complementary regions within the 3'UTR of their target genes. Computational methods play an important role in target prediction and assume that the miRNA "seed region" (nt 2 to 8) is required for functional targeting, but typically only identify ~80% of known bindings. Recent studies have highlighted a role for the entire miRNA, suggesting that a more flexible methodology is needed. We present a novel approach for miRNA target prediction based on Deep Learning (DL) which, rather than incorporating any knowledge (such as seed regions), investigates the entire miRNA and 3'TR mRNA nucleotides to learn a uninhibited set of feature descriptors related to the targeting process. We collected more than 150,000 experimentally validated homo sapiens miRNA:gene targets and cross referenced them with different CLIP-Seq, CLASH and iPAR-CLIP datasets to obtain ~20,000 validated miRNA:gene exact target sites. Using this data, we implemented and trained a deep neural network-composed of autoencoders and a feed-forward network-able to automatically learn features describing miRNA mRNA interactions and assess functionality. Predictions were then refined using information such as site location or site accessibility energy. In a comparison using independent datasets, our DL approach consistently outperformed existing prediction methods, recognizing the seed region as a common feature in the targeting process, but also identifying the role of pairings outside this region. Thermodynamic analysis also suggests that site accessibility plays a role in targeting but that it cannot be used as a sole indicator for functionality. Data and source code available at: https://bitbucket.org/account/user/bipous/projects/MIRAW. PMID- 30005073 TI - Decoding the chromatin proteome of a single genomic locus by DNA sequencing. AB - Transcription, replication, and repair involve interactions of specific genomic loci with many different proteins. How these interactions are orchestrated at any given location and under changing cellular conditions is largely unknown because systematically measuring protein-DNA interactions at a specific locus in the genome is challenging. To address this problem, we developed Epi-Decoder, a Tag chromatin immunoprecipitation-Barcode-Sequencing (TAG-ChIP-Barcode-Seq) technology in budding yeast. Epi-Decoder is orthogonal to proteomics approaches because it does not rely on mass spectrometry (MS) but instead takes advantage of DNA sequencing. Analysis of the proteome of a transcribed locus proximal to an origin of replication revealed more than 400 interacting proteins. Moreover, replication stress induced changes in local chromatin proteome composition prior to local origin firing, affecting replication proteins as well as transcription proteins. Finally, we show that native genomic loci can be decoded by efficient construction of barcode libraries assisted by clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Thus, Epi-Decoder is an effective strategy to identify and quantify in an unbiased and systematic manner the proteome of an individual genomic locus by DNA sequencing. PMID- 30005076 TI - Correction: Functional male accessory glands and fertility in Drosophila require novel ecdysone receptor. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006788.]. PMID- 30005075 TI - A potential biomarker hsa-miR-200a-5p distinguishing between benign thyroid tumors with papillary hyperplasia and papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most common endocrine cancer with a significantly increase of the incidence recently. Several cytokines, such as thyroid peroxidase (TPO), cluster of differentiation 56 (CD56), Galectin-3, mesothelial cell (MC), cytokeratin 19 (CK19) and BRAF (B-raf) were recommended to be tested by immunohistochemistry (IHC) for a definitive diagnosis, but were still limited in clinical use because of their relative lower sensitivity and specificity. MicroRNA (miRNA), as a new molecular biomarkers, however, has not been reported yet so far. To address this, hsa-miR-200a-5p, a miRNA, was selected and detected in PTC patients by in situ hybrization with benign thyroid tumor with papillary hyperplasia as a control, and the differential expression of hsa miR-200a-5p between fresh PTC tissues and control was detected by qRT-PCR. Expressive levels of cytokines of TPO, CD56, Galectin-3, MC, CK19 and B-raf were also detected by immunohistochemistry. The correlation was analyzed by SPSS software using Spearman methods. As expected, the hsa-miR-200a-5p expressive level was significantly increased in PTC patients, compared to that of control, and was consistent with that of TPO, CD56, Galectin-3, MC, CK19 and B-raf. In addition, expression of hsa-miR-200a-5p showed negative correlation to that of TPO (rs = - 0.734; **: P < 0.01) and CD56 (rs = - 0.570; **: P < 0.01), but positive correlation to that of Galectin-3 (rs = 0.601; **: P < 0.01), MC (rs = 0.508; **: P < 0.01), CK19 (rs = 0.712; **: P < 0.01) and B-raf (rs = 0.378; **: P < 0.01). PTC and papillary benign thyroid papillary hyperplasia are difficult to distinguish in morphology, so requiring immunohistochemistry to further differentiate the diagnosis, however, for the existing clinical common diagnostic marker for immunohistochemistry, the sensitivity and accuracy are low, it is easy to miss diagnosis. Therefore, there is an urgent need for a rapid and sensitive molecular marker. So miR-200a-5p can be used to assist in the diagnosis of PTC at the molecular level, and as a biomarker, can be effectively used to distinguish between PTC and benign thyroid tumor with papillary hyperplasia. PMID- 30005077 TI - Functional atlases for analysis of motor and neuropsychological outcomes after medial globus pallidus and subthalamic stimulation. AB - Anatomical atlases have been developed to improve the targeting of basal ganglia in deep brain stimulation. However, the sole anatomy cannot predict the functional outcome of this surgery. Deep brain stimulation is often a compromise between several functional outcomes: motor, fluency and neuropsychological outcomes in particular. In this study, we have developed anatomo-clinical atlases for the targeting of subthalamic and medial globus pallidus deep brain stimulation. The activated electrode coordinates of 42 patients implanted in the subthalamic nucleus and 29 patients in the medial globus pallidus were studied. The atlas was built using the representation of the volume of tissue theoretically activated by the stimulation. The UPDRS score was used to represent the motor outcome. The Stroop test was represented as well as semantic and phonemic fluencies. For the subthalamic nucleus, best motor outcomes were obtained when the supero-lateral part of the nucleus was stimulated whereas the semantic fluency was impaired in this same region. For the medial globus pallidus, best outcomes were obtained when the postero ventral part of the nucleus was stimulated whereas the phonemic fluency was impaired in this same region. There was no significant neuropsychological impairment. We have proposed new anatomo-clinical atlases to visualize the motor and neuropsychological consequences at 6 months of subthalamic nucleus and pallidal stimulation in patients with Parkinson's disease. PMID- 30005078 TI - pH plays a role in the mode of action of trimethoprim on Escherichia coli. AB - Metabolomics-based approaches were applied to understand interactions of trimethoprim with Escherichia coli K-12 at sub-minimum inhibitory concentrations (MIC~0.2, 0.03 and 0.003 mg L-1). Trimethoprim inhibits dihydrofolate reductase and thereby is an indirect inhibitor of nucleic acid synthesis. Due to the basicity of trimethoprim, two pH levels (5 and 7) were selected which mimicked healthy urine pH. This also allowed investigation of the effect on bacterial metabolism when trimethoprim exists in different ionization states. UHPLC-MS was employed to detect trimethoprim molecules inside the bacterial cell and this showed that at pH 7 more of the drug was recovered compared to pH 5; this correlated with classical growth curve measurements. FT-IR spectroscopy was used to establish recovery of reproducible phenotypes under all 8 conditions (3 drug levels and control in 2 pH levels) and GC-MS was used to generate global metabolic profiles. In addition to finding direct mode-of-action effects where nucleotides were decreased at pH 7 with increasing trimethoprim levels, off target pH-related effects were observed for many amino acids. Additionally, stress-related effects were observed where the osmoprotectant trehalose was higher at increased antibiotic levels at pH 7. This correlated with glucose and fructose consumption and increase in pyruvate-related products as well as lactate and alanine. Alanine is a known regulator of sugar metabolism and this increase may be to enhance sugar consumption and thus trehalose production. These results provide a wider view of the action of trimethoprim. Metabolomics indicated alternative metabolism areas to be investigated to further understand the off target effects of trimethoprim. PMID- 30005079 TI - Efficacy of Hank's balanced salt solution compared to other solutions in the preservation of the periodontal ligament. A systematic review and meta-analysis. AB - This systematic review and meta-analysis (MA) aimed to verify the capacity of different storage media to preserve viability of periodontal ligament cells in comparison to Hank's Balanced Salt Solution. The searches, selection process, data extraction and Risk of Bias control were conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Five MA were conducted to compare the cell viability between milk versus Hank's balanced salt solution (HBSS) in a dichotomous (1) or continuous (2) data model; tap water versus HBSS (3); medicinal herbals versus HBSS (4); and saline solution versus HBSS (5). 693 potentially studies were identified, with 18 studies included in the qualitative and 8 studies included in the quantitative analysis. Most of the articles presented a low risk of bias. HBSS medium showed a superior ratio of cell viability compared to tap water (RR 0.26; 95% CI [0.21, 0.32]; p < 0.00001; I2 = 96%) and saline solution (RR 0.76; 95% CI [0.69, 0.84]; p < 0.0001; I2 = 99%). Herbal medicines showed a similar ratio of cell viability when compared to HBSS (RR 0.97; 95% CI [0.94, 1.00]; p = 0.08; I2 = 50%). Mixed results were observed between milk and HBSS: a superior ratio of HBSS was observed in an overall evaluation (RR 0.26; 95% CI [0.21, 0.32]; p < 0.00001; I2 = 96%), and a similar ratio was achieved when periodontal ligament (PDL) cells were removed prior to immersion in the solution (RR 0.94; 95% CI [0.87, 1.01]; p = 0.10; I2 = 0%) or rinsed in tap water or maintained in open air prior to immersion (RR 0.63; 95% CI [0.35, 1.12]; p = 0.11; I2 = not applicable). This systematic review and MA suggests that milk and herbal medicines could represent an alternative to HBSS. However, more studies are necessary to obtain a reliable conclusion. PMID- 30005080 TI - Are maternal healthcare services accessible to vulnerable group? A study among women with disabilities in rural Nepal. AB - BACKGROUND: Studies report that vulnerable groups like people with disabilities have less access to healthcare. This study compares health service access between women with and without disabilities in general and explores the challenges encountered by women with disabilities in accessing maternal healthcare services during pregnancy. METHODS: A mixed method study was conducted in Rupandehi district of Nepal implementing a cross-sectional survey among 354 women including 79 women with disabilities, supplemented by 43 in-depth interviews. Descriptive and bivariate statistical analysis of quantitative data using Pearson's Chi square test for association was carried out, while qualitative data were analysed following the theme content analysis using a framework approach. RESULTS: The vast majority of women from both groups, women with and without disabilities (71% vs 74%) reported that the nearest health facility from their location was more than 30 minutes walking distance (P>0.05). Half of the women with disabilities walked to health facilities for ANC check-ups. Over one-third of women without disabilities and a slightly lesser proportion of women with disabilities (29%) used a low-cost means of transport (rikshaw, bi/tri-cycles) (P>0.05). Distribution of health facilities found uneven and poorly linked with road transport facilities. None of the health facilities accommodated the needs of women with disabilities with accessible buildings and convenient opening time. The travel cost and the extra cost of services, staff shortage, often delayed and inadequate drug supplies were common problems for both women with and without disabilities. Unavailability of beds during delivery, insensitive providers with negative attitudes and abusive behaviour, inadequate knowledge and experience in providing services to the people with disabilities as well as unwelcoming health facility environment made services particularly inaccessible to women with disabilities. CONCLUSION: Maternal healthcare services are not easily and equitably accessible to women with disabilities. To increase access to healthcare for this vulnerable group, improvements are needed in distribution and management of resources from transportation through service delivery, as well as improved provider knowledge and awareness of a human rights approach to disability and health. PMID- 30005081 TI - Impact of psychotic symptoms on clinical outcomes in delirium. AB - Delirium is an acute disturbance in attention and awareness in response to one or more physiological stressors that is closely related to poor clinical outcomes. The aim of this study is to investigate whether delirium patients with psychotic symptoms (PS) would have unique clinical characteristics and outcomes. A retrospective chart review was performed on the patients with delirium due to general medical conditions to assess clinical characteristics and outcomes. All patients were assessed by Delirium Rating Scale-revised-98 and classified as having PS when scored two or more on at least one of the psychotic symptom items (perceptual disturbances, delusions, and thought process abnormalities). Of 233 patients with delirium, 116 (49.8%) manifested PS. Patients with PS were younger, more likely to use antipsychotics to manage delirium, and had more hyperactive motor subtype than patients without PS. Logistic regression analysis showed that odds ratio of psychotic symptoms for having in-hospital mortality was 0.27 (95% CI = 0.08-0.94) after controlling age, sex, disease severity, comorbidity, number of medications, etiologies, motor subtypes, delirium severity and use of antipsychotics. The present study demonstrated that PS of delirium was associated with unique clinical characteristics and may affect the clinical course in a psychiatry-referral sample. PMID- 30005082 TI - Pregestational overweight and obesity are associated with differences in gut microbiota composition and systemic inflammation in the third trimester. AB - The obesity epidemic is a global challenge, and the velocity of propagation is high in the population at reproductive age. Overweight and obesity during pregnancy have been associated with high birth weight and an increased risk of childhood obesity, reinforcing the risk of other non-communicable diseases. Obesity involves chronic low-grade systemic inflammation. New biomarkers for early detection of obesity risk are urgently required. The aim of this study was to identify the connection between pregestational BMI (pre-BMI) status and inflammatory biomarkers during the third trimester of pregnancy and their association with intestinal microbiota composition. Fifty-four pregnant women were classified according to pre-pregnancy BMI as normoweight, overweight, or obese. Weight gain, inflammatory biomarkers (hs_CRP, haptoglobin, and suPAR), and microbiota composition were assessed during the third trimester. A significant lower weight gain for obese mothers and a positive correlation between pre-BMI and inflammatory biomarkers were detected (Spearman's correlation). Haptoglobin levels were significantly higher in overweight and obese mothers. Higher Firmicutes levels and a higher ratio Firmicutes/Bacteroidetes were observed in the overweight and obese subjects. High hs_CRP and haptoglobin levels were also correlated with decreased microbiota diversity (Shannon index), whereas haptoglobin and hs_CRP values were correlated with several microbiota components, such as Ruminococcus gnavus and Faecalibacterium, and with specific phyla in the normoweight and overweight mothers; no significant associations with microbiota were found for suPAR. In conclusion, haptoglobin and hs_CRP reflected pregestational BMI status and related microbiota components, but haptoglobin was a better biomarker for microbiota associated with overweight. suPAR was associated with low grade inflammation dependent on pre-pregnancy BMI, but it was not related to deviated microbiota profiles. PMID- 30005083 TI - Prognostic value of platelet count and lymphocyte to monocyte ratio combination in stage IV non-small cell lung cancer with malignant pleural effusion. AB - INTRODUCTION: A combination of platelet and lymphocyte to monocyte ratio (LMR) (abbreviated as COP-LMR) has been recently evaluated as systemic inflammatory marker for prognostication in lung cancer. While previous study on COP-LMR has evaluated its prognostic value in NSCLC patients who underwent curative resections, the combination of these two markers has not been evaluated in advanced NSCLC yet. OBJECTIVES: In this study, we evaluated the prognostic value of COP-LMR in stage IV NSCLC with malignant pleural effusion under active anticancer treatment. METHODS: Between January 2012 and July 2016, 217 patients with stage IV NSCLC and MPE undergoing active anticancer treatment were selected for evaluation. If patients had both low LMR (< 2.47) and increased platelet (> 30.0 *104 mm-3), they were assigned to COP-LMR group 2. Patients with one parameter were assigned to COP-LMR group 1. If none, patients were assigned to COP-LMR group 0. RESULTS: Median overall survival (OS) (P < 0.001), progression free survival (PFS) (P < 0.001) and histological feature (P = 0.003) showed significant differences among COP-LMR groups. For COP-LMR groups 0, 1 and 2, median survival times were 35.9, 14.7 and 7.4 months, respectively, while median progression free times were 19.2, 13.3 and 7.4 months, respectively. Older age, male, low albumin, high CRP and high COP-LMR (0 vs 1, P = 0.021, hazard ratio (HR): 1.822, 95% confidence interval (CI): 1.096-3.027 and 0 vs 2, P = 0.003, HR: 2.464, 95% CI: 1.373-4.421) were independent predictive factors for shorter OS. Age, sex, histology, albumin, or CRP had no significant influence on PFS. High COP-LMR was the significant factor in predicting shorter PFS (0 vs 1, P = 0.116 and 0 vs 2, P = 0.007, HR: 1.902, 95% CI: 1.194-3.028). CONCLUSIONS: A combination of pretreatment LMR and platelet levels can be used to predict short survival in stage IV NSCLC patients who underwent active anticancer treatment. PMID- 30005084 TI - Monitoring and predicting land use and land cover changes using remote sensing and GIS techniques-A case study of a hilly area, Jiangle, China. AB - Land use and land cover change research has been applied to landslides, erosion, land planning and global change. Based on the CA-Markov model, this study predicts the spatial patterns of land use in 2025 and 2036 based on the dynamic changes in land use patterns using remote sensing and geographic information system. CA-Markov integrates the advantages of cellular automata and Markov chain analysis to predict future land use trends based on studies of land use changes in the past. Based on Landsat 5 TM images from 1992 and 2003 and Landsat 8 OLI images from 2014, this study obtained a land use classification map for each year. Then, the genetic transition probability from 1992 to 2003 was obtained by IDRISI software. Based on the CA-Markov model, a predicted land use map for 2014 was obtained, and it was validated by the actual land use results of 2014 with a Kappa index of 0.8128. Finally, the land use patterns of 2025 and 2036 in Jiangle County were determined. This study can provide suggestions and a basis for urban development planning in Jiangle County. PMID- 30005085 TI - Epidemiological significance of dengue virus genetic variation in mosquito infection dynamics. AB - The kinetics of arthropod-borne virus (arbovirus) transmission by their vectors have long been recognized as a powerful determinant of arbovirus epidemiology. The time interval between virus acquisition and transmission by the vector, termed extrinsic incubation period (EIP), combines with vector mortality rate and vector competence to determine the proportion of infected vectors that eventually become infectious. However, the dynamic nature of this process, and the amount of natural variation in transmission kinetics among arbovirus strains, are poorly documented empirically and are rarely considered in epidemiological models. Here, we combine newly generated empirical measurements in vivo and outbreak simulations in silico to assess the epidemiological significance of genetic variation in dengue virus (DENV) transmission kinetics by Aedes aegypti mosquitoes. We found significant variation in the dynamics of systemic mosquito infection, a proxy for EIP, among eight field-derived DENV isolates representing the worldwide diversity of recently circulating type 1 strains. Using a stochastic agent-based model to compute time-dependent individual transmission probabilities, we predict that the observed variation in systemic mosquito infection kinetics may drive significant differences in the probability of dengue outbreak and the number of human infections. Our results demonstrate that infection dynamics in mosquitoes vary among wild-type DENV isolates and that this variation potentially affects the risk and magnitude of dengue outbreaks. Our quantitative assessment of DENV genetic variation in transmission kinetics contributes to improve our understanding of heterogeneities in arbovirus epidemiological dynamics. PMID- 30005086 TI - Influence of the moving fluoroscope on gait patterns. AB - Video-fluoroscopic analysis can provide important insights for the evaluation of outcome and functionality after total knee arthroplasty, allowing the in vivo assessment of tibiofemoral kinematics without soft tissue artefacts. To enable measurement of the knee throughout activities of daily living such as gait, robotic systems like the moving fluoroscope have been developed that follow the knee movement and maintain the joint in front of the image intensifier. Since it is unclear whether walking while being accompanied by moving fluoroscope affects normal gait, the objective of this study was to investigate its influence on gait characteristics in healthy subjects. In addition, the impact of the motors' noise was analysed. By means of skin markers analysis (VICON MX system, Oxford Metrics Group, UK) and simultaneous measurement of ground reaction forces (Kistler force plates, Kistler, Switzerland), gait characteristics when walking with and without the moving fluoroscope as well as with and without ear protectors in combination with the moving fluoroscope, were obtained in young (n = 10, 24.5y +/- 3.0y) and elderly (n = 9, 61.6y +/- 5.3y) subjects during level gait and stair descent. Walking with the moving fluoroscope significantly decreased gait velocity in level gait and stair descent over the respective movement without the fluoroscope. Statistical analysis, including gait velocity as a covariate, resulted in no differences on the ground reaction force parameters. However, some kinematic parameters (ankle, knee and hip ranges of motion, minimal knee angle in late stance phase, maximal knee angles in stance and swing phase) seemed to be modified by the presence of the moving fluoroscope, but statistical comparison was limited due to velocity differences between the conditions. Wearing ear protectors to avoid the influence of motor sound during walking with the moving fluoroscope caused no significant difference. Walking with the moving fluoroscope has been shown to decrease gait velocity and small alterations in kinematic parameters were observed. Therefore, gait and movement alterations due to the moving fluoroscope cannot completely be excluded. However, based on the absence of differences in ground reaction force parameters (when adjusted for velocity within ANCOVA), as well as based on the comparable shape of the angular curves to the slow control condition, it can be concluded that changes in gait when walking with the moving fluoroscope are small, especially in comparison to natural slow walking. In order to allow assessment of joint replacement with the moving fluoroscope, including an understanding of the effects of joint pain, clinical analyses can only be compared to gait activities showing similarly reduced velocities. Importantly, the reduced gait speeds observed in this study are similar to those observed after total knee arthroplasty, suggesting that analyses in such subjects are appropriate. However, the moving fluoroscope would likely need to be optimized in order to detect natural gait characteristics at the higher gait velocities of healthy young subjects. The moving fluoroscope can be applied for comparisons between groups measured with the moving fluoroscope, but care should be taken when comparing data to subjects walking at self-selected speed without the moving fluoroscope. PMID- 30005087 TI - Correction: The gamma33 subunit of R-phycoerythrin from Gracilaria chilensis has a typical double linked phycourobilin similar to beta subunit. AB - [This corrects the article DOI: 10.1371/journal.pone.0195656.]. PMID- 30005088 TI - Hypobaric hypoxia induced renal damage is mediated by altering redox pathway. AB - Systemic hypobaric hypoxia is reported to cause renal damage; nevertheless the exact pathophysiological mechanisms are not completely understood. Therefore, the present study aims to explore renal pathophysiology by using proteomics approach under hypobaric hypoxia. Six to eight week old male Sprague Dawley rats were exposed to hypobaric hypoxia equivalent to altitude of 7628 metres (pO2-282mmhg) at 28 degrees C and 55% humidity in decompression chamber for different time intervals; 1, 3, and7 days. Various physiological, proteomic and bioinformatic studies were carried out to examine the effect of chronic hypobaric hypoxia on kidney. Our data demonstrated mild to moderate degenerative tubular changes, altered renal function, injury biomarkers and systolic blood pressure with increase in duration of hypobaric hypoxia exposure. Renal proteomic analysis showed 38 differential expressed spots, out of which 25 spots were down regulated and 13 were up regulated in 7 dayhypobarichypoxic exposure group of rats as compared to normoxia control. Identified proteins were involved in specific molecular changes pertinent to endogenous redox pathways, cellular integrity and energy metabolism. The study provides an empirical evidence of renal homeostasis under hypobaric hypoxia by investigating both physiological and proteomics changes. The identification of explicit key proteins provides a valuable clue about redox signalling mediated renal damage under hypobaric hypoxia. PMID- 30005090 TI - Straight-Line Vector Planning for Optimal Results With Silhouette InstaLift in Minimally Invasive Tissue Repositioning for Facial Rejuvenation. AB - BACKGROUND: Absorbable suspension sutures for tissue repositioning represent a minimally invasive approach to facial rejuvenation. With 2015 FDA 510(k) approval of Silhouette InstaLiftTM (Sinclair Pharma, Irvine, CA), a completely absorbable device comprised of 82% PLLA/18% PLGA sutures and bi-directional cones, came the challenge of developing optimal technique for achieving effective, precise, and durable tissue repositioning. Here, the authors discuss the importance of straight-line vector planning (SLVP) and positioning of the suture perpendicular to the plane to be elevated in obtaining optimal results for tissue repositioning. Both the scientific underpinnings of SLVP are presented, along with detailed discussion of technique for suture placement in the mid-face, jawline/jowls, and neck. METHODS: The authors are some of the earliest adopters of absorbable suspension sutures in the United States and have both used InstaLiftTM sutures for tissue repositioning and facial recontouring in treatment of more than 500 patients and developed the principles of SLVP as a method to ensure optimal outcomes. RESULTS: Patient case studies illustrating the importance of SLVP are presented. In over 500 patients treated within the authors' practices since InstaLift approval there have been no serious adverse events and noticeable bruising has occurred in less than 5% of patients. Results of repositioning and recontouring are evident for up to 24 months. CONCLUSIONS: Absorbable suspension sutures are a highly adaptable, non-invasive device for lifting and repositioning of descended facial tissue. Outcomes are dependent upon proper technique, including SLVP. J Drugs Dermatol. 2018;17(7):786-793. PMID- 30005091 TI - The Hyperhidrosis Disease Severity Measure-Axillary: Conceptualization and Development of Item Content. AB - INTRODUCTION: Patients with primary axillary hyperhidrosis (AHH) suffer from a variety of symptoms. Improved patient-reported outcome (PRO) measures are needed to better assess and categorize the severity of AHH symptoms experienced by patients because the widely used Hyperhidrosis Disease Severity Scale (HDSS) is a single-item measure that cannot capture the broad scope of disease impact. METHODS: The Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) was developed for determining the severity of excessive sweating in patients with primary focal AHH based on face-to-face concept elicitation interviews with 58 AHH patients, a literature review, and expert clinical input. Two waves of face to-face cognitive interviews (n=26 and n=27) were conducted to evaluate HDSM-Ax clarity and relevance. Additional interviews (n=5) were conducted to confirm content. Adding Rasch Measurement Theory (RMT) analyses allowed for an iterative streamlined approach to documenting content validity and other cross-sectional measurement properties of the new HDSM-Ax measurement. RESULTS: The 11-item HDSM Ax PRO scale (0-4 scale per item; 0-44 total scale) represents an AHH symptom range of 0 (no sweating) to 44 (worst possible sweating). Content validity of the HDSM-Ax was documented by showing that chronologically-grouped interviews demonstrated saturation in AHH symptom severity concepts. Cognitive debriefing interviews provided evidence that item content is complete, comprehensible, meaningful, and relevant. RMT-based exploration indicated that targeting of the HDSM-Ax was adequate, suggesting good matching between items and persons; item fit was adequate, suggesting a clinically cohesive scale; and items appeared to be stable between subgroups, thereby supporting a summary score. CONCLUSIONS: The HDSM-Ax is a well-developed measure of AHH severity based on patient-reported signs and symptoms. It is a superior measure to the HDSS and can be used in clinical research and clinical practice to quantify changes in symptom severity in response to treatment. J Drugs Dermatol. 2018;17(7):707-714. PMID- 30005089 TI - Epidermal growth factor receptor inhibition with Gefitinib does not alter lung responses to mechanical ventilation in fetal, preterm lambs. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is important for airway branching and lung maturation. Mechanical ventilation of preterm lambs causes increases in EGFR and EGFR ligand mRNA in the lung. Abnormal EGFR signaling may contribute to the development of bronchopulmonary dysplasia. HYPOTHESIS: Inhibition of EGFR signaling will decrease airway epithelial cell proliferation and lung inflammation caused by mechanical ventilation in preterm, fetal sheep. METHODS: Following exposure of the fetal head and chest at 123+/-1 day gestational age and with placental circulation intact, fetal lambs (n = 4 6/group) were randomized to either: 1) Gefitinib 15 mg IV and 1 mg intra-tracheal or 2) saline IV and IT. Lambs were further assigned to 15 minutes of either: a) Injurious mechanical ventilation (MV) or b) Continuous positive airway pressure (CPAP) 5 cmH2O. After the 15 minute intervention, the animals were returned to the uterus and delivered after i) 6 or ii) 24 hours in utero. RESULTS: MV caused lung injury and inflammation, increased lung mRNA for cytokines and EGFR ligands, caused airway epithelial cell proliferation, and decreased airway epithelial phosphorylated ERK1/2. Responses to MV were unchanged by Gefitinib. Gefitinib altered expression of EGFR mRNA in the lung and liver of both CPAP and MV animals. Gefitinib decreased the liver SAA3 mRNA response to MV at 6 hours. There were no differences in markers of lung injury or inflammation between CPAP animals receiving Gefitinib or saline. CONCLUSION: Inhibition of the EGFR pathway did not alter acute lung inflammation or injury from mechanical ventilation in preterm sheep. PMID- 30005092 TI - Nitric Oxide Releasing Nanoparticles as a Strategy to Improve Current Onychomycosis Treatments. AB - Topical antimicrobials are the ideal mode of onychomycosis treatment for efficient drug delivery and avoidance of sytemic effects associated with oral medications. However, high treatment costs, tissue penetration limitations, and low cure rates have continued to pose major challenges. To capitalize on the progress made by topical efinaconazole solution, efinaconazole was combined with inexpensive, previously-characterized nitric oxide releasing nanoparticles (NO np), which have been shown to offer sustained nitric oxide release over time and enhanced barrier penetration, while exerting broad spectrum antimicrobial and immunomodulating properties. NO-np were combined with efinaconazole in varying concentrations and applied against reference strains of Trichophyton rubrum using a checkerboard method. Results demonstrated synergism of NO-np+efinaconazole against T. rubrum, which is noteworthy given the barriers present in the topical treatment of onychomycosis, and the multiple potential benefits offered by NO-np. Overall, this study illustrates the untapped potential of nanotechnology in the treatment of disorders of the skin, hair, and nails where drug delivery remains a challenge. J Drugs Dermatol. 2018;17(7):717-720. PMID- 30005093 TI - Halobetasol 0.01%/Tazarotene 0.045% Lotion in the Treatment of Moderate-to-Severe Plaque Psoriasis: Maintenance of Therapeutic Effect After Cessation of Therapy. AB - BACKGROUND: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Topical corticosteroids (TCS) are the mainstay of treatment. Long-term safety remains a concern, limiting use, and posttreatment flare is common. Tazarotene has also been shown to be effective in psoriasis, with efficacy maintained several weeks posttreatment. Fixed combination therapy with TCS and tazarotene may improve psoriasis signs and minimize posttreatment flare or rebound. OBJECTIVE: To investigate the maintenance of effect posttreatment with a once-daily application of halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion in comparison with its active ingredients and vehicle in patients with moderate-to-severe plaque psoriasis. METHODS: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Patients randomized (2:2:2:1 ratio) to receive HP/TAZ, individual active ingredients, or vehicle, once-daily for 8 weeks with a 4-week posttreatment follow-up. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score, and 'clear' or 'almost clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion. RESULTS: At the end of the 4-week posttreatment period, 38.2% of patients who had been treated with HP/TAZ were treatment successes; compared with 21.0%, 12.8% and 6.9% of patients who had been treated with HP (P=0.042), TAZ (P=0.004), or vehicle (P=0.002). HP/TAZ lotion was also superior in maintaining reductions in psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At the end of the 4-week posttreatment period, 49.1%, 54.5%, and 54.5% of patients, respectively, were treatment successes: compared with 38.7% (P=0.26), 48.4% (P=0.51), and 48.4% (P=0.51) of patients who had been treated with HP; 29.8% (P=0.049), 31.9% (P=0.022), and 23.4% (P=0.001) who had been treated with TAZ; and 13.8% (P=0.002), 20.7% (P=0.003), and 20.7% (P=0.003) who had been treated with vehicle. Side effects were minimal and tended to resolve during the posttreatment period. CONCLUSIONS: In conclusion, HP 0.01%/TAZ 0.045% lotion provides synergistic efficacy following 8 weeks' therapy that is sustained after a 4-week posttreatment period. J Drugs Dermatol. 2018;17(7):723-726. PMID- 30005094 TI - Topical Transdermally Delivered Lidocaine and Benzocaine Compared to Compounded Lidocaine/Tetracaine During Microfocused Ultrasound With Visualization Treatment. AB - OBJECTIVE: The efficacy of various pre-medication strategies for comfort management during microfocused ultrasound with visualization (MFU-V) treatment has not been studied. The present objective was to compare 2 topical analgesics (lidocaine 4% and benzocaine 20%) formulated with a novel transdermal delivery system with compounded lidocaine 23%/tetracaine 7% (23/7) to mitigate discomfort during MFU-V treatment. METHODS: This was a randomized, double-blinded, split face study. One hour before MFU-V, subjects (N=14 females) received 50 mg IM meperidine/25 mg IM promethazine/5 mg oral diazepam. Fifteen minutes before treatment, 1 side of the face was treated with 1 application of 4% lidocaine, followed by 1 application of 20% benzocaine; the contralateral side was treated with 2 applications of 23/7 (to maintain blinding). Numbness was assessed by blinded evaluator (scale: 1=completely numb to 4=not numb) pre-treatment. Subject pain scores (scale: 0=no pain to 10=worst pain) were collected post-treatment. Adverse events and subjective clinician measures were also assessed. RESULTS: Mean subject pain scores for 23/7 and lidocaine 4%/benzocaine 20% were 5.6 and 5.7, respectively. Mean numbness scores were similar for 23/7 (2.5) and lidocaine 4%/benzocaine 20% (3.0). Clinicians rated both products as "very easy" to apply. For lidocaine 4%/benzocaine 20%, 7.1% of subjects required no pauses during treatment, vs 14.3% for 23/7. However, more subjects required 4+ pauses with 23/7 (21.4% vs 7.1%). Lidocaine 4%/benzocaine 20% was preferred by 78.5% of subjects; 35.7% rated lidocaine/benzocaine 20% 4% as "Very Effective" vs 7.1% for 23/7. No adverse events were reported. CONCLUSIONS: Lidocaine 4% and benzocaine 20% formulations utilizing a novel transdermal delivery system perform similarly to compounded lidocaine 23%/tetracaine 7% for discomfort mitigation during MFU-V treatment. More subjects preferred lidocaine 4%/ benzocaine 20% and rated it as "very effective" vs the compounded product. Fewer treatment pauses due to patient discomfort when using the lidocaine 4%/benzocaine 20% may translate to time efficiency. J Drugs Dermatol. 2018;17(7):729-734. PMID- 30005095 TI - The Importance of Early Treatment in Psoriasis and Management of Disease Progression. AB - Psoriasis is a chronic, immune-mediated, inflammatory disease that if left untreated can result in prolonged subclinical inflammation that affects a variety of organs, including the heart, liver, kidney, and intestines, as well as joints and muscles. Relatedly, psoriasis significantly increases patients' risks for developing certain comorbidities. Disease progression in psoriasis is unpredictable, and some patients have mild disease that is stable for many years, while in others, mild disease quickly progresses to moderate-to-severe psoriasis. Adding to the complexity of this disease, subclinical systemic inflammation is present in patients with either mild or moderate-to-severe psoriasis. In this review, key factors in psoriasis progression, including the role that systemic inflammation has in psoriasis pathogenesis and the development of comorbidities, are highlighted along with the ability of various therapies to potentially stop or slow the progression of psoriasis and its associated comorbidities. Additionally, practical guidance is provided for physicians regarding treatment and monitoring of disease progression based on psoriasis severity and the risk of comorbidities. J Drugs Dermatol. 2018;17(7):737-742. PMID- 30005096 TI - Primary Axillary Hyperhidrosis Treatment Using High Intensity Focused Fractional Radiofrequency Microneedling. AB - Primary axillary hyperhidrosis (PAH), or excessive sweating limited to the axillary area, is a debilitating disease that severely and negatively impacts social and psychological well-being. Several treatment options are available for PAH; however, these options have been shown to provide varying effectiveness. Recent studies have suggested another treatment alternative offering an effective PAH treatment option with reported long-term results. High intensity focused fractional radiofrequency (HIFRF) microneedling is FDA cleared for the treatment of facial wrinkles. The system is designed with a unique technology that is safe for use on patients presenting with all skin types. Based on its unique design and the clinical trial experience reported in the literature by Kim, et al1 and others,2,5 we offer it to our patients as a beneficial treatment option for primary axillary hyperhidrosis (PAH). We present here a clinical experience summary from three US centers providing hyperhidrosis treatments using the high intensity radio-frequency device, including treatment parameters, clinical outcomes, and pre- and post-treatment images. J Drugs Dermatol. 2018;17(7):745 748. PMID- 30005097 TI - Economic Evaluation of Dupilumab for Moderate-to-Severe Atopic Dermatitis: A Cost Utility Analysis. AB - BACKGROUND: Moderate-to-severe atopic dermatitis can be difficult and costly to treat. The long-term health and economic outcomes of a new therapy, dupilumab, have yet to be evaluated. We aimed to identify the cost-effectiveness of dupilumab compared to usual care in moderate-to-severe atopic dermatitis. METHODS: We compared dupilumab to usual care with emollients for adults with moderate-to-severe atopic dermatitis inadequately controlled with topical therapy, or for whom topical therapies were medically inadvisable. Subpopulations of moderate and severe patients were examined separately. We used a lifetime Markov model from a US payer perspective with health states categorized by the percent decrease in Eczema Area and Severity Index (EASI) score after a patient began an intervention: at least a 50% decrease (EASI 50), 75% decrease (EASI 75), 90% decrease (EASI 90), or no response. RESULTS: The expected lifetime cost for patients treated with dupilumab was $509,600, including $267,800 in dupilumab drug costs and $241,800 in other healthcare costs. Average lifetime cost for usual care was $271,500. Dupilumab provided an additional 1.91 quality-adjusted life years (QALYs) over the remaining lifetime of a patient, leading to an incremental cost-effectiveness ratio (ICER) of $124,500. The ICER was lower for patients with severe atopic dermatitis ($95,800) than those with moderate atopic dermatitis ($160,000). Key drivers of the model were utility values for quality of-life for non-responders, and the price of dupilumab. CONCLUSIONS: This study was limited by data for health outcomes and costs over long time periods, particularly stratified by severity. We estimated that dupilumab improved health outcomes compared to usual care but with additional costs, with an ICER below commonly cited thresholds for cost-effectiveness. Dupilumab was projected to be more cost-effective in patients with severe atopic dermatitis, but even in patients with moderate atopic dermatitis, the ICER remained below the upper range of commonly cited thresholds. J Drugs Dermatol. 2018;17(7):750-756. PMID- 30005098 TI - Clinical Improvements in Very Dry Skin from a Natural Ingredient-Based Moisturizing Cream Compared With a Leading Colloidal Oatmeal Control. AB - The objective of this 6-week clinical study was to demonstrate the effectiveness of a natural ingredient-based moisturizing cream versus a colloidal oatmeal moisturizing cream in improving the hydration, barrier function, appearance, and feel of dry leg skin. Thirty-two subjects completed the study. After a 5-day washout, subjects used the natural ingredient-based moisturizing cream and oatmeal-containing cream on randomly-assigned legs twice a day for a period of three weeks. For the following two weeks subjects did not use any moisturizer on their legs. Skin moisture measurements showed a statistically significant increase in hydration for both products at all time points during the treatment phase of the study. Both products reduced transepidermal water loss measurements during the treatment phase of the study, showing their abilities to improve stratum corneum barrier function. Clinical evaluations showed that both products significantly decreased visual dryness and tactile roughness during the treatment phase. Improvements in the assessed clinical parameters persisted even after treatment cessation. In conclusion, the natural ingredient-based moisturizing cream was highly effective in providing moisturization and improving the skin barrier of subjects with very dry leg skin. It also produced significant improvements in visual dryness and tactile roughness that persisted during regression. Overall, these results show that the natural ingredient-based moisturizing cream delivers comparable benefits to that of a colloidal oatmeal containing benchmark product and is an option for health care providers and consumers who seek relief from dry skin and prefer a product with all-natural ingredients. J Drugs Dermatol. 2018;17(7):758-764. PMID- 30005099 TI - Clinical Characteristics of Lower Extremity Surgical Site Infections in Dermatologic Surgery Based Upon 24-Month Retrospective Review. AB - Dermatologic surgery performed on the lower extremities has an increased risk for surgical site infections (SSI). Our objective was to evaluate the clinical characteristics associated with SSI following Mohs micrographic surgery (MMS) and wide local excisions (WLE) performed below the knee. We performed a single-center retrospective chart review of patients (n=271) that underwent these procedures. Within 14 days of the lower extremity procedure, four of 175 MMS patients (2.3%) developed SSI compared to eight of 96 WLE patients (8.3%; P=0.029). Subcuticular sutures and vertical mattress sutures as a group were associated with reduced 30 day infection rate when compared to other suture methods (P=0.006). Comparison of patients on prophylactic antibiotics to control patients without antibiotics did not reveal a statistically significant difference in infection rate. MMS infection rates trended lower as compared to WLE in the 14-day post-operative window. Doxycycline prophylaxis did not produce a statistically significantly lower rate of SSI, though results approached significance. A prospective study may be warranted to further compare cephalexin and doxycycline for dermatologic surgery below the knee. Subcuticular or vertical mattress sutures may be preferred when closing wounds due to their association with reduced infection rate. J Drugs Dermatol. 2018;17(7):766-771. PMID- 30005100 TI - Novel Topical Cytokinin Improves Coarse Wrinkles and Skin Roughness Without Skin Irritation. AB - OBJECTIVE: To evaluate the efficacy and tolerance of topical 4HBAP (para-topolin [6-(4-hydroxybenzylamino) purine], a new aromatic cytokinin, in subjects with mild to moderate facial photodamage. METHODS: In this single-center, 12-week study subjects (n=39) applied topical 0.10% 4HBAP (the test article) and sunblock (SPF30) twice daily, in the early morning and in the evening. The efficacy and safety of the treatment were evaluated at study entry (baseline) and at 2, 4, 8 and 12 weeks. Results were evaluated by investigators and subjects using high resolution photography and objectively by transepidermal water loss (skin barrier function), and a Novameter(r) (skin moisture content). RESULTS: Topical 4HBAP significantly improved the appearance of coarse wrinkles after 4, 8, and 12 weeks of continued use without irritating the skin or eliciting erythema. Topical 4HBAP also improved the appearance of fine wrinkles, hyperpigmentation, and skin roughness while significantly reducing facial erythema and the overall severity of acne lesions. The investigators global assessment, the overall severity of skin aging and skin color, showed significant improvement at weeks 8 and 12. Subject-assessed improvements were also highly favorable. In the 25 subjects that had acne at baseline, the number of non-inflammatory lesions and the total number of acne lesions decreased significantly at weeks 8 and 12. Topical 4HBAP significantly increased skin hydration at weeks 2, 8, and 12. CONCLUSION: Topical 4HBAP (0.10%) significantly improves the appearance of fine lines and coarse wrinkles, reduces skin roughness, hyperpigmentation, facial erythema, and non inflammatory acne lesions, and improves skin hydration without any observed side effects. J Drugs Dermatol. 2018;17(7):772-779. PMID- 30005101 TI - Combined Hyperthermic 1060nm Diode Laser Lipolysis With Topical Skin Tightening Treatment: Case Series. AB - BACKGROUND: As body contouring procedures have become more popular, post procedural skin laxity is a concern. Non-invasive body contouring technologies may effectively reduce body fat, but modestly affect skin tightening. OBJECTIVE: To assess the efficacy and safety of a topical skin tightening agent in combination with hyperthermic diode laser lipolysis. METHODS: Herein, we describe five patients in which a skin tightening concentrate of 5% yeast extract, 2% hydrolyzed rice protein content, and 2.5% tripeptide was used after 1500-2100 J/cm2 of hyperthermic 1060 nm diode laser. RESULTS: Overall, all patients had a subjective positive response and high satisfaction with the combined treatment results of improvement in skin laxity and fat reduction. In all five cases, patients demonstrated visible fat reduction and skin improvement on photographs taken between weeks 6-18 compared to baseline. Blinded investigators correctly predicted the order of the photographs based on treatment results. No adverse events were reported. CONCLUSION: This case series demonstrated that a combined topical skin tightening concentrate with a hyperthermic laser lipolysis device may achieve improved aesthetic outcomes without adverse events. J Drugs Dermatol. 2018;17(7):780-785. PMID- 30005102 TI - Patient Reported Improvement in Quality of Life Associated With Successful Laser Hair Reduction at Hemodialysis Site With 1064-nm Nd:YAG Laser. AB - Laser hair reduction is a well-established modality for a wide range of medical indications. Laser hair reduction can be beneficial for hemodialysis patients who undergo repeated adhesive tape application and removal at their hemodialysis site during hemodialysis sessions. There is a paucity of published literature on efficacious laser hair removal treatments for hemodialysis patients. Herein, we present a case of a 50-year-old male (Fitzpatrick III) with end-stage renal disease on hemodialysis, who achieved successful laser hair reduction at his hemodialysis vascular access site with five sessions of a neodymium:yttrium aluminium-garnet (Nd:YAG) laser (1064 nm) to improve his quality of life by reducing the hair burden at the adhesive tape site application. We recommend providing this safe and effective hair reduction treatment option for hemodialysis patients given the decreased quality of life associated with end stage renal disease and hemodialysis. J Drugs Dermatol. 2018;17(7):794-795. PMID- 30005103 TI - Combination Ablative Approach to Laser Therapy in Advanced Aging of the Face. AB - BACKGROUND AND OBJECTIVE: Misperceptions have persisted regarding scanning full field erbium laser that have caused it to be overshadowed by fractional ablative resurfacing. This can lead to sub-optimally treating the periocular and perioral skin. Our report describes the utility of a combined approach of fractional ablative CO2 with full-field erbium ablation for full face rejuvenation. Each laser has a role in creating the optimal outcomes for advanced photoaging in the fewest treatments. METHODS: A patient with severe photodamage and etched-in lines underwent full face fractional ablative CO2 (CO2RE, Syneron Candela) and full field ablative perioral and periocular erbium laser (Contour TRL, Sciton Inc.). The pre-procedure consultations included evaluation of the severity of the photodamage and etched-in lines, as well as discussion of patient goals and appropriate treatment options. Photos of similar patients and post-treatment recovery were reviewed. Fully ablative lasers are generally avoided in Fitzpatrick skin type IV-VI. Prior to treatment, full face nerve blocks and topical anesthesia was provided. Full facial fractional ablative CO2 laser was then applied in one orthoganol pass to the whole face. This was followed by treating the infraorbital and perioral skin with four passes of full field erbium laser. Visualized residual lines were focally treated. Marked improvement was seen in a single treatment session. RESULTS: Standardized digital imaging revealed dramatic improvement in skin texture and etched lines. CONCLUSION: For appropriately selected patients, combination fractional ablative CO2 and full field ablative erbium resurfacing for facial rejuvenation is safe, efficacious and merits consideration. J Drugs Dermatol. 2018;17(7):796-799. PMID- 30005104 TI - Successful Treatment of Severe Alopecia Areata With Oral or Topical Tofacitinib. AB - Alopecia areata is an autoimmune disease involving the hair follicle with a chronic, relapsing course. Tofacitinib is Janus kinase inhibitor approved for treatment of rheumatoid arthritis that has been shown to be effective in treatment of alopecia areata. We present a case series of 11 patients with severe alopecia areata on longstanding, regular to high dose oral tofacitinib with marked hair regrowth. Additionally, we present a case of moderate to severe alopecia areata successfully treated with topical tofacitinib cream. J Drugs Dermatol. 2018;17(7):800-803. PMID- 30005105 TI - The Evaluation of Cutaneous Metastasis from an Unknown Primary. AB - We present the case of a man that had a rapidly growing nodule on his face. Removal of the lesion was more difficult than anticipated because it was tightly adherent to adjacent tissue. Pathology from the lesion showed a malignant neoplasm thought to have arisen at a distant site. The evaluation of this patient may provide insights into the workup for patients that present with cutaneous metastatic malignancies of unknown etiology. In general, these patients need to be fully evaluated in an attempt to locate the primary lesion. When a primary lesion can not be ascertained, careful surveillance of the patient is warranted. We present suggestions for evaluation of patients with cutaneous metastatic lesions without an obvious primary. It is clear that molecular pathology will provide additional information to help identify the primary lesion. Scanning of areas likely to be the source using CT PET/ CT and MRI studies may also yield information. Finally, a careful history and physical examination are also important for these patients. J Drugs Dermatol. 2018;17(7):804-806. PMID- 30005106 TI - Severe Oral Mucositis: A Rare Adverse Event of Pembrolizumab. AB - Treatment of malignancy with anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors can cause mucocutaneous side effects resulting from T cell activation. Due to their recent development, the full side effect profile remains to be fully elucidated, however dermatologic adverse events are most common. The main oral toxicities of these immune checkpoint inhibitors include: xerostomia, dysgeusia, and lichenoid reactions. Oral mucositis occurs more rarely in the setting of PD-1 inhibition, and few other reports of a Grade 3 or higher, severe, stomatitis have been reported in the literature. We present a case of a 78-year old woman with Grade 3 ulcerative oral mucositis that occurred 13 months after initiation of PD-1 inhibitor, pembrolizumab, for the treatment for lung adenocarcinoma. She was successfully treated with prednisone, and pembrolizumab was temporarily held by her oncologist. Physicians should be aware of the possibility of severe mucositis in the setting of PD-1 inhibitors, as well as the management. J Drugs Dermatol. 2018;17(7):807-809. PMID- 30005107 TI - Margin Assessment for Punch and Shave Biopsies of Dysplastic Nevi. AB - INTRODUCTION: Biopsies of atypical melanocytic nevi are among the most commonly performed procedures by dermatologists. Margin assessment is often used to guide re-excision, but can be a point of confusion as negative margins reported in the planes of sections examined do not always reflect complete removal of a lesion. This study investigates the rates of false negative margins after both punch and shave biopsies. METHODS: We performed a retrospective analysis of 50 consecutive punch and shave biopsy specimens (1) diagnosed as DN, and (2) reported as having clear margins in the planes of section examined. Identified specimen blocks were then sectioned through to examine true margin involvement. RESULTS: Of the 50 specimens identified, 20% (n = 10) were found to have positive margins upon additional sectioning. We found no difference between the groups with respect to biopsy technique, type of nevus, degree of atypia, or gender. CONCLUSION: This study observed false negative peripheral margin status in a sizeable proportion of biopsy specimens, which did not vary significantly based on biopsy technique or pathologic characteristics. This finding reflects a limitation of standard tissue processing, in which a limited proportion of the true margin is evaluated, and may be of note to many dermatologists who base their decision to re-excise on the reporting of margin involvement. J Drugs Dermatol. 2018;17(7):810-812. PMID- 30005108 TI - Yes to Appropriate Compounding, No to Illegal Compounding. AB - Dermatology is often described as a "visual" specialty. While it is true that many of our diagnoses can be made based on a relatively quick recognition of morphology, such a characterization of our profession overlooks the reality that dermatologists are "doers" in the clinic. From aesthetic injections to biopsies and cryosurgery, much of our patient care time is spent performing minor and major procedures. We are well known for our in-office efficiency and cost saving practices. PMID- 30005109 TI - The Practice of Compounding, Associated Compounding Regulations, and the Impact on Dermatologists. AB - Medication compounding gained national attention in the fall of 2012 after contaminated compounded medications produced in the New England Compounding Center infected 800 people with fungal meningitis and led to several fatalities. This prompted Congress to pass regulations on compounding through the Drug Quality and Security Act (DQSA) in 2013. The act increased oversight of patient specific drug compounding taking place in compounding pharmacies, created 503(b) outsourcing facilities to obtain compounded drugs, and added regulations for obtaining compounded drugs from traditional 503(a) pharmacies. These regulations also had a broader overall impact by triggering federal and state-specific policies, which have ultimately limited a physician's ability to perform low risk, in-office compounding. This article provides an overview of the different types of compounding restrictions, reviews the current federal and state regulations and/or guidelines, discusses how newly proposed policies may affect the practice of dermatology, and presents an algorithm on how the practicing dermatologist should approach compounding. J Drugs Dermatol. 2018;17(7 Suppl):s17 22. PMID- 30005111 TI - Preparing the Personal Physician for Practice: What We've Learned and Where We Need to Go. PMID- 30005110 TI - Lessons From the P4 Project. PMID- 30005112 TI - Innovating Family Medicine Residency Education Through Collaboration. PMID- 30005113 TI - Redesigning Residency Training: Summary Findings From the Preparing the Personal Physician for Practice (P4) Project. AB - BACKGROUND AND OBJECTIVES: The Preparing the Personal Physician for Practice (P4) project (2007 to 2014) involved a comparative case study of experiments conducted by 14 selected family medicine programs designed to evaluate new models of residency education that aligned with the patient-centered medical home (PCMH). Changes in length, structure, content, and location of training were studied. METHODS: We conducted both a critical review of P4 published Evaluation Center and site-specific papers and a qualitative narrative analysis of process reports compiled throughout the project. We mapped key findings from P4 to results obtained from a survey of program directors on their top 10 "need to know" areas in family medicine education. RESULTS: Collectively, 830 unique residents took part in P4, which explored 80 hypotheses regarding 44 innovations. To date, 39 papers have resulted from P4 work, with the P4 Evaluation Center producing 17 manuscripts and faculty at individual sites producing 22 manuscripts. P4 investigators delivered 21 presentations and faculty from P4 participating programs delivered 133 presentations at national meetings. For brevity, we present findings derived from the analyses of project findings according to the following categories: (1) how residency training aligned with PCMH; (2) educational redesign and assessment; (3) methods of financing new residency experiences; (4) length of training; (5) scope of practice; and (6) setting standards for conducting multisite educational research. CONCLUSIONS: The P4 project was a successful model for multisite graduate medical education research. Insights gained from the P4 project could help family medicine educators with future residency program redesign. PMID- 30005114 TI - Transforming a Family Medicine Residency Into a Community-Oriented Learning Environment. AB - BACKGROUND AND OBJECTIVES: Improvement in population health has become a key goal of health systems and payers in the United States. Because 80% of health outcomes are driven by social determinants of health beyond medical care and health care access, such improvements require attention to factors outside of the conventional areas of expertise for clinicians. Yet primary care physicians often graduate from training programs with few skills in population and community health. METHODS: In 2011, the University of Wisconsin Department of Family Medicine began transformative work to become a Department of Family Medicine and Community Health (DFMCH). As part of this effort, educators in the department addressed deficiencies in its residency's community and population health curriculum by implementing curricular change and faculty development. A set of guiding principles, "Three Community Health Responsibilities for Family Doctors," was developed to provide background and structure to current and future work. RESULTS: An annual program evaluation survey was administered to faculty and residents between 2012 and 2016. Respondents reported a significant increase in their understanding of population and community health over the prior year in each year this was assessed (P<0.001). CONCLUSIONS: Community and population health principles have become part of the fabric of the entire residency curriculum in the DFMCH. Faculty development was a key part of this work and will be integral to sustaining improvements. PMID- 30005115 TI - The Growing Trend of Health Coaches in Team-Based Primary Care Training A Multicenter Pilot Study. AB - BACKGROUND AND OBJECTIVES: Team-based care with health coaches has improved the quality and cost effectiveness of chronic disease management and prevention. Clinical health coaches partner with patients to identify health goals, create action plans, overcome barriers to change, reinforce physician recommendations, and coordinate care. It is important to train resident physicians to practice in team-based settings. To date, there have been no studies of resident family physician exposure to health coaches. METHODS: We surveyed 465 residency directors through a larger omnibus survey sent out by CERA; the response rate was 53.7%. Directors were asked about resident exposure to health coaches, the types of patients seen by health coaches, and the training background of the health coaches. We used chi-square tests to examine the relationship among these variables and program characteristics including status as a patient-centered medical home. RESULTS: Almost two-thirds of the programs reported at least some residents had exposure to health coaches. Residents who trained in continuity sites with a PCMH certification of level 3 were more likely to have any exposure to health coaches (P<.05). There were multiple significant relationships between populations of patients seen and the training background of health coaches. CONCLUSIONS: To improve quality, reduce costs, and become more patient centered, primary care is rapidly transforming into a team sport with a broadening roster of new players, including health coaches. This study documents positive rates of resident exposure to health coaches but also great variability in types and amount of exposure that merit further investigation and exploration of ways to grow family medicine residency contact with a diversifying practice team. PMID- 30005116 TI - A Pilot Study to Address Tolerance of Uncertainty Among Family Medicine Residents. AB - BACKGROUND AND OBJECTIVES: Because patients often present to their family physicians with undifferentiated medical problems, uncertainty is common. Family medicine residents must manage both the ambiguity inherent in the field as well as the very real uncertainty of learning to become a skilled physician with little experience to serve as a guide. The purpose of this analysis was to assess the impact of a new curriculum on family medicine residents' tolerance of ambiguity. METHODS: We conducted an exploratory quasi-experimental study to assess the impact of a novel curriculum designed to improve family medicine residents' tolerance of ambiguity. Four different surveys were administered to 25 family medicine residents at different stages in their training prior to and immediately and 6 months after the new curriculum. RESULTS: Although many constructs remained unchanged with the intervention, one important construct, namely perceived threats of ambiguity, showed significant and sustained improvement relative to before undertaking this curriculum (score of 26.2 prior to the intervention, 22.1 immediately after, and 22.0 6 months after the intervention). CONCLUSIONS: A new curriculum designed to improve tolerance to ambiguity appears to reduce the perceived threats of ambiguity in this small exploratory study. PMID- 30005117 TI - DERM: A Four-Step Dermatology Education Digital Tool Kit for Nondermatologists. AB - BACKGROUND AND OBJECTIVES: Dermatology is often an overlooked and underemphasized area of training in postgraduate primary care medical education, with an abundance of dermatological educational resources available, but no clear guidelines on how to best take advantage of them. The objective of this study was to develop a dermatology digital tool kit designed to describe, evaluate, recognize, and manage (DERM) common dermatological conditions in primary care residency education and to evaluate potential improvement in clinical confidence. METHODS: A total of 14 family medicine (FM) and 33 internal medicine (IM) residents were given the DERM tool kit to complete over 7 weeks. Effects on residents' self-reported comfort with dermatology and resources used were measured by voluntary anonymous surveys distributed before and after DERM completion. RESULTS: A response rate of 100% (14/14) for FM residents and 52% (17/33) for IM residents was achieved. The majority of residents (61%) recalled minimal dermatology education-less than 2 weeks-in medical school and 71% agreed that there is not enough dermatology in their residency curriculum. A statistically significant increase in resident comfort with describing (P=0.002), recognizing and diagnosing (P<0.001), and managing (P=0.001) dermatologic conditions was observed postcompletion. Residents reported they would recommend this tool to other primary care residents. CONCLUSIONS: Implementing the DERM digital tool kit is feasible with primary care residents and appears to improve comfort with describing, recognizing and diagnosing, and managing dermatologic conditions. PMID- 30005118 TI - Dear Mr C, Thank You, and I'm Sorry. PMID- 30005119 TI - Finding a Doctor to Trust: The Journey of a Sexual Minority Patient. PMID- 30005121 TI - Expecting Better: Why the Conventional Pregnancy Wisdom is Wrong-and What You Really Need to Know. PMID- 30005120 TI - A Gambian Woman. PMID- 30005122 TI - Attending Others. PMID- 30005123 TI - Medical Taylorism: Comment on Ledford and Young et al. PMID- 30005124 TI - Engaging Students in New Models of Care. PMID- 30005125 TI - Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus. AB - Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by gamma-aminobutyric acid type A (GABAA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5alpha-dihydroprogesterone, pregnanolone and allopregnanolone were, respectively, 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's rho = 0.4335, p < 0.01), allopregnanolone (rho = 0.4121, p < 0.05) and pregnanolone (rho = 0.592, p < 0.001) levels significantly increased by aging in controls. We conclude that neurosteroidogenesis is defective in patients with SE. PMID- 30005126 TI - Review: Revisiting the human cholinergic nucleus of the diagonal band of Broca. AB - Although the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB) is the second largest cholinergic nucleus in the basal forebrain, after the nucleus basalis of Meynert, it has not generally been a focus for studies of neurodegenerative disorders. However, the nvlDBB has an important projection to the hippocampus and discrete lesions of the rostral basal forebrain have been shown to disrupt retrieval memory function, a major deficit seen in patients with Lewy body disorders. One reason for its neglect is that the anatomical boundaries of the nvlDBB are ill defined and this area of the brain is not part of routine diagnostic sampling protocols. We have reviewed the history and anatomy of the nvlDBB and now propose guidelines for distinguishing nvlDBB from other neighbouring cholinergic cell groups for standardizing future clinicopathological work. Thorough review of the literature regarding neurodegenerative conditions reveals inconsistent results in terms of cholinergic neuronal loss within the nvlDBB. This is likely to be due to the use of variable neuronal inclusion criteria and omission of cholinergic immunohistochemical markers. Extrapolating from those studies showing a significant nvlDBB neuronal loss in Lewy body dementia, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the CA2 subfield in the hippocampus which may be especially vulnerable in Lewy body disorders. PMID- 30005127 TI - Periodontal status of liver transplant candidates and healthy controls. AB - BACKGROUND: This study aimed to compare the periodontal status of liver transplant candidates (LTCs) with healthy controls. METHODS: Fifty liver transplant candidates (LTC group) and fifty patients without liver disease (control group) underwent a complete periodontal examination. The groups were matched according to sex, age, and smoking status. A structured questionnaire was applied to record demographic data, systemic health, and information related to liver disease. Full-mouth complete periodontal examination of six sites per tooth was performed: gingival recession (GR), probing depth (PD), attachment loss (AL), bleeding on probing (BOP), and visible plaque index (VPI). The groups were compared in regard to periodontal clinical variables. RESULTS: Patients with cirrhosis had greater prevalence of periodontitis than healthy controls (P < 0.001). In addition, they had greater mean percentage of sites with AL >=3 mm (P = 0.008) and AL >=5 mm (P = 0.023), greater mean AL (P = 0.003), greater mean gingival recession (P < 0.001), and more missing teeth than in the control group (P = 0.02). CONCLUSION: Liver transplant candidates presented greater prevalence, extent, and severity of periodontitis than matched control patients. PMID- 30005128 TI - Echocardiographic measures associated with the presence of left ventricular thrombus in patients with chemotherapy-related cardiac dysfunction. AB - BACKGROUND: Previous studies have not evaluated the prevalence and specific risk factors for the development of left ventricular (LV) thrombus in patients with severely reduced left ventricular dysfunction due to chemotherapy-related cardiomyopathy. We sought to evaluate the prevalence and potential markers of LV thrombus in this patient population. METHODS: From January 2009 to December 2013, patients with chemotherapy-related severe LV dysfunction (LV ejection fraction [LVEF] <= 30%) identified from MD Anderson Cancer Center database were reviewed. Patient characteristics and echocardiographic parameters were analyzed to determine potential risk factors for LV thrombus. RESULTS: A total of 121 patients met inclusion criteria (age 54.8 +/- 15.2 years; female 63.6%; LVEF 26.3 +/- 4%). LV thrombus was present in 9 patients (7.4%). Patients with LV thrombus have significantly lower LVEF compared to those without (18.7 +/- 3.8% vs 26.9 +/ 3.4%, P < .0001). Prevalence of LV thrombus increased as LVEF decreased and was the highest in patients with LVEF < 20%. By univariate analysis, decreased LVEF, particularly LVEF < 20% (OR 36.30, 95% CI 7.35-179.25, P < .0001) and restrictive LV filling pattern (OR 18.13, 95% CI 4.17-78.89, P = .0001) were associated with presence of LV thrombus. CONCLUSION: In patients with severely reduced LV systolic function due to chemotherapy-induced cardiomyopathy, LV thrombus was found in 7.4% of subjects. Severely decreased LVEF (<20%) and restrictive LV filling pattern were associated with the presence of LV thrombus. PMID- 30005131 TI - Discontinuation of Angiotensin Converting Enzyme Inhibitors due to Dry Cough: Incidence and Clinical Determinants. PMID- 30005130 TI - Effects of neuromuscular presynaptic muscarinic M1 receptor blockade on rocuronium-induced neuromuscular blockade in immobilized tibialis anterior muscles. AB - This in vivo study tested the hypothesis that the modulation of acetylcholine (ACh) release by the M1 muscarinic receptor (mAChR) in the neuromuscular junction of disused muscles may affect the tensions of the muscles during the neuromuscular monitoring of a rocuronium-induced neuromuscular block and compared the results with those obtained from normal muscles. A total of 20 C57BL/6 (wild type) and 10 alpha7 knock out (alpha7KO) mice were used in this experiment. As a pre-experimental procedure, knee and ankle joints of right hind limbs were fixed by needle pinning at the 90 degrees flexed position. After 2 weeks, the main experiment was performed. Both tendons of the tibialis anterior (TA) muscles were obtained, and the muscle tensions were recorded while the dose-responses of rocuronium were measured three times in the same mouse by the serial administration of pirenzepine (0, 0.001 and 0.01 MUg/g). Weight losses were observed after 2 weeks of immobilization in both groups, and a decrease in the mass of TA muscles at the immobilized side was observed compared to those of the contralateral nonimmobilized side. Tension depression of the TA muscles at immobilized side of the alpha7KO group was faster than those of the wild-type group, but these differences decreased after the administration of pirenzepine. The tension depressions were similar regardless of the pirenzepine doses at the same side in the group. Tension depression may become more rapid in the alpha7 AChR-expressed disused muscles by the decreased release of ACh release upon neuronal firing by the blockade of facilitatory M1 mAChR. PMID- 30005129 TI - Correlates of positive parental attitudes towards adolescent indoor tanning in the U.S.A. PMID- 30005132 TI - A clinical application of preload stress echocardiography for predicting future hemodynamic worsening in patients with early-stage heart failure. AB - AIM: To improve the prognosis of patients with heart failure, risk stratification in their early stage is important. We assessed whether the change in transmitral flow (TMF) velocity pattern during preload augmentation can predict future hemodynamic worsening in early-stage heart failure patients with impaired relaxation TMF pattern. METHODS: We designed a prospective cohort study that included 155 consecutive patients with impaired relaxation (IR) pattern at rest. Preload stress echocardiography was achieved using leg-positive pressure (LPP), and changes in TMF pattern during the LPP was observed during baseline echocardiographic examination. The patients whose TMF pattern developed to pseudonormal (PN) pattern throughout the study period were classified into the change to PN group, and patients whose TMF pattern stayed in IR pattern were classified into the stay in IR group. RESULTS: The median follow-up period was 17 months. The average age was 68 +/- 11 years old, and 97 patients (63%) were male. Among 155 patients, 27 were classified into the change to PN group. A Cox proportional hazard analysis confirmed that the change in the peak atrial systolic TMF velocity during the LPP (DeltaA, hazard ratio = 0.58 per 1SD; 95% CI = 0.39-0.88, P = 0.010) was the powerful independent predictor of change into PN pattern. Kaplan-Meier analysis revealed that the patients with DeltaA <= -7 cm/s had more likely to develop into PN pattern than patients with DeltaA > -7 cm/s (P = 0.001). CONCLUSIONS: Evaluation of a response in TMF during the LPP might provide an incremental diagnostic value to detect future overt heart failure in patients with early-stage heart failure. PMID- 30005133 TI - JAK2V617F Megakaryocytes Promote Hematopoietic Stem/Progenitor Cell Expansion in Mice Through Thrombopoietin/MPL Signaling. AB - The myeloproliferative neoplasms (MPNs) are stem cell disorders characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The acquired kinase mutation JAK2V617F plays a central role in these disorders. The mechanisms responsible for HSPC expansion in MPNs are not fully understood, limiting the effectiveness of current treatments. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. Previously, we reported that JAK2V617F-bearing MKs cause a murine myeloproliferative syndrome with HSPC expansion. Here we show that JAK2V617F MKs promote MPN stem cell function by inducing HSPC quiescence with increased repopulating capacity. In addition, we demonstrate that thrombopoietin and its receptor MPL are critical for the JAK2V617F-bearing MK-induced myeloproliferation, both by directly affecting the quantity and quality of MKs and by altering the MK-endothelial interaction and vascular niche function. Therefore, targeting HSPC niche-forming MKs and/or their interactions within the vascular niche could provide novel, more effective therapeutic strategies in patients with MPNs. Stem Cells 2018;36:1676-1684. PMID- 30005134 TI - A practical application of onychomycosis cure - combining patient, physician and regulatory body perspectives. AB - Due to the high relapse rates and the rise of predisposing factors, the need for curing onychomycosis is paramount. To effectively address onychomycosis, the definition of cure used in a clinical setting should be agreed upon and applied homogeneously across therapies (e.g. oral, topical and laser treatments). In order to determine what is or what should be used to define cure in a clinical setting, a literature search was conducted to identify methods used to evaluate treatment success. The limitations, strengths, prevalence and utility of each outcome measure were investigated. Seven ways to measure treatment success were identified; mycological cure, patient/investigator assessments, complete cure, quality of life instruments, severity indexes, clinical cure and temporary clearance. Despite its shortcomings, mycological cure is the most objective and consistent outcome measure used across onychomycosis studies. It is suggested that diagnostic goals of onychomycosis should be used to define cure in a clinical setting. Modifications to outcome measures such as incorporating molecular-based techniques could be a future avenue to explore. PMID- 30005135 TI - Response to "Discontinuation of Angiotensin Converting Enzyme Inhibitors Due to Dry Cough: Incidence and Clinical Determinants". PMID- 30005136 TI - Mutational analysis of a Drosophila neuroblast enhancer governing nubbin expression during CNS development. AB - While developmental studies of Drosophila neural stem cell lineages have identified transcription factors (TFs) important to cell identity decisions, currently only an incomplete understanding exists of the cis-regulatory elements that control the dynamic expression of these TFs. Our previous studies have identified multiple enhancers that regulate the POU-domain TF paralogs nubbin and pdm-2 genes. Evolutionary comparative analysis of these enhancers reveals that they each contain multiple conserved sequence blocks (CSBs) that span TF DNA binding sites for known regulators of neuroblast (NB) gene expression in addition to novel sequences. This study functionally analyzes the conserved DNA sequence elements within a NB enhancer located within the nubbin gene and highlights a high level of complexity underlying enhancer structure. Mutational analysis has revealed CSBs that are important for enhancer activation and silencing in the developing CNS. We have also observed that adjusting the number and relative positions of the TF binding sites within these CSBs alters enhancer function. PMID- 30005137 TI - Management of organ transplant recipients attending a high-throughput skin cancer surgery and surveillance clinic in Queensland. AB - BACKGROUND: The incidence of skin cancer in organ transplant recipients (OTRs) is very high, due mainly to long-term immunosuppressive therapy. The problem is particularly severe for OTRs living in Queensland, Australia, and results in significant mortality. OBJECTIVES: To describe the experience of the first dedicated outpatient high-throughput transplant skin clinic in Queensland. METHODS: This prospective evaluation study was conducted at a newly established, outpatient transplant skin cancer surgery and surveillance clinic. Participants (89 OTRs and 12 non-OTRs) were referred to the Princess Alexandra Hospital Transplant Skin Clinic during December 2016 to May 2017, and were each followed for 3 months. Self-completed questionnaires were administered at baseline and the end of follow-up (n = 94), and details of any skin cancers occurring in that period were extracted from hospital records. RESULTS: In the 3-month follow-up of 101 participants, a total of 615 skin lesions were detected in the 3-month follow up of 101 participants, of which 478 (78%) were treated in the clinic and 55 (9%) were referred to another specialist. Of the 478 treated lesions, 268 were histopathologically confirmed skin cancers, equivalent to 2.7 (95% confidence interval 2.5-2.8) skin cancers per participant per 3 months. The overall number needed to treat for any skin cancer was 1.4 (95% confidence interval 1.3-1.5). Three-quarters (374) of in-clinic treatments were surgical, and most (90%) were complete excisions. The median time from detection of skin cancer to excision was 7 days. CONCLUSIONS: This high-volume surgical outpatient transplant skin clinic enables efficient treatment of skin cancers in very-high-risk OTRs. PMID- 30005138 TI - Effects of multiple stressors on cyanobacteria abundance vary with lake type. AB - Blooms of cyanobacteria are a current threat to global water security that is expected to increase in the future because of increasing nutrient enrichment, increasing temperature and extreme precipitation in combination with prolonged drought. However, the responses to multiple stressors, such as those above, are often complex and there is contradictory evidence as to how they may interact. Here we used broad scale data from 494 lakes in central and northern Europe, to assess how cyanobacteria respond to nutrients (phosphorus), temperature and water retention time in different types of lakes. Eight lake types were examined based on factorial combinations of major factors that determine phytoplankton composition and sensitivity to nutrients: alkalinity (low and medium-high), colour (clear and humic) and mixing intensity (polymictic and stratified). In line with expectations, cyanobacteria increased with temperature and retention time in five of the eight lake types. Temperature effects were greatest in lake types situated at higher latitudes, suggesting that lakes currently not at risk could be affected by warming in the future. However, the sensitivity of cyanobacteria to temperature, retention time and phosphorus varied among lake types highlighting the complex responses of lakes to multiple stressors. For example, in polymictic, medium-high alkalinity, humic lakes cyanobacteria biovolume was positively explained by retention time and a synergy between TP and temperature, while in polymictic, medium-high alkalinity, clear lakes only retention time was identified as an explanatory variable. These results show that, although climate change will need to be accounted for when managing the risk of cyanobacteria in lakes, a "one-size fits-all" approach is not appropriate. When forecasting the response of cyanobacteria to future environmental change, including changes caused by climate and local management, it will be important to take this differential sensitivity of lakes into account. PMID- 30005140 TI - A Preview of Selected Articles - August 2018. PMID- 30005139 TI - Vitamin C Promotes Astrocyte Differentiation Through DNA Hydroxymethylation. AB - Previous studies have reported that vitamin C (VC) promotes neural stem/precursor cell (NSC) differentiation toward dopamine (DA) neurons via DNA hydroxymethylation-induced transcriptional activation of DA neuron-specific genes. To further understand the VC effects on NSC differentiation, we profiled the transcriptome and DNA methylome/hydroxymethylome using high-throughput sequencing. Interestingly, RNA sequencing analyses have shown that, in addition to DA neuronal genes, astrocytic genes Gfap, Slc1a3, and S100a16 were also upregulated in NSC cultures differentiated with VC treatment. Consistently, enhanced GFAP+ astrocytic yields were manifested in the differentiated cultures with VC treatment, collectively indicating that VC promotes astrocytic differentiation. In genome-wide hydroxymethylome analyses, VC treatment induces enrichment of DNA hydroxymethylation (5-hydroxymethyl cytosine; 5hmC) near the consensus binding motifs of nuclear factor I (NFI). Furthermore, we showed that VC significantly enhanced recruitment of NFI and STAT3, key transcription factors for astrogenesis, in the 5hmC-enriched regions of the astrocyte-specific genes. These findings suggest that VC play important roles in astrocytogenesis during brain development. Stem Cells 2018;36:1578-1588. PMID- 30005141 TI - Clinical and imaging features of pulmonary artery sling: The experience in one major medical center. AB - This case series describes echocardiographic and computed tomography angiographic (CTA) characteristics, clinical features, diagnosis, and treatment in 15 patients of Pulmonary artery sling (PAS). Echocardiography is effective in diagnosing PAS, when the main pulmonary artery extends to the right pulmonary artery directly with the left pulmonary artery arising from the right pulmonary artery. CTA, clearly demonstrating the position and extent of trachea compression, the anatomy of PAS and the spatial relationships among the PAS, trachea and the esophagus, is necessary for the final diagnosis. Clinical presentations are caused by the compression of the tracheobronchial tree rather than the PAS itself. Left pulmonary artery reimplantation is the treatment of choice. PMID- 30005142 TI - Recent developments in the management of pleural infection: A comprehensive review. AB - OBJECTIVES: Pleural infection is a condition commonly encountered by the respiratory physician. This review aims to provide the reader with an update on the most recent data regarding the epidemiology, microbiology, and the management of pleural infection. DATA SOURCE: Medline was searched for articles related to pleural infection using the terms "pleural infection," "empyema," and "parapneumonic." The search was limited to the years 1997-2017. Only human studies and reports in English were included. RESULTS: A rise in the incidence of pleural infection is seen worldwide. Despite the improvement in healthcare practices, the mortality from pleural infection remains high. The role of oral microflora in the etiology of pleural infection is firmly established. A concise review of the recent insights on the pathogenesis of pleural infections is presented. A particular focus is made on the role of tPA, DNAse and similar substances and their interaction with inflammatory cells and how this affects the pathogenesis and treatment of pleural infection. CONCLUSION: Pleural infection is a common disease with significant morbidity and mortality, as well as a considerable economic burden. The role of medical management is expanding thanks to the widespread use of newer treatments. PMID- 30005143 TI - A Simplified and Efficient Protocol for Derivation and Maintenance of High Quality Mouse Primed Pluripotent Stem Cells Using Wnt Inhibition. AB - Epiblast stem cells (EpiSCs) are primed pluripotent stem cells (PSCs) derived from mouse postimplantation embryos. Interestingly, EpiSCs share many characteristics with human PSCs such as human embryonic stem cells (hESCs) and human induced PSCs (hiPSC). Thus, EpiSCs can serve as a model for studying primed states of pluripotency. This article describes a simple yet highly efficient protocol for EpiSC derivation and maintenance of homogenous EpiSCs using an inhibitor of WNT secretion. Using this method, EpiSCs can be readily derived from mouse strains with different genetic background including C57BL/6N. The EpiSCs derived by this protocol maintain a homogenous, undifferentiated status, yet retain high differentiation potential. Unlike EpiSCs established by the original protocol, the new EpiSC lines require the continued presence of WNT inhibitor, suggesting intrinsic differences from EpiSCs made by the original method. This new version of EpiSCs will provide clues to understand the nature of primed states of mammalian pluripotent cells and may facilitate establishment of a better protocol for directed differentiation from the primed state. (c) 2018 by John Wiley & Sons, Inc. PMID- 30005144 TI - The PEth Blood Test in the Security Environment: What it is; Why it is Important; and Interpretative Guidelines. AB - Testing for phosphatidylethanol (PEth) is a relatively new tool for detecting and grossly quantifying a person's use of alcohol in a variety of security, medical, and legal environments. The basic chemistry of PEth is explained with a particular focus on factors that make it highly suitable as a biomarker for alcohol use in such situations. This article meets the need for a literature review that synthesizes PEth laboratory findings and suggests updated guidelines for interpretation. Several ethanol biomarkers have been used for detection or monitoring alcohol use but have significant limitations. Based on this review, the authors propose three guidelines for evaluating PEth values: Light or no Consumption (<20 ng/mL), Significant Consumption (20-199 ng/mL), and Heavy Consumption (>200 ng/mL). These guidelines are important in employment and security environments, but also have applicability in such diverse activities as alcohol treatment programs, organ transplant decisions, and monitoring impaired medical professionals. PMID- 30005146 TI - Dear Mr. Neutropenic Fever. PMID- 30005147 TI - M. chimaera: A Multi-Headed Pathogen. AB - We present the case of a 64-year-old man with Mycobacterium chimaera prosthetic aortic valve endocarditis likely acquired through exposure to a contaminated heater-cooler device used for cardiopulmonary bypass during valve replacement. This case demonstrates multi-system involvement with a non-tuberculous mycobacterial species that was previously not considered a significant human pathogen. We review the key features of the case and review published literature regarding an international outbreak of M. chimaera arising from point-source contamination during the manufacturing process. This report highlights the importance of clinician awareness of this international outbreak. PMID- 30005145 TI - Clearing for Deep Tissue Imaging. AB - Biologic tissues are generally opaque due to optical properties that result in scattering and absorption of light. Preparation of tissues for optical microscopy often involves sectioning to a thickness of 50-100 um, the practical limits of light penetration and recovery. A researcher who wishes to image a whole tissue must acquire potentially hundreds of individual sections before rendering them into a three-dimensional volume. Clearing removes strongly light-scattering and light-absorbing components of a tissue and equalizes the refractive index of the imaging medium to that of the tissue. After clearing, the maximum depth of imaging is often defined by the microscope optics rather than the tissue. Such visibility enables the interrogation of whole tissues and even animals without the need to section. Researchers can study a biological process in the context of its three-dimensional environment, identify rare events in large volumes of tissues, and trace cells and cell-cell interactions over large distances. This article describes four popular clearing protocols that are relevant to a wide variety of scenarios across biologic disciplines: CUBIC, CLARITY, 3DISCO, and SeeDB. (c) 2018 by John Wiley & Sons, Inc. PMID- 30005148 TI - Epstein-Barr Virus Positive Mucocutaneous Ulcer: A Case Report. AB - Epstein-Barr virus (EBV) is known to be associated with B-cell lymphoproliferative disorders, and EBV-positive mucocutaneous ulcer (EBV-MCU) is a recently described entity observed in immunocompromised individuals. EBV-MCU is an aggressive appearing ulcerated lesion seen in the skin, oral cavity, and gastrointestinal tract. The process has Hodgkin-like features with a self limited, indolent course, generally responding well to conservative management. We present a case of EBV-MCU recently encountered in a 54-year-old renal transplant recipient. She had persistent rectal pain and bleeding for over a year following hemorroidectomy. A large ulcer in the distal rectum with excoriation and granular margins was noted on examination, and an initial biopsy from the lesion was inconclusive. A repeat biopsy demonstrated ulcerated squamous and colonic mucosa with a polymorphic lymphoid infiltrate in the submucosa that contained large atypical cells. The large atypical cells were positive for PAX-5 and CD30 and demonstrated EBV RNA by in situ hybridization. EBV-MCU is a recently described occurrence in transplant patients, and awareness of this recently described entity is necessary for appropriate diagnosis and treatment. PMID- 30005149 TI - Evaluation of a Formal Pediatric Faculty Mentorship Program. AB - INTRODUCTION: The purpose of this article is to describe how a formal mentoring program in pediatrics can prepare new physicians and scientists for their roles and conflicting responsibilities within a community-based medical school. While research supports the impact of faculty mentoring, quality partnerships are reportedly low in academic medicine and can negatively affect junior faculty who are preparing for certifying examinations, orienting to a new role and balancing career and personal life. METHODS: Data were collected from mentors and mentees in six rollouts (71 pairs) of a formal mentoring program in the Department of Pediatrics of the University of South Dakota Sanford School of Medicine/Sanford Children's Specialty Clinic in Sioux Falls, South Dakota. Specifically, focus groups, surveys and objective data (promotion, retention and board pass rates) were used for formative and summative evaluation and reported in this article. RESULTS: The results indicated high program satisfaction including 97 percent of participants would recommend the program to other faculty. Reported benefits included career development, retention, promotion and academic productivity. Challenges identified were lack of time, promotion criteria ambiguity and poor mentee initiative. CONCLUSIONS: Although the sample sizes were small for pre-post comparisons, the results provided a longitudinal evaluation and program best practices. Overall, a structured mentoring program was of value to faculty and resulted in partnerships that likely would not occur otherwise. The findings suggest that programs should assist junior faculty with onboarding and enculturation, career goals and focus, time management, work-life balance and promotion clarification and preparation. PMID- 30005150 TI - Collaborating to Enhance Faculty Development through Structured Funding. AB - PROBLEM: Faculty development is critical to individual career growth and success in academic medicine and it enhances the overall academic climate of an institution. Despite these well-recognized benefits, time and financial constraints often limit participation of faculty members. To address this issue, the University of South Dakota Sanford School of Medicine (SSOM) developed a novel policy and process to support participation in faculty development programs. APPROACH: In 2014, the SSOM Office of Continuing Professional Development (OCPD) implemented a process for funding faculty members' participation in external career and educational development programs. A subcommittee of the Faculty Development Committee reviewed and selected applications based on the benefit to the applicant's career and the SSOM as whole. Selected applicants were required to disseminate new knowledge from the external programs to other SSOM faculty, staff, and trainees. OUTCOMES: With the implementation of this program, 17 faculty members received funding. The race/ethnicities of the selected applicants reflected the overall demographics of the larger SSOM community. The majority of the selected applicants were female (n=12, 70 percent), assistant professors (n=9, 53 percent), and members of clinical departments (n=12, 70 percent). Upon completion of the program, five participants achieved academic promotion. This novel funding mechanism greatly increased faculty participation in external programs and participants reported enhanced networking opportunities, leadership experience, and career opportunities. NEXT STEPS: Challenges observed with implementation of the program have led to revision of the application process, tracking of participant demographic data, and confirmation of knowledge dissemination. PMID- 30005151 TI - Amiodarone Refractory Electrical Storm Post-Revascularization for Anterior ST Elevation Myocardial Infarction: A Case Report and Brief Review of the Literature. AB - "Electrical storm" is a life-threatening condition defined as the occurrence of at least two episodes of malignant ventricular arrhythmia in a 24-hour period despite anti-arrhythmic therapy. It leads to unpredictable degrees of clinical instability - in the most severe cases mechanical support for circulation and oxygenation and for definitive therapy radiofrequency ablation or cardiac sympathetic denervation. We describe a case of medication refractory electrical storm complicating severe left ventricular dysfunction after an anterior ST elevation myocardial infarction. PMID- 30005152 TI - The Patient as Reformation - Here We Stand Part One - The Incredible Shrinking Patient. AB - The U.S. is currently embroiled in a divisive healthcare reform debate. It is therefore important to understand how the principles of reformation might embolden the development of physician-reformers, who are willing to step out as advocates. Martin Luther, who heavily influenced reformers like Martin Luther King, Jr., set the standard for reformation on the singular idea of legitimate authority - rooted in the inestimable worth of the person. Patient-centeredness is that singular truth for healthcare and is the only cure for the incredible shrinking patient, who is being diminished by powers far stronger than it. PMID- 30005153 TI - Novel Interleukin-5 Targeted Treatment Options for Severe Eosinophilic Asthma. PMID- 30005154 TI - Quality Focus: Telemedicine Benefits and Evolution. PMID- 30005155 TI - Diversity-Oriented Approach Toward the Syntheses of Amaryllidaceae Alkaloids via a Common Chiral Synthon. AB - Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize a broad range of Amaryllidaceae alkaloids (AAs) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-mesembrine, (-) maritidine, (-)-oxomaritidine, and (+)-mesembrane is reported. Scaffold 1 is found as a prime structural motif in a wide variety of the AAs and is a novel synthon toward designing a divergent route for the synthesis of these natural products. This is established in a few steps, starting from a chiral aza-bicyclo heptene sulfone scaffold (2) via conjugate addition and concomitant stereoselective ring opening with allylmagnesium bromide, a key step that generates a crucial quaternary stereocenter, fixing the stereochemistry of the rest of the molecule at an early stage. One carbon truncation followed by intramolecular reductive amination led to the desired core 1 in a multigram scale. PMID- 30005156 TI - Hydrogen Bond Surrogate Stabilization of beta-Hairpins. AB - Peptide secondary and tertiary structure motifs frequently serve as inspiration for the development of protein-protein interaction (PPI) inhibitors. While a wide variety of strategies have been used to stabilize or imitate alpha-helices, similar strategies for beta-sheet stabilization are more limited. Synthetic scaffolds that stabilize reverse turns and cross-strand interactions have provided important insights into beta-sheet stability and folding. However, these templates occupy regions of the beta-sheet that might impact the beta-sheet's ability to bind at a PPI interface. Here, we present the hydrogen bond surrogate (HBS) approach for stabilization of beta-hairpin peptides. The HBS linkage replaces a cross-strand hydrogen bond with a covalent linkage, conferring significant conformational and proteolytic resistance. Importantly, this approach introduces the stabilizing linkage in the buried beta-sheet interior, retains all side chains for further functionalization, and allows efficient solid-phase macrocyclization. We anticipate that HBS stabilization of PPI beta-sheets will enhance the development of beta-sheet PPI inhibitors and expand the repertoire of druggable PPIs. PMID- 30005157 TI - One-Pot Synthesis of pH/Redox Responsive Polymeric Prodrug and Fabrication of Shell Cross-Linked Prodrug Micelles for Antitumor Drug Transportation. AB - Shell cross-linked (SCL) polymeric prodrug micelles have the advantages of good blood circulation stability and high drug content. Herein, we report on a new kind of pH/redox responsive dynamic covalent SCL micelle, which was fabricated by self-assembly of a multifunctional polymeric prodrug. At first, a macroinitiator PBYP- ss- iBuBr was prepared via ring-opening polymerization (ROP), wherein PBYP represents poly[2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane]. Subsequently, PBYP- hyd-DOX- ss-P(DMAEMA- co-FBEMA) prodrug was synthesized by a one-pot method with a combination of atom transfer radical polymerization (ATRP) and a Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction using a doxorubicin (DOX) derivative containing an azide group to react with the alkynyl group of the side chain in the PBYP block, while DMAEMA and FBEMA are the abbriviations of N, N-(2 dimethylamino)ethyl methacrylate and 2-(4-formylbenzoyloxy)ethyl methacrylate, respectively. The chemical structures of the polymer precursors and the prodrugs have been fully characterized. The SCL prodrug micelles were obtained by self assembly of the prodrug and adding cross-linker dithiol bis(propanoic dihydrazide) (DTP). Compared with the shell un-cross-linked prodrug micelles, the SCL prodrug micelles can enhance the stability and prevent the drug from leaking in the body during blood circulation. The average size and morphology of the SCL prodrug micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The SCL micelles can be dissociated under a moderately acidic and/or reductive microenvironment, that is, endosomal/lysosomal pH medium or high GSH level in the tumorous cytosol. The results of DOX release also confirmed that the SCL prodrug micelles possessed pH/reduction responsive properties. Cytotoxicity and cellular uptake analyses further revealed that the SCL prodrug micelles could be rapidly internalized into tumor cells through endocytosis and efficiently release DOX into the HeLa and HepG2 cells, which could efficiently inhibit the cell proliferation. This study provides a fast and precise synthesis method for preparing multifunctional polymer prodrugs, which hold great potential for optimal antitumor therapy. PMID- 30005158 TI - Additional Benefits of Federal Air-Quality Rules: Model Estimates of Controllable Biogenic Secondary Organic Aerosol. AB - Atmospheric models that accurately describe the fate and transport of trace species for the right reasons aid in the development of effective air-quality management strategies that safeguard human health. Controllable emissions facilitate the formation of biogenic secondary organic aerosol (BSOA) to enhance the atmospheric fine particulate matter (PM2.5) burden. Previous modeling with the EPA's Community Multiscale Air Quality (CMAQ) model predicted that anthropogenic primary organic aerosol (POA) emissions had the greatest impact on BSOA. That experiment included formation processes involving semivolatile partitioning but not aerosol liquid water (ALW), a ubiquitous PM constituent. We conduct 17 summertime CMAQ simulations with updated chemistry and evaluate changes in BSOA due to the removal of individual pollutants and source sectors for the contiguous U.S. CMAQ predicts SO2 from electricity generating units, and mobile source NOX emissions have the largest impacts on BSOA. The removal of anthropogenic NOX, SO2, and POA emissions during the simulation reduces the nationally averaged BSOA by 23, 14, and 8% and PM2.5 by 9.2, 14, and 5.3%, respectively. ALW mass concentrations decrease by 10 and 35% in response to the removal of NOX and SO2 emissions. This work contributes chemical insight into ancillary benefits of Federal NOX and SO2 rules that concurrently reduce organic PM2.5 mass. PMID- 30005159 TI - A Nonequilibrium Molecular Dynamics Study of Infrared Perturbed Electron Transfer. AB - Infrared (IR) excitation is known to change electron-transfer kinetics in molecules. We use nonequilibrium molecular dynamics (NEqMD) simulations to explore the molecular underpinnings of how vibrational excitation may influence nonadiabatic electron-transfer. NEqMD combines classical molecular dynamics simulations with nonequilibrium semiclassical initial conditions to simulate the dynamics of vibrationally excited molecules. We combine NEqMD with electronic structure computations to probe IR effects on electron transfer rates in two molecular species, dimethylaniline-guanosine-cytidine-anthracene (DMA-GC-Anth) and 4-(pyrrolidin-1-yl)phenyl-2,6,7-triazabicyclo[2.2.2]octatriene-10 cyanoanthracen-9-yl (PP-BCN-CA). In DMA-GC-Anth, the simulations find that IR excitation of the NH2 scissoring motion and the subsequent intramolecular vibrational energy redistribution (IVR) do not significantly alter the mean squared donor-acceptor (DA) coupling interaction. This finding is consistent with earlier computational analysis of static systems. In PP-BCN-CA, IR excitation of the bridging C?N bond changes the bridge-mediated coupling for charge separation and recombination by ~30-40%. The methods described here enable detailed explorations of how IR excitation may perturb charge-transfer processes at the molecular scale. PMID- 30005160 TI - Bioinspired pH- and Temperature-Responsive Injectable Adhesive Hydrogels with Polyplexes Promotes Skin Wound Healing. AB - Despite great potential, the delivery of genetic materials into cells or tissues of interest remains challenging owing to their susceptibility to nuclease degradation, lack of permeability to the cell membrane, and short in vivo half life, which severely restrict their widespread use in therapeutics. To surmount these shortcomings, we developed a bioinspired in situ-forming pH- and temperature-sensitive injectable hydrogel depot that could control the delivery of DNA-bearing polyplexes for versatile biomedical applications. A series of multiblock copolymer, comprised of water-soluble poly(ethylene glycol) (PEG) and pH- and temperature-responsive poly(sulfamethazine ester urethane) (PSMEU), has been synthesized as in situ-forming injectable hydrogelators. The free-flowing PEG-PSMEU copolymer sols at high pH and room temperature (pH 8.5, 23 degrees C) were transformed to stable gel at the body condition (pH 7.4, 37 degrees C). Physical and mechanical properties of hydrogels, including their degradation rate and viscosity, are elegantly controlled by varying the composition of urethane ester units. Subcutaneous administration of free-flowing PEG-PSMEU copolymer sols to the dorsal region of Sprague-Dawley rats instantly formed hydrogel depot. The degradation of the hydrogel depot was slow at the beginning and found to be bioresorbable after two months. Cationic protein or DNA-bearing polyplex-loaded PEG-PSMEU copolymer sols formed stable gel and controlled its release over 10 days in vivo. Owing to the presence of urethane linkages, the PEG-PSMEU possesses excellent adhesion strength to wide range of surfaces including glass, plastic, and fresh organs. More importantly, the hydrogels effectively adhered on human skin and peeled easily without eliciting an inflammatory response. Subcutaneous implantation of PEG-PSMEU copolymer sols effectively sealed the ruptured skin, which accelerated the wound healing process as observed by the skin appendage morphogenesis. The bioinspired in situ-forming pH- and temperature-sensitive injectable adhesive hydrogel may provide a promising platform for myriad biomedical applications as controlled delivery vehicle, adhesive, and tissue regeneration. PMID- 30005162 TI - Reversible Assembly and Dynamic Plasmonic Tuning of Ag Nanoparticles Enabled by Limited Ligand Protection. AB - Dynamic manipulation of optical properties through the reversible assembly of plasmonic nanoparticles offers great opportunities for practical applications in many fields. The previous success, however, has been limited to Au nanoparticles. Reversible assembly and plasmonic tuning of Ag nanoparticles (AgNPs) have remained a significant challenge due to difficulty in finding an appropriate surface agent that can effectively stabilize the particle surface and control their interactions. Here, we overcome the challenge by developing a limited ligand-protection (LLP) strategy for introducing poly(acrylic acid) with precisely controlled coverage to the AgNP surface to not only sufficiently stabilize the nanoparticles but also enable effective control over the surface charge and particle interaction through pH variation. The as-synthesized AgNPs can be reversibly assembled and disassembled and accordingly display broadly tunable coupling of plasmonic properties. Compared to the Au-based system, the success in the reversible assembly of AgNPs represents a significant step toward practical applications such as colorimetric pressure sensing because they offer many advantages, including broader spectral tuning range, higher color contrast, a one-pot process, and low materials and production cost. This work also highlights LLP as a new avenue for controlling the interparticle forces, their reversible assembly, and dynamic coupling of physical properties. PMID- 30005161 TI - Internal Nanostructure Diagnosis with Hyperbolic Phonon Polaritons in Hexagonal Boron Nitride. AB - Imaging materials and inner structures with resolution below the diffraction limit has become of fundamental importance in recent years for a wide variety of applications. We report subdiffractive internal structure diagnosis of hexagonal boron nitride by exciting and imaging hyperbolic phonon polaritons. On the basis of their unique propagation properties, we are able to accurately locate defects in the crystal interior with nanometer resolution. The precise location, size, and geometry of the concealed defects are reconstructed by analyzing the polariton wavelength, reflection coefficient, and their dispersion. We have also studied the evolution of polariton reflection, transmission, and scattering as a function of defect size and photon frequency. The nondestructive high-precision polaritonic structure diagnosis technique introduced here can be also applied to other hyperbolic or waveguide systems and may be deployed in the next-generation biomedical imaging, sensing, and fine structure analysis. PMID- 30005163 TI - Core-Shell Type Ionic Liquid/Metal Organic Framework Composite: An Exceptionally High CO2/CH4 Selectivity. AB - Here, we present a new concept of a core-shell type ionic liquid/metal organic framework (IL/MOF) composite. A hydrophilic IL, 1-(2-hydroxyethyl)-3 methylimidazolium dicyanamide, [HEMIM][DCA], was deposited on a hydrophobic zeolitic imidazolate framework, ZIF-8. The composite exhibited approximately 5.7 times higher CO2 uptake and 45 times higher CO2/CH4 selectivity at 1 mbar and 25 degrees C compared to the parent MOF. Characterization showed that IL molecules deposited on the external surface of the MOF, forming a core (MOF)-shell (IL) type material, in which IL acts as a smart gate for the guest molecules. PMID- 30005164 TI - Bioinspired Hybrid Protein Oxygen Nanocarrier Amplified Photodynamic Therapy for Eliciting Anti-tumor Immunity and Abscopal Effect. AB - An ideal cancer therapeutic strategy is expected to possess potent ability to not only ablate primary tumors but also prevent distance metastasis and relapse. In this study, human serum albumin was hybridized with hemoglobin by intermolecular disulfide bonds to develop a hybrid protein oxygen nanocarrier with chlorine e6 encapsulated (C@HPOC) for oxygen self-sufficient photodynamic therapy (PDT). C@HPOC realized the tumor-targeted co-delivery of photosensitizer and oxygen, which remarkably relieved tumor hypoxia. C@HPOC was favorable for more efficient PDT and enhanced infiltration of CD8+ T cells in tumors. Moreover, oxygen-boosted PDT of C@HPOC induced immunogenic cell death, with the release of danger associated molecular patterns to activate dendritic cells, T lymphocytes, and natural killer cells in vivo. Notably, C@HPOC-mediated immunogenic PDT could destroy primary tumors and effectively suppress distant tumors and lung metastasis in a metastatic triple-negative breast cancer model by evoking systemic anti-tumor immunity. This study provides a paradigm of oxygen-augmented immunogenic PDT for metastatic cancer treatment. PMID- 30005165 TI - Magnetically Recyclable Fe3O4@Zn xCd1- xS Core-Shell Microspheres for Visible Light-Mediated Photocatalysis. AB - Magnetically recyclable photocatalyst has drawn considerable research interest because of its importance in practical applications. Herein, we demonstrate a facile hydrothermal process to fabricate magnetic core-shell microspheres of Fe3O4@Zn xCd1- xS, successfully using Fe3O4@ZnS core-shell microspheres as sacrificed templates. The as-prepared magnetically recyclable photocatalysts show efficient photochemical reduction of Cr(VI) under irradiation of visible light. The photochemical reduction mechanism has been studied to illustrate the reduction-oxidation ability of the photogenerated electrons (e-) and holes (h+), which play an important role in the reduction of Cr(VI) to Cr(III) and oxidation of organic dyes. The as-prepared Fe3O4@Zn0.55Cd0.45S core-shell microspheres show good chemical stability and only a slight decrease in the photocatalytic activity after four recycles. In particular, the as-prepared photocatalysts could be easily recycled and reused by an external magnetic field. Therefore, this work would provide a facile chemical approach for controlled synthesis of magnetic nanostructures combined with alloyed semiconductor photocatalysts for wastewater treatment. PMID- 30005166 TI - Influence of Renner-Teller Coupling between Electronic States on H + CO Inelastic Scattering. AB - We examine the excitation of carbon monoxide from its rovibrational ground state via collisions with a hydrogen atom. Calculations employ the Multi-Configuration Time-Dependent Hartree method and treat the nonadiabatic dynamics with the inclusion of both the ground and the Renner-Teller coupled first excited electronic states. For this purpose, a new set of recently presented global HCO Potential Energy Surfaces (PESs) that cover the 0-3 eV range of energy is used. The results obtained here considering only the ground state (without the Renner Teller coupling) are in qualitative agreement with those available in the literature. The Renner-Teller effect is known to have an important effect on the spectroscopy of the system, and its inclusion and effects on the dynamics for the processes described in this paper are fairly significant also. The results of this study indicate that for certain very particular initial conditions rather dramatic effects can be observed. PMID- 30005167 TI - Mechanistical Insights into the Bioconjugation Reaction of Triazolinediones with Tyrosine. AB - The bioconjugation at tyrosine residues using cyclic diazodicarboxamides, especially 4-substituted 3 H-1,2,4-triazole-3,5(4 H)-dione (PTAD), is a highly enabling synthetic reaction because it can be employed for orthogonal and site selective (multi)functionalizations of native peptides and proteins. Despite its importance, the underlying mechanisms have not been thoroughly investigated. The reaction can proceed along four distinctive pathways: (i) the SEAr path, (ii) along a pericyclic group transfer pathway (a classical ene reaction), (iii) along a stepwise reaction path, or (iv) along an unusual higher order concerted pericyclic mechanism. The product mixtures obtained from reactions of PTAD with 2,4-unsubstituted phenolate support the SEAr mechanism, but it remains unclear if other mechanisms also take place. In the present work, the various mechanisms are compared using high-level quantum chemistry approaches for the model reaction of 4 H,3 H-1,2,4-triazole-3,5(4 H)-dione (HTAD) with p-cresol and p-cresolate. In a protic solvent (water), the barriers of the SEAr mechanism and the ene reaction are similar but still too high to explain the available experimental observations. This is only possible if the SEAr reaction of cresolate with HTAD is taken into account for which nearly vanishing barriers are computed. This satisfactorily explains measured conversion rates in buffered aqueous solutions and the strong activation effects observed upon addition of bases. PMID- 30005168 TI - Results of Scarf Osteotomy Without Implant Fixation in the Treatment of Hallux Valgus. AB - BACKGROUND:: The main goal of the study was to evaluate the costs, clinical and radiologic results, and complications of hallux valgus surgery using scarf osteotomy, depending on the type of fixation (with or without screws). METHODS:: We evaluated 169 patients who underwent scarf osteotomy between January 2013 and August 2016. The patients were separated into 3 groups depending on the type of stabilization: A, 2 screws (50 patients); B, modified with 1 screw (55 patients); C, modified without implant (64 patients). We assessed duration of surgery, additional procedures, pre- and postoperative hallux valgus angle (HVA) and intermetatarsal angle (IMA) on anteroposterior and lateral foot weightbearing radiographs, the American Orthopaedic Foot & Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal scale for the clinical assessment preoperatively and at the 12-month follow-up. We recorded all the complications and compared the costs between the groups. RESULTS:: Both the average HVA (A: from 33.7 to 12.6 degrees, B: 35.0 to 13.2 degrees, C: 34.7 to 12.4 degrees) and IMA (A: from 14.9 to 7.5 degrees, B: 15.2 to 6.9 degrees, C: 15.5 to 7.8 degrees) decreased in all groups without significant intergroup differences. The average AOFAS score improved in all the groups (A: from 40 to 88 points, B: 38 to 89 points, C: 42 to 91 points). A similar complication rate was observed (A: 9%, B: 10%, C: 11%). In group C, we noted a shorter time of surgery, and the procedure was the most cost-effective. CONCLUSION:: Scarf osteotomy without implant stabilization was faster and cost-effective and gave comparable results. It was technically demanding and required patient compliance. LEVEL OF EVIDENCE:: Level III, retrospective comparative study. PMID- 30005169 TI - Proteomics and pulse azidohomoalanine labeling of newly synthesized proteins: what are the potential applications? AB - INTRODUCTION: Measuring the immediate changes in cells that arise from changing environmental conditions is crucial to understanding the underlying mechanisms involved. These changes can be measured with metabolic stable isotope fully labeled proteomes, but requires looking for changes in the midst of a large background. In addition, labeling efficiency can be an issue in primary and fully differentiated cells. Area covered: Azidohomoalanine (AHA), an analog of methionine, can be accepted by cellular translational machinery and incorporated into newly synthesized proteins (NSPs). AHA-NSPs can be coupled to biotin via CuAAC-mediated click-chemistry and enriched using avidin-based affinity purification. Thus, AHA-containing proteins or peptides can be enriched and efficiently separated from the whole proteome. In this review, we describe the development of mass spectrometry (MS) based AHA strategies and discuss their potential to measure proteins involved in immune response, secretome, gut microbiome, and proteostasis as well as their potential for clinical uses. Expert commentary: AHA strategies have been used to identify synthesis activity and to compare two biological conditions in various biological model organisms. In combination with instrument development, improved sample preparation and fractionation strategies, MS-based AHA strategies have the potential for broad application, and the methods should translate into clinical use. PMID- 30005170 TI - The Safety of Mother's Milk(r) Tea: Results of a Randomized Double-Blind, Controlled Study in Fully Breastfeeding Mothers and Their Infants. AB - BACKGROUND: Various natural products are reported to improve maternal milk supply yet are not necessarily safe for infants. Researchers have not systematically studied galactagogue teas for safety. Research Aim: This study evaluates the safety of a galactagogue tea in breastfeeding women and their infants, assessing short- and long-term adverse effects. METHODS: Healthy, exclusively/fully breastfeeding women ( N = 60) with no milk insufficiency were randomized into (1) an all-natural tea containing fruits of bitter fennel, anise, and coriander; fenugreek seed; and other herbs (Mother's Milk(r) herbal tea; test) group or (2) a lemon verbena leaf (placebo) group. Maternal diaries captured self-reported maternal and infant adverse effects, tea consumed, and perceived infant satisfaction. Maternal quality of life and psychological state were assessed at baseline and 2 and 4 weeks. Poststudy calls assessed adverse effects through the infants' age of 12 months. RESULTS: No adverse effects attributable to the interventions were reported at any time point. No differences were found between test and placebo groups in sociodemographic characteristics, maternal or infant adverse symptoms, quality of life, breastfeeding self-efficacy, maternal psychological measures, infant growth, and infant satisfaction (all p > 0.05). CONCLUSIONS: This double-blind, randomized controlled trial (RCT) of an herbal galactagogue versus placebo among healthy, exclusively/fully breastfeeding mothers and infants found no adverse events associated with the test tea across the 30-day study or the first year of their infant's life. This composite tea appears to present no safety risk for mothers or their young babies. PMID- 30005171 TI - A Geospatial Analysis of the Impact of the Baby-Friendly Hospital Initiative on Breastfeeding Initiation in North Carolina. AB - BACKGROUND: Significant disparities in breastfeeding support and practice exist in North Carolina. The Baby-Friendly Hospital Initiative is a worldwide intervention that encourages birth facilities to adopt specific practices in support of breastfeeding. Research aim: This study aimed to evaluate the impact of the Baby-Friendly Hospital Initiative on breastfeeding initiation in North Carolina, with special attention to rural areas. METHODS: To better understand disparities in breastfeeding initiation across North Carolina, we conducted a secondary analysis of birth certificate data from 2011 to 2014. Univariate and multivariate logistic regression models were used to estimate the association between breastfeeding initiation and (a) birth at a Baby-Friendly hospital and (b) maternal residence in a county with a Baby-Friendly hospital. Model residuals were aggregated by county and analyzed for spatial autocorrelation. RESULTS: Birth at a Baby-Friendly hospital was associated with increased odds of breastfeeding initiation, adjusted odds ratio = 1.7, 95% confidence interval [1.65, 1.89]. Model residuals showed significant clustering by county, with some rural areas' rates systematically overestimated. Whereas presence of a Baby Friendly hospital in a mother's community of residence was not associated with increased initiation, birth at a Baby-Friendly hospital was associated with smaller disparities in initiation between rural and urban births. CONCLUSION: Birth at a Baby-Friendly hospital is associated with improved breastfeeding initiation and reduced disparities in initiation between rural and urban counties in North Carolina. PMID- 30005172 TI - Intergroup Contact as an Agent of Cognitive Liberalization. AB - Intergroup contact is widely recognized as one of the most validated methods of improving attitudes toward out-groups. Yet what is intergroup contact "good for" beyond this function? To answer this question we take a panoramic view of the literature, beginning with the recognition that contact is multifaceted in both form (e.g., face-to-face, indirect, simulated) and outcome (e.g., attitudes, cognition, behavior). Taking this highly inclusive view of what contact is and what contact does suggests that it plays a fundamental role in the shaping of human cognition. An increasingly diverse body of research demonstrates that contact exerts a generalizing reaction across target out-groups, making respondents less inward looking and more open to experiences. Contact shapes ideology regarding how the world ought to operate (i.e., ideologies about social hierarchy or regulation); over time, it can promote new ways of problem-solving, enhance cognitive flexibility, and foster creativity. For these reasons, we believe that contact is a key liberalizing agent that shapes human cognition and experience; consequently, contact theory should now share the stage with other prominent theories (e.g., cognitive dissonance) that speak to a broader understanding of human nature. PMID- 30005173 TI - Biomechanical Comparison of Syndesmotic Repair Techniques During External Rotation Stress. AB - BACKGROUND:: The purpose of this study was to compare mechanical behavior of conventional syndesmosis fixation devices with new anatomic repair techniques incorporating various repair augmentations to determine which approach would return rotational ankle mechanics closer to those of an intact ankle. METHODS:: Ten pairs of fresh-frozen through-the-knee cadaveric lower limbs were subjected to 7.5 Nm of external rotation torque while under 750 N of axial compression. After testing specimens intact and with the deltoid and syndesmotic ligament complexes completely destabilized, specimens underwent syndesmotic fixation using a screw, a suture button construct, a prototype structurally augmented flexible trans-syndesmotic fixation device, or the prototype device plus suture repairs of the anterior-inferior tibiofibular ligament and deep deltoid ligament. Syndesmotic repair devices were exchanged between tests so that each specimen was tested with 2 different fixation techniques. Whole-foot rotation angles at 7.5 Nm of applied torque were measured for comparison of the different repair strategies, and reflective markers mounted on the tibia, fibula, and talus were used to track translations and rotations of the talus and the fibula relative to the tibia during testing. RESULTS:: Syndesmotic destabilization significantly ( P < .001) increased whole-foot, talus, and fibula rotation in an axial plane and posterior fibula translation under 7.5 Nm of torque. Neither the suture button nor the augmented flexible trans-syndesmotic fixation device reduced those increases. Screw fixation or addition of anatomic ligament repairs to the augmented flexible fixation device successfully reduced axial plane rotations and sagittal plane translations to near intact levels. CONCLUSION:: Flexible trans syndesmotic fixation alone was found to be insufficient for restoring rotational stability to the ankle/talus or preventing sagittal plane displacement of the fibula. CLINICAL RELEVANCE:: Repairs to simulate anatomic structures disrupted during a syndesmosis injury were required to restore rotational stability to the foot when using flexible trans-syndesmotic fixation that may have clinical applicability. PMID- 30005174 TI - Sensitivity and Positive Predictive Value of Death Certificate Data Among Deaths Caused by Legionnaires' Disease in New York City, 2008-2013. AB - OBJECTIVES: Death certificates are an important source of information for understanding life expectancy and mortality trends; however, misclassification and incompleteness are common. Although deaths caused by Legionnaires' disease might be identified through routine surveillance, it is unclear whether Legionnaires' disease is accurately recorded on death certificates. We evaluated the sensitivity and positive predictive value of death certificates for identifying deaths from confirmed or suspected Legionnaires' disease among adults in New York City. METHODS: We deterministically matched death certificate data from January 1, 2008, through December 31, 2013, on New York City residents aged >=18 years to surveillance data on confirmed and suspected cases of Legionnaires' disease from January 1, 2008, through October 31, 2013. We estimated sensitivity and positive predictive value by using surveillance data as the reference standard. RESULTS: Of 294 755 deaths, 27 (<0.01%) had an underlying cause of death of Legionnaires' disease and 33 (0.01%) had any mention of Legionnaires' disease on the death certificate. Of 1211 confirmed or suspected cases of Legionnaires' disease, 267 (22.0%) matched to a record in the death certificate data set. The sensitivity of death certificates that listed Legionnaires' disease as the underlying cause of death was 17.3% and of death certificates with any mention of Legionnaires' disease was 20.9%. The positive predictive value of death certificates that listed Legionnaires' disease as the underlying cause of death was 70.4% and of death certificates with any mention of Legionnaires' disease was 69.7%. CONCLUSIONS: Death certificates had limited ability to identify confirmed or suspected deaths with Legionnaires' disease. Provider trainings on the diagnosis of Legionnaires' disease, particularly hospital settings, and proper completion of death certificates might improve the sensitivity of death certificates for people who die of Legionnaires' disease. PMID- 30005175 TI - Enhancement of letter identification by concurrent auditory stimuli of varying duration. AB - Previously it has been shown that the concurrent presentation of a sound can improve processing of visual information at higher perceptual levels, for example, in letter identification tasks. Moreover, increasing the duration of the concurrent sounds can enhance performance in low-level tasks as contrast detection, which has been attributed to a sustained visual activation corresponding to the duration of the sound. Yet, the role of sound duration has so far not been investigated in higher-level visual processing. In a series of five Experiments, we again demonstrated that the mere presence of a concurrent sound can enhance the identification of a masked, centrally presented letter compared to unimodal presentation, even though this benefit was absent in one experiment for high-contrast letters yielding an especially high level of task performance. In general, however, the sound-induced benefit was not modulated by a variation of target contrast or by the duration of the target-to-mask interstimulus interval. Taking individual performance differences into account, a further analysis suggested that the sound-induced facilitation effect may nevertheless be most pronounced at specific performance levels. Beyond this general sound-induced facilitation, letter identification performance was not further affected by the duration of the concurrent sounds, even though in a control experiment it could be established that letter identification performance improved with increasing letter duration, and perceived letter duration was prolonged with increasing auditory duration. The results and their interpretation with respect to the large observed interindividual performance differences are discussed in terms of potential underlying mechanisms of multisensory facilitation, as preparedness enhancement, signal enhancement, and object enhancement. PMID- 30005177 TI - Characteristics of intracellular algogenic organic matter and its reactivity with hydroxyl radicals. AB - The aim of this study was to investigate the reactivity of intracellular algogenic organic matter (IOM) with hydroxyl radicals (.OH), a key reaction species in advanced oxidation processes. IOM was extracted from two green algae, Chlamydomonas reinhardtii and Scenedesmus sp., and two blue-green algae, Anabaena sp. and Microcystis aeruginosa using a freeze-thaw method. The second-order rate constants of the extracted IOM with .OH were determined as 7.95 * 108 MC-1 s-1 (Chlamydomonas reinhardtii), 6.71 * 108 MC-1 s-1 (Scenedesmus sp.), 4.02 * 108 MC 1 s-1 (Anabaena sp.), and 4.45 * 108 MC-1 s-1 (Microcystis aeruginosa). These rate constants were significantly higher than values reported for dissolved organic matter in various water sources. This implies that IOM formation during algal bloom season could change the .OH water matrix demand and adversely affect the performance of advanced oxidation processes. To investigate the physical and chemical composition characteristics of IOM and their relationship to the rate constants determined for the reaction between IOM and .OH, liquid chromatography organic carbon detection (LC-OCD) and fluorescence excitation-emission matrix & parallel factor analysis (FEEM-PARAFAC) were used. The IOM mainly consisted of low molecular weight (LMW) matter and protein-related compounds, as evidenced LMW neutrals (38-65%), biopolymers (7-19%), and tryptophan-like compounds (74-94%). Based on the composition characteristics of IOM, it was concluded that the molecular weight and the presence of nitrogen-containing compounds are influential parameters for determining the reactivity of IOM with .OH. PMID- 30005179 TI - Ruminative and dampening responses to positive affect in bipolar disorder and major depressive disorder. AB - BACKGROUND: Although previous research has focused on distinguishing cognitive styles between Bipolar Disorder (BD) and Major Depressive Disorder (MDD), little is known about differences in positive affect regulation between these affective groups. The aim of the present study was to extend previous research by investigating such differences between BD and MDD, and between the bipolar subtypes (BD-I vs. BD-II and predominant polarities), using large, clinical, outpatient samples. METHODS: In total, 298 participants (96 BD-I, 27 BD-II, and 175 MDD) were included. All completed the Responses to Positive Affect (RPA) questionnaire. Mood symptoms in BD patients were clinically assessed by means of the Clinical Global Impression for Bipolar Disorders (CGI-BP), while depressive symptom severity in MDD patients were assessed by means of the Inventory of Depressive Symptomatology (IDS-SR). RESULTS: Results showed differences between affective groups and bipolar subtypes. The most salient finding was that both BD I and BD-II patients were more likely to ruminate about positive affect than MDD patients, while MDD patients were more likely to engage in dampening responses to positive affect. CONCLUSIONS: Differentiation of responses to positive affect between BD and MDD may have relevant clinical implications in terms of symptomatology, course, and treatment. PMID- 30005178 TI - The need to consume: Hoarding as a shared psychological feature of compulsive buying and binge eating. AB - INTRODUCTION: Compulsive buying and binge eating are two frequently co-occurring psychiatric conditions. Hoarding, which is the psychological need to excessively gather and store items, is frequently associated with both compulsive buying severity and binge eating severity. In the present study, we explored whether different dimensions of hoarding are a shared feature of compulsive buying and binge eating. METHOD: Participants consisted of 434 people seeking treatment for compulsive buying disorder. Registered psychiatrists confirmed the diagnosis of compulsive buying through semi-structured clinical interviews. Participants also completed measures to assess compulsive buying severity, binge eating severity, and dimensions of hoarding (acquisition, difficulty discarding, and clutter). Two hundred and seven participants completed all three measures. RESULTS: Significant correlations were found between compulsive buying severity and the acquisition dimension of hoarding. Binge eating severity was significantly correlated with all three dimensions of hoarding. Hierarchical regression analysis found that compulsive buying severity was a significant predictor of binge eating severity. However, compulsive buying severity no longer predicted binge eating severity when the dimensions of hoarding were included simultaneously in the model. Clutter was the only subscale of hoarding to predict binge eating severity in step two of the regression analysis. CONCLUSION: Our results suggest that the psychological need to excessively gather and store items may constitute a shared process that is important in understanding behaviors characterized by excessive consumption such as compulsive buying and binge eating. PMID- 30005180 TI - Delusional disorder: The role of personality and emotions on delusional ideation. AB - The relationship between personality and Delusional Disorder in still debated. The present study aimed to evaluate the role of personality features and emotional dispositions on the proneness to delusional beliefs, through the lens of a dimensional approach. 91 outpatients were administered the Structured Interview for DSM-IV Personality Disorders, the Pathological Narcissism Inventory, the Positive and Negative Affect Schedule and the Peters et al. Delusions Inventory. Delusion proneness was positively related to the "Hiding the Self" domain of narcissistic vulnerability and to paranoid traits and negatively related to "Positive Affect". Paranoid traits and "Hiding the Self" significantly interacted in influencing delusion ideation. These data suggest that proneness to delusion depends, at least in part, on a complex interplay between specific emotional and paranoid dispositions within personality. PMID- 30005176 TI - Pepper mild mottle virus: A plant pathogen with a greater purpose in (waste)water treatment development and public health management. AB - An enteric virus surrogate and reliable domestic wastewater tracer is needed to manage microbial quality of food and water as (waste)water reuse becomes more prevalent in response to population growth, urbanization, and climate change. Pepper mild mottle virus (PMMoV), a plant pathogen found at high concentrations in domestic wastewater, is a promising surrogate for enteric viruses that has been incorporated into over 29 water- and food-related microbial quality and technology investigations around the world. This review consolidates the available literature from across disciplines to provide guidance on the utility of PMMoV as either an enteric virus surrogate and/or domestic wastewater marker in various situations. Synthesis of the available research supports PMMoV as a useful enteric virus process indicator since its high concentrations in source water allow for identifying the extent of virus log-reductions in field, pilot, and full-scale (waste)water treatment systems. PMMoV reduction levels during many forms of wastewater treatment were less than or equal to the reduction of other viruses, suggesting this virus can serve as an enteric virus surrogate when evaluating new treatment technologies. PMMoV excels as an index virus for enteric viruses in environmental waters exposed to untreated domestic wastewater because it was detected more frequently and in higher concentrations than other human viruses in groundwater (72.2%) and surface waters (freshwater, 94.5% and coastal, 72.2%), with pathogen co-detection rates as high as 72.3%. Additionally, PMMoV is an important microbial source tracking marker, most appropriately associated with untreated domestic wastewater, where its pooled-specificity is 90% and pooled sensitivity is 100%, as opposed to human feces where its pooled-sensitivity is only 11.3%. A limited number of studies have also suggested that PMMoV may be a useful index virus for enteric viruses in monitoring the microbial quality of fresh produce and shellfish, but further research is needed on these topics. Finally, future work is needed to fill in knowledge gaps regarding PMMoV's global specificity and sensitivity. PMID- 30005182 TI - Factors associated with a prolonged hospital stay during induction chemotherapy in newly diagnosed high risk pediatric acute lymphoblastic leukemia. AB - BACKGROUND: High Risk (HR) or Very High Risk (VHR) acute lymphoblastic leukemia (ALL) treated with 4 drug induction chemotherapy is often associated with adverse events. The aim of this study was to identify risk factors associated with a prolonged inpatient length of stay LOS during induction chemotherapy. PROCEDURE: Data from patients (N = 73) (age<21 years) was collected through a retrospective chart review. Univariable and multivariable logistic regression was used to test for statistical significance. The overall survival and disease (leukemia)-free survival were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of the 73 patients, 42 (57%) patients were discharged on day 4 of induction (short LOS, group A), while 31 (43%) patients (group B) experienced a prolonged LOS or an ICU stay (16 +/- 27.7 days, median hospital stay = 8 days vs 4 days (group A), p = 0.02) due to organ dysfunction, infectious or metabolic complications. Group B patients were more likely to have a lower platelet count, serum bicarbonate, and a higher blood urea nitrogen (BUN) on day 4 of treatment (OR = 4.52, 8.21, and 3.02, respectively, p < 0.05). Multivariable analysis identified low serum bicarbonate (p = 0.002) and a platelet count<20,000/MUL (p = 0.02) on day 4 of induction to be predictive of a prolonged LOS. Twenty six (group A (n = 16, 36%) and B (n = 11, 35%), p = 0.8) patients experienced unplanned admissions, within 30 days of discharge. CONCLUSIONS: A significant proportion of newly diagnosed HR or VHR pediatric ALL patients experience a prolonged LOS and unplanned re-admissions. Aggressive discharge planning and close follow up is indicated in this cohort of patients. PMID- 30005183 TI - Management of melanoma in patients with chronic lymphocytic leukemia. AB - Melanoma is significantly more common and is associated with a poorer prognosis in patients with an underlying B-cell malignancy. This study reports on the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and a subsequent diagnosis of melanoma. In the Wilmot Cancer Institute CLL cohort, which includes 470 patients followed for 2849 person-years, 18 patients (3.8%) developed 22 melanomas. Fourteen melanomas were invasive, a significantly higher rate as compared with the age and sex matched general population (standardized incidence ratio [SIR] 6.32 (95% CI 3.45; 10.60). Melanomas were most often detected (n = 15; 68.2%) through active surveillance in a dermatology clinic. Most melanomas (n = 17; 77.3%) were detected at a non advanced stage (pathological stage grouping < III). The most common management was wide local excision without sentinel lymph node biopsy (n = 13, 59.1%). Management for the 4 (18.2%) patients with metastatic disease included the immune checkpoint inhibitor (ICI) pembrolizumab (n = 1), systemic chemotherapy with dacarbazine (n = 1), and palliative care (n = 2). The patient treated with ICI is in sustained remission of her melanoma after 23 cycles of therapy while her TP53 disrupted CLL continues to respond to ibrutinib therapy. We conclude that patients with CLL may benefit from active surveillance for melanoma leading to early excision of locally-manageable disease. In patients with metastatic melanoma, combined treatment with targeted kinase inhibitors and ICIs can be successful and tolerable. Larger prospective studies should be considered to further evaluate these approaches. PMID- 30005181 TI - Impaired discriminative fear conditioning during later training trials differentiates generalized anxiety disorder, but not panic disorder, from healthy control participants. AB - BACKGROUND: Fear conditioning is implicated as a central psychopathological mechanism of anxiety disorders. People with anxiety disorders typically demonstrate reduced affective discrimination between conditioned danger and safety cues. Here, affective discrimination refers to the ability to selectively display fear to dangerous but not safe situations. Though both generalized anxiety disorder (GAD) and panic disorder (PD) are linked to impaired affective discrimination, the clinical phenomenology of these disorders suggests that people with GAD versus PD might be less able to overcome such deficits. It is unclear how this potential difference would manifest during lab-based conditioning. METHODS: We used a classical fear conditioning paradigm over two discrimination training sessions to examine whether those with GAD, but not PD, would display persistent discrimination deficits. Sixty-seven participants (21 GAD, 19 PD, 27 Healthy Controls) completed a task in which conditioned fear was measured psychophysiologically (fear-potentiated startle), behaviorally, and via self-report. RESULTS: Although similar levels of impaired discrimination were found for both GAD and PD groups during initial training, such impairments tended to persist across a subsequent training session only for patients with GAD when compared with Controls. CONCLUSION: Our results provide a foundation for additional research of discrimination deficits in specific anxiety disorders, with an ultimate goal of improved customization of psychological treatments. PMID- 30005184 TI - Pediatric acute lymphoblastic leukemia-Conquering the CNS across the choroid plexus. AB - Despite the high prevalence of central nervous system (CNS) involvement in relapsing pediatric acute lymphoblastic leukemia (ALL), our understanding of CNS invasion is still vague. As lymphoblasts have to overcome the physiological blood CNS barriers to enter the CNS, we investigated the cellular interactions of lymphoblasts with the choroid plexus (CP) epithelium of the blood-cerebrospinal fluid barrier (BCSFB). Both a precurser B cell ALL (pB-ALL) cell line (SD-1) and a T cell ALL (T-ALL) cell line (P12-Ishikawa) were able to actively cross the CP epithelium in a human in vitro model. We could illustrate a transcellular and (supposedly) paracellular transmigration by 3-dimensional immunofluorescence microscopy as well as electron microscopy. Chemotactic stimulation with CXCL12 during this process led to a significantly increased transmigration and blocking CXCL12/CXCR4-signaling by the CXCR4-inhibitor AMD3100 inhibited this effect. However, CXCR4 expression in primary ALL samples did not correlate to CNS disease, indicating that CXCR4-driven CNS invasion across the BCSFB might be a general property of pediatric ALL. Notably, we present a unique in vitro BCSFB model suitable to study CNS invasion of lymphoblasts in a human setting, providing the opportunity to investigate experimental variables, which may determine CNS disease childhood ALL. PMID- 30005186 TI - Association between diurnal temperature range and mortality modified by temperature in Japan, 1972-2015: Investigation of spatial and temporal patterns for 12 cause-specific deaths. AB - Many previous literatures suggested that high temperature and diurnal temperature range (DTR) are prominent risk factors to increase risk of mortality. However, the role of effect modification of temperature on the DTR-related mortality is unclear. We examined whether temperature was an effect modifier on the DTR mortality association and how the modification patterns differed by cause of deaths and different regional climates using a nationwide 47 prefecture data in Japan (1972-2015). We used a two-stage analysis. For the first stage, we used a time-series regression with a distributed lag model to estimate the DTR-mortality association according to five levels of temperature (extreme cold, cold, moderate, hot, and extreme hot days) for each prefecture stratified by twelve cause-specific deaths. Then, we applied a meta-analysis to pool the estimates across the 47 prefectures in Japan and separately by cooler vs. warmer regions. Our findings showed that the risk of mortality associated with DTR was strongly modified by temperature for all causes and cardiovascular deaths (p < 0.001) in the total population, suggesting that the influence of DTR on mortality increases at higher levels of temperature. These findings were consistent across warmer and cooler regions. Similar patterns were observed for respiratory and renal disease deaths which demonstrated the associations with DTR were the highest during extreme hot days, although it was statistically not significant and varied depending on the climate regions. Our findings suggest that the DTR-related mortality may be modified by daily mean temperature and the most elevated during extremely hot temperatures. PMID- 30005185 TI - WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of exposure to long working hours and of the effect of exposure to long working hours on stroke. AB - BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years from stroke attributable to exposure to long working hours, to inform the development of the WHO/ILO joint methodology. OBJECTIVES: We aim to systematically review studies on occupational exposure to long working hours (called Systematic Review 1 in the protocol) and systematically review and meta-analyse estimates of the effect of long working hours on stroke (called Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework, conducting both systematic reviews in tandem and in a harmonized way. DATA SOURCES: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Medline, EMBASE, Web of Science, CISDOC and PsychINFO. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand-search reference list of previous systematic reviews and included study records; and consult additional experts. STUDY ELIGIBILITY AND CRITERIA: We will include working-age (>=15 years) workers in the formal and informal economy in any WHO and/or ILO Member State, but exclude children (<15 years) and unpaid domestic workers. For Systematic Review 1, we will include quantitative prevalence studies of relevant levels of occupational exposure to long working hours (i.e. 35-40, 41-48, 49-54 and >=55 h/week) stratified by country, sex, age and industrial sector or occupation, in the years 2005-2018. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case control studies and other non-randomized intervention studies with an estimate of the relative effect of a relevant level of long working hours on the incidence of or mortality due to stroke, compared with the theoretical minimum risk exposure level (i.e. 35-40 h/week). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO registration number: CRD42017060124. PMID- 30005187 TI - Association between birthweight and ambient PM2.5 in the United States: Individually-varied susceptibility and spatial heterogeneity. AB - The association between maternal exposure to PM2.5 and birthweight varies geographically, which may be caused by susceptibility. Whether this population level association is a function of mixtures of individuals with different susceptibilities is unclear. We investigated the probability distribution of individuals with different susceptibilities to PM2.5-related birthweight change, and evaluated spatial variation of the effect across the United States (US). We estimated the individual-level susceptibility using the effect of PM2.5 among a homogenous subpopulation, which was defined by a specific combination of modifiers. According to frequencies for all combinations, we derived the probability distribution of differential susceptibilities across the US and by states. From birth certificates across the US (1999-2004), we analyzed a total of 18,317,707 samples of singletons. Of the samples, 54-55% were assigned valid exposures, and linked to PM2.5. The subpopulation-specific associations of PM2.5 on birthweight change (i.e., susceptibilities) ranged from negative to positive. For the first-trimester exposure, 61.4% of the associations were negative, and the mean was -1.01 g (95% confidence interval, CI: -1.63, -0.38) of birthweight change per 5 MUg/m3 increase of PM2.5. The state-level associations varied (from 2.04 g [-2.76, -1.31] in New Hampshire to -0.30 g [-1.01, 0.41] in Texas) with demographic compositions in the US. The between-state variations of maternal race and education level were the greatest contributors to the spatial heterogeneity. Our findings may be useful to the policymaker in planning interventions for subpopulations susceptible to ambient pollution. PMID- 30005188 TI - Prenatal exposure to persistent organic pollutants and methylation of LINE-1 and imprinted genes in placenta: A CHECK cohort study. AB - Prenatal exposure to persistent organic pollutants (POPs) has been linked to numerous adverse birth outcomes among newborn infants in many epidemiological studies. Although epigenetic modifications have been suggested as possible explanations for those associations, studies have rarely reported a relationship between POP exposure during pregnancy and DNA methylation in the placenta. In the present study, we investigated the association between prenatal exposure to several POPs, including organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs), and methylation levels of long interspersed element 1 (LINE-1), as well as imprinted genes in placental DNAs among Korean mother-child pairs (N = 109). We assessed the association of DNA methylation not only with each target POP (single-POP models) but also with multiple POPs applying principal component analysis (multiple-POP models). Potential associations between placental DNA methylation and birth outcomes of newborn infants were also estimated. In single-POP models, significant associations were detected between OCP measurements and placental DNA methylation. Elevated concentrations of beta-hexachlorhexane (beta-HCH) in maternal serum collected during delivery were significantly associated with a decrease in methylation of LINE-1 in the placenta. Higher levels of p,p' dichlorodiphenyltrichloroethane (p,p'-DDT) in maternal serum were associated with hypermethylation of insulin-like growth factor 2 (IGF2). In multiple-POP models, a significant and positive association between DDTs and IGF2 methylation was also observed. Placental LINE-1 methylation was inversely associated with birth length. Our observations indicate that prenatal exposure to several POPs including DDTs is associated with the changes in methylation of genes, including major imprinted genes in the placenta. The consequences of these epigenetic alterations in placenta during development deserve further investigation. PMID- 30005189 TI - High serum levels of tenascin-C are associated with suicide attempts in depressed patients. AB - The proteomic study reported that Tenascin-C might be a diagnostic biomarker for major depressive disorder, but clinical studies of this potential relationship are lacking. Here we examined the association between tenascin-C levels in serum and suicide attempts. Serum tenascin-C concentrations were compared among depressive patients who had not attempted suicide (n = 86), patients who had attempted it (n = 43), and healthy controls (n = 109). All participants were aged between 18 and 68 years. The association between concentration and suicide attempts was assessed by multivariate analysis after adjusting for sociodemographics, lifestyle and health indicators. Tenascin-C concentrations were higher in patients than in controls, and higher in patients who had attempted suicide than in patients who had not. Higher concentrations were associated with greater risk of attempting suicide. Among patients who had attempted suicide, tenascin-C concentrations were associated with severity of depression. Our results suggest that high tenascin-C levels in depressive patients correlate with suicide attempts and severity of depression. Tenascin-C may contribute to risk of suicide attempts in depressed patients. PMID- 30005190 TI - Connections that moderate risk of non-suicidal self-injury among transgender and gender non-conforming youth. AB - We examined associations between social connections and non-suicidal self-injury (NSSI) among transgender/gender non-conforming (TGNC) youth. Data came from the 2016 Minnesota Student Survey (N = 2168). Logistic regression analyses determined connectedness factors associated with any past-year NSSI and repetitive NSSI, as well as moderating effects of significant connectedness factors on different risk factors. Almost 55% of TGNC students engaged in NSSI, and 40% of self-injurers reported repetitive self-injury. Parent connectedness, connections to non parental adults, and school safety emerged as robust protective factors. Strategies to prevent/reduce NSSI should focus on fostering connections with prosocial adults, and ensuring schools represent safe places. PMID- 30005192 TI - Optimising magnetic resonance sampling patterns for parametric characterisation. AB - Sampling strategies are often central to experimental design. Choosing efficiently which data to acquire can improve the estimation of parameters and reduce the acquisition time. This work is focused on designing optimal sampling patterns for Nuclear Magnetic Resonance (NMR) applications, illustrated with respect to the best estimate of the parameters characterising a lognormal distribution. Lognormal distributions are commonly used as fitting models for distributions of spin-lattice relaxation time constants, spin-spin relaxation time constants and diffusion coefficients. A method for optimising the choice of points to be sampled is presented which is based on the Cramer-Rao Lower Bound (CRLB) theory. The method's capabilities are demonstrated experimentally by applying it to the problem of estimating the emulsion droplet size distribution from a pulsed field gradient (PFG) NMR diffusion experiment. A difference of <5% is observed between the predictions of CRLB theory and the PFG NMR experimental results. It is shown that CLRB theory is stable down to signal-to-noise ratios of ~10. A sensitivity analysis for the CRLB theory is also performed. The method of optimizing sampling patterns is easily adapted to distributions other than lognormal and to other aspects of experimental design; case studies of optimising the sampling scheme for a fixed acquisition time and determining the potential for reduction in acquisition time for a fixed parameter estimation accuracy are presented. The experimental acquisition time is typically reduced by a factor of 3 using the proposed method compared to a constant gradient increment approach that would usually be used. PMID- 30005191 TI - Optimization-based image reconstruction from sparsely sampled data in electron paramagnetic resonance imaging. AB - Electron paramagnetic resonance imaging (EPRI) can yield information about the 3 dimensional (3D) spatial distribution of the unpaired-electron-spin density from which the spatial distribution of oxygen concentration within tumor tissue, referred to as the oxygen image or electron paramagnetic resonance (EPR) image in this work, can be derived. Existing algorithms for reconstruction of EPR images often require data collected at a large number of densely sampled projection views, resulting in a prolonged data-acquisition time and consequently numerous practical challenges especially to in vivo animal EPRI. Therefore, a strong interest exists in shortening data-acquisition time through reducing the number of data samples collected in EPRI, and one approach is to acquire data at a reduced number of sparsely distributed projection views from which existing algorithms may reconstruct images with prominent artifacts. In this work, we investigate and develop an optimization-based technique for image reconstruction from data collected at sparsely sampled projection views for reducing scanning time in EPRI. Specifically, we design a convex optimization program in which the EPR image of interest is formulated as a solution and then tailor the Chambolle Pock (CP) primal-dual algorithm to reconstruct the image by solving the convex optimization program. Using computer-simulated EPRI data from numerical phantoms and real EPRI data collected from physical phantoms, we perform studies on the verification and characterization of the optimization-based technique for EPR image reconstruction. Results of the studies suggest that the technique may yield accurate EPR images from data collected at sparsely distributed projection views, thus potentially enabling fast EPRI with reduced acquisition time. PMID- 30005193 TI - Automated classification of food products using 2D low-field NMR. AB - In this work, low-field proton (1H) and sodium (23Na) relaxation and diffusion measurements are used to detect and classify different types of food products. A compact and low-cost system based on a small 0.5 T permanent magnet has been developed to autonomously authenticate such products. The system uses a simple but efficient double-tuned matching network suitable for 1H/23Na NMR. Various machine learning algorithms are used to classify food samples based on T1-T2 and D-T2 data generated by the system, and the accuracy and prediction speed of these algorithms are studied in detail. The influence of temperature drift upon prediction accuracy is also studied. Experimental results demonstrate reliable classification of cooking oils, milk, and soy sauces. PMID- 30005194 TI - A single chip electron spin resonance detector based on a single high electron mobility transistor. AB - Single-chip microwave oscillators are promising devices for inductive electron spin resonance spectroscopy (ESR) experiments on nanoliter and subnanoliter samples. Two major problems of the previously reported designs were the large minimum microwave magnetic field (0.1-0.7 mT) and large power consumption (0.5 200 mW), severely limiting their use for the investigation of samples having long relaxation times and for operation at low temperatures. Here we report on the design and characterization of a single-chip ESR detector operating with a microwave magnetic field and a power consumption orders of magnitude lower compared with previous designs. These significant improvements are mainly due to the use of a high electron mobility transistor (HEMT) technology instead of a complementary metal-oxide semiconductor (CMOS) technology. The realized single chip ESR detector, which operates at 11.2 GHz, consists of an LC Colpitts oscillator realized with a single high-electron mobility transistor and a co integrated single turn planar coil having a diameter of 440 MUm. The realized detector operates from 300 K down to 1.4 K, at least. Its minimum microwave magnetic field is 0.4 MUT at 300 K and 0.06 MUT at 1.4 K, whereas its power consumption is 90 MUW at 300 K and 4 MUW at 1.4 K, respectively. The experimental spin sensitivity on a sensitive volume of about 30 nL, as measured with a single crystal of alpha,gamma-bisdiphenylene-beta-phenylallyl (BDPA)/benzene complex, is of 8 * 1010 spins/Hz1/2 at 300 K and 2 * 109 spins/Hz1/2 at 10 K, respectively. In a volume of about 100 pL, located in proximity to the coil wire, the spin sensitivity improves by two orders of magnitude. PMID- 30005195 TI - The effects of atmospheric hydrogen sulfide on peripheral blood lymphocytes of chickens: Perspectives on inflammation, oxidative stress and energy metabolism. AB - Excessive hydrogen sulfide (H2S) affects poultry health. Exposure to air pollution induces inflammation, oxidative stress, energy metabolism dysfunction and adverse health effects. However, few detailed studies have been conducted on the molecular mechanisms of H2S-induced injury in poultry. To understand how H2S drives its adverse effects on chickens, twenty-four 14-day-old chickens were randomly divided into two groups. The chickens in the control group were raised in a separate chamber without H2S, and the chickens in the treatment group were exposed to 30 ppm H2S. After 14 days of exposure, peripheral blood samples were taken and the lymphocytes were extracted to detect inflammation, oxidative stress and energy metabolism in broilers. Overall, an increase in the inflammatory response was detected in the peripheral blood lymphocytes following H2S exposure compared to the control group, and the expression levels of the heat shock proteins (HSPs) and the transcription factors nuclear factor kappaB (NF-kappaB), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) were up regulated in the H2S group, which further suggested that H2S induced an inflammatory response via the NF-kappaB pathway. Because of the activation of NF kappaB, which is a major regulator of oxidative stress, we also observed that reactive oxygen species (ROS) production was elevated under H2S exposure. In addition, we presumed that energy metabolism might be damaged due to the increased ROS production, and we found that H2S down-regulated the expression levels of energy metabolism-related genes, which indicated the occurrence of energy metabolism dysfunction. Altogether, this study suggests that exposure to excessive atmospheric H2S induces an inflammatory response, oxidative stress and energy metabolism dysfunction, providing a reference for comparative medicine. PMID- 30005196 TI - Brain methylmercury uptake in fetal, neonate, weanling, and adult rats. AB - Fetuses and neonates are known to be highly susceptible to methylmercury (MeHg) toxicity, but little is known about the relative uptake of MeHg from blood to the developing brain. We measured time-course changes in mercury (Hg) concentrations in the brain of fetal, neonate, weanling, and adult rats after an injection of 0.08 MUg (0.4 nmol) Hg/g MeHg. In the prenatal experiment, MeHg was subcutaneously injected to pregnant dams on embryonic days 17, 18, 18.5, 19, 19.5, or 20, and Hg concentrations in tissues were measured in both mothers and fetuses on embryonic day 21 (1 day before parturition). Brain Hg levels in fetuses peaked 2 days after injection and were approximately 1.5 times higher than in mothers. In the postnatal experiment, the same MeHg dose was injected subcutaneously to male rats on postnatal days 1 (neonates), 35 (weanlings), or 56 (adults). Mercury concentrations in tissues were measured 1, 2, 3, 4, 5, or 6 days after the injection. Brain Hg levels peaked most rapidly in neonates, and were approximately 1.5 times higher than levels in weanlings or adults. Throughout the examined period, peak Hg levels in the brain and the Hg brain/blood ratio 24 h after injection were highest in fetuses, followed by the levels in neonates, and decreased with life stage. These findings suggest that relatively higher brain MeHg uptake is an important factor in the vulnerability of fetuses and neonates to MeHg exposure. PMID- 30005197 TI - Contribution of climate and land cover changes to reduction in soil erosion rates within small cultivated catchments in the eastern part of the Russian Plain during the last 60 years. AB - The eastern part of the Russian Plain is an important agricultural region of European Russia with high proportion of cultivated lands in the steppe, forest steppe and forest (southern part) landscape zones. Soil erosion is the main process of land degradation and surface water contamination there. Climate and land cover changes have been observed in this region during the last 30 years. However, field quantitative assessments of soil erosion rates are not available for the eastern part of European Russia due to the lack of monitoring data as well as the evaluation of erosion/deposition processes in cultivated catchments using other field methods. Three representative small cultivated catchments with high (> 80%) proportion of cultivated lands were selected in the forest (southern part), forest-steppe and steppe zones of the study region to evaluate sedimentation rates in dry valley bottoms of the catchments for two-time intervals (1963-1986 and 1987-2016) based on the application of the bomb-derived and Chernobyl-derived 137Cs isotope for sediment dating. The 3-4 depth 137Cs profiles were used to assess the sedimentation rates within the each investigated catchment. It was established that the sedimentation rates have considerably decreased (at least 2-3 times) over the last 30 years compared to 1963-1986 in all the investigated catchments. This is in agreement with results of erosion rate calculations using erosion models for the forest zone, however not consistent with erosion rates assessments for the forest-steppe and steppe zones. According to the model calculations, erosion rates show a slight decrease in the forest-steppe zone and increase in the steppe zone. The reduction in surface runoff during snowmelt period is one of the reasons for decrease in erosion rates within cultivated slopes for all the investigated catchments. The increase in proportion of perennial grasses in the regional crop rotation is another important reason for the decrease in erosion rates for the catchment located in the south of the forest zone. The importance of land cover changes in a major decrease of soil losses from the cultivated fields of the investigated catchments located in the forest-steppe and steppe zones cannot be identified due to the lack detailed information about crop rotation for those particular sites. However, available regional information about crop rotation changes for the two time intervals (1960-1980 and 1996-2012) do not explain very high reduction in sedimentation rates in the dry valley bottoms after 1986. PMID- 30005198 TI - Influence of CeO2 nanoparticles on viscoelastic properties of sludge: Role of extracellular polymeric substances. AB - Cerium oxide nanoparticles (CeO2 NPs) affected the production of extracellular polymeric substances (EPSs), and thus might bring challenges for sludge pumping and mixing. In the present study, we investigated the rheological behavior of sludge before and after extraction of different EPSs fractions under various CeO2 NPs concentrations. It was found that the removal of loosely bound EPSs (LB-EPSs) could affect the shear stress (tau) and apparent viscosity (eta), and the changes were dependent on CeO2 NPs concentrations. The removal of tightly bound EPSs (TB EPSs) either with or without the addition of CeO2 NPs significantly decreased the yield stress (tauy) and the limiting viscosity (etainfinity). Furthermore, the dynamic (strain, frequency and time) sweep measurements proved that the storage modulus (G') decreased after the extraction of TB-EPSs, indicating the weakened elastic and solid-like properties. The fluctuated content of polysaccharide in LB EPSs and the increased amount of protein in TB-EPSs were likely to contribute to the variation of viscoelastic behaviors after the removal of LB-EPSs and TB-EPSs, respectively. In addition, the decreased rheological properties of sludge was also related to the increased zeta potential, decreased particle size and the removal of key organic matters of (104-106 Da) with the extraction of stratified EPSs. These results were significant to take advantages of the rheological properties for sludge treatment in the presence of NPs. PMID- 30005199 TI - Hourly land-use regression models based on low-cost PM monitor data. AB - Land-use regression (LUR) models provide location and time specific estimates of exposure to air pollution and thereby improve the sensitivity of health effects models. However, they require pollutant concentrations at multiple locations along with land-use variables. Often, monitoring is performed over short durations using mobile monitoring with research-grade instruments. Low-cost PM monitors provide an alternative approach that increases the spatial and temporal resolution of the air quality data. LUR models were developed to predict hourly PM concentrations across a metropolitan area using PM concentrations measured simultaneously at multiple locations with low-cost monitors. Monitors were placed at 23 sites during the 2015/16 heating season. Monitors were externally calibrated using co-located measurements including a reference instrument (GRIMM particle spectrometer). LUR models for each hour of the day and weekdays/weekend days were developed using the deletion/substitution/addition algorithm. Coefficients of determination for hourly PM predictions ranged from 0.66 and 0.76 (average 0.7). The hourly-resolved LUR model results will be used in epidemiological studies to examine if and how quickly, increases in ambient PM concentrations trigger adverse health events by reducing the exposure misclassification that arises from using less time resolved exposure estimates. PMID- 30005200 TI - Design, synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis. AB - In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6 fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H37Ra with an MIC value of 77 uM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated forin vitrostudies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6 fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3 carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2 fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 uM against Mtb H37Ra, respectively. PMID- 30005201 TI - Cytotoxic macrocyclic diterpenoids from Jatropha multifida. AB - Nine new macrocyclic diterpenoids (1-9), jatromultones A-I, along with eight known analogues (10-17) were isolated from the trunks of Jatropha multifida. The structures of the new compounds, including their absolute configurations, were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, Rh2(OCOCF3)4-induced CD method, and chemical correlations. All compounds were screened for the cytotoxicity against five cancer cell lines, including one drug-resistant cell line, and seven compounds exhibited significant activity with IC50 values less than 10 MUM. Compound 4 with IC50 values ranging from 2.69 to 6.44 MUM toward all cell lines was selected for further mechanistic study, which showed that 4 could arrest cell cycle at G2/M phase and induce apoptosis. The brief structure-activity relationships (SARs) of these macrocyclic diterpenoids were also discussed. PMID- 30005202 TI - New C-2 diastereomers of flavanone glycosides conjugated with 3-hydroxy-3 methylglutaric acid from the pericarp of Citrus grandis (L.) Osbeck. AB - Two new 3-hydroxy-3-methylglutaryl (HMG) flavanone 7-O-diglycosides, cigranosides A and B (1 and 2), the known naringenin 7-(2''-alpha-rhamnosyl-6''-(3''''-hydroxy 3''''-methylglutaryl)-glucoside (melitidin, 3), their common biosynthetic precursor flavanone 7-O-diglycoside (naringin, 4), and one known flavone 7-O diglycoside (rhoifolin, 5) were isolated from the pericarp of Citrus grandis (L.) Osbeck. The structures of these compounds were elucidated by spectroscopic and chemical techniques. The relative ratios and absolute configurations of the C-2 diastereomers of compounds 1, 2 and 4 were determined by online normal-phase HPLC CD using a Chiralcel column. The absolute configuration of the HMG fragment in compounds 1-3 was assigned to be S through spectroscopic analysis of the mevalonamide obtained by amidation and reduction of the HMG moiety. The NO inhibitory activities of compounds 1-5 were evaluated using lipopolysaccharide induced RAW264.7 cells. Compounds 1-5 were not cytotoxic to RAW264.7 cells at 10 MUM. PMID- 30005203 TI - Design, synthesis of novel isoindoline hybrids as COX-2 inhibitors: Anti inflammatory, analgesic activities and docking study. AB - A group of novel isoindoline hybrids incorporating oxime, hydrazone, pyrazole, chalcone or aminosulfonyl pharmacophores (9-14) was designed and characterized by spectral data and elemental analyses results. All newly synthesized compounds were evaluated as COX-2 inhibitors, anti-inflammatory and analgesic agents. Six hybrid derivatives (10b, 10c, 11a, 11d, 13, 14) were moderate COX-2 inhibitors (IC50 = 0.11-0.18 uM) close to standard celecoxib (IC50 = 0.09 uM). The most active compounds showed outstanding in vivo anti-inflammatory activity (% edema inhibition = 41.7-50, 1 h; 40.7-67.4, 3 h; 20-46.7, 6 h) better than reference drug diclofenac (% edema inhibition = 29.2, 1 h; 22.2, 3 h; 20, 6 h). Most compounds showed significant peripheral and/or central analgesic activity. The moderate selective COX-2 inhibitor; dimethoxychalcone 11d (SI = 103) displayed excellent anti-inflammatory activity (% edema inhibition = 45.8-59.3) and increased thermal pain threshold (50-92.85%) comparable to piroxicam (75%). Molecular docking studies have been established. PMID- 30005204 TI - Red light-emitting diode irradiation regulates oxidative stress and inflammation through SPHK1/NF-kappaB activation in human keratinocytes. AB - Oxidative stress, in which the amount of oxidants exceeds the capacity of antioxidant defense system, is a well-accepted pathogenesis of several human diseases. Light-emitting diode irradiation (LEDI) is an efficient strategy to counteract this condition. The biological effect of phototherapy, using visible light, has attracted recent attention especially in dermatological practice. However, little is known about the molecular mechanism of the anti-oxidant and anti-inflammatory effects of red light irradiation. We evaluated these effects of LEDI in HaCaT human keratinocyte cells under phorbol-12-myristate-13-acetate (PMA) induced reactive oxygen species (ROS). Microarray analysis revealed changes in 309 genes after LEDI. LEDI at 625 nm produced ROS scavenging and anti inflammatory effects. One of the most important genes identified by microarray analysis was sphingosine kinase-1 (SPHK1), which is a key molecule in sphingolipid metabolism. SPHK1 knock-down drastically reduced ROS scavenging efficiency as well as expression levels of inflammation-related proteins in PMA treated HaCaT cells. These results not only indicate the potential for the clinical application of 625-nm LEDI in treating skin disorders via ROS and/or inflammation, but also suggest SPHK1 as a potential therapeutic target in phototherapy. PMID- 30005205 TI - 970 nm low-level laser affects bone metabolism in orthodontic tooth movement. AB - OBJECTIVE: During orthodontic tooth movement (OTM), the speed of movement depends on the rate of bone turnover. In this study, we used a rat model to investigate the effect of 970 nm low-level laser therapy (LLLT) on OTM under different dose and frequency protocols. METHODS: We first compared the OTM rates between the OTM only control and the OTM + LLLT group (1250 J/cm2) in Experiment 1 and showed that LLLT significantly increased OTM. In Experiment 2, we employed 3 different LLLT protocols: the low-dose group and the high-dose group receiving 5 doses of 750 J/cm2 and 15,000 J/cm2 of LLLT every 3 days, respectively, and the early high dose group which received 5 daily doses at 15,000 J/cm2 at the beginning of the experiments. The OTM-only control group received no LLLT. Tooth movement rate was measured through sequential silicone impressions. MicroCT was also performed to evaluate bone de-mineralization rate. Bone histmorphometry was used to compare the bone turnover rate between LLLT group and control group. Finally, TRAP, Osteocalcin, and VEGF expression is evaluated by immunohistochemistry (IHC) in tissue sections. RESULTS: When LLLT treatment was given every three days, both the 1250 J/cm2 and 15,000 J/cm2 groups showed significantly increased OTM compared to the control group. No significant difference was observed in the 750 J/cm2 group, or in the early irradiation group, when compared with controls, although 750 J/cm2 showed the same trend of accelerating OTM. The MicroCT result of rat maxilla demonstrated that LLLT increased bone remodeling and showed decreased bone mineral density and bone volume/total volume in the furcation areas of the maxillary first molars at the end of experiment. LLLT without OTM increased bone turnover as evidenced by fluorochrome incorporation. Immunohistochemistry analyses revealed high osteocalcin expression at later stages of OTM in the LLLT group, while VEGF expression was highly induced in the LLLT + OTM group at an early stage. CONCLUSION: Our results suggest that the 970 nm LLLT increases the rate of OTM in a dose-sensitive and frequency-dependent manner. Further animal and human studies are needed to determine the optimal timing and dosage of LLLT for OTM acceleration. PMID- 30005206 TI - Portal vein abnormalities: an imaging review. AB - The portal vein is the main vascular channel of the liver and is affected by many pathologies. Imaging plays an important role in the detection and characterization of these abnormalities, guiding the surgeon and the interventional radiologist in planning further management. We discuss the imaging appearances of various abnormalities affecting the portal vein and the imaging modalities used in their diagnosis. We also briefly discuss the radiological interventions done in some of these cases. PMID- 30005207 TI - Second opinion interpretation of breast ultrasound images-Is it worth another look? AB - PURPOSE: To determine if real-time breast ultrasound (RTUR) after second opinion reinterpretation of submitted static ultrasound images at a comprehensive cancer center impacts clinical management, specifically by detecting additional cancer and preventing unnecessary biopsy. MATERIALS AND METHODS: In this IRB-approved and HIPAA-compliant retrospective study, 209 patients were included who had breast ultrasound studies from outside facilities submitted for second opinion review between January 2013 and May 2014, and who subsequently underwent RTUR at our institution within three months of the outside study. Findings on submitted exams were compared with those on RTUR and disagreements between them were annotated to indicate the presence or absence of suspicious lesions and recommendation for biopsy. Changes in management were defined as any additional biopsies performed or biopsies averted after RTUR and reported as frequencies and percentages using 95% confidence intervals. RESULTS: Following RTUR, 49 additional biopsies were performed in 43/209 patients (20.6%; 95% CI 15.1-26.1%). Additional cancer was found in 12/49 (24.5%) biopsies in 11/209 patients (5.3%; 95% CI 2.2-8.2%). Forty biopsies in 31/209 (14.8%; CI 10.0-19.7%) patients originally recommended were canceled after RTUR. Overall, a change in management after RTUR was observed in 68/209 patients (32.5%; 95% CI 26.1-38.9%), including patients with either additional biopsies performed or biopsies averted. CONCLUSION: RTUR was found to be an important tool in the management of patients at our comprehensive cancer center. Although additional false-positive lesions may be detected on RTUR, a great number of patients will benefit from RTUR in finding additional cancers or avoiding unnecessary biopsies. PMID- 30005208 TI - Molecular Imaging of Pancreatic Duct Adenocarcinoma Using a Type 2 Cannabinoid Receptor-Targeted Near-Infrared Fluorescent Probe. AB - Imaging probes targeting type 2 cannabinoid receptor (CB2R) overexpressed in pancreatic duct adenocarcinoma (PDAC) tissue have the potential to improve early detection and surgical outcome of PDAC. The aim of our study was to evaluate the molecular imaging potential of a CB2R-targeted near-infrared (NIR) fluorescent probe (NIR760-XLP6) for PDAC. CB2R overexpression was observed in both PDAC patient tissues and various pancreatic cancer cell lines. In vitro fluorescence imaging indicated specific binding of NIR760-XLP6 to CB2R in human PDAC PANC-1 cells. In a xenograft mouse tumor model, NIR760-XLP6 showed remarkable 50- (ex vivo) and 3.2-fold (in vivo) tumor to normal contrast enhancement with minimal liver and kidney uptake. In a PDAC lymph node metastasis model, significant signal contrast was observed in bilateral axillary lymph nodes with PDAC metastasis after injection of the probe. In conclusion, NIR760-XLP6 exhibits promising characteristics for imaging PDAC, and CB2R appears to be an attractive target for PDAC imaging. PMID- 30005209 TI - Histogram Analysis Parameters Apparent Diffusion Coefficient for Distinguishing High and Low-Grade Meningiomas: A Multicenter Study. AB - Low grade meningiomas have better prognosis than high grade meningiomas. The aim of this study was to measure apparent diffusion coefficient (ADC) histogram analysis parameters in different meningiomas in a large multicenter sample and to analyze the possibility of several parameters for predicting tumor grade and proliferation potential. Overall, 148 meningiomas from 7 institutions were evaluated in this retrospective study. Grade 1 lesions were diagnosed in 101 (68.2%) cases, grade 2 in 41 (27.7%) patients, and grade 3 in 6 (4.1%) patients. All tumors were investigated by MRI (1.5 T scanner) by using diffusion weighted imaging (b values of 0 and 1000 s/mm2). For every lesion, the following parameters were calculated: mean ADC, maximum ADC, minimum ADC, median ADC, mode ADC, ADC percentiles P10, P25, P75, P90, kurtosis, skewness, and entropy. The comparison of ADC values was performed by Mann-Whitney-U test. Correlation between different ADC parameters and KI 67 was calculated by Spearman's rank correlation coefficient. Grade 2/3 meningiomas showed statistically significant lower ADC histogram analysis parameters in comparison to grade 1 tumors, especially ADC median. A threshold value of 0.82 for ADC median to predict tumor grade was estimated (sensitivity = 82.2%, specificity = 63.8%, accuracy = 76.4%, positive and negative predictive values were 83% and 62.5%, respectively). All ADC parameters except maximum ADC showed weak significant correlations with KI 67, especially ADC P25 (P = -.340, P = .0001). PMID- 30005210 TI - Characterization of long non-coding RNAs and MEF2C-AS1 identified as a novel biomarker in diffuse gastric cancer. AB - Previous studies proved that long noncoding RNAs (lncRNAs) play important role in human cancer. However, the knowledge of genome scale expression of lncRNAs and their potential biological function in gastric cancer is still lacking. Next generation RNA sequencing (RNA-seq) was performed on tumor tissues and matched adjacent normal tissues of six diffuse gastric cancer (DGC) patients. Then we performed a comprehensive analysis on lncRNAs and mRNA. Fifty-eight lncRNAs were upregulated and 54 lncRNAs were downregulated in diffuse gastric cancer tissue compared with adjacent tissue. The numbers of up- and downregulated mRNAs were 306 and 161, respectively. In addition, we inferred the function of lncRNAs by construction of a co-expression network for deregulated mRNAs and lncRNAs. Co expressed genes of MEF2C-AS1 and FENDRR were enriched to RAS and TGF-beta signaling pathway. MEF2C-AS1 and FENDRR expression were re-evaluated by Real-time Quantitative PCR in 42 DGC patients' tumor and normal tissues, and other 46 DGC patents' and 21 healthy controls' plasma. Validation data showed MEF2C-AS1 and FENDRR were significantly downregulated in tumor tissues compared with normal tissues. And decreased FENDRR are associated with aggressive tumor characteristics including more advanced stage (P = .030), poor differentiation (P = .043) and lymphatic metastasis (P = .001). The expression level MEF2C-AS1 was significantly lower in DGC patients' plasma than that in healthy controls' plasma. In gastric cancer cell lines, knock-down of MEF2C-AS1 or FENDRR reduced the protein levels of FAT3, NTN1 and LYVE1 (the co-expressed genes), which were related with gastric cancer cell proliferation and invasion by previous studies. In addition, knock-down of MEF2C-AS1 or FENDRR promoted aggressive tumor behaviors in in-vitro assays. In this study, we provide a valuable resource of lncRNAs which might play important roles in the function of oncogenes or tumor suppressors affecting the development and progression of diffuse gastric cancer. PMID- 30005211 TI - Reprint of "Beverages containing low energy sweeteners do not differ from water in their effects on appetite, energy intake and food choices in healthy, non obese French adults". AB - The usefulness of replacement of caloric sugars by low-calorie sweeteners (LCS) for weight management has been questioned on the grounds that the uncoupling of LCS sweet taste and dietary energy may confuse physiological mechanisms, leading potentially to higher energy and sugar intake. The aim of the present study was to determine whether LCS beverages compared to water, when consumed with meals, differ in their effects on energy and food intake in acute trials and after long term habituation. Ad libitum food intake of 166 (80 women; 86 men) healthy non obese adults (BMI between 19 and 28 kg/m2), infrequent consumers of LCS was measured in four 2-consecutive-day testing sessions (Day 1 in the laboratory, Day 2 free-living). During the first 3 sessions, held one-week apart, participants were required to drink either water or commercial non-carbonated LCS lemonade (330 ml) with their main meals (randomised cross-over design). On Day 1, motivational ratings were obtained using visual analogue scales and ad libitum food intakes (amounts and types of foods selected) were measured using the plate waste method. On Day 2, participants reported their ad libitum intakes using a food diary. After Session 3, participants were randomly assigned to the LCS habituation group or to the water control group. The habituation (660 ml LCS lemonade daily vs 660 ml water) lasted 5 weeks. The fourth and final test session measured food intakes and motivational ratings after habituation. Water and LCS beverage did not differ in their effects on total energy intake, macronutrient intakes or the selection of sweet foods and on motivational ratings. Similar results were obtained in both LCS-naive and LCS-habituated individuals. PMID- 30005212 TI - Small sharp spikes as EEG markers of mesiotemporal lobe epilepsy. AB - OBJECTIVE: Mesial temporal lobe epilepsy (mTLE) is the most common type of focal epilepsy, but often lacks scalp EEG correlates. We ask if hippocampal epileptiform discharges that are characteristic of mTLE are associated with small sharp spikes (SSS) recorded on scalp EEG. SSS are considered benign waveforms, so are not currently used as markers of epilepsy. METHODS: To determine if there is a relationship between SSS and hippocampal discharges, simultaneous scalp and hippocampal depth electrode EEGs were recorded from 27 patients being evaluated for possible mTLE. Scalp EEG waveforms were assessed at the time of hippocampal discharges identified on intracranial hippocampal depth electrodes. RESULTS: 15 of 27 patients had SSS on scalp EEG that were time locked to hippocampal epileptiform discharges measured intracranially. These hippocampal spikes tended to have overlying high frequency oscillations and to co-localize with a seizure onset zone, suggesting that they were pathological discharges. CONCLUSIONS: There is a tight coupling between a subset of pathological hippocampal discharges and SSS. SIGNIFICANCE: SSS can be scalp EEG markers of mTLE rather than normal EEG variants. PMID- 30005213 TI - Altered electrophysiological correlates of motor inhibition and performance monitoring in Tourette's syndrome. AB - OBJECTIVE: Whether motor inhibition capabilities are impaired in Tourette's syndrome (TS) remains inconclusive. The ability to suppress tics has been proposed to ensure normal motor control in uncomplicated, adult patients. The aim of the present study was to characterize cortical processes of motor inhibition and performance monitoring using event-related potentials (ERPs) elicited by a visual stop signal task. METHODS: 15 TS patients and 15 matched healthy controls performed a stop signal task while multi-channel EEG were recorded. RESULTS: The behavioral results revealed no significant differences in inhibitory capabilities between groups. The latency of the P3 was discriminative of inhibition success, with shorter latencies for successful inhibition in both groups. P3 amplitude was not altered by inhibition success, but significantly attenuated for TS patients. Furthermore, the amplitude of the error-related negativity (ERN) was elevated while the error positivity (PE) was diminished for TS patients. CONCLUSION: In the stop signal task performance is not altered in adult TS patients but ERPs related to motor inhibition and performance monitoring are altered suggesting potential compensatory mechanisms. SIGNIFICANCE: The results support the hypothesis of compensatory cortical mechanisms to ensure sufficient motor performance. PMID- 30005214 TI - Impact of non-brain anatomy and coil orientation on inter- and intra-subject variability in TMS at midline. AB - OBJECTIVE: To investigate inter-subject variability with respect to cerebrospinal fluid thickness and brain-scalp distance, and to investigate intra-subject variability with different coil orientations. METHODS: Simulations of the induced electric field (E-Field) using a figure-8 coil over the vertex were conducted on 50 unique head models and varying orientations on 25 models. Metrics exploring stimulation intensity, spread, and localization were used to describe inter subject variability and effects of non-brain anatomy. RESULTS: Both brain-scalp distance and CSF thickness were correlated with weaker stimulation intensity and greater spread. Coil rotations show that for the dorsal portion of the stimulated brain, E-Field intensities are highest when the anterior-posterior axis of the coil is perpendicular to the longitudinal fissure, but highest for the medial portion of the stimulated brain when the coil is oriented parallel to the longitudinal fissure. CONCLUSIONS: Normal anatomical variation in healthy individuals leads to significant differences in the site of TMS, the intensity, and the spread. These variables are generally neglected but could explain significant variability in basic and clinical studies. SIGNIFICANCE: This is the first work to show how brain-scalp distance and cerebrospinal fluid thickness influence focality, and to show the disassociation between dorsal and medial TMS. PMID- 30005215 TI - Do scalp-recorded slow potentials during neuro-feedback training reflect the cortical activity? AB - OBJECTIVE: Neuro-feedback (NFB) training by the self-regulation of slow potentials (SPs) <0.5 Hz recorded from the vertex scalp has been applied for seizure suppression in patients with epilepsy. However, SP is highly susceptible to artifact contamination, such as the galvanic skin response (GSR). This study aimed to evaluate the correlation between SPs recorded from the scalp and intracranial electroencephalography (EEG) by event-related coherence analysis. METHODS: The scalp and subdural SPs were simultaneously recorded during NFB training by the DC-EEG machine while undergoing invasive recordings before epilepsy surgery in 10 patients with refractory partial epilepsy. The SPs at the vertex electrode were used as a reference for coherence analysis. RESULTS: The coherence of SPs negatively correlated with the distance between the subdural and scalp electrodes. A significant negative correlation was noted between the linear subdural-scalp electrode distance and the coherence value (r = - 0.916, p < 0.001). CONCLUSION: Scalp-recorded SPs from the vertex area primarily reflect the cortical activity of high lateral convexity. SIGNIFICANCE: Our results strongly suggest that SPs in NFB recorded from the vertex scalp electrode is derived from the cortices of high lateral convexity but not from the artifacts, such as GSR. PMID- 30005216 TI - Frontal EEG asymmetry in extremely low birth weight adult survivors: Links to antenatal corticosteroid exposure and psychopathology. AB - OBJECTIVE: Extremely low birth weight (ELBW; <1000 g) survivors are exposed to significant perinatal adversity. In many cases, mothers of these infants receive antenatal corticosteroids (ACS), which reduce offspring neonatal mortality but may have lasting neuropsychiatric effects. However, the long-term neurophysiological effects of being born at ELBW and exposed to ACS are unknown. METHODS: We compared resting frontal electroencephalogram (EEG) alpha asymmetry in ELBW survivors (n = 51), some of whom were exposed to antenatal corticosteroids (ELBW-S; n = 23) versus non-exposed (ELBW-NS; n = 28), and normal birth weight controls (NBW; n = 66) in adulthood (mage = 32.3 years). RESULTS: ELBW survivors exhibited greater relative right frontal EEG alpha (11.5 to 13.5 Hz) asymmetry at rest relative to NBW controls. A linear relation was observed between increased exposure to perinatal adversity (NBW vs. ELBW-NS vs. ELBW-S) and greater relative right frontal asymmetry. Relative right frontal asymmetry was also linked to contemporaneous psychopathology in all individuals. CONCLUSION: In the fourth decade of life, exposure to perinatal adversity was associated with patterns of frontal brain activity that reflect risk for psychopathology. Exposure to additional physiological stresses such as antenatal corticosteroids may amplify these effects. SIGNIFICANCE: The mental health of ELBW survivors, particularly those exposed to antenatal corticosteroids, should be monitored into adulthood. PMID- 30005217 TI - Association between mismatch negativity and voxel-based brain volume in schizophrenia. AB - OBJECTIVE: This study aimed to investigate the association between mismatch negativity (MMN) and volumes of several brain regions measured using a semi automated method in patients with schizophrenia and healthy controls. METHODS: MMN in response to duration deviants and magnetic resonance imaging were acquired from 36 schizophrenia patients and 14 healthy controls. FreeSurfer was used for volumetric analysis. MMN amplitudes, brain volumes and their association were compared between schizophrenia and controls. Correlation analysis and multiple linear regression analysis were used to examine the correlated variables of MMN. RESULTS: MMN amplitude was significantly lower in the schizophrenia group. In schizophrenia, MMN was positively correlated with age and negatively correlated with left hippocampal and right pars opercularis volumes. The association between left hippocampal volume and MMN in schizophrenia remained significant after controlling for potential confounders. CONCLUSIONS: Smaller hippocampal volume may play a role in the abnormal manifestation of MMN in schizophrenia. SIGNIFICANCE: The significant association between MMN and left hippocampal volume may suggest unique neurobiological contribution of hippocampus in auditory processing in schizophrenia. PMID- 30005218 TI - Optimal timing and differential significance of postoperative awake and sleep EEG to predict seizure outcome after temporal lobectomy. AB - OBJECTIVE: To evaluate the prognostic value of postoperative EEGs to estimate post anterior temporal lobectomy (ATL) seizure outcome. METHODS: We studied postoperative EEGs in 325 consecutive patients who had minimum five years of post ATL followup. Interictal epileptiform discharges (IEDs) present only during sleep were classified as sleep IEDs. We defined favorable final-year outcome as no seizures during the final one year and favorable absolute-postoperative outcome as no seizures during the entire postoperative period. RESULTS: At mean follow-up of 7.3 +/- 1.8 years, 281 (86.5%) patients had favorable final-year outcome while 161 (49.5%) had favorable absolute-postoperative outcome. IEDs on three months and one year EEG were associated with unfavorable outcomes while IEDs at 7th day had no association with outcomes. Sleep record increased the yield of IEDs by 30% at each time-point without compromising predictive value. EEG at one year predicted the risk of seizure recurrence on drug withdrawal. CONCLUSION: While EEG at three months and at one-year after ATL predicted seizure outcome, EEG at 7th day was not helpful. Sleep record increases the sensitivity of postoperative EEG without compromising specificity. SIGNIFICANCE: Both awake and sleep EEG provide useful information in postoperative period following ATL. PMID- 30005219 TI - Resting cranial and upper cervical muscle activity is increased in patients with migraine. AB - OBJECTIVE: To compare comprehensive measures of scalp-recorded muscle activity in migraineurs and controls. METHOD: We used whole-of-head high-density scalp electrical recordings, independent component analysis (ICA) and spectral slope of the derived components, to define muscle (electromyogram-containing) components. After projecting muscle components back to scalp, we quantified scalp spectral power in the frequency range, 52-98 Hz, reflecting muscle activation. We compared healthy subjects (n = 65) and migraineurs during a non-headache period (n = 26). We also examined effects due to migraine severity, gender, scalp-region and task (eyes-closed and eyes-open). We could not examine the effect of pre-ictal versus inter-ictal versus post-ictal as this information was not available in the pre existing dataset. RESULTS: There was more power due to muscle activity (mean +/- SEM) in migraineurs than controls (respectively, -13.61 +/- 0.44 dB versus -14.73 +/- 0.24 dB, p = 0.028). Linear regression showed no relationship between headache frequency and muscle activity in any combination of region and task. There was more power during eyes-open than eyes-closed (respectively, -13.42 +/- 0.34 dB versus -14.92 +/- 0.34 dB, p = 0.002). CONCLUSIONS: There is an increase in cranial and upper cervical muscle activity in non-ictal migraineurs versus controls. This raises questions of the role of muscle in migraine, and the possible differentiation of non-ictal phases. SIGNIFICANCE: This provides preliminary evidence to date of possible cranial muscle involvement in migraine. PMID- 30005220 TI - Enhancement and bilateral synchronization of ripples in atypical benign epilepsy of childhood with centrotemporal spikes. AB - OBJECTIVE: To determine whether the characteristics of scalp-recorded high frequency oscillations, especially ripples, can predict the "atypical forms" of benign epilepsy of childhood with centrotemporal spikes (ABECTS), in BECTS. METHODS: Seven patients with ABECTS and eighteen patients with BECTS underwent electroencephalography (EEG) in the secondary bilateral synchrony (SBS) and non SBS periods for ABECTS patients. SBS period is that when more than 50% of the interictal epileptiform discharges (IEDs) are bilaterally synchronized. We determined the IED-ripple co-occurrence rate, performed time frequency analysis, and calculated the asymmetry index (AI). RESULTS: The IEDs-ripple co-occurrence rate increased in the SBS compared to the non-SBS period. Time frequency analysis showed higher high-frequency activity rate and peak power in the SBS than in the non-SBS period. The AI was lower in ABECTS than BECTS, both in the non-SBS and SBS periods. CONCLUSIONS: Ripples were enhanced in the SBS period of ABECTS, and bilaterally synchronized both in the non-SBS and SBS periods, whereas ripples in BECTS were localized unilaterally. SIGNIFICANCE: Bilaterally synchronized ripples in the non-SBS period of ABECTS may distinguish ABECTS from BECTS in the non-SBS period of IEDs, and may be helpful for early detection of progressive neurophysiological regression leading to early intervention. PMID- 30005221 TI - The 1967 Abortion Act fifty years on: Abortion, medical authority and the law revisited. AB - The recent 50th anniversary of the 1967 Abortion Act provides the opportunity to revisit what has been termed the 'remarkable authority' this Act ascribes to doctors. This paper does so using as its starting point a seminal commentary on this question by the renowned medical sociologist Sally Macintyre, published in this journal in 1973 as 'The Medical Profession and the 1967 Abortion Act in Britain'. We revisit themes from that paper through an analysis of the findings of interviews with 14 doctors who, throughout lengthy careers, have provided abortions and led the development of the abortion service in England and Wales. We contrast our findings with Macintyre's, and argue that our interviews highlight the shifting meaning of medical authority and medical professionalism. We show that those doctors most involved in providing abortions place moral value on this work; uphold the authority of women (not doctors) in abortion decision making; view nurses and midwives as professional collaborators; and consider their professional and clinical judgement impeded by the present law. We conclude that medical sociologists have much to gain by taking abortion provision as a focus for the further exploration of the shifting meaning of medical authority. PMID- 30005222 TI - Friend or frenemy? Experiential homophily and educational track attrition among premedical students. AB - Support from experientially similar others-individuals who have been through the same life transition or faced a similar set of stressful circumstances-has been shown to be effective for coping with issues ranging from chronic illness to bereavement. Less research has examined how networks comprised of experientially similar others may shape academic outcomes. Using longitudinal egocentric network data collected from early career premedical students at a large research university (n = 268), results indicate that greater experiential homophily in premeds' networks are associated with a lower likelihood of departing from the premedical career track at the end of the academic year. Interview data (n = 39) highlight three support functions provided by premedical peers that help to explain this relationship: 1) concrete task assistance with assignments and studying, 2) empathic understanding and emotional support, and 3) advice and reassurance from more advanced peers. Results hint at the potential utility of peer support for the retention of students at-risk of straying from the premedical career track, and have implications for other fields of study. PMID- 30005223 TI - Complex narratives of health, stigma and control: Antimicrobial resistance screening among non-hospitalized refugees. AB - Antimicrobial resistance (AMR) is often presented as a major public health problem globally. Screening for AMR usually takes place in clinical settings. Recent developments in microbiology stimulated a series of studies focusing on AMR in communities, and particularly in travelers (any mobile individual), which was argued to be important for identifying potential public health risks. Against this background, microbiologists have become interested in non-hospitalized refugees as one of the traveler groups. However, this attention to refugees has provoked some professional debates on potential stigmatization of refugees as dangerous "others". To contribute to these debates, and to explore the idea of AMR screening of non-hospitalized refugees from different perspectives, we conducted a qualitative study among four groups of stakeholders who were chosen because of their associations with potential microbiological screening: microbiologists, public health physicians, public health nurses, and refugees. The study took place in a Dutch city from June to August 2016 and had 17 participants: five microbiologists, two public health nurses, four public health physicians, and six refugees. While microbiologists and public health physicians demonstrated a de-contextualized biomedical narrative in arguing that AMR screening among non-hospitalized refugees could be important for scientific research as well as for AMR prevention in communities, public health nurses displayed a more contextualized narrative bringing the benefits for individuals at the center and indicating that screening exclusively among refugees may provoke fear and stigmatization. Refugees were rather positive about AMR screening but stressed that it should particularly contribute to their individual health. We conclude that to design AMR prevention strategies, it is important to consider the complex meanings of AMR screening, and to design these strategies as a process of co-production by diverse stakeholders, including the target populations. PMID- 30005224 TI - Legacy and social media respectively influence risk perceptions and protective behaviors during emerging health threats: A multi-wave analysis of communications on Zika virus cases. AB - OBJECTIVE: Both legacy media, such as television and newspapers, and online social media are potentially important but incompletely understood sources of information in the face of emerging public health risks. This research aimed to understand media effects on risk perceptions and behaviors concerning the Zika virus in the United States. METHODS: We analyzed a multi-wave nationally representative survey (N = 29,062) and the volume of communications in social and legacy media (i.e., legacy media data from news sources and databases, N = 2,660 and social media data from Twitter, N = 1,605,752) in the United States between April and October 2016, dates coinciding with the early cases of local transmission of Zika in the United States (i.e., 25 weeks). The present study conducted econometric analyses (i.e., Granger causality tests) to assess the associations of legacy and social media coverage with risk perceptions and protective behaviors in the total sample and specific groups separated by pregnancy status/intent, geographic region, income, education level, age, and ethnicity. RESULTS: The results from the overall sample suggested that changes in the volume of information in legacy and social media (i.e., Twitter) were followed by different changes in community risk perceptions and protective behaviors. Specifically, social media coverage correlated with the level of risk perceptions, whereas the legacy media coverage correlated with the level of protective behaviors. Analyses across different subpopulations, including those of different pregnancy status/intent, geographic Zika risk, income, education level, age, and ethnicity, replicated the social media associations with risk perceptions in most cases. However, legacy media and protective behaviors were linked only in some vulnerable subpopulations (e.g., the less-educated populations). CONCLUSION: Understanding how media coverage relates to Zika risk perceptions and protective behaviors will help to facilitate effective risk communications by healthcare professionals and providers, particularly when a health risk emerges. PMID- 30005225 TI - Rabies response, One Health and more-than-human considerations in Indigenous communities in northern Australia. AB - Australia is currently canine rabies free; however, the spread of rabies in eastern Indonesia poses an increasing risk to northern Australia. Domestic dogs are numerous in East Arnhem Land (EAL) and the Northern Peninsular Area (NPA), usually unrestrained and living in close relationships with humans. The response to any rabies outbreak on Australian territory will focus on dog vaccination, controlling dog movements and depopulation. A One Health approach to zoonotic disease control should seek to co-promote human and animal health, whilst also seeking to accommodate the preferences of affected communities. We report on 5 collaborative workshops and 28 semi-structured interviews conducted between January 2017 and June 2018 with: (i) EAL and NPA community members; (ii) Indigenous Rangers in EAL and NPA; and (iii) residents of Cairns, the local regional centre. Storyboard methodologies were used to work with participants and explore what rabies response measures they thought were justified or unacceptable, why they held these views, and what other steps they believed needed to be taken. Key findings include that the capacity of the NPA and EAL communities to contribute/adapt to a biosecurity response is limited by structural disadvantage including poor infrastructure (such as lockable premises and intact fences) and appropriate information, dominant cultural norms and food security concerns. Dogs and dingoes can have great cultural and social importance; key interventions might be accommodated within cultural beliefs and long-standing norms of dog management if sufficient effort is made to adapt interventions to local contexts and community preferences. Adopting such a 'strengths-based' approach mandates that the communities at greatest risk need help to prepare for and develop strategies to manage a biosecurity response to a rabies incursion. This would include listening to individual and community concerns and attending to the educational and infrastructural needs for supporting different groups to respond appropriately. PMID- 30005226 TI - CXCR5+ CD8 T cells displayed higher activation potential despite high PD-1 expression, in tumor-involved lymph nodes from patients with thyroid cancer. AB - Thyroid cancer is one of the malignancies with better clinical outcomes. However, a minority of patients develops an aggressive anaplastic thyroid carcinoma. Development of innovative and multimodal therapeutic strategies is urgently needed. Here, we investigated the role of CXCR5+ CD8 T cells in the peripheral blood, tumor-involved lymph nodes (TILN), and tumor mass of thyroid cancer patients. In peripheral blood mononuclear cells, CXCR5+ cells represented 1.4% +/ 0.84% (mean +/- s.d.) of total CD8 T cells, while in TILN and in tumor, the frequencies of CXCR5+ CD8 T cells were significantly higher at 27.7% +/- 7.8% and 15.5% +/- 2.9%, respectively. Compared to CXCR5- CD8 T cells, CXCR5+ CD8 T cells presented significantly higher PD-1 expression and lower or comparable TIM-3 and CTLA-4 expression. To compare and contrast the functional characteristics of CXCR5+ CD8 T cells and CXCR5- CD8 T cells, these cells were separated from TILNs and were TCR-stimulated via anti-CD3/CD28. Upon stimulation, CXCR5+ CD8 T cells presented stronger downregulation of CD27, higher expression of proinflammatory cytokines IL-2, IFN-gamma, and TNF-alpha, and higher proliferation capacity than CXCR5- CD8 T cells. Moreover, CXCR5+ CD8 T cells presented higher expression of cytotoxic molecules Gzm-A, Gzm-B, and perforin. Overall, these results demonstrated that in thyroid cancer patients CXCR5+ CD8 T cells infiltrated the TILNs and the tumors, and were functionally more potent compared to their CXCR5- counterpart. PMID- 30005227 TI - Anti-inflammatory properties of cilostazol: Its interruption of DNA binding activity of NF-kappaB from the Toll-like receptor signaling pathways. AB - Cilostazol, a selective inhibitor of phosphodiesterase type III with anti platelet, anti-mitogenic, and vasodilating properties, is widely used to treat ischemic symptoms of peripheral vascular disease. Ample evidence has suggested that cilostazol also exhibits an anti-inflammatory effect, but its anti inflammatory mechanism is not fully understood. Here, we showed that cilostazol specifically inhibited expression of cytokines, which are induced by nuclear factor-kappaB (NF-kappaB) activation, in RAW264.7 macrophage cells stimulated with different Toll-like receptor (TLR) ligands. Cilostazol was found to significantly reduce TLR-4 and TLR-3 ligands-stimulated NF-kappaB transcriptional activity, which was quantified by luciferase reporter assays. However, cilostazol was without effect on IkappaBalpha degradation and NF-kappaB p65 phosphorylation and nuclear translocation after challenge with the TLR-4 ligand lipopolysaccharide (LPS). Cilostazol did not also prevent the LPS-induced increase in phosphorylated levels of the mitogen-activated protein kinase (MAPK) family. On the other hand, using chromatin immunoprecipitation assays, we demonstrated that cilostazol reduced the LPS-induced transcriptional activities of interleukin-6 and tumor necrosis factor-alpha by preventing the recruitment of NF-kappaB p65 to these gene promoters. When cilostazol was given to mice by oral gavage daily for 7 days, LPS-induced aberrant pro-inflammatory cytokine production and end-organ tissue injury were significantly reduced. The results of this study suggest that cilostazol is capable of directly interrupting DNA binding activity of NF-kappaB proteins from the TLR signaling pathways. The therapy to specifically intervene in this pathway may be potentially beneficial for the prevention of different inflammatory disorders. PMID- 30005228 TI - The characteristics of beta 2-glycoprotein I-dependent anticardiolipin antibody and blood coagulation status in subjects with classical biological false-positive syphilis reactions. AB - Anticardiolipin antibody (ACA) includes beta2-glycoprotein I-dependent (beta2-GPI dependent) and beta2-GPI-independent forms. The appearance of beta2-GPI-dependent ACA and its association with blood coagulation have never been investigated in subjects with classical biological false-positive syphilis reactions (CBFP). In total, 146 CBFP subjects, 465 syphilis patients and 64 presumed antiphospholipid antibody syndrome (pAPS) patients were enrolled, and beta2-GPI-dependent ACA IgA/IgG/IgM and anti-beta2-GPI IgA/IgG/IgM antibodies were detected via chemiluminescence assay. Conventional blood coagulation indices were measured to analyze their associations with these autoantibodies. In current study, the positive rate of beta2-GPI-dependent ACA in CBFP subjects was 22.60%, which was significantly higher than that in syphilis patients (3.87%) (P < 0.001) and similar to that in pAPS patients (32.81%) (P = 0.119). The predominant autoantibody isotypes were IgG in CBFP subjects and pAPS patients and IgM in syphilis patients. Positive autoantibody rates were independent of rapid plasma reagin titers. CBFP and pAPS subjects had longer prothrombin times (P < 0.001) and activated partial thromboplastin times (APTTs, P < 0.001) but lower fibrinogen concentrations (P = 0.022) and platelet counts (P < 0.001) than syphilis patients. APTTs were prolonged in CBFP, syphilis and pAPS subjects with positive autoantibodies compared with those in subjects with negative autoantibodies (P < 0.05). In conclusion, ACAs in CBFP and syphilis subjects are heterogeneous; beta2-GPI-dependent ACA constitutes a significant proportion of ACAs in CBFP subjects, while beta2-GPI-independent ACA predominates in syphilis patients. CBFP subjects are more prone to blood coagulation disorders than syphilis patients, and these autoantibodies may impact the intrinsic coagulation cascade in CBFP subjects, similar to pAPS patients. PMID- 30005229 TI - Activation profile of THP-1 derived dendritic cells stimulated by allergen Mal f 1 beyond its IgE-binding ability. AB - BACKGROUND: Mal f 1, the first allergen cloned from Malassezia furfur, has positive IgE reactivity in sera from atopic dermatitis (AD) patients. The mechanism by which Mal f 1 induces the maturation of human dendritic cells (DCs) and maintains the symptoms of AD is not well understood. OBJECTIVE: The present study aims to explore the activation profile of THP-1 derived dendritic cells (TDDCs) stimulated by recombinant Mal f 1, as well as to explore the IgE-binding ability of rMal f 1 and its correlation with IgE-binding activity of complete allergens of M. furfur. METHODS: rMal f 1 was produced by expression in E. coli and purification with affinity chromatography. The ability of rMal f 1 and ImmunoCAP complete allergens of M. furfur to bind to serum specific IgE was assayed in parallel by ELISA and immunoblotting. Immature TDDCs were stimulated with rMal f 1 or an enzyme-digested product of rMal f 1. The expression levels of markers, CD83, CD80, CD86, and HLA-DR, were investigated by flow cytometry. The levels of interleukin (IL)-6, IL-10, IL-12p70 and tumor necrosis factor (TNF) alpha in culture supernatants were determined by ELISA. RESULTS: Eighteen patient sera were identified that reacted positively to the complete allergens of M. furfur as determined by ImmunoCAP and also showed positive responses to rMal f 1. Five patient sera were identified that had no reaction to ImmunoCAP complete allergens of M. furfur and also exhibited negative response to rMal f 1. All sera, except for one, had no reaction to the unrelated allergen Bet v 1. rMal f 1 upregulated the maturation surface marker CD83 on TDDCs. In addition, rMal f 1 also induced high levels of CD80 and CD86. Increased expression of HLA-DR, a first signal for T cell activation, was observed. Secretion of IL-6, TNF-alpha and IL-10 by TDDCs increased significantly (P < 0.0001 for IL-6, P < 0.01 for TNF alpha and P < 0.05 for IL-10) after stimulation by rMal f 1, while the IL-12p70 level was unaltered. CONCLUSION: We have shown that rMal f 1 has ideal IgE binding ability and good correlation with binding activity to M. furfur. Moreover, we have revealed a hitherto unknown DC activation profile after rMal f 1 stimulation whereby TNF-alpha, IL-6, and IL-10 were significantly increased and IL-12 was unaltered, suggesting that rMal f 1 can predispose a DC bias toward the TH22/TH17 pathway beyond the routine IgE-dependent TH2 pathway, thus providing intriguing clues for clinical treatment involving both pathways. PMID- 30005230 TI - Polyethyleneimine-functionalized Luffa cylindrica for efficient uranium extraction. AB - Novel Luffa cylindrica (LC) adsorbent modified with polyethyleneimine (PEI) was prepared by "grafting-from" approach (LC-EPI-PEI) and "grafting-to" approach (LC PGMA-PEI) and employed for the adsorption of U(VI) from seawater. The critical factors affecting U(VI) adsorption from aqueous solution were exploited, such as pH, initial concentration and contact time. The results showed that the adsorption of U(VI) on LC-EPI-PEI and LC-PGMA-PEI was strongly dependent on pH. The adsorption isotherm was satisfactorily simulated by the Langmuir model and the maximum monolayer adsorption capacities of U(VI) was 208.3 mg/g on LC-EPI-PEI and 438.5 mg/g on LC-PGMA-PEI. The accordance of kinetic data with the pseudo second order model suggested that the adsorption reaction was controlled chemical process. In addition, LC-PGMA-PEI exhibited excellent reusability even after ten recycles. Moreover, LC-PGMA-PEI displayed excellent adsorption properties at low concentration of U(VI) (MUg/L) in aqueous solution as well as in simulated seawater. PMID- 30005231 TI - Facile assembling of novel polypyrrole nanocomposites theranostic agent for magnetic resonance and computed tomography imaging guided efficient photothermal ablation of tumors. AB - Multifunctional nanocomposites for image-guided cancer therapy are highly desired in clinical application. Herein, a novel theranostic agent based on gold and ferroferric oxide nanoparticles coating polypyrrole particles (PPy@Fe3O4/Au nanocomposites) for computed tomography (CT) and magnetic resonance (MR) imaging guided photothermal therapy was successfully assembled by a very facile electrostatic adsorption method. PPy@Fe3O4/Au nanocomposites exhibit good biocompatibility in vitro and in vivo. Because of high r2 relaxivity of Fe3O4 and high X-ray attenuation ability of Au, the PPy@Fe3O4/Au nanocomposites exhibited desirable CT and MR imaging performance, which provide more comprehensive and accurate diagnostic information. Moreover, PPy@Fe3O4/Au nanocomposites can efficiently kill cancer cells by hyperthermia with the guiding of CT and MR imaging, even completely ablate tumours. Hence, the electrostatic adsorption assembled PPy@Fe3O4/Au nanocomposites have great potential in clinical application for diagnosing and treating tumour in the future. PMID- 30005232 TI - Hierarchically porous cobalt-carbon nanosphere-in-microsphere composites with tunable properties for catalytic pollutant degradation and electrochemical energy storage. AB - Unreliable energy supply and environmental pollution are two major concerns of the human society in this century. Herein, we report a rational approach on preparation of hierarchically-structured cobalt-carbon composites with tunable properties for a number of applications. A facile hydrothermal treatment of cobalt nitrate and sucrose results in the formation of a metallic cobalt amorphous carbon composite with cobalt nanospheres anchored homogenously on an amorphous carbon substrate. Tuning the calcination conditions in air will generate either a metallic cobalt-cobalt oxide core-shell structure with magnetism or a fully oxidized Co3O4 composite. The different materials are demonstrated as anodes for lithium-ion batteries (LIBs) and catalysts for advanced oxidation-based wastewater remediation. A fully oxidized composite (FC@CS, fully oxidized Co loaded on carbon spheres) as a LIB anode exhibits superior electrochemical performance, possessing a high reversible capacity, high initial columbic efficiency, outstanding cycling performance and excellent rate capability. The anode performance is superior to most reported Co3O4-based electrodes. Meanwhile, the partially oxidized composite (PC@CS, partially oxidized Co loaded on carbon spheres) functions as an efficient and stable catalyst for removal of phenol via peroxymonosulfate (PMS) activation, which is demonstrated via electron paramagnetic resonance (EPR) and quenching experiments for generation of radicals. More importantly, the recycled PC@CS can be further applied as a LIBs anode after full oxidation regeneration, performing comparably to FC@CS. This FC@CS -> PC@CS -> FC@CS transformation provides an innovative approach for efficient material synthesis, recycling and application. PMID- 30005233 TI - Facile synthesis of bimetallic (In,Ga)2(O,S)3 oxy-sulfide nanoflower and its enhanced photocatalytic activity for reduction of Cr(VI). AB - Hexavalent chromium is one of the most chronic and harmful to human beings, animals, and environmental well-being, and hence needs a high attention to detoxify it. For this purpose, bimetallic (In,Ga)2(O,S)3 oxy-sulfide nanoflower catalyst with different Ga contents was successfully synthesized at a low temperature of 150 degrees C via a facile method. It was systematically characterized and the visible light-driven photocatalytic reduction of toxic Cr(VI) was 100% completed at 4 min. The Cr(VI) reduction reaction rate constant was 13.8 fold higher than that of Ga-free In2(O,S)3 catalyst. It also showed lower recombination of photogenerated charge carriers, faster interfacial reaction rate, and higher electrical conductivity. The photoexcited electrons and H+ ions played crucial roles in the reduction of Cr(VI). The Cr(III) composition was 12.0% of the total atomic composition. The as-synthesized catalyst showed a tremendously fast Cr(VI) reduction activity and hence, it is promising for detoxification of hazardous Cr(VI). PMID- 30005234 TI - Coralloidal carbon-encapsulated CoP nanoparticles generated on biomass carbon as a high-rate and stable electrode material for lithium-ion batteries. AB - Architecture of electrode materials plays an important role in achieving favorable electrochemical performance via providing fast electronic transport pathway and shorten lithium ion diffusion distance. Herein, ultrafine CoP nanoparticles were successfully embedded in carbon nanorod, which were grown on the biomass-derived carbon (BC). When applied as anode materials for lithium-ion batteries, these CoP@C/BC displayed capable specific capacity, remarkable rate ability and outstanding long-term cycling performance. The capacity was governed by combination of diffusion-controlled and capacitive processes, according to quantitative kinetic analysis. The good electrochemical performance is attributed to hierarchical construction of nanosized CoP embedded in carbon nanorod and BC with high conductivity composite, which relieve the volume changing of CoP and provide large electrode/electrolyte interface. The present design of hierarchical architecture can be extended to other transition metal-based oxides, sulfide and phosphide electrode materials for high performance alkali metal ion batteries. PMID- 30005235 TI - Numerical investigation of oblique impact of multiple drops on thin liquid film. AB - HYPOTHESIS: When multiple drops impact on a thin liquid film, the interaction dynamic between two impinging drops is prominent. High-speed (>50 m/s) oblique impacts of drops on a liquid film result in asymmetrical splashing patterns and further complicate the phenomenon. To understand the interaction between injected crowns from splashing, numerical simulations are very useful to study the flow behaviors. SIMULATIONS: Three-dimensional simulations are performed to investigate the impact of two adjacent drops on a thin liquid layer using a multiphase flow solver. The solver solves Navier-Stokes equations on Cartesian grids and uses the moment-of-fluid method for interface reconstruction. The numerical code is first validated with three experimental studies and good agreements are obtained. Simulations of oblique impacts of two adjacent drops are then conducted for low-speed and high-speed impacts. FINDINGS: The numerical results show that strong interaction occurs when the crowns formed by two adjacent drops interfere with each other. For low-speed impact, drops deposit on to the liquid film with short and thick crater rims formed and the interaction region is a superposition of the crater edges. For high-speed impact, crowns break up to form splashing and the interaction behavior becomes complicated. PMID- 30005236 TI - Confining nano-sized platinum in nitrogen doped ordered mesoporous carbon: An effective approach toward efficient and robust hydrogen evolution electrocatalyst. AB - Despite recent progress in the development of earth abundant electrochemical catalyst for hydrogen evolution reaction (HER), Pt based materials still stand as the state of the art HER catalyst. Due to the high cost of Pt, it is desirable to increase the utilization efficiency of Pt in practical HER process to a realize cost effective hydrogen production. Herein, we repot a novel nitrogen doped ordered mesoporous carbon supported Pt (Pt@NOMC-A) catalyst with a low Pt loading of 7.2 wt% and show that the synergy between Pt nanoparticles and carbon support, as well as the physical confinement offered by the carbon support enhance the electrochemical performance of the novel catalyst. Pt@NOMC-A exhibits a low HER overpotential comparable with commercial 20 wt% Pt/C catalyst under acidic, neutral and alkaline condition. Furthermore, Pt@NOMC-A shows a superior electrochemical stability under working conditions suppressing that of commercial Pt/C catalyst. PMID- 30005237 TI - Anomalous variations in the viscous activation energy of suspensions induced by fractal structuring. AB - HYPOTHESIS: In suspensions, the activation energy of viscous flow is an important property that controls the temperature dependence of the viscosity. However, the differentiated roles of the properties of the liquid phase and the structure of the solid particles in controlling the activation energy remain unclear. We propose here that particle fractal structuring yields an anomalous behavior in the activation energy of viscous flow. EXPERIMENTS: The rheology of two series of suspensions consisting of glass beads suspended in poly(1-decene) was investigated over a wide range of solid volume fractions (0.00 <= phi <= 0.55). These suspensions were characterized by their viscosity (eta, Pa?s) via shear rate sweeps and by their yield stress (Pa) via oscillatory amplitude sweeps. FINDINGS: Interestingly, for suspensions consisting of nominally smaller particles (d50 ~ 5 um), we observe an anomalous decrease in the activation energy (Ea, kJ/mol) of viscous flow with increasing solid fraction. Based on oscillatory rheology analyses, it is suggested that such anomalous behavior arises due to entropic effects that result from the formation of fractally-architected cooperatively rearranging regions (i.e., agglomerates) in the suspension. PMID- 30005238 TI - Doped ZnO nanoparticles impregnated on Kaolinite (Clay): A reusable nanocomposite for photocatalytic disinfection of multidrug resistant Enterobacter sp. under visible light. AB - Water contamination by multidrug resistant (MDR) enteric bacteria can be considered as the foremost cause of gastrointestinal infections and poses a threat to global public health. Therefore, there is an urgent need to pursue unorthodox techniques with potential of community scale applications for purging of water borne pathogenic bacteria. We communicate visible-light assisted photocatalytic disinfection (PCD) of an enteric MDR bacterium; Enterobacter sp. using Fe-doped ZnO nanoparticles impregnated on Kaolinite (Clay) (ZnO/K). ZnO/K was synthesized by co-precipitation technique and was found to be more effective than Fe-doped ZnO (ZnO) and Kaolinite for PCD process. Analysis from fluorescence microscopy and electron microscopy (FESEM) proposed complete bacterial cell death via PCD due to damage of bacterial cell membrane. Experimental evidences indicated that O2- could be acting as the most significant component in disinfection of MDR Enterobacter sp. in visible-light assisted PCD process in presence of ZnO/K. Considering the experimental data of Resazurin assay, it is proposed that reactive oxygen species (ROS) generated during PCD might have impeded the oxido-reductase enzyme system of the bacteria and hence trammeling its metabolic activity. Crystal structure and particle size of ZnO/K was found to be unaltered during the photocatalytic process indicating its potential for reusability. When ZnO/K was exposed to HCT-116 Human Colorectal Carcinoma cell lines, about 79% cell survivability was noticed. The synthesized material was successful in completely disinfecting the target microorganism in Zebra Fish model, without producing any adverse effects on the Fish itself, further reinforcing its biocompatibility factor. High effectiveness of PCD process using ZnO/K under visible light in disinfecting enteric MDR bacteria, might have promising outcome as an alternative water disinfection technology to prevent the spread of infectious and resistant bacteria without producing any adverse effect on non-specific flora and fauna. PMID- 30005239 TI - Anthracene-decorated TiO2 thin films with the enhanced photoelectrochemical performance. AB - New insight of introducing new organic compounds for the efficient photogenerated charge separation is vitally important for the current solar energy conversion. Herein, (2Z,2'Z)-4,4'-(anthracene-2,6-diylbis(azanediyl))bis(4-oxobut-2-enoic acid) (ADA)/TiO2 composite thin film is fabricated through the wet-impregnation strategy, which exhibits excellent photoelectrochemical performance (PEC). A combined study of ultraviolet-visible absorption spectra, scanning Kelvin probe maps, electrochemical and photoelectrochemical measurements reveals that the ADA/TiO2 composite with narrow bandgap of 2.42 eV extends the photo response to the visible light region. The photocurrent generated by the optimal ADA/TiO2 is 2.5 times higher than that of the pristine TiO2. The result is attributed to the broader light absorption range and the separation of photoelectrons and holes prompted by ADA. Moreover, the high stability of the ADA/TiO2 composite favors the practical application. The present work may offer a promising strategy for the low-cost PEC cell in the clean solar hydrogen production. PMID- 30005240 TI - Protein adsorption mechanisms at rough surfaces: Serum albumin at a gold substrate. AB - Adsorption kinetics of human serum albumin (HSA) at a gold substrate was studied using the quartz microbalance (QCM), atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). Measurements were performed at pH 3.5 for various bulk suspension concentrations and ionic strengths. The QCM experimental data were compared with the dry coverage of HSA derived from AFM and from the solution of the mass transfer equation acquired using a hybrid random sequential adsorption model. In this way, the water factor and the dynamic hydration function for HSA monolayers were quantitatively evaluated as a function of dry coverage for various ionic strengths. A comparison of these results with previously known for a silica sensor confirmed that the QCM kinetic measurements are sensitive to the roughness of the sensor characterized in terms of the rms parameter. For the more rough gold sensor (rms = 2.5 nm, average surface feature size 6 nm) the QCM mass transfer rate constant was 2.6 times lower than for the silica sensor characterized by rms = 0.86 nm. This gives for the gold sensor the apparent water factor equal to one and zero hydration function. Moreover, the hydration function increased for larger HSA coverage and was dependent on ionic strength in contrast to the silica substrate. This unexpected behavior was interpreted in terms of the buoyancy effect where the HSA molecules adsorbing in cavities existing at rough surfaces replace the stagnant (hydrodynamically bound) water. Hence, these results confirm that the sensor roughness of the size comparable with protein molecule dimensions exerts a decisive influence on their adsorption kinetic derived from QCM measurements. PMID- 30005241 TI - Understanding element composition of medicinal plants used in herbalism-A case study by analytical atomic spectrometry. AB - This review article is focused on element composition of medicinal plants and herbs as well as their decoctions and infusions determined by atomic spectrometry methods. Considering quality and safety of these herbal beverages, widely practiced in herbalism for medicinal and supplementing purposes, element analysis is important, and quality of its results should not raise any doubts about reliability. Hence, original researches devoted to element analysis of decoctions and infusions of medicinal plants and herbs, published after 2000, have been surveyed in details, particularly focusing on sources of elements in medicinal plants, their availability for the intake during preparation of infusions and decoctions as well as different methodological aspects related to element analysis by atomic spectrometry, including sample pretreatment and preparation before measurements, calibration methods used, and verification of reliability of results. PMID- 30005242 TI - Development, validation and application of a novel HPLC-MS/MS method for the quantification of atorvastatin, bisoprolol and clopidogrel in a large cardiovascular patient cohort. AB - Cardiovascular disease is a leading cause of morbidity, mortality, and healthcare expenditure worldwide. Importantly, there is interindividual variation in response to cardiovascular medications, leading to variable efficacy and adverse events. Therefore a rapid, selective, sensitive and reproducible multi-analyte HPLC-MS/MS assay for the quantification in human plasma of atorvastatin, its major metabolites 2-hydroxyatorvastatin, atorvastatin lactone and 2 hydroxyatorvastatin lactone, plus bisoprolol and clopidogrel-carboxylic acid has been developed, fully validated, and applied to a large patient study. Fifty microliter plasma samples were extracted with a simple protein precipitation procedure involving acetonitrile with acetic acid (0.1%, v/v). Chromatographic separation was via a 2.7 MUm Halo C18 (50 * 2.1 mm ID, 90 A) column and gradient elution at a flow rate of 500 MUL/min consisting of a mobile phase of water (A) and acetonitrile (B), each containing 0.1% formic acid (v/v), over a 6.0 min run time. The six analytes and their corresponding six deuterated internal standards underwent positive ion electrospray ionisation and were detected with multiple reaction monitoring. The developed method was fully validated with acceptable selectivity, carryover, dilution integrity, and within-run and between-run accuracy and precision. Mean extraction recovery for the analytes was 92.7 108.5%, and internal standard-normalised matrix effects had acceptable precision (coefficients of variation 2.2-12.3%). Moreover, all analytes were stable under the tested conditions. Atorvastatin lactone to acid interconversion was assessed and recommendations for its minimisation are made. The validated assay was successfully applied to analyse 1279 samples from 1024 patients recruited to a cardiovascular secondary prevention prospective study. PMID- 30005244 TI - Effect of imidazolium-based ionic liquids with varying carbon chain lengths on Arabidopsis thaliana: Response of growth and photosynthetic fluorescence parameters. AB - As green and novel solvents, ionic liquids (ILs) are popular in many industries, which may threaten ecosystems. The effects of three imidazolium-based ILs with different alkyl chain lengths, including 1-octyl-3-methylimidazolium chloride ([C8mim]Cl), 1-decyl-3-methylimidazolium chloride ([C10mim]Cl), and 1-dodecyl-3 methylimidazolium chloride ([C12mim]Cl) on growth and photosystem of Arabidopsis thaliana were investigated. Root length, fresh weight, cell membrane permeability, and chlorophyll content of whole plant were significantly affected by ILs. Vein clearing, leaf chlorosis, and browning on the A. thaliana leaf abaxial surface occurred, with a dose-response relationship. The effect of ILs on whole plant increased with alkyl chain lengths. Chlorophyll fluorescence parameters of photosynthetic system II (PSII) were all affected in [C8mim]Cl and [C10mim]Cl treatments, electron-transfer was blocked, and photochemical energy conversion was damaged. There were no significant changes in chlorophyll fluorescence of newly-growing leaves in [C12mim]Cl treatment, but has severe effect on aged leaves. The number and size of starch granules and osmiophilic globules increased, plasmolysis and the chloroplast swelling occurred in [C8mim]Cl, [C10mim]Cl treatments and on aged leaves in [C12mim]Cl treatment, but no significant damages occurred on newly-growing leaves of [C12mim]Cl treatment, perhaps due to plant self-protection of plant. The results indicating the appropriate use of ILs is needed. PMID- 30005245 TI - Novel ternary nanohybrids of tetraethylenepentamine and graphene oxide decorated with MnFe2O4 magnetic nanoparticles for the adsorption of Pb(II). AB - Novel ternary nanohybrids, consisting of tetraethylenepentamine (TEPA), graphene oxide (GO) and manganese ferrite magnetic nanoparticles (TEPA-GO/MnFe2O4), were prepared by a facile hydrothermal method and utilized to remove Pb(II) from aqueous solution effectively. The adsorbents were characterized by SEM, TEM, XRD, FTIR, zeta potential analysis, magnetization hysteresis loop, BET and XPS. These nanoparticles exhibited superparamagnetic behavior as well as high removal efficiency for Pb(II). Moreover, numerous amino groups of the functionalized pendant TEPA on GO coupled with the porous structure of TEPA-GO/MnFe2O4 contribute to high Pb(II) adsorption capacity. The maximum Pb(II) adsorption capacity of TEPA-GO/MnFe2O4 was determined to be 263.2 mg/g at the optimized solution pH of 5.5, much higher than that of GO/MnFe2O4 (133.3 mg/g) and GO (196.1 mg/g). The kinetics and isotherm data fitted well with the pseudo-second order kinetics and the Langmuir isotherm model, respectively. Thermodynamic studies revealed that the Pb(II) adsorption of TEPA-GO/MnFe2O4 was a endothermic and spontaneous process. The experimental results corroborated that TEPA GO/MnFe2O4 can be efficaciously reused after washed with HCl, indicative of its potential applications in environmental cleanup. PMID- 30005243 TI - Simultaneous quantification of EVT201, a novel partial positive allosteric GABAA receptor modulator, and its two metabolites in human plasma by UHPLC/MS/MS. AB - A sensitive, accurate and rapid UHPLC-MS/MS method was developed and validated for the simultaneous determination of EVT201 and its two metabolites, Ro46-1927 and Ro18-5528, in human plasma. D6-EVT201 was used as the internal standard (IS). Plasma samples were extracted using ethyl acetate after being alkalized with saturated sodium carbonate solution. Chromatographic separation was carried out on an Acquity BEH C18 column (2.1 * 50 mm, 1.7 MUm) with a gradient mobile phase at a flow-rate of 0.50 mL/min. The analytical run time was 5.5 min. For mass spectrometric detection, multiple reaction monitoring (MRM) was used. The MRM ion transitions were m/z 373.2 -> 58.0 for EVT201, m/z 359.2 -> 316.1 for Ro46-1927, m/z 291.2 -> 274.1 for Ro18-5528 and m/z 379.3 -> 64.0 for the IS. The linear range was 0.2-200 ng/mL for each analyte, with a correlation coefficient (r) over 0.9900. The intra-/inter- precision was within 7.9% and 4.5% for EVT201, 13.2% and 6.3% for Ro46-1927, 3.7% and 4.1% for Ro18-5528. For the accuracy, the relative bias of intra-/inter- run was no more than 6.4% and 4.6% for EVT201, 9.4% and 7.9% for Ro46-1927, -6.9% and -7.5% for Ro18-5528. The validated method was successfully applied to the analysis of more than 1500 samples from a Phase I clinical trial. The incurred sample reanalysis (ISR) of 146 samples from the study was evaluated and the results met the acceptance criteria. It indicated that the method could be used for the pharmacokinetic study of EVT201. PMID- 30005246 TI - A solar responsive photocatalytic fuel cell with the membrane electrode assembly design for simultaneous wastewater treatment and electricity generation. AB - In this work, a photocatalytic fuel cell (PFC) with membrane electrode assembly (MEA) structure was designed for simultaneous organic compounds degradation and electricity generation. For the photoanode, the TiO2 with the quantum-dot sensitization by CdS-ZnS was used to broaden the absorption spectrum to visible light. For the cathode, an air-breathing mode was utilized to enhance the oxygen transport. The performance of the developed PFC was evaluated under different operation conditions, including the light intensity, liquid flow rate, concentrations of electrolyte and organics. Results indicated that the designed PFC could yield good performance. The increase of the light intensity and electrolyte concentration could improve the PFC performance. It is also found that when the flow rate was increased, the PFC performance dropped down in the testing range. Too high organics concentration led to the decrease of the PFC performance. PMID- 30005247 TI - Ultrafine Pt NPs-Decorated SnO2/alpha-Fe2O3 Hollow Nanospheres with Highly Enhanced Sensing Performances for Styrene. AB - Styrene, a chronic toxic gas, is of great harm to human health. It is urgently required to develop a portable, efficient, and inexpensive method to detect this toxic gas. Chemiresistive gas sensor based on semiconductor metal-oxides is considered as one of the best candidate suited to above features, while its sensitivity and selectivity are not enough high for the applications. Herein, the ultrafine Pt NPs embellished SnO2/alpha-Fe2O3 hollow nanoheterojunctions were achieved by in-situ reduction and subsequent calcination treatment. Particularly, such yielding products exhibited excellent styrene sensing performances with a detection limit of 50 ppb and extremely fast response/recovery time (3/15 s, respectively). More importantly, this SnO2/alpha-Fe2O3/Pt sensing platform revealed improved styrene selectivity against other malodorous gases. Additionally, the significant enhancement for styrene sensing response was also obtained compared to other two sensors (pristine SnO2 and SnO2/alpha-Fe2O3, respectively). Further studies demonstrated that such enhanced performances possibly be owing to the "catalytic sensitization" effect driven by Pt NPs and "electronic sensitization" effect triggered through the formation of Schottky junction as well as n-n nanoheterojunction. Based on these sensing features, it is probably great promising in the detection of styrene gas in the future. PMID- 30005248 TI - Assessing bioaccumulation behaviour of hydrophobic organic contaminants in a tropical urban catchment. AB - The bioaccumulation behaviour of halogenated flame retardant (HFRs), synthetic musks (SMs), organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in plankton, invertebrates and fish was assessed in an urban catchment in Singapore which is a tropical island country highly populated. The studied contaminants ranged widely in physical-chemical properties, with KOW values ranging between approximately 103-1011. BDE-47 and dechlorane plus (DPs) were the predominant HFRs, while galaxolide (HHCB) and tonalide (AHTN) were the predominant synthetic musk compounds in biota from the studied freshwater system. Concentrations of organochlorine contaminants such as chlordanes, DDE, DDD, PCB 138 and PCB 153 were generally higher than those of the HFRs and SMs. On a wet weight basis, bioaccumulation factors (BAFs) of the current use HFRs were in some cases higher than the bioaccumulation criteria value of 5000 L/kg wet weight. Conversely, BAFs of SMs were found to be less than the 5000 L/kg guideline. Lipid adjusted BAFs (L/kg lipid) of the studied contaminants varied among the different aquatic species, which is likely due to organism trophic level and metabolic transformation capacity differences. BAFs were highly correlated with the chemical KOW values. For fish, log BAFs of the studied contaminants increased with increasing log KOW, between a log KOW range of approximately 3-7, after which BAFs subsequently decreased. A similar relationship was observed for BAFs in the studied invertebrates. For plankton, a simple linear regression was observed between log BAF and log KOW over the target analyte KOW range (log KOW's between 3-11). Predicted BAF values derived from a mechanistic bioaccumulation model for hydrophobic organic contaminants were generally consistent with the observed BAFs. However, in some cases the model substantially overestimated bioaccumulation potential based on the chemical's hydrophobicity, which may be due to a high degree of biotransformation of those compounds. The study provides important information regarding bioaccumulation potential of several emerging organic contaminants of concern. PMID- 30005249 TI - Nano-porous SAPO-34 enhanced thin-film nanocomposite polymeric membrane: Simultaneously high water permeation and complete removal of cationic/anionic dyes from water. AB - Thin-film nanocomposite (TFN) membranes were prepared by embedding nano-porous SAPO-34 nanoparticles in a polypyrrole thin-film layer polymerized on PES substrate. SEM, EDX, AFM, hydrophilicity, zeta potential and MWCO measurements were applied to verify characteristics of membranes. TFN membranes presented considerably higher pure water permeability (by more than 300%) due to high hydrophilicity and also nano-channels created in thin-film. Performance of TFN membranes were also evaluated by removal of different anionic and cationic dyes (methyl violet 6B, reactive blue 4 and acid blue 193) from water. TFN membranes effectively removed 100% of all dyes from feed aqueous solutions with a low concentration (50 mg/l). Moreover, TFN membrane prepared with the highest amount of nano-filler presented an elevated water flux in filtration of solutions containing each dyes (e.g. more than 500% for reactive blue 4), a reduced flux decline ratio (36%) and also a higher flux recovery ratio (85%) in comparison with the pristine thin-film membrane, consequently indicating high performance of TFN membranes and potential of recovery just after a simple water washing. TFN membranes also revealed an efficient performance in filtration of high concentrations of dye solutions as well as in treatment of a real wastewater produced by a weaving company. PMID- 30005250 TI - A pilot study on the disinfection efficacy of localized UV on the flushing generated spread of pathogens. AB - The process of toilet-flushing can generate flushing-associated water droplets which can potentially expose humans to pathogen-laden aerosols. Very little is known about such aerosol dissemination or the means for minimizing exposure to these aerosols. This study has evaluated the efficacy of ultraviolet waveband C (UV-C) for disinfection of flushing-generated pathogen-laden aerosols through tests with localized disinfection systems for airborne and surface contaminations. Three types of bacteria were chosen for investigation: Staphylococcus epidermidis, Escherichia coli, and Salmonella typhimurium. Tests were conducted with UV-C tubes of 5 W and 10 W. High levels of disinfection efficacies were observed, ranging from 76% to 97% for bacteria-laden aerosols at sources of emission, and efficiencies of 53% to 79% for surface samples in localized systems. The results from the localized systems were further compared with those obtained with an upper-room ultraviolet germicidal irradiation (UVGI) system. As it is important to note, the UV-C doses and ozone emissions for the localized systems were found well below the limits recommended in current guidelines. This research has shown that the disinfection of flushing-generated pathogen-laden aerosols in proximity to the source of emission was more effective than at the more distant sites where aerosols may be dispersed to the environment. PMID- 30005251 TI - Direct-acting DNA ethylating agents associated with tobacco use primarily originate from the tobacco itself, not combustion. AB - Unburnt tobacco and tobacco smoke contain a variety of carcinogens, exposure to which are causally associated with the incidence of several human cancers. Herein, we used isotope-dilution LC-MS/MS for the quantification of alkylated purines in DNA, following in vitro exposure to aqueous extracts of tobacco itself, and tobacco smoke. Our results demonstrated the presence of direct-acting ethylating agent(s) in unburnt tobacco, which 4.0-6.3 times exceeded that in the particulate phase of sidestream cigarette smoke and 6.8-8.9 times exceeded that in mainstream smoke. Interestingly, particulate phase of sidestream cigarette smoke exhibited higher ethylating potency than that in mainstream smoke. This finding refutes the previous assumptions that the ethylating agent(s) associated with smoking, are derived from cigarette smoke. Indeed, our data show that combustion of tobacco actually decreases the ethylating potency of tobacco. Although the identity of this agent(s) remains unknown, our data suggest that it is highly hydrophilic, and hence likely to be easily extracted by saliva. This would allow intimate contact with the tissues of the oropharyngeal cavity. Taken together, these results have profound implications for tobacco use, in particular for tobacco chewers and passive smokers, whose exposure to ethylating agent(s) is greater than previously thought. PMID- 30005252 TI - Household biomass fuel use, blood pressure and carotid intima media thickness; a cross sectional study of rural dwelling women in Southern Nigeria. AB - BACKGROUND: Rising prevalence of cardiovascular disease requires in-depth understanding of predisposing factors. Studies show an association between air pollution and CVD but this association is not well documented in southern Nigeria where the use of biomass fuels (BMF) for domestic purposes is prevalent. PURPOSE: This study aimed to explore the association between household BMF use and blood pressure (BP) and carotid intima media thickness (CIMT) among rural-dwelling women. METHODS: A cross-sectional study of 389 women aged 18 years and older. Questionnaires were used to obtain data on predominant fuel used and a brief medical history. Wood, charcoal and agricultural waste were classified as BMF while kerosene, bottled gas and electricity were classified as non-BMF. Blood pressure and CIMT were measured using standard protocols. Regression analysis was used to assess the relationship between fuel type and BP, CIMT, pre-hypertension and hypertension after adjusting for confounders. RESULTS: There was a significant difference in the mean (standard deviation) systolic BP (135.3, 26.7 mmHg vs 123.8, 22.6 mmHg; p < 0.01), diastolic BP (83.7, 18.5 mmHg vs 80.1, 13.8 mmHg; p = 0.043) and CIMT (0.63, 0.16 mm vs 0.56, 0.14 mm; p = 0.004) among BMF users compared to non-BMF users. In regression analysis, the use of BMF was significantly associated with 2.7 mmHg higher systolic BP (p = 0.040), 0.04 mm higher CIMT (p = 0.048) in addition to increased odds of pre-hypertension (OR 1.67 95% CI 1.56, 4.99, P = 0.035) but not hypertension (OR 1.23 95% CI 0.73, 2.07, P = 0.440). CONCLUSION: In this population, there was a significant association between BMF use and increased SBP, CIMT and pre-hypertension. This requires further exploration with a large-scale longitudinal study design because there are policy implications for countries like Nigeria where a large proportion of the population still rely on BMF for domestic energy. PMID- 30005253 TI - Impact of changes in climate on air pollution in Slovenia between 2002 and 2017. AB - Air pollutant levels depend on emissions but can also be affected by the meteorological situation. We examined air pollutant trends (PM10, NO2, O3 and SO2) in Slovenia, where in the past the main issue were SO2 levels. Now, the population is still exposed to PM10 and ozone levels that are above the recommended levels. Our goal was to assess if the levels of air pollutants were decreasing from 2002 to 2017 due to emission ceilings or were more influenced by changes in the meteorological situation. We modelled the relationship between levels, meteorological parameters, and seasonality and then used the models with the best estimated generalisation to adjust levels for meteorology. Models showed a significant relationship between meteorological parameters and PM10, NO2, and O3 levels, but not SO2. We analysed trends of raw and adjusted levels and compared them. Trends of PM10 and SO2 were decreasing at all locations for raw and adjusted data. The largest decrease was observed in SO2 levels where the largest decrease in emissions occurred. Trends of NO2 were also significant and negative at most locations. Levels of O3 did not exhibit a significant trend at most locations. Results show that changes in the meteorological situation affected PM10 levels the most, especially where the entire period (2002-2017) could be observed. There is strong empirical evidence that changes in meteorological parameters contributed to the decrease in PM10 levels while the decrease in NO2 and SO2 levels can be attributed to emission ceilings. PMID- 30005255 TI - Denitrifier communities impacted by heavy metal contamination in freshwater sediment. AB - Heavy metals are widely detected in natural environments, however their impacts on denitrifier community in freshwater ecosystem remain unclear. The present study investigated the changes of denitrifier communities (based on nosZ (nitrous oxide reductase) gene) in a freshwater reservoir contaminated by a severe accidental spill of heavy metals. The abundance of nosZ-denitrifiers drastically decreased, and their community richness, diversity and structure also showed considerable variations. The mainly detected denitrifying bacteria included Pseudogulbenkiania, Pseudomonas and two unknown groups. These major nosZ denitrifier groups responded in different ways to heavy metal pollution. Metal contamination could exert a profound influence on denitrifier community in freshwater sediment. This work could provide some new insights to the impact of metal pollution on nitrogen cycling. PMID- 30005254 TI - Biodegradation of microcystin-LR using acclimatized bacteria isolated from different units of the drinking water treatment plant. AB - Bacterial community isolated from different units of a Drinking Water Treatment Plant (DWTP) including pre-ozonation unit (POU), the effluent-sludge mixture of the sedimentation unit (ESSU) and top-sand layer water sample from the filtration unit (TSFU) were acclimatized separately in the microcystin-leucine arginine (MC LR)-rich environment to evaluate MC-LR biodegradation. Maximum biodegradation efficiency of 97.2 +/- 8.7% was achieved by the acclimatized-TSFU bacterial community followed by 72.1 +/- 6.4% and 86.2 +/- 7.3% by acclimatized-POU and acclimatized-ESSU bacterial community, respectively. Likewise, the non acclimatized bacterial community showed similar biodegradation efficiency of 71.1 +/- 7.37%, 86.7 +/- 3.19% and 94.35 +/- 10.63% for TSFU, ESSU and POU, respectively, when compared to the acclimatized ones. However, the biodegradation rate increased 1.5-folds for acclimatized versus non-acclimatized conditions. The mass spectrometry studies on MC-LR degradation depicted hydrolytic linearization of cyclic MC-LR along with the formation of small peptide fragments including Adda molecule that is linked to the reduced toxicity (qualitative toxicity analysis). This was further confirmed quantitatively by using Rhizobium meliloti as a bioindicator. The acclimatized-TSFU bacterial community comprised of novel MC-LR degrading strains, Chryseobacterium sp. and Pseudomonas fragi as confirmed by 16S rRNA sequencing. PMID- 30005256 TI - Exposure to ZnO nanoparticles alters neuronal and vascular development in zebrafish: Acute and transgenerational effects mitigated with dissolved organic matter. AB - Exposure to ZnO-nanoparticles (NPs) in embryonic zebrafish reduces hatching rates which can be mitigated with dissolved organic material (DOM). Although hatching rate can be a reliable indicator of toxicity and DOM mitigation potential, a fish that has been exposed to ZnO-NPs or any other toxicant may also exhibit other abnormal phenotypes not readily detected by the unaided eye. In this study, we moved beyond hatching rate analysis to investigate the consequences of ZnO-NPs exposure on the nervous and vascular systems in developing zebrafish. Zebrafish exposed to ZnO-NPs (1-100 ppm) exhibited an array of cellular phenotypes including: abnormal secondary motoneuron (SMN) axonal projections, abnormal dorsal root ganglion development and abnormal blood vessel development. Dissolved Zn (<10 kDa) exposure also caused abnormal SMN axonal projections, but to a lesser extent than ZnO-NPs. The ZnO-NPs-induced abnormal phenotypes were reversed in embryos concurrently exposed with various types of DOM. In these acute mitigation exposure experiments, humic acid and carbohydrate, along with natural organic matter obtained from the Suwannee River in Georgia and Milwaukee River in Wisconsin, were the best mitigators of ZnO-NPs-induced motoneuron toxicity at 96 h post fertilization. Further experiments were performed to determine if the ZnO NPs-induced, abnormal axonal phenotypes and the DOM mitigated axonal phenotypes could persist across generations. Abnormal SMN axon phenotypes caused by ZnO-NPs exposure were detected in F1 and F2 generations. These are fish that have not been directly exposed to ZnO-NPs. Fish mitigated with DOM during the acute exposure (F0 generation) had a reduction in abnormal motoneuron axon errors in larvae of subsequent generations. Therefore, ZnO-NPs exposure results in neurotoxicity in developing zebrafish which can persist from one generation to the next. Mitigation with DOM can reverse the abnormal phenotypes in an acute embryonic exposure context, as well as across generations, resulting in healthy fish. PMID- 30005257 TI - Biomarker responses in fish exposed to polycyclic aromatic hydrocarbons (PAHs): Systematic review and meta-analysis. AB - Biomarkers of antioxidant and biotransformation systems are commonly used to assess polycyclic aromatic hydrocarbons (PAHs) pollution in fish. Despite their extensive application of biomarkers, contradictory results are vastly reported in the literature, even for the same species in similar contamination scenarios. This study aims to verify response patterns of biomarkers in fish exposed to PAHs. Through systematic reviews and meta-analyses, we were able to evaluate: (i) overall magnitude of PAHs effects on biotransformation and oxidative stress biomarkers; (ii) patterns of response among experimental approaches (laboratory, field and active biomonitoring), environment (marine and freshwater) and fish habitat (pelagic, demersal, etc.); (iii) effects of exposure route, time and concentration of PAHs; and (iv) which biomarkers respond best to PAHs exposure. Overall, biomarker responses were significantly affected by PAHs exposure. The activities of ethoxyresorufin-O-deethylase (EROD), glutathione S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx) and levels of oxidized glutathione (GSSG) and lipid peroxide (LPO) significantly increased in fish exposed to PAHs, whereas catalase (CAT) and glutathione reductase (GR) activities and levels of reduced glutathione (GSH) were not affected. Amongst responsive biomarkers, EROD and GST activities significantly differed among approaches and between marine and freshwater environments, but were not affected by fish habitat. GSSG levels were higher in fish from laboratory bioassays compared to the field, but did not differ between environments nor habitats. Exposure route played a major role only for GST and GPx responses. Finally, increasing PAHs concentration and exposure time had a significant effect on all assessed biomarkers, except for CAT. We conclude that EROD and GST are robust biomarkers to assess PAHs effects in fish. Contrarily, CAT is an inadequate biomarker of PAHs exposure since no significant response was observed. Our study also highlighted some research gaps in PAHs contamination studies, such as a clear lack of active biomonitoring experiments. PMID- 30005258 TI - Oxidation of benzo[a]pyrene by laccase in soil enhances bound residue formation and reduces disturbance to soil bacterial community composition. AB - Laccases are capable of rapidly oxidizing benzo[a]pyrene. It is thought that the metabolites with an increase in water solubility caused by the oxidation of benzo[a]pyrene may stimulate the subsequent mineralization. However, to date, there has been no experimental evidence to support this. In this study, the fate of benzo[a]pyrene in soil affected by laccase amendment and the resulting soil bacterial responses were investigated. Laccase amendment promoted benzo[a]pyrene dissipation (15.6%) from soil, accompanied by trace mineralization (<0.58 +/- 0.02%) and substantial bound residue formation (~80%). An increase of ~15% in the bound residue fraction was observed by laccase amendment, which mainly resulted from covalent binding of the residues to humin fraction. During the incubation, the abundance of bacterial 16S rRNA and polycyclic aromatic hydrocarbon ring hydroxylating dioxygenase genes did not change markedly. In contrast, benzo[a]pyrene treated with laccase resulted in a smaller shift in the bacterial community composition, indicating a reduced disturbance to the soil microbial communities. These results here suggest that benzo[a]pyrene contaminated soil can be detoxified by laccase amendment mainly due to the enhanced bound residue formation to soil organic matter via covalent binding. PMID- 30005259 TI - Interspecific variation of essential and non-essential trace elements in sympatric seabirds. AB - Chemical pollution is a growing issue for ocean ecosystems, threatening especially apex predators because they bioaccumulate persistent chemical pollutants such as non-essential trace elements. The trophic position is thus a key aspect when assessing the impacts of environmental pollution in marine organisms. Here we investigate the differences in the concentrations of essential (Cu, Cr, Se, and Zn) and non-essential elements (Hg, Al, As, Cd, and Sr), in muscular and hepatic tissues of four sympatric non-migratory seabirds (namely Sula leucogaster, Larus dominicanus, Fregata magnificens, and Thalasseus acuflavidus), which were found stranded along the Brazilian coast. The observed hepatic and muscular interspecific differences in elemental concentrations indicated that these sympatric seabirds are differently exposed to persistent contaminants circulating in the food web due to differences with respect to known feeding behaviours and prey preferences. Moreover, we found a consistent co accumulative relationship between Se and Hg molar levels in liver tissues with mean Se:Hg molar ratio above 1. This relationship supports previous studies indicating that Se, via the formation of SeHg complexes, plays an essential biochemical role in the detoxification process of methyl mercury in seabirds. Our results suggest that feeding behaviour is an important factor associated to the interspecific differences of trace element concentrations in seabirds. However, traits other than feeding preferences (e.g. age) may also play an important role in the accumulation of these elements. PMID- 30005260 TI - Indirect N2O emissions with seasonal variations from an agricultural drainage ditch mainly receiving interflow water. AB - Nitrogen (N)-enriched leaching water may act as a source of indirect N2O emission when it is discharged to agricultural drainage ditches. In this study, indirect N2O emissions from an agricultural drainage ditch mainly receiving interflow water were measured using the static chamber-gas chromatography technique during 2012-2015 in the central Sichuan Basin in southwestern China. We found the drainage ditch was a source of indirect N2O emissions contributing an inter annual mean flux of 6.56 +/- 1.12 MUg N m-2 h-1 and a mean indirect N2O emission factor (EF5g) value of 0.03 +/- 0.003%. The mean EF5g value from literature review was 0.51%, which was higher than the default EF5g value (0.25%) proposed by the Intergovernmental Panel on Climate Change (IPCC) in 2006. Our study demonstrated that, more in situ observations of N2O emissions as regards N leaching are required, to account for the large variation in EF5g values and to improve the accuracy and confidence of the default EF5g value. Indirect N2O emissions varied with season, higher emissions occurred in summer and autumn. These seasonal variations were related to drainage water NO3--N concentration, temperature, and precipitation. Our results showed that intensive precipitation increased NO3--N concentrations and N2O emissions, and when combined with warmer water temperatures, these may have increased the denitrification rate that led to the higher summer and autumn N2O emissions in the studied agricultural drainage ditch. PMID- 30005261 TI - Satellite-based short- and long-term exposure to PM2.5 and adult mortality in urban Beijing, China. AB - Severe and persistent haze accompanied by high concentrations of fine particulate matter (PM2.5) has become a great public health concern in urban China. However, research on the health effects of PM2.5 in China has been hindered by the lack of high-quality exposure estimates. In this study, we assessed the excess mortality associated with both short- and long-term exposure to ambient PM2.5 simultaneously using satellite-derived exposure data at a high spatiotemporal resolution. Adult registries of non-accidental, respiratory and cardiovascular deaths in urban Beijing in 2013 were collected. Exposure levels were estimated from daily satellite-based PM2.5 concentrations at 1 km spatial resolution from 2004 to 2013. Mixed Poisson regression models were fitted to estimate the cause specific mortality in association with PM2.5 exposures. With the mutual adjustment of short- and long-term exposure of PM2.5, the percent increases associated with every 10 MUg/m3 increase in short-term PM2.5 exposure were 0.09% (95% CI: -0.14%, 0.33%; lag 01), 1.02% (95% CI: 0.08%, 1.97%; lag 04) and 0.09% (95% CI: -0.23%, 0.42%; lag 01) for non-accidental, respiratory and cardiovascular mortality, respectively; those attributable to every 10 MUg/m3 increase in long-term PM2.5 exposure (9-year moving average) were 16.78% (95% CI: 10.58%, 23.33%), 44.14% (95% CI: 20.73%, 72.10%) and 3.72% (95% CI: -3.75%, 11.77%), respectively. Both associations of short- and long-term exposure with the cause-specific mortality decreased after they were mutually adjusted. Associations between short-term exposure to satellite-based PM2.5 and cause specific mortality were larger than those estimated using fixed measurements. Satellite-based PM2.5 predictions help to improve the spatiotemporal resolution of exposure assessments and the mutual adjustment model provide better estimation of PM2.5 associated health effects. Effects attributable to long-term exposure of PM2.5 were larger than those of short-term exposure, which should be more concerned for public health. PMID- 30005262 TI - Mycotoxins induce developmental toxicity and behavioural aberrations in zebrafish larvae. AB - Mycotoxins are secondary metabolites produced by varieties of fungi that contaminate food and feed resources and are capable of inducing a wide range of toxicity. In the current study, we investigated developmental and behavioural toxicity in zebrafish larvae after exposure to six different mycotoxins; ochratoxin A (OTA), type A trichothecenes mycotoxin (T-2 toxin), type B trichothecenes mycotoxin (deoxynivalenol - DON), and zearalenone (ZEN) and its metabolites alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL). Developmental defects, hatching time, and survival were monitored until 96 h post fertilisation (hpf). The EC50, LC50, and IC50 values were calculated. Subsequently, to assess behavioural toxicity, new sets of embryos were exposed to a series of non-lethal doses within the range of environmental and/or developmental concern. Results indicated that all the tested mycotoxins were toxic, they all induced developmental defects, and with the exception of OTA, all affected hatching time. Behavioural effects were only observed following exposure to OTA and ZEN and its metabolites, alpha ZOL and beta ZOL. These results demonstrate that mycotoxins are teratogenic and can influence behaviour in a vertebrate model. PMID- 30005263 TI - The effects of insecticides on butterflies - A review. AB - Pesticides, in particular insecticides, can be very beneficial but have also been found to have harmful side effects on non-target insects. Butterflies play an important role in ecosystems, are well monitored and are recognised as good indicators of environmental health. The amount of information already known about butterfly ecology and the increased availability of genomes make them a very valuable model for the study of non-target effects of pesticide usage. The effects of pesticides are not simply linear, but complex through their interactions with a large variety of biotic and abiotic factors. Furthermore, these effects manifest themselves at a variety of levels, from the molecular to metapopulation level. Research should therefore aim to dissect these complex effects at a number of levels, but as we discuss in this review, this is seldom if ever done in butterflies. We suggest that in order dissect the complex effects of pesticides on butterflies we need to integrate detailed molecular studies, including characterising sequence variability of relevant target genes, with more classical evolutionary ecology; from direct toxicity tests on individual larvae in the laboratory to field studies that consider the potentiation of pesticides by ecologically relevant environmental biotic and abiotic stressors. Such integration would better inform population-level responses across broad geographical scales and provide more in-depth information about the non-target impacts of pesticides. PMID- 30005264 TI - Polycyclic aromatic hydrocarbons in surface sediments of the mid-Adriatic and along the Croatian coast: Levels, distributions and sources. AB - This study provides contamination levels, distributions and source apportionment of PAHs in surface sediments in the mid-Adriatic and along the Croatian coast. Median summed concentrations of parent and alkyl-PAHs are circa 10 times lower in the off-shore transect stations of the mid-Adriatic (22.3 and 18.2 MUg.kg-1 d.w.) than the ranges determined at the coastal stations, including those of Kastela bay (227-331 and 11.7-197 MUg.kg-1 d.w., respectively). The highest levels, circa 20 times higher, were found in Sibenik bay (median 6603 and 3051 MUg.kg-1). The overall range of PAH concentrations spans more than 2000 times between the lowest and the highest contamination level. The geographical distributions reflect the presence of strong gradients at local and regional scales. A major factor influencing sedimentary PAH distributions at local scale appears to be the distance from their known continental and coastal upstream emission sites (urban, industrial, harbour ...), whereas at regional scale, this distribution depends more on the routes of entry of PAHs into the study area. Two combustion and one petroleum model source profiles of PAHs were determined by alternative least square analysis. Benzo[b+j]fluoranthenes and fluoranthene/pyrene are compounds characterizing two pyrogenic sources respectively, while signatures of alkyl substituted homologues (phenanthrenes/anthracenes, fluranthenes/pyrenes, chrysenes and dibenzothiophenes) delineate a petrogenic source profile. The quantitative apportionment of source contributions shows significant geographical differences, with a dominant petrogenic source found along the mid-Adriatic transect (approximately 74%) and in Kastela bay (61%). In the coastal sediments about a fifty-fifty contamination mix is assigned to a petrogenic/pyrogenic source of PAHs (47% and 53% respectively), whereas in Sibenik bay a strong predominance is apportioned to the combustion compounds (81%). PMID- 30005265 TI - Lake sediment records of persistent organic pollutants and polycyclic aromatic hydrocarbons in southern Siberia mirror the changing fortunes of the Russian economy over the past 70 years. AB - Persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs) have previously been detected in the surface sediments, water, and endemic organisms of Lake Baikal, a UNESCO World Heritage Site. The Selenga River is the primary source of freshwater to Lake Baikal, and transports pollutants accumulating in the Selenga River basin to the lake. Sources of POPs and PAHs in the Selenga River basin grew through the 20th century. In the present study, temporal changes in the concentrations of PAHs and POPs were reconstructed from two lakes in the Selenga River basin over the past 150 years using paleolimnological techniques. Increased concentrations in PAHs and PCBs were recorded initially in the 1930s. The 1940s-1980s was the period of greatest exposure to organic contamination, and concentrations of dichlorodiphenyltrichloroethane (DDT), polychlorinated biphenyls (PCBs), hexachlorocyclohexanes (HCHs) and many PAHs peaked between the 1960s and 1980s in the two lakes. Declines in concentrations and fluxes were recorded for most PAHs and POPs in the 1980s and 1990s. Temporal trends in concentrations of total and individual compounds/congeners of PAH, PCBs, and polybrominated diphenyl ethers (PBDEs) indicate the contribution of both local and regional sources of contamination in the 20th and 21st centuries. Temporal variations in contaminants can be linked to economic and industrial growth in the former USSR after World War II and the economic decline of Russia in the late-1980s and early-1990s, as well as global trends in industrialization and development during the mid-20th century. PMID- 30005266 TI - Spatial variability of on-bicycle black carbon concentrations in the megacity of Sao Paulo: A pilot study. AB - In 2015, a controversial bicycle lane was installed on Paulista Avenue -a thoroughfare in the heart of the megacity of Sao Paulo with a high rate of motorised vehicles. For the first time, on-bicycle air pollution concentrations were assessed along this lane using black carbon (BC) as an indicator of fossil fuel combustion. We measured BC concentrations with a hand-held microaethalometer at a high temporal resolution, enabling the capture of fine spatial gradients along the route. Although this new link expanded the city's cycling network, our pioneering study showed that BC concentrations were large (mean 8.5 MUg m-3) with extreme values reaching 24.0 MUg m-3, comparable to concentrations found in many megacities. In agreement with other studies, we observed that concentrations decreased about 1.6 times on a section of the bicycle lane running through a calmer neighbourhood, which could indicate the potential to safeguard the health of cyclists by installing lanes with greater separation from main roads, such as Paulista Avenue. This pilot work paves the way to more detailed studies aiming to map out the spatial distribution of other traffic-related pollutants across the city's 458-km long bicycle network. PMID- 30005267 TI - Trichlorfon inhibits proliferation and promotes apoptosis of porcine trophectoderm and uterine luminal epithelial cells. AB - Trichlorfon is an organophosphate insecticide widely used in agriculture. Additionally, it is applied to pigs for control of endo- and ectoparasites. Previous studies have shown the effects of trichlorfon in pigs during late stages of gestation; however, little is known about its effects during early pregnancy, including implantation and placentation. We investigated whether trichlorfon affects proliferation and apoptosis of porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. Trichlorfon inhibited the proliferation of pTr and pLE cells, as evidenced by cell cycle arrest, and altered the expression of proliferation-related proteins. In addition, trichlorfon induced cell death and apoptotic features, such as loss of mitochondrial membrane potential and DNA fragmentation, in pTr and pLE cells. Moreover, trichlorfon treatment decreased concentrations of Ca2+ in the cytoplasm in both cell lines and increased concentrations of Ca2+ in mitochondria of pTr cells. Trichlorfon inhibited the activation of phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling pathways in pTr and pLE cells. Therefore, we suggest that trichlorfon treated pTr and pLE cells exhibited abnormal cell physiology which might lead to early pregnancy failure. PMID- 30005268 TI - Sensing environmental and developmental signals via cellooligomers. AB - Roots respond to a cocktail of chemicals from microbes in the rhizosphere. Infochemicals in nmol concentrations activate receptor-mediated signal pathways, which reprogram the plant responses to environmental changes. The microbial signals have to pass the cell wall to activate pattern recognition receptors at the surface of the plant plasma membrane. The structure of the cell wall is not only a barrier for the signaling molecules, but also changes permanently during growth and development, as well as in response to microbial attacks or abiotic stress. Recently, cellooligomers (COMs) were identified as novel chemical mediators in Arabidopsis thaliana, which inform the cell about the alterations in and around the cell wall. They can be of microbial and plant origin and represent novel invasion patterns (Cook et al., 2015). COMs initiate Ca2+-dependent signaling events that reprogram the cell and adjust the expression and metabolite profiles as well as innate immunity in response to changes in their rhizosphere environment and the state of the cell wall. COMs operate synergistically with other signals or their recognition machineries and activates local and systemic responses in the entire plant. They also adjust the performance of the areal parts of the plant to signals perceived by the roots. Here, I summarize our current knowledge about COMs and propose strategies for future investigations. PMID- 30005269 TI - Perception of noise-vocoded tone complexes: A time domain analysis based on an auditory filterbank model. AB - When a wideband harmonic tone complex (wHTC) is passed through a noise vocoder, the resulting sounds can have spectra with large peak-to-valley ratios, but little or no periodicity strength in the autocorrelation functions. We measured judgments of pitch strength for normal-hearing listeners for noise-vocoded wideband harmonic tone complexes (NV-wHTCs) relative to standard and anchor stimuli. The standard was a 1-channel NV-wHTC and the anchor was either the unprocessed wHTC or an infinitely-iterated rippled noise (IIRN). Although there is variability among individuals, the magnitude judgment functions obtained with the IIRN anchor suggest different listening strategies among individuals. In order to gain some insight into possible listening strategies, test stimuli were analyzed at the output of an auditory filterbank model based on gammatone filters. The weak periodicity strengths of NV-wHTCs observed in the stimulus autocorrelation functions are augmented at the output of the gammatone filterbank model. Six analytical models of pitch strength were evaluated based on summary correlograms obtained from the gammatone tone filterbank. The results of the filterbank analysis suggest that, contrary to the weak or absent periodicity strengths in the stimulus domain, temporal cues contribute to pitch strength perception of noise-vocoded harmonic stimuli such that listeners' judgments of pitch strength reflect a nonlinear, weighted average of the temporal information between the fine structure and the envelope. PMID- 30005270 TI - The effect of 'smart' financial incentives on driving behaviour of novice drivers. AB - Recent studies have demonstrated that financial incentives can improve driving behaviour but high-value incentives are unlikely to be cost-effective and attempts to amplify the impact of low-value incentives have so far proven disappointing. The present study provides experimental evidence to inform the design of 'smart' and potentially more cost-effective incentives for safe driving in novice drivers. Study participants (n = 78) were randomised to one of four financial incentives: high-value penalty; low-value penalty; high-value reward; low-value reward; allowing us to compare high-value versus low-value incentives, penalties versus rewards, and to test specific hypotheses regarding motivational crowding out and gain/loss asymmetry. Results suggest that (i) penalties may be more effective than rewards of equal value, (ii) even low-value incentives can deliver net reductions in risky driving behaviours and, (iii) increasing the dollar-value of incentives may not increase their effectiveness. These design principles are currently being used to optimise the design of financial incentives embedded within PAYD insurance, with their impact on the driving behaviour of novice drivers to be evaluated in on-road trials. PMID- 30005272 TI - Characterization of hydrothermal carbonization products (hydrochars and spent liquor) and their biomethane production performance. AB - To optimize the energy yield (EY) of food waste (FW) via hydrothermal carbonization (HTC), a response surface method was applied. Hydrochars and spent liquor were further conducted to evaluate their characterization and anaerobic digestion potential. Results found that optimal parameters for HTC of FW were suggested as temperature of 260 degrees C, reaction time of 4 h and moisture of 80%, with higher EY of 66.1%. Higher heating value, good combustion quality, lower H/C and O/C ratios indicated that hydrochar could be utilized as a safe solid fuel. Biochemical methane potential (BMP) experiment showed that spent liquor and hydrochars could be used as feedstocks for anaerobic digestion. Interestingly, hydrochars added in the spent liquor could promote the specific methane yield, which was 2.53 times higher than no addition of hydrochars. The finding of this study could provide useful information for HTC of FW and the utilization of hydrochars and spent liquor. PMID- 30005271 TI - Synthesis of novel modified magnetic chitosan particles and their adsorption performance toward Cr(VI). AB - Novel adsorbents, poly([2-(methacryloxy)ethyl]trimethylammonium chloride) modified magnetic chitosan particles (DMCPs), were synthesized via free radical polymerization and applied to adsorb Cr(VI) from aqueous solution. The effects of pH (2-11), Cr(VI) concentration (10-200 mg/L) and contact time (0-420 min) on the adsorption performance were evaluated. The results showed that the adsorption capacity of DMCPs was much larger than that of magnetic chitosan particles (MCPs) in the examined pH range and decreased with Cl- concentration increasing, indicating that electrostatic interaction and ion exchange are the governing mechanisms of Cr(VI) adsorption by DMCPs. The Langmuir isotherm model and pseudo second-order kinetic model fitted the experimental data well. The maximum adsorption capacity of DMCPs is 153.85 mg/g. Besides, Cr(VI)-loaded DMCPs could be easily separated and efficiently regenerated. Therefore, DMCPs are promising candidates for Cr(VI) adsorption owing to their excellent performance in a wide pH range, easy separation and good reusability. PMID- 30005274 TI - The genetics of antithrombin. AB - Antithrombin is a key endogenous anticoagulant whose deficiency constitutes a strong risk factor for thrombosis. The study of antithrombin deficiency has generated excellent, and in some cases, surprising results that may be extrapolated to other thrombophilia and genetic disorders. Routine diagnosis of antithrombin deficiency is based on functional assays. Few specialized laboratories also perform genetic analysis, even though nowadays it is a simple, fast and cheap process that generates relevant information with clinical usefulness. Molecular analysis of SERPINC1, the gene encoding antithrombin, has been restricted so far to cases with confirmed or familial antithrombin deficiency. However, some pathogenic mutations are not detected by current functional methods and other gene defects may have functional consequences only observed under specific conditions. Thus, molecular analysis may be the best method to identify antithrombin deficiency. Up to 80% of patients with antithrombin deficiency have SERPINC1 gene defects, mostly (90% of the 315 gene defects described so far) point mutations or small deletions or insertions affecting the 7 exons or flanking regions. The description of new SERPINC1 gene defects may reveal new residues with functional or structural relevance and new mechanisms causing deficiency of this endogenous anticoagulant. Moreover, other genes and mechanisms may also be involved in antithrombin deficiency. Thus, disorders of N-glycosylation explain up to 5% of cases with antithrombin deficiency. However, there are still up to 10-15% of cases with antithrombin deficiency of unknown cause, whose study may reveal new genes and mechanisms involved in thrombosis. PMID- 30005273 TI - Non-genetic and genetic risk factors for adult cerebral venous thrombosis. AB - INTRODUCTION: A wide variety of non-genetic and genetic factors have been shown to associate with increased risk for cerebral venous thrombosis (CVT). However, there is a paucity of risk factor data and conclusions about their impact are often conflicting. Herein, we quantified the associations of non-genetic and genetic risk factors for CVT in adults. MATERIALS AND METHODS: Electronic databases were searched up to January 2017. Meta-analyses were performed (RevMan v5.3) to determine pooled odds ratios (ORs and 95% CIs) for risk factors, interstudy heterogeneity and publication bias. RESULTS: Twenty non-genetic (n = 2314) and 33 genetic (n = 2117) studies up to January 2017 met the selection criteria. For non-genetic factors, CVT risk increased in the presence of glucocorticosteroid therapy by 18.3-fold (3.3-102.6), alcohol consumption 2.7 fold (1.8-3.9), infection 7.5-fold (2.6-21.6), surgery 9.6-fold (1.1-83.5), hypercholesterolaemia 2.4-fold (1.3-4.4), hyperhomocysteinaemia 3.1-fold (2.1 4.6), antiphospholipid antibodies 7.0-fold (2.1-23.6), autoimmune diseases 5.6 fold (2.3-13.6), anaemia 4.0-fold (2.1-7.9), malignancy 3.2-fold (1.4-7.1) and pregnancy/puerperium 11.4-fold (5.7-24.3). Smoking, hypertension and diabetes did not associate with CVT risk. For genetic factors, CVT risk increased in the presence of factor V Leiden (G1691A) by 2.5-fold (1.9-3.3), protein C deficiency 10.7-fold (3.1-37.7), protein S deficiency 5.7-fold (1.4-22.4), antithrombin deficiency 3.8-fold (1.0-13.8), prothrombin (G20210A) 5.5-fold (4.0-7.27) and TAFI gene variant (C1040T) 1.6-fold (1.0-2.4). Prothrombin G20210A and factor V Leiden polymorphisms tended to have higher ORs for CVT than for ischaemic stroke. CONCLUSIONS: We provide quantitative data supporting a strong basis for genetic and non-genetic risk factors in CVT. Its genetic liability seems higher when compared with sporadic ischaemic stroke. PMID- 30005275 TI - Prevalence of venous thromboembolism following head and neck cancer surgery: A systematic review and meta-analysis. PMID- 30005276 TI - Violence in Colombia and Mexico: trend and impact on life expectancy of homicide mortality between 1998 and 2015. AB - OBJECTIVES: Colombia is considered one of the most violent countries in the world even though homicide mortality has decreased since 2002. Mexico's homicide rate has tripled since 2008, after a period of decreasing mortality; this fact has been compared with Colombia in the 1990s and defined as a 'Colombianization' of violence in Mexico. We analyzed and compared the trend and impact of homicide mortality in Colombia and Mexico between 1998 and 2015. STUDY DESIGN: Cross sectional descriptive study. METHODS: We calculated the standardized mortality rates and the years of life lost using data from the National Institute of Statistics and Geography in Mexico and the National Management Department of Statistics in Colombia. We used the joinpoint regression analysis to identify significant changes in the mortality trend. RESULTS: During the 1990s, Colombia reached the highest homicide mortality rates in the world, but these rates have since decreased significantly. In Mexico, homicide mortality had a decreasing trend from 1998 to 2007; however, since 2008, the rate grew significantly, and although mortality tended to decrease after reaching its peak in 2011, a slight upturn was observed in 2015. CONCLUSIONS: We found that the trend in mortality in both countries has had certain similarities, such as the increase in mortality after the implementation of antidrug policies and the subsequent decrease; however, the political processes, the level of mortality reached, its impact on life expectancy, and its distribution by gender are dissimilar. We consider speaking of a 'Colombianization' of violence in Mexico to be inaccurate. PMID- 30005277 TI - Placing meta-stable states of consciousness within the predictive coding hierarchy: The deceleration of the accelerated prediction error. AB - While many studies have linked prediction errors and event related potentials at a single processing level, few consider how these responses interact across levels. In response, we present a factorial analysis of a multi-level oddball task - the local-global task - and we explore it when participants are sedated versus recovered. We found that the local and global levels in fact interact. This is of considerable current interest, since it has recently been argued that the MEEG response evoked by the global effect corresponds to a distinct processing mode that moves beyond predictive coding. This interaction suggests that the two processing modes are not distinct. Additionally, we observed that sedation modulates this interaction, suggesting that conscious awareness may not be completely restricted to a single (global) processing level. PMID- 30005278 TI - Depressive symptoms and adipokines in women: Study of women's health across the nation. AB - Small clinical studies suggest depression is associated with alterations in adiponectin and leptin, adipocyte-derived secretory proteins involved in metabolic regulation; however, longitudinal data on these association are lacking. This study examined cross-sectional and longitudinal associations of depressive symptoms and major depressive disorder (MDD) with adiponectin and leptin in healthy middle-aged women (mean (SD) age, 45.6 (2.5) years). Cross sectional analyses included 575 women with baseline adipokine data; longitudinal analyses included 262 women with 2-4 adipokine measurements over 5 years. The 20 item Center for Epidemiologic Studies Depression scale (CES-D) was used to assess depressive symptoms; history of MDD was determined by the Structured Clinical Interview for DSM-IV. Adipokines were assayed from stored serum specimens; values were log-transformed for analyses. Linear and repeated measure random effects regression models evaluated associations of baseline CES-D scores with baseline adipokine concentrations and changes over time, respectively. Secondary analyses evaluated the relation of MDD history with adipokine concentrations. Mean (SD) baseline concentrations of adiponectin and leptin were 9.90 (4.92) MUg/mL and 27.02 (20.06) ng/mL; both increased over time (p < .0001). CES-D scores were associated with lower adiponectin at baseline (per 1-SD: estimate=-0.04, SE=.02, p=.03) and over time (per 1-SD: estimate=-0.055, SE = .024, p=.02). Associations were unchanged in risk factor-adjusted models. Women with elevated CES-D scores (>=16) had 6.9% (95% CI: -1.1%, 14.3%; p = .089) lower median adiponectin at baseline and 11.5% (95% CI: 1.5%, 20.4%, p = .025) lower median adiponectin over time in adjusted models, compared to women with CES-D<16. Rate of change in adipokines did not vary by baseline depressive symptoms or MDD history. Depressive symptoms and MDD history were unrelated to leptin. In women at midlife, depressive symptoms are associated with lower adiponectin, a critical anti-inflammatory biomarker involved in metabolic and cardiovascular conditions. PMID- 30005279 TI - Polymorphic variation in the SLC5A7 gene influences infant autonomic reactivity and self-regulation: A neurobiological model for ANS stress responsivity and infant temperament. AB - OBJECTIVE: To examine the impact of polymorphic variation in the solute carrier family 5 member 7 (SLC5A7) gene on autonomic nervous system (ANS) reactivity indexed by respiratory sinus arrhythmia (RSA) and heart rate (HR) in infants during a dyadic stressor, as well as maternal report of infant self-regulation. Given evidence of race differences in older individuals, race was specifically examined. METHODS: RSA and HR were collected from 111 infants during the still face paradigm (SFP). Mothers completed the Infant Behavior Questionnaire-Revised short-form. Multi-level mixed effects models examined the impact of SLC5A7 genotype on RSA and HR across the SFP. Linear models tested the influence of genotype on the relation between RSA, HR, and maternal report of infant self regulation. RESULTS: SLC5A7 genotype significantly predicted RSA stress responsivity (beta = -0.023; p = 0.028) and HR stress responsivity (beta = 0.004; p = 0.002). T-allele carriers exhibited RSA suppression and HR acceleration in response to stress while G/G homozygotes did not suppress RSA and exhibited less HR acceleration. All infants exhibited modest RSA augmentation and HR deceleration during recovery. Race-stratified analyses revealed that White T allele carriers drove the overall results for both RSA (beta = -0.044; p = 0.007) and HR (beta = 0.006; p = 0.008) with no relation between SLC5A7 genotype and RSA or HR in Black infants. Maternal report of infant orienting/regulation was predicted by the interaction of SLC5A7 genotype and both RSA recovery (beta = 0.359; p = 0.001) and HR recovery (beta = -1.659; p = 0.020). RSA augmentation and HR deceleration during recovery were associated with higher maternal reports of self-regulation among T-allele carriers, a finding again primarily driven by White infants. CONCLUSIONS: Early in development, genetic contributions to ANS are evident and predict maternal report of infant self-regulation within White infants, consistent with prior literature. The lack of associations in Black infants suggest that race differences in physiological reactivity and self regulation are emerging during the first year of life potentially providing early evidence of disparities in health risk trajectories. PMID- 30005280 TI - Differential effect of the DRD3 genotype on inflammatory cytokine responses during abstinence in amphetamine-dependent women. AB - Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1beta) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1beta levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence. PMID- 30005282 TI - Progressive habituation to separation alleviates the negative effects of weaning in the mother and foal. AB - Early and definitive separation between offspring and their mothers has negative consequences on behavioral and physiological responses. This study compared sudden and definitive weaning (Sudd group, N = 16) and weaning involving progressive habituation to separation using a fence line during the month preceding definitive separation (Prog group, N = 18). The impact of these two methods was assessed in both foals and their mothers through behavioral and biological parameters, including salivary cortisol, telomere length and blood transcriptomes. On the day of definitive separation, Prog foals neighed and trotted less and presented lower cortisol levels than Sudd foals. The weaning type also acted on the foals' personality development; Prog foals became more curious, less fearful and less gregarious than Sudd foals, and the effects remained visible for at least 3 months. In principal component analysis, the Sudd and Prog groups were well separated along a factor where fear, reactivity and gregariousness correlated with high cortisol levels, but curiosity was associated with an increased telomere length and higher expression of genes involved in mitochondrial functions. Progressive weaning was also beneficial in mares. Principal component analysis showed that most Sudd group mares had higher cortisol levels and displayed more alert postures, neighs and activity on the day of weaning, indicating higher stress levels, while Prog mares had profiles that were characterized by more time spent resting on the day of weaning and longer telomere lengths. In conclusion, this study shows that progressive habituation to separation alleviates the negative effect of definitive weaning on both the mother and her young compared to sudden separation. PMID- 30005283 TI - Elevated salivary alpha-amylase levels at awakening in patients with depression. AB - BACKGROUND: Specific Major Depressive Disorder (MDD) biomarkers could help improve our understanding of MDD pathophysiology and aid in the refinement of current MDD criteria. While salivary cortisol (SC) can differentiate between healthy controls and patients with psychiatric disorders, salivary alpha amylase (sAA), may be a putative candidate biomarker for MDD specifically. METHODS: In a naturalistic cohort of consecutive out-patients and healthy controls, sAA and SC were determined in 833 participants (97 MDD patients, 142 patients with other mood, anxiety, and/or somatoform (MAS-) disorders, and 594 healthy controls). Samples were collected at 7 different time points (at awakening, after 30, 45, and 60 min, at 10:00 p.m., at 11:00 p.m., and at awakening on day 2). RESULTS: The mean age of the sample was 43.8 years (SD = 12.9; 63.9% female). Concerning sAA, MDD patients had higher sAA levels upon awakening on two consecutive days (p = 0.04, p = 0.01 respectively), as well as a higher area under the curve with respect to the increase (AUCi; p = 0.04) in comparison to both controls and the other MAS-disorders group. Regarding SC, mean levels of evening SC were elevated in MDD patients (p = 0.049) in comparison to both controls and the other MAS disorders group. SC values on day 2 after ingestion of dexamethasone were elevated in both MDD patients and the other MAS-disorders group (p = 0.04, p = 0.047 respectively). CONCLUSIONS: sAA at awakening and not cortisol differentiates MDD from other psychiatric disorders in outpatients. This suggests that sAA may be a valuable candidate biomarker specifically for MDD. PMID- 30005281 TI - Disruption of microglia histone acetylation and protein pathways in mice exhibiting inflammation-associated depression-like symptoms. AB - BACKGROUND: Peripheral immune challenge can elicit microglia activation and depression-related symptoms. The balance of inflammatory signals in the tryptophan pathway can skew the activity of indoleamine-pyrrole 2,3 dioxygenase (IDO1) towards the metabolization of tryptophan into kynurenine (rather than serotonin), and towards neuroprotective or neurotoxic metabolites. The proteome changes that accompany inflammation-associated depression-related behaviors are incompletely understood. METHODS: The changes in microglia protein abundance and post-translational modifications in wild type (WT) mice that exhibit depression like symptoms after recovery from peripheral Bacille Calmette-Guerin (BCG) challenge were studied. This WT_BGG group was compared to mice that do not express depression-like symptoms after BCG challenge due to IDO1 deficiency by means of genetic knockout (BCG_KO group), and to WT Saline-treated (Sal) mice (WT_Sal group) using a mass spectrometry-based label-free approach. RESULTS: The comparison of WT_BCG relative to WT_Sal and KO_BCG mice uncovered patterns of protein abundance and acetylation among the histone families that could influence microglia signaling and transcriptional rates. Members of the histone clusters 1, 2 and 3 families were less abundant in WT_BCG relative to WT_Sal whereas members in the H2A family exhibited the opposite pattern. Irrespective of family, the majority of the histones were less abundant in WT_BCG relative to KO_BCG microglia. Homeostatic mechanisms may temper the potentially toxic effects of high histone levels after BCG challenge to levels lower than Sal. Histone acetylation was highest in WT_BCG and the similar levels observed in WT_Sal and KO_BCG. This result suggest that histone acetylation levels are similar between IDO1 deficient mice after immune challenge and unchallenged WT mice. The over abundance of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation proteins (14-3-3 series) in WT_BCG relative to KO_BCG is particularly interesting because these proteins activate another rate-limiting enzyme in the tryptophan pathway. The over-representation of alcoholism and systemic lupus erythematosus pathways among the proteins exhibiting differential abundance between the groups suggest that these disorders share microglia activation pathways with BCG challenge. The over-representation of phagosome pathway among proteins differentially abundant between WT_BCG and KO_BCG microglia suggest an association between IDO1 deficiency and phagocytosis. Likewise, the over representation of the gap junction pathway among the differentially abundant proteins between KO_BCG and WT_Sal suggest a multifactorial effect of BCG and IDO1 deficiency on cell communication. CONCLUSIONS: The present study of histone acetylation and differential protein abundance furthers the understanding of the long lasting effects of peripheral immune challenges. Our findings offer insights into target proteins and mechanisms that provide clues for therapies to ameliorate inflammation-associated depression-related behaviors. PMID- 30005284 TI - Identification and quantification of proteins at adsorption layer of emulsion stabilized by pea protein isolates. AB - This study adopted the method of quantitative proteomics to analyze the adsorbed proteins in oil-in-water emulsions stabilized by pea protein isolate (PPI). Adsorbed proteins were precipitated by an optimized precipitation method and precipitates were labeled and subjected to a reversed-phase high performance liquid chromatography coupled to tandem mass spectrometry (RPLC-ESI-MS/MS) for protein identification and quantification. In total, 77 proteins were identified, of which 49 proteins with significant differences were observed. There were 25 upregulated proteins (fold change > 1) and 24 downregulated proteins (fold change < 1). The interfacial adsorption abilities of these proteins were compared according to the classification of protein families. The results showed that all isoforms of vicilins exhibited high adsorption abilities at the oil-water interface. Compared with vicilin, convicilin showed opposite adsorption capacity. Different legumin families showed significantly different affinities on the oil water interface. In contrast to albumin-1, albumin-2 was preferentially adsorbed to the interface. The amino acid sequence alignment and hydropathy profile analysis of these proteins showed that the proteins well-balanced between hydrophobic and hydrophilic amino acid groups displayed high interfacial activity. In contrast, a long hydrophilic or hydrophobic fragment could adversely influence protein interfacial activity. This study provides an insight into the interfacial behaviors of proteins by supplying detailed quantitative information of interfacial layer. PMID- 30005285 TI - Colloidal HSA - Graphene oxide nanosheets for sustained release of oxaliplatin: Preparation, release mechanism, cytotoxicity and electrochemical approaches. AB - A novel sustained release carrier of graphene oxide nanosheets functionalized by human serum albumin nanoparticles (FGO-NSs) was synthesized and characterized by field emission scanning electron microscopy (FESEM), zeta sizer analysis, absorption spectroscopy (UV-vis) and Fourier transform infrared spectroscopy (FTIR) studies. The cell viability of GO-NSs, HSA-NPs and FGO-NSs has been tested against human foreskin fibroblast normal cell line, HFFF2 by MTT assay technique. Loading efficiency and release properties of oxaliplatin (OX), as an effective chemotherapeutic agent in the treatment of cancers, from HSA-NPs and FGO-NSs were studied. The results showed high drug loading (DL), drug entrapment efficiency (DEE) and sustained release of OX from FGO-NSs (DL = 61 +/- 4% and DEE = 1.2 +/- 0.2%) in comparison with HSA-NPs (DL = 51 +/- 3% and DEE = 0.9 +/- 0.04%) due to the large surface area of GO sheets. The diffusion coefficient was evaluated by cyclic voltammetry (CV) and confirmed the obtained results of UV-vis spectroscopy. Finally, release mechanism studies indicated that the release of OX from HSA-NPs is controlled by Fickian diffusion while the release mechanism of FGO-NSs/OX is occurred through non-Fickian diffusion. The results showed that the FGO-NSs could be suitable for reducing cytotoxicity of GO-NSs and enhancement of drug loading and sustained drug release in comparison with HSA-NPs in cancer therapy. PMID- 30005286 TI - Gold nanorods-based thermosensitive hydrogel produces selective long-lasting regional anesthesia triggered by photothermal activation of Transient Receptor Potential Vanilloid Type-1 channels. AB - Long-lasting regional anesthesia and selective sensory block are useful in post operative analgesia and treatment of pathological pain. Previous studies have demonstrated that activation of TRPV1 (Transient Receptor Potential Vanilloid Type-1) channels facilitated the potency of QX-314 for selective long-lasting regional anesthesia in vivo. Hydrogel is a solid jelly-like material covering a wide range of properties from soft and weak to hard and tough. Gold nanorods are nanoparticles, which can be used for hyperthermia by exposure to near-infrared radiation. We fabricated a gold nanorods and QX-314 containing hydrogel. The molecular weight of hydrogel was adjusted to achieve a targeted phase transition temperature. Gold nanorods with a desired photothermal conversion efficacy and QX 314 were mixed with hydrogel to produce a gold nanorods-QX-314/hydrogel nanocomposite. A rat model of sciatic nerve block was applied to evaluate the regional anesthetic effect of the gold nanorods-QX-314/hydrogel nanocomposite. Upon exposure to near-infrared irradiation, the gold nanorods-QX-314/hydrogel nanocomposite activated TRPV1 channels through photothermal conversion and release of QX-314 at the same time. The gold nanorods and QX-314 loaded hydrogel exhibited a long-lasting regional anesthetic effect with selective sensory function block. Sensory block duration of the nanocomposite was significantly longer than of 1% lidocaine (90.0 +/- 12.2 vs. 37.5 +/- 12.5 min, P < 0.01). Motor block by the nanocomposite was observed for only 40% of rats with significantly shorter duration than its sensory block (42.5 +/- 17.1 vs. 90.0 +/- 12.2 min, P < 0.01). The gold nanorods-QX-314/hydrogel nanocomposite can produce a selective long-lasing regional anesthetic effect in a rat model of sciatic nerve block. PMID- 30005287 TI - Aptamer-functionalized albumin-based nanoparticles for targeted drug delivery. AB - Proteins have been extensively explored as versatile nanocarriers for drug delivery due to their complete biocompatibility, ease of surface modification, and lack of toxicity and immunogenicity. In this study, a facile strategy was used to construct aptamer-functionalized albumin-based nanoparticles for effective drug delivery and targeted cancer therapy. A hydrophobic drug, doxorubicin (DOX) was employed to trigger the self-assembly of bovine serum albumin (BSA) to from stable nanoparticles via hydrophobic interaction, and then a tumor targeting aptamer AS1411 was incorporated to the surface of DOX loaded BSA. Due to the specific recognition between AS1411 and its receptor over expressed on tumor cells, the aptamer-modified nanoparticles show higher cellular uptake and stronger cell inhibitory efficacy against cancerous MCF-7 cells as compared with the nanoparticles without aptamer modification. In addition, DOX loaded aptamer-functionalized nanoparticles can induce more significant down regulation of Bcl-2 and PCNA as well as up-regulation of pRB, PARP and Bax in MCF 7 cells compared with unmodified nanoparticles, indicating the aptamer modification can induce cell apoptosis more effectively. Besides, aptamer modified nanoparticles exhibit a significantly improved capability in up regulating p16, p21 and E-cadherin, and down-regulating EpCAM, vimentin, Snail, MMP-9, CD44 and CD133, implying the favorable effects of drug delivery on the prevention of tumor progression and metastasis. PMID- 30005289 TI - Fabrication of two distinct hydroxyapatite coatings and their effects on MC3T3-E1 cell behavior. AB - How the surface topography of hydroxyapatite (HAP) coatings remodels hard tissue is of utmost importance and a contributing factor to ambiguity regarding this subject. Here, HAP coatings with different topographies of a rod-like nanoarray with c-axis orientation and a flake-like micro-flower array with a(b)-axis orientation on a Ti substrate were synthesized via hydrothermal-electrodeposition by controlling the concentration of electrolytes. XRD, TEM and SAED analyses indicated that the rod-like HAP nanoarray was predominant with an orientation of (001), while the HAP micro-flower samples were based on an orientation of (100). Compared to the flake-like HAP, the rod-like nanoarray HAP possessed better hydrophilic properties and lower roughness, which not only enhanced adsorption of specific fibronectin proteins but also promoted the spreading and growth of MC3T3 E1 cells. Runx2, alkaline phosphatase, collagen and osteocalcin were also analyzed by RT-PCR on the two distinctive HAP-coated samples. MC3T3-E1 cells on the rod-like nanoarray coating had higher osteo-related gene expression. This finding suggested that the ordered assembly structure of the HAP might cause topography-dependent coordination with biomolecules for enhancing osteoblast-like cell proliferation and osteogenic differentiation. This study provided an understanding of the surface's features for biomaterials to ensure better bioactivity. PMID- 30005288 TI - Tailoring weight ratio of PCL/PLA in electrospun three-dimensional nanofibrous scaffolds and the effect on osteogenic differentiation of stem cells. AB - Three-dimensional (3D) scaffolds as artificial ECMs have been extensively studied to mimic the critical features of natural ECMs. To develop more clinically relevant 3D scaffolds, electrospun nanofibrous scaffolds with different weight ratios of PCL/PLA (i.e., 100/0, 60/40, and 20/80) were fabricated via the thermally induced (nanofiber) self-agglomeration (TISA) method. The hypothesis was that, with the weight ratio increase of stiffer and more bioactive PLA in the 3D PCL/PLA blend scaffolds, the osteogenic differentiation of human mesenchymal stem cells (hMSCs) would be enhanced. The results indicated that, all of the 3D scaffolds were elastic/resilient and possessed interconnected and hierarchical pores with sizes from sub-microns to ~300 MUm; therefore, the morphological structures of these scaffolds were similar to those of natural ECMs. The PLA80 scaffolds exhibited the best overall properties in terms of density, porosity, water absorption capacity, mechanical properties, bioactivity, and cell viability. Furthermore, with increasing the PLA weight ratio, the alkaline phosphatase (ALP) activity, calcium content, and gene expression level were also increased, probably due to the improved stiffness/bioactivity of scaffold. Hence, the novel 3D electrospun PLA80 nanofibrous scaffold might be desired/favorable for the osteogenic differentiation of hMSCs. PMID- 30005291 TI - Developmental genetic programs and activity-dependent mechanisms instruct neocortical area mapping. AB - The subdivision of the mammalian neocortex into specialized modality-specific areas is responsible for the processing of sensory information followed by an adequate motor response. This process, called arealization, depends on the graded expression of transcription factors in neocortical progenitors and postmitotic neurons prenatally, and on external activity-dependent cues driven by thalamocortical axons during postnatal stages. Thalamic inputs are guided within an intrinsically determined genetic framework to selectively target and innervate layer 4 (L4) cortical neurons in a somatotopic manner. L4 spiny stellate neurons are excitatory locally projecting neurons, which undergo a drastic dendrite remodeling during the first postnatal week and represent the principal sensory gateway to the neocortex. In this review, we will discuss the way intrinsic cortical gene regulation and extrinsic activity-dependent inputs instruct the cellular reorganization of L4 spiny stellate neurons, necessary for proper formation of the barrel cortex during the development of primary somatosensory maps. PMID- 30005290 TI - Raman spectroscopy of pH-induced release of zidovudine from lactobionic acid conjugated PEGylated gold colloids. AB - Zidovudine (AZT) adsorbed on colloidal gold nanoparticles (AuNPs) undergoes pH induced conformational changes according to spectral changes in surface-enhanced Raman scattering (SERS). In acidic pH values conditions, AZT assumes the C(2') endo conformer, which binds more weakly to AuNPs than under neutral and alkaline conditions. In this study, density functional theory (DFT) calculations were performed; these calculations also supported the conformation-dependent binding energies. A lactobionic acid-conjugated PEGylated (LA-PEG-SH; molecular weight: 3400) unit was attached to AuNPs to target the asialoglycoprotein receptors overexpressed in hepatocarcinoma cells of Huh7 and SNU-354. The loading efficiency values were measured to be ~44-49% and ~66-68% at pH values of 7 and 10, respectively. At an acidic pH of 4.5, they were estimated to be only ~35-38%. pH-dependent spectral changes were observed for the asymmetric stretching modes of the azide (NNN) bands at 2183 cm-1 (in acidic pH) and at 2129 cm-1 (in basic pH). Cell viability analysis indicated that the LA-PEG-capped, AZT-coated AuNPs specifically inhibited the growth of the targeted hepatocarcinoma cells with better cancer cell killing efficiency than was observed with the LA-PEG-capped AuNPs without AZT. PMID- 30005293 TI - Selfie-Objectification: Self-Objectification and Positive Feedback ("Likes") are Associated with Frequency of Posting Sexually Objectifying Self-Images on Social Media. AB - The present study is the first to examine the extent to which young adult women post objectifying self-images on social media, and whether the frequency of posting such content can be predicted by self-objectification and positive feedback (likes). Eighty-six young adult women from the UK (Age M = 19.88; SD = 1.34, Range = 18-24) completed self-report measures of self-objectification and social media use. The 20 most recent images they had posted on their personal Instagram accounts were downloaded (Image N = 1720) and content analysed for self objectifying content. The analysis found that 29.77% of participants' Instagram images were objectified, though there were individual differences. Higher frequency of posting objectified self-images was associated with trait self objectification and receiving more likes on this type of self-image, relative to non-objectified self-images. The implications of the novel findings for objectification theory are discussed within. PMID- 30005292 TI - Identification of putative drug targets and annotation of unknown proteins in Tropheryma whipplei. AB - Tropheryma whipplei (T. whipplei) is the causative agent of Whipple's disease and blood culture-negative endocarditis. Due to the variability of symptoms, the disease is often poorly diagnosed. Treatment for this bacterial infection is often lengthy, and improper uptake of antibiotics has resulted in relapses in many patients. In the present study, using available bioinformatic tools and databases such as the Cluster Database at High Identity with Tolerance (CD-HIT), the Basic Local Alignment Search Tool for proteins (BLASTp), the Database of Essential Genes (DEG), and the DrugBank database, 13 putative drug targets were identified in T. whipplei by subtractive genome analysis that could be targeted with currently available drugs (experimental or approved). Further, a 3D model was generated for one of these putative drug targets, the T. whipplei DNA ligase, and in silico docking was performed with pyridochromanone and adenosine-derived inhibitors using the AutoDock Vina. Additionally, many of the T. whipplei protein sequences in the National Center for Biotechnology Information (NCBI) protein database were unknown/uncurated. Using available web servers e.g. the KEGG Automatic Annotation Server (KAAS), the BLASTp, the Conserved Domain Architecture Retrieval Tool (CDAT) and the Protein families (Pfam), the function/remote/domain homology for nearly 80% of these uncurated protein sequences were annotated. The data obtained in the present study will aid physicians and researchers alike in curbing this bacterial infection. PMID- 30005294 TI - The association between intraoperative dexmedetomidine and 1 year morbidity and mortality after cardiac surgery: A propensity matched analysis of over 1400 patients. AB - STUDY OBJECTIVE: Dexmedetomidine is widely used during surgery. Recent studies have demonstrated that dexmedetomidine administered perioperatively is associated with lower postoperative mortality and complications in patients undergoing cardiac surgery. DESIGN: This study was designed to investigate the effects of dexmedetomidine during cardiac surgery in Chinese patients. PATIENTS/INTERVENTIONS: We conducted a retrospective review of 1477 consecutive patients who underwent cardiac surgery at our institution. Of these patients, 1077 received dexmedetomidine during their surgery (dexmedetomidine group) and 400 did not (control group). All patients were followed for 1 year. Their short- and long-term outcomes were compared by the inverse-probability of treatment weighted adjustment to reduce treatment selectmen bias. Propensity-score matching yielded two well-matched groups for further comparison. MAIN RESULTS: After adjusting for differences in baseline risk factors with the inverse probability of treatment weighting, the risk of perioperative mortality (Odds ratio [OR]:1.02; 95% confidence interval [CI]:0.32 to 3.28, P = 0.97) and cardiovascular complications were not significantly different between the two groups. After 1 year of follow-up, the two groups showed no differences in mortality (hazard ratio [HR]:0.70; 95% CI 0.28 to 1.73, P = 0.44) and major adverse cardiovascular and cerebrovascular events (MACCE) (HR 1.08; 95% CI 0.69 to 1.68, P = 0.74).However, postoperative atrial fibrillation was lower in the dexmedetomidine group (OR: 0.53; 95% CI: 0.31 to 0.90, P = 0.02). CONCLUSIONS: Dexmedetomidine administered perioperatively reduced postoperative atrial fibrillation, but was not effective in decreasing short and long-term mortality or cardiovascular complications in a Chinese population. PMID- 30005295 TI - Aligning Anesthesiology and Perioperative Services with Value-Based Care: Proceedings of the Annual Meeting of the Association of Anesthesia Clinical Directors (AACD). PMID- 30005296 TI - Perioperative cardiac arrests - A subanalysis of the anesthesia -related cardiac arrests and associated mortality. AB - STUDY OBJECTIVE: To determine the incidence, risk factors, and predictors of survival of perioperative cardiac arrests (PCAs) occurring in patients who underwent non-cardiac and non-obstetric surgery from January 2008 to May 2015 at a tertiary hospital; determine the incidence and risk factors of anesthesia related PCA. DESIGN: Retrospective observational study. SETTING: Operating room and postoperative recovery area. PATIENTS: Sixty-two PCA cases from an anesthesia database of 122,289 anesthetics. INTERVENTIONS: Each PCA was classified as anesthesia-related, partially anesthesia-related, or anesthesia unrelated. The main outcome variables were occurrence of PCA, survival at least 1 h after initial resuscitation and survival to hospital discharge. To determine the risk factors for PCA, for each patient who suffered a PCA, two other patients that underwent anesthesia on the same day and in the same operating suite were selected. MEASUREMENTS: Three sets of variables were collected; patient-related, surgical procedure-related, and PCA-related. MAIN RESULTS: The incidence of PCAs of all causes was 5.07 per 10,000 anesthetics, and the associated mortality was 2.9 per 10,000 anesthetics. The independent risk factors for occurrence were: ASA PS score higher than 3, diagnosed cardiac disease, and the use of vasopressors. Decreased survival was associated with: higher ASA PS score, urgent surgical procedures of a higher complexity, use of vasopressors, documented hypotension prior to PCA, and arrests due to bleeding. The incidence of anesthesia-related PCAs was 0.74 per 10,000 anesthetics, and the associated mortality was 0.08 per 10,000 anesthetics. The main causes of anesthesia-related PCAs were associated with medication and airway/ventilation, and the independent risk factors for occurrence were: ASA PS score higher than 3 and diagnosed cardiac disease. CONCLUSIONS: Most PCAs were not due to anesthesia-related causes, and anesthesia related PCAs were associated with improved survival. Improvements in the management of high-risk patients, medication administration, and airway/ventilation management may result in better outcomes. PMID- 30005297 TI - H2O2 decomposition mechanism and its oxidative desulfurization activity on hexagonal boron nitride monolayer: A density functional theory study. AB - Hydrogen peroxide (H2O2) decomposition mechanism and its oxidative desulfurization activity on hexagonal boron nitride monolayer (h-BN) have been explored by density functional theory (DFT) at M06-2X/6-311 + G (d,p) level. A cluster model which contains seven rings has been constructed to simulate the h BN surface. It is found that 7 possible species will be generated after the decomposition of H2O2. Among them, 2H*+O2* and 2H*+2O* are relatively unstable while other species, such as HOO*+H*, HO*+HO*, H*+HO + O*, H2O*+O* are relatively stable and may exist in the current system. In addition, 4 decomposition pathways have been explored. Results show that the H2O2* will first undergo an O-H bond break (HOO*+H*), then the HO-O bond decomposes into H*+HO*+O* (Pathway (b)). By considering the concentration and activation energy together, the H2O*+O* is proposed to be the most possible active species for oxidative desulfurization due to the relative higher concentration and lower activation energy. PMID- 30005298 TI - Actin Assemblies in the Axon Shaft - some Open Questions. AB - The actin cytoskeleton in neurons plays critical roles in axonal growth and synaptic organization. Until recently, most studies on axonal actin were limited to terminal growth cones or synapses, whereas the organization of actin along the shaft of the axon was relatively ignored. However, experiments using super resolution microscopy and live imaging have revealed previously unknown actin structures along the axonal shaft, such as periodic 'actin rings' circumferentially wrapping underneath the plasma membrane and dynamic actin pools deeper within the axon shaft (termed actin 'hotspots' and 'trails'). In this short review, we highlight some open questions that have surfaced as a direct result of these discoveries. PMID- 30005299 TI - Lasers and ion mobility: new additions to the glycosaminoglycanomics toolkit. AB - Glycosaminoglycans are biopolymers present in mammalian cells or in the extracellular matrix. To address their structure, the nature of the hexuronic acids and the position of sulfate groups must be determined. Tandem mass spectrometry using collision induced dissociation or electron-based fragmentation techniques, is a well-established approach for the identification of glycans but suffers from the frequent lack of diagnostic fragments in the case of glycosaminoglycans. This review presents alternative fragmentation techniques, namely photofragmentation in the IR and the UV ranges. Alternative approaches based on the direct analysis of the molecular structure, including ion mobility spectrometry and ion spectroscopies are reviewed. The potential of future multidimensional workflows for glycosaminoglycanomics is discussed. PMID- 30005300 TI - Focal epilepsy as a late complication of congenital dacryocystocele. PMID- 30005301 TI - Accidental dual humidification in intensive care units: Repeated alerts and system changes are not enough. AB - PURPOSE: The inadvertent, simultaneous use of heat and moisture exchangers (HMEs) and heated humidifiers (HHs) can result in waterlogging of the filter and sudden ventilation tube occlusion, with potentially fatal consequences. Following an NHS England Safety Alert, a near miss and educational reminders in our institution, we introduced new guidelines to solely use HHs in the intensive care unit and HMEs only for patient transfers. No further incidents have occurred, however this solution is potentially fallible. Two years later, we sought to assess staff knowledge and likelihood of recognising this error should it occur. MATERIALS AND METHODS: In a simulation study, a tracheally intubated and ventilated mannequin had a breathing circuit containing both a HME and a HH. Participants were asked to assess the circuit, identify errors and undertake corrective measures. RESULTS: Only 30% (6/20) recognised and undertook corrective measures. CONCLUSIONS: Despite educational efforts and system changes, recognition of this error remained poor. System changes may reduce the likelihood of the error occurring, but when it does, recognition may not occur. Substantial reductions or elimination of this error may be achieved through a safety-engineered fail-safe within the equipment, which alerts staff to improve recognition and prevent the mistake. PMID- 30005302 TI - Emergence of antimicrobial resistance to piperacillin/tazobactam or meropenem in the ICU: Intermittent versus continuous infusion. A retrospective cohort study. AB - BACKGROUND: Prolonged infusion of beta-lactam antibiotics is broadly recognized as a strategy to optimize antibiotic therapy by achieving a higher percentage of time that concentrations remain above the minimal inhibitory concentration (% fT>MIC), i.e. the pharmacokinetic/pharmacodynamic (PK/PD) index. However, %fT>MIC may not be the PK/PD index of choice for inhibition of resistance emergence and it is therefore unsure what impact prolonged infusion of beta-lactam antibiotics may have on the emergence of resistance. METHODS: A retrospective cohort study including 205 patients receiving either intermittent (101 patients) or continuous (104 patients) infusion of piperacillin/tazobactam or meropenem was conducted in the ICU of the Ghent University Hospital. Logistic regression analysis was used to develop a prediction model and to determine whether the mode of infusion was a predictor of emergence of antimicrobial resistance. RESULTS: Resistant strains emerged in 24 out of the 205 patients (11.7%). The mode of infusion was no predictor of emergence of antimicrobial resistance. Infection with Pseudomonas aeruginosa was associated with a significantly higher risk for emergence of resistance. CONCLUSIONS: In this retrospective cohort study, the emergence of antimicrobial resistance to piperacillin/tazobactam or meropenem was not related to the mode of infusion. PMID- 30005303 TI - Evaluating the risk profile of quetiapine in treating delirium in the intensive care adult population: A retrospective review. AB - PURPOSE: Dosing regimens of quetiapine to treat delirium in critically ill patients are titrated to effect, and may utilize doses higher than previously reported. This study aimed to assess the safety of quetiapine for this indication. MATERIALS AND METHODS: A retrospective medical chart review was conducted, identifying 154 critically ill adults that were initiated on quetiapine to treat delirium and monitored for QTc prolongation. RESULTS: The median average daily dose was 150 mg (79-234) and median max dose was 225 mg (100 350). The overall range was 25-800 mg daily. The time to peak dose was 3 days (1 8). Patients with QTc prolongation were significantly older (age 54 +/- 11 vs 45 +/- 17 years (p = 0.002)) and with higher baseline QTc (454 +/- 33 vs 442 +/- 30 (p = 0.045)). Regression analysis revealed only dose as a significant factor (OR = 1.006 (1.003-1.009) (p < 0.001)). CONCLUSION: The dose of quetiapine has very little correlation with QTc and change from baseline. A small number of side effects were observed. Overall, titrating quickly to large doses of quetiapine is safe for treating delirium. PMID- 30005304 TI - Out-of-bed mobilization of patients undergoing mechanical ventilation with orotracheal tubes: A survey study. AB - PURPOSE: The aim of this study is to clarify intensive care unit (ICU)-level factors facilitating out-of-bed mobilization defined as a range of activities from sitting on edge of bed up to walking in mechanically ventilated patients with orotracheal tubes. MATERIALS AND METHODS: We conducted a survey of all intensive care units (ICUs) certified by the Japanese Society of Intensive Care Medicine (excluding pediatric ICUs) as training facilities for intensivists. RESULTS: We surveyed 294 ICUs, with a response rate of 57% (n = 168). A dedicated physical and/or occupational and/or speech therapy team was present in 34 ICUs (20%). In 86 ICUs (51%), mechanically ventilated patients with orotracheal tubes also routinely underwent out-of-bed mobilization, and 38 ICUs (23%) used a written mobilization protocol. Factors independently associated with routine out of-bed mobilization were the presence of a dedicated therapist in the ICU (odds ratio [OR], 6.83; 95% confidence interval [CI], 2.17-21.50; p = 0.001) and a high intensity physician staffing (OR, 2.37; 95% CI, 1.03-5.51; p = 0.043). CONCLUSIONS: Based on impression of professionals, the presence of dedicated therapist in the ICU, and the high intensity physician staffing are significantly associated with an increased rate of out-of-bed mobilization for mechanically ventilated patients with orotracheal tubes. PMID- 30005305 TI - Prognostic ability of quick-SOFA across different age groups of patients with suspected infection outside the intensive care unit: A cohort study. AB - OBJECTIVES: Sepsis identification in older patients is challenging. We evaluated the performance of qSOFA across different age groups of patients with suspected infection outside the intensive care unit (ICU). METHODS: Retrospective cohort in a tertiary hospital in Brazil, from January 2016 to December 2016. Outcomes were hospital mortality, ICU admission and bacteremia. Performance of qSOFA was compared over three age groups: (1) reference: <=65 years, (2) old: 65 to 79 years and (3) very old: >=80 years. RESULTS: There were 420 patients in the study, of which 259 (61.7%) were <=65 years, 80 (19%) were 65 to 79 years and 81 (19.3%) were >=80 years. Old and very old patients had higher qSOFA scores and lower SIRS scores. Overall, qSOFA >=2 was associated to hospital mortality [OR (95% CI) = 5.8 (3.3-10.4), p < 0.001], ICU admission [OR (95% CI) = 2.7 (1.6 4.6), p < 0.001] and bacteremia [OR (95% CI) = 3.1 (1.7-5.8), p < 0.001]. Those associations were stronger in old and very old patients. qSOFA and SIRS demonstrated overall AUROCs for hospital mortality of 0.72 and 0.50, respectively. CONCLUSION: qSOFA demonstrated good overall accuracy and was more strongly associated to outcomes in old and very old patients, when compared to younger patients. PMID- 30005307 TI - Reversal of behavioral decline and neuropathology by a complex vitamin supplement involves modulation of key neurochemical stressors. AB - Metal ions are crucial for normal neurochemical signaling and perturbations in their homeostasis have been associated with neurodegenerative processes. Hypothesizing that in vivo modulation of key neurochemical processes including metal ion regulation (by transferrin receptor-1: TfR-1) in cells can improve disease outcome, we investigated the efficacy of a complex vitamin supplement (CVS) containing B-vitamins and ascorbic acid in preventing/reversing behavioral decline and neuropathology in rats. Wistar rats (eight weeks-old) were assigned into five groups (n = 8), including controls and those administered CVS (400 mg/kg/day) for two weeks before or after AlCl3 (100 mg/kg)-induced neurotoxicity. Following behavioral assessments, prefrontal cortex (PFC) and hippocampus were prepared for biochemical analyses, histology and histochemistry. CVS significantly reversed reduction of exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety. These correlated with CVS-dependent modulation of TfP-1 expression that were accompanied by significant reversal of neural oxidative stress in expressed superoxide dismutase, nitric oxide, catalase, glutathione peroxidase and malondialdehyde. Furthermore, CVS inhibited neural bioenergetics dysfunction, with increased labelling of glucokinase within PFC and hippocampus correlating with increased glucose-6-phosphate dehydrogenase and decreased lactate dehydrogenase expressions. These relates to inhibition of over-expressed acetylcholinesterase and increased total protein synthesis. Histological and Nissl staining of thin sections corroborated roles of CVS in reversing AlCl3 induced neuropathology. Summarily, we showed the role of CVS in normalizing important neurochemical molecules linking concurrent progression of oxidative stress, bioenergetics deficits, synaptic dysfunction and cellular hypertrophy during neurodegeneration. PMID- 30005306 TI - Blood-brain barrier breakdown, memory impairment and neurotoxicity caused in mice submitted to orally treatment with thymol. AB - Several evidences have related the biochemical and pharmacological properties of thymol, but the possible neurotoxic effects of this compound remain unknown and not evaluated. Thus, the purpose of this study was to evaluate whether intake of thymol in different doses (10, 20 and 40 mg/kg) induce neurotoxicity and behavioral alterations using mice as experimental model, as well as the involvement of blood-brain barrier (BBB) and brain neurotransmitters in these alterations. Thymol (20 and 40 mg/kg) significantly decrease latency time to inhibitory avoidance task when compared to control group, indicating a memory loss after 30 days of oral treatment. Also, thymol (20 and 40 mg/kg) induced a significant increase on BBB permeability to Evan's blue dye when compared to control group, which is an indicative of BBB breakdown. Moreover, a significant increase of brain acetylcholinesterase (AChE) was observed in mice treated with 40 mg/kg of thymol, while the activity of sodium-potassium pump (Na+, K+-ATPase) was inhibited in mice treated with 20 and 40 mg/kg thymol when compared to control group. Finally, mice that received 20 and 40 mg/kg thymol showed a significant increase on cerebral reactive oxygen species (ROS) levels and cerebral xanthine oxidase (XO) activity compared to control group. Based on these evidences, the rupture of BBB can be considered an important pathway linked in thymol-induced memory loss. Also, the augmentation of brain ROS levels elicited by increase on XO activity may be a via involved in the damage to BBB, and an oxidative pathway that impairs the activity of brain neurotransmitters, as AChE and Na+, K+-ATPase. In summary, the dose of 10 mg/kg thymol can be safe and without neurotoxic effects in a period of 30 days of intake. PMID- 30005308 TI - Stress-responsive genes (hsp70 and mt) and genotoxicity elicited by roxarsone exposure in Carassius auratus. AB - In this study, comet assay (single-cell gel electrophoresis), real-time quantitative PCR (qPCR) and proteomics approach were used to comprehensively assess toxicity elicited by roxarsone exposure in C. auratus at 50, 150 and 300 MUg/L for 7, 14 and 21 days. Results of comet assay showed that DNA were seriously damaged under the pressure of roxarsone, especially the concentration of 50 MUg/L that always maintained a sustained and increased damage effect to fish liver cell during the 21 days experiment. The expressions of biomarker genes showed that hsp70 gene expressions raised significantly and the group of 50 MUg/L also showed a continued increased response effect, whereas mt gene was only slightly increased. Results of proteomics for the concentration of 300 MUg/L found that thirty six significantly changed proteins were identified by MALDI TOF/TOF-MS. They are involved in many important processes including energy producing, cytoskeleton stabilization, substance metabolism and stress response. Among these metabolites, carbohydrate metabolism (mainly occurred during day 1 14) and cytoskeleton proteins (mainly occurred during day 14-21) were the most identified proteins. These results revealed that the low levels of 50 MUg/L probably led to a continuous damage than the higher groups during the experiment time. Furthermore, proteomics results might implied that though cell system expected to mobilize almost all the functional proteins to quickly establish a new homeostasis together when facing the roxarsone at first, but in the end the destroyed cell cytoskeleton structure might burst the bubble. PMID- 30005309 TI - Neuropsychiatric characterization of individuals with inhalant use disorder and polysubstance use according to latent profiles of executive functioning. AB - BACKGROUND: Inhalant use disorder (IUD) is associated with deficits in executive functions (EFs). We described latent profiles of EFs and distribution of neuropsychiatric disorders and patterns of severity of use across these profiles. METHODS: Individuals with IUD were recruited at community-based residential facilities for substance use treatment in Mexico City. Latent profile analysis was conducted with the following tasks: self-ordered pointing, Stroop, Iowa gambling, Wisconsin Card Sorting and Tower of Hanoi. RESULTS: Three latent profiles were extracted from n = 165: lowest performances of inhibition of response and processing speed; lowest performance of self-monitoring, intermediate performance of inhibition of response and relatively spared processing speed; and intermediate performance of processing speed and self monitoring, and relatively spared inhibition of response. CONCLUSION: Between group differences were observed mainly for antisocial personality disorder and lifetime suicidal. Findings remark the need for identifying distinct profiles of EFs within these populations to better understand the transdiagnostic heterogeneity of EFs. PMID- 30005310 TI - Risks of fatal opioid overdose during the first year following nonfatal overdose. AB - BACKGROUND: Little is known about risk factors for repeated opioid overdose and fatal opioid overdose in the first year following nonfatal opioid overdose. METHODS: We identified a national retrospective longitudinal cohort of patients aged 18-64 years in the Medicaid program who received a clinical diagnosis of nonfatal opioid overdose. Repeated overdoses and fatal opioid overdoses were measured with the Medicaid record and the National Death Index. Rates of repeat overdose per 1000 person-years and fatal overdose per 100,000 person-years were determined. Hazard ratios of repeated opioid overdose and fatal opioid overdose were estimated by Cox proportional hazards. RESULTS: Nearly two-thirds (64.8%) of the patients with nonfatal overdoses (total n = 75,556) had filled opioid prescriptions in the 180 days before initial overdose. During the 12 months after nonfatal overdose, the rate of repeat overdose was 295.0 per 1000 person-years and that of fatal opioid overdose was 1154 per 100,000 person-years. After controlling for age, sex, race/ethnicity, and region, the hazard of fatal opioid overdose was increased for patients who had filled a benzodiazepine prescription in the 180 days prior to their initial overdose (HR = 1.71, 95%CI: 1.46-1.99), whose initial overdose involved heroin (HR = 1.57, 95%CI:1.30-1.89), or who required mechanical ventilation at the initial overdose (HR = 1.86, 95%CI = 1.50 2.31). CONCLUSIONS: Adults treated for opioid overdose frequently have repeated opioid overdoses in the following year. They are also at high risk of fatal opioid overdose throughout this period, which underscores the importance of efforts to engage and maintain patients in evidence-based opioid treatments following nonfatal overdose. PMID- 30005312 TI - The worksite heart health improvement project's impact on behavioral risk factors for cardiovascular disease in long-term care: A randomized control trial. AB - BACKGROUND: Long-term care workers are at high risk for cardiovascular disease, in part because of their poor health habits. OBJECTIVE: The purpose of this study is to test the impact of the Worksite Heart Health Improvement Project (WHHIP) on subjective behavioral cardiovascular risk factors over time among long-term care staff. DESIGN: The WHHIP was a 12-month cluster randomized control trial conducted in four long-term care facilities. The exercise, nutrition, and stress management intervention lasted 9-months and was implemented during paid work time. SETTING AND PARTICIPANTS: Ninety-eight long-term care workers consented to participate in the study. METHODS: Survey data included: mood, dietary salt intake, dietary fat intake, sleep quality, and sleep duration. RESULTS: A significant positive short-term intervention effect at 9-month (p = .037) and long-term effect at 12-month for mood (p = .039) was found, signifying reduction in mood symptoms in the treatment group over time. The intervention group also showed longer sleep time (p = .016) and better sleep quality (p = .046) at 12 months. The intervention group had less dietary sodium intake at 9-months (p = .036); yet, this was not maintained over time. CONCLUSION: The WHHIP demonstrated the ability to improve participants' mood, sleep and sodium intake over time. Lessons learned particularly the challenges faced implementing the WHHIP and the solutions recommended provide critical insights to strengthen future programs with this population. PMID- 30005313 TI - Frequent attenders in primary health care: A concept analysis. AB - OBJECTIVES: Frequent attendance is a well-known phenomenon in health care systems. A small proportion of patients make a high rate of visits to primary health care physicians. However, due to the diversity of this phenomenon, there is no generally accepted definition of the frequent attender. The aim of this analysis was to define the concept of the frequent attender in primary health care. DESIGN: A concept analysis. DATA SOURCES: The literature was searched using electronic databases (MEDLINE, CINAHL, and Scopus) and a manual search was performed for studies published from 2000 to 2016. The inclusion criteria covered frequent attenders in primary health care examined by quantitative or qualitative studies published in English or Finnish. REVIEW METHODS: Walker and Avant's (2010) strategy for concept analysis was used. Uses of the concept were studied, and attributes, antecedents, and consequences of the concepts were defined. RESULTS: A total of 59 articles provided data for this concept analysis. Four defining attributes of frequent attenders were identified: the feelings of symptoms, perceived poor health status, lower quality of life and frequent visits to a primary health care provider. Antecedents included the patient's individual characteristics, the primary health care system, and the patient-physician relationship. Consequences were divided into two categories: those for frequent attenders and those for society. Consequences for frequent attenders included: follow-up investigations and visits, social disadvantages, and economic costs. Consequences for society included: the costs to the national economy and the consumption of health care resources. CONCLUSION: A theoretical definition and a conceptual model of the frequent attender were developed. The definition and the proposed empirical referents of all four attributes can be used to validate the presence of frequent attenders and to develop theory-based applications. Future research on frequent attenders is needed to develop and assess possible interventions. PMID- 30005311 TI - Socio-cognitive functioning in stimulant polysubstance users. AB - BACKGROUND: Using more than one psychotropic substance is accompanied by increased risks for psychiatric and physical disorders. Accordingly, deficits in basal cognitive functions have been consistently associated with polysubstance use (PSU), whereas little is known about potential impairments in more complex socio-cognitive skills, which are relevant for daily-life functioning. Therefore, we investigated the effects of toxicological validated stimulant PSU on social cognition under consideration of potential cumulative effects. METHODS: We compared socio-cognitive performances of 47 individuals with stimulant PSU with 59 matched stimulant-naive controls using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). Additionally, social network size was assessed by the Social Network Questionnaire (SNQ). Hair and urine testing was employed to categorize three PSU subgroups (3, 4, and >=5 substances used) and to ensure drug abstinence in controls. RESULTS: Individuals with stimulant PSU showed lower emotional empathy (MET) and a smaller social network (SNQ) compared to controls (both with linear trends for increasing number of used substances: p < .05). In contrast, cognitive empathy (MET and MASC) was largely unaffected by PSU. Additional linear regression analyses within PSU individuals revealed number of used substances as the best predictor for inferior performance in emotional empathy (p < .01), while severity of the use of single substances or substance-classes did not show a significant impact. CONCLUSION: These findings demonstrate cumulative adverse effects of stimulant PSU on an important facet of socio-cognitive functioning. Therefore, emotional empathy deficits should be targeted in future interventions and rehabilitations for individuals with PSU. PMID- 30005314 TI - Facilitating transition from children's to adult services for young adults with life-limiting conditions (TASYL): Programme theory developed from a mixed methods realist evaluation. AB - BACKGROUND: Improvements in care and treatment have led to more young adults with life-limiting conditions living beyond childhood, necessitating a transition from children's to adult services. Given the lack of evidence on interventions to promote transition, it is important that those creating and evaluating interventions develop a theoretical understanding of how such complex interventions may work. OBJECTIVES: To develop theory about the interventions, and organisational and human factors that help or hinder a successful transition from children's to adult services, drawing on the experience, knowledge, and insights of young adults with life-limiting conditions, their parents/carers, and service providers. DESIGN: A realist evaluation using mixed methods with four phases of data collection in the island of Ireland. Phase one: a questionnaire survey of statutory and non-statutory organisations providing health, social and educational services to young adults making the transition from children's to adult services in Northern Ireland and one Health Services Executive area in the Republic of Ireland. Phase two: interviews with eight young adults. Phase three: two focus groups with a total of ten parents/carers. Phase four: interviews with 17 service providers. Data were analysed seeking to explain the impact of services and interventions, and to identify organisational and human factors thought to influence the quality, safety and continuity of care. RESULTS: Eight interventions were identified as facilitating transition from children's to adult services. The inter-relationships between these interventions supported two complementary models for successful transition. One focused on fostering a sense of confidence among adult service providers to manage the complex care of the young adult, and empowering providers to make the necessary preparations in terms of facilities and staff training. The other focused on the young adults, with service providers collaborating to develop an autonomous young adult, whilst actively involving parents/carers. These models interact in that a knowledgeable, confident young adult who is growing in decision-making abilities is best placed to take advantage of services - but only if those services are properly resourced and run by staff with appropriate skills. No single intervention or stakeholder group can guarantee a successful transition. Rather, service providers could work with young adults and their parents/carers to consider desired outcomes, and the range of interventions, in light of the organisational and human resources available in their context. This would allow them to supplement the organisational context where necessary and select interventions that are more likely to deliver outcomes in that context. PMID- 30005315 TI - Growth of mesophilic Aeromonas salmonicida in an experimental model of nigiri sushi during cold storage. AB - The genus Aeromonas includes human pathogenic bacteria frequently isolated from seafood, and the increased consumption of ready-to-eat seafood poses new food safety issues regarding the presence of potentially pathogenic Aeromonas spp. in stored products for raw consumption, such as retail sushi with a shelf life of up to three days. This study assessed 1) the growth kinetics of a mesophilic A. salmonicida strain during storage at 4 degrees C and 8 degrees C in a nigiri sushi model, and 2) the strain variability in growth at pH ranging from 3.5 to 10 for a subset of mesophilic Aeromonas strains previously isolated from sushi. Inoculated slices of raw salmon were compared with and without rice. A predictive model for A. hydrophila (ComBase Predictor) did not sufficiently predict growth of the tested strain under the intrinsic conditions of nigiri sushi or salmon at both temperatures. Refrigeration alone (4 degrees C) did not inhibit growth of A. salmonicida on salmon. Within the first 72 h, representing the typical shelf life of retail sushi products, we observed a 10-fold increase in the concentration of the inoculated strain (including a lag-phase of approximately 34 h). Contact with acidified rice, resulting in a pH drop in the salmon, was the reason for the decreased bacterial viability in the nigiri sushi samples. However, the effect of acidification decreased at 8 degrees C, resulting in a 2 fold increase in the growth rate and a reduced lag-phase compared to refrigeration. Variability in the ability to grow in different pH levels was observed between strains. The highest color formation rates, representing cellular respiration analyzed in a phenotypic microarray system, were observed between pH 5 and 8. A few strains, including the A. salmonicida strain applied in the nigiri sushi model, were able to grow at pH 4.5 (at optimal temperature). The results demonstrated that mesophilic Aeromonas spp. can represent a microbiological hazard in retail sushi products during cold storage. Rice acidification in combination with low storage temperature (<=4 degrees C) are prerequisites to prevent growth of potentially pathogenic Aeromonas species during the relatively short shelf life. PMID- 30005316 TI - Supporting healthy weight gain and management in pregnancy: Does a mandatory training education session improve knowledge and confidence of midwives? AB - OBJECTIVE: To examine if a brief midwifery education and training session incorporated into annual mandatory training improves the knowledge and confidence of midwives to support healthy weight gain and management in pregnancy. DESIGN: An implementation evaluation using a pre-post study design was used. Midwives completed a self- administered questionnaire prior to and following completion of the training session. Objective knowledge, perceived knowledge and confidence in relation to nutrition, physical activity and healthy weight gain and management, and process measures related to the training were assessed. PARTICIPANTS AND SETTING: All midwives from a tertiary birthing hospital in Brisbane Australia who attended the annual mandatory training day in 2015 were invited to participate. MEASUREMENT AND FINDINGS: Of the 270 midwives who attended the training 154 pre and 114 post training questionnaires were returned. An increase in perceived knowledge across topic areas was reported by 70-97% of respondents, while perceived confidence increased for 83-91% of respondents across each topic area. Objective knowledge score increased from 11 pre-training to 15 post training (maximum score 17) (p < 0.001). Ninety six percent of respondents agreed the training provided practical communication strategies and 100% would recommend the training to others. KEY CONCLUSIONS: This brief education session integrated into an existing mandatory training program, improved the knowledge and confidence of midwives in delivering advice and support for healthy pregnancy weight gain. IMPLICATIONS FOR PRACTICE: This improvement is the first step in changing practice to prevent excess weight gain during the antenatal period. This program offers an innovative model to support midwives implement change across other health services. A low cost intervention that was well received by midwives can address identified barriers to the provision of best practice care that supports a healthy pregnancy weight gain in a sustainable forum. PMID- 30005317 TI - The influence of clear speech on auditory-perceptual judgments of electrolaryngeal speech. AB - PURPOSE: To determine the influence of clear speech on auditory-perceptual judgments of speech acceptability and listener comfort for electrolaryngeal speech. METHOD: Voice recordings were obtained from 10 electrolaryngeal speakers. Each speaker read the Rainbow Passage in two conditions: habitual speech and clear speech. Speakers were encouraged to speak as clearly as possible and over articulate in the clear speech condition. Auditory-perceptual rating tasks were completed by 20 normal-hearing adults who evaluated 20 randomized voice recordings. Two counterbalanced listening sessions were used to gather ratings of speech acceptability and listener comfort. RESULTS: A significant effect of speaking condition was found on listener judgments of speech acceptability, but not listener comfort. However, listener scores for speech acceptability and listener comfort were found to be significantly related. For all speakers, objective temporal measures indicated reduced speaking rates in the clear speech condition. CONCLUSIONS: These findings suggest that volitional attempts to improve electrolaryngeal speech using clear speech might negatively impact listener judgments of speech acceptability, but not listener comfort. Further, the data suggest that speech acceptability and listener comfort might address unique perceptual entities. Overall, the strong relationship between these auditory-perceptual dimensions provide support for the use of scaled measurements to assess the impact of speech rehabilitation on individuals who use the electrolarynx. PMID- 30005318 TI - Atypical language characteristics and trajectories in children with 22q11.2 deletion syndrome. AB - BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a genetic condition associated with a highly variable phenotypic expression. During childhood speech and language deficits are commonly observed. Findings of cross-sectional studies suggest syndrome-specific and changing language profiles, but a longitudinal approach to identify developmental changes is still lacking to date. AIMS: The present study aimed to delineate language characteristics and trajectories by comparing the performance of Dutch-speaking school-aged children with 22q11.2DS (n = 18) to those of peers with idiopathic intellectual disability (IID, n = 19) and to those of children with IID and comorbid autism spectrum disorder (IID + ASD, n = 23). The literature shows contradictory findings regarding language comprehension difficulties in children with 22q11.2DS, we focused on the receptive-expressive language discrepancy. Given their relative strength for verbal short-term memory (VSTM) tasks, a fine-grained error categorization was included to elucidate a possible influence of VSTM on the expressive language outcomes. Finally, we suggested that the inability of children with 22q11.2DS to use contextual information could interfere with morphosyntactic measures. METHODS: All groups (22q11.2DS, IID, and IID + ASD) were matched for nonverbal fluid reasoning (Gf) using the Analogies and Categories subtests of the Snijders Oomen Nonverbal Intelligence Test or the Matrix Reasoning and Picture Concepts subtests of the Wechsler Preschool and Primary Scale of Intelligence. Several structural language skills were measured using the Clinical Evaluation of Language Fundamentals and Peabody Picture Vocabulary Test. The same instruments were re-administered after 18 to 24 months. A fine-grained error analysis of the Formulating and Recalling Sentences subtests, both measuring expressive syntax, explored factors contributing to expressive language deficits. RESULTS: In children with 22q11.2DS the relative advantage of receptive over expressive language had decreased compared to children with IID. For children with 22q11.2DS, complex sentence comprehension remained very challenging over time. Expressive language skills seemed less limited compared to children with IID, and were accompanied by less VSTM difficulties. In children with 22q11.2DS and children with IID + ASD, variable patterns of strengths and weaknesses were demonstrated, resulting in subtle differences between these groups. Error analyses indicated disregard of content-contextual cues and use of vague and elliptic language as being typical for children with 22q11.2DS. CONCLUSIONS: We recommend that in children with 22q11.2DS the impact of the receptive language impairment should be comprehensively examined and followed-up since it can have a negative effect on their social communication skills, adaptive functioning and academic achievement. Error analysis underscores that multiple measures should be used to evaluate the child's expressive language ability. Further research should focus on developmental trajectories of social communication skills and on the use of intervention strategies to improve language comprehension and pragmatics in school-aged children with 22q11.2DS. PMID- 30005319 TI - Treatment delivery of the community reinforcement approach in outpatient addiction treatment. AB - OBJECTIVE: Treatment model adherence is an important predictor of treatment outcome. In clinical practice evidence-based treatments are delivered in widely varying degrees. This study examines which Community Reinforcement Approach (CRA) procedures are delivered by addiction care therapists and how this is associated with therapist characteristics. METHOD: The study integrated two observational designs. Firstly, using a prospective design, 24 therapists registered every CRA procedure delivered during every patient contact over a six month period. Secondly, using a cross-sectional design, personal characteristics of 69 therapists were assessed including their self-reported delivery of CRA procedures and their perceptions with regard to the meaningfulness and complexity of these procedures. RESULTS: The number of CRA procedures delivered varied substantially among therapists both at session and patient level. More experienced therapists and those that had received advanced training previously, delivered more CRA procedures. Finally, the delivery of CRA procedures was positively associated with experienced meaningfulness and negatively associated with difficulty. CONCLUSIONS: The results confirm the relation between treatment delivery and experienced meaningfulness and difficulty of CRA procedures and provides support for advanced training to enhance the delivery of a wider range of CRA procedures. PMID- 30005320 TI - Exploration of the experiences, practices and needs of health promotion professionals when evaluating their interventions and programmes. AB - INTRODUCTION: The aim of this study was to describe the practices of health promotion professionals when evaluating interventions and their transferability and to identify these professionals' needs in relation to a tool that will guide them during monitoring and evaluation. METHOD: A survey was carried out among health promotion actors, which focussed on the interventions they had carried out. RESULTS: Of the 1017 organisations (covering the whole of France) approached, 246 responded to the survey. More than 60% of the respondents had faced difficulties during the construction of the process evaluation, and more than 50% had faced difficulties during its implementation. These difficulties related to data collection, the conception or choice of indicators, criteria and relevant evaluation tools, and lack of time and personnel. Eighty per cent reported that they had carried out the same action in different places and had been faced with two main obstacles, namely budget and environment. Recognition, positive evaluation, existing collaborations and willingness to work in partnership plus the capacity to adapt to local contexts were identified as factors fostering transferability. DISCUSSION: Despite the many recommendations available, constructing and carrying out evaluations is not systematic. Actors are confronted with many difficulties, which could be overcome with an IT tool that incorporates the actors' suggestions during its development. PMID- 30005321 TI - Theoretical framework of statistical noise in scanning transmission electron microscopy. AB - Statistical noise, or shot noise, dominates experimental image quality in scanning transmission electron microscopy because efficiencies of recent detectors are close to ideal. We establish a general framework for the statistical noise taking into account two random processes in the electron incidence and the electron scattering. Using this framework, in terms of signal to-noise ratio, we evaluate several STEM coherent imaging techniques: annular bright field, enhanced annular bright field, differential phase contrast, and ptychography and show that ptychography is the most efficient imaging for weak phase objects. Moreover, we find that normalizing annular-bright-field image by total electron count in the bright field significantly suppress the noise. PMID- 30005322 TI - Resolution of transmission electron backscatter diffraction in aluminum and silver: Effect of the atomic number. AB - This work aims to investigate the influence of intrinsic and extrinsic factors on the physical resolution of the transmission electron backscattered diffraction technique (t-EBSD) in aluminum and silver. Here, we focus on the intrinsic factors, namely, atomic number and thickness of the specimen, and extrinsic set up factors, which include the electron beam voltage, working distance, and specimen tilt. The working distance and tilt angle, which are selected as 12 mm and 60 degrees for Al and 12 mm and 50 degrees for Ag, respectively, reveal a sharp pattern with high contrast. The physical resolutions at the lateral and longitudinal directions depend on the depth resolution. The depth and lateral and longitudinal resolutions increase in Al but decrease in Ag with increased accelerating voltage. The decrease in specimen thickness for Al and Ag from 400 nm to 100 nm reduces the lateral and longitudinal resolutions. The most ideal depth and lateral and longitudinal resolutions obtained under a thickness of 100 nm are 22.7, 18.9, and 33.7 nm at 30 kV for Ag and 34.7, 22.8, and 36.6 nm at 15 kV for Al, respectively. PMID- 30005324 TI - Eukaryotic DNA polymerases. AB - The eukaryotic DNA replication machinery is conserved from yeast to humans and requires the actions of multiple DNA polymerases. In addition to replicative DNA polymerases for duplication of the leading and lagging DNA strands, another group of specialized polymerases is required for DNA repair and/or translesion DNA synthesis (TLS). We emphasize here recent findings that accelerate our understanding of the structure and mechanisms of these remarkable enzymes. We also highlight growing evidence on the role of DNA polymerases in the origin of certain cancers, and paradoxically as emerging targets for cancer therapy. PMID- 30005323 TI - Effect of cation ratio and order on magnetic circular dichroism in the double perovskite Sr2Fe1+xRe1-xO6. AB - Superexchange-based magnetic coupling of the two B-site cations in rock-salt ordered double perovskite oxides is extremely sensitive to the cation ratio and degree of order. However, as a result of the limited spatial resolution of most magnetic characterization techniques, it is challenging to establish a direct relationship between magnetic properties and structure in these materials, including the effects of elemental segregation and cation disorder. Here, we use electron energy-loss magnetic chiral dichroism together with aberration-corrected electron microscopy and spectroscopy to record magnetic circular dichroism (MCD) spectra at the nm scale, in combination with structural and chemical information at the atomic scale from the very same region. We study nanoscale phases in ordered Sr2[Fe][Re]O6, ordered Sr2[Fe][Fe1/5Re4/5]O6 and disordered Sr[Fe4/5Re1/5]O3 individually, in order to understand the role of cation ratio and order on local magnetic coupling. When compared with ordered Sr2[Fe][Re]O6, we find that antiferromagnetic Fe3+-O2--Fe3+superexchange interactions arising from an excess of Fe suppress the MCD signal from Fe cations in ordered Sr2[Fe][Fe1/5Re4/5]O6, while dominant Fe3+-O2--Fe3+antiferromagnetic coupling in disordered Sr[Fe4/5Re1/5]O3 leads to a decrease in MCD signal down to the noise level. Our work demonstrates a protocol that can be used to correlate crystallographic, electronic and magnetic information in materials such as Sr2Fe1+xRe1-xO6, in order to provide insight into structure-property relationships in double perovskite oxides at the atomic scale. PMID- 30005325 TI - Social participation and depressive symptoms among Chinese older adults: A study on rural-urban differences. AB - BACKGROUND: Although studies conducted in developed countries have reported a negative relationship between social participation and depressive symptoms, few studies have examined rural-urban differences in the relationship between participation in various types of social activities and depressive symptoms among Chinese older adults. OBJECTIVES: This study examined the association between participation in paid work, political, and voluntary activities and depressive symptoms among Chinese older adults in urban and rural areas. METHODS: Data were obtained from the China Longitudinal Ageing Social Survey conducted in 2014, and bivariate linear regression and multivariable linear regression analyses were conducted. RESULTS: The prevalence of depressive symptoms was significantly higher among older adults residing in rural areas than among older adults in urban areas. Participation in paid work activities was significantly associated with fewer depressive symptoms among older adults in urban and rural areas, whereas participation in political or voluntary activities was negatively associated with depressive symptoms only among older adults in urban areas. Older adults who participated in two or three types of activities (paid work, political, and voluntary activities) tended to have fewer depressive symptoms both in urban and rural areas. LIMITATIONS: Because this study comprised a cross sectional design, causality could not be established between social participation and depressive symptoms. CONCLUSIONS: Social participation plays a protective role against depressive symptoms among Chinese older adults, especially among those in urban areas. Urban-rural differences exist between participation in different types of social activities and depression symptoms. PMID- 30005326 TI - Smoking among adults with serious psychological distress: Analysis of anonymized data from a national cross-sectional survey in Japan. AB - BACKGROUND: Smoking behavior among people with serious psychological distress (SPD) has not been fully investigated in Asia, although smoking has become a public health concern worldwide. Many Western population-based studies indicate that people with psychological distress are more likely to smoke. METHODS: This study used a national representative data set from the 2010 Comprehensive Survey of Living Conditions of Japan. SPD was defined as scores >=13 or greater on the Kessler Psychological Distress Scale (K6). Multivariate logistic regression analyses were conducted to analyze the association between SPD and current smoking in Japanese adults. RESULTS: In both men (n = 27,937) and women (n = 30,786), SPD was significantly associated with current smoking (adjusted odds ratios [95% confidence intervals]: 1.169 [1.030-1.328] for men and 1.677 [1.457 1.931] for women). Among men, SPD was significantly associated with current smoking only in people aged >=50 years (1.519 [1.232-1.874]) and married (1.456 [1.228-1.728]). SPD was significantly associated with current smoking in women of all ages. SPD had a greater impact on current smoking for women aged 20-49 years than for those aged >=50 years (1.832 [1.552-2.162] and 1.445 [1.099-1.900], respectively). LIMITATIONS: The cross-sectional design precludes assumptions about the direction of causality. In addition, smoking status was self-reported. CONCLUSIONS: SPD was significantly associated with current smoking in Japan and the association was much stronger for younger women. Clinical strategies are needed to reduce the prevalence of smoking among people with SPD to reduce excess mortality in this population. PMID- 30005327 TI - Negative effects of psychotherapies for adult depression: A meta-analysis of deterioration rates. AB - BACKGROUND: The risk for deterioration in patients receiving psychotherapy for adult depression has not been examined extensively and it is not clear whether psychotherapy reduces this risk or may even increase it in some patients. We conducted a meta-analysis of trials comparing these psychotherapies with control conditions that report deterioration rates. METHODS: We used an existing database of randomized trials on psychotherapies for adult depression which was updated up to 1/1/2017, through systematic searches in bibliographic databases. We included trials that reported clinically significant deterioration rates. RESULTS: We included 18 studies with 23 comparisons between therapy and control groups. The pooled risk ratio of deterioration was 0.39 (95% CI: 0.27~0.57), indicating that patients in the psychotherapy groups have a 61% lower chance to deteriorate than patients in the control groups. We found that 20 patients need to be treated with psychotherapy in order to avoid one case of deterioration, compared to the control conditions. The median deterioration rate in the therapy groups was 4%, and in some studies more than 10%, indicating that clinicians should always be aware of the risk of deterioration. LIMITATIONS: The results should be considered with caution because most studies had at least some risk of bias. Only 6% of all trials comparing psychotherapy with a control condition reported deterioration rates, using different ways to define deterioration which made pooling the prevalence rates across treatments and control groups impossible. CONCLUSIONS: Psychological treatments of adult depression may reduce the risk for deterioration, compared to control groups, but this should be considered with caution because of the small proportion of studies reporting deterioration rates. PMID- 30005328 TI - Venus and Mars on the benches of the faculty: Influence of gender on mental health and behavior of medical students. Results from the BOURBON national study. AB - : Medical student wellness has emerged as an important issue in medical education. OBJECTIVE: To evaluate the gender influence on psychiatric and/or psychological follow-up, psychotropic and illicit drug consumption, addictive behaviors, quality of life and motives for consumption in a large multicentric national sample of medical students. METHODS: Medical students of the 35 French Medicine faculties were recruited through mailing lists and social networks between December 2016 and May 2017 and fulfilled Internet anonymized questionnaires. RESULTS: Overall, 10,985 medical students were included in the present study (mean age 21.8 years, 9640 (87.8%) women). Compared to men, women were found to smoke tobacco and cannabis less frequently (aOR = 0.8 [0.7-0.9], p < 0.0001 and aOR = 0.3 [0.3-0.4], p < 0.0001 respectively), to have lower rate of alcohol use disorders (aOR = 0.7 [0.6-0.7], p < 0.0001). Men were also found to consume more frequently ecstasy, cocaine, mushrooms, amphetamine, LSD, codeine and ketamine (all p < 0.0001) for pleasure and novelty seeking, group effect, but also alleviating anxiety, sedative and stimulant effect and stress before exam (all p < 0.001) while women were more frequently followed-up by a psychiatrist and/or a psychologist (aOR = 2.0 [1.7-2.3],p < 0.0001), consumed more frequently anxiolytics (aOR = 1.6[1.3-1.9], p < 0.0001) and antidepressants (aOR = 1.4[1.1 1.9], p = 0.01), reported lower rates of physical and mental quality of life in all subscores (all p < 0.0001). They were more frequently exposed to sexual assault (aOR = 4.1 [2.5-6.9], p < 0.0001) and domestic violence (aOR = 1.6[1.1 2.5], p = 0.02) while men were more frequently exposed to physical assault (aOR = 0.4[0.4-0.5], p < 0.0001) during their medical studies. CONCLUSIONS: Medical students are mostly women. While men and women are both exposed to professional and personal stress with differences, men are more frequently involved in addictive behavior and psychoactive substance consumption while women are mostly followed-up by psychiatrist and/or psychologist and psychotropic drug consumers, with more impaired self-reported mental and physical quality of life scores. These results should orientate future health strategies for the prevention of later mental illness onset and stress at work in hospital. PMID- 30005329 TI - Effects of sucralose on insulin and glucagon-like peptide-1 secretion in healthy subjects: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVES: Emerging evidence shows that non-nutritive sweeteners might induce glucose intolerance. This study aims to determine the effects of chronic exposure to sucralose on glycemic response, insulin secretion and sensitivity, and glucagon-like peptide-1 (GLP-1) release in healthy subjects. METHODS: Healthy volunteers who did not use non-nutritive sweeteners and were normoglycemia after oral glucose tolerance test (OGTT) were recruited. Subjects underwent a 75-g OGTT on two separate occasions, preceded by blindly consuming pills containing either 200 mg sucralose or placebo for 4 wk in a randomized crossover trial. Plasma glucose, insulin, and active GLP-1 levels were obtained after ingesting 75-g glucose. On the following day, intravenous glucose tolerance test (IVGTT) was performed to evaluate the acute insulin response (AIR). RESULTS: Fifteen participants (11 females, age 31.9 +/- 10 y, body mass index 23.1 +/- 3 kg/m2) participated in the study. AIR was lower after exposure to sucralose than placebo (58.9 +/- 48.61 versus 69.94 +/- 73.81 uU/mL, P < 0.001). Whole-body insulin sensitivity (estimated using the Matsuda index) was lower in sucralose than placebo (4.69 +/- 1.67 versus 5.31 +/- 2.56, P < 0.005). AUC of active GLP-1 was significantly higher in the sucralose than placebo (23.16 +/- 18.86 versus 18.5 +/- 22.22 pmol/L ? 120 min, P < 0.001). CONCLUSIONS: The continuous exposure to sucralose reduced AIR, decreased insulin sensitivity, and enhanced GLP-1 release in healthy subjects. However, the clinical significance of these results needs to be investigated in longer follow-up studies. PMID- 30005331 TI - Low calcium intakes among Australian adolescents and young adults are associated with higher consumption of discretionary foods and beverages. AB - OBJECTIVES: Calcium is an essential nutrient required for peak bone mass growth during adolescence and into young adulthood. The aim of this study was to examine the calcium intake of Australian adolescents and young adults from both food sources and supplements; and the relationship between calcium intake and intake of food groups. METHODS: Dietary data from 770 adolescents (14-18 y of age) and 774 young adults (19-25 y of age) from the 2011 to 12 National Nutrition and Physical Activity Survey were used. Analysis of covariances were conducted to identify associations between calcium intake and consumption of food groups. RESULTS: For adolescents, 83% of males and 95% of females did not meet the Estimated Average Requirement (EAR); whereas for young adults, 69% of males and 83% of females failed to meet the EAR. Food sources contributing to calcium intake were similar across age groups and sex. The largest contributors included regular milk (15-24%), cheese (10-12%), refined low-fiber bread (10%), and low fat milk (7-9%). For both age groups, the lowest consumers of calcium were the poorest consumers of dairy products and the highest consumers of discretionary food choices and alcoholic beverages. A higher consumption of calcium was associated with a higher intake of dairy products and lower intakes of meat and alternatives and all discretionary choices. CONCLUSIONS: Calcium intake among Australian adolescents and young adults remains below recommendations, particularly in females. A higher intake of calcium was associated with a better dietary pattern. Further investment in interventions is indicated. PMID- 30005330 TI - Changes in food habits in cancer patients in Italy: a survey. AIOM - SINPE - FAVO. AB - OBJECTIVES: The aim of this study was to investigate the prevalence of cancer patients changing their diet in relation to cancer site, sex, age and geographic distribution. Furthermore, we aimed to explore the rationale behind dietary changes and to identify sources of information in order to plan specific educational training. METHODS: Patients >=18 y of age who accessed the Italian Cancer Patients, Families and Friends Association information points were invited to participate. An ad hoc self-report questionnaire was used. The questionnaire asked patients about changes made to the major food groups. A minimum sample of 100 patients for the most common cancers was planned. We analyzed 1257 questionnaires. We assessed the prevalence of, reasons for, and type of dietary changes. Logistic regression was used to analyze the main determinants of dietary changes. RESULTS: Of the 1257 patients, 705 (56.1%) reported changes since receiving the diagnosis of cancer. On the logistic regression analysis, age and tumor site were significantly associated with dietary changes (P <0.001), mainly in patients <50 y of age and in those with upper gastrointestinal cancers. Slightly more than half (50.8%) of patients adopted a healthier diet, with 31.3% doing so to deal with eating-related side effects and 17.9% due to cancer sites. Regardless of the reasons for changing, the most common food items to result in a decrease in consumption were alcohol, red and processed meats, and sugary drinks. Only 15% of patients reported receiving specific nutrition indication. CONCLUSION: Italian patients are attentive to the importance of diet during cancer treatment. Personal choices reflect some indications for cancer prevention as there is still a shortage of guidelines for a correct diet during treatment. Nutrition indications are rarely given within the oncologic center. PMID- 30005332 TI - The effects of self-regulation strategies following moderate intensity exercise on ad libitum smoking. AB - INTRODUCTION: The purpose of the present study was to examine whether self regulation strategies can further extend the effect of moderate intensity exercise on smoking delay. METHOD: Participants were 40 adult smokers who were randomly assigned into two groups: control and self-regulation. A repeated measures design was adopted including a neutral condition (20 min video) and an exercise condition (20 min moderate intensity exercise). RESULTS: The results showed that smoking delay increased significantly for both groups; however, the increase for the self-regulation group was significantly larger than that of the control group. CONCLUSIONS: The results support the anti-smoking effects of acute exercise; furthermore, they highlight the usefulness of self-regulation strategies, and in particular goal setting, in extending smoking delay. The present findings provide important evidence for the exercise and smoking literature and useful directions for the development of smoking cessation interventions. PMID- 30005333 TI - Frequent solitary drinking mediates the associations between negative affect and harmful drinking in emerging adults. AB - INTRODUCTION: Depression and anxiety are highly comorbid conditions that are associated with harmful drinking. Social learning theory proposes that depressed or anxious individuals learn that drinking can reduce negative affect, which makes them susceptible to harmful drinking. Consistent with theory, evidence suggests that negative affect increases risk for harmful drinking. But, less is known about mediators of negative affect-pathways to harmful drinking. Research has demonstrated that solitary drinking is an underlying mechanism of harmful drinking among emerging adults with high levels of negative affect. However, much of this work is cross-sectional. We conducted a longitudinal study to examine solitary drinking as a key explanatory variable in the negative-affect pathway to harmful drinking. METHODS: Emerging adults (N = 308) completed online self reports of depression and anxiety at Time 1 (the beginning of their first semester in university), and drinking context and harmful drinking at Time 2 (the end of their first semester of university). RESULTS: Structural equation modeling supported indirect effects from negative affect to harmful drinking via solitary drinking. Specifically, emerging adults with high levels of negative affect at the beginning of their first semester engaged in frequent solitary drinking over the rest of the semester, and subsequently experienced increased harmful drinking (controlling for Time 1 solitary/social drinking and harmful use). Social drinking was not a mediator of this effect. CONCLUSIONS: The findings reveal that solitary drinking uniquely mediated the relation between negative affect and harmful drinking. Reducing solitary drinking might mitigate negative affect related risk for harmful drinking in emerging adults. PMID- 30005334 TI - Personality and prescription drug use/misuse among first year undergraduates. AB - Emerging adults (18-25 year olds) endorse the highest rates of prescription drug misuse. Attending college or university may confer additional risk. Previous research suggests that personality is an important predictor of many addictive behaviours. Four traits have been consistently implicated: anxiety sensitivity, hopelessness, sensation seeking, and impulsivity. Published studies on personality as a predictor of prescription drug abuse are limited, however, by a primary focus on overall prescription drug use, inconsistent operationalisation of misuse, and failure to control for alcohol use. Sample sizes have been small and non-specific. We sought to better understand how personality predicted the overall use, the medically-sanctioned use, and the misuse of prescription sedatives/tranquilizers, opioids, and stimulants. A large (N = 1755) sample of first year Canadian undergraduate students (mean age = 18.6 years; 68.9% female) was used. We predicted that: anxiety sensitivity would be related to sedatives/tranquilizers, hopelessness to opioids, sensation seeking to stimulants, and impulsivity to all three. Save for the impulsivity to opioid use path, predictions were fully supported in our "any use" model. For medically sanctioned use: anxiety sensitivity predicted sedative/tranquilizers, hopelessness predicted opioids, and impulsivity predicted stimulants. For misuse: anxiety sensitivity (marginally) predicted sedatives/tranquilizers, sensation seeking predicted stimulants, and impulsivity predicted all three. Our models support using personality-matched interventions. Specifically, results suggest targeting anxiety sensitivity for sedative/tranquilizer misuse, sensation seeking for stimulant misuse, and impulsivity for unconstrained prescription drug misuse. Interventions with early coping skills that pertain to all four traits might be useful for preventing prescription drug uptake and later misuse. PMID- 30005335 TI - Synergistic effects of tumor necrosis factor-alpha and insulin-like growth factor I on survival of human trophoblast-derived BeWo cell line. AB - OBJECTIVE: Trophoblast survival is regulated by cytokines and growth factors. While the pharmacological levels (10-100 ng/mL) of tumor necrosis factor (TNF)- alpha affect trophoblasts survival in vitro, the effects of the physiological levels (1-10 pg/mL) of TNF-alpha remain unknown. We investigated the effects of the physiological levels of TNF-alpha on proliferation and apoptosis of human trophoblast cells by using BeWo cells. Insulin-like growth factor (IGF)-I is also a potent regulator of trophoblast survival and has been known to exert synergistic effects with other hormones. The interaction of IGF-I and TNF-alpha on BeWo cells survival was also examined. METHODS: After incubating BeWo under the presence of TNF-alpha (10-105 pg/mL) and IGF-I (102 ng/mL), we assessed cell number by WST-1 assay and cell proliferation by BrdU uptake assay and immunocytochemistry with anti-Ki67 antibody. Apoptosis was evaluated by TUNEL assay and caspase-3, 8 activity assays. RESULTS: Under the presence of IGF-I, cell number, BrdU uptake, and Ki-67 expression of BeWo were dose-dependently enhanced by low TNF-alpha (10-102 pg/mL), while no such effects were detected without IGF-I. Higher levels of TNF-alpha (104-105 pg/mL) showed inhibiting effects on cell number and cell proliferation. The number of TUNEL positive cells were decreased and caspase activities were suppressed by lower levels (10-102 pg/mL) of TNF-alpha and IGF-I independently. Higher levels of TNF-alpha (104-105 pg/mL) showed promoting effects on apoptosis irrespective of IGF-I. CONCLUSION: The physiological levels of TNF-alpha and IGF-I had synergetic effects on enhancing cell proliferation and also independently inhibited apoptosis of Bewo cells. PMID- 30005336 TI - Age estimation: Cameriere's open apices methodology accuracy on a southeast Brazilian sample. AB - Age estimation plays an important role in clinical and forensic dentistry. Cameriere's 2007 open apices method for age estimation was applied in a sample of 612 digital panoramic orthopantomographs from Brazilian subadult individuals of known age and sex. The sample was composed of 290 males and 322 females individuals aged between four and 16 years of age from Sao Paulo metropolitan area who had undertaken radiographs for clinical purposes. Participant's ethnicity data was not available. An open code computer-aided drafting software (ImageJ) was used to measure the variables according to the author's published guidelines. Subjects' age was firstly estimated under the application of the European formula (2007) showing under-estimation (-1.24yr). On the other hand, the linear regression analysis modeled for this specific population was able to explain 91.2% of the chronological age variation with a standard error of 0.91yr. Residual analyses confirmed independent errors and a normal distribution. In conclusion, the present results support Cameriere's method for age estimation in Brazilian subadults to be a reliable method, although correlations may vary between specific groups and, hence, specific formulae may be useful for an accurate prediction. PMID- 30005338 TI - Aortic dissection in cocaine abuse: A fatal case. PMID- 30005337 TI - Cervical artery dissections: Factors that influence causation determination in litigated cases. AB - In litigated cases, the suspected causes of cervical artery dissections (CADs) are a source of considerable debate among experts. In this study, we sought to examine the factors influencing court decisions and discover how Canadian tribunals analyzed and arbitrated conflicting expert opinions in CAD cases. Cases for this review were identified through searches of the Canadian CANLII database. First, the results of this study show that there is no standardized methodology to assist health care personnel in the processing and interpretation of data in individual cases of CAD. This leads to wide ranges of personal interpretations and opinions which may confuse tribunals. Of concern is the implication of treating physicians who may not have the objectivity to act as expert witnesses when one of their patients is engaged in a legal proceeding. PMID- 30005339 TI - Which mosquitoes (Diptera: Culicidae) are candidates for DNA extraction in forensic practice? AB - Mosquitoes can be of importance in forensic context as a source of the perpretator's DNA. The aim of this study was to find how can we optimize the selection of appropriate mosquito individuals. The study was based on the data of 177833 trapped female mosquitoes and 105236 individuals which were collected directly from human skin. The mean human-specific biting willingness value of Aedes species was the highest (mean: 0.8). Significant differences were found between the human-specific biting willingness value variances of Aedes and Culex (p=0.0117) and barely significant differences between Anopheles and Culiseta (p = 0.5412), as well as between Aedes and Culiseta genera (p = 0.0562). Culiseta species showed the lowest human-specific biting willingness values (mean = 0.16). The mean of the human-specific biting willingness values of univoltine and multivoltine mosquitoes were 0.43 and 0.37 which means no significant difference between the variances of the two groups (p = 0.625). The mean of the human specific biting willingness values of the predominantly mammal biting and non mammal biting mosquitoes were 0.45 and 0.03 with a very significant difference (p<0.0001). Only five mosquito species have a relative biting risk index equal or more than 0.03 in Hungary, namely of Aedes vexans (0.43), Ochlerotatus cantans: (0.25), Ochlerotatus sticticus: (0.11), Culex modestus: (0.07) and Aedes cinereus: (0.03). It can be concluded that the mean human-specific biting willingness of mosquitoes depends on the genera, the host preference and it is independent of the annual number of generations or the breeding habitat preference. The relative biting risk index reflects the actual and annual relative abundances and the usefulness and availability of a mosquito for legal purposes reducing the financial and time requirements of the investigations. PMID- 30005340 TI - Geochemical indices and regression tree models for estimation of ambient background concentrations of copper, chromium, nickel and zinc in soil. AB - Geochemical ratios between elements of environmental concern and Fe have been recommended for estimation of "background" concentrations of Cr, Cu, Ni and Zn in soil. However, little research has occurred to assess the consistency of geochemical ratios across soils developed in different environments. Broad application of generic geochemical ratios could result in under or over estimation of anthropogenic impacts to soil and subsequent inaccurate assessment of risk to the environment. A soil survey was undertaken in Victoria, Australia, including collection of samples (n = 622) from surface (0-0.1 m below ground level) and sub-surface (0.3-0.6 m below ground level) soils, overlying Tertiary Quaternary basalt, Tertiary sediments and Silurian siltstones and sandstones. Samples were analyzed for metals and soil physical and chemical properties (particle size, cation exchange capacity, organic matter and pH). Geochemical correlations between elements in soils from different parent materials and environments were compared against geochemical relationships reported in Australia and internationally. Ratios of Cr and Fe were relatively consistent across parent materials, and comparable to published models for estimation of background Cr. Conversely, ratios between Cu, Ni, and Zn with Fe, were variable between soils developed in different weathering environments and/or soil depths. Alternative regression equations and rule based regression tree models were developed as an improved means for prediction of ambient background Cu, Ni and Zn concentrations in soil. Ambient background concentrations of Ni and Cr were predictable across parent materials and depths, allowing these models to be extended to soils across Australia and potentially internationally. PMID- 30005341 TI - Pesticide fate in cultivated mountain basins: The improved DynAPlus model for predicting peak exposure and directing sustainable monitoring campaigns to protect aquatic ecosystems. AB - Agricultural activities can involve the use of plant protection products (PPPs) and the use of such chemicals can occur near surface waters bodies, thus creating a potential for adverse effects on aquatic ecosystems. In mountain watersheds, where runoff fluxes are particularly rapid due to side slopes, exposure is generally characterized by short but intense concentration peaks. Monitoring campaigns are often inadequate or too expensive to be carried out and modelling tools are therefore vital for exposure assessment and their use is encouraged by current legislation. However, currently adopted models and scenarios (e.g., FOCUS for PPPs) are often too conservative and/or "static" to accurately capture exposure variability, and the need for more realistic and dynamic tools is now one of the major challenges for risk assessment. In a previous work, the new fate model DynAPlus was developed to improve pesticide fate predictions in cultivated mountain basins and was successfully evaluated against chlorpyrifos water concentrations measured in a mountain stream in Northern Italy. However, the need for some model improvements (e.g., the inclusion of dissolved organic matter and macrophytes in water) was highlighted. In this work, DynAPlus was improved by replacing the water-sediment unit with ChimERA fate, a recently-published model capable of predicting bioavailable chemical concentrations in shallow water environments accounting for the presence and temporal variations of particulate/dissolved organic carbon and primary producers. The model was applied to preliminarily characterize the risk associated to the use of four PPPs (two insecticides and two fungicides) in a sub-basin of the Adda River (Valtellina Valley, Northern Italy), surrounded by apple orchards. Results revealed the potential magnitude of exposure peaks for the four PPPs and suggested that monitoring campaigns should prioritize, in the selected case study, chlorpyrifos, etofenprox and fluazinam. The potential role of DynAPlus in providing more realistic exposure predictions for ecological risk assessment, as well as for planning efficient monitoring campaigns and help pesticide management practices, was also stressed. PMID- 30005342 TI - Molecular understanding of the interaction of amino acids with sulfuric acid in the presence of water and the atmospheric implication. AB - Amino acids are important components of atmospheric aerosols. Despite the diversity of amino acids structures, however, the role of amino acids with additional non-characteristic functional groups in new particle formation (NPF) has almost remained unexplored. Herein, the interaction of serine (Ser) and threonine (Thr), which feature a hydroxyl group and differ by a methyl substitution, with sulfuric acid (SA) and up to three water (W) molecules has been investigated at the M06-2X/6-311++G (3df, 3pd) level of theory. The effects of structural differences of amino acids on the structure and properties of clusters were also pointed out. Results show that serine may play more important role in stabilizing sulfuric acid to promote NPF in initial steps compared with threonine, glycine and alanine. Meanwhile, threonine may participate in ion induced nucleation due to the high dipole moment of (Thr) (SA) isomers. Moreover, the effects of structure differences of amino acids can be seen in several aspects. Firstly, methyl substitution and hydroxyl group of amino acids have great influence on the structure of clusters. Secondly, hydrated (Ser) (SA) and (Tur) (SA) clusters could retain water even at low relative humidity, which may due to the hydroxyl group in serine and threonine. In addition, the Rayleigh light scattering intensities of amino acid-containing clusters are higher than trimethylamine, monoethanolamine and oxalic acid-involved counterparts. The effect of carboxyl group and methyl substitution on optical properties of clusters is also discussed. This study may bring new insight into the role of amino acids with additional non-characteristic functional groups in initial steps of NPF. PMID- 30005343 TI - Photodegradation of amitriptyline in Fe(III)-citrate-oxalate binary system: Synergistic effect and mechanism. AB - Fe(III) and carboxylic acids are ubiquitous in surface water and atmospheric water droplets. Numerous documents have reported the photochemistry of Fe(III) carboxylate complexes, typically including Fe(III)-oxalate and Fe(III)-citrate. Our previous study preliminarily showed that oxalate enhances the photoreactivity of Fe(III)-citrate system. Here, we further investigate the synergistic effect of Fe(III)-citrate-oxalate binary system at different conditions with pharmaceutical amitriptyline (AMT) as the model pollutant. In the Fe(III)-oxalate system, the photodegradation of AMT decreased with increasing pH from 3.0 to 8.0. In the Fe(III)-citrate system, the optimal pH for AMT degradation is around 5.0 in the same pH range. For the Fe(III)-citrate-oxalate system, the photodegradation of AMT decreased with increasing pH, indicating the combined effect of both oxalate and citrate on the photoreactivity. The addition of oxalate to the Fe(III) citrate system markedly accelerated the photodegradation of AMT. The Fe(III) carboxylate binary system exhibited excellent photoreactivity and up to 90% AMT was removed after 30 min at pH 6.0 with Fe(III)/citrate/oxalate ratio of 10:150:500 (MUM). Synergistic effect was observed in Fe(III)-citrate-oxalate binary system in the pH range of 5.0-8.0. The presence of oxalate promoted the depletion of citrate in the Fe(III)-citrate system. The higher concentration ratios of oxalate to citrate facilitated the synergistic effect in the Fe(III) citrate-oxalate system. By LC-MS analyses, a possible pathway of AMT degradation was proposed based on hydroxyl radicals (OH) mechanism. This finding could be helpful for the better understanding of synergistic mechanism of Fe(III)-citrate oxalate binary complexes, which will be of great potential application in environmental photocatalysis at near neutral pH. PMID- 30005344 TI - Distribution and contamination status of phthalic acid esters in the sediments of a tropical monsoonal estuary, Cochin - India. AB - Phthalic acid esters (PAEs) are a group of endocrine-disrupting chemicals listed as priority pollutants by United States Environmental Protection Agency (USEPA, 2009). This study provides baseline information on seasonal distribution and contamination status of six phthalic acid esters (?6PAEs) in sediments of a tropical estuary (Cochin-India). In general, the sediments accumulated more PAEs during the post monsoon (mean 2325 ngg-1; between 1402 and 3121 ngg-1) and monsoon (mean 1372 ngg-1; between 331 and 4015 ngg-1) periods indicating land run off as the major transport pathway. Moderate run off and comparatively high residence time lead to effective sorption and settling of PAEs in the surface sediments during post monsoon season. Despite a high discharge of PAEs in to the water column, their deposition on to the sediments occurs at a lower rate during monsoon than that post monsoon season. PAEs were (mean 810 ngg-1; between 44 and 1722 ngg-1) lowest in pre monsoon season. The pre monsoon season is characterized by a minimal runoff consequent to the trapping of these organic pollutants in the river catchment area. The mid and high molecular PAEs (DEHP-Di ethylhexyl phthalate, BBP-Benzyl butyl phthalate and DnBP-Di-n-butyl phthalate) were the dominant congeners relative to the low molecular weight congeners (DMP-Dimethyl phthalate and DEP-Diethyl phthalate). DEHP and BBP levels exceeded permissible risk levels indicating a serious ecological hazard to the estuarine ecosystem. PMID- 30005345 TI - Influence of aromatic structure and substitution of carboxyl groups of aromatic acids on their sorption to biochars. AB - In order to clarify the influence of aromatic structure and COOH substitution of aromatic acids on their sorption to biochars, benzoic acid (BA), phthalic acid (PA), hemimellitic acid (HA), 2-biphenylcarboxylic acid (2-BA), 1-naphthoic acid (1-NA) and naphthalene were selected as model sorbates. Batch experiments on sorption of them to wheat straw-derived biochars at 300 degrees C (WS300) and 700 degrees C (WS700) were conducted. Results showed that WS700 with higher specific surface area and pore volume had faster and higher sorption of aromatic acids than WS300. Sorption affinity of aromatic acids decreased with increasing number of aromatic rings (BA > 1-NA > 2-BA), and was weakened by COOH substitution (BA > PA > HA). This was likely due to the pi-electron delocalization into additional ring, reduced contact area of nonplanar aromatic structure on biochar surfaces, size exclusion of larger molecules in smaller pores of biochars and decreased hydrophobicity of aromatic acids by COOH substitution that abated the sorption. Dissociation of COOH substitution of aromatic acids also weakened their sorption to biochars due to the lower hydrophobicity of anionic species, and electrostatic repulsion between anionic species and negatively charged surface of biochars. PMID- 30005346 TI - PAHs and heavy metals in the surrounding soil of a cement plant Co-Processing hazardous waste. AB - The Chinese government is encouraging domestic cement producers to move from traditional coal power sources to the co-processing of waste as the primary energy source for the industry. In this study, 32 samples collected from the soil surrounding a cement plant in Beijing were analyzed for the presence of 16 U.S. EPA priority polycyclic aromatic hydrocarbons (PAHs) and 12 heavy metals. Ten samples were selected for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) analysis. The pollution distribution patterns, sources, and potential risks to human health and the environment were investigated and evaluated. The highest concentrations of PCDD/Fs occurred 1200 m downwind from the cement plant. The levels of ?16 PAHs ranged from 130.6 to 1134.3 MUg kg-1 in the sampled soils. Source identification analysis suggested that the cement plant was the most likely source of PAH contamination. The concentrations of most of the heavy metals detected in the sampled soils were close to background levels, except for the levels of cadmium (Cd) and mercury (Hg), which were, on average, two times and six times higher than background values, respectively. The co incineration of sludge, coal, and hazardous waste in the cement plant is a major contributing cause for the high levels of Hg in the surrounding soil. Risk assessment models, both the incremental lifetime cancer risks (ILCRs) for PAHs and the potential ecological risk index (RI) for heavy metals, indicate potential risks to the population and the environment surrounding the cement plant. PMID- 30005347 TI - In-situ establishment of binary composites alpha-Fe2O3/Bi12O17Cl2 with both photocatalytic and photo-Fenton features. AB - A set of binary composites alpha-Fe2O3/Bi12O17Cl2 were established through an in situ deposition route and these samples were systematically characterized by a collection of analytical techniques. Scanning electron microscopy, UV-vis diffuse reflectance spectroscopy, and X-ray photoelectron spectroscopy proved the coexistence of expected two components. High resolution transmission electron microscopy and selected-area electron diffraction indicated the formation of heterojunction domains with the intimate contact of both semiconductors. The degradation behavior of as-synthesized samples was evaluated under visible-light irradiation and the enhanced outcome was observed over dye methyl orange (MO) and colorless 2,4-dichlorophenol (2,4-DCP), mainly attributing to favorable optical and morphological merits, and a suitable well-aligned band structure in these binary composites with a suitable phase composition as well. In addition, these composites showed an obvious photo-Fenton feature that significantly improved the catalytic degradation efficiency over 2,4-DCP when the reagent H2O2 was introduced, indicating the destruction efficiency was controlled by a synergtic effect from both photocatalytic and photo-Fenton degradation routes. Based upon the detection of reactive radical species, a primary synergistic mechanism was eventually speculated. PMID- 30005348 TI - Bioaccumulation, tissue distribution and joint toxicity of erythromycin and cadmium in Chinese mitten crab (Eriocheir sinensis). AB - The bioaccumulation of erythromycin (ETM) and cadmium (Cd) in Chinese mitten crab (Eriocheir sinensis) and subsequent toxicity on pathological changes and enzymatic activities were investigated during 21-day exposure to ETM, Cd, and Cd + ETM mixture. The bioaccumulation of Cd and ETM residues in crab tissues decreased as gill > hepatopancreas > muscle > ovary, with higher Cd bioaccumulation than ETM. The highest Cd bioaccumulation in crab reached 1.15 mg/g dry weight in gill and 461.29 MUg/g in hepatopancreas, on the 14th day of Cd treatment. Cd exposure promoted the bioaccumulation of ETM in four tissues. ETM exposure caused tubular vacuolization in epithelial and edema and degeneration of hepatic ducts in hepatopancreas, and disconnected gill epithelial layer and indistinctly cellular structure in gill. During Cd exposure, mitochondria acted as a main biomarker to identify the damage, including reduced and swollen mitochondria, and broken mitochondrial structure. Moreover, Chinese mitten crab showed defence capability against ETM and Cd exposure by physiological adjustment of metabolic enzymes glutathione S-transferase activity. PMID- 30005349 TI - Determination of short-term changes in levoglucosan and dehydroabietic acid in aerosols with Condensation Growth Unit - Aerosol Counterflow Two-Jets Unit - LC MS. AB - Residential areas in urban agglomerations and also in the countryside are often burdened with high concentrations of aerosol in winter, this originating from local combustion sources. Aerosol sources can be identified by a monitoring of organic markers of biomass burning. Abundant markers of biomass and softwood burning are levoglucosan and dehydroabietic acid, respectively. The aim of this research was to develop an analytical method for the determination of levoglucosan and dehydroabietic acid in aerosol over short time periods involving aerosol sampling into liquid samples, quantitative pre-concentration of analytes, and their determination by liquid chromatography - mass spectrometry. A Condensation Growth Unit - Aerosol Counterflow Two-Jets Unit (CGU-ACTJU) sampler was used for the quantitative collection of aerosol directly into water. Dehydroabietic acid was pre-concentrated from the aqueous phase by solid phase extraction (C-18). Afterwards, levoglucosan in water samples was concentrated on a vacuum evaporator. The detection limits of levoglucosan and dehydroabietic acid were 28 ng m-3 and 5.5 ng m-3, respectively. The results obtained by the developed method were compared with an independent determination of both markers in aerosol by means of the sampling of aerosols on a filter and subsequent analysis by GC-MS. The developed method demonstrated sufficient agreement with the independent determination for generated standard aerosol as well as for urban aerosol over an eight-day winter campaign. The presented method allows the monitoring of concentration changes in biomass burning markers in 2-h intervals. PMID- 30005350 TI - Computational calculation identified optimal binding sites in nano-sized magnetic cored dendrimer. AB - Magnetic-cored dendrimers (MDs) with amino groups were prepared with the formation of poly(amidoamine) dendrimer on the surface of magnetite nanoparticles (MNPs). The experiment involved the binding of four different heavy metal ions including Pb (II), Cu (II), Zn (II), and Cr (VI). Density functional theory (DFT) calculation was applied to the experimental results to determine the optimal configurations between the heavy metal species and generation 1 amino (NH2) functionalized MD (G1-NH2-MD). Different binding configurations among the possible binding positions of inner and outer G1-NH2-MD were determined with the ionic radius and coordination number of each heavy metal ion. Although Pb2+ and Zn2+ were stable in the terminal positions, Cu2+ was the most stable in the internal position. The oxygen and hydrogen atoms of HCrO4- formed a hydrogen bond with the NH2 groups, and thus dipole-nonpolar molecular interaction occurred with the CH2 groups of G1-NH2-MD. Specific binding positions and energies of different heavy metal species were identified through the DFT calculation in the study. The DFT calculation results also contributed to an understanding of the binding priority of each metal ions in the mixed solution. Furthermore, Pb2+ was preferably adsorbed in the mixed solution of Pb2+, Cu2+, and Zn2+. PMID- 30005351 TI - Accurate determination of hexabromocyclododecane diastereomers in extruded high impact polystyrene: Development of an analytical method as a candidate reference method. AB - Herein, an isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS) method was developed as a candidate reference method for the accurate quantitation of hexabromocyclododecane (HBCDD) diastereomers in plastics. The repeatability, reproducibility, and uncertainty results showed that developed ID LC/MS/MS method is reliable and reproducible. As homogeneous samples, HBCDD containing extruded high-impact polystyrene (HIPS) pellets were fabricated via an extrusion process. Notably, we detected alpha-, beta-, gamma-, delta-, epsilon-, eta-, and theta-HBCDDs in the extruded HIPS pellets, and then determined their exact mass fractions using the ID-LC-MS/MS method. The relative contents (average +/- standard deviation) of HBCDD diastereomers in HIPS obtained using the phenyl hexyl column were 67.08 +/- 0.41% (alpha-HBCDD), 19.73 +/- 0.37% (beta-HBCDD), 11.59 +/- 0.16% (gamma-HBCDD), and 1.6 +/- 0.07% (sum of delta-, epsilon-, eta-, and theta-HBCDDs). These values differed significantly from the ones determined for the technical HBCDD mixtures (10.42% alpha-HBCDD, 5.30% beta-HBCDD, 82.13% gamma-HBCDD, 2.15% minor HBCDDs) used to fabricate the HIPS pellets and thus demonstrating the HBCDD isomerization during the extrusion. The proportion of minor HBCDDs was smaller than the uncertainty of the total HBCDD and that the sum of alpha-, beta-, and gamma-HBCDDs was comparable to the total HBCDD in the investigated samples. Notably, a real-life sample (expanded polystyrene board obtained from a local construction site) also showed a similar HBCDD profile, being rich in alpha-HBCDD. PMID- 30005352 TI - Toxicity of biomining effluents to Daphnia magna: Acute toxicity and transcriptomic biomarkers. AB - Increasing metal consumption is driving the introduction of new techniques such as biomining to exploit low grade ores. The biomining impacts notably aquatic ecosystems, yet, the applicability of ecotoxicological tests to study the complex mixture effects of mining waters is insufficiently understood. The aim of the present work was to test if transcriptomic biomarkers are suitable and sensitive for the ecotoxicity assessment of biomining affected waters. The study site had been affected by a multimetal biomine, and the studied water samples formed a concentration gradient of contamination downstream from the biomining site. Cadmium and nickel were used as positive controls in the toxicity tests. Selected transcriptomic biomarkers, previously shown to be differentially regulated by metals, were used to evaluate the ecotoxicity of the water samples. Parallel samples were used to compare the transcriptomic biomarkers with the conventional acute D. magna toxicity test. In the acute test, one sample was acutely toxic to D. magna, when pH was adjusted according to the standard, whereas, in the native pH, three samples caused total immobility. Monooxygenase was up-regulated by the highest concentration of Cd in control samples and three of the water samples. Vtg-SOD was up-regulated by one of the water samples, and catalase by the second highest concentration of Cd. The results show that transcriptomic biomarkers in D. magna can be used as sensitive bioindicators for metal mixture toxicity assessment in complex environmental water samples. PMID- 30005353 TI - A combination of ternary classification models and reporter gene assays for the comprehensive thyroid hormone disruption profiles of 209 polychlorinated biphenyls. AB - Computational toxicology is widely applied to screen tens and thousands of potential environmental endocrine disruptors (EDCs) for its great efficiency and rapid evaluation in recent years. Polychlorinated biphenyls (PCBs) with 209 congeners have not been comprehensively tested for their ability to interact with the thyroid receptor (TR), which is one of the most extensively studied targets related to the effects of EDCs. In this study, we aimed to determine the thyroid disrupting mechanisms of 209 PCBs through the combination of a novel computational ternary classification model and luciferase reporter gene assay. The reporter gene assay was performed to examine the hormone activities of 22 PCBs via TR to classify their profiles as agonistic, antagonistic or inactive. Thus, six agonists, eleven antagonists and seven inactive chemicals against TR were identified in in vitro assays. Then, six relevant variables, including molecular structural descriptors and molecular docking scores, were selected for describing compounds. Machine learning methods (i.e., linear discriminant analysis (LDA) and support vector machines (SVM)) were used to build classification models. The optimal model was obtained by using SVM, with an accuracy of 88.24% in the training set, 80.0% in the test set and 75.0% in 10 fold cross-validation. The remaining 187 PCB congeners' hormone activities were predicted using the obtained models. Out of these PCBs, the SVM model predicted 38 agonists and 81 antagonists. The findings revealed that higher chlorinated PCBs tended to have TR-antagonistic activities, whereas lower chlorinated PCBs were agonists. This study provided a reference for further exploring PCBs' thyroid effect. PMID- 30005355 TI - Patient awareness about family planning represents a major knowledge gap in multiple sclerosis. AB - BACKGROUND: The purpose of the survey was to assess the knowledge of family planning issues associated with disease modifying therapies (DMTs) among patients diagnosed with multiple sclerosis (MS). METHODS: 590 Danish MS patients responded to an online questionnaire about family planning in MS, collecting demographics, disease characteristics, disease modifying treatment, knowledge of potential teratogenic effects in DMTs, number of children, occurrence of unplanned pregnancies and outcome, and sources of information. RESULTS: 488 females and 102 males, mean age 40 years, responded. On average, it was 6.5 and 10.9 years since diagnosis and first symptoms, respectively. 16% of female and 19% of male respondents did not receive DMT at the time of responding to the survey. 30% of all had received only one DMT, 37%, 19%, 8%, and 5% had received two, three, four, and five different treatments, respectively. 42% of female and 74% of male respondents said they did not know if the medication they were taking had teratogenic risks. 83% of females and 85% of males responded that they did not know, whether DMT in male MS patients may expose healthy partners to teratogenic risks; hereto, 13% and 10%, respectively, answered that no transmission occurs. On average respondents had two children; three of four children reported in the study were born prior to the respondents being diagnosed with MS. 50% of both female and male respondents without children wanted a family and 25% of females and 16% of males wanted to start a family within the next two years. 91% of female respondents would discontinue DMT during pregnancy. Among male respondents 32% would continue treatment during a partner's pregnancy and 47% did not know whether they would continue or discontinue treatment. 10% of the female patients had had unplanned pregnancies during MS treatment, of these 49% chose to have an abortion. 53% of all felt they were well informed about MS treatment and family planning. 22% and 41% of the respondents received information from the neurologist about teratogenic risks in female MS patients and about teratogenic risks in women with male MS patients as partners, respectively; 27% and 34%% retrieved information from the internet on these two issues. CONCLUSION: This survey uncovered a low level of knowledge about DMTs' teratogenic risks among MS patients irrespective of sex. Knowledge about potential teratogenic risks for male MS patients receiving DMTs while planning to start a family was largely absent. 10% of female patients had experienced unplanned pregnancies on MS treatment. In general, patients use the internet and their neurologist to the same extent for information on parenthood planning. PMID- 30005354 TI - Spatial distribution, mobility and bioavailability of arsenic, lead, copper and zinc in low polluted forest ecosystem in North-western Mexico. AB - A geochemical-environmental mapping was carried for a low polluted forest in North-western Mexico (Santiago Papasquiaro mining area), as part of the North American forests accounting for environmental behavior of arsenic (As), lead (Pb), zinc (Zn) and copper (Cu) in soil and tree components (stem wood and aciculums). Spectroscopic and microscopic techniques along with standard protocols were used to determine the mineralogical phases containing these elements, and their corresponding spatial distributions in soil and forests and mobility. In soil, total As, Pb, Zn and Cu ranged from 4.9 to 98.3, 19.6 to 768.6, 19.6 to 407.1, and 1.6 to 63.8 mg kg-1, respectively. Ultrafine particles (<5-10 MUm) of arsenopyrite and sphalerite (and complex Zn-Fe phase) were the main As and Zn-bearing phases determined by SEM-EDS, respectively. Complex Pb-Cu Fe and Cu-O oxide-like phases were the only ones containing Pb and Cu, respectively. Mobility was low for Pb, Zn and Cu, whereas a significant mobility was assessed for As. Concentrations vs. depth profiles suggested progressive accumulations of As, Pb, Zn and Cu in top soil. Total As, Pb, Zn and Cu in pine stem wood varied from 11.5 to 184.5, 98.9 to 7359.8, 3242.7 to 22197.3, 689.2 to 7179.6 MUg kg-1, respectively. The respective concentrations in the pine needles ranged from 50 to 624.2, 100 to 16353.1, 120 to 46440.9 and 720 to 7200 MUg kg-1, indicating an active bioaccumulation of As, Pb, Zn and Cu. A prospective environmental behavior was discussed for As, Pb, Zn and Cu in the low-polluted forest. PMID- 30005356 TI - Incorporating machine learning approaches to assess putative environmental risk factors for multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) incidence has increased recently, particularly in women, suggesting a possible role of one or more environmental exposures in MS risk. The study objective was to determine if animal, dietary, recreational, or occupational exposures are associated with MS risk. METHODS: Least absolute shrinkage and selection operator (LASSO) regression was used to identify a subset of exposures with potential relevance to disease in a large population-based (Kaiser Permanente Northern California [KPNC]) case-control study. Variables with non-zero coefficients were analyzed in matched conditional logistic regression analyses, adjusted for established environmental risk factors and socioeconomic status (if relevant in univariate screening),+/- genetic risk factors, in the KPNC cohort and, for purposes of replication, separately in the Swedish Epidemiological Investigation of MS cohort. These variables were also assessed in models stratified by HLA-DRB1*15:01 status since interactions between risk factors and that haplotype have been described. RESULTS: There was a suggestive association of pesticide exposure with having MS among men, but only in those who were positive for HLA-DRB1*15:01 (OR pooled = 3.11, 95% CI 0.87, 11.16, p = 0.08). CONCLUSIONS: While this finding requires confirmation, it is interesting given the association between pesticide exposure and other neurological diseases. The study also demonstrates the application of LASSO to identify environmental exposures with reduced multiple statistical testing penalty. Machine learning approaches may be useful for future investigations of concomitant MS risk or prognostic factors. PMID- 30005357 TI - Limbic encephalitis associated with systemic sclerosis. AB - We report the case of a patient affected by systemic sclerosis (SSc) who developed autoimmune limbic encephalitis, which improved under immunosuppressant agents and high-dose intravenous immunoglobulins. In our patient the autoimmune encephalitis occurred during apparently quiescent SSc, though concomitantly with novel arthritis. Moreover, our patient showed auto-antibodies directed against SSA antigen but the panel of auto-antibodies associated with autoimmune encephalitis was negative. We discuss the potential for immunopathogenic inflammatory events affecting the central nervous system in SSc then favoring the occurrence of autoimmune encephalitic disorders. The possibility of a "neuro scleroderma" may have important consequences in terms of therapeutic approaches. PMID- 30005358 TI - A stable zinc(II)-mediated base pair in a parallel-stranded DNA duplex. AB - A stable zinc(II)-mediated base pair was formed within a parallel-stranded DNA duplex comprising a GNA (glycol nucleic acid) functionalized nucleoside analog containing the artificial nucleobase 1H-imidazo[4,5-f][1,10]phenanthroline (P). The formation of the metal-mediated base pair was confirmed by UV and CD spectroscopic analyses. In the Zn(II)-mediated homo base pairs of the type P Zn(II)-P, the metal ion adopts a [2 + 2] coordination environment. CD spectroscopic data suggest that the chiral metal complex is formed enantiospecifically, likely induced by the helical chirality of the surrounding DNA duplex. The Zn(II)-mediated base pair stabilizes the DNA oligonucleotide duplex by 9 degrees C. This stable Zn(II)-mediated base pair within a parallel stranded duplex extends the scope of site-specific functionalization of nucleic acids by virtue of metal-mediated base pairing. PMID- 30005359 TI - Engineering virus resistance via CRISPR-Cas systems. AB - In prokaryotes, CRISPR/Cas adaptive immunity systems target and destroy nucleic acids derived from invading bacteriophages and other foreign genetic elements. In eukaryotes, the native function of these systems has been exploited to combat viruses in mammals and plants. Rewired CRISPR/Cas9 and CRISPR/Cas13 systems have been used to confer resistance against DNA and RNA viruses, respectively. Here, we discuss recent approaches employing CRISPR/Cas systems to combat viruses in eukaryotes, highlight key challenges, and provide future perspectives. Moreover, we discuss the application of CRISPR/Cas systems in genome-wide screens to identify key host factors for virus infection to enhance our understanding of basic virus biology and to identify and study virus-host interactions. PMID- 30005360 TI - Hypersensitivity to orthopaedic implant manifested as erythroderma: Timing of implant removal. AB - INTRODUCTION: Incidence of hypersensitivity to orthopaedic implant, once estimated in less than 1% of population, recently has increased to 10%. Controversies about the timing of implant removal remain, especially due to the fact that implant hypersensitivity may be a contributing factor to implant failure. We present a case report and literature reviews to establish the decision making for the timing of implant removal in the presence of implant hypersensitivity. PRESENTATION OF CASE: Female, 42 years old with nonunion of mid shaft tibia and fibula which was treated with ORIF with conventional SAE16 stainless steel plate and bone graft. A week after, she developed a generalized rash, which is later diagnosed as erythroderma, that relapsed despite adequate systemic corticosteroid. Poor healing of surgical site wound were marked. After the implant removal, the cutaneous condition improved and no relapse were found. DISCUSSION: Management of hypersensitivity to implants involved corticosteroid administration, removal or replacement of implants, or implants coating with polytetrafluoroethylene. Currently there are no specific guidelines regulating the management of implant allergy based on the timing of the onset, especially in fracture cases. The decision-making would be straightforward if union was already achieved. Otherwise, controversies would still occur. In this paper, we proposed an algorithm regarding the steps in managing metal allergy due to implant in fracture cases. CONCLUSION: Despite the concerns regarding implant survival in hypersensitivity cases, the decision whether the implant should be removed or replaced should be based on the time and condition of the fracture healing process. PMID- 30005361 TI - Laparoscopic repair with cone-shaped mesh implantation for perineal hernia occurred after laparoscopic abdominoperineal resection. AB - INTRODUCTION: Perineal hernia after abdominoperineal resection (APR) is a rare complication, and no standard surgical procedures are established. We describe a simple laparoscopic mesh implantation technique utilizing a large synthetic flat mesh. PRESENTATION OF CASE: We report a case of perineal hernia after APR. We performed laparoscopic repair using a soft and large synthetic mesh with simple technique. The essence of this technique is that mesh is inserted into the abdominal cavity without trimming and it forms in a conical shape to better adjust to the pelvic cavity. DISCUSSION: The perineal and laparoscopic approaches for perineal hernia repair have been performed most commonly in recent years, but the recurrence rate after repair remains high (24.1%). Using a large mesh could cover the hernial orifice with a sufficient margin, reducing a risk of recurrence caused by shrinkage and slippage of the mesh. CONCLUSION: Our technique utilizing a large, lightweight, synthetic mesh can be practical and useful for perineal hernia repair after laparoscopic APR. PMID- 30005362 TI - Handlebar hernia - A rare complication from blunt trauma. AB - INTRODUCTION: Handlebar hernias are rare; they result from blunt force impacting the abdomen. This focal blunt trauma causes a tear of the underlying abdominal muscle and fascia without necessarily disrupting the skin. The site of the hernia is usually remote from the site of trauma so clinicians may be falsely reassured if they locally explore the site of bruising. The physical examination of such patient may not obviously suggest such an injury and the diagnosis can be easily missed. CASE PRESENTATION: A fit and well 10-year-old boy presented to the emergency department with left sided abdominal pain following a pushbike accident. He fell from his bicycle resulting in an impact of the handlebar to the left side of his abdomen. No obvious hernia was found on physical examination but there was a circular-shaped bruise in the left lower quadrant. An abdominal CT scan was then performed and the unusual diagnosis of a handlebar hernia was made. A prompt laparoscopic herniorrhaphy was performed and his post-operative recovery was uneventful. DISCUSSION: A high level of suspicion is required to diagnose handlebar hernias. Even relatively low-speed trauma can result in this insidious injury. Laparoscopic repair has been demonstrated to be successful in this case. CONCLUSION: Despite being a rare entity, handlebar hernias should be suspected when significant blunt force is applied to the abdominal wall from a handle bar injury. They may not be obvious on physical examination and therefore further imaging is often important. Management involves prompt surgical repair to prevent complications. PMID- 30005364 TI - Perforated diverticulitis in the setting of ulcerative colitis: An unusual case report. AB - INTRODUCTION: The association of diverticulitis with ulcerative colitis (UC) is rare and not well described. The sequelae of inflammatory bowel disease (IBD) such as perforation and fistula formation can mimic diverticular complications. Therefore, in an IBD patient, it can be difficult to distinguish the etiology of such complications and render definitive care. PRESENTATION OF CASE: A 43-year old man with a long history of UC presented with spontaneous sigmoid perforation and subsequent complications of colovesicular and colocutaneous fistulae requiring multiple procedural interventions. Ultimately, the etiology was confirmed as perforated diverticulitis superimposed on severe ulcerative colitis. DISCUSSION: As perforated diverticulitis superimposed on UC is a rare entity in the current literature and there are many diagnostic difficulties that complicate this scenario. It is important to rule out other entities such as misdiagnosis of IBD or segmental colitis associated with diverticula (SCAD) that may have overlapping features. CONCLUSION: Although diverticulitis in the setting of UC is an uncommon presentation, it remains important for medical practitioners to consider this scenario when encountering patients who may present in a similar fashion. As such, we put forth a process to aid in a diagnosis and management such that definitive care may not be delayed. PMID- 30005363 TI - Successful treatment of hepatic gas gangrene by open drainage: A case report and review of the Japanese literature. AB - INTRODUCTION: Liver gas gangrene is rare and has a low prognosis. This case, reports a successful treatment of hepatic gas gangrene using an open drainage technique, followed by antibiotics and hyperbaric oxygen therapy (HBO). PRESENTATION OF THE CASE: An 82-year-old male with a history of left hepatectomy and bile duct resection for hilar cholangiocarcinoma presented with chilling, lethargy and dyspnea. He had a history of diabetes mellitus, hypertension, atrial fibrillation, and angina pectoris. Physical examination revealed scleric icterus, right hypochondrium tenderness and percussion tenderness of the liver, with warm extremities. Laboratory findings revealed leukocytosis and increased levels of hepatobiliary enzymes. A computed tomography (CT) scan showed gas accumulation in an S8 lesion with portal vein gas. Percutaneous drainage was performed immediately, and broad-spectrum antibiotics were started, but the drainage was insufficient. Consequently, laparotomy drainage was carried out, followed by HBO. No abscess was detected at one-year of follow-up. DISCUSSION: Hepatic gas gangrene progresses rapidly and has a high mortality rate. Malignant disease and diabetes mellitus may be predisposing factors. While half of non-clostridial cases survive, most cases of hepatic gas gangrene are associated with clostridial infection and have a fatal outcome. CONCLUSION: All survival cases of hepatic gas gangrene were treated by laparotomy drainage, thus immediate laparotomy seems essential to prevent a fatal outcome. PMID- 30005365 TI - Left colic artery-preserving D3 lymphadenectomy using near-infrared spectroscopy was effective for double advanced cancers of the transverse colon and rectum: A case report. AB - INTRODUCTION: Exact assessment of intestinal viability is necessary, since the risk of anastomotic complications increases due to the reduction in anastomotic blood supply. Near-infrared spectroscopy is useful in assessing blood flow because it allows real-time monitoring and quantifying of tissue oxygen saturation. Herein, we report a case in which two intestinal resections were performed safely by using near-infrared spectroscopy to evaluate the blood flow at the anastomotic sites. PRESENTATION OF CASE: A 67-year-old man was diagnosed with multiple cancers of the transverse colon and rectum. Laparoscopic transverse colon resection and low anterior resection were performed along with left colic artery-preserving lymphadenectomy, including tissues around the origin of the inferior mesenteric artery. After mesenteric dissection, the tissue oxygen saturation of the proximal side and distal side stumps were 93% and 87%, respectively. The tissue oxygen saturation of the anastomotic proximal side after mesenteric dissection was 76%, thus confirming sufficient blood flow. DISCUSSION: Performance of transverse colon resection and low anterior resection for multiple cancers of the transverse colon and rectum resulted in blockage of the blood flow to the descending colon; therefore, it was necessary to preserve the blood flow to the descending colon by preserving the left colic artery. Near-infrared spectroscopy was used to evaluate blood flow to the anastomotic sites, in order to perform the surgery safely. CONCLUSION: Near-infrared spectroscopy is a safe, simple and low-cost method for assessing blood flow intraoperatively in conjunction with left colic artery-preserving surgery. PMID- 30005366 TI - Pseudolymphoma with atrophic parenchyma of the liver: Report of a case. AB - INTRODUCTION: Pseudolymphoma of the liver is a very rare disease. It is usually resected and pathologically diagnosed because of the difficulty of discrimination from the malignant neoplasm. For this reason, few cases which were observed for several years have been reported. We present a case of this disease observed and slightly enlarged for two years. PRESENTATION OF CASES: The patient was a 46-year old woman who underwent laparoscopic partial nephrectomy for right renal cell carcinoma two years ago. The preoperative computed tomography (CT) showed the mass 7 mm in diameter with localized parenchymal atrophy of the liver (segment VI). Two years later, CT showed enlarged mass from 7 to 11 mm in diameter. We performed laparoscopic partial hepatectomy because the patient desired definite diagnosis by surgery. The resected specimen showed white and solid mass. The lymphocyte and plasma cells are histologically observed. Immunohistological staining showed CD10 positive, Bcl-2 negative, and cyclin D1 negative. The pathological diagnosis was pseudolymphoma of the liver. DISCUSSION: Pseudolymphoma is rarely observed in the liver. It is reported that chronic hepatitis, collagen diseases, and malignant diseases were often accompanied, but detail pathogenesis has been unknown. She had the history of renal carcinoma, but the lesion was not vanished regardless of clearance of renal neoplasm. Surgical resection is usually performed because discrimination with malignant neoplasm is difficult. The present case is probably the first one, which is followed for long term duration. CONCLUSION: The present case may contribute to clarify the pathophysiology of this entity. PMID- 30005367 TI - Isolated primary subcutaneous hydatid in right hypochondrium region: Case report. AB - INTRODUCTION: Hydatid cyst (HC) disease is a serious health problem in endemic areas, solitary primary subcutaneous hydatid cyst is not frequent and the only symptom is generally a silent growing mass. Total excision remains the mainstay of treatment. The aim of the study was to present a case surgically treated. CASE PRESENTATION: 48-year-old female farmer presented with HC of the right hypochondrium who was managed surgically. DISCUSSION: The mechanism of primary subcutaneous localization is unclear. There are two potential mechanisms; (a) direct subcutaneous contamination through an injured skin or (b) subcutaneous colonization of ingested eggs after passing liver and lungs. I believe that subcutaneous colonization of the parasite in the circulation after ingestion is an only reliable mechanism than the other contact theory, because of the cases in literature occur without any direct contamination. CONCLUSION: Primary subcutaneous hydatid cyst must always be considered in the differential diagnosis of silent growing mass in soft tissues or subcutaneous. History and physically associated with ultrasound and magnetic resonance imaging are sufficient to achieve a correct preoperative diagnosis. PMID- 30005368 TI - Waiting and working for rewards: Attention-Deficit/Hyperactivity Disorder is associated with steeper delay discounting linked to amygdala activation, but not with steeper effort discounting. AB - OBJECTIVE: Children and adolescents with ADHD have a relatively strong preference for smaller immediate rewards over larger delayed rewards (steep delay discounting). It is unknown whether such steep discounting of rewards is specific for delayed rewards, i.e., supporting the delay aversion account of ADHD, or whether it is also present for effortful rewards, i.e., representing general reward insensitivity. Therefore, this study examined behavioral and BOLD responses during delay discounting (DD) and effort discounting (ED) in ADHD. METHOD: Thirty adolescents with ADHD and 28 controls (12-17 years) were scanned while performing a DD-ED task (fMRI findings were based on 21 and 25 participants, respectively). During DD, participants were presented with a series of choices between a small reward delivered immediately and a larger reward delivered after 5-25s. During ED, participants were presented with choices between a small reward that was delivered after exerting 15% of their maximal hand grip strength and a larger reward delivered after exerting 30-90% of their strength. RESULTS: Analyses on the subjective values of delayed and effortful rewards and on the Area Under the discounting Curves (AUCs) indicated that adolescents with ADHD showed steeper discounting than controls for DD, but not for ED. This was accompanied by a slightly stronger delay dose-response relationship in the amygdala for adolescents with ADHD who reported to be more delay averse in daily life. CONCLUSION: Together, these results-steeper DD in the ADHD group and a stronger delay dose-response relationship in the amygdala, while no evidence for group differences in ED was found-support the delay aversion account of ADHD. PMID- 30005370 TI - Diminished facial EMG responses to disgusting scenes and happy and fearful faces in Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder associated with impaired facial emotion recognition and altered subjective experience of emotion. These impairments likely result from the effects of the disease on underlying neurobiological mechanisms. Studies using self-report to examine emotional experiences have been ambiguous regarding whether experiences are diminished or exaggerated, possibly due to cognitive impairment and lack of insight in HD. To infer affective states more objectively and overcome the limitations of self report, we used facial EMG to measure muscle responses to emotionally-evocative scenes. Further, we examined muscle responses to emotionally-expressive faces, because facial mimicry is thought to facilitate emotion recognition and social affiliation. Twenty-three HD participants (late pre-manifest and early symptomatic) were compared to twenty-five healthy controls in a scene condition and a face condition. EMG activity was measured from facial muscles associated with expressing particular emotions: 1) corrugator supercilii for anger, 2) frontalis for fear, 3) levator labii for disgust, and 4) both zygomaticus major and orbicularis oculi for happiness. Compared to controls, HD participants showed diminished responses to disgusting scenes, and to happy and fearful faces. Our findings provide evidence for a loss of disgust experience in HD. Further, consistent with the alleged affiliative function of facial mimicry, diminished mimicry responses may be relevant to social-emotional changes in HD. Our findings help understand the neural mechanisms underlying emotion processing impairments in HD. PMID- 30005369 TI - Reaffirming the link between chronic phantom limb pain and maintained missing hand representation. AB - Phantom limb pain (PLP) is commonly considered to be a result of maladaptive brain plasticity. This model proposes that PLP is mainly caused by reorganisation in the primary somatosensory cortex, presumably characterised by functional degradation of the missing hand representation and remapping of other body part representations. In the current study, we replicate our previous results by showing that chronic PLP correlates with maintained representation of the missing hand in the primary sensorimotor missing hand cortex. We asked unilateral upper limb amputees to move their phantom hand, lips or other body parts and measured the associated neural responses using functional magnetic resonance imaging (fMRI). We confirm that amputees suffering from worse chronic PLP have stronger activity in the primary sensorimotor missing hand cortex while performing phantom hand movements. We find no evidence of lip representation remapping into the missing hand territory, as assessed by measuring activity in the primary sensorimotor missing hand cortex during lip movements. We further show that the correlation between chronic PLP and maintained representation of the missing hand cannot be explained by the experience of chronic non-painful phantom sensations or compensatory usage of the residual arm or an artificial arm (prosthesis). Together, our results reaffirm a likely relationship between persistent peripheral inputs pertaining to the missing hand representation and chronic PLP. Our findings emphasise a need to further study the role of peripheral inputs from the residual nerves to better understand the mechanisms underlying chronic PLP. PMID- 30005371 TI - Dorsal and ventral visual stream contributions to preserved reading ability in patients with central alexia. AB - We investigated the role of the left temporo-parietal regions in supporting reading abilities of 23 patients with central alexia (CA). For the behavioural data, we employed principal components analysis (PCA), which identified two components: 'reading aloud' and 'reading for meaning'. Voxel-based morphometry of the PCA results showed an association between reading aloud and grey matter density in the left supramarginal gyrus, part of the dorsal visual stream. By contrast, reading for meaning was associated with a large cluster in the left ventral visual stream, from the collateral sulcus to the anterior temporal pole. Most of the peaks were within the group lesion map, indicating that sparing of these areas results in better preservation of reading ability. However, one white matter (WM) cluster in the medial occipitotemporal lobe was outside the lesioned area. A post-hoc test demonstrated that WM density here was equivalent to controls, suggesting that this was not driven by lesion effects. The two likeliest explanations for this correlation are: 1) that pre-morbid, inter individual differences in brain structure mitigate the effects of CA; 2) that post-morbid practice-based with reading caused compensatory plasticity. We hope to adjudicate between these explanations with longitudinal therapy data collected in this cohort. PMID- 30005372 TI - Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice. AB - Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1-10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1alpha induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1alpha, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC 1alpha, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD. PMID- 30005373 TI - Impact of antipsychotic treatment on methylation status of Interleukin-6 [IL-6] gene in Schizophrenia. AB - Immunopathogenesis of schizophrenia has emerged as one of the predominant research paradigms in recent times. Based on the altered serum levels as well as gene expression, IL-6 has been considered as a peripheral biomarker of schizophrenia. However, the precise mechanism underlying the altered expression of IL6 in schizophrenia is inadequately known. Given the profound influence of environmental factors on schizophrenia risk, it is important to understand the effect of epigenetic changes on schizophrenia risk. Further, it is not known whether epigenetic changes modulate the expression of IL6 and its subsequent effects on the risk and progression of schizophrenia. In this study, we analysed and compared the methylation status of IL6 promoter sequence from -1200bp to +27bp in antipsychotic-naive/free schizophrenia patients (N = 47) and matched healthy controls (N = 47) using bisulfite sequencing method. In addition, we also examined the methylation status in these patients at least after 3-months of treatment with antipsychotics (N = 40). At baseline, a state of hypomethylation was observed in the IL6 promoter of schizophrenia subjects in comparison to healthy controls. This state of hypomethylation was shown to be reversed by the administration of antipsychotics. In summary, our observations emphasize a significant role for IL-6 promoter methylation in schizophrenia pathogenesis as well as treatment with antipsychotic medications. PMID- 30005374 TI - Mechanisms of the bactericidal effects of nitrate and nitrite in cured meats. AB - For cured meat products, nitrite is recognized for its antimicrobial effects against pathogenic bacteria, even though the specific inhibitory mechanisms are not well known. Nitrite contributes to oxidative stress by being the precursor of peroxynitrite (ONOO-), which is the major strong oxidant. Thus, bacterial stress (highly pH-very low partial pressure of oxygen-dependent) is enhanced by the nitrate-nitrite-peroxynitrite system which is also highly pH- and low partial pressure of oxygen-dependent. Nitrite is a hurdle technology which effectiveness depends on several other hurdle technologies including sodium chloride (accelerating the autoxidation of oxymyoglobin and promote peroxynitrite formation), ascorbate (increasing ONOO- synthesis), and Aw. In this environment, certain species are more resistant than others to acidic, oxidative, and nitrative stresses. The most resistant are gram-negative aerobic/facultative anaerobic bacteria (Escherichia coli, Salmonella), and the most fragile are gram positive anaerobic bacteria (Clostridium botulinum). This position review highlights the major chemical mechanisms involved, the active molecules and their actions on bacterial metabolisms in the meat ecosystem. PMID- 30005375 TI - Target-triggered three-way junction in conjugation with catalytic concatemers functionalized nanocomposites provides a highly sensitive colorimetric method for miR-21 detection. AB - With the great advances in DNA nanotechnology, scientists have shown interest in developing dynamic nanostructures for theranostic applications, analyte sensing and cargo delivery. Here, we present a specific enzyme-free ultrasensitive platform based on a multilayer coupled signal amplification strategy to quantify miR-21 molecule. The biosensor was integrated based on three signal amplification gadgets, namely a translator-mediated catalytic hairpin assembly (CHA), a multilayer DNA concatemer on the surface of gold decorated magnetic nanoparticle (GMNP), and a DNAzyme-mediated catalytic signal amplification. MiR-21 mediates the release of a DNA translator from an immobilized duplex to engage in a CHA reaction using three hairpins, including a GMNP-conjugated hairpin 1 (H1), biotin labeled hairpin 2 (H2) and a GMNP-conjugated hairpin 3 (H3) to form a three-way junction (3WJ). Meanwhile, a plenty of initiator strand 0 (S0) on GMNPs - each of which has been bifunctionalized with S0/H1 or S0/H3 - drive several multilayer peroxidase-mimicking DNAzyme concatemers in the presence of two accessory oligonucleotides; strand 1 (S1) and strand 2 (S2). Since a G-rich sequence was attached at the 5'-end of S1 strand, in the presence of hemin cofactor, an active G-quadruplex DNAzyme with peroxidase activity was formed. The concatemers on the surface of GMNPs can convert a colorless substrate to a green product. The biosensor can detect as low as 1 aM of miR-21 and provide an excellent capability to discriminate single-base mismatches. The required time for the formulation of the assay reagents is about three days and the reaction time for the detection of miR-21 takes place in less than four hours. PMID- 30005376 TI - A competitive photoelectrochemical immunosensor for the detection of diethylstilbestrol based on an Au/UiO-66(NH2)/CdS matrix and a direct Z-scheme Melem/CdTe heterojunction as labels. AB - A novel photoelectrochemical (PEC) bioassay protocol for diethylstilbestrol (DES) was systematically proposed. The Au/UiO-66(NH2) hybrid with countless active sites was fabricated using an in situ reduction strategy and was subsequently decorated with CdS nanoparticles (NPs) by a sequential chemical bath deposition process. The resulting Au/UiO-66(NH2)/CdS composites were exploited as a sensing matrix for the first time. The excellent photocurrent response of the as-prepared hybrid under visible light is attributed to its improved photo-electric conversion efficiency due to the local surface plasma resonance (LSPR) effect of Au and the matching energy-level structure between UiO-66(NH2) and CdS. In addition, the competitive strategy for the detection of DES was devised by employing the direct Z-scheme Melem/CdTe heterojunction covalently conjugated with bovine serum albumin (BSA)-DES as signal tags. As a consequence, a cascade like band-edge level was obtained, which could effectively promote the transfer of photogenerated charges and markedly improve the photocurrent. On the basis of the above strategy, the concentrations of DES could be detected through the competitive binding of DES antibodies (Anti-DES) with either Melem/CdTe/BSA-DES or free DES. Under optimal conditions, the linear range for the detection of DES was 0.1 pg mL-1 to 20 ng mL-1. The detection limit was as low as 0.06 pg mL-1 (S/N = 3). Furthermore, the designed PEC DES-sensing approach has acceptable selectivity, reproducibility, and stability and offers great promise for the detection of small molecules in biomedical, food and environmental samples. PMID- 30005377 TI - Fast and sensitive isothermal DNA assay using microbead dielectrophoresis for detection of anti-microbial resistance genes. AB - Antimicrobial resistant pathogens are a growing worldwide threat to human health. This study describes a novel method for rapid and sensitive detection of antimicrobial resistance (AMR) genes, specifically blaCTX-M-15 which encodes for the enzyme that offers resistance to extended spectrum beta-lactam antibiotics. The method combines isothermal DNA amplification by recombinase polymerase amplification (RPA), with microbead dielectrophoresis (DEP)-based DNA detection. The RPA amplicon is captured onto dielectric microbeads, and the amount of amplicon determined by dielectrophoretic impedance measurement (DEPIM) of the microbeads. Amplicon-labeled microbeads were prepared by either a two-step or one step method. A purified recombinant plasmid containing blaCTX-M-15 and genomic DNA (with plasmid) extracted from an AMR bacteria (Escherichia coli NCTC 13441) were used as target samples. A one-step method in which RPA and DNA immobilization on the microbeads is carried out simultaneously, has a detection limit of 2 copies/reaction for pure plasmid and 50 copies/reaction for genomic DNA. The assays are quantitative with a dynamic range up to 105 copies/reaction, with a total detection time of 26 min. Both methods are easy, rapid, and unlike lateral flow detection are quantitative. PMID- 30005378 TI - Photoelectrochemical biosensing of disease marker on p-type Cu-doped Zn0.3Cd0.7S based on RCA and exonuclease III amplification. AB - In this work, a new "signal-on" split-type photoelectrochemical (PEC) sensing platform for prostate-specific antig e n (PSA) detection was successfully constructed using p-type Cu-doped Zn0.3Cd0.7S as the photosensitive semiconductor material and target-triggered rolling circle amplification (RCA) for signal amplification. The signal derived from Cu-doped Zn0.3Cd0.7S was amplified by hemin/G-quadruplex. Upon target PSA introduction, the aptamer-primer probe (apt pri) was captured by capture antibody-conjugated magnetic bead (MB-mAb) to form the sandwiched MB-mAb/PSA/apt-pri. The complex could initiate the RCA reaction to produce a long single-stranded DNA that provided binding sites for G-rich DNA and to form long single-stranded DNA/G-quadruplex/hemin. Upon the addition of exonuclease III (Exo III), the hemin/G-quadruplex immobilized on the RCA long product could be released by the digestion of Exo III. The hemin/G-quadruplex complexes in this study were used as efficient electron acceptors to neutralize the photoelectrons generated from the semiconductor and hindered the recombination of charges, thus enhancing the photocurrent. Under the optimum conditions, the developed sensing system displayed a good analytical performance with a linear range of 0.05-40 ng mL-1 PSA and a detection limit of 16.3 pg mL-1. Furthermore, good selectivity, high anti-interference ability, satisfactory reproducibility, and good accuracy were also achieved. These prominent analytical properties revealed that our strategy might be a potential and reliable tool for the detection of PSA. PMID- 30005379 TI - Salt-templated three-dimensional porous carbon for electrochemical determination of gallic acid. AB - We report an electrochemical sensor based on three-dimensional porous amorphous carbon (3DPAC) for the sensitive and selective determination of gallic acid (GA). The tailor-made carbon was prepared via salt-templating in which the organic molecular precursor, i.e., glucose, was simply ground and carbonized with a eutectic mixture of LiBr and KBr at 800 degrees C in an inert atmosphere. Salt removal from the carbon-salt mixture with water yielded 3DPAC with a hierarchical porous structure and oxygen-containing functional groups. When employed as an electrochemical sensor, 3DPAC exhibited remarkable sensitivity (0.1045 uA pM-1 cm 2) with a lower detection limit of 0.434 pM at a signal-to-noise ratio of 3 and a linear response up to 1-150 pM for determination of GA. Under optimized test conditions, 3DPAC showed a superior peak current response for GA as compared to the glassy carbon electrode. In addition, ascorbic, uric, and caffeic acids did not interfere with the voltammetric detection of GA in terms of selectivity, stability, and repeatability. We envision that 3DPAC can provide a promising platform for the development of electrochemical sensors. PMID- 30005380 TI - Analyte induced AuNPs aggregation enhanced surface plasmon resonance for sensitive detection of paraquat. AB - Paraquat (PQ) residue is harmful for people's health. This work fabricated an efficient approach to determine PQ sensitively. We exploited a novel surface plasmon resonance (SPR) detection system based on the analyte induced network architecture of supermolecules modified gold nanoparticles (AuNPs) on the chip surface. para-Sulfonatocalix[4]arene (pSC4) were used as a recognition molecule for paraquat. PQ can mediate the aggregation of pSC4 capped AuNPs (pSC4-AuNPs) through the host-guest recognition, which can be used as signal amplification for PQ assay. This achievement is due to several outstanding properties of this detection system: first, local SPR and high refractive index of AuNPs can enhance the signal of SPR dramatically; second, AuNPs is more stable and biocompatible and diffusely used in colorimetric methods; third, the network AuNPs structure has unique photo characterization for enhancement of SPR. Analyte induced AuNPs aggregation amplified SPR assay shows dramatic signal enhancement ability. The detection limit for PQ was found to be 2.2 pM This strategy provides a new concept for developing sensitive SPR sensors for the highly selective detection of small molecules. PMID- 30005381 TI - Multiplexed detection of DOCK8, PGM3 and STAT3 proteins for the diagnosis of Hyper-Immunoglobulin E syndrome using gold nanoparticles-based immunosensor array platform. AB - Multiplexed biosensors hold great promise for early diagnosis of diseases where the detection of multiple biomarkers is required. Hyper Immunoglobulin E syndromes (HIES) are rare primary immunodeficiency disorders associated with mutations either in the signal transducer and activator of transcription 3 (STAT3), dedicator of cytokinesis 8 DOCK8) or phosphoglucomutase 3 (PGM3) genes. Yet, the diagnosis of HIES is challenged by the complexity of the existing laboratory assays. Here, we report for the first time the development of a multiplexed electrochemical immunosensor for the simultaneous detection of DOCK8, STAT3 and PGM3 proteins. The immunosensor was constructed on carbon array electrodes that were first modified by electrodeposition of gold nanoparticles (AuNPs). The array electrodes were then used to immobilize specific antibodies for the three proteins after the functionalization of the electrodes with cysteamine/glutaraldehyde linkers. The simultaneous detection of the DOCK8, PGM3 and STAT3 proteins was successfully realized by the immunosensor with respective limits of detections of 3.1, 2.2 and 3.5 pg/ml. The immunosensor has shown good sensitivity as well as selectivity against other proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and Duchenne Muscular Dystrophy (DMD). Moreover, the immunosensor was successfully applied in human serum samples showing capability to distinguish the HIES from the control samples. PMID- 30005382 TI - Electrochemical ELISA-based platform for bladder cancer protein biomarker detection in urine. AB - A novel fluidic-based electrochemical ELISA platform is descried for estimation of the bladder cancer protein markers nuclear mitotic apparatus protein 1 (NUMA1) and complement factor H-related 1 (CFHR1). The platform uses an off-site chamber for a sandwich immunoassay and performs the electrochemistry on-chip in a separate chamber. The off-site matrices were connected to the sensor chip in a manner that the sensors were exposed only to the final electroactive product for signal detection, thus avoiding interference from other molecules present in the sample. Two off-site matrices using 3D polymethyl methacrylate (PMMA) sheets and 2D polycarbonate (PC) membranes modified with the desired antibodies were investigated. Antibodies for NUMA1 and CFHR1 were utilized for the immunoassay and hair comb structured gold electrodes were used for sensing. Results in 10% synthetic urine reveal that the system can detect NUMA1 and CFHR1 in the 1-100 ng/ml range with high sensitivities of 260 nA/(ng/ml) and 310 nA/(ng/ml), for NUMA1 and CFHR1, respectively; negligible interference from the diluted urine and other molecules has been observed. A fully automated fluidic prototype has also been developed to demonstrate that automation of the process and multiplexing of detection can be achieved in a small footprint benchtop device. The use of off site matrix-based platforms paves the way towards a new generation of electrochemical immunosensors for biomarker estimation with negligible non specific interactions and false signals in complex samples. PMID- 30005383 TI - High-performance bioelectronic tongue using ligand binding domain T1R1 VFT for umami taste detection. AB - Numerous efforts have been made to measure tastes for various purposes. However, most taste information is still obtained by human sensory evaluation. It is difficult to quantify a degree of taste or establish taste standard. Although artificial taste sensors called electronic tongues utilizing synthetic materials such as polymers, semiconductors, or lipid membranes have been developed, they have limited performance due to their low sensitivity and specificity. Recently, bioelectronic tongues fabricated by integrating human taste receptors and nanomaterial-based sensor platforms have been found to have high performance for measuring tastes with human-like taste perception. However, human umami taste receptor is heterodimeric class C GPCR composed of human taste receptor type 1 member 1 (T1R1) and member 3 (T1R3). Such complicated structure makes it difficult to fabricate bioelectronic tongue. The objective of this study was to develop a protein-based bioelectronic tongue for detecting and discriminating umami taste with human-like performance using umami ligand binding domain called venus flytrap (VFT) domain originating from T1R1 instead of using the whole heterodimeric complex of receptors. Such T1R1 VFT was produced from Escherichia coli (E. coli) with purification and refolding process. It was then immobilized onto graphene-based FET. This bioelectronic tongue for umami taste (BTUT) was able to detect monosodium L-glutamate (MSG) with high sensitivity (ca. 1 nM) and specificity in real-time. The intensity of umami taste was enhanced by inosine monophosphate (IMP) that is very similar to the human taste system. In addition, BTUT allowed efficient reusable property and storage stability. It maintained 90% of normalized signal intensity for five weeks. To develop bioelectronic tongue, this approach using the ligand binding domain of human taste receptor rather than the whole heterodimeric GPCRs has advantages in mass production, reusability, and stability. It also has great potential for various industrial applications such as food, beverage, and pharmaceutical fields. PMID- 30005384 TI - Fiber-optic surface plasmon resonance glucose sensor enhanced with phenylboronic acid modified Au nanoparticles. AB - A highly sensitive surface plasmon resonance (SPR) sensor is reported for glucose detection using self-assembled p-mercaptophenylboronic acid (PMBA) monolayer on Au coated optical fibers. The cis-diol group of saccharides, such as for glucose, interacted with the self-assembled PMBA monolayers on the optical fibers, but the low molecular mass of glucose is insufficient for measuring a significant shift in SPR wavelength. The response for glucose was thus enhanced with Au nanoparticles (Au NPs) modified with 2-aminoethanethiol (AET) and PMBA. Selectivity was assured since glucose has the ability to capture the signal amplification tags (Au NPs/AET- PMBA) through secondary binding with another set of syn-periplanar diol groups and the PMBA on the gold surface. Accordingly, a glucose concentration-dependent sandwich structure was formed and the coupling between Au NPs and Au film results in the red shift of SPR resonance wavelength. The experimental results demonstrated that this SPR sensor responded to glucose within a range of 0.01-30 mM better than to fructose and galactose. The minimum concentration for quantify glucose is as low as 80 nM, which is lower than the physiological blood glucose level. Glucose was then accurately detected in urine sample, which indicated the potential application of the sensor for the analysis of glucose in urine. We believe that our proposed PMBA-modified single amplification tag and sensing principle can also be used for biomolecules consisting of carbohydrate structures, particularly for DNA-associated bioanalysis. PMID- 30005385 TI - Visually multiplexed quantitation of heavy metal ions in water using volumetric bar-chart chip. AB - Heavy metal ions monitoring in water is practically significant for the environment and the human health. In this work, a lab-on-a-chip biosensor was developed for multiplexed quantitation of heavy metal ions by the integration of triple-channel volumetric bar-chart chip with DNA-nanoparticle probes. This method possesses the capability for rapid detection of Cu2+, Pb2+ and Hg2+ simultaneously with high sensitivity, selectivity and accuracy. Due to the highly catalase-like activity of the urchin-like platinum nanoparticles, this sensor exhibits high sensitivity with the detection limits of 1.0 nM, 1.0 nM and 1.8 nM for sensing of Cu2+, Pb2+ and Hg2+ respectively, which are much lower than the requirement of the United States Environmental Protection Agency (EPA) in drink water and superior to the colorimetric method based on the metal ion-specific DNA assay. The accuracy and reliability were verified by our Atomic Absorption Spectrometry (AAS) and Atomic Fluorescence Spectroscopy (AFS) measurements of real water sample. As the results can be directly read out without the need of the external instruments or complicate data processing, this sensor is extremely practical for environmental applications. PMID- 30005386 TI - Polyhedral-AuPd nanoparticles-based dual-mode cytosensor with turn on enable signal for highly sensitive cell evalution on lab-on-paper device. AB - A novel dual-mode cytosensor based on polyhedral AuPd alloy nanoparticles (PH AuPd NPs) and three-dimentional reduced graphene oxide (3D-rGO) was constructed for highly sensitive detection of MCF-7 cells. The 3D-rGO was in situ synthesized on the paper working electrode (PWE) by a pollution-free hydrothermal method, increasing the specific surface area and further facilitating the modification of Au nanoparticles (AuNPs). After modified with AuNPs, the Au@ 3D-rGO/PWE was then functionalized by aptamer H1 to trap MCF-7 cells. To construct the cytosensor, PH AuPd NPs was prepared as a novel catalytic material, and further modified with aptamer H2 for recognizing MCF-7 cells. With the occurrence of efficient recognition of MCF-7 cells, PH-AuPd NPs were bound onto the surface of the cells, and could catalyze H2O2 to generate *OH, leading to an amplified electrochemical signal. Meanwhile, as the electrolyte solution flowed, the *OH are transferred outward to the colorimetric detection zone, and catalyzed a chromogenic substrate TMB forms a colored product. The electrical signal measurement and colorimetric detection were carried out on a compatibly designed lab-on-paper device (LPD), realizing a dual-mode signal readout. This paper-based dual-mode cytosensor provided a relatively low detection limit of 20 cells mL-1 and a sensitive detection from 50 cells mL-1 to 107 cells mL-1 for MCF-7 cells, providing a reliable pathway of sensitively detecting cancer cells in clinical applications. PMID- 30005387 TI - All-printed cell counting chambers with on-chip sample preparation for point-of care CD4 counting. AB - We demonstrate the fabrication of fully printed microfluidic CD4 counting chips with complete on-chip sample preparation and their applicability as a CD4 counting assay using samples from healthy donors and HIV-infected patients. CD4 counting in low-income and resource-limited point-of-care settings is only practical and affordable, if disposable tests can be fabricated at very low cost and all manual sample preparation is avoided, while operation as well as quantification is fully automated and independent of the skills of the operator. Here, we show the successful use of (inkjet) printing methods both to fabricate microfluidic cell counting chambers with controlled heights, and to deposit hydrogel layers with embedded fluorophore-labeled antibodies for on-chip sample preparation and reagent storage. The maturation process of gelatin after deposition prevents antibody wash-off during blood inflow very well, while temperature-controlled dissolution of the matrix ensures complete antibody release for immunostaining after the inflow has stopped. The prevention of antibody wash-off together with the subsequent complete antibody release guarantees a homogeneous fluorescence background, making rapid and accurate CD4 counting possible. We show the successful application of our fully printed CD4 counting chips on samples from healthy donors as well as from HIV-infected patients and find an excellent agreement between results from our method and from the gold standard, flow cytometry, in both cases. PMID- 30005389 TI - Transcriptional response to low temperature in the yellow drum (Nibea albiflora) and identification of genes related to cold stress. AB - The yellow drum (Nibea albiflora) is an economically important maricultured fish in China, but the aquaculture of this species is severely affected by overwinter mortality associated with cold stress. Characterization of the molecular mechanisms underlying the susceptibility of the yellow drum to cold might increase our understanding of how this fish adapts to environmental challenges. Here, the transcriptional response of the yellow drum to cold stress (7.5 degrees C) was investigated with RNA-Seq analysis. We compared brain and muscle transcriptomes among cold-tolerant (Tol) fish that survived the cold treatment, cold-sensitive (Sen) fish that were killed by the cold treatment, and control (Con) fish that were not subjected to cold. Our analysis recovered 233,245 unigenes. The genes (DEGs) differentially expressed in the brain and muscle of the Tol versus Con group, the Sen versus Con group, and the Tol versus Sen group had tissue-specific expression patterns. Gene ontology, enrichment, and pathway analyses indicated the most highly enriched pathways in the DEGs were signaling molecules and interaction, signal transduction, carbohydrate metabolism, lipid metabolism, digestive system, and endocrine system pathways. These pathways were all associated with biological functions relevant to cold adaptation in the yellow drum, including transduction of stress signals, energy metabolism, and stress-induced cell membrane changes. We identified genes likely to be involved in cold-susceptibility and -tolerance as those differentially expressed in the Tol group as compared to the Sen group. Further investigation and characterization of these candidate genes might improve our understanding of the mechanisms underlying cold adaptation in the yellow drum. PMID- 30005388 TI - Transgenerational effects of chemotherapy: Both male and female children born to women exposed to chemotherapy have fewer children. AB - BACKGROUND: There is little known about the transgenerational effect of chemotherapy. For example, chemotherapy is known to decrease fecundity in women. But if women are able to have offspring after chemotherapy exposure, do these children also have decreased fecundity? METHODS: This study is a retrospective cohort study utilizing the Utah Population Database (UPDB), a comprehensive resource that links birth, medical, death and cancer records for individuals in the state of Utah. The male and female children (F1 generation) of chemotherapy exposed women (F0 generation) were identified. The number of live births (F2 generation) to this F1 generation was compared to two sets of chemotherapy unexposed, matched controls using conditional Poisson regression models (regression coefficient, 95% confidence interval, P-value). The first unexposed was established using the general population and the second unexposed was established using first cousins to the F1 generation. RESULTS: The exposed F1 individuals had 77.2% fewer children (-1.48; -2.51 to -0.70; p = 0.001) relative to the unexposed general population. F1 males had 86.9% fewer children (-2.03; 4.91 to -0.51; p = 0.005) and F1 females had 70.5% fewer children (-1.22; -2.40 to -0.36; p = 0.016). When comparing to their unexposed cousins, the F1 generation (both sexes combined) had 74.3% (-1.36; -2.82 to -0.29; p = 0.029) fewer children. CONCLUSION: The sons and daughters (F1 generation) of chemotherapy-exposed women have fewer live births when compared to both matched, unexposed general population and cousin controls. Chemotherapy may have a transgenerational effect in exposed women which needs further investigation. PMID- 30005390 TI - Response of detoxification and immune genes and of transcriptome expression in Mythimna separata following chlorantraniliprole exposure. AB - The oriental armyworm Mythimna separata is a serious polyphagous pest in China and there are major efforts to control this pest. In the present study, an RNA Seq method was used to explore transcriptome data of M. separata and identify the responses of genes to chlorantraniliprole. Sequencing and de novo assembly yielded 134,533 transcripts that were further assembled into 77,628 unigenes with an N50 length of 2165 bp. A total of 76 unigenes encoding insecticide targets were identified. Furthermore, 62 cytochrome P450s, 34 glutathione S-transferase (GSTs)and 64 carboxylesterase (CCEs) were curated to construct phylogenetic trees. In addition, we identified 647 the differentially expressed genes following treatment with chlorantraniliprole. The pathways of calcium signaling was identified as response to the pesticide The transcriptome data we generated represents a comprehensive genomic resource for further studies focused on control of M. separata. The response of genes to chlorantraniliprole treatment will elucidate the molecular mechanisms of insecticide resistance and allow for the development of new chemical pesticides to control this pest. PMID- 30005391 TI - Coronary pathology of inherited generalized arterial calcification of infancy: a case report. AB - Generalized arterial calcification of infancy (GACI), or idiopathic infantile arterial calcification, is a rare autosomal-recessive disease recognized aAs an inherited disorder characterized by severe pathologic calcification of large- and medium-sized arteries accompanied by smooth muscle cell (SMC) hyperplasia leading to vascular obstruction [1]. The prognosis is extremely poor, with 85% of affected infants dying within the first 6 months of life. Loss-of-function mutations in the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene is recognized as the main defect associated with GACI [1]. The underlying pathogenesis of osteogenic transition leading to calcification and severe stenosis in GACI, however, is poorly understood. Herein, we present a case of a GACI patient with cardiac complications who exhibited extensive vascular disease at autopsy. PMID- 30005392 TI - Pathological evidence of adrenergic cardiac denervation in a patient with congestive heart failure. PMID- 30005393 TI - Intramural capillary hemangioma of gallbladder artery: age-related or treatment induced change? PMID- 30005394 TI - Mesothelial/monocytic incidental cardiac excrescences (MICE): report of a case and review of literature with focus on pathogenesis. AB - Mesothelial/monocytic incidental cardiac excrescence (MICE) is a benign lesion composed of histiocytes and mesothelial cells, usually found during cardiac surgery. To date, no more than 50 cases are reported in literature, and pathogenesis is still unclear even if different theories have been proposed. Here we report a case of MICE encountered during aortic valve replacement with typical histological features and extensive immunohistochemical investigation. To date, little information is available about the pathogenesis of MICE. We review the current literature focusing on the role of adhesion molecules such as CD31. PMID- 30005395 TI - Candida parapsilosis endocarditis in an intravenous drug abuser: an autopsy report. AB - Candida parapsilosis is a rare cause of endocarditis, which is seen to affect the native valves in patients who are known intravenous drug abusers or following contamination during surgery for prosthetic valves. We discuss a unique constellation of autopsy findings in a 35-year-old chronic opium abuser who presented with left-sided weakness followed by low-grade fever. He was diagnosed to have C. parapsilosis native valve endocarditis with septic emboli involving the myocardial vessels, left middle cerebral artery, spleen, and common iliac artery. In addition, autopsy highlighted a right basal ganglia infarct, focal segmental glomerulonephritis, and talc granulomatosis in the lungs and liver. PMID- 30005396 TI - Effect of dietary supplementation with Yarrowia lipolytica or Saccharomyces cerevisiae yeast and probiotic additives on haematological parameters and the gut microbiota in piglets. AB - The objective of the study was to compare the efficiency of two species of yeast, Yarrowia lipolytica (YL) and Saccharomyces cerevisiae (SC), with or without a probiotic supplement, added to feed for piglets, on the basis of haematological blood indices and the gut microbiota. A total of 360 piglets (the average 27-d old) were allotted to dietary treatments: 1) the basal control(C) diet, 2) the C diet + probiotic(P) (a mixture of Bacillus licheniformis and Bacillus subtilis), 3) the C diet +3%YL(Y), 4) the C diet +3%YL + probiotic(YP), 5) the C diet +3%SC(S) and 6) the C diet +3%SC + probiotic(SP). The study showed that YL yeast can be used in compound feeds for piglets interchangeably with SC yeast. The effect of YL on haematological blood parameters and the microbes colonizing the gut proved to be more beneficial than the effect of SC yeast. The combined application of YL or SC with a probiotic had a more favourable effect on the gut microbiota than the use of yeast alone. It should be noted, however, that supplementation of the compound feed with YL in combination with a probiotic reduced the multiplication of coliform bacteria and Escherichia coli in the intestinal contents, while the feed containing SC together with a probiotic did not. The dietary study confirmed that YL in combination with a probiotic is highly suitable for feeding piglets. PMID- 30005397 TI - Investigation into the genetic diversity in toll-like receptors 2 and 4 in the European badger Meles meles. AB - The Toll-like receptor (TLR) genes are a conserved family of genes central to the innate immune response to pathogen infection. They encode receptor proteins, recognise pathogen associated molecular patterns (PAMPs) and trigger initial immune responses. In some host-pathogen systems, it is reported that genetic differences, such as single nucleotide polymorphisms (SNPs), associate with disease resistance or susceptibility. Little is known about TLR gene diversity in the European badger (Meles meles). We collected DNA from UK badgers, carried out PCR amplification of the badger TLR2 gene and exon 3 of TLR4 and determined DNA sequences for individual badgers for TLR2 (n = 61) and TLR4 exon 3 (n = 59). No polymorphism was observed in TLR4. Three TLR2 amino acid haplotype variants were found. Ninety five percent of badgers were homozygous for one common haplotype (H1), the remaining three badgers had genotypes H1/H3, H1/H2 and H2/H2. By broad comparison with other species, diversity in TLR genes in badgers seems low. This could be due to a relatively localised sampling or inherent low genetic diversity. Further studies are required to assess the generality of the low observed diversity and the relevance to the immunological status of badgers. PMID- 30005399 TI - Cow mortality as an indicator of animal welfare in dairy herds. AB - Welfare assessments based on herd visits are time consuming - and thus costly - and only measure welfare at specific points in time. This makes the use of routinely recorded indicators of animal welfare interesting. Such an indicator must - among other things - meet the following requirements: 1) the indicator must have a well-documented association with animal welfare and 2) data on the indicator must be easily available. Focussing on these two requirements, the objective of this paper was to evaluate the possibility of using routinely recorded cow mortality data as an indicator of animal welfare in dairy cattle herds. A literature review identified 10 articles describing varying degrees of associations between cow mortality and animal welfare in dairy herds. According to EU legislation, information about cow mortality should be routinely available in all EU member states. However, to what degree this is in fact the case, and how easily available the data are, remains to be elucidated further. In conclusion, most studies found at least some association between cow mortality and animal welfare. Therefore, the use of routinely collected data on cow mortality as an indicator of animal welfare in dairy herds may be relevant, but further research is needed to document 1) the association between cow mortality and animal welfare and 2) the availability of routinely collected cow mortality data. PMID- 30005398 TI - Short- and long term follow-up of 150 sports horses diagnosed with tendinopathy or desmopathy by ultrasonographic examination and treated with high-power laser therapy. PMID- 30005400 TI - Long-term shedding of Canine alphaherpesvirus 1 in naturally infected newborn pups. AB - The long-term shedding of Canine alphaherpesvirus 1 (CaHV-1) by neonatal pups with natural infection is reported. The pups belonged to a litter of 11 pointers of a breeding kennel in southern Italy, 9 of which developed a fatal form of systemic infection, as resulted by the detection of CaHV-1 in internal organs (kidney, liver, lung and brain) of one of this dogs and in the vaginal swab of their mother. The two remaining animals displayed a milder form of disease, with one pup showing ocular involvement, and underwent a progressive recovery. These pups were monitored from 11 to 36 days of age, showing a long-term shedding of the virus through the nasal and ocular secretions and the faeces. CaHV-1 shedding, as assessed by means of a specific and sensitive real-time PCR assay, occurred mainly through the nasal secretions, although the pup displaying ocular disease shed the virus at high titres and for a long period even in the ocular secretions. PMID- 30005401 TI - Environmental concentrations of azinphos-methyl cause different toxic effects without affecting the main target (cholinesterases) in the freshwater gastropod Biomphalaria straminea. AB - Organophosphate insecticides (OPs) are commonly used in Argentina and around the world for pest control in food crops. They exert their toxicity through the inhibition of the enzyme acetylcholinesterase. In the present study, we aimed to evaluate biochemical and reproductive effects in Biomphalaria straminea, a freshwater gastropod naturally distributed in Argentina, of subchronic exposures to environmental azinphos-methyl concentrations (20 and 200 ug L-1). For biochemical parameters, adult organisms were exposed for 14 days and the activity of cholinesterases (ChEs), carboxylesterases (CEs), glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), the production of reactive oxygen species (ROS), the total antioxidant capacity (TAC), glycogen and proteins were determined. For reproductive parameters, the egg masses of B. straminea were exposed to azinphos-methyl for one month, and the hatching time and success as well as the offspring survival were registered. We found different toxic effects elicited by the insecticide on the studied biomarkers. CEs activity was significantly inhibited while CAT and GST activities, ROS production and TAC were significantly increased, with respect to the solvent control group. ChE and SOD activities and protein and glycogen contents were not altered by azinphos-methyl. The hatching time and success were not statistically different from control. Nevertheless, the offspring survival was severely affected by the insecticide. Our results show that the primary target of the insecticide (ChE) was not inhibited but CEs, GST, CAT, ROS, TAC and offspring survival were sensitive biomarkers and valuable endpoints for subchronic toxicity assessments in this species. PMID- 30005402 TI - Comprehensive assessment of microbial aggregation characteristics of activated sludge bioreactors using fuzzy clustering analysis. AB - Understanding microbial aggregation dynamics in response to the often violent environmental fluctuations is important for activated sludge wastewater biotreatment practice, yet remains poorly understood. We investigated microbial aggregation process of an activated sludge reactor in response to various operating conditions of resource limitations, disinfectant and pH stresses, and quantified aggregation characteristics by employing a fuzzy clustering analysis (FCA) method. The results revealed that the FCA provided a means for comprehensive assessment of microbial aggregation dynamics of the bioreactor relying solely on simple parameter estimation. Proper disinfectant stress (of NaClO 1.00% or 2.00%) is a promising strategy to improve the comprehensive performance of microbial aggregation and sludge settleability. Nitrogen- (of C/N ratio > 40) and dissolved oxygen-limitations (of DO < 0.2 mg/L) had medium influence on the comprehensive performance of the activated sludge system, while little impacts for acidic and alkaline conditions. These quantitative estimations offer insights into the underlying bio-physicochemical processes of an activated sludge bioreactor in response to practical fluctuations that is often beyond typical assessment practice. In addition, it may represent a step towards uncoupling the complex biophysical interactions that is essential for optimized designing and proper engineering practice of biological wastewater treatment reactors. PMID- 30005403 TI - Commercial personal care product mixtures exhibit hormetic concentration responses to Vibrio qinghaiensis sp.-Q67. AB - The biological effects related to personal care products (PCPs) are almost induced by some active ingredients in the PCPs rather than the PCP itself. In this study, 23 common and widely used toner, skin water, and make-up water (TSM) commodities were directly taken as mixture samples, and Vibrio qinghaiensis sp. Q67 (Q67) was used as the test organism. The toxicities of the TSMs to Q67 were determined via microplate toxicity analysis at 0.25 h and 12 h. Each TSM commodity can be regarded as a complicated mixture (relative concentration is 1). It was shown that the concentration-response curves (CRCs) of 23 TSMs are monotonic sigmoid-shaped (S-shaped) at 0.25 h, the CRCs of six TSMs are also S shaped but the other 17 TSMs are non-monotonic hormetic or J-shaped at 12 h. In addition, to effectively characterize the nature of the stimulation and inhibition phases, it is suggested that five parameters such as the ECL (the median stimulation effective concentration (left)), Emin (the maximum stimulation effect), ECmin (the maximum stimulation effective concentration), ZEP (zero effect point where the effect is 0 and the concentration is ZEP), and EC50 can depict the non-monotonic CRC. To the best of our knowledge, this is the first study about the hormetic CRCs of commercial PCP mixtures. PMID- 30005404 TI - Rhizobium inoculation enhances copper tolerance by affecting copper uptake and regulating the ascorbate-glutathione cycle and phytochelatin biosynthesis-related gene expression in Medicago sativa seedlings. AB - Despite numerous reports that legume-rhizobium symbiosis alleviates Cu stress in plants, the possible roles of legume-rhizobium symbiosis and the regulatory mechanisms in counteracting Cu toxicity remain unclear. Here, Sinorhizobium meliloti CCNWSX0020 was used for analyzing the effects of rhizobium inoculation on plant growth in Medicago sativa seedlings under Cu stress. Our results showed that rhizobium inoculation alleviated Cu-induced growth inhibition, and increased nitrogen concentration in M. sativa seedlings. Moreover, the total amount of Cu uptake in inoculated plants was significantly increased compared with non inoculated plants, and the increase in the roots was much higher than that in the shoots, thus decreasing the transfer coefficient and promoting Cu phytostabilization. Cu stress induced lipid peroxidation and reactive oxygen species production, but rhizobium inoculation reduced these components' accumulation through altering antioxidant enzyme activities and regulating ascorbate-glutathione cycles. Furthermore, legume-rhizobium symbiosis regulated the gene expression involved in antioxidant responses, phytochelatin (PC) biosynthesis, and metallothionein biosynthesis in M. sativa seedlings under Cu stress. Our results demonstrate that rhizobium inoculation enhanced Cu tolerance by affecting Cu uptake, regulating antioxidant enzyme activities and the ascorbate-glutathione cycle, and influencing PC biosynthesis-related gene expression in M. sativa. The results provide an efficient strategy for phytoremediation of Cu-contaminated soils. PMID- 30005405 TI - Metal concentrations in recent ash fall of Popocatepetl volcano 2016, Central Mexico: Is human health at risk? AB - The present study addresses the metal concentration pattern and associated human health risks in ash samples of Popocatepetl volcano. In this regard, 12 ash samples from different regions of Puebla City were collected and analyzed for 28 major and trace metals, out of which exclusively 8 metals of potential risk (Cd, Co, Cr, Cu, Mn, Ni, Pb & Zn) were selected for human health risk validation. The metal concentration pattern showed an enriching trend for ferromagnesium and carbonate elements compared to previous ash eruptions. Enrichment factor and geoaccumulation indices displayed a least significant enhancement of metals from baseline concentrations. More likely, the potential ecological risk index suggested no harmful biological effects due to the presence of these metals in ash. Concurrently, in the human health risk assessment model, the hazard quotient and hazard index values < 1 indicated safe levels and no carcinogenic effects. All-inclusive, this study highlights the context of metals in ash fall of Popocatepetl which presents no adverse effects over the human population. PMID- 30005406 TI - Water treatment residuals as soil amendments: Examining element extractability, soil porewater concentrations and effects on earthworm behaviour and survival. AB - Drinking water treatment residuals (WTRs), the by-product of water clarification processes, are routinely disposed of via landfill however there is a growing body of research that demonstrates the material has great potential for beneficial use in environmental applications. Application to agricultural land is one option showing great promise (i.e. a low cost disposal route that provides organic matter input to soils and other potential benefits), however questions remain as to the impact such applications may have on earthworm survival and behaviour and also on the potential effects it may have on soil porewater chemistry. This study examined the leachability of elements within two types of WTRs (one Al- and one Fe- based) from England via 0.001 M CaCl2 solution, at varying pH, and via the Community Bureau of Reference (BCR) sequential extraction scheme. Earthworm avoidance, survival, growth, reproduction and element concentrations were examined in WTR-amended sandy soils (0%, 5%, 10%, 20% w/w), while soil porewaters were also recovered from experimental units and examined for element concentrations. The results revealed leachable element concentrations to be very low in both types of WTRs tested and so element leaching from these WTRs would be unlikely to pose any threat to ecosystems under typical agricultural soil conditions. However, when the pH was lowered to 4.4 there was a substantial release of Al from the Al-WTRs (382 mg/kg). Soil porewater element concentrations were influenced to some degree by WTR addition, warranting further examination in terms of any potential implications for nutrient supply or limitation. Earthworm avoidance of WTR-amended soil was only observed for Al-WTRs and only at the maximum applied rate (20% w/w), while survival of earthworms was not affected by either WTR type at any application rate. Earthworm growth and reproduction (cocoon production) were not affected at a statistically significant level but this needs further examination over a longer period of exposure. Increased assimilation of Al and Fe into earthworm tissues was observed at some WTR application rates (maximum fresh weight concentrations of 42 mg/kg for Al and 167 mg/kg for Fe), but these were not at levels likely to pose environmental concerns. PMID- 30005407 TI - Role of carbon ion beams irradiation in mitigating cold stress in Arabidopsis thaliana. AB - Carbon ion beams irradiation as an important type of ionizing radiation is one of the major approaches used to create mutants in plants. This study investigated the role of carbon ion beams irradiation in mitigating cold stress in Arabidopsis thaliana seedlings. The results showed that 50-Gy carbon ion beam irradiation appeared stimulatory effects on root length and fresh weight in Arabidopsis seedlings under cold stress. In comparison with control, the content of hydrogen peroxide, the production rate of superoxide anion radical, hydroxyl radical generation activity, and malondialdehyde content were obviously decreased in 50 Gy carbon ion beam irradiated seedlings in response to cold stress. Moreover, irradiated 50-Gy carbon ion beam in Arabidopsis seedlings were significantly triggered the efficiency of antioxidant under cold stress. Furthermore, we investigated the expression of cold-related genes in irradiated and non irradiated samples. Carbon ion beams irradiation up-regulated the expression levels of C-REPEAT BINDING FACTORS (CBFs), INDUCER OF CBF EXPRESSION 1 (ICE1), ICE2, CALMODULIN-BINDING TRANSCRIPTION ACTIVATOR 3 (CAMTA3) and cold-regulated COR genes, in response to cold stress. This study suggests that low-dose carbon ion beams irradiation can modulate the physiological responses and up-regulate cold signaling genes in mitigating cold stress in the growth of Arabidopsis seedlings. PMID- 30005408 TI - Cow manure-loaded biochar changes Cd fractionation and phytotoxicity potential for wheat in a natural acidic contaminated soil. AB - The current study aims to investigate the implications of amending a soil contaminated with Cd with peanut residues biochar (BP) solely or in combination with cow manure (CMPB) at different rates on phytotoxicity of Cd for wheat plants and its distribution in a mine contaminated soil. Soil pH and EC increased progressively in soils amended with either PB or CMPB. Exchangeable Cd was decreased while its non-exchangeable fractions were increased. Dry weights of wheat straw, roots and grains increased when soils amended with either PB or CMPB, especially at the higher application rate. Such increases were correlated significantly with the extractable soil-Cd. Concentrations of Cd in roots were higher than those in straw; whereas, the concentrations in grains seemed to be the lowest. Generally, values of bio-concentration and translocation factors did not exceed "1" and decreased with application of either PB or CMPB. In conclusion, enriching biochar with cow manure is a recommended strategy to reduce Cd uptake and translocation to straw and seeds. Moreover, Concentrations of Cd did not exceed the permissible levels in grains when soils amended with the highest rate of CMPB. PMID- 30005409 TI - Folate receptor-mediated celastrol and irinotecan combination delivery using liposomes for effective chemotherapy. AB - Drug targeting using functionalized nanoparticles provides a new standard in anticancer therapy. Liposomes, safe and effective drug delivery carriers, can incorporate both hydrophilic and hydrophobic drugs for combination chemotherapy treatment of cancers. The objectives of the current study were to synthesize and test the effectiveness of a nanotechnology-based strategy utilizing folic acid (FA)-conjugated liposomes that incorporate both celastrol (Cs) and irinotecan (Ir) for targeted breast cancer therapy. Our results revealed the successful preparation of Cs and Ir-loaded folate-targeted liposomes (Lipo/Cs/Ir-FA) with a small particle size (~190 nm) and polydispersity index (~0.10). The formulation exhibited higher drug release profiles for both Ir and Cs at pH 5.0 compared to those at physiological pH, favoring cancer cell-targeted release. Furthermore, in vitro cell studies showed high uptake and enhanced apoptosis in folate receptor positive breast cancer cells (MCF-7 and MDA-MB-231), but not in folate receptor negative lung cancer cells (A549). Moreover, an in vivo study in a mouse tumor model using MDA-MB-231 xenografts supported effective drug delivery behavior of the folate-conjugated liposomes by selective targeting of tumor tissue and minimizing systemic adverse effects. Therefore, our formulation could provide an effective therapy for targeted cancer treatment. PMID- 30005410 TI - Substrate stiffness affects neural network activity in an extracellular matrix proteins dependent manner. AB - Neuronal growth, differentiation, extension, branching and neural network activity are strongly influenced by the mechanical property of extracellular matrix (ECM). However, the mechanism by which substrate stiffness regulates a neural network activity, and the importance of ECM composition in conferring substrate stiffness sensing have not been explored. To address this question, the hippocampal neurons were seeded on the polydimethylsiloxane (PDMS) substrate with different stiffness, which were coated with fibronectin and laminin respectively. Our results show that voltage-gated Ca2+ channel currents are greater in neurons on the stiff substrate than on the soft substrate. In addition, the neurons exhibit a greater increase of Ca2+ currents on laminin-coated stiff substrate than on those coated with fibronectin, indicating that the composition of ECM can modulate responses to substrate stiffness of neurons. Paired patch-clamp recordings have shown that upregulation of neural effective synaptic connectivity is greater on the laminin-coated stiff substrate than on the fibronectin-coated ones. Consistently, laminin-coated stiff substrate enhances Ca2+ oscillations of neurons is greater that compared with the fibronectin-coated ones. Our study demonstrates that a direct role for substrate stiffness in regulating neuronal network activity and indicate that this modulation is dependent on a specific type of ECM protein, which should be taken into account for the design of biomaterials for neuronal tissue engineering. PMID- 30005411 TI - Novel two-stage solid-state fermentation for erythritol production on okara buckwheat husk medium. AB - An economical model of two-stage solid state fermentation (SSF) (prefermentation stage with Mucor flavus and in situ erythritol fermentation stage with Yarrowia lipolytica) for enhancing erythritol production was investigated. Buckwheat husk (BH) was utilized as inert support for the first time and okara as the substrate. Morphological properties suggested yeast cells were exposed in adequate oxygen leading to high erythritol yield, and enzyme activities analysis indicated M. flavus and Y. lipolytica grew and cooperated well during the two ferment stages. Maximum erythritol production (143.3 mg/gds) was obtained from okara-BH mixture (5:2, w/w) supplemented with 0.01 g/gds NaCl, with an initial moisture content of 60% and pH of 4.0 for 192 h, while undesired mannitol and citric acid were suppressed. Compared with submerged fermentation, two-stage SSF was short period, energy conserving and operable for erythritol production from insoluble wastes, and this is the first report on erythritol production via SSF. PMID- 30005412 TI - Performance and microbial community of hydrogenotrophic methanogenesis under thermophilic and extreme-thermophilic conditions. AB - In this study, hydrogenotrophic methanogenesis with respect to methanogenic activity and microbial structures under extreme-thermophilic conditions were examined, and compared with the conventional thermophilic condition. The hydrogenotrophic methanogens were successfully acclimated to the temperatures of 55, 65 and 70 degrees C. Although acclimation was slower at 65 and 70 degrees C, hydrogenotrophic methanogenesis remained fairly stable. High-throughput sequencing using 16S rRNA analysis showed that the higher temperatures resulted in single archaea community dominated by hydrogenotrophic Methanothermobacter. Moreover, the syntrophic bacteria changed from Coprothermobacter and Thermodesulfovibrio at 55 degrees C to Thermodesulfovibrio at 70 degrees C. Specific hydrogenotrophic methanogenic rate at 70 degrees C was 98.6 +/- 4.2 Nml CH4/g VS/hr, which was over 4-folds higher than that 8at 55 degrees C. The lag phase under extreme-thermophilic conditions was longer than thermophilic condition, which was probably due to the archaeal structure with low diversity. Extreme-thermophilic condition resulted in a shift in methanogenesis pathway from acetoclastic methanogenesis to hydrogenotrophic methanogenesis with the enrichment of Methanothermobacter thermautotrophicus. PMID- 30005413 TI - Discrepant effects of metal and metal oxide nanoparticles on anammox sludge properties: A comparison between Cu and CuO nanoparticles. AB - Metal and metal oxide nanoparticles (NPs) show differences in antimicrobial activity due to different chemical and physical properties. Using copper as a representative example, this study compared the NP effects on anaerobic ammonium oxidation (anammox) bacteria in wastewater treatment. Long-term exposure to 5 mgCu L-1 CuNPs reduced the physiological activity and abundance of anammox bacteria, thereby causing deterioration of reactor performance. However, anammox granules exhibited stronger resistance and resilience to perturbation by 1-160 mgCu L-1 CuONPs, and no adverse effects on performance were observed. Moreover, the level of Cu(II) released from NPs in the influent exhibited good correlations with variations of the community structure and sludge properties. Therefore, the effects of Cu-based NPs on anammox sludge properties are dependent on their forms and levels, and their discrepant effects are partially attributed to their ability to release ionic copper. PMID- 30005415 TI - Methods to reliably estimate faecal sludge quantities and qualities for the design of treatment technologies and management solutions. AB - Sanitation access in urban areas of low-income countries is provided through unstandardized onsite technologies containing accumulated faecal sludge. The demand for infrastructure to manage faecal sludge is increasing, however, no reliable method exists to estimate total accumulated quantities and qualities (Q&Q) This proposed approach averages out complexities to estimate conditions at a centralized to semi-centralized scale required for management and treatment technology solutions, as opposed to previous approaches evaluating what happens in individual containments. Empirical data, demographic data, and questionnaires were used in Kampala, Uganda to estimate total faecal sludge accumulation in the city, resulting in 270 L/cap?year for pit latrines and 280 L/cap?year for septic tanks. Septic tank sludge was more dilute than pit latrine sludge, however, public toilet was not a distinguishing factor. Non-household sources of sludge represent a significant fraction of the total and have different characteristics than household-level sludge. Income level, water connection, black water only, solid waste, number of users, containment volume, emptying frequency, and truck size were predictors of sludge quality. Empirical relationships such as a COD:TS of 1.09 +/- 0.56 could be used for more resource efficient sampling campaigns. Based on this approach, spatially available demographic, technical and environmental (SPA-DET) data and statistical relationships between parameters could be used to predict Q&Q of faecal sludge. PMID- 30005416 TI - Seasonal prescribed fire variation decreases inhibitory ability of Poa pratensis L. and promotes native plant diversity. AB - Global biodiversity is threatened by invasive plant species. Without a thorough understanding of effective management strategies, minimizing their impacts while improving native species diversity will be challenging. Burning in fire-prone landscapes has been successful for managing invasive species and increasing native biodiversity, but it is unclear how specific fire regimes improve restoration practices in novel ecosystems where invasive plants have a similar growth phenology to native plants. We investigated fire as a restoration practice in the Northern Great Plains to decrease the cover of Kentucky bluegrass Poa pratensis (bluegrass), a perennial cool-season invasive grass phenologically similar to dominant native cool-season grasses, by 1) evaluating season of burn (early-growing season, late-growing season, and dormant season) in a field experiment to test differences in plant community composition and 2) manipulating fine fuels (3000-5000 kg ha-1) in an experimental approach to determine the effects of fire on plant survivability of selected native grasses and bluegrass. Bluegrass cover decreased 27% on all field burned plots the first year post-fire. Three years post-fire, late-growing season and dormant season treatments had 35% less bluegrass, whereas the early-growing season treatment was not significantly different from the control. Overall, fire altered the native plant community, with native plants more associated with burned plots. However, native plant community changes were only evident three years post-fire in late-growing season and dormant season burn treatments. In the experimental approach, native grasses and bluegrass experienced high rates of mortality (40-50%) at fuel loads above 4000 kg ha-1 and heat dosages above 30,000 degrees C.sec, features commonly associated with early-growing season burns. Therefore, early-growing season burns meant to reduce bluegrass may also impact native plants dominant in the region. Invasive species management is complicated in novel ecosystems when invasive plants have similar growth phenologies to native species. Control efforts should consider how different management strategies impact invasive and native plants alike. We found that late-growing season and dormant season burns, along with higher fuel loads, decreased bluegrass cover. Determining mechanisms of control in fire-prone landscapes is a crucial step to improving invasive plant control and increasing native biodiversity. PMID- 30005414 TI - Effect of nickel-containing activated carbon on food waste anaerobic digestion. AB - Anaerobic digestion (AD) is frequently restricted with the long lag phase and low methane (CH4) production rate. Laboratory batch experiments were conducted to investigate the impact of different supplements on the performance of food waste AD, including AC-Ni, AC, and Ni. Results showed that the lag phase of AD was reduced with the addition of those supplementations. Compared with the control group without any supplementation, the AC-Ni could shorten the lag phase by 67% and increase the maximum CH4 production rate by 50%, respectively. The speciation analysis indicated that the environmental risks of the AC-Ni was reduced by 30% after digestion. Microbial community structure analysis revealed that the AC-Ni promoted the evolution and activity of the hydrolytic-fermentative bacteria (e.g. Firmicutes and Bacteroidetes) and methanogens (e.g. Methanobacterium, Methanoregula and Methanomassiliicoccus). This study suggested that the AC-Ni waste could be feasible to be applied to enhance the performance of AD. PMID- 30005417 TI - Anaerobic co-digestion of foodwaste with liquid dairy manure or manure digestate: Co-substrate limitation and inhibition. AB - Process instability has been a challenge to anaerobic digestion of foodwaste at higher organic loading rates. Co-digestion is one of the measures to improve stability. This study conducted batch experiments to compare liquid dairy manure and dairy manure digestate as a co-substrate for anaerobic digestion of foodwaste. The batch co-digestion experiments showed a two-stage biogas production process, which could be simulated with a modification of the Gompertz model. The specific biogas yields derived with the two-stage biogas production model was further simulated against the co-substrate ratios with substrate limitation - inhibition models for identifying the optimal co-substrate ratio. The Haldane model was the best to simulate co-substrate limitation - inhibition kinetics in anaerobic co-digestion of foodwaste. A higher ratio of dairy manure could result in co-substrate inhibition to biogas production due to recalcitrance of cellulose and toxicity of lignin and lignin derivatives. Kinetic modeling shows that the optimal volatile solids (VS) ratio of liquid dairy manure is 16.6%, at which the maximum specific methane yield is 0.54 L/g VS. Semi continuous co-digestion of 88% foodwaste and 12% liquid dairy manure at a hydraulic retention time of 14 d attained 94% of the simulated maximum methane yield. Although co-digestion of foodwaste and manure digestate resulted in lower biogas yields than co-digestion with liquid dairy manure, manure digestate is still an attractive co-substrate that has several operational advantages compared with liquid dairy manure. PMID- 30005418 TI - Effective tree distribution and stand structures in a forest for tsunami mitigation considering the different tree-breaking patterns of tree species. AB - The effectiveness of coastal forests to mitigate a tsunami has received increased attention. However, many trees are broken, overturned, or washed out in large tsunami events like the 2011 Great East Japan tsunami (GEJT). For quantitatively estimating the advantages and disadvantages of a coastal forest, it is important to reproduce the forest breakage, especially paying attention to the production of driftwood and the trapping ability of standing trees. The objective of this study was to analyze the tree-breaking mode in detail, considering the stand structure of trees, to demonstrate an energy reduction even when trees are broken, and to utilize the information about the breaking pattern to design and manage a coastal forest properly. In this regard, one location, Misawa, the forest of which was affected by the GEJT, was selected for model validation, and coastal forests in two locations, Shiranuka Town and Taiki Town, in Hokkaido, Japan, were selected because a large tsunami is expected to occur there in the future. A numerical simulation of two tsunami magnitudes at the two Hokkaido sites demonstrated that a tree whose crown is far from the ground tends to be broken at the tree trunk. Dahurian larch (Larix gmelinii) and Daimyo oak (Quercus dentata) tend to be overturned and broken at the tree trunk, respectively. However, the tendency changed with the tsunami magnitude. In addition, even when trees with a dense crown were overturned, they contributed to tsunami resistance to some extent. The fluid force was reduced not only with the forest thickness but also with the tree species and the destruction mode. To maintain the fluid force reduction and to reduce secondary damage by driftwood, mixed planting is recommended in which tree stand structures are different and large diameter trees at the landward side of forest are planted to trap the driftwood produced from the sea side. PMID- 30005419 TI - A sensitive method for the determination of the gender difference of neuroactive metabolites in tryptophan and dopamine pathways in mouse serum and brain by UHPLC MS/MS. AB - Tryptophan (TRP) and dopamine (DA) pathways are of great importance for their related pathology and physiology. In the present study, a new reliable and sensitive analytical method was developed and validated for 12 neuroactive metabolites in TRP and DA pathways in mouse serum and brain by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC MS/MS). The method exhibited good sensitivity as the lower limit of detections ranged from 0.10 to 0.50 ng/ml and the lower limit of quantifications ranged from 0.20 to 2.00 ng/ml by derivatization with dansyl chloride (DNS-Cl) following solid phase extraction (SPE) on C18 cartridges. Good linearity (R2 > 0.99), intra day precision (<9.8% in serum and <8.8% in brain), inter-day precision (<8.9% in serum and <8.5% in brain) and accuracy (90.3%-110.3% in serum and 86.5%-114.0% in brain) were obtained. The method was successfully applied in measuring 12 neuroactive metabolites in TRP and DA pathways in serum and brain samples of male and female mice to explore the differences between genders. As a result, DA and the turnover of DA to 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxtryptamine (5-HT) to TRP and 5-hydroxyindole acetic acid (5-HIAA) to 5-HT in the serum and norepinephrine (NE) in the brain were significantly different between genders. PMID- 30005421 TI - Scaption kinematics of reverse shoulder arthroplasty do not change after the sixth postoperative month. AB - BACKGROUND: Changes over time in shoulder kinematics and function after reverse shoulder arthroplasty have not been reported. The purpose of this study was to compare shoulder kinematics and function at 6 months and 1 year after reverse shoulder arthroplasty. METHODS: Twenty patients with a mean age of 74 years (range, 63-91 years) were enrolled in this study. Fluoroscopic images during scapular plane elevation were recorded at the mean of 6 months (range, 5-8 months) and 14 months (range, 11-21 months). CT-derived glenosphere models and computer-aided design humeral implant models were matched with the silhouette of the implants in the fluoroscopic images using model-image registration techniques. Glenosphere and humeral implant kinematics during scaption were compared between the two time points. Patients were also clinically examined with active range of motion and Constant score, and postoperative improvement in shoulder function were assessed. RESULTS: Active flexion and Constant score improved after surgery (p < 0.001 for both), but there was no significant improvement after six months. There was no significant improvement in active external rotation at either postoperative exam. There were no significant differences in glenosphere or humeral kinematics between six months and one year. INTERPRETATION: There was no significant additional improvement in either shoulder kinematics during scapular plane elevation or function between the sixth and twelfth postoperative months. We can assess kinematics at six months after reverse shoulder arthroplasty to determine how the shoulder will move. Clinically, treatment in the first six postoperative months should be emphasized to achieve better surgical outcomes. PMID- 30005420 TI - Risk behaviours and viral infections among drug injecting migrants from the former Soviet Union in Germany: Results from the DRUCK-study. AB - BACKGROUND: High prevalence of drug use and injection-related risk behaviours have been reported among former Soviet Union (FSU)-migrants. To investigate hepatitis C (HCV) and HIV seroprevalence and related risk behaviours in this subgroup in Germany, we compared first generation FSU-migrants and native Germans using data from a sero-behavioural survey of people who inject drugs (PWID). METHODS: Current injectors were recruited using respondent-driven sampling in eight German cities in 2011-2014. Questionnaire-based interviews were conducted and dried blood spots collected and tested for anti-HCV, HCV-RNA, and anti HIV1/2. Descriptive and multivariable analyses (MVA) were performed. RESULTS: A total of 208 FSU-born and 1318 native German PWID were included in the analysis. FSU-migrants were younger than Germans (median age: 33 vs. 39 years), and more often male (83.1% vs. 75.9%, p = 0.022). HCV seroprevalence was 74.5% in FSU migrants vs. 64.6% in Germans (p = 0.006), HIV seroprevalence was 5.8% and 4.6%, respectively (p = 0.443). The proportion of FSU-migrants reporting injecting related risk behaviours was higher than among Germans: injecting daily (39.4% vs. 30.2%, p = 0.015), with friends (39.2% vs. 31.2%, p = 0.038), cocaine (32.7% vs. 23.8%, p = 0.044), more than one drug (18.2% vs. 9.6%, p = 0.006), and sharing filters/cookers (35.5% vs. 28.0%, p = 0.045). No statistically significant differences were observed in HIV/HCV testing rates (range: 50.7%-65.6%), opioid substitution treatment (43.9% vs. 50.5%), and access to clean needles/syringes (89.8% vs. 90.3%). In MVA, risk for HCV-infection was increased in male FSU migrants compared to German males (OR 3.32, p = 0.006), no difference was identified between female FSU-migrants and German females (OR: 0.83, p = 0.633). CONCLUSION: Male FSU-migrants were at highest risk of being HCV infected. Therefore, targeted actions are needed to ensure access and acceptance of harm reduction measures, including HCV-testing and -treatment for this subpopulation of PWID. PMID- 30005422 TI - Varus malalignment of cementless hip stems provides sufficient primary stability but highly increases distal strain distribution. AB - BACKGROUND: Varus position of cementless stems is a common malalignment in total hip arthroplasty. Clinical studies have reported a low rate of aseptic loosening but an increased risk for thigh pain. This in vitro study aimed to evaluate these clinical observations from a biomechanical perspective. METHODS: A conventional cementless stem (CLS Spotorno) was implanted in a regular, straight (size 13.75) as well as in a varus position (size 11.25) in 6 composite femora (Sawbones), respectively. Primary stability was assessed by recording 3-dimensional micromotions under dynamic load bearing conditions and stress shielding was evaluated by registering the surface strain before and after stem insertion. FINDINGS: Primary stability for stems in varus malposition revealed significantly lower micromotions (p < 0.05) for most regions compared to stems in neutral position. The greatest difference was observed at the tip of the stem where the straight aligned implants exceeded the critical upper limit for osseous integration of 150 MUm. The surface strains for the varus aligned stems revealed a higher load transmission to the femur, resulting in a clearly altered strain distribution. INTERPRETATION: This biomechanical study confirms the clinical findings of a good primary stability of cementless stems in a varus malposition, but impressively demonstrates the altered load transmission with the risk for postoperative thigh pain. PMID- 30005423 TI - Mechanomyography responses characterize altered muscle function during electrical stimulation-evoked cycling in individuals with spinal cord injury. AB - BACKGROUND: Investigation of muscle fatigue during functional electrical stimulation (FES)-evoked exercise in individuals with spinal cord injury using dynamometry has limited capability to characterize the fatigue state of individual muscles. Mechanomyography has the potential to represent the state of muscle function at the muscle level. This study sought to investigate surface mechanomyographic responses evoked from quadriceps muscles during FES-cycling, and to quantify its changes between pre- and post-fatiguing conditions in individuals with spinal cord injury. METHODS: Six individuals with chronic motor complete spinal cord injury performed 30-min of sustained FES-leg cycling exercise on two days to induce muscle fatigue. Each participant performed maximum FES-evoked isometric knee extensions before and after the 30-min cycling to determine pre- and post- extension peak torque concomitant with mechanomyography changes. FINDINGS: Similar to extension peak torque, normalized root mean squared (RMS) and mean power frequency (MPF) of the mechanomyography signal significantly differed in muscle activities between pre- and post-FES-cycling for each quadriceps muscle (extension peak torque up to 69%; RMS up to 80%, and MPF up to 19%). Mechanomyographic-RMS showed significant reduction during cycling with acceptable between-days consistency (intra-class correlation coefficients, ICC = 0.51-0.91). The normalized MPF showed a weak association with FES-cycling duration (ICC = 0.08-0.23). During FES-cycling, the mechanomyographic-RMS revealed greater fatigue rate for rectus femoris and greater fatigue resistance for vastus medialis in spinal cord injured individuals. INTERPRETATION: Mechanomyographic-RMS may be a useful tool for examining real time muscle function of specific muscles during FES-evoked cycling in individuals with spinal cord injury. PMID- 30005424 TI - Coordination stability between the legs is reduced after anterior cruciate ligament reconstruction. AB - BACKGROUND: The study was designed to examine coordination differences in walking between individuals with an anterior cruciate ligament reconstruction compared with healthy matched controls. Predictions from the extended Haken, Kelso, and Bunz coupled oscillator model were tested in these populations. METHODS: Seventeen persons with anterior cruciate ligament reconstruction and 17 matched controls participated in the study. Sagittal plane angular knee displacement was recorded using electrogoniometers over the lateral right and left knee joints while participants walked at five walking speeds overground. Coordination pattern and stability between the knees were quantified by mean and standard deviation of relative phase, respectively. FINDINGS: Mean relative phase was not influenced by walking speed or group. For both groups, coordination stability was maximal when individual's walked at their preferred gait speed. However, the anterior cruciate ligament reconstruction group demonstrated reduced coordination stability compared with healthy controls across the five speeds. Multiple regression analyses found that people with anterior cruciate ligament reconstruction who deviated more from antiphase coordination had decreased coordination stability. INTERPRETATION: Anterior cruciate ligament reconstruction results in decreased coordination stability, indicative of reduced coupling strength between the legs. This change in gait coordination, which has not previously been found in the literature, may contribute to the increased rate of re-injury and degeneration in individuals who have had this reconstructive surgery. Application of a motor control model enhances our understanding of the influence of an injury on coordination during gait. PMID- 30005425 TI - Immediate effect of scapula-focused exercises performed with kinematic biofeedback on scapular kinematics in individuals with subacromial pain syndrome. AB - BACKGROUND: Given the changes in the patterns of muscular activation and scapular movement in individuals with subacromial pain syndrome, the use of neuromuscular training has been considered in rehabilitation protocols. There is currently no evidence of the effects of the use of three-dimensional (3D) kinematic biofeedback on individuals with subacromial pain syndrome. This study aimed to determine the immediate effect of scapular motor control exercises using 3D kinematic biofeedback on the scapular kinematics, inter-segment coordination and pain of individuals with subacromial pain syndrome. METHOD: The kinematics of the scapulothoracic joint of 26 subjects with subacromial pain syndrome were assessed in the movement arm elevation and lowering in the sagittal plane before and after performance of three scapula-focused exercises using kinematic biofeedback. The individuals were familiarized with the selected exercises to acquire a greater scapular posterior tilt, while kinematic biofeedback, with visual and auditory stimuli, was used in real time. Scapular kinematics, pain, and subjective perception of exertion were the pre- and post-test measures. FINDINGS: In the movement of arm elevation and lowering, no differences were found in scapular tilt and on coordination between the segments pre- and post-test and the effect size was considered small. INTERPRETATION: Our results demonstrate that the performance of scapula-focused exercises using kinematic biofeedback does not cause immediate changes in the magnitude of scapular movement. However, inter segmental coordination showed evidence of changes for scapular tilt in the lowering of the arm and internal rotation in the elevation and the lowering of the arm in individuals with subacromial pain syndrome. PMID- 30005426 TI - Test-retest reliability of two-dimensional video analysis during running. AB - OBJECTIVES: To examine test-retest reliability of two-dimensional measured frontal and sagittal plane kinematics during running, and to determine how many steps to include to reach and maintain a stable mean. DESIGN: Reliability study. SETTING: Research laboratory. PARTICIPANTS: Twenty-one recreational runners. MAIN OUTCOME MEASURES: Lateral trunk position, contralateral pelvic drop, femoral adduction, hip adduction, knee flexion and ankle dorsiflexion during midstance, and foot and tibia inclination at initial contact were measured with two dimensional video analysis during running for 10 consecutive steps for both legs. All participants were tested twice one week apart. A sequential estimation method was used to determine the number of steps needed to reach a stable mean. Intraclass correlation coefficients (ICC) and smallest detectable differences (SDD) were calculated. RESULTS: The minimal number of steps was 6.3 +/- 0.3. Lateral trunk position, femoral adduction and foot inclination showed excellent reliability (ICC 0.90-0.99; SDD 1.3 degrees -2.3 degrees ). Tibia inclination and ankle dorsiflexion showed good to excellent reliability (ICC 0.73-0.92; SDD 2.2 degrees -4.8 degrees ). Hip adduction and knee flexion showed good reliability (ICC 0.82-0.89; SDD 2.3 degrees -3.8 degrees ). Contralateral pelvic drop showed moderate to good reliability (ICC 0.59-0.77; SDD 2.7 degrees -2.8 degrees ). CONCLUSION: Two-dimensional video analysis is reliable to assess running kinematics on different days. The mean of at least 7 steps should be included. PMID- 30005427 TI - [Head & Neck Merkel Cell Carcinoma]. AB - Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Even if it is quite rare, the incidence has increased about two fold during the last twenty years. Mortality is higher than in malignant melanoma. Risk factors are chronic UV exposition and immunosuppression. MCC are most common in patients over 70 years and half of them manifest in the head and neck region. They early metastasize to regional lymph nodes. Surgical therapy should include wide resection of the primary tumor and diagnostic lymph node excision. In the head and neck region this means usually ipsilateral selective neck dissection. Adjuvant radiotherapy of the primary tumor bed and associated lymph nodes of the head and neck region decreases recurrence and should be performed in every patient regardless of the T- and N-stage. In the head and neck region adjuvant radiotherapy can only be spared in selected patients with low-risk profile (wide excisional margins > 2 cm, primary tumor size > 1 cm, absent lymphovascular infiltration, no immunosuppression and pathologic negative cervical lymph nodes). Isolated radiotherapy or systemic therapies are usually applied in patients with metastasized MCC. Disease recurrence is most common in the first two years after initial diagnosis. Patients should be examined at short intervals during this time. PMID- 30005428 TI - Rapid and Simultaneous Determination of Three Active Components in Raw and Processed Root Samples of Scutellaria baicalensis by Near-infrared Spectroscopy. AB - Motivated by the wide use of Scutellariae Radix (SR) in the food and pharmaceutical industries, a rapid and non-destructive near-infrared spectroscopy (NIRS) method was developed for the simultaneous analysis of three main active components in raw SR and SR processed by stir-frying with wine. From seven geographical areas, 58 samples were collected. The reference contents for the SR components baicalin, baicalein, and wogonin were determined by high-performance liquid chromatography. Two multivariate analysis methods, partial least-squares (PLS) regression as a linear regression method and artificial neural networks (ANN) as a nonlinear regression method, were applied to the NIR data, and their results were compared. In the PLS model, different model parameters (i.e., 11 spectral pre-treatment methods), spectral region, and latent variables were investigated to optimize the calibration model; additionally, the ANN model was applied with five different spectral pre-treatment methods and six algorithms. For the optimal model parameters, the correlation coefficients of the calibration set for baicalin, baicalein, and wogonin were 0.9979, 0.9786, and 0.9773, respectively; the correlation coefficients of the prediction set were 0.9756, 0.9843, and 0.9592, respectively; the root mean square error of validation values were 0.215, 0.321, and 0.174, respectively. The optimal NIR models were then employed to analyze the effects of processing and geographical regions on analyte contents. The established NIR methods were robust, accurate, and reproducible. NIRS may be a promising approach for the routine screening and quality control of traditional Chinese medicines. PMID- 30005429 TI - [3-D Optics for Thoracoscopic Vertebral Body Replacement - Essential Technical Progress or Just Nice to Have?] AB - BACKGROUND: Three-dimensional (3-D) endoscopic optics use 2 cameras to simulate the different perspectives of the right and left eye, creating the illusion of spatial depth. Optimised orientation as well as improved hand-eye coordination compared to 2-D-optics could be proven in standardised test setups (black box) and in laparoscopic use. This retrospective study examines whether these results can also be applied to thoracoscopic vertebral body replacement at the thoracolumbar junction. HYPOTHESES: 1. Ventral vertebral body replacement using 3 D-thoracoscopy results in a shorter operation time than with 2-D-thoracoscopy. 2. Perioperative blood loss is less, due to better spatial orientation (faster haemostasis) and reduced tissue laceration. MATERIAL AND METHODS: 29 patients met the inclusion criteria of this retrospective study. Between 08 - 2012 and 08 - 2017, all of these received ventral thoracoscopic vertebral replacement at the thoracolumbar junction (Th11 to L2). Patients with additional anterior procedures (e.g. anterolateral plate) were excluded. Perioperative data such as blood loss, duration of surgery and length of hospital stay were analysed. Conventional 2-D optics were used in n = 14 patients and 3-D-optics in 15 patients. Aesculap EinsteinVision(r) 2.0 was used as the 3-D-optics. Statistical significance was calculated using Student's t-test. RESULTS: The most common diagnosis was a L1 fracture (n = 18, 62%). Mean OR time was 24 minutes shorter in the 3-D group (149 +/- 29, 107 - 198 min) than in the 2-D group (173 +/- 39, 125 - 260 min), but this difference was not significant. Total perioperative blood loss in the 3-D group was significantly lower than in the 2-D group (**p = 0.043). Proportional intraoperative blood loss in the 3-D group was also lower (mean around 115 ml), but not significantly so. Significantly lower values were found for the delivery rate of the thoracic drainage in the 3-D group (248 vs. 560 ml, *p = 0.195). Inpatient stay with the 3-D group was on average 1.5 days (d) shorter (8.7 d for the 3-D group, 10.2 d for the 2-D group) but this difference was not significant (p = 0.27). CONCLUSION: Thoracoscopic-assisted vertebral body replacement at the thoracolumbar junction is a safe and reliable surgical procedure using conventional 2-D-optics or the new 3-D-optics. Both methods allow thoracoscopic vertebral body replacement in comparable operation times but in our study the 3-D group presented with significantly lower postoperative blood loss. Due to the small number of cases and because of the retrospective design, the present study is considered to be a pilot study only. PMID- 30005430 TI - [Medication Plans at Hospital Admission - a Multicentre Analysis Using Statutory Health Insurance Data]. AB - INTRODUCTION: Changes in drug therapy at intersectoral interfaces can lead to clinically relevant drug-related problems. This study aimed, therefore, at comparing the drug prescription continuity of patients with and without a medication plan at hospital admission. METHODS: After ethical approval, patients of a health insurance company in 6 hospitals in Saxony were consecutively assigned to this study from November 2011 to January 2012 after written informed consent. We assessed the following drug-related data for patients with and without medication plan at hospital admission: (i) the medication prescribed by the hospital physician on the day of hospital admission and (ii) the medication of the hospital discharge letter. Patient-individual claims data were assigned to the inpatient data for a period of 6 months before and after inpatient treatment (data linkage). RESULTS: Of the 279 study participants, 173 (62 %) used a medication plan at hospital admission. Patients with a medication plan had a statistically significantly older age, higher numbers of drugs and diagnoses and fewer emergency admissions. At admission 53 % of the drugs were continued in patients with medication plan and 40 % in patients without a medication plan (p < 0.001). At hospital discharge 66 % and 64 % were continued after discharge (n. s.). Medication plans were mostly written by their GP (38 %) and in 12 % by the patients themselves. DISCUSSION: Even before implementation of the national medication plan, nearly two third of the patients had a medication plan at hospital admission. However, in many cases it had been prepared by the patients themselves. The existence of a medication plan can have an impact on the continuity of the drug prescription during hospitalisation but not after discharge. PMID- 30005431 TI - ["Critical discussion should be encouraged!" - a qualitative analysis of medical students' evaluation of a complementary medicine course]. AB - BACKGROUND: In 2002, the new version of the German Medical Licensure Act integrated Naturopathy and Complementary Medicine into the cross-sectoral unit 12 "Rehabilitation, Physical Medicine and Naturopathy" (QB12) of the medical undergraduate course. At the University of Heidelberg, Complementary Medicine (CAM) is an obligatory clinical subject of the medical undergraduate curriculum and is delivered in the form of lectures and small group work. As a central educational objective, medical students should be able to explain the principles of classical Naturopathy and the most commonly used CAM procedures. The aim was to explore the attitudes, learning needs and interests of medical students with regard to Naturopathy and CAM, and thus establish the teaching requirements. METHODS: The lectures and internships were evaluated using a faculty-based teaching evaluation form. The free-text of the evaluation forms between winter semester 2011/2012 and summer semester 2013 were assessed using Mayring qualitative content analysis. RESULTS: The free-texts were divided into three deductive main categories (Attitudes, Learning Needs and Interests) and further subcategories. A central topic was the polarization of views in medical students regarding CAM; it ranged from lively resistance to great enthusiasm. Strikingly, comments often showed that students had significant reservations with respect to CAM and would require further evidence from the teachers in order to embrace this concept. This was particularly prominent in the use of non-pharmaceutical methods. DISCUSSION: Our results show that evidence-based teaching, combined with practical experience, contributes positively to the critical appraisal of CAM amongst medical students. These findings can serve as the basis for planning, implementation and realization of CAM teaching within mainstream undergraduate medical education. PMID- 30005432 TI - [Immune Therapy in Oncology: Are we Approaching the Breakthrough?] PMID- 30005433 TI - [A 27-year old patient with sudden onset of itchy nodules with central lenticular plug]. PMID- 30005434 TI - [Immuno-Oncology: A Brief Overview]. AB - Pioneering work has unraveled the role of the immune system in the development and control of cancer. This knowledge has set the basis for the successful implementation of immunotherapy into the standard of care for a large number of cancer types. Based on response rates and prolongation of overall survival, immunotherapeutic approaches have been approved in a growing number of tumor diseases. Activation or therapeutic utilization of T cells represent the basis of these concepts. Checkpoint inhibitory antibodies inhibiting CTLA-4, PD1 and PD-L1 receptors and ligands induce long-term clinical tumor control in a significant number of cancer patients including metastatic melanoma and non-small cell lung cancer. As an alternative concept of T cell activation, the dual CD19 - CD3 targeting bispecific antibody blinatumomab has been approved for refractory acute lymphatic B-cell leukemia (ALL). Moreover, T cells genetically engineered with an anti-CD19-chimeric antigen receptor have also been approved for ALL and malignant B-cell lymphoma by the food and drug administration (FDA). In all of these immunotherapies, severe side effects may occur and require a well-trained team of physicians. Moreover, the growing number of clinically investigated and validated novel compounds as well as cellular therapeutics accentuate the complexity and challenge of this treatment modality. This review highlights the most prominent recent clinical developments in the field of immuno-oncology. PMID- 30005435 TI - [Immuncheckpoint Inhibitors: Current Indications and Possible Future Concepts]. AB - Immuno-oncological therapy concepts have already achieved great success in the treatment of a number of advanced malignancies, thereby rapidly gaining access to clinical practice. Immuncheckpoint inhibitors are also being reviewed in the adjuvant setting. In malignant melanoma, they have already shown efficacy. Different combination strategies of Immuncheckpoint inhibitors are currently undergoing clinical evaluation to further improve treatment outcomes. However, this has so far also been associated with a significantly increased immune mediated rate of side effects. Effective and safe immuno-oncology requires good clinical management of immune-mediated side effects. Radiological assessment is challenging under immunotherapy and requires new standards (iRECIST). Encouraging is the fact that immunotherapy also causes long-term remissions in some of the patients. This raises the hope for a fundamentally curative potential of immuno oncological therapeutic approaches. PMID- 30005436 TI - [Challenges in Immuno-Oncology - Possibilities for Optimization]. AB - Immuno-oncology has undoubtedly started a new era in the treatment of malignant diseases. Within a short time immunotherapeutic therapy concepts have become part of the standard therapy for many tumors. Already, immunotherapy is one of the most potent therapeutic options for the treatment of many malignancies. Despite its impressive achievements, there is still a significant need for improvement and many aspects of the practical application of immunotherapeutic modalities of therapy are unclear. If it succeeds in solving the challenges discussed here, immuno-oncology will certainly be one of the most important pillars of successful tumor therapy in the future. Immunotherapeutic combination therapies offer the opportunity to improve treatment outcomes. The immunological side effects of immunotherapy may sometimes be life-threatening, but if adequately treated they may be associated with a good prognosis. The development of predictive biomarkers is indispensable for effective immunotherapy. The costs of immuno-oncological therapies are sometimes very high. Therefore reasonable solutions must be found. PMID- 30005437 TI - [High-Quality Endoscopic Mucosal Resection - The Process Explained]. AB - Colonoscopy with polypectomy has been shown to reduce the risk of colon cancer development. It is considered a fundamental skill for all endoscopists who perform colonoscopy. A variety of polypectomy techniques and devices are available, and their use can vary greatly based on local availability and preferences. Polyps that are difficult to remove due to location or size require advanced resection techniques, such as endoscopic mucosal resection (EMR) and the use of special devices for safe and effective removal. However, colonic EMR is not routinely part of the standard endoscopic curriculum that is normally offered to gastroenterologists. It requires dedicated training in advanced endoscopic resection techniques, clinical and interpretive skills, and the knowledge and ability to manage complications.The two most common post-polypectomy complications are bleeding and perforation. Their frequency can be limited with the use of meticulous polypectomy techniques and the application of some prophylactic manoeuvres.This paper gives a review of the step by step technique of polypectomy and its complications from the perspective of the practicing gastroenterologist. PMID- 30005438 TI - [Fluid Resuscitation and Management in Patients with Sepsis and Septic Shock]. AB - Sepsis and septic shock are common diseases with high mortality rates. Although volume therapy has been a central component of sepsis therapy for decades, the choice of optimal fluid and fluid intake is unclear. This paper summarizes findings on pathophysiology, clinical trial results, and current recommendations for optimal volume and fluid management in sepsis. PMID- 30005439 TI - Snacking is Common in People with Diabetes Type 1 and Type 2 with Insulin Therapy and Is Not Associated With Metabolic Control or Quality of Life. AB - OBJECTIVE: The aim of this observational study was to analyse snacking pattern and satisfaction with snacking, and to associate snacking patterns with metabolic control and quality of life in people with diabetes type 1 and 2 on insulin therapy. METHODS: In 2017, 390 people with diabetes were interviewed in a university outpatient department: 132 diabetes type 1 (56.1y, diabetes duration 24.2y, HbA1c 7.0%), 89 diabetes type 2/biphasic insulin (72.8y, diabetes duration 22.0y, HbA1c 7.1%) and 169 diabetes type 2/prandial insulin (66.7y, diabetes duration 20.5y, HbA1c 7.0%). Standardised questionnaires were used to assess eating patterns, satisfaction with snacking, treatment satisfaction and quality of life. RESULTS: The far majority snacked regardless of diabetes type and type of insulin therapy (70.5% type 1, 80.9% type 2/biphasic insulin, 74.6% type 2/prandial insulin) and liked to do so or did not mind (type 1 diabetes 79.5%, type 2 diabetes/biphasic insulin 84.8%, type 2 diabetes/prandial insulin 83.5%). Snacking because of recommendations of healthcare professionals was rare (10.8% type 1 diabetes, 8.2% type 2 diabetes/biphasic insulin, 9.4% type 2 diabetes/prandial insulin). Snacking and not snacking participants did not differ in respect to HbA1c, quality of life or treatment satisfaction. CONCLUSIONS: Snacking seems to be a common habit in individuals with diabetes and most of them like to snack. Snacking is not associated with better or worse metabolic control or quality of life. The decision to snack or not to snack can be left to the individual and integrated into the therapy without danger for the glycaemic control. PMID- 30005440 TI - [Clinical Evaluation of a Novel Intraocular Lens with Enhanced Depth of Focus (EDOF) to Increase Visual Acuity for Intermediate Distances]. AB - BACKGROUND: Modern intraocular lens surgery has made great progress over the last few years towards creating independency of spectacles in daily life. Especially in the areas of distant and near visual acuity, optimisation has been possible. Nevertheless, with new media and requirements in professional life, there is an increasing need for optimisation of the intermediate range. In a prospective, non randomised clinical study, the functional and refractive results after implantation of a novel intraocular lens with enhanced depth of focus were analysed. PATIENTS/MATERIAL AND METHODS: We have evaluated eleven patients after binocular implantation of the AT LARA 829MP (Carl Zeiss Meditec AG, Germany) 3 months after surgery. We examined refraction, corrected and uncorrected monocular and binocular distant visual acuity (CDVA, UDVA) as well as distance-corrected monocular and binocular visual acuity at different intermediate distances (with DCIVA 90, 80 and 60 cm) and 40 cm (DCNVA). We also performed defocus curve analysis. RESULTS: We found a mean increase of monocular CDVA from 0.35 to - 0.01 logMAR. Binocular DCIVA at 90, 80 and 60 cm was - 0.07, 0.04 and 0.07 logMAR, respectively. Even with a principle focus on intermediate distances, we found a functional DCNVA of 0.33 logMAR. Defocus curve analysis showed a visual acuity of 0.3 logMAR in a range of - 2.5 D to + 1.0 D. CONCLUSION: Binocular implantation of the AT LARA 829MP targeting emmetropia gives stable visual acuity from the distant to the near intermediate range, still with functional vision at the near distance of 40 cm. PMID- 30005441 TI - [Traumatic Macular Hole]. AB - The traumatic macular hole (TMH) is a rare complication of a blunt or an open injury of the globe and can lead to permanent loss of vision. The pathomechanism of TMH differs from that of the idiopathic macular hole (IMH). A sudden compression and expansion of the globe leads to vitreous traction, which can result in a TMH. The final visual acuity depends on the severity of the disruption of the photoreceptors and the retinal pigment epithelial cells. The posttraumatic approach is discussed controversially. A spontaneous closure and, therefore, a conservative approach should be considered in young patients with minor defects and good visual acuity without detachment of the posterior vitreous body. In these cases, it is advisable to wait for months. In the absence of adhesion at the edges of the hole and concomitant pathologies of the pigment epithelium, the spontaneous closure is improbable. In this case, a pars plana vitrectomy with removal of the vitreous and epiretinal membranes can lead to anatomical reconstruction and improvement of the visual acuity. The success of an operative intervention is complex and is associated with the experience of the surgeon as well as the characteristics of the trauma. PMID- 30005442 TI - [Assessment of complex posttraumatic stress disorder with the revised Trauma Symptom Inventory (TSI-2)]. AB - BACKGROUND: This study tested whether it is possible to diagnose complex posttraumatic stress disorder (CPTSD) according to the beta version of ICD-11 by means of the Trauma Symptom Inventory 2 (TSI-2). Currently, there is no established measurement for this. METHODS: An algorithm for the TSI-2 was developed. This was tested in a sample of 100 psychiatric patients, who had experienced aversive and/or traumatic events. The frequency of CPTSD and differences regarding gender, age and traumatic events will be reported. RESULTS: On the basis of this TSI-2 algorithm, 5% of the sample were estimated to suffer from CPTSD. A trend towards more women being affected was observed, and younger patients were more affected than older ones. Traumatized individuals reported more mental health problems than non-traumatized ones. CONCLUSION: Tentatively, these results indicate that it may be possible to use a combination of certain scales of the TSI-2 to diagnose CPTSD in line with its current definition by the ICD-11. PMID- 30005443 TI - [Social Anxiety in individuals with clinical high-risk state for psychosis]. AB - In recent years an increased comorbidity of schizophrenic disorders with anxiety disorders has been reported. Thus, among patients with a disorder from the schizophrenia spectrum, a general anxiety disorder was found in 38.3 % of patients, with 14.9 % of these with social phobia (SP). Especially social anxiety (SA) is of particular importance because it is often associated with depression and can contribute to psychosocial disabilities in patients with psychosis.Anxiety disorders already seem to occur prior to the first psychotic manifestation in the clinical high-risk state (CHR). Therefore, the questions arise as to whether this comorbidity is also dominated by SP in this patient group and, if so, what its consequences are on early detection and prevention of psychotic disorders. To clarify these questions, the present paper provides a systematic review of all published studies on social anxiety (SA) in the CHR.A total of 124 studies were included comprising 1702 CHR individuals, 445 healthy controls, 67 relatives / siblings of patients with psychotic disorders and 95 patients with a psychosis. In the most meaningful study, anxiety disorders were generally highly significant in CHR individuals (51 %) compared to control subjects from the normal population (4 %). Among those with anxiety disorders, 14.4 % suffered from SP compared to 0.36 % in normal controls and thus SP was almost as frequent as the prevalence of this type of anxiety disorders in the schizophrenic spectrum (14.9 %). Also, the degree of SA in CHR individuals (SIAS score = 34.4, SD = 6.11) (SIAS-Score = 22.1, SD = 8.7), measured with the Social Interaction and Anxiety Scale (SIAS) in 9 studies, was almost as high as in psychotic patients (SIAS score = 35.0, SD = 9.56) and healthy controls (SIAS score = 14.,6; SD = 7,28). This degree of SA was also related to the attenuated psychotic symptomatology of the CHR individuals. However, the only study investigating the relationship between SA and a possible transition to a first psychotic manifestation did not reveal any predictive power. The feared psychosocial loss of function, which is already present in CHR, seems to be connected not only to the strong SA, but also to the similarly frequent comorbid depressive disorders.Moreover, one study has already provided some evidence that it is promising to address the SA as well as functional impairments in the CHR through newly developed specialized cognitive behavioural therapies. PMID- 30005444 TI - Selective application of fully covered biliary stents and narrow-diameter esophageal stents for proximal esophageal indications. AB - BACKGROUND: Proximal esophageal stents are poorly tolerated and have a high risk of complications. We report our experience using fully covered, biliary, self expandable metal stents (B-SEMS) and narrow-diameter, esophageal, self-expandable metal stents (NDE-SEMS) for this group of patients. METHODS: 24 patients underwent placement of B-SEMS or NDE-SEMS for proximal esophageal lesions between 1 January 2011 and 31 July 2016. The outcomes included improvement of dysphagia, healing of fistulas, and adverse events. RESULTS: 10 patients received B-SEMS and 14 had NDE-SEMS. Median follow-up time was 11.5 months (range 0.5 - 62 months). In both cohorts, stents were left in place for a mean of 6 weeks. The dysphagia score decreased in 7 (70 %) and 10 (71.4 %) patients, and fistulas resolved in 3/5 (60.0 %) and 5/8 (62.5 %) patients with B-SEMS and NDE-SEMS, respectively. Stent migration occurred in three patients (30.0 %) with B-SEMS and five patients (35.7 %) with NDE-SEMS. CONCLUSIONS: Both stents were well tolerated and resulted in overall improvement of dysphagia in 70.8 % of patients. B-SEMS appeared to be more favorable for cervical esophageal lesions with narrower diameters, while NDE-SEMS may be better for more distal lesions. PMID- 30005445 TI - Cross-over study in hyperammonemia patients for efficacy, safety, and acceptability of a new lactulose preparation (SK-1202) compared to approved drug. AB - AIM: A novel jelly lactulose preparation (SK-1202) has been developed to improve compliance and reduce the elevation of blood glucose levels in diabetic patients. To compare the equivalence in the efficacy and safety of SK-1202 and an approved commercially available syrup preparation, we undertook a randomized multicenter cross-over study in hyperammonemia patients with liver cirrhosis who were taking lactulose. METHODS: Forty-four patients were enrolled and took each preparation for 2 weeks. Efficacy was evaluated using the Number Connection Test, blood ammonia concentration, coma grade, and the flapping tremor grade. Safety was evaluated by the number of adverse events observed, vital signs, and laboratory tests. We also examined the acceptability of each preparation using questionnaires evaluating sweetness, aftertaste, ease of use, and preference of the preparations. RESULTS: There were no differences in efficacy or safety between SK-1202 and the approved syrup preparation. With regard to the acceptability evaluation, given over 80% of the participants chose the SK-1202 preparation, it appears to be preferred by patients. CONCLUSIONS: It is expected that SK-1202 could represent a useful agent for patients with hepatic encephalopathy. PMID- 30005446 TI - Ratio between estimated glomerular filtration rates of creatinine and cystatin C predicts overall survival in patients with hepatocellular carcinoma. AB - AIM: Hepatocellular carcinoma (HCC) patients with sarcopenia have a poor survival, but there are no predictive markers for survival relating to muscle mass and liver function. Therefore, we investigated whether the ratio between estimated glomerular filtration rates of serum creatinine (Scre) and serum cystatin C (Scys) (eGFRcre/eGFRcys) can be used as a predictive marker of survival in HCC patients. METHODS: First, the correlation between Scre/Scys ratio and muscle mass was examined in 50 patients with chronic liver disease. Second, a change in Scre/Scys ratio relating to liver function was investigated in cirrhotic rats. Finally, the relationship between the eGFRcre/eGFRcys ratio and survival was assessed in 86 HCC patients. RESULTS: The Scre/Scys ratio was correlated with skeletal muscle mass index (r = 0.331, P = 0.019) and psoas muscle area index (r = 0.397, P = 0.004) in chronic liver disease patients. In cirrhotic rats, Scre and Scre/Scys ratio were decreased corresponding with liver function. Thirty-five of 86 HCC patients died within the average follow-up period of 35 months. The patients with an eGFRcre/eGFRcys ratio <1.26 had significantly longer rates of survival compared to patients with an eGFRcre/eGFRcys ratio >=1.26 (28.8 vs. 18.5 months, P = 0.001). Using multivariate Cox regression analyses, the patient-related eGFRcre/eGFRcys ratio (hazard ratio [HR], 4.178; P = 0.007), as well as the tumor-related factors alpha-fetoprotein (HR, 1.000; P < 0.001) and Barcelona Clinic Liver Cancer stage (HR, 2.589; P < 0.001), were independent predictors of survival. CONCLUSION: The Scre/Scys ratio is associated with muscle mass and liver function. Furthermore, the eGFRcre/eGFRcys ratio could serve as a useful predictive marker for survival of HCC. PMID- 30005447 TI - Artistic representations of short stature, a tentative diagnosis. AB - Throughout human history, disease-related short stature has represented a source of fascination. Following the recent advances in genetics and molecular biology, several hundreds of possible causes are now to be considered. We present herein a few examples of the diagnosis approach of such cases from art sources (sculptures, paintings or photographs for the most recent periods), associated or not with biographical data, allowing semiological and anthropological analyses. The explored period spans from antic great civilizations to 19th Century Western societies. The palaeopathological diagnosis method is based upon medical approach. It includes a search for possible associated abnormalities and the distinction between proportioned, mainly related to hormonal disorders (particularly growth hormone deficiency), and non-proportioned cases especially associated with genetic skeletal dysplasias. Among this latter category, achondroplasia is the most represented cause of short stature. Other more exceptional etiologies are also reported. PMID- 30005448 TI - A commentary of in Plaute Cappadox in his Curculio by Dr. J. A. Vander Linden. AB - In 1656, some Selecta medica of Dr Johannes A. Vander Linden (1609-1664) were published in Leiden. Among these miscellaneous, it was quite unexpected to come on a medical commentary on a fictional character from Plautus' theatre : Cappadox hepaticus, or the Bilious. Today unknown, full of erudite quotations, this scholarly doctor's commentary is both philological and medical, on twenty densely printed pages in Latin. Every term used by Plautus is analized, weighed up, and confronted with texts or contemporary situations, thereby drawing knowlegde for his everyday work, how to define a bilious, hydropical affection. PMID- 30005449 TI - Charriere's scale. AB - The writer explains the origin of the scale measuring the external diameter of different types of bougies, catheter or probes. That scale has turned out to be an essential tool for the best of several specialities created in the 19th century, namely urology. An instrument maker close to the surgeons whose ideas he would quickly grasp, Joseph F. B. Charriere, proposed a scale with thirty holes that would make it possible to get external gauge of the third of a millimetre. Several people tried to imitate his device but his scale was eventually recognized as the most efficient one all over Europe, accepted even by the British and then the Americans. Its usefullness goes on to this day as the French scale has become universal together with the unit that it entails, the Charrire unit, which is still the reference to measure all the diameters used by surgeons and doctors. PMID- 30005450 TI - Kusomoto Ine, the 1st woman-doctor in Japan. AB - Kusumoto Ine was the first woman to practice Western medicine in Japan. Born in 1827, she will live at a turning point in the history of the country: the end of the Edo period (1600-1868) and the beginning of the Meiji period (1868-1912). Her birth, as mysterious and romantic as the-rest of her existence, has unleashed the imagination of writers, feuilleton, Japanese manga artists, so much so that - in the burgeoning romances more or less vapid who made her today a popular heroine - the search for authentic life data is sometimes difficult. The socio-cultural status of Japan in the nineteenth century - which provides information on the status of women - reveals a much less romantic story, but still as prodigious. In France, where his father, Philipp von Siebold, a German physician, great Traveller and marvelous botanist, is well known, a biography Kusumoto Ine had never yet been made. PMID- 30005451 TI - A strange imaginotheca by Louis de Caseneuve. AB - Our purpose was to analyse the treatment of one of Galen's major contributions, his systematization of the doctrine of the four temperaments he inherited from his predecessors (Aristotle, Alcmaeon of Crotone, Empedocles, Philolaus), in Lodovico Casanova's Hieroglyphicorum et medicorum emblematum dodekakrounous (Lugduni, Sumptibus Pauli Frellon, 1626). We concentrated on the four temperaments to study how in medical emblems, allegory and symbols are used to represent medical knowledge through the device of visual loci destined to be decoded and memorized. PMID- 30005452 TI - Theodore Tronchin (1709-1781) and his friend Louis de Jaucourt (1704-1779). AB - Tronchin's main importance lies in his contribution to personal hygiene, more than to pioneering research. He was an industrious promotor of the inoculations of smallpox against all opposition offered by conservative physicians politicians and theologists. As an inoculator he was most successful in France, the Netherlands and Switzerland. He always tried to suppress malpractice committed by his colleagues and never ran away from conflicts. PMID- 30005453 TI - L'Ennemi de la Mort, the fight against the fevers'realm. AB - The plot of the Ennemi de la Mort, published in 1908, one year after the death of the author Eugne Le Roy, is briefly presented: in 1820, the young practitioner Daniel Charbonniere, who is of Huguenot origin, comes home to the French "Double" region in Dordogne. For a while, he is enticed by his cousin Minna de Lege, having saved her life. But, as Charbonniere thinks that their inequality of wealth is a barrier, he disregards her desire, which leads the very devout cousin to marry the nephew of her spiritual adviser. Daniel Charbonniere shows himself a disinterested physician, dedicated to the ill peasants suffering from malaria caused by the waters of the Double marshes. He aims to obtain the dry draining of these pools., With the help of a mayor and a priest, the physician also distributes inoculation against poxes and, otherwise, saves the life of a young lady, who later on becomes his companion. Confronted with charlatanry and the hostility of the landlords owning the pools, Daniel Charbonniere is beaten up by the peasants. Dispossessed by his very embittered cousin Minna, the physician goes to live with his wife and children in a decrepit sheep shelter. The persecutions go on and the peasants, instigated by the clergymen, murder Daniel's wet nurse and profane his ancestor's tombs. He ends his life in loneliness. The character of the physician is then analyzed more thoroughly ; under the aspect of his convictions and his humanistic engagement, in the name of which he doesn't accept any accommodation with a wealth-driven society, Charbonniere appears as a freethinker and a very indulgent practitioner, a scientist and a wholehearted mind shaped by the Enlightenment's spirit. In appendix to this analysis follows the rapid description of a litigation, which occurred in 1862 in the village of Les Riceys (Aube district), about a pool, of which Dr. Gabiot, the physician in charge of the epidemics, struggled to obtain the dry draining, in order to eradicate typhoid fever and dysentery. This practitioner stumbled upon the local public authorities, and, despite the support of the prefect, lost his fight. PMID- 30005454 TI - The effects of World War I upon French ophthalmology. AB - Among the health emergency of World War 1, the one relating to the visual organs injuries is one of the most serious. The use of weapons of new type (grenades, shells, shrapnel) that produce chips that are projected on faces, brings the number of soldiers eye injured to an already impressive quantity at the end of the first year of conflict. This emergency is completely unexpected and it is particularly serious because this kind of trauma was extremely disabling. This situation cause a reaction by French ophthalmologists who start working to improve the organization of assistance, to administer effective treatments and surgery, and even on some issues beyond the medical field (legislation, assistance for war blinds). This article presents the main issues that French ophthalmologists have had to confront with during the Great War and, through this, to question the impact of the First World War on the development of ophthalmology as a medical specialty. PMID- 30005455 TI - Edouard Toulouse as a psychiatric counsellor of Paul and Victor Margueritte, brothers and novelists. AB - A bunch of letters unpublished until to-day and preserved in the collections of the Bibliotheque interuniversitaire de santj in Paris makes it possible to understand the role of Dr. Edouard Toulouse as a psychiatric counsellor among the literary world in Paris, both in vivo and in libris, and this especially concerning the brothers Paul and Victor Margueritte, novelists, essayists and playwrights. PMID- 30005456 TI - A leisurely comment on the list of medical saints by Abraham Bzowski in 1621. AB - The author presents a booklet dating back to 1621 printed in Rome, the work of a preacher, brother Abraham Bzowski (Bzovius), one of the writers of the famous Annals of Cardinal Baron. He draws up a list of 29 doctors who have been sanctified by the Roman Catholic Church. PMID- 30005458 TI - Public Health Implications of Medical Marijuana. PMID- 30005459 TI - Pediatric Screening in Primary Care Settinas. PMID- 30005457 TI - Blood transfusion during World War I (1914 - 1918). AB - In august 1914, at the start of World War I, blood transfusion remains quite infrequent, with rough methods, inaccurate indications and poor results. The direct surgical techniques of arteriovenous anastomosis proved ill-adapted to the emergency conditions of war wounds. Indirect techniques with syringes and storage tubes were frequently limited, and complicated, by blood-clotting. Moreover, despite Landsteiner's discovery of ABC blood groups in 1901, compatibility testing was poorly known and often considered unnecessary. At the beginning of the war, none of the belligerent armies'medical services was specifically organized for blood transfusion. In the early years of the war (1914-1916), blood transfusions remain rare. The first transfusion in the French army was performed by Emile Jeanbrau on 16 October 1914. The main impulse, however, came from surgeons of the Canadian Army Medical Corps (CAMC), who had learned about transfusion from doctors in the United States (Bruce Robertson, Edward Archibald). Transfusions became increasingly frequent, particularly as part of pre-operative preparation in cases of wound shock and hemorrhage. The last years (1917-1918) were marked by the arrival of the American Army in France, with a growing medical influence of American doctors. Oswald Robertson introduced the use of citrated blood in glass bottles, being subsequently called "the first blood banker". Blood transfusion remained throughout the war infrequent and technically imperfect. Wartime, however, by the efforts of some young Canadian and American doctors, was a tremendous opportunity for diffusion and improvement. PMID- 30005460 TI - Collaboration between Pediatric Primary Care Providers and Child and Adolescent Psychiatrists in Arkansas: Where to Start?. AB - There is a considerable shortage of child and adolescent psychiatrists (CAPs) in Arkansas. Collaboration between pediatric primary care providers (PCPs) and CPSs is an innovative model of care that may address this shortage. A tiered model of collaboration, ranging from brief speciality consultation to intensive psychiatric services, may help with early treatment and expeansion of available services to a larger population. We describe the current state of collaboration in Arkansas between the two specialties and steps for additional collaboration. PMID- 30005461 TI - Hypertrophic Cardiomyopathy in an Adolescent. PMID- 30005462 TI - Absurdities from the Wrong Side of the Sheets Part 3 - Experiences as a Patient. PMID- 30005463 TI - LATINA ADOLESCENTS' PERSPECTIVES ON RELATIONSHIPS. AB - OBJECTIVE: To explore adolescent Latinas' perspectives on relationships and generate knowledge to inform interventions. SETTING: Seven Latina adolescents participated. DESIGN: This qualitative study was guided by principles of community-based participatory research and utilized the photovoice method. METHOD: Participants took photos depicting elements of relationships and participated in guided discussions. They identified and named five elements of healthy relationships. RESULTS: The five elements included commitment, communication, faith, amigos y amores (friends and lovers) and play. These elements occur across all forms of relationships. CONCLUSION: The results revealed important information that may be used to tailor health promotion interventions for Latina/o youth. PMID- 30005464 TI - CULTURE OF OPPRESSION IN AFRICAN-AMERICANS WITH HEART FAILURE. AB - African-Americans are disproportionately affected and have a greater incidence of heart failure compared to other populations. Current literature identifies many contributory factors, among which is the role of culture. Culture, defined to include socioeconomic status and the historical and sociological experience of African-Americans, may play a pivotal role in how clients manage their symptoms of heart failure. This study attempts to explain how culture contributes to the lack of successful management of heart failure among African-Americans using the framework of Hofstede's cultural dimensions of power distance and individualism. PMID- 30005465 TI - NANDI TRADITIONAL HEALERS: SENTINELS IN AN UNDERSERVED ENVIRONMENT. AB - : Project Purpose: Discuss the healing practices and expressions as well as any perceived barriers to practice of traditional Nandi healers working as specialized herbalists (three) and midwife (one) in a rural community in Western Kenya. METHODOLOGY: This Doctorate of Nursing Practice (DNP) project used qualitative approaches including individual recorded interviews conducted in private in a community in rural western Kenya, which were later transcribed and reviewed with key messages identified. The key messages were then corroborated by the participants and reviewed by the doctoral project committee. PARTICIPANTS: Four traditional healers, self-identified as herbalists and/or midwives. FINDINGS: Five key messages emerged from the data which included; knowledge related to traditional healing, practice of traditional healing, compensation, outsiders, and the future of traditional healing in this community. PMID- 30005466 TI - EXPLORING HEALTHCARE PERSPECTIVES OF BURMESE CHIN REFUGEES. AB - The objective of this study was to understand the Burmese Chin refugees' experiences with and perspectives on the United States healthcare system. Using a mixed-methods study design, a survey was distributed and focus groups were conducted. Thirty-seven surveys were completed. Five major themes emerged from the focus group discussions: time, language barriers, relationships with healthcare providers, traditional medicine, and adolescents'roles in their community. Refugee healthcare perspectives give health providers insights on how to work towards providing culturally appropriate care. PMID- 30005467 TI - THE PERCEPTIONS AND REFLECTIONS ON RACIAL/ETHNICITY DIVERSITY IN OUTDOOR RECREATION. AB - The collaborative, student-led research team was concerned with race and ethnic diversity in outdoor recreation and explored this issue by interviewing outdoor instructors. Video action research and pedagogy was used based on characteristics of critical thinking, research, reflection, and social justice. The result indicate the disparity of outdoor recreation participation and factors contributing to it. The reflections show an interest, on the part of the next generation of outdoor recreation professionals and student researchers, to address the disparity issue and analyze thefieldfrom a new perspective. PMID- 30005468 TI - About a singular anatomic specimen given by Dominique Larrey to Paris medical school. AB - The Dupuytren Museum in Paris has a remarkable anatomic specimen which figures in the surgeon Larrey's works of 1812 and 1829. It consists of a soldier's skull impaled by the ramrod of the musket of one of his co-soldiers. The wounded soldier survived two days with this ramrod through his head. Besides this singular case, Larrey reports several observations of the uses and misuses of trephination with local and general appropriate cares to provide. Indications are also exposed in the Dictionnaire des sciences medicales Panckoucke published in 1821. PMID- 30005469 TI - Guy Patin and his martyrology of those dead because of antimony. AB - Antimony was a chemical drug, similar to arsenic and lead, which was used in medicine since the 16th century. It brought intense controversy: for his supporters, it possessed exceptional properties, with three simultaneous effects, summarized by Libavius formula : vomere, cacare, sudare ... appreciable qualities at a time when Humorous theory was anchored in the minds. The detractors of antimony, among whom Guy Patin (1602-1671), pointed out that many patients treated with this remedy died... Patin's reflexions against the use of antimony in medicine are found in his letters, with a cumulative list of accidents that Patin liked to call his "martyrology of antimony", an expression he used, for example, in a letter to Andri Falconet on March 20, 1654. Our aim is to place Guy Patin's writings in the medical and social debate of his time, when several writers such as Benserade, Molire and Boileau also participated. PMID- 30005470 TI - A French interpretation of Galen's anatomy of the late Middle ages. AB - The main objective of this research was,for the first time, to partially edit an anatomical text in middle french, the ms FR 19.991, a 15th century manuscript held by the Bibliotheque Nationale de France. After restitution of the text (transcription, expansion of abbreviations and identification of rubricated sections) a glossary of all terms was compiled. The analysis of this anatomical treatise following the arabic galenic tradition revealed that it results from the assembly of at least three previous texts, the largest part of it (18 / 22 sections) following very closely the anatomia ricardi salertinani, translated from arabic to latin in the 12th century in the Salernitan school of medicine. The use of this treatise remains to be elucidated. PMID- 30005471 TI - The mortality rate of military men at Boulogne-Sur-Mer hospital during the 18th century. AB - Rebuilt at the end of the 17th century on the ruins of the Ospital du Bourg, the civilian and military hospital St Louis in Boulogne-sur-Mer was in charge all over the 18th century. About 4000 persons - from whom 25% military men- died there. Beyond the data found among the death certficates, the analysis of the registers gives information about the Protestant soldiers, the burial time, the original making of a skeleton according to the rules of classical anatomy ... The wars in Europe or outside concerned Great Britain, France and their allies. The consequences are found in the agenda of the surgeons' meetings in town. PMID- 30005472 TI - The preservation of the museums of medical history. AB - The survival of French museums of the history of medicine is very much threatened by the lack of interest shown by their supervisory authorities. Their collections are invaluable both from a patrimonial point of view and from their interest in research, teaching future health professionals, raising public awareness of health issues and their memory importance in relation to the suffering of generations of Sick people. As part of the "Ile de la Cite" project, the opening of a large health museum on part of the site of the Hotel-Dieu in Paris would be a strong signal to enhance this extraordinary heritage. PMID- 30005473 TI - The value of chrtmogenic activity assay in diagnosis and therapeitic monitoring of hemophlia. PMID- 30005474 TI - Insulin, insulin antibodies and insulin autoantibodies. PMID- 30005475 TI - Complications resulting from uncontrolled diabetes. PMID- 30005476 TI - Integration in digital pathology. PMID- 30005477 TI - Digital pathology enhances cancer diagnostics. PMID- 30005479 TI - Better bioinformatics will help labs manage genetic testing. PMID- 30005478 TI - The role of clinical informatics in patient care and resource management. PMID- 30005480 TI - What's new in today's LIS?. PMID- 30005481 TI - The LIS in our patient-centric time. PMID- 30005482 TI - Physician office labs leverage information systems to prepare for more fee schedule cuts. PMID- 30005483 TI - Special sample types for urine MDx. PMID- 30005484 TI - 900 MHz wireless hospital temperature monitoring: an alternative to WiFi. PMID- 30005485 TI - New administration, continuing challenges Clinical lab leaders will work with political leaders to make the best policy choices for diagnostics. PMID- 30005486 TI - The end of flu season is in view: How did your lab do with POCT?. PMID- 30005487 TI - Advances in POCT technologies outpace regulatory and accreditation requirements. PMID- 30005488 TI - 3 Lessons from Your Quest for Quality. PMID- 30005489 TI - Hospitals try Zika clinic, school partnerships to minimize risk. PMID- 30005490 TI - What a general can teach physicians about leadership. PMID- 30005491 TI - Three questions for: Christopher Dawes. PMID- 30005492 TI - Departing hearty. PMID- 30005493 TI - Using pop health analytics for collaborative care plans. PMID- 30005495 TI - Green fund delivers results. PMID- 30005494 TI - CASTING THE NET Sentara Healthcare manages quality at the system level. PMID- 30005496 TI - Active approach works best for battling opioid addiction among clinicians. PMID- 30005497 TI - The 4 Forces that Will Reshape Nursing. PMID- 30005499 TI - 'Genius Bar' Links Patients Devices for Better Engagement, and Outcomes. PMID- 30005498 TI - Expanding Global Reach Academic medical centers lead efforts to build international partnerships and business development. PMID- 30005501 TI - Strengthening our Commitment to Health Equity. PMID- 30005500 TI - The power of hospital and community partnerships. PMID- 30005502 TI - Florida hospital proves an active-shooter plan can save lives. PMID- 30005503 TI - More than a medical home for the mentally ill. PMID- 30005504 TI - Hospitals and libraries 'go by the books'. PMID- 30005505 TI - Rigorous cleaning standards help to prevent spread of new E. coli strain. PMID- 30005506 TI - Three questions for Kevin Vermeer. PMID- 30005508 TI - Tapping the Potential of Community Paramedicine. PMID- 30005507 TI - THE PAIN PARADOX. AB - If he had remained on prescription painkillers for much longer, Anthony Newberry was fairly certain he would have taken his life. It had been about 15 months since a giant metal bar fell at the construction site where he was working and crushed his foot, nearly severing his toes. Newberry, 38, of Millington, Ill., had been taking opioids for months to relieve the pain, with improperly healed nerves making it feel as if his foot and leg were "a pack of firecrackers, all day everyday. Just like someone lighting one every day, every second." Opioids helped to mask the pain, but he didn't feel like himself on the drugs and couldn't regain his commercial driver's license while medicated. One night, in a moment of desperation, he dumped the pills in the toilet and promised he'd find another way to return to his normal life. Heroin and prescription painkiller abuse kills tens of thousands of Americans each year and ensnares many more in crippling addiction. The tragic phenomenon corresponds with -- and to an alarming degree, arises from -- an epidemic of pain that affects millions, driving them to seek relief at hospital emergency departments and primary care clinics. Now, health care providers are confronting the intertwined epidemics by working to break their own long-entrenched proclivity toward prescribing opioids to treat their patients' pain. PMID- 30005509 TI - Strengthening Pediatric Services. PMID- 30005510 TI - When Hospitals Come Together, So Must Their Boards Integrated health care systems redefine governance at the local and system levels. PMID- 30005511 TI - Getting the Most Value From Your Physicians Hospitals have improved medical group operations, but bundled payment and other challenges loom. PMID- 30005512 TI - REVISITING "THE INVISIBLE CULTURE OF THE MULTIRACIAL, MULTIETHNIC INDIVIDUAL: A TRANSCULTURAL IMPERATIVE". AB - Past and present policies, politics, myths, stereotypes, and societal attitudes influence the lived experience of multiple heritage individuals, often resulting in marginalization, disparities, invisibility, cultural pain, and/or unmet needs. This article offers commentary about the past and present with thought-provoking questions for future direction regarding "The Invisible Culture of the Multiracial, Multiethnic Individual: A Transcultural Imperative." The commentary revisits and reminds readers about the 2001 article on the same topic, quickly brings them to the reality of the present, and challenges nurses and other professionals to dismantle disparities through cultural congruent care that focuses on making the invisible culture visible. PMID- 30005513 TI - THE INVISIBLE CULTURE OF THE MULTIRACIAL, MULTIETHNIC INDIVIDUAL: A TRANSCULTURAL IMPERATIVE (REPRINT FROM 2001). AB - The main purpose of this introauctory article is to evoKe professional awareness, spark interest, stimulate thought, and disseminate information concerning multiracial, multiethnic (multiple heritage) individuals within the United States. General background information, terms, definitions, ethno-historical influences, practice implications, and current issues will be highlighted. Areasforfurther exploration will be proposed. Transcultural imperatives urge all nurses and other health care professionals to become active participants in the new cultural evolution of a different, broader worldview that uncovers the "invisible" culture of multiple heritage individuals. The new vision challenges nurse and other health care professionals to embark upon a new journey in the quest for cultural congruent care for all individuals. PMID- 30005514 TI - IMMIGRANT CHILDREN IN THE CONTEXT OF MULTICULTURAL EARLY CHILDHOOD EDUCATION. AB - In a multicultural country, such as New Zealand, multicultural education has become the subject of early childhood polices and research. Increased national and international attention towards minority rights has resulted in the development and implementation of multicultural practice for realizing quality early childhood education for children and families of diverse cultural backgrounds. The study addressed in this paper set out to examine the multicultural education of early childhood set- tings in New Zealand from the experiences and perspectives of Chinese immigrant young children, their teachers and parents. It analyses data in the conceptualization of children as active agents, with the emphasis on the influence of their homes and the early childhood centres, giving rise to a tension between the children's needs to fit in the centres and the children's and their parents' right to inclusion and be different. PMID- 30005515 TI - ENHANCING CULTURALLY COMPETENT NURSING CARE IN SAUDI ARABIA. AB - This study examined the cultural competence of expatriate nurses using self reported individual assessment tool, and evaluated if there was an improvement after the educational training provided by nurse educators. Utilizing the Individual Assessment of Cultural Competence tool, questionnaires were administered to nurses (n=584) before the educational training and six months thereafter. A response rate of 90% was obtained. The data revealed that there was no significant difference between pre-test mean score and post-test mean score, (p-value=0.488). However, nurses' self-reported cultural competence was improved, (mean post-test gain = 0.020). Nurses'cultural competence was enhanced through the designed educational training program. PMID- 30005516 TI - Canada Health Act 2.0: Are the Fundamental Principles Still Current, or Do They Need to be Revisited? AB - The Canada Health Act was passed in the run-up to the 1984 Federal Election to meet a political problem - perceived inequities in access to care due to extra billing by physicians and hospitals. At that time, health care as a right of citizenship was still a topic of debate. Health care was for the sick, and effective interventions were few and inexpensive. The provision of health care was seen as a morally justified social cost. Today the problem is different. We are in the midst of the largest transformation in biological understanding since the invention of the microscope. New treatments are being found powerfully effective, yet costly. A new, high value added, economic sector has developed: health innovation. Health care is an unquestioned social right. Yet, although a disproportionate amount of the foundational science has come from Canada, increasingly we are unable to access the medical, economic and social benefits of a global health economy. We need a permissive, catalytic, legislative framework (CHA 2.0) that will bring together the economic strength of health innovation and the delivery of its benefits to the health and wellness of Canadians. It would espouse the following seven principles: 1. Health care and health innovation are parts of a nationally critical health economy, with a global perspective. 2. Public and private sector involvement and accountability. 3. Change and innovation mandated and rewarded. 4. Labour mobility across jurisdictions, and role mobility across professions. 5. Patient-centred care. 6. Holistic and comprehensive, based on evidence. 7. Outcome (not process) driven, and transparent in implementation. PMID- 30005517 TI - The Canada Health Act for the Twenty-First Century?. AB - As the participants in the Canada Health Act, Version 2.0 conference made clear, there is a strong case to be made that this key piece of legislation no longer captures some key challenges to managing health care in Canada. Particular issues include 'portability' across provincial/territorial boundaries, and the definition of insured services. However, the CHA is not a barrier to reform; it acts as a floor, rather than a ceiling. Health reform may thus require a combination of new legislation to set conditions for which new services should be insured, and developing mechanisms to identify priorities, ensure appropriateness, and improve efficiency, which are unlikely to be addressed through overarching legislation. The CHA should thus be maintained, recognizing that it is necessary, but not sufficient. PMID- 30005518 TI - Putting People First: Critical Reforms for Canada's Health Care System. AB - For over 70 years, since the Dominion Provincial Conferences at the end of the Second World War, Canadians have viewed health care as a right of citizenship. The Canada Health Act (CHA, 1984) formally entrenched the five principles that guide our current publicly operated, single payer, provincially managed system: public administration, comprehensiveness, universality, portability and accessibility. The health care system that has sprung up around the CHA has become increasingly complex, costly and strained. Our gradual descent through the rankings of major health care suggests that we are reaching the limits of what the current health care system can provide. Unfortunately, constructive political debate around this issue is often choked by intense ideological positioning. System reform is urgently needed to address the rapidly changing biological and demographic drivers of health. We do not feel that diverting ever larger flows of money into the status quo is a sustainable solution. Our nation's health and the means to advance it must be seen as assets rather than costs. We believe it is possible to meet increasing demands by expanding the supply and acknowledging the wealth of resources (scientific, human, managerial and educational) that we currently possess. In this paper we propose a cultural shift from an institution centered system bent on cost control, to a patient-centered system that fosters a true health economy. We identify a series of interventions (some bold and others less so) to achieve a clear and evaluable goal: maximizing the well-being and debility-free life expectancy of each individual. To achieve a patient-centred system-we discuss strategies to address costs and utilization, the setting of real performance standards, the elimination of conflicts of interest and the provision of truly accessible care for all Canadians. To create a health economy, we discuss the importance of innovation, the need for a reinvigorated public health system and steps to overhaul the health care human resources environment. The goal of health care reform in Canada should be a system that is dynamic, evidence based, wealth creating and a global leader. We believe that, with leadership and vision, this goal is eminently achievable. PMID- 30005519 TI - Addressing Ten Unhelpful Myths about the Canada Health Act and Why It Matters. AB - Since its enactment in 1984, the iconic Canada Health Act (CHA) has been at the centre of a polarized debate on whether universal coverage should be expanded or restricted in Canada. This discussion on the future direction of Canadian medicare has been vexed by prevailing myths about the CHA. These myths are unhelpful in that they perpetuate misleading notions about the ambit and impact of the CHA. This article deconstructs 10 of the more common myths to get at the realities of the CHA and the extent to which it sets national standards and constrains - or does not constrain - provincial health reform and innovation. Understanding the realities of the CHA is becoming a critical litmus test for the courts as they interpret the CHA and the provincial laws and regulations, which were established in conformity with five criteria - public administration, comprehensiveness, universality, portability, and accessibility). Separating myths from realities also allows practitioners and scholars to better understand the limits of the CHA. PMID- 30005520 TI - Six Myths About Pharmacare. AB - Canada is the only country with a universal public health care system that does not include coverage for prescription drugs; lack of drug coverage leads to underuse of necessary medications. Arguments have been advanced for and against a national pharmacare plan. This article investigates six commonly cited reasons for not introducing such a program in order to determine their validity - private plans are doing a good job, public plans should only cover the poor, strengthening the pan-Canadian Pharmaceutical Alliance is all that is needed, a public plan will deny people access to important new drugs, pharmacare will cost too much and pharmacare is just about money. The evidence presented shows that these are just myths. PMID- 30005521 TI - How Much is Too Much? In response to opioid prescribing guidelines, two Arkansas physicians weigh in. PMID- 30005522 TI - CPC Plus Will Continue Health Improvement, Lower Costs. PMID- 30005523 TI - Midshaft Clavicle Fractures. PMID- 30005524 TI - A rare case of intra and extra testicular varicocele caused by giant hemangioma of liver. PMID- 30005525 TI - Trends in Lifetime use of Tobacco, Alcohol, and Cannabis among Arkansas Teens from 1995 to 2013. AB - Trends in adolescent use of substance can inform public policy and preventive efforts. Using data from the Arkansas samples in the CDC's your Risk Behavior Surveys (YRBS) from 1995 to 2013 we report and test for trends regarding use of tobacco, alcohol, and cannabis. Trends were also described by gender and race/ethnicity. Lifetime use of tobacco among Arkansas high school students significantly declined from 74.4% in 1995 to 52.1% in 2013 - a decline observed across gender and race. Lifetime use of alcohol declined from 79.3% in 1995 to 67.3% in 2013 - similar except among African-American females which showed no significant decline but remained the group with the lowest reported use of alcohol. Lifetime use of cannabis showed no significant change from 38.8% in 1995 to 36.9% in 2013 - except for African-American males with a significant decline from 47.8% in 1995 to 36.6% in 2013. While adolescent use of tobacco and alcohol has declined in the last 20 years, the use of cannabis has remained stable. These trends point to the success of public policies targeting teen use of cigarettes and alcohol while presenting a challenge regarding the perception and use of cannabis. PMID- 30005526 TI - Amid Change, Hospitals Forge Ahead. PMID- 30005528 TI - Coders confident that ICD-10 changes can be implemented easily. PMID- 30005527 TI - Portland providers donate $21.5 million to housing initiative. PMID- 30005529 TI - New overtime rules could upend pay structures. PMID- 30005530 TI - Partnering with employers to simplify cancer care. PMID- 30005531 TI - UCMC empowers quality with data-driven workflows. PMID- 30005532 TI - Three questions with: Richard Afable, M.D. PMID- 30005533 TI - 'Food is part of their health care'. PMID- 30005535 TI - Playing to where the puck is going in health care. PMID- 30005534 TI - MILLENNIALS Who they are, what they want, & why you need them. PMID- 30005537 TI - It Had a Hold on Me. PMID- 30005536 TI - TRAINING Hospitals look to prevention for better security. PMID- 30005538 TI - Adenoid Cystic Carcinoma of the Maxillary Sinus with Isolated Trigeminal Anesthesia. AB - Adenoid cystic carcinoma (ACC) is a rare malignant secretory gland tumor. It is characterized by slow growth, long clinical course, local recurrences, and distant metastases. In the sinonasal tract, it most commonly arises in the maxillary sinus. It often presents at an advanced stage with perineural spread (PNS). Our patient presented with left-sided facial numbness without other symptoms. The numbness was localized to the left cheek, left side of nose, and left upper lip. Magnetic resonance imaging (MRI) of the brain revealed an enhancing lesion involving the left maxillary sinus with orbital invasion and posterior extension into the cavernous sinus. Transnasal endoscopic exploration with tissue removal revealed ACC. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan revealed no evidence of distant metastases. Presentation of sinonasal ACC (SNACC) is variable depending on the involved structures. Characteristic PNS with ACC may cause neuropathic symptoms. This case displays a unique presentation of an advanced ACC of the maxillary sinus manifesting as isolated unilateral trigeminal anesthesia without sinonasal symptoms. The patient also failed to demonstrate any ocular or oculomotor symptoms despite extensive involvement of the orbit and surrounding structures. This case highlights the importance of recognizing ACC due to its association with late symptomatic manifestations. It also reinforces the need for clinical diligence with the workup of new onset neuropathic symptoms in the maxillary distribution of the trigeminal nerve. PMID- 30005539 TI - Case Report: Intraductal Papillary Mucinous Neoplasms of the Biliary Tract. AB - The present case report describes intraductal papillary mucinous neoplasms of the biliary tract (IPMN-BT), a rare neoplasm of the biliary tract that is described as the biliary counterpart of intraductal papillary mucinous neoplasms of the pancreas (IPMN-P). The importance of appropriate diagnosis and awareness of the clinical manifestations is highlighted. IPMN-BT has a more favorable prognosis and is easier to resect than other forms of intrahepatic cholangiocarcinomas; therefore, early and accurate diagnosis is required for planning of the best treatment strategies for this neoplasm. PMID- 30005540 TI - Catch Me If You Can. AB - Nocardia is a genus of anaerobic gram-positive bacteria that most commonly infect persons with compromised immunity. Pneumonia and soft tissue infections are seen most frequently; osteomyelitis is an uncommonly reported manifestation of nocardiosis. We report a case of pelvic osteomyelitis due to Nocardia asteroides in a patient with unrecognized acquired immune deficiency syndrome (AIDS) without evidence of concomitant pulmonary or skin infection. PMID- 30005541 TI - Bilateral Chronic Exertional Compartment Syndrome of the Leg: A Rare but often Debilitating Condition in Athletes. AB - This report discusses an unusual case of bilateral chronic exertional compartment syndrome (CECS) of the lower leg, a syndrome found mainly in young athletes. Pathophysiology includes exercise-induced muscle expansion against noncompliant fibro-osseous membranes separating compartments of the lower leg. A 24-year-old female distance runner with a history significant for misdiagnosed shin splints and tibial stress fracture presented with acute-on-chronic right lower leg pain. History revealed exertional pain and numbness, alleviated by rest. Subsequent MRI found no tibial abnormalities, and intracompartmental pressure testing demonstrated four compartment pressure elevations, confirming a CESC diagnosis. A minimally-invasive four compartment fasciotomy was performed in the operating room. Two months after return to running, symptoms were improved in the right leg, but appeared in the left leg. Subsequent pressure testing on the left revealed CESC, and four compartment fasciotomy was performed. Her symptoms significantly improved and she returned to running at six weeks without pain bilaterally. PMID- 30005542 TI - CKDu - An Emerging Management Challenge in Rural Communities. PMID- 30005543 TI - Eugene Milton Stansbury, MD: Physician, Surgeon, and Entrepreneur in Vermillion, South Dakota, during the First Half of the 20th Ceutury. PMID- 30005544 TI - The Patient as Reformation - Here We Stand Part Two - A Reformer Among Us. AB - All social reform, as evidenced by Martin Luther, requires disrupters who are willing to speak truth to power. Donald Berwick, as the most Lutheresque figure in the healthcare reform debate, has been doing just that, having defined the singular truth of patient-centeredness and its implications for both the regulated and unregulated parts of medicine. He has consequently been asking wicked questions concerning unproven assumptions, such as competition driven by the integer, over cooperation driven by the immortal. Above all he is reminding physicians of our dual role - clinical healer and social advocate - and that silence in the latter, is no longer an option. Physician-reformers must follow Berwick through this opened door and apply the principles of reformation, on behalf of the patient. PMID- 30005546 TI - Quality Focus: Promoting Patient and Family Engagement Strategies to Improve Health Outcomes. PMID- 30005545 TI - Medication Adherence: A Therapeutic Opportunity. PMID- 30005548 TI - Erratum. PMID- 30005547 TI - Corrigendum to "Second generation anticoagulant rodenticides in predatory birds: Probabilistic characterisation of toxic liver concentrations and implications for predatory bird populations in Canada" [Environ. Int. 37 (2011) 914-920]. PMID- 30005549 TI - Erratum. PMID- 30005550 TI - Erratum. PMID- 30005551 TI - Corrigendum to "Targeted biodegradable dendritic MRI contrast agent for enhanced tumor imaging" [J. Control. Release 169 (2013) 239-245]. PMID- 30005552 TI - Dietary Patterns and Mediterranean Diet Score and Hazard of Recurrent Coronary Heart Disease Events and All-Cause Mortality in the REGARDS Study. AB - BACKGROUND: Previously, we reported on associations between dietary patterns and incident acute coronary heart disease (CHD) in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. Here, we investigated the associations of dietary patterns and a dietary index with recurrent CHD events and all-cause mortality in REGARDS participants with existing CHD. METHODS AND RESULTS: We included data from 3562 participants with existing CHD in REGARDS. We used Cox proportional hazards regression to examine the hazard of first recurrence of CHD events-definite or probable MI or acute CHD death-and all-cause mortality associated with quartiles of empirically derived dietary patterns (convenience, plant-based, sweets, Southern, and alcohol and salads) and the Mediterranean diet score. Over a median 7.1 years (interquartile range, 4.4, 8.9 years) follow-up, there were 581 recurrent CHD events and 1098 deaths. In multivariable-adjusted models, the Mediterranean diet score was inversely associated with the hazard of recurrent CHD events (hazard ratio for highest score versus lowest score, 0.78; 95% confidence interval, 0.62-0.98; PTrend=0.036). The Southern dietary pattern was adversely associated with the hazard of all-cause mortality (hazard ratio for Q4 versus Q1, 1.57; 95% confidence interval, 1.28-1.91; PTrend<0.001). The Mediterranean diet score was inversely associated with the hazard of all-cause mortality (hazard ratio for highest score versus lowest score, 0.80; 95% confidence interval, 0.67-0.95; PTrend=0.014). CONCLUSIONS: The Southern dietary pattern was associated with a greater hazard of all-cause mortality in REGARDS participants. Greater adherence to the Mediterranean diet was associated with both a lower hazard of recurrent CHD events and all-cause mortality. PMID- 30005553 TI - High-Normal Thyroid-Stimulating Hormone Shows a Potential Causal Association With Arrhythmia Recurrence After Catheter Ablation of Atrial Fibrillation. AB - BACKGROUND: Hypothyroidism has been shown to contribute to enhanced atrial arrhythmogenesis, resulting in atrial fibrillation (AF) development in animal models and clinical populations. We aimed to elucidate whether high thyroid stimulating hormone (TSH) levels are related to outcomes of catheter ablation of AF. METHODS AND RESULTS: Of 477 consecutive patients who underwent first-time pulmonary vein isolation-based radiofrequency catheter ablation of AF, 456 with TSH above the lower limit of the normal range (age, 65.5+/-9.9 years; men, 73.9%; paroxysmal AF, 56.8%) were analyzed for this study. Atrial tachyarrhythmia recurrence for 3 years was compared across groups with hypothyroidism (n=23) and TSH quartile groups with euthyroidism (normal-range TSH levels, n=433). Atrial tachyarrhythmia recurrence occurred in 179 patients (39%) after the first session. Patients with hypothyroidism had increased recurrence compared with patients with normal TSH levels (crude hazard ratio, 3.14 after the last session; P=0.001). When focusing on patients with normal TSH levels, recurrence-free survivals after both the first and last sessions were significantly reduced in euthyroid patients with the highest quartile of TSH levels (quartile 4) compared with others (quartiles 1-3). Cox regression analysis identified high TSH levels as an independent predictor of atrial tachyarrhythmia recurrence after both the first (adjusted hazard ratio, 1.51; P=0.018) and last (adjusted hazard ratio, 1.86; P=0.023) sessions. The difference was more pronounced in patients with paroxysmal AF than in those with nonparoxysmal AF. CONCLUSIONS: Not only hypothyroidism but also high-normal TSH levels may be an independent predictor of atrial tachyarrhythmia recurrence after catheter ablation of AF. PMID- 30005554 TI - Magnesium Sulfate-Mediated Vascular Relaxation and Calcium Channel Activity in Placental Vessels Different From Nonplacental Vessels. AB - BACKGROUND: Magnesium sulfate (MgSO4) has been used as a common therapy for preeclampsia and eclampsia for many years. MgSO4 decreases peripheral vascular resistance so as to reduce maternal blood pressure. Whether placental blood vessels react to MgSO4 in the same patterns as that in maternal vessels is largely unknown. METHODS AND RESULTS: This study compared placental vessels (PV) versus nonplacental vessels (non-PV) in human and animal models. MgSO4-caused vascular dilation was significantly weaker in PV than that in non-PV. Prostaglandin I2 synthetase affected MgSO4-mediated vasodilatation in PV, not in umbilical vessels, while cyclooxygenase did not influence MgSO4-induced relaxation in both PV and non-PV. Mg2+-caused vasodilatation was mainly through calcium channels. In PV, calcium channel activities were significantly weaker in PV than that in non-PV. Relative mRNA expression of CACNA1D, CACNB2, and CACNB3 was significantly higher in PV than those in umbilical vessels, despite the fact that the expression of CACNA1F was less in PV. The contractile phenotype of smooth muscle cell marker (CALD1) was less and the synthetic phenotype (MYH10) was more in PV than that in UV. CONCLUSIONS: These results demonstrated that PV were characterized by much weaker responses to MgSO4 compared with nonplacental vessels. The difference was related to weaker calcium channel activity and minor contractile phenotype smooth muscle cells in PV, providing important information for further understanding treatments with MgSO4 in preeclampsia. PMID- 30005555 TI - Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy. AB - BACKGROUND: Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done. METHODS AND RESULTS: We conducted a subanalysis of 3 single-center, randomized, and blinded clinical trials: (1) TAC-HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1-year cardiac structure and function and quality of-life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within-group, P=0.002) compared to ICM (1.5%; within-group, P=0.14; between-group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (-0.2 mL; P=0.73; between group, P=0.02). End-diastolic volume improved only in ICM (10.6 mL; P=0.04) and end-systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (-0.04; P=0.0002). End-diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (-4.1 g; P=0.34; between-group, P=0.007). The 6 minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between-group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between-group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (-19.5; P=0.002) and ICM (-6.4; P=0.03; delta between-group difference P=0.042) patients. CONCLUSIONS: Mesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: TAC-HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON-DCM: NCT01392625. PMID- 30005556 TI - Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways. AB - BACKGROUND: Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI. METHODS AND RESULTS: Adult male Sprague-Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff-perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of ERK1/2 (extracellular signal-regulated kinase 1/2), AKT (protein kinase B), and STAT3 (signal transducer and activator of transcription 3), indicating its ability to activate the RISK (reperfusion injury salvage kinase) and SAFE (survivor activating factor enhancement) pathways. The presence of inhibitors of ERK1/2, AKT, or STAT3 abrogated the gastrin-mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the CCK2R blocker CI988 prevented the gastrin-mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes. CONCLUSIONS: These results indicate that gastrin can reduce myocardial IRI by activation of the RISK and SAFE pathways. PMID- 30005557 TI - Sex and Race Differences in the Utilization and Outcomes of Coronary Artery Bypass Grafting Among Medicare Beneficiaries, 1999-2014. AB - BACKGROUND: With over a decade of directed efforts to reduce sex and racial differences in coronary artery bypass grafting (CABG) utilization, and post-CABG outcomes, we sought to evaluate how the use of CABG and its outcomes have evolved in different sex and racial subgroups. METHODS AND RESULTS: Using data on all fee for-service Medicare beneficiaries undergoing CABG in the United States from 1999 to 2014, we examined differences by sex and race in calendar-year trends for CABG utilization and post-CABG outcomes (in-hospital, 30-day, and 1-year mortality and 30-day readmission). A total of 1 863 719 Medicare fee-for-service beneficiaries (33.6% women, 4.6% black) underwent CABG from 1999 to 2014, with a decrease from 611 to 245 CABG procedures per 100 000 person-years. Men compared with women and whites compared with blacks had higher CABG utilization, with declines in all subgroups. Higher post-CABG annual declines in mortality (95% confidence interval) were observed in women (in-hospital, -2.70% [-2.97, -2.44]; 30-day, 2.29% [-2.54, -2.04]; and 1-year mortality, -1.67% [-1.88, -1.46]) and blacks (in hospital, -3.31% [-4.02, -2.60]; 30-day, -2.80% [-3.49, -2.12]; and 1-year mortality, -2.38% [-2.92, -1.84]), compared with men and whites, respectively. Mortality rates remained higher in women and blacks, but differences narrowed over time. Annual adjusted 30-day readmission rates remained unchanged for all patient groups. CONCLUSIONS: Women and black patients had persistently higher CABG mortality than men and white patients, respectively, despite greater declines over the time period. These findings indicate progress, but also the need for further progress. PMID- 30005559 TI - The fine structure of the spermatozoa of Siphonaria algesirae (Gastropoda, Pulmonata). AB - The sperm of Siphonaria algesirae (Gastropoda, Pulmonata), a species with internal fertilization, was studied by light and electron microscopy. The spermatozoon is a very long, uniflagellate cell composed of a conical head with an apical acrosome, a midpiece with a helically coiled external sheath containing a complex mitochondrial derivative with a wavelength of ~ 5.5 MUm, and an endpiece. There are no axonemal microtubules. Instead, nine homogeneous coarse fibers with transverse striations in the apical zone project toward the anterior section of the midpiece. In the posterior zone of the midpiece the coarse fibers are differentiated in a common microtubular axoneme. The complex mitochondrial derivative of the midpiece shows an organized group of 100 A diameter spherical particles. Externally the midpiece is surrounded along its length by a cylinder formed by two membranes. A complex structure separates the transitional zone between the midpiece and the endpiece. PMID- 30005561 TI - The follicle cell-oocyte interaction in ovarian follicles of the stick insect Bacillus rossius (Rossi): (Insecta: Phasmatodea). AB - Developing ovarian follicles of Bacillus rossius have been examined ultrastructurally in an attempt to understand how inception of vitel-logenesis is controlled. Early vitellogenic follicles are characterized by a thick cuboidal epithelium that is highly interlocked with the oocyte plasma membrane. Gap junctional contacts are present both at the follicle cell/oocyte interface and in between adjacent follicle cells. In addition, microvilli of follicle cells protrude deeply into the cortical ooplasm of these early vitellogenic oocytes. With the onset of vitellogenesis, wide intercellular spaces appear in the follicle cell epithelium and at the follicle cell/oocyte interface. Gap junctions become progressively reduced both on the follicle cell surface and on the oocyte plasma membrane. Microvilli from the two cell types no longer interlock. From a theoretical standpoint each of the two structural differentiations present at the follicle cell/oocyte interface-gap junctions and follicle cell microvilli-could potentially trigger inception of vitellogenesis. Gap junctions might permit the passage of a regulatory molecule, transferring from follicle cells to oocyte, which would control the assembly of coated pits on the oocyte plasma membrane. Alternatively cell interaction via microvilli might induce the appearance of coated pits, thus creating a membrane focus for vitellogenin receptors. Both possibilities are discussed in relation to current literature. PMID- 30005560 TI - The hemocytes of Heliothis armigera: Ultrastructure, functions, and evolution in the course of larval development. AB - Five types of hemocytes, prohemocytes, typical plasmatocytes, coagulocytes, spherule cells, and oenocytoides, have been defined in the last larval instar of Heliothis armigera on the basis of ultrastructural microscopy, smears, and optical phase-contrast microscopy. Modifications in typical plasmatocytes and coagulocytes have been evidenced in the course of development in this instar, which suggests that these hemocytes are involved in physiological processes of development. Only coagulocytes exhibit endocytotic capacities. Phenoloxidase activity was observed in oenocytoides. PMID- 30005562 TI - The digestive system of the lobster, Homarus americanus: I. Connective tissue of the digestive gland. AB - The digestive gland (midgut gland, hepatopancreas) of the American lobster, Homarus americanus (Decapoda: Nephropidae), has one continuous network of connective tissue in which the tubules are embedded and suspended and which forms the limiting layer of the organ. Light- and electron-microscopical observations show that the outer connective-tissue layer investing the entire digestive gland is a typical, fibrous connective tissue, containing hemal sinuses and a variety of cell types embedded in a collagenous matrix. This outer layer is continuous with the connective tissue among the tubules, which lacks a substantial fibrous matrix and lies peripheral to the digestive epithelium of each tubule. It consists of a complex, two-layered, epithelial basement membrane, an area containing cells, a tunica propria, and hemal sinuses. Several types of cells are present between the basement membrane and the tunica propria: contractile cells form a network of circular and longitudinal processes around each tubule, and several types of granulocytes are found in areas where tubules abut. The previously applied terms "myoepithelium" and "myoendothelium" are inappropriate to describe the tissue among the tubules. Instead, the extraepithelial elements are interpreted as forming an extensive connective tissue supporting the functional units of the digestive gland. PMID- 30005558 TI - Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD-J (Flow-Mediated Dilation Japan) Study A. AB - BACKGROUND: The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. METHODS AND RESULTS: We measured flow-mediated vasodilation (FMD) and brachial-ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver-operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06-0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09-0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01-3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23-3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. CONCLUSIONS: In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification. CLINICAL TRIAL REGISTRATION: URL: www.umin.ac.jp. Unique identifier: UMIN000012950. PMID- 30005563 TI - The development and homology of the chelonian carpus and tarsus. AB - The long-standing controversies involving the number and homologies of the elements of the carpus and tarsus of turtles are reviewed from a developmental perspective. The analysis is based on a detailed description of the chondrogenesis of the carpus and tarsus in the species Chelydra serpentina and Chrysemys picta. The first stage described is the differentiation of a Y-shaped chondrogenetic condensation involving the humerus (femur)-radius/ ulna (tibia/fibula). This stage is followed by the early formation of a series of connected condensations off the distal end of the postaxial element (ulna or fibula). This linear array, which we refer to as the primary axis, comprises the ulnare-distal carpal 4-metacarpal 4 in the carpus and the fibulare-distal tarsal 4-metatarsal 4 in the tarsus. There are two precondensations that branch off the primary axis. The proximal one will soon form the intermedium while the distal one will generate a digital arch that will give rise sequentially to digits 3-2 1, in this order. Digit 5 is not part of the digital arch and forms as an independent condensation. We emphasize that chondrogenetic foci often form as "branches" off existing condensations. This well-defined pattern of connectivity is used to establish unambiguous homologies and allows comparisons with other vertebrates. We conclude that preaxial elements such as the radiale and tibiale are absent in the turtles examined and probably in all turtles. The observed proximal elements that form in the anterior region of the limb and that are often homologized as radiale or tibiale have clear connections to the postaxial elements. For this reason we argue that these elements should be homologized as centralia. Therefore, we find two chondrogenetic condensations in the tarsus and three in the carpus, which we consider centralia. They subsequently fuse with neighboring elements in a complex pattern. We also describe the variable presence of a late-developing element in the tarsus of Chelydra, which, to our knowledge, has never been described. We propose this element to be an atavistic pretarsale. Comparison of the chondrogenetic pattern in turtles with those described in the literature for other vertebrates indicates that there are two invariant patterns in all tetrapods with the exception of the urodeles. These are (1) the primary axis and (2) the digital arch. PMID- 30005564 TI - The fine structure of early tooth formation in an lguanid lizard, Anolis carolinensis. AB - Cytodifferentiation and hard tissue formation were studied in Anolis to collect information regarding the phylogenetic history of enamel and the functional significance of the events seen in the mammalian tooth during differentiation. The differentiation of the ameloblasts of Anolis, like that of mammals, shows two phases: In the early phase, the cells are short and rich in free ribosomes, in the late phase the cells elongate, develop an extensive rough endoplasmic reticulum, and the Golgi apparatus moves into that part of the cell next to the basal lamina (the cell apex). The early epithelial-mesenchymal interface resembles that of mammals, suggesting that early mechanisms of induction and epithelial-mesenchymal interaction are similar in Anolis and in mammals. Preameloblast processes and preameloblast-preodontoblast contacts in Anolis are rudimentary compared to those of mammals. While in mammals the preameloblast processes shape the future DEJ (dentin-enamel junction), their involvement in establishing the shape of the DEJ of Anolis is questionable. We suggest that the great development of preameloblast-preodontoblast contacts in mammals may simply increase the efficiency of inductive interactions between these cell types. PMID- 30005565 TI - The cardiovascular chromaffin cell system of the southern hemisphere lamprey, Geotria australis gray. AB - This study demonstrates that the silver technique of Grimelius (Acta Soc. Med. Ups. 73:243-270, 68) is ideally suited for the study of cardiovascular chromaffin cells in lampreys. This method showed that in the Southern Hemisphere lamprey, Geotria australis, the distribution of chromaffin cells differs from that described for holarctic species. In G. australis, the chromaffin cells are found mainly in the sinus venosus, atrium, and nearby regions of the cardinal and jugular veins, and they are absent from the ventricle and conus arteriosus. The location and discreteness of the large accumulation of chromaffin cells in the lateral wall of the right posterior cardinal vein of adults resemble those of the precardiac axillary bodies of elasmobranchs. Chromaffin cells become more abundant during metamorphosis. The possible phylogenetic and functional significance of lamprey chromaffin cells is briefly discussed. PMID- 30005566 TI - The fine structure of the lateral-line organs of larval Ichthyophis (Amphibia: Gymnophiona). AB - Light and electron microscopic observations of the lateral-line organs of larval Ichthyophis kohtaoensis confirmed earlier reports of the occurrence of two different types of lateral-line organs. One type, the ampullary organ, possesses 15-26 egg-shaped sensory cells. Each sensory cell extends a single kinocilium surrounded by a few microvilli into the ampullary lumen. This is in contrast to the ampullary organs of urodele amphibians that contain only microvilli. The second type of organ, the ordinary neuromast, has 15-24 pear-shaped sensory cells arranged in two to three rows. Each sensory cell shows a kinocilium that is asymmetrically placed with respect to both a basal plate and approximately 60 stereovilli. The sensory cells of ampullary organs are always separated by supporting cells; those of neuromasts are occasionally in contact with one another. Numerous (neuromasts) or few (ampullary organs) mantle cells separate the organs from the epidermal cells. Only afferent synapses are found in the ampullary organs whereas vesicle-filled fibers together with afferent nerve terminals are found in neuromasts. Both organs contain similarly sized presynaptic spheres adjacent to the afferent fibers. It is suggested that the neuromasts have a mechanoreceptive function, whereas the ampullary organs have an electroreceptive one. PMID- 30005567 TI - The innervation of some proboscis structures involved in feeding behavior of the blowfly (Calliphora vicina). AB - The microtopology of the motoneurons involved in protraction and retraction of the proboscis of the blowfly (Calliphora vicina) has been studied. In addition, taste input from the labellar hairs was investigated. As a result of this study it appears that protraction movements are controlled by two while retraction movements are guided by three motoneurons on each side. The neurons in each group apear to be in ipsicontralateral communication with each other. The musculi protractores fulcri (MPF) probably contain a proprioceptive cell group which projects to the MPF motoneurons. It is proposed that the proboscis motor system can be modulated by proprioception as well as by chemosensory labellar input. Neurosecretory cells may be involved in adjusting muscle power. PMID- 30005568 TI - The heart of the dugong (Dugong dugon) and the west indian manatee (Trichechus manatus) (Sirenia). AB - Thirty-eight dugong (Dugong dugon) hearts and 28 Florida manatee (Trichechus manatus) hearts were obtained from stranding programs in Australia and the United States. In addition to a double ventricular apex, a feature that has astonished scientists since the eighteenth century, the hearts of both animals have a double subvalvular conus and a dorsal left atrium. The heart lies in a vertical plane at right angles to that of the completely dorsal, symmetrical lungs. The dugong heart has a deeper interventricular cleft and a more conical left ventricle. The latter features may be part of a general morphological trend toward specialization for a more energetic aquatic existence. The presence of a bulbous ascending aorta in the manatee but not in the dugong is without explanation. PMID- 30005569 TI - Hydrolytically Labile Linkers Regulate Release and Activity of Human Bone Morphogenetic Protein-6. AB - Release of growth factors while simultaneously maintaining their full biological activity over a period of days to weeks is an important issue in controlled drug delivery and in tissue engineering. In addition, the selected strategy to immobilize growth factors largely determines their biological activity. Silica surfaces derivatized with glycidyloxy propyl trimethoxysilane and poly(glycidyl methacrylate) brushes yielded epoxide-functionalized surfaces onto which human bone morphogenetic protein-6 (hBMP-6) was immobilized giving stable secondary amine bonds. The biological activity of hBMP-6 was unleashed by hydrolysis of the surface siloxane and ester bonds. We demonstrate that this type of labile bonding strategy can be applied to biomaterial surfaces with relatively simple and biocompatible chemistry, such as siloxane, ester, and imine bonds. Our data indicates that the use of differential hydrolytically labile linkers is a versatile method for functionalization of biomaterials with a variety of growth factors providing control over their biological activity. PMID- 30005570 TI - Structure-Dependent Activity of Polybrominated Diphenyl Ethers and Their Hydroxylated Metabolites on Estrogen Related Receptor gamma: in Vitro and in Silico Study. AB - Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor having functional cross-talk with classical estrogen receptors. Here, we investigated whether ERRgamma is a potential target of polybrominated diphenyl ethers (PBDEs) and their hydroxylated metabolites (OH-PBDEs). By using a fluorescence competitive binding method established in our laboratory, the binding potencies of 30 PBDEs/OH-PBDEs with ERRgamma were determined for the first time. All of the tested OH-PBDEs and some PBDEs bound to ERRgamma with Kd values ranging from 0.13 13.61 MUM. The OH-PBDEs showed much higher binding potency than their parent PBDEs. A quantitative structure-activity relationship (QSAR) model was developed to analyze the chemical binding potencies in relation to their structural and chemical characteristics. The QSAR model indicated that the molecular size, relative ratios of aromatic atoms, and hydrogen bond donors and acceptors were crucial factors for PBDEs/OH-PBDEs binding. By using a reporter gene assay, we found that most of the low-brominated PBDEs/OH-PBDEs exerted agonistic activity toward ERRgamma, while high-brominated PBDEs/OH-PBDEs had no effect on the basal ERRgamma activity. The docking results showed that the low-brominated PBDEs/OH PBDEs tended to take an agonistic binding mode while the high-brominated ones tended to take an antagonistic binding mode. Overall, our results suggest ERRgamma to be a potential novel target for PBDEs/OH-PBDEs. PMID- 30005572 TI - Cooperation of the Neutral and the Cationic Leaving Group Pathways in Acid Catalyzed O-Benzylation of TriBOT. AB - The reaction profile of acid-catalyzed O-benzylation with 2,4,6-tris(benzyloxy) 1,3,5-triazine (TriBOT) was analyzed to study the reaction kinetics. The first order kinetic constant for the formation of benzyl cation species from N protonated TriBOT (neutral leaving group pathway) was estimated and compared with that of the model compound for TriBOT. Since rapid consumption of TriBOT in the late stage could not be explained solely by this pathway, cooperation of another reaction mechanism, the cationic leaving group pathway, was proposed to rationalize the rate acceleration. PMID- 30005571 TI - Affimers as an Alternative to Antibodies in an Affinity LC-MS Assay for Quantification of the Soluble Receptor of Advanced Glycation End-Products (sRAGE) in Human Serum. AB - Antibodies are indispensable tools in biomedical research, but their size, complexity, and sometimes lack of reproducibility created a need for the development of alternative binders to overcome these limitations. Affimers are a novel class of affinity binders based on a structurally robust protease inhibitor scaffold (i.e., Cystatin A), which are selected by phage display and produced in a rapid and simple E. coli protein expression system. These binders have a defined amino acid sequence with defined binding regions and are versatile, thereby allowing for easy engineering. Here we present an affimer-based liquid chromatography-mass spectrometry (LC-MS) method for quantification of the soluble Receptor of Advanced Glycation End-products (sRAGE), a promising biomarker for chronic obstructive pulmonary disease. The method was validated according to European Medicines Agency and U.S. Food and Drug Administration guidelines and enabled quantitation of serum sRAGE between 0.2 and 10 ng/mL. Comparison between the affimer-based method and a previously developed, validated antibody-based method showed good correlation ( R2 = 0.88) and indicated that 25% lower sRAGE levels are reported by the affimer-based assay. In conclusion, we show the first time application of affimers in a quantitative LC-MS method, which supports the potential of affimers as robust alternatives to antibodies. PMID- 30005574 TI - Investigating the Formation of Giant {Pd72}Prop and {Pd84}Gly Macrocycles Using NMR, HPLC, and Mass Spectrometry. AB - The formation of giant polyoxometalate (POM) species is relatively underexplored, as their self-assembly process is complex due to the rapid kinetics. Polyoxopalladates (POPds) are a class of POMs based on Pd, the largest of which is the {Pd84}Ac wheel, and its slower kinetics mean the system is more amenable to systematic study. Here, we show that it is possible to follow the assembly of two types of Pd wheels, {Pd84}Gly and the smaller {Pd72}Prop, formed using glycolate and propionate ligands, respectively. We analyzed the formation of {Pd72}Prop and {Pd84}Gly using mass spectrometry (SEC-HPLC-MS and preparative desalting followed by MS). This was accompanied by studies that followed the chemical shift differences between the outer/inner ligands and the free ligand in solution for the {Pd84}Ac, {Pd72}Prop, and {Pd84}Gly species using NMR, which showed it was possible to track the formation of the wheels. Our findings confirm that the macrocycles assemble from smaller building blocks that react together to form the larger species over a period of days. These findings open the way for further structural derivatives and exploration of their host-guest chemistry. PMID- 30005573 TI - Design and Synthesis of Natural Product Inspired Libraries Based on the Three Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space. AB - A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines. PMID- 30005576 TI - Langmuir Analysis of the Binding Affinity and Kinetics for Surface Tethered Duplex DNA and a Ligand-Apoprotein Complex. AB - In this work, the hybridization and dehybridization of ssDNA with 20 bases at gold coated sensor surfaces modified with complementary 20 bases capture probe ssDNA was investigated at 18 degrees C by quartz crystal microbalance measurements with dissipation monitoring (QCM-D). A sequence of 20 base pairs with a melting temperature of about 64 degrees C was chosen, since in many biosensor studies the target molecules are DNA or RNA oligomers of similar length. It turned out that at the applied experimental conditions the DNA hybridization was irreversible, and therefore the hybridization and dehybridization process could not be described by the Langmuir model of adsorption. Nevertheless, quantitative dehybridization could be achieved by rinsing the sensor surface thoroughly with pure water. When in contrast the hybridization of a target with only 10 bases complementary to the outermost 10 bases of the 20 bases capture probe was studied, binding and unbinding were reversible, and the hybridization/dehybridization process could be satisfactorily described by the Langmuir model. For the 10 base pair sequence, the melting temperature was about 36 degrees C. Apparently, for Langmuir behavior, it is important that the experiments are applied at a temperature sufficiently close to the melting temperature of the sequence under investigation to ensure that at least traces of the target molecules are unhybridized (i.e., there needs to be an equilibrium between hybridized and dehybridized target molecules). To validate the reliability of our experimental approach we also studied the reconstitution and disassembly of the flavoprotein dodecin at flavin-terminated DNA monolayers, as according to previous studies it is assumed that the apododecin-flavin system can be well described by the Langmuir model. As a result, this assumption could be verified. Using three different approaches, KD values were obtained that differ not more than by a factor of 4. PMID- 30005575 TI - UVA- and Visible-Light-Mediated Generation of Carbon Radicals from Organochlorides Using Nonmetal Photocatalyst. AB - Carbon radicals are reactive species useful in various organic transformations. The C-X bond cleavage of organohalides by photoirradiation is a common method to generate carbon radicals in a controlled fashion. The use of organochloride substrates is still a formidable challenge due to the low reduction potential and the high dissociation energy of the C-Cl bond. In this report, we address these issues by using a nonmetal organic molecule with a relatively simple structure as a photocatalyst. In this catalyst (bis(dimethylamino)carbazole), the amino groups increase both the HOMO and LUMO energy levels, especially in the former. As a result, compared to the parent molecule, the new catalyst shows experimentally red-shifted absorption in the visible region and forms an excited state with better reducing capability. This photocatalyst was used in the reduction of unactivated aryl chlorides and alkyl chlorides in the presence of hydrogen atom donor at room temperature. The catalytic system can also be applied to the coupling of aryl chlorides with electron-rich arene and heteroarenes to affect the C-C bond-forming reactions. Our mechanistic study results support the assumption that carbon radicals are formed from the organochlorides via a single electron-transfer step. PMID- 30005577 TI - Provider Adherence to Nutrition and Physical Activity Best Practices Within Early Care and Education Settings in Minnesota, Helping to Reduce Early Childhood Health Disparities. AB - Licensed child care providers, and the early care and education settings in which they operate, are uniquely situated to influence children's healthy eating and physical activity through practices, attitudes, and supportive physical and social environments. However, preliminary research indicates that child-, family , and provider-level characteristics affect adherence to best practices across early care and education settings. The current article used survey data ( n = 618) to characterize differences in child care providers' adherence to nutrition, physical activity, and mealtime best practices, based on child-, family- and provider-level characteristics, and to describe secular trends in adherence to nutrition and physical activity best practices between 2010 and 2016. Results indicate that differences exist across certain characteristics, including child race/ethnicity, family's use of child care assistance, language spoken at home, and provider educational attainment; however, it is notable that in most cases providers serving children of minority race and children in low-income families have a higher rate of compliance with the nutrition and physical activity best practices studied. Additionally, the comparison of adherence to best practices from 2010 to 2016 suggests that, while there was an increase in mean adherence from 2010 to 2016, overall trends in adherence across child-, family- and provider-level characteristics have been consistent across time. Public health professionals should continue to advocate for opportunities for providers to learn how to best incorporate best practices within their setting (e.g., education and training opportunities) as well as for the development and adoption of systems-level changes (e.g., expansion of food assistance programs) to reduce barriers to adherence to best practices. PMID- 30005578 TI - Recent advancements toward therapeutic vaccines against Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by protein aggregates of amyloid beta (Abeta) and tau. These proteins have normal physiological functions, but in AD, they undergo a conformational change and aggregate as toxic oligomeric and fibrillar species with a high beta-sheet content. Areas covered: Active and passive immunotherapeutic approaches are among the most attractive methods for targeting misfolded Abeta and tau. Promising preclinical testing of various immunotherapeutic approaches has yet to translate to cognitive benefits in human clinical trials. Knowledge gained from these past failures has led to the development of second-generation Abeta-active immunotherapies, anti-Abeta monoclonal antibodies targeting a wide array of Abeta conformations, and to a number of immunotherapies targeting pathological tau. This review covers the more recent advances in vaccine development for AD from 2016 to present. Expert commentary: Due to the complex pathophysiology of AD, greatest clinical efficacy will most likely be achieved by concurrently targeting the most toxic forms of both Abeta and tau. PMID- 30005579 TI - Influenza Vaccine Intention After a Medically Attended Acute Respiratory Infection. AB - BACKGROUND: Little is known about vaccine intention behavior among patients recovering from a medically attended acute respiratory infection. METHODS: Adults >= 18 years old with an acute respiratory infection in the 2014-2015, 2015-2016, and 2016-2017 influenza seasons were tested for influenza and completed surveys. Across seasons, unvaccinated participants were grouped into those who intended to receive the influenza vaccine in the following season (vaccine intention) and those who did not (no vaccine intention). In 2016-2017, participants were asked the reasons for their vaccination behavior. RESULTS: Of the 837 unvaccinated participants, 308 (37%) intended to be vaccinated the next season. The groups did not differ in demographic or overall health factors. In logistic regression, non Whites, those reporting wheezing or nasal congestion, and those receiving an antiviral prescription were more likely to be in the vaccine intention group. That group was significantly more likely to cite perceived behavioral control reasons for not being vaccinated (forgot), while the no vaccine intention group was significantly ( p < .001) more likely to report knowledge/attitudinal reasons (side effects). CONCLUSION: Because influenza vaccine is given annually, adults must make a conscious decision to receive the vaccine each year. Understanding the factors related to vaccination behavior and intent can help shape interventions to improve influenza vaccination rates. A medical visit at the time of an acute respiratory illness, especially one in which the provider suspects influenza, as evidenced by an antiviral prescription, is an ideal opportunity to recommend influenza vaccine in the next season, to prevent a similar experience. PMID- 30005580 TI - Adaptive medical education research. AB - This commentary reflects on what the four research articles in this issue of Medical Teacher tell us about adaptive learning and how adaptive medical education research can be conducted. Adaptive medical education researchers must think disruptively and embrace nontraditional collaborations, research methods, and means of dissemination in pursuit of evidence that enhances adaptive learning. PMID- 30005581 TI - Carotid endarterectomy: neither shunting nor patching technique. AB - Introduction The role of carotid shunting in carotid endarterectomy is controversial. Many studies have concluded that patch angioplasty is preferable to primary closure, while others found that it had no value. The aim of this study was to report the results of our first series of patients undergoing carotid endarterectomy with a non-shunting technique and primary closure of the arteriotomy. Methods From October 2014 to October 2017, 63 patients with unilateral or bilateral carotid artery stenosis underwent carotid endarterectomy. There were 48 males and 15 females, the mean age was 63.16 years, and all were symptomatic. Conventional endarterectomy was performed without a shunt in all cases. All arteriotomies were closed primarily. We analysed the early and late outcomes of this procedure with at least 18 months of follow-up. Results Diabetes was the most frequent comorbidity. Most of the patients had a history of transient ischemic attack (49.2%) or stroke (44.4%). All patients had significant (moderate to severe) carotid artery stenosis. Postoperatively, 2 (3.2%) patients developed ischemic stroke, one (1.6%) suffered hypoglossal nerve injury, and one had a postoperative cervical hematoma. During follow-up, one patient developed asymptomatic total occlusion of the endartrectomized carotid artery at 18 months. Conclusion Carotid endarterectomy without shunting is a safe procedure. The short and longer-term outcomes are not significantly inferior to those of the routine or selective shunting technique, and the rate of restenosis is not higher than that of patch angioplasty closure. PMID- 30005582 TI - Return to work recommendations after carpal tunnel release: a survey of UK hand surgeons and hand therapists. AB - : There is a limited evidence base from which to derive recommendations for safe and effective return to different types of occupation after carpal tunnel release surgery. The current practice of members of the British Society for Surgery of the Hand and the British Association of Hand Therapists was investigated with a questionnaire. In total, 173 surgeons and 137 therapists responded from an estimated sample of 1959. Median recommended return-to-work times were 7 days for desk-based duties, 15 days for repetitive light manual duties and 30 days for heavy manual duties. However, the responses were wide-ranging: 0-30 days for desk based; 1-56 days for repetitive light manual; and 1-90 days for heavy manual. Variation in the recommended timescales for return to work and other functional activities after carpal tunnel release suggests that patients are receiving different and possibly even conflicting advice. LEVEL OF EVIDENCE: V. PMID- 30005583 TI - Snake venomics - from low-resolution toxin-pattern recognition to toxin-resolved venom proteomes with absolute quantification. AB - INTRODUCTION: Venoms are integrated phenotypes used by a wide range of organisms for predatory and defensive purposes. The study of venoms is of great interest in diverse fields, such as evolutionary ecology and biotechnology. Omics technologies have contributed to understanding the evolutionary mechanisms that molded snake venoms to their present-day structural and functional variability landscape. Areas covered: This review article reflects on two recent implementations in venomics: absolute quantification of intact proteins by elemental mass spectrometry, and top-down molecular mass spectrometry. Expert commentary: Leveraging on a new way of polyatomic interference removal, a triple quadrupole inductively coupled plasma mass spectrometry configuration has proven feasible for the absolute quantification of venom toxins via sulfur detection. A major advantage of this approach over quantitative molecular mass spectrometry techniques is that only a generic S-standard is required to quantify all the chromatographically separated sulfur-containing fractions. Top-down venomics is in its infancy but, due to recent hardware and software developments, is gaining momentum. Proteoform-resolved venom proteomes are needed to understand the spatio temporal variability landscape underlying the adaptations that drive intraspecific venom evolution. Integrating top-down venomics and absolute proteoform quantification into a novel elemental and molecular mass spectrometry configuration will represent a quantitative leap in the study of individual venoms. PMID- 30005584 TI - Dialectical behavior therapy skills training affects defense mechanisms in borderline personality disorder: An integrative approach of mechanisms in psychotherapy. AB - OBJECTIVE: Borderline personality disorder (BPD) is characterized by immature defense mechanisms. Dialectical behavior therapy (DBT) is an effective treatment for BPD. However, understanding the underlying mechanisms of change is still limited. Using a transtheoretical framework, we investigated the effect of DBT skills training on defense mechanisms. METHOD: In this randomized controlled trial, 16 of 31 BPD outpatients received DBT skills training adjunctive to individual treatment as usual (TAU), while the remaining 15 received only individual TAU. Pre-post changes of defense mechanisms, assessed with the Defense Mechanism Rating Scale, were compared between treatment conditions using ANCOVAs. Partial correlations and linear regressions were conducted to explore associations between defenses and symptom outcome. RESULTS: Overall defense function improved significantly more in the skills training condition (F(1, 28) = 4.57, p = .041). Borderline defenses decreased throughout skills training, but not throughout TAU only (F(1, 28) = 5.09, p = .032). In the skills training condition, an increase in narcissistic defenses was associated with higher symptom scores at discharge (beta = 0.58, p = .02). CONCLUSIONS: Although DBT does not explicitly target defense mechanisms, skills training may have favorable effects on defense function in BPD. Our findings contribute to an integrative understanding of mechanisms of change in BPD psychotherapy. PMID- 30005585 TI - Leukocyte Distribution in the Open Eye Tears of Normal and Dry Eye Subjects. AB - PURPOSE: Leukocytes accumulate in the eye with sleep, but little is known about the presence or absence of leukocytes in awake, open eye tears. This study sought to compare normal and dry eye subjects for daily variation in open eye leukocyte composition. MATERIALS AND METHODS: Ten normal subjects and nine dry eye subjects were enrolled. Subjects were trained for self-collection of tear samples using an ocular surface wash with 5 mL of phosphate buffered saline per eye. Subjects performed washes at awakening, between 8 and 9 am, between 11 am and 12 pm, and between 4 pm and 5 pm on four separate days. Leukocytes were isolated from the wash and were counted with a cell counter before staining with an anti-CD45 antibody and viability stain. Stained leukocytes were then analyzed via flow cytometry. Side scatter characteristics were used to distinguish granulocytes from lymphocytes. Results were interpreted both by time of wash as well as time from awakening. RESULTS: At awakening, dry eye subjects had approximately twice as many recovered leukocytes and had a statistically significantly higher granulocyte-to-lymphocyte ratio as compared to normals. Leukocytes were rapidly cleared from the eye with a significant decrease in leukocyte counts at the 8 am time point as compared to awakening. Leukocyte counts across all open eye time points appeared to be consistent, with no differences between normal and dry eye subjects. CONCLUSIONS: There is a low level, constitutively expressed population of leukocytes in the open eye tears of normal and dry eye subjects. Higher levels of granulocytes in dry eye disease subjects warrants further investigation into this population of cells, and their role in homeostasis and dysregulation. PMID- 30005586 TI - Dropout from interpersonal psychotherapy for mental health disorders: A systematic review and meta-analysis. AB - OBJECTIVE: Dropout is one factor that might limit the effectiveness of interpersonal psychotherapy (IPT). Improved understanding of IPT dropout is an important research priority. This meta-analysis examined dropout rates from IPT in randomized controlled trials. METHOD: Seventy-two trials met inclusion criteria. RESULTS: The weighted mean dropout rate from IPT was 20.6% (95% CI = 17.4-24.2). Dropout rates were similar for depressive (20.9%; 95% CI = 17.2 25.2), anxiety (16.1%; 95% CI = 11.1-22.9), and eating disorders (18.7%; 95% CI = 11.6-28.8). Dropout was highest when more stringent definitions of dropout were applied (e.g., failure to complete the entire IPT protocol versus failure to complete at least 50% of sessions) and was lowest when adolescent patients were sampled. There was some evidence that IPT was associated with significantly lower rates of dropout than both CBT and non-specific supportive therapies. These effects were generally replicated when analysing trials that provided a clear definition of treatment (rather than study) dropout. CONCLUSIONS: Overall, findings provide preliminary evidence to suggest that IPT may be an accepted and tolerated treatment option for patients with common mental health disorders. This review also highlights the need for future trials to rigorously report detail pertaining to patient dropout. PMID- 30005587 TI - Zoledronic acid-induced orbital inflammation in a patient with multiple myeloma. AB - Multiple myeloma is a cancer of malignant plasma cells which stimulates osteoclasts and is associated with increased bone turnover and osteolysis. Bisphosphonates including zolendronic acid are used to prevent skeletal complications in patients with multiple myeloma. Orbital inflammation is a rare but serious complication following use of bisphosphonates. The diagnosis is made by excluding other possible causes in patients with myeloma and rapid initiation of therapy is required. Corticosteroids are the mainstay of therapy but the ideal treatment course has not been delineated. This report describes a case of this rare complication and provides a review of the literature. PMID- 30005588 TI - Rampant infection & multi-resistance. PMID- 30005589 TI - Locked-in syndrome in post snake bite: can it be unlocked? PMID- 30005590 TI - Effective automated pipeline for 3D reconstruction of synapses based on deep learning. AB - BACKGROUND: The locations and shapes of synapses are important in reconstructing connectomes and analyzing synaptic plasticity. However, current synapse detection and segmentation methods are still not adequate for accurately acquiring the synaptic connectivity, and they cannot effectively alleviate the burden of synapse validation. RESULTS: We propose a fully automated method that relies on deep learning to realize the 3D reconstruction of synapses in electron microscopy (EM) images. The proposed method consists of three main parts: (1) training and employing the faster region convolutional neural networks (R-CNN) algorithm to detect synapses, (2) using the z-continuity of synapses to reduce false positives, and (3) combining the Dijkstra algorithm with the GrabCut algorithm to obtain the segmentation of synaptic clefts. Experimental results were validated by manual tracking, and the effectiveness of our proposed method was demonstrated. The experimental results in anisotropic and isotropic EM volumes demonstrate the effectiveness of our algorithm, and the average precision of our detection (92.8% in anisotropy, 93.5% in isotropy) and segmentation (88.6% in anisotropy, 93.0% in isotropy) suggests that our method achieves state-of-the-art results. CONCLUSIONS: Our fully automated approach contributes to the development of neuroscience, providing neurologists with a rapid approach for obtaining rich synaptic statistics. PMID- 30005592 TI - Estimated divergence times of Hirsutella (asexual morphs) in Ophiocordyceps provides insight into evolution of phialide structure. AB - BACKGROUND: Hirsutella Pat genus, the asexual morphs of the Ophiocordyceps Sung, is globally distributed entomopathogenic fungi, which infect a variety of arthropods, mites and nematodes. The fungal species also have shown potential application in the field of biological control, bio-medicine and food development. Although these fungi are synonymized under Ophiocordyceps, formal taxonomic assignments remain necessary for classification of species in Hirsutella. However, due to the heterogeneity and complexity of Hirsutella genus, more detailed taxonomic and phylogenetic analyses are required to address the following subjects: (1) the relationships between the phialide morphological characteristics and phylogenetic information of Hirsutella with asexual morphs, (2) the origin and evolution of the phialide structure, and (3) host specificity and fungal pathogenicity. RESULTS: Five typical phialide structures are summarized, in which the variation in phialide characteristics overlaps well with phylogenetic information. A new member of the special twisted neck clade in the Hirsutella-like group, Ophiocordyceps retorta, was reported based on these analyses. The molecular clock calibration analysis based on one fossil record revealed that Hirsutella (asexual morph) species originated from a common ancestor approximately 102 million years ago (Mya) (Early Cretaceous, Lower Albian) and then resolved into two major lineages. One lineage was typically phialidic, which was a larger shape, including H. guyana, H. nodulosa and H. sinensis clades (86.9 Mya, 95% highest posterior density (HPD): 69.1-101.4 Mya). Another main lineage of the phialides was more diversified and smaller than the former, which included H. citriformis and H. thompsonii clades (71.9 Mya, 95% HPD: 41.8-99.6 Mya). CONCLUSIONS: Our results showed that certain phialide characteristics of Hirsutella were phylogenetically informative for two groups of taxa. The differentiation of the phialides structures in the major clades demonstrated a clear evolutionary path of Hirsutella (asexual morph) species, which exhibited two trends depending on the host size. Fungi in one of the groups displayed elongated conidiogenous cells with increased complexity of auxiliary structures from the mycelia. The species in another group reduced the volume of phialides and spores, which might be due to an energy-efficient strategy. These results suggested that a common origin allowed for diversification of given clades into separate niches. The distinct parallel evolutionary path combined with the specific phialides structure might result in the host specificity of Hirsutella (asexual morphs). A direct relationship between Hirsutella (asexual morphs) and the Cretaceous-Tertiary extinction was not found, which suggested that the diversity of phialides is more likely to be caused by long-term environmental adaptation and evolution rather than dramatic extinction events. This evolutionary result might correspond to the background of important biological and geological events in the late Cretaceous occurring near the divergence times of Hirsutella (asexual morphs). PMID- 30005591 TI - An integrative network-based approach to identify novel disease genes and pathways: a case study in the context of inflammatory bowel disease. AB - BACKGROUND: There are different and complicated associations between genes and diseases. Finding the causal associations between genes and specific diseases is still challenging. In this work we present a method to predict novel associations of genes and pathways with inflammatory bowel disease (IBD) by integrating information of differential gene expression, protein-protein interaction and known disease genes related to IBD. RESULTS: We downloaded IBD gene expression data from NCBI's Gene Expression Omnibus, performed statistical analysis to determine differentially expressed genes, collected known IBD genes from DisGeNet database, which were used to construct a IBD related PPI network with HIPPIE database. We adapted our graph-based clustering algorithm DPClusO to cluster the disease PPI network. We evaluated the statistical significance of the identified clusters in the context of determining the richness of IBD genes using Fisher's exact test and predicted novel genes related to IBD. We showed 93.8% of our predictions are correct in the context of other databases and published literatures related to IBD. CONCLUSIONS: Finding disease-causing genes is necessary for developing drugs with synergistic effect targeting many genes simultaneously. Here we present an approach to identify novel disease genes and pathways and discuss our approach in the context of IBD. The approach can be generalized to find disease-associated genes for other diseases. PMID- 30005593 TI - Phospholipase Cgamma2 is critical for Ca2+ flux and cytokine production in anti fungal innate immunity of human corneal epithelial cells. AB - BACKGROUND: Fungal keratitis (FK) is a sight-threatening disease, accounting for a significant portion with its complex presentation, suboptimal efficacy of the existing therapies and uncontrollable excessive innate inflammation. Phospholipase C-gamma2 (PLCgamma2) is a non-receptor tyrosine kinase that plays an important role at the early period of innate immunity. This study aimed to identify the role of PLCgamma2 in Dectin-1-mediated Ca2+ Flux and its effect on the expression of proinflammatory mediators at the exposure to Aspergillus fumigatus (A. fumigatus) hyphae antigens in human corneal epithelial cells (HCECs). METHODS: The HCECs were preincubated with or without different inhibitors respectively before A. fumigatus hyphae stimulation. Intracellular calcium flux in HCECs and levels of PLCgamma2 and spleen-tyrosine kinase (Syk) were detected by fluorescence imaging and Western Blotting. The expression of proinflammatory mediators was determined by reverse transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: We demonstrated that an intracellular Ca2+ flux in HCECs was triggered by A. fumigatus hyphae and could be reduced by pre-treatment with PLCgamma2-inhibitor U73122. A. fumigatus hyphae induced PLCgamma2 phosphorylation was regulated by Dectin-1 via Syk. Furthermore, PLCgamma2-deficient HCECs showed a drastic impairment in the Ca2+ signaling and the secretion of IL-6, CXCL1 and TNF-alpha. CONCLUSIONS: PLCgamma2 plays a critical role for Ca2+ Flux in HCECs stimulated by A. fumigatus hyphae. Syk acts upstream of PLCgamma2 in the Dectin-1 signaling pathway. The expressions of proinflammatory mediators induced by A. fumigatus are regulated by the activation of Dectin-1-mediated PLCgamma2 signaling pathway in HCECs. PMID- 30005594 TI - Treatment results for severe psychiatric illness: which method is best suited to denote the outcome of mental health care? AB - BACKGROUND: The present study investigates the suitability of various treatment outcome indicators to evaluate performance of mental health institutions that provide care to patients with severe mental illness. Several categorical approaches are compared to a reference indicator (continuous outcome) using pretest-posttest data of the Health of Nation Outcome Scales (HoNOS). METHODS: Data from 10 institutions and 3189 patients were used, comprising outcomes of the first year of treatment by teams providing long-term care. RESULTS: Findings revealed differences between continuous indicators (standardized pre-post difference score ES and DeltaT) and categorical indicators (SEM, JTRCI, JTCS, JTRCI&CS, JTrevised) on their ranking of institutions, as well as substantial differences among categorical indicators; the outcome according to the traditional JT approach was most concordant with the continuous outcome indicators. CONCLUSIONS: For research comparing group averages, a continuous outcome indicator such as ES or DeltaT is preferred, as this best preserves information from the original variable. Categorical outcomes can be used to illustrate what is accomplished in clinical terms. For categorical outcome, the classical Jacobson-Truax approach is preferred over the more complex method of Parabiaghi et al. with eight outcome categories. The latter may be valuable in clinical practice as it allows for a more detailed characterization of individual patients. PMID- 30005595 TI - Development of a web-based tool for undergraduate engagement in medical research; the ProjectPal experience. AB - BACKGROUND: We report the development and evaluation of a web-based tool designed to facilitate student extra-curricular engagement in medical research through project matching students with academic supervisors. UK based university students were surveyed to explore their perceptions of undergraduate research, barriers and facilitators to current engagement. Following this, an online web-based intervention ( www.ProjectPal.org ) was developed to support access of students to research projects and supervisors. A pilot intervention was undertaken across a London-based university in January 2013 to February 2016. In March 2016, anonymised data were extracted from the prospective data log for analysis of website engagement and usage. Supervisors were surveyed to evaluate the website and student outputs. RESULTS: Fifty-one students responded to the electronic survey. Twenty-four (47%) reported frustration at a perceived lack of opportunities to carry out extra-curricular academic projects. Major barriers to engaging in undergraduate research reported were difficulties in identifying suitable supervisors (33/51; 65%) and time pressures (36/51; 71%) associated with this. Students reported being opportunistic in their engagement with undergraduate research. Following implementation of the website, 438 students signed up to ProjectPal and the website was accessed 1357 times. Access increased on a yearly basis. Overall, 70 projects were advertised by 35 supervisors. There were 86 applications made by students for these projects. By February 2016, the 70 projects had generated 5 peer-review publications with a further 7 manuscripts under peer-review, 14 national presentations, and 1 national prize. CONCLUSION: The use of an online platform to promote undergraduate engagement with extra curricular research appears to facilitate extra-curricular engagement with research. Further work to understand the impact compared to normal opportunistic practices in enhancing student engagement is now underway. PMID- 30005596 TI - Plasma myeloperoxidase-conjugated DNA level predicts outcomes and organ dysfunction in patients with septic shock. AB - BACKGROUND: Recent studies have suggested that excessive formation of neutrophil extracellular traps (NETs) plays a critical role in the pathogenesis of sepsis. Although elevation of the plasma level of cell-free DNA (cf-DNA) has been reported in sepsis patients, there has been little direct measurement of circulating free NETs such as myeloperoxidase-conjugated DNA (MPO-DNA). The objectives of this study were to detect NETs in the bloodstream of patients with septic shock, and to assess the correlations of circulating NET levels with organ dysfunction, disease severity, and mortality. METHODS: Fifty-five patients with septic shock admitted to the intensive care units (ICUs) of 35 Japanese hospitals were studied. Septic shock was diagnosed according to the 1997 definition of the American College of Chest Physicians/Society of Critical Care Medicine. To detect circulating NETs, plasma levels of MPO-DNA and cf-DNA were measured by sandwich enzyme-linked immunosorbent assay and by fluorometric assay on days 1, 3, and 7 after the onset of septic shock. Physiological and mortality data were collected from the clinical database. RESULTS: On days 1, 3, and 7, the patients showed a marked increase in plasma MPO-DNA levels compared with healthy volunteers, whereas the plasma cf-DNA level was only increased significantly on day 1 and then decreased rapidly. A high MPO-DNA level on days 3 and 7 were associated with 28-day mortality. On days 3 and 7, the MPO-DNA levels were inversely correlated with both the mean arterial pressure and the PaO2/FIO2 ratio, whereas the cf-DNA level was not correlated with either parameter. There was a positive correlation between the plasma MPO-DNA level and the sepsis-related organ failure assessment score on days 3 and 7. Neither cf-DNA nor MPO-DNA levels were correlated with the disseminated intravascular coagulation (DIC) score or the platelet count. CONCLUSION: The increase in circulating MPO-DNA in patients with septic shock indicates acceleration of NET formation in the early stages of sepsis. High MPO DNA levels are associated with the severity of organ dysfunction and 28-day mortality due to septic shock, but not with the DIC score. These results suggest that excessive NET formation contributes to the pathogenesis of septic shock. PMID- 30005597 TI - From squiggle to basepair: computational approaches for improving nanopore sequencing read accuracy. AB - Nanopore sequencing is a rapidly maturing technology delivering long reads in real time on a portable instrument at low cost. Not surprisingly, the community has rapidly taken up this new way of sequencing and has used it successfully for a variety of research applications. A major limitation of nanopore sequencing is its high error rate, which despite recent improvements to the nanopore chemistry and computational tools still ranges between 5% and 15%. Here, we review computational approaches determining the nanopore sequencing error rate. Furthermore, we outline strategies for translation of raw sequencing data into base calls for detection of base modifications and for obtaining consensus sequences. PMID- 30005600 TI - Correction to: A systematic review of the literature describing the outcomes of near-peer mentoring programs for first year medical students. AB - Following publication of the original article [1], the author reported incorrect referencing in Table 1 as the references of the papers in the table don't match with the text. PMID- 30005598 TI - Anaemia and depression before and after birth: a cohort study based on linked population data. AB - BACKGROUND: To investigate the rates of hospitalisation for anaemia and depression in women in the six-year period (3 years before and after birth). To compare hospital admissions for depression in women with and without anaemia. METHODS: This is a population-based cohort study. Women's birth records (New South Wales (NSW) Perinatal Data Collection) were linked with NSW Admitted Patients Data Collection records between 1 January 2001 and 31 December 2010, so that hospital admissions for mothers could be traced back for 3 years before birth and followed up 3 years after birth. SETTING: NSW Australia. SUBJECTS: all women who gave birth to their first child in NSW between 1 January 2004 and 31 December 2008. RESULTS: Hospital admissions for both anaemia and depression were increased significantly in the year just before and after birth compared with the years before and after. Women with anaemia were more likely to be admitted to hospital for depression than those without (for principal diagnosis of depression, adjusted OR = 1.62, 95% CI = 1.25-2.11; for all diagnosis of depression, adjusted OR = 2.01, 95% CI = 1.70-2.38). CONCLUSIONS: Depression was associated with anaemia in women before and after birth. This finding highlight the important role of primary care providers in assessing for both anaemia and depressive symptomatology together, given the relationship between the two. Treating or preventing anaemia may help to prevent postnatal depression. PMID- 30005599 TI - A study of virulence and antimicrobial resistance pattern in diarrhoeagenic Escherichia coli isolated from diarrhoeal stool specimens from children and adults in a tertiary hospital, Puducherry, India. AB - BACKGROUND: Emergence of atypical enteropathogenic Escherichia coli (EPEC) and hybrid E. coli (harboring genes of more than one DEC pathotypes) strains have complicated the issue of growing antibiotic resistance in diarrhoeagenic Escherichia coli (DEC). This ongoing evolution occurs in nature predominantly via horizontal gene transfers involving the mobile genetic elements like integrons notably class 1 integron. This study was undertaken to determine the virulence pattern and antibiotic resistance among the circulating DEC strains in a tertiary care center in south of India. METHODS: Diarrhoeal stool specimens were obtained from 120 children (< 5 years) and 100 adults (> 18 years), subjected to culture and isolation of diarrhoeal pathogens. Conventional PCR was performed to detect 10 virulence and 27 antimicrobial resistance (AMR) genes among the E. coli isolated. RESULTS: DEC infection was observed in 45 (37.5%) children and 18 (18%) adults, among which [18 (40%), 10 (10%)] atypical EPEC was most commonly detected followed by [6 (13.3%), 4 (4%)] ETEC, [5 (11.1%) 2 (2%)] EAEC, [(3 (6.6%), 0 (0%)] EIEC, [3 (6.6%), 0 (0%] typical EPEC, and [4 (8.8%), 1 (1%)] STEC, and no NTEC and CDEC was detected. DEC co-infection in 3 (6.6%) children, and 1(1%) adult and sole hybrid DEC infection in 3 (6.6%) children was detected. The distribution of sulphonamide resistance genes (sulI, sulII, and sulIII were 83.3 and 21%, 60.41 and 42.1%, and 12.5 and 26.3%, respectively) and class 1 integron (int1) genes (41.6 and 26.31%) was higher in DEC strains isolated from children and adults, respectively. Other AMR genes detected were qnrS, qnrB, aac(6')Ib-cr, dhfr1, aadB, aac(3)-IV, tetA, tetB, tetD, catI, blaCTX, blaSHV, and blaTEM. None harbored qnrA, qnrC, qepA, tetE, tetC, tetY, ermA, mcr1, int2, and int3 genes. CONCLUSIONS: Atypical EPEC was a primary etiological agent of diarrhea in children and adults among the DEC pathotypes. Detection of high numbers of AMR genes and class 1 integron genes indicate the importance of mobile genetic elements in spreading of multidrug resistance genes among these strains. PMID- 30005601 TI - Pyruvate carboxylase supports the pulmonary tropism of metastatic breast cancer. AB - BACKGROUND: Overcoming systemic dormancy and initiating secondary tumor grow under unique microenvironmental conditions is a major rate-limiting step in metastatic progression. Disseminated tumor cells encounter major changes in nutrient supplies and oxidative stresses compared to the primary tumor and must demonstrate significant metabolic plasticity to adapt to specific metastatic sites. Recent studies suggest that differential utilization of pyruvate sits as a critical node in determining the organotropism of metastatic breast cancer. Pyruvate carboxylase (PC) is key enzyme that converts pyruvate into oxaloacetate for utilization in gluconeogenesis and replenishment of the TCA cycle. METHODS: Patient survival was analyzed with respect to gene copy number alterations and differential mRNA expression levels of PC. Expression of PC was analyzed in the MCF-10A, D2-HAN and the 4 T1 breast cancer progression series under in vitro and in vivo growth conditions. PC expression was depleted via shRNAs and the impact on in vitro cell growth, mammary fat pad tumor growth, and pulmonary and non pulmonary metastasis was assessed by bioluminescent imaging. Changes in glycolytic capacity, oxygen consumption, and response to oxidative stress were quantified upon PC depletion. RESULTS: Genomic copy number increases in PC were observed in 16-30% of metastatic breast cancer patients. High expression of PC mRNA was associated with decreased patient survival in the MCTI and METABRIC patient datasets. Enhanced expression of PC was not recapitulated in breast cancer progression models when analyzed under glucose-rich in vitro culture conditions. In contrast, PC expression was dramatically enhanced upon glucose deprivation and in vivo in pulmonary metastases. Depletion of PC led to a dramatic decrease in 4 T1 pulmonary metastasis, but did not affect orthotopic primary tumor growth. Tail vein inoculations confirmed the role of PC in facilitating pulmonary, but not extrapulmonary tumor initiation. PC-depleted cells demonstrated a decrease in glycolytic capacity and oxygen consumption rates and an enhanced sensitivity to oxidative stress. CONCLUSIONS: Our studies indicate that PC is specifically required for the growth of breast cancer that has disseminated to the lungs. Overall, these findings point to the potential of targeting PC for the treatment of pulmonary metastatic breast cancer. PMID- 30005602 TI - Wolf outside, dog inside? The genomic make-up of the Czechoslovakian Wolfdog. AB - BACKGROUND: Genomic methods can provide extraordinary tools to explore the genetic background of wild species and domestic breeds, optimize breeding practices, monitor and limit the spread of recessive diseases, and discourage illegal crossings. In this study we analysed a panel of 170k Single Nucleotide Polymorphisms with a combination of multivariate, Bayesian and outlier gene approaches to examine the genome-wide diversity and inbreeding levels in a recent wolf x dog cross-breed, the Czechoslovakian Wolfdog, which is becoming increasingly popular across Europe. RESULTS: Pairwise FST values, multivariate and assignment procedures indicated that the Czechoslovakian Wolfdog was significantly differentiated from all the other analysed breeds and also well distinguished from both parental populations (Carpathian wolves and German Shepherds). Coherently with the low number of founders involved in the breed selection, the individual inbreeding levels calculated from homozygosity regions were relatively high and comparable with those derived from the pedigree data. In contrast, the coefficient of relatedness between individuals estimated from the pedigrees often underestimated the identity-by-descent scores determined using genetic profiles. The timing of the admixture and the effective population size trends estimated from the LD patterns reflected the documented history of the breed. Ancestry reconstruction methods identified more than 300 genes with excess of wolf ancestry compared to random expectations, mainly related to key morphological features, and more than 2000 genes with excess of dog ancestry, playing important roles in lipid metabolism, in the regulation of circadian rhythms, in learning and memory processes, and in sociability, such as the COMT gene, which has been described as a candidate gene for the latter trait in dogs. CONCLUSIONS: In this study we successfully applied genome-wide procedures to reconstruct the history of the Czechoslovakian Wolfdog, assess individual wolf ancestry proportions and, thanks to the availability of a well-annotated reference genome, identify possible candidate genes for wolf-like and dog-like phenotypic traits typical of this breed, including commonly inherited disorders. Moreover, through the identification of ancestry-informative markers, these genomic approaches could provide tools for forensic applications to unmask illegal crossings with wolves and uncontrolled trades of recent and undeclared wolfdog hybrids. PMID- 30005603 TI - Transcriptomic analyses of rice (Oryza sativa) genes and non-coding RNAs under nitrogen starvation using multiple omics technologies. AB - BACKGROUND: Nitrogen (N) is a key macronutrient essential for plant growth, and its availability has a strong influence on crop development. The application of synthetic N fertilizers on crops has increased substantially in recent decades; however, the applied N is not fully utilized due to the low N use efficiency of crops. To overcome this limitation, it is important to understand the genome-wide responses and functions of key genes and potential regulatory factors in N metabolism. RESULTS: Here, we characterized changes in the rice (Oryza sativa) transcriptome, including genes, newly identified putative long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) and their target mRNAs in response to N starvation using four different transcriptome approaches. Analysis of rice genes involved in N metabolism and/or transport using strand-specific RNA-Seq identified 2588 novel putative lncRNA encoding loci. Analysis of previously published RNA-Seq datasets revealed a group of N starvation-responsive lncRNAs showing differential expression under other abiotic stress conditions. Poly A primed sequencing (2P-Seq) revealed alternatively polyadenylated isoforms of N starvation-responsive lncRNAs and provided precise 3' end information on the transcript models of these lncRNAs. Analysis of small RNA-Seq data identified N starvation-responsive miRNAs and down-regulation of miR169 family members, causing de-repression of NF-YA, as confirmed by strand-specific RNA-Seq and qRT PCR. Moreover, we profiled the N starvation-responsive down-regulation of root specific miRNA, osa-miR444a.4-3p, and Degradome sequencing confirmed MADS25 as a novel target gene. CONCLUSIONS: In this study, we used a combination of multiple RNA-Seq analyses to extensively profile the expression of genes, newly identified lncRNAs, and microRNAs in N-starved rice roots and shoots. Data generated in this study provide an in-depth understanding of the regulatory pathways modulated by N starvation-responsive miRNAs. The results of comprehensive, large-scale data analysis provide valuable information on multiple aspects of the rice transcriptome, which may be useful in understanding the responses of rice plants to changes in the N supply status of soil. PMID- 30005605 TI - Expression profile analysis reveals that Aspergillus fumigatus but not Aspergillus niger makes type II epithelial lung cells less immunological alert. AB - BACKGROUND: Aspergillus fumigatus is the main causative agent of aspergillosis. Infections rarely occur in immunocompetent individuals, indicating efficient clearance of conidia by pulmonary defense mechanisms. Other aspergilli like Aspergillus niger also cause infections but to a much lesser extent. Our previous studies showed that A. fumigatus and A. niger have different behavior in the presence of type II alveolar A549 epithelial cells. A. fumigatus conidia are more efficiently internalized by these cells and germination is delayed when compared to A. niger. In addition, hyphae that have escaped the epithelial cells grow parallel to the epithelium, while A. niger grows away from this cell layer. RESULTS: Here it is shown that global gene expression of A. fumigatus and A. niger is markedly different upon contact with A549 cells. A total of 545 and 473 genes of A. fumigatus and A. niger, respectively, were differentially expressed when compared to growth in the absence of A549 cells. Notably, only 53 genes (approximately 10%) were shared in these gene sets. The different response was also illustrated by the fact that only 4 out of 75 GO terms were shared that were enriched in the differentially expressed gene sets. The orthologues of A. fumigatus genes involved in hypoxia regulation and heat shock were also up regulated in A. niger, whereas thioredoxin reductase and allergen genes were found up-regulated in A. fumigatus but down-regulated in A. niger. Infection with A. fumigatus resulted in only 62 up and 47 down-regulated genes in A549. These numbers were 17 and 34 in the case of A. niger. GO terms related with immune response were down-regulated upon exposure to A. fumigatus but not in the case of A. niger. This indicates that A. fumigatus reprograms A549 to be less immunologically alert. CONCLUSIONS: Our dual transcriptomic analysis supports earlier observations of a marked difference in life style between A. fumigatus and A. niger when grown in the presence of type II epithelial cells. The results indicate important differences in gene expression, amongst others down regulation of immune response genes in lung epithelial cells by A. fumigatus but not by A niger. PMID- 30005606 TI - Certainty of paternity in two coucal species with divergent sex roles: the devil takes the hindmost. AB - BACKGROUND: Certainty of paternity is considered an important factor in the evolution of paternal care. Several meta-analyses across birds support this idea, particularly for species with altricial young. However, the role of certainty of paternity in the evolution and maintenance of exclusive paternal care in the black coucal (Centropus grillii), which is the only known altricial bird species with male-only care, is not well understood. Here we investigated whether the differences in levels of paternal care in the black coucal and its sympatric congener, the bi-parental white-browed coucal (Centropus superciliosus), are shaped by extra-pair paternity. RESULTS: We found that male black coucals experienced a substantially higher loss of paternity than white-browed coucals. Further, unlike any previously reported bird species, extra-pair offspring in black coucals represented mainly the last hatchlings of the broods, and these last hatchlings were more likely to disappear during partial-brood loss. CONCLUSION: The results suggest that exclusive paternal care in black coucals is not maintained by male certainty of parentage, and extra-pair fertilizations are unlikely to be a female strategy for seeking 'good genes'. Extra-pair paternity in black coucals may reflect the inability of males to guard and copulate with the female after the onset of incubation, and a female strategy to demonstrate her commitment to other males of her social group. PMID- 30005604 TI - Refining a steroidogenic model: an analysis of RNA-seq datasets from insect prothoracic glands. AB - BACKGROUND: The prothoracic gland (PG), the principal steroidogenic organ of insects, has been proposed as a model for steroid hormone biosynthesis and regulation. RESULTS: To validate the robustness of the model, we present an analysis of accumulated transcriptomic data from PGs of two model species, Drosophila melanogaster and Bombyx mori. We identify that the common core components of the model in both species are encoded by nine genes. Five of these are Halloween genes whose expression differs substantially between the PGs of these species. CONCLUSIONS: We conclude that the PGs can be a model for steroid hormone synthesis and regulation within the context of mitochondrial cholesterol transport and steroid biosynthesis but beyond these core mechanisms, gene expression in insect PGs is too diverse to fit in a context-specific model and should be analysed within a species-specific framework. PMID- 30005607 TI - Minimum InDel pattern analysis of the Zika virus. AB - BACKGROUND: The Zika virus (ZIKV) can cause microcephaly and congenital abnormalities in the foetus. Recent studies have provided insights into the evolution of ZIKV from the current and previous outbreaks, but the types have not been determined. RESULTS: We analysed the insertions and deletions (InDels) in 212 ZIKV polyproteins and 5 Dengue virus (DENV) reference sequences. Spearman correlation tests for the minimum InDel (minInDel) patterns were used to assess the type of polyprotein. Using the minInDel frequencies calculated from polyproteins with 11 elements, likelihood estimation was conducted to correct the evolutionary distance. The minInDel-corrected tree topology clearly distinguished between the ZIKV types (I and II) with a unique minInDel character in the E protein. From the 10-year average genetic distance, the African and Asian lineages of ZIKV-II were estimated to have occurred ~ 270 years ago, which is unlikely for ZIKV-I. CONCLUSIONS: The minInDel pattern analysis showed that the minInDel in the E protein is targetable for the rapid detection and determination of the virus types. PMID- 30005608 TI - Health literacy in a population-based sample of Australian women: a cross sectional profile of the Geelong Osteoporosis Study. AB - BACKGROUND: The term health literacy refers to the abilities and resources required to find, understand and use health information in managing health. This definition is reflected in the recent development of multidimensional health literacy tools that measure multiple facets of health literacy. The aim of this study was to determine the health literacy profile of a randomly selected, population-based sample of Australian women using a multidimensional tool, the Health Literacy Questionnaire (HLQ). A second aim was to investigate associations between independent HLQ scales, sociodemographic characteristics and lifestyle and anthropometric risk factors for chronic disease. METHODS: We surveyed women involved in the Geelong Osteoporosis Study (GOS), a longitudinal, population based study. We included demographic data, lifestyle information and anthropometric measures as well as the HLQ. The HLQ has 44 items, scored on either 4- or 5-point scales, within nine conceptually distinct scales. Means for each scale were calculated, and HLQ scales were regressed on educational level and socioeconomic status. Risk factors for chronic disease were investigated using analysis of variance (ANOVA) and calculation of effect sizes. RESULTS: Higher mean scores were seen for the scales 'Feeling understood and supported by healthcare professionals' (mean 3.20, +/- SD 0.52) and 'Understanding health information well enough to know what to do' (mean 4.28, +/-SD 0.54), and lower mean scores were seen for 'Appraisal of health information' (mean 2.81, +/-SD 0.48) and 'Navigating the healthcare system' (mean 4.09, +/- SD 0.57). Associations were also seen between lower HLQ scores and poor health behaviours including smoking and being more sedentary, in addition to greater body mass index and waist circumference. Positive gradients were seen between several HLQ scales and education level, as well as SES. For some HLQ scales, these associations were non-linear. CONCLUSIONS: The profile of this population-based cohort of women demonstrated associations between low health literacy and low SES, lower levels of education, increasing age, and anthropometric and lifestyle risk factors for chronic disease. These findings suggest implications of health literacy for health policy makers focusing on improving lifestyle prevention of chronic disease and promoting health equity at a population level. PMID- 30005609 TI - Does body mass index early in pregnancy influence the risk of maternal anaemia? An observational study in Indonesian and Ghanaian women. AB - BACKGROUND: Anaemia is common among pregnant women, especially in low- and middle income countries (LMICs). While body mass index (BMI) relates to many risk factors for anaemia in pregnancy, little is known about the direct relation with anaemia itself. This is particularly relevant in Southeast Asia and Sub-Saharan Africa where the prevalence of anaemia in pregnancy and the associated adverse outcomes is among the highest worldwide. This study aimed to assess the association between early pregnancy BMI and anaemia at first antenatal care visit in Indonesian and Ghanaian women. In addition, the associations between early pregnancy anaemia and adverse birth outcomes was assessed. METHODS: Prospective cohort studies of women in early pregnancy were conducted in Jakarta, Indonesia (n = 433) and in Accra, Ghana (n = 946), between 2012 and 2014. Linear regression analysis was used to assess relations between early pregnancy BMI and pregnancy haemoglobin levels at booking. Logistic regression analyses were used to assess associations between early pregnancy anaemia as defined by the World Health Organization (WHO) criteria and a composite of adverse birth outcomes including stillbirth, low birth weight and preterm birth. RESULTS: Indonesian women had lower BMI than Ghanaian women (23.0 vs 25.4 kg/m2, p < 0.001) and higher mean haemoglobin levels (12.4 vs 11.1 g/dL, p < 0.001), corresponding to anaemia prevalence of 10 and 44%, respectively. Higher early pregnancy BMI was associated with higher haemoglobin levels in Indonesian (0.054 g/dL/kg/m2, 95% CI 0.03 to 0.08, p < 0.001) and Ghanaian women (0.044 g/dL/kg/m2, 0.02 to 0.07, p < 0.001). Accordingly, risk for anaemia decreased with higher early pregnancy BMI for Indonesians (adjusted OR 0.88, 0.81 to 0.97, p = 0.01) and Ghanaians (adjusted OR 0.95, 0.92 to 0.98, p < 0.001). No association between anaemia and the composite of adverse birth outcomes was observed. CONCLUSION: Higher BMI in early pregnancy is associated with higher haemoglobin levels at antenatal booking and with a reduced risk of anaemia in Indonesian and Ghanaian women. PMID- 30005611 TI - The effects of public health policies on health inequalities in high-income countries: an umbrella review. AB - BACKGROUND: Socio-economic inequalities are associated with unequal exposure to social, economic and environmental risk factors, which in turn contribute to health inequalities. Understanding the impact of specific public health policy interventions will help to establish causality in terms of the effects on health inequalities. METHODS: Systematic review methodology was used to identify systematic reviews from high-income countries that describe the health equity effects of upstream public health interventions. Twenty databases were searched from their start date until May 2017. The quality of the included articles was determined using the Assessment of Multiple Systematic Reviews tool (AMSTAR). RESULTS: Twenty-nine systematic reviews were identified reporting 150 unique relevant primary studies. The reviews summarised evidence of all types of primary and secondary prevention policies (fiscal, regulation, education, preventative treatment and screening) across seven public health domains (tobacco, alcohol, food and nutrition, reproductive health services, the control of infectious diseases, the environment and workplace regulations). There were no systematic reviews of interventions targeting mental health. Results were mixed across the public health domains; some policy interventions were shown to reduce health inequalities (e.g. food subsidy programmes, immunisations), others have no effect and some interventions appear to increase inequalities (e.g. 20 mph and low emission zones). The quality of the included reviews (and their primary studies) were generally poor and clear gaps in the evidence base have been highlighted. CONCLUSIONS: The review does tentatively suggest interventions that policy makers might use to reduce health inequalities, although whether the programmes are transferable between high-income countries remains unclear. TRIAL REGISTRATION: PROSPERO registration number: CRD42016025283. PMID- 30005612 TI - Clinical practice guidelines for diagnosis of autism spectrum disorder in adults and children in the UK: a narrative review. AB - BACKGROUND: Research suggests that diagnostic procedures for Autism Spectrum Disorder are not consistent across practice and that diagnostic rates can be affected by contextual and social drivers. The purpose of this review was to consider how the content of clinical practice guidelines shapes diagnoses of Autism Spectrum Disorder in the UK; and investigate where, within those guidelines, social factors and influences are considered. METHODS: We electronically searched multiple databases (NICE Evidence Base; TRIP; Social Policy and Practice; US National Guidelines Clearinghouse; HMIC; The Cochrane Library; Embase; Global health; Ovid; PsychARTICLES; PsychINFO) and relevant web sources (government, professional and regional NHS websites) for clinical practice guidelines. We extracted details of key diagnostic elements such as assessment process and diagnostic tools. A qualitative narrative analysis was conducted to identify social factors and influences. RESULTS: Twenty-one documents were found and analysed. Guidelines varied in recommendations for use of diagnostic tools and assessment procedures. Although multidisciplinary assessment was identified as the 'ideal' assessment, some guidelines suggested in practice one experienced healthcare professional was sufficient. Social factors in operational, interactional and contextual areas added complexity to guidelines but there were few concrete recommendations as to how these factors should be operationalized for best diagnostic outcomes. CONCLUSION: Although individual guidelines appeared to present a coherent and systematic assessment process, they varied enough in their recommendations to make the choices available to healthcare professionals particularly complex and confusing. We recommend a more explicit acknowledgement of social factors in clinical practice guidelines with advice about how they should be managed and operationalised to enable more consistency of practice and transparency for those coming for diagnosis. PMID- 30005610 TI - Correlations between exploratory eye movement, hallucination, and cortical gray matter volume in people with schizophrenia. AB - BACKGROUND: Widespread cortical gray matter alternations in people with schizophrenia are correlated with both psychotic symptoms and cognitive/behavioral abnormalities, including the impairments of exploratory eye movement (EEM). Particularly, the loss of gray matter density is specifically related to deficits of the responsive search score (RSS) of EEM in schizophrenia. It is unknown, however, whether the schizophrenia-related RSS deficits are associated with certain psychotic symptoms, such as hallucinations. METHODS: In 33 participants with schizophrenia, the measurement of EEM, assessment of the hallucination severity using Positive and Negative Syndrome Scale (PANSS) and a voxel-based morphometric analysis of cortical gray matter volume (GMV) were conducted to investigate the relationships between the RSS of EEM, symptom severity, and GMV. In 29 matched healthy controls, the measurement of EEM and a voxel-based morphometric analysis of cortical GMV were also conducted to investigate the relationship between the RSS of EEM and GMV. RESULTS: In participants with schizophrenia, the hallucination severity was significantly negatively correlated with both the RSS and the GMV of a large number of brain regions in the frontal, temporal, parietal, orbitofrontal, calcarine, cingulate, and insular cortices, and rolandic operculum, hippocampus, parahippocampal gyrus, and thalamus. Also in participants with schizophrenia, the RSS was significantly positively correlated with the GMV in the left supplementary motor area (SMA), left superior frontal cortex (SFG), bilateral precentral gyri, bilateral postcentral gyri, and bilateral middle frontal cortices. More importantly, the GMV of the SMA, SFG, and precentral gyrus in the left hemisphere was not only significantly negatively correlated with the hallucination severity but also significantly positively correlated with the RSS. No significant correlation could be revealed between the RSS and the GMV of any brain regions in healthy controls. CONCLUSIONS: There was a significantly negative association between the hallucination severity and the RSS of EEM, suggesting that the RSS may be a potential biomarker for predicting the hallucination severity of schizophrenia. Also, the GMV of the left SMA, SFG, and precentral gyrus may be the common substrates underlying both hallucination induction and the RSS in people with schizophrenia. PMID- 30005613 TI - The design and implementation of the re-vitalised integrated disease surveillance and response (IDSR) in Uganda, 2013-2016. AB - BACKGROUND: Uganda adopted and has been implementing the Integrated Disease Surveillance (IDSR) strategy since 2000. The goal was to build the country's capacity to detect, report promptly, and effectively respond to public health emergencies and priorities. The considerable investment into the program startup realised significant IDSR core performance. However, due to un-sustained funding from the mid-2000s onwards, these achievements were undermined. Following the adoption of the revised World Health Organization guidelines on IDSR, the Uganda Ministry of Health (MoH) in collaboration with key partners decided to revitalise IDSR and operationalise the updated IDSR guidelines in 2012. METHODS: Through the review of both published and unpublished national guidelines, reports and other IDSR program records in addition to an interview of key informants, we describe the design and process of IDSR revitalisation in Uganda, 2013-2016. The program aimed to enhance the districts' capacity to promptly detect, assess and effectively respond to public health emergencies. RESULTS: Through a cascaded, targeted skill-development training model, 7785 participants were trained in IDSR between 2015 and 2016. Of these, 5489(71%) were facility-based multi-disciplinary health workers, 1107 (14%) comprised the district rapid response teams and 1188 (15%) constituted the district task forces. This training was complemented by other courses for regional teams in addition to the provision of logistics to support IDSR activities. Centrally, IDSR implementation was coordinated and monitored by the MoH's national task force (NTF) on epidemics and emergencies. The NTF and in close collaboration with the WHO Country Office, mobilised resources from various partners and development initiatives. At regional and district levels, the technical and political leadership were mobilised and engaged in monitoring and overseeing program implementation. CONCLUSION: The IDSR re-vitalization in Uganda highlights unique features that can be considered by other countries that would wish to strengthen their IDSR programs. Through a coordinated partner response, the program harnessed resources which primarily were not earmarked for IDSR to strengthen the program nation-wide. Engagement of the local district leadership helped promote ownership, foster accountability and sustainability of the program. PMID- 30005614 TI - Sidelobe reduction for plane wave compounding with a limited frame number. AB - BACKGROUND: In ultrasound plane wave imaging (PWI), image details are often blurred by the off-axis artefacts resulting from high sidelobe. Recently plane wave compounding (PWC) is proposed as a promising technique for the sidelobe suppression in the PWI. However, its high demand for the frame number results in an obvious frame rate loss, which is intolerable in the ultrafast imaging modality. To reduce the number of frames required for compounding, coherence in the compounding frames should be exploited. METHODS: In this paper, we propose a global effective distance-based sidelobe suppressing method for the PWC with a limited frame number, where the global effective distance is introduced to measure the inter-frame coherence. Specifically, the effective distance is firstly computed by using a sparse representation-based algorithm. Then, the sidelobe localization is carried out on the basis of the effective distance. Finally, the target-dependent weighting factor is adopted to suppress the sidelobe. RESULTS: To assert the superiority of our proposed method, we compare the performances of different sidelobe reduction methods on both simulated and experimental PWC data. In case of 5 steering angles, our method shows a 19 dB reduction in the peak sidelobe level compared to the normal PWC in the point spread function test, and the contrast ratio is enhanced by more than 10% in both the simulation and phantom studies. CONCLUSIONS: Consequently, the proposed method is convinced to be a promising approach in enhancing the PWC image quality. PMID- 30005615 TI - Cryobiopsies are diagnostic in Pleuroparenchymal and Airway-centered Fibroelastosis. AB - BACKGROUND: Idiopathic pulmonary fibroelastosis (iPPFE) is a rare lung lesion characterized by pleural and subpleural parenchymal thickening due to accumulation of fibroelastotic tissue. Only recently, a few cases with a peribronchiolar distribution of fibroelastotic tissue have been reported. These lesions are more prominent in the upper lobes. Even though high resolution computed tomography (HRCT) scan features are considered characteristic, a histological confirmation is suggested, mainly when the clinical setting is not clearly defined. However, due to non-negligible complications, a surgical lung biopsy is not often recommended. The prognosis is usually poor and currently, the only effective treatment is lung transplantation. METHOD: Patients with a multidisciplinary diagnosis of iPPFE or airway-centered fibroelastosis (airway centered FE), with histological confirmation by transbronchial cryobiopsy, were identified from an ongoing interstitial lung disease registry. Data on patient demographics, HRCT patterns, size and number of biopsies, histology patterns and complications were registered. RESULTS: Seven patients were diagnosed with iPPFE and one patient was diagnosed with airway-centered FE. Pneumothorax was documented in three cases, but none of them required a chest tube. No other complications during or after the procedure were observed. CONCLUSION: This study suggests that using cryobiopsies in the diagnostics of PPFE and airway-centered FE is safe and effective. PMID- 30005616 TI - Diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for screening malaria in peripheral and placental blood samples from pregnant women in Colombia. AB - BACKGROUND: Pregnant women frequently show low-density Plasmodium infections that require more sensitive methods for accurate diagnosis and early treatment of malaria. This is particularly relevant in low-malaria transmission areas, where intermittent preventive treatment is not recommended. Molecular methods, such as polymerase chain reaction (PCR) are highly sensitive, but require sophisticated equipment and advanced training. Instead, loop mediated isothermal amplification (LAMP) provides an opportunity for molecular detection of malaria infections in remote endemic areas, outside a reference laboratory. The aim of the study is to evaluate the performance of LAMP for the screening of malaria in pregnant women in Colombia. METHODS: This is a nested prospective study that uses data and samples from a larger cross-sectional project conducted from May 2016 to January 2017 in three Colombian endemic areas (El Bagre, Quibdo, and Tumaco). A total of 531 peripheral and placental samples from pregnant women self-presenting at local hospitals for antenatal care visits, at delivery or seeking medical care for suspected malaria were collected. Samples were analysed for Plasmodium parasites by light microscopy (LM), rapid diagnostic test (RDT) and LAMP. Diagnostic accuracy endpoints (sensitivity, specificity, predictive values, and kappa scores) of LM, RDT and LAMP were compared with nested PCR (nPCR) as the reference standard. RESULTS: In peripheral samples, LAMP showed an improved sensitivity (100.0%) when compared with LM 79.5% and RDT 76.9% (p < 0.01), particularly in afebrile women, for which LAMP sensitivity was two-times higher than LM and RDT. Overall agreement among LAMP and nPCR was high (kappa value = 1.0). Specificity was similar in all tests (100%). In placental blood, LAMP evidenced a four-fold improvement in sensitivity (88.9%) when compared with LM and RDT (22.2%), being the only method, together with nPCR, able to detect placental infections in peripheral blood. CONCLUSIONS: LAMP is a simple, rapid and accurate molecular tool for detecting gestational and placental malaria, being able to overcome the limited sensitivity of LM and RDT. These findings could guide maternal health programs in low-transmission settings to integrate LAMP in their surveillance systems for the active detection of low-density infections and asymptomatic malaria cases. PMID- 30005617 TI - Determinants of HIV infection among children born to mothers on prevention of mother to child transmission program of HIV in Addis Ababa, Ethiopia: a case control study. AB - BACKGROUND: Despite wide spread use of Antiretroviral Therapy (ART) by pregnant women living with Human Immunodeficiency Virus (HIV), the transmission rate is still higher by 18% after breastfeeding ends. The aim of this study was to identify factors affecting mother-to-child HIV transmission. METHODS: Unmatched case-control study was conducted in Addis Ababa, from April to May, 2017. A case was HIV positive mother who had been on PMTCT program with her child confirmed HIV positive at or before 24 months and control was HIV positive mother who had been on PMTCT program with her child tested definitive HIV negative at 24 months. Accordingly, 44 cases were identified and for each case four controls with the nearest date of birth to the cases were selected from same health facilities. Primary data collected from the mothers were supplemented by record reviews and entered to Epidata version 3.1 and analyzed using SPSS version 22. Multivariate logistic regression was fitted to identify factors independently associated with mother-to-child HIV transmission. RESULTS: Lack of participation in mother-to mother support program (AOR: 5.1; 95% CI: 1.4, 18.1), low partner involvement (AOR: 6.9; 95% CI: 1.4, 13.4), poor ART adherence (AOR:3.1; 95% CI: 1.3, 7.5), positive syphilis test results (AOR: 3.2; 95% CI: 1.2, 8.6), maternal malnutrition (AOR: 3.1; 95% CI: 1.4, 6.8), unplanned pregnancy (AOR: 10.3; 95% CI: 3.9, 27.2), home delivery (AOR: 5.3; 95% CI: 1.4, 19.4) and mixed feeding of the child during first six months of life (AOR: 12.5; 95% CI: 2.9, 52.7) were significantly associated with MTCT of HIV. CONCLUSIONS: Mother-to-mother support, male partner involvement in PMTCT of HIV, strengthening antenatal care, counseling mothers on appropriate infant feeding options are important to reduce mother -to- child transmission of HIV. PMID- 30005618 TI - Incidence of acute diarrheal illness in Chinese communities: a meta-analysis. AB - BACKGROUND: Acute diarrheal illness (ADI) is an important public health problem worldwide. We estimated the morbidity, distribution, and burden of self-reported ADI in China over the last three decades. METHODS: We used the keywords "diarrhea and morbidity" to identify studies published in Chinese by searching CNKI, WANFANG, Chongqing VIP, and SinoMed. Studies published in English were identified using the keywords "diarrhea, morbidity, and China" to search Pubmed/Medline, Embase, and Cochrane Library Data. All articles published before Dec 31, 2014 were included in the search. Data were extracted and the pooled 2-week incidence rate of ADI was calculated using the fixed-effects or random-effects model according to statistical testing for homogeneity. The incidences of each subgroup (organized by age, location, study period) were also calculated. Publication bias was examined using Begg's test. Data manipulation and statistical analyses were undertaken using R-2.15.1 software. RESULTS: We estimated that the pooled 2-week prevalence of ADI in China was 2.04% (95% CI: 1.48-2.79) and that the corresponding incidence rate was 0.53 (95% CI: 0.38-0.73) episodes per person year. The ADI rate was highest among children aged < 5 years (1.43 episodes per person-year), and it was slightly higher in males than in females (0.58 vs 0.52 episodes per person-year). From 1980 to 2012, there was a significant decrease in the incidence of ADI, from 0.82 to 0.48 episodes per person-year, but the ADI incidence was consistent over the last two decades. Additionally, the incidence of ADI was higher in rural areas and in west China and peaked in the summer months. CONCLUSIONS: The current study indicates that ADI caused a substantial disease burden in China in the last 30 years, especially in rural areas and west China, where sanitation conditions were relatively poor. These findings highlight the importance of further investigation of the specific causes of and effective preventive measures for ADI. PMID- 30005619 TI - Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: a case report. AB - BACKGROUND: Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. CASE PRESENTATION: A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in 115G-L-W117 motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. CONCLUSIONS: We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved 115G-L-W117 motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient. PMID- 30005621 TI - Highly efficient conversion of xylose to ethanol without glucose repression by newly isolated thermotolerant Spathaspora passalidarum CMUWF1-2. AB - BACKGROUND: Efficient bioconversion of lignocellulosic biomass to bioethanol is one of key challenges in the situation of increasing bioethanol demand. The ethanologenic microbes for such conversion are required to possess abilities of utilization of various sugars including xylose and arabinose in lignocellulosic biomass. As required additional characteristics, there are a weak or no glucose repression that allows cells to simultaneously utilize various sugars together with glucose and thermotolerance for fermentation at high temperatures, which has several advantages including reduction of cooling cost. Spathaspora passalidarum ATCC MYA-4345, a type strains, isolated previously have mainly of these abilities or characteristics but its thermotolerance is not so strong and its glucose repression on xylose utilization is revealed. RESULTS: Newly isolated S. passalidarum CMUWF1-2 was found to have a high ability to produce ethanol from various sugars included in lignocellulosic biomass at high temperatures. The strain achieved ethanol yields of 0.43 g, 0.40 g and 0.20 g ethanol/g xylose at 30 degrees C, 37 degrees C and 40 degrees C, respectively. Interestingly, no significant glucose repression was observed in experiments with mixed sugars, being consistent with the strong resistance to 2-deoxyglucose, and antimycin A showed no effect on its growth in xylose medium. Moreover, the strain was tolerant to glucose and ethanol at concentrations up to 35.0% (w/v) and 8.0% (v/v), respectively. CONCLUSIONS: S. passalidarum CMUWF1-2 was shown to achieve efficient production of ethanol from various sugars and a high ethanol yield from xylose with little accumulation of xylitol. The strain also exhibited stress resistance including thermotolerance and no detectable glucose repression as beneficial characteristics. Therefore, S. passalidarum CMUWF1-2 has remarkable potential for conversion of lignocellulosic biomass to bioethanol. PMID- 30005620 TI - Lactic acid Bacteria isolated from European badgers (Meles meles) reduce the viability and survival of Bacillus Calmette-Guerin (BCG) vaccine and influence the immune response to BCG in a human macrophage model. AB - BACKGROUND: Bovine tuberculosis (bTB) caused by Mycobacterium bovis is the most serious endemic disease affecting livestock in the UK. The European badger (Meles meles) is the most important wildlife reservoir of bTB transmission to cattle, making eradication particularly difficult. In this respect, oral vaccination with the attenuated M. bovis vaccine Bacillus Calmette-Guerin (BCG) has been suggested as a wide-scale intervention to reduce bTB infection in badgers. However, experimental studies show variable protection. Among the possibilities for this variation is that the resident gut bacteria may influence the success of oral vaccination in badgers; either through competitive exclusion and/or inhibition, or via effects on the host immune system. In order to explore this possibility, we have tested whether typical gut commensals such as Lactic Acid Bacteria (LAB) have the capacity to impact on the viability and survival rate of BCG and to modulate the immune response to BCG using an in vitro model. RESULTS: Twelve LAB isolated from badger faeces displayed inhibitory activity to BCG that was species dependent. Weissella had a bacteriostatic effect, whereas isolates of enterococci, lactobacilli and pediococci had a more bactericidal activity. Furthermore, BCG-induced activation of the pro-inflammatory transcription factor NF-kappaB in human THP-1 macrophages was modulated by LAB in a strain-dependent manner. Most pediococci enhanced NF-kappaB activation but one strain had the opposite effect. Interestingly, isolates of enterococci, lactobacilli and weissella had different effects as immunomodulators of BCG-induced macrophage responses as some had no significant influence on NF-kappaB activation, but others increased it significantly. CONCLUSIONS: Our in vitro results show that LAB isolated from badgers exhibit significant inhibitory activity against BCG and influence the immune activation mediated by BCG in a human macrophage assay. These findings suggest that gut commensal bacteria could play a role in influencing the outcome of oral BCG vaccination. Inactivated cells of LAB, or LAB that are bacteriostatic but have a synergistic immunostimulatory effect with BCG, could be potential adjuvants to be used for oral vaccination in badgers. Further work is needed to take into account the complex nature of the gut microbiome, specific immunity of the badger and the in vivo context. PMID- 30005622 TI - Clinical Frailty Scale (CFS) reliably stratifies octogenarians in German ICUs: a multicentre prospective cohort study. AB - BACKGROUND: In intensive care units (ICU) octogenarians become a routine patients group with aggravated therapeutic and diagnostic decision-making. Due to increased mortality and a reduced quality of life in this high-risk population, medical decision-making a fortiori requires an optimum of risk stratification. Recently, the VIP-1 trial prospectively observed that the clinical frailty scale (CFS) performed well in ICU patients in overall-survival and short-term outcome prediction. However, it is known that healthcare systems differ in the 21 countries contributing to the VIP-1 trial. Hence, our main focus was to investigate whether the CFS is usable for risk stratification in octogenarians admitted to diversified and high tech German ICUs. METHODS: This multicentre prospective cohort study analyses very old patients admitted to 20 German ICUs as a sub-analysis of the VIP-1 trial. Three hundred and eight patients of 80 years of age or older admitted consecutively to participating ICUs. CFS, cause of admission, APACHE II, SAPS II and SOFA scores, use of ICU resources and ICU- and 30-day mortality were recorded. Multivariate logistic regression analysis was used to identify factors associated with 30-day mortality. RESULTS: Patients had a median age of 84 [IQR 82-87] years and a mean CFS of 4.75 (+/- 1.6 standard deviation) points. More than half of the patients (53.6%) were classified as frail (CFS >= 5). ICU-mortality was 17.3% and 30-day mortality was 31.2%. The cause of admission (planned vs. unplanned), (OR 5.74) and the CFS (OR 1.44 per point increase) were independent predictors of 30-day survival. CONCLUSIONS: The CFS is an easy determinable valuable tool for prediction of 30-day ICU survival in octogenarians, thus, it may facilitate decision-making for intensive care givers in Germany. TRIAL REGISTRATION: The VIP-1 study was retrospectively registered on ClinicalTrials.gov (ID: NCT03134807 ) on May 1, 2017. PMID- 30005623 TI - Levels and prognostic impact of circulating markers of inflammation, endothelial activation and extracellular matrix remodelling in patients with lung cancer and chronic obstructive pulmonary disease. AB - BACKGROUND: The development of both chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is influenced by smoking related chronic pulmonary inflammation caused by an excessive innate immune response to smoke exposure. In addition, the smoking induced formation of covalent bonds between the carcinogens and DNA and the accumulation of permanent somatic mutations in critical genes are important in the carcinogenic processes, and can also induce inflammatory responses. How chronic inflammation is mirrored by serum markers in COPD and LC and if these markers reflect prognosis in patients with LC is, however, largely unknown. METHODS: Serum levels of 18 markers reflecting inflammation, endothelial activation and extracellular matrix remodelling were analysed in 207 patients with non-small lung carcinoma (NSCLC) before surgery and 42 COPD patients. 56% of the LC patients also suffered from COPD. The serum samples were analysed by enzyme immunoassays. RESULTS: Serum levels of OPG, PTX3, AXL, ALCAM, sCD163, CD147, CatS and DLL1 were significantly higher in patients with COPD as compared to patients with LC. High sTNFR1 levels were associated with improved progression free survival (PFS) and overall survival (OS) in LC patients with (PFS hazard ratio (HR) 0.49, OS HR 0.33) and without COPD (OS HR 0.30). High levels of OPG were associated with improved PFS (HR 0.17) and OS (HR 0.14) for LC with COPD. CRP was significantly associated with overall survival regardless of COPD status. CONCLUSION: Several markers reflecting inflammation, endothelial activation and extracellular matrix remodelling are elevated in serum from patients with COPD compared to LC patients. Presence of COPD might influence the levels of circulating biomarkers. Some of these markers are also associated with prognosis. PMID- 30005625 TI - Anthropometric and blood parameters for the prediction of NAFLD among overweight and obese adults. AB - BACKROUND: Non-alcoholic fatty liver disease (NAFLD) comprises non-progressive steatosis and non-alcoholic steatohepatitis (NASH), the latter of which may cause cirrhosis and hepatocellular carcinoma (HCC). As NAFLD detection is imperative for the prevention of its complications, we evaluated whether a combination of blood-based biomarkers and anthropometric parameters can be used to predict NAFLD among overweight and obese adults. METHODS: 143 overweight or obese non-smokers free of diabetes (50% women, age: 35-65 years) were recruited. Anthropometric indices and routine biomarkers of metabolism and liver function were measured to predict magnetic resonance (MR) - derived NAFLD by multivariable logistic regression models. In addition, we evaluated to which degree the use of more novel biomarkers (adiponectin, leptin, resistin, C-reactive protein, TNF-alpha, IL-6, IL-8 and interferon-gamma) could improve prediction models. RESULTS: NAFLD was best predicted by a combination of age, sex, waist circumference, ALT, HbA1c, and HOMA-IR at an area under the receiver operating characteristic curve (AUROC) of 0.87 (95% CI: 0.81, 0.93) before and 0.85 (95% CI: 0.78, 0.91) after internal bootstrap validation. The use of additional biomarkers of inflammation and metabolism did not improve NAFLD prediction. Previously published indices predicted NAFLD at AUROCs between 0.71 and 0.82. CONCLUSIONS: The AUROC of > 0.8 obtained by our regression model suggests the feasibility of a non-invasive detection of NAFLD by anthropometry and circulating biomarkers, even though further increments in the capacity of prediction models may be needed before NAFLD indices can be applied in routine clinical practice. PMID- 30005624 TI - Arabidopsis thaliana ambient temperature responsive lncRNAs. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as new class of regulatory molecules in animals where they regulate gene expression at transcriptional and post-transcriptional level. Recent studies also identified lncRNAs in plant genomes, revealing a new level of transcriptional complexity in plants. Thousands of lncRNAs have been predicted in the Arabidopsis thaliana genome, but only a few have been studied in depth. RESULTS: Here we report the identification of Arabidopsis lncRNAs that are expressed during the vegetative stage of development in either the shoot apical meristem or in leaves. We found that hundreds of lncRNAs are expressed in these tissues, of which 50 show differential expression upon an increase in ambient temperature. One of these lncRNAs, FLINC, is down-regulated at higher ambient temperature and affects ambient temperature-mediated flowering in Arabidopsis. CONCLUSION: A number of ambient temperature responsive lncRNAs were identified with potential roles in the regulation of temperature-dependent developmental changes, such as the transition from the vegetative to the reproductive (flowering) phase. The challenge for the future is to characterize the biological function and molecular mode of action of the large number of ambient temperature-regulated lncRNAs that have been identified in this study. PMID- 30005626 TI - Prognostic and clinicopathological significance of MLKL expression in cancer patients: a meta-analysis. AB - BACKGROUND: MLKL is the most important executor of necroptosis pathway. Recent studies have demonstrated that MLKL could serve as a potential prognostic biomarker for cancer patients. However, most studies reported so far are limited in discrete outcome and sample size. METHODS: We systematically searched PubMed, Embase, Web of Science and CNKI to obtain all relevant articles about the prognostic value of abnormally expressed MLKL in patients with any type of tumor. Odds ratios or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) were pooled to estimate the association between MLKL expression and clinicopathological characteristics or survival of cancer patients. RESULTS: A total of 6 eligible studies with 613 cancer patients were enrolled in our meta analysis. Our results demonstrated that decreased expression level of MLKL was significantly associated with poor overall survival (OS) (pooled HR 0.26, 95%CI 0.17-0.40, high/low) and event-free survival (EFS) (pooled HR 0.45, 95%CI 0.23 0.87, high/low) in cancer patients. Furthermore, subgroup analysis divided by type of cancer, sample size, follow-up time and Newcastle-Ottawa Scale (NOS) score showed consistent prognostic value. In addition, our analysis revealed that decreased expression level of MLKL was significantly associated with advanced tumor stage, more lymph node metastasis and older age. CONCLUSIONS: In conclusion, our meta-analysis suggested that decreased MLKL expression might be a convinced unfavorable prognostic factor that could help the clinical decision making process. PMID- 30005627 TI - Chromoanasynthesis is a common mechanism that leads to ERBB2 amplifications in a cohort of early stage HER2+ breast cancer samples. AB - BACKGROUND: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events. METHODS: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information. RESULTS: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation. CONCLUSION: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events. PMID- 30005628 TI - Evaluation of peripapillary choroidal distribution in children by enhanced depth imaging optical coherence tomography. AB - BACKGROUND: To evaluate the peripapillary choroidal thickness (PPCT) in Chinese children aged 6 to 12 years old and to analyze correlative factors. METHODS: PPCT was measured with enhanced depth imaging optical coherence tomography (EDI-OCT) in 154 children (76 myopes and 78 emmetropia) aged 6 to 12 years, with spherical equivalent refractive errors between + 0.50 and - 5.50 diopters(D). Peripapillary choroidal imaging was performed using circular scans of a diameter of 3.4 mm around the optic disc. PPCT and the corresponding peripapillary retinal thickness (PPRT) were measured by EDI-OCT at nine positions: I, inferior; IN, inferonasal; IT, inferotemporal; N, nasal; T, temporal; S, superior; SN, superonasal; ST, superotemporal, and the Fovea Centralis. RESULTS: The mean global PPCT was 165.80 +/- 39.86 MUm.The mean global PPRT was 101.47 +/- 10.74 MUm. The Inferior had the thinnest PPCT but the thickest PPRT (p < 0.001), while the Nasal had thickest PPCT but the thinnest PPRT (p < 0.001). Significant differences in RT between the myopic group and the emmetropic group were found at all positions except T, TS, S and the fovea. Myopic group had thinner choroidal thickness (CT) than that of emmetropic group at all measured positions. Choroidal thickness had negative relation with the corresponding retinal thickness, age and axial length. CONCLUSION: The peripapillary choroid was thicker nasally and thinner inferiorly, while the peripapillary retina was thickest inferiorly and thinnest nasally. Myopic group had thinner PPCT. The axial length was found to be negatively correlated to PPCT. PMID- 30005629 TI - Evaluation of electrical impedance tomography for determination of urinary bladder volume: comparison with standard ultrasound methods in healthy volunteers. AB - BACKGROUND: Continuous non-invasive urinary bladder volume measurement (cystovolumetry) would allow better management of urinary tract disease. Electrical impedance tomography (EIT) represents a promising method to overcome the limitations of non-continuous ultrasound measurements. The aim of this study was to compare the measurement accuracy of EIT to standard ultrasound in healthy volunteers. METHODS: For EIT of the bladder a commercial device (Goe MF II) was used with 4 different configurations of 16 standard ECG electrodes attached to the lower abdomen of healthy participants. To estimate maximum bladder capacity (BCmax) and residual urine (RU) two ultrasound methods (US-Ellipsoid and US-L * W * H) and a bedside bladder scanner (BS), were performed at the point of urgency and after voiding. For volume reference, BCmax and RU were validated by urine collection in a weight measuring pitcher. The global impedance method was used offline to estimate BCmax and RU from EIT. RESULTS: The mean error of US Ellipsoid (37 +/- 17%) and US-L * W * H (36 +/- 15%) and EIT (32 +/- 18%) showed no significant differences in the estimation of BCmax (mean 743 +/- 200 ml) normalized to pitcher volumetry. BS showed significantly worse accuracy (55 +/- 9%). Volumetry of RU (mean 152.1 +/- 64 ml) revealed comparable higher errors for both EIT (72 +/- 58%) and BS (63 +/- 24%) compared to US-Ellipsoid (54 +/- 25%). In case of RU, EIT accuracy is dependent on electrode configuration, as the Stripes (41 +/- 25%) and Matrix (38 +/- 27%) configurations revealed significantly superior accuracy to the 1 * 16 (116 +/- 62%) configuration. CONCLUSIONS: EIT-cystovolumetry compares well with ultrasound techniques. For estimation of RU, the selection of the EIT electrode configuration is important. Also, the development of an algorithm should consider the impact of movement artefacts. Finally, the accuracy of non-invasive ultrasound accepted as gold standard of cystovolumetry should be reconsidered. PMID- 30005630 TI - Diagnostic value of intraoperative ultrasonography in assessing thoracic recurrent laryngeal nerve lymph nodes in patients with esophageal cancer. AB - BACKGROUD: The incidence of recurrent laryngeal nerve (RLN) injury has increased due to RLN lymph node dissection. The aim of this study was to evaluate the ability of intraoperative ultrasonography (IU) to detect RLN nodal metastases in esophageal cancer patients. METHODS: Sixty patients with esophageal cancer underwent IU, computed tomography (CT), and endoscopic ultrasonography (EUS) to assess for RLN nodal metastasis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared. RESULTS: The sensitivities of IU, CT, and EUS in diagnosing right RLN nodal metastases were 71.4, 14.3, and 30.0%, respectively, and a significant difference among these three examinations was observed (chi2 = 10.077, P = .006). The specificities of IU, CT, and EUS for diagnosing right RLN nodal metastasis were 67.4, 97.8, and 95.0%, respectively, and a significant difference was observed (chi2 = 21.725, P < .001). No significant differences in either PPV or NPV were observed when diagnosing right RLN nodal metastases. For diagnosis of left RLN lymph nodal metastases, the sensitivities of IU, CT, and EUS were 91.7, 16.7, and 40.0% respectively. There was a significant difference among these diagnostic sensitivities (chi2 = 14.067, P = .001). The specificities of IU, CT, and EUS for diagnosis of left RLN nodal metastases were 79.2, 100, and 82.5%, respectively and a significant difference was observed (chi2 = 10.819, P = .004). No significant differences were observed in PPV or NPV for these examinations when diagnosing left RLN nodal metastases. CONCLUSION: Intraoperative ultrasonography showed superior sensitivity compared with preoperative CT or EUS in detecting RLN lymph node metastasis in patients with thoracic esophageal cancer. PMID- 30005631 TI - Prenatal care among rural to urban migrant women in China. AB - BACKGROUND: There is a very large population of internal migrants in China, and the majority of migrant women are of childbearing age. Little is known about their utilization of prenatal care and factors that influence this. We examined this using data from a large national survey of migrants. METHODS: 5372 married rural to urban migrant women aged 20-34 who were included in the 2014 National Dynamic Monitoring Survey on Migrants and who delivered a baby within the previous two years were studied. We examined demographic and migration experience predictors of prenatal care in the first trimester and of adequate prenatal visits. RESULTS: 12.6% of migrant women reported no examination in the first trimester and 27.6% had less than 5 prenatal visits during their latest pregnancy. Multivariate analysis indicated that demographic predictors of delayed and inadequate care included lower educational level, lower income and not having childbearing insurance. Migrating before pregnancy, longer time since migration, having migrated a greater distance, and not returning to their home town for delivery were correlated with better prenatal care. CONCLUSIONS: Many internal migrant women in China do not receive adequate prenatal care. While internal migration before pregnancy seems to promote adequate prenatal care, it also creates barriers to receiving care. Strategies to improve prenatal care utilization include expanding access to childbearing insurance and timely education for women before and after they migrate. PMID- 30005632 TI - Rehydration with fructose worsens dehydration-induced renal damage. AB - BACKGROUND: Increasing evidence suggests heat stress induced chronic kidney disease (CKD) may be mediated by endogenous fructose generation and may be exacerbated by rehydration by fructose-containing solutions. We have recently reported a model of CKD induced by heat stress. Here we test the hypothesis that rehydration with fructose may induce worse kidney injury than rehydration with equal amounts of water, and we also test if this fructose-induced injury is associated with activation of inflammasomes in the kidney. METHODS: Mice were recurrently exposed to heat (39.5 C0 for 30 min/h, 5 times daily for 5 wks) with rehydration consisting of 6 ml each night of water (Heat, n = 7) or fructose (Heat+F, 10%, n = 7), and were compared to control mice on water (Control, n = 7) or fructose (Fructose, n = 7). Various markers of renal injury were assessed. RESULTS: Compared to control animals, there was a progressive worsening of renal injury (inflammation and fibrosis) with fructose alone, heat stress alone, and heat stress with fructose rehydration (P < 0.01 by ANOVA). The combination of heat stress with rehydration with fructose was associated with increased intrarenal expression of the inflammasome markers, NLRP3 and IL-18, compared to heat stress alone. In addition, heat stress with or without fructose was associated with increased expression of caspase - 3 and monocyte chemoattractant protein-1 levels. Fructose administration was also associated with an increase in serum copeptin levels (a biomarker of vasopressin) and elevated copeptin was also observed in mice undergoing heat stress alone. CONCLUSIONS: These studies suggest that heat stress may activate intrarenal inflammasomes leading to inflammation and renal injury, and provide evidence that rehydration with fructose may accelerate the renal injury and inflammatory response. PMID- 30005633 TI - Recurrent tumor-specific regulation of alternative polyadenylation of cancer related genes. AB - BACKGROUND: Alternative polyadenylation (APA) results in messenger RNA molecules with different 3' untranslated regions (3' UTRs), affecting the molecules' stability, localization, and translation. APA is pervasive and implicated in cancer. Earlier reports on APA focused on 3' UTR length modifications and commonly characterized APA events as 3' UTR shortening or lengthening. However, such characterization oversimplifies the processing of 3' ends of transcripts and fails to adequately describe the various scenarios we observe. RESULTS: We built a cloud-based targeted de novo transcript assembly and analysis pipeline that incorporates our previously developed cleavage site prediction tool, KLEAT. We applied this pipeline to elucidate the APA profiles of 114 genes in 9939 tumor and 729 tissue normal samples from The Cancer Genome Atlas (TCGA). The full set of 10,668 RNA-Seq samples from 33 cancer types has not been utilized by previous APA studies. By comparing the frequencies of predicted cleavage sites between normal and tumor sample groups, we identified 77 events (i.e. gene-cancer type pairs) of tumor-specific APA regulation in 13 cancer types; for 15 genes, such regulation is recurrent across multiple cancers. Our results also support a previous report showing the 3' UTR shortening of FGF2 in multiple cancers. However, over half of the events we identified display complex changes to 3' UTR length that resist simple classification like shortening or lengthening. CONCLUSIONS: Recurrent tumor-specific regulation of APA is widespread in cancer. However, the regulation pattern that we observed in TCGA RNA-seq data cannot be described as straightforward 3' UTR shortening or lengthening. Continued investigation into this complex, nuanced regulatory landscape will provide further insight into its role in tumor formation and development. PMID- 30005634 TI - Effect of incision on visual outcomes after implantation of a trifocal diffractive IOL. AB - BACKGROUND: To evaluate visual acuity, corneal astigmatism and corneal higher order aberrations (HOAs) after implantation of trifocal diffractive IOLs operated with either a corneal steep-axis incision or 135 degrees incision. METHOD: This prospective study enrolled patients randomly assigned to different groups. According to preoperative corneal astigmatism, 101 eyes of 77 patients were assigned into group A1 (0 ~ 0.50 D) or A2 (0.51 ~ 1.00 D) with a corneal steep axis incision or group B1 (0 ~ 0.50 D) or B2 (0.51 ~ 1.00 D) with a 135 degrees incision. Visual acuity, corneal astigmatism and corneal higher-order aberrations (HOAs) were followed-up for 3 months. RESULTS: Corneal astigmatism in group A2 significantly decreased 3 months after surgery (P < 0.01) and was significantly lower than that in group B2 1 day, 2 weeks, 1 month, and 3 months postoperatively (all values of P < 0.01). The following parameters were better in group A2 than in group B2: uncorrected intermediate visual acuity (UIVA) at 1 day, 2 weeks, 1 month, and 3 months (P = 0.00, 0.00, 0.01, 0.01, respectively);uncorrected distance visual acuity (UDVA) at 1 day and 2 weeks (P = 0.00, 0.01); and uncorrected near visual acuity (UNVA) at 1 day, 2 weeks, and 1 month postoperatively (P = 0.00, 0.01, 0.02, respectively). CONCLUSIONS: After a corneal steep-axis incision, patients with preoperative corneal astigmatism of 0.51 D to 1.00 D exhibited reduced corneal astigmatism and achieved better UIVA and early postoperative UDVA/UNVA. TRIAL REGISTRATION: Retrospectively Registered Trials ISRCTN10086721 , 23/06/2018. PMID- 30005635 TI - Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-delta/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity. AB - BACKGROUND: Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. In the present study, we investigated whether the chronic effects of Ang II via AT1 receptor (AT1R) would result in endoplasmic reticulum (ER) stress/PKC-delta/p38 MAPK stimulation, and consequently podocyte apoptosis. METHODS: Wistar rats were treated with Ang II (200 ng.kg-1.min-1, 42 days) and or losartan (10 mg.kg-1.day-1, 14 days). Immortalized mouse podocyte were treated with 1 MUM Ang II and/or losartan (1 MUM) or SB203580 (0.1 MUM) (AT1 receptor antagonist and p38 MAPK inhibitor) for 24 h. Kidney sections and cultured podocytes were used to evaluate protein expression by immunofluorescence and immunoblotting. Apoptosis was evaluated by flow cytometry and intracellular pH (pHi) was analyzed using microscopy combined with the fluorescent probe BCECF/AM. RESULTS: Compared with controls, Ang II via AT1R increased chaperone GRP 78/Bip protein expression in rat glomeruli (p < 0.001) as well as in podocyte culture (p < 0.01); increased phosphorylated eIf2-alpha (p < 0.05), PKC-delta (p < 0.01) and p38 MAPK (p < 0.001) protein expression. Furthermore, Ang II induced p38 MAPK mediated late apoptosis and increased the Bax/Bcl-2 ratio (p < 0.001). Simultaneously, Ang II via AT1R induced p38 MAPK-NHE1-mediated increase of pHi recovery rate after acid loading. CONCLUSION: Together, our results indicate that Ang II-induced podocyte apoptosis is associated with AT1R/ER stress/PKC-delta/p38 MAPK axis and enhanced NHE1-mediated pHi recovery rate. PMID- 30005636 TI - Defining myocardial fibrosis in haemodialysis patients with non-contrast cardiac magnetic resonance. AB - BACKGROUND: Extent of myocardial fibrosis (MF) determined using late gadolinium enhanced (LGE) predicts outcomes, but gadolinium is contraindicated in advanced renal disease. We assessed the ability of native T1-mapping to identify and quantify MF in aortic stenosis patients (AS) as a model for use in haemodialysis patients. METHODS: We compared the ability to identify areas of replacement-MF using native T1-mapping to LGE in 25 AS patients at 3 T. We assessed agreement between extent of MF defined by LGE full-width-half-maximum (FWHM) and the LGE 3 standard-deviations (3SD) in AS patients and nine T1 thresholding-techniques, with thresholds set 2-to-9 standard-deviations above normal-range (1083 +/- 33 ms). A further technique was tested that set an individual T1-threshold for each patient (T11SD). The technique that agreed most strongly with FWHM or 3SD in AS patients was used to compare extent of MF between AS (n = 25) and haemodialysis patients (n = 25). RESULTS: Twenty-six areas of enhancement were identified on LGE images, with 25 corresponding areas of discretely increased native T1 signal identified on T1 maps. Global T1 was higher in haemodialysis than AS patients (1279 ms +/- 5.8 vs 1143 ms +/- 12.49, P < 0.01). No signal-threshold technique derived from standard-deviations above normal-range associated with FWHM or 3SD. T11SD correlated with FWHM in AS patients (r = 0.55) with moderate agreement (ICC = 0.64), (but not with 3SD). Extent of MF defined by T11SD was higher in haemodialysis vs AS patients (21.92% +/- 1 vs 18.24% +/- 1.4, P = 0.038), as was T1 in regions-of-interest defined as scar (1390 +/- 8.7 vs 1276 ms +/- 20.5, P < 0.01). There was no difference in the relative difference between remote myocardium and regions defined as scar, between groups (111.4 ms +/- 7.6 vs 133.2 ms +/- 17.5, P = 0.26). CONCLUSIONS: Areas of MF are identifiable on native T1 maps, but absolute thresholds to define extent of MF could not be determined. Histological studies are needed to assess the ability of native-T1 signal thresholding techniques to define extent of MF in haemodialysis patients. Data is taken from the PRIMID-AS (NCT01658345) and CYCLE-HD studies (ISRCTN11299707). PMID- 30005637 TI - Pulmonary vein anatomy variants as a biomarker of atrial fibrillation - CT angiography evaluation. AB - BACKGROUND: It has been suggested that changes in pulmonary veins (PV) and left atrium (LA) anatomy may have an influence on initiating atrial fibrillation (AF) and the effectiveness of pulmonary vein isolation (PVI) in patients (pts) with atrial fibrillation. The aim of the study was to assess anatomy abnormalities of the PV and LA in the patients with the history of AF and compare it with the control group(CG). METHODS: The multi-slice tomography (MSCT) scans were performed in 224 AF pts. before PVI (129 males, mean age 59 +/- 9 yrs). The CG consisted of 40 pts. without AF (26 males, age 45 +/- 9 yrs). LA and PV anatomy were evaluated. Diameters of PV ostia were measured in two directions: anterior posterior (AP) and superior-inferior (SI) automatically using Vitrea 4.0. RESULTS: Pulmonary veins anatomy variants were observed more frequently in the atrial fibrillation group - 83 pts. (37%) vs 6 pts. (15%) in CG; 9% (21 pts) left common ostia (CO), 2% (5 pts) right CO, 19% (42 pts) additional right PV (APV), (1.8%) 4 pts. APV left, 8% right early branching (EB) and 3.5% left EB. The LA diameter differed significantly in AF vs CG group (41.2 +/- 6 mm vs 35 +/- 4.2 mm, p < 0.0001) respectively. CONCLUSIONS: The anomalies of pulmonary vein anatomy occurred more often in pts. with AF. They can be defined as an image biomarkers of atrial fibrillation. Right additional (middle) pulmonary vein was the most important anomaly detected in AF patients as well as enlargered diameters of the LA and PV ostia. PMID- 30005638 TI - Presence of protein production enhancers results in significantly higher methanol induced protein production in Pichia pastoris. AB - BACKGROUND: The yeast Komagataella phaffii, better known as Pichia pastoris, is a commonly used host for recombinant protein production. Here expression vectors are reported that address the different steps of the transcription-translation secretion pathway of heterologous protein production. RESULTS: Transcription and translation enhancing elements were introduced in an expression cassette for the production of recombinant Aspergillus niger feruloyl esterase A. The yield was increased by threefold as compared to the yield without these elements. Multiple copy strains were selected using a zeocin resistance marker in the expression cassette and showed another sixfold higher yield. Modification of the C-terminal amino acid sequence of the secretion signal did not significantly improve the production yield. Similar data were obtained for the production of another protein, recombinant human interleukin 8. Upscaling to fed-batch fermentation conditions resulted in a twofold increase for reference strains, while for strains with enhancing elements a tenfold improvement was observed. CONCLUSIONS: Pichia pastoris is used for recombinant protein production in industrial fermentations. By addressing the transcription and translation of mRNA coding for recombinant protein, significant yield improvement was obtained. The yield improvement obtained under microscale conditions was maintained under fed-batch fermentation conditions. These data demonstrate the potential of these expression vectors for large scale application as improved production of proteins has major implications on the economics and sustainability of biocatalyst dependent production processes e.g. for the production of pharmaceuticals and for the bioconversions of complex molecules. PMID- 30005639 TI - Association between DSCAM polymorphisms and non-syndromic Hirschsprung disease in Chinese population. AB - BACKGROUND: Hirschsprung disease (HSCR, aganglionic megacolon) is the most frequent genetic cause of congenital intestinal obstruction. DSCAM was identified as associated to HSCR with Down Syndrome (DS-HSCR) in European population,but failed to replicate in the non-syndromic HSCR patients. We aim to further investigate the relationship of DSCAM with non-sydromic HSCR in a South Chinese cohort, the largest case-control study so far. METHOD: We analyzed 1394 HSCR patients and 973 healthy controls. Two polymorphisms (rs2837770 A > G, rs8134673 A > G) on DSCAM were genotyped using Sequenom Massarray platform. RESULTS: Both SNPs were confirmed as associated with non-syndromic HSCR in the South Chinese population (P = 1.69E-03, OR = 1.29 for SNP rs2837770 and P = 3.00E-03, OR = 1.27 for SNP rs8134637). Of note, we demonstrated the associated SNPs were more likely to affect a subgroup of patients with short-segment aganglionosis (S-HSCR) (P = 3.06E-03,OR = 1.21 for SNP rs2837770 and P = 3.33E-03,OR = 1.21 for SNP rs8134637). CONCLUSION: There is an association between DSCAM polymorphisms and non-syndromic HSCR in South Chinese population. PMID- 30005640 TI - Hand-Assisted laparoscopic donor nephrectomy PERiumbilical versus Pfannenstiel incision and return to normal physical ACTivity (HAPERPACT): study protocol for a randomized controlled trial. AB - BACKGROUND: Hand-assisted laparoscopic living donor nephrectomy (HALDN) using a periumbilical or Pfannenstiel incision was developed to improve donor outcome after a kidney transplant. The aim of this study was to investigate two methods of hand assistance and kidney removal during HALDN and their effect on the time it takes for the donor to return to normal physical activity. METHODS/DESIGN: This study was initiated in November 2017 and is expected to last for 2 years. To be eligible for the study, donors must be more than 20 years of age and must not be receiving permanent pain therapy. Only donors with a single artery and vein in the graft are being enrolled in this trial. Donors with infections or scars in the periumbilical or hypogastric area, bleeding disorders, chronic use of immunosuppressive agents, or active infection will be excluded. Donors will be randomly allocated to either a control arm (periumbilical incision) or an intervention arm (Pfannenstiel incision). The sample size was calculated as 26 organ donors in each group. The primary endpoint is the number of days it takes the donor to return to normal physical activity (up to 4 weeks after the operation). Secondary endpoints are intraoperative outcomes, including estimated blood loss, warm ischemia time, and duration of the operation. Postoperative pain will be assessed using the visual analog scale, rescue analgesic use, and peak expiratory flow rate. Length of hospital stay, physical activity score, time to return to work, donor satisfaction, cosmetic score, postoperative complications, and all-cause mortality in living donors will also be reported. Delayed graft function, primary non-function, serum creatinine levels, and glomerular filtration rate will also be assessed in the recipients after transplantation. DISCUSSION: This is the first randomized controlled trial to compare the time it takes the living donor to return to normal physical activity after HALDN using two different types of incision. The comprehensive findings of this study will help decide which nephrectomy procedure is best for living donors with regard to patient comfort and satisfaction as well as graft function in the recipient after transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03317184 . Registered on 23 October 2017. PMID- 30005641 TI - Widespread arenavirus occurrence and seroprevalence in small mammals, Nigeria. AB - BACKGROUND: Lassa fever, killing thousands of people annually, is the most reported viral zoonotic disease in Nigeria. Recently, different rodent species carrying diverse lineages of the Lassa virus (LASV) in addition to a novel Mobala like genetic sequence were detected within the country. Here, screening 906 small mammal specimens from 11 localities for IgG antibodies and incorporating previous PCR detection data involving the same populations, we further describe arenavirus prevalence across Nigeria in relation to host species and geographical location. METHODS: Small mammals were trapped during the period 2011-2015 according to geographical location (endemic and non-endemic zones for Lassa fever), season (rainy and dry seasons between 2011 and 2012 for certain localities) and habitat (indoors, peridomestic settings and sylvatic vegetation). Identification of animal specimens from genera such as Mastomys and Mus (Nannomys) was assisted by DNA sequencing. Small mammals were tested for LASV IgG antibody using an indirect immunofluorescence assay (IFA). RESULTS: Small mammals were infected in both the endemic and non-endemic zones for Lassa fever, with a wider range of species IgG positive (n = 8) than those which had been previously detected to be PCR-positive (n = 3). IgG-positive species, according to number of infected individuals, were Mastomys natalensis (n = 40), Mastomys erythroleucus (n = 15), Praomys daltoni (n = 6), Mus baoulei (n = 5), Rattus rattus (n = 2), Crocidura spp. (n = 2), Mus minutoides (n = 1) and Praomys misonnei (n = 1). Multimammate mice (Mastomys natalensis and M. erythroleucus) were the most ubiquitously infected, with animals testing positive by either PCR or IgG in 7 out of the 11 localities sampled. IgG prevalence in M. natalensis ranged from 1% in Abagboro, 17-36 % in Eguare Egoro, Ekpoma and Ngel Nyaki, up to 52 % in Mayo Ranewo. Prevalence according to locality, season and age was not, however, statistically significant for M. natalensis in Eguare Egoro and Ekpoma, localities that were sampled longitudinally. CONCLUSIONS: Overall, our study demonstrates that arenavirus occurrence is probably more widely distributed geographically and in extent of host taxa than is currently realized. This expanded scope should be taken into consideration in Lassa fever control efforts. Further sampling should also be carried out to isolate and characterize potential arenaviruses present in small mammal populations we found to be seropositive. PMID- 30005642 TI - Relative lymphocyte count as an indicator of 3-year mortality in elderly people with severe COPD. AB - BACKGROUND: Prognostic stratification of elderly patients with chronic obstructive pulmonary disease (COPD) is difficult due to the wide inter individual variability in the course of the disease. No marker can exactly stratify the evolution and natural history of COPD patients. Studies have shown that leukocyte count is associated with increased risk of mortality in COPD patients. The aim of this study was to evaluate the possible role of relative lymphocyte count as a risk marker for mortality in elderly patients with COPD. METHODS AND RESULTS: This is a3-year prospective study. A total of 218patients, mean age 75.2+/-7 years, with moderate to severe COPD and free from conditions affecting lymphocyte count were enrolled. The population was divided into two groups according to the relative lymphocyte count, with a cut-off of 20%. Eighty five patients (39%) had a relative lymphocyte count <=20%. Three-year mortality rates from any cause in patients with relative lymphocyte count <= or > 20% were 68 and 51%, respectively (p = 0.0012). Survival curve analysis showed higher mortality in patients with relative lymphocyte count <=20% (p = 0.0005). After adjustment for age and sex, the hazard ratio for mortality risk according to lymphocyte count was 1.79 (95% confidence interval [CI]: 1.26-2.57, p = 0.0013), even in the analysis limited to the 171 patients without congestive heart failure (1.63; 95% CI: 1.03-2.58, p = 0.038). CONCLUSIONS: Low relative lymphocyte count was associated with higher mortality in elderly patients with severe COPD. PMID- 30005643 TI - Effectiveness of peer support to increase uptake of retinal examination for diabetic retinopathy: study protocol for the DURE pragmatic cluster randomized clinical trial in Kirinyaga, Kenya. AB - BACKGROUND: All patients with diabetes are at risk of developing diabetic retinopathy (DR), a progressive and potentially blinding condition. Early treatment of DR prevents visual impairment and blindness. The natural history of DR is that it is asymptomatic until the advanced stages, thus annual retinal examination is recommended for early detection. Previous studies show that the uptake of regular retinal examination among people living with diabetes (PLWD) is low. In the Uptake of Retinal Examination in Diabetes (DURE) study, we will investigate the effectiveness of a complex intervention delivered within diabetes support groups to increase uptake of retinal examination. METHODS: The DURE study will be a two-arm pragmatic cluster randomized clinical trial in Kirinyaga County, Kenya. Diabetes support groups will be randomly assigned to either the intervention or usual care conditions in a 1:1 ratio. The participants will be 700 PLWD who are members of support groups in Kirinyaga. To reduce contamination, the unit of randomization will be the support group. Peer supporters in the intervention arm will receive training to deliver the intervention. The intervention will include monthly group education on DR and individual member reminders to take the eye examination. The effectiveness of this intervention plus usual care will be compared to usual care practices alone. Participant data will be collected at baseline. The primary outcome is the proportion of PLWD who take up the eye examination at six months. Secondary outcomes include the characteristics of participants and peer supporters associated with uptake of eye examination for DR. Intention-to-treat analysis will be used to evaluate the primary and secondary outcomes. DISCUSSION: Eye care programs need evidence of the effectiveness of peer supporter-led health education to improve attendance to retinal screening for the early detection of DR in an African setting. Given that the intervention combines standardization and flexibility, it has the potential to be adopted in other settings and to inform policies to promote DR screening. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201707002430195 , registered 25 July 2017, www.pactr.org. PMID- 30005644 TI - Safety and Optimal Neuroprotection of neu2000 in acute Ischemic stroke with reCanalization: study protocol for a randomized, double-blinded, placebo controlled, phase-II trial. AB - BACKGROUND: The potential of neuroprotective agents should be revisited in the era of endovascular thrombectomy (EVT) for acute large-artery occlusion because their preclinical effects have been optimized for ischemia and reperfusion injury. Neu2000, a derivative of sulfasalazine, is a multi-target neuroprotectant. It selectively blocks N-methyl-D-aspartate receptors and scavenges for free radicals. This trial aimed to determine whether neuroprotectant administration before EVT is safe and leads to a more favorable outcome. METHODS: This trial is a phase-II, multicenter, three-arm, randomized, double-blinded, placebo-controlled, blinded-endpoint drug trial that enrolled participants aged >= 19 years undergoing an EVT attempt less than 8 h from symptom onset, with baseline National Institutes of Health Stroke Scale (NIHSS) score >= 8, Alberta Stroke Program Early CT score >= 6, evidence of large-artery occlusion, and at least moderate collaterals on computed tomography angiography. EVT-attempted patients are randomized into control, low-dose (2.75 g), and high dose (5.25 g) Neu2000KWL over 5 days. Seventy participants per group are enrolled for 90% power, assuming that the treatment group has a 28.4% higher proportion of participants with functional independence than the placebo group. The primary outcome, based on intention-to-treat criteria is the improvement of modified Rankin Scale (mRS) scores at 3 months using a dichotomized model. Safety outcomes include symptomatic intracranial hemorrhage within 5 days. Secondary outcomes are distributional change of mRS, mean differences in NIHSS score, proportion of NIHSS score 0-2, and Barthel Index > 90 at 1 and 4 weeks, and 3 months. DISCUSSION: The trial results may provide information on new therapeutic options as multi-target neuroprotection might mitigate reperfusion injury in patients with acute ischemic stroke before EVT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02831088 . Registered on 13 July 2016. PMID- 30005645 TI - Are sleeping site ecology and season linked to intestinal helminth prevalence and diversity in two sympatric, nocturnal and arboreal primate hosts (Lepilemur edwardsi and Avahi occidentalis)? AB - BACKGROUND: Various factors, such as climate, body size and sociality are often linked to parasitism. This constrains the identification of other determinants driving parasite infections. Here, we investigate for the first time intestinal parasites in two sympatric arboreal primate species, which share similar activity patterns, feeding ecology, body size and sociality, and cope with the same climate conditions, but differ in sleeping site ecology: the Milne-Edward's sportive lemur (Lepilemur edwardsi) and the Western woolly lemur (Avahi occidentalis). Comparison of these two species aimed to test whether differences in sleeping sites are related to differences in parasite infection patterns. Additionally, gender and seasonal factors were taken into account. Animals were radio-collared to record their sleeping site dynamics and to collect fecal samples to assess intestinal parasitism during both the dry and the rainy season. RESULTS: Only low parasite diversity was detected, which is attributable to the strict arboreal lifestyle of these lemurs, limiting their contact with infective parasite stages. L. edwardsi, which sleeps in tree holes and repeatedly uses the same sleeping site, excreted eggs of strongyle and oxyurid nematodes, whereby strongyles always occurred in coinfection with oxyurids. In contrast, A. occidentalis, which sleeps on open branches and frequently changes sleeping sites, only excreted eggs of strongyle nematodes. This difference can be attributed to a potential favorable environment presented by tree holes for infective stages, facilitating parasitic transmission. Additionally, Strongylida in A. occidentalis were only observed in the rainy season, suggesting an arrested development during the dry season in the nematodes' life cycle. Males and females of both lemur species showed the same frequency of parasitism. No differences in body mass of infected and non-infected individuals were observed, indicating that the animals' body condition remains unaffected by the detected gastrointestinal parasites. CONCLUSIONS: The comparison of two primate hosts with a very similar lifestyle suggests an influence of the sleeping site ecology on intestinal parasites. In A. occidentalis there was a clear seasonal difference in strongyle egg excretion. These results improve our understanding of the parasite ecology in these endangered primate species, which may be critical in the light of species conservation. PMID- 30005647 TI - Impact of passenger engagement through road safety bus stickers in public service vehicles on road traffic crashes in Zambia: a randomized controlled trial. AB - BACKGROUND: Road Traffic Crashes (RTCs) are the third highest cause of death in Zambia, claiming about 2000 lives annually, with pedestrians and cyclists being the most vulnerable. Human error accounts for 87.3% of RTCs. Minibus and big bus public service vehicles (PSVs) are among the common vehicle types involved in these crashes. Given the alarmingly high rate of road traffic crashes involving PSV minibuses and big buses within Zambia, there is a need to mitigate this through innovative solutions. In other settings, it has been shown that stickers in PSVs encouraging passengers to speak out against reckless driving can reduce RTCs, but it is unclear whether such an intervention could work in Zambia. Based on this evidence, the Zambia Road Transport and Safety Agency (RTSA) has developed a road safety bus sticker campaign for PSVs and before national scale up, RTSA is interested in evidence of the impact of these stickers. METHODS: This evaluation will be a stratified two-arm randomized controlled trial with a one-to one ratio. The sample will be stratified by vehicle type, thus creating a two-arm trial for minibuses and a separate two-arm trial for big buses. The sample will include 2110 minibuses and 300 big buses from four towns in Zambia. The primary outcome of interest will be the difference in the rate of RTCs over a 14-month period (7-months before the intervention and 7 months after) between buses with and without the new RTSA road safety bus stickers. DISCUSSION: This study will provide evidence on the impact of the Zambian sticker program on road traffic crashes as implemented through minibuses and big buses, that can help inform the scale up of a national 'Zambia road safety bus sticker campaign'. TRIAL REGISTRATION: PACT-R, PACTR201711002758216 . Registered 13 November 2017 Retrospectively registered. PMID- 30005646 TI - A hospital-wide evaluation of delirium prevalence and outcomes in acute care patients - a cohort study. AB - BACKGROUND: Delirium is a well-known complication in cardiac surgery and intensive care unit (ICU) patients. However, in many other settings its prevalence and clinical consequences are understudied. The aims of this study were: (1) To assess delirium prevalence in a large, diverse cohort of acute care patients classified as either at risk or not at risk for delirium; (2) To compare these two groups according to defined indicators; and (3) To compare delirious with non-delirious patients regarding hospital mortality, ICU and hospital length of stay, nursing hours and cost per case. METHODS: This cohort study was performed in a Swiss university hospital following implementation of a delirium management guideline. After excluding patients aged < 18 years or with a length of stay (LOS) < 1 day, 29'278 patients hospitalized in the study hospital in 2014 were included. Delirium period prevalence was calculated based on a Delirium Observation Scale (DOS) score >= 3 and / or Intensive Care Delirium Screening Checklist (ICDSC) scores >=4. RESULTS: Of 10'906 patients admitted, DOS / ICDSC scores indicated delirium in 28.4%. Delirium was most prevalent (36.2-40.5%) in cardiac surgery, neurosurgery, trauma, radiotherapy and neurology patients. It was also common in geriatrics, internal medicine, visceral surgery, reconstructive plastic surgery and cranio-maxillo-facial surgery patients (prevalence 21.6-28.6%). In the unadjusted and adjusted models, delirious patients had a significantly higher risk of inpatient mortality, stayed significantly longer in the ICU and hospital, needed significantly more nursing hours and generated significantly higher costs per case. For the seven most common ICD-10 diagnoses, each diagnostic group's delirious patients had worse outcomes compared to those with no delirium. CONCLUSIONS: The results indicate a high number of patients at risk for delirium, with high delirium prevalence across all patient groups. Delirious patients showed significantly worse clinical outcomes and generated higher costs. Subgroup analyses highlighted striking variations in delirium period-prevalence across patient groups. Due to the high prevalence of delirium in patients treated in care centers for radiotherapy, visceral surgery, reconstructive plastic surgery, cranio-maxillofacial surgery and oral surgery, it is recommended to expand the current focus of delirium management to these patient groups. PMID- 30005648 TI - Cell distribution and cytokine levels in induced sputum from healthy subjects and patients with asthma after using different nebulizer techniques. AB - BACKGROUND: Sputum induction is an important noninvasive method for analyzing bronchial inflammation in patients with asthma and other respiratory diseases. Most frequently, ultrasonic nebulizers are used for sputum induction, but breath controlled nebulizers may target the small airways more efficiently. This treatment may produce a cell distribution similar to bronchoalveolar lavage (less neutrophils and more macrophages) and provide deeper insights into the underlying lung pathology. The goal of the study was to compare both types of nebulizer devices and their efficacy in inducing sputum to measure bronchial inflammation, i.e., cell composition and cytokines, in patients with mild allergic asthma and healthy controls. METHODS: The population of this study consisted of 20 healthy control subjects with a median age of 17 years, range: 8-25 years, and 20 patients with a median age of 12 years, range: 8-24 years, presenting with mild, controlled allergic asthma who were not administered an inhaled steroid treatment. We induced sputum in every individual using both devices on two separate days. The sputum weight, the cell composition and cytokine levels were analyzed using a cytometric bead assay (CBA) and by real-time quantitative PCR (qRT-PCR). RESULTS: We did not observe significant differences in the weight, cell distribution or cytokine levels in the sputum samples induced by both devices. In addition, the Bland-Altman correlation revealed good concordance of the cell distribution. As expected, eosinophils and IL-5 levels were significantly elevated in patients with asthma. CONCLUSIONS: The hypothesis that sputum induction with a breath-controlled "smart" nebulizer is more efficient and different from an ultrasonic nebulizer was not confirmed. The Bland-Altman correlations showed good concordance when comparing the two devices. TRIAL REGISTRATION: NCT01543516 Retrospective registration date: March 5, 2012. PMID- 30005649 TI - Understanding barriers for research involvement among paediatric trainees: a mixed methods study. AB - BACKGROUND: Child Health research is reported to be at worryingly low level by the Royal College of Paediatrics and Child Health. Recent survey showed that 54.5% of paediatric consultants in the United Kingdom do not do any research at all. We conducted a mixed methods study to understand barriers and facilitators for research involvement among paediatric trainees who are going to fill these consultant posts in the future. METHODS: A questionnaire based on a validated index for research and development was completed by 136 paediatric trainees within a region in the North of England (Yorkshire and Humber). Twelve semi structured interviews were conducted with stratified purposive sampling. Descriptive statistics and Chi-Square test for independence were used for quantitative analysis. Thematic content analysis was done for interviews based on analysis method framework. RESULTS: 136 out of 396 trainees responded to the survey. There was a significant relationship between confidence in using research in practice and ability to understand research terminology. This was not related to research experience or training. Males were significantly more likely to have presented a research paper, know how research influences practice and have more confidence in using research in practice than females. There was no significant relationship between gender and research training or highest qualification. Time constraints and lack of academic culture were the most frequently mentioned barriers in the survey. Over-arching themes identified from the interviews were related to lack of academic culture, opportunities provided in current training scheme and constraints related to time availability along with workforce management. CONCLUSION: Paediatric research requires a supportive academic culture with more flexibility in training scheme and immediate attention to a pressing staffing crisis. PMID- 30005650 TI - Trends of socioeconomic inequality in using maternal health care services in Lao People's Democratic Republic from year 2000 to 2012. AB - BACKGROUND: Socioeconomic inequalities in access to maternal health care have received more attention as it challenges the sustainability of the ongoing achievement in reducing maternal mortality. By promoting access to maternal health care as one of the core targets of the Health Sector Reform, Lao People's Democratic Republic has reduced maternal mortality dramatically over the last decade. In spite of this improvement, little has been known about the secular trends in disparities of service utilization across different socioeconomic subgroups. METHODS: Two waves of the Multiple Indicator Cluster Survey in the years 2000 and 2012 were pooled for the analysis. We used logistic regression to estimate the likelihood of using antenatal care (ANC) and delivery services with skilled birth attendants (SBA) across different socioeconomic subgroups. Difference-in-difference method was applied to examine the inequality trends across the years by analyzing the interaction terms of the survey years and socioeconomic factors (education, wealth, ethnicity, and residential areas). RESULTS: Urban-rural disparity was improved over time while there were no educational disparity changes. Rural residential areas showed significant changes than urban areas over time [OR = 2.40; 95% CI: 1.52-3.77 for ANC and OR = 2.16; 95% CI: 1.36-3.42 for SBA]. However, there were aggravations in the disparities between major and minor ethnic group as well as worsening disparities between the rich and poor: i.e. Ethnic minority showed significant aggravation over time [OR = 0.62; 95% CI: 0.44-0.89 for ANC and OR = 0.65; 95% CI: 0.44-0.97 for SBA]. CONCLUSIONS: Efforts to increase maternal health service utilization in poor and minority ethnic groups should be emphasized to reduce social inequalities, thus encompassing multiple-sector interventions rather than focusing only on health sector related interventions. PMID- 30005651 TI - Ipomoea batatas L. Lam. ameliorates acute and chronic inflammations by suppressing inflammatory mediators, a comprehensive exploration using in vitro and in vivo models. AB - BACKGROUND: Ipomoea batatas L. Lam. is a functional food and belongs to family Convolvulaceae. It is used as an antiinflammatory, aphrodisiac, antiasthmatic, anticonvalescent, antitumor, antanemic and antidiabetic agent by local communities. This study has been planned to evaluate its antiinflammatory and antiarthritic potentials. METHODS: Dry powder of I. batatas tuber and roots were extracted with ethyl acetate (IPT-EA, IPR-EA) and methanol (IPT-M, IPR-M), respectively. These extracts were tested for total phenolic and flavonoid contents (TPC and TFC), HPLC finger printing, multidimensional in vitro and in vivo antioxidant potential and albumin denaturation inhibition. Carrageenan induced paw edema, croton oil-induced ear and anal edema inhibition and Complete Freund's Adjuvant (CFA)-induced antiarthritic assays were executed at a dose of 300 mg/kg body weight on Sprague-Dawley rats. Serum levels of interleukins IL 1beta and IL-6 and nitric oxide (NO) were assessed to measure the inhibition of inflammation. RESULTS: Maximal TPC (319.81 +/- 14.20 MUg GAE/mg dry extract) and TFC (208.77 +/- 9.09 MUg QE/mg DE) were estimated in IPR-EA extract. IPT-EA and IPR-EA yielded the maximum amounts of rutin (7.3 +/- 1.12 and 4.5 +/- 0.55), caffeic acid (1.60 +/- 0.25 and 2.17 +/- 0.26) and myricetin (2.7 +/- 0.14 and 1.01 +/- 0.08 MUg/mg DE), respectively in HPLC-DAD analysis. All extracts showed dose dependent response in in vitro antioxidant assays. Best inhibition (76.92 +/ 3.07%) of albumin denaturation was shown by IPT-EA in comparison to ibuprofen (79.48 +/- 4.71%). IPR-EA exhibited highest edema inhibition in models of carrageenan-induced paw edema (79.11 +/- 5.47%) and croton oil-induced ear and anal edema (72.01 +/- 7.80% and 70.80 +/- 4.94%, respectively). Significant inhibition of CFA-induced arthritic edema and arthritic score were observed by IPR-EA as compared to ibuprofen. Suppression of pro-inflammatory cytokines (IL 1beta, IL-6) and NO levels was shown by IPR-EA and IPT-EA, respectively. CONCLUSION: These results depict that richness of polyphenols and phytoconstituents in I. batatas ameliorates oxidative stress and inflammation of acute and chronic nature. Dose dependent antioxidant potential and inhibition of inflammatory edema, pro-inflammatory cytokines and hematological, biochemical and histological changes prove I. batatas therapeutic potential as an antiinflammatory and antiarthritic agent. PMID- 30005652 TI - Effective antioxidant, antimicrobial and anticancer activities of essential oils of horticultural aromatic crops in northern Egypt. AB - BACKGROUND: Identifying ornamental plants as new natural antioxidant and antimicrobial sources is always of great importance for the ornamental and horticultural industries. METHODS: The antimicrobial activities of leaves and fruits peel essential oils of twelve ornamental and horticultural crops were determined by screening against wide spectrum of fungi and bacteria, and their respective in vitro antioxidant capacity was evaluated. Furthermore, the anticancer activities against several cancer cells, and one normal human cell line (HEK-293) were examined. RESULTS: Origanum vulgare L. essential oil showed the best antioxidant, antibacterial and anticancer activities compared to screened crops by means of the DPPH and linoleic acid assays for antioxidants, MIC and MBC values for antibacterial activities and IC50 for antiproliferative activities. Such important activities in O. vulgare was attributed to high pulegone ratio (77.45%) as revealed by the GC/MS assay. Rosmarinus officinallis L. essential oil showed the highest antifungal activities by means of lowest MIC and MFC values which might be attributed to 1, 8-cineole (19.60%), camphor (17.01%) and alpha-pinene (15.12%). CONCLUSION: We suggest that oxygenated monoterpenes (i.e. linalool, terpinen-4-ol and pulegone) and monoterpene hydrocarbons play an important role in the essential oil antioxidant, antibacterial, antifungal and anticancer activities of diverse Egyptian ornamental and horticultural crops. Some species showed bioactivities similar to standards compounds and might be suitable for pharmaceutical and food industries. PMID- 30005654 TI - Effect, process, and economic evaluation of a combined resistance exercise and diet intervention (ProMuscle in Practice) for community-dwelling older adults: design and methods of a randomised controlled trial. AB - BACKGROUND: Exercise and nutrition are important for older adults to maintain or to regain their muscle mass, function, strength, and ultimately quality of life. The effectiveness of combined resistance exercise and diet interventions is commonly evaluated in controlled clinical studies, but evidence from real-life settings is lacking. This article describes the effectiveness, process, and economic evaluation design of a combined nutrition and exercise intervention for community-dwelling older adults in a Dutch real-life setting. METHODS: The ProMuscle in Practice study is a randomised controlled multicentre intervention study, conducted in five municipalities in the Netherlands. Two hundred community dwelling older adults (>=65 years) who are frail or pre-frail based on Fried frailty criteria or who experience strength loss are randomised over an intervention and control group by municipality. In the first 12-week intensive support intervention, participants in the intervention group perform resistance exercise training guided by a physiotherapist twice a week and increase protein intake by consuming protein-rich products under the supervision of a dietitian. Afterwards, they continue with a 12-week moderate support intervention. The control group receives only regular care during the two 12-week periods. Effect outcomes are measured at all locations at baseline, 12 weeks, 24 weeks, 36 weeks and only at three locations at 52 weeks. The primary outcome is physical functioning (Short Physical Performance Battery). Secondary outcomes include leg muscle strength, lean body mass, activities of daily living, social participation, food intake, and quality of life. Qualitative and quantitative implementation process data are collected during the intervention. Healthcare use and intervention costs are registered for the economic evaluation. DISCUSSION: Evaluating the effects, implementation, and costs of this combined intervention provides valuable insight into the feasibility of this intervention for community dwelling older adults and into the intervention's ability to improve or to maintain physical functioning and quality of life. TRIAL REGISTRATION: Netherlands Trial Register ( NTR6038 ) since 30 August 2016. PMID- 30005653 TI - Epidemiology and ecology of West Nile virus in sub-Saharan Africa. AB - West Nile virus (WNV) is the aetiological agent of the mosquito-borne zoonotic disease West Nile fever. The virus, first isolated in Uganda in 1937, evolved into two distinct lineages in sub-Saharan Africa (SSA) that subsequently spread to most continents where the virus has evolved further as evident through phylogenetic analysis of extant genomes. Numerous published reports from the past 70 years from countries in SSA indicate that the virus is endemic across the region. However, due in part to the limited availability of diagnostic methods across large areas of the continent, the human burden of WNV is poorly understood. So too are the drivers for translocation of the virus from countries south of the Sahara Desert to North Africa and Europe. Migratory birds are implicated in this translocation although the transient viraemia, measured in days, and the time taken to migrate, measured in weeks, suggest a more complex mechanism is in play. This review considers the evidence for the presence of WNV across SSA and the role of migratory birds in the emergence of the virus in other continents. PMID- 30005656 TI - Tau GSTs involved in regulation of leaf abscission by comparison the gene profiling of MeGSTs in various abscission-promoting treatments in cassava abscission zones. AB - BACKGROUND: Glutathione S-transferases (GSTs) have been reported to regulate the plant tolerance to environmental stresses. Many plant GSTs exhibited the roles on promoting tolerance to drought stress, oxidative stress and plant hormones. The biological function of GSTs has been well characterized in Arabidopsis thaliana in response to exogenous environmental stresses. However, their regulation function under exogenous environmental stresses regulating leaf abscission in cassava (Manihot esculenta Crantz) remained unknown. RESULTS: Here, 83 GSTs were identified from tropical plant cassava. The amino acid motifs and phylogenetic analyses indicated that MeGSTs were divided into 9 classes. The global expression analyses were carried out to analyze the gene expression patterns of MeGST in cassava abscission zones by comparing the MeGST genes expression patterns in both ethylene and drought induced cassava leaf abscission. Totally, 34 GSTs were detected to express in both ethylene and drought induced leaf abscission in cassava abscission zones. Comparison of GST expression profiling between ethylene and drought induced leaf abscission suggested that Tau GST genes showed with the similar expression in both treatments induced leaf abscission in cassava abscission zone. GO annotation indicated that all 17 Tau GST genes participated in the pathway of toxin catabolism (GO: 0009407). The expression levels of 17 Tau MeGST genes were analyzed in two cassava cultivars, 'SC124' and 'Arg7', the two cultivars exhibit different levels of leaf abscission when suffered from the same environmental stress. Higher expression levels of Tau MeGSTs were detected in the precocious abscission Arg7 cultivar, while lower expression levels in delayed abscission SC124 cultivar. All the results indicated that Tau MeGSTs have the function in regulation the cassava leaf abscission under environmental stresses. CONCLUSION: Analysis of the expression patterns of GSTs in various abscission promoting treatments in cassava abscission zones helps us to understand the possible roles of GSTs in cassava leaf abscission. PMID- 30005655 TI - The prevention of 2,4-dinitrochlorobenzene-induced inflammation in atopic dermatitis-like skin lesions in BALB/c mice by Jawoongo. AB - BACKGROUND: Jawoongo is an herbal mixture used in traditional medicine to treat skin diseases. This study aimed to investigate whether Jawoongo ameliorates Atopic dermatitis (AD)-like pathology in mice and to understand its underlying cellular mechanisms. METHODS: AD was induced by 2, 4-Dinitrocholrlbenzene (DNCB) in BALB/c mice. Treatment with Jawoongo was assessed to study the effect of Jawoongo on AD in mice. Histological Analysis, blood analysis, RT-PCR, western blot analysis, ELISA assay and cell viability assay were performed to verify the inhibitory effect of Jawoongo on AD in mice. RESULTS: We found that application of Jawoongo in an ointment form on AD-like skin lesions on DNCB-exposed BALB/c mice reduced skin thickness and ameliorated skin infiltration with inflammatory cells, mast cells and CD4+ cells. The ointment also reduced the mRNA levels of IL 2, IL-4, IL-13 and TNF-alpha in the sensitized skin. Leukocyte counts and the levels of IgE, IL-6, IL-10 and IL-12 were decreased in the blood of the DNCB treated mice. Furthermore, studies on cultured cells demonstrated that Jawoongo exhibits anti-inflammatory activities, including the suppression of proinflammatory cytokine expression, nitric oxide (NO) production, and inflammation-associated molecule levels in numerous types of agonist-stimulated innate immune cell, including human mast cells (HMC-1), murine macrophage RAW264.7 cells, and splenocytes isolated from mice. CONCLUSION: These findings indicate that Jawoongo alleviates DNCB-induced AD-like symptoms via the modulation of several inflammatory responses, indicating that Jawoongo might be a useful drug for the treatment of AD. PMID- 30005657 TI - A qualitative study of health care professionals' views and experiences of paediatric advance care planning. AB - BACKGROUND: Good end-of-life care planning is vital to ensure optimal care is provided for patients and their families. Two key factors are open and honest advance care planning conversations between the patient (where possible), family, and health care professionals, focusing on exploring what their future wishes are; and the development of an advance care plan document. However, in paediatric and neonatal settings, there has been little research to demonstrate how advance care planning conversations take place. This study explored health care professionals' views and experiences of paediatric advance care planning in hospitals, community settings and hospices. METHODS: A qualitative methodology was employed using purposive sampling of health care professionals involved in the end-of-life care for children aged 0-18 years known to the hospital palliative care team, and had died at least three months before, but less than 18 months prior to the study. Ethics committee approval was obtained for the study. Located in the North of England, the study involved three hospitals, a children's hospice, and community services. Data were collected using semi-structured, digitally recorded, telephone interviews. All interviews were transcribed verbatim and subjected to thematic analysis. RESULTS: Twenty-one health care professionals participated, including generalist paediatric staff as well as specialist palliative care staff. Two themes were generated from the study: The timing of planning conversations, including waiting for the relationship with the family to form; the introduction of parallel planning; avoiding a crisis situation. Secondly, supporting effective conversations around advance care planning, including where to have the conversation; introducing the conversation; and how to approach the topic encompassing the value of advance care planning and documentation for families. CONCLUSION: The timing of when to start the advance care planning conversations remains an issue for health care professionals. The value of doing it in stages and considering the environment where the conversations are held was noted. Timely planning was seen as vital to avoid difficult conversations at a crisis point and for co-ordination of care. Good advance care planning is to provide the best person-centred care for the child and experience for the family. PMID- 30005659 TI - Learning from OCTET - exploring the acceptability of clinical trials management methods. AB - BACKGROUND: Conducting research can be time consuming, difficult and challenging. Guidance and pragmatic advice focussing on randomised controlled trial conduct are available but do not necessarily constitute comprehensive guidance. A successful trial is one that recruits to time and target and collects high quality data within the originally agreed budget. Standardised trial management tools have outlined key project management elements for a successful trial as a method of ensuring good practice in research trials: initiation, planning, execution, monitoring and closure. Lessons are also frequently learnt during the development and conduct of trials but rarely shared for the benefit of others. For the wider research team, the key focus will always be on the execution and delivery of a study. The aim of this study was to evaluate the acceptability of clinical trials management methods, focussing on study execution and monitoring, as implemented in the National Institute for Health Research Health Technology Assessment Programme-funded Obsessive Compulsive Treatment Efficacy Trial (OCTET). METHODS: Workshops, questionnaires and semi-structured interviews were used to explore acceptability of trial management methods with members of the OCTET Trial research team. Nine members participated in the focus group, 10 completed a questionnaire and 20 were interviewed as part of qualitative work for the main OCTET study. Data was collected and analysed using thematic analysis. RESULTS: Six key themes were identified: support; communication; processes; resources; training and ethos. Clear and open communication, enthusiasm and accessibility of the trial managers and chief investigator were consistently noted as an important facet of the successful running of the trial. Clear resources and training materials were also found to be crucial in helping staff to work within the trial setting. Constructive suggestions were also made for improvement of these resources; for example, including both checklists and flowcharts within trial processes. CONCLUSION: Organisation, openness and positivity are crucial for executing a trial successfully, whilst clear and focussed processes and resources are essential in monitoring and controlling the trial progress. Although derived from a single study, these findings are likely to be applicable to the successful conduct of all trials. Trial managers should consider developing these elements when setting up a study. TRIAL REGISTRATION: Clinical Trial Registry, ID: ISRCTN73535163 . Registered prospectively on 5 April 2011. PMID- 30005658 TI - Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease. AB - BACKGROUND: Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. METHODS: This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ). RESULTS: In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF 36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [rho = (- 0.54)-(- 0.32)] and the physical component summary (PCS) score (rho = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, rho = 0.34-0.58; PCS score, rho = - 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [rho = (- 0.29)-(- 0.55)] and the PCS score (rho = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. CONCLUSIONS: Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis. PMID- 30005660 TI - Mission of Mercy emergency dental clinics: an opportunity to promote general and oral health. AB - BACKGROUND: Mission of Mercy (MOM) emergency dental clinics are a resource for populations lacking access to dental care. We designed a MOM event incorporating health equity components with established community partners who shared a common vision of addressing the oral health, physical health, and social service needs of Maryland and Washington, DC area residents. Although studies have explored associations between oral and chronic health conditions, few studies to our knowledge have examined the relationship between these conditions and receipt of dental services. Therefore, this study explored these associations and the opportunity for better care coordination. METHODS: Oral health data from the 2014 Mid-Maryland Mission of Mercy and Health Equity Festival event was analyzed. A descriptive analysis assessed frequencies and percentages of participant sociodemographics characteristics, oral health and chronic disease risk(s), and dental services delivered. Chi-square tests and multivariate logistic regression were conducted to determine the associations between 1) oral health and chronic disease risk(s) and dental services; and 2) oral health and chronic disease risk(s) and participant characteristics. RESULTS: Approximately 66.2% (n = 666) of the 1007 participants had one or more chronic conditions and/or risk factors (diabetes, high blood pressure, and tobacco use). These individuals had a significantly higher likelihood of receiving an oral surgery procedure (specifically, tooth extraction) (only one condition/risk: OR = 2.40, 95%, CI = 1.48-3.90, p < .001; two conditions/risks: OR = 3.12, 95% CI = 1.78-5.46, p < .001). CONCLUSION: The 2014 Mid-Maryland Mission of Mercy emergency dental clinic attracted people with risk factors for oral and chronic diseases. Those with one or more risk factors were more likely to receive oral surgery (specifically, tooth extraction). These findings strongly suggest that organizers of MOM emergency dental clinics include wrap-around primary care, health promotion and disease prevention services along with provision of dental services. While such events will not solve the general and oral health challenges of participants, we believe they provide an opportunity to provide basic preventive services. These findings also present an opportunity to inform planning for future MOMs and emphasize the importance of using these public health events to create linkages with other services to support follow-up and care coordination. PMID- 30005661 TI - Construction of a trifunctional cellulase and expression in Saccharomyces cerevisiae using a fusion protein. AB - BACKGROUND: Cellulose is the most important component of lignocellulose, and its degradation requires three different types of enzymes to act synergistically. There have been reports of single gene duality, but no gene has been described to have more than two functions. Cloning and expression of fusion cellulases containing more than two kinds of catalytic domains has not been reported thus far. RESULTS: We synthesized three different cellulase genes and linked the three catalytic domains with a (G4S)3 flexible linker. The trifunctional cellulase gene (BCE) containing three types of cellulase functions was constructed and expressed in S. cerevisiae successfully. The beta-glucosidase, the exoglucanase and the endoglucanase activity of the trifunctional cellulase BCE reached 16.80 IU/mg, 2.26 IU/mg and 20.67 IU/mg, which was 46.27, 6.73 and 46.20% higher than the activities of the beta-glucosidase BG, the endoglucanase CBH and the endoglucanase EG. The filter paper enzyme activity of BCE was higher than those of BG, CBH and EG, reached 2.04 IU/mg. CONCLUSIONS: The trifunctional cellulase BCE was designed based on beta-glucosidase BG, endoglucanase EG and exoglucanase CBH, and it possessed beta-glucosidase activity, endoglucanase activity and exoglucanase activity simultaneously. The BCE has better filter paper activity, it means the potential practical application. PMID- 30005662 TI - The development of a training course for clubfoot treatment in Africa: learning points for course development. AB - BACKGROUND: Clubfoot is a common congenital musculoskeletal disorder that causes mobility impairment. There is a lack of trained mid-level personnel to provide clubfoot treatment in Africa and there is no standard training course. This prospective study describes the collaborative and participatory approach to the development of a training course for the treatment of clubfoot in children in resource constrained settings. METHODS: We used a systems approach to evaluate the development of the training course. Inputs: The research strategy included a review of context and available training materials, and the collection of data on current training practices. Semi-structured interviews were conducted with seven expert clubfoot trainers. A survey of 32 international and regional trainers was undertaken to inform practical issues. The data were used to develop a framework for training with advice from two technical groups, consisting of regional and international stakeholders and experts. PROCESS: A consensus approach was undertaken during workshops, meetings and the sharing of documents. The design process for the training materials took twenty-four months and was iterative. The training materials were piloted nine times between September 2015 and February 2017. Processes and materials were reviewed and adapted according to feedback after each pilot. RESULTS: Fifty-one regional trainers from Africa (18 countries), 21 international experts (11 countries), 113 local providers of clubfoot treatment (Ethiopia, Rwanda and Kenya) and local organising teams were involved in developing the curriculum and pilot testing. The diversity of the two technical advisory groups allowed a wide range of contributions to the collaboration. Output: The resulting curriculum and content comprised a two day basic training and a two day advanced course. The basic course utilised adult learning techniques for training novice providers in the treatment of idiopathic clubfoot in children under two years old. The advanced course builds on these principles. CONCLUSION: Formative research that included mixed methods (both qualitative and quantitative) was important in the development of an appropriate training course. The process documentation from this study provides useful information to assist planning of medical training programmes and may serve as a model for the development of other courses. PMID- 30005663 TI - Effectiveness of an "Exclusive Intervention Strategy" to increase medical male circumcision uptake among men aged 25-49 years in South Africa. AB - BACKGROUND: South Africa introduced medical male circumcision (MMC) to reduce HIV incidence. Mathematical modeling suggested that targeting MMC services to men aged 20-34 years could provide the most immediate impact on HIV incidence. However the majority of MMCs performed have been among males aged <=25 years. We evaluated an intervention package to increase MMC uptake among men aged 25-49 years. METHODS: We conducted a pre-post study to compare the proportion of men (aged 25-49 years) presenting for MMC during the formative (Phase 1) and intervention (Phase 2) phases in Ekurhuleni, Johannesburg, South Africa. The intervention included infrastructure changes that separated adults from adolescents at the MMC site, an exclusive men's health club, adult-specific demand generation materials, and discussions with community members. RESULTS: Overall 2817 enrolled in the study with 1601 from Phase 1 and 1216 in Phase 2. A higher proportion of participants aged 25-49 years accessed MMC in Phase 2 compared to Phase 1 (59.4% vs. 54.9%; Prevalence Ratio = 1.08; 95% Confidence Interval: 1.01-1.15; p = 0.019). Participants with multiple partners in the past 12 months in Phase 2 were more likely to access MMC services compared to participants in Phase 1 (unadjusted Odds Ratio, 1.37; 95% CI:1.17-1.61; p < 0.001). After adjusting for age, multiple partners remained a risk factor in Phase 2 (adjusted OR, 1.39; 95% CI: 1.18-1.63; p < 0.001). CONCLUSIONS: The "Exclusive Intervention Strategy" was associated with a slight increase in the proportion of participants aged 25-49 years accessing MMC services, and an increase in those with HIV risk behaviors, during the intervention phase. These findings may provide important insights to overcoming barriers for accessing MMC services among men aged 25-49 years. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov , number NCT02352961 . PMID- 30005664 TI - pXST, a novel vector for TA cloning and blunt-end cloning. AB - BACKGROUND: With the rapid development of sequencing technologies, increasing amount of genomic information has been accumulated. To clone genes for further functional studies in large scale, a cheap, fast and efficient cloning vector is desired. RESULTS: A bifunctional vector pXST has been constructed. The pXST vector harbors a XcmI-ccdB-XcmI cassette and restriction site SmaI. Digestion the vector with XcmI generates a single thymidine (T) overhang at 3' end which facilitates TA cloning, and SmaI gives blunt end that enables the blunt-end ligation. Multiple products with various sizes were amplified from cassava genome by PCR and each PCR fragment was separately cloned into a pXST using TA cloning and blunt-end ligation methods. In general, the TA cloning gave higher transformation efficiency than blunt-end ligation for inserts with all different sizes, and the transformation efficiency significantly decreased with increasing size of inserts. The highest transformation efficiency (8.6 * 106 transformants/MUg) was achieved when cloning 517 bp DNA fragment using TA cloning. No significant difference observed in the positive cloning efficiency between two ligation methods and the positive cloning efficiency could reach as high as 100% especially for small inserts (e.g. 517 and 957 base pairs). CONCLUSIONS: We describe a simple and general method to construct a novel pXST vector. We confirm the feasibility of using pXST vector to clone PCR products amplified from cassava genome with both TA cloning and blunt-end ligation methods. The pXST plasmid has several advantages over many currently available vectors in that (1) it possesses XcmI-ccdB-XcmI cassette and restriction site SmaI, enabling both TA cloning and blunt-end ligation. (2) it allows direct selection of positive recombinant plasmids in Escherichia coli through disruption of the ccdB gene. (3) it improves positive cloning efficiency by introducing the ccdB gene, reducing the possibility of self-ligation from insufficient digested plasmids. (4) it could be used by high performance and cost-effective cloning methods. Therefore, this dual function vector would offer flexible alternatives for gene cloning experiments to researchers. PMID- 30005665 TI - Decomposition of gendered income-related inequalities in multiple biological cardiovascular risk factors in a middle-aged population. AB - BACKGROUND: Socioeconomic inequalities in cardiovascular disease seem to widen or endure in Sweden. However, research on inequalities in antecedent cardiovascular risk factors (CVRFs), and particularly what underpins them, is scarce. The present study aimed 1) to estimate income-related inequalities in eight biological cardiovascular risk factors in Swedish middle-aged women and men; and 2) to examine the contribution of demographic, socioeconomic, behavioural and psychosocial determinants to the observed inequalities. METHODS: Participants (N = 12,481) comprised all 40- and 50-years old women and men who participated in the regional Vasterbotten Intervention Programme in Northern Sweden during 2008, 2009 and 2010. All participants completed a questionnaire on behavioural and psychosocial conditions, and underwent measurements with respect to eight CVRFs (body mass index; waist circumference; total cholesterol; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; triglycerides; systolic/diastolic blood pressure; glucose tolerance). Data on cardiovascular risk, psychosocial and health behaviours were linked to national register data on income and other socioeconomic and demographic factors. To estimate income inequalities in each CVRF concentration indexes were calculated, and to examine the contribution of the underlying determinants to the observed inequalities a Wagstaff-type decomposition analysis was performed separately for women and men. RESULTS: Health inequalities ranged from small to substantial with generally greater magnitude in women. The highest inequalities among women were seen in BMI, triglycerides and HDL-cholesterol (Concentration index = - 0.1850; - 0.1683 and - 0.1479 respectively). Among men the largest inequalities were seen in glucose regulation, BMI and abdominal obesity (Concentration index = - 0.1661; - 0.1259 and - 0.1172). The main explanatory factors were, for both women and men socioeconomic conditions (contributions ranging from 54.8 to 76.7% in women and 34.0-72.6% in men) and health behaviours (contributions ranging from 6.9 to 20.5% in women and 9.2 to 26.9% in men). However, the patterns of specific dominant explanatory factors differed between CVRFs and genders. CONCLUSION: Taken together, the results suggest that the magnitude of income-related inequalities in CVRFs and their determinants differ importantly between the risk factors and genders, a variation that should be taken into consideration in population interventions aiming to prevent inequalities in manifest cardiovascular disease. PMID- 30005667 TI - The outcomes of Perthes' disease of the hip: a study protocol for the development of a core outcome set. AB - BACKGROUND: Perthes' disease is an idiopathic osteonecrosis of a developmental hip that is most frequent in Northern Europe. Currently, the absence of a common set of standardised outcomes makes comparisons between studies of different interventions challenging. This study aims to summarise the outcomes used in clinical research of interventions for Perthes' disease and define a set of core outcomes (COS) to ensure that the variables of primary importance are measured and reported in future research studies investigating Perthes' disease. METHODS: A systematic review of the current literature will be used to identify a list of outcomes reported in previous studies. Additional important outcomes will be sought by interviewing a group of children with Perthes' disease, adults who were treated with the disease in infancy and parents of children with the disease. This list will then be evaluated by experts in Perthes' disease using a Delphi survey divided into two rounds to ascertain the importance of each outcome. The final outcomes list obtained from the Delphi survey will be then discussed during a consensus meeting of representative key stakeholders in order to define the COS to be reported in future clinical trials related to Perthes' disease. DISCUSSION: The absence of high-quality research and clear guidelines concerning the management of Perthes' disease is, at least in part, due to the difficulties in the comparing the results from previous studies. The development of a COS seeks to standardise outcomes collected in future research studies to enable comparisons between studies to be made and to facilitate meta-analyses of results. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials Initiative (COMET), 1003 . Registered on 20 July 2017. Prospero International Prospective Register of Systematic Reviews, CRD 42017069742 . Registered on 10 July 2017. PMID- 30005666 TI - Comparison of immunological characteristics between paired mismatch repair proficient and -deficient colorectal cancer patients. AB - BACKGROUND: Currently, mismatch repair-deficient (dMMR) status is a promising candidate for targeted immune checkpoint inhibition therapy in colorectal cancer (CRC) patients, however, the potential immunological mechanism has not yet been well clarified and some other predictors need to be excavated as well. METHODS: We collected 330 CRC patients by the match of mismatch repair-proficient (167) and dMMR (163), explored the relationship between MMR status and some important immune molecules including MHC class I, CD3, CD4, CD8, CD56, programmed death-1 and programmed death ligand-1, and investigated the risk factors for dMMR status as well as low MHC class I expression. The Pearson Chi square test was used for analyzing the associations between clinicopathological and immune characteristics and MMR status, and two categories logistic regression model was used for univariate and multivariate analysis to predict the odds ratio of risk factors for dMMR status and low MHC class I expression. RESULTS: Multivariate logistic regression analysis showed that low MHC class I and CD4 expression and high CD8 expression were significant risk factors for dMMR status [odds ratio (OR) = 24.66, 2.94 and 2.97, respectively; all p < 0.05] and dMMR status was the only risk factor for low MHC class I expression (OR = 15.34; p < 0.001). CONCLUSIONS: High CD8 and low MHC class I expression suggests the contradiction and complexity of immune microenvironment in dMMR CRC patients. Some other immunocytes such as CD56+ cells might also participate in the process of immune checkpoint inhibition, whereas needs further investigations. PMID- 30005668 TI - Binding mechanism of anti-cancer chemotherapeutic drug mitoxantrone to DNA characterized by magnetic tweezers. AB - BACKGROUND: Chemotherapeutic agents (anti-cancer drugs) are small cytostatic or cytotoxic molecules that often bind to double-stranded DNA (dsDNA) resulting in modifications of their structural and nanomechanical properties and thus interfering with the cell proliferation process. METHODS: We investigated the anthraquinone compound mitoxantrone that is used for treating certain cancer types like leukemia and lymphoma with magnetic tweezers as a single molecule nanosensor. In order to study the association of mitoxantrone with dsDNA, we conducted force-extension and mechanical overwinding experiments with a sensitivity of 10-14 N. RESULTS: Using this method, we were able to estimate an equilibrium constant of association Ka ~ 1 * 105 M-1 as well as a binding site size of n ~ 2.5 base pairs for mitoxantrone. An unwinding angle of mitoxantrone intercalation of theta ~ 16 degrees was determined. CONCLUSION: Moreover, we observed a complex concentration-dependent bimodal binding behavior, where mitoxantrone associates to dsDNA as an intercalator and groove binder simultaneously at low concentrations and as a mere intercalator at high concentrations. PMID- 30005669 TI - Liprin-alpha1 modulates cancer cell signaling by transmembrane protein CD82 in adhesive membrane domains linked to cytoskeleton. AB - BACKGROUND: PPFIA1 is located at the 11q13 region commonly amplified in cancer. The protein liprin-alpha1 encoded by PPF1A1 contributes to the adhesive and invasive structures of cytoskeletal elements and is located at the invadosomes in cancer cells. However, the precise mechanism of liprin-alpha1 function in cancer progression has remained elusive. METHODS: Invasion regulating activity of liprin alpha1 was examined by analyzing the functions of squamous cell carcinoma of head and neck (HNSCC) cell lines in three-dimensional collagen I after RNAi mediated gene knockdown. Transcriptome profiling and Gene Set Enrichment Analysis from HNSCC and breast cancer cells were used to identify expression changes relevant to specific cellular localizations, biological processes and signaling pathways after PPFIA1 knockdown. The significance of the results was assessed by relevant statistical methods (Wald and Benjamini-Hochberg). Localization of proteins associated to liprin-alpha1 was studied by immunofluorescence in 2D and 3D conditions. The association of PPFIA1 amplification to HNSCC patient survival was explored using The Cancer Genome Atlas data. RESULTS: In this study, we show that liprin-alpha1 regulates biological processes related to membrane microdomains in breast carcinoma, as well as protein trafficking, cell-cell and cell-substrate contacts in HNSCC cell lines cultured in three-dimensional matrix. Importantly, we show that in all these cancer cells liprin-alpha1 knockdown leads to the upregulation of transmembrane protein CD82, which is a suppressor of metastasis in several solid tumors. CONCLUSIONS: Our results provide novel information regarding the function of liprin-alpha1 in biological processes essential in cancer progression. The results reveal liprin-alpha1 as a novel regulator of CD82, linking liprin-alpha1 to the cancer cell invasion and metastasis pathways. PMID- 30005670 TI - Orthokeratinized odontogenic cysts: a Spanish tertiary care centre study based on HPV DNA detection. AB - BACKGROUND: The role of human papillomavirus (HPV) in orthokeratinized odontogenic cysts (OOCs) has rarely been studied. The objective is to describe the clinicopathological findings in a series of OOCs from a Spanish population that were investigated in relation to the possible presence of HPV. METHODS: A clinicopathological retrospective analysis followed by a molecular analysis of 28 high- and low-risk HPV genotypes was performed in OOC samples of patients seen during the last 15-years in a Spanish tertiary care center. RESULTS: Of 115 odontogenic cysts with keratinization, 16 cases of OOCs were confirmed and evaluated. OOCs occurred predominantly in the mandible of males (mean age 36.06 +/- 13.16 years). Swelling of the jaw followed by pain were the most common clinical symptoms, and 56.5% of the OOC cases were associated with an unerupted tooth. After a mean post-cystectomy follow-up of 3.8 years, only one recurrent case was observed, resulting in a verrucous cystic lesion that was considered premalignant after immunohistological examination. DNA extraction was successful from 14 of the 16 OOC cases. None of the primary OCCs or the single recurrent OOC were positive for HPV in the molecular analysis. CONCLUSIONS: OOCs show a very limited potential for recurrence. Our results suggest that neither high- or low risk HPV subtypes are likely to play a role in the etiology or neoplastic transformation of OOC, at least in the Spanish population. PMID- 30005672 TI - Body -to-head transplant; a "caputal" crime? Examining the corpus of ethical and legal issues. AB - Neurosurgeon Sergio Canavero proposed the HEAVEN procedure - i.e. head anastomosis venture - several years ago, and has recently received approval from the relevant regulatory bodies to perform this body-head transplant (BHT) in China. The BHT procedure involves attaching the donor body (D) to the head of the recipient (R), and discarding the body of R and head of D. Canavero's proposed procedure will be incredibly difficult from a medical standpoint. Aside from medical doubt, the BHT has been met with great resistance from many, if not most bio- and neuroethicists.Given both the known challenges and unknown outcomes of HEAVEN, several important neuroethical and legal questions have emerged should Canavero be successful, including: (1) What are the implications for transplantology in the U.S., inclusive of issues of expense, distributive justice, organizational procedures, and the cost(s) of novel insight(s)? (2) How do bioethical and neuroethical principles, and legal regulations of human subject research apply? (3) What are the legal consequences for Canavero (or any other surgeon) performing a BHT? (4) What are the tentative implications for the metaphysical and legal identity of R should they survive post-BHT? These questions are analyzed, issues are identified, and several solutions are proposed in an attempt to re-configure HEAVEN into a safe, clinically effective, and thus (more) realistically viable procedure.Notably, the permissibility of conducting the BHT in China fosters additional, important questions, focal to (1) whether Western ethics and professional norms be used to guide the BHT - or any neuroscientific research and its use - in non-Western countries, such as China; (2) if the models of responsible conduct of research are identical, similar, or applicable to the intent and conduct of research in China; and (3) what economic and political implications (for China and other countries) are fostered if/when such avant garde techniques are successful.These questions are discussed as a further impetus to develop a globally applicable neuroethical framework that would enable both local articulation and cosmopolitan inquiry and oversight of those methods and approaches deemed problematic, if and when rendered in more international settings. PMID- 30005671 TI - Repeated vital sign measurements in the emergency department predict patient deterioration within 72 hours: a prospective observational study. AB - BACKGROUND: More than one in five patients presenting to the emergency department (ED) with (suspected) infection or sepsis deteriorate within 72 h from admission. Surprisingly little is known about vital signs in relation to deterioration, especially in the ED. The aim of our study was to determine whether repeated vital sign measurements in the ED can differentiate between patients who will deteriorate within 72 h and patients who will not deteriorate. METHODS: We performed a prospective observational study in patients presenting with (suspected) infection or sepsis to the ED of our tertiary care teaching hospital. Vital signs (heart rate, mean arterial pressure (MAP), respiratory rate and body temperature) were measured in 30-min intervals during the first 3 h in the ED. Primary outcome was patient deterioration within 72 h from admission, defined as the development of acute kidney injury, liver failure, respiratory failure, intensive care unit admission or in-hospital mortality. We performed a logistic regression analysis using a base model including age, gender and comorbidities. Thereafter, we performed separate logistic regression analyses for each vital sign using the value at admission, the change over time and its variability. For each analysis, the odds ratios (OR) and area under the receiver operator curve (AUC) were calculated. RESULTS: In total 106 (29.5%) of the 359 patients deteriorated within 72 h from admission. Within this timeframe, 18.3% of the patients with infection and 32.9% of the patients with sepsis at ED presentation deteriorated. Associated with deterioration were: age (OR: 1.02), history of diabetes (OR: 1.90), heart rate (OR: 1.01), MAP (OR: 0.96) and respiratory rate (OR: 1.05) at admission, changes over time of MAP (OR: 1.04) and respiratory rate (OR: 1.44) as well as the variability of the MAP (OR: 1.06). Repeated measurements of heart rate and body temperature were not associated with deterioration. CONCLUSIONS: Repeated vital sign measurements in the ED are better at identifying patients at risk for deterioration within 72 h from admission than single vital sign measurements at ED admission. PMID- 30005673 TI - Multimodal treatment of pediatric patients with Askin's tumors: our experience. AB - BACKGROUND: We report our experience and outcomes about the management of Askin's tumors [AT], which are rare primitive neuroectodermal tumors (PNETs) that develop within the soft tissue of the thoracopulmonary region, typically in children and adolescents. METHODS: We retrospectively analyzed the charts of 9 patients affected by AT (aged 6-15 years), treated at the Paediatric Oncology Unit of Gemelli University Hospital in Rome between January 2001 and December 2016. RESULTS: All nine patients underwent to biopsy followed by neoadjuvant chemotherapy. At the end of the neoadjuvant chemotherapy, they underwent to surgical removal of the residual tumor. Five patients with positive tumor margins and/or necrosis< 90% received local radiotherapy. Two patients with metastasis received an intensified treatment, with the addition of high dose adjuvant chemotherapy followed by peripheral blood stem cells rescue. No statistically significant correlation was found between outcome and gender; the presence of any metastasis and the radiotherapy. The overall survival was 65.14 months (95% confidence interval [95%CI], 45.81-84.48), and the 5 years survival was 60%, at a median follow-up of 53.1 months. CONCLUSION: Our study confirms that a multimodal treatment with surgery, chemotherapy, and radiotherapy may increase the survival in AT pediatric patients. PMID- 30005674 TI - Emotional processes and stress in children affected by hereditary angioedema with C1-inhibitor deficiency: a multicenter, prospective study. AB - BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent edema of unpredictable frequency and severity. Stress, anxiety, and low mood are among the triggering factors most frequently reported. Impaired regulation and processing of emotions, also known as alexithymia, may influence outcomes. The aim of this study was to confirm the presence of alexithymia and stress in children with C1-INH-HAE, to determine whether they are also present in children affected by other chronic diseases, and to investigate their relationship with C1-INH-HAE severity. Data from children with C1-INH-HAE (n = 28) from four reference centers in Italy were compared with data from children with type 1 diabetes (T1D; n = 23) and rheumatoid arthritis (RA; n = 25). Alexithymia was assessed using the Alexithymia Questionnaire for Children scale; perceived stress was assessed using the Coddington Life Event Scale for Children (CLES-C). RESULTS: Mean age (standard deviation [SD]) in the C1-INH-HAE, T1D, and RA groups was 11.8 (3.3), 11.7 (2.9), and 11.1 (2.6) years, respectively. Mean C1-INH-HAE severity score was 5.9 (2.1), indicating moderate disease. Alexithymia scores were similar among disease groups and suggestive of difficulties in identifying and describing emotions; CLES-C scores tended to be worse in C1-INH-HAE children. C1-INH-HAE severity was found to correlate significantly and positively with alexithymia (p = 0.046), but not with perceived stress. Alexithymia correlated positively with perceived stress. CONCLUSIONS: Alexithymia is common in children with chronic diseases. In C1-INH-HAE, it may result in increased perceived stress and act as a trigger of edema attacks. Comprehensive management of C1-INH-HAE children should consider psychological factors. PMID- 30005675 TI - Health-related quality of life and burden of illness in adults with newly diagnosed attention-deficit/hyperactivity disorder in Sweden. AB - BACKGROUND: This observational, cross-sectional, retrospective chart review aimed to identify factors determining health-related quality of life (HRQoL) in adults with newly diagnosed attention-deficit/hyperactivity disorder (ADHD) in Sweden. METHODS: Adult participants with a new clinical diagnosis of ADHD were enrolled from two specialist outpatient clinics in Stockholm, Sweden, from 2013 to 2015. Data extracted from patient records included demographics, clinical characteristics and comorbid psychiatric diagnoses identified using the Mini International Neuropsychiatric Interview (MINI). Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale - Self-reported (MADRS-S). The self-rated five-dimension EuroQol questionnaire (EQ-5D) was used to measure HRQoL. Predictors of EQ-5D index score were identified using multivariate linear regression adjusting for age, sex, education level, and main income source. RESULTS: The mean age of the 189 enrolled patients was 35.2 years (standard deviation [SD], 12.3), and 107 (57%) were female. Psychiatric comorbidities were present in 92 patients (49%), with anxiety and depression being the most common diagnoses. The mean EQ-5D index score was 0.63 (SD, 0.28). Low EQ-5D index scores were significantly associated with high MADRS-S scores, multiple comorbid psychiatric disorders, low educational achievement, female sex, and not having a main income derived from employment or self-employment. CONCLUSIONS: These findings suggest that adults with newly diagnosed ADHD experience low HRQoL, which may often be exacerbated by psychiatric comorbidities such as anxiety and depression. Patients presenting with ADHD and psychiatric comorbidities in adulthood may require particular care and resources in the management of their ADHD. PMID- 30005676 TI - Cross-cultural adaptation and validation of the VISA-A questionnaire for Chilean Spanish-speaking patients. AB - BACKGROUND: The purpose of this study is to translate, culturally adapt, and validate the VISA-A questionnaire for Chilean Spanish speakers with Achilles tendinopathy (AT), which has been originally developed for English-speaking population. METHODS: According to the guidelines published by Beaton et al., the questionnaire was translated and culturally adapted to Chilean patients in six steps: initial translation, synthesis of the translation, back translation, expert committee review, test of the pre-final version (cohort n = 35), and development of VISA-A-CH. The resulting Chilean version was tested for validity on 60 patients: 20 healthy individuals (group 1), 20 patients with a recently diagnosed AT (group 2), and 20 with a severe AT that already initiated conservative treatment with no clinical improvement (group 3). The questionnaire was completed three times by each participant: at the time of study enrollment, after an hour, and after a week of the initial test. RESULTS: All six steps were successfully completed for the translation and cultural adaptation of the VISA-A CH. VISA-A-CH final mean scores in the healthy group was significantly higher than those in the other groups. Group 3 had the lowest scores. Validity showed excellent test-retest reliability (rho c = 0.999; Pearson's r = 1.000) within an hour and within a week (rho c = 0.837; Pearson's r = 0.840). CONCLUSIONS: VISA-A was translated and validated to Chilean Spanish speakers successfully, being comparable to the original version. We believe that VISA-A-CH can be recommended as an important tool for clinical and research settings in Chilean and probably Latin-American Spanish speakers. PMID- 30005677 TI - Orofacial symptoms and oral health-related quality of life in juvenile idiopathic arthritis: a two-year prospective observational study. AB - BACKGROUND: Little is known about the chronicity of orofacial symptoms and how this influences the oral health-related quality of life in juvenile idiopathic arthritis (JIA). Therefore, our objectives were to study the long-term changes in self-reported orofacial symptoms, and to define the impact of orofacial symptoms on oral health-related quality of life in JIA. METHODS: At baseline (T0), 157 consecutive JIA patients <=20 years completed a patient pain questionnaire that incorporates domains related to the orofacial area. At the 2 year follow-up (T1), 113 patients completed the same questionnaire (response rate 72%) in addition to the Child Perception's Questionnaire; a validated 31-item questionnaire addressing oral health-related quality of life. RESULTS: At T0, 53% (60/113) of patients reported the presence of orofacial pain, and 36% (41/113) of patients reported compromised orofacial function. At T1, 77% (46/60) of patients with pain at T0 reported persistent pain, and 66% (27/41) of patients with functional disability at T0 reported persistent disability. Patients with orofacial symptoms reported a significantly greater prevalence of negative impact of orofacial conditions on general quality of life and within the domains of emotional and social well-being compared to asymptomatic patients. CONCLUSION: Self-reported orofacial pain and functional disability were common findings in a cohort of JIA patients followed over 2 years. These symptoms seem to persist over time in most patients, and have a significant negative impact on oral health-related quality of life. PMID- 30005678 TI - Paramount therapy for young and fit patients with mantle cell lymphoma: strategies for front-line therapy. AB - The natural history of mantle cell lymphoma (MCL) is a continuous process with the vicious cycle of remission and recurrence. Because MCL cells are most vulnerable before their exposure to therapeutic agents, front-line therapy could eliminate MCL cells at the first strike, reduce the chance for secondary resistance, and cause long-term remissions. If optimized, it could become an alternative to cure MCL. The key is the intensity of front-line therapy. Both the Nordic 2 and the MD Anderson Cancer Center HCVAD trials, with follow-up times greater than 10 years, achieved long-term survivals exceeding 10 years. But the Achilles heel in both trials were the severe toxicities, such as secondary malignancies including myelodysplastic syndromes /leukemia. Therefore, intensive therapies can act as a double-edged sword providing long term survival at the cost of severe toxicities. In our opinion, although intensive chemotherapy can cause detrimental side effects, it is indispensable given that we run the risk of sacrificing long-term survivals in these young and fit patients. We must seek for a powerful alternative at the front-line. Furthermore, minimal residual disease negativity should be the optimal therapeutic goal to achieve before and after autologous stem cell transplantation. Some novel therapeutic strategies have shown to improve outcomes, but it is not yet clear as to how these results translate in population. Of note, MCL patients need to be stratified at diagnosis and be provided with different intensities of front-line regimen. In this review, we discuss current strategies for the treatment of young patients with newly diagnosed MCL. PMID- 30005679 TI - Development of rapid guidelines: 3. GIN-McMaster Guideline Development Checklist extension for rapid recommendations. AB - BACKGROUND: Practice guidelines require a substantial investment of resources and time, often taking between 1 and 3 years from conceptualisation to publication. However, urgent situations require the development of recommendations in a shorter timeframe. In this third and final article in the series exploring challenges and solutions in developing rapid guidelines (RGs), we propose guiding principles for the development of RGs. METHODS: We utilised the Guideline International Network-McMaster Guideline Development Checklist (GDC) as a starting point for elements to consider during RG development. We built on those elements using the findings from a systematic review of guideline manuals, a survey of international organisations conducting RGs, and interviews of guideline developers within WHO. We reviewed initial findings and developed an intermediate list of elements, as well as narrative guidance. We then invited experts to validate the intermediate list, reviewing for placement, brevity and redundancy. We used this iterative process and group consensus to determine the final elements for RG development guidance. RESULTS: Our work identified 21 principles within the topics of the Guideline International Network-McMaster GDC to guide the planning and development of RGs. Principles fell within 15 of the 18 checklist topics, highlighting strategies to streamline and expedite the guideline development process. CONCLUSIONS: We defined principles to guide the development of RGs, while maintaining a standardised, rigorous and transparent process. These principles will serve as guidance for guideline developers responding to urgent situations such as public health urgencies. Integration of these principles within currently disseminated guideline development standards will facilitate the use of those tools in situations necessitating RG recommendations. PMID- 30005680 TI - Enchondromas and atypical cartilaginous tumors at the proximal humerus treated with intralesional resection and bone cement filling with or without osteosynthesis: retrospective analysis of 42 cases with 6 years mean follow-up. AB - BACKGROUND: Enchondromas and atypical cartilaginous tumors (ACT) are often located at the proximal humerus. Most lesions can be followed conservatively, but surgical resection may alleviate pain, avoid pathological fractures, and prevent transformation into higher grade chondrosarcomas. Rigorous intralesional resection and filling with polymethylmethacrylate bone cement has been proposed for enchondromas but also for ACT, as an alternative for extralesional resection. We intended to analyze radiological, clinical, and functional outcome of this strategy and compare bone cement without osteosynthesis to bone cement compound osteosynthesis, which has not been analyzed so far. METHODS: We retrospectively analyzed 42 consecutive patients (mean follow-up 73 months; range 8-224) after curettage and bone cement filling with or without osteosynthesis. Exclusion criteria were Ollier's disease and cancellous bone filling. Twenty-five patients only received bone cement. Seventeen patients received additional proximal humerus plate for compound osteosynthesis to increase stability after curettage. Demographics and radiological and clinical outcome were analyzed including surgery time, blood loss, hospitalization, recurrences, and complications. An additional telephone interview at the final follow-up assessed postoperative satisfaction, pain, and function in the quick disabilities of the arm, shoulder, and hand (DASH) score and the Musculoskeletal Tumor Society (MSTS) score. Statistics included the Student T tests, Mann-Whitney U tests, and chi-square tests. RESULTS: No osteosynthesis compared to compound osteosynthesis showed smaller tumors (4.2 (+/- 1.5) cm versus 6.6 (+/- 3.0) cm; p = 0.005) and smaller bone cement fillings after curettage (5.7 (+/- 2.1) cm versus 9.6 (+/- 3.2) cm; p = 0.0001). A score evaluating preoperative scalloping and soft-tissue extension did not significantly differ (1.9 (+/- 0.9) versus 2.0 (+/- 1.0); rating scale 0 4; p = 0.7). Both groups showed high satisfaction (9.2 (+/- 1.5) versus 9.2 (+/- 0.9); p = 0.5) and low pain (1.0(+/-1.7) versus 1.9(+/-1.8); p = 0.1) in a rating scale from 0 to 10. Clinical and functional outcome was excellent for both groups in the DASH score (6.0 (+/- 11.8) versus 11.0 (+/- 13.2); rating scale 0-100; p = 0.2) and the MSTS score (29.0 (+/- 1.7) versus 28.7 (+/- 1.1); rating scale 0-30; p = 0.3). One enchondroma recurrence was found in the group without osteosynthesis. Complications (one fracture and one intra-articular screw) were only detected after osteosynthesis. Osteosynthesis had longer surgery time (70 (+/- 21) min versus 127 (+/- 22) min; p < 0.0001), more blood loss (220 (+/- 130) ml versus 460 (+/- 210) ml; p < 0.0001), and longer stay in the hospital (6 (+/- 2) days versus 8 (+/- 2) days; p = 0.004). CONCLUSIONS: Intralesional tumor resection was oncologically safe and clinically successful with or without osteosynthesis. Osteosynthesis did not reduce the risk for fracture but was more invasive. PMID- 30005681 TI - Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and developed drug resistance has represented one of the most challenging tasks for management. The current therapeutic regimens may select and enrich cancer stem-like cells (CSCs) resulting in the increased resistance against treatment, metastatic potential and mortality. Regorafenib is a multi kinase inhibitor, an FDA-approved last-of-line treatment for patients with chemo refractory metastatic CRC. However, regorafenib's potential effects on CSCs have not been fully elucidated. METHODS: Here, we developed two 5-FU resistant CRC cell lines, HCT-116R and DLD-1R and showed the increased CSCs characteristics such as increased side-population cells, tumor sphere formation and expression of stemness markers. These cell lines and CSCs properties were used for evaluating the potential of regorafenib in suppressing CSCs. RESULTS: We showed that regorafenib treatment decreased the stemness phenotypes including tumor sphere formation, and side-population, of both HCT-116R and DLD-1R cells. Additionally, regorafenib suppressed the cell viability in both cell lines synergistically with 5-FU. In vivo, the combination of regorafenib and 5-FU significantly suppressed the tumorigenesis and stemness markers of 5-FU resistant DLD-1R. Mechanistically, regorafenib-mediated effects were associated with the induction of tumor suppressor miR-34a and suppression of WNT/beta-catenin signaling. Our findings demonstrated that regorafenib treatment was associated with the increased level of miR-34a, resulting in reversing drug resistance and cancer-initiating cell phenotypes by degrading WNT/beta-catenin in CRC. CONCLUSION: Regorafenib might be a potential drug for colon cancer stem-like cells and it should be investigated in future clinical trials. PMID- 30005682 TI - Neurologic outcome after out-of-hospital cardiac arrest could be predicted with the help of bispectral-index during early targeted temperature management. AB - BACKGROUND: Outcome prediction is crucial for out-of-hospital cardiac arrest (OHCA) survivors. Several attempts have been made to use the bispectral index (BIS) for this purpose. We aimed to investigate the prognostic power of the BIS during the early stage of targeted temperature management (TTM) after OHCA. METHODS: From Jan 2014 to Feb 2017, the BIS was determined in OHCA patients as soon as possible after the start of TTM. We injected a neuro-muscular blocking agent and recoded the BIS value and the time when the electromyographic (EMG) factor reached zero. The primary outcome was the cerebral performance category scale (CPC) score at 6 months, and a poor outcome was defined as a CPC score of 3, 4, or 5. The exclusion criteria were age under 18 years, traumatic cardiac arrest, and BIS data with a non-zero EMG factor. RESULTS: Sixty-five patients were included in this study. Good outcomes were observed for 16 patients (24.6%), and poor outcomes were observed for 49 patients (75.4%). The mean time of BIS recording was 2.3 +/- 1.0 h after return of spontaneous circulation (ROSC). The mean BIS values of the good outcome and poor outcome groups were 35.6 +/- 13.1 and 5.5 +/- 9.2, respectively (p < 0.001). The area under the curve was 0.961. Use of a cut-off value of 20.5 to predict a good outcome yielded a sensitivity of 87.5% and specificity of 93.9%. Use of a cut-off value of 10.5 to predict a poor outcome yielded a sensitivity of 87.8% and specificity of 100%. CONCLUSION: With the help of BIS, physicians could predict that a patient who has BIS value over 20.5 after ROSC could have a big chance to get good neurological outcome in less than three hours. PMID- 30005683 TI - Diagnostic performance of commercial IgM and IgG enzyme-linked immunoassays (ELISAs) for diagnosis of Zika virus infection. AB - BACKGROUND: Serologic detection of Zika virus (ZIKV) infections is challenging because of antigenic similarities among flaviviruses. OBJECTIVE: To evaluate the sensitivity and specificity of commercial ZIKV IgM and IgG enzyme-linked immunoassay (ELISA) kits. METHODS: We used sera from febrile patients with RT-PCR confirmed ZIKV infection to determine sensitivity and sera from RT-PCR-confirmed dengue cases and blood donors, both of which were collected before ZIKV epidemics in Brazil (2009-2011 and 2013, respectively) to determine specificity. RESULTS: The ZIKV IgM-ELISA positivity among RT-PCR ZIKV confirmed cases was 0.0% (0/14) and 12.5% (1/8) for acute- and convalescent-phase sera, respectively, while its specificity was 100.0% (58/58) and 98.3% (58/59) for acute- and convalescent phase sera of dengue patients, and 100.0% (23/23) for blood donors. The ZIKV IgG ELISA sensitivity was 100.0% (6/6) on convalescent-phase sera from RT-PCR confirmed ZIKV patients, while its specificity was 27.3% (15/55) on convalescent phase sera from dengue patients and 45.0% (9/20) on blood donors' sera. The ZIKV IgG-ELISA specificity among dengue confirmed cases was much greater among patients with primary dengue (92.3%; 12/13), compared to secondary dengue (7.1%; 3/42). CONCLUSIONS: In a setting of endemic dengue transmission, the ZIKV IgM ELISA had high specificity, but poor sensitivity. In contrast, the ZIKV IgG-ELISA showed low specificity, particularly for patients previously exposed to dengue infections. This suggests that this ZIKV IgM-ELISA is not useful in confirming a diagnosis of ZIKV infection in suspected patients, whereas the IgG-ELISA is more suitable for ZIKV diagnosis among travelers, who reside in areas free of flavivirus transmission, rather than for serosurveys in dengue-endemic areas. PMID- 30005684 TI - Characterization of T cell activation and regulation in children with asymptomatic Plasmodium falciparum infection. AB - BACKGROUND: Asymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication. Increasing levels of regulatory T cells (Tregs) in Plasmodium falciparum infections have been associated with the risk of developing clinical disease, suggesting that individuals with asymptomatic infections may have reduced Treg frequency. However, the relationship between Tregs, cellular activation and parasite control in asymptomatic malaria remains unclear. METHODS: In a cross-sectional study, the levels of Tregs and other T cell activation phenotypes were compared using flow cytometry in symptomatic, asymptomatic and uninfected children before and after stimulation with infected red blood cell lysates (iRBCs). In addition, the association between these T cell phenotypes and parasitaemia were investigated. RESULTS: In children with asymptomatic infections, levels of Tregs and activated T cells were comparable to those in healthy controls but significantly lower than those in symptomatic children. After iRBC stimulation, levels of Tregs remained lower for asymptomatic versus symptomatic children. In contrast, levels of activated T cells were higher for asymptomatic children. Strikingly, the pre stimulation levels of two T cell activation phenotypes (CD8+CD69+ and CD8+CD25+CD69+) and the post-stimulation levels of two regulatory phenotypes (CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+) were significantly positively correlated with and explained 68% of the individual variation in parasitaemia. A machine learning model based on levels of these four phenotypes accurately distinguished between asymptomatic and symptomatic children (sensitivity = 86%, specificity = 94%), suggesting that these phenotypes govern the observed variation in disease status. CONCLUSION: Compared to symptomatic P. falciparum infections, in children asymptomatic infections are characterized by lower levels of Tregs and activated T cells, which are associated with lower parasitaemia. The results indicate that T cell regulatory and activation phenotypes govern both parasitaemia and disease status in paediatric malaria in the studied sub-Saharan African population. PMID- 30005685 TI - Assessment of healthiness among long term inhabiting army soldiers in dry zone of Sri Lanka. AB - OBJECTIVES: Military personnel, because of the unique nature of their duties, are reluctant to face stressors. Living in hot and humid conditions they frequently suffer dehydration. Army soldiers living in dry zone of Sri Lanka, were screened for chronic kidney disease (CKD), common non-communicable diseases and methicillin resistant Staphylococcus aureus (MRSA) colonization. Albumin creatinine ratio > 30 mg/g urine taken as cut-off for detection of CKD. RESULTS: Screened 417 soldiers, all were men and body mass index were 21.4 +/- 2.2 kg/m2. They smoke 0.5 +/- 0.1 pack years while consume alcohol 32 +/- 3 units/week and were having 100/min average daily moderate physical activity. Eight of them (0.2%) were having essential hypertension, 4 (0.1%) of them were having diabetes mellitus. Blood cholesterol was within normal range. CKD unknown etiology (CKDu) prevalence among screened army soldiers was 0.009. All were from native army recruits. Further, 71.2% had MRSA colonization. In a group of middle aged army recruits, despite tobacco smoking and moderate level of alcohol consumption while continuously having healthy dietary practices with physical activities would leads to low prevalence of communicable diseases. Further, compared to native group of solders, visitors but living long time recruits CKDu incidence is zero. PMID- 30005686 TI - Caveolin-1 is dispensable for early lymphoid development, but plays a role in the maintenance of the mature splenic microenvironment. AB - OBJECTIVE: Caveolin-1 (CAV1) is known for its role as both a tumor suppressor and an oncogene, harboring a highly context-dependent role within a myriad of malignancies and cell types. In an immunological context, dysregulation of CAV1 expression has been shown to alter immunological signaling functions and suggests a pivotal role for CAV1 in the facilitation of proper immune responses. Nonetheless, it is still unknown how Cav1-deficiency and heterozygosity would impact the development and composition of lymphoid organs in mice. Herein, we investigated the impacts of Cav1-dysregulation on the lymphoid organs in young (12 weeks) and aged (36 weeks) Cav1+/+, Cav1+/-, and Cav1-/- mice. RESULTS: We observed that only Cav1-deficiency is associated with persistent splenomegaly at all timepoints. Furthermore, no differences in overall body weight were detected (and without sexual dimorphisms). Both aged Cav1+/- and Cav1-/- mice present with decreased CD19+CD22+ B cells and secondary-follicle atrophy, specifically in the spleen, compared with wild-type controls and irrespective of splenomegaly status. Consequently, the demonstrated effects on B cell homeostasis and secondary follicle characteristics prompted our investigation into follicle-derived human B cell lymphomas. Our investigation points toward CAV1 as a dysregulated protein in follicle-derived B-cell malignancies without harboring a differential expression between more aggressive and indolent hematological malignancies. PMID- 30005687 TI - Do emotions influence the motivations and preferences of keepers of stingless bees? AB - BACKGROUND: According to the biophilia hypothesis, an emotional affiliation with nature has been inherited during human biocultural evolution. Research on beekeeping can contribute to the scientific understanding of the influence of emotions in the human-nature relationship, since this activity provides concrete experiences of beneficial interaction between the human being and the environment by stimulating conservation-friendly values among practitioners. In this study, we investigated motivations and preferences driving beekeepers' choices. We hypothesized that emotional criteria would be the main motivators in choosing to include beekeeping into small-scale farming systems. We also assumed that, once beekeeping has been chosen, the preference among species of bees for raising would also be influenced mainly by emotional criteria. METHODS: Data were collected from free lists and semi-structured interviews with 52 keepers of stingless bees from Sitio Xixa in the state of Pernambuco, Brazil. The content analysis technique was used to analyze data from interviews. The underlying criteria for motivation and preference quoted in the free lists were analyzed with Smith's Salience Index. RESULTS: Emotional and esthetic criteria were the most salient motivations for choosing beekeeping as one of the activities in small-scale farming systems. On the other hand, honey productivity and bee behavior were the most salient criteria for the preference for certain bee species to be kept. CONCLUSIONS: Emotional criterion had an especially notable influence on the motives for practicing beekeeping, but not on the preference of species to be raised. This demonstrates that the scenario under study represents a panorama of multiple influences in which emotions are one, but not the only, important component. Finally, our results indicate that the emotional domain should be taken into account in environmental education efforts and in the planning of bee management and nature conservation policies. PMID- 30005688 TI - Synergy in the adulticidal efficacy of essential oils for the improvement of permethrin toxicity against Aedes aegypti L. (Diptera: Culicidae). AB - BACKGROUND: In a previous screening program for mosquitocides from local edible plants in Thailand, essential oils (EOs) of Cyperus rotundus, Alpinia galanga and Cinnamomum verum, were found to possess promising adulticidal activity against Aedes aegypti. With the aim of reducing usage of conventional insecticides and improving the management of resistant mosquito populations, this study was designed to determine the potential synergism in the adulticidal efficacy of EOs on permethrin toxicity against Ae. aegypti, both pyrethroid-resistant and susceptible strains. METHODS: EOs extracted from rhizomes of C. rotundus and A. galanga as well as C. verum barks were evaluated for chemical compositions and adulticidal activity against Muang Chiang Mai-susceptible (MCM-S) and Pang Mai Dang-resistant (PMD-R) strains of Ae. aegypti. Adulticidal bioassays of EO permethrin mixtures for synergistic activity were also performed on these Ae. aegypti strains. RESULTS: Chemical characterization by the GC-MS analytical technique demonstrated that 48 compounds were identified from the EOs of C. rotundus, A. galanga and C. verum, representing 80.22%, 86.75% and 97.24%, respectively, of all compositions. Cyperene (14.04%), beta-bisabolene (18.27%) and cinnamaldehyde (64.66%) were the main constituents of C. rotundus, A. galanga and C. verum oils, respectively. In adulticidal bioassays, EOs of C. rotundus, A. galanga and C. verum were effective in killing Ae. aegypti, both MCM-S and PMD-R strains, with LD50 values of 10.05 and 9.57 MUg/mg female, 7.97 and 7.94 MUg/mg female, and 3.30 and 3.22 MUg/mg female, respectively. The adulticidal efficacy against MCM-S and PMD-R Ae. aegypti of these EOs was close to that of piperonyl butoxide (PBO, LD50 values = 6.30 and 4.79 MUg/mg female, respectively) but less pronounced than that of permethrin (LD50 values = 0.44 and 3.70 ng/mg female, respectively). Nevertheless, combination-based bioassays discovered the accomplished synergism of EOs together with permethrin. Significant synergistic effects with permethrin against both the strains of Ae. aegypti were recorded in the EOs of C. rotundus and A. galanga. Addition of C. rotundus and A. galanga oils decreased the LD50 values of permethrin against MCM-S dramatically from 0.44 to 0.07 and 0.11 ng/mg female, respectively, with synergism ratio (SR) values of 6.28 and 4.00, respectively. Furthermore, EOs of C. rotundus and A. galanga also reduced the LD50 values of permethrin against PMD-R drastically from 3.70 to 0.42 and 0.003 ng/mg female, respectively, with SR values of 8.81 and 1233.33, respectively. CONCLUSIONS: The synergy of enhanced adulticidal toxicity recorded from EO-permethrin combinations against both strains of Ae. aegypti presents a promising role of EOs as a synergist for improving mosquitocidal efficacy, particularly in situations where conventional compounds are ineffective or inappropriate. PMID- 30005690 TI - Helicobacter pylori and its relationship with variations of gut microbiota in asymptomatic children between 6 and 12 years. AB - OBJECTIVE: To determine the variations in the composition of the intestinal microbiota in asymptomatic children infected with Helicobacter pylori in comparison with children without the infection. RESULTS: Children infected with H. pylori doubled their probability of presenting 3 of 9 genera of bacteria from the gut microbiota, including: Proteobacteria (p = 0.008), Clostridium (p = 0.040), Firmicutes (p = 0.001) and Prevotella (p = 0.006) in comparison to patients without the infection. We performed a nutritional assessment and found that growth stunting was statistically significantly higher in patients infected with H. pylori (p = 0.046). PMID- 30005689 TI - Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS). AB - BACKGROUND: Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Predicting non response to MTX could enable earlier access to alternative or additional medications and control of disease progression. We aimed to identify baseline predictors of non-response to MTX and combine these into a prediction algorithm. METHODS: This study included patients recruited to the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre prospective observational study of patients with RA or undifferentiated polyarthritis, commencing MTX for the first time. Non-response to MTX at 6 months was defined as "no response" using the European League Against Rheumatism (EULAR) response criteria, discontinuation of MTX due to inefficacy or starting biologic therapy. The association of baseline demographic, clinical and psychosocial predictors with non-response was assessed using logistic regression. Predictive performance was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. RESULTS: Of 1050 patients, 449 (43%) were classified as non-responders. Independent multivariable predictors of MTX non-response (OR (95% CI)) were rheumatoid factor (RF) negativity (0.62 (0.45, 0.86) for RF positivity versus negativity), higher Health Assessment Questionnaire score (1.64 (1.25, 2.15)), higher tender joint count (1.06 (1.02, 1.10)), lower Disease Activity score in 28 joints (0.29 (0.23, 0.39)) and higher Hospital Anxiety and Depression Scale anxiety score (1.07 (1.03, 1.12)). The optimism-corrected AUC was 0.74. CONCLUSIONS: This is the first model for MTX non-response to be developed in a large contemporary study of patients commencing MTX in which demographic, clinical and psychosocial predictors were considered. Patient anxiety was a predictor of non-response and could be addressed at treatment commencement. PMID- 30005691 TI - HNF4A-related Fanconi syndrome in a Chinese patient: a case report and review of the literature. AB - BACKGROUND: The p.R63W mutation in hepatocyte nuclear factor-4 alpha (HNF4A) leads to a heterogeneous group of disorders with various clinical presentations. Recently, patients with congenital hyperinsulinism and Fanconi syndrome due to the p.R63W mutation in HNF4A have been described. Although other clinical variations such as liver dysfunction have been associated with HNF4A mutations, hearing impairment has not previously been associated. We report the case of a patient with Fanconi syndrome and hyperinsulinemic hypoglycemia caused by the mutation of HNF4A presenting with additional auditory phenotypes. CASE PRESENTATION: We present a case report of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. CONCLUSIONS: This is the first case of HNF4A mutation associated with an auditory phenotype. It expands the clinical phenotypes and supports speculation in the literature that HNF4A may be a candidate gene for deafness. In conclusion, hearing loss may be found in children with HNF4A-related Fanconi syndrome, and auditory function should be assessed. PMID- 30005692 TI - Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer. AB - BACKGROUND: 5-Hydroxymethylcytosine (5hmC) is converted from 5-methylcytosine (5mC) by a group of enzymes termed ten-eleven translocation (TET) family dioxygenases. The loss of 5hmC has been identified as a hallmark of most types of cancer and is related to tumorigenesis and progression. However, the role of 5hmC in bladder cancer is seldom investigated. Vitamin C was recently reported to induce the generation of 5hmC by acting as a cofactor for TET dioxygenases. In this study, we explored the role of 5hmC in bladder cancer and the therapeutic efficacy of vitamin C in increasing the 5hmC pattern. RESULTS: 5hmC was decreased in bladder cancer samples and was related to patient overall survival. Genome wide mapping of 5hmC in tumor tissues and vitamin C-treated bladder cancer cells revealed that 5hmC loss was enriched in cancer-related genes and that vitamin C treatment increased 5hmC levels correspondingly. Vitamin C treatment shifted the transcriptome and inhibited the malignant phenotypes associated with bladder cancer cells in both in vitro cell lines and in vivo xenografts. CONCLUSIONS: This study provided mechanistic insights regarding the 5hmC loss in bladder cancer and a rationale for exploring the therapeutic use of vitamin C as a potential epigenetic treatment for bladder cancer. PMID- 30005694 TI - Determinants of access to improved sanitation facilities in rural districts of southern Ghana: evidence from Dodowa Health and Demographic Surveillance Site. AB - OBJECTIVE: Access to improved sanitation facilities is critical to the health and well-being of individuals and communities. However, globally, over 2.5 billion people live without access to safe sanitation facilities and more than 40% of the world population, do not use a toilet, but defecate in the open or in unsanitary places. In Ghana, only 14% of the population have access to improved sanitation facilities with great disparities between rural (8%) and urban (19%) dwellers. This paper sought to examine the determinants of access to improved sanitation facilities by households among rural dwellers in two districts in southern Ghana. RESULTS: This study, which involved 16,353 household heads from the Dodowa Health and Demographic Surveillance System, found that sanitation facilities used by households were significantly influenced by age, gender, level of education, occupation, marital and socioeconomic status of household heads. It further revealed that a large proportion (85.94%) of the study participants did not have access to improved sanitation facilities. The study therefore recommends that the national sanitation laws must strictly be enforced to ensure each household in Ghana has decent and hygienic toilet facility. PMID- 30005693 TI - Doublecortin-expressing cell types in temporal lobe epilepsy. AB - Doublecortin (DCX) is widely regarded as a marker of immature and migrating neurons during development. While DCX expression persists in adults, particularly in the temporal lobe and neurogenic regions, it is unknown how seizures influence its expression. The aim of the present study was to explore the distribution and characteristics of DCX-expressing cells in surgical and postmortem samples from 40 adult and paediatric patients, with epilepsy and with or without hippocampal sclerosis (HS), compared to post mortem controls. The hippocampus (pes and body), parahippocampal gyrus, amygdala, temporal pole and temporal cortex were examined with DCX immunohistochemistry using four commercially-available DCX antibodies, labelled cells were quantified in different regions of interest as well as their co-expression with cell type specific markers (CD68, Iba1, GFAP, GFAP?, nestin, SOX2, CD34, OLIG2, PDGFRbeta, NeuN) and cell cycle marker (MCM2). Histological findings were compared with clinical data, as well as gene expression data obtained from the temporal cortex of 83 temporal lobe epilepsy cases with HS. DCX immunohistochemistry identified immature (Nestin-/NeuN-) neurons in layer II of the temporal neocortex in patients with and without epilepsy. Their number declined significantly with age but was not associated with the presence of hippocampal sclerosis, seizure semiology or memory dysfunction. DCX+ cells were prominent in the paralaminar nuclei and periamygdalar cortex and these declined with age but were not significantly associated with epilepsy history. DCX expressing cells with ramified processes were prominent in all regions, particularly in the hippocampal subgranular zone, where significantly increased numbers were observed in epilepsy samples compared to controls. DCX ramified cells co-expressed Iba1, CD68 and PDGFRbeta, and less frequently MCM2, OLIG2 and SOX2, but no co-localization was observed with CD34, nestin or GFAP/GFAP ?. Gene expression data from neocortical samples in patients with TLE and HS supported ongoing DCX expression in adults. We conclude that DCX identifies a range of morphological cell types in temporal lobe epilepsy, including immature populations, glial and microglial cell types. Their clinical relevance and biological function requires further study but we show some evidence for alteration with age and in epilepsy. PMID- 30005695 TI - Distribution of resistance genes encoding ESBLs in Enterobacteriaceae isolated from biological samples in health centers in Ouagadougou, Burkina Faso. AB - OBJECTIVE: Resistance to antibiotics most especially third generation cephalosporins has assumed a worrisome dimension globally. Genes conferring these resistance which are mediated by enzymes known as extended spectrum beta lactamases (ESBLs) are now wide spread among several Enterobacteriaceae species. However there is paucity of data regarding the distribution of these genes in Burkina Faso. Hence this prospective study aims to determine the prevalence and distribution of ESBL encoding genes in ESBL producing Enterobacteriaceae strains isolated from clinical samples of patients attending the three major hospitals in Ouagadougou Burkina Faso. RESULTS: ESBL-encoding genes were assayed in 187 ESBL producing Enterobacteriaceae strains. Among these isolates, the prevalence of ESBL-producing strains with blaTEM, blaSHV and blaCTX-M genes were 26.2% (49/187), 5.9% (11/187) and 40.1% (75/187) respectively. The association of ESBL encoding genes with health centers was statistically significant (p = 0.0209). Approximately 39.6% of E. coli harbored CTX-M and Klebsiella spp. 5.9%. This study demonstrates the dissemination of TEM, SHV and CTX-M genes in ESBL producing Enterobacteriaceae strains in Ouagadougou. Continuous spread of these bacteria poses great public health risk, thus increased surveillance and regulation of antibiotics use is imperative in Burkina Faso. PMID- 30005696 TI - Patients' perception of using telehealth for type 2 diabetes management: a phenomenological study. AB - BACKGROUND: There is a growing body of evidence that supports the uses of telehealth to monitor and manage people with diabetes at a distance. Despite this, the uptake of telehealth has been low. The objective of this study is to explore patients' perceptions of using telehealth for type 2 diabetes management. METHODS: Semi-structured interviews were undertaken with 10 patients from the NHS Newham area in London, UK. Data were collected using recorded semi-structured interviews. The interviews were transcribed verbatim and the analysis was guided by the phenomenological analysis approach. RESULTS: We identified three main themes for facilitating positive patient experience or acceptance of telehealth and these included: technology consideration, service perceptions and empowerment. All patients asserted that they were pleased with the technology and many also proclaimed that they could not see themselves being without it. Moreover, very few negative views were reported with respect to the use of telehealth. CONCLUSION: The patients' perceived telehealth as a potential to enhance their quality of life, allow them to live independently at home as well as help them take and be in more control over their own health state. The findings of this study therefore supports the use of telehealth for the routine care of people with type 2 diabetes. However, one must interpret the results with caution due to limitations identified in the sample. PMID- 30005697 TI - Intrapapillary hemorrhage with concurrent peripapillary and vitreous hemorrhage in two healthy young patients. AB - BACKGROUND: Cases of intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage usually appear in myopic eyes with tilted optic discs, can improve without any specific treatment, and very rarely recur. But there has been no report of the use of advanced multimodal imaging such as spectral domain optical coherence tomography. We describe two rare cases of intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage in an 11-year-old female and a 16-year-old male. CASE PRESENTATION: An 11-year-old female with no past history presented with floaters in her right eye. Her BCVA (best-corrected visual acuity) by the Snellen was 20/20. Fundus examination, optical coherence tomography (OCT) revealed intrapapillary hemorrhage, peripapillary subretinal hemorrhage. After 3 weeks, all hemorrhage was resolved. Similarly, a 16-year-old male with no past history presented with blurry vision, black filamentous floaters. His BCVA was 20/20 in both eyes. Fundus examination showed intrapapillary hemorrhage, peripapillary subretinal hemorrhage while OCT revealed peripapillary edema in his right eye. Multimodal imaging did not reveal any presence of optic disc drusen. After 4 weeks of observation, the hemorrhage resolved. Cases of intrapapillary hemorrhage with peripapillary subretinal hemorrhage have rarely been reported. CONCLUSIONS: This condition generally affects monocularly, in myopic eyes with tilted discs. Despite an unknown cause, the hemorrhages spontaneously resolved without any treatment. Consistent with the good visual prognosis reported previously, the vision, optic nerve function of the two patients were preserved. It should be differentiated from other causes of subretinal hemorrhage. PMID- 30005698 TI - Control measures to prevent the increase of paratuberculosis prevalence in dairy cattle herds: an individual-based modelling approach. AB - Paratuberculosis, a gastrointestinal disease caused by Mycobacterium avium subsp. paratuberculosis (Map), can lead to severe economic losses in dairy cattle farms. Current measures are aimed at controlling prevalence in infected herds, but are not fully effective. Our objective was to determine the most effective control measures to prevent an increase in adult prevalence in infected herds. We developed a new individual-based model coupling population and infection dynamics. Animals are characterized by their age (6 groups) and health state (6 states). The model accounted for all transmission routes and two control measures used in the field, namely reduced calf exposure to adult faeces and test-and cull. We defined three herd statuses (low, moderate, and high) based on realistic prevalence ranges observed in French dairy cattle herds. We showed that the most relevant control measures depend on prevalence. Calf management and test-and-cull both were required to maximize the probability of stabilizing herd status. A reduced calf exposure was confirmed to be the most influential measure, followed by test frequency and the proportion of infected animals that were detected and culled. Culling of detected high shedders could be delayed for up to 3 months without impacting prevalence. Management of low prevalence herds is a priority since the probability of status stabilization is high after implementing prioritized measures. On the contrary, an increase in prevalence was particularly difficult to prevent in moderate prevalence herds, and was only feasible in high prevalence herds if the level of control was high. PMID- 30005699 TI - Rac1 activation links tau hyperphosphorylation and Abeta dysmetabolism in Alzheimer's disease. AB - One of the earliest pathological features characterizing Alzheimer's disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Abeta and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics. PMID- 30005700 TI - Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways. AB - Altered DNA methylation events contribute to the pathogenesis and progression of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Investigations of global DNA methylation patterns in liver biopsies representing severe NAFLD fibrosis have been limited. We used the HumanMethylation 450K BeadChip to analyze genome-wide methylation in patients with biopsy-proven grade 3/4 NAFLD fibrosis/cirrhosis (N = 14) and age- and sex-matched controls with normal histology (N = 15). We identified 208 CpG islands (CGIs), including 99 hypomethylated and 109 hypermethylated CGIs, showing statistically significant evidence (adjusted P value < 0.05) for differential methylation between cirrhotic and normal samples. Comparison of beta values for each CGI to the read count of its corresponding gene obtained from RNA-sequencing analysis revealed negative correlation (adjusted P value < 0.05) for 34 transcripts. These findings provide supporting evidence for a role for CpG methylation in the pathogenesis of NAFLD related cirrhosis, including confirmation of previously reported differentially methylated CGIs, and contribute new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis. PMID- 30005701 TI - Oral vaccination of dogs: a well-studied and undervalued tool for achieving human and dog rabies elimination. AB - The mass vaccination of dogs is a proven tool for rabies prevention. Besides parenteral delivery of inactivated vaccines, over the past several decades, several self-replicating biologics, including modified-live, attenuated and recombinant viruses, have been evaluated for the oral vaccination of dogs against rabies. Vaccines are included within an attractive bait for oral consumption by free-ranging dogs. Due to the high affinity between dogs and humans, such biologics intended for oral vaccination of dogs (OVD) need to be efficacious as well as safe. Baits should be preferentially attractive to dogs and not to non target species. Although many different types have been evaluated successfully, no universal bait has been identified to date. Moreover, high bait acceptance does not necessarily mean that vaccine efficacy and programmatic success is predictable. The use of OVD in the laboratory and field has demonstrated the safety and utility of this technology. Within a One Health context, OVD should be considered as part of a holistic plan for the global elimination of canine rabies. PMID- 30005702 TI - Intranasal administration of cationic liposomes enhanced granulocyte-macrophage colony-stimulating factor expression and this expression is dispensable for mucosal adjuvant activity. AB - OBJECTIVE: Infectious diseases remain a threat to human life. Vaccination against pathogenic microbes is a primary method of treatment as well as prevention of infectious diseases. Particularly mucosal vaccination is a promising approach to fight against most infectious diseases, because mucosal surfaces are a major point of entry for most pathogens. We recently developed an effective mucosal adjuvant of cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and 3beta-[N-(N',N'-dimethylaminoethane)-carbamoyl] (DC-chol) (DOTAP/DC-chol liposomes). However, the mechanism(s) underlying the mucosal adjuvant effects exerted by the cationic liposomes have been unclear. In this study, we investigated the role of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was reported to act as a mucosal adjuvant, on the mucosal adjuvant activities of DOTAP/DC-chol liposomes when administered intranasally to mice. RESULTS: Here, we show that, although intranasal vaccination with cationic liposomes in combination with antigenic protein elicited GM-CSF expression at the site of administration, blocking GM-CSF function by using an anti-GM-CSF neutralizing antibody did not alter antigen-specific antibody production induced by DOTAP/DC-chol liposomes, indicating that GM-CSF may not contribute to the mucosal adjuvant activity of the cationic liposomes when administered intranasally. PMID- 30005703 TI - Exosomes from acellular Wharton's jelly of the human umbilical cord promotes skin wound healing. AB - BACKGROUND: Compromised wound healing has become a global public health challenge which presents a significant psychological, financial, and emotional burden on patients and physicians. We recently reported that acellular gelatinous Wharton's jelly of the human umbilical cord enhances skin wound healing in vitro and in vivo in a murine model; however, the key player in the jelly which enhances wound healing is still unknown. METHODS: We performed mass spectrometry on acellular gelatinous Wharton's jelly to elucidate the chemical structures of the molecules. Using an ultracentrifugation protocol, we isolated exosomes and treated fibroblasts with these exosomes to assess their proliferation and migration. Mice were subjected to a full-thickness skin biopsy experiment and treated with either control vehicle or vehicle containing exosomes. Isolated exosomes were subjected to further mass spectrometry analysis to determine their cargo. RESULTS: Subjecting the acellular gelatinous Wharton's jelly to proteomics approaches, we detected a large amount of proteins that are characteristic of exosomes. Here, we show that the exosomes isolated from the acellular gelatinous Wharton's jelly enhance cell viability and cell migration in vitro and enhance skin wound healing in the punch biopsy wound model in mice. Mass spectrometry analysis revealed that exosomes of Wharton's jelly umbilical cord contain a large amount of alpha-2 macroglobulin, a protein which mimics the effect of acellular gelatinous Wharton's jelly exosomes on wound healing. CONCLUSIONS: Exosomes are being enriched in the native niche of the umbilical cord and can enhance wound healing in vivo through their cargo. Exosomes from the acellular gelatinous Wharton's jelly and the cargo protein alpha-2-macroglobulin have tremendous potential as a noncellular, off-the-shelf therapeutic modality for wound healing. PMID- 30005704 TI - Bionomics of the oriental latrine fly Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae): temporal fluctuation and reproductive potential. AB - BACKGROUND: Chrysomya megacephala is a blow fly species of medical and forensic importance worldwide. Understanding its bionomics is essential for both designing effective fly control programs and its use in forensic investigations. METHODS: The daily flight activity, seasonal abundance related to abiotic factors (temperature, relative humidity and rainfall) and reproductive potential of this species was investigated. Adult flies were sampled twice a month for one year from July 2013 to June 2014 in three different ecotypes (forest area, longan orchard and palm plantation) of Chiang Mai Province, northern Thailand, using semi-automatic funnel traps. One-day tainted beef offal was used as bait. RESULTS: A total of 88,273 flies were sampled, of which 82,800 flies (93.8%) were caught during the day (from 06:00 to 18:00 h); while 5473 flies (6.2%) were caught at night (from 18:00 to 06:00 h). Concurrently, the abundance of C. megacephala was higher in the forest area (n = 31,873; 36.1%) and palm plantation (n = 31,347; 35.5%), compared to the longan orchard (n = 25,053; 28.4%). The number of females was significantly higher than that of males, exhibiting a female to male sex ratio of 2.36:1. Seasonal fluctuation revealed the highest abundance of C. megacephala in summer, but low numbers in the rainy season and winter. Fly density was significantly positively correlated with temperature, but negatively correlated with relative humidity. No correlation between numbers of C. megacephala with rainfall was found. Activity occurred throughout the daytime with high numbers from 06:00 to 18:00 h in summer and 12:00 to 18:00 h in the rainy season and winter. As for the nocturnal flight activity, a small number of flies were collected in summer and the rainy season, while none were collected in the winter. Dissection of the females indicated that fecundity was highest during the rainy season, followed by winter and summer. CONCLUSIONS: Since the assessment of daily, seasonal activity and the reproductive potential of C. megacephala remains a crucial point to be elucidated, this extensive study offers insights into bionomics, which may be considered for integrated fly control strategies and forensic entomology issues. PMID- 30005706 TI - Loss of maternal EED results in postnatal overgrowth. AB - BACKGROUND: Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes. RESULTS: In this study, we used oocyte specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed. CONCLUSIONS: This study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation. PMID- 30005705 TI - Complex multiple risk intervention to promote healthy behaviours in people between 45 to 75 years attended in primary health care (EIRA study): study protocol for a hybrid trial. AB - BACKGROUND: Health promotion is a key process of current health systems. Primary Health Care (PHC) is the ideal setting for health promotion but multifaceted barriers make its integration difficult in the usual care. The majority of the adult population engages two or more risk behaviours, that is why a multiple intervention might be more effective and efficient. The primary objectives are to evaluate the effectiveness, the cost-effectiveness and an implementation strategy of a complex multiple risk intervention to promote healthy behaviours in people between 45 to 75 years attended in PHC. METHODS: This study is a cluster randomised controlled hybrid type 2 trial with two parallel groups comparing a complex multiple risk behaviour intervention with usual care. It will be carried out in 26 PHC centres in Spain. The study focuses on people between 45 and 75 years who carry out two or more of the following unhealthy behaviours: tobacco use, low adherence to the Mediterranean dietary pattern or insufficient physical activity level. The intervention is based on the Transtheoretical Model and it will be made by physicians and nurses in the routine care of PHC practices according to the conceptual framework of the "5A's". It will have a maximum duration of 12 months and it will be carried out to three different levels (individual, group and community). Incremental cost per quality-adjusted life year gained measured by the tariffs of the EuroQol-5D questionnaire will be estimated. The implementation strategy is based on the "Consolidated Framework for Implementation Research", a set of discrete implementation strategies and an evaluation framework. DISCUSSION: EIRA study will determine the effectiveness and cost-effectiveness of a complex multiple risk intervention and will provide a better understanding of implementation processes of health promotion interventions in PHC setting. It may contribute to increase knowledge about the individual and structural barriers that affect implementation of these interventions and to quantify the contextual factors that moderate the effectiveness of implementation. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03136211 .Retrospectively registered on May 2, 2017. PMID- 30005707 TI - Effectiveness and safety of acupuncture for elderly overactive bladder population in Hong Kong: study protocol for a randomized controlled trial. AB - BACKGROUND: Overactive bladder (OAB) is defined as "urgency, with or without urge incontinence, usually with frequency and nocturia". Acupuncture is one of the most popular alternative treatment methods for OAB. Little established evidence is available to support the effectiveness of acupuncture for OAB. This study is a pioneer randomized, double-blinded, sham-controlled trial to assess the effectiveness and safety of acupuncture in the elderly population with overactive bladder in Hong Kong. METHODS/DESIGN: This is a randomized, double-center, patient and outcome assessor blinded, sham-controlled trial. The study sample size is 100 patients. Eligible subjects aged between 60 to 90 years old will be recruited into this study. All subjects will be randomly allocated into the active acupuncture group or sham acupuncture group in a 1: 1 ratio. Participants who are allocated into the active acupuncture group will receive a standardized 30-min real acupuncture treatment session for a total of 16 sessions on the top of standard routine care, whilst those who are randomized to the sham acupuncture arm will receive sham acupuncture in addition to standard routine care. Non penetrating needles will be utilized as sham acupuncture. The primary outcome measure is the 7-day voiding diary and the secondary outcome measures are urine nerve growth factor (NGF) level, the Incontinence Impact Questionnaire (IIQ-7), Urogenital Distress Inventory (UDI-6) and OAB Symptom Score (OABSS). All outcome measures will be collected at baseline, the end of treatment and 3 months after treatment completion. DISCUSSION: The objectives of this study include (1) to evaluate the effectiveness and safety of acupuncture treatment in patients with OAB on reduction in the frequency of incontinence episodes as derived from a 7 day voiding diary, (2) to evaluate whether acupuncture treatment could improve subjective symptoms in patients with OAB and (3) to examine the feasibility of using NGF as a biomarker for overactive bladder and test correlation with the effectiveness of acupuncture intervention. The finding of this study will provide preliminary evidence on the effectiveness and safety of acupuncture for treatment of OAB. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-INR-16010048 . Registered on 29 Nov 2016. PMID- 30005708 TI - Associations between symptoms of attention-deficit/ hyperactivity disorder and life satisfaction in medical students: the mediating effect of resilience. AB - BACKGROUND: Research on symptoms of attention-deficit/hyperactivity disorder (ADHD) in medical students is rather scant. Studying the disorder in this population, especially its associations with positive psychological constructs can further the understanding of mental health in future physicians. The objectives of the present study were to investigate the prevalence of ADHD symptoms in medical students, to examine the relationships between ADHD symptoms and life satisfaction, and to explore the mediating role of resilience on the associations. METHODS: This cross-sectional study was carried out at one medical university in China, in June 2016. Self-reported questionnaires consisting of Adult ADHD Self-Report Scale (ASRS), Wender Utah Rating Scale (WURS), Conner Davidson Resilience Scale (CD-RISC), Satisfaction With Life Scale (SWLS), and socio-demographic characteristics, were distributed to the students. Hierarchical linear regression analyses were used to examine the effects of ADHD symptoms on life satisfaction, and asymptotic and resampling strategies were used to explore the mediating role of resilience. RESULTS: A total number of 521 medical students became final subjects. Based on the cutoffs of the scales, 1.54% of the medical students were highly likely to have ADHD, and 6.91% of the students were likely to have ADHD. Only inattention was negatively correlated with life satisfaction in the students. Resilience functioned as a mediator in the relationship between inattention and life satisfaction. CONCLUSIONS: The prevalence of ADHD symptoms among Chinese medical students could be relatively high. Inattention is significantly related to life satisfaction among the students. Early identification of medical students with ADHD symptoms should be warranted. Resilience intervention programs might be undertaken to enhance life satisfaction in medical students, especially for those with inattention symptoms. PMID- 30005710 TI - Development of rapid guidelines: 2. A qualitative study with WHO guideline developers. AB - BACKGROUND: Situations such as public health emergencies and outbreaks necessitate the development and publication of high-quality recommendations within a condensed timeframe. For example, WHO has produced examples of and guidance for the development of rapid guidelines (RGs). However, more information is needed to understand the experiences and perceptions of guideline developers. This is the second of a series of three articles addressing methodological issues around RGs. This study describes the perceptions and experiences of guideline developers at WHO about RGs. METHODS: We conducted interviews consisting of open- and closed-ended questions with guideline developers at WHO. Our analysis described the definition and rationale of RGs, the differences from regular guidelines with regard to timelines from topic definition until publication, barriers to identifying the evidence and the lack of a standard methodology to develop RGs. RESULTS: We interviewed 10 participants, the majority of whom were comfortable with the current WHO definition of RGs. Most stated that the rationale for developing RGs should be in response to new evidence about efficacy, cost-effectiveness or safety. Respondents differed with regards to the amount of time RGs should take. While the majority of participants agreed that guidelines should be based on a systematic review, this step in the process was considered the most time and resource intensive. Challenges for developing RGs included limited personnel and financial resources as well as the lack of evidence. Facilitators, in turn, that may improve RG development include additional financial and personnel resources as well as the use of virtual meetings. CONCLUSIONS: While our study suggests a strong need and rationale for the development of RGs, standardisation of timelines and guidance on panel composition, peer-review process, conduct of meetings and sources of permissible evidence require further research. PMID- 30005709 TI - Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy. AB - BACKGROUND: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. METHODS: All ART naive HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log rank test. RESULTS: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. CONCLUSIONS: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability. PMID- 30005711 TI - Association between Blood Glucose and cardiac Rhythms during pre-hospital care of Trauma Patients - a retrospective Analysis. AB - BACKGROUND: Deranged glucose metabolism is frequently observed in trauma patients after moderate to severe traumatic injury, but little data is available about pre hospital blood glucose and its association with various cardiac rhythms and cardiac arrest following trauma. METHODS: We retrospectively investigated adult trauma patients treated by a nationwide helicopter emergency medical service (34 bases) between 2005 and 2013. All patients with recorded initial cardiac rhythms and blood glucose levels were enrolled. Blood glucose concentrations were categorised; descriptive and regression analyses were performed. RESULTS: In total, 18,879 patients were included, of whom 185 (1.0%) patients died on scene. Patients with tachycardia (>=100/min, 7.0 +/- 2.4 mmol/L p < 0.0001), pulseless ventricular tachycardia (9.8 +/- 1.8, mmol/L, p = 0.008) and those with ventricular fibrillation (9.0 +/- 3.2 mmol/L, p < 0.0001) had significantly higher blood glucose concentrations than did patients with normal sinus rhythm between 61 and 99/min (6.7 +/- 2.1 mmol/L). In patients with low (<=2.8 mmol/L, 7/79; 8.9%, p < 0.0001) and high (> 10.0 mmol/L, 70/1271; 5.5%, p < 0.0001) blood glucose concentrations cardiac arrest was more common than in normoglycaemic patients (166/9433, 1.8%). ROSC was more frequently achieved in hyperglycaemic (> 10 mmol/L; 47/69; 68.1%) than in hypoglycaemic (<=4.2 mmol/L; 13/31; 41.9%) trauma patients (p = 0.01). CONCLUSIONS: In adult trauma patients, pre-hospital higher blood glucose levels were related to tachycardic and shockable rhythms. Cardiac arrest was more frequently observed in hypoglycaemic and hyperglycaemic pre-hospital trauma patients. The rate of ROSC rose significantly with rising blood glucose concentration. Blood glucose measurements in addition to common vital parameters (GCS, heart rate, blood pressure, breathing frequency) may help identify patients at risk for cardiopulmonary arrest and dysrhythmias. PMID- 30005712 TI - Development of rapid guidelines: 1. Systematic survey of current practices and methods. AB - BACKGROUND: Guidelines in the healthcare field generally should contain evidence based recommendations to inform healthcare decisions. Guidelines often require 2 years or more to develop, but certain circumstances necessitate the development of rapid guidelines (RGs) in a short period of time. Upholding methodological rigor while meeting the reduced development timeframe presents a challenge for developing RGs. Our objective was to review current practices and standards for the development of RGs. This is the first of a series of three articles addressing methodological issues around RGs. METHODS: We conducted a systematic survey of methods manuals and published RGs to identify reasons for the development of RGs. Data sources included existing guideline manuals, published RGs, Trip Medical Database, MEDLINE, EMBASE and communication with guideline developers until February 2018. RESULTS: We identified 46 guidelines that used a shortened timeframe for their development. Nomenclature describing RGs varied across organisations, wherein the United States Centers for Disease Control and Prevention produced 'Interim Guidelines', the National Institute for Health and Care Excellence in the United Kingdom developed 'Short Clinical Guidelines', and WHO provided 'Rapid Advice'. The rationale for RGs included response to emergencies, rapid increases in cases of a condition or disease severity, or new evidence regarding treatment. In general, the methods to assess the quality of evidence, the consensus process and the management of the conflict of interest were not always clear. While we identified another 11 RGs from other institutions, there was no reference to timeframe and reasons for conducting a RG. The three organisations mentioned above provide guidance for the development of RGs. CONCLUSIONS: There is a lack of standardised nomenclature and definitions regarding RGs and there is inconsistency in the methods described in manuals and in RG. It is therefore important that all RGs provide a detailed and transparent description of their methods in order for readers and end-users to be able to assess their quality and validate their findings. PMID- 30005713 TI - Adolescent deliveries in urban Cameroon: a retrospective analysis of the prevalence, 6-year trend and adverse outcomes. AB - OBJECTIVE: Adolescent deliveries remain a public health problem in most developing countries. The aim of our study was to determine the prevalence, trends and outcome of adolescent deliveries in an urban setting in Cameroon. We carried out a retrospective register analysis over a 6-year period (January 2010 December 2015) at the Saint Albert Le Grand hospital Douala. RESULTS: The overall prevalence of adolescent deliveries was 8.2% (662 out of 8056). There was a significant decrease over the 6-year period (p-trend: < 0.05). Adolescents were at higher risk of preterm deliveries (gestational age < 37 weeks; odds ratio [OR], 1.7; 95% confidence interval [CI]; 1.3-2.2; p < 0.01): low birth weight (defined as birth weight < 2650 g, OR; 1.7, CI 1.4-2.2, p < 0.01) and asphyxia at 1st minute (OR, 1.5; 95% CI 1.1-2.2; p = 0.02). There was no difference in delivery outcomes between early and late adolescents. Our results suggest that the prevalence of adolescent deliveries is lower in urban settings. Adolescent deliveries are more likely to result in adverse fetal outcomes than adult deliveries. Measures directed towards the prevention of adolescent pregnancies should be implemented to reduce neonatal morbidity and mortality. PMID- 30005714 TI - CART cells are prone to Fas- and DR5-mediated cell death. AB - Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3zeta, CD28 or 4-1BB. Importantly, the dominant role of the Fas and DR5 pathways in CART cell apoptosis is demonstrated by the significant rescue of CART cells upon in vivo blockade by combined Fas-Fc and DR5-Fc recombinant proteins. These observations are of crucial importance for the long-term persistence of CART cells and for the development of new applications including the combined TCR and CAR activation against solid tumors. PMID- 30005715 TI - Determinants of condom use among parous women in North Central and South Western Nigeria: a cross-sectional survey. AB - OBJECTIVES: There appears to be an increasing trend of condom use for pregnancy prevention among nulliparous and multiparous women in developing countries. Drawing from a cross-sectional survey involving 1227 women selected using a 3 stage cluster random sampling technique, the study examines the rates of condom use and its determinants among parous women in three states in North Central and South Western Nigeria. RESULTS: The rate of condom use among parous women was 13.8% and 23.2% among women using any form of contraceptives. After adjusting for confounding factors (religion and marital status, socioeconomic status and access to a health facility in the resident community), women aged 26-35 (AOR 2.7; CI 1.6-4.5), urban residence (AOR: 3.6; CI 2.2-5.8), no income (AOR: 2.7; CI 1.4 4.9), living in Ekiti State (AOR: 1.8; CI 1.2-2.8) and having a tertiary level of education (AOR: 4.5; CI 1.3-15.6) were the independent predictors of condom use. There is an increasing trend of condom use among parous women. PMID- 30005716 TI - Facility-wide Eradication of Corynebacterium bovis by using PCR-validated Vaporized Hydrogen Peroxide. AB - Facility-wide Corynebacterium bovis eradication was established using vaporized hydrogen peroxide (VHP) decontamination guided by C. bovis PCR surveillance. Prior attempts limited to culling PCR-positive mice and decontaminating affected rooms were ineffective in preventing recurrence. Because research aims often require trafficking to and use of procedural cores, a 12-mo facility-wide C. bovis PCR surveillance of 2064 specimens was performed and documented that, despite the presence of few clinically hyperkeratotic mice, 35% of the murine housing and use space was contaminated by C. bovis. The airways of IVC racks and air-handling units (AHU) provided a substantive niche for C. bovis survival, comparable to the primary enclosure, with 26% of murine and 22% of airway specimens PCR-positive for C. bovis. Equipment airway VHP sterilization in a 'flex room' required an 'active-closed' setting with the IVC rack connected to the AHU set to the VHP cycle, because 12% of specimens from 'static-open' VHP exposed airways remained PCR-positive for C. bovis, whereas 0% of specimens from active-closed VHP exposures were positive. VHP decontamination of the 29,931-ft2 facility was completed in 2 mo. C. bovis PCR testing of IVC exhaust plenums for 200 d in previously C. bovis-affected rooms confirmed that none of the 259 specimens tested were PCR-positive for the organism. Monthly surveillance identified a single recurrence during June 2017 (month 9), ensuring rapid culling of C. bovis PCR-positive mice and acute VHP decontamination of equipment and rooms. Molecular persistence of C. bovis was resolved in procedural and personnel areas, and no murine or housing specimens tested C. bovis PCR-positive during study months 11 and 12. Furthermore, since the conclusion of the 12-mo study, none of the 452 additional murine, cell biologic, environmental, and monthly equipment surveillance specimens tested were C. bovis PCR-positive, documenting an 11-mo period of facility-wide C. bovis eradication to date. Study invalidation due to C. bovis can be avoided through PCR surveillance for the organism, immediate culling of PCR-positive mice, and acute VHP decontamination of affected areas. PMID- 30005717 TI - Quantitative Detection of Chicken and Turkey Contamination in Cooked Meat Products by ELISA. AB - Background: Concerns about the contamination of meat products with undeclared meats and new regulations for the declaration of meat adulterants have established the need for a rapid test to detect chicken and turkey adulteration. Objective: To address this need, Microbiologique, Inc. has developed an ELISA that can quantify the presence of chicken and turkey down to 0.1% (w/w) in cooked pork, horse, beef, goat, and lamb meats. Results: This chicken/turkey authentication ELISA has an analytical sensitivity of 0.000037% and 0.000048% (w/v) for cooked and autoclaved chicken, respectively, and an analytical range of quantitation of 0.025-2% (w/v), in the absence of other meats. The assay cross reacts with cooked duck and pheasant but does not demonstrate any cross reactivity with cooked pork, horse, beef, goat, and lamb meats, egg, or common food matrixes. Conclusions: The assay is rapid, can be completed in 70 min, and can detect a 0.1% level of meat adulteration. Highlights: The Microbiologique Cooked Chicken/Turkey ELISA can quantitate cooked chicken/turkey in the presence of pork, horse, chicken, goat, or sheep meat to 0.1% (w/w) and is not affected by common food matrixes. PMID- 30005719 TI - Efficacy and safety of CalliSpheres(r) drug-eluting beads transarterial chemoembolization in Barcelona Clinic Liver Cancer stage C patients. AB - This study aimed to investigate the efficacy and safety of drug eluting beads transarterial chemoembolization (DEB-TACE) treatment in Barcelona Clinic Liver Cancer (BCLC) stage C liver cancer patients. In 39 patients with BCLC stage C liver cancer, after the first cycle of DEB-TACE, 2 (5.1%) and 24 (61.5%) patients achieved complete response (CR) and partial response (PR) to give an overall objective response rate (ORR) of 66.7%. With respect to the second cycle of therapy, the ORR was higher in patients receiving DEB-TACE compared with cTACE (57.1% vs 11.1%). Post first cycle of DEB-TACE treatment, the percentages of abnormal albumin (ALB), total protein (TP), total bilirubin (TBIL) and alanine aminotransferase (ALT) worsened at 1 week and recovered at 1 month. The number of patients with abnormal aspartate aminotransferase (AST) did not increase at 1 week but elevated at 1 month. After the second cycle of DEB-TACE or cTACE treatment, no difference was observed between cTACE and DEB-TACE in terms of all adverse events (AEs) at all visits, and most of the AEs did not change after the second cycle in both groups. The most common AEs after the first and second treatment cycle were pain, fever, and nausea/vomiting. These results demonstrate that DEB-TACE offers patients with BCLC stage C liver cancer with a clinically active short-term treatment that is safe and relatively well-tolerated. PMID- 30005718 TI - Phytochemical Composition and Antioxidant Activity of Petals of Six Rosa Species from Iran. AB - Background: The petals of Rosa species are used in the food industry and various traditional medicinal products, but few studies exist on the phytochemical composition and antioxidant activity of petals of Rosa L. species grown in Iran. Objective: Phytochemical characteristics and antioxidant activity and some phenolic compounds of petals of six Rosa L. species were studied. Methods: Total phenolic content, total flavonoid content, and antioxidant activity were determined using Folin-Ciocalteu reagent, aluminum chloride method, ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays, respectively. An HPLC system was used for quantitative analysis of phytochemical compounds. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were performed among the variables analyzed using Minitab software. Also, heat maps were used to visualize phytochemical characteristics and antioxidant activity in each species using GraphPad Prism software. Results: The amount of total phenol content, total flavonoid content, and antioxidant activity were in the range of 25.13-52.01 mg gallic acid equivalents/g dry weight (DW), 0.61-0.82 mg quercetin equivalents/g DW, 11.47 20.93 umol Fe++/g DW (FRAP), and 31.66-74.44% (DPPH), respectively. The p coumaric acid (647.28 MUg/g DW) and chlorogenic acid (24.37-135.23 MUg/g DW) were found to be the most abundant phenolic compounds in the extracts of rose petals. The HCA and PCA revealed three distinct categories of species based on phytochemical composition and antioxidant activity. Conclusions: These results showed that phytochemical characteristics of different rose species widely correlated with species type and are promising sources of natural antioxidants beneficial for use in the food or pharmaceutical industries. Highlights: Iran is one of the main centers for genetic diversity of Rosa L. The petals of Rosa species are used in the food industry and various traditional medicinal products, but few studies exist on the phytochemical composition and antioxidant activity of petals of Rosa L. species grown in Iran. Antioxidant activity and phytochemical compound of Six Rosa L. species petals grown in Iran were studied. Phenolic compounds in petals of Rosa were analyzed by HPLC. The color parameters, amount of total phenolic, total flavonoids, antioxidant activity and some individual phenolic compounds were significantly variable amongst Rosa species. PMID- 30005720 TI - Development of a Method for Simultaneous Determination of Two Stilbenes and Four Anthraquinones from Polygonum Cuspidatum by RP-HPLC. AB - Background: Polygonum cuspidatum Sieb. et Zucc. (named Huzhang in China) is a traditional and popular Chinese medicinal herb used in removing jaundice, clearing heat-toxin, improving blood circulation, expelling stasis, dispelling wind and dampness, repelling phlegm, and suppressing cough. It is widely used in drug and functional food fields and distributed throughout the world, including in China, Japan, and North America. Objective: To control the quality of Polygonum cuspidatum, an effective, reliable, and simple method for simultaneous determination of two stilbenes (polydatin, resveratrol) and four anthraquinones (emodin, physcion, rhein, and anthraglycoside B) was developed and validated for the first time in this study by reversed-phase HPLC (RP-HPLC). Methods: Separation was carried out on Agilent C18 column (250 * 4.6 mm I.D., 5 MUm) with acetonitrile and 0.10% aqueous phosphoric acid as mobile phase and gradient elution at a flow rate of 0.8 mL/min. Detection was conducted with mobile wavelength at 30 degrees C. Results: Good validation of the method including linearity, precision, repeatability, and recovery was performed. The contents of the studied analytes are significantly different, and resveratrol and rhein in particular existed in greater fluctuation among the samples. Conclusion: A simple, reliable, and sensitive method has been successfully established and applied to the analysis for simultaneous determination of the target compounds in 11 batches of samples. Highlights: Separation and quantitative analysis of two stilbenes and four anthraquinones from P. cuspidatum were developed by RP-HPLC. This method is convenient, sensitive, and accurate and can provide a reliable basis for further applications of P. cuspidatum in drug or food fields. PMID- 30005721 TI - Invasive Basal Cell Carcinoma of the Skin Treated Successfully with Vismodegib: A Case Report. AB - INTRODUCTION: Basal cell carcinoma (BCC) is the most common skin cancer. It is primarily a local disease, and it very rarely causes metastatic disease. Chemotherapeutic agents had limited success in management of metastatic disease until the introduction of vismodegib. In this case report, we describe the presentation of a metastatic BCC that was not amenable to surgical resection or local treatment options and was treated successfully with vismodegib. CASE PRESENTATION: A 69-year-old white man was referred to our surgical clinic for evaluation of an erosive left shoulder lesion. Biopsy in the clinic showed BCC with evidence of metastases on positron emission tomography-computed tomography scan. Tumors had invaded multiple bony structures and multiple organs, making surgical resection not an option. The decision was made to treat the patient with vismodegib. At 1-year follow-up, the patient's left shoulder lesion had improved with no evidence of metabolically active distant metastasis. DISCUSSION: Although BCC is the most common skin cancer, it is usually a local disease and treated with local measures. Metastatic BCC is extremely rare, and in cases when surgical resection or local radiation are not viable options, chemotherapeutic agents typically offer very limited improvement. Vismodegib is an oral selective sonic hedgehog pathway inhibitor that shows benefit in patients with locally advanced or metastatic disease. PMID- 30005722 TI - The Unmet Challenge of Medication Nonadherence. AB - Medication nonadherence for patients with chronic diseases is extremely common, affecting as many as 40% to 50% of patients who are prescribed medications for management of chronic conditions such as diabetes or hypertension. This nonadherence to prescribed treatment is thought to cause at least 100,000 preventable deaths and $100 billion in preventable medical costs per year. Despite this, the medical profession largely ignores medication nonadherence or sees it as a patient problem and not a physician or health system problem. Much of the literature on nonadherence focuses on barriers to adherence, with the assumption that appropriate adherence is the normal course of events and nonadherence is an aberration. This approach minimizes and oversimplifies the problem. It is not easy for humans to change their behavior, even for what many physicians see as a minor change such as taking prescription medications. Improving medication adherence has not been well studied, but a Cochrane review shows that multifactorial interventions are more effective. In at least one integrated health care system, Kaiser Permanente Northern California, a combination of approaches centered on the electronic health record has improved medication adherence rates to above 80%. Using similar elements would be feasible in other health care systems but would require motivation and planning. Effective change will not happen until key players decide to take on this challenge and reimbursement systems are changed to reward health systems that improve medication adherence and chronic disease control. PMID- 30005724 TI - Pigments and Medicine. PMID- 30005723 TI - Impact of Body Mass Index on Postconcussion Symptoms in Teenagers Aged 13 to 18 Years. AB - CONTEXT: Adolescent obesity and sports-related concussion are rising in prevalence, yet there is minimal research exploring the relationship between these two conditions. OBJECTIVE: To assess the impact of body mass index (BMI) percentile on duration of recovery and reported symptoms after sports-related concussion in adolescents. DESIGN: Retrospective chart review at a regional concussion program located at an academic medical center. Medical records of all patients aged 13 to 18 years treated from March 2006 through January 2012 were reviewed. Two hundred fifty-two patients met the inclusion criteria of sports related concussion and having BMI data. MAIN OUTCOME MEASURES: Outcome variables included reported emotional symptoms, sleep-related symptoms, physical symptoms (headache), and time to recovery after a concussion. Explanatory variables in this analysis were BMI percentile and sex. RESULTS: More male patients were obese and overweight than were females (42% vs 27%, p = 0.02). There was no statistically significant difference in recovery time between obese and overweight patients and others. Obese and overweight patients were more likely than healthy-weight patients to report symptoms of irritability (p = 0.05) and impulsivity (p = 0.01), and less likely to report headache (p = 0.03). CONCLUSION: After concussion, irritability and impulsivity may be more likely than headaches in overweight and obese patients. There was no difference in recovery time between obese and healthy-weight teens. These findings may have importance in the evaluation, treatment, and anticipatory guidance of patients with concussions. PMID- 30005725 TI - Pyeloduodenal Fistula in Xanthogranulomatous Pyelonephritis: A Series of Two Cases. AB - Xanthogranulomatous inflammation, characterized by destruction and replacement of tissues with chronic inflammatory cells, including foamy histiocytes and hemosiderin-laden macrophages, is uncommon. In patients with xanthogranulomatous pyelonephritis, inflammation may extend from the kidney to the overlying duodenum, creating a pyeloduodenal fistula that further complicates medical and surgical management. We present two cases with recurrent kidney infections who each ultimately received a nephrectomy and repair of their duodenal fistula. PMID- 30005727 TI - Image Diagnosis: Plummer-Vinson Syndrome: An Unusual Cause of Dysphagia. PMID- 30005728 TI - Cathartic Poetry: Healing Through Narrative. AB - This article explores the efficacy of writing and reading poetry as a means to help people living with chronic pain to explore and express their narratives in their own unique way. Throughout our narrative we have interwoven poems from Eugene Feig, one of the authors of this article. His poetry is sent out almost weekly to the members of our pain support group as a method of sharing his own experiences of living with pain, as well as to support and to inspire hope in others. The style of poetry we are presenting is that of a person who is not knowledgeable about poetry in a formal sense but who has an understanding of how it has helped him learn to live with his own chronic pain and suffering. These poems are the author's expression of the meaning of living with chronic pain for over 20 years. This article is a philosophical hermeneutic conversation about pain and poetry. PMID- 30005726 TI - Relapse Prevention in Ulcerative Colitis by Plant-Based Diet Through Educational Hospitalization: A Single-Group Trial. AB - CONTEXT: No known published study has focused on a plant-based diet (PBD) in the treatment of ulcerative colitis (UC). OBJECTIVE: To investigate relapse prevention in UC after consumption of a PBD during educational hospitalization in Japan. DESIGN: Prospective study of patients with mild UC or UC in remission who did not need immediate treatment. A PBD and dietary guidance were provided during a two-week hospitalization. MAIN OUTCOME MEASURES: The primary end point was relapse (a flare-up that required more aggressive treatment) during the follow-up period. Kaplan-Meier analysis was used to calculate the cumulative relapse rate. Secondary end points were immediate improvement in symptoms or laboratory data during hospitalization and a chronologic change in the PBD score, which evaluated adherence to the PBD. RESULTS: Sixty cases were studied: 29 initial episode cases and 31 relapse cases. Of these, 31 involved proctitis; 7, left-sided colitis; and 22, extensive colitis. Thirty-seven patients were receiving medication; 23 were not. The median age was 34 years; median follow-up was 3 years 6 months. Eight cases relapsed during follow-up. The cumulative relapse rates at 1, 2, 3, 4, and 5 years of follow-up were 2%, 4%, 7%, 19%, and 19%, respectively. Most patients (77%) experienced some improvement such as disappearance or decrease of bloody stool during hospitalization. The short- and long-term PBD scores after the hospitalization were higher than baseline PBD scores. CONCLUSION: Relapse rates after educational hospitalization providing a PBD were far lower than those reported with medication. Educational hospitalization is effective at inducing habitual dietary changes. PMID- 30005729 TI - Image Diagnosis: Allergic Fungal Sinusitis. PMID- 30005730 TI - Improving the Insulin Pump Initiation Process for Pediatric Patients with Type 1 Diabetes through Application of Lean Quality Improvement Methods. AB - CONTEXT: Our pediatric diabetes center initiated insulin pump therapy for more than 250 patients with type 1 diabetes in 2014, but onboarding was inefficient. OBJECTIVE: To decrease time from the decision to initiate pump therapy to the ambulatory encounter after pump start (lead time) for new pump users from 132.5 days to less than 110 days within 5 months. DESIGN: Define, Measure, Analyze, Improve, Control method. We identified key problems: Long wait for training classes, unclear metrics, complicated scheduling, and nonstandardized processes. We then implemented 17 changes, including shortened classes, increased class offerings and space, clarified metrics, built a reporting dashboard, designated and cross-trained staff, created appeals letter templates, and educated clinicians. At project conclusion, we established a reaction plan if the processes were not performing as designed. MAIN OUTCOME MEASURES: Outcomes of pump orders placed before and after improvements were implemented. RESULTS: During this project, 229 patients initiated the pump start process. Median lead time decreased from 132.5 to 98.5 days (p = 0.007). Patients with lead time under 110 days increased from 37% to 60% (p = 0.001). There were 31 pump nonstarters, with no significant association between group and whether the patient was a starter or nonstarter (p = 0.58). Nonstarters had a longer diabetes duration (median = 3.43 vs 2.05 years, p = 0.001). CONCLUSION: Project goals were met. A high proportion of patients not starting pump therapy was discovered, but this was not affected by the project. We implemented further changes and a process monitoring system. PMID- 30005731 TI - Obstructive Uropathy and Sepsis Caused by an Inguinoscrotal Bladder Hernia: A Case Report. AB - INTRODUCTION: Inguinoscrotal bladder hernia is a very rare pathology, occurring in up to 4% of all inguinal hernias in the general population. We present a case of an inguinoscrotal bladder hernia causing obstructive uropathy and sepsis. CASE PRESENTATION: A 59-year-old obese man presented with left-sided flank and abdominal pain that radiated to his left groin. On initial clinical examination, there was no evidence of an inguinal hernia. A computed tomography scan revealed a left inguinoscrotal bladder hernia with associated left-sided upper tract urinary obstruction. Two days later, his clinical course deteriorated and he developed sepsis of urinary origin. The patient underwent multiple procedures, including left ureteral stent placement, left percutaneous nephrostomy tube placement, and left inguinal herniorrhaphy. As of this writing, he remains with a left nephrostomy tube in place because of persistence of left hydroureteronephrosis, but he is doing well clinically. DISCUSSION: We highlight the fact that in cases where there is upper urinary tract obstruction and sepsis, it is prudent to first stabilize the patient via decompression of the upper urinary tract and antibiotics before herniorrhaphy. This report illustrates a unique case of this interesting pathology, as well as the multiple complications and pitfalls that may arise from it. PMID- 30005732 TI - The Effect of Abnormal Vitamin D Levels in Athletes. AB - Vitamin D is a lipophilic prohormone integral to musculoskeletal, autoimmune, oncologic, cardiovascular, and mental health. Of particular importance to the orthopedic surgeon is the role of vitamin D in the regulation of bone mass, muscle strength, and physical performance. Although vitamin D-related skeletal pathologies are rare in industrialized nations, emerging research in the field has shown that most American adults have inadequate levels of vitamin D. Even among athletes, there is a high prevalence of vitamin D deficiency, which may place competitors at risk of stress fractures, illness, and delayed muscle recovery. Adequately identifying vitamin D-deficient individuals in need of supplementation is important to help optimize performance and prevent future injury. The goal of this review is to describe the epidemiology of vitamin D deficiency and its effects on athletic performance and musculoskeletal health. Future double-blinded studies of vitamin D supplementation in athletes are needed. We recommend treating athletes who have insufficient or deficient vitamin D levels. PMID- 30005733 TI - Metastatic Angiosarcoma of the Scalp Presenting with Cystic Lung Lesions: A Case Report and Review of Cystic Lung Diseases. AB - INTRODUCTION: Angiosarcomas are rare, malignant vascular tumors that affect endothelial cells of blood vessels. Angiosarcomas most commonly occur on the scalp or face of elderly individuals and are highly aggressive, with a 5-year survival rate below 15%. Cutaneous angiosarcomas often metastasize to the lung, where they can present with cystic lesions, solid lesions, pneumothorax, and/or hemothorax. CASE PRESENTATION: We report the case of an 83-year-old woman who presented with a scalp lesion, which was initially thought to be caused by scalp trauma but was later found to be an angiosarcoma. She initially refused any therapy for the tumor. She returned several months later with a cough and shortness of breath and was found to have multiple pulmonary cysts. She was treated with paclitaxel, but her tumor did not respond to the therapy and she died 2 months later. DISCUSSION: We discuss the common presentation of cutaneous angiosarcomas and their tendency to metastasize to the lung and present as cystic lesions. We also review the common conditions that can cause cystic changes in the lungs. PMID- 30005734 TI - Endogenous Group A Streptococcal Endophthalmitis in a Healthy 42-Year-Old Man: A Case Report. AB - INTRODUCTION: Endogenous endophthalmitis is a rare condition that is caused by hematogenous spread of bacteria or fungi and is usually seen in patients with predisposed medical conditions. We are reporting an unusual case of group A streptococcal infection causing endogenous endophthalmitis and septic arthritis in a healthy 42-year-old man. CASE PRESENTATION: A previously healthy 42-year-old man presented to the Emergency Department with chills, fever, left wrist pain, left eye pain, and vision loss. Owing to the acute onset of the septic arthritis and the patient's bandemia, the Ophthalmology Department was consulted for suspicion of endophthalmitis. Blood cultures, left wrist synovial fluid cultures, and vitreous cultures grew group A streptococcus. An incision and drainage of the left wrist was performed, and intravitreal injection of vancomycin was given. The patient's vision was responsive only to light on discharge from the hospital. The patient underwent a left eye evisceration 2 months later. DISCUSSION: Endophthalmitis provides a difficult diagnostic and therapeutic challenge. However, even with prompt treatment, visual outcomes may be poor. PMID- 30005735 TI - Inconsistent relation of nonlinear heart rate variability indices to increasing vagal tone in healthy humans. AB - BACKGROUND: Prior work has found that linear heart rate variability (HRV) indices do not accurately reflect cardiac vagal control, and nonlinear indices of HRV have been proposed as alternative tools that may better capture cardiac vagal effects. We used progressive low dose atropine to induce changes in cardiac vagal tone to test the hypotheses that nonlinear HRV indices accurately reflect cardiac vagal control, and that their changes in response to low dose atropine correlate with those in RR interval. METHODS: Changes in RR interval and HRV indices during intravenous injections of saline (control) and 6 cumulative doses of atropine (from 1.4 to 7.2 MUg/kg) during controlled breathing at 15 breaths per minute were assessed in 14 young healthy individuals. RESULTS: As expected, low dose atropine increased average RR interval (vagotonic effect). There was no strong association between vagotonic changes in RR interval and the majority of nonlinear HRV indices, either within or among subjects. CONCLUSIONS: These data suggest an inconsistent relationship between responses of nonlinear HRV indices and RR interval to changes in cardiac vagal tone. Therefore, nonlinear HRV indices may not be reliable indices of cardiac vagal control in healthy humans. PMID- 30005736 TI - Effect of electroacupuncture on porcine cardiac excitability induced by left stellate ganglion stimulation. AB - Augmentation of cardiac sympathetic tone has been shown to induce ventricular arrhythmias. Acupuncture has been clinically used to treat hypertension, angina pectoris, and atrial arrhythmias. However, the effects of acupuncture on ventricular electrophysiology and autonomic tone remain unknown. We hypothesized that acupuncture attenuates cardiac excitability and corrects the imbalance of autonomic tone during sympathetic hyperactivity. Fourteen Yorkshire pigs were randomized to electroacupuncture (EA, 2 Hz, 0.3-0.5 mA, 0.5 ms duration) or control (without EA) groups. Animals were sedated with terazol. General anesthesia consisted of isoflurane and fentanyl during surgical preparation and was transitioned to alpha-chloralose during experimental protocols. Through a median sternotomy, the heart was exposed and fitted with an elastic epicardial 56 electrode sock. Cardiac excitability was measured via activation recovery interval (ARI) and dispersion of repolarization (DOR) while autonomic balance was evaluated by heart rate variability (HRV) power spectrum analysis at baseline and during left stellate ganglion stimulation (LSS) with and without EA delivered at P 5-6 acupoints. 30-min of EA did not alter the baseline ARI and DOR, but significantly suppressed cardiac excitability during LSS through attenuation of ARI shortening (EA 2.1 +/- 0.3% vs. control 5.2 +/- 0.7%, P < 0.05) and DOR (EA 74.3 +/- 26.9% vs., control 110.1 +/- 22.9%, P < 0.05). EA significantly attenuated the increase in LF/HF (EA 0.6 +/- 0.1 vs. control 1.1 +/- 0.2, P < 0.05). In conclusion, EA reduces the cardiac excitability induced by LSS through correction of cardiac sympathovagal balance. This study provides mechanistic insights underlying cardiac neuromodulation of EA during sympathoexcitation. PMID- 30005737 TI - Heart rate variability in individuals with Down syndrome - A systematic review and meta-analysis. AB - INTRODUCTION: Down syndrome (DS) results in many changes, including dysfunction in cardiac autonomic modulation. Heart rate variability (HRV) analysis evaluates the autonomic function and it is a predictor of adverse cardiovascular events. OBJECTIVE: To present results of a systematic review and a meta-analysis about heart rate variability in individuals with DS. METHOD: A systematic review was performed on PubMed, PubMed Central and Web of science databases. We included articles that exhibited all the terms: "Down Syndrome", "heart rate variability", "autonomic nervous system", "autonomic dysfunction" and "cardiac autonomic modulation". We conducted the meta-analysis to compare "DS" to "controls" during rest. Random effects models were used, as were appropriate tests for heterogeneity. RESULTS: From 271 studies, 13 were included in our review. These are conducted with volunteers from a wide age range, of either gender, and not taking medications. Meta-analysis displayed that there were no significant differences between the groups at rest, except the RMSSD, which revealed a significant (Z = -2.80, p = 0.005) main effect (Hedge's g = -0.55, 95% CI [-0.93; -0.16]), indicating difference in individuals with DS compared with controls. CONCLUSION: There is autonomic dysfunction in individuals with DS, which may or may not be expressed at rest, but it is usually demonstrated in an autonomic task. Meta-analysis specified that there was no significant alteration between DS and the controls during rest, except RMSSD index which was lower in DS than controls. PROSPERO: CRD42017068647. PMID- 30005738 TI - Impaired pupillary control in "schizophrenia-like" WISKET rats. AB - Patients with schizophrenia show impairments in autonomic regulation, including pupillomotor control. The aim of this study was to explore the changes of pupillary light reflex in a new substrain (WISKET) with several schizophrenia like alterations. Male WISKET rats housed individually (for four weeks) and treated with ketamine (for 3 * 5 days) after weaning and naive group-housed Wistar rats (controls) were involved in the study. The pupillary light reflex was studied in two series after sedation (diazepam) or anesthesia (chloral hydrate). Video recordings were evaluated with custom made video analyzer software. Several significant changes were observed between the two groups: the initial and minimum pupil diameters were greater, the degree of the constriction was lower, and the flatness of the curve and the total duration of constriction were shorter in the sedated WISKET rats. No other pupillary parameters (latency, amplitude and redilation) showed significant alterations. Chloral hydrate anesthesia prolonged the constriction and redilation processes compared to the sedated animals, and diminished the differences between the groups. In conclusion, WISKET rats showed disturbances in the pupillary light reflex, suggesting a general shift of autonomic balance towards a sympathetic predominance. The results provide further evidence to support the validity of WISKET rats as a complex, chronic animal model of schizophrenia. PMID- 30005739 TI - Metabolic syndrome impact on cardiac autonomic modulation and exercise capacity in obese adults. AB - : Obesity is often associated with increased risk of cardiometabolic morbidities and mortality. However, evidence shows that some obese individuals are more likely to develop such risk factors early in life, including those with Metabolic Syndrome (MetS). Whether the presence of MetS in obese people impairs cardiac autonomic modulation (CAM) remains to be investigated. METHODS: Cross-sectional study. Sixty-six subjects were classified as normal-weight (NW, n = 24) or obese (BMI >= 30 kg.m-2): metabolically healthy (MHO, n = 19) vs unhealthy (MUHO, n = 23: NCEP/ATPIII-MetS criteria). Body composition (bioimpedance), metabolic (glucose-insulin/lipid) and inflammatory profiles were determined. Linear and nonlinear heart rate variability (HRV) indices were computed at rest and during the submaximal six-minute step test (6MST). Blood pressure (BP) and metabolic and ventilatory variables were assessed (oxygen uptake, VO2; carbon dioxide production, VCO2; minute ventilation, VE) during the 6MST and the maximal cardiopulmonary exercise testing (CPX). RESULTS: All groups reached the same 6MST intensity (VO2 ~ 80% and HR ~ 87% of CPX peak values). Both obese groups, independently of MetS, presented higher BP and lower maximal VO2 than NW. However, HRV differed between groups according to MetS at rest and during exercise: MUHO had lower meanRRi and SD1 than NW and lower RMSSD and pNN50 than MHO at rest; during exercise, the lowest SDNN, TINN, SD1 and Shannon entropy were observed for MUHO. Significant correlations were found between MetS, insulin resistance and HRV indices; and between insulin resistance and aerobic capacity (VO2peak). CONCLUSION: Obesity per se impairs aerobic-hemodynamic responses to exercise. However, MetS in obese young adults negatively impacts overall HRV, parasympathetic activity and HRV complexity. PMID- 30005741 TI - Effects of caveolae depletion and urothelial denudation on purinergic and cholinergic signaling in healthy and cyclophosphamide-induced cystitis in the rat bladder. AB - Cholesterol rich membrane invaginations, caveolae, have important roles in various cellular activities, one of them being signal transduction. This signaling pathway seems to be affected during various bladder disorders and the current study aimed to elucidate the plausible involvement of caveolae mediated signal transduction during cyclophosphamide induced cystitis. Furthermore, the urothelial cholinergic part of ATP-evoked contractions and its possible link to caveolae were investigated. Cholinergic, as well as purinergic, contractile responses in rat urinary bladders were examined using a classic organ bath set-up with full-thickness strip preparations or a whole bladder model that enabled luminal administration of substances. Furthermore, sub groups with and without urothelium were examined. The expression of caveolin-1 was also tested using western blot and immunofluorescence. Caveolae cholesterol depletion by methyl beta-cyclodextrin entailed a significant decrease of ATP-evoked bladder contractility. Interestingly, after muscarinic blockade the ATP induced contractions were significantly reduced in the same manner. Furthermore, this atropine-sensitive part of ATP-evoked responses was absent in denuded as well as inflamed bladders. A tendency towards a reduced expression of caveolin-1 was observed in rats with experimental cystitis. The cholinergic part of ATP-induced contractile responses seemed to be affected by urothelium denudation as well as caveolae depletion. Removing one of these structures nullifies the effect of the other, suggesting an important interaction between the urothelium and the caveolar structures. These effects are absent in inflamed animals and might be one pathophysiological aspect behind BPS/IC. PMID- 30005740 TI - S. Typhimurium challenge in juvenile pigs modulates the expression and localization of enteric cholinergic proteins and correlates with mucosal injury and inflammation. AB - The cholinergic system plays a central role in regulating critical gastrointestinal functions, including motility, secretion, barrier and immune function. In rodent models of acute, non-infectious gastrointestinal injury, the cholinergic system functions to inhibit inflammation; however, during inflammation local expression and regulation of the cholinergic system is not well known, particularly during infectious enteritis. The objective of this study was to determine the intrinsic expression of the enteric cholinergic system in pig ileum following an acute challenge with Salmonella enterica serovar Typhimurium DT104 (S. Typhimurium). At 2 d post-challenge, a three-fold reduction in ileal acetylcholine (ACh) levels was observed in challenged animals, compared with controls. Ileal acetylcholinesterase (AChE) activity was decreased (by four fold) while choline acetyltransferase (ChAT) expression was increased in both the ileum and mesenteric lymph nodes. Elevated ChAT found to localize preferentially to mucosa overlying lymphoid follicles of the Peyers patch in challenged pigs, with more intense labeling for ChAT in S. Typhimurium challenged pigs compared to controls. Ileal mRNA gene expression of muscarinic receptor 1 and 3 was also increased in challenged pigs, while muscarinic receptor 2 and the nicotinic receptor alpha 7 subunit gene expression were unaffected. A positive correlation was observed between ChAT protein expression in the ileum, rectal temperature, and histopathological severity in challenged animals. These data show that inflammation from S. Typhimurium challenge alters enteric cholinergic expression by down-regulating acetylcholine concentration and acetylcholine degrading enzymes while increasing acetylcholine synthesis proteins and receptors. Given the known anti-inflammatory role of the cholinergic system, the divergent expression of cholinergic genes may represent an attempt to limit tissue damage by preserving cholinergic signaling in the face of low ligand availability. PMID- 30005742 TI - Role of microglia M1/M2 polarisation in the paraventricular nucleus: New insight into the development of stress-induced hypertension in rats. AB - The lack of precise therapies for stress-induced hypertension highlights the need to explore the process of blood pressure changes. Studies have shown that neuroinflammation in the central nervous system is associated with hypertension, although the mechanisms remain elusive. Microglia, are known to play dualistic protective and destructive roles, representing logical but challenging targets for improving stress-induced hypertension. Here, as a model, we used rats with stress-induced hypertension, and found that a switch from an immunoregulatory (M2) to a pro-inflammatory (M1) dominant response occurred in microglia during development of stress-induced hypertension. Administration of minocycline, which is commonly used to inhibit microglial M1 polarisation, attenuated the increase in activated microglia and M1 microglial markers expression in the hypothalamic paraventricular nucleus of rats with stress-induced hypertension. To shed further light on development of stress-induced hypertension, we examined changes in pro- and anti-inflammatory cytokines, and found increased expression of M2 microglial markers during early pathogenesis. Based on these results, we propose the possibility that M1/M2 microglia are related to development of stress-induced hypertension. Consequently, a target molecule that skews M2 polarisation of microglia may be a beneficial therapy for this disease. PMID- 30005743 TI - Differential effects of lipophilic and hydrophilic statins on muscle sympathetic nerve activity in heart failure with preserved left ventricular ejection fraction. AB - Augmented sympathetic nerve activity is associated with heart failure with preserved left ventricular ejection fraction (HFpEF). Lipophilic statins reduce sympathetic nerve activity in patients with heart failure with reduced left ventricular ejection fraction. However, little is known about whether all types of statins, regardless of solubility, reduce sympathetic nerve activity in HFpEF. We evaluated the effect of atorvastatin, a lipophilic statin, and rosuvastatin, a hydrophilic statin, on muscle sympathetic nerve activity (MSNA) in HFpEF patients. This study was conducted as a prospective, randomized, open-label, crossover trial. Ten HFpEF patients with untreated hyperlipidemia participated in this study. Subjects were assigned to either the atorvastatin (lipophilic) or the rosuvastatin (hydrophilic) group with each drug administered for 8 weeks. Atorvastatin and rosuvastatin treatment resulted in a similar reduction in low density lipoprotein cholesterol (LDL-C) levels. There was no difference in the effect of either treatment on blood pressure, heart rate, or left ventricular function. Atorvastatin significantly decreased MSNA frequency compared with baseline (31.5 +/- 6.3 vs. 47.5 +/- 10.7 bursts/min, p < 0.01), but rosuvastatin had no effect on MSNA (40.9 +/- 7.3 bursts/min). MSNA was significantly lower in the atorvastatin group than rosuvastatin group (p < 0.05). However, the reduction in MSNA seen in either group did not correlate with the reduction in LDL-C. No significant differences were observed in either the baroreflex control of heart rate or MSNA between the two groups. These results suggest that lipophilic statins have a favorable effect on sympathetic nerve activity beyond lowering LDL C in HFpEF, but hydrophilic statins do not. PMID- 30005744 TI - Delayed orthostatic hypotension: Severity of clinical symptoms and response to medical treatment. AB - INTRODUCTION: Severity of orthostatic intolerance and the benefit of medical treatment in patients with delayed OH have not been elucidated. This study aimed to compare the symptom severity between classic and delayed OH and evaluate the efficacy of midodrine or pyridostigmine in patients with delayed OH. METHODS: This was an adjunctive study of previously reported randomized, open-label clinical trials evaluating the efficacy and safety of midodrine or pyridostigmine for classic OH. Seventeen patients with delayed OH were enrolled and also received midodrine (2.5 mg twice a day) or pyridostigmine (30 mg twice a day) alone or combined. Result of initial orthostatic vital sign and questionnaires were compared between the patients with delayed OH and previously reported 87 patients with classic OH. Delayed OH patients were followed up at 1 and 3 months post-treatment and the vital sign measurements and questionnaires were repeated during the follow-up period. RESULTS: Questionnaire scores regarding OH-related symptoms, depression and health-related quality of life (HRQOL) were comparable between the classic and delayed OH patients at baseline. OH-related symptoms and depression were significantly improved after 3 months of medical treatment. CONCLUSION: Patients with delayed OH exhibited orthostatic intolerance similar to that of classic OH. This study shows that these patients may benefit from medical treatment with either midodrine or pyridostigmine. PMID- 30005745 TI - Imbalance of cardiac autonomic nervous activity and increase of ventricular repolarization dynamicity induced by thyroid hormones in hyperthyroidism. AB - OBJECTIVE: To investigate the effects of thyroid hormones on cardiac autonomic nervous activity and ventricular repolarization dynamicity in hyperthyroidism. METHODS: 57 consecutive patients first diagnosed of hyperthyroidism (HT group) and 55 age and sex-matched healthy volunteers (Control group) from March 2012 to March 2013 in our center were enrolled. All subjects underwent standard 12-lead ECG and 24 h Holter recording at baseline. For the HT group, free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were monitored, and after they returned to normal all the examinations were redone. Heart rate variability (HRV) was assessed to determine the cardiac autonomic nervous activity. QTe/RR slope (QT end) and QTp/RR slope (QT apex) were calculated to evaluate the ventricular repolarization dynamicity. RESULTS: The HT patients before treatment had significantly higher LF/HF, QTe/RR slope and QTp/RR slope, and larger QT dispersion than the controls and after treatment (P < 0.05 for all). Correlation analyses revealed that FT3 was positively correlated with QTe/RR and QTp/RR slopes (r = 0.689 and 0.665 respectively, P < 0.001 for both), and similarly in FT4 (r = 0.665 and 0.668 respectively, P < 0.001 for both). While TSH was negatively correlated with QTe/RR and QTp/RR slopes (r = -0.660 and -0.680 respectively, P < 0.001 for both). FT3 and FT4 levels were independent predictors of QTe/RR slopes (P < 0.001, beta = 0.007; P = 0.017, beta = 0.001, respectively) and QTp/RR slopes (P < 0.001, beta = 0.008; P = 0.002, beta = 0.001, respectively). CONCLUSIONS: High-level thyroid hormones induce the cardiac sympathetic overactivity and increases ventricular repolarization dynamicity, and the impact can be attenuated after euthyroidism restored. PMID- 30005746 TI - Use and Misuse of Cost-Effectiveness Analysis Thresholds in Low- and Middle Income Countries: Trends in Cost-per-DALY Studies. AB - OBJECTIVES: To determine what thresholds are most often cited in the cost effectiveness literature for low- and middle-income countries (LMICs), given various recommendations proposed and used in the literature to date, and thereafter to assess whether studies appropriately justified their use of threshold values. METHODS: We reviewed the contents of the Tufts Medical Center Global Health Cost-Effectiveness Analysis Registry, a repository of all English language cost-per-disability-adjusted life-year averted studies indexed in PubMed. Our review included all catalogued cost-per-disability-adjusted life-year studies published from 2000 through 2015. We restricted attention to studies that investigated interventions in LMICs. RESULTS: Our analysis identified 381 studies (80%) focused on LMICs. Of these studies, 250 (66%) cited the World Health Organization's 1 to 3 times gross domestic product per capita threshold. A full text review of 60 (24%) of these articles (randomly selected) revealed that none justified use of this threshold in the particular country or countries studied beyond citing (generic) guideline documents. CONCLUSIONS: Cost-effectiveness analysis can help inform health care spending, but its value depends on incorporating assumptions that are valid for the applicable setting. Rather than rely on commonly used, generic economic thresholds, we encourage authors to use context-specific thresholds that reflect local preferences. PMID- 30005747 TI - Best Methods of Communicating Clinical Trial Data to Improve Understanding of Treatments for Patients with Multiple Sclerosis. AB - BACKGROUND: Patients' understanding of treatment risks and benefits is a prerequisite for shared decision making. Yet, patients with multiple sclerosis (MS) do not accurately understand treatment information provided in regular clinical consultations. OBJECTIVES: To identify the best methods of communicating clinical trial data to improve the understanding of treatments among patients with MS and to also examine the relationship between patients' understanding with decisional conflict, individual traits, and MS symptoms. METHODS: A repeated measures study was used. A sample of relapsing-remitting patients with MS was recruited from National Health Service sites in the United Kingdom. Patients were presented with hypothetical treatment risks and benefits from faux clinical trials. Treatments were communicated using absolute terms, relative terms, and numbers needed to treat/harm. The presence of baseline information with each method was also manipulated. Patients' understanding and conflict in treatment decisions were assessed. Individual traits and MS symptoms were also recorded. RESULTS: Understanding was better when treatments were communicated in absolute terms (mean 3.99 +/- 0.93) compared with relative terms (mean 2.93 +/- 0.91; P < 0.001) and numbers needed to treat/harm (mean 2.89 +/- 0.88; P < 0.001). Adding baseline information to all methods significantly improved understanding (mean 5.04 +/- 0.96) compared with no baseline information (mean 1.50 +/- 0.74; P < 0.001). Understanding was not related to conflict in treatment decisions (r = 0.131; P = 0.391). Numeracy, IQ, and cognitive impairments were significantly related to patients' understanding of treatments. CONCLUSIONS: Treatment risks and benefits should ideally be communicated using absolute terms, alongside baseline information. Patients with MS with low numeracy, low IQ, and reduced cognitive skills should be supported during treatment education. PMID- 30005748 TI - Effect of Level Overlap and Color Coding on Attribute Non-Attendance in Discrete Choice Experiments. AB - OBJECTIVE: The aim of this study was to test the hypothesis that level overlap and color coding can mitigate or even preclude the occurrence of attribute nonattendance in discrete choice experiments. METHODS: A randomized controlled experiment with five experimental study arms was designed to investigate the independent and combined impact of level overlap and color coding on respondents' attribute nonattendance. The systematic differences between the study arms allowed for a direct comparison of observed dropout rates and estimates of the average number of attributes attended to by respondents, which were obtained by using augmented mixed logit models that explicitly incorporated attribute non attendance. RESULTS: In the base-case study arm without level overlap or color coding, the observed dropout rate was 14%, and respondents attended, on average, only two out of five attributes. The independent introduction of both level overlap and color coding reduced the dropout rate to 10% and increased attribute attendance to three attributes. The combination of level overlap and color coding, however, was most effective: it reduced the dropout rate to 8% and improved attribute attendance to four out of five attributes. The latter essentially removes the need to explicitly accommodate for attribute non attendance when analyzing the choice data. CONCLUSIONS: On the basis of the presented results, the use of level overlap and color coding are recommendable strategies to reduce the dropout rate and improve attribute attendance in discrete choice experiments. PMID- 30005749 TI - Cost-Effectiveness Analysis in Telehealth: A Comparison between Home Telemonitoring, Nurse Telephone Support, and Usual Care in Chronic Heart Failure Management. AB - OBJECTIVES: To assess the cost effectiveness of home telemonitoring (HTM) and nurse telephone support (NTS) compared with usual care (UC) in the management of patients with chronic heart failure, from a third-party payer's perspective. METHODS: We developed a Markov model with a 20-year time horizon to analyze the cost effectiveness using the original study (Trans-European Network-Home-Care Management System) and various data sources. A probabilistic sensitivity analysis was performed to assess the decision uncertainty in our model. RESULTS: In the original scenario (which concerned the cost inputs at the time of the original study), HTM and NTS interventions yielded a difference in quality-adjusted life years (QALYs) gained compared with UC: 2.93 and 3.07, respectively, versus 1.91. An incremental net monetary benefit analysis showed ?7,697 and ?13,589 in HTM and NTS versus UC at a willingness-to-pay (WTP) threshold of ?20,000, and ?69,100 and ?83,100 at a WTP threshold of ?80,000, respectively. The incremental cost effectiveness ratios were ?12,479 for HTM versus UC and ?8,270 for NTS versus UC. The current scenario (including telenurse cost inputs in NTS) yielded results that were slightly different from those for the original scenario, when comparing all New York Heart Association (NYHA) classes of severity. NTS dominated HTM, compared with UC, in all NYHA classes except NYHA IV. CONCLUSIONS: This modeling study demonstrated that HTM and NTS are viable solutions to support patients with chronic heart failure. NTS is cost-effective in comparison with UC at a WTP of ?9000/QALY or higher. Like NTS, HTM improves the survival of patients in all NYHA classes and is cost-effective in comparison with UC at a WTP of ?14,000/QALY or higher. PMID- 30005750 TI - Economic Evaluation of the Hepatitis C Virus Treatment Extension to Early-Stage Fibrosis Patients: Evidence from the PITER Real-World Cohort. AB - OBJECTIVES: To conduct a cost-effectiveness analysis of two planning strategies of the second-generation direct-acting antiviral interferon-free regimens for the treatment of chronic hepatitis C virus infection. METHODS: A lifetime multicohort model comprised 8125 real-life patients enrolled in the PITER (Italian platform for the study of viral hepatitis) registry, implemented by the ISS (Istituto Superiore di Sanita). Two treatment planning strategies were compared: 1) policy 1-treat all patients regardless of the stage of fibrosis (F0-F4) with second generation direct-acting antivirals and 2) policy 2-treat patients at F3/F4 stage and those who are prioritized by the scientific guidelines first, and the remaining patients when they reach the F3 stage. Clinical outcomes and costs were evaluated by using a lifetime horizon Markov model and adopting the third-party payer perspective. Health outcomes were expressed in terms of quality-adjusted life-years (QALYs). A sensitivity analysis was run to explore first- and second order uncertainty and heterogeneity. An expected value of perfect information analysis was also conducted. RESULTS: Policy 1 exhibits an incremental cost effectiveness ratio of ?8,775/QALY gained and remains less than ?30,000/QALY in 94% of realizations produced by the Monte-Carlo simulation. Such a proportion increases to 97% when adopting a threshold of ?40,000/QALY gained. CONCLUSIONS: Moving from the urgency criterion to evidence-based escalating strategies when prioritizing the access to new anti-hepatitis C virus treatments is a good investment in health, whose affordability should be explored through context specific budget impact analyses. PMID- 30005752 TI - Personalized Mammography Screening and Screening Adherence-A Simulation and Economic Evaluation. AB - OBJECTIVE: Personalized breast cancer screening has so far been economically evaluated under the assumption of full screening adherence. This is the first study to evaluate the effects of nonadherence on the evaluation and selection of personalized screening strategies. METHODS: Different adherence scenarios were established on the basis of findings from the literature. A Markov microsimulation model was adapted to evaluate the effects of these adherence scenarios on three different personalized strategies. RESULTS: First, three adherence scenarios describing the relationship between risk and adherence were identified: 1) a positive association between risk and screening adherence, 2) a negative association, or 3) a curvilinear relationship. Second, these three adherence scenarios were evaluated in three personalized strategies. Our results show that it is more the absolute adherence rate than the nature of the risk adherence relationship that is important to determine which strategy is the most cost-effective. Furthermore, probabilistic sensitivity analyses showed that there are risk-stratified screening strategies that are more cost-effective than routine screening if the willingness-to-pay threshold for screening is below US $60,000. CONCLUSIONS: Our results show that "nonadherence" affects the relative performance of screening strategies. Thus, it is necessary to include the true adherence level to evaluate personalized screening strategies and to select the best strategy. PMID- 30005751 TI - Long-Term Health and Economic Value of Improved Mobility among Older Adults in the United States. AB - BACKGROUND: Mobility impairments have substantial physical and mental health consequences, resulting in diminished quality of life. Most studies on the health economic consequences of mobility limitations focus on short-term implications. OBJECTIVES: To examine the long-term value of improving mobility in older adults. METHODS: Our six-step approach used clinical trial data to calibrate mobility improvements and estimate health economic outcomes using a microsimulation model. First, we measured improvement in steps per day calibrated with clinical trial data examining hylan G-F 20 viscosupplementation treatment. Second, we created a cohort of patients 51 years and older with osteoarthritis. In the third step, we estimated their baseline quality of life. Fourth, we translated steps-per-day improvements to changes in quality of life using estimates from the literature. Fifth, we calibrated quality of life in this cohort to match those in the trial. Last, we incorporated these data and parameters into The Health Economic Medical Innovation Simulation model to estimate how mobility improvements affect functional status limitations, medical expenditures, nursing home utilization, employment, and earnings between 2012 and 2030. RESULTS: In our sample of 12.6 million patients, 66.7% were female and 70% had a body mass index of more than 25 kg/m2. Our model predicted that a 554-step-per-day increase in mobility would reduce functional status limitations by 5.9%, total medical expenditures by 0.9%, and nursing home utilization by 2.8%, and increase employment by 2.9%, earnings by 10.3%, and monetized quality of life by 3.2% over this 18-year period. CONCLUSIONS: Interventions that improve mobility are likely to reduce long-run medical expenditures and nursing home utilization and increase employment. PMID- 30005754 TI - Value of External Data in the Extrapolation of Survival Data: A Study Using the NJR Data Set. AB - BACKGROUND: Extrapolation of time-to-event data can be a critical component of cost-effectiveness analysis. OBJECTIVES: To contrast the value of external data on treatment effects as a selection aid in model fitting to the clinical data or for the direct extrapolation of survival. METHODS: We assume the existence of external summary data on both treatment and control and consider two scenarios: availability of external individual patient data (IPD) on the control only and an absence of external IPD. We describe how the summary data can be used to extrapolate survival or to assess the plausibility of extrapolations of the clinical data. We assess the merit of either approach using a comparison of cemented and cementless total hip replacement as a case study. Merit is judged by comparing incremental net benefit (INB) obtained in scenarios with incomplete IPD with that derived from modeling external IPD on both treatment and control. RESULTS: Measures of fit with the external summary data did not identify survival model specifications that best estimated INB. Addition of external IPD for the control only did not improve estimates of INB. Extrapolation of survival using the external summary data comparing treatment and control improved estimates of INB. CONCLUSIONS: Our case study indicates that summary data comparing treatment and control are more valuable than IPD limited to the control when extrapolating event rates for cost-effectiveness analysis. These data are best exploited in direct extrapolation of event rates rather than as an aid to select extrapolations on the basis of the clinical data. PMID- 30005753 TI - Time to Entry for New Cancer Medicines: From European Union-Wide Marketing Authorization to Patient Access in Belgium, Estonia, Scotland, and Sweden. AB - OBJECTIVES: First, to quantify the median time from European Union (EU)-wide approval to first use (launch) for a sample of cancer medicines and number of launches in Belgium, Estonia, Scotland, and Sweden as of June 2015. Second, to assess whether longer times to launch or lack of launches affected medicines with high or low expected additional clinical benefit. Third, to identify possible determinants of the probability of a cancer medicine to be launched. METHODS: Correlation between time to launch and a set of variables hypothesized to affect launch was tested using a complementary log-log model for a sample of 46 cancer medicines that obtained EU-wide marketing authorization between 2000 and 2014. RESULTS: In median, for a sample of 24 cancer medicines that obtained marketing authorization between 2010 and 2014, the expected time from EU-wide marketing authorization to first use of a medicine was shortest in Sweden, 3.1 months, followed by Scotland (9.3 months), Belgium (14.8 months), and Estonia (27.8 months). Median times to launch were longer for the entire sample of 46 cancer medicines that obtained marketing authorization between 2000 and 2014. In the all country model, medicines with shorter times to submission for reimbursement, local manufacturers headquarter (or local sales representative), and a Food and Drugs Administration priority review or a combination of expedited approval programs and medicines launched in Scotland and Sweden were associated with a higher hazard of launch. Longer times since EU-wide approval initially correlate with an increased hazard but as time further elapses they negatively affect the hazard of launch. CONCLUSIONS: Median times from marketing authorization to first use of cancer medicines were shorter for medicines launched between 2010 and 2014 versus sample-wide (2000-2014). In Estonia, more medicines than in the other countries were not yet launched at the end of the observation period. There was no correlation between Prescrire and European School of Medical Oncology Magnitude of Clinical Benefit Scale ratings of added clinical value and time to launch. PMID- 30005755 TI - Can Social Care Needs and Well-Being Be Explained by the EQ-5D? Analysis of the Health Survey for England. AB - BACKGROUND: The recent shift to an integrated approach to health and social care aims to provide cohesive support to those who are in need of care, but raises a challenge for resource allocation decision making, in particular for comparison of diverse benefits from different types of care across the two sectors. OBJECTIVE: To investigate the relationship of social care needs and well-being with a generic health status measure using multivariate regression. METHODS: We empirically compared responses to health and well-being measures and social care needs from a cross-sectional data set of the general population (the Health Survey for England). Multivariate regression analyses were conducted to examine whether social care needs measured by the Barthel index can be explained by health status as captured by the EuroQol five-dimensional questionnaire (EQ-5D) and two well-being measures-the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) and the General Health Questionnaire (GHQ-12). RESULTS: Our study found that poor overall scores for EuroQol visual analogue scale, EQ-5D index, GHQ-12, and WEMWBS indicated a need for social care. Investigation of the dimensions found that the EQ-5D dimensions self-care and pain/discomfort were statistically significantly associated with the need for social care. Two dimensions of the WEMWBS ("been feeling useful" and "had energy to spare") were statistically significantly associated with the Barthel index, but none of the GHQ-12 dimensions were. CONCLUSIONS: The results show that the need for social care, which is dependent on the ability to perform personal day-to-day activities, is more closely related to the EQ-5D dimensions than the well-being measures WEMWBS and GHQ-12. PMID- 30005756 TI - Informing a priori Sample Size Estimation in Qualitative Concept Elicitation Interview Studies for Clinical Outcome Assessment Instrument Development. AB - OBJECTIVE: Evidence-based recommendations for the a priori estimation of sample size are needed for qualitative concept elicitation (CE) interview studies in clinical outcome assessment (COA) instrument development. Saturation is described as the point at which no new data is expected to emerge from the conduct of additional qualitative interviews. STUDY DESIGN: A retrospective evaluation of 26 CE interview studies conducted with patients between 2006 and 2013 was completed to assess the point at which saturation of concept was achieved in each study. METHODS: For each of the 26 interview studies, saturation of symptom concepts was assessed by dividing the sample into quartiles and then comparing the number of responses elicited from the first 25% of participants to the next 25% of participants, from the first 50% of participants to the next 25% of participants, and then from the first 75% of participants to the last 25% of participants. The number of interviews required to achieve saturation was documented for each study and then summarized across studies. RESULTS: Findings indicate that 84% of symptom concepts emerged by the 10th interview, 92% emerged by the 15th interview, 97% emerged by the 20th interview, and 99% by the 25th interview. CONCLUSIONS: Results provide practical guidance for estimating the number of interviews that may be needed to achieve saturation in a qualitative CE interview study for COA instrument development; address an important gap in qualitative research for the development of COAs in the context of medical product development; and offer useful information for study design and implementation. PMID- 30005757 TI - What Characteristics of Nursing Homes Are Most Valued by Consumers? A Discrete Choice Experiment with Residents and Family Members. AB - OBJECTIVES: To generate a scoring algorithm weighted on the preferences of consumers for assessing the quality of care in nursing homes (i.e., aged care homes or institutions) in six key domains. METHODS: A discrete choice experiment was undertaken with residents of nursing homes (n = 126) or family member proxies (n = 416) in cases where severe cognitive impairment precluded resident participation. Analysis was undertaken using conditional and mixed logit regression models to determine preferences for potential attributes. RESULTS: The findings indicate that all six attributes investigated were statistically significant factors for participants. Feeling at home in the resident's own room was the most important characteristic to both residents and family members. Care staff being able to spend enough time with residents, feeling at home in shared spaces, and staff being very flexible in care routines were also characteristics identified as important for both groups. The results of the Swait-Louviere test rejected the null hypothesis that the estimated parameters between residents and family members were the same, indicating that data from these two groups could not be pooled to generate a single weighted scoring algorithm for the Consumer Choice Index-Six Dimension instrument. Preferences were therefore encapsulated to generate scoring algorithms specific to residents and family members. CONCLUSIONS: This study provides important insights into the characteristics of nursing home care that are most valued by consumers. The Consumer Choice Index Six Dimension instrument may be usefully applied in the evaluation, planning, and design of future services. PMID- 30005758 TI - Uncertainty and the Undervaluation of Services for Severe Health States in Cost Utility Analyses. AB - OBJECTIVES: To test the hypothesis that the "severity effect"-the preference for more than utility-maximizing expenditure on severe health states-may be the result of, or exacerbated by, the uncertainty associated with the chance of contracting the illness that causes the severe health state. METHODS: Survey respondents were asked to imagine that they will contract one of two illnesses and asked to allocate a budget between two insurance policies, each of which provides services for the treatment of one of the illnesses. A person's final health state varied with the amount of insurance purchased for the illness that occurred and therefore with the level of treatment. The relative cost of the two policies was altered and the selected levels of insurance compared with the levels that would be provided by a health authority that sought to maximize total utility or quality-adjusted life-years from its own budget. RESULTS: Respondents selected more than utility-maximizing insurance for protection against severe health states. A number of psychological factors that affect measurement under uncertainty do not affect utility as currently measured. This difference may explain the present results and also explain the "severity paradox" that personal preferences as presently measured imply less expenditure on severe health states than do "social preferences" for the treatment of strangers. CONCLUSIONS: Uncertainty alters preferences. Incorporating these preferences in decision making would result in greater spending on severe health states. PMID- 30005759 TI - Critical Analysis of Markov Models Used for the Economic Evaluation of Colorectal Cancer Screening: A Systematic Review. AB - BACKGROUND: The economic evaluation of colorectal cancer screening is challenging because of the need to model the underlying unobservable natural history of the disease. OBJECTIVES: To describe the available Markov models and to critically analyze their main structural assumptions. METHODS: A systematic search was performed in eight relevant databases (MEDLINE, Embase, Econlit, National Health Service Economic Evaluation Database, Health Economic Evaluations Database, Health Technology Assessment database, Cost-Effective Analysis Registry, and European Network of Health Economics Evaluation Databases), identifying 34 models that met the inclusion criteria. A comparative analysis of model structure and parameterization was conducted using two checklists and guidelines for cost effectiveness screening models. RESULTS: Two modeling techniques were identified. One strategy used a Markov model to reproduce the natural history of the disease and an overlaying model that reproduced the screening process, whereas the other used a single model to represent a screening program. Most of the studies included only adenoma-carcinoma sequences, a few included de novo cancer, and none included the serrated pathway. Parameterization of adenoma dwell time, sojourn time, and surveillance differed between studies, and there was a lack of validation and statistical calibration against local epidemiological data. Most of the studies analyzed failed to perform an adequate literature review and synthesis of diagnostic accuracy properties of the screening tests modeled. CONCLUSIONS: Several strategies to model colorectal cancer screening have been developed, but many challenges remain to adequately represent the natural history of the disease and the screening process. Structural uncertainty analysis could be a useful strategy for understanding the impact of the assumptions of different models on cost-effectiveness results. PMID- 30005760 TI - Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis. AB - BACKGROUND: Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted. OBJECTIVES: To conduct the first network meta-analysis simultaneously comparing all available drugs used in acromegaly treatment so as to provide more robust evidence in this field. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration recommendations (PROSPERO database under the registration number CRD42017059880). The electronic searches were conducted in PubMed (MEDLINE), Scopus, and Web of Science databases. Randomized controlled trials comparing any drug for the treatment of acromegaly head-to-head or versus placebo were included. Outcomes concerning the efficacy and safety of treatments were evaluated. The statistical analyses were performed using Aggregate Data Drug Information System version 1.16.8 (drugis.org, Groningen, The Netherlands). RESULTS: The initial search retrieved 2059 articles. Of these, 10 randomized controlled trials were included in a qualitative analysis and 7 in a quantitative analysis. The network meta analysis for the efficacy outcome (number of patients achieving insulinlike growth factor 1 control) showed that pegvisomant and lanreotide autogel were statistically superior to placebo (odds ratio [95% credible interval] 0.06 [0.00 0.55] and 0.09 [0.01-0.88]). No further differences were found. The probability rank indicated that pegvisomant and pasireotide have the highest probabilities (33% and 34%, respectively) of being the best therapeutic options. No major side effects were noted. CONCLUSIONS: Pegvisomant is still a good option for acromegaly treatment, but pasireotide seems to be a promising alternative. Nevertheless, other important key factors such as drug costs and effectiveness (real-world results) should be taken into account when selecting acromegaly treatment. PMID- 30005761 TI - Economic Burden of Cardiovascular Disease in Type 2 Diabetes: A Systematic Review. AB - BACKGROUND: Cardiovascular diseases (CVDs) constitute major comorbidities in type 2 diabetes mellitus (T2DM), contributing substantially to treatment costs for T2DM. An updated overview of the economic burden of CVD in T2DM has not been presented to date. OBJECTIVE: To systematically review published articles describing the costs associated with treating CVD in people with T2DM. METHODS: Two reviewers searched MEDLINE, Embase, and abstracts from scientific meetings to identify original research published between 2007 and 2017, with no restrictions on language. Studies reporting direct costs at either a macro level (e.g., burden of illness for a country) or a micro level (e.g., cost incurred by one patient) were included. Extracted costs were inflated to 2016 values using local consumer price indexes, converted into US dollars, and presented as cost per patient per year. RESULTS: Of 81 identified articles, 24 were accepted for analysis, of which 14 were full articles and 10 abstracts. Cardiovascular comorbidities in patients with T2DM incurred a significant burden at both the population and patient levels. From a population level, CVD costs contributed between 20% and 49% of the total direct costs of treating T2DM. The median annual costs per patient for CVD, coronary artery disease, heart failure, and stroke were, respectively, 112%, 107%, 59%, and 322% higher compared with those for T2DM patients without CVD. On average, treating patients with CVD and T2DM resulted in a cost increase ranging from $3418 to $9705 compared with treating patients with T2DM alone. CONCLUSIONS: Globally, CVD has a substantial impact on direct medical costs of T2DM at both the patient and population levels. PMID- 30005762 TI - Heterogeneity and Uncertainties Specific to Genome-Based Health Technological Assessments. PMID- 30005763 TI - A multigene test could cost-effectively help extend life expectancy for women at risk of hereditary breast cancer-Reply to letter to the editor by Petelin et al. PMID- 30005764 TI - CORRECTION. PMID- 30005765 TI - Editorial: Danger-associated molecular patterns in health and disease. PMID- 30005766 TI - Screening Mammography: Recommendations and Controversies. AB - Over the past several years, there have been numerous changes in the guidelines for screening mammography. Additionally, different societies have released guidelines with variance in the recommendations of age to initiate and frequency of imaging. The current recommendations as well as the importance of screening mammography for early detection and survival are discussed. PMID- 30005767 TI - Breast Cancer Genetics and Indications for Prophylactic Mastectomy. AB - As more genetic information becomes available to inform breast cancer treatment, screening, and risk-reduction approaches, clinicians must become more knowledgeable about possible genetic testing and prevention strategies, including outcomes, benefits, risks, and limitations. The aim of this article is to define and distinguish high- and moderate-risk breast cancer predisposition genes, summarize the clinical recommendations that may be considered based on the identification of pathogenic variants (mutations) in these genes, and indications for risk-reducing and contralateral prophylactic mastectomy. PMID- 30005768 TI - Incorporating Biologic Factors into the American Joint Committee on Cancer Breast Cancer Staging System: Review of the Supporting Evidence. AB - The American Joint Committee on Cancer staging system has evolved in response to improved imaging, refined surgical techniques, enhanced pathologic evaluation, and greater understanding of tumor biology. The 8th edition has introduced clinical and pathologic prognostic stages for breast cancer that incorporate biologic variables (grade, estrogen/progesterone receptor status, HER2 status, multigene panels) with TNM categories that define the anatomic stage. The prognostic staging system facilitates more refined stratification than the anatomic stage with respect to survival and is an important advance that maintains the clinical relevance of the staging system by taking into account tumor biology and current treatment algorithms. PMID- 30005769 TI - Impact of Advancing Technology on Diagnosis and Treatment of Breast Cancer. AB - New emerging breast imaging techniques have shown great promise in breast cancer screening, evaluation of extent of disease, and response to neoadjuvant therapy. Tomosynthesis, allows 3-dimensional imaging of the breast, and increases breast cancer detection. Fast abbreviated MRI has reduced time and costs associated with traditional breast MRI while maintaining cancer detection. Diffusion-weighted imaging is a functional MRI technique that does not require contrast and has shown potential in screening, lesion characterization and also evaluation of treatment response. New image-guided preoperative localizations are available that have increased patient satisfaction and decreased operating room delays. PMID- 30005771 TI - Management of the Axilla in the Patient with Breast Cancer. AB - Evaluation of the axillary lymph nodes is critical in the management of breast cancer because it is a key predictor of survival outcome. Surgeons must not only be able to perform sentinel lymph node dissection with high accuracy but also understand the implications of the results. Management of clinically node negative and node-positive cases can vary significantly, as described in this review. With emerging data, management of the axilla in breast cancer will continue to evolve. PMID- 30005770 TI - Ductal Carcinoma In Situ. AB - Ductal carcinoma in situ has been stable in incidence for a decade and has an excellent prognosis. Breast conservation therapy is safe and effective for most patients. Adjuvant whole breast radiation therapy is recommended to reduce the risk of local recurrence. Accelerated partial breast irradiation is a promising alternative to decrease toxicity and improve cosmetic results. Adjuvant hormonal therapy can reduce local recurrence, but should be used cautiously. Future directions in management include developing predictive tools for guidance for use of adjuvant therapy and selecting low-risk patients with ductal carcinoma in situ in whom surgery may be safely omitted. PMID- 30005772 TI - Definition and Management of Positive Margins for Invasive Breast Cancer. AB - Breast-conserving surgery (BCS) followed by radiation therapy is the current standard of care for early stage breast cancer. Successful BCS necessitates complete tumor resection with clear margins at the pathologic assessment of the specimen ("no ink on tumor"). The presence of positive margins warrants additional surgery to obtain negative final margins, which has significant physical, psychological, and financial implications for the patient. The challenge lies in developing accurate real-time intraoperative margin assessment techniques to minimize the presence of "ink on tumor" and the subsequent need for additional surgery. PMID- 30005773 TI - Future Developments in Neoadjuvant Therapy for Triple-Negative Breast Cancer. AB - Breast cancer is the 2nd leading cause of cancer-related death in women in the United States. In general, advances in targeted treatment for breast cancer have improved over the last twenty years, except in the triple-negative breast cancer (TNBC) subtype. TNBC is an aggressive breast cancer subtype with limited treatment options as compared to hormone positive breast cancers. Recently, genomic profiling of TNBC shows promise in aiding clinicians to develop personalized targeted agents. Prioritizing novel molecular-based therapies in the neoadjuvant setting may help investigators understand mechanisms of resistance and ultimately improve patient outcomes in TNBC. PMID- 30005774 TI - Inflammatory Breast Cancer: What to Know About This Unique, Aggressive Breast Cancer. AB - Inflammatory breast cancer (IBC) is a rare form of breast cancer that accounts for only 2% to 4% of all breast cancer cases. Despite its low incidence, IBC contributes to 7% to 10% of breast cancer caused mortality. Despite ongoing international efforts to formulate better diagnosis, treatment, and research, the survival of patients with IBC has not been significantly improved, and there are no therapeutic agents that specifically target IBC to date. The authors present a comprehensive overview that aims to assess the present and new management strategies of IBC. PMID- 30005775 TI - The Evolving Role of Postmastectomy Radiation Therapy. AB - Throughout various eras of breast cancer therapy, postmastectomy radiation therapy (PMRT) has played an important role in the treatment of locally advanced breast cancer. PMRT decreases locoregional recurrence and may improve overall survival in patients with tumors over 5 cm or positive lymph nodes. As novel cancer therapies improve survival in breast cancer, the role of radiation therapy is evolving. Individualized recommendations for PMRT dependent on pathologic response after neoadjuvant systemic therapy are under investigation. This review summarizes the role of PMRT during breast cancer therapy and discusses open questions that may change the landscape of future breast cancer treatment. PMID- 30005777 TI - Evolution of Operative Technique for Mastectomy. AB - The radical mastectomy was the mainstay of breast cancer treatment through the majority of the twentieth century. However, as the understanding of breast cancer increased, the indications for more extensive surgical intervention decreased. The mastectomy has evolved so that skin-sparing or nipple-sparing mastectomy can be performed in the majority of women who undergo mastectomy currently. Today, nearly 40% of all women undergo mastectomy for breast cancer. The improved cosmetic appearance associated with skin- or nipple-sparing mastectomies does not compromise oncologic outcomes. PMID- 30005776 TI - Breast Cancer in the Elderly. AB - With increasing life expectancy and growth of the elderly US population, it becomes paramount that breast cancer research focuses more on the prevention, screening, and treatment of these patients. Age is no longer a cutoff for managing breast cancer in the elderly. Studies have shown the current undertreatment of cancer undermines survival, but the tide is turning to provide evidence-based medicine for the elderly. More often, clinicians and surgeons look not only at tumor-specific characteristics of breast cancer but also the functionality, tolerance, comorbidities, and life expectancy of patients to determine the best treatment. PMID- 30005778 TI - Breast Reconstruction. AB - Breast reconstruction is offered to women undergoing mastectomy or breast conservation, given its safe nature and highly aesthetic reconstructive outcomes. Breast implants are safe, offer flexibility of sizes and projections, and shorter recovery. Autologous flaps allow women to avoid prosthetic devices, using skin and fat to replace breast tissue. The increasing frequency of nipple-sparing mastectomy, autologous fat grafting, use of acellular dermal matrices, and prepectoral prosthetic reconstruction have enhanced aesthetic outcomes. Breast conservation outcomes have been enhanced by immediate oncoplastic breast reconstruction to reduce the risks of contour deformities and breast asymmetry, and maintain excellent, oncologically safe, aesthetic outcomes. PMID- 30005779 TI - Role of Operative Management in Stage IV Breast Cancer. AB - The role of operative therapy in stage IV breast cancer continues to evolve with advances in therapy and improvements in survival among this population. Traditionally surgery was performed with palliative intent to alleviate symptoms related to the intact breast primary. Several retrospective studies have challenged this paradigm, demonstrating survival advantage with surgery in de novo metastatic disease. Prospective studies are ongoing and maturing data. A comprehensive approach to local therapy following systemic therapy may be beneficial to achieve improved survival outcome associated with stage IV- no evidence of disease and to decrease local failure in inflammatory breast cancer. PMID- 30005780 TI - Sarcomas of the Breast. AB - Sarcoma of the breast is extremely rare and differs from epithelial breast carcinomas in staging and treatment. Diagnostic workup includes breast imaging and core biopsy as in breast epithelial carcinoma. Surgical management is often wide local excision in the form of breast conservation if possible for primary breast sarcoma or total mastectomy. Radiation-associated breast angiosarcomas often require total mastectomy with radical excision of skin. Breast sarcomas have a hematogenous spread so lymph node evaluation is not a part of treatment or staging. Local recurrence rates are high; prognosis remains poor despite on-going advances in the treatment of epithelial breast carcinoma. PMID- 30005781 TI - Foreword. PMID- 30005783 TI - Surgical Anatomy of the Asian Nose. AB - Rhinoplasty for Asian noses is markedly different from that for white noses. As rhinoplasty becomes increasingly popular among Asian people, it is important that the rhinoplasty surgeons master relevant anatomy and become skilled in required techniques to serve this segment of population. In this article, distinct characteristics of Asian noses are briefly described. Noses in the Asia population exhibit broad phenotypic variations. There is no typical Asian nose. Therefore, the terms of Asian noses in this article are confined to noses of people from East Asian (eg, Korea, Japan, and China). PMID- 30005784 TI - Hybrid Approach for Asian Rhinoplasty: Open Approach Without Transcolumellar Incision. AB - The hybrid approach delivers unlimited exposure and technical access, enabling all the procedures of the open approach. In addition, the hybrid approach is flexible in its extent of "dissection/ exposure" It can be more of a classic endonasal or limited access approach in some cases or open structural rhinoplasty and reconstruction in others. The benefits of the nonopen approach deserve equal attention among Asian rhinoplasty surgeons and residents-in-training courses. The difference is not merely that it spares an incision, it is an opportunity to fine tune minor millimeters of changes in every step of rhinoplasty, a real and significant benefit. PMID- 30005785 TI - Augmentation Rhinoplasty Using Silicone Implants. AB - Augmentation rhinoplasty is one of the most common aesthetic procedures in Asian countries with silicone implant being the most widely used material for augmentation rhinoplasty. Despite potential advantages, use of alloplastic materials in rhinoplasty is often discouraged in Western countries because of concern for possible risk of infection and extrusion of the implant. The collective experience of long-term favorable outcomes in Asia makes the silicone augmentation rhinoplasty a common procedure. Complication rates for silicone implants vary significantly, depending on surgeon experience, surgical technique, and implant design. Silicone implants can be safely used for nasal dorsal augmentation if precautions are taken. PMID- 30005786 TI - Dorsal Augmentation Using Autogenous Tissues. AB - Autogenous materials used for Asian dorsal augmentation are temporal fascia, dermofat, solid block type of costal cartilage, and diced cartilage. The temporal fascia is used for radix augmentation or correction of minor focal depression. Dermofat, solid block costal cartilage, and diced cartilage are recommended for major dorsal augmentation. The vertically oriented folded dermal graft curtails use of the fat component. Diced cartilage wrapped in temporal fascia exhibits a lower resorption rate, and may easily fit into the contour of the dorsum. This graft is thought to have low predictability of final height, as opposed to that of block cartilage. PMID- 30005787 TI - Homologous Tissue for Dorsal Augmentation. AB - Homologous graft materials for dorsal augmentation are safe and biocompatible with a low risk of complications. Acellular dermal matrix (ADM) provides natural appearance of the nose and long-term structural integrity without extrusion, showing favorable augmentation results. Tutoplast-processed fascia lata (TPFL) is soft and easy to manipulate, providing a smooth postoperative contour of the nasal dorsum with low risk of infection or extrusion. ADM and TPFL carry low risk of major complications, such as infection, foreign body reaction, and graft extrusion. ADM and TPFL are suitable graft materials that deliver proper dorsal augmentation and patient satisfaction in primary and revision rhinoplasty. PMID- 30005788 TI - Injection Rhinoplasty Using Filler. AB - Rhinoplasty is a commonly performed cosmetic surgery in Asia. Rhinoplasty using filler is preferred because has fewer side effects and shorter down time. The part of external nose between the skin and bone or cartilages consists of 4 layers. To prevent vascular compromise, the injection should be into deep fatty layer, preventing embolization. Filler is usually injected in the order of radix, rhinion, tip, and the supratip area. To minimize asymmetry, the surgeon should always mark the midline on the nasal bridge and perform the procedure without deviating from it. PMID- 30005789 TI - Septal Extension Graft in Asian Rhinoplasty. AB - A septal extension graft (SEG) can control nasal tip projection, shape, and rotation. SEG and dorsal alloplastic implants have predominated in Asian rhinoplasty, leading to iatrogenic complications such as a foreshortened nose and destruction of remaining septum. The lower nasal two-thirds can be enhanced anteriorly and caudally using the septal L-strut extension graft in Asians with relatively small noses. The septal L-strut extension graft is indicated in primary cases in which the bony dorsum is acceptable but the cartilaginous dorsum is relatively hypoplastic, and in secondary cases with an iatrogenic short-nose deformity due to alloplastic implants. PMID- 30005790 TI - Tip Grafting for the Asian Nose. AB - Tip surgery during rhinoplasty is particularly difficult in Asians. Tip grafting is the best approach. Conchal cartilage with perichondrium and costal cartilage are powerful grafting materials. The most important grafting techniques are tip onlay grafting, shield grafting, and multilayer tip grafting. Tip-onlay grafts are useful for dorsal convexity. Shield grafts require sufficient support to prevent bending. Multilayer tip grafts (usually 2 layers) are versatile. Asians vary in cartilage configuration, skin thickness, and aesthetic desires: tip grafting strategies must be tailored to meet the aesthetic goals of individuals. Tip-grafting complications (eg, visible graft contour and infection) are not uncommon and should be considered. PMID- 30005791 TI - Hump Nose Correction in Asians. AB - Nasal hump surgery is frequently regarded as a reduction surgery in most Western rhinoplasty textbooks and referred to as reduction rhinoplasty. Most Asian hump noses have a small hump frequently associated with a low nasal dorsum and underprojection of the nasal tip. Correcting a hump nose in Asians has distinct differences in concept and technique. A small hump and additional need for augmentation of the dorsum and the tip often minimizes the amount of hump removal or obviates resection itself. Characteristics of the Asian hump nose with emphasis on surgical techniques commonly used to obtain reliable results are presented. PMID- 30005792 TI - Alar Base Reduction and Alar-Columellar Relationship. AB - Nasal base modification can improve nostril shape and orientation, reduce alar flaring, improve nasal base width, correct nasal hooding, improve symmetry, and create overall facial harmony. For the correction of alar rim deformities, careful examination, consultation, and analysis and consideration of the condition of the skin are essential. Understanding the ala and surrounding tissue, supporting the lower lateral cartilage, and selecting the proper technique produce functionally and aesthetically good results. PMID- 30005793 TI - Correction of Short Nose. AB - To correct an Asian short nose with low dorsum, short columella, and poorly defined nose tip, augmentation rhinoplasty has been popularized. A simple augmentation no longer is considered an efficient rhinoplasty approach for Asians aesthetically; most surgeons simultaneously perform nasal elongation and augmentation during rhinoplasty. To extend the nose length successfully, important factors are cartilages, mucosal and skin conditions, and presence and degree of fibrotic changes. In addition, surgeons should consider preoperatively how much should be extended from an aesthetics perspective. This article introduces the current practice of surgical correction of the short nose in Asians. PMID- 30005794 TI - Rhinoplasty for South East Asian Nose. AB - The South East Asian nose is usually small with voluminous thick skin, low dorsum, wide and hanging ala, bulbous tip, and retracted premaxilla. The surgical approach of rhinoplasty for these types of noses includes the following: dorsal augmentation, counterrotation and projection of the tip, and correction of hanging ala and alar flare/base. A usual ideal rhinoplasty outcome of a South East Asian nose should be a nose that fits the face with good function and has all the aesthetic landmarks achieved: natural looking dorsum, supratip break, tip, subtip break, columellar show, good alar-columellar relationship, improved premaxilla, improved nostril, and improved alar flare. PMID- 30005796 TI - Mycosporine-like amino acids (MAAs)-producing Microcystis in Lake Erie: Development of a qPCR assay and insight into its ecology. AB - Mycosporine-like amino acids (MAAs) are UV-absorbing metabolites found in cyanobacteria. While their protective role from UV in Microcystis has been studied in a laboratory setting, a full understanding of the ecology of MAA producing versus non-MAA-producing Microcystis in natural environments is lacking. This study presents a new tool for quantifying MAA-producing Microcystis and applies it to obtain insight into the dynamics of MAA-producing and non-MAA producing Microcystis in Lake Erie. This study first developed a sensitive, specific TaqMan real-time PCR assay that targets MAA synthetase gene C (mysC) of Microcystis (quantitative range: 1.7 * 101 to 1.7 * 107 copies/assay). Using this assay, Microcystis was quantified with a MAA-producing genotype (mysC+) in water samples (n = 96) collected during March-November 2013 from 21 Lake Erie sites (undetectable - 8.4 * 106 copies/ml). The mysC+ genotype comprised 0.3-37.8% of the Microcystis population in Lake Erie during the study period. The proportion of the mysC+ genotype during high solar UV irradiation periods (mean = 18.8%) was significantly higher than that during lower UV periods (mean = 9.7%). Among the MAAs, shinorine (major) and porphyra (minor) were detected with HPLC-PDA-MS/MS from the Microcystis isolates and water samples. However, no significant difference in the MAA concentrations existed between higher and lower solar UV periods when the MAA concentrations were normalized with Microcystis mysC abundance. Collectively, this study's findings suggest that the MAA-producing Microcystis are present in Lake Erie, and they may be ecologically advantageous under high UV conditions, but not to the point that they exclusively predominate over the non-MAA-producers. PMID- 30005797 TI - Screening of cyclic imine and paralytic shellfish toxins in isolates of the genus Alexandrium (Dinophyceae) from Atlantic Canada. AB - The dinoflagellate genus Alexandrium Halim has frequently been associated with harmful algal blooms. Although a number of species from this genus are known to produce paralytic shellfish toxins (PST) and/or cyclic imines (CI), studies on comprehensive toxin profiling using techniques capable of detecting the full range of PST and CI analogues are limited. Isolates of Alexandrium spp. from Atlantic Canada were analyzed by targeted and untargeted liquid chromatography tandem mass spectrometry (LC-MS). Results showed a number of distinct profiles and wide ranging cell quotas of PST and spirolides (SPX) in both A. catenella (Whedon & Kofoid) Balech and A. ostenfedii (Paulsen) Balech & Tangen. The concentration of PST in A. catenella ranged from 0.0029 to 54 fmol cell-1 with the major components being C2 and GTX4. In addition, putative PST metabolites were confirmed for the first time in A. catenella by high resolution MS/MS. By comparison, A. ostenfeldii isolates showed much lower concentrations of PST (975 cells/mL at a Secchi depth >6 m and up to 874 cells/mL during flood tide. A threshold value <1 cell/mL for Pseudochattonella cf. verruculosa was found to be associated with anomalous salmon behavior, which significantly increased at a water temperature of 11 degrees C. Evidence for a relationship between fish behavior and mortality is provided. PMID- 30005801 TI - Behavioral and mechanistic characteristics of the predator-prey interaction between the dinoflagellate Dinophysis acuminata and the ciliate Mesodinium rubrum. AB - Predator-prey interactions of planktonic protists are fundamental to plankton dynamics and include prey selection, detection, and capture as well as predator detection and avoidance. Propulsive, morphology-specific behaviors modulate these interactions and therefore bloom dynamics. Here, interactions between the mixotrophic, harmful algal bloom (HAB) dinoflagellate Dinophysis acuminata and its ciliate prey Mesodinium rubrum were investigated through quantitative microvideography using a high-speed microscale imaging system (HSMIS). The dinoflagellate D. acuminata is shown to detect its M. rubrum prey via chemoreception while M. rubrum is alerted to D. acuminata via mechanoreception at much shorter distances (89 +/- 39 MUm versus 41 +/- 32 MUm). On detection, D. acuminata approaches M. rubrum with reduced speed. The ciliate M. rubrum responds through escape jumps that are long enough to detach its chemical trail from its surface, thereby disorienting the predator. To prevail, D. acuminata uses capture filaments and/or releases mucus to slow and eventually immobilize M. rubrum cells for easier capture. Mechanistically, results support the notion that the desmokont flagellar arrangement of D. acuminata lends itself to phagotrophy. In particular, the longitudinal flagellum plays a dominant role in generating thrust for the cell to swim forward, while at other times, it beats to supply a tethering or anchoring force to aid the generation of a posteriorly-directed, cone-shaped scanning current by the transverse flagellum. The latter is strategically positioned to generate flow for enhanced chemoreception and hydrodynamic camouflage, such that D. acuminata can detect and stealthily approach resting M. rubrum cells in the water column. PMID- 30005803 TI - Variability and profiles of lipophilic toxins in bivalves from Great Britain during five and a half years of monitoring: Okadaic acid, dinophysis toxins and pectenotoxins. AB - Official control biotoxin testing of bivalve molluscs from Great Britain has been conducted by Cefas for over a decade. Reflecting the changes in legislation, bioassays were gradually replaced by analytical methods, firstly for analysis of Paralytic shellfish toxins, followed by introduction of liquid chromatography tandem mass spectrometric (LCMS/MS) method for lipophilic toxins (LTs) in 2011. Twelve compounds, representing three main groups of regulated lipophilic toxins, as well as two non-regulated cyclic imines were examined in over 20,500 samples collected between July 2011 and December 2016. The toxins belonging to Okadaic acid (OA) group toxins were the most prevalent and were quantified in 23% of samples, predominantly from Scotland. The temporal pattern of OA group occurrences remained similar each year, peaking in summer months and tailing off during autumn and winter, however their abundance and magnitude varied between years significantly, with concentrations reaching up to 4993 MUg OA eq./kg. Three toxin profiles were identified, reflecting the relative contribution of the two main toxins, OA and dinophysis toxin-2 (DTX2). Dinophysis toxin-1 (DTX1) was less common and was never detected in samples with high proportions of DTX2. Inter annual changes in profiles were observed within certain regions, with the most notable being an increase of DTX2 occurrences in north-west Scotland and England in the last three years of monitoring. In addition, seasonal changes of profiles were identified when OA, the dominant toxin in early summer, was replaced by higher proportions of DTX2 in late summer and autumn. The profile distribution possibly reflected the availability of individual Dinophysis species as a food source for shellfish, however persistence of DTX2 during autumn and winter in mussels might have also been attributed to their physiology. Mussels were the only species with higher average proportions of non-esterified toxins, while Pacific oysters, cockles, surf clams, razors and queen scallops contained almost exclusively ester forms. In addition, a temporal change in proportion of OA and DTX2 free form was observed in mussels. Pectenotoxin-2 (PTX2) was quantified only on rare occasions. PMID- 30005804 TI - Environmental factors influencing the distribution and abundance of Alexandrium catenella in Kachemak bay and lower cook inlet, Alaska. AB - Despite the long history of paralytic shellfish poisoning (PSP) events in Alaska, little is known about the seasonal distribution and abundance of the causative organism, Alexandrium, or the environmental factors that govern toxic bloom development. To address this issue, a five year study (2012-2017) was undertaken in Kachemak Bay and lower Cook Inlet Alaska to determine how the occurrence of Alexandrium catenella, the dominant PSP-causing Alexandrium species, was influenced by temperature, salinity, nutrient concentrations, and other environmental factors. Cell concentrations from 572 surface water samples were estimated using quantitative PCR. Monthly sampling revealed a seasonal pattern of A. catenella bloom development that was positively correlated with water temperature. Prevailing salinity conditions did not significantly affect abundance, nor was nutrient limitation a direct factor. Elevated cell concentrations were detected in 35 samples from Kachemak Bay (100-3050 cell eq. L 1) while a maximum abundance of 67 cell eq. L-1 was detected in samples from lower Cook Inlet sites. Monitoring data showed average water temperatures in Kachemak Bay increased by ~2 degrees C over the course of the study and were accompanied by an increase in Alexandrium abundance. Based on these findings, 7-8 degrees C appears to represent a temperature threshold for significant bloom development in Kachemak Bay, with the greatest risk of shellfish toxicity occurring when temperatures exceed 10-12 degrees C. The role of temperature is further supported by time series data from the Alaska Coastal Current (station GAK1), which showed that summertime shellfish toxicity events in Kachemak Bay generally followed periods of anomalously high winter water temperatures. These data indicate monitoring changes in water temperatures may be used as an early warning signal for subsequent development of shellfish toxicity in Kachemak Bay. PMID- 30005805 TI - A closely-related clade of globally distributed bloom-forming cyanobacteria within the Nostocales. AB - In order to better understand the relationships among current Nostocales cyanobacterial blooms, eight genomes were sequenced from cultured isolates or from environmental metagenomes of recent planktonic Nostocales blooms. Phylogenomic analysis of publicly available sequences placed the new genomes among a group of 15 genomes from four continents in a distinct ADA clade (Anabaena/Dolichospermum/Aphanizomenon) within the Nostocales. This clade contains four species-level groups, two of which include members with both Anabaena-like and Aphanizomenon flos-aquae-like morphology. The genomes contain many repetitive genetic elements and a sizable pangenome, in which ABC-type transporters are highly represented. Alongside common core genes for photosynthesis, the differentiation of N2-fixing heterocysts, and the uptake and incorporation of the major nutrients P, N and S, we identified several gene pathways in the pangenome that may contribute to niche partitioning. Genes for problematic secondary metabolites-cyanotoxins and taste-and-odor compounds-were sporadically present, as were other polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) gene clusters. By contrast, genes predicted to encode the ribosomally generated bacteriocin peptides were found in all genomes. PMID- 30005806 TI - The Patient Safety Indicator Perioperative Pulmonary Embolism or Deep Vein Thrombosis: Is there associated surveillance bias in the Veterans Health Administration? AB - BACKGROUND: Studies disagree whether surveillance bias is associated with perioperative venous thromboembolism (VTE) performance measures. A prior VA study used a chart-based outcome; no studies have used the fully specified administrative data-based AHRQ Patient Safety Indicator, PSI-12, as their primary outcome. If surveillance bias were present, we hypothesized that inpatient surveillance rates would be associated with higher PSI-12 rates, but with lower post-discharge VTE rates. METHODS: Using VA data, we examined Pearson correlations between hospital-level VTE imaging rates and risk-adjusted PSI-12 rates and post-discharge VTE rates. To determine the robustness of findings, we conducted several sensitivity analyses. RESULTS: Hospital imaging rates were positively correlated with both PSI-12 (r = 0.24, p = 0.01) and post-discharge VTE rates (r = 0.16, p = 0.09). Sensitivity analyses yielded similar findings. CONCLUSIONS: Like the prior VA study, we found no evidence of PSI-12-related surveillance bias. Given the use of PSI-12 in nationwide measurement, these findings warrant replication using similar methods in the non-VA setting. PMID- 30005807 TI - Postoperative development of sarcopenia is a strong predictor of a poor prognosis in patients with adenocarcinoma of the esophagogastric junction and upper gastric cancer. AB - BACKGROUND: There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC). METHODS: Patients with AEG and UGC who were judged as non sarcopenic before surgery were reassessed the presence of postoperative development of sarcopenia 6 months after surgery. Patients were divided into the development group or non-development group, and clinicopathological factors and prognosis between these two groups were analyzed. RESULTS: The 5-year overall survival rates were significantly poorer in the development group than non development group (68.0% vs. 92.6%, P = 0.0118). Multivariate analyses showed that postoperative development of sarcopenia was an independent prognostic factor for poor overall survival (P = 0.0237). CONCLUSIONS: Postoperative development of sarcopenia was associated with a poor prognosis in patients with AEG and UGC. PMID- 30005808 TI - Adoption and outcomes of radioguided seed localization for non-palpable invasive and in-situ breast cancer at three academic tertiary care centers. AB - INTRODUCTION: Radioguided seed localization (RSL) is an alternative technique to wire-guided localization (WL) for localizing non-palpable breast lesions for breast conserving surgery. The purpose of this study was to assess adoption and outcomes of RSL at 3 academic hospitals in our city. METHODS: Data for consecutive invasive and in-situ breast cancer cases localized with RSL or WL at 3 hospitals between January 2012 and February 2016 were abstracted. Data analysis was conducted using the Student's t-test, ANOVA with Tukey's HSD test for post hoc multiple comparisons, and chi-squared test. RESULTS: There were 803 consecutive cases. Hospital 1 exclusively used RSL (247 cases), whereas H2 adopted RSL (109 cases), but continued to use WL (347 cases). Hospital 3 exclusively used WL (100 cases). There was no difference between RSL and WL groups in positive margin rate (p = 0.337), re-operation (p = 0.413), or mean specimen volume (p = 0.190). DISCUSSION: There has been variable adoption of RSL in our city. Despite this, relevant surgical outcomes have been similar across groups. The causes of variable adoption of this novel technique merit further investigation. PMID- 30005809 TI - Comparison of faculty versus structured peer-feedback for acquisitions of basic and intermediate-level surgical skills. AB - PURPOSE: Video feedback and faculty feedback has been shown to improve surgical performance; however, consistent access to faculty is challenging. We studied the utility of structured peer-feedback (PF) compared to faculty-feedback (FF) during acquisition of basic and intermediate surgical skills. METHODOLOGY: Two randomized non-inferiority trials were conducted with 1st (n = 30) and 2nd year (n = 29) medical students learning skin-lesion excision and closure (S), and single-layer hand-sewn bowel anastomosis (B), respectively. Five attempts were performed. PF participants used an Objective Structured Assessment of Technical Skills tool to guide feedback. Blinded raters assessed video-recorded performance, time and Integrity of the completed task were also assessed. RESULTS: For both tasks performance by PF was comparable to FF (P = 0.111). Both groups improved significantly: performance (B:P < 0.0001, S:P = 0.035), time (B:P = 0.043, S:P < 0.0001) and integrity (B:P < 0.0001, S:P < 0.032). CONCLUSION: Structured peer-feedback is equivalent to faculty-feedback in the acquisition of basic and intermediate surgical skills, giving students freedom to practice independently. PMID- 30005811 TI - Corrigendum to 'Restoration of severely damaged endodontically treated premolars. The influence of the endo-core length on marginal integrity and fatigue resistance of lithium disilicate CAD-CAM ceramic endocrowns." [J. Dent. 68C (2018) 41-50]. PMID- 30005810 TI - [Comparison of King Vision video laryngoscope and Macintosh laryngoscope: a prospective randomized controlled clinical trial]. AB - BACKGROUND AND OBJECTIVES: We compared the efficiency of the King Vision video laryngoscope and the Macintosh laryngoscope, when used by experienced anesthesiologists on adult patients with varying intubating conditions, in a prospective randomized controlled clinical trial. METHODS: A total of 388 patients with an American Society of Anesthesiologists physical status of I or II, scheduled for general anesthesia with endotracheal intubation. Each patient was intubated with both laryngoscopes successively, in a randomized order. Intubation success rate, time to best glottic view, time to intubation, time to ventilation, Cormack-Lehane laryngoscopy grades, and complications related to the laryngoscopy and intubation were analyzed. RESULTS AND CONCLUSIONS: First pass intubation success rates were similar for the King Vision and the Macintosh (96.6% vs. 94.3%, respectively, p>0.05). King Vision resulted in a longer average time to glottic view (95% CI 0.5-1.4s, p<0.001), and time to intubation (95% CI 3 4.6s, p<0.001). The difference in time to intubation was similar when unsuccessful intubation attempts were excluded (95% CI 2.8-4.4s, p<0.001). Based on the modified Mallampati class at the preoperative visit, the King Vision improved the glottic view in significantly more patients (220 patients, 56.7%) compared with the Macintosh (180 patients, 46.4%) (p<0.001). None of the patients had peripheral oxygen desaturation below 94%. Experienced anesthesiologists may obtain similar rates of first pass intubation success and airway trauma with both laryngoscopes. King Vision requires longer times to visualize the glottis and to intubate the trachea, but does not cause additional desaturation. PMID- 30005812 TI - Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience. AB - OBJECTIVE: To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. METHODS: Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). RESULTS: 19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 +/- 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). CONCLUSIONS: Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population. PMID- 30005813 TI - Brain malformations associated to Aldh7a1 gene mutations: Report of a novel homozygous mutation and literature review. AB - BACKGROUND: The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder. AIM: The present study aims at describing the phenotype associated with a novel homozygous ALDH7A1 mutation and the spectrum of brain malformations associated with pyridoxine dependent epilepsy. METHODS: We conducted a literature review on the Internet database Pubmed (up to November 2017) searching for ALDH7A1 mutations associated with brain malformations and brain MRI findings. RESULTS: We present the case of two siblings, children of related parents. The proband presented neonatal focal seizures not responding to conventional antiepileptic drugs. Electroencephalography showed a suppression burst pattern and several multifocal ictal patterns, responsive to pyridoxine. Brain MRI was normal. Molecular analysis by targeted next-generation sequencing panel for epileptic encephalopathy disclosed a homozygous missense mutation of ALDH7A1. The same mutation was then found in a stored sample of DNA from peripheral blood of an older sister dead 3 years earlier. This girl presented a complex brain malformation diagnosed with a foetal MRI and had neonatal refractory seizures with suppression burst pattern. She died at 6 months of age. LITERATURE REVIEW: The brain abnormalities most frequently reported in pyridoxine-dependent epilepsy include: agenesia/hypoplasia of the corpus callosum, not specific white matter abnormalities, large cisterna magna, ventriculomegaly, haemorrhages, cerebellum hypoplasia/dysplasia, and, more rarely, dysplasia of the brainstem and hydrocephalus. DISCUSSION AND CONCLUSIONS: ALDH7A1 mutations have been associated to different brain abnormalities, documented by MRI only in few cases. The study cases expand the clinical spectrum of ALDH7A1 associated conditions, suggesting to look for ALDH7A1 mutations not only in classical phenotypes but also in patients with brain malformations, mainly if there is a response to a pyridoxine trial. PMID- 30005814 TI - Road safety data considerations. PMID- 30005815 TI - Thirty-Day Readmission Rate in Acute Heart Failure Patients Discharged Against Medical Advice in a Matched Cohort Study. AB - OBJECTIVE: To determine the readmission rate in patients with acute heart failure (AHF) discharged against medical advice (AMA). METHODS: We performed a retrospective analysis using the 2014 National Readmission Database. Patients admitted with a primary diagnosis of AHF were selected. Only those discharged to home and who left AMA were included in the study. The primary outcome was 30-day readmission. We compared the readmission rates among those discharged AMA vs routinely discharged patients using propensity score matching (PSM) to address imbalance in variables between the 2 groups. We matched 3 routinely discharged patients to 1 patient who left AMA. RESULTS: We identified 273,489 patients with AHF, of whom 116,869 qualified for further study analysis. A total of 2014 patients (1.7%) were in the AMA group and 114,855 (98.3%) were in the routinely discharged group. After PSM, 6042 routinely discharged patients were matched with 2014 patients from the AMA group. The standard mean difference for each variable was less than 10% postmatching. The 30-day readmission rate among those who left AMA was higher than among those routinely discharged (33% vs 20.1%; P<.001). Heart failure (44.8%) was the most common cause of readmission in the AMA group. Patients who left AMA were more likely to be readmitted to a different hospital compared with those routinely discharged (37.4 vs 23.1%; P<.001). They also had a high rate of leaving AMA during the readmission (18 vs 2%; P<.001). CONCLUSION: Patients with AHF discharged AMA had a significantly higher 30-day readmission rate than did the routinely discharged group. PMID- 30005816 TI - United States Food and Drug Administration Advisory Committee outcomes and agency approval analysis from 2010 to 2015. AB - OBJECTIVES: This analysis sought to quantify voting behavior and other characteristics of advisory committee (AC) meetings and compare that with the U.S. Food and Drug Administration's (FDA) approval decisions from 2010 to 2015. METHODS: The analysis of the Center for Drug Evaluation and Research AC meetings was conducted using publicly available information from the FDA website and the sponsors' websites. RESULTS: There were 163 voting sessions, 207 votes, and 229 meetings. Voting questions assessed approval (63%), acceptable risk-benefit profile (19%), efficacy (8%), safety and efficacy (7%), and safety (3%). The AC voted in favor of approval 67% of the time and against approval 33% of the time, although it heavily favored one outcome when voting favorably or unfavorably. The FDA approval decision supported the committee's decision in 90% of cases. When such agreement did not occur, it was due to differences in clinical opinion (43%), manufacturing deficiencies (14%), lack of manufacturing data (14%), and a post-AC event (5%). There was insufficient information to determine why there was a differing opinion in 24% of cases. When FDA had a differing opinion, the agency typically did not approve a substance in which the committee recommended approval (81%). CONCLUSION: The results support past research examining the topic from 2001 to 2010. Voting patterns were relatively constant, and they generally heavily favored one outcome. The FDA's ultimate approval decision was in line with the AC vote the vast majority of cases. Any disagreement was usually due to FDA having a differing opinion regarding clinical importance, furthering the notion that AC insight is heavily considered but not the final determinant in agency action. This topic has importance in understanding pharmaceutical approval in the United States, and this has clinical practice implications. PMID- 30005817 TI - Rationale for assessing the therapeutic potential of resveratrol in hematological malignancies. AB - Promising results from pre-clinical studies on the naturally-occurring polyphenol resveratrol have generated considerable interest and somewhat excessive expectations regarding the therapeutic potential of this compound for treating or preventing various diseases, including cardiovascular and neurodegenerative disorders and cancer. Resveratrol has potent inhibitory activity in vitro against various tumor types, including cell lines derived from virtually all blood malignancies. Pharmacological studies have shown that resveratrol is safe for humans but has poor bioavailability, due to its extensive hepatic metabolism. Curiously, a substantial proportion of the orally administered resveratrol can reach the bone marrow compartment. Notably, various pathways dysregulated in blood cancers are known to be molecular targets of resveratrol, thus substantiating the potential utility of this agent in blood malignancies. In this review, we primarily focus on the scientific evidence that supports the potential utility of resveratrol for the management of select hematological malignancies. In addition, potential clinical trials with resveratrol are suggested. PMID- 30005818 TI - Solitary, observer, parallel, and social object play in the bottlenose dolphin (Tursiops truncatus). AB - Many comparative studies have focused on the emergence of solitary and social play in early development, however, few consider observer and parallel forms of play. In this study, we analyzed approximately 21 h of video recordings and revealed a significant difference between the frequency of solitary, observer, parallel, and social object play states, in calf, juvenile, subadult, and adult bottlenose dolphins (Tursiops truncatus). While juveniles engaged in solitary play significantly more than other age groups, both juveniles and calves engaged in observer and social play significantly more than adults and subadults. Within their own age group, calves, juveniles, and subadults all showed a significant preference for solitary play. Calves preferred juvenile partners, while juveniles preferred calves during social play and other juveniles during observer play. Calves and juveniles preferred non-kin partners, especially during observer play. Together, these results have implications for social learning and behavioral transmission through observational play. With this knowledge, we can provide the appropriate social environment to dolphins in managed care with limited or constrained social availability, increasing learning opportunities and developmental outcomes. PMID- 30005819 TI - Considerations Identified from the Dialogue Focused on Evidence-Based Decision Making and Vitamin D: Implications for the Nutrition Care Process. PMID- 30005821 TI - Dietary Guidelines 2020-2025: Update on Academy Efforts. PMID- 30005820 TI - Dietary Intake, Nutrient Status, and Growth Parameters in Children with Autism Spectrum Disorder and Severe Food Selectivity: An Electronic Medical Record Review. AB - BACKGROUND: Food selectivity is common in children with autism spectrum disorder (ASD). The clinical characteristics, however, of severe food selectivity in children with ASD is not well documented. OBJECTIVE: This study examined the demographic characteristics, anthropometric parameters, risk of nutritional inadequacy, dietary variety, and problematic mealtime behaviors in a sample of children with ASD with severe food selectivity. DESIGN: The study involved a cross-sectional electronic medical record review. Data extraction followed a systematic protocol for data extraction. PARTICIPANTS/SETTING: Children (age 2 to 17 years) with ASD, severe food selectivity, and complete nutritional data who received a multidisciplinary evaluation at a specialty feeding clinic in the southeastern United States between January 2014 and January 2016. Criteria for severe food selectivity used in this clinical practice required complete omission of one or more food groups (eg, fruit, vegetable, protein, grain, dairy) or consuming a narrow range of items on a weekly basis (eg, five or fewer total food items). MAIN OUTCOME MEASURES: Analyses examined demographic characteristics, dietary preferences, risk for nutritional inadequacies, anthropometric parameters, and problematic mealtime behaviors. RESULTS: Of the 279 patients evaluated during the 24-month period, 70 children with ASD and severe food selectivity met inclusion criteria. Caregivers reported 67% of the sample (n=47) omitted vegetables and 27% omitted fruits (n=19). Seventy-eight percent consumed a diet at risk for five or more inadequacies. Risk for specific inadequacies included vitamin D (97% of the sample), fiber (91%) vitamin E (83%), and calcium (71%). Children with five or more nutritional inadequacies (n=55) were more likely to make negative statements during meals (P<0.05). Severe food selectivity was not associated with compromised growth or obesity. CONCLUSION: Children with ASD and severe food selectivity may be at increased risk for nutritional inadequacies. Future research should examine causes, consequences, and remediation of severe food selectivity in this population. PMID- 30005822 TI - Considerations in Dietetic Counseling for Vitamin D. PMID- 30005823 TI - The Vocal Score Profile in Verdi's Characters. AB - OBJECTIVES: Selecting the appropriate repertoire for an opera singer may be crucial for both the prevention of voice disorders and the career progression. Here, we reviewed the score of 14 Verdi's operas to gain the data for the creation of the vocal score profile of each role. MATERIALS AND METHODS: Seven musicians were involved in the analysis process. Notes were counted and reported as absolute and relative frequency. Pitch measurements included pitch range, percentage of high-pitched notes, percentage of medium-pitched notes, percentage of low-pitched notes, high-pitched and low-pitched notes rate, percentage of the notes in the passaggio, identification of the prevalent octave, percentage of notes in the prevalent octave, and percentage of notes in a moderate range tessitura. The total phonation time was calculated for each character. RESULTS: A heterogeneity among pitch and duration measurement was found among roles within the same voice type, leading to highly different vocal efforts required by the performer. CONCLUSIONS: Data on 67 Verdi characters were gained, and the vocal demand of each role was discussed. Potentially, these results may support singers, singing teachers, and vocal coaches in the selection of the repertoire. The data may also assist clinicians in the conduction of counseling and during eventual voice therapy. Future studies must investigate the predictive value of the vocal score profile in appraising the risk of vocal injury. PMID- 30005824 TI - Acoustic and Aerodynamic Characteristics of Choral Singers. AB - OBJECTIVES: The study aimed to investigate and compare the acoustic and aerodynamic characteristics of choral singers and nonsingers. METHOD: Twenty choral singers and 20 nonsingers in the age range of 20-30 years with no vocal pathology participated in the study. For acoustic analysis, the voice sample was recorded and analyzed using Praat software (Phonetic Sciences, University of Amsterdam, Amsterdam, Netherlands) version 6.0.33 and for aerodynamic evaluation, Helios 401 PC based spirometer (Recorders & Medicare System Pvt. Ltd., Panchkula, Haryana, India) was used. RESULTS: The results from acoustic analysis of female groups revealed higher F0 in singers than nonsingers; higher jitter, shimmer, and noise-to-harmonics ratio (NHR) values were obtained for nonsingers compared to singers. Results from acoustic analysis of male groups revealed significantly higher F0 in singers than nonsingers and significantly higher shimmer and NHR values for nonsingers compared to singers. Results from aerodynamic analysis for both male and female groups revealed higher vital capacity, forced vital capacity, and slow vital capacity in singers than nonsingers. CONCLUSION: The results revealed better control over phonatory and respiratory subsystems among singers compared to nonsingers, although the singers were untrained. This could be possible due to the fact that long-term singing practices involving vocal modulation and changes in the breathing pattern, better respiratory control during the expiratory phase among singers. However, as the participants of the singing group are untrained, further studies are required to compare the acoustic and the aerodynamic characteristics with trained singers. PMID- 30005825 TI - Impact of magnetic steering on gastric transit time of a capsule endoscopy (with video). AB - BACKGROUNDS AND AIMS: Delayed gastric transit of the capsule may lead to incomplete small bowel examination, reducing the diagnostic yield. Thus, this study was designed to determine if magnetic steering could enhance capsule gastric emptying and mucosal visualization within the duodenum. METHODS: The intervention group comprised 100 patients undergoing magnetic-controlled capsule endoscopy between May to September 2017 in whom magnetic control was used to assist transpyloric passage of the capsule and duodenal inspection. A cohort of 100 patients who had undergone the procedure before May 2017 was randomly selected from the database as an historic control group in whom transpyloric movement of the capsule occurred spontaneously (without magnetic assistance). The difference in the pyloric transit time (PTT) and duodenal papilla detection rate (DPDR) between the 2 groups were compared, and related factors were also investigated. RESULTS: Transpyloric passage of the capsule under magnetic control was successfully performed in 59 patients (59%). Median PTT was greatly reduced in the intervention group from 58.38 minutes (range, 13.45-87.47) to 4.69 minutes (range, 1.56-55.00; P < .001), and DPDR was also greatly improved with magnetic steering (30.5% vs 9%, P < .001). Magnetic steering, male gender, and higher body mass index were independently associated with reduced gastric transit time and magnetic steering with an enhanced DPDR. CONCLUSIONS: Magnetic steering of the capsule can enhance gastric emptying of the capsule and may prove useful in nonobese and female patients who appeared to have longer gastric transit time and achieved a better DPDR than that under the action of peristalsis alone. (Clinical trial registration number: NCT03441945.). PMID- 30005827 TI - Reframing addiction: habit, choice, cues and compulsivity. PMID- 30005828 TI - Age-related heterogeneity in dental caries and associated risk factors in individuals with cystic fibrosis ages 6-20 years: A pilot study. AB - BACKGROUND: The literature conflicts regarding dental caries risk in cystic fibrosis (CF) relative to controls. METHODS: Prospective, observational study of age-related heterogeneity in caries rates and potential risk factors in individuals with CF ages 6-20 at a single clinic in Washington state (N=85). Caries rates for enrolled CF participants and historical controls from NHANES were compared using cubic spline regression models. Generalized linear regression models identified correlates of age and caries in CF. RESULTS: Children ages 6-9 with CF had significantly lower caries than controls (Holm's P<0.05). There was no difference for ages 10-20 by CF status (Holm's P>0.05). Various biological/intraoral, medical, and behavioral factors were associated with caries and age in CF. CONCLUSIONS: Younger children with CF may be protected from caries, but there is apparent loss of protection in early adolescence associated with multiple risk factors. Additional studies are needed to confirm these findings. PMID- 30005829 TI - Tuberculosis screening in asylum seekers in Germany: a need for better data. PMID- 30005826 TI - LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. AB - B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention. PMID- 30005830 TI - Overexpression of GRIM-19 accelerates radiation-induced osteosarcoma cells apoptosis by p53 stabilization. AB - AIMS: Osteosarcoma is one of the most aggressive types of primary bone cancer that responds poorly to radiotherapy frequently. The gene associated with retinoid-interferon mortality (GRIM-19) is a tumor suppressor that mediates cell apoptosis in multiple cancer types. However, the role of GRIM-19 in osteosarcoma and the underlying mechanism remain unclear. This study was designed to investigate the role and the underlying mechanism of GRIM-19 in osteosarcoma progression. MATERIALS AND METHODS: Osteosarcoma tissues and cell lines were utilized to analyze the expressions of GRIM-19 in osteosarcoma by qRT-PCR and Western blot. Methods containing flow cytometry, irradiation exposure, cells inoculation, plasmid transfection, and protein immunoprecipitation were used to investigate the underlying mechanisms of GRIM-19 in osteosarcoma progression. KEY FINDINGS: GRIM-19 is downregulated in osteosarcoma tissues and cell lines. Exposure to radiation induces osteosarcoma cell apoptosis by upregulation of p53 both in U2OS (p53-wt) and exogenous p53-introduced MG-63 (p53-null) osteosarcoma cells. Overexpression of GRIM-19 accelerates radiation-induced osteosarcoma cells apoptosis by p53 stabilization ex vivo and in vivo. Mechanistically, forced expression of GRIM-19 diminishes the activity of E3 ubiquitin-protein ligase mouse double minute 2 homolog (MDM2), a specific p53 protease, results in the accumulation of p53 and activation of p53-mediated apoptosis. SIGNIFICANCE: GRIM 19 was proved to modulate radiation-induced osteosarcoma cells apoptosis in a p53 dependent manner by mediating MDM2 activity, which sheds light on the development of GRIM-19-based molecular target therapy on osteosarcoma. PMID- 30005831 TI - Effect of timing of pulmonary metastasis occurrence on the outcome of metastasectomy in osteosarcoma patients. AB - BACKGROUND: Complete metastasectomy is the best predictor of survival in patients with osteosarcoma pulmonary metastases. There has been some controversy in the literature regarding the prognostic significance of the timing of occurrence of lung metastasis. METHODS: We reviewed the clinical course of all osteosarcoma patients with pulmonary metastases treated by metastasectomy in our hospital from January 2008 through December 2016. Each patient who underwent metastasectomy was placed into one of three groups based on whether lung metastases were present at initial presentation (Group 1), developed during chemotherapy (Group 2), or appeared after completion of chemotherapy (Group 3). Data were obtained retrospectively and follow-up was obtained until the end of June 2017. RESULTS: We identified 170 patients with pulmonary nodules of whom 99 (58.2%) underwent at least one metastasectomy (149 thoracotomies). Eleven patients had benign pulmonary nodules and were excluded. The other 88 patients were classified as Group 1 (37), Group 2 (18) or Group 3 (33). The median follow-up was 35 months (range 8 to 99). Postmetastasis 5-year overall survival (OS) was 38.1 +/- 6.4%; event-free survival (EFS) was 25 +/- 5.3%. By group, postmetastasis 5-year OS and EFS were 34.3 +/- 13% and 18 +/- 9.3% in Group 1, 8 +/- 6.5% and 6.5 +/- 5% in Group 2, and 52 +/- 11.4% and 25 +/- 9% in Group 3 (P < 0.001). In univariate analysis, the only significant factors associated with survival were timing of occurrence of lung metastasis and the number of lung nodules found. CONCLUSION: The timing of occurrence of lung metastasis is an important prognostic factor among osteosarcoma patients eligible for metastasectomy. Patients whose metastases occurred during chemotherapy had the worst survival. LEVEL OF EVIDENCE: Level II. PMID- 30005832 TI - Evaluation of a novel automatic screening tool for determining eligibility for a subcutaneous implantable cardioverter-defibrillator. AB - BACKGROUND: The manufacturer has developed a new ECG screening tool to determine eligibility for the subcutaneous ICD (S-ICD), the "automatic screening tool" (AST), which may render manual ECG-screening unnecessary. The aim of the study was to determine the eligibility for the S-ICD using two methods (manual ECG screening versus AST) in different patient categories including patients with cardiomyopathy, congenital heart disease and inherited primary arrhythmia syndrome. METHODS: We prospectively evaluated the ECG suitability for an S-ICD in consecutive patients at our outpatient clinic between February and June 2017. The primary endpoint of the study was ECG eligibility defined as at least 1 successful vector in both supine and sitting postures. RESULTS: A total of 254 patients (167 men; mean age 45 +/- 16 years) were screened using both methods. Overall, there was a high ECG eligibility using either method (93% versus 92%, P = 0.45). Overall agreement between both methods was 94%. Patients with hypertrophic cardiomyopathy (HCM) more often had a failed screening test using either test in comparison to the patients without HCM (manual: odds ratio [OR] 3.3, 95% confidence interval [CI] 1.2-9.3, P = 0.02; AST: OR 3.0, 95% CI 1.2-7.6, P = 0.02). CONCLUSION: AST showed a high agreement with manual ECG-screening for S-ICD. Overall there was a high ECG eligibility for S-ICD, although patients with HCM had a lower passing rate irrespective of the screening method. PMID- 30005833 TI - Racial and ethnic healthcare disparities in patients undergoing laser lead extraction. AB - BACKGROUND: The rate of cardiovascular implantable electronic device infections (CIEDIs) has mirrored or exceeded the increased use of implantable cardiac devices in the United States. The presence of racial and ethnic disparities associated with CIEDIs has not been published. Our aim is to describe the presence of racial and ethnic disparities with respect to the management of CIEDIs. METHODS: We reviewed a prospective single-center registry for patients undergoing removal of an implantable cardiac device between 1/2004 and 1/2016. 1173 consecutive patients underwent device extraction. 699 patients were identified as having an infection, 305 were identified as Caucasian and 394 were minorities (91 African Americans, 303 Hispanics). Patients had pre-operative transesophageal echocardiograms (TEEs) and collection of blood and exudate cultures. All underwent complete hardware extraction; leads were removed through the use of locking stylets and traction or laser extraction. En-bloc capsulectomy was performed with intraoperative specimen collection from pocket tissue, exudate, lead tips, and vegetations. RESULTS: Minority patients were: younger (67.9 +/- 14.5 years vs 72.4 +/- 13.2 years), had a higher proportion of male gender, diabetes, and chronic renal failure (p < 0.001). Minorities experienced a higher rate of complications during extraction and a longer hospitalization (15.3 +/- 9.9 days versus 17.4 +/- 13.4 days, p < 0.001). There was no significant difference between the proportion of types of infection in both groups. CONCLUSION: Minority patients with CIEDIs experienced more procedural complications during extraction and had a significantly longer length of index hospitalization than Caucasian patients. PMID- 30005834 TI - Change in natremia as a prognostic marker in patients with acute heart failure. PMID- 30005835 TI - Unfavorable and favorable changes in modifiable risk factors and incidence of coronary heart disease: The Whitehall II cohort study. AB - BACKGROUND: Few studies have examined long-term associations of unfavorable and favorable changes in vascular risk factors with incident coronary heart disease (CHD). We examined this issue in a middle-aged disease-free population. METHODS: We used repeat data from the Whitehall II cohort study. Five biomedical, behavioral and psychosocial examinations of 8335 participants without CHD produced up to 20,357 person-observations to mimic a non-randomized pseudo-trial. After measurement of potential change in 6 risk factors twice (total cholesterol, blood pressure, smoking, overweight, psychological distress, problems in social relationships), a 5-year follow-up of CHD was undertaken. RESULTS: Incidence of CHD was 7.4/1000 person-years. Increases from normal to high cholesterol (hazard ratio, HR = 1.59, 95% CI 1.26-2.00) and from normal to high blood pressure (HR = 1.64, 95% CI 1.33-2.03), as compared to remaining at the normal level, were associated with increased risk of CHD. In contrast, decreases from high to low levels of cholesterol (HR = 0.73, 95% CI 0.58-0.91), psychological distress (HR = 0.68, 95% CI 0.51-0.90), and problems in social relationships (HR = 0.65, 95% CI 0.50-0.85), and quitting smoking (HR = 0.49, 95% CI 0.29-0.82) were associated with a reduced CHD risk compared to remaining at high risk factor levels. The highest absolute risk was associated with persistent exposure to both high cholesterol and hypertension (incidence 18.1/1000 person-years) and smoking and overweight (incidence 17.7/1000 person-years). CONCLUSIONS: While persistent exposures and changes in biological and behavioral risk factors relate to the greatest increases and reductions in 5-year risk of CHD, also favorable changes in psychosocial risk factors appear to reduce CHD risk. PMID- 30005836 TI - Morphine, a potential inhibitor of myeloperoxidase activity. AB - Morphine is an opioid alkaloid commonly used in clinical practice for its analgesic properties. The phenolic hydroxyl group of that phenanthrene derivative is pivotal for binding to opioid receptors but it may also be responsible for the antioxidant behavior of morphine reported in several in vitro experiments. In this study, we assessed the effect of morphine on myeloperoxidase (MPO), a hemic enzyme from azurophilic granules of polymorphonuclear neutrophils involved in the production of cytotoxic and microbicidal reactive oxidants during inflammatory response. Specific immunological extraction followed by enzyme detection (SIEFED) and molecular modeling (docking) were performed to study the potential anti catalytic action of morphine on MPO in comparison with the inhibitory effects of reference antioxidant molecules quercetin, gallic acid and ascorbic acid. The reducing action of morphine on the MPO peroxidase cycle has been investigated using electron paramagnetic resonance (EPR) and UV-visible absorption spectroscopy. Morphine acted as a reducing substrate in the peroxidase cycle of MPO and therefore protected the enzyme against the suicide action of its natural substrate, hydrogen peroxide. The SIEFED experiments associated with the docking study, further demonstrated a lack of strong and sustained anti-catalytic activity of morphine. In summary, from the results of this study, it appears that morphine acts as a weak and reversible inhibitor of MPO that may nonetheless contribute to immunomodulatory and antioxidant effects of this opioid analgesic in vivo. PMID- 30005837 TI - Adaptive Networks for Restoration Ecology. AB - The urgent need to restore biodiversity and ecosystem functioning challenges ecology as a predictive science. Restoration ecology would benefit from evolutionary principles embedded within a framework that combines adaptive network models and the phylogenetic structure of ecological interactions. Adaptive network models capture feedbacks between trait evolution, species abundances, and interactions to explain resilience and functional diversity within communities. Phylogenetically-structured network data, increasingly available via next-generation sequencing, inform constraints affecting interaction rewiring. Combined, these approaches can predict eco-evolutionary changes triggered by community manipulation practices, such as translocations and eradications of invasive species. We discuss theoretical and methodological opportunities to bridge network models and data from restoration projects and propose how this can be applied to the functional restoration of ecological interactions. PMID- 30005838 TI - Reply to Karim et al.: "Pre-hospital invasive ventilation in patients with septic shock: Is hyperoxemia an unwanted company?" PMID- 30005839 TI - In reply: Confounding biases in the association between fentanyl use and hypotension after rapid sequence intubation. PMID- 30005840 TI - Health care utilization following motor vehicle collision is poorly stratified by chronic pain risk: Lessons from the CRASH study. PMID- 30005841 TI - Emergency medicine stakeholder perspectives on value-based alternative payment models: A qualitative study. PMID- 30005842 TI - Laparoscopic Colposuspension for Recurrent Stress Incontinence after Tension-free Vaginal Tape. AB - STUDY OBJECTIVE: To demonstrate laparoscopic colposuspension for recurrent stress incontinence after failed tension-free vaginal tape (TVT). DESIGN: A technical video showing laparoscopic colposuspension for previously surgically treated stress incontinence (Canadian Task Force classification III). SETTING: A university hospital. PATIENT: A 58-year-old woman with previous TVT presents with recurrent stress urinary incontinence. MEASUREMENTS AND MAIN RESULTS: Midurethral slings have equivalent cure rates to the more invasive colposuspension. They are preferentially used for stress urinary incontinence despite a mesh erosion rate of 3.5% with 2.5% requiring further surgery, sling removal, or revision over 9 years [1,2]. Recent negative publicity concerning synthetic mesh tape has led to a resurgence of interest in mesh-free alternatives, including urethral bulking agents, rectus fascia slings, and colposuspension. Laparoscopic colposuspension is a well-established minimally invasive surgery that avoids synthetic mesh, with a quicker recovery, less scarring, and equivalent success to an open approach [3]. Bladder neck mobility is an important marker during selection of this technique. In this video, we demonstrate our transperitoneal technique of colposuspension in the case of failed TVT. This technique allows clear visualization of the operating field and is faster and less bloody than a full dissection. Because complications can ensue from extensive excision and extraction, unless the previous TVT has caused problems such as pain, we normally leave it in situ. Careful dissection is undertaken into the Retzius space to the paravaginal tissues where the iliopectineal ligament is located. On each side, we apply 2 extracorporeally tied nonabsorbable Ethibond (Johnson and Johnson Medical NV, Bruxelles, Belgium) sutures as recommended [4], caudal and lateral to the TVT, lifting the paravaginal tissues to the ligament. The knot is placed on the ligament side to minimize erosion risk. The peritoneal defect is closed with a Vicryl 2.0 (Johnson and Johnson Medical NV) suture. This technique offers a viable mesh-free option for the treatment of recurrent stress incontinence in women who have had failed TVT. PMID- 30005843 TI - You can do that?!: Feasibility of virtual reality exposure therapy in the treatment of PTSD due to military sexual trauma. AB - This initial feasibility study examined the use of virtual reality exposure therapy (VRE) in the treatment of MST-related PTSD, with newly developed content tailored to MST. Participants included 15 veterans (26% male) with MST-related PTSD. Assessment of PTSD, depression, and psychophysiological indicators of distress occurred at pre-treatment, post-treatment, and 3-month follow-up. Treatment included 6-12 VRE sessions. There were significant reductions in pre- to post-treatment PTSD (CAPS severity: t(10) = 3.69, p = .004; PCL-5: t(10) = 3.79, p = .004) and depressive symptoms, (PHQ-9: t(8) = 2.83, p = .022), which were maintained at follow-up. There also was a significant pre- to post-treatment reduction in heart rate response to a trauma cue. Cohen's d effect sizes were large (CAPS: d = 1.11; PCL-5: d = 1.14, PHQ-9: d = .94), and the percentage of participants meeting PTSD criteria continued to decline from post-treatment (53%) to follow-up (33%). Findings indicate VRE can be safely delivered and is a promising treatment for MST-related PTSD. PMID- 30005844 TI - Effects of manipulating the number of targets in U9, U11, U15 and U17 futsal players' tactical behaviour. AB - This study identified how the manipulation in the number of goal targets affects the tactical behaviour of players from different age groups (U9, U11, U15 and U17). Forty youth futsal players performed two small-sided games based on Gk + 4vs4 + Gk situation with one regular and two small targets. TACTO software was used to capture players and ball displacements. The following variables were computed and presented as absolute values, coefficient of variation and regularity (approximate entropy): (i) distance from each player to the team centre (DtC); (ii) distance from each player to the ball (DtB); (iii) distance between team centres (DbTC); and (iv) distance from team centre to the ball (DCtB). The team dispersion increased with two goal targets (mainly the DbTC, U9 and U17, large effects; U11 and U15, very large effects). Also, the use of two goal targets condition increased the variability in the DbTC (U9, small effects; U11 and U15 moderate effects; U17, very large effects) and DCtB (U9 and U17 moderate effects and U11 and U15 small effects). Overall, the approximate entropy values showed higher regularity in the condition with two targets. All age groups were sensitive to the manipulation of goal targets, however, the U9 were the most sensitive to the changes, as seen by the dispersion of players in the field. Thus, coaches can use one target to promote movement irregularity of players and two targets to increase the team dispersion, mainly in younger age groups that tend to be agglomerated around the ball. PMID- 30005845 TI - Entraining chaotic dynamics: A novel movement sonification paradigm could promote generalization. AB - Tasks encountered in daily living may have instabilities and more dimensions than are sampled by the senses such as when carrying a cup of coffee and only the surface motion and overall momentum are sensed, not the fluid dynamics. Anticipating non-periodic dynamics is difficult but not impossible because mutual coordination allows for chaotic processes to synchronize to each other and become periodic. A chaotic oscillator with random period and amplitude affords being stabilized onto a periodic trajectory by a weak input if the driver incorporates information about the oscillator. We studied synchronization with predictable and unpredictable stimuli where the unpredictable stimuli could be non-interactive or interactive. The latter condition required learning to control a chaotic system. We expected better overall performance with the predictable but more learning and generalization with unpredictable interactive stimuli. Participants practiced an auditory-motor synchronization task by matching their sonified hand movements to sonified tutors: the Non-Interactive Predictable tutor (NI-P) was a sinusoid, the Non-Interactive Unpredictable (NI-U) was a chaotic system, the Interactive Unpredictable (I-U) was the same chaotic system with an added weak input from the participant's movement. Different pre/post-practice stimuli evaluated generalization. Quick improvement was seen in NI-P. Synchronization, dynamic similarity, and causal interaction increased with practice in I-U but not in NI U. Generalization was seen for few pre-post stimuli in NI-P, none in NI-U, and most stimuli in I-U. Synchronization with novel chaotic dynamics is challenging but mutual interaction enables the behavioral control of such dynamics and the practice of complex motor skills. PMID- 30005846 TI - Noninvasive Cerebral Imaging and Monitoring Using Electrical Impedance Tomography During Total Aortic Arch Replacement. AB - OBJECTIVE: To explore the feasibility of using electrical impedance tomography (EIT) to provide noninvasive cerebral imaging and monitoring in total aortic arch replacement (TAAR). DESIGN: A prospective, observational study. SETTING: Department of cardiovascular surgery in a university hospital. PARTICIPANTS: Forty-two patients undergoing TAAR using hypothermic circulatory arrest and unilateral antegrade cerebral perfusion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cerebral impedances of the patients were monitored intraoperatively by an EIT system. The prognostic information of the patients, including postoperative neurological dysfunction, was collected during their hospitalizations. Eight (19.0%) subjects had at least 1 postoperative neurological dysfunction complication. The results show that cerebral impedance was related negatively to perfusion flow, and the gradual increase in cerebral resistivity might reflect the evolving process of brain tissue caused by hypoxia. Maximum resistivity asymmetry index was extracted from the reconstructed images to quantify the pathological changes of the brain. The area under the receiver operating characteristic curve of maximum resistivity asymmetry index for postoperative neurological dysfunction was 0.864. In multivariate logistic regression, maximum resistivity asymmetry index was the strongest independent predictor of neurological dysfunction with an odds ratio of 24.3. CONCLUSION: EIT is a promising technique to provide noninvasive cerebral imaging and monitoring in TAAR. PMID- 30005847 TI - Vasopressin-Magic Bullet in Vasoplegia Syndrome After Cardiac Surgery? PMID- 30005848 TI - Non-invasive early detection of malignant pulmonary nodules by FISH-based sputum test. AB - BACKGROUND: Early detection decreases lung cancer mortality. The Target-FISH Lung Cancer Detection (LCD) Test is a non-invasive test designed to detect chromosomal changes (deletion or amplification) via Fluorescence in situ Hybridization (FISH) in sputum specimens from persons suspected of having lung cancer. We evaluated the performance of the LCD test in patients with highly suspicious pulmonary nodules who were scheduled for a biopsy procedure. METHODS: Induced sputum was collected from patients who were scheduled for biopsy of a solitary pulmonary nodule (0.8-3 cm) in one of 6 tertiary medical centers in the US and Israel. The lung cancer detection (LCD) Test combined sputum cytology and Target-FISH analysis on the same target cells and the results were compared to the pathology. Participants with non-surgical negative biopsy results were followed for 2 years to determine their final diagnosis. RESULTS: Of the 173 participants who were evaluated, 112 were available for analysis. Overall, the LCD test had a sensitivity of 85.5% (95% CI, 76.1-92.3), specificity of 69% (95% CI, 49.2-84.7) and an accuracy of 81.3% (95% CI, 72.8-88). The positive and negative predictive values (PPV, NPV) were 88.8% and 62.5%, respectively. The LCD test was positive in 9 of 11 lung cancer patients who had an initial negative biopsy. CONCLUSIONS: In a cohort of patients with highly suspicious lung nodules, the LCD test is a non-invasive option with good sensitivity and a high positive predictive value. A positive LCD test reinforces the need to aggressively pursue a definitive diagnosis of suspicious nodules. PMID- 30005849 TI - Clonal neutrophil infiltrates in concurrent Sweet's syndrome and acute myeloid leukemia: A case report and literature review. AB - Sweet's syndrome (SS), also known as acute febrile neutrophilic dermatosis is often associated with a hematological malignancy, especially acute myeloid leukemia (AML) and myeloid dysplasia syndrome. Histopathologically, SS is characterized by diffuse infiltrates in the upper dermis, predominantly consisting of mature neutrophils. The origin of neutrophils invading the skin remains unknown. Herein, we report a patient with concurrent acute monoblastic leukemia and SS who initially presented with discrete erythematous papules and nodules on the neck. Single nucleotide polymorphism (SNP) array and next generation sequencing (NGS) revealed a concordant fms-related tyrosine kinase-3 (FLT-3) gene mutation in the bone marrow and skin lesion, indicating that the neutrophilic infiltrates were clonally related to the underlying myeloid neoplasm. This is the first case report of concurrent SS and AML, in which SNP array and NGS analysis were applied to confirm the clonality of the neutrophilic infiltrates. PMID- 30005850 TI - Challenges in next generation sequencing analysis of somatic mutations in transplant patients. AB - Analysis of somatic mutations in solid tumors and hematologic malignancies using targeted next generation sequencing (NGS)-based assays has become part of routine oncology practice as well as clinical trials. The use of paired tumor-normal DNA samples increases confidence of somatic calls. NGS assays that utilize unique patient identifiers (SNP IDs) allow further comparison of samples within a run or paired tumor/normal samples. The sources of germline DNA include peripheral blood (PB) and formalin-fixed paraffin-embedded tissue (FFPE). However, the source of normal can be problematic, especially in transplant setting. Herein, we report two cases of NGS-based molecular testing in a patient with mycosis fungoides treated with stem cell transplant [SCT] (Pt1) and a patient with lung adenocarcinoma who previously had acute leukemia cured by SCT. These cases highlight the importance of selecting an appropriate normal sample for excluding germline polymorphisms during somatic mutation testing. Initial analyses that included concurrent PB sample failed to filter known germline polymorphisms. Repeat analyses using pre-transplant PB/bone marrow allowed for the successful subtraction of germline variants. Somatic mutations in PTEN and ERBB4 (Pt1) and CDKN2A, KRAS, KDR, and TP53 (Pt2) were reported with confidence. Selection of an appropriate source of germline DNA for NGS-based somatic mutation testing for patients with SCT transplant can be challenging. Particular attention to the clinical history is crucial for accurate interpretation and reporting. PMID- 30005851 TI - Differentially expressed LncRNAs as potential prognostic biomarkers for glioblastoma. AB - Glioblastoma (GBM) is the most common and aggressive brain tumor with the poor clinical outcome. LncRNAs (Long non-coding RNAs) play an important role in the occurrence and development of glioblastoma. We aimed to explore the role that lncRNAs play in regulating glioblastoma and the pathways they are enriched in. The expression data of a total of 516 GBM samples were downloaded from TCGA (The Cancer Genome Atlas). We identified the differentially expressed lncRNAs between cancer and normal tissues and performed annotation of differentially expressed lncRNAs to figure out the functions and pathways they were enriched in. Finally, cluster analysis was performed on the expression data of lncRNA and the samples were divided into four kinds, which were then used in the survival analysis. A total of 90 down-regulated lncRNAs and 224 up-regulated lncRNAs were screened out, which were mostly enriched in pathways of Alzhermer's disease and apoptosis. Their neighborhood genes were mostly enriched in genes sets of RTN1 and MAPK10.The characterization of differentially expressed lncRNAs was found out and the mostly enriched pathways were obtained to figure out the regulation mechanism of lncRNA. Our findings may provide evidence of the potential role of lncRNA in the diagnosis, prognosis and target therapy of GBM. PMID- 30005852 TI - SH2B3 aberrations enriched in iAMP21 B lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) represents the most common childhood malignancy. Although survival for pediatric B-ALL has approached 90%, variability in outcome among and within cytogenetically defined subgroups persists. While G banding and fluorescence in situ hybridization (FISH) have been used to characterize leukemic clones, there is added value of chromosomal microarray and next generation sequencing in screening genome-wide for copy number aberrations, copy neutral loss of heterozygosity and nucleotide variations. Evaluation of novel genetic aberrations can provide information about the biologic mechanisms of cytogenetically defined subgroups associated with poor prognosis, explain heterogeneity in patient outcome and identify novel targets for therapeutic intervention. The high risk B-ALL intrachromosomal amplification of chromosome 21, (iAMP21), subtype is characterized by amplification of a region of chromosome 21 that typically encompasses the RUNX1 gene and is associated with poor prognosis. Analysis of chromosomal microarray and FISH data revealed that deletions of SH2B3, encoding a negative regulator of multiple tyrosine kinase and cytokine signaling pathways, are enriched among leukemias harboring iAMP21. Enrichment of SH2B3 aberrations in the iAMP21 subtype may indicate that loss of SH2B3 contributes to disease progression and raises the possibility that these leukemias may be sensitive to tyrosine kinase inhibitors. PMID- 30005853 TI - Efficacy and patient satisfaction in the use of subcutaneous immunoglobulin immunotherapy for the treatment of auto-immune neuromuscular diseases. AB - We reviewed the efficacy of SCIg administration in terms of muscle strength maintenance and patient satisfaction comparing with IVIg in the treatment of auto immune neuromuscular diseases. A systematic review was conducted, and identified studies from databases (PUBMED, EMBASE, EBSCO, Web of Science and Google Scholar) which were analyzed. The methodological quality of the selected publications was evaluated using the Newcastle-Ottawa Scale. Data were extracted from a total of 11 studies Fixed and random-effect model meta-analyses were performed. For the maintenance of muscle strength, Overall Neuropathy Limitations Scale (ONLS) data from 100 patients diagnosed with multifocal mononeuropathy (MMN) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were pooled together. Switching to subcutaneous immunoglobulin administration led to a significant improvement (fixed effects model, p = 0.002). In data collected using the Medical Research Council Scale for Muscle Strength data from 140 patients with a wider range of disorders, a small but significant improvement in overall strength was observed in the SCIg group (p < 0.0001). In addition, the results of two studies measuring health-related quality of life and patient satisfaction were pooled. Data from 49 patients suffering from MMN, CIDP, and a variety of different myopathies demonstrated a small but significant increase in the mean 36-Item Short Form Survey (SF-36) scores (p < 0.0001). A highly significant difference was revealed when comparing data from 119 patients' responses to the Life Quality Index questionnaire (LQI) assessing patient satisfaction (p < 0.0001). This is the first analysis showing that SCIg is more effective than IVIg in improving Patient Reported Outcomes in auto-immune neuromuscular disease. These results should permit a broad range of patients to self-administer immunoglobulin treatments at home, potentially improving patient acceptability while reducing hospital visits and healthcare costs for the treatment of chronic auto-immune neuropathies. PMID- 30005854 TI - Drug-induced lupus: Traditional and new concepts. AB - Drug-induced lupus (DIL) includes a spectrum of drug-induced reactions often characterised by a clinical phenotype similar to that of idiopathic systemic lupus eruthematosus (SLE) but usually lacking major SLE complications. Different drugs may be associated with distinct clinical and serological profiles, and early recognition is crucial. Drugs traditionally associated with DIL include procainamide, hydralazine, quinidine and others, but strong associations with newer agents, such as TNF alpha (TNFalpha) inhibitors, are increasingly recognised. The pathogenic mechanisms explaining how drugs that have heterogeneous chemical structure and function lead to autoimmunity are only partially understood. However, it is likely that traditional DIL-associated agents can boost innate immune responses, particularly neutrophil responses, with neutrophil extracellular trap (NET) formation and exposure of autoantigens. Research in the field of DIL is evolving and may provide interesting models for the study of autoimmunity. PMID- 30005855 TI - Letter to the Editor: Autoimmune pathogenic mechanisms in Huntington's disease. PMID- 30005856 TI - Inflammation and dementia: Using rheumatoid arthritis as a model to develop treatments? AB - Dementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia. PMID- 30005857 TI - Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory. AB - Spondyloarthritides (SpA) include inflammatory joint diseases with various clinical phenotypes that may also include the axial skeleton and/or entheses. SpA include psoriatic arthritis, reactive arthritis, enteropathic arthritis and ankylosing spondylitis; the latter is frequently associated with extra-articular manifestations, such as uveitis, psoriasis, and inflammatory bowel disease. SpA are associated with the HLA-B27 allele and recognize T cells as key pathogenetic players. In contrast to other rheumatic diseases, SpA affect women and men equally and are not associated with detectable serum autoantibodies. In addition, but opposite to rheumatoid arthritis, SpA are responsive to treatment regimens including IL-23 or IL-17-targeting biologics, yet are virtually unresponsive to steroid treatment. Based on these differences with prototypical autoimmune diseases, such as rheumatoid arthritis or connective tissue diseases, SpA may be better classified among autoinflammatory diseases, with a predominant innate immunity involvement. This would rank SpA closer to gouty arthritis and periodic fevers in the spectrum of rheumatic diseases, as opposed to autoimmune predominant diseases. We herein provide available literature on risk factors associated with SpA in support of this hypothesis with a specific focus on genetic and environmental factors. PMID- 30005859 TI - Classification of primary antiphospholipid syndrome as systemic lupus erythematosus: Analysis of a cohort of 214 patients. AB - OBJECTIVES: To assess the limitations of the SLICC (Systemic Lupus International Collaborating Clinics) classification criteria for systemic lupus erythematosus (SLE), in patients with primary antiphospholipid syndrome (PAPS). METHODS: Retrospective study of a cohort of APS patients (Sydney criteria). We successively excluded patients with (1) at least one "SLE-specific" manifestation (biopsy-proven SLE nephropathy, arthritis, cutaneous, or neurologic SLE manifestations, pericarditis, autoimmune haemolytic anaemia, oral and nasal ulcers, non-scarring alopecia, anti-dsDNA, and anti-Sm antibodies), (2) any other autoimmune connective tissue disease, and/or (3) antinuclear antibodies >1/320. Careful file review confirmed PAPS among the remaining patients. We then assessed the number of SLICC criteria each patient met. RESULTS: Among these 214 APS patients, we excluded 85 with at least one SLE-specific manifestation, 8 with another connective tissue disease, and 21 with antinuclear antibodies >1/320, leaving 100 patients with primary APS. Among them, 28% met at least 4 SLICC classification criteria including one clinical and one immunological criterion (antiphospholipid antibodies, aPL, by definition) and could thus theoretically be classified with SLE. Fourteen had an arterial phenotype (50%), 9 a history of catastrophic APS (32%), and 18 a triple-positive profile for aPL (64%). None had developed SLE during a median follow-up of 12 [6.5-17] years. CONCLUSION: Because 28% of our patients with longstanding and strictly defined PAPS could be mistakenly classified as SLE, they were at risk of deleterious therapeutic management. We therefore suggest that any future classification for SLE should specifically require at least one SLE-specific criterion for patients with aPL. PMID- 30005858 TI - Subclinical cardiovascular disease and Systemic Sclerosis: A comparison between risk charts, quantification of coronary calcium and carotid ultrasonography. AB - BACKGROUND AND OBJECTIVES: Recently published population-based cohort studies have shown a high prevalence of cardiovascular disease in Systemic Sclerosis (SSc) patients. The aim of this study is to compare three different methods to measure cardiovascular risk in patients with scleroderma. METHODS: Forty-three SSc patients were included. A prospective study was performed for evaluation of cardiovascular risk and subclinical atheromatosis using 3 non-invasive methods: cardiovascular risk tables, carotid Doppler ultrasonography and quantification of coronary calcium by computerized tomography (CT). RESULTS: The cardiovascular risk charts for the Spanish population did not identify patients at high cardiovascular risk. Framingham-REGICOR identified 13 intermediate-risk patients. Twenty-two patients (51.2%) had plaques on carotid ultrasonography. We performed a ROC curve to identify the best cutoff point for the quantification of coronary artery calcium (CACscore), the value of CACscore > 28 AU (Agatston Units) had the highest sensitivity (73%) and specificity (81%) for the diagnosis of subclinical atheromatosis. In the multiple regression study, age and decreased HDL cholesterol levels were identified as independent factors for subclinical atherosclerotic disease. No disease-related factors were associated with increased subclinical arteriosclerosis. CONCLUSION: Carotid ultrasound and CACscore are useful for identifying subclinical atheromatosis in patients with SSc and are superior compared to risk charts used for general population. HDL cholesterol and age were independent factors for the presence of subclinical atherosclerotic disease. A carotid ultrasound or CT should be performed for early detection of subclinical atheromatosis if these factors are present. PMID- 30005860 TI - Therapy of scleroderma renal crisis: State of the art. AB - Scleroderma renal crisis (SRC) is an uncommon but still life-threatening manifestation of systemic sclerosis (SSc). The incidence of SRC has decreased in the last few decades, probably due to a widespread use of vasodilators in SSc patients. It is well-recognized that exposure to different drugs can trigger SRC (corticosteroids, cyclosporine) or might prevent its occurrence (iloprost, calcium channel blockers). The prognosis of this life-threatening manifestation has not substantially improved since 1980s, when ACE-inhibitors were introduced in its treatment. ACE-inhibitors remain the mainstay in the therapy of SRC due to their efficacy in controlling malignant hypertension; indeed, the prognosis largely depends on the rapid improvement of the ongoing renal ischemia. Calcium channel blockers and in third line diuretics and alpha-blockers should be used as additional therapy if blood pressure control remains suboptimal despite maximum tolerated doses of ACE-inhibitors. Given the growing evidence on the role of complement activation and endothelin-1 in the pathogenesis of SRC, recent case series and case reports have suggested the use of C5-inhibitors and endothelin receptor antagonists in the therapy of SRC, mainly in the refractory cases. Plasma-exchange seems to give some benefits in patients with SRC and microangiopathy or intolerant to ACE-inhibitors. Renal transplantation is the last treatment option and its outcome is similar to that reported in other connective tissue disorders, with a 5-year patient survival rate of about 82%. In this review we summarize the current knowledge in the treatment of SRC. PMID- 30005861 TI - Support of precision medicine through risk-stratification in autoimmune liver diseases - histology, scoring systems, and non-invasive markers. AB - Autoimmune liver diseases (AILDs) are complex conditions, which arise from the interaction between a genetic susceptibility and unknown environmental triggers. They represent a relevant cause of liver failure and liver transplantation worldwide. As a testimony of our progress in understanding the biology of AILDs and the disease progression is the overall median survival which has increased over the last decade. However, there are still major challenges such as the lack of therapies and surveillance strategies in primary sclerosing cholangitis (PSC), the management and treatment of non-responders to first-line therapies in primary biliary cholangitis (PBC) and the need for tailoring immunosuppressive drugs in autoimmune hepatitis (AIH). The different disease course and treatment response in patients with AILDs might be related to a heterogeneous genetic background between individuals which translates in a heterogeneous clinical phenotype. Thus, it becomes essential to personalise management and treatment based on specific risk profiles, e.g. low-risk and high-risk, based on genetic and molecular signatures. It is now possible, thanks to the development of large-scale AILDs patient cohorts, that such diseases can be analysed using various high-throughput methods like gene expression profiling, next generation sequencing and other omics technologies to identify unique fingerprints based on which a personalised or tailor-made management and therapy can be developed. The final aim being to facilitate treatment decision-making that balances patient-specific risks and preferences. This is critical especially now with the current and forthcoming availability of more efficacious medications. To reach this point we need specific interventions such as creating bigger biobanks, sequencing more genomes and linking biological information to health-related data. We have already identified subsets of patients with different risk profiles among patients with PBC, PSC and AIH by using clinical tools such as liver histology, laboratory investigation and non-invasive methods. In this manuscript, we review the clinical features and investigations that already enable us to individualize the care of PBC patients and that might support the development of precision medicine (PM) in AILDs. PMID- 30005863 TI - Comment on: comparative effectiveness of bariatric procedures among adolescents: the PCORnet Bariatric Study. PMID- 30005862 TI - Pathogenic role of tissue-resident memory T cells in autoimmune diseases. AB - The tissue-resident memory T (TRM) cells constitute a newly identified subset of memory T cells which are non-circulating and they persist for long-term in epithelial barrier tissues, including skin, lung, gastrointestinal tract and reproductive tract, and in non-barrier tissues, including brain, kidney, pancreas and joint. These cells provide rapid on-site immune protection against previous exposed pathogens in peripheral tissues. There cells are transcriptionally, functionally and phenotypically distinguished from circulating effector memory T cells. In addition to their protective functions, increasing evidence reveals that autoreactive and/or aberrantly activated TRM cells may be involved in the pathogenesis of autoimmune disorders such as psoriasis and, as recently reported, may contribute to vitiligo, autoimmune hepatitis and rheumatoid arthritis. Therefore, this review aims to summarize the current progress in the biology of TRM cells, such as the newly identified TRM markers, upstream regulators, and the functions of TRM cells. We also discuss the contributions of TRM cells to the development of autoimmunity to broaden our understanding of autoimmune diseases and to provide novel potential therapeutic strategies for these diseases. PMID- 30005864 TI - Comment on: diagnostic value of computed tomography for detecting anastomotic or staple line leakage after bariatric surgery. PMID- 30005865 TI - Personalized Cancer Vaccine Platform for Clinically Relevant Oncolytic Enveloped Viruses. AB - The approval of the first oncolytic virus for the treatment of metastatic melanoma and the compiling evidence that the use of oncolytic viruses can enhance cancer immunotherapies targeted against various immune checkpoint proteins has attracted great interest in the field of cancer virotherapy. We have developed a novel platform for clinically relevant enveloped viruses that can direct the virus-induced immune response against tumor antigens. By physically attaching tumor-specific peptides onto the viral envelope of vaccinia virus and herpes simplex virus 1 (HSV-1), we were able to induce a strong T cell-specific immune response toward these tumor antigens. These therapeutic peptides could be attached onto the viral envelope by using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat N-terminally fused to the tumor specific peptides or, alternatively, therapeutic peptides could be conjugated with cholesterol for the attachment of the peptides onto the viral envelope. We used two mouse models of melanoma termed B16.OVA and B16-F10 for testing the efficacy of OVA SIINFEKL-peptide-coated viruses and gp100-Trp2-peptide-coated viruses, respectively, and show that by coating the viral envelope with therapeutic peptides, the anti-tumor immunity and the number of tumor-specific CD8+ T cells in the tumor microenvironment can be significantly enhanced. PMID- 30005866 TI - Global Transcriptional Response to CRISPR/Cas9-AAV6-Based Genome Editing in CD34+ Hematopoietic Stem and Progenitor Cells. AB - Genome-editing technologies are currently being translated to the clinic. However, cellular effects of the editing machinery have yet to be fully elucidated. Here, we performed global microarray-based gene expression measurements on human CD34+ hematopoietic stem and progenitor cells that underwent editing. We probed effects of the entire editing process as well as each component individually, including electroporation, Cas9 (mRNA or protein) with chemically modified sgRNA, and AAV6 transduction. We identified differentially expressed genes relative to control treatments, which displayed enrichment for particular biological processes. All editing machinery components elicited immune, stress, and apoptotic responses. Cas9 mRNA invoked the greatest amount of transcriptional change, eliciting a distinct viral response and global transcriptional downregulation, particularly of metabolic and cell cycle processes. Electroporation also induced significant transcriptional change, with notable downregulation of metabolic processes. Surprisingly, AAV6 evoked no detectable viral response. We also found Cas9/sgRNA ribonucleoprotein treatment to be well tolerated, in spite of eliciting a DNA damage signature. Overall, this data establishes a benchmark for cellular tolerance of CRISPR/Cas9-AAV6-based genome editing, ensuring that the clinical protocol is as safe and efficient as possible. PMID- 30005867 TI - Therapeutic Effects of Adipose Stem Cells from Diabetic Mice for the Treatment of Type 2 Diabetes. AB - To assess the potential therapeutic effects of adipose tissue-derived mesenchymal stem cells (ASCs) for the treatment of type 2 diabetes (T2D), we compared the phenotype and functionality of ASCs isolated from high-fat diet and streptozotocin (STZ)-induced T2D and the leptin receptor-deficient (db/db) mice with cells from healthy C57BL/6 mice. ASCs from T2D or db/db mice showed similar expression patterns of cellular markers and abilities to differentiate into adipocytes, osteoblasts, and chondrocytes. However, the rate of proliferation was reduced. ASCs from db/db mice secreted less hepatocyte growth factor (HGF). T2D mice receiving a single intravenous injection of T2D or db/db ASCs showed increased insulin sensitivity, reduced inflammation and fat content in adipose tissue and the liver and increased pancreatic beta cell mass through 5 weeks post infusion. Our data show that, although ASCs from T2D or db/db mice had inferior proliferative capacity compared to cells from healthy controls, improved insulin sensitivity and less beta cell death was seen in T2D mice receiving mesenchymal stem cell (MSC) therapy. This study offers evidence that ASCs from diabetic donors have the potential to be used for cell therapy in the treatment of insulin resistance and T2D. PMID- 30005868 TI - MicroRNA-125b Interacts with Foxp3 to Induce Autophagy in Thyroid Cancer. AB - Thyroid cancer is rapidly increasing in incidence worldwide. Although most thyroid cancer can be cured with surgery, radioactive iodine, and/or chemotherapy, thyroid cancers still recur and may become chemoresistant. Autophagy is a complex self-degradative process that plays a dual role in cancer development and progression. In this study, we found that miR-125b was downregulated in tissue samples of thyroid cancer as well as in thyroid cancer cell lines, and the expression of Foxp3 was upregulated. Further, we demonstrated that miR-125b could directly act on Foxp3 by binding to its 3' UTR and inhibit the expression of Foxp3. A negative relationship between miR-125b and Foxp3 was thus revealed. Overexpression of miR-125b markedly sensitized thyroid cancer cells to cisplatin treatment by inducing autophagy through an Atg7 pathway in vitro and in vivo. Taken together, our findings demonstrate a novel mechanism by which miR-125b has the potential to negatively regulate Foxp3 to promote autophagy and enhance the efficacy of cisplatin in thyroid cancer. miR-125 may be of therapeutic significance in thyroid cancer. PMID- 30005871 TI - Diosgenin inhibited the expression of TAZ in hepatocellular carcinoma. AB - Emerging evidence has supported that TAZ (transcriptional co-activator with PDZ binding motif), one transcription co-activator in Hippo signaling pathway, plays an oncogenic role in liver carcinogenesis. Targeting TAZ could be a potential therapeutic approach for liver cancer patients. In the current study, we aim to determine whether diosgenin could be an inhibitor of TAZ in liver cancer cells. We found that diosgenin inhibited the expression of TAZ in liver cancer cells. Moreover, we found that diosgenin inhibited cell growth, induced apoptosis, suppressed cell migration and invasion in part via inhibition of TAZ in liver cancer cells. Our study provides the evidence to support that diosgenin could be a potential agent for treating human liver cancer. PMID- 30005870 TI - Rab3IP interacts with SSX2 and enhances the invasiveness of gastric cancer cells. AB - RAB3A interacting protein (Rab3IP) has been determined to be involved in cancer progression; however, its expression pattern and function in gastric cancer remain unknown. The aim of this study was to determine the association between Rab3IP and gastric cancer, in addition to its functional role in this disease. Overexpression of Rab3IP in gastric cancer was verified at both transcriptional and translational levels. Analysis of clinical data indicated its role as an independent risk factor for survival. Cellular studies showed that Rab3IP could induce an aggressive phenotype in gastric cancer cells and that its expression was correlated with markers of the epithelial-mesenchymal transition (EMT). In addition, we verified the co-expression of and interplay between Rab3IP and SSX2 during gastric cancer progression. Thus, these findings elucidated the central role of Rab3IP in inducing an invasive phenotype in gastric cancer cells, in addition to its involvement in EMT. Our results could be exploited for the clinical prognosis and treatment of this important disease. PMID- 30005869 TI - Exosome-Mediated Small RNA Delivery: A Novel Therapeutic Approach for Inflammatory Lung Responses. AB - Exosomes (EXOs) are a type of extracellular nanovesicles released from living cells. Accumulating evidence suggests that EXOs are involved in the pathogenesis of human diseases, including lung conditions. In recent years, the potential of EXO-mediated drug delivery has gained increasing interest. In this report, we investigated whether inhaled EXOs serve as an efficient and practical delivery vehicle to activate or inhibit alveolar macrophages (AMs), subsequently modulating pulmonary immune responses. We first identified the recipient cells of the inhaled EXOs, which were labeled with PKH26. We found that only lung macrophages efficiently take up intratracheally instilled EXOs in vivo. Using modified calcium chloride-mediated transformation, we manipulated small RNA molecules in serum-derived EXOs, including siRNAs, microRNA (miRNA) mimics, and miRNA inhibitors. Via intratracheal instillation, we successfully delivered siRNA and miRNA mimics or inhibitors into lung macrophages using the serum-derived EXOs as vehicles. Furthermore, EXO siRNA or miRNA molecules are functional in modulating LPS-induced lung inflammation in vivo. Beneficially, serum-derived EXOs themselves do not trigger lung immune responses, adding more favorable features to serve as drug delivery agents. Collectively, we developed a novel protocol using serum-derived EXOs to deliver designated small RNA molecules into lung macrophages in vivo, potentially shedding light on future gene therapy of human lung diseases. PMID- 30005873 TI - Chd1p recognizes H3K36Ac to maintain nucleosome positioning near the transcription start site. AB - In Saccharomyces cerevisiae, the ATP-dependent chromatin remodeler, Chd1p, globally affects nucleosome positioning at coding regions, where nucleosomes are specifically and directionally aligned with respect to the transcription start site (TSS). Various auxiliary domains of remodelers play critical roles by performing specialized functions that are unique to the type of remodeler. Here, we report that yeast Chd1p directly binds to acetylated histone H3K36 (H3K36Ac) via its chromodomain, and that H3K36Ac stimulates the nucleosome sliding activity of Chd1p in vitro. Furthermore, we use genome-wide analysis to demonstrate that H3K36Ac promotes the remodeling activity of Chd1p to maintain chromatin stability at the 5' ends of genes in vivo. Our work linking Chd1p with H3K36Ac provides novel insights into how the nucleosome remodeling activity of Chd1p is controlled near the TSS. PMID- 30005872 TI - The FGF2 aptamer inhibits the growth of FGF2-FGFR pathway driven lung cancer cells. AB - Cancers, including lung cancer, are a leading cause of death worldwide. To overcome this deadly disease, multiple modality inhibitors have been developed. These include cytotoxic agents, molecular targeted small molecules, such as tyrosine kinase inhibitors, and neutralizing antibodies. An aptamer is a short single-stranded nucleic acid molecule that is selected in vitro from a large random sequence library based on its high and specific affinity to a target molecule. Aptamers can be applied to therapeutics of various types of diseases, including cancer, due to their strong and specific neutralizing activities. However, the efficacy of aptamer-based therapy for cancer cells is not well characterized. In this study, we aimed to show that the FGF2 aptamer is effective for the treatment of FGF2 dependent lung cancer cells. We previously developed PC9GR lung cancer cells, whose proliferation is dependent on EGFR and FGF2-FGFR pathways in a cell autonomous manner. Using PC9GR cells, we demonstrate that the addition of the FGF2 aptamer induces more significant inhibition of PC9GR cell proliferation than does the addition of EGFR inhibitor alone. Furthermore, the addition of the FGF2 aptamer more significantly inhibits the downstream signals and induces apoptosis to a higher extent than does the addition of EGFR inhibitor alone. Our results show that the FGF2 aptamer inhibits the growth of FGF2-FGFR pathway-dependent lung cancer cells. The findings provide preclinical evidence that aptamers can be useful for cancer treatment. PMID- 30005874 TI - Palmitate induces lipoapoptosis in Schwann cells through ROS generation-mediated STAMP2 downregulation. AB - Free fatty acids (FFAs) are considered the principal inducers of lipotoxicity, leading to cell dysfunction and/or cell death. Lipotoxicity in Schwann cells (SCs) damages neurons, which may be associated with peripheral neuropathies and axon degeneration. However, the molecular mechanism by which FFAs exert lipotoxicity in SCs remains to be established. In the present study, we demonstrate that palmitate exerts lipotoxicity in SCs through apoptosis and that palmitate-induced lipotoxicity in SCs is mediated through reactive oxygen species (ROS) generation. We observed that the six-transmembrane protein of prostate 2 (STAMP2), which plays a pivotal role in lipid homeostasis, is expressed in SCs. We further demonstrate that palmitate induces lipoapoptosis in SCs through ROS generation-mediated STAMP2 downregulation and that STAMP2 depletion accelerates the palmitate-exerted lipoapoptosis in SCs, indicating that STAMP2 confers on SCs the ability to resist palmitate-induced lipotoxicity. In conclusion, palmitate induces lipoapoptosis in SCs through ROS generation-mediated STAMP2 downregulation. Our findings indicate that ROS and STAMP2 may represent suitable targets for pharmacological interventions targeting lipotoxicity-associated peripheral neuropathies and axon degeneration. PMID- 30005875 TI - Characterization of diterpene synthase genes in the wild rice species Oryza brachyatha provides evolutionary insight into rice phytoalexin biosynthesis. AB - Cultivated rice (Oryza sativa; Os) produces a variety of labdane-related diterpenoids; not only phytohormone gibberellins (GAs) but also phytoalexins for defense including phytocassanes, momilactones and oryzalexins. Their carbon skeleton diterpenes are constructed from geranylgeranyl diphosphate via ent copalyl diphosphate (ent-CDP) or its diastereomer syn-CDP. These two-step reactions are successively catalyzed by homologs of the two diterpene synthases, ent-CDP synthase (ent-CPS) and ent-kaurene synthase (KS) that are responsible for the biosynthesis of GAs; e.g. OsCPS4 and OsKSL8 that are involved in the biosynthesis of oryzalexin S, a rice phytoalexin. Oryza brachyantha (Ob) is the most distant wild rice species from Os among the Oryza genus. We previously reported that the Ob genome contains ObCPS_11g, ObKSL8-a, ObKSL8-b and ObKSL8-c for specialized metabolism at a locus similar to the OsKSL8 locus on chromosome 11. These Ob genes are closely related to OsCPS4 and OsKSL8, respectively. We herein characterize the diterpene synthase genes in Ob, using functional analyses and expression analysis. Recombinant OsKSL8 and ObKSL8-a showed the same in vitro function when syn-CDP or normal-CDP were used as substrates. Nonetheless, our results suggest that Ob produces normal-CDP-related diterpenoid phytoalexins, presumably via ObKSL8-a, while Os produces a syn-CDP-related phytoalexin, oryzalexin S, via OsKSL8. This difference must be due to the kinds of CPS that are present in each species; Os has OsCPS4 encoding syn-CPS, while Ob has ObCPS_11g encoding normal-CPS. Thus, we propose the evolutionary history underlying oryzalexin S biosynthesis: the gain of a syn-CPS was a critical event allowing the biosynthesis of oryzalexin S. PMID- 30005876 TI - The role of lncRNA XIST/miR-211 axis in modulating the proliferation and apoptosis of osteoarthritis chondrocytes through CXCR4 and MAPK signaling. AB - Long noncoding RNAs (lncRNAs) participate in multiple diverse diseases, including osteoarthritis (OA). Here, we explored the role of lncRNA XIST in OA and identified the potential molecular mechanisms. The expression of XIST in cartilage samples in patients with OA was significantly upregulated. XIST knockdown remarkably suppressed IL-1beta-suppressed OA chondrocyte proliferation while promoted IL-1beta-induced cell apoptosis. By employing online tools, miRNAs related to CXCR4, a major contributor to chondrocyte apoptosis, and XIST were selected. miR-211 expression could be significantly inhibited by IL-1beta stimulation, and miR-211 negatively regulated XIST expression and CXCR4 protein levels. Through direct binding, XIST served as a ceRNA for miR-211 to counteract miR-211-mediated CXCR4 repression, thereby modulating chondrocyte proliferation and apoptosis through downstream MAPK signaling. In OA tissues, miR-211 expression was significantly downregulated while CXCR4 mRNA expression was upregulated. miR-211 was negatively correlated with XIST and CXCR4, respectively, while XIST and CXCR4 was positively correlated in tissue samples. In conclusion, the study revealed that lncRNA XIST can promote the proliferation of OA chondrocytes and promote apoptosis through the miR-211/CXCR4 axis. Thus, lncRNA XIST might be considered as a potential therapeutic target for OA treatment. PMID- 30005877 TI - Structural insights into a novel functional dimer of Staphylococcus aureus RNase HII. AB - RNase HII exists ubiquitously in organisms and functions as a monomer in prokaryotes. We determined the crystal structure of Staphylococcus aureus RNase HII (Sa-RNase HII), which displays a novel dimer conformation, with the active site of each monomer covered by the other one. Both small-angle X-ray scattering and gel-filtration analysis confirmed that Sa-RNase HII exists as a homodimer in solution. Enzymatic analysis revealed that the "self-inhibited" dimeric form is catalytically active. Furthermore, continuous-wave electron paramagnetic resonance experiments clarified that the Sa-RNase HII dimer undergoes a large conformational change upon substrate binding, but remains a dimer to catalyze the reaction. Our structural and biochemical studies identified a novel functional dimer of Sa-RNase HII with distinct regulation mechanism for its catalytic activity. PMID- 30005880 TI - Infratemporal fossa tumors: When to suspect a malignant tumor? A retrospective cohort study of 62 cases. AB - OBJECTIVES: Infratemporal fossa (ITF) tumors are rare and little is known about their general epidemiology, making it sometimes difficult for clinicians, who seldom encounter them, to distinguish between benign and malignant forms on the basis of the initial clinical and radiological work-up alone. The objectives of this retrospective study were: (i) to determine the respective prevalences of the various histologic types of ITF tumor, and (ii) to assess associations between certain clinical and radiological features and malignancy. METHODS: A single center observational study in a university hospital included all new consecutive cases of ITF tumor treated from January 2000 to December 2016. Histologic type, demographics, clinical presentation and imaging findings were analyzed. RESULTS: In total, 62 patients were included. 74% of tumors were benign (n=46) and 26% malignant. Juvenile nasopharyngeal angiofibroma, adenoid cystic carcinoma and schwannoma were the most frequent histologic types, accounting for 47%, 16% and 10% of cases, respectively. The only clinical or imaging signs significantly associated with malignancy were trismus, facial pain, facial hypoesthesia and neural invasion on magnetic resonance imaging (all P-values<0.05). CONCLUSION: This study provides general epidemiological data on ITF tumors, and identified several clinical and radiologic signs to help clinicians suspect malignancy. PMID- 30005882 TI - The paradox between randomized controlled trials and propensity score-matched real-world data: Moving from dissonance to dialog? PMID- 30005881 TI - Toxoplasma ubiquitin-like protease 1, a key enzyme in sumoylation and desumoylation pathways, is under the control of non-coding RNAs. AB - Sumoylation and desumoylation are reversible pathways responsible for modification of protein structures and functions by the reversible covalent attachment of a small ubiquitin-like modifier (SUMO) peptide. These pathways are important for a wide range of cellular processes and require a steady supply of SUMO, which is generated by an enzymatic reaction catalysed by the ubiquitin-like protease (Ulp) family. Here we show by functional complementation analysis that the Ulp1 of Toxoplasma gondii (TgUlp1) can rescue a growth-deficient phenotype of a yeast-Ulp1 knockout. Recombinant TgUlp1 is an active enzyme capable of removing SUMO from a sumoylated substrate. Using a clonal transgenic strain of T. gondii expressing an epitope-tagged version of TgUlp1, we detected that the expression of TgUlp1 is modulated by Tg-miR-60, the most abundant species of micro RNA found in the T. gondii type 1 strain. The introduction of Tg-miR-60 inhibitor caused an increase in TgUlp1 expression and its enzymatic activity, as well as affecting the parasite's growth fitness. Moreover, we discovered a polyadenylated antisense RNA transcribed from the TgUlp1 locus, referred to as TgUlp1-NAT1 (TgUlp1-natural antisense transcript 1). Both Tg-miR-60 and TgUlp1-NAT1 confer a regulatory function by down-regulating the expression of TgUlp1 and affecting the sumoylation and desumoylation pathways in T. gondii. PMID- 30005879 TI - Neuronal modulation of brown adipose activity through perturbation of white adipocyte lipogenesis. AB - OBJECTIVE: Crosstalk between adipocytes and local neurons may be an important regulatory mechanism to control energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) expands sympathetic neurons within white adipose tissue (WAT) and stimulates the appearance of "beige" adipocytes. Here we tested whether WAT DNL activity can also influence neuronal regulation and thermogenesis in brown adipose tissue (BAT). METHODS AND RESULTS: Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. This increased sympathetic innervation could be observed at both 22 degrees C and 30 degrees C, indicating it is not a response to heat loss but rather adipocyte signaling. In contrast, selective ablation of FASN in brown adipocytes of mice (iUCP1FASNKO) failed to modulate sympathetic innervation and the thermogenic program in BAT. Surprisingly, DNL in brown adipocytes was also dispensable in maintaining euthermia when UCP1FASNKO mice were cold-exposed. CONCLUSION: These results indicate that DNL in white adipocytes influences long distance signaling to BAT, which can modify BAT sympathetic innervation and expression of genes involved in thermogenesis. PMID- 30005883 TI - Surgical pulmonary embolectomy and catheter-based therapies for acute pulmonary embolism: A contemporary systematic review. AB - OBJECTIVES: Mortality in acute pulmonary embolism (PE) is believed to be principally due to the subgroup of PEs that are massive. Systemic thrombolysis is the therapeutic mainstay for acute massive PE, despite evidence suggesting limited survival benefits. Both catheter-based therapies (CBT) and surgical pulmonary embolectomy (SE) are well-accepted alternatives to treat acute PE. However, the comparative effectiveness of these approaches is difficult to study. We conducted a systematic review of CBT and SE for acute PE. METHODS: The PubMed database was queried for CBT- and SE-related publications between January 1998 and June 2017. A minimum of 10 patients undergoing intervention(s) was required for inclusion, and studies must not have excluded patients with massive PE. End points examined included hospital mortality, and additionally for CBT, procedural success rate. RESULTS: A total of 75 studies (41 of CBT, 34 of SE) were identified, with 1650 patients undergoing CBT and 1101 undergoing SE. Patients undergoing SE were more critically ill than those undergoing CBT (massive PE, 545 out of 975 [55.9%] for SE vs 742 out of 1553 [47.8%] for CBT). Cardiopulmonary resuscitation (CPR) was required in 217 out of 1015 patients undergoing SE (21.4%) versus 38 out of 983 patients undergoing CBT (4.0%). The hospital mortality of SE was 14.0%, versus 5.6% for CBT, in the entire patient group. However, the hospital mortality of SE in patients with pre-SE CPR was 46.3%, whereas it was 6.8% in those patients without pre-SE CPR. Although CPR was associated with an increased risk of mortality both for CBT and SE, it accounted for all of the mortality effect on SE (the adjusted odds ratio for CPR in a random effects model with treatment considered was 9.79 (95% confidence interval, 4.98-19.17; P < .0001). The adjusted odds ratio for mortality for SE relative to CBT was 1.36 (95% confidence interval, 0.80-2.32; P = .84). Moreover, CBT was associated with a procedural failure rate of 8.3%. CONCLUSIONS: Both CBT and SE were associated with satisfactory published outcomes. SE is associated with greater absolute postprocedure mortality than CBT, but has been undertaken in more critically ill populations. The markedly higher incidence of CPR in SE accounts for the differential mortality between the patients undergoing SE and those undergoing CBT. Decision making with respect to best therapy must take into account potential needs for periprocedure artificial mechanical right ventricle and lung support, institutional experience and outcomes, anticipated therapeutic efficacy and benefit, and approach-specific risks. PMID- 30005884 TI - Discussion. PMID- 30005878 TI - The impact of ERalpha action on muscle metabolism and insulin sensitivity - Strong enough for a man, made for a woman. AB - BACKGROUND: The incidence of chronic disease is elevated in women after menopause. Natural variation in muscle expression of the estrogen receptor (ER)alpha is inversely associated with plasma insulin and adiposity. Moreover, reduced muscle ERalpha expression levels are observed in women and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction impacts nearly a quarter of the U.S. adult population and elevates chronic disease risk including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed. SCOPE OF THE REVIEW: This review will provide evidence supporting a critical and protective role for skeletal muscle ERalpha in the regulation of metabolic homeostasis and insulin sensitivity, and propose novel ERalpha targets involved in the maintenance of metabolic health. MAJOR CONCLUSIONS: Studies identifying ERalpha-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutics to improve the metabolic health of women while limiting secondary complications that have plagued traditional hormone replacement interventions. PMID- 30005885 TI - Factors impacting long-term pulmonary autograft durability after the Ross procedure. AB - OBJECTIVE: Although the Ross procedure provides excellent long-term survival and a high quality of life, its use has been limited to relatively few centers. In this study, we evaluated long-term Ross procedure results in adults to assess the predictors of pulmonary autograft durability. METHODS: Between 1998 and 2015, 793 consecutive adult patients underwent the Ross procedure. The total root replacement technique was used in all patients. RESULTS: The early mortality rate was 2.9%. The mean follow-up duration was 6.5 +/- 3.2 years, and the 10-year survival rate was 90.4%. Longitudinal mixed-effects ordinal regression identified a combination of bicuspid aortic valve and aortic insufficiency (odds ratio, 2.19; P < .001) as predictors for progression of autograft valve insufficiency at follow-up. The cumulative incidence of autograft reoperations at 10 years was 8.6%. Competing risk regression identified bicuspid aortic valve insufficiency as the independent predictor of autograft reoperation (subdistribution hazard ratio, 2.16; P = .030). Moreover, patients with bicuspid aortic valve and aortic insufficiency had greater increases in annulus (P < .001), sinus (P < .001), and ascending aorta (P < .001) diameters over time. CONCLUSIONS: For patients undergoing the Ross procedure, a combination of bicuspid aortic valves and aortic insufficiency is the main risk factor for late autograft dilatation and dysfunction. PMID- 30005886 TI - Inflammatory and neurohormonal modulation for congenital heart surgery: The quest continues. PMID- 30005887 TI - Surgical unroofing of hemodynamically significant myocardial bridges in a pediatric population. AB - BACKGROUND: Although myocardial bridges (MBs) are traditionally regarded as incidental findings, it has been reported that adult patients with symptomatic MBs refractory to medical therapy benefit from unroofing. However, there is limited literature in the pediatric population. The aim of our study was to evaluate the indications and outcomes for unroofing in pediatric patients. METHODS: We retrospectively reviewed all pediatric patients with MB in our institution who underwent surgical relief. Clinical characteristics, relevant diagnostic data, intraoperative findings, and postoperative outcomes were evaluated. RESULTS: Between 2012 and 2016, 14 pediatric patients underwent surgical unroofing of left anterior descending artery MBs. Thirteen patients had anginal symptoms refractory to medical therapy, and 1 patient was asymptomatic until experiencing aborted sudden cardiac arrest during exercise. Thirteen patients underwent exercise stress echocardiography, all of which showed mid septal dys-synergy. Coronary computed tomography imaging confirmed the presence of MBs in all patients. Intravascular ultrasound imaging confirmed the length of MBs: 28.2 +/- 16.3 mm, halo thickness: 0.59 +/- 0.24 mm, and compression of left anterior descending artery at resting heart rate: 33.0 +/- 11.6%. Invasive hemodynamic assessment with dobutamine confirmed the physiologic significance of the MBs with diastolic fractional flow reserve: 0.59 +/- 0.13. Unroofing was performed with the patient under cardiopulmonary bypass (CPB) in the initial 9 cases and without CPB in the subsequent 5 cases. All patients were discharged without complications. The 13 symptomatic patients reported resolution of symptoms on follow-up, and improvement in symptoms and quality of life was documented using the Seattle Angina Questionnaire version 7. CONCLUSIONS: Unroofing of MBs can be safely performed in pediatric patients, with or without use of CPB. In symptomatic patients, unroofing can provide relief of symptoms refractory to medical therapy. PMID- 30005888 TI - So, you are looking for a job: Pearls for a successful first cardiothoracic job search. AB - The final year of cardiothoracic surgery residency is an exciting time for most trainees because it marks the culmination of many years of hard work and dedication. However, it is not uncommon for trainees to also experience some degree of anxiety or uncertainty, particularly when it comes to understanding the necessary steps and finer details involved in seeking out and securing that much anticipated and well-deserved first job. This article explores the philosophy, strategy, and etiquette essential to navigating the various stages of one's initial job search, providing valuable information and perspective to those hoping to find a position that is best suited to one's skill set, needs, and long term career goals. PMID- 30005889 TI - Evidence of lipid rafts based on the partition and dynamic behavior of sphingomyelins. AB - Sphingomyelin (SM)-rich membrane nano-domains, called lipid rafts, have attracted the interest of researchers due to their potential involvement in the formation of signaling platform. Although there are many studies on lipid rafts, the direct observation of lipid rafts is still challenging owing to two critical reasons. One is the lack of an appropriate fluorescent probe mimicking the native behavior of raft lipids; fluorescent labeling often alters the intrinsic disposition of raft lipids. The other is their spatio-temporal stability; the size of lipid rafts is much smaller than the optical resolution of usual microscopy and their lifetime is much shorter than image acquisition duration. These issues are hampering the visualization of lipid rafts. Our review highlights the recent advances in microscopic techniques to visualize the partition and dynamic behavior of SMs, disclosing the detailed structure of lipid rafts. Moreover, we will elucidate the importance of SM-SM interactions in the stabilization of signaling platforms as lipid rafts. PMID- 30005890 TI - Diagnosing in art. AB - The aim of this article is to present an appealing tool for teaching breast imaging that uses the muses of Renaissance and Baroque artists. The examples described here show how medicine and art can be combined to arouse interest in newcomers to breast imaging. PMID- 30005891 TI - Effect of Ambient Fine Particulate Matter Air Pollution and Colder Outdoor Temperatures on High-Density Lipoprotein Function. AB - Fine particulate matter (PM2.5) air pollution and environmental temperatures influence cardiovascular morbidity and mortality. Recent evidence suggests that several air pollutants can promote dyslipidemia; however, the impact of ambient PM2.5 and temperature on high-density lipoprotein (HDL) function remains unclear. We hypothesized that daily exposures to higher levels of ambient PM2.5 and colder outdoor temperatures would impair HDL functionality. Lipoproteins, serum cholesterol efflux capacity (CEC), and HDL oxidation markers were measured twice in 50 healthy adults (age 32.1 +/- 9.6 years) living in southeast Michigan and associated with ambient and personal-level exposures using mixed models. Although previous 7-day mean outdoor temperature (4.4 +/- 9.8 degrees C) and PM2.5 levels (9.1 +/- 1.8 ug/m3) were low, higher ambient PM2.5 exposures (per 10 ug/m3) were associated with significant increases in the total cholesterol-to-HDL-C ratio (rolling average lag days 1 and 2) as well as reductions in CEC by -1.93% (lag day 5, p = 0.022) and -1.62% (lag day 6, p = 0.032). Colder outdoor temperatures (per 10 degrees C) were also associated with decreases in CEC from -0.62 to 0.63% (rolling average lag days 5 and 7, p = 0.027 and 0.028). Previous 24-hour personal-level PM2.5 and temperature exposures did not impact outcomes, nor were any exposures associated with changes in HDL-oxidation metrics. In conclusion, we provide the first evidence that ambient PM2.5 (even at low levels) and outdoor temperatures may influence serum CEC, a critical antiatherosclerotic HDL function. PMID- 30005892 TI - [An analysis of breast cancer treatment waiting times: Experience of a tertiary referral center in Morocco]. AB - Measuring waiting times is a good indicator of quality and performance of cancer care. However, no detailed evaluation of these deadlines has been carried out in Morocco. The aim of this study was to determine the waiting times of medical care of breast cancer in a national tertiary referral center. The study was carried out by retrospective analysis of 373 cases of patients randomly selected among the cases recruited during the year 2015. Twelve delays of the care pathway were evaluated. The mean age was of 50,7 years. The deadline of access to this center was 9+/-8days. The deadline of access to the diagnosis was 33.5+/-21.2 days. The deadlines of access to multidisciplinary team meeting pre-therapeutic was 20.4+/ 16.9 days. The access to the first treatment was 51.1+/-34.3 days for the neoadjuvant chemotherapy and 75.5+/-34.8 days for surgery. The deadline of access to the postoperative therapeutic proposal was on average 49.2+/-25.2 days. The deadline of access to the postoperative chemotherapy was 83.7+/-28.8 days and 284+/-43.8 days for postoperative radiotherapy in case of adjuvant chemotherapy. The global deadline mammography-radiotherapy was 372+/-66.5 days. Many of our deadlines were long compared to international recommendations. The factors associated with these delays must be analyzed in order to introduce improvement measures to control these indicators. PMID- 30005893 TI - Some benefit from non-oximes MB408, MB442 and MB444 in combination with the oximes HI-6 or obidoxime and atropine in antidoting sarin or cyclosarin poisoned mice. AB - The effect of three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with the oxime HI-6 or obidoxime) of acute poisoning by two nerve agents (sarin and cyclosarin) in mice was studied. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-oximes was evaluated by determination of the 24 h LD50 values of the nerve agents studied and by measurement of the survival time after supralethal poisoning. Addition of all tested non-oximes increased the therapeutic efficacy of atropine in combination with an oxime against sarin poisoning; however, the differences were not significant. The non-oximes also positively influenced the number of surviving mice 6 h after supralethal poisoning with sarin. In the case of cyclosarin, they were also slightly beneficial in the treatment of acute poisoning. The higher dose of MB444 was able to significantly increase the therapeutic efficacy of standard antidotal treatment of poisoning with cyclosarin. The benefit of each bispyridinium non oxime compound itself was obviously dose-dependent. In summary, the addition of MB compounds to the standard antidotal treatment of acute nerve agent poisoning was beneficial for the antidotal treatment of sarin or cyclosarin poisoning, although their benefit at 24 h after poisoning was not significant, with the exception of the higher dose of MB444 against cyclosarin. PMID- 30005894 TI - Histone acetylation and methylation marks in chromatin of Panstrongylus megistus (Hemiptera, Reduviidae). AB - Panstrongylus megistus, a potential vector of Chagas disease, currently occupies a wider geographic distribution in Brazil than Triatoma infestans, another member of the hemipteran Reduviidae family and a vector of the same disease. A small heterochromatic body (chromocenter) formed by the Y chromosome is evident in the somatic cells of P. megistus, differing in size and chromosome type contribution from the well-studied chromocenters present in T. infestans. While the overall distribution of histone epigenetic marks differ when comparing the heterochromatin and euchromatin territories in T. infestans, no similar data have been established for other hemipteran reduviids, including P. megistus. In the present work, histone acetylation and methylation marks were investigated in cells of Malpighian tubules of P. megistus 5th instar nymphs using immunocytochemical assays and compared to previously published data for T. infestans. Although similarities between these species were found regarding absence of acetylated H3K9, H4K8 and H4K16, and H3K9me and H3K9me2 in the chromocenter, presence of these marks in euchromatin, and presence of H3K9me3 in the chromocenter, no intimate association of acetylated H4K8 and 18S rDNA was revealed in the chromocenter of P. megistus. The elevated abundance of H3K9me2 marks at the nuclear periphery in P. megistus cells, differing from data for T. infestans, is suggested to reflect differences in the interaction of lamina associated chromatin domains with the nuclear lamina, methyl-transferase modulation and/or association with the last DNA endoreplication step in 5th instar nymphs, which is a matter for further investigation. PMID- 30005895 TI - Pien Tze Huang ameliorates liver injury by inhibiting the PERK/eIF2alpha signaling pathway in alcohol and high-fat diet rats. AB - OBJECTIVE: To explore whether Pien Tze Huang (PTH) exerts a hepatoprotective effect via inhibiting the PERK/eIF2alpha signaling pathway using an experimental animal model of alcoholic and high-fat diet rats. METHODS: A liver injury rat model was established and treated with PTH. Pathological changes in the liver were evaluated by hematoxylin and eosin staining. Hepatic biochemical indexes were detected using an automatic biochemical analyzer. The level of Hcy in serum samples was analyzed using an ELISA. Levels of mRNAs related to ER stress signaling were measured by real-time quantitative-PCR, and protein expression levels were measured by Western blot analysis. RESULTS: PTH ameliorated the defects in hepatic function, hepatic pathology and the impairment in lipid metabolism observed in the alcoholic and high-fat diet rats. Moreover, PTH reduced the serum Hcy level and inhibited the PERK/eIF2alpha pathway in response to ER stress. CONCLUSIONS: These results suggest that the administration of PTH ameliorated the severity of alcoholic and high-fat diet rats possibly by inhibiting the Hcy-induced PERK/eIF2alpha pathway. PMID- 30005896 TI - Rabies pre-exposure prophylaxis: A 10-year experience of vaccination in international travelers. PMID- 30005897 TI - Substantial evidence for the rhododendrol-induced generation of hydroxyl radicals that causes melanocyte cytotoxicity and induces chemical leukoderma. AB - BACKGROUND: Rhododendrol (4-(4-hydroxyphenyl)-2-butanol) has been used as a lightening/whitening cosmetic but was recently reported to induce leukoderma. Although rhododendrol has been shown to be transformed by tyrosinase to hydroxyl rhododendrol, which is cytotoxic to melanocytes, its detailed mechanism of action including the involvement of reactive oxygen species is not clearly understood. OBJECTIVE: To confirm the relationship of hydroxyl radical generation to melanocyte cytotoxicity induced by rhododendrol, this study was performed. METHODS: An electron spin resonance method with a highly sensitive detection system was utilized to monitor hydroxyl radicals generated from two distinct normal human epidermal melanocyte lines with different levels of tyrosinase activity after the addition of various amounts of rhododendrol. Cytotoxicity of rhododendrol was analyzed by AlamarBlue assay under the same condition. RESULTS: Hydroxyl radicals were generated depending on the amounts of rhododendrol and/or tyrosinase. After the correlation between hydroxyl radical generation with melanocyte viability was confirmed, an inhibitor of oxidative stress, N-acetyl cysteine, was shown to dramatically diminish rhododendrol-induced generation of hydroxyl radicals and melanocyte cytotoxicity by increasing glutathione levels. In contrast, buthionine sulfoximine, which depletes glutathione, augmented both of those parameters. CONCLUSION: Suppressing oxidative stress would prevent and/or mitigate some phenol derivative-induced leukoderma by avoiding hydroxyl radical-initiated melanocyte cytotoxicity. PMID- 30005898 TI - Video Media in Clinic Waiting Areas Increases Interest in Most Effective Contraceptive Methods. AB - OBJECTIVE: To examine the utility of a patient-level information video as part of the contraception consultation visit. Specifically, to assess the impact of the video on women's contraception choice, and, further, to assess patient and provider acceptability of incorporating the video into the patient visit. METHODS: A pre-post study design was used to assess the impact on patients' contraceptive choices and knowledge. Participants (n = 49) answered questions regarding contraceptive preferences and knowledge of long-acting reversible contraception (LARC), then watched a 12-minute patient-level counselling video that presented evidence-based information about contraception in descending order of effectiveness. Clinicians (n = 39) also viewed the video and completed a survey. A retrospective chart review of 100 contraception visits was completed. RESULTS: Patient preference for IUDs increased significantly, whereas condoms decreased pre-to-post video (hormonal: 8.2% to 20.4%; copper: 0% to 16%; condoms: 32.7% to 18%, P < 0.05). Although 74.4% of clinicians believed that the hormonal IUD was the "ideal" form of contraception when no contraindications were present, 95% stated that the oral contraceptive pill was most often prescribed, and a chart review revealed that the oral contraceptive pill was discussed at 88% of contraceptive counselling visits. Both patients and clinicians found the video useful and acceptable. CONCLUSION: A patient-level contraceptive information video improved interest in LARC. Both patients and clinicians viewed the video as an acceptable addition to the contraceptive counselling visit. PMID- 30005899 TI - The Effect of a Parental Visitation Program on Emergence Delirium Among Postoperative Children in the PACU. AB - PURPOSE: The purpose of this study was to examine the effects of parental presence on the incidence of emergence delirium (ED) of children in the postanesthesia care unit (PACU). DESIGN: A quasi-experimental pretest and post test study with nonequivalent and nonsynchronized control groups. METHODS: About 93 children aged 3 to 6 years undergoing general anesthesia for tonsillectomy were divided into two groups: parental presence and absence. ED was recorded using the Pediatric Anesthesia Emergence Delirium Scale at 0, 10, 20, and 30 minutes after PACU admission. FINDINGS: ED score at each time point in the experimental group was lower than the control group, but not statistically significant. ED score in the experimental group significantly decreased over time (F = 6.98; P = .010). CONCLUSIONS: Parental visitation programs could be effective on the degree of ED in children in the PACU setting. This result may contribute to the establishment of PACU visitation program policy in South Korea. PMID- 30005900 TI - ESPEN guideline on clinical nutrition and hydration in geriatrics. AB - BACKGROUND: Malnutrition and dehydration are widespread in older people, and obesity is an increasing problem. In clinical practice, it is often unclear which strategies are suitable and effective in counteracting these key health threats. AIM: To provide evidence-based recommendations for clinical nutrition and hydration in older persons in order to prevent and/or treat malnutrition and dehydration. Further, to address whether weight-reducing interventions are appropriate for overweight or obese older persons. METHODS: This guideline was developed according to the standard operating procedure for ESPEN guidelines and consensus papers. A systematic literature search for systematic reviews and primary studies was performed based on 33 clinical questions in PICO format. Existing evidence was graded according to the SIGN grading system. Recommendations were developed and agreed in a multistage consensus process. RESULTS: We provide eighty-two evidence-based recommendations for nutritional care in older persons, covering four main topics: Basic questions and general principles, recommendations for older persons with malnutrition or at risk of malnutrition, recommendations for older patients with specific diseases, and recommendations to prevent, identify and treat dehydration. Overall, we recommend that all older persons shall routinely be screened for malnutrition in order to identify an existing risk early. Oral nutrition can be supported by nursing interventions, education, nutritional counseling, food modification and oral nutritional supplements. Enteral nutrition should be initiated if oral, and parenteral if enteral nutrition is insufficient or impossible and the general prognosis is altogether favorable. Dietary restrictions should generally be avoided, and weight-reducing diets shall only be considered in obese older persons with weight-related health problems and combined with physical exercise. All older persons should be considered to be at risk of low-intake dehydration and encouraged to consume adequate amounts of drinks. Generally, interventions shall be individualized, comprehensive and part of a multimodal and multidisciplinary team approach. CONCLUSION: A range of effective interventions is available to support adequate nutrition and hydration in older persons in order to maintain or improve nutritional status and improve clinical course and quality of life. These interventions should be implemented in clinical practice and routinely used. PMID- 30005901 TI - A dietary pattern derived using B-vitamins and its relationship with vascular markers over the life course. AB - BACKGROUND: Diet may influence vascular function through elevated homocysteine (Hcy) concentrations. However the relationship between dietary patterns (DP), characterised by Hcy and its associated nutrients is unknown. OBJECTIVE: To identify a DP characterised by plasma Hcy, dietary folate and dietary vitamin B12, and examine its associations with two markers of vascular function: carotid intima-media thickness (cIMT) and pulse wave velocity (PWV). METHODS: 1562 participants of the MRC National Survey of Health and Development (NSHD), a British birth cohort, with dietary data measured at least once between 36 and 60 64 years, and cIMT or PWV measured at 60-64 years were included. DPs were derived using reduced rank regression with three intermediate variables: 1) plasma Hcy (MUmol/L) 2) folate intake (MUg/1000 kcal) 3) vitamin B12 intake (MUg/1000 kcal). Multiple regression models assessed associations between the derived DP z-scores and vascular function adjusting for dietary misreporting, socioeconomic position, BMI, smoking, physical activity and diabetes. RESULTS: A DP explaining the highest amount of shared variation (4.5%) in plasma Hcy, dietary folate and dietary vitamin B12 highly correlated with folate (r = 0.96), moderately correlated with vitamin B12 (r = 0.27), and weakly correlated with Hcy (r = 0.10). This "high B-vitamin" DP (including folate) was characterised by high intakes of vegetables, fruit and low fibre breakfast cereal, and low intakes of processed meat, white bread, sugar and preserves. No associations were observed between DP z-scores and vascular function at any time point following adjustment for covariates. CONCLUSION: This study explored a specific hypothesised pathway linking diet to vascular function. Although we found no consistent evidence for an association between a high B-vitamin DP and vascular function, we did observe an association with CRP and triglycerides in secondary analyses. Further analyses using strongly correlated and biologically relevant intermediate variables are required to refine investigations into diet and CVD in longitudinal cohort data. PMID- 30005902 TI - Refeeding syndrome in adults receiving total parenteral nutrition: An audit of practice at a tertiary UK centre. AB - BACKGROUND & AIMS: The key to preventing refeeding syndrome (RS) is identifying and appropriately managing patients at risk. We evaluated our clinical management of RS risk in patients starting total parenteral nutrition (TPN). METHODS: Patients commencing TPN at University College London Hospital between January and July 2015 were prospectively followed-up for 7-days. Eighty patients were risk assessed for RS and categorized into risk groups. High and low risk RS groups were compared focussing on the onset of biochemical features of RS (hypophosphatemia, hypokalaemia and hypomagnesemia) and initial clinical assessment. Statistical analysis was conducted using t-tests and Mann-Whitney U tests. RESULTS: Sixty patients (75%) were identified as high-risk for RS and received lower initial calories (12.8 kcal/kg/day, p < 0.05). All high-risk patients received a high potency vitamin preparation compared to 35% in the low risk group (p < 0.05). Daily phosphate, magnesium and potassium plasma levels were monitored for seven days in 25%, 30% and 53.8% of patients, respectively. Hypophosphatemia developed in 30% and hypomagnesaemia and hypokalaemia in 27.5% of all patients. Approximately 84% of patients had one or more electrolyte abnormalities, which occurred more frequently in high-risk RS patients (p < 0.05). Low risk patients developed mild hypophosphatemia at a much lower percentage than high-risk RS (20% vs 33.3%, respectively). CONCLUSION: A significant proportion of patients commencing TPN developed biochemical features of RS (but no more serious complications) despite nutritional assessment, treatment, and follow up in accordance with national recommendations. High vs low risk RS patients were more likely to have electrolyte abnormalities after receiving TPN regardless of preventative measures. Additional research is required to further optimise the initial nutritional approach to prevent RS in high-risk patients. PMID- 30005903 TI - Direct costs of a home parenteral nutrition programme. AB - BACKGROUND & AIMS: Home parenteral nutrition (HPN) is a lifesaving treatment for people with chronic intestinal failure and its cost has been reported to be very high. The purpose of the present paper was to study the direct healthcare and non healthcare costs associated with the HPN programme managed by a tertiary hospital. METHODS: Observational, retrospective study of all adult patients on HPN from 11.1.2014 to 10.31.2015 treated at Gregorio Maranon University Hospital (Madrid, Spain). An economic evaluation was undertaken to calculate the direct healthcare (HPN provision, outpatient monitoring and management of complications) and non-healthcare costs (transportation process) of the HPN programme. The variables were collected from medical records, the dispensary and the hospital's financial services. The unit costs were taken from official price lists. RESULTS: Thirty-two patients met the inclusion criteria. Total direct healthcare and non healthcare costs amounted to ?13,363.53 per patient (?124.02 per patient per day). The direct healthcare costs accounted for 98.32% of overall costs, while the non-healthcare costs accounted for the remaining 1.68%. HPN provision accounted for the majority of the costs (74.25%), followed by management of complications (21.85%) and outpatient monitoring (2.23%). CONCLUSIONS: The direct healthcare costs accounted for the majority of HPN expenditure, specifically HPN provision was the category with the highest percentage. PMID- 30005904 TI - Novel VCP mutations expand the mutational spectrum of frontotemporal dementia. AB - Valosin-containing protein (VCP) mutations are rare causes of autosomal dominant frontotemporal dementias associated with Paget's disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis. We analyzed the VCP gene in a cohort of 199 patients with frontotemporal dementia and identified 7 heterozygous mutations in unrelated families, including 3 novel mutations segregating with dementia. This expands the VCP mutation spectrum and suggests that although VCP mutations are rare (3.5% in this study), the gene should be analyzed even in absence of the full syndromic complex. Reporting genetic variants with convincing arguments for pathogenicity is important considering the large amount of data generated by next-generation sequencing and the growing difficulties to interpret rare genetic variants identified in isolated cases. PMID- 30005905 TI - Monocultures of primary porcine brain capillary endothelial cells: Still a functional in vitro model for the blood-brain-barrier. AB - The main obstacle for the treatment of brain diseases is the restriction of the passage of pharmaceuticals across the blood-brain barrier. Endothelial cells line up the cerebral micro vessels and prevent the uncontrolled transfer of polar substances by intercellular tight junctions. In addition to this physical barrier, active transporters of the multi-drug-resistance prevent the passage of hydrophobic substances by refluxing them back to the blood stream. This paper reviews the development and selected applications of an in vitro porcine brain derived primary cell culture system established in the authors lab that closely resembles the BBB in vivo and could thus be used to study beyond other applications drug delivery to the brain. An essential technique to control the intactness or destruction of the barrier, the impedance spectroscopy, will be introduced. It will be shown that nanoparticles can cross the blood brain barrier by two mechanisms: opening the tight junctions and thus allowing parallel import of substances into the brain as well as receptor mediated endocytosis using brain specific target molecules. However cytotoxic effects have to be considered as well which beside standard cytotoxicity assays could be also determined by impedance technology. Moreover it will be shown that enzymes e.g. for enzyme replacement therapy could be transferred across the barrier by proper tuning or chemical modification of the enzyme. Since this review is based on a conference presentation it will mainly focus on applications of the monoculture system developed in the authors lab which under given culture conditions is useful due to its easy availability, robustness, good reproducibility and also due to its simplicity. Improvements of this model made by other groups will be acknowledged but not discussed here in detail. PMID- 30005906 TI - Non-invasive tri-modal visualisation via PET/SPECT/MUCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept. AB - Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 MUg/ml; n = 4). Bone formation was monitored using micro computed tomography (MUCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via MUCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration. PMID- 30005907 TI - Modular approach for theranostic polymer conjugates with activatable fluorescence: Impact of linker design on the stimuli-induced release of doxorubicin. AB - The introduction of cleavable motifs by dynamic covalent chemistry is widely applied in the design of drug delivery systems (DDS) to introduce controlled release properties. Since the cleavable moieties can be triggered by various exogenous or endogenous stimuli, the choice of the linker has substantial implications on the performance of the DDS. Here, we present a pair of theranostic polymer conjugates (TPC) to study the influence of the cleavable bond on the cell-mediated drug release by a facile in vitro fluorescence assay. The TPC represent model DDS that consist of dendritic polyglycerol as polymeric carrier labeled with an indodicarbocyanine (IDCC) dye and the chemotherapeutic drug doxorubicin (Dox) conjugated through different cleavable linkers. Cleavage of the conjugate can be mediated by either acidic environment or protease activity. The spatial proximity of the IDCC dye and the fluorescent drug led to effective quenching of Dox fluorescence when bound to the carrier. The stimuli induced linker cleavage was correlated with the recovery of fluorescence giving real-time information about the stimuli-dependent drug release. By tracking the fluorescence recovery in a cell-based high throughput microplate assay, we were able to obtain characteristic release profiles of Dox for different cell lines. Here, we found that the pH-cleavable linker was more suitable for drug delivery applications since the enzyme-sensitive system suffered premature release due to the presence of extracellular proteases. This had a pronounced effect on the treatment of a multidrug-resistant cell line where an intracellular drug release is crucial to overcome the resistance mechanisms. We want to highlight that the modular synthetic approach combined with the cell-based assay has potential to extend the common in vitro methods to evaluate DDS performance and suitability as the design can be easily employed for diverse carrier/linker systems as well as various cell lines. PMID- 30005908 TI - Coral reef systems of the Mexican Caribbean: Status, recent trends and conservation. AB - Over the last four decades the Mexican Caribbean has experienced intensive coastal development, and change on the reef system condition has already been observed. This paper describes the reef system characteristics, at local and seascape scales, and discusses the current status and trends, considering the main research efforts from academia and Non-Governmental Organizations. To date, the coral cover of most reefs in the region is between 15 and 20%, following a slight recovery on mean coral cover over the last decade. During this same period, fleshy macroalgae and herbivorous fish biomass appear to have increased. At seascape scales, an increase of macroalgae and the loss of seagrass habitat have been observed. Considering that anthropogenic and environmental disturbances will most likely increase, the establishment of newly protected areas in the Mexican Caribbean is appropriate, but sufficient accompanying funding is required. PMID- 30005909 TI - Anti-hypercholesterolemic impacts of barley and date palm fruits on the ovary of Wistar albino rats and their offspring. AB - A high cholesterol diet is related to ovarian dysfunction and infertility which has been increased among young ages consuming processed food products. The present study was conducted to evaluate the role of a high cholesterol diet on the ovaries of young female rats via assessments of histopathology, immunohistochemistry, oxidative stress and apoptic markers. Also, mating of hypercholesterolemic female rats was carried out to measure the fertility and numbers of their offspring. At the same time, phytotherapy was carried out through supplementing the diet with barley and/ or date palm fruits (10%) during the experiment to assess the phyto-therapeutic impacts in attenuation of drastic hypercholesterolemic effects. Hypercholesterolemic diet-fed rats exhibited damage of the ovarian follicles and increased follicular atresia. Furthermore, expression of cleaved caspase-3 was upregulated, while PCNA was downregulated in granulosa, theca and stroma cells. Hypercholesterolemic female rats showed marked depletion of antioxidative enzymes, increased lipid peroxidation and apoptotic markers. Alterations to the female serum hormones were detected. Offspring maternally fed on hypercholesterolemic diet showed a significant decrease of body weight and altered sex ratio. However, concomitant supplementation of barley and or date fruits to hypercholesterolemic groups revealed marked improvement of ovarian structure and function. On the basis of these evidences, it is believed that the enhanced synergistic effects of barley and/or date palm fruits in the amelioration of ovarian structure and functions were elicited by the potential antioxidant activity of their phytomicronutrients, polyphenols, beta-glucan and trace elements. These materials scavenge free radicals from inflamed cells that can be used to establish an effective and novel therapeutic strategy for activating ovarian cell regeneration. PMID- 30005911 TI - Uncertainty about how timing of soft-tissue augmentation affects soft-tissue outcomes. PMID- 30005912 TI - There seem to be no differences between the clinical performances of glass ionomer cement and composite resin when used for Class II restorations in primary teeth. PMID- 30005910 TI - Anti-diabetic effect and mechanism of Kursi Wufarikun Ziyabit in L6 rat skeletal muscle cells. AB - Kursi Wufarikun Ziyabit (KWZ) is a traditional prescription that used in folk tea drinking for its health care effect in treatment of type 2 diabetes mellitus (T2DM) in central Asia. However, the underlying mechanism of KWZ in T2DM has not been investigated extensively. This study designed to observe the effect of KWZ on glucose consumption and assess the molecular mechanism on associated proteins in insulin signaling and ER stress pathway in L6 rat skeletal muscle cells. The results showed that, KWZ exhibited proteins of PTP-1B and alpha-glycosidase inhibitory activity in vitro. No cytotoxicity of KWZ was found on L6 cell line. The best effect of glucose consumption of cells was shown at 6.25 MUg/mL after KWZ treatment for 12 h. Expression of PTP-1B protein was inhibited by KWZ in L6 moytubes. PI3K-dependent Akt phosphorylation was found to be activated by KWZ. Moreover, the insulin-mediated induction of IRS-1 and GSK-3 were also activated by KWZ. Western blot results indicated that KWZ significantly improved the levels of ER stress proteins, which reduced the expression of GRP78, enhanced the expression of the PERK, eIF2alpha and XBP1s. The activation of PERK/eIF2alpha was likely consequence of GRP78 inhibition, and this might be beneficial for improving the stability of ER and alleviating insulin resistance. These results suggest that KWZ might be serving as the potential drug for the prevention and treatment of T2DM. PMID- 30005913 TI - There seems to be no benefit from using epsilon-aminocaproic acid in addition to routine postextraction advice in patients receiving anticoagulation therapy. PMID- 30005914 TI - Laser Doppler flowmetry and pulse oximetry seem to have high accuracy in detecting vital and nonvital teeth and perform better than cold, heat, and electric pulp testing. PMID- 30005915 TI - From bed to bench: How in silico medicine can help ageing research. AB - Driven by the raising ethical concerns surrounding animal experimentation, there is a growing interest for non-animal methods, in vitro or in silico technologies that can be used to reduce, refine, and replace animal experimentation. In addition, animal experimentation is being critically revised in regard to its ability to predict clinical outcomes. In this manuscript we describe an initial exploration where a set of in vivo imaging based subject-specific technologies originally developed to predict the risk of femoral strength and hip fracture in osteoporotic patients, were adapted to assess the efficacy of bone drugs pre clinically on mice. The CT2S technology we developed generates subject-specific models based on Computed Tomography that can separate fractured and non-fractured patients with an accuracy of 82%. When used in mouse experiments the use of in vivo imaging and modelling was found to improve the reproducibility of Bone Mineral Content measurements to a point where up to 63% less mice would be required to achieve the same statistical power of a conventional cross-sectional study. We also speculate about a possible approach where animal-specific and patient-specific models could be used to better translate the observation made on animal models into predictions of response in humans. PMID- 30005916 TI - Erratum to "First-line ribociclib plus letrozole for postmenopausal women with HR+, HER2- ABC: MONALEESA-2 safety results" [Breast 36 (Suppl. 1) (November 2017) S44-S45]. PMID- 30005917 TI - Intra- and extra-axonal axial diffusivities in the white matter: Which one is faster? AB - A two-compartment model of diffusion in white matter, which accounts for intra- and extra-axonal spaces, is associated with two plausible mathematical scenarios: either the intra-axonal axial diffusivity Da,|| is higher than the extra-axonal De,|| (Branch 1), or the opposite, i.e. Da,|| < De,|| (Branch 2). This duality calls for an independent validation of compartment axial diffusivities, to determine which of the two cases holds. The aim of the present study was to use an intracerebroventricular injection of a gadolinium-based contrast agent to selectively reduce the extracellular water signal in the rat brain, and compare diffusion metrics in the genu of the corpus callosum before and after gadolinium infusion. The diffusion metrics considered were diffusion and kurtosis tensor metrics, as well as compartment-specific estimates of the WMTI-Watson two compartment model. A strong decrease in genu T1 and T2 relaxation times post-Gd was observed (p < 0.001), as well as an increase of 48% in radial kurtosis (p < 0.05), which implies that the relative fraction of extracellular water signal was selectively decreased. This was further supported by a significant increase in intra-axonal water fraction as estimated from the two-compartment model, for both branches (p < 0.01 for Branch 1, p < 0.05 for Branch 2). However, pre-Gd estimates of axon dispersion in Branch 1 agreed better with literature than those of Branch 2. Furthermore, comparison of post-Gd changes in diffusivity and dispersion between data and simulations further supported Branch 1 as the biologically plausible solution, i.e. Da,|| > De,||. This result is fully consistent with other recent measurements of compartment axial diffusivities that used entirely different approaches, such as diffusion tensor encoding. PMID- 30005918 TI - Intrinsic overlapping modular organization of human brain functional networks revealed by a multiobjective evolutionary algorithm. AB - A wealth of research on resting-state functional MRI (R-fMRI) data has revealed modularity as a fundamental characteristic of the human brain functional network. The modular structure has recently been suggested to be overlapping, meaning that a brain region may engage in multiple modules. However, not only the overlapping modular structure remains inconclusive, the topological features and functional roles of overlapping regions are also poorly understood. To address these issues, the present work utilized the maximal-clique based multiobjective evolutionary algorithm to explore the overlapping modular structure of the R-fMRI data obtained from 57 young healthy adults. Without prior knowledge, brain regions were optimally grouped into eight modules with wide overlap. Based on the topological features captured by graph theory analyses, overlapping regions were classified into an integrated club and a dominant minority club through clustering. Functional flexibility analysis found that overlapping regions in both clubs were significantly more flexible than non-overlapping ones. Lesion simulations revealed that targeted attack at overlapping regions were more damaging than random failure or even targeted attack at hub regions. In particular, overlapping regions in the dominant minority club were more flexible and more crucial for information communication than the others were. Together, our findings demonstrated the highly organized overlapping modular architecture and revealed the importance as well as complexity of overlapping regions from both topological and functional aspects, which provides important implications for their roles in executing multiple tasks and maintaining information communication. PMID- 30005919 TI - Inulin fiber dose-dependently modulates energy balance, glucose tolerance, gut microbiota, hormones and diet preference in high-fat-fed male rats. AB - Inulin, a popular prebiotic fiber, has been reported to promote satiety and fat loss; however, the dose-response effects of inulin on energy balance and diet preference, and whether the metabolic effects are independent of calorie restriction are not well characterized. Therefore, we compared the effects of diets varying in inulin concentrations on food intake, energy expenditure, body composition, gut microbiota and hormones, and assessed whether inulin-induced hypophagia was due to reduced diet preference. In experiment 1, male rats were randomized to six high-fat diet groups: control (CON, 0% inulin), 2.5% inulin (2.5IN), 10% inulin (10IN), 25% inulin (25IN), 25% cellulose (25CE) or pair-fed to 25IN (25PF) for 21 days. We demonstrate that inulin dose-dependently decreased caloric intake and respiratory quotient; improved glucose tolerance; increased the abundance of Bacteroidetes and Bifidobacterium spp.; decreased Clostridium clusters I and IV; increased butyryl-CoA:acetate CoA-transferase in cecum; upregulated peptide YY, cholecystokinin and proglucagon transcripts in the cecum and colon; and increased plasma peptide YY and glucagon-like peptide-1 concentrations. Importantly, unlike 25PF, 25IN attenuated the reduction in energy expenditure associated with calorie restriction and decreased adiposity. In experiment 2, following four training periods, diet preferences were determined. Although 10IN and 25IN decreased caloric intake, and 25CE increased caloric intake, during training, all high-fiber diets were less preferred. Taken together, this work demonstrates that inulin dose-dependently decreased caloric intake, modulated gut microbiota and upregulated satiety hormones, with metabolic effects being largely independent of caloric restriction. PMID- 30005920 TI - Interesterified soybean oil promotes weight gain, impaired glucose tolerance and increased liver cellular stress markers. AB - Interesterified fats have largely replaced hydrogenated vegetable fat, which is rich in trans fatty acids, in the food industry as an economically viable alternative, generating interest to study their health effects. The aim of this study was to evaluate the effect that interesterification of oils and fat has on lipid-induced metabolic dysfunction, hepatic inflammation and ER stress. Five week-old male Wistar rats were randomly divided into three experimental groups, submitted to either normocaloric and normolipidic diet containing 10% of lipids from unmodified soybean oil (SO) or from interesterified soybean oil (ISO), and one more group submitted to a high fat diet (HFD) containing 60% of fat from lard as a positive control, for 8 or 16 weeks. Metabolic parameters and hepatic gene expression were evaluated. The HFD consumption led to increased body mass, adiposity and impaired glucose tolerance compared to SO and ISO at both time points of diet. However, the ISO group showed an increased body mass gain, retroperitoneal WAT mass, fasting glucose, and impaired glucose tolerance during ipGTT at 16 weeks compared to SO. Moreover, at 8 weeks, hepatic gene expression of Atf3 and Tnf were increased in the ISO group compared to the SO group. Thus, replacement of natural fat with interesterified fat on a normocaloric and normolipidic diet negatively modulated metabolic parameters and resulted in impaired glucose tolerance in rats. PMID- 30005921 TI - Racial and Ethnic Disparities in Dementia Risk Among Individuals With Low Education. AB - INTRODUCTION: As higher dementia prevalence in ethnic minority groups could be attributed to low education, we studied individuals with low education and explored potential factors driving dementia disparities. METHODS: We examined differences in dementia risk between low-educated non-Hispanic whites, Hispanics, and African Americans, and the impact of lifetime risk factors using data from the nationally representative Aging, Demographics, and Memory Study (N = 819). RESULTS: As indicated by Cox regression modeling, dementia risk of low-educated individuals was not significantly different between ethnic groups but was related to having an APOE e4 allele (hazard ratio [HR] 1.89), depression (HR 1.67), stroke (HR 1.60), and smoking (HR 1.32). Further, even in people with low education, every additional year of education decreased dementia risk (HR 0.95). DISCUSSION: Our findings imply that higher dementia prevalence in ethnic minorities may be attributable to low education, especially among Hispanics, in addition to other risk factors. PMID- 30005923 TI - Erratum to "Severe hypoglycemia in pregnant women with type 2 diabetes-A relevant clinical problem" [Diabetes Res. Clin. Pract. 102 (2013) e17-e18]. PMID- 30005922 TI - Monitoring heart rate in the delivery room. AB - Resuscitation algorithms and guidelines highlight the importance of heart rate (HR) in determining interventions and assessing their effect. However, the actual HR values used are historical based upon normal physiology, and HR at birth may be affected by mode of delivery and timing of cord clamping as well as respiratory status and condition at delivery. Furthermore, the most accurate and effective ways to assess and monitor HR in the newborn infant are only now becoming established. This article examines the importance of HR values and the most widely used methods of estimation as well as some newer modalities which are being developed. PMID- 30005924 TI - Effect of Adjusting for Tanner Stage Age on Prevalence of Short and Tall Stature of Youths in the United States. AB - OBJECTIVE: To evaluate the extent to which pubertal timing alters the classification of extremes of attained stature across race-ethnicity groups of youths in the US. STUDY DESIGN: We performed analyses of height and Tanner staging data of 3206 cross-sectional national sample of youths ages 8-18 years (53% male, n = 1606), 72% of whom were non-Hispanic white, 9% Mexican American, and 19% non-Hispanic black . Specialized growth models were used to derive Tanner stage-age-adjusted z scores (TSAHAZ). The prevalence of shortness (<-1SD) and tallness (>=+1SD) status was quantified using TSAHAZ. RESULTS: Highly variable patterns of prevalence of shortness and tallness via chronologic age height z score (CAHAZ) were observed in results stratified by race-ethnicity and sex. Tallness CAHAZ prevalence was high among non-Hispanic white and non-Hispanic black male youths relative to Mexican American (40.0%-43.3% vs 20.5%) with a similar pattern in female youths. In both sexes, this pattern was eliminated with TSAHAZ, with Mexican American youth becoming statistically not different from their non-Hispanic white and non-Hispanic black peers. CONCLUSIONS: Differences in timing of puberty between race-ethnicity groups affects estimated prevalence of shortness and tallness of attained height that remains uncaptured with CAHAZ. Adjustment for pubertal development might help isolate crucial determinants of attained stature and other aspects of body composition that may be most responsive to intervention programs in populations. The curves developed by adjusting for pubertal status may help the clinician avoid misclassification of children with early and late pubertal development. PMID- 30005925 TI - Global Reach. PMID- 30005926 TI - Motivation dynamically increases noise resistance by internal feedback during movement. AB - Motivation improves performance, pushing us beyond our normal limits. One general explanation for this is that the effects of neural noise can be reduced, at a cost. If this were possible, reward would promote investment in resisting noise. But how could the effects of noise be attenuated, and why should this be costly? Negative feedback may be employed to compensate for disturbances in a neural representation. Such feedback would increase the robustness of neural representations to internal signal fluctuations, producing a stable attractor. We propose that encoding this negative feedback in neural signals would incur additional costs proportional to the strength of the feedback signal. We use eye movements to test the hypothesis that motivation by reward improves precision by increasing the strength of internal negative feedback. We find that reward simultaneously increases the amplitude, velocity and endpoint precision of saccades, indicating true improvement in oculomotor performance. Analysis of trajectories demonstrates that variation in the eye position during the course of saccades is predictive of the variation of endpoints, but this relation is reduced by reward. This indicates that motivation permits more aggressive correction of errors during the saccade, so that they no longer affect the endpoint. We suggest that such increases in internal negative feedback allow attractor stability, albeit at a cost, and therefore may explain how motivation improves cognitive as well as motor precision. PMID- 30005927 TI - Orthographic and phonological selectivity across the reading system in deaf skilled readers. AB - People who are born deaf often have difficulty learning to read. Recently, several studies have examined the neural substrates involved in reading in deaf people and found a left lateralized reading system similar to hearing people involving temporo-parietal, inferior frontal, and ventral occipito-temporal cortices. Previous studies in typical hearing readers show that within this reading network there are separate regions that specialize in processing orthography and phonology. We used fMRI rapid adaptation in deaf adults who were skilled readers to examine neural selectivity in three functional ROIs in the left hemisphere: temporoparietal cortex (TPC), inferior frontal gyrus (IFG), and the visual word form area (VWFA). Results show that in deaf skilled readers, the left VWFA showed selectivity for orthography similar to what has been reported for hearing readers, the TPC showed less sensitivity to phonology than previously reported for hearing readers using the same paradigm, and the IFG showed selectivity to orthography, but not phonology (similar to what has been reported previously for hearing readers). These results provide evidence that while skilled deaf readers demonstrate coarsely tuned phonological representations in the TPC, they develop finely tuned representations for the orthography of written words in the VWFA and IFG. This result suggests that phonological tuning in the TPC may have little impact on the neural network associated with skilled reading for deaf adults. PMID- 30005928 TI - Characterization of damage on Listeria innocua surviving to pulsed light: Effect on growth, DNA and proteome. AB - The effect of pulsed light treatment on the lag phase and the maximum specific growth rate of Listeria innocua was determined in culture media at 7 degrees C. Fluences of 0.175, 0.350 and 0.525 J/cm2 were tested. The lag phase of the survivors increased as fluence did, showing significant differences for all the doses; an 8.7-fold increase was observed at 0.525 J/cm2. Pulsed light decreased the maximum specific growth rate by 38% at the same fluence. Both parameters were also determined by time-lapse microscopy at 25 degrees C in survivors to 0.525 J/cm2, with an increase of 13-fold of the lag phase and a 45% decrease of the maximum specific growth rate. The higher the fluence, the higher the variability of both parameters was. To characterize pulsed light damage on L. innocua, the formation of dimers on DNA was assessed, and a proteomic study was undertaken. In cells treated with 0.525 J/cm2, cyclobutane pyrimidine dimers and pyrimidine (6 4) pyrimidone photoproducts were detected at 5:1 ratio. Pulsed light induced the expression of three proteins, among them the general stress protein Ctc. Furthermore, treated cells showed an up-regulation of proteins related to metabolism of nucleotides and fatty acids, as well as with translation processes, whereas flagellin and some glucose metabolism proteins were down-regulated. Differences in the proteome of the survivors could contribute to explain the mechanisms of adaptation of L. innocua after pulsed light treatment. PMID- 30005929 TI - Comparison between RT droplet digital PCR and RT real-time PCR for quantification of noroviruses in oysters. AB - Oysters are frequently associated with norovirus outbreaks, but the presence of norovirus RNA in oysters does not necessarily imply a health risk to humans. There is a close link between human illness and consumption of oysters with high levels of norovirus RNA, but oysters with low levels of norovirus RNA are more unlikely to be associated with illness. Reliable and precise quantification methods are therefore important for outbreak investigations and risk assessments. This study optimised and validated RT droplet digital PCR (RT-ddPCR) assays for quantification of norovirus genogroups I and II in artificially contaminated oysters, and compared them with the standard method, RT real-time PCR (RT-qPCR). The two methods had comparable 95% limits of detection, but RT-ddPCR generally showed greater precision in quantification. Differences between fluorometric measurements and quantification with RT-ddPCR were determined on in vitro transcribed RNA with targets for norovirus genogroups I and II. Quantification by RT-ddPCR was on average 100 times lower than the fluorometric value for norovirus GI and 15.8 times lower than the fluorometric value for norovirus GII. The large inter-assay difference observed highlights the need for monitoring the RT efficiency in RT-ddPCR, especially when results from different assays are compared. Overall, this study suggests that RT-ddPCR can be a suitable method for precise quantification of norovirus genogroups I and II in oysters. PMID- 30005930 TI - Occurrence, antimicrobial resistance and whole-genome sequencing analysis of Salmonella isolates from chicken carcasses imported into Iraq from four different countries. AB - Salmonella is a major cause of human foodborne illnesses worldwide; however, little is known about its occurrence and genomic characteristics in food sources in many developing countries. This study investigates the occurrence, serotypes distribution, antimicrobial resistance, and multilocus sequence types (ST) of Salmonella isolated from 400 imported frozen chicken carcasses sold in the markets of Thi-Qar, south-eastern Iraq. Salmonella was detected in 46 out of 400 tested samples [11.5% (95% confidence interval: 8.5%-15.0%)]. S. Typhimurium was the most abundant (30.4%) among 14 different serotypes recovered from the tested frozen carcasses. Antimicrobial resistance was most frequently detected against tetracycline (84.4%), nalidixic acid (80.4%), streptomycin (69.6%) and trimethoprim/sulfamethoxazole (65.2%). Whole-genome sequencing (WGS) analysis revealed that 18 isolates harbored four beta-lactamase resistance genes, with blaCARB-2 was the most commonly (14/18) detected. It was possible to identify 8 multilocus sequence types from the WGS analysis of 40 out of the 46 Salmonella isolates; with ST-11 (among S. Enteritidis) and ST-19 (among S. Typhimurium) were the most frequently detected. These results add to our understanding of the global epidemiology of Salmonella. Our work stands as one of the first reports on WGS analysis of Salmonella from retail chicken in a Middle-Eastern country. Results from this study could be valuable for guiding an informed import risk analysis aiming at reducing the exposure risk from Salmonella through imported chicken carcasses into Iraq. This work demonstrates the value of WGS as a promising tool for supporting evidence-based food safety hazard characterization. PMID- 30005931 TI - Cooperation and sensitivity to social feedback during group interactions in schizophrenia. AB - Patients with schizophrenia show reduced cooperation and less sensitivity to social cues in pairwise interactions, however, it remains unclear whether these mechanisms are also present in interactions within social groups. We used a public goods game to investigate cooperation and sensitivity to social feedback in group interactions in 27 patients with schizophrenia and 27 healthy controls. Participants played 40 trials in two conditions: 1) no fine (20 trials): participants had the choice of investing into the public good (i.e. cooperating) or not (i.e. defecting), 2) fine (20 trials): participants had the same choice but defectors could be punished by the other players. On the first trial, patients invested less in the public good than healthy controls. In the no fine condition, controls decreased their investments over time, but patients did not. The possibility of being fined for defecting and actually being fined led to significantly higher cooperation in both groups. This shows that the groups were equally sensitive to social enforcement and social feedback. Our findings suggest that patients tend to approach social group interactions with less cooperative behaviour, which could contribute to social dysfunction in daily-life. However, an intact sensitivity to social enforcement and feedback indicates that patients can adjust their behaviour accordingly in group interactions. PMID- 30005932 TI - Role of frontal white matter and corpus callosum on social function in schizophrenia. AB - Patients with schizophrenia show severe impairment in social function and have difficulty in their daily social life. Although a recent large-scale multicenter study revealed alterations in white matter microstructures, the association between these anatomical changes and social dysfunction in schizophrenia remains unknown. Therefore, we investigated the association between the white matter integrity of regions of interest and social function in schizophrenia. A total of 149 patients with schizophrenia and 602 healthy comparison subjects (HCS) underwent DTI and completed the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-Third Edition and the Finance subscale of the University of California, San Diego, Performance-Based Skills Assessment Brief, as social indices of interest. The fractional anisotropy (FA) in the anterior corona radiata and corpus callosum was significantly lower in patients than in HCS, and the radial diffusivity (RD) in the anterior corona radiata and corpus callosum was significantly higher in patients. The Picture Arrangement and Finance scores were both significantly impaired in patients. The effect of the FA of the right anterior corona radiata on the Finance score and the Picture Arrangement score, of the RD of the right anterior corona radiata on the Picture Arrangement score, and of the RD of the corpus callosum on the Picture Arrangement score were significant. In conclusion, our results confirmed the association between structural connectivity in the right frontal white matter and corpus callosum and social function in schizophrenia. These findings may provide a foundation for developing an intervention for functional recovery in schizophrenia. PMID- 30005934 TI - Comment on 'Conceptual disorganization and dissociative symptoms in women with first episode psychosis' (). PMID- 30005933 TI - A meta-analysis of factors associated with quality of life in first episode psychosis. AB - OBJECTIVE: Improving quality of life for people with first episode psychosis is an important aspect of recovery. Our objective was to review the associative factors on quality of life in first episode psychosis. A meta-analysis was conducted on the associations between quality of life, symptom severity, and duration of untreated psychosis. METHOD: Fifty-one articles were identified (published through 08/29/2016) that provided data on the relationship between quality of life and at least one other outcome measure of interest in first episode psychosis. Of those studies, 21 were included in a meta-analysis (n = 3992) of the relationship between quality of life, severity of psychosis, and duration of untreated psychosis. RESULTS: Meta-analysis identified significant negative correlations between quality of life and severity of symptoms (total symptom scores: r = -0.32, p < 0.001) and quality of life and duration of untreated psychosis (r = -0.21, p < 0.001). Heinrich's quality of life scale emerged as being more sensitive to the presence of psychotic symptoms than other measures of quality of life. CONCLUSIONS: Associations were found between certain disease specific variables and quality of life in first episode psychosis, highlighting the relationship between symptom presentation and quality of life and the need for early intervention. Proper assessment of quality of life is important to promote improved quality of life in patients with first episode psychosis. Future research is needed to examine the interacting effects of symptom presentation, duration of untreated psychosis, and other variables, such as neurocognition, on quality of life. PMID- 30005935 TI - Second-generation LAI are associated to favorable outcome in a cohort of incident patients diagnosed with schizophrenia. AB - OBJECTIVE: Investigate the associations of long-acting injectable (LAI) second generation antipsychotic drugs with number of relapses, psychiatric admissions, days hospitalized, intentional self-harm events, and costs linked to hospitalizations in incident patients diagnosed with schizophrenia. METHOD: A nationwide, population-based, retrospective study utilizing mirror-image models before and after initiation of LAI SGA. RESULTS: 10,509 patients were included as study population, with analyses being conducted on 2223 patients in a six-month period, 1383 in a 12-month period, 713 in a 24-month period. After initiation of LAI antipsychotics, patients experienced a reduction in number of relapses with an incidence rate ratio (IRR) of 0.60 for the first six months, IRR 0.64 for the first 12 months and IRR 0.64 for the first 24 months following initiation of LAI, all P < 0.001. The number of psychiatric admissions was reduced in a similar manner with respective IRR of 0.59, 0.60 and 0.64, all P < 0.001. Psychiatric bed days were reduced with 58, 100 and 164 days for the respective periods after LAI initiation, all P < 0.001. In a Cox regression model in patients initiated on LAI, higher age at diagnosis, hazard rate ratio (HR) 0.99, 95%CI(0.98-0.99), P < 0.001, and a later calendar year of diagnosis, HR 0.99, 95%CI(0.98-1.00), P < 0.05, were associated with a lower risk of relapse, whereas mainly psychiatric comorbidity, HR 1.07, 95% CI (1.04-1.11), P < 0.001, and cardiovascular disease, HR 1.12, 95%CI(1.01-1.26), P < 0.05, were associated with relapse. CONCLUSION: Even though the design does not allow inferences regarding causality, these population-based findings support the use of second generation LAI antipsychotics. PMID- 30005936 TI - Exceptional Response to Cabozantinib of Rapidly Evolving Brain Metastases of Renal Cell Carcinoma: A Case Report and Review of the Literature. PMID- 30005937 TI - Weight and height documentation: Does ICU measure up? AB - BACKGROUND: Reliable assessment and documentation of weight and height are essential for the accurate delivery of many critical care interventions. METHODS: We conducted a 3-month retrospective, cross-sectional, single-centre audit to determine the prevalence of weight and height documentation in the clinical records of patients admitted to the intensive care unit (ICU) for the period from 3 months prior to hospital admission up to hospital discharge. RESULTS: One hundred forty-one index ICU admissions were identified from October-December 2015 with 138 medical records available for analysis. Median (interquartile range) age was 64.5 (50.8-75.3) years, the majority were male (60.9%, 84/138), and the ICU admission Acute Physiology and Chronic Health Evaluation II score was 19.0 (14.0 25.0). Overall, weight and height were recorded in 90 (65.2%) and 63 (45.6%) patients, respectively. For elective postoperative admissions (n = 20), weight and height were recorded in 20 (100%) and 19 (95%) patients. For emergency medical and surgical admissions, 70 (59.3%) and 44 (37.2%) patients had weight and height recorded in both the 3-month period prior to hospital admission and the in-hospital period. A moderate, positive correlation was shown, r = 0.55, P < 0.001, with a longer hospital length of stay being associated with a greater number of weight and height records for each patient. In the emergency patient cohort, 81.7% (n = 215/263) of weight- and/or height-based interventions occurred before or during the ICU admission, of which 69.9% (n = 184/263) required consideration of ideal body weight. CONCLUSION: Measurement and medical record documentation of weight and height is infrequently performed in ICU patients. Given the clinical requirement for accurate measurement and documentation, further research to understand the barriers to perform and document this important process of care is necessary. PMID- 30005938 TI - Understanding how medications contribute to clinical deterioration and are used in rapid response systems: A comprehensive scoping review. AB - BACKGROUND: In hospitals, rapid response systems (RRSs) identify patients who deteriorate and provide critical care at their bedsides to stabilise and escalate care. Medications, including oral and parenteral pharmaceutical preparations, are the most common intervention for hospitalised patients and the most common cause of harm. This connection between clinical deterioration and medication safety is poorly understood. OBJECTIVES: To inform improvements in prevention and management of clinical deterioration, this review aimed to examine how medications contributed to clinical deterioration and how medications were used in RRSs. REVIEW METHODS: A scoping review was undertaken of medication data reported in studies of clinical deterioration or RRSs in diverse hospital settings between 2005 and 2017. Bibliographic database searches used permutations of "rapid response system," "medical emergency team," and keyword searching with medication-related terms. Independent selection, quality assessment, and data extraction informed mapping against four medication themes: causes of deterioration, predictors of deterioration, RRS use, and management. RESULTS: Thirty articles were reviewed. Quality was low: limited by small samples, observational, single-centre designs and few primary medication-related outcomes. Adverse drug reactions and potentially preventable medication errors, involving sedatives, analgesics, and cardiovascular agents, contributed to clinical deterioration. While sparsely reported, outcomes included death and escalation of care. In children, administration of antibiotics or nebulised medications appeared to predict subsequent deterioration. Cardiovascular medications, sedatives, and analgesics commonly were used to manage deterioration but further detail was lacking. Despite reported potential for patient harm, evaluation of medication management systems was limited. CONCLUSIONS: Medications contributed to potentially preventable clinical deterioration, with considerable harm, and were common interventions for its management. When assessing deteriorating patients or caring for patients who require escalation to critical care, clinicians should consider medication errors and adverse reactions. Studies with more specific medication-related, patient-centred end points could reduce medication-related deterioration and refine RRS medication use and management. PMID- 30005939 TI - The impact of the addition of nurse practitioners to surgical intensive care units: A retrospective cohort study. AB - BACKGROUND: Demand for surgical critical care is increasing, but work-hour restrictions on residents have affected many hospitals. Recently, the use of nurse practitioners (NPs) as providers in the intensive care unit (ICU) has expanded rapidly, although the impacts on quality of care have not been evaluated. OBJECTIVES: To compare the outcomes of critically ill surgical patients before and after the addition of NPs to the ICU team. METHODS: We conducted a retrospective cohort study in a Taiwanese surgical ICU. We compared the outcomes of patients admitted to ICU during the 2-year period before and after the addition of NPs to the ICU team. Patients admitted in the 1-year transition phase were excluded from comparisons. The primary endpoint was ICU mortality. Secondary endpoints included ICU length of stay and incidence of unplanned extubation. RESULTS: A total of 8747 patients were included in the study. For all eligible admissions, primary and secondary outcomes did not differ significantly between the two groups. For scheduled ICU admissions, ICU mortality was significantly lower after the addition of NPs (2.2% before vs. 1.1% after addition of NPs, p = 0.014). For unscheduled ICU admissions, ICU mortality did not differ significantly between the two groups. In the multivariate analysis, admission after the addition of NPs was associated with significantly reduced ICU mortality (odds ratio = 0.481; 95% confidence interval = 0.263-0.865; p = 0.015) among scheduled admissions. CONCLUSION: Incorporating NPs in the ICU team was associated with improved outcomes in scheduled admissions to surgical ICU when compared with a traditional, resident-based team. PMID- 30005941 TI - Development of a Retention Time Interpolation scale (RTi) for liquid chromatography coupled to mass spectrometry in both positive and negative ionization modes. AB - The accuracy and sensitivity of high resolution mass spectrometry (HRMS) enables the identification of candidate compounds with the use of mass spectrometric databases among other tools. However, retention time (RT) data in identification workflows has been sparingly used since it could be strongly affected by matrix or chromatographic performance. Retention Time Interpolation scaling (RTi) strategies can provide a more robust and valuable information than RT, gaining more confidence in the identification of candidate compounds in comparison to an analytical standard. Up to our knowledge, no RTi has been developed for LC-HRMS systems providing information when acquiring in either positive or negative ionization modes. In this work, an RTi strategy was developed by means of the use of 16 isotopically labelled reference standards, which can be spiked into a real sample without resulting in possible false positives or negatives. For testing the RTi performance, a mixture of several reference standards, emulating suspect analytes, were used. RTi values for these compounds were calculated both in solvent and spiked in a real matrix to assess the effect of either chromatographic parameters or matrix in different scenarios. It has been demonstrated that the variation of injection volume, chromatographic gradient and initial percentage of organic solvent injected does not considerably affect RTi calculation. Column aging and solid support of the stationary phase of the column, however, showed strong effects on the elution of several test compounds. Yet, RTi permitted the correction of elution shifts of most compounds. Furthermore, RTi was tested in 47 different matrices from food, biological, animal feeding and environmental origin. The application of RTi in both positive and negative ionization modes showed in general satisfactory results for most matrices studied. The RTi developed can be used in future LC-HRMS screening analysis giving an additional parameter, which facilitates tedious processing tasks and gain more confidence in the identification of (non)-suspect analytes. PMID- 30005940 TI - Metabolomic analysis of mammalian cells and human tissue through one-pot two stage derivatizations using sheathless capillary electrophoresis-electrospray ionization-mass spectrometry. AB - Analysis of metabolites is often performed using separations coupled to mass spectrometry which is challenging due to their vast structural heterogeneity and variable charge states. Metabolites are often separated based on their class/functional group which in large part determine their acidity or basicity. This charge state dictates the ionization mode and efficiency of the molecule. To improve the sensitivity and expand the coverage of the mammalian metabolome, multifunctional derivatization with sheathless CE-ESI-MS was undertaken. In this work, amines, hydroxyls and carboxylates were labeled with tertiary amines tags. This derivatization was performed in under 100 min and resulted in high positive charge states for all analytes investigated. Amino acids and organic acids showed average limits of detection of 76 nM with good linearity of 0.96 and 10% RSD for peak area. Applying this metabolomic profiling system to bovine aortic endothelial cells showed changes in 15 metabolites after treatment with high glucose. The sample injection volume on-capillary was <300 cells for quantitative analyses. Targeted metabolites were found in human tissue, which indicates possible application of the system complex metabolome quantitation. PMID- 30005942 TI - Chiral capillary zone electrophoresis in enantioseparation and analysis of cinacalcet impurities: Use of Quality by Design principles in method development. AB - A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity and of impurities of the chiral calcimimetic drug cinacalcet hydrochloride has been developed following Quality by Design principles. The scouting phase was aimed to select the separation operative mode and to identify a suitable chiral selector. Among the tested cyclodextrins, (2-carboxyethyl)-beta cyclodextrin and (2-hydroxypropyl)-gamma-cyclodextrin (HPgammaCyD) showed good chiral resolving capabilities. The selected separation system was solvent modified capillary zone electrophoresis with the addition of HPgammaCyD and methanol. Voltage, buffer pH, methanol concentration and HPgammaCyD concentration were investigated as critical method parameters by a multivariate strategy. Critical method attributes were represented by enantioresolution and analysis time. A Box-Behnken Design allowed the contour plots to be drawn and quadratic and interaction effects to be highlighted. The Method Operable Design Region (MODR) was identified by applying Monte-Carlo simulations and corresponded to the multidimensional zone where both the critical method attributes fulfilled the requirements with a desired probability pi>=90%. The working conditions, with the MODR limits, corresponded to the following: capillary length, 48.5cm; temperature, 18 degrees C; voltage, 26kV (26-27kV); background electrolyte, 150mM phosphate buffer pH 2.70 (2.60-2.80), 3.1mM (3.0-3.5mM) HPgammaCyD; 2.00% (0.00 8.40%) v/v methanol. Robustness testing was carried out by a Plackett-Burman matrix and finally a method control strategy was defined. The complete separation of the analytes was obtained in about 10min. The method was validated following the International Council for Harmonisation guidelines and was applied for the analysis of a real sample of cinacalcet hydrochloride tablets. PMID- 30005943 TI - Magnetic beads-based neuraminidase enzyme microreactor as a drug discovery tool for screening inhibitors from compound libraries and fishing ligands from natural products. AB - Neuraminidase (NA) is a glycoside hydrolase that has been proposed as a potential therapeutic target for influenza. Thus, the identification of compounds that modulate NA activity could be of great therapeutic importance. The aim of this study is to develop a drug discovery tool for the identification of novel modulators of NA from both compound libraries and natural plant extracts. NA was immobilized onto the surface of magnetic beads and the inherent catalytic activity of NA-functionalized magnetic beads was characterized. Based on the enzymatic activity (hydrolysis ratio), the inhibitory activities of 12 compounds from plant secondary metabolites were screened, and the desired anti-NA activities of flavonoids were certified. Ligand fishing with the immobilized enzyme was optimized using an artificial test mixture consisting of oseltamivir, lycorine and matrine prior to carrying out the proof-of-concept experiment with the crude extract of Flos Lonicerae. The combination of ligand fishing and HPLC MS/MS identified luteolin-7-O-beta-D-glucoside, luteolin, 3,5-di-O-caffeoylquinic acid and 3,4-di-O-caffeoylquinic acid as neuraminidase inhibitory ligands in Flos Lonicerae. This is the first report on the use of neuraminidase functionalized magnetic beads for the identification of active ligands from a botanical matrix, and it sets the basis for the de novo identification of NA modulators from complex biological mixtures. PMID- 30005945 TI - Radiation Therapy Availability in Africa and Latin America: Two Models of Low and Middle Income Countries. AB - Access to radiation facilities in low- and middle-income countries (LMIC) is far from optimal. Latin America and Africa represent 55% of LMIC, and radiation therapy facilities are available in only 70% and 46% of the countries, respectively. Only 3 countries in both regions meet the International Atomic Energy Agency's recommendation of 250,000 population per megavoltage machine (MVM). In Africa, the mean population served by 1 MVM is 3.56 million, compared with 0.65 million in Latin America. The distribution of radiation facilities in both regions varies according to income group. In Latin America, lower-middle income countries have a distribution of 1.64 million inhabitants per MVM, as opposed to 0.64 and 0.49 million inhabitants per MVM in upper-middle- and high income countries, respectively. In Africa, a distribution of 39.8, 2.47, and 0.8 million people per MVM is present in low-, lower-middle-, and upper-middle-income countries, respectively. Significant correlations were clearly demonstrated between population per MVM and gross domestic product (GDP) per capita (r = -0.3, P = .014), percentage of current health expenditure from GDP (r = -0.4, P = .014), life expectancy (r = -0.5, P = .0007), and cancer mortality incidence ratio (r = 0.4, P = .003). Stepwise multivariate regression showed that life expectancy was the only statistically significant factor (P = .001). These findings may indicate the detrimental impact of low radiation therapy coverage on life expectancy and cancer mortality incidence ratio in LMIC. It is noteworthy that in Latin America, a significant negative correlation was noted between population per MVM and GDP per capita (r = -0.6, P = .0004), as opposed to Africa (r = -0.4, P = .075). This indicates that African countries face challenges other than income level in addressing radiation therapy needs. More international efforts are urgently required to address the crisis of unmet radiation therapy needs in LMIC. PMID- 30005944 TI - Validation of mobile in situ measurements of dairy husbandry emissions by fusion of airborne/surface remote sensing with seasonal context from the Chino Dairy Complex. AB - Mobile in situ concentration and meteorology data were collected for the Chino Dairy Complex in the Los Angeles Basin by AMOG (AutoMObile trace Gas) Surveyor on 25 June 2015 to characterize husbandry emissions in the near and far field in convoy mode with MISTIR (Mobile Infrared Sensor for Tactical Incident Response), a mobile upwards-looking, column remote sensing spectrometer. MISTIR reference flux validated AMOG plume inversions at different information levels including multiple gases, GoogleEarth imagery, and airborne trace gas remote sensing data. Long-term (9-yr.) Infrared Atmospheric Sounding Interferometer satellite data provided spatial and trace gas temporal context. For the Chino dairies, MISTIR AMOG ammonia (NH3) agreement was within 5% (15.7 versus 14.9 Gg yr-1, respectively) using all information. Methane (CH4) emissions were 30 Gg yr-1 for a 45,200 herd size, indicating that Chino emission factors are greater than previously reported. Single dairy inversions were much less successful. AMOG MISTIR agreement was 57% due to wind heterogeneity from downwind structures in these near-field measurements and emissions unsteadiness. AMOG CH4, NH3, and CO2 emissions were 91, 209, and 8200 Mg yr-1, implying 2480, 1870, and 1720 head using published emission factors. Plumes fingerprinting identified likely sources including manure storage, cowsheds, and a structure with likely natural gas combustion. NH3 downwind of Chino showed a seasonal variation of a factor of ten, three times larger than literature suggests. Chino husbandry practices and trends in herd size and production were reviewed and unlikely to add seasonality. Higher emission seasonality was proposed as legacy soil emissions, the results of a century of husbandry, supported by airborne remote sensing data showing widespread emissions from neighborhoods that were dairies 15 years prior, and AMOG and MISTIR observations. Seasonal variations provide insights into the implications of global climate change and must be considered when comparing surveys from different seasons. PMID- 30005946 TI - In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection. AB - Human T-cell leukemia virus type 1 (HTLV-1) has infected as many as 10 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal. However, patients with chronic HTLV-1 infection have high frequencies of HTLV-1-activated CD8+ T cells, and the two main HLA alleles (A2, A24) are present in 88% of infected individuals. We thus utilized an immunoproteomics approach to characterize MHC-I restricted epitopes presented by HLA-A2+, A24+ MT-2 and SLB-1 cell lines. Unlike traditional motif prediction algorithms, this approach identifies epitopes associated with cytotoxic T-cell responses in their naturally processed forms, minimizing differences in antigen processing and protein expression levels. Out of nine identified peptides, we confirmed six novel MHC-I restricted epitopes that were capable of binding HLA-A2 and HLA-A24 alleles and used in vitro and in vivo methods to generate CD8+ T cells specific for each of these peptides. MagPix MILLIPLEX data showed that in vitro generated epitope-specific CD8+ T cells secreted IFN-gamma, granzyme B, MIP-1alpha, TNF-alpha, perforin and IL-10 when cultured in the presence of MT-2 cell line. Degranulation assay confirmed cytotoxic response through surface expression of CD107 on CD8+ T cells when cultured with MT-2 cells. A CD8+ T-cell killing assay indicated significant antiviral activity of CD8+ T cells specific against all identified peptides. In vivo generated CD8+ T cells similarly demonstrated immunogenicity on ELISpot, CD107 degranulation assay, and MagPix MILLIPLEX analysis. These epitopes are thus candidates for a therapeutic peptide-based vaccine against HTLV-1, and our results provide preclinical data for the advancement of such a vaccine. PMID- 30005947 TI - Mixing is required for uniform reconstitution of filter-dried protein antigens in a single-injection vaccine formulation. AB - Ambient temperature filter dried vaccine formulations have been proposed to simultaneously achieve thermostability and offer a ready-to-use immunisation device that combines reconstitution and injection. Vaccine concentration should be uniform at the point of injection, but the uniformity following direct reconstitution of filter-dried vaccines has not been reported. We present here a study of vaccine mixing and release following dissolution of filter-dried model protein and toxoid antigens within a single syringe, filter and needle unit. Release was better for filters made from glass than cellulose. Without additional mixing, uniformity was poor and only 41% of input protein was released from protein filter-dried onto glass fiber. In contrast, adding a simple glass bead and mixing by inversion, 100% release antigen solution was achieved, with uniform concentration at exit from the needle throughout a simulated injection. Adsorption onto alum adjuvant had no detectable effect on vaccine dissolution and mixing. The uniformity and yield of low doses of diphtheria and tetanus toxoid was also improved by mixing, albeit with a lower yield of 60-68%. We conclude that uniformity and mixing should be studied to ensure safety and efficacy of directly reconstituted filter-dried vaccine formulations. PMID- 30005949 TI - Streptococcus pneumoniae serotype 19A in Latin America and the Caribbean 2010 2015: A systematic review and a time series analysis. AB - BACKGROUND: This systematic review aims to describe the prevalence, trends, and antibiotic resistance of Streptococcus pneumoniae serotype 19A (Spn19A) that causes invasive and non-invasive diseases in children <5 years in Latin-American and Caribbean countries. METHODS: We searched for published (between January 2010 and February 2016) observational and clinical studies within the region including effectiveness and impact on Spn19A after pneumococcal conjugate vaccine (PCV) introduction. We calculated prevalence estimates by country and standardized the frequency of isolates to conduct an interrupted time series analysis for selected countries and to assess the potential changes in disease trends, overall and for Spn19A. RESULTS: We identified and reviewed full-text of 89 publications and included 59 in the analysis. Data from the laboratory surveillance network, SIREVA, were included in 43 (74%) of the invasive pneumococcal disease reports. There are differences in the sensitivity, representativeness, and heterogeneity of laboratory surveillance. There has been and overall reduction in the trend and number of invasive S. pneumoniae isolates in children <5 years after PCVs introduction. To date, the prevalence of Spn19A has increased, however, there has been no observed change in the trend. CONCLUSIONS: This updated systematic review provides evidence of a reduction in the total number of invasive pneumococcal disease isolates after the introduction of PCVs in the region but cannot yet conclude a change in the trend of Spn19A disease. PMID- 30005948 TI - Safety and immunogenicity of the Cuban heptavalent pneumococcal conjugate vaccine in healthy infants. Results from a double-blind randomized control trial Phase I. AB - BACKGROUND: Cuba has a new pneumococcal conjugate vaccine candidate (PCV7-TT). This study evaluates the safety and immunogenicity in healthy infants using 2p+1 vaccination schedule. METHODS: A phase I, controlled, randomized and double blind clinical trial was designed. 30 unvaccinated healthy infants were included. 20 subjects were assigned to study group (PCV7-TT) and 10 to control group (Synflorix(r)) to receive the vaccines at 7, 8 months of age (primary series) and 11 months (booster dose). Blood samples were collected 30 days after second dose and post booster for antibodies measure analysis by ELISA and OPA. The statistics analysis included the frequency of occurrence for adverse events and the immune response. Non-parametric tests were used to compare the immune response. The clinical trial was published in the Cuban Public Register of Clinical Trials with code RPCEC00000173 available at http://registroclinico.sld.cu. RESULTS: Overall, the safety profile of PCV7-TT was similar to Synflorix(r). Local reactions were predominant and systemic events were mild in severity. Swelling and redness were frequently associated with PCV7-TT mainly after the first dose (50% and 40% respectively). 15% and 10% of subject reported severe swelling after first dose with PCV7-TT and after second dose with Synflorix(r). Mild fever (>=38-<=39), vomiting and sleep disturb were the systemic events reported. 100% of infants achieved pneumococcal IgG antibody concentrations >=0.35 ug/ml after booster dose for serotypes 1, 14, 18C and 19F in each vaccine group. For serotypes 5, 6B and 23F, more than 80% infants vaccinated with Synflorix(r) or PCV7-TT achieved protective IgG GMC >= 0.35 ug/ml after booster dose. OPA proportion's responders to the seven common serotypes were 89.5% or more after the primary dose and 100% after booster dose in vaccinated with PCV7-TT. CONCLUSIONS: The Cuban PCV7-TT is safe, well tolerated and immunogenic in healthy infants. PMID- 30005950 TI - How to Eliminate Uncertainty in Clinical Medicine - Clues from Creation of Mathematical Models Followed by Scientific Data Mining. PMID- 30005952 TI - Attitudes and Social Norms Are Related to Attendance at Childhood Obesity Prevention Classes in a Rural Mexican-Heritage Community. AB - OBJECTIVE: To examine factors related to attendance of Mexican-heritage parents at community-based nutrition classes to prevent childhood obesity. METHODS: Starting in 2011, interviewers collected baseline data from Ninos Sanos Familia Sana (Healthy Children, Healthy Families) participants in rural California. Educators maintained attendance logs from 2012 to 2014. Informed by the Theory of Planned Behavior, interviewers administered an exit survey in 2015 to collect data on attitudes, subjective norms, health motivations, and perceived control related to attendance. Multivariable ordinal logistic regression analysis examined the correlates of attendance (n = 194, intervention group only). RESULTS: Controlling for mother's age, marital status, acculturation, and employment, attitudes and subjective norms were significantly related to attendance (odds ratio = 1.27; 95% confidence interval [CI], 1.18-1.37; P < .001). CONCLUSIONS AND IMPLICATIONS: In these Mexican-heritage participants, attitudes and subjective norms were significant correlates of attendance. The Theory of Planned Behavior may shed light on attendance of high-risk groups but further testing of instruments is needed. PMID- 30005953 TI - The impact of margin reduction on outcome and toxicity in head and neck cancer patients treated with image-guided volumetric modulated arc therapy (VMAT). AB - BACKGROUND AND PURPOSE: In recent decades, outcomes of patients with head and neck cancer (HNC) have improved as a result of implementing several strategies, such as chemoradiation. However, these improvements were achieved at the cost of increased toxicity. One way to reduce radiation-related toxicity is by reducing the margins. MATERIALS AND METHODS: Between 2013 and 2016, 206 consecutive patients were treated with CTV-PTV margin of 5 mm and subsequently 208 patients with 3 mm margin. This study evaluates the impact of reducing clinical target volume (CTV) to planning target volume (PTV) margin on outcome and toxicity. RESULTS: All patients were treated with volumetric modulated arc therapy (VMAT) with daily-image guidance using cone-beam CT (CBCT). Overall acute grade 3 toxicity was significantly lower in 3 mm-group, compared to 5 mm-group (53.8% vs. 65%, respectively, p = 0.032). The same was true for acute grade 3 mucositis (30.8% vs. 42.2%, p = 0.008) and for acute grade 3 dysphagia (feeding tube dependence) (22.1% vs. 33.5%, p = 0.026). The incidence of ongoing feeding tube dependence after 3 months of radiotherapy was 11.1% and 20.4%, respectively (p = 0.012). The 2-year incidence of late grade >=2 xerostomia was 15.8% and 19.4% (p = 0.8). The 2-year loco-regional control rates of patients treated in 3 mm and 5 mm-groups were 79.9% and 79.2% (p = 1.0). The figures for disease-free survival were 71.5% and 72.7 (p = 0.6) and for overall survival were 75.2% and 75.1% (p = 0.9). CONCLUSION: Reducing the CTV-PTV margin from 5 to 3 mm combined with daily CBCT-guided VMAT reduced the severity, frequency, and duration of radiation related toxicity without jeopardizing outcome. PMID- 30005951 TI - The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer. AB - An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock-regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy. PMID- 30005954 TI - Tumor to cervical spinal cord standardized uptake ratio (SUR) improves the reproducibility of 18F-FDG-PET based tumor segmentation in head and neck squamous cell carcinoma in a multicenter setting. AB - BACKGROUND: In quantitative FDG-PET data analysis, normalization of the standardized uptake value (SUV) with an internal image-derived standard improves its reproducibility. In this study, the cervical spinal cord is proposed as an internal standard that is within the field of view of the radiotherapy planning PET/CT-scan in head and neck cancer. The aim is to evaluate if the tumor to cervical spinal cord standardized uptake ratio (SUR) can improve the reproducibility of a model to determine the metabolic tumor volume (MTV) on FDG PET/CT in a multicenter setting. MATERIALS AND METHODS: Ninety-five radiotherapy planning FDG-PET/CT-scans of patients with head and neck cancer were analyzed using the Bland-Altman method to evaluate differences in FDG-uptake in the cervical spinal cord and the mediastinal blood pool. Non-linear regression analysis was used to determine the optimal MTV using the gross tumor volume (GTV) as ground truth and a spatial overlap-index as statistical validation metric. Reproducibility was evaluated using the Bland-Altman method and external validation was performed in an independent dataset consisting of 62 patients. RESULTS: Bland-Altman's analyses demonstrated equivalence of FDG-uptake in the mediastinal blood pool and the cervical spinal cord. Reproducibility of the models improved when using SUR instead of SUV. These results were confirmed in the validation cohort. CONCLUSION: The use of the tumor to cervical spinal cord SUR instead of SUV improves the reproducibility of a model to determine the MTV on FDG-PET/CT in a multicenter setting. This study indicates that SUR may be preferred over SUV based approaches. PMID- 30005955 TI - Ginger (Zingiber officinale Roscoe) for the treatment and prevention of necrotizing enterocolitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Necrotizing enterocolitis (NEC) is the most important gastrointestinal emergency affecting especially preterm infants and causes severe morbidities and mortality. However, there is no cure. Oxidant stress, inflammation, apoptosis, as well as prematurity are believed to responsible in the pathogenesis of the disease. Ginger and its compounds have anti-inflammatory, antimicrobial, anti-oxidant properties and immunomodulatory, cytoprotective/regenerative actions. AIM OF THE STUDY: This study aimed to evaluate the beneficial effects of ginger on the intestinal damage in an experimental rat model of NEC. MATERIALS AND METHODS: Thirty newborn Wistar rats were divided into three groups: NEC, NEC + ginger and control in this experimental study. NEC was induced by injection of intraperitoneal lipopolysaccharide, feeding with enteral formula, hypoxia-hyperoxia and cold stress exposure. The pups in the NEC + ginger group were orally administered ginger at a dose of 1000 mg/kg/day. Proximal colon and ileum were excised. Histopathological, immunohistochemical (TUNEL for apoptosis, caspase 3 and 8) and biochemical assays including xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malonaldehyde (MDA) and myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), interleukin1beta (IL-1beta), and interleukin 6 (IL-6) activity were evaluated. RESULTS: Compared with the NEC group, the rat pups in the NEC + ginger group had better clinical disease scores and weight gain (p < 0.05). Macroscopic evaluation, Histopathologic and apoptosis assessment (TUNEL, caspase 3 and 8) releaved that severity of intestinal damage were significantly lower in the NEC + ginger group (p < 0.05). The levels of TNF alpha, IL-1beta and IL-6 in the ginger treated group were significantly decreased (P < 0.05). The GSH-Px and SOD levels of the ginger treated group were significantly preserved in the NEC + ginger group (p < 0.05). The tissue XO, MDA and MPO levels of the NEC + ginger group were significantly lower than those in the NEC group (P < 0.05). CONCLUSION: Ginger therapy efficiently ameliorated the severity of intestinal damage in NEC and may be a promising treatment option. PMID- 30005957 TI - Future perspectives on neural mechanisms underlying rhythm and music based neurorehabilitation in Parkinson's disease. AB - Parkinson's disease (PD) is characterized primarily by a dysfunctional basal ganglia (BG) system, producing motor and non-motor symptoms. A significant number of studies have demonstrated that rhythmic auditory stimulation can improve gait and other motor behaviors in PD that are not well managed by the conventional therapy. As music, being highly complex stimulus, can modulate brain activity/function in distributed areas of brain, the therapeutic properties of music potentially extend to alleviate non-motor symptoms of PD. Despite the clinical, behavioral evidence and promises of rhythm and music based interventions, the neural substrates underlying the effectiveness are poorly understood. The goal of this review is to appraise the current state of knowledge in order to direct further neuroimaging studies that help to determine the therapeutic effects of rhythm and music based interventions for motor and non motor symptoms of PD. PMID- 30005956 TI - Assessing medicinal plants traditionally used in the Chirang Reserve Forest, Northeast India for antimicrobial activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Knowledge on the use of plants for different ailments by the tribals of the Chirang Reserve Forest (CRF, Northeast India) was used to assess the potential of these plants for treating viral, bacterial and fungal infections. MATERIALS AND METHODS: Fieldwork in the CRF documented the use of plants for the treatment of various human ailments. The ethnobotanical data were analysed using different quantitative indices viz. Informant Consensus Factor (ICF), Relative Frequency Citation (RFC), Fidelity Level (FL), Relative Popularity Level (RPL) and Rank Order Priority (ROP). For each plant, four extracts were prepared with different solvents (water, ethanol, acetone and hexane) and tested for bioactivity such as antiviral (Enterovirus 71) and antimicrobial (E. coli, S. aureus, C. albicans) effects. To develop fingerprints, thin layer chromatography (TLC) was carried out with at least one extract of each active plant. RESULTS: Thirty-seven plant species belonging to 26 families used frequently in the CRF were categorised into twenty disease(s) and markedly high ICF values (0.5-1) were found. The FL of the 19 most important plant species ranged from 10% to 100%. Aglaia spectabilis, Actinodaphne obovata, Bischofia javanica, Gmelina arborea, Hodgsonia macrocarpa and Mesua ferrea were the most popular plant species with RPL values > 0.4. The most commonly treated diseases were skin infections, worm infections, diarrhoea, dysentery, common cold and throat infections, cough and respiratory problems, fever, malaria, rheumatism, pain, stomach ache and gastric problems. Among the taxonomic families, the most represented are Lauraceae (4 species); Meliaceae (3 species), Euphorbiaceae, Elaecarpoceae, Magnoliaceae, Malvaceae, Moraceae and Myrtaceae (2 species each). Of these, 35 plants (95%) with 91 of their extracts were found to be active against S. aureus (inhibition > 50%). Similarly, over half of the tested plants inhibited growth of E. coli (19 plants with 31 extracts) while 9 plants with 14 extracts were active against C. albicans. Moreover, one-third (12) of the plants showed anti-enteroviral activity. TLC analysis of the extracts indicates the presence of different phytochemical classes such as alkaloids, flavonoids, glycosides, terpenoids and saponins based on observing characteristic spots under visible or UV light (254 or 360 nm), with or without derivatisation. CONCLUSIONS: Thirty-seven plants commonly used by the tribes of the CRF as anti-infective agents offer perspectives for further research, as the phytochemistry and phytopharmacology for most of these plants have not been published to date. PMID- 30005958 TI - Incidence and progression of diabetic retinopathy: a systematic review. AB - Diabetic retinopathy is a leading cause of vision impairment and blindness. We systematically reviewed studies published from Jan 1, 1980, to Jan 7, 2018, assessed the methodological quality, and described variations in incidence of diabetic retinopathy by region with a focus on population-based studies that were conducted after 2000 (n=8, including two unpublished studies). Of these eight studies, five were from Asia, and one each from the North America, Caribbean, and sub-Saharan Africa. The annual incidence of diabetic retinopathy ranged from 2.2% to 12.7% and progression from 3.4% to 12.3%. Progression to proliferative diabetic retinopathy was higher in individuals with mild disease compared with those with no disease at baseline. Our Review suggests that more high-quality population-based studies capturing data on the incidence and progression of diabetic retinopathy with stratification by age and sex are needed to consolidate the evidence base. Our data is useful for conceptualisation and development of major public health strategies such as screening programmes for diabetic retinopathy. PMID- 30005959 TI - Towards a RAS mutation status in a single day for patients with advanced colorectal cancers. Authors' reply. PMID- 30005960 TI - Molecular imaging in gastroenterology: A route for personalized endoscopy. AB - With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel diseases and cancer and the increase in oncological patients in gastroenterology, visualization of single receptor or molecular target expression and the subsequent initiation of expression tailored therapy are gaining increasing attention. Through the combination of utilizing fluorescently labeled probes with high specificity towards defined molecular targets and their subsequent detection and visualization with endoscopic devices, molecular imaging is a new emerging field focusing on the receptor expression within the mucosa on a cellular level rather than on macroscopic changes. In the past years various new technological and molecular probes have been successfully utilized for molecular imaging. Within this review, we summarize different technologies as well as molecular probes applied in molecular imaging and review current and past approaches for functional imaging with molecular endoscopy within the GI Tract and resulting clinical applications. It can be expected that molecular imaging allows for individualized diagnostic approaches and patient tailored medicine in the future. PMID- 30005961 TI - Should prophylactic embolization of spontaneous portosystemic shunts be routinely performed during transjugular intrahepatic portosystemic shunt placement? PMID- 30005962 TI - Surveillance of Pediatric Hypertension Using Smartphone Technology. AB - INTRODUCTION: Elevated blood pressure is becoming increasingly common in the pediatric population. Hypertension costs nearly $51 billion/year, and cardiovascular disease is responsible for 17% of the nation's health care expenditures. Traditionally, time-consuming and complicated interpretation standards result in infrequent pediatric blood pressure screenings. This may lead to the under-diagnosis of pediatric hypertension. Early detection of elevated blood pressure is important in order to prevent hypertension related conditions such as, target organ damage, left ventricular hypertrophy, and cerebrovascular disease. The aim of this study was to observe the prevalence of pediatric hypertension among children and adolescents age 3-18 using the smartphone application Pedia BP(r). The purpose of this study was to (1) identify the prevalence of elevated blood pressure in a sample of children and adolescents and (2) evaluate any association between BMI, age, and blood pressure classification. METHOD: A quantitative, descriptive study was conducted to evaluate the prevalence of pediatric hypertension in 81 preschool and school age children. App users were trained with the online take2heart course available at take2heart.com. The manual systolic and diastolic blood pressure readings were entered into the application, along with the patient's gender, age, height, and weight. Pedia BP(r) instantly calculated the blood pressure classification of the patient based on percentiles. Quantitative data from the Pedia BP(r) data repository were analyzed using descriptive statistics. RESULTS: We found that 54.3% of our sample were normotensive, 23.5% had prehypertension, 13.6% had stage 1 hypertension, and 8.6% had stage 2 hypertension. As seen in Figure 3, the majority of subjects with stage 1 (72.7%) and stage 2 hypertension (57.1%) were found in school-age children. We found that 3.7% of children were underweight, 48.1% were at a healthy weight, 21% were overweight, and 27.2% were obese. DISCUSSION: Pedia BP(r) was shown to be an effective screening tool to easily classify blood pressure readings on an individual basis. The prevalence of hypertension in our sample was higher than previously reported in the literature. Annual evaluation of blood pressures in preschool and school age children are warranted to identify and address hypertension. Pedia BP(r) was shown to be an effective screening tool to easily classify blood pressure readings on an individual basis. Pedia BP(r) offers benefits not only for patients, but for primary care providers, nurses, economists, insurance companies, hospitals, and clinics. Ultimately, Pedia BP(r) (1) increases awareness of elevated blood pressures among children and adolescents, (2) engages the health care community to screen for elevated blood pressures, (3) implements innovative technology, and (4) activates the potential for a population-based surveillance tool. PMID- 30005963 TI - Micro-computed tomography (micro-CT) for intraoperative surgical margin assessment of breast cancer: A feasibility study in breast conserving surgery. AB - PURPOSE: Around 15%-30% of patients receiving breast-conserving surgery (BCS) for invasive breast carcinoma or ductal carcinoma in situ (DCIS) need a reoperation due to tumor-positive margins at final histopathology. Currently available intraoperative surgical margin assessment modalities all have specific limitations. Therefore, we aimed to assess the feasibility and accuracy of micro computed tomography (micro-CT) as a novel method for intraoperative margin assessment in BCS. METHODS: Lumpectomy specimens from 30 consecutive patients diagnosed with invasive breast cancer or DCIS were imaged using a micro-CT. Margin status was assessed on micro-CT images by two investigators who were blinded to the final histopathological margin status. The micro-CT margin status was compared with the histopathological margin status. RESULTS: The margin status could be assessed by micro-CT in 29 out of 30 patients. Of these, nine patients had a positive tumor margin and 20 a negative tumor margin at final histopathology. Margin status evaluation by micro-CT took always less than 15 min. The margin status in 25 patients was correctly predicted by micro-CT. There were four false-negative predictions. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of micro-CT in margin status prediction were 86%, 56%, 100%, 100% and 83%, respectively. With micro-CT, the positive margin rate could potentially have been reduced from 31% to 14%. CONCLUSIONS: Whole lumpectomy specimen micro-CT scanning is a promising technique for intraoperative margin assessment in BCS. Intraoperative quick feedback on the margin status could potentially lead to a reduction in the number of reoperations. PMID- 30005965 TI - Experimental Evaluation of Endovascular Fenestration Scissors in an Ovine Model of Aortic Dissection. AB - OBJECTIVE/BACKGROUND: To evaluate the experimental feasibility of endovascular fenestration using specific endovascular scissor prototypes in an ovine model of acute aortic dissection (AD). METHODS: A previously described endovascular technique was used to create a model of acute type B AD in sheep. Endovascular fenestrations using either endovascular scissor prototypes or a long sheath were compared. Four prototypes of endovascular fenestration scissors were evaluated. Both validity of the experimental model of AD and technical success of endovascular fenestration were assessed by haemodynamic criteria, completion angiography, transesophageal echocardiography, and post-procedural analysis of harvested aortas. RESULTS: Experimental acute AD was created by endovascular means in 17 sheep, with a technical success rate of 82%. Systolic blood pressure was lower in the false lumen than in the true lumen (58 +/- 5 vs. 79 +/- 3 mmHg, respectively; p < .001). Endovascular fenestration was performed in 11 models (endovascular scissors n = 8; long sheath n = 3). Controlled endovascular fenestration was obtained by the use of endovascular scissors (n = 5/8), resulting in a significant rise in false lumen systolic blood pressure after fenestration (60 +/- 2 vs. 67 +/- 9 mmHg before and after fenestration, respectively; p < .047). Long sheath fenestration resulted in an uncontrolled flap motion, leading to either pseudo-coarctation syndrome or aortic rupture (58 +/- 6 vs. 40 +/- 2 mmHg before and after fenestration, respectively; p < .001). CONCLUSION: In this experimental study, a reproducible AD model has been developed in sheep using endovascular procedures exclusively to evaluate endovascular fenestration techniques. Endovascular fenestration using a long sheath appeared hazardous and risky in vivo. Endovascular scissors constitute a dedicated and suitable tool to perform a safe controlled and effective endovascular fenestration in an ovine model. PMID- 30005966 TI - Three-Year Morbidity and Mortality Rates After Nontraumatic Transmetatarsal Amputation. AB - Patients requiring a nontraumatic transmetatarsal amputation (TMA) typically have multiple comorbidities that place them at high risk of postoperative complications and additional surgery. The present study identified the demographic, clinical, and surgical risk factors that predict complications after a nontraumatic TMA, including the incidence of 3-year mortality, proximal limb amputation, and lack of healing. The electronic medical records of patients who had undergone TMA within a Kaiser Permanente Northern California facility from March 2007 to January 2012 (n = 375) were reviewed. We used bivariate and multivariate analyses to examine the variations in the rates of TMA complications according to sex, age, race, and comorbid conditions, including nonpalpable pedal pulses, end-stage renal disease, coronary artery disease, hypertension, smoking status, and preoperative albumin <3.5 mg/dL. After a nontraumatic TMA, 136 (36.3%) patients had died within 3 years, 138 (36.8%) had required a more proximal limb amputation, and 83 (22.1%) had healed without complications. The patients with nonpalpable pedal pulses had 3 times the odds of requiring a proximal limb amputation (adjusted odds ratio [aOR] 3.07; 95% confidence interval [CI] 1.84 to 5.11), almost twice the odds of dying within 3 years (aOR 1.70; 95% CI 0.98 to 2.93), and >2 times the odds of not healing after the TMA (aOR 2.45; 95% CI 1.40 to 4.31). The patients with end-stage renal disease had 3 times the odds of dying within 3 years (aOR 3.10; 95% CI 1.69 to 5.70). The present findings can help us identify patients with an increased risk of postoperative complications after nontraumatic TMA, including patients with nonpalpable pedal pulses or end-stage renal disease, and suggest the vulnerability of this patient population. PMID- 30005967 TI - Factors Associated With Wound- and Implant-Related Complications After Surgical Treatment of Ankle Fractures. AB - We have described the epidemiology of complications after surgical treatment of ankle fractures and assessed which factors are associated with the most frequent complications. We conducted a retrospective cohort study at 2 level 2 and 1 level 1 trauma center in a single trauma region in the Netherlands. The study variables were collected from the electronic medical patient records; all ankle fractures were classified using the Lauge-Hansen classification, and the complications were recorded. A total of 989 patients were included from 3 hospitals, with 173 complications in 156 patients (15.8%). The most frequent complication was wound related, occurring in 101 patients (10.2%). Implant-related complications occurred in 44 patients (4.4%). Other complications, such as cast pressure spots, posttraumatic dystrophy, nonunion, impingement, and pneumonia occurred in 28 patients (2.8%). The 2 most important complications were further analyzed for risk factors. Multivariate analysis showed the risk factors for wound-related complications were advanced age, increased American Society of Anesthesiologists classification, smoking, right side symptomatic, open fracture, and initial external fixation. Most implant-related complications were caused by malreduction (n = 22) or untreated syndesmotic injury (n = 19). Malreduction was associated with supination eversion fractures (p = .059), and untreated syndesmotic injury occurred more often with pronation external rotation fractures (p < .001). The most frequent complications after ankle fracture surgery were wound- and implant related complications. Postoperative wound-related complications were multifactorial and dependent on a combination of trauma-, patient-, and treatment related factors. In contrast, implant-related complications resulted from the interaction between the fracture type and subsequent surgical treatment. PMID- 30005968 TI - Haplosporidium pinnae sp. nov., a haplosporidan parasite associated with mass mortalities of the fan mussel, Pinna nobilis, in the Western Mediterranean Sea. AB - This study provides morphological and molecular characterization of a new species, Haplosporidium pinnae), very likely responsible for mass mortality of fan mussels, Pinna nobilis, in the Western Mediterranean Sea. The parasite was found in dead or moribund P. nobilis but did not occur in healthy fan mussels from locations that were not affected by abnormal mortality. Histological examination of infected fan mussels showed uninucleate cells of a haplosporidan parasite throughout the connective tissue and hemolymph sinuses of the visceral mass and binucleate cells and, rarely, multinucleate plasmodia were also detected in the connective tissue. Additionally, stages of sporulation occurred in the epithelium of the host digestive gland tubules. Spores were slightly ellipsoidal with a hinged operculum in one pole. Typical haplosporosomes were not found with TEM but vesicles with two concentric membranes resembling haplosporosomes were abundant in the cytoplasm of the multinucleate plasmodia occurring in host digestive gland tubules. SEM analysis showed multiple structures on the spore surface; some spores had two or four long tape-like filaments attached to the spore wall. Phylogenetic analysis based on the SSU rDNA sequence placed this parasite within a large clade including species of the order Haplosporida, not in the Bonamia/Minchinia subclade or the subclade containing most Haplosporidium species, but within a subclade of Haplosporidium sp. from Penaeus vannamei. Our results suggested that H. pinnae and the parasite of P. vannamei may represent a distinct new genus within the order Haplosporida. PMID- 30005964 TI - Identification and Analysis of Human Sex-biased MicroRNAs. AB - Sex differences are widely observed under various circumstances ranging from physiological processes to therapeutic responses, and a myriad of sex-biased genes have been identified. In recent years, transcriptomic datasets of microRNAs (miRNAs), an important class of non-coding RNAs, become increasingly accessible. However, comprehensive analysis of sex difference in miRNA expression has not been performed. Here, we identified the differentially-expressed miRNAs between males and females by examining the transcriptomic datasets available in public databases and conducted a systemic analysis of their biological characteristics. Consequently, we identified 73 female-biased miRNAs (FmiRs) and 163 male-biased miRNAs (MmiRs) across four tissues including brain, colorectal mucosa, peripheral blood, and cord blood. Our results suggest that compared to FmiRs, MmiRs tend to be clustered in the human genome and exhibit higher evolutionary rate, higher expression tissue specificity, and lower disease spectrum width. In addition, functional enrichment analysis of miRNAs show that FmiR genes are significantly associated with metabolism process and cell cycle process, whereas MmiR genes tend to be enriched for functions like histone modification and circadian rhythm. In all, the identification and analysis of sex-biased miRNAs together could provide new insights into the biological differences between females and males and facilitate the exploration of sex-biased disease susceptibility and therapy. PMID- 30005969 TI - Conjugation of chitosan oligosaccharides enhances immune response to porcine circovirus vaccine by activating macrophages. AB - Porcine circovirus type 2 (PCV2)-associated diseases have led to great economic losses to the pig industry. Our lab previously found that conjugation of chitosan oligosaccharides (COS) or via a carrier protein enhanced the immunogenicity of PCV2 vaccine against infectious pathogens. However, precise mechanisms and signal transduction pathways underlying the efficacy of COS conjugation remains poorly defined. In this study, to better understand the effects and mechanism of COS conjugates maintain the adjuvant potential in vivo, we investigated its augmentation of macrophage function, including cell activation, NO production, cytokine production and phagocytosis. Additionally, the role of Toll-like receptors (TLR) proteins in this process was also assessed. The results indicate that, as compared to the PCV and PCV/COS, conjugation of COS effectively enhanced the NO production, cytokines generation and phagocytosis activity of macrophages. Noticeably, the generation of NO and proinflammatory cytokines was closely related to the TLR2/4 signaling pathways, strongly suggesting that conjugation of COS regulates innate and adaptive immunity by activation of macrophages, resulting in immune enhancement. In summary, the present study provides a potential mechanism of COS conjugation as a novel adjuvant to improve immune responses against various diseases. PMID- 30005970 TI - Inhibition of RhoA and mTORC2/Rictor by Fingolimod (FTY720) induces p21-activated kinase 1, PAK-1 and amplifies podosomes in mouse peritoneal macrophages. AB - Macrophage functions in the immune response depend on their ability to infiltrate tissues and organs. The penetration between and within the tissues requires degradation of extracellular matrix (ECM), a function performed by the specialized, endopeptidase- and actin filament- rich organelles located at the ventral surface of macrophage, called the podosomes. Podosome formation requires local inhibition of small GTPase RhoA activity, and depends on Rac 1/Rho guanine nucleotide exchange factor 7, beta-PIX and its binding partner the p21-activated kinase (PAK-1). The activity of RhoA and Rac 1 is in turn regulated by mTOR/mTORC2 pathway. Here we showed that a fungus metabolite Fingolimod (FTY720, Gilenya), which is clinically approved for the treatment of multiple sclerosis, down-regulates Rictor, which is a signature molecule of mTORC2 and dictates its substrate (actin cytoskeleton) specificity, down-regulates RhoA, up-regulates PAK 1, and causes amplification of podosomes in mouse peritoneal macrophages. PMID- 30005971 TI - HIV-specific CD4+Th17 cells from HIV infected long-term non-progressors exhibit lower CTLA-4 expression and reduced apoptosis. AB - Progressive HIV infection is marked with reduced frequency and impaired function of Th17 cells. Since T-cell functional responses are regulated by various inhibitory receptors; we examined the expression profile of CTLA-4, PD-1, Tim-3 and apoptotic marker: Caspase-3 on virus-specific Th17 cells from HIV-infected Long-Term Non-Progressors (LTNPs), chronic disease progressors and HIV-uninfected healthy controls (HC) using flowcytometry. Real-time PCR was done to analyze the mRNA expression of Th17 and Treg specific genes. LTNPs showed higher frequencies of HIV-specific Th17 cells; higher mRNA expression of IL-17, IL-22 while lower expression of IL-10; along with lower Caspase-3 expression than the progressors. Among inhibitory receptors, expression of CTLA-4 was 27 and 8 fold; PD-1 was 8 and 6 fold while Tim-3 was 7 and 6 fold higher in progressors and LTNPs respectively than HC. Among HIV-infected patients, LTNPs had 3-fold lower expression of CTLA-4 on HIV-specific Th17 cells than progressors (p = 0.06). Caspase-3+ve Th17 cells were associated with HIV-specific Th17 cells expressing CTLA-4 (r = 0.66;p < 0.0001), PD-1 (r = 0.40;p = 0.02) and Tim-3 (r = 0.35;p = 0.04). To conclude, virus-specific Th17 cells from LTNP maintained IL-17 production, expressed low levels of CTLA-4 and reduced apoptosis. The study suggests that such functional competence of Th17 cells could be one of the factors in maintenance of non-progressive HIV infection. PMID- 30005972 TI - The evolution of linguistic theory and the new 'core'. PMID- 30005973 TI - Space, time, and language: Comment on "Rethinking foundations of language from a multidisciplinary perspective" by Tao Gong, Lan Shuai and Yicheng Wu. PMID- 30005974 TI - Organoaxial Volvulus. PMID- 30005975 TI - 5-HT1A receptor-mediated activation of neuroendocrine responses and multiple protein kinase pathways in the peripubertal rat hypothalamus. AB - Increasing evidence suggests that multiple factors can produce effects on the immature brain that are distinct and more long-lasting than those produced in adults. The hypothalamic paraventricular nucleus (PVN) is a region integral to the hypothalamic-pituitary-adrenal axis and is affected by anxiety, depression, and drugs used to treat these disorders, yet receptor signaling mechanisms operative in hypothalamus prior to maturation remain to be elucidated. In peripubertal male rats, systemic injection of the selective serotonin 1A (5-HT1A) receptor agonist (+)8-OH-DPAT (0.2 mg/kg) markedly elevated plasma levels of oxytocin and adrenocorticotropic hormone (ACTH) at 5 and 15 min post-injection. The 5-HT1A receptor selectivity was demonstrated by the ability of the 5-HT1A receptor selective antagonist WAY100635 to completely block both oxytocin and ACTH responses at 5 min, with some recovery of the ACTH response at 15 min. At 15 min post-injection, (+)8-OH-DPAT also increased levels of phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated protein kinase B (pAkt) in the PVN. As previously observed in adults, (+)8-OH-DPAT reduced levels of pERK in hippocampus. WAY100635 also completely blocked (+)8-OH-DPAT-mediated elevations in hypothalamic pERK and pAkt and the reductions in hippocampal pERK, demonstrating 5-HT1A receptor selectivity of both kinase responses. This study provides the first demonstration of functional 5-HT1A receptor-mediated ERK and Akt signaling pathways in the immature hypothalamus, activated by a dose of (+)8 OH-DPAT that concomitantly stimulates neuroendocrine responses. This information is fundamental to identifying potential signaling pathways targeted by biased agonists in the development of safe and effective treatment strategies in children and adolescents. PMID- 30005977 TI - Assessing the efficacy of the new protocol for chest compressions before definitive cardiac arrest in emergency medical service-witnessed adult out-of hospital cardiac arrests. AB - AIMS: Japanese emergency medical services (EMS) personnel providing advance life support confirm the absence of a carotid pulse before initiating chest compressions (CCs) in adult out-of-hospital cardiac arrest (OHCA). This study aims to investigate the efficacy of a new protocol facilitating early CCs before definitive cardiac arrest in enhancing the outcomes of OHCA. METHODS: The 2011 new protocol facilitated EMS to initiate CCs when the carotid pulse was weak and/or <50/min in comatose adult patients with respiratory arrest (apnoea or agonal breathing) and loss of the radial pulse. During 2008-2015, we compared the neurologically favourable 1-year survival rate of EMS-witnessed OHCA and EMS confirmed out-of-hospital respiratory arrest (OHRA) in adults before (N = 257 and 34, respectively) and after (N = 255 and 54, respectively) the implementation of the new protocol. RESULTS: After the new protocol, EMS initiated CCs >1.5 min before definitive cardiac arrest in 31% (80/255) and 33% (18/54) of EMS-witnessed OHCA and EMS-confirmed OHRA, respectively. While the new protocol was not significantly associated with survival of EMS-confirmed OHRA, it was significantly associated with survival of EMS-witnessed OHCA: 9.0% and 14.9%, before and after, P by univariate analysis <0.03; adjusted OR (95% CI) by multivariable logistic regression analysis, 2.01 (1.04-3.90). Neither early start of CCs nor the new protocol was associated with the progression to cardiac arrest in 212 cases with impending cardiac arrest. CONCLUSIONS: A new EMS protocol facilitating early CCs before definitive cardiac arrest was associated with higher survival of EMS-witnessed OHCA. PMID- 30005978 TI - Debunking another CPR myth: Lay the patient flat, or head up CPR? PMID- 30005976 TI - Investigating the role of mGluR2 versus mGluR3 in antipsychotic-like effects, sleep-wake architecture and network oscillatory activity using novel Han Wistar rats lacking mGluR2 expression. AB - Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in a number of psychiatric disorders. They also control sleep-wake architecture and may offer novel therapeutic targets. However, the roles of the mGluR2 versus mGluR3 subtypes are not well understood. Here, we have taken advantage of the recently described mutant strain of Han Wistar rats, which do not express mGluR2 receptors, to investigate behavioural, sleep and EEG responses to mGluR2/3 ligands. The mGluR2/3 agonist, LY354740 (10 mg/kg), reversed amphetamine- and phencyclidine-induced locomotion and rearing behaviours in control Wistar but not in mGluR2 lacking Han Wistar rats. In control Wistar but not in Han Wistar rats the mGluR2/3 agonist LY379268 (3 & 10 mg/kg) induced REM sleep suppression with dose-dependent effects on wake and NREM sleep. By contrast, the mGluR2/3 antagonist LY3020371 (3 & 10 mg/kg) had wake-promoting effects in both rat strains, albeit smaller in the mGluR2-lacking Han Wistar rats, indicating both mGluR2 and mGluR3-mediated effects on wakefulness. LY3020371 enhanced wake cortical oscillations in the theta (4-9 Hz) and gamma (30-80 Hz) range in both Wistar and Han Wistar rat strains, whereas LY379268 reduced theta and gamma oscillations in control Wistar rats, with minimal effects in Han Wistar rats. Together these studies illustrate the significant contribution of mGluR2 to the antipsychotic-like, sleep and EEG effects of drugs acting on group II mGluRs. However, we also provide evidence of a role for mGluR3 activity in the control of sleep and wake cortical theta and gamma oscillations. PMID- 30005979 TI - Current etiology, clinical features and outcomes of bacteremia in older patients with solid tumors. AB - PURPOSE: To assess the etiology, clinical features and outcomes of bacteremia in older patients with solid tumors. METHODS: All episodes of bacteremia in hospitalized patients with solid tumors were prospectively collected. Patients aged >=70 years were compared to patients aged <70 years. Risk factors for case fatality rates in older patients were identified. RESULTS: We compared 217 episodes of bacteremia involving older patients and 525 occurring in younger patients. Older patients had more frequently other comorbidities, but were less commonly neutropenic and carried less frequently central venous catheters. Bacteremia from an abdominal source was more common in patients >=70, whereas an endogenous source and catheter-related infection were less frequently observed. Streptococcus bovis group (3.7% vs. 0.8%, p = .01) and Listeria monocytogenes (4.6% vs. 1.9%, p = .04) were more common in older patients, whereas coagulase negative staphylococci were less frequently found (1.4% vs. 5.3% p = .01). Infection due to multi-drug resistant (MDR) strains was significantly higher in older patients (17.1% vs. 10.9%, p = .02), who in addition, presented higher overall mortality (35.4% vs 27.7%, p = .04). In older patients, lung tumor, neutropenia, and low grade fever were associated with early mortality, whereas comorbidities, corticosteroids, septic shock and inadequate empirical antibiotic therapy were associated with overall mortality. CONCLUSIONS: We identified remarkable differences in the etiology and sources of bacteremia between older and younger cancer patients with bacteremia. Older patients had more frequent infection due to MDR organisms and presented a higher overall mortality. Corticosteroids and inadequate empirical antibiotic therapy are modifiable factors associated with mortality. PMID- 30005980 TI - Management and supportive treatment of frail patients with metastatic pancreatic cancer. AB - Data regarding management of frail patients with pancreatic ductal adenocarcinoma practice is currently very scarce. Randomized clinical trials usually exclude these subgroup of patients and the majority of the publications only consider chronological age and ECOG performance status for their classification. Therefore, the current available data do not reflect daily clinical practice. Only data from a phase two study (FRAGANCE study), designed to select a tolerable dose-schedule of nab-placitaxel + gemcitabine (Phase oneNCT02382263) and to evaluate the efficacy of the selected regimen (Phase two) in patients with ECOG-2 and previously untreated advanced PDAC, are currently available. Management of these particular patients is exceedingly complex and requires collaboration of multidisciplinary teams and intensive support treatment. This article reviews the literature available regarding the management of the so-called frail patients and provide guidance for chemotherapy as well as supportive care treatments. PMID- 30005981 TI - Perspectives on Geriatric Oncology Research presented at the 2018 American Society of Clinical Oncology Annual Meeting. PMID- 30005982 TI - Frailty assessment predicts toxicity during first cycle chemotherapy for advanced lung cancer regardless of chronologic age. AB - BACKGROUND: Improved assessment strategies are needed to individualize treatment for adults of all ages receiving palliative chemotherapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate the utility of the Fried Frailty Index (FFI) and a cancer-specific geriatric assessment (GA) to predict chemotherapy toxicity and overall survival (OS). METHODS: We conducted a multi-site pilot study of 50 patients with newly diagnosed advanced NSCLC, age >= 18 years. All participants received carboplatin AUC 6, paclitaxel 200 mg/m2 every 3 weeks. FFI and the GA were administered prior to chemotherapy. A GA toxicity risk score was calculated. Grade 3-5 toxicity was assessed during 1st two cycles of chemotherapy. OS was measured from chemotherapy initiation. Logistic regression and Cox proportional hazards models were fit to estimate the association between baseline characteristics and toxicity and OS respectively. RESULTS: Among 50 participants, 48 received chemotherapy and were evaluable. The mean age was 68.5 y (range 42-86), 79% male, 85% KPS >=80. The median OS was 8 months. Many (27%) met FFI criteria for frailty with >=3 impairments. Impairments detected by the GA were common. In multivariable analyses both FFI >= 3 and GA toxicity risk score > 7 were independently associated with higher odds of toxicity (Odds ratio [OR] 7.0; 95% confidence interval [CI] 1.1-44.6 and OR 4.3; 95% CI 1.0-17.7, respectively) in first cycle chemotherapy. Neither score was associated with OS. CONCLUSIONS: Frailty predicts chemotherapy toxicity during first cycle. Frailty assessment may inform toxicity risk regardless of chronologic age. PMID- 30005983 TI - Effects of Hydrogen Bond Acceptor Ability of Solvents on Molecular Self-Assembly of Sulfadiazine Solvates. AB - The solvate formation of sulfadiazine (SDZ) was systematically studied in the 4 selected solvents with the aids of experiment and simulation methods. The intermolecular interactions between solute and solvent molecules in different solid states were analyzed and compared through their single crystal structures, and the solution behavior of SDZ was discussed using molecular dynamics simulations. The results indicated that SDZ was easy to form solvates with the solvents having strong hydrogen bond acceptor ability, which determined the formation of hydrogen bonding synthon. Furthermore, the SDZ molecules conformation and packing were compared in various crystal structures. In addition, the desolvation processes of SDZ solvates were studied to investigate the role of solvent in different solvate structures. PMID- 30005985 TI - Imaging Techniques to Characterize Cake Appearance of Freeze-Dried Products. AB - Pharmaceutically elegant lyophilisates are highly desirable implying a stable and robust freeze-drying process. To ensure homogenous and intact cake appearance after process scale-up and transfer, characterization of lyophilisates during formulation and cycle development is required. The present study investigates different imaging techniques to characterize lyophilisates on different levels. Cake appearance of freeze-dried bovine serum albumin formulations with different dextran/sucrose ratios was studied by visual inspection, three-dimensional laser scanning, polydimethylsiloxane embedding, scanning electron microscopy, and microcomputed tomography (MU-CT). The set of techniques allowed a holistic evaluation of external cake appearance and internal structure providing complementary information at macroscopic and microscopic scale. In comparison to state of the art technologies like visual inspection or scanning electron microscopy, three-dimensional laser scanning and MU-CT provided quantitative information allowing comparison of visual cake appearance. In particular MU-CT enables a global, qualitative, and quantitative characterization of external and internal cake structure with a single measurement detecting heterogeneities of lyophilisates. We even demonstrated the use of noninvasive MU-CT for qualitative imaging of internal cake structure through the glass vial. Providing meaningful characterization of the entire lyophilisate, MU-CT can serve as a powerful tool during development of freeze-drying cycles, process scale-up, and transfer. PMID- 30005984 TI - Preparation and Characterization of Poloxamer 407 Solid Dispersions as an Alternative Strategy to Improve Benznidazole Bioperformance. AB - Benznidazole (BZL), the first line drug for Chagas disease treatment, presents a low solubility, limiting the possibilities for its formulation. In this work, solid dispersions' (SDs) technology was exploited to increase BZL kinetic solubility and dissolution rate, seeking for an improvement in its bioperformance. A physical mixture (PM) and an SD using Poloxamer 407 as carrier were prepared and characterized. Dissolution tests were performed, and data were analyzed with the lumped model, which allowed to calculate different parameters of pharmaceutical relevance. A bioactivity assay was also carried out to probe the SD anti-trypanocidal activity. Among the most relevant results, the initial dissolution rate of the BZL SD was near 3, 4 and about 400-fold faster than the PM, a commercial formulation (CF) and an extracted BZL, respectivley. The times needed for an 80% of drug dissolution were 3.6 (SD), 46.4 (PM), and 238.7 min (CF); while the dissolution efficiency values at 30 min were 85.2 (SD), 71.2 (PM), and 65.0% (CF). Survival curves suggested that using Poloxamer 407 as carrier did not alter the anti-trypanocidal activity of BZL. These results allow to conclude that SDs can be an effective platform for immediate release of BZL in an oral administration. PMID- 30005986 TI - Pharmacokinetic and Pharmacodynamic Evaluation of Different PEGylated Human Interleukin-11 Preparations in Animal Models. AB - Treating thrombocytopenia induced by chemotherapy remains an unmet-medical need. The use of recombinant human interleukin-11 (rhIL-11) requires repeated injections and induces significant fluid retention in some patients. Modification of human interleukin-11 with chemically inert polyethylene glycol polymer (PEG) may extend the peripheral circulation half-life leading to an improved pharmacokinetic and pharmadynamic profile. In this study, a number of rhIL-11 PEG conjugates were created to determine the optimal approach to prolong circulating half-life with the most robust pharmacological effect. The lead candidate was found to be a single 40-kDa Y-shaped PEG linked to the N-terminus, which produced a long-lasting circulating half-life, enhanced efficacy and alleviated side effect of dilutional anemia in healthy rat models. This candidate was also shown to be effective in myelosuppressive rats in preventing the occurrence of severe thrombocytopenia while ameliorating dilutional anemia, compared to rats receiving daily administration of unmodified rhIL-11 at the same dose. These data indicated that a single injection of the selected modified rhIL-11 for each cycle of chemotherapy regimen is potentially feasible. This approach may also be useful in treating patients of acute radiation syndrome when frequent administration is not feasible in a widespread event of a major radiation exposure. PMID- 30005987 TI - Assessment of Patient Exposure to Leachables From Lyophilized Drug Formulations Following Reconstitution, Storage, and Administration via Polymeric Packaging/Delivery Systems. AB - It has been demonstrated that lyophilized drug formulations have an increased propensity to leach substances from the rubber stoppers comprising their primary packaging system when compared to aqueous liquid formulations stored in the same manner. Unfortunately, patient exposure to leachables originating in lyophilized drug products is not known. To that end, the goal of this study was to assess patient exposure to these leachables after reconstitution, storage, and administration of the lyophilized drug. To achieve this goal, several leachables present in 2 commercial lyophilized drug products were quantified after contact with polyvinyl chloride and non-polyvinyl chloride medication bags as well as an infusion set for durations of 15 min to 7 days at refrigerated and ambient temperature. The results obtained from this study showed that the bag's material of construction and the drugs formulation did not impact the mass of the leachables administered. Conversely, the mass of each leachable administered to the patient was reduced or eliminated as the contact duration with the intravenous bag and the temperature increased. However, for shorter contact durations, refrigerated storage, and higher molecular weight compounds, the patient would be exposed to a majority of the leachables originating from the vial. PMID- 30005988 TI - Estimated versus achieved maximal oxygen consumption in severely burned children maximal oxygen consumption in burned children. AB - PURPOSE: In burned children, exercise training increases maximal oxygen consumption (VO2 max) and can be combined with the nonspecific beta-blocker propranolol to decrease cardiac work. VO2 max is estimated if indirect calorimetry is not available. We compared measured and estimated VO2 max in severely burned children treated with or without propranolol to determine the suitability of commonly used formulas in these populations. METHODS: Patients received propranolol or placebo (control) during acute hospitalization. VO2 max was measured during a modified Bruce treadmill test at discharge and compared to values obtained using the Cooper, Bruce, American College of Sports Medicine, and Porro formulas. Pearson correlations and Bland-Altman analyses were used to compare measured and estimated values. RESULTS: Ninety-nine children (propranolol n=46,control n=53) admitted at our facility between 2003 and 2016 were analyzed. Age at burn (propranolol 12+/-4years, control 12+/-3years,p=0.893) and total body surface area burned (propranolol 44+/-15%,control 49+/-14%,p=0.090) were comparable between groups. Measured VO2 max was higher in the propranolol group (25.5+/-6.0mL/min/kg vs. 22.0+/-4.7mL/min/kg,p=0.002) and was generally lower than estimated values. Age, sex, inhalation injury, body mass index, exercise time, and maximal speed were predictive of measured VO2 max in the control group. Age, sex, and maximal speed were predictive in the propranolol group. Backward selection yielded the formula [7.63+ 2.16*sex(females=0,males=1)+0.41*age(years)+0.15*maximal speed(m/min)] (R2=0.6525). CONCLUSIONS: Propranolol seems to have beneficial effects on cardiorespiratory capacity in burned children. However, estimated VO2 max with common formulas were too high. The VO2 max formula reported here is suitable for propranolol-treated children and the Porro formula for non-propranolol-treated children. PMID- 30005989 TI - Microbial cellulose dressing compared with silver sulphadiazine for the treatment of partial thickness burns: A prospective, randomised, clinical trial. AB - BACKGROUND: The current treatment for partial thickness burns at the trial site is silver sulphadiazine, as it minimises bacterial colonisation of wounds. Its deleterious effect on wound healing, together with the need for repeated, often painful, procedures, has brought about the search for a better treatment. Microbial cellulose has shown promising results that avoid these disadvantages. The aim of this study was therefore to compare microbial cellulose with silver sulphadiazine as a dressing for partial thickness burns. METHOD: All patients who presented with partial thickness (superficial and deep dermal) burns from October 2014 to October 2016 were screened for this randomised clinical trial. Twenty patients were included in each group: the cellulose group was treated with microbial cellulose sheets and the control group with silver sulphadiazine cream 10mg/g. The wound was evaluated every third day. Pain was assessed using the Face, Legs, Activity, Cry, Consolability (FLACC) scale during and after each procedure. Other variables recorded were age, sex, percentage total body surface area burned (TBSA%), clinical signs of infection, time for epithelialisation and hospital stay. Linear multivariable regression was used to analyse the significance of differences between the treatment groups by adjusting for the size and depth of the burn, and the patient's age. RESULTS: Median TBSA% was 9% (IQR 5.5-12.5). The median number of dressing changes was 1 (IQR 1-2) in the cellulose group, which was lower than that in the control group (median 9.5, IQR 6-16) (p<0.001). Multivariable regression analysis showed that the group treated with microbial cellulose spent 6.3 (95% CI 0.2-12.5) fewer days in hospital (p=0.04), had a mean score that was 3.4 (95% CI 2.5-4.3) points lower during wound care (p<0.001), and 2.2 (95% CI 1.6-2.7) afterwards (p<0.001). Epithelialisation was quicker, but not significantly so. CONCLUSION: These results suggest that the microbial cellulose dressing is a better first choice for treatment of partial thickness burns than silver sulphadiazine cream. Fewer dressings of the wound were done and, combined with the low pain scores, this is good for both the patients and the health care system. The differences in randomisation of the area of burns is, however, a concern that needs to be included in the interpretation of the results. PMID- 30005990 TI - Impact of primary payer status on outcomes among patients with burn injury: A nationwide analysis. AB - OBJECTIVE: To study the relationship between insurance provider and important outcomes among patients with burn injury. METHODS: Adults with burn injury were selected from the National Inpatient Sample. The primary outcome was inpatient mortality. Secondary outcomes were morbidity (septic shock and prolonged mechanical ventilation (PMV)), treatment metrics (time to surgery and parenteral or enteral nutrition (P/E-nutrition)) and resource utilization (length of stay (LOS) and total hospitalization costs and charges). Confounders were adjusted for using multivariate regression analysis. RESULTS: Insurance did not affect in hospital mortality rate. Compared with private insurance, Medicaid was associated with higher septic shock rate (aOR: 2.14 (1.04-4.39), longer LOS (adjusted mean difference (aMD): 2.79 (0.50-5.08) days) and higher costs (aMD: $16,161 ($4789 $27,534) while uninsured patients has shorter LOS (aMD: -2.57 (-4.59--0.55) days), lower charges (aMD: $-37,792 $(-65,550-$-10,034) and costs (aMD: $-8563 ($15,581-$-1544)). Insurance did not affect PMV rates or time to surgery or P/E nutrition. CONCLUSIONS: Primary payer does not affect in-hospital mortality or treatment metrics among patients admitted for burn injury. However, compared with private insurance, Medicaid was associated with both higher morbidity and resource utilization, whereas uninsured patients had lower resource utilization. PMID- 30005991 TI - Care in patients with epidermal necrolysis in burn units. A nursing perspective. AB - OBJECTIVE: To describe how nursing care is delivered to patients with epidermal necrolysis in burn units/specialized units in Spain and a selection of countries. METHOD: Descriptive cross-sectional study. Data were collected through a structured questionnaire which was sent to nurse managers in all burn units in Spain and a selection of countries. Descriptive statistics was used to summarize the results. RESULTS: All BU/SUs in Spain (n=12) and seven BU/SUs from a selection of countries completed the questionnaire. A lack of specific nursing protocols on Epidermal Necrolysis was observed in most burn units in Spain. Skin cleansing techniques such as showering were only reported by participants from Spain. Use of antiseptics was less frequent in other countries. Conservative skin management was the most extended practice reported by all participants. The use of vaginal molds to prevent synechiae and coverage of the ocular surface with amniotic membrane to minimize sequelae were rarely reported. Pain assessment was not always documented in sedated patients and few participants reported the use of specific scales for this purpose. All nurses agreed in the need for consensus nursing care guidelines on the disease. CONCLUSIONS: Nursing care in patients with epidermal necrolysis varied between burn units in Spain. Differences and similarities were observed when compared with burn units in other countries. Genital and ocular care were outdated in all BU/SUs. Pain assessment documentation was suboptimal. Evidence-based nursing care guidelines were generally demanded by all participants to help reduce mortality and morbidity of this rare and often devastating disease. PMID- 30005992 TI - Preoperative risk analysis index for frailty predicts short-term outcomes after hepatopancreatobiliary surgery. AB - BACKGROUND: The Risk Analysis Index (RAI) for frailty is a rapid survey for comorbidities and performance status, which predicts mortality after general surgery. We aimed to validate the RAI in predicting outcomes after hepatopancreatobiliary surgery. METHODS: Associations of RAI, determined in 162 patients prior to undergoing hepatopancreatobiliary surgery, with prospectively collected 30-day post-operative outcomes were analyzed with multivariate logistic and linear regression. RESULTS: Patients (age 62 +/- 14, 51% female) had a median RAI of 7, range 0-25. With every unit increase in RAI, length of stay increased by 5% (95% CI: 2-7%), odds of ICU admission increased by 10% (0-20%), ICU length of stay increased by 21% (9-34%), and odds of discharge to a nursing facility increased by 8% (0-17%) (all P < 0.05). Particularly in patients who suffered a first post-operative complication, RAI was associated with additional complications (1.6 unit increase in Comprehensive Complication Index per unit increase in RAI, P = 0.002). In a direct comparison in a subset of 74 patients, RAI and the ACS-NSQIP Risk Calculator performed comparably in predicting outcomes. CONCLUSION: While RAI and ACS-NSQIP Risk Calculator comparatively predicted short-term outcomes after HPB surgery, RAI has been specifically designed to identify frail patients who can potentially benefit from preoperative prehabilitation interventions. PMID- 30005993 TI - Minimally invasive management of the entire treatment sequence in patients with stage IV colorectal cancer: a propensity-score weighting analysis. AB - BACKGROUND: In patients with stage IV colorectal cancer (CRC), minimally invasive surgery (MIS) may offer optimal oncologic outcome with low morbidity. However, the relative benefit of MIS compared to open surgery in patients requiring multistage resections has not been evaluated. METHODS: Patients who underwent totally minimally invasive (TMI) or totally open (TO) resections of CRC primary and liver metastases (CLM) in 2009-2016 were analyzed. Inverse probability of weighted adjustment by propensity score was performed before analyzing risk factors for complications and survival. RESULTS: The study included 43 TMI and 121 TO patients. Before and after adjustment, TMI patients had significantly less cumulated postoperative complications (41% vs. 59%, p = 0.001), blood loss (median 100 vs. 200 ml, p = 0.001) and shorter length of hospital stay (median 4.5 vs. 6.0 days, p < 0.001). Multivariate analysis identified TO approach vs. MIS (OR = 2.4, p < 0.001), major liver resection (OR = 4.4, p < 0.001), and multiple CLM (OR = 2.3, p = 0.001) as independent risk factors for complications. 5-year overall survival was comparable (81% vs 68%, p = 0.59). CONCLUSION: In patients with CRC undergoing multistage surgical treatment, MIS resection contributes to optimal perioperative outcomes without compromise in oncologic outcomes. PMID- 30005994 TI - Clinical update on management of pancreatic trauma. AB - BACKGROUND: Pancreatic injury is rare and optimal diagnosis and management is still debated. The aim of this study was to review the existing data and consensus on management of pancreatic trauma. METHODS: Systematic literature review until May 2018. RESULTS: Pancreas injury is reported in 0.2-0.3% of all trauma patients. Severity is scored by the organ injury scale (OIS), with new scores including physiology needing validation. Diagnosis is difficult, clinical signs subtle, and imaging by ultrasound (US) and computed tomography (CT) non specific with <60% sensitivity for pancreatic duct injury. MRCP and ERCP have superior sensitivity (90-100%) for detecting ductal disruption. Early ERCP with stent is a feasible approach for initial management of all branch-duct and most main-duct injuries. Distal pancreatectomy (+/-splenectomy) may be required for a transected gland distal to the major vessels. Early peripancreatic fluid collections are common in ductal injuries and one-fifth may develop pseudocysts, of which two-thirds can be managed conservatively. Non-operative management has a high success rate (50-75%), even in high-grade injuries, but associated with morbidity. Mortality is related to associated injuries. CONCLUSION: Pancreatic injuries are rare and can often be managed non-operatively, supported by percutaneous drainage and ductal stenting. Distal pancreatectomy is the most common operative procedure. PMID- 30005995 TI - A voxel-based morphometry study on adult attachment style and affective loss. AB - The successful recovery from affective loss (i.e., bereavement, relationship breakup) has been linked to adult attachment style (AAS), a personality trait. Up to now, the association between AAS, affective loss experiences and brain gray matter volume is unclear. In 192 healthy subjects we investigated the association between MRI brain gray matter volume, applying voxel based morphometry, AAS (Relationship Scales Questionnaire (RSQ), subscales "avoidance" (AV) and "anxiety" (ANX)), and number of affective losses within the last 5 years (AL; List of Threatening Experiences Questionnaire). In a whole-brain analysis (p < 0.05 FWE-corrected) ANX compared to AV was significantly more positively associated with brain gray matter volume in the left insula and in the pars opercularis of left inferior frontal gyrus. In additional region-of-interest (ROI) analyses (p < 0.05 FWE-corrected), based on previously reported findings, no significant associations were observed. ANX and AV differently correlate with local volumes of the left insula and pars opercularis of the left inferior frontal gyrus, which are implicated in emotion processing, empathy and emotion regulation among other functions. Our results support the notion that individual attachment styles, which develop in the interplay of genes and social environment, differ in their correlation with brain structure. PMID- 30005996 TI - Low-risk Prostate Cancer Prior to or After Kidney Transplantation. AB - CONTEXT: Organ transplantation requires immunosuppression, which was regarded as a risk factor for tumor induction and tumor progression in all types of malignancy. Until recently, any form of active neoplasia was, therefore, regarded as contraindicative to organ transplantation. However, there is growing evidence that the increased tumor risk by immunosuppression is restricted to particular subgroups of malignancy, whereas others such as prostate cancer (PCa) are not negatively influenced. OBJECTIVE: To compare life expectancy (LE) under various low-risk situations of PCa (untreated low-risk primary tumor, slowly progressing asymptomatic biochemical recurrence after curative treatment) with LE under renal replacement therapy. To discuss the question whether or not low-risk untreated or incurable situations of PCa must be regarded contraindicative to kidney transplantation (KT) or to transplantation of other organs. EVIDENCE ACQUISITION: A systematic literature search was conducted using PubMed to identify original and review articles regarding PCa risk after KT as well as the natural history of untreated and treated situations of PCa. Articles published between 1991 and 2018 were reviewed and selected with the consensus of all the authors. EVIDENCE SYNTHESIS: No evidence could be found that KT and immunosuppression are associated with an increased PCa-related risk, neither in incidence nor in aggressiveness. CONCLUSIONS: Screening for and treatment of PCa in applicants for KT or in patients after KT should be performed in an individualized manner on the basis of lifetime risk calculations. In particular, untreated or incurable low risk manifestations (presumed LE >10 yr) of PCa cannot be regarded as strictly contraindicative against KT. PATIENT SUMMARY: For prostate cancer, even when left untreated, a number of low-risk situations can be defined which are associated with a life expectancy (LE) of 15 yr and more. The LE of elderly patients suffering from end-stage renal failure often does not significantly exceed 15 yr even after kidney transplantation (KT). When remaining on dialysis, however, their further LE is significantly reduced and often far below 15 yr. To the best of the presently available knowledge, KT does not worsen or accelerate the course of untreated low-risk prostate cancer. Even in the presence of untreated low-risk prostate cancer, patients with end-stage renal failure must, therefore, be expected to significantly benefit from KT. PMID- 30005997 TI - Manufacturing and the Market: Rationalizing the Shortage of Bacillus Calmette Guerin. AB - Bacillus Calmette-Guerin (BCG) is used as first-line intravesical therapy following tumor resection of non-muscle-invasive bladder cancer. Primary producers of BCG announced shortages within the last decade, leading to a worldwide shortage. We review the literature examining the BCG shortage and propose solutions to cope with this problem. PMID- 30005998 TI - MateSim: Monte Carlo simulation for the generation of mating tables. AB - In species with sexual reproduction, the mating pattern is an important element for understanding evolutionary and speciation processes. Given a mating pool where individuals can encounter each other randomly, the individual mating preferences define the mating frequencies in the population. However, in every mating process we can distinguish two different steps. First, the encounter between partners, and second, the actual mating once the encounter has occurred. Yet, we cannot always assume that the observed population patterns accurately reflect the individuals' preferences. In some scenarios, individuals may have difficulties to achieve their preferred matings, such as in monogamous species with low population size, where the mating process is similar to a sampling without replacement. In this case, the encounter process will introduce some noise that may disconnect the individual preferences from the obtained mating pattern. Such a difference between mating patterns and mating preferences has previously been shown by different modeling scenarios. Here I present a program that simulates the mating process for both discrete and continuous traits, under different encounter models and individual preference functions, and including effects such as time dependence and aging. The utility of the software is demonstrated by replicating and extending a recent study that showed how patterns of positive assortative mating, or marriage in human societies, may arise from non-assortative individual preferences. The previous result is confirmed and is shown to be caused by the marriage among the "ugliest" and oldest individuals, who after many attempts were finally able to mate among themselves. In fact, I show that the assortative pattern vanishes if an aging process prevents these individuals from mating altogether. The software MateSim is available jointly with the user's manual, at http://acraaj.webs.uvigo.es/MateSim/matesim.htm. PMID- 30005999 TI - A general framework dedicated to computational morphogenesis Part I - Constitutive equations. AB - In order to understand living organisms, considerable experimental efforts and resources have been devoted to correlate genes and their expressions with cell, tissue, organ and whole organisms' phenotypes. This data driven approach to knowledge discovery has led to many breakthrough in our understanding of healthy and diseased states, and is paving the way to improve the diagnosis and treatment of diseases. Complementary to this data-driven approach, computational models of biological systems based on first principles have been developed in order to deepen our understanding of the multi-scale dynamics that drives normal and pathological biological functions. In this paper we describe the biological, physical and mathematical concepts that led to the design of a Computational Morphogenesis (CM) platform baptized Generic Modeling and Simulating Platform (GMSP). Its role is to generate realistic 3D multi-scale biological tissues from virtual stem cells and the intended target applications include in virtuo studies of normal and abnormal tissue (re)generation as well as the development of complex diseases such as carcinogenesis. At all space-scales of interest, biological agents interact with each other via biochemical, bioelectrical, and mechanical fields that operate in concert during embryogenesis, growth and adult life. The spatio-temporal dependencies of these fields can be modeled by physics based constitutive equations that we propose to examine in relation to the landmark biological events that occur during embryogenesis. PMID- 30006000 TI - Attentional capture by incongruent object/background scenes in patients with Alzheimer disease. AB - AIM: Object/background association is critical to understand the context of visual scenes but also in daily life tasks like object search. Patients with Alzheimer disease (AD) exhibit impairment in scene processing at different levels: perception, recognition, memory and spatial navigation. We explored whether patients with AD make use of contextual information in congruent and incongruent target/background conditions in three different saccadic choice tasks. EXPERIMENT: We recruited 36 participants (12 young, 12 patients with AD at a moderate stage and 12 age-matched controls). Pairs of scenes (one congruent and one incongruent object/background) were displayed. In a free viewing task we recorded whether the participants spontaneously direct their gaze (eye tracker recordings) toward the congruent or the incongruent scene. In a task referred as "implicit", the participants had to saccade toward a pre-defined target (animal or piece of furniture) in a scene (congruent or not with the target). In a task, called "explicit", participants had to saccade towards the congruent scene. RESULTS: In contrast with both young and older controls patients with AD showed difficulties to refrain a first saccade toward incongruent scenes in the free viewing and the implicit tasks. They were at chance level in the explicit task. When given time to explore the two scenes, in a manual response condition, they were able to accomplish the implicit and explicit tasks with good accuracy. CONCLUSION: In contrast to healthy controls patients with AD exhibited a strong, significant, bias towards incongruent object/background scenes, even in the free viewing task, suggesting that unfamiliar or deviant stimuli attract their attention spontaneously. This result is in line with studies showing impairments in filtering out irrelevant distractors in visual search tasks and with studies suggesting inefficient top-down control to select relevant information at early stage of the disease. PMID- 30006001 TI - Red disperse dyes (DR 60, DR 73 and DR 78) at environmentally realistic concentrations impact biochemical profile of early life stages of zebrafish (Danio rerio). AB - Dyes have been used for more than twenty thousand years in textile, pharmaceutical, food, cosmetic, and photographic industries, among others. Despite their importance in these applications, dyes can be toxic and resistant to many degradation processes used in wastewater treatment plants. Although a large number of dyes have been released in the environments in high amounts, studies into the environmental toxicity of these substances are still scarce. The aim of this study was to evaluate the potential toxic effects of textile dyes Disperse Red 60, Disperse Red 73 and Disperse Red 78 in zebrafish early life stages. To this end, biochemical biomarkers were selected to evaluate non enzimatic antioxidant (Total Glutathione), antioxidant enzymes (Glutathione S transferase and Catalase), oxidative stress (lipid peroxidation), neurotransmission (acetylcholinesterase) and energetic metabolism parameters (energy available and energy consumed) after 96 h exposure to these dyes. Our results demonstrated that these disperse dyes induce biochemical alterations in zebrafish embryos at environmental realistic concentrations and that the discharge of these disperse dyes into water bodies should be carefully evaluated. The selected biomarkers were sensitive as early-warning endpoints of disperse dyes toxicity on zebrafish embryos. Implications for risk assessment and indications for future research are discussed. PMID- 30006002 TI - Mathematical analysis to prioritise strategies for malaria elimination. AB - Malaria and some other tropical diseases are currently targeted for elimination and eventually eradication. Since resources are limited, prioritisation of countries or areas for elimination is often necessary. However, this prioritisation is frequently conducted in an ad hoc manner. Lower transmission areas are usually targeted for elimination first, but for some areas this necessitates long and potentially expensive surveillance programs while transmission is eliminated from neighbouring higher transmission areas. We use a mathematical model to compare the implications of prioritisation choices in reducing overall burden and costs. We show that when the duration of the elimination program is independent of the transmission potential, burden is always reduced most by targeting high transmission areas first, but to reduce costs the optimal ordering depends on the actual transmission levels. In general, when overall transmission potential is low and the surveillance cost per secondary case compared to the cost per imported case is low, targeting the higher transmission area for elimination first is favoured. PMID- 30006005 TI - Device-guided anticoagulation in atrial fibrillation: Not yet ready for prime time. PMID- 30006003 TI - Geometric surrogates of abdominal aortic aneurysm wall mechanics. AB - The maximum diameter criterion is the most important factor in the clinical management of abdominal aortic aneurysms (AAA). Consequently, interventional repair is recommended when an aneurysm reaches a critical diameter, typically 5.0 cm in the United States. Nevertheless, biomechanical measures of the aneurysmal abdominal aorta have long been implicated in AAA risk of rupture. The purpose of this study is to assess whether other geometric characteristics, in addition to maximum diameter, may be highly correlated with the AAA peak wall stress (PWS). Using in-house segmentation and meshing algorithms, 30 patient-specific AAA models were generated for finite element analysis using an isotropic constitutive material for the AAA wall. PWS, evaluated as the spatial maximum of the first principal stress, was calculated at a systolic pressure of 120 mmHg. The models were also used to calculate 47 geometric indices characteristic of the aneurysm geometry. Statistical analyses were conducted using a feature reduction algorithm in which the 47 indices were reduced to 11 based on their statistical significance in differentiating the models in the population (p < 0.05). A subsequent discriminant analysis was performed and 7 of these indices were identified as having no error in discriminating the AAA models with a significant nonlinear regression correlation with PWS. These indices were: Dmax (maximum diameter), T (tortuosity), DDr (maximum diameter to neck diameter ratio), S (wall surface area), Kmedian (median of the Gaussian surface curvature), Cmax (maximum lumen compactness), and Mmode (mode of the Mean surface curvature). Therefore, these characteristics of an individual AAA geometry are the highest correlated with the most clinically relevant biomechanical parameter for rupture risk assessment. We conclude that the indices can serve as surrogates of PWS in lieu of a finite element modeling approach for AAA biomechanical evaluation. PMID- 30006004 TI - Enterovirus 71 inhibits cytoplasmic stress granule formation during the late stage of infection. AB - Stress granules (SGs) are host translationally silent ribonucleo-proteins formed in cells in response to multiple types of environmental stress, including viral infection. We previously showed that the nuclear protein, 68-kDa Src-associated in mitosis protein (Sam68), is recruited to cytoplasm and form the Sam68-positive SGs at 6 hpi, but the Sam68-positive SGs disassembled beyond 12 hpi, suggesting that the SGs might be inhibited during the late stage of Enterovirus 71 (EV71) infection. However, the mechanism and function of this process remains poorly understood. Thus in this study, we demonstrated that EV71 initially induced SGs formation at the early stage of EV71 infection, and confirmed that 2Apro of EV71 was the key viral component that triggered SG formation. In contrast, SGs were diminished as EV71 infection proceeding. At the same time, arsenite-induced SGs were also blocked at the late stage of EV71 infection. This disruption of SGs was caused by viral protease 3Cpro-mediated G3BP1 cleavage. Furthermore, we demonstrated that over-expression of G3BP1-SGs negatively impacted viral replication at the cytopathic effect (CPE), protein, RNA, and viral titer levels. Our novel finding may not only help us to better understand the mechanism how EV71 interacts with the SG response, but also provide mechanistic linkage between cellular stress responses and innate immune activation during EV71 infection. PMID- 30006006 TI - The Bowman's shield: a tribute to translational science and Detlef Schlondorff. PMID- 30006007 TI - Modelling hyaluronan degradation by streptococcus pneumoniae hyaluronate lyase. AB - Hyaluronic acid (Hyaluronan) is a linear, high molecular weight polysaccharide that forms an important component of the extracellular matrix. It is an excellent biomaterial, and it is increasingly being used in biotechnology, biomedical applications, and drug delivery. Polymer chains of hyaluronan occur in many different lengths in nature, and can be as large as multiples of ten thousand. Since the biological function of a hyaluronan chain often depends on its molecular weight, it is of value for applications to develop reliable quantitative descriptions of the degradation processes of hyaluronan. In particular, the development of such models should assist with the rational design of production processes to create polymer chains in a given molecular weight category for a specific application. In this paper, we propose a new mathematical model for the degradation of hyaluronan by the enzyme streptococcus pneumoniae hyaluronate lyase. The model is based on a processive kinetic mechanism and consists of a coupled system of nonlinear ordinary differential equations for the species of interest. The model parameters are estimated using published experimental data, and good agreement between theory and experiment is found. Numerical experimentation and a Sobol global sensitivity analysis reveal that the key model parameters are the initial enzyme concentration and the rate constants for enzyme adsorption and catalysis. PMID- 30006008 TI - Multichromosomal structure of the onion mitochondrial genome and a transcript analysis. AB - The structures of plant mitochondrial genomes are more complex than those of animals. One of the reasons for this is that plant mitochondrial genomes typically have many long and short repeated sequences and intra- and intermolecular recombination may create various DNA molecules in this organelle. Recombination may sometimes create a novel gene that causes cytoplasmic male sterility (CMS). The onion has several cytoplasm types, with some causing CMS while others do not. The complete mitochondrial genome sequence of the onion was reported for an inbred line with CMS-S cytoplasm; however, the number of differences between onion strains remains unclear, and studies on purified mitochondrial DNA (mtDNA) have not yet been performed. Furthermore, analyses of transcripts in the mitochondrial genome have not been conducted. In the present study, we examined the mitochondrial genome of the onion variety "Momiji-3" (Allium cepa L.) possessing CMS-S-type cytoplasm using next-generation sequencing (NGS). The "Momiji-3" mitochondrial genome mainly exists as three circles as a result of recombination through repeated sequences and we herein succeeded for the first time in visualizing its structure using pulsed field gel electrophoresis (PFGE). The ability to clarify the structure of the mitochondrial genome is rare in plant mitochondria; therefore, "Momiji-3" represents a good example for elucidating complex plant mitochondrial genomes. We also mapped transcript data to the mitochondrial genome in order to identify the RNA-editing positions in all gene-coding regions and estimate the expression levels of genes. We identified 635 editing positions in gene-coding regions. Start and stop codons were created by RNA editing in six genes (nad1, nad4L, atp6, atp9, ccmFC, and orf725). The transcript amounts of novel open reading frames (ORFs) were all markedly lower than those of functional genes. These results suggest that a new functional gene was not present in the mitochondrial genome of "Momiji-3", and that the candidate gene for CMS is orf725, as previously reported. PMID- 30006009 TI - Hydration dynamics of collagen in aqueous buffer solution as studied by time domain dielectric spectroscopy. AB - Dielectric relaxation studies of collagen in aqueous buffer solution (pH 3.7) have been carried out at four different temperatures 283, 288, 293 and 298 K as a function of collagen concentration between 0.033 MUM and 0.2 MUM in the frequency range of 1 GHz to 25 GHz using time domain dielectric spectroscopy technique. Apart from the dominant mode at high frequency around 14 GHz which is assigned to the free water relaxation; we have detected one more pronounced peak close to 1.8 GHz in the delta-dispersion range of the loss spectrum of collagen in aqueous buffer solution. The peak around 1.8 GHz is attributed to hydration water reorientation of the collagen macromolecules and has obtained detailed information on its temperature and concentration dependence. The retardation imposed on the hydration water by collagen is found to be ~4.7, since collagen can cause long range perturbations beyond the first hydration shell. The activation enthalpy and activation entropy for the dipolar orientation for collagen at different concentrations have been calculated from the Arrhenius plot and is found to be 32 kJ/mol and 4.2 J/mol K respectively. The increase of thermodynamic activation enthalpy and decrease of activation entropy of collagen in buffer in the present study compared to the water have supported the idea that the water associated with collagen is highly ordered. PMID- 30006010 TI - Characterization of alpha-D-glucan produced by a probiont Enterococcus hirae KX577639 from feces of south Indian Irula tribals. AB - Exopolysaccharide (EPS) producing probiotic strain Enterococcus hirae KX577639 were isolated from the feces of South Indian Irula tribes. EPS yield was 18.57 g/L (dry weight) at 48 h in 2% sucrose supplemented MRS medium. TLC and GC-MS analysis confirmed the presence of predominant glucose monomer indicating the homopolysaccharide nature of EPS. FTIR and NMR studies revealed that the EPS were branched alpha-D-glucan polymer with alpha-(1 -> 6) and alpha-(1 -> 3) linkages. SEM analysis of glucan-EPS revealed porous and starch like cracked granules of aggregation. AFM studies proved spherical lumps and dense, grainy like network. The thermal behavior of glucan-EPS showed degradation temperature of 315.98 degrees C and melting point of 296.67 degrees C. The XRD analysis confirmed the amorphous nature of EPS with a crystalline index of 0.48. The water solubility index and water holding capacity of glucan-EPS showed 46.5% and 202.04%. These distinctive features of the glucan EPS could find its potential application in functional food products as the alpha-(1 -> 3) linkage are resistant to human digestive enzymes and can serve as a nutrient to gut bacteria. This the first study reporting the EPS production by Enterococcus hirae. PMID- 30006011 TI - Development of pH indicator from PLA/PEO ultrafine fibers containing pigment of microalgae origin. AB - Phycocyanin is a pigment of intense blue color, constituting the biomass of microalga such as Spirulina. This pigment is sensitive to pH and this instability results in color change. Thus, phycocyanin fading may become interesting for application in intelligent packaging. The objective of the study was to develop PLA/PEO ultrafine fibers containing phycocyanin to be used as pH indicators membranes for food packaging. The ultrafine fibers were formed by electrospinning process. The average diameter of 1318 nm was obtained for PLA/PEO ultrafine fibers with 2% (w.v-1) of phycocyanin and 921 nm for those developed with 3% (w.v 1) of the dye. PLA/PEO ultrafine fibers with 3% (w.v-1) of the phycocyanin presented the best responses regarding the perception of color change (DeltaE). With the highest thickness (68.7 MUm) of the ultrafine fibers developed from 3% (w.v-1) of phycocyanin, the DeltaE value found was 18.85 to the variation of pH 3 to 4 and for variation from pH 5 to 6 the value of DeltaE was 18.66. Thus, the use of PLA/PEO ultrafine fibers containing phycocyanin as pH indicator is an innovative application for intelligent packaging, since the color of pigment changes depending on pH variation. PMID- 30006012 TI - Rheological and thermo-mechanical evaluation of bio-based chitosan/pectin blends with tunable ionic cross-linking. AB - Bio-based chitosan/pectin blend films were prepared by solution casting and fully characterized in terms of their viscoelastic, thermo-mechanical and water affinity properties. Dynamic light scattering and rheological analyses served as a probe that polyelectrolyte complexes were formed through COO-/NH3+ ionic cross linking, changing the chitosan/pectin solutions from Newtonian to pseudoplastic gel-like systems. The highest degree of ionic cross-linking has been found at a specific mass ratio (chitosan/pectin 25/75) and solid-state data were obtained in detail using dynamic mechanical thermal analysis. Ionic cross-linking was determining on the physical properties of chitosan/pectin blends, which was demonstrated by the thermo-mechanical spectra, high water contact angle and tensile strength of films. The specific thermo-mechanical properties of the chitosan/pectin films can be specifically modulated according to the chitosan/pectin mass ratio to ensure successfully applications in medicine, drug delivery, agricultural and food coatings. PMID- 30006013 TI - Enzymes and nanoparticles: Modulation of enzymatic activity via nanoparticles. AB - Enzymes are biocatalysts that speed up the reactions taking place inside the cell. They are widely used in industries, scientific research and clinical diagnostics. Enzymes are specific for their substrates. They increase the rate of reaction by lowering the activation energy required to convert the substrates into the products. The catalysis by an enzyme is influenced by the nature of medium, substrate, enzyme concentration, temperature, pH, and the presence of activators and inhibitors. Nanoparticles are solid dispersion particulates of size range 10-1000 nm. They cause enhancement of particle mobility, diffusion, thermal stability, storage capacity, greater surface area and also modulate catalytic activity of the attached enzymes. Enzymes can be immobilized on nanoparticles by simple adsorption or via chemical linkages. Immobilization is a commercially applicable and a convenient method because it usually results in enhanced thermal and pH stabilities of the enzyme, lower cost of production, reusability with easy handling and separation. Primary objective of writing this review is to give an overview of the various aspects of enzymology, enzyme catalysis, enzyme immobilization and modulation of enzyme activity with special emphasis on modulation through different types of nanoparticles including their synthesis, characterization and applications. PMID- 30006014 TI - Access to and Confidence in Using Technology Among Homebound Older Adults and Caregivers. PMID- 30006015 TI - Effect of Low-Dose Statins and Apolipoprotein E Genotype on Cerebral Small Vessel Disease in Older Hypertensive Patients: A Subgroup Analysis of a Randomized Clinical Trial. AB - OBJECTIVES: To investigate the effect of low-dose statins and apolipoprotein E (APOE) genotypes on cerebral small vessel disease (CSVD) to prevent CSVD in older hypertensive patients. DESIGN: A subgroup analysis of a randomized clinical trial. SETTING: Shandong area, China. PARTICIPANTS: Hypertensive patients aged >=60 years were recruited from April 2008 to November 2010. MEASUREMENTS: Patients were randomly assigned to rosuvastatin (10 mg/day) or placebo groups. APOE genotypes were categorized as epsilon4 carriers and non-epsilon4 carriers. White matter hyperintensities (WMH), Fazekas scale, lacunes, and microbleeds were assessed. RESULTS: After an average of intervention period of 61.8 months, WMH volume increased 1.45 +/- 0.52 mL. There were 107 new-incident Fazekas scale >=2, 65 new-incident lacunes, and 63 new-incident microbleeds. The increase in WMH volume was significantly lower in the rosuvastatin group than in the placebo group and was higher in APOE epsilon4 carriers than in non-epsilon4 carriers (all adjusted P < .001). The risk of new-incident Fazekas scale >=2 was higher in the placebo group than in the rosuvastatin group (hazard ratio 2.150, 95% confidence interval 1.443-3.203; P < .001). APOE epsilon4 carriers were associated with an increased risk of new-incident Fazekas scale >=2 compared with non-epsilon4 carriers (hazard ratio 1.973, 95% confidence interval 1.334-2.920; P = .001). There were no statistically significant differences in the risk of new-incident cerebral microbleeds between the rosuvastatin and placebo groups or between APOE epsilon4 carriers and non-epsilon4 carriers. There were no significant interactions between rosuvastatin use and APOE epsilon4 status regarding increased WMH volume (F = 1.020, P = .313) or for new-incident Fazekas scale >=2 (P = .377), lacunes (P = .232), and microbleeds (P = .362). CONCLUSIONS/IMPLICATIONS: Low-dose rosuvastatin is an effective and safe therapy for CSVD. The presence of APOE epsilon4 allele may not be able to predict rosuvastatin treatment outcomes for preventing and/or treating CSVD in older hypertensive patients. PMID- 30006016 TI - Cardiovascular Risk Factors and the Risk of Disability in Older Adults: Variation by Age and Functional Status. AB - OBJECTIVES: We aimed to quantify the increased risk of disability associated with cardiovascular risk factors among older adults, and to verify whether this risk may vary by age and functional status. DESIGN: Longitudinal population-based cohort study. SETTING: Urban area of Stockholm, Sweden. PARTICIPANTS: Community dwelling and institutionalized adults >=60 years in the Swedish National study on Aging and Care in Kungsholmen free of cardiovascular diseases and disability (n = 1756) at baseline (2001-2004). MEASURES: Incident disability in activities of daily living (ADL) was ascertained over 9 years. Cardiovascular risk factors (physical inactivity, alcohol consumption, smoking, high blood pressure, diabetes, high body mass index, high levels of total cholesterol, and high C reactive protein) and walking speed were assessed at baseline. Data were analyzed using Cox proportional hazards models, stratifying by younger-old (age 60-72 years) and older-old (>=78 years). RESULTS: During the follow-up, 23 and 148 persons developed ADL-disability among the younger- and older-old, respectively. In the younger-old, the adjusted hazard ratio (HR) of developing ADL-disability was 4.10 (95% confidence interval [CI] 1.22-13.76) for physical inactivity and 5.61 (95% CI 1.17-26.82) for diabetes. In the older-old, physical inactivity was associated with incident ADL-disability (HR 1.99, 95% CI 1.36-2.93), and there was a significant interaction between physical inactivity and walking speed limitation (<0.8 m/s), showing a 6-fold higher risk of ADL-disability in those who were both physically inactive and had walking speed limitation than being active with no limitation, accounting for a population-attributable risk of 42.7%. CONCLUSIONS/IMPLICATIONS: Interventions targeting cardiovascular risk factors may be more important for the younger-old in decreasing the risk of disability, whereas improving physical function and maintaining physical activity may be more beneficial for the older-old. PMID- 30006017 TI - BAPRAS and BAAPS Scientific Meetings: Are we sticking our noses up at rhinoplasty? PMID- 30006018 TI - Role of oligodendrocyte-neurovascular unit in white matter repair. AB - White matter injury caused by acute or chronic neuropathologies is a major characteristic of many CNS diseases, and an effective treatment is still out of our reach. White matter damage is associated with the collapse of the axon-myelin complex and with blood-brain barrier (BBB) breakdown, which results in disruption of white matter function. While white matter damage cannot completely resolve spontaneously, some compensative responses may occur after the injury. Oligodendrocyte lineage cells perform critical functions in repairing damaged white matter. In this mini-review, we will focus on the reparative actions of the oligodendrocytes, and highlight the important role of oligodendrocyte lineage cells in brain recovery after injury. PMID- 30006019 TI - Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors. AB - Cancer cells are characterized by high metabolic demand. The substrates in demand include oxygen, glucose, glutamine and lipids. Oxygen serves as a key substrate in cellular metabolism and bioenergetics. Hypoxia or low oxygen abundance is a common feature of the tumor microenvironment that occurs due to an imbalance in supply and demand. Many of the metabolic responses to hypoxia in both cancer cells and stromal cells are orchestrated by hypoxia-inducible factors (HIFs). In this review we summarize our current understanding of how HIFs modulate the metabolism of hypoxic cancer cells and immune cells, and how altered metabolism plays a role in cancer progression. PMID- 30006020 TI - A pilot investigation of the effect of electronic cigarettes on smoking behavior among opioid-dependent smokers. AB - INTRODUCTION: Compared to the general population, smoking rates are 2-4 times higher among individuals with opioid use disorders (OUDs). These smokers also have poor long-term cessation rates, even with pharmacotherapy or other interventions. Low success rates with traditional approaches may prompt smokers with OUDs to try more novel products like electronic cigarettes (ECIGs). This pilot study was designed to examine the feasibility, acceptability, and effect of ECIGs on smoking behavior among smokers with OUD. METHODS: Participants (N = 25) were daily smokers receiving buprenorphine/naloxone for OUD at an outpatient clinic. They were randomized to use a second-generation ECIG (0 or 18 ng/ml nicotine) ad libitum for two weeks while completing assessments via text messaging daily, and also via in-person visits at baseline, end of the two-week intervention, and a 4-week follow-up. RESULTS: Feasibility was evidenced by high enrollment (93.9%) and retention (70.9%) rates. ECIG adherence was relatively high as measured by self-report (80.6% active, 91.7% placebo), while the average volume of liquid used per week was low (~3 ml). Both ECIG doses produced reductions in self-reported cigarettes per day that were not supported by average carbon monoxide levels. Biologically-confirmed smoking abstinence was observed in 8% of participants. CONCLUSIONS: Preliminary results suggest that smokers with OUD are interested in using ECIGs, but their adherence may be less than ideal. Poor medication adherence rates are often observed in this disparate population, and future work should consider the use of other ECIG device types and a combination of methods to verify and quantify ECIG use. PMID- 30006021 TI - Increased use of heroin as an initiating opioid of abuse: Further considerations and policy implications. AB - INTRODUCTION: Previously, we reported a marked increase in the use of heroin as an initiating opioid in non-tolerant, first time opioid users. In the current paper, we sought to update and expand upon these results, with a discussion of the policy implications on the overall opioid epidemic. METHODS: Opioid initiation data from the original study were updated to include surveys completed through 2017 (N = 8382) from a national sample of treatment-seeking opioid users. In addition, past month abuse of heroin and prescription were analyzed as raw numbers of treatment program entrant in the last five years (2013-2017), drawing from only those treatment centers that participated every year in that time frame. RESULTS: The updated data confirm and extend the results of our original study: the use of heroin as an initiating opioid increased from 8.7% in 2005 to 31.6% in 2015, with increases in overall Ns per initiation year reflecting a narrowing of the "treatment gap", the time lag between opioid initiation from 2005 to 2015 and later treatment admission (up to 2017). Slight decreases were observed in treatment admissions, but this decline was totally confined to prescription opioid use, with heroin use continuing to increase in absolute numbers. CONCLUSIONS: Given that opioid novices have limited tolerance, the risk of fatal overdose for heroin initiates is elevated compared to prescription opioids, particularly given non-oral administration and often unknown purity/adulterants (i.e., fentanyl). Imprecision of titrating dose among opioid novices may explain observed increases opioid overdoses. Future policy decisions should note that prescription opioid-specific interventions may have little impact on a growing heroin epidemic. PMID- 30006022 TI - Chemical shift-encoded MRI for assessment of bone marrow adipose tissue fat composition: Pilot study in premenopausal versus postmenopausal women. AB - OBJECT: To quantify and compare subregional proximal femur bone marrow fat composition in premenopausal and postmenopausal women using chemical shift encoded-MRI (CSE-MRI). MATERIALS AND METHODS: A multi gradient-echo sequence at 3 T was used to scan both hips of premenopausal (n = 9) and postmenopausal (n = 18) women. Subregional fat composition (saturation, poly-unsaturation, mono unsaturation) was quantitatively assessed in the femoral head, femoral neck, Ward's triangle, greater trochanter, and proximal shaft in bone marrow adipose tissue and separately within red and yellow marrow adipose tissue. RESULTS: Significant differences in fat composition in postmenopausal compared to premenopausal women, which varied depending on the subregion analyzed, were found. Within both whole and yellow marrow adipose tissue, postmenopausal women demonstrated higher saturation (+14.7% to +43.3%), lower mono- (-11.4% to -33%) and polyunsaturation (-52 to -83%) (p < 0.05). Within red marrow adipose tissue, postmenopausal women demonstrated lower fat quantity (-16% to -24%) and decreased polyunsaturation (-80 to -120%) in the femoral neck, greater trochanter, and Ward's triangle (p < 0.05). CONCLUSION: CSE-MRI can be used to detect subregional differences in proximal femur marrow adipose tissue composition between pre- and post-menopausal women in clinically feasible scan times. PMID- 30006023 TI - Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers. AB - Curcumin is a widely studied natural compound which has shown tremendous in vitro therapeutic potential. Despite that, the clinical efficacy of the native curcumin is weak due to its low bioavailability and high metabolism in the gastrointestinal tract. During the last decade, researchers have come up with different formulations with a focus on improving the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with the varying range of enhanced bioavailability. The purpose of this review is to collate the published clinical studies of curcumin products with improved bioavailability over conventional (unformulated) curcumin. Based on the literature search, 11 curcumin formulations with available human bioavailability and pharmacokinetics data were included in this review. Further, the data on clinical study design, analytical method, pharmacokinetic parameters and other relevant details of each formulation were extracted. Based on a review of these studies, it is evident that better bioavailability of formulated curcumin products is mostly attributed to improved solubility, stability, and possibly low first-pass metabolism. The review hopes to provide a quick reference guide for anyone looking information on these bioavailable curcumin formulations. Based on the published reports, NovaSol(r) (185), CurcuWin(r) (136) and LongVida(r) (100) exhibited over 100-fold higher bioavailability relative to reference unformulated curcumin. Suggested mechanisms accounting for improved bioavailability of the formulations and details on the bioanalysis methods are also discussed. PMID- 30006025 TI - The function of long non-coding RNA MT1JP in the development and progression of gastric cancer. AB - Gastric cancer is one of the most common malignant tumors with the third mortality rate of cancer in world. A larger number of researches showed that genetic factors played an important role in the development of gastric cancer. More and more evidences have indicated that lncRNAs can regulate the gene expression through the transcription, post transcription and epigenetic levels including cancer invasion and metastasis, cell differentiation and apoptosis. However, the mechanisms of lncRNAs in the pathogenesis of gastric cancer remaining unclear. LncRNA MT1JP overexpression vector was constructed and then transfected into gastric cancer cells. Further CCK-8 and transwell detection showed that lncRNA MT1JP exerted an evident inhibition role on proliferation, migration and invasion. By combining molecular cell biology experiments of the reporter gene, cell overexpression or interference and Western blot, we found that lncRNA MT1JP may regulate FBXW7 expression involved in the occurrence and development of gastric cancer. The results of this study not only explain the role of lncRNA MT1JP in the development of gastric cancer, but also provide important ideas and clues for the study of genetic regulation mechanism in gastric cancer. PMID- 30006024 TI - The Hepatitis C-Alcohol Reduction Treatment (Hep ART) intervention: Study protocol of a multi-center randomized controlled trial. AB - INTRODUCTION: Among patients with hepatitis C virus (HCV) infection, alcohol synergistically increases the risk of cirrhosis, hepatocellular carcinoma, and death. Randomized controlled trials of integrated models of HCV-alcohol treatment have been recommended but only performed in patients with severe alcohol use disorders. OBJECTIVES: This pragmatic randomized controlled trial seeks to compare clinical effectiveness and cost-effectiveness of integrated alcohol treatment compared to enhanced treatment as usual (TAU) on alcohol consumption and economic outcomes among patients ever infected with HCV. METHODS: Patients recruited from three liver centers who had current or prior chronic HCV and qualifying alcohol screener scores were randomly assigned to enhanced TAU or the Hepatitis C-Alcohol Reduction Treatment (Hep ART) intervention. All patients received enhanced TAU, consisting of a patient-administered alcohol screener and care from medical providers who were trained in Screening, Brief Intervention and Referral to Treatment (SBIRT), including brief motivational interviewing counseling. The Hep ART intervention combined enhanced TAU with up to six months of integrated co-located individual and/or group therapy that provided motivational, cognitive, and behavioral strategies to reduce alcohol consumption. The Timeline Followback (TLFB) Method was used to evaluate alcohol use at baseline, 3, 6, and 12 months. Primary outcomes are alcohol abstinence and fewer heavy drinking days, and for the cost-effectiveness analysis, measures included grams of alcohol consumed. DISCUSSION: This study will determine whether Hep ART, a six-month integrated alcohol treatment, compared to enhanced TAU, is both clinically effective and cost-effective in patients with a history of comorbid HCV and alcohol use. PMID- 30006026 TI - Crash Risk and Risky Driving Behavior Among Adolescents During Learner and Independent Driving Periods. AB - PURPOSE: Novice adolescents' crash rates are highly elevated early in licensure, despite substantial practicedriving during the learner period. The objectives of this study were to examine the variability in measures of driving risk among adolescents during the learner and early independent driving periods and evaluate how risk varies by driving experience, gender, time of day, and road surface conditions. METHODS: Objective driving data were collected in a naturalistic cohort study of 90 adolescent drivers with learner driving permit and 131 experienced adult drivers. Participants' private vehicles were equipped with data acquisition system documenting driving kinematics, miles driven, and video recordings of the driver and the driving environment. Crash/near-crash (CNC) and kinematic risky driving (KRD) rates were calculated during the learner and early independent driving periods by gender (female/male), time of day (day/night), and road surface conditions (wet/dry) for adolescents and adults. RESULTS: CNC and KRD rates of adolescents were similar to adult drivers during the learner period (CNC: incident rate ratio [IRR] = 1.67, confidence interval [CI] = .98-2.82 and KRD: IRR = 1.04, CI = .78-1.40, respectively), but dramatically higher in the first year of independent driving (CNC: IRR = 6.51, CI = 4.03-10.51 and KRD: IRR = 3.95, CI = 2.96-5.26, respectively), and particularly elevated the first 3months of licensure. Adolescent KRD rates were higher for males than females and invariably higher than adult rates during day and night, wet and dry conditions. CONCLUSIONS: While the learner driving period was relatively safe for adolescents, the transition to independent driving was typified by a dramatic increase in risk among adolescents that was higher than adult rates overall and under varying driving conditions. PMID- 30006027 TI - Building Competencies to Prevent Youth Substance Use in Kazakhstan: Mixed Methods Findings From a Pilot Family-Focused Multimedia Trial. AB - PURPOSE: The knowledge-based approach to substance use and HIV prevention, commonly used in Central Asia, does not equip at-risk adolescents with risk reduction skills. This pilot study aims to adapt and test the feasibility and estimate the effect size parameters of a skill-based and family-focused intervention for at-risk adolescents from communities affected by heroin trade and use in Kazakhstan, located on the major drug trafficking route from Afghanistan. METHODS: This National Institute on Drug Abuse-funded pilot trial used a mixed-methods approach and included 181 adolescents (ages 14-17) that reported at least one risk factor (e.g., substance-using family members or friends and parental criminal history). In addition to the school-based health education program, intervention-arm adolescent-caregiver dyads received three computerized pilot sessions focusing on risk reduction self-efficacy, resistance to peer pressure, and strengthening of family relationships. Adolescents completed baseline, 3- and 6-month Audio Computer-Assisted Self-Interview surveys in Russian and treatment group adolescents (n = 12) also participated in postintervention focus groups. RESULTS: Small size effects were observed for youth-level theoretical mediators associated with lower substance use. Compared to the control group, intervention-arm adolescents showed improvement in personal and social competencies such as assertiveness (Cohen's d = .21) and self-esteem (d = .22) at 3 months and increased engagement in prosocial activities at 6 months (d = .41). Adolescents from the intervention group also reported improved self-control skills helping alleviate emotional distress (an increase in anger and tension management d = .30 at 3 months and a reduction in temper d = -.27 at 6 months) along with a lower likelihood of binge drinking at 6 months (odds ratio = .18, p = .023). CONCLUSIONS: In middle-income countries like Kazakhstan, an intervention that utilizes interactive technologies and combines an empirically tested skills-based approach with family involvement may be an engaging, acceptable, and culturally appropriate tool for preventing substance use among at risk youth. PMID- 30006028 TI - The occurrence, diversity and blood feeding patterns of potential vectors of dengue and yellow fever in Kacheliba, West Pokot County, Kenya. AB - INTRODUCTION: Yellow fever (YF) and dengue (DEN) viruses are important re emerging mosquito-borne viruses sharing similar vectors and reservoirs. The last documented YF outbreak in Kenya occurred in 1992-95. However, YF virus is re emerging in bordering countries including Uganda, Ethiopia and South Sudan with the potential for spread to the neighboring regions in Kenya. Dengue is endemic in Kenya with outbreaks being detected in various towns in the north and the coast. This study reports on the Aedes (Stegomyia) mosquito species occurrence, diversity, and blood feeding patterns, as means of measuring the risk of transmission of YF and DEN in Kacheliba sub-county, West Pokot County, which borders previous YF outbreak areas in eastern Uganda. METHODOLOGY: Adult mosquitoes were collected using CO2-baited BG Sentinel traps at three time points during the rainy season. Mosquitoes were identified to the species level. Species abundance during the three sampling periods were compared, with emphasis on Aedes aegypti and other Stegomyia species, using generalized linear models that included mosquito diversity. Individually blood-fed mosquitoes were analyzed by DNA amplification of the 12S rRNA gene followed by sequencing to determine the source of blood meal. RESULTS: Overall, 8605 mosquitoes comprising 22 species in 5 genera were collected. Sampled Stegomyia species included Ae. aegypti (77.3%), Ae. vittatus (11.4%), Ae. metallicus (10.2%) and Ae. unilineatus (1.1%). Ae. aegypti dominated the blood-fed specimens (77%, n = 68) and were found to have fed mostly on rock hyraxes (79%), followed by goats (9%), humans and cattle (each 4%), with a minor proportion on hippopotamus and rock monitor lizards (each comprising 1%). CONCLUSION: Our findings reveal the presence of important Stegomyia species, which are known potential vectors of YF and DEN viruses. In addition, evidence of more host feeding on wild and domestic animals (hyrax and goat) than humans was observed. How the low feeding on humans translates to risk of transmission of these viruses, remains unclear, but calls for further research including vector competence studies of the mosquito populations for these viruses. This forms part of a comprehensive risk assessment package to guide decisions on implementation of affordable and sustainable vaccination (YF) and vector control plans in West Pokot County, Kenya. PMID- 30006029 TI - Causative agents and antimicrobial resistance patterns of human skin and soft tissue infections in Bagamoyo, Tanzania. AB - Few epidemiological studies have been carried out to assess the aetiology and antimicrobial susceptibility patterns of pathogens giving rise to skin and soft tissue infections (SSTIs) in sub-Saharan Africa. In the present study from six healthcare facilities in Bagamoyo, Tanzania, wound swabs from outpatients with SSTIs were analysed by a suite of methods, including microbiological culture techniques, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry and resistance testing. Among 185 patients with SSTIs, 179 (96.8%) swabs showed microbiological growth. In total, 327 organisms were found, of which 285 were of potential aetiological relevance. Staphylococcus aureus was the predominant pathogen (prevalence: 71.4%), followed by the Gram-negative bacteria Enterobacter cloacae complex (14.6%), Klebsiella pneumoniae (12.4%) and Pseudomonas aeruginosa (11.8%). While one out of three isolates of S. aureus showed resistance to macrolides, tetracyclines, cotrimoxazole and clindamycin, only a single methicillin-resistant S. aureus (MRSA) strain was found. In Gram negative bacteria, resistance to ampicillin and cotrimoxazole was common, while extended-spectrum beta-lactamases were rarely detected (<1%). We conclude that S. aureus was the most frequently detected pathogen in community-acquired SSTIs in Bagamoyo, Tanzania. Resistance to commonly prescribed oral antibiotics was considerable, but multi-resistant strains were rarely encountered. Monitoring of antibiotic susceptibility patterns in SSTIs is important to provide specific data for tailoring treatment recommendations. PMID- 30006030 TI - Mobile contraceptive application use in a clinical setting in addition to standard contraceptive counseling: A randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of miPlan, a waiting-room contraceptive counseling mobile application (app), on interest in discussing long-acting reversible contraception (LARC) during the clinical encounter and LARC uptake. STUDY DESIGN: This randomized controlled trial evaluated the miPlan contraceptive counseling app. African American and Latina young women ages 15-29 years attending four family planning clinics in a large Midwestern city were randomized to either: (1) use miPlan (intervention) prior to the contraceptive clinic visit or (2) contraceptive clinic visit alone (control). Groups were compared on knowledge of contraceptive effectiveness, interest in discussing LARC, behavioral intentions to use LARC, and LARC uptake. RESULTS: From February 2015 to January 2016, 207 young women were randomized to intervention (n=104) or control (n=103) group. Immediately following app use, the intervention group had an increase in knowledge and interest in learning about the implant. Immediate post visit, there was no significant difference in uptake of LARC between the two groups (p>.05). At three months post intervention, app users reported more knowledge of IUD effectiveness (52.3% vs 30.8%, p=.001) compared to controls. There was no significant difference in LARC use. CONCLUSION: App use was not associated with an increase in using LARC methods. It was associated with increased knowledge of contraceptive effectiveness, an interest in learning about the implant, and behavioral intentions to use LARC methods. IMPLICATIONS: The miPlan app is a feasible clinic adjunct for increasing contraceptive knowledge and intentions, however, it is not associated with increased LARC use. Mobile applications can offer an accessible complement to the contraceptive counseling visit. PMID- 30006031 TI - A 74-year-old woman with acute chest pain. PMID- 30006032 TI - Trajectories of survival in patients with nonspecific complaints. PMID- 30006033 TI - Investigating the influence of social support on experimental pain and related physiological arousal: A systematic review and meta-analysis. AB - Social support is demonstrated to have mixed effects on both pain and related physiological arousal. In this study, a meta-analysis was conducted to characterise these effects. A total of 2416 studies were identified in a systematic search, among which 21 were eligible for the quantitative review. The mere presence of another person was not sufficient to modulate pain perception. However, the presence of a stranger was identified to decrease pain-related arousal (SMD = -0.31), and the presence of a significant other increased facial expression of pain (SMD = 0.21). We further found verbal support to decrease pain (SMD = -0.69) and arousal (SMD = -0.99), and we demonstrated moderate to large analgesic effects of intimate relationships through touching (SMD = -0.95) and viewing (SMD = -0.60) of a romantic partner. Finally, we presented evidence of publication bias for pain-related arousal but not for behavioural pain outcomes. Together, our findings suggest that the impact of social support on pain is context-dependent with the verbal communication of support and intimate relationships being of particular importance. PMID- 30006034 TI - Safinamide effect on sleep disturbances and daytime sleepiness in motor fluctuating Parkinson's disease patients: A validated questionnaires-controlled study. PMID- 30006035 TI - Genome-wide analysis of Excretory/Secretory proteins in Trypanosoma brucei brucei: Insights into functional characteristics and identification of potential targets by immunoinformatics approach. AB - Trypanosoma brucei brucei (T.b.brucei) is an extra-cellular parasite that causes Animal African Trypanosomiasis (AAT) disease in animals. Till day, this disease is more difficult to treat and control due to lack of efficient vaccines and early diagnosis of the parasite infection. T.b.brucei Excretory/Secretory (ES) proteins were involved in pathogenesis and key for understanding the host parasite interactions. Functions of T.b.brucei's ES proteins were poorly investigated and experimental identification is expensive and time-consuming. Bioinformatics approaches are cost-effective by facilitating the experimental analysis of potential drug targets for parasitic diseases. Here we applied several bioinformatics tools to predict and functionalize the annotation of 1104 ES proteins and immunoinformatics approaches carried out to predict and evaluate the epitopes in T.b.brucei. Secretory information, functional annotations and potential epitopes of each ES proteins were available at http://tbb.insilico.in. This study provides functional information of T.b.brucei for experimental studies to identify potential targets for diagnosis and therapeutics development. PMID- 30006036 TI - Breakpoint mapping of a novel de novo translocation t(X;20)(q11.1;p13) by positional cloning and long read sequencing. AB - Disease associated chromosomal rearrangements often have break points located within disease causing genes or in their vicinity. The purpose of this study is to characterize a balanced reciprocal translocation in a girl with intellectual disability and seizures by positional cloning and whole genome sequencing. The translocation was identification by G- banding and confirmed by WCP FISH. Fine mapping using BAC clones and whole genome sequencing using Oxford nanopore long read sequencing technology for a 1.46 X coverage of the genome was done. The positional cloning showed split signals with BAC RP11-943 J20. Long read sequencing analysis of chimeric reads carrying parts of chromosomes X and 20 helped to identify the breakpoints to be in intron 2 of ARHGEF9 gene on Xp11.1 and on 20p13 between RASSF2 and SLC23A2 genes. This is the first report of translocation which successfully delineated to single base resolution using Nanopore sequencing. The genotype-phenotype correlation is discussed. PMID- 30006037 TI - beta-Carboline derivatives as novel antivirals for herpes simplex virus. AB - Several commercial and novel synthetic beta-carbolines (betaCs) were evaluated for their antiviral activity against herpes simplex virus type 1 (HSV-1) using an adapted MTS assay. Of 21 drugs tested, although 11 exerted antiviral activity at non-cytotoxic concentrations, only 3 of them [9-methyl-norharmane (9-Me-nHo), 9 methyl-harmane (9-Me-Ho) and 6-methoxy-harmane (6-MeO-Ho)] completely avoided virus-driven cytopathic effects. Half-maximal effective concentrations (EC50 values) (4.9 +/- 0.4, 5.9 +/- 0.8 and 19.5 +/- 0.3 uM, respectively) and selectivity indexes (88.8, 40.2 and 7.0, respectively) of the latter three betaCs against HSV-1 were determined by MTS, flow cytometry and plaque reduction assays. The mode of action of these drugs was also evaluated. According to time-of addition assays, the selected compounds were not virucidal and did not interfere with attachment or penetration of HSV-1, but interfered with later events of virus infection. Western blot studies showed that early and late protein expression was significantly delayed or even suppressed. Herpes simplex virus type 2 (HSV-2) was also inhibited by the selected substances in a similar manner. Interestingly, 6-MeO-Ho, 9-Me-Ho and 9-Me-nHo restricted HSV-1 ICP0 localisation to the nucleus during later stages of infection, possibly affecting its functionality in the cytoplasm where ICP0 normally inhibits antiviral signalling and promotes viral replication. In silico prediction of ADME (Absorption, Distribution, Metabolism and Excretion) properties showed that all compounds fulfilled Lipinski's rule and their calculated absorptions were >95%. PMID- 30006039 TI - The endoplasmic reticulum-the caring mother of the cell. AB - In eukaryotic cells, various cellular functions are compartmentalized and performed by sophisticated and specialized organelles. However, the membrane bounded organelles need to communicate with each other and with the cytoplasm, and sense the outside through the plasma membrane to coordinate various functions and to maintain cellular homeostasis. To maintain homeostasis, the information on the cellular state must be collected and appropriate responses initiated. The endoplasmic reticulum fulfils these functions. In this review, I will discuss various aspects of how the ER senses and relays information and acts to protect the cell, in what sometimes could be interpreted as an altruistic behavior. PMID- 30006038 TI - Interacting organelles. AB - Eukaryotic cells are organized into membrane-bound organelles. These organelles communicate with one another through vesicular trafficking pathways and membrane contact sites (MCSs). MCSs are sites of close apposition between two or more organelles that play diverse roles in the exchange of metabolites, lipids and proteins. Organelle interactions at MCSs also are important for organelle division and biogenesis. For example, the division of several organelles, including mitochondria and endosomes, seem to be regulated by contacts with the endoplasmic reticulum (ER). Moreover, the biogenesis of autophagosomes and peroxisomes involves contributions from the ER and multiple other cellular compartments. Thus, organelle-organelle interactions allow cells to alter the shape and activities of their membrane-bound compartments, allowing them to cope with different developmental and environmental conditions. PMID- 30006040 TI - Integration of RNAi and RNA-seq uncovers the immune responses of Epinephelus coioides to L321_RS19110 gene of Pseudomonas plecoglossicida. AB - Pseudomonas plecoglossicida is a threatening and important pathogen in aquaculture and causes heavy losses. Expression of L321_RS19110 was found significant up-regulated at 18 degrees C than at 28 degrees C, which was confirmed by quantitative real-time PCR. RNAi significantly reduced the content of L321_RS19110 mRNA of P. plecoglossicida, and exhibited the best efficiency of gene silencing with a reduction of 84.9%. Compared with the wild type strain, the infection of L321_RS19110-RNAi-1 strain resulted in the onset time delay, and 30% reduction in mortality of Epinephelus coioides, as well as alleviates in the symptoms of E. coioides spleen. Moreover, compared with wild type strain, the gene silence of L321_RS19110 in P. plecoglossicida resulted in a significant change in transcriptome of infected E. coioides. The results of KEGG analysis showed that genes of chemokine signaling pathway and cytokine-cytokine receptor interaction, digestion and absorption of proteins (non-specific immune) and antigen processing and presentation pathways were most affected by L321_RS19110 RNAi of P. plecoglossicida. In these immune pathways, the most affected immune genes were associated with different number of non-coding RNAs. Among them, most lncRNAs and miRNAs exerted negative regulation on immune genes. The results indicated that L321_RS19110 was an important virulent gene of P. plecoglossicida, the up-regulation of the immune pathways made E. coioides more likely to remove L321_RS19110-RNAi strain than the wild type strain of P. plecoglossicida, the expression of immune genes were regulated by miRNA and lncRNA in a complex way. PMID- 30006041 TI - Bitter peptides from enzymatically hydrolyzed protein increase the number of leucocytes and lysozyme activity of large yellow croaker (Larimichthys crocea). AB - The large yellow croakers (Larimichthys crocea) are mainly present in the Chinese coast and near seas with high economic importance, but vulnerable to many diseases, especially in the breeding and aquaculture. The purpose of this research was to boost the innate immune system of the large yellow croaker by administering bitter peptides into their peritoneal cavity. Total 120 Juvenile of large yellow croakers in very even weight of 60 g were divided into 4 different groups in 200/300 L of water tank, respectively. Fish growth were observed for 3 months before and after different treatments. The bitter peptides from pepsin hydrolysis were applied because they possess the highest bitter sensory scores. The blood of fish from the different groups was collected and tested for different immune parameters to evaluate the effectiveness of bitter peptides as immune stimulants after administration for 8 weeks. The average ratio of leukocytes/total blood cells (%) for control was found at 14.6%, for the low dose of bitter peptides 0.6 mg/fish was at 29.3%, for middle dose of 1.2 mg/fish was at 35%, and high dose of 2.4 mg/fish was at 30%. The lysozyme assay showed that the OD (optical density) units of relative progress lysis activity at 60 min were 0.17, 0.101, 0.307 and 0.198, respectively. Similarly in the same order as in phagocyte assay, most importantly the middle dose (1.2mg/fish) gave the highest survival rate throughout the assay. The results showed that bitter peptides can be used as immune boosters for the yellow croakers and the optimum dose was 1.2 mg/fish due to both leukocytes and lysozyme activity in the treated samples increased significantly compared with the control group. According to the results obtained, we suggest that the incorporation of middle dose of bitter peptides into fish feeds may reduce the fish diseases in aquaculture, at least for large yellow croakers. PMID- 30006042 TI - Transcriptome analysis of Artemia sinica in response to Micrococcus lysodeikticus infection. AB - To enhance genomic resources and understand the molecular immune mechanisms underlying the response topathogens, we first performed a comparative gene transcription analysis from Micrococcus lysodeikticus-immunized Artemia sinica and from a control group through RNA-Seq technology, meanwhile the differentially expressed genes (DEGs) were investigated. In total, 80, 113, 984 clean reads were obtained and then assembled into 71,536 unigenes with an average length of 1115 bp and an N50 of 1783 bp. Unigenes were annotated by comparing against nr, Swiss Prot?KEGG? COG? KOG? GO and Pfam databases, and 27,689 unigenes (38.7%) were annotated in at least one database. After bacterial challenge, 183 and 298 genes were identified as remarkably up-regulated or down-regulated, respectively, amongst 481 were associated with 168 pathways, including classical immune-related pathways, such as 'Toll-like receptor signaling', 'the complement cascades', 'MAPK signaling pathway' and 'Apoptosis'. Besides, eight genes which were differently expressed immune-related were confirmed by using quantitative real time PCR. This study characterized a gene expression pattern for normal and M. lysodeikticus -immunized A. sinica for the first time and sheds new light on the molecular mechanisms thus enabling future efforts on disease control programs in this valuable aquaculture species. PMID- 30006043 TI - Cloning and characterization of serpin from red king crab Paralithodes camtschaticus. AB - Serpins are a family of serine protease inhibitors that are involved in numerous physiological processes and are known to regulate innate immunity pathways. To advance our understanding of their role in P. camtschaticus, a commercially significant species, we cloned and characterized a serpin from this species, designated serpin PC, that has anticoagulant and anticomplement effects on human blood. We found that serpin PC is a secreted protein with a typical serpin-like primary structure that is similar to other known crustacean serpins. Recombinant serpin PC was found to have inhibitory activity against R/K-specific bovine cationic trypsin. The reaction proceeds through the formation of a stable covalent complex of peptidase with P1 residue R383 of serpin PC. This interaction is characterized by a relatively high overall inhibition constant kass=(2.3 +/- 0.7) * 106 M-1s-1 and an SI of 4.7 +/- 0.8. Protein localization by western blotting showed that serpin PC is present in the muscles and, to a lesser extent, the heart, whereas it is transcribed predominantly in hemocytes and the heart. Through peptidase activity profiling of hemocytes and plasma, we found that serpin PC inhibits at least two R/K-specific activities and showed that it inhibits phenoloxidase (PO) activity induction in hemocytes. PMID- 30006044 TI - The characterization and initial immune functional analysis of SCARA5 in turbot (Scophthalmus maximus L.). AB - Scavenger receptors (SRs) are a group of membrane-bound receptors that could bind to a variety of ligands including endogenous proteins and pathogens. SRs have been recognized to play vital roles in innate immune response against pathogen infection in both vertebrates and invertebrates. In this regard, one SmSCARA5 gene was captured in turbot (Scophthalmus maximus). The full-length SmSCARA5 transcript contains an open reading frame (ORF) of 1494 bp. SmSCARA55 showed both the highest identity and similarity to half-smooth tongue sole (Cynoglossus semilaevis), and a high degree of conservation of genomic structure to the teleost species. In addition, the phylogenetic tree analysis showed SmSCARA5 had the closest relationship to half-smooth tongue sole, the syntenic analysis revealed a relatively conserved synteny pattern of SmSCARA5 to other species. Moreover, SmSCARA5 was ubiquitously expressed in all the examined tissues, with the highest expression level in brain and the lowest expression level in blood. And it was significantly down-regulated in intestine following Gram-negative bacteria Vibrio anguillarum, and Gram-positive bacteria Streptococcus iniae challenge. Finally, the recombinant SmSCARA5 showed the highest affinity to lipopolysaccharide (LPS), followed by peptidoglycan (PGN) and lipoteichoic acid (LTA), as well as the strong inhibition effect on the growth of V. anguillarum. Taken together, our results suggested SmSCARA5 plays vital roles in innate immune response in teleost, further studies should be carried out to better understand its regulatory mechanism for innate inflammation response in teleost. PMID- 30006045 TI - Viral metagenomics, genetic and evolutionary characteristics of Crimean-Congo hemorrhagic fever orthonairovirus in humans, Kosovo. AB - Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) is a tick-borne virus which causes severe disease in humans with fatality cases up to 30%. We investigated the genetic and evolutionary characteristics of CCHFV in Kosovo, in particular in humans and found that different virus variants of genotype V circulate, with Turkey as a possible origin for the progenitor of southern European CCHF outbreaks. Phylogenetic analyses also revealed a single introduction event and in situ evolution of CCHFV in this country. The viral metagenomics revealed a more abundant virome in the fatal CCHF cases and the presence of a novel tick-borne segmented RNA virus belonging to the recently discovered Jingmenvirus group which raises questions about the potential pathogenic effect of this novel virus on human and animal health. PMID- 30006046 TI - Population structure of Pseudomonas aeruginosa through a MLST approach and antibiotic resistance profiling of a Mexican clinical collection. AB - Pseudomonas aeruginosa is one of the most important pathogens worldwide. Population genetics studies have shown that the P. aeruginosa population has an epidemic structure with highly conserved clonal complexes. Nonetheless, epidemiological studies of P. aeruginosa have been historically absent or infrequent in developing countries, in which different medical treatments, conditions and infrastructure may have an impact in population dynamics and evolutionary outcomes, including antibiotic resistance profiles. In this study we contribute to fill this gap by analyzing 158 P. aeruginosa isolates from the most extensive nosocomial collection in Mexico City. We investigated the population genetic structure through a MLST approach together with a classical microbiology antibiotic resistance profiling, one of the associated concerns in the evolution of this pathogen. On the one hand, our results are in accordance with previous studies on the epidemic structure of P. aeruginosa, as well as the existence of three main phylogroups, that are not related to environmental parameters. On the other hand, antibiotic resistance profiles indicate higher prevalence in our sample of multi drug resistant (75.15%), extremely drug resistant (17.72%) and pan-drug resistant (9.49%) than resistance reported in developed countries. It is important to reflect on the causes that make less developed countries hotspots of antibiotic resistance, considering the multifactorial aspects of the socio political context of such countries that include, but are not restricted to, public policy implementation and enforcement regarding access to antibiotics, as well as health care personnel education and other obstacles related to poverty and unequal access to health services and information. PMID- 30006048 TI - Common food flavors are safe in patients with urticaria or atopic dermatitis. PMID- 30006047 TI - Genes under positive selection in the core genome of pathogenic Bacillus cereus group members. AB - In this comparative genomics study our aim was to unravel genes under positive selection in the core genome of the Bacillus cereus group. Indeed, the members of this group share close genetic relationships but display a rather large phenotypic and ecological diversity, providing a unique opportunity for studying how genomic changes reflect ecological adaptation during the divergence of a bacterial group. For this purpose, we screened ten completely sequenced genomes of four pathogenic Bacillus species, finding that 254 out of 3093 genes have codon sites with dN/dS (omega) values above one. These results remained unchanged after having disentangled the confounding effects of recombination and selection signature in a Bayesian framework. The presumably adaptive nucleotide polymorphisms are distributed over a wide range of biological functions, such as antibiotic resistance, DNA repair, nutrient uptake, metabolism, cell wall assembly and spore structure. Our results indicate that adaptation to animal hosts, whether as pathogens, saprophytes or symbionts, is the major driving force in the evolution of the Bacillus cereus group. Future work should seek to understand the evolutionary dynamics of both core and accessory genes in an integrative framework to ultimately unravel the key networks involved in host adaptation. PMID- 30006049 TI - Immediate local and systemic hypersensitivity due to etanercept and adalimumab. PMID- 30006050 TI - The multiple usages of Notch signaling in development, cell differentiation and cancer. AB - Notch is a well-conserved signaling pathway all through evolution that is crucial to specify different cell fates. Although there is a strong context dependent component in each decision, the basic mechanisms that originate from the interplay among ligands and receptors is greatly preserved. In this review we will cover the latest findings on the different mechanisms for Notch activation and signaling. The regulation of this pathway is essential to understand development, cell differentiation and disease. PMID- 30006051 TI - Targeting the integrin interactome in human disease. AB - Integrins comprise one of the most important families of cell-cell or cell-matrix adhesion receptors. Integrin interaction with their extracellular ligands is tunable by microenvironment signals, such as chemokines and growth factors, which modulate their interaction with other transmembrane proteins and cytoplasmic interactors. Integrins are important in different disease contexts, particularly inflammatory diseases and cancer. Clinical trials targeting integrins began in the early 2000s, leading to an increasingly clear picture: agents against integrins and their interactome control inflammatory diseases; whereas their efficacy as anti-cancer targets remains dubious. Here, we discuss the success of integrin targeting to treat autoimmunity and its failure in cancer, which is rooted in the plasticity and adaptability of the cancer cell. PMID- 30006052 TI - An evolutionary perspective of regulatory landscape dynamics in development and disease. AB - The organization of animal genomes into topologically associating domains (TADs) provides a structural scaffold in which cis-regulatory elements (CREs) operate on their target genes. Determining the position of CREs and genes relative to TADs has become instrumental to trace gene expression changes during evolution and in diseases. Here we will review recent studies and discuss TADs as structural units with respect to their conservation and stability during genome reorganization. Furthermore, we describe how TAD restructuring contributed to morphological novelties during evolution but also their deleterious effects associated with disease. Despite considering TADs as structural units, the nested and dynamic scaffold within TADs contributes to tissue-specific gene expression, implying that such changes can also account for gene expression differences during evolution. PMID- 30006053 TI - Contribution of epithelial-mesenchymal transitions to organogenesis and cancer metastasis. AB - The epithelial-to-mesenchymal transition (EMT) plays crucial roles during development, and inappropriate activation of EMTs are associated with tumor progression and promoting metastasis. In recent years, increasing studies have identified developmental contexts where cells undergo an EMT and transition to a partial-state, downregulating just a subset of epithelial characteristics and increasing only some mesenchymal traits, such as invasive motility. In parallel, recent studies have shown that EMTs are rarely fully activated in tumor cells, generating a diverse array of transition states. As our appreciation of the full spectrum of intermediate phenotypes and the huge diversity in underlying mechanisms grows, cross-disciplinary collaborations investigating developmental EMTs and cancer-EMTs will be fundamental in order to achieve a full mechanistic understanding of this complex cell process. PMID- 30006054 TI - Brain organoids as models to study human neocortex development and evolution. AB - Since their recent development, organoids that emulate human brain tissue have allowed in vitro neural development studies to go beyond the limits of monolayer culture systems, such as neural rosettes. We present here a review of organoid studies that focuses on cortical wall development, starting with a technical comparison between pre-patterning and self-patterning brain organoid protocols. We then follow neocortex development in space and time and list those aspects where organoids have succeeded in emulating in vivo development, as well as those aspects that continue to be pending tasks. Finally, we present a summary of medical and evolutionary insight made possible by organoid technology. PMID- 30006055 TI - Diaphanospondylodysostosis: Refining the prenatal diagnosis of a rare skeletal disorder. AB - Diaphanospondylodysostosis (DSD) is a rare autosomal recessive skeletal disorder, characterized mainly by ossification defects in vertebrae, thorax malformations, renal cystic dysplasia and usually death in the perinatal period. DSD is caused by mutations in the bone morphogenetic protein-binding endothelial regulator (BMPER) gene. We describe the prenatal findings of a non-consanguineous Jewish couple (shared Balkan origin), with three affected fetuses that presented with malformations in the spine and chest, reduced ossification of the skull and spine, horseshoe kidney and increased nuchal translucency. The unique combination of these ultrasound (US) features raised the possibility of DSD, which was confirmed by whole exome sequencing (WES) performed on a single fetal DNA and familial segregation. In the three fetuses, a novel homozygous mutation in BMPER (c.410T > A; p.Val137Asp) was found. This mutation, which segregated in the family, was not found in 65 controls of Jewish Balkan origin, and in several large databases. Taken together, the combination of a detailed prenatal US examination and WES may be highly effective in confirming the diagnosis of a rare genetic disease, in this case DSD. PMID- 30006056 TI - Characterization of VHL promoter variants in patients suspected of Von Hippel Lindau disease. AB - Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome in which carriers are at an increased risk of developing a variety of tumors in multiple organ systems. A clinical diagnosis of VHL is determined by the presence of specific clinical manifestations while a molecular genetic diagnosis results from a pathogenic variant in the VHL gene. The majority of mutations occur in VHL coding exons and DNA analysis of these regions has a reported sensitivity of nearly 100%. However, rare variants in the VHL gene promoter may be detected in some cases of suspected VHL disease. We report two cases where VHL promoter variants were detected and describe the role of multi-step mRNA and protein analysis in the diagnostic evaluation of these cases. PMID- 30006057 TI - Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency. AB - BACKGROUND/AIM: Primary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient. PATIENT AND METHODS: An adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelectXT DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing. RESULTS: Two rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants. CONCLUSION: Our results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency. PMID- 30006058 TI - Further delineation of the phenotype caused by loss of function mutations in PRMT7. AB - PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling. PMID- 30006059 TI - Novel mutations in HINT1 gene cause the autosomal recessive axonal neuropathy with neuromyotonia. AB - Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare form of hereditary neuropathy. Mutations in HINT1 gene have been identified to be the cause of this disorder. We report two unrelated patients who presented gait impairment, progressive distal muscle weakness and atrophy, neuromyotonia and foot deformities. Electrophysiological studies showed axonal motor neuropathy and neuromyotonic discharges. Using Next-generation sequencing, we identified two homozygous mutations, NM_005340.6: c.112T > C; p.(Cys38Arg) and NM_005340.6: c.289G > A; p.(Val97Met) in HINT1 gene. Based on the clinical presentation and molecular genetic analyses, ARAN-NM was diagnosed in both patients and NM_005340.6: c.112T > C; p.(Cys38Arg) and NM_005340.6: c.289G > A; p.(Val97Met) in HINT1 gene were believe to be causative for the disorder. PMID- 30006060 TI - LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters. AB - Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features. PMID- 30006061 TI - Pharmacists opinions of the value of specific applicant attributes in hiring decisions for entry-level pharmacists. AB - OBJECTIVE: The Hiring Intent Reasoning Examination (HIRE) was designed to (1) explore the relative value of applicant-specific attributes evaluated during the hiring of entry-level pharmacists; (2) examine how each of these attributes influences hiring decisions; and (3) identify which attributes practicing pharmacists perceive as most and least valuable. METHODS: An electronic questionnaire was developed and sent to 36,817 pharmacists; 3723 (11%) responded representing a broad cross-section of practice settings and job roles. Forty eight attributes were analyzed, 24 character traits and 24 markers of academic success. Respondents identified: 1) the relative importance the possession of each attribute would play in the decision to hire an applicant; 2) the relative importance the lack of possession of the attribute would play on the decision to hire an applicant; 3) the 10 most important attributes used when considering an applicant, and; 4) the 10 least important attributes used when considering an applicant. After investigating the relative importance of the 48 traits, a factor analysis to further group the traits was undertaken. RESULTS: Character traits were consistently ranked higher than academic traits, both in importance and as more likely to effect the hiring decision. Additionally, "the top ten most important attributes" were dominated by character traits and "the top ten least important attributes" used in the hiring of an entry-level pharmacist were dominated by the academic traits. A factor analysis provided further evidence of the distinction of the character traits from the academic success markers. CONCLUSION: When selecting employees from a pool of qualified applicants, the most important attributes used in hiring decision relate to the character of the pharmacist. The results are similar across all practice settings and types of respondents completing the survey. PMID- 30006063 TI - The improvement of lysosome targetability with oligoethyleneoxy chains linked benzo[a]phenoxazine. AB - In order to improve lysosome targetability of probes, fluorescent probes based on benzo[a]phenoxazine attaching different length oligoethyleneoxy chains were designed and prepared. Probes 2a-c containing N-pyridineium-3-yl exhibited almost ON-OFF near-infrared emission responses at 697-701 nm from pH 2.8 to 7.2, and the calculated pKa values of 2a-c were 4.90, 4.92 and 5.03 respectively. More importantly, fluorescent imaging experiments indicated that probes 2a-c were all lysosome biomarkers for Ges-1 and HeLa cells, which was because the introduction of oligoethyleneoxy groups improved the biocompatibility of probes, so that the probes 2a-c were better transported to lysosomes via the endocytosis pathway of the cells. Moreover, the probe 2a was selected as a representative, which not only showed good reversibility and selectivity, but used to successfully image lysosomal pH increases induced by chloroquine. PMID- 30006064 TI - Synthesis and evaluation of a [18F]formyl-Met-Leu-Phe derivative: A positron emission tomography imaging probe for bacterial infections. AB - The tripeptide formyl-Met-Leu-Phe (fMLF) is a prototype of N-formylated chemotactic peptides for neutrophils owing to its ability to bind and activate the G protein-coupled formyl peptide receptor (FPR). Here, we developed an 18F labeled fMLF derivative targeting FPR as a positron emission tomography (PET) imaging probe for bacterial infections. The study demonstrates that the fMLF derivative fMLFXYk(FB)k (X = Nle) has a high affinity for FPR (Ki = 0.62 +/- 0.13 nM). The radiochemical yield and purity of [18F]fMLFXYk(FB)k were 16% and >96%, respectively. The in vivo biodistribution study showed that [18F]fMLFXYk(FB)k uptake was higher in the bacterial infected region than in the non-infected region. We observed considerably higher infection-to-muscle ratio of 4.6 at 60 min after [18F]fMLFXYk(FB)k injection. Furthermore, small-animal PET imaging studies suggested that [18F]fMLFXYk(FB)k uptake in the bacterial infected region was clearly visualized 60 min after injection. PMID- 30006062 TI - Polyamine-containing etoposide derivatives as poisons of human type II topoisomerases: Differential effects on topoisomerase IIalpha and IIbeta. AB - Etoposide is an anticancer drug that acts by inducing topoisomerase II-mediated DNA cleavage. Despite its wide use, etoposide is associated with some very serious side-effects including the development of treatment-related acute myelogenous leukemias. Etoposide targets both human topoisomerase IIalpha and IIbeta. However, the contributions of the two enzyme isoforms to the therapeutic vs. leukemogenic properties of the drug are unclear. In order to develop an etoposide-based drug with specificity for cancer cells that express an active polyamine transport system, the sugar moiety of the drug has been replaced with a polyamine tail. To analyze the effects of this substitution on the specificity of hybrid molecules toward the two enzyme isoforms, we analyzed the activity of a series of etoposide-polyamine hybrids toward human topoisomerase IIalpha and IIbeta. All of the compounds displayed an ability to induce enzyme-mediated DNA cleavage that was comparable to or higher than that of etoposide. Relative to the parent drug, the hybrid compounds displayed substantially higher activity toward topoisomerase IIbeta than IIalpha. Modeling studies suggest that the enhanced specificity may result from interactions with Gln778 in topoisomerase IIbeta. The corresponding residue in the alpha isoform is a methionine. PMID- 30006065 TI - N-Acylhydrazones as drugs. AB - Over the last two decades, N-acylhydrazone (NAH) has been proven to be a very versatile and promising motif in drug design and medicinal chemistry. Herein, we discuss the current and future challenges in the emergence of bioactive NAH-based scaffolds and to developing strategies to overcome the failures in drug discovery. The NAH-related approved drugs nitrofurazone, nitrofurantoin, carbazochrome, testosterone 17-enanthate 3-benzilic acid hydrazine, nifuroxazide, dantrolene, and azumolene are already used as therapeutics in various countries. PAC-1 is an NAH-based therapeutic agent that entered clinical trials in 2015. Another NAH-derived scaffold, LASSBio-294, is in preclinical trials. This review highlights the detailed comprehensive assessment and therapeutic landscape of bioactive NAH motif scaffolds in preclinical and clinical studies published to date and their promise and associated challenges in current and future drug discovery of NAH-based drugs that will progress to clinical use. PMID- 30006066 TI - Design, synthesis and antimycobacterial activity of 3,5-dinitrobenzamide derivatives containing fused ring moieties. AB - We report herein the design, synthesis and antimycobacterial activity of 3,5 dinitrobenzamide derivatives containing fused ring moieties. Results reveal that many of the target compounds have considerable in vitro antitubercular activity. Especially, N-((2-(4-fluorophenyl)/N-((2-(3-fluorobenzyl)-1,2,3,4 tetrahydroisoquilin-6-yl)methyl)-3,5-dinitrobenzamides 18a and 20e exhibit potent MIC values of 0.056-0.078 MUg/mL against both drug-sensitive Mycobacterium tuberculosis (MTB) H37Rv strain and two clinically isolated multidrug-resistant MTB (MDR-MTB) strains, opening a new direction for further SAR studies. PMID- 30006068 TI - Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection. AB - Treatment of chronic hepatitis C virus infection has been revolutionised by the development of direct-acting antivirals (DAAs). All-oral, once-daily, 8- to 12 week treatment regimens are now standard of care, with viral eradication possible in >95% of patients across different populations. Despite these advances, several unresolved issues remain, including treatment of patients with hepatitis C virus genotype 3, chronic kidney disease, and those in whom DAA therapy has previously failed. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are the most recently approved DAA regimens. Given the overwhelming success of modern DAA based therapies, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Herein, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms. PMID- 30006069 TI - Cost-effectiveness of Daratumumab-based Triplet Therapies in Patients With Relapsed or Refractory Multiple Myeloma. AB - PURPOSE: The prominent efficacy of the addition of daratumumab to lenalidomide and dexamethasone (DRd) or the addition to bortezomib and dexamethasone (DVd) was proven previously for patients with relapsed or refractory multiple myeloma (RRMM). However, the cost-effectiveness of adding daratumumab to traditional doublet regimens versus doublet regimens alone (DRd vs Rd; DVd vs Vd) was unknown. METHODS: We developed a semi-Markov model by using a US payer perspective and 10-year time horizon to estimate the cost and quality-adjusted life years (QALYs) for treatments. Clinical data were obtained from the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) and CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trials. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. FINDINGS: The incremental cost effectiveness ratio (ICER) for DVd compared with Vd was $284,180 per QALY; the ICER for DRd compared with Rd was $1,369,062 per QALY. Only when the price of daratumumab was reduced to 37% (US $702/vial) of the current price could the addition of daratumumab to Vd be cost-effective under the US willingness-to-pay (WTP) of $50,000/QALY. However, under no discount level of the daratumumab price is the addition of daratumumab to Rd acceptable. When the WTP increased to $300,000/QALY, the addition of DVd had a 56.7% probability of being cost effective compared with the Vd regimen. IMPLICATIONS: Due to the high price of daratumumab, neither the addition of daratumumab to Rd nor Vd proved to be cost effective under US WTP. However, if the daratumumab price fell to a certain discount level, the DVd regimen might be cost-effective. PMID- 30006070 TI - Challenge and Change at the Forefront of Regenerative Medicine. PMID- 30006067 TI - Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. AB - BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. METHODS: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. RESULTS: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl 1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. CONCLUSIONS: These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY: Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins. PMID- 30006071 TI - The role of glucocorticoids as adjunctive treatment for sepsis in the modern era. AB - Glucocorticoids have been used as adjunctive therapy in patients with sepsis and septic shock for more than four decades. The rationale for the use of glucocorticoids is that this class of drugs downregulates the proinflammatory response and limits the anti-inflammatory response while preserving innate immunity. Between 1976 and 2017, 22 randomised placebo-controlled trials have been published evaluating the benefit of glucocorticoids in patients with community-acquired pneumonia, sepsis, and septic shock. These studies produced conflicting results. In 2018, two large randomised controlled trials (RCTs) were published evaluating the role of hydrocortisone in patients with septic shock. The Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial reported a reduction in 90-day mortality whereas the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial reported no mortality benefit. This Viewpoint critically appraises these two RCTs and evaluates the use of glucocorticoids in the treatment of sepsis and septic shock in the modern era. PMID- 30006072 TI - A new alliance joins the fight against antimicrobial resistance. PMID- 30006073 TI - Dangers of COPD and asthma under-recognised among Hajj pilgrims. PMID- 30006074 TI - Lessons from Cleomaceae, the Sister of Crucifers. AB - Cleomaceae is a diverse group well-suited to addressing fundamental genomic and evolutionary questions as the sister group to Brassicaceae, facilitating transfer of knowledge from the model Arabidopsis thaliana. Phylogenetic and taxonomic revisions provide a framework for examining the evolution of substantive morphological and physiology diversity in Cleomaceae, but not necessarily in Brassicaceae. The investigation of both nested and contrasting whole-genome duplications (WGDs) between Cleomaceae and Brassicaceae allows comparisons of independently duplicated genes and investigation of whether they may be drivers of the observed innovations. Further, a wealth of outstanding genetic research has provided insight into how the important alternative carbon fixation pathway, C4 photosynthesis, has evolved via differential expression of a suite of genes, of which the underlying mechanisms are being elucidated. PMID- 30006075 TI - ? PMID- 30006076 TI - ? PMID- 30006077 TI - Constancy of cervical vertebral maturation indicator in adults: A cross-sectional study. AB - OBJECTIVES: The aim of this study was to assess and compare the cervical vertebral maturation stages in adults with different skeletal bases. MATERIALS AND METHODS: A total of 133 lateral cephalograms were selected and allotted in to three groups A (50), B (43) and C (40) having Class I, Class II and Class III skeletal base respectively. Cervical vertebral maturation (CVM) using was assessed using Hassel and Farman method. The morphology of the vertebrae was evaluated by calculating the amount of concavities in the inferior borders of C2, C3 and C4 and the base to anterior height ratio (BAR) and posterior to anterior height ratio (PAR) for C3 and C4. RESULTS: The overall distribution of CVMI 6 was the least followed by stages 5 and 4. The amount of concavities in C2, 3 and 4 were statistically significant (P<0.05) and was highest in Group C. The distribution of C3 and C4 BAR<0.96 was the least. The distribution of CVM 4 and C4 BAR>1.045 was greater in Group B compared to other groups. CONCLUSION: Increased prevalence of lower levels of cervical vertebral maturation was observed in adult lateral cephalograms and in Class II skeletal base in particular. PMID- 30006078 TI - Bacteremia after micro-osteoperforation. AB - OBJECTIVE: To find out the presence of bacteremia following micro osteoperforation. MATERIAL AND METHODS: The sample consisted of 28 Class I orthodontic patients (21 women, 7 men; mean age, 18.11+/-0.4 years). The micro osteoperforation was performed 4 weeks following bonding of fixed orthodontic appliances. Using aseptic technique, 20-mL blood sample was collected before the micro-osteoperforation and another 20-mL, 60 seconds after the first micro osteoperforation. The blood was inoculated into culture bottles and incubated at 37 degrees C for 1 week. Bacterial growth was investigated by using Gram staining technique. The results were analysed using the McNemar test. RESULT: No significant difference between the preoperative and postoperative samples was found with respect to bacteremia (P=0.229). CONCLUSION: Micro-osteoperforation technique is not related to transitory bacteremia. PMID- 30006079 TI - Bond strength of pre-coated flash-free adhesive ceramic brackets. An in vitro comparative study on the second mandibular premolars. AB - CONTEXT/OBJECTIVES: Clinical studies show a mean bond failure rate of orthodontic brackets, which ranges between 6% and 8%, with a predominance for the second mandibular premolars. The pre-coated flash-free adhesive ceramic brackets allow to obtain, according to their manufacturer, a low bond failure rate, while ensuring a simplified implementation. The aim of this study was to measure the shear bond strength of ceramic brackets bonded with the direct method using a pre coated flash-free adhesive system, and to compare it with the shear bond strength of the old generation precoated brackets and that of operator coated brackets to the buccal surface of the second mandibular premolars. MATERIEL AND METHODS: 45 second mandibular premolars extracted for orthodontic purposes were randomly distributed into 3 groups of 15 teeth each. In the first group, the brackets were precoated with the APCTM Flash-Free(r) system (3M Unitek; in the second group, with the APC Plus(r) system (3M Unitek), and in the third group, the brackets were bonded manually with the Transbond XT(r) composite (3M Unitek). The enamel surface was prepared in the same way for the 3 groups: etching using 36% orthophosphoric acid, followed by the application of the Transbond XT(r) primer adhesive (3M Unitek). Each sample was submitted to shear bond strength forces using a Universal Testing Machine LRX(r) (Lloyd Instruments LTD., Fareham, UK) in shear mode with a crosshead speed of 1.0mm/min. The bond strength values of the brackets were recorded in megapascals (MPa) for each tooth. The mean values were then compared using the one-way ANOVA test. RESULTS: Although the mean shear bond strength value for the APC Flash-Free(r) group was lower than those of the two other groups, this difference was not statistically significant (P=0.276). CONCLUSION: Given the experimental conditions of this in vitro study, the shear bond strength of the brackets precoated with the APC Flash-Free(r) system is comparable to the two other conventional systems. PMID- 30006080 TI - Comparison of shear bond strength of three different adhesives used as temporary bite raiser in daily orthodontic practice. AB - OBJECTIVE: The aim of this study was to evaluate the shear bond strength of three different adhesives (Transbond XT, Light Cure Adhesive, 3M Unitek; Transbond Plus, Light Cure Band Adhesive, 3M Unitek; Transbond Supreme LV, Low Viscosity Light Cure Adhesive, 3M Unitek), which were applied to the etched enamel of occlusal faces of mandibular molar teeth to gain bite opening. The null hypothesis was that there is no statistically significant difference between shear bond strength of these three adhesives. MATERIALS AND METHODS: Forty-eight human molar teeth were equally divided into three groups (n=16). Teeth were embedded in self-curing acrylic resin and were polished and etched. Adhesives were applied on the teeth and all adhesives were light cured for 20seconds. Universal Testing Machine was used for shear bond strength tests with a crosshead blade loaded at a crosshead speed of 1mm/min. Evaluating the type of failure was done by using Adhesive Remnant Index (ARI) was used to evaluate the remaining adhesive on the tooth. RESULTS: One-way analysis of variance (ANOVA) was used to determine the significant differences between the three different orthodontic adhesives. There was no significant difference (P=0.774) between the groups according to ANOVA test. According to Kruskal-Wallis test there was no statistically significant differences in ARI scores among groups (P<0.01). CONCLUSION: The null hypothesis was accepted. There was no statistically significant difference among their bond strength values. All of three materials can be used as temporary bite openers. PMID- 30006081 TI - ? PMID- 30006082 TI - Comparison of the effect of premolar extraction and non-extraction on the position and developmental changes of the lower third molars. AB - The aim of the present study was to comprehensively assess the posttreatment effect of premolar extraction versus non-extraction on the position and development of the lower third molars. The sample consisted of 227 patient's pre- and posttreatment panoramic radiographs (53 with four premolar extractions, 174 without extractions). The position and developmental stage of the lower third molars were evaluated by using Pell-Gregory's, Winter's, modified Miloro-DaBell's and Demirjian's classifications, respectively. Premolar extraction had a considerably positive influence on the position and development of the lower third molars and therefore could provide better prognosis for their eruption. PMID- 30006083 TI - ? PMID- 30006084 TI - ? PMID- 30006085 TI - Migration intentions of Lithuanian physicians, nurses, residents and medical students. AB - Due to a flow of healthcare professionals and students from emerging to industrialized economies, healthcare systems in source countries are facing increasing threats to a people-centered quality of care. This study investigates the prevalence and underlying reasons for emigration intentions among physicians, nurses, residents, and medical students in Lithuania (total N = 1080). In our sample, 39% of students, 21% of residents, 12% of nurses, and 6% of physicians had decided to emigrate within the next two years. Based on statistical analyses of the survey data, we conclude that emigration decisions are linked to socio demographic (age, gender, family situation), financial, organizational (teamwork climate in hospital) and social (perceived social worth) factors. Implications for policy-making and retention of healthcare workforce are discussed. PMID- 30006086 TI - Production of live young with cryopreserved sperm from the endangered livebearing fish Redtail Splitfin (Xenotoca eiseni, Rutter, 1896). AB - Previous studies of sperm cryopreservation of livebearing fish have been limited to two genera within the family Poeciliidae. The goal of the present study was to investigate the feasibility to produce live young of livebearing goodeids (family Goodeidae) with cryopreserved sperm, using aquarium-trade populations of the endangered species Redtail Splitfin (Xenotoca eiseni, Rutter, 1896). Reproductive condition of females was evaluated by histological categorization of ovarian development. A total of 117 females were inseminated with cryopreserved sperm, 81 were inseminated with fresh sperm, 27 were mixed with males for natural breeding, and 30 were maintained without males or insemination. Histological images of 34 mature females indicated 68% of ovaries had primary- or secondary-growth oocytes, and 32% had ovulated eggs. Ovarian development had no significant relationship (P = 0.508) with body wet weight, but had a relationship (P < 0.001) with ovary weight and gonadosomatic index. Sperm cells were observed within ovaries that were fixed at 12 h after insemination with fresh sperm. A total of 29 live young were produced from two females inseminated with thawed sperm (8% post-thaw motility with HBSS300 as extender, 20 min incubation in 15% DMSO, cooling rate at 10 degrees C/min, and thawing at 40 degrees C for 7 s), 12 were produced from two females with fresh sperm (1%-20% motility), 41 were produced from five naturally spawned females, and no live young were produced from the female-only group. This study provides a foundation for establishment of germplasm repositories for endangered goodeids to assist conservation programs. PMID- 30006087 TI - Biochemical and biophysical characterization of water-soluble pectin from Opuntia ficus-indica and its potential cytotoxic activity. AB - This work aims to fill the gap in the present knowledge about the structure of pectin from Opuntia ficus-indica. The water-soluble pectin (WSP) fraction, extracted with the Microwave Assisted Extraction (MAE), was further deproteinated (dWSP) and analyzed through several biophysical and biochemical techniques. HPSEC, light scattering and FTIR data showed that dWSP is low methylated high molecular weight pectin. The biochemical structure of dWSP, after methanolysis, silylation, carboxyl reduction showed that dWSP belongs to rhamnogalacturonan I class. Then, dWSP was heat-modified (HM) to obtain small-molecular weight deproteinated fraction (HM-dWSP). Both species, dWSP and HM-dWSP, were tested in LAN5 and NIH 3T3 model cells to study their biological effect. Results indicated that both dWSP and HM-dWSP exerted cytotoxic activity affecting selectively LAN5 cancer cells, without any effect on NIH 3T3 normal cells. PMID- 30006088 TI - Peptides from the Soft Coral-associated Fungus Simplicillium sp. SCSIO41209. AB - Five new peptides, Sinulariapeptides A-E together with seven known peptides (6 12) were isolated from the soft coral associated fungus Simplicillium sp. SCSIO 41209. The structures of the new compounds and their absolute configurations were established on the basis of spectroscopic analysis including NMR, MS and ECD. All the Compounds (except sinulariapeptides B-D) were tested for the inhibitory activities of Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB), and antifungal activities against five plant pathogenic fungi. Simplicilliumtides B and cyclo(L-Val-L-Pro) showed inhibitory activity with the IC50 values of 35.0 and 25.9 MUM, sinulariapeptides A, simplicilliumtides J, verlamelins A and B exhibited potent inhibition against Colletotrichum asianum with the MIC values of range from 4.9 to 9.8 MUg/mL and simplicilliumtides J, verlamelins A and B displayed inhibition against Pyricularia oryza Cav with the MIC values in the range of 19.5-78.1 MUg/ml, respectively. PMID- 30006089 TI - Lycodine-type alkaloids and their glycosides from Lycopodiastrum casuarinoides. AB - Thirteen previously undescribed lycodine-type Lycopodium alkaloids, namely, five alkaloids (lycocasuarines D-H) each possessing an uncommon five-membered C ring and eight Lycopodium alkaloid glycosides (casuarinosides A-H), together with a known analog, were isolated from the aerial parts of Lycopodiastrum casuarinoides (Spring) Holub ex R.D.Dixit (Lycopodiaceae). The structures of the compounds were elucidated by extensive spectroscopic analysis, single-crystal X-ray diffraction, and chemical methods. In addition, the acetylcholinesterase inhibitory activity of the isolated compounds was evaluated. PMID- 30006090 TI - Aporphine Alkaloids from Illigera aromatica from Guangxi Province, China. AB - Three undescribed aporphine alkaloids laurodionine B (1), illigerine A (2), and N formyl-laurolitsine (3) were isolated from the methanolic extracts of the Chinese medicinal plant, Illigera aromatica, together with three known analogues (4-6). The chemical structures of 1-6 were identified by spectroscopic methods including 1D and 2D NMR (1H, 13C, COSY, HSQC, and HMBC) and high resolution mass spectrometry (HRESIMS). Compounds 1-3 showed moderate inhibitory activities in vitro against two cultured tumor cell lines, Hela and SMMC7721, with IC50 values of 32.42-62.90 MUM. Only compound 1 had in vitro cytotoxic activity against Bcap37 cells, with the IC50 value of 90.61 MUM. PMID- 30006091 TI - Incomplete synchrony of inflorescence scent and temperature patterns in Arum maculatum L. (Araceae). AB - In many Araceae both scent and heat production are known to temporally vary throughout anthesis, and in several species strong scents are released for pollinator attraction when thermogenesis is also strong. However, it is not known whether the temporal patterns of both scent emission and temperature are strictly synchronous and, for example, reach their maxima at the same time. We studied Arum maculatum, a brood-site deceptive species attracting its moth fly pollinators with strong fetid scents, to study temporal patterns in scent emission and temperature during anthesis. Inflorescence scents were collected and analysed by dynamic headspace and gas chromatography-mass spectrometry (GC-MS) or by proton-transfer-reaction-time-of-flight mass spectrometry (PTR-TOFMS), and the temperature of the appendix, which is the heating osmophore during pollinator attraction, was recorded by a thermocouple. We overall found that scent emission and temperature patterns were strongly correlated. However, in none of the seven studied individuals was the highest amount of scent released at times with the maximum temperature difference. Thus, patterns of scent emission and temperature are somewhat asynchronous suggesting that high scent emission rates and temporal scent patterns in plants with thermogenesis cannot be solely explained by temperature patterns. This calls for more in-depth studies to better understand the interplay between scent emission and thermogenesis. PMID- 30006092 TI - An unnecessary pain: A commentary on Gao et al. (2018). PMID- 30006093 TI - Real-world clinical experience of Xultophy in the management of patients with type 2 diabetes in a secondary care clinic. AB - AIMS: Xultophy is the first fixed co-formulation pen containing insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide, authorized for type 2 diabetes patients since 2014. The aim was to review the clinical effectiveness of Xultophy across two hospitals in Wales. METHODS: Retrospective review of patients commenced on Xultophy between April 2016 and January 2018 was taken. Data related to glycemic control, weight and medication use were collected. RESULTS: Ninety-one patients were initiated on Xultophy, and 60 patients had follow-up for at least 6 months with a mean age of 57.3 years (47% male). Xultophy was well-tolerated, however, abdominal cramps and nausea limited use in three patients. Baseline HbA1c and weight were 84.7 mmol/mol and 101.5 kg. There were significant HbA1c reductions of 9.9 mmol/mol (p < 0.0001) and 13.4 mmol/mol (p < 0.008) at 6 and 12 months, and non-significant changes in weight. Patients with an HbA1c over 84 mmol/mol showed the greatest HbA1c improvement over 6 months. Those prescribed insulin prior to Xultophy had less significant improvements in HbA1c than those previously prescribed GLP-1 analogues. CONCLUSIONS: There were significant reductions in HbA1c and statistically insignificant weight gain over 12 months. Switching from GLP-1 analogues to Xultophy was associated with a greater HbA1c reduction compared to switching from insulin. PMID- 30006097 TI - Mechanisms of unusual collective cell movement lacking a free front edge in Drosophila. AB - The shape and structure of tissues are generated by the dynamic behavior of various cell collectives during morphogenesis. These behaviors include collective cell movement, in which cells move coordinately in a given direction while maintaining cell-cell attachments throughout the collective. For a cell collective to acquire mobility, the cell collective generates forces, and the cells in the front sense extrinsic cues to decide the direction of the movement. However, some collectives that fill a confined space move even though they lack such front cells. These dynamic cell behaviors have been studied in detail in egg chamber rotation and male genitalia rotation in Drosophila; however, similar phenomena are found in mammals. Here we review how the movements of such front edgeless cell collectives are generated. PMID- 30006098 TI - The contribution of mechanosensing to epidermal cell fate specification. AB - In land plants, the aerial epidermis is essential for growth control, protection and environmental interactions. Epidermal cell fate is specified early during embryogenesis and maintained throughout plant life. Molecular actors of epidermal specification have been characterized, but how epidermal fate is maintained during growth remains unclear. DEFECTIVE KERNEL 1 (DEK1) is required for epidermal cell fate maintenance during both embryonic and post-embryonic plant development. The activation of a mechanosensitive Ca2+ channel was recently shown to depend on DEK1, suggesting that the interpretation of mechanical cues could be critical for maintaining epidermal cell fate. Here, we integrate these findings into the epidermal specification network and propose a model explaining why epidermal specification may depend upon the sensing of epidermal tension. PMID- 30006099 TI - Biomechanics of epithelial fold pattern formation in the mouse female reproductive tract. AB - Tubular organs and tissues often show various morphological fold patterns in their luminal epithelia. Computational studies have revealed that these patterns could be explained by mechanical deformation of the epithelia. However, experimental validations of this are sparse, and the mechanisms linking genetic and cellular functions to fold mechanics are poorly understood. In the oviduct of the female reproductive tract, the epithelium forms multiple well-aligned straight folds. Disruption of Celsr1, a planar cell polarity-related gene, causes ectopically-branched folds in mice. Here we discuss the pattern formation of the folds with respect to the growth and mechanics of the epithelium, and the cellular and genetic functions, and compare these with other tubular organs such as the gut. PMID- 30006100 TI - Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale. AB - INTRODUCTION: Klunk et al. recently proposed a means of standardizing quantitation of amyloid burden from positron emission tomography scans to a common Centiloid scale, and we have applied that method to florbetapir. METHODS: Florbetapir and Pittsburgh compound B scans were acquired for 46 mixed clinical presentation subjects within 18 +/- 20 days. Florbetapir and Pittsburgh compound B cortical standardized uptake value ratio (SUVr) values were well correlated for both standard Centiloid (R2 = 0.894) and Avid (R2 = 0.901) volume of interests (VOIs). The methods of Klunk et al. were applied to establish a conversion first from florbetapir SUVr values obtained using standard Centiloid VOIs to Centiloids and then from Avid VOIs (Joshi et al.) to Centiloids. RESULTS: The equation for conversion of florbetapir SUVr from Avid VOIs to the Centiloid scale was as follows: Florbetapir Centiloids = 183 * SUVrAvid - 177. The threshold that discriminated neuropathologically verified none or sparse versus moderate to frequent plaques in autopsy-confirmed data is 24.1 Centiloids. DISCUSSION: These findings may allow improved tracer-independent amyloid quantitation. PMID- 30006101 TI - gammadelta T cells are associated with inflammation and immunopathogenesis of leprosy reactions. AB - BACKGROUND: Leprosy reactions appear episodically in leprosy patients, which lead to high inflammation, morbidity and peripheral nerve damage. The role of Th17 cell has been well studied in leprosy reactions but the role of gammadelta or unconventional T cells which is an other major source of IL-17 in many diseases, not studied in leprosy reactional episodes. OBJECTIVE: The aim of the present study to elucidate the role of gammadelta T cells in leprosy reactions. METHODOLOGY: A total of 40 untreated non-reaction and reactions patients were recruited. PBMCs were isolated and stimulated with M. leprae sonicated antigen (MLSA) for 48 h and immuno-phenotyping was done using flow cytometry. Moreover, gammadelta T cells were isolated by Magnetic beads technology and mRNA expression of IL-17, IFN-gamma, TGF-beta and FOXP3 were analyzed by real-time PCR (qPCR) and cytokine was estimated in the culture supernatant by ELISA. RESULTS: gammadelta T cells were significantly increased in both Reversal reaction (RR) and Erythema nodosum leprosum (ENL) reaction patients. These cells produced significant amount of IL-17 and IFN-gamma. Furthermore, CD3+TCRgammadelta+ T cells expressed transient FOXP3 with a low amount of TGF-beta in both reactions as compared to stable patients. Moreover, low TGF-beta producing TCR-gammadelta cells were associated with low phosphorylation of STAT5A. CONCLUSION: This study will add to our understanding of the immunological features that mediate and regulate the pathogenesis of leprosy and may helpful to reduce the immuno-pathogenesis of leprosy reaction by targeting these cells. PMID- 30006103 TI - Cardiovascular effects of radiation therapy. AB - Radiation therapy (RT) plays a prominent role in the treatment of many cancers. With increasing use of RT and high overall survival rates, the risks associated with RT must be carefully considered. Of these risks, the cardiovascular and autonomic toxicities have been of significant concern. In fact, cardiovascular disease is the leading cause of nonmalignancy-related death in cancer survivors. The manifestations of radiation induced cardiac injury include the acute toxicities of myopericarditis and late toxicities including constrictive pericarditis, restrictive cardiomyopathy, coronary artery disease, valvular heart disease, heart failure, and conduction abnormalities. Neck and cranial RT have also been associated with significant long-term toxicities including accelerated occlusive carotid artery disease, autonomic dysfunction due to baroreceptor damage, and development of metabolic syndromes due to damage to the hypothalamic pituitary axis. The clinical manifestations of radiation induced disease may not present until several years following the delivery of radiation. We review the adverse effects of RT on these organ systems and discuss risk reduction strategies that may effectively mitigate some of these adverse outcomes. PMID- 30006102 TI - Droplet digital PCR for absolute quantification of proviral load of human T-cell lymphotropic virus (HTLV) types 1 and 2. AB - BACKGROUND: Human T-lymphotrophic virus (HTLV) types 1 and 2 cause lifelong infection whereby most infected individuals are asymptomatic whilst a minority develop infection-related disease. These latter patients invariably have been found to have high proviral load (PVL). Therefore, infected patients are monitored by determining the proportion of lymphocytes that are infected with HTLV-1/2. An increase in PVL has been shown to represent an increasing risk of developing HTLV-associated diseases. Monitoring of PVL requires a reliable and sensitive method. In this study assays based on droplet digital PCR (ddPCR) were established and evaluated for detection and quantification of HTLV-1/2. OBJECTIVES: To develop two parallel assays to detect the tax genes and determine the PVL of HTLV-1 and -2. STUDY DESIGN: Sixty-seven clinical samples from patients infected with HTLV-1 or HTLV-2 were analysed. The samples had previously been analysed with a qPCR and a comparison between ddPCR and qPCR was performed. The specificity of the assays were determined by analyzing samples from 20 healthy blood donors. RESULTS: The ddPCR was a stable and sensitive method for detection and quantification of HTLV-1 and -2. When comparing the qPCR and ddPCR the correlation was high (Pearsons correlation coefficient 0.96). The variability of the ddPCR was very low with intra-assay coefficient of variation (CV) of 0.97 3.3% (HTLV-1) and 1.7-8.2% (HTLV-2) and inter-assay CV of 1.8-6.1% (HTLV-1) and 1.2-12.9% (HTLV-2). CONCLUSIONS: The ddPCR reliably quantified HTLV DNA in clinical samples and could be a useful tool for monitoring of PVLs in HTLV infected individuals. PMID- 30006104 TI - Crosscultural adaptation and validation into Spanish of the questionnaire National Eye Institute Visual Function Questionnaire 25. AB - INTRODUCTION: Advances in medicine have contributed to a higher average life expectancy, as well as an increasing number of chronic diseases patients. This longevity means that the assessment of the quality of life, particularly that related to vision, has become very relevant. OBJECTIVE: The validation of the translation and cross-cultural adaptation into Spanish of one of the most widely used vision-related quality of life questionnaires. It has sought to ensure that the Spanish version of the questionnaire was equivalent in semantic, conceptual, and technical content and criteria level, compared to its already validated English version. METHOD: An analytical observational study was conducted using a cohort of patients, in whom their quality of life related to vision was analysed. The study was developed in two steps; the first was the translation and cross cultural adaptation to Spanish of the NEI VFQ-25 questionnaire. The second one was the psychometric study of the reliability and validity of the scale of the Spanish version. RESULTS: The analysis of the terms of reliability and validity showed that the translation and cross-cultural adaptation met the expected requirements and was well accepted by users. CONCLUSION: There is now a possibility of having a Spanish validated questionnaire available to assess the quality of life related to vision in patients with chronic diseases, such as age related macular degeneration. PMID- 30006105 TI - A generic method for servo tuning based on dynamic modeling and task description. AB - In robotics or machining, task quality is strongly linked to servo tuning. Indeed, geometrical and dynamic behavior of the mechanical structure could be degraded when a coarse tuning is achieved. Several P/PI or PID tuning methods can be used but generally uncorrelated with industrial context or mechanical considerations. In this paper, we propose a generic tuning method based on dynamic modeling of the mechanical structure and model parameters experimental identification. Therefore, the proposed tuning is adapted to the real dynamic behavior of the mechanical structure under task load while being sufficiently simple to be implemented in an industrial context. The method is illustrated on a vertical axis. PMID- 30006106 TI - Influence of hydrodynamic pressure and vein strength on the super-elasticity of honeybee wings. AB - The wings of honeybees (Apis mellifera L.) usually produce bending and torsional deformations during flapping wing movement. These deformations endow honeybees with perfect aerodynamic control to escape predators and exploit scattered resources. However, the mechanisms by which honeybee wings recover from large deformations are unclear. This study demonstrates that honeybee wings are super elastic that they can recover rapidly from one extreme contorted state to their original position. A comparative experiment is conducted to evaluate the difference in super-elastic recovery between attached and detached wings. Results show that the structural stiffness of wings is affected by the reticulate vein and the haemolymph pressure generated by the blood circulation. Further analysis indicates that the haemolymph pressure can increase the stiffness of honeybee wings, especially that of the subcostal veins. This phenomenon shortens the recovery time of wing deflection behaviour. PMID- 30006108 TI - Age and Outcomes of Medial Meniscal-Bearing Unicompartmental Knee Arthroplasty. AB - BACKGROUND: National joint registries report increasing revision rates with decreasing patient age for all types of joint arthroplasty. This study aimed to explore the effect of age on function and revision risk in patients undergoing medial meniscal-bearing UKA. METHODS: A prospectively followed cohort of 1000 consecutive medial meniscal-bearing UKAs at a designer center was analyzed. All knees were implanted for recommended indications and had mean 10-year follow-up. Patients were grouped by age at surgery (<55, 55 to <65, 65 to <75, 75+). Oxford Knee Scores (OKS) were assessed at 5 and 10 years. Component-time revision incidence rates and Kaplan-Meier implant survival were calculated. RESULTS: Mean patient age at surgery was 66.6 years (range, 33-88). All age-groups had significant (P < .001) improvement in OKS over time, and at 5 years achieved a median OKS of 44. At 10 years, median OKS, from youngest group to eldest, were 44, 45, 42, and 39, with the eldest group having a significantly lower OKS (P < .01). Ten-year implant survival rates were 97%, 94%, 94%, and 93%, respectively, and was not significantly associated with age at UKA. CONCLUSION: Medial meniscal bearing UKA provides good functional outcomes in all age-groups; however, in older patients (75+), the functional outcome deteriorated at 10 years presumably due to deteriorating health. Contrary to registry observations, the revision rate was not higher in younger patients. These results suggest that, with correct indications, patient age should not be considered a contraindication to medial meniscal-bearing UKA. PMID- 30006107 TI - Comparison of reproductive traits of foundresses in a native and an invasive hornet in Europe. AB - The population dynamics of annual social hymenoptera such as vespids depend largely on the fertility of the foundresses, which, in turn, is a key factor in the context of biological invasions. The native European hornet Vespa crabro (Vc) and the invasive Asian hornet Vespa velutina (Vv) have generally similar ecological traits, e.g. nesting and feeding habits, although they differ in colony size, which is higher in Vv. Furthermore, in contrast to Vc, Vv is more specialized in its predatory habits, intensively hunting honey bees at the hive. Comparing the morphological and reproductive traits of two closely related species occupying the same ecological niche, one of which is a native species and the other an alien, can help us to gain an understanding of the invasion process. To this end, we here compare reproductive (ovarian size and maturation, fat level, spermatheca size and sperm stock, fecundity) and morphological traits (head size, weight) of the foundresses of these two hornet species. We observed that ovarian maturation began approximately one month earlier in Vv than in Vc, and that the fat level in the former was lower. We found twice the number of sperm in the mated foundresses of Vv than in those of Vc (more than 100 * 103 and less than 50 * 103 sperm, respectively), in a 16% smaller spermatheca in Vc. Furthermore, the sperm of Vv was found to be 65% shorter than that of Vc. The precocity and higher potential fecundity of Vv queens may have favoured this species over Vc in terms of predatory behaviour, and thereby contributed to its invasiveness. PMID- 30006109 TI - Acute Kidney Injury Following Failed Total Hip and Knee Arthroplasty. AB - BACKGROUND: Acute kidney injury (AKI) can complicate primary total joint arthroplasty (TJA) of the hip and knee, although the incidence of AKI following revision TJA including prosthetic joint infection (PJI) is poorly defined. We assessed the incidence and risk factors for AKI following revision TJA including surgical treatment of PJI with placement of an antibiotic-loaded cement (ALC) spacer. METHODS: We retrospectively reviewed 3218 consecutive failed TJAs. Patients with aseptic failure were compared to those with PJI. AKI was determined by RIFLE creatinine criteria. PJIs treated with placement of ALC were compared to PJIs without. Risk factors for AKI were determined by multivariable analysis within the whole group and within those with PJI. RESULTS: AKI developed in 3.4% of 2147 patients revised for aseptic reasons and in 45% of 281 with PJI, including 29% of 197 receiving an ALC and 82% of 84 patients treated with other procedures. By multivariable analysis, age, surgery for PJI, total number of surgeries, and estimated GFR 60-90 compared to >90 cc/min/1.73 m2 were significantly associated with AKI in the whole cohort. Among PJI patients, age, Charlson comorbidity index, and reimplantation surgery were associated with AKI by multivariable analysis. No differences were found between patients with PJI treated with or without ALC. No modifiable factors were found. CONCLUSION: AKI develops following aseptic revision TJA at a rate similar to primary TJA, but at a significantly higher rate following surgery for PJI with or without placement of ALC. PMID- 30006110 TI - [Haemophagocytic syndrome secondary to Mediterranean spotted fever]. AB - INTRODUCTION: Haemophagocytic syndrome (HS) is a rare disease with a severe prognosis that is defined by clinical, laboratory and histopathological criteria. Infections represent the classical cause of HS. HS secondary to Mediterranean spotted fever (MSF) is rare with only a few cases being reported in the literature. OBSERVATIONS: We report two cases of HS secondary to MSF in 2 men aged 77 and 63 years presenting a febrile maculo-purpuric eruption with inoculation ulcer associated with laboratory abnormalities (cytopenia, elevated ferritin, hypertriglyceridaemia). Haemophagocytosis was present in 2 cases. Serology and PCR for Rickettsia conorii were positive and militated in favour of recent infection responsible for the diagnosis of MSF. DISCUSSION: The first case of HS was described in 1979. Sixteen cases of HS secondary to MSF are described in the literature. Cytopenia associated with hyperferritinaemia and hypertriglyceridaemia strongly suggests MSF complicated by HS. The prognosis depends on the time elapsed since diagnosis and host-specific factors. Immunosuppressants and antibiotics may be necessary to ensure healing. CONCLUSION: Rickettsioses can induce HS, and this potential complication with a severe prognosis must be known. PMID- 30006111 TI - Effect of harmonic rank on sequential sound segregation. AB - The ability to segregate sounds from different sound sources is thought to depend on the perceptual salience of differences between the sounds, such as differences in frequency or fundamental frequency (F0). F0 discrimination of complex tones is better for tones with low harmonics than for tones that only contain high harmonics, suggesting greater pitch salience for the former. This leads to the expectation that the sequential stream segregation (streaming) of complex tones should be better for tones with low harmonics than for tones with only high harmonics. However, the results of previous studies are conflicting about whether this is the case. The goals of this study were to determine the effect of harmonic rank on streaming and to establish whether streaming is related to F0 discrimination. Thirteen young normal-hearing participants were tested. Streaming was assessed for pure tones and complex tones containing harmonics with various ranks using sequences of ABA triplets, where A and B differed in frequency or in F0. The participants were asked to try to hear two streams and to indicate when they heard one and when they heard two streams. F0 discrimination was measured for the same tones that were used as A tones in the streaming experiment. Both streaming and F0 discrimination worsened significantly with increasing harmonic rank. There was a significant relationship between streaming and F0 discrimination, indicating that good F0 discrimination is associated with good streaming. This supports the idea that the extent of stream segregation depends on the salience of the perceptual difference between successive sounds. PMID- 30006112 TI - Local drug delivery to the inner ear: Principles, practice, and future challenges. PMID- 30006113 TI - Hearing preservation at low frequencies by insulin-like growth factor 1 in a guinea pig model of cochlear implantation. AB - The hybrid or electric-acoustic stimulation cochlear implant is indicated in patients with a residual hearing at low frequencies. It provides electric and acoustic stimulation for compensating for high- and low-frequency sounds, respectively. However, the implantation procedure damages the cochlea, resulting in loss of the residual-hearing and diminished effects of the acoustic-hearing in several patients. To prevent hearing loss after implantation, corticosteroids have been used clinically although their effects are limited. As an alternative to corticosteroids, insulin-like growth factor 1 (IGF1) has shown potent effects in various types of cochlear injury. In this study, the effects of IGF1 on hearing preservation were examined after cochlear implantation to a normal hearing guinea pig model. The electrode was inserted in an atraumatic way through the round window membrane of guinea pigs with the application of a gelatin-sponge soaked with IGF1 or saline. The auditory brainstem response (ABR) was recorded pre-operatively, immediately after cochlear implantation, and 7, 14, 28, and 56 days after electrode insertion. In comparison to the control group, the IGF1 treated group showed better hearing preservation at low frequencies, 7 days after surgery. IGF1 application was effective at low frequencies (2 and 4 kHz) throughout the period of examination. Histological studies revealed that outer hair cell numbers, in the IGF1-treated group, were maintained in the cochlear region responsible for low-frequency hearing (upper midbasal turn) and that there was less fibrous tissue formation around the electrode. Both the outer hair cell counts and the extent of fibrosis significantly correlated with the ABR threshold shifts at low frequencies. These results indicate that IGF1 might attenuate loss of low-frequency hearing after cochlear implantation, suggesting its possible clinical use in soft surgeries involving cochlear implants with electric-acoustic stimulation for hearing preservation. PMID- 30006114 TI - Increased Pulmonary-Systemic Pulse Pressure Ratio Is Associated With Increased Mortality in Group 1 Pulmonary Hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular (RV) failure. The failing RV, through interventricular uncoupling, deleteriously impacts the left ventricle and overall cardiac efficiency. We hypothesised that the ratio of the pulmonary artery pulse pressure to the systemic pulse pressure ("pulmonary systemic pulse pressure ratio", or PS-PPR) would be associated with mortality in PAH. METHODS: We conducted a retrospective analysis of 262 patients in the National Institute of Health Primary Pulmonary Hypertension Registry (NIH-PPH). We evaluated the association between the PS-PPR and mortality after adjustment for the Pulmonary Hypertension Connection (PHC) risk equation. RESULTS: Among 262 patients (mean age 37.5+/-15.8years, 62.2% female), median PS-PPR was 1.04 (IQR 0.79-1.30). In the Cox proportional hazards regression model, each one unit increase in the PS-PPR was associated with more than a two-fold increase in mortality during follow-up (HR 2.06, 95% CI 1.40-3.02, p=0.0002), and this association of PS-PPR with mortality remained significant in the multivariable Cox model adjusted for the PHC risk equation, mean pulmonary artery pressure, and body mass index (BMI) (adjusted HR 1.81, 95% CI 1.13-2.88, p=0.01). Furthermore, PS-PPR in the upper quartile (>1.30) versus quartiles 1-3 was associated with a 68% increase in mortality after adjustment for these same covariates (adjusted HR 1.68, 95% CI 1.13-2.50, p=0.01). CONCLUSIONS: Pulmonary-systemic pulse pressure ratio, a marker of biventricular efficiency, is associated with survival in PAH even after adjustment for the PHC risk equation. Further studies are needed on the wider applications of PS-PPR in PAH patients. PMID- 30006115 TI - ST-Elevation Acute Myocardial Infarction in Australia-Temporal Trends in Patient Management and Outcomes 1999-2016. AB - BACKGROUND: Increased access to reperfusion for ST elevation myocardial infarction (STEMI) has contributed to reduced mortality internationally. We describe temporal trends in pre-hospital care, in-hospital management and outcomes of the STEMI population in Australia. METHODS: Temporal trends with multiple regression analysis on the management and outcomes of STEMI patients enrolled across 46 Australian hospitals in the Australian cohort of the Global Registry of Acute Coronary Events (GRACE) and the Cooperative National Registry of Acute Coronary Care Guideline Adherence and Clinical Events (CONCORDANCE) between February 1999 and August 2016. RESULTS: 4110 patients were treated for STEMI, mean age 62.5+/-13.7years (SD). The median door-to-balloon time of primary percutaneous coronary intervention (PPCI) decreased by 11minutes (p<0.01) although there was no increase in rates of PPCI (p=0.35). Access to non-primary PCI increased by 39% (p<0.01), provisioning of fibrinolysis decreased by 13% (p<0.01) and the median door-to-needle time of 35minutes remained unchanged (p=0.09). Prescription of medical therapies in-hospital remained high, and at discharge there was an increase in prescription of statins (p<0.01); aspirin including antiplatelets (p<0.01), beta blockers (p=0.023) and ACE/ARB (p=0.02). The occurrence of any in-hospital adverse clinical events declined by 78% (p<0.01) albeit, there was no reduction in mortality in-hospital (p=0.84) or within 6 months (p=0.81). CONCLUSIONS: Over time, there has been increased access to non-primary PCI; shorter door-to-balloon times for PPCI; less adverse events in-hospital and fewer readmissions for unplanned revascularisation without the realisation of reduced mortality in-hospital or at 6 months. TRIAL REGISTRATION: CONCORDANCE Registry ACTRN: 12614000887673. PMID- 30006116 TI - Restoring root-canal treated molars: Cost-effectiveness-analysis of direct versus indirect restorations. AB - OBJECTIVES: Root-canal treated molars can be directly restored, usually using resin-based-composite restorations (RBCs), or indirectly restored using full or partial crowns (FCs/PCs). Both the initial treatment costs and the risks of restorative and endodontic complications differ between RBCs and FCs/PCs. We aimed to assess the cost-effectiveness of RBCs versus FCs/PCs for restoring root canal treated molars. METHODS: A mixed public-private payer's perspective within German healthcare was taken. Risks of complications were extracted from large cohort studies or systematic reviews. Costs were estimated using fee-items catalogues of public and private German insurance. A Markov-model was constructed to follow up a root-canal treated molar receiving different restorations in an initially 50-year-old patient over his lifetime. Monte Carlo-microsimulations were performed to assess lifetime costs and effectiveness (tooth retention time), and the resulting cost-effectiveness. RESULTS: RBCs were less costly than FCs/PCs (749 Euro versus 782 Euro), but also less effective (22 years versus 24 years), the incremental-cost-effectiveness-ratio was 10.80 Euro/year. This ratio increased if costs for direct restorations decreased, or costs for indirect restorations increased. If no teeth were replaced, RBC was far more cost effective (the incremental cost-effectiveness ratios was 52.95 Euro/year). If all teeth were replaced, FC was both more effective and less costly. CONCLUSIONS: RBCs showed lower costs, but also lower effectiveness than FCs/PCs. Consequently, the cost-effectiveness of both strategies depended on the willingness-to-pay of patients or other payers, i.e. their willingness to invest in higher effectiveness. Clinically, a large number of tooth, patient and dentist-related factors will impact on decision-making and should be considered. CLINICAL SIGNIFICANCE: We found composite restorations to be less costly, but also less effective than indirect restorations for root-canal treated teeth. Over a long term period, the initial treatment costs and associated cost-differences between strategies may be outweighed by costs of follow-up treatments. PMID- 30006117 TI - Effectiveness of immediately loaded single-implant mandibular overdentures versus mandibular complete dentures: A 1-year follow-up of a randomized clinical trial. AB - OBJECTIVE: This randomized clinical trial (RCT) aimed to assess the 1-year effectiveness of single-implant mandibular overdentures (SIMO) compared to conventional complete dentures (CCD). METHODS: In the first phase of the study, participants received new maxillary and mandibular CCDs. Then, they were randomly allocated to one of the study groups (CCD or SIMO). Participants in SIMO group received an external hexagon implant in the mandibular midline, with the immediate connection of an O-Ring/ball attachment. Oral health-related quality of life (OHIP-EDENT) and patient satisfaction in both groups were assessed before allocation and at 6- and 12-month follow-up visits. Both intention-to-treat (ITT) and per-protocol approaches were used for analyses. Statistical analyses were performed using the Wilcoxon Signed Ranks test and the Generalized Estimating Equations. RESULTS: Eighty-four participants (CCD n = 42; SIMO n = 42) were included, out of which 70 completed the 12-month follow-up (CCD n = 34; SIMO n = 36). ITT analysis showed no changes for the CCD group in the longitudinal assessment compared to baseline. Participants in SIMO group had a significant improvement in OHIP-EDENT scores and satisfaction with the mandibular denture. No changes for the maxillary denture were observed in either groups. Similar results were found when per-protocol analysis was performed. CONCLUSIONS: SIMO treatment resulted in a significant improvement in patient perceived outcomes compared to the CCD. SIMO may be considered as an alternative treatment modality for patients with poorly adapted and/or unstable mandibular dentures (ClinicalTrials.gov NCT03463174). CLINICAL RELEVANCE: The immediately loaded single-implant mandibular overdenture markedly improved patient satisfaction and oral health related quality of life of conventional denture wearers after a 12-month follow up. PMID- 30006118 TI - Hepatic oxidative stress in pigmented P23H rhodopsin transgenic rats with progressive retinal degeneration. AB - Retinitis pigmentosa (RP) comprises a group of inherited retinal degenerative conditions characterized by primary degeneration of the rod photoreceptors. Increased oxidative damage is observed in the retina, aqueous humor, and plasma of RP animal models and patients. The hepatic oxidative status may also be affected in RP due to oxidative damage influencing soluble macromolecules exiting the retina or to alterations in the melanopsin system resulting in chronic circadian desynchronization that negatively alters the oxidative stress defense system. P23H rats were crossed with pigmented Long Evans rats to produce offspring exhibiting the clinical conditions of RP. We measured hepatic malondialdehyde and 4-hydroxyalkenal concentrations as oxidative stress markers; nitrite level as a total nitrosative damage marker; total antioxidant capacity; and the activities of catalase, superoxide dismutase (SOD), and glutathione S transferase. Retinal visual function was assessed based on optomotor and electroretinogram responses. P23H transgenic rats exhibited diminished visual acuity, contrast sensitivity, and electroretinographic responses according to the level of retinal degeneration. P23H rats at 30 days of age already demonstrated only 47% of the hepatic total antioxidant capacity of wild-type animals. Hepatic catalase and SOD activities were also reduced in P23H rats after 120 days, but we detected no difference in glutathione S-transferase activity. P23H rats had increased hepatic oxidative and nitrosative damage markers. GSH/GSSG ratio showed a significant diminution in P23H rats at P120 compared to WT. We conclude that the liver is under increased oxidative stress in P23H rats. Further studies are required, however, to clarify the contribution of systemic oxidative damage to the pathogenesis of RP. PMID- 30006119 TI - Increased interleukin-32, interleukin-1, and interferon-gamma levels in serum from hepatitis B patients and in HBV-stimulated peripheral blood mononuclear cells from healthy volunteers. AB - BACKGROUND: Few studies showed the changes in cytokine profiles after infection by hepatitis B virus (HBV), the most common viral liver disease worldwide. This study examined the relationship between interleukin (IL)-32, IL-1, and interferon (IFN)-gamma levels and HBV load. METHODS: IL-32, IL-1, and IFN-gamma levels in hepatitis B patients serum and HBV-stimulated PBMCs were measured by ELISA. Gene transcripts in PBMCs from hepatitis B patients and HBV-stimulated PBMCs from healthy controls were measured by real-time PCR. RESULTS: IL-32, IL-1, and IFN gamma protein levels in serum from hepatitis B patients were significantly higher than those in healthy volunteers (P<0.05). Hepatitis B patients showed significantly higher expression of IL-32, IL-1, and IFN-gamma transcripts than healthy volunteers (P<0.05). IL-32, IL-1, and IFN-gamma levels in PBMCs stimulated by different amounts of HBV were significantly higher than those in HBV-unstimulated PBMCs (P<0.05). Real-time PCR results were consistent with the ELISA results. CONCLUSIONS: The levels of IL-32, IL-1, and IFN-gamma protein and transcripts in serum and PBMCs from hepatitis B patients were higher than those in healthy volunteers. Similarly, both were higher in PBMCs from healthy volunteers stimulated by HBV in vitro. However, the changes in cytokine levels were not proportional to the viral load. PMID- 30006120 TI - HLA-G protein expression in colorectal cancer evaluated by immunohistochemistry and western blot analysis: Its expression characteristics remain enigmatic. AB - HLA-G protein expression could play a role in evasion of tumor immune surveillance. Accumulating evidence demonstrates that HLA-G is expressed in different types of malignancies, including colorectal cancer (CRC). The purpose of the current study was to further unravel whether HLA-G protein expression could play a role in immune evasion of CRC. Therefore, to firmly establish HLA-G protein expression, eight early passage human CRC cell lines and five human rectal cancer tissues were analyzed by western blot analysis. The results obtained by western blot analysis were compared with immunohistochemistry on tumor tissue sections of the same patient. Furthermore, multiple monoclonal antibodies (mAbs), 4H84, MEM-G/1 and 5A6G7, targeting HLA-G were used to unravel staining patterns. We showed that results obtained with immunohistochemistry did not correlate with protein expression detected by western blot analysis, using three different HLA-G targeting mAbs. Furthermore, with respect to the specificity of the mAbs employed, additional immune reactivity was detected using the mAbs MEM-G/1 and 5A6G7 in western blot analysis with K562 control cell lines overexpressing HLA-A2 or HLA-G, all tumor tissues and in two out of eight CRC cell lines. Based on the current study and our previously reported results, we conclude that claiming HLA-G plays a role in immune modulation of CRC seems premature, as results from anti-body based detection of HLA-G protein remain inconclusive. Until the time that detection of HLA-G is sensitive enough to detect all aspects of HLA-G expression in biological samples, rather than transfected cells or long time cultured cell lines, conclusions should be drawn with great care. PMID- 30006121 TI - Urinary prostaglandin metabolites as Duchenne muscular dystrophy progression markers. AB - BACKGROUND: Patients with Duchenne muscular dystrophy (DMD) exhibit increased prostaglandin D2 (PGD2) expression in necrotic muscle and increased PGD2 metabolites in their urine. In mouse models, inhibiting PGD2 production suppresses muscle necrosis, suggesting a possible intervention through PGD2 mediated activities. OBJECTIVE: We investigated the involvement of PGD2 and its potential use as a marker of pathological progression in DMD. METHODS: Sixty-one male children with DMD and thirty-five age-matched controls were enrolled in the study. DMD patients were divided into "ambulant" and "non-ambulant" groups, which were further subdivided into "steroid" and "non-steroid" therapy groups. Levels of the PGD2 metabolite tetranor-PGDM (t-PGDM) and creatinine were measured in both spot and 24-hour urine samples, with comparisons between groups made according to geometric mean values. RESULTS: DMD patients had significantly higher levels of creatinine-corrected t-PGDM in spot urine samples as compared with the control group. Additionally, both ambulant and non-ambulant DMD groups had significantly higher levels of t-PGDM as compared with controls, with no significant difference in t-PGDM levels observed between steroid and non-steroid groups. Moreover, total creatinine excretion in 24-hour urine samples was significantly lower in DMD patients as compared with controls, and although DMD patients had lower muscle mass than controls, their overall levels of t-PGDM did not differ significantly from those in the non-ambulant and control groups. CONCLUSION: PGD2 might help explain the progression and symptomatic presentations (e.g., ambulatory difficulty) associated with DMD, suggesting it as a useful pathological marker and use of a selective PGD2 inhibitor as a potential treatment modality. PMID- 30006122 TI - Diversity matters: combinatorial information coding by GABAA receptor subunits during spatial learning and its allosteric modulation. AB - In the hippocampus, GABA inhibition tunes network oscillations and shapes synchronous activity during spatial learning and memory coding. Once released from the presynapse, GABA primarily binds to ionotropic GABAA receptors (GABAARs), which are heteropentamers combinatorially assembled from nineteen known subunits to induce Cl- currents postsynaptically. Dissecting GABAAR subtype specificities in neurobiology is daunting because of differences in their developmental dynamics, regional distribution and subcellular compartmentalization. Here, we review recent data to show that the combination of single-cell mRNA-seq and neuroanatomy can reveal unprecedented cell-type and network-specificity of GABAAR subunits and limit the permutation in subunit configurations, thus rationalizing GABAAR physiology and pharmacology. By comparing RNA-seq data on principal cells and interneurons we discuss a tight match between GABAAR subunit allocation, diversity in the origins of GABA inputs and operational rules at synaptic and extrasynaptic sites. We propose that coincident analysis of all GABAAR subunits, particularly in relation to specific behaviors, could overcome existing pitfalls of the genetic and pharmacological manipulation of single subunits. By using alpha1 and alpha5 GABAAR subunits, we single out hippocampal spatial learning as a process in which, despite the many studies available to date, neither consensus nor causality exists with regards to GABAAR subtype requirements, curtailing a unifying concept on postsynaptic coding of GABA signals. Finally, we address the modulation of GABAAR subunits by dopamine and endocannabinoids through receptor heteromerization, cross-modulation of signal transduction and allostery. In sum, data in this review infer that multiparametric computation gains momentum to improve knowledge on GABAARs function in cognition and neuropsychiatric illnesses. PMID- 30006123 TI - Transforming growth factor beta1 suppresses proinflammatory gene program independent of its regulation on vascular smooth muscle differentiation and autophagy. AB - Transforming growth factor beta (TGFbeta) signaling plays crucial roles in maintaining vascular integrity and homeostasis, and is established as a strong activator of vascular smooth muscle cell (VSMC) differentiation. Chronic inflammation is a hallmark of various vascular diseases. Although TGFbeta signaling has been suggested to be protective against inflammatory aortic aneurysm progression, its exact effects on VSMC inflammatory process and the underlying mechanisms are not fully unraveled. Here we revealed that TGFbeta1 suppressed the expression of a broad array of proinflammatory genes while potently induced the expression of contractile genes in cultured primary human coronary artery SMCs (HCASMCs). The regulation of TGFbeta1 on VSMC contractile and proinflammatory gene programs appeared to occur in parallel and both processes were through a SMAD4-dependent canonical pathway. We also showed evidence that the suppression of TGFbeta1 on VSMC proinflammatory genes was mediated, at least partially through the blockade of signal transducer and activator of transcription 3 (STAT3) and NF-kappaB pathways. Interestingly, our RNA-seq data also revealed that TGFbeta1 suppressed gene expression of a battery of autophagy mediators, which was validated by western blot for the conversion of microtubule-associated protein light chain 3 (LC3) and by immunofluo-rescence staining for LC3 puncta. However, impairment of VSMC autophagy by ATG5 deletion failed to rescue TGFbeta1 influence on both VSMC contractile and proinflammatory gene programs, suggesting that TGFbeta1-regulated VSMC differentiation and inflammation are not attributed to TGFbeta1 suppression on autophagy. In summary, our results demonstrated an important role of TGFbeta signaling in suppressing proinflammatory gene program in cultured primary human VSMCs via the blockade on STAT3 and NF-kappaB pathway, therefore providing novel insights into the mechanisms underlying the protective role of TGFbeta signaling in vascular diseases. PMID- 30006124 TI - Dual Food and Energy Hardship and Associated Child Behavior Problems. AB - OBJECTIVE: To examine dual food and energy hardship and internalizing and externalizing behavior problems in 9-year-old children. METHODS: We conducted a cross-sectional analysis of the Fragile Families and Child Wellbeing Study, a prospective national urban birth cohort, when the children were 9 years old. Maternal-reported "food hardship" (ever hungry and/or ever received free food) and "energy hardship" (ever unable to pay utility bill and/or utility shutoff) within the past year, and child behavior using the Child Behavior Checklist for Ages 6-18 were assessed. Multiple logistic regression analyses estimated associations between individual and dual food and energy hardship and child behavior problems, adjusting for a priori covariates (ie, child sex, health insurance, maternal sociodemographic characteristics, poverty, reported health, attention deficit hyperactivity disorder, depressive symptoms, smoking, and substance and alcohol abuse). RESULTS: Approximately 10% of households reported dual food and energy hardship. Children experiencing dual food and energy hardship had 3 times greater odds of withdrawn/depressed behaviors (adjusted odds ratio [AOR], 2.8; 95% confidence interval [CI], 1.4-5.5), threefold greater odds of somatic complaints (AOR, 3.2; 95% CI, 1.5-6.9), and 4 times greater odds of rule-breaking behavior (AOR, 3.7; 95% CI, 1.5-9.2) in the borderline/clinical range than children with no hardship, and had fourfold greater odds of borderline/clinical range somatic complaints (AOR, 4.2; 95% CI, 1.7-10.3) than children with only energy hardship. CONCLUSIONS: Children experiencing dual food and energy hardship have greater odds of coexisting internalizing and externalizing behaviors after controlling for possible confounders. Providers can consider screening and resource referrals for these addressable hardships alongside behavior assessments in the clinical setting. PMID- 30006125 TI - Breast mass characterization using shear wave elastography and ultrasound. AB - PURPOSE: To evaluate the role of SWE in characterizing breast masses and ascertain whether additional use of SWE to ultrasound for evaluating BI-RADS 3 and 4a masses could help reduce long-term follow-up and unnecessary biopsies of these suspicious breast masses. MATERIALS AND METHODS: This prospective, cross sectional study was performed between June 2013 and November 2014. All enrolled patients underwent clinical breast examination, ultrasound, SWE and ultrasound guided core biopsy of the breast mass. Breast Imaging Reporting and Data System (BI-RAD) categories were assigned to breast masses. For qualitative and quantitative variables of SWE, cut-off values for differentiation between benign and malignant breast masses were estimated. Modified BIRADS' (up/downgrading of BIRADS category) was done for BI-RADS 3/4a masses by combining individual SWE parameters and ultrasound findings. Sensitivity, specificity, positive and negative predictive value of modified BI-RADS' and ultrasound BI-RADS were compared. RESULTS: A total of 119 women (mean age, 42.3+/-13.6 [SD] years; range: 13-87 years) with a single breast mass each were enrolled. Histopathologically, 57/119 (48%) breast masses were benign and 62 (52%) were malignant. On ultrasound, 42 breast masses were BI-RADS3 and 77 were BI-RADS 4 (4a, n=10; 4b, n=24; 4c, n=43) leading to 96.8% sensitivity and 70.2% specificity. On SWE, benign breast masses were oval/round, homogenous/reasonably homogenous, blue/green with lower elasticity values and malignant breast masses were irregular, inhomogeneous, red/orange with high elasticity values. On modified BI RADS' using E-color and E-mean/E-max, specificity improved to 78.9% and 75.4% respectively. CONCLUSION: Addition of SWE to ultrasound improves characterization of BI-RADS 3 and 4a masses. E-max, E-mean and E-color are the most useful SWE parameters to differentiate between malignant and benign breast masses. PMID- 30006126 TI - Association of equine sperm population parameters with outcome of intracytoplasmic sperm injections. AB - Limited clinical information is available regarding sperm population parameters that are important for use with equine intracytoplasmic sperm injection (ICSI). Therefore, the appropriateness of a sample of sperm is typically not known before ICSI. The aim of our study was to determine which sperm population characteristics were predictive of ICSI outcome. Frozen-thawed sperm samples (n = 114) from 37 stallions in a clinical program were analyzed after ICSI for percentages of normal morphology (MORPH+), live as assessed by eosin/nigrosin stain (LIVE+), membrane intact as assessed by hypoosmotic swelling test (HOS+), and DNA fragmentation determined by sperm chromatin dispersion (DNA-). ICSI was performed on 147 oocytes, and cleavage (>=2 cells), embryo development (morula or blastocyst), and pregnancy status after embryo transfer were determined. Among the examined sperm parameters, LIVE + correlated positively with MORPH+ and HOS+, and MORPH + negatively with DNA-; no other significant correlations were observed. When used for ICSI, sperm population percentages for MORPH+ and DNA- were not predictive of ICSI outcome, including cleavage, embryo development, and establishment of a pregnancy. Sperm population percentages significantly affecting ICSI outcomes were LIVE+ and HOS + for oocyte cleavage, LIVE + for embryo development, and HOS + for establishment of a pregnancy. The probability of a pregnancy was significantly higher for sperm populations having HOS+ >=40% than populations having HOS+ <=20%. The mean age of the donor mare per sperm injected oocyte did not differ for oocyte cleavage, embryo production, or establishment of pregnancy. In our study, the probability of sperm-injected oocytes to develop into an embryo (morula or blastocyst) improved when sperm were selected from a population with higher indicators of membrane integrity (LIVE+ and HOS+). PMID- 30006127 TI - Mutations in cytochrome B gene effects female reproduction of Ghungroo pig. AB - Cytochrome B is an important polypeptide of the mitochondria helpful in energy metabolism through oxidative phosphorylation. Cytochrome B plays an immense role in the reproduction of animals and due to its mutation prone nature, it can affect the basic physiology of animals. Cytochrome B affects reproductive system in males and equally plays an important role in transferring and providing energy in the development of the embryo, zygote, and oocytes precisely in females. The present study was conducted on Ghungroo pig to study their molecular and reproductive traits and the effect of the cytochrome B gene in the female reproduction of the Ghungroo pig. Although studies are available for cytochrome B gene analysis for evolutionary studies through phylogenetic analysis. This is the first report for the study of Cytochrome B gene on reproduction in pigs. Cytochrome B gene was sequenced and seven SNPs were observed out of which three were non-synonymous. INDEL mutation was detected in Variant B which had lead to Frame Shift mutation resulting in a stop codon AGA. The effect in the reproductive traits of the sow was studied due to the occurrence of nucleotide substitution. Bioinformatics analysis (I-mutant, PROVEAN, and SIFT) had revealed that the mutations were deleterious for the mutant type. Mutation leading to alterations in post-translational modification sites as phosphorylation site, leucine-rich nuclear export signal, occurrence of transmembrane helices, arginine and lysine peptide cleavage site for the mutant variant had resulted in a reduced physiological response. 3 D protein structure, (predicted through bioinformatics analysis) for cytochrome B has revealed distinct structural differences in mutated form with truncated protein by RMSD analysis through TM-Align software. Associated studies of genotype variants with reproductive traits have revealed the significant effect of variants of cytochrome B gene on reproductive traits namely litter size at first, second and third furrowing, piglet mortality, age at first furrowing and furrowing interval. Mitochondrial gene as Cytochrome B variants might be used as a marker for studying female reproduction of Ghungroo sow in future. PMID- 30006128 TI - Arterial ovarian blood flow in the periovulatory period of GnRH-induced and spontaneous estrous cycles of bitches. AB - The aim of this study was to compare arterial blood flow determined by repeated Doppler sonographic examinations in the periovulatory period in GnRH-induced and spontaneous estrous cycles of bitches. The study was performed on 10 bitches with GnRH agonist implant-induced estrus (Suprelorin(r) containing 4.7 mg deslorelin), and 10 bitches with spontaneous estrus (group B), which served as a control. Pulsed-wave Doppler ultrasonography was performed daily from the beginning of proestrus until early metestrus. The ovarian blood flow parameters in the left and right ovarian arteries, including systolic peak velocity (SPV), end diastolic velocity (EDV) and resistance index (RI), were measured. Obtained outcomes from the period of three days before ovulation (Days -3, -2, -1), ovulation (day 0) and three days after ovulation (Days +1, +2, +3) were evaluated statistically. There were no differences between blood flow variables in the bitches with spontaneous and induced cycles recorded on the same day. The values of SPV and EDV were higher (p < 0.05) on days -1, 0, +1, +2 and + 3 than the velocimetric variables collected on days -3 and -2. Then, a significant increase in blood flow was detected one day before ovulation and was continued during next 3 days (p < 0.05). In contrast, the mean RI values remained constant during the entire experiment or even showed a slight declining trend in both groups (p > 0.05). We concluded that arterial blood flow measured around ovulation does not allow for precise detection of exact ovulation time in bitches in induced and spontaneous cycles. PMID- 30006129 TI - Evaluation of pigeon egg yolk for post thaw quality, enzyme leakage and fertility of buffalo (Bubalus bubalis) bull spermatozoa. AB - Egg yolk is used as a cryoprotectant in semen preservation. However, its composition varies according to the species which may influence its effectiveness during the freeze-thaw process. Therefore, study was conducted to identify the optimum level of pigeon egg yolk (PEY) in Tris citric acid (TCA) extender for freezability and in vivo fertility of buffalo semen. Semen was collected at weekly intervals for a period of three weeks (replicates) from 6 Nili Ravi buffalo bulls (2 ejaculates/bull/replicate) and diluted with TCA extender (50 * 106 motile spermatozoa ml-1) containing 5%, 10%, 15% and 20% PEY or 20% CEY (control) and cryopreserved. Post-thaw sperm quality and extracellular enzymes leakage was assessed after thawing. Sperm motility, plasma membrane integrity, livability and viability was significantly higher in extenders containing 10% and 15% PEY compared to 5% PEY, 20% PEY or 20% CEY (controls). A dose-dependent decrease was recorded in the chromatin damage for the PEY, being lowest for the 15% and 20% PEY which was significantly less compared to controls (20% CEY). The extracellular GOT and LDH leakage was significantly lower (P < 0.05) in extender containing 10% and 15% PEY compared to the controls. Semen collected from 2 bulls, cryopreserved in extenders containing 15% PEY or 20% chicken egg yolk was assessed for fertility after artificial inseminations. A total of 400 buffaloes were inseminated (100 inseminations/extender/bull). The overall fertility rate was significantly higher (P < 0.05) with semen cryopreserved in extender containing 15% PEY (56%) compared to 20% CEY (42%; controls). In conclusion, pigeon egg yolk at 15% offers advantages over 20% chicken egg yolk in terms of in vitro post-thaw semen quality and in vivo fertility of buffalo. PMID- 30006130 TI - Embryotrophic effect of a short-term embryo coculture with bovine luteal cells. AB - The coculture with somatic cells is an alternative to improve suboptimal in vitro culture (IVC) conditions and promote embryo development. Several cell types have been used for this purpose, but there is no information about using luteal cells in short-term coculture with embryos. Consequently, this study aimed to assess the effect of a short-term coculture of early bovine embryos-luteal cells on the in vitro development and embryo quality. Presumptive embryos were cultured from day 0 to day 2 in medium alone (control) or cocultured with bovine luteal cells (BLC-1). Then, embryos from both groups were cultured in medium alone from day 2 to day 8. The development rates on day 8 were compared between groups. The level of reactive oxygen species (ROS) and proliferation rates were evaluated in day 2 embryos and late apoptosis and proliferation rates were determined in day 7 blastocysts. Our results showed that the coculture with bovine luteal cells increased the blastocyst rate compared to the control (50.4% vs. 29.8%; P < 0.01), but there were no differences in the cleavage rates on day 2. The rate of stage 6 blastocysts was higher in the coculture (37.3% vs. 23.8% control; P < 0.01), without differences in the expansion and hatching rates compared to the control. The ROS level in day 2 embryos was higher in the coculture than the control (82 vs. 57.1; P < 0.05), and the cell proliferation rate was higher in the coculture (48% vs. 13% control; P < 0.01), without differences in the mean number of cells between groups. In day 7 blastocysts, the apoptosis rate decreased in the coculture with bovine luteal cells from day 0 to day 2 (4.1% vs. 10.9% control; P < 0.01), whereas the cell proliferation rate and the mean number of cells did not differ between groups. This is the first report of a short-term coculture of in vitro produced embryos and bovine luteal cells. Our model could be an alternative to increase the efficiency of the in vitro production of embryos in cattle. PMID- 30006131 TI - When Appearance Is Everything: Chylous Ascites. PMID- 30006132 TI - A Vanishing Entity: Rheumatoid Vasculitis. PMID- 30006133 TI - Letter to the Editor on "Correlation between surgical site infection and preoperative immune nutrition of patients after surgery for colorectal perforation or obstruction". PMID- 30006135 TI - Ablation of carotenoid cleavage enzymes (BCO1 and BCO2) induced hepatic steatosis by altering the farnesoid X receptor/miR-34a/sirtuin 1 pathway. AB - beta-Carotene-15, 15'-oxygenase (BCO1) and beta-carotene-9', 10'-oxygenase (BCO2) are essential enzymes in carotenoid metabolism. While BCO1/BCO2 polymorphisms have been associated with alterations to human and animal carotenoid levels, experimental studies have suggested that BCO1 and BCO2 may have specific physiological functions beyond the cleavage of carotenoids. In the present study, we investigated the effect of ablation of both BCO1/BCO2 in the development of non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism(s). BCO1/BCO2 double knock out (DKO) mice developed hepatic steatosis (8/8) and had significantly higher levels of hepatic and plasma triglyceride and total cholesterol compared to WT (0/8). Hepatic changes in the BCO1/BCO2 DKO mice were associated with significant: 1) increases in lipogenesis markers, and decreases in fatty acid beta-oxidation markers; 2) upregulation of cholesterol metabolism markers; 3) alterations to microRNAs related to TG accumulation and cholesterol metabolism; 4) increases in an hepatic oxidative stress marker (HO-1) but decreases in anti-oxidant enzymes; and 5) decreases in farnesoid X receptor (FXR), small heterodimer partner (SHP), and sirtuin 1 (SIRT1). The present study provided novel experimental evidence that BCO1 and BCO2 could play a significant role in maintaining normal hepatic lipid and cholesterol homeostasis, potentially through the regulation of the FXR/miR-34a/SIRT1 pathway. PMID- 30006136 TI - Effects of polyamines on cadmium- and copper-mediated alterations in wheat (Triticum aestivum L) and sunflower (Helianthus annuus L) seedling membrane fluidity. AB - We investigated if wheat (Wh) and sunflower (Sf) plants watering with 1 mM CdCl2 or CuCl2 for 5-15 d during germination and seedling altered membrane fluidity (MF) of their leaves and roots, and if plant pre-treatment with the polyamines (PAs) putrescine (Put), spermidine (Spd) or spermine (Spm) prevented those alterations. Cd impaired Wh and Sf growth, while Cu only affected Sf growth. Cu and Cd increased MF of leaves of both plant species, while Cd decreased MF of Sf roots. Plant treatment for 15 d with 0.1 mM Put, Spd or Spm did not affect plant growth and had opposed effects on the MF of both plants. Finally, Wh and Sf were pre-treated with PAs for either 5 or 10 days followed by metal treatment until day 15. While Put did not affect membrane MF, Spd and Spm decreased it between 5 and 10 d of plant treatment. Together, experimental results demonstrate that during plant development (a) Cd and Cu have noxious effects on plants membrane biophysical properties that could be partially responsible of their toxicity, and (b) this deleterious effect could be only partially prevented by plant pretreatment with the PAs. PMID- 30006134 TI - Home Versus Rehabilitation: Factors that Influence Disposition After Minimally Invasive Surgery in Adult Spinal Deformity Surgery. AB - BACKGROUND: Minimally invasive surgery (MIS) correction for adult spinal deformity (ASD) may reduce the need the need for postoperative skilled nursing facility (SNF) or inpatient rehabilitation (IR) placement following surgery. The likelihood of requiring placement in a facility rather than home disposition may be influenced by various factors. In addition, the associations between discharge location and outcomes and complication rates have not been elucidated in these patients. In this study, we aimed to define factors predicting disposition to an SNF/IR and to elucidate the rates of complications occurring in patients sent to home versus to a facility. METHODS: A retrospective review of a multicenter ASD database, which included patients who underwent surgery between 2009 and 2014. Inclusion criteria were age >18 years, MIS as part of index surgery, location of discharge, and at least 1 of the following: pelvic tilt >20 degrees , sagittal vertical axis >5 cm, pelvic incidence-lumbar lordosis mismatch >10, or lumbar scoliosis >20 degrees . Patients with a 2-year follow-up were included. Preoperative demographic and radiographic data, postoperative (<30 day) complications, and health-related quality of life were analyzed. RESULTS: A total of 182 patients met our inclusion criteria, including 113 who were discharged to home and 69 who were discharged to an SNF/IR. Older patients (>50 years) were more likely to be discharged to an SNF/IR (P = 0.043). Those aged >70 years were 6-fold more likely to go to an SNF/IR. No association was identified between discharge to an SNF/IR and any radiographic parameters except preoperative pelvic tilt (odds ratio [OR], 1.11; P = 0.009). Staged cases were more likely to be discharged to an SNF/IR (OR, 3.24; 95% confidence interval, 1.11-9.46; P = 0.032); otherwise, there was no difference in levels treated, operating time, estimated blood loss, osteotomy, or length of hospital stay. Patients requiring discharge to an SNF/IR had a higher rate of complications (58% vs. 39.8%; P = 0.017), including major complications (19.5% vs. 42%; P = 0.001), perioperative complications (14.2% vs. 31.9%; P = 0.004) and infections (3.5% vs. 13%; P = 0.016). Patients discharged to an SNF/IR had a higher rate of revision (19.5% vs. 33%; P = 0.035). Health-related quality of life measures were similar regardless of disposition. CONCLUSIONS: Older patients and those undergoing staged MIS deformity correction have a higher likelihood of postoperative disposition to an SNF/IR. Complications occurred more commonly in those patients requiring transfer to an SNF/IR after hospitalization. PMID- 30006137 TI - Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice. AB - Sigma-1 receptor (Sig-1R) activation has been shown to decrease infarct volume and enhance neuronal survival after brain ischemia-reperfusion (IR) in rodent models. The present study aims to investigate first the effect of Sig-1R activation on blood-brain barrier (BBB) disruption during experimental stroke. Male C57BL/6 mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 15 min, and the worst BBB leakage was observed on the 7th day after brain IR. To confirm the BBB protective role of Sig-1R, mice were divided into five groups (sham group, BCCAO group, PRE084 group, BD1047 group, PRE084 and BD1047 group; 29-35 mice for each group), and treated with agonist PRE084 (1 mg/kg) and/or antagonist BD1047 (1 mg/kg) for 7 days intraperitoneally once a day after BCCAO. Interestingly, PRE084 administration significantly improved neurobehavioral performance as well as healing of neuron damage and white matter lesions. PRE084 also reduced the leakage of Evans blue and IgG and attenuated the disassembly of BBB structural proteins, while the neuroprotective and BBB protective functions of PRE084 were blocked by BD1047. Furthermore, in Sig-1R knockout (Sig-1R KO) mice, brain IR produced more serious IgG leakage and degradation of BBB structural proteins than in wild-type model mice. In addition, the protective effect of PRE084 against the BBB was lost in Sig-1R KO mice after brain IR. Finally, treatment with PRE084 significantly increased the expression of Sig-1R in brain microvascular endothelial cells of mice that were subjected to brain IR and increased translocation of Sig-1R to the cell plasmalemma. Thus, we identified a previously unexplored role of Sig-1R in alleviating BBB disruption in stroke processes and have demonstrated that reversing BBB rupture through Sig 1R activation may be another promising method for cerebral protection against IR injury. PMID- 30006138 TI - Bruce Ransom: energy, inspiration, and curiosity. PMID- 30006139 TI - Ethnic variation in the incidence of biliary atresia correlates with the frequency of the most prevalent haplotype in its population. AB - The cause of biliary atresia (BA) remains an enigma. However, an ethnic diversity in the incidence of BA is so unique that anthropological approach may provide some etiopathogenetic implications in the disease mechanism. We previously reported that an association of maternal microchimerism (MMc) in BA and a significant compatibility of HLA-A between the patient with BA and their mother. Across the 10 countries (Japan, South Korea, Taiwan, Philippines, New Zealand (Maori population), UK, France, Germany, Norway, and Sweden), we determined the frequency of the most prevalent HLA haplotypes of each country from Allele Frequency Database and found that it was significantly correlated with the incidence of BA of the respective country (p = 0.0126). This observation better fits the MMc theory as an etiopathogenesis, that is, maternal effector cells are likely to migrate into the fetus in a relatively homogenous population and may damage the developing bile duct structure and portal vein endothelium, depending on materno-fetal tolerance and immunity. PMID- 30006140 TI - Calcium signaling defects underlying salivary gland dysfunction. AB - Salivary glands secrete saliva, a mixture of proteins and fluids, which plays an extremely important role in the maintenance of oral health. Loss of salivary secretion causes a dry mouth condition, xerostomia, which has numerous deleterious consequences including opportunistic infections within the oral cavity, difficulties in eating and swallowing food, and problems with speech. Saliva secretion is regulated by stimulation of specific signaling mechanisms within the acinar cells of the gland. Neurotransmitter-stimulated increase in cytosolic [Ca2+] ([Ca2+]i) in acinar cells is the primary trigger for salivary fluid secretion from salivary glands, the loss of which is a critical factor underlying dry mouth conditions in patients. The increase in [Ca2+]i regulates multiple ion channel and transport activities that together generate the osmotic gradient which drives fluid secretion across the apical membrane. Ca2+ entry mediated by the Store-Operated Ca2+ Entry (SOCE) mechanism provides the essential [Ca2+]i signals to trigger salivary gland fluid secretion. Under physiological conditions depletion of ER-Ca2+ stores is caused by activation of IP3R by IP3 and this provides the stimulus for SOCE. Core components of SOCE in salivary gland acinar cells are the plasma membrane Ca2+ channels, Orai1 and TRPC1, and STIM1, a Ca2+-sensor protein in the ER, which regulates both channels. In addition, STIM2 likely enhances the sensitivity of cells to ER-Ca2+ depletion thereby tuning the cellular response to agonist stimulation. Two major, clinically relevant, conditions which cause irreversible salivary gland dysfunction are radiation treatment for head-and-neck cancers and the autoimmune exocrinopathy, Sjogren's syndrome (pSS). However, the exact mechanism(s) that causes the loss of fluid secretion, in either condition, is not clearly understood. A number of recent studies have identified that defects in critical Ca2+ signaling mechanisms underlie salivary gland dysfunction caused by radiation treatment or Sjogren's syndrome (pSS). This chapter will discuss these very interesting and important studies. PMID- 30006141 TI - In reply to comments from the maxillofacial team concerning our article on temporal artery biopsy. PMID- 30006142 TI - The genome-wide sequence specificity of DNA cleavage by bleomycin analogues in human cells. AB - Bleomycin (BLM) is a cancer chemotherapeutic agent that cleaves cellular DNA at specific sequences. Using next-generation Illumina sequencing, the genome-wide sequence specificity of DNA cleavage by two BLM analogues, 6'-deoxy-BLM Z and zorbamycin (ZBM), was determined in human HeLa cells and compared with BLM. Over 200 million double-strand breaks were examined for each sample, and the 50,000 highest intensity cleavage sites were analysed. It was found that the DNA sequence specificity of the BLM analogues in human cells was different to BLM, especially at the cleavage site (position "0") and the "+1" position. In human cells, the 6'-deoxy-BLM Z had a preference for 5'-GTGY*MC (where * is the cleavage site, Y is C or T, M is A or C); it was 5'-GTGY*MCA for ZBM; and 5' GTGT*AC for BLM. With cellular DNA, the highest ranked tetranucleotides were 5' TGC*C and 5'-TGT*A for 6'-deoxy-BLM Z; 5'-TGC*C, 5'-TGT*A and 5'-TGC*A for ZBM; and 5'-TGT*A for BLM. In purified human genomic DNA, the DNA sequence preference was 5'-TGT*A for 6'-deoxy-BLM, 5'-RTGY*AYR (where R is G or A) for ZBM, and 5' TGT*A for BLM. Thus, the sequence specificity of the BLM analogue, 6'-deoxy-BLM Z, was similar to BLM in purified human DNA, while ZBM was different. PMID- 30006143 TI - Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines. AB - A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the BTK protein. All these findings provided new clues about the pyrimidine scaffold as an effective BTK inhibitor for the treatment of B-cell lymphoma. PMID- 30006144 TI - Development of efficient one-pot three-component assembly of trityl olmesartan medoxomil. AB - We have elaborated a one-pot three-component assembly of trityl olmesartan medoxomil starting from commercially available ethyl 4-(2-hydroxypropan-2-yl)-2 propyl-1H-imidazole-5-carboxylate, 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1 trityl-1H-tetrazole and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one intermediates. The developed and optimized one-pot process provides 72-75% yield of trityl olmesartan medoxomil over three steps, which represents in average ca. 90% yield per synthetic step, on a 300 g scale. The process is conducted in simple fashion and provides highly pure trityl olmesartan medoxomil (up to 97.5% by HPLC), which can be easily converted to olmesartan medoxomil that fully complies with all ICH requirements. Furthermore, the described process significantly improves the primary process to trityl olmesartan medoxomil by drastic reduction of required unit operations and application of single reaction solvent through the reaction sequence. Moreover, the amount of used organic solvents was notably reduced. The developed process has provided solid bases for industrial production of trityl olmesartan medoxomil. PMID- 30006145 TI - Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts. AB - Lysine acylation of proteins is a crucial chemical reaction, both as a post translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system. PMID- 30006146 TI - Nitro-fatty acid formation and metabolism. AB - Nitro-fatty acids (NO2-FA) are pleiotropic modulators of redox signaling pathways. Their effects on inflammatory signaling have been studied in great detail in cell, animal and clinical models primarily using exogenously administered nitro-oleic acid. While we know a considerable amount regarding NO2 FA signaling, endogenous formation and metabolism is relatively unexplored. This review will cover what is currently known regarding the proposed mechanisms of NO2-FA formation, dietary modulation of endogenous NO2-FA levels, pathways of NO2 FA metabolism and the detection of NO2-FA and corresponding metabolites. PMID- 30006149 TI - Protective C allele of the single-nucleotide polymorphism rs1335532 is associated with strong binding of Ascl2 transcription factor and elevated CD58 expression in B-cells. AB - CD58 is expressed on the surface of antigen-presenting cells, including B-cells, and provides co-stimulation to regulatory T-cells (Treg) through CD2 receptor binding. Tregs appear to be essential suppressors of tissue-specific autoimmune responses. Thereby, CD58 plays protective role in multiple sclerosis (MS) and CD58 was identified among several loci associated with MS susceptibility. Minor (C) variant of the single-nucleotide polymorphism (SNP) rs1335532 is associated with lower MS risk according to genome-wide association studies (GWAS) and its presence correlates with higher CD58 mRNA levels in MS patients. We found that genomic region containing rs1335532 has enhancer properties and can significantly boost the CD58 promoter activity in lymphoblast cells. Using bioinformatics and pull-down assay we found that the protective (C) rs1335532 allele created functional binding site for ASCL2 transcription factor, a target of the Wnt signaling pathway. Both in B-lymphoblastoid cell lines and in primary B-cells, as well as in a monocytic cell line, activation of Wnt signaling resulted in an increased CD58 promoter activity in the presence of the protective but not the risk allele of rs1335532, whereas ASCL2 knockdown abrogated this effect. In summary, our results suggest that ASCL2 mediates the protective function of rs1335532 minor (C) allele in MS. PMID- 30006150 TI - Missense mutation of SPAST protein (I344K) results in loss of ATPase activity and prolonged the half-life, implicated in autosomal dominant hereditary spastic paraplegia. AB - The spastin protein (SPAST) contains an ATPase with diverse cellular activities (AAA) domain and regulates microtubule dynamics. Missense mutations of the SPAST gene are frequently detected in patients with hereditary spastic paraplegias (HSPs) and represent the main reason of loss of SPAST function; however, the pathogenicity of mutant SPAST is heterogeneous. Here, SPAST variant with an I344K mutation (I344K-SPAST) was identified in a Korean family with autosomal dominant type HSP. We investigated the role of the I344K-SPAST in HSP to provide a therapeutic mechanism. The I344K-SPAST mutation prolonged the half-life of the protein compared to wild-type SPAST (WT-SPAST) in cells by modulating post translational modifications for proteasomal degradation. I344K-SPAST was localized in microtubule but defective in microtubule severing and ATPase activity compared to WT-SPAST in vitro and in cells. Mutant M87 isoform harboring the same mutation with I344K-M1 SPAST also increased protein stability and loss of MT severing activity, but the pathogenicity was not stronger than I344K-M1 SPAST in neurite outgrowth. Overexpression of I344K-SPAST resulted in microtubule accumulation following inhibited neurite growth in neuroblastoma, neural progenitor cells and mouse primary cortical neurons. Conversely, these pathogenic effects of I344K-SPAST were reduced by overexpression of WT-M1 SPAST in a dose dependent manner since WT-SPAST could interact with I344K-SPAST. Our data therefore provide proof-of-concept that gene transfer of WT-M1 SPAST may serve as a valid therapeutic option for HSPs. PMID- 30006151 TI - Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca2+ handling. AB - Intracellular neurofibrillary tangles (NFT) composed by tau and extracellular amyloid beta (Abeta) plaques accumulate in Alzheimer's disease (AD) and contribute to neuronal dysfunction. Mitochondrial dysfunction and neurodegeneration are increasingly considered two faces of the same coin and an early pathological event in AD. Compelling evidence indicates that tau and mitochondria are closely linked and suggests that tau-dependent modulation of mitochondrial functions might be a trigger for the neurodegeneration process; however, whether this occurs either directly or indirectly is not clear. Furthermore, whether tau influences cellular Ca2+ handling and ER-mitochondria cross-talk is yet to be explored. Here, by focusing on wt tau, either full-length (2N4R) or the caspase 3-cleaved form truncated at the C-terminus (2N4RDeltaC20), we examined the above-mentioned aspects. Using new genetically encoded split-GFP based tools and organelle-targeted aequorin probes, we assessed: i) tau distribution within the mitochondrial sub-compartments; ii) the effect of tau on the short- (8-10 nm) and the long- (40-50 nm) range ER-mitochondria interactions; and iii) the effect of tau on cytosolic, ER and mitochondrial Ca2+ homeostasis. Our results indicate that a fraction of tau is found at the outer mitochondrial membrane (OMM) and within the inner mitochondrial space (IMS), suggesting a potential tau-dependent regulation of mitochondrial functions. The ER Ca2+ content and the short-range ER-mitochondria interactions were selectively affected by the expression of the caspase 3-cleaved 2N4RDeltaC20 tau, indicating that Ca2+ mis-handling and defects in the ER-mitochondria communications might be an important pathological event in tau-related dysfunction and thereby contributing to neurodegeneration. Finally, our data provide new insights into the molecular mechanisms underlying tauopathies. PMID- 30006152 TI - Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells. AB - Circulating histones have been proposed as targets for therapy in sepsis and hyperinflammatory symptoms. However, the proposed strategies have failed in clinical trials. Although different mechanisms for histone-related cytotoxicity are being explored, those mediated by circulating histones are not fully understood. Extracellular histones induce endothelial cell death, thereby contributing to the pathogenesis of complex diseases such as sepsis and septic shock. Therefore, the comprehension of cellular responses triggered by histones is capital to design effective therapeutic strategies. Here we report how extracellular histones induce autophagy and apoptosis in a dose-dependent manner in cultured human endothelial cells. In addition, we describe how histones regulate these pathways via Sestrin2/AMPK/ULK1-mTOR and AKT/mTOR. Furthermore, we evaluate the effect of Toll-like receptors in mediating autophagy and apoptosis demonstrating how TLR inhibitors do not prevent apoptosis and/or autophagy induced by histones. Our results confirm that histones and autophagic pathways can be considered as novel targets to design therapeutic strategies in endothelial damage. PMID- 30006147 TI - Pluripotent Stem Cell Platforms for Drug Discovery. AB - Use of human pluripotent stem cells (hPSCs) and their differentiated derivatives have led to recent proof-of-principle drug discoveries, defining a pathway to the implementation of hPSC-based drug discovery (hPDD). Current hPDD strategies, however, have inevitable conceptual biases and technological limitations, including the dimensionality of cell-culture methods, cell maturity and functionality, experimental variability, and data reproducibility. In this review, we dissect representative hPDD systems via analysis of hPSC-based 2D monolayers, 3D culture, and organoids. We discuss mechanisms of drug discovery and drug repurposing, and roles of membrane drug transporters in tissue maturation and hPDD using the example of drugs that target various mutations of CFTR, the cystic fibrosis transmembrane conductance regulator gene, in patients with cystic fibrosis. PMID- 30006148 TI - The Impact of Systemic Inflammation on Neurodevelopment. AB - Inflammatory mediators affect the brain during development. Neurodevelopmental disorders such as autism spectrum disorders, cognitive impairment, cerebral palsy, epilepsy, and schizophrenia have been linked to early life inflammation. Recent advances have shown the effects of systemic inflammation on children's neurodevelopment. We discuss the potential mechanisms by which inflammatory molecules can exert their effects on the developing brain and consider the roles of MHC class I molecules, the HPA axis, glial cells, and monoamine metabolism. Methods to prevent the effects of cytokine imbalance may lead to the development of new therapeutics for neuropsychiatric disorders. Future research should focus on identifying at-risk individuals and early effective interventions to prevent long-term neurodevelopmental disabilities. PMID- 30006153 TI - Pre-pregnancy maternal obesity associates with endoplasmic reticulum stress in human umbilical vein endothelium. AB - Obesity associates with the endoplasmic reticulum (ER) stress-induced endothelial dysfunction. Pregnant women with pre-pregnancy maternal obesity (PGMO) may transfer this potential risk to their offspring; however, whether ER stress occurs and associates with foetoplacental endothelial dysfunction in PGMO is unknown. We studied the l-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells (HUVECs) from women with PGMO or with a normal pre-pregnancy weight. We analysed the expression and activation of the ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1alpha (IRE1alpha), and activating transcription factor 6 (ATF6). PGMO associated with lower endothelial NO synthase activity due to increased Thr495-inhibitor and decreased Ser1177-stimulator phosphorylation. However, higher expression and activity of the human cationic amino acid transporter 1 was found. PGMO caused activation of PERK and its downstream targets eukaryotic initiation factor 2 (eIF2alpha), C/EBP homologous protein 10 (CHOP), and tribbles-like protein 3 (TRB3). Increased IRE1alpha protein abundance (but not its phosphorylation or X-box binding protein 1-mRNA splicing) and increased c-Jun N-terminal kinase 1 phosphorylation was seen in PGMO. A preferential nuclear location of the activating transcription factor 6 (ATF6) was found in HUVECs from PGMO. All the changes seen in PGMO were blocked by TUDCA but unaltered by tunicamycin. Thus, PGMO may determine a state of ER stress via upregulation of the PERK-eIF2alpha-CHOP-TRB3 axis signalling in HUVECs. This phenomenon results in foetoplacental vascular endothelial dysfunction at birth. PMID- 30006154 TI - GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid deposition and oxidative stress. It has been demonstrated that general control nonderepressible 2 (GCN2) is required to maintain hepatic fatty acid homeostasis under conditions of amino acid deprivation. However, the impact of GCN2 on the development of NAFLD has not been investigated. In this study, we used Gcn2-/- mice to investigate the effect of GCN2 on high fat diet (HFD)-induced hepatic steatosis. After HFD feeding for 12 weeks, Gcn2-/- mice were less obese than wild type (WT) mice, and Gcn2-/- significantly attenuated HFD-induced liver dysfunction, hepatic steatosis and insulin resistance. In the livers of the HFD fed mice, GCN2 deficiency resulted in higher levels of lipolysis genes, lower expression of genes related to FA synthesis, transport and lipogenesis, and less induction of oxidative stress. Furthermore, we found that knockdown of GCN2 attenuated, whereas overexpression of GCN2 exacerbated, palmitic acid-induced steatosis, oxidative & ER stress, and changes of peroxisome proliferator activated receptor gamma (PPARgamma), fatty acid synthase (FAS) and metallothionein (MT) expression in HepG2 cells. Collectively, our data provide evidences that GCN2 deficiency protects against HFD-induced hepatic steatosis by inhibiting lipogenesis and reducing oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in the liver may provide a novel approach to attenuate NAFLD development. PMID- 30006156 TI - Synthesis and study of benzofuran-pyran analogs as BMP-2 targeted osteogenic agents. AB - Twenty-four novel benzofuran-pyran derivatives were synthesized and evaluated for their anti-osteoporotic activity in primary cultures of rat calvarial osteoblasts in vitro. Among all the compounds screened for the alkaline phosphatase activity, three compounds 4e, 4j and 4k showed potent activity at picomolar concentrations in osteoblast differentiating stimulation. Additionally, these compounds were found effective in mineralization, assessed by alizarin red-S staining assay. Compounds were again validated through a series of other in vitro experiments. Moreover, molecular dynamics simulations demonstrated that both benzofuran and pyran moieties are requisite to fit into the active site of BMP-2 receptor, a key target of the osteogenic agents. The obtained results strongly convey that compound 4e is a potential bone anabolic agent among synthesized series, which can be further explored as a drug lead for treating osteoporosis. PMID- 30006155 TI - Synthesis and antimicrobial evaluation of amino sugar-based naphthoquinones and isoquinoline-5,8-diones and their halogenated compounds. AB - Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4 naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8 dione analogues with minimum inhibitory concentration (MIC = 4-32 MUg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08-256 MUg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria. PMID- 30006157 TI - Benzofuran hydrazones as potential scaffold in the development of multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity. AB - New benzofuranhydrazones 3-12 were easily prepared and assayed for their radical scavenging ability. Hydrazones 3-12 showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety. High antioxidant activity is showed by the 2-hydroxy-4-(diethylamino)benzylidene derivative 11. Furthermore, hydrazones 3-12 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The antiproliferative effects of the hydrazones 3-12 was tested on erythroleukemia K562 and Colo-38 melanoma human cells. All the compounds showed growth inhibition in the micromolar to sub micromolar concentration range. If taken together these results points to benzofuran hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 5, 7 and 11 correlated to their high antiproliferative activity. PMID- 30006159 TI - Piperlongumine (piplartine) as a lead compound for anticancer agents - Synthesis and properties of analogues: A mini-review. AB - Piperlongumine, also known as piplartine, is an amide alkaloid of Piper longum L. (long piper), a medical plant known from Ayurvedic medicine. Although was discovered well over fifty years ago, its pharmacological properties have been uncovered in the past decade. In particular, piperlongumine has been most extensively studied as a potential anticancer agent. Piperlongumine has exhibited cytotoxicity against a broad spectrum of human cancer cell lines, as well as demonstrated antitumor activity in rodents. Piperlongumine has also been found to be a proapoptotic, anti-invasive, antiangiogenic agent and synergize with modern chemotherapeutic agents. Because of its clinical potential, several studies were undertaken to obtain piperlongumine analogues, which have exhibited more potent activity or more appropriate drug-like parameters. In this review, the synthesis of piperlongumine analogues and piperlongumine-based hybrid compounds, as well as their anticancer properties and the molecular basis for their activity are explored. General structure-activity relationship conclusions are drawn and directions for the future research are indicated. PMID- 30006158 TI - Arylamino containing hydroxamic acids as potent urease inhibitors for the treatment of Helicobacter pylori infection. AB - A novel series of aniline-containing hydroxamic acids were designed, synthesized and evaluated as anti-virulence agents for the treatment of gastritis and gastric ulcer caused by Helicobacter pylori. In vitro enzyme-based screen together with in vivo assays and structure-activity relationship (SAR) studies led to the discovery of three potent urease inhibitors 3-(3,5-dichlorophenylamino)N hydroxypropanamide (3a), 3-(2-chlorophenylamino)N-hydroxypropanamide (3d) and 3 (2,4-dichlorophenylamino)N-hydroxypropanamide (3n). Compounds 3a, 3d and 3n showed excellent urease inhibition with IC50 values 0.043 +/- 0.005, 0.055 +/- 0.008 and 0.018 +/- 0.002 MUM, and significantly depressed gastritis developing at the dose of 32 mg/kg b. i.d with eradication rates of H. pylori reaching 92.3, 84.6 and 100%, respectively. Preliminary safety studies (acute toxicity in mice) disclosed that 3a, 3d and 3n was well-tolerated in KM mice with LD50s of 2982.8, 3349.4 and 3126.9 mg/kg, respectively. Collectively, the data obtained in this study indicate that 3a, 3d and 3n, in particular 3n, could considered as promising candidates for the potential treatment of H. pylori caused gastritis and gastric ulcer, and hence merit further studies. PMID- 30006160 TI - Synthesis and biological evaluation of (1-aryl-1H-pyrazol-4-yl) (3,4,5 trimethoxyphenyl)methanone derivatives as tubulin inhibitors. AB - A series of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanones (8a-p, 9a p) and ketoxime (10c) derivatives were designed and synthesized as antitubulin agents. All of the target compounds were evaluated for the in vitro anti proliferative activities against three tumor cell lines (A549, HT-1080, SGC 7901). The most promising compounds in this class were (1-(p-tolyl)-1H-pyrazol-4 yl) (3,4,5-trimethoxyphenyl)methanone (9c) and its ketoxime derivative (10c), which significantly inhibited tumor cells growth with IC50 value of 0.054-0.16 MUM. Meanwhile, compound 9c exhibited effectively inhibitory activity of tubulin polymerization. Consistent with its antitubulin activity, compound 9c could destructively damage microtubule network and arrest SGC-7901 cell cycle at G2/M phase significantly. The structure-activity relationship (SAR) and conformational analysis indicate that methyl group at C4-position of C-ring is critical for the activities and the amino group at the C5-position of B-ring plays a negative role in maintaining bioactivity. Furthermore, a molecular docking study was performed to elucidate its binding mode at the colchicine site in the tubulin heterodimer. PMID- 30006161 TI - Fluorescent organometallic rhodium(I) and ruthenium(II) metallodrugs with 4 ethylthio-1,8-naphthalimide ligands: Antiproliferative effects, cellular uptake and DNA-interaction. AB - Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties. PMID- 30006162 TI - Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site. AB - Tubulin inhibitors that target the colchicine binding site continue to emerge as promising anticancer agents. In this study, based on the anti-proliferative activities, a novel tubulin inhibitor 7a3 targeting the colchicine binding site was designed, synthesized, and optimized from a series of novel cis-restricted pyrazole analogues of combretastatin A-4. The structure-activity relationships (SARs) of these newly synthesized compounds are summarized indicating that the methyl substituent at the N1 position and deamination were significantly important for the anti-proliferative efficacy. The optimized compound 7a3 exhibited the ability to arrest the cell cycle in the G2/M phase, induce cell apoptosis, and inhibit cell migration in tumour cells. The results of the immunofluorescence analysis using confocal microscopy and the tubulin polymerization assay revealed that tubulin assembly was disrupted by 7a3 in vitro. Furthermore, the targeting identification of 7a3 was illuminated by solving the crystal structure of 7a3 in complex with tubulin at a resolution of 3.2 A (PDB code 5Z4U), which confirmed the result of molecular docking and further demonstrated that 7a3 binds to the site of colchicine. Moreover, the pharmacokinetic analysis in mouse plasma showed that 7a3 rapidly reached a peak concentration at 0.25 h after intraperitoneal administration, and the T1/2, Cmax, and AUC0-inf were 1.67 +/- 0.28 h, 882 +/- 71 ng mL-1, and 1166 +/- 129 h ng.mL 1, respectively, after a single-dose administration analysed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In addition, the in vivo study indicated that 7a3 significantly inhibited the tumour growth of the SK-OV-3 xenograft in a nude mouse model. In conclusion, our study proved 7a3 to be a potential microtubule-targeting drug for cancer therapy. The SARs and mechanism of action studies of 7a3 based on the X-ray co-crystal structure provided insights into the next-generation tubulin inhibitors for cancer therapy. PMID- 30006163 TI - Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery. AB - The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed in Xenopus laevis oocytes: binding affinities ranged from approximately 0.1 to 2 mM. Compounds which showed robust transport in an oocyte trans-stimulation assay were then tested for transcellular transport in Caco-2 cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability. PMID- 30006164 TI - Discovery and synthesis of novel magnolol derivatives with potent anticancer activity in non-small cell lung cancer. AB - EGFR T790 M accounts for 50% to 60% of cases of non-small-cell lung carcinoma (NSCLC) resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs). Hence, identifying novel compounds with activity against TKIs resistant is of great value. In this study, twenty honokiol and magnolol derivatives were isolated from the EtOH extract of Magnolia officinalis and the antiproliferative activity was evaluated on HCC827 (19del EGFR mutation), H1975 (L858 R/T790 M EGFR mutation), and H460 (KRAS mutation) cell lines. Among the isolated compounds, piperitylmagnolol (a 3-substituted magnolol derivative) showed the best antiproliferative activity against those three cell lines with the IC50 values of 15.85, 15.60 and 18.60 MUM, respectively, which provided a direction for the structural modification of magnolol. Further structural modification led to the synthesis of thirty-one magnolol derivatives, and compounds A13, C1, and C2 exhibited significant and broad-spectrum antiproliferative activity with the IC50 values ranging from 4.81 to 13.54 MUM, which were approximately 4- and 8-fold more potent than those of honokiol and magnolol, respectively. Moreover, their aqueous solubility was remarkably improved with 12-, 400- and 105 fold greater than those of honokiol and magnolol. Anti-tumor mechanism research revealed that these three compounds were able to induce cell cycle arrest at G0/G1 phase, cause efficient apoptosis in H1975 cells, and also prevent the migration of HUVECs in a dose-dependent manner through Cdk2, Cdk4, Cyclin E, and Cyclin D1 inhibition as well as up-regulation of cleaved-PARP and cleaved-caspase 3 levels. In in vivo antitumor activity, C2 (10, 30 and 100 mg/kg, po) dose-dependently inhibited the tumor growth in H1975 xenograft model with the tumor inhibition rate of 46.3%, 59.3% and 61.2% respectively, suggesting that C2 is a potential oral anticancer agent deserving further investigation. PMID- 30006165 TI - Design, synthesis and biological evaluation of 3-piperazinecarboxylate sarsasapogenin derivatives as potential multifunctional anti-Alzheimer agents. AB - A series of multifunctional 3-piperazinecarboxylate sarsasapogenin derivatives were designed and synthesized against Alzheimer's disease (AD). The protection against H2O2-triggered oxidative stress in PC12 cells, and inhibition on LPS induced NO production in RAW264.7 cell lines in vitro by these derivatives were firstly evaluated. Most of the compounds showed better antioxidant and antiinflammatory activities compared with sarsasapogenin, especially AA34 and AA36. Structure-activity relationships revealed that benzyl group, electron donating group and intramolecular hydrogen bond might be beneficial to enhancing their neuroprotective activities. Moreover, Abeta42 was the optimum predicted target based on the high 3D molecular similarity between compound AA36 and caprospinol. In the following experiments, AA36 significantly protected PC12 cells from Abeta-induced damage and improved learning and memory impairments in Abeta-injected mice. Thus AA36 is regarded as a potent anti-AD agent and N substituted piperazinecarboxylate can be served as a promising structural unit for anti-AD drug design. PMID- 30006166 TI - A novel Anti-Cancer Stem Cells compound optimized from the natural symplostatin 4 scaffold inhibits Wnt/beta-catenin signaling pathway. AB - Cancer stem cells (CSCs) are responsible for carcinogenesis, cancer progression, relapse, metastasis and drug resistance. Therefore, the development of drug molecules targeting CSCs plays a vital role in medicinal researching field. However, there are extremely rare molecules that selectively ablate CSCs. The research and development of drugs targeting CSCs is limited due to a lack of anti CSCs lead compounds. In this study, an anti-CSCs lead compound 35b was discovered, which was derived from the natural chemical scaffold of Symplostatin 4. This compound exhibited a significantly suppressive effect on tumor growth both in vitro and in vivo. Additionally, 35b could significantly reduce the number of melanoma tumor spheres and decrease the percentage of ALDH+ melanoma cells. Further mechanism study illustrated that compound 35b could eliminate the melanoma CSCs by efficiently blocking Wnt/beta-catenin signaling pathway. Collectively, our findings would provide a novel chemical scaffold and alternative idea of molecular design for development of anti-CSCs drugs. PMID- 30006167 TI - Copper(I) oxide nanoparticles catalyzed click chemistry based synthesis of melampomagnolide B-triazole conjugates and their anti-cancer activities. AB - A series of thirty one melampomagnolide B-triazole conjugates was synthesized via Copper(I) oxide nanoparticles catalyzed click chemistry. These conjugates were evaluated for their anti-cancer activities against a panel of five human cancer cell lines. The most active compound 6e showed high activity against HCT116 cell line with IC50 value of 0.43 MUM, which demonstrated 11.5-fold improvement compared to that of the parent compound melampomagnolide B (IC50 = 4.93 MUM). Compound 6e showed significant efficacy of inducing apoptosis, inhibiting proliferation and migration of HCT116 cells. The preliminary molecular mechanism of 6e was also investigated. On the base of these results, compound 6e might be considered as a promising candidate for further evaluation as a potential anti cancer drug. PMID- 30006168 TI - Synthesis, in vitro antiproliferative activity, and kinase inhibitory effects of pyrazole-containing diarylureas and diarylamides. AB - Twenty pyrazole-containing diarylureas and diarylamides were designed and synthesized. They were tested for in vitro antiproliferative activity over a 58 cancer cell line panel at the NCI, USA. The diarylurea derivatives 1b-e and 1g exerted the strongest antiproliferative activity. Among them, compound 1e possessing 3,5-bis(trifluoromethyl)phenyl terminal ring and 3'-methoxy-5' chlorophenyl ring attached to the central pyrazole ring was the most potent. Its IC50 values were in sub-micromolar range against most of the tested cell lines. It showed superior potency than sorafenib, a reference diarylurea drug, over all the tested cell lines. It was also extremely selective towards cancer cells than non-cancerous cells (IC50 against RAW 264.7 macrophages was higher than 100 MUM). At molecular level, compound 1e selectively inhibited V600E mutated B-RAF kinase (IC50 = 0.39 MUM). It also stimulated caspase 3/7 enzymes in RPMI-8226 leukemia cells (2.79 fold increase at 10 MUM concentration, EC50 = 1.52 MUM). So compound 1e may kill cancer cells through induction of apoptosis. This promising candidate can be considered further for development of new efficient anticancer agents. PMID- 30006169 TI - Structure-activity relationships in fungal nucleobases transporters as dissected by the inhibitory effects of novel purine analogues. AB - We have previously rationally designed, synthesized and tested a number of 3 deazapurine analogues, which inhibit the ubiquitous fungal nucleobase transporter FcyB, through binding in its major substrate binding site, by specifically interacting with Asn163. Here, in an effort to further understand the molecular details of structure-activity relationships in all three major nucleobase transporters of fungi, we extend this study by designing, based on our previous experience, synthesizing and testing further 3-deazapurine analogues. We thus identify seven new compounds with relatively high affinity (19-106 MUMU) for the FcyB binding site. Importantly, four of these compounds can also efficiently inhibit AzgA, a structurally and evolutionary distinct, but functionally similar, purine transporter. Contrastingly, none of the new compounds tested had any effect on the transport activity of the uric acid-xanthine transporter UapA, albeit this being a structural homologue of AzgA. Besides the apparent importance for understanding how nucleobase transporter specificity is determined at the molecular level, our work might constitute a critical step in the design of novel purine-related antifungals. PMID- 30006170 TI - Synthesis, molecular docking and biological evaluation of novel phthaloyl derivatives of 3-amino-3-aryl propionic acids as inhibitors of Trypanosoma cruzi trans-sialidase. AB - In the last two decades, trans-sialidase of Trypanosoma cruzi (TcTS) has been an important pharmacological target for developing new anti-Chagas agents. In a continuous effort to discover new potential TcTS inhibitors, 3-amino-3 arylpropionic acid derivatives (series A) and novel phthaloyl derivatives (series B, C and D) were synthesized and molecular docking, TcTS enzyme inhibition and determination of trypanocidal activity were carried out. From four series obtained, compound D-11 had the highest binding affinity value (-11.1 kcal/mol) compared to reference DANA (-7.8 kcal/mol), a natural ligand for TS enzyme. Furthermore, the 3D and 2D interactions analysis of compound D-11 showed a hydrogen bond, pi-pi stacking, pi-anion, hydrophobic and Van der Waals forces with all important amino acid residues (Arg35, Arg245, Arg314, Tyr119, Trp312, Tyr342, Glu230 and Asp59) on the active site of TcTS. Additionally, D-11 showed the highest TcTS enzyme inhibition (86.9% +/- 5) by high-performance ion exchange chromatography (HPAEC). Finally, D-11 showed better trypanocidal activity than the reference drugs nifurtimox and benznidazole with an equal % lysis (63 +/- 4 and 65 +/- 2 at 10 MUg/mL) and LC50 value (52.70 +/- 2.70 MUM and 46.19 +/- 2.36 MUM) on NINOA and INC-5 strains, respectively. Therefore, D-11 is a small molecule with potent TcTS inhibition and a strong trypanocidal effect that could help in the development of new anti-Chagas agents. PMID- 30006171 TI - Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus. AB - Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy. PMID- 30006172 TI - Influence of the C-5 substitution in polysubstituted pyrimidines on inhibition of prostaglandin E2 production. AB - As a part of a broader structure-activity relationship study of substituted 2 aminopyrimidines, the influence of the C-5 substitution on inhibition of prostaglandin E2 (PGE2) production was studied. Thirty compounds were prepared starting from the corresponding 2-amino-4,6-dichloropyrimidines using Suzuki cross-coupling. It was shown previously that 2-amino-4,6-dichloropyrimidines with smaller C-5 substituent (hydrogen and methyl) were devoid of significant activity, while 5-butyl derivatives exhibited prominent potency. In this study, on the other hand, both monoaryl- and bisarylpyrimidines were potent inhibitors of PGE2 production regardless the length of the C-5 substituent (hydrogen, methyl, n-butyl). Moreover, the shorter the C-5 substituent the higher potency to inhibit PGE2 production was observed. 2-Amino-4,6-diphenylpyrimidine was the best inhibitor of PGE2 production with IC50 = 3 nM and no cytotoxicity. The most potent inhibitors deserve further preclinical evaluation as potential anti inflammatory agents. PMID- 30006173 TI - Synthesis of pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazoles and their evaluation as potential anticancer agents. AB - A series of hybrid aza heterocycles containing pyrazolo[3,4-d]pyrimidin-4(5H) ones tethered to 1,2,3-triazole scaffold were synthesized from 1,3-dipolar cycloaddition reaction of pyrazolopyrimidinone based alkyne with azides using Cu(II) catalyst in presence of sodium ascorbate and evaluated for their anticancer efficacy in vitro against C6 rat and U87 human glioma cell lines. These compounds induced a concentration dependent inhibition of C6 rat and U87 human glioma cell proliferation. Compound 5f arrested the cells at S-phase of the cell cycle and induced apoptosis in U87 GBM cell lines. Further, apoptosis was evidenced by the cleavage of Caspase-3, PARP and up regulation of p53. In silico docking studies reveal that the compounds 5a, 5f and 5l were more effective in binding with TGFBR2 than other compounds. PMID- 30006174 TI - Biological evaluation and structure-activity relationships of imidazole-based compounds as antiprotozoal agents. AB - We discovered a series of azole antifungal compounds as effective antiprotozoal agents. They displayed promising inhibitory activities within the micromolar submicromolar range against P. falciparum, L. donovani, and T. b. rhodesiense. Moreover, most of such compounds showed excellent nanomolar IC50 against T. cruzi, showing also very low cytotoxicity. Discussion of structure-activity relationships and biological data for these compounds are provided against the different parasites. To assess the mechanism of action against T. cruzi we proved that the most potent compounds (3b, 3j-l) inhibited the T. cruzi CYP51. Moreover, the most active derivative 3j dramatically reduced parasitemia in T. cruzi mouse model without acute toxicity. PMID- 30006175 TI - Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases. AB - Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target. PMID- 30006177 TI - 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10. AB - Human Diphtheria toxin-like ADP-ribosyltranferases (ARTD) 10 is an enzyme carrying out mono-ADP-ribosylation of a range of cellular proteins and affecting their activities. It shuttles between cytoplasm and nucleus and influences signaling events in both compartments, such as nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) signaling and S phase DNA repair. Furthermore, overexpression of ARTD10 induces cell death. We recently reported on the discovery of a hit compound, OUL35 (compound 1), with 330 nM potency and remarkable selectivity towards ARTD10 over other enzymes in the human protein family. Here we aimed at establishing a structure-activity relationship of the OUL35 scaffold, by evaluating an array of 4-phenoxybenzamide derivatives. By exploring modifications on the linker between the aromatic rings, we identified also a 4-(benzyloxy)benzamide derivative, compound 32, which is potent (IC50 = 230 nM) and selective, and like OUL35 was able to rescue HeLa cells from ARTD10 induced cell death. Evaluation of an enlarged series of derivatives produced detailed knowledge on the structural requirements for ARTD10 inhibition and allowed the discovery of further tool compounds with submicromolar cellular potency that will help in understanding the roles of ARTD10 in biological systems. PMID- 30006176 TI - Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile. AB - A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes. PMID- 30006178 TI - Aggressive conditions during primary drying as a contemporary approach to optimise freeze-drying cycles of biopharmaceuticals. AB - Freeze-drying is the method of choice to dry formulations with biopharmaceutical drugs, to enhance protein stability. This is usually done below the glass transition temperature of maximally freeze-concentrated solutions (Tg'), to avoid protein aggregation, preserve protein activity, and obtain pharmaceutically 'elegant' cakes. Unfortunately, this is a lengthy and energy-consuming process. However, it was recently shown that drying above Tg' or even above the collapse temperature (Tc) is not necessarily detrimental for stability of biopharmaceuticals, and hence provides an attractive option for freeze-drying cycle optimisation. The goal of the present study was to optimise the freeze drying cycle for a model IgG monoclonal antibody (20 mg/mL) in sucrose and sucrose/glycine formulations, by reducing primary drying time. To study the impact of shelf temperature (Ts) and chamber pressure on product temperature (Tp), one conventional and five aggressive cycles were tested. Aggressive conditions during primary drying were achieved by increasing Ts from -20 degrees C (conventional cycle) to 30 degrees C, with chamber pressure set to 0.1 mbar, 0.2 mbar or 0.3 mbar. These combinations of Ts and chamber pressure resulted in Tp well above Tg', and in some cases, even above Tc, without causing macrocollapse. Other critical quality attributes of the products were also within the expected ranges, such as reconstitution time and residual water content. Physical stability was tested using size exclusion chromatography, dynamic light scattering, and micro-flow imaging. All of the lyophilised samples were exposed to stress and the intended storage conditions, with no impacts on the product seen. These data show that implementation of aggressive conditions for the investigated formulations is possible and can significantly contribute to the reduction of primary drying times by up to 54% (from 48 to 22 h) in comparison to conventional freeze-drying. PMID- 30006179 TI - Gastric fluid composition in a paediatric population: Age-dependent changes relevant for gastrointestinal drug disposition. AB - This work aimed to (i) expand the dataset on gastric fluid composition in the paediatric population (0-18 years old) and (ii) improve our understanding of age dependent changes in gastric fluid characteristics involved in gastrointestinal drug disposition. For this purpose, gastric fluids from preterm neonates, term neonates, infants, children and adolescents were collected during routine medical procedures. Gastric fluid constituents relevant for gastrointestinal drug disposition were characterized i.e., pH, osmolality and bile salts (concentration + composition). Differences in gastric fluid composition compared to adults were most prominent in neonates. In this context, the fact that neonates are rarely fasted due to frequent feedings should be taken into account during paediatric drug product development. It remains to be explored to what extent the observed variability and differences in gastric fluid characteristics within and between age groups translates to variability and/or differences in oral drug disposition. PMID- 30006180 TI - Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. AB - In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log Po/w values obtained by shake flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form. PMID- 30006181 TI - A high-sensitivity HPLC-ELSD method for HPMC-AS quantification and its application in elucidating the release mechanism of HPMC-AS based amorphous solid dispersions. AB - Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the most widely used polymers used in amorphous solid dispersions (ASD) for solubility and bioavailability enhancement of poorly water-soluble drugs. Once released from ASDs, HPMC-AS was often found to be highly effective in maintaining drug supersaturation, and this capability is dependent on the concentration and substitution types of this pH-dependent polymer. Therefore, accurate quantification of different grades of HPMC-AS allows us to better understand the release and supersaturation mechanisms of HPMC-AS based ASDs. Since previously reported analytical methods were unable to quantify HPMC-AS in a complex medium with enough sensitivity, we hereby developed a high-sensitivity HPLC-ELSD (evaporative light scattering detector) method with satisfactory specificity, linearity, accuracy and precision, to quantify HPMC-AS down to 20 MUg/mL in dissolution media, with the presence of various commonly used pharmaceutical excipients. With the assistance of this method, we compared the intrinsic dissolution rates (IDR) of both the drug and the polymer of posaconazole ASDs based on different types of HPMC-AS. We observed that: 1) For ASDs that were spray dried and uniformly mixed, drug and polymer released simultaneously into the medium with practically identical IDRs slower than the IDR of pure HPMC-AS; 2) For ASDs that were heterogeneously mixed, IDRs of the drug and polymer were significantly slower or faster than the IDRs of the drug and polymer of the uniform ASDs, respectively. In summary, the high sensitivity HPLC-ELSD method established here can be readily applied to quantify HPMC-AS in various dissolution media, thus helps to reveal the release kinetics and mechanisms of different HPMC-AS based ASDs. PMID- 30006183 TI - Community pharmacist-led intervention to identify persons with diabetes not on statin therapy. AB - OBJECTIVES: To demonstrate the effectiveness of a community pharmacist-led intervention to identify persons with diabetes not receiving statin therapy. SETTING: Five pharmacy locations within 1 district of a chain community pharmacy. PRACTICE DESCRIPTION: Walgreens Pharmacy is a national retail chain community pharmacy with global affiliations. Walgreens Pharmacy locations use clinical pharmacy services to provide complete quality patient care. PRACTICE INNOVATION: A pharmacist intervention workflow model and screening algorithm for the Centers for Medicare and Medicaid Services (CMS) Statin Use in Persons with Diabetes quality measure were developed to identify measure-eligible patients in a community pharmacy setting. This new measure was implemented within the Electronic Quality Improvement Platform for Plans and Pharmacies (EQuIPP) dashboard. The study aimed to demonstrate that community pharmacist intervention is effective for helping to close therapy gaps; the focus of this study was identifying patients who have diabetes but are not on statin therapy. EVALUATION: The primary outcome included the percentage of patients flagged for intervention by the pharmacist, and the secondary outcome included the number of statin prescriptions received for the measure-eligible intervention population. RESULTS: At study initiation, EQuIPP reported a total of 103 patients were SUPD measure eligible at the intervention pharmacies (combined). After the 90-day study duration, 29.1% (n = 30) of SUPD measure-eligible patients were identified with the use of the workflow intervention. From those identified, 40% (n = 12) gave verbal consent for the pharmacist to intervene with their physician, and of those, 58.3% (n = 7) received statin prescriptions. Pharmacy A increased their EQuIPP-based performance measure by 3.3%, Pharmacy B 4.2%, Pharmacy D 2.4%, and Pharmacy E 3.5%, and Pharmacy C decreased by 1.0%. CONCLUSION: Implementation of a community pharmacist-led identification process successfully identified SUPD measure-eligible patients. Community pharmacist-led intervention resulted in an increase in the number of statin prescriptions written for measure-eligible patients. PMID- 30006182 TI - Financial impact of patients enrolled in a medication adherence program at an independent community pharmacy. AB - OBJECTIVES: To determine the financial impact of attributed patients enrolled in a medication adherence program at Community Pharmacy Enhanced Services Network (CPESN) pharmacies. SETTING: Five independently owned Moose Pharmacy locations in rural North Carolina, which are CPESN pharmacies. PRACTICE DESCRIPTION: Moose Pharmacy has a longstanding history of innovative change. Each Moose Pharmacy location provides enhanced pharmacy services, including adherence packaging, medication synchronization programs, immunizations, home visits, home delivery, comprehensive medication review, disease state management programs, point-of-care testing, and compounding. PRACTICE INNOVATION: Certain CPESN pharmacies, including Moose Pharmacy, were attributed complex Medicare or Medicaid patients having at least 1 chronic medication and at least 80% of medications filled at a CPESN pharmacy. Patients were included if they were attributed to a study location and enrolled in the Moose Medication Adherence Program (MooseMAP) for more than 12 months. Patients were excluded if they were younger than 18 years of age or had less than 12 months of prescription fill data. Reviewed data included patient demographics, chronic and acute medications, immunizations, MooseMAP type, number of chronic medication prescribers, chronic medication class, payer, and patient health risk indicators. Yearly profit for prescriptions filled was determined per patient. Independent-samples t test was used to assess data. EVALUATION: Yearly profit per prescription was $10.35 for combined chronic, acute, and immunization prescriptions, $10.57 for chronic prescriptions, $26.95 for acute prescriptions, and $27.69 for immunizations. Mean profit for strip packaging was $1561.82 per year compared with $1208.01 per year with bottles (P = 0.021). There was a positive correlation between profit and number of prescriptions filled per 12 months (r = 0.56; P < 0.001), number of medication classes (r = 0.27; P < 0.001), and higher-risk indicator scores (r = 0.21; P < 0.001). CONCLUSION: Enrolling complex patients in a medication adherence program can benefit community pharmacies, particularly CPESN pharmacies, through chronic medication fills and yearly profit. Greater profit is generated when prescriptions are dispensed in strip packaging instead of bottles. PMID- 30006184 TI - Evaluating patient satisfaction with pharmacist-administered long-acting injectable antipsychotics in the community pharmacy. AB - OBJECTIVE: To evaluate patient satisfaction with pharmacist-administered long acting injectable antipsychotics (LAIAs) in the community pharmacy. DESIGN: Prospective survey. SETTING: Albertsons Companies community pharmacies during December 2016 to February 2017. PARTICIPANTS: Patients receiving LAIAs at participating pharmacies. MAIN OUTCOME MEASURES: A survey assessed patients' satisfaction with pharmacist-administered LAIAs in the community pharmacy. RESULTS: LAIA recipients (N = 104) reported satisfaction with community pharmacist-administered LAIAs. Participants who had received the service at other types of health clinics (N = 57) also reported higher satisfaction with current service compared to a similar service received elsewhere. Participants indicated that they would recommend service to others and that service was more convenient than a similar service received in an alternative setting. There was not a statistically significant relationship between patient demographic characteristics and likelihood of recommending service to others. CONCLUSION: Patients were satisfied with a pharmacist-administered LAIA service in the community pharmacy, and they found it more convenient than similar services provided elsewhere. PMID- 30006185 TI - Perspectives of athletes and pharmacists on pharmacist-provided sports supplement counseling: An exploratory study. AB - OBJECTIVES: To identify athletes' interests in receiving advice about sports supplements from a pharmacist in a supermarket setting and to identify pharmacists' knowledge, confidence, and enthusiasm for providing counseling on various sports supplements. METHODS: Two cross-sectional surveys were developed and administered. One survey was administered to athletes at local northwestern Ohio fitness facilities, and 1 survey was administered to pharmacists in chain pharmacies during mid-February to mid-March 2017. The athlete survey gathered demographic information, information sources, products purchased, including their location and selection factors, and perceptions of pharmacists providing sports supplement counseling. The pharmacist survey gathered demographic information; knowledge, confidence, and enthusiasm for providing sports supplement counseling; perceptions of counseling benefit; and barriers to implementation of providing a sports supplement counseling service. RESULTS: The athlete survey had 129 participants. Athletes primarily reported obtaining sports supplement information from supplement stores, and only 2% indicated using a pharmacist. Although 52% said they would talk to a pharmacist about sports supplements, 66% said their perception of a pharmacist's fitness level would influence whether or not they would approach him or her. The pharmacist survey had 143 participants. On a 5 point Likert-type scale (1 = strongly disagree and 5 = strongly agree), the mean (SD) of their knowledge, confidence, and enthusiasm statements were 2.49 (0.89); 2.61 (0.94); and 3.54 (0.87), respectively. Ninety-two percent (n = 130) of pharmacists thought it would be beneficial to provide counseling on sports supplements. Perceived barriers included lack of knowledge, evidence, and time. CONCLUSION: Pharmacists were not identified as a primary resource for sports supplements, but athletes would be willing to discuss this topic with knowledgeable and physically fit pharmacists. Pharmacists felt that they lacked knowledge and confidence regarding sports supplement products but noted enthusiasm to provide counseling. Sports pharmacy counseling could be a viable expansion of pharmacy services in community pharmacies with proper education and tools. PMID- 30006186 TI - Community-based pharmacy residents: Transforming the health care landscape. PMID- 30006187 TI - Identifying barriers to dispensing naloxone: A survey of community pharmacists in North Carolina. AB - OBJECTIVES: The primary objective of this study was to identify barriers to dispensing naloxone under the North Carolina statewide standing order in the community pharmacy setting. Secondary objectives included identifying areas for additional training. METHODS: This study was conducted as a cross-sectional survey distributed to community pharmacists in North Carolina through an Internet based questionnaire platform. The questions assessed pharmacists' training regarding naloxone, willingness to dispense naloxone, knowledge of naloxone and opioid overdose, perceived barriers to implementing a naloxone distribution program, and demographic information. Descriptive statistics and Pearson correlation coefficient were used in data analysis. RESULTS: Only 30% of survey respondents scored greater than 90% on the knowledge assessment portion of the survey. Furthermore, more than 50% of respondents indicated that they were not very comfortable dispensing naloxone, based on their responses to a series of Likert-type scale statements. A statistically significant positive correlation (r = 0.288; P < 0.001) was found between pharmacists' knowledge of naloxone and opioid overdose and willingness to dispense naloxone. The majority of respondents indicated that lack of training was a major barrier to dispensing naloxone. Additional training needs included information regarding naloxone, strategies to initiate patient discussion, identifying eligible patients, and workflow implementation. More than 95% of respondents indicated that the pharmacy in which they are employed would benefit from additional naloxone training. CONCLUSION: Community pharmacists in North Carolina would like to receive additional training regarding naloxone and opioid overdose. Given the statistically significant positive correlation between knowledge concerning naloxone and opioid overdose and willingness to dispense naloxone, it is possible that increased pharmacist training could lead to increased willingness to dispense naloxone under the statewide standing order. These results can be used in a meaningful way to determine the best ways to better educate pharmacists on naloxone and improve patient access to this life-saving medication. PMID- 30006188 TI - Patient awareness, willingness, and barriers to point-of-care hepatitis C screening in community pharmacy. AB - OBJECTIVES: To determine patients' awareness of the screening recommendations for hepatitis C virus (HCV) in "Baby Boomers," to assess patients' willingness to receive a point-of-care HCV screening test in the pharmacy, and to determine patients' barriers to receiving a point-of-care HCV screening test in a community pharmacy. METHODS: An anonymous 12-question survey was developed. Five shareholder pharmacies of American Pharmacy Services Corporation (APSC) volunteered to participate. Surveys were mailed to participating pharmacies with instructions to distribute to patients born in 1945 to 1965 at the pharmacy point of-sale. Data were collected over a 12-week period from October 2016 to January 2017. Completed surveys were collected by participating pharmacies and mailed to the primary investigator. Data were analyzed with the use of descriptive statistics. RESULTS: Ninety-five eligible surveys were returned and analyzed. A majority of respondents were female (63.00%) and held a bachelor degree or higher (63.16%); 38.95% of patients were aware of HCV age-based risk factors and screening recommendations. Only 9.80% of patients were aware of the fingerstick point-of-care testing (POCT) option for HCV. Nearly three-fourths (71.70%) were willing to receive POCT at a community pharmacy. A majority of patients (65.52%) were unwilling to pay an amount that would cover the cost of testing. Descriptive statistics, including a Pearson chi-square test, were used to analyze the data. Significant differences in the distribution of the percentages of people willing to receive testing and to pay for testing were found among levels of annual household income. CONCLUSION: A majority of patients are willing to receive POCT at a community pharmacy. Patients were unwilling to pay for testing, however, so pharmacies looking to offer point-of-care HCV screening would need to secure further financial resources, such as insurance reimbursement or grant funding, for this service to be financially feasible. PMID- 30006189 TI - Public attitudes and beliefs about Virginia community pharmacists dispensing and administering naloxone. AB - OBJECTIVES: To determine awareness concerning naloxone and perceived severity of opioid overdose, to identify attitudes and beliefs concerning naloxone, and to assess perceived benefits and barriers related to naloxone dispensed and administered by community pharmacists. METHODS: The project was conducted in 3 phases. Phase 1 consisted of survey development and pretesting to identify unclear questions. The survey used principles of the health belief model, focusing on perceived severity of opioid overdose, perceived barriers and benefits to community pharmacists dispensing and administering naloxone, naloxone awareness, sources of health information, and attitudes and beliefs about naloxone. Question types were 5-point Likert response scale with several multiple choice and dichotomous questions. In phase 2, the paper-based survey was distributed to adults in the Richmond area from December 2016 to June 2017. Phase 3 consisted of data analysis using descriptive statistics. RESULTS: One hundred twenty-nine individuals with a mean age of 35.4 years (56.7% male and 44.4% white) completed the survey. Opioid overdose was identified as a serious problem in the Richmond area and the United States by 71.9% and 81.3% of respondents, respectively. Among respondents, 39.5% had heard of naloxone before the survey. Most respondents were comfortable with a community pharmacist dispensing and administering naloxone (66.4% and 64.0%, respectively). Of the 31 respondents who were not comfortable with pharmacists dispensing or administering naloxone, 18 respondents identified promoting drug abuse and misuse and 12 respondents identified promoting reckless behavior as a perceived barrier. CONCLUSIONS: While most survey respondents were not aware of naloxone before completing the survey, the majority were in favor of community pharmacists in Virginia dispensing and administering naloxone. The most commonly identified concern is that pharmacists dispensing naloxone would promote drug abuse and misuse, which should be addressed with patient education. PMID- 30006190 TI - Care team perspectives on community pharmacy enhanced services. AB - OBJECTIVES: To determine the awareness, collaboration, and perceived values and barriers of enhanced pharmacy services from care managers and primary care practice responders. METHODS: An electronic questionnaire was sent to 1648 primary care practices and 600 care managers that work in 76 North Carolina counties containing an enhanced-service community pharmacy. Questionnaires were distributed in January 2017 and responses collected for 7 weeks. The questionnaire collected data on the awareness and perceived value of enhanced pharmacy services, preferred method and level of communication for referral, and barriers to using enhanced services. Data were gathered with the use of Likert type, rank-order, dichotomous, and multiple-choice questions. Data were analyzed with the use of descriptive statistics, and group mean responses were compared by means of t tests. RESULTS: Data analysis was performed in March 2017. Response rates were 5.4% (n = 89) from practice responders and 45% (n = 270) from care managers. In the responses received, 35% of practice responders and 88% of care managers were familiar with enhanced services offered by community pharmacies. A majority of respondents thought that enhanced pharmacy services are valuable, with more than 85% of practice responders agreeing that partnering with an enhanced-service pharmacy can help to improve patient health outcomes. Lack of knowledge of enhanced-service pharmacies, services offered, and the referral process were identified as significant barriers for practice responders. CONCLUSION: Community-based pharmacies have an opportunity to collaborate with patient-centered medical home teams to provide enhanced pharmacy services, but provider outreach and education on enhanced services offered and the referral process are necessary to maximize this collaboration. PMID- 30006191 TI - Pharmacists' comfort level and knowledge about prescribing hormonal contraception in a supermarket chain pharmacy. AB - OBJECTIVES: To compare community pharmacists' comfort levels and knowledge prescribing hormonal contraception before and after a training session and to identify perceived barriers and resources needed to prescribe hormonal contraception. METHODS: In this pre-post convenience sample survey study, all 350 pharmacists in the Mid-Atlantic Division of Kroger (which spans parts of Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia) were surveyed before and after a training session. The survey consisted of several sections: 1) questions rating comfort, 2) knowledge-based multiple-choice assessment questions, 3) perceptions of barriers and resources needed to prescribe hormonal contraception, and 4) demographics. The training session was a 1-hour continuing education about hormonal contraception. Data were analyzed with the use of univariate and bivariate statistics to compare pre- and post-training survey information. RESULTS: Seventy-eight pharmacists completed both surveys (22.3% response rate). Pharmacists averaged 14 years in pharmacy practice, and 66.6% were female. More pharmacists (31.8%) perceived liability concern as the greatest barrier to pharmacist-initiated contraception. Pharmacist knowledge about hormonal contraception increased in some domains after the training session (P < 0.001). If allowed as a scope of practice in their state, the comfort level of pharmacists in prescribing any type of hormonal contraceptive significantly increased after the training session (P < 0.004). CONCLUSION: Pharmacists have an initial lack of knowledge and perceived lack of comfort with prescribing hormonal contraception if allowed in their state of practice. A training session was identified as an effective tool and intervention to increase pharmacists' comfort levels in prescribing hormonal contraception. PMID- 30006192 TI - Serum 25-hydroxyvitamin D and bone mineral density among children and adolescents in a Northwest Chinese city. AB - Although vitamin D is essential for bone health, little is known about prevalence of vitamin D deficiency and low bone mineral density (BMD) among children, especially those in developing countries. It also remains unclear whether serum 25-hydroxyvitamin D [25(OH)D] is associated with BMD among children. We investigated these questions among children and adolescents in Yinchuan (latitude: 38 degrees N), Ningxia, an economically underdeveloped province in Northwest China. A total of 1582 children (756 boys and 826 girls), aged 6-18 years, were recruited from schools using the stratified random sampling method in fall 2015. Serum 25(OH)D concentrations were measured by enzyme-linked immunosorbent assay, and BMD was quantified by dual-energy X-ray absorptiometry. Vitamin D deficiency (defined as serum 25(OH)D <= 37.5 nmol/L) was present in 35.5% of study subjects. There were no clear patterns of differences in serum 25(OH)D concentrations across the four age groups compared (6-9 years, 10-13 years, 14-16 years, and 17-18 years). The prevalence of low total body less head (TBLH) BMD (defined as a Z-score of <= -2.0 standard deviations away from the mean BMD values of the Chinese pediatric reference population) among children examined was 1.8% and was not significantly different among the four age groups considered. Linear regression analysis revealed that age, weight, and height were significantly and positively associated with TBLH BMD and that the strongest determinant of TBLH BMD was age in boys and weight in girls. There were no significant correlations between serum 25(OH)D concentrations and BMD obtained for total body and at various skeletal sites (r ranged from -0.005 to 0.014) regardless of whether children evaluated were sufficient, insufficient, or deficient in vitamin D. In conclusion, more than one-third of children and adolescents in a Northwest Chinese city were deficient in vitamin D but only <2% of them developed low BMD. PMID- 30006193 TI - Pharmacological intervention of liver triacylglycerol lipolysis: The good, the bad and the ugly. AB - Excessive triacylglycerol (TG) accumulation is the distinctive feature of obesity. In the liver, sustained TG accretion leads to nonalcoholic fatty liver disease (NAFLD), eventually progressing to non-alcoholic steatohepatitis (NASH) and cirrhosis, which is associated with complications including hepatic failure, hepatocellular carcinoma and death. Pharmacological interventions are actively pursued to prevent lipid accumulation in hepatocytes and, therefore, to ameliorate the associated pathophysiological conditions. Here, we sought to provide an overview of the pharmacological approaches to up- or downregulate the expression and activities of the enzymes involved in hepatic TG hydrolysis. Fatty acids (FA) released by hydrolysis of hepatic TG can be used for beta-oxidation, signaling, and for very low-density lipoprotein (VLDL)-TG synthesis. Originally, lipolysis was believed to be centered in the adipose and to be catalyzed by only two lipases, hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MAGL). However, genetic ablation of HSL expression in mice failed to erase TG hydrolysis in adipocytes leading to the identification of a third lipase termed adipose triglyceride lipase (ATGL). Although these three enzymes are considered to be the main players governing lipolysis in the adipocyte, other lipolytic enzymes have been described to contribute to hepatic TG metabolism. These include adiponutrin/patatin-like phospholipase domain containing 3 (PNPLA3), some members of the carboxylesterase family (CES/Ces), arylacetamide deacetylase (AADAC), lysosomal acid lipase (LAL) and hepatic lipase (HL). This review highlights the consequences of pharmacological interventions of liver lipases that degrade TG in cytosolic lipid droplets, in the endoplasmic reticulum, in the late endosomes/lysosomes and along the secretory route. PMID- 30006194 TI - EB-3D a novel choline kinase inhibitor induces deregulation of the AMPK-mTOR pathway and apoptosis in leukemia T-cells. AB - Choline kinase alpha 1 (ChoKalpha1) has recently become an interesting therapeutic target since its overexpression has been associated to tumorigenesis in many cancers. Nevertheless, little is known regarding hematological malignancies. In this manuscript, we investigated the effect of a novel and selective ChoKalpha inhibitor EB-3D in T acute lymphoblastic leukemia (T-ALL). The effect of EB-3D was evaluated in a panel of T-leukemia cell lines and ex-vivo primary cultures derived from pediatric T-ALL patients. We also evaluated in detail, using Reverse Phase Protein Array (RPPA), protein phosphorylation level changes in T-ALL cells upon treatment. The drug exhibits a potent antiproliferative activity in a panel of T-leukemia cell lines and primary cultures of pediatric patients. Moreover, the drug strongly induces apoptosis and more importantly it enhanced T-leukemia cell sensitivity to chemotherapeutic agents, such as dexamethasone and l-asparaginase. In addition, the compound induces an early activation of AMPK, the main regulator of cellular energy homeostasis, by its phosphorylation at residue T712 of catalytic subunit alpha, and thus repressing mTORC1 pathway, as shown by mTOR S2448 dephosphorylation. The inhibition of mTOR in turn affects the activity of several known downstream targets, such as 4E-BP1, p70S6K, S6 Ribosomal Protein and GSK3 that ultimately may lead to a reduction of protein synthesis and cell death. Taken together, our findings suggest that targeting ChoKalpha may be an interesting option for treating T-ALL and that EB-3D could represent a valuable therapeutic tool. PMID- 30006195 TI - Prevalence and Incidence of Immune Thrombocytopenia in Patients With Prostate Cancer. PMID- 30006196 TI - Congenital Absence of Left Coronary Artery Accompanied by Premature Ventricular Complexes. PMID- 30006197 TI - Metabolic aspects of neuronal degeneration: From a NAD+ point of view. AB - Cellular metabolism maintains the life of cells, allowing energy production required for building cellular constituents and maintaining homeostasis under constantly changing external environments. Neuronal cells maintain their structure and function for the entire life of organisms and the loss of neurons, with limited neurogenesis in adults, directly causes loss of complexity in the neuronal networks. The nervous system organizes the neurons by placing cell bodies containing nuclei of similar types of neurons in discrete regions. Accordingly, axons must travel great distances to connect different types of neurons and peripheral organs. The enormous surface area of neurons makes them high-energy demanding to keep their membrane potential. Distal axon survival is dependent on axonal transport that is another energy demanding process. All of these factors make metabolic stress a potential risk factor for neuronal death and neuronal degeneration often associated with metabolic diseases. This review discusses recent findings on metabolic dysregulations under neuronal degeneration and pathways protecting neurons in these conditions. PMID- 30006198 TI - Acute polyradiculoneuritis revealing Behcet's disease. PMID- 30006200 TI - Evidence for an effect of landscape connectivity on Borrelia burgdorferi sensu stricto dispersion in a zone of range expansion. AB - In North America, different strains of the Lyme disease-causing bacterium Borrelia burgdorferi sensu stricto cluster into phylogenetic groups that are associated with different levels of pathogenicity and, for some, specific rodent reservoir hosts. Here we explore whether landscape connectivity, by impacting host dispersal, influences B. burgdorferi s.s. spread patterns. This question is central to modelling spatial patterns of the spread of Lyme disease risk in the zone of northward range-expansion of B. burgdorferi s.s. in southeastern Canada where the study was conducted. We used multi-locus sequence typing (MLST) to characterise B. burgdorferi s.s. in positive ticks collected at 13 sites in southern Quebec, Canada during the early stages of B. burgdorferi s.s. invasion. We used mixed effects logistic regression to investigate whether landscape connectivity (probability of connectivity; PC) affected the probability that samples collected at different sites were of the same strain (MLST sequence type: ST). PC was calculated from a habitat map based on high spatial resolution (15 m) Landsat 8 imagery to identify woodland habitat that are preferred by rodent hosts of B. burgdorferi s.s. There was a significant positive association between the likelihood that two samples were of the same ST and PC, when PC values were grouped into three categories of low, medium and high. When analysing data for individual STs, samples at different sites were significantly more likely to be the same when PC was higher for the rodent-associated ST1. These findings support the hypothesis that dispersion trajectories of B. burgdorferi s.s. in general, and some rodent-associated strains in particular, are at least partly determined by landscape connectivity. This may suggest that dispersion of B. burgdorferi s.s. is more common by terrestrial mammal hosts (which would likely disperse according to landscape connectivity) than by birds, the dispersal of which is likely less constrained by landscape. This study suggests that accounting for landscape connectivity may improve model-based predictions of spatial spread patterns of B. burgdorferi s.s. The findings are consistent with possible past dispersal patterns of B. burgdorferi s.s. as determined by phylogeographic studies. PMID- 30006199 TI - Volume of the Human Hippocampus and Clinical Response Following Electroconvulsive Therapy. AB - BACKGROUND: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome. METHODS: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice. RESULTS: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 +/- 2.2%, d = 1.5; right unilateral, 1.6 +/- 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 +/- 1.7%, d = 1.8; right unilateral, 2.7 +/- 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Asberg Depression Rating Scale change 1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069). CONCLUSIONS: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome. PMID- 30006201 TI - Factors associated with hard tick (Acari: Ixodidae) parasitism in medium-sized mammals in the Atlantic Rainforest region of Argentina. AB - Associations with environmental and host parameters were assessed to describe tick parasitism patterns in two medium-sized mammals of the Atlantic rainforest region of Argentina. Ticks found on 93 specimens of Nasua nasua and 26 specimens of Didelphis aurita captured at six sites in the Iguazu National Park were collected. Generalized linear models were constructed to explain the presence and abundance of ticks and the most appropriate ones were selected after stepwise simplification. The season, site and host body mass variables were important to explain the abundance of Amblyomma coelebs nymphs, while site was important to describe larval abundance of this species. Season was the most important variable for larvae and nymphs of Haemaphysalis juxtakochi, while Amblyomma brasiliense nymphs were associated with host age. Amblyomma ovale larvae were related to host age, and adult ticks with host sex. The results indicate that these medium-sized mammals are important to support the immature tick stages and that both host and environmental factors may be associated with parasite loads. PMID- 30006202 TI - Intracorporeal Biventricular Assist Device Therapy in an 8-Year-Old Child. PMID- 30006203 TI - Conversion of Left- to a Right-Sided Aortic Arch: A Radical Approach for Select Indications. AB - Thoracic aortic graft infections, anomalous arch anatomy, and vascular rings may cause tracheal and/or esophageal compression. These circumstances often create challenging clinical dilemmas such that anatomical repair either does not eliminate the pathologic process completely or poses a measurable risk of recurrence. We describe a novel approach that facilitates complete relocation of the thoracic aorta to either prevent graft placement in an infected field or prevent tracheal and/or esophageal compression that effectively converts left sided to right-sided arch anatomy. PMID- 30006204 TI - Outcome of Percutaneous Radiofrequency Thoracic Sympathectomy for Palmar Hyperhidrosis. AB - The impact of upper thoracic percutaneous sympathectomy with radiofrequency on the quality of life (QOL) of patients with palmar hyperhidrosis was evaluated. Thirty-six patients with palmar hyperhidrosis were selected for a prospective observational study. Treatment consisted of percutaneous radiofrequency thoracic sympathectomy of T3 and T4 ganglions in all cases. QOL questionnaires were applied preoperatively, on the 1st postoperative (PO) day, and on the 30th, 90th, 180th, and 360th PO days. Furthermore, compensatory hyperhidrosis (HDSSc) scale measures were used simultaneously, in order to evaluate the rate and frequency of this side effect. The QOL questionnaire evaluation showed preoperative values of 83.94 +/- 4.74 (meaning poor quality of life), decreasing to 24.61 +/- 2.86 on the 1st PO day, 25.14 +/- 3.12 on the 30th PO day, 31.28 +/- 4.42 on the 90th PO day, 32.97 +/- 4.54 on the 180th PO day, and 33.94 +/- 4.6 on the 360th PO day (all postoperative results with values below 35 were considered optimal). Compensatory hyperhidrosis (HDSSc) scale values were 1.14 +/- 0.35 on the 1st PO day, 1.42 +/- 0.55 on the 30th PO day, 1.83 +/- 0.85 on the 90th PO day, 1.92 +/- 0.91 on the 180th PO day, and 1.92 +/- 0.91 on the 360th PO day (meaning that hyperhidrosis was mainly unnoticed). Patients' subjective satisfaction was considered very good and the majority of patients would recommend the treatment procedure. Percutaneous radiofrequency thoracic sympathectomy had a positive impact on the quality of life of patients with palmar hyperhidrosis, compared to the surgical treatment, with a low rate and intensity of HDSSc and without other complications. PMID- 30006206 TI - Erratum. PMID- 30006205 TI - Erratum. PMID- 30006207 TI - Erratum. PMID- 30006208 TI - Electrophysiological interrogation of asymmetric droplet interface bilayers reveals surface-bound alamethicin induces lipid flip-flop. AB - The droplet interface bilayer (DIB) method offers simple control over initial leaflet compositions in model membranes, enabling an experimental path to filling gaps in our knowledge about the interplay between compositional lipid asymmetry, membrane properties, and the behaviors of membrane-active species. Yet, the stability of lipid leaflet asymmetry in DIBs has received very little attention, particularly in the presence of peptides and ion channels that are often studied in DIBs. Herein, we demonstrate for the first time parallel, capacitance-based measurements of intramembrane potential with arrays of asymmetric DIBs assembled in a microfluidic device to characterize the stability of leaflet asymmetry over many hours in the presence and absence of membrane-active peptides. DIBs assembled from opposing monolayers of the ester (DPhPC) and ether (DOPhPC) forms of diphytanoyl-phosphatidylcholine yielded asymmetric bilayers with leaflet compositions that were stable for at least 18 h as indicated by a stable |137 mV| intramembrane potential. In contrast, the addition of surface-bound alamethicin peptides caused a gradual, concentration-dependent decrease in the magnitude of the dipole potential difference. Intermittent current-voltage measurements revealed that alamethicin in asymmetric DIBs also shifts the threshold voltage required to drive peptide insertion and ion channel formation. These outcomes take place over the course of 1 to 5 h after membrane formation, and suggest that alamethicin peptides promote lipid flip-flop, even in the un-inserted, surface bound state, by disordering lipids in the monolayer to which they bind. Moreover, this methodology establishes the use of parallel electrophysiology for efficiently studying membrane asymmetry in arrays of DIBs. PMID- 30006209 TI - The relation between gain in cognition during rehabilitation on functional outcome among hip fracture adult patients with and without pre- hip fracture dementia. AB - The purpose of the present study was focused on the relationship between change in cognition and the functional outcome during rehabilitation in demented and non demented adult hip fracture patients. We studied seventy consecutive adult patients with hip fracture admitted to our rehabilitation wards. Functional outcome was assessed by the Functional Independence Measure (FIM). The gain in cognition during the rehabilitation process was measured by the difference in Mini Mental State Examination scores at admission and discharge. Data was analyzed by t-test, chi square-test and linear regression. Patients without dementia presented and discharged from the rehabilitation ward with statistically significant higher total, motor, and gain functional independence measure scores compared to patients with dementia. In a multiple regression analyses, gain in Mini Mental State scores examination were not independently associated with higher total and motor functional independence measure scores at discharge (beta = 0.086, p = 0.194; beta = 0.077, p = 0.309, respectively). Our findings suggest that there is no association between functional outcome and cognitive gain at the end of the rehabilitation process among adult hip fracture patients with and without dementia. However hip fracture adult patients with dementia should not be deprived of a post-acute rehabilitation. PMID- 30006210 TI - Does negative information about aging influence older adults' physical performance and subjective age? AB - This study investigated the way negative stereotypes influence older adults' physical performance and how old they feel mentally and physically. Sixty-four older adults aged 65 years and older performed different physical tasks using a 3D optoelectronic system under a low or high stereotype threat condition. Self perceptions of aging were considered as a moderator of the effects of threat. Overall, the effects of threat on physical performance were mostly not significant across tasks. However, threat condition influenced older adults' mental subjective age after they had performed the physical tests; people in the high-threat condition felt closer to their chronological age. Threat also influenced participants' physical subjective age, and this effect was moderated by self-perceptions of aging. More precisely, participants in the high-threat condition felt 7% physically older than their chronological age when they had more negative self-perceptions, while participants in the low-threat condition felt 13% younger. No differences emerged for participants who had more positive self-perceptions. The present findings suggest that performing physical tests under stereotype threat might worsen older people's subjective experience of their own aging by making them feel older. PMID- 30006211 TI - Changes in objectively measured outdoor time and physical, psychological, and cognitive function among older adults with cognitive impairments. AB - BACKGROUND: Older adults with cognitive impairment are at higher risk for various health problems. Although previous studies have suggested going outdoors more frequently might be effective to promote health, no longitudinal studies have examined objectively measured outdoor time in this population. This study examined the relationships between changes in objectively measured outdoor time and physical, psychological, and cognitive functions among older adults with cognitive impairments. METHODS: This study was a secondary analysis of a randomized controlled trial (n = 145). The baseline and 1-year follow-up data of outdoor time per day measured by the global positioning system, physical functions (6-minute walk test, 5-repetition chair stand test), psychological functions (Geriatric Depression Scale, simplified World Health Organization Five Well-being Index), and cognitive functions (tablet versions of the Trail-making Test, Symbol Digit Substitution Test, Word Memory Test, Story Memory Test) were used. RESULTS: Multiple regression analyses revealed that changes in outdoor time were significantly associated with changes in 6-minute walk (standardized beta = 0.20, p = 0.048) and 5-repetition chair stand tests (standardized beta = -0.19, p = 0.032) after adjusting for baseline data, basic factors, and trial allocation. However, significant relationships between changes in outdoor time and psychological and cognitive functions were not revealed. CONCLUSIONS: The results indicate that maintaining or increasing outdoor time would be effective to prevent declines in physical functions but that a quantitative aspect of going outdoors would have limited impact on psychological and cognitive functions among older adults with cognitive impairment. PMID- 30006212 TI - Place of death and associated gender difference in Korea 2006-2014: Evidence from exit interviews of the Korean Longitudinal Study of Ageing. AB - Previous research has revealed that many people wish to die at home; however, most die in healthcare institutions. This study explored factors related to the place of death and gender differences in this regard among older adults in South Korea. Participants included older adults from the Korean Longitudinal Study of Ageing. Multinomial logistic regression was used to examine relationships between place of death and relevant factors. Most older adults died in hospitals, followed by at home and in assisted living residences. Hospital and assisted living residence deaths increased while home deaths decreased. In both men and women, higher daily living dependency increased the probability of dying in an assisted living residence. Women were more likely to die in assisted living residences than men, and for persons living in urban areas, there was a decreased likelihood of home death only in women. Findings support that end-of-life care is performed mostly by institutions in Korea and there are gendered patterns. To achieve aging in place, the place of death and community-based terminal care should be more considered when implementing long-term care policies. PMID- 30006213 TI - High-Frequency Micro-Ultrasound Imaging and Optical Topographic Imaging for Spinal Surgery: Initial Experiences. AB - High frequency micro-ultrasound (uUS) transducers with central frequencies up to 50 MHz facilitate dynamic visualization of patient anatomy with minimal disruption of the surgical work flow. Micro-ultrasound improves spatial resolution over conventional ultrasound imaging from millimeter to micrometer, but compromises depth penetration. This trade-off is sufficient during an open surgery in which the bone is removed and theultrasound probe can be placed into the surgical cavity. By fusing uUS with pre-operative imaging and tracking the ultrasound probe intra-operatively using our optical topographic imaging technology, we can provide dynamic feedback during surgery, thus affecting clinical decision making. We present our initial experience using high-frequency uUS imaging during spinal procedures. Micro-ultrasound images were obtained in five spinal procedures. Medical rationale for use of uUS was provided for each patient. Surgical procedures were performed using the standard clinical practice with bone removal to facilitate real-time ultrasound imaging of the soft tissue. During surgery, the uUS probe was registered to the pre-operative computed tomography and magnetic resonance images. Images obtained comprised five spinal decompression surgeries (four tumor resections, one cystic synovial mass). Micro ultrasound images obtained during spine surgery delineated exquisite detailing of the spinal anatomy including white matter and gray matter tracts and nerve roots and allowed accurate assessment of the extent of decompression/tumor resection. In conclusion, tracked uUS enables real-time imaging of the surgical cavity, conferring significant qualitative improvement over conventional ultrasound. PMID- 30006215 TI - Functionally generated path technique to fabricate a crown in group function on a deciduous maxillary canine. PMID- 30006214 TI - Evaluation of Gastric Emptying by Transabdominal Ultrasound after Oral Administration of Semisolid Cellulose-Based Gastric Ultrasound Contrast Agents. AB - Many previous studies have found that transabdominal ultrasound may allow precise measurement of gastric emptying of liquid meals. However, the clinical use of this technique has been hampered by the limitation that transabdominal ultrasound might not accurately measure gastric emptying of solid meals. It is more important to measure gastric emptying of solids instead of liquids, as gastric emptying of solids is more often delayed than gastric emptying of liquids in gastric motility disorders. Recently, transabdominal ultrasound after oral administration of a cellulose-based gastric contrast agents (TUS-OSCA) has been suggested to be effective in initial screening of gastric lesions. The aim of this study was to explore the accuracy of TUS-OSCA in the evaluation of gastric emptying of a semisolid meal. Twenty healthy young patients (10 males and 10 females aged 25.5 +/- 2.5 y) were studied. Concurrent measurements of gastric emptying by scintigraphy and TUS-OSCA were performed after ingestion of 350 mL semisolid ultrasound agent labeled with 20 MBq 99mTc-sulfur colloid. There was no significant difference in the overall curves for gastric emptying time between scintigraphy and TUS-OSCA. There was a good correlation between the gastric 50% emptying times determined by scintigraphy (89.4 +/- 1.8 min) and TUS-OSCA (92.5 +/- 1.7 min). The correlation coefficient was r = 0.922 (p = 0.000). Current results indicate that TUS-OSCA is accurate, and the results are similar to those obtained by scintigraphy for gastric emptying of a semisolid meal. PMID- 30006216 TI - Effect of mucostatic and selective pressure impression techniques on residual ridge resorption in individuals with different bone mineral densities: A prospective clinical pilot study. AB - STATEMENT OF PROBLEM: Although different impression techniques have been advocated for complete denture prosthodontics, objective studies that predict their effect on alveolar bone resorption are lacking. PURPOSE: The purpose of this prospective clinical pilot study was to objectively evaluate the effect of complete dentures fabricated by different impression techniques on mandibular residual ridge resorption in individuals with different bone mineral density. MATERIAL AND METHODS: Ninety-six participants with edentulism, selected according to inclusion criteria, underwent bone mineral density assessment and were divided into normal, osteopenic, and osteoporotic groups. Half of the participants in each group were provided with dentures fabricated by selective pressure impression technique (subgroup SIT), and the other half were provided with dentures fabricated by mucostatic impression technique (subgroup MIT). Computed tomographic scans of the mandible were made at denture delivery and 1 year after prosthesis use to assess alveolar bone height and width difference at marked locations at and after denture delivery. The data obtained were analyzed with the Student t test (alpha=.05). RESULTS: Significantly less reduction in mandibular ridge height and width was found in the MIT versus the SIT subgroups in both osteopenic and osteoporotic participants (P<.05). No significant subgroup difference was found for normal bone mineral density group, although resorption increased in height and width for the SIT subgroup. CONCLUSIONS: Mandibular residual ridge resorption was reduced for dentures fabricated using the mucostatic impression technique compared with the selective pressure impression technique in individuals with diminished bone density. PMID- 30006217 TI - Assessment of the trueness and tissue surface adaptation of CAD-CAM maxillary denture bases manufactured using digital light processing. AB - STATEMENT OF PROBLEM: Limited information is available evaluating the trueness and tissue surface adaptation of computer-aided design and computer-aided manufacturing (CAD-CAM) maxillary denture bases fabricated using digital light processing (DLP). PURPOSE: The purpose of this in vitro study was to evaluate the trueness of DLP-fabricated denture bases and to compare the tissue surface adaptation of DLP with milling (MIL) and pack and press (PAP). MATERIAL AND METHODS: The maxillary denture bases were virtually designed on the reference cast and were fabricated using DLP and MIL. Their intaglio surfaces were scanned and superimposed on the reference computer-aided design denture base to evaluate the trueness. A total of 20 denture bases (10 per technique) were also fabricated on the duplicated master casts using DLP and MIL. Ten denture bases were additionally made using PAP. The intaglio surfaces of the dentures were scanned and superimposed on the corresponding casts to compare the degree of tissue surface adaptation among the 3 techniques. The Mann-Whitney test and Kruskal Wallis ANOVA were used for statistical analyses (alpha=.05). RESULTS: The trueness of the DLP denture base was significantly better than that of the MIL denture base (P<.001). Statistically significant differences were detected with respect to tissue surface adaptation of the denture base among the groups (P<.001). The DLP denture base showed the best denture base fit among the 3 techniques with a small interquartile range. CONCLUSIONS: Within the limitations of this in vitro study, the DLP maxillary denture base showed better trueness and tissue surface adaptation of <=100 MUm of the 3-dimensional surface deviation than the MIL and PAP denture bases. PMID- 30006218 TI - Implant placement for patients with cleft lip and palate: A clinical report and guidelines for treatment. AB - The multidisciplinary teams involved in the treatment of individuals with cleft lip and palate are challenged when implants are indicated in the cleft area. Difficulties include obtaining a healthy peri-implant area and, especially, obtaining the natural-looking papilla essential for esthetic success. The area affected by the cleft has a bone deficiency, which is typically augmented with an alveolar bone graft at adolescence. Guidelines for the 3-dimensional placement of implants at the cleft area are presented based on clinical reports. The patients were followed up for at least 1 year. Adoption of the proposed guidelines enables satisfactory esthetic and functional outcomes in patients with cleft lip and palate. PMID- 30006219 TI - Discrepancy of complete-arch titanium frameworks manufactured using selective laser melting and electron beam melting additive manufacturing technologies. AB - STATEMENT OF PROBLEM: Titanium frameworks for implant-supported prostheses can be additively manufactured using different powder-based fusion technologies, including selective laser melting (SLM) and electron beam melting (EBM). Some manufacturers have developed a technique that combines the printing of the framework with the subsequent machining of the implant interface. Whether these technologies produce frameworks with acceptable accuracies is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the discrepancy obtained from the digitizing procedures of the definitive cast, the implant-prosthesis discrepancy, and the distortion of the manufacturing processes in the fabrication of titanium frameworks for implant-supported complete-arch prostheses manufactured using SLM and EBM additive manufacturing technologies. MATERIAL AND METHODS: A completely edentulous mandibular definitive cast with 4 implant analogs and a replica of a screw-retained interim restoration was obtained. A standard tessellation language (STL) file of the framework design was prepared using dental software (Exocad). Six frameworks were manufactured using either SLM (3D Systems) or EBM (Arcam) technologies. Discrepancy (MUm) was measured at the x (mesiodistal), y- (buccolingual), and z- (occlusogingival) axes by using the formula 3D=x2+y2+z2 three times by best-fit superimposure of the definitive cast STL file, the definitive cast titanium framework, and the framework STL file by using a coordinate measuring machine (CMM) controlled by software (Geomagic). The Kruskal-Wallis and Mann-Whitney U statistical tests were used (alpha=.05). RESULTS: The digitizing procedures of the definitive cast showed a mean accuracy of 3 +/-3 MUm. Except for the z-axis (P<.05), no significant differences were observed between the SLM and EBM technologies for implant prosthesis discrepancy for the x- or y-axis (P>.05). The most favorable results were obtained in the z axis, representing the occlusogingival direction. Three-dimensional discrepancy measurements in all comparisons ranged between (60 +/-18 MUm and 69 +/-30 MUm) and were not statistically significant (P>.05). The highest discrepancy was observed in the y-axis (37 to 56 MUm), followed by the x- (16 to 44 MUm) and z- (6 to 11 MUm) axes (P<.05). CONCLUSIONS: The titanium frameworks analyzed for a complete-arch implant-supported prosthesis fabricated using either the SLM or EBM additive technologies showed a clinically acceptable implant-prosthesis discrepancy, where similar discrepancies on the x-, y-, and z-axes were found between the additive manufacturing technologies. Both technologies showed comparable abilities to manufacture the STL file additively on the x-, y-, and z axes. PMID- 30006221 TI - 3D-printed custom trays with a Gothic arch for centric relation recording and definitive impression making for complete dentures: A dental technique. AB - An appliance was designed and fabricated by using computer-aided design and computer-aided manufacturing (CAD-CAM) and 3-dimensional (3D) printing to combine a custom tray with an intraoral Gothic arch. This helped simplify centric relation recording and combined definitive impression making and centric relation recording into a single step. PMID- 30006220 TI - Oral health-related quality of life after prosthodontic treatment for patients with partial edentulism: A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: Clinicians are currently unable to quantify the psychosocial, functional, and esthetic effects of prosthetic interventions to replace teeth. Understanding the effects of treatment to replace teeth on oral health-related quality of life (OHRQoL) is important for informed consent. A systematic review of the evidence of OHRQoL improvements with prosthodontic tooth replacement and a comparison of outcomes between treatment modalities is therefore indicated. PURPOSE: The purpose of this systematic review was to examine the OHRQoL of patients with partial edentulism after different dental prosthetic treatments. MATERIAL AND METHODS: Electronic database and manual searches were conducted to identify cohort studies and clinical trials reporting on the OHRQoL of individuals receiving implant-supported crowns (ISCs), implant supported fixed dental prostheses (IFDPs), implant-supported removable dental prostheses (IRDPs), tooth-supported fixed dental prostheses (TFDPs), and removable partial dentures (RPDs). Two reviewers independently conducted article selection, data extraction, and quality assessment. Random-effects models were used to compare OHRQoL change scores (standardized mean change, 95% confidence intervals). RESULTS: Of the 2147 identified studies, 2 randomized controlled trials and 21 cohort studies met the inclusion criteria. Overall, studies were of low or moderate risk of bias. Pooled mean OHRQoL change <=9 months was 15.3 for TFDP, 11.9 for RPD, and 14.9 for IFDP. Pooled standardized mean change OHRQoL change >9 months was 13.2 for TFDP and 15.8 for IFDP. Direct comparisons <=9 months between TFDP against IFDP and RPD against IFDP significantly favored IFDP in both cases. CONCLUSIONS: TFDP and IFDP had short- and long-term positive effects on OHRQoL. RPDs positively affected OHRQoL in the short term. IFDP showed greater short-term improvement in OHRQoL than RPD and TFDP. PMID- 30006222 TI - An esthetic modification of a nasal conformer. AB - Facial contractures caused by burns can collapse the nasal aperture and lead to airway obstruction. Management in such situations requires surgical and prosthetic intervention. Prosthetically, although a nasal conformer is the treatment of choice, even a well-fabricated nasal conformer may be esthetically unappealing and require an aid for enhanced retention. Expensive implant-aided conformers are not always a viable option. This article introduces a technique for fabricating a nasal conformer that is both esthetically appealing and cost effective. The technique is illustrated by the treatment of a 12-year-old girl who presented with a history of burn injuries leading to nasal contracture that was effectively managed with this concept. PMID- 30006223 TI - Effects of modifying implant screw access channels on the amount of extruded excess cement and retention of cement-retained implant-supported dental prostheses: A systematic review. AB - STATEMENT OF PROBLEM: Cement-retained implant-supported prostheses eliminate screw loosening and enhance esthetics. However, retrievability and the possibility of removing extruded excess cement (EEC) have been problematic. PURPOSE: The purpose of this systematic review was to analyze the effects of modifying the screw access channel (SAC) on the amount of EEC and the retention of cement-retained implant-supported prostheses. MATERIAL AND METHODS: PubMed, Web of Science, Scopus, and Google Scholar databases were searched with appropriate key words. Related titles and abstracts published up to June 2017 were screened and selected on the basis of defined inclusion criteria. Full texts of all studies were read and subjected to quality assessments. After the initial search, 1521 articles were included in the study. Of these, 11 studies were subjected to critical appraisal, and 10 of them were reliable enough in methodology to be systemically reviewed. RESULTS: All the studies were in vitro and described a total of 260 specimens. According to the interpreted results, closed SACs caused lower retention with a higher amount of EEC, whereas open SACs caused the reverse. Also, as the abutment height decreased, retention decreased. CONCLUSIONS: Extending the crown's margin into the SAC, leaving the SAC open, and using internal vents in the SAC space are possible methods of modifying the SAC to gain higher retentive values. Also, the use of internal vents in the SAC system and open or partially filled SAC space reduce the amount of EEC. PMID- 30006224 TI - Abutment screw loosening in angulation-correcting implants: An in vitro study. AB - STATEMENT OF PROBLEM: Techniques that allow angulation correction for screw retained implant-supported restorations are now available. However, whether angulation correction built into the head of the implant affects abutment screw loosening is unclear. PURPOSE: The purpose of this in vitro study was to assess abutment screw loosening in angulation-correcting implants and straight implants subjected to simulated nonaxial occlusal loading. MATERIAL AND METHODS: Seven external connection 12-degree angulation-correcting implants and 7 straight implants were embedded in an acrylic resin housing, and titanium abutments were secured with titanium screws tightened to 32 Ncm. Each specimen was secured in a tooth wear machine and subjected to 1 000 000 cycles of 50-N nonaxial load to simulate 1 year of clinical service. The mean abutment screw removal torque values were calculated, and the association between number of cycles and the abutment screw removal torque was analyzed using a linear mixed-effects model and statistical software (alpha=.05) RESULTS: The mean abutment screw torque loss was 59.8% for the angulation-correcting implant group and 68.7% for the straight implant group. A statistically significantly greater mean abutment screw removal torque was recorded in the angulation-correcting implant group compared with the straight implant group after 1 000 000 cycles (P=.019). CONCLUSIONS: A significant loss of abutment screw torque was found in both implant groups with increased cycles of occlusal loading. The angulation-correcting implants resisted screw loosening significantly more than the straight implants because of the reduced angle of abutment screw loading. PMID- 30006225 TI - Fabrication of a custom pediatric nasal mask for noninvasive ventilation using a maxillofacial elastomer: A straightforward technique. AB - The facial masks commercially available for noninvasive positive pressure ventilation therapy for children with clinical conditions of hypoventilation are limited by size and hardness. The present report describes a straightforward method of developing a nasal mask from a room-temperature vulcanizing silicone elastomer for daily contact with the nasal mucosa of babies during noninvasive positive pressure ventilation. The fabrication of the silicone mask with nasal tubes is based on maxillofacial prosthesis techniques, with retention with steel prongs and elastics. PMID- 30006226 TI - Prognosis of dental implants in patients with low bone density: A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: Osteoporosis is a risk factor for implant success. Evidence for the prognosis of dental implants in patients with osteoporosis is still unclear. PURPOSE: The purpose of this systematic review was to compare implant success in patients with low versus normal bone density and to evaluate special techniques used to enhance implant success in these patients. MATERIAL AND METHODS: Searches were performed electronically in 4 databases (PubMed, LILACS, Cochrane, and Grey Literature) through July 2017 and manually to identify studies addressing the subject. Randomized and nonrandomized clinical trials and cohort studies were included. RESULTS: Eleven studies met the eligibility criteria, with a total of 1071 participants. Seven studies compared implant success in low and normal bone density, and 4 compared implant success in special and conventional techniques of implant placement. The risk of bias in the assessment of cohort studies was critical; of nonrandomized clinical trials, serious; and of randomized clinical trials, high. The meta-analysis showed no significant difference between implant survival in patients with low and normal bone density 5 years after implant placement. CONCLUSIONS: Implant survival in patients with low bone density seems to be feasible with special precautions. Implant placement using special adopted techniques might provide equivalent implant stability, survival, and marginal bone loss to normal bone. The quality of evidence is still unclear. PMID- 30006227 TI - Differences in micromorphology of the implant-abutment junction for original and third-party abutments on a representative dental implant. AB - STATEMENT OF PROBLEM: Evidence for micromorphology and precision of fit of third party prosthetic components compared with the original manufacturer's components is lacking. PURPOSE: The purpose of this in vitro pilot study was to evaluate the micromorphological differences among different commercial brands of zirconia, titanium, and gold abutments for dental implants in terms of tight surface contact. MATERIAL AND METHODS: The following abutments (n=3 per type) were preloaded on Straumann Bone Level implants according to the manufacturer's instructions for zirconia (Zr, Zr2, Zr3), titanium (Ti and Ti2), and gold (Gold 1, Gold 2). The micromorphology of the implant-abutment units was investigated by using scanning electron microscopy (original magnification *10 to *500) after microtome sectioning. After we calibrated, the length of the areas with tight contact (TC) (discrepancy <=3 MUm) was calculated at the level of conical connection (CC), lower internal connection (LIC), and screw threads (STs). The interexaminer agreement was assessed by using intraclass correlation coefficient(s) (ICC). One-way ANOVA was used for the overall comparison of the Zr groups, and the Student paired t test was used for pairwise comparisons of the abutments of the same group. After we adjusted for multiple comparisons, the significance level for the overall and pairwise comparisons of Ti and Gold groups was set at a P value of .008 and a P value of .003 for the Zr groups. RESULTS: Major differences were found among the different abutment types in terms of design and extent of surface contact. The TC showed significant differences among the abutments of Zr group, depending on the side and level of evaluation (Zr1 > Zr2 > Zr3 on the left side for CC; Zr1, Zr2 > Zr3 on the right side for CC, and, Zr2 > Zr3 on the right side for LIC; P<.003). In Ti group, no significant differences were found (P>.008). The Gold and Gold 2 groups had significantly greater contact on the left side of CC (P<.008). CONCLUSIONS: A difference in design of the abutments was apparent. The tight surface contact was significantly different among the examined abutments or abutment screws and the respective area of the inner surface of the implants. PMID- 30006228 TI - Accuracy of 9 intraoral scanners for complete-arch image acquisition: A qualitative and quantitative evaluation. AB - STATEMENT OF PROBLEM: Different intraoral scanners (IOSs) are available for digital dentistry. However, information on the accuracy of various IOSs for complete-arch digital scans is limited. PURPOSE: The purpose of this in vitro study was to evaluate the trueness and precision of complete-arch digital scans produced by 9 IOSs, using the superimposition method, and to compare them based on characteristics including the data capture principle and mode and the need for powder coating. MATERIAL AND METHODS: Nine IOSs were used to obtain standard tessellation language (STL) data for a bimaxillary complete-arch model with various cavity preparations (N=10). The scanning performance was evaluated quantitatively and qualitatively. For quantitative evaluation, the images were processed and analyzed using 3-dimensional (3D) analysis software. After we superimposed the datasets, trueness was obtained by comparing it with the reference scan, and precision was obtained from intragroup comparisons. The IOSs were compared based on the data capture principle and mode and the need for powder coating. Statistical analyses were conducted using a Kruskal-Wallis test, followed by multiple Mann-Whitney U tests for pairwise comparisons among groups (alpha=.05). For qualitative evaluation, surface smoothness and sharp edge reproducibility of the digital images were compared. RESULTS: The median precision values were lowest in the Trios model (average, 34.70 MUm; maximum, 263.55 MUm) and highest in the E4D model (average, 357.05 MUm; maximum 2309.45 MUm). Median average trueness values were lowest in the Trios model (42.30 MUm) and highest in the Zfx IntraScan model (153.80 MUm). The CS 3500 model had the lowest median maximum trueness values (450.75 MUm); the E4D model had the highest values (2680.55 MUm). Individual image and video sequence data captures showed similar median average trueness values (P>.05); the median maximum values of individual images were higher than those of the video sequence (P<.05). Swept source optical coherence tomography (SS-OCT) exhibited higher trueness values than those of other scanning principles (P<.05). The FastScan and True Definition, which require powder coating, showed significantly better trueness than other IOSs that did not require powdering (P<.05). The E4D, PlanScan, and Zfx IntraScan models had an increased tendency to produce images with imperfect surface features and to round off sharp edges. CONCLUSIONS: The E4D and Zfx IntraScan models did not perform as accurately as the other IOSs. The data capture principle of SS-OCT and the mode of individual image acquisition exhibited inferior trueness. The FastScan and True Definition, which require powder coating, exhibited better trueness. The qualitative aspects of the IOSs varied in terms of polygon shapes, sharp edge reproducibility, and surface smoothness. PMID- 30006229 TI - Real-time monitoring of HT29 epithelial cells as an in vitro model for assessing functional differences among intestinal microbiotas from different human population groups. AB - Several in vitro screening tests have been used for selecting probiotic strains; however they often show low predictive value and only a limited number of strains have demonstrated functionality in vivo. The most used in vitro tests represent a very simplified version of the gut environment, especially since they do not consider the accompanying microbiota. Therefore, there is a need to develop sensitive and discriminating in vitro models including the microbiota. Here we developed an in vitro model to discriminate among microbiotas/fecal waters from different population groups. To this end samples were obtained from seven healthy adults, five IBD-patients, ten full-term and ten preterm newborns. Fecal microbiotas were purified and their impact, as well as that of the fecal waters, on HT29 cells was continuously monitored for 22 h using a real-time cell analyzer (RTCA). The composition of the purified microbiotas was assessed by 16S rRNA gene profiling and qPCR and the levels of short chain fatty acids (SCFA) determined by gas chromatography. The microbiota fractions and SCFA concentrations obtained from IBD-patients, full-term and preterm babies, showed clear differences with regard to those of the control group (healthy adults). Moreover, the purified intestinal microbiotas and fecal waters also differed from the control group in the response induced on the HT29 cells assay developed. In short, we have developed a real-time, impedance-based in vitro model for assessing the functional response induced by purified microbiotas and fecal waters upon intestinal epithelial cells. The capability of the assay for discriminating the functional responses induced, by microbiotas or fecal waters from different human groups, promises to be of help on the search for compounds/strains to restore the functionality of the microbiota-host's interaction. PMID- 30006230 TI - p53 Throws CRISPR a Curve. AB - The efficacy of the powerful CRISPR-Cas9 genome-editing platform depends on DNA repair activities in the cells being targeted. Two new papers show that the low efficiency of targeting in some primary human cell lines is the result of p53 dependent cell arrest in response to the Cas9-induced break. This limitation must be overcome for some anticipated therapies. PMID- 30006232 TI - Is prophylactic nasogastric tube decompression necessary in patients undergoing laparoscopic adrenalectomy for unilateral benign adrenal tumor. AB - BACKGROUND/PURPOSE: This study aims to investigate the safety and feasibility of laparoscopic adrenalectomy for benign adrenal tumor without peri-operative NGT decompression. METHODS: From July 2010 to March 2014, 82 consecutive patients with benign unilateral adrenal tumor underwent elective laparoscopic adrenalectomy by a single surgeon were recruited for this study. We compared the clinico-demographic profile, estimated blood loss, operative time, time to full diet, time to ambulate, the length of hospital staying, analgesics use and complications between two groups stratified by the use of NGT. RESULTS: There were no significant differences in the clinico-demographic profile of the two groups, including age, laterality, body mass index, gender, ASA classification, tumor diameter and histologic types between two groups. Peri-operative parameters were similar between NGT and Non-NGT groups (estimated blood loss, 55.85 vs. 54.4 ml; operative time, 110.3 vs. 112.3 min; p > 0.05) The post-operative outcome of interests, including days to full oral intake (3.32 vs. 3.34 days), days to ambulate (2.07 vs. 2.10 days), hospital stay (4.32 vs. 4.34 days), and analgesics use (6.00 vs. 5.83 mg; all p > 0.05) showed no significant difference between NGT and non-NGT group. CONCLUSION: Laparoscopic adrenalectomy in patients with benign unilateral adrenal tumor without the use of peri-operative nasogastric tube decompression is safe and feasible. PMID- 30006231 TI - Detection of mucopolysaccharidosis III-A (Sanfilippo Syndrome-A) in dried blood spots (DBS) by tandem mass spectrometry. AB - BACKGROUND: With ongoing efforts to develop improved treatments for Sanfilippo Syndrome Type A (MPS-IIIA), a disease caused by the inability to degrade heparan sulfate in lysosomes, we sought to develop an enzymatic activity assay for the relevant enzyme, sulfamidase, that uses dried blood spots (DBS). METHODS: We designed and synthesized a new sulfamidase substrate that can be used to measure sulfamidase activity in DBS using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Sulfamidase activity was readily detected in DBS using the new substrate and LC-MS/MS. Sulfamidase activity showed acceptable linearity proportional to the amount of enzyme and reaction time. Sulfamidase activity in 238 random newborns was well elevated compared to the range of activities measured in DBS from 8 patients previously confirmed to have MPS-IIIA. CONCLUSIONS: This is the first report of an assay capable of detecting sulfamidase in DBS. The new assay could be useful in diagnosis and potentially for newborn screening of MPS-IIIA. PMID- 30006233 TI - Transplantation of hepatitis C infected kidneys into uninfected recipients. Why not? PMID- 30006234 TI - Corrigendum to "Phylogenomic re-assessment of the thermophilic genus Geobacillus" [Syst. Appl. Microbiol. 39 (2016) 527-533]. PMID- 30006235 TI - On modeling wave dispersion characteristics of protein lipid nanotubules. AB - In this article, wave propagation characteristics of protein lipid nanotubules are covered with respect to scale effects utilizing nonlocal strain gradient theory. The structure is supposed to be modeled as a simply supported beam and the kinematic relations are derived based on the classical beam theory (CBT). Implementing an energy based approach, the Euler-Lagrange equations of the lipid tubules are obtained. Moreover, the final governing equations are solved analytically to achieve the wave frequency and phase velocity of propagated waves. Influences of small size and wave number on the wave dispersion responses of lipid nanotubules are shown in detail in different diagrams for both phase velocity and wave frequency. Also, accuracy of introduced model is verified comparing responses of present model with those of former papers. PMID- 30006236 TI - Validation of model-predicted tibial tray-synthetic bone relative motion in cementless total knee replacement during activities of daily living. AB - As fixation of cementless total knee replacement components during the first 4-6 weeks after surgery is crucial to establish bony ingrowth into the porous surface, several studies have quantified implant-bone micromotion. Relative motion between the tray and bone can be measured in vitro, but the full micromotion contour map cannot typically be accessed experimentally. Finite element models have been employed to estimate the full micromotion map, but have not been directly validated over a range of loading conditions. The goal of this study was to develop and validate computational models for the prediction of tray bone micromotion under simulated activities of daily living. Gait, stair descent and deep knee bend were experimentally evaluated on four samples of a cementless tibial tray implanted into proximal tibial SawbonesTM constructs. Measurements of the relative motion between the tray and the anterior cortical shell were collected with digital image correlation and used to validate a finite element model that replicated the experiment. Additionally, a probabilistic analysis was performed to account for experimental uncertainty and determine model sensitivity to alignment and frictional parameters. The finite element models were able to distinguish between activities and capture the experimental trends. Best-matching simulations from the probabilistic analysis matched measured displacement with an average root mean square (RMS) difference of 14.3 um and Pearson-product correlation of 0.93, while the mean model presented an average RMS difference of 27.1 um and a correlation of 0.8. Maximum deviations from average experimental measurements were 40.5 and 87.1 um for the best-matching and average simulations, respectively. The computational pipeline developed in this study can facilitate and enhance pre-clinical assessment of novel implant components. PMID- 30006237 TI - Psoas hematoma formation after violation of the intertransverse plane during posterior spinal surgery for adolescent idiopathic scoliosis. AB - Psoas hematoma is a rare yet potentially serious complication following posterior spinal surgery as it is a possible nidus for infection. We present a case of psoas hematoma formation following scoliosis surgery due to intraoperative violation of the intertransverse plane. A 13-year-old female patient with adolescent idiopathic scoliosis underwent a posterior deformity correction and instrumented fusion which was complicated with intraoperative inadvertent violation of the intertransverse plane during dissection of the posterolateral gutter leading to a unilateral psoas hematoma. She experienced abdominal pain and a CT scan confirmed the presence of a psoas hematoma. Antibiotic coverage was provided in view of positive blood culture of Bacillus species to avoid infective seeding of the hematoma. Resolution of the hematoma was observed on the reassessment CT one month postoperatively. It is not uncommon for patients to develop atrophic transverse processes due to spinal deformity. This may cause difficulties in identification of the anatomy intraoperatively and thus, extra caution should be exercised during dissection to prevent violation of the intertransverse plane and subsequent psoas hematoma complication. PMID- 30006238 TI - Excellent results and low complication rate for anatomic polyaxial locking plates in comminuted proximal ulna fractures. AB - BACKGROUND: Comminuted fractures of the proximal ulna remain a great challenge in orthopedic surgery. The purpose of this study was to report the outcomes of comminuted proximal ulna fractures treated with a new construct type-anatomically preformed polyaxial locking compression plates. METHODS: Between 2013 and 2016, 46 patients with isolated comminuted fractures were treated with a 2.7-/3.5-mm VA LCP Olecranon Plate (Synthes, Umkirch, Germany). Of these, 44 were available for an assessment after a mean follow-up period of 2.5 years (range, 12-50 months). We evaluated range of motion, time to recovery, revision rate, and indications, as well as functional scores. Radiographs were analyzed. RESULTS: The study included 8 Mayo IB, 29 Mayo IIB, and 7 Mayo IIIB fractures. All fractures showed bony union, and only 2 revision surgical procedures were performed because of a new trauma. No other complications occurred. Mean range of motion was 139 degrees (range, 105 degrees -150 degrees ), and the mean pain level was less than 1 on a visual analog scale. Regarding elbow function, we found a mean Mayo Elbow Performance Score of 98; a mean Oxford Elbow Score of 44; and a mean Disabilities of the Arm, Shoulder and Hand score of 6. Of the plates, 41% were removed after an average time of 16 months, whereby a significant improvement in extension deficit was detected (P < .01). Ninety-five percent of all patients returned to their pretrauma sports level. CONCLUSION: The 2.7-/3.5-mm VA-LCP Olecranon Plate represents an effective option with excellent fracture reduction, sufficient stability for early postoperative functional rehabilitation, and a minimum of complications. PMID- 30006239 TI - Holistic Approaches in Lipid Production by Yarrowia lipolytica. AB - Concerns about climate change have driven research on the production of lipid derived biofuels as an alternative and renewable liquid fuel source. Using oleaginous yeasts for lipid synthesis creates the potential for cost-effective industrial-scale operations due to their ability to reach high lipid titer, yield, and productivity resulting from their unique metabolism. Yarrowia lipolytica is the model oleaginous yeast, with the best-studied lipid metabolism, the greatest number of genetic tools, and a fully sequenced genome. In this review we highlight multiomics studies that elucidate the mechanisms allowing this yeast to achieve lipid overaccumulation and then present several major metabolic engineering efforts that enhanced the production metrics in Y. lipolytica. Recent achievements that applied novel engineering strategies are emphasized. PMID- 30006240 TI - Association between noise exposure and diabetes: A systematic review and meta analysis. AB - BACKGROUND: The prevalence of diabetes is on rise worldwide and environmental factors are being increasingly recognized to be involved in this rise. An emerging body of evidence has evaluated the impact of long-term exposure to noise on diabetes mellitus, highlighting the need to synthesize this evidence. OBJECTIVES: To systematically review and conduct meta-analysis of the available evidence on the association between long-term exposure to transport and occupational noise exposure and diabetes mellitus. METHODS: Selected databases were searched for available evidence published till September 13th, 2017 following MOOSE guidelines. The quality of articles was assessed using the Newcastle-Ottawa Scale. Random effects meta-analysis was applied to abstract combined estimates for diabetes mellitus per 5 dB increase in noise exposure. We evaluated the heterogeneity applying Cochran's Q test and quantified it using I2 statistic. Meta-regressions were conducted to identify sources of heterogeneity. Publication bias was evaluated using funnel plot and Egger's test. RESULTS: Fifteen studies met our inclusion criteria of which nine including five prospective cohorts, two cross-sectional and two case-control studies with a total number of 444460 adult participants and 17430 diabetes mellitus cases included in meta-analyses. We observed a 6% (95% confidence interval (CI): 3%, 9%) increase in the risk of diabetes mellitus per 5 dB increase in noise exposure regardless of its source. Source-specific analyses were suggestive for stronger associations for air traffic noise (combined odds ratio: 1.17; 95% CI: 1.06, 1.29 per 5 dB increase in exposure) flowed by road traffic noise (combined odds ratio: 1.07; 95% CI: 1.02, 1.12). We observed some indications of publication bias; however the findings were robust after trim and fill test. Meta-regression analyses showed that the adjustment in general, and not specifically related to air pollution, could predict the between-study heterogeneity in reported associations. CONCLUSIONS: The results indicate an increased risk of diabetes mellitus associated with noise exposure, mainly related to air and road traffic. PMID- 30006241 TI - Massive myocardial infarction due to the complete occlusion of the left anterior descending coronary artery after blunt chest trauma. PMID- 30006242 TI - Accelerating implementation of shared decision-making in the Netherlands: An exploratory investigation. AB - OBJECTIVE: To prioritize strategies to implement shared decision-making (SDM) in daily practice, resulting in an agenda for a nationwide approach. METHODS: This was a qualitative, exploratory investigation involving: Interviews (N = 43) to elicit perceived barriers to and facilitators of change, focus group discussions (N = 51) to develop an implementation strategy, and re-affirmation through written feedback (n = 19). Professionals, patients, researchers and policymakers from different healthcare sectors participated. Determinants for change were addressed at four implementation levels: (1) the concept of SDM, (2) clinician and/or patient, (3) organizational context and (4) socio-political context. RESULTS: Following the identification of perceived barriers, four strategies were proposed to scale up SDM: 1) stimulating intrinsic motivation among clinicians via an integrated programmatic approach, 2) training and implementation in routine practice, 3) stimulating the empowerment of patients, 4) creating an enabling socio-political context. CONCLUSION: Clinicians mentioned that applying SDM makes their job more rewarding and indicated that implementation in daily practice needs ground-up redesign. The challenge is to effectively influence the behavior of clinicians and patients alike, and adapt clinical pathways to facilitate the exploration of patient values. PRACTICE IMPLICATIONS: Stakeholders should connect nationwide initiatives to pool information, and make the healthcare system supportive of implementing SDM. PMID- 30006243 TI - Monoubiquitinated gamma-H2AX: Abundant product and specific biomarker for non apoptotic DNA double-strand breaks. AB - DNA double-strand breaks (DSBs) are a highly toxic form of DNA damage produced by a number of carcinogens, drugs, and metabolic abnormalities. Involvement of DSBs in many pathologies has led to frequent measurements of these lesions, primarily via biodosimetry of S139-phosphorylated histone H2AX (gamma-H2AX). However, gamma H2AX is also induced by some non-DSB conditions and abundantly formed in apoptosis, raising concerns about the overestimation of potential genotoxic agents and accuracy of DSB assessments. DSB-triggered gamma-H2AX undergoes RNF168 mediated K13/K15 monoubiquitination, which is rarely analyzed in DSB/genotoxicity studies. Here we identified critical methodological factors that are necessary for the efficient detection of mono- (ub1) and diubiquitinated (ub2) gamma-H2AX. Using optimized technical conditions, we found that gamma-H2AX-ub1 was a predominant form of gamma-H2AX in three primary human cell lines containing mechanistically distinct types of DSBs. Replication stress-associated DSBs also triggered extensive formation of gamma-H2AX-ub1. For DSBs induced by oxidative damage or topoisomerase II, both gamma-H2AX and gamma-H2AX-ub1 showed dose dependent increases whereas gamma-H2AX-ub2 plateaued at low levels of breaks. Despite abundance of gamma-H2AX, gamma-H2AX-ub1,2 formation was blocked in apoptosis, which was associated with proteolytic cleavage of RNF168. Chromatin damage also caused only the production of gamma-H2AX but not its ub1,2 forms. Our results revealed a major contribution of ubiquitinated forms to the overall gamma H2AX response and demonstrated the specificity of monoubiquitinated gamma-H2AX as a biodosimeter of non-apoptotic DSBs. PMID- 30006244 TI - Impact of mucoadhesive polymeric nanoparticulate systems on oral bioavailability of a macromolecular model drug. AB - Nanoparticles (NP) only different in mucoadhesivity are compared for impact on drug oral bioavailability. Two polymeric NP types based on quaternary ammonium chitosan (NP QA-Ch) and S-protected thiolated derivative thereof (NP QA-Ch-S pro), respectively, containing the macromolecular drug model, FD4, were prepared by crosslinking each polymer with reduced MW hyaluronic acid. The structure of basic polymers was determined by H1NMR analysis. NP were similar in size (371 +/- 38 vs. 376 +/- 82 nm); polydispersity index (0.39 +/- 0.08 vs. 0.41 +/- 0.10); zeta potential (13.4 +/- 0.9 vs. 11.9 +/- 1.2 mV); reversible interactions with drug (bound drug, 67 vs. 66%); encapsulation efficiency (23 +/- 5 vs. 23 +/- 8%); release properties (15% released in 15 h in both cases); and apparent permeation across excised rat intestine (Papp, 8.8 +/- 0.8 vs. 10 +/- 1 cm/s). Then the differences in NP transport ratio through mucus (TR, 0.75 vs. 0.37) and adhesion to excised rat intestinal mucosa (adsorbed fraction, 23 +/- 3 vs. 45 +/- 2%) were ascribed to higher mucoadhesivity of NP QA-Ch-S-pro compared to NP QA-Ch. This directly influenced drug oral bioavailability in rats (Tmax, 1 vs. 2 h; AUC, 1.7 +/- 0.3 vs. 2.9 +/- 0.4 MUg/mL min, for NP QA-Ch and NP QA-Ch-S-pro, respectively). Mucoadhesivity increases drug bioavailability by retaining NP at its absorption site and opposing its transit down the GI tract. Data on drug accumulation in rat liver allows the assertion that NP is absorbed by transcytosis across intestinal epithelium and transported from blood into liver by Kuppfer cells. PMID- 30006246 TI - Parenteral protein formulations: An overview of approved products within the European Union. AB - The study presented is a comprehensive overview of commercial parenteral protein formulations, approved by the European Medicines Agency (EMA), 1995-2018. The objective of this overview was to analyse current trends in the design of commercial parenteral protein products and thereby support formulation scientists in the design of new formulations. The main data source was the publicly available European Public Assessment Reports (EPARs) published by the EMA for each authorised product. An analysis of the percentage of formulations in a liquid and lyophilised form was conducted. In addition, the number of products containing individual excipients, classified into functional categories is provided. Finally, the overview includes comprehensive details of product compositions obtained from EMA, US Food and Drug Administration (FDA) and product Marketing Authorisation Holder. Data analysis highlighted trends in the number of products approved, and the higher percentage of liquid parenteral protein formulations (66%) compared to lyophilised formulations (34%). This overview identifies the most commonly incorporated excipients employed as buffering agents, stabilisers/bulking agents, surfactants, preservatives and tonicifiers, including their concentration ranges of use in both liquid and lyophilised formulation approaches. Finally, antibody-based formulations were a particular focus of this overview. The relationship between parenteral routes of administration and antibody concentrations in approved products was also investigated. PMID- 30006245 TI - Investigation of orally delivered carbon monoxide for postoperative ileus. AB - Endogenously produced carbon monoxide (CO) has antioxidant and anti-inflammatory effects which is why CO has been investigated as a possible therapeutic agent for inflammatory disorders in different body systems, including the gastrointestinal (GI) tract. In an effort to develop an easy to use platform for CO delivery to the GI tract, we recently introduced the Oral CO Release System (OCORS) and demonstrated its preventive effect for experimental colitis in a rodent model. Building off on a comprehensive preclinical dataset on efficacy of inhaled and intraperitoneal CO in reducing postoperative ileus (POI), which is being defined as GI transit retardation after abdominal surgery, we evaluated an adapted OCORS platform to ameliorate POI by local CO delivery to the murine small intestine. To match design characteristics of OCORS with the murine physiology we developed a miniaturized version of the OCORS and tailored its release pattern to release CO for 2 h following first order kinetics. Upon intragastric gavage of 20 tablets, 55% of the tablets reached the murine small intestine after 1 h while triggering a blood carboxyhemoglobin rise to 5.2%. Although this is in line with previous systemic CO dosing protocols, GI muscular inflammation and transit retardation by small intestinal manipulation, performed at 1 h after gavage of 20 tablets, was not prevented while the positive control - intravenous nitrite - prevented POI. The results show that local CO treatment of POI is insufficient - suggesting a strong systemic component for effective therapy - thereby providing critical insight into effective design of CO drug delivery in POI. PMID- 30006247 TI - In vitro synergy and postantibiotic effect of colistin combinations with meropenem and vancomycin against Enterobacteriaceae with multiple carbapenem resistance mechanisms. AB - AIM: The aim of the study was to determine in vitro synergy and postantibiotic effect of colistin alone and combined with meropenem or vancomycin against Enterobacteriaceae producing multiple carbapenemases; combinations of two metallo beta-lactamases (MBL) or MBL with OXA-48. Colistin-resistant strain positive for OXA-48 was also included in the study. METHODS: The antibiotic susceptibility was tested by broth microdilution method. Synergy was tested by chequerboard, time kill and 2-well method. PAE was determined by viable counting. RESULTS: The chequerboard analysis revealed synergy for colistin combination with meropenem in all isolates with FICI values ranging from 0.12 to 0.24. FICI values for combinations with vancomycin were below 0.5 indicating synergy in two out of four isolates. K. pneumoniae 609815 positive for OXA-48 and colistin resistant showed the most pronounced and consistent synergy effect with meropenem in both chequerboard and time-kill method. Synergy effect in time-kill curves, was observed for K pneumoniae 145846 with two MBLs and colistin resistant K. pneumoniae 609815 positive for OXA-48, with both combinations including meropenem and vancomycin. Colistin alone exhibited short postantibiotic effect (PAE) against all tested isolates. Meropenem markedly prolonged the PAE in two isolates in contrast to vancomycin which did not demonstrate significant effect on the duration of PAE. CONCLUSIONS: The synergy effect and the duration of PAE was strain and antibiotic dependent but not related to the resistance gene content. PMID- 30006248 TI - False-positive elevation of 1,3-beta-D-glucan caused by continuous administration of penicillin G. AB - The 1,3-beta-D-Glucan (BDG) assay is widely used for the diagnosis of fungal infections, especially in patients with hematologic malignancies. Some antimicrobials have been reported to cause false-positive results for BDG, but there has been no report on the effect of penicillin G (PCG) on BDG levels. We experienced a patient who developed false-positive BDG elevation during the administration of PCG for osteomyelitis due to Streptococcus pneumoniae infection. The serum BDG level increased up to 81.0 pg/ml during the continuous administration of PCG at 24 million units per day. However, chest and paranasal CT scan showed no evidence of fungal infection. The BDG level decreased to 38.0 pg/ml at 14 hours after the discontinuation of PCG. The amount of BDG in one vial of PCG inferred from these serum BDG levels is very similar to the actual BDG concentration in a vial of PCG. Therefore, during the administration of PCG, elevated BDG levels should be interpreted with caution, as they may be false positive results. PMID- 30006249 TI - Diagnosing superinfection keratitis with multiplex polymerase chain reaction. AB - PURPOSE: To report the potential usefulness of multiplex polymerase chain reaction (mPCR) for diagnosing superinfection keratitis caused by herpes simplex virus-1 (HSV-1), bacteria and fungus. METHODS: Case series. Corneal scrapings were analyzed with mPCR for human herpes virus 1-8, bacterial 16S ribosomal DNA (rDNA) and fungal 28S rDNA. RESULTS: Case 1 was a 69-year-old man who presented with refractory infectious keratitis. PCR examination was positive for bacterial 16S rDNA and negative for fungal 28S rDNA. HSV-1 was not examined at this time. A geographic ulcer arose after 2 months of intensive antibacterial treatment. Herpes simplex keratitis (HSK) was suspected; PCR analysis was positive for HSV 1. Corneal scrapings obtained at the initial visit were re-analyzed and found to be HSV-1 positive. Thus, it turned out that this was a case of superinfection keratitis caused by bacteria and HSV-1. Case 2 was a 60-year-old man with corneal ulcer who had received unsuccessful treatment with antibiotics. mPCR analysis was positive for HSV-1, bacterial 16S rDNA and fungal 28S rDNA. The patient was diagnosed with superinfection keratitis caused by HSV-1, bacteria and fungus. Case 3 was an 82-year-old woman who had been treated for HSK and then developed bacterial keratitis during treatment. mPCR analysis was positive for HSV-1 and bacterial 16S rDNA. The patient was diagnosed with superinfection keratitis caused by HSV-1 and bacteria. CONCLUSION: Superinfection keratitis is hard to diagnose because of its atypical manifestation. mPCR has the potential to allow prompt diagnosis and appropriate treatment in these cases. PMID- 30006250 TI - Chemokines in pregnant women with sickle cell disease. AB - Pregnancy in sickle cell disease is a problem due to the adverse outcomes related to the disease. Research into the role of chemokines in sickle cell disease is available, but studies investigating the disease in pregnancy are scarce. Our data show the chemokine profiles of pregnant women with sickle cell disease compared with control groups. There were no differences in MCP-1 level among the groups, but IL-8 and MIG were likely related with disease activity. In addition, levels of IP-10 were higher in pregnant women with sickle cell disease and, interestingly, RANTES levels were higher in normal pregnancy when compared to pregnancy in sickle cell disease. More studies should be encouraged to fully elucidate chemokine activity during pregnancy in sickle cell disease. PMID- 30006251 TI - Short interpregnancy interval and adverse birth outcomes in women of advanced age: a population-based study. AB - PURPOSE: Short interpregnancy interval (IPI) has been linked with adverse birth outcomes. However, the association in advanced age women needs further investigation. This study aims to examine the association between short IPI and adverse birth outcomes including preterm birth, post-term birth, low birth weight, and macrosomia, in a population of advanced age U.S. women. METHODS: The 2016 U.S. public-use natality data was analyzed. Analysis was restricted to women with second-order singleton live births who were >=35 years at first live birth (n = 46,684). Multinomial logistic regression analysis was used to examine the association between short IPI and adverse birth outcomes. RESULTS: Short IPI in advanced age women was significantly associated with higher odds of extremely preterm birth (0-5 months IPI: adjusted odds ratio [AOR] = 2.43, 95% confidence interval [CI] = 1.07-5.52; 6-11 months IPI: AOR = 2.17, 95% CI = 1.09-4.31), very preterm birth (0-5 months IPI: AOR = 1.63, 95% CI = 1.04-2.56), and extremely low birth weight (0-5 months IPI: AOR = 2.43, 95% CI = 1.28-4.60) in the second delivery. An inverse relationship between short IPI and post-term birth was observed and no significant association between short IPI and macrosomia was found. CONCLUSIONS: Short IPI in advanced age women increases the odds of adverse birth outcomes in the second delivery. PMID- 30006252 TI - Endocrine Disruption: Current approaches for regulatory testing and assessment of plant protection products are fit for purpose. AB - The ongoing debate concerning the regulation of endocrine disruptors, has increasingly led to questions concerning the current testing of chemicals and whether this is adequate for the assessment of potential endocrine disrupting effects. This paper describes the current testing approaches for plant protection product (PPP) active substances in the European Union and the United States and how they relate to the assessment of endocrine disrupting properties for human and environmental health. This includes a discussion of whether the current testing approaches cover modalities other than the estrogen, androgen, thyroid and steroidogenesis (EATS) pathways, sensitive windows of exposure, adequate assessment of human endocrine disorders and wildlife species, and the determination of thresholds for endocrine disruption. It is concluded, that the scope and nature of the core and triggered data requirements for PPP active substances are scientifically robust to address adverse effects mediated through endocrine mode(s) of action and to characterise these effects in terms of dose response. PMID- 30006253 TI - The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity. AB - One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r2 = 0.46; p = 0.004, r2 = 0.33; p = 0.002, r2 = 0.37; p = 0.02, r2 = 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics. PMID- 30006254 TI - Wide Local Excision Versus Oncoplastic Breast Surgery: Differences in Surgical Outcome for an Assumed Margin (0, 1, or 2 mm) Distance. AB - INTRODUCTION: Oncoplastic breast surgery (OBS) can be applied in larger tumors or in patients with high tumor-to-breast ratio without compromising oncologic safety. Inherent larger excisions may increase the probability of clear margins. We compare postoperative outcomes between simple wide local excision (WLE) and OBS assuming 3 different margin distances. PATIENTS AND METHODS: Single oncoplastic surgeon data between April 2014 and September 2016, including tumor and treatment details, for WLE or OBS were reviewed. Relative incidence of margin positivity at 3 assumed distinct margin distances (2, 1, and 0 mm) and reexcision rates were compared. Statistical comparisons were performed by the Student t and chi-square tests. RESULTS: Available data from 201 patients revealed similar patient age and respective tumor phenotypes between 2 cohorts (166 WLE and 35 OBS). Though both the preoperative (30 vs. 16 mm, P < .001) and postoperative tumor (30 vs. 19 mm, P = .001) sizes were greater in the OBS group, margin positivity rates were significantly lower, at 1 mm (5.7% vs. 20.8%, P = .036). Though similar rates of reexcision were observed, completion mastectomies were required in 5.4% of WLE versus 0 OBS. Similar rates of margin positivity and reexcision were observed between mammoplasties and chest wall perforator flaps. CONCLUSION: OBS is not inferior to standard WLE at providing a safe and clear oncologic margin regardless of margin distance (up to 2 mm) despite larger tumor size. The additional benefit of improved cosmesis, particularly in patients with larger tumor-to-breast ratio, offers a suitable and safe alternative, thus increasing patient choice and reducing the incidence of reexcision and completion mastectomy. PMID- 30006255 TI - Obstructive sleep apnea syndrome and olfactory perception: An OERP study. AB - Obstructive Sleep Apnea Syndrome (OSA) is characterized by snoring associated with repeated apnea and/or obstructive hypopnea. The nasal airways of OSA patients, measured via acoustic rhinometry, could be significantly narrower than healthy subjects and this reduced nasal structure can impair olfactory function. The relationship between nasal structure and olfactory function, assessed via behavioral test results, indicates that there is a high prevalence of nasal airflow problems. Based on these assumptions, the purpose of this study was to carry out an assessment of olfactory perception in OSA patients through the Chemosensory Event-Related Potentials (CSERP), investigating the N1 component and the Late Positive Component (LPC). Twelve OSA patients, non-smokers, were recruited in the Pulmonary Rehabilitation Unit, scored with the Epworth Sleepiness Scales, after Polygraphic Recording, Apnea Hypopnea Index and Body Mass Index evaluation. The control group consisted of twelve healthy controls, non-smokers, recruited as volunteers. Subjects, during an EEG recording, performed an oddball olfactory recognition task based on two scents: rose and eucalyptus. Main results highlighted differences in N1 and LPC between OSA and controls. OSA patients presented faster N1 latencies and greater amplitude. The same trend was found in LPC, where OSA showed decreased latency and increased amplitude during rose stimulation, in the right inferior frontal cortex. and faster latencies in left centroparietal cortex OERP results can suggest an impairment in endogenous components. This result could be the consequence of the exogenous perceptual difficulty highlighted in N1 component. The increased arousal could also be related to the respiratory activity involved during the olfactory task. PMID- 30006256 TI - Differences in early career operative experiences among pediatric urologists. AB - INTRODUCTION: Previous research suggests that pediatric urologists feel well trained by their fellowship for cases encountered early in their career. We questioned the complexity and diversity of cases new pediatric urologists were actually performing. OBJECTIVE: The aim was to identify the frequency with which newly trained pediatric urologists are performing various procedures, investigate which factors are associated with case complexity and diversity, and evaluate for differences between male and female surgeons. STUDY DESIGN: Case logs of urologists from July 30, 2007, to June 30, 2013, initially applying for the certifying examination who self-identified as pediatric urologists were reviewed. Data points included cases/dates, and surgeon demographics. An in-depth analysis was performed on 51 index cases from the 71 included pediatric urologists, for which a level of complexity was assigned. RESULTS: Compared with the bottom volume quartile, surgeons in the top quartile performed more cases of minimal (115.9 +/- 8.7 vs. 51.7 +/- 8.7, p < 0.001), moderate (31.1 +/- 2.7 vs. 10.1 +/- 1.0, p < 0.001) and significant (10.8 +/- 1.9 vs. 2.0 +/- 0.4, p < 0.001) complexity. More than 90% logged circumcisions, orchiopexies, and inguinal hernia repairs, while less than 1.5% logged open nephroureterectomies or complete male epispadias repair. Surgeons submitted at least one of 17.2 +/- 0.5 (range 5-28) unique codes. The figure presents the percentage of current procedural terminology (CPT) codes performed by each urologist. Surgeons with the least case diversity performed a higher percentage of low-complexity cases, and lower percentages of moderate and complex cases (p < 0.001). Males, comprising 60.6% of urologists, performed more cases than females (342.9 +/- 30.9 vs. 229.1 +/- 18.1, p = 0.007), averaging more cases of minimal (95.0 +/- 6.6 vs. 73.3 +/- 4.6, p = 0.018) and significant (6.7 +/- 1.0 vs. 2.8 +/- 0.5, p = 0.005) complexity. There was no difference in cases of moderate complexity (22.0 +/- 1.9 vs. 18.1 +/- 2.1, p = 0.201). DISCUSSION: In general, pediatric urologists should expect to perform many minor cases when they enter practice. Women are entering urology in increasing numbers. In our study, female urologists performed fewer cases. This could have implications for the workforce, which in urology in general is expected to decrease. CONCLUSIONS: Case diversity and degree of complexity vary among newly trained pediatric urologists. The urologist with the greatest case diversity never performed 45% of the 51 analyzed CPT codes, while the one with the least case diversity never performed 90% of the codes. Male surgeons performed more operations, particularly those of minimal and significant complexity. The variability in operative experience reinforces the importance of continuing education and mentorship after completion of fellowship. PMID- 30006257 TI - Endoscopic management of primary obstructive megaureter in pediatrics. AB - AIMS: The aims of this study were to evaluate the efficacy and safety of endoscopic treatment of primary obstructive megaureter in children, and to assess its long-term outcome. METHODS: Case files of 35 children who had endoscopic treatment of symptomatic primary obstructive megaureter between 2006 and 2016 were retrospectively analyzed. All children had ureterovesical junction dilatation with one or more ureteral dilators, and insertion of a JJ stent. An analysis of the case files and a comparison between pre- and postoperative ultrasound and scintigraphy findings were performed. RESULTS: The study population consisted of 22 boys and 13 girls aged between 2 months and 16 years. The follow-up period ranged from 8 months to 10 years. Twenty-one children (60%) were under 2 years at the time of treatment. The average duration of JJ stenting was 7 weeks (3-16 weeks). Thirty-four of 35 children (97%) were considered definitively cured, that is, asymptomatic with preserved renal function. Two children required open surgery for a failed endoscopic treatment procedure. Secondary reimplantation surgery was only necessary in one case (1/35) after technically satisfactory endoscopic treatment. Twelve of 35 children had a complication, including two Clavien III complications. Comparison of pre- and postoperative ultrasonography showed a significant decrease in ureteral diameter in 31 cases. Postoperative scintigraphy showed a significant improvement in the ureteral leaking curve in 20 children. CONCLUSION: In our experience, endoscopic treatment of congenital obstructive megaureter in pediatrics seems to be safe and effective. It is proposed as a first-line treatment for children requiring an intervention, even for young children under 2 years. PMID- 30006258 TI - Molecular Minimal Residual Disease Testing in Acute Myeloid Leukemia: A Review for the Practicing Clinician. AB - Minimal residual disease (MRD) testing in acute myeloid leukemia is increasingly being used to assess treatment response and stratify the risk of relapse for individual patients. Molecular methods for MRD testing began with PCR-based assays for individual recurrent mutations. To date, there is robust evidence for testing NPM1, CBFB-MYH11, and RUNX1/RUNXT1 mutations using this approach, though the best timing and threshold level for each mutation varies. More recent approaches have been with PCR-based multigene panels, occasionally combined with flow cytometric techniques, and next-generation sequencing techniques. This review outlines the various techniques used in molecular approaches to MRD, the evidence behind individual mutation testing, and the novel approaches for evaluating multigene MRD so that clinicians can understand and incorporate these evaluations into their practice. PMID- 30006259 TI - Open-label use of highly purified CBD (Epidiolex(r)) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. AB - OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for >=10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, chi2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow up. SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies. PMID- 30006260 TI - The etiology and prognosis of super-refractory convulsive status epilepticus in children. AB - BACKGROUND: Both refractory convulsive status epilepticus (SE) and super refractory SE are medical emergencies. However, there are limited data on super refractory SE in children. Thus, this study focuses on characterizing the demographics, outcomes, and prognostic factors for super-refractory SE in children. METHODS: This study was a retrospective analysis of super-refractory SE treated in a tertiary referral center in Taiwan. The functional outcome was evaluated by modified Rankin scale (mRS). Significant functional decline was defined as an mRS difference (before hospital admission and at discharge) of more than 2. The variates and the follow-up mRS values were then analyzed statistically. RESULTS: We enrolled 134 patients with 191 episodes of convulsive SE and identified 30 patients with 38 episodes of convulsive super-refractory SE. The incidence of convulsive super-refractory SE in the group with SE was 19.9%, and the age ranged from 2.5 months to 17 years. In-hospital mortality was 13.3%, which was much lower than that of adult cohorts. Newly acquired epilepsy and cognitive deficit occurred in 100% and 88.5%, respectively. Newly acquired epilepsy, as a sequel of super-refractory SE, was observed in all 18 patients (100%) who survived and had no history of epilepsy. Significant functional decline (mRS difference of more than 2) at discharge occurred in 76.7%. Poor functional outcome was associated with acute symptomatic etiology (P < 0.001) and the number of anesthetic agents (P = 0.002). The functional outcome improved after 1 year of follow-up in our population. CONCLUSIONS: Super-refractory SE is associated with significant morbidity and mortality in children. However, the in hospital mortality rate is much lower compared with adults. The functional outcome in children is associated with acute symptomatic etiology and the number of anesthetic agents and may improve after long-term follow-up. PMID- 30006261 TI - Internet-based treatment of depression in Indonesia. PMID- 30006262 TI - Internet-based behavioural activation with lay counsellor support versus online minimal psychoeducation without support for treatment of depression: a randomised controlled trial in Indonesia. AB - BACKGROUND: Depression is one of the leading contributors to the global burden of disease. However, treatment availability is often very poor in low-income and middle-income countries. In a randomised clinical trial, we investigated the efficacy of internet-based behavioural activation with lay counsellor support compared with online minimal psychoeducation without support for depression in Indonesia (a middle-income country). METHODS: We did a community-based, two group, randomised controlled trial in Indonesia. Eligible participants were aged 16 years or older, scored 10 or above on the Patient Health Questionnaire 9 (PHQ 9), met the criteria for major depressive disorder or persistent depressive disorder based on the Structured Clinical Interview for DSM-5, were proficient in Bahasa Indonesia, and could use the internet. Participants were randomly allocated (1:1) by a research assistant using a web-based randomisation program to online behavioural activation with lay support (termed Guided Act and Feel Indonesia [GAF-ID]) or online psychoeducation without further support. Randomisation was done within a random permuted block design and was stratified by sex and depression severity (ie, PHQ-9 10-14 vs >=15). The primary outcome was self-reported PHQ-9 score at 10 weeks from baseline. Research assistants were masked to group allocation until after the assessment of the primary outcome. Interventions were described to participants during the consent procedure and after randomisation, but no indication was given as to which was the intervention of interest and which was the control. Analysis was by intention to treat. The trial was registered in the Netherlands Trial Register, number NTR5920. It is closed to new particpants, and follow-up has been completed. FINDINGS: Between Sept 6, 2016, and May 1, 2017, 313 participants were enrolled and randomly assigned, 159 to the GAF-ID group and 154 to the online psychoeducation group. At 10 weeks, PHQ-9 scores were significantly lower in the GAF-ID group than in the online psychoeducation group (mean difference -1.26 points [95% CI -2.29 to 0.23]; p=0.017), and participants in the GAF-ID group had a 50% higher chance of remission at 10 weeks (relative risk 1.50 [95% CI 1.19 to 1.88]; p<0.0001). An effect size of 0.24 for the GAF-ID group compared with the control group at 10 weeks was sustained over time (effect size 0.24 at 3 months, and 0.27 at 6 months). No adverse events were reported in either group. INTERPRETATION: To our knowledge, ours is the first adequately powered randomised clinical trial of an internet-based intervention for depression in a low-income or middle-income country. Online behavioural activation with lay counsellor support efficaciously reduced symptoms of depression, and could help to bridge the mental health gap in low-income and middle-income countries. FUNDING: Indonesia Endowment Fund for Education, University of Groningen. PMID- 30006263 TI - Are Women With Threatened Preterm Labor More Dehydrated Than Women Without It? AB - OBJECTIVE: To determine if women who present to the labor and delivery unit at 23 0/7 to 36 6/7 weeks gestation with threatened preterm labor (TPTL) are more likely to be dehydrated than women who present at the same gestational age for other reasons. DESIGN: Retrospective cohort study. SETTING: An academic medical center in the northeastern United States. PARTICIPANTS: All women at preterm gestational ages 23 0/7 to 36 6/7 weeks who presented to the labor and delivery unit for care in 2014. METHODS: We compared hydration status by urine specific gravity of women with TPTL to that of women with other chief complaints. Women for whom data were missing and those with hypertension, diabetes, renal disease, vaginal bleeding, ruptured membranes, advanced dilation (>3 cm), multiple gestation, or fetal demise were excluded. Chi-square statistic and a receiver operating characteristic (ROC) curve were used for data analysis. RESULTS: A total of 840 women at 23 0/7 to 36 6/7 weeks gestation presented during the study period; 188 of these had TPTL, 261 had other chief complaints, and 391 were excluded. The proportion of women diagnosed with dehydration was similar between those with TPTL (39%) and those with other complaints (46%, p = .12). An ROC curve showed no association between TPTL and hydration status (area under the curve = 0.57, 95% confidence interval [0.46, 0.67]). CONCLUSION: At 23 0/7 to 36 6/7 weeks gestation, the hydration status of women with TPTL was not different from those without TPTL. Because there is no relationship, it is unlikely that hydration is a worthwhile therapy for women with TPTL, although additional prospective study is warranted. PMID- 30006265 TI - How Mitochondrial Metabolism Contributes to Macrophage Phenotype and Functions. AB - Metabolic reprogramming of cells from the innate immune system is one of the most noteworthy topics in immunological research nowadays. Upon infection or tissue damage, innate immune cells, such as macrophages, mobilize various immune and metabolic signals to mount a response best suited to eradicate the threat. Current data indicate that both the immune and metabolic responses are closely interconnected. On account of its peculiar position in regulating both of these processes, the mitochondrion has emerged as a critical organelle that orchestrates the coordinated metabolic and immune adaptations in macrophages. Significant effort is now underway to understand how metabolic features of differentiated macrophages regulate their immune specificities with the eventual goal to manipulate cellular metabolism to control immunity. In this review, we highlight some of the recent work that place cellular and mitochondrial metabolism in a central position in the macrophage differentiation program. PMID- 30006264 TI - Masticatory function of conventional complete denture wearers changing to 2 implant retained mandibular overdentures: clinical factor influences after 1year of function. AB - PURPOSE: Evaluate how clinical factors related to conventional complete denture (CCD) wearers, can influence masticatory function (MF) of totally edentulous patients before and after one-year transitioning to implant-retained mandibular overdentures (IMO). METHODS: Forty patients using CCD were rehabilitated with IMO and their MF was evaluated by: (i) ST_X50: theoretical aperture through which 50% of the weight of the particles would pass; (ii) STB: distribution homogeneity of the crushed particles. The clinical parameters analyzed were: atrophy, retention, stability, facial type, anteroposterior skeletal discrepancy, and type of loading. The statistical association was tested through crude and adjusted logistic regression. RESULTS: IMO promoted improvements in the MF, irrespective of the clinical parameters. CCD wearers with poor retention had 86% less chance of achieving a good ST_X50. STB was associated with stability, facial type, and anteroposterior discrepancy. Subjects with poor mandibular CCD stability had a 76% lower chance of achieving a good test food homogenization, whereas brachyfacial individuals were 1.3 times more likely to have a good STB. Class II patients had an 89% lower chance of having a good homogenization of the particles as CCD users and after transition to IMO. CONCLUSIONS: CCD users with poor retention achieved an inferior ST_X50. The STB performance can be compromised by poor stability or Class II characteristics, while brachyfacial individuals achieve better homogenezation of the food bolus. Although the transition to IMO improved the masticatory function, the anteroposterior discrepancy still maintained an association with STB, as Class II individuals still presented difficulties homogenizing food. PMID- 30006266 TI - De Novo Designed alpha-Sheet Peptides Inhibit Functional Amyloid Formation of Streptococcus mutans Biofilms. AB - Streptococcus mutans is a bacterial species that predominates in the oral microbiome. S. mutans binds to the tooth surface, metabolizes sugars and produces acid, leading to cavity formation. S. mutans can also cause infectious endocarditis. Recent evidence suggests that S. mutans biofilms contain amyloid fibrils. Amyloids are insoluble fibrillar protein aggregates, and bacteria use functional amyloids to improve robustness of their biofilms. While the functional amyloids in bacteria such as Escherichia coli and Staphylococcus aureus have been heavily investigated, little is known about the mechanism of S. mutans amyloid formation. Previous results from our laboratory with the amyloidogenic proteins and peptides from the aforementioned bacteria and other mammalian amyloid systems suggest that amyloid formation progresses via an intermediate that adopts a unique secondary structure-alpha-sheet. De novo designed peptides with alternating l- and d-amino acid also adopt an alpha-sheet secondary structure and inhibit amyloid formation by binding to soluble oligomeric species during amyloidogenesis. Inhibition of fibrillization by alpha-sheet peptides suggests the presence of alpha-sheet during amyloid formation. To investigate the mechanism of functional amyloid formation in S. mutans, alpha-sheet peptides were compared to epigallocatechin gallate for their ability to inhibit fibril formation in S. mutans. Inhibition was demonstrated in a biofilm plate assay and on hydroxyapatite surfaces both in S. mutans alone and in bacteria from human saliva. The observed inhibition suggests that an alpha-sheet mediated mechanism may be operative during functional amyloid formation. PMID- 30006267 TI - Metanephric Adenoma in the Pediatric Population: Diagnostic Challenges and Follow up. AB - OBJECTIVE: To discuss the presenting features, imaging findings, and recommended management of patients with Metanephric adenoma (MA) focusing on the diagnostic challenges and indications for follow up. MATERIALS AND METHODS: In this case report, we present a case of a 10-year-old female with MA who eventually underwent nephron sparing surgery with a partial nephrectomy. We performed a literature review of previous cases of metanephric adenoma and their respective management and follow-up. RESULTS: Renal ultrasound demonstrated a heterogeneous, echogenic mass measuring 3.8 cm at the upper pole of the right kidney. Further investigations consisted of computed tomography scan, magnetic resonance imaging, and magnetic resonance angiography. The patient underwent robotic-assisted partial nephrectomy. The immunohistochemical staining pattern, gross, and microscopic appearance of the lesion were consistent with the diagnosis of MA. The combination of CK7, EMA, and S-100 negativity and WT1 and CD57 positivity is considered characteristic of metanephric adenoma as described in the literature. CONCLUSION: MA is a rare benign tumor and especially in the pediatric population can cause significant concern over a possible malignant lesion. Although, no follow-up recommendations currently exist in cases of completely resected MA, we standardly perform postoperative surveillance. Although Metanephric Adenoma is difficult to diagnose preoperatively, given the advances in nephron sparing surgery and the utilization of nonionizing radiation modalities for follow up, we can manage these patients safely and with lower morbidity by preserving renal parenchyma. PMID- 30006268 TI - Abdominal Radiography With Digital Tomosynthesis: An Alternative to Computed Tomography for Identification of Urinary Calculi? AB - OBJECTIVE: To compare the accuracy of plain abdominal radiography (kidneys, ureter, and bladder [KUB]) with digital tomosynthesis (DT) to noncontrast computed tomography (NCCT), the gold standard imaging modality for urinary stones. Due to radiation and cost concerns, KUB is often used for diagnosis and follow-up of nephrolithiasis. DT, a novel technique that produces high-quality radiographs with less radiation and/or cost than low-dose NCCT, has not been assessed in this situation. MATERIALS AND METHODS: Seven fresh tissue cadavers were implanted with stones of known size and/or composition and imaged with KUB, DT, and NCCT. Four blinded readers (2 urologists, 2 radiologists) evaluated KUBs for presence and/or location of calculi. They then re-evaluated with addition of tomograms to assess additional value. After a memory extinction period, readers evaluated NCCT images. Accuracy of detection was determined using nearest neighbor match with generalized linear mixed modeling. RESULTS: Total of 59 stones were identified on reference read. Overall, NCCT and DT were both superior to KUB alone (P < .001) while the difference between DT and NCCT was not significant (P = .06). When evaluating uric acid stones, NCCT and DT outperformed KUB (P < .01 and P < .05, respectively) while DT and NCCT were similar (P = .16). Intrarenal stones were better evaluated on DT and NCCT (P < .001 compared to KUB), while DT and NCCT were similar (P = 1.00). Accuracy was lower than anticipated across modalities due to use of the cadaver model. CONCLUSION: Our study demonstrates DT is superior to KUB for identification of intrarenal calculi and could replace routine use of KUB or NCCT for detecting renal stones, even those composed of uric acid. PMID- 30006269 TI - Cerebral blood flow modulations during preparatory attention and proactive inhibition. AB - This study investigated cerebral blood flow modulations during task preparation in a precued saccade paradigm. Bilateral blood flow velocities in the middle cerebral arteries were recorded in 48 subjects using functional transcranial Doppler sonography. Video-based eye-tracking was applied for ocular recording. Antisaccade and prosaccade trials were presented in both block-wise and interleaved order. A right dominant flow response arose during task preparation. While the response was stronger during antisaccade than prosaccade trials, the degree of lateralisation did not differ between the two trial types. Direction error rates were higher and latencies were longer for antisaccades than prosaccades. There were no differences between block-wise and interleaved trials in blood flow or performance. The stronger blood flow increases during antisaccade than prosaccade preparation reflects the complexity of the upcoming task demands as well as proactive inhibition. The right hemispheric lateralisation may be attributed to preparatory attention independent of demands on inhibitory control. PMID- 30006270 TI - First identification of Naegleria species and Vahlkampfia ciguana in Nile water, Cairo, Egypt: Seasonal morphology and phylogenetic analysis. AB - BACKGROUND/PURPOSE: In Egypt, there is a scarcity of data concerning Naegleria (N.) family, with a shortage of phylogenetic studies. This study's aim was molecular detection, sequencing and phylogenetic analysis of morphologically identified Nagleria and to determine natural seasonal distribution of Nagleria species in water sources of Greater Cairo, Egypt. METHODS: A total of 120 water samples were collected during each season over a year. Every water sample was filtrated and cultured on non-nutrient agar (NNA). Morphologically positive Nagleria-like isolates were subjected to Nagleria genus and species-specific PCR targeting rDNA gene, PCR products were sequenced and obtained sequences were phylogenetic analyzed. RESULTS: Nile River water was the only source found to contained Naegleria. For the first time in Egypt, Vahlkampfia ciguana and the Naegleria species N.australiensis, N.philippinensis and N.neojejuensis were identified from the Nile water. The pathogenic Naegleria fowleri, previously reported in Egypt, was however not detected in this study. CONCLUSION: Interestingly, there were no seasonal variations in prevalence of Naegleria spp.; yet, there was seasonal diversity in the water samples of the same site. These newly discovered Vahlkampfiidae in Egyptian aquatic environments indicate the need for further phylogenetic investigations using bigger sample sizes in order to determine their potential risk for human health. PMID- 30006271 TI - Effects of Different Parameters of Continuous Training and High-Intensity Interval Training in the Chronic Phase of a Mouse Model of Complex Regional Pain Syndrome Type I. AB - This study evaluated the effects of continuous and interval running on a treadmill on mechanical hyperalgesia in an animal model of chronic postischemia pain and analyzed the mechanism of action of this effect. Different groups of male Swiss mice with chronic postischemia pain, induced by 3 hours of paw ischemia followed by reperfusion, ran on the treadmill in different protocols-the speed (10, 13, 16, or 19 m/min), duration (15, 30, or 60 minutes), weekly frequency (3 or 5 times), weekly increase in continuous and interval running speed-were tested. Mechanical hyperalgesia was evaluated by von Frey filament 7, 14, and 21 days after paw ischemia followed by reperfusion. On day 11 after paw ischemia followed by reperfusion and after 5 days of continuous and interval running, concentrations of cytokines, oxidative stress parameters, and extracellular signal-regulated kinase 1/2 and AKT 1/2/3 expression in the spinal cord were measured. The results showed that continuous running has an antihyperalgesic effect that depends on intensity and volume. Interval running has a longer-lasting antihyperalgesic effect than continuous running. The antihyperalgesic effect depends on intensity and volume in continuous running, and increasing speed maintains the antihyperalgesic effect in both protocols. In the spinal cord, both runs decreased tumor necrosis factor-alpha and interleukin 6 levels and increased interleukin-10. Both running protocols reduced oxidative damage in the spinal cord. Only interval running had lower concentrations of phosphorylated extracellular signal-regulated kinase 1/2 in the spinal cord. Interval running presented a great antihyperalgesic potential with more promising results than continuous running, which may be owing to the fact that the interval running can activate different mechanisms from those activated by continuous running. PERSPECTIVE: A minimum of .5-hour sessions of moderate to high intensity >=3 times a week are essential parameters for continuous and interval running induced analgesia. However, interval running was shown to be more effective than continuous running and can be an important adjuvant treatment to chronic pain. PMID- 30006272 TI - Autoantibody profiling in intraocular fluid of patients with uveitis. AB - A high prevalence of serum antiretinal antibodies (ARAs) in patients with uveitis has been previously described, though their clinical role remains elusive. Assessment of intraocular ARAs may provide further insight into the pathogenesis of diverse uveitis entities. In this study we investigate the prevalence of multiple specific anti-ocular antibodies (AOcAs), including ARAs, in intraocular fluid of patients with uveitis. Autoantibody profiling with 188 different ocular antigens was performed by a multiplex immunoassay with intraocular fluid samples of 76 patients with uveitis. Clinical data from uveitis patients were collected and statistical analyses were executed to evaluate associations between intraocular AOcAs and clinical characteristics. Controls consisted of 19 intraocular fluid samples from cataract patients. A spectrum of 22 different AOcAs was present in higher levels in patients with uveitis than in controls (p < 0.05), but in moderately elevated titers (<2x). High elevations of intraocular AOcAs in uveitis (>5x compared to cataract) were observed in varicella zoster virus-induced uveitis, multiple sclerosis-associated uveitis and patients with unexplained uveitis but positive quantiferon test. Presence of macular edema was associated with increased intraocular levels of tyrosinase antibodies. Our results show that patients with uveitis are characterized by the presence of a broad spectrum of moderately elevated levels of intraocular AOcAs, and high intraocular AOcA levels were found in several specific uveitis entities. This study favors secondary production of AOcAs and not their inciting role. PMID- 30006273 TI - Fixation instability during binocular viewing in anisometropic and strabismic children. AB - PURPOSE: Strabismus or anisometropia disrupts binocularity and results in fixation instability, which is increased with amblyopia. Fixation instability has typically been assessed for each eye individually. Recently, vergence instability was reported in exotropic adults and monkeys during binocular viewing. We evaluated fixation instability during binocular viewing in children treated for anisometropia and/or strabismus. METHODS: 160 children age 4-12 years with treated esotropia and/or anisometropia (98 amblyopic, 62 nonamblyopic) were compared to 46 age-similar controls. Fixation instability was recorded during binocular fixation of a 0.3 deg diameter dot for 20 s using a 500 Hz remote video binocular eye tracker (EyeLink 1000; SR Research). The bivariate contour ellipse area (BCEA; log deg2) for fixation instability was calculated for each eye (nonpreferred, preferred) and for vergence instability (left eye position - right eye position). Best-corrected visual acuity, Randot Preschool stereoacuity, and extent of suppression scotoma (Worth 4-Dot) were also obtained. RESULTS: When binocularly viewing, both amblyopic and nonamblyopic children treated for anisometropia and/or strabismus had larger fixation instability and vergence instability than controls. Amblyopia primarily added to the instability of the nonpreferred eye. Anisometropic children had less nonpreferred eye instability and vergence instability than those with strabismus or combined mechanism. Nonpreferred eye instability and vergence instability were related to poorer stereoacuity and a larger suppression scotoma. Preferred eye instability was not related to any visual outcome measure. No relationships were found with visual acuity. CONCLUSIONS: Fixation instability and vergence instability during binocular viewing suggests that discordant binocular visual experience during childhood, especially strabismus, interferes with ocular motor development. Amblyopia adds to instability of the nonpreferred eye. Vergence instability may limit potential for recovery of binocular vision in these children. PMID- 30006274 TI - Establishment of a conditionally immortalized mouse optic nerve astrocyte line. AB - Optic nerve astrocytes play a major role in axonal degeneration and regeneration. Astrocyte lines are an important tool to elucidate the responsible cellular mechanisms. In this study, we established a conditionally immortalized mouse optic nerve astrocyte line. Astrocytes were cultured from explants derived from postnatal day 4-5 H-2kb-tsA58 transgenic mouse optic nerves. Cells were cultured in defined astrocyte culture medium under permissive (33 degrees C) or non permissive (38.5 degrees C) temperatures with or without interferon-? (IFN-?). Astrocytes were characterized by immunocytochemistry staining using antibodies against glial fibrillary acidic protein (GFAP) and neural cell adhesion molecule (NCAM). Cell proliferation rates were determined by cell growth curves and percentage of Ki67 positive cells. Karyotyping was performed to validate the mouse origin of established cell line. Conditional immortalization was assessed by western blot-determined expression levels of SV40 large T antigen (TAg), p53, GFAP and NCAM in non-permissive culture conditions. In addition, phagocytic activity of immortalized cells was determined by flow cytometry-based pHrodo fluorescence analysis. After 5 days in culture, cells migrated out from optic nerve explants. Immunocytochemistry staining showed that migrating cells expressed astrocyte makers, GFAP and NCAM. In permissive conditions, astrocytes had increased expression levels of TAg and p53, exhibited a greater cell proliferation rate as well as a higher percentage of Ki67 positive cells (n = 3, p < 0.05) compared to cells cultured in non-permissive conditions. One cell line (ImB1ON) was further maintained through 60 generations. Karyotyping showed that ImB1ON was of mouse origin. Flow cytometry-based pHrodo fluorescence analysis demonstrated phagocytic activity of ImB1ON cells. Quantitative PCR showed mRNA expression of trophic factors. Non-permissive culture conditions decreased expression of TAg and p53 in ImB1ON, and increased the expression of NCAM. A conditionally immortalized mouse optic nerve astrocyte line was established. This cell line provides an important tool to study astrocyte biological processes. PMID- 30006275 TI - Mechanical reliability of dental grade zirconia after laser patterning. AB - The aim of this work is to test the mechanical properties of dental zirconia surfaces patterned with Nd:YAG laser interference (lambda = 532 nm and 10 ns pulse). The laser treatment produces an alteration of the topography, engraving a periodic striped pattern. Laser-material interaction results mainly in thermal effects producing microcracking, phase transformation and texturization. The role of such microstructural modifications and collateral damage on the integrity and mechanical performances has been assessed. Laser patterned discs of zirconia doped with 3% mol yttria (3Y-TZP) have been tested before and after a thermal treatment to anneal residual stresses and revert phase transformation. Both groups of samples behave in a similar manner, excluding residual stresses and phase transformation from the origin of properties modification. Result show that laser patterning induces a minor decrease in mechanical properties and surface integrity of 3Y-TZP surfaces. The biaxial strength decreases as a consequence of the damage induced by laser patterning. Fractographic observations identify preexisting defects enlarged by local laser interaction as the fracture origins. The Hardness and Young modulus of treated surfaces tested with nanoindentation also decrease slightly after laser treatment and this may be attributed to laser induced microcracking. PMID- 30006276 TI - Phase pure, high hardness, biocompatible calcium silicates with excellent anti bacterial and biofilm inhibition efficacies for endodontic and orthopaedic applications. AB - Here we report for the very first time the synthesis of 100% phase pure calcium silicate nanoparticles (CSNPs) of the alpha-wollastonite phase without using any surfactant or peptizer at the lowest ever reported calcination temperature of 850 degrees C. Further, the phase purity is confirmed by quantitative phase analysis. The nano-network like microstructure of the CSNPs is characterized by FTIR, Raman, XRD, FESEM, TEM, TGA, DSC etc. techniques to derive the structure property correlations. The performance efficacies of the CSNPs against gram positive e.g., S. pyogenes and S. aureus (NCIM2127) and gram-negative e.g., E. coli (NCIM2065) bacterial strains are studied. The biocompatibility of the CSNPs is established by using the conventional mouse embryonic osteoblast cell line (MC3T3). In addition, the biofilm inhibition efficacies of two varieties of CSNPs e.g., CSNPs(W) and CSNPs(WC) are investigated. Further, the interconnection between ROS e.g., superoxide (O2.-) and hydroxyl radical (.OH) generation capabilities of CSNPs and their biofilm inhibition efficacies is clearly established for the very first time. Finally, the mechanical responses of the CSNPs at the microstructural length scale are investigated by nanoindentation. The results confirm that the alpha-wollastonite phases present in CSNPs(W) and CSNPs(WC) possess extraordinarily high nanohardness and Young's moduli values. Therefore, these materials are well suited for orthopaedic and endodontic applications. PMID- 30006277 TI - Mechanical properties, structure, bioactivity and cytotoxicity of bioactive Na-Ca Si-P-O-(N) glasses. AB - Bioactive glasses are able to bond to bone through formation of carbonated hydroxyapatite in body fluids. However, because of their poor strength their use is restricted to non-load-bearing applications. The effects of nitrogen addition on the physical and mechanical properties and structure of bioactive oxynitride glasses in the system Na-Ca-Si-P-O-N have been studied. Glasses with compositions (mol.%): 29Na2O-13.5CaO-2.5P2O5-(55 -3x)SiO2-xSi3N4 (x is the no. of moles of Si3N4) were synthesised with up to 1.5 at% P and 4.1 at% N. A novel 3-step process was used for addition of P and N and this proved successful in minimising weight losses and producing homogeneous glasses with such high SiO2 contents. The substitution of 4.12 at% N for oxygen results in linear increases in density (1.6%), glass transition temperature (6%), hardness (18%) and Young's modulus (74%). Vickers Indentation Fracture (VIF) resistance (Kifr) was calculated from various relationships depending on the load, indent diagonal, crack lengths and Young's modulus to hardness (E/H) ratio. Firstly, Meyer's index n is calculated from the slope of the logarithmic plot of load versus indent diagonal. Then by comparing the experimental slopes of the logarithmic plots of crack lengths versus load it is concluded that the cracking mode is Radial Median type. The substitution of 4.12 at% N for oxygen results in an increase in Kifr of 40%. These increases in properties are consistent with the incorporation of N into the glass structure in three-fold coordination with silicon which results in extra cross-linking of the glass network. The structure of these bioactive oxynitride glasses was investigated by solid state nuclear magnetic resonance (MAS NMR) of 31P and 29Si. The structure reveals that all the N atoms are bonded to Si atoms with the formation of SiO3N, SiO2N2 and Q4 structural units with extra bridging anions at the expense of Q3 units. The bioactivity of the glasses has been evaluated by soaking them in simulated body fluid (SBF) and results confirm that all these oxynitride glasses are bioactive. Cytotoxicity tests based on different concentrations of these bioactive glass powders in a cell growth environment have also shown that they are not cytotoxic. PMID- 30006278 TI - Biomechanical evaluation of hMSCs-based engineered cartilage for chondral tissue regeneration. AB - Articular cartilage regeneration is still an open challenge in the field of tissue engineering. Although autologous chondrocytes seeded on collagen scaffolds (CSs) have already showed interesting results in the long-term repair of chondral lesions, they are not exempt from disadvantages that could be overcome using mesenchymal stem cells (MSCs). The ability of polymeric scaffolds to support MSCs proliferation and differentiation has been widely documented. However, few studies assessed their mechanical performances and additionally performing a single mechanical test, i.e. stress-strain or stress-relaxation in compression. Articular cartilage, though, possesses unique and multifaceted mechanical properties that can be exhaustively described only implementing a complete set of mechanical tests. Hence, the final aim of this study was to in depth assess the mechanical properties of human MSCs-cultured collagen scaffolds applying unconfined stress-strain, stress-relaxation and dynamic compression tests and identify key mechanical parameters. Firstly, plain CSs were fabricated and cultured under chondrogenic conditions with human MSCs (hMSCs). CSs displayed a high-interconnected porosity permitting uniform hMSCs distribution along the scaffold depth. Within CSs, hMSCs differentiated in chondroblasts, characterized by the presence of the lacunae and by a pericellular matrix positive for GAGs and for type 2 collagen deposition. The deep implemented mechanical characterization highlighted that the engineered constructs display (i) higher resistance to compression, (ii) more marked viscoelastic behavior over time and (iii) increased dynamic properties compared to naked CSs. In particular, stress-strain testes showed significant increase in the engineered constructs' stiffness that can be related to the proteoglycan deposition, observed by histology at the end of culture. Stress-relaxation and dynamic tests pointed out a substantial increase of peak and equilibrium stresses, relaxation time and dynamic modulus in the engineered constructs compared to empty CSs, suggesting a considerable decrease in scaffold permeability due to a strong chondral matrix deposition. Overall, the obtained results indicate a significant improvement of cell/CS mechanical performance toward a cartilage-like mechanical behavior. PMID- 30006279 TI - Loading and kinematic profiles for patellofemoral durability testing. AB - Patellar complications after total knee replacement (TKR), such as maltracking, fracture, wear, and loosening, can lead to implant failure and revision surgery. However, few in vitro patellofemoral durability tests for the implanted joint have been developed. Existing standards for patellofemoral loading profiles (ISO 14243-5, draft) are generic (not implant-specific) and do not include patient variability. The goal of this study was to derive implant-specific loading profiles to simulate a motor task that reaches high knee flexion and include patient variability. In vivo data, including motion capture and stereo radiographic images at the knee, were collected for eleven rotating platform TKR patients performing a single-leg lunge activity. Quadriceps forces during the activity were estimated for each patient from marker data and ground forces with a musculoskeletal model. Patellofemoral contact forces were estimated with patient-specific finite element models of the implanted knees. Stereo-radiography patellofemoral kinematics and estimated contact loads were combined to derive seven loading profiles that span the observed inter-patient variability. The loading profiles were experimentally evaluated in a 6-degree-of-freedom testing machine and worst-case loading profiles were identified. The two profiles that generated the highest stresses in the patellar button (43% and 46% of the volume surpassed yield stress, respectively) included the largest internal (4.4 degrees ) and external (13.0 degrees ) patellar rotation, and greater medio/lateral contact forces (up to 915 N). The same profiles were also tested in a finite element model of the experimental simulator, which was able to adequately replicate location and magnitude of the peak deformations measured in the prostheses after the experiment. The kinematic and loading profiles developed in this study simulated a high-demand motor task and incorporated inter-patient variability, capturing worst-case patellofemoral configurations, and can be utilized for pre-clinical testing of new patellar designs. PMID- 30006281 TI - Environmental contamination by bacteria in hospital washrooms according to hand drying method: a multi-centre study. AB - BACKGROUND: Hand hygiene is a fundamental component of infection prevention, but few studies have examined whether hand-drying method affects the risk of dissemination of potential pathogens. AIM: To perform a multi-centre, internal crossover study comparing bacterial contamination levels in washrooms with hand drying by either paper towels (PT) or jet air dryer (JAD; Dyson). METHODS: A total of 120 sampling sessions occurred over 12 weeks in each of three hospitals (UK, France, Italy). Bacteria were cultured from air, multiple surfaces, and dust. Washroom footfall (patients/visitors/staff) was monitored externally. FINDINGS: Footfall was nine times higher in UK washrooms. Bacterial contamination was lower in PT versus JAD washrooms; contamination was similar in France and the UK, but markedly lower in Italian washrooms. Total bacterial recovery was significantly greater from JAD versus PT dispenser surfaces at all sites (median: 100-300 vs 0-10 cfu; all P < 0.0001). In the UK and France, significantly more bacteria were recovered from JAD washroom floors (median: 24 vs 191 cfu, P < 0.00001). UK meticillin-susceptible Staphylococcus aureus recovery was three times more frequent and six-fold higher for JAD vs PT surfaces (both P < 0.0001). UK meticillin-resistant S. aureus recovery was three times more frequent (21 vs 7 cfu) from JAD versus PT surfaces or floors. Significantly more enterococci and extended-spectrum beta-lactamase (ESBL)-producing bacteria were recovered from UK JAD versus PT washroom floors (P < 0.0001). In France, ESBL-producing bacteria were recovered from dust twice as often during JAD versus PT use. CONCLUSION: Multiple examples of significant differences in surface bacterial contamination, including by faecal and antibiotic-resistant bacteria, were observed, with higher levels in JAD versus PT washrooms. Hand-drying method affects the risk of (airborne) dissemination of bacteria in real-world settings. PMID- 30006280 TI - Biomechanical, structural and biological characterisation of a new silk fibroin scaffold for meniscal repair. AB - Meniscal injury is typically treated surgically via partial meniscectomy, which has been shown to cause cartilage degeneration in the long-term. Consequently, research has focused on meniscal prevention and replacement. However, none of the materials or implants developed for meniscal replacement have yet achieved widespread acceptance or demonstrated conclusive chondroprotective efficacy. A redesigned silk fibroin scaffold, which already displayed promising results regarding biocompatibility and cartilage protection in a previous study, was characterised in terms of its biomechanical, structural and biological functionality to serve as a potential material for permanent partial meniscal replacement. Therefore, different quasi-static but also dynamic compression tests were performed. However, the determined compressive stiffness (0.56 +/- 0.31 MPa and 0.30 +/- 0.12 MPa in relaxation and creep configuration, respectively) was higher in comparison to the native meniscal tissue, which could potentially disturb permanent integration into the host tissue. Nevertheless, u-CT analysis met the postulated requirements for partial meniscal replacement materials in terms of the microstructural parameters, like mean pore size (215.6 +/- 10.9 um) and total porosity (80.1 +/- 4.3%). Additionally, the biocompatibility was reconfirmed during cell culture experiments. The current study provides comprehensive mechanical and biological data for the characterisation of this potential replacement material. Although some further optimisation of the silk fibroin scaffold may be advantageous, the silk fibroin scaffold showed sufficient biomechanical competence to support loads already in the early postoperative phase. PMID- 30006282 TI - Novel biomarker for neurodegenerative diseases- motor neuron disease (MND), cerebellar ataxia (CA) and Parkinson's disease (PD). AB - Oxygen is the most mandatory component of living organism and it may at times produce highly reactive species, the free radicals, which are destructive to normal living tissues. Degenerative diseases of central nervous system (CNS) are quite common, contributing significantly to morbidity as well as mortality %. In neurodegenerative diseases such as motor neuron disease (MND), Cerebellar Ataxia (CA) and Parkinson's disease (PD), there is no direct evidence for involvement of metals and free radicals in the etiology but circumstantial evidence provides a hypothesis that alteration in metals and free radicals contribute to the pathogenesis of neurodegeneration in these disorders. The aim of the present study was to estimate free radicals cascade i.e. damage caused in terms of malondialdehyde (MDA) and defense system Superoxide dismutase (SOD) and catalase in blood and cerebro-spinal fluid (CSF) of neurodegenerative diseases (MND, CA and PD), to analyze correlation with level of free radical and the clinical variables like age, severity of diseases and duration of illness and any possibility from this clinical parameters to identify a biomarker for diagnosis of neurodegenerative diseases. The level of MDA in CSF was 0.46 +/- 0.17 in case of MND, 0.49 +/- 0.13 in case of CA and 0.47 +/- 0.16 in case of PD as compared control group (0.22 +/- 0.06) whereas in blood MDA level was 0.10 +/- 0.04 in case of MND, 0.33 +/- 0.41 in case of CA and 0.47 +/- 0.46 in case of PD as compared control group (0.04 +/- 0.03). It was found to be highly significant (p < .001). In CSF and blood both catalase activity was statistically significantly higher as compared to control group of all cases (MND, CA and PD) and SOD activity was statistically significantly lower as compared to control group of all cases. Free radical parameters in human CSF might be a novel biomarker for the early clinical identification of neurodegenerative diseases. PMID- 30006283 TI - Utility of cystatin C-based equations in patients undergoing dialysis. AB - Serum cystatin C (CysC) measurement is regarded as a simple and practical alternative to measure residual renal function for dialysis patients. Recent studies have shown that CysC has better diagnostic accuracy or at least equivalence to creatinine in predicting the early stages of renal damage, and is closely related to clinical outcomes of dialysis patients. Thus, the applicability of CysC-derived equations in patients undergoing dialysis should be paid attention. Here, we review the role of CysC in diagnosis, renal function evaluation, and prognosis outcomes for dialysis patients, so as to provide them with useful suggestions on evaluating renal function and predicting adverse outcomes in clinical practice. PMID- 30006284 TI - Investigation of metabolic degradation of new ALK inhibitor: Entrectinib by LC MS/MS. AB - Entrectinib (ENC) is a potent orally available anaplastic lymphoma kinase (ALK) inhibitor. In 10 July 2017, biotechnology company (Ignyta) announced that granted orphan drug designation approval was given by the FDA to ENC for "treatment of NTRK fusion-positive solid tumors". A validated LC-MS/MS methodology was developed for ENC quantification in human plasma matrix. The supposed method characterized by high speed, specificity and sensitivity. This established method was applied for metabolic degradation assessment of ENC. Reversed stationary phase (C18 column) and elution mobile phase (48% 10 mM ammonium formate in H2O (pH: 4.2 adjusted by adding few drops of formic acid): 52% ACN) were utilized for chromatographic resolution of ENC and lapatinib as internal standard (IS). Total elution time, flow rate and injection volume were 4 min., 0.25 mL/min., and 5 MUL, respectively. Electrospray ionization source was used for ions generation, while positive multiple reactions monitoring (MRM) mode was used for ion analysis. The data of calibration curve of ENC in human plasma was linear in the range of 5-500 ng/mL with correlation coefficient (r2) >0.999. LOQ and LOD for ENC were 2.17 ng/mL and 0.71 ng/mL, respectively. Inter-day and intra-day precision and accuracy were 97.52 to 101.83%, and 0.38 to 1.32%, respectively. Intrinsic clearance (Clint) and in vitro half-life (t1/2) were equal to 15.67 mL/min/kg and 9.1 min, respectively. To our knowledge, this is considered the first method for ENC quantification in human plasma and its metabolic degradation assessment. PMID- 30006285 TI - The pretreatment albumin to globulin ratio as a significant predictor in patients with diffuse large B cell lymphoma. AB - BACKGROUND: The pretreatment albumin to globulin ratio (AGR) has been used to predict survival in several types of tumors. However, whether AGR can predict outcomes in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. We evaluated the prognosis value of AGR in DLBCL patients. METHODS: We retrospectively analyzed the available serum biochemical results of 335 patients with newly diagnosed DLBCL before treatment. The AGR was calculated as: albumin (g/L)/globulin. X-tile program was used to generate an optimal cut-off value of 1.3 for AGR. And all patients were respectively divided into the low AGR and high AGR groups according to the cut-off value. RESULTS: The low AGR group displayed more adverse clinical chacteristics, including old age, sex (female), increased beta2-microglobulinpoor (beta2-MG), increased lactate dehydrogenase (LDH), B symptoms, poor performance status (PS), advanced stage, number of extranodal sites >= 2 and higher International Prognostic Index (IPI). AGR was negatively correlated with age, IPI score, ECOG score, Ann Arbor stage, B symptoms, beta2 MG, LDH, and extranodal involvement, while positively correlated with gender. Patients with a low AGR presented with significantly poorer overall survival (OS, P = .001). Multivariate analysis further demonstrated that a low AGR was an independent adverse predictor for OS (HR = 0.613; 95% CI = 0.412-0.910, P = .015). In addition, AGR distinguished patients with different prognosis in stage III-IV and the non-germinal center B cell-like lymphoma (non-GCB) groups, a low AGR was also significantly associated with poor OS in 2 groups. CONCLUSION: Pretreatment AGR was a simple and effective clinical marker of survival in patients with DLBCL, and may had an additional prognostic value based on Ann Arbor stage and cell of origin for DLBCL. PMID- 30006286 TI - Cardiometabolic index as a useful discriminator for the risk of increased arterial stiffness. PMID- 30006287 TI - Paper-based enzymatic platform coupled to screen printed graphene-modified electrode for the fast neonatal screening of phenylketonuria. AB - INTRODUCTION: The PKU is an inborn error of amino acid metabolism, in which phenylalanine (Phe) accumulated in the blood causing alterations at the central nervous system. We report a novel paper-based enzymatic platform coupled to screen printed graphene-modified electrode for the neonatal screening of phenylketonuria (PKU0. METHODS: The paper-based analytical device coupled to electrochemical detection (EPAD) is based on the use of paper microzones modified with phenylalanine dehydrogenase enzyme (PheDH). The modified PADs were placed on the surface of an electrode modified with electrochemically reduced graphene (ERGO). PheDH in the presence of NAD+ catalyzes the reversible deamination of Phe to form phenylpyruvate, ammonia, and NADH. The electrochemical oxidation of NADH was monitored by differential pulse amperometry (DPA) at 0.6 V. The method was linear in the concentration range from 1 to 600 MUmol/L of Phe with a LOQ of 1 MUmol/L and LOD of 0.2 MUmol/L. Within day precision was 5.7% across 3 levels of control samples. Between-day precision was 8.3%. The comparison with the standard Phe enzyme assay kit showed good agreement. The time required for the overall assay was <5 min. The non-sophisticated equipment required, the short assay time and the appropriate LOQ and LOD achieved by our EPAD make it an attractive and easy to use alternative compared to existing methods applied to the screening of PKU in neonatal samples. PMID- 30006288 TI - Anti-AChR, MuSK, and LRP4 antibodies coexistence: A rare and distinct subtype of myasthenia gravis from Indian subcontinent. AB - BACKGROUND: Myasthenia gravis is B-cell mediated autoimmune disease and is associated with antibodies against the acetylcholine receptor (AChR), muscle specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) in the postsynaptic membrane at the neuromuscular junction. There are few studies on the concurrent presence of two positive antibodies in the sera of patients with myasthenia gravis. CASE DESCRIPTION: A 32-year male admitted to the hospital with progressive neuromuscular weakness. He was diagnosed with Myasthenia gravis disorder mimicking Amyotrophic Lateral Sclerosis. We herein report a rare co existence of three antibodies (anti-AChR, MuSK, and LRP4 antibodies) in the patient's serum. CONCLUSION: We present a detailed clinical and laboratory analysis of the patient. This case report will emphasize the importance of evaluating anti-MuSK and anti-LRP4 antibodies even in patients with anti-AChR antibodies. PMID- 30006289 TI - Vitamin E-stabilized UHMWPE: Biological response on human osteoblasts to wear debris. AB - UHMWPE doped with vitamin E was introduced to provide oxidation resistance upon sterilization, without affecting UHMWPE's mechanical properties. Particle-induced macrophage activation leads to periprosthetic bone resorption, requiring total joint replacements. During osteolysis, osteoblasts produce osteoimmunological factors such as RANKL and OPG, and the inhibitors of the Wnt pathway DKK-1 and Sclerostin. This study investigated in vitro how vitamin E-blended-UHMWPE wear debris might affect osteoblast-mediated osteolysis and the production of RANKL, OPG, Sclerostin and DKK-1, compared to conventional UHMWPE wear debris. Human osteoblastic SaOS2 cells were incubated with wear particles from Vitamin E doped and conventional UHMWPE and the gene expression and protein production of IL-6, RANKL, OPG, DKK-1, and Sclerostin was evaluated, RANKL, a bone erosion marker, was reduced, while OPG, a bone protective marker, were increased by the vitamin E blended UHMWPE compared to conventional UHMWPE. Vitamin E doped UHMWPE reduced Sclerostin level, and partially affected DKK-1 production, thereby protecting against bone erosion. In conclusion, Vitamin E-blended UHMWPE induced an osteoimmunological response in bone cells that had positive effects on the osteolysis induced by wear debris, reducing aseptic loosening of the implants. In conclusion, this is the first study showing that Vitamin E-blended UHMWPE induced an osteoimmunological response in bone cells that positively affect the osteolysis induced by wear debris, thereby reducing the aseptic loosening of the implants. PMID- 30006290 TI - Prognostic and clinicopathological value of PBRM1 expression in renal cell carcinoma. AB - BACKGROUND: The prognostic value of PBRM1 expression in renal cell carcinoma (RCC) had been investigated in previous studies; however, the results remain inconclusive. We investigated the prognostic value and clinicopathological significance of PBRM1 protein expression in RCC. METHODS: PubMed, Embase, Web of Science, and Cochrane database were searched for studies investigating the relationships between PBRM1 expression and outcomes in RCC. Hazard ratios (HRs) for survival outcomes and odds ratios (ORs) for clinical parameters were extracted from eligible studies. Heterogeneity was assessed using the I2 value. The fixed-effects model was used if there was no evidence of heterogeneity; otherwise, the random-effects model was used. Publication bias was evaluated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 2942 patients from 7 studies were included in the meta-analysis. The results showed that decreased expression of PBRM1 is associated with poor overall survival (OS) (HR = 2.11, 95% CI: 1.52-2.96), cancer-specific survival (CSS) (HR = 1.32, 95% CI: 1.10-1.58), and progression-free survival/ recurrence-free survival (PFS/RFS) (HR = 1.57, 95%CI: 1.34-1.85) in RCC. In addition, PBRM1 positive expression was significantly associated with earlier TNM stage (III/IV vs. I/II, OR = 0.53, 95% CI: 0.30-0.94), primary tumor stage (pT3/4 vs. pT1/2, OR = 0.32, 95% CI: 0.20 0.52), and Fuhrman grade (3/4 vs. 1/2, OR = 0.69, 95% CI: 0.46-1.02), but not related to Necrosis or Sex. CONCLUSIONS: Decreased expression of PBRM1 is correlated with poor prognosis and advanced clinicopathological features in patients with RCC. PMID- 30006292 TI - Pepper with and without a sting: Brain processing of intranasal trigeminal and olfactory stimuli from the same source. AB - Humans have distinct and overlapping brain regions for the processing of intranasal olfactory or trigeminal stimuli. It may be assumed that trigeminal stimulants and "trigeminal-free" odorous stimuli from the same source are processed differently in the human brain. Using functional magnetic resonance imaging (fMRI), this study investigated the question whether the black pepper (Piper nigrum) derived trigeminal active compound piperine and the trigeminal free pepper essential oil (pepperEO) are processed in relation to their degree of trigeminal stimulation. Twenty-one young healthy adults underwent a fMRI scan where piperine and pepperEO were delivered orthonasally using an olfactometer. Ratings for intensity, irritability, and pleasantness of each stimulus were obtained at the end of the scanning session. Results showed brain activation of the trigeminal network in response to piperine, and olfactory-related areas in response to pepperEO. PepperEO induced larger activations in the trigeminal network as compared to piperine. This was possibly due to the associative learning for the pungent sensations of pepperEO. In addition, conjunction analyses showed that the secondary somatosensory area, insula, and thalamus were involved in the processing of both piperine and pepperEO. In conclusion, the results strongly suggest that the cerebral representations of trigeminal irritants can be evoked by learned associations. PMID- 30006291 TI - Generation of monoclonal antibodies against 17alpha-hydroxyprogesterone for newborn screening of congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by the deficiency of one of the five enzymes involved in the biosynthesis of corticosteroids. The most common form of the disease is the lack of 21 hydroxylase which provokes an accumulation of high levels of 17alpha hydroxyprogesterone (17-OHP), the main biochemical marker for illness detection. Given the significance of neonatal diagnosis for ensuring a timely treatment to patients suffering from CAH, newborn screening is worldwide performed for the determination of 17-OHP from dried blood spots on filter paper. The non specificity of antisera employed in immunoassays and the cross-reaction with fetal adrenal hormones produce an overestimation in the 17-OHP quantification. Immunization of mice with 17-OHP-3-(O-carboxymethyl) oxime-bovine serum albumin led to the generation of 15 anti-17-OHP IgG1-and-IgG2b-secreting hybridomas. The 6E2G9 monoclonal antibody presents cross-reactivity values similar to those achieved by rabbit antibodies employed in the solid phase of UMELISA(r) 17-OH Progesterona Neonatal, assay for the newborn screening of CAH in Cuba. Additionally, the use of 6E2G9 in the evaluation of dried blood spots samples from newborns on filter paper showed a decrease in the mean 17-OHP levels, thus demonstrating it can replace the conventional rabbit antisera. PMID- 30006293 TI - Correlation between tumor necrosis factor alpha mRNA and microRNA-155 expression in rat models and patients with temporal lobe epilepsy. AB - Accumulative evidence demonstrates that there is an inseparable connection between inflammation and temporal lobe epilepsy (TLE). Some recent studies have found that the multifunctional microRNA-155 (miR-155) is a key regulator in controlling the neuroinflammatory response of TLE rodent animals and patients. The aim of the present study was to investigate the dynamic expression pattern of tumor necrosis factor alpha (TNF-alpha) as a pro-inflammatory cytokine and miR 155 as a posttranscriptional inflammation-related miRNA in the hippocampus of TLE rat models and patients. We performed real-time quantitative PCR (qRT-PCR) on the rat hippocampus 2 h, 7 days, 21 days and 60 days following kainic acid-induced status epilepticus (SE) and on hippocampi obtained from TLE patients and normal controls. To further characterize the relationship between TNF-alpha and miR-155, we examined the effect of antagonizing miR-155 on TNF-alpha secretion using its antagomir. Here, we found that TNF-alpha secretion and miR-155 expression levels were correlated after SE. The expression of TNF-alpha reached peak levels in the acute phase (2h post-SE) of seizure and then gradually decreased; however, it rose again in the chronic phase (60 days post-SE). miR-155 expression started to increase 2 h post-SE, reached peak levels in the latent phase (7 days post-SE) of seizure and then gradually decreased. The variation in the trend of miR-155 lagged behind that of TNF-alpha. In patients with TLE, the expression levels of both TNF-alpha and miR-155 were also significantly increased. Furthermore, antagonizing miR-155 inhibited the production of TNF-alpha in the hippocampal tissues of TLE rat models. Our findings demonstrate a critical role for miR-155 in the physiological regulation of the TNF-alpha pro-inflammatory response and elucidate the role of neuroinflammation in the pathogenesis of TLE. Therefore, regulation of the miR-155/TNF-alpha axis may be a new therapeutic target for TLE. PMID- 30006294 TI - The recovery from transient cognitive dysfunction induced by propofol was associated with enhanced autophagic flux in normal healthy adult mice. AB - Propofol is the most widely accepted intravenous anesthetic available for clinical use. However, neurotoxicity of propofol in the developing brain has been reported. This study investigated the effects of propofol on cognitive function in normal healthy adult mice. Thirty-three GFP-LC3 adult mice were included. Propofol was injected for anesthesia (n = 22). The sham control (n = 11) received intralipid injections. The mice completed a Y-maze test on 3 and 7 days after being anesthetized. Western blotting, immunofluorescence staining, and transmission electron microscopic (TEM) analyses were performed with their hippocampi. In addition, we conducted a separate ex vivo experiment using organotypic hippocampal slice cultures (OHSCs) to investigate the effects of propofol on induced autophagy. There was a significantly lower percentage of alternation in the Y-maze test on day 3 after propofol anesthesia than the control, but no difference was observed on day 7. Western blot analyses and immunofluorescence assays showed that the levels of cognitive function-related proteins significantly decreased in the propofol group compared to the control on day 3 but had recovered by day 7. In terms of autophagy-related proteins, western blot analyses and immunofluorescence assays showed that propofol increased autophagic induction, flux, and degradation of autophagosomes. Ex vivo experiments showed that propofol enhanced autophagic flux of the induced autophagy. In conclusion, although transient cognitive dysfunction occurred, adult mice recovered their cognitive function after the administration of propofol anesthesia. And this finding may be associated with enhanced autophagic flux. PMID- 30006295 TI - Resting heart rate variability in young women is a predictor of EEG reactions to linguistic ambiguity in sentences. AB - Recent research has found a relationship between heart rate variability (HRV) and cognitive control mechanisms underlying various experimental tasks. This study explored the interaction between gender and resting-state HRV in brain oscillatory activity during visual recognition of linguistic ambiguity while taking state and trait anxiety scores into account. It is well known that stress or anxiety increases arousal levels, particularly under uncertainty situations. We tasked 50 young Mandarin speakers (26 women; average age 26.00 +/- 4.449) with the recognition of linguistic ambiguity in English (foreign) sentences with the purpose of imposing a sense of uncertainty in decision-making. Our results revealed a dependency between resting-state HRV and theta/alpha power in individual women. Low HRV women showed stronger theta/alpha desynchronization compared with their high HRV counterparts, independent of topographic localization. However, low and high HRV men exhibited comparable theta/alpha activity. Trait anxiety scores affected alpha power in the parieto-occipital regions, whereas men with higher scores and women with lower scores showed stronger alpha desynchronization. We posit that stress-provoking situations may impose additional effects on theta/alpha desynchronization in the frontal and temporal regions, a condition in which the interdependency between brain oscillatory activity and resting-state HRV could interact with cognitive control differently in men and women. PMID- 30006297 TI - Vitamin D, homocysteine and n-3PUFA status according to physical and cognitive functions in older adults with subjective memory complaint: Results from cross sectional study of the MAPT trial. AB - OBJECTIVE: The aim of this study was to investigate the nutritional markers (Vitamin D, homocysteine, n-3PUFA) status of older subjects aged 70 years and older with subjective memory complaint, according to their physical and cognitive function. MAIN OUTCOME MEASURES: This study is a secondary analysis of the MAPT study. Subjects were classified into four groups: 1) Physical limitation with cognitive impairment (PLCI), 2) cognitive impairment (CI), 3) physical limitation (PL) and 4) no physical or cognitive deficits (NPCD). Baseline nutritional characteristics of the four groups according to Vitamin D (n = 732), Omega-3 polyunsaturated fatty acid (n-3PUFA) (n = 1537) and plasma total homocysteine (tHcy) (n = 729) status were investigated. Analysis was performed taking continuous and dichotomized value for Vitamin D insufficiency ([25(OH)D] < 30 ng/ml, high homocysteine level (tHcy >= 15 MUmol/L) and low n-3PUFA (DHA + EPA <= 4.82%) nutritional markers for clinical relevance. RESULTS: PLCI group showed the lowest mean level of Vitamin D and highest level tHcy compared to the other groups. In multivariate analysis, taking continuous nutritional markers, only high Vitamin D was associated with reduced likelihood of PLCI (OR 0.97, 95% CI (0.95 to 0.99) P = 0.011). While taking the dichotomized values the group with low levels of n-3PUFA showed higher likelihood of PL only (OR 1.55, 95% CI (1.12 to 2.15), P = 0.009). Furthermore, our sensitivity analysis for Vitamin D with cut-off [25(OH)D] < 20 ng/ml,(i.e., Vitamin D deficiency), showed more likelihood of PL (OR 1.62, 95% CI (1.01 to 2.60) P = 0.046), CI (OR 1.90, 95% CI (1.16 to 3.10) P = 0.010), and highest likelihood of PLCI (OR 1.99, 95% CI (1.21 to 3.28) P = 0.006). CONCLUSION: In older adults with subjective memory complaints, Vitamin D deficiency status may present higher likelihood of functional deficits, including coexisting or separate physical and cognitive decline. While older adults with low level of n-3PUFA were more likely to demonstrate physical decline only. PMID- 30006296 TI - Chronic mild hypoxia increases expression of laminins 111 and 411 and the laminin receptor alpha6beta1 integrin at the blood-brain barrier. AB - The laminin family of glycoproteins are major constituents of the basal lamina of blood vessels, and play a fundamental role in promoting endothelial differentiation and blood-brain barrier (BBB) stability. Chronic mild hypoxia (CMH), in which mice are exposed to 8% O2 for two weeks, induces a strong vascular remodeling response in the central nervous system (CNS) that includes endothelial proliferation, angiogenesis, arteriogenesis as well as increased expression of tight junction proteins, suggestive of enhanced vascular integrity. As previous studies highlight an important role for laminin in promoting vascular differentiation and BBB stability, the goal of this study was to determine if CMH influences the expression of the laminins and their cell surface receptors in cerebral blood vessels. Our studies revealed that over a 14 day period of CMH, blood vessels in the brain showed strong upregulation of the specific laminin subunits alpha1 and alpha4, corresponding to increased expression of laminins 111 and 411 respectively, with no discernible changes in the expression levels of the alpha2 or alpha5 laminin subunits. This was accompanied by marked endothelial upregulation of the laminin receptor alpha6beta1 integrin but no alterations in the other laminin receptors alpha1beta1 integrin or dystroglycan. In light of the instructive role for laminins in promoting vascular differentiation and stability, these data suggest that upregulation of the laminin-alpha6beta1 integrin axis is part of the molecular response triggered by mild hypoxia that leads to enhanced BBB stability. PMID- 30006298 TI - ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats. AB - The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 * Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved. PMID- 30006299 TI - Changes in regional cerebral blood flow associated with a 45 day course of the ketogenic agent, caprylidene, in patients with mild to moderate Alzheimer's disease: Results of a randomized, double-blinded, pilot study. AB - BACKGROUND: Caprylidene is a ketogen that, when metabolized, produces the ketones beta-hydroxybutyrate and acetoacetate, which can cross the blood brain barrier. It has been hypothesized that ketone bodies can be used as an alternate energy source by neurons with impaired glucose utilization. Caprylidene has been shown to improve cognition in patients with mild-to-moderate Alzheimer's disease (AD) who lacked an AD-predisposing allele (E4) of the gene for apolipoprotein E. In this pilot study, we examined the effects of caprylidene on regional cerebral blood flow (rCBF) in patients with mild to moderate AD. METHODS: Sixteen subjects with mild-to-moderate AD, based on NINCDS-ADRDA criteria, were enrolled in a double-blinded, placebo-controlled, randomized clinical trial. Fourteen subjects received treatment with caprylidene, and 2 subjects were given placebo. Subjects received 4 15O-water PET scans over the course of the study to assess rCBF: once before receiving a standard caprylidene or placebo dose and 90 min after the dose, on the first day and after 45 days of daily caprylidene or placebo consumption. The scans were examined by standardized volumes of interest (sVOI) and voxel-based statistical parametric mapping (spm) methods of analysis. RESULTS: Subjects lacking an E4 allele had significantly elevated rCBF in the left superior lateral temporal cortex by sVOI analysis after adopting a caprylidene diet for 45 days (p = 0.04), which was further corroborated by spm. The anterior cerebellum, left inferior temporal cortex, and hypothalamus were also found by spm to be regions of long-term increase in rCBF in these subjects. In contrast, patients who possessed the E4 allele did not display these changes in rCBF. CONCLUSION: Daily ingestion of caprylidene over 45 days was associated with increased blood flow in specific brain regions in patients lacking an apolipoprotein E4 allele. PMID- 30006300 TI - Enhancement of the antibacterial activity of an E. faecalis strain by the heterologous expression of enterocin A. AB - The genus Enterococcus occurs as native microbiota of fermented products due to its broad environmental distribution and its resistance to salt concentrations. Enterococcus faecalis F, a non-pathogenic strain isolated from a ripened cheese, has demonstrated useful enzymatic capabilities, a probiotic behavior and antibacterial activity against some food-borne pathogens, mainly due to peptidoglycan hydrolase activity. Its use as a natural pathogen-control agent could be further enhanced through the production of a bacteriocin, e.g. Enterocin A, because of its remarkable antilisterial activity. In this work, a markerless allelic insertion method was used to obtain an enterococcal strain capable of producing a functional enterocin. Agar diffusion tests showed that the recombinant strain was active against Staphylococcus aureus, Listeria monocytogenes and the pathogenic strain E. faecalis V583. When grown in liquid culture together with L. monocytogenes, it attained a two-log reduction of the pathogen counts in lesser time relative to the native strain. Because the DNA construction is integrated into the chromosome, the improved strain avoids the use of antibiotics as selective pressure; besides, it does not require an inductor because of the inclusion of a constitutive promoter in the construction. Its technological and antibacterial capabilities make the improved E. faecalis strain a potential culture for use in the food industry. PMID- 30006301 TI - The Importance of Recognizing an Association Between Obstructive Sleep Apnea and Post-Traumatic Stress Disorder. PMID- 30006302 TI - Effects of Biomineralization on Osseointegration of Pure Titanium Implants in the Mandible of Beagles. AB - PURPOSE: The purpose of this study was to investigate the effect of a biologically active dental implant surface (treated with sandblasting and acid etching [SLA] followed by immersion in simulated body fluid [SBF]) on osseointegration. MATERIALS AND METHODS: We randomly divided 9 healthy adult male beagles (aged 8 months; body weight, 12 kg) into 3 groups: machined, SLA, and SLA biomineralization (SLA-Bio). Six pure titanium implants (diameter of 3.5 mm and length of 8 mm) were used in the mandible of each dog after observation of the surface morphology, as well as analysis of the composition of the surface elements by scanning electron microscopy-energy dispersive x-ray spectroscopy. At 4, 8, and 12 weeks after implantation, animals were euthanized to collect the mandibles so that we could perform the removal torque test to evaluate the implant stability in bone and histomorphometry to analyze the implant-bone osseointegration. RESULTS: Scanning electron microscopy results showed that uniformly distributed sponge-like structures were found on the SLA-treated surface and an apatite layer was observed on the SLA-SBF-treated surface (SLA-Bio group). In the energy dispersive x-ray spectroscopy analysis, the elements titanium, oxygen, carbon, calcium, and phosphorus were found on the surfaces of the SLA-Bio group, whereas titanium was the only element found in the other groups. The removal torque test showed that the peak removal torque values of the 3 groups increased gradually with the passage of time, and the peak removal torque values of the SLA-Bio group were significantly higher than those of the other groups (P < .01) at 4, 8, and 12 weeks after implantation. Histomorphometric analysis showed that osseointegration was being enabled more rapidly in the SLA-Bio group, as well as that the mineral apposition rate and percentage of bone-to-implant contact of the SLA-Bio group were higher than those of the remaining groups at 4, 8, and 12 weeks after implantation (P < .01). CONCLUSIONS: Treating titanium implants with SLA-SBF can improve osseointegration as well as increase the interfacial shear strength. PMID- 30006303 TI - Host-Derived Serine Protease Inhibitor 6 Provides Granzyme B-Independent Protection of Intestinal Epithelial Cells in Murine Graft-versus-Host Disease. AB - Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT) that limits the therapeutic potential of this treatment. Host antigen-presenting cells (APCs) play a vital role in activating donor T cells that subsequently use granzyme B (GzmB) and other cytotoxic molecules to damage host normal tissues. Serine protease inhibitor 6 (Spi6), known as the sole endogenous inhibitor of GzmB, has been implicated in protecting T cells and APCs against GzmB-inflicted damage. In this study we used murine models to examine the previously unknown role of host derived Spi6 in GVHD pathogenesis. Our results indicated that host Spi6 deficiency exacerbated GVHD as evidenced by significantly increased lethality and clinical and histopathologic scores. Using bone marrow chimera system, we found that Spi6 in nonhematopoietic tissue played a dominant role in protecting against GVHD and was significantly upregulated in intestinal epithelial cells after allo HCT, whereas Spi6 in hematopoietic APCs surprisingly suppressed alloreactive T cell response. Interestingly, the protective effect of Spi6 and its expression in intestinal epithelial cells appeared to be independent of donor-derived GzmB. We used in silico modeling to explore potential targets of Spi6. Interaction tested in silico demonstrated that Spi6 could inhibit caspase-3 and caspase-8 with the same functional loop that inhibits GzmB but was not capable of forming stable interaction with caspase-1 or granzyme A. Using an in vitro co-culture system, we further identified that donor T cell-derived IFN-gamma was important for inducing Spi6 expression in an intestinal epithelial cell line. Altogether, our data indicate that host Spi6 plays a novel, GzmB-independent role in regulating alloreactive T cell response and protecting intestinal epithelial cells. Therefore, enhancing host-derived Spi6 function has the potential to reduce GVHD. PMID- 30006304 TI - Ex Vivo Generated Human Cord Blood Myeloid-Derived Suppressor Cells Attenuate Murine Chronic Graft-versus-Host Diseases. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with anti-inflammatory activity, and expanded murine MDSCs are capable of attenuating preclinical acute graft-versus-host disease (aGVHD) severity. Two murine cGVHD models were used to evaluate the effectiveness of ex vivo cultured human cord blood (hCB) MDSCs in chronic GVHD (cGVHD). First, GVHD recipients surviving in a classic C57BL/6 into MHC-mismatched BALB/c aGVHD model developed cGVHD. Second, donor pretreatment with granulocyte colony-stimulating factor (G-CSF) induced cGVHD. hCB-MDSCs (1 * 106) were intravenously injected to determine their preventive effects (on days 5, 7, 10, and 21) or therapeutic effects (on days 21, 28, and 35). In the first model the onset of clinical cutaneous cGVHD was significantly delayed in preventive hCB-MDSCs-treated allogeneic recipients. Pathologic scoring of target organs confirmed these clinical results. Importantly, thymic tissues of GVHD mice treated with hCB-MDSCs were less severely damaged, showing higher numbers of double (CD4 and CD8) positive T cells with reduced expansion of donor-type CD4 and CD8 T cells. Moreover, late infusion of hCB-MDSCs controlled the severity of established cGVHD that had occurred in control recipients. In the second model, cGVHD induced by G CSF-mobilized stem cell graft was associated with promotion of Th 17 and Th 2 differentiation. hCB-MDSCs attenuated clinical and pathologic cGVHD severity. Increased production of IL-17 and more infiltration of T cells and macrophages in cGVHD mice were markedly reduced after hCB-MDSCs treatment. Importantly, Foxp3+ regulatory T cells and IFN-gamma-producing T cells were expanded, whereas IL-17- and IL-4-producing T cells were decreased in allogeneic recipients of hCB-MDSCs. Taken together, these results showed that hCB-MDSCs have preclinical capability of attenuating cGVHD by preserving thymus function and regulating Th 17 signaling, suggesting a possible therapeutic strategy for clinical application. PMID- 30006305 TI - Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial. AB - We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25-127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection. PMID- 30006306 TI - Aflatoxin B1 induced multiple epigenetic modulators in human epithelial cell lines. AB - The compulsive and insidious secondary metabolite aflatoxin B1, produced by the opportunistic fungi Aspergillus flavus, upholds a distinguished place in midst of the toxicants causing fatal hazards to humans. Aflatoxins alter the function of host cells by inducing multiple effects through genetic and non-genetic pathways. Epigenetic mechanisms drag major attention towards finding novel and new mechanisms involved in this process. Our present work intends to study the functional expression profile of multiple epigenetic regulators. AFB1 modulates multiple epigenetic regulators like DNA methyltransferases (DMNTs), histones modifying enzymes and polycomb proteins. AFB1 upregulates the expression of DNMTs at gene and protein level in a dose dependent manner. It reduced the histone acetyl transferase (HAT) activity significantly with a remarkable increase in histone deacetylase (HDAC) activity along with an induction in expression of HDACs gene and protein in a dose dependent manner. The gene and protein expression of polycomb repressor proteins B cell specific moloney murine leukemia virus integration site 1 (BMI-1) and enhancer of zeste homolog 2 (EZH2) was significantly over expressed with enhanced trimethylation of H3K27 and ubiquitination of H2AK119. In summary, our results show impact of aflatoxin B1 on multiple epigenetic modulations known to be pivotal in oncogenic processes. PMID- 30006308 TI - Teachers' knowledge about type 1 diabetes in south of Spain public schools. AB - AIMS: To evaluate the knowledge of teachers in educative public centres (pre-, primary, and secondary schools) about type 1 diabetes (T1D) in the Puerto Real University Hospital area (Cadiz, Spain). METHODS: Descriptive observational study in which 756 teachers' answers on the Test of Diabetes Knowledge for Teachers (TDKT) were analysed. Teachers from 44 educative public centres in the Puerto Real University Hospital area (Cadiz, Spain) were selected by randomized sampling (mean age, 44.3 +/- 8 years; 61.7% women). RESULTS: Although 43.2% survey respondents recognised having had or currently having children or adolescent students with T1D, most demonstrated they did not have enough knowledge about T1D (mean score, 6.0 +/- 4.3 points from a maximum of 16), and only 5.1% had sufficient knowledge (13-16 points) to be an effective support person to students with diabetes in school. However, the vast majority of survey respondents correctly answered questions about symptoms (74.2%) and hypoglycaemia treatment (85.9%). Univariate analysis of factors associated with teachers' knowledge about diabetes revealed that teachers with <= 15 years of teaching experience and physical education teachers had better knowledge than their co-workers. CONCLUSIONS: It is necessary to improve teachers' knowledge about diabetes in our health area with the aim of improving the security of children and adolescent students with T1D in school centres. PMID- 30006307 TI - Time- and frequency-domain measures of heart rate variability predict cardiovascular outcome in patients with type 2 diabetes. AB - AIMS: To evaluate the association between impaired heart rate variability (HRV) and cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). METHODS: A total of 655 patients with T2DM who underwent cardiovascular autonomic function testing were consecutively recruited and followed up prospectively. Time and frequency-domain HRV were assessed for 5 min by beat-to-beat heart rate recording. We estimated the development of CVD events during a follow-up period. RESULTS: During a median follow-up of 7.8 years, 9.6% (n = 49) of patients developed CVD (10.6 per 1000 patient-years). The mean age and diabetes duration were 54.9 +/- 8.6 years and 9.4 +/- 7.3 years, respectively. Patients who had cardiovascular autonomic neuropathy (CAN) had decreased HRV compared with those with normal autonomic function. Multivariable cox hazard regression analysis revealed the lowest 10th percentile of the SD of the normal-to-normal interval (HR 2.62; 95% CI 1.30-5.31), total power (HR 2.81; 95% CI 1.37-5.79), low frequency power (HR 2.68; 95% CI 1.28-5.59), and high-frequency power (HR 2.24; 95% CI 1.09-4.59) were significant predictors for developing CVD in patients with T2DM. CONCLUSIONS: Time- and frequency-domain measures of HRV independently predicted cardiovascular outcome in patients with T2DM. PMID- 30006309 TI - Visceral fat accumulation is associated with increased plasma sphingosine-1 phosphate levels in type 2 diabetes mellitus. AB - OBJECTIVE: Accumulating evidence has shown that sphingosine-1-phosphate (S1P) plays roles in glucose and fat metabolism. However, the association between plasma S1P levels and fat mass, especially visceral fat mass, remains unknown. METHODS: In this cross-sectional study, 80 men with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of plasma S1P levels with body fat parameters. Visceral (VFA) and subcutaneous fat (SFA) areas were evaluated by performing computed tomography scan, and fat mass (FM) and lean body mass (LBM) were examined by whole body dual-energy X-ray absorptiometry. RESULTS: Multiple regression analysis adjusted for age, T2DM duration, serum creatinine, and body mass index (BMI) showed that S1P was significantly and positively associated with fasting plasma glucose (beta = 0.25, p = 0.027), HbA1c (beta = 0.28, p = 0.012), and urine C-peptide (beta = 0.29, p = 0.014). Moreover, multiple regression analysis adjusted for age, T2DM duration, serum creatinine, HbA1c, and urine C-peptide showed that BMI (beta = 0.32, p = 0.008), VFA (beta = 0.33, p = 0.008), SFA (beta = 0.26, p = 0.039), FM (beta = 0.37, p = 0.003), and LBM (beta = 0.35, p = 0.01). FM was significantly and positively associated with S1P after additional adjustment for LBM (beta = 0.29, p = 0.028), whereas LBM was not after adjustment for FM. Moreover, VFA was significantly and positively associated with S1P after additional adjustment for SFA (beta = 0.27, p = 0.039), whereas SFA was not after adjustment for VFA. CONCLUSION: This is the first study to show that increased plasma S1P levels are associated with blood glucose levels and accumulation of fat mass, especially visceral fat mass, in men with T2DM. PMID- 30006312 TI - Tumor microenvironment-labile polymer-doxorubicin conjugate thermogel combined with docetaxel for in situ synergistic chemotherapy of hepatoma. AB - : Topical chemotherapy with complementary drugs is one of the most promising strategies to achieve an effective antitumor activity. Herein, a synergistic strategy for hepatoma therapy by the combination of tumor microenvironment sensitive polymer-doxorubicin (DOX) conjugate thermogel, containing a DNA intercalator DOX, and docetaxel (DTX), a microtubule-interfering agent, was proposed. First, cis-aconitic anhydride-functionalized DOX (CAD) and succinic anhydride-modified DOX (SAD) were conjugated onto the terminal hydroxyl groups of poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co glycolide) (PLGA-PEG-PLGA), yielding the acid-sensitive CAD-PLGA-PEG-PLGA-CAD and the insensitive SAD-PLGA-PEG-PLGA-SAD conjugates, respectively. The prodrug aqueous solution exhibited a thermoreversible sol-gel transition between room and physiological temperature. Meantime, appropriate mechanical property, biodegradability, as well as a sustained release profile were revealed in such prodrug thermogels. More importantly, the addition of DTX to the DOX-conjugated thermogels (i.e., Gel-CAD and Gel-SAD) was verified with enhanced curative effect against tumor, where the antitumor efficacy of Gel-CAD+DTX was obviously higher than the other groups. A reliable security in vivo was also showed in the Gel CAD+DTX group. Taken together, such combination of tumor microenvironment-labile prodrug thermogel and a complementary drug exhibited fascinating prospect for local synergistic antineoplastic therapy. STATEMENT OF SIGNIFICANCE: Multidrug chemotherapy with synergistic effect has been proposed recently for hepatoma treatment in the clinic. However, the quick release, fast elimination, and unselectivity of multidrugs in vivo always limit their further application. To solve this problem, a synergistic combination of tumor microenvironment-sensitive polymeric doxorubicin (DOX) prodrug thermogel for DNA intercalation and a microtubule-interfering agent docetaxel (DTX) is developed in the present study for the local chemotherapy of hepatoma. Interestingly, a pH-triggered sustained release behavior, an enhanced antitumor efficacy, and a favorable security in vivo are observed in the combined dual-drug delivery platform. Therefore, effectively combining tumor microenvironment-labile polymeric prodrug thermogel with a complementary drug provides an advanced system and a promising prospect for local synergistic hepatoma chemotherapy. PMID- 30006310 TI - Predicting physical stability of ternary amorphous solid dispersions using specific mechanical energy in a hot melt extrusion process. AB - This study focuses on the relationship between drug dissolution properties, physical stability against recrystallization, and specific mechanical energy (SME) from a hot melt extrusion (HME) process of ternary amorphous solid dispersions (ASDs) containing indomethacin (IND), HPMC and mesoporous silica (XDP) prepared using different HME screw condition (the number of kneading zones/rotation speed). The screw condition greatly influenced the amorphous characteristics of the processed material and SME values. The higher SME samples demonstrated a larger parachute effect in dissolution test and reduced the rate of recrystallization upon exposure to elevated temperature/humidity conditions, which can be explained from the enhanced miscibility and interactions of IND/HPMC/XDP. The molecular investigation by solid-state NMR (ssNMR) suggested that higher SME input produced better IND/HPMC miscibility and interaction. Interestingly, XDP showed distinct contacts with IND and HPMC in the high-SME samples. The IND-HPMC interaction is not sufficient to maintain a highly mixed ASD at a high drug load without the assistance of XDP. Therefore, SME is a critical parameter for predicting enhanced dissolution and physical stability of IND in ASDs. Moreover, multi-nuclear and multi-dimensional ssNMR provide mechanistic understanding of molecular properties and bring new perspectives for preparation, analysis, and applications of XDP as a pharmaceutical carrier. PMID- 30006311 TI - Hypericin-functionalized graphene oxide for enhanced mitochondria-targeting and synergistic anticancer effect. AB - : Effective targeting of mitochondria has emerged as a beneficial strategy in cancer therapy. However, the development of mitochondria-targeting ligands is difficult because of the low permeability of the mitochondrial double membrane. We found that hypericin (HY), a natural product isolated from Hypericum perforatum L., is an effective mitochondria-targeting ligand. HY-functionalized graphene oxide (GO) loaded with doxorubicin (GO-PEG-SS-HY/DOX) increased the synergistic anticancer efficacy of phototherapy and chemotherapy in the absence of apparent adverse side effects. In vitro and in vivo assays suggested GO-PEG-SS HY/DOX induced the expression of the key proteins of the mitochondria-mediated apoptosis pathway and caused apoptosis of breast carcinoma cells. In addition, GO vehicle exhibited low toxicity toward normal cells, indicating high safety of functionalized GO preparations in antitumor therapy. Therefore, HY-functionalized GO can be successfully used as a platform technology to target mitochondria in cancer cells and improve the therapeutic efficacy of chemotherapeutic drugs. STATEMENT OF SIGNIFICANCE: Induction of mitochondria-mediated apoptosis is a promising approach in cancer therapy. However, mitochondria are difficult to access and permeate because of their negative membrane potential and highly dense double membrane. Mitochondria-targeting ligands can be conjugated to nanoparticles or small-molecule drugs to enhance their antitumor effect. Here, we showed that the natural photosensitizer hypericin is a novel mitochondria targeting ligand and that graphene oxide particles co-loaded with hypericin and the chemotherapeutic agent doxorubicin exhibited a synergistic antitumor effect mediated by the mitochondrial-mediated apoptosis. Treatment with such particles in combination with laser irradiation led to apoptosis of the tumor MDA-MB-231 and MCF-7 cells in vitro and in vivo. Furthermore, treatment with hypericin/doxorubicin-functionalized graphene oxide had low cellular toxicity. PMID- 30006313 TI - The strength of the protein-material interaction determines cell fate. AB - : Extracellular matrix (ECM) proteins are key mediators of cell/material interactions. The surface density and conformation of these proteins adsorbed on the material surface influence cell adhesion and the cellular response. We have previously shown that subtle variations in surface chemistry lead to drastic changes in the conformation of adsorbed fibronectin (FN). On poly(ethyl acrylate) (PEA), FN unfolds and displays domains for cell adhesion and FN-FN interaction, whereas on poly(methyl acrylate) (PMA) - with only one methyl group less - FN remains globular as it is in solution. The effect of the strength of the protein/material interaction in cell response, and its relation to protein density and conformation, has received limited attention so far. In this work, we used FN-functionalized AFM cantilevers to evaluate, via force spectroscopy, the strength of interaction between fibronectin and the underlying polymer which controls FN conformation (PEA and PMA). We found that the strength of FN/PEA interaction is significantly higher than FN/PMA, which limits the mobility of FN layer on PEA, reduces the ability of cells to mechanically reorganize FN and then leads to enhanced proteolysis and degradation of the surrounding matrix with compromised cell viability. By contrast, both PEA and PMA support cell adhesion when FN density is increased and also in the presence of serum or other serum proteins, including vitronectin (VN) and bovine serum albumin (BSA), which provide a higher degree of mobility to the matrix. STATEMENT OF SIGNIFICANCE: The identification of parameters influencing cell response is of paramount importance for the design of biomaterials that will act as synthetic scaffolds for cells to anchor, grow and, eventually, become specialised tissues. Cells interact with materials through an intermediate layer of proteins adsorbed on the material surface. It is known that the density and conformation of these proteins determine cell behaviour. Here we show that the strength of protein/material interactions, which has received very limited attention so far, is key to understand the cellular response to biomaterials. Very strong protein/material interactions reduce the ability of cells to mechanically reorganize proteins at the material interface which results in enhanced matrix degradation, leading ultimately to compromised cell viability. PMID- 30006314 TI - Methotrexate-based amphiphilic prodrug nanoaggregates for co-administration of multiple therapeutics and synergistic cancer therapy. AB - : The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy. STATEMENT OF SIGNIFICANCE: This work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can "switch on" the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy. PMID- 30006315 TI - Sortase A as a cross-linking enzyme in tissue engineering. AB - : The bacterial ligase Sortase A (SA) and its mutated variants have become increasingly popular over the last years for post-translational protein modifications due to their unparalleled specificity and efficiency. The aim of this work was to study SA as a cross-linking enzyme for hydrogel-based tissue engineering. For this, we optimized SA pentamutant production and purification from E. coli to achieve high yields and purity. Then using hyaluronan (HA) as a model biopolymer and modifying it with SA-substrate peptides, we studied the cross-linking kinetics obtained with SA, the enzyme stability, cytocompatibility, and immunogenicity, and compared those to state-of-the-art standards. The transglutaminase activated factor XIII (FXIIIa) was used as the reference cross linking enzyme, and the clinical collagen scaffold Chondro-Gide (CG) was used as a reference biocompatible material for in vivo studies. We found SA could be produced in large amounts in the lab without special equipment, whereas the only viable source of FXIIIa is currently a prescription medicine purified from donated blood. SA was also remarkably more stable in solution than FXIIIa, and it could provide even much faster gelation, making it possible to achieve nearly instantaneous gel formation upon delivery with a double-barrel syringe. This is an interesting improvement for in vivo work, to allow in situ gel formation in a wet environment, and could also be useful for applications like bioprinting where very fast gelation is needed. The cytocompatibility and lack of immunogenicity were still uncompromised. These results support the use of SA as a versatile enzymatic cross-linking strategy for 3D culture and tissue engineering applications. STATEMENT OF SIGNIFICANCE: Enzymatic crosslinking has immense appeal for tissue engineers as one of the most biocompatible methods of hydrogel crosslinking. Sortase A has a number of unique advantages over previous systems. We show an impressive and tunable range of crosslinking kinetics, from almost instantaneous gelation to several minutes. We also demonstrate that Sortase A crosslinked hydrogels have good cytocompatibility and cause no immune reaction when implanted in vivo. With its additional benefits of excellent stability in solution and easy large-scale synthesis available to any lab, we believe this novel crosslinking modality will find multiple applications in high throughput screening, tissue engineering, and biofabrication. PMID- 30006316 TI - Substrate curvature affects the shape, orientation, and polarization of renal epithelial cells. AB - : The unique structure of kidney tubules is representative of their specialized function. Because maintaining tubular structure and controlled diameter is critical for kidney function, it is critical to understand how topographical cues, such as curvature, might alter cell morphology and biological characteristics. Here, we examined the effect of substrate curvature on the shape and phenotype of two kinds of renal epithelial cells (MDCK and HK-2) cultured on a microchannel with a broad range of principal curvature. We found that cellular architecture on curved substrates was closely related to the cell type-specific characteristics (stiffness, cell-cell adherence) of the cells and their density, as well as the sign and degree of curvature. As the curvature increased on convex channels, HK-2 cells, having lower cell stiffness and monolayer integrity than those of MDCK cells, aligned their in-plane axis perpendicular to the channel but did not significantly change in morphology. By contrast, MDCK cells showed minimal change in both morphology and alignment. However, on concave channels, both cell types were elongated and showed longitudinal directionality, although the changes in MDCK cells were more conservative. Moreover, substrate curvature contributed to cell polarization by enhancing the expression of apical and basolateral cell markers with height increase of the cells. Our study suggests curvature to be an important guiding principle for advanced tissue model developments, and that curved and geometrically ambiguous substrates can modulate the cellular morphology and phenotype. STATEMENT OF SIGNIFICANCE: In many tissues, such as renal tubules or intestinal villi, epithelial layers exist in naturally curved forms, a geometry that is not reproduced by flat cultures. Because maintaining tubular structure is critical for kidney function, it is important to understand how topographical cues, such as curvature, might alter cell morphology and biological characteristics. We found that cellular architecture on curved substrates was closely related to cell type and density, as well as the sign and degree of the curvature. Moreover, substrate curvature contributed to cell polarization by enhancing the expression of apical and basolateral cell markers with height increase. Our results suggested that substrate curvature might contribute to cellular architecture and enhance the polarization of kidney tubule cells. PMID- 30006317 TI - Cartilage tissue formation through assembly of microgels containing mesenchymal stem cells. AB - : Current clinical approaches to treat articular cartilage degeneration provide only a limited ability to regenerate tissue with long-term durability and functionality. In this application, injectable bulk hydrogels and microgels containing stem cells can provide a suitable environment for tissue regeneration. However insufficient cell-cell interactions, low differentiation efficiency and poor tissue adhesion hinder the formation of high-quality hyaline type cartilage. Here, we have designed a higher order tissue-like structure using injectable cell laden microgels as the building blocks to achieve human bone marrow-derived mesenchymal stem cell (hBMSC) long-term maintenance and chondrogenesis. We have demonstrated that a 4-arm poly(ethylene glycol)-N-hydroxysuccinimide (NHS) crosslinker induces covalent bonding between the microgel building blocks as well as the surrounding tissue mimic. The crosslinking process assembles the microgels into a 3D construct and preserves the viability and cellular functions of the encapsulated hBMSCs. This assembled microgel construct encourages upregulation of chondrogenic markers in both gene and glycosaminoglycan (GAG) expression levels. In addition, the regenerated tissue in the assembled microgels stained positively with Alcian blue and Safranin O exhibiting unique hyaline-like cartilage features. Furthermore, the immunostaining showed a favourable distribution and significantly higher content of type II collagen in the assembled microgels when compared to both the bulk hydrogel and pellet cultures. Collectively, this tissue adhesive hBMSC-laden microgel construct provides potential clinical opportunities for articular cartilage repair and other applications in regenerative medicine. STATEMENT OF SIGNIFICANCE: A reliable approach to reconstruct durable and fully functional articular cartilage tissue is required for effective clinical therapies. Here, injectable hydrogels together with cell-based therapies offer new treatment strategies in cartilage repair. For effective cartilage regeneration, the injectable hydrogel system needs to be bonded to the surrounding tissue and at the same time needs to be sufficiently stable for prolonged chondrogenesis. In this work, we utilised injectable hBMSC-laden microgels as the building blocks to create an assembled construct via N hydroxysuccinimide-amine coupling. This crosslinking process also allows for rapid bonding between the assembled microgels and a surrounding tissue mimic. The resultant assembled microgel-construct provides both a physically stable and biologically dynamic environment for hBMSC chondrogenesis, leading to the production of a mature hyaline type cartilage structure. PMID- 30006318 TI - Bloodstream infection caused by Bacteroides denticanum, a close relative of Bacteroides pyogenes, misidentified by MALDI TOF- mass spectrometry. AB - Bacteroides pyogenes can cause infections in humans. We describe a case of bloodstream infection caused by Bacteroides denticanum that probably originated from a dog bite. MALDI-TOF MS misidentified this new species as B. pyogenes. Subsequent analysis using the 16S rRNA sequencing approach identified the species as B. denticanum. PMID- 30006319 TI - The effects of photodynamic and low-level laser therapy for treatment of oral lichen planus-A systematic review and meta-analysis. AB - BACKGROUND: Oral lichen planus (OLP) is a chronic immune-mediated disorder that inflicts oral mucosa in 0.5-2% of the population. Surgery, photodynamic therapy, laser therapy and most commonly pharmacological therapy (like corticosteroids) has been used for treating OLP. New phototherapy approaches have been shown to have positive effects on treating some oral lesions and the aim of our study was to assess the effects of different phototherapy treatments on OLP. METHODS: We conducted a comprehensive electronic search using the determined search strategy in MEDLINE, EMBASE and CENTRAL electronic databases. A hand search of the reference list of the relevant studies and related systematic reviews was also performed. RESULTS: For low-level laser therapy, before and after studies showed a significant difference in pain (MD = -4.39, CI = 95% -4.83, -3.96) and sign score (MD = -1.86, CI = 95% -2.53, -1.19) after treatment. The comparison between corticosteroid therapy and LLLT also showed a significant difference in their effects for severity (MD = 0.57, CI = 95% 0.04, 1.09), but no differences in sign (MD = 0.21, CI = 95% -0.83, 1.24)and pain (MD = -0.10, CI = 95% -0.57,0.38) score was found between these two methods. Before and after studies of photodynamic therapy did not reveal any differences in lesion size. (MD = -1.95, CI = 95% 4.39, 0.490). CONCLUSION: Low-level laser therapy seems to be a reliable alternative to corticosteroids for treating OLP without the adverse effects associated with the pharmacological method. No conclusive evidence for the effectiveness of photodynamic therapy in treating OLP lesion exists. PMID- 30006320 TI - Effects of ALA-PDT on biofilm structure, virulence factor secretion, and QS in Pseudomonas aeruginosa. AB - AIM: To investigate the effects of ALA-PDT on biofilm structure, virulence factor secretion, and quorum sensing (QS) in Pseudomonas aeruginosa. MATERIALS AND METHODS: We used confocal laser scanning microscopy (CLSM), an XTT assay, scanning electron microscopy (SEM), a virulence factor assay and qRT-PCR in this study. RESULTS: The XTT assay showed that ALA-PDT significantly inhibited the growth of planktonic P. aeruginosa. CLSM and SEM showed that ALA-PDT destroyed both bacterial and biofilm structures. The virulence factor assay showed that pyocyanin and elastase secretion were significantly inhibited in the ALA-PDT groups. qRT-PCR assays demonstrated that ALA-PDT significantly reduced the mRNA expression of QS-related genes. CONCLUSION: ALA-PDT kills planktonic and viable biofilm-associated P. aeruginosa cells, destroys biofilm structures, reduces virulence factor secretion and affects QS system gene expression. PMID- 30006321 TI - Immunotherapy for the prevention of atherosclerotic cardiovascular disease: Promise and possibilities. AB - Cardiovascular disease remains the leading cause of death worldwide with coronary atherosclerotic heart disease being the largest contributor. The mechanisms behind the presence and progression of atherosclerosis remain an area of intense scientific focus. Immune dysregulation and inflammation are key contributors to the development of an atherosclerotic plaque and its progression to acute coronary syndromes. Increased circulating levels of biomarkers of systemic inflammation including hsCRP are correlated with a higher cardiovascular risk. Targeting specific inflammatory pathways implicated in atherosclerotic plaque formation is an exciting area of ongoing research. Target specific therapies directed at pro-inflammatory cytokines such as IL-1beta, IL-6, TNFalpha, and CCL2 have demonstrated slowing in the progression of atherosclerosis in animal models and improved cardiovascular outcomes in human subjects. Most notably, treatment with the monoclonal antibody canakinumab, which directly targets and neutralizes IL-1beta, was recently shown to be associated with reduced risk of adverse cardiovascular events compared to placebo in a randomized, placebo-controlled trial. Several other therapies including colchicine, methotrexate and leukotriene inhibitors demonstrate the potential for lowering cardiovascular risk through immunomodulation, though further studies are needed. Understanding the role of inflammation in atherosclerosis and the development of targeted immunotherapies continues to be an evolving area of research that is rapidly becoming clinically relevant for the 21st century cardiac patient. PMID- 30006322 TI - Lipoprotein (a) levels and outcomes in stable outpatients with symptomatic artery disease. AB - BACKGROUND AND AIMS: Although genetic and epidemiological studies support that people with high lipoprotein (a) [Lp(a)] levels are at an increased risk for arterial disease, its prognostic value in patients with established artery disease has not been consistently evaluated. METHODS: FRENA is a prospective registry of consecutive outpatients with coronary, cerebrovascular or peripheral artery disease. We assessed the risk for subsequent myocardial infarction, ischemic stroke or limb amputation according to Lp(a) levels at baseline. RESULTS: As of December 2016, 1503 stable outpatients were recruited. Of these, 814 (54%) had levels <30 mg/dL, 319 (21%) had 30-50 mg/dL and 370 (25%) had >=50 mg/dL. Over a mean follow-up of 36 months, 294 patients developed subsequent events (myocardial infarction 122, ischemic stroke 114, limb amputation 58) and 85 died. On multivariable analysis, patients with Lp(a) levels of 30-50 mg/dL were at a higher risk for myocardial infarction (hazard ratio [HR]: 4.67; 95%CI: 2.77-7.85), ischemic stroke (HR: 8.27; 95%CI: 4.14-16.5) or limb amputation (HR: 3.18; 95%CI: 1.36-7.44) than those with normal levels. Moreover, patients with levels >=50 mg/dL were at increased risk for myocardial infarction (HR: 19.5; 95%CI: 10.5-36.1), ischemic stroke (HR: 54.5; 95%CI: 25.4-116.7) or limb amputation (HR: 22.7; 95%CI: 9.38-54.9). CONCLUSIONS: Stable outpatients with symptomatic artery disease and Lp(a) levels >30 mg/dL were at a 5-fold higher risk for subsequent myocardial infarction, stroke or limb amputation. Those with levels >50 mg/dL were at an over 10-fold higher risk. PMID- 30006323 TI - Carotid circumferential wall stress is not associated with cognitive performance among individuals in late middle age: The Maastricht Study. AB - BACKGROUND AND AIMS: Arterial remodelling aims at normalising circumferential wall stress (CWS). Greater CWS in the carotid artery has previously been associated with the prevalence and severity of cerebral small vessel disease, a major cause of ageing-related cognitive decline. Here we test the hypothesis that greater carotid CWS is associated with poorer cognitive performance. METHODS: We studied 722 individuals (60 +/- 8 years, 55% men, 42.5% highly educated, blood pressure 137 +/- 19/77 +/- 11 mmHg, n = 197 with type 2 diabetes) who completed a neuropsychological assessment and underwent vascular ultrasound to measure the intima-media thickness (IMT) and interadventitial diameter (IAD) of the left common carotid artery at a plaque-free site. From IMT and IAD, lumen diameter (LD) was calculated. These structural measures were then combined with local carotid pulse pressure and brachial mean arterial pressure to obtain a measure of pulsatile (CWSpulsatile) and average (CWSmean) mechanical load on the vessel wall. Cognitive domains assessed were memory, executive function and attention, and processing speed. RESULTS: After adjustment for age, sex, and education, regression analyses showed that neither CWSpulsatile nor CWSmean were associated with measures of cognitive performance (p-values >=0.31). This null association did not differ by age or educational level, and was observed in both individuals with and without carotid plaque, diabetes and/or hypertension. In addition, none of the individual measures of carotid structure (i.e. IMT, IAD, and LD) was related to cognitive performance. CONCLUSIONS: The present cross-sectional study shows that carotid CWS is not associated with cognitive performance, at least not among relatively highly educated individuals in late middle age with adequately controlled cardiovascular risk factors. PMID- 30006324 TI - How an Environment of Stress and Social Risk Shapes Student Engagement With Social Media as Potential Digital Learning Platforms: Qualitative Study. AB - BACKGROUND: Social media has been increasingly used as a learning tool in medical education. Specifically, when joining university, students often go through a phase of adjustment, and they need to cope with various challenges such as leaving their families and friends and trying to fit into a new environment. Research has shown that social media helps students to connect with old friends and to establish new relationships. However, managing friendships on social media might intertwine with the new learning environment that shapes students' online behaviors. Especially, when students perceive high levels of social risks when using social media, they may struggle to take advantage of the benefits that social media can provide for learning. OBJECTIVE: This study aimed to develop a model that explores the drivers and inhibitors of student engagement with social media during their university adjustment phase. METHODS: We used a qualitative method by interviewing 78 undergraduate students studying medical courses at UK research-focused universities. In addition, we interviewed 6 digital technology experts to provide additional insights into students' learning behaviors on social media. RESULTS: Students' changing relationships and new academic environment in the university adjustment phase led to various factors that affected their social media engagement. The main drivers of social media engagement were maintaining existing relationships, building new relationships, and seeking academic support. Simultaneously, critical factors that inhibited the use of social media for learning emerged, namely, collapsed online identity, uncertain group norms, the desire to present an ideal self, and academic competition. These inhibitors led to student stress when managing their social media accounts, discouraged them from actively engaging on social media, and prevented the full exploitation of social media as an effective learning tool. CONCLUSIONS: This study identified important drivers and inhibitors for students to engage with social media platforms as learning tools. Although social media supported students to manage their relationships and support their learning, the interaction of critical factors, such as collapsed online identity, uncertain group norms, the desire to present an ideal self, and academic competition, caused psychological stress and impeded student engagement. Future research should explore how these inhibitors can be removed to reduce students' stress and to increase the use of social media for learning. More specifically, such insights will allow students to take full advantage of being connected, thus facilitating a richer learning experience during their university life. PMID- 30006325 TI - Reimagining Health Data Exchange: An Application Programming Interface-Enabled Roadmap for India. AB - In February 2018, the Government of India announced a massive public health insurance scheme extending coverage to 500 million citizens, in effect making it the world's largest insurance program. To meet this target, the government will rely on technology to effectively scale services, monitor quality, and ensure accountability. While India has seen great strides in informational technology development and outsourcing, cellular phone penetration, cloud computing, and financial technology, the digital health ecosystem is in its nascent stages and has been waiting for a catalyst to seed the system. This National Health Protection Scheme is expected to provide just this impetus for widespread adoption. However, health data in India are mostly not digitized. In the few instances that they are, the data are not standardized, not interoperable, and not readily accessible to clinicians, researchers, or policymakers. While such barriers to easy health information exchange are hardly unique to India, the greenfield nature of India's digital health infrastructure presents an excellent opportunity to avoid the pitfalls of complex, restrictive, digital health systems that have evolved elsewhere. We propose here a federated, patient-centric, application programming interface (API)-enabled health information ecosystem that leverages India's near-universal mobile phone penetration, universal availability of unique ID systems, and evolving privacy and data protection laws. It builds on global best practices and promotes the adoption of human-centered design principles, data minimization, and open standard APIs. The recommendations are the result of 18 months of deliberations with multiple stakeholders in India and the United States, including from academia, industry, and government. PMID- 30006326 TI - Using Mobile Health to Enhance Outcomes of Noncommunicable Diseases Care in Rural Settings and Refugee Camps: Randomized Controlled Trial. AB - BACKGROUND: Rural areas and refugee camps are characterized by poor access of patients to needed noncommunicable disease (NCD)-related health services, including diabetes and hypertension. Employing low-cost innovative eHealth interventions, such as mobile health (mHealth), may help improve NCDs prevention and control among disadvantaged populations. OBJECTIVE: The aim of this study was to assess the effect of employing low-cost mHealth tools on the accessibility to health services and improvement of health indicators of individuals with NCDs in rural areas and refugee camps in Lebanon. METHODS: This is a randomized controlled trial study in which centers were allocated randomly into control and intervention sites. The effect of an employed mHealth intervention is assessed through selected quality indicators examined in both control and intervention groups. Sixteen primary health care centers (eight controls, eight interventions) located in rural areas and Palestinian refugee camps across Lebanon were included in this study. Data on diabetic and hypertensive patients-1433 in the intervention group and 926 in the control group-was extracted from patient files in the pre and postintervention periods. The intervention entailed weekly short message service messages, including medical information, importance of compliance, and reminders of appointments or regular physician follow-up. Internationally established care indicators were utilized in this study. Descriptive analysis of baseline characteristics of participants, bivariate analysis, logistic and linear regression were conducted using SPSS (IBM Corp). RESULTS: Bivariate analysis of quality indicators indicated that the intervention group had a significant increase in blood pressure control (P=.03), as well as a significant decrease in the mean systolic blood pressure (P=.02), mean glycated hemoglobin (HbA1c; P<.01), and in the proportion of HbA1c poor control (P=.02). Separate regression models controlling for age, gender, and setting showed a 28% increase in the odds of blood pressure control (P=.05) and a 38% decrease in the odds of HbA1c poor control (P=.04) among the intervention group in the posttest period. Females were at lower odds of HbA1c poor control (P=.01), and age was statistically associated with annual HbA1c testing (P<.01). Regression models for mean systolic blood pressure, mean diastolic blood pressure, and mean HbA1c showed that a mean decrease in HbA1c of 0.87% (P<.01) pretest to posttest period was observed among the intervention group. Patients in rural areas belonging to the intervention group had a lower HbA1c score as compared with those in refugee camps (P<.01). CONCLUSIONS: This study underlines the importance of employing integrative approaches of diseases prevention and control in which existing NCD programs in underserved communities (ie, rural and refugee camps settings) are coupled with innovative, low-cost approaches such as mHealth to provide an effective and amplified effect of traditional NCD-targeted care that can be reflected by improved NCD-related health indicators among the population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03580330; https://clinicaltrials.gov/ct2/show/NCT03580330 (Archived by WebCite at http://www.webcitation.org/70mhVEUwQ). PMID- 30006327 TI - Effectiveness of a Blended Care Self-Management Program for Caregivers of People With Early-Stage Dementia (Partner in Balance): Randomized Controlled Trial. AB - BACKGROUND: The benefits of electronic health support for dementia caregivers are increasingly recognized. Reaching caregivers of people with early-stage dementia could prevent high levels of burden and psychological problems in the later stages. OBJECTIVE: The current study evaluates the effectiveness of the blended care self-management program, Partner in Balance, compared to a control group. METHODS: A single-blind randomized controlled trial with 81 family caregivers of community-dwelling people with mild dementia was conducted. Participants were randomly assigned to either the 8-week, blended care self-management Partner in Balance program (N=41) or a waiting-list control group (N=40) receiving usual care (low-frequent counseling). The program combines face-to-face coaching with tailored Web-based modules. Data were collected at baseline and after 8 weeks in writing by an independent research assistant who was blinded to the treatment. The primary proximal outcome was self-efficacy (Caregiver Self-Efficacy Scale) and the primary distal outcome was symptoms of depression (Center for Epidemiological Studies Depression Scale). Secondary outcomes included mastery (Pearlin Mastery Scale), quality of life (Investigation Choice Experiments for the Preferences of Older People), and psychological complaints (Hospital Anxiety and Depression Scale-Anxiety and Perceived Stress Scale). RESULTS: A significant increase in favor of the intervention group was demonstrated for self-efficacy (care management, P=.002; service use P=.001), mastery (P=.001), and quality of life (P=.032). Effect sizes were medium for quality of life (d=0.58) and high for self-efficacy care management and service use (d=0.85 and d=0.93, respectively) and mastery (d=0.94). No significant differences between the groups were found on depressive symptoms, anxiety, and perceived stress. CONCLUSIONS: This study evaluated the first blended-care intervention for caregivers of people with early stage dementia and demonstrated a significant improvement in self-efficacy, mastery, and quality of life after receiving the Partner in Balance intervention, compared to a waiting-list control group receiving care as usual. Contrary to our expectations, the intervention did not decrease symptoms of depression, anxiety, or perceived stress. However, the levels of psychological complaints were relatively low in the study sample. Future studies including long-term follow up could clarify if an increase in self-efficacy results in a decrease or prevention of increased stress and depression. To conclude, the program can provide accessible preventative care to future generations of caregivers of people with early-stage dementia. TRIAL REGISTRATION: Netherlands Trial Register NTR4748; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4748 (Archived by WebCite at http://www.webcitation.org/6vSb2t9Mg). PMID- 30006329 TI - The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis. AB - ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra-large von Willebrand factor (VWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMAs) and thrombotic disorders, such as ischemic stroke and coronary artery disease. Through its action on VWF, ADAMTS13 can have prothrombotic and proinflammatory properties, not only when its activity is severely deficient, but also when it is only moderately low. Here, we will discuss the biology of ADAMTS13 and the different assays developed to evaluate its function in the context of TTP, in the acute setting and during follow-up. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. This information will be useful for clinicians not only when evaluating patients who present with microangiopathic hemolytic anemia and thrombocytopenia, but also when making clinical decisions regarding the follow-up of patients with TTP. PMID- 30006328 TI - Clinical Feasibility of Monitoring Resting Heart Rate Using a Wearable Activity Tracker in Patients With Thyrotoxicosis: Prospective Longitudinal Observational Study. AB - BACKGROUND: Symptoms and signs of thyrotoxicosis are nonspecific and assessing its clinical status is difficult with conventional physical examinations and history taking. Increased heart rate (HR) is one of the easiest signs to quantify this, and current wearable devices can monitor HR. OBJECTIVE: We assessed the association between thyroid function and resting HR measured by a wearable activity tracker (WD-rHR) and evaluated the clinical feasibility of using this method in patients with thyrotoxicosis. METHODS: Thirty patients with thyrotoxicosis and 10 controls were included in the study. Participants were instructed to use the wearable activity tracker during the study period so that activity and HR data could be collected. The primary study outcomes were verification of changes in WD-rHR during thyrotoxicosis treatment and associations between WD-rHR and thyroid function. Linear and logistic model generalized estimating equation analyses were performed and the results were compared to conventionally obtained resting HR during clinic visits (on-site resting HR) and the Hyperthyroidism Symptom Scale. RESULTS: WD-rHR was higher in thyrotoxic patients than in the control groups and decreased in association with improvement of thyrotoxicosis. A one standard deviation-increase of WD-rHR of about 11 beats per minute (bpm) was associated with the increase of serum free T4 levels (beta=.492, 95% CI 0.367-0.616, P<.001) and thyrotoxicosis risk (odds ratio [OR] 3.840, 95% CI 2.113-6.978, P<.001). Although the Hyperthyroidism Symptom Scale showed similar results with WD-rHR, a 1 SD-increase of on-site rHR (about 16 beats per minute) showed a relatively lower beta and OR (beta=.396, 95% CI 0.204-0.588, P<.001; OR 2.114, 95% CI 1.365-3.273, P<.001) compared with WD rHR. CONCLUSIONS: Heart rate data measured by a wearable device showed reasonable predictability of thyroid function. This simple, easy-to-measure parameter is clinically feasible and has the potential to manage thyroid dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT03009357; https://clinicaltrials.gov/ct2/show/NCT03009357 (Archived by WebCite at http://www.webcitation.org/70h55Llyg). PMID- 30006331 TI - Cardiovascular and Noncardiovascular Death After Percutaneous Coronary Intervention: Insights From 32 882 Patients Enrolled in 21 Randomized Trials. AB - BACKGROUND: Despite advances in technology and technique, a substantial proportion of patients still die within several years after percutaneous coronary intervention (PCI). The relative rates of cardiovascular and noncardiovascular death after PCI remain uncertain. METHODS AND RESULTS: We pooled individual patient-level data from 21 randomized clinical trials of PCI performed in 32 882 patients. All studies had independent adjudication of clinical events. We calculated the relative ratio of cardiovascular to noncardiovascular death in each trial up to 5 years and identified predictors of all-cause, cardiovascular, and noncardiovascular death. At the end of the follow-up period, 1980 patients had died (Kaplan-Meier estimated mortality rate, 9.19%). The rates of cardiovascular and noncardiovascular mortality at 5 years were 4.23% (945) and 5.17% (1035), respectively. The rate of cardiovascular death was higher than noncardiovascular death in the first 30 days after PCI (relative ratio, 6.99; 95% confidence interval, 3.16-15.42; P<0.001), similar between 30 days and 1 year, and lower between 1 and 5 years (relative ratio, 0.70; 95% confidence interval, 0.58-0.84; P=0.0005). Any adverse cardiac event (definite stent thrombosis, spontaneous myocardial infarction, or repeat revascularization) preceded cardiovascular and noncardiovascular mortality in 292 (30.9%) and 151 (14.6%) patients, respectively. In a multivariable model with adverse events entered as time-adjusted covariates, myocardial infarction and definite ST were associated with early and late all-cause and cardiovascular mortality but not noncardiovascular mortality. CONCLUSIONS: In this large-scale study of patients undergoing PCI, the 5-year rates of cardiovascular and noncardiovascular mortality were similar, but their relative timing was different. PMID- 30006330 TI - Benefit of Prolonged Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stent for Coronary Bifurcation Lesions: Results From the Coronary Bifurcation Stenting Registry II. AB - BACKGROUND: Whether prolonged dual antiplatelet therapy (DAPT) improves clinical outcomes after percutaneous coronary intervention for coronary bifurcation lesion is uncertain. METHODS AND RESULTS: We evaluated 2082 patients who were treated with drug-eluting stent for bifurcation lesions and were event free (no death, myocardial infarction [MI], cerebrovascular accident, stent thrombosis, or any revascularization) at 12 months after the index procedure. Patients were divided into 2 groups: DAPT >=12-month group (n=1776) and DAPT <12-month group (n=306). Primary outcome was all-cause death or MI. At 4 years after the index procedure, death or MI occurred less frequently in the DAPT >=12-month group than the DAPT <12-month group (2.8% versus 12.3%; adjusted hazard ratio, 0.21; 95% confidence interval, 0.13-0.35; P<0.001). After propensity score matching, incidence of death or MI was still lower in the DAPT >=12-month group than the DAPT <12-month group (2.6% versus 12.3%; adjusted hazard ratio, 0.22; 95% confidence interval, 0.12-0.38; P<0.001). In subgroup analysis, the treatment effect of prolonged DAPT was consistent across subgroups regardless of lesion location, stenting technique, or type of used drug-eluting stent. CONCLUSIONS: The risk of all-cause death or MI was significantly lower in the >=12-month DAPT group than the <12 month DAPT group after percutaneous coronary intervention for bifurcation lesion using drug-eluting stent. Our results suggest that prolonged DAPT may improve long-term clinical outcomes after percutaneous coronary intervention for bifurcation lesions. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01642992. PMID- 30006332 TI - Impact of Elective Percutaneous Coronary Intervention on Global Absolute Coronary Flow and Flow Reserve Evaluated by Phase-Contrast Cine-Magnetic Resonance Imaging in Relation to Regional Invasive Physiological Indices. AB - BACKGROUND: Few studies have documented changes in global absolute coronary blood flow and global coronary flow reserve after percutaneous coronary intervention (PCI) in relation to regional physiological measures. Phase-contrast cine magnetic resonance of the coronary sinus is a promising approach to quantify global absolute coronary blood flow. We aimed to assess the impact of elective PCI on global absolute coronary blood flow and global coronary flow reserve by quantifying coronary sinus flow (CSF) using phase-contrast cine-magnetic resonance in relation to regional physiological indices. METHODS AND RESULTS: We prospectively studied 54 patients with stable angina undergoing elective PCI for a single proximal lesion. Phase-contrast cine-magnetic resonance was used to assess CSF and CSF reserve at rest and during maximum hyperemia, before and after PCI. Regional physiological indices were obtained during PCI. A complete data set was obtained in 50 patients. Hyperemic CSF increased significantly after PCI (pre PCI, 230.2 [167.4-282.8] mL/min; post-PCI, 267.4 [224.1-346.2] mL/min; P<0.01), although 12 patients (24.0%) showed a decrease, despite successful PCI and improved fractional flow reserve. CSF reserve numerically, albeit not statistically significant (P=0.19), increased from 2.65 (1.95-3.96) to 2.98 (2.13 4.32). Patients with decreased CSF after PCI were associated with significantly greater pre-PCI hyperemic CSF, lower global coronary vascular resistance, lower regional microcirculatory resistance, and higher fractional flow reserve (all P<0.01). CONCLUSIONS: Fractional flow reserve-guided PCI in patients with single de novo lesions was associated with increased absolute hyperemic CSF, although 24% of patients showed decreased hyperemic CSF, despite successful and uncomplicated PCI. The present approach combining regional and global physiological assessments may provide a novel insight into the dynamic behavior of the coronary hemodynamics and microvascular function after PCI. PMID- 30006333 TI - Impact of Frailty on Clinical Outcomes in Patients With Critical Limb Ischemia. AB - BACKGROUND: The predictive ability of patient frailty on clinical outcomes after revascularization in patients with critical limb ischemia remains largely unknown. METHODS AND RESULTS: We enrolled 643 patients with critical limb ischemia treated with endovascular therapy (N=486) or bypass surgery (N=157) in January 2010 to January 2016, and prospectively assessed them using a 9-level clinical frailty scale (CFS). Patients were divided into 3 groups according to CFS levels: low (CFS level, 1-3; N=234), intermediate (CFS level, 4-6; N=196), and high (CFS level, 7-9; N=213) groups. Clinical follow-up rate was 95.8% at 2 years. In the low, intermediate, and high CFS groups, 2-year overall survival rates were 80.5%, 63.1%, and 49.3% (P<0.001) and amputation-free survival rates were 77.9%, 60.5%, and 46.2% (P<0.001), respectively. In multivariable analysis, higher frailty was independently associated with all-cause death (intermediate CFS group: adjusted hazard ratio, 1.64; 95% confidence interval, 1.12-2.42; P=0.01; high CFS group: adjusted hazard ratio, 2.22; 95% confidence interval, 1.52-3.23; P<0.001) and a composite of all-cause death and major amputation (intermediate CFS group: adjusted hazard ratio, 1.72; 95% confidence interval, 1.19-2.48; P=0.004; high CFS group: adjusted hazard ratio, 2.34; 95% confidence interval, 1.64-3.35; P<0.001). Frailty was also independently associated with overall survival and amputation-free survival in patients aged <=75 and >75 years, those who underwent endovascular therapy or bypass surgery, and those with or without chronic renal failure, without significant interactions. CONCLUSIONS: Frailty was independently associated with 2-year overall survival and amputation free survival in patients with critical limb ischemia treated with revascularization, irrespective of age, revascularization mode, and chronic renal failure status. PMID- 30006334 TI - Can We Improve Long-Term Outcomes Postbifurcation Stenting by Prolonged Dual Antiplatelet Therapy? PMID- 30006335 TI - Mortality After Percutaneous Coronary Intervention: Narrowing the Knowledge Gap. PMID- 30006336 TI - Frailty for Critical Limb Ischemia: Fruitful or Futile? PMID- 30006338 TI - Challenge Trump on women's health during UK visit, doctors urge May. PMID- 30006337 TI - Going Against the Flow: Assessing Coronary Hemodynamics Combining Invasive and Noninvasive Physiology. PMID- 30006339 TI - Brexit: money released from EU membership will help fund long term NHS, says May. PMID- 30006340 TI - Hypothalamic gamma-melanocyte stimulating hormone gene delivery reduces fat mass in male mice. AB - gamma-melanocyte stimulating hormone (gamma-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long-term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of gamma-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R-agonism is dependent on the state of energy balance and nutrition. Lentiviral gene-delivery was used to induce a continuous expression of gamma-MSH only in the ARC of male C57Bl/6N mice. Parameters of body energy homeostasis were monitored as food was changed from chow (6 weeks) to Western diet (13 weeks) and back to chow (7 weeks). The gamma-MSH-treatment decreased the fat mass to lean mass ratio on chow, but the effect was attenuated on Western diet. After the switch back to chow, an enhanced loss in weight (-15% vs. -6%) and fat mass (-37% vs. -12%) and reduced cumulative food intake were observed in gamma-MSH-treated animals. Fasting-induced feeding was increased on chow diet only, however, voluntary running wheel activity on Western diet was increased. The gamma-MSH-treatment also modulated the expression of key neuropeptides in the ARC favoring weight loss. We have shown that a chronic treatment intended to target ARC MC3Rs modulates energy balance in nutritional state -dependent manner. Enhancement of diet-induced weight loss could be beneficial in treatment of obesity. PMID- 30006341 TI - Thyroid Function Disruptors: from nature to chemicals. AB - The modern concept of thyroid disruptors includes man-made chemicals and bioactive compounds from food that interfere with any aspect of the hypothalamus pituitary-thyroid axis, thyroid hormone biosynthesis and secretion, blood and transmembrane transport, metabolism and local action of thyroid hormones. This review highlights relevant disruptors that effect populations through their diet: directly from food itself (fish oil and polyunsaturated fatty acids, pepper, coffee, cinnamon and resveratrol/grapes), through vegetable cultivation (pesticides) and from containers for food storage and cooking (bisphenol A, phthalates and polybrominated diphenyl ethers). Due to the vital role of thyroid hormones during every stage of life, we review effects from the gestational period through to adulthood, including evidence from in vitro studies, rodent models, human trials and epidemiological studies. PMID- 30006342 TI - Integrated Omics: Tools, Advances, and Future Approaches. AB - With the rapid adoption of high-throughput omic approaches to analyze biological samples such as genomics, transcriptomics, proteomics, and metabolomics, each analysis can generate tera- to peta-byte sized data files on a daily basis. These data file sizes, together with differences in nomenclature among these data types, make the integration of these multi-dimensional omics data into biologically meaningful context challenging. Variously named as integrated omics, multi-omics, poly-omics, trans-omics, pan-omics, or shortened to just 'omics', the challenges include differences in data cleaning, normalization, biomolecule identification, data dimensionality reduction, biological contextualization, statistical validation, data storage and handling, sharing, and data archiving. The ultimate goal is towards the holistic realization of a 'systems biology' understanding of the biological question in hand. Commonly used approaches in these efforts are currently limited by the 3 i's - integration, interpretation, and insights. Post integration, these very large datasets aim to yield unprecedented views of cellular systems at exquisite resolution for transformative insights into processes, events, and diseases through various computational and informatics frameworks. With the continued reduction in costs and processing time for sample analyses, and increasing types of omics datasets generated such as glycomics, lipidomics, microbiomics, and phenomics, an increasing number of scientists in this interdisciplinary domain of bioinformatics face these challenges. We discuss recent approaches, existing tools, and potential caveats in the integration of omics datasets for development of standardized analytical pipelines that could be adopted by the global omics research community. PMID- 30006343 TI - Circumstances of Death among Undocumented Immigrants Who Rely on Emergency-Only Hemodialysis. PMID- 30006344 TI - Chlorpyrifos oxon promotes tubulin aggregation via isopeptide cross-linking between diethoxyphospho-Lys and Glu or Asp: Implications for neurotoxicity. AB - Exposure to organophosphorus toxicants (OP) can have chronic adverse effects that are not explained by inhibition of acetylcholinesterase, the cause of acute OP toxicity. We therefore hypothesized that OP-induced chronic illness is initiated by the formation of organophosphorus adducts on lysine residues in proteins, followed by protein cross-linking and aggregation. Here, Western blots revealed that exposure to the OP chlorpyrifos oxon converted porcine tubulin from its original 55-kDa mass to high-molecular-weight aggregates. Liquid chromatography tandem MS analysis of trypsin-digested samples identified several diethoxyphospho lysine residues in the OP-treated tubulin. Using a search approach based on the Batch Tag program, we identified cross-linked peptides and found that these chemically activated lysines reacted with acidic amino acid residues creating gamma-glutamyl-epsilon-lysine or aspartyl-epsilon-lysine isopeptide bonds between beta- and alpha-tubulin. Of note, these cross-linked tubulin molecules accounted for the high-molecular-weight aggregates. To the best of our knowledge, this is the first report indicating that chlorpyrifos oxon-exposed tubulin protein forms intermolecular cross-links with other tubulin molecules, resulting in high molecular-weight protein aggregates. It is tempting to speculate that chronic illness from OP exposure may be explained by a mechanism that starts with OP adduct formation on protein lysines followed by protein cross-linking. We further speculate that OP-modified or cross-linked tubulin can impair axonal transport, reduce neuron connections, and result in neurotoxicity. PMID- 30006346 TI - Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations. AB - Human mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key enzymes in the mitochondrial protein translation system and catalyze the charging of amino acids on their cognate tRNAs. Mutations in their nuclear genes are associated with pathologies having a broad spectrum of clinical phenotypes, but with no clear molecular mechanism(s). For example, mutations in the nuclear genes encoding mt AspRS and mt-ArgRS are correlated with the moderate neurodegenerative disorder leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) and with the severe neurodevelopmental disorder pontocerebellar hypoplasia type 6 (PCH6), respectively. Previous studies have shown no or only minor impacts of these mutations on the canonical properties of these enzymes, indicating that the role of the mt-aaRSs in protein synthesis is mostly not affected by these mutations, but their effects on the mitochondrial localizations of aaRSs remain unclear. Here, we demonstrate that three human aaRSs, mt-AspRS, mt-ArgRS, and LysRS, each have a specific sub-mitochondrial distribution, with mt ArgRS being exclusively localized in the membrane, LysRS exclusively in the soluble fraction, and mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions, whereas mt-ArgRS uses hydrophobic interactions. We also report that novel mutations in mt-AspRS and mt-ArgRS genes from individuals with LBSL and PCH6, respectively, had no significant impact on the mitochondrial localizations of mt-AspRS and mt-ArgRS. The variable sub-mitochondrial locations for these three mt-aaRSs strongly suggest the existence of additional enzyme properties, requiring further investigation to unravel the mechanisms underlying the two neurodegenerative disorders. PMID- 30006347 TI - Subcutaneous adipose tissue imaging of human obesity reveals two types of adipocyte membranes: Insulin-responsive and -nonresponsive. AB - In adipose tissue, resistance to insulin's ability to increase glucose uptake can be induced by multiple factors, including obesity. Impaired insulin action may take place at different spatial loci at the cellular or subcellular level. To begin to understand the spatial response to insulin in human subcutaneous adipose tissue (hSAT), we developed a quantitative imaging method for activation of a major signaling node in the glucoregulatory insulin signaling pathway. After treatment with insulin or control media, biopsied tissues were immunostained for Akt phosphorylation at Thr-308/9 (pAkt) and then imaged by confocal fluorescence microscopy automated to collect a large grid of high resolution fields. In hSAT from 40 men and women with obesity, substantial heterogeneity of pAkt densities in adipocyte membranes were quantified in each image mosaic using a spatial unit of at least twice the size of the point spread function. Statistical analysis of the distribution of pAkt spatial units was best fit as the weighted sum of two separate distributions, corresponding to either a low or high pAkt density. A "high pAkt fraction" metric was calculated from the fraction of high pAkt distributed units over the total units. Importantly, upon insulin stimulation, tissues from the same biopsy showed either a minimal or a substantial change in the high pAkt fraction. Further supporting a two-state response to insulin stimulation, subjects with similar insulin sensitivity indices are also segregated into either of two clusters identified by the amount of membrane localized pAkt. PMID- 30006348 TI - Interaction of the alpha7-nicotinic subunit with its human-specific duplicated dupalpha7 isoform in mammalian cells: Relevance in human inflammatory responses. AB - The alpha7 nicotinic receptor subunit and its partially duplicated human-specific dupalpha7 isoform are coexpressed in neuronal and non-neuronal cells. In these cells, alpha7 subunits form homopentameric alpha7 nicotinic acetylcholine receptors (alpha7-nAChRs) implicated in numerous pathologies. In immune cells, alpha7-nAChRs are essential for vagal control of inflammatory response in sepsis. Recent studies show that the dupalpha7 subunit is a dominant-negative regulator of alpha7-nAChR activity in Xenopus oocytes. However, its biological significance in mammalian cells, particularly immune cells, remains unexplored, as the duplicated form is indistinguishable from the original subunit in standard tests. Here, using immunocytochemistry, confocal microscopy, coimmunoprecipitation, FRET, flow cytometry, and ELISA, we addressed this challenge in GH4C1 rat pituitary cells and RAW264.7 murine macrophages transfected with epitope- and fluorescent protein-tagged alpha7 or dupalpha7. We used quantitative RT-PCR of dupalpha7 gene expression levels in peripheral blood mononuclear cells (PBMCs) from patients with sepsis to analyze its relationship with PBMC alpha7 mRNA levels and with serum concentrations of inflammatory markers. We found that a physical interaction between dupalpha7 and alpha7 subunits in both cell lines generates heteromeric nAChRs that remain mainly trapped in the endoplasmic reticulum. The dupalpha7 sequestration of alpha7 subunits reduced membrane expression of functional alpha7-nAChRs, attenuating their anti-inflammatory capacity in lipopolysaccharide-stimulated macrophages. Moreover, the PBMC's dupalpha7 levels correlated inversely with their alpha7 levels and directly with the magnitude of the patients' inflammatory state. These results indicate that dupalpha7 probably reduces human vagal anti-inflammatory responses and suggest its involvement in other alpha7-nAChR-mediated pathophysiological processes. PMID- 30006345 TI - Correcting the F508del-CFTR variant by modulating eukaryotic translation initiation factor 3-mediated translation initiation. AB - Inherited and somatic rare diseases result from >200,000 genetic variants leading to loss- or gain-of-toxic function, often caused by protein misfolding. Many of these misfolded variants fail to properly interact with other proteins. Understanding the link between factors mediating the transcription, translation, and protein folding of these disease-associated variants remains a major challenge in cell biology. Herein, we utilized the cystic fibrosis transmembrane conductance regulator (CFTR) protein as a model and performed a proteomics-based high-throughput screen (HTS) to identify pathways and components affecting the folding and function of the most common cystic fibrosis-associated mutation, the F508del variant of CFTR. Using a shortest-path algorithm we developed, we mapped HTS hits to the CFTR interactome to provide functional context to the targets and identified the eukaryotic translation initiation factor 3a (eIF3a) as a central hub for the biogenesis of CFTR. Of note, siRNA-mediated silencing of eIF3a reduced the polysome-to-monosome ratio in F508del-expressing cells, which, in turn, decreased the translation of CFTR variants, leading to increased CFTR stability, trafficking, and function at the cell surface. This finding suggested that eIF3a is involved in mediating the impact of genetic variations in CFTR on the folding of this protein. We posit that the number of ribosomes on a CFTR mRNA transcript is inversely correlated with the stability of the translated polypeptide. Polysome-based translation challenges the capacity of the proteostasis environment to balance message fidelity with protein folding, leading to disease. We suggest that this deficit can be corrected through control of translation initiation. PMID- 30006349 TI - Transcriptional up-regulation of relaxin-3 by Nur77 attenuates beta-adrenergic agonist-induced apoptosis in cardiomyocytes. AB - The relaxin family peptides have been shown to exert several beneficial effects on the heart, including anti-apoptosis, anti-fibrosis, and anti-hypertrophy activity. Understanding their regulation might provide new opportunities for therapeutic interventions, but the molecular mechanism(s) coordinating relaxin expression in the heart remain largely obscured. Previous work demonstrated a role for the orphan nuclear receptor Nur77 in regulating cardiomyocyte apoptosis. We therefore investigated Nur77 in the hopes of identifying novel relaxin regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) data indicated that ectopic expression of orphan nuclear receptor Nur77 markedly increased the expression of latexin-3 (RLN3), but not relaxin-1 (RLN1), in neonatal rat ventricular cardiomyocytes (NRVMs). Furthermore, we found that the beta-adrenergic agonist isoproterenol (ISO) markedly stimulated RLN3 expression, and this stimulation was significantly attenuated in Nur77 knockdown cardiomyocytes and Nur77 knockout hearts. We showed that Nur77 significantly increased RLN3 promoter activity via specific binding to the RLN3 promoter, as demonstrated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Furthermore, we found that Nur77 overexpression potently inhibited ISO-induced cardiomyocyte apoptosis, whereas this protective effect was significantly attenuated in RLN3 knockdown cardiomyocytes, suggesting that Nur77-induced RLN3 expression is an important mediator for the suppression of cardiomyocyte apoptosis. These findings show that Nur77 regulates RLN3 expression, therefore suppressing apoptosis in the heart, and suggest that activation of Nur77 may represent a useful therapeutic strategy for inhibition of cardiac fibrosis and heart failure. PMID- 30006350 TI - Isomer-specific effect of microRNA miR-29b on nuclear morphology. AB - Targeting mRNAs via seed region pairing is the canonical mechanism by which microRNAs (miRNAs) regulate cellular functions and disease processes. Emerging evidence suggests miRNAs might also act through other mechanisms. miRNA isomers that contain identical seed region sequences, such as miR-29a and miR-29b, provide naturally occurring, informative models for identifying those miRNA effects that are independent of seed region pairing. miR-29a and miR-29b are both expressed in HeLa cells, and miR-29b has been reported to localize to the nucleus in early mitosis because of unique nucleotide sequences on its 3' end. Here, we sought to better understand the mechanism of miR-29b nuclear localization and its function in cell division. We hypothesized that its nuclear localization may be facilitated by protein-miRNA interactions unique to miR-29b. Specific blockade of miR-29b resulted in striking nuclear irregularities not observed following miR 29a blockade. We also observed that miR-29b, but not miR-29a, is enriched in the nucleus and perinuclear clusters during mitosis. Targeted proteomic analysis of affinity-purified samples identified several proteins interacting with synthetic oligonucleotides mimicking miR-29b, but these proteins did not interact with miR 29a. One of these proteins, ADP/ATP translocase 2 (ANT2), known to be involved in mitotic spindle formation, colocalized with miR-29b in perinuclear clusters independently of Argonaute 2. Of note, ANT2 knockdown resulted in nuclear irregularities similar to those observed following miR-29b blockade and prevented nuclear uptake of endogenous miR-29b. Our findings reveal that miR-29 regulates nuclear morphology during mitosis and that this critical function is unique to the miR-29b isoform. PMID- 30006353 TI - Reference Ranges for the Size of the Fetal Cardiac Outflow Tracts From 13 to 36 Weeks Gestation: A Single-Center Study of Over 7000 Cases. AB - BACKGROUND: Assessment of the outflow tract views is an integral part of routine fetal cardiac scanning. For some congenital heart defects, notably coarctation of the aorta, pulmonary valve stenosis, and aortic valve stenosis, the size of vessels is important both for diagnosis and prognosis. Existing reference ranges of fetal outflow tracts are derived from a small number of cases. METHODS AND RESULTS: The study population comprised 7945 fetuses at 13 to 36 weeks' gestation with no detectable abnormalities from pregnancies resulting in normal live births. Prospective measurements were taken of (1) the aortic and pulmonary valves in diastole at the largest diameter with the valve closed, (2) the distal transverse aortic arch on the 3 vessel and trachea view beyond the trachea at the distal point at its widest systolic diameter, and (3) the arterial duct on the 3 vessel and trachea view at its widest systolic diameter. Regression analysis, with polynomial terms to assess for linear and nonlinear contributors, was used to establish the relationship between each measurement and gestational age. The measurement for each cardiac diameter was expressed as a z score (difference between observed and expected value divided by the fitted SD corrected for gestational age) and percentile. Analysis included calculation of gestation specific SDs. Regression equations are provided for the cardiac outflow tracts and for the distal transverse aortic arch:arterial duct ratio. CONCLUSIONS: The study established reference ranges for fetal outflow tract measurements at 13 to 36 weeks' gestation that are useful in clinical practice. PMID- 30006354 TI - Measuring Up Before Birth: The New Normal. PMID- 30006351 TI - Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue. AB - Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL 37 (1 MUg/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1beta, tumor necrosis factor alpha (TNFalpha), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1beta, TNFalpha, and IL-6 and reduced intracellular levels of IL 1alpha in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pm IL 37 reduced spontaneous release of TNFalpha and 50% of lipopolysaccharide-induced TNFalpha. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity. PMID- 30006355 TI - Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations. AB - Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4-ALK fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations.Implications: DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAF V600E or BRAF V600D mutations. Mol Cancer Res; 16(10); 1491-8. (c)2018 AACR. PMID- 30006356 TI - Atrophied Thymus, a Tumor Reservoir for Harboring Melanoma Cells. AB - Tumor metastatic relapse is the primary cause for cancer-associated mortality. Metastatic relapse is believed to arise from quantities of tumor cells that are below detectable thresholds, which are able to resist radio/chemotherapy by obtaining a dormant state and hiding in certain organs, i.e., tumor reservoirs. The thymus, a central T-cell immune organ, has been suggested to be a premetastatic tumor reservoir for B-lymphoma cells. However, it remains unknown whether the thymus is able to harbor nonlymphoid solid tumor cells, and whether chemotherapy can thoroughly eliminate cancer cells in the thymus. If chemotherapy is not able to eliminate these cells in the thymus, then what processes allow for this? Melanoma cell-inoculated and genotoxic doxorubicin-treated mouse model systems were used to determine that the thymus, particularly the atrophied thymus, was able to harbor blood stream-circulating melanoma cells. In addition, a chemotherapy-induced DNA-damage response triggered p53 activation in nonmalignant thymic cells, which in turn resulted in thymocyte death and thymic epithelial cell senescence to develop an inflammatory thymic microenvironment. This inflammatory condition induced thymic-harbored minimal tumor cells to acquire a chemoresistant state.Implications: Here, the thymus serves as a premetastatic reservoir for nonlymphoid solid tumor cells during chemotherapy, which could be a novel target of minimal residual disease in antitumor therapy, thus preventing tumor metastatic relapse. Mol Cancer Res; 16(11); 1652-64. (c)2018 AACR. PMID- 30006352 TI - Fluorogenic structure activity library pinpoints molecular variations in substrate specificity of structurally homologous esterases. AB - Cellular esterases catalyze many essential biological functions by performing hydrolysis reactions on diverse substrates. The promiscuity of esterases complicates assignment of their substrate preferences and biological functions. To identify universal factors controlling esterase substrate recognition, we designed a 32-member structure-activity relationship (SAR) library of fluorogenic ester substrates and used this library to systematically interrogate esterase preference for chain length, branching patterns, and polarity to differentiate common classes of esterase substrates. Two structurally homologous bacterial esterases were screened against this library, refining their previously broad overlapping substrate specificity. Vibrio cholerae esterase ybfF displayed a preference for gamma-position thioethers and ethers, whereas Rv0045c from Mycobacterium tuberculosis displayed a preference for branched substrates with and without thioethers. We determined that this substrate differentiation was partially controlled by individual substrate selectivity residues Tyr-119 in ybfF and His-187 in Rv0045c; reciprocal substitution of these residues shifted each esterase's substrate preference. This work demonstrates that the selectivity of esterases is tuned based on transition state stabilization, identifies thioethers as an underutilized functional group for esterase substrates, and provides a rapid method for differentiating structural isozymes. This SAR library could have multifaceted future applications, including in vivo imaging, biocatalyst screening, molecular fingerprinting, and inhibitor design. PMID- 30006357 TI - Canadian government ordered to release unpublished Tamiflu data in landmark ruling. PMID- 30006358 TI - Correction: SHP-1 regulates hematopoietic stem cell quiescence by coordinating TGF-beta signaling. PMID- 30006359 TI - Doctors and vets working together for antibiotic stewardship. PMID- 30006360 TI - Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N. AB - Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. Among pyrophosphates generated by IP6Ks, diphosphoinositol pentakisphosphate (IP7), and bis-diphosphoinositol tetrakisphosphate have been extensively characterized. IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. We report that IP6K2 binds protein 4.1.N with high affinity and specificity. Nuclear translocation of 4.1N, which is required for its principal functions, is dependent on IP6K2. Both of these proteins are highly expressed in granule cells of the cerebellum where their interaction regulates Purkinje cell morphology and cerebellar synapses. The deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. Moreover, the disruption of IP6K2-4.1N interactions impairs cell viability. Thus, IP6K2 and its interaction with 4.1N appear to be major determinants of cerebellar disposition and psychomotor behavior.SIGNIFICANCE STATEMENT Inositol phosphates are produced by a family of inositol hexakisphosphate kinases (IP6Ks)-IP6K1, IP6K2, and IP6K3. Of these, the physiological roles of IP6K2 in the brain have been least characterized. In the present study, we report that IP6K2 binds selectively to the neuronal protein 4.1N. Both of these proteins are highly expressed in granule cells of the cerebellum. Using IP6K2 knock-out (KO) mice, we establish that IP6K2 4.1N interactions in granule cells regulate Purkinje cell morphology, the viability of cerebellar neurons, and psychomotor behavior. PMID- 30006362 TI - A Generic Mechanism for Perceptual Organization in the Parietal Cortex. AB - Our visual system's ability to group visual elements into meaningful entities and to separate them from others is referred to as scene segmentation. Visual motion often provides a powerful cue for this process as parallax or coherence can inform the visual system about scene or object structure. Here we tested the hypothesis that scene segmentation by motion cues relies on a common neural substrate in the parietal cortex. We used fMRI and a set of three entirely distinct motion stimuli to examine scene segmentation in the human brain. The stimuli covered a wide range of high-level processes, including perceptual grouping, transparent motion, and depth perception. All stimuli were perceptually bistable such that percepts alternated every few seconds while the physical stimulation remained constant. The perceptual states were asymmetric, in that one reflected the default (nonsegmented) interpretation, and the other the non default (segmented) interpretation. We confirmed behaviorally that upon stimulus presentation, the default percept was always perceived first, before perceptual alternations ensued. Imaging results showed that across all stimulus classes perceptual scene-segmentation was associated with an increase of activity in the posterior parietal cortex together with a decrease of neural signal in the early visual cortex. This pattern of activation is compatible with predictive coding models of visual perception, and suggests that parietal cortex hosts a generic mechanism for scene segmentation.SIGNIFICANCE STATEMENT Making sense of cluttered visual scenes is crucial for everyday perception. An important cue to scene segmentation is visual motion: slight movements of scene elements give away which elements belong to the foreground or background or to the same object. We used three distinct stimuli that engage visual scene segmentation mechanisms based on motion. They involved perceptual grouping, transparent motion, and depth perception. Brain activity associated with all three mechanisms converged in the same parietal region with concurrent deactivation of early visual areas. The results suggest that posterior parietal cortex is a hub involved in structuring visual scenes based on different motion cues, and that feedback modulates early cortical processing in accord with predictive coding theory. PMID- 30006361 TI - Beta-Blocker Propranolol Modulates Decision Urgency During Sequential Information Gathering. AB - Arbitrating between timely choice and extended information gathering is critical for effective decision making. Aberrant information gathering behavior is thought to be a feature of psychiatric disorders such as schizophrenia and obsessive compulsive disorder, but we know little about the underlying neurocognitive control mechanisms. In a double-blind, placebo-controlled drug study involving 60 healthy human subjects (30 female), we examined the effects of noradrenaline and dopamine antagonism on information gathering during performance of an information sampling task. We show that modulating noradrenaline function with 40 mg of the beta-blocker propranolol leads to decreased information gathering behavior. Modulating dopamine function via a single dose of 400 mg of amisulpride revealed some effects that were intermediate between those of propranolol and placebo. Using a Bayesian computational model, we show that sampling behavior is best explained by inclusion of a nonlinear urgency signal that promotes commitment to an early decision. Noradrenaline blockade promotes the expression of this decision-related urgency signal during information gathering. We discuss the findings with respect to psychopathological conditions that are linked to aberrant information gathering.SIGNIFICANCE STATEMENT Knowing when to stop gathering information and commit to a choice option is nontrivial. This is an important element in arbitrating between information gain and energy conservation. In this double-blind, placebo-controlled drug study, we investigated the role of catecholamines noradrenaline and dopamine on sequential information gathering. We found that blockade of noradrenaline led to a decrease in information gathering. Dopamine blockade showed an intermediate, but nonsignificant, effect. Using a Bayesian computational model, we show that this noradrenaline effect is driven by increased decision urgency, a signal that reflects an escalating subjective cost of sampling. The observation that noradrenaline modulates decision urgency suggests new avenues for treating patients that show information gathering deficits. PMID- 30006364 TI - The Successor Representation: Its Computational Logic and Neural Substrates. AB - Reinforcement learning is the process by which an agent learns to predict long term future reward. We now understand a great deal about the brain's reinforcement learning algorithms, but we know considerably less about the representations of states and actions over which these algorithms operate. A useful starting point is asking what kinds of representations we would want the brain to have, given the constraints on its computational architecture. Following this logic leads to the idea of the successor representation, which encodes states of the environment in terms of their predictive relationships with other states. Recent behavioral and neural studies have provided evidence for the successor representation, and computational studies have explored ways to extend the original idea. This paper reviews progress on these fronts, organizing them within a broader framework for understanding how the brain negotiates tradeoffs between efficiency and flexibility for reinforcement learning. PMID- 30006363 TI - Efficient Coding in Visual Working Memory Accounts for Stimulus-Specific Variations in Recall. AB - Recall of visual features from working memory varies in both bias and precision depending on stimulus parameters. Whereas a number of models can approximate the average distribution of recall error across target stimuli, attempts to model how error varies with the choice of target have been ad hoc Here we adapt a neural model of working memory to provide a principled account of these stimulus specific effects, by allowing each neuron's tuning function to vary according to the principle of efficient coding, which states that neural responses should be optimized with respect to the frequency of stimuli in nature. For orientation, this means incorporating a prior that favors cardinal over oblique orientations. While continuing to capture the changes in error distribution with set size, the resulting model accurately described stimulus-specific variations as well, better than a slot-based competitor. Efficient coding produces a repulsive bias away from cardinal orientations, a bias that ought to be sensitive to changes in the environmental statistics. We subsequently tested whether shifts in the stimulus distribution influenced response bias to uniformly sampled target orientations in human subjects (of either sex). Across adaptation blocks, we manipulated the distribution of nontarget items by sampling from a bimodal congruent (incongruent) distribution with peaks centered on cardinal (oblique) orientations. Preadaptation responses were repulsed away from the cardinal axes. However, exposure to the incongruent distribution produced systematic decreases in repulsion that persisted after adaptation. This result confirms the role of prior expectation in generating stimulus-specific effects and validates the neural framework.SIGNIFICANCE STATEMENT Theories of neural coding have been used successfully to explain how errors in recall from working memory depend on the number of items stored. However, recall of visual features also shows stimulus specific variation in bias and precision. Here we unify two previously unconnected theories, the neural resource model of working memory and the efficient coding framework, to provide a principled account of these stimulus specific effects. Given the importance of working memory limitations to multiple aspects of human and animal behavior, and the recent high-profile advances in theories of efficient coding, our modeling framework provides a richer, yet parsimonious, description of how orientation encoding influences visual working memory performance. PMID- 30006366 TI - Deep(er) Learning. AB - Animals successfully thrive in noisy environments with finite resources. The necessity to function with resource constraints has led evolution to design animal brains (and bodies) to be optimal in their use of computational power while being adaptable to their environmental niche. A key process undergirding this ability to adapt is the process of learning. Although a complete characterization of the neural basis of learning remains ongoing, scientists for nearly a century have used the brain as inspiration to design artificial neural networks capable of learning, a case in point being deep learning. In this viewpoint, we advocate that deep learning can be further enhanced by incorporating and tightly integrating five fundamental principles of neural circuit design and function: optimizing the system to environmental need and making it robust to environmental noise, customizing learning to context, modularizing the system, learning without supervision, and learning using reinforcement strategies. We illustrate how animals integrate these learning principles using the fruit fly olfactory learning circuit, one of nature's best characterized and highly optimized schemes for learning. Incorporating these principles may not just improve deep learning but also expose common computational constraints. With judicious use, deep learning can become yet another effective tool to understand how and why brains are designed the way they are. PMID- 30006368 TI - Healthcare outcomes and quality in the NHS: how do we compare and how might the NHS improve? PMID- 30006365 TI - Large-Scale, High-Resolution Comparison of the Core Visual Object Recognition Behavior of Humans, Monkeys, and State-of-the-Art Deep Artificial Neural Networks. AB - Primates, including humans, can typically recognize objects in visual images at a glance despite naturally occurring identity-preserving image transformations (e.g., changes in viewpoint). A primary neuroscience goal is to uncover neuron level mechanistic models that quantitatively explain this behavior by predicting primate performance for each and every image. Here, we applied this stringent behavioral prediction test to the leading mechanistic models of primate vision (specifically, deep, convolutional, artificial neural networks; ANNs) by directly comparing their behavioral signatures against those of humans and rhesus macaque monkeys. Using high-throughput data collection systems for human and monkey psychophysics, we collected more than one million behavioral trials from 1472 anonymous humans and five male macaque monkeys for 2400 images over 276 binary object discrimination tasks. Consistent with previous work, we observed that state-of-the-art deep, feedforward convolutional ANNs trained for visual categorization (termed DCNNIC models) accurately predicted primate patterns of object-level confusion. However, when we examined behavioral performance for individual images within each object discrimination task, we found that all tested DCNNIC models were significantly nonpredictive of primate performance and that this prediction failure was not accounted for by simple image attributes nor rescued by simple model modifications. These results show that current DCNNIC models cannot account for the image-level behavioral patterns of primates and that new ANN models are needed to more precisely capture the neural mechanisms underlying primate object vision. To this end, large-scale, high-resolution primate behavioral benchmarks such as those obtained here could serve as direct guides for discovering such models.SIGNIFICANCE STATEMENT Recently, specific feedforward deep convolutional artificial neural networks (ANNs) models have dramatically advanced our quantitative understanding of the neural mechanisms underlying primate core object recognition. In this work, we tested the limits of those ANNs by systematically comparing the behavioral responses of these models with the behavioral responses of humans and monkeys at the resolution of individual images. Using these high-resolution metrics, we found that all tested ANN models significantly diverged from primate behavior. Going forward, these high-resolution, large-scale primate behavioral benchmarks could serve as direct guides for discovering better ANN models of the primate visual system. PMID- 30006367 TI - Selective Role of RGS9-2 in Regulating Retrograde Synaptic Signaling of Indirect Pathway Medium Spiny Neurons in Dorsal Striatum. AB - In the striatum, medium spiny neurons (MSNs) are heavily involved in controlling movement and reward. MSNs form two distinct populations expressing either dopamine receptor 1 (D1-MSN) or dopamine receptor 2 (D2-MSN), which differ in their projection targets and neurochemical composition. The activity of both types of MSNs is shaped by multiple neuromodulatory inputs processed by GPCRs that fundamentally impact their synaptic properties biasing behavioral outcomes. How these GPCR signaling cascades are regulated and what downstream targets they recruit in D1-MSN and D2-MSN populations are incompletely understood. In this study, we examined the cellular and molecular mechanisms underlying the action of RGS9-2, a key GPCR regulator in MSNs implicated in both movement control and actions of addictive drugs. Imaging cultured striatal neurons, we found that ablation of RGS9-2 significantly reduced calcium influx through NMDARs. Electrophysiological recordings in slices confirmed inhibition of NMDAR function in MSNs, resulting in enhanced AMPAR/NMDAR ratio. Accordingly, male mice lacking RGS9-2 displayed behavioral hypersensitivity to NMDAR blockade by MK-801 or ketamine. Recordings from genetically identified populations of striatal neurons revealed that these changes were selective to D2-MSNs. Surprisingly, we found that these postsynaptic effects resulted in remodeling of presynaptic inputs to D2-MSNs increasing the frequency of mEPSC and inhibiting paired-pulse ratio. Pharmacological dissection revealed that these adaptations were mediated by the NMDAR-dependent inhibition of retrograde endocannabinoid signaling from D2-MSNs to CB1 receptor on presynaptic terminals. Together, these data demonstrate a novel mechanism for pathway selective regulation of synaptic plasticity in MSNs controlled by GPCR signaling.SIGNIFICANCE STATEMENT This study identifies a role for a major G-protein regulator in controlling synaptic properties of striatal neurons in a pathway selective fashion. PMID- 30006370 TI - Uncertainty surrounds anticoagulation risks and benefits in patients with chronic kidney disease with atrial fibrillation. PMID- 30006369 TI - Effects of oils and solid fats on blood lipids: a systematic review and network meta-analysis. AB - The aim of this network meta-analysis (NMA) is to compare the effects of different oils/solid fats on blood lipids. Literature searches were performed until March 2018. Inclusion criteria were as follows: i) randomized trial (?3 weeks study length) comparing at least two of the following oils/solid fats: safflower, sunflower, rapeseed, hempseed, flaxseed, corn, olive, soybean, palm, and coconut oil, and lard, beef-fat, and butter; ii) outcomes LDL-cholesterol (LDL-C), total cholesterol (TC), HDL-cholesterol (HDL-C), and triacylglycerols (TGs). A random dose-response (per 10% isocaloric exchange) NMA was performed and surface under the cumulative ranking curve (SUCRA) was estimated. Fifty-four trials were included in the NMA. Safflower oil had the highest SUCRA value for LDL-C (82%) and TC (90%), followed by rapeseed oil (76% for LDL-C, 85% for TC); whereas, palm oil (74%) had the highest SUCRA value for TG, and coconut oil (88%) for HDL-C. Safflower, sunflower, rapeseed, flaxseed, corn, olive, soybean, palm, and coconut oil as well beef fat were more effective in reducing LDL-C (-0.42 to 0.23 mmol/l) as compared with butter. Despite limitations in these data, our NMA findings are in line with existing evidence on the metabolic effects of fat and support current recommendations to replace high saturated-fat food with unsaturated oils. PMID- 30006371 TI - Cryopreserved Human Intestinal Mucosal Epithelium: A Novel In Vitro Experimental System for the Evaluation of Enteric Drug Metabolism, Cytochrome P450 Induction, and Enterotoxicity. AB - We report here a novel in vitro enteric experimental system, cryopreserved human intestinal mucosa (CHIM), for the evaluation of enteric drug metabolism, drug drug interaction, drug toxicity, and pharmacology. CHIM was isolated from the small intestines of four human donors. The small intestines were first dissected into the duodenum, jejunum, and ileum, followed by collagenase digestion of the intestinal lumen. The isolated mucosa was gently homogenized to yield multiple cellular fragments, which were then cryopreserved in a programmable liquid cell freezer and stored in liquid nitrogen. After thawing and recovery, CHIM retained robust cytochrome P450 (P450) and non-P450 drug-metabolizing enzyme activities and demonstrated dose-dependent induction of transcription of CYP24A1 (approximately 300-fold) and CYP3A4 (approximately 3-fold) by vitamin D3 as well as induction of CYP3A4 (approximately 3-fold) by rifampin after 24 hours of treatment. Dose-dependent decreases in cell viability quantified by cellular ATP content were observed for naproxen and acetaminophen, with higher enterotoxicity observed for naproxen, consistent with that observed in humans in vivo. These results suggest that CHIM may be a useful in vitro experimental model for the evaluation of enteric drug properties, including drug metabolism, drug-drug interactions, and drug toxicity. PMID- 30006372 TI - Bilateral adrenal hyperplasia and NR3C1 mutations causing glucocorticoid resistance: Is there an association? AB - Glucocorticoids signal through their cognate, ubiquitously expressed glucocorticoid receptor (GR), which influences the transcription of a large number of target genes. Several genetic defects, including point mutations, deletions or insertions in the NR3C1 gene that encodes the GR, have been associated with familial or sporadic generalized glucocorticoid resistance or Chrousos syndrome. One of the clinical manifestations of this rare endocrine condition is bilateral adrenal hyperplasia due to compensatory elevations of plasma ACTH concentrations. In this commentary, we discuss the interesting findings of the recently published French MUTA-GR Study, and present our perspective on the evolving field of NR3C1 pathology. PMID- 30006373 TI - Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms. AB - Objective Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas, however their prognosis differs significantly upon their proliferative state which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of 5 miRNAs on an independent validation cohort of sixty three primary PanNEN samples. Cox proportional hazards survival regression model was fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results 19 miRNAs displayed differential expression between tumor grades. The altered expression of 3 out of 5 chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were up-regulated in more proliferative PanNENs compared to grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b expression of primary PanNENs predicted worse progression-free and overall survival, however multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs. PMID- 30006374 TI - Qualified Biolayer Interferometry Avidity Measurements Distinguish the Heterogeneity of Antibody Interactions with Plasmodium falciparum Circumsporozoite Protein Antigens. AB - Ab avidity is a measure of the overall strength of Ab-Ag interactions and hence is important for understanding the functional efficiency of Abs. In vaccine evaluations, Ab avidity measurements can provide insights into immune correlates of protection and generate hypotheses regarding mechanisms of protection to improve vaccine design to achieve higher levels of efficacy. The commonly used Ab avidity assays require the use of chaotropic reagents to measure avidity index. In this study, using real-time detection of Ab-Ag binding by biolayer interferometry (BLI) technique, we have developed a qualified assay for measuring avidity of vaccine-induced Abs specific for Plasmodium falciparum circumsporozoite protein (CSP) Ags. Human mAb derived from plasmablasts of recipients of RTS,S/AS01 (RTS,S), the most advanced malaria vaccine candidate, were used in the assay development to measure Ag-specific binding responses and rate constants of association and dissociation. The optimized BLI binding assay demonstrated 1) good precision (percentage of coefficient of variation <20), 2) high specificity, 3) a lower limit of detection and quantitation in the 0.3-3.3 nM range, and 4) a range of linearity up to 50-100 nM for the CSP Ags tested. Analysis of polyclonal sera of malaria vaccinees demonstrated the suitability of this method to distinguish among vaccinees and rank Ab responses by avidity. These results demonstrate that precise, specific, and sensitive BLI measurements of Ab avidity in polyclonal sera from malaria vaccinees can map Ab response heterogeneity and potentially help to determine the role of Ab avidity as an immune correlate of protection for vaccines. PMID- 30006375 TI - IL-7 Enables Antibody Responses to Bacterial Polysaccharides by Promoting B Cell Receptor Diversity. AB - Polysaccharide vaccines such as the Vi polysaccharide (ViPS) of Salmonella enterica serovar Typhi induce efficient Ab responses in adults but not in young children. The reasons for this difference are not understood. IL-7 dependency in B cell development increases progressively with age. IL-7Ralpha-mediated signals are required for the expression of many VH gene segments that are distal to DH-JH in the IgH locus and for the complete diversification of the BCR repertoire. Therefore, we hypothesized that B cells generated in the absence of IL-7 do not recognize a wide range of Ags because of a restricted BCR repertoire. Compared with adult wildtype mice, young wildtype mice and IL-7-deficient adult mice generated a significantly reduced Ab response to ViPS. Additionally, ViPS-binding B cells in adult wildtype mice predominantly used distal VH gene segments. Transgenic expression of either IL-7 or a BCR encoded by a distal VH gene segment permitted young mice to respond efficiently to bacterial polysaccharides. These results indicate that restricted VH gene usage early in life results in a paucity of Ag-specific B cell precursors, thus limiting antipolysaccharide responses. PMID- 30006376 TI - Correction: Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment. PMID- 30006377 TI - Effector T Cell Resistance to Suppression and STAT3 Signaling during the Development of Human Type 1 Diabetes. AB - Dysregulation of regulatory T cell (Treg)-mediated suppression and, in particular, resistance of CD4+ effector T cells (Teffs) to suppression have been implicated in the pathogenesis of human type 1 diabetes (T1D). However, the mechanistic basis behind this resistance and the time frame during which it develops in relation to the onset of clinical T1D remain unclear. In this study, we analyzed the capacity of peripheral blood Teffs isolated both from patients with T1D and from prediabetic at-risk subjects positive for multiple diabetes associated autoantibodies (AAb+) to be suppressed by Tregs. Because STAT3 activation through IL-6 has previously been implicated in mediating Teff resistance, we also investigated the surface expression of IL-6R as well as IL-6- and TCR-mediated phosphorylation of STAT3 in T cells from our study subjects. Teff resistance to suppression was observed both in patients with newly diagnosed and long-standing T1D but not in AAb+ subjects and was shown to be STAT3 dependent. No alterations in IL-6R expression or IL-6-mediated STAT3 activation were observed in T cells from patients with T1D or AAb+ subjects. However, faster STAT3 activation after TCR stimulation without concomitant increase in IL-6 expression was observed in T cells from patients with T1D. These experiments suggest that Teff resistance in T1D patients is STAT3 dependent but not directly linked with the capacity of Teffs to produce or respond to IL-6. In conclusion, Teff resistance to Treg-mediated suppression is likely a feature of disease progression in human T1D and can potentially be targeted by immune therapies that block STAT3 activation. PMID- 30006379 TI - CDK12 Changes Telling in Prostate Cancer. AB - A recent study established that patients with metastatic castration-resistant prostate cancer who had mutations that inactivated both CDK12 alleles also exhibited other genetic changes. Results of a small, related study suggest these genetic changes may make tumors more responsive to PD-1 inhibitors. PMID- 30006380 TI - MEK Inhibition Induces Differentiation in RAS-Driven Rhabdomyosarcoma. AB - In fusion-negative rhabdomyosarcoma (FN-RMS), MEK inhibition relieves ERK2 mediated repression of MYOG. PMID- 30006381 TI - Genomic Ribonucleotides Produce PARP-Trapping Lesions. AB - Mutations in RNASEH2B impair ribonucleotide excision repair to confer PARP inhibitor sensitivity. PMID- 30006378 TI - Sucrose Nonfermenting 1-Related Protein Kinase 1 Phosphorylates a Geminivirus Rep Protein to Impair Viral Replication and Infection. AB - Geminiviruses are single-stranded DNA viruses that infect a wide variety of plants and cause severe crop losses worldwide. The geminivirus replication initiator protein (Rep) binds to the viral replication origin and catalyzes DNA cleavage and ligation to initiate rolling circle replication. In this study, we found that the Tomato golden mosaic virus (TGMV) Rep is phosphorylated at serine 97 by sucrose nonfermenting 1-related protein kinase 1 (SnRK1), a master regulator of plant energy homeostasis and metabolism. Phosphorylation of Rep or the phosphomimic S97D mutation impaired Rep binding to viral DNA. A TGMV DNA-A replicon containing the Rep S97D mutation replicated less efficiently in tobacco (Nicotiana tabacum) protoplasts than in wild-type or Rep phosphorylation deficient replicons. The TGMV Rep-S97D mutant also was less infectious than the wild-type virus in Nicotiana benthamiana and was unable to infect tomato (Solanum lycopersicum). Nearly all geminivirus Rep proteins have a serine residue at the position equivalent to TGMV Rep serine-97. SnRK1 phosphorylated the equivalent serines in the Rep proteins of Tomato mottle virus and Tomato yellow leaf curl virus and reduced DNA binding, suggesting that SnRK1 plays a key role in combating geminivirus infection. These results established that SnRK1 phosphorylates Rep and interferes with geminivirus replication and infection, underscoring the emerging role for SnRK1 in the host defense response against plant pathogens. PMID- 30006382 TI - Natural Killer Cells Enhance Immune Checkpoint Blockade Efficacy. AB - Natural killer (NK) cell interactions with stimulatory dendritic cells (SDC) enhance immunotherapy. PMID- 30006383 TI - PI3K Inhibitor-Induced Insulin Feedback Activates PI3K Signaling. AB - Hyperinsulinemia drives resistance to PI3Kalpha inhibitors in tumors. PMID- 30006384 TI - CCG blocks GP at Hand's request to expand to Birmingham over safety concerns. PMID- 30006385 TI - Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to Gs-, to Gi-, and to Gq-coupled effector signaling. PMID- 30006386 TI - Phosphorylation-mediated structural changes within the SOAR domain of stromal interaction molecule 1 enable specific activation of distinct Orai channels. PMID- 30006387 TI - A sirtuin's role in preventing senescence by protecting ribosomal DNA. AB - Ribosomes are encoded by many copies of ribosomal DNA (rDNA) packed into the nucleolus. High rates of transcription combined with highly repetitive sequences render rDNA loci particularly vulnerable to genomic instability, a proposed underlying cause of cellular senescence. The molecular mechanisms that maintain rDNA stability have remained unclear. A new paper elucidates a sirtuin-dependent mechanism that protects rDNA loci from genomic instability and prevents cellular senescence via heterochromatin silencing mediated by the chromatin remodeler SNF2H. This finding extends our understanding of chromatin dynamics within rDNA regions and offers new mechanistic insights into aging-related pathologies associated with genomic instability. PMID- 30006388 TI - MP-4 contributes to snake venom neutralization by Mucuna pruriens seeds through an indirect antibody-mediated mechanism. PMID- 30006389 TI - Looking back at the last two years: Coming home to JBC. PMID- 30006390 TI - Mediation analysis as a means of identifying dietary components that affect the fecal microbiota of infants weaned by modified baby-led, compared to traditional, approaches. AB - The introduction of 'solids' (i.e. complementary foods) to the milk-only diet of early infancy affects the development of the gut microbiota. The aim of this study was to determine whether a 'baby-led' approach to complementary feeding, that encourages early introduction of an adult type diet, results in alterations to gut microbiota composition compared to traditional spoon-feeding. The Baby-Led Introduction to SolidS (BLISS) study randomized 206 infants to BLISS (a modified version of Baby-Led Weaning (BLW): introduction of solids at 6 months of age, followed by self-feeding of family foods) or Control (traditional spoon-feeding of purees) groups. Fecal microbiotas and 3-day weighed diet records were analysed from a subset of 74 infants at 7 and 12 months of age. The composition of the microbiota was determined by sequencing 16S rRNA genes amplified by PCR from bulk DNA extracted from feces. Diet records were used to estimate food and dietary fiber intake. Alpha diversity (number of Operational Taxonomic Units; OTUs) was significantly lower in BLISS infants at 12 months (difference, 95% CI: 31, 3.4 to 58.5; p = 0.028) and, while there were no significant differences between Control and BLISS infants in relative abundances of Bifidobacteriaceae, Enterobacteriaceae, Veillonellaceae, Bacteroidaceae, Erysipelotrichaceae, Lachnospiraceae or Ruminococcaceae at 7 or 12 months of age, OTUs representing the genus Roseburia were less prevalent in BLISS microbiotas at 12 months. Mediation models demonstrated that 'fruit and vegetables' and 'dietary fiber' intake explained 29% and 25% respectively of the relationship between group (BLISS versus Control) and alpha diversity.IMPORTANCE The introduction of solid foods (complementary feeding, weaning) to infants leads to more complex compositions of microbial communities (microbiota, microbiome) in the gut. In Baby Led Weaning (BLW), infants are given only finger foods they can pick up and feed themselves - there is no parental spoon-feeding of pureed baby foods - and infants are encouraged to eat family meals. BLW is a new approach to infant feeding that is increasing in popularity in the United States, New Zealand, the United Kingdom and Canada. We used mediation modeling, commonly used in health research but not until now in microbiota studies, to identify particular dietary components that affected the development of the infant gut microbiota. PMID- 30006391 TI - Stable Expression of Modified Green Fluorescent Protein in Group B Streptococci To Enable Visualization in Experimental Systems. AB - Group B streptococcus (GBS) is a Gram-positive bacterium associated with various diseases in humans and animals. Many studies have examined GBS physiology, virulence, and microbe-host interactions using diverse imaging approaches, including fluorescence microscopy. Strategies to label and visualize GBS using fluorescence biomarkers have been limited to antibody-based methods or nonspecific stains that bind DNA or protein; an effective plasmid-based system to label GBS with a fluorescence biomarker would represent a useful visualization tool. In this study, we developed and validated a green fluorescent protein (GFP) variant-expressing plasmid, pGU2664, which can be applied as a marker to visualize GBS in experimental studies. The synthetic constitutively active CP25 promoter drives strong and stable expression of the GFPmut3 biomarker in GBS strains carrying pGU2664. GBS maintains GFPmut3 activity at different phases of growth. The application of fluorescence polarization enables easy discrimination of GBS GFPmut3 activity from the autofluorescence of culture media commonly used to grow GBS. Differential interference contrast microscopy, in combination with epifluorescence microscopy to detect GFPmut3 in GBS, enabled visualization of bacterial attachment to live human epithelial cells in real time. Plasmid pGU2664 was also used to visualize phenotypic differences in the adherence of wild-type GBS and an isogenic gene-deficient mutant strain lacking CovR (the control of virulence regulator) in adhesion assays. The system for GFPmut3 expression in GBS described in this study provides a new tool for the visualization of this organism in diverse research applications. We discuss the advantages and consider the limitations of this fluorescent biomarker system developed for GBS.IMPORTANCE Group B streptococcus (GBS) is a bacterium associated with various diseases in humans and animals. This study describes the development of a strategy to label and visualize GBS using a fluorescence biomarker, termed GFPmut3. We show that this biomarker can be successfully applied to track the growth of bacteria in liquid medium, and it enables the detailed visualization of GBS in the context of live human cells in real-time microscopic analysis. The system for GFPmut3 expression in GBS described in this study provides a new tool for the visualization of this organism in diverse research applications. PMID- 30006392 TI - Neospora caninum Dense Granule Protein 7 Regulates the Pathogenesis of Neosporosis by Modulating Host Immune Response. AB - Neospora caninum is a protozoan parasite closely related to Toxoplasma gondii Neosporosis caused by N. caninum is considered one of the main causes of abortion in cattle and nervous-system dysfunction in dogs, and identification of the virulence factors of this parasite is important for the development of control measures. Here, we used a luciferase reporter assay to screen the dense granule proteins genes of N. caninum, and we found that NcGRA6, NcGRA7, and NcGRA14 are involved in the activation of the NF-kappaB, calcium/calcineurin, and cAMP/PKA signals. To analyze the functions of these proteins and Neospora cyclophilin, we successfully knocked out their genes in the Nc1 strain using plasmids containing the CRISPR/Cas9 components. Among the deficient lines, the NcGRA7-deficient parasites showed reduced virulence in mice. An RNA sequencing analysis of infected macrophage cultures showed that NcGRA7 mainly regulates the host cytokine and chemokine production. The levels of gamma interferon in the ascites fluid, CXCL10 expression in the peritoneal cells, and CCL2 expression in the spleen were lower 5 days after infection with the NcGRA7-deficient parasite than after infection with the parental strain. The parasite burden and the degree of necrosis in the brains of mice infected with the NcGRA7-deficient parasite were also lower than in those of the parental strain. Collectively, our data suggest that both the NcGRA7-dependent activation of the inflammatory response and the parasite burden are important in Neospora virulence.IMPORTANCENeospora caninum invades and replicates in a broad range of host species and cells within those hosts. The effector proteins exported by Neospora induce its pathogenesis by modulating the host immunity. We show that most of the transcriptomic effects in N. caninum-infected cells depend upon the activity of NcGRA7. A deficiency in NcGRA7 reduced the virulence of the parasite in mice. This study demonstrates the importance of NcGRA7 in the pathogenesis of neosporosis. PMID- 30006393 TI - Enterococcal Concentrations in a Coastal Ecosystem Are a Function of Fecal Source Input, Environmental Conditions, and Environmental Sources. AB - Fecal pollution at coastal beaches requires management efforts to address public health and economic concerns. Feces-borne bacterial concentrations are influenced by different fecal sources, environmental conditions, and ecosystem reservoirs, making their public health significance convoluted. In this study, we sought to delineate the influences of these factors on enterococcal concentrations in southern Maine coastal recreational waters. Weekly water samples and water quality measurements were conducted at freshwater, estuarine, and marine beach sites from June through September 2016. The samples were analyzed for total and particle-associated enterococcal concentrations, total suspended solids, and microbial source tracking markers (PCR: Bac32, HF183, CF128, DF475, and Gull2; quantitative PCR [qPCR]: AllBac, HF183, and GFD). Water, soil, sediment, and marine sediment samples were also subjected to 16S rRNA sequencing and SourceTracker analysis to determine the influence from these environmental reservoirs on water sample microbial communities. Enterococcal and particle associated enterococcal concentrations were elevated in freshwater, but the concentrations of suspended solids were relatively similar. Mammal fecal contamination was significantly elevated in the estuary, with human and bird fecal contaminant levels similar between sites. A partial least-squares regression model indicated particle-associated enterococcal and mammal marker concentrations had the most significant positive relationships with enterococcal concentrations across marine, estuary, and freshwater environments. Freshwater microbial communities were significantly influenced by underlying sediment, while estuarine/marine beach communities were influenced by freshwater, high tide height, and estuarine sediment. Elevated enterococcal levels were reflective of a combination of increased fecal source input, environmental sources, and environmental conditions, highlighting the need for encompassing microbial source tracking (MST) approaches for managing water quality issues.IMPORTANCE Enterococci have long been the federal standard in determining water quality at estuarine and marine environments. Although enterococci are highly abundant in the intestines of many animals, they are not exclusive to that environment and can persist and grow outside fecal tracts. This presents a management problem for areas that are largely impaired by nonpoint source contamination, as fecal sources might not be the root cause of contamination. This study employed different microbial source tracking methods for delineating the influences from fecal source input, environmental sources, and environmental conditions to determine which combination of variables are influencing enterococcal concentrations in recreational waters at a historically impaired coastal town. The results showed that fecal source input, environmental sources, and conditions all play roles in influencing enterococcal concentrations. This highlights the need to include an encompassing microbial source tracking approach to assess the effects of all important variables on enterococcal concentrations. PMID- 30006394 TI - Sheep as a Potential Source of Zoonotic Cryptosporidiosis in China. AB - In this study, we assessed the prevalence and genetic characteristics of Cryptosporidium in sheep from 10 provinces in China. Fecal samples from 1,035 sheep originating from 16 farms were collected, and 295 (28.5%) were found to be Cryptosporidium positive by nested PCR. Cryptosporidium was detected at all farms, with infection rates between 5.7% and 50.0%. Three Cryptosporidium species were identified, including Cryptosporidium xiaoi (73.2%, 216/295), Cryptosporidium ubiquitum (21.7%, 64/295), and Cryptosporidium parvum (5.1%, 15/295). The distribution of Cryptosporidium species differed by province and by farm. All three species were detected in lambs and adult sheep but the highest infection rate was found in postweaned lambs. All three species were detected in all four seasons, with the highest prevalence found in autumn. Four C. parvum subtypes (IIaA15G2R1, IIaA17G2R1, IIdA18G1, and IIdA19G1) and one C. ubiquitum subtype (XIIa) were identified. For most provinces in this study, we are not aware of a previously published description or molecular characterization of Cryptosporidium infections in sheep. This information will improve our knowledge and understanding of the epidemiology of cryptosporidiosis in China.IMPORTANCECryptosporidium is an important zoonotic parasite that causes diarrhea in humans and animals worldwide. Previous studies suggested geographic differences in the distribution of Cryptosporidium species in sheep. However, molecular characterization studies of Cryptosporidium species in sheep have been carried out in only a few provinces in China, and the limited data available do not reflect the real situation. In this study, five districts, covering most areas where sheep are bred in China, were selected for examination of Cryptosporidium species, and Cryptosporidium infections were detected at all farms assessed, suggesting that Cryptosporidium is widespread in sheep in China. We also found geographic differences in the distribution of Cryptosporidium species but did not detect any differences between sheep age groups or seasons. Subtyping analyses showed that all of the subtypes identified in this study have been reported in humans, suggesting that sheep may be a potential source of zoonotic cryptosporidiosis. PMID- 30006395 TI - Quantitative PCR Analysis of Gut Disease-Discriminatory Phyla for Determining Shrimp Disease Incidence. AB - There is evidence that gut microbial signatures are indicative of host health status. However, few efforts have been devoted to establishing an applicable technique for determining disease incidence by using gut microbial signatures. Herein, we established a quantitative PCR (qPCR)-based approach to detect the relative abundances of gut disease-discriminatory phyla, which in turn afforded independent variables for quantitatively determining the incidence of shrimp disease. Given the temporal dynamics of gut bacterial communities as healthy shrimp aged, we identified disease-discriminatory phyla after ruling out age discriminatory phyla. The top 10 disease-discriminatory phyla contributed to an overall 93.2% accuracy in diagnosis (n = 103 samples from shrimp that were determined with high confidence to be healthy or that exhibited apparent disease symptoms and subsequent death), with 70% diagnosis accuracy at the disease onset stage, when symptoms or signs of disease were not apparent. 16S rRNA gene targeted group-specific primers of five disease-discriminatory phyla were then designed according to their compositions within shrimp gut microbiota, and other primers were borrowed from previous studies. The relative abundances of the 10 disease-discriminatory phyla assayed by qPCR exhibited a high consistency (r = 0.946, P < 0.001) with those detected by Illumina sequencing. Notably, using the profiles of disease-discriminatory phyla assayed by qPCR and the corresponding weight coefficients as independent variables, we were able to accurately estimate the incidences of future disease outcome. This work establishes an applicable technique to quantitatively determine the incidence and onset of shrimp disease, which is a valuable attempt to translate scientific research into a practical application.IMPORTANCE Current studies have identified gut microbial signatures of host health using high-throughput sequencing (HTS) techniques. However, HTS is still expensive and time-consuming and requires a high technical ability, thereby impeding its application in routine monitoring in aquaculture. Hence, it is necessary to seek an alternative strategy to overcome these shortcomings. Herein, we establish a qPCR-based approach to detect the relative abundances of gut disease-discriminatory phyla, which in turn afford independent variables to quantitatively determine the incidence and onset of shrimp disease. Notably, there is a high consistency between the accuracies of disease diagnosis achieved by qPCR and HTS. This applicable technique makes important progress toward defining a diseased state in shrimp and toward solving an important animal health management-driven economic problem. PMID- 30006397 TI - Nitrosospira Cluster 8a Plays a Predominant Role in the Nitrification Process of a Subtropical Ultisol under Long-Term Inorganic and Organic Fertilization. AB - Long-term effects of inorganic and organic fertilization on nitrification activity (NA) and the abundances and community structures of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) were investigated in an acidic Ultisol. Seven treatments applied annually for 27 years comprised no fertilization (control), inorganic NPK fertilizer (N), inorganic NPK fertilizer plus lime (CaCO3) (NL), inorganic NPK fertilizer plus peanut straw (NPS), inorganic NPK fertilizer plus rice straw (NRS), inorganic NPK fertilizer plus radish (NR), and inorganic NPK fertilizer plus pig manure (NPM). In nonfertilized soil, the abundance of AOA was 1 order of magnitude higher than that of AOB. Fertilization reduced the abundance of AOA but increased that of AOB, especially in the NL treatment. The AOA communities in the control and the N treatments were dominated by the Nitrososphaera and B1 clades but shifted to clade A in the NL and NPM treatments. Nitrosospira cluster 8a was found to be the most dominant AOB in all treatments. NA was primarily regulated by soil properties, especially soil pH, and the interaction with AOB abundance explained up to 73% of the variance in NA. When NL soils with neutral pH were excluded from the analysis, AOB abundance, especially the relative abundance of Nitrosospira cluster 8a, was positively associated with NA. In contrast, there was no association between AOA abundance and NA. Overall, our data suggest that Nitrosospira cluster 8a of AOB played an important role in the nitrification process in acidic soil following long-term inorganic and organic fertilization.IMPORTANCE The nitrification process is an important step in the nitrogen (N) cycle, affecting N availability and N losses to the wider environment. Ammonia oxidation, which is the first and rate-limiting step of nitrification, was widely accepted to be mainly regulated by AOA in acidic soils. However, in this study, nitrification activity was correlated with the abundance of AOB rather than that of AOA in acidic Ultisols. Nitrosospira cluster 8a, a phylotype of AOB which preferred warm temperatures, and low soil pH played a predominant role in the nitrification process in the test Ultisols. Our results also showed that long-term application of lime or pig manure rather than plant residues altered the community structure of AOA and AOB. Taken together, our findings contribute new knowledge to the understanding of the nitrification process and ammonia oxidizers in subtropical acidic Ultisol under long-term inorganic and organic fertilization. PMID- 30006396 TI - Thiaminase I Provides a Growth Advantage by Salvaging Precursors from Environmental Thiamine and Its Analogs in Burkholderia thailandensis. AB - Thiamine is essential to life, as it serves as a cofactor for enzymes involved in critical carbon transformations. Many bacteria can synthesize thiamine, while thiamine auxotrophs must obtain it or its precursors from the environment. Thiaminases degrade thiamine by catalyzing the base-exchange substitution of thiazole with a nucleophile, and thiaminase I specifically has been implicated in thiamine deficiency syndromes in animals. The biological role of this secreted enzyme has been a long-standing mystery. We used the thiaminase I-producing soil bacterium Burkholderia thailandensis as a model to ascertain its function. First, we generated thiamine auxotrophs, which are still able to use exogenous precursors (thiazole and hydroxymethyl pyrimidine), to synthesize thiamine. We found that thiaminase I extended the survival of these strains, when grown in defined media where thiamine was serially diluted out, compared to isogenic strains that could not produce thiaminase I. Thiamine auxotrophs grew better on thiamine precursors than thiamine itself, suggesting thiaminase I functions to convert thiamine to useful precursors. Furthermore, our findings demonstrate that thiaminase I cleaves phosphorylated thiamine and toxic analogs, which releases precursors that can then be used for thiamine synthesis. This study establishes a biological role for this perplexing enzyme and provides additional insight into the complicated nature of thiamine metabolism and how individual bacteria may manipulate the availability of a vital nutrient in the environment.IMPORTANCE The function of thiaminase I has remained a long-standing, unsolved mystery. The enzyme is only known to be produced by a small subset of microorganisms, although thiaminase I activity has been associated with numerous plants and animals, and is implicated in thiamine deficiencies brought on by consumption of organisms containing this enzyme. Genomic and biochemical analyses have shed light on potential roles for the enzyme. Using the genetically amenable thiaminase I producing soil bacterium Burkholderia thailandensis, we were able to demonstrate that thiaminase I helps salvage precursors from thiamine derivatives in the environment and degrades thiamine to its precursors, which are preferentially used by B. thailandensis auxotrophs. Our study establishes a biological role for this perplexing enzyme and provides insight into the complicated nature of thiamine metabolism. It also establishes B. thailandensis as a robust model system for studying thiamine metabolism. PMID- 30006398 TI - Spatial Distribution and Diverse Metabolic Functions of Lignocellulose-Degrading Uncultured Bacteria as Revealed by Genome-Centric Metagenomics. AB - The mechanisms by which specific anaerobic microorganisms remain firmly attached to lignocellulosic material, allowing them to efficiently decompose organic matter, have yet to be elucidated. To circumvent this issue, microbiomes collected from anaerobic digesters treating pig manure and meadow grass were fractionated to separate the planktonic microbes from those adhered to lignocellulosic substrate. Assembly of shotgun reads, followed by a binning process, recovered 151 population genomes, 80 out of which were completely new and were not previously deposited in any database. Genome coverage allowed the identification of microbial spatial distribution in the engineered ecosystem. Moreover, a composite bioinformatic analysis using multiple databases for functional annotation revealed that uncultured members of the Bacteroidetes and Firmicutes follow diverse metabolic strategies for polysaccharide degradation. The structure of cellulosome in Firmicutes species can differ depending on the number and functional roles of carbohydrate-binding modules. In contrast, members of the Bacteroidetes are able to adhere to and degrade lignocellulose due to the presence of multiple carbohydrate-binding family 6 modules in beta-xylosidase and endoglucanase proteins or S-layer homology modules in unknown proteins. This study combines the concept of variability in spatial distribution with genome centric metagenomics, allowing a functional and taxonomical exploration of the biogas microbiome.IMPORTANCE This work contributes new knowledge about lignocellulose degradation in engineered ecosystems. Specifically, the combination of the spatial distribution of uncultured microbes with genome centric metagenomics provides novel insights into the metabolic properties of planktonic and firmly attached to plant biomass bacteria. Moreover, the knowledge obtained in this study enabled us to understand the diverse metabolic strategies for polysaccharide degradation in different species of Bacteroidetes and Clostridiales Even though structural elements of cellulosome were restricted to Clostridiales species, our study identified a putative mechanism in Bacteroidetes species for biomass decomposition, which is based on a gene cluster responsible for cellulose degradation, disaccharide cleavage to glucose, and transport to cytoplasm. PMID- 30006400 TI - Heterologous Expression of Pseudomonas putida Methyl-Accepting Chemotaxis Proteins Yields Escherichia coli Cells Chemotactic to Aromatic Compounds. AB - Escherichia coli, commonly used in chemotaxis studies, is attracted mostly by amino acids, sugars, and peptides. We envisioned modifying the chemotaxis specificity of E. coli by expressing heterologous chemoreceptors from Pseudomonas putida enabling attraction either to toluene or benzoate. The mcpT gene encoding the type 40-helical bundle (40H) methyl-accepting chemoreceptor for toluene from Pseudomonas putida MT53 and the pcaY gene for the type 40H receptor for benzoate and related molecules from P. putida F1 were expressed from the trg promoter on a plasmid in motile wild-type E. coli MG1655. E. coli cells expressing McpT accumulated in chemoattraction assays to sources with 60 to 200 MUM toluene, although less strongly than the response to 100 MUM serine, but statistically significantly stronger than that to sources without any added attractant. An McpT mCherry fusion protein was detectably expressed in E. coli and yielded weak but distinguishable membranes and polar foci in 1% of cells. E. coli cells expressing PcaY showed weak attraction to 0.1 to 1 mM benzoate, but 50 to 70% of cells localized the PcaY-mCherry fusion to their membrane. We conclude that implementing heterologous receptors in the E. coli chemotaxis network is possible and, upon improvement of the compatibility of the type 40H chemoreceptors, may bear interest for biosensing.IMPORTANCE Bacterial chemotaxis might be harnessed for the development of rapid biosensors, in which chemical availability is deduced from cell accumulation to chemoattractants over time. Chemotaxis of Escherichia coli has been well studied, but the bacterium is not attracted to chemicals of environmental concern, such as aromatic solvents. We show here that heterologous chemoreceptors for aromatic compounds from Pseudomonas putida at least partly functionally complement the E. coli chemotaxis network, yielding cells attracted to toluene or benzoate. Complementation was still inferior to native chemoattractants, like serine, but our study demonstrates the potential for obtaining selective sensing for aromatic compounds in E. coli. PMID- 30006401 TI - Quorum Sensing in Pseudomonas savastanoi pv. savastanoi and Erwinia toletana: Role in Virulence and Interspecies Interactions in the Olive Knot. AB - The olive knot disease (Olea europea L.) is caused by the bacterium Pseudomonas savastanoi pv. savastanoi. P. savastanoi pv. savastanoi in the olive knot undergoes interspecies interactions with the harmless endophyte Erwinia toletana; P. savastanoi pv. savastanoi and E. toletana colocalize and form a stable community, resulting in a more aggressive disease. P. savastanoi pv. savastanoi and Etoletana produce the same type of the N-acylhomoserine lactone (AHL) quorum sensing (QS) signal, and they share AHLs in planta In this work, we have further studied the AHL QS systems of P. savastanoi pv. savastanoi and Etoletana in order to determine possible molecular mechanism(s) involved in this bacterial interspecies interaction/cooperation. The AHL QS regulons of P. savastanoi pv. savastanoi and Etoletana were determined, allowing the identification of several QS-regulated genes. Surprisingly, the P. savastanoi pv. savastanoi QS regulon consisted of only a few loci whereas in Etoletana many putative metabolic genes were regulated by QS, among which are several involved in carbohydrate metabolism. One of these loci was the aldolase-encoding gene garL, which was found to be essential for both colocalization of P. savastanoi pv. savastanoi and Etoletana cells inside olive knots as well as knot development. This study further highlighted that pathogens can cooperate with commensal members of the plant microbiome.IMPORTANCE This is a report on studies of the quorum sensing (QS) systems of the olive knot pathogen Pseudomonas savastanoi pv. savastanoi and olive knot cooperator Erwinia toletana These two bacterial species form a stable community in the olive knot, share QS signals, and cooperate, resulting in a more aggressive disease. In this work we further studied the QS systems by determining their regulons as well as by studying QS-regulated genes which might play a role in this cooperation. This represents a unique in vivo interspecies bacterial virulence model and highlights the importance of bacterial interspecies interaction in disease. PMID- 30006402 TI - Long-Term Colonization Dynamics of Enterococcus faecalis in Implanted Devices in Research Macaques. AB - Enterococcus faecalis is a common opportunistic pathogen that colonizes cephalic recording chambers (CRCs) of macaques used in cognitive neuroscience research. We previously characterized 15 E. faecalis strains isolated from macaques at the Massachusetts Institute of Technology (MIT) in 2011. The goal of this study was to examine how a 2014 protocol change prohibiting the use of antimicrobials within CRCs affected colonizing E. faecalis strains. We collected 20 E. faecalis isolates from 10 macaques between 2013 and 2017 for comparison to 4 isolates previously characterized in 2011 with respect to the sequence type (ST) distribution, antimicrobial resistance, biofilm formation, and changes in genes that might confer a survival advantage. ST4 and ST55 were predominant among the isolates characterized in 2011, whereas the less antimicrobial-resistant lineage ST48 emerged to dominance after 2013. Two macaques remained colonized by ST4 and ST55 strains for 5 and 4 years, respectively. While the antimicrobial resistance and virulence factors identified in these ST4 and ST55 strains remained relatively stable, we detected an increase in biofilm formation ability over time in both isolates. We also found that ST48 strains were typically robust biofilm formers, which could explain why this ST increased in prevalence. Finally, we identified mutations in the DNA mismatch repair genes mutS and mutL in separate ST55 and ST4 strains and confirmed that strains bearing these mutations displayed a hypermutator phenotype. The presence of a hypermutator phenotype may complicate future antimicrobial treatment for clinically relevant E. faecalis infections in macaques.IMPORTANCEEnterococcus faecalis is a common cause of health care associated infections in humans, largely due to its ability to persist in the hospital environment, colonize patients, acquire antimicrobial resistance, and form biofilms. Understanding how enterococci evolve in health care settings provides insight into factors affecting enterococcal survival and persistence. Macaques used in neuroscience research have long-term cranial implants that, despite best practices, often become colonized by E. faecalis This provides a unique opportunity to noninvasively examine the evolution of enterococci on a long-term indwelling device. We collected E. faecalis strains from cephalic implants over a 7-year period and characterized the sequence type, antimicrobial resistance, virulence factors, biofilm production, and hypermutator phenotypes. Improved antimicrobial stewardship allowed a less-antimicrobial-resistant E. faecalis strain to predominate at the implant interface, potentially improving antimicrobial treatment outcomes if future clinical infections occur. Biofilm formation appears to play an important role in the persistence of the E. faecalis strains associated with these implants. PMID- 30006399 TI - Diversity and Proliferation of Metallo-beta-Lactamases: a Clarion Call for Clinically Effective Metallo-beta-Lactamase Inhibitors. AB - The worldwide proliferation of life-threatening metallo-beta-lactamase (MBL) producing Gram-negative bacteria is a serious concern to public health. MBLs are compromising the therapeutic efficacies of beta-lactams, particularly carbapenems, which are last-resort antibiotics indicated for various multidrug resistant bacterial infections. Inhibition of enzymes mediating antibiotic resistance in bacteria is one of the major promising means for overcoming bacterial resistance. Compounds having potential MBL-inhibitory activity have been reported, but none are currently under clinical trials. The need for developing safe and efficient MBL inhibitors (MBLIs) is obvious, particularly with the continuous spread of MBLs worldwide. In this review, the emergence and escalation of MBLs in Gram-negative bacteria are discussed. The relationships between different class B beta-lactamases identified up to 2017 are represented by a phylogenetic tree and summarized. In addition, approved and/or clinical phase serine beta-lactamase inhibitors are recapitulated to reflect the successful advances made in developing class A beta-lactamase inhibitors. Reported MBLIs, their inhibitory properties, and their purported modes of inhibition are delineated. Insights into structural variations of MBLs and the challenges involved in developing potent MBLIs are also elucidated and discussed. Currently, natural products and MBL-resistant beta-lactam analogues are the most promising agents that can become clinically efficient MBLIs. A deeper comprehension of the mechanisms of action and activity spectra of the various MBLs and their inhibitors will serve as a bedrock for further investigations that can result in clinically useful MBLIs to curb this global menace. PMID- 30006403 TI - Microbial Community Dynamics and Assembly Follow Trajectories of an Early-Spring Diatom Bloom in a Semienclosed Bay. AB - Harmful algal blooms (HABs) are serious ecological disasters in coastal areas, significantly influencing biogeochemical cycles driven by bacteria. The shifts in microbial communities during HABs have been widely investigated, but the assembly mechanisms of microbial communities during HABs are poorly understood. Here, using 16S rRNA gene amplicon sequencing, we analyzed the microbial communities during an early-spring diatom bloom, in order to investigate the dynamics of microbial assembly processes. Rhodobacteraceae, Flavobacteriaceae, and Microbacteriaceae were the main bacterial families during the bloom. The 30 most abundant operational taxonomic units (OTUs) segregated into 4 clusters according to specific bloom stages, exhibiting clear successional patterns during the bloom process. The succession of microbial communities correlated with changes in the dynamics of algal species. Based on the beta-nearest taxon distance, we constructed a simulation model, which demonstrated that the assembly of microbial communities shifted from strong heterogenous selection in the early stage of the bloom to stochasticity in the middle stage and then to strong homogeneous selection in the late and after-bloom stages. These successions were driven mainly by chlorophyll a contents, which were affected mainly by Skeletonema costatum Moreover, functional prediction of microbial communities showed that microbial metabolic functions were significantly related to nitrogen metabolism. In summary, our results clearly suggested a dominant role of determinacy in microbial community assembly in HABs and will facilitate deeper understanding of the ecological processes shaping microbial communities during the algal bloom process.IMPORTANCE Harmful algal blooms (HABs) significantly influence biogeochemical cycles driven by bacteria. The shifts in microbial communities during HABs have been studied intensively, but the assembly mechanisms of microbial communities during HABs are poorly understood, with limited investigation of the balance of deterministic and stochastic processes in shaping microbial communities in HABs. In this study, the dynamics and assembly of microbial communities in an early-spring diatom bloom process were investigated. Our data both confirm previously observed general microbial successional patterns and show new detailed mechanisms for microbial assembly in HABs. These results will facilitate deeper understanding of the ecological processes shaping microbial communities in HABs. In addition, predictions of metabolic potential in this study will facilitate understanding of the influence of HABs on nitrogen metabolism in marine environments. PMID- 30006404 TI - Bacterial Endospores as Phage Genome Carriers and Protective Shells. AB - Bacterial endospores can serve as phage genome protection shells against various environmental stresses to enhance microbial control applications. The genomes of polyvalent lytic Bacillus phages PBSC1 and PBSC2, which infect both B. subtilis subsp. subtilis and B. cereus NRS 248, were incorporated into B. subtilis endospores (without integration into the host chromosome). When PBSC1 and PBSC2 were released from germinating endospores, they significantly inhibited the growth of the targeted opportunistic pathogen B. cereus Optimal endospore entrapment was achieved when phages were introduced to the fast-sporulating prespores at a multiplicity of infection of 1. Longer endospore maturation (48 h versus 24 h) increased both spore yield and efficiency of entrapment. Compared with free phages, spore-protected phage genomes showed significantly higher resistance toward high temperatures (60 to 80 degrees C), extreme pH (pH 2 or pH 12), and copper ions (0.1 to 10 mg/liter). Endospore germination is inducible by low concentrations of l-alanine or by a germinant mixture (l-asparagine, d glucose, d-fructose, and K+) to trigger the expression, assembly, and consequent release of phage particles within 60 to 90 min. Overall, the superior resiliency of polyvalent phages protected by endospores might enable nonrefrigerated phage storage and enhance phage applications after exposure to adverse environmental conditions.IMPORTANCE Bacteriophages are being considered for the control of multidrug-resistant and other problematic bacteria in environmental systems. However, the efficacy of phage-based microbial control is limited by infectivity loss during phage delivery and/or storage. Here, we exploit the pseudolysogenic state of phages, which involves incorporation of their genome into bacterial endospores (without integration into the host chromosome), to enhance survival in unfavorable environments. We isolated polyvalent (broad-host-range) phages that efficiently infect both benign and opportunistically pathogenic Bacillus strains and encapsulated the phage genomes in B. subtilis endospores to significantly improve resistance to various environmental stressors. Encapsulation by spores also significantly enhanced phage genome viability during storage. We also show that endospore germination can be induced on demand with nutrient germinants that trigger the release of active phages. Overall, we demonstrate that encapsulation of polyvalent phage genomes into benign endospores holds great promise for broadening the scope and efficacy of phage biocontrol. PMID- 30006405 TI - Cooperative Involvement of Glycosyltransferases in the Transfer of Amino Sugars during the Biosynthesis of the Macrolactam Sipanmycin by Streptomyces sp. Strain CS149. AB - Macrolactams comprise a family of natural compounds with important bioactivities, such as antibiotic, antifungal, and antiproliferative activities. Sipanmycins A and B are two novel members of this family, with two sugar moieties attached to the aglycon. In the related macrolactam vicenistatin, the sugar moiety has been proven to be essential for cytotoxicity. In this work, the gene cluster responsible for the biosynthesis of sipanmycins (sip cluster) in Streptomyces sp. strain CS149 is described and the steps involved in the glycosylation of the final compounds unraveled. Also, the cooperation of two different glycosyltransferases in each glycosylation step is demonstrated. Additionally, the essential role of SipO2 as an auxiliary protein in the incorporation of the second deoxy sugar is addressed. In light of the results obtained by the generation of mutant strains and in silico characterization of the sip cluster, a biosynthetic pathway for sipanmycins and the two deoxy sugars attached is proposed. Finally, the importance of the hydroxyl group at C-10 of the macrolactam ring and the sugar moieties for cytotoxicity and antibiotic activity of sipanmycins is shown.IMPORTANCE The rapid emergence of infectious diseases and multiresistant pathogens has increased the necessity for new bioactive compounds; thus, novel strategies have to be developed to find them. Actinomycetes isolated in symbiosis with insects have attracted attention in recent years as producers of metabolites with important bioactivities. Sipanmycins are glycosylated macrolactams produced by Streptomyces sp. CS149, isolated from leaf-cutting ants, and show potent cytotoxic activity. Here, we characterize the sip cluster and propose a biosynthetic pathway for sipanmycins. As far as we know, it is the first time that the cooperation between two different glycosyltransferases is demonstrated to be strictly necessary for the incorporation of the same sugar. Also, a third protein with homology to P450 monooxygenases, SipO2, is shown to be essential in the second glycosylation step, forming a complex with the glycosyltransferase pair SipS9-SipS14. PMID- 30006406 TI - Cobalamin activity-based probe enables microbial cell growth and finds new cobalamin-protein interactions across domains. AB - Understanding the factors that regulate microbe function and microbial community assembly, function, and fitness is a grand challenge. A critical factor and an important enzyme cofactor and regulator of gene expression is cobalamin (vitamin B12). Our knowledge of the roles of vitamin B12 is limited because technologies that enable in situ characterization of microbial metabolism and gene regulation with minimal impact on cell physiology are needed. To meet this need we show that a synthetic probe mimic of B12 supports growth of B12 auxotrophic bacteria and archaea. We demonstrate that a B12 activity-based probe (B12-ABP) is actively transported into Escherichia coli cells, and converted to adenosyl-B12-ABP akin to native B12 Identification of the proteins that bind the B12-ABP in vivo in E. coli, a Rhodobacteraceae sp. and Haloferax volcanii, demonstrate the specificity for known and novel B12 protein targets. The B12-ABP also regulates the B12 dependent RNA riboswitch btuB and the transcription factor EutR. Our results demonstrate a new approach to gain knowledge about the role of B12 in microbe functions. Our approach provides a powerful, non-disruptive tool to analyze B12 interactions in living cells, and can be used to discover the role of B12 in diverse microbial systems.Importance We demonstrate that a cobalamin chemical probe can be used to investigate in vivo roles of vitamin B12 in microbial growth and regulation, by supporting growth of B12 auxotrophic bacteria and archaea, enabling biological activity with three different cell macromolecules (RNA, DNA, and proteins), and facilitating functional proteomics to characterize B12-protein interactions. The B12-ABP is both transcriptionally and translationally able to regulate gene expression analogous to natural vitamin B12 The application of the B12-ABP at biologically relevant concentrations facilitates a unique way to measure B12 microbial dynamics and identify new B12 protein targets in bacteria and archaea. We demonstrate that the B12-ABP can be used to identify in vivo protein interactions across diverse microbes, from E. coli to microbes isolated from naturally occurring phototrophic biofilms, to the salt-tolerant archaea Haloferax volcanii. PMID- 30006407 TI - A Specific Single Nucleotide Polymorphism in the ATP Synthase Gene Significantly Improves Environmental Stress Tolerance of Synechococcus elongatus PCC 7942. AB - In response to a broad range of habitats and environmental stresses, cyanobacteria have evolved various effective acclimation strategies, which will be helpful for improving the stress tolerances of photosynthetic organisms, including higher plants. Synechococcus elongatus UTEX 2973 and PCC 7942 possess genomes that are 99.8% identical but exhibit significant differences in cell growth and stress tolerance. In this study, we found that a single amino acid substitution at FoF1 ATP synthase subunit alpha (AtpA), C252Y, is the primary contributor to the improved stress tolerance of S. elongatus UTEX 2973. Site saturation mutagenesis experiments showed that point mutations of cysteine 252 to any of the four conjugated amino acids could significantly improve the stress tolerance of S. elongatus PCC 7942. We further confirmed that the C252Y mutation increases AtpA protein levels, intracellular ATP synthase activity, intracellular ATP abundance, transcription of psbA genes (especially psbA2), photosystem II activity, and glycogen accumulation in S. elongatus PCC 7942. This work highlights the importance of AtpA in improving the stress tolerance of cyanobacteria and provides insight into how cyanobacteria evolve via point mutations in the face of environmental selection pressures.IMPORTANCE Two closely related Synechococcus strains showed significantly different tolerances to high light and high temperature but limited genomic differences, providing us opportunities to identify key genes responsible for stress acclimation by a gene complementation approach. In this study, we confirmed that a single point mutation in the alpha subunit of FoF1 ATP synthase (AtpA) contributes mainly to the improved stress tolerance of Synechococcus elongatus UTEX 2973. The point mutation of AtpA, the important ATP-generating complex of photosynthesis, increases AtpA protein levels, intracellular ATP synthase activity, and ATP concentrations under heat stress, as well as photosystem II activity. This work proves the importance of ATP synthase in cyanobacterial stress acclimation and provides a good target for future improvement of cyanobacterial stress tolerance by metabolic engineering. PMID- 30006409 TI - Valproic acid is protective in cellular and worm models of oculopharyngeal muscular dystrophy. AB - OBJECTIVE: To explore valproic acid (VPA) as a potentially beneficial drug in cellular and worm models of oculopharyngeal muscular dystrophy (OPMD). METHODS: Using a combination of live cell imaging and biochemical measures, we evaluated the potential protective effect of VPA in a stable C2C12 muscle cell model of OPMD, in lymphoblastoid cell lines derived from patients with OPMD and in a transgenic Caenorhabditis elegans OPMD model expressing human mutant PABPN1. RESULTS: We demonstrated that VPA protects against the toxicity of mutant PABPN1. Of note, we found that VPA confers its long-term protective effects on C2C12 cell survival, proliferation, and differentiation by increasing the acetylated level of histones. Furthermore, VPA enhances the level of histone acetylation in lymphoblastoid cell lines derived from patients with OPMD. Moreover, treatment of nematodes with moderate concentrations of VPA significantly improved the motility of the PABPN-13 Alanines worms. CONCLUSIONS: Our results suggest that VPA helps to counteract OPMD-related phenotypes in the cellular and C elegans disease models. PMID- 30006410 TI - Cervical puncture to deliver nusinersen in patients with spinal muscular atrophy. AB - OBJECTIVE: To report our experience delivering intrathecal nusinersen through cervical puncture in patients with spinal muscular atrophy (SMA) with no lumbar access. BACKGROUND: SMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells. Nusinersen, the first Food and Drug Administration-approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible. Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections. Therefore we have used C1/C2 puncture as an alternative to administer nusinersen. METHOD: Retrospective chart review. RESULTS: Intrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbosacral spinal fusion: a 12-year-old girl with type 1 SMA and 2 17-year-old girls with type 2 SMA. Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1-C2 interspace and full dose of nusinersen (12 mg/5 mL) was injected after visualizing free CSF flow. Patients completed their 4 loading doses and first maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated. CONCLUSION: Cervical puncture is a feasible alternative delivery route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access when done by providers with expertise in this procedure. PMID- 30006408 TI - Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses. AB - Establishing and maintaining beneficial interactions between the host and associated gut microbiota are pivotal requirements for host health. Autophagy is an important catabolic recycling pathway that degrades long-lived proteins and some organelles by lysosome to maintain cellular homeostasis. Although impaired autophagy is thought to be closely correlated with Crohn's disease (CD), the functional role of autophagy in the maintenance of gut microbiota is poorly understood. As autophagy-related 5 (Atg5) is a key gene associated with the extension of the phagophoric membrane in autophagic vesicles, we established a gut-specific Atg5 knockout mouse model, and we found that the disruption of autophagic flux in the intenstinal epithelium cells dramatically altered the composition of the gut microbiota and reduced alpha diversity. Microbial function prediction indicated that the pathway allocated for infectious diseases was enriched in Atg5-/- mice. "Candidatus Arthromitus" and the Pasteurellaceae family were increased in Atg5-/- mice, whereas Akkermansia muciniphila and the Lachnospiraceae family were reduced. Transcriptome analysis revealed that two key inflammatory bowel disease (IBD)-related transcription factors, RORC and TBX21, of host cells were upregulated in Atg5-/- mice, thus elevating the Muc2-related immunological response. The findings suggest that intestinal autophagy plays a vital role in modulating the diversity and composition of gut microbiota.IMPORTANCE The homeostasis of host-microbiota interactions is of great importance to host health. Previous studies demonstrated that disruption of autophagy was linked to inflammatory bowel disease. However, the interaction mechanism of gut microbiota regulated by autophagy was obscure. In an intestinal epithelium-specific autophagy-related 5 (Atg5) knockout mouse model, we observed a significant alteration and decreased diversity in the gut microbiota of Atg5 deficient mice compared with that of wild-type mice. Although the numbers of some organisms (e.g., Akkermansia muciniphila and members of the Lachnospiraceae family) associated with the control of inflammation decreased, those of proinflammationory bacteria (e.g., "Candidatus Arthromitus") and potential pathogens (the Pasteurellaceae family) increased in Atg5-/- mice. Differential gene expression analysis revealed that two key genes, RORC and TBX21, involved in inflammatory bowel disease were upregulated in Atg5-/- mice. Our study suggests that Atg5 deficiency results in an imbalance of the host-microbe interaction and deterioration of the gut microenvironment. PMID- 30006411 TI - The spike onset zone: The region where epileptic spikes start and from where they propagate. AB - OBJECTIVE: To determine whether the maximum hemodynamic response to scalp interictal epileptic discharges (IEDs) corresponds to the region where IEDs originate and from where they propagate. METHODS: We studied 19 patients who underwent first an EEG-fMRI showing responses in the gray matter, and then intracranial EEG (iEEG). We coregistered the hemodynamic responses to the iEEG electrode contacts and analyzed IEDs in the iEEG channel adjacent to a maximum response (labeled the main channel), in relation to IEDs in other channels during a widespread intracranial IED event. IEDs in the main channel were aligned at their peak, and IEDs in each channel were averaged time-locked to these instants. The beginning and peak of IEDs in the averaged trace were identified, blinded to the identity of the main channel. The latency of IEDs was computed between the earliest and all other channels. RESULTS: The median latency of IEDs in the main channel was significantly smaller than in other channels for either the peak (15.5 vs 67.5 milliseconds, p = 0.00037) or the beginning (46.5 vs 118.4 milliseconds, p = 0.000048). The latency of IED was significantly correlated to the distance from the maximum hemodynamic response (p < 0.0001 for either the peak or the beginning). CONCLUSION: IED adjacent to a maximum hemodynamic response, which often corresponds to the seizure onset zone, is more likely to precede IEDs in remote locations during a widespread intracranial discharge. Thus, EEG-fMRI is a unique noninvasive method to reveal the origin of IEDs, which we propose to label the spike onset zone. PMID- 30006412 TI - The efficacy of nonpharmacologic intervention for orthostatic hypotension associated with aging. AB - OBJECTIVE: To determine the efficacy and safety of nonpharmacologic interventions for orthostatic hypotension (OH) secondary to aging. METHODS: A total of 150 orthostatic challenges were performed in 25 older people (age 60-92 years) to determine cardiovascular responses to bolus water drinking, compression stockings, abdominal compression, and physical countermaneuvers. Primary outcome was response rate as assessed by proportion of participants whose systolic blood pressure (SBP) drop improved by >=10 mm Hg. RESULTS: The response rate to bolus water drinking was 56% (95% confidence interval [CI] 36.7-74.2), with standing SBP increasing by 12 mm Hg (95% CI 4-20). Physical countermaneuvers were efficacious in 44% (95% CI 25.8-63.3) but had little effect on standing SBP (+7.5 mm Hg [95% CI -1 to 16]). Abdominal compression was efficacious in 52% (95% CI 32.9-70.7) and improved standing SBP (+10 mm Hg [95% CI 2-18]). Compression stockings were the least efficacious therapy (32% [95% CI 16.1-51.4]) and had little effect on standing SBP (+6 mm Hg [95% CI -1, 13]). No intervention improved symptoms during standing. There were no adverse events. CONCLUSIONS: Bolus water drinking should become the standard first-line nonpharmacologic intervention, whereas compression stockings should be disregarded in this population. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for older people with OH, bolus water drinking is superior to other nonpharmacologic interventions in decreasing SBP drop. PMID- 30006413 TI - CORL Expression and Function in Insulin Producing Neurons Reversibly Influences Adult Longevity in Drosophila. AB - CORL proteins (known as SKOR in mice, Fussel in humans and fussel in Flybase) are a family of CNS specific proteins related to Sno/Ski oncogenes. Their developmental and adult roles are largely unknown. A Drosophila CORL (dCORL) reporter gene is expressed in all Drosophila insulin-like peptide 2 (dILP2) neurons of the pars intercerebralis (PI) of the larval and adult brain. The transcription factor Drifter is also expressed in the PI in a subset of dCORL and dILP2 expressing neurons and in several non-dILP2 neurons. dCORL mutant virgin adult brains are missing all dILP2 neurons that do not also express Drifter. This phenotype is also seen when expressing dCORL-RNAi in neurosecretory cells of the PI. dCORL mutant virgin adults of both sexes have a significantly shorter lifespan than their parental strain. This longevity defect is completely reversed by mating (lifespan increases over 50% for males and females). Analyses of dCORL mutant mated adult brains revealed a complete rescue of dILP2 neurons without Drifter. Taken together, the data suggest that dCORL participates in a neural network connecting the insulin signaling pathway, longevity and mating. The conserved sequence and CNS specificity of all CORL proteins imply that this network may be operating in mammals. PMID- 30006416 TI - Fibroblast Growth Factor-23 Is Not a Single Bystander in Chronic Kidney Disease Mortality. PMID- 30006415 TI - Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling. AB - BACKGROUND: The slit diaphragm is a specialized adhesion junction between opposing podocytes, establishing the final filtration barrier that prevents passage of proteins from the capillary lumen into the urinary space. Nephrin, the key structural and signaling adhesion molecule expressed in the slit diaphragm, contains an evolutionally conserved, atypical PDZ-binding motif (PBM) reported to bind to a variety of proteins in the slit diaphragm. Several mutations in NPHS1 (the gene encoding nephrin) that result in nephrin lacking an intact PBM are associated with glomerular diseases. However, the molecular basis of nephrin-PBM mediated protein complexes is still unclear. METHODS: Using a combination of biochemic, biophysic, and cell biologic approaches, we systematically investigated the interactions between nephrin-PBM and PDZ domain-containing proteins in the slit diaphragm. RESULTS: We found that nephrin-PBM specifically binds to one member of the membrane-associated guanylate kinase family of scaffolding proteins, MAGI1, but not to another, MAGI2. The complex structure of MAGI1-PDZ3/nephrin-PBM reveals that the Gly at the -3 position of nephrin-PBM is the determining feature for MAGI1-PDZ3 recognition, which sharply contrasts with the typical PDZ/PBM binding mode. A single gain-of-function mutation within MAGI2 enabled nephrin-PBM binding. In addition, using our structural analysis, we developed a highly efficient inhibitory peptide capable of specifically blocking the nephrin/MAGI1 interaction. CONCLUSIONS: MAGI1 interacts with nephrin-PBM with exquisite specificity. A newly developed, potent inhibitory peptide that blocks this interaction may be useful for future functional investigations in vivo. Our findings also provide possible explanations for the diseases caused by NPHS1 mutations. PMID- 30006418 TI - Authors' Reply. PMID- 30006417 TI - Acute Declines in Renal Function during Intensive BP Lowering and Long-Term Risk of Death. AB - BACKGROUND: During intensive BP lowering, acute declines in renal function are common, thought to be hemodynamic, and potentially reversible. We previously showed that acute declines in renal function >=20% during intensive BP lowering were associated with higher risk of ESRD. Here, we determined whether acute declines in renal function during intensive BP lowering were associated with mortality risk among 1660 participants of the African American Study of Kidney Disease and Hypertension and the Modification of Diet in Renal Disease Trial. METHODS: We used Cox models to examine the association between percentage decline in eGFR (<5%, 5% to <20%, or >=20%) between randomization and months 3-4 of the trials (period of therapy intensification) and death. RESULTS: In adjusted analyses, compared with a <5% eGFR decline in the usual BP arm (reference), a 5% to <20% eGFR decline in the intensive BP arm was associated with a survival benefit (hazard ratio [HR], 0.77; 95% confidence interval [95% CI], 0.62 to 0.96), but a 5% to <20% eGFR decline in the usual BP arm was not (HR, 1.01; 95% CI, 0.81 to 1.26; P<0.05 for the interaction between intensive and usual BP arms for mortality risk). A >=20% eGFR decline was not associated with risk of death in the intensive BP arm (HR, 1.18; 95% CI, 0.86 to 1.62), but it was associated with a higher risk of death in the usual BP arm (HR, 1.40; 95% CI, 1.04 to 1.89) compared with the reference group. CONCLUSIONS: Intensive BP lowering was associated with a mortality benefit only if declines in eGFR were <20%. PMID- 30006414 TI - Variant antigen repertoires in Trypanosoma congolense populations and experimental infections can be profiled from deep sequence data using universal protein motifs. AB - African trypanosomes are vector-borne hemoparasites of humans and animals. In the mammal, parasites evade the immune response through antigenic variation. Periodic switching of the variant surface glycoprotein (VSG) coat covering their cell surface allows sequential expansion of serologically distinct parasite clones. Trypanosome genomes contain many hundreds of VSG genes, subject to rapid changes in nucleotide sequence, copy number, and chromosomal position. Thus, analyzing, or even quantifying, VSG diversity over space and time presents an enormous challenge to conventional techniques. Indeed, previous population genomic studies have overlooked this vital aspect of pathogen biology for lack of analytical tools. Here we present a method for analyzing population-scale VSG diversity in Trypanosoma congolense from deep sequencing data. Previously, we suggested that T. congolense VSGs segregate into defined "phylotypes" that do not recombine. In our data set comprising 41 T. congolense genome sequences from across Africa, these phylotypes are universal and exhaustive. Screening sequence contigs with diagnostic protein motifs accurately quantifies relative phylotype frequencies, providing a metric of VSG diversity, called the "variant antigen profile." We applied our metric to VSG expression in the tsetse fly, showing that certain, rare VSG phylotypes may be preferentially expressed in infective, metacyclic stage parasites. Hence, variant antigen profiling accurately and rapidly determines the T. congolense VSG gene and transcript repertoire from sequence data, without need for manual curation or highly contiguous sequences. It offers a tractable approach to measuring VSG diversity across strains and during infections, which is imperative to understanding the host-parasite interaction at population and individual scales. PMID- 30006420 TI - Genomic Medicine Takes the Stage, Again! PMID- 30006421 TI - Response to Checkpoint Inhibitor Therapy in Advanced Classic Kaposi Sarcoma: A Case Report and Immunogenomic Study. AB - Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as TP53, CDKN2A, NOTCH1, and KRAS Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease. PMID- 30006419 TI - Significantly Lower Rates of Kidney Transplantation among Candidates Listed with the Veterans Administration: A National and Local Comparison. AB - BACKGROUND: The process for evaluating kidney transplant candidates and applicable centers is distinct for patients with Veterans Administration (VA) coverage. We compared transplant rates between candidates on the kidney waiting list with VA coverage and those with other primary insurance. METHODS: Using the Scientific Registry of Transplant Recipients database, we obtained data for all adult patients in the United States listed for a primary solitary kidney transplant between January 2004 and August 2016. Of 302,457 patients analyzed, 3663 had VA primary insurance coverage. RESULTS: VA patients had a much greater median distance to their transplant center than those with other insurance had (282 versus 22 miles). In an adjusted Cox model, compared with private pay and Medicare patients, VA patients had a hazard ratio (95% confidence interval) for time to transplant of 0.72 (0.68 to 0.76) and 0.85 (0.81 to 0.90), respectively, and lower rates for living and deceased donor transplants. In a model comparing VA transplant rates with rates from four local non-VA competing centers in the same donor service areas, lower transplant rates for VA patients than for privately insured patients persisted (hazard ratio, 0.72; 95% confidence interval, 0.65 to 0.79) despite similar adjusted mortality rates. Transplant rates for VA patients were similar to those of Medicare patients locally, although Medicare patients were more likely to die or be delisted after waitlist placement. CONCLUSIONS: After successful listing, VA kidney transplant candidates appear to have persistent barriers to transplant. Further contemporary analyses are needed to account for variables that contribute to such differential transplant rates. PMID- 30006422 TI - Addressing Survivorship in Cancer Care. AB - As a disease, cancer can affect an individual's well-being, from physical to psychological, social, and even spiritual wellness. The cancer survivor population must navigate a complex, constantly evolving field, with the assistance of their care team, to conquer the disease. To address the unmet needs of the cancer survivorship community, NCCN conducted an environmental scan of existing and emerging aspects of survivorship cancer care through stakeholder meetings with survivors and patient advocacy groups to discuss needs, opportunities, and challenges in providing high-quality, patient-centered cancer survivorship care. The findings of this environmental scan directly informed the corresponding NCCN Patient Advocacy Summit: Addressing Survivorship in Cancer Care, held in Washington, DC, on December 1, 2017. In addition to the many patient advocacy groups, the summit featured stakeholders from all relevant areas of survivorship care. This article encapsulates the findings of the thorough environmental scan and the discussion from the NCCN Patient Advocacy Summit, including identified gaps and needs in addressing survivorship in cancer care. PMID- 30006424 TI - Evaluation of a Completion Total Mesorectal Excision in Patients After Local Excision of Rectal Cancer: A Word of Caution. AB - Background: According to Dutch guidelines, locally excised, low-risk, pT1 or ypT0 1 rectal cancer should not necessarily be followed by completion total mesorectal excision (cTME) in contrast to rectal cancers with higher T stages or unfavorable features. This study evaluated cTME after local excision at a national level with possible determinants for decision-making. Methods: All patients in the Dutch Colorectal Audit (DCRA) who underwent local excision of rectal cancer between 2012 and 2015 were included. Guideline adherence for performing cTME was determined with univariate and multivariate analyses to identify factors related to noncompliance. Results: According to the guidelines, of 530 included patients, cTME was indicated in 283 (53%), and among those, was performed in 82 (29%). Guideline adherence for performing cTME improved significantly (P<.001), from 10% in 2012 to 44% in 2015. Lower Charlson comorbidity index in patients with high risk pT1 rectal cancer and younger patients (aged 61-70 years vs >=80 years) with pT>=2 rectal cancer were associated with increased performance of cTME (odds ratio [OR], 13.50; 95% CI, 1.39-131.32, and OR, 6.25; 95% CI, 1.83-21.31, respectively). Conclusions: In this population-based study from the Netherlands, only a minority of patients underwent cTME after local excision of rectal cancer with pathologic features indicating the need for further treatment according to the guidelines. Although the percentage of patients undergoing cTME increased over time, the study indicated a tendency toward rectal-preserving treatment with potential oncologic risks. PMID- 30006423 TI - NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018. AB - The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added. PMID- 30006425 TI - Geographic Variation in Postoperative Imaging for Low-Risk Breast Cancer. AB - Background: The objective of this study was to examine the presence and magnitude of US geographic variation in use rates of both recommended and high-cost imaging in young patients with early-stage breast cancer during the 18 month period after surgical treatment of their primary tumor. Methods: Using the Truven Health MarketScan Commercial Database, a descriptive analysis was conducted of geographic variation in annual rates of dedicated breast imaging and high-cost body imaging of 36,045 women aged 18 to 64 years treated with surgery for invasive unilateral breast cancer between 2010 and 2012. Multivariate hierarchical analysis examined the relationship between likelihood of imaging and patient characteristics, with metropolitan statistical area (MSA) serving as a random effect. Patient characteristics included age group, BRCA1/2 carrier status, family history of breast cancer, combination of breast surgery type and radiation therapy, drug therapy, and payer type. All MSAs in the United States were included, with areas outside MSAs within a given state aggregated into a single area for analytic purposes. Results: Descriptive analysis of rates of imaging use and intensity within MSA regions revealed wide geographic variation, irrespective of treatment cohort or age group. Increased probability of recommended postoperative dedicated breast imaging was primarily associated with age and treatment including both surgery and radiation therapy, followed by MSA region (odds ratio, 1.42). Increased probability of PET use-a high-cost imaging modality for which postoperative routine use is not recommended in the absence of specific clinical findings-was primarily associated with surgery type followed by MSA region (odds ratio, 1.82). Conclusions: In patients with breast cancer treated for low-risk disease, geography has effects on the rates of posttreatment imaging, suggesting that some patients are not receiving beneficial dedicated breast imaging, and high-cost nonbreast imaging may not be targeted to those groups most likely to benefit. PMID- 30006426 TI - Searching for Survivor-Specific Services at NCI-Designated Comprehensive Cancer Centers: A Qualitative Assessment. AB - Background: Cancer survivorship presents unique medical, psychosocial, and logistical challenges for survivors, their caregivers, and clinicians. NCI designated Comprehensive Cancer Centers (CCCs) serve a unique role in the delivery of cancer care because they not only provide care but also serve as a model for community oncologists and clinics through the development and dissemination of standards of care. Survivors, their caregivers, and clinicians look to CCCs to provide information about how to navigate the transition from active to posttreatment care. However, there is wide variability in the types of resources CCCs make available on their websites. The goal of our assessment was to understand the types of posttreatment survivor-specific resources CCCs are providing on their website. Methods: We analyzed the websites of the 47 CCCs to evaluate survivor-specific resources around the 4 components of survivorship care described by the Institute of Medicine guidelines for survivorship care plans: surveillance, prevention, intervention, and coordination. Results: Of the 47 CCCs, 74.5% (n=35) had discoverable survivor-specific services on their websites. Despite our inclusive approach to coding, few websites contained extensive information targeted at survivors, their caregivers, or clinicians. Only the coordination and intervention elements were discussed by at least half of the CCCs. From the vantage point of cancer survivors, their lay caregivers, loved ones, or clinicians, there is limited information about survivor-specific services on the websites of the 47 CCCs. This dearth of information translates into substantial work for these groups to find the resources they may need. Conclusions: The CCCs have an opportunity to serve as information hubs and to lessen the amount of work associated with survivorship. As models of cancer care delivery, the CCCs can also set the standard for community oncologists and clinics for delivery of care that improves the quality of life for survivors. PMID- 30006427 TI - Outcomes Following Neoadjuvant Chemotherapy for Breast Cancer in Women Aged 40 Years and Younger: Impact of Pathologic Nodal Response. AB - Purpose: We sought to evaluate whether pathologic nodal response was predictive of outcomes in women aged <=40 years with breast cancer treated with neoadjuvant chemotherapy (NAC). Methods: A total of 220 patients treated with NAC between 1991 and 2015 were retrospectively reviewed. Pathologic complete response (pCR) was defined as no evidence of residual invasive tumor in the breast and lymph nodes (LNs) (ypT0/Tis ypN0); partial response if there was no tumor in the LNs but residual tumor in the breast (ypT+ ypN0) or residual tumor in the LNs (ypT0/Tis ypN+); and limited response if there was residual tumor in both the breast and the LNs (ypT+ ypN+). Kaplan-Meier and Cox proportional hazards analyses were performed to identify factors predictive for overall survival (OS). Results: A total of 155 patients were included. Following NAC, 39 patients (25.2%) achieved pCR, 57 (36.8%) achieved a partial response (either ypT+ ypN0 or ypT0/Tis ypN+), and 59 (38.1%) had a limited response. A total of 22 patients (14.2%) experienced local failure, 20 (12.9%) experienced regional failure, and 59 (38.1%) experienced distant failure. Median OS for patients who achieved pCR was not reached, and was significantly worse for patients who had residual disease in the breast and/or LNs (P<.001). No difference in OS was seen among patients who had residual disease in the breast alone versus those who remained LN-positive (97 vs 83 months, respectively; P=.25). Subset analysis did not reveal differences in OS based on year of treatment or cN1 disease at the time of initial diagnosis. Conclusions: Women aged <=40 years who achieved pCR had excellent outcomes; however, those who achieved a pathologic response in the LNs but had residual disease in the breast continued to have outcomes similar to those who remained LN-positive. PMID- 30006428 TI - Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. AB - The NCCN Guidelines for Anal Carcinoma provide recommendations for the management of patients with squamous cell carcinoma of the anal canal or perianal region. Primary treatment of anal cancer usually includes chemoradiation, although certain lesions can be treated with margin-negative local excision alone. Disease surveillance is recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is essential for optimal patient care. PMID- 30006429 TI - Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. AB - The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer. This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection. PMID- 30006430 TI - Role of Immunotherapy in the Treatment of Squamous Cell Carcinoma of the Anal Canal. AB - Anal cancer is a rare malignancy for which cisplatin with 5-fluorouracil is the recommended treatment for patients with metastatic disease. Because most cases of anal cancer are linked to prior infection with oncogenic strands of the human papillomavirus, immunotherapeutic approaches have been of great interest in the development of new treatments for this virally driven tumor. This article reviews the early successes of anti-PD-1 therapies and adoptive T-cell therapies for metastatic anal cancer as a potential foundation for novel combination immunotherapy trials in the future. PMID- 30006431 TI - Evolving Treatment Paradigm in the Treatment of Locally Advanced Rectal Cancer. AB - Locally advanced rectal cancer (LARC) carries higher risks of local and distant recurrence when treated with surgical resection alone. Multiple treatment strategies have been investigated to reduce recurrence risk and improve survival. Currently, there are 3 primary strategies for managing LARC: (1) preoperative long-course radiotherapy (RT) combined with radiosensitizing chemotherapy, which is better tolerated than postoperative chemoradiotherapy and provides tumor downstaging and improved pathologic complete response (pCR), followed by postoperative chemotherapy; (2) preoperative short-course RT alone as an alternative strategy for reducing the risk of local recurrence, followed by adjuvant postoperative chemotherapy; and (3) total neoadjuvant therapy with induction chemotherapy followed by chemoradiotherapy to improve pCR and reduce the difficulty of delivering chemotherapy in the postoperative setting. In addition to these currently recommended treatment paradigms, promising new strategies are available for treatment reduction. Neoadjuvant chemotherapy alone may allow for omission of RT in select patients with favorable LARC. For patients who have complete clinical responses to neoadjuvant chemotherapy and RT, nonoperative management is being considered for sphincter preservation, with surgery used as salvage. These are active areas of investigation in both institutional and cooperative group trials. The results are anticipated to provide better tailoring of neoadjuvant therapy based on patient tumor and disease response characteristics. PMID- 30006432 TI - Appropriate Use of Imaging to Detect Primary, Second Primary, and Recurrent Breast Cancer. PMID- 30006434 TI - So many WNBA embolization options. PMID- 30006435 TI - ASHP-HOPA guidelines on the roles and responsibilities of the pharmacy technician in ambulatory oncology pharmacy. PMID- 30006436 TI - Updating formulations for compounded oral liquid medications in a university health system. AB - PURPOSE: The development of a compounded oral liquid medication formulary and subsequent implementation of revised standard formulations in a university health system are described. METHODS: A standard assessment form was developed to direct evaluation of published literature and current compounding resources for all oral liquid formulations prepared by health-system pharmacies. Specific variables reviewed included concentration, components, beyond-use dating, and storage recommendations. After their review and approval, revised formulations were typed into distinct templates that incorporated additional safety features. An online departmental repository was developed to house the revised formulations. RESULTS: Modifications were made to 136 (78%) of the 175 compounded formulations reviewed. Changes in storage conditions and extension of beyond-use dating were the most common revisions in 77 (44%) and 42 (24%) of compounds, respectively. In addition, strawberry syrup was removed as a component of 38 (22%) formulations, reducing exposure of pediatric patients to red dye. Presentations were given at several forums to inform pharmacy staff of the goals of the project and details regarding implementation. In addition, e-mail communications were sent to share the online location of the updated formulations and compounding sheets. Nursing, medical, and pharmacy staff were notified of concentration changes through the pharmacy newsletter and e-mail. CONCLUSION: A comprehensive review resulted in updates to over 75% of oral liquid medications prepared by pharmacies in a university health system. Revised formulations were made available through an online repository, ensuring consistency of compounding procedures with respect to concentrations, components, and storage requirements. PMID- 30006437 TI - GATA4 is a negative regulator of contractility in testicular peritubular myoid cells. AB - Reduced contractility of the testicular peritubular myoid (PTM) cells may contribute to human male sub- or infertility. Transcription factor GATA4 in Sertoli and Leydig cells is essential for murine spermatogenesis; but limited attention has been paid to the potential role of GATA4 in PTM cells. In primary cultures of mouse PTM cells, siRNA knockdown of GATA4 increased the contractile activity, while GATA4 overexpression significantly attenuated the contractility of PTM cells using a collagen gel contraction assay. Using RNA sequencing and qRT PCR, we identified a set of genes that exhibited opposite expressional alternation between Gata4 siRNA vs nontargeting siRNA-treated PTM cells and Gata4 adenovirus vs control adenovirus-treated PTM cells. Notably, ion channels, smooth muscle function, cytokines and chemokines, cytoskeleton, adhesion and extracellular matrix were the top four enriched pathways, as revealed by cluster analysis. Natriuretic peptide type B (NPPB) content was significantly upregulated by GATA4 overexpression in both PTM cells and their culture supernatant. More importantly, the addition of 100 MUM NPPB could abolish the promoting effect of Gata4 silencing on PTM cell contraction. Taken together, we suggest that the inhibitory action of GATA4 on PTM cell contraction is mediated at least partly by regulating genes belonging to smooth muscle contraction pathway (e.g. Nppb). PMID- 30006438 TI - MATERNAL NUTRITION AND REPRODUCTIVE FUNCTIONS OF FEMALE AND MALE OFFSPRING. AB - This study aimed to investigate the effects of maternal unhealthy nutrition on the reproductive functions of female and male adult offspring. This was an animal study carried out with 24 virgin female Wistar rats(dams) and their male and female offspring. Rats were divided standard diet (SD) or cafeteria diet (CD) groups, after 10 weeks of feeding, all rats were paired with a Wistar stud male, and each group was again divided into CD and SD groups during the pregnancy and lactation periods. After birth, 6 female and 6 male pups in each group, were subjected to study. Following 3 weeks of lactation, the pups were fed with SD for 8 weeks and sacrificed when they were considered adult at 11th week for analysis. Primordial and antral follicle counts, serum anti-Mullerian hormone(AMH) and phosphatase and tensin homolog (PTEN) in the oocyte cytoplasm were examined to evaluate ovarian function, and E-cadherin and integrin-beta1 levels were examined in endometrial tissues for the evaluation of endometrial receptivity in female offspring. Sperm analysis was performed in male offspring. In groups in which the dams were fed CD, primordial follicular pool, PTEN, and endometrial receptivity were reduced. In contrast, anti-Mullerian hormone and the number of antral follicles were not changed. In male offspring, the testicles were smaller, testosterone production decreased, AMH increased, and the number and function of sperm were not changed. Sperm analysis results were not changed. All negative effects on reproductive functions were more apparent in groups fed with the CD during the pregestational period. PMID- 30006440 TI - Women with schizophrenia are at increased risk of breast cancer. PMID- 30006439 TI - IRF5 is increased in labouring myometrium and regulates pro-labour mediators. AB - Preterm birth continues to be the leading cause of neonatal mortality and morbidities that can extend into adult life. Few treatment options stem from our incomplete understanding of the mechanisms of human labour and delivery. Activation of the inflammatory response in gestational tissues by inflammation and/or infection leads to the production of pro-inflammatory and pro-labour mediators, thus preterm birth. Interferon regulatory factor 5 (IRF5) has recently emerged as an important pro-inflammatory transcription factor involved in acute and chronic inflammation. The aims of this study were to determine the expression of IRF5 in human myometrium from labouring and non-labouring women, and whether IRF5 is involved in the genesis of pro-inflammatory and pro-labour mediators induced by pro-inflammatory cytokines or toll-like receptor (TLR) ligands. IRF5 mRNA and protein expression was significantly higher in human myometrium after spontaneous term labour, compared to non-labouring tissues. IRF5 mRNA expression was also significantly higher in primary myometrial cells treated with the pro inflammatory cytokines IL1B or TNF. In primary myometrial cells, IRF5 knockdown by siRNA (siIRF5) was associated with significantly decreased expression and or secretion of pro-inflammatory cytokines (IL1A, IL6), chemokines (CXCL8, CCL2), adhesion molecules (ICAM1, VCAM1) and contraction-associated proteins PTGS2, PGF2alpha and PTGFR when in the presence of IL1B, TNF, fsl-1 (TLR2/6 ligand) or flagellin (TLR5 ligand). siIRF5-transfected cells also displayed decreased NF kappaB RELA transcriptional activity in the presence of these preterm birth mediators. Our study suggests a novel role for IRF5 in the regulation of the inflammatory response in human myometrium. PMID- 30006441 TI - Women with a history of postpartum affective disorder at increased risk of recurrence in future pregnancies. PMID- 30006442 TI - Ten simple rules for conducting umbrella reviews. AB - OBJECTIVE: Evidence syntheses such as systematic reviews and meta-analyses provide a rigorous and transparent knowledge base for translating clinical research into decisions, and thus they represent the basic unit of knowledge in medicine. Umbrella reviews are reviews of previously published systematic reviews or meta-analyses. Therefore, they represent one of the highest levels of evidence synthesis currently available, and are becoming increasingly influential in biomedical literature. However, practical guidance on how to conduct umbrella reviews is relatively limited. METHODS: We present a critical educational review of published umbrella reviews, focusing on the essential practical steps required to produce robust umbrella reviews in the medical field. RESULTS: The current manuscript discusses 10 key points to consider for conducting robust umbrella reviews. The points are: ensure that the umbrella review is really needed, prespecify the protocol, clearly define the variables of interest, estimate a common effect size, report the heterogeneity and potential biases, perform a stratification of the evidence, conduct sensitivity analyses, report transparent results, use appropriate software and acknowledge the limitations. We illustrate these points through recent examples from umbrella reviews and suggest specific practical recommendations. CONCLUSIONS: The current manuscript provides a practical guidance for conducting umbrella reviews in medical areas. Researchers, clinicians and policy makers might use the key points illustrated here to inform the planning, conduction and reporting of umbrella reviews in medicine. PMID- 30006443 TI - A male with multiple cardiac masses. AB - : SummaryThirty-seven-year-old male presented with cough, dyspnea, significant weight loss (20 kg) and subacute fever for the past 2 months. Physical examination revealed inspiratory and expiratory wheezing bilaterally. A normal S1, S2 and a 3/6 systolic ejection murmur at the left upper parasternal border with respiratory variation were found during cardiac auscultation. Kidney and bone marrow biopsy reported a high-grade B-cell lymphoma. Echocardiography and cardiac CT findings consisted of multiple intracardiac masses affecting the right ventricular (RV) outflow track, RV apex, medial portion of the right atrium and posterior left atrium, as well as mild impairment of the RV systolic function. The masses in the RV outflow track caused partial obstruction (pulmonary valve peak velocity 2.3 m/s) with a RV systolic pressure of 43 mmHg. The infiltrative mass in the interatrial septum extended into both the right and left atrial cavities. The right superior pulmonary vein was occluded. This patient was treated with aggressive chemotherapy and had a good clinical response that resulted in mass size reduction after the first course of chemotherapy. Multimodality imaging techniques such as echocardiography, cardiac CT and PET scan can provide complementary information to better evaluate, stage and manage these patients. LEARNING POINTS: Lymphoma can be found as a primary tumor in cardiac tissue, but secondary cardiac lymphoma is far more common.Appropriate investigation, histopathology, immunophenotype, staging and risk assessment are required for definite diagnosis and treatment.Cardiac lymphoma frequently manifests as an ill-defined, infiltrative mass. Typical location is in the atrium (right atrium is the most common site). Pericardial thickening or effusion is also common.Echocardiography is a quick, bedside, non-invasive assessment of anatomical involvement and hemodynamics affected by cardiac lymphoma. Echocardiographic findings of cardiac lymphoma include a hypoechoic, ill-defined infiltrative masses in the myocardium, nodular protrusion into cardiac chambers and pericardial effusion. Obstruction of inflow/outflow track can also be found.If a diagnosis of cardiac lymphoma is made, the most effective treatment is chemotherapy. Surgical treatment may have a role when hemodynamic compromise does not respond to chemotherapy and radiotherapy. PMID- 30006444 TI - "GAPPS" in Patient Safety. PMID- 30006445 TI - Adverse Events in Hospitalized Pediatric Patients. AB - : : media-1vid110.1542/5789657761001PEDS-VA_2017-3360Video Abstract BACKGROUND: Patient safety concerns over the past 2 decades have prompted widespread efforts to reduce adverse events (AEs). It is unclear whether these efforts have resulted in reductions in hospital-wide AE rates. We used a validated safety surveillance tool, the Global Assessment of Pediatric Patient Safety, to measure temporal trends (2007-2012) in AE rates among hospitalized children. METHODS: We conducted a retrospective surveillance study of randomly selected pediatric inpatient records from 16 teaching and nonteaching hospitals. We constructed Poisson regression models with hospital random intercepts, controlling for patient age, sex, insurance, and chronic conditions, to estimate changes in AE rates over time. RESULTS: Examining 3790 records, reviewers identified 414 AEs (19.1 AEs per 1000 patient days; 95% confidence interval [CI] 17.2-20.9) and 210 preventable AEs (9.5 AEs per 1000 patient days; 95% CI 8.2-10.8). On average, teaching hospitals had higher AE rates than nonteaching hospitals (26.2 [95% CI 23.7-29.0] vs 5.1 [95% CI 3.7-7.1] AEs per 1000 patient days, P < .001). Chronically ill children had higher AE rates than patients without chronic conditions (33.9 [95% CI 24.5-47.0] vs 14.0 [95% CI 11.8-16.5] AEs per 1000 patient days, P < .001). Multivariate analyses revealed no significant changes in AE rates over time. When stratified by hospital type, neither teaching nor nonteaching hospitals experienced significant temporal AE rate variations. CONCLUSIONS: AE rates in pediatric inpatients are high and did not improve from 2007 to 2012. Pediatric AE rates were substantially higher in teaching hospitals as well as in patients with more chronic conditions. PMID- 30006446 TI - Intracardiac or intrapulmonary shunts were present in at least 35% of adults with homozygous sickle cell disease followed in an outpatient clinic. PMID- 30006447 TI - Recurrent heteroplasmy for the MT-ATP6 p.Ser148Asn (m.8969G>A) mutation in patients with syndromic congenital sideroblastic anemia of variable clinical severity. PMID- 30006448 TI - Physician uncertainty aversion impacts medical decision making for older patients with acute myeloid leukemia: results of a national survey. AB - Elderly patients with acute myeloid leukemia can be treated with intensive chemotherapy, low-intensity therapy such as low-dose aracytine or hypomethylating agents, or best supportive care. The choice between these treatments is a function of many patient-related and physician-related factors. We investigated how physicians' behavioral characteristics, in particular their attitudes towards risk and uncertainty affect medical decision-making between intensive and non intensive therapy in this setting. A nationwide cross-sectional online survey of hematologists collected data on medical decision-making for six clinical vignettes involving older acute myeloid leukemia patients that were representative of routine practice. Questionnaires elicited physicians' demographic and occupational characteristics along with their individual behavioral characteristics according to decision theory framework. From the pattern of responses to the vignettes, a K-means clustering algorithm was used to distinguish those who were likely to prescribe more intensive therapy and those who were likely to prescribe less intensive or no therapy. Multivariate analyses were used to identify physician characteristics predictive of medical decision making. We obtained 290 answers to the questionnaire, including 230 assessable answers, which represented an adjusted response rate of 45.4%, calculated according to the American Association of Public Opinion Research. A multivariate model (n=210) revealed that uncertainty averse physicians recommend significantly more IC (OR [95% CI] = 1.15 [1.01;1.30], p=0.039), and that male physicians who do not conform to the expected utility model (assumed as economically irrational) tended to recommend more IC (OR [95% CI] = 3.45 [1.34; 8.85], p=0.01). Patient volume per physician also correlated with therapy intensity (OR [95% CI] = 0.98 [0.96; 0.99], p=0.032). The physicians' medical decision-making was not affected by their age, years of experience, or hospital facility. In this cross-sectional survey, attitudes towards uncertainty attitude influenced a physician's choice between intensive and non-intensive strategies for older patients with acute myeloid leukemia. This significant association identifies a novel non-biological factor that may affect patient outcomes and explain practice variations. It should also encourage the use of validated predictive models and the description of novel biomarkers to best select patients for intensive chemotherapy or low intensity therapy. PMID- 30006450 TI - EuroPrevall: insights into the allergic disease epidemic. PMID- 30006451 TI - We should eat freshly cooked meals. PMID- 30006453 TI - Releasing the Cytokinin Brakes on Root Growth. PMID- 30006449 TI - Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy. AB - Evading immune eradication is a prerequisite for neoplastic progression and one of the hallmarks of cancer. Here, we review the different immune escape strategies of lymphoma and classify them into two main mechanisms. First, lymphoma cells may "hide" to become invisible to the immune system. This can be achieved by losing or downregulating MHC and/or molecules involved in antigen presentation (including antigen processing machinery and adhesion molecules), thereby preventing their recognition by the immune system. Second, lymphoma cells may "defend" themselves to become resistant to immune eradication. This can be achieved in several ways: by becoming resistant to apoptosis, by expressing inhibitory ligands that deactivate immune cells and/or by inducing an immunosuppressive (humoral and cellular) microenvironment. These immune escape mechanisms may have therapeutic implications. Their identification may be used to guide "personalized immunotherapy" for lymphoma. PMID- 30006452 TI - A high-throughput method to identify trans-activation domains within transcription factor sequences. AB - Even though transcription factors (TFs) are central players of gene regulation and have been extensively studied, their regulatory trans-activation domains (tADs) often remain unknown and a systematic functional characterization of tADs is lacking. Here, we present a novel high-throughput approach tAD-seq to functionally test thousands of candidate tADs from different TFs in parallel. The tADs we identify by pooled screening validate in individual luciferase assays, whereas neutral regions do not. Interestingly, the tADs are found at arbitrary positions within the TF sequences and can contain amino acid (e.g., glutamine) repeat regions or overlap structured domains, including helix-loop-helix domains that are typically annotated as DNA-binding. We also identified tADs in the non native reading frames, confirming that random sequences can function as tADs, albeit weakly. The identification of tADs as short protein sequences sufficient for transcription activation will enable the systematic study of TF function, which-particularly for TFs of different transcription activating functionalities is still poorly understood. PMID- 30006455 TI - Subcellular Spice Trade Routes: Crocin Biosynthesis in the Saffron Crocus (Crocus sativus). PMID- 30006454 TI - Managing Competing Interests: Partitioning S between Glutathione and Protein Synthesis. PMID- 30006456 TI - Save Time and Fish for the Clock. PMID- 30006457 TI - Cellulose Synthase Stoichiometry Varies among Species and Tissues. PMID- 30006458 TI - Mechanisms of acute adductor longus injuries in male football players: a systematic visual video analysis. AB - BACKGROUND: Change of direction and kicking have been described as the main actions resulting in adductor longus injury. Video descriptions of inciting events are lacking. OBJECTIVE: Perform a standardised visual video analysis of a series of acute adductor longus injuries in football. STUDY DESIGN: Cross sectional. METHODS: Video footage was reviewed by players, and assessed independently by five sports medicine professionals. Inciting events were described and categorised using standardised scoring, including playing situation, player/opponent behaviour, movement and body positions. RESULTS: Videos of acute adductor longus injuries in 17 professional male football players were analysed. Most injuries occurred in non-contact situations (71%), following a quick reaction to a change in play (53%). Injury actions were: change of direction (35%), kicking (29%), reaching (24%) and jumping (12%). Change of direction and reaching injuries were categorised as closed chain movements (59%), characterised by hip extension and abduction with external rotation. Kicking and jumping injuries were categorised as open chain (41%), characterised by a change from hip extension to hip flexion, and hip abduction to adduction, with external rotation. CONCLUSION: Acute adductor longus injuries in football occur in a variety of situations. Player actions can be categorised into closed (change of direction and reaching) and open (kicking and jumping) chain movements involving triplanar hip motion. A rapid muscle activation during a rapid muscle lengthening appears to be the fundamental injury mechanism for acute adductor longus injuries. PMID- 30006459 TI - Sports medicine highlights from other journals. PMID- 30006460 TI - Sorting the trash: Micronucleophagy gets selective. AB - During micronucleophagy, the nucleolus is targeted by autophagic degradation, but although nucleolar proteins are recycled, ribosomal DNA is spared. Mostofa et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201706164) reveal that the separation of these two nucleolar components is mediated by the CLIP and cohibin complexes and is vital for cell survival during starvation. PMID- 30006461 TI - gamma-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection. AB - Despite their importance as human pathogens, entry of human papillomaviruses (HPVs) into cells is poorly understood. The transmembrane protease gamma secretase executes a crucial function during the early stages of HPV infection, but the role of gamma-secretase in infection and the identity of its critical substrate are unknown. Here we demonstrate that gamma-secretase harbors a previously uncharacterized chaperone function, promoting low pH-dependent insertion of the HPV L2 capsid protein into endosomal membranes. Upon membrane insertion, L2 recruits the cytosolic retromer, which enables the L2 viral genome complex to enter the retrograde transport pathway and traffic to the Golgi en route for infection. Although a small fraction of membrane-inserted L2 is also cleaved by gamma-secretase, this proteolytic event appears dispensable for HPV infection. Our findings demonstrate that gamma-secretase is endowed with an activity that can promote membrane insertion of L2, thereby targeting the virus to the productive infectious pathway. PMID- 30006463 TI - A new look for the growing microtubule end? AB - What does the end of a growing microtubule look like? In this issue, McIntosh et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201802138) use electron tomography to provide state-of-the-art three-dimensional images of microtubule ends in cells and in vitro, yielding an unexpected answer to this fundamental question. PMID- 30006462 TI - The force-sensitive protein Ajuba regulates cell adhesion during epithelial morphogenesis. AB - The reorganization of cells in response to mechanical forces converts simple epithelial sheets into complex tissues of various shapes and dimensions. Epithelial integrity is maintained throughout tissue remodeling, but the mechanisms that regulate dynamic changes in cell adhesion under tension are not well understood. In Drosophila melanogaster, planar polarized actomyosin forces direct spatially organized cell rearrangements that elongate the body axis. We show that the LIM-domain protein Ajuba is recruited to adherens junctions in a tension-dependent fashion during axis elongation. Ajuba localizes to sites of myosin accumulation at adherens junctions within seconds, and the force-sensitive localization of Ajuba requires its N-terminal domain and two of its three LIM domains. We demonstrate that Ajuba stabilizes adherens junctions in regions of high tension during axis elongation, and that Ajuba activity is required to maintain cell adhesion during cell rearrangement and epithelial closure. These results demonstrate that Ajuba plays an essential role in regulating cell adhesion in response to mechanical forces generated by epithelial morphogenesis. PMID- 30006464 TI - MR1 displays the microbial metabolome driving selective MR1-restricted T cell receptor usage. AB - MR1-restricted T cells (MR1Ts) are a T cell subset that recognize and mediate host defense to a broad array of microbial pathogens, including respiratory pathogens (e.g., Mycobacterium tuberculosis, Streptococcus pyogenes, and Francisella tularensis) and enteric pathogens (e.g., Escherichia coli and Salmonella species). Mucosal-associated invariant T (MAIT) cells, a subset of MR1Ts, were historically defined by the use of a semi-invariant T cell receptor (TCR) and recognition of small molecules derived from the riboflavin biosynthesis pathway presented on MR1. We used mass spectrometry to identify the repertoire of ligands presented by MR1 from the microbes E. coli and Mycobacterium smegmatis We found that the MR1 ligandome is unexpectedly broad, revealing functionally distinct ligands derived from E. coli and M. smegmatis The identification, synthesis, and functional analysis of mycobacterial ligands reveal that MR1T ligands can be distinguished by MR1Ts with diverse TCR usage. These data demonstrate that MR1 can serve as an immune sensor of the microbial ligandome. PMID- 30006466 TI - Simple scaling law predicts peak efficiency in oscillatory propulsion. PMID- 30006467 TI - Acceleration of hydrogen absorption by palladium through surface alloying with gold. AB - Enhancement of hydrogen (H) absorption kinetics improves the performance of hydrogen-purifying membranes and hydrogen-storage materials, which is necessary for utilizing hydrogen as a carbon-free energy carrier. Pd-Au alloys are known to show higher hydrogen solubility than pure Pd. However, the effect of Au on the hydrogen penetration from the surface into the subsurface region has not been clarified so far. Here, we investigate the hydrogen absorption at Pd-Au surface alloys on Pd(110) by means of thermal desorption spectroscopy (TDS) and hydrogen depth profiling with nuclear reaction analysis (NRA). We demonstrate that alloying the Pd(110) surface with submonolayer amounts of Au dramatically accelerates the hydrogen absorption. The degree of acceleration shows a volcano shaped form against Au coverage. This kinetic enhancement is explained by a reduced penetration barrier mainly caused by a destabilization of chemisorbed surface hydrogen, which is supported by density-functional-theory (DFT) calculations. The destabilization of chemisorbed surface hydrogen is attributed to the change of the surface electronic states as observed by angle-resolved photoemission spectroscopy (ARPES). If generalized, these discoveries may lead to improving and controlling the hydrogen transport across the surfaces of hydrogen absorbing materials. PMID- 30006465 TI - Time-resolved neural reinstatement and pattern separation during memory decisions in human hippocampus. AB - Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding may be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar). During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high-frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated with the strength (HFA power) of hippocampal encoding. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events. PMID- 30006469 TI - Mutation of G51 in SepF impairs FtsZ assembly promoting ability of SepF and retards the division of Mycobacterium smegmatis cells. AB - The role of FtsZ-associated proteins in the regulation of the assembly dynamics of Mycobacterium smegmatis FtsZ is not clear. In this work, we examined the effect of M. smegmatis SepF on the assembly and stability of M. smegmatis FtsZ polymers. We discovered a single dominant point mutation in SepF (G51D or G51R) that renders the protein inactive. SepF promoted the polymerization of FtsZ, induced the bundling of FtsZ filaments, stabilized FtsZ filaments and reduced the GTPase activity of FtsZ. Surprisingly, both G51D-SepF and G51R-SepF neither stabilized FtsZ filaments nor showed a discernable effect on the GTPase activity of FtsZ. The binding affinity of SepF to FtsZ was found to be stronger than the binding affinity of G51R/D-SepF to FtsZ. Interestingly, the binding affinity of SepF to G51R-SepF was determined to be 45 times stronger than FtsZ. In addition, the interaction of SepF with G51R-SepF was found to be 2.6 times stronger than SepF-SepF interaction. Furthermore, G51R-SepF impaired the ability of SepF to promote the assembly of FtsZ. In addition, the overexpression of G51R-SepF in M. smegmatis mc2 155 cells retarded the proliferation of these cells and increased the average length of the cells. The results indicated that SepF positively regulates the assembly of M. smegmatis FtsZ and the G51 residue has an important role in the functioning of SepF. PMID- 30006468 TI - Mechanics of spontaneously formed nanoblisters trapped by transferred 2D crystals. AB - Layered systems of 2D crystals and heterostructures are widely explored for new physics and devices. In many cases, monolayer or few-layer 2D crystals are transferred to a target substrate including other 2D crystals, and nanometer scale blisters form spontaneously between the 2D crystal and its substrate. Such nanoblisters are often recognized as an indicator of good adhesion, but there is no consensus on the contents inside the blisters. While gas-filled blisters have been modeled and measured by bulge tests, applying such models to spontaneously formed nanoblisters yielded unrealistically low adhesion energy values between the 2D crystal and its substrate. Typically, gas-filled blisters are fully deflated within hours or days. In contrast, we found that the height of the spontaneously formed nanoblisters dropped only by 20-30% after 3 mo, indicating that probably liquid instead of gas is trapped in them. We therefore developed a simple scaling law and a rigorous theoretical model for liquid-filled nanoblisters, which predicts that the interfacial work of adhesion is related to the fourth power of the aspect ratio of the nanoblister and depends on the surface tension of the liquid. Our model was verified by molecular dynamics simulations, and the adhesion energy values obtained for the measured nanoblisters are in good agreement with those reported in the literature. This model can be applied to estimate the pressure inside the nanoblisters and the work of adhesion for a variety of 2D interfaces, which provides important implications for the fabrication and deformability of 2D heterostructures and devices. PMID- 30006471 TI - The secret sauce: secrets of high performing neonatal intensive care units. PMID- 30006470 TI - Fetal surgery for spina bifida aperta. AB - Spina bifida aperta (SBA) is one of the most common congenital malformations. It can cause severe lifelong physical and neurodevelopmental disabilities. Experimental and clinical studies have shown that the neurological deficits associated with SBA are not simply caused by incomplete neurulation at the level of the lesion. Additional damage is caused by prolonged exposure of the spinal cord and nerves to the intrauterine environment and a suction gradient due to cerebrospinal fluid leakage, leading to progressive downward displacement of the hindbrain. This natural history can be reversed by prenatal repair. A randomised controlled trial demonstrated that mid-gestational maternal-fetal surgery for SBA decreases the need for ventriculoperitoneal shunting and hindbrain herniation at 12 months and improves neurological motor function at 30 months of age. This came at the price of maternal and fetal risks, the most relevant ones being increased prematurity and a persistent uterine corporeal scar. Recently minimally invasive fetal approaches have been introduced clinically yet they lack extensive experimental or clinical trials. We aim to provide clinicians with the essential information necessary to counsel SBA parents as the basis for considering referral of selected patients to expert fetal surgery centres. We review the reported clinical outcomes and discuss recent developments of potentially less invasive fetal SBA approaches. PMID- 30006475 TI - Jack V. Tu, 1965-2018. PMID- 30006473 TI - Controlling the regioselectivity and stereospecificity of FAD-dependent polyamine oxidases with the use of amine-attached guide molecules as conformational modulators. AB - Enzymes generally display strict stereospecificity and regioselectivity for their substrates. Here by using FAD-dependent human acetylpolyamine oxidase (APAO), human spermine (Spm) oxidase (SMOX) and yeast polyamine oxidase (Fms1), we demonstrate that these fundamental properties of the enzymes may be regulated using simple guide molecules, being either covalently attached to polyamines or used as a supplement to the substrate mixtures. APAO, which naturally metabolizes achiral N1-acetylated polyamines, displays aldehyde-controllable stereospecificity with chiral 1-methylated polyamines, like (R)- and (S)-1 methylspermidine (1,8-diamino-5-azanonane) (1-MeSpd). Among the novel N1-acyl derivatives of MeSpd, isonicotinic acid (P4) or benzoic acid (Bz) with (R)-MeSpd had Km of 3.6 +/- 0.6/1.2 +/- 0.7 uM and kcat of 5.2 +/- 0.6/4.6 +/- 0.7 s-1 respectively, while N1 -AcSpd had Km 8.2 +/- 0.4 uM and kcat 2.7 +/- 0.0 s-1 On the contrary, corresponding (S)-MeSpd amides were practically inactive (kcat < 0.03 s-1) but they retained micromole level Km for APAO. SMOX did not metabolize any of the tested compounds (kcat < 0.05 s-1) that acted as non-competitive inhibitors having Ki >= 155 uM for SMOX. In addition, we tested (R,R)-1,12-bis methylspermine (2,13-diamino-5,10-diazatetradecane) (R,R)-(Me2Spm) and (S,S) Me2Spm as substrates for Fms1. Fms1 preferred (S,S)- to (R,R)-diastereoisomer, but with notably lower kcat in comparison with spermine. Interestingly, Fms1 was prone to aldehyde supplementation in its regioselectivity, i.e. the cleavage site of spermidine. Thus, aldehyde supplementation to generate aldimines or N-terminal substituents in polyamines, i.e. attachment of guide molecule, generates novel ligands with altered charge distribution changing the binding and catalytic properties with polyamine oxidases. This provides means for exploiting hidden capabilities of polyamine oxidases for controlling their regioselectivity and stereospecificity. PMID- 30006474 TI - Randomized Controlled Trial of E-Counseling for Hypertension: REACH. AB - BACKGROUND: The efficacy of internet-based interventions to improve hypertension management is not established. We evaluated the therapeutic benefit of e counseling by adapting best evidence guidelines for behavioral counseling. METHODS AND RESULTS: This multicenter double-blind randomized controlled trial included assessments at baseline, 4 months, and 12 months. Participants were 35 to 74 years of age and diagnosed with hypertension: systolic/diastolic blood pressure (BP) 130 to 180/85 to 110 mm Hg. BP was assessed by automated office measurement. E-Counseling used multimedia and interactive tools to increase motivation and skill for self-care (exercise, diet, medication adherence, and smoking cessation). Control used self-care education. Frequency of contact by our e-platform was equal for both trial arms. Primary end points were change at 4 and 12 months in systolic BP, diastolic BP, pulse pressure, total lipoprotein cholesterol, low-density lipoprotein cholesterol, total lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, non-high-density lipoprotein cholesterol, and Framingham 10-year cardiovascular risk index. Intention-to-treat analysis used generalized linear models adjusted for baseline measures, sex, and medications. Among 264 participants, mean age was 57.6 years (SE, 0.6), 58% were women, with 83% on antihypertensive medications. At 12 months, e-counseling versus control evoked greater reduction in systolic BP ( 10.1 mm Hg [95% confidence interval (CI), -12.5, -7.6] versus -6.0 mm Hg [95% CI, -8.5, -3.5]; P=0.02); pulse pressure (-5.2 mm Hg [95% CI, -6.9, -3.5] versus -2.7 mm Hg [95% CI, -4.5, -0.9]; P=0.04), and Framingham risk index (-1.9% [95% CI, 3.3, -0.5] versus -0.02% [95% CI, -1.2, 1.7]; P=0.02), respectively. Among males in e-counseling versus control, 12-month end points included lower diastolic BP (P=0.01), non-high-density lipoprotein cholesterol (P=0.04), total lipoprotein cholesterol (P=0.03), and a trend for total lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (P=0.07). CONCLUSIONS: To our knowledge, this is the first double-blind randomized trial of e-counseling for hypertension. Added benefit for medical therapy was achieved by combining available technology with a clinically organized protocol of motivational and cognitive-behavioral counseling. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT01541540. PMID- 30006476 TI - Dual Antidepressant Duloxetine Blocks Nicotinic Receptor Currents, Calcium Signals and Exocytosis in Chromaffin Cells Stimulated with Acetylcholine. AB - The inhibition of nicotinic acetylcholine receptors (nAChRs) has been proposed as a potential strategy to develop new antidepressant drugs. This is based on the observation that antidepressants that selectively block noradrenaline (NA) or serotonin (5-HT) reuptake also inhibit nAChRs. Dual antidepressants blocking both NA and 5-HT reuptake were proposed to shorten the delay in exerting their clinical effects; whether duloxetine, a prototype of dual antidepressants, also blocks nAChRs is unknown. Here we explored this question in bovine chromaffin cells (BCCs) that express native alpha3, alpha5, and alpha7 nAChRs and in cell lines expressing human alpha7, alpha3beta4, or alpha4beta2 nAChRs. We have found that duloxetine fully blocked the acetylcholine (ACh)-elicited nicotinic currents in BCCs with an IC50 of 0.86 uM. Such blockade seemed to be noncompetitive, voltage dependent, and partially use dependent. The ACh-elicited membrane depolarization, the elevation of cytosolic calcium ([Ca2+]c), and catecholamine release in BCCs were also blocked by duloxetine. This blockade developed slowly, and the recovery of secretion was also slow and gradual. Duloxetine did not affect Na+ or Ca2+ channel currents neither the high-K+-elicited [Ca2+]c transients and secretion. Of interest was that in cell lines expressing human alpha7, alpha3beta4, and alpha4beta2 nAChRs, duloxetine blocked nicotinic currents with IC50 values of 0.1, 0.56, and 0.85 uM, respectively. Thus, in blocking alpha7 receptors, which are abundantly expressed in the brain, duloxetine exhibited approximately 10-fold to 100- fold higher potency with respect to reported IC50 values for various antidepressant drugs. This may contribute to the antidepressant effect of duloxetine. PMID- 30006477 TI - Communicating, consulting, and caring differently. PMID- 30006478 TI - Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection. AB - In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13 fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-gamma, with marked increases in tumor necrosis factor (TNF)-alpha, TNF-beta and interleukin 1beta. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3 hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-gamma and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection. PMID- 30006479 TI - Correction: Combinatorial actions of Tgfbeta and Activin ligands promote oligodendrocyte development and CNS myelination (doi:10.1242/dev.106492). PMID- 30006480 TI - PPARgamma is a nexus controlling alternative activation of macrophages via glutamine metabolism. AB - The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARgamma ligand, in a PPARgamma-dependent manner. Moreover, PPARgamma is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARgamma dramatically affects the oxidation of glutamine. Both glutamine and PPARgamma have been implicated in alternative activation (AA) of macrophages, and PPARgamma was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARgamma contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARgamma functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARgamma expression is itself markedly increased by IL4. This suggests that PPARgamma functions at the center of a feed-forward loop that is central to AA of macrophages. PMID- 30006482 TI - A preventive injection of endothelial progenitor cells prolongs lifespan in stroke-prone spontaneously hypertensive rats. AB - There is a pressing need for new approaches to prevent stroke. Endothelial progenitor cells (EPCs) promote vascular repair and revascularization in the ischemic brain. The present study sought to evaluate whether preventive delivery of EPCs could prevent or protect against stroke. Stroke-prone spontaneously hypertensive rats (SHR-SP) received a single injection of EPCs, and their survival time was monitored. In addition, at 28 and/or 42 days after a single injection of EPCs, SHR-SP and mice were subjected to cerebral ischemia, and cerebral ischemic injury, local angiogenesis and in vivo EPC integration were determined. Other experiments examined the effects of EPC conditioned medium, and the distribution of donor EPCs taken from GFP transgenic mice. It was found that EPC-pretreated SHR-SP showed longer lifespans than untreated controls. A single preventive injection of EPCs could produce persistent protective effects against cerebral ischemic injury (lasting at least 42 days), and promote local angiogenesis in the ischemic brain, in two types of animals (SHR-SP and normotensive mice). EPCs of donor origin could be detected in the recipient peripheral blood, and integrated into the recipient ischemic brains. Furthermore, it was suggested that mouse EPCs might exert paracrine effects on cerebral ischemic injury in addition to their direct angiogenic effects. In conclusion, a single preventive injection of EPCs prolonged the lifespan of SHR-SP, and protected against cerebral ischemic injury for at least 7 weeks. It is implied that EPC injection might be a promising candidate for a preventive role in patients at high risk for stroke. PMID- 30006481 TI - Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease. AB - Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects lung function in these patients. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-alpha, and lipopolysaccharide (LPS) and is known to regulate cell proliferation. ASM cells from COPD patients are hyperproliferative to mitogens in vitro However, the role of ASK1 in ASM growth is not established. Here, we aim to determine the effects of ASK1 inhibition on ASM growth and pro-mitogenic signaling using ASM cells from COPD patients. We found greater expression of ASK1 in ASM bundles of COPD lung when compared with non-COPD. Pre-treatment of ASM cells with highly selective ASK1 inhibitor, TC ASK 10 resulted in a dose-dependent reduction in mitogen (FBS, PDGF, and EGF; 72 h) induced ASM growth as measured by CyQUANT assay. Further, molecular targetting of ASK1 using siRNA in ASM cells prevented mitogen-induced cell growth. In addition, to anti-mitogenic potential, ASK1 inhibitor also prevented TGFbeta1-induced migration of ASM cells in vitro Immunoblotting revealed that anti-mitogenic effects are mediated by C-Jun N-terminal kinase (JNK) and p38MAP kinase-signaling pathways as evident by reduced phosphorylation of downstream effectors JNK1/2 and p38MAP kinases, respectively, with no effect on extracellular signal-regulated kinase (ERK) 1/2 (ERK1/2). Collectively, these findings establish the anti mitogenic effect of ASK1 inhibition and identify a novel pathway that can be targetted to reduce or prevent excessive ASM mass in COPD. PMID- 30006484 TI - Outcomes of Implementation of a NICU-Based Late Preterm Infant Feeding Guideline. AB - BACKGROUND AND OBJECTIVES: Late preterm (LPT) infants are at risk for feeding difficulties. Our objectives were to reduce the use of intravenous (IV) fluids and increase breastfeeding at discharge among LPT infants admitted to our NICU. METHODS: We implemented a feeding guideline and evaluated its effect using a pre post design. We examined rates of our main outcomes, IV fluid use, and any or exclusive breastfeeding at discharge, as well as several secondary outcomes, including hypoglycemia (glucose <50 mg/dL) at >8 hours of life, by using chi2 and t tests. We excluded infants that were <2000 g, admitted to the NICU at >8 hours of life, or needed IV fluids at <=8 hours of life for a medical reason. We used multivariable logistic regression to examine odds ratios and 95% confidence intervals of our main outcomes. RESULTS: Fifty percent of infants were eligible. Of those eligible, 18 of 52 (35%) vs 14 of 65 (22%) received IV fluids at >8 hours of life (P = .06). In the 24 hours before discharge, 35 of 52 (75%) vs 46 of 65 (78%) received any breast milk (P = .67), and 10 of 52 (30%) vs 10 of 65 (21%) received exclusive breast milk (P = .43). More infants had hypoglycemia in the posttime period (16 of 65 [25%]) compared with the pretime period (3 of 52 [6%]; P = .01). CONCLUSIONS: After implementation of a LPT feeding guideline in our NICU that defined specific expected feeding volumes, we did not find changes in IV fluid use or breastfeeding. PMID- 30006483 TI - LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis. AB - Although differentiation of lung fibroblasts into alpha-smooth muscle actin (alphaSMA)-positive myofibroblasts is important in the progression of idiopathic pulmonary fibrosis (IPF), few biomarkers reflecting the fibrotic process have been discovered. We performed microarray analyses between FACS-sorted steady state fibroblasts (lineage (CD45, TER-119, CD324, CD31, LYVE-1, and CD146) negative and PDGFRalpha-positive cells) from untreated mouse lungs and myofibroblasts (lineage-negative, Sca-1-negative, and CD49e-positive cells) from bleomycin-treated mouse lungs. Amongst several genes up-regulated in the FACS sorted myofibroblasts, we focussed on Ltbp2, the gene encoding latent transforming growth factor-beta (TGF-beta) binding protein-2 (LTBP2), because of the signal similarity to Acta2, which encodes alphaSMA, in the clustering analysis. The up-regulation was reproduced at the mRNA and protein levels in human lung myofibroblasts induced by TGF-beta1. LTBP2 staining in IPF lungs was broadly positive in the fibrotic interstitium, mainly as an extracellular matrix (ECM) protein; however, some of the alphaSMA-positive myofibroblasts were also stained. Serum LTBP2 concentrations, evaluated using ELISA, in IPF patients were significantly higher than those in healthy volunteers (mean: 21.4 compared with 12.4 ng/ml) and showed a negative correlation with % predicted forced vital capacity (r = -0.369). The Cox hazard model demonstrated that serum LTBP2 could predict the prognosis of IPF patients (hazard ratio for death by respiratory events: 1.040, 95% confidence interval: 1.026-1.054), which was validated using the bootstrap method with 1000-fold replication. LTBP2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF. PMID- 30006485 TI - D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells. AB - Purpose: Somatic mutations in the isocitrate dehydrogenase (IDH)-1 and -2 genes are remarkably penetrant in diffuse gliomas. These highly effective gain-of function mutations enable mutant IDH to efficiently metabolize isocitrate to D-2 hydroxyglutarate (D 2-HG) that accumulates to high concentrations within the tumor microenvironment. D 2-HG is an intracellular effector that promotes tumor growth through widespread epigenetic changes in IDH-mutant tumor cells, but its potential role as an intercellular immune regulator remains understudied.Experimental Design: Complement activation and CD4+, CD8+, or FOXP3+ T-cell infiltration into primary tumor tissue were determined by immunohistochemistry using sections from 72 gliomas of World Health Organization (WHO) grade III and IV with or without IDH mutations. Ex vivo experiments with D 2-HG identified immune inhibitory mechanisms.Results: IDH mutation associated with significantly reduced complement activation and decreased numbers of tumor infiltrating CD4+ and CD8+ T cells with comparable FOXP3+/CD4+ ratios. D 2-HG potently inhibited activation of complement by the classical and alternative pathways, attenuated complement-mediated glioma cell damage, decreased cellular C3b(iC3b) opsonization, and impaired complement-mediated phagocytosis. Although D 2-HG did not affect dendritic cell differentiation or function, it significantly inhibited activated T-cell migration, proliferation, and cytokine secretion.Conclusions: D 2-HG suppresses the host immune system, potentially promoting immune escape of IDH-mutant tumors. Clin Cancer Res; 24(21); 5381-91. (c)2018 AACR. PMID- 30006486 TI - The Impact of Oncogenic EGFRvIII on the Proteome of Extracellular Vesicles Released from Glioblastoma Cells. AB - Glioblastoma multiforme (GBM) is a highly aggressive and heterogeneous form of primary brain tumors, driven by a complex repertoire of oncogenic alterations, including the constitutively active epidermal growth factor receptor (EGFRvIII). EGFRvIII impacts both cell-intrinsic and non-cell autonomous aspects of GBM progression, including cell invasion, angiogenesis and modulation of the tumor microenvironment. This is, at least in part, attributable to the release and intercellular trafficking of extracellular vesicles (EVs), heterogeneous membrane structures containing multiple bioactive macromolecules. Here we analyzed the impact of EGFRvIII on the profile of glioma EVs using isogenic tumor cell lines, in which this oncogene exhibits a strong transforming activity. We observed that EGFRvIII expression alters the expression of EV-regulating genes (vesiculome) and EV properties, including their protein composition. Using mass spectrometry, quantitative proteomic analysis and Gene Ontology terms filters, we observed that EVs released by EGFRvIII-transformed cells were enriched for extracellular exosome and focal adhesion related proteins. Among them, we validated the association of pro-invasive proteins (CD44, BSG, CD151) with EVs of EGFRvIII expressing glioma cells, and downregulation of exosomal markers (CD81 and CD82) relative to EVs of EGFRvIII-negative cells. Nano-flow cytometry revealed that the EV output from individual glioma cell lines was highly heterogeneous, such that only a fraction of vesicles contained specific proteins (including EGFRvIII). Notably, cells expressing EGFRvIII released EVs double positive for CD44/BSG, and these proteins also colocalized in cellular filopodia. We also detected the expression of homophilic adhesion molecules and increased homologous EV uptake by EGFRvIII-positive glioma cells. These results suggest that oncogenic EGFRvIII reprograms the proteome and uptake of GBM-related EVs, a notion with considerable implications for their biological activity and properties relevant for the development of EV-based cancer biomarkers. PMID- 30006487 TI - Reactive Metabolite-induced Protein Glutathionylation: A Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity. AB - Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells. Proteo-metabonomic mapping provided evidence that APAP-induced glutathionylation resulted in functional deficits in energy metabolism, elevations in oxidative stress and cytosolic calcium, as well as mitochondrial dysfunction that correlate strongly with the well-established toxicity features of APAP. We also provide novel evidence that APAP-induced glutathionylation of carnitine O-palmitoyltransferase 1 (CPT1) and voltage-dependent anion-selective channel protein 1 are respectively involved in inhibition of fatty acid beta oxidation and opening of the mitochondrial permeability transition pore. Importantly, we show that the inhibitory effect of CPT1 glutathionylation can be mitigated by PPARalpha induction, which provides a mechanistic explanation for the prophylactic effect of fibrates, which are PPARalpha ligands, against APAP toxicity. Finally, we propose that APAP-induced protein glutathionylation likely occurs secondary to covalent binding, which is a previously unknown mechanism of glutathionylation, suggesting that this post-translational modification could be functionally implicated in drug-induced toxicity. PMID- 30006488 TI - Universal Plant Phosphoproteomics Workflow and Its Application to Tomato Signaling in Response to Cold Stress. AB - Phosphorylation-mediated signaling transduction plays a crucial role in the regulation of plant defense mechanisms against environmental stresses. To address the high complexity and dynamic range of plant proteomes and phosphoproteomes, we present a universal sample preparation procedure that facilitates plant phosphoproteomic profiling. This advanced workflow significantly improves phosphopeptide identifications, enabling deep insight into plant phosphoproteomes. We then applied the workflow to study the phosphorylation events involved in tomato cold tolerance mechanisms. Phosphoproteomic changes of two tomato species (N135 Green Gage and Atacames) with distinct cold tolerance phenotypes were profiled under cold stress. In total, we identified more than 30,000 unique phosphopeptides from tomato leaves, representing about 5500 phosphoproteins, thereby creating the largest tomato phosphoproteomic resource to date. The data, along with the validation through in vitro kinase reactions, allowed us to identify kinases involved in cold tolerant signaling and discover distinctive kinase-substrate events in two tomato species in response to a cold environment. The activation of SnRK2s and their direct substrates may assist N135 Green Gage tomatoes in surviving long-term cold stress. Taken together, the streamlined approach and the resulting deep phosphoproteomic analyses revealed a global view of tomato cold-induced signaling mechanisms. PMID- 30006489 TI - Cannabinoids, the Heart of the Matter. PMID- 30006490 TI - Coronary Plaque Characteristics in Patients With Diabetes Mellitus Who Presented With Acute Coronary Syndromes. AB - BACKGROUND: Diabetes mellitus (DM) is a major risk factor for cardiovascular events. We aimed to investigate the coronary plaque phenotype of diabetic patients who presented with acute coronary syndromes by optical coherence tomography. METHODS AND RESULTS: A total of 322 patients with acute coronary syndromes who underwent preintervention optical coherence tomography imaging of the culprit lesion were included. Culprit plaque characteristics were compared between patients with DM (n=95) and those without DM (n=227). In the subgroup of 250 patients in whom sufficient length of nonculprit region in the culprit vessel was imaged by optical coherence tomography, the characteristics of nonculprit plaques were also evaluated. Patients with DM had a higher prevalence of lipid rich plaque (58.9% versus 44.9%, P=0.030) and macrophage accumulation (60.0% versus 44.9%, P=0.019) in the culprit lesion compared with patients without DM. The prevalence of plaque rupture (33.7% versus 30.4%, P=0.896) and plaque erosion (21.1% versus 22.0%, P=0.458) was similar. In the nonculprit lesions, the DM group had greater maximal lipid arc (248.9 degrees +/-83.9 degrees versus 179.9 degrees +/-58.3 degrees , P=0.006), thinner fibrous cap thickness (103.3+/-56.2 MUm versus 140.7+/-70.0 MUm, P=0.013), and a higher prevalence of thin-cap fibroatheroma (17.2% versus 6.3%, P=0.031), compared with the non-DM group. CONCLUSIONS: Compared with patients without DM, those with DM had more vulnerable features in both culprit and nonculprit lesions, thus indicating a higher level of panvascular instability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538. PMID- 30006491 TI - Protein Biomarkers of Cardiovascular Disease and Mortality in the Community. AB - BACKGROUND: The discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk-stratification methods and may be informative regarding biological pathways contributing to disease. METHODS AND RESULTS: We used a discovery proteomic platform that targeted high-value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable-adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all-cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P-value ranges, 9.8*10-34 to 3.6*10-2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 1 (IGFBP1), insulin-like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N-terminal pro-b-type natriuretic peptide, C-reactive protein, and leptin were associated with incident heart failure, and C-type lectin domain family 3 member B (CLEC3B; tetranectin), N-terminal pro-b-type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin-C were associated with all cause mortality in a multimarker model. CONCLUSIONS: We identified numerous protein biomarkers that predicted cardiovascular outcomes and all-cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention. PMID- 30006492 TI - Prognostic Value of Hepatorenal Function By Modified Model for End-stage Liver Disease (MELD) Score in Patients Undergoing Tricuspid Annuloplasty. AB - BACKGROUND: The Model for End-stage Liver Disease excluding international normalized ratio (MELD-XI) score and the modified MELD score with albumin replacing international normalized ratio (MELD-Albumin) score, which reflect both liver and renal function, have been reported as predictors of adverse events in liver and heart disease. Nonetheless, their prognostic value in patients undergoing tricuspid annuloplasty has not been addressed. METHODS AND RESULTS: A total of 394 patients who underwent tricuspid annuloplasty were evaluated. Baseline clinical, laboratory, and echocardiographic parameters were recorded. Adverse outcome was defined as the occurrence of heart failure requiring admission or all-cause mortality. Patients who underwent tricuspid annuloplasty had a high prevalence of preoperative hepatorenal dysfunction that was more common in patients with severe tricuspid regurgitation than those with mild to moderate tricuspid regurgitation. The MELD-XI and MELD-Albumin scores were excellent predictors of 1-year adverse outcome (area under the curve: 0.69 and 0.75, respectively). Kaplan-Meier survival curve demonstrated that a high score on MELD-XI (>=12.0) and MELD-Albumin (>=10.7) was associated with an increased risk of adverse events. During a median follow-up of 40 months, both MELD-XI and MELD-Albumin scores were significantly associated with adverse outcome, even after adjusting for potential confounding factors. Significant improvement of hepatorenal function at 1 year postoperation was noted only in patients who had no adverse events, not in those who experienced an adverse outcome. CONCLUSIONS: Both MELD-XI score and MELD-Albumin score can provide useful information to predict adverse outcome in patients undergoing tricuspid annuloplasty. The present study supports monitoring of modified MELD score to improve preoperative risk stratification of these patients. PMID- 30006494 TI - Proton pump inhibitors and gastric cancer: association is not causation. PMID- 30006495 TI - Inequalities in asthma mortality: a specific case of a general issue of health inequalities. PMID- 30006493 TI - Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease. AB - BACKGROUND: Endothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD. METHODS AND RESULTS: We analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow-mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post-kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow-mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro. CONCLUSION: The alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD-associated vascular disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202. PMID- 30006496 TI - Persistent variations in national asthma mortality, hospital admissions and prevalence by socioeconomic status and region in England. AB - BACKGROUND: The UK-wide National Review of Asthma Deaths sought to identify avoidable factors from the high numbers of deaths, but did not examine variation by socioeconomic status (SES) or region. METHODS: We used asthma deaths in England over the period 2002-2015 obtained from national deaths registers, summarised by quintiles of Index of Multiple Deprivation (IMD) and Government Office Region. Emergency asthma admissions were obtained from Hospital Episode Statistics for England 2001-2011. The prevalence of asthma was derived from the Health Survey for England 2010. Associations of mortality, admissions and prevalence with IMD quintile and region were estimated cross-sectionally using incidence rate ratios (IRRs) adjusted for age and sex and, where possible, smoking. RESULTS: Asthma mortality decreased among more deprived groups at younger ages. Among 5-44 year olds, those in the most deprived quintile, mortality was 19% lower than those in the least deprived quintile (IRR 0.81 (95% CI 0.69 to 0.96). In older adults, this pattern was reversed (45-74 years: IRR 1.37 (1.24-1.52), >=75 years: IRR 1.30 (1.22-1.39)). In 5-44 year olds the inverse trend with asthma mortality contrasted with large positive associations for admissions (IRR 3.34 (3.30-3.38)) and prevalence of severe symptoms (IRR 2.38 (1.70-3.33)). Prevalence trends remained after adjustment for smoking. IRRs for asthma mortality, admissions and prevalence showed significant heterogeneity between English regions. CONCLUSIONS: Despite asthma mortality, emergency admissions and prevalence decreasing over recent decades, England still experiences significant SES and regional variations. The previously undocumented inverse relation between deprivation and mortality in the young requires further investigation. PMID- 30006498 TI - Correction: Identifying patients at risk for severe exacerbations of asthma: development and external validation of a multivariable prediction model. PMID- 30006501 TI - The Micro-Hospital: 5G Telemedicine-Based Care. AB - Today's medical service delivery platforms provide everything from small urgent care 'offices' to large medical centers. Since 2007, an intermediate entity for care has been established, namely, the micro-hospital. Micro-hospitals are 24 hour, small inpatient facilities with an average of 2 to 10 beds, designed to provide a diversity of healthcare services consistent with community demands. In addition, they seek to combine a cost-effective healthcare vehicle with potential time-dependent triage/transfer capabilities to a nearby large medical center. This smaller cost-effective entity represents an ideal vehicle for telemedicine, whereby specialists are always on hand for interpretation and consultation, with minimal patient waiting. In all likelihood, telemedicine, including cloud data storage and retrieval, will develop at a faster pace due to emerging 5G technology. Appropriate modification of the micro-hospital may also lead to creation of specialized centers devoted to endocrine and metabolic disorders, pulmonary diseases, and addiction medicine, which are certainly within the realm of medical necessity. PMID- 30006499 TI - SNRP-27, the C. elegans homolog of the tri-snRNP 27K protein, has a role in 5' splice site positioning in the spliceosome. AB - The tri-snRNP 27K protein is a component of the human U4/U6-U5 tri-snRNP and contains an N-terminal phosphorylated RS domain. In a forward genetic screen in C. elegans, we previously identified a dominant mutation, M141T, in the highly conserved C-terminal region of this protein. The mutant allele promotes changes in cryptic 5' splice site choice. To better understand the function of this poorly characterized splicing factor, we performed high-throughput mRNA sequencing analysis on worms containing this dominant mutation. Comparison of alternative splice site usage between the mutant and wild-type strains led to the identification of 26 native genes whose splicing changes in the presence of the snrp-27 mutation. The changes in splicing are specific to alternative 5' splice sites. Analysis of new alleles suggests that snrp-27 is an essential gene for worm viability. We performed a novel directed-mutation experiment in which we used the CRISPR-cas9 system to randomly generate mutations specifically at M141 of SNRP-27. We identified eight amino acid substitutions at this position that are viable, and three that are homozygous lethal. All viable substitutions at M141 led to varying degrees of changes in alternative 5' splicing of native targets. We hypothesize a role for this SR-related factor in maintaining the position of the 5' splice site as U1snRNA trades interactions at the 5' end of the intron with U6snRNA and PRP8 as the catalytic site is assembled. PMID- 30006500 TI - Adenine protonation enables cyclic-di-GMP binding to cyclic-GAMP sensing riboswitches. AB - In certain structural or functional contexts, RNA structures can contain protonated nucleotides. However, a direct role for stably protonated nucleotides in ligand binding and ligand recognition has not yet been demonstrated unambiguously. Previous X-ray structures of c-GAMP binding riboswitch aptamer domains in complex with their near-cognate ligand c-di-GMP suggest that an adenine of the riboswitch either forms two hydrogen bonds to a G nucleotide of the ligand in the unusual enol tautomeric form or that the adenine in its N1 protonated form binds the G nucleotide of the ligand in its canonical keto tautomeric state. By using NMR spectroscopy we demonstrate that the c-GAMP riboswitches bind c-di-GMP using a stably protonated adenine in the ligand binding pocket. Thereby, we provide novel insights into the putative biological functions of protonated nucleotides in RNA, which in this case influence the ligand selectivity in a riboswitch. PMID- 30006502 TI - Protective Effect of Dexmedetomidine on Endotoxin-Induced Acute Lung Injury in Rats. AB - BACKGROUND The purpose of this study was to investigate whether DEX exerts protective mechanisms in rats with acute lung injury (ALI) induced by the endotoxin lipopolysaccharide (LPS). The mortality rate of ALI is extremely high. DEX, an a2 adrenergic receptor agonist, has potent anti-inflammatory and organ protective effects in addition to its sedative and analgesic properties. We sought to elucidate whether DEX can attenuate acute lung injury. MATERIAL AND METHODS Forty-eight Wister rats were randomly divided into 4 groups (n=12, per group): the normal saline control (NS) group, receiving tail-vein injection of 0.9% normal saline (5 mL/kg); the LPS (L) group, receiving tail-vein injection of LPS (8 mg/kg); the LPS+DEX (L+D) group, receiving tail-vein injection of LPS (8 mg/kg), 0.5h before treated with DEX (50 ug/kg); and the DEX+LPS (D+L) group, receiving tail-vein injection of LPS (8 mg/kg) 0.5 h after being treated with DEX (50 ug/kg). Then, we measured the wet-to-dry weight ratio of lung tissue, the ALI pathology score, and HE staining of lung tissue, and assessed the Oxygen Tension index. RESULTS The present study revealed that LPS-induced rats exhibited significant lung injury, characterized by the deterioration of histopathology, ALI Pathology Score, wet-to-dry weight ratio, and Oxygen Tension index (MBP, PaO2, PaCO2, PH, HCO3-, and Lac), which were attenuated by DEX treatment. CONCLUSIONS Collectively, the present results demonstrate elucidate the molecular mechanisms by which DEX ameliorates LPS-induced ALI. PMID- 30006503 TI - Bilateral Pneumothoraces: A Rare Complication of Septic Pulmonary Emboli in Intravenous Drug Abusers. AB - BACKGROUND Right-sided infective endocarditis is a classic complication of intravenous drug abuse. Without timely bactericidal antibiotics, the disease process can progress to septic pulmonary emboli. Rarely, a pneumothorax can occur as a result of the emboli, and progressive persistent valvular disease may require a valve replacement. Tricuspid valve replacement has a high morbidity rate even in stable patients. CASE REPORT We present a case of tricuspid valve replacement in a 39-year-old man with peripheral intravenous drug abuse who had bilateral pneumothoraces secondary to septic pulmonary emboli originating on large tricuspid valve infected vegetations. The patient died 21 days after the valve replacement. CONCLUSIONS Tricuspid valve replacement is an especially dangerous procedure in intravenous drug abusers who present with bilateral pneumothoraces and advanced cardiopulmonary pathology. PMID- 30006505 TI - Publisher Correction: Environmental fluctuations accelerate molecular evolution of thermal tolerance in a marine diatom. AB - The PDF version of this Article was updated shortly after publication following an error which resulted in the Phi symbol being omitted from the left hand side of equation 8. The HTML version was correct from the time of publication. PMID- 30006504 TI - A broad-spectrum antibiotic, DCAP, reduces uropathogenic Escherichia coli infection and enhances vorinostat anticancer activity by modulating autophagy. AB - The cellular recycling pathway of autophagy plays a fundamental role in adaptive responses to nutrient deprivation and other forms of stress under physiological and pathological conditions. However, autophagy can also be a double-edge sword during certain bacterial infections (such as urinary tract infections) and in cancer, where it can be hijacked by the pathogens and cancer cells, respectively, to promote their own survival. Thus, autophagy modulation can potentially have multiple effects in multiple contexts and this property can be leveraged to improve outcomes. In this report, we identify that a broad-spectrum antibiotic, 2 ((3-(3, 6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl) amino)-2-(hydroxymethyl) propane-1, 3-diol (DCAP) modulates autophagy. We employed combined biochemical, fluorescence microscopy and correlative light electron microscopy approaches to demonstrate that DCAP treatment blocks autophagy at the late stages by preventing autophagolysosome maturation and interrupting the autophagic flux. We further show that, DCAP significantly reduces UPEC infection in urinary tract epithelial cells via inhibition of autophagy. Finally, we reveal that DCAP enhances the anticancer activity of the histone acetyltransferase (HDAC) inhibitor, vorinostat, which has been reported to increase susceptibility to bacterial infections as a common adverse effect. Collectively, our data support the concept that DCAP represents a valuable chemical scaffold for the development of an innovative class of bactericidal autophagy inhibitors for treatment of urinary tract infections and/or for adjuvant therapy in cancer treatment. PMID- 30006506 TI - SUMO2 conjugation of PCNA facilitates chromatin remodeling to resolve transcription-replication conflicts. AB - During DNA synthesis, DNA replication and transcription machinery can collide, and the replication fork may temporarily dislodge RNA polymerase II (RNAPII) to resolve the transcription-replication conflict (TRC), a major source of endogenous DNA double-strand breaks (DSBs) and common fragile site (CFS) instability. However, the mechanism of TRC resolution remains unclear. Here, we show that conjugation of SUMO2, but not SUMO1 or SUMO3, to the essential replication factor PCNA is induced on transcribed chromatin by the RNAPII-bound helicase RECQ5. Proteomic analysis reveals that SUMO2-PCNA enriches histone chaperones CAF1 and FACT in the replication complex via interactions with their SUMO-interacting motifs. SUMO2-PCNA enhances CAF1-dependent histone deposition, which correlates with increased histone H3.1 at CFSs and repressive histone marks in the chromatin to reduce chromatin accessibility. Hence, SUMO2-PCNA dislodges RNAPII at CFSs, and overexpressing either SUMO2-PCNA or CAF1 reduces the incidence of DSBs in TRC-prone RECQ5-deficient cells. PMID- 30006507 TI - The genetic structure of Squalidus multimaculatus revealing the historical pattern of serial colonization on the tip of East Asian continent. AB - Separated river systems could create confluences via two geological processes, estuary coalescence in response to decreasing sea levels and headwater capture, allowing primary freshwater species to disperse across rivers. Squalidus multimaculatus, is an endemic and primary freshwater species restricted to the southeast coast of the Korean Peninsula. The distribution of this species is unique, given that other congeneric species, including its closely related S. gracilis majimae, as well as other cyprind species are observed throughout the peninsula except for the east coast. Phylogeographic analyses were conducted using three mitochondrial loci to identify the origin of S. multimaculatus and the historical pathways of dispersal. A strong phylogenetic affinity between S. multimaculatus and S. g. majimae and the genetic structure among populations indicated that S. multimaculatus originated from the eastward colonization of the common ancestor between S. g. majimae and S. multimaculatus via headwater capture through fault zones within successive mountain range. Following colonization, the ancestral S. multimaculatus likely migrated towards north via estuary coalescence along a well-developed continental shelf. Our study was the first empirical attempt providing insights into how freshwater organisms dispersed to the southernmost tip of East Asia, despite the potential loss of such historical imprints with anthropogenic interference. PMID- 30006509 TI - Keystone Arctic paleoceanographic proxy association with putative methanotrophic bacteria. AB - Foraminifera in sediments exposed to gas-hydrate dissociation are not expected to have cellular adaptations that facilitate inhabitation of chemosynthesis-based ecosystems because, to date, there are no known endemic seep foraminifera. To establish if foraminifera inhabit sediments impacted by gas-hydrate dissociation, we examined the cellular ultrastructure of Melonis barleeanus (Williamson, 1858) from the Vestnesa gas hydrate province (Arctic Ocean, west of Svalbard at ~79 degrees N; ~1200-m depth; n = 4). From sediments with gas hydrate indicators, living M. barleeanus had unusual pore plugs composed of a thick, fibrous meshwork; mitochondria were concentrated at the cell periphery, under pore plugs. While there was no evidence of endosymbioses with prokaryotes, most M. barleeanus specimens were associated with what appear to be Type I methanotrophic bacteria. One foraminifer had a particularly large bolus of these microbes concentrated near its aperture. This is the first documented instance of bona fide living M. barleeanus in gas-hydrate sediments and first documentation of a foraminifer living in close association with putative methanotrophs. Our observations have implications to paleoclimate records utilizing this foundational foraminiferal species. PMID- 30006510 TI - Sustainable Syntheses of (-)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site. AB - The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-( )-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development. PMID- 30006511 TI - Long-term in vivo biodistribution and toxicity study of functionalized near infrared persistent luminescence nanoparticles. AB - Near-infrared (NIR) persistent luminescence nanoparticles (NPLNPs) have become one of the most promising candidates for bioimaging. Different from the other fluorescence nanoprobes, the NIR persistent luminescence of NPLNPs can last for a long time after excitation, double exposure that is nanoparticles and light exist during the long-term bioimaging. However, to date, the potential risk of nanoparticles and NIR persistent luminescence of NPLNPs is still unknown. In this study, Cr3 + -doped zinc gallate, Zn1.1Ga1.8Sn0.1O4:Cr3+ (ZGO), the most promising NPLNPs in bioimaging, was chosen as a representative for potential risk assessment. We evaluated the potential risk of nanoparticles and NIR persistent luminescence of ZGO for a long period of time. In vitro study showed that the ZGO possessed a low cytotoxicity. In vivo biodistribution results showed that the ZGO mainly accumulated in the reticuloendothelial system after intravenous injection and could be gradually cleared from the body by digestive system. In addition, the ZGO did not exhibit appreciable toxicity in mice over a period of 60 days. It's also worth mentioning that long-term NIR persistent luminescence of ZGO did not exhibit obvious toxicities both in vitro and in vivo. Our results provide important information with regards to the risk of NPLNPs in long-term bioimaging. PMID- 30006508 TI - Effects of BNN27, a novel C17-spiroepoxy steroid derivative, on experimental retinal detachment-induced photoreceptor cell death. AB - Retinal detachment (RD) leads to photoreceptor cell death secondary to the physical separation of the retina from the underlying retinal pigment epithelium. Intensifying photoreceptor survival in the detached retina could be remarkably favorable for many retinopathies in which RD can be seen. BNN27, a blood-brain barrier (BBB)-permeable, C17-spiroepoxy derivative of dehydroepiandrosterone (DHEA) has shown promising neuroprotective activity through interaction with nerve growth factor receptors, TrkA and p75NTR. Here, we administered BNN27 systemically in a murine model of RD. TUNEL+ photoreceptors were significantly decreased 24 hours post injury after a single administration of 200 mg/kg BNN27. Furthermore, BNN27 increased inflammatory cell infiltration, as well as, two markers of gliosis 24 hours post RD. However, single or multiple doses of BNN27 were not able to protect the overall survival of photoreceptors 7 days post injury. Additionally, BNN27 did not induce the activation/phosphorylation of TrkAY490 in the detached retina although the mRNA levels of the receptor were increased in the photoreceptors post injury. Together, these findings, do not demonstrate neuroprotective activity of BNN27 in experimentally-induced RD. Further studies are needed in order to elucidate the paradox/contradiction of these results and the mechanism of action of BNN27 in this model of photoreceptor cell damage. PMID- 30006512 TI - Carbohydrate Syntrophy enhances the establishment of Bifidobacterium breve UCC2003 in the neonatal gut. AB - The non-digestible oligosaccharide fraction of maternal milk represents an important of carbohydrate and energy source for saccharolytic bifidobacteria in the gastrointestinal tract during early life. However, not all neonatal bifidobacteria isolates can directly metabolise the complex sialylated, fucosylated, sulphated and/or N-acetylglucosamine-containing oligosaccharide structures present in mothers milk. For some bifidobacterial strains, efficient carbohydrate syntrophy or crossfeeding is key to their establishment in the gut. In this study, we have adopted advanced functional genomic approaches to create single and double in-frame deletions of the N-acetyl glucosamine 6-phosphate deacetylase encoding genes, nagA1 and nagA2, of B. breve UCC2003. In vitro phenotypic analysis followed by in vivo studies on co-colonisation, mother to infant transmission, and evaluation of the relative co-establishment of B. bifidum and B. breve UCC2003 or UCC2003DeltanagA1DeltanagA2 in dam-reared neonatal mice demonstrates the importance of crossfeeding on sialic acid, fucose and N-acetylglucosamine-containing oligosaccharides for the establishment of B. breve UCC2003 in the neonatal gut. Furthermore, transcriptomic analysis of in vivo gene expression shows upregulation of genes associated with the utilisation of lactose, sialic acid, GlcNAc-6-S and fucose in B. breve UCC2003, while for UCC2003DeltanagA1DeltanagA2 only genes for lactose metabolism were upregulated. PMID- 30006513 TI - Effect of gender on the acute effects of whey protein ingestion on energy intake, appetite, gastric emptying and gut hormone responses in healthy young adults. AB - BACKGROUND/OBJECTIVES: Protein supplements, usually drinks rich in whey protein, are used widely for weight loss purposes in overweight adults. Information comparing the effects of whey protein on appetite and energy intake in men and women is limited. The objective was to compare the acute effects of whey-protein intake on energy intake, appetite, gastric emptying and gut hormones in healthy young men and women. SUBJECTS/METHODS: Gastric emptying (3D-ultrasonography), blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations (0-180 min), appetite (visual analogue scales), and ad libitum energy intake from a buffet meal (180-210 min) were determined after ingestion of 30 g (120 kcal) or 70 g (280 kcal) whey protein, or a flavoured-water control drink (~2 kcal) in 8 healthy young men (25 +/- 2 y, 72 +/- 3 kg, 23 +/- 1 kg/m2) and 8 women (23 +/- 1 y, 64 +/- 2 kg, 24 +/- 0.4 kg/m2). RESULTS: There was a protein-load effect on gastric emptying, blood glucose, plasma insulin, glucagon, ghrelin, CCK, GIP and GLP-1 concentrations, and perceptions of hunger, desire to eat and prospective food consumption (P < 0.05). Ad libitum energy intake (average decrease of 206 +/- 39 kcal (15 +/- 2%) for men and of 46 +/- 54 kcal (0 +/- 26%) for women for the mean of the intakes after the 30 and 70 g whey-protein loads) and hunger were suppressed more by whey-protein ingestion in men than women (P = 0.046). There was no difference in suppression of energy intake between the 30 and 70 g protein loads (P = 0.75, interaction effect P = 0.19). Consequently, total energy intake (protein drink plus buffet meal) increased more compared to control in women than men (P = 0.010). The drinks emptied more slowly, and plasma glucagon, CCK and GLP-1 increased less after the protein drinks, in women than men (P < 0.05). CONCLUSION: The acute effects of whey protein ingestion on appetite, energy intake, gastric emptying and gut hormone responses are influenced by gender in healthy young adults. PMID- 30006515 TI - A rigid and healable polymer cross-linked by weak but abundant Zn(II)-carboxylate interactions. AB - Achieving a desirable combination of solid-like properties and fast self-healing is a great challenge due to slow diffusion dynamics. In this work, we describe a design concept that utilizes weak but abundant coordination bonds to achieve this objective. The designed PDMS polymer, crosslinked by abundant Zn(II)-carboxylate interactions, is very strong and rigid at room temperature. As the coordination equilibrium is sensitive to temperature, the mechanical strength of this polymer rapidly and reversibly changes upon heating or cooling. The soft-rigid switching ability sigma, defined as G'max /G'min, can reach 8000 when DeltaT = 100 degrees C. Based on these features, this polymer not only exhibits fast thermal-healing properties, but is also advantageous for various applications such as in orthopedic immobilization, conductive composites/adhesives, and 3D printing. PMID- 30006514 TI - Zika convalescent macaques display delayed induction of anamnestic cross neutralizing antibody responses after dengue infection. AB - Structural similarities between Zika (ZIKV) and dengue virus (DENV) leads to the induction of cross-reactive responses. We have previously demonstrated that ZIKV exposed macaques significantly enhance DENV viremia. Here we show that this enhancement of DENV infection occurred in the presence of high levels of DENV cross-reactive IgG1 subclass of binding antibodies (bAb) with low DENV neutralizing antibody (nAb) activity (<1:10). The DENV-2 nAb titres after ZIKV infection were, however, higher than those induced in DENV-2 only infected animals suggesting that ZIKV induced low titres of cross-nAb against DENV. Surprisingly, DENV-2 infection of animals previously infected with ZIKV was not accompanied by an anamnestic increase in cross-nAb titres till about 1 week after DENV-2 infection. This delay coincided with enhanced DENV-2 viremia indicating that high levels of cross-bAb in the absence of high nAb contributes to enhancement of DENV infection. Serum collected 8 weeks after DENV-2 infection had high levels of nAb and showed delayed antibody dependent enhancement (ADE) of infection (1:100 dilution) as compared with serum that was collected from ZIKV infected animals prior to DENV-2 infection (1:10 dilution). Examination of serum from macaques that were simultaneously infected with both ZIKV and DENV-2 showed high levels of nAb and delayed ADE responses raising the possibility that the low levels of cross-nAb induced by ZIKV infection could be overcome by co immunization against ZIKV and DENV infection. Taken together, our results provide additional insights into the nature and kinetics of cross-reactive antibody responses and identify a critical correlate that could potentially prevent enhancement of DENV infection during ZIKV convalescence. PMID- 30006517 TI - Non-invasive prediction of NAFLD severity: a comprehensive, independent validation of previously postulated serum microRNA biomarkers. AB - Liver biopsy is currently the only reliable method to establish nonalcoholic fatty liver disease (NAFLD) severity. However, this technique is invasive and occasionally associated with severe complications. Thus, non-invasive diagnostic markers for NAFLD are needed. Former studies have postulated 18 different serum microRNA biomarkers with altered levels in NAFLD patients. In the present study, we have re-examined the predictive value of these serum microRNAs and found that 9 of them (miR-34a, -192, -27b, -122, -22, -21, -197, -30c and -16) associated to NAFLD severity in our independent cohort. Moreover, miR-192, -27b, -22, -197 and 30c appeared specific for NAFLD, when compared with patients with drug-induced liver injury. Preliminary serum RNAseq analysis allowed identifying novel potential miRNA biomarkers for nonalcoholic steatohepatitis (NASH). The classification performance of validated miRNAs (and their ratios) for NASH was better than that reached by AST, whereas for advanced fibrosis prediction miRNAs did not perform better than the FIB-4 algorithm. Cross-validated models combining both clinical and miRNA variables showed enhanced predictivity. In conclusion, the circulating microRNAs validated demonstrate a better diagnostic potential than conventional serum markers to identify NASH patients and could complement and improve current fibrosis prediction algorithms. The research in this field is still open. PMID- 30006516 TI - Structure and energy based quantitative missense variant effect analysis provides insights into drug resistance mechanisms of anaplastic lymphoma kinase mutations. AB - Anaplastic lymphoma kinase (ALK) is considered as a validated molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the effectiveness of molecularly targeted therapies using ALK inhibitors is almost universally limited by drug resistance. Drug resistance to molecularly targeted therapies has now become a major obstacle to effective cancer treatment and personalized medicine. It is of particular importance to provide an improved understanding on the mechanisms of resistance of ALK inhibitors, thus rational new therapeutic strategies can be developed to combat resistance. We used state of-the-art computational approaches to systematically explore the mutational effects of ALK mutations on drug resistance properties. We found the activation of ALK was increased by substitution with destabilizing mutations, creating the capacity to confer drug resistance to inhibitors. In addition, results implied that evolutionary constraints might affect the drug resistance properties. Moreover, an extensive profile of drugs against ALK mutations was constructed to give better understanding of the mechanism of drug resistance based on structural transitions and energetic variation. Our work hopes to provide an up-to-date mechanistic framework for understanding the mechanisms of drug resistance induced by ALK mutations, thus tailor treatment decisions after the emergence of resistance in ALK-dependent diseases. PMID- 30006519 TI - Influence of a transverse static magnetic field on the orientation and peritectic reaction of Cu-10.5 at.% Sn peritectic alloy. AB - Peritectic alloy Cu-10.5 at.% Sn was directionally solidified at various growth speeds under a transverse static magnetic field. The experimental results indicated that the magnetic field caused the deformation of macroscopic interface morphology, the crystal orientation of primary phase along solidification direction, and the occurrence of peritectic reaction. The numerical simulations showed that the application of the magnetic field induced the formation of a unidirectional thermoelectric magnetic convection (TEMC), which modified solute transport in the liquid phase thereby enriching the solute concentration both at the sample and tri-junction scales. The modification of solidification structures under the magnetic field should be attributed to TEMC driven heat transfer and solute transport. PMID- 30006518 TI - Inhibition of the miR-192/215-Rab11-FIP2 axis suppresses human gastric cancer progression. AB - Less than a century ago, gastric cancer (GC) was the most common cancer throughout the world. Despite advances in surgical, chemotherapeutic, and radiotherapeutic treatment, GC remains the number 3 cancer killer worldwide. This fact highlights the need for better diagnostic biomarkers and more effective therapeutic targets. RAB11-FIP2, a member of the Rab11 family of interacting proteins, exhibits potential tumor suppressor function. However, involvement of RAB11-FIP2 in gastric carcinogenesis is yet to be elucidated. In this study, we demonstrated that RAB11-FIP2 was downregulated in GC tissues and constituted a target of the known onco-miRs, miR-192/215. We also showed that functionally, Rab11-FIP2 regulation by miR-192/215 is involved in GC-related biological activities. Finally, RAB11-FIP2 inhibition by miR-192/215 affected the establishment of cell polarity and tight junction formation in GC cells. In summary, this miR-192/215-Rab11-FIP2 axis appears to represent a new molecular mechanism underlying GC progression, while supplying a promising avenue of further research into diagnosis and therapy of GC. PMID- 30006520 TI - Absolute Configurations of 14,15-Hydroxylated Prenylxanthones from a Marine Derived Aspergillus sp. Fungus by Chiroptical Methods. AB - Determination of the absolute configrations for natural products is one of the most important and challenging tasks, especially when the molecules display high conformational flexibility. In this paper, eight new prenylxanthones, aspergixanthones A-H (1-8), and one known analogue (9), were isolated from the marine-derived fungus Aspergillus sp. ZA-01. The absolute configurations of C-14 and C-15 in 1-8 were difficult to be assigned due to the high conformational flexibility of the chains. To solve this problem, the experimental ECD, ORD, and VCD spectra of 1 were combined for analysis with the corresponding theoretical predictions for its different diastereomers. This study suggested that a concerted application of more than one chiroptical methods could be used as a preferable approach for the stereochemical characterizations of flexible molecules. Compounds 1-9 were evaluated for their cytotoxic and antibacterial activities. Among them, 6 showed cytotoxicity against the A-549 cell line with the IC50 value of 1.1 MUM, and 7 exhibited antibacterial activity against Micrococcus lysodeikticus with the MIC value of 0.78 MUg/mL. PMID- 30006521 TI - Author Correction: A novel atypical sperm centriole is functional during human fertilization. AB - In the original version of this Article, the affiliation details for Jadranka Loncarek and Vito Mennella were incorrectly given as 'Cell Biology Program, The Hospital for Sick Children, Department of Biochemistry, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada' and 'Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, 1050 Boyles Street, Frederick, MD, 21702, USA', respectively. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30006522 TI - Novel triadius-like N4 specie of iron nitride compounds under high pressure. AB - Various nitrogen species in nitrides are fascinating since they often appear with these nitride as superconductors, hard materials, and high-energy density. As a typical complex, though iron nitride has been intensively studied, nitrogen species in the iron-nitrogen (Fe-N) compounds only have been confined to single atom (N) or molecule nitrogen (N2). Using a structure search method based on the CALYPSO methodology, unexpectedly, we here revealed two new stable high pressure (HP) states at 1:2 and 1:4 compositions with striking nitrogen species. The results show that the proposed FeN2 stabilizes by a break up of molecule N2 into a novel planar N4 unit (P63/mcm, >228 GPa) while FeN4 stabilizes by a infinite 1D linear nitrogen chains Ninfinity (P-1, >50 GPa; Cmmm, >250 GPa). In the intriguing N4 specie of P63/mcm-FeN2, we find that it possesses three equal N = N covalent bonds and forms a perfect triadius-like configuration being never reported before. This uniqueness gives rise to a set of remarkable properties for the crystal phase: it is identified to have a good mechanical property and a potential for phonon-mediated superconductivity with a Tc of 4-8 K. This discovery puts the Fe-N system into a new class of desirable materials combining advanced mechanical properties and superconductivity. PMID- 30006523 TI - Quorum sensing in the immune system. PMID- 30006524 TI - UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma. AB - To explain the excess cancer rate in males, several candidates for "escape from X inactivation tumor-suppressor" (EXITS) were recently identified. In this report we provide direct experimental evidence supporting UTX's role as an EXITS gene. Using a mouse lymphoma model, we show clear dosage effect of UTX copy number during tumorigenesis, which strongly supports the EXITS theory. Importantly, UTX deletion not only accelerates lymphomagenesis, it also strongly promotes tumor progression. UTX-knockout tumors are more aggressive, showing enhanced brain dissemination and formation of blood vessels. Efnb1 is overexpressed in UTX KO tumors and can lead to such phenotypes. In human patients, lymphomas with low UTX expression also express high levels of Efnb1, and cause significantly poor survival. Lastly, we show that UTX deficiency renders lymphoma sensitive to cytarabine treatment. Taken together, these data highlight UTX loss's profound impacts on tumor initiation and drug response. PMID- 30006525 TI - Infralimbic cortex is required for learning alternatives to prelimbic promoted associations through reciprocal connectivity. AB - Prefrontal cortical areas mediate flexible adaptive control of behavior, but the specific contributions of individual areas and the circuit mechanisms through which they interact to modulate learning have remained poorly understood. Using viral tracing and pharmacogenetic techniques, we show that prelimbic (PreL) and infralimbic cortex (IL) exhibit reciprocal PreL<->IL layer 5/6 connectivity. In set-shifting tasks and in fear/extinction learning, activity in PreL is required during new learning to apply previously learned associations, whereas activity in IL is required to learn associations alternative to previous ones. IL->PreL connectivity is specifically required during IL-dependent learning, whereas reciprocal PreL<->IL connectivity is required during a time window of 12-14 h after association learning, to set up the role of IL in subsequent learning. Our results define specific and opposing roles of PreL and IL to together flexibly support new learning, and provide circuit evidence that IL-mediated learning of alternative associations depends on direct reciprocal PreL<->IL connectivity. PMID- 30006526 TI - Aberrant imprinting may underlie evolution of parthenogenesis. AB - Genomic imprinting confers parent-of-origin-specific gene expression, thus non equivalent and complementary function of parental genomes. As a consequence, genomic imprinting poses an epigenetic barrier to parthenogenesis in sexual organisms. We report aberrant imprinting in Boechera, a genus in which apomicts evolved from sexuals multiple times. Maternal activation of a MADS-box gene, a homolog of which is imprinted and paternally expressed in the sexual relative Arabidopsis, is accompanied by locus-specific DNA methylation changes in apomicts where parental imprinting seems to be relaxed. PMID- 30006527 TI - Distinct effects of social motivation on face evaluations in adolescents with and without autism. AB - Individual differences in social motivation have an influence on many behaviours in both clinical and non-clinical populations. As such, social motivation has been identified as a biological trait that is particularly well-suited for dimensional approaches cutting across neuropsychological conditions. In the present paper, we tested whether social motivation had a similar impact in the general population and in a neuropsychological condition characterized by diminished social motivation: Autism Spectrum Disorders (ASD). More precisely, we evaluated the effect of social motivation on face evaluations in 20 adolescents with ASD and 20 matched controls using avatars parametrically varying in dominance and trustworthiness. In line with previous research, we found in the control group that participants with higher levels of social motivation relied more on perceived trustworthiness when producing likeability judgments. However, this pattern was not found in the ASD group. Social motivation thus appears to have a different effect in ASD and control populations, which raises questions about the relevance of subclinical or non-clinical populations to understand ASD. PMID- 30006529 TI - Skilful forecasting of global fire activity using seasonal climate predictions. AB - Societal exposure to large fires has been increasing in recent years. Estimating the expected fire activity a few months in advance would allow reducing environmental and socio-economic impacts through short-term adaptation and response to climate variability and change. However, seasonal prediction of climate-driven fires is still in its infancy. Here, we discuss a strategy for seasonally forecasting burned area anomalies linking seasonal climate predictions with parsimonious empirical climate-fire models using the standardized precipitation index as the climate predictor for burned area. Assuming near perfect climate predictions, we obtained skilful predictions of fire activity over a substantial portion of the global burnable area (~60%). Using currently available operational seasonal climate predictions, the skill of fire seasonal forecasts remains high and significant in a large fraction of the burnable area (~40%). These findings reveal an untapped and useful burned area predictive ability using seasonal climate forecasts, which can play a crucial role in fire management strategies and minimise the impact of adverse climate conditions. PMID- 30006528 TI - Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection. AB - Plasmodium species produce an ortholog of the cytokine macrophage migration inhibitory factor, PMIF, which modulates the host inflammatory response to malaria. Using a novel RNA replicon-based vaccine, we show the impact of PMIF immunoneutralization on the host response and observed improved control of liver and blood-stage Plasmodium infection, and complete protection from re-infection. Vaccination against PMIF delayed blood-stage patency after sporozoite infection, reduced the expression of the Th1-associated inflammatory markers TNF-alpha, IL 12, and IFN-gamma during blood-stage infection, augmented Tfh cell and germinal center responses, increased anti-Plasmodium antibody titers, and enhanced the differentiation of antigen-experienced memory CD4 T cells and liver-resident CD8 T cells. Protection from re-infection was recapitulated by the adoptive transfer of CD8 or CD4 T cells from PMIF RNA immunized hosts. Parasite MIF inhibition may be a useful approach to promote immunity to Plasmodium and potentially other parasite genera that produce MIF orthologous proteins. PMID- 30006530 TI - Integrated deep visual and semantic attractor neural networks predict fMRI pattern-information along the ventral object processing pathway. AB - Recognising an object involves rapid visual processing and activation of semantic knowledge about the object, but how visual processing activates and interacts with semantic representations remains unclear. Cognitive neuroscience research has shown that while visual processing involves posterior regions along the ventral stream, object meaning involves more anterior regions, especially perirhinal cortex. Here we investigate visuo-semantic processing by combining a deep neural network model of vision with an attractor network model of semantics, such that visual information maps onto object meanings represented as activation patterns across features. In the combined model, concept activation is driven by visual input and co-occurrence of semantic features, consistent with neurocognitive accounts. We tested the model's ability to explain fMRI data where participants named objects. Visual layers explained activation patterns in early visual cortex, whereas pattern-information in perirhinal cortex was best explained by later stages of the attractor network, when detailed semantic representations are activated. Posterior ventral temporal cortex was best explained by intermediate stages corresponding to initial semantic processing, when visual information has the greatest influence on the emerging semantic representation. These results provide proof of principle of how a mechanistic model of combined visuo-semantic processing can account for pattern-information in the ventral stream. PMID- 30006532 TI - Magnetostatic twists in room-temperature skyrmions explored by nitrogen-vacancy center spin texture reconstruction. AB - Magnetic skyrmions are two-dimensional non-collinear spin textures characterized by an integer topological number. Room-temperature skyrmions were recently found in magnetic multilayer stacks, where their stability was largely attributed to the interfacial Dzyaloshinskii-Moriya interaction. The strength of this interaction and its role in stabilizing the skyrmions is not yet well understood, and imaging of the full spin structure is needed to address this question. Here, we use a nitrogen-vacancy centre in diamond to measure a map of magnetic fields produced by a skyrmion in a magnetic multilayer under ambient conditions. We compute the manifold of candidate spin structures and select the physically meaningful solution. We find a Neel-type skyrmion whose chirality is not left handed, contrary to preceding reports. We propose skyrmion tube-like structures whose chirality rotates through the film thickness. We show that NV magnetometry, combined with our analysis method, provides a unique tool to investigate this previously inaccessible phenomenon. PMID- 30006531 TI - Extracting the Energy Sensitivity of Charge Carrier Transport and Scattering. AB - It is a challenge to extract the energy sensitivity of charge carriers' transport and scattering from experimental data, although a theoretical estimation in which the existing scattering mechanism(s) are preliminarily assumed can be easily done. To tackle this problem, we have developed a method to experimentally determine the energy sensitivities, which can then serve as an important statistical measurement to further understand the collective behaviors of multi carrier transport systems. This method is validated using a graphene system at different temperatures. Further, we demonstrate the application of this method to other two-dimensional (2D) materials as a guide for future experimental work on the optimization of materials performance for electronic components, Peltier coolers, thermoelectricity generators, thermocouples, thermopiles, electrical converters and other conductivity and/or Seebeck-effect-related sensors. PMID- 30006535 TI - Visualizing hypoxia. PMID- 30006533 TI - Damage to the myogenic differentiation of C2C12 cells by heat stress is associated with up-regulation of several selenoproteins. AB - This study was conducted to profile the selenoprotein encoding genes or proteins in mouse C2C12 cells and integrate their roles in the skeletal cell damage induced by heat stress (HS). Cells were cultured at 37.0 degrees C or 41.5 degrees C for 4, 6 or 8 days. The mRNA expression of 24 selenoprotein encoding genes and abundance of 5 selenoproteins were investigated. HS suppressed myogenic differentiation and impaired the development of muscle myotubes. HS down regulated (P < 0.01) mRNA abundance of MYOD and MYOGENIN, and decreased (P < 0.01) MYOGENIN protein expression, HS elevated (P < 0.01) HSP70 and (P < 0.01) the ratio of BCL-2 to BAX at both mRNA and protein level. Meanwhile, HS up regulated (P < 0.01-0.05) expressions of 18, 11 and 8 selenoprotein encoding genes after 4, 6 and 8 days of hyperthermia, and only down-regulated (P < 0.01) DIO2 after 6 and 8 days of hyperthermia, respectively. Furthermore, HS influenced expression of selenoproteins and up-regulated (P < 0.01-0.05) GPX1, GPX4 and SEPN1 after 6 days of HS. The damage to development of mouse skeletal muscle myotubes by HS accompanied with the up-regulation of both selenoprotein encoding genes and proteins, which suggested a potential protective effect of selenoprotein on hyperthermia associated damage in C2C12 cells. PMID- 30006534 TI - Ganglion cell-inner plexiform layer thickness by swept-source optical coherence tomography in healthy Korean children: Normative data and biometric correlations. AB - The purpose of this study was to identify the normative values of ganglion cell inner plexiform layer (GCIPL) thickness in healthy Korean children using swept source optical coherence tomography (SS-OCT) and to investigate the correlations of age, refractive error, axial length (AL), retinal nerve fiber layer (RNFL) thickness and cup-to-disc (C/D) ratio with GCIPL thickness. Children aged between 3 and 17 who had visited our pediatric ophthalmology clinic were enrolled. Each subject underwent full ophthalmic examinations including RNFL thickness, C/D ratio and GCIPL thickness measurement by SS-OCT as well as AL measurement by partial-coherence interferometry. A total of 254 eyes of 127 children were included. The mean average GCIPL thickness was 71.5 +/- 5.35 MUm; the thickest sector was the superonasal and the thinnest the inferior. According to multivariate regression analysis, average GCIPL thickness was significantly associated with spherical equivalent and RNFL thickness (P < 0.0001 for both): the higher the myopia or the thinner the RNFL thickness, the thinner the GCIPL thickness. In conclusion, this study provides an SS-OCT-based pediatric normative database of GCIPL thickness that can serve as a reference for early detection and follow-up of glaucoma and optic nerve diseases in children. PMID- 30006536 TI - Revealing the complex genetic structure of cultivated amaryllis (Hippeastrum hybridum) using transcriptome-derived microsatellite markers. AB - Although amaryllis (Hippeastrum hybridum) plants are commonly used in physiological and ecological research, the extent of their genomic and genetic resources remains limited. The development of molecular markers is therefore of great importance to accelerate genetic improvements in Hippeastrum species. In this study, a total of 269 unique genes were defined that might regulate the flower spathe development of amaryllis. In addition, 2000 simple sequence repeats (SSRs) were detected based on 171,462 de novo assembled unigenes from transcriptome data, and 66,4091 single nucleotide polymorphisms (SNPs) were also detected as putative molecular markers. Twenty-one SSR markers were screened to evaluate the genetic diversity and population structure of 104 amaryllis accessions. A total of 98 SSR loci were amplified for all accessions. The results reveal that Nei's gene diversity (H) values of these markers ranged between 0.055 and 0.394, whereas the average values of Shannon's Information index (I) ranged between 0.172 and 0.567. Genetic tree analysis further demonstrates that all accessions can be grouped into three main clusters, which can be further divided into two subgroups. STRUCTURE-based analysis revealed that the highest DeltaK values were observed when K = 5, K = 6, K = 7 and K = 8. The results of this study enable large-scale transcriptomics and classification of Hippeastrum genetic polymorphisms and will be useful in the future for resource conservation and production. PMID- 30006538 TI - Functional and morphological differences of the lung upon acute and chronic ozone exposure in mice. AB - Environmental air pollutants including ozone cause severe lung injury and aggravate respiratory diseases such as asthma and COPD. Here we compared the effect of ozone on respiratory epithelium injury, inflammation, hyperreactivity and airway remodeling in mice upon acute (1ppm, 1 h) and chronic exposure (1.5ppm, 2 h, twice weekly for 6 weeks). Acute ozone exposure caused respiratory epithelial disruption with protein leak and neutrophil recruitment in the broncho alveolar space, leading to lung inflammation and airway hyperresponsiveness (AHR) to methacholine. All these parameters were increased upon chronic ozone exposure, including collagen deposition. The structure of the airways as assessed by automatic numerical image analysis showed significant differences: While acute ozone exposure increased bronchial and lumen circularity but decreased epithelial thickness and area, chronic ozone exposure revealed epithelial injury with reduced height, distended bronchioles, enlarged alveolar space and increased collagen deposition, indicative of peribronchiolar fibrosis and emphysema as characterized by a significant increase in the density and diameter of airspaces with decreased airspace numbers. In conclusion, morphometric numerical analysis enables an automatic and unbiased assessment of small airway remodeling. The structural changes of the small airways correlated with functional changes allowing to follow the progression from acute to chronic ozone induced respiratory pathology. PMID- 30006537 TI - Multidrug-resistant Citrobacter freundii ST139 co-producing NDM-1 and CMY-152 from China. AB - The emergence of carbapenemase-producing Citrobacter freundii poses a significant threat to public health worldwide. Here, we reported a C. freundii strain CWH001 which was resistant to all tested antimicrobials except tetracycline. Whole genome sequencing and analysis were performed. The strain, which belonged to a new sequence type ST139, showed close relationship with other foreign C. freundii strains through phylogenetic analysis. A novel variant of the intrinsic blaCMY gene located on the chromosome was identified and designated as blaCMY-152. Coexistence of blaNDM-1 with qnrS1 was found on a conjugative IncN plasmid, which had a backbone appearing in various plasmids. Other class A ESBL genes (blaVEB-3 and blaTEM-1) were also detected on two different novel plasmids. The emergence of multidrug-resistant C. freundii is of major concern, causing great challenges to the treatment of clinical infections. Great efforts need to be taken for the specific surveillance of this opportunistic pathogen. PMID- 30006539 TI - The crustal geophysical signature of a world-class magmatic mineral system. AB - World-class magmatic mineral systems are characterised by fluid/melt originating in the deep crust and mantle. However, processes that entrain and focus fluids from a deep-source region to a kilometre-scale deposit through the crust are unclear. A magnetotelluric (MT) and reflection seismic program across the margin of the Gawler Craton, Australia yield a distinct signature for a 1590 Ma event associated with emplacement of iron-oxide copper gold uranium (IOCG-U) deposits. Two- and three-dimensional MT modelling images a 50 km wide lower-crustal region of resistivity <10 Omegam along an accreted Proterozoic belt. The least resistive (~1 Omegam) part terminates at the brittle-ductile transition at ~15 km, directly beneath a rifted sedimentary basin. Above the brittle-ductile transition, three narrow low-resistivity zones (~100 Omegam) branch to the surface. The least resistive zone is remarkably aligned with the world-class IOCG-U Olympic Dam deposit and the other two with significant known IOCG-U mineral occurrences. These zones are spatially correlated with narrow regions of low seismic reflectivity in the upper crust, and the deeper lower-crust conductor is almost seismically transparent. We argue this whole-of-crust imaging encapsulates deep mineral system and maps pathways of metalliferous fluids from crust and mantle sources to emplacement at discrete locations. PMID- 30006540 TI - Wnt7a induces satellite cell expansion, myofiber hyperplasia and hypertrophy in rat craniofacial muscle. AB - Craniofacial muscles drive critical functions in the head, including speech, feeding and expression. Compared with their counterparts in trunk and limbs, craniofacial muscles are of distinct embryonic origins, which might consequently lead to different growth patterns and regenerative potential. In this study, rat levator veli palatini muscle and masseter muscle were compared with tibialis anterior muscle in their response to exogenous Wnt7a stimulus, which has been proved effective in promoting muscle regeneration in the limbs. Histological, cellular and molecular analyses were performed both under basal condition and after a single dose injection of recombinant human Wnt7a. Under basal condition, levator veli palatini muscle demonstrated considerably more satellite cells than the others. After Wnt7a administration, regeneration-related activities, including satellite cell expansion, myofiber hyperplasia and hypertrophy were generally observed in all three muscles, but with obvious differences in the extent. The composition of fast/slow myofibers underwent substantial alterations, and the pattern varied among the three muscles. Location-specific alterations in the expression level of core components in planar cell polarity pathway, Akt/mTOR pathway and myostatin pathway were also observed. In conclusion, both craniofacial and limb muscles could be effectively expanded by exogenous Wnt7a stimulus, but muscle-to-muscle variations in response patterns existed. PMID- 30006542 TI - Vesicular stomatitis virus G protein transmembrane region is crucial for the hemi fusion to full fusion transition. AB - Viral fusion proteins are essential for enveloped virus infection. These proteins mediate fusion between the virus envelope and host cellular membrane to release the viral genome into cells. Vesicular stomatitis virus G (VSV G) protein is a typical type III viral fusion protein. To study the mechanism of VSV G protein mediated membrane fusion, we set up a cell-cell fusion system in which cells are marked by different fluorescent proteins. Taking advantage of this system, we performed real-time recording and quantitative analysis of the cell fusion mediated by VSV G. We found that the time scale required for VSV G mediated cell cell fusion was approximately 1-2 minutes. Next, we specifically examined the function of the transmembrane (TM) region of VSV G protein in membrane fusion by replacing the TM region with those of other fusion proteins. The TM region replacements dramatically impaired VSV G protein function in the cell-cell fusion assay and diminished VSV G mediated lentivirus and recombinant VSV infection efficiency. Further experiments implied that the TM region played a role in the transition from hemi-fusion to full fusion. Several residues within the TM region were identified as important for membrane fusion. Overall, our findings unraveled the important function of the TM region in VSV G mediated viral fusion. PMID- 30006541 TI - Transcriptional downregulation of miR-133b by REST promotes prostate cancer metastasis to bone via activating TGF-beta signaling. AB - High avidity of bone metastasis is an important characteristic in prostate cancer (PCa). Downexpression of miR-133b has been reported to be implicated in the development, progression and recurrence in PCa. However, clinical significance and biological roles of miR-133b in bone metastasis of PCa remain unclear. Here we report that miR-133b is downregulated in PCa tissues and further decreased in bone metastatic PCa tissues. Downexpression of miR-133b positively correlates with advanced clinicopathological characteristics and shorter bone metastasis free survival in PCa patients. Upregulating miR-133b inhibits invasion, migration in vitro and bone metastasis in vivo in PCa cells. Mechanistically, we find that miR-133b suppresses activity of TGF-beta signaling via directly targeting TGF beta receptor I and II, which further inhibits bone metastasis of PCa cells. Our results further reveal that overexpression of REST contributes to miR-133b downexpression via transcriptional repression in PCa tissues. Importantly, silencing miR-133b enhances invasion and migration abilities in vitro and bone metastasis ability in vivo in REST-silenced PCa cells. The clinical correlation of miR-133b with TGFBRI, TGFBRII, REST and TGF-beta signaling activity is verified in PCa tissues. Therefore, our results uncover a novel mechanism of miR 133b downexpression that REST transcriptionally inhibits miR-133b expression in PCa cells, and meanwhile support the notion that administration of miR-133b may serve as a rational regimen in the treatment of PCa bone metastasis. PMID- 30006543 TI - Investigation of Wolbachia spp. and Spiroplasma spp. in Phlebotomus species by molecular methods. AB - The aim of this study was to determine the presence of Wolbachia spp. and Spiroplasma spp. in natural populations of sand flies in Turkey by molecular methods. A total of 40 Phlebotomus specimens (19 female and 21 male) were used in this study. Genomic DNA from whole sand flies was isolated and Wolbachia spp. infection prevalence was investigated by using Wolbachia gene specific primer sets (wsp and GroEL). In addition, the DNA were analyzed for the presence of Spiroplasma infections utilizing bacterium specific 16 S rDNA PCR-amplification primers. Results of this analysis showed a Wolbachia infection prevalence of 70% (28/40). There was no sex-bias in infection prevalence, being 76% (16/21) and 63% (12/19) in males and females, respectively. Analysis of Spiroplasma infections indicated that 26% (5/19) of female sand flies were positive for infection, while none of the screened males (0/21) were positive. Of the 40 sand fly samples, only 2 were found to be positive for both Wolbachia spp. and Spiroplasma spp. The present study demonstrates the presence of Wolbachia and Spiroplasma infections in the natural sand fly populations in Turkey. This is the first report on Spiroplasma infection in the sand flies from Turkey. PMID- 30006545 TI - September ECI biocommentary. PMID- 30006546 TI - Treatment of Cutting Fluid Waste using Activated Carbon Fiber Supported Nanometer Iron as a Heterogeneous Fenton Catalyst. AB - Addressing the problem of high chemical oxygen demands (COD) of cutting fluid waste generated in the machining process, its complex composition, and the specific conditions required for the treatment process, a heterogeneous Fenton fibre catalyst (NZVI@ACF) made of nanometer-iron supported on activated carbon fiber using dip-molding was developed. NZVI was homogeneously loaded onto ACF surfaces to form NZVI@ACF, with a specific surface area (SBET) of 726.3642 m2/g. Using a multistage chemical pretreatment, the NZVI@ACF/H2O2 system was used to effectively treat cutting fluid waste. The results indicated that the rate of COD removal in the cutting fluid waste liquid pretreated with NZVI@ACF/H2O2 system was 99.8% when the reactions conditions were optimized to 20 nmol/L H2O2, 6 g/L NZVI@ACF, total reaction time of 120 min and pH 5. The treated waste solution passed China's tertiary wastewater discharge standards. NZVI@ACF/H2O2 demonstrated an excellent catalytic performance compared to the traditional Fenton catalyst, increased the effective pH reaction range and had an adsorption effect on the waste liquid after the reaction. PMID- 30006544 TI - HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development. AB - Formation of the lymphatic system requires the coordinated expression of several key regulators: vascular endothelial growth factor C (VEGFC), its receptor FLT4, and a key transcriptional effector, PROX1. Yet, how expression of these signaling components is regulated remains poorly understood. Here, using a combination of genetic and molecular approaches, we identify the transcription factor hematopoietically expressed homeobox (HHEX) as an upstream regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation in vertebrates. By analyzing zebrafish mutants, we found that hhex is necessary for sprouting angiogenesis from the posterior cardinal vein, a process required for lymphangiogenesis. Furthermore, studies of mammalian HHEX using tissue-specific genetic deletions in mouse and knockdowns in cultured human endothelial cells reveal its highly conserved function during vascular and lymphatic development. Our findings that HHEX is essential for the regulation of the VEGFC/FLT4/PROX1 axis provide insights into the molecular regulation of lymphangiogenesis. PMID- 30006547 TI - Twinning-induced strain hardening in dual-phase FeCoCrNiAl0.5 at room and cryogenic temperature. AB - A face-centered-cubic (fcc) oriented FeCoCrNiAl0.5 dual-phase high entropy alloy (HEA) was plastically strained in uniaxial compression at 77K and 293K and the underlying deformation mechanisms were studied. The undeformed microstructure consists of a body-centered-cubic (bcc)/B2 interdendritic network and precipitates embedded in <001>-oriented fcc dendrites. In contrast to other dual phase HEAs, at both deformation temperatures a steep rise in the stress-strain curves occurs above 23% total axial strain. As a result, the hardening rate associated saturates at the unusual high value of ~6 GPa. Analysis of the strain partitioning between fcc and bcc/B2 by digital image correlation shows that the fcc component carries the larger part of the plastic strain. Further, electron backscatter diffraction and transmission electron microscopy evidence ample fcc deformation twinning both at 77K and 293K, while slip activity only is found in the bcc/B2. These results may guide future advancements in the design of novel alloys with superior toughening characteristics. PMID- 30006548 TI - KIF20A/MKLP2 regulates the division modes of neural progenitor cells during cortical development. AB - Balanced symmetric and asymmetric divisions of neural progenitor cells (NPCs) are crucial for brain development, but the underlying mechanisms are not fully understood. Here we report that mitotic kinesin KIF20A/MKLP2 interacts with RGS3 and plays a crucial role in controlling the division modes of NPCs during cortical neurogenesis. Knockdown of KIF20A in NPCs causes dislocation of RGS3 from the intercellular bridge (ICB), impairs the function of Ephrin-B-RGS cell fate signaling complex, and leads to a transition from proliferative to differentiative divisions. Germline and inducible knockout of KIF20A causes a loss of progenitor cells and neurons and results in thinner cortex and ventriculomegaly. Interestingly, loss of function of KIF20A induces early cell cycle exit and precocious neuronal differentiation without causing substantial cytokinesis defect or apoptosis. Our results identify a RGS-KIF20A axis in the regulation of cell division and suggest a potential link of the ICB to regulation of cell fate determination. PMID- 30006549 TI - Planktonic fungal community structures and their relationship to water quality in the Danjiangkou Reservoir, China. AB - Planktonic fungi are important components of aquatic ecosystems, and analyses of their community composition and function have far-reaching significance for the ecological management and maintenance of reservoir environments. However, few studies have investigated the composition, distribution, and function of planktonic fungi in reservoir ecosystems and their relationship with water quality. Here, the composition of the planktonic fungal community in the surface water layer of the Danjiangkou Reservoir is investigated using Illumina MiSeq sequencing. According to the results, the reservoir community is primarily composed of 7 phyla, including Ascomycota, Rozellomycota, Basidiomycota, Chytridiomycota, and Zygomycota, comprising 294 genera, demonstrating the rich diversity of this community. Redundancy analysis (RDA) of the planktonic fungal community and environmental factors showed dissolved oxygen (DO), chemical oxygen demand (COD), total nitrogen (TN), chlorophyll a (Chl a), and permanganate (CODMn) to be important factors influencing the distribution of planktonic fungi. Spearman correlation analysis of the planktonic fungal community composition and diversity indices with physical and chemical water quality parameters showed that the impacts of TN, COD and DO were the most significant. The results of this study on the planktonic fungal community in the Danjiangkou Reservoir area using high-throughput sequencing revealed that the community is sensitive to water quality parameters. This result provides a reference for studying the composition and distribution of the planktonic fungal community in Danjiangkou Reservoir and its role in the biogeochemical cycle. PMID- 30006550 TI - Influence of atomic site-specific strain on catalytic activity of supported nanoparticles. AB - Heterogeneous catalysis is an enabling technology that utilises transition metal nanoparticles (NPs) supported on oxides to promote chemical reactions. Structural mismatch at the NP-support interface generates lattice strain that could affect catalytic properties. However, detailed knowledge about strain in supported NPs remains elusive. We experimentally measure the strain at interfaces, surfaces and defects in Pt NPs supported on alumina and ceria with atomic resolution using high-precision scanning transmission electron microscopy. The largest strains are observed at the interfaces and are predominantly compressive. Atomic models of Pt NPs with experimentally measured strain distributions are used for first principles kinetic Monte Carlo simulations of the CO oxidation reaction. The presence of only a fraction of strained surface atoms is found to affect the turnover frequency. These results provide a quantitative understanding of the relationship between strain and catalytic function and demonstrate that strain engineering can potentially be used for catalyst design. PMID- 30006551 TI - Author Correction: Dynamics of a qubit while simultaneously monitoring its relaxation and dephasing. AB - The original version of this Article omitted the following from the Acknowledgements: Z. Leghtas' primary affiliation is Centre Automatique et Systemes, Mines ParisTech. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30006553 TI - On the role of ocular torsion in binocular visual matching. AB - When an observer scans the visual surround, the images cast on the two retinae are slightly different due to the different viewpoints of the two eyes. Objects in the horizontal plane of regard can be seen single by aligning the lines of sight without changing the torsional stance of the eyes. Due to the peculiar ocular kinematics this is not possible for objects above or below the horizontal plane of regard. We provide evidence that binocular fusion can be achieved independently of viewing direction by adjusting the mutual torsional orientation of the eyes in the frontal plane. We characterize the fusion positions of the eyes across the oculomotor range by deriving simple trigonometric equations for the required torsion as a function of gaze direction and compute the iso-torsion contours yielding binocular fusion. Finally, we provide experimental evidence that eye positions in far-to-near re-fixation saccades indeed converge towards the predicted positions by adjusting the torsion of the eyes. This is the first report that describes the three-dimensional orientation of the eyes at binocular fusion positions based on the three-dimensional ocular kinematics. It closes a gap between the sensory and the motor side of binocular vision and stereoscopy. PMID- 30006552 TI - Calcium-activated chloride channels clamp odor-evoked spike activity in olfactory receptor neurons. AB - The calcium-activated chloride channel anoctamin-2 (Ano2) is thought to amplify transduction currents in olfactory receptor neurons (ORNs), a hypothesis supported by previous studies in dissociated neurons from Ano2-/- mice. Paradoxically, despite a reduction in transduction currents in Ano2-/- ORNs, their spike output for odor stimuli may be higher. We examined the role of Ano2 in ORNs in their native environment in freely breathing mice by imaging activity in ORN axons as they arrive in the olfactory bulb glomeruli. Odor-evoked responses in ORN axons of Ano2-/- animals were consistently larger for a variety of odorants and concentrations. In an open arena, Ano2-/- animals took longer to approach a localized odor source than Ano2+/+ animals, revealing clear olfactory behavioral deficits. Our studies provide the first in vivo evidence toward an alternative or additional role for Ano2 in the olfactory transduction cascade, where it may serve as a feedback mechanism to clamp ORN spike output. PMID- 30006554 TI - Spiking neurons with short-term synaptic plasticity form superior generative networks. AB - Spiking networks that perform probabilistic inference have been proposed both as models of cortical computation and as candidates for solving problems in machine learning. However, the evidence for spike-based computation being in any way superior to non-spiking alternatives remains scarce. We propose that short-term synaptic plasticity can provide spiking networks with distinct computational advantages compared to their classical counterparts. When learning from high dimensional, diverse datasets, deep attractors in the energy landscape often cause mixing problems to the sampling process. Classical algorithms solve this problem by employing various tempering techniques, which are both computationally demanding and require global state updates. We demonstrate how similar results can be achieved in spiking networks endowed with local short-term synaptic plasticity. Additionally, we discuss how these networks can even outperform tempering-based approaches when the training data is imbalanced. We thereby uncover a powerful computational property of the biologically inspired, local, spike-triggered synaptic dynamics based simply on a limited pool of synaptic resources, which enables them to deal with complex sensory data. PMID- 30006555 TI - Relationships of Age and Sex with Cytokine Content and Distribution in Human Platelet Fibrin Gels. AB - We aimed to determine relationships between age and sex with cytokine content and distribution in human platelet-rich fibrin (PRF) gel. Rabbit PRF was harvested from whole blood (n = 6). Human PRF was collected from 36 healthy volunteers (1:1 men:women) without systemic diseases and not current undergoing medical treatment. Histological analysis and optical microscopy were used to assess the three-dimensional structure of the PRF network. Enzyme-linked immunosorbent assays, quantification of adenosine triphosphate, and bioluminescence imaging of PRF sections were used to assess cytokine and entrapped platelet distribution. Three-dimensional structures of fibrin networks revealed concentration gradients of the platelet-derived growth factor beta beta homodimer and the transforming growth factor-beta 1. Histological analysis of PRF sections (from the red blood cell end to the plasma end of a clot) showed a gradual increase in average porosity, most prominently in PRF clots from young and middle-aged men and women, and a decrease in compactness along the longitudinal axis of the PRF gel. The end of the PRF gel closest to the red blood cell layer is the essence of the PRF clot, and the ability to generate platelets depends on sex and age in humans. PMID- 30006557 TI - Probing disorder in pyrochlore oxides using in situ synchrotron diffraction from levitated solids-A thermodynamic perspective. AB - Pyrochlore, an ordered derivative of the defect fluorite structure, shows complex disordering behavior as a function of composition, temperature, pressure, and radiation damage. We propose a thermodynamic model to calculate the disordering enthalpies for several RE2Zr2O7 (RE = Sm, Eu, Gd) pyrochlores from experimental site distribution data obtained by in situ high temperature synchrotron X-ray diffraction. Site occupancies show a gradual increase in disorder on both cation and anion sublattices with increasing temperature and even greater disorder is achieved close to the phase transition to defect fluorite. The enthalpy associated with cation disorder depends on the radius of the rare earth ion, while the enthalpy of oxygen disordering is relatively constant for different compositions. The experimental data support trends predicted by ab initio calculations, but the obtained enthalpies of disordering are less endothermic than the predicted values. Thermal expansion coefficients are in the range (8.6 10.8) * 10-6 K-1. These new experimental determinations of defect formation energies are important for understanding the stability of pyrochlore oxides and their disordering mechanisms, which are essential in the context of their potential applications in nuclear waste management and other technologies. PMID- 30006556 TI - Characterization of multi-cellular dynamics of angiogenesis and vascular remodelling by intravital imaging of the wounded mouse cornea. AB - Establishment of the functional blood vasculature involves extensive cellular rearrangement controlled by growth factors, chemokines and flow-mediated shear forces. To record these highly dynamic processes in mammalians has been technically demanding. Here we apply confocal and wide field time-lapse in vivo microscopy to characterize the remodelling vasculature of the wounded mouse cornea. Using mouse lines with constitutive or inducible endogenous fluorescent reporters, in combination with tracer injections and mosaic genetic recombination, we follow processes of sprouting angiogenesis, sprout fusion, vessel expansion and pruning in vivo, at subcellular resolution. We describe the migratory behaviour of endothelial cells of perfused vessels, in relation to blood flow directionality and vessel identity. Live-imaging following intravascular injection of fluorescent tracers, allowed for recording of VEGFA induced permeability. Altogether, live-imaging of the remodelling vasculature of inflamed corneas of mice carrying endogenous fluorescent reporters and conditional alleles, constitutes a powerful platform for investigation of cellular behaviour and vessel function. PMID- 30006558 TI - Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes. AB - MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain. General anesthetics have potential long-lasting neurotoxic effects on the developing brain, resulting in behavioral changes in adulthood. We first carried out an unbiased profiling approach to examine the effect of single-episode neonatal general anesthetic, sevoflurance (sevo), exposure on miRNA expression of the brain. Neonatal sevo has a significant effect on the expression of specific miRNAs of the whole brain and the hippocampus that is both immediate - directly after neonatal treatment, as well as long-lasting - during adulthood. Functionally, neonatal sevo-associated miRNA gene-targets share potential neurodevelopmental pathways related to axon guidance, DNA transcription, protein phosphorylation and nervous system development. Our understanding on the role of miRNAs provides a putative epigenetic/molecular bridge that links neonatal general anesthetic's effect with its associated functional change. PMID- 30006559 TI - Autophagy as a promoter of longevity: insights from model organisms. AB - Autophagy is a conserved process that catabolizes intracellular components to maintain energy homeostasis and to protect cells against stress. Autophagy has crucial roles during development and disease, and evidence accumulated over the past decade indicates that autophagy also has a direct role in modulating ageing. In particular, elegant studies using yeasts, worms, flies and mice have demonstrated a broad requirement for autophagy-related genes in the lifespan extension observed in a number of conserved longevity paradigms. Moreover, several new and interesting concepts relevant to autophagy and its role in modulating longevity have emerged. First, select tissues may require or benefit from autophagy activation in longevity paradigms, as tissue-specific overexpression of single autophagy genes is sufficient to extend lifespan. Second, selective types of autophagy may be crucial for longevity by specifically targeting dysfunctional cellular components and preventing their accumulation. And third, autophagy can influence organismal health and ageing even non-cell autonomously, and thus, autophagy stimulation in select tissues can have beneficial, systemic effects on lifespan. Understanding these mechanisms will be important for the development of approaches to improve human healthspan that are based on the modulation of autophagy. PMID- 30006560 TI - Vertical-type two-dimensional hole gas diamond metal oxide semiconductor field effect transistors. AB - Power semiconductor devices require low on-resistivity and high breakdown voltages simultaneously. Vertical-type metal-oxide-semiconductor field-effect transistors (MOSFETs) meet these requirements, but have been incompleteness in diamond. Here we show vertical-type p-channel diamond MOSFETs with trench structures and drain current densities equivalent to those of n-channel wide bandgap devices for complementary inverters. We use two-dimensional hole gases induced by atomic layer deposited Al2O3 for the channel and drift layers, irrespective of their crystal orientations. The source and gate are on the planar surface, the drift layer is mainly on the sidewall and the drain is the p+ substrate. The maximum drain current density exceeds 200 mA mm-1 at a 12 um source-drain distance. On/off ratios of over eight orders of magnitude are demonstrated and the drain current reaches the lower measurement limit in the off state at room temperature using a nitrogen-doped n-type blocking layer formed using ion implantation and epitaxial growth. PMID- 30006561 TI - Assessing the tolerance to room temperature and viability of freeze-dried mice spermatozoa over long-term storage at room temperature under vacuum. AB - Freeze-drying has been frequently used to preserve food and microorganisms at room temperature (RT) for extended periods of time; however, its application to mammalian species is difficult. Here, we developed a method to prolong the stability of freeze-dried (FD) mice spermatozoa at RT for more than one year without using any cryoprotectant agents. Our data showed that maintaining a vacuum in ampoules is critical to ensuring the viability of FD spermatozoa, as the stability of spermatozoa DNA increased when imperfectly vacuumed ampoules were detected using a non-destructive test and eliminated. Finally a large number of healthy offspring were obtained from mice oocytes fertilized with FD spermatozoa stored at RT for more than one year. Although the birth rate from three-month stored spermatozoa was lower than that from one-day stored spermatozoa, no further reduction was observed even in one-year stored spermatozoa. Therefore, FD spermatozoa preserved in this study were highly tolerant to warm temperatures. This method of storage shows a great potential for the preservation of genetic resources of mammalian species, such as genetically modified mouse strains, without the use of electric power. PMID- 30006562 TI - Genetic markers associated to arbuscular mycorrhizal colonization in durum wheat. AB - In this work we investigated the variability and the genetic basis of susceptibility to arbuscular mycorrhizal (AM) colonization of wheat roots. The mycorrhizal status of wild, domesticated and cultivated tetraploid wheat accessions, inoculated with the AM species Funneliformis mosseae, was evaluated. In addition, to detect genetic markers in linkage with chromosome regions involved in AM root colonization, a genome wide association analysis was carried out on 108 durum wheat varieties and two AM fungal species (F. mosseae and Rhizoglomus irregulare). Our findings showed that a century of breeding on durum wheat and the introgression of Reduced height (Rht) genes associated with increased grain yields did not select against AM symbiosis in durum wheat. Seven putative Quantitative Trait Loci (QTLs) linked with durum wheat mycorrhizal susceptibility in both experiments, located on chromosomes 1A, 2B, 5A, 6A, 7A and 7B, were detected. The individual QTL effects (r2) ranged from 7 to 16%, suggesting a genetic basis for this trait. Marker functional analysis identified predicted proteins with potential roles in host-parasite interactions, degradation of cellular proteins, homeostasis regulation, plant growth and disease/defence. The results of this work emphasize the potential for further enhancement of root colonization exploiting the genetic variability present in wheat. PMID- 30006563 TI - Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning. AB - Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type 1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications. PMID- 30006564 TI - Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis. AB - Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence. PMID- 30006566 TI - Novel natural killer cell-mediated cancer immunotherapeutic activity of anisomycin against hepatocellular carcinoma cells. AB - Despite advances in the clinical management of hepatocellular carcinoma (HCC), this form of cancer remains the second leading cause of cancer-related death worldwide. Currently, there are few treatment options for advanced HCC. Therefore, novel treatment strategies for HCC are required. Here, we described the promising antitumour effects of anisomycin, which exerts both direct killing effects and natural killer cell (NK)-mediated immunotherapeutic effects in HCC. To better elucidate the mechanisms through which anisomycin mediates its antitumour effects, we performed a genome-scale transcriptional analysis. We found that anisomycin treatment of HCC differentially modulated a broad range of immune regulation-associated genes. Among these immune regulation-associated genes, we found that lymphocyte function-associated antigen-3 (LFA-3, also called CD58), whose expression was significantly increased in anisomycin-treated HCC cells, was a critical player in NK-mediated immunotherapeutic effects. Furthermore major histocompatibility complex molecules class I (MHC-I) on HCC cells were also significantly regulated by treatment of anisomycin. Those adhesion molecules like CD58, MHC-I, and ICAM4 should be important for immune synapse formation between NK cells and HCC cells to boost NK-mediated immunotherapeutic effects. Notably, this is the first report of NK-dependent immunomodulatory effects of anisomycin suggesting anisomycin as a novel therapeutic drug for treatment of HCC. PMID- 30006565 TI - Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. AB - Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies. PMID- 30006568 TI - VHL inactivation without hypoxia is sufficient to achieve genome hypermethylation. AB - VHL inactivation is a key oncogenic event for renal carcinomas. In normoxia, VHL suppresses HIF1a-mediated transcriptional response, which is characteristic to hypoxia. It has previously been shown that hypoxic conditions inhibit TET dependent hydroxymethylation of cytosines and cause DNA hypermethylation at gene promoters. In this work, we performed VHL inactivation by CRISPR/Cas9 and studied its effects on gene expression and DNA methylation. We showed that even without hypoxia, VHL inactivation leads to hypermethylation of the genome. Hypermethylated cytosines were evenly distributed throughout the genome with a slight preference for AP-1 (JUN and FOS) binding sites. Hypermethylated cytosines tended to be enriched within the binding sites of transcription factors that showed increased gene expression after VHL inactivation. We also observed promoter hypermethylation associated with decreased gene expression for several regulators of transcription and DNA methylation including SALL3. PMID- 30006569 TI - Female-biased dispersal and non-random gene flow of MC1R variants do not result in a migration load in barn owls. AB - Non-random gene flow is a widely neglected force in evolution and ecology. This genotype-dependent dispersal is difficult to assess, yet can impact the genetic variation of natural populations and their fitness. In this work, we demonstrate a high immigration rate of barn owls (Tyto alba) inside a Swiss population surveyed during 15 years. Using ten microsatellite loci as an indirect method to characterize dispersal, two-third of the genetic tests failed to detect a female biased dispersal, and Monte Carlo simulations confirmed a low statistical power to detect sex-biased dispersal in case of high dispersal rate of both sexes. The capture-recapture data revealed a female-biased dispersal associated with an excess of heterozygote for the melanocortin-1 receptor gene (MC1R), which is responsible for their ventral rufous coloration. Thus, female homozygotes for the MC1RWHITE allele might be negatively selected during dispersal. Despite the higher immigration of females that are heterozygote at MC1R, non-random gene flow should not lead to a migration load regarding this gene because we did not detect an effect of MC1R on survival and reproductive success in our local population. The present study highlights the usefulness of using multiple methods to correctly decrypt dispersal and gene flow. Moreover, despite theoretical expectations, we show that non-random dispersal of particular genotypes does not necessarily lead to migration load in recipient populations. PMID- 30006567 TI - Fate of mesoangioblasts in a vaginal birth injury model: influence of the route of administration. AB - Currently cell therapy is considered as an experimental strategy to assist the healing process following simulated vaginal birth injury in rats, boosting the functional and morphologic recovery of pelvic floor muscles and nerves. However, the optimal administration route and dose still need to be determined. Mesangioblasts theoretically have the advantage that they can differentiate in skeletal and smooth muscle. We investigated the fate of mesoangioblasts transduced with luciferase and green fluorescent protein reporter genes (rMABseGFP/fLUC) using bioluminescence, immunofluorescence and RT-PCR in rats undergoing simulated birth injury. rMABseGFP/fLUC were injected locally, intravenously and intra-arterially (common iliacs and aorta). Intra-arterial delivery resulted in the highest amount of rMABseGFP/fLUC in the pelvic organs region and in a more homogeneous distribution over all relevant pelvic organs. Sham controls showed that the presence of the injury is important for recruitment of intra-arterially injected rMABseGFP/fLUC. Injection through the aorta or bilaterally in the common iliac arteries resulted in comparable numbers of rMABseGFP/fLUC in the pelvic organs, yet aortic injection was faster and gave less complications. PMID- 30006570 TI - Highly efficient RNA-guided base editing in rabbit. AB - Cytidine base editors (CBEs) and adenine base editors (ABEs), composed of a cytidine deaminase or an evolved adenine deaminase fused to Cas9 nickase, enable the conversion of C.G to T.A or A.T to G.C base pair in organisms, respectively. Here, we show that BE3 and ABE7.10 systems can achieve a targeted mutation efficiency of 53-88% and 44-100%, respectively, in both blastocysts and Founder (F0) rabbits. Meanwhile, this strategy can be used to precisely mimic human pathologies by efficiently inducing nonsense or missense mutations as well as RNA mis-splicing in rabbit. In addition, the reduced frequencies of indels with higher product purity are also determined in rabbit blastocysts by BE4-Gam, which is an updated version of the BE3 system. Collectively, this work provides a simple and efficient method for targeted point mutations and generation of disease models in rabbit. PMID- 30006571 TI - Fibulin-3 knockdown inhibits cervical cancer cell growth and metastasis in vitro and in vivo. AB - To explore the function of fibulin-3 in cervical carcinoma malignant cell growth and metastasis, fibulin-3 expression in normal cervical tissue, cervical intraepithelial neoplasia (CIN), and cervical carcinoma were evaluated by immunohistochemistry. Quantitative real-time-polymerase chain reaction, western blotting, and immunocytochemistry were performed to assess the expression of fibulin-3 at mRNA and protein levels in different invasive clone sublines. Fibulin-3 shRNA and fibulin-3 cDNA were used to transfect the strongly and weakly invasive clone sublines. Using in vitro and in vivo functional assays, we investigated the effects of down-regulating and up-regulating fibulin-3 expression on the proliferation and invasion of different clone sublines. Epithelial mesenchymal transition (EMT) and its signaling pathways PI3K/AKT and ERK were studied carefully in lentiviral transfection systems. Fibulin-3 was upregulated in cervical carcinoma, and its overexpression was significantly related with malignant phenotype and poor prognosis of cervical carcinoma. Fibulin-3 promoted cervical cancer cell invasive capabilities by eliciting EMT and activating the PI3K-Akt-mTOR signal transduction pathway. Fibulin-3 could facilitate the process of cervical cancer development. The results presented here will help develop novel prognostic factors and possible therapeutic options for patients with cervical cancer. PMID- 30006572 TI - ATP synthase F1 subunits recruited to centromeres by CENP-A are required for male meiosis. AB - The histone H3 variant CENP-A epigenetically defines the centromere and is critical for chromosome segregation. Here we report an interaction between CENP-A and subunits of the mitochondrial ATP synthase complex in the germline of male Drosophila. Furthermore, we report that knockdown of CENP-A, as well as subunits ATPsyn-alpha, -betalike (a testis-specific paralogue of ATPsyn-beta) and -gamma disrupts sister centromere cohesion in meiotic prophase I. We find that this disruption is likely independent of reduced ATP levels. We identify that ATPsyn alpha and -betalike localise to meiotic centromeres and that this localisation is dependent on the presence of CENP-A. We show that ATPsyn-alpha directly interacts with the N-terminus of CENP-A in vitro and that truncation of its N terminus perturbs sister centromere cohesion in prophase I. We propose that the CENP-A N terminus recruits ATPsyn-alpha and -betalike to centromeres to promote sister centromere cohesion in a nuclear function that is independent of oxidative phosphorylation. PMID- 30006574 TI - Random Matrix Analysis for Gene Interaction Networks in Cancer Cells. AB - Investigations of topological uniqueness of gene interaction networks in cancer cells are essential for understanding the disease. Although cancer is considered to originate from the topological alteration of a huge molecular interaction network in cellular systems, the theoretical study to investigate such complex networks is still insufficient. It is necessary to predict the behavior of a huge complex interaction network from the behavior of a finite size network. Based on the random matrix theory, we study the distribution of the nearest neighbor level spacings P(s) of interaction matrices of gene networks in human cancer cells. The interaction matrices are computed using the Cancer Network Galaxy (TCNG) database which is a repository of gene interactions inferred by a Bayesian network model. 256 NCBI GEO entries regarding gene expressions in human cancer cells have been used for the inference. We observe the Wigner distribution of P(s) when the gene networks are dense networks that have more than ~38,000 edges. In the opposite case, when the networks have smaller numbers of edges, the distribution P(s) becomes the Poisson distribution. We investigate relevance of P(s) both to the sparseness of the networks and to edge frequency factor which is the reliance (likelihood) of the inferred gene interactions. PMID- 30006573 TI - Modulation of anti-tumor immunity by the brain's reward system. AB - Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression. PMID- 30006576 TI - Sub-nanoliter, real-time flow monitoring in microfluidic chips using a portable device and smartphone. AB - The ever-increasing need for portable, easy-to-use, cost-effective, and connected point-of-care diagnostics (POCD) has been one of the main drivers of recent research on lab-on-a-chip (LoC) devices. A majority of these devices use microfluidics to manipulate precisely samples and reagents for bioanalysis. However, filling microfluidic devices with liquid can be prone to failure. For this reason, we have implemented a simple, yet efficient method for monitoring liquid displacement in microfluidic chips using capacitive sensing and a compact (75 mm * 30 mm * 10 mm), low-cost ($60), and battery-powered (10-hour autonomy) device communicating with a smartphone. We demonstrated the concept using a capillary-driven microfluidic chip comprising two equivalent flow paths, each with a total volume of 420 nL. Capacitance measurements from a pair of electrodes patterned longitudinally along the flow paths yielded 17 pL resolution in monitoring liquid displacement at a sampling rate of 1 data/s (~1 nL/min resolution in the flow rate). We characterized the system using human serum, biological buffers, and water, and implemented an algorithm to provide real-time information on flow conditions occurring in a microfluidic chip and interactive guidance to the user. PMID- 30006575 TI - Cell surface nucleolin interacts with and internalizes Bothrops asper Lys49 phospholipase A2 and mediates its toxic activity. AB - Phospholipases A2 are a major component of snake venoms. Some of them cause severe muscle necrosis through an unknown mechanism. Phospholipid hydrolysis is a possible explanation of their toxic action, but catalytic and toxic properties of PLA2s are not directly connected. In addition, viperid venoms contain PLA2-like proteins, which are very toxic even if they lack catalytic activity due to a critical mutation in position 49. In this work, the PLA2-like Bothrops asper myotoxin-II, conjugated with the fluorophore TAMRA, was found to be internalized in mouse myotubes, and in RAW264.7 cells. Through experiments of protein fishing and mass spectrometry analysis, using biotinylated Mt-II as bait, we found fifteen proteins interacting with the toxin and among them nucleolin, a nucleolar protein present also on cell surface. By means of confocal microscopy, Mt-II and nucleolin were shown to colocalise, at 4 degrees C, on cell membrane where they form Congo-red sensitive assemblies, while at 37 degrees C, 20 minutes after the intoxication, they colocalise in intracellular spots going from plasmatic membrane to paranuclear and nuclear area. Finally, nucleolin antagonists were found to inhibit the Mt-II internalization and toxic activity and were used to identify the nucleolin regions involved in the interaction with the toxin. PMID- 30006577 TI - Entanglement Availability Differentiation Service for the Quantum Internet. AB - A fundamental concept of the quantum Internet is quantum entanglement. In a quantum Internet scenario where the legal users of the network have different priority levels or where a differentiation of entanglement availability between the users is a necessity, an entanglement availability service is essential. Here we define the entanglement availability differentiation (EAD) service for the quantum Internet. In the proposed EAD framework, the differentiation is either made in the amount of entanglement with respect to the relative entropy of entanglement associated with the legal users, or in the time domain with respect to the amount of time that is required to establish a maximally entangled system between the legal parties. The framework provides an efficient and easily implementable solution for the differentiation of entanglement availability in experimental quantum networking scenarios. PMID- 30006578 TI - Metabolically healthy and unhealthy obesity phenotypes and risk of renal stone: a cohort study. AB - BACKGROUND/OBJECTIVES: Although obesity is considered an independent risk factor of nephrolithiasis, little is known about the effect of obesity on nephrolithiasis according to metabolic health status. We investigated the association between body mass index (BMI) category and the incidence of nephrolithiasis in metabolically healthy and unhealthy individuals. SUBJECTS/METHODS: The cohort consisted of 270,190 Korean adults free of nephrolithiasis at baseline, who were followed-up annually or biennially for a median of 4.1 years. Nephrolithiasis were determined based on ultrasonographic findings. Being metabolically healthy was defined as not having any metabolic syndrome component. A parametric Cox model was used to estimate the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During 1,415,523.0 person-years of follow-up, 13,450 participants developed nephrolithiasis (incidence rate, 9.5 per 1000 person-years). Obesity was positively associated with an increased risk of incident nephrolithiasis in dose response manner, but the association was stronger in metabolically healthy individuals. Among metabolically healthy individuals, the multivariable-adjusted HRs (95% CIs) for incident nephrolithiasis comparing BMIs 23-24.9, 25-29.9, and >=30 with a BMI of 18.5-22.9 kg/m2 as the reference were 1.02 (0.95-1.10), 1.12 (1.03-1.22), and 1.72 (1.21-2.44), respectively, whereas corresponding HRs (95% CIs) in metabolically unhealthy individuals were 1.10 (1.04-1.17), 1.27 (1.20 1.34), and 1.36 (1.22-1.51), respectively. The association between obesity and incident nephrolithiasis was stronger in men and current smokers. CONCLUSIONS: Obesity was associated with a higher incidence of nephrolithiasis in both metabolically healthy and unhealthy individuals, indicating obesity per se as an independent risk factor for nephrolithiasis. PMID- 30006579 TI - Comparing BMI with skinfolds to estimate age at adiposity rebound and its associations with cardio-metabolic risk markers in adolescence. AB - BACKGROUND: Body mass index (BMI) reaches a nadir in mid-childhood, known as the adiposity rebound (AR). Earlier AR is associated with a higher risk of cardio vascular diseases in later life. Skinfolds, which are a more direct measure of adiposity, may give better insight into the relationship between childhood adiposity and later obesity and cardio-metabolic risk. OBJECTIVE: We aimed to assess whether AR corresponds to a rebound in skinfolds, and compare associations of BMI-derived AR and skinfold-derived AR with cardio-metabolic risk markers in adolescence. METHODS: We used penalised splines with random coefficients to estimate BMI and skinfold trajectories of 604 children from the Mysore Parthenon Birth Cohort. Age at AR was identified using differentiation of the BMI and skinfold growth curves between 2 and 10 years of age. At 13.5 years, we measured blood pressure, and glucose, insulin and lipid concentrations. RESULTS: BMI and skinfolds had different growth patterns. Boys reached BMI-derived AR earlier than skinfold-derived AR (estimated difference: 0.41 years; 95% CI:[0.23, 0.56]), whereas the opposite was observed in girls (estimated difference: -0.71 years; 95% CI:[-0.90, -0.54]). At 13.5 years, children with earlier BMI-derived AR had higher BMI (-0.58 SD per SD increase of AR; 95%CI:[-0.65, -0.52]), fat mass ( 0.44; 95%CI:[-0.50, -0.37]), insulin resistance (HOMA-IR: -0.20; 95%CI:[-0.28, 0.12]) and systolic blood pressure (-0.20; 95%CI:[-0.28, -0.11]), and lower HDL cholesterol (0.12; 95%CI:[0.04, 0.21]). The associations were independent of BMI at time of rebound, but were fully explained by fat mass at 13.5 years. Similar associations were found for skinfold-derived AR. CONCLUSION: BMI-derived adiposity rebound predicts later cardio-metabolic risk markers similarly to that derived from skinfolds, a direct measure of adiposity. PMID- 30006580 TI - Zinc alpha2 glycoprotein protects against obesity-induced hepatic steatosis. AB - BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS: ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD) induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS: ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARalpha, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-KB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS: Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation. PMID- 30006581 TI - Variable oxytocin levels in humans with different degrees of obesity and impact of gastric bypass surgery. AB - Exogenous oxytocin administration in obese mice, rats, and monkeys was shown to induce sustained weight loss, mostly due to a decrease in fat mass, accompanied by an improvement of glucose metabolism. A pilot study in obese humans confirmed the weight-reducing effect of oxytocin. Knowledge about circulating oxytocin levels in human obesity might help indicating which obese subjects could potentially benefit from an oxytocin treatment. Conclusive results on this topic are missing. The aim of this study was to measure circulating oxytocin levels in lean (n = 37) and obese (n = 72) individuals across a wide range of body mass index (BMI) values (18.5-60 kg/m2) and to determine the impact of pronounced body weight loss following gastric bypass surgery in 12 morbidly obese patients. We observed that oxytocin levels were unchanged in overweight and in class I and II obese subjects and only morbidly obese patients (obesity class III, BMI > 40 kg/m2) exhibited significantly higher levels than lean individuals, with no modification 1 year after gastric bypass surgery, despite substantial body weight loss. In conclusion, morbidly obese subjects present elevated oxytocin levels which were unaltered following pronounced weight loss. PMID- 30006583 TI - Maternal high-fat diet reversal improves placental hemodynamics in a nonhuman primate model of diet-induced obesity. AB - BACKGROUND: In a Japanese macaque model of diet-induced obesity, we have previously demonstrated that consumption of a high-fat, "Western-style" diet (WSD) is associated with placental dysfunction and adverse pregnancy outcomes, independent of an obese maternal phenotype. Specifically, we have reported decreased uterine placental blood flow and increased inflammation with maternal WSD consumption. We also previously investigated the use of a promising therapeutic intervention that mitigated the adverse placental effects of a WSD but had unexpected detrimental effects on fetal pancreatic development. Thus, the objective of the current study was to determine whether simple preconception diet reversal (REV) would improve placental function. METHODS: Female Japanese macaques were divided into three groups: REV animals (n = 5) were switched from a chronic WSD (36% fat) to a low fat, CON diet (14% fat) prior to conception and throughout pregnancy. The CON (n = 6) and WSD (n = 6) cohorts were maintained on their respective diets throughout pregnancy. Maternal body weight and composition were regularly assessed and advanced noninvasive imaging was performed at midgestation (gestational day 90, G90, or 0.5 of gestation, where full term is G175), and G129, 1 day prior to C-section delivery at G130 (0.75 of gestation). Imaging studies comprised Doppler ultrasound (US), contrast-enhanced US, and dynamic contrast-enhanced magnetic resonance imaging to assess uteroplacental hemodynamics and maternal-side placental perfusion. RESULTS: Dietary intervention resulted in significant maternal weight loss prior to pregnancy, and improved lean to fat mass ratio. By advanced imaging we demonstrated that a chronic WSD led to decreased blood flow velocity in the intervillous space, delayed blood flow transfer through the maternal spiral arteries, and reduced total placental blood flow compared to CON fed animals. Dietary reversal ameliorated these concerning derangements, restoring these hemodynamic parameters to CON levels. CONCLUSIONS: Preconception dietary modification has beneficial effects on the maternal metabolic phenotype, and results in improved placental hemodynamics. PMID- 30006584 TI - Maternal pre-pregnancy obesity and health care utilization and costs in the offspring. AB - BACKGROUND/OBJECTIVE: The association between maternal pre-pregnancy obesity and adverse child health outcomes is well described, but there are few data on the relationship with offspring health service use. We examined the influence of maternal pre-pregnancy obesity on offspring health care utilization and costs over the first 18 years of life. METHODS: This was a population-based retrospective cohort study of children (n = 35,090) born between 1989 and 1993 and their mothers, who were identified using the Nova Scotia Atlee Perinatal Database and linked to provincial administrative health data from birth through 2014. The primary outcome was health care utilization as determined by the number and cost of physician visits, hospital admissions and days, and high utilizer status (>95th percentile of physician visits). The secondary outcome was health care utilization by ICD chapter. Maternal pre-pregnancy weight was categorized as normal weight, overweight, or obese. Multivariable-adjusted regression models were used to examine the association between maternal weight status and offspring health care use. RESULTS: Children of mothers with pre-pregnancy obesity had more physician visits (10%), hospital admissions (16%), and hospital days (10%) than children from mothers of normal weight over the first 18 years of life. Offspring of mothers with obesity had C$356 higher physician costs and C$1415 hospital costs over 18 years than offspring of normal weight mothers. Children of mothers with obesity were 1.74 times more likely to be a high utilizer of health care and had higher rates of physician visits and hospital stays for nervous system and sense organ disorders, respiratory disorders, and gastrointestinal disorders compared to children of normal weight mothers. CONCLUSION: Our findings suggest that maternal pre-pregnancy overweight and obesity are associated with slightly higher offspring health care utilization and costs in the first 18 years of life. PMID- 30006582 TI - Physical activity intensity, bout-duration, and cardiometabolic risk markers in children and adolescents. AB - OBJECTIVES: To determine the role of physical activity intensity and bout duration in modulating associations between physical activity and cardiometabolic risk markers. METHODS: A cross-sectional study using the International Children's Accelerometry Database (ICAD) including 38,306 observations (in 29,734 individuals aged 4-18 years). Accelerometry data was summarized as time accumulated in 16 combinations of intensity thresholds (>=500 to >=3000 counts/min) and bout-durations (>=1 to >=10 min). Outcomes were body mass index (BMI, kg/m2), waist circumference, biochemical markers, blood pressure, and a composite score of these metabolic markers. A second composite score excluded the adiposity component. Linear mixed models were applied to elucidate the associations and expressed per 10 min difference in daily activity above the intensity/bout-duration combination. Estimates (and variance) from each of the 16 combinations of intensity and bout-duration examined in the linear mixed models were analyzed in meta-regression to investigate trends in the association. RESULTS: Each 10 min positive difference in physical activity was significantly and inversely associated with the risk factors irrespective of the combination of intensity and bout-duration. In meta-regression, each 1000 counts/min increase in intensity threshold was associated with a -0.027 (95% CI: -0.039 to -0.014) standard deviations lower composite risk score, and a -0.064 (95% CI: -0.09 to 0.038) kg/m2 lower BMI. Conversely, meta-regression suggested bout-duration was not significantly associated with effect-sizes (per 1 min increase in bout duration: -0.002 (95% CI: -0.005 to 0.0005) standard deviations for the composite risk score, and -0.005 (95% CI: -0.012 to 0.002) kg/m2 for BMI). CONCLUSIONS: Time spent at higher intensity physical activity was the main determinant of variation in cardiometabolic risk factors, not bout-duration. Greater magnitude of associations was consistently observed with higher intensities. These results suggest that, in children and adolescents, physical activity, preferably at higher intensities, of any bout-duration should be promoted. PMID- 30006586 TI - Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). AB - DISCLAIMER: This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes. METHODS: A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors. RESULTS: Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1. CONCLUSION: Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic. PMID- 30006585 TI - Inflammation-linked adaptations in dermal microvascular reactivity accompany the development of obesity and type 2 diabetes. AB - BACKGROUND/OBJECTIVES: The increased prevalence of obesity has prompted great strides in our understanding of specific adipose depots and their involvement in cardio-metabolic health. However, the impact of obesity on dermal white adipose tissue (dWAT) and dermal microvascular functionality remains unclear. This study aimed to investigate the temporal changes that occur in dWAT and dermal microvascular functionality during the development of diet-induced obesity and type 2 diabetes in mice. METHODS: Metabolic phenotyping of a murine model of hypercaloric diet (HCD)-induced obesity and type 2 diabetes was performed at three time points that reflected three distinct stages of disease development; 2 weeks of HCD-overweight-metabolically healthy, 4 weeks of HCD-obese-prediabetic and 12 weeks of HCD-obese-type 2 diabetic mice. Expansion of dWAT was characterized histologically, and changes in dermal microvascular reactivity were assessed in response to pressure and the vasodilators SNP and Ach. RESULTS: HCD resulted in a progressive expansion of dWAT and increased expression of pro inflammatory markers (IL1beta and COX-2). Impairments in pressure-induced (PIV) and Ach-induced (endothelium-dependent) vasodilation occurred early, in overweight-metabolically healthy mice. Residual vasodilatory responses were NOS independent but sensitive to COX inhibition. These changes were associated with reductions in NO and adiponectin bioavailability, and rescued by exogenous adiponectin or hyperinsulinemia. Obese-prediabetic mice continued to exhibit impaired Ach-dependent vasodilation but PIV appeared normalized. This normalization coincided with elevated endogenous adiponectin and insulin levels, and was sensitive to NOS, COX and PI3K, inhibition. In obese-type 2 diabetic mice, both Ach-stimulated and pressure-induced vasodilatory responses were increased through enhanced COX-2-dependent prostaglandin response. CONCLUSIONS: We demonstrate that the development of obesity, metabolic dysfunction and type 2 diabetes, in HCD-fed mice, is accompanied by increased dermal adiposity and associated metaflammation in dWAT. Importantly, these temporal changes are also linked to disease stage-specific dermal microvascular reactivity, which may reflect adaptive mechanisms driven by metaflammation. PMID- 30006588 TI - Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. AB - Modulation of the biochemical composition of the tumour microenvironment is a new frontier of cancer therapy. Several immunosuppressive mechanisms operate in the milieu of most tumours, a condition that makes antitumour immunity ineffective. One of the most potent immunosuppressive factors is adenosine, which is generated in the tumour microenvironment owing to degradation of extracellular ATP. Accruing evidence over the past few years shows that ATP is one of the major biochemical constituents of the tumour microenvironment, where it acts at P2 purinergic receptors expressed on both tumour and host cells. Stimulation of P2 receptors has different effects depending on the extracellular ATP concentration, the P2 receptor subtype engaged and the target cell type. Among P2 receptors, the P2X purinergic receptor 7 (P2X7R) subtype appears to be a main player in host tumour cell interactions. Preclinical studies in several tumour models have shown that P2X7R targeting is potentially a very effective anticancer treatment, and many pharmaceutical companies have now developed potent and selective small molecule inhibitors of P2X7R. In this Review, we report on the multiple mechanisms by which extracellular ATP shapes the tumour microenvironment and how its stimulation of host and tumour cell P2 receptors contributes to determining tumour fate. PMID- 30006587 TI - Dynamics of Plasma Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes - Type 1 Diabetes Prediction and Prevention Study (DIPP). AB - Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched controls (CTR). Sphingomyelins were found to be persistently downregulated in PT1D when compared to the P1Ab and CTR groups. Triacylglycerols and phosphatidylcholines were mainly downregulated in PT1D as compared to P1Ab at the age of 3 months. Our study suggests that distinct lipidomic signatures characterize children who progressed to islet autoimmunity or overt T1D, which may be helpful in the identification of at-risk children before the initiation of autoimmunity. PMID- 30006591 TI - Comparison of oxidation in uni-directionally and randomly oriented Cu films for low temperature Cu-to-Cu direct bonding. AB - Cu-to-Cu direct bonding has attracted attention because it has been implemented in CMOS image sensors. Prior to the bonding, the oxides on the Cu surface needs to be removed, yet the surface may oxidize right after cleaning. Thus, oxidation is an inherent issue in the application of Cu direct bonding. Our previous study reported that Cu direct bonding can be achieved below 250 degrees C by using (111)-oriented nanotwinned Cu because it has the fastest surface diffusivity. However, the oxidation behavior of the nanotwinned Cu is unclear. Here, we examined the oxidation behavior of highly (111) and (200) oriented, and randomly oriented Cu films at temperatures ranging from 120 to 250 degrees C. Transmission electron microscopy was used to measure the oxide thickness. The results show that the oxidation rate of (111)-oriented nanotwinned Cu has the lowest oxidation rate among them. Together, it is unique to possess the combination of the fastest surface diffusivity and the lowest oxidation rate. PMID- 30006590 TI - Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity. AB - It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression. PMID- 30006589 TI - Population genomics of hypervirulent Klebsiella pneumoniae clonal-group 23 reveals early emergence and rapid global dissemination. AB - Severe liver abscess infections caused by hypervirulent clonal-group CG23 Klebsiella pneumoniae have been increasingly reported since the mid-1980s. Strains typically possess several virulence factors including an integrative, conjugative element ICEKp encoding the siderophore yersiniabactin and genotoxin colibactin. Here we investigate CG23's evolutionary history, showing several deep branching sublineages associated with distinct ICEKp acquisitions. Over 80% of liver abscess isolates belong to sublineage CG23-I, which emerged in ~1928 following acquisition of ICEKp10 (encoding yersiniabactin and colibactin), and then disseminated globally within the human population. CG23-I's distinguishing feature is the colibactin synthesis locus, which reportedly promotes gut colonisation and metastatic infection in murine models. These data show circulation of CG23 K. pneumoniae decades before the liver abscess epidemic was first recognised, and provide a framework for future epidemiological and experimental studies of hypervirulent K. pneumoniae. To support such studies we present an open access, completely sequenced CG23-I human liver abscess isolate, SGH10. PMID- 30006594 TI - IEC mitophagy promotes anti-tumour immunity. PMID- 30006592 TI - Intrasession and Between-Visit Variability of Retinal Vessel Density Values Measured with OCT Angiography in Diabetic Patients. AB - In clinical practice the measurement error of an instrument has special importance in analyzing and interpreting data, and acknowledging limitations. The purpose of this study was to evaluate intrasession and between-visit reproducibility of OCT angiography measurements in diabetic patients. A total of 54 eyes of 27 diabetic patients underwent OCT angiography imaging. Foveal avascular zone (FAZ) area and superficial retinal vessel density (VD) at 3 mm were calculated using the AngioAnalytics software. Three consecutive images were acquired at first visit and one image 1 month later. Intrasession and between visit reproducibility of parameters were characterized by intraclass correlation coefficient (ICC), coefficient of variation (CV), and coefficient of repeatability (CR) values. We measured excellent (>0.90) ICC values both in intrasession and between-visit comparisons. CV was higher for the FAZ area compared to VD both in intrasession (7.79% vs. 2.87%) and in between-visit (12.33% vs. 2.95%) comparisons. Between-visit CR value for VD was 4.53% (95% CI: 3.72-5.79%). These data suggest that OCT angiography shows excellent repeatability in diabetic patients, indicating that this non-invasive technology might be suitable for longitudinal assessment of microvascular complications. PMID- 30006593 TI - Comparative genomics and genotype-phenotype associations in Bifidobacterium breve. AB - Bifidobacteria are common members of the gastro-intestinal microbiota of a broad range of animal hosts. Their successful adaptation to this particular niche is linked to their saccharolytic metabolism, which is supported by a wide range of glycosyl hydrolases. In the current study a large-scale gene-trait matching (GTM) effort was performed to explore glycan degradation capabilities in B. breve. By correlating the presence/absence of genes and associated genomic clusters with growth/no-growth patterns across a dataset of 20 Bifidobacterium breve strains and nearly 80 different potential growth substrates, we not only validated the approach for a number of previously characterized carbohydrate utilization clusters, but we were also able to discover novel genetic clusters linked to the metabolism of salicin and sucrose. Using GTM, genetic associations were also established for antibiotic resistance and exopolysaccharide production, thereby identifying (novel) bifidobacterial antibiotic resistance markers and showing that the GTM approach is applicable to a variety of phenotypes. Overall, the GTM findings clearly expand our knowledge on members of the B. breve species, in particular how their variable genetic features can be linked to specific phenotypes. PMID- 30006595 TI - Socio-demographic, Clinical, and Genetic Determinants of Quality of Life in Lung Cancer Patients. AB - Patient reported health-related quality of life (QOL) is a major component of the overall well-being of cancer patients, with links to prognosis. In 6,420 lung cancer patients, we identified patient characteristics and genetic determinants of QOL. Patient responses from the SF-12 questionnaire was used to calculate normalized Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Further, we analyzed 218 single nucleotide polymorphisms (SNPs) in the p38 MAPK signaling pathway, a key mediator of response to cellular and environmental stress, as genetic determinants of QOL in a subset of the study population (N = 641). Trends among demographic factors for mean PCS and MCS included smoking status (PCS Ptrend < 0.001, MCS Ptrend < 0.001) and education (PCS Ptrend < 0.001, MCS Ptrend < 0.001). Similar relationships were seen for MCS. The homozygous rare genotype of MEF2B: rs2040562 showed an increased risk of a poor MCS (OR: 3.06, 95% CI: 1.05-8.92, P = 0.041). Finally, survival analysis showed that a low PCS or a MCS was associated with increased risks of five-year mortality (HR = 1.63, 95% CI: 1.51-1.77, HR = 1.23, 95% CI: 1.16-1.32, respectively) and there was a significant reduction in median survival time (Plog rank < 0.001). These findings suggest that multiple factors contribute to QOL in lung cancer patients, and baseline QOL can impact survival. PMID- 30006596 TI - Controlled gene and drug release from a liposomal delivery platform triggered by X-ray radiation. AB - Liposomes have been well established as an effective drug delivery system, due to simplicity of their preparation and unique characteristics. However conventional liposomes are unsuitable for the on-demand content release, which limits their therapeutic utility. Here we report X-ray-triggerable liposomes incorporating gold nanoparticles and photosensitizer verteporfin. The 6 MeV X-ray radiation induces verteporfin to produce singlet oxygen, which destabilises the liposomal membrane and causes the release of cargos from the liposomal cavity. This triggering strategy is demonstrated by the efficiency of gene silencing in vitro and increased effectiveness of chemotherapy in vivo. Our work indicates the feasibility of a combinatorial treatment and possible synergistic effects in the course of standard radiotherapy combined with chemotherapy delivered via X-ray triggered liposomes. Importantly, our X-ray-mediated liposome release strategy offers prospects for deep tissue photodynamic therapy, by removing its depth limitation. PMID- 30006597 TI - Optimal fluorescent protein tags for quantifying protein oligomerization in living cells. AB - Fluorescence fluctuation spectroscopy has become a popular toolbox for non disruptive analysis of molecular interactions in living cells. The quantification of protein oligomerization in the native cellular environment is highly relevant for a detailed understanding of complex biological processes. An important parameter in this context is the molecular brightness, which serves as a direct measure of oligomerization and can be easily extracted from temporal or spatial fluorescence fluctuations. However, fluorescent proteins (FPs) typically used in such studies suffer from complex photophysical transitions and limited maturation, inducing non-fluorescent states. Here, we show how these processes strongly affect molecular brightness measurements. We perform a systematic characterization of non-fluorescent states for commonly used FPs and provide a simple guideline for accurate, unbiased oligomerization measurements in living cells. Further, we focus on novel red FPs and demonstrate that mCherry2, an mCherry variant, possesses superior properties with regards to precise quantification of oligomerization. PMID- 30006599 TI - Long-term Progression and Risk Factors of Fundus Tessellation in the Beijing Eye Study. AB - To assess the progression of fundus tessellation, color fundus photographs of the participants of the longitudinal population-based Beijing Eye Study were examined. The study included 4439 subjects in 2001 and 2695 (66.4% of the surviving) individuals in 2011. Larger progression in macular fundus tessellation (mean: 0.24 +/- 0.48 grades) was associated (multivariate analysis; correlation coefficient r: 0.53) with thinner subfoveal choroidal thickness in 2011 (P < 0.001; standardized regression coefficient beta: -0.37), older age (P < 0.001; beta: 0.22), higher level of education (P < 0.001; beta: 0.09), more myopic change in refractive error (P < 0.001; beta: -0.09) and lower cognitive function score (P = 0.02; beta: -0.05). Larger increase in peripapillary fundus tessellation (mean: 0.19 +/- 0.26 grades) correlated with thinner peripapillary choroidal thickness in 2011 (P < 0.001; beta: -0.35), older age (P < 0.001; beta: 0.20), worse best corrected visual acuity (P = 0.001; beta: 0.07), more myopic change in refractive error (P < 0.001; beta: -0.07) and higher prevalence of ever smoking (P = 0.004; beta: 0.05). The increase in macular fundus tessellation, as a surrogate for thinning of the posterior choroid, was associated with lower cognitive function, after adjusting for choroidal thickness, age, educational level and change in refractive error. The findings point to the clinical value of the assessment of fundus tessellation and suggest potential associations between cognitive function and fundus tessellation/choroidal thickness. PMID- 30006600 TI - Computational delineation and quantitative heterogeneity analysis of lung tumor on 18F-FDG PET for radiation dose-escalation. AB - Quantitative measurement and analysis of tumor metabolic activities could provide a more optimal solution to personalized accurate dose painting. We collected PET images of 58 lung cancer patients, in which the tumor exhibits heterogeneous FDG uptake. We design an automated delineation and quantitative heterogeneity measurement of the lung tumor for dose-escalation. For tumor delineation, our algorithm firstly separates the tumor from its adjacent high-uptake tissues using 3D projection masks; then the tumor boundary is delineated with our stopping criterion of joint gradient and intensity affinities. For dose-escalation, tumor sub-volumes with low, moderate and high metabolic activities are extracted and measured. Based on our quantitative heterogeneity measurement, a sub-volume oriented dose-escalation plan is implemented in intensity modulated radiation therapy (IMRT) planning system. With respect to manual tumor delineations by two radiation oncologists, the paired t-test demonstrated our model outperformed the other computational methods in comparison (p < 0.05) and reduced the variability between inter-observers. Compared to standard uniform dose prescription, the dosimetry results demonstrated that the dose-escalation plan statistically boosted the dose delivered to high metabolic tumor sub-volumes (p < 0.05). Meanwhile, the doses received by organs-at-risk (OAR) including the heart, ipsilateral lung and contralateral lung were not statistically different (p > 0.05). PMID- 30006598 TI - Single neurons may encode simultaneous stimuli by switching between activity patterns. AB - How the brain preserves information about multiple simultaneous items is poorly understood. We report that single neurons can represent multiple stimuli by interleaving signals across time. We record single units in an auditory region, the inferior colliculus, while monkeys localize 1 or 2 simultaneous sounds. During dual-sound trials, we find that some neurons fluctuate between firing rates observed for each single sound, either on a whole-trial or on a sub-trial timescale. These fluctuations are correlated in pairs of neurons, can be predicted by the state of local field potentials prior to sound onset, and, in one monkey, can predict which sound will be reported first. We find corroborating evidence of fluctuating activity patterns in a separate dataset involving responses of inferotemporal cortex neurons to multiple visual stimuli. Alternation between activity patterns corresponding to each of multiple items may therefore be a general strategy to enhance the brain processing capacity, potentially linking such disparate phenomena as variable neural firing, neural oscillations, and limits in attentional/memory capacity. PMID- 30006602 TI - Following the genetic clues towards treatment of hand OA. PMID- 30006601 TI - IL-17 in the immunopathogenesis of spondyloarthritis. AB - Spondyloarthritis (SpA) is a term that refers to a group of inflammatory diseases that includes psoriatic arthritis, axial SpA and nonradiographic axial SpA, reactive arthritis, enteropathic arthritis and undifferentiated SpA. The disease subtypes share clinical and immunological features, including joint inflammation (peripheral and axial skeleton); skin, gut and eye manifestations; and the absence of diagnostic autoantibodies (seronegative). The diseases also share genetic factors. The aetiology of SpA is still the subject of research by many groups worldwide. Evidence from genetic, experimental and clinical studies has accumulated to indicate a clear role for the IL-17 pathway in the pathogenesis of SpA. The IL-17 family consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL 17F, of which IL-17A is the best studied. IL-17A is a pro-inflammatory cytokine that also has the capacity to promote angiogenesis and osteoclastogenesis. Of the six family members, IL-17A has the strongest homology with IL-17F. In this Review, we discuss how IL-17A and IL-17F and their cellular sources might contribute to the immunopathology of SpA. PMID- 30006604 TI - The major depressive disorder GWAS-supported variant rs10514299 in TMEM161B-MEF2C predicts putamen activation during reward processing in alcohol dependence. AB - Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in the TMEM161B-MEF2C region (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA: n = 1858 (1123 cases, 735 controls); SAGE: n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis (n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level; p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82, p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (beta = 1.25, p = 0.02); this association was driven by the African American ancestry subgroup (beta = 2.11, p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 in TMEM161B-MEF2C predicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders. PMID- 30006603 TI - Hippo pathway affects survival of cancer patients: extensive analysis of TCGA data and review of literature. AB - The disruption of the Hippo pathway occurs in many cancer types and is associated with cancer progression. Herein, we investigated the impact of 32 Hippo genes on overall survival (OS) of cancer patients, by both analysing data from The Cancer Genome Atlas (TCGA) and reviewing the related literature. mRNA and protein expression data of all solid tumors except pure sarcomas were downloaded from TCGA database. Thirty-two Hippo genes were considered; for each gene, patients were dichotomized based on median expression value. Survival analyses were performed to identify independent predictors, taking into account the main clinical-pathological features affecting OS. Finally, independent predictors were correlated with YAP1 oncoprotein expression. At least one of the Hippo genes is an independent prognostic factor in 12 out of 13 considered tumor datasets. mRNA levels of the independent predictors coherently correlate with YAP1 in glioma, kidney renal clear cell, head and neck, and bladder cancer. Moreover, literature data revealed the association between YAP1 levels and OS in gastric, colorectal, hepatocellular, pancreatic, and lung cancer. Herein, we identified cancers in which Hippo pathway affects OS; these cancers should be candidates for YAP1 inhibitors development and testing. PMID- 30006606 TI - Improving the efficiency of rear emitter silicon solar cell using an optimized n type silicon oxide front surface field layer. AB - Optical and electrical characteristics of n-type nano-crystalline-silicon oxide (n-uc-SiO:H) materials can be varied to optimize and improve the performance of a solar cell. In silicon heretojunction (SHJ) solar cells, it can be used to improve carrier selectivity and optical transmission at the front side, both of which are vitally important in device operation. For this purpose, the n-uc-SiO:H was investigated as the front surface field (FSF) layer. During film deposition, an increased CO2 flow rate from 0 to 6 sccm resulted in changes of crystalline volume fractions from 57 to 28%, optical band-gaps from 1.98 to 2.21 eV, dark conductivities from 7.29 to 1.1 * 10-5 S/cm, and activation energies from 0.019 to 0.29 eV, respectively. In device applications, a minimum optical reflection was estimated for the FSF layer that was fabricated with 4 sccm CO2 (FSF-4), and therefore obtained the highest external quantum efficiency, although short circuit current density (Jsc) was 38.83 mA/cm2 and power conversion efficiency (PCE) was 21.64%. However, the highest PCE of 22.34% with Jsc = 38.71 mA/cm2 was observed with the FSF prepared with 2 sccm CO2 (FSF-2), as the combined opto electronic properties of FSF-2 were better than those of the FSF-4. PMID- 30006605 TI - Nonstimulatory peptide-MHC enhances human T-cell antigen-specific responses by amplifying proximal TCR signaling. AB - Foreign antigens are presented by antigen-presenting cells in the presence of abundant endogenous peptides that are nonstimulatory to the T cell. In mouse T cells, endogenous, nonstimulatory peptides have been shown to enhance responses to specific peptide antigens, a phenomenon termed coagonism. However, whether coagonism also occurs in human T cells is unclear, and the molecular mechanism of coagonism is still under debate since CD4 and CD8 coagonism requires different interactions. Here we show that the nonstimulatory, HIV-derived peptide GAG enhances a specific human cytotoxic T lymphocyte response to HBV-derived epitopes presented by HLA-A*02:01. Coagonism in human T cells requires the CD8 coreceptor, but not T-cell receptor (TCR) binding to the nonstimulatory peptide-MHC. Coagonists enhance the phosphorylation and recruitment of several molecules involved in the TCR-proximal signaling pathway, suggesting that coagonists promote T-cell responses to antigenic pMHC by amplifying TCR-proximal signaling. PMID- 30006607 TI - Quantum Zeno Effect assisted Spectroscopy of a single trapped Ion. AB - The quantum Zeno effect (QZE) is not only interesting as a manifestation of the counterintuitive behavior of quantum mechanics, but may also have practical applications. When a spectroscopy laser is applied to target atoms or ions prepared in an initial state, the Rabi flopping of an auxiliary transition sharing one common level can be inhibited. This effect is found to be strongly dependent on the detuning of the spectroscopy laser and offers a sensitive spectroscopy signal which allows for high precision spectroscopy of transitions with a small excitation rate. We demonstrate this method with direct frequency comb spectroscopy using the minute power of a single mode to drive a dipole allowed transition in a single trapped ion. Resolving the individual modes of the frequency comb demonstrates that the simple instantaneous quantum collapse description of the QZE can not be applied here, as these modes need several pulses to build up. PMID- 30006608 TI - Author Correction: Citrus peel essential oil nanoformulations to control the tomato borer, Tuta absoluta: chemical properties and biological activity. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30006609 TI - Glucocorticoid receptor in astrocytes regulates midbrain dopamine neurodegeneration through connexin hemichannel activity. AB - The precise contribution of astrocytes in neuroinflammatory process occurring in Parkinson's disease (PD) is not well characterized. In this study, using GRCx30CreERT2 mice that are conditionally inactivated for glucocorticoid receptor (GR) in astrocytes, we have examined the actions of astrocytic GR during dopamine neuron (DN) degeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). The results show significantly augmented DN loss in GRCx30CreERT2 mutant mice in substantia nigra (SN) compared to controls. Hypertrophy of microglia but not of astrocytes was greatly enhanced in SN of these astrocytic GR mutants intoxicated with MPTP, indicating heightened microglial reactivity compared to similarly-treated control mice. In the SN of GR astrocyte mutants, specific inflammation-associated transcripts ICAM-1, TNF-alpha and Il-1beta as well as TNF-alpha protein levels were significantly elevated after MPTP neurotoxicity compared to controls. Interestingly, this paralleled increased connexin hemichannel activity and elevated intracellular calcium levels in astrocytes examined in acute midbrain slices from control and mutant mice treated with MPP+ . The increased connexin-43 hemichannel activity was found in vivo in MPTP-intoxicated mice. Importantly, treatment of MPTP-injected GRCx30CreERT2 mutant mice with TAT-Gap19 peptide, a specific connexin-43 hemichannel blocker, reverted both DN loss and microglial activation; in wild type mice there was partial but significant survival effect. In the SN of post mortem PD patients, a significant decrease in the number of astrocytes expressing nuclear GR was observed, suggesting the participation of astrocytic GR deregulation of inflammatory process in PD. Overall, these data provide mechanistic insights into GR-modulated processes in vivo, specifically in astrocytes, that contribute to a pro-inflammatory state and dopamine neurodegeneration in PD pathology. PMID- 30006610 TI - Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation. AB - Cathepsin S (CTSS) is a cysteine protease that is thought to play a role in many physiological and pathological processes including tumor growth, angiogenesis, and metastasis; it has been identified as a radiation response gene. Here, we examined the role of CTSS in regulating the DNA damage response in breast cancer cells. Activating CTSS (producing the cleavage form of the protein) by radiation induced proteolytic degradation of BRCA1, which ultimately suppressed DNA double strand break repair activity. Depletion of CTSS by RNAi or expression of a mutant type of CTSS enhanced the protein stability of BRCA1 by inhibiting its ubiquitination. CTSS interacted with the BRCT domain of BRCA1 and facilitated ubiquitin-mediated proteolytic degradation of BRCA1, which was tightly associated with decreased BRCA1-mediated DNA repair activity. Treatment with a pharmacological CTSS inhibitor inhibited proteolytic degradation of BRCA1 and restored BRCA1 function. Depletion of CTSS by shRNA delayed tumor growth in a xenograft mouse model, only in the presence of functional BRCA1. Spontaneously uced rat mammary tumors and human breast cancer tissues with high levels of CTSS expression showed low BRCA1 expression. From these data, we suggest that CTSS inhibition is a good strategy for functional restoration of BRCA1 in breast cancers with reduced BRCA1 protein stability. PMID- 30006611 TI - Effect of temperature on the oxidation of Cu nanowires and development of an easy to produce, oxidation-resistant transparent conducting electrode using a PEDOT:PSS coating. AB - Oxidation can strongly influence the performance of Cu nanowires (CuNWs) by decreasing their conductivity. Here, we identify and investigate a way to prevent the oxidation process of CuNWs to maintain the high conducting performance of CuNWs as transparent electrodes. CuNWs were synthesised using an aqueous method. We prepared several temperature treatments (from 0-300 degrees C) to represent oxidation of CuNWs in different environments, to study the oxidation process and changes in morphology in detail. Depending on the temperature, smooth and uniform CuNWs exposed to oxidation produced rough Cu2O and CuO nanowires. We then suggest a method of protecting nanowires from oxidation, using the Mayer rod coating method to apply a layer of PEDOT:PSS to a transparent conducting film of CuNWs. The result indicates that this method of protection can protect the film, and maintain a stable, and constant resistance over of time, without effecting the excellent conductivity properties of pure CuNWs. PMID- 30006613 TI - Mettl3-Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells. PMID- 30006612 TI - ACGH detects distinct genomic alterations of primary intrahepatic cholangiocarcinomas and matched lymph node metastases and identifies a poor prognosis subclass. AB - Lymph node metastases (LNM) are an important prognostic factor for patients with intrahepatic cholangiocarcinoma, but underlying genetic alterations are poorly understood. Whole genome array comparative genomic hybridization (aCGH) was performed in 37 tumors and 14 matched LNM. Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA). Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p). LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)]. Unsupervised clustering revealed a poor prognosis subclass with increased alterations significantly associated to tumor differentiation and survival. TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases. Pathway analyses revealed association to cancer-associated pathways. Advanced tumor stage, microvascular/perineural invasion, and microscopic positive resection margin (R1) were significantly correlated to metastases, while N1-status, R1-resection, and poor tumor differentiation were significantly correlated to survival. ACGH identified clear differences between N0 (no LNM) and N1 tumors, while N1 tumors and matched LNM displayed high clonality with exclusive gains in the metastases. A novel subclass with increased CNAs and poor tumor differentiation was significantly correlated to survival. PMID- 30006614 TI - Switching of the Chiral Magnetic Domains in the Hybrid Molecular/Inorganic Multiferroic (ND4)2[FeCl5(D2O)]. AB - (ND4)2[FeCl5(D2O)] represents a promising example of the hybrid molecular/inorganic approach to create materials with strong magneto-electric coupling. Neutron spherical polarimetry, which is directly sensitive to the absolute magnetic configuration and domain population, has been used in this work to unambiguously prove the multiferroicity of this material. We demonstrate that the application of an electric field upon cooling results in the stabilization of a single-cycloidal magnetic domain below 6.9 K, while poling in the opposite electric field direction produces the full population of the domain with opposite magnetic chirality. We prove the complete switchability of the magnetic domains at low temperature by the applied electric field, which constitutes a direct proof of the strong magnetoelectric coupling. Additionally, we refine the magnetic structure of the ordered ground state, deducing the underlying magnetic space group consistent with the direction of the ferroelectric polarization, and we provide evidence of a collinear amplitude-modulated state with magnetic moments along the a-axis in the temperature region between 6.9 and 7.2 K. PMID- 30006615 TI - Vitamin D deficiency and clinical outcomes related to septic shock in children with critical illness: a systematic review. AB - PURPOSE: Low vitamin D blood levels are related to many clinical outcomes in children with critically illness. However, the relationship of it and septic shock has not been systematically analyzed. The objective of this review was to evaluate the effect of vitamin D on septic shock and predict if vitamin D administration can improve prognosis of it. MATERIALS AND METHODS: Online databases were searched up to June 1st, 2017 for studies on the relation of vitamin D deficiency (VDD) and clinical outcomes on septic shock in children with critical illness. The primary end point was the effect of VDD on occurrence of septic shock. The secondary endpoints were the association of VDD and clinical outcomes related to septic shock. We summarized the strength of association between VDD and each factor on septic shock. Individual factors were defined as strong, moderate, weak, or inconclusive according to the numbers of the article supporting the relation between them. RESULTS: Eight studies published between 2012 and 2017, for a total of 1367 patients, were included in the final analysis. We extracted eight patient-level factors and among them one showed strong association of VDD and septic shock. Four factors demonstrated moderate or weak strength of evidence for it: nonresolution of shock, catecholamine refractory shock, fluid boluses, vasopressor use. But evidence for the association between VDD and severity of illness, stay of pediatric intensive care unit (PICU), are weak. Most of the articles showed no significant association between VDD and mortality. CONCLUSIONS: Among critically ill children, VDD might be associated with the occurrence and resolution of septic shock. A larger multicenter trial could conclusively confirm these findings. Further research is also needed to identify vitamin D administration for better outcomes in pediatric patients. PMID- 30006616 TI - Safety and efficacy of n-3 fatty acid-based parenteral nutrition in patients with obstructive jaundice: a propensity-matched study. AB - BACKGROUND: It is reported that lipid emulsion enriched in n-3 fatty acids (FAs) helps us to improve postoperative recovery for surgical patients with biliary tract disease. Its role for postoperative patients with obstructive jaundice is as yet unclear. The object of this study was to evaluate the safety and efficacy of n-3 fatty acid-based parenteral nutrition (PN) for patients with obstructive jaundice following surgical procedures. METHODS: Data were collected from patients with obstructive jaundice who received PN, including n-3 PUFA-enriched lipid emulsions and standard non-enriched lipid emulsions (e.g., soybean oil). We then calculated a propensity score, the probability of receiving different PN, by the propensity score matched (PSM) method. After matching, we compared isonitrogenous total PN with 20% Structolipid and 10% n-3 fatty acid (Omegaven, Fresenius-Kabi, Germany) (treatment group) to Structolipid alone (control group) for 5 days postoperatively, in the absence of enteral nutrition. RESULTS: Before the propensity score matching, there were 226 patients enrolled. After propensity score stratification, 108 cases remained, and all covariates were balanced. Among matched patients with PN, patients in the control group were at a higher risk for long-term jaundice recovery (12.9 +/- 8.5 VS 16.4 +/- 7.9 P = 0.029), lower velocity of reduction in jaundice (P = 0.045), and lower pre-albumin (P = 0.002). No significant difference as found in terms of comorbidities, white blood cell (WBC), albumin and other aspects. CONCLUSION: PN with n-3 PUFA-enriched lipid emulsions was safe and effective in accelerating jaundice recovery for patients after surgical procedures. This trial was registered at clinicaltrials.gov as NCT03376945. PMID- 30006618 TI - Retraction Note: New molecular tools in Neospora caninum for studying apicomplexan parasite proteins. AB - This paper has been retracted at the request of the authors. PMID- 30006617 TI - Codon usage clusters correlation: towards protein solubility prediction in heterologous expression systems in E. coli. AB - Production of soluble recombinant proteins is crucial to the development of industry and basic research. However, the aggregation due to the incorrect folding of the nascent polypeptides is still a mayor bottleneck. Understanding the factors governing protein solubility is important to grasp the underlying mechanisms and improve the design of recombinant proteins. Here we show a quantitative study of the expression and solubility of a set of proteins from Bizionia argentinensis. Through the analysis of different features known to modulate protein production, we defined two parameters based on the %MinMax algorithm to compare codon usage clusters between the host and the target genes. We demonstrate that the absolute difference between all %MinMax frequencies of the host and the target gene is significantly negatively correlated with protein expression levels. But most importantly, a strong positive correlation between solubility and the degree of conservation of codons usage clusters is observed for two independent datasets. Moreover, we evince that this correlation is higher in codon usage clusters involved in less compact protein secondary structure regions. Our results provide important tools for protein design and support the notion that codon usage may dictate translation rate and modulate co translational folding. PMID- 30006620 TI - Limits to growth of forest biomass carbon sink under climate change. AB - Widely recognized as a significant carbon sink, North American forests have experienced a history of recovery and are facing an uncertain future. This growing carbon sink is dictated by recovery from land-use change, with growth trajectory modified by environmental change. To address both processes, we compiled a forest inventory dataset from North America to quantify aboveground biomass growth with stand age across forest types and climate gradients. Here we show, the biomass grows from 90 Mg ha-1 (2000-2016) to 105 Mg ha-1 (2020 s), 128 Mg ha-1 (2050 s), and 146 Mg ha-1 (2080 s) under climate change scenarios with no further disturbances. Climate change modifies the forest recovery trajectory to some extent, but the overall growth is limited, showing signs of biomass saturation. The future (2080s) biomass will only sequester at most 22% more carbon than the current level. Given such a strong sink has limited growth potential, our ground-based analysis suggests policy changes to sustain the carbon sink. PMID- 30006621 TI - Radiocaesium transfer and radiation exposure of frogs in Fukushima Prefecture. AB - The International Commission on Radiological Protection has proposed an environmental assessment framework. This includes ionising radiation exposure assessment for different frog life-stages, but radiocaesium transfer parameters are unavailable. We collate data from the Fukushima Prefecture (contaminated by the Fukushima accident) and estimate radiocaesium concentration ratio (CRwo water) values for tadpoles and adult frogs, presenting the largest available amphibian CRwo-water dataset. In total, 513 adult frogs and 2540 tadpoles were analysed in 62 and 59 composite samples respectively. Results suggest that equilibrium was reached between water and amphibian radiocaesium activity concentrations circa one-year after the accident. Radiocaesium transfer to tadpoles was higher than to adult frogs. Dose rates were estimated for different life-stages and species in both the aquatic and terrestrial environment. Estimated dose rates to adults and tadpoles were typically similar because external exposure dominated for both organisms; frogspawn dose rates were estimated to be orders of magnitude lower than other life-stages. For the two sites assessed, which were outside of the most contaminated areas of the Fukushima Prefecture, estimated dose rates were below those anticipated to present a risk to wildlife populations; it is likely that dose rates in more contaminated areas were in excess of some effects benchmark values. PMID- 30006619 TI - Reactive astrocytic S1P3 signaling modulates the blood-tumor barrier in brain metastases. AB - Brain metastases are devastating complications of cancer. The blood-brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood-tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients' brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability. PMID- 30006623 TI - High-quality genomes reveal new differences between the great apes. PMID- 30006622 TI - The thrombopoietin mimetic romiplostim leads to the complete rescue of mice exposed to lethal ionizing radiation. AB - For the primary treatment of emergency exposure to high-dose radiation, such as in the event of a radiation accident, the top priority is the reconstitution and restoration of haematopoiesis. In most radiation accidents, drug therapy is chosen as the most suitable treatment; the chosen drug should already be approved domestically, stably supplied and regularly stockpiled. In the present study, a single administration of romiplostim (RP), an approved thrombopoietin receptor agonist, produced a 100% survival rate in C57BL/6 J mice exposed to a lethal dose (7 Gy) of 137Cs gamma-rays, and all irradiated mice survived for more than 30 days with both 3- and 5-day consecutive administrations. By day 30, the peripheral blood cells, bone marrow cells and haematopoietic progenitor cells of the RP-administered irradiated mice had all recovered to a level that was not significantly different from that in non-irradiated mice. In contrast to myelosuppression, which did not fully recover until day 30, the expression of several bone marrow cell surface antigens recovered sooner, and DNA repair concurrently increased in haematopoietic cells, speeding the resolution of double strand breaks and reducing the rates of apoptosis. These findings suggest that RP may be a clinic-ready countermeasure to treat victims of radiation accidents. PMID- 30006624 TI - Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum. AB - Nicotine use can lead to dependence through complex processes that are regulated by both its rewarding and aversive effects. Recent studies show that aversive nicotine doses activate excitatory inputs to the interpeduncular nucleus (IPN) from the medial habenula (MHb), but the downstream targets of the IPN that mediate aversion are unknown. Here we show that IPN projections to the laterodorsal tegmentum (LDTg) are GABAergic using optogenetics in tissue slices from mouse brain. Selective stimulation of these IPN axon terminals in LDTg in vivo elicits avoidance behavior, suggesting that these projections contribute to aversion. Nicotine modulates these synapses in a concentration-dependent manner, with strong enhancement only seen at higher concentrations that elicit aversive responses in behavioral tests. Optogenetic inhibition of the IPN-LDTg connection blocks nicotine conditioned place aversion, suggesting that the IPN-LDTg connection is a critical part of the circuitry that mediates the aversive effects of nicotine. PMID- 30006625 TI - The Drosophila microbiome has a limited influence on sleep, activity, and courtship behaviors. AB - In animals, commensal microbes modulate various physiological functions, including behavior. While microbiota exposure is required for normal behavior in mammals, it is not known how widely this dependency is present in other animal species. We proposed the hypothesis that the microbiome has a major influence on the behavior of the vinegar fly (Drosophila melanogaster), a major invertebrate model organism. Several assays were used to test the contribution of the microbiome on some well-characterized behaviors: defensive behavior, sleep, locomotion, and courtship in microbe-bearing, control flies and two generations of germ-free animals. None of the behaviors were largely influenced by the absence of a microbiome, and the small or moderate effects were not generalizable between replicates and/or generations. These results refute the hypothesis, indicating that the Drosophila microbiome does not have a major influence over several behaviors fundamental to the animal's survival and reproduction. The impact of commensal microbes on animal behaviour may not be broadly conserved. PMID- 30006626 TI - CD200-CD200R imbalance correlates with microglia and pro-inflammatory activation in rat spinal cords exposed to amniotic fluid in retinoic acid-induced spina bifida. AB - Spina bifida aperta is a congenital malformation characterized by the failure of neural tube closure resulting in an unprotected fetal spinal cord. The spinal cord then undergoes progressive damage, likely due to chemical and mechanical factors related to exposure to the intrauterine environment. Astrogliosis in exposed spinal cords has been described in animal models of spina bifida during embryonic life but its relationship with neuroinflammatory processes are completely unknown. Using a retinoic acid-induced rat model of spina bifida we demonstrated that, when exposed to amniotic fluid, fetal spinal cords showed progressive astrogliosis with neuronal loss at mid-gestation (E15) compared to unexposed spinal cords. The number of microglial cells with a reactive phenotype and activation marker expression increased during gestation and exhibited progressive disruption in the inhibitory immune ligand-receptor system. Specifically we demonstrate down-regulation of CD200 expression and up-regulation of CD200R. Exposed spinal cords demonstrated neuroinflammation with increased tissue water content and cytokine production by the end of gestation (E20), which correlated with active Caspase3 expression in the exposed layers. Our findings provide new evidence that microglia activation, including the disruption of the endogenous inhibitory system (CD200-CD200R), may participate in the pathogenesis of spina bifida through late gestation. PMID- 30006627 TI - Single-molecule insights into surface-mediated homochirality in hierarchical peptide assembly. AB - Homochirality is very important in the formation of advanced biological structures, but the origin and evolution mechanisms of homochiral biological structures in complex hierarchical process is not clear at the single-molecule level. Here we demonstrate the single-molecule investigation of biological homochirality in the hierarchical peptide assembly, regarding symmetry break, chirality amplification, and chirality transmission. We find that homochirality can be triggered by the chirality unbalance of two adsorption configuration monomers. Co-assembly between these two adsorption configuration monomers is very critical for the formation of homochiral assemblies. The site-specific recognition is responsible for the subsequent homochirality amplification and transmission in their hierarchical assembly. These single-molecule insights open up inspired thoughts for understanding biological homochirality and have general implications for designing and fabricating artificial biomimetic hierarchical chiral materials. PMID- 30006629 TI - Strong plates enhance mantle mixing in early Earth. AB - In the present-day Earth, some subducting plates (slabs) are flattening above the upper-lower mantle boundary at ~670 km depth, whereas others go through, indicating a mode between layered and whole-mantle convection. Previous models predicted that in a few hundred degree hotter early Earth, convection was likely more layered due to dominant slab stagnation. In self-consistent numerical models where slabs have a plate-like rheology, strong slabs and mobile plate boundaries favour stagnation for old and penetration for young slabs, as observed today. Here we show that such models predict slabs would have penetrated into the lower mantle more easily in a hotter Earth, when a weaker asthenosphere and decreased plate density and strength resulted in subduction almost without trench retreat. Thus, heat and material transport in the Earth's mantle was more (rather than less) efficient in the past, which better matches the thermal evolution of the Earth. PMID- 30006628 TI - In vivo MRI with Concurrent Excitation and Acquisition using Automated Active Analog Cancellation. AB - Magnetic resonance imaging (MRI) provides excellent cross-sectional images of the soft tissues in patients. Unfortunately, MRI is intrinsically slow, it exposes patients to severe acoustic noise levels, and is limited in the visualization of certain tissues such as bone. These limitations are partly caused by the timing structure of the MRI exam which first generates the MR signal by a strong radio frequency excitation and later acquires the weak MRI signal. Concurrent excitation and acquisition (CEA) can overcome these limitations, but is extremely challenging due to the huge intensity difference between transmit and receive signal (up to 100 dB). To suppress the strong transmit signals during signal reception, a fully automated analog cancellation unit was designed. On a 3 Tesla clinical MRI system we achieved an on-resonance analog isolation of 90 dB between the transmit and receive path, so that CEA images of the head and the extremities could be acquired with an acquisition efficiency of higher than 90% at sound pressure levels close to background noise. CEA with analog cancellation might provide new opportunities for MRI in tissues with very short T2 relaxation times, and it offers a silent and time-efficient MRI acquisition. PMID- 30006630 TI - Cell-specific pattern of berberine pleiotropic effects on different human cell lines. AB - The natural alkaloid berberine has several pharmacological properties and recently received attention as a potential anticancer agent. In this work, we investigated the molecular mechanisms underlying the anti-tumor effect of berberine on glioblastoma U343 and pancreatic carcinoma MIA PaCa-2 cells. Human dermal fibroblasts (HDF) were used as non-cancer cells. We show that berberine differentially affects cell viability, displaying a higher cytotoxicity on the two cancer cell lines than on HDF. Berberine also affects cell cycle progression, senescence, caspase-3 activity, autophagy and migration in a cell-specific manner. In particular, in HDF it induces cell cycle arrest in G2 and senescence, but not autophagy; in the U343 cells, berberine leads to cell cycle arrest in G2 and induces both senescence and autophagy; in MIA PaCa-2 cells, the alkaloid induces arrest in G1, senescence, autophagy, it increases caspase-3 activity and impairs migration/invasion. As demonstrated by decreased citrate synthase activity, the three cell lines show mitochondrial dysfunction following berberine exposure. Finally, we observed that berberine modulates the expression profile of genes involved in different pathways of tumorigenesis in a cell line-specific manner. These findings have valuable implications for understanding the complex functional interactions between berberine and specific cell types. PMID- 30006631 TI - Chemosensitivity profiling of osteosarcoma tumour cell lines identifies a model of BRCAness. AB - Osteosarcoma (OS) is an aggressive sarcoma, where novel treatment approaches are required. Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) patterns reminiscent of BRCA1 or BRCA2 mutant tumours. This raises the possibility that PARP inhibitors (PARPi), used to treat BRCA1/2 mutant cancers, could be used to target OS. Using high-throughput drug sensitivity screening we generated chemosensitivity profiles for 79 small molecule inhibitors, including three clinical PARPi. Drug screening was performed in 88 tumour cell lines, including 18 OS TCLs. This identified known sensitivity effects in OS TCLs, such as sensitivity to FGFR inhibitors. When compared to BRCA1/2 mutant TCLs, OS TCLs, with the exception of LM7, were PARPi resistant, including those with previously determined BRCAness LoH profiles. Post-screen validation experiments confirmed PARPi sensitivity in LM7 cells as well as a defect in the ability to form nuclear RAD51 foci in response to DNA damage. LM7 provides one OS model for the study of PARPi sensitivity through a potential defect in RAD51-mediated DNA repair. The drug sensitivity dataset we generated in 88 TCLs could also serve as a resource for the study of drug sensitivity effects in OS. PMID- 30006632 TI - Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia. AB - Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors. PMID- 30006633 TI - Simple Physical Model Unravels Influences of Chemokine on Shape Deformation and Migration of Human Hematopoietic Stem Cells. AB - We studied the dynamic behavior of human hematopoietic stem cells (HSC) on the in vitro model of bone marrow surfaces in the absence and presence of chemokine (SDF1alpha). The deformation and migration of cells were investigated by varying the chemokine concentration and surface density of ligand molecules. Since HSC used in this study were primary cells extracted from the human umbilical cord blood, it is not possible to introduce molecular reporter systems before or during the live cell imaging. To account for the experimental observations, we propose a simple and general theoretical model for cell crawling. In contrast to other theoretical models reported previously, our model focuses on the nonlinear coupling between shape deformation and translational motion and is free from any molecular-level process. Therefore, it is ideally suited for the comparison with our experimental results. We have demonstrated that the results in the absence of SDF1alpha were well recapitulated by the linear model, while the nonlinear model is necessary to reproduce the elongated migration observed in the presence of SDF1alpha. The combination of the simple theoretical model and the label-free, live cell observations of human primary cells opens a large potential to numerically identify the differential effects of extrinsic factors such as chemokines, growth factors, and clinical drugs on dynamic phenotypes of primary cells. PMID- 30006634 TI - Probiotics in human gut microbiota can degrade host glycosaminoglycans. AB - Glycosaminoglycans (GAGs) (e.g. heparin, chondroitin sulfate, and hyaluronan) show various significant physiological functions as a major component of extracellular matrix in animals. Some bacteria target GAGs for adhesion and/or infection to host cells, although no probiotics have been known to degrade GAGs. Here, we show GAG degradation by probiotics from human gut microbiota and their adhesion to human intestinal cells through a GAG. GAG-degrading bacteria were isolated from human faeces and identified as Enterococcus faecium, and some typical probiotics such as Lactobacillus casei, Lactobacillus rhamnosus and Enterococcus faecalis were also found to degrade heparin. GAG-degrading lactobacilli and enterococci including the isolated E. faecium possessed a genetic cluster encoding GAG-degrading/metabolising enzymes in the bacterial genome. KduI and KduD enzymes encoded in the GAG cluster of L. rhamnosus functioned as 4-deoxy-l-threo-5-hexosulose-uronate ketol-isomerase and 2-keto-3 deoxy-d-gluconate dehydrogenase, respectively, both of which were crucial for GAG metabolism. GAG-degrading L. rhamnosus and E. faecium attached to human intestinal Caco-2 cells via heparin. Some species of Bacteroides, considered to be the next generation probiotics, degraded chondroitin sulfate C and hyaluronan, and genes coding for the Bacteroides GAG-degrading enzyme were frequently detected from human gut microbiota. This is the first report on GAG-degrading probiotics in human gut microbiota. PMID- 30006635 TI - Hemostatic nanoparticles increase survival, mitigate neuropathology and alleviate anxiety in a rodent blast trauma model. AB - Explosions account for 79% of combat related injuries and often lead to polytrauma, a majority of which include blast-induced traumatic brain injuries (bTBI). These injuries lead to internal bleeding in multiple organs and, in the case of bTBI, long term neurological deficits. Currently, there are no treatments for internal bleeding beyond fluid resuscitation and surgery. There is also a dearth of treatments for TBI. We have developed a novel approach using hemostatic nanoparticles that encapsulate an anti-inflammatory, dexamethasone, to stop the bleeding and reduce inflammation after injury. We hypothesize that this will improve not only survival but long term functional outcomes after blast polytrauma. Poly(lactic-co-glycolic acid) hemostatic nanoparticles encapsulating dexamethasone (hDNPs) were fabricated and tested following injury along with appropriate controls. Rats were exposed to a single blast wave using an Advanced Blast Simulator, inducing primary blast lung and bTBI. Survival was elevated in the hDNPs group compared to controls. Elevated anxiety parameters were found in the controls, compared to hDNPs. Histological analysis indicated that apoptosis and blood-brain barrier disruption in the amygdala were significantly increased in the controls compared to the hDNPs and sham groups. Immediate intervention is crucial to mitigate injury mechanisms that contribute to emotional deficits. PMID- 30006637 TI - Transcriptional and post-transcriptional regulation of PenA beta-lactamase in acquired Burkholderia pseudomallei beta-lactam resistance. AB - Therapy of Burkholderia pseudomallei acute infections is largely limited to a few beta-lactam antibiotics such as ceftazidime or meropenem. Although relatively rare, resistance emergence during therapy leads to treatment failures with high mortality rates. In the absence of acquired external resistance determinants in B. pseudomallei emergence of beta-lactam resistance is invariably caused by mutational modification of genomically encoded factors. These include the deletion of the ceftazidime target penicillin-binding protein 3 or amino acid changes in the Class A PenA beta-lactamase that expand its substrate spectrum, as well as penA gene duplication and amplification or its overexpression via transcriptional up-regulation. Evidence is presented that penA is co-transcribed with the upstream nlpD1 gene, that the transcriptional terminator for nlpD1 serves as a penA attenuator and that generation of a new promoter immediately upstream of the terminator/attenuator by a conserved G to A transition leads to anti-termination and thus constitutive PenA expression and extended beta-lactam resistance. Further evidence obtained with the extensively beta-lactam resistant clinical isolate Bp1651 shows that in addition to PenA overexpression and structural mutations other adaptive mechanisms contribute to intrinsic and acquired B. pseudomallei beta-lactam resistance. PMID- 30006636 TI - The Functional Alterations in Top-Down Attention Streams of Parkinson's disease Measured by EEG. AB - Early and moderate Parkinson's disease patients seem to have attention dysfunctions manifested differentially in separate attention streams: top-down and bottom-up. With a focus on the neurophysiological underpinnings of such differences, this study evaluated source-localized regional activity and functional connectivity of regions in the top-down and bottom-up streams as well as any discordance between the two streams. Resting state electroencephalography was used for 36 Parkinson's disease patients and 36 healthy controls matched for age and gender. Parkinson's disease patients showed disproportionally higher bilateral gamma activity in the bottom-up stream and higher left alpha2 connectivity in the top-down stream when compared to age-matched controls. An additional cross-frequency coupling analysis showed that Parkinson's patients have higher alpha2-gamma coupling in the right posterior parietal cortex, which is part of the top-down stream. Higher coupling in this region was also associated with lower severity of motor symptoms in Parkinson's disease. This study provides evidence that in Parkinson's disease, the activity in gamma frequency band and connectivity in alpha2 frequency band is discordant between top-down and bottom-up attention streams. PMID- 30006638 TI - Tracking aluminium impurities in single crystals of the heavy-fermion superconductor UBe13. AB - The influence of Al incorporation on the heavy fermion superconductor UBe13 was investigated to explain the sample dependence of physical properties. Clear evidence for incorporated Al in flux-grown UBe13 single crystals is presented by results from X-ray diffraction, nuclear magnetic resonance and X-ray spectroscopy. The increase of the lattice parameter and the concomitant change of the superconducting properties are caused by substitution of Be in the compound by 1-2 at.% Al. The minute amounts of Al in the structure were located by atomic resolution transmission electron microscopy. Specific heat measurements reveal the strong influence of incorporated Al on the physical properties of UBe13. Upon long-term annealing, Al incorporated in single crystals can leave the structure, restoring properties of Al-free polycrystalline UBe13. PMID- 30006640 TI - Selective ablation of TRPV1 by intrathecal injection of resiniferatoxin in rats increases renal sympathoexcitatory responses and salt sensitivity. AB - This study tested the hypothesis that selective ablation of transient receptor potential vanilloid type 1 (TRPV1)-positive nerve fibers by intrathecal injection of resiniferatoxin (RTX) enhances renal sympathoexcitatory responses and salt sensitivity. Intrathecal injection of RTX (1.8 MUg/kg) to the levels of lower thoracic and upper lumbar spinal cord (T8-L3) increased mean arterial pressure (MAP) in rats fed a normal (NS, 1% NaCl) or high-sodium (HS, 8% NaCl) diet for 4 weeks compared to vehicle-treated rats (NS: 121 +/- 2 vs. 111 +/- 2; HS: 154 +/- 2 vs. 134 +/- 2 mm Hg, both P < 0.05), with a greater increase in HS compared to NS rats (9 +/- 1% vs. 15 +/- 1%, P < 0.05). TRPV1 contents were decreased in T8 L3 segments of spinal dorsal horn but not in corresponding dorsal root ganglia and the kidney following RTX treatment (P < 0.05). Selective activation of GABA-A receptors with intrathecal T8-L3 segment-injection of muscimol (3 nmol/kg) decreased renal sympathetic nerve activity and increased urinary excretion in both NS and HS rats, with a greater effect in RTX-treated compared to vehicle treated rats (P < 0.05). Chronic activation of GABA-A receptors with muscimol (50 mg/kg/day * 2, p.o.) abolished RTX treatment-induced pressor effects in NS and HS rats. GAD65/67, a GABA synthetase, in the spinal cord was downregulated and tyrosine hydroxylase in the kidney upregulated in NS or HS rats treated with RTX (P < 0.05). Thus, selective ablation of TRPV1-positive central terminals of sensory neurons plays a prohypertensive role possibly via inhibition of spinal GABA system especially with HS intake, suggesting that activation of TRPV1 in central terminals of sensory neurons may convey an antihypertensive effect. PMID- 30006639 TI - Vigour of self-paced reaching movement: cost of time and individual traits. AB - People usually move at a self-selected pace in everyday life. Yet, the principles underlying the formation of human movement vigour remain unclear, particularly in view of intriguing inter-individual variability. It has been hypothesized that how the brain values time may be the cornerstone of such differences, beyond biomechanics. Here, we focused on the vigour of self-paced reaching movement and assessed the stability of vigour via repeated measurements within participants. We used an optimal control methodology to identify a cost of time (CoT) function underlying each participant's vigour, considering a model of the biomechanical cost of movement. We then tested the extent to which anthropometric or psychological traits, namely boredom proneness and impulsivity, could account for a significant part of inter-individual variance in vigour and CoT parameters. Our findings show that the vigour of reaching is largely idiosyncratic and tend to corroborate a relation between the relative steepness of the identified CoT and boredom proneness, a psychological trait relevant to one's relationship with time in decision-making. PMID- 30006641 TI - Intravascular imaging, histopathological analysis, and catecholamine quantification following catheter-based renal denervation in a swine model: the impact of prebifurcation energy delivery. AB - The purpose of this study was to evaluate the impact of prebifurcation renal denervation in a swine model and assess its safety through optical coherence tomography (OCT). Prebifurcation renal denervation with a multi-electrode catheter was performed in one renal artery of 12 healthy pigs, with the contralateral artery and kidney being used as controls. Angiograms and OCT pullbacks were obtained peri-procedurally and 1 month post procedure. Renal tissue catecholamines were quantified, and the arterial wall and peri-adventitial tissue were analyzed histologically. Intraluminal changes (endothelial swelling, spasm, and thrombus formation) were observed acutely by OCT in most of the treated arteries and were no longer visible at follow-up. Histology revealed a statistically significant accumulation of collagen (fibrosis) and a near absence of tyrosine hydroxylase labeling in the denervated artery, suggesting a clear reduction in nervous terminals. Renal tissue catecholamine levels were similar between both sides, probably due to the low number of ablation points and the renorenal reflex. The present study demonstrates that renal denervation is associated with acute intimal disruptions, areas of fibrosis, and a reduction in nervous terminals. The lack of difference in renal tissue catecholamine levels is indicative of the need to perform the highest and safest number of ablation points in both renal arteries. These findings are important because they demonstrate the histological consequences of radiofrequency energy application and its medium-term safety. PMID- 30006643 TI - CT-based tissue segmentation to assess knee joint inflammation and reactive bone formation assessed by 18F-FDG and 18F-NaF PET/CT: Effects of age and BMI. AB - OBJECTIVE: This study was conducted to determine the role of computed tomography (CT)-based segmentation methodology to semi-quantify the degree of inflammation and reactive bone formation in the knee joints by fluorine-18-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride positron emission tomography/CT (18F-NaF PET/CT) imaging, respectively. Furthermore, we assessed the impact of aging and body mass index (BMI) on these biological responses. SUBJECTS AND METHODS: In this retrospective study, we examined a total of 97 subjects who had undergone both 18F-FDG and 18F-NaF PET/CT scanning. The mean age was 49.3+/-14.9 (21-75) and the mean BMI was 26.7+/-4.3 (17.7-42.0). Whole joint compartments and osseous compartments were segmented on fused PET/CT images using a 3D-growing algorithm with an adjustable upper/lower Hounsfield Units (HU) thresholds and manual tools. The metabolic activity and volume of each compartment was measured, values from the osseous compartment were subtracted from the whole joint to get the volume and metabolic activity of the soft tissue. The metabolic activity was correlated with age and BMI. RESULTS: Fluorine-18-FDG uptake in the soft tissues surrounding the joint was 0.35+/-0.07 while 0.19+/-0.04 in the osseous structures (P<0.0001). Aging positively correlated with 18F-FDG uptake in the soft tissue (r=0.37, P=0.0001). Body mass index positively correlated with 18F-FDG uptake in the soft tissue (r=0.53, P<0.0001), osseous compartment (r=0.58, P<0.0001) and 18F-NaF uptake in the joint (r=0.37, P=0.0001). A positive association was noted between the degree of new bone formation and the inflammatory reaction (P<0.01). CONCLUSION: The PET-based molecular imaging probes along with the CT-based segmentation techniques revealed an association between aging and the inflammatory activity of the soft tissue compartment. Similarly, a positive correlation was noted between BMI and inflammation and reactive bone f ormation of the knee joint compartments. PMID- 30006642 TI - Global temporal lobe asymmetry as a semi-quantitative imaging biomarker for temporal lobe epilepsy lateralization: A machine learning classification study. AB - OBJECTIVE: The purpose of this study was to evaluate the utility of global semi quantitative analysis via fluorine-18-flurodeoxyglucose positron emission tomography (18F-FDG PET) at lateralizing seizure foci and diagnosing patients with unilateral temporal lobe epilepsy (TLE). METHODS: Seventeen patients with unilateral TLE (11 right TLE and 6 left TLE) were retrospectively selected for semi-quantitative 18F-FDG PET analysis. Twenty-three control subjects with a Mini Mental State Examination (MMSE) score of 29 or greater were selected for comparison. Globally averaged standardized uptake value (gSUVmean) was computed for each temporal lobe. Lateralization indices (LI) and the absolute value of lateralization indices (|LI|) were calculated to assess the degree of asymmetry in each subject. Logistic regression analyses were performed at a probability cutoff of 0.5 to classify TLE patients as left or right TLE and to discriminate patients from control subjects. Receiver operating characteristic (ROC) curves were generated to evaluate the utility of LI and |LI| as classification predictors. The Bland Altman test was used to evaluate the reproducibility of the measurements. RESULTS: There was a statistically significant difference in gSUVmean computed LI between left and right TLE patients (P<0.01). There was no statistically significant difference in |LI| between the patient and control groups (P=0.22). Logistic regression revealed that 82% of TLE patients were lateralized correctly using LI as the sole predictor. The area under the ROC curve (AUC) was 0.80. Logistic regression using |LI| on the combined patient/control population showed a diagnostic accuracy of 65% and an AUC of 0.44. Bland Altman analysis revealed an intra-observer reproducibility of 96% and an inter-observer reproducibility of 96% and 91% on successive trials. CONCLUSION: We conclude that gSUVmean computed LI is a reliable and reproducible measure for predicting seizure lateralization in unilateral TLE patients. However, gSUVmean computed |LI| does not appear to be particularly effective at diagnosing TLE patients from control subjects. Further studies with more patients should investigate other machine learning techniques that combine gSUVmean with other diagnostic predictors. PMID- 30006644 TI - More accurate than MRI measurement of tumor size in breast cancer by using the peri-tumoral halo uptake layer method of the 18F-FDG PET/CT scan. AB - OBJECTIVE: To evaluate the reliability of a method using the peri-tumoral halo layer (PHL) for assessing tumor size in breast cancer patients on the fluorine-18 fluorodeoxy glucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan compared to MRI and pathology. SUBJECTS AND METHODS: Among 121 patients with breast cancer who underwent both 18F-FDG PET/CT and MRI between March 2013 and June 2016, 59 patients were included in this study. Exclusion criteria were as follows: history of neoadjuvant therapy, history of pre operative mammotome, insufficient pathologic/radiologic size report, clustered tumor, positive tumor resection margin, 18F-FDG non-avid tumor. The PHL was examined by two nuclear medicine physicians. Tumor sizes (longest diameters) on 18F-FDG PET/CT were estimated using margins defined as the inner line of the PHL. Pathologic tumor sizes were utilized as reference standards. RESULTS: The PHL of each tumor was most commonly designated as the 20%-30% band of the maximum standardized uptake value (SUVmax) it exhibited an inverse correlation with tumor SUVmax. Tumor size on 18F-FDG PET/CT showed a more linear correlation with pathology than that on MRI (r2=0.91 vs 0.65). In Bland-Altman analysis, 18F-FDG PET/CT showed significantly lower bias in size difference relative to pathology, compared with MRI (0.6+/-9.6cm vs. -1.9+/-17.3cm). Fluorine-18-FDG PET/CT showed more accurate T staging with pathology, especially in T3 cases, than MRI. CONCLUSION: A method of tumor size determination, using PHL on 18F-FDG PET/CT, showed more linear relationship and smaller size differences with pathology than MRI (average 0.6 vs. 1.9cm). It provides sufficient reliability and reproducibility for measuring tumor size in breast cancer. PMID- 30006645 TI - Iodine-125 labeled Australian frog tree host-defense peptides caerin 1.1 and 1.9 better inhibit human breast cancer cells growth than the unlabeled peptides. 125I caerin 1.9 may better be used for the treatment of breast cancer. AB - OBJECTIVE: We recently showed that host defense caerin peptides isolated from Australian frog tree were able to inhibit cervical cancer tumour cell growth in vitro. We wished to determine if radioactive isotope iodine-125 (125I) can be labeled to caerin 1.9 peptide and if this peptide is bioactive for breast cancer cells treatment. SUBJECTS AND METHODS: The biological function of caerin (1.1 and 1.9) peptides were investigated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. The anti-cancer effect of 125I labeled caerin 1.9 was compared with unlabeled caerin 1.9 peptide. The tissue distribution of 125I labeled caerin 1.9 peptide was further studied in mice. RESULTS: In the current paper, we demonstrated that caerin peptides (1.1 and 1.9) were separately able to inhibit the viability of two breast cancer cell lines in vitro and this inhibition was more profound when these peptides were simultaneously applied. Moreover, 125I can be stably attached to caerin 1.9 peptide with high efficiency. Iodine-125 labeled caerin 1.9 inhibited breast cancer cells line MCF-7 viability more efficiently than free 125I and also than unlabeled caerin 1.9. Additionally, iodine-125 labeled caerin 1.9 in vivo imaging demonstrated that although slightly, it could be accumulated in tumor tissue. CONCLUSION: Our results from this totally original study indicated that radioactive isotope 125I labeled to caerin peptide 1.9 may be used to treat breast cancer while at the same time the response to treatment may be monitored by simultaneous imaging. PMID- 30006646 TI - Renal output efficiency and normalized residual activity examined by technetium 99m-DTPA renography have by far greater specificity to diagnose obstructive disease as compared to other conventional parameters of the renogram. First such study of output efficiency. AB - OBJECTIVE: The aim of this study was to assess the diagnostic ability of renal output efficiency (OE), normalized residual activity (NORA) and conventional interpretation of the diethylene triamine pentaacetic acid (99mTc-DTPA) diuretic renogram (CIR) in diagnosing urine flow obstruction. SUBJECTS AND METHODS: Group A consisted of 73 obstructed kidneys and Group B of 80 kidneys with dilated upper urinary tract. Forty eight kidneys were examined as the control Group C. A 40min acquisition with 240 of 10sec images was applied. Furosemide was administered after 20min (F+20). Post-void image was acquired at 50min. Output efficiency was calculated at 20min (OE20) and 20min after furosemide test (OE40) and NORA at 20min (NORA20) and on the post-micturition acquisition (NORAPM). RESULTS: Both the above parameters (OE40 and NORAPM) had high sensitivity (92% and 97%), specificity (99% for both) and accuracy (95% and 98%) in differentiating between obstructed and dilated unobstructed kidneys. The test of NORAPM correctly reclassified 40 out of 41 indeterminate or false positive results of the conventional interpretations of renograms (CIR) as obstructed (12 cases) or dilated (28 cases). Cut-off values for obstruction were <80% and >=0.23 for OE40 and NORAPM, respectively. Compared to CIR, both parameters showed better specificity, especially NORAPM. CONCLUSION: Factors of OE40 and especially NORAPM of the renogram by 99mTc-DTPA were able to diagnose urine outflow obstruction better than CIR. Specifically, these factors well differentiated obstruction from urinary tract dilatation. PMID- 30006648 TI - Pituitary gland and bone involvement of Langerhans cell histiocytosis in a boy and brief review of the literature. AB - A 3 years old boy was hospitalized with a month's history of polydipsia, polyuria and low fever. There was no relevant family history. This is a rare case of Langerhans cell histiocytosis (LCH) with both bone and pituitary infiltration shown on the technetium-99m methylene diphosphonate (99mTc-MDP) scan and brain magnetic resonance imaging (MRI). Sagittal and coronal T1-weighted images on MRI showed the typical lack of high signal intensity of the posterior pituitary which corresponded to the central signs of diabetes insipidus (DI). The diagnosis of LCH was suspected by 99mTc-MDP whole-body bone scan showing multiple bone lesions. The disease was further confirmed by pathology of the biopsy specimen from the right tibia. Brain MRI and bone scan are indicated for pediatric patients with DI. The high signal intensity of the posterior pituitary on MRI and the bone lytic lesions on scintigraphy suggested the diagnosis of LCH. This paper is original because it is the first full description of bone and pituitary involvement detected by bone scan and brain MRI in a pediatric LCH. PMID- 30006647 TI - More than the prostate: Intrapancreatic accessory spleen and papillary thyroid cancer detected with 18F-PSMA PET/CT. AB - OBJECTIVE: Prostate specific membrane antigen (PSMA) positron emission tomography diagnostic computed tomography (PET/CT) is gaining an increasing role in the staging of prostate cancer and restaging in cases of biochemical recurrence. Our understanding of PSMA affinity for incidental pathological and non-pathological entities is also maturing although certain cases do present as diagnostic and management dilemmas. SUBJECT AND METHODS: We present a case of a 55 years old man with prostate adenocarcinoma, with incidentally found pancreatic and thyroid lesions showing PSMA avidity. RESULTS: We were able to utilize a heat damaged red blood cell single photon emission tomography (SPET)/CT scan and ultrasound guided fine needle aspiration (FNA) to accurately diagnose co-existent thyroid papillary carcinoma and intra-pancreatic accessory spleen (IPAS) tissue, respectively. The patient avoided invasive pancreatic tissue sampling and subsequent staging with fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT. CONCLUSION: This is the first case to our knowledge describing both such lesions in one patient and the first case describing the use of 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl) amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL)-PSMA PET/CT to detect IPAS. Furthermore we highlight the value of nuclear medicine diagnostic work up in complex cases. PMID- 30006649 TI - Bone scan findings in erythromelalgia. AB - The use of hyaluronic acid nanoshells has been proposed to encapsulate prodrugs and exploit the mechanisms of interactions between living cells, like endocytes or cancer cells and hyaluronic acid, which is a natural component of the extracellular matrix. In this review we describe the potential and the limits of this promising research trend and discuss the theoretical advantages of such an engineering approach. Is it a possible scalability to increase the efficacy and biodegradability of molecules like contrast media and radiotracers especially for neuroradiology and nuclear medicine studies. PMID- 30006650 TI - Erdheim-Chester disease diagnosed by 99mTc-MDP bone scintigraphy and brief literature review. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with lipid-laden macrophages and fibrosis. Although ECD is a multisystemic disease, the most common finding is sclerotic bone involvement in the diametaphyseal regions of bilateral distal femur and in proximal and distal tibia. We present a 40 years old woman who for the last two years had various systemic symptoms, especially knee pain, polyuria and polydipsia. Although a "hot knee" pattern was seen in bone scintigraphy (BS), a femur biopsy was performed, due to the preliminary diagnosis of haematologic malignancy. The biopsy specimen showed only intense fibrosis. One year later while the patient was in our clinic, BS showed characteristic for ECD bone involvement. Bone biopsy specimens stained in hematoxylin and eosin showed dense fibrosis but not histiocytosis. However, after immunohistochemical staining with CD-68, histiocytes were discerned. In conclusion, the authors underline that ECD was diagnosed at a second diagnostic attempt both clinically and by specific staining pathology specimens. PMID- 30006651 TI - Changes in esophageal mucosal morphology and in growth of breast feeding rats fed with milk of low or high temperature. AB - Dear Editor, This rather original investigation was performed some time ago but is still unpublished. Its aim was to estimate the effect of low or high temperature cow's milk given to breast feeding rats in order to study possible influence of this diet to rats, to their physical growth and also esophageal mucosal pathology. Ten white female Wistar rats, 20 days of age were separated from their mothers and divided in 2 groups of 5 members each. Five of them were fed with milk kept at 42oC by using a special warming device. The other 5 animals were fed with cold milk kept at 4oC during feeding. The duration of feeding was 34 days. Animals were finally sacrificed with a lethal dose of ether. The two groups were examined and compared. The group of rats fed by the warm milk was better grown as indicated by gaining more body weight, being more active and drinking more milk. Specimens were taken from the middle esophagus and after specific treatment were examined under the electronic microscope. We found: In both groups the most impressive finding in esophageal mucosa was an edematous intercellular space in all epithelial layers with many microorganisms in these layers. Acantholysis was often identified while in other areas a keratin transformation was noticed even in the basic layers, while basic membrane was absent. Epithelial cells showed edematous mitochondria and formation of myelin bodies. Degenerative changes and interstitial edema were noticed in the chorio. The above findings suggest that hot milk but not cold milk improves the growth of the rats studied. Cold and also hot milk had a damaging effect on the rats' esophageal mucosa. It is obvious that many options for further research arise related to the range of temperature of food intake that will not cause damage to gastric epithelium. PMID- 30006652 TI - [Acute neural hearing loss after cervical spine injection treatment]. AB - This article presents the case of a 39-year-old woman receiving injection therapy for cervicalgia. Due to accidental injection into the cervical spinal cord, the patient suffered from syncope, sensomotoric deficit, and bilateral neural hearing loss. Injection therapies for spinal disorders are routinely carried out in clinical practice, despite a low level of evidence and potentially severe complications. In the event of neuro-otologic complications, prompt evaluation by an otologist should be sought and rehabilitation initiated if necessary. PMID- 30006653 TI - Effect of the temperature of nasal lavages on mucociliary clearance: a randomised controlled trial. AB - BACKGROUND: The respiratory epithelium is mainly constituted by caliciform (produces mucus, responsible of keeping moisture and trapping particles) and ciliated cells (transports mucus into the pharynx, by the movement of multiple cilia). For centuries, nasal lavages have been used for different rhinosinusal conditions. Some studies suggest not only a direct effect on the mobilisation of secretions, but also an improvement in mucociliary clearance rates. To our knowledge, the impact of temperature in nasal lavages has been scarcely studied. METHODOLOGY/PRINCIPAL: We used the saccharin test-applying it in the inferior turbinate and timing the detection of its taste-, to estimate mucociliary clearance rates before and after nasal lavages with saline solution at room (20 degrees C) or body (37 degrees C) temperatures. RESULTS: 78 healthy subjects were studied, with a mean saccharin test time of 13.88 min. Then, a nasal lavage was performed, half with 20 degrees C saline and the other with 37 degrees C. In both, times improved from baseline (from 13.66 to 11.59 and 14.06 to 9.4 min, respectively) with p values < 0.05. CONCLUSIONS: Nasal lavages with saline solution improve mucociliary clearance as measured by saccharin test. Temperature seems to matter, which should be taken into account when indicating nasal lavages to our patients. PMID- 30006654 TI - Pullout fixation for medial meniscus posterior root tears: clinical results were not age-dependent, but osteoarthritis progressed. AB - PURPOSE: This study investigated the outcomes of pullout fixation for medial meniscus posterior root tears (MMPRTs) in patients <= 60 years old versus patients > 60 years old. It was hypothesized that older patients would demonstrate results comparable with those of younger patients. METHODS: Patients with pullout fixation who were followed-up for more than 5 years were included. Patients were categorized into two groups based on age (group A, <= 60 years; group B, > 60 years). The Lysholm score, Kellgren-Lawrence (K-L, 0/1/2/3/4) grade, and medial joint space width were evaluated retrospectively. Preoperative results were compared with the final results in each group, which were compared between groups. RESULTS: Twenty-five patients in group A (mean age, 54.7 +/- 3.8 years) and 22 patients in group B (mean age, 65.6 +/- 4.4 years) were recruited. The mean follow-up duration was 70.9 months. The Lysholm score (group A, 53.0 +/- 9.1 to 86.0 +/- 12.1, P < 0.001; group B, 51.1 +/- 7.1 to 82.9 +/- 9.7, P < 0.001) improved significantly. However, the joint space width (group A, 4.7 +/- 1.1 to 3.9 +/- 1.1 mm, P < 0.001; group B, 4.7 +/- 0.9 to 3.8 +/- 0.9 mm, P < 0.001) and K-L grade (group A, 3/17/5/0/0 to 0/7/11/7/0, P < 0.001; group B, 2/14/6/0/0 to 0/3/14/5/0, P < 0.001) worsened significantly. No significant differences between groups were observed in final outcomes, including Lysholm score (n.s.), K-L grade (n.s.), and joint space narrowing (n.s.). No case with operation failure that require total knee arthroplasty was not observed. CONCLUSION: MMPRT fixation did not prevent the progression of arthrosis completely. However, clinical outcomes were not age-dependent. Thus, age may not be a critical factor to consider when applying fixation. LEVEL OF EVIDENCE: Retrospective case-control study; Level of evidence, IV. PMID- 30006655 TI - Factors causing prolonged mechanical ventilation and peri-operative morbidity after robot-assisted coronary artery bypass graft surgery. AB - Robot-assisted coronary artery bypass graft [robot-assisted (coronary artery bypass grafting (CABG)] surgery is the latest treatment for coronary artery disease. However, the surgery extensively affects cardiac and pulmonary function, and the risk factors associated with peri-operative morbidity, including prolong mechanical ventilation (PMV), have not been fully examined. In this retrospective cohort study, a total of 382 patients who underwent robot-assisted internal mammary artery harvesting with mini-thoracotomy direct-vision bypass grafting surgery (MIDCABG) from 2005 to 2012 at our tertiary care hospital were included. The definition of PMV was failure to wean from mechanical ventilation more than 48 h after the surgery. Risk factors for PMV, and peri-operative morbidity and mortality were analyzed with a multivariate logistic regression model. Forty three patients (11.3%) developed PMV after the surgery, and the peri-operative morbidity and mortality rates were 38 and 2.6%, respectively. The risk factors for PMV were age, left ventricular ejection fraction (LVEF), the duration of one lung ventilation for MIDCABG (beating time), and peak airway pressure at the end of the surgery. Furthermore, age and anesthesia time were found to be independent risk factors for peri-operative morbidity, whereas age, LVEF, and anesthesia time were the risk factors for peri-operative mortality. These findings may help physicians to properly choose patients for this procedure, and provide more attention to patients with higher risk after surgery to achieve better clinical outcomes. PMID- 30006656 TI - Impact of the angiographic burden on the incidence of out-of-hospital ventricular fibrillation in patients with acute myocardial infarction. AB - Ventricular fibrillation (VF) is a catastrophic complication of spontaneous (type 1) acute myocardial infarction (AMI). This study sought to clarify the angiographic coronary characteristics related to out-of-hospital VF in AMI patients. We retrospectively reviewed 464 consecutive cases of suspicious AMI, including type 1 AMI, with or without out-of-hospital VF. In addition to patient demographics, proximal left coronary artery (LCA) disease, multivessel disease (MVD), and chronic total occlusion (CTO) were assessed via coronary angiography and compared between patients with and without out-of-hospital VF. Coronary angiography was evaluated for 74 patients with out-of-hospital VF and for 237 without. Male sex (93.2 vs. 83.1%; P = 0.036), Killip class >= 2 (89.2 vs. 16.5%; P < 0.001), and ST elevation myocardial infarction (83.8 vs. 66.7%; P = 0.003) were more frequent in the out-of-hospital VF group. The culprit lesions located in the proximal left coronary artery (62.2 vs. 29.5%; P < 0.001), MVD (75.7 vs. 41.8%, P < 0.001), and CTO (43.2 vs. 10.5%, P < 0.001) were more frequently observed in patients with out-of-hospital VF. Multivariate logistic regression analysis identified the culprit lesion located in the proximal LCA [odds ratio (OR) 2.86; 95% confidence interval (CI) 1.34-6.08], the presence of CTO (OR 8.52; 95% CI 3.35-21.65), and MVD (OR 3.69; 95% CI 1.57-8.65) as predictors of out-of hospital VF. For type 1 AMI patients, advanced disease burden including the culprit lesion located in the proximal LCA and coexistence of CTO or MVD might be associated with out-of-hospital VF. PMID- 30006657 TI - Evolution and expression patterns of the trehalose-6-phosphate synthase gene family in drumstick tree (Moringa oleifera Lam.). AB - MAIN CONCLUSION: Moringa oleifera TPSs were genome-wide identified for the first time, and a phylogenetic analysis was performed to investigate evolutionary divergence. The qRT-PCR data show that MoTPS genes response to different stress treatments. The trehalose-6-phosphate synthase (TPS) family is involved in a wide range of stress-resistance processes in plants. Its direct product, trehalose-6 phosphate, acts as a specific signal of sucrose status and a regulator to modulate carbon metabolism within the plant. In this study, eight TPS genes were identified and cloned based on the M. oleifera genome; only MoTPS1 exhibited TPS activity among Group I proteins. The characteristics of the MoTPS gene family were determined by analyzing phylogenetic relationships, gene structures, conserved motifs, selective forces, and expression patterns. The Group II MoTPS genes were under relaxed purifying selection or positive selection. The glycosyltransferase family 20 domains generally had lower Ka/Ks ratios and nonsynonymous (Ka) changes compared with those of trehalose-phosphatase domains, which is consistent with stronger purifying selection due to functional constraints in performing TPS enzyme activity. Phylogenetic analyses of TPS proteins from M. oleifera and 17 other plant species indicated that TPS were present before the monocot-dicot split, whereas Group II TPSs were duplicated after the separation of dicots and monocots. Quantitative real-time PCR analysis showed that the expression patterns of TPSs displayed group specificities in M. oleifera. Particularly, Group I MoTPS genes closely relate to reproductive development and Group II MoTPS genes closely relate to high temperature resistance in leaves, stem, stem tip and roots. This work provides a scientific classification of plant TPSs, dissects the internal relationships between their evolution and expressions, and promotes functional researches. PMID- 30006658 TI - From early beginnings to elaborate tools: contribution of German electrophysiology to the interventional treatment of cardiac arrhythmias : The German Cardiac Society welcomes ESC in Munich 2018. AB - Catheter ablation evolved from the early days of cardiac electrophysiology (EP), in which invasive electrophysiological studies were mainly a tool to find the correct diagnosis and to evaluate the most effective anti-arrhythmic drug for the patient. Today, catheter ablation is the most effective treatment option for patients suffering from supraventricular and ventricular arrhythmias. The understanding of cardiac arrhythmias and treatment strategies improved because of physicians and scientists from all over the world. The work of German cardiologists led to new achievements in the field of cardiac EP and catheter ablation. In this article, we summarize selective contributions of German EP centres in the field. PMID- 30006659 TI - High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. AB - Collagen synthesis is severely diminished in osteoarthritis; thus, enhancing it may help the regeneration of cartilage. This requires large amounts of glycine, proline and lysine. Previous works of our group have shown that glycine is an essential amino acid, which must be present in the diet in large amounts to satisfy the demands for collagen synthesis. Other authors have shown that proline is conditionally essential. In this work we studied the effect of these amino acids on type II collagen synthesis. Bovine articular chondrocytes were cultured under a wide range of different concentrations of glycine, proline and lysine. Chondrocytes were characterized by type II collagen immunocytochemistry of confluence monolayer cultures. Cell growth and viability were assayed by trypan blue dye exclusion method. Type II collagen was measured in the monolayer, every 48 h for 15 days by ELISA. Increase in concentrations of proline and lysine in the culture medium enhances the synthesis of type II collagen at low concentrations, but these effects decay before 1.0 mM. Increase of glycine as of 1.0 mM exceeds these effects and this increase continues more persistently by 60 75%. Since the large effects produced by proline and lysine are within the physiological range, while the effect of glycine corresponds to a much higher range, these results demonstrated a severe glycine deficiency for collagen synthesis. Thus, increasing glycine in the diet may well be a strategy for helping cartilage regeneration by enhancing collagen synthesis, which could contribute to the treatment and prevention of osteoarthritis. PMID- 30006660 TI - Intestinal microbiome as a risk factor for urinary tract infections in children. AB - As urinary tract infection (UTI) pathogens originate from the gut, we hypothesized that the gut environment reflected by intestinal microbiome influences the risk of UTI. Our prospective case-control study compared the intestinal microbiomes of 37 children with a febrile UTI with those of 69 healthy children. We sequenced the regions of the bacterial 16S rRNA gene and used the LefSe algorithm to calculate the size of the linear discriminant analysis (LDA) effect. We measured fecal lactoferrin and iron concentrations and quantitative PCR for Escherichia coli. At the phylum level, there were no significant differences. At the genus level, Enterobacter was more abundant in UTI patients with an LDA score > 3 (log 10), while Peptostreptococcaceae were more abundant in healthy subjects with an LDA score > 3 (log 10). In total, 20 OTUs with significantly different abundances were observed. Previous use of antimicrobials did not associate with intestinal microbiome. The relative abundance of E. coli was 1.9% in UTI patients and 0.5% in controls (95% CI of the difference-0.8 to 3.6%). The mean concentration of E.coli in quantitative PCR was 0.14 ng/MUl in the patients and 0.08 ng/MUl in the controls (95% CI of the difference-0.04 to 0.16). Fecal iron and lactoferrin concentrations were similar between the groups. At the family and genus level, we noted several differences in the intestinal microbiome between children with UTI and healthy children, which may imply that the gut environment is linked with the risk of UTI in children. PMID- 30006662 TI - Current state of the art in continuous bioprocessing. AB - There is an upsurge of interest in continuous bioprocessing, but currently continuous downstream bioprocessing has not been implemented to generate clinical material. This review focusses on the current state of the art of continuous downstream processing, highlighting the key advantages over traditional batch manufacturing. This allows the identification of scenarios where continuous downstream processing may be critical for commercial manufacturing success. PMID- 30006661 TI - [Importance of phototherapy in the treatment of chronic pruritus]. AB - Phototherapy and photochemotherapy (PUVA) are important treatment modalities in inflammatory skin diseases such as psoriasis and atopic dermatitis as well as in cutaneous T-cell lymphoma (e.g., mycosis fungoides/Sezary syndrome). Many of these skin diseases are accompanied by distracting pruritus. In addition, patients may suffer from intense pruritus in systemic diseases of the kidney and liver as well as of the endocrine and hematopoietic system. UV-light during phototherapy is capable of not only improving the inflammatory skin lesions but also of reducing the pruritus in skin and systemic diseases. The significant antipruritic effect, the usually low rate of well-known side effects, as well as the possibility to treat adults of any age, pregnant and lactating women, and under certain circumstances also children, make phototherapy a valuable treatment option for pruritus of various origin. Thus, the use of phototherapy should be considered early in the course of antipruritic therapy, when topical treatment modalities are insufficient to significantly improve pruritus. PMID- 30006663 TI - Functional brain mapping: overview of techniques and their application to neurosurgery. AB - Functional brain mapping (FBM) is an integral part of contemporary neurosurgery. It is crucial for safe and optimal resection of brain lesions like gliomas. The eloquent regions of the cortex like motor, somatosensory, Wernicke's, and Broca are usually mapped, either preoperatively or intraoperatively. Since its birth in the nineteenth century, FBM has witnessed immense modernization, radical refinements, and the introduction of novel techniques, most of which are non invasive. Direct electrical stimulation of the cortex, despite its high invasiveness, remains the technique of choice. Non-invasive techniques like fMRI and magnetoencephalography allow us the convenience of multiple mappings with minimal discomfort to the patients. They are quick, easy to do, and allow thorough study. Different modalities are now being combined to yield better delineations like fMRI and diffusion tensor imaging. This article reviews the physical principles, applications, merits, shortcomings, and latest developments of nine FBM techniques. Other than neurosurgical operations, these techniques have also been applied to studies of stroke, Alzheimer's, and cognition. There are strong indications that the future of brain mapping shall see the non invasive techniques playing a more dominant role as they become more sensitive and accurate due to advances in physics, refined algorithms, and subsequent validation against invasive techniques. PMID- 30006665 TI - Assessing health-related quality of life in patients with breast cancer: a reply to Ribi et al. PMID- 30006664 TI - The impact of depression on health-related quality of life and wellbeing: identifying important dimensions and assessing their inclusion in multi-attribute utility instruments. AB - PURPOSE: Wellbeing measures have been proposed for inclusion in economic evaluation to measure the effect of depression and compensate for shortcomings of existing multi-attribute utility instruments (MAUIs). The aims of this study were to identify dimensions of health-related quality of life (HRQoL) and wellbeing that are most affected by depression and to examine the extent to which these are captured by MAUIs. METHODS: Data were used from the Multi-Instrument Comparison study. Dimensions of HRQoL (SF-36v2 and AQoL-8D dimensions), capability wellbeing (ICECAP-A), and subjective wellbeing (including PWI, SWLS, and IHS) were identified that distinguished most individuals with depression from a healthy public. The extent to which these dimensions explain the content of five existing MAUIs (15D, AQoL-8D, EQ-5D-5L, HUI-3, and SF-6D) was examined using regression analyses. Additionally, the sensitivity of all MAUIs was also assessed towards depression-specific symptoms measured by DASS-21 and K-10. RESULTS: The sample consisted of 917 individuals with self-reported depression and 1760 healthy subjects. Dimensions that distinguished most individuals with depression from the healthy group (effect size > 2) included AQoL-8D coping, AQoL-8D happiness, AQoL 8D self-worth, ICECAP-A, SF-36 mental health, and SF-36 social functioning. The AQoL-8D was most sensitive to the dimensions above as well as towards the depression-specific measures, the K10, DASS-S, and DASS-D. CONCLUSIONS: This study has shown that psychosocial dimensions of HRQoL have the greatest ability to capture the impact of depression when compared with dimensions of capability wellbeing and SWB. Some MAUIs, such as the AQoL-8D, are sensitive to most distinguishing dimensions of HRQoL and wellbeing, which may obviate the need for supplementary wellbeing instruments. PMID- 30006666 TI - Correlation of CT imaging and histology to guide bone graft selection in scaphoid non-union surgery. AB - INTRODUCTION: For the treatment of scaphoid non-unions (SNU), different surgical techniques, including vascularized and non-vascularized bone grafts, are applied. Besides stability, vascularity, and the biological situation at the non-union site are important for healing and the appropriate choice of treatment. We assessed the healing potential of SNUs by histological parameters and compared it to CT parameters of bone structure and fracture location. Based on the results, we developed a CT classification and a treatment algorithm to impact graft selection in SNU surgery. PATIENTS AND METHODS: Preoperative 2D-CT reformations of 29 patients were analyzed for trabecular structure, sclerosis, and fragmentation of the proximal fragment. The fracture location was assessed on 3D CT reconstructions and grouped in three zones depending on the potential blood supply. Samples were taken during surgery for histological evaluation. Histological parameters of bone healing were defined and a bone healing capacity score (BHC), reflecting histological bone viability, was calculated. CT findings were compared to BHC, age of SNU, and time to union. RESULTS: Cases with trabecular structure and without fragmentation showed a statistically significant higher BHC. Time to union was significantly faster if trabecular structure was present and sclerosis was absent. In intraarticular proximal pole non-unions, where no blood supply is assumed, the BHC was statistically significantly lower and time to union was longer compared to SNUs of the other locations. A statistically significant correlation between BHC and time to union was found in the proximal and distal fragment with higher BHC associated with faster healing. CONCLUSIONS: CT parameters of bone structure and fracture location can reflect histological healing capacity of SNUs. This can guide bone graft selection in SNU surgery. PMID- 30006667 TI - Development of Friendship and Task Values in a New School: Friend Selection for the Arts and Physical Education but Socialization for Academic Subjects. AB - Friends provide important social contexts for student development. Research has shown that adolescent friends are similar to each other in their interest and values for different school subjects. Yet our current understanding does not extend to knowing whether selection, deselection, or socialization processes are responsible for this phenomena. Without this knowledge, it is very difficult for parents, teachers, and schools to know how and when to intervene. This study investigated selection, deselection, and socialization effects on adolescent students' task values for academic (languages, math and science, and social sciences) and non-academic subject areas (the arts and physical education). A social network approach was used to examine two waves of annual data collected from school-based networks of adolescents in the first and second years of high school education in Finland (N = 1419; female = 48.6%; mean age at first measurement point = 16). The results revealed that adolescents tended to select friends with similar levels of task values (friend selection) for the arts and physical education, but friends did not become more similar in these areas over time (friend socialization). In contrast, there was evidence of friend socialization, but not friend selection, for the academic school subjects. Across all subjects, differences in task values did not predict friendship dissolution (friend deselection). These findings suggest that to a significant extent, students make agentic choices in developing friendship with schoolmates based on their task values in non-academic subjects. The resultant friend contexts that individuals created, in turn, affected their task values in academic subject areas. These results shed light on the complexity of friend effect mechanisms on task values at the subject domain-specific level. PMID- 30006668 TI - Trajectories of Social and Emotional Competencies according to Cyberbullying Roles: A Longitudinal Multilevel Analysis. AB - Current cyberbullying literature lacks longitudinal studies clarifying its predictors and consequences. This 1-year longitudinal study investigated how social and emotional competencies develop according to Portuguese middle school students' involvement in cyberbullying, and whether class size influences this relationship. There were 455 participants (Mage = 12.58; SD = 0.94; 46% girls), and data collection through self-reports took place in three different moments during 12 months. The results showed that students involved in cyberbullying in any role displayed negative trajectories during 1 year in self-control and social awareness, while victims and bully-victims displayed a more pronounced decrease in self-esteem and relationship skills during the same period. Additionally, girls displayed higher initial social awareness levels, while larger classes were associated with higher levels of self-control and responsible decision making. These results supported the importance of conducting longitudinal research and using a multilevel approach to address this topic. PMID- 30006669 TI - Exercise-induced trunk fatigue decreases double poling performance in well trained cross-country skiers. AB - PURPOSE: To examine the effects of exercise-induced trunk fatigue on double poling performance, physiological responses and trunk strength in cross-country skiers. METHODS: Sixteen well-trained male cross-country skiers completed two identical pre- and post-performance tests, separated by either a 25-min trunk fatiguing exercise sequence or rest period in a randomized, controlled cross-over design. Performance tests consisted of a maximal trunk flexion and extension test, followed by a 3-min double poling (DP) test on a ski ergometer. RESULTS: Peak torque during isometric trunk flexion (- 66%, p < .001) and extension (- 7.4%, p = .03) decreased in the fatigue relative to the control condition. Mean external power output during DP decreased by 14% (p < .001) and could be attributed both to reduced work per cycle (- 9%, p = .019) and a reduced cycle rate (- 6%, p = .06). Coinciding physiological changes in peak oxygen uptake (- 6%, p < .001) and peak ventilation (- 7%, p < .001) could be observed. Skiers chose a more even-pacing strategy when fatigued, with the performance difference between fatigue and control condition being most prominent during the first 2 min of the post-test. CONCLUSIONS: In well-trained cross-country skiers, exercise induced trunk fatigue led to a substantial decrease in DP performance, caused by both decreased work per cycle and cycle rate and accompanied by reduced aerobic power. Hence, improved fatigue resistance of the trunk may therefore be of importance for high-intensity DP in cross-country skiing. PMID- 30006670 TI - Muscle fatigue in response to low-load blood flow-restricted elbow-flexion exercise: are there any sex differences? AB - PURPOSE: This study aimed to determine whether men and women display a different magnitude of muscle fatigue in response to high-load (HL) and low-load blood flow restricted (LLBFR) elbow-flexion exercise. We also explored to which extent both exercise protocols induce similar levels of muscle fatigue (i.e., torque decrement). METHODS: Sixty-two young participants (31 men and 31 women) performed dynamic elbow flexions at 20 and 75% of one-repetition maximum for LLBFR and HL exercise, respectively. Maximum voluntary isometric contractions were performed before and after exercise to quantify muscle fatigue. RESULTS: Men and women exhibited similar magnitude of relative torque decrement after both exercise protocols (p > 0.05). HL was more fatiguing (? torque output: 11.9 and 23 N.m in women and men, respectively) than LLBFR resistance exercise (? torque output: 8.3 and 15.4 N.m in women and men, respectively) in both sexes, but this was largely attenuated after controlling for the differences in volume load between protocols (p > 0.05). CONCLUSIONS: These data show that torque decrement in response to LLBFR and HL dynamic elbow-flexion exercise does not follow a sexually dimorphic pattern. Our data also indicate that, if performed in a multiple-set fashion and prescribed for a given volume load, elbow-flexion LLBFR exercise induces similar levels of fatigue as HL acute training. Importantly, this occurs similarly in both sexes. PMID- 30006672 TI - Efficacy and acceptability of psychological interventions for social anxiety disorder in children and adolescents: a meta-analysis of randomized controlled trials. AB - Social anxiety disorder (SAD) is highly prevalent and persistent in children and adolescents. However, evidence for the efficacy and acceptability of psychological interventions for SAD in children and adolescents remains unclear. Seven electronic databases (PubMed, CENTRAL, Embase, Web of Science, PsycINFO, CINAHL, and ProQuest) were searched. Randomized controlled trials (RCTs) that compared psychological interventions for SAD with control conditions in children and adolescents were included. Primary outcomes were the efficacy (mean change in anxiety symptom scores) and acceptability (dropouts for all reasons). Secondary outcomes were remission, quality of life/functional improvement, and depressive symptoms measures. Seventeen RCTs were included in this meta-analysis. Psychological interventions (including cognitive behavioral therapy and behavioral therapy) were significantly more effective than control conditions, with a standardized mean difference (SMD) of - 1.13, and remission with a risk ratio (RR) of 8.99, the number needed to treat was 3.3. There was no statistically significant difference between psychological interventions and control conditions for all-cause dropouts (RR = 1.00). Psychological interventions were superior to control conditions in improving quality of life/functioning (SMD = 0.79) and reducing depressive symptoms (SMD = - 0.39). Given considerable heterogeneity of primary efficacy outcome, a series of subgroup analyses of different variables were conducted. Psychological interventions are probably efficacious in the treatment of SAD among children and adolescents, and may markedly improve quality of life and functioning in this population. However, this finding should be interpreted with caution because of the high heterogeneity of trials and low literature quality. PMID- 30006671 TI - Muscle health and performance in monozygotic twins with 30 years of discordant exercise habits. AB - INTRODUCTION: Physical health and function depend upon both genetic inheritance and environmental factors (e.g., exercise training). PURPOSE: To enhance the understanding of heritability/adaptability, we explored the skeletal muscle health and physiological performance of monozygotic (MZ) twins with > 30 years of chronic endurance training vs. no specific/consistent exercise. METHODS: One pair of male MZ twins (age = 52 years; Trained Twin, TT; Untrained Twin, UT) underwent analyses of: (1) anthropometric characteristics and blood profiles, (2) markers of cardiovascular and pulmonary health, and (3) skeletal muscle size, strength, and power and molecular markers of muscle health. RESULTS: This case study represents the most comprehensive physiological comparison of MZ twins with this length and magnitude of differing exercise history. TT exhibited: (1) lower body mass, body fat%, resting heart rate, blood pressure, cholesterol, triglycerides, and plasma glucose, (2) greater relative cycling power, anaerobic endurance, and aerobic capacity (VO2max), but lower muscle size/strength and poorer muscle quality, (3) more MHC I (slow-twitch) and fewer MHC IIa (fast-twitch) fibers, (4) greater AMPK protein expression, and (5) greater PAX7, IGF1Ec, IGF1Ea, and FN14 mRNA expression than UT. CONCLUSIONS: Several measured differences are the largest reported between MZ twins (TT expressed 55% more MHC I fibers, 12.4 ml/kg/min greater VO2max, and 8.6% lower body fat% vs. UT). These data collectively (a) support utilizing chronic endurance training to improve body composition and cardiovascular health and (b) suggest the cardiovascular and skeletal muscle systems exhibit greater plasticity than previously thought, further highlighting the importance of studying MZ twins with large (long-term) differences in exposomes. PMID- 30006673 TI - The developmental course of inattention symptoms predicts academic achievement due to shared genetic aetiology: a longitudinal twin study. AB - Symptoms of attention-deficit hyperactivity disorder, in particular inattention symptoms, are associated with academic achievement. However, whether and why the developmental course of inattention symptoms (i.e. systematic decreases or increases of symptoms with age) predicts academic achievement remains unclear. A total of 5634 twin pairs born in the UK were included in the current study. We used latent growth curve modelling to estimate the baseline level and the developmental course of inattention symptoms (assessed at ages 8, 11, 14 and 16 years) and test whether they predicted the General Certificate of Secondary Education scores (GCSE, at age 16 years). We then implemented multivariate twin modelling to determine the role of genetic and environmental factors in explaining the relationship between inattention symptoms and GCSE scores. Increasing inattention symptoms across childhood and adolescence predicted poorer GCSE scores independently of the baseline level of inattention. Genetic factors explained most of this relationship, i.e. genetic factors contributing to individual differences in the developmental course of inattention also influenced GCSE scores. In conclusion, our study demonstrates that genetic factors underlying the developmental course of inattention symptoms across childhood and adolescence also influence academic achievement. This may result from indirect mechanism, whereby genetic factors explain systematic changes in inattention levels with age, which in turn impact academic achievement. The shared genetic aetiology may also suggest common neurobiological processes underlying both the developmental course of inattention symptoms and academic achievement. PMID- 30006674 TI - Baseline 18F-Fluorocholine PET/CT and bone scan in the outcome prediction of patients treated with radium 223 dichloride. AB - AIM: To establish the utility of baseline 18F-Fluorocholine (FCH) PET/CT and bone scintigraphy (BS) in the outcome prediction of patients with castration-resistant prostate cancer and bone metastases (CRPC-BM) treated with 223Ra. METHODS: Prospective, multicenter and non-randomized study (ChoPET-Rad study). FCH PET/CT and BS were performed before the initiation of 223Ra (basal FCH PET/CT and BS). Bone disease was classified attending the number of lesions in baseline BS and PET/CT. FCH PET/CT was semiquantitatively evaluated. Gleason score, baseline levels of prostate-specific antigen (PSA), alkaline phosphatase and lactate dehydrogenase were determined. Progression-free survival (PFS) and overall survival (OS) since the onset of 223Ra treatment was calculated. PFS was defined by PSA rising. Relations between clinical and imaging variables with PFS and OS were evaluated by Pearson, Mann-Whitney tests and Kapplan-Meier analysis. Univariate and multivariate Cox regression analysis was performed. RESULTS: Forty patients were evaluated. The median PFS and OS were of 3.0 +/- 2.3 and 23.0 +/- 4.2 months, respectively. 33 patients progressed and 13 died during the follow up. The extension of the bone disease by FCH PET/CT (p = 0.011, chi2 = 10.63), BS (p = 0.044, chi2 = 8.04), SUVmax (p = 0.012) and average SUVmax (p = 0.014) were related to OS. No significant association was found for the PFS. ROC analysis revealed significant association of SUVmax, average SUVmax and basal PSA with OS. Only therapeutic failure was associated with OS in the multivariate analysis (HR = 3.6, p = 0.04). CONCLUSION: FCH PET/CT and BS had prognostic aim in the prediction of OS. None clinical or imaging variable was able to predict the PFS, probably due to the high rate of progressive disease. PMID- 30006676 TI - A quantitative tool to establish magic number clusters, epsilon3, applied in small silicon clusters, Si2-11. AB - The present work focuses on establishing a function to rank the stability of small silicon clusters to characterize their magic numbers. This function is composed by a thermodynamic descriptor, the atomization Gibbs free energy, and indirect kinetic descriptors, the highest occupied molecular orbital energy and the lowest excitation energy of each system. The silicon clusters geometries were optimized using density functional theory within a hybrid meta-GGA approximation (M06), while the electronic energy was corrected by single-point calculation using CASPT2 level of theory to obtain the molecular properties. Both methodologies were combined with polarized diffused triple zeta, 6 311++G(3df,3pd), basis set for all atoms. Some molecular properties and their combinations were considered to create the aforementioned function to represent the clusters chemical stability and their magic numbers. The chosen stability ranking function, called epsilon3, presents results in agreement with the previous mass spectrometry experimental data identifying 4, 6, 7 and 10 as magic numbers for small silicon clusters. We believe this stability ranking function can be useful to study other intramolecular atomic and molecular clusters. Graphical abstract Stability ranking function, epsilon31, applied on Sin (n = 2 - 11) clusters showing Fukui's functions for the Sin (n = 2 - 11) obtained by the electronic density difference through CASPT2//M06/6-311++G(3df,3pd) with an isosurface value equal to 0.003. PMID- 30006675 TI - A paper-based optical probe for chromium by using gold nanoparticles modified with 2,2'-thiodiacetic acid and smartphone camera readout. AB - A paper based analytical device is presented for the determination of Cr(III) and Cr(VI) using gold nanoparticles (AuNPs) modified with 2,2'-thiodiacetic acid. The modified AuNPs were characterized using UV-Vis spectrophotometry, Fourier transform infrared, dynamic light scattering, zeta potential, energy dispersive spectroscopy and transmission electron microscopy. Cr(III) ions induce the aggregation of the modified AuNPs, and the color of the nanoprobe changes from red to blue. This can be detected visually, or by colorimetry, or with a camera. No interference is observed in the presence of 19 other cations and anions. Cr(VI) (chromate) can be determined by after reduction to Cr(III) by using ascorbic acid and then quantified total Cr(III). The concentration of Cr(VI) is obtained by subtracting the concentration of Cr(III) from that of total chromium. Under optimal conditions, the ratio of the absorbances measured at 670 (blue) and 522 (red) increases linearly in the 1.0 nM to 22.1 MUM chromium concentration range, with 0.66 nM (0.034 ppb) limit of detection (LOD) in solution. In case of the paper device, the linear range extends from 1.0 nM to 0.1 mM, and the LOD is 0.64 nM (0.033 ppb). The method was applied to the determination of chromium in spiked water, urine and dilutes human plasma, and results were confirmed by GF AAS analysis. This method is highly selective, fast and portable, requires minimum volume of reagents and samples and no washing steps. Graphical abstract A paper based analytical device is presented for determination of Cr(III) and Cr(VI) using gold nanoparticles modified with 2,2'-thiodiacetic acid. In paper optical probe, linear range and limit of detection are 1.0 nM to 0.1 mM and 0.64 nM, respectively. The method was applied to the determination of total chromium in spiked water, urine and dilutes human plasma, and results were confirmed by GF AAS analysis. PMID- 30006677 TI - Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile. PMID- 30006678 TI - A magnetic beads-based portable flow cytometry immunosensor for in-situ detection of marine biotoxin. AB - Okadaic acid (OA), a representative diarrhetic shellfish poisoning toxin, mainly produced by toxigenic dinoflagellates, has significant hazard to public health. Traditional methods for detection of OA can not give the consideration to the need of rapid, high sensitive, quantitative and in-situ detection at the same time. Herein, a new effective detection method of OA was developed based on fluorescence immunosensor and flow cytometry (FCM). In this assay, Streptavidin coated magnetic beads (MBs) were used as the supporter to immobilize the biotinylated OA. Modified MBs competed with the free OA in the sample solution to bind with the anti-OA monoclonal antibody (OA-MAb). The R-phycoerythrin (R-PE) dye labeled IgG was served as a secondary antibody to perform fluorescence detection. A portable flow cytometry was applied for the in-situ fluorescence quantification. The results showed that the OA concentration was inversely proportional to the R-PE fluorescence intensity. The detection method took within 50 min with a limit of detection (LOD) was 0.05 MUg/L and range from 0.2 to 20 MUg/L for OA detection. Moreover, the matrix effect and the recovery rate were assessed during real sample measurement, showing a high recovery. Performance features such as high sensitivity, low LOD, speediness and simplicity of the analysis protocol, shows this biosensing-systems as a promising tool for routine use. PMID- 30006679 TI - Dose Escalation with Simultaneous Integrated Boost (SIB) Using Volumetric Modulated Arc Therapy (VMAT) in Rectal Cancer. AB - PURPOSE: Assess feasibility-rate of PCR, short-term toxicity after neoadjuvant concurrent chemoradiation (NACRT) delivered via simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique for locally advanced rectal cancer. METHODS: Retrospective evaluation of patients with locally advanced rectal cancer treated with VMAT-SIB technique preoperatively at an academic tertiary care center in Riyadh, Saudi Arabia between February 2013 and March 2017. RESULTS: One hundred patients with depth of invasion staged as T3/T4 or T2 in 93 and seven patients, respectively. Lymph node metastasis was staged as N1/N2 or N0 in 87 and 13 patients, respectively. Circumferential radial margin (CRM) was involved radiologically prior to treatment in 50 patients. A dose of 55 or 50 Gy was given to 71 and 29 patients, respectively. All treatments were completed without interruption. Grade 3/4 toxicity was not observed. Low anterior resection and abdominoperineal resection were performed with negative proximal, distal, and radial margins in 72 and 28 patients, respectively. There were no immediate significant postoperative complications. Histologically, no residual tumor (grade 0) was noted in 20 patients (pCR). Regression grade 1, 2, and 3 were noted in 31, 34, and 15 patients. Average number of lymph nodes retrieved in the surgical specimen was 12 (range 6-22). Lymph nodes were negative for cancer in 80 patients. CONCLUSION: Dose escalation with SIB-VMAT as NACRT for rectal cancer is feasible. Moreover, it can increase the rate of pathological complete response with a favorable toxicity profile. Clinical benefit of this approach needs to be validated in a larger cohort of patients with longer follow up. PMID- 30006680 TI - Responses of the zooplankton community to peak and waning periods of El Nino 2015 2016 in Kavaratti reef ecosystem, northern Indian Ocean. AB - The study addressed the impact of the El Nino 2015-2016 on the ecosystem functioning and the subsequent effects on the distribution and community structure of zooplankton in the Kavaratti reef, a prominent coral atoll in the tropical Indian Ocean. The elevated ocean temperature (SST) associated with El Nino resulted in a mass bleaching event affecting > 60% of the live corals of the Kavaratti atoll. The concomitant changes observed in the nutrient concentration, coral health, and phytoplankton of the reef environment during the course of the El Nino led to discernible variations in the zooplankton community with markedly higher abundance and heterogeneity in distribution during the peak period of El Nino compared to its waning phase. A notable shift was also evident in the community structure of Copepoda, the dominant zooplankton taxon, with a predominance of calanoids and poecilostomatoids in the peak period and by harpacticoid copepods in the waning phase of the El Nino. The harpacticoid, Macrosetella gracilis, dominated in the waning phase because of their unique adaptability in the utilization of Trichodesmium erythraeum, both as nutritional and physical substrates in the nutrient-depleted environment of the reef ecosystem. PMID- 30006682 TI - Chlorogenic Acid Prevents AMPA-Mediated Excitotoxicity in Optic Nerve Oligodendrocytes Through a PKC and Caspase-Dependent Pathways. AB - In the CNS, including the optic nerve, oligodendrocytes play a critical role in the myelination of axons. Oligodendrocytes are exceptionally sensitive to insults to the CNS, such as injury, ischemia, or inflammation, which result in the loss of oligodendrocytes and myelin and eventually secondary axon degeneration. Oligodendrocytes are sensitive to excitotoxic insults mediated by overactivation of their AMPA ionotropic glutamate receptors. Phenolic compounds, which are widely distributed in fruits and vegetables, received the great attention of scientists due to their antioxidant activities and free radical scavenging abilities. Chlorogenic acid (CGA) has been demonstrated to possess potent neuroprotective activities against oxidative stress in various cellular models and pathological conditions. Hence, CGA protect against oxidative stress and excitotoxic insults mediated by AMPA receptors and that the protective mechanisms involve free radical scavenging, Ca2+ handling in the cytosol, and modulating antioxidant enzyme system. CGA was associated with the protein kinase A (PKC) signaling pathways transduction. Caspases and calpains have been studied as apoptotic mediators and cell death in this model of AMPA toxicity. Inhibitors of caspases initiators, caspases 1, 8, and 9, the upstream of caspase 3 effectors, have totally abrogated the protective activity of CGA. Inhibitors of calpains also totally abrogated the protective activity of CGA. In addition, a potential role for the CGA in inhibiting Bax in oligodendrocyte cell model undergoing AMPA is inducing excitotoxic death. Our results indicate that CGA exhibits a protective potential via antioxidant and apoptosis caspases and calpains dependent against AMPA-mediated excitotoxicity, and these finding indicate that CGA is able to be a good candidate for preventive approach for neurodegenerative disorders associated with loss and damage in oligodendrocytes and AMPA-mediated excitotoxicity. PMID- 30006681 TI - Molecular biology as a tool for the treatment of cancer. AB - Cancer is a genetic disease characterized by uncontrolled cell growth and metastasis. Cancer can have a number of causes, such the activation of oncogenes, the inactivation of tumor-suppressing genes, mutagenesis provoked by external factors, and epigenetic modifications. The development of diagnostic tools and treatments using a molecular biological approach permits the use of sensitive, low-cost, noninvasive tests for cancer patients. Biomarkers can be used to provide rapid, personalized oncology, in particular the molecular diagnosis of chronic myeloid leukemia, and gastric, colon, and breast cancers. Molecular tests based on DNA methylation can also be used to direct treatments or evaluate the toxic effects of chemotherapy. The adequate diagnosis, prognosis, and prediction of the response of cancer patients to treatment are essential to ensure the most effective therapy, reduce the damaging effects of treatment, and direct the therapy to specific targets, and in this context, molecular biology has become increasingly important in oncology. In this brief review, we will demonstrate the fundamental importance of molecular biology for the treatment of three types of cancer-chronic myeloid leukemia, hereditary diffuse gastric cancer, and astrocytomas (sporadic tumors of the central nervous system). In each of these three models, distinct biological mechanisms are involved in the transformation of the cells, but in all cases, molecular biology is fundamental to the development of personalized analyses for each patient and each type of neoplasia, and to guarantee the success of the treatment. PMID- 30006684 TI - Nicotine-Induced Neuroprotection in Rotenone In Vivo and In Vitro Models of Parkinson's Disease: Evidences for the Involvement of the Labile Iron Pool Level as the Underlying Mechanism. AB - Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Clinical and experimental evidence suggest that the activation of the nicotinic acetylcholine receptor (nAChR) could be protective for PD. In this study, we investigated the neuroprotective capacity of nicotine in a rat PD model. Considering that iron metabolism has been implicated in PD pathophysiology and nicotine has been described to chelate this metal, we also studied the effect of nicotine on the cellular labile iron pool (LIP) levels. Rotenone (1 MUg) was unilaterally injected into the median forebrain bundle to induce the degeneration of the nigrostriatal pathway. Nicotine administration (1 mg/K, s.c. daily injection, starting 5 days before rotenone and continuing for 30 days) attenuated the dopaminergic cell loss in the SNpc and the degeneration of the dopaminergic terminals provoked by rotenone, as assessed by immunohistochemistry. Furthermore, nicotine partially prevented the reduction on dopamine levels in the striatum and improved the motor deficits, as determined by HPLC-ED and the forelimb use asymmetry test, respectively. Studies in primary mesencephalic cultures showed that pretreatment with nicotine (50 MUM) improved the survival of tyrosine hydroxylase-positive neurons after rotenone (20 nM) exposure. Besides, nicotine induced a reduction in the LIP levels assessed by the calcein dequenching method only at the neuroprotective dose. These effects were prevented by addition of the nAChRs antagonist mecamylamine (100 MUM). Overall, we demonstrate a neuroprotective effect of nicotine in a model of PD in rats and that a reduction in iron availability could be an underlying mechanism. PMID- 30006683 TI - Telmisartan Ameliorates Astroglial and Dopaminergic Functions in a Mouse Model of Chronic Parkinsonism. AB - Many studies reported the neuroprotective effects of angiotensin II type 1 receptor (AT1R) antagonists in Parkinson's disease (PD). However, the role of AT1R blockade on astroglial, in turn, dopaminergic functions in chronic PD is still to be studied. In the present study, telmisartan (TEL; 3 and 10 mg/kg/day; p.o), was used to study the effects AT1R blockade on astrocytic and dopaminergic functions in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinsonism (250 mg/kg, i.p, in 10 equally divided doses at 3.5 days interval) in C57BL/6 J mice. TEL significantly downregulated glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), TNFalpha and IL1beta expressions and nitric oxide (NO) content. Significant upregulation glial cell derived neurotrophic factor (GDNF) expression and increased glutathione (GSH) content reveal the ameliorating effects of TEL on astroglial functions. On the other hand, TEL upregulated tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) expressions. Finally, TEL improved dopamine and its turnover and restored locomotor performance. Present experiment reveals that TEL has the potential to alleviate astroglial functions, apart from restoring dopaminergic functions, at least in part. To conclude, TEL may be a better disease-modifying therapeutic regimen in the management of Parkinsonism, acting primarily via astroglial-dopaminergic functions. PMID- 30006685 TI - Factors influencing the effective dose associated with CBCT: a systematic review. AB - INTRODUCTION: Due to potential impact of the effects of ionizing radiation used in medical and dental examinations on public health in recent years, many studies are being conducted to quantify the radiation dose values, evaluate scanners, and indicate factors that could influence or reduce radiation doses. OBJECTIVES: This study aimed to evaluate, by a systematic review, the factors that influence the effective radiation dose associated with cone beam computed tomography and respective effects, and compared the effective dose of different cone beam computed tomography (CBCT) scanners with similar exposure parameters. MATERIALS AND METHODS: A search was conducted on five databases from 2007 to 2015. RESULTS: The search identified 741 abstracts, among which 44 eligible articles were retrieved in full text. Twenty-three studies met the inclusion criteria and were included. Additional copper filter was evaluated in one study, patient size in 2 studies, region of interest in 1 study, use of a thyroid shield in 2 studies, scan angle in 3 studies, exposure time in 10 studies, FOV diameter in 17 studies, FOV height in 17 studies, kV in 16 studies, mA in 18 studies, mAs in 13 studies, voxel in 8 studies, and resolution in 3 studies. When similar exposure parameters were evaluated, it was observed that CBCT scanner with lower effective dose was Kodak(r) 9000C 3D (mean 21.2 MUSv) in selected studies. CONCLUSIONS: Thirteen factors were related to changes in the effective dose emitted by different scanners. More studies are needed to identify the image quality requirements in addition to measure the radiation. CLINICAL RELEVANCE: Studies that give more information for professionals who request and interpret the exams and for technicians who perform 3D images about effective radiation dose associated with CBCT are necessary. PMID- 30006686 TI - Oral findings in children and adolescents with Prader-Willi syndrome. AB - OBJECTIVE: To assess the significance of changes in the saliva in the etiology of gingivitis and tooth wear in children and adolescents with Prader-Willi syndrome (PWS). MATERIALS AND METHODS: The study included 80 (2.8-18 years old; 39 girls and 41 boys): 40 in PWS group (mean age 8.0 +/- 4.24 years) and 40 in control group (mean age 7.9 +/- 4.12 years). General condition, oral para-functional habits, tooth wear (modified TWI), oral hygiene and gingival status (Plaque Index (PLI) and Gingival Index (GI)), localization of gingivitis, and salivary characteristics were assessed. The chi-square test, the Mann-Whitney U test, Spearman's rank correlation, and odds ratio based on logistic regression in a statistical analysis were applied. RESULTS: Chances of gingivitis were increased by low PLI (odds ratio (OR) = 32.53), low resting salivary flow (OR = 3.96), increased viscosity of saliva (OR = 3.54), and mouth breathing (OR = 8.17). For gingivitis in anterior regions, low PLI (OR = 107.67), low resting (OR = 5.73) and stimulated (OR = 1.86) salivary flow, increased viscosity of saliva (OR = 5.87), mouth breathing (OR = 10.00), and low stimulated salivary flow (OR = 3.18) were observed. Tooth wear rates were increased by teeth grinding (OR = 16.20), mouth breathing (OR = 4.33), increased viscosity of saliva (OR = 11.67) and low resting (OR = 6.07), and stimulated (OR = 4.22) salivary flow. CONCLUSIONS: In PWS, reduced salivary secretion, increased viscosity, of saliva and mouth breathing increase the risk of plaque-induced gingivitis and tooth wear. CLINICAL RELEVANCE: The prevention and treatment of tooth wear and gingivitis in PWS patients is necessary not only to treat bruxism and mouth breathing but also to limit the influence of negative changes of saliva. PMID- 30006687 TI - Oral health status of pre-school children of incarcerated mothers in United Arab Emirates prison nurseries and oral health knowledge and attitudes of their caregivers. AB - AIM: To evaluate the oral-health of preschool-children of incarcerated-mothers at nine United Arab Emirates (UAE) prison-nurseries and assess the oral-health knowledge and attitudes of the prison nurseries' caregivers. STUDY DESIGN: Cross sectional comparative study. METHODS: A total of 128 and 254 preschool children formed the study and control groups respectively. All were examined clinically for dental caries using the dmft score and oral health and hygiene status indices. Knowledge and attitudes of all caregivers (n = 45) at prison nurseries were assessed using an interview questionnaire. RESULTS: The prevalence of caries was not significantly different between the two groups with 89.9% [mean-dmft 4.97 (+/- 3.61)] in the study group and 92.1% [mean-dmft 4.48 (+/- 3.60)] in the controls. Oral-hygiene in the control group was better with 18.2% having good oral-hygiene compared to 6.2% in the study-group. Oral-health knowledge and attitude of the caregivers of prison nurseries were not satisfactory. CONCLUSIONS: Despite the non-significant difference in the caries prevalence between the study and control groups, oral hygiene and care level of vulnerable children of incarcerated-mothers were significantly poorer. Prisons' caregivers had poor knowledge and attitude of dental health matters. PMID- 30006688 TI - Regulator ThnR and the ThnDE ABC transporter proteins confer autoimmunity to thurincin H in Bacillus thuringiensis. AB - The structural gene that encodes thurincin H, a bacteriocin produced by Bacillus thuringiensis, is harboured in a genetic cluster (thnP, E, D, R, A1, A2, A3, B, T, I) that controls its synthesis, modification, secretion and autoimmunity. The specific genes in the cassette that confer immunity in B. thuringiensis to thurincin H are unknown. To identify these immunity determinants, we generated constructs that were used to transform a natural thurincin H-sensitive B. thuringiensis strain (i.e. Btk 404), and resistance or susceptibility to the bacteriocin in resultant recombinants was evaluated. When Btk 404/pHT3101 ThnARDEP and Btk 404/pHT3101-ThnABTI were exposed to thurincin H, immunity was demonstrated by the former only, indicating that ThnI does not play a role in resistance to the bacteriocin as previously proposed. Furthermore, we generated different sub-cassettes under the control of divergent promoters pThnR and pThur of the thurincin H locus, and pChi, and using the green fluorescent protein gene as reporter, which demonstrated that all promoters were recognised by ThnR, except pChi. We show for the first time that the small operon composed of thnR, thnD and thnE is required for immunity of B. thuringiensis to thurincin H, and thnI is not necessary for this response. PMID- 30006689 TI - Young Age and Risk of Lymph Node Metastasis in Differentiated Type Early Gastric Cancer. AB - BACKGROUND: Young patients with gastric cancer reportedly have a worse prognosis than older patients due to delayed diagnosis and more aggressive tumor behavior. However, it is unclear whether this applies to early gastric cancer (EGC), for which endoscopic resection is indicated. We investigated the association between age and lymph node metastasis (LNM). METHODS: We identified 4055 patients diagnosed with EGC of differentiated histology who underwent surgery. The association between age and LNM was examined using logistic regression for each T stage separately with adjustments for multiple covariates. We compared LNM rates for each of the Japanese Endoscopic Resection Guidelines criteria in younger (< 40 years) and older patients (40 years). RESULTS: The median number of lymph nodes examined was the same for T1a and T1b stages (n = 34). The median number of lymph nodes examined was not significantly different within T1a stage (P = 0.093), but within T1b stage, the number of lymph nodes examined was significantly different (P = 0.019). The highest number was between 50 and 59 years (median = 37), and the lowest number was in the 20 to 49 years and older than 70 age brackets (median = 34). LNM rate and age were not significantly associated within each stage (P values 0.269, 0.783 for T1a and T1b, respectively). Among patients fulfilling endoscopic resection criteria, the LNM rate in younger patients was lower than in older patients. CONCLUSIONS: In differentiated-type EGC, young age at diagnosis was not associated with LNM rate. Therefore, endoscopic resection criteria for early gastric cancer can be applied to younger patients. PMID- 30006690 TI - Triple Mapping to Optimize Axillary Management in Breast Cancer Patients After Neoadjuvant Therapy. PMID- 30006691 TI - Assessment of Computed Tomography (CT)-Defined Muscle and Adipose Tissue Features in Relation to Short-Term Outcomes After Elective Surgery for Colorectal Cancer: A Multicenter Approach. AB - BACKGROUND: Sarcopenia, visceral obesity (VO), and reduced muscle radiodensity (myosteatosis) are suggested risk factors for postoperative morbidity in colorectal cancer (CRC), but usually are not concurrently assessed. Published thresholds used to define these features are not CRC-specific and are defined in relation to mortality, not postoperative outcomes. This study aimed to evaluate body composition in relation to length of hospital stay (LOS) and postoperative outcomes. METHODS: Pre-surgical computed tomography (CT) images were assessed for total area and radiodensity of skeletal muscle and visceral adipose tissue in a pooled Canadian and UK cohort (n = 2100). Sex- and age-specific values for these features were calculated. For 1139 of 2100 patients, LOS data were available, and sex- and age-specific thresholds for sarcopenia, myosteatosis, and VO were defined on the basis of LOS. Association of CT-defined features with LOS and readmissions was explored using negative binomial and logistic regression models, respectively. RESULTS: In the multivariable analysis, the predictors of LOS (P < 0.001) were age, surgical approach, major complications (incidence rate ratio [IRR] 2.42; 95% confidence interval [CI] 2.18-2.68), study cohort, and three body composition profiles characterized by myosteatosis combined with either sarcopenia (IRR, 1.27; 95% CI 1.12-1.43) or VO (IRR, 1.25; 95% CI 1.10-1.42), and myosteatosis combined with both sarcopenia and VO (IRR, 1.58; 95% CI 1.29-1.93). In the multivariable analysis, risk of readmission was associated with VO alone (odds ratio [OR] 2.66; 95% CI 1.18-6.00); P = 0.018), VO combined with myosteatosis (OR, 2.72; 95% CI 1.36-5.46; P = 0.005), or VO combined with myosteatosis and sarcopenia (OR, 2.98; 95% CI 1.06-5.46; P = 0.038). Importantly, the effect of body composition profiles on LOS and readmission was independent of major complications. CONCLUSION: The findings showed that CT-defined multidimensional body habitus is independently associated with LOS and hospital readmission. PMID- 30006692 TI - The spectrum of tuberculosis of the spine in pediatric age group: a review. AB - INTRODUCTION: Pediatric spinal tuberculosis is characterized by rapid bone destruction and carries the risk of rapid onset neurological deficits and severe deformity of the spine. Behavior of spinal deformity over time is affected by growth of spine. Owing to this dynamic behavior of pediatric spinal tuberculosis both in active phase and in healed phase, it presents with challenges which are quite different from adults with caries spine. A clinician must have high index of suspicion for accurate and early diagnosis of spinal tuberculosis in the pediatric population and should also have a thorough knowledge of differences in natural history between adult and pediatric spinal tuberculosis. DISCUSSION: This is based on the senior author's experience of dealing with tuberculosis of the spine in children over the last two decades. Recent advances in field of rapid diagnosis of tuberculosis based on nuclear material-related diagnostic tests have further improved the management of tuberculosis. At the same time, the basic treatment principles remain the same. However, the threshold for surgical vs conservative treatment have subtle differences when compared to adult population. The importance of long-term follow-up after treatment must be appreciated. CONCLUSION: Tuberculosis in the spine in children needs early attention. Prompting to diagnostic and medical therapy measures can avoid neurological sequellae and delayed deformity. PMID- 30006694 TI - Resuscitation with centhaquin and 6% hydroxyethyl starch 130/0.4 improves survival in a swine model of hemorrhagic shock: a randomized experimental study. AB - PURPOSE: To investigate the effects of the combination of centhaquin and 6% hydroxyethyl starch 130/0.4 (HES 130/0.4) in a swine model of hemorrhagic shock. METHODS: Twenty Landrace-Large White pigs were instrumented and subjected to hemorrhagic shock. The animals were randomly allocated in two experimental groups, the control (group CO, n = 10) and the centhaquin groups (0.015 mg/kg, n = 10, group CH). Acute hemorrhage was induced by stepwise blood withdrawal (18 mL/min) from the internal jugular vein until MAP decreased to 40-45 mmHg, whereas anesthesia remained constant. All animals received HES 130/0.4 solution in the resuscitation phase until their mean arterial pressure (MAP) reached 90% of the baseline. The animals were observed for 60 min, during which no further resuscitation was attempted. RESULTS: The total amount of blood and the bleeding time did not differ significantly between group CO and group CH (120 +/- 13 vs. 120 +/- 14 mL, p = 0.6; 20 +/- 2 vs. 20 +/- 1 min, p = 0.62, respectively). During the hemorrhagic phase, only a difference in heart rate (97.6 +/- 4.4 vs. 128.4 +/- 3.6 beats/min, p = 0.038) was observed between the two groups. The time required to reach the target MAP was significantly shorter in the centhaquin group compared to controls (13.7 +/- 0.4 vs. 19.6 +/- 0.84 min, p = 0.012). During the resuscitation phase, a statistical significant difference was observed in MAP (75.2 +/- 1.6 vs. 89.8 +/- 2.1 mmHg, p = 0.02) between group CO and group CH. During the observation phase, a statistical significant difference was observed in SVR (1109 +/- 32.65 vs. 774.6 +/- 21.82 dyn s/cm5, p = 0.039) and cardiac output (5.82 +/- 0.31 vs. 6.9 +/- 0.78 L/min, p = 0.027) between the two groups. Two animals of group CO and seven animals of group CH survived for 24 h (p = 0.008). We observed a marked increase in microvascular capillary permeability in group CO compared to group CH, with the wet/dry weight ratio being significantly higher in group CO compared to group CH (4.8 +/- 1.6 vs. 3.08 +/- 0.6, p < 0.001). CONCLUSIONS: The combination of centhaquin 0.015 mg/kg and HES 130/0.4 resulted in shorter time to target MAP, lower wet-to-dry ratio, and better survival rates after resuscitation from hemorrhagic shock. PMID- 30006693 TI - Coexpression network revealing the plasticity and robustness of population transcriptome during the initial stage of domesticating energy crop Miscanthus lutarioriparius. AB - KEY MESSAGE: Coexpression network revealing genes with Co-variation Expression pattern (CE) and those with Top rank of Expression fold change (TE) played different roles in responding to new environment of Miscanthus lutarioriparius. Variation in gene expression level, the product of genetic and/or environmental perturbation, determines the robustness-to-plasticity spectrum of a phenotype in plants. Understanding how expression variation of plant population response to a new field is crucial to domesticate energy crops. Weighted Gene Coexpression Network Analysis (WGCNA) was used to explore the patterns of expression variation based on 72 Miscanthus lutarioriparius transcriptomes from two contrasting environments, one near the native habitat and the other in one harsh domesticating region. The 932 genes with Co-variation Expression pattern (CE) and other 932 genes with Top rank of Expression fold change (TE) were identified and the former were strongly associated with the water use efficiency (r >= 0.55, P <= 10-7). Functional enrichment of CE genes were related to three organelles, which well matched the annotation of twelve motifs identified from their conserved noncoding sequence; while TE genes were mostly related to biotic and/or abiotic stress. The expression robustness of CE genes with high genetic diversity kept relatively stable between environments while the harsh environment reduced the expression robustness of TE genes with low genetic diversity. The expression plasticity of CE genes was increased less than that of TE genes. These results suggested that expression variation of CE genes and TE genes could account for the robustness and plasticity of acclimation ability of Miscanthus, respectively. The patterns of expression variation revealed by transcriptomic network would shed new light on breeding and domestication of energy crops. PMID- 30006695 TI - Contemporary scope of inborn errors of metabolism involving epilepsy or seizures. AB - Many inborn errors of metabolism may present with epilepsy or seizures, however, current scope of these diseases is unknown. Due to available precision medicine approaches in many inborn errors of metabolism and sophisticated traditional diagnostics, this group of disorders is of special relevance to clinicians. Besides, as current treatment is challenging and unsuccessful in more than 30% of all epilepsy patients, these diseases may provide valuable models for ictogenesis and epileptogenesis studies and potentially pave the ways to identification of novel treatments. The aim of this study was to elucidate genetic architecture of inborn errors of metabolism involving epilepsy or seizures and to evaluate their diagnostic approaches. After extensive search, 880 human genes were identified with a considerable part, 373 genes (42%), associated with inborn errors of metabolism. The most numerous group comprised disorders of energy metabolism (115, 31% of all inborn errors of metabolism). A substantial number of these diseases (26%, 97/373) have established specific treatments, therefore timely diagnosis comes as an obligation. Highly heterogenous, overlapping and non specific phenotypes in most of inborn errors of metabolism presenting with epilepsy or seizures usually preclude phenotype-driven diagnostics. Besides, as traditional diagnostics involves a range of specialized metabolic tests with low diagnostic yields and is generally inefficient and lengthy, next-generation sequencing-based methods were proposed as a cost-efficient one-step way to shorten "diagnostic odyssey". Extensive list of 373 epilepsy- or seizures associated inborn errors of metabolism genes may be of value in development of gene panels and as a tool for variants' filtration. PMID- 30006697 TI - Electron Microscopy for the Analysis of Peripheral Nerve Myelin. AB - Transmission electron microscopy (TEM) can provide excellent high-resolution images of cellular structures. A critical step with this technique is sample preparation. Here we describe our protocol for the preparation of semithin and ultrathin sections of mouse peripheral nerves in order to visualize the structure and pathological features of peripheral myelin with TEM. PMID- 30006698 TI - Immunohistochemical Analysis of Myelin Structures. AB - Immunochemistry (immunocytochemistry for cells and immunohistochemistry for tissues) is a method used to label specific antigens, based on highly specific antibody-epitope interactions. The resulting labeling can be visualized and imaged through microscopy adapted to the type of detection system used (fluorophore, peroxidase, etc.). In the nervous system, myelin is a complex membrane structure, generated by myelinating glial cells, which ensheath axons and facilitate electrical conduction. Myelin alteration has been shown to occur in various neurological diseases, in which it is associated with functional deficits. Here, we focus on myelin detection by immunofluorescence using immunochemistry protocols based on antibodies directed against major myelin proteins. PMID- 30006696 TI - Impact of missense mutations in survival motor neuron protein (SMN1) leading to Spinal Muscular Atrophy (SMA): A computational approach. AB - Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the mutations in survival motor neuron 1 gene (SMN1). The molecular pathology of missense mutations in SMN1 is not thoroughly investigated so far. Therefore, we collected all missense mutations in the SMN1 protein, using all possible search terms, from three databases (PubMed, PMC and Google Scholar). All missense mutations were subjected to in silico pathogenicity, conservation, and stability analysis tools. We used statistical analysis as a QC measure for validating the specificity and accuracy of these tools. PolyPhen-2 demonstrated the highest specificity and accuracy. While PolyPhen-1 showed the highest sensitivity; overall, PolyPhen2 showed better measures in comparison to other in silico tools. Three mutations (D44V, Y272C, and Y277C) were identified as the most pathogenic and destabilizing. Further, we compared the physiochemical properties of the native and the mutant amino acids and observed loss of H-bonds and aromatic stacking upon the cysteine to tyrosine substitution, which led to the loss of aromatic rings and may reduce protein stability. The three mutations were further subjected to Molecular Dynamics Simulation (MDS) analysis using GROMACS to understand the structural changes. The Y272C and Y277C mutants exhibited maximum deviation pattern from the native protein as compared to D44V mutant. Further MDS analysis predicted changes in the stability that may have been contributed due to the loss of hydrogen bonds as observed in intramolecular hydrogen bond analysis and physiochemical analysis. A loss of function/structural impact was found to be severe in the case of Y272C and Y277C mutants in comparison to D44V mutation. Correlating the results from in silico predictions, physiochemical analysis, and MDS, we were able to observe a loss of stability in all the three mutants. This combinatorial approach could serve as a platform for variant interpretation and drug design for spinal muscular dystrophy resulting from missense mutations. PMID- 30006699 TI - Visualization and Time-Lapse Microscopy of Myelinating Glia In Vivo in Zebrafish. AB - In vivo time-lapse microscopy provides important information about the kinetics of cellular events and their control by interactions with neighboring cells. Here, we describe the generation and use of transgenic zebrafish to visualize dynamics of myelinating glia using cell type-specific expression and microscopy of genetically encoded fluorescent proteins. With this method, we are able to simultaneously separate and trace up to three different colors over time. PMID- 30006700 TI - Lipidomics Profiling of Myelin. AB - Lipidomics is a powerful approach that can provide quantitative characterization of hundreds of lipid species from biological samples. Recent studies have highlighted the value of lipidomics to study myelin biology. This chapter provides a detailed description for the application of multidimensional mass spectrometry shotgun lipidomics (MDMS-SL) to neuroscience research and particularly to the analysis of brain lipidomes with a particular emphasis on myelin lipids, from sample preparation to bioinformatics analyses. Sample preparation includes brain sample harvesting, homogenization, and lipid extraction. Lipid content is determined and quantified, in an unbiased manner and with wide coverage, using MDMS-SL. Overall, the approach described herein is applicable for whole brain tissue or specific brain regions (e.g., hippocampus, cerebellum), and is expected to yield new insights on various aspects of myelin biology and lipid metabolism. PMID- 30006701 TI - Mapping Lipid Distribution in Rat Sciatic Nerve Using Imaging Mass Spectrometry. AB - Lipids are essential components of cells and tissues. They play active and central roles in signaling and many biological functions and therefore their dysregulation is very often the first signal of function alteration. Here we describe the protocol to analyze not only lipid expression in rat sciatic nerve but also the lipid distribution along its different anatomic areas. The protocol combines results from MALDI-IMS and UHPLC-MS/MS to identify and cartography the maximum number of lipid species in the tissue. PMID- 30006702 TI - Proteomics Analysis of Myelin Composition. AB - The identification and functional characterization of the repertoire of myelin proteins provides a valuable foundation for understanding molecular mechanisms of myelination and the pathogenesis of human myelin disease. Here we provide a procedure for the purification of myelin from rodent or human brains and a large scale analysis of the myelin proteome, using the shotgun approach of one dimensional PAGE and liquid chromatography (LC)/tandem mass spectrometry (MS). PMID- 30006703 TI - Isolation and Purification of Primary Rodent Schwann Cells. AB - Schwann cells are the main glial cells of the peripheral nervous system (PNS) and play key roles in peripheral nerve development and function, including providing myelin that is essential for normal movement and sensation in the adult. Schwann cells can be readily destabilized by a wide variety of distinct conditions that range from nerve injury to immune assaults, metabolic disturbances, microbial infections, or genetic defects, leading to the breakdown of myelin (demyelination) and a subsequent switch in phenotypic states. This striking feature of Schwann cells forms the cornerstone of several debilitating and even fatal PNS neurological disorders that include the demyelinating neuropathies Guillain Barre syndrome (GBS) and Charcot-Marie-Tooth disease (CMT), and PNS cancers, including Neurofibromatosis.Primary Schwann cell cultures have proved a valuable tool to dissect key mechanisms that regulate proliferation, survival, differentiation, and myelination of these glial cell types. In this chapter, we describe the steps involved in the isolation and purification of Schwann cells from rodent peripheral nerves and the use of these cultures to model myelination in vitro. PMID- 30006704 TI - Isolation, Expansion, and Maturation of Oligodendrocyte Lineage Cells Obtained from Rat Neonatal Brain and Optic Nerve. AB - Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS) and their loss or dysfunction is a hallmark of CNS demyelinating diseases, such as multiple sclerosis (MS), hypoxic-ischemic demyelination, or spinal cord injury. In the rodent CNS, oligodendrocyte progenitor cells (OPCs) arise in multiple ventral and dorsal locations of the forebrain during late embryogenesis and early postnatal periods. OPCs migrate out from these germinal zones and disperse throughout the CNS, to populate the developing white and gray matter. There, OPCs can begin to mature through a series of intermediate states characterized by the expression of stage-specific proteins until completely differentiated into postmitotic myelinating oligodendrocytes. Elucidating the cellular and molecular mechanisms that control oligodendrocyte maturation requires isolating OPCs and premyelinating oligodendrocytes by rapid and reliable methods that provide high yield, pure and viable culture, being a powerful tool to characterize their differentiation and potential capacity for myelin repair after injury. This chapter describes in detail two simple and efficient protocols for the preparation of highly enriched rat OPC populations and immature oligodendrocytes derived from mixed glial cultures and optic nerves, respectively. Functional oligodendrocytes obtained with these protocols can be cocultured with primary neurons to study myelination. PMID- 30006705 TI - DRG Neuron/Schwann Cells Myelinating Cocultures. AB - Our understanding of the processes controlling peripheral nervous system myelination have been significantly benefited by the development of an in vitro myelinating culture system in which primary Schwann cells are cocultured together with primary sensory neurons. In this chapter, we describe the protocol currently used in our laboratories to establish Schwann cells neuronal myelinating cocultures. We also include a detailed description of the various substrates that can be used to establish it. PMID- 30006706 TI - Neuron/Oligodendrocyte Myelination Coculture. AB - Myelination cell culture systems are useful tools for studying myelin biology and myelin-related disorders. Compared to a number of established protocols for dissociated pure oligodendrocyte (OL) culture, methods for myelination culture are limited. We recently developed a mixed neuron-glia coculture system that generates robust and efficient myelination. By optimizing cell culture conditions, dissociated neural progenitor cells from embryonic rat spinal cords develop into neurons and glial cells including profiles of oligodendrocyte (OL) lineage. Within 4 weeks, OL progenitor cells (OPC) proliferate, differentiate into mature OLs, and myelinate axons. The formation of compact myelin sheath is confirmed by electron microscopy. For morphological analysis by light microscopy, cells grown on glass coverslips are fixed and immunostained for various myelin related proteins, including those embedded within the myelin sheath and those clustered at the node of Ranvier. Myelinated axons can be quantified readily by either manual counting or ImageJ software. The culture system may also be used for electron microscopic analysis by slightly modifying the cell culture procedure. PMID- 30006707 TI - Organotypic Slice Cultures to Study Oligodendrocyte Proliferation, Fate, and Myelination. AB - Oligodendrocyte development and myelination are processes in the central nervous system that are regulated by cell intrinsic and extrinsic mechanisms. Organotypic slice cultures provide a simple method for studying factors that affect oligodendrocyte proliferation, differentiation, and myelination in the context of the local cellular environment. Here we show that major glial cell types and neurons are preserved in slice cultures from postnatal mouse forebrain, and their morphological characteristics are retained. We further demonstrate that cellular processes requiring interactions with neighboring cells such as myelination can proceed in slice culture. PMID- 30006708 TI - Modeling PNS and CNS Myelination Using Microfluidic Chambers. AB - Modeling myelination in vitro allows mechanistic study of developmental myelination and short-term myelin maintenance, but analyses possible to carry out using currently available models are usually limited because of high cell density and the lack of separation between neurons and myelinating cells. Furthermore, regeneration studies of myelinated systems after lesion require compartmentalization of neuronal cell bodies, axons, and myelinating cells. Here we describe a compartmentalized method using microfluidics that allows live-cell imaging at the single-cell level to follow short- and long-term dynamic interactions of neurons and myelinating cells and large-scale analyses, e.g., RNA sequencing on pure or highly enriched neurons or myelinating cells, separately. PMID- 30006709 TI - Modeling CNS Myelination Using Micropillar Arrays. AB - Myelination necessitates axons to initiate concentric membrane wrapping by oligodendroglia in the CNS. Here, we describe an in vitro system that models CNS myelination with a minimally permissive environment, termed Binary Indicant for myelination using Micropillar Arrays (BIMA). Engineered with conical micropillar arrays, BIMA allows for rapid translation of oligodendroglial wrapping and differentiation into binary readout under confocal microscopy. Fabricated into 96 or 384-well plates, BIMA serves as a high-throughput screening platform for compounds that may promote oligodendroglial differentiation and myelination. BIMA is also amenable for examining molecular signals and pathways that regulate axon glia interaction and recognition. PMID- 30006710 TI - A Central Nervous System Axonal Myelination Assay for High-Throughput Screening. AB - The formation of new myelin in persistent multiple sclerosis (MS) lesions is compromised, leading to a reduction in neuron function and subject to degeneration and death. Current MS therapies can control autoimmune-mediated demyelination, but none directly promote the regeneration of myelin in the central nervous system (CNS). To identify new drugs that stimulate remyelination, we established a high-throughput cell-based assay to identify compounds that promote myelination. Methods were developed for initiating myelination in vitro using a preparation of primary embryonic rat cortical cells. We developed an immunofluorescent phenotypic image analysis method to quantify the morphological alignment of myelin characteristic of the initiation of myelination. The assay scalability and consistency was validated by screening the NIH clinical collection library of 727 compounds and identified ten compounds that promote myelination (Lariosa-Willingham et al., BMC Neurosci 17:16, 2016). Here, we present the detailed methods for a high capacity in vitro assay that assesses myelination of live axons. PMID- 30006711 TI - Analyzing Autophagic Flux in Nerve Cultures. AB - Autophagy is a key cellular mechanism involved in the degradation of long-lived proteins and organelles. We and others have previously shown that Schwann cells are able to degrade their own myelin by a form of selective autophagy, or myelinophagy. There is now increasing evidence that myelinophagy could also be aberrantly activated in other demyelinating diseases, including hereditary or inflammatory neuropathies, implicating this pathway in the pathogenesis of these disorders. In this chapter, we describe our protocol to monitor autophagy in peripheral nerves, using the autophagy flux assay. This assay can be useful to compare basal and demyelination-induced autophagy in genetic mice models, or after treatment with specific compounds. PMID- 30006712 TI - Subcellular Optogenetic Stimulation Platform for Studying Activity-Dependent Axon Myelination In Vitro. AB - Activity-dependent myelination modulates neuron conduction velocity and as such it is essential for a correct wiring of a whole nervous system. Increasing myelination through inducing neuron activity has been proposed as a treatment strategy for demyelination diseases. Yet, the mechanisms and the effects of activity-dependent myelination remain elusive-new tools are needed. In this chapter, we describe a novel compartmentalized device integrated with an optogenetic stimulator for studying activity-dependent myelination in vitro. The platform can be modified to include multiple cell types, stimulation modes, and experimental readouts to answer a specific research question. This versatility combined with a precise control over spatial extent of the stimulation and the stimulation pattern make the proposed platform a valuable tool for molecular myelination studies. PMID- 30006713 TI - Active Induction of Experimental Autoimmune Encephalomyelitis (EAE) with MOG35-55 in the Mouse. AB - Experimental autoimmune encephalomyelitis (EAE) is one of the most popular animal models of multiple sclerosis (MS). There are a number of EAE models, being actively induced EAE in strains such as C57Bl/6 mice very robust and reproducible. We herewith present details of the materials and methods for active EAE. Mice are immunized with an emulsion of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) + complete Freund's adjuvant (supplemented with Mycobacterium tuberculosis), and treated with Bordetella pertussis toxin, to induce EAE. Sham-EAE mice are immunized with bovine serum albumin instead of MOG35-55. PMID- 30006714 TI - Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin. AB - Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease in the central nervous system (CNS) characterized by loss of oligodendrocytes, myelin axons, and neurons. Remyelination is an endogenous repair mechanism, which recovers the loss of myelin and is able to preserve functional axons. The hope is that the development of new treatments aiming at promoting remyelination will halt and potentially partially reverse the progressive neurological decline in MS. The development of such drugs requires adequate models. In this chapter, we will discuss the surgical procedure of injection of lysolecithin into ventral thoraco-lumbar spinal cord white matter of mice, which is particularly suitable for investigating remyelination using transgenic animals. PMID- 30006715 TI - Myelin Protein Zero180-199 Peptide Induced Experimental Autoimmune Neuritis in C57BL/6 Mice. AB - Mouse models of peripheral demyelinating neuropathy play an important role in enabling the study of disease pathogenesis. Further, induction in transgenic mice allows for the precise interrogation of disease mechanisms, as well as the analysis of the efficacy and mechanisms of potential new therapies. Here we describe a method to successfully induce experimental autoimmune neuritis (EAN) using myelin protein zero (P0)180-199 peptide in combination with Freund's complete adjuvant and pertussis toxin in the C57BL/6 mouse strain. We also outline a sensitive paradigm of accurately assessing the extent of functional deficits occurring in murine EAN. PMID- 30006716 TI - Transection and Crush Models of Nerve Injury to Measure Repair and Remyelination in Peripheral Nerve. AB - Injury to the peripheral nervous system begins a well-characterized process within both neurons and Schwann cells to allow axonal regrowth, remyelination, and functional repair. Models of peripheral nerve injury have been widely used to study the behavior of Schwann cells, neurons, and other cell types such as macrophages as the events of Wallerian degeneration and regeneration take place. The most commonly used approaches in rodent models to model nerve injury in human patients are sciatic nerve transection and nerve crush, and both have well established time courses of demyelination, immune cell influx, axonal regrowth, and remyelination. We describe the techniques of sciatic nerve surgery for transection and crush injury, together with methods for the analysis of events within peripheral nerve repair in these two models. PMID- 30006717 TI - In Vivo Introduction of Transgenes into Mouse Sciatic Nerve Cells Using Viral Vectors. AB - Myelinated fibers are essential for the rapid and efficient propagation of nerve information throughout the body. These fibers result from an intimate crosstalk between myelinating glia and the myelinated axons and, because it is difficult to fully reproduce these interactions in vitro, the basic molecular mechanisms that regulate myelination, demyelination, and remyelination remain unclear. Schwann cells produce myelin in the peripheral nervous system (PNS) and remain associated with the axons of peripheral neurons throughout axonal migration to the target. In order to investigate more closely the biology of myelinated fibers, we developed a local transgenesis approach based on the injection of engineered viral vectors in the sciatic nerve of mice to locally transduce peripheral nerve cells. This approach represents an alternative to germline modifications as it facilitates and speed up the investigation of peripheral nerve biology in vivo. Indeed the protocol we describe here requires just 3 weeks to complete. The injection of engineered viral vectors in the sciatic nerve of mice is a reproducible and straightforward method for introducing exogenous factors into myelinating Schwann cells and myelinated axons in vivo in order to investigate specific molecular mechanisms. PMID- 30006718 TI - Intrathecal Delivery of Viral Vectors for Gene Therapy. AB - Gene delivery to the peripheral nervous system for therapeutic applications remains technically challenging but could eventually have a significant impact on the development of innovative treatments not only for inherited but also for acquired peripheral neuropathies. Here we describe the method for lumbar intrathecal injection of viral vectors in experimental mice. This gene delivery route provides widespread and stable over time Schwann cell-targeted or ubiquitous gene expression in the peripheral nervous system. PMID- 30006719 TI - Efficient Gene Transfer to Myelinating Schwann Cells in the Rodent Sciatic Nerve Using In Vivo Electroporation. AB - To study the signaling mechanism of the development and maintenance of myelinating Schwann cells (SCs) in the peripheral nervous system, in vivo techniques for SC-selective gene manipulation are useful. The present protocol describes an in vivo electroporation method that allows efficient transfection of myelinating SCs in rodent sciatic nerves. This technique allows us to introduce the genes of interest into myelinating SCs by simply applying electric pulses to the sciatic nerve after plasmid DNA injection. PMID- 30006721 TI - Kennedy's disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease. AB - Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, X-linked hereditary lower motor neuron disease, characterized by progressive muscular weakness. An expanded trinucleotide repeat (CAG > 37) in the androgen receptor gene (AR), encoding glutamine, is the mutation responsible for Kennedy's disease. Toxicity of this mutant protein affects both motor neurons and muscles. In this review, we provide a comprehensive, clinically oriented overview of the current literature regarding Kennedy's disease, highlighting gaps in our knowledge that remain to be addressed in further research. Kennedy's disease mimics are also discussed, as are ongoing and recently completed therapeutic endeavours. PMID- 30006720 TI - Gliotoxin penetrates and impairs the integrity of the human blood-brain barrier in vitro. AB - Cerebral fungal infections represent an important public health concern, where a key element of pathophysiology is the ability of the fungi to cross the blood brain barrier (BBB). Yet the mechanism used by micro-organisms to cross such a barrier and invade the brain parenchyma remains unclear. This study investigated the effects of gliotoxin (GTX), a mycotoxin secreted by Aspergillus fumigatus, on the BBB using brain microvascular endothelial cells (BMECs) derived from induced pluripotent stem cells (iPSCs). We observed that both acute (2 h) and prolonged (24 h) exposure to GTX at the level of 1 MUM or higher compromised BMECs monolayer integrity. Notably, acute exposure was sufficient to disrupt the barrier function in iPSC-derived BMECs, resulting in decreased transendothelial electrical resistance (TEER) and increased fluorescein permeability. Further, our data suggest that such disruption occurred without affecting tight junction complexes, via alteration of cell-matrix interactions, alterations in F-actin distribution, through a protein kinase C-independent signaling. In addition to its effect on the barrier function, we have observed a low permeability of GTX across the BBB. This fact can be partially explained by possible interactions of GTX with membrane proteins. Taken together, this study suggests that GTX may contribute in cerebral invasion processes of Aspergillus fumigatus by altering the blood-brain barrier integrity without disrupting tight junction complexes. PMID- 30006722 TI - Primary progressive freezing gait with impressive response to laser light visual cueing: a video case report. PMID- 30006723 TI - Highly passivated phosphorous and nitrogen co-doped carbon quantum dots and fluorometric assay for detection of copper ions. AB - Carbon quantum dots are becoming powerful fluorophore materials for metal ion analysis. Here, highly passivated green phosphorous and nitrogen co-doped carbon quantum dots (C-dots) were prepared using low-temperature carbonization route. Strong green fluorescence emission around 490 nm and excitation wavelength independent C-dots were obtained. Morphological, surface, and optical properties of the C-dots were characterized. Fluorescence emission of C-dots was quenched selectively by copper ions and restored by adding copper chelators, such as EDTA and sulfide ions. Thus, C-dots were successfully used for direct determination of copper ions. Detection limit as low as 1.5 nM (s/n = 3) was achieved for copper ions. Such a low detection limit is very significant for metal analysis using our proposed facile method and low-cost substrates. Experimental results showed that the prepared C-dots demonstrated high sensitivity and selectivity for Cu2+ ion detection and the method is robust and rugged. Graphical abstract ?. PMID- 30006724 TI - Comparison of accuracy and precision between multipoint calibration, single point calibration, and relative quantification for targeted metabolomic analysis. AB - Targeted metabolomics requires accurate and precise quantification of candidate biomarkers, often through tandem mass spectrometric (MS/MS) analysis. Differential isotope labeling (DIL) improves mass spectrometric (MS) analysis in metabolomics by derivatizing metabolites with two isotopic forms of the same reagent. Despite its advantages, DIL-liquid chromatographic (LC)-MS/MS can result in substantial increase in workload when fully validated quantitative methods are required. To decrease the workload, we hypothesized that single point calibration or relative quantification could be used as alternative methods. Either approach will result in significant saving in resources and time. To test our hypothesis, six urinary metabolites were selected as model compounds. Urine samples were analyzed using a fully validated multipoint dansyl chloride-DIL-LC-MS/MS method. Samples were reprocessed using single point calibration and relative quantification modes. Our results demonstrated that the performance of single point calibration or relative quantification was inferior, for some metabolites, to multipoint calibration. The lower limit of quantification failed in the quantification of ethanolamine in most of participant samples using single point calibration. In addition, its precision was not acceptable in one participant during serine and ethanolamine quantification. On the other hand, relative quantification resulted in the least accurate data. In fact, none of the data generated from relative quantification for serine was comparable to that obtained from multipoint calibration. Finally, while single point calibration showed an overall acceptable performance for the majority of the model compounds, we cannot extrapolate the findings to other metabolites within the same analytical run. Analysts are advised to assess accuracy and precision for each metabolite in which single point calibration is the intended quantification mean. PMID- 30006725 TI - Magnetic-assisted biotinylated single-chain variable fragment antibody-based immunoassay for amantadine detection in chicken. AB - A sensitive competitive immunoassay with simple operation was developed for the detection of the anti-virus drug amantadine (AMD). The single-chain variable fragment (scFv) antibody against AMD was site-specific biotinylated and overexpressed as a secreted body in Escherichia coli AVB101. Horseradish peroxidase-labeled streptavidin-biotinylated scFv antibody (HRP-SA-BIO-scFv) could specifically bind to AMD-functionalized magnetic beads (MBs) and then the immune complexes were separated from the matrix solution by magnet. The concentration of the AMD could be known by the measurement of the signal produced by the horseradish peroxidase. The newly established assay provides a significant improvement in comparison to the conventional ELISA without SA-BIO signal amplification and MBs separation. The limit of detection and assay time was 0.64 vs. 8.4 ng/mL and 50 vs. 150 min, respectively. The recoveries ranged from 77.8 to 112% with the coefficient of variation less than 13%. The immunoassay exhibited an obvious cross-reactivity to rimantadine (84%), 1-(1 adamantyl)ethylamine (72%), and somantadine (63%). These results demonstrated that the developed immunoassay provided a sensitive, rapid, and accurate approach for the detection of AMD in chicken by employing MBs as solid phase and SA-BIO as signal amplification. When applied in natural chicken samples, the newly established method provided results consistent with those from UPLC-MS/MS, suggesting that the proposed method could be used for rapid screening of the target of interest; the new immunoassay could also be extended to other small molecular contaminants and thus represents a universal strategy for food safety analysis. Graphical abstract ?. PMID- 30006726 TI - Measurement of human serum unconjugated estriol without derivatization using liquid chromatography-tandem mass spectrometry candidate reference method and compared with two immunoassays. AB - A candidate reference measurement procedure (RMP) for measurement of unconjugated estriol in human serum has been developed and validated. The proposed method is highly reliable and uses isotope dilution coupled with liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) and requires no derivatization. An appropriate amount of serum was accurately weighed and spiked with an isotopically labeled internal standard. Unconjugated estriol and its internal standard were extracted from serum matrix using liquid-liquid extraction prior to reversed-phase LC-MS/MS. Calibrator bracketing was used to give higher specificity and accuracy for assigning serum level. The accuracy of the candidate RMP was validated by split-sample comparison to established RMPs. The lowest limit of detection (LLoD) and lowest limit of quantification (LLoQ) for developed RMP was estimated to be 0.14 nmol/L and 0.35 nmol/L, respectively. Both intra- and inter-assay imprecisions were <=2.19% at 1.39, 17.34 and 69.35 nmol/L, respectively. Recoveries were 98.54% to 100.34% and linear response ranged from 0.35 to 173.38 nmol/L. No interference was observed. Biases were 5.6% and 2.8% against the targets of RELA2015A (3.87 nmol/L) and RELA2015B (40.62 nmol/L), respectively. Moreover, the candidate RMP was successfully applied to measure level of unconjugated estriol in serum samples of pregnant women (n = 3) and compared with two immunoassays in clinical laboratory. Our developed method is simple, accurate, and can be used as a candidate RMP to determine total unconjugated estriol level in human serum. Further improvement of certain immunoassays in accuracy and precision is needed. Graphical abstract Selected ion chromatograms by LC-MS/MS using a C18 column for uE3 from a serum sample. PMID- 30006727 TI - Postpartum Depression and Anxiety Among Mothers Whose Child was Placed in Care of Child Protection Services at Birth: A Retrospective Cohort Study Using Linkable Administrative Data. AB - Objectives This study examines whether mothers involved with child protection services (CPS) at the birth of their first child had higher rates of postpartum depression and anxiety. Methods A retrospective cohort of mothers whose first child was born in Manitoba, Canada between April 1, 1995 and March 31, 2015 is used. Postpartum depression and anxiety among mothers whose first child was placed in care at birth (n = 776) was compared with mothers who received services from CPS (but whose children were not placed in care) (n = 4,270), and a 3:1 matched group of mothers who had no involvement with CPS in the first year of their firstborn's life (n = 2,328). Adjusted odds ratios (AOR) of depression and anxiety diagnoses in the first year postpartum were obtained from logistic regression models. Adjusted rate ratios (ARR) of antidepressant use obtained using Poisson models. Results Mothers whose children were taken into care have greater odds of having a postpartum depression or anxiety diagnosis than mothers receiving services (AOR = 1.31; 95% CI 1.08-1.59) and those not involved with CPS (AOR = 2.13; 95% CI 1.67-2.73). Among mothers who had a postpartum depression or anxiety diagnosis, mothers whose children were placed in care had significantly higher rates of antidepressant use than mothers receiving services only (ARR = 2.00; 1.82, 2.19) and mothers who were not involved with CPS (ARR = 2.42; 95% CI 1.94-3.51). Conclusions for Practice Targeted programs should be implemented to address postpartum mental illness among mothers who are involved with CPS at the birth of their child. PMID- 30006729 TI - Breastfeeding Discontinuation Not Associated with Maternal Pregravid BMI But Associated with Native Hawaiian or Other Pacific Islander Race in Hawaii and Puerto Rico WIC Participants. AB - Objectives This study investigated the association between maternal pregravid body mass index (BMI) and breastfeeding discontinuation at 4-6 months postpartum in Hawaii and Puerto Rico participants from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Methods A secondary data analysis was conducted from a text message-based intervention in WIC participants in Hawaii and Puerto Rico. The analysis included 87 women from the control group who initiated breastfeeding and whose breastfeeding status was known at the end of the study when infants were 4-6 months old. Pregravid BMI and breastfeeding discontinuation were assessed using questionnaires. Results The association between pregravid BMI and breastfeeding discontinuation was not significant in the unadjusted model or in the adjusted model. Native Hawaiian or Other Pacific Islander (NHOPI) participants showed significantly increased odds of discontinuing breastfeeding (adjusted odds ratio [AOR] 7.12; 95% CI 1.34, 37.97; p = .02) compared to all the other racial/ethnic participants, as did older women ages 32-39 years versus women who were 25-31 years old (AOR 4.21; 95% CI 1.13, 15.72; p = .03). Women who took vitamins while breastfeeding had decreased odds of discontinuing breastfeeding (AOR 0.15; 95% CI 0.05, 0.46; p = .0009). Conclusions for Practice Pregravid BMI was not significantly associated with breastfeeding discontinuation at 4-6 months postpartum in women from Hawaii and Puerto Rico WIC, but NHOPIs and women who were older had higher odds of discontinuing breastfeeding. The results of this study may inform strategies for breastfeeding promotion and childhood obesity prevention but should be further investigated in larger studies. ClinicalTrials.gov Identifier: NCT02903186. PMID- 30006728 TI - Understanding of Key Obstetric Quality Terminology by Asian and Pacific Islander Subgroups: Implications for Patient Engagement and Health Equity. AB - Introduction Comprehension of healthcare terminology across diverse populations is critical to patient education and engagement. Methods Women in Oahu, Hawai'i with a recent delivery were interviewed about their understanding of ten common obstetric terms. Health literacy was assessed by the rapid estimate of adult literacy in medicine (REALM). Multivariable models predicted total terms comprehended by demographic factors. Results Of 269 participants, self-reported primary race was 20.5% Japanese, 19.0% Native Hawaiian, 19.0% White, 16.7% Filipino, 11.5% other Asian, 9.7% other Pacific Islander, and 3.7% other race/ethnicity; 12.7% had low health literacy. On average, participants understood 6.0 (SD: 2.2) of ten common obstetric terms. Comprehension varied by term, ranging from 97.8% for "Breastfeeding" to 27.5% for "VBAC routinely available." Models showed (1) being Filipino, Japanese, Native Hawaiian, or other Pacific Islander (vs. white); (2) having low (vs. adequate) health literacy; (3) having a high school (vs. a college) degree; and (4) being under 25-years-old (vs. 35 +) were significantly associated with less comprehension. Discussion Participants were unfamiliar with common obstetrics terminology. Comprehension struggles were more common among populations with maternal health disparities, including Asian and Pacific Islander subgroups, and those with low health literacy. PMID- 30006730 TI - Ohio's Medicaid Expansion and Unmet Health Needs Among Low-Income Women of Reproductive Age. AB - Objective To examine changes in the prevalence and odds of unmet healthcare needs and healthcare utilization among low-income women of reproductive age (WRA) after Ohio's 2014, ACA-associated Medicaid expansion, which extended coverage to non senior adults with a family income <= 138% of the federal poverty level. Methods We analyzed publically available data from the 2012 and 2015 Ohio Medicaid Assessment Survey (OMAS), a cross-sectional telephone survey of Ohio's non institutionalized adult population. The study included 489 low-income women in 2012 and 1273 in 2015 aged 19-44 years who were newly eligible for Medicaid after expansion in January 2014. Four unmet healthcare need and three healthcare utilization measures were examined. We fit survey-weighted logistic regression models adjusted for race/ethnicity, working status, and educational attainment to determine whether the odds of each measure differed between 2012 and 2015. Results In 2015, low-income WRA had a significantly lower odds of reporting an unmet dental care need (ORadj = 0.72, 95% CI 0.54, 0.95), unmet vision care need (ORadj = 0.68, 95% CI 0.50, 0.93), unmet mental health need (ORadj = 0.57, 95% CI 0.39, 0.83), and unmet prescription need (ORadj = 0.39, 95% CI 0.45, 0.80) compared to 2012. There were no significant differences in the odds of seeing a doctor or dentist in the past year or of having a usual source of care for low income WRA in 2012 and 2015. Conclusions for Practice After Ohio's 2014 Medicaid expansion the odds of low-income WRA having unmet healthcare needs was reduced. Future research should examine outcomes after a longer period of follow-up and include additional measures, such as self-rated health status. PMID- 30006731 TI - Advancing Leadership Skills: A Multiyear Examination of LEND Trainee Self Efficacy Growth. AB - Purpose The current healthcare system requires Maternal and Child Health (MCH) professionals with strong interdisciplinary leadership competence. MCH training programs utilize a conceptual framework for leadership and 12 validated MCH Leadership Competencies. Examining Trainee Perceived Leadership Competence (TPLC) through the competencies has the potential to inform our understanding of leadership development. Description Five cohorts of NH-ME leadership education in neurodevelopmental disabilities trainees (n = 102) completed the MCH Leadership Competencies Self-Assessment at three time points. Paired-sample t tests examined TPLC scores. A one-way analysis of variance tested for statistically significant differences in mean difference scores. A General Linear Model was used to examine the extent to which TPLC scores changed when controlling for specific variables. Assessment Statistically significant differences in mean scores between Time 1 and Time 3 were found. Cohen's d effect sizes fell in the moderate range. A one way ANOVA demonstrated significant differences between groups in the spheres of self and others. TPLC mean scores between Time 1 and Time 3 in the sphere of wider community had the highest increases in four out of five cohorts. Age, discipline, experience, and relationship to disability did not contribute to the model. Conclusion On average, cohorts began the year with very different evaluations of their leadership competence but finished the year with similar scores. This suggests participation in the NH-ME LEND Program consistently supported the development of leadership self-identity. Small sample sizes limit the ability to draw definitive conclusions from these results. Further study with a larger sample may reveal relationships between cohort characteristics and change scores. PMID- 30006732 TI - Gestational Weight Loss: Comparison Between the Birth Certificate and the Medical Record, Florida, 2012. AB - Objective Examine agreement with the medical record (MR) when gestational weight loss (GWL) on the Florida birth certificate (BC) is >= 0 pounds (lbs). Methods In 2012, 3923 Florida-resident women had a live, singleton birth where BC indicated GWL >= 0 lbs. Of these, we selected a stratified random sample of 2141 and abstracted from the MR prepregnancy and delivery weight data used to compute four estimates of GWL (delivery minus prepregnancy weight) from different sources found within the MR (first prenatal visit record, nursing admission record, labor/delivery records, BC worksheet). We assessed agreement between the BC and MR estimates for GWL categorized as 0, 1-10, 11-19, and >= 20 lbs. Results Prepregnancy or delivery weight was missing or source not in the MR for 23-81% of records. Overall agreement on GWL between the BC and the four MR estimates ranged from 39.1 to 57.2%. Agreement by GWL category ranged from 10.6 to 38.0% for 0 lbs, 47.6 to 64.3% for 1-10 lbs, 49.5 to 60.0% for 11-19 lbs, and 47.8 to 67.7% for >= 20 lbs. Conclusions Prepregnancy and delivery weight were frequently missing from the MR or inconsistently documented across the different sources. When the BC indicated GWL >= 0 lbs, agreement with different sources of the MR was moderate to poor revealing the need to reduce missing data and better understand the quality of weight data in the MR. PMID- 30006733 TI - Molecular characterization of Hb H disease in southern Thailand. AB - Genotypes of 260 individuals with hemoglobin H (Hb H) disease originating from various provinces in southern Thailand were characterized by multiplex PCR (M PCR) and reverse dot blot hybridization (RDB). M-PCR was used to amplify target fragments and then hybridized with allele-specific oligonucleotide (ASO) probes which were bound on a nylon membrane. A total of eight alpha-thalassemia (alpha thal) mutations, which produced eight Hb H disease genotypes (alpha0-thal/alpha+ thal), were detected. The most common form of alpha0-thal was -SEA with a frequency of 99.23%. The other form (0.77%) of alpha0-thal mutation was a THAI deletion (-THAI). The deletional alpha+-thal mutations comprised 3.7 kb ( alpha3.7) and 4.2 kb (-alpha4.2) deletions which were found in 172 (66.15%) and 5 (1.92%) alleles, respectively. The incidence of non-deletional alpha+-thal in decreasing order was Hb Constant Spring (Hb CS, alphaCS) 28.85%, Hb Quong Sze (Hb QS, alphaQS) 1.54%, and Hb Pakse (Hb PS, alphaPS) 0.77%. The genotype characterization of Hb H disease and the development of the RDB technic for detection of alpha-thal mutations presented in this study enable the prenatal diagnosis of Hb Bart's hydrops fetalis syndrome. PMID- 30006734 TI - Current trends in pharmacovigilance: value and gaps of patient reporting. PMID- 30006735 TI - Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-beta accumulation in Alzheimer's disease. AB - Alzheimer's disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-beta (Abeta) in human brain is still not well understood. To identify novel genes that cause accumulation of Abeta in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Abeta level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Abeta accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis. PMID- 30006736 TI - Phenotypic and genotypic overlap between mosaic NF2 and schwannomatosis in patients with multiple non-intradermal schwannomas. AB - Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult. PMID- 30006737 TI - Admixture mapping and fine-mapping of birth weight loci in the Black Women's Health Study. AB - Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight. In addition, we performed a replication analysis of 11 previously identified index single nucleotide polymorphisms (SNPs), and fine-mapped those genetic loci to identify better or new genetic variants associated with birth weight in African-Americans. We found that high African ancestry at 12q14 was associated with low birth weight, and we identified multiple independent birth weight-lowering variants in this genomic region. We replicated the association of a previous GWAS SNP in ADRB1 and our fine-mapping efforts suggested the presence of new birth weight-associated variants in ADRB1, HMGA2, and SLC2A4. Further studies are needed to determine whether birth weight-associated loci can in part explain race-associated birth weight disparities. PMID- 30006738 TI - Does patient age influence anti-cancer immunity? AB - Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient's own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti cancer immunity may be compromised in the elderly due to (i) their low amounts of naive T cells (potentially leading to holes in the repertoire for neoantigens), (ii) "exhaustion" of potentially tumor-specific memory T cells, and (iii) higher amounts of suppressive cells. Encouragingly, but only anecdotally, accumulated clinical experience suggests that advanced age does not result in poorer responses or greater toxicity in elderly patients treated with anti-CTLA-4 or anti-PD-1/PD-L1 antibodies. Here, I briefly contrast immune features of the elderly with the young, commonly referred to as "immunosenescence," and the influence of patient age on the outcome of checkpoint blockade. As newer agents are licensed, and new combinations tested, broader and more detailed studies focusing on the age question will be crucial and should be taken into consideration when designing clinical trials. PMID- 30006739 TI - Cancer immune therapy for lymphoid malignancies: recent advances. AB - Immunotherapy has played an important part in improving the life of patients with lymphoproliferative diseases especially since the addition of rituximab to chemotherapy in the CD20-positive neoplasms in the 1990s. While this field of passive immunotherapy is continuously evolving, several breakthroughs will expand the treatment modalities to include more active immunotherapy. With the approval of immune checkpoint-blocking antibodies for Hodgkin lymphoma and bispecific antibodies for acute lymphoblastic leukemia (ALL), activation of endogenous T cells already plays a role in several lymphoid malignancies. With the approval of cellular therapies with CAR-T cells for ALL and diffuse large B cell lymphoma, the impact of the manipulation of immune responses is taken even further. Vaccines are cellular therapies in the opposite end of the spectrum in terms of side effects, and while the big breakthrough is still to come, the prospect of a very low-toxic immunotherapy which could be applicable also in premalignant states or in frail patients drives a considerable research activity in the area. In this review, we summarize the mechanisms of action and clinical data on trials in the lymphoid neoplasms with chimeric antigen receptor T cells, bispecific antibodies, immune checkpoint-blocking antibodies, and antineoplastic vaccination therapy. PMID- 30006740 TI - B. Leonard Holman, MD. (1941-1998). PMID- 30006741 TI - Poor tracking of myocardial walls and inaccurate estimation of systolic parameters in myocardial hypertrophy on gated myocardial perfusion SPECT resulted from erroneous placement of region of interest and contouring: A pitfall of commercially available software packages for cardiac analysis. PMID- 30006742 TI - Acupuncture for cancer-related fatigue in lung cancer patients: methodological and statistical issues. PMID- 30006743 TI - [Seasonal variation in surgical diseases : Is an economic resource management necessary?] AB - BACKGROUND: The registration of diagnoses and diagnose-related groups (DRG) allows conclusions to be drawn about the distribution over the course of the year. Seasonal variations can be recognized and used to plan further resource management. METHODS: From 2006 to 2016 a total of 30,999 main diagnoses and DRGs were registered at the hospital for visceral surgery of the University Medical Hospital in Leipzig. The data were sorted on a monthly and seasonal basis and compared to meteorological data received from the German Meteorological Service. Furthermore, epidemiological information about the patients was recorded. RESULTS: The most frequently registered main diagnosis was malignant neoplasms of the liver and intrahepatic bile ducts with 1589 cases (C22), followed by acute appendicitis with 1557 cases (K35). There was a significant seasonal and monthly variation for cholelithiasis (K80) with 1013 cases (p = 0.002++), inguinal hernia (K40), 887 cases (p = 0.002++), ventral hernia (K43), 696 cases (p < 0.001++) and varices of the lower limbs (I83), 352 cases (p < 0.001++). A similar correlation could be shown for daily sunshine hours and case numbers for patients with the main diagnosis groups I83 (r = -0.12, p = 0.036+) and K43 (r = -0.08, p = 0.041+). Another significant correlation was observed between patients' epidemiological information and medical data: patient-related clinical severity (PCCL) ~ age (r = 0.27, p < 0.001++), length of hospital stay ~ age (r = 0.25, p < 0.001++), duration of ventilation ~ age (r = 0.07, p < 0.001++) and mortality ~ age (r = 0.09, p < 0.001++). CONCLUSION: A seasonal variation in case numbers for individual main diagnoses could be registered and elective and therefore plannable surgeries were mostly affected. An adequate resource management can reveal economic benefits. Older patients consume a high amount of resources and should be given a higher priority. PMID- 30006744 TI - [Speech therapy after thyroid gland operations in Germany: analysis of routine data from 50,676 AOK patients]. AB - BACKGROUND: This study investigated the frequency of postoperative speech therapy in the context of vocal cord palsy after thyroid surgery based on nationwide routine data. Additionally, volume-outcome relationships were examined. MATERIAL AND METHODS: Nationwide routine data from insured patients of the Local Health Insurance Fund (AOK) who underwent thyroid surgery for a benign thyroid disease between 2013 and 2015 were analyzed. Postoperative speech therapy was determined based on prescription data. Transient and permanent vocal cord palsy were determined using indicators. The effect of hospital volumes (volume quintiles) on prescription of postoperative speech therapy was determined by multivariate logistic regression. RESULTS: A total of 50,676 thyroid gland operations were identified. The overall frequency of postoperative speech therapy prescription was 6.5%. In AOK patients with transient or permanent vocal cord palsy, the frequencies of postoperative speech therapy prescription were 56.1% and 75.2%, respectively. The prescription volume of the normal case (>=21 units of speech therapy) was exceeded in 0.7% of the AOK patients. In the two lowest case volume categories the risk of postoperative speech therapy exceeding the prescription volume of the normal case was significantly higher compared to the highest case volume hospitals (odds ratios: 1.2 and 1.8, respectively). CONCLUSION: This study presents the reality of healthcare with respect to the frequency of speech therapy prescription after thyroid gland surgery in Germany. In addition, it was determined that the risk of postoperative speech therapy prescription exceeding the volume of the normal case after thyroid gland operations decreases with increasing case volumes of hospitals. PMID- 30006745 TI - A one-dimensional mathematical model of collecting lymphatics coupled with an electro-fluid-mechanical contraction model and valve dynamics. AB - We propose a one-dimensional model for collecting lymphatics coupled with a novel Electro-Fluid-Mechanical Contraction (EFMC) model for dynamical contractions, based on a modified FitzHugh-Nagumo model for action potentials. The one dimensional model for a deformable lymphatic vessel is a nonlinear system of hyperbolic Partial Differential Equations (PDEs). The EFMC model combines the electrical activity of lymphangions (action potentials) with fluid-mechanical feedback (circumferential stretch of the lymphatic wall and wall shear stress) and lymphatic vessel wall contractions. The EFMC model is governed by four Ordinary Differential Equations (ODEs) and phenomenologically relies on: (1) environmental calcium influx, (2) stretch-activated calcium influx, and (3) contraction inhibitions induced by wall shear stresses. We carried out a stability analysis of the stationary state of the EFMC model. Contractions turn out to be triggered by the instability of the stationary state. Overall, the EFMC model allows emulating the influence of pressure and wall shear stress on the frequency of contractions observed experimentally. Lymphatic valves are modelled by extending an existing lumped-parameter model for blood vessels. Modern numerical methods are employed for the one-dimensional model (PDEs), for the EFMC model and valve dynamics (ODEs). Adopting the geometrical structure of collecting lymphatics from rat mesentery, we apply the full mathematical model to a carefully selected suite of test problems inspired by experiments. We analysed several indices of a single lymphangion for a wide range of upstream and downstream pressure combinations which included both favourable and adverse pressure gradients. The most influential model parameters were identified by performing two sensitivity analyses for favourable and adverse pressure gradients. PMID- 30006748 TI - Facile Synthesis of Ligand-Free Iridium Nanoparticles and Their In Vitro Biocompatibility. AB - High-density inorganic nanoparticles have shown promise in medical applications that utilize radiation including X-ray imaging and as radiation dose enhancers for radiotherapy. We have developed an aqueous synthetic method to produce small (~ 2 nm) iridium nanoparticles (IrNPs) by reduction of iridium(III) chloride using a borohydride reducing agent. Unlike other solution-based synthesis methods, uniform and monodispersed IrNPs are produced without the use of surfactants or other solubilizing ligands. These nanoparticles are highly crystalline as observed by X-ray diffraction and high-resolution transmission electron microscopy (TEM). In vitro metabolic toxicity assays using hepatocyte and macrophage cells demonstrate that both IrNPs and iridium(III) chloride are well tolerated at concentrations of up to 10 MUM iridium. Furthermore, the IrNPs were assessed in a hemolytic assay and found to have no significant impact on red blood cells when exposed to concentrations up to 100 MUM. Overall, these results support the potential for the in vivo application of this nanomaterial. PMID- 30006749 TI - Health effects among a cohort exposed to low-level arsenic in a geothermal area of Tuscany, Italy. AB - BACKGROUND: Studies on low-level As exposure have not found an association with cancer, while increased risks were reported for skin lesions, respiratory and cardiovascular diseases and reproductive outcomes. Prospective observational studies with individual exposure measures are needed to study low-level As exposure effects. In a geothermal area in Southern Tuscany (Italy), characterized by a natural presence of As in drinking water (< 50 ug/l), As urinary concentrations were measured in a survey in 1998 and cohort members were followed to evaluate the effects on health. METHODS: Around 900 subjects (20-55 years old) randomly sampled in 4 municipalities of the area (Monte Amiata), have been followed from 1999 to 2015, by hospitalisation and mortality registries. Standardized Hospitalisation Ratios (SHRs) were performed, compared to a reference area. Competing-risks regression models were performed to test the association between As urinary concentration and risk of first hospitalisation. RESULTS: SHRs show various increased risks, more frequently among males. Internal analyses show a positive association between As and skin diseases in the general population, the Hazard Ratio (HR) for 1 ug/l increase of As urinary concentration is 1.06 (90%CI 1.01-1.11) and in males, HR 1.08 (90%CI 1.02-1.14), between As and circulatory system diseases in males, HR 1.03 (90%CI 1.01-1.05). CONCLUSIONS: The results suggest an effect on skin diseases and circulatory system diseases and, considering the relative young age of cohort members, they could be considered also as predictive of future severer diseases. PMID- 30006751 TI - The mechanistic role of oxidative stress in cigarette smoke-induced cardiac stem cell dysfunction and prevention by ascorbic acid. AB - Cigarette smoking causes a vast array of diseases including cardiovascular diseases. Our laboratory focuses on investigating cigarette smoke (CS)-induced cardiovascular malfunction and the responsible mechanisms utilizing the model, c kit-positive cardiac stem cells (CSCs). The main objective of our study is to investigate whether CS extracts (CSEs) cause impairment of CSC functions via oxidative damage. We hypothesized that CSE, via oxidative modifications of CSC proteins and antioxidant enzymes, can modulate CSC functions and these modifications can be attenuated by ascorbate treatment. Our specific aims are (1) to investigate CSE-induced oxidative modification of CSC proteins via carbonylation, and prevention by ascorbic acid; (2) to investigate CSE-induced oxidative modification of antioxidant enzymes and ascorbic acid-mediated modulations; and (3) to investigate CSE-induced changes in CSC functions and protection by ascorbic acid. CSCs were cultured, and the aqueous extracts of CSE were prepared. CSE-induced modulations of CSC viability, oxidative modification of proteins, and antioxidant enzyme activities were detected using standard assays including Apostain, bromodeoxyuridine, and Oxiblot. CSE caused oxidative modification of CSC proteins, changed antioxidant enzyme levels, attenuated CSC proliferation, and accelerated CSC apoptosis. Ascorbic acid prevented CSE-induced CSC malfunctions, and ascorbic acid therapy might be useful in smoker CSC recipients and to condition CSCs prior to the transplant in the future. Cardiac stem cell therapy is currently undergoing in clinical trials. PMID- 30006750 TI - Platelet-rich plasma does not reduce skeletal muscle fibrosis after distraction osteogenesis. AB - BACKGROUND: Skeletal muscle fibrosis caused by an increase in collagen deposition often occurs after distraction osteogenesis. Although studies are available reporting the effects of platelet-rich plasma (PRP) on tissue healing following injury, current findings remain controversial. This study focused on determining whether PRP reduces skeletal muscle fibrosis caused by distraction osteogenesis. METHODS: Tibial osteotomies were performed on 8-week-old wild type mice, and tibiae were distracted at a rate of 0.42 mm/day for 2 weeks, starting 1 week after osteotomy. Immediately after distraction was completed (3 weeks after osteotomy), PRP or phosphate buffered saline (as a sham) was injected into the gastrocnemius (GC) muscle. The GC muscles were harvested and analyzed. RESULTS: The amount and area of collagenous tissue increased in both the PRP and control groups following distraction osteogenesis, but the changes were not significantly different between both groups at all time points (p = 0.89, 0.45, 0.33 and 0.52 at 4, 6, 8 and 10 weeks). CONCLUSION: From this study, our results suggest that PRP did not significantly reduce skeletal muscle fibrosis due to distraction osteogenesis. PMID- 30006752 TI - Prognostic value of 68 Ga PSMA I&T PET/CT SUV parameters on survival outcome in advanced prostat cancer. AB - OBJECTIVE: To determine the association of 68 Ga-PSMA-I&T PET/CT SUV parameters with survival outcome in advanced prostate cancer patients. METHODS: A total of 148 consecutive patients mean age: 69.3 +/- 7.8 years with advanced prostate cancer who underwent 68 Ga-PSMA-I&T PET/CT were included in this retrospective study. Data on previous treatments, serum PSA levels (ng/mL), 68 Ga-PSMA-I&T PET/CT findings metastases as well as survival data were recorded. RESULTS: Multivariate regression analysis revealed that Level 1 LN SUV/Liver SUV ratios > 2.17 (OR 4.262; 95% CI 1.104-16.453, p = 0.035), bone SUV > 10.7(OR 23.650; 95% CI 4.056-137.888, p < 0.001), bone SUV/spleen SUV ratio > 1.842 (OR 25.324; 95% CI 4.204-152.552, p < 0.001), highest SUVmax/liver SUV ratio > 2.32 (OR 19.309; 95% CI 1.730-209.552, p = 0.016) and highest SUVmax/spleen SUV ratio > 1.842 (OR 22.354; 95% CI 2.637-189.493, p = 0.004) were significant in the determination of increased mortality risk in advanced prostate cancer patients. CONCLUSION: Our findings, for the first time in literature, provided evidence on potential utility of tracer uptake (SUV) cut-off values on 68 Ga-PSMA PET/CT in identification of the survival outcome of patients with metastatic disease and thereby in assisting in the selection of individualized therapeutic strategies tailored to the expected prognosis. PMID- 30006753 TI - Differential expression of E-cadherin and P-cadherin in pT3 prostate cancer: correlation with clinical and pathological features. AB - Cadherins seem to play and important role in prostate cancer (PCa) progression. E cadherin loss of expression has been associated with poor prognosis; P-cadherin's role is still elusive. Although pT3 PCa is often considered "high-risk cancer," it does not exhibit an uniformly poor prognosis. Herein, we assessed the prognostic value and survival impact of E-cadherin and P-cadherin immunoexpression in pT3 PCa. Radical prostatectomy (RP) specimens from 102 pT3 PCa patients treated between 1991 and 2014 in a single institution were designated for E-cadherin and P-cadherin immunoexpression analysis. A representative block from each specimen was selected for tissue micro-array (TMA) construction, using 3 cores per case. E-cadherin immunoexpression was assessed via a digital image analysis system. For P-cadherin, scoring criteria for HER2 in gastric cancer were used. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow-up data. E-cadherin-low PCa patients displayed worse disease-specific survival (DSS), although not reaching statistical significance (HR 2.65, 95%CI 0.81-7.88). However, considering the pT3b group only, those with low E-cadherin immunoexpression displayed significantly worse overall-survival (OS) and DSS (HR 3.69, 95%CI 1.18 11.50; HR 5.90, 95%CI 1.40-24.81). No significant differences in survival were found for P-cadherin differential immunoexpression. Furthermore, an association between E-cadherin and P-cadherin immunoexpression (p = 0.019) was found, as among E-cadherin-low PCa, 96.6% were P-cadherin negative. We demonstrated that low E-cadherin immunoexpression discriminates among pT3b PCa patients those with poorer survival and which might benefit from specific therapy. The role of P cadherin in PCa seems context-dependent deserving further investigation. PMID- 30006755 TI - Skin toxicity with anti-EGFR monoclonal antibody in cancer patients: a meta analysis of 65 randomized controlled trials. AB - We performed a meta-analysis to fully investigate the skin toxicities of anti EGFR monoclonal antibody (EGFR-MoAbs) in cancer patients. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with EGFR MoAbs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till November 2017. The relevant RCTs in cancer patients treated with EGFR-MoAbs were retrieved and the systematic evaluation was conducted. 65 RCTs and 25994 patients were included. The current meta-analysis suggests that the use of EGFR-MoAbs significantly increases the risk of developing all-grade and high-grade skin toxicity, such as rash, hand-foot syndrome, dry skin and oral mucositis. Rash was the most common skin toxicity. Patients receiving nimotuzumab were associated with the least risk of skin toxicity. The risk of high-grade skin toxicity tended to be higher in the study in which the EGFR-MoAbs treatment duration was longer. The available data suggested that the use of EGFR-MoAbs significantly increases the risk of developing skin toxicity. Physicians should be aware of skin toxicity and should monitor cancer patients when receiving EGFR-MoAbs. PMID- 30006754 TI - Photodynamic and photobiological effects of light-emitting diode (LED) therapy in dermatological disease: an update. AB - Benefit deriving from the use of light is known since ancient time, but, only in the last decades of twentieth century, we witnessed the rapid expansion of knowledge and techniques. Light-emitted diode (LED)-based devices represent the emerging and safest tool for the treatment of many conditions such as skin inflammatory conditions, aging, and disorders linked to hair growth. The present work reviews the current knowledge about LED-based therapeutic approaches in different skin and hair disorders. LED therapy represents the emerging and safest tool for the treatment of many conditions such as skin inflammatory conditions, aging, and disorders linked to hair growth. The use of LED in the treatment of such conditions has now entered common practice among dermatologists. Additional controlled studies are still needed to corroborate the efficacy of such kind of treatment. PMID- 30006757 TI - CRISPR/Cas9-mediated homologous recombination in tobacco. AB - KEY MESSAGE: Co-transformation of multiple T-DNA in a binary vector enabled CRISPR/Cas9-mediated HR in tobacco. HR occurred in a limited region around the gRNA target site. In this study, CRISPR/Cas9-mediated homologous recombination (HR) in tobacco (Nicotiana tabacum L. 'SR-1') was achieved using binary vectors comprising two (T1-T2) or three (T1-T2-T3) independent T-DNA regions. For HR donor with the tobacco acetolactate synthase gene, SuRB, T-DNA1 contained DeltaSuRBW568L, which lacked the N-terminus region of SuRB and was created by three nucleotide substitutions (ATG to GCT; W568L), leading to herbicide chlorsulfuron (Cs) resistance, flanked by the hygromycin (Hm)-resistant gene. T DNA2 consisted of the hSpCas9 gene and two gRNA inserts targeting SuRB and An2. For the 2nd HR donor with the tobacco An2 gene encoding a MYB transcription factor involved in anthocyanin biosynthesis, T-DNA3 had a 35S promoter-driven An2 gene lacking the 3rd exon resulting in anthocyanin accumulation after successful HR. After selecting for Hm and Cs resistance from among the 7462 Agrobacterium inoculated explants, 77 independent lines were obtained. Among them, the ATG to GCT substitution of endogenous SuRB was detected in eight T1-T2-derived lines and two T1-T2-T3-derived lines. Of these mutations, four T1-T2-derived lines were bi allelic. All the HR events occurred across the endogenous SuRB and 5' homology arm of the randomly integrated T-DNA1. HR of the SuRB paralog, SuRA, was also found in one of the T1-T2-derived lines. Sequence analysis of its SuRA-targeted region indicated that the HR occurred in a limited (< 153 bp) region around the gRNA target site. Even though some T1-T2-T3-derived lines introduced three different T-DNAs and modified the An2 gRNA target site, no signs of HR in the endogenous An2 could be observed. PMID- 30006756 TI - Variability of Some Milk-Associated Genes and Proteins in Several Breeds of Saudi Arabian Camels. AB - To gain knowledge on the molecular basis of diversity of several clans of Saudi camel (Camelus dromedarius) characterization of these animals was conducted at both genetic and protein levels. To this end, blood and milk samples were collected from several camel breeds at different Saudi Arabia locations (northern Jeddah, Riyadh, and Alwagh governorates). Genomic DNA was extracted from blood of four Saudi camel breeds (Majahem, Safra, Wadha, and Hamara), and DNA fragments of the casein and alpha-lactalbumin genes were amplified. The retrieved DNA sequences were analyzed for genetic variability. The inter-simple sequence repeat technique was used for confirming the relationships among the analyzed camel breeds, and the PCR-RFLP with two restriction enzymes was utilized for exploring their molecular variations. The number of haplotypes, gene diversity, nucleotide diversity, average number of nucleotide differences, and sequence conservation were calculated for all the analyzed DNA sequences. These analyses revealed the presence of several single nucleotide polymorphisms in the analyzed DNA sequences. A group of neighbor joining trees was built for inferring the evolutionary variations among the studied animals. Protein profiling of milk from different camel clans was also conducted, and differences between and within the Saudi camel clans were easily found based on the isoelectric focusing (IEF) profiles using ampholytes with different IEF range. This study revealed that analyzed camel breeds show low levels of genetic differences. This may be a reflection of the evolutionary history of C. dromedarius that was domesticated based on a highly homogeneous ancestor ecotype. PMID- 30006758 TI - Hard ticks as vectors-some basic issues. AB - There are various arthropods (e.g. insects, chiggers, mites, ticks) that take one or more blood meals on terrestrial vertebrates in the course of their lifetime. Among them are ixodid ticks (Acari, Ixodidae), all of which are obligately hematophagous. Their parasitic lifestyle predestines them to act as transmitters or vectors of microparasites, often pathogenic to humans and/or domestic animals. The list of ixodid tick-borne pathogens is long, encompassing viruses, bacteria, protozoans, and nematodes. The present mini-review gives a brief overview of the most relevant biological attributes that make ixodid ticks very efficient vectors compared with other hematophagous arthropod taxa. PMID- 30006761 TI - Neonatal Dexamethasone Treatment Suppresses Hippocampal Estrogen Receptor alpha Expression in Adolescent Female Rats. AB - Previous studies showed that neonatal dexamethasone treatment (NDT) transiently impaired hippocampal function in male rats. Hippocampal estrogen receptors (ERs) participate in avoidance learning. As previous studies focused on males only, this study was aimed to investigate the NDT effects on the hippocampal function of female rats. Newborn Wistar female rats were subjected to a tapering dose of dexamethasone (0.5 mg, 0.3 mg, and 0.1 mg/kg, subcutaneously) from postnatal days 1 to 3 and were subjected to experiments at the age of 6 weeks (adolescence). Brain slice extracellular recording and the inhibitory avoidance (IA) test were used to evaluate the NDT effects on hippocampal function. The results showed that NDT completely blocked the hippocampal long-term potentiation (LTP) formation and IA learning of adolescents. The expression of hippocampal estrogen receptor alpha (ERalpha) was attenuated in NDT subjects. Reduced histone acetylation of the ERalpha gene was found, possibly explaining the reduced hippocampal ERalpha expression in NDT female rats. Suprafusion of estradiol (E2) partially restored the hippocampal LTP formation in adolescent NDT female rats. Coadministration of the histone deacetylase inhibitor trichostatin-A restored the hippocampal ERalpha expression, hippocampal LTP formation, and IA learning in adolescent NDT female rats. Collectively, these results suggested that NDT has an epigenetic modulation effect on the expression of hippocampal ERalpha, which is responsible for its adverse effect on hippocampal function. PMID- 30006760 TI - Multigroup latent class model of musculoskeletal pain combinations in children/adolescents: identifying high-risk groups by gender and age. AB - BACKGROUND: To investigate the combinations of Musculoskeletal pain (MSP) (neck, shoulder, upper and low back pain) among a sample of Iranian school children. METHODS: The MSP combinations was modeled by latent class analysis (LCA) to find the clusters of high-risk individuals and multigroup LCA taking into account the gender and age (<= 13 years and >= 14 years of age categories). RESULTS: The lowest and highest prevalence of MSP was 14.2% (shoulder pain in boys aged >=14 years) and 40.4% (low back pain in boys aged <=13 years), respectively. The likelihood of synchronized neck and low back pain (9.4-17.7%) was highest, while synchronized shoulder and upper back pain (4.5-9.4%) had the lowest probability. The probability of pain at three and four locations was significantly lower in boys aged >=14 years than in other gender-age categories. The LCA divided the children into minor, moderate, and major pain classes. The likelihood of shoulder and upper back pain in the major pain class was higher in boys than in girls, while the likelihood of neck pain in the moderate pain class and low back pain in the major pain class were higher in children aged >=14 years than those aged <=13 years. Gender-age specific clustering indicated a higher likelihood of experiencing major pain in children aged <=13 years. CONCLUSIONS: The findings highlight the importance of gender- and age-specific data for a more detailed understanding of the MSP combinations in children and adolescents, and identifying high-risk clusters in this regard. PMID- 30006762 TI - The effect of resistance training on cognitive function in the older adults: a systematic review of randomized clinical trials. AB - BACKGROUND: Aging is often accompanied by decline in aspects of cognitive function. Cognitive decline has harmful effects on living independence and general health. Resistance training is seen as a promising intervention to prevent or delay cognitive deterioration, yet the evidence from reviews is less consistent. AIM: To assess the effect of resistance training on cognition in the elderly with and without mild cognitive impairment and to provide an up-to-date overview. METHODS: A search was conducted using PUBMED, Web of science, MEDLINE, CINAHL, Cochrane Library, EMBASE, Wan Fang, and China National Knowledge Infrastructure. The searches were limited to articles published in English or Chinese from January 2010 to September 2017. RESULTS: The search returned 2634 records, of which 12 articles were included in the systematic review. Main results showed that resistance training had positive effects on the executive function and global cognitive function of the elderly, and short-term interventions had little positive effect on memory and attention. Secondary results demonstrated that there was a significant benefit of triweekly resistance training in global cognitive function and biweekly in executive function of the elderly. CONCLUSIONS: Resistance training had positive effects on the executive cognitive ability and global cognitive function among the elderly; however, it had a weak-positive impact on memory. No significant improvement was found in attention. Triweekly resistance training has a better effect on general cognitive ability than biweekly. Further studies are needed focusing on the development and application of resistance training among the elderly. PMID- 30006763 TI - An 87-year-old female with interest in music, botany, trekking stories, politics and ... junk. PMID- 30006759 TI - Ludwig Boltzmann Cluster Oncology (LBC ONC): first 10 years and future perspectives. AB - In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The general aim of the LBC ONC is to improve treatment of hematopoietic neoplasms by eradicating cancer-initiating and disease propagating cells, also known as leukemic stem cells (LSC) in the context of leukemia. In a first phase, the LBC ONC characterized the phenotype and molecular aberration profiles of LSC in various malignancies. The LSC phenotypes were established in acute and chronic myeloid leukemia, in acute lymphoblastic leukemia and in chronic lymphocytic leukemia. In addition, the concept of preleukemic (premalignant) neoplastic stem cells (pre-L-NSC) was coined by the LBC ONC and was tested in myelodysplastic syndromes and myeloproliferative neoplasms. Phenotypic characterization of LSC provided a solid basis for their purification and for the characterization of specific target expression profiles. In a second phase, molecular markers and targets were validated. This second phase is ongoing and should result in the development of new diagnostics parameters and novel, more effective, LSC-eradicating, treatment strategies; however, many issues still remain to be solved, such as sub-clonal evolution, LSC niche interactions, immunologic control of LSC, and LSC resistance. In the forthcoming years, the LBC ONC will concentrate on developing LSC-eradicating strategies, with special focus on LSC resistance, precision medicine and translation of LSC-eradicating concepts into clinical application. PMID- 30006764 TI - GUROPA survey: genito-urinary radiation oncology prescription attitudes. AB - AIMS: To investigate the role of Radiation Oncology in the management of genito urinary (GU) cancer excluding prostate and penile cancer. METHODS: The questionnaire was focused on the evaluation of the degree of involvement of radiation oncologists in the work-up of bladder, renal cell carcinoma and testicular cancer (TC). RESULTS: Eighty-eight radiation oncologists completed the survey. The majority (85.4%) of participating radiation oncologists were senior consultants (> 5 years of experience). Sixty-four (73.6%) carried out a multidisciplinary tumor board discussion of GU cases, while 23 (26.4%) did not. Seventy-five percent of responders reported that, every year, visited < 50 GU patients (pts), 18.1% visited 50-100 pts and 6.9% visited > 100 pts. Bladder cancer, curative radiotherapy (RT) as part of trimodality approach was claimed to be adopted in less than 10 cases per year. Regarding renal cell carcinoma (RCC) patients, primary tumor directed RT was adopted only in 8 cases (9.4%) in at least 10 pts per year. Palliative RT was more frequent in RCC (48.2%) in over than 10 pts per year. In case of TC, the prescription of RT was limited (< 10 patients per year) due to the low incidence of disease and recent shift to surveillance as a first option in stage I seminoma. CONCLUSIONS: Our survey showed that radiation oncologists are rarely involved in the decision making strategy of GU cancer, despite many clinical trials support RT use. These patients probably deserve a more uniform approach based on updated, detailed and evidence-based recommendations. PMID- 30006765 TI - Crossed cerebellar hyperperfusion in patients with seizure-related cerebral cortical lesions: an evaluation with arterial spin labelling perfusion MR imaging. AB - PURPOSE: Crossed cerebellar (CC) diaschisis refers to a decrease in cerebellar perfusion in the presence of contralateral supratentorial lesions. Most of the previous studies have examined stroke patients. In contrast to strokes, seizure related cerebral cortical lesions (SCCLs) usually show hyperperfusion, and therefore, cerebellar perfusion patterns are expected to be different from those of strokes. With arterial spin labelling (ASL), we evaluated the cerebellar perfusion status in patients with SCCLs. MATERIALS AND METHODS: Using a search of the recent database over the last 31 months, 26 patients were enrolled in this study. The inclusion criteria were as follows: (1) a history of seizures, (2) MR examination taken within 24 h from the last seizure, (3) the presence of SCCLs on T2/FLAIR or DWI, (4) hyperperfusion in the corresponding areas of SCCLs on ASL, and (5) no structural abnormality in the cerebellum. The perfusion status in the contralateral cerebellum was evaluated and categorized as hyper-, iso- and hypoperfusion. The asymmetric index (AI) of cerebellar perfusion was calculated by ROI measurement of the signal intensity on ASL. RESULTS: The mean time between the last seizure and MR examinations was 5 h 30 min. CC hyperperfusion was observed in 17 patients (65.4%), hypoperfusion in 7 (26.9%) and isoperfusion in 2 (7.7%). Regarding the location of SCCLs, CC hyperperfusion was more frequent (71.4 vs. 58.3%), and the mean AI was higher (42.0 vs. 11.5) when the lesion involved the frontal lobe. CONCLUSIONS: In patients with SCCLs, CC hyperperfusion occurred more often than hypo- and isoperfusion, especially when the lesions involved the frontal lobe. PMID- 30006767 TI - Targeting the Neuromuscular Junction in ALS. PMID- 30006766 TI - Inflammatory Bowel Disease in the Baby to Baby Boomer: Pediatric and Elderly Onset of IBD. AB - PURPOSE OF REVIEW: Early- and late-onset of inflammatory bowel disease (IBD) may perhaps be etiologically distinct and potentially attributed to genetics, environmental or microbial factors. We review disease factors and clinical characteristics, as well as unique management and treatment strategies to consider when caring for the "baby" or "baby boomer" with IBD. RECENT FINDINGS: Around 25% of cases of initial diagnosis of IBD is made before the age of 18 years old, and another 15-20% made after the age of 60. Crohn's disease (CD) typically presents as ileocolonic and stricturing or penetrating phenotype among early-onset, whereas among late-onset, it is mainly colonic and inflammatory. Pediatric ulcerative colitis (UC) is mostly pan-colonic versus primarily left sided among the elderly. Treatment goal for both age groups is primarily symptom control, with growth and development also considered among pediatric patients. Due to alterations in pharmacokinetics, careful monitoring and reduced dose should be considered. A multidisciplinary care team is necessary to ensure better clinical outcomes. Onset of disease at either spectrum of age requires careful management and treatment, with both unique disease- and age-appropriate factors carefully considered. PMID- 30006768 TI - EHealth literacy in patients with cancer and their usage of web-based information. AB - OBJECTIVE: Our aim was to learn more about the association between the sources of information cancer patients and caregivers use and their eHealth literacy. METHODS: We distributed a standardized questionnaire among participants of a lecture program on complementary and alternative medicine (CAM). RESULTS: Among 182 attendants, the Internet was the third most important source of information (57%), preceded by the oncologist (67%) and print media (61%). Print media was associated with female participants and web-based information with younger ones. Regarding eHealth literacy, more than half (58.5%) had an above average eHEALS score. Nevertheless, the biggest concern was not being able to differentiate between reliable and not reliable websites. The correlation between a high eHealth literacy and regular search of web-based cancer information was significant (p < 0.001). CONCLUSION: The number of people using the Internet as a source of cancer information has increased over the past years and will rise in the future. However, only half of the population has the knowledge and capability to access and differentiate the massive web-based data. Improving eHealth literacy within the public will expand the knowledge of regular patients and help them become a well-informed and equal partner in decision making. PMID- 30006769 TI - [The slit lamp as videography console : Video article]. AB - BACKGROUND: Today's slit lamps have been optimized to realise the principle of focal illumination. When doing clinical work the result is that the slit lamp can be operated simply by using intuition; however, other applications are excluded due to the rigid construction principle. These other applications are summarized in the accompanying film (available online). METHODS: First, the slit lamp's classical fields of application are shown. Thereafter, a description follows of how modern methods of image processing and also simple alterations in the slit lamp illumination and observation optics open up exciting new perspectives for diagnostics and documentation. RESULTS: By relying on the freely available image processing program Hugin, conventional use of the illumination and observation units can generate much larger panoramic views of the anterior parts of the eye. By using an ophthalmoscope as the light source, early stage keratoconus can be diagnosed by leaving the slit lamp's observation unit unchanged and noting the arrangement of Purkinje images 1, 2 and 4. With the same arrangement a relative afferent pupil deficit can be reliably detected. If the observation optics are changed by holding a corrective concave lens in front of the slit lamp's objective lens, the plane of focus can be shifted to capture oculoplastic and strabismus findings. Finally, the film shows that the slit lamp in its present form has much less potential than a future-oriented fundus videography. CONCLUSION: By relying on thorough knowledge of the slit lamp's fundamental optics it is possible to suitably document all essential fields of ophthalmology using slit lamp videography. Slit lamp videography opens up a wide range of documentation possibilities, especially for the routine clinical work of general ophthalmologists. PMID- 30006770 TI - Transcranial electrical stimulation (tES) mechanisms and its effects on cortical excitability and connectivity. AB - In this review, we describe transcranial electrical stimulation (tES) techniques currently being used in neuroscientific research, including transcranial direct current (tDCS), alternating current (tACS) and random noise (tRNS) stimulation techniques. We explain how these techniques are used and summarise the proposed mechanisms of action for each technique. We continue by describing how each method has been used to alter endogenous neuronal oscillations and connectivity between brain regions, and we conclude by highlighting the varying effects of stimulation and discussing the future direction of these stimulation techniques in research. PMID- 30006772 TI - MED31 involved in regulating self-renewal and adipogenesis of human mesenchymal stem cells. AB - Regulation of gene expression is critical for the maintenance of cell state and homeostasis. Aberrant regulation of genes can lead to unwanted cell proliferation or misdirected differentiation. Here we investigate the role of MED31, a highly conserved subunit of the Mediator complex, to determine the role this subunit plays in the maintenance of human mesenchymal stem cell (hMSC) state. Using siRNA mediated knockdown of MED31 we demonstrate a decrease in self-renewal based on cell assays and monitoring of gene expression. In addition, in the absence of MED31, hMSCs also displayed a reduction in adipogenesis as evidenced by diminished lipid vesicle formation and expression of specific adipogenic markers. These data present evidence for a significant role for MED31 in maintaining adult stem cell homeostasis, thereby introducing potential novel targets for future investigation and use in better understanding stem cell behavior and adipogenesis. PMID- 30006771 TI - The application of gene marker-assisted selection and proteomics for the best meat quality criteria and body measurements in Qinchuan cattle breed. AB - In the past few decades, enhancement of animal productivity has been gaining increasing attention among decisions-makers, politicians, mangers, and breeders, because of the increasing of world population and shortage of natural resources. The selection of high productivity animals is the main goal, through the application of genetic improvement programs. The use of molecular genetics has conferred significant breeding advantages over conventional breeding techniques. In this regard, many economic characteristics are controlled by a small number of multiple gene loci, each of which is responsible for trait diversity and hence they are referred to as quantitative trait loci (QTL). Single-nucleotide polymorphisms (SNPs), which have recently been discovered through DNA sequencing, are considered one of the most useful types of genetic marker. SNPs are found where different nucleotides occur at the same position in the DNA sequence. They are found in both coding and noncoding regions of the genome and are present at one SNP in every 1000 b. Strategies for the identification and application of markers are based on reference to examples of loci that can control various traits. Furthermore, markers for growth, body measurements, and meat quality traits are preferred, because they can be used to predict the performance of animals, via blood samples, in the first few days of animal life. Marker-assisted selection using SNPs, such asSIRT1, SIRT2, LPL, CRTC2, SIX4, UCPs, and ZBTB38as selection criteria of body measurements and meat traits in beef cattle, will be beneficial in selection and breeding programs. The proteomic is a novel marker and a new approache of biotechnology which increases the understanding of the biological processes, besides being a remarkable biomarker that interrelated to growth and meat quality traits. Proteomics is a vigorous tool as usage for deduces molecular processes between quality traits and muscle proteins, which are helpful in analyzing the mechanisms of biochemistry that influence quality. So they could be potential biomarker for some meat quality traits. Among them, Actin, Myosin, Heat shock proteins are used a novel approaches in the field of biotechnology to understand the proteomics changes. This review article highlights the novel findings on the potential use of MAS and proteomics as biomarker for the selection for meat quality and carcass traits in Qinchuan cattle breed. PMID- 30006774 TI - Surgical correction of double major adolescent idiopathic scoliosis. PMID- 30006773 TI - Safety Profile of Benznidazole in the Treatment of Chronic Chagas Disease: Experience of a Referral Centre and Systematic Literature Review with Meta Analysis. AB - INTRODUCTION: Benznidazole is the preferred drug for treatment of Chagas disease. However, it is toxic and of limited value in chronic infection. OBJECTIVE: We aimed to estimate the rates of and factors related to adverse reactions (ARs) to benznidazole and treatment discontinuations (TDs). METHODS: A meta-analysis was performed using an electronic search of the published literature with no language restrictions until June 2017. Prospective studies were included of chronically infected patients in which at least one treatment arm included benznidazole. Data were added from a prospective cohort of patients with Chagas disease at our centre (January 2007-June 2017). Weighted rates of ARs and TDs were estimated, and potentially related factors were analysed. RESULTS: Some 413 studies were found, from which we chose 42 (nine clinical trials and 33 observational studies, including ours), comprising data for 7822 patients. The weighted rate of ARs to benznidazole was 44.1% (95% confidence interval [CI] 37.2-51.2). ARs were more frequent in adults than in children (51.6 vs. 24.5%), with the most common being skin reactions (34%), gastrointestinal complaints (12.6%) and neurological symptoms (11.5%). Grade 4 ARs were recorded in 3% of cases. The weighted rate of TDs was 11.4% (95% CI 8.5-14.5); TDs were more frequent in adults than in children (14.2 vs. 3.8%). In our cohort, only female sex was related to an increased rate of ARs but not to TDs. CONCLUSION: Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women. Optimised dosing schedules and/or new drugs are urgently needed. PMID- 30006775 TI - Full endoscopic, bilateral over-the-top decompression for lumbar spinal stenosis. PMID- 30006776 TI - Lumbar epidural and cervical facet joint injection techniques. PMID- 30006777 TI - ALIF L5/S1 in adolescent patient with osteochondrosis. PMID- 30006778 TI - Nutritional planning for Nellore heifers post-weaning to conception at 15 months of age: performance and nutritional, metabolic, and reproductive responses. AB - The objective of this study was to evaluate the effects of strategic supplementation in the dry period and dry/rainy transition period on the performance and nutritional, metabolic, and reproductive responses of Nellore heifers grazing Urochloa decumbens. Forty-eight Nellore heifers with age and body weight (BW) of eight months and 235 +/- 3.3 kg, respectively, were used. The experimental design was a completely randomized design, with four treatments, all with 12 replications. The evaluated strategies were as follows: low supplementation (LOHI; 0.2% of BW/heifer/day) in the first 90 days and high supplementation (0.6% of BW/heifer/day) in the 90 days thereafter; average supplementation (AVER) with 0.4% of BW/heifer/day for 180 days; high supplementation (HILO; 0.6% of BW/heifer/day) in the first 90 days and low supplementation (0.2% of BW/heifer/day) in the 90 days thereafter; only mineral mix (MM) ad libitum during the 180 days. Data were evaluated using orthogonal contrasts. Supplementation improved the performance of the animals during of dry period (P < 0.05) and dry/rainy transition period (P < 0.05). Supplemented animals had higher longissimus muscle area (LMA) and subcutaneous fat thickness (SFT) at the end of the experiment (P < 0.05). Multiple supplementation increased intake of dry matter (DM), organic matter (OM), and crude protein (CP) in kg/day throughout the experiment. The supplementation increased the digestibility of DM, OM, CP, apNDF, and TDN (P < 0.05). Serum urea nitrogen (SUN), glucose (GLUC), insulin (INS), and progesterone (PROG) were higher in supplemented heifers (P < 0.05). Supplementation reduced the concentrations of non-esterified fatty acids (NEFA) (P < 0.05) and increased conception rate (P < 0.05). In summary, the supplementation strategies adopted in this study improve the performance, metabolic status, and carcass traits of heifers under grazing, allowing an improvement in the conception rate of 15-month-old Nellore heifers. PMID- 30006779 TI - Differential effect of Androctonus australis hector venom components on macrophage KV channels: electrophysiological characterization. AB - Neurotoxins of scorpion venoms modulate ion channels. Voltage-gated potassium (KV) channels regulate the membrane potential and are involved in the activation and proliferation of immune cells. Macrophages are key components of the inflammatory response induced by scorpion venom. The present study was undertaken to investigate the effect of Androctonus australis hector (Aah) venom on KV channels in murine resident peritoneal macrophages. The cytotoxicity of the venom was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) -based assay and electrophysiological recordings were performed using the whole-cell patch clamp technique. High doses of Aah venom (50, 125, 250 and 500 ug/ml) significantly decreased cell viability, while concentrations of 0.1-25 ug/ml were not cytotoxic towards peritoneal macrophages. Electrophysiological data revealed a differential block of KV current between resting and LPS activated macrophages. Aah venom significantly reduced KV current amplitude by 62.5 +/- 4.78% (n = 8, p < 0.05), reduced the use-dependent decay of the current, decreased the degree of inactivation and decelerated the inactivation process of KV current in LPS-activated macrophages. Unlike cloned KV1.5 channels, Aah venom exerted a similar blocking effect on KV1.3 compared to KV current in LPS activated macrophages, along with a hyperpolarizing shift in the voltage dependence of KV1.3 inactivation, indicating a direct mechanism of current inhibition by targeting KV1.3 subunits. The obtained results, demonstrating that Aah venom differentially targets KV channels in macrophages, suggest differential outcomes for their inhibitions, and that further investigations of scorpion venom immunomodulatory potential are required. PMID- 30006780 TI - Feasibility of serum CGRP measurement as a biomarker of chronic migraine: a critical reappraisal. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) has been reported as elevated in chronic migraine. We aimed to validate the role of interictal serum CGRP concentration in peripheral blood samples as a biomarker of chronic migraine. METHODS: We prospectively recruited patients with episodic and chronic migraine and normal controls (NCs) in the Samsung Medical Center between August 2015 and May 2016. Blood samples were collected interictally from antecubital veins per prespecified protocol. Serum CGRP measurement was performed in the central laboratory by a single experienced technician blinded to clinical information. Migraine subtype, headache days in the previous month, and the presence and characteristics of headache at +/-2 days of measurement were evaluated at every visit. RESULTS: A total of 156 migraineurs (106 episodic and 50 chronic) and 27 NCs were recruited in this study. Compared to NCs (75.7 +/- 20.07 pg/mL) and patients with episodic migraine (67.0 +/- 20.70 pg/mL), patients with chronic migraine did not show an interictal elevation of serum CGRP levels (64.9 +/- 15.32 pg/mL). Serum CGRP concentration was not associated with headache status (ictal vs. interictal), migraine subtype (migraine with vs. without aura), use of preventive or acute medications, and comorbid medication overuse. Higher serum CGRP concentration did not predict treatment response in patients with chronic migraine. CONCLUSIONS: Serum CGRP concentration may not be a feasible biomarker for chronic migraine. Further validation is necessary before CGRP can be used in the clinical practice. PMID- 30006781 TI - miR-9 inhibits the metastatic ability of hepatocellular carcinoma via targeting beta galactoside alpha-2,6-sialyltransferase 1. AB - Glycosylation of cell surface proteins regulates critical cellular functions, including invasion and metastasis in cancer cells. Emerging evidence has shown that microRNAs (miRNAs) are involved in regulating both the glycosylation modifications on cell surface and the progression of cancer. In this study, we investigated the role of miR-9 in alpha-2,6-linked sialylation and the metastasis of mouse hepatocellular carcinoma (HCC). According to array-based miRNA expression profiling data of HCC cell lines Hepa1-6, Hca-P, and Hca-F with different lymphatic metastatic capacities, reverse correlation was found between miR-9 expression levels and the metastatic potential in these HCC cells. Additionally, beta-galactoside alpha-2,6-sialyltransferase 1 (St6gal1) expression level is associated negatively with miR-9 and positively with metastatic potential. Bioinformatics analysis indicated that miR-9 could target St6gal1, which was verified by luciferase reporter assays. miR-9 overexpression reduced expression of St6gal1, which subsequently suppressed HCC cells metastatic potential. Moreover, upregulation of miR-9 could inhibit integrin-beta1/FAK mediated cell motility and migration signaling in mouse HCC cells. Together, our results suggest that miR-9 could act as a tumor suppressor and regulate mouse HCC cells migration and invasion by inhibiting the alpha-2,6-linked sialylation. This finding may provide insight into the relationship between abnormal miRNA expression and aberrant cell surface glycosylation during tumor lymphatic metastasis. PMID- 30006782 TI - Functional analysis of the mitochondrial alternative oxidase gene (aox1) from Aspergillus niger CGMCC 10142 and its effects on citric acid production. AB - In this work, we constructed the aox1 disruption strains 3-4 and 4-10, as well as the aox1 overexpression strains 72 and 102 in Aspergillus niger. The energy metabolism, EMP, TCA pathways, and flux were investigated for the citric acid (CA) overproduction via the aox1 overexpression among them. As expected, the overexpression of the aox1 gene enabled a higher growth rate than that of the rate of its parent strain in medium with respiratory chain inhibitors. In liquefied corn starch medium supplemented with 0.2 MUg/mL antimycin A, the CA production of the overexpression strain 102 reached up to 169.1 g/L, whereas the highest value of the parent strain was 158.9 g/L. For the perspective of the aox1 disruption strain 4-10, the yield of CA dropped to 125.6 g/L, and the loose mycelial pellets forming in the medium also revealed that the fundamentally important role of AOX in A. niger lies in the resistance to oxidative stress under fully aerobic conditions. Based on real-time qPCR gene expression analysis and measurement of intracellular ATP and NADH levels, we came to a conclusion that the higher NADH oxidation rate resulting from the overexpression of the aox1 gene mainly contributed to rate-limited step's acceleration and strengthened metabolic flow via mycelia and led to the CA yield in these strains increased by 13.5 and 10.8%, respectively. Subsequently, it was found that overexpression strains had higher AOX relative content and more oxygen consumption at different fermentation stages, which fully confirmed the close relationship between aox1 gene and energy metabolism, and comprehensively revealed aox1 gene function through the combination with the above conclusions. PMID- 30006783 TI - Riboregulator elements as tools to engineer gene expression in cyanobacteria. AB - Cyanobacteria are an ideal host for biofuel production. Although efforts have been made to genetically engineer cyanobacteria for efficient production of biofuels and other important chemicals, the tools that can be applied to cyanobacteria are still limited. A new gene regulation tool, riboregulator, has been examined for application in cyanobacteria. A riboregulator is a nature inspired RNA tool, which is composed of two artificially designed RNA fragments. Owing to its high specificity and efficacy, it is suitable for metabolic engineering in cyanobacteria, and several studies have been done to optimize and improve the function of the riboregulator. In this review, we focus on the recent improvements made to riboregulators and compare them with other RNA-mediated gene regulation tools developed in cyanobacteria to investigate future applications of riboregulators. PMID- 30006784 TI - Metabolic engineering for the production of isoprene and isopentenol by Escherichia coli. AB - The biotechnological production of isoprene and isopentenol has recently been studied. Isoprene, which is currently made mainly from petroleum, is an important platform chemical for synthesizing pesticides, medicines, oil additives, fragrances, and more and is especially important in the rubber production industry. Isopentenols, which have better combustion properties than well-known biofuels (ethanol), have recently received more attention. Supplies of petroleum, the conventional source of isoprene and isopentenols, are unsustainable, and chemical synthesis processes could cause serious environmental problems. As an alternative, the biosynthesis of isoprene and isopentenols in cell factories is more sustainable and environmentally friendly. With a number of advantages over other microorganisms, Escherichia coli is considered to be a powerful workhorse organism for producing these compounds. This review will highlight the recent advances in metabolic engineering for isoprene and isopentenol production, especially using E. coli cell factories. PMID- 30006786 TI - The diagnostic value of human epididymis protein 4 as a novel biomarker in patients with renal dysfunction. AB - PURPOSE: In this study, we investigated the diagnostic value of human epididymis protein 4 (HE4) in acute and chronic renal dysfunction and analyzed the correlation between HE4 levels and the results of routine renal function tests. We aimed to provide evidence to establish HE4 as a novel biomarker of renal injury and its appropriate application as a marker of ovarian cancer. METHODS: We collected 259 serum samples from hospitalized patients with different causes of renal damage. HE4 serum levels were detected by chemiluminescence and the levels of serum creatinine, urea, and cystatin C were tested by conventional clinical chemical methods. RESULTS: The levels of HE4 were highest in the acute kidney injury groups and chronic kidney disease groups, although other groups were also significantly higher than the control group. HE4 and creatinine, urea, and cystatin C had a positive linear correlation. In contrast, HE4 and estimated glomerular filtration rate (eGFR) had a negative linear correlation, with a correlation coefficient of - 0.674 (P < 0.01). Area under the receiver-operating characteristic curve analysis showed that HE4 has higher diagnostic value compared with creatinine, urea, and cystatin C in both acute and chronic renal injury patients; however, HE4 and creatinine have a similar diagnostic value. Notably, HE4 concentration gradually increased with a decline of glomerular filtration rate, with significant differences evident between different eGFR stages. CONCLUSION: HE4 is a potential biomarker of kidney injury in acute and chronic renal dysfunction. Importantly, clinicians should be aware of this when using HE4 to diagnose ovarian cancer. PMID- 30006785 TI - Ghrelin and acyl ghrelin levels are associated with inflammatory and nutritional markers and with cardiac and vascular dysfunction parameters in hemodialysis patients. AB - PURPOSE: Exogenous ghrelin is associated with cardiovascular protection in experimental and human studies. Nevertheless ESRD patients have increased ghrelin levels and severe cardiovascular comorbidities. This study aims to elucidate the metabolic factors influencing endogenous ghrelin/acyl ghrelin levels and to analyze the relation between endogenous ghrelin/acyl ghrelin levels and cardiac and vascular function markers in hemodialysis patients. METHODS: The cross sectional study was conducted in hemodialysis patients (n = 88); 50 of them were men, mean age 61.1 +/- 13.5 years, 17% had diabetes. We assessed nutritional and inflammatory status and analyzed the determinants of ghrelin/acyl ghrelin and their relation with cardiac and vascular function. RESULTS: Ghrelin is correlated with IL-1beta (r = 0.88, p < 0.0001), triglycerides, total cholesterol (TC), and Kt/V. IL-1beta is the strongest predictor of ghrelin levels (p < 0.0001). Acyl ghrelin is correlated with TC (r = 0.36, p = 0.001), LDL-cholesterol, serum bicarbonate, body mass index. TC is the strongest predictor for acyl ghrelin levels (p = 0.038). Patients with high ghrelin levels had significantly decreased nitroglycerin-mediated dilation (p = 0.05) and higher IL-1beta levels (p < 0.001); increased NT-proBNP is associated with lower levels of acyl ghrelin (r = 0.33, p = 0.02) in male patients. CONCLUSION: The inflammatory marker IL-1beta is in our study the strongest predictor of ghrelin levels while the nutritional marker-total cholesterol is the strongest predictor for acyl ghrelin levels in HD patients. High endogenous ghrelin level is associated with high IL-1beta and with vascular smooth muscle cell dysfunction. Low acyl ghrelin level is associated with high NT-proBNP (a cardiac dysfunction marker) in male HD patients. There is a direct correlation between endogenous ghrelin level and inflammatory markers, which is not related with cardiovascular protection. PMID- 30006787 TI - The biocompatibility and bioactivity of hemodialysis membranes: their impact in end-stage renal disease. AB - End-stage renal disease is a growing health problem with increasing prevalence and high health care costs. Patients suffering from end-stage renal disease exhibit higher morbidity and mortality rates compared to the general population. These patients, who are treated using hemodialysis, typically suffer from anemia, inflammation, and oxidative stress. Inadequate dialyzer membrane biocompatibility exacerbates these negative side effects. Modifications of the composition of hemodialysis membranes have improved their biocompatibility and improve the patients' quality of life. Recently, the use of dialyzer membranes coated with bioactive compounds has also been proposed to further ameliorate dialysis associated problems. Based on a survey of the current literature, application of bioactive membranes decreases the inflammation and oxidative stress of patients treated with hemodialysis. PMID- 30006788 TI - Decision making processes of women who seek elective oocyte cryopreservation. AB - PURPOSE: The aim of this study is to analyze women's opinions and their decision making processes regarding elective oocyte cryopreservation (OC). METHODS: One hundred twenty-four women who had elective OC counseling at the CHA Seoul Fertility Center were asked to complete a survey after their first visit. Data collection regarding age, marital status, monthly income, occupation, religion, reproductive history, questions about the participant's view on their own fecundity, and future parenthood were included. The modified Reproductive Concerns After Cancer scale and the Decisional Conflict Scale were used for analysis. RESULTS: The participants' mean age was 37.1 +/- 4.8 years old. Eighty six percent of the participants had regular periods. Ninety-two percent thought it was important to have their own biological offspring, and 86% were willing to pursue OC. Forty-nine percent appeared to have high DCS scores regarding making a decision of OC. Sixty-eight percent pursued OC, and the mean number of oocytes cryopreserved per patient was 10.5 +/- 8.3. Multivariate analysis revealed that age was the only factor associated with high DCS scores (P = 0.002). Feeling less fertile than other women of same age and low DCS scores were the factors associated with pursuing OC (P = 0.02 and 0.004, respectively) after adjusting for possible confounding factors, including age. CONCLUSIONS: Older women had more difficulties in making decisions about OC. Adjusting for age, women who thought that they were less fertile than other women of same age and those with lower decisional conflict were more likely to pursue OC. Further studies should focus on the validation of older women's decisional conflicts regarding OC. PMID- 30006790 TI - Who Will Show? Predicting Missed Visits Among Patients in Routine HIV Primary Care in the United States. AB - Missed HIV medical visits predict poor clinical outcomes. We sought to identify patients at high risk of missing visits. We analyzed 2002-2014 data from six large US HIV clinics. At each visit, we predicted the likelihood of missing the next scheduled visit using demographic, clinical, and patient-reported psychosocial variables. Overall, 10,374 participants contributed 105,628 HIV visits. For 17% of visits, the next scheduled appointment was missed. The strongest predictor of a future missed visit was past-year missed visits. A model with only this predictor had area under the receiver operator curve = 0.65; defining "high risk" as those with any past-year missed visits had 73% sensitivity and 51% specificity in correctly identifying a future missed visit. Inclusion of other clinical and psychosocial predictors only slightly improved performance. Past visit attendance can identify those at increased risk for future missed visits, allowing for proactive allocation of resources to those at greatest risk. PMID- 30006789 TI - Retroviruses and reproduction revisited. AB - Thanks to effective anti-HIV medications, deaths from acquired immunodeficiency disease (AIDS) have plummeted, although the incidence of new HIV infections has decreased little, approximately 36,000 annually in the USA. The CDC estimates 1.1 million persons, mostly men, are living with HIV in the USA, with approximately 14% unaware they are infected. Since the global blood supply is essentially free of HIV today, infected semen is fueling the pandemic (88% of new infections in the USA), with needle sharing among IV drug abusers (7% of new US infections) and female to male transmission (5% of new infections) accounting for the balance. In spite of the importance to disease prevention and strategies for safe conception, semen transmission of HIV is not well understood. Because anti-HIV therapy does not eliminate HIV from semen, the Centers for Disease Control (CDC) for the past 25 years has espoused condom use as the safest approach to prevent HIV transmission, as well as other sexually transmitted diseases. A few months ago, however, an MMWR was circulated by the CDC that suggested condomless sex might be safe if the HIV-infected partner's medications achieved an undetectable viral load in his blood. This new opinion was based on reports by three teams of investigators cited in the MMWR: "All three studies observed no HIV transmission to the uninfected partner while the partner with HIV was virologically suppressed with ART." Unfortunately, this CDC statement does not fully describe the data presented in the studies, and abandoning condom use puts uninfected partners, including women seeking to conceive, at risk for infection by HIV and other STDs. PMID- 30006792 TI - Theory-Based Text-Messaging to Reduce Methamphetamine Use and HIV Sexual Risk Behaviors Among Men Who Have Sex with Men: Automated Unidirectional Delivery Outperforms Bidirectional Peer Interactive Delivery. AB - Project Tech Support2 was a randomized controlled trial that tested three methods of text message delivery for reducing methamphetamine use and HIV risks among MSM. From March 2014 to January 2016, 286 methamphetamine-using MSM were randomized into: (1) interactive text conversations with Peer Health Educators, plus five-times-a-day automated theory-based messages, plus a weekly self monitoring text-message assessment (TXT-PHE; n = 94); or, (2) the daily automated messages and weekly self-monitoring assessment (TXT-Auto; n = 99); or, (3) weekly self-monitoring assessment only (AO; n = 93). All three conditions demonstrated reductions in methamphetamine use (coef. = - 0.10), sex on methamphetamine (coef. = - 0.09), and condomless anal intercourse (CAI) with casual male partners (coef. = - 0.06). Only participants in TXT-PHE and TEXT-Auto also reduced CAI with main male partners (coefTXT-PHE = - 0.19; coef.TXT-Auto = - 0.16), and only TEXT-Auto participants reduced CAI with anonymous male partners (coef. = - 0.05). Additionally, both theory-based text-messaging interventions achieved sustained reductions in five of the six outcomes through 9 months. Overall, automated delivery outperformed peer-delivered messaging. PMID- 30006791 TI - Patterns of Oral PrEP Adherence and HIV Risk Among Eastern African Women in HIV Serodiscordant Partnerships. AB - Understanding how women use PrEP is important for developing successful implementation programs. We hypothesized there are distinct patterns of adherence, related to HIV risk and other factors. We identified patterns of PrEP adherence and HIV risk behavior over the first 6 months of PrEP use, using data from 233 HIV-uninfected women in high-risk serodiscordant couples in a demonstration project in Kenya & Uganda. We modeled PrEP adherence, assessed by daily electronic monitoring, and HIV risk behavior using group-based trajectory models. We tested baseline covariates and risk behavior group as predictors of adherence patterns. There were four distinct adherence patterns: high steady adherence (55% of population), moderate steady (29%), late declining (8%), and early declining (9%). No baseline characteristics significantly differed between adherence patterns. Adherence patterns differed in average weekly doses (6.7 vs 5.4 vs 4.1 vs 1.5, respectively). Two risk behavior groups were identified: steady HIV risk (78% of population) and declining (22%). Compared to women with declining HIV risk behavior, women with steady risk behavior were more likely to have high steady adherence (61% vs 35%) and less likely to have early (6% vs 17%) or late (4% vs 19%) declining adherence. Women's use of PrEP was associated with concurrent HIV risk behavior; higher risk was associated with higher, sustained adherence. PMID- 30006793 TI - Consistent Condom Use by Married and Cohabiting Female Sex Workers in India: Investigating Relational Norms with Commercial Versus Intimate Partners. AB - This study examines determinants of consistent condom use (CCU) among married and cohabiting female sex workers (FSW) in India. Although CCU with clients is normative in the study area, most FSW do not consistently use condoms with intimate partners. Multiple logistic regression models indicated that condom use with intimate partners was associated with relationship status, cohabitation, HIV knowledge, STI symptoms, and being offered more money for sex without a condom by clients. Additionally, more days of sex work in the last week, serving as a peer educator, and participating in community mobilization activities were associated with higher odds of CCU across all partner types. Although improving economic security may increase CCU with clients, mobilization to reduce stigma and promote disclosure of sex work to non-cohabiting partners may be necessary to increase CCU overall. PMID- 30006794 TI - The eyes have it: lateralized coping strategies in cattle herds responding to human approach. AB - We report a range of lateralized coping strategies adopted by large social groups of cattle in response to mild challenges posed by humans of varying degrees of familiarity. At either 14 or 18 pens at a commercial feedlot, with 90 to 200 cattle in each, we conducted a series of video recorded 'pressure tests'. 'Frontal' pressure tests involved walking from a position perpendicular to the concrete feed bunk of a given pen, towards the geometric centre of the line of feeding cattle. 'Bunk-side' pressure tests involved experimenters walking closely past a pen of feeding cattle in one direction, before returning in the opposite direction shortly afterwards. Experimenters wore white dust masks to alter their facial features in the bunk-side pressure tests. In both frontal and bunk-side pressure tests, distance from the experimenter influenced cattle's choice of binocular viewing, cessation of feeding, standing or stepping backwards to monitor the approach and leaving the feed bunk. The frequency of these coping strategies differed in a lateralized manner. The cattle were more likely to accept the close positioning of a generally familiar, unmasked human on their left, which is traditionally referred to as the "near" side. By contrast, when responding to the approach of an unfamiliar, masked human, cattle conformed to the general vertebrate model and were more likely to remove themselves from the potential threat viewed within the left and not right visual field. We argue that the traditional terms for livestock sidedness as "near" (left) and "off" (right) sides demonstrate a knowledge of behavioural lateralization in domestic livestock that has existed for over 300 years of stock handling. PMID- 30006795 TI - Screening status, tumour subtype, and breast cancer survival: a national population-based analysis. AB - PURPOSE: We examined whether demographic and tumour characteristics (including subtype) were different for women with breast cancer diagnosed via mammography screening compared with women with interval breast cancers, lapsed attenders of the screening programme and non-participants of the screening programme. In addition, we explored whether there were survival differences between the groups, taking into account lead time bias. METHODS: We used linked data from National Cancer Registry Ireland and the national breast screening programme BreastCheck. Multinomial logistic regression was used to test the association of covariates with screening status. For survival analysis, we corrected the survival time for screen-detected cases for lead time bias, examined Kaplan-Meier curves and then used Cox regression to investigate differences in survival by screening status. RESULTS: Subtype (HER2 over-expressing, triple negative), stage (III/IV), grade (poor), having co-morbidities, area of deprivation, smoking status and age were associated with having interval cancer or being a non-participant of the screening programme in the multivariable model. After correcting for lead time bias, and adjusting for variables associated with screening status, there was no evidence that risk of breast-cancer death for women with screen-detected cancer was different from women with interval cancer (HR = 0.76, 95% CI 0.56-1.03), non participants (HR = 1.07, 95% CI 0.84-1.37) and lapsed attenders (HR = 0.97, 95% CI 0.65-1.45). CONCLUSIONS: Screening status was strongly associated with subtype and this association persisted after adjustment for covariates including tumour stage and grade. After correcting for lead-time bias and adjusting for stage, subtype, grade and socio-demographic variables, no significant survival difference was demonstrated for women with screen-detected cancer in the 5-year period post-diagnosis. Since we are adjusting for stage, subtype and other variables, the lack of difference between these groups would be expected but has not been demonstrated in studies which do not correct for lead time bias. PMID- 30006797 TI - Evaluation of chromium removal efficiency at varying operating conditions of a novel bioelectrochemical system. AB - The assessment of chromium removal efficiency (CRE) was studied using experimental trials with variations in operating conditions for evaluating performance efficiency of the Bioelectrochemical system (BES). During the study, maximum CRE of 88.36 +/- 8.16% was obtained at cathode pH 2 +/- 0.1 from the varied cathode pH (pH 1, 2, 3, 4, 5, 6, 7). With varying reactor temperatures from 25 to 45 degrees C (25, 30, 35, 40, 45 degrees C), BES resulted in maximum CRE of 85.93 +/- 9.62% at 40 degrees C. CRE increased from 78.50 +/- 5.24 to 88.66 +/- 8.40% with an increase in substrate concentration from 500 to 2000 mg/L chemical oxygen demand (COD). CRE decreased from 95.9 +/- 2.9 to 89.56 +/- 1.74% with an increase in initial chromium concentration from 10 to 100 mg/L. Correlation analysis revealed a positive correlation with COD reduction, COD, and temperature, whereas a negative correlation was observed for pH and initial chromium concentration. PMID- 30006796 TI - Cost-effectiveness of monitoring endoxifen levels in breast cancer patients adjuvantly treated with tamoxifen. AB - PURPOSE: Breast cancer is the most common malignancy in women worldwide. Recurrence rates in breast cancer are considered to be dependent on the serum concentration of endoxifen, the active metabolite of tamoxifen. The goal of this study is to investigate the cost-effectiveness of periodically monitoring serum concentrations of endoxifen in adjuvant estrogen receptor alfa (ERalpha) positive breast cancer patients treated with tamoxifen in the Netherlands. METHODS: A Markov model with disease-free survival (DFS), recurrent disease (RD), and death states was constructed. The benefit of drug monitoring was modeled via a difference in the fraction of patients achieving adequate serum concentrations. Robustness of results to changes in model assumptions were tested through deterministic and probabilistic sensitivity analyses. RESULTS: Monitoring of endoxifen added 0.0115 quality-adjusted life-years (QALYs) and saved ? 1564 per patient in the base case scenario. Deterministic sensitivity analysis demonstrated a large effect on the incremental cost-effectiveness ratio (ICER) of the differences in costs and utilities between the DFS and RD states. Probabilistic sensitivity analysis showed that the probability of cost effectiveness at a willingness to pay of ? 0 per quality-adjusted life-year (QALY) was 89.8%. CONCLUSIONS: Based on this model, monitoring of endoxifen in adjuvant ERalpha + breast cancer patients treated with tamoxifen is likely to add QALYs and save costs from a healthcare payer perspective. We advise clinicians to consider integrating serum endoxifen concentration monitoring into standard adjuvant tamoxifen treatment of ERalpha + breast cancer patients. PMID- 30006798 TI - Enhanced production of succinic acid from methanol-organosolv pretreated Strophanthus preussii by recombinant Escherichia coli. AB - A biorefinery process for high yield production of succinic acid from biomass sugars was investigated using recombinant Escherichia coli. The major problem been addressed is utilization of waste biomass for the production of succinic acid using metabolic engineering strategy. Here, methanol extract of Strophanthus preussii was used for fermentation. The process parameters were optimized. Glucose (9 g/L), galactose (4 g/L), xylose (6 g/L) and arabinose (0.5 g/L) were the major sugars present in the methanol extract of S. preussii. E. coli K3OS with overexpression of soluble nucleotide pyridine transhydrogenase sthA and mutation of lactate dehydrogenase A (ldhA), phosphotransacetylase acetate kinase A (pta-ackA), pyruvate formate lyase B (pflB), pyruvate oxidase B (poxB), produced a final succinic acid concentration of 14.40 g/L and yield of 1.10 mol/mol total sugars after 72 h dual-phase fermentation in M9 medium. Here, we show that the maximum theoretical yield using methanol extracts of S. preussii was 64%. Hence, methanol extract of S. preussii could be used for the production of biochemicals such as succinate, malate and pyruvate. PMID- 30006799 TI - Evaluating the Effectiveness of Human Papillomavirus Educational Intervention among Oral Health Professionals. AB - This study aims to evaluate the effectiveness of an educational intervention that was designed to increase human papillomavirus (HPV) awareness and knowledge among oral health providers (OHPs). HPV educational lectures and a dental information toolkit on HPV were offered to OHPs in New England in 2016-2017. OHPs included dentists and dental hygienists. Post intervention surveys were distributed 1 month later. A total of 230 participants attended the educational lectures and received the toolkit. Descriptive statistics were used to compare the difference in knowledge and preparedness about HPV before and after the intervention. Eighty nine OHPs completed the surveys. The response rate was 38.7%; however, for each question, the number of responses varied. Fifty-four (54%) (n = 26) of survey respondents were between 55 and 75 years of age with 73.5% (n = 36) being female and 55% (n = 45) working in private practice. Post intervention, 67.5% (n = 27) of the respondents felt more prepared, 82.6% (n = 38) reported clarity of their roles in educating their patients about HPV, and 91.6% (n = 44) reported an increase in knowledge about HPV. The HPV educational intervention was well received and successful at improving self-reported knowledge, comfort level, and preparedness of OHPs in discussing HPV with their patients. OHPs have the great opportunity to educate their patients about HPV and HPV vaccination. Further continuing education efforts may improve OHPs' participation in HPV prevention. PMID- 30006800 TI - A motor evoked potential trending system may discriminate outcome: retrospective application with three cases. AB - This report presents a method for tracking Motor Evoked Potential (MEP) amplitudes over the course of a case using a moving least squares linear regression (LSMAs). During a case, newly obtained MEP amplitudes are compared to those predicted by a just previous linear regression (least squares moving average or LSMA). When detected by this comparison, a set criterion amplitude loss will then trigger linear regression of ensuing MEP amplitudes on an expanding step function which tracks the persistence of the amplitude loss for the remainder of the case. Three cases are presented. One in which the patient woke up with a newly acquired weakness in the left tibialis anterior and another in which MEP amplitudes were suddenly lost from the right foot, but after intervention, they were restored again. In a third case the patient again woke up with a new post-operative deficit, but MEP trial sampling had been more limited and variable than in the first two cases. When the linear trending method was applied to the affected myotome in the first case, the expanding step function regression was triggered after the moment of MEP loss and remained at a high level until the end of case. In the second case, the expanding step function regression was also triggered in the relevant myotome at the time of the reported MEP change, but diminished by end of case. In the third case the tracking method again successfully triggered a predictive R-Square despite the limited number of pre-event trials. The R-Square value of the expanding step function regression appears to have discriminative capability with regard to new post-op deficit. Given the importance of the intra-operative MEP for monitoring motor functioning and the high degree of variability that can affect it, the development of new quantitative, statistical methods to detect real from apparent MEP change will be necessary. PMID- 30006802 TI - Cultural Considerations in the Assessment of Survivors of Torture. AB - The cultural and ethnic landscape of North America is becoming increasingly diverse, with many refugees fleeing torture and persecution and seeking safety in the United States and Canada. In working with this population, clinicians must implement culturally appropriate methods of assessing and treating individuals from diverse backgrounds. Culture can exert a powerful and often misunderstood influence on psychological assessment, and the critical challenge is to account for both subjective experience of the client and the objective symptoms or behaviors present. The present review explores the literature on cross-cultural issues in the assessment of survivors of torture. I summarize best practices and review the theoretical and statistical bases for establishing the equivalence of constructs across cultures. Discussion centers around the utility of a cross culturally valid measure of distress, and it is hoped that this review will encourage collaboration between clinicians and psychometricians to develop assessments for use with this vulnerable population. PMID- 30006803 TI - Distribution of metabolic/obese phenotypes and association with diabetes: 5 years' cohort based on 22,276 elderly. AB - AIMS: To describe the distribution and changes of different metabolic/obese phenotypes among more than 22,000 male elderly in China, and also explore the association with diabetes incidence. METHODS: A cohort study based on 22,276 male elderly was conducted in Beijing, from 2009 to 2013. Multiple Cox model was used to calculate the relative risk. RESULTS: There were only 53.8% of total participants who kept the same phenotype for the 5 years. On the whole, participants with metabolically unhealthy phenotypes had higher relative risks (RRs) than those with metabolically healthy phenotypes. RRs for diabetes showed an increasing trend along with metabolic abnormalities (p < 0.001). However, no statistically significant difference was found across different obese status with the same number of metabolic abnormalities. Changes of metabolic/obese status also showed the same trend. Those who had kept metabolic unhealthy had the highest RRs for diabetes incidence, which was higher than those who kept obesity. CONCLUSIONS: Both metabolically healthy obesity and metabolically unhealthy normal weight phenotypes had an increased risk for diabetes incidence, and metabolic abnormalities might have more influence on diabetes than obesity itself. Changes of metabolic/obese status also had an important impact on diabetes incidence. PMID- 30006804 TI - Tension band wiring versus locking plate fixation for simple, two-part Mayo 2A olecranon fractures: a comparison of post-operative outcomes, complications, reoperations and economics. AB - PURPOSE: Simple displaced transverse olecranon fractures are traditionally managed operatively with a tension band wire device (TBW). We compared clinical outcomes, morbidity and the cost of treatment of TBW versus pre-countered low profile locking plates for the treatment of Mayo 2A fractures. PATIENT AND METHODS: All olecranon fractures admitted to our unit between 2008 and 2014 were identified (n = 129). Patient notes and radiographs were studied from presentation to final follow-up. Patient outcomes were recorded using the QuickDASH (Disabilities of Arm, Shoulder and Hand) score. Patient demographics and nature of complications were recorded as were the rate and nature of any repeat operation. RESULTS: Eighty-nine patients had Mayo 2A fractures (69%). Sixty-four underwent TBW (n = 48) or locking plate fixation (n = 16). The mean ages of both groups were similar at 57 (15-93) and 60 (22-80), respectively. In the TBW group, the mean post-injury QuickDASH was 12.9, compared with 15.0 for the locking plate group. There was no statistically significant difference between the outcomes for either group. Nineteen of the 48 TBW patients had complications (39.6%). Sixteen of the 48 TBW patients had reoperations (33.3%). In particular, we would highlight that 13 (27.1%) of patients treated with TBW underwent subsequent removal of metalwork for hardware irritation. There were no complications and or reoperations in the 16 patients who received locking plate fixation. Both complication and reoperation rates were statistically significantly different. Despite being initially more expensive, when the cost of reoperation for TBW group was included, locking plates were found to be on average L236.33 less per patient than for TBW. CONCLUSIONS: We suggest that locking plates are superior to TBW concerning post-operative morbidity, reoperation rate and cost for Mayo 2A fractures in contrast to previous articles. LEVEL OF EVIDENCE: Therapeutic study, III. PMID- 30006801 TI - General and Domain-Specific Effectiveness of Cognitive Remediation after Stroke: Systematic Literature Review and Meta-Analysis. AB - Cognitive remediation (CR) has been shown to improve cognitive abilities following a stroke. However, an updated quantitative literature review is needed to synthesize recent research and build understanding of factors that may optimize training parameters and treatment effects. Randomized controlled trials of CR were retrieved from seven electronic databases. Studies specific to adult stroke populations were included. Treatment effects were estimated using a random effects model, with immediate and longer-term follow-up outcomes, and moderator effects, examined for both overall and domain-specific functioning. Twenty-two studies were identified yielding 1098 patients (583 in CR groups). CR produced a small overall effect (g = 0.48, 95% CI 0.35-0.60, p < 0.01) compared with control conditions. This effect was moderated by recovery stage (p < 0.01), study quality (p = 0.04), and dose (p = 0.04), but not CR approach (p = 0.63). Significant small to medium (g = 0.25-0.75) post-intervention gains were evident within each individual outcome domain examined. A small overall effect (g = 0.27, 95% CI 0.04 0.51, p = 0.02) of CR persisted at follow-up (range 2-52 weeks). CR is effective and efficient at improving cognitive performance after stroke. The degree of efficacy varies across cognitive domains, and further high-quality research is required to enhance and sustain the immediate effects. Increased emphasis on early intervention approaches, brain-behavior relationships, and evaluation of activity and participation outcomes is also recommended. PMID- 30006806 TI - Molecular verification of transplacental transmission of Theileria lestoquardi in goat. AB - Ovine and caprine malignant theileriosis (OCMT), a critical condition in small ruminant production, causes lethal infections. In September 2016, a total number of 400 goats of Marghoz breed (the largest population of goat breed in Iran), in northwest of Iran, were examined for approximately 25 pre-partum abortions and 7 goats' mortality for a period of 3 days. A dead goat and her aborted fetus were brought into the Urmia Veterinary Hospital for further diagnostic investigations. The microbiological assessments including direct microscopical examination of the vaginal discharges and placentome with respect to the differential staining (Gram's staining method), conventional pure culturing, fetal abomasal contents, and the liver were negative. Microscopic examinations of blood smears of the goat and the fetus revealed characteristic of Theileria spp. piroplasms and impression smear samples from goat liver and fetal spleen were positive for Theileria Koch blue bodies. DNA analysis was performed using PCR technique and specific primers derived from the nucleotide sequences of 18S rRNA gene of T. lestoquardi; following extraction from blood samples, placentome, goat liver, and spleen of the fetus. The amplified DNA was sequenced afterwards and the corresponding sequence was registered under GenBank accession number MG208059. The sequence alignment showed that the products of PCR had a homology of 99% to known T. lestoquardi sequence registered under accession numbers of KY352037.1, KC778786.1, and JQ917458.1 in the GenBank. To our knowledge, this is a report demonstrating molecular verification of T. lestoquardi transplacental transmission in a neonatal kid of Marghoz breed of goats, its feasible role in induction of perinatal deaths and abortion in goat flocks. PMID- 30006805 TI - RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis. AB - Extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and can modify immune reactions. Response gene to complement (RGC)-32 plays an important role in the mediation of TGF-beta downstream effects, but its role in gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis, we investigated its involvement in TGF-beta-induced ECM expression and the upregulation of the reactive astrocyte markers alpha-smooth muscle actin (alpha-SMA) and nestin. In cultured neonatal rat astrocytes, collagens I, IV, and V, fibronectin, alpha-SMA, and nestin were significantly induced by TGF-beta stimulation, and RGC-32 silencing resulted in a significant reduction in their expression. Using astrocytes isolated from RGC-32 knock-out (KO) mice, we found that the expression of TGF-beta-induced collagens I, IV, and V, fibronectin, and alpha-SMA was significantly reduced in RGC-32 KO mice when compared with wild-type (WT) mice. SIS3 inhibition of Smad3 phosphorylation was also associated with a significant reduction in RGC-32 nuclear translocation and TGF-beta-induced collagen I expression. In addition, during experimental autoimmune encephalomyelitis (EAE), RGC-32 KO mouse astrocytes displayed an elongated, bipolar phenotype, resembling immature astrocytes and glial progenitors whereas those from WT mice had a reactive, hypertrophied phenotype. Taken together, our data demonstrate that RGC 32 plays an important role in mediating TGF-beta-induced reactive astrogliosis in EAE. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS. PMID- 30006807 TI - New insights into the clinico-histopathological and molecular features of Pelecitus (Filarioidea: Onchocercidae) from a raptor bird. AB - Some Onchocercidae nematodes such as Pelecitus are parasites of medical and veterinary importance. The adult stage of Pelecitus has been reported infecting birds, and the microfilaria has been associated to human blindness. However, in some of these cases, the nematode was incompletely identified at the species level due to the scarcity of morphological taxonomic keys and, also, to the lack of molecular diagnostic analysis. Here, we report a new Pelecitus species in a crested caracara (Caracara cheriway) producing a severe tenosynovitis and microfilarial dermatitis. It is also the first record of Pelecitus in an American bird of prey. Clinical and histopathological features are described, contributing towards our understanding of the pathogenesis of Pelecitus and the health and conservation of wild bird populations. Our study also provides new information on the molecular diagnosis of this parasite and highlights the potential role of wild birds as Pelecitus reservoirs, and health risk for humans and wildlife. PMID- 30006808 TI - Exploring tumourigenic potential of the parasite Anisakis: a pilot study. AB - Anisakiasis is a global disease caused by consumption of raw or lightly cooked fish parasitised with Anisakis spp. third-stage larvae. Cases in the literature show colocalised anisakiasis and colorectal cancer, and the incidental finding of Anisakis larvae at the tumour site was reported. Data from our group suggested an epidemiological link between previous infection and gastrointestinal cancer. Furthermore, it has recently been reported that Anisakis products lead to inflammation and DNA damage. Based on these facts, the aim was to investigate whether Anisakis antigens are able to induce changes in the proliferation of epithelial cells in vitro or in the expression of serum microRNA (miRNA) in Sprague-Dawley rats. Anisakis complete extract (CE) induced increases in cell proliferation and decreases in apoptosis compared with nontreated cells, which resulted in a significant increase in the absolute number of viable cells at 48 h of exposure (P < .05). Furthermore, the miRNAs mmu-miR-1b-5p and mmu-miR-10b-5p (a cancer-related miRNA) were significantly decreased (P < .05) in sera from the rats inoculated with Anisakis CE, compared with control rats inoculated with saline. Additionally, based on their relative quantification values, four other cancer-related miRNAs were considered to be differently expressed, rno-miR-218a 5p and mmu-miR-224-5p (decreased) and rno-miR-125a-3p and rno-miR-200c-3p (increased). Anisakis CE was able to induce changes both in epithelial cells in vitro and in an animal model. The results obtained with Anisakis CE, in terms of increasing cell proliferation, decreasing apoptosis and inducing changes in the expression of serum cancer-related miRNAs in rats, suggest that Anisakis could have tumourigenic potential. PMID- 30006809 TI - A novel molecular and chromosomal lineage of the anthropophilic Simulium (Simulium) rufibasis subgroup (Diptera: Simuliidae) in Taiwan. AB - The Simulium rufibasis subgroup is one of three subgroups of the Simulium (Simulium) tuberosum species-group; it is characterized by a pair of clustered stout hairs on the ventral surface of female abdominal segment 7. A member of the S. rufibasis subgroup in Taiwan was investigated morphologically and genetically using the universal cytochrome c oxidase subunit I (COI) barcoding gene and polytene chromosomal banding pattern. The Taiwanese material is morphologically similar to S. rosliramlii Takaoka & Chen from Vietnam and represents the second species of the S. rufibasis subgroup known from Taiwan. It also represents a novel molecular lineage that is distinct from three other primary lineages identified as S. doipuiense, S. doipuiense/S. rufibasis, and S. weji previously reported from Thailand. The mitochondrial evidence for a distinct lineage in Taiwan is supported by chromosomal analysis, which revealed unique sex chromosomes. For nomenclatural stability, we associate the name S. arisanum Shiraki with the Taiwanese entity. Originally described from females from Taiwan, S. arisanum until now has remained an enigmatic species. PMID- 30006811 TI - Influence of Ag Nanoparticles with Different Sizes and Concentrations Embedded in a TiO2 Compact Layer on the Conversion Efficiency of Perovskite Solar Cells. AB - In this study, Ag nanoparticles with diverse particle size and concentration, fabricated via the polyol method, were embedded in a TiO2 compact film to improve the power conversion efficiency of perovskite solar cells. Obtained results showed that Ag nanoparticles embedded in the TiO2 compact film do not affect the crystal structure of TiO2, while the size of the Ag nanoparticles can strongly influence the light absorption capacity of perovskite materials. However, the absorption intensity and power conversion efficiency of perovskite cells decreased with the increase in size of Ag nanoparticles. The amount of Ag nanoparticles was also an important factor for the performance of perovskite solar cells, and Ag nanoparticles in the compact layer were optimized to measure 10 nm in diameter, being embedded at a molar ratio of 1.5% (Ag:Ti = 1.5 mol%). Compared with hole-conductor-free perovskite solar cells that use carbon as counter electrodes, without Ag nanoparticles incorporated in the compact film, the enhanced efficiency of cells developed in this study can be mainly ascribed to the accelerated charge transfer, decreased charge recombination, and enhanced light absorption of the perovskite material in the visible region. PMID- 30006812 TI - The Role of E-Cadherin as a Prognostic Biomarker in Head and Neck Squamous Carcinoma: A Systematic Review and Meta-Analysis. AB - PURPOSE: In this study, we systematically investigated and analyzed articles focusing on the prognostic value of E-cadherin (E-cad) in human head and neck squamous cell carcinoma (HNSCC). METHODS: Searching through the different databases, the studies examining the associations between E-cad and HNSCC prognosis were identified. Outcomes such as disease-specific survival and overall survival were considered acceptable. Hazard ratio (HR) with 95% confidence interval (CI) was used to demonstrate prognostic value. RESULTS: A total of 40 studies were systematically analyzed, and finally, 1939 subjects were included in our meta-analysis. Our findings showed that significant aberrant expression of E cad was associated with poor survival. However, some studies showed increased expression of E-cad in metastatic lesions was associated with poor prognosis. Alteration in location of E-cad expression also showed significant association with cancer survival, i.e., increased cytoplasmic E-cad. We conducted a meta analysis on the eligible articles using a random effect model because of moderate heterogeneity. Strong association between aberrant expression of E-cad and poor survival was demonstrated (pooled HR = 2.28; 95% CI 1.78-2.91). CONCLUSIONS: Aberrant expression of E-cad may be a promising prognostic signature for HNSCC, especially when it is used with other prognostic markers. PMID- 30006813 TI - Mobility of metal(loid)s at the sediment-water interface in two tourist port areas of the Gulf of Trieste (northern Adriatic Sea). AB - One of the main environmental issues affecting coastal marine environments is the accumulation of contaminants in sediments and their potential mobility. In situ benthic chamber experiments were conducted at two tourist ports (marinas) located in the Gulf of Trieste, one in Slovenia and one in Italy. The aim was to understand if and where recycling at the sediment-water interface (SWI) may affect metal(loid)s. Short sediment cores were also collected near the chamber to investigate the solid (sediments) and dissolved phases (porewaters). Both diffusive and benthic fluxes were estimated to elucidate the release of metal(loid)s at the SWI. Total element concentrations and their labile fractions were determined in sediments to quantify their potential mobility. The total element contents were found to be two orders of magnitude higher in the Italian marina than in the Slovenian one, especially for Hg (up to 1000 mg kg-1), whereas the labile fraction was scarce or null. The opposite occurred in the Slovenian marina. Metal(loid)s in porewaters showed a clear diagenetic sequence and a close dependence upon the suboxic/anoxic conditions of sediments. The results suggest that although the sediments of the Italian marina exhibit the highest total metal(loid) concentration, these elements are scarcely remobilisable. Conversely, in the Slovenian marina, sediments seem to be comparatively more prone to release metal(loid)s at the SWI. PMID- 30006810 TI - International Group for Reducing Inappropriate Medication Use & Polypharmacy (IGRIMUP): Position Statement and 10 Recommendations for Action. AB - Globally, the number of drug prescriptions is increasing causing more adverse drug events, which is now a significant cause of mortality, morbidity, and disability that has reached epidemic proportions. The risk of adverse drug events is correlated to very old age, multiple co-morbidities, dementia, frailty, and limited life expectancy, with the major contributor being polypharmacy. Each characteristic alters the risk-benefit balance of medications, typically reducing anticipated benefits and amplifying risk. Current clinical guidelines are based on evidence proven in younger/healthier adult populations using a single disease model and their application to older adults with multimorbidity, in whom testing has not been conducted, yields a different risk-benefit prospect and makes inappropriate medication use and polypharmacy inevitable. Applying inappropriate clinical practice guidelines to older adults is antithetical to good healthcare, is likely to increase health inequity, and is associated with substantial negative clinical, economic, and social implications for health systems. The casualties are on the scale of a war or epidemic, yet are usually invisible in measures of healthcare quality and formal recommendations. Radical and rapid action is required to achieve a better quality of life for older populations and to remain true to the principles of medical professionalism and evidence-based medicine that place patients' interests and autonomy at the fore. This first International Group for Reducing Inappropriate Medication Use & Polypharmacy position statement briefly details the causes, consequences, and extent of inappropriate medication use and polypharmacy. This article outlines current strategies to reduce inappropriate medication use, provides evidence for their effect, and then proposes recommendations for moving forward with 10 recommendations for action and 12 recommendations for research. We conclude that an urgent integrated effort to reduce inappropriate medication use and polypharmacy should be a leading global target of the highest priority. The cornerstone of this position statement from the International Group for Reducing Inappropriate Medication Use & Polypharmacy is the understanding that without evidence of definite relevant benefit, when it comes to prescribing, for many older patients 'less is more'. This approach differs from most other current recommendations and guidance in medical care, as the focus is on what, when, and how to stop, rather than on when to start medications/interventions. Disrupting the framework that indiscriminately applies standard guidelines to older adults requires a new approach that better serves patients with multimorbidity. This transition requires a shift in medical education, research, and diagnostic frameworks, and re-examination of the measures used as quality indicators. In achieving this objective, we promote a return to some of the original concepts of evidence-based medicine: which considers scientific data (where it exists), clinical judgment, patient/family preference, and context. A shift is needed: from the current model that focuses on single conditions to one that simultaneously considers multiple conditions and patient priorities. This approach reframes the clinician's role as a professional providing care, rather than a disease technician. PMID- 30006814 TI - Industrial water use, income, trade, and employment: environmental Kuznets curve evidence from 17 Taiwanese manufacturing industries. AB - This paper investigated the relationships between industrial water use, income, trade, and employment for 17 Taiwanese industries from 1998 to 2015. We explored cross-sectional dependent unit root, panel cointegration, and causality tests to estimate their long-term relationships and causal nexus. There existed long-term equilibrium relationships among the variables. The long-term elasticity estimates of industrial water use with respect to income, squared income, trade, and employment are 4.27, - 0.15, 0.22, and 0.92, respectively. The results do not confirm an inverted U-shaped environmental Kuznets curve. A unidirectional causal relationship is found between water use and income, and a bidirectional causal relationship is identified between water use and employment. Exports cause industrial water use. As expected, both employment and exports lead to income. Hence, policy makers should promote investment into water efficiency and water recycling. Various governments reward firms for water efficiency and lower consumption without negative long-term effects on economic growth. PMID- 30006815 TI - Unraveling molecular targets of bisphenol A and S in the thyroid gland. AB - Bisphenol A (BPA) is a well-known endocrine disruptor with several effects on reproduction, development, and cancer incidence, and it is highly used in the plastic industry. Bisphenol S (BPS) was proposed as an alternative to BPA since it has a similar structure and can be used to manufacture the same products. Some reports show that BPA interferes with thyroid function, but little is known about the involvement of BPS in thyroid function or how these molecules could possibly modulate at the same time the principal genes involved in thyroid physiology. Thus, the aims of this work were to evaluate in silico the possible interactions of BPA and BPS with the thyroid transcription factors Pax 8 and TTF1 and to study the actions in vivo of these compounds in zebrafish thyroid gene expression. Adult zebrafish treated with BPA or BPS showed that sodium iodide symporter, thyroglobulin, and thyroperoxidase genes were negatively or positively regulated, depending on the dose of the exposure. Human Pax 8 alignment with zebrafish Pax 8 and Rattus norvegicus TTF1 alignment with zebrafish TTF1 displayed highly conserved regions in the DNA binding sites. Molecular docking revealed the in silico interactions between the protein targets Pax 8 and TTF1 with BPA and BPS. Importance of some amino acids residues is highlighted and ratified by literature. There were no differences between the mean energy values for BPA docking in Pax 8 or TTF1. However, BPS energy values were lower in TTF1 docking compared to Pax 8 values. The number of amino acids on the protein interface was important for Pax 8 but not for TTF1. The main BPA interactions with proteins occurred through Van der Waals forces and pi-alkyl and alkyl interactions, while BPS interactions mainly occurred through carbon hydrogen bonds and conventional hydrogen bonds in addition to Van der Waals forces and pi-alkyl interactions. These data point to a possible interaction of BPA and BPS with Pax 8 and TTF1. PMID- 30006817 TI - Mechanical Characterization of the Lamellar Structure of Human Abdominal Aorta in the Development of Atherosclerosis: An Atomic Force Microscopy Study. AB - Atherosclerosis is a major risk factor for cardiovascular disease. However, mechanisms of interaction of atherosclerotic plaque development and local stiffness of the lamellar structure of the arterial wall are not well established. In the current study, the local Young's modulus of the wall and plaque components were determined for three different groups of healthy, mildly diseased and advanced atherosclerotic human abdominal aortas. Histological staining was performed to highlight the atherosclerotic plaque components and lamellar structure of the aortic media, consisting of concentric layers of elastin and interlamellar zones. The force spectroscopy mode of the atomic force microscopy was utilized to determine Young's moduli of aortic wall lamellae and plaque components at the micron level. The high variability of Young's moduli (E) at different locations of the atherosclerotic plaque such as the fibrous cap (E = 15.5+/- 2.6 kPa), calcification zone (E = 103.7+/-19.5 kPa), and lipid pool (E = 3.5+/-1.2 kPa) were observed. Reduction of elastin lamellae stiffness (18.6%), as well as stiffening of interlamellar zones (50%), were detected in the diseased portion of the medial layer of abdominal aortic wall compared to the healthy artery. Additionally, significant differences in the stiffness of both elastin lamellae and interlamellar zones were observed between the diseased wall and disease-free wall in incomplete plaques. Our results elucidate the alternation of the stiffness of different lamellae in the human abdominal aortic wall with atherosclerotic plaque development and may provide new insight on the remodeling of the aortic wall during the progression of atherosclerosis. PMID- 30006816 TI - Maintenance Adalimumab Concentrations Are Associated with Biochemical, Endoscopic, and Histologic Remission in Inflammatory Bowel Disease. AB - BACKGROUND: A treat-to-target therapeutic approach is emerging as the new standard of care for treating inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). AIMS: We aimed to investigate the association of serum adalimumab concentrations during maintenance therapy with biochemical, endoscopic, and histologic remission in IBD. METHODS: This retrospective multicenter study included consecutive IBD patients on adalimumab maintenance therapy who had a C-reactive protein (CRP) within 1 week and/or endoscopic evaluation within 12 weeks of therapeutic drug monitoring between July 2013 and December 2016. Biochemical remission was defined as a normal CRP (<= 5 mg/L). Endoscopic remission was defined as the absence of any ulceration/erosion or a Rutgeerts score of <= i1 for patients with an ileocolonic resection for CD and a Mayo endoscopic score of <= 1 for UC. Histologic remission was defined as the absence of any sign of active inflammation. Adalimumab concentrations were measured using the homogeneous mobility shift assay. RESULTS: Ninety-one CRP levels and 72 colonoscopies from 98 IBD patients [CD: n = 72 (73%)] were evaluated. Based on receiver operating characteristic analyses, we identified an adalimumab concentration threshold of 11.8, 12, and 12.2 MUg/mL in CD and 10.5, 16.2, and 16.2 MUg/mL in UC to stratify patients with or without biochemical, endoscopic, or histologic remission, respectively. Adalimumab concentrations >= 12 MUg/mL (OR 8; 95% CI 2-31.9; p = 0.003) and >= 12.2 MUg/mL (OR 9.6; 95% CI 1.7 56.1; p = 0.012) were independently associated with endoscopic and histologic remission in CD, respectively. CONCLUSIONS: This study demonstrates that higher maintenance adalimumab concentrations are associated with objective therapeutic outcomes in IBD. PMID- 30006818 TI - Preparation of Thermoresponsive Polymer Nanogels of Oligo(Ethylene Glycol) Diacrylate-Methacrylic Acid and Their Property Characterization. AB - Stimuli-responsive polymers have received growing attention in recent years owing to their wide applications in diverse fields. A novel stimuli-responsive polymer, based on oligo(ethylene glycol) diacrylate (OEGDA) and methacrylic acid (MAA), P(OEGDA-MAA), is prepared by precipitation polymerization and is shown to have a LCST-type VPTT (volume phase transition temperature) at 33 degrees C in water and a UCST-type VPTT at 43 degrees C in ethanol, all at concentration of 1 mg/mL. Both VPTTs are strongly concentration and pH dependent, providing an easy way to tune the phase transition temperature. The polymer is characterized with regard to its composition and its morphology in water and in ethanol at different concentration. The two transitions are studied and interpreted based on the results. This work provides a novel way for the preparation of a new type of stimuli-responsive polymer with great potential for different applications, particularly those in biomedical areas because PEG-based stimuli-responsive polymers are known to be nontoxic and non-immunogenic. PMID- 30006819 TI - Gadobutrol: A Review in Contrast-Enhanced MRI and MRA. AB - Intravenous gadobutrol [GadovistTM (EU); Gadavist(r) (USA)] is a second generation, extracellular non-ionic macrocyclic gadolinium-based contrast agent (GBCA) that is approved for use in paediatric (including term neonates) and adult patients undergoing diagnostic contrast-enhanced (CE) MRI for visualization of pathological lesions in all body regions or for CE MRA to evaluate perfusion and flow-related abnormalities. Its unique physicochemical profile, including its high thermostability and proton relaxation times, means that gadobutrol is formulated at twice the gadolinium ion concentration of other GBCAs, resulting in a narrower bolus and consequently, improved dynamic image enhancement. Based on > 20 years of experience in the clinical trial and real-world settings (> 50 million doses) and its low risk for developing nephrogenic systemic fibrosis (NSF), gadobutrol represents an effective and safe diagnostic GBCA for use in CE MRI and MRA to visualize pathological lesions and vascular perfusion and flow related abnormalities in all body regions in a broad spectrum of patients, including term neonates and other paediatric patients, young and elderly adult patients, and those with moderate or severe renal or hepatic impairment or cardiovascular (CV) disease. PMID- 30006820 TI - Toward a standard ontology of surgical process models. AB - PURPOSE: The development of common ontologies has recently been identified as one of the key challenges in the emerging field of surgical data science (SDS). However, past and existing initiatives in the domain of surgery have mainly been focussing on individual groups and failed to achieve widespread international acceptance by the research community. To address this challenge, the authors of this paper launched a European initiative-OntoSPM Collaborative Action-with the goal of establishing a framework for joint development of ontologies in the field of SDS. This manuscript summarizes the goals and the current status of the international initiative. METHODS: A workshop was organized in 2016, gathering the main European research groups having experience in developing and using ontologies in this domain. It led to the conclusion that a common ontology for surgical process models (SPM) was absolutely needed, and that the existing OntoSPM ontology could provide a good starting point toward the collaborative design and promotion of common, standard ontologies on SPM. RESULTS: The workshop led to the OntoSPM Collaborative Action-launched in mid-2016-with the objective to develop, maintain and promote the use of common ontologies of SPM relevant to the whole domain of SDS. The fundamental concept, the architecture, the management and curation of the common ontology have been established, making it ready for wider public use. CONCLUSION: The OntoSPM Collaborative Action has been in operation for 24 months, with a growing dedicated membership. Its main result is a modular ontology, undergoing constant updates and extensions, based on the experts' suggestions. It remains an open collaborative action, which always welcomes new contributors and applications. PMID- 30006821 TI - Apomorphine and levodopa infusion for motor fluctuations and dyskinesia in advanced Parkinson disease. AB - Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden. If patients continue to experience off-time with functional impact on activities of daily living after best medication adjustments, implementation of infusion with apomorphine or levodopa, and surgical therapies should be considered. Presence of troublesome dyskinesia would also favor the choice of an advanced treatment. Compared with pulsatile oral therapy, both apomorphine and levodopa infusion determine more continuous striatal dopamine receptors stimulation than oral levodopa resulting in significant reduction of off-time and dyskinesia, particularly peak-dose, although not in their complete resolution. This observation proves that abnormal synaptic plasticity and connectivity changes cannot be reversed once they are established. Early implementation of these therapeutic strategies ideally would target patients as soon as motor complications begin rather than at late stage of advanced Parkinson's disease (PD) before dyskinesia have manifested. Preliminary evidence from early deep brain stimulation in patients with short disease duration and modest motor complications suggests that this approach can positively impact quality of life. It is conceivable that changing our PD treatment algorithm and implementing device-aided therapies at the beginning of the advanced phase before dyskinesia has established, will provide more stable motor conditions and longer functional autonomy. PMID- 30006823 TI - Tissue and blood establishments: the demise of mad hatters in a decade. AB - The EU Directives for human tissues and cells (Directive 2004/23/EC) and for blood and blood components (Directive 2002/98/EC, with their related Directives), promotes the principle to minimise or remove potential sources of contamination (e.g. foreign particles, microorganisms, processing agents). Under this framework, mercury thermometers are of interest; as these devices present potential hazards through their use in preparation processes (for the verification of temperature criteria) or temperature monitoring systems (for the preservation of materials and reagents). This article outlines the potential hazards of mercury thermometers, the current available alternatives and the initiatives for the decline of mercury usage. PMID- 30006822 TI - Structural Investigation of the Hormone Melatonin and Its Alkali and Alkaline Earth Metal Complexes in the Gas Phase. AB - Gas phase infrared dissociation spectra of the radical cation, deprotonated and protonated forms of the hormone melatonin, and its complexes with alkali (Li+, Na+, and K+) and alkaline earth metal ions (Mg2+, Ca2+, and Sr2+) are measured in the spectral range 800-1800 cm-1. Minimum energy geometries calculated at the B3LYP/LACVP++** level are used to assign structural motifs to absorption bands in the experimental spectra. The melatonin anion is deprotonated at the indole-N. The indole-C linking the amide chain is the most favored protonation site. Comparisons between the experimental and calculated spectra for alkali and alkaline earth metal ion complexes reveal that the metal ions interact similarly with the amide and methoxy oxygen atoms. The amide I band undergoes a red shift with increasing charge density of the metal ion and the amide II band shows a concomitant blue shift. Another binding motif in which the metal ions interact with the amide-O and the pi-electron cloud of the aromatic group is identified but is higher in energy by at least 18 kJ/mol. Melatonin is deprotonated at the amide-N with Mg2+ and the metal ion coordinates to the amide-N and an indole-C or the methoxy-O. These results provide information about the intrinsic binding of metal ions to melatonin and combined with future studies on solvated melatonin metal ion complexes may help elucidate the solvent effects on metal ion binding in solution and the biochemistry of melatonin. These results also serve as benchmarks for future theoretical studies on melatonin-metal ion interactions. Graphical Abstract ?. PMID- 30006824 TI - Effects of supercritical fluid CO2 and 25 kGy gamma irradiation on the initial mechanical properties and histological appearance of tendon allograft. AB - Tendon allografts, when autograft options are limited or when obtaining an autograft is not aligned with the patients' best interest, play an important role in tendon and ligament reconstruction. To minimize the risk of infectious disease transmission tissue banks perform screening tests and the allografts cleaned are sterilized. The current study examines and compares the initial mechanical properties and histological appearance of supercritical CO2 (SCCO2)-treated and gamma-irradiated porcine extensor tendons. Thirty intact porcine forelimb extensor tendons randomized equally into three groups: control group, gamma irradiation group, and SCCO2-treated group. Once treated, histological assessment and histomorphologic measurements were made on the histological sections obtained from each tendon while stiffness and ultimate failure loads were evaluated from tensile testing. Histological evaluation of gamma-irradiated tendons showed significant disruption to the hierarchical morphology of the fascicle bundles, which was not evident in SCCO2-treated specimens. Histomorphologic measurements showed a significant increase for measured dead space (void) between tendon fibrils of the gamma-irradiated group comparing to both control and SCCO2 treated groups (p < 0.01). There was a significant reduction in the ultimate failure load for tendons treated by gamma-irradiation compared to the control group (p < 0.05). No statistically significant difference was detected between control and SCCO2-treated tendons in the ultimate failure load. Stiffness values were not significantly different between three-study groups. This study suggests that while gamma-irradiation has a deleterious effect on mechanical properties of tendon tissue, SCCO2 does not alter the biomechanical properties and the histological structure of porcine extensor tendons. PMID- 30006825 TI - Coronary Toxicities of Anti-PD-1 and Anti-PD-L1 Immunotherapies: a Case Report and Review of the Literature and International Registries. AB - Immunotherapy medications that target programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1), such as nivolumab, pembrolizumab, and atezolizumab, are currently used in the first- or second-line treatment of non small cell lung cancers, among other indications. However, these agents are associated with immune-related side effects, the most common of which are endocrinopathies, colitis, hepatitis, and interstitial pneumonitis. In contrast, coronary toxicities are rarely reported and remain poorly understood. Here, we describe the case of a patient who developed an acute coronary syndrome when treated with nivolumab as second-line therapy for metastatic pulmonary adenocarcinoma. A review of the literature, the French pharmacovigilance registry, and the World Health Organization pharmacovigilance database led to the identification of four cases of patients with coronary manifestations attributable to anti-PD1 immunotherapy (with no reported cases of patients undergoing anti-PD-L1 immunotherapy), which we describe herein. The potential mechanisms causing adverse coronary reactions to this type of therapy, which is used to treat lung cancer as well as other solid and hematological neoplastic diseases, are also discussed. PMID- 30006827 TI - Utility of radial reformation of three-dimensional fat-suppressed multi-echo gradient-recalled-echo images for the evaluation of acetabular labral injuries and femoroacetabular impingement. AB - OBJECTIVES: To assess the utility of the radial reformation of three-dimensional fat-suppressed multi-echo gradient-recalled-echo (3D FS me-GRE) for evaluating acetabular labral injuries and femoroacetabular impingement (FAI). MATERIALS AND METHODS: A total of 25 patients with suspected acetabular labral injuries were examined using 3D FS me-GRE and radial 2D T2*-weighted imaging (T2*WI) on a 3-T magnetic resonance imaging (MRI) scanner. The range of acetabular labral injuries was evaluated by radial reformation through the center of the acetabulum perpendicular to the plane across the entire acetabular rim (type 1 radial reformation) of 3D FS me-GRE and radial 2D T2*WI. To evaluate the FAI morphology, we performed radial reformation perpendicular to the central axis of the femoral head and neck (type 2 radial reformation) of 3D FS me-GRE. RESULTS: Acetabular labral injuries were identified in 23 patients, and no acetabular labral injury was seen in two patients on type 1 radial reformation of 3D FS me-GRE and radial 2D T2*WI. The diagnostic concordance rate for the range of acetabular labral injuries between the two imaging methods was 76.0%, and there was excellent agreement for the injured angles (r = 0.977, p < 0.001). FAI morphology could be evaluated in all patients (no FAI, n = 8; cam, n = 10; pincer, n = 4; combined cam and pincer, n = 3) using type 2 radial reformation of 3D FS me-GRE. CONCLUSIONS: Type 1 and type 2 radial reformations of 3D FS me-GRE imaging were useful for evaluating acetabular labral injuries and determining whether patients with acetabular labral injuries have FAI, respectively. PMID- 30006828 TI - Interobserver variability and stiffness measurements of normal common extensor tendon in healthy volunteers using shear wave elastography. AB - OBJECTIVES: The purposes of our study are to determine the quantitative elasticity values of normal common extensor tendon (CET) and to assess the interobserver variability of stiffness measurements using shear wave elastography (SWE). MATERIALS AND METHODS: A total of 60 CETs of 30 (15 female, 15 male, mean age 30.2 years) healthy volunteers without any symptoms of lateral epicondylitis were examined by two radiologists. Age, sex, height, weight, body mass index (BMI), and dominant hand of all participants were noted. The first observer performed B-mode and SWE imaging, and the second observer performed only SWE imaging. Tendon thickness and stiffness values in kPa were measured. RESULTS: The mean thickness of CETs was 3.57 +/- 0.36 mm. The mean stiffness values of CETs for two observers were 45.28 +/- 9.82 kPa and 45.80 +/- 9.72 kPa respectively. Tendon thickness had a weak correlation with weight (r = 0.281, p = 0.03), and moderate correlation with stiffness values (r = 0.429, p < 0.001). The mean interobserver difference of CET stiffness measurements was -0.5% of the mean CET stiffness values. Range of measurement error, defined as 95% limits of agreement, was +/-23.5%. There was no significant difference between absolute values of interobserver measurements (p = 0.741). CONCLUSION: Shear wave elastography is a reproducible imaging technique for the evaluation of CET elasticity and the standard stiffness values of normal CET can be used as reference data to differentiate normal from pathological tissues. PMID- 30006829 TI - Metrics of the Aesthetically Perfect Breast. AB - Breast surgery has long been viewed as an art more than a science. However, defining and objectively measuring the ideal breast morphology and aesthetic proportions are fundamental for surgical planning and to setting the goals of surgery as well as to evaluate surgical outcomes. Despite the fact that much has been written about aesthetic and reconstructive breast surgery, there is still no real consensus about what the attributes are of an ideal breast. Moreover, there are in fact no objective standard measurement systems and guidelines to describe ideal or even normal breast shape. Though there is great variability in the perception of beauty among patients and surgeons alike due to many factors among which are age, sex, and sociocultural background, there is common agreement that beauty is a universal phenomenon that has a universal standard present across all civilizations and centuries, and that perceived beauty is enhanced and optimal aesthetics are achieved when proper measurements are made and anthropometric proportions as well as attractive harmonious ratios are respected. The current review is an attempt to summarize the most relevant information available trying to introduce some harmony in our perception of aesthetic ideals of breast surgery. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30006826 TI - MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours. AB - Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours. PMID- 30006830 TI - Risk factors for 30-day hospital readmission after radical gastrectomy: a single center retrospective study. AB - BACKGROUND: Hospital readmission is gathering greater attention as a measure of health care quality. The introduction of fast-track surgery has led to shorter lengths of hospitalization without increasing the risk of postoperative complications and readmission. The collection of comprehensive readmission data is essential for the further improvement of patient care. The aim of the present study is to evaluate the risk factors for readmission within 30 days of discharge after gastrectomy. METHODS: A total of 1929 patients who underwent radical gastrectomy at Shizuoka Cancer Center were included in this study. A risk analysis with a stepwise logistic regression model was conducted to identify the risk factors for 30-day hospital readmission. RESULTS: The 30-day readmission rate was 2.70%. Common causes of readmission were an intolerance of oral intake and the presence of an intra-abdominal abscess. The C reactive protein (CRP) level on postoperative day (POD) 3 was significantly higher in the readmitted group; however, the other surgical outcomes, including the incidence of postoperative complications, did not differ to a statistically significant extent. The stepwise logistic regression analysis revealed that CRP on POD3 >= 12 mg/dl [odds ratio (OR) 2.08, 95% confidence interval (CI) 1.09-3.95, p = 0.025], laparoscopic surgery (OR 2.25, 95% CI 1.17-4.31, p = 0.015), and TG (OR 2.23, 95% CI 1.17-4.78, p = 0.023) were found to be independent risk factors for readmission. CONCLUSIONS: CRP on POD3 >= 12 mg/dl, laparoscopic surgery, and TG were identified as independent risk factors for readmission. PMID- 30006831 TI - The value of intraoperative percutaneous aspiration of the mucocele of the gallbladder for safe laparoscopic management. AB - Mucocele of the gallbladder is an overdistended gallbladder filled with mucoid content. It is under-reported in humans, and literature review showed insufficient data about the incidence and the factors affecting the laparoscopic management. We aim to evaluate the intraoperative aspiration of the mucoid contents of the gallbladder as a factor influencing the outcome of the treatment. A prospective cohort database analysis of the results of patients who were diagnosed as mucocele of the gallbladder and treated laparoscopically between January 2003 and December 2012 was done. Diagnostic results, ultrasound findings, operative diagnosis, duration of symptoms, length of hospitalization, and complications were analyzed. 57 patients were diagnosed with mucocele of the gallbladder. The incidence rate was 5.85%. Male to female ratio was 1:1.48 and the mean age of patients was 37.41 +/- 7.12 years. Ultrasound suspected mucocele in 24 (42%) patients. Laparoscopic cholecystectomy was performed in all 57 (100%) patients, and aspiration of mucoid fluid was done to all. Aspiration of the mucocele contents intraoperatively as a factor for safe laparoscopic management of mucocele of the gallbladder was found to represent a significant difference statistically (P = 0.02). Morbidity and mortality rates were recorded as zero (0%). Laparoscopic cholecystectomy could efficiently manage mucocele of the gallbladder with morbidity and mortality rates as low as 0%. The most important factor influencing the success of the procedure is the intraoperative aspiration of the mucoid contents of the gallbladder. Collapsing of the gallbladder wall was a keystone in the non-complicated laparoscopic procedure. PMID- 30006832 TI - Augmented reality in open surgery. AB - Augmented reality (AR) has been successfully providing surgeons an extensive visual information of surgical anatomy to assist them throughout the procedure. AR allows surgeons to view surgical field through the superimposed 3D virtual model of anatomical details. However, open surgery presents new challenges. This study provides a comprehensive overview of the available literature regarding the use of AR in open surgery, both in clinical and simulated settings. In this way, we aim to analyze the current trends and solutions to help developers and end/users discuss and understand benefits and shortcomings of these systems in open surgery. We performed a PubMed search of the available literature updated to January 2018 using the terms (1) "augmented reality" AND "open surgery", (2) "augmented reality" AND "surgery" NOT "laparoscopic" NOT "laparoscope" NOT "robotic", (3) "mixed reality" AND "open surgery", (4) "mixed reality" AND "surgery" NOT "laparoscopic" NOT "laparoscope" NOT "robotic". The aspects evaluated were the following: real data source, virtual data source, visualization processing modality, tracking modality, registration technique, and AR display type. The initial search yielded 502 studies. After removing the duplicates and by reading abstracts, a total of 13 relevant studies were chosen. In 1 out of 13 studies, in vitro experiments were performed, while the rest of the studies were carried out in a clinical setting including pancreatic, hepatobiliary, and urogenital surgeries. AR system in open surgery appears as a versatile and reliable tool in the operating room. However, some technological limitations need to be addressed before implementing it into the routine practice. PMID- 30006834 TI - The Influence of Age, Gender and Religion on Willingness to be an Organ Donor: Experience of Religious Muslims Living in Sweden. AB - The transplantation of organs is one of the most successful medical advances in recent decades, and transplantation is the treatment of choice for severe organ failure worldwide. Despite this situation and the general acknowledgment of organ donation (OD) as a global priority, the demand for organs outstrips the supply in virtually every country in the world. The study aims to elucidate whether age, gender and religion influence decision-making about organ donation in religious Muslims living in Sweden Data were collected through three group interviews using open-ended questions and qualitative content analysis. Twenty-seven participants, 15 males and 12 females from four countries, participated in the focus group interviews. The analysis of the collected data resulted in three main categories: "Information and knowledge about organ donation," "The priorities when deciding about organ donation" and "The religious aspects of organ donation," including a number of subcategories. Good information about and knowledge of OD, priorities in OD, importance of the fact that religion must be studied and taught daily and religious education were only a few of the factors informants emphasized as predictors of the total and successful donation of organs. Age, gender or religion did not have an impact on organ donation. High levels of education through religious education and good information via various media, as well as a good knowledge of the Swedish language, are predictors of improved OD. In order to overcome religious ideology as a source of misinformation relating to OD and to promote increased OD in the future, specific intervention studies and the improved involvement of religious communities and education in schools and the healthcare system are vital and must be a starting point for improved OD. PMID- 30006833 TI - Management of Appendicitis Globally Based on Income of Countries (MAGIC) Study. AB - BACKGROUND: Our aim is to compare the management approaches and clinical outcomes of acute appendicitis according to annual Gross National Income per Capita (GNI/Capita) of countries. METHODS: Consecutive patients who were diagnosed to have acute appendicitis from 116 centers of 44 countries were prospectively studied over a 6-month period (April-September 2016). Studied variables included demography, Alvarado score, comorbidities, radiological and surgical management, histopathology, and clinical outcome. Data were divided into three groups depending on the GNI/Capita. RESULTS: A total of 4271 patients having a mean (SD) age of 33.4 (17.3) years were studied. Fifty-five percent were males. Two hundred and eighty patients were from lower-middle-income (LMI) countries, 1756 were from upper-middle-income (UMI) countries, and 2235 were from high-income (HI) countries. Patients in LMI countries were significantly younger (p < 0.0001) and included more males (p < 0.0001). CT scan was done in less than 8% of cases in LMI countries, 23% in UMI countries, and 38% in HI countries. Laparoscopy was performed in 73% of the cases in the HI countries, while open appendectomy was done in more than 60% of cases in both LMI and UMI countries (p < 0.0001). The longest mean hospital stay was in the UMI group (4.84 days). There was no significant difference in the complication or death rates between the three groups. The overall death rate was 3 per 1000 patients. CONCLUSIONS: There is great variation in the presentation, severity of disease, radiological workup, and surgical management of patients having acute appendicitis that is related to country income. A global effort is needed to address this variation. Individual socioeconomic status could be more important than global country socioeconomic status in predicting clinical outcome. PMID- 30006835 TI - Prevalence and predictors of blood transfusion after pediatric kidney transplantation. AB - BACKGROUND: Blood transfusion after kidney transplant carries a risk of sensitization to the graft as well as blood borne infections. The aim of this study was to describe the prevalence of blood transfusions in pediatric recipients of kidney transplants and to determine the factors associated with transfusions during the perioperative period. Additionally, to describe the changes in hemoglobin levels during the first 12 months following transplant. METHOD: A retrospective, single center analysis using data collected prospectively between 2010 and 2017. Red blood cell transfusion within the first week after transplant and anemia at 3 months were used as outcomes. Multivariate analysis was performed on significant variates with results described according to odds ratio (OR) and interquartile range (IQR). RESULTS: Transfusions were given after 21 of 42 (50%) transplants in recipients aged between 1 and 17 years (median 14 years). Age, height, weight, and pre-transplant hemoglobin predicted transfusion in univariate analyses. Regression analysis identified pre-transplant hemoglobin as an independent factor (OR 0.85, IQR 0.73-0.98; p = 0.02). Anemia was present at 3 months after 15 (36%) transplants. Anemia at 3 months was associated with older and larger recipients, lower pre-transplant hemoglobin, and lower estimated glomerular filtration rate (eGFR) on univariate analysis. Logistic regression analysis identified eGFR at 3 months as the only independent predictor of anemia at 3 months (OR 0.93, IQR 0.87-0.99; p = 0.04). CONCLUSIONS: Transfusions are prevalent in the perioperative period after pediatric kidney transplantation. Lower pre-transplant hemoglobin increases the risk of transfusion. Graft function predicts hemoglobin levels at 3 months. PMID- 30006837 TI - [Interdisciplinary pain psychology II : Risk factors, diagnostic workup, therapy and transfer in clinical practice]. PMID- 30006836 TI - Pyramiding of nine transgenes in maize generates high-level resistance against necrotrophic maize pathogens. AB - Key message Nine transgenes from different categories, viz. plant defense response genes and anti-apoptosis genes, played combined roles in maize to inhibit the necrotrophic pathogens Rhizoctonia solani and Bipolaris maydis. Maize sheath blight and southern corn leaf blight are major global threats to maize production. The management of these necrotrophic pathogens has encountered limited success due to the characteristics of their lifestyle. Here, we presented a transgenic pyramiding breeding strategy to achieve nine different resistance genes integrated in one transgenic maize line to combat different aspects of necrotrophic pathogens. These nine genes, selected from two different categories, plant defense response genes (Chi, Glu, Ace-AMP1, Tlp, Rs-AFP2, ZmPROPEP1 and Pti4), and anti-apoptosis genes (Iap and p35), were successfully transferred into maize and further implicated in resistance against the necrotrophic pathogens Rhizoctonia solani and Bipolaris maydis. Furthermore, the transgenic maize line 910, with high expression levels of the nine integrated genes, was selected from 49 lines. Under greenhouse and field trial conditions, line 910 showed significant resistance against maize sheath blight and southern corn leaf blight diseases. Higher-level resistance was obtained after the pyramiding of more resistance transgenes from different categories that function via different mechanisms. The present study provides a successful strategy for the management of necrotrophic pathogens. PMID- 30006838 TI - Mesorectal fat area as a useful predictor of the difficulty of robotic-assisted laparoscopic total mesorectal excision for rectal cancer. AB - BACKGROUND: Various predictors of the difficulty of total mesorectal excision for rectal cancer have been described. Although a bulky mesorectum was considered to pose technical difficulties in total mesorectal excision, no studies have evaluated the influence of mesorectum morphology on the difficulty of total mesorectal excision. Mesorectal fat area at the level of the tip of the ischial spines on magnetic resonance imaging was described as a parameter characterizing mesorectum morphology. This study aimed to evaluate the influence of clinical and anatomical factors, including mesorectal fat area, on the difficulty of total mesorectal excision for rectal cancer. METHODS: This study enrolled 98 patients who underwent robotic-assisted laparoscopic low anterior resection with total mesorectal excision for primary rectal cancer, performed by a single expert surgeon, between 2010 and 2015. Magnetic resonance imaging-based pelvimetry data were collected. Linear regression was performed to determine clinical and anatomical factors significantly associated with operative time of the pelvic phase, which was defined as the time interval from the start of rectal mobilization to the division of the rectum. RESULTS: The median operative time of the pelvic phase was 68 min (range 33-178 min). On univariate analysis, the following variables were significantly associated with longer operative time of the pelvic phase: male sex, larger tumor size, larger visceral fat area, larger mesorectal fat area, shorter pelvic outlet length, longer sacral length, shorter interspinous distance, larger pelvic inlet angle, and smaller angle between the lines connecting the coccyx to S3 and to the inferior middle aspect of the pubic symphysis. On multiple linear regression analysis, only larger mesorectal fat area remained significantly associated with longer operative time of the pelvic phase (p = 0.009). CONCLUSIONS: Mesorectal fat area may serve as a useful predictor of the difficulty of total mesorectal excision for rectal cancer. PMID- 30006839 TI - Digital single-operator cholangioscopy: a useful tool for selective guidewire placements across complex biliary strictures. AB - BACKGROUND: Treatment of biliary strictures is challenging. Digital single operator cholangioscopes (SOCs) equipped with an improved imaging quality, were recently introduced and may be useful for selective guidewire placement in difficult biliary strictures. METHODS: A total of 167 digital SOC procedures performed between 2015 and 2018 were retrospectively analyzed for successful guidewire placements across biliary strictures. Only cases with previous failed conventional guidewire placement approaches were included. RESULTS: In total, 30 examinations with a digital SOC-assisted guidewire placement across biliary strictures, performed in 23 patients, were identified. In 52% of all patients, the stricture was benign with post-liver-transplant strictures (75%) as the most frequent finding; in 48% of all patients the stricture was malignant with cholangiocellular carcinoma as the most frequent type (64%). Guidewire placement was successful in 21 of 30 procedures (70%). According to a subgroup analysis, digital SOC-assisted guidewire placements were significantly more successful in patients with benign strictures than those in patients with malignant strictures (88.2% vs. 46.2%; p = 0.02). Furthermore, the technical success rate tended to be increased in cases of initial examinations (78.3%) than in patients with repeated examinations (42.9%; p = 0.15). Adverse events, such as post-interventional pancreatitis or cholangitis as well as severe bleeding occurred in 16.7% of all examinations. CONCLUSIONS: Digital SOC-assisted guidewire placements have high technical success rates, especially in benign biliary strictures. This technique can help to avoid more invasive procedures such as percutaneous transhepatic or endoscopic ultrasound-guided biliary drainage. PMID- 30006840 TI - Self-expandable metallic stenting as a bridge to surgery for malignant colorectal obstruction: pooled analysis of 426 patients from two prospective multicenter series. AB - BACKGROUND: Self-expandable metallic stenting (SEMS) for malignant colorectal obstruction (MCO) as a bridge to elective surgery (BTS) is a widely used procedure. The aim of this study was to assess short-term outcomes of SEMS for MCO as BTS. METHODS: This study analyzed pooled data from BTS patients who were enrolled in two multicenter prospective single-arm observational clinical studies that used different stent types. Both studies were conducted by the Japan Colonic Stent Safe Procedure Research Group (JCSSPRG). The first study evaluated the WallFlexTM colonic stent for BTS or palliative treatment (PAL) from May 2012 to October 2013 and the second evaluated the Niti-STM colonic stent from October 2013 to May 2014. Fifty-three facilities in Japan participated in the studies. Before each study started, the procedure had been shared with the participating institutions by posting details of the standard methods of SEMS placement on the JCSSPRG website. Patients were followed until discharged after surgery. RESULTS: A total of 723 consecutive patients were enrolled in the two studies. After excluding nine patients, the remaining 714 patients were evaluated as a per protocol cohort. SEMS placement was performed in 426 patients (312 WallFlex and 114 Niti-S) as BTS and in 288 as PAL. In the 426 BTS patients, the technical success rate was 98.1% (418/426). The clinical success rate was 93.8% (392/418). SEMS-related preoperative complications occurred in 8.5% of patients (36/426), perforations in 1.9% (8/426), and stent migration in 1.2% (5/426). Primary anastomosis was possible in 91.8% of patients (391/426), 3.8% of whom (15/393) had anastomosis leakage. The overall stoma creation rate was 10.6% (45/426). The postoperative complication rate was 16.9% (72/426) and mortality rate was 0.5% (2/426). CONCLUSIONS: SEMS placement for MCO as BTS is safe and effective with respect to peri-procedural outcomes. Further investigations are needed to confirm long-term oncological outcomes. PMID- 30006841 TI - Retroperitoneoscopic partial nephrectomy in children: a multicentric international comparative study between lateral versus prone approach. AB - BACKGROUND: Very limited informations are currently available about the best approach to perform retroperitoneoscopic surgery. This multicentric international study aimed to compare the outcome of lateral versus prone approach for retroperitoneoscopic partial nephrectomy (RPN) in children. METHODS: The records of 164 patients underwent RPN in 7 international centers of pediatric surgery over the last 5 years were retrospectively reviewed. Sixty-one patients (42 girls and 19 boys, average age 3.8 years) were operated using lateral approach (G1), whereas 103 patients (66 girls and 37 boys, average age 3.0 years) underwent prone RPN (G2). The two groups were compared in regard to operative time, postoperative outcome, postoperative complications, and re-operations. RESULTS: The average operative time was significantly shorter in G2 (99 min) compared to G1 (160 min) (p = 0.001). Only 2 lateral RPN required conversion to open surgery. There was no significant difference between the two groups as for intraoperative complications (G1:2/61, 3.3%; G2:6/103, 5.8%; p = 0.48), postoperative complications (G1:9/61, 14.7%; G2:17/103, 16.5%; p = 0.80), and re-operations (G1:2/61, 3.3%; G2:4/103, 3.8%; p = 0.85). Regarding postoperative complications, the incidence of symptomatic residual distal ureteric stumps (RDUS) was significantly higher in G2 (7/103, 6.8%) compared to G1 (1/61, 1.6%) (p = 0.001). Most re-operations (4/6, 66.6%) were performed to remove a RDUS . CONCLUSIONS: Both lateral and prone approach are feasible and reasonably safe to perform RPN in children but the superiority of one approach over another is not still confirmed. Although prone technique resulted faster compared to lateral approach, the choice of the technique remains dependent on the surgeon's personal preference and experience. Our results would suggest that the lateral approach should be preferred to the prone technique when a longer ureterectomy is required, for example in cases of vesico-ureteral reflux into the affected kidney moiety, in order to avoid to leave a long ureteric stump that could become symptomatic and require a re-intervention. PMID- 30006842 TI - Diagnosis and treatment of gastric antral webs in pediatric patients. AB - BACKGROUND: Gastric antral webs are mucosal structures, varying from fenestrated diaphragms to mucosal crescents, resulting in varying degrees of foregut obstruction. Patients commonly present with vomiting, failure to thrive, and abdominal pain. Prevalence is unknown, and diagnosis can be difficult. METHODS: We performed an IRB-approved retrospective review of patients from 4/1/2015 4/1/2018 at a Level I Children's Surgery Center undergoing gastric antral web resection. Data obtained included demographics, preoperative workup, surgical repair, and outcomes. RESULTS: Twenty-one patients were identified; 67% were male with an average age of 30 months at diagnosis. Initial diagnosis was established by a combination of fluoroscopy and esophagogastroduodenoscopy (EGD) in all patients. Patients presented with emesis (76%), failure to thrive (57%), need for post-pyloric tube feeds (33%), and abdominal pain (14%). Web localization without intraoperative EGD (n = 3) was initially challenging. As a result, intraoperative EGD was combined with operative antral web resection to facilitate web localization (n = 18). Web marking techniques have evolved from marking with suture (n = 1) and tattoo (n = 2), to endoscopic clip application (n = 12). All 21 patients underwent web resection, 2 were performed laparoscopically. Twenty underwent Heineke-Mikulicz pyloroplasty during the initial surgery. Average length of stay was 5.5 days. There were no intraoperative complications or deaths. Permanent symptom resolution occurred in 90% of patients immediately, with a statistically significant decrease in emesis (p < 0.001), failure to thrive (p < 0.001), and need for post-pyloric tube feeding (p = 0.009) within 6 months of surgery. CONCLUSION: Gastric antral webs should be considered in the differential diagnosis for a child with persistent vomiting. Web resection with the use of intraoperative endoscopic localization can result in permanent symptom resolution in the majority of these patients. PMID- 30006843 TI - Bile duct injuries (BDI) in the advanced laparoscopic cholecystectomy era. AB - BACKGROUND: Laparoscopic cholecystectomy is the most commonly performed laparoscopic procedure. It is superior in nearly every regard compared to open cholecystectomies. The one significant aspect where the laparoscopic approach is inferior regards the association with bile duct injuries (BDI). The BDI rate with laparoscopic cholecystectomy is approximately 0.5%; nearly triple the rate compared to the open approach. We propose that 0.5% BDI rate with the laparoscopic approach is no longer accurate. METHODS: The National Surgical Quality Improvement Program (NSQIP) registry was retrospectively reviewed. All laparoscopic cholecystectomies performed between 2012 and 2016 were extracted. A total of 217,774 cases meeting inclusion criteria were analyzed. The primary data points were the overall BDI incidence rate and time of diagnosis. BDI were identified by ICD-9 and ICD-10 codes. Secondary data points were variables associated with BDI. RESULTS: The BDI rate was 0.19%. 77% of cases were diagnosed after the index surgical admission. Intra-operative cholangiography (IOC) use was associated with a higher BDI rate and higher identification rate of a BDI intraoperatively (P value < 0.0001). Resident teaching cases were protective with a RR score of 0.56 (P value < 0.0001). The presence of cholecystitis increased the risk of a BDI with a RR score of 1.20 (P value < 0.0001). There was a low conversion rate of 0.04% however converted cases had a nearly hundredfold increase in BDI at 15% (P value < 0.0001). CONCLUSIONS: The performance of laparoscopic cholecystectomies in North America is no longer associated with higher BDI rates compared to open. IOC use still is not protective against BDI, and cholecystitis continues to be a risk factor for BDI. When a cholecystectomy requires conversion from a laparoscopic to an open approach the BDI increases a hundredfold; which may raise the concern if this approach is still a safe bailout method for a difficult laparoscopic dissection. PMID- 30006845 TI - Minimal versus obligatory dissection of the diaphragmatic hiatus during magnetic sphincter augmentation surgery. AB - BACKGROUND: The magnetic sphincter augmentation (MSA) device was initially implanted with minimal hiatal dissection (MHD) at the diaphragmatic hiatus. Due to concern of possible MSA device dysfunction if herniated into an occult or small hiatal hernia, and increased understanding to the role of defective crura in reflux disease, the operative procedure was changed to planned obligatory dissection (OD) of the hiatus at the time of all implantations. METHODS: Between December 2012 and September 2016, 182 patients underwent MSA implant at a single medical center and have complete records available for review through September 2017. The MHD dissection period extended from December 2012 to September 2015, from September 2015 to 2016 all patients underwent OD. RESULTS: MHD occurred 53% (96/182) versus OD in 47% (86/182), mean follow-up time in days for MHD and OD was 554 (SD 427) versus 374 (298) days. Intraoperative measurement of hernia size for the MHD versus OD was 0.77 (1.1) versus 3.95 (2.4) cm, p < 0.001. At first visit follow-up, there was no difference in any dysphagia (p = 0.11). Recurrent GERD (defined as resumption of PPI after successful initial post-operative wean) was less frequent after OD than after MHD, 3.6 versus 16.3%, p = 0.006. Delayed onset dysphagia was 1.2% in the OD group versus 8.6% in the MHD group, p = 0.04. Recurrent hiatal hernia of 2 cm or greater occurred in 0.0% of the OD and 11.5% of the MHD, p = 0.03. Repeat surgery for hiatal hernia repair has occurred in 0% of the OD and 6.6% of the MHD, p = 0.02. CONCLUSION: OD of the hiatus with crural closure resulted in less recurrence of reflux symptoms and hiatal hernia, despite an increased proportion of patients with larger hiatal hernia and more complex anatomic disease at the time of operation. PMID- 30006844 TI - Robotic transanal minimally invasive surgery (TAMIS) with the newest robotic surgical platform: a multi-institutional North American experience. AB - BACKGROUND: Transanal minimally invasive surgery (TAMIS) offers intra-luminal full-thickness excision of rectal neoplasia. Robotic TAMIS (RT) allows for greater versatility in motion while operating in the limited space of the rectum. We present our experience with this technique in practice using the DaVinci XiTM platform. METHOD: This is a multi-institutional retrospective analysis for patient undergoing Robotic TAMIS for resection of rectal lesions at two tertiary referral hospitals in the United States. Morbidity, mortality, anatomic measurement, and final pathology were analyzed. RESULTS: Thirty-four patients planned for Robotic TAMIS were identified. Average follow-up was 188 days. The average BMI was 29.5 +/- 5.9. All patients had an American Society of Anesthesiologist (ASA) Class of 2 or greater and 21 (62%) were ASA 3 or greater. Rectal lesions located from 2 to 15 cm from the dentate line were successfully resected. Lesions up to 4.5 cm in the longest dimension were successfully resected. The average operative time was 100 +/- 70 min, which correlated to a robotic console time of 76 +/- 67 min. Patients were placed in Lithotomy in 32 (94%) cases and were prone in only 2 (6%) cases. There were no intraoperative complications or conversions to another technique. The only postoperative complication was a medically managed Clostridium difficile infection in 1 patient. Three patients were upstaged to T2 on final pathology and underwent successful formal resections. BMI was a statistically significant predictor of a longer operation. CONCLUSIONS: With increased reach and operative range of motion, Robotic TAMIS is a safe and effective method for excising low-risk rectal neoplasia with a wide range of anatomical measurements. Higher BMI is a significant predictor of a longer and likely more challenging operation. PMID- 30006846 TI - Short-term outcomes of single-incision plus one-port laparoscopic versus conventional laparoscopic surgery for rectosigmoid cancer: a randomized controlled trial. AB - OBJECTIVE: The objective of the study is to evaluate the short-term outcomes of single-incision plus one-port surgery (SILS + 1) compared with conventional laparoscopic surgery (CLS) for colonic cancer. BACKGROUND: At present, single incision laparoscopic colectomy remains technically challenging. The use of SILS + 1 as an alternative has gained increasing attention; however, its safety and efficacy remain controversial. METHODS AND PATIENTS: Between April 2014 and July 2016, 198 patients with clinical stage T1-4aN0-2 M0 rectosigmoid cancer were enrolled. The participants were randomly assigned to either SILS + 1 (n = 99) or CLS (n = 99). The morbidity and mortality within 30 days, operative and pathologic outcomes, postoperative recovery course, inflammation and immune responses, and pain intensity were compared. RESULTS: There was no significant difference in overall complications between the two groups (17.2 vs. 16.3%, P = 1.000). The total operating time for the SILS + 1 group was significantly shorter (100.8 +/- 30.4 vs. 116.6 +/- 36.6, P = 0.002). Blood loss was significantly greater in the CLS group (20 vs. 50, P < 0.001). Thirteen patients (14%) in the CLS group required additional postoperative analgesics, which was significantly more than four patients in the SILS + 1 group. Notably, on postoperative day three, the visual analogue scale score of the CLS group was greater than that of the SILS + 1 group (1.3 +/- 1.1 vs. 1.7 +/- 1.3, P = 0.023). Tumor diameter, pathologic stage, length of the proximal and distal margins, and number of lymph nodes harvested were similar, other values were also similar between the two groups. CONCLUSION: Our findings suggest that SILS + 1 might be safe and feasible for rectosigmoid cancer when performed by experienced surgeons. It offers minimal invasiveness without compromising oncologic treatment principles. Trial Registration This trial was registered on ClinicalTrials.gov (NCT02117557). PMID- 30006847 TI - Three-year interval for endoscopic screening may reduce the mortality in patients with gastric cancer. AB - BACKGROUND: Endoscopic screening has been adopted in South Korea for the national screening of gastric cancer (GC). This study aimed to assess the effect on overall survival of GC patients and determine the optimal endoscopic screening interval. METHODS: The baseline characteristics and overall survival of GC patients treated at the National Cancer Center, Korea, between 2010 and 2016 were compared between those without a history of endoscopic evaluation (group N) and those in whom the interval between the last endoscopic evaluations and diagnosis of GC was <= 1, 1-2, 2-3, 3-4, or > 4 years (groups 1-5, respectively). RESULTS: A total of 2362 patients met the criteria for the study (1060 in group N and 1302 in groups 1-5). More patients in groups 1-5 were diagnosed with stage I GC (83.7, 83.7, 71.8, 78.2, and 71.6%, respectively) than in group N (62.4%, P < 0.001) and were treated endoscopically (38.8, 33.8, 24.7, 21.8, and 15.5%, respectively, vs. 13.5%; P < 0.001). Group 2 had less-advanced tumor stages (P = 0.001) and was more likely to have received endoscopic treatments (P = 0.026) than group 3. Hazard ratios for death were significantly lower in groups 2 (0.45; 95% confidence interval [CI], 0.32-0.64) and 3 (0.57; 95% CI, 0.33-0.98) than in group N; the decrease was not significant in group 4 (0.49, 95% CI, 0.20-1.20). CONCLUSIONS: Endoscopic screening every 3 years may reduce the mortality of GC patients, though screenings at least every 2 years may benefit patients with less advanced stages. PMID- 30006848 TI - GTS-21 attenuates loss of body mass, muscle mass, and function in rats having systemic inflammation with and without disuse atrophy. AB - Muscle changes of critical illness are attributed to systemic inflammatory responses and disuse atrophy. GTS-21 (3-(2,4-dimethoxy-benzylidene)anabaseine), also known as DMBX-A) is a synthetic derivative of the natural product anabaseine that acts as an agonist at alpha7-acetylcholine receptors (alpha7nAChRs). Hypothesis tested was that modulation of inflammation by agonist GTS-21 (10 mg/kg b.i.d. intraperitoneally) will attenuate body weight (BW) and muscle changes. Systemic sham inflammation was produced in 125 rats by Cornyebacterium parvum (C.p.) or saline injection on days 0/4/8. Seventy-four rats had one immobilized limb producing disuse atrophy. GTS-21 effects on BW, tibialis muscle mass (TMM), and function were assessed on day 12. Systemically, methemoglobin levels increased 26-fold with C.p. (p < 0.001) and decreased significantly (p < 0.033) with GTS-21. Control BW increased (+ 30 +/- 9 g, mean +/- SD) at day 12, but decreased with C.p. and superimposed disuse (p = 0.005). GTS-21 attenuated BW loss in C.p. (p = 0.005). Compared to controls, TMM decreased with C.p. (0.43 +/- 0.06 g to 0.26 +/- 0.03 g) and with superimposed disuse (0.18 +/- 0.04 g); GTS-21 ameliorated TMM loss to 0.32 +/- 0.04 (no disuse, p = 0.028) and to 0.22 +/- 0.03 (with disuse, p = 0.004). Tetanic tensions decreased with C.p. or disuse and GTS 21 attenuated tension decrease in animals with disuse (p = 0.006) and in animals with C.p. and disuse (p = 0.029). C.p.-induced 11-fold increased muscle alpha7nAChR expression was decreased by > 60% with GTS-21 treatment. In conclusion, GTS-21 modulates systemic inflammation, evidenced by both decreased methemoglobin levels and decrease of alpha7nAChR expression, and mitigates inflammation-mediated loss of BW, TMM, fiber size, and function. PMID- 30006849 TI - What Is Required for Neuronal Calcium Waves? A Numerical Parameter Study. AB - Neuronal calcium signals propagating by simple diffusion and reaction with mobile and stationary buffers are limited to cellular microdomains. The distance intracellular calcium signals can travel may be significantly increased by means of calcium-induced calcium release from internal calcium stores, notably the endoplasmic reticulum. The organelle, which can be thought of as a cell-within-a cell, is able to sequester large amounts of cytosolic calcium ions via SERCA pumps and selectively release them into the cytosol through ryanodine receptor channels leading to the formation of calcium waves. In this study, we set out to investigate the basic properties of such dendritic calcium waves and how they depend on the three parameters dendrite radius, ER radius and ryanodine receptor density in the endoplasmic membrane. We demonstrate that there are stable and abortive regimes for calcium waves, depending on the above morphological and physiological parameters. In stable regimes, calcium waves can travel across long dendritic distances, similar to electrical action potentials. We further observe that abortive regimes exist, which could be relevant for spike-timing dependent plasticity, as travel distances and wave velocities vary with changing intracellular architecture. For some of these regimes, analytic functions could be derived that fit the simulation data. In parameter spaces, that are non trivially influenced by the three-dimensional calcium concentration profile, we were not able to derive such a functional description, demonstrating the mathematical requirement to model and simulate biochemical signaling in three dimensional space. PMID- 30006850 TI - Expression Profile of Defense Genes in Rice Lines Pyramided with Resistance Genes Against Bacterial Blight, Fungal Blast and Insect Gall Midge. AB - BACKGROUND: Rice, a major food crop of the world, endures many major biotic stresses like bacterial blight (BB), fungal blast (BL) and the insect Asian rice gall midge (GM) that cause significant yield losses. Progress in tagging, mapping and cloning of several resistance (R) genes against aforesaid stresses has led to marker assisted multigene introgression into elite cultivars for multiple and durable resistance. However, no detailed study has been made on possible interactions among these genes when expressed simultaneously under combined stresses. RESULTS: Our studies monitored expression profiles of 14 defense related genes in 11 rice breeding lines derived from an elite cultivar with different combination of R genes against BB, BL and GM under single and multiple challenge. Four of the genes found implicated earlier under combined GM and BB stress were confirmed to be induced (>= 2 fold) in stem tissue following GM infestation; while one of these, cytochrome P450 family protein, was also induced in leaf in plants challenged by either BB or BL but not together. Three of the genes highlighted earlier in plants challenged by both BB and BL were also found induced in stem under GM challenge. Pi54 the target R gene against BL was also found induced when challenged by GM. Though expression of some genes was noted to be inhibited under combined pest challenge, such effects did not result in compromise in resistance against any of the target pests. CONCLUSION: While R genes generally tended to respond to specific pest challenge, several of the downstream defense genes responded to multiple pest challenge either single, sequential or simultaneous, without any distinct antagonism in expression of resistance to the target pests in two of the pyramided lines RPNF05 and RPNF08. PMID- 30006852 TI - Autonomy-Centered Healthcare. AB - In this paper, I aim to demonstrate that the consequences of the current United States health insurance scheme on both physician and patient autonomy is dire. So dire, in fact, that the only moral solution is something other than what we have now. The United States healthcare system faces much criticism at present. But my focus is particular: I am interested in the ways in which insurance interferes with physician and patient autonomy. (I do not consider The Affordable Care Act much of a change in this aspect of the system, for it still relies heavily on private insurance, albeit often subsidized.) I will argue in favor of an expansion of the traditional conception of what I call "medical autonomy" or "healthcare autonomy" and the usual role it plays in bioethical discussions. More generally, I show that in morally designing or evaluating any healthcare system, serious attention should be paid to how this system helps foster what I call active autonomy. PMID- 30006851 TI - 90Y-PET/CT-based dosimetry after selective internal radiation therapy predicts outcome in patients with liver metastases from colorectal cancer. AB - BACKGROUND: The aim of this work was to confirm that post-selective internal radiation therapy (SIRT) 90Y-PET/CT-based dosimetry correlates with lesion metabolic response and to determine its correlation with overall survival (OS) in liver-only metastases from colorectal cancer (mCRC) patients treated with SIRT. Twenty-four mCRC patients underwent pre/post-SIRT FDG-PET/CT and post-SIRT 90Y PET/CT. Lesions delineated on pre/post-SIRT FDG-PET/CT were classified as non metabolic responders (total lesion glycolysis (TLG)-decrease < 15%) and high metabolic responders (TLG-decrease >= 50%). Lesion delineations were projected on the anatomically registered 90Y-PET/CT. Voxel-based 3D dosimetrywas performed on the 90Y-PET/CT and lesions' mean absorbed dose (Dmean) was measured. The coefficient of correlation between Dmean and TLG-decrease was calculated. The ability of lesion Dmean to predict non-metabolic response and high-metabolic response was tested and two cutoff values (Dmean-under-treated and Dmean-well treated) were determined using ROC analysis. Patients were dichotomised in the "treated" group (all the lesions received a Dmean > Dmean-under-treated) and in the "under-treated" group (at least one lesion received a Dmean < Dmean-under treated). Kaplan-Meier product limit method was used to describe OS curves. RESULTS: Fifty-seven evaluable mCRC lesions were included. The coefficient of correlation between Dmean and TLG-decrease was 0.82. Two lesion Dmean cutoffs of 39 Gy (sensitivity 80%, specificity 95%, predictive-positive-value 86% and negative-predictive-value 92%) and 60 Gy (sensitivity 70%, specificity 95%, predictive positive-value 96% and negative-predictive-value 63%) were defined to predict non-metabolic response and high-metabolic response respectively. Patients with all lesions Dmean> 39 Gy had a significantly longer OS (13 months) than patients with at least one lesion Dmean < 39 Gy (OS = 5 months) (p = 0.012;hazard ratio, 2.6 (95% CI 0.98-7.00)). CONCLUSIONS: In chemorefractory mCRC patients treated with SIRT, lesion Dmean determined on post-SIRT 90Y-PET/CT correlates with metabolic response and higher lesion Dmean is associated with prolonged OS. PMID- 30006853 TI - Spatiotemporal distribution and dynamic modeling of atmospheric gaseous polycyclic aromatic hydrocarbons in a rapidly urbanizing city: Nanjing, China. AB - Multiple studies have evaluated the concentration and lung cancer risk of polycyclic aromatic hydrocarbons (PAHs). However, the monitoring and dynamic modeling of PAHs with a high resolution were relatively insufficient. We investigated the spatiotemporal distribution of gaseous PAH concentrations using passive air samplers with high sampling density in an industrial city of Nanjing, China (January and October 2015) and found that the gaseous PAH concentrations in western Nanjing were higher than those in eastern Nanjing, mainly because of emission source distribution and wind action. There were notable seasonal changes in PAH concentrations: winter > autumn > spring > summer. We developed an atmospheric PAH dynamic model with a high resolution of 1 km2 based on the advection-diffusion equation and coupled with an emissions inventory and atmospheric transportation processes. Acenaphthene was selected as a proxy for gaseous PAHs. The modeled acenaphthene concentrations were similar to the concentrations measured. Moreover, we used the model to identify the impact of meteorological factors on gaseous PAHs via scenario analysis and found that a narrow-range temperature change and even heavy rainfall may not significantly affect atmospheric gaseous PAH concentrations, whereas the wind played an important part in transferring PAHs and changing their geographic distribution. PMID- 30006854 TI - Increased Liver Enzymes After Gastric Bypass Surgery. PMID- 30006855 TI - A five-step protocol for estimating forest cover and rate of change in the New York City watershed. AB - New York City drinking water quality depends on retention of forest cover in its Catskill Mountains watersheds, yet multiple published analyses of temporally approximate satellite imagery derived no definitive nor agreed upon quantification of either forest cover in the watershed, or, more importantly, its rate of change over time. The objective of this work was to reduce uncertainty surrounding these estimates. We developed a five-pronged protocol that included (1) creation of a 1975-2002 time-series of land use/land cover (LULC) using Cross Correlation Analysis (CCA); (2) a corrective post classification logic-based algorithm to correct for illogical transitions; (3) a probability-based stratified random sample accuracy assessment; (4) joint probability calculations of the "true" 2002 class proportions; and (5) verification of quantities of our LULC classification, and those of other researchers, versus the statistically derived true proportions. The estimated true percent of forest cover as of 2002 is 72%, far less than that reported by other studies, even with a net reforestation between 1975 and 2002. This protocol is an enhancement over previous LULC monitoring methods. Its more robust estimates of both historic trends and 2002 forest cover reveal information that is vitally important to monitoring and managing future water quality for the nation's largest city. PMID- 30006856 TI - Estimating asymmetric information effects in health care with uninsurable costs. AB - We use a structural approach to separately estimate moral hazard and adverse selection effects in health care utilization using hospital invoices data. Our model explicitly accounts for the heterogeneity in the non-insurable transactions costs associated with hospital visits which increase the individuals' total cost of health care and dampen the moral hazard effect. A measure of moral hazard is derived as the difference between the observed and the counterfactual health care consumption. In the population of patients with non life-threatening diagnoses, our results indicate statistically significant and economically meaningful moral hazard. We also test for the presence of adverse selection by investigating whether patients with different health status sort themselves into different health insurance plans. Adverse selection is confirmed in the data because patients with estimated worse health tend to buy the insurance coverage and patients with estimated better health choose not to buy the insurance coverage. PMID- 30006857 TI - [What rheumatologists can learn from pneumologists]. AB - BACKGROUND: Pulmonary involvement in patients with underlying autoimmune diseases poses a major diagnostic and therapeutic challenge to the treating physician. Due to the associated increased mortality risk, early diagnosis is crucial. OBJECTIVE: The incidence and mortality rate of connective tissue disease-related interstitial lung diseases (CTD-ILD) and pulmonary hypertension (PH) were evaluated in patients with rheumatic disease including clinical aspects, diagnostic procedure, prognosis and treatment recommendations. MATERIAL AND METHODS: An analysis of remarkable publications was carried out and guidelines are presented. RESULTS: The CTD-ILD and PH are frequent comorbidities with significantly increased mortality risk, especially in patients with systemic sclerosis (SSc). In primary fibrotic and non-inflammatory CTD-ILD, as occurs especially in patients with rheumatoid arthritis, immunosuppressive therapy is only partially effective. Currently, in some eligible patients only lung transplantation remains as a definitive therapy. CONCLUSION: The diagnostics and treatment of CTD-ILD and PH in patients with an underlying autoimmune disease requires an interdisciplinary approach. The effectiveness of antifibrotic treatment needs to be evaluated in the future. PMID- 30006858 TI - Infectious agents and different course of multiple sclerosis: a systematic review. AB - Multiple sclerosis (MS) causes demyelination of white matter of central nervous system and neuro-degeneration due to inflammation. Different types of MS, as well as disease progression, come with different pathology and pathophysiology. The objective of this study was to evaluate the possible association between different micro-organisms and the relapse or progression of MS. Studies indexed in Medline/PMC, Scopus and Web of Science published without time and language limitation until March 2017 were identified through the search terms "infection" or "infectious" and "multiple sclerosis". A total of 20878 abstracts were identified through the initial search terms. Selection of articles and assessment of their quality was done based on Cochrane library guidelines. Full texts were reviewed for 33 articles out of which 14 articles met the criteria for inclusion. Different micro-organisms are known to play roles in the pathogenesis of MS and its relapse; including Human herpesvirus 6 (HHV-6), Human herpesvirus 7 (HHV-7), Epstein-Barr virus (EBV), Chlamydia pneumoniae and Torque teno virus (TTV). But in this review only HHV-6, C. pneumoniae and TTV have been considered to play a role in disease progression in some studies and not all of them. This review concluded that some micro-organisms such as HHV-6, C. pneumoniae and TTV have been considered as cofactors to make MS a progressive type. It should be considered that these findings do not necessarily rule out the role of other pathogens in MS progression but may represent population differences or different sensitivity of the technique used. PMID- 30006859 TI - Migraine with aura and white matter tract changes. AB - We aimed to explore whether a migraine with aura (MA) is associated with structural changes in tracts of a white matter and to compare parameters of diffusivity between subgroups in migraineurs. Forty-three MA and 20 healthy subjects (HS), balanced by sex and age, were selected for this study. Analysis of diffusion tensor parameters was used to identify differences between MA patients and HS, and then between MA subgroups. A diffusion tensor probabilistic tractography analysis showed that there is no difference between MA patients and HS. However, using more-liberal uncorrected statistical threshold, we noted a trend in MA patients toward lower diffusivity indices of selected white matter tracts located in the forceps minor and right anterior thalamic radiation (ATR), superior longitudinal fasciculus (temporal part) (SLFT), cingulum-cingulate tract, and left uncinate fasciculus. Migraineurs who experienced somatosensory and dysphasic aura, besides visual symptoms, had tendency toward lower diffusivity indices, relative to migraineurs who experienced only visual symptoms, in the right inferior longitudinal fasciculus, forceps minor, and right superior longitudinal fasciculus (parietal part), SLFT, and cingulum-angular bundle. Aura frequency were negatively correlated with axial diffusivity and mean diffusivity of the right ATR (partial correlation = - 0.474; p = 0.002; partial correlation = - 0.460; p = 0.002), respectively. There were no significant differences between MA patients and HS, neither between MA subgroups. Migraineurs with abundant symptoms during the aura possibly have more myelinated fibers relative to those who experience only visual symptoms. Lower diffusivity indices of the right ATR are linked to more frequent migraine with aura attacks. PMID- 30006860 TI - Long-term brain effects of N-back training: an fMRI study. AB - Neurobehavioral effects of cognitive training have become a popular research issue. Specifically, behavioral studies have demonstrated the long-term efficacy of cognitive training of working memory functions, but the neural basis for this training have been studied only at short-term. Using fMRI, we investigate the cerebral changes produced by brief single n-back training immediately and 5 weeks after finishing the training. We used the data from a sample of 52 participants who were assigned to either an experimental condition (training group) or a no contact control condition. Both groups completed three fMRI sessions with the same n-back task. Behavioral and brain effects were studied, comparing the conditions and sessions in both groups. Our results showed that n-back training improved performance in terms of accuracy and response speed in the trained group compared to the control group. These behavioral changes in trained participants were associated with decreased activation in various brain areas related to working memory, specifically the frontal superior/middle cortex, inferior parietal cortex, anterior cingulate cortex, and middle temporal cortex. Five weeks after training, the behavioral and brain changes remained stable. We conclude that cognitive training was associated with an improvement in behavioral performance and decreased brain activation, suggesting better neural efficiency that persists over time. PMID- 30006861 TI - Standard vs delayed ligature of the dorsal vascular complex during robot-assisted radical prostatectomy: results from a randomized controlled trial. AB - PURPOSE: Prospective randomized trial to compare standard vs delayed approach to dorsal vascular complex (s-DVC vs d-DVC) in robot-assisted radical prostatectomy (RARP). METHODS: Patients scheduled for RARP were randomized into a 1:1 ratio to receive either s-DVC or d-DVC by two experienced surgeons. In s-DVC arm an eight shaped single stitch was given at the beginning of the procedure and the DVC was subsequently cut at time of apical dissection; in d-DVC arm the plexus was transected at the end of prostatectomy, prior to apex dissection and then sutured. Primary endpoint was difference in estimated blood loss (EBL) and a sample size of 226 cases was calculated; ad interim analysis was planned after 2/3 of recruitment. RESULTS: Endpoint was reached at ad interim analysis after 162 cases (81 s-DVC, 81 d-DVC) and recruitment was, therefore, interrupted. Baseline and tumor characteristics were overlapping. EBL was significantly higher in d-DVC arm (mean EBL 107 vs 65 ml, p = 0.003), but without differences in post operative hemoglobin, transfusions and complications. Overall PSM rate was higher in d-DVC arm (21.0 vs 14.8%, p = 0.323), with statistical significance relatively to organ-confined disease (15.5 vs 3.6%, p = 0.031). Apical involvement was instead significantly higher in s-DVC arm (prevalence in PSM patients 66.7 vs 23.5%, p = 0.020). Post-operative PSA, continence and potency rates were similar between groups. CONCLUSIONS: Standard and delayed approaches to DVC are safe and lead to similar functional outcomes. A delayed approach exposes to a higher risk of PSM in organ-confined disease but with a lower risk of apical involvement. PMID- 30006862 TI - A randomised trial to compare the increase in intracranial pressure as correlated with the optic nerve sheath diameter during propofol versus sevoflurane maintained anesthesia in robot-assisted laparoscopic pelvic surgery. AB - : Robot-assisted surgery can cause raised intracranial pressures (ICP) due to steep trendelenburg position and pneumoperitoneum. The choice of anesthetic agents can influence the ICP, which can be measured indirectly by correlating it with the sonographically measured optic nerve sheath diameter (ONSD). In this study, our primary aim was to compare the change from baseline of the ONSD during propofol versus sevoflurane-maintained anesthesia in patients undergoing robotic pelvic surgery. In this prospective, interventional, double-blinded study, we randomised 50 patients into two groups P and S. Subjects in group P received intravenous propofol infusion while those in group S received inhalation sevoflurane for maintenance of anesthesia. The ONSD at fixed intervals was noted as the mean of four values measured using ultrasound in both eyes by two independent anesthesiologists who were blinded to the group allocation. The patient demographics and baseline parameters were similar. The mean maximum rise in ONSD from baseline was 0.01 +/- 0.01 cm in group P while it was 0.03 +/- 0.01 cm in group S (p = 0.001). Percentage change from baseline in group P was 3.41 +/ 1.81% and 8.00 +/- 2.95% in group S (p = 0.001). We found a positive correlation between the duration of surgery and the maximum rise in ONSD in group S (p = 0.003), but not in group P. Propofol-based total intravenous anesthesia is more effective than inhalation sevoflurane in attenuating the increase in ICP as correlated with the ONSD during robotic pelvic surgery. CLINICAL TRIAL REGISTRATION: Yes; Principal investigator: Nambiath Sujata; Trial number: REF/2016/11/012713 (registered); Trial registry: CTRI- http://ctri.nic.in . PMID- 30006863 TI - Erratum to: Drug Sensitivity Assays of Human Cancer Organoid Cultures. PMID- 30006864 TI - Melanoblasts as Multipotent Cells in Murine Skin. AB - Melanoblasts (MBs) are melanocyte precursors that are derived from neural crest cells (NCCs). We recently demonstrated the multipotency of MBs; they differentiate not only into pigmented melanocytes but also other NCC derivatives. We herein describe methods for the isolation of MBs from mouse skin by flow cytometry. Methods to culture isolated MBs that retain their multipotency and isolation methods for MBs using gene-modified mouse are also described. PMID- 30006865 TI - High-Grade Purification of Third-Generation HIV-Based Lentiviral Vectors by Anion Exchange Chromatography for Experimental Gene and Stem Cell Therapy Applications. AB - Lentiviral vectors (LVs) have been increasingly used in clinical gene therapy applications particularly due to their efficient gene transfer ability, lack of interference from preexisting viral immunity, and long-term gene expression they provide. Purity of LVs is essential in in vivo applications, for a high therapeutic benefit with minimum toxicity. Accordingly, laboratory scale production of LVs frequently involves transient cotransfection of 293T cells with packaging and transfer plasmids in the presence of CaPO4. After clearance of the cellular debris by low-speed centrifugation and filtration, lentivectors are usually concentrated by high-speed ultracentrifugation in sucrose cushion. Concentrated viral samples are then purified by anion exchange chromatography (AEX) after benzonase treatment to remove the residual cellular DNA. Here, we describe an improved practical method for LV purification using AEX, useful for experimental studies concerning gene and stem cell therapy. PMID- 30006866 TI - Effect of Prior Biologic Use on Cost-Effectiveness of Brodalumab vs. Ustekinumab for Treatment of Moderate-to-Severe Psoriasis in the United States. AB - INTRODUCTION: Clinical trials have shown brodalumab to have better efficacy than ustekinumab for the treatment of moderate-to-severe psoriasis. An estimation of the cost-effectiveness of brodalumab vs. ustekinumab is warranted and may be useful for treatment decision-making processes, especially in the context of the cost considerations of the current US healthcare system. Therefore, we compared the cost-effectiveness of brodalumab with ustekinumab for treatment of moderate to-severe psoriasis in biologic-naive and biologic-experienced patients in the USA. METHODS: An Excel-based economic model was developed to estimate and compare total annual costs to health plans associated with treatment with brodalumab vs. ustekinumab per achievement of Psorasis Area and Severity Index (PASI) 75, 90, and 100 for patients with moderate-to-severe psoriasis. RESULTS: For treatment with brodalumab vs. ustekinumab, total annual treatment costs per PASI 75, 90, and 100 were $31,106, $57,776, and $163,069, respectively, lower for a patient naive to prior biologic treatment; they were $40,535, $65,472, and $223,610, respectively, lower for a patient experienced with prior biologic treatment. In an additional analysis among patients with and without prior biologic failure, they were $52,822, $93,309, and $365,606, respectively, lower for a patient with failure and they were $31,660, $57,128, and $164,996, respectively, lower for a patient without failure. CONCLUSION: Compared to ustekinumab, treatment with brodalumab was associated with better cost-effectiveness ratios for biologic naive and experienced-patients and also patients with and without prior biologic treatment failure. The greater cost-effectiveness of brodalumab was most prominent for biologic-experienced and prior biologic treatment failure patients. FUNDING: Ortho Dermatologics. PMID- 30006867 TI - Anti-prostate cancer activity of 8-hydroxyquinoline-2-carboxaldehyde thiosemicarbazide copper complexes in vivo by bioluminescence imaging. AB - Copper 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazide complex (CuHQTS) is a copper complex with strong anticancer activity against cisplatin-resistant neuroblastoma and prostate cancer cells in vitro by cell proliferation assay or fluorescent microscopic imaging. This study aimed to evaluate anti-prostate cancer activity of CuHQTS in vivo by bioluminescence imaging (BLI) and tumor size measurement, using athymic nu/nu mice implanted with prostate cancer cells carrying luciferase reporter gene (Luc-PC3). Growth of Luc-PC3 cells (1 * 105 cells) implanted in athymic nu/nu mice treated with CuHQTS for 2 weeks was suppressed by measurement of luciferase signals (6.18 * 107 to 5.36 * 107 p/s/cm2/sr) with BLI, compared with luciferase signals of Luc-PC3 cells (4.66 * 107 to 1.51 * 108 p/s/cm2/sr, p < 0.05) in the mice treated with normal saline of placebo control. Moreover, the size of PC-3 xenograft tumor (126.5 +/- 34.2 mm3) in athymic nu/nu mice treated with CuHQTS was significantly smaller than the size of PC-3 xenograft tumor (218.6 +/- 48.0 mm3, p < 0.05) in athymic nu/nu mice treated with normal saline of placebo control, suggesting in vivo tumor growth inhibition activity of CuHQTS on prostate cancer. The findings of this study support further investigation of CuHQTS as a promising new anticancer agent for the treatment of metastatic prostate cancer refractory to anticancer drugs currently available. PMID- 30006868 TI - Antenna effect and phosphorescence spectra to find the location of drug tetracycline in bovine beta-lactoglobulin A. AB - A ternary system comprising of a Eu(III) complex of the drug Tetracycline hydrochloride (Eu3TC) bound to bovine beta-lactoglobulin variant A (BLGA) in aqueous buffer at physiological pH (pH = 7.4) has been investigated to exploit the enhanced "antenna effect" to locate the bound drug and find the microenvironment of the binding site. Steady-state and time-resolved emission studies at room temperature as well as at 77 K have been carried out to evaluate the binding parameters in the binary system consisting of BLGA and tetracycline hydrochloride (TC). Low-temperature phosphorescence studies at 77 K of pure BLGA confirm Trp 19 to be the emitting residue, while Trp 61 is silent. Enhancement of BLGA phosphorescence emission in the ternary system at 77 K indicates that Trp 19 is very close to Eu(III) in the Eu3TC complex. The molecular docking results further confirm that TC binds close to Trp 19 in a hydrophobic domain. The results thus obtained can provide guidelines to design and synthesize target oriented drugs as well as suitable bio-probes. PMID- 30006869 TI - The international health elective: a stepping stone for tomorrow's global surgeons and anaesthetists. PMID- 30006870 TI - Future physician-scientists: could we catch them young? Factors influencing intrinsic and extrinsic motivation for research among first-year medical students. AB - INTRODUCTION: The medical field is currently facing a physician-scientist shortage. One possible solution is to direct medical students towards a research oriented career. To do so, knowledge is needed on how to motivate medical students to do research. Therefore, this study examines motivation for research and identifies factors influencing intrinsic and extrinsic motivation for research among first-year medical students. METHODS: First-year medical students were surveyed at the beginning of their bachelor's program in 2016. On a 7-point Likert scale, students reported their motivation for research, self-efficacy, perceptions of research, curiosity, and need for challenge. Regression analyses were used to examine the influence of these factors on students' motivation for research. RESULTS: Out of 316 approached students, 315 participated (99.7%). On average, students scored 5.49 on intrinsic, and 5.66 on extrinsic motivation for research. All factors measured influenced intrinsic and extrinsic motivation for research significantly and positively, also after adjusting for gender and age. Cumulative regression showed that these factors explained 39.6% of the variance in intrinsic, and 14% in extrinsic motivation for research. DISCUSSION: All factors play an important role in intrinsic and, to a lesser extent, extrinsic motivation for research. First-year medical students' motivation for research could be enhanced by stimulating positive self-efficacy beliefs, positive perceptions of research, and curiosity. Also, it is important to fulfil students' needs for challenge by stimulating them to actively conduct research. Thus, to catch students young and cultivate physician-scientists, students should be stimulated to engage in research from the beginning of medical training. PMID- 30006872 TI - Dynamics of Changes in Metabolic and Hematological Parameters after Transplantation of Pancreatic Islet Cells on TiNi Scaffold in Experimental Diabetes Mellitus. AB - The dynamics of the development of the pancreatic islet cells in the porous TiNi scaffold was studied by electron microscopy. Changes in the metabolism of glucose and glycosylated hemoglobin and parameters of the peripheral blood and bone marrow were shown after transplantation of pancreatic islet cells on porous permeable TiNi scaffold during alloxan-induced diabetes. The cells administered on the porous biocompatible scaffold produced more prolonged anti-diabetic effect and normalized hemopoiesis parameters in comparison with their intraperitoneal administration. The experiment on pancreatic islet cells showed that porous permeable TiNi scaffold is a unique cell incubator acceptable for usage for tissue engineering. PMID- 30006873 TI - Mitigating Effect of Nitrates (Monizol) on Pharmacodynamic Shifts in the Cardiovascular System Caused by Radioprotector Indralin. AB - We studied the effect of radioprotector indralin (B-190) alone or in combination with monizol on BP and HR in rabbits, reduction of blood supply and spleen weight in rats and (CBA*C57Bl/6)F1 hybrids mice, and on blood loss from a wound on tip of the tail in mice. Being an alpha1-adrenomimetic, indralin caused hypertensive reaction with the development of bradycardia, reduced blood supply and spleen weight, and sharply reduced blood loss from the wound. Monizol as nitrate reduced BP without affecting HR and reduced blood loss from the wound. Monizol administered prior to indralin eliminated radioprotector-induced hypertensive reaction, reduced bradycardia by more than 2 times, and attenuated the effect of indralin on spleen weight and blood loss from the wound by 1.6-1.8 times. Monizol administered after indralin had no effect on shifts in peripheral blood supply caused by the radioprotector. PMID- 30006871 TI - Guidelines for clinical evaluation of chronic kidney disease : AMED research on regulatory science of pharmaceuticals and medical devices. PMID- 30006874 TI - The Effect of Dihydroquercetin on Catalytic Activity of Iron (II) Ions in the Fenton Reaction. AB - Dihydroquercetin is a natural flavonoid with antioxidant properties that are determined by its ability to scavenge free radicals and chelate transition metal ions. Chemiluminescent studies showed that iron (II) ions in complex with dihydroquercetin are inactive and cannot catalyze decomposition of hydrogen peroxide (Fenton reaction). PMID- 30006875 TI - Influence of Specific Bacteriophage on the Level of Vesicle Formation and Morphology of Cells of Yersinia pseudotuberculosis. AB - Incubation of Yersinia pseudotuberculosis cells grown on a solid medium with pseudotuberculous diagnostic bacteriophage for 20 min at 37oC led to a significant decrease in the concentration of both components of the system. This effect was absent when the bacteria were grown in a fluid medium. At the same time, this incubation regimen promoted vesicle formation and typical morphological changes in bacteria grown in both surface and suspension cultures. Co-incubation of the bacteriophage with suspension of vesicles isolated from the suspension culture of Y. pseudotuberculosis grown at 10oC (but not 37oC) led to a decrease in plaque-forming activity of the bacteriophage. PMID- 30006876 TI - Autophagy in Hepatocytes during Distant Tumor Growth. AB - Structural changes in the liver of CBA mice were studied during the development of experimental hepatocarcinoma-29 inoculated into the hip. A decrease in the volume density of hepatocyte cytoplasm, mitochondria, endoplasmic reticulum, and lipid inclusions and an increase in the volume density of lysosomal structures during tumor growth were observed. All stages of intracellular autophagy were recorded by the method of electron microscopy. These stages included the appearance of autophagosomes, autophagolysosomes, and secondary lysosomes in the hepatocyte cytoplasm. Fragments of cytoplasm, glycogen rosettes, mitochondria, and fragments of endoplasmic reticulum with ribosomes were found in autophagosomes. The obtained data indicate the development of non-selective autophagy in the liver during distant tumor growth in aimed at the maintenance of intracellular homeostasis in hepatocytes and energy and trophic homeostasis of organism. PMID- 30006878 TI - Experimental Evaluation of Velocity Constants for Ozone Interaction with Individual Fatty Acids. AB - The kinetics of ozone interaction with 14 saturated and unsaturated fatty acids with different molecular structures was studied and velocity constants of these reactions were measured. The relationships between the measured constants and some parameters of fatty acid (length of the aliphatic chain, number of double bonds, location of the double bonds, and its configuration) were detected. The highest velocity constant is recorded for monounsaturated oleic fatty acid: 2.58*105 (M*sec)-1. Other studied fatty acids had 1.5-5-lower constants depending on their molecular structures. PMID- 30006877 TI - Cytogenetic Analysis of the Results of Genome Editing on the Cell Model of Parkinson's Disease. AB - We performed a cytogenetic analysis of the results of CRISPR/Cas9-correction of G2019S mutation in LRRK2 gene associated with Parkinson's disease. Genome editing was performed on induced pluripotent stem cells derived from fibroblasts of a patient carrying this mutation. A mosaic variant of tetraploidy 92 XXYY/46,XY (24 43% cells from various clones) was found in neuronal precursors differentiated from the induced pluripotent stem cells after gene editing procedure. Solitary cases of translocations and chromosome breaks were observed. These data confirm the importance of the development of new approaches ensuring genome stability in CRISPR/Cas9-edited cultures. PMID- 30006879 TI - Evaluation of the Possibility of Correction of Doxorubicin-Induced Chronic Heart Failure in the Experiment with 3-Hydroxypyridine Acetylcysteinate and 3 Hydroxypyridine Succinate. AB - The possibility of correction of morphological changes in the myocardium and biochemical parameters of the blood with 3-hydroxypyridine acetylcysteinate in a dose of 25 mg/kg was studied in the model of doxorubicin-induced chronic heart failure in rats. It was found that 3-hydroxypyridine acetylcysteinate in a dose of 25 mg/kg produced less pronounced cardio-protective effect in experimental chronic heart failure than 3-hydroxypyridine succinate. PMID- 30006880 TI - Effect of Water-Soluble Echinochrome Analog on Arrhythmia Severity in Experimental Model of Acute Myocardial Ischemia. AB - The effects of therapeutic or preventive-therapeutic administration of water soluble echinochrome analog U-441 on arrhythmia severity assessed by a set of myocardial spatio-temporal depolarization and repolarization parameters were examined on the model of acute myocardial ischemia in cats. Coronary occlusion increased activation time and decreased repolarization time in the ischemic zone; in addition, it increased both global and borderline (local) dispersions of repolarization. The linear regression model showed that only activation time values measured at the initial state and at termination of occlusion were associated with total arrhythmia score during ischemia (regression coefficient beta=0.338, 95%CI=0.074-0.602, p=0.015 and beta=0.720, 95%CI=0.323-1.117, p=0.001, respectively). The study revealed no association between administration of echinochrome analog U-441 and arrhythmia severity. PMID- 30006881 TI - Specific Features of Transcription Activity of Cancer-Testis Antigens in Patients with Metastatic and Non-Metastatic Breast Cancer. AB - Cancer-testis antigens, effective markers of tissue malignant transformation, are characterized by heterogonous transcription depending on the pathological features of breast cancer. We performed screening of transcription profile of cancer-testis antigens specific for breast tumor tissues in female patients with and without regional metastasis. The relative expression of 16 genes (MAGEA1, MAGEA2, MAGEA3, MAGEA4, MAGEB1, MAGEB2, GAGE1, GAGE3, GAGE4, MAGEC1, BAGE, XAGE3, NY-ESO1, SSX2, SYCP1, and PRAME1) was analyzed by RT-qPCR method in biopsy specimens of the mammary gland tissues obtained during surgery from 25 patients. Differential transcription activity of cancer-testis antigens genes was observed in patients with metastatic (enhanced expression of MAGEA2, MAGEB1, and XAGE3 genes) and non-metastatic (enhanced expression of GAGE3 and PRAME1 genes) breast cancer. PMID- 30006882 TI - Spontaneous Changes in Functional Connectivity of Independent Components of fMRI Signal in Healthy Volunteers at Rest and in Subjects with Mild Depression. AB - Depression is associated with changes in the pattern of interaction of cerebral networks, which can reflect both existing symptoms and compensatory processes. The study is based on analysis of resting state fMRI data from 15 patients with mild depression and 19 conventionally healthy individuals. From fMRI signal recorded at rest for 4 min, the independent components were reconstructed. The intergroup differences and dynamics of functional connectivity from the first to the second recording were analyzed. Initially, depressive patients demonstrated weaker connectivity between cerebellar declive network (CN) and left central executive network (CEN) and also sensorimotor network (SMN); left CEN and primary visual network (PVN). During the second recording, the patients demonstrated more intensive reciprocal connection of the dorsal domain of default mode network (DMN) and auditory network (AN). In healthy subjects, positive correlations of the dorsal DMN and left CEN, right CEN and CN, and negative correlation of dorsal DMN and visuospatial network weakened from the first to second record. In the depression group, the interaction of AN with PVN, the right CEN with the anterior salience network and with ventral DMN weakened. At the same time, the connectivity between SMN and CN were strengthened. The results can be interpreted as spontaneous normalization of brain activity, but no direct evidence for their relation to the improvement of depression symptoms was found. PMID- 30006883 TI - Pigment configuration in the light-harvesting protein of the xanthophyte alga Xanthonema debile. AB - The soil chromophyte alga Xanthonema (X.) debile contains only non-carbonyl carotenoids and Chl-a. X. debile has an antenna system denoted Xanthophyte light harvesting complex (XLH) that contains the carotenoids diadinoxanthin, heteroxanthin, and vaucheriaxanthin. The XLH pigment stoichiometry was calculated by chromatographic techniques and the pigment-binding structure studied by resonance Raman spectroscopy. The pigment ratio obtained by HPLC was found to be close to 8:1:2:1 Chl-a:heteroxanthin:diadinoxanthin:vaucheriaxanthin. The resonance Raman spectra suggest the presence of 8-10 Chl-a, all of which are 5 coordinated to the central Mg, with 1-3 Chl-a possessing a macrocycle distorted from the relaxed conformation. The three populations of carotenoids are in the all-trans configuration. Vaucheriaxanthin absorbs around 500-530 nm, diadinoxanthin at 494 nm and heteroxanthin at 487 nm at 4.5 K. The effective conjugation length of heteroxanthin and diadinoxanthin has been determined as 9.4 in both cases; the environment polarizability of the heteroxanthin and diadinoxanthin binding pockets is 0.270 and 0.305, respectively. PMID- 30006886 TI - The invaluable observation of a hazardous patient with a floating and Gecko-like shaped right atrial thrombus diagnosed by echocardiography and computed tomography imaging. PMID- 30006884 TI - The association between alcohol consumption and risk of hip fracture differs by age and gender in Cohort of Norway: a NOREPOS study. AB - : The association between alcohol consumption and hip fracture differed by gender: Men aged 30-59 years drinking frequently or 14+ gl/week had higher risk than moderate drinkers. No significant association was seen in older men. Women not drinking alcohol had higher risk than those drinking moderately both regarding frequency and amount. INTRODUCTION: We aimed to examine alcohol consumption and risk of hip fracture according to age and gender in the population-based Cohort of Norway (1994-2003). METHODS: Socio-demographics, lifestyle, and health were self-reported and weight and height were measured in 70,568 men and 71,357 women >= 30 years. Information on subsequent hip fractures was retrieved from hospitals' electronic patient registries during 1994-2013. Frequency of alcohol consumption was categorized: never/seldom, moderate (<= 2-3 times/week), or frequent (>= 4 times/week), and amount as number of glasses per week: 0, 1-6, 7-13, 14-27, and 28+. Type of alcohol (wine vs. beer/hard liquor) was also examined. Cox's proportional hazards regression was used to estimate hazard ratios (HRs) stratified on gender and baseline age < 60 and >= 60 years. RESULTS: During median 15-year follow-up, 1558 men and 2511 women suffered a hip fracture. Using moderate drinkers as reference, men < 60 years drinking frequently had multivariable adjusted HR = 1.73 (CI 1.02-2.96) for hip fracture and more than 2.5 times higher risk if they consumed 14+ glasses compared to 1-6 glasses per week. In other groups of age and gender, no statistically significant increased risk was found in those consuming the highest levels of alcohol. Compared to women with moderate or frequent alcohol use, never/seldom-drinking women had the highest fracture risk. In women, use of wine was associated with lower fracture risk than other types of alcohol. CONCLUSIONS: Risk of hip fracture was highest in men < 60 years with the highest frequency and amount of alcohol consumption and in non-drinking women. PMID- 30006885 TI - Monocytes from male patients with ankylosing spondylitis display decreased osteoclastogenesis and decreased RANKL/OPG ratio. AB - : The present study investigates the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) in male patients with ankylosing spondylitis (AS). We demonstrated that monocytes from these patients display a lower capacity to generate osteoclasts compared to cells from healthy controls, and osteoclastogenesis was negatively correlated with disease duration. INTRODUCTION: Ankylosing spondylitis (AS) is a disease characterized by new bone growth that leads to syndesmophyte formation but AS patients frequently present with low bone mineral density/fractures. Osteoclastogenesis in AS patients is poorly studied and controversial. The aim of this study is to determine if the osteoclastogenic capacity of PBMCs is different in AS patients compared to controls and the relationship between osteoclastogenesis and clinical/laboratory parameters. METHODS: PBMCs from 85 male AS patients and 59 controls were tested for CD16+ cells and induced to differentiate into osteoclasts over 3 weeks in vitro. Serum levels of RANKL, osteoprotegerin (OPG), C-terminal telopeptide of type I collagen (CTX), and amino-terminal pro-peptide of type I collagen (P1NP) were also evaluated. RESULTS: PBMCs from AS patients had fewer CD16+ cells and produced fewer osteoclasts compared to controls. Apoptosis occurred less frequently in osteoclasts obtained from AS patients than in osteoclasts from the controls. A lower RANKL/OPG and CTX/P1NP were observed in AS patients compared to controls. AS patients taking NSAIDs presented no difference regarding the number of OCs produced and the percentage of CD16+ cells compared to controls. However, patients taking TNF inhibitors (TNFi) presented lower OC numbers than controls. A negative correlation was demonstrated between the number of osteoclasts generated from PBMCs of AS patients and disease duration. CONCLUSION: Monocytes from male AS patients display a lower capacity to generate osteoclasts in vitro compared to cells from controls. Osteoclastogenesis was negatively correlated with disease duration. This finding supports the idea that osteoclasts play a role in the physiopathology of bone disease in AS patients. PMID- 30006887 TI - Action plan interrupted: resolution of proactive interference while coordinating execution of multiple action plans during sleep deprivation. AB - The ability to retain an action plan to execute another is necessary for most complex, goal-directed behavior. Research shows that executing an action plan to an interrupting event can be delayed when it partly overlaps (vs. does not overlap) with the retained action plan. This phenomenon is known as partial repetition costs (PRCs). PRCs reflect proactive interference, which may be resolved by inhibitory, executive control processes. We investigated whether these inhibitory processes are compromised due to one night of sleep deprivation. Participants were randomized to a sleep-deprived group or a well-rested control group. All participants performed an action planning task at baseline after a full night of sleep, and again either after a night of sleep deprivation (sleep deprived group) or a full night of sleep (control group). In this task, two visual events occurred in a sequence. Participants retained an action plan to the first event in working memory while executing a speeded action to the second (interrupting) event; afterwards, they executed the action to the first event. The two action plans either partly overlapped (required the same hand) or did not (required different hands). Results showed slower responses to the interrupting event during sleep deprivation compared to baseline and the control group. However, the magnitude of the PRCs was no different during sleep deprivation compared to baseline and the control group. Thus, one night of sleep deprivation slowed global responses to the interruption, but inhibitory processes involved in reducing proactive interference while responding to an interrupting event were not compromised. These findings are consistent with other studies that show sleep deprivation degrades global task performance, but does not necessarily degrade performance on isolated, executive control components of cognition. The possibility that our findings involve local as opposed to central inhibition is also discussed. PMID- 30006889 TI - Tay-Sachs Disease Presenting as Refractory Epilepsy with Autistic Regression Secondary to a Novel Mutation in HEXA Gene. PMID- 30006888 TI - Effects of lead and lead-melatonin exposure on protein and gene expression of metal transporters, proteins and the copper/zinc ratio in rats. AB - Human lead (Pb) exposure induces many adverse health effects, including some related to lead accumulation in organs. Although lead bio-distribution in the body has been described, the molecular mechanism underlying distribution and excretion is not well understood. The transport of essential and toxic metals is principally mediated by proteins. How lead affects the expression of metal transporter proteins in the principal metal excretory organs, i.e., the liver and kidney, is unknown. Considering that co-administration of melatonin and lead reduces the toxic effects of lead and lead levels in the blood in vivo, we examined how lead and co-administration of lead and melatonin affect the gene and protein expression of metal transporter proteins (ZIP8, ZIP14, CTR1 and DMT1) in these organs. Rats were exposed intraperitoneally to lead or lead-melatonin. Our results show that Pb exposure induces changes in the protein and gene expression of ZIP8, ZIP14 and CTR1. Alterations in the copper/zinc ratio found in the blood, liver and kidney were likely related to these changes. With DMT1 expression (gene and protein), a positive correlation was found with lead levels in the kidney. Co administration of melatonin and lead reduced lead-induced DMT1 expression through an unknown mechanism. This effect of melatonin relates to reduced lead levels in the blood and kidney. The metal transport protein function and our results suggest that DMT1 likely contributes to lead accumulation in organs. These data further elucidate the effects of lead on Cu and Zn and the molecular mechanism underlying lead bio-distribution in animals. PMID- 30006890 TI - A Prospective Clinical Study of a Percutaneous Vascular Access System for Hemodialysis Catheters. AB - INTRODUCTION: Dysfunctional or infected hemodialysis polyester-cuffed catheters often require removal and are dissected out. The DermaPortTM, percutaneous vascular access system (PVAS) permanently integrates a titanium mesh with the skin forming a stable, sterile barrier that allows for catheter placement, adjustment, or catheter exchange. This study aimed to describe the use and clinical outcomes of the DermaPort PVAS. METHODS: Thirty-eight patients who were receiving hemodialysis via a tunneled catheter were enrolled in this prospective open-label study. Assessments were performed biweekly for the first month and monthly thereafter, which included physical examination of the site of implantation for infection, catheter blood flow, and need for interventions to maintain catheter patency. Patient satisfaction was assessed with a visual analog score. RESULTS: Implantation of technical success was 100% with the implantation site demonstrating early tissue incorporation after 2 weeks and full incorporation within 4 weeks. The DermaPortTM successfully enabled 31 catheter exchanges and 10 repositions thru the port without dissection in 18 patients with nine repositions (90%) performed at bedside. The mean primary patency of the DermaPortTM was 172 +/- 150 days, and mean secondary patency was 430 +/- 203 days. There were no reportable serious adverse events in 12,100 catheter days of use and zero explantations of the device attributed to infection. The observed catheter infection rate was 0.33/1000 days. CONCLUSIONS: The DermaPortTM system can be effectively implanted and facilitates catheter interventions in hemodialysis patients requiring long-term catheter use and has a lower infection rate than historical catheter infection rates. Clinical Trial Protocol Number DermaPort-001 (no clinicaltrials.gov number as study was performed 9 years ago). Health Canada Reference Application Number: 118393. PMID- 30006891 TI - Comparison of Cone-Beam Tomography and Cross-Sectional Imaging for Volumetric and Dosimetric Calculations in Resin Yttrium-90 Radioembolization. AB - PURPOSE: To compare the use of cone-beam computed tomography versus contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI) in the calculation of liver volume and planned dose for yttrium-90 radioembolization. MATERIALS AND METHODS: The study retrospectively assessed 47 consecutive patients who underwent resin Y-90 radioembolization consecutively over a 2-year period at a single center. Volume calculation software was used to determine perfused lobar liver volumes from cone-beam CT (CBCT) images obtained during mapping angiography. CBCT-derived volumes were compared with perfused lobar volume derived from contrast-enhanced CT and MRI. Nominal activities as determined by the SIR-Spheres Microspheres Activity Calculator were similarly calculated and compared using both CBCT and conventionally acquired volumes. RESULTS: A total of 82 hepatic lobes were assessed in 47 patients. The mean percentage difference between combined CT-MRI- and CBCT-derived calculated lobar volumes was 25.3% (p = 0.994). The mean percentage difference in calculated dose between the two methods was 21.8 +/- 24.6% (p = 0.42). Combined left and right lobar CT-derived dose difference was less than 10% in 22 lobes, between 10 and 25% in 20 lobes, between 25 and 50% in 13 lobes and greater than 50% in 5 lobes. Combined left and right lobar MRI-derived dose difference was less than 10% in 11 lobes, between 10 and 25% in 7 lobes, between 25 and 50% in 2 lobes and greater than 50% in 1 lobe. CONCLUSIONS: Although volume measurements derived from CT/MRI did not differ significantly from those derived from CBCT, variability between the two methods led to large and unexpected differences in calculated dose. PMID- 30006892 TI - Terlipressin or norepinephrine, or both in septic shock? PMID- 30006893 TI - Plateau and driving pressure in the presence of spontaneous breathing. PMID- 30006894 TI - Endomyocardial fibrosis complicating primary hypereosinophilic syndrome. PMID- 30006895 TI - Acute sulfamethoxazole-induced crystal nephropathy. PMID- 30006896 TI - Loeffler endocarditis associated with a massive right intraventricular thrombus. PMID- 30006897 TI - Professional medical societies: do we have any conflict of interest with industry? PMID- 30006898 TI - Simultaneous deployment of multiple device occluders and the anchor wire technique for a treatment of paravalvular defect of a surgical mitral ring. PMID- 30006901 TI - The Effects of Oral Taurine on Resting Blood Pressure in Humans: a Meta-Analysis. AB - PURPOSE OF REVIEW: The aims of this meta-analysis were to investigate the effects of orally administered isolated taurine on resting systolic blood pressure (SBP) and diastolic blood pressure (DBP) in humans. RECENT FINDINGS: There is growing evidence that taurine deficiency is associated with hypertension and that oral supplementation can have antihypertensive effects in humans. However, these investigations have been conducted across a number of decades and populations and have not been collectively reviewed. A search was performed using various databases in May 2018 and later screened using search criteria for eligibility. There were seven peer-reviewed studies meeting the inclusion criteria, encompassing 103 participants of varying age and health statuses. Taurine ingestion reduced SBP (Hedges' g = - 0.70, 95% CI - 0.98 to - 0.41, P < 0.0001) and DBP (Hedges' g = - 0.62, 95% CI - 0.91 to - 0.34, P < 0.0001). These results translated to mean ~ 3 mmHg reductions in both SBP (range = 0-15 mmHg) and DBP (range = 0-7 mmHg) following a range of doses (1 to 6 g/day) and supplementation periods (1 day to 12 weeks), with no adverse events reported. These preliminary findings suggest that ingestion of taurine at the stated doses and supplementation periods can reduce blood pressure to a clinically relevant magnitude, without any adverse side effects. Future studies are needed to establish the effects of oral taurine supplementation on targeted pathologies and the optimal supplementation doses and periods. PMID- 30006902 TI - Who are the users of synthetic DNA? Using metaphors to activate microorganisms at the center of synthetic biology. AB - Synthetic biology, a multidisciplinary field involving designing and building with DNA, often designs and builds in microorganisms. The role of these microorganisms tends to be understood through metaphors making the microbial cell like a machine and emphasizing its passivity: cells are described as platforms, chassis, and computers. Here, I point to the efficacy of such metaphors in enacting the microorganism as a particular kind of (non-)participant in the research process, and I suggest the utility of employing metaphors that make microorganisms a different kind of thing-active participants, contributors, and even collaborators in scientific research. This suggestion is worth making, I argue, because enabling the activity of the microorganism generates opportunities for learning from microorganisms in ways that may help explain currently unexplained phenomena in synthetic biology and suggest new experimental directions. Moreover, "activating the microorganism" reorients relationships between human scientists and nonhuman experimental participants away from control over nonhuman creatures and toward respect for and listening to them, generating conditions of possibility for exploring what responsible research means when humans try to be responsible toward and even with creatures across species boundaries. PMID- 30006903 TI - Gene Expression of ABHD6, a Key Factor in the Endocannabinoid System, Can Be Modulated by Female Hormones in Human Immune Cells. AB - One of the main risk factors for the development of an autoimmune disease is to be a woman. Much attention has been given to the involvement of female hormones in their etiology and sexual bias, although the mechanisms behind this potentially strong contribution in disease susceptibility are poorly understood. ABHD6 gene was recently identified as a risk factor for system lupus erythematosus and the risk was correlated with overexpression of the gene. ABHD6 is an enzyme that degrades the 2-arachidonoylglycerol, an endocannabinoid with immunomodulatory effects. Thus its degradation could contribute to immune dysregulation and development of autoimmune reactions. Sex hormones, such as estrogens, are believed to regulate important genes in the endocannabinoid pathway. However, no study was available regarding the effect of these hormones in human immune cells. In this study, ABHD6 expression was evaluated by quantitative PCR in leukocytes from healthy male and females and in the presence of estrogen or progesterone (PG). A statistical increase in ABHD6 expression could be detected in women. In the presence of estrogen or PG, a statistical upregulation of ABHD6 was observed, and in a sex-dependent manner, as only female cells responded to stimulation. Our results suggest that female hormones can promote the overexpression of ABHD6 in immune cells. This can potentially contribute to a pro-inflammatory scenario and partially explain the association of this gene in the development of LES, a highly female-biased disease. PMID- 30006904 TI - Hepatocellular carcinoma as a leading cause of cancer-related deaths in Japanese type 2 diabetes mellitus patients. AB - BACKGROUND: We reported a cross-sectional study on causes of liver injury in Japanese type 2 diabetes mellitus (T2D) patients (JG 2013). We assessed overall and cause-specific mortality risk during follow-up of patients enrolled in JG 2013. METHODS: This was a longitudinal, multicenter cohort study. Of the 5642 Japanese T2D patients who visited T2D clinics of nine hospitals in the original study, 3,999 patients were followed up for an average of 4.5 years. Expected deaths in T2D patients were estimated using age-specific mortality rates in the general population (GP) of Japan. Standardized mortality ratios (SMRs) were calculated to compare mortality between T2D patients and GP. RESULTS: All-cancer mortality was significantly higher in T2D patients than in the GP [SMR 1.58, 95% confidence interval (CI) 1.33-1.87]. Among malignancies, hepatocellular carcinoma (HCC) conferred the highest mortality risk in T2D patients (SMR 3.57, 95% CI 2.41 5.10). HCC-associated mortality risk in T2D patients remained significantly high (SMR 2.56, 95% CI 1.64-3.97) after adjusting for high positivity rates of hepatitis B surface antigen (1.7%) and anti-hepatitis C virus (5.3%). In T2D patients with platelet counts < 200 * 103/MUl, SMR of HCC increased from 3.57 to 6.58 (95% CI 4.34-9.58). T2D patients with platelet count > 200 * 103/MUl showed no increase in mortality risk (SMR 0.68) of HCC. CONCLUSIONS: HCC-associated mortality risk was the highest among all cancers in Japanese T2D patients. Regular follow-up may be important for T2D patients with platelet counts < 200 * 103/MUl for early detection of HCC. PMID- 30006905 TI - Efficacy of fumagillin bicyclohexylamine on experimental corneal neovascularization in rat model. AB - PURPOSE: Fumagillin has been previously used to treat corneal microsporidial keratitis and also identified as an angiogenesis inhibitor. This study aimed to evaluate efficacy of fumagillin bicyclohexylamine on the rat model of corneal neovascularization induced by silver nitrate cauterization. METHODS: Twenty-four Albino Wistar rats (n = 24) were divided into three groups. Following silver nitrate-induced corneal injury, eyes in Group 1 received one drop of 5 mg/mL topical fumagillin bicyclohexylamine four times daily for 10 days. Group 2 received subconjunctival injection of 0.1 mL fumagillin bicyclohexylamine (2.5 mg/mL) on day 1 and day 5. Group 3 received artificial tears and lubricants four times daily for 10 days as control. On day 10, animals were sacrificed. Corneal specimens were obtained and prepared to assess vascular endothelial growth factor (VEGF-C) levels and corneal angiogenic microvessel density. RESULTS: There was no significant difference in VEGF-C levels between the groups (P = 0.994). Assessment of angiogenic microvessel density for peripheral corneal zone also did not reveal significant difference between the groups (P = 0.113). However, mean vascular density in Group 1 and Group 2 was significantly higher for both midperipheral and central corneal zones in comparison with Group 3 (P = 0.003, P = 0.015). CONCLUSIONS: Previously proved to be effective for treatment of microsporidial keratitis in humans, topical and subconjunctival concentration or dosing of fumagillin bicyclohexylamine failed to reduce corneal neovascularization induced by silver nitrate in this study. Further studies comparing different concentrations and dosing may detect inhibitory effects of fumagillin on corneal neovascularization without inducing toxicity. PMID- 30006906 TI - Sexual Health, STI and HIV Risk, and Risk Perceptions Among American Indian and Alaska Native Emerging Adults. AB - Emerging adulthood (18-25) is a period of increased risk for adverse sexual health outcomes. While anyone in this age group is at elevated risk, American Indian and Alaska Native (AI/AN) youth and emerging adults face unique factors that influence their risk for sexually transmitted infections (STIs). To address this increased risk among AI/AN youth, culturally appropriate interventions are necessary. This study reports the results of a video-based sexual health intervention designed specifically for AI/AN youth and emerging adults (15-24 years old) on risk changing perceptions. This intervention was evaluated using a group-randomized design with three conditions: (1) fact sheet alone, (2) fact sheet and video, and (3) fact sheet, video, and facilitated discussion. Using data from 199 AI/AN emerging adults (18-24 years old) who participated in the Native VOICES evaluation, we used multiple multinomial logistic regressions to determine if changes in risk perceptions were significantly different between study arms from baseline to post-intervention, and from post-intervention to 6 month follow-up. Few differences in STI risk perceptions were found at baseline and observed differences in STI risk perceptions between study arms disappeared after including baseline risk perceptions in the model. Similarly, few differences in HIV risk perceptions between study arms were observed at baseline, and all differences in HIV risk perceptions between study arms disappeared after controlling for baseline risk perceptions, demographics, and baseline sexual risk factors. Overall, this study points to the need for interventions that specifically address the behaviors, social and sexual contexts, and risk perceptions of AI/AN emerging adults, an age group for whom few culturally relevant sexual health interventions exist. PMID- 30006907 TI - Effect of urodynamic preoperative detrusor overactivity on the outcomes of transurethral surgery in patients with male bladder outlet obstruction: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the effect of urodynamic detrusor overactivity (DO) on the outcomes of transurethral surgery in patients with male bladder outlet obstruction (BOO). MATERIALS AND METHODS: We systematically searched the PubMed, Embase, and Cochrane Library databases for articles published between January 1989 and June 2017. All results of eligible studies were synthesized. RESULTS: Nine articles met the eligibility criteria. These studies included a total of 932 patients with a median number of 92 patients per study (range 40-190). Of the nine studies, the conventional transurethral prostatectomy was adopted in four studies, photoselective vaporization of prostate in three studies, and other surgical modalities in two studies. In patients with DO positive, the pooled mean difference (MD) was not significant for a better or poorer improvement in the International Prostate Symptom Score [pooled MD, - 0.27; 95% confidence interval (CI), - 1.75 to 1.22; studies, 9; participants, 827], quality-of-life score (pooled MD, - 0.14; 95% CI, - 0.46 to 0.18; studies, 7; participants, 734), maximal flow rate (pooled MD, 0.79; 95% CI, - 1.57 to 3.14; studies, 8; participants, 781), and post-void residual volume (pooled MD, 2.81; 95% CI, - 4.70 to 10.32; studies, 6; participants, 509) compared to patients with DO negative. Some comparisons showed between-study heterogeneity despite the strict criteria of the eligible studies. However, there was no clear evidence of publication bias in the funnel plots. CONCLUSIONS: Our meta-analysis results demonstrated that preoperative urodynamic DO has no diagnostic role in the prediction of surgical outcomes in patients with male BOO. PMID- 30006908 TI - Salvage robotic-assisted radical prostatectomy: oncologic and functional outcomes from two high-volume institutions. AB - INTRODUCTION: While no consensus on the optimal salvage treatment exists, only 3% of these patients will get salvage radical prostatectomies due to the assumed technical challenges of this procedure. OBJECTIVES: Our goal is to analyze the perioperative, oncologic and functional outcomes of patients undergoing salvage robotic-assisted radical prostatectomy (sRARP) after primary treatment failure. MATERIALS AND METHODS: Data were prospectively collected and retrospectively reviewed from a combined database of more than 14,800 patients who had undergone RARP. We identified 96 patients who underwent sRARP after RT or ablative techniques. Primary cancer characteristics, surgical data, pathology results, perioperative complications, oncologic and functional outcomes were analyzed. RESULTS: Sixty-eight patients (70.8%) received some source of RT as a primary treatment. The remaining 28 patients: 18 (18.75%) received cryotherapy, seven (7.92%) HIFU, one electroporation, one microwave and one Tookad. complication was seen in 25 (26%) patients (21 minor and 4 major complications). Anastomotic leak was the most common complication, found in 14 (14.6%) of the cases. No rectal injuries occurred. Fourteen (15%) patients had a biochemical failure after a median follow-up of 14 (IQR 5-24) months. Fifty-five (57.3%) of them self reported to be pad-free at 12 months. Seventeen (55%) of 31 pre-operative potent patients (SHIM score > 21), were potent with or without the use of PDE5i at 12 months. CONCLUSIONS: sRARP is a feasible alternative for PCa recurrence. Technically the procedure is challenging and should be performed by experienced PCa surgeons. Major complications are uncommon. Continence and potency recovery is possible, but at lower rates than for non-salvage patients. PMID- 30006909 TI - Suprapubic versus urethral catheter drainage in robotic-assisted laparoscopic prostatectomy: advancing systematic review quality. PMID- 30006910 TI - Effects of two contrasted arbuscular mycorrhizal fungal isolates on nutrient uptake by Sorghum bicolor under drought. AB - Drought is a limiting factor for crop production, especially in arid and semi arid climates. In this study, Sorghum bicolor plants were inoculated, or not, with Rhizophagus irregularis, an arbuscular mycorrhizal (AM) strain typical for temperate climates, or Rhizophagus arabicus, a strain endemic to hyper-arid ecosystems. Plants were grown under well-watered or drought conditions in compartmented microcosms. Transpiration rates, plant growth, and nutrient uptake (using 15N as a tracer) were determined to assess the impact of drought stress on sorghum plants in AM symbiosis. Although AM colonization did not affect the bulk biomass of host plants, R. arabicus improved their transpiration efficiency and drought tolerance more than R. irregularis. Moreover, R. arabicus was able to extract more 15N from the soil under both water regimes, and AM-driven enhancement of the nitrogen and phosphorus content of sorghum, especially when water was limiting, was greater for R. arabicus-inoculated plants than for R. irregularis-inoculated plants. Our work demonstrates close links between AM hyphal phosphorus and nitrogen transport and uptake by AM plants for both AM fungal species. It also underscores that, under the drought stress conditions we applied, R. arabicus transfers significantly more nitrogen to sorghum than R. irregularis. PMID- 30006911 TI - Association between albumin administration and survival in cardiac surgery: a retrospective cohort study. AB - PURPOSE: Albumin is widely used during and after on-pump cardiac surgery, although it is unclear whether this therapy improves clinical outcomes. METHODS: This observational study utilized the Cerner Health Facts(r) database (a large HIPAA-compliant clinical-administrative database maintained by Cerner Inc., USA) to identify a cohort of 6,188 adults that underwent on-pump cardiac surgery for valve and/or coronary artery procedures between January 2001 and March 2013. Of these, 1,095 patients who received 5% albumin with crystalloid solutions and 1,095 patients who received crystalloids alone on the day of or the day following cardiac surgery were selected by propensity-score matching. The primary outcome was all-cause in-hospital mortality. Three secondary outcomes analyzed include acute kidney injury severity, major morbidity composite, and all-cause 30-day readmissions. RESULTS: In the propensity-score matched cohort, receipt of perioperative 5% albumin was associated with decreased risk of in-hospital mortality (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3 to 0.9; P = 0.02) and lower all-cause 30-day readmission rates (OR, 0.7; 98.3% CI, 0.5 to 0.9; P < 0.01). Albumin therapy was not associated with differences in overall major morbidity (OR, 0.9; 98.3% CI, 0.7 to 1.2; P = 0.39; composite) or acute kidney injury severity (OR, 0.9; 98.3% CI, 0.6 to 1.4; P = 0.53) compared with therapy with crystalloid solutions. CONCLUSIONS: In this large retrospective study, use of 5% albumin solution was associated with significantly decreased odds of in-hospital mortality and all-cause 30-day readmission rate compared with administration of crystalloids alone in adult patients undergoing on-pump cardiac surgery. These results warrant further studies to examine fluid receipt, including 5% albumin, in surgical populations via randomized-controlled trials. PMID- 30006912 TI - Epithelioid sarcoma in the chest wall: a case report and literature review. AB - BACKGROUND: Epithelioid sarcoma (ES) is a rare variant of soft tissue sarcoma. The proximal type of ES occurs in various locations. We present a resected case with proximal-type ES that occurred in the chest wall and discuss the relevant literature. CASE PRESENTATION: A 47-year-old woman was referred for a 6-month history of a right anterior chest mass with tenderness. Chest computed tomography showed an invasive chest wall mass with calcification surrounding the third rib. Aspiration biopsy cytology suggested malignancy. We performed wide resection, including the middle part of the pectoralis major muscle, the pectoralis minor muscle, the third and fourth ribs, and reconstruction of the chest wall, using a 2-mm polytetrafluoroethylene patch. Severe deformation of the chest wall was avoided. Postoperative physical therapy of the shoulder was effective for the continuous pain and weakness of the arm. She has remained alive for 1 year and 10 months without recurrence. Our literature review showed five previously reported cases of ES in the chest wall, and all of these were surgically resected. Two of these patients suffered from frequent local recurrence and died of disease. CONCLUSIONS: ES in the chest wall is rare. Previous reports have indicated that surgical resection with tumor-free margins is essential for treatment. We performed complete resection of the tumor in our case, and a polytetrafluoroethylene patch was effective for reconstructing the deficit in the chest wall. PMID- 30006914 TI - Prevalence and Factors Associated with High Levels of Aluminum, Arsenic, Cadmium, Lead, and Mercury in Hair Samples of Well-Nourished Thai Children in Bangkok and Perimeters. AB - Toxic element exposure increases risk of neurodevelopmental disorders. However, hair element profiles of well-nourished urban resident children were largely unknown. We identified prevalence and the contributing factors of high hair aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg) levels in 111 Thai children (aged 3-7 years old). Most participants were well-nourished with high socioeconomic status. Since ROC curve of hair element data showed inadequate sensitivity for cutoff set-up, US reference hair levels were used to categorize high and low level groups. Nevertheless, compared to the current reference at 5 MUg/dL, blood lead cutoff at 2.15 MUg/dL provided more consistent results with that of hair lead levels. High As and Pb levels were the first and second most prevalent element, while Al was the element found in highest amount in hair. High hair Al (12% prevalence) levels were associated with being male regardless of age or nutritional status. High hair As levels were associated with living in Bangkok (OR = 6.57) regardless of school type. High hair Pb levels were associated with being under 5 years old and living in Bangkok (OR = 3.06). However, no associations were found between blood Pb, hair Cd, Hg, and tested factors. These findings suggested that under 5-year-old boys living in capital city like Bangkok may be at risk of exposure to multiple toxic elements. Future studies in these children are warranted to identify their exposure sources and proper risk management strategies. PMID- 30006913 TI - Low Rates of Poliovirus Antibodies in Primary Immunodeficiency Patients on Regular Intravenous Immunoglobulin Treatment. AB - PURPOSE: Poliovirus has been nearly eliminated as part of a world-wide effort to immunize and contain circulating wild-type polio. Nevertheless, poliovirus has been detected in water supplies and represents a threat to patients with humoral immunodeficiencies where infection can be fatal. To define the risk, we analyzed antibodies to poliovirus 1, 2, and 3 in serum samples collected over a year from patients with primary immunodeficiency diseases (PID) on regular intravenous immunoglobulin (IVIG) replacement. METHODS: Twenty-one patients on regular IVIG replacement therapy were evaluated: Twelve patients with common variable immune deficiency (CVID), six with X-linked agammaglobulinemia (XLA), and three with hyper IgM syndrome (HIGM). Over 1 year, four blood samples were collected from each of these patients immediately before immunoglobulin infusion. One sample of IVIG administered to each patient in the month before blood collection was also evaluated. Poliovirus antibodies were quantified by seroneutralization assay. RESULTS: All IVIG samples had detectable antibodies to the three poliovirus serotypes. Despite that, only 52.4, 61.9, and 19.0% of patients showed protective antibody titers for poliovirus 1, 2, and 3, respectively. Only two patients (9.5%) had protective antibodies for the three poliovirus serotypes on all samples. Most patients were therefore susceptible to all three poliovirus serotypes. CONCLUSIONS: This study demonstrates the need for ongoing vigilance regarding exposure of patients with PID to poliovirus in the community. PMID- 30006915 TI - Determination of Similarity Margin in Comparative Clinical Studies to Support the Development of Biosimilar Products of Neupogen(r) (Filgrastim, Granulocyte Colony Stimulating Factor [G-CSF]). AB - To demonstrate a biological product is biosimilar to a reference product, the applicant needs to show that the product is highly similar and has no clinically meaningful differences. Comparative clinical studies are often conducted to support the conclusion of no clinically meaningful differences, as a part of totality of evidence. The FDA has published several guidance documents to facilitate the development of biosimilar products. While the guidance documents define the role and objective of comparative clinical studies, they do not provide details about the determination of the similarity margin. In this paper, we illustrate a similarity margin derivation for a surrogate endpoint in comparative clinical studies conducted to assess whether clinically meaningful differences exist between Neupogen(r) (Filgrastim, granulocyte colony-stimulating factor) and products proposed to be biosimilar to Neupogen(r). PMID- 30006916 TI - Baricitinib, a Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. AB - Janus kinases (JAKs) play an important role in intracellular signaling for multiple cytokines in the pathogenesis of RA. Baricitinib is an oral, selective JAK 1 and 2 inhibitor which has been shown to be effective in the treatment of RA in several clinical trials. This meta-analysis aims to aggregate currently available data to assess the overall efficacy and safety of baricitinib in RA. We searched PubMed, EMBASE, and Cochrane CENTRAL from inception through 09/24/17 with restriction to English language. We excluded meeting abstracts without full text publication. We used RevMan 5.3 to perform meta-analysis between groups on baricitinib (2 and 4 mg daily) and placebo using random effect model calculating odds ratio (OR) as well as 95% confidence interval (CI). Compared to placebo, 2 mg of baricitinib was more effective in achieving ACR20 [54 vs. 36.6%; OR 2.09; 95% CI 1.60-2.71; p < 0.00001; I2 0%], ACR50 [31.6 vs. 10.3%; OR 2.3; 95% CI 1.68 3.15; p < 0.00001; I2 0%], and ACR70 responses [18.7 vs. 5.1%; OR 4.05; 95% CI 2.54-6.44; p < 0.00001; I2 0%]. Similarly, 4 mg of baricitinib daily was more effective than placebo. Baricitinib 2 mg once daily did not increase any adverse events [65.3 vs. 62.4%; OR 1.03; 95% CI 0.80-1.34; p = 0.8; I2 0%], serious adverse events [3.5 vs. 5%; OR 0.68; 95% CI 0.37-1.27; p = 0.22; I2 0%], and herpes zoster [1.2 vs. 0.4%; OR 2.34; 95% CI 0.27-20.47; p = 0.44; I2 37%] as compared to placebo. Similarly, 4 mg of baricitinib did not increase the risk of serious adverse events but increased herpes zoster infection [OR 3.88; 95% CI 1.36-11.06; p = 0.01; I2 0%] when compared to placebo. Baricitinib is effective in treatment of RA, and did not appear to have significant safety concerns during the first 6 months of treatment. PMID- 30006917 TI - Long-term follow-up of nailfold videocapillaroscopic changes in dermatomyositis versus systemic sclerosis patients. AB - To identify nailfold videocapillaroscopy (NVC) changes in patients with dermatomyositis (DM) during a 3-year follow-up and to compare the NVC findings between DM and systemic sclerosis (SSc) patients at their first visit. Retrospective study of 24 DM and 24 SSc patients, matched for age and disease duration at first NVC. Capillaroscopic patterns/scores and clinical parameters had been yearly assessed. Nineteen out of 24 DM patients (79%) showed a NVC "scleroderma-like pattern." No statistically significant variation of all the capillaroscopic scores was observed during the 3-year follow-up. By comparing DM patients with or without anti-Jo-1 positivity, no statistically significant difference of the scores of the main capillary parameters was observed at baseline between the groups. Comparing at baseline DM with SSc patients, the giant capillary and microhemorrhage scores were significantly higher in SSc than those in DM patients (p = 0.04 and p = 0.05, respectively), while capillary density, ramification (abnormally shaped capillaries, expression of angiogenesis), and disorganization scores were higher in DM patients (p = 0.05, p = 0.002, p = 0.004, respectively). The absolute number of ramified capillaries was significantly higher in DM patients (p = 0.002), while the absolute capillary number was significantly higher in SSc patients (p = 0.05) at baseline. This pilot study demonstrates, for the first time, over long-term, that the capillaroscopic manifestations of DM persist in contrast to the progressive changes described in SSc patients, and the anti-Jo-1 positivity does not seem to modify the NVC pattern. PMID- 30006918 TI - Serum-soluble CXCL16 in juvenile systemic lupus erythematosus: a promising predictor of disease severity and lupus nephritis. AB - Juvenile systemic lupus erythematosus (jSLE) is a multisystem autoimmune disease of unpredicted course and prognosis. Rates of organ involvement in SLE are higher in children, and overt lupus nephropathy is more often a presenting manifestation of SLE in children than adults. Inflammatory soluble chemokine CXC motif-ligand 16 (sCXCL16) is an important pathogenic mediator in inflammatory diseases as SLE. Herein, we aimed to evaluate serum level of sCXCL16 in jSLE patients in comparison to healthy controls and to correlate it with disease activity and extent of cutaneous and renal affection, to detect its possible role in disease pathogenesis. Serum level of sCXCL16 was determined by ELISA in 27 patients with jSLE (mean age 12.35 years +/- 2.26 SD) in addition to 30 age- and sex-matched healthy controls and correlated with clinical and laboratory parameters in lupus group. Serum sCXCL16 was significantly higher in jSLE patients than controls (P <= 0.001), and it correlated positively with SLE disease activity, severity of lupus nephritis, 24-h urinary protein, anti-dsDNA titre, blood pressure, and ESR, while it correlated negatively with serum C3 levels. Serum sCXCL16 was higher in jSLE patients with alopecia and malar erythema. Serum sCXCL16 might play a role in inflammatory pathogenesis of jSLE particularly in periods of disease activity. It might serve as a future useful laboratory test for detection of jSLE activity, renal insult, and its severity which might limit the need for invasive renal biopsies in such a delicate patient population. PMID- 30006919 TI - Prevalence of overlap of antineutrophil cytoplasmic antibody associated vasculitis with systemic autoimmune diseases: an unrecognized example of poliautoimmunity. AB - We aimed to estimate the frequency of overlap of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with systemic autoimmune diseases. Retrospective single-center study to identify patients with AAV diagnosis and concomitant autoimmune systemic diseases, simultaneously, before or after the diagnosis of AAV. Sociodemographic characteristics, such as comorbidities; follow up time; type of AAV; disease duration; relapses; treatment and response; clinical, serological, and histological characteristics; disease activity and damage; prognosis; dialysis requirements, and death were assessed. Twenty-eight of two hundred and forty-seven patients (11.3%) with AAV had a concomitant diagnosis of autoimmune disease. The predominant AAV type was renal-limited vasculitis (39%), followed by granulomatosis with polyangiitis (29%), mycroscopic polyangiitis (25%), and eosinophilic granulomatosis with polyangiitis (7%). Mean age at AAV diagnosis was 50 +/- 17 years and 24/28 were ANCA positive. The main clinical manifestations were renal (79%), otorhinolaryngologic (43%), and pulmonary and peripheral neuropathy (32%). Sixteen patients (57%) experienced partial or total remission at a median follow-up of 34 months, and four patients (14%) died. The most frequent autoimmune disease overlapped was rheumatoid arthritis (39%), followed by Sjogren's syndrome and systemic sclerosis (14%), mixed connective tissue disease (11%), systemic lupus erythematosus and juvenile idiopathic arthritis (7%), and ankylosing spondylitis and IgG4-related disease (4%). In nine patients (32%), both diagnoses were simultaneous; in the rest, median time elapsed between the autoimmune disease and AAV diagnosis was 173 months. The prevalence of overlap AAV with other autoimmune diseases was low. The most common AAV phenotype was renal-limited vasculitis, and the most frequent overlap disease was rheumatoid arthritis. PMID- 30006921 TI - Equity in Physical Activity: A Misguided Goal. AB - Rates of participation in physical activity are often not the same between groups in a given demographic category. These differences have been termed 'inequities,' and major health organizations are advocating large-scale initiatives to create 'equity' in physical activity. The aim of this paper is to explain why equity in physical activity is a misguided goal. Equity is a misguided goal because it ignores absolute rates of physical activity (i.e., it is a metric of how one group compares with another), and because it is an automated goal that ignores sizes of 'gaps' between groups. Moreover, equity initiatives incorrectly assume that groups with relatively high physical activity rates are always at lower health risk; that non-targeted groups will remain static in their levels of physical activity; that individuals are part of only one demographic category; that complete equity can be achieved; that the causal relationship between equity initiatives and their desired outcome can be known; and that differences in physical activity rates between groups are due to differences in 'opportunity.' Due to these issues, health organizations should abandon the goal of equity. Instead, they should aim to increase physical activity in groups that are most sedentary and/or at greatest health risk to a level that is as high as is feasible and possible, irrespective of how that new level compares with other groups. This goal is objective and not based on the misguided premises that underpin the current equity narrative. PMID- 30006920 TI - A Web-Based Atlas Combining MRI and Histology of the Squirrel Monkey Brain. AB - The squirrel monkey (Saimiri sciureus) is a commonly-used surrogate for humans in biomedical research. In the neuroimaging community, MRI and histological atlases serve as valuable resources for anatomical, physiological, and functional studies of the brain; however, no digital MRI/histology atlas is currently available for the squirrel monkey. This paper describes the construction of a web-based multi modal atlas of the squirrel monkey brain. The MRI-derived information includes anatomical MRI contrast (i.e., T2-weighted and proton-density-weighted) and diffusion MRI metrics (i.e., fractional anisotropy and mean diffusivity) from data acquired both in vivo and ex vivo on a 9.4 Tesla scanner. The histological images include Nissl and myelin stains, co-registered to the corresponding MRI, allowing identification of cyto- and myelo-architecture. In addition, a bidirectional neuronal tracer, biotinylated dextran amine (BDA) was injected into the primary motor cortex, enabling highly specific identification of regions connected to the injection location. The atlas integrates the results of common image analysis methods including diffusion tensor imaging glyphs, labels of 57 white-matter tracts identified using DTI-tractography, and 18 cortical regions of interest identified from Nissl-revealed cyto-architecture. All data are presented in a common space, and all image types are accessible through a web-based atlas viewer, which allows visualization and interaction of user-selectable contrasts and varying resolutions. By providing an easy to use reference system of anatomical information, our web-accessible multi-contrast atlas forms a rich and convenient resource for comparisons of brain findings across subjects or modalities. The atlas is called the Combined Histology-MRI Integrated Atlas of the Squirrel Monkey (CHIASM). All images are accessible through our web-based viewer ( https://chiasm.vuse.vanderbilt.edu /), and data are available for download at ( https://www.nitrc.org/projects/smatlas/ ). PMID- 30006922 TI - The Association of Shorter Interval of Biopsy-Radical Prostatectomy and Surgical Difficulty. AB - PURPOSE: We discuss the safety and perioperative outcomes of a 2-week interval between prostate biopsy and laparoscopic radical prostatectomy (LRP). MATERIALS AND METHODS: We retrospectively reviewed the medical records of 182 patients with prostate cancer (PCa) who underwent transperitoneal LRP 2 weeks after prostate biopsy between 2012 and 2015. We evaluated the following perioperative outcomes: operative time, estimated blood loss (EBL), infection, conversion to open surgery, positive surgery margins (PSM), and complications. We also reviewed studies discussing a shorter interval between biopsy and LRP in peer-reviewed publications. RESULTS: The mean operative time and EBL were 100.2 min and 82.2 ml, respectively. There were no rectal injuries or conversions to open surgery, totally 19 (10.4%) patients experienced complications (Clavien-Dindo Grade I and II): fever occurred in six patients (3.3%), urinary leak in four (2.2%), incomplete paralytic ileus in four (2.2%), deep vein thrombosis in two (1.1%), and postoperative anemia in four. The average bedrest time after surgery was 2.5 days. PSM was detected in twenty-one patients (11.5%) . 167 patients (91.7%) recovered continence.Follow-up ranged from 13-37 months, the biochemical recurrence (BCR) rate was 10.4% (19/182).The seven peer-reviewed studies we reviewed that a shorter interval was safe and did not influence surgical outcomes. CONCLUSION: Our study shows that a 2-week interval between biopsy and LRP is safe and does not negatively affect surgical outcomes. PMID- 30006923 TI - Multicentre international trial of laparoscopic lavage for Hinchey III acute diverticulitis (LLO Study). AB - BACKGROUND: Laparoscopic lavage was proposed in the 1990s to treat purulent peritonitis in patients with perforated acute diverticulitis. Prospective randomized trials had mixed results. The aim of this study was to determine the success rate of laparoscopic lavage in sepsis control and to identify a group of patients that could potentially benefit from this treatment. METHODS: This retrospective multicentre international study included consecutive patients from 24 centres who underwent laparoscopic lavage from 2005 to 2015. RESULTS: A total of 404 patients were included, 231 of whom had Hinchey III acute diverticulitis. Sepsis control was achieved in 172 patients (74.5 per cent), and was associated with lower Mannheim Peritonitis Index score and ASA grade, no evidence of free perforation, absence of extensive adhesiolysis and previous episodes of diverticulitis. The operation was immediately converted to open surgery in 19 patients. Among 212 patients who underwent laparoscopic lavage, the morbidity rate was 33.0 per cent; the reoperation rate was 13.7 per cent and the 30-day mortality rate 1.9 per cent. Twenty-one patients required readmission for early complications, of whom 11 underwent further surgery and one died. Of the 172 patients discharged uneventfully after laparoscopic lavage, a recurrent episode of acute diverticulitis was registered in 46 (26.7 per cent), at a mean of 11 (range 2-108) months. Relapse was associated with younger age, female sex and previous episodes of acute diverticulitis. CONCLUSION: Laparoscopic lavage showed a high rate of successful sepsis control in selected patients with perforated Hinchey III acute diverticulitis affected by peritonitis, with low rates of operative mortality, reoperation and stoma formation. PMID- 30006924 TI - Triptolide inhibits Wnt signaling in NSCLC through upregulation of multiple Wnt inhibitory factors via epigenetic modifications to Histone H3. AB - In the last decade, it has become clear that epigenetic changes act together with genetic mutations to promote virtually every stage of tumorigenesis and cancer progression. This knowledge has triggered searches for "epigenetic drugs" that can be developed into new cancer therapies. Here we report that triptolide reduced lung cancer incidence from 70% to 10% in a Fen1 E160D transgenic mouse model and effectively inhibited cancer growth and metastasis in A549 and H460 mouse xenografts. We found that triptolide induced lung cancer cell apoptosis that was associated with global epigenetic changes to histone 3 (H3). These global epigenetic changes in H3 are correlated with an increase in protein expression of five Wnt inhibitory factors that include WIF1, FRZB, SFRP1, ENY2, and DKK1. Triptolide had no effect on DNA methylation status at any of the CpG islands located in the promoter regions of all five Wnt inhibitory factors. Wnt expression is implicated in promoting the development and progression of many lung cancers. Because of this, the potential to target Wnt signaling with drugs that induce epigenetic modifications provides a new avenue for developing novel therapies for patients with these tumor types. PMID- 30006925 TI - Statin therapy and association with ovarian cancer risk in the New England Case Control (NEC) study. AB - Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Here we present data from a large case-control study addressing whether statin use can lower the risk for epithelial ovarian cancer (EOC). Between 1992 and 2008, data including medications used for at least 6 months were collected from 2,040 cases with EOC and 2,100 frequency-matched controls without the disease who participated in the New England Case Control study. We used unconditional logistic regression controlling for matching factors and potential confounders to examine the association between statin use and the risk for EOC. Overall, women who used statins had 32% lower risk of ovarian cancer compared to non-users (Odds ratio (OR) 0.68, 95% Confidence Interval (CI): 0.54-0.85), adjusting for the matching factors and other covariates. The reduced risk was most apparent in women taking a lipophilic statin who began use after age 49, and who had used them 2-4.9 years. Statin use was associated with lower risks for both serous and non-serous histologic subtypes with the strongest effect seen for mucinous and mixed epithelial subtypes. The association became apparent about a decade after the introduction of statins and did not appear to be confounded by indications for use of statins or medications used concomitantly. In this case-control study, statins were found to lower the risk for both serous and non-serous EOC and especially mucinous EOC. PMID- 30006926 TI - Teaching children with autism to identify and respond appropriately to the preferences of others during play. AB - We observed three children with autism spectrum disorder during structured play dates in which play partners displayed interest or disinterest in the toys with which they were playing. We then taught subjects to identify play partners' preferences and to make appropriate toy offers using a multiple-exemplar training package consisting of rules, midplay preference questions, prompting, and praise with observed generalization across untrained partners. PMID- 30006927 TI - GATA3 as a master regulator and therapeutic target in ovarian high-grade serous carcinoma stem cells. AB - Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells. GATA3 expression associates with poor prognosis of ovarian HGSC patients, and was found to recruit the histone H3, lysine 27 (H3K27) demethylase, UTX, activate stemness markers, and promote stem-like phenotypes in ovarian HGSC cell lines. Targeting UTX by its inhibitor, GSKJ4, impeded GATA3-driven stemness phenotypes, and enhanced apoptosis of GATA3-expressing cancer cells. Combinations of gemcitabine or paclitaxel with GSKJ4, resulted in a synergistic cytotoxic effect. Our findings provide evidence for a new role for GATA3 in ovarian HGSC stemness, and demonstrate that GATA3 may serve as a biomarker for precision epigenetic therapy in the future. PMID- 30006928 TI - The power of the Mediator complex-Expanding the genetic architecture and phenotypic spectrum of MED12-related disorders. AB - MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X-linked intellectual disability syndromes (FG, Lujan-Fryns, and Ohdo). Here, we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser), and p.(Arg1148His), the latter being first reported in affected females) associated with a continuum of symptoms rather than distinct syndromes. The variants expanded the genetic architecture and phenotypic spectrum of MED12-related disorders. New clinical symptoms included brachycephaly, anteverted nares, bulbous nasal tip, prognathism, deep set eyes, and single palmar crease. We showed that MED12 variants, initially implicated in X-linked recessive disorders in males, may predict a potential risk for phenotypic expression in females, with no correlation of the X chromosome inactivation pattern in blood cells. Molecular modeling (Yasara Structure) performed to model the functional effects of the variants strongly supported the pathogenic character of the variants examined. We showed that molecular modeling is a useful method for in silico testing of the potential functional effects of MED12 variants and thus can be a valuable addition to the interpretation of the clinical and genetic findings. PMID- 30006929 TI - Evaluation of a novel cricothyroidotomy introducer in a simulated obese porcine model: a randomised crossover comparison with scalpel cricothyroidotomy. AB - The Difficult Airway Society 2015 guidelines for management of unanticipated difficulties in tracheal intubation in adults have generated much discussion regarding Plan D: emergency front-of-neck access with a scalpel-bougie cricothyroidotomy technique. There is concern that this technique may not provide an adequate pathway for the bougie and subsequently the tracheal tube, especially in obese patients with deeper airway structures. This could lead to the formation of a false passage, trauma and failure. A novel cricothyroidotomy introducer, 8 mm wide and 170 mm long, with a sharp leading edge and guiding channel to pass a bougie into the trachea, has been designed to complement the scalpel cricothyroidotomy technique. A comparison study of the use of this novel introducer with the scalpel technique in a simulated obese porcine laryngeal model demonstrated shorter insertion times (median (IQR [range]) 85 (65-123 [48 224]) s vs. 84 (72-184 [46-377]) s, p = 0.030). All 26 (100%) participants successfully performed cricothyroidotomy in the introducer group, whereas only 24 (92%) participants were successful in the scalpel group. The introducer group required fewer attempts to access the trachea compared with the scalpel group (p = 0.046). False passages occurred eight (31%) times in the introducer group compared with 17 (65%) times in the scalpel group (p = 0.022). There were no statistical differences in tracheal trauma (p = 0.490), ease of use (p = 0.220) and device preference (p = 0.240). This novel cricothyroidotomy introducer has shown promising results in securing the airway in an emergency front-of-neck access situation. With robust training, this introducer could potentially be complementary to the scalpel-bougie cricothyroidotomy technique. PMID- 30006931 TI - A comprehensive methylation signature identifies lymph node metastasis in esophageal squamous cell carcinoma. AB - Treatment modalities in esophageal squamous cell carcinoma (ESCC) depend largely on lymph node metastasis (LNM) status. With suboptimal detection sensitivity of existing imaging techniques, we propose a methylation signature which identifies patients with LNM with greater accuracy. This would allow precise stratification of high-risk patients requiring more aggressive treatment from low-risk ESCC patients who can forego radical surgery. An unbiased genome-wide methylation signature for LNM detection was established from an initial in silico discovery phase. The signature was tested in independent clinical cohorts comprising of 249 ESCC patients. The prognostic potential of the methylation signature was compared to clinical variables including LNM status. A 10-probe LNM associated signature (LNAS) was developed using stringent bioinformatics analyses. The area under the curve values for LNAS risk scores were 0.81 and 0.88 in the training and validation cohorts respectively, in association with lymphatic vessel invasion and tumor stage. High LNAS risk-score was also associated with worse overall survival [HR (95% CI) 3 (1.8-4.8), p < 0.0001 training and 3.9 (1.5-10.2), p = 0.001 validation cohort]. In conclusion, our novel methylation signature is a powerful biomarker that identifies LNM status robustly and is also associated with worse prognosis in ESCC patients. PMID- 30006932 TI - Response to: "Enlisting Emergency Medicine Clinicians to Help Reduce Strokes in High-Risk Patients With Atrial Fibrillation and Flutter". PMID- 30006930 TI - Toward a real liquid biopsy in metastatic breast and prostate cancer: Diagnostic LeukApheresis increases CTC yields in a European prospective multicenter study (CTCTrap). AB - Frequently, the number of circulating tumor cells (CTC) isolated in 7.5 mL of blood is too small to reliably determine tumor heterogeneity and to be representative as a "liquid biopsy". In the EU FP7 program CTCTrap, we aimed to validate and optimize the recently introduced Diagnostic LeukApheresis (DLA) to screen liters of blood. Here we present the results obtained from 34 metastatic cancer patients subjected to DLA in the participating institutions. About 7.5 mL blood processed with CellSearch(r) was used as "gold standard" reference. DLAs were obtained from 22 metastatic prostate and 12 metastatic breast cancer patients at four different institutions without any noticeable side effects. DLA samples were prepared and processed with different analysis techniques. Processing DLA using CellSearch resulted in a 0-32 fold increase in CTC yield compared to processing 7.5 mL blood. Filtration of DLA through 5 MUm pores microsieves was accompanied by large CTC losses. Leukocyte depletion of 18 mL followed by CellSearch yielded an increase of the number of CTC but a relative decrease in yield (37%) versus CellSearch DLA. In four out of seven patients with 0 CTC detected in 7.5 mL of blood, CTC were detected in DLA (range 1-4 CTC). The CTC obtained through DLA enables molecular characterization of the tumor. CTC enrichment technologies however still need to be improved to isolate all the CTC present in the DLA. PMID- 30006933 TI - Breast Cancer Screening Program in Morocco: Status of implementation, organization and performance. AB - Breast Cancer Screening Program was introduced and rolled out in Morocco in 2010. Women between 40 and 69 years are screened at the primary health centers (PHC) with clinical breast examination (CBE). A comprehensive evaluation of the program was conducted in 2016-2017 for quality assurance and mid-term course correction. The evaluation process involved: in-depth interviews of program managers; focus group discussions with service-providers of screening, diagnosis and treatment; supportive supervisory visits to randomly selected PHCs and diagnostic centers; desk review of the national guidelines and other published documents; and analysis of the performance data compiled by the program-in-charge. We found that the program has strong political support, a well-organized management structure and documented national policy and protocol. In absence of a mechanism to identify and invite the eligible women individually, the program is opportunistic in nature. Every PHC is provided with an annual target to be screened. A highly visible annual campaign to educate and motivate women has a major impact on participation. Record keeping and data collection are paper-based. In the years 2015 and 2016, 1.1 and 1.5 million women were screened, respectively. In the year 2015, 62.8% of the annual target population was covered, CBE positivity was 3.2%, a further assessment rate of screen-positive women was 34.1% and the breast cancer detection rate was 1.0/1000 women. Systematic paper-based data collection enabled the assessment of some of the process and outcome indicators. The screening coverage was moderate and the cancer detection rate was low. PMID- 30006935 TI - Comparison of two commercial quality control sera for adrenocorticotropin (ACTH) used in Elecsys(r) immunoassay system. AB - OBJECTIVES: The purpose of our study was to investigate whether the storage time and temperature of internal quality control (IQC) material influence the result of ACTH in IQC measurements. DESIGN AND METHODS: Five levels of IQC materials from two manufacturers were tested through the precision of ACTH, the three freeze/thaw cycles, and the storage time and temperature to evaluate the stability of IQC material. All commercial control materials were simultaneously tested three times a day for five consecutive days. RESULTS: Total precision of three levels of Bio-Rad IQC sera was 13.93%, 16.45%, and 15.98%, respectively, but repeatability was <2%. The concentration of ACTH decreased by 30%-50% after 3 freeze/thaw cycles. At room temperature, the concentration of ACTH from 3 levels decreased by 16.60%, 17.98%, and 17.20%, respectively, after 0.5 hours, and 70.54%, 74.36%, and 72.03%, respectively, after 4 hours. However, after 2 hours of storage at 4 degrees C, the decline in the measured ACTH IQC was 8.04%, 11.84%, and 10.11%, respectively. Total precision of Roche IQC was 1.17% and 1.08%, respectively. After 3 freeze/thaw cycles, the concentration of ACTH decreased <5%. After 4 hours, the change of ACTH still steadied within 5% both at the room temperature and at 4 degrees C. CONCLUSION: Roche is a better choice for ACTH of IQC material in Elecsys(r) immunoassay system in our study. If Bio-Rad control materials be used in Elecsys(r) immunoassay system for ACTH IQC testing material, it should be stored at 4 degrees C and testing should be completed within 1 hours. PMID- 30006934 TI - The Jury Is Still Out on the Benefits and Harms of Methylphenidate for Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. AB - Much remains unclear about the benefits and harms of methylphenidate for children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Between 2012 and 2018, we conducted two Cochrane systematic reviews on methylphenidate for ADHD. This article explores the main findings in relation to evidence-based practice and our current understanding of ADHD. PMID- 30006937 TI - Lip repositioning with or without myotomy: A randomized clinical trial. AB - BACKGROUND: Lip repositioning is a conservative surgical method for the correction of excess gingival display (EGD) by limiting the upward retraction of the lips. Lip repositioning presents a simple method for the treatment of gummy smile. The aim of this randomized clinical trial (RCT) was to assess lip repositioning, compared to lip repositioning with muscle severance for efficacy in treatment of EGD and resultant stability. METHODS: A single-blinded, controlled, parallel-group RCT was performed. Twenty patients with EGD were enrolled in the study, treated with lip repositioning with and without muscle severance. Participants were assessed for EGD reduction, changes in lip length and result stability at 3, 6 and 12 months. Additionally, pain, swelling and satisfaction, were assessed. RESULTS: Classic lip repositioning was found capable of reducing EGD by 2.73 mm (SD +/- 1.281), while lip repositioning with muscle severance offered an improved reduction in EGD with a mean reduction of 3.57mm (SD +/- 1.62). Lip length, swelling and pain scores were found comparable between the two techniques. CONCLUSION: Lip repositioning is an effective method for treating EGD, however, muscle severance provides a more stable result at 12 months when compared to the classical technique. More studies are necessary to fully assess this procedure. PMID- 30006938 TI - Weight loss improves arterial blood gases and respiratory parameters in obese dogs. AB - Canine obesity is a common medical disorder and a known risk factor for associated diseases; it can seriously influence various physiological functions, thereby limiting the longevity of the animal. In this study, we evaluated potential respiratory alterations in obese dogs before and after being subjected to caloric restriction to decrease their body weight by 20%, and compared those dogs with control dogs with ideal body condition score. The animals were divided into three experimental groups: GI (obese dogs; n = 11); GII (obese dogs after weight loss, same animals as in GI); GIII (control dogs; n = 11). We evaluated lung function by spirometry and arterial blood gases. Statistical analysis included paired or non-paired Student's t test. Compared with dogs within an ideal body condition score (GIII), obese dogs (GI) had a low arterial partial pressure of oxygen (p < 0.05); decreased tidal volume (p < 0.005), inspiratory time and expiratory time (p < 0.05); and an increased respiratory rate (p < 0.005). After losing weight (GII), no differences with control dogs (GIII) were verified. The results suggested that obese dogs have an improvement in respiratory function with weight loss, but further investigations in a larger group of dogs are advised to confirm these findings. PMID- 30006936 TI - Does lactic fermentation influence soy yogurt protein digestibility: a comparative study between soymilk and soy yogurt at different pH. AB - BACKGROUND: Lactic acid bacteria fermentation allows soymilk to form a yogurt like product accompanied by protein acidic coagulation. It is not known whether the coagulation of soy protein during fermentation influences protein digestibility when ingested. In the present study, soymilk (pH 6.3) and soy yogurt (SY) at different pH (6.0, 5.7, 5.4 and 5.1) were subjected to in vitro gastrointestinal digestion (GIS) and a comparison study was conducted. RESULTS: Lactic fermentation allowed the pH of soymilk to reduce gradually to 5.1 in 330.0 min. A decline in pH resulted in the volume-weighted mean diameters D[4,3] and D[v,90] increasing from 0.81 to 97 um and 1.82 to 273 um, respectively. Predominant proteins lost their solubility between pH 6.0 and 5.7. Application of GIS allowed SY samples, especially SY-5.7, SY-5.4 and SY-5.1, to reveal particles with a predominant peak at approximately 10 um and also lower soluble proteins compared to soymilk, with reduction percentages of 18%, 28% and 43%. The cleavage pattern of soy protein during GIS was scarcely affected by the sample pH. However, a lower quantity of the band at 33.9 kDa was found in SY-5.7, SY-5.4 and SY-5.1. CONCLUSION: The results of the present study demonstrate that lactic fermentation altered soy protein digestibility. With the process of protein coagulation, SY-5.7, 5.4 and 5.1 had a lower bioaccessible protein content compared to that of soymilk. (c) 2018 Society of Chemical Industry. PMID- 30006939 TI - Use of Interferon-gamma release assay for the diagnosis of female genital tuberculosis in Northwest China. AB - BACKGROUND: Female genital tuberculosis (FGTB) is one of the major causes of infertility. However, nonspecific manifestations and the lack of easy access to gold-standard diagnostic test render a diagnostic difficult for FGTB. The objective of this study was to determine T-SPOT.TB (an interferon-gamma release assay, IGRA) performance in patients with FGTB. METHODS: A total of 213 female patients with validated T-SPOT.TB results were recruited in this retrospective study. Among which, 103 were confirmed FGTB, and 110 were excluded from tuberculosis (control). Of the confirmed FGTB patients, 52 were confirmed by microbiologically/histopathologically examination, while the remaining 51 were clinically confirmed (successfully responsive to anti-tuberculosis treatment). T SPOT.TB test was performed in both FGTB and control group during the diagnostic procedure. RESULTS: The overall sensitivity and specificity of T-SPOT.TB were 86.41% and 75.45% respectively. Sensitivity of T-SPOT.TB was significantly higher when compared with conventional tuberculosis diagnostic tests. Moreover, T SPOT.TB test using pelvic effusion (PE) showed higher sensitivity than using corresponding peripheral blood (PB) (94.44% vs 72.22%, P < 0.001). Mean value of spot forming cells (SFCs) of T-SPOT.TB using PE was significantly higher than that of PB in FGTB group (193 (IQR 105-280) SFCs/2.5 * 105 PEMCs vs 71 (IQR 36 107) SFCs/2.5 * 105 PBMCs, P = 0.01), while this was not detected in control group (11 (IQR 0-22) SFCs/2.5 * 105 PEMCs vs 9 (IQR 0-18) SFCs/2.5 * 105 PBMCs, P = 0.77). CONCLUSION: These results demonstrated that T-SPOT.TB, especially PE T SPOT.TB, is an useful adjunct in FGTB diagnosis. PMID- 30006940 TI - A longitudinal assessment of periodontal health status in 53 Labrador retrievers. AB - OBJECTIVES: To determine the incidence and rates of progression of gingivitis and periodontitis in Labrador retrievers. MATERIALS AND METHODS: Fifty-three dogs, aged 1.1 to 5.9 years, had their periodontal health assessed every 6 months for up to 2 years. The extent of gingivitis and periodontitis was measured around the whole gingival margin of every tooth under general anaesthesia. RESULTS: All dogs had gingivitis at the initial assessment. The majority (64.2%) of tooth aspects had very mild gingivitis. The palatal/lingual aspect of all tooth types was most likely to show bleeding when probed: 63.0% of these aspects had mild or moderate gingivitis. Over 2 years, 56.6% of dogs developed periodontitis and dogs as young as 1.9 years were affected. There was a significant positive correlation between the proportion of teeth with periodontitis and age. In total, 124 teeth (5.7%) developed periodontitis; 88 (71.0%) of these were incisors. The palatal/lingual aspect of the incisors developed the disease first (2.8% of incisor aspects). CLINICAL SIGNIFICANCE: Periodontitis developed in regions that are difficult to see in conscious dogs implying that detection and treatment of disease requires periodic sedation or anaesthesia. PMID- 30006941 TI - First aspects on acetate metabolism in the yeast Dekkera bruxellensis: a few keys for improving ethanol fermentation. AB - Dekkera bruxellensis is continuously changing its status in fermentation processes, ranging from a contaminant or spoiling yeast to a microorganism with potential to produce metabolites of biotechnological interest. In spite of that, several major aspects of its physiology are still poorly understood. As an acetogenic yeast, minimal oxygen concentrations are able to drive glucose assimilation to oxidative metabolism, in order to produce biomass and acetate, with consequent low yield in ethanol. In the present study, we used disulfiram to inhibit acetaldehyde dehydrogenase activity to evaluate the influence of cytosolic acetate on cell metabolism. D. bruxellensis was more tolerant to disulfiram than Saccharomyces cerevisiae and the use of different carbon sources revealed that the former yeast might be able to export acetate (or acetyl-CoA) from mitochondria to cytoplasm. Fermentation assays showed that acetaldehyde dehydrogenase inhibition re-oriented yeast central metabolism to increase ethanol production and decrease biomass formation. However, glucose uptake was reduced, which ultimately represents economical loss to the fermentation process. This might be the major challenge for future metabolic engineering enterprises on this yeast. PMID- 30006943 TI - The effect of post-harvest technologies on selected metabolites in persimmon (Diospyros kaki Thunb.) fruit. AB - BACKGROUND: Tannins are frequently a main focus in the investigation of de astringency treatments of persimmon, and the effect of a controlled atmosphere on other phytochemicals is often overlooked. In the present study, changes in the content of total soluble and insoluble phenolics, soluble tannins, saponins, and carotenoids, as well as changes in primary metabolites, were monitored. RESULTS: Generally, treatment with ethylene induced a decrease in total phenolic content, whereas, when treated with CO2 , the content of total phenolics remained unchanged compared to the level of total phenolics before treatment. Treatment with apple-sourced ethylene did not significantly affect the level of total phenolics. Additionally, for both varieties, 'Kaki Tipo' and 'Rojo Brillante', the share of insoluble phenolics strongly increased when treated with CO2 , whereas, when treated with ethylene, the same change applied for the ratio of soluble phenolics. The content of carotenoids varied markedly among treatments and varieties, whereas the content of total saponins remained unchanged, regardless of the treatment and variety. CONCLUSION: The results obtained in the present study show that the content of metabolites in persimmon was affected markedly and variedly using post-harvest technology. Apart from the treatment used, changes in the content of metabolites are also affected markedly by the persimmon variety. (c) 2018 Society of Chemical Industry. PMID- 30006942 TI - Enlisting Emergency Medicine Clinicians to Help Reduce Strokes in High-Risk Patients With Atrial Fibrillation and Flutter. PMID- 30006944 TI - Genetic diagnosis for X-linked hypohidrotic ectodermal dysplasia family with a novel Ectodysplasin A gene mutation. AB - AIM: To make a gene diagnosis for a family with Ectodysplasin A (EDA) gene mutation as well as prenatal diagnosis, and report a novel EDA gene mutation. METHODS: All coding sequences and flanking sequences of EDA gene were analyzed by Sanger sequencing in the proband, and then, according to EDA gene mutation in the proband, the EDA gene sequencing was performed on the family members. Based on the results above, the pathogenic mutation in EDA gene was finally identified, which was used for making prenatal diagnosis. RESULTS: Sanger sequencing revealed c.302_303delCC [p.Pro101HisfsX11] mutation in EDA gene of the proband. This mutation induced EDA gene frame shift mutation which led to early termination of EDA gene translation because there was a termination codon TAA at the 11th codon behind the mutational site. Heterozygous deletion mutation (CC/--) at this locus was observed in the proband's mother and proband's grandmother, but the proband's aunt had no mutation at this locus. The analyses of amniotic fluid samples indicated negative sex-determining region on Y (SRY), and c.302_303delCC heterozygous deletion mutation. CONCLUSION: We identified a pathogenetic mutation in EDA gene for the X-linked hypohidrotic ectodermal dysplasia family, made a prenatal diagnosis for the female carrier, and reported a novel EDA gene mutation. PMID- 30006945 TI - Anatomical variations of the axillary vein in the "pinch-off area": The "pinch off" sign and venography as a poor's man ultrasound. PMID- 30006946 TI - A novel dried blood spot LC-MS/MS method for the quantification of apalutamide in mouse whole blood: Application to pharmacokinetic study in mice. AB - A simple, sensitive and rapid assay method has been developed and validated for the estimation of apalutamide on mouse dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The method utilizes liquid extraction of apalutamide from 3 mm punched disks from DBS cards (spiked or study samples). The extracted sample was chromatographed on an Atlantis dC18 column using gradient elution with 0.2% formic acid and acetonitrile at a flow rate of 1.00 mL/min. The total run time was 3.0 min. The MS/MS ion transitions monitored were m/z 478 -> 450 for apalutamide and m/z 481 -> 453 for the IS (apalutamide-d3 ). Method validation was performed as per regulatory guidelines. The assay was linear in the range of 0.95-2030 ng/mL. The intra- and inter-day precisions were in the ranges of 2.37 8.53 and 6.76-11.5%, respectively. Stability studies showed that apalutamide was stable on DBS cards for one month. This novel method has been applied to analyze the DBS samples of apalutamide obtained from a pharmacokinetic study in mice. PMID- 30006947 TI - Chromatographic method for the simultaneous quantification of dapsone and clofazimine in nanoformulations. AB - The low bioavailability and nonspecific distribution of dapsone and clofazimine, commonly applied in combination for the treatment of leprosy, can produce toxic effects. Nanotechnological approaches enhance the delivery of these drugs. Therefore, a high-performance liquid chromatography method was developed for the simultaneous determination of dapsone and clofazimine loaded in nanoformulations for quality control purposes. Chromatographic separation was achieved on a reversed-phase Kinetex core-shell C18 column, followed by spectrophotometric detection at 280 nm. Considering the different physicochemical properties of dapsone and clofazimine, elution was performed in gradient mode using an aqueous acetate buffer (50 mmol/L, pH 4.8) and an increasing acetonitrile content from 27 to 63% v/v at a flow rate of 1.0 mL/min with retention times of 6.2 and 14.0 min, respectively. The method was validated according to the European Medicines Agency guideline and it was found to be specific, accurate (99.6-114.0%), and precise for intra- (RSD <= 1.8%) and interday assays (RSD <= 12.5%). Both drugs showed stability after 24 h at room temperature and over three freeze-thaw cycles with recoveries >=86.2%. Low temperature (4 degrees C) in the autosampler caused the precipitation of clofazimine and must be avoided. The validated method was successfully applied in the quantification of both drugs in nanoformulations. PMID- 30006948 TI - Nickel(II) Complexes with Tritopic Nimine CNHC Namine Pincer Ligands. AB - Tritopic NCNHC N' ligands containing a central N-heterocyclic carbene (NHC) donor flanked by two chemically-different nitrogen donors (Nimine and Namine ) were evaluated as potential tridentate pincer-type ligands in NiII complexes. The imidazolium chloride [(ImH){C(Me)=NDipp}(C2 NMe2 )]Cl (1) and the ammonium imidazolium dichlorides [(ImH){C(Me)=NDipp}(C2 NHMe2 )]Cl2 (4) and [(ImH){C(Me)=NDipp}(C3 NHMe2 )]Cl2 (5), differing by the length (C2 or C3 ) of the alkyl spacer were used as precursors. Oxidative addition of 1 to [Ni(cod)2 ] afforded the dinuclear bis-NHC NiII complex [Ni2 Cl2 {MU-C(Me)=NDipp-kappa2 Nimine ,C}{MU-Im(C2 NMe2 )-kappa3 Namine ,CNHC ,Nimid }{Im[C(Me)=NDipp](C2 NMe2 ) kappa1 CNHC }] (2) resulting from partial ligand rearrangement. A dinuclear byproduct 3 was also isolated. The salt [NiCl{Im[C(Me)=NDipp](C2 NMe2 )-kappa3 Nimine ,CNHC ,Namine }]2 [NiCl4 ] (6) containing two Nimine CNHC Namine pincer NiII complex cations was obtained from 4. In contrast, the reaction of closely related 5 yielded [NiCl{Im[C(Me)=NDipp](C3 NMe2 )-kappa2 Nimine ,CNHC }{MU Im[C(Me)=NDipp](C3 NMe2 NiCl3 }-kappa2 Namine ,CNHC }] (7 a), a dinickel(II) complex that contains a Nimine ,CNHC -chelating and a bridging kappa2 Namine ,CNHC ligand. The molecular structures of 2, 3, 6, 7 a?THF, 7 b, an isomer of 7 a, and 8?CH2 Cl2 have been determined by single-crystal X-ray diffraction. Our results emphasize the often-underestimated importance of seemingly minor changes in the length of the spacers connecting a NHC donor group to its N-bound lateral functionalities. PMID- 30006950 TI - Mean cell volume of reticulocyte-A new parameter for diagnosing sub-clinical cobalamin deficiency in blood donors. PMID- 30006949 TI - Inexpensive but Highly Efficient Co-Mn Mixed-Oxide Catalysts for Selective Oxidation of 5-Hydroxymethylfurfural to 2,5-Furandicarboxylic Acid. AB - A highly active and inexpensive Co-Mn mixed-oxide catalyst was prepared and used for selective oxidation of 5-hydroxymethylfurfural (HMF) into 2, 5 furandicarboxylic acid (FDCA). Co-Mn mixed-oxide catalysts with different Co/Mn molar ratios were prepared through a simple solid-state grinding method-a low cost and green catalyst preparation method. The activity of these catalysts was evaluated for selective aerobic oxidation of HMF into FDCA in water. Excellent HMF conversion (99 %) and FDCA yield (95 % ) were obtained under the best reaction conditions (i.e., 120 degrees C, 5 h, Co-Mn mixed-oxide catalyst with a Co/Mn molar ratio of 0.25 calcined at 300 degrees C (Co-Mn-0.25) and 1 MPa O2 ). The catalyst could be reused five times without a significant decrease in activity. The results demonstrated that the catalytic activity and selectivity of the Co-Mn mixed-oxide catalysts prepared through solid-state grinding were superior to the same Co-Mn catalyst prepared through a conventional coprecipitation method. The high catalytic activity of the Co-Mn-0.25 catalyst was attributed to its high lattice oxygen mobility and the presence of different valence states of manganese. The high activity and low cost of the Co-Mn mixed oxide catalysts prepared by solid-state grinding make it promising for industrial application for the manufacturing of polyethylene furanoate, a bioreplacement for polyethylene terephthalate, from sustainable bioresources. PMID- 30006951 TI - Bowls, Hoops, and Saddles: Synthetic Approaches to Curved Aromatic Molecules. AB - This review summarizes recent advances in the chemistry of curved aromatic molecules. By focusing on the key accomplishments of the last decade, we provide a general overview of synthetic methods capable of efficient induction of internal strain in pi-conjugated frameworks. The review is structured according to the topology change involved in the strain-inducing reaction step (cyclizations, eliminations, ring expansions and contractions), and highlights the striking diversity of structures achievable with modern synthetic methodology. PMID- 30006953 TI - Remote Nucleophilic Allylation by Allylrhodium Chain Walking. AB - Metal migration through a carbon chain is a versatile method for achieving remote functionalization. However, almost all known examples involve the overall net migration of alkylmetal species. Here, we report that allylrhodium species obtained from hydrorhodation of 1,3-dienes undergo chain walking toward esters, amides, or (hetero)arenes over distances of up to eight methylene units. The final, more highly conjugated allylrhodium species undergo nucleophilic allylation with aldehydes and with an imine to give Z-homoallylic alcohols and amines, respectively. PMID- 30006952 TI - Arterial damage and cognitive decline in chronic kidney disease patients. AB - In the general population aortic stiffening, assessed by carotid femoral pulse wave velocity (cf-PWV), is associated with cognitive dysfunction (CO/DY). Data in chronic kidney disease (CKD) are limited. This study tests the hypothesis that large artery stiffness and microvascular damage in CKD patients are related to the damage of brain microcirculation reflected by impaired cognitive function. A cross-sectional study enrolled 151 patients (mean age 58.4 years; 64.5% males; 44 patients with CKD stage 1; 47 with stage 2; 25 with stage 3; and 35 with stage 4). Cognitive impairment, assessed by the Mini Mental State Examination (MMSE), the Clock - drawing test (Clock-test), and the Instrumental Activity of Daily Living (IADL), was considered as primary outcome. We measured systolic and pulse pressures at the brachial and aortic sites and cf-PWV. Our patients revealed a significant linear deterioration in all the domains of cognitive function according to CKD stages. High values of cf-PWV (P = 0.029) and aortic pulse pressure (aPP) (P < 0.026) were independent determinants of cognitive decline assessed by the MMSE. The present trial supports the hypothesis of an interaction between the kidney, large artery damage, central pressure pulsatility, and the injury of brain microcirculation. In clinical practice, cf-PWV and aPP measurements may help to predict cognitive decline. Whether the reduction in aortic stiffness following an aggressive treatment translates into improved cognitive outcomes remains to be determined. PMID- 30006954 TI - Ethical issues surrounding the study of nocebo effects: Recommendations for deceptive research. PMID- 30006955 TI - Clinical evaluation of a novel and highly sensitive immunoassay for anti hepatitis B core antigen using a fully automated immunochemical analyzer. AB - AIM: Recently, the measurement of hepatitis B surface antigen and anti-hepatitis B core antigen (HBcAb) and/or anti-hepatitis B surface antigen has been recommended before various therapies to identify patients at risk of hepatitis B virus (HBV) reactivation. However, a recent study reported that HBV reactivation occurred in HBcAb-negative patients, indicating that it is challenging to identify patients with a history of HBV infection using conventional HBcAb reagent. We developed a highly sensitive HBcAb (HBcAb-HS) assay for reducing the risk of HBV reactivation. METHODS: The HBcAb-HS assay is an automated chemiluminescent enzyme immunoassay system, which is suitable for clinical use. The cut-off was set at 0.020 IU/mL from the distribution patterns of HBcAb negative specimens, and we evaluated the performance of this assay compared with conventional reagents. RESULTS: This new assay showed a 27-81-fold greater sensitivity than conventional HBcAb reagents; the quantified measurement range was from 0.005 IU/mL to 1.500 IU/mL, and it showed excellent quantitative performance and correlated well with two conventional assays, using the HBcAb positive specimens. Moreover, it showed 100% specificity for the 469 purchased HBcAb-negative specimens. Notably, this newly developed HBcAb-HS assay showed positivity in the preserved specimens before HBV reactivation, for which conventional HBcAb reagents gave negative results, and the HBcAb-HS assay could detect the lower HBcAb levels even after intensive immunosuppressive therapies, including autologous hematopoietic stem cell transplantation. CONCLUSIONS: The clinical efficacy of the newly developed, highly sensitive HBcAb assay would enable the identification of patients at risk of HBV reactivation more accurately. PMID- 30006956 TI - Long non-coding RNA NNT-AS1 sponges miR-424/E2F1 to promote the tumorigenesis and cell cycle progression of gastric cancer. AB - Long non-coding RNAs (lncRNAs) have been illustrated to function as important regulators in carcinogenesis and cancer progression. However, the roles of lncRNA NNT-AS1 in gastric cancer remain unclear. In the present study, we investigate the biological role of NNT-AS1 in gastric cancer tumorigenesis. Results revealed that NNT-AS1 expression level was significantly up-regulated in GC tissue and cell lines compared with adjacent normal tissue and normal cell lines. The ectopic overexpression of NNT-AS1 indicated the poor prognosis of GC patients. In vitro experiments validated that NNT-AS1 knockdown suppressed the proliferation and invasion ability and induced the GC cell cycle progression arrest at G0/G1 phase. In vivo xenograft assay, NNT-AS1 silencing decreased the tumour growth of GC cells. Bioinformatics online program predicted that miR-424 targeted the 3' UTR of NNT-AS1. Luciferase reporter assay, RNA-immunoprecipitation (RIP) and RNA pull-down assay validated the molecular binding within NNT-AS1 and miR-424, therefore jointly forming the RNA-induced silencing complex (RISC). Moreover, E2F1 was verified to act as the target gene of NNT-AS1/miR-424, indicating the NNT-AS1/miR-424/E2F1 axis. In conclusion, our study indicates that NNT-AS1 sponges miR-424/E2F1 to facilitate GC tumorigenesis and cycle progress, revealing the oncogenic role of NNT-AS1 for GC. PMID- 30006957 TI - Expanding the Balz-Schiemann Reaction: Organotrifluoroborates Serve as Competent Sources of Fluoride Ion for Fluoro-Dediazoniation. AB - The Balz-Schiemann reaction endures as a method for the preparation of (hetero)aryl fluorides yet is eschewed due to the need for harsh conditions or high temperatures along with the need to isolate potentially explosive diazonium salts. In a departure from these conditions, we show that various organotrifluoroborates (RBF3 - s) may serve as fluoride ion sources for solution phase fluoro-dediazoniation in organic solvents under mild conditions. This methodology was successfully extended to a one-pot process obviating aryl diazonium salt isolation. Sterically hindered (hetero)anilines are fluorinated under unprecedentedly mild conditions in good-to-excellent yields. Taken together, this work expands the repertoire of RBF3 - s to act as fluorine ion sources in an update to the classic Balz-Schiemann reaction. PMID- 30006960 TI - Highly Diastereo- and Enantioselective Synthesis of Cyclohepta[b]indoles by Chiral-Phosphoric-Acid-Catalyzed (4+3) Cycloaddition. AB - A highly enantio- and diastereoselective formal (4+3) cycloaddition of 1,3-diene 1-carbamates with 3-indolylmethanols in the presence of a chiral phosphoric acid catalyst is reported. The approach described herein provides efficient access to 6-aminotetrahydrocyclohepta[b]indoles in good yields with mostly complete diastereoselectivity and excellent levels of enantioselectivity (>98:2 dr and up to 98 % ee). Mild reaction conditions, facile scale-up, and versatile derivatization highlight the practicality of this methodology. A mechanistic study suggests that cycloaddition occurs in a stepwise fashion, after the formation of an ion pair between the chiral catalytic phosphate and the intermediate carbocation. PMID- 30006958 TI - Risk factors for diabetes are higher among non-heterosexual US high-school students. AB - Low physical activity (PA), high sedentary behavior (SB), and overweight and obesity have been shown to associate with increased Type 2 diabetes risk among adolescents. We investigated PA, SB, and overweight and obesity among Youth Risk Behavior Survey (YRBS) respondents to determine if non-heterosexual youth may be at increased diabetes risk compared to heterosexual youth. Weighted city and state YRBS data were pooled across 44 jurisdictions biennially from 2009 to 2015, resulting in a sample size of 350 673 students. Overall, 88.4% identified as heterosexual, 2.1% as gay or lesbian, 5.7% as bisexual, and 3.7% as unsure. With the exception of lesbian female students, after adjusting for age, race/ethnicity, body mass index, and survey year, all non-heterosexual youth reported significantly fewer days per week of PA compared to their sex-matched heterosexual counterparts. Similarly, compared to heterosexual female youth, bisexual and not sure female youth reported significantly more hours per day of SB. These PA and SB findings remained significant after adjustment for depressive symptoms and in-school bullying among bisexual female youth only. In fully adjusted models, lesbian students were 1.85 times more likely to be overweight and lesbian, bisexual, and not sure female youth were 1.55 to 2.07 times more likely to be obese than heterosexual female students. No significant differences in SB, overweight, or obesity were found among gay, bisexual, or unsure male youth compared to heterosexual male youth. Non-heterosexual youth may be at increased risk for developing type 2 diabetes mellitus compared to heterosexual youth. Future studies should characterize diabetes prevalence among non heterosexual youth. PMID- 30006959 TI - Optimal search strategies for identifying moderators and predictors of treatment effects in PubMed. AB - BACKGROUND: Treatment effects differ across patients. To guide selection of treatments for patients, it is essential to acknowledge these differences and identify moderators or predictors. Our aim was to generate optimal search strategies (commonly known as filters) for PubMed to retrieve papers identifying moderators and predictors of treatment effects. METHODS: Six journals were hand searched for articles on moderators or predictors. Selected articles were randomly allocated to a development and validation set. Search terms were extracted from the development set and tested for their performance. Search filters were created from combinations of these terms and tested in the validation set. RESULTS: Of 4407 articles, 198 were considered to be relevant. The most sensitive filter in the development set '("Epidemiologic Methods" [MeSH] OR assign* OR control*[tiab] OR trial*[tiab]) AND therapy*[sh]' yielded in the validation set a sensitivity of 89% [88%-90%] and a specificity of 80% [79%-82%]. CONCLUSIONS: The search filters created in this study can help to efficiently retrieve evidence on moderators and predictors of treatment effect. Testing of the filters in multiple domains should reveal robustness across disciplines. These filters can facilitate the retrieval of evidence on moderators and predictors of treatment effects, helping the implementation of stratified or personalised health care. PMID- 30006963 TI - Author Guidelines. PMID- 30006962 TI - The association of sex hormone-binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes. AB - BACKGROUND: Serum sex hormone-binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM). OBJECTIVES: To confirm the association of serum sex hormone-binding globulin with mortality and then determine whether this association is mediated by age and total testosterone concentration. MATERIALS AND METHODS: We studied 364 men (median age: 66 years) with T2DM over a median follow-up of 4.3 years using the Cox regression to study associations between sex hormone-binding globulin, age, total testosterone, and mortality. RESULTS: Mortality was significantly and independently associated with sex hormone-binding globulin, age, and total testosterone. In pairwise combinations of age and sex hormone-binding globulin dichotomized by median values, the association of sex hormone-binding globulin with mortality was age dependent. Relative to the combination of age >66 years/SHBG >35 nmol/L (mortality 22.5%), the other combinations were associated with significantly less mortality (mortality in men <=66 years/SHBG <= 35 nmol/L was 3.23%). In men >66 years, SHBG <= 35 nmol/L was associated with decreased mortality (HR: 0.41, p = 0.037) compared with SHBG > 35 nmol/L. In men <=66 years, there was no significant difference between those with sex hormone-binding globulin above or below the median (HR: 1.73, p = 0.56, reference: SHBG <= 35 nmol/L). TT < 12 nmol/L was associated with increased mortality in both age categories. Men >66 years with the reference combination of SHBG > 35 nmol/L and TT < 12 nmol/L (36.84%) nmol/L had significantly higher mortality than those with SHBG > 35 nmol/L and TT >= 12 (18.06%) and those with SHBG <= 35 nmol/L and TT < 12 nmol/L (13.79%). DISCUSSION: Our data suggest sex hormone-binding globulin and total testosterone have particular impact on mortality in men aged over 66 years. Further, in older men, the combination of high sex hormone-binding globulin levels and low total testosterone is associated with greater risk than either high sex hormone-binding globulin or low total testosterone individually. CONCLUSIONS: Our findings are compatible with data suggesting the importance of sex hormone-binding globulin lies in mediating free testosterone levels. PMID- 30006961 TI - Glycine-betaine ionic liquid analogues as novel phase-forming components of aqueous biphasic systems. AB - Given the biotechnology advances observed in recent years in terms of upstream, the development of effective downstream processes becomes mandatory to decrease the associated costs of biotechnological-based products. Although a large interest has been devoted to ionic-liquid-based aqueous biphasic systems (IL based ABS) as tailored separation platforms, imidazolium-based ILs have been the preferred choice as phase-forming agents. To overcome some toxicity and biodegradability issues associated to imidazolium-based ILs, novel ABS composed of ILs analogues of glycine-betaine (AGB-ILs) are here proposed and investigated. Five AGB-ILs were synthesized, characterized in terms of ecotoxicity, and applied toward the development of novel ABS formed with Na2 SO4 . Three commercial ILs were also investigated for comparison purposes. The respective ABS ternary phase diagrams, as well as the tie-lines and tie-line lengths, were determined at 25 degrees C. Finally, their performance as extraction strategies was evaluated with five amino acids (L-tryptophan, L-phenylalanine, D-phenylalanine, L-tyrosine and L-3,4-dihydroxyphenylalanine/L-dopa). In all studied systems amino acids preferentially migrate to the IL-rich phase, and with AGB-ILs, the amino acid extraction efficiencies to the IL-rich phase range between 65% and 100%, obtained in a single-step. Furthermore, the studied AGB-ILs display a higher ability to form ABS and to extract amino acids than ABS composed of more traditional and commercial ILs. In summary, novel ABS composed of AGB-ILs can be formed and used as separation routes of value-added compounds of biotechnological interest. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018 (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1205-1212, 2018. PMID- 30006964 TI - Core circadian clock gene expression in human dental pulp-derived cells in response to L-mimosine, hypoxia and echinomycin. AB - Core circadian clock genes set the pace for a wide range of physiological functions, including regeneration. The role of these genes and their regulation in the dental pulp, in particular under hypoxic conditions, is unknown. Here we investigated if core clock genes are expressed in human dental pulp-derived cells (DPC) and if their expression is modulated by the hypoxia mimetic agent, L mimosine (L-MIM), hypoxia or echinomycin. Dental pulp-derived cells in monolayers and spheroids were treated with L-MIM, hypoxia or echinomycin. mRNA levels of the core circadian clock genes were analysed using quantitative PCR (qPCR) and their protein levels were analysed by western blot. All core clock genes and proteins were produced in DPC monolayer and spheroid cultures. The expression of cryptochrome circadian regulators and period circadian regulators was reduced by L-MIM, hypoxia and echinomycin at mRNA, but not at protein levels. Time course experiments indicated that modulations were based on alterations in overall mRNA levels of core circadian clock genes. Our results suggest a potential role of the core circadian clock in the response of dental pulp to hypoxia. Future studies need to consider that regulation of the core circadian clock at mRNA levels might not be paralleled by modulation of protein levels. PMID- 30006965 TI - Synergistic effects of ischemic preconditioning and immediate post-conditioning in the protection against ischemia/reperfusion injury in rabbit submandibular glands. AB - Submandibular gland autotransplantation is an effective approach for treating severe keratoconjunctivitis sicca. However, ischemia/reperfusion (I/R) injury, which inevitably occurs during transplantation, is involved in the hypofunction and structural damage that occur early after transplantation. Therefore, it is critical to identify effective strategies to ameliorate I/R injury in submandibular glands. In this study, we investigated the ability of immediate post-conditioning combined with ischemic preconditioning to attenuate I/R injury. We observed that after I/R injury, the level of reactive oxygen species was increased, inflammatory response was strengthened, and severe apoptosis had occurred. In addition, the salivary flow rate was greatly decreased. However, the pathogenesis of I/R injury was significantly ameliorated by ischemia post conditioning or ischemia preconditioning treatments. In addition, the combination of ischemia preconditioning and post-conditioning achieved synergistic protective effects against I/R injury compared with ischemia preconditioning or ischemia post-conditioning alone. The secretion function was restored in the combination group. Furthermore, the combination treatment involved the same mechanisms of ischemia preconditioning or ischemia post-conditioning, including suppression of the inflammatory reaction and neutrophil accumulation, attenuation of oxidation stress, and inhibition of apoptosis. In conclusion, the combination of ischemia preconditioning and ischemia post-conditioning treatment is a simple and effective approach for treating I/R injury in submandibular glands. PMID- 30006966 TI - The implementation of a haptic feedback virtual reality simulation clinic with dynamic patient interaction and communication for medical imaging students. AB - INTRODUCTION: An immersive virtual reality (VR) simulation clinic with dynamic patient interaction and communication was developed to facilitate the training of medical radiation science students. The software "CETSOL VR Clinic" was integrated into the Medical Imaging programme at Monash University in 2016 in order to benchmark student experiences against existing simulation techniques (ShaderwareTM). METHODS: An iterative approach to development, based on two cycles of user feedback, was used to develop and refine the simulated clinical environment. This environment uses realistic 3D models, embedded clinical scenarios, dynamic communication, 3D hand gesture interaction, gaze and positional stereoscopic tracking and online user capabilities using the UnityTM game and physics engines. Students' perceptions of educational enhancement of their positioning skills following the use of the simulation tools were analysed via a 5-point Likert scale questionnaire. RESULTS: Student perception scores indicated a significant difference between simulation modalities in favour of the immersive CETSOL VR Clinic, chi2 (4, N = 92) = 9.5, P-value <0.001. CONCLUSION: Student perception scores on improvement of their clinical and technical skills were higher for the hand-positioning tasks performed with the CETSOL VR ClinicTM than with the comparative benchmark simulation that did not provide dynamic patient interaction and communication. PMID- 30006967 TI - Degradation of Single-Layer and Few-Layer Graphene by Neutrophil Myeloperoxidase. AB - Biodegradability of graphene is one of the fundamental parameters determining the fate of this material in vivo. Two types of aqueous dispersible graphene, corresponding to single-layer (SLG) and few-layer graphene (FLG), devoid of either chemical functionalization or stabilizing surfactants, were subjected to biodegradation by human myeloperoxidase (hMPO) mediated catalysis. Graphene biodegradation was also studied in the presence of activated, degranulating human neutrophils. The degradation of both FLG and SLG sheets was confirmed by Raman spectroscopy and electron microscopy analyses, leading to the conclusion that highly dispersed pristine graphene is not biopersistent. PMID- 30006968 TI - Sequencing and phylogenetic analyses of talaromyces amestolkiae from amazon: A producer of natural colorants. AB - The population interest in health products is increasing day-by-day. Thus, the demand for natural products to be added in food and pharmaceutical commodity is also rising. Among these additives, colorants, which provides color to products, can be produced by microorganism through bioprocess. Looking for new source of natural colorants, fungi have been employed to this purpose producing novel and safer natural colorants. So, the main goal of this study was to describe a Talaromyces species able to produce natural colorants and investigate nutritional parameters of colorants production using statistical tool. The taxonomy classified the microorganism as Talaromyces amestolkiae. The statistical design evaluated pH and glucose, meat extract and meat peptone concentration as independent variables, and red colorants production as main response. Under the best condition (g/L: glucose 30, meat extract 1, meat peptone 10, and initial pH of 7.0) an increase of 229% in the red colorant production was achieved as compared with the initial media used. The dried fermented broth containing red colorants showed low cytotoxicity against fibroblasts cells (IC50 > 187.5 g/L) and effective antimicrobial activity against S. aureus (MIC of 2.5 g/L). Thus, T. amestolkiae colorants can be attractive to food and pharmaceutical applications as it does not produce toxic compounds and can promote protection against microorganism contaminants. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 1-12, 2018. PMID- 30006969 TI - Applying Multivalent Biomolecular Interactions for Biosensors. AB - Multivalent interactions between more than one interconnected biomolecule are easily found in diverse natural systems. With the cooperation of many interacting pairs, this clustered binding can achieve highly enhanced affinities. Whereas the binding of an individual pair remains reversible, the binding between multivalent biomolecules can become nearly irreversible. Although the underlying principles of the multivalent effect have yet to be revealed, this intriguing concept of multivalent interaction has been widely applied to diverse fields. Multivalency has become a key strategy to increase the potency of inhibitors against target pathogens and, more recently, enhanced target binding by multivalency has offered an attractive strategy for biosensing. In this article, the current status of multivalent interaction studies and their progress in the biosensing area will be discussed. PMID- 30006970 TI - Using systematic reviews in guideline development: the GRADE approach. AB - Systematic reviews are essential to produce trustworthy guidelines. To assess the certainty of a body of evidence included in a systematic review the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group has developed an approach that is currently used by over 100 organisations, including the World Health Organization and the Cochrane Collaboration. GRADE provides operational definitions and instructions to rate the certainty of the evidence for each outcome in a review as high, moderate, low, or very low for the effects of interventions, prognostic estimates, values and preferences, test accuracy and resource utilization. The assessment includes assessing risk of bias, imprecision, inconsistency, indirectness, and publication bias, the magnitude of effects, dose-response relations and the impact of residual confounding and bias. Summary statistical information and assessments of certainty are presented in GRADE evidence summary tables, which can be produced using GRADE's official GRADEpro software tool (www.gradepro.org/). The evidence summary tables feed into the GRADE Evidence to Decision frameworks which guideline panels can use to produce recommendations. PMID- 30006971 TI - Do composition and diversity of bacterial communities and abiotic conditions of spring water reflect characteristics of groundwater ecosystems exposed to different agricultural activities? AB - Modern agricultural practices have undeniably increased global food production. On the other hand, agricultural practices not only lead to a degradation of natural ecosystems but also affect the functioning of ecosystems and the related services they provide. Even though impacts of anthropogenic activities vary across ecosystems, freshwater ecosystems are among those affected to a higher degree. In comparison to surface water ecosystems, groundwater ecosystems are less affected by anthropogenic pollutants, as the overlaying soil retains organic and inorganic substances. However, it has become evident that the excessive use of fertilizers has led to the eutrophication of many aquifers. Bacterial communities, which significantly contribute to the cycling of matter due to their metabolic capacities, are prone to environmental perturbations, and structural variation of bacterial communities may consequently affect the functioning of groundwater ecosystems. Our present paper intends to evaluate the impact of anthropogenic activities on environmental conditions as well as on the structural properties of bacterial communities in groundwater. We repeatedly sampled emerging groundwater at five spring sites belonging to different catchments and determined the concentration of abiotic variables as well as the diversity and composition of bacterial communities on a local scale. We hypothesized that anthropogenic activities influence the concentration of abiotic variables, especially of nitrate, as well as the composition and diversity of bacterial communities in groundwater. Our results show that underground spring catchment areas only slightly differ regarding the concentration of abiotic variables as well as the structure of bacterial communities. Furthermore, abiotic variables, presumably influenced by anthropogenic activities, do not correlate with the diversity and composition of bacterial communities. Although supported only by circumstantial evidence, we suggest that upwelling groundwater from the deeper aquifer affects the diversity and composition of bacterial communities, and we argue that bacterial communities act as useful indicators for environmental changes. PMID- 30006972 TI - LIMK2 acts as an oncogene in bladder cancer and its functional SNP in the microRNA-135a binding site affects bladder cancer risk. AB - LIM kinases modulate multiple aspects of cancer development, including cell proliferation and survival. As the mechanisms of LIMK-associated tumorigenesis are still unclear, we analyzed the tumorigenic functions of LIM kinase 2 (LIMK2) in human bladder cancer (BC) and explored whether the newly identified LIMK2 3' UTR SNP rs2073859 (G-to-A allele) is correlated with clinical features. Expression levels of LIMK2 in 38 human BC tissues and eight cell lines were examined using quantitative real-time PCR and immunohistochemistry. LIMK2 was overexpressed in most BC tissues (27/38, 71%) and BC-derived cell lines (6/8), and was more frequently overexpessed in high-grade than low-grade BC (80% vs. 47%). The effects of LIMK2 on BC cell proliferation, survival and migration, were studied by overexpression and RNA interference approaches in vitro and in vivo. LIMK2 overexpression promoted proliferation, migration and invasion of BC cells, while LIMK2 depletion inhibited cell invasion and viability and induced growth arrest in vitro and in vivo. PCR-Restriction Fragment Length Polymorphism (RFLP) was used to genotype LIMK2 SNP rs2073859 and multivariate logistic regression applied to assess the relationship between allele frequency and clinical features in 139 BC patients. Functional analyses localized SNP rs2073859 within the microRNA-135a seed-binding region and revealed significantly lower LIMK2 G allele expression. The frequency of A genotypes (AG + AA) was higher in the BC group than normal controls and correlated with risks of high-grade and high-stage BC. In conclusion, LIMK2 may function as an oncogene in human BC, while allele specific regulation by microRNA-135a may influence disease risk. PMID- 30006973 TI - A Circumplex Model of Couple Configurations in Relational Trauma Context: An Example of Practice-Based Model Development. AB - We propose a circumplex model and typology of patterns of couple engagement to help therapists assess and shape positive couple engagement, prerequisite to successful resolution of relational trauma. View or value of self in relation to other (VSIRO) is conceived as a primary engine organizing couple relationships and patterns of engagement. VSIRO is conceptualized along a continuum anchored at opposite poles by inflated (self-aggrandizing) versus collapsed (self-negating) VSIRO, with a balanced (egalitarian) VSIRO as the target position, consisting of self and other mutuality, respect, and equality. Two axes (one for each partner) form the circumplex model of five couple configurations-four quadrants plus a balanced, mid-axes region. Using couple configuration conceptualization to address patterns of engagement is an essential prerequisite to resolving couple relational trauma. PMID- 30006975 TI - The risk of Telling: A Dyadic Perspective on Romantic Partners' Responses to Child Sexual Abuse Disclosure and Their Associations with Sexual and Relationship Satisfaction. AB - Among 70 community couples who reported childhood sexual abuse (CSA) and disclosure to their partner, this study examined associations between survivors' perception of partner responses to their disclosure, and both partners' sexual and relationship satisfaction. Participants completed self-report questionnaires online. Results of path analyses within an actor-partner interdependence model indicated that survivors' perceived partner responses of emotional support to disclosure were associated with their own and their partners' higher sexual satisfaction. Survivors' perceived responses of being stigmatized/treated differently by the partner were associated with their own and their partners' poorer relationship satisfaction. Findings suggest that survivor-perceived partner responses to the disclosure of CSA can have a positive and a negative impact on the sexual and relationship satisfaction of both partners. PMID- 30006974 TI - Association of HLA-DQA1 gene polymorphisms with the risk of children primary nephrotic syndrome in Chinese population. AB - BACKGROUND: The association between gene polymorphisms and the risk of primary nephrotic syndrome (PNS) is uncovering recently. This study aims to investigate the relationship between single nucleotide polymorphisms (SNPs) on HLA-DQA1 gene and the risk of PNS. METHODS: In this study, we genotyped eight single nucleotide polymorphisms (SNPs) in the HLA-DQA1 gene in 501 PNS patients and 532 healthy people in Chinese population. Then we analyzed associations of these SNPs with the clinical features in primary nephrotic syndrome of children in Chinese population. RESULTS: Significant associations with PNS were found on missense SNP rs1129740 (GG vs AA, odds ratio (OR) = 1.987, 95% confidence interval (CI) = 1.468-2.652, P = 0.00177049) and rs1047992 (AA vs GG, OR = 1.857, 95% CI = 1.325 2.391, P = 1.1073E-10) of the HLA-DQA1 gene. CONCLUSIONS: This work suggests SNPs of HLA-DQA1 are risk factors for PNS in Chinese population, which implies roles of immune response in the pathogenesis of PNS. PMID- 30006976 TI - Transmission potential of Mayaro virus in Florida Aedes aegypti and Aedes albopictus mosquitoes. AB - Mayaro virus (MAYV) is an emerging mosquito-borne arbovirus present in Central and South America that causes arthralgia and febrile illness. Domestic mosquitoes Aedes aegypti (Diptera: Culicidae) and Aedes albopictus are potential vectors of MAYV that may allow for transmission to humans in urban settings. The present paper assesses susceptibility to infection, disseminated infection and transmission potential in Florida Ae. aegypti and Ae. albopictus for MAYV. Oral infection was significantly higher in Ae. albopictus (85-100%) than in Ae. aegypti (67-82%). Viral dissemination to the haemocoel in Ae. aegypti and Ae. albopictus mosquitoes was rapid and co-occurred with infection of the salivary glands. Rates of disseminated infection were generally higher in Ae. aegypti (45 85%) than in Ae. albopictus (38-76%), although the difference was significant only at 9 days after feeding on MAYV-infected blood. Both mosquito species exhibited low rates of MAYV infection in saliva expectorates. Viral titres in the bodies of mosquitoes increased in line with the number of days post-blood feeding and were higher in Ae. aegypti than in Ae. albopictus. Although Florida mosquito vectors have the potential to transmit MAYV and thus to initiate an urban cycle after having fed on higher titres of MAYV-infected blood, lower viraemia in infected humans is likely to limit transmission potential. PMID- 30006977 TI - Accurate light microscopic diagnosis of South-East Asian ovalocytosis. AB - INTRODUCTION: South-East Asian ovalocytosis (SAO) is a common inherited red blood cell polymorphism in South-East Asian and Melanesian populations, coinciding with areas of malaria endemicity. Validation of light microscopy as a diagnostic alternative to molecular genotyping may allow for its cost-effective use either prospectively or retrospectively by analysis of archived blood smears. METHODS: We assessed light microscopic diagnosis of SAO compared to standard PCR genotyping. Three trained microscopists each assessed the same 971 Giemsa-stained thin blood films for which SAO genotypic confirmation was available by PCR. Generalized mixed modeling was used to estimate the sensitivity, specificity, positive predictive value, and negative predictive value of light microscopy vs "gold standard" PCR. RESULTS: Among red cell morphologic parameters evaluated, knizocytes, rather than ovalocytic morphology, proved the strongest predictor of SAO status (odds ratio [OR] = 19.2; 95% confidence interval [95% CI] = 14.6-25.3; P <= 0.0001). The diagnostic performance of a knizocyte-centric microscopic approach was microscopist dependent: two microscopists applied this approach with a sensitivity of 0.89 and a specificity of 0.93. Inter-rater reliability among the microscopists (kappa = 0.20) as well as between gold standard and microscopist (kappa = 0.36) underperformed due to misclassification of stomatocytes as knizocytes by one microscopist, but improved substantially when excluding the error-prone reader (kappa = 0.65 and 0.74, respectively). CONCLUSION: Light microscopic diagnosis of SAO by knizocyte visual cue performed comparable to time-consuming and costlier molecular methods, but requires specific training that includes successful differentiation of knizocytes from stomatocytes. PMID- 30006978 TI - The Structure of [HSi9 ]3- in the Solid State and Its Unexpected Highly Dynamic Behavior in Solution. AB - We report on the first unambiguous detection of the elusive [HSi9 ]3- anion in solutions of liquid ammonia by various 29 Si and 1 H NMR experiments including chemical exchange saturation transfer (CEST). The characteristic multiplicity patterns of both the 29 Si and 1 H resonances together with CEST and a partially reduced 1 H,29 Si coupling constant indicate the presence of a highly dynamic Si8 entity and a Si-H moiety with slow proton hopping. Theoretical calculations corroborate both reorganization of Si8 on the picosecond timescale via low vibrational modes and proton hopping. In addition, in a single-crystal X-ray study of (K(DB[18]crown-6))(K([2.2.2]crypt))2 [HSi9 ]?8.5 NH3 , the H atom was unequivocally localized at one vertex of the basal square of the monocapped square-antiprismatic cluster. Thus experimental studies and theoretical considerations provide unprecedented insight into both the structure and the dynamic behavior of these cluster anions, which hitherto had been considered to be rigid. PMID- 30006979 TI - Comparative physiological analysis in the tolerance to salinity and drought individual and combination in two cotton genotypes with contrasting salt tolerance. AB - Soil salinity and drought are the two most common and frequently co-occurring abiotic stresses limiting cotton growth and productivity. However, physiological mechanisms of tolerance to such condition remain elusive. Greenhouse pot experiments were performed to study genotypic differences in response to single drought (4% soil moisture; D) and salinity (200 mM NaCl; S) stress and combined stresses (D + S) using two cotton genotypes Zhongmian 23 (salt-tolerant) and Zhongmian 41 (salt-sensitive). Our results showed that drought and salinity stresses, alone or in combination, caused significant reduction in plant growth, chlorophyll content and photosynthesis in the two cotton genotypes, with the largest impact visible under combined stress. Interestingly, Zhongmian 23 was more tolerant than Zhongmian 41 under the three stresses and displayed higher plant dry weight, photosynthesis and antioxidant enzymes activities such as superoxide dismutase (SOD), peroxidase (POD) catalase (CAT) and ascorbate peroxidase (APX) activities compared to control, while those parameters were significantly decreased in salt-stresses Zhongmian 41 compared to control. Moreover, Na+ /K+ -ATPase activity was more enhanced in Zhongmian 23 than in Zhongmian 41 under salinity stress. However, under single drought stress and D + S stress no significant differences were observed between the two genotypes. No significant differences were detected in Ca2+ /Mg2+ -ATPase activity in Zhongmian 41, while in Zhongmian 23 it was increased under salinity stress. Furthermore, Zhongmian 23 accumulated more soluble sugar, glycine-betaine and K+ , but less Na+ under the three stresses compared with Zhongmian 41. Obvious changes in leaf and root tips cell ultrastructure was observed in the two cotton genotypes. However, Zhongmian 23 was less affected than Zhongmian 41 especially under salinity stress. These results give a novel insight into the mechanisms of single and combined effects of drought and salinity stresses on cotton genotypes. PMID- 30006980 TI - Dramatic loss of seagrass habitat under projected climate change in the Mediterranean Sea. AB - Although climate warming is affecting most marine ecosystems, the Mediterranean is showing earlier impacts. Foundation seagrasses are already experiencing a well documented regression in the Mediterranean which could be aggravated by climate change. Here, we forecast distributions of two seagrasses and contrast predicted loss with discrete regions identified on the basis of extant genetic diversity. Under the worst-case scenario, Posidonia oceanica might lose 75% of suitable habitat by 2050 and is at risk of functional extinction by 2100, whereas Cymodocea nodosa would lose only 46.5% in that scenario as losses are compensated with gained and stable areas in the Atlantic. Besides, we predict that erosion of present genetic diversity and vicariant processes can happen, as all Mediterranean genetic regions could decrease considerably in extension in future warming scenarios. The functional extinction of Posidonia oceanica would have important ecological impacts and may also lead to the release of the massive carbon stocks these ecosystems stored over millennia. PMID- 30006981 TI - Teaching installation and use of child passenger safety restraints. AB - Correctly installed child passenger safety restraints may reduce the risk of child injury and death during accidents. The present study evaluated behavioral skills training and self-monitoring to teach correct installation and use of a child passenger safety restraint in the rear-facing position. Extension probes were conducted with untrained installations and harnessing positions. Training was successful in teaching participants all installation methods and harnessing positions. PMID- 30006983 TI - Biophotonics for lymphatic theranostics in animals and humans. PMID- 30006982 TI - Direct and indirect caecotrophy behaviour in paca (Cuniculus paca). AB - The colonic separation mechanism in lagomorphs and some rodents, associated with caecotrophy, serves to retain microbial protein. As tropical fruits have low protein concentrations, caecotrophy could be an important microbial protein source in frugivorous rodents such as the paca (Cuniculus paca). Due to conflicting reports on the occurrence of caecotrophy in this species, we obtained digestive tracts of three adult animals and observed the behaviour of four specimens maintained on a diet of a pelleted feed (P) and a supplemental mix of fruits and sweet potato (S, a source of structural fibre). In a Latin square design, P and S were both offered either in the morning (M) or in the afternoon (A), or with one item in the morning and the other in the afternoon (SP or PS). The paca's proximal colon is characterized by a distinct furrow typical for the colonic separation mechanism of hystricomorph rodents. Caecotrophy, both "direct" (from the anus) and "indirect" (from a pile of defecated faeces), was a regular component of the paca's behavioural repertoire, and caecotrophs contained more nitrogen and less fibre than hard faeces. Higher food intake led to less overall caecotrophy. With afternoon feeding of S, the onset of caecotrophy was delayed and the proportion of indirect caecotrophy increased, with hard faeces and caecotrophs often defecated together. No indirect caecotrophy occurred on treatment M. The results suggest that the time available after ingestion of structural fibre determines the efficiency of the colonic mechanism for the separation of hard faeces and caecotrophs. PMID- 30006984 TI - The cost of facing fear: Visual working memory is impaired for faces expressing fear. AB - Previous research has identified numerous factors affecting the capacity and accuracy of visual working memory (VWM). One potentially important factor is the emotionality of the stimuli to be encoded and held in VWM. We often must hold in VWM information that is emotionally charged, but much is still unknown about how the emotionality of stimuli impacts VWM performance. In the current research, we performed four studies examining the impact of fearful facial expressions on VWM for faces. Fearful expressions were found to produce a consistent cost to VWM performance. This cost was modulated by encoding time, but not set size. This cost was only present for faces in an upright orientation consistent with this cost being a product of the emotionality of the faces rather than lower-level perceptual differences between neutral and fearful faces. These findings are discussed in the context of existing theoretical accounts of the impact of emotion on information processing. We suggest that a number of competing effects drive both costs and benefits and are at play when emotional information must be stored in VWM, with the task context determining the balance between them. PMID- 30006985 TI - Sociopolitical Control for Immigrants: The Role of Receiving Local Contexts. AB - This study examines the individual and contextual factors associated with sociopolitical control expressed by immigrants in southern Spain. We used hierarchical linear modeling to evaluate the relations between individual (community participation, social connectedness, and perceived cultural competence of receiving community services) and municipality characteristics (city community participation, city social connectedness, and city community services' cultural competence) and immigrants' feelings of sociopolitical control. Data were analyzed using a two-level model based on 707 Moroccan immigrants in 25 municipalities. After adjusting for gender, educational level, and psychosocial confounding factors, we observed a positive association between social connectedness and sociopolitical control at the individual level. At the contextual level, we observed a positive association between (a) city community participation, (b) city social connectedness, and (c) city community services' cultural competence, and sociopolitical control. Indeed, living in a municipality where there are community services with high levels of cultural competence and where, on average, many people participate in organizations and neighbors are connected, was associated with higher levels of perceived control in the sociopolitical domain for immigrants. We also discuss implications for community based research and practice. PMID- 30006988 TI - Health science libraries in Sweden: new directions, expanding roles. AB - Librarians in Sweden are facing huge challenges in meeting the demands of their organisations and users. This article looks at four key areas: coping with open science/open access initiatives; increasing demands from researchers for support doing systematic reviews; understanding user experiences in Swedish health science libraries; and the consequences of expanding roles for recruitment and continuing professional development. With regard to changing roles, there is an increasing shift from the generalist towards the expert role. The authors raise the issue as to how to prepare those new to the profession to the changing environment of health science libraries. PMID- 30006987 TI - Capillary electrophoresis in the enantioseparation of modern antidepressants: An overview. AB - Chirality is a key subject in modern drug research as well as in the pharmaceutical industry and drug development. Almost all second-generation modern antidepressants are chiral substances; however in therapy some are used as racemic mixtures while others are used as pure enantiomers. The development of enantioseparation methods of chiral antidepressants and their metabolites is one of the keys in understanding their enantioselective drug action. For this purpose, efficient and reliable analytical methods are needed, and capillary electrophoresis has proved to be an interesting and advantageous alternative to the more frequently used chromatographic techniques. In this review electrodriven methods available for the chiral discrimination of selective serotonin reuptake inhibitors (fluoxetine, citalopram, sertraline) and selective serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine) are presented and discussed. PMID- 30006989 TI - Results from the prospective German TPK clinical cohort study: Treatment algorithms and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. AB - Pancreatic cancer is a highly lethal malignancy. Developments in recent years have broadened our therapeutic armamentarium. Novel drugs such as nab-paclitaxel, liposomal irinotecan and chemotherapy regimens such as FOLFIRINOX have been successfully tested in clinical trials. Data on patients outside of clinical trials are scarce but necessary to assess and improve the standard of care. We present data on treatment and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. Between February 2014 and June 2017, patients were recruited by 104 sites at start of first-line therapy into the ongoing, prospective clinical cohort study TPK (Tumour Registry Pancreatic Cancer). As first-line therapy, 89% of patients received one of the three treatment regimens: gemcitabine monotherapy (23%), nab-paclitaxel plus gemcitabine (42%), or FOLFIRINOX (24%). The corresponding subgroups differed: Patients receiving gemcitabine monotherapy were older and more comorbid (median age 78 years, 73% ECOG >= 1) than patients receiving nab-paclitaxel plus gemcitabine (median age 71, 64% ECOG >= 1) or patients receiving FOLFIRINOX (median age 60, 52% ECOG >= 1). At least 40% of patients died before receiving second-line treatment. First-line progression-free survival was 4.6 months (95% CI: 3.7-5.2) for gemcitabine, 5.6 months (95% CI: 5.0-6.2) for nab-paclitaxel plus gemcitabine, and 6.3 months (95% CI: 5.5-6.9) for FOLFIRINOX. Our data represent the treatment reality in a German community setting. Although there are no stringent inclusion criteria for our cohort study, overall survival is comparable to that reported by randomised clinical trials. PMID- 30006986 TI - Molecular mechanisms of force production in clathrin-mediated endocytosis. AB - During clathrin-mediated endocytosis (CME), a flat patch of membrane is invaginated and pinched off to release a vesicle into the cytoplasm. In yeast CME, over 60 proteins-including a dynamic actin meshwork-self-assemble to deform the plasma membrane. Several models have been proposed for how actin and other molecules produce the forces necessary to overcome the mechanical barriers of membrane tension and turgor pressure, but the precise mechanisms and a full picture of their interplay are still not clear. In this review, we discuss the evidence for these force production models from a quantitative perspective and propose future directions for experimental and theoretical work that could clarify their various contributions. PMID- 30006990 TI - Donor lymphocyte infusion leads to diversity of specific T cell responses and reduces regulatory T cell frequency in clinical responders. AB - T cell responses against malignant cells play a major role in maintaining remission and prolonging overall survival in patients after allogeneic stem cell transplantation and donor lymphocyte infusion (DLI) due to graft-versus-leukemia effect. For better characterization of the T cell responses, we assessed frequency and diversity of leukemia-associated antigen (LAA)-specific cytotoxic T cells using ELISpot and pMHC multimer assays and analyzed the frequency of regulatory T cells (Treg) as well as cytokine profiles before/after DLI. The data were correlated to the clinical course of patients. Significantly more LAA derived T cell epitopes (p = 0.02) were recognized in clinical responders (R) when compared to nonresponders (NR). In addition, pMHC multimer-based flow cytometry showed a significantly higher frequency of LAA-specific T cells in R versus NR. The frequency of Treg in R decreased significantly (p = 0.008) while keeping stable in NR. No differences in T cell subset analysis before/after DLI were revealed. Clinical responders were correlated to specific immune responses and all clinical responders showed an increase of specific immune responses after DLI. Cytokine assays using enzyme-linked immunosorbent assay showed a significant increase of IL-4 after DLI. Taken together, an increase of specific CTL responses against several LAA after DLI was detected. Moreover, this study suggests that enhanced LAA diversity in T cell responses as well as decreasing numbers of Treg contribute to clinical outcome of patients treated with DLI. PMID- 30006991 TI - The Saccharomyces cerevisiae poly (A) binding protein (Pab1): Master regulator of mRNA metabolism and cell physiology. AB - Pab1, the major poly (A) binding protein of the yeast Saccharomyces cerevisiae, is involved in many intracellular functions associated with mRNA metabolism, such as mRNA nuclear export, deadenylation, translation initiation and termination. Pab1 consists of four RNA recognition motifs (RRM), a proline-rich domain (P) and a carboxy-terminal (C) domain. Due to its modular structure, Pab1 can simultaneously interact with poly (A) tails and different proteins that regulate mRNA turnover and translation. Furthermore, Pab1 also influences cell physiology under stressful conditions by affecting the formation of quinary assemblies and stress granules, as well as by stabilizing specific mRNAs to allow translation re initiation after stress. The main goal of this review is to correlate the structural complexity of this protein with the multiplicity of its functions. PMID- 30006992 TI - Severe vision loss caused by cosmetic filler augmentation: Case series with review of cause and therapy. AB - Hyaluronic acid (HA) injection is a popular nonsurgical, facial rejuvenating procedure. Due to the rapidly expanding use of HA injections, significant potential complications have also increased in frequency. Among these complications, the rare but most devastating one is arterial occlusion, which can result in skin necrosis or blindness. To describe the mechanisms behind vision loss secondary to hyaluronic acid injection and the efficacy of treatments to restore vision and associated ocular functionality. We reviewed six cases of patients from October 2011 to December 2017 who experienced vision loss after receiving facial HA injections and the subsequent treatments undertaken to attempt to reverse the vision loss and additional eye complications. Of the six patients, four received nose, one received forehead, and another one received temple injections. All six patients developed vision loss secondary to hyaluronic acid embolization in retinal or ophthalmic arteries. Additional complications included severe periorbital pain, ptosis, impairment of extraocular muscle functionality. Recovery of vision was dependent on the type, frequency, and duration of subsequent treatment. Vision loss is a rare but catastrophic complication caused by hyaluronic injection that occurs secondary to hyaluronic acid embolization in retinal or ophthalmic arteries due to retrograde flow from facial vascular anastomoses. We suggest the early supratrochlear/supraorbital hyaluronidase injection, ocular massage, and re-breathing into a plastic bag as safe, uncomplicated and effective methods to restore the retinal circulation and reverse vision loss. PMID- 30006993 TI - Determination of optical properties of human brain tumor tissues from 350 to 1000 nm to investigate the cause of false negatives in fluorescence-guided resection with 5-aminolevulinic acid. AB - The optical properties of human brain tumor tissues, including glioblastoma, meningioma, oligodendroglioma, and metastasis, that were classified into "strong," "vague," and "unobservable" fluorescence by a neurosurgeon were measured and compared. The optical properties of the tissues were measured with a double integrating sphere and the inverse Monte Carlo technique from 350 to 1000 nm. Using reasons of ex-vivo measurement, the optical properties at around 420 nm were potentially affected by the hemoglobin content in tissues. Significant differences were not observed between the optical properties of the glioblastoma regions with "strong" and "unobservable" fluorescence. Sections of human brain tumor tissue with "strong" and "unobservable" fluorescence were stained with hematoxylin and eosin. The cell densities [mean +/- standard deviation (S.D.)] in regions with "strong" and "unobservable" fluorescence were 31 +/- 9 * 102 per mm2 and 12 +/- 4 * 102 per mm2, respectively, which is a statistically significant difference. The higher fluorescence intensity is associated with higher cell density. The difference in cell density modified the scattering coefficient yet it does not lead to significant differences in the reduced scattering coefficient and thus does not affect the propagation of the diffuse fluorescent light. Hence, the false negatives, which mean a brain tumor only shows "unobservable" fluorescence and is hence classified incorrectly as nontumor, in using 5-ALA for detection of human glioblastoma do not result from the differences in optical properties of human brain glioblastoma tissues. Our results suggest that the primary cause of false negatives may be a lack of PpIX or a low accumulation of PpIX. PMID- 30006995 TI - Leaderless mRNAs in the Spotlight: Ancient but Not Outdated! AB - Previously, leaderless mRNAs (lmRNAs) were perceived to make up only a minor fraction of the transcriptome in bacteria. However, advancements in RNA sequencing technology are uncovering vast numbers of lmRNAs, particularly in archaea, Actinobacteria, and extremophiles and thus underline their significance in cellular physiology and regulation. Due to the absence of conventional ribosome binding signals, lmRNA translation initiation is distinct from canonical mRNAs and can therefore be differentially regulated. The ribosome's inherent ability to bind a 5'-terminal AUG can stabilize and protect the lmRNA from degradation or allow ribosomal loading for downstream initiation events. As a result, lmRNAs remain translationally competent during a variety of physiological conditions, allowing them to contribute to multiple regulatory mechanisms. Furthermore, the abundance of lmRNAs can increase during adverse conditions through the upregulation of lmRNA transcription from alternative promoters or by the generation of lmRNAs from canonical mRNAs cleaved by an endonucleolytic toxin. In these ways, lmRNA translation can continue during stress and contribute to regulation, illustrating their importance in the cell. Due to their presence in all domains of life and their ability to be translated by heterologous hosts, lmRNAs appear further to represent ancestral transcripts that might allow us to study the evolution of the ribosome and the translational process. PMID- 30006994 TI - Cross-Regulation between Bacteria and Phages at a Posttranscriptional Level. AB - The study of bacteriophages (phages) and prophages has provided key insights into almost every cellular process as well as led to the discovery of unexpected new mechanisms and the development of valuable tools. This is exemplified for RNA based regulation. For instance, the characterization and exploitation of the antiphage CRISPR (clustered regularly interspaced short palindromic repeat) systems is revolutionizing molecular biology. Phage-encoded proteins such as the RNA-binding MS2 protein, which is broadly used to isolate tagged RNAs, also have been developed as valuable tools. Hfq, the RNA chaperone protein central to the function of many base-pairing small RNAs (sRNAs), was first characterized as a bacterial host factor required for Qbeta phage replication. The ongoing studies of RNAs are continuing to reveal regulatory connections between infecting phages, prophages, and bacteria and to provide novel insights. There are bacterial and prophage sRNAs that regulate prophage genes, which impact bacterial virulence as well as bacterial cell killing. Conversely, phage- and prophage-encoded sRNAs modulate the expression of bacterial genes modifying metabolism. An interesting subcategory of the prophage-encoded sRNAs are sponge RNAs that inhibit the activities of bacterial-encoded sRNAs. Phages also affect posttranscriptional regulation in bacteria through proteins that inhibit or alter the activities of key bacterial proteins involved in posttranscriptional regulation. However, what is most exciting about phage and prophage research, given the millions of phage encoded genes that have not yet been characterized, is the vast potential for discovering new RNA regulators and novel mechanisms and for gaining insight into the evolution of regulatory RNAs. PMID- 30006996 TI - Bacterial Y RNAs: Gates, Tethers, and tRNA Mimics. AB - Y RNAs are noncoding RNAs (ncRNAs) that are present in most animal cells and also in many bacteria. These RNAs were discovered because they are bound by the Ro60 protein, a major target of autoantibodies in patients with some systemic autoimmune rheumatic diseases. Studies of Ro60 and Y RNAs in Deinococcus radiodurans, the first sequenced bacterium with a Ro60 ortholog, revealed that they function with 3'-to-5' exoribonucleases to alter the composition of RNA populations during some forms of environmental stress. In the best-characterized example, Y RNA tethers the Ro60 protein to the exoribonuclease polynucleotide phosphorylase, allowing this exoribonuclease to degrade structured RNAs more effectively. Y RNAs can also function as gates to regulate access of other RNAs to the Ro60 central cavity. Recent studies in the enteric bacterium Salmonella enterica serovar Typhimurium resulted in the discovery that Y RNAs are widely present in bacteria. Remarkably, the most-conserved subclass of bacterial Y RNAs contains a domain that mimics tRNA. In this review, we discuss the structure, conservation, and known functions of bacterial Y RNAs as well as the certainty that more bacterial Y RNAs and additional roles for these ncRNAs remain to be uncovered. PMID- 30006999 TI - Authors' reply to the letter to editor. PMID- 30006997 TI - Quantifying the Stiffness of Achilles Tendon: Intra- and Inter-Operator Reliability and the Effect of Ankle Joint Motion. AB - BACKGROUND The objectives of the present study were to examine the intra- and inter-operator reliability of the MyotonPRO device in quantifying the stiffness of the Achilles tendon and the device's ability to examine the modulation in stiffness of the Achilles tendon during ankle joint flexion. MATERIAL AND METHODS Twenty asymptomatic participants (10 males and 10 females; mean age: 25.0+/-3.1 years) were recruited for this study. The stiffness of the Achilles tendon was quantified using the MyotonPRO device. RESULTS The results revealed excellent intra- and inter-operator reliability for quantifying Achilles tendon stiffness with the ankle joint in a neutral position and detected a 13.9% increase in stiffness of the Achilles tendon between 0 degrees and 30 degrees of ankle joint flexion. The minimal detectable change (MDC) in tendon stiffness was 45 Newton/meter (N/m). CONCLUSIONS Our findings indicated that the MyotonPRO device is a feasible method to quantify the stiffness of the Achilles tendon and monitor its changes. Thus, it is an essential tool to use to examine the modulation in the stiffness of the Achilles tendon due to pathology or interventions for future studies. PMID- 30006998 TI - Analgesic effects of ASP3662, a novel 11beta-hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain. AB - BACKGROUND AND PURPOSE: Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11beta hydroxysteroid dehydrogenase 1 (11beta-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11beta-HSD1 inhibitor, on neuropathic and dysfunctional pain. EXPERIMENTAL APPROACH: The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats. KEY RESULTS: ASP3662 inhibited human, mouse and rat 11beta-HSD1 but not human 11beta-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats. CONCLUSIONS AND IMPLICATIONS: ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11beta-HSD1. The effects of ASP3662 suggest that selective inhibition of 11beta-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia. PMID- 30007002 TI - Organic Carbonyl Compounds for Sodium-Ion Batteries: Recent Progress and Future Perspectives. AB - Sodium-organic batteries, which use organic materials as the electrodes in sodium ion batteries, are an attractive alternative to conventional lithium-ion batteries for next-generation sustainable and versatile energy storage devices owing to the abundant sodium resources and environmental friendly features. However, organics used in sodium-ion batteries also encounter some issues such as low redox potential, high solubility in the electrolyte, and low conductivity. In response, altering the aromatic system/attaching electron-withdrawing groups, constructing polymers, and incorporating a conductive matrix are effective strategies. This review summarizes and briefly discusses recent organic carbonyl compounds for sodium-organic batteries from the viewpoint of function-oriented design, including function evolution from small-molecule compounds to polymers, then composites, and finally flexible electrodes. In particular, as a timely overview, carbonyl-based organic flexible electrodes for sodium-organic batteries are also highlighted for the first time. PMID- 30007001 TI - Systematic review of the prevalence, impact and mitigating strategies for bullying, undermining behaviour and harassment in the surgical workplace. AB - BACKGROUND: Bullying, undermining behaviour and harassment (BUBH) have been reported in entertainment, politics and sport. Such behaviours may also be common in surgery, and are frequently associated with poor patient care and inferior outcomes. The aim was to define the prevalence and impact of this behaviour in the international surgical workplace, and to explore counterstrategies. METHODS: A systematic review was conducted by searching EMBASE, Medline, PsycINFO and the Cochrane Database of Systematic Reviews in August 2017. Original research studies (Oxford Centre for Evidence-based Medicine levels 1-4) investigating the prevalence and impact of BUBH in surgery, and/or counterstrategies, were eligible for inclusion. The review was conducted in accordance with PRISMA guidelines. RESULTS: Of 2692 papers, 32 were eligible for inclusion. Twenty-two reported the prevalence of BUBH in surgery, 11 studied the impact of this behaviour and six investigated counterstrategies. Prevalence data showed that BUBH are common in the surgical workplace. Their impact can be profound, compromising mental health, reducing job satisfaction, and inducing suicidal ideation. Formal reporting systems were perceived as ineffective and even potentially harmful to victims. CONCLUSION: Bullying, undermining behaviour and harassment are highly prevalent within surgery, and extremely damaging to victims. There is little high-quality research into counterstrategies, although professionalism training using simulated scenarios may be useful. PMID- 30007000 TI - Dual role of nitrergic neurotransmission in the bed nucleus of the stria terminalis in controlling cardiovascular responses to emotional stress in rats. AB - BACKGROUND AND PURPOSE: The aim of the present study was to assess the interaction of nitrergic neurotransmission within the bed nucleus of the stria terminalis (BNST) with local glutamatergic and noradrenergic neurotransmission in the control of cardiovascular responses to acute restraint stress in rats. EXPERIMENTAL APPROACH: Interaction with local noradrenergic neurotransmission was evaluated using local pretreatment with the selective alpha1 -adrenoceptor antagonist WB4101 before microinjection of the NO donor NOC-9 into the BNST. Interaction with glutamatergic neurotransmission was assessed by pretreating the BNST with a selective inhibitor of neuronal NOS (nNOS), Nomega-propyl-L-arginine (NPLA) before local microinjection of NMDA. The effect of intra-BNST NPLA microinjection in animals locally pretreated with WB4101 was also evaluated. KEY RESULTS: NOC-9 reduced the heart rate (HR) and blood pressure increases evoked by restraint stress. These effects of NOC-9 on HR, but not in blood pressure, was inhibited by pretreatment of BNST with WB4101. NMDA enhanced the restraint-evoked HR increase, and this effect was abolished following BNST pretreatment with NPLA. Administration of NPLA to the BNST of animals pretreated locally with WB4101 decreased the HR and blood pressure increases induced by restraint. CONCLUSION AND IMPLICATIONS: These results indicate that inhibitory control of stress-evoked cardiovascular responses by nitrergic signalling in the BNST is mediated by a facilitation of local noradrenergic neurotransmission. The present data also provide evidence of an involvement of local nNOS in facilitatory control of tachycardia during stress by NMDA receptors within the BNST. PMID- 30007003 TI - The Three S's for Aptamer-Mediated Control of DNA Nanostructure Dynamics: Shape, Self-Complementarity, and Spatial Flexibility. AB - DNA aptamers are ideal tools to enable modular control of the dynamics of DNA nanostructures. For molecular recognition, they have a particular advantage over antibodies in that they can be integrated into DNA nanostructures in a bespoke manner by base pairing or nucleotide extension without any complex bioconjugation strategy. Such simplicity will be critical upon considering advanced therapeutic and diagnostic applications of DNA nanostructures. However, optimizing DNA aptamers for functional control of the dynamics of DNA nanostructure can be challenging. Herein, we present three considerations-shape, self-complementarity, and spatial flexibility-that should be paramount upon optimizing aptamer functionality. These lessons, learnt from the growing number of aptamer nanostructure reports thus far, will be helpful for future studies in which aptamers are used to control the dynamics of nucleic acid nanostructures. PMID- 30007004 TI - Extrathoracic subclavian-axillary vein location over the first rib for pacemaker and defibrillator lead implantation. PMID- 30007006 TI - Hydrophobic ionic liquid modified thermoresponsive molecularly imprinted monolith for the selective recognition and separation of tanshinones. AB - A hydrophobic ionic liquid modified thermoresponsive molecularly imprinted monolith was synthesized using N-isopropylacrylamide as a thermoresponsive monomer and a long-chain hydrophobic ionic liquid as an auxiliary modification monomer. The ionic-liquid-modified thermoresponsive molecularly imprinted polymer was characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. When the column temperature was 50 degrees C, the synthesized monolithic column was successfully applied to the selective separation of homologue tanshinones within 7 min and eluted only by water (mobile phase) (theoretical plates more than 1.00 * 105 per meter). The negative Gibbs free energy (<=-2.37) values showed that the transfer of the tanshinones from the mobile phase to the stationary phase on this monolithic column was a thermodynamically spontaneous process. Good linearity of the five tanshinones by thermoresponsive monolith was obtained in the range of 0.100-25.0 MUg/mL. The limit of detection (S/N = 3) and limit of quantitation (S/N = 10) were less than 0.0390 and 0.0630 MUg/mL, respectively, with a relative standard deviation of <4.8%. In this proposed thermoresponsive chromatography method, the separation of homologue analytes can be achieved by changing the column temperature, and the use of water as the mobile phase would decrease the economic cost and organic pollution. PMID- 30007005 TI - Dimethyl fumarate-induced IL-17low IFN-gammalow IL-4+ Th cells protect mice from severe encephalomyelitis. AB - Dimethyl fumarate (DMF) promotes an IL-17Alow IFN-gammalow IL-4+ CD4+ T cell phenotype. Adoptive transfer of in vitro DMF-treated myelin peptide-reactive IL 17Alow IFN-gammalow IL-4+ CD4+ T cells prior to immunization for EAE reduces the severity of encephalomyelitis. This beneficial effect of transferred DMF-treated CD4+ T cells requires an early in vivo recall. PMID- 30007007 TI - Chronic pruriginous papules years after a stay in Cameroon. PMID- 30007008 TI - Prospective investigation of applicability and the prognostic significance of bone marrow involvement in patients with neuroblastoma detected by quantitative reverse transcription PCR. AB - BACKGROUND: Detection of bone marrow (BM) involvement in patients with neuroblastoma is crucial for staging and defining prognosis. Furthermore, the persistence of residual tumor cells in the BM is associated with an unfavorable outcome. METHODS: Expression of PHOX2B, TH, ELAVL4, and B4GALNT1 (GD2-synthase) was analyzed by quantitative polymerase chain reaction in neuroblastoma cell lines, control BM samples, and in BM samples from patients. The threshold level of expression for each gene was established through receiver operator characteristic analysis and used to determine the diagnostic test performance. The prognostic significance of BM involvement was assessed by survival rates calculations. The median of follow-up time was 36.1 months. RESULTS: Neither PHOX2B nor TH expression was detected in control BM, while expression of ELAVL4 was found in 20 (76.9%) and GD2-synthase in 15 (57.7%) of 26 samples. The overall correct predictive value for TH, ELAVL4, and GD2-synthase, based on thresholds levels, was 0.952, 0.828, and 0.767, respectively, whereas the overall correct predictive value for PHOX2B was 0.994. The PHOX2B/TH expression in diagnostic BM of patients with neuroblastoma corresponded with a decreased survival rate (P < 0.001) in the total cohort and in different risk groups. Predominance of normalized expression of PHOX2B over TH > 1.68 in the diagnostic BM samples demonstrated an adverse prognostic effect (P = 0.006). Persistence of PHOX2B/TH expression in the BM during and after induction chemotherapy resulted in dismal outcome (P = 0.022 and P = 0.012). CONCLUSION: PHOX2B and TH are the most optimal markers for detection of BM involvement, allowing identification of high-risk patients. Predominance of PHOX2B expression over TH has a strong adverse prognostic impact. PMID- 30007009 TI - Sickle cell vasculopathy: vascular phenotype on fire! PMID- 30007010 TI - Negative regulation of resistance protein-mediated immunity by master transcription factors SARD1 and CBP60g. AB - Salicylic acid (SA) is an essential defence hormone in plants. Upon pathogen infection, induced biosynthesis of SA is mediated by Isochorismate synthase 1 (ICS1), whose gene transcription is controlled mainly through two redundant transcription factors, SAR Deficient 1 (SARD1) and Calmodulin-binding protein 60 like g (CBP60g). Although these master transcription factors regulate not only positive, but also negative regulators of immunity, how they control signaling events downstream of different immune receptors is unclear. Using autoimmune mutants activating immunity mediated by different receptors we show that, although the sard1 cbp60g double mutant almost fully suppresses the activation of defence mediated by suppressor of npr1-1, constitutive 2 (snc2), it strikingly enhances snc1, which carries a gain-of-function mutation in an intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptor. This negative regulation of immunity is achieved through the transcriptional regulation of negative regulators, such as Nudix hydrolase homolog 6 (NUDT6). Our study highlights the diverse roles, especially the negative ones, in the regulation of plant immunity by the two master immune transcription factors SARD1 and CBP60g. PMID- 30007011 TI - Histone deacetylase 11 inhibits interleukin 10 in B cells of subjects with allergic rhinitis. AB - BACKGROUND: The interleukin (IL)-10 expression in B cells plays an important role in immune tolerance. The regulation of IL-10 expression in B cells is not fully understood yet. Tumor necrosis factor (TNF) is increased in allergic rhinitis (AR) patients. This study tests a hypothesis that TNF enhances histone deacetylase (HDAC)11 expression to inhibit the expression of IL-10 in B cells of AR patients. METHODS: Peripheral B cells were collected from healthy persons and patients with AR. The B cells were analyzed by immune assay and molecular biological approaches for the expression of IL-10. RESULTS: The expression of HDAC11 was higher in B cells of patients with AR than that in healthy persons. The expression of IL-10 in B cells was lower in AR patients than that in healthy subjects. The levels of HDAC11 in B cells were negatively correlated with the levels of IL-10. Exposure of B cells to TNF in the culture inhibited the expression of IL-10, in which HDAC11 played a critical role in the interference with the Il10 gene transcription. Inhibition of HDAC11 restored the IL-10 expression in B cells from AR patients and attenuated the experimental AR. CONCLUSION: TNF can suppress the expression of IL-10 in B cells via enhancing the expression of HDAC11. Inhibition of HDAC11 restores the IL-10 expression in B cells of AR subjects. HDAC11 may be a novel target for the treatment of AR. PMID- 30007013 TI - Bullous pemphigoid with hyperkeratosis and palmoplantar keratoderma: Three cases. AB - The clinical features of bullous pemphigoid are extremely polymorphous. Several atypical forms of bullous pemphigoid have been described, and the diagnosis critically relies on immunopathological findings. We describe three bullous pemphigoid patients characterized by palmoplantar keratoderma, diffused hyperkeratotic cutaneous lesions and extremely high levels of immunoglobulin E serum. The diagnosis of bullous pemphigoid should be taken into account in patients presenting diffused hyperkeratotic cutaneous lesions and palmoplantar keratoderma, even in the absence of blisters. Alteration of the keratinization process, that could occur in patients with genetic mutations in desmosomal and hemidesmosomal genes, may also be due to circulating autoantibodies against hemidesmosomal proteins in these bullous pemphigoid patients. PMID- 30007014 TI - Regulators of the transsulfuration pathway. AB - The transsulfuration pathway is a metabolic pathway where transfer of sulfur from homocysteine to cysteine occurs. The pathway leads to the generation of several sulfur metabolites, which include cysteine, GSH and the gaseous signalling molecule hydrogen sulfide (H2 S). Precise control of this pathway is critical for maintenance of optimal cellular function and, therefore, the key enzymes of the pathway, cystathionine beta-synthase and cystathionine gamma-lyase, are regulated at multiple levels. Disruption of the transsulfuration pathway contributes to the pathology of several conditions such as vascular dysfunction, Huntington's disease and during ageing. Treatment with donors of hydrogen sulfide and/or stimulation of this pathway have proved beneficial in several of these disorders. In this review, we focus on the regulation of the transsulfuration pathway pertaining to cysteine and H2 S, which could be targeted to develop novel therapeutics. PMID- 30007012 TI - Stimulation of brain nicotinic acetylcholine receptors activates adrenomedullary outflow via brain inducible NO synthase-mediated S-nitrosylation. AB - BACKGROUND AND PURPOSE: We have demonstrated that i.c.v.-administered (+/-) epibatidine, a nicotinic ACh receptor (nAChR) agonist, induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla with dihydro-beta-erythroidin (an alpha4beta2 nAChR antagonist)-sensitive brain mechanisms. Here, we examined central mechanisms for the (+/-)-epibatidine induced responses, focusing on brain NOS and NO-mediated mechanisms, soluble GC (sGC) and protein S-nitrosylation (a posttranslational modification of protein cysteine thiol groups), in urethane-anaesthetized (1.0 g.kg-1 , i.p.) male Wistar rats. EXPERIMENTAL APPROACH: (+/-)-Epibatidine was i.c.v. treated after i.c.v. pretreatment with each inhibitor described below. Then, plasma catecholamines were measured electrochemically after HPLC. Immunoreactivity of S-nitrosylated cysteine (SNO-Cys) in alpha4 nAChR subunit (alpha4)-positive spinally projecting neurones in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of adrenomedullary outflow) after i.c.v. (+/-)-epibatidine administration was also investigated. KEY RESULTS: (+/-)-Epibatidine-induced elevation of plasma catecholamines was significantly attenuated by L-NAME (non-selective NOS inhibitor), carboxy-PTIO (NO scavenger), BYK191023 [selective inducible NOS (iNOS) inhibitor] and dithiothreitol (thiol-reducing reagent), but not by 3-bromo 7-nitroindazole (selective neuronal NOS inhibitor) or ODQ (sGC inhibitor). (+/-) Epibatidine increased the number of spinally projecting PVN neurones with alpha4- and SNO-Cys-immunoreactivities, and this increment was reduced by BYK191023. CONCLUSIONS AND IMPLICATIONS: Stimulation of brain nAChRs can induce elevation of plasma catecholamines through brain iNOS-derived NO-mediated protein S nitrosylation in rats. Therefore, brain nAChRs (at least alpha4beta2 subtype) and NO might be useful targets for alleviation of catecholamines overflow induced by smoking. PMID- 30007015 TI - Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance. AB - NEW FINDINGS: What is the central question of this study? The aim was to investigate the potential metabolic and redox mechanisms that impaired exercise performance after 21 days of supplementation with 300 mg (kg body weight)-1 of nicotinamide riboside in rats. What is the main finding and its importance? Nicotinamide riboside disturbed energy and redox metabolism and impaired exercise performance in heathy rats. Exogenously administered redox agents in heathy populations might lead to adverse effects. ABSTRACT: Nicotinamide riboside is a recently discovered form of vitamin B3 that can increase NAD(P) levels. NAD(P) plays key roles in energy metabolism, and its main function is the transfer of electrons in various cellular reactions. Research in aged or diseased mice reported that nicotinamide riboside increases NAD(H) levels, reduces morbidity and improves health and muscle function. We have recently shown that in healthy young rats, chronic administration of nicotinamide riboside marginally non significantly decreased exercise performance by 35% (P = 0.071). As a follow-up to this finding, we analysed samples from these animals, in an attempt to reveal the potential mechanisms driving this adverse effect, focusing on redox homeostasis and bioenergetics. Thirty-eight Wistar rats were divided into four groups: control (n = 10), exercise (n = 9), nicotinamide riboside (n = 10) and exercise plus nicotinamide riboside (n = 9). Nicotinamide riboside was administered for 21 days [300 mg (kg body weight)-1 daily]. At the end of administration, the exercise and the exercise plus nicotinamide riboside groups performed an incremental swimming performance test until exhaustion. Nicotinamide riboside supplementation increased the levels of NADPH in the liver (P = 0.050), increased the levels of F2 -isoprostanes in plasma (P = 0.047), decreased the activity of glutathione peroxidase (P = 0.017), glutathione reductase (P < 0.001) and catalase (P = 0.024) in erythrocytes, increased the level of glycogen in the liver (P < 0.001) and decreased the concentration of glucose (P = 0.016) and maximal lactate accumulation in plasma (P = 0.084). These findings support the prevailing idea that exogenously administered redox agents in heathy populations might lead to adverse effects and not necessarily to beneficial or neutral effects. PMID- 30007016 TI - Are on-line patient portals meeting test result preferences of caregivers of children with cancer? A qualitative exploration. AB - BACKGROUND: Management of pediatric cancer entails frequent laboratory and radiology testing to monitor response to treatment, side effects, and possible relapse of disease. Little is known about how caregivers of children with cancer would like to receive results of these tests and whether on-line patient portals may meet those preferences. PROCEDURES: One-on-one semistructured interviews were conducted with 19 caregivers of children with cancer purposively sampled for breadth on demographic characteristics. Inductive qualitative content coding/analysis was utilized to distill caregiver's preferred methods for test result acquisition and their views of using an on-line patient portal to do so. RESULTS: The relative prioritization of speed of information and mode of communication (i.e., "in person," by phone, etc.) revealed three preference styles. Factors including type of testing, type of result, and the time course within their child's care modified these preferences, and the desire to reduce anxiety played a central role. Caregivers recognized advantages of portal use including getting results "fast," being able to visualize trends in results, "keeping a record," and not interfering with clinic flow. Perceived disadvantages included the results being "complicated" or easily misunderstood, and learning results prior to disclosure by care team. CONCLUSION: This study provides insight into the importance of understanding of how caregivers want test results and how they utilize the portal. Preferences for result acquisition vary on many factors and include the desire to decrease anxiety. As portal use increases, we have a duty to integrate this technology responsibly. PMID- 30007017 TI - The socioeconomic determinants for transsphenoidal pituitary surgery: a review of New York State from 1995 to 2015. AB - BACKGROUND: Prolonged length of stay (pLOS), disease-related complications, and 30-day readmissions are important quality metrics under the Affordable Care Act. The purpose of our study was to investigate the effect of patient-level and hospital-level factors on these outcomes for patients admitted for transsphenoidal pituitary surgery. METHODS: The Statewide Planning and Research Cooperative System (SPARCS) database was queried to investigate 30-day readmissions and pLOS for transsphenoidal pituitary surgery in New York from 1995 to 2015. Multivariate logistic regression, adjusting for patient and hospital characteristics, was performed to assess the effect of these variables on the outcomes of interest. RESULTS: A total of 9950 patients underwent transsphenoidal pituitary surgery; 7122 (72%), 2394 (24%), and 434 (4%) patients were treated at high-volume, medium-volume, and low-volume centers, respectively. Patient factors associated with treatment at high-volume centers (HVCs) included: top income quartile, private insurance, urban residence, and white or Asian race (p < 0.05). Patient variables associated with treatment at low-volume centers (LVCs) included: age >65 years, elevated Charlson comorbidity index (CCI) scores, bottom income quartile, Medicaid and Medicare insurance, rural residence, black race, and Hispanic ethnicity (p < 0.05). Variables predictive of prolonged hospitalizations in our multivariable model included black race, Hispanic ethnicity, Medicaid insurance, low income, female gender, LVC, and comorbidities (panhypopituitarism, hypothyroidism, diabetes insipidus [DI], visual disturbances, CCI) while predictors of readmissions included Asian race, female gender, and comorbidities (Cushing syndrome, DI, CCI). CONCLUSION: Patients undergoing transsphenoidal pituitary surgery at HVCs have shorter hospitalizations, fewer postoperative electrolyte abnormalities, and lower charges; however, socioeconomic factors may influence access to quality care. PMID- 30007018 TI - Outcomes of pancreas retransplantation in patients with pancreas graft failure. AB - BACKGROUND: Pancreas retransplantation is still a controversial option after loss of a pancreatic graft. This article describes the experience of pancreas retransplantation at a high-volume centre. METHODS: This was a retrospective observational study of all pancreas retransplantations performed in a single centre between 1997 and 2013. Pancreatic graft loss was defined by the return to insulin dependence. Risk factors for graft loss as well as patient and graft survival were analysed using logistic and time-to-event regression models. RESULTS: Of 409 pancreas transplantations undertaken, 52 (12.7 per cent) were identified as pancreas retransplantations. After a median follow-up of 65.0 (range 0.8-174.3) months, 1- and 5-year graft survival rates were 79 and 69 per cent respectively, and 1- and 5-year patient survival rates were 96 and 89 per cent. During the entire follow-up, 22 grafts (42 per cent) were lost. Patient survival was not associated with any of the donor- or recipient-related factors investigated. Five-year graft survival was better after simultaneous kidney pancreas retransplantation than pancreas retransplantation alone: 80 per cent (16 of 20) versus 63 per cent (20 of 32) (P = 0.226). Acute rejection (odds ratio 4.49, 95 per cent c.i. 1.59 to 12.68; P = 0.005) and early surgical complications (OR 3.29, 1.09 to 9.99, P = 0.035) were identified as factors with an independent negative effect on graft survival. CONCLUSION: Pancreas retransplantation may be considered for patients whose previous graft has failed. PMID- 30007019 TI - Formation of Alkanethiol Supported Hybrid Membranes Revisited. AB - A phospholipid monolayer supported on an alkanethiol self-assembled monolayer (SAM) constitutes a supported hybrid membrane, a model of biological membranes optimized for electronic access through the underlying metal support surface. It is believed that phospholipids, when deposited from aqueous liposome suspension, spontaneously cover the alkanethiol-modified surface, owing to the reduction of surface free energy of the hydrophobic alkane surface exposed to the solution. However, the formation of the hybrid layer has to overcome significant energy barriers in rupturing the vesicle and "unzipping" the membrane leaflets; hence drivers of the spontaneous hybrid membrane formation are unclear. In this work, the authors studied the efficiency of the liposome deposition method to form hybrid membranes on octanethiol and hexadecanethiol SAMs in aqueous environment. Using quartz crystal microbalance to monitor the deposition process it was found that the hybrid membrane did not form spontaneously; the deposit was dominated by hemi-fused liposomes that can only be removed by applying osmotic stress. However, osmotic stress yielded a reproducible layer characterized by ~-5Hz frequency change that is also confirmed by fluorescence microscopy imaging, irrespective of lipid concentration and the chain length of the SAMs. The frequency change is ~20% of the frequency change expected for a tightly bound bilayer membrane, or 40% of a single leaflet, suggesting that the lipid layer is in a different conformation compared to a bilayer membrane: the acyl chains are most likely parallel to the SAM surface, likely due to strong hydrophobic interaction. Comparing these results to the literature it appears that the initial formation of hybrid membranes is inhibited by the ionic environment, while osmotic stress leads to the observed unique layer conformation. PMID- 30007020 TI - Alcohol-induced respiratory symptoms improve after aspirin desensitization in patients with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic rhinosinusitis, nasal polyps, asthma, and respiratory sensitivity to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). In addition to sensitivity to aspirin and NSAIDs, the majority of patients with AERD have been reported to have respiratory intolerance associated with the consumption of alcohol. METHODS: A multicenter prospective cohort study was performed. Patients with AERD confirmed by aspirin challenge were eligible to participate. Those who described themselves as able to tolerate alcohol consumption were excluded. Patients underwent aspirin desensitization following endoscopic sinus surgery. A questionnaire was distributed to patients before and after desensitization to determine pre-desensitization and post-desensitization symptoms associated with alcohol ingestion. RESULTS: Forty-five patients were enrolled and 37 patients completed the study. The most common pre-desensitization symptoms were nasal congestion (95.6%), rhinorrhea (46.7%), and wheezing (40%). Improvement in the ability to tolerate alcohol was noted in 86.5% of participants (95% confidence interval [CI], 75.5% to 97.5%) and 70.3% of participants (95% CI, 55.5% to 85.0%) described desensitization to be "very helpful" or "extremely helpful" for their ability to tolerate alcohol. CONCLUSION: The majority of patients with AERD who experience respiratory symptoms with alcohol consumption describe improvement in this domain following aspirin desensitization. PMID- 30007021 TI - What Should Physicians and Chaplains Do When a Patient Believes God Wants Him to Suffer? AB - When physicians encounter a patient who gives religious reasons for wanting to suffer, physicians should maintain their commitment to the patient's health while making room for religiously informed understandings of suffering and respecting the patient's authority to refuse medically indicated interventions. Respecting the patient can include challenging the patient's reasoning, and physicians can decline to participate in interventions that they believe contradict their professional commitments. Chaplains likewise should both support and possibly respectfully challenge a patient in instances that involve desire to suffer for religious reasons, and physicians should draw on chaplains' expertise in these situations to attend to the patient's spiritual concerns. Finally, conversations involving spiritual and existential suffering might include members of the patient's religious community when the patient is open to this option. PMID- 30007022 TI - How Should Clinicians Respond to Requests from Patients to Participate in Prayer? AB - Over the past 20 years, physicians have shifted from viewing a patient's request for prayer as a violation of professional boundaries to a question deserving nuanced understanding of the patient's needs and the clinician's boundaries. In this case, Mrs. C's request for prayer can reflect religious distress, anxiety about her clinical circumstances, or a desire to better connect with her physician. These different needs suggest that it is important to understand the request before responding. To do this well requires that Dr. Q not be emotionally overwhelmed by the request and that she has skill in discerning potential reasons for the request. PMID- 30007023 TI - Should Clinicians Challenge Faith-Based Institutional Values Conflicting with Their Own? AB - Catholic health care organizations generally prohibit their employees from prescribing contraceptives for the purpose of birth control. This restriction might go against a clinician's own beliefs and the explicit wishes of a patient. In this case, Dr. N is being asked by a patient, Ms. K, to code oral contraception as treatment for acne, a noncontraceptive benefit of birth control pills, although both parties know Ms. K's primary desire is to prevent pregnancy. We examine the legal and moral arguments surrounding contraceptive provision in this case and offer guidance for how Dr. N and Ms. K might work to find a tenable solution. PMID- 30007024 TI - Fostering Discussion When Teaching Abortion and Other Morally and Spiritually Charged Topics. AB - Best practices for teaching morally and spiritually charged topics, such as abortion, to those early in their medical training are elusive at best, especially in our current political climate. Here we advocate that our duty as educators requires that we explore these topics in a supportive environment. In particular, we must model respectful discourse for our learners in these difficult areas. PMID- 30007025 TI - Best Practices for Partnering with Ethnic Minority-Serving Religious Organizations on Health Promotion and Prevention. AB - Faith-based organizations (FBOs) serve as effective sites for community-based health promotion, but there is a lack of research on this work in ethnic minority serving religious institutions such as mosques, temples, and gurdwaras. This article will share best practices, challenges, and special considerations in engaging these sites through two projects: Racial and Ethnic Approaches to Community Health for Asian Americans (REACH FAR) and Muslim Americans Reaching for Health and Building Alliances (MARHABA). We also discuss the Consolidated Framework for Implementation Research and how we used this framework in the two projects to facilitate implementation of health promotion initiatives within ethnic minority-serving religious institutions. To successfully implement such initiatives within these sites, efforts should leverage trusted internal and external relationships through iterative engagement, include adaptable interventions, and address sustainability from the outset. PMID- 30007026 TI - Training Physicians as Healers. AB - Spirituality is increasingly recognized as an essential element of patient care and health. It is often during illness that patients experience deep spiritual and existential suffering. With clinicians' care and compassion, patients are able to find solace and healing through their spiritual beliefs and values. This article chronicles a history of spirituality and health education, including the development of consensus-based clinical guidelines and competencies in health professions education that have influenced the curricular development. PMID- 30007027 TI - Balance of Principles. AB - Each work in this collection explores, from patients' or their loved ones' points of view, balance between patients' experiences and one or more of 4 well-known principles of ethics in health care. PMID- 30007028 TI - Healing Body and Spirit. AB - This drawing considers how achieving balance between allopathic, Western medical practices and spiritual practices can be critical for clinicians hoping to offer compassionate health care. Ethical and clinical challenges of consistently offering compassionate care to patients from all backgrounds requires cultivating and practicing spiritual awareness while maintaining professional boundaries. PMID- 30007030 TI - Special Issue: Annual Education Issue Writing a Review Article for Publication as Part of a Graduate Engineering Course. PMID- 30007029 TI - Chaplains' Roles as Mediators in Critical Clinical Decisions. AB - Chaplains provide spiritual care and support to patients, families, and hospital staff. What may be less familiar is that chaplains also help mediate decisions among patients, family members, and clinical teams. How clinicians, patients, and families formulate and articulate their goals and concerns can be informed either directly or indirectly by religious values. Finding common ground and common language can be helpful for both the medical team and the family. Physicians can use their clinical and social authority to try to ameliorate distress and offer recommendations based on patients' and families' goals and values; conversely, physicians' hesitancy to use their authority in these ways can generate moral distress among patients, families, and caregivers. However, when the medical team engages in conversation with a willingness to be informed by patients' religious worldview, more effective decision making may ensue. PMID- 30007031 TI - Parenting Stress and Maternal Coherence: Mothers With Deaf or Hard-of-Hearing Children. AB - Purpose: The aim of this study was to develop a substantive theory that explains parenting stress among mothers of deaf or hard-of-hearing (D/HH) children. Method: Fifteen hearing mothers of children with severe-to-profound sensorineural hearing loss were interviewed. Interviews were transcribed verbatim, and a grounded theory approach was used to inductively analyze parental stress in mothers of D/HH children. Theory generation was achieved through triangulation of data sources and systematic organization of data into codes. The coding process identified salient themes that were constantly cross-checked and compared across data to further develop categories, properties, and tentative hypotheses. Results: In general, two main themes emerged from the interviews: the contextual stressors and stress-reducing resources. The contextual stressors were labeled as distress over audiology-related needs, pressure to acquire new knowledge and skills, apprehension about the child's future, and demoralizing negative social attitudes. The stress-reducing resources that moderated parenting stress were identified to be the child's progress, mother's characteristics, professional support, and social support. The interaction between the identified stressors and adjustment process uncovered a central theme termed maternal coherence. Conclusion: The substantive theory suggests that mothers of D/HH children can effectively manage parenting stress and increase well-being by capitalizing on relevant stress-reducing resources to achieve maternal coherence. PMID- 30007032 TI - Integrating Treatment at the Intersection of Opioid Use Disorder and Infectious Disease Epidemics in Medical Settings: A Call for Action After a National Academies of Sciences, Engineering, and Medicine Workshop. PMID- 30007034 TI - Response to: "The Role of Quantitative Systems Pharmacology in the Design of First-in-Human Trials". PMID- 30007035 TI - Contribution of local rarity and climatic suitability to local extinction and colonization varies with species traits. AB - Changes in species distributions through local extinction and colonization events are a major consequence of climate change. The mechanisms underlying these processes, however, are yet to be fully understood. We investigate the effects of climatic suitability and local rarity on local extinction and colonization of British birds. We test the hypothesis that local extinction and colonization on decadal scales are driven by both climatic suitability and the prevalence of the species within an area and that the balance between these two is affected by species traits. We use spatially explicit conditional autoregressive models to determine the effect size of local rarity and climatic suitability (extracted from climate envelope models) on local extinction and colonization events. We then use phylogenetically constrained, generalized least-square models to estimate the association of extinction and colonization predictors with body mass, clutch size and national range of each species. Both local rarity and climatic suitability of an area contributed to local extinctions and colonizations, but the importance of these predictors varied between species. This interspecific variation was explained, in part, by species traits, in particular national range, which influenced the importance of local rarity and climatic suitability to both local extinction and colonization. These results further our knowledge of the mechanisms underlying changes in species occupancy due to climate change. This can inform predictive models as well as contribute to more focussed avian conservation efforts. PMID- 30007037 TI - Refined structure of BeM9 reveals arginine hand, an overlooked structural motif in scorpion toxins affecting sodium channels. AB - Sodium channel alpha-toxins from scorpion venom (alpha-NaTx) inhibit the inactivation of voltage-gated sodium channels. We used solution NMR to investigate the structure of BeM9 toxin from Mesobuthus eupeus scorpion, a prototype alpha-NaTx classified as an "alpha-like" toxin due to its wide spectrum of activity on insect and mammalian channels. We identified a new motif that we named "arginine hand," whereby arginine side chain forms several hydrogen bonds with main chain atoms. The arginine hand was found in the "specificity module," a part of the molecule that dictates toxin selectivity; and just single arginine-to lysine point mutation drastically changed BeM9 selectivity profile. PMID- 30007036 TI - Calprotectin protects against experimental colonic inflammation in mice. AB - BACKGROUND AND PURPOSE: Calprotectin is a heterodimer composed of two myeloid related proteins, S100A8 and S100A9, that is abundant in neutrophils and monocytes/macrophages. Faecal levels of calprotectin are used routinely to monitor inflammatory bowel disease activity. EXPERIMENTAL APPROACH: We aimed to assess the role of calprotectin in intestinal inflammation, using the dextran sulfate sodium model of colitis in mice. Calprotectin was administered (50 or 100 MUg.day-1 ) by the intrarectal or by i.p. injection (50 MUg.day-1 only). The condition of the mice was characterized by morphological and biochemical methods. KEY RESULTS: Intrarectal calprotectin protected significantly against colitis, as shown by lower levels of macroscopic and microscopic damage, colonic myeloperoxidase activity and decreased expression of TNFalpha and toll-like receptor 4. IL-17 production by spleen and mesenteric lymph node cells was reduced. Calprotectin had no effect on body weight loss or colonic thickening. There were no effects of calprotectin after i.p. injection. Calprotectin had virtually no effects in control, non-colitic mice. Calprotectin had almost no effect on the colonic microbiota but enhanced barrier function. Treatment of rat IEC18 intestinal epithelial cells in vitro with calprotectin induced output of the chemokines CXL1 and CCL2, involving the receptor for advanced glycation end products- and NFkappaB. CONCLUSION AND IMPLICATIONS: Calprotectin exerted protective effects in experimental colitis when given by the intrarectal route, by actions that appear to involve effects on the epithelium. PMID- 30007038 TI - Prognostic value of histone H3 serine 10 phosphorylation and histone H4 lysine 12 acetylation in oral squamous cell carcinoma. AB - AIMS: Studies on epigenetics in oral squamous cell carcinoma (OSCC) are rare. Histone modifications comprise epigenetic mechanisms that perform a key role in gene transcription and may regulate tumour development. Thus, the aim of this study was to determine whether two post-translational histone modifications, i.e. phosphorylation of serine 10 in histone H3 and acetylation of lysine 12 in histone H4, have prognostic value for OSCC patients. METHODS AND RESULTS: Paraffin-embedded tissue samples of 90 patients diagnosed with OSCC were obtained and subjected to immunohistochemical staining with antibodies against histone H3 with phosphorylation of serine 10 (H3S10ph) and histone H4 with acetylation of lysine 12 (H4K12ac). The associations of H3S10ph and H4K12ac expression levels with clinicopathological factors were determined. Five-year survival analysis and univariate and multivariate analyses were also performed. Both H3S10ph and H4K12ac were expressed in the nuclei of tumour cells. A low median of H3S10ph expression was significantly associated with cervical lymph node metastasis. Tumours with high H4K12ac expression were significantly associated with gender, alcohol consumption, and cervical lymph node metastasis. H4K12ac was also shown to have independent prognostic value in the multivariate analysis. Tumours with high H3S10ph expression, size >40 mm, an advanced stage and the presence of cervical lymph node metastases were associated with a better 5-year survival rate. Tumours with low H4K12ac expression, size >40 mm, an advanced stage and cervical lymph node metastasis were associated with a better 5-year survival rate. CONCLUSIONS: These findings suggest that H3S10ph, and mainly H4K12ac, may play a role in OSCC progression and the occurrence of cervical lymph node metastasis. Also, the expression level of H4K12ac could be an independent prognostic factor for OSCC patients. PMID- 30007039 TI - Clinico-radiographic evaluation of 1% Alendronate gel as an adjunct and smart blood derivative platelet rich fibrin in grade II furcation defects. AB - BACKGROUND: The treatment of molar furcation involvement is unpredictable due to the complex anatomy and poor access for instrumentation. Previous studies have reported successful regeneration with endogenous regenerative material such as platelet rich fibrin (PRF) and bisphosphonates as alendronate (ALN). Hence, the present study was aimed to evaluate clinically and radiographically the efficacy of 1% ALN gel in combination with PRF (PRF+ALN) and PRF alone in the treatment of grade II furcation defects. METHODS: A split mouth study with 40 bilateral furcation defects was randomly divided into PRF group and PRF+ALN group. Bone defect volume was the primary outcome evaluated at the end of 6 months with CBCT while the secondary outcomes being changes in clinical parameters including Probing pocket depth (PPD), Clinical attachment level (CAL) and Horizontal probing depth (HPD) recorded at baseline, 3 and 6 months. RESULTS: The mean reduction in PPD, CAL and HPD was 1.85 +/- 0.59 mm, 1.9 +/- 0.64 mm and 1.7 +/- 0.73 mm respectively for PRF group and 2.85 +/- 0.88 mm, 3.05 +/- 0.98 mm and 2.3 +/- 0.73 mm respectively for PRF+ ALN group (p < 0.05). At the end of 6 months, mean reduction in bone defect volume for PRF and PRF+ ALN group was 8.65 +/- 3.84 mm3 and 11.98 +/- 4.13 mm3 respectively. CONCLUSION: PRF+ ALN treated defects exhibited better clinical and radiographic outcomes suggestive of enhanced periodontal regeneration when compared to PRF alone treated sites. PMID- 30007040 TI - Analytical Method for Pesticides in Avocado and Papaya by Means of Ultra-High Performance Liquid Chromatography Coupled to a Triple Quadrupole Mass Detector: Validation and Uncertainty Assessment. AB - : In this work, the uncertainty estimation for the determination of ametryn, carbofuran, atrazine, carbaryl, and methyl parathion in papaya and avocado is presented, along with other validation parameters. The analytical method was developed using Quick, Easy, Cheap, Effective, Rugged, and Safe extraction and ultrahigh performance liquid chromatography coupled to a triple quadrupole mass detector. The method validation showed that the linear correlation coefficients were higher than 0.99 for both fruits. The limits of detection for avocado and papaya were in the range of 0.022 to 0.46 and 0.003 to 0.109 MUg/g, respectively. Intermediate precision varied from 5.3% to 13.0% in papaya, and from 4.8% to 20.2% in avocado. Recoveries obtained for each pesticide in both matrices ranged between 61.3% and 119.0%. Matrix effect was calculated for all compounds in both fruits. Finally, the overall uncertainty was lower than 36% for both fruits. PRACTICAL APPLICATION: The present analytical method could be used for pesticides determination in different kind of fruits as papaya and avocado and as a practical guide for uncertainty and matrix effect determination. PMID- 30007042 TI - Nano-evidence for joint microbleeds in hemophilia patients. AB - The concept of joint microbleeding in hemophilia patients was first proposed over 10 years ago. This was based on unexpected abnormalities found in medical imaging studies of asymptomatic joints. Since then, there have been no published studies confirming the presence of joint microbleeds. This critique will review the evidence for and against joint microbleeding in hemophilia patients and the potential implications. PMID- 30007043 TI - Inter-laboratory test for oxygen and hydrogen stable isotope analyses of geothermal fluids: Assessment of reservoir fluid compositions. AB - RATIONALE: Knowledge of the accuracy and precision for oxygen (delta18 O values) and hydrogen (delta2 H values) stable isotope analyses of geothermal fluid samples is important to understand geothermal reservoir processes, such as partial boiling-condensation and encroachment of cold and reinjected waters. The challenging aspects of the analytical techniques for this specific matrix include memory effects and higher scatter of delta values with increasing total dissolved solids (TDS) concentrations, deterioration of Pt-catalysts by dissolved/gaseous H2 S for hydrogen isotope equilibration measurements and isotope salt effects that offset isotope ratios determined by gas equilibration techniques. METHODS: An inter-laboratory comparison exercise for the determination of the delta18 O and delta2 H values of nine geothermal fluid samples was conducted among eleven laboratories from eight countries (CeMIEGeo2017). The delta values were measured by dual inlet isotope ratio mass spectrometry (DI-IRMS), continuous flow IRMS (CF IRMS) and/or laser absorption spectroscopy (LAS). Moreover, five of these laboratories analyzed an additional sample set at least one month after the analysis period of the first set. Statistical evaluation of all the results was performed to obtain the expected isotope ratios of each sample, which were then subsequently used in deep reservoir fluid composition calculations. RESULTS: The overall analytical precisions of the measurements were +/- 0.20/00 for delta18 O values and +/- 2.00/00 for delta2 H values within the 95% confidence interval. CONCLUSIONS: The measured and calculated delta18 O and delta2 H values of water sampled at the weir box, separator and wellhead of geothermal wells suggest the existence of hydrogen and oxygen isotope-exchange equilibrium between the liquid and vapor phases at all sampling points in the well. Thus, both procedures for calculating the isotopic compositions of the deep geothermal reservoir fluid - using either the analytical data of the liquid phase at the weir box together with those of vapor at the separator or the analytical data of liquid and vapor phases at the separator -are equally valid. PMID- 30007041 TI - Development of a standardized chart review method to identify drug-related hospital admissions in older people. AB - AIMS: We aimed to develop a standardized chart review method to identify drug related hospital admissions (DRA) in older people caused by non-preventable adverse drug reactions and preventable medication errors including overuse, underuse and misuse of medications: the DRA adjudication guide. METHODS: The DRA adjudication guide was developed based on design and test iterations with international and multidisciplinary input in four subsequent steps: literature review; evaluation of content validity using a Delphi consensus technique; a pilot test; and a reliability study. RESULTS: The DRA adjudication guide provides definitions, examples and step-by-step instructions to measure DRA. A three-step standardized chart review method was elaborated including: (i) data abstraction; (ii) explicit screening with a newly developed trigger tool for DRA in older people; and (iii) consensus adjudication for causality by a pharmacist and a physician using the World Health Organization-Uppsala Monitoring Centre and Hallas criteria. A 15-member international Delphi panel reached consensus agreement on 26 triggers for DRA in older people. The DRA adjudication guide showed good feasibility of use and achieved moderate inter-rater reliability for the evaluation of 16 cases by four European adjudication pairs (71% agreement, kappa = 0.41). Disagreements arose mainly for cases with potential underuse. CONCLUSIONS: The DRA adjudication guide is the first standardized chart review method to identify DRA in older persons. Content validity, feasibility of use and inter-rater reliability were found to be satisfactory. The method can be used as an outcome measure for interventions targeted at improving quality and safety of medication use in older people. PMID- 30007044 TI - Conditional survival of patients with small renal masses undergoing active surveillance. AB - OBJECTIVES: To determine conditional survival for patients with small renal masses (SRMs) undergoing active surveillance (AS). MATERIALS AND METHODS: Patients were enrolled in a prospective AS protocol at our institution between May 2005 and January 2016. Patients with SRMs <=4 cm with serial cross-sectional imaging available in-house for review were included. Overall survival (OS) was estimated using the Kaplan-Meier method and modelled via Cox proportional hazards models. The primary endpoints analysed were the conditional probability of survival and tumour growth over time. Landmark analysis was used to evaluate survival outcomes beyond the 2-year mark after the initial scan. The relative conditional survival of patients on AS was compared to those undergoing partial nephrectomy (PN) using inverse probability of treatment weighting. RESULTS: A total of 272 patients were included in this analysis. The mean initial SRM size was 1.74 +/- 0.77 cm, and the mean mass size closest to the 2-year mark was 1.97 +/- 0.83 cm. The likelihood of continued survival to 5 years improved after the 2 year landmark. Patients with masses <3 cm who survived the first 2 years on AS had a 0.84-0.85 chance of surviving to 5 years, and if they survived 3 years, the probability of surviving to 5 years improved to 0.91. A slow tumour growth (beta: 0.12; P < 0.001) with parallel growth rates was found for tumours <3 cm. Patients on AS and those who underwent PN had similar OS for ~7 years, beyond which PN demonstrated a trend of lower risk of death compared with AS (hazard ratio 0.57; P = 0.07). CONCLUSIONS: The conditional survival probability of patients with SRMs <3 cm on AS increased after 2 years. This information may prove useful to urologists and patients who are considering continuing AS vs intervention after the first 2 years on AS. PMID- 30007045 TI - Covalent Whey Protein-Rosmarinic Acid Interactions: A Comparison of Alkaline and Enzymatic Modifications on Physicochemical, Antioxidative, and Antibacterial Properties. AB - The covalent interactions between whey protein isolate (WPI) and rosmarinic acid (RosA) at two different conditions, alkaline (pH 9) and enzymatic (in the presence of tyrosinase, PPO), at room temperature with free atmospheric air were studied. The conjugates formed between WPI and RosA were characterized in terms of their physicochemical and functional properties. The changes in protein structure were analyzed by intrinsic fluorescence and binding of 8-anilino-1 naphthalenesulfonic acid. The findings show that the covalent interactions caused a decrease in free amino and thiol groups and tryptophan content at both conditions. The decrease at enzymatic conditions was lower than at alkaline conditions. In addition, modified WPI at alkaline conditions exhibited higher antioxidative capacity compared to the modification at enzymatic conditions. However, WPI modified at enzymatic condition showed mild antimicrobial activity against Staphylococcus aureus LMG 10147 and MU50 compared to WPI modified at alkaline conditions and unmodified WPI (control). The modified WPI can be used as multifunctional ingredient into various food products with an additional health promoting effect of the bound phenolic compounds. PMID- 30007047 TI - Handgrip strength and the number of teeth among Korean population. AB - BACKGROUND: Handgrip strength is easily assessed by muscle strength and is an important factor for health and physical performance. Empirical evidence for the association between the number of teeth and handgrip strength remains controversial. The objective of this study was to investigate the association between the number of teeth and handgrip strength. METHODS: Data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2014 to 2015 were used (N = 7,741). The number of teeth was categorized into three groups: 0 to 9 teeth, 10 to 19 teeth, and 20 to 28 teeth. Handgrip strength of the participants was measured using a digital hand dynamometer. Multivariate linear regression and logistic regression models were fitted to assess the association between the number of teeth and hand grip strength after adjusting for sociodemographic factors, general health behaviors, and oral and general health factors. RESULTS: Reduced handgrip strength was much more frequent in male and female participants with a lower number of teeth. Each tooth increased handgrip strength by 0.12 kg and 0.07 kg in males and females, respectively (P < 0.001 for both males and females). The association between the number of teeth and handgrip strength disappeared in females in the fully adjusted models, but the odds ratio of participants with 0 to 9 teeth was 1.73 (95% confidence interval: 1.02 to 2.95), which was higher than the reference group in males. CONCLUSION: Our results showed a significant association between the number of teeth and handgrip strength in Korean adults. PMID- 30007046 TI - Target-specific forebrain projections and appropriate synaptic inputs of hESC derived dopamine neurons grafted to the midbrain of parkinsonian rats. AB - Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson's disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non-human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC-derived progenitors were grafted into the midbrain of 6-hydroxydopamine-lesioned rats, and analyzed at 6, 18, and 24 weeks for a time-course evaluation of specificity and extent of graft-derived fiber outgrowth as well as potential for functional recovery. To investigate synaptic integration of the transplanted cells, we used rabies-based monosynaptic tracing to reveal the origin and extent of host presynaptic inputs to grafts at 6 weeks. The results reveal the capacity of grafted neurons to extend axonal projections toward appropriate forebrain target structures progressively over 24 weeks. The timing and extent of graft-derived dopaminergic fibers innervating the dorsolateral striatum matched reduction in amphetamine-induced rotational asymmetry in the animals where recovery could be observed. Monosynaptic tracing demonstrated that grafted cells integrate with host circuitry 6 weeks after transplantation, in a manner that is comparable with endogenous midbrain connectivity. Thus, we demonstrate that VM patterned hESC-derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESC-derived DA neurons to the midbrain. PMID- 30007048 TI - Assessment of whole blood coagulation with a microfluidic dielectric sensor. AB - : Essentials ClotChip is a novel microsensor for comprehensive assessment of ex vivo hemostasis. Clinical samples show high sensitivity to detecting the entire hemostatic process. ClotChip readout exhibits distinct information on coagulation factor and platelet abnormalities. ClotChip has potential as a point-of-care platform for comprehensive hemostatic analysis. SUMMARY: Background Rapid point of-care (POC) assessment of hemostasis is clinically important in patients with a variety of coagulation factor and platelet defects who have bleeding disorders. Objective To evaluate a novel dielectric microsensor, termed ClotChip, which is based on the electrical technique of dielectric spectroscopy for rapid, comprehensive assessment of whole blood coagulation. Methods The ClotChip is a three-dimensional, parallel-plate, capacitive sensor integrated into a single-use microfluidic channel with miniscule sample volume (< 10 MUL). The ClotChip readout is defined as the temporal variation in the real part of dielectric permittivity of whole blood at 1 MHz. Results The ClotChip readout exhibits two distinct parameters, namely, the time to reach a permittivity peak (Tpeak ) and the maximum change in permittivity after the peak (Deltaepsilonr,max ), which are, respectively, sensitive towards detecting non-cellular (i.e. coagulation factor) and cellular (i.e. platelet) abnormalities in the hemostatic process. We evaluated the performance of ClotChip using clinical blood samples from 15 healthy volunteers and 12 patients suffering from coagulation defects. The ClotChip Tpeak parameter exhibited superior sensitivity at distinguishing coagulation disorders as compared with conventional screening coagulation tests. Moreover, the ClotChip Deltaepsilonr,max parameter detected platelet function inhibition induced by aspirin and exhibited strong positive correlation with light transmission aggregometry. Conclusions This study demonstrates that ClotChip assesses multiple aspects of the hemostatic process in whole blood on a single disposable cartridge, highlighting its potential as a POC platform for rapid, comprehensive hemostatic analysis. PMID- 30007049 TI - Factor XI promotes hemostasis in factor IX-deficient mice. AB - : Essentials Mice lacking factor IX (FIX) or factor XI (FXI) were tested in a saphenous vein bleeding model. FIX-deficient mice displayed a hemostatic defect and FXI-deficient mice were similar to wild type mice. Infusion of FXI or over expression of FXI in FIX-deficient mice improved hemostasis. FXI may affect the phenotype of FIX-deficiency (hemophilia B). SUMMARY: Background In humans, deficiency of coagulation factor XI may be associated with a bleeding disorder, but, until recently, FXI-deficient mice did not appear to have a hemostatic abnormality. A recent study, however, indicated that FXI-deficient mice show a moderate hemostatic defect in a saphenous vein bleeding (SVB) model. Objectives To study the effect of FXI on bleeding in mice with normal levels of the FXI substrate FIX and in mice lacking FIX (a murine model of hemophilia B). Methods Wild-type mice and mice lacking either FIX (F9- ) or FXI (F11-/- ) were tested in the SVB model. The plasma levels of FXI in F11-/- mice were manipulated by infusion of FXI or its active form FXIa, or by overexpressing FXI by the use of hydrodynamic tail vein injection. Results F9- mice showed a significant defect in the SVB model, whereas F11-/- mice and wild-type mice were indistinguishable. Intravenous infusion of FXI or FXIa into, or overexpression of FXI in, F9- mice improved hemostasis in the SVB model. Overexpression of a FXI variant lacking a FIX-binding site also improved hemostasis in F9- mice. Conclusions Although we were unable to demonstrate a hemostatic defect in F11-/- mice in the SVB model, our results support the premise that supraphysiological levels of FXI improve hemostasis in F9- mice through FIX-independent pathways. PMID- 30007051 TI - Clinical insights about the evolution of root coverage procedures: The flap, the graft, and the surgery. PMID- 30007050 TI - Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect. AB - Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p.(Ala367Val)], an individual with AVSD and heterotaxy [p.(Val210Met)], and a subject with AVSD, heterotaxy, and oculo-auriculo-vertebral spectrum (OAVS) [p.(Ala696Thr)], respectively. The latter was also heterozygous for a missense change in TBX1 [p.(Pro86Leu)]. Targeted resequencing of genes associated with AVSD, heterotaxy, or OAVS excluded additional hits in the three mutation-positive subjects. Functional characterization of NFATC1 mutants documented defective nuclear translocation and decreased transcriptional transactivation activity. When expressed in zebrafish, the three NFATC1 mutants caused cardiac looping defects and altered atrioventricular canal patterning, providing evidence of their functional relevance in vivo. Our findings support a role of defective NFATC1 function in the etiology of isolated and heterotaxy-related AVSD. PMID- 30007052 TI - Establishment and application of a new HPLC qualitative and quantitative assay for Gentiana Macrophyllae Radix based on characteristic constituents of anofinic acid and its derivatives. AB - Gentiana Macrophylla Radix (GMR) is officially used as traditional Chinese medicine, but easily confused with Gentianae Radix et Rhizoma (GRR) and adulterants. This study aimed to establish an HPLC method for qualitative and quantitative analysis of GMR based on characteristic components, anofinic acid and its derivatives. HPLC analysis was performed on a C18 column with gradient elution using acetonitrile and 0.1% phosphoric acid as mobile phase, and detected at 240 nm by conventional methodology validation. For fingerprint analysis, RSDs of relative retention times and relative peak areas of the characteristic peaks were within 0-1.10 and 0-4.08%, respectively. For determination of 2 methoxyanofinic acid, the calibration curve showed good linearity (R2 > 0.9999) within the test range. The RSDs of precision, repeatability and stability test did not exceed 2.46, 0.83 and 1.11%, respectively. The average recoveries were between 95.08 and 103.05% with RSDs <=2.29%. The results showed that there was no significant difference among the four species of GMR, but there were significant differences among GMR, GRR and spurious breeds by principal component analysis and hierarchical cluster analysis. Anofinic acid and its derivatives, as the characteristic markers, could be used for the identification and quality control of GMR. PMID- 30007053 TI - Binding and structural studies of the complexes of type 1 ribosome inactivating protein from Momordica balsamina with uracil and uridine. AB - Ribosome inactivating protein (RIP) catalyzes the cleavage of glycosidic bond formed between adenine and ribose sugar of ribosomal RNA to inactivate ribosomes. Previous structural studies have shown that RNA bases, adenine, guanine, and cytosine tend to bind to RIP in the substrate binding site. However, the mode of binding of uracil with RIP was not yet known. Here, we report crystal structures of two complexes of type 1 RIP from Momordica balsamina (MbRIP1) with base, uracil and nucleoside, uridine. The binding studies of MbRIP1 with uracil and uridine as estimated using fluorescence spectroscopy showed that the equilibrium dissociation constants (KD ) were 1.2 * 10-6 M and 1.4 * 10-7 M respectively. The corresponding values obtained using surface plasmon resonance (SPR) were found to be 1.4 * 10-6 M and 1.1 * 10-7 M, respectively. Structures of the complexes of MbRIP1 with uracil (Structure-1) and uridine (Structure-2) were determined at 1.70 and 1.98 A resolutions respectively. Structure-1 showed that uracil bound to MbRIP1 at the substrate binding site but its mode of binding was significantly different from those of adenine, guanine and cytosine. However, the mode of binding of uridine was found to be similar to those of cytidine. As a result of binding of uracil to MbRIP1 at the substrate binding site, three water molecules were expelled while eight water molecules were expelled when uridine bound to MbRIP1. PMID- 30007054 TI - Oral flurbiprofen spray for mucosal graft harvesting at the palatal area: A randomized placebo-controlled study. AB - BACKGROUND: Flurbiprofen which is a non-steroidal anti-inflammatory drug (NSAID), has been safely used for the control of postoperative patient's morbidity after periodontal plastic surgeries requiring palatal graft harvesting, but there is little information on the efficacy of topical use. The aim of the study was to evaluate whether patient pain perception was reduced and patient morbidity was improved by using oral spray of flurbiprofen after palatal graft harvesting. METHODS: Forty-eight patients (21 males and 27 females), scheduled for subepithelial connective tissue graft (SCTG) and free gingival graft (FGG) requiring periodontal plastic surgeries were selected. The patients were randomly assigned to each group and used oral spray of flurbiprofen or placebo three times a day for a week. The palatal donor area was evaluated at 1, 3, 7, 14, 21, 28, 42, and 56-day follow-up after the surgery for postoperative pain, patients' discomfort, complete epithelialization, changes in dietary habits, burning sensation, color match, the amount of systemic analgesic consumption and the presence of delayed bleeding. Wound healing scores were recorded at 14-day follow up. RESULTS: The prevalance of complete epithelialization was significantly higher in the placebo-FGG group than flurbiprofen-FGG group at 21 days postoperatively (P < 0.05), while there was no significant alteration for both flurbiprofen-SCTG and placebo-SCTG groups at any follow-up periods. In flurbiprofen-FGG group, significant improvements were observed for postoperative pain, patients' discomfort and burning sensation at 14 days postoperatively (P < 0.05). CONCLUSION: Oral flurbiprofen spray reduces patient's morbidity, however it might have negative effects on epithelialization of secondary wound healing after FGG operations. PMID- 30007055 TI - Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressing alpha-ketoglutarate production in mice. AB - Reprograming of metabolic pathways is critical in governing the polarization of macrophages into classical proinflammatory M1 or alternative anti-inflammatory M2 phenotypes in metabolic diseases, such as diabetes. Porphyromonas gingivalis, a keystone pathogen of periodontitis, causes an imbalance in M1/M2 activation, resulting in a hyperinflammatory environment that promotes the pathogenesis of periodontitis. However, whether P. gingivalis infection modulates metabolic pathways to alter macrophage polarization remains unclear. Bone-marrow-derived macrophages (BMDMs) were collected from 6-week-old female C57BL/6 mice and stimulated with P. gingivalis, P. gingivalis-derived LPS or IL-4. Relative gene expression and protein production were measured by quantitative real-time PCR, RNA sequencing and western blotting. Colorimetric assays were also performed to assess the amounts of alpha-ketoglutarate (alpha-KG) and succinate. P. gingivalis or P. gingivalis-derived LPS-induced inflammatory responses enhanced M1 macrophages and suppressed M2 macrophages, even in the presence of IL-4. P. gingivalis inhibited Idh1/2 and Gpt1/2 mRNA expression, and increased Akgdh mRNA expression, thus decreasing the ratio of alpha-KG/succinate. Supplementation of cell-permeable dimethyl-alpha-KG dramatically restored M2 activation during P. gingivalis infection. Our study suggests that P. gingivalis maintains a hyperinflammatory state by suppressing the production of alpha-KG by M2 macrophages. PMID- 30007056 TI - Mind the overlap: how system problems contribute to cognitive failure and diagnostic errors. PMID- 30007057 TI - The effects of oral pregabalin on post-Lichtenstein herniorrhaphic pain: a randomized clinical trial. AB - Background Pregabalin is a gamma-aminobutyric acid analog which seems to be effective in different neuropathic pains, as well as in incisional and inflammatory injuries. This study evaluated the effectiveness and safety of pregabalin on pain relief post herniorrhaphy. Methods In this randomized clinical trial, 60 men were chosen for unilateral inguinal herniorrhaphy under spinal anesthesia. The participants were randomly divided into two groups. The investigation (pregabalin) group received 300 mg of oral pregabalin 2 h before and 150 mg of pregabalin 12 and 24 h after surgery in addition to routine postoperative medication and 1 mg/kg of pethidine as needed. The control (placebo) group received placebo capsules similar to the investigation group, as well as routine medication and 1 mg/kg of pethidine as needed. All surgeries were done with the same technique. Post-surgery pain was evaluated in the walking and lying positions with a visual analog scale at 12 and 24 h and at 3 and 7 days after the surgery. Pethidine consumption and adverse effects of pregabalin were also assessed. Results The investigation group had less pain and lower visual analog scale scores at 12 and 24 h and also at 3 days after surgery and consumed less pethidine compared to the control group (p<0.05). Conclusions Pregabalin reduces pain and opioid consumption in the first 3 days after surgery. The adverse effects of pregabalin are limited to the first 12 h after surgery. Pregabalin can be suggested for pain relief, but it should be used with caution in the elderly. PMID- 30007058 TI - Influence of age and gender on blood pressure variability and baroreflex sensitivity in a healthy population in the Indian sub-continent. AB - Background The current exploratory study was aimed at estimating measures of blood pressure variability (BPV) and baroreflex sensitivity (BRS) in a healthy population in the Indian sub-continent. Methods One hundred and forty-two healthy subjects were recruited for the study. Blood pressure (BP) was recorded continuously for 15 min using the Finometer (Finapres Medical Systems, The Netherlands). For offline analysis, Nevrokard cardiovascular parameter analysis (CVPA) software (version 2.1.0) was used for BPV analysis. BRS was determined by spectral and sequence methods. One-way ANOVA and Bonferroni's test were used to compare parameters. Pearson's correlation coefficient was employed to look for possible associations between age and other continuous variables. Results Out of 196 screened volunteers, 54 were excluded and 142 subjects were grouped based on ages as 10-19 years (group 1), 20-29 years (group 2), 30-39 years (group 3), 40 49 years (group 4), and 50-59 years (group 5). Within groups, body mass index (BMI, p=0.000) and BP (systolic and diastolic) were significantly different. Post hoc analysis showed mean blood pressure (MBP) and diastolic blood pressure (DBP) differing significantly between groups 1 and 4 (p<0.05 for both) along with other cardiovascular parameters. Age correlated positively with BMI and all parameters of BP. Significant gender differences were observed for stroke volume, cardiac output, up BRS, total BRS, peripheral resistance (PR), and aortic impedance. Conclusions Our study has provided reference values for BPV and BRS in an Indian population. It also indicates age-related neurocardiac imbalance and possible utility of these tests for screening at the start of neurocardiac damage in a healthy population. PMID- 30007059 TI - On the relation between the true and sample correlations under Bayesian modelling of gene expression datasets. PMID- 30007060 TI - Reduced endogenous pain inhibition in adolescent girls with chronic pain. AB - Background and aims Chronic pain is affecting a growing number of individuals including adolescents. Different endogenous pain inhibitory systems could confer protection against development of chronic pain. Decreased pain perception can be observed following intense pain (i.e. conditioned pain modulation - CPM) or after physical exercise (i.e. exercise-induced analgesia - EIA). Reduced effectiveness of pain inhibitory mechanisms have been reported in several chronic pain conditions. However, the extent of these dysfunctions has not been thoroughly investigated in adolescents suffering from chronic pain. Our hypothesis was that adolescents suffering from chronic pain have less effective CPM and EIA than pain free teenagers. Methods Twenty-five healthy adolescent girls and 16 teenage girls with chronic pain participated in this study. Only girls were included in this investigation, since chronic pain is more prevalent in females. The effectiveness of CPM was assessed by comparing heat pain stimulations (individually adapted to induce mild pain intensity) performed with a thermode before and after a cold pressor test (CPT; 2 min, 10 degrees C). EIA was evaluated by comparing pain intensity produced by an ice cube placed on the forearm before and after a graded exercise test on a cycle ergometer. Results Pain intensity produced by heat pain stimulations decreased following CPT in healthy (p<0.05), but not in chronic pain adolescent girls (p=0.4). Pain intensity induced by the ice cube was reduced after exercise in healthy (p<0.05), but not in chronic pain adolescents (p=0.9). The effectiveness of CPM and EIA was inferior in teenage girls suffering from chronic pain compared to healthy participants (p<0.05). Conclusions Endogenous pain inhibitory mechanisms triggered by intense pain or by physical exercise are effective in healthy adolescent girls. Teenage girls living with chronic pain do not show diminished pain perception after a CPT or a graded exercise test. These results suggest that pain inhibitory mechanisms such as CPM and EIA are ineffective in adolescent girls suffering from chronic pain. Implications In a wider context, the findings of the present research could help understand better the mechanisms involved in the development of chronic pain. Improved comprehension of this subject might help prevent chronic pain conditions and thus, reduce the negative impacts of this burden. PMID- 30007061 TI - Assessment of CPM reliability: quantification of the within-subject reliability of 10 different protocols. AB - Background and aims Conditioned Pain Modulation (CPM) is a well-established phenomenon and several protocols have shown acceptable between-subject reliability [based on intraclass correlation coefficient (ICC) values] in pain free controls. Recently, it was recommended that future CPM test-retest reliability studies should explicitly report CPM reliability based on CPM responders and non-responders (within-subject reliability) based on measurement error of the test stimulus. Identification of reliable CPM paradigms based on responders and non-responders may be a step towards using CPM as a mechanistic marker in diagnosis and individualized pain management regimes. The primary aim of this paper is to investigate the frequency of CPM responders/non-responders, and to quantify the agreements in the classification of responders/non-responders between 2 different days for 10 different CPM protocols. Methods Data from a previous study investigating reliability of CPM protocols in healthy subjects was used. In 26 healthy men, the test-stimuli used on both days were: Pain thresholds to electrical stimulation, heat stimulation, manual algometry, and computer controlled cuff algometry as well as pain tolerance to cuff algometry. Two different conditioning stimuli (CS; cold water immersion and a computer controlled tourniquet) were used in a randomized and counterbalanced order in both sessions. CPM responders were defined as a larger increase in the test stimulus response during the CS than the standard error of measurement (SEM) for the test-stimuli between repeated baseline tests without CS. Results Frequency of responders and non-responders showed large variations across protocols. Across the studied CPM protocols, a large proportion (from 11.5 to 73.1%) of subjects was classified as CPM non-responders when the test stimuli standard error of measurements (SEM) was considered as classifier. The combination of manual pressure algometry and cold water immersion induced a CPM effect in most participants on both days (n=16). However, agreement in the classification of CPM responders versus non-responders between days was only significant when assessed with computer-controlled pressure pain threshold as test-stimulus and tourniquet cuff as CS (kappa=0.36 [95% CI, 0.04-0.68], p=0.037). Conclusions and implications Agreements in classification of CPM responders/non-responders using SEM as classifier between days were generally poor suggesting considerable intra individual variation in CPM. The most reliable paradigm was computer-controlled pressure pain threshold as test-stimulus and tourniquet cuff as conditioning stimulus. However while this CPM protocol had the greatest degree of agreement of classification of CPM responders and non-responders across days, this protocol also failed to induce a CPM response in more than half of the sample. In contrast, the commonly used combination of manual pressure algometry and cold water immersion induced a CPM effect in most participants however it was inconsistent in doing so. Further exploration of the two paradigms and classification of responders and non-responders in a larger heterogeneous sample also including women would further inform the clinical usefulness of these CPM protocols. Future research in this area may be an important step towards using CPM as a mechanistic marker in diagnosis and in developing individualized pain management regimes. PMID- 30007062 TI - Laparoscopic repair of incisional hernia. Risk factors for the conversion. AB - INTRODUCTION: Some factors may affect the conversion to open of the laparoscopic treatment of incisional hernia. Their presence can help to choose the most appropriate technique identifying patients at high risk conversion. METHODS: A retrospective study has been performed on a cohort of 306 patients, selected among those undergone to elective laparoscopic surgery for post incisional hernia between 2005 and 2015. Only symptomatic patients with single site wall defect, diameter between 5 and 10 cm, ASA <=3, have been included. Patients were divided in 2 groups, Laparoscopic (L) and Converted (C) and preoperatory data were evaluated and statistically analyzed. RESULTS: The L group accounted for 228 patients and C group for 78 patients. The univariate analysis showed that risk factor for conversion included BMI >= 30, Smoking, Diabetes mellitus, Prior emergency surgery. Age > 60 years was associate with lower risk of conversion. CONCLUSIONS: The result of this retrospective study allows us to say that the choice of the technique, in the presence of multiple risk factors, should be carefully assessed and discussed with the patient. A prospective study with a larger number of patients would allow a better definition of the risk determined by individual factors and the development of a score that could be used in practice to simplify the risk assessment KEY WORDS: Conversion to open surgery, Incisional hernia, Laparoscopy, Risk factors. PMID- 30007064 TI - Comparison of next-generation droplet digital PCR with quantitative PCR for enumeration of Naegleria fowleri in environmental water and clinical samples. AB - : Naegleria fowleri in recreational waters is a serious health threat. A rapid and accurate method to determine this pathogen in water is vital to develop effective control strategies. In this study, we compared two molecular methods: droplet digital polymerase chain reaction (ddPCR) and quantitative PCR (qPCR) assays in identifying N. fowleri from clinical and environmental samples. Strong agreement between ddPCR and qPCR methods over clinical DNA samples was observed. The limit of detection (LOD) for ddPCR and qPCR assays were 2.5 and 25 N. fowleri per reaction respectively. In the comparative analysis using N. fowleri genomic DNA, quantitative results obtained from ddPCR and qPCR assays showed no significant difference. The assay specificity for ddPCR and qPCR assays were 100 and 86% respectively. Results from both PCR assays indicated N. fowleri was present in surface water samples from Lake Pontchartrain during our study period. In general, the ddPCR performance demonstrated in this study on clinical and environmental samples lead to greater confidence of ddPCR technology on field application. For precise quantification using qPCR, we recommend using ddPCR to quantify the standard materials before qPCR application. SIGNIFICANCE AND IMPACT OF THE STUDY: This study explored the application of ddPCR and qPCR methods in identifying Naegleria fowleri from both clinical and environmental water samples. Strong agreement between ddPCR and qPCR methods over clinical DNA samples was observed. Naegleria fowleri was present in surface water samples from Lake Pontchartrain during our study period. The ability of N. fowleri to survive in brackish water is therefore a potential risk factor for people who engage in water-related recreational activities. The ddPCR performance demonstrated in this study on clinical and environmental samples lead to greater confidence of ddPCR technology on field application. PMID- 30007065 TI - Primary cutaneous CD30+ anaplastic large-cell lymphoma associated with fingolimod. PMID- 30007063 TI - Two-Plane Assessment of Knee Muscles Isometric and Isokinetic Torques After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND We tested the hypothesis that, in patients participating in 17 weeks of postoperative physiotherapy after anterior cruciate ligament reconstruction (ACLR), maximal isometric torque (IT) and peak torque (PT) generated by the muscles affecting the operated knee joint in the sagittal and transverse planes are not restored. We also present the application of IT and PT measurements of the muscles affecting the knee joint in 2 planes of motion. MATERIAL AND METHODS IT and PT of the knee extensor and flexor muscles and the muscles internally rotating the shin were measured in 30 males who participated in postoperative physiotherapy for 17 weeks after ACLR (ACLR group) and 30 males with no injuries (control group). RESULTS Significantly lower IT and PT values were noted in the operated knee extensors and flexors. The differences were also noted in the PT for the muscles internally rotating the shin and in the IT of those muscles in the position of 25 degrees of internal rotation. Significantly lower relative IT and PT values were noted for studied muscle groups in comparison to the control group. CONCLUSIONS Seventeen weeks of postoperative physiotherapy after ACLR did not result in complete restoration of IT and PT of the muscles affecting the operated knee joint, suggesting that even after 17 weeks of physiotherapy following ACLR, athletes may not be ready to return to sports. The results demonstrate the usefulness of biplanar analysis of muscle strength under isometric and isokinetic conditions in the monitoring and assessment of physiotherapeutic procedures. PMID- 30007066 TI - To determine the optimal ultrasonographic screening method for rectal/rectosigmoid deep endometriosis: Ultrasound "sliding sign," transvaginal ultrasound direct visualization or both? AB - INTRODUCTION: The study aim was to evaluate the transvaginal sonography (TVS) "sliding sign" alone, direct visualization of the bowel with TVS, and the combination of both methods (ie "sliding sign" and direct visualization of the bowel), to determine the optimal TVS method for the prediction of rectal/rectosigmoid deep endometriosis (DE). MATERIAL AND METHODS: Multicenter prospective observational study (January 2009-February 2017). All women underwent TVS to determine whether the "sliding sign" was positive/negative and whether rectal/rectosigmoid DE was present, followed by laparoscopic surgery. The association between a negative TVS "sliding sign" alone and the direct visualization of a rectal/rectosigmoid DE nodule alone during the TVS were correlated with the presence of rectal/rectosigmoid DE at laparoscopy. Accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LRs) were evaluated. Data were analyzed using Fisher's exact test. RESULTS: During the recruitment period, 410 consecutive women with suspected endometriosis were included. Complete TVS and laparoscopic surgical outcomes were available for 376 of the women (91.7%). Complete TVS and laparoscopic data were available for 376 women. Of the 376 women 76 (20.2%) had rectal/rectosigmoid DE at laparoscopy. The accuracy, sensitivity, specificity, PPV, NPV, positive and negative LRs for each method to predict bowel DE were: negative "sliding sign": 87%, 73.7%, 90.3%, 65.9%, 93.1%, 7.62, and 0.29, respectively; direct visualization: 91.0%, 86.8%, 92.3%, 74.2%, 96.5%, 11.3, and 0.14, respectively; combined approach: 90.2%, 69.7%, 95.3%, 79.1%, 92.6%, 14.94, and 0.32, respectively. A negative TVS "sliding sign" was significantly associated with the need for bowel surgery (P < 0.05). CONCLUSIONS: The combination of the TVS "sliding sign" and direct visualization of the bowel during TVS appears to provide the most accurate assessment for the identification of rectal/rectosigmoid DE preoperatively. PMID- 30007067 TI - Impact of interfractional motion on hypofractionated pencil beam scanning proton therapy and VMAT delivery for prostate cancer. AB - PURPOSE: Hypofractionated radiotherapy of prostate cancer is gaining clinical acceptance given its potential increase in therapeutic ratio and evidence for noninferiority and lack of added late toxicities compared to conventional fractionation. However, concerns have been raised that smaller number of fractions might lead to larger dosimetric influence by interfractional motion. We aim to compare the effect of these variations on hypofractionated pencil beam scanning (PBS) proton therapy and volumetric modulated arc therapy (VMAT) for localized prostate cancer. METHODS: Weekly CT images were acquired for 6 patients participating in a randomized clinical trial. PBS plans featuring bilateral (BL) and a combination of lateral and anterior-oblique beams (AOL), and VMAT plans were created. All patients were treated to a conventional 79.2 Gy total dose in 44 fractions. For this study, hypofractionated dose to the prostate gland was 51.6 Gy in 12 fractions or 36.25 Gy in 5 fractions, and 32.8, and 23.1 Gy to proximal seminal vesicles, respectively. Patients were simulated with endorectal balloons to aid gland immobilization. Three fiducial markers were implanted for setup guidance. All plans were recomputed on the weekly CT images after aligning with the simulation CT. The entire set of 9 CT images was used for dose recalculation for 12-fraction and only 5 used for the 5-fraction case. Adaptive range adjustments were applied to anterior-oblique beams assuming clinical availability of in vivo range verification. Fractional doses were summed using deformable dose accumulation to approximate the delivered dose. Biologically equivalent dose to 2 Gy(EQD2) was calculated assuming alpha/beta of 1.5 Gy for prostate and 3 Gy for bladder and rectum. RESULTS: The median delivered prostate D98 was 0.13/0.14/0.13 Gy(EQD2) smaller than planned for PBS-BL, 0.13/0.27/0.17 Gy(EQD2) for PBS-AOL and 0.59/0.66/0.59 Gy(EQD2) for VMAT, for 44/12/5 fractions, respectively. The largest D98 reduction was 1.5 and 3.5 Gy(EQD2) for CTV1 and CTV2, respectively. Target dose degradation was comparable for all fractionation schemes within each modality. The maximum increase in rectum D2 was 0.98 Gy(EQD2) for a 5-fraction PBS case. CONCLUSIONS: The robustness of PBS and VMAT were comparable for all patients for the studied fractionations. The delivered target dose generally remained within clinical tolerance and the deviations were relatively minor for both fractionation schemes. The delivered OAR dose stayed in compliance with the RTOG hypofractionation constraints for all cases. PMID- 30007068 TI - Antibiotic resistance and relevance to general dental practice in Australia. AB - Antibiotic resistance is a well-established global public health crisis, with the use and misuse of antibiotics being the principal cause of bacterial resistance. Studies in both Australia and overseas have demonstrated that the dental prescribing of antibiotics is increasing and that dentists tend to prescribe antibiotics unnecessarily and for incorrect clinical indications. Dental practitioners in Australia also prefer to prescribe moderate to broad-spectrum antibacterial agents and make some inappropriate antibiotic prescribing choices. This review aims to inform dentists about the overall scope and development of bacterial resistance, approaches and challenges to reducing resistance and, ultimately, the role of dental prescribers in practising with optimal antibiotic stewardship. PMID- 30007069 TI - Psychiatric morbidity and suicidal behaviour in psoriasis: a primary care cohort study. AB - BACKGROUND: Psychological distress among people with psoriasis may lead to elevated risks of suicide and nonfatal self-harm. OBJECTIVES: To investigate psychiatric comorbidity, psychotropic medication prescribing and risk of suicidality in people with psoriasis. METHODS: A cohort of patients with psoriasis (1998-2014) was delineated using the Clinical Practice Research Datalink, with linkage to Hospital Episode Statistics and Office for National Statistics mortality records. Each patient with psoriasis was matched with up to 20 patients without psoriasis on age, sex and general practice. A stratified Cox regression model was used to estimate the hazard ratios (HRs) for suicide or nonfatal self-harm risks adjusted for socioeconomic status. RESULTS: At baseline, among 56 961 and 876 919 patients with and without psoriasis, higher prevalence for histories of alcohol misuse, bipolar disorder, depression, anxiety disorders, self-harm and psychotropic drug prescription were observed. The deprivation adjusted HR indicated lower suicide risk in people with psoriasis [HR 0.59, 95% confidence interval (CI) 0.41-0.85]. The risk of suicide varied according to age: it was lower in people with psoriasis diagnosed at >= 40 years (HR 0.38, 95% CI 0.21-0.66), whereas there was no difference in risk of suicide in people with psoriasis diagnosed before age 40 years (HR 0.92, 95% CI 0.58-1.46). Conversely, there was a small increased risk for self-harm (HR 1.15, 95% CI 1.04-1.27) associated with psoriasis. CONCLUSIONS: The prevalence of mental illness was raised in people with psoriasis, and this may lead to a greater risk of self harm. Nevertheless, having psoriasis does not appear to be associated with an increased risk of suicide. Healthcare professionals caring for patients with psoriasis should continue to monitor and tackle effectively the psychological needs of these individuals. PMID- 30007070 TI - Comparison of dienogest and progesterone effects on uterine contractility in the extracorporeal perfusion model of swine uteri. AB - INTRODUCTION: Endometriosis is associated with hyperperistalsis and dysperistalsis in the uterus, and it has been shown that progesterone leads to a decrease in uterine contractility. The synthetic gestagen dienogest is often administered in women who are receiving conservative treatment for endometriosis, and it may be the treatment of choice. The present study investigated the effects of dienogest on uterine contractility in comparison with the known inhibitory effect of progesterone. MATERIAL AND METHODS: Eighty swine uteri were examined using an established extracorporeal perfusion model. The uteri were perfused for at least 4 hours with progesterone, dienogest, or a modified Krebs-Ringer solution as the control group, with uterine contractions being measured using an intrauterine microchip catheter. The amplitude and frequency of contractions and the area under the curve (AUC), reflecting overall contractility, were measured at two separate locations (the isthmus and fundus). RESULTS: Progesterone led to a significant decrease in the amplitude of uterine contractions and to reduced overall pressure (AUC) at the isthmus and fundus. Dienogest led to a significant decrease in the amplitude of contractions and overall pressure (AUC) in the area of the isthmus, but the decrease near the fundus was not significant. The frequency of uterine contractions was not influenced by either progesterone or dienogest. CONCLUSIONS: These results confirm the known inhibitory effect of progesterone on uterine contractility (relative to amplitude of contractions and overall contractility), affecting the whole organ. Perfusion of the uterus with dienogest also led to a general decrease in uterine contractility similar to the effect of progesterone. PMID- 30007072 TI - Early allograft inflammation and scarring associate with graft dysfunction and poor outcomes in renal transplant recipients with delayed graft function: a prospective single center cohort study. AB - Early histological progression that associates with delayed graft function (DGF) and its relationship to graft outcomes is less well-understood. We systematically evaluated early acute and chronic histological changes associated with DGF through serial biopsies (protocol: 3 and 12 months; for-cause) and related them to graft outcomes. 56/294 (19.04%) of our patients had DGF. DGF was associated with a progressive increase in both Banff 't' and 'i' scores from 2 weeks to 3 and 12 months with a resultant increase in T cell mediated rejection (TCMR) that was significantly greater than those with primary graft function (PGF). This increase in TCMR was predominantly sub-clinical TCMR diagnosed on protocol biopsy. Furthermore, TCMR in patients with DGF was recurrent/persistent at 12 months. Importantly, the combination of DGF and TCMR was associated with significantly worse interstitial fibrosis and tubular atrophy (IFTA) and interstitial fibrosis with inflammation (IF + 'i') as early as 3 months and worse renal function. Finally, DGF with TCMR was associated with significantly worse graft loss. In this regard, DGF without TCMR had comparable chronic histology and outcomes to PGF. Thus, DGF with TCMR (predominantly sub-clinical), represents a high-risk patient group who may benefit from early novel immunosuppression augmentation strategies to improve graft outcomes. PMID- 30007073 TI - IgE levels are negatively correlated with clinical response to ciclosporin in chronic spontaneous urticaria. PMID- 30007071 TI - The controversies of silicon's role in plant biology. AB - Contents Summary 67 I. Introduction 68 II. Silicon transport in plants: to absorb or not to absorb 69 III. The role of silicon in plants: not just a matter of semantics 71 IV. Silicon and biotic stress: beyond mechanical barriers and defense priming 76 V. Silicon and abiotic stress: a proliferation of proposed mechanisms 78 VI. The apoplastic obstruction hypothesis: a working model 79 VII. Perspectives and conclusions 80 Acknowledgements 81 References 81 SUMMARY: Silicon (Si) is not classified as an essential plant nutrient, and yet numerous reports have shown its beneficial effects in a variety of species and environmental circumstances. This has created much confusion in the scientific community with respect to its biological roles. Here, we link molecular and phenotypic data to better classify Si transport, and critically summarize the current state of understanding of the roles of Si in higher plants. We argue that much of the empirical evidence, in particular that derived from recent functional genomics, is at odds with many of the mechanistic assertions surrounding Si's role. In essence, these data do not support reports that Si affects a wide range of molecular-genetic, biochemical and physiological processes. A major reinterpretation of Si's role is therefore needed, which is critical to guide future studies and inform agricultural practice. We propose a working model, which we term the 'apoplastic obstruction hypothesis', which attempts to unify the various observations on Si's beneficial influences on plant growth and yield. This model argues for a fundamental role of Si as an extracellular prophylactic agent against biotic and abiotic stresses (as opposed to an active cellular agent), with important cascading effects on plant form and function. PMID- 30007074 TI - Morphology and tumour-infiltrating lymphocytes in high-stage, high-grade serous ovarian carcinoma correlated with long-term survival. AB - AIMS: Advanced-stage ovarian high-grade serous carcinoma (HGSC) is a poor prognosis cancer; however, a small and poorly characterised subset of patients shows long-term survival. We aimed to establish a cohort of HGSC long-term survivors for histopathological and molecular analysis. METHODS AND RESULTS: Paraffin blocks from 151 patients with primary FIGO III/IV HGSC and progression free survival (PFS) >5 years were collected within the Tumorbank Ovarian Cancer (TOC) Network; 77 HGSC with a PFS <3 years were used as a control group. A standardised analysis of histological type and morphological features was performed. Ki67 index, tumour-infiltrating lymphocytes (TILs) and major histocompatibility complex expression (MHC1/2) were determined by immunohistochemistry. A total of 117 of 151 tumours (77.5%) in the long-term survivor group fulfilled the World Health Organisation (WHO) criteria of HGSC after review, and of these, 83 patients (70.9%) fulfilled all clinical criteria for inclusion into our cohort. Tumours of long-term survivors had significantly higher CD3+ and CD8+ TILs and were more frequently positive for MHC2 than controls (P = 0.004, P = 0.025, P = 0.048). However, there were also long-term survivors (up to 20%) with low TILs or low MHC expression. TILs and MHC had no impact on survival in long-term survivors. Morphological and Ki67 analysis revealed no differences between long-term survivors and controls. CONCLUSIONS: HGSC from long-term survivors have higher-level T cell infiltration and antigen presentation capacity; however, this is not a prerequisite for an excellent prognosis. Histopathological criteria are not capable to identify these patients. Further extensive clinical and molecular characterisation of this enigmatic subgroup is ongoing to understand the reasons of long-term survival in HGSC. PMID- 30007075 TI - Synthetic head and neck and phantom images for determining deformable image registration accuracy in magnetic resonance imaging. AB - PURPOSE: Magnetic resonance imaging (MRI) provides noninvasive evaluation of patient's anatomy without using ionizing radiation. Due to this and the high soft tissue contrast, MRI use has increased and has potential for use in longitudinal studies where changes in patients' anatomy or tumors at different time points are compared. Deformable image registration can be useful for these studies. Here, we describe two datasets that can be used to evaluate the registration accuracy of systems for MR images, as it cannot be assumed to be the same as that measured on CT images. ACQUISITION AND VALIDATION METHODS: Two sets of images were created to test registration accuracy. (a) A porcine phantom was created by placing ten 0.35 mm gold markers into porcine meat. The porcine phantom was immobilized in a plastic container with movable dividers. T1-weighted, T2-weighted, and CT images were acquired with the porcine phantom compressed in four different ways. The markers were not visible on the MR images, due to the selected voxel size, so they did not interfere with the measured registration accuracy, while the markers were visible on the CT images and were used to identify the known deformation between positions. (b) Synthetic images were created using 28 head and neck squamous cell carcinoma patients who had MR scans pre-, mid-, and postradiotherapy treatment. An inter- and intrapatient variation model was created using these patient scans. Four synthetic pretreatment images were created using the interpatient model, and four synthetic post-treatment images were created for each of the pretreatment images using the intrapatient model. DATA FORMAT AND USAGE NOTES: The T1-weighted, T2-weighted, and CT scans of the porcine phantom in the four positions are provided. Four T1-weighted synthetic pretreatment images each with four synthetic post-treatment images, and four T2 weighted synthetic pretreatment images each with four synthetic post-treatment images are provided. Additionally, the applied deformation vector fields to generate the synthetic post-treatment images are provided. The data are available on TCIA under the collection MRI-DIR. POTENTIAL APPLICATIONS: The proposed database provides two sets of images (one acquired and one computer generated) for use in evaluating deformable image registration accuracy. T1- and T2-weighted images are available for each technique as the different image contrast in the two types of images may impact the registration accuracy. PMID- 30007076 TI - Self-presentational motives and public self-consciousness: Why do people dress a certain way? AB - OBJECTIVE: This study examines the self-presentational motives underlying people's selection of their daily dress and relationships between these motives and public self-consciousness. METHOD: Participants in this study, 61 working adults, described their motives for choosing what they wore each day for 2 weeks. They also provided trait-level measures of self-consciousness, social anxiety, and self-monitoring. RESULTS: Multilevel modeling analyses found positive relationships between public self-consciousness and the strength of various self presentational motives for why people chose the clothes they wore each day. In contrast, there were few relationships between the strength of these motives and private self-consciousness, social anxiety, and self-monitoring. Participants felt better about themselves when they received compliments from others about their attire and when they were more (vs. less) satisfied with how they had dressed each day. CONCLUSIONS: The results suggest that dispositional public self consciousness manifests itself in daily life in the form of motives for choosing daily attire, specifically for motives that involve self-presentation. PMID- 30007077 TI - Uniparental disomy as a mechanism for CERS3-mutated autosomal recessive congenital ichthyosis. PMID- 30007078 TI - Measurement error of state variables creates substantial bias in results of demographic population models. AB - Integral projection and matrix population models are commonly used in ecological and conservation studies to assess the health and extinction risk of populations. These models use one (or more) measurable state variable(s), such as size or age, to predict individual performance, which, ideally, is the sole determinant of an individual's expected fate. However, even if ecologists successfully identify and measure the observable state variable(s) that best predicts individual fate, we are rarely, if ever, able to perfectly measure state for many species, especially those with size structure, where total plant biomass or starch stores, for example, may be the best predictors of fate. Here, we used a series of simulations to test how this imperfect quantification of actual state ("measurement error") leads to inaccurate prediction of state-dependent fates and influences the predictions of structured population models. We simulated 10 yr of best practice field data collection using known vital rate functions and incorporated measurement error of different magnitudes and types (completely random, temporal, and individual based) for two size-structured life histories. We found that even for conservative error rates, most types of measurement error increased the median predicted population growth rate by 1-2% growth per year. However, the magnitude of this error differed substantially with life history strategy and error type, with some scenarios resulting in >8% median overestimation of population growth rate. This effect arises largely from the well-known econometrics problem of "regression dilution" (overestimation of the intercept and underestimation of the slope of a regression when the predictor variable is measured with error), which in our simulations typically results in overly optimistic predictions of small or young individuals' vital rates. Our results suggest that the problem of measurement error for state variables, present in many demographic studies but virtually unacknowledged in the ecological literature, may lead to substantial misestimation of population behavior, resulting in erroneous inferences about not only growth, but also extinction risk and other aspects of population dynamics. PMID- 30007079 TI - Triamcinolone injection and filling method to prevent stricture after esophageal endoscopic submucosal dissection. PMID- 30007080 TI - Health-related quality of life in women with endometriosis, compared with the general population and women with rheumatoid arthritis. AB - INTRODUCTION: Women with endometriosis have reduced health-related quality of life (HRQoL). However, comparisons to the general population and other patient groups are lacking. MATERIAL AND METHODS: The present cross-sectional questionnaire study included 157 women with endometriosis, 156 women from the general population, and 837 women with rheumatoid arthritis (RA). During a period from 2012 to 2013, women aged 18-45 years were recruited from the Norwegian Endometriosis Association and from a random sample of women residing in Oslo, Norway. HRQoL data from women with RA were included from a survey conducted in 2009 among patients of the Oslo Rheumatoid Arthritis Register. The Short Form-36 (SF-36) questionnaire was used to measure HRQoL. RESULTS: Compared with the control group, the endometriosis group had significantly reduced mean scores for all SF-36 scales. The difference was largest for the scale bodily pain with a mean score of 47.6 in the endometriosis group vs 81.5 in the control group. Compared with the RA group, the endometriosis group had significantly reduced mean scores for the three SF-36 scales vitality, social functioning, and mental health. The mean scores of these scales in the endometriosis group were 33.4, 62.7, and 66.3, respectively, vs 42.7, 68.8, and 72.6 in the RA group. CONCLUSIONS: Women with moderate to severe endometriosis seem to have overall impaired HRQoL compared with women from the general population, and poorer mental HRQoL compared with women with RA. PMID- 30007081 TI - Folliculotropic mycosis fungoides in a pediatric patient with response to psoralen-ultraviolet A phototherapy. AB - Mycosis Fungoides is the most common cutaneous T-cell lymphoma however, it is rare in children. We present the case of a Folliculotropic Mycosis Fungoides in a 13-year-old boy which initially presented as a plaque on his face and was treated with local PUVA therapy. Afterwards the lesions spread so the treatment was changed to systemic PUVA with good response. Although the experience in the treatment of Mycosis Fungoides in pediatric patients is limited, PUVA therapy seems to be an effective and safe option. PMID- 30007082 TI - Antibacterial and anti-PmrA activity of plant essential oils against fluoroquinolone-resistant Streptococcus pneumoniae clinical isolates. AB - Streptococcus pneumoniae (pneumococcus) is recognized as one of the major cause of infections in communities and hospitals. In this study, anti-pneumococcal and anti-efflux pump activity of two medicinal plants (Thymus daenensis and Origanum vulgare) essential oils were evaluated. Checkerboard assay test was performed for investigation of the effects of selected EOs on ciprofloxacin (CIP) and ethidium bromide (EtBr) uptake in pmrA-overexpressed fluoroquinolone-resistant pneumococcus. Using quantitative real-time RT-PCR the PmrA efflux pump gene (pmrA) expression was evaluated following treatment with selected EOs. Gas chromatography-mass spectrometry analysis was performed for identifying the major components of the tested EOs. The minimum inhibitory concentration (MIC) values for pneumococcus isolates were 0.625-2.5 MUl ml-1 for T. daenensis and 1.25-5 MUl ml-1 for O. vulgare EOs. We confirmed that in all strains T. daenensis and O. vulgare have a total or partial synergistic effects with CIP and EtBr (FICI from 0.14 to 0.75). In other hand MIC/2 concentration of T. daenensis and O. vulgare EOs caused a significant downregulation of pmrA gene (P < 0.05) in seven of eight strains. This study showed that T. daenensis and O. vulgare EOs have strong antimicrobial and anti-efflux pump activity against clinical isolates of S. pneumoniae and might be useful in controlling pneumococcal infections. SIGNIFICANCE AND IMPACT OF THE STUDY: This study introduced Thymus daenensis and Origanum vulgare essential oil as new antibacterial and anti-efflux pump agents against fluoroquinolone-resistant Streptococcus pneumoniae clinical isolates. These findings indicate that combination of these two essential oils with fluoroquinolone antibiotics may provide alternative methods to overcome the fluoroquinolone-resistant S. pneumoniae. PMID- 30007083 TI - Late recurrent bleeding episodes from duodenojejunostomy after pancreas transplantation. AB - In response to a number of late, repetitive bleeding episodes from the site of the enteric anastomosis, we herein analyze the clinical courses and etiologies of 379 consecutively performed pancreas transplants between January 2000 and December 2016. Duodenojejunostomies for enteric drainage were performed at the upper jejunum in a side to side, double layer fashion. Five patients (1.3%) developed recurrent late hemorrhagic episodes originating from the graft duodenal anastomosis. Bleeding from the anastomotic site was associated with hematochezia, hemodynamic instability and decrease in serum hemoglobin. Mean onset was 6.4(+/ 2.8) years after transplantation. Bleeding was recurrent (mean 5.2 +/- 2.6) and required 9(+/-2.5) interventions. Hypervascularization, mucosal vulnerability, and bleeding at the site of the enteric anastomosis could be identified in all cases. In four patients, the enteric pancreas anastomosis was resected and a new duodenojejunostomy was performed. No pancreas graft loss occurred due to bleeding. In two patients, hepatic cirrhosis and portal hypertension were identified, one patient had a liver fibrosis as putative cause for the repetitive bleeding episodes. Late anastomotic hemorrhage is a rare but severe complication following pancreas transplantation. The treatment is challenging and includes endoscopy, interventional radiology, and surgery. Hepatic conditions with an increased portal pressure may be the underlying cause. PMID- 30007084 TI - A morphological and molecular study of proposed early forms of traditional serrated adenoma. AB - AIMS: Traditional serrated adenoma (TSA) is the least common subtype of serrated colorectal polyp. Large protuberant lesions are easily recognised; however, the origins of TSAs are not known, and early forms have not been described. Some large TSAs present with a flat 'shoulder' component surrounding the central protuberant component. We hypothesised that small polyps with the same histology as these shoulder regions may represent early TSAs. Thus the primary aim of the study is to describe the histology of these presumptive early TSAs. METHODS AND RESULTS: We collected 70 small (<10 mm) polyps that may represent early TSAs on the basis of typical TSA cytology covering the luminal surface. We also identified 12 large TSAs with a shoulder component resembling these small polyps. The study polyp patients had a mean age of 58 years, and 54% were female; the polyps had a mean diameter of 4.1 mm and were predominantly distal (71%). Morphologically, slit-like serrations were present in 81%, ectopic crypt formations were present in 67%, and a villous component was present in 47%. These histological features were similar to those of the 12 shoulder lesions. Immunohistochemical stains showed an absence of beta-catenin nuclear expression in 96% of the small polyps, retained expression of MLH1 in 100%, and Ki67 positivity restricted to the crypt bases and ectopic crypt formations. BRAF and KRAS mutations were identified in 47% and 31% of the polyps, respectively. BRAF mutated polyps were more likely than KRAS-mutated polyps to arise in a precursor polyp (82% versus 18%, P < 0.001), and were more likely to have slit-like serrations (100% versus 73%, P = 0.003). CONCLUSIONS: These morphological, immunohistochemical and molecular findings are similar to what has been reported in large TSAs, and support the hypothesis that these polyps represent early forms of TSA. PMID- 30007085 TI - Phosphorus Particles Embedded in Reduced Graphene Oxide Matrix to Enhance Capacity and Rate Capability for Capacitive Potassium-Ion Storage. AB - Early studies indicate that graphite is feasible as the negative electrode of a potassium-ion battery, but its electrochemical performance still cannot meet the demands of applications. More efforts should be focused on increasing the specific capacity and improving the rate capability in the meantime. Thus, stainless-steel autoclave technology has been utilized to prepare phosphorus nanoparticles encapsulated in reduced graphene oxide matrix as the electrode materials for a potassium-ion battery. As a result, the composite matrix affords high reversible capacities of 354 and 253 mA h g-1 at 100 and 500 mA g-1 , respectively. The superior electrochemical performance is mainly because the composite matrix possesses better electronic conductivity and a robust structure, which can promote the electron-transfer performance of the electrode. Furthermore, phosphorus particles can contribute to the high capacity through an alloying mechanism. In addition, the silklike, ultrathin, film composite with a high surface area is conducive to capacitive potassium-ion storage, which plays a more important role in rate performance and a high current density capability. PMID- 30007086 TI - An efficient synthesis of trace amine-associated receptor agonist [1-14 C]tyramine. AB - The 2-step synthesis of [1-14 C]tyramine hydrochloride is described with the product being characterized by TLC, HPLC, and UV spectroscopy. Several methods are provided to purify [1-14 C]tyramine hydrochloride, and its storage and stability are also discussed. PMID- 30007087 TI - Immune thrombocytopenia: Effectiveness of frontline steroids and comparison of azathioprine, splenectomy, and rituximab as second-line treatment. AB - OBJECTIVE: For immune thrombocytopenia (ITP), efficacy of frontline steroids is well established. However, clinical data comparing various treatment options for refractory or relapsed ITP are limited. We aimed to investigate the outcome of frontline steroid treatment for ITP patients and compare common second-line modalities in a single institute in Taiwan. METHODS: We collected the complete outpatient list over a 6-month period. Patients were identified from the list, and medical records were reviewed to capture the data retrospectively. The diagnosis of ITP was made by excluding other etiologies. RESULTS: Among 665 patients with thrombocytopenia, the diagnosis of ITP was made in 375. Two hundred and fifty-seven patients (51 males, median age 45.5) received treatment. Response to steroids was evaluable for 184 patients. Complete response (CR) was achieved in 120 (65.2%) and partial response in 43 (23.3%). In 21 (11.4%) patients, ITP was refractory to steroids. Among those with CR, 76 (63%) patients relapsed in a median of 9.5 months. After relapse or steroid failure, 57 (49%) received azathioprine treatment and 38 (32%) underwent splenectomy. Response rate was 71.4% (38.1% CR) for azathioprine and 91.4% (77.1% CR) for splenectomy. Rituximab was effective in 8 of 10 patients. CONCLUSION: Steroids are effective frontline treatment for ITP, but relapse is common. Both azathioprine and splenectomy are effective treatment after steroid failure. Rituximab appears to a reasonable second-line treatment option in our limited experience. PMID- 30007089 TI - Expression of phosphatase and tensin homologue in imprint smears of endometrial carcinoma. AB - OBJECTIVE: The aims of this study were to determine the expression of phosphatase and tensin homologue (PTEN) in endometrial adenocarcinomas (as a potential prognostic indicator before treatment) in imprint smears and to correlate the results with clinicopathological parameters of primary untreated endometrial cancer patients. METHODS: A total of 126 patients with endometrial carcinoma were evaluated with samples freshly resected after a total abdominal hysterectomy during a 29-month period. The expression of PTEN was assessed by immunocytochemistry. RESULTS: In total, 102 cases were type I and 24 type II endometrial adenocarcinomas. High expression of PTEN was more frequent in type I (42/102) compared to type II (6/24) adenocarcinomas, to less advanced and aggressive clinical stage (stage I: 41/79, stage II: 5/13, stage III: 2/19, stage IV: 1/15) as well as in low grade (grade 1: 26/42, grade 2: 20/57) compared to high-grade (grade 3: 8/27) carcinomas. The nonaffected lymph nodes showed high expression of PTEN (in 43.3%) than the affected lymph nodes (in 5.9%). Also, in 45 out of 74 cases with myometrial invasion <50%, there was positive expression of PTEN in contrast to 12 out of 52 cases with depth of myometrial invasion >50%. CONCLUSIONS: Immunocytochemical findings from PTEN stain, in addition to cytomorphological features, appeared to be a useful marker in the diagnosis and in the postoperative prognosis of endometrial carcinoma in endometrial cytology with imprint smears and that high PTEN expression is related to morphological features of less aggressiveness tumours. PMID- 30007088 TI - Donor cell-derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplantation. AB - Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell-derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long-term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI. PMID- 30007090 TI - Not all tendon swellings are giant cell tumours. PMID- 30007091 TI - Contraceptive use and reproductive intentions among women requesting contraceptive counseling. AB - INTRODUCTION: Limited attention has been paid to the use of contraception in relation to women's family planning intentions. The aim of this study was to investigate the use of contraception during the most recent intercourse as well as the reproductive intentions of Swedish-speaking women requesting contraceptive counseling. MATERIAL AND METHODS: A cross-sectional baseline survey in a randomized controlled trial regarding reproductive life planning (before randomization). Women requesting contraceptive counseling answered questions about contraception and whether they wanted to have children/more children in the future. RESULTS: In total, 1946 women participated: 33.7% (n = 656) parous and 65.7% (n = 1279) nulliparous. The majority, 87.1% (n = 1682), had used contraception during their latest intercourse; 64.6% (n = 1239) used short-acting reversible contraception, 22.8% (n = 443) used long-acting reversible contraception (LARC), and 12.9% (n = 251) had not used any contraception. A combined oral contraceptive was more common among nulliparous and LARC among parous. Among all women, 64.8% (n = 1253) intended to have children/more children in the future, among parous women 35.7% (n = 220) and among nulliparous 80.0% (n = 1033). Among women who did not intend to have children/more children, 22.6% (n = 60) of parous and 10% (n = 8) of nulliparous had not used contraceptives during their most recent intercourse. CONCLUSIONS: Women did not always use contraceptives that were suitable for their reproductive intentions. Questioning women who request contraceptive counseling about their pregnancy intention can give healthcare providers better opportunities for individualized counseling. PMID- 30007092 TI - Upregulation of IL-6 expression in human salivary gland cell line by IL-17 via activation of p38 MAPK, ERK, PI3K/Akt, and NF-kappaB pathways. AB - BACKGROUND: The human salivary gland (HSG) cell line has so far been used as in vitro models for study of the influence of cytokines and pharmacologic agents on salivary glands, as well as a model system for inflammation in Sjogren's syndrome (SS). This study aimed to determine the effect of IL-17 on IL-6 production and the underlying molecular mechanism regulated by the HSG cell line. METHODS: Immunofluorescence analyses, RT-PCR, and Western blot were conducted to evaluate the IL-17 receptor (IL-17R) expression in cultured HSG cells. Real-time PCR and ELISA were then utilized to establish the mRNA and protein levels of IL-6 in IL 17-stimulated HSG cells. Western blot, flow cytometry, immunofluorescence, and inhibitor analyses were conducted to elucidate the involved signaling pathways. RESULTS: The HSG cells reliably expressed the IL-17R mRNA and its encoded surface bound protein. The expression of IL-6 mRNA and protein was upregulated by stimulation of HSG cells with IL-17; this effect was impeded by IL-17- or IL-17R neutralizing antibodies. IL-17 stimulation ended up with the fast phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), Akt, and translocation of nuclear factor-kappaB (NF-kappaB) in the HSG cells. p38 MAPK, Akt, and NF-kappaB inhibitors significantly subdued IL-6 generation in HSG cells stimulated by IL-17. PD98059, an ERK inhibitor, decreased IL-6 generation under low dose of IL-17 but not with high dose. CONCLUSIONS: The HSG cells expressed IL-17R and reacted to IL-17 to generate IL-6 via the stimulation of ERK, p38 MAPK, Akt, and NF-kappaB signaling pathways. PMID- 30007093 TI - Clinical characteristics and analysis of treatment result in children with Ph positive acute lymphoblastic leukaemia in Poland between 2005 and 2017. AB - OBJECTIVE: The aim of this study was to analyse the clinical characteristics and outcome of children diagnosed with Ph+ ALL. MATERIAL AND METHODS: A total of 2591 newly diagnosed ALL children were treated in Poland between the years 2005 and 2017. Of those, 44 were diagnosed with Ph(+) ALL. The patients were treated according to protocols: ALL IC-BFM 2002 and 2009 (26 patients), EsPhALL (12 patients), initially ALL IC-BFM and then EsPhALL (6 patients). RESULTS: The median of follow-up in the observed group was 3 years. Overall survival (OS) and event-free survival (EFS) of Ph+ ALL group were 0.73 and 0.64. OS and EFS of patients after HSCT were 0.78 and 0.66, while without HSCT were 0.6 and 0.6, P = 0.27 and 0.63. OS was 0.8 for patients treated with chemotherapy plus imatinib and 0.61 for chemotherapy alone, P = 0.22, while EFS was 0.66 (imatinib therapy) and 0. 61 (without imatinib), P = 0.41. CONCLUSION: Our study suggests that adding imatinib to intensive chemotherapy seems to improve outcome. However, this study was limited by a small number of patients and a variety of chemotherapy regimens with or without imatinib. PMID- 30007094 TI - Criterion learning-A neglected aspect of training in cytopathology? PMID- 30007096 TI - Erosion rates of 3.5-cm artificial urinary sphincter cuffs are similar to larger cuffs. AB - OBJECTIVE: To compare long-term outcomes and erosion rates of 3.5-cm artificial urinary sphincter (AUS) cuffs vs larger cuffs amongst men with stress urinary incontinence (SUI), with and without a history of pelvic radiotherapy (RT). PATIENTS AND METHODS: We reviewed the records of all men who underwent AUS placement by a single surgeon between September 2009 and June 2017 at our tertiary urban medical centre. A uniform perineal approach was used to ensure cuff placement around the most proximal corpus spongiosum after precise spongiosal measurement. Patients were stratified by cuff size and RT status, and patient demographics and surgical outcomes were analysed. Cases of AUS revision in which a new cuff was not placed were excluded. Success was defined as patient reported pad use of <=1 pad/day. RESULTS: Amongst 410 cases included in the analysis, the 3.5-cm cuff was used in 166 (40.5%), whilst 244 (59.5%) received larger cuffs (>=4.0 cm). Over a median follow-up of 50 months, there was AUS cuff erosion in 44 patients at a rate nearly identical in the 3.5-cm cuff (10.8%, 18/166) and the >=4-cm cuff groups (10.7%, 26/244, P = 0.7). On multivariate logistic regression, clinical factors associated with AUS cuff erosion included a history of pelvic RT, prior AUS cuff erosion, prior urethroplasty, and a history of inflatable penile prosthesis (IPP) placement. Patient demographics were similar between the cuff-size groups; including age, body mass index, comorbidities, smoking history, RT history, prior AUS, and prior IPP placement. Continence rates were high amongst all AUS patients, with similar success in both groups (82% for 3.5-cm cuff, 90% for >=4-cm cuff, P = 0.1). CONCLUSIONS: After 8 years of experience and extended follow-up, the outcomes of the 3.5-cm AUS cuff appear to be similar to >=4-cm cuffs for effectiveness and rates of urethral erosion. RT patients have a higher risk of cuff erosion regardless of cuff size. PMID- 30007097 TI - Relationship of MR imaging of submandibular glands to hyposalivation in Sjogren's syndrome. AB - OBJECTIVE: We analysed the correlation between magnetic resonance images of the parotid and submandibular glands and the salivary flow rate in patients with Sjogren's syndrome. METHODS: We retrospectively reviewed magnetic resonance images (heterogeneous signal-intensity distribution and gland volume on T1- and fat-suppressed T2-weighted images, and multiple high-signal-intensity spots on magnetic resonance sialograms in the parotid and submandibular glands) obtained from 66 patients who were diagnosed with Sjogren's syndrome. We evaluated the relationship between these imaging features and their salivary flow rates in stimulated and unstimulated conditions. RESULTS: We found that as the disease progressed, both the heterogeneous signal-intensity distribution and the volumes of the parotid and the submandibular glands were significantly related to the stimulated and the unstimulated salivary flow rate. These imaging features were more highly correlated in assessments of the submandibular gland than in those of the parotid gland for both stimulated and unstimulated salivary flow rates. CONCLUSIONS: Magnetic resonance image features of heterogeneity and smaller volume in the submandibular gland are reliable for predicting hyposalivation related to the progression of Sjogren's syndrome. PMID- 30007098 TI - Core outcome set for induction of labour trials: what's the expectation? PMID- 30007095 TI - Heterogeneity of tumor lymphangiogenesis: Progress and prospects. AB - Lymphangiogenesis and increased expression of lymphangiogenic growth factors are associated with high rates of lymph node (LN) metastasis and with poor prognosis in some, but not all, solid tumors. In addition to its involvement in metastasis, lymphangiogenesis has been shown to have other roles in tumor pathogenesis, such as the niche function of tumor stem cells and regulatory functions of antitumor immune responses. In contrast, evidence has accumulated that tumor-induced lymphangiogenesis displays the heterogeneity in gene signature, structure, cellular origins and functional plasticity. This review summarizes the advances in the research on the heterogeneity of tumor lymphangiogenesis and discusses how it may contribute to functional complexity and multiplicity of lymphangiogenesis in tumor progression. PMID- 30007099 TI - Cytomorphological clues for a correct diagnosis of anaplastic lymphoma kinase positive large B-cell lymphoma. PMID- 30007100 TI - A radiative forcing analysis of tropical peatlands before and after their conversion to agricultural plantations. AB - The tropical peat swamp forests of South-East Asia are being rapidly converted to agricultural plantations of oil palm and Acacia creating a significant global "hot-spot" for CO2 emissions. However, the effect of this major perturbation has yet to be quantified in terms of global warming potential (GWP) and the Earth's radiative budget. We used a GWP analysis and an impulse-response model of radiative forcing to quantify the climate forcing of this shift from a long-term carbon sink to a net source of greenhouse gases (CO2 and CH4 ). In the GWP analysis, five tropical peatlands were sinks in terms of their CO2 equivalent fluxes while they remained undisturbed. However, their drainage and conversion to oil palm and Acacia plantations produced a dramatic shift to very strong net CO2 equivalent sources. The induced losses of peat carbon are ~20* greater than the natural CO2 sequestration rates. In contrast, a radiative forcing model indicates that the magnitude of this shift from a net cooling to warming effect is ultimately related to the size of an individual peatland's carbon pool. The continuous accumulation of carbon in pristine tropical peatlands produced a progressively negative radiative forcing (i.e., cooling) that ranged from -2.1 to -6.7 nW/m2 per hectare peatland by 2010 CE, referenced to zero at the time of peat initiation. Peatland conversion to plantations leads to an immediate shift from negative to positive trend in radiative forcing (i.e., warming). If drainage persists, peak warming ranges from +3.3 to +8.7 nW/m2 per hectare of drained peatland. More importantly, this net warming impact on the Earth's radiation budget will persist for centuries to millennia after all the peat has been oxidized to CO2 . This previously unreported and undesirable impact on the Earth's radiative balance provides a scientific rationale for conserving tropical peatlands in their pristine state. PMID- 30007101 TI - Different responses of predator and prey functional diversity to fragmentation. AB - The study of functional diversity, or the range of species' ecological roles in a community, is a rapidly expanding area in ecology. Given the extent that ecosystems are being altered, effort should shift toward assessing variation in functional diversity across landscapes with the goal of improving land use management decisions. We construct a workflow that creates three-dimensional surfaces and maps of functional diversity to examine changes in beetle functional diversity across an Indiana, USA landscape. We sampled 105 prey wood-borer and predator beetle species along a gradient of forest fragmentation across Indiana and used a number of functional traits from literature sources to capture their functional roles. We developed newly measured functional traits to estimate several traits relevant to beetles' ecological function that was unknown and not easily measured. Functional diversity indices (FRic, FDis, FDiv, and FEve) were calculated from species abundance and functional traits and used to assess changes in functional diversity along the fragmentation gradient. We predicted that habitat fragmentation would have a greater negative impact on predator beetle functional diversity than prey wood-borer functional diversity. Landscape metrics most important to the functional diversity of both wood-borer and predator beetle communities were landscape division index (LDI, an assessment of landscape subdivision) and mean shape index (MSI, a measure of patch shape complexity). Overall, three-dimensional surfaces of functional diversity and functional diversity maps across the Indiana landscape revealed that beetle functional diversity was greatest with minimal landscape subdivision. Opposite to what we predicted, we found that the prey wood-borer functional diversity was more negatively impacted by LDI than the predator beetle functional diversity. Furthermore, predator beetle functional diversity was greater with increasing MSI. The map predicted predator FRic to be highest in forested areas with intact habitat and also less sensitive to habitat fragmentation adjacent to more continuous forest. We propose that land management may be guided by revealing landscapes that are most appropriate for maximizing functional diversity of multiple communities or shifting the relative abundance within prey and beneficial predator beetle functional groups with the use of three-dimensional plots or maps. PMID- 30007102 TI - Chemo-Enzymatic Synthesis of Position-Specifically Modified RNA for Biophysical Studies including Light Control and NMR Spectroscopy. AB - The investigation of non-coding RNAs requires RNAs containing modifications at every possible position within the oligonucleotide. Here, we present the chemo enzymatic RNA synthesis containing photoactivatable or 13 C,15 N-labelled nucleosides. All four ribonucleotides containing ortho-nitrophenylethyl (NPE) photocages, photoswitchable azobenzene C-nucleotides and 13 C,15 N-labelled nucleotides were incorporated position-specifically in high yields. We applied this approach for the synthesis of light-inducible 2'dG-sensing riboswitch variants and detected ligand-induced structural reorganization upon irradiation by NMR spectroscopy. This chemo-enzymatic method opens the possibility to incorporate a wide range of modifications at any desired position of RNAs of any lengths beyond the limits of solid-phase synthesis. PMID- 30007104 TI - Pathways regulating decreased soil respiration with warming in a biocrust dominated dryland. AB - A positive soil carbon (C)-climate feedback is embedded into the climatic models of the IPCC. However, recent global syntheses indicate that the temperature sensitivity of soil respiration (RS ) in drylands, the largest biome on Earth, is actually lower in warmed than in control plots. Consequently, soil C losses with future warming are expected to be low compared with other biomes. Nevertheless, the empirical basis for these global extrapolations is still poor in drylands, due to the low number of field experiments testing the pathways behind the long term responses of soil respiration (RS ) to warming. Importantly, global drylands are covered with biocrusts (communities formed by bryophytes, lichens, cyanobacteria, fungi, and bacteria), and thus, RS responses to warming may be driven by both autotrophic and heterotrophic pathways. Here, we evaluated the effects of 8-year experimental warming on RS , and the different pathways involved, in a biocrust-dominated dryland in southern Spain. We also assessed the overall impacts on soil organic C (SOC) accumulation over time. Across the years and biocrust cover levels, warming reduced RS by 0.30 MUmol CO2 m-2 s-1 (95% CI = -0.24 to 0.84), although the negative warming effects were only significant after 3 years of elevated temperatures in areas with low initial biocrust cover. We found support for different pathways regulating the warming-induced reduction in RS at areas with low (microbial thermal acclimation via reduced soil mass specific respiration and beta-glucosidase enzymatic activity) vs. high (microbial thermal acclimation jointly with a reduction in autotrophic respiration from decreased lichen cover) initial biocrust cover. Our 8-year experimental study shows a reduction in soil respiration with warming and highlights that biocrusts should be explicitly included in modeling efforts aimed to quantify the soil C climate feedback in drylands. PMID- 30007103 TI - Five-day regimen of azacitidine for lower-risk myelodysplastic syndromes (refractory anemia or refractory anemia with ringed sideroblasts): A prospective single-arm phase 2 trial. AB - Although azacitidine is the first-line drug for higher-risk myelodysplastic syndrome (MDS) patients, its efficacy for lower-risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5-day regimen of azacitidine (AZA-5) for lower-risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower-risk MDS based on the French-American-British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51-88). These patients received AZA 5 (75 mg/m2 ; once daily for 5 sequential days). The median number of AZA-5 courses was 8 (range: 1-57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA-5 is feasible and effective for lower-risk MDS patients as well as for higher-risk MDS patients. PMID- 30007106 TI - A definitive randomised controlled trial addressing the impact of vaginal birth on incontinence. PMID- 30007105 TI - Professional occupation and the risk of Parkinson's disease. AB - BACKGROUND AND PURPOSE: Creativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre-diagnostic phase of PD, are prone to choose highly structured 'conventional' professional occupations and avoid highly creative 'artistic' occupations. METHODS: At baseline of the population-based Rotterdam Study, we asked 12 147 individuals aged >=45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow-up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case-control study (Radboud Study). RESULTS: At baseline, conventional occupations were common [n = 4356 (36%)], whereas artistic occupations were rare [n = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi-square, 14.61; P = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00-1.31; P = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95-1.66; P = 0.10). The direction and magnitude of ORs were similar in cross-sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08-0.52; P < 0.001) for artistic and 1.23 (95% CI, 0.92-1.67; P = 0.08) for conventional occupations. CONCLUSIONS: The risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre-diagnostic phase of PD. PMID- 30007107 TI - A male's seminal fluid increases later competitors' productivity. AB - Polyandrous females allow for sexual selection to persist after mating. In the event that females successfully mate with more than one male, sperm competition can occur. Seminal fluid proteins can indirectly affect a male's success in sperm competition through reducing the remating behaviour of females and can directly influence sperm competition through directly displacing competitor sperm or inducing females to eject it. These direct effects on competitor sperm are thought to contribute to the 'second male advantage', whereby the second male to mate sires the majority of offspring. Here, we show an additional mechanism where seminal proteins already present within a mated female appear to enhance offspring production of later competitor males, and contribute to second male advantage. Counter to expectation, increased offspring production was not due to a priming effect of greater early female productivity, nor was it through a general and consistent increase in offspring production. Instead, enhanced productivity was solely through lengthening the time that offspring are sired by the second male, indicating that seminal proteins from the first male to mate may enhance second male advantage through a presumably unintended protective effect on subsequent competitor sperm. PMID- 30007108 TI - Insight into the Chemical Diversity of Late/Ice Harvest Gewurztraminer Wine. AB - Late harvest (LHW) and ice harvest (IHW) Gewurztraminer wine samples from Croatia (Ilok) were investigated. Their technological parameters, chromaticity coordinates, total phenols content, and antioxidant capacity were determined. 5 (Hydroxymethyl)furfural, xanthine, and trans-caftaric acid were analyzed in the samples by high performance liquid chromatography (HPLC-DAD). Headspace solid phase microextraction (HS-SPME) followed by gas chromatography and mass spectrometry (GC/MS) analysis revealed isoamyl alcohol as predominant compound (21.25 - 60.30%). Diethyl succinate, 2-phenylethanol, and benzaldehyde were also abundant. Ethyl octanoate (1.48 - 5.70%) and ethyl caprate (0.48 - 4.83%) decreased significantly in LHW, being the lowest in IHW. Two solvents were applied for the samples extraction (solvent A - pentane/diethyl ether 1:2 (v/v) and solvent B - dichloromethane), and the extracts were analyzed by GC/MS. Ethyl hydrogen succinate (solvent A: 27.30 - 52.04%; solvent B: 28.04 - 46.69%) and diethyl succinate (solvent A: 5.21 - 18.2%; solvent B: 2.66 - 7.72%) were predominant in IHW and LHW. Aromatic alcohols were also found: 2-phenylethanol (solvent A: 7.07 - 21.09%; solvent B: 5.50 - 11.82%), 4-hydroxybenzyl alcohol (solvent A: 1.45 - 6.68%; solvent B: 2.47 - 12.16%) and benzyl alcohol (solvent A: 0.10 - 0.77%). The obtained results complement a previous study on IHW (Gewurztraminer) from Croatia providing new features and indicating great chemical diversity among the samples. PMID- 30007109 TI - Oral and maxillofacial trauma in motorcyclists in an Iranian subpopulation. AB - BACKGROUND/AIMS: Road traffic accidents are considered a major cause of oral and maxillofacial trauma. Given that many traumatic injuries and deaths involve motorcyclists, the aim of this study was to investigate this vulnerable group in terms of oral and maxillofacial injuries following accidents. MATERIALS AND METHODS: This cross-sectional study was conducted on 330 patients with oral and maxillofacial injuries at Shahid Rajaee Hospital in Shiraz, Iran, from April to September 2017. A questionnaire with questions regarding age, gender, helmet use, and driver's license was completed for all the patients and their injury type (including dental injuries). Data were analyzed using descriptive statistics and the chi-squared test with a significance level of 95%. RESULTS: Of the 330 patients, 291 (88.2%) were male and 39 (11.8%) were female. There were 283 (85.75%) patients aged 21-30 years, and their mean age was 27.2 +/- 6.5. Most of them (287, 87%) had not been wearing helmets at the time of the accident. Dental injuries were observed in 168 (50.9%) of the patients. Uncomplicated crown fractures were diagnosed in 25.4% of the patients, luxation injuries in 23.2%, and avulsion in 18.9%. Only 19.9% of the patients under the age of 25 had suffered facial injuries. CONCLUSION: Most injuries in motorcycle accidents were dental trauma in men due to not wearing a helmet. Dental injuries had the highest frequency of damage. PMID- 30007110 TI - Risk factors for intracranial hemorrhage during vitamin K antagonist therapy in patients with nonvalvular atrial fibrillation: A case-control study. AB - BACKGROUND: Intracranial hemorrhage (ICH) is the most fearful side effect of oral anticoagulant therapy. It is still unclear which risk factor is involved in ICH during vitamin K antagonists (VKAs) treatment and if commonly used bleeding risk scores are able to predict ICH. PURPOSE: Search for individual risk factors and bleeding risk scores (HAS-BLED, ATRIA and ORBIT) associated with ICHs in patients with atrial fibrillation treated with VKAs. METHODS: This is a retrospective case control study in a single Thrombosis Center. During a 7-year period, patients with nonvalvular atrial fibrillation (NVAF) who developed ICH during VKAs were identified as cases. Four control patients matched for gender, age and length of VKAs were assigned to each case. The association between considered risk factors and ICHs was evaluated using a linear logistic regression method and expressed as odds ratio. Receiver operator characteristic (ROC) curves to assess the predictive ability of bleeding risk scores HAS-BLED, ATRIA and ORBIT were also evaluated. RESULTS: Fifty-one cases of ICH, most of whom were 80 years of age or older (72.5%), were retrieved from the Thrombosis Center's database. Compared to 204 controls, no individual risk factors were associated with ICH. Poor ability to predict ICH was also found using ROC curves (C-statistic for HAS-BLED, ATRIA, and ORBIT were 0.55, 0.53 and 0.54, respectively). CONCLUSIONS: ICHs during VKA therapy preferentially occur in very elderly patients. The risk of ICH is not predicted by the commonly used risk scores. PMID- 30007111 TI - Laboratory criteria for antiphospholipid syndrome: reply. PMID- 30007112 TI - Early and rapid prediction of postoperative infections following percutaneous nephrolithotomy in patients with complex kidney stones. AB - OBJECTIVES: To obtain more accurate and rapid predictors of postoperative infections following percutaneous nephrolithotomy (PCNL) in patients with complex kidney stones, and provide evidence for early prevention and treatment of postoperative infections. PATIENTS AND METHODS: A total of 802 patients with complex kidney stones who underwent PCNL, from September 2016 to September 2017, were recruited. Urine tests, urine cultures (UCs) and stone cultures (SCs) were performed, and the perioperative data were prospectively recorded. RESULTS: In all, 19 (2.4%) patients developed postoperative urosepsis. A multivariate logistic regression analysis revealed that an operating time of >=100 min, urine test results with both positive urine white blood cells (WBC+) and positive urine nitrite (WBC+NIT+), positive UCs (UC+), and positive SCs (SC+) were independent risk factors of urosepsis. The incidence of postoperative urosepsis was higher in patients with WBC+NIT+ (10%) or patients with both UC+ and SC+ (UC+SC+; 8.3%) than in patients with negative urine test results or negative cultures (P < 0.01). Preoperative WBC+NIT+ was predictive of UC+SC+, with an accuracy of >90%. The main pathogens found in kidney stones were Escherichia coli (44%), Proteus mirabilis (14%) and Staphylococcus (7.4%); whilst the main pathogens found in urine were E. coli (54%), Enterococcus (9.4%) and P. mirabilis (7.6%). The incidence of E. coli was more frequent in the group with urosepsis than in the group without urosepsis (P < 0.05). CONCLUSIONS: WBC+NIT+ in preoperative urine tests could be considered as an early and rapid predictor of UC+SC+ and postoperative urosepsis. Urosepsis following PCNL was strongly associated with E. coli infections in patients with complex kidney stones. PMID- 30007113 TI - Urinary stress incontinence and other maternal outcomes 2 years after caesarean or vaginal birth for twin pregnancy: a multicentre randomised trial. AB - OBJECTIVE: Does planned caesarean compared with planned vaginal birth lower the risk of problematic urinary stress, faecal, or flatal incontinence? DESIGN: Women between 320/7 and 386/7 weeks of gestation with a twin pregnancy were randomised to planned caesarean or planned vaginal birth. SETTING: The trial took place at 106 centres in 25 countries. POPULATION: A total of 2305 of the 2804 women enrolled in the study completed questionnaires at 2 years (82.2% follow-up): 1155 in the planned caesarean group and 1150 in the planned vaginal birth group. METHODS: A structured self-administered questionnaire completed at 2 years postpartum. MAIN OUTCOME MEASURES: The primary maternal outcome of the Twin Birth Study was problematic urinary stress, or fecal, or flatal incontinence at 2 years RESULTS: Women in the planned caesarean group had lower problematic urinary stress incontinence rates compared with women in the planned vaginal birth group [93/1147 (8.11%) versus 140/1143 (12.25%); odds ratio, 0.63; 95% confidence interval, 0.47-0.83; P = 0.001]. Among those with problematic urinary stress incontinence, quality of life (measured using the Incontinence Impact Questionnaire, IIQ-7) was not different for planned caesarean versus planned vaginal birth groups [mean (SD): 18.4 (21.0) versus 19.1 (21.5); P = 0.82]. There were no differences in problematic faecal or flatal incontinence, or in other maternal outcomes. CONCLUSIONS: Among women with a twin pregnancy and no prior history of urinary stress incontinence, a management strategy of planned caesarean compared with planned vaginal birth reduces the risk of problematic urinary stress incontinence at 2 years postpartum. Our findings show that the prevalence but not the severity of urinary stress incontinence was associated with mode of birth. FUNDING: Canadian Institutes of Health Research (CIHR) (grant no. MCT-63164). TWEETABLE ABSTRACT: For women with twins, planned caesarean compared with planned vaginal birth is associated with decreased prevalence but not severity of urinary stress incontinence at 2 years. PMID- 30007114 TI - Laboratory criteria for antiphospholipid syndrome: comment. PMID- 30007117 TI - Comment on the global gaming industry's statement on ICD-11 gaming disorder: a corporate strategy to disregard harm and deflect social responsibility? PMID- 30007115 TI - Exosomal zinc transporter ZIP4 promotes cancer growth and is a novel diagnostic biomarker for pancreatic cancer. AB - Pancreatic cancer is one of the deadliest cancers with rapid disease progression. Further elucidation of its underlying molecular mechanisms and novel biomarkers for early detection is necessary. Exosomes are small extracellular vesicles that are released by multiple cell types acting as message carriers during intercellular communication and are promising biomarker candidates. However, the role of pancreatic cancer cell-derived exosomes in cancer progression and the application of these vesicles as novel diagnostic biomarkers have not been fully studied. In this study, we found that PC-1.0 (a highly malignant pancreatic cell line) cell-derived exosomes could be taken up by and enhance PC-1 (a moderately malignant pancreatic cell line) cell proliferation, migration and invasion abilities. We identified ZIP4 as the most upregulated exosomal protein in PC-1.0 cells from our proteomic analysis. In vitro and in vivo (a subcutaneous BALB/c nude mouse model) studies showed that exosomal ZIP4 can significantly promote pancreatic cancer growth. Using clinical blood samples, we compared the diagnostic values of serum exosomal ZIP4 levels between malignant pancreatic cancer patients (n = 24) and benign pancreatic disease patients (n = 32, AUC = .89), and between biliary disease patients (n = 32, AUC = .8112) and healthy controls (n = 46, AUC = .8931). In conclusion, exosomal ZIP4 promotes cancer growth and is a novel diagnostic biomarker for pancreatic cancer. PMID- 30007116 TI - Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism. AB - : Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY: Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996 1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to >= 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE. PMID- 30007118 TI - Small molecule targeting the Rac1-NOX2 interaction prevents collagen-related peptide and thrombin-induced reactive oxygen species generation and platelet activation. AB - : Essentials Reactive oxygen species (ROS) generation by NOX2 plays a critical role in platelet activation. Rac1 regulation of NOX2 is important for ROS generation. Small molecule inhibitor of the Rac1-p67phox interaction prevents platelet activation. Pharmacologic targeting of Rac1-NOX2 axis can be a viable approach for antithrombotic therapy. SUMMARY: Background Platelets from patients with X-linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX2 exhibit diminished reactive oxygen species (ROS) generation and platelet activation. Binding of Rac1 GTPase to p67phox plays a critical role in NOX2 activation by facilitating the assembly of the NOX2 enzyme complex. Objective We tested the hypothesis that Phox-I, a rationally designed small molecule inhibitor of Rac p67phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Results Collagen-related peptide (CRP) induced ROS generation in a time-dependent manner. Platelets from Rac1-/- mice or human platelets treated with NSC23766, a specific Rac inhibitor, produced significantly less ROS in response to CRP. Treatment of platelets with Phox-I inhibited diverse CRP-induced responses, including: (i) ROS generation; (ii) release of P-selectin; (iii) secretion of ATP; (iv) platelet aggregation; and (v) phosphorylation of Akt. Similarly, incubation of platelets with Phox-I inhibited thrombin-induced: (i) secretion of ATP; (ii) platelet aggregation; (iii) rise in cytosolic calcium; and (iv) phosphorylation of Akt. In mouse models, intraperitoneal administration of Phox-I inhibited: (i) collagen-induced platelet aggregation without affecting the tail bleeding time and (ii) in vivo platelet adhesion/accumulation at the laser injury sites on the saphenous vein without affecting the time for complete cessation of blood loss. Conclusions Small molecule targeting of the Rac1-p67phox interaction may present an antithrombosis regimen by preventing GPVI- and non-GPVI-mediated NOX2 activation, ROS generation and platelet function without affecting the bleeding time. PMID- 30007119 TI - The effect of immediate controlled forces on periodontal healing of teeth replanted after short dry time in dogs. AB - BACKGROUND/AIM: The extra-alveolar dry period and storage medium in which a tooth is kept prior to replantation remain critical factors affecting the survival and repair potential of the periodontal ligament in avulsed teeth. When replantation is not immediate, replacement root resorption (RRR) is the most common complication. The aim of this histological study was to evaluate the effect of immediate controlled-orthodontic forces in periodontal healing of replanted teeth in a canine model. MATERIAL AND METHODS: Sixty maxillary and mandibular premolar roots were endodontically treated in vivo and subsequently hemisected and extracted. Roots were replanted after an extraoral dry time of 20 minutes and randomly assigned to two experimental groups: Group 1: root was stabilized with a flexible and passive bracket/stainless steel wire splint for 2 weeks; Group 2: root was stabilized with a flexible bracket/NiTi wire splint activated with orthodontic elastics for 2 weeks. After 4 months, the dogs were euthanized, and all specimens were processed for histology and microscopically evaluated. RESULTS: The mean percentage of RRR for Group 2 was 3.17 compared with 12.13 in Group 1. Eighty-three percent of specimens from Group 2 exhibited similar healing to the negative control group, compared to 60.5% of the specimens from Group 1. No statistical difference was found in periodontal healing between experimental groups. CONCLUSION: Immediate application of mild and controlled orthodontic forces was not detrimental to the periodontal healing of teeth replanted after 20 minutes extraoral dry time, although no significant improvement on periodontal healing was observed. PMID- 30007120 TI - Toward a transdiagnostic tool to evaluate depressive symptoms across mental disorders: Validation of the Calgary depression rating scale in patients with major depressive disorder. AB - The severity of depressive symptoms across two discrete mental disorders should be evaluated with the same psychometrically validated tools. In patients with schizophrenia the Calgary Depression Rating Scale (CDSS) is recommended for evaluating depressive symptoms. The aim of this study was to validate the CDSS in patients with major depressive disorder. The CDSS exhibit satisfactory psychometric properties for evaluating depressive symptoms in major depressive disorder. Clinicians and researchers now have a validated scale at their disposal to evaluate depressive symptoms in various mental disorders using a transdiagnostic approach. PMID- 30007121 TI - Towards a greater understanding of anxiety sensitivity across groups: The construct validity of the Anxiety Sensitivity Index-3. AB - The present study examined the factor structure, invariance properties, reliability, and validity of the Anxiety Sensitivity Index-3 (ASI-3, Taylor et al., 2007). Participants were recruited from a large, ethnically diverse southwestern university (n = 3651; 77.8% female; Mage = 22.06 years; 28% non Hispanic White). Findings supported a bifactor structure for the ASI-3, which demonstrated measurement invariance across sex, race/ethnicity, age, and sexual minority status. Furthermore, the ASI-3 demonstrated strong reliability and validity, with the anxiety sensitivity general and specific factors (physical, cognitive, and social concerns) evidencing unique patterns of relations with symptoms of depression, suicidality, anxious arousal, and social anxiety. Clinically, these findings generally support the validity of the ASI-3 in measuring anxiety sensitivity across sex, age, race/ethnicity, and sexual minority status. Future work is needed to better understand the role anxiety sensitivity plays within specific demographic subgroups, particularly African Americans, Asian Americans, and sexual minorities. PMID- 30007122 TI - Banzhaf random forests: Cooperative game theory based random forests with consistency. AB - Random forests algorithms have been widely used in many classification and regression applications. However, the theory of random forests lags far behind their applications. In this paper, we propose a novel random forests classification algorithm based on cooperative game theory. The Banzhaf power index is employed to evaluate the power of each feature by traversing possible feature coalitions. Hence, we call the proposed algorithm Banzhaf random forests (BRFs). Unlike the previously used information gain ratio, which only measures the power of each feature for classification and pays less attention to the intrinsic structure of the feature variables, the Banzhaf power index can measure the importance of each feature by computing the dependency among the group of features. More importantly, we have proved the consistency of BRFs, which narrows the gap between the theory and applications of random forests. Extensive experiments on several UCI benchmark data sets and three real world applications show that BRFs perform significantly better than existing consistent random forests on classification accuracy, and better than or at least comparable with Breiman's random forests, support vector machines (SVMs) and k-nearest neighbors (KNNs) classifiers. PMID- 30007123 TI - A self-organizing short-term dynamical memory network. AB - Working memory requires information about external stimuli to be represented in the brain even after those stimuli go away. This information is encoded in the activities of neurons, and neural activities change over timescales of tens of milliseconds. Information in working memory, however, is retained for tens of seconds, suggesting the question of how time-varying neural activities maintain stable representations. Prior work shows that, if the neural dynamics are in the 'null space' of the representation - so that changes to neural activity do not affect the downstream read-out of stimulus information - then information can be retained for periods much longer than the time-scale of individual-neuronal activities. The prior work, however, requires precisely constructed synaptic connectivity matrices, without explaining how this would arise in a biological neural network. To identify mechanisms through which biological networks can self organize to learn memory function, we derived biologically plausible synaptic plasticity rules that dynamically modify the connectivity matrix to enable information storing. Networks implementing this plasticity rule can successfully learn to form memory representations even if only 10% of the synapses are plastic, they are robust to synaptic noise, and they can represent information about multiple stimuli. PMID- 30007124 TI - Distributed zero-sum differential game for multi-agent systems in strict-feedback form with input saturation and output constraint. AB - This paper investigates the distributed differential game tracking problem for nonlinear multi-agent systems with output constraint under a fixed directed graph. Each follower can be taken as strict-feedback structure with uncertain nonlinearities and input saturation. Firstly, by utilizing the command filtered backstepping technique, the distributed tracking control problem of multi-agent systems in strict-feedback form can be transformed into an equivalent distributed differential game problem of tracking error dynamics in affine form by designing a distributed feedforward tracking controller, in which neural networks (NNs) and the auxiliary system are introduced to deal with the unknown nonlinearities and input saturation, respectively. Especially, a novel barrier Lyapunov function (BLF) is firstly introduced to tackle with the output constraint. Subsequently, by using adaptive dynamic programming (ADP) technique, the distributed zero-sum differential game strategy is derived, in which a critic network is constructed to approximate the cooperative cost function online with a novel updating law. Therefore, the whole distributed control scheme not only guarantees the closed loop signals to be cooperatively uniformly ultimately bounded (CUUB), but also ensures the cooperative cost function to be minimized. Meanwhile, the output constraint and input saturation are not violated. Finally, simulation results demonstrate the effectiveness of the proposed method. PMID- 30007125 TI - RAS GTPase-dependent pathways in developmental diseases: old guys, new lads, and current challenges. AB - Deregulated RAS signaling is associated with increasing numbers of congenital diseases usually referred to as RASopathies. The spectrum of genes and mutant alleles causing these diseases has been significantly expanded in recent years. This progress has triggered new challenges, including the origin and subsequent selection of the mutations driving these diseases, the specific pathobiological programs triggered by those mutations, the type of correlations that exist between the genotype and the clinical features of patients, and the ancillary genetic factors that influence the severity of the disease in patients. These issues also directly impinge on the feasibility of using RAS pathway drugs to treat RASopathy patients. Here, we will review the main developments and pending challenges in this research topic. PMID- 30007126 TI - The mechanobiology of zebrafish cardiac valve leaflet formation. AB - Over a lifetime, rhythmic contractions of the heart provide a continuous flow of blood throughout the body. An essential morphogenetic process during cardiac development which ensures unidirectional blood flow is the formation of cardiac valves. These structures are largely composed of extracellular matrix and of endocardial cells, a specialized population of endothelial cells that line the interior of the heart and that are subjected to changing hemodynamic forces. Recent studies have significantly expanded our understanding of this morphogenetic process. They highlight the importance of the mechanobiology of cardiac valve formation and show how biophysical forces due to blood flow drive biochemical and electrical signaling required for the differentiation of cells to produce cardiac valves. PMID- 30007127 TI - Bench to bedside: Current advances in regenerative medicine. AB - Regenerative medicine is a diverse and rapidly evolving field, employing core expertise from biologists, engineers, and clinicians. Recently the field has made significant progress towards regenerating or replacing tissues lost to age, disease or injury. Current strategies include transplantation of adult or pluripotent stem cells to replace tissue or support tissue healing. Promising approaches for the future of regenerative medicine include stimulating endogenous stem cells for in situ repair, transplantation of organoids to repair minor tissue injury, and the use of interspecies chimerism to produce functional metabolic organs for transplantation. In our review we focus on these emerging strategies, paying particular attention to their current and prospective translational impacts and challenges. PMID- 30007128 TI - Common traits between the beige fat-inducing stimuli. AB - Adipose tissues play an essential role in regulating the metabolic homeostasis and can be found in almost all parts of the body. Excessive adiposity leads to obesity and can contribute to metabolic and other disorders. Adipocytes show remarkable plasticity in their function, which can be pushed toward energy storage, or energy expenditure-a 'browning' of fat. Browning is controlled by the cellular milieu of the adipose tissue, with sympathetic innervation and by immune responses as key integrators of the signals that promote browning. Here, we describe the latest contributions to our understanding of how different metabolic stimuli can shape the adipocyte function. We especially focus on the role of the gut microbiota and the negative energy balance in regulating the browning. PMID- 30007129 TI - Out with the old, in with the new: senescence in development. AB - Cellular senescence is a ubiquitous stress response that restricts the proliferative capacity of cells. During ageing, senescent cells accumulate in various tissues leading to a number of age-related pathologies and physiological decline. Previously thought to be a process restricted to adult organisms, cellular senescence has been recently demonstrated to occur during embryonic development of animals ranging from fish to mammals. Together, these studies suggest that developmentally programmed senescence is a transient but intrinsic biological process that contributes to the remodelling of developing structures by promoting immune-mediated cell clearance of particular cell populations or modifying the tissue microenvironment. These observations have important implications for the evolutionary origins of this essential, yet paradoxical mechanism. PMID- 30007130 TI - Brain-derived neurotrophic factor in serum as an animal welfare indicator of environmental enrichment in pigs. AB - Environment enrichment is a rising topic for animal welfare but measures to identify effective enrichment interventions are lacking. In humans and rodent species, environmental enrichment increases brain-derived neurotrophic factor (BDNF), the most abundant neurotrophin in the brain. Higher BDNF concentration is ultimately linked to higher stress resilience, and BDNF in the hippocampus enhances learning and memory. In addition, BDNF concentrations in the brain and blood are correlated, offering the opportunity to use peripheral BDNF as a minimally invasive measure of effective enrichment reflecting neural changes. This study investigated changes in serum BDNF following the provision of environmental enrichment to pigs. Pigs were housed in different environments during lactation (enriched vs barren) and after weaning (enriched vs barren), using a 2 * 2 factorial design and the provision of a foraging block as enrichment. Pigs provided with foraging enrichment during lactation or after weaning tended to have higher serum BDNF concentrations than pigs housed in a barren environment, and this effect was significant for pigs enriched during lactation when sampled 5 wk after weaning. Brain-derived neurotrophic factor concentration reduced as the pigs aged from 3 to 11 wk. The measurement of BDNF in serum brings a practical approach to study the effects of environmental enrichment on neurobiological changes in domestic animals. A better understanding of the factors modulating BDNF and its link to welfare states could bring insight into the benefits of stimulating an animal's life. PMID- 30007131 TI - Influences of maternal nutrient restriction and arginine supplementation on visceral metabolism and hypothalamic circuitry of offspring. AB - Maternal nutrient restriction during gestation can exert long-term negative effects on offspring health and performance. Arginine supplementation may rescue some of the negative effects elicited by maternal nutrient restriction. We tested the hypothesis that maternal arginine supplementation during gestation would rescue deleterious effects of nutrient restriction on in vitro O2 consumption in the liver and jejunum and hypothalamic protein expression of proopiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AgRP), and neuronal nitric oxide synthase (nNOS), and the colocalization of nNOS and active phosphor-signal transducer and activator of transcription 3 (pSTAT3) in female offspring. Multiparous ewes were assigned to dietary treatment at 54 d of gestation: 100% of requirements (Con), 60% of control (Res), or Res plus rumen-protected arginine (Res-Arg; 180 mg/kg). At parturition, offspring were immediately removed from their dam and placed on a common diet. At 54 +/- 4 d of age, female lambs (n = 6 per treatment) were weighed, the liver and jejunum were weighed, and samples were collected for in vitro measurement of O2 consumption. The hypothalamus was collected to determine protein expression of POMC, NPY, AgRP, and nNOS, and the colocalization of nNOS and pSTAT3 (n = 3, 4, and 4 for Con, Res, and Res-Arg, respectively). Hepatic consumption of O2 in vitro (mol/min/liver) was decreased (P = 0.04) in the Res and Res-Arg group compared with Con. Intensity of staining for NPY-containing fibers tended to decrease (P = 0.10) in Res and Res-Arg compared with Con. Number of POMC neuronal cells in the arcuate nucleus (ARC) of the hypothalamus decreased (P <= 0.03) in the Res group compared with Res-Arg. These observations demonstrate that maternal nutrient restriction decreases energy utilization in the liver and number of POMC cells in the ARC of offspring. Supplementation of arginine to the gestating ewe failed to influence hepatic use of energy in lambs from Res ewes. Numbers of POMC-containing cells were increased in the ARC in lambs from ewes restricted to 60% of nutritional requirements and supplemented with rumen-protected arginine, potentially influencing feeding behavior and hepatic energy metabolism. PMID- 30007132 TI - Libet's experiment: A complex replication. AB - Libet's experiment is an influential classical study, which does not stop provoking heated debates. However, a full-scale replication has not been carried out to this day. Libet-style studies have usually focused on isolated ideas and concepts and never on the whole experiment in all its complexity. This paper presents detailed methodological description and results of a complex replication study. The methodology follows Libet's directions closely in most cases; when it does not, the differences are described and elaborated. The results replicate Libet's key findings, but substantial differences were found in some of the results' categories, such as the introspective reports or the number of readiness potentials found. The discussion also addresses some current problems pertaining the methodology of the Libet-style experiments and provides some recommendations based on a detailed process evaluation. PMID- 30007133 TI - Sense of agency for movements. AB - In this paper, we argue that the comparator model is not a satisfactory model of sense of agency (SoA). We present a theoretical argument and experimental studies. We show (1) most studies of SoA neglect a distinction between SoA associated with movements (narrow SoA) and SoA associated with environmental events (broad SoA); (2) the comparator model emerges from experimental studies of sensory consequences narrowly associated with movements; (3) narrow SoA can be explained by a comparator model, but a motor signal model is simpler and explain narrow SoA equally well; and (4) standard experimental paradigms study only broad SoA. Finally, we present results from two experiments, where we have failed to induce illusory narrow SoA in healthy participants. We believe our experimental approaches should have led to illusory SoA, if the comparator model of SoA was correct. The results challenge proponents of the comparator model of narrow SoA. PMID- 30007134 TI - Diagnostics and treatment of thrombotic antiphospholipid syndrome (APS): A personal perspective. AB - Antiphospholipid Syndrome (APS) is a condition characterized by the occurrence of thromboembolic events and/or pregnancy loss combined with one laboratory criterion among Lupus Anticoagulant- LAC, anticardiolipin -aCL, and anti beta2 Glycoprotein I -abeta2GPI antibodies. Several hypotheses were put forward to explain the causal role of antibodies in the clinical events but none is fully convincing. Current laboratory diagnosis is based on three tests (LAC, IgG/IgM abeta2GPI and IgG/IgM aCL antibodies). The triple-positive profile (all the three tests positive, same isotype) is associated with a higher risk for thrombosis. The mainstay of therapy in thrombotic APS is anticoagulation, with VKAs being the cornerstone. Low dose aspirin in combination or alone may have a role in arterial thrombosis, and in primary thromboprophylaxis. The Non-Vitamin K Antagonists Oral Anticoagulants (NOACs) role in the therapy of APS is under investigation but not verified. Alternative treatment options including rituximab and eculizumab have been successfully reported in few cases of catastrophic APS. PMID- 30007135 TI - Unrecognized prolonged viral replication in the pathogenesis of human RSV infection. AB - BACKGROUND: Respiratory symptoms in RSV persist long after the virus is no longer detected by culture. Current concepts of RSV pathogenesis explain this by RSV inducing a long-lasting pathogenic immune cascade. We alternatively hypothesized that prolonged unrecognized RSV replication may be responsible and studied this possibility directly in a human wild-type RSV experimental infection model. OBJECTIVE: The objective of the current report was to define the duration of true human RSV replication by studying it directly in immunocompetent adults experimentally infected with a clinical strain of RSV utilizing this previously established safe and reproducible model. STUDY DESIGN: 35 healthy adult volunteers were inoculated with RSV-A (Memphis-37, a low11 passage clinical strain virus, manufactured from a hospitalized bronchiolitic infant) and evaluated over 12 days. Viral load by culture, parallel quantitative PCR (genomic, message) and RSV-specific IgA, were measured twice daily from serially collected nasal washes. RESULTS: After inoculation, 77% (27/35) of volunteers became RSV infected. As expected, culture-detectable RSV ceased abruptly by the 5 6 t h 15 infection day. However, infected volunteers demonstrated prolonged RSV presence by both genomic and message PCR. RSV-specific IgA rose within respiratory secretions of infected volunteers during same time frame. CONCLUSIONS: RSV replication appears to continue in humans far longer than previously thought. The rise in nasal RSV-specific IgA shortly after infection likely neutralizes culture detectable virus producing misleadingly short durations of infection. Prolonged viral replication helps explain RSV's extended disease manifestations and increases the potential utility of antivirals. PMID- 30007136 TI - Evaluation of a rapid point-of-care HIV screening program in an emergency department setting in Detroit, Michigan. PMID- 30007137 TI - Comparison of the Biofire FilmArray Respiratory Panel, Seegene AnyplexII RV16, and Argene for the detection of respiratory viruses. AB - BACKGROUND: Respiratory infections are common reasons for hospital admission, and are associated with enormous economic burden due to significant morbidity and mortality. The wide spectrum of microbial agents underlying the pathology renders the diagnosis of respiratory infections challenging. Molecular diagnostics offer an advantage to the current serological and culture-based methods in terms of sensitivity, coverage, hands-on time, and time to results. OBJECTIVES: This study aimed to compare the clinical performance of three commercial kits for respiratory viral detection. STUDY DESIGN: The performance of FilmArray Respiratory Panel, AnyplexII RV16, and Argene was compared using clinical respiratory samples (n = 224, comprising 189 nasopharyngeal swabs in Universal Transport Medium (UTM) and 35 endotracheal aspirates), based on common overlapping targets across the platforms. Influenza A "equivocal" and "no subtype" samples by FilmArray were further compared to a laboratory-developed Influenza A/B test. RESULTS AND CONCLUSIONS: The overall performance of all three platforms appeared to be comparable with regards to sensitivities (95.8-97.9%) and specificities (96.1-98.0%), detection of coinfections, and distinguishment of influenza from non-influenza cases. "Equivocal" and "no-subtype" samples by FilmArray mostly represented weak Influenza A by laboratory-developed test. Lower respiratory tract samples had comparable final-run success-rates and discordant rates as compared to UTM. Coronavirus HKU1, which was not targeted by AnyplexII RV16, were detected as OC43. The expected test volume would be the main determinant for the selection of platform. Among the platforms, the FilmArray is the most automated but is of the lowest-throughput and has the highest reagent cost. PMID- 30007139 TI - Evaluating the aptima HIV-1 quant Dx, HCV quant Dx and HBV quant assays against the Abbott HIV-1, HCV and HBV RealTime assays. AB - BACKGROUND: Viral load measurement is routine for the management of patients infected with HIV, HCV or HBV, using sensitive, quantitative, nucleic acid amplification tests (NAATs). However, platforms are not equivalent in terms of turnaround time, random access capability and operator hands-on time. OBJECTIVES AND STUDY DESIGN: We compared the performance of the Hologic Panther transcription-mediated amplification based Aptima assays for HIV, HBV and HCV viral load measurement with the corresponding Abbott m2000 RealTime assays. All Aptima assays were run according to the manufacturer's instructions, on archived patient samples for HIV (n = 251 including subtypes 01_AE, A (A1), B, BG recombinant, C CRF02_AG and G), HBV (n = 117 including genotypes A, B, C and D) and HCV (n = 82 including genotypes 1, 2, 3 and 4). Additional testing was performed with WHO international standards and expanded HIV-1 subtype and HCV NIBSC genotype panels. RESULTS: The Hologic Panther Aptima assays for HIV-1 RNA, HBV DNA and HCV RNA viral load measurements performed equivalently to the Abbott m2000 RealTime assays. The performance of the Aptima assays was also acceptable on the WHO and NIBSC standards and subtype/genotype panels. CONCLUSIONS: The Aptima Panther platform offers equivalent clinical performance for the viral load measurement of these three viruses, with the added benefits of reduced turnaround time, random access capability and reduced 'hands-on time' for staff, resulting in a potentially superior workflow for diagnostic laboratories. PMID- 30007138 TI - Evaluation of the virtues and pitfalls in an HIV screening algorithm based on two fourth generation assays - A step towards an improved national algorithm. AB - BACKGROUND: Fourth-generation immunoassays used for HIV screening, simultaneously detect anti-HIV antibodies and HIV-1 P24 antigen, but are prone to false-positive results. Usually, they are followed by highly specific third-generation assay, able to differentiate between HIV-1/2 infections. In Israel, screening algorithm is based on consecutive testing by two fourth-generation assays and confirmation by a third-generation test. OBJECTIVES: To evaluate the performance of this algorithm. STUDY DESIGN: Architect HIV1/2 Combo (Combo) reactive results were tested by Vidas HIV Duo Ultra (VD). Confirmation was by INNO-LIA HIV 1/2 or Geenius assays. Five-year results were retrospectively analyzed. HIV true positives (TPs), acute infected (AI), false-positives (FPs) and HIV negatives, were as defined by the algorithm. RESULTS: 501,338 individuals were screened, of which 956 were TPs, 64 AI and 30 F Ps. Specificity was almost 100% and positive predictive value 97%. VD was negative in 94% of confirmed Combo false-reactive individuals. The Combo results in the first tested sample differed substantially between TPs, AI and FPs, enabling the determination of a cutoff value that distinguished 94% of TPs and AI from FPs. CONCLUSIONS: An algorithm is suggested that will use a single sample collection. HIV negative diagnosis will be based on Combo unreactive or Combo reactive/VD negative results. HIV positive diagnosis will be based on Combo reactive/ VD positive results, given a Combo value above a designated cutoff. Below this cutoff samples will be tested by a molecular assay. Since HIV-2 rarely occurs in Israel, the use of a third-generation confirmation assay should be discussed. PMID- 30007140 TI - Exploring nursing students' experiences of a drop-in support-centre: A mixed methods study. AB - BACKGROUND: The increased use of blended learning approaches in undergraduate nursing programs has resulted in reduced on-campus contact with academic staff and other students. OBJECTIVES: To explore student's experiences of a Drop-In Support-Centre and assess the impact of attendance on academic performance. DESIGN: Concurrent mixed-methods. SETTING: A large metropolitan, multi-campus university in Sydney, Australia. PARTICIPANTS: Undergraduate nursing students enrolled in a 3-year Bachelor of Nursing program. METHODS: In March 2016, to support students' learning, a weekly Drop-In-Support-Centre (DISC) initiative was piloted. The DISC provided an informal, learning space one day a week for students to access academic support. Baseline quantitative data was extracted from the University administrative dataset with a 12-month follow-up Grade Point Average (GPA) in January 2017. Attendance at the DISC was collected progressively throughout 2016. Qualitative data were collected using semi-structured interviews. RESULTS: Of 1016 undergraduate nursing students enrolled on the campus, 163 (16%) attended DISC at least once. Attendees were older, more likely to be Overseas-born (74% versus 45% native-born, p < 0.001). Sub-group analysis of first year students revealed attendees had a higher grade point average than non-attendees (4.20 versus 3.85, p = 0.005). Controlling for demographic factors, they were over three times more likely (Adjusted Odds Ratio: 3.75, 95% CI: 1.44 9.78) to achieve a higher GPA (>4.0) compared to non-attendees. Thirteen students were interviewed. Two main themes emerged; 1) 'Home away from home' and 2) 'A sense of community: Everyone supports each other' with three accompanying sub themes. CONCLUSIONS: This study supports the usefulness of a Drop-In-Support Centre in enhancing students' learning experiences and outcomes. The success of the program is highlighted by an improvement in academic performance of students who attended the DISC. PMID- 30007141 TI - The efficacy of simulation-based and peer-learning handover training for new graduate nurses. AB - BACKGROUND: Nursing handovers are a crucial nursing practice for patient safety and continuity of nursing care. As a strategy to improve nursing handovers, it has been suggested that new graduate nurses receive training in how to conduct handovers. OBJECTIVES: The purpose of this study was to examine the effects of simulation-based handover training and peer-learning handover training on clinical competence regarding handovers and clinical judgment among new graduate nurses. DESIGN: Quasi-experimental research using a nonequivalent control group post-test design. PARTICIPANTS: A convenience sample of 55 new graduate nurses with no clinical experience who expected to work at a university hospital were selected. METHODS: We measured participants' clinical competence regarding handovers and clinical judgment immediately after completing a training program and after 1 month of working at a hospital to examine the immediate and latent effects of simulation-based and peer-learning handover training, respectively. A researcher-developed clinical competence instrument regarding handovers and a clinical judgment instrument based on the Lasater Clinical Judgment Rubric were used. To identify differences in the effects of simulation-based and peer learning handover training, we analyzed the data using the independent t-test and paired t-test. When evaluating the latent effects, the participants wrote self reflection reports. RESULTS: There were no significant differences in the immediate effects of the simulation-based training and the peer-learning training. In contrast, in the evaluation of the latent effects, new graduate nurses who received simulation-based training showed significantly higher clinical competence regarding handovers (p = .020) and clinical judgment (p = .033) than their counterparts who received peer-learning training. In the self reflection reports, 19 participants stated that they had gained more confidence with handovers. CONCLUSION: We suggest that simulation-based handover training contributes more to the improvement of new graduate nurses' clinical competence regarding handovers and clinical judgment than peer-learning training. PMID- 30007143 TI - Definitively unfinished: Why the growth mindset is vital for educators and academic workplaces. PMID- 30007142 TI - Nursing students' knowledge, attitude and practices of infection prevention and control guidelines at a tertiary institution in the Western Cape: A cross sectional study. AB - BACKGROUND: Nurses in sub-Saharan Africa are particularly at a higher risk of acquiring nosocomial infections, considering the increased prevalence of infectious diseases. It is therefore imperative that these nurses have a sound knowledge and understanding of infection prevention procedures. OBJECTIVE: The main objective of this study was to describe the knowledge, attitudes and practices concerning infection prevention and control precautions among nursing students in a resource limited setting. METHOD: A cross sectional study design was employed. A self-administered questionnaire concerning infection prevention and control guidelines were made available to students enrolled in a mainstream programme for completion of an undergraduate nursing degree. SETTING AND PARTICIPANTS: A total of 301 students at second, third and final years of study from a tertiary institution in the Western Cape were invited to participate. RESULTS: The final cohort comprised of 301 students with the majority between the ages of 17-26 (88.2%), with a mean age of 23 +/- 4.7 (SD) years and the dominant gender being female (83.4%). According to the classification system used in this study, the majority of the students were overall evaluated as having good level of knowledge (47.4%) and poor attitude (41.7%) scores, with little difference in practice scores observed between different years of study. There was a positive correlation found between students' total attitude and total practice scores (r = 0.48 p < 0.01). Results showed that significant associations between gender and knowledge (p < 0.05), attitudes (p < 0.05) and practice (p < 0.05) exists. There was also a significant association between province and those who repeated a year with total knowledge scores (p < 0.05). CONCLUSION: Based on the results of this study, it is recommended that interactive infection control courses that promote critical thinking are implemented at undergraduate level along with more stringent forms of assessments focusing on infection prevention and control, during clinical training. PMID- 30007144 TI - Unique experiences of direct entry BSN/BS-PhD nursing students: A Delphi study. AB - BACKGROUND: Given the aging nursing education workforce and the persistent high demand for doctorally-prepared nursing faculty, there is a critical need to increase the number of nurses entering and completing PhD programs. To fill this need, accelerated PhD education pathways, such as the direct entry BSN/BS-PhD education pathway, have become popular. OBJECTIVE: The objective of this study was to explore the unique characteristics of the direct entry BSN/BS-PhD student experience. This study defines and details the experiences of current and past direct entry BSN/BS-PhD students. DESIGN: This was a qualitative, descriptive study. SETTING: Web-based journals and feedback. PARTICIPANTS: Our sample includes four former and current direct entry BSN/BS-PhD students. METHODS: We used the Delphi method to first analyze participants' journal entries on their lived experiences, and then iteratively summarize and classify the experiences into summative themes. RESULTS: We found four themes unique to participants' experiences: commitment to science, nursing identity, exploring prospects, and balancing family and student expectations. CONCLUSIONS: To ensure that BSN/BS-PhD students have a high-quality education, nurse leaders should be aware of the unique perspectives of direct entry BSN/BS-PhD students. Results from this study can be used to evaluate BSN/BS-PhD programs from students' perspectives. PMID- 30007145 TI - The impact of burnout on doctorate nursing faculty's intent to leave their academic position: A descriptive survey research design. AB - BACKGROUND: Despite the fact that the great demands placed on many nursing faculty put them at high risk for job burnout; there are limited studies exploring the relationship between burnout and leaving their academic positions. OBJECTIVE: The objective of this study is to address the national nursing faculty shortage by examining demographics, teaching preparation in the doctoral program, and burnout to determine intent to leave nursing academia among PhD and DNP prepared nursing faculty. DESIGN: A descriptive survey research design was used to identify the most significant factors related to faculty intent to leave their academic position. SETTINGS: An online national survey of doctorate faculty throughout the U.S. was administered. PARTICIPANTS: Full-time nursing faculty who had earned a PhD or DNP degree in nursing with four or less years ofteaching experience after doctoral program graduation were recruited. METHODS: Data was collected from an the online survey posted on Qualtrics. Logistical regression models were used to interpret data significance. RESULTS: A total of 146 nursing faculty responded to the online survey. 51.4% of the respondents (n = 75) had a DNP degree and 48.6% (n = 71) had a PhD degree. 61% of the respondents were over the age of 50 with the remaining 39% of the respondents between ages 20 and 49. PhD-prepared faculty reported higher emotional exhaustion compared to DNP prepared faculty. Findings revealed that degree type (PhD versus DNP), age, and emotional exhaustion and depersonalization in burnout were significant predictors related to intent to leave nursing academia. CONCLUSIONS: To address the nursing faculty shortage issue, it is critical to create supportive and positive working environments to promote the well-being of nursing faculty, provide additional emotional support for the specific PhD-prepared faculty needs that contribute to burnout, and encourage nurses to begin an academic career earlier to help retain nursing faculty in academic settings. PMID- 30007146 TI - A qualitative study of nurses' perceptions of a behavioural strategies e-learning program to reduce interruptions during medication administration. AB - OBJECTIVES: We sought to evaluate the perceptions of nurses of an e-learning educational program to encourage the use of behavioural strategies-blocking, engaging, mediating, multitasking, and preventing-to reduce the negative effects of interruptions during medication administration. DESIGN: A qualitative design was used to evaluate the impact of this e-learning educational intervention on nurses' behaviour. SETTINGS: Two wards (palliative care and aged care) from two different hospitals within a large local health service within Sydney Australia, were included in the study. These wards were also involved in a cluster randomised trial to test the effectiveness of the program. PARTICIPANTS: A purposive sample participated comprising nine registered and enrolled nurses certified to conduct medication administration, who had reviewed the educational modules. METHODS: Two focus groups were conducted and these sessions were digitally recorded and transcribed verbatim. Thematic analysis identified seven themes. RESULTS: The major themes identified included: perceptions of interruptions, accessing the program, content of the program, impact, maintaining good practice and facilitators and barriers to changing behaviour. CONCLUSIONS: The use of embedded authentic images of patient interruptions and management strategies increased some nurses' perceived use of strategies to manage interruptions. Nurses varied in their perception as to whether they could change their behaviour with some describing change at the individual and ward team levels, while others described patient caseload and other health professionals as a barrier. The use of this innovative educational intervention is recommended for staff orientation, student nurses, medical officers and allied health staff. Further research is required in how this e-learning program can be used in combination with other effective interventions to reduce interruptions. PMID- 30007147 TI - Intellectual disability content within pre-registration nursing curriculum: How is it taught? AB - BACKGROUND: Despite experiencing higher rates of physical and mental health conditions compared with the general population, people with intellectual disability face inequitable access to healthcare services. Improving education of healthcare professionals is one way to reduce these inequalities. OBJECTIVE: To determine how intellectual disability content is taught within Australian nursing schools. DESIGN: A two-phase audit of Australian nursing curricula content was conducted using an interview and online survey. SETTING: Nursing schools Australia-wide providing pre-registration courses. PARTICIPANTS: For Phase 1, course coordinators from 31 nursing schools completed an interview on course structure. Teaching staff from 15 schools in which intellectual disability content was identified completed an online survey for Phase 2. METHODS: Methods used to teach intellectual disability content and who taught the content were audited using an online survey. RESULTS: Across the 15 schools offering intellectual disability content, lectures were the most common teaching method (82% of units), followed by tutorials (59%), workshops (26%), then other methods (e.g. e-learning; 12%). Approximately three-quarters of intellectual disability teaching used some problem-and/or enquiry-based learning. Only one nursing school involved a person with intellectual disability in delivering teaching content. Six (19%) participating schools identified staff who specialise in intellectual disability, and seven (23%) identified staff with a declared interest in the area. CONCLUSION: While some nursing schools are using diverse methods to teach intellectual disability content, many are not; as a result, nursing students may miss out on acquiring the attributes which enable them to address the significant health inequalities faced by this group. A specific deficit was identified relating to inclusive teaching and clinical contact with people with intellectual disability. PMID- 30007148 TI - Increasing nursing capacity in genomics: Overview of existing global genomics resources. AB - BACKGROUND: Global genomic literacy of all health professions, including nurses, remains low despite an inundation of genomic information with established clinical and analytic validity and clinical utility. Genomic literacy and competency deficits contribute to lost opportunities to take advantage of the benefits that genomic information provides to improve health outcomes, reduce healthcare costs, and increase patient quality and safety. Nurses are essential to the integration of genomics into healthcare. The greatest challenges to realizing their potential in successful integration include education and awareness. Identification of resources, their focus, whether they targeted at nursing, and how to access them, form the foundation for a global genomic resource initiative led by the Global Genomics Nursing Alliance. OBJECTIVES: The aim was to identify existing global genomic resources and competencies, identifying the source, type and accessibility. DESIGN: Cross sectional online descriptive survey to ascertain existing genomic resources. SETTINGS: Limited to eighteen countries and seven organizations represented by delegates attending the inaugural meeting in 2017 of the Global Genomics Nursing Alliance. PARTICIPANTS: A purposive sample of global nursing leaders and representatives of national and international nursing organizations. METHODS: The primary method was by online survey administered following an orientation webinar. Given the small numbers of nurse leaders in genomics within our sample (and indeed within the world), results were analyzed and presented descriptively. Those identifying resources provided further detailed resource information. Additional data were collected during a face-to-face meeting using an electronic audience-response system. RESULTS: Of the twenty-three global delegates responding, 9 identified existing genomic resources that could be used for academic or continuing genomics education. Three countries have competence frameworks to guide learning and 5 countries have national organizations for genetics nurses. CONCLUSIONS: The genomic resources that already exist are not readily accessible or discoverable to the international nursing community and as such are underutilized. PMID- 30007149 TI - Predictors for nurses and midwives' readiness towards self-directed learning: An integrated review. AB - AIM: To systematically review the existing evidence on predictors for nurses and midwives' readiness towards Self-directed Learning (SDL). BACKGROUND: Increased complexities in healthcare settings demand that nurses and midwives become involved in lifelong learning by means of self-directed learning (SDL) for delivering quality healthcare. More evidence is available for the self-directed learning readiness (SDLR) of nursing and midwifery students, less is systematically derived on predictors for nurses and midwives' readiness to SDL. DESIGN: An integrative systematic review. METHODS: Systematic searches were carried out using the following five electronic databases: PubMed, Science Direct, Google Scholar, Ovid Medline and Embase. Studies published in English language from 2000 to 2017 were included. The integrative systematic review framework developed by Whittemore and Knafl (2005) was used to analyse and summarise the key themes. RESULTS: Of 804 initial screening papers, in total of eight eligible studies (six quantitative and two qualitative) were found. Integrative analysis resulted in four themes as predictors for nurses and midwives' readiness towards SDL: 1) personal characteristics, 2) working environment, 3) online learning and SDLR, and 4) process of SDL. Review found that, although demographic characteristics of nurses and midwives do not influence their SDLR, work environment often influences their SDLR. Furthermore, nurses and midwives have a positive interest in online learning that is often used to improve their knowledge acquisition. CONCLUSION: The review concludes that qualified nurses and midwives have a unique SDL predictors and process; hence, a personalized SDL programme should be prescribed based on personality traits so as to achieve better SDL outcomes. Future research should address the facilitating factors for SDLR, barriers to SDLR and strategies to improve SDLR among nurses and more importantly midwives, as limited evidence is available with respect to the latter. PMID- 30007150 TI - Designing for online computer-based clinical simulations: Evaluation of instructional approaches. AB - BACKGROUND: Online computer-based simulations are becoming more widespread in nursing education. Therefore, an understanding of when and how to implement the variety of instructional strategies related to these simulations is fundamental. OBJECTIVES: This study compares the effectiveness of online computer-based simulations designed using two alternative instructional approaches-Productive Failure and Simple-to-Complex sequencing-on learning of clinical reasoning skills. PARTICIPANTS: Participants in this study were undergraduate nursing students (n = 103, mean age = 23.4 +/- 2.1) enrolled at a university in Israel. METHODS: Participants completed two online simulations designed using Productive Failure approach (emergency medicine, mental health) and two online simulations using Simple-to-Complex approach (cardiovascular health, pediatrics). Pre- and post-test clinical reasoning evaluations were administered prior to and immediately following each simulation. RESULTS: Clinical reasoning learning gains were significantly higher for online simulations designed with the Simple-to Complex approach than simulations designed with Productive Failure approach (F (3, 288) = 9.656, P < 0.001). Students devoted significantly more time (F (1, 102) = 260.15, P < 0.001) and more attempts (F (1, 102) = 167.39, P < 0.001) in learning with Simple-to-Complex simulations than they did with Productive Failure simulations. The amount of time that students were engaged in learning with simulations was significantly associated with learning gains scores. CONCLUSIONS: This study proposes that well-designed online simulations can improve nursing students' clinical reasoning. The Simple-to-Complex approach was found to be more efficient than Productive Failure for online learning. Learning with Simple-to Complex approach was behaviorally more engaging and students' achievements were higher, which implies that instructional process facilitates learning, and therefore have to be taken in consideration by nurse educators. Integration of computerized educational modalities within nursing education is discussed. PMID- 30007151 TI - The use of assessment rubrics to enhance feedback in higher education: An integrative literature review. AB - OBJECTIVE: To explore the literature relating to the use of rubrics in Higher Education. DESIGN: A systematic search using three databases was undertaken, the question used to guide the search strategy was: What are the benefits and challenges of using rubrics as part of the assessment process in Higher Education? DATA SOURCES: Three electronic databases were searched: British Education Index, Education Resources Information Centre and the Cumulative Index to Nursing and Allied Health Literature. REVIEW METHODS: The review utilised an integrative approach to the retrieval and appraisal of the research. As the papers retrieved used different methodologies to explore the use of rubrics they were analysed using either thematic analysis or narrative synthesis. RESULTS: Fifteen papers were identified that met the inclusion and exclusion criteria for the review, these spanned a range of disciplines including education, medicine and design. Four main themes related to the use of rubrics were identified: the reliability and validity of the rubric, student performance, students' perceptions of the rubric and the implementation of the rubric. CONCLUSIONS: Student self-assessment, self-regulation and understanding of assessment criteria were all found to be enhanced by the use of rubrics. However students also reported that rubrics could be restrictive and student stress related to assessments could be increased. Student involvement in the design and implementation of a rubric was identified as being critical to their success. Rubrics were judged favourably by the studies reviewed in this paper, however they were found to be most effective when used as part of an overall assessment strategy that was co-created with students. PMID- 30007152 TI - Temporal variations in kidney metal concentrations and their implications for retinoid metabolism and oxidative stress response in wild yellow perch (Perca flavescens). AB - The objective of this study was to determine if temporal variations in tissue metal concentrations are related to biomarkers of retinoid metabolism and oxidative stress responses in juvenile yellow perch (Perca flavescens). To this end, kidney metal (Cd, Cu and Zn) concentrations were measured in fish sampled in spring and fall 2012 in four lakes representing a wide range of water and sediment metal contamination in the Rouyn-Noranda (Quebec) region. Lakes Opasatica and Helene were considered as reference lakes while lakes Dufault and Marlon were metal-contaminated. Kidney concentrations of Cd, Cu and Zn varied widely between spring and fall in fish from both clean and metal-contaminated lakes. An inter-lake difference in renal metal concentrations was only observed for Cd, with fish from Lake Marlon consistently displaying higher concentrations. In the spring, the concentrations of liver dehydroretinol, dehydroretinyl palmitate and total vitamin A esters were higher in fish sampled in the most contaminated lake. Strong temporal variations in the concentrations of these metabolites, as well as in the percentage of liver free dehydroretinol and the epidermal retinol dehydrogenase 2 transcription levels, were observed in fish living in the most metal-impacted lake, with generally higher values in the spring. In contrast to liver, in muscle, no clear seasonal variations in the concentrations of dehydroretinol, dehydroretinyl stearate or in the percentage of free dehydroretinol were observed in fish captured in the most contaminated lake. Temporal variations of traditional biomarkers of oxidative stress response were also observed in the most metal-impacted lake. For example, the transcription level of the gene encoding Cu/Zn superoxide dismutase-1 in liver and muscle catalase activity of perch sampled in the most contaminated lake were higher in spring than in fall. Positive relationships were found between kidney Cd concentrations and the transcription level of the gene encoding glucose 6 phosphate dehydrogenase, and all forms of retinoid concentrations in liver in spring, except with the percentage of free dehydroretinol where the correlation was negative. Our results translate to a state of stress caused by Cd and illustrate that temporal variations in tissue metal concentrations affect retinoid metabolism and antioxidant capacities in juvenile wild yellow perch. Overall this study contributes to highlight the importance of considering temporal variations when investigating the consequences of metal contamination on the physiology of wild fish. PMID- 30007153 TI - Cadmium-mediated morphological, biochemical and physiological tuning in three different Anabaena species. AB - Cyanobacteria are a natural inhabitant of paddy field and enhance the crop productivity in an eco-friendly manner. Cadmium (Cd) is a perilous trace metal element which not only limits the crop productivity but also inhibits the growth and nitrogen-fixing ability of these diazotrophs as well as the biodiversity of rice field semiaquatic agroecosystems. However, the impact of Cd toxicity in diazotrophic cyanobacteria is yet not adequately addressed. Therefore, in the present study, three diazotrophic cyanobacterial species, i.e., Anabaena sp. PCC7120, Anabaena L31, and Anabaena doliolum were subjected to their LC50 doses of Cd, and their physiological (PSII, Psi, respiration, energy status and nitrogen fixation rate), biochemical variables (such as antioxidant contents and antioxidant enzymes) together with morphological parameters were evaluated. The results of physiological variables suggested that the Cd exposure adversely affects the photosynthesis, respiration, and biological nitrogen fixation ability across three Anabaena species. The results of biochemical variables in terms of accumulation of antioxidants (glutathione, thiol, phytochelatin and proline) content as well as antioxidant enzymes such as glutathione S-transferase (GST), glutathione reductase (GR), catalase-peroxidase (CAT), ascorbate peroxidase (APX) and superoxide dismutase (SOD) revealed that their inter-species stress tolerance behavior may be attributed to the differential accumulation of antioxidants as well as differential antioxidant enzyme activity in three species. Furthermore, the enhanced antioxidant enzymes activity such as GST, GR, CAT, and SOD in Anabaena L31 advocated significantly higher as compared to Anabaena PCC7120 and Anabaena doliolum. In conclusion, Cd-toxicity assessment regarding physiological, biochemical and morphological aspects across three species identified Anabaena L31 as Cd-resistant species than the other two tested species, i.e., Anabaena PCC7120 and Anabaena doliolum. PMID- 30007154 TI - Transcriptomics investigation of thyroid hormone disruption in the olfactory system of the Rana [Lithobates] catesbeiana tadpole. AB - Thyroid hormones (THs) regulate vertebrate growth, development, and metabolism. Despite their importance, there is a need for effective detection of TH disruption by endocrine disrupting chemicals (EDCs). The frog olfactory system substantially remodels during TH-dependent metamorphosis and the objective of the present study is to examine olfactory system gene expression for TH biomarkers that can evaluate the biological effects of complex mixtures such as municipal wastewater. We first examine classic TH-response gene transcripts using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) in the olfactory epithelium (OE) and olfactory bulb (OB) of premetamorphic Rana (Lithobates) catesbeiana tadpoles after 48 h exposure to biologically-relevant concentrations of the THs, 3,5,3'-triiodothyronine (T3) and L-thyroxine (T4), or 17-beta estradiol (E2); a hormone that can crosstalk with THs. As the OE was particularly sensitive to THs, further RNA-seq analysis found >30,000 TH responsive contigs. In contrast, E2 affected 267 contigs of which only 57 overlapped with THs suggesting that E2 has limited effect on the OE at this developmental phase. Gene ontology enrichment analyses identified sensory perception and nucleoside diphosphate phosphorylation as the top affected terms for THs and E2, respectively. Using classic and additional RNA-seq-derived TH response gene transcripts, we queried TH-disrupting activity in municipal wastewater effluent from two different treatment systems: anaerobic membrane bioreactor (AnMBR) and membrane enhanced biological phosphorous removal (MEBPR). While we observed physical EDC removal in both systems, some TH disruption activity was retained in the effluents. This work lays an important foundation for linking TH-dependent gene expression with olfactory system function in amphibians. PMID- 30007155 TI - Atrazine promotes immunomodulation by melanomacrophage centre alterations in spleen and vascular disorders in gills from Oreochromis niloticus. AB - Atrazine is a herbicide that is banned in Europe but remains widely used on different types of crops in several countries in the American continent. Atrazine is known to be an endocrine disruptor and its effects on gonads have been extensively reported, but the toxic action on other organs is poorly documented. In this paper, we investigated the toxicity of atrazine on the gills and spleens of Nile tilapia (Oreochromis niloticus). The median lethal concentration (LC50), capable of killing one-half of the test animals was calculated, and sublethal concentrations of atrazine were used in a semistatic and subchronic assay. The following four experimental groups were formed: control not exposed to atrazine, a group exposed to 1 ppm atrazine for 15 days, a group exposed to 2 ppm for 7 days, and a group exposed to 2 ppm for 15 days. The concentrations were verified during the study by high performance liquid chromatography. The gills and spleens were stained with hematoxylin and eosin and histopathological findings were made. The Perls technique was used on the spleens to identify hemosiderin, lipofuscin, and melanin pigments in the cells from melanomacrophage centres (MMCs). The spleens were submitted to proliferating cell nuclear antigen (PCNA) and inducible nitric oxide synthase (iNOS) immunohistochemistry, and morphometry was used to assess splenocyte proliferation and melanomacrophage iNOS expression. Finally, a colorimetric assay for caspase-3 was performed on the spleens to identify apoptosis. Vascular and structural alterations, such as venous sinus congestion, aneurysm, hemorrhage, pillar cell hypertrophy, disarrangement of secondary lamellae, and epithelial lifting were observed in the gills. The frequency of individuals with aneurysms was higher in the groups treated with 2 ppm than in other groups. Atrazine had an immunomodulatory effect on the spleen, observed by the alteration in the percentage of red and white pulp, alteration of the MMC area, changes in the melanomacrophage pigment content, slight iNOS suppression, decrease in splenocyte proliferation under 1 ppm atrazine, and increased caspase 3 activity under 2 ppm atrazine after 7 and 15 d. Such effects could compromise oxygenation and the immune response and, ultimately, the survival and fitness of the fish. PMID- 30007156 TI - Integrated multi-biomarker responses of juvenile seabass to diclofenac, warming and acidification co-exposure. AB - Pharmaceutical drugs, such as diclofenac (DCF), are frequently detected in the marine environment, and recent evidence has pointed out their toxicity to non target marine biota. Concomitantly, altered environmental conditions associated with climate change (e.g. warming and acidification) can also affect the physiology of marine organisms. Yet, the underlying interactions between these environmental stressors (pharmaceutical exposure and climate change-related stressors) still require a deeper understanding. Comprehending the influence of abiotic variables on chemical contaminants' toxicological attributes provides a broader view of the ecological consequences of climate change. Hence, the aim of this study was to assess the ecotoxicological responses of juvenile seabass Dicenthrachus labrax under the co-exposure to DCF (from dietary sources, 500 +/- 36 ng kg-1 dw), warming (DeltaToC = +5 degrees C) and acidification (DeltapCO2 ~1000 MUatm, equivalent to DeltapH = -0.4 units), using an "Integrated Biomarker Response" (IBR) approach. Fish were exposed to these three stressors, acting alone or combined, for 28 days in a full cross-factorial design, and blood, brain, liver and muscle tissues were subsequently collected in order to evaluate: i) animal/organ fitness; ii) hematological parameters and iii) molecular biomarkers. Results not only confirmed the toxicological attributes of dietary exposure to DCF in marine fish species at the tissue (e.g. lower HSI), cellular (e.g. increased ENAs and lower erythrocytes viability) and molecular levels (e.g. increased oxidative stress, protein degradation, AChE activity and VTG synthesis), but also showed that such attributes are altered by warming and acidification. Hence, while acidification and/or warming enhanced some effects of DCF exposure (e.g. by further lowering erythrocyte viability, and increasing brain GST activity and Ub synthesis in muscle), the co-exposure to these abiotic stressors also resulted in a reversion/inhibition of some molecular responses (e.g. lower CAT and SOD inhibition and VTG synthesis). IBRs evidenced that an overall higher degree of stress (i.e. high IBR index) was associated with DCF and warming co-exposure, while the effects of acidification were less evident. The distinct responses observed when DCF acted alone or the animals were co-exposed to the drug together with warming and acidification not only highlighted the relevance of considering the interactions between multiple environmental stressors in ecotoxicological studies, but also suggested that the toxicity of pharmaceuticals can be aggravated by climate change-related stressors (particularly warming), thus, posing additional biological challenges to marine fish populations. PMID- 30007157 TI - Chlorine toxicity to Navicula pelliculosa and Achnanthes spp. in a flow-through system: The use of immobilised microalgae and variable chlorophyll fluorescence. AB - Chlorination is a widely used antifouling method for freshwater and marine applications. Chlorine added to seawater reacts to form oxidants that are toxic to biofouling organisms. Further, the oxidants that result are short-lived, but may nevertheless affect non-target species in waterbodies receiving the antifouling effluent. This study evaluated the toxicity of chlorinated seawater (e.g. following sodium hypochlorite addition) on two different species of marine benthic diatoms (Achnanthes spp., and Navicula pelliculosa), which are representative of microphytobenthos communities - an important component in coastal habitats that may be exposed to chlorinated seawater. To evaluate the growth inhibition over a 72 h period, algae were immobilised in alginate beads and exposed to different levels of chlorination in a flow through system. Growth rates and physiological condition of the microalgae were evaluated using a Fast Repetition Rate fluorometer (FRRf). To determine whether alginate influenced the sensitivity of algal response, studies were also conducted in a static test system (without renewal of test solutions) using both free cells and immobilised cells with initial chlorine added to achieve a similar range of concentrations as those used in the flow-through study. Within the first hour of the exposure period there was an indication that, for both species, the free algal cells in the static system were more sensitive to exposure to chlorinated seawater than were alginate-immobilised cells in the flow through system. Immobilised cells in a static system with a single addition of chlorine were also less sensitive to chlorination than free algal cells. However, for periods of 24 h or more due to decay of TRO in the static system the exposure of immobilised algae in the flow through system had a greater impact and hence lower effect concentrations. For the flow-through studies Achnanthes spp. was the most sensitive after 72 h exposure with a potential no effect concentration EC10 value of 0.02 mg l-1 as Cl2 equivalents expressed as total residual oxidants (TRO) compared 0.04 mg l-1 TRO for N. pelliculosa. Immobilisation of algal cells in alginate was found to be an effective means of determining the impact of chlorination and is likely to be effective for other non-persistent substances. Based on the data produced, the extent and significance of ecological effects of chlorination upon algal species typical of microphytobenthos are likely to be limited providing discharges comply with a maximum allowable concentration of 0.01 mg l-1 TRO at the edge of an agreed mixing zone. PMID- 30007158 TI - Stoichiometric responses to nano ZnO under warming are modified by thermal evolution in Daphnia magna. AB - Effects of stressors on body stoichiometry are important as these may cascade through food webs. Contamination and global warming are two key anthropogenic stressors, yet their effects on body stoichiometry have been rarely tested. Further, while thermal evolution may increase the ability to deal with warming, it is unknown how thermal evolution modifies the effect of contaminants under warming. Using resurrection ecology, we studied two Daphnia magna subpopulations (old/recent) of which the recent subpopulation evolved a higher heat tolerance. We exposed both subpopulations to a sublethal concentration of nano zinc oxide (nZnO) and 4 degrees C warming and quantified their effects on body stoichiometry: carbon (C), nitrogen (N), phosphorus (P) contents and their ratios (C:N, C:P, N:P). In the old subpopulation, nZnO only marginally decreased the C content and had no effect on N and P contents and their ratios. In contrast, in the recent subpopulation nZnO strongly increased the body P content (+51%) and reduced the C:P (-34%) and N:P (-34%) ratios at 24 degrees C but not at 20 degrees C. Moreover, these stoichiometric changes were not explained by changes of corresponding macromolecules as assumed by theory. Our results indicate that the stoichiometric responses to nZnO in Daphnia are temperature-dependent and modified by rapid evolution. The observed changes in body stoichiometry may affect the food quality of this important prey and have the potential to cascade through food webs and shape nutrients cycling. PMID- 30007159 TI - Sema3E/PlexinD1 inhibition is a therapeutic strategy for improving cerebral perfusion and restoring functional loss after stroke in aged rats. AB - Brain tissue survival and functional recovery after ischemic stroke greatly depend on cerebral vessel perfusion and functional collateral circulation in the ischemic area. Semaphorin 3E (Sema3E), one of the class 3 secreted semaphorins, has been demonstrated to be a critical regulator in embryonic and postnatal vascular formation via binding to its receptor PlexinD1. However, whether Sema3E/PlexinD1 signaling is involved in poststroke neovascularization remains unknown. To determine the contribution of Sema3E/PlexinD1 signaling to poststroke recovery, aged rats (18 months) were subjected to a transient middle cerebral artery occlusion. We found that depletion of Sema3E/PlexinD1 signaling with lentivirus-mediated PlexinD1-specific-shRNA improves tissue survival and functional outcome. Sema3E/PlexinD1 inhibition not only increases cortical perfusion but also ameliorates blood-brain barrier damage, as determined by positron emission tomography and magnetic resonance imaging. Mechanistically, we demonstrated that Sema3E suppresses endothelial cell proliferation and angiogenic capacity. More importantly, Sema3E/PlexinD1 signaling inhibits recruitment of pericytes by decreasing production of platelet derived growth factor-BB in endothelial cells. Overall, our study revealed that inhibition of Sema3E/PlexinD1 signaling in the ischemic penumbra, which increases both endothelial angiogenic capacity and recruitment of pericytes, contributed to functional neovascularization and blood-brain barrier integrity in the aged rats. Our findings imply that Sema3E/PlexinD1 signaling is a novel therapeutic target for improving brain tissue survival and functional recovery after ischemic stroke. PMID- 30007160 TI - Guanfacine treatment for prefrontal cognitive dysfunction in older participants: a randomized clinical trial. AB - This study evaluated the effect of the alpha-2A-adrenoceptor agonist guanfacine on prefrontally mediated cognitive functions, as well as quality of life and global function in healthy older participants. One hundred twenty-three participants aged 75 years and older were randomly assigned to guanfacine 0.5 mg, 0.1 mg, or placebo daily for 12 weeks. The primary outcome measure was the change in z-score for 6 prefrontal executive function tasks over 12 weeks (PEF6). Neither dose of guanfacine improved PEF6 z-score relative to placebo. The rate of mean change (95% confidence interval) in PEF6 z-score over 12 weeks was 0.270 (0.159, 0.380) for placebo, compared with 0.121 (0.011, 0.232) for guanfacine 0.1 mg (p = 0.06, compared to placebo) and 0.213 (0.101, 0.324) for 0.5 mg (p = 0.47). Neither dose of guanfacine improved the quality of life or global function relative to placebo. Among common adverse events, only dry mouth was significantly more frequent on guanfacine compared to placebo. Guanfacine failed to ameliorate prefrontal cognitive function in older individuals, who were cognitively normal for age. PMID- 30007161 TI - No association of salivary total tau concentration with Alzheimer's disease. AB - There is a need for an accessible biomarker that can complement current cerebrospinal fluid and imaging biomarkers in an accurate and early diagnosis of Alzheimer disease (AD). Saliva is a rich source of potential biomarkers and proteins related to neurodegenerative disorders have been shown to be present in this matrix, including tau. In this study, we quantified salivary total tau (t tau) concentration in 160 healthy elderly control, 68 mild cognitive impairment, and 53 AD participants using ultrasensitive Single molecule array (Simoa) technology. No median difference in salivary t-tau concentration was found between AD and mild cognitive impairment or healthy elderly control (12.3 ng/L, 9.8 ng/L and 9.6 ng/L, respectively, p = 0.219). In addition, there was no association of salivary t-tau concentration with neurophysiological assessment or structural magnetic resonance imaging. Despite a nominal increase in AD, due to the large overlaps in concentrations between clinical groups, we conclude that salivary t-tau is a suitable biomarker neither for AD nor for cognitive impairment. PMID- 30007162 TI - Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models. AB - beta-Amyloid oligomers (AbetaOs) and neuroinflammation are 2 main culprits to counteract in Alzheimer's disease (AD). Doxycycline (DOXY) is a second generation antibiotic of the tetracycline class that are promising drugs tested in many clinical trials for a number of different pathologies. DOXY is endowed with antiamyloidogenic properties and better crosses the blood-brain barrier, but its efficacy has never been tested in AD mice. We herein show that 15- to 16-month old APP/PS1dE9 (APP/PS1) AD mice receiving DOXY under different treatment regimens recovered their memory without plaque reduction. An acute DOXY treatment was, also, sufficient to improve APP/PS1 mouse memory, suggesting an action against soluble AbetaOs. This was confirmed in an AbetaO-induced mouse model, where the AbetaO-mediated memory impairment was abolished by a DOXY pretreatment. Although AbetaOs induce memory impairment through glial activation, assessing the anti-inflammatory action of DOXY, we found that in both the AbetaO-treated and APP/PS1 mice, the memory recovery was associated with a lower neuroinflammation. Our data promote DOXY as a hopeful repositioned drug counteracting crucial neuropathological AD targets. PMID- 30007163 TI - The temporal sequence of improved mitochondrial function on the dynamics of respiration, mobility, and cognition in aged Drosophila. AB - Aging is associated with mitochondrial decline and reduced adenosine triphosphate (ATP) production leading to cellular dysfunction, but this is improved by long wavelength light absorbed by cytochrome c oxidase, increasing cytochrome c oxidase activity, ATP production and improving metabolism, sensory motor function, and cognition. Yet, the sequence of these events is unknown. We give old flies a single 90-minute 670-nm pulse and measure temporal sequences of changes in respiration, ATP, motor, and cognitive ability. Respiration increased significantly 20 minutes after light initiation and remained elevated for 4 days. Measurable ATP increased at 1 hour, peaking at 3 hours, and then declined rapidly. Respiration improved before ATP increased, which indicates an early ATP sink. Flies explore environments stereotypically, which is lost with aging but is reestablished for 7 hours after light exposure. However, again, there are improvements before there are peaks in ATP production. Improved mobility and cognitive function persist after ATP levels return to normal. Hence, elevated ATP in age may initiate independent signaling mechanisms that result in improvements in aged metabolism and function. PMID- 30007165 TI - Frequency and amplitude modulation of resting-state fMRI signals and their functional relevance in normal aging. AB - The intrinsic composition and functional relevance of resting-state blood oxygen level-dependent signals are fundamental in research using functional magnetic resonance imaging (fMRI). Using the Hilbert-Huang Transform to estimate high resolution time-frequency spectra, we investigated the instantaneous frequency and amplitude modulation of resting-state fMRI signals, as well as their functional relevance in a large normal-aging cohort (n = 420, age = 21-89 years). We evaluated the cognitive function of each participant and recorded respiratory signals during fMRI scans. The results showed that the Hilbert-Huang Transform effectively categorized resting-state fMRI power spectra into high (0.087-0.2 Hz), low (0.045-0.087 Hz), and very-low (<=0.045 Hz) frequency bands. The high frequency power was associated with respiratory activity, and the low-frequency power was associated with cognitive function. Furthermore, within the cognition related low-frequency band (0.045-0.087 Hz), we discovered that aging was associated with the increased frequency modulation and reduced amplitude modulation of the resting-state fMRI signal. These aging-related changes in frequency and amplitude modulation of resting-state fMRI signals were unaccounted for by the loss of gray matter volume and were consistently identified in the default mode and salience network. These findings indicate that resting-state fMRI signal modulations are dynamic during the normal aging process. In summary, our results refined the functionally related blood oxygen level-dependent frequency band in a considerably narrow band at a low-frequency range (0.045 0.087 Hz) and challenged the current method of resting-fMRI preprocessing by using low-frequency filters with a relatively wide range below 0.1 Hz. PMID- 30007164 TI - Aging-associated changes in cerebral vasculature and blood flow as determined by quantitative optical coherence tomography angiography. AB - Normal aging is associated with significant alterations in brain's vascular structure and function, which can lead to compromised cerebral circulation and increased risk of neurodegeneration. The in vivo examination of cerebral blood flow (CBF), including capillary beds, in aging brains with sufficient spatial detail remains challenging with current imaging modalities. In the present study, we use 3-dimensional (3-D) quantitative optical coherence tomography angiography (OCTA) to examine characteristic differences of the cerebral vasculatures and hemodynamics at the somatosensory cortex between old (16 months old) and young mice (2 months old) in vivo. The quantitative metrics include cortical vascular morphology, CBF, and capillary flow velocity. We show that compared with young mice, the pial arterial tortuosity increases by 14%, the capillary vessel density decreases by 15%, and the CBF reduces by 33% in the old mice. Most importantly, changes in capillary velocity and heterogeneity with aging are quantified for the first time with sufficiently high statistical power between young and old populations, with a 21% (p < 0.05) increase in capillary mean velocity and 19% (p <= 0.05) increase in velocity heterogeneity in the latter. Our findings through noninvasive imaging are in line with previous studies of vascular structure modification with aging, with additional quantitative assessment in capillary velocity enabled by advanced OCTA algorithms on a single imaging platform. The results offer OCTA as a promising neuroimaging tool to study vascular aging, which may shed new light on the investigations of vascular factors contributing to the pathophysiology of age-related neurodegenerative disorders. PMID- 30007166 TI - The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier. AB - Cerebral amyloid angiopathy (CAA), in which amyloid accumulates predominantly in the walls of arterioles and capillaries, is seen in most patients with Alzheimer disease (AD) and may contribute to compromise of blood-brain barrier (BBB) function seen in AD. We investigated the effects of CAA on BBB integrity by examining the expression of the endothelial marker CD31, basement membrane protein collagen IV (COL4), tight junction protein claudin-5, and fibrinogen, a marker of BBB leakage, by immunohistochemistry in the occipital cortex of autopsy brains with AD and capillary CAA (CAA type 1; n = 8), AD with noncapillary CAA (CAA type 2; n = 10), and AD without CAA (n = 7) compared with elderly controls (n = 10). Given the difference in pathogenesis of capillary and noncapillary CAA, we hypothesize that features of BBB breakdown are observed only in capillary CAA. We found decreased expression of CD31 in AD subjects with CAA types 1 and 2 compared with AD without CAA and an increase in COL4 in AD without CAA compared with controls. Furthermore, there was increased immunoreactivity for fibrinogen in AD with CAA type 1 compared with controls. These findings suggest that capillary CAA is associated with morphologic and possibly physiologic alterations of the neurovascular unit and increased BBB permeability in AD. PMID- 30007167 TI - Acute psychosocial stress in mid-aged male rats causes hyperthermia, cognitive decline, and increased deep sleep power, but does not alter deep sleep duration. AB - Aging is associated with altered sleep architecture and worsened hippocampus dependent cognition, highly prevalent clinical conditions that detract from quality of life for the elderly. Interestingly, exposure to psychosocial stress causes similar responses in young subjects, suggesting that age itself may act as a stressor. In prior work, we demonstrated that young animals show loss of deep sleep, deficits in cognition, and elevated body temperature after acute stress exposure, whereas aged animals are hyporesponsive on these measures. However, it is unclear if these age-altered stress responses occur in parallel over the course of aging. To address this, here we repeated the experiment in mid-aged animals. We hypothesized that mid-aged stress responses would be intermediate between those of young and aged subjects. Sixteen mid-aged (12 months) male F344 rats were implanted with EEG/EMG emitters to monitor sleep architecture and body temperature, and were trained on the Morris water maze for 3 days. On the fourth day, half of the subjects were restrained for 3 hours immediately before the water maze probe trial. Sleep architecture and body temperature were measured during the ensuing inactive period, and on the following day, endpoint measures were taken. Restrained mid-aged animals showed resistance to deep sleep loss, but demonstrated stress-induced water maze probe trial performance deficits as well as postrestraint hyperthermia. Taken in the context of prior work, these data suggest that age-related loss of sleep architecture stress sensitivity may precede both cognitive and body temperature-related stress insensitivity. PMID- 30007169 TI - Enhanced postsynaptic inhibitory strength in hippocampal principal cells in high performing aged rats. AB - Hyperactivity within the hippocampal formation, frequently observed in aged individuals, is thought to be a potential contributing mechanism to the memory decline often associated with aging. Consequently, we evaluated the postsynaptic strength of excitatory and inhibitory synapses in the granule cells of the dentate gyrus and CA1 pyramidal cells of a rat model of aging, in which each individual was behaviorally characterized as aged impaired (AI) or aged unimpaired (AU, with performance comparable to young (Y) individuals). In hippocampal slices of these 3 aged groups (Y, AI, AU), we found that compared to the young, the miniature excitatory and inhibitory currents (mEPSCs and mIPSCs) were larger in amplitude in the granule cells of the AU group and smaller in the AI group. In contrast, in CA1 cells, neither the mEPSCs nor the mIPSCs were affected by age, whereas the extrasynaptic conductance responsible for tonic inhibition was selectively enhanced in CA1 cells of AU individuals. Tonic inhibition conductance was not affected by age in the granule cells. These results support the notion that upregulation of synaptic inhibition could be a necessary condition for the maintenance of performance during aging. These findings also underscore the notions that successful aging requires adaptive upregulation, not merely the preservation of youthful functionality, and that age effects are not homogeneous across hippocampal subfields. PMID- 30007168 TI - An isoform-selective p38alpha mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer's disease. AB - Neuroinflammation is a fundamental mechanism in Alzheimer's disease (AD) progression. The stress-induced activation of the p38alpha mitogen-activated protein kinase (MAPK) leads to increased production of proinflammatory cytokines and neurodegeneration. We investigated the effects of an isoform selective p38alpha MAPK inhibitor, MW01-18-150SRM (MW150), administered at 2.5 mg/kg/d (i.p.; 14 days) on early entorhinal cortex (EC) alterations in an AD mouse model carrying human mutations of the amyloid precursor protein (mhAPP). We used electrophysiological analyses with long-term potentiation induction in EC containing brain slices and EC-relevant associative memory tasks. We found that MW150 was capable of rescuing long-term potentiation in 2-month old mhAPP mice. Acute delivery of MW150 to brain slices was similarly effective in rescuing long term potentiation, with a comparable efficacy to that of the widely used multikinase inhibitor SB203580. MW150-treated mhAPP mice demonstrated improved ability to discriminate novel associations between objects and their position/context. Our findings suggest that the selective inhibition of the stress-activated p38alpha MAPK with MW150 can attenuate the EC dysfunctions associated with neuroinflammation in an early stage of AD progression. PMID- 30007170 TI - The neural bases of price estimation: Effects of size and precision of the estimate. AB - People are often confronted with the need of estimating the market price of goods. An important question is how people estimate prices, given the variability of products and prices available. Using event-related fMRI, we investigated how numerical processing modulates the neural bases of retail price estimation by focusing on two numerical dimensions: the size and precision of the estimates. Participants were presented with several product labels and made market price estimates for those products. Measures of product buying frequency and market price variability were also collected. The estimation of higher prices required longer response times, was associated with greater variation in responses across participants, and correlated with increasing medial and lateral prefrontal cortex (PFC) activity. Moreover, price estimates followed Weber's law, a hallmark feature of numerical processing. Increasing accuracy in price estimation, indexed by decreasing Weber fraction, engaged the intraparietal sulcus (IPS), a critical region in numerical processing. Our findings provide evidence for distinguishable neural mechanisms associated with the size and the precision of price estimates. PMID- 30007171 TI - Disordered eating in three different age groups in Cyprus: a comparative cross sectional study. AB - OBJECTIVE: The objective of this study was to evaluate disordered eating behaviours (DEBs) in different age groups in a Cypriot non-clinical population sample. STUDY DESIGN: Comparative cross-sectional study. METHOD: A total of 1716 participants from the Cyprus component of the I.Family study completed the Eating Attitudes Test-26 (EAT-26). The EAT-26 score >=20 was used to define participants at risk for DEBs. Participants were divided according to age: adolescence (12-18 years old), young adulthood (25-45 years old) and middle adulthood (46-60 years old). RESULTS: Mean EAT-26 total scores were higher for middle adulthood men and women compared with the two younger age groups. Young adulthood women had the highest percentage of behavioural symptoms of DEBs: binge eating (35%) and laxatives/diet pills/diuretics (12%) compared with the other age groups. Men and women in young adulthood had the highest percentage of participants with EAT-26 scores >=20. In logistic regression analysis, age group did not prove a significant predictor of DEB risk in a model adjusting for sex, body mass index and physical activity. CONCLUSION: DEB can present at any age and was not confined to adolescence. PMID- 30007172 TI - Vaccination against pertussis and influenza in pregnancy: a qualitative study of barriers and facilitators. AB - OBJECTIVES: Influenza and pertussis vaccination programmes have been in place for pregnant women in the UK since 2009 and 2012, respectively. In 2015, vaccine uptake rates were 55% for influenza and 63% for pertussis in Northern Ireland. We conducted a qualitative study with the aim of learning about the views of pregnant women and identifying potential barriers to vaccination in pregnancy. STUDY DESIGN: Qualitative study using focus groups and in-depth interviews. METHODS: We conducted focus group discussions and interviews on vaccination in pregnancy using a discussion guide developed in consultation with stakeholders and service users. Pregnant women were recruited on-street. We performed inductive coding of transcripts and thematic analysis, using a phenomenological approach. RESULTS: Sixteen pregnant women participated. We identified six key themes. Information and knowledge: Vaccinated and unvaccinated women demonstrated similar levels of knowledge and desire for information, preferring direct communication with healthcare professionals. The influence of others: Some vaccinated participants reported firm endorsements of vaccination by healthcare professionals including midwives, while some unvaccinated women recalled neutral or reticent staff. Acceptance and trust: Most women expressed trust of health professionals. Fear and distrust: Vaccinated individuals expressed concerns about side-effects more than unvaccinated women. A few unvaccinated women expressed distrust of vaccines and healthcare systems. Responsibility for the baby: Both groups prioritised protecting the baby but unvaccinated participants were concerned about vaccine-related harm. Accessing vaccination: Multiple appointments, lack of childcare, time off work and having responsibility to organise vaccination hindered some participants from getting immunised. Some women were willing to be vaccinated but did not recall being offered vaccination or were not sufficiently motivated to make arrangements themselves. CONCLUSION: Healthcare professionals appear to have a vital influential role in pregnant women's decisions about vaccination. Involving midwives and improving convenience of vaccination access may increase uptake. Strategies to develop interventions should address the aforementioned barriers to meet the pregnant women's needs. PMID- 30007173 TI - Cryoprotectant effects of egg yolk on Indian red jungle fowl (Gallus gallus murghi) sperm. AB - Egg yolk is a good external cryoprotectant of mammalian sperm and some wild bird's sperm, but, at least in domestic breeds of chicken (Gallus gallus domesticus), it may inhibit eventual fertilization of ova when high concentrations are used. We hypothesized that egg yolk can protect the sperm from cryo-induced damages providing adequate fertilization in one phylogenetic wild ancestor of current chicken breeds: the Indian red jungle fowl (Gallus gallus murghi). To test the hypothesis, the present study was designed to evaluate different concentrations of egg yolk in extender in comparison with glycerol. Semen collected from Indian red jungle fowl cocks (n = 8) was cryopreserved using different egg yolk concentrations (10%, 15%, 20% and 25%) or 20% glycerol (control group) following routine protocol of cryopreservation. During cryopreservation, sperm motility (67.5 +/- 2.5%), plasma membrane integrity (66.3 +/- 2.4%), viability (58.8 +/- 1.3%) and acrosomal integrity (60.0.8 +/- 2.0%) were recorded highest in an extender with 15% egg yolk compared to other experimental extenders and control at post-dilution, cooling, equilibration and thawing. The no. of fertilized eggs (26.6 +/- 0.7, 21.6 +/- 1.2), percent fertility (55.9 +/- 4.4, 46.5 +/- 2.2), no. of hatched chicks (23.6 +/- 1.0, 17.2 +/- 1.0), percent hatch (49.5 +/- 3.2, 37.1 +/- 2.5%) and hatchability of the fertile eggs (89.4 +/- 2.2, 79.7 +/- 3.7) were recorded higher (P < 0.05) with semen cryopreserved with 15% egg yolk compared to control (20% glycerol). It is concluded that 15% egg yolk can be used in cryopreservation protocol of Indian red jungle fowl sperm. PMID- 30007174 TI - Dry-aging improves meat quality attributes of grass-fed beef loins. AB - The objective of this study was to evaluate the effect of dry-aging on meat quality and microbiological properties of grass-fed beef loins. At 7 d postmortem, eighteen bone-in loins (M. longissimus lumborum) from 9 beef carcasses (USDA Select) were obtained. Each loin was cut in half yielding a total of 36 sections, which were assigned to three aging methods: wet-aging (WA); dry aging (DA); and dry-aging in a water permeable bag (DW). DA resulted in greater shrink and trim loss compared to WA (P < 0.05). However, DW minimized moisture and trim loss resulting in an increase in total saleable yield up to 4%. DA samples were lowest in both aerobic/anaerobic bacteria (P < 0.05). DA steaks had significantly higher flavor and tenderness preferences compared to WA counterparts. Consumers determined DW to have greater juiciness compared with WA (P < 0.05). Our findings indicate that dry-aging could improve eating quality attributes of low marbled grass-fed beef without adversely affecting microbial characteristics. PMID- 30007175 TI - Comparative evaluation of the quality and fatty acid profile of meat from brown hares and domestic rabbits offered the same diet. AB - Since animal diets have a strong influence on meat quality, a comparative study on farmed brown hares and domestic rabbits offered the same diet was undertaken to assess the physical and chemical properties of their meat. Ten brown hares and ten domestic rabbits were used to characterize the traits of meat from the foreleg, hind leg, and Longissimus lumborum muscles. The study indicated higher protein content in hare meat than in rabbit meat. The meat of hares had a concentration of heme iron that was more than twice as high as that of rabbits. Lower SFA and MUFA content and higher PUFA content contributed to the superior PUFA/SFA ratio in hares. An unfavorable n-6/n-3 ratio but superior atherogenic and thrombogenic indices was observed for hare meat. The higher TBARS of hares indicated a higher susceptibility of hare meat to lipid oxidation. Hare meat was also characterized by a higher water holding capacity and higher color indices (redness and chroma). PMID- 30007176 TI - Meat packaging, preservation, and marketing implications: Consumer preferences in an emerging economy. AB - Meat is a perishable food which appears in the market in a variety of forms. Using a choice experiment survey conducted across four Chinese cities, this paper studies consumers' preferences for packaging and preservation methods and place of origin for fresh pork. Results showed that Chinese consumers preferred chilled and locally produced pork packaged in plastic. They discounted frozen and imported pork more than hot pork. Consumers believed that meat, which had been frozen or preserved over a long period, was not as fresh. Many consumers believe their own perceptions about meat preservation methods are correct when in fact they may be wrong. When scientific information about meat preservation methods was introduced, a significantly positive effect could be observed on their preferences and on the willingness-to-pay for frozen meat, chilled meat, and imported meat. This suggests that using science-based information to educate consumers can increase the economic value of pork. The implications on the marketing and trade of pork are explored. PMID- 30007177 TI - Quantitative analysis of the cyclic peptide GG-8-6 in rat plasma using LC-MS/MS and its application to a pharmacokinetic study. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The discovery of new anticancer compounds is of great significance. GG-8-6, cyclo-(Val1-Leu2-Pro3-Ile4-Leu5-Leu6-Leu7-Val8-Leu9), a new synthetic cyclic peptide, might be a potential candidate for developing new anti HCC drugs. GG-8-6 shares no structural homology to current anti-HCC drugs. Therefore, it was necessary to develop a quantitative method for the determination of GG-8-6 in vivo. Herein, a simple, specific and sensitive liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) was developed and validated for the analysis of GG-8-6 in rat plasma. GG-8-6 and the internal standard (IS), A6, cyclo-(Val1-Leu2-Pro3-Ala4-Leu5-Leu6-Leu7-Val8-Leu9), were extracted from rat plasma by ethyl acetate. Chromatographic separation was performed on an Agilent Eclipse XDB-C18 column (4.6 * 150 mm, 5 MUm) with a mobile phase consisting of acetonitrile-water containing 0.1% formic acid (90:10, v/v) with isocratic elution at a flow rate of 0.5 mL/min for 8.0 min. Multiple reaction monitoring (MRM) mode was performed with ion pairs of m/z: 974.8 -> 861.8 for GG-8-6 and 932.7 -> 819.8 for A6. The selectivity, matrix effects, recovery, intra- and inter-day precision and accuracy were validated with acceptable results in accordance with the US Food and Drug Administration guidelines. The calibration curve was linear (r2 > 0.99) over a concentration range of 1-1000 ng/mL with a lower limit of quantification (LLOQ) of 1 ng/mL. The method was successfully applied to the pharmacokinetic study of GG-8-6 in rats. PMID- 30007178 TI - Identification of degradation products of praziquantel during the mechanochemical activation. AB - Praziquantel (PZQ) is an inexpensive, low toxicity BCS II class anthelmintic drug used for the treatment of neglected tropical diseases. In earlier papers a mechanochemical activation has been used to induce physical transformations on the drug which would ameliorate its solubility and hence its bioavailability and a systematic study of the effects of varying temperature, frequency and time of milling on drug melting enthalpy and drug recovery was given. In this communication, the focus is on the degradation products that are formed during this mechanical treatment of Praziquantel. In the cogrinding process with povidone and crospovidone several degradation products are formed. Different degradation products are formed, which depend on the type of polymer rather than the process conditions. Two of the most prominent degradation products were identified and their structure proposed on the basis of information obtained from GC-MS, UPLC-MS and 1H NMR techniques. PMID- 30007179 TI - Discovery of quality control markers from traditional Chinese medicines by fingerprint-efficacy modeling: Current status and future perspectives. AB - Quality control (QC) is crucial for ensuring the safety and effectiveness of traditional Chinese medicines (TCMs). Due to extremely complicated phytochemical matrices and characteristic mode of "multi-component, multi-target, integrated adjustment", discovering of QC markers from TCMs is a big challenge. Fingerprint efficacy (FE) modeling method is currently proposed as an effective and reasonable attempt. This review summarizes the methodologies of FE modeling and applications in screening QC markers, meanwhile the future perspectives are also briefly discussed so as to provide inspiration and reference for follow-up study of FE relationship for TCMs. PMID- 30007180 TI - The long-term impact of multiple sclerosis on the risk of divorce. AB - BACKGROUND: Several studies have investigated the impact of multiple sclerosis (MS) on the risk of divorce. However, current evidence is inconclusive and limited by e.g. small sample populations, short follow-up, and/or lack of a control group. The objective of this retrospective, observational study was to estimate the long-term impact of MS on the risk of divorce. METHODS: Swedish patients diagnosed with MS between 1975 and 2012 were identified in a nationwide disease-specific register (the Swedish Multiple Sclerosis Registry) and matched with general population controls based on age, sex, region of residency, and marital status. We used survival analysis to estimate the cumulative incidence proportion of divorce after index (i.e. the MS diagnosis date). RESULTS: Our final sample comprised 3998 patients and 15,992 general population controls (mean age 44 years; 73% female). Mean follow-up was 10 years (range: 1-37 years). Unadjusted Kaplan-Meier failure functions revealed no significant differences in the cumulative incidence proportion of divorce between patients and controls (log rank test, p = 0.902), or women with MS and female controls (p = 0.157). In contrast, men with MS were estimated to have a notably higher incidence of divorce compared with male controls (p = 0.040). Cox proportional-hazards model outcomes showed that men with MS had a 21% higher risk (HR: 1.21, p = 0.032) of divorce across follow-up compared with male controls when controlling for age, region of residency, and year of diagnosis. No significant adjusted risk increase was found for women with MS. CONCLUSIONS: We show that MS is associated with an increased risk of divorce among men, but not women. Our result should be helpful to inform health policy and clinical interventions, such as relationship counselling programs, and highlight the socio-economic burden of the disease. PMID- 30007181 TI - Application of the time-strain superposition - Part II: Prediction of the frequency-dependent behaviour of brain tissue. AB - Knowing the real material properties of brain tissue is of great importance when it comes to the precise prediction of its mechanical response. The efficiency of these procedures depends on the adequacy of experimental data and the analytical and numerical tools utilized. In this study, we combine existing approaches within the theory of viscoelasticity in order to predict the frequency-dependent behaviour of the porcine brain from the known stress relaxation data. Time-strain superposition is applied to the brain shear relaxation segments for the construction of the long-term master curve in the linear viscoelastic range. A widely-used and well-established numerical procedure is then utilized for the prediction of the frequency-dependent modulus based on the constructed master curve. The demonstrated methodology is evaluated using the porcine brain experimental data available from the literature. The results show reasonably good agreement between the predicted and the previously measured and published storage modulus data in the whole frequency range investigated. On the other hand, prediction of the loss modulus is only possible within certain frequency ranges related to the time frame of experimentally known relaxation behaviour. Nevertheless, the outcomes of the paper speak in favour of the validity of the linear viscoelastic interconversion relations between the time- and frequency dependent material functions of the porcine brain tissue exposed to strain up to the tissue's linear viscoelastic limit. PMID- 30007182 TI - Enhanced bone healing in porous Ti implanted rabbit combining bioactive modification and mechanical stimulation. AB - To improve the bone healing efficiency of porous titanium implants, desired biological properties of implants are mandatory, involving bioactivity, osteoconductivity, osteoinductivity and a stable environment. In this study, bare porous titanium (abbr. pTi) with the porosity of 70% was fabricated by vacuum diffusion bonding of titanium meshes. Hydroxyapatite-coated pTi (abbr. Hap-pTi) was obtained by successively subjecting pTi to alkali heat treatment, pre calcification and simulated body fluid. Both pTi and Hap-pTi were respectively implanted into the tibia defect model (phi10 mm * 6 mm) in New Zealand white rabbits, then subjected to non-invasively axial compressive loads at high magnitude low-frequency (HMLF), which were denoted as F-pTi and F-Hap-pTi, respectively. Bone repairing efficiencies were analyzed by postoperative X-ray examination, optical observation and HE staining after 14 and 30 days of implantation. ALP and OCN contents in serum were also examined at 30 days. Results showed that the sham group and sham group with mechanical stimulation (abbr. F-sham) preferably caused bone fractures. Qualitatively, Hap-pTi reduced the risk of bone fractures and enhanced bone healing slightly more effectively compared to bared pTi. However, both Hap-pTi combined with mechanical stimulation and F-pTi in the case of bioactive modification could result in a higher bone healing efficiency (F-Hap-pTi). The molecular signaling investigation of ALP and OCN contents in serum further revealed a probable synergistic effect of Hap coating coupling with HMLF compression on improving bone repairing efficiency. It provides a candidate of clinically applicable therapy for osseous defects. PMID- 30007183 TI - Hard to be killed: Load-bearing capacity of the leech Hirudo nipponia. AB - With the evolution for several millions of years, leeches have developed a perfect capability to resist mechanical loads, which provides many inspirations to engineer new materials and new devices. To uncover the mechanism of its strong survival ability, several mechanical approaches, such as compression, tension, adhesion, impact and blood suction experiments were tried. Our experimental results show that a leech (Hirudo nipponia) can surprisingly withstand a compressive force of nearly 106 times its body weight. In tension, this animal demonstrates large deformation and its strain can reach a value bigger than 3. To avoid being removed from the host skin, it produces an adhesion force superior to 118 times its body weight, and it can endure an impact force at least 1500 times its weight. Also the leech skin can bear an internal fluid pressure of around 6 times the atmospheric pressure. These data show that the leech cannot be killed easily through normal mechanical loading approaches. All these amazing performances lie in hierarchical structures and ductility of the skin with highly developed and compact annuluses, and this feature is beneficial to leech's survival. PMID- 30007184 TI - Estimation of the Young's moduli of fresh human oropharyngeal soft tissues using indentation testing. AB - Finite element (FE)-based biomechanical simulations of the upper airway are promising computational tools to study abnormal upper airway deformations under obstructive sleep apnea (OSA) conditions and to help guide minimally invasive surgical interventions in case of upper airway collapse. To this end, passive biomechanical properties of the upper airway tissues, especially oropharyngeal soft tissues, are indispensable. This research aimed at characterizing the linear elastic mechanical properties of the oropharyngeal soft tissues including palatine tonsil, soft palate, uvula, and tongue base. For this purpose, precise indentation experiments were conducted on freshly harvested human tissue samples accompanied by FE-based inversion schemes. To minimize the impact of the probable nonlinearities of the tested tissue samples, only the first quarter of the measured force-displacement data corresponding to the linear elastic regime was utilized in the FE-based inversion scheme to improve the accuracy of the tissue samples' Young's modulus calculations. Measured Young's moduli of the oropharyngeal soft tissues obtained in this study are presented. They include first estimates for palatine tonsil tissue samples while measured Young's moduli of other upper airway tissues were obtained for the first time using fresh human tissue samples. PMID- 30007185 TI - Electrospun nanofibers hybrid composites membranes for highly efficient antibacterial activity. AB - Safety of drinking-water is an urgent for human health. It is critical to promote the cheap technologies for water purification to guarantee the free-pathogens drinking water. The present study has been investigated the antibacterial activity of polyacrylonitrile (PAN) nanofibers membranes which decorated by Ag, CuO or ZnO nanoparticles as bactericides. The hybrid nanofiber composites were fabricated by electrospinning technique and the obtained membranes were characterized using SEM, EDX and FTIR. Their antibacterial activity was evaluated against E. coli and S. aureus. The data was revealed that the functionalization was successfully obtained by the incorporation of nanoparticles as an additive into the polymer solution which associated many superior properties. Continuous PAN membrane fibers with average diameters from 170 to 250 nm without any beads of plain and its hybrid membrane composites were obtained. The antimicrobial activity was estimated using both disk diffusion tests and growth kinetic models. The antibacterial activity was improved as the concentrations of nanoparticles enhanced. This study provided the real solution for production and inactivation of bacteria which related to the impregnated the PAN nanofibers membrane with Ag, CuO or ZnO NPs. The results have significant implications for finding a safe and an inexpensive path to solve the problems of drinking water, especially in the developing countries. PMID- 30007186 TI - Proteomic profile in the mussel Perna viridis after short-term exposure to the brown tide alga Aureococcus anophagefferens. AB - Blooms of Aureococcus anophagefferens, referred to as brown tides are responsible for massive mortalities and recruitment failure of some bivalves. However, the molecular mechanisms underlying the toxicity remain elusive despite its biological significance, and the information currently available on the molecular effects is still insufficient. In this study, to evaluate the toxicity and associated mechanism of A. anophagefferens on bivalves, we analyzed the protein expression profiles in digestive glands of the A. anophagefferens-exposed Perna viridis by using iTRAQ. A total of 3138 proteins were identified in the digestive glands of A. anophagefferens-exposed P. viridis based on iTRAQ. Amongst, a repertoire of 236 proteins involved in cell, cell part, catalytic activity, metabolic process, biological regulation, immune system process, and response to stimulus were found to be differentially expressed. Functional analysis of the differentially expressed proteins demonstrated that innate immune system of P. viridis was activated, and some proteins associated with stress response and lipid metabolism were induced after exposure to A. anophagefferens. Additionally, MDA content, SOD activity and GSH-Px activity was increased significantly in the digestive gland of A. anophagefferens-exposed P. viridis. Taken together, our results indicated that the A. anophagefferens could induce oxidative stress, activate complement system and alter fat acid metabolism of P. viridis. PMID- 30007187 TI - In-situ growth of lepidocrocite on Bi2O3 rod: A perfect cycle coupling photocatalysis and heterogeneous fenton-like process by potential-level matching with advanced oxidation. AB - gamma-FeOOH was grown in situ on the surface of rod Bi2O3 to construct a perfect cycle coupling photocatalysis and heterogeneous Fenton-like process. The degradation efficiency of this system was detected under the irradiation of visible light. gamma-FeOOH/Bi2O3 showed better degradation efficiency than pure Bi2O3 and gamma-FeOOH, and the amount of TOC was decreased to 4.3, suggesting that the system exhibits outstanding oxidation ability that MO and phenol could be degraded to CO2 and H2O totally. PL spectra, trapping experiments and ESR test were also carried out to confirm the mechanism of photocatalysis with heterogeneous Fenton-like process, and the suitable conduction band (CB) of Bi2O3 matches the electric potential of iron ions was proved to be the key to keep the perfect cycle. Then optimal concentration of H2O2, the effect of pH and the stability of the photocatalyst were also investigated. PMID- 30007188 TI - Revisiting elimination half live as an indicator for bioaccumulation in fish and terrestrial mammals. AB - Current bioaccumulation regulation is focused on bioconcentration in fish. An extension to terrestrial mammals, e.g. rat, is urgently needed but will have to use a different metric, most likely the BMF. While both metrics are thermodynamically not equivalent the regulative testing requirements for both might be reduced to the investigation of the respective elimination rate constants k2 for fish or rat. These k2 values could be derived from animal tests or from in vitro - in vivo extrapolation and could be combined with estimated uptake rate constants to yield either a BCF or a BMF value. The possibility to use in vitro methods for k2 has the advantage that animal tests can be avoided and it bears the chance to experimentally cover species differences which are currently ignored in bioaccumulation regulation. Existing data for BCF and the respective k2 values for fish - either from feeding studies or from BCF studies themselves-indicate that this approach works. For terrestrial bioaccumulation this approach still needs further experimental support. PMID- 30007189 TI - Climatic variations and de-coupling between arsenic and iron in arsenic contaminated ground water in the lowlands of Nepal. AB - As widely known, in several countries in South East Asia, arsenic concentrations in ground water extracted from Quaternary alluvial sediments frequently exceed the World Health Organization (WHO) drinking water guideline of 10 MUg/L. The broadly accepted hypothesis states that reductive dissolution of Fe-bearing minerals releases As-oxyanions contained within these minerals. According to the results presented in this article, As and Fe concentrations in ground water in the lowlands (Terai) of Nepal are highly variable as a function of location and there is a de-coupling of As and Fe concentrations resulting in a loss of correlation between these two elements. The mean concentrations of As and of Fe in 35 wells were slightly higher in the post-monsoon than in the pre-monsoon season. Even though As is mainly associated with iron(hydr)oxides, a substantial portion of As and Fe can be retained by clay minerals (including micas). During pre-monsoon (dry season) clayey sediments are chemically weathered losing Na and K thus remaining relatively enriched in less mobile elements such as Fe and Al. As long as reducing conditions persist, As remains relatively mobile. This article includes a detailed discussion referring to the very weak correlation or decoupling between aqueous As and Fe in the ground water and addresses possible consequences for water treatment. It sheds light on the original reservoir of arsenic being incorporated and released from clay minerals as well as from iron(hydr)oxides. PMID- 30007190 TI - Considerations on the use of equilibrium models for the characterisation of HOC microplastic interactions in vector studies. AB - The association of hydrophobic organic contaminants (HOCs) to microplastics (MPs) in the aquatic environment and the possible perturbation of how biota and HOCs interact (i.e. 'MP vector effect') is a much researched topic in the emergent field of aquatic MP pollution. Consensus on whether the vector-effect is relevant can in part be ascertained using laboratory experimentation. Such studies, of which there are now many examples, have as a mandatory component a characterisation of the HOC-MP interaction. However, important considerations must be made when planning and executing such laboratory experiments, and subsequently when choosing equilibria models to fit sorption curves, as it is necessary to recognize that simplified conceptual models (i.e. Freundlich or Langmuir models) do not fit all HOC-MP interactions under all circumstances. The sorption equilibrium of HOCs to most plastic particles occurs as a combination of surface adsorption in the crystalline regions of the polymer (typically characterized by Langmuir models) and internal partition into amorphous regions (modelled with Freundlich relations), but this is rarely recognized. In this discussion we highlight some considerations needed when both characterizing the interactions between MPs and HOCs and improving the environmental realism of vector studies through the use of, for instance, weathered particles, adequate time for HOC-MP equilibria to be reached and working at lower concentrations. Increasing environmental realism of vector studies corresponds to a greater complexity in the equilibria model, but ultimately allows better understanding of any potential HOC-MP vector effect in nature. PMID- 30007191 TI - Exposure to ambient fine particulate matter during pregnancy and gestational weight gain. AB - BACKGROUND: Gestational weight gain (GWG) is increasingly reported to be associated with adverse birth outcomes. However, the effect of PM2.5 exposure during pregnancy on GWG is unknown. OBJECTIVES: We investigated the associations between the exposure to PM2.5 and GWGs during three pregnancy trimesters based on a prospective birth cohort. METHODS: Data were obtained from 2029 pregnant women who participated in a birth cohort between January 2013 and October 2014 in Wuhan, China. A spatial-temporal land use regression model was used to estimate the trimester and overall pregnancy exposures of PM2.5 of each pregnant woman. The relationships between PM2.5 exposure and GWG were estimated using linear mixed models. RESULTS: The median value of GWG was 2.0 kg (interquartile range (IQR): 4.0) in the first trimester, 6.5 kg (IQR: 3.5) in the second trimester, and 7.0 kg (IQR: 3.5) in the third trimester, respectively. The exposure to PM2.5 was peaked in the first trimester (median concentration: 117.3 MUg/m3 (IQR: 71.9)). After adjustment for potential confounders, each 10 MUg/m3 increase in PM2.5 was consistently associated with increases in GWG in overall pregnancy (0.14 kg, 95% confidence interval (CI): 0.12, 0.17), the first (0.15 kg, 95%CI: 0.12, 0.18), second (0.15 kg, 95%CI: 0.10, 0.19) and third trimester (0.13 kg, 95%CI: 0.09, 0.17). Further stratified analysis indicated that pregnant women who delivered in spring or summer gained more body weight associated with PM2.5 exposure. CONCLUSIONS: This study provides evidence on the effect of exposure to PM2.5 on GWG and it is the first report on the importance of reducing the ambient PM2.5 in controlling of GWG in pregnant women. PMID- 30007192 TI - New insight of tertiary-amine modified bentonite amendment on the nitrogen transformation and volatile fatty acids during the chicken manure composting. AB - In this study, the main objective was to investigate the potential effect of tertiary-amine modified bentonite (TAMB) on the nitrogen transformation and the volatile fatty acids (VFAs) degradation during the chicken manure (CM) composting. Six dosages of TAMB (0%, 2%, 4%, 6%, 8% and 10%) were amended into the mixture of CM and wheat straw and then composted for 50 days. The results revealed the TAMB amendment could prolong the thermophilic phase and enhance the organic matter (OM) degradation. With the increasing dosage of TAMB, the ammonia volatilization was reduced by 15.41%-65.35%. Meanwhile, the TAMB addition had a positive effect on VFAs degradation and reducing odor unitMAX (OUMAX) by 17.61% 59.24%. Moreover, CH4 was reduced by 12.15%-32.78% in TAMB applied treatments compared to control. Finally, combined with all results, it indicated that TAMB amendment could reduce VFAs, CH4 emission and nitrogen loss to improve the compost quality. PMID- 30007193 TI - Application of anaerobic dynamic membrane bioreactor (AnDMBR) for the successful enrichment of Anammox bacteria using mixed anaerobic and aerobic seed sludge. AB - This study investigated a novel bioreactor configuration coupled with a side stream dynamic membrane (DM) for Anammox enrichment as an alternative for conventional membrane. Bioreactor was fed with synthetic feed and seeded with a mix of anaerobic and aerobic sludge. In situ mechanical cleaning was employed for DM cleaning. DM development and performance was analysed over two polyamide-nylon meshes (200 and 52 um). Solid-liquid separation of 52 um mesh outperformed 200 um with an average effluent turbidity of 2.4 +/- 0.1 NTU. The system was operated at a maximum nitrogen loading rate of 696 mg-N L-1 d-1 and achieved a maximum nitrogen removal rate of 611.6 mg-N L-1 d-1. At steady state, the average ammonium, nitrite and total nitrogen removal efficiencies were 87 +/- 0.6%, 98.5 +/- 0.15% and 87.5 +/- 0.56% respectively. Digital realtime PCRSequence analysis showed that Planctomycetales belonging to ascertained Anammox-specific genera progressively increased their presence in the reactor consistently with its nitrogen removal performance. PMID- 30007194 TI - Graphitic carbon nitride nanosheets anchored with BiOBr and carbon dots: Exceptional visible-light-driven photocatalytic performances for oxidation and reduction reactions. AB - The aim of this work is the fabrication of very efficient visible-light-driven photocatalysts through anchoring carbon dots and BiOBr over nanosheets of graphitic carbon nitride. Hence, a series of g-C3N4 nanosheets/Carbon dots/BiOBr (denoted as CNNS/CDs/BiOBr) nanocomposites with different amounts of BiOBr were synthesized by refluxing route. The resultant photocatalysts were characterized by XRD, EDX, SEM, TEM, HRTEM, AFM, XPS, FT-IR, UV-vis DRS, TGA, BET, and PL instruments. Among the photocatalysts, the CNNS/CDs/BiOBr (20%) nanocomposite exhibited the highest photocatalytic performance for degradations of RhB, MB, and MO under visible light, which is about 129, 29.8, and 20.5 times as superior as the CN powder, respectively. Also, photoreduction of Cr(VI) to Cr(III) over the ternary nanocomposite with 20% of BiOBr showed high photoactivity, which was 21.7 folds higher than that of the pristine CN. Reactive species trapping experiments revealed that superoxide anion radicals and hydroxyl radicals played significant role in degradation reaction of RhB. The utilized photocatalyst was recycled with negligible loss in the activity, which is important in photocatalytic processes. Finally, by studying the electrochemical behavior, the band alignments of the semiconductors were obtained and the preliminary mechanism was suggested as a direct Z-scheme system for the enhanced interfacial charge separation and transfer, which leads to the exceptional photocatalytic performance. PMID- 30007195 TI - An innovative yttrium nanoparticles/PVA modified PSF membrane aiming at decontamination of arsenate. AB - Arsenic contamination due to anthropogenic and natural activities has posted a great risk to humans through several pathways. As such, development of cost effective technologies for arsenic decontamination is very important from both social and economic standpoints. In this paper, we are reporting a novel adsorptive yttrium nanoparticles (YNPs)/polyvinyl alcohol (PVA) modified polysulfone (PSF) membrane for the efficient treatment of arsenic. In the preparation of membrane, the porous PSF membrane fabricated with hydrophilic polyacrylic acid (PAA) polymer was coated by a PVA thin layer and then loaded with YNPs through an in-situ precipitation method using an ammonia vapor. We found that spherical YNPs were uniformly distributed onto the surface and within the matrix of membrane. The adsorption capacity as high as 35.56 mg-As/g was obtained at pH around 7. The membrane worked well across pH 4.0-8.0, with the best performance at pH 5.0. 90% of ultimate adsorption capacity was achieved in 2 h with the initial arsenic concentration of 10 mg/L and at the membrane dosage of 0.2 g/L. The kinetics data can be better fitted by the pseudo-second-order model. The Langmuir isotherm well described the adsorption isothermal data. The filtration studies with an initial arsenate concentration of 94.8 MUg/L showed that the treatment capacities of the composite membrane at pH 7.0 and 5.0 were 296 and 692 L/m2, respectively. The X-ray photoelectron spectroscopy (XPS) analysis suggested that ligand exchange between yttrium-hydroxyl groups and arsenate species may play as the main adsorption mechanism. Our study demonstrates that the membrane is a better material for arsenic decontamination than previously reported adsorptive membranes. PMID- 30007196 TI - A method for quantifying in plane permeability of porous thin films. AB - The in-plane permeability of porous thin films is an important fluid mechanical property that determines wicking and pressure-driven flow behavior in such materials. This property has so far been challenging to measure directly due to the small sidewall cross-sectional area of thin films available for flow. In this work, we propose and experimentally demonstrate a novel technique for directly measuring in-plane permeability of porous thin films of arbitrary thicknesses, in situ, using a manifold pressed to the top surface of the film. We both measure and simulate the influence of the two dimensional flow field produced in a film by the manifold and extract the permeability from measurements of pressure drop at fixed flow rates. Permeability values measured using the technique for a periodic array of channels are comparable to theoretical predictions. We also determine in-plane permeability of arrays of pillars and electrodeposited porous copper films. This technique is a robust tool to characterize permeability of thin films of arbitrary thicknesses on a variety of substrates. In Supplementary material, we provide a solid model, which is useful in three-dimensional printer reproductions of our device. PMID- 30007197 TI - Xurography-based microfluidic algal biosensor and dedicated portable measurement station for online monitoring of urban polluted samples. AB - A critical need exists to develop rapid, in situ, and real-time tools to monitor the impact of pollution discharge toxicity on aquatic ecosystems. The present paper deals with the development of a novel, simple-to-use, low-cost, portable, and user-friendly algal biosensor. In this study, a complete and autonomous portable fluorimeter was developed to assess the A-chlorophyll fluorescence of microalgae, inserted by capillarity into low-cost and disposable xurography-based microfluidic chips. Three microalgae populations were used to develop the biosensor: Chlorella vulgaris, Pseudokirchneriella subcapitata, and Chlamydomonas reinhardtii. Biosensor feasibility and sensitivity parameters, such as algal concentration and light intensity, were optimized beforehand to calibrate the biosensor sensitivity with Diuron, a pesticide known to be very toxic for microalgae. Finally, the biosensor was employed in 10 aqueous urban polluted samples (7 urban wet-weather discharges and 3 wastewater) in order to prove its reliability, reproducibility, and performance in the detection of toxic discharges in the field. PMID- 30007198 TI - Signal amplification strategies for DNA-based surface plasmon resonance biosensors. AB - DNA has well-defined ability to recognize a wide variety of targets, such as small biological molecules, proteins, inorganic ions and small organic molecules. As molecular recognition elements, DNA can be used to build simple, rapid and sensitive biosensors for detection of these targets. DNA-based SPR sensors are considered to be a real-time and label-free tool. We present a systematical and critical review on DNA-based SPR biosensors and their signal amplification via various strategies, focusing on recent advances in nanomaterials, novel DNA amplifications, redox reactions on surface, enzyme amplifications, as well as promising multiplex amplification strategies. PMID- 30007199 TI - Carbon dots-decorated Na2W4O13 composite with WO3 for highly efficient photocatalytic antibacterial activity. AB - Photodisinfection by semiconductors has been proven to be an effective method for achieving antibacterial or antifungal activity. However, the toxicity of the nanomaterial to the environment and organisms is a major concern. Herein, a highly efficient and environmentally friendly photodisinfection material of a carbon dots (CDs) decorated Na2W4O13 composite with WO3 photocatalyst was fabricated via a facile hydrothermal-calcination approach. The TEM (transmission electron microscopy) images showed that CDs decorated the surface of the Na2W4O13 flakes. Compared with the samples without incorporated CDs, the as-synthesized composite of CDs/Na2W4O13/WO3 exhibited excellent antimicrobial activity against E. coli under visible light illumination. Electron spin resonance (ESR) spectroscopy and reactive species scavenging experiments revealed that the hydroxyl radicals and superoxide radical anions played the most important role in the photocatalytic bacterial inactivation. Furthermore, the cytotoxicity of the CDs/Na2W4O13/WO3 composite was evaluated by analyzing the viability of HepG2 and Chinese hamster lung (V79) cells using Cell Counting Kit-8 (CCK-8). PMID- 30007200 TI - Intercropping wheat and maize increases the uptake of phthalic acid esters by plant roots from soils. AB - Whether crop intercropping can affect the uptake of phthalic acid esters (PAEs) by plant roots from soils is unclear. In this study, we compare the PAE uptake by plant roots between the wheat/maize intercropping and the wheat and maize monocropping in a field work. We show that the PAE bioconcentration factors of wheat and maize roots are remarkably higher under wheat/maize intercropping than under monocropping, indicating that intercropping may significantly increase the biouptake of PAEs as compared to monocropping. The wheat/maize intercropping can increase the electron transfer capacity (ETC) of water-extractable organic matter (WEOM) in soils by increasing the abundance of redox-active functional groups in WEOM. The ETC-enhanced WEOM may be an important reason for facilitating the reduction of ferric iron [Fe(III)] minerals to soluble ferrous iron [Fe(II)] by acting as electron shuttle, thus leading to the release of the PAEs originally occluded in Fe(III) minerals into soil pore water. The increased bioavailable PAEs distributed in the soil pore water under wheat/maize intercropping eventually result in the increase in the uptake of PAEs by plant roots from soils. The results can provide insights into the link between the uptake of PAEs by crops and the cropping practices in agricultural ecosystems. PMID- 30007201 TI - Selection of indigenous yeast strains for the production of sparkling wines from native Apulian grape varieties. AB - We report the first polyphasic characterization of native Saccharomyces cerevisiae in order to select candidate strains for the design of starter cultures tailored for Apulian sparkling wines obtained from local grape variety. In addition, it is the first survey in our region that propose the selection of autochthonous starter cultures for sparkling wine i) including a preliminary tailored genotypic and technological screening, and ii) monitoring analytical contribution during secondary fermentation in terms of volatile compounds (VOCs). Furthermore, we exploit the potential contribute of autochthonous cultures throughout the productive chain, including the possible improvement of base wine. One representative strain from each cluster was characterized i) for tolerance to abiotic and biotic stressors peculiar of sparkling wine fermentation, ii) for the performances in base wine production, and iii) for the aptitudes to promote in bottle secondary fermentation in white and rose sparkling wines, both obtained from Apulian grape varieties. Genetic characterization led to group 164 S. cerevisiae in 16 genetic clusters based on interdelta profiles. Stress tolerance assays shown a certain correlation with fermentative attitude. Our evidences demonstrated a different fermentative behavior and release of VOCs of the different strains in association with primary and secondary fermentations and as function of wine and rose sparkling wine. Furthermore, performances in white/rose sparkling wines have been found to be strain-dependent characters. Overall, we propose different strains as biotechnological resources suitable to improve the quality of regional sparkling wines and to provide a driver of innovation/segmentation in the market. PMID- 30007202 TI - A unified conceptual framework for prediction and control of microbiomes. AB - Microbiomes impact nearly all systems on Earth, and despite vast differences among systems, we contend that it is possible and highly beneficial to develop a unified conceptual framework for understanding microbiome dynamics that is applicable across systems. The ability to robustly predict and control environmental and human microbiomes would provide impactful opportunities to sustain and improve the health of ecosystems and humans alike. Doing so requires understanding the processes governing microbiome temporal dynamics, which currently presents an enormous challenge. We contend, however, that new opportunities can emerge by placing studies of both environmental and human microbiome temporal dynamics in the context of a unified conceptual framework. Our conceptual framework poses that factors influencing the temporal dynamics of microbiomes can be grouped into three broad categories: biotic and abiotic history, internal dynamics, and external forcing factors. Both environmental and human microbiome science study these factors, but not in a coordinated or consistent way. Here we discuss opportunities for greater crosstalk across these domains, such as leveraging specific ecological concepts from environmental microbiome science to guide optimization of strategies to manipulate human microbiomes towards improved health. To achieve unified understanding, it is necessary to have a common body of theory developed from explicit iteration between models and molecular-based characterization of microbiome dynamics across systems. Only through such model-experiment iteration will we eventually achieve prediction and control across microbiomes that impact ecosystem sustainability and human health. PMID- 30007203 TI - Preeclampsia serum induces human glomerular vascular endothelial cell hyperpermeability via the HMGB1-Caveolin-1 pathway. AB - To explore new ideas about the pathogeny of preeclampsia (PE) proteinuria, this study focused on whether severe PE serum (PES) could induce high-molecular-weight protein (HMWP) hyperpermeability in glomerular endothelial cells (GEC) via the HMGB1-Caveolin-1 (CAV-1) pathway. Normal pregnancy serum (NPS) and severe PES were used to treat primary human GEC monolayer for 24 h. The CAV-1 inhibitor methyl-beta-cyclodextrin (MBCD), the HMGB1 inhibitor glycyrrhizicacid (GA), recombinant HMGB1 (rHMGB1) were also used to treat GEC monolayer that were stimulated by NPS or severe PES. The dynamic permeability of GEC to HMWP was detected by Evans blue-labeled BSA and CAV-1 expression in GEC was analyzed by immunofluorescence staining and Western blotting. We detected HMGB1 expression in placenta and serum in normal pregnancy and severe PE. The results showed that severe PES significantly promoted GEC hyperpermeability and CAV-1 expression. By inhibiting CAV-1 expression, MBCD reversed severe PES-induced GEC monolayer permeability. HMGB1 expression in PE placenta and serum was significantly increased. Compared with that in normal placenta, HMGB1expression was increased in the cytoplasm of syncytiotrophoblast cells in PE placenta. GA decreased the severe PES-induced hyperpermeability and CAV-1 expression in GEC. rHMGB1 induced high expression levels of CAV-1 and HMWP hyperpermeability in GEC. In conclusion, HMGB1 is increased in severe PE patients and induces the expression of CAV-1 in GEC. High expression of CAV-1 in GEC can promote HMWP hyperpermeability, which may contribute to the development of PE proteinuria. PMID- 30007204 TI - Importance of RIP140 and LCoR Sub-Cellular Localization for Their Association With Breast Cancer Aggressiveness and Patient Survival. AB - New markers are needed to improve diagnosis and to personalize treatments for patients with breast cancer (BC). Receptor-interacting protein of 140 kDa (RIP140) and ligand-dependent corepressor (LCoR), two transcriptional co regulators of estrogen receptors, strongly interact in BC cells. Although their role in cancer progression has been outlined in the last few years, their function in BC has not been elucidated yet. In this study, we investigated RIP140 and LCoR localization (cytoplasm vs nucleus) in BC samples from a well characterized cohort of patients (n = 320). RIP140 and LCoR were expressed in more than 80% of tumors, (predominantly in the cytoplasm), and the two markers were highly correlated. Expression of RIP140 and LCoR in the nucleus was negatively correlated with tumor size. Conversely, RIP140 and LCoR cytoplasmic expression strongly correlated with expression of two tumor aggressiveness markers: N-cadherin and CD133 (epithelial mesenchymal transition and cancer stem cell markers, respectively). Finally, high RIP140 nuclear expression was significantly correlated with longer overall survival, whereas high total or cytoplasmic expression of RIP140 was associated with shorter disease-free survival. Our study strongly suggests that the role of RIP140 and LCoR in BC progression could vary according to their prevalent sub-cellular localization, with opposite prognostic values for nuclear and cytoplasmic expression. The involvement in BC progression/invasiveness of cytoplasmic RIP140 could be balanced by the anti-tumor action of nuclear RIP140, thus explaining the previous contradictory findings about its role in BC. PMID- 30007205 TI - Conductometric biosensor for arginine determination in pharmaceutics. AB - A new conductometric biosensor based on coimmobilized urease and arginase has been developed for arginine determination in pharmaceutics. First, the main parameters of the selected method of immobilization (concentrations of arginase, urease, and glutaraldehyde, time of incubation) were optimized. An influence of the solution parameters (buffer ionic strength, capacity, pH, Mn2+ concentration) on the biosensor operation was studied, working conditions were optimized. After biosensor optimization, the main analytical characteristics were as follows. The limit of detection - 2.5 MUM, the linear range - 2.5-500 MUM, the sensitivity to arginine 13.4 +/- 2.4 MUS/mM, the response time - 20 s. The signals repeatability and operational stability in continuous exploitation were studied over one working day and during one week. Additionally, the selectivity of the developed biosensor towards arginine was essayed relative to other amino acids. The developed biosensor has been used to measure arginine concentrations in some drugs. The results obtained were in high correlation with the characteristics declared by producers. PMID- 30007206 TI - A novel approach for the selective analysis of l-lysine in untreated human serum by a co-crosslinked l-lysine-alpha-oxidase/overoxidized polypyrrole bilayer based amperometric biosensor. AB - An amperometric biosensor based on an l-lysine-alpha-oxidase (LO) layer immobilized by co-crosslinking onto the surface of an overoxidized polypyrrole modified Pt electrode (Pt/oPPy) and able to analyse l-lysine (Lys) in untreated human serum is described. The sensing electrode has been characterised and a proper enzyme kinetics optimisation permits to use a low specific enzyme as LO from Trichoderma viride for the selective biorecognition of Lys in the presence of other interferent amino acids; a kinetics study of LO evidenced also the allosteric behaviour of this enzyme, a kinetic feature which was never reported before for this enzyme. The biosensor showed a sensitivity of 0.11 MUA/mM mm2, linear responses up to 4 mM and a limit of detection of 2 MUM; the within-a-day coefficients of variation for replicate (n = 5) were 0.92% and 1.35% at 4 mM and 0.2 mM Lys levels, respectively. The permselective behaviour of Pt/oPPy modified electrode assured an interference- and fouling-free determination of Lys even in untreated serum samples. The determination of Lys in human serum from healthy donors gave Lys levels in good agreement with the expected values so that the use of the proposed biosensor appears promising in the relevant clinical fields. PMID- 30007207 TI - Challenges for successful implantation of biofuel cells. AB - There is a growing interest in the design and engineering of operational biofuel cells that can be implanted. This review highlights the recent progress in the electrochemistry of biofuel cell technologies, but with a particular emphasis on the medical and physiological aspects that impact the biocompatibility of biofuel cells operating inside a living body. We discuss the challenge of supplying power to implantable medical devices, with regard to the limitations of lithium battery technology and why implantable biofuel cells can be a promising alternative to provide the levels of power required for medical devices. In addition to the challenge of designing a biofuel cell that provides a stable level of sufficient power, the review highlights the biocompatibility and biofouling problems of implanting a biofuel cell that have a major impact on the availability of the substrates inside body that provide fuel for the biofuel cell. These physiological challenges and associated ethical considerations are essential to consider for biofuel cells that are designed to be implanted for long-term operation inside a living animal and eventually to human clinical applications. PMID- 30007208 TI - Single cell dielectrophoresis study of apoptosis progression induced by controlled starvation. AB - Nutrient depletion in fed-batch cultures and at the end of batch cultures is among the main causes of stress on cells and a trigger of apoptosis. In this study, we investigated changes in the cytoplasm conductivity of Chinese hamster ovary (CHO) cells under controlled starvation. Employing a single-cell dielectrophoresis (DEP) cytometer, we measured the DEP response of CHO cells incubated in a medium without glucose and glutamine over a 48-h period. Using the measured data in conjunction with numerical simulations, we determined the cytoplasm conductivity of viable and apoptotic cell subpopulations. The results show that a small subpopulation of apoptotic cells emerges after 24 to 36 h of starvation and increases rapidly over a short period of time, <12 h. The apoptotic cells have a dramatically lower cytoplasm conductivity, ~0.05 S/m, than viable cells, ~0.45 S/m. Viability of starvation cultures was measured by fluorescent cytometry, DEP cytometry, and trypan blue exclusion assays. DEP, Annexin V, caspase-8, and 7-AAD assays show a similar decline in viability after 36 h of starvation and indicate a very low viability after 48 h. Trypan blue exclusion assay fails to detect early-stage viability decline and estimates a much higher viability after 48 h. PMID- 30007209 TI - Effects of solidification cooling rate on the corrosion resistance of a biodegradable beta-TCP/Mg-Zn-Ca composite. AB - Biodegradable beta-tricalcium phosphate (beta-TCP) particle reinforced magnesium metal matrix composites (Mg-MMC) have attracted increasing interest for application as implant materials. This investigation was conducted to study the effect of cooling rate on the microstructure and corrosion behavior of a biodegradable beta-TCP/Mg-Zn-Ca composite. The composite was fabricated under a series of cooling rates using a wedge-shaped casting mold. The microstructure of the composite was examined by optical and scanning electron microscopy, and the corrosion behavior was investigated using an electrochemical workstation and immersion tests in a simulated body fluid (SBF). Faster cooling rates were shown to refine the secondary phase and grain size, and produce a more homogenous microstructure. The refined microstructure resulted in a more uniform distribution of beta-TCP particles, which is believed to be beneficial in the formation of a stable and compact corrosion product layer, leading to improved corrosion resistance for the composite. PMID- 30007210 TI - Splenectomy had no significant impact on lipid metabolism and atherogenesis in Apoe deficient mice fed on a severe atherogenic diet. AB - BACKGROUND: For a long time, our major understanding of the spleen is to function as a blood filter for the removal of aged erythrocytes and circulating microorganisms. Splenectomy, therefore, has been widely performed in case of trauma and a variety of hematologic disorders. Although some studies have indicated an increased rate of developing hyperlipidemia and atherosclerotic cardiovascular diseases in splenectomized patients, our recognition of the splenic regulation on lipid metabolism and atherogenesis is still lacking. Here we explored this issue in Apoe deficient (Apoe-/-) mice fed on an atherogenic diet containing 0.5% cholesterol and 20% fat. METHODS: 7-week-old male Apoe-/- mice were randomly divided into splenectomy group and sham operation group. After 1-week recovery from the surgery, mice were subjected to the atherogenic diet for the next 8 weeks. RESULTS: The atherogenic diet induced a severe hypercholesterolemia (about 1500 mg/dl), steatohepatitis and accelerated atherogenesis in the Apoe-/- mice. Splenectomy, compared to sham operation, did not alter plasma lipid levels or lipoprotein profiles; it also did not alter hepatic or adipose lipid deposition. Meanwhile, splenectomy did not alter atherosclerotic plaque burden or composition; it also did not alter aortic gene expression associated with macrophage inflammatory responses. CONCLUSIONS: Our data suggested that splenectomy had no significant impacts on lipid metabolism and atherogenesis in Apoe-/- mice fed on a severe atherogenic diet. PMID- 30007211 TI - Applying a random parameters Negative Binomial Lindley model to examine multi vehicle crashes along rural mountainous highways in Malaysia. AB - Road safety in rural mountainous areas is a major concern as mountainous highways represent a complex road traffic environment due to complex topology and extreme weather conditions and are associated with more severe crashes compared to crashes along roads in flatter areas. The use of crash modelling to identify crash contributing factors along rural mountainous highways suffers from limitations in data availability, particularly in developing countries like Malaysia, and related challenges due to the presence of excess zero observations. To address these challenges, the objective of this study was to develop a safety performance function for multi-vehicle crashes along rural mountainous highways in Malaysia. To overcome the data limitations, an in-depth field survey, in addition to utilization of secondary data sources, was carried out to collect relevant information including roadway geometric factors, traffic characteristics, real-time weather conditions, cross-sectional elements, roadside features, and spatial characteristics. To address heterogeneity resulting from excess zeros, three specialized modelling techniques for excess zeros including Random Parameters Negative Binomial (RPNB), Random Parameters Negative Binomial - Lindley (RPNB-L) and Random Parameters Negative Binomial - Generalized Exponential (RPNB-GE) were employed. Results showed that the RPNB-L model outperformed the other two models in terms of prediction ability and model fit. It was found that heavy rainfall at the time of crash and the presence of minor junctions along mountainous highways increase the likelihood of multi-vehicle crashes, while the presence of horizontal curves along a steep gradient, the presence of a passing lane and presence of road delineation decrease the likelihood of multi-vehicle crashes. Findings of this study have significant implications for road safety along rural mountainous highways, particularly in the context of developing countries. PMID- 30007212 TI - Adoption and learning across hospitals: The case of a revenue-generating practice. AB - Performance-raising practices tend to diffuse slowly in the health care sector. To understand how incentives drive adoption, I study a practice that generates revenue for hospitals: submitting detailed documentation about patients. After a 2008 reform, hospitals could raise their Medicare revenue over 2% by always specifying a patient's type of heart failure. Hospitals only captured around half of this revenue, indicating that large frictions impeded takeup. Exploiting the fact that many doctors practice at multiple hospitals, I find that four-fifths of the dispersion in adoption reflects differences in the ability of hospitals to extract documentation from physicians. A hospital's adoption of coding is robustly correlated with its heart attack survival rate and its use of inexpensive survival-raising care. Hospital-physician integration and electronic medical records are also associated with adoption. These findings highlight the potential for institution-level frictions, including agency conflicts, to explain variations in health care performance across providers. PMID- 30007213 TI - N1-methyladenosine methylome in messenger RNA and non-coding RNA. AB - Chemical modifications to rRNA, tRNA and mRNA provide a new regulatory layer of gene expression, which is termed as the 'epitranscriptome'. N1-methyladenosine (m1A), first characterized more than 50 years ago, is a well-known modification in rRNA and tRNA. m1A in these abundant non-coding RNAs plays important roles in maintaining their biological functions. Recent studies also reveal that m1A is present in both nuclear-encoded and mitochondrial-encoded mRNA and is dynamically regulated by environmental and developmental conditions; m1A is found in a subset of nuclear-encoded long non-coding RNAs as well. Finally, we also discuss the potential challenges of identifying m1A modification in the human transcriptome. PMID- 30007214 TI - Magnetic resonance imaging of cancer metabolism with hyperpolarized 13C-labeled cell metabolites. AB - Hyperpolarization of 13C-labeled substrates can increase their 13C NMR signal by more than 10000-fold, which has allowed magnetic resonance imaging (MRI) of metabolic reactions in vivo. This has already provided a unique insight into the dysregulated metabolic pathways and microenvironment of tumors. Perhaps the best known of the cancer-associated metabolic aberrations is the Warburg effect, which has been imaged in patients using hyperpolarized [1-13C]pyruvate. In clinical oncology there is a requirement to diagnose tumors earlier, better determine their aggressiveness and prognosis, identify novel treatment targets and detect response to treatment earlier. Here we consider some of the hyperpolarized substrates that have been developed and have the potential to meet these requirements and become the precision imaging tools of the future. PMID- 30007215 TI - Sixteen-month-old infants are sensitive to competence in third-party observational learning. AB - Observational learning is important to development, but not all adult models are equally informative and accurate. Selectivity is important in observational learning. Past research studies have not always differentiated competence and confidence, so the current study investigated infants' selective imitation after observing third-party interactions, when confidence and competence were varied independently. Forty-eight 16-month-olds watched a model demonstrate the function of tools while displaying high or low levels of confidence and competence. Infants were significantly more likely to imitate individuals who were competent and were influenced less by their confidence level. Infants were more likely to reach for and use the working tool if the model was competent in her tool choice, but infant behavior was less affected by differences in confidence. Results suggest that by 16-months of age infants are sensitive to the competence of a demonstrator, suggesting a bias in social learning towards more valuable information. PMID- 30007216 TI - Watch and listen - A cross-cultural study of audio-visual-matching behavior in 4.5-month-old infants in German and Swedish talking faces. AB - Investigating infants' ability to match visual and auditory speech segments presented sequentially allows us to understand more about the type of information they encode in each domain, as well as their ability to relate the information. One previous study found that 4.5- month-old infants' preference for visual French or German speech depended on whether they had previously heard the respective language, suggesting a remarkable ability to encode and relate audio visual speech cues and to use these to guide their looking behavior. However, French and German differ in their prosody, meaning that perhaps, the infants did not base their matching on phonological or phonetic cues, but on prosody patterns. The present study aimed to address this issue by tracking the eye gaze of 4.5-month-old German and Swedish infants cross-culturally in an intersensory matching procedure, comparing German and Swedish, two same-rhythm-class languages differing in phonetic and phonological attributes but not in prosody. Looking times indicated that even when distinctive prosodic cues were eliminated, 4.5- month-olds were able to extract subtle language properties and sequentially match visual and heard fluent speech. This outcome was the same for different individual speakers for the two modalities, ruling out the possibility that the infants matched speech patterns specific to one individual. This study confirms a remarkably early emerging ability of infants to match auditory and visual information. The fact that the types of information were matched despite sequential presentation demonstrates that the information is retained in short term memory, and thus goes beyond purely perceptual - here-and-now processing. PMID- 30007217 TI - Child and adolescent sleep duration recommendations in relation to psychological and somatic complaints based on data between 1985 and 2013 from 11 to 15 year olds. AB - PURPOSE: To investigate the association between sleep duration, sleep initiation difficulties and psychological and somatic complaints. METHODS: We used three cohorts of cross-sectional Swedish questionnaire data, from the Health Behaviours of School aged Children (1985/1986, 2005/2006, 2013/2014, n=>18 000, aged 11-15). Specific complaints (e.g. pain) and total complaint load were used as outcomes of sleep duration, sleep initiation difficulties and the combination of them both. RESULTS: Sleeping less than recommended and sleep initiation difficulties were associated with increased odds of specific complaints and belonging to the group with the greatest complaint load. The combination of short sleep duration and sleep initiation difficulties were associated with higher odds than either sleep issue alone. No interaction effects between time and sleep variables were found regarding complaints. CONCLUSIONS: The findings support recent sleep duration recommendations. Further, sleep issues warrant a broad health assessment as they indicate a high likelihood of other complaints. PMID- 30007218 TI - Body mass index and relative dose intensity does not affect the response and outcome of high-risk MDS patients treated with azacytidine. Results from the Hellenic (Greek) MDS study group. PMID- 30007219 TI - Surface modification of nanoporous anodic titanium dioxide layers for drug delivery systems and enhanced SAOS-2 cell response. AB - Nowadays, titanium and its alloys are the most commonly used implantable materials. The surface topography and chemistry of titanium-based implants are responsible for osseointegration. One of the methods to improve biocompatibility of Ti implants is a modification with sodium hydroxide (NaOH) or 3 aminopropyltriethoxysilane (APTES). In the present study, anodic titanium dioxide (ATO) layers were electrochemically fabricated, and then immersed in a NaOH solution or in NaOH and APTES solutions. The functionalized samples were characterized by using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). All samples were examined as drug delivery systems and scaffolds for cell culturing. Based on the parameters of the fitted desorption desorption-diffusion (DDD) model parameters, it was concluded that the modification with NaOH increased the amount of released ibuprofen and inhibited the release process. Osteoblast-like cell line (SAOS-2) was used to investigate the cell response on the non-modified and modified ATO samples. The MTS test and immunofluorescent staining were carried out to examine cell adhesion and proliferation. The data showed that the modification of nanoporous TiO2 layers with small molecules such as APTES enhanced metabolic activity of adhered cells compared with the non-modified and NaOH-modified TiO2 layers. In addition, the cells had a polygonal-like morphology with distinct projecting actin filaments and were well dispersed over the whole analyzed surface. PMID- 30007220 TI - Generation of integration-free induced pluripotent stem cells from a patient with spina bifida. AB - A skin biopsy was obtained from a 14-year-old female patient with a history of Myelomeningocele. Dermal fibroblasts were isolated and reprogrammed with Sendai virus (SeV) vectors encoding OCT3/4, SOX2, KLF4, and c-MYC. The generated induced Pluripotent Stem Cell (iPSC) clones NTDi4_09A were free of genomically integrated reprogramming genes, had a stable normal karyotype and expressed pluripotency markers. The iPSCs formed teratomas in mice, which were differentiated towards derivatives of the three germ layers in vivo. This iPSC line offers a useful resource to study a genetic profile of a patient with spina bifida. PMID- 30007226 TI - New approach in Auger elemental relative sensitive factor calculation by using TEM-EDS analysis based on bi-layers of pure elements. AB - In fabrication of microelectronic devices two important steps are often recognized: i) all the processes performed on the wafer in order to build the active part of the devices and, ii) the assembly and packaging processes, typically performed on a chip, in order to fabricate interconnections between active part and exterior. The wafer back side is an active part of power devices and is normally coated with a stack of Ti-Ni-Au or Ti-Ni-Ag layers to ensure the best electrical contact with the frame on which the device is attached prior to the packaging. An important failure mechanism related to this particular process step is related to the diffusion of Ni to the surface of the stack that causes its oxidation on the back metal surface, inhibiting the correct connection to the metallic frame. Auger Electron Spectroscopy (AES) is a powerful analytical technique that can be used to detect this failure mechanism for its very high sensitivity in the characterization of surface layers. Unfortunately, its results are mainly qualitative. Quantitative extrapolations can be inaccurate using library Elemental Relative Sensitive Factor (ERSF) because they are mainly referred to a silicon substrate and could be not valid for a different matrix. A most accurate evaluation of the ERSF is based on the analysis, under identical experimental condition, of standard materials (with known concentration) that should be similar to the unknown sample and having the same matrix. However, the production of this kind of standard is not easy due to the mobility of Ni in Au and Ag. Another commonly used technique is the Energy Dispersive X-ray Spectrometry (EDS) which is less sensitive than the Auger and not sufficiently adequate for a quantitative analysis due to the limitation of the matrix correction methods. Recently, a new method to perform quantitative analysis by using Transmission Electron Microscopy (TEM) EDS was proposed, starting from bi layers of pure elements. In this work we show how the use of TEM-EDS quantification of Ni in Ag could be a successful method for ERSF evaluation in order to overcome matrix effect in Auger quantification. For this purpose suitable foils of Ag/Al and Ni/Al were used. The validation of the method was performed on a sample with a tri-metal stack of Ti/Ni/Ag previously stimulated by means of a thermal budget to induce Ni migration on Ag surface. The quantitative analysis allowed us to use this characterized sample as AES standard for ERSF calculation. PMID- 30007227 TI - The research progress of LncRNA involved in the regulation of inflammatory diseases. AB - Long non-coding RNA (lncRNA)is a non-coding RNA which lacks a complete open reading frame(ORF) and plays an important role in biological processes such as cell proliferation,differentiation and apoptosis. At present,the expression of lncRNA has been found to be abnormal in inflammatory reaction and inflammatory diseases. It might be involved in the development and progression of inflammatory diseases by regulating the expression of multiple genes and activation of signaling pathways. This article overviewed the progress in study on relationship between lncRNA and inflammatory diseases. PMID- 30007221 TI - Shisa2 regulates the fusion of muscle progenitors. AB - Adult skeletal muscles are comprised of multinuclear muscle cells called myofibers. During skeletal muscle development and regeneration, mononuclear progenitor cells (myoblasts) fuse to form multinuclear myotubes, which mature and become myofibers. The molecular events mediating myoblast fusion are not fully understood. Here we report that Shisa2, an endoplasmic reticulum (ER) localized protein, regulates the fusion of muscle satellite cell-derived primary myoblasts. Shisa2 expression is repressed by Notch signaling, elevated in activated compared to quiescent satellite cells, and further upregulated during myogenic differentiation. Knockdown of Shisa2 inhibits the fusion of myoblasts without affecting proliferation. Conversely, Shisa2 overexpression in proliferating myoblasts inhibits their proliferation but promotes premature fusion. Interestingly, Shisa2-overexpressing nascent myotubes actively recruit myoblasts to fuse with. At the molecular level, Rac1/Cdc42-mediated cytoskeletal F-actin remodeling is required for Shisa2 to promote myoblast fusion. These results provide a novel mechanism through which an ER protein regulates myogenesis. PMID- 30007228 TI - Generation of a T cell receptor (TCR)-like single domain antibody (sDAb) against a Mycobacterium Tuberculosis (Mtb) heat shock protein (HSP) 16kDa antigen presented by Human Leukocyte Antigen (HLA)-A*02. AB - The discovery of heat shock protein 16 kDa antigen protein has deepen the understanding of latent tuberculosis since it was found to be primarily expressed by Mycobacterium tuberculosis during latent phase leading to the rapid optimization and development in terms of diagnosis and therapeutics. Recently, T cell receptor-like antibody has been explored extensively targeting various diseases due to its dual functionality (T cell receptor and antibody). In this study, a TCR-like domain antibody (A2/Ab) with the binding capacity to Mtb heat shock protein (HSP) 16 kDa antigen presented by major histocompatible complex (MHC) HLA-A*02 was successfully generated via biopanning against human domain antibody library. The generated antibody (A2/Ab) exhibited strong functionality and binding capacity against the target assuring the findings of this study to be beneficial for the development of latent tuberculosis diagnosis and immunotherapeutics in future. PMID- 30007229 TI - Comparison of rabies virus protection by single chain and leucine zipper Fv fragments cocktail derived from a monoclonal antibody cocktail. AB - Monoclonal antibodies (MAbs) are a unique and attractive class of biologics and are potential substitutes for post-exposure rabies prophylaxis. The safety, tolerance, and broad neutralization efficiency of a MAb cocktail called CL184, composed of the antibodies CR4098 and CR57, was confirmed in a phase I clinical trial. We have prepared a series of single-chain Fv fragments (scFvs) and leucine zipper Fv fragments (zipFvs) from CR57 and CR4098. In this study, we selected and formed scFv and zipFv cocktails and compared their protective effects against the rabies virus. Mice and hamster challenge models demonstrated the improved protection of the zipFv cocktail compared with scFv cocktail, because of its stronger affinity. The results indicate that zipFv production is a promising novel method for the genetic engineering of antibody fragments and improving affinity through systematic screening may be important when designing small molecule antibodies against RV. PMID- 30007230 TI - MYC inhibition increases PD-L1 expression induced by IFN-gamma in hepatocellular carcinoma cells. AB - The effectiveness of immunotherapy targeting the immune checkpoint PD-L1/PD-1 pathway highlights importance of elucidating the regulatory mechanisms of PD-L1 expression in cancer cells. Previous studies demonstrate that oncogene MYC up regulates PD-L1 expression in lymphomas. In the present study, we investigated the regulatory role of MYC in the PD-L1 expression induced by IFN-gamma in HCC cells. Unexpectedly, knockdown of MYC expression using siRNA assay increased the inducible expression of PD-L1 both at mRNA and protein levels. Mechanistically, the inhibition of MYC elevated expression of STAT1, a critical component of IFN gamma signaling pathway, leading to the elevation of PD-L1 expression in HCC cells exposed to IFN-gamma. These results suggest that MYC may down-regulate PD L1 expression in the context of HCC. This study implicates that a combination therapy targeting MYC function and PD-L1/PD-1 pathway might be effective for treatment of HCC. PMID- 30007231 TI - Triptolide inhibits the inflammatory activities of neutrophils to ameliorate chronic arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cellular infiltration into the joints and cartilage destruction. Neutrophils play a crucial role in the pathogenesis of RA. Triptolide (TP) is a bioactive compound derived from Tripterygium wilfordii Hook F, which has been used in folk medicine as a treatment for a variety of inflammatory disorders, including RA, for many centuries. Previous studies have shown that TP possesses anti-arthritic activity. However, the anti-arthritic mechanism of TP remains to be fully defined. In the present study, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TP on RA and neutrophil function. TP alleviated AA by reducing neutrophil recruitment and suppressing the expression of interleukin-6 and tumour necrosis factor-alpha in vivo. TP also suppressed the expression of pro-inflammatory cytokines in neutrophils, promoted neutrophil apoptosis and inhibited the migration, NETosis and autophagy of neutrophils in vitro. Based on our findings, TP effectively ameliorates RA by down-regulating neutrophil inflammatory functions, indicating that TP represents a potential therapeutic agent for RA. PMID- 30007232 TI - Erythropoietin alleviates hyperglycaemia-associated inflammation by regulating macrophage polarization via the JAK2/STAT3 signalling pathway. AB - BACKGROUND: Erythropoietin (EPO), which is clinically used for renal anaemia, reportedly exerts beneficial pleiotropic effects in atherosclerosis. This aim of this study was to investigate the effects of EPO on macrophage inflammation and polarization under hyperglycaemic conditions and to identify the effects of EPO treated macrophage supernatants (SNs) on endothelial cell (EC) function. METHODS: Peritoneal macrophages (pMPhis) were isolated from normal, diabetic or EPO injected mice. Pro-inflammatory factors were detected by qRT-PCR and ELISA, and macrophage phenotype markers were evaluated by flow cytometry. High glucose culture was used to mimic the hyperglycaemic microenvironment of diabetes mellitus (DM) in vitro. After exposure to various doses of stimuli, macrophage inflammation and phenotype were detected via ELISA, qRT-PCR and flow cytometry. The underlying mechanism was investigated through western blotting. To examine the communication between macrophages and ECs, ECs were cultured with the SN of macrophages treated with different stimuli, and the tube formation ability of ECs was detected using Matrigel. The VEGF, ICAM-1 and VCAM-1 protein expression levels were determined by western blotting, and the nitric oxide (NO) and endothelin-1 (ET-1) expression levels were measured with a nitric oxide indicator and by ELISA, respectively. RESULTS: EPO treatment increased the M2 macrophage population and decreased the number of M1 macrophages. EPO decreased the secretion of pro-inflammatory factors, including TNF-alpha, iNOS and IL-6. The JAK2/STAT3 signalling pathway was also identified as being involved in the M1 macrophage transition. The SN of macrophages treated with EPO (SN-EPO) presented increased NO and ET-1 levels and decreased ICAM-1 and VCAM-1 levels. Tube formation assays revealed that the SN-EPO promoted the ability of ECs to form capillary-like structures in vitro. In contrast, AZD1480, a JAK2 inhibitor, abolished this SN-EPO effect. CONCLUSION: EPO treatment alleviated the inflammatory reaction in DM mice and inhibited M1 polarization through the JAK2/STAT3 pathway. Moreover, EPO treatment promoted the tube formation ability of ECs in a VEGF-dependent manner and decreased the production of adhesion molecules, a vasodilator and a vasoconstrictor. PMID- 30007233 TI - (Mis)understanding the intersection between development policies and data collection: Experiences in Afghanistan. AB - There is a misalignment between a development community focused on improving the welfare of vulnerable populations and the challenges of addressing widespread illicit drug crop production in drug producing countries. Drawing on the example of Afghanistan, this paper argues that the reasons for the development communities failure to engage is in large part a function of the way that illicit opium poppy and the illicit economy is currently perceived and understood by policy makers, practitioners and scholars. Much of the problem lies with the various statistics used to describe and quantify opium production in Afghanistan, many of them produced by UNODC and cited repeatedly in media coverage and the academic literature. These statistics shape how we have come to understand the scale and nature of the drugs problem, and thereby have informed policy responses. This paper argues that it is critical that policy makers and scholars fully understand the veracity of drug related statistics, including their methodological and conceptual limitations, before using them as the foundations for development programmes or policy responses. Indeed, this paper argues that many of these statistics have presented a simplified and 'profit maximising' model of the factors influencing farmers' livelihoods choices, which has proven deeply misleading and further alienated the development community from engaging constructively with the challenges of illicit drug production in developing countries. PMID- 30007234 TI - Psychometric properties of the Tilburg Frailty Indicator in older Spanish people. AB - BACKGROUND: The Tilburg Frailty Indicator (TFI) is a 15-item scale. It diagnoses frailty in the elderly based on three domains: physical, psychological and social. A Spanish cross-cultural adaptation and its psychometric properties are presented here. MATERIALS AND METHODS: Independent, non-institutionalized >=70 year-olds were recruited. The TFI structure was assessed with Kuder-Richardson (KR-20) and confirmatory factor analyses. Sperman's correlations (rs) with Timed Up-and-Go, Self-assessed-health, Fried criteria, Short Physical Performance Battery, Gerontopole Frailty tool, assessed convergent validity. Known groups' validity and test-retest reliability were tested. RESULTS: Based on n = 856 participants, domain and total scale KR-20 were <0.70. The social domain and certain physical items did not fit adequately. Most physical and total scalers were 0.31-0.48. Social domain rs were <0.30. The TFI differentiated frail and no frail subjects, but test-retest variation was considerable. DISCUSSION: TFI applicability at different social contexts and frailty stages are worth of additional study. Certain scale aspects should be reconsidered. PMID- 30007235 TI - Conversion of industrial biowastes to clean solid fuels via hydrothermal carbonization (HTC): Upgrading mechanism in relation to coalification process and combustion behavior. AB - The aim of this work was to study the correlation between dynamic mechanisms of carbon structure associated with their upgrading effects with the help of XPS, 13C NMR and 2D-PCIS methods. Results showed the fuel qualifies of biowastes were improved and became comparable to lignite or even bitumite after HTC. The carbon chemical bonds of -C-H and -C-O in biowaste components (mainly protein and polysaccharide) were thermally cracked and enriched in liquid phase in the form of soluble intermediates, which subsequently generated coal-like structures via cyclization as well as polymerization at higher temperatures. The further investigation on thermogravimetric analysis found that the conversion of "-C-H/C O to aromatic -C-C/CC" was beneficial for stabilizing their combustion behavior by integrating two stages of biowastes (devolatilization stage and combustion stage) into one stage of hydrochars (combustion stage). PMID- 30007236 TI - Simultaneous removal of thiocyanate and nitrogen from wastewater by autotrophic denitritation process. AB - Pollutants containing sulfur as electron donors will play an important role in the energy-saving denitritation process when organic carbon source was insufficient in wastewater. However, thiocyanate (SCN-), a hazardous pollutant, has not been characterized in denitritation. In this study, the effects of key environmental factors on removal of thiocyanate and nitrogen were investigated in denitritation. The results showed that the maximum removal efficiency of nitrogen was observed in complete removal of thiocyanate and nitrite. The elemental sulfur was observed prior to complete depletion of thiocyanate. The efficiency of denitritation was promoted by NaHCO3 and weakly-alkaline environment. In the sludge containing dominant Thiobacillus genus, nitrite was reduced in the conversion of thiocyanate into elemental sulfur and further into sulfate. The stoichiometric ratio of NO2--N to SCN--N was close to 2.0 when thiocyanate was converted completely into sulfate, which verified complete removal of thiocyanate and nitrite at the NO2--N/SCN--N ratio of 2.0. PMID- 30007237 TI - Effects of combined pretreatment with rod-milled and torrefaction on physicochemical and fuel characteristics of wheat straw. AB - The mechanism of rod-milling combined with torrefaction as well as its effects on physicochemical and fuel properties of wheat straw were investigated. Rod-milling and hammer-milling samples were torrefied under three temperatures (250, 275, and 300 degrees C) with a duration time of 30 min. The results indicated that combined rod-milling and torrefaction pretreatment (CRT) significantly elevated carbon content, higher heating value, fuel ratio, and reduced oxygen content and atomic H/C and O/C ratios in wheat straw. Moreover, CRT significantly reduced cellulose crystallinity, and increased the specific surface area and pore volume of wheat straw, which lowered the wheat straw's degrading pyrolysis temperature. These peak values appeared under 300 degrees C. Devolatilization index (Di) was improved by rod-milling pretreatment under identical torrefaction conditions except 275 degrees C. Therefore, the combination of rod-milling with torrefaction under 300 degrees C has the advantage of enhancing fuel properties of lignocellulosic biomass materials. PMID- 30007238 TI - Accuracy of an online tool to assess appropriateness for an epilepsy surgery evaluation-A population-based Swedish study. AB - OBJECTIVE: The Canadian Appropriateness of Epilepsy Surgery (CASES) tool was developed to help physicians identify patients who should be referred for an epilepsy surgery evaluation. The aim of this study was to determine the accuracy of this tool using a population-based cohort registry (the Swedish National Epilepsy Surgery Register) of patients who underwent epilepsy surgery between 1990 and 2012. METHODS: Overall, 1044 patients met eligibility criteria for the study and were deemed to be surgical candidates by epilepsy experts. Demographic and epilepsy related characteristics were examined and summarized using descriptive statistics. A CASES appropriateness score was calculated for each of these patients. Chi squared analyses or fisher's exact tests were used to determine if there were any relationships between demographic and epilepsy related characteristics not captured in the tool and appropriateness scores. RESULTS: The mean appropriateness score was 8.6 and 985 (Sensitivity: 94.35%; 95% CI, 92.77%-95.60%) patients were appropriate, 46 (4.41%; 95% CI, 3.31%-5.84%) were uncertain, and 13 (1.25%; 95% CI, 0.72%-2.13%) were inappropriate for an epilepsy surgery evaluation. The mean necessity score, which was only calculated for the 985 appropriate patients, was 8.7. All 13 inappropriate patients had tried less than two anti-epileptic drugs (AEDs). In addition, age at onset of epilepsy and age at epilepsy surgery were both significantly associated with appropriateness score. CONCLUSIONS: These results demonstrate that the CASES tool is highly sensitive as it designated 94.3% of epilepsy surgery patients as appropriate for an epilepsy surgery evaluation. All of those classified as inappropriate were not drug resistant, as they had not yet tried two AEDs. PMID- 30007239 TI - Clinical topography relationship in patients with parenchymal neurocysticercosis and seizures. AB - OBJECTIVE: Discordances between imaging findings of parenchymal neurocysticercosis and seizure expression have been reported, and as such the possibility that neurocysticercosis and seizures may frequently coexist by chance has been raised. In this study, we evaluate the topographic relationship between seizure foci based on semiology and electroencephalography with the location of parenchymal neurocysticercotic lesions. METHODS: Seizure information, neuroimaging (computed tomography and magnetic resonance imaging [MRI]) and electroencephalographic data from three randomized clinical trials of individuals with parenchymal neurocysticercosis and focal seizures were analyzed. Blinded epileptologists defined a potential seizure onset zone and a symptomatogenic zone for each individual based on semiology. The topographic relationship between semiology, either lesion location or areas of perilesional edema on baseline MRI, and electroencephalographic abnormalities were assessed. RESULTS: Fifty-eight patients with one or two parenchymal neurocysticercotic lesions were included in this study. From them, 50 patients (86%; 95% CI, 75%-93%) showed a clinical topography relationship with the potential seizure onset zone, and 44 (76%) also with the symptomatogenic zone. From the eight patients with no topographic relationship, five had focal seizures 30 days before or after the baseline MRI and showed perilesional edema. All of these five patients showed a clinical topography relationship between such seizures and an area of perilesional edema, making a total of 55 patients (95%; 95% CI, 85%-99%) with clinical-topography relationship when perilesional edema is considered. Most patients with focal epileptiform discharges (7/8, 88%) had a topographic association between electroencephalographic focality, the potential seizure onset zone and a cysticercotic lesion. CONCLUSION: Seizure semiology and focal epileptiform discharges are topographically related to neurocysticercotic lesions in most patients. These data strongly support seizure origin in the cortex surrounding these lesions. PMID- 30007240 TI - TRPV1 mediates the anticonvulsant effects of acetaminophen in mice. AB - OBJECTIVE: Acetaminophen is one of the most commonly used analgesic and antipyretic drugs. It has been reported that acetaminophen has anticonvulsant effects in several animal models of seizure. An active metabolite of acetaminophen, AM404, inhibits the uptake of the endocannabinoid anandamide. However, the mechanism of the anticonvulsant effect of acetaminophen is unknown. METHODS: This study was performed to examine whether or not acetaminophen can protect against pentylenetetrazol-induced kindling in mice and to investigate the precise mechanisms of the anticonvulsant effect of acetaminophen using the fully kindled mouse models. RESULTS: Repeated administration of acetaminophen significantly delayed the progression of seizure severity induced by pentylenetetrazol. Additionally, acetaminophen showed a dose-dependent anticonvulsant activity against fully pentylenetetrazol-kindled seizures. AM404 also exhibited a dose-dependent anticonvulsant activity in fully kindled animals. The anticonvulsant activity of acetaminophen was antagonized by capsazepine and AMG9810, two transient receptor potential vanilloid-1 (TRPV1) antagonists. However, the transient receptor potential ankyrin 1 (TRPA1) antagonist HC030031 and CB1 receptor antagonist AM251 had no effect. CONCLUSION: These findings suggest that acetaminophen has an anticonvulsant effect in pentylenetetrazol kindled mouse models and TRPV1 mediates the anticonvulsant action. PMID- 30007241 TI - Long-term effect of levetiracetam monotherapy on haematological parameters in children with epilepsy: A prospective study. AB - Studies evaluating the effect of Levetiracetam (LEV) on haematological parameters in patients with epilepsy are very limited. Short-term effects on haematological parameters in children with epilepsy, at 2 and 6 months of LEV treatment, have been previously reported in the literature. Purpose of the current study was to further investigate the long-term changes on haematological parameters in children with epilepsy during LEV monotherapy. White blood cell, neutrophils, lymphocytes, monocytes, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelets were measured in 20 children (11 females, mean age 6,5 +/- 4,4 years, range 2-15 years) with epilepsy, before and after 12 months of LEV monotherapy. Lymphocyte count was significantly decreased at 12 months (p = 0.003) of LEV treatment. Three children (15%) at 12 months of treatment had lymphocyte count below 10th percentile for age. Neutrophils counts were significantly increased and platelets counts were significantly decreased at 12 months of treatment (p = 0.046 and p = 0.006, respectively). In addition, haematocrit and mean corpuscular volume were significantly increased at 12 months of treatment (p = 0.036 and p = 0.031, respectively). There were no significant alterations in the other parameters evaluated during the study. No association was found between all parameters and LEV dosage (mg/kg) at 12 months of treatment. Large, prospective studies are needed to investigate the clinical significance of the above haematological changes and whether these parameters should be monitored periodically in children taking LEV. PMID- 30007242 TI - Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet. AB - OBJECTIVE: The aim of this study was to investigate the characteristics and composition of intestinal microbiota in children with refractory epilepsy after ketogenic diet (KD) therapy and to explore the bacterial biomarkers related to clinical efficacy. METHODS: We prospectively analyzed 20 patients (14 males, 6 females) treated with KD. Clinical efficacy, electroencephalogram (EEG) changes, and laboratory tests were evaluated, and fecal specimens were obtained prior to and 6 months after therapy. The composition of gut microbiota was analyzed by 16S rDNA sequencing, and we screened the possible flora associated with efficacy of the KD. RESULTS: After 6 months of treatment, 2 patients were seizure free, 3 had >= 90% seizure reduction, 5 had a reduction of 50-89%, and 10 had < 50% reduction. All 10 responders showed an improvement in EEG. Compared with baseline, fecal microbial profiles showed lower alpha diversity after KD therapy and revealed significantly decreased abundance of Firmicutes and increased levels of Bacteroidetes. We also observed that Clostridiales, Ruminococcaceae, Rikenellaceae, Lachnospiraceae, and Alistipes were enriched in the non-responsive group. CONCLUSIONS: The results show that the KD can reduce the species richness and diversity of intestinal microbiota. The changes of gut microbiota may be associated with different efficacy after KD, and specific gut microbiota may serve as an efficacy biomarker and a potential therapeutic target in patients with refractory epilepsy. PMID- 30007243 TI - Corrigendum to "Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity" [Eur. J. Med. Chem. 138 (2017) 128-139]. PMID- 30007244 TI - Dynamic interplay of cell fate, polarity and force generation in ascidian embryos. AB - A fundamental challenge in developmental biology is to understand how forces produced by individual cells are patterned in space and time and then integrated to produce stereotyped changes in tissue-level or embryo-level morphology. Ascidians offer a unique opportunity to address this challenge by studying how small groups of cells collectively execute complex, but highly stereotyped morphogenetic movements. Here we highlight recent progress and open questions in the study of ascidian morphogenesis, emphasizing the dynamic interplay of cell fate determination, cellular force generation and tissue-level mechanics. PMID- 30007245 TI - Therapeutic effects of 5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanone (LM49) in an experimental rat model of acute pyelonephritis by immunomodulation and anti inflammation. AB - Antibiotics are still the primary therapy for acute pyelonephritis (APN); rarely, natural polyphenols are also used. LM49 is a novel marine bromophenol derivative displaying strong anti-inflammatory effects. We investigated the therapeutic efficacy of LM49 in an experimental rat model of APN. The model was established by injecting 0.5 mL Escherichia coli (ATCC 25922, 108 CFU/mL) into the urinary bladders of Sprague Dawley rats. This model showed increased kidney viscera indices and renal bacterial growth scores, as well as pathological changes in kidneys. We also performed a broth microdilution antimicrobial susceptibility test of the E. coli strain. Both norfloxacin and LM49 treatment reduced kidney viscera indices and decreased microbial counts in urine cultures and kidney homogenates in APN rats. However, in vitro experiments showed that LM49 did not directly inhibit bacteria. Rather, LM49 treatment inhibited inflammatory cell infiltration or abscess and improved tissue lesions in the renal medullary junction, renal pelvis, and calyx, and high-dose LM49 treatment inhibited the production of inflammatory interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in serum. CD4+ T cells were higher in the LM49 groups treated with high, medium, and low doses than in the model group, whereas only high-dose LM49 treatment increased the number of CD8+ T cells, as compared with that in the model group. However, LM49 treatment did not influence hematological parameters. Our results show that LM49 therapeutic effects in an APN animal model may be achieved by regulating immune responses and inhibiting inflammatory mediators, suggesting it as a candidate APN treatment. PMID- 30007246 TI - The use of p16/Ki-67 dual staining technology on cervical cytology of patients undergoing a LLETZ procedure. AB - OBJECTIVES: The main objective of this prospective observational study was to investigate the diagnostic performance of the p16/Ki-67 dual stain technique (DST) for detecting CIN 2+ in a LLETZ referral setting. Test performances were compared with HR-HPV testing and Pap cytology. METHODS: All patients referred for a LLETZ procedure were candidates for participation in this trial. A total of 110 patients were enrolled between October 2016 and March 2017. From each participant, a cervical cytology sample was obtained before the onset of the LLETZ procedure. On each sample, the dual stain technique (Roche CINtec PLUS (r) test), Pap cytology and an HPV DNA assay (identifying 17 different HPV types) were performed. RESULTS: The overall disease prevalence of CIN 2+ was 56%. The mean age was 41 years, with 38% of patients being younger than 35 years. The overall sensitivity and specificity of the dual stain technique for detecting CIN 2+ was 94% (95% CI: 84.30-98.21%) and 58% (95% CI: 43.21-72.93%) respectively with a PPV of 74% (95% CI: 67.34-80.31%) and a NPV of 88% (95% CI: 72.48-94.90%). HR-HPV testing results in a similar sensitivity of 92% (95% CI: 82.17-97.33%) but considerable lower specificity of 21% (95% CI: 11.17-33.35%) compared to the dual stain technique. At an ASCUS or worse threshold, Pap cytology had the lowest sensitivity of 89% (95% CI 78.11-95.34%) compared to dual staining and HR-HPV testing. Specificity was better (48% with 95% CI of 33.29-62.81%) than that of HR HPV testing but not as good as the DST. CONCLUSION: p16/Ki-67 dual staining provides high sensitivity and improved specificity compared to HR-HPV testing and Pap cytology for detecting CIN 2+, making it an interesting tool for identifying relevant disease in patients referred for a LLETZ procedure. PMID- 30007247 TI - Maternal concentrations of human chorionic gonadotropin (hCG) and risk for cerebral palsy (CP) in the child. A case control study. AB - BACKGROUND: Intrauterine conditions may be important in the development of cerebral palsy in the child. The hormone, human chorionic gonadotropin (hCG), is synthesized in the placenta, and hCG plays an important role in placental angiogenesis and development. Thus, maternal hCG concentrations may be an indicator of placental function and thereby the intrauterine environment for the offspring. We studied the associations of maternal concentrations of hCG during pregnancy with cerebral palsy in the child. METHODS: We performed a case-control study nested within a cohort of 29,948 pregnancies in Norway during 1992-1994. Cases were all women within the cohort who gave birth to a singleton child with cerebral palsy diagnosed before five years of age (n = 63). Controls were a random sample of women with a singleton child without cerebral palsy (n = 182). RESULTS: The adjusted odds ratio (OR) for cerebral palsyin the child was 0.78 (95% CI: 0.55-1.10) per log-transformed unit of maternal hCG in the 1 st trimester, and the OR was 1.42 (95% CI: 0.94-2.16) in the 2nd trimester. Thus, women who did not have high hCG concentrations in the 1 st trimester and low hCG concentrations in the 2nd trimester, had increased risk for giving birth to a child with cerebral palsy. Adjustments were made for pregnancy week of serum sampling, maternal age and parity. CONCLUSIONS: The abnormal hCG concentrations in pregnancies with cerebral palsy in the offspring, could suggest placental factors as causes of cerebral palsy. PMID- 30007248 TI - The use of O-ring retractors at Caesarean section : A systematic review and meta analysis. AB - : O-ring retractors (Alexis/Mobius) have been shown to reduce the risk of Surgical site infection (SSI) following general abdominal surgery. The benefit at caesarean section (CS) remains to be established given the relatively high cost. OBJECTIVES: To assess the efficacy of O-ring retractors when used at CS. STUDY DESIGN: Systematic review and meta-analysis. Electronic databases were searched from inception of each database until January 2018. No language restrictions were applied. All randomised controlled trials (RCTs) which compared the use of an O ring retractor to routine care at CS were included. Primary outcome was SSI. Secondary outcomes were operating time, estimated blood loss, need for blood transfusion, need to exteriorise the uterus, requirement for additional postoperative analgesia and adequate operative field visualisation. Analysis was performed using Revman 5.3. RESULTS: 6 RCTs were included in the qualitative synthesis and the meta-analysis. This included 1669 women. The use of O-ring retractors did not reduce the risk of SSI when used at CS RR 0.76 (95% CI 0.34 1.70). Nor did the use of O-ring retractors reduce the operating time, estimated blood loss, the need for blood transfusion or the need for additional postoperative analgesia. The use O-ring retractors did reduce the need for exteriorisation of the uterus RR 0.48 (95% CI 0.33-0.69), and did increase the rate of adequate visualisation of the operative field RR 1.05 (95% CI 1.00-1.10). In a planned subgroup analysis there was a reduction in the rate of SSI with the use of O-ring retractors in women with a BMI < 35 RR 0.34(95% CI 0.12-0.98). CONCLUSION: This review has shown that O-ring retractors do not reduce the incidence of the common measurable complications of CS; SSI, blood loss, need for blood transfusion and need for additional postoperative analgesia. There may be a subgroup where these retractors are useful, but present evidence does not justify their routine use at CS. PMID- 30007249 TI - An alternate surgical approach to reduce hemorrhage and complications during cesarean hysterectomy for adherent placenta. AB - BACKGROUND: Cesarean hysterectomy for adherent placenta is associated with increased maternal morbidity due to massive hemorrhage requiring large volume blood transfusion, bladder or ureteric injury, intensive care unit (ICU) admission and prolonged hospital stay. There is an ongoing effort to improve the outcome of these women and measures to reduce blood loss. OBJECTIVE: The purpose of the present study was to develop an alternate surgical approach for performing a Cesarean hysterectomy in women with adherent placenta in order to reduce hemorrhage and urinary tract injuries, and thereby improve the maternal outcome. STUDY DESIGN: A prospective observational study in a tertiary care hospital in North India. The surgical approach described in the present study was practiced in 12 women who underwent Cesarean hysterectomy for adherent placenta previa. In this approach, dissection of the bladder flap as close as to the cervix was made prior uterine incision and delivery of the baby. During dissection of the bladder flap, the blood vessels traversing between uterus and bladder were ligated and divided. RESULT: These 12 women underwent Cesarean hysterectomy under general anesthesia. The interval from induction of anesthesia to delivery of the baby ranged from 40 to 79 min, and none of the babies had birth asphyxia. No woman had bladder or ureteric injury. All women had histopathological proven adherent placenta, 5 had placenta percreta, one had placenta increta and 6 had placenta accreta. The average blood loss was 1.46 l and the mean number of blood transfusions was 2.1 units. None of the women required post-operative ventilatory support or ICU admission, and all women were discharged from hospital between 4 to 7 days following Cesarean hysterectomy CONCLUSION: The present series describes an alternate surgical approach for Cesarean hysterectomy in adherent placenta. Dissection of the bladder flap prior to delivery of the baby followed by hysterectomy reduced the hemorrhage and there was no bladder or ureteric injury. This surgical approach requires no additional resources and may easily be followed in a low-resource setting. PMID- 30007250 TI - Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study. AB - OBJECTIVE: To assess the impact of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain on endometriosis-associated pelvic pain. STUDY DESIGN: Multicenter, open-label, non-comparative clinical trial in a representative sample of women with endometriosis-associated pelvic pain. RESULTS: In total, 398 patients with a mean age of 34.6 +/- 7.2 years were treated with a combination of N-acetyl cysteine, alpha lipoic acid and bromelain for 6 months. At baseline, 92.7% of the patients had pain intensity > 4 on the visual analogue scale (VAS); at 3 months of treatment, this percentage decreased to 87.2% (p = 0.074) and at 6 months the percentage was 82.7% (p < 0.05). CONCLUSIONS: Women with endometriosis who wish to become pregnant and are treated with a preparation containing N-acetyl cysteine, alpha lipoic acid and bromelain experienced a significant improvement in endometriosis-associated pelvic pain and required lower intake of rescue analgesics. PMID- 30007251 TI - Control of dioxin emissions from alternative fuels via regulated activated carbon injection and fluegas recirculation. AB - Energy from renewable sources and alternative fuels (AFs) including biomass and refuse or waste derived fuels is spreading worldwide towards resource recovery and sustainability. Hazardous emissions including persisting organic and inorganic pollutants (PPs) such as dioxins/furans and metals are of high concern due to bioaccumnulation and toxic effects. Compliance achieved by excessive overdesign of air pollution control systems (APCS) or process retrofitting with halogen and metal bypass systems, carries along substantial costs. It is shown that (a) traditional injection of activated carbon prior to the APCS based solely on fluegas flowrate may not ensure PP compliance under high precursor varability (e.g., PVC plastic, metals in AFs), while at low precursor rates it leads to excessive activated carbon consumption and PP contaminated flyash, (b) a cost effective system with feedforward regulated AC injection ensures compliance under high AF precursor variability and averts AC overdosing, (c) An activated carbon injection regulation that guarantees both compliance and reduced emission rates is proposed, (d) Fluegas recirculation offers additional advantages towards more efficient abatement of hazardous PPs, by reducing the overall offgas flowrate and increasing the APCS residence time and removal efficiency. The results may promote efficient reduction of hazardous emissions from AF energy facilities. PMID- 30007252 TI - Synthesis and characterization of a heterojunction rGO/ZrO2/Ag3PO4 nanocomposite for degradation of organic contaminants. AB - Synergy between surface adsorption and photocatalysis is key for effective contaminant degradation in the liquid phase. Herein, we report a heterojunction photocatalyst of reduced graphene oxide (rGO)/zirconium dioxide (ZrO2)/silver phosphate (Ag3PO4) that incorporates this synergy for 4-nitrophenol (PNP) removal. Compared with other photocatalyst combinations, ZrO2 and Ag3PO4 coupling generates reactive species with greater degradation potential. ZrO2 and rGO were synthesized by a green approach using a one-step hydrothermal reaction in ethanol water. The growth of rGO/ZrO2 and Ag3PO4 were accomplished and the functions of each part were well developed together. The rGO/ZrO2/Ag3PO4 composite exhibited enhanced light absorption and a low band gap energy (2.3 eV) owing to rGO and Ag3PO4 integration. The composite's photocatalytic activity was much higher than that of ZrO2, Ag3PO4, or ZrO2/Ag3PO4. The maximal adsorption of PNP was 26.88 mg/g, and a pseudo-first-order model described the PNP degradation kinetics (k = 0.034 min-1). Synergy between the three components resulted in 97% PNP removal in 90 min, and even after five cycles, 94% PNP removal was obtained. The quantum yield of the system (7.31 * 10-5 molecules/photon) was compared with those in previous reports to assess the photocatalytic performance and energy requirements. PMID- 30007253 TI - Weakly-supervised convolutional neural networks for multimodal image registration. AB - One of the fundamental challenges in supervised learning for multimodal image registration is the lack of ground-truth for voxel-level spatial correspondence. This work describes a method to infer voxel-level transformation from higher level correspondence information contained in anatomical labels. We argue that such labels are more reliable and practical to obtain for reference sets of image pairs than voxel-level correspondence. Typical anatomical labels of interest may include solid organs, vessels, ducts, structure boundaries and other subject specific ad hoc landmarks. The proposed end-to-end convolutional neural network approach aims to predict displacement fields to align multiple labelled corresponding structures for individual image pairs during the training, while only unlabelled image pairs are used as the network input for inference. We highlight the versatility of the proposed strategy, for training, utilising diverse types of anatomical labels, which need not to be identifiable over all training image pairs. At inference, the resulting 3D deformable image registration algorithm runs in real-time and is fully-automated without requiring any anatomical labels or initialisation. Several network architecture variants are compared for registering T2-weighted magnetic resonance images and 3D transrectal ultrasound images from prostate cancer patients. A median target registration error of 3.6 mm on landmark centroids and a median Dice of 0.87 on prostate glands are achieved from cross-validation experiments, in which 108 pairs of multimodal images from 76 patients were tested with high-quality anatomical labels. PMID- 30007254 TI - Synthesizing retinal and neuronal images with generative adversarial nets. AB - This paper aims at synthesizing multiple realistic-looking retinal (or neuronal) images from an unseen tubular structured annotation that contains the binary vessel (or neuronal) morphology. The generated phantoms are expected to preserve the same tubular structure, and resemble the visual appearance of the training images. Inspired by the recent progresses in generative adversarial nets (GANs) as well as image style transfer, our approach enjoys several advantages. It works well with a small training set with as few as 10 training examples, which is a common scenario in medical image analysis. Besides, it is capable of synthesizing diverse images from the same tubular structured annotation. Extensive experimental evaluations on various retinal fundus and neuronal imaging applications demonstrate the merits of the proposed approach. PMID- 30007255 TI - Size-dependent transport and retention of micron-sized plastic spheres in natural sand saturated with seawater. AB - A series of one-dimensional column experiments were conducted to investigate the transport and retention of micron-sized plastic spheres (MPs) with diameters of 0.1-2.0 MUm in seawater-saturated sand. In seawater with salinity of 35 PSU (practical salinity units), the mass percentages recovered from the effluent (Meff) of the larger MPs increased from 13.6% to 41.3%, as MP size decreased from 2.0 MUm to 0.8 MUm. This occurred because of the gradual reduction of physical straining effect of MPs in the pores between sands. The smaller MPs (0.6, 0.4, and 0.1 MUm) showed the stronger inhibition of MPs mobility, with Meff values of 11.5%, 11.9%, and 9.8%, respectively. This was due to the lower energy barriers (from 108 kBT to 16 kBT) between the smaller MPs and the sand surface, when compared with the larger MPs (from 296 kBT to 161 kBT). In particular, the aggregation of MPs (0.6 or 0.4 MUm) triggered a progressive decrease in MP concentration in the effluent. Retention experiments showed that the vertical migration distance of most MP colloids was 0-4 cm at the inlet of column. For 0.6 or 0.4 MUm MPs, the particles were concentrated over a 0-2 cm vertical distance. Moreover, the salinity (35-3.5 PSU) did not affect the transport of the larger MPs (2.0-0.8 MUm). However, as seawater salinity decreased from 35 PSU to 17.5 or 3.5 PSU, the aggregation of the smaller MPs (0.6-0.1 MUm) was dramatically inhibited or completely prevented. Meanwhile, ripening of the sand surface by the MPs (0.6 and 0.4 MUm) no longer occurred. By contrast, all MPs in deionized water (0 PSU) achieved complete column breakthroughs because of the strong repulsive energy barrier (from 218 kBT to 4192 kBT) between the MPs and the sand surface. Consequently, we find that the transport and retention of MPs in sandy marine environment strongly relies on both the MP size and the salinity levels. PMID- 30007256 TI - What do consumers think about recycling human urine as fertiliser? Perceptions and attitudes of a university community in South India. AB - Sanitation systems based on source separation and valorisation of human urine can improve the environmental sustainability of wastewater management. Yet, the social acceptability of such new, resource-oriented sanitation practices have not been assessed systematically. We attempt to address this research gap by reporting the findings of a survey conducted at a South Indian university that evaluated support for urine recycling among 1252 Indian consumers. We place our findings in the context of the Theory of Planned Behaviour, quantify consumer attitude to urine recycling through an exploratory numerical approach, and identify explanatory factors that shape consumer beliefs and perceptions. Overall, a moderately positive attitude was observed: 68% stated human urine should not be disposed but recycled, 55% considered it as fertiliser, but only 44% would consume food grown using it. While 65% believed using urine as crop fertiliser could pose a health risk, majority (80%) believed it could be treated so as to not pose a risk. The respondents' 'willingness to consume' urine fertilised food was found to be strongly influenced by their willingness to pay. Consumer environmental attitudes, as evaluated using the New Ecological Paradigm scale, did not influence their attitude towards urine recycling behaviour. We thus believe that simply appealing to people's environmental sensitivities is not enough for introducing environmentally-friendly technologies like urine recycling, but that more targeted marketing messages are needed. We find sufficient support among our surveyed consumers for urine recycling but highlight that further research is needed to identify what information and agency will help translate positive attitudes into action and behaviour. PMID- 30007257 TI - Physical structure determines compression of membrane biofilms during Gravity Driven Membrane (GDM) ultrafiltration. AB - Increasing transmembrane pressure (TMP) can compress and increase the hydraulic resistance of membrane biofilms. The purpose of the present study is to evaluate how compression of membrane biofilms occurs and how structural rearrangement can affect hydraulic resistance. Biofilms with heterogeneous and homogeneous physical structures were grown in membrane fouling simulators (MFS) in dead-end mode for 20 days with either (i) a nutrient enriched condition with a nutrient ratio of 100:30:10 (C: N: P), (ii) a phosphorus limitation (C: N: P ratio: 100:30:0), or (iii) river water (C: N: P ratio: ca. 100:10:1). The structural and hydraulic response of membrane biofilms to (a) changes in transmembrane pressures (0.06-0.1 0.5-0.1-0.06 bar) and (b) changes in permeate flux (10-15-20-15-10 L/m2/h) were investigated. Optical coherence tomography (OCT) was used to monitor biofilm structural response, and OCT images were processed to quantify changes in the mean biofilm thickness and relative roughness. Nutrient enriched and river water biofilms had heterogeneous physical structures with greater surface roughness (Ra' > 0.2) than homogeneous P limiting biofilms (Ra' < 0.2). Compression of biofilms with rough heterogeneous structures (Ra' > 0.2) was irreversible, indicated by irreversible decrease in surface roughness, partial relaxation in mean biofilm thickness and irreversible increase in hydraulic resistance. Compression of homogeneous biofilm (Ra' < 0.2) was on the other hand reversible, indicated by full relaxation of the biofilms structure and restoration of initial hydraulic resistance. Hydraulic response (i.e., change in the specific biofilm resistance) did not correspond with the change in physical structure of heterogeneous biofilms. The presented study provides a fundamental understanding of how biofilm physical structure can affect the biofilm's response to a change in TMP, with practical relevance for the operation of GDM filtration systems. PMID- 30007258 TI - Using photocatalyst powder to enhance the coagulation and sedimentation of cyanobacterial cells and enable the sludge to be self-purified under visible light. AB - Removing harmful cyanobacteria intact by coagulation can prevent cell lysis and toxin release, which provides many benefits for drinking water production, including reduction of the burden on subsequent processes and guaranteeing the water quality. But the electronegativity and buoyancy of cyanobacterial cells make them settle slowly and their accumulation and concentration in flocs would still have severe adverse effects. In this study, we introduced a photocatalyst powder to act as a ballasting agent in the coagulation process and to degrade the cells and cyanotoxins during sludge storage. Results showed that adding N-TiO2 would decrease the coagulant dose to half of the conventional value, and also allow Microcystis aeruginosa cells to completely settle within 10 min. During sludge storage, the algal cells, cyanotoxins and other organics in sludge would be degraded to safe levels after 32 h' visible-light irradiation. Meanwhile, the N-TiO2, water and some of the coagulant in purified sludge will be directly and safely reused. Thus, this is an environmentally friendly and cost-effective technology which incorporates photocatalyst in algal flocs to enhance coagulation and sedimentation and to enable the sludge produced to be self-purified under visible-light. PMID- 30007259 TI - Accounting for variation in rainfall intensity and surface slope in wash-off model calibration and prediction within the Bayesian framework. AB - Exponential wash-off models are the most widely used method to predict sediment wash-off from urban surfaces. In spite of many studies, there is still a lack of knowledge on the effect of external drivers such as rainfall intensity and surface slope on wash-off predictions. In this study, a more physically realistic "structure" is added to the original exponential wash-off model (OEM) by replacing the invariant parameters with functions of rainfall intensity and catchment surface slope, so that the model can better represent catchment and rainfall conditions without the need for lookup tables and interpolation/extrapolation. In the proposed new exponential model (NEM), two such functions are introduced. One function describes the maximum fraction of the initial load that can be washed off by a rainfall event for a given slope and the other function describes the wash-off rate during a rainfall event for a given slope. The parameters of these functions are estimated using data collected from a series of laboratory experiments carried out using an artificial rainfall generator, a 1 m2 bituminous road surface and a continuous wash-off measuring system. These experimental data contain high temporal resolution measurements of wash-off fractions for combinations of five rainfall intensities ranging from 33 to 155 mm/h and three catchment slopes ranging from 2 to 8%. Bayesian inference, which allows the incorporation of prior knowledge, is implemented to estimate parameter values. Explicitly accounting for model bias and measurement errors, a likelihood function representative of the wash-off process is formulated, and the uncertainty in the prediction of the NEM is quantified. The results of this study show: 1) even when the OEM is calibrated for every experimental condition, the NEM's performance, with parameter values defined by functions, is comparable to the OEM. 2) Verification indices for estimates of uncertainty associated with the NEM suggest that the error model used in this study is able to capture the uncertainty well. PMID- 30007260 TI - Price competition in pharmaceuticals - Evidence from 1303 Swedish markets. AB - We study the short- and long-term price effects of the number of competing firms, using panel-data on 1303 distinct pharmaceutical markets for 78 months within a reference-price system. We use actual transaction prices in an institutional setting with little scope for non-price competition and where simultaneity problems can be addressed effectively. In the long term, the price of generics is found to decrease by 81% when the number of firms selling generics with the same strength, form and similar package size is increased from 1 to 10. Nearly only competition at this fine-grained level matters; the effect of firms selling other products with the same active substance, but with different package size, form, or strength, is only a tenths as large. Half of the price reductions take place immediately and 70% within three months. Also, prices of originals are found to react to competition, but far less and much slower. PMID- 30007261 TI - Quality disclosure and the timing of insurers' adjustments: Evidence from medicare advantage. AB - Mandatory quality disclosure often includes a period over which the quality of new entrants is unreported. This provides the opportunity for forward-looking firms to adjust product characteristics in advance of disclosure. Using comprehensive data on Medicare Advantage (MA) from 2007 to 2015, I exploit the design of the MA Star Rating program to examine the presence of forward-looking behavior among insurers. I find that high-quality insurers reduce prices leading up to quality disclosure, while low-quality insurers increase prices in advance of quality disclosure. These dynamics are consistent with firms anticipating a future change in consumer inertia and updating current-period prices accordingly. PMID- 30007262 TI - Adrenergic cardiomyopathy and cardiogenic shock as initial presentation of pheochromocytoma. A case report and review of the literature. AB - INTRODUCTION: Pheochromocytomas are infrequent tumors arised from the chromaphine cells of the adrenal sympathetic system. The excess of circulating catecholamines may lead to different cardiovascular disorders from silent alterations of the myocardial conduction to different forms of cardiomyopathy. The onset as cardiogenic shock is exceptional. PRESENTATION OF CASE: A 35-year-old male, with a known history of acute myopericarditis of unknown origin which debuted as acute pulmonary edema, was admitted with dyspnea in the context of a new heart failure episode with pulmonary edema. An initial ECG showed segmentary repolarization changes, reversed in subsequent ECGs. The echocardiogram showed severe left ventricular dysfunction and lateral and apical hypokinesia. Subsequent echocardiograms showed partial recovery of alterations and preserved systolic function. A cardiac MRI showed a subepicardial minimum catchment focus and myocardial edema suggestive of adrenergic myocarditis. A solid nodular lesion was found in the left adrenal gland, suggesting a pheochromocytoma. Laparoscopic left adrenalectomy confirmed a 30 mm adrenal tumor without signs of locoregional invasion. The patient had normal catecholamine excretion and heart function a few weeks after surgery. Histopathology confirmed the diagnosis of pheochromocytoma. DISCUSSION AND CONCLUSIONS: Adrenergic cardiomyopathy is a rare entity with a variable clinical presentation. The onset as cardiogenic shock is exceptional. The differential diagnosis of a patient with cardiogenic shock of unknown origin should consider the presence of an underlying pheocromocytoma as well as other states of adrenergic hyperstimulation. The reversibility of the myocardial affection in pheocromocytoma-associated myocardiopathy is common after the tumor resection. PMID- 30007263 TI - Laparoscopic management of refractory chylous ascites using fluorescence navigation with indocyanine green: A case report. AB - INTRODUCTION: Postoperative chylous ascites is a rare complication of colorectal surgery. Conservative management is usually effective in most cases of the postoperative chylous ascites. However, surgical intervention is performed for refractory cases. PRESENTATION OF CASE: A 31-year-old man with neuroendocrine carcinoma developed chylous ascites after laparoscopic descending colectomy with D3 lymphadenectomy. Conservative treatment including total parenteral nutrition and somatostatin analogue failed and surgical intervention via laparoscopy was performed for the refractory chylous ascites. Lymphatic leakage was detected at the upper part of the inferior mesenteric artery during the laparoscopic exploration and was reconfirmed by intraoperative indocyanine green injection with an infrared camera system. Moreover, we injected the ICG into the other sites of the lymphadenectomy performed and identified the lymphatic flow. We confirmed there was no other lymphatic leakage. The lesion was ligated and closed with fibrin glue. Five months after the surgical intervention, no symptom was noted. DISCUSSION: It is frequently difficult to detect the site of lymphatic leakage intraoperatively. Intraoperative indocyanine green injection is useful for detecting a lymphatic leakage site and especially making sure without other leakages. Additionally, laparoscopic surgery seems safe and effective for refractory chylous ascites. CONCLUSION: we reported successful laparoscopic management of refractory chylous ascites using fluorescence navigation with indocyanine green. PMID- 30007264 TI - Internal hernia of the small intestine around biliary catheter after living-donor liver transplantation: A case report. AB - INTRODUCTION: Biliary reconstruction is a cornerstone of living-donor liver transplantation (LDLT). The routine uses of trans-anastomotic biliary catheters in biliary reconstruction had been a controversial issue. We describe a rare complication related to the use of trans-anastomotic biliary catheter after LDLT. In this case, intestinal obstruction occurred early after LDLT due to internal herniation of the small bowel around trans-anastomotic biliary catheter. PRESENTATION: A 42 years male patient with end stage liver disease underwent LDLT utilizing a right hemi-liver graft. Biliary reconstruction was done by single duct-to-duct anastomosis over trans-anastomotic biliary catheter. The patient was doing well apart from early postoperative ascites that was managed medically. Three weeks after surgery, the patient developed severe agonizing central abdominal pain not responding to anti-spasmodics and analgesics. The decision was to proceed for surgical exploration. Exploration revealed internal herniation of the small bowel loops around the trans-anastomotic biliary catheter without strangulation. Reduction of the internal hernia was done by releasing the fixation of the biliary catheter from the anterior abdominal wall. Small bowel resection was not required. The patient had smooth postoperative course and was discharged 10 days after surgery. DISCUSSION: Awareness regarding this rare complication plus early surgical intervention can prevent the development of postoperative morbidity and mortality. To the best of our knowledge this is the first report to describe such are complication after LDLT. CONCLUSION: We report the first case of internal herniation of small bowel around biliary catheter early after LDLT. PMID- 30007266 TI - Novel mechanism of cannabidiol-induced apoptosis in breast cancer cell lines. AB - Studies have emphasized an antineoplastic effect of the non-psychoactive, phyto cannabinoid, Cannabidiol (CBD). However, the molecular mechanism underlying its antitumor activity is not fully elucidated. Herein, we have examined the effect of CBD on two different human breast cancer cell lines: the ER-positive, well differentiated, T-47D and the triple negative, poor differentiated, MDA-MB-231 cells. In both cell lines, CBD inhibited cell survival and induced apoptosis in a dose dependent manner as observed by MTT assay, morphological changes, DNA fragmentation and ELISA apoptosis assay. CBD-induced apoptosis was accompanied by down-regulation of mTOR, cyclin D1 and up-regulation and localization of PPARgamma protein expression in the nuclei and cytoplasmic of the tested cells. The results suggest that CBD treatment induces an interplay among PPARgamma, mTOR and cyclin D1 in favor of apoptosis induction in both ER-positive and triple negative breast cancer cells, proposing CBD as a useful treatment for different breast cancer subtypes. PMID- 30007267 TI - Link between estrogen deficiency osteoporosis and susceptibility to bone metastases: A way towards precision medicine in cancer patients. AB - Different fields of cancer management consider bone health to be of increasing clinical importance for patients: 1) presence of bone metastases in many solid tumors, 2) use of bone-targeted treatments in the reduction of bone metastasis, 3) effects of cancer treatment on reproductive hormones, critical for normal bone remodeling maintenance. Additionally, bone microenvironment is further complicated by the decline of ovarian sex steroid production and by the related increase in inflammatory factors linked to menopause, which result in accelerated bone loss and increased risk of osteoporosis (OP). Similarly, cancers and metastasis to bone showed a close relationship with sex hormones (particularly estrogen). Thus, these findings raise a question: Could pre-existing estrogen deficiency OP promote and/or influence cancer cell homing and tumor growth in bone? Although some preclinical and clinical evidence exists, it is mandatory to understand this aspect that would be relevant in the clinical theatre, where physicians need to understand the treatments available to reduce the risk of skeletal disease in cancer patients. This descriptive systematic review summarizes preclinical and clinical studies dealing with bimodal interactions between pre-existing estrogen deficiency OP and bone metastasis development and provides evidence supporting differences in tumor growth and colonization between healthy and OP status. Few studies evaluated the impact of estrogen deficiency OP on the susceptibility to bone metastases. Therefore, implementing biological knowledge, could help researchers and clinicians to have a better comprehension of the importance of pre- and post-menopausal bone microenvironment and its clinical implications for precision medicine in cancer patients. PMID- 30007265 TI - Case study of spring haze in Beijing: Characteristics, formation processes, secondary transition, and regional transportation. AB - Continuous haze monitoring was conducted from 12:00 3 April to 12:00 8 April 2016 in Beijing, China to develop a more detailed understanding of spring haze characteristics. The PM2.5 concentration ranged from 6.30 to 165 MUg m-3 with an average of 63.8 MUg m-3. Nitrate was the most abundant species, accounting for 36.4% of PM2.5, followed by organic carbon (21.5%), NH4+ (19.3%), SO42- (18.8%), and elemental carbon (4.10%), indicating the key role of nitrate in this haze event. Species contribution varied based on the phase of the haze event. For example, sulfate concentration was high during the haze formation phase, nitrate was high during the haze, and secondary organic carbon (SOC) had the highest contribution during the scavenging phase. The secondary transition of sulfate was influenced by SO2, followed by relative humidity (RH) and Ox (O3+NO2). Nitrate formation occurred in two stages: through NO2 oxidation, which was vulnerable to Ox; and by the partitioning of N (+5) which was susceptible to RH and temperature. SOC tended to form when Ox and RH were balanced. According to hourly species behavior, sulfate and nitrate were enriched during haze formation when the mixed layer height decreased. However, SOC accumulated prior to the haze event and during formation, which demonstrated the strong contribution of secondary inorganic aerosols, and the limiting contribution of SOC to this haze case. Investigating backward trajectories showed that high speed northwestern air masses following a straight path corresponded to the clear periods, while southwesterly air masses which traversed heavily polluted regions brought abundant pollutants to Beijing and stimulated the occurrence of haze pollution. Results indicate that the control of NO2 needs to be addressed to reduce spring haze. Finally, the correlation between air mass trajectories and pollution conditions in Beijing reinforce the necessity of inter-regional cooperation and control. PMID- 30007268 TI - Prospective study to optimize care and improve knowledge on ovarian function and/or fertility preservation in young breast cancer patients: Results of the pilot phase of the PREgnancy and FERtility (PREFER) study. AB - BACKGROUND: Despite the availability of different strategies for ovarian function and/or fertility preservation in young breast cancer patients candidates for chemotherapy, limited data are available on patients' actual need of these options. PATIENTS AND METHODS: The PREFER study is a prospective cohort study including premenopausal women with newly diagnosed early stage breast cancer between the age of 18 and 45 years and candidates for chemotherapy. The study aimed to investigate patients' preferences and their choices of the different available strategies for ovarian function and/or fertility preservation (i.e. acceptance rate) and reasons for refusal. RESULTS: A total of 131 consecutive patients referred from a single breast unit were included. Median age was 38.9 years with 92 patients (70.3%) diagnosed at <= 40 years. The majority of patients (122, 93.1%) were concerned about the risk of treatment-induced premature ovarian insufficiency (POI) and/or infertility. A total of 120 (91.6%) patients underwent temporary ovarian suppression with gonadotropin-releasing hormone agonists during chemotherapy for ovarian function preservation. Among patients with <=40 years, only 11 (12.0%) decided to access cryopreservation strategies for fertility preservation. The main reason for not accessing the fertility unit was completion of family planning before breast cancer diagnosis; for patients who accessed the fertility unit, fear of the procedure was the main reason to refuse the proposed cryopreservation strategies. CONCLUSION: Despite the majority of young breast cancer patients are concerned about the risk of treatment-induced POI and/or infertility, only a limited number of them required to access the fertility unit to undergo cryopreservation strategies. PMID- 30007269 TI - Stereotactic radiotherapy in metastatic breast cancer. AB - The treatment of metastatic breast cancer is largely focused on systemic therapy. However, over the past decades, there has been growing interest in the use of metastasis-directed therapy in selected cases presenting with an oligometastatic phenotype, i.e. low disease burden with a more indolent biology. Identification of the oligometastatic breast cancer population has, so far, proven elusive. Stereotactic radiotherapy offers an effective, non-invasive approach to ablate metastatic disease both in the brain and in extra-cranial settings. The advent of advanced imaging techniques for target definition, along with the ability to achieve highly conformal dose deposition with steep dose fall-off, enable safe implementation of extreme hypofractionated and single fraction regimens with ablative intent. There is growing evidence that radiation-based treatments are more cost-effective when compared to other ablative modalities. This article provides preliminary evidence that metastasis-direct ablation, with advanced radiotherapy techniques, may play an important role in the management of metastatic breast cancer patients, potentially improving clinical outcomes with minimal toxicity. However, prospective randomized controlled trials are needed to further the understanding of the interaction between systemic therapy and ablative irradiation. Additionally, research in genomic and molecular profiling is needed to characterize metastatic breast cancer patients who will most likely benefit from such combined treatment approaches. PMID- 30007270 TI - Omission of chemotherapy for low-grade, luminal A N1 breast cancer: Patterns of care and clinical outcomes. AB - PURPOSE: Multiple ongoing randomized studies are assessing the impact of omission of chemotherapy (CT) in low-risk node-positive Luminal A breast. The goal of this investigation was to evaluate trends and practice patterns of adjuvant CT use in Luminal A pT1-3N1 breast cancer, along with determining the clinical benefit from adjuvant CT in this patient population. METHODS: The National Cancer Data Base was queried (2004-2014) for women with pT1-3N1 luminal A invasive ductal carcinoma receiving adjuvant hormonal therapy (HT). Multivariable logistic regression ascertained factors associated with adjuvant CT administration. Kaplan Meier analysis evaluated overall survival (OS) between patients treated with CT/HT vs. HT alone, while sub-stratifying patients by age. RESULTS: Of 8548 total patients, 5182 (61%) received CT/HT, while 3366 (39%) received HT alone. A steady rise in omission of adjuvant CT was observed, from 14% (2004-2005) to 41% (2012 2014). A decision not to use CT was more likely in more recent time periods, in older patients, at academic centers, following lumpectomy, and with lower T classification (p < 0.05 for all). CT was associated with higher OS in all patients (p < 0.001) and women <=50 years old (p = 0.030), but not for ages 51-60 (p = 0.116), 61-70 (p = 0.222), or >70 (p = 0.239). CONCLUSIONS: Using CT for Luminal A N1 breast cancer is decreasing over time, primarily in older patients and at academic centers. Although CT is still associated with an OS advantage in all patients, subgroup analysis demonstrated no OS benefit in women >50 years of age. These results have implications on the ongoing randomized trials. PMID- 30007271 TI - Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up. AB - PURPOSE: This paper studies the Quality of Life (QL) of elderly early-stage breast cancer survivors. The aims are to compare the QL scores of these patients after follow-up with their scores before the start of radiotherapy (RT) and compare QL among different axillary treatment groups. METHODS: Of 173 patients over 65 who began treatment and completed the EORTC QLQ-C30 and QLQ-BR23 and the Interview for Deterioration in Daily Living Activities in Dementia (IDDD) before RT, 138 also completed these questionnaires three years after RT. Longitudinal changes in QL were assessed for the whole sample using linear mixed-effect models. Also assessed were differences in QL scores between axillary treatment groups (axillary node dissection ALND, sentinel lymph node biopsy SLNB, and no surgery) at the end of the follow-up (Anova or Kruskal-Wallis) and differences in the evolution of QL from baseline among these groups (linear regression models). RESULTS: QL scores in the follow-up were high (>70/100 points) in most QL areas, with moderate limitations (>30) in sexual functioning and enjoyment. Five areas (pain, nausea/vomiting, financial impact, breast symptoms and IDDD) improved significantly (<6 points) in the follow-up. The ALND group scored less for the future perspective item (15-20 points) in the follow-up than the other two axillary treatment groups. No differences between the pre-treatment and follow up assessments regarding treatment were found among the axillary treatment groups. CONCLUSIONS: Our results suggest that early-stage breast cancer patients adapted well both to their disease and treatments over the follow-up period and to the administration of RT. There were few QL differences between the axillary treatment groups. PMID- 30007273 TI - Lateralized expression of left-right axis formation genes is shared by adult brains of lefty and righty scale-eating cichlids. AB - Variation in the laterality often exists within species and can be maintained by frequency-dependent selection. Although the molecular developmental mechanisms underlying the left-right axis formation have been investigated, the genomic mechanisms underlying variation in laterality remain largely unknown. The scale eating cichlid Perissodus microlepis in Lake Tanganyika exhibit lateralized predation; lefty individuals with the mouth opening toward the right preferentially attack on the prey's left trunk, while righty individuals with the opposite opening attacks on the right trunk. Here, we performed RNA-sequencing and subsequent confirmation with quantitative-PCR in the telencephalon, optic tectum, and hindbrain of the cichlid and identified five genes (pkd1b, ntn1b, ansn, pde6g, and rbp4l1) that were differentially expressed between the hemispheres regardless of the laterality. Surprisingly, pkd1b and ntn1b are involved in nodal and netrin signalling, respectively, which are important for left-right asymmetry formation during early embryogenesis. This result indicates that nodal- and netrin-related signals may also play important roles in the maintenance of asymmetry in adult brain. By contrast, no genes showed reversal of lateral differences between lefty and righty individuals in any brain regions examined, suggesting that laterality in the scale-eating cichlid does not simply result from inversion of the left-right asymmetry of gene expression. PMID- 30007272 TI - Performance of four published risk models to predict sentinel lymph-node involvement in Australian women with early breast cancer. AB - BACKGROUND: Sentinel lymph-node biopsy has reduced the need for extensive axillary surgery for staging. It still exposes women to associated morbidity. Risk models that use clinical and pathology information of the primary tumour to predict sentinel lymph-node metastasis may allow further improvements in care. This study assessed the performance of four published risk models for predicting sentinel lymph-node metastasis in Australian women with early breast cancer; including one model developed in an Australian population. METHODS: The Sentinel Node Biopsy Versus Axillary Clearance (SNAC) trial dataset was used to assess model discrimination by calculating the area under the receiver-operating characteristic curve (AUC) and the false-negative rate for sentinel lymph-node metastasis using model-predicted risk cut-points of 10%, 20%, 30%, and calibration using Hosmer-Lemeshow tests and calibration plots. RESULTS: The sentinel node was positive in 248 of 982 (25.2%) women (158 macrometastasis, 90 micrometastasis). The AUCs of risk models ranged from 0.70 to 0.74 for prediction of any sentinel-node metastasis; 0.72 to 0.75 for macrometastasis. Calibration was poor for the three models developed outside of Australia (lack-of-fit statistics, P < 0.001). For women with a model-predicted risk of sentinel lymph node metastasis <=10%, observed risk was 0-13% (three models <10%), false negative rate 0-9%; 1-17% of women were classified in this range. CONCLUSION: All four models showed good discrimination for predicting sentinel lymph-node metastasis, in particular for macrometastasis. With further development such risk models could have a role in the provision of reassurance to low risk women with normal nodes sonographicaally for whom no axillary surgery is contemplated. PMID- 30007274 TI - The Influence of Fat Grafting on Skin Quality in Cosmetic Foot Grafting: A Randomized, Cross-Over Clinical Trial. AB - Background: Pedal fat grafting is a cosmetic procedure indicated to treat the functional and aesthetic sequelae of pedal fat pad atrophy. Fat grafting has been found to mitigate these symptoms, but the exact mechanism is unknown. Objectives: We hypothesize that pedal fat grafting may improve skin quality, accounting for prolonged symptomatic improvement despite loss of grafted fat. Methods: Patients with pedal atrophy were enrolled in a randomized crossover clinical trial. Group 1 underwent fat grafting upon enrollment with 2-year follow-up. Group 2 was managed conservatively for one year then crossed over into the fat grafting group with 1-year follow-up. Patients underwent pedal ultrasounds to determine thicknesses of the fat pad and dermis and had photographs taken to assess skin quality. Results: Three men and 20 women were enrolled in the study with an average age of 63 +/- 6 years and an average BMI of 26.0 +/- 4.6 kg/m2. 26 feet were injected in Group 1, and 17 were injected in Group 2. In Group 1, dermal thickness increased at 6 months post-injection (p<0.05). This increase persisted through 24 months. In Group 2, dermal thickness decreased prior to injection (p<0.05) but returned to baseline after injection and through 12-month follow-up (p<0.05). Fat pad thickness returned to baseline by study completion in both groups (p<0.05). Conclusions: Pedal fat grafting yielded a significant, sustained increase in dermal thickness, though grafted fat was not retained. These results demonstrate that fat grafting may improve skin quality, which could contribute to improved clinical outcomes despite loss of grafted fat. PMID- 30007275 TI - Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments. AB - Background: It remains uncertain which diet is best for people with type 2 diabetes (T2D). Objective: We compared the effects of dietary carbohydrate restriction with fat restriction on markers of metabolic syndrome and quality of life in people with T2D. Design: This systematic review of randomized controlled trials (RCTs) and controlled clinical trials (CCTs) compares the effects of a low carbohydrate [<=40% of energy (%)] diet with those of a low-fat (<=30%) diet over a period of >=4 wk in patients with T2D. Two investigators independently selected studies, extracted data, and assessed risk of bias. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was used to assess the certainty of evidence. Pooled mean differences (MDs) and 95% CIs were calculated with the use of a random-effects model. Results: Thirty-three RCTs and 3 CCTs (n = 2161) were included. Glycated hemoglobin declined more in people who consumed low-carbohydrate food than in those who consumed low-fat food in the short term (MD: -1.38%; 95% CI: -2.64%, -0.11%; very-low-certainty evidence). At 1 y, the MD was reduced to -0.36% (95% CI: -0.58%, -0.14%; low-certainty evidence); at 2 y, the difference had disappeared. There is low to high (majority moderate) certainty for small improvements of unclear clinical importance in plasma glucose, triglycerides, and HDL concentrations favoring low-carbohydrate food at half of the prespecified time points. There was little to no difference in LDL concentration or any of the secondary outcomes (body weight, waist circumference, blood pressure, quality of life) in response to either of the diets (very-low- to high-certainty evidence). Conclusions: Currently available data provide low- to moderate-certainty evidence that dietary carbohydrate restriction to a maximum of 40% yields slightly better metabolic control of uncertain clinical importance than reduction in fat to a maximum of 30% in people with T2D. This systematic review is registered at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017052467 as CRD42017052467. PMID- 30007277 TI - Functional characteristics of novel pancreatic Pax6 regulatory elements. AB - Complex diseases, such as diabetes, are influenced by comprehensive transcriptional networks. Genome-wide association studies have revealed that variants located in regulatory elements for pancreatic transcription factors are linked to diabetes, including those functionally linked to the paired box transcription factor Pax6. Pax6 deletions in adult mice cause rapid onset of classic diabetes, but the full spectrum of pancreatic Pax6 regulators is unknown. Using a regulatory element discovery approach, we identified two novel Pax6 pancreatic cis-regulatory elements in a poorly characterized regulatory desert. Both new elements, Pax6 pancreas cis-regulatory element 3 (PE3) and PE4, are located 50 and 100 kb upstream and interact with different parts of the Pax6 promoter and nearby non-coding RNAs. They drive expression in the developing pancreas and brain and code for multiple pancreas-related transcription factor binding sites. PE3 binds CCCTC-binding factor (CTCF) and is marked by stem cell identity markers in embryonic stem cells, whilst a common variant located in the PE4 element affects binding of Pax4, a known pancreatic regulator, altering Pax6 gene expression. To determine the ability of these elements to regulate gene expression, synthetic transcriptional activators and repressors were targeted to PE3 and PE4, modulating Pax6 gene expression, as well as influencing neighbouring genes and long non-coding RNAs, implicating the Pax6 locus in pancreas function and diabetes. PMID- 30007278 TI - Malpractice Concerns, Defensive Medicine, and the Histopathology Diagnosis of Melanocytic Skin Lesions. AB - Objectives: The impact of malpractice concerns on pathologists' use of defensive medicine and interpretations of melanocytic skin lesions (MSLs) is unknown. Methods: A total of 207 pathologists interpreting MSLs responded to a survey about past involvement in malpractice litigation, influence of malpractice concerns on diagnosis, and use of assurance behaviors (defensive medicine) to alleviate malpractice concerns. Assurance behaviors included requesting second opinions, additional slides, additional sampling, and ordering specialized tests. Results: Of the pathologists, 27.5% reported that malpractice concerns influenced them toward a more severe MSL diagnosis. Nearly all (95.2%) pathologists reported practicing at least one assurance behavior due to malpractice concerns, and this practice was associated with being influenced toward a more severe MSL diagnosis (odds ratio, 2.72; 95% confidence interval, 1.41-5.26). Conclusions: One of four US skin pathologists upgrade MSL diagnosis due to malpractice concerns, and nearly all practice assurance behaviors. Assurance behaviors are associated with rendering a more severe MSL diagnosis. PMID- 30007280 TI - The Impact of Adherence to Treatment for ADHD on the Quality of Military Service The Israeli Military Experience. AB - Introduction: Attention deficit hyperactive disorder (ADHD) is prevalent in 5.9 7.1% of children and adolescents, and 5% of adults. It results in poor academic, occupational, and social functioning. Pharmacotherapy improves core symptoms; however, average adherence levels are low and decrease at 16-17 years of age, just before the recruitment age to Israel Defense Forces (IDF). This study evaluated the effect of adherence to ADHD pharmacotherapy on occupational performance among soldiers. Materials and Methods: Retrospective data were collected for the study cohort, which included all soldiers serving in the IDF from 2008 through 2012 (n > 500,000). Each soldier in the cohort was categorized based on adherence to treatment, as measured by prescriptions filled monthly: (1) no treatment, (2) low adherence (<2/year), (3) medium adherence (2-6/year), and (4) high adherence (>6/year). Occupational performance was evaluated by 3 indicative parameters: (1) number of sick days, (2) number of exemptions from daily activities, and (3) military profession disqualification, including sub analysis to military profession groups. Results: ADHD pharmacotherapy adherence correlated inversely with occupational performance, as exhibited by more sick days and exemptions from daily activities. All soldiers pharmacologically treated for ADHD had higher professional disqualification rates compared with soldiers who did not require ADHD treatment. In contrast to the general trend, in the military drivers group, higher rates of ADHD adherence correlated with lower professional disqualification rates. Conclusions: Our hypothesis that greater adherence would correlate positively with better occupational performance was refuted. We speculate that increased adherence levels are indicative of more severe ADHD and thus, accompanied by lower occupational performance. The correlation between increased adherence and improved driving ability could be attributed to the nature of driving professions, which require a high level of concentration. Due to the importance of driving in both military and civilian settings, interventions designed to enhance adherence to treatment for ADHD among drivers could have a broad effect on driving consequences, and should be considered by policymakers. PMID- 30007279 TI - Template-assisted synthesis of adenine-mutagenized cDNA by a retroelement protein complex. AB - Diversity-generating retroelements (DGRs) create unparalleled levels of protein sequence variation through mutagenic retrohoming. Sequence information is transferred from an invariant template region (TR), through an RNA intermediate, to a protein-coding variable region. Selective infidelity at adenines during transfer is a hallmark of DGRs from disparate bacteria, archaea, and microbial viruses. We recapitulated selective infidelity in vitro for the prototypical Bordetella bacteriophage DGR. A complex of the DGR reverse transcriptase bRT and pentameric accessory variability determinant (Avd) protein along with DGR RNA were necessary and sufficient for synthesis of template-primed, covalently linked RNA-cDNA molecules, as observed in vivo. We identified RNA-cDNA molecules to be branched and most plausibly linked through 2'-5' phosphodiester bonds. Adenine mutagenesis was intrinsic to the bRT-Avd complex, which displayed unprecedented promiscuity while reverse transcribing adenines of either DGR or non-DGR RNA templates. In contrast, bRT-Avd processivity was strictly dependent on the template, occurring only for the DGR RNA. This restriction was mainly due to a noncoding segment downstream of TR, which specifically bound Avd and created a privileged site for processive polymerization. Restriction to DGR RNA may protect the host genome from damage. These results define the early steps in a novel pathway for massive sequence diversification. PMID- 30007281 TI - Estimate of the Prevalence of Anti-Gastric Parietal Cell Autoantibodies in Healthy Individuals Is Method Dependent. AB - Objectives: Anti-parietal cell antibodies (APCA) are a serologic marker of autoimmune gastritis. Their prevalence in healthy individuals is not well defined. Methods: We evaluated APCA prevalence in 515 healthy blood-donors by rat/primate tissue indirect immunofluorescence (IIF), enzyme-linked immunosorbent assay (ELISA), and immunoblot. Results: Fifty-three of 515 (10.3%) subjects were positive for APCA by at least one method: 18 only by ELISA, 10 by rodent tissue IIF, and one by primate tissue IIF; 18 were positive by ELISA and primate tissue IIF, and one by ELISA and rodent tissue IIF. Two were positive by both IIF methods, and three were triple positive. APCA positivity was confirmed by immunoblot in 100% of ELISA positive, in 95.8% of positive primate tissue IIF, and in 50% of positive rat tissue IIF. Conclusions: A great discrepancy in APCA prevalence detected by different methods in this cohort was apparent. Thus, the results on APCA prevalence in healthy individuals are likely method-dependent. PMID- 30007282 TI - Canada considers a basic income guarantee: can it achieve health for all? AB - There is little doubt that the implementation of a Basic Income Guarantee (BIG) in Canada and other liberal welfare states would alleviate some of the most egregious examples of absolute poverty that contribute to poor health such as lack of adequate food and shelter and inability to meet basic household and personal needs. BIG would likely improve the health of the most disadvantaged by moving them closer to the relative poverty line. Yet, advocacy for and implementation of BIG carries potential dangers. Since health improves with every step up the income ladder, simply moving people closer to the relative poverty line without providing additional universal benefits and supports common to most other developed nations would limit its health promotion potential. In addition, governing authorities in liberal political economies can use BIG to justify continuing imbalances in economic and political power that skews the distribution of the social determinants of health. In addition, implementation of BIG -- despite its more progressive advocates calls for maintaining or enhancing of existing social programs -- can serve as justification for reducing or removing these programs, thereby threatening health. PMID- 30007284 TI - Continuous quality and patient safety improvement from developing countries to developed countries. PMID- 30007285 TI - A renewed media-mix, based on the dynamic transactional model, for communicating the harms of alcohol to women in New Zealand. AB - Public health messages are traditionally disseminated using mass media that typically are unidirectional or one-way communication. Consequent to the current media proliferation, two-way communication channels are also available for publishing health messages. Though they differ in operation, they co-exist which is explained by the media complementarity theory. This study reports research that identified the sources that women of childbearing age in New Zealand prefer when seeking information concerning alcohol and pregnancy. Service-dominant logic provided a framework for simultaneously examining the media that were fundamentally different. The information sources were formulated into a media-mix based on the theory of dynamic transactional model (DTM). DTM accounted for media complementarity, combining the one-way and two-way communication channels into a unified communication process and is recommended for use in health promotion. PMID- 30007286 TI - STAIR Group Treatment for Veterans with PTSD: Efficacy and Impact of Gender on Outcome. AB - Introduction: Group Skills Training in Affective and Interpersonal Regulation (STAIR) is an evidence-based, manualized treatment for individuals with post traumatic stress symptoms, that focuses on improving functioning through mood management (e.g., emotion regulation) and relationship skills development. To date, no study has evaluated the potential benefit of group STAIR among Veterans. Feasibility of delivering STAIR in a mixed-gender group format and the potential impact of gender on outcome were examined. Materials and Methods: Participants (n = 39) were Veterans enrolled in a post-traumatic stress disorder (PTSD) Clinic at a large VA Medical Center. Veterans participated in one of four mixed-gender STAIR groups and completed self-report questionnaires of PTSD symptoms and general psychological distress at pre-treatment and post-treatment. Institutional review board approval was obtained for this study. Results: There was significant pre-treatment to post-treatment improvements in PTSD symptoms as measured by the Post-traumatic Stress Checklist (PCL) (Cohen's d = 0.91), as well as in general psychological distress as measured by the Brief Symptom Inventory (BSI) (Cohen's d = 0.90). Change in PTSD symptoms from pre-treatment to post-treatment did not differ across gender. However, the interaction between gender and time on change in (BSI) was significant, where change in general psychological distress significantly decreased from pre-treatment to post-treatment for male Veterans but not for female Veterans. Conclusion: The results from this study demonstrate the feasibility and initial effectiveness of STAIR delivered in a mixed-gender group format for Veterans with PTSD. It should be noted, however, that male Veterans benefited more from this approach than female Veterans. The findings suggest the value of investigating Veterans' attitudes and beliefs about the benefits and drawbacks of mixed-gender group therapy for trauma-related difficulties. PMID- 30007287 TI - Biodiversity and human health: mechanisms and evidence of the positive health effects of diversity in nature and green spaces. AB - Introduction: Natural environments and green spaces provide ecosystem services that enhance human health and well-being. They improve mental health, mitigate allergies and reduce all-cause, respiratory, cardiovascular and cancer mortality. The presence, accessibility, proximity and greenness of green spaces determine the magnitude of their positive health effects, but the role of biodiversity (including species and ecosystem diversity) within green spaces remains underexplored. This review describes mechanisms and evidence of effects of biodiversity in nature and green spaces on human health. Sources of data: We identified studies listed in PubMed and Web of Science using combinations of keywords including 'biodiversity', 'diversity', 'species richness', 'human health', 'mental health' and 'well-being' with no restrictions on the year of publication. Papers were considered for detailed evaluation if they were written in English and reported data on levels of biodiversity and health outcomes. Areas of agreement: There is evidence for positive associations between species diversity and well-being (psychological and physical) and between ecosystem diversity and immune system regulation. Areas of concern: There is a very limited number of studies that relate measured biodiversity to human health. There is more evidence for self-reported psychological well-being than for well-defined clinical outcomes. High species diversity has been associated with both reduced and increased vector-borne disease risk. Growing points: Biodiversity supports ecosystem services mitigating heat, noise and air pollution, which all mediate the positive health effects of green spaces, but direct and long-term health outcomes of species diversity have been insufficiently studied so far. Areas timely for research: Additional research and newly developed methods are needed to quantify short- and long-term health effects of exposure to perceived and objectively measured species diversity, including health effects of nature-based solutions and exposure to microbiota. PMID- 30007288 TI - Identification, Characterization and High-Performance Liquid Chromatography Quantification for Process-Related Impurities in Abiraterone Acetate Bulk Drug. AB - During the synthesis of abiraterone acetate bulk drug in some laboratory batches, two unreported impurities were detected by high-performance liquid chromatography analysis at levels ranging from 0.05 to 0.10% according to the United States Pharmacopeia method. The structures of two impurities were characterized and confirmed by NMR and MS, which were proposed to be [3beta-acetoxy-16-(3beta acetoxy-androsta-5,16-dien-17-yl)-17-(3-pyridyl)-androsta-5,16-di-ene] and [3beta acetoxy-16-(3beta-acetoxy-androsta-5,16-dien-17-yl)-17-androsta-5,16-di-ene]. It was proved that these impurities come into being during the preparation process of penultimate intermediate (abiraterone). The newly developed LC-UV method was used to monitor the impurity profile in the penultimate intermediate (abiraterone), which was validated by its satisfactory specificity, precision, accuracy and sensitivity. The probable origin of the impurity was also discussed. PMID- 30007289 TI - Behaviour disorder caused by Cushing's syndrome in an older person. AB - An 81-year-old woman was hospitalised for behavioural disorders that had been progressively emerging over a period of few weeks. The symptoms appeared to worsen over time. A diagnosis of vascular dementia, complicated by psychosis, was initially hypothesised. The inefficacy of the antipsychotic/benzodiazepine medications used, along with the presence of hypertension, hypokalaemia and metabolic alkalosis (resistant to pharmacological attempts of correction), as well as the hirsutism and the development of several infections, led us to consider Cushing's syndrome. Endocrinological analysis suggested ectopic adrenocorticotropic hormone (ACTH) secretion. Although endogenous Cushing's syndrome is rare in older people, it should always be considered among the differential diagnosis of behavioural disorders. PMID- 30007291 TI - Predictors of Postdeployment Prescription Opioid Receipt and Long-term Prescription Opioid Utilization Among Army Active Duty Soldiers. AB - Introduction: Little is known about long-term prescription opioid utilization in the Military Health System. The objectives of this study were to examine predictors of any prescription opioid receipt, and predictors of long-term opioid utilization among active duty soldiers in the year following deployment. Materials and Methods: The analytic sample consisted of Army active duty soldiers returning from deployment to Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn in fiscal years 2008-2014 (N = 540,738). The Heckman probit procedure was used to jointly examine predictors of any opioid prescription receipt and long-term opioid utilization (i.e., an episode of 90 days or longer where days-supply covered at least two-thirds of days) in the postdeployment year. Predictors were based on diagnoses and characteristics of opioid prescriptions. Results: More than one-third of soldiers (34.8%, n = 188,211) had opioid receipt, and among those soldiers, 3.3% had long-term opioid utilization (or 1.1% of the cohort, n = 6,188). The largest magnitude predictors of long-term opioid utilization were receiving a long-acting opioid within the first 30 days of the episode, diagnoses of chronic pain (no specified source), back/neck pain, or peripheral/central nervous system pain, and severe pain score in vital records. Conclusions: Soldiers returning from deployment were more likely to receive an opioid prescription than the overall active duty population, and 1.1% initiated a long-term opioid episode. We report a declining rate of opioid receipt and long-term opioid utilization among Army members from fiscal years 2008-2014. This study demonstrates that the most important predictors of opioid receipt were not demographic factors, but generally clinical indicators of acute pain or physical trauma. PMID- 30007283 TI - The Biology of Normal Zona Glomerulosa and Aldosterone-Producing Adenoma: Pathological Implications. AB - The identification of several germline and somatic ion channel mutations in aldosterone-producing adenomas (APAs) and detection of cell clusters that can be responsible for excess aldosterone production, as well as the isolation of autoantibodies activating the angiotensin II type 1 receptor, have rapidly advanced the understanding of the biology of primary aldosteronism (PA), particularly that of APA. Hence, the main purpose of this review is to discuss how discoveries of the last decade could affect histopathology analysis and clinical practice. The structural remodeling through development and aging of the human adrenal cortex, particularly of the zona glomerulosa, and the complex regulation of aldosterone, with emphasis on the concepts of zonation and channelopathies, will be addressed. Finally, the diagnostic workup for PA and its subtyping to optimize treatment are reviewed. PMID- 30007290 TI - Genetic analysis of carcass and meat quality traits in Nelore cattle. AB - The objective of this study was to estimate genetic parameters for carcass and meat quality traits, as well as their genetic correlations using pedigree and genomic information. A total of 3,716; 3,702; 3,439; 3,705; and 3,714 records of 12th-13th rib LM area (LMA), backfat thickness (BF), HCW, marbling score (MARB), and Warner-Bratzler peak shear force (WBSF), respectively, were used. Animals were genotyped with BovineHD BeadChip and GeneSeek Genomic Profiler Indicus HD - GGP75Ki panel. The (co)variance components were estimated by Bayesian inference using a multitrait ssGBLUP analysis. The animal model included fixed effects of contemporary group (defined by the combination of farm and year of birth, and management group at yearling) and age of animal at slaughtering as a covariate (linear). Direct additive genetic and residual effects were fitted as random. The posterior means and SD of heritabilities for LMA, BF, HCW, MARB, and WBSF were 0.28 (0.03), 0.21 (0.04), 0.21 (0.04), 0.12 (0.04), and 0.11 (0.03), respectively. The posterior means for genetic correlations between LMA and meat quality were positive and moderate with MARB (0.38 +/- 0.12) and negative with WBSF (-0.47 +/- 0.12). Low genetic correlations were estimated between BF and WBSF (-0.03 +/- 0.16) and between HCW and MARB (-0.04 +/- 0.14), indicating that these traits are not controlled by the same set or linked genes. Carcass traits (LMA, BF, and HCW) presented moderate heritability providing quick response to the selection purpose. The estimates of heritability for meat quality traits (MARB and WBSF) were low and indicate that the rate of genetic improvement for these traits would be slow. Genetic correlations indicated that selection for carcass traits would not be strongly antagonistic for improving meat quality. PMID- 30007292 TI - Can definitive chemoradiotherapy be an alternative to surgery for early-stage oesophageal cancer? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: Can definitive chemoradiotherapy (CRT) be an alternative to surgery for early-stage oesophageal cancer? A total of 622 papers were found using the reported search, of which 5 cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Three cohort studies with very limited sample size reported that definitive CRT yielded comparable overall survival to surgery, whereas the other 2 studies with large sample size reported that definitive CRT yielded worse survival than surgery. Two of the cohort studies also reported that definitive CRT was associated with significantly higher rates of recurrence than surgery. The available evidence, while both scarce and of poor quality, suggests that definitive CRT for early stage oesophageal cancer resulted in worse overall survival and more recurrence when compared to surgery. Therefore, we would recommend that surgery still remains the standard treatment for patients with early-stage oesophageal cancer, whereas definitive CRT could be an alternative to surgery for patients unfit for surgery, although with slightly inferior outcomes. PMID- 30007293 TI - Determinants of health care utilisation: the case of Timor-Leste. AB - Background: Health financing and delivery reforms designed to achieve universal health coverage (UHC) need to be informed by an understanding of factors that both promote access to health care and undermine it. This study examines the level of health care utilisation in Timor-Leste and the factors that drive it. Methods: Data from a nationally representative cross-sectional survey of health care utilisation in 1712 households were used to develop multilevel models exploring how need and predisposing and enabling factors explain health care utilisation at both primary and secondary care facilities. Results: Need was found to be the key driver in seeking both primary care and hospital services. Rural households were less likely to go to hospital (odds ratio 0.7) than urban households. The poorest quintile was also less likely to use more expensive hospital services than other socio-economic groups. Conclusions: Understanding the determinants of seeking health care in Timor-Leste is of considerable policy significance, because health care is free at the point of use. Our findings indicate that the public resources for health care are subsidising the rich more than the poor. Health care reforms in Timor-Leste need to reduce the 'other' costs of health care, such as distance barriers, to address these inequities. PMID- 30007294 TI - Evaluation of the effects of feeding dried algae containing beta-1,3-glucan on broilers challenged with Eimeria. AB - This study determined the effect of a dried algae product containing beta-1,3 glucan on broiler performance and immunity during an Eimeria challenge. Heterotrophically grown Euglena gracilis, which contained ~55% beta-1,3-glucan, was dried and milled for inclusion into a non-medicated starter diet. Two experiments were conducted to evaluate dietary treatments containing 0, 50, 100, 150, and 200 g/ton dried algae. In both experiments, male broilers were orally challenged on day 14 with a coccidial inoculum consisting of E. acervulina, E. maxima, and E. tenella. Fecal matter was collected 120-144 hours post-exposure to determine relative amounts of oocyte shedding and birds were sacrificed on day 20 for lesion scoring. Broiler performance was assessed on a weekly basis. In the first experiment, birds receiving dried algae at 50 and 200 g/ton showed a significant improvement in FCR compared to the infected control during the challenge period (days 14-20). In the second experiment, the dried algae treatment had no significant effect on FCR, but lesion scores were significantly reduced in the groups receiving 50, 150, and 200 g/ton dried algae relative to the infected control. In both experiments, the dried algae treatment did not significantly impact mortality or oocyte shedding. In the second experiment, staining of intestinal samples with fluorescently tagged antibodies demonstrated that dried algae at 100 g/ton increased the number of intestinal macrophages compared to the infected control. A significant and dose-dependent increase in intestinal MHC-II+ expression was also observed for birds fed dried algae, with an 8-fold increase observed in the 200 g/ton group relative to the infected control. Similarly, increased total immune cell density (measured by the mean fluorescence intensity of CD45+ cells) was also observed at 150 and 200 g/ton. Overall, these data suggest that dried algae rich in beta-1,3-glucan can help improve gut immunity and host protection, thereby reducing morbidity associated with coccidiosis. PMID- 30007295 TI - Prevalence and control of hypertension by 48-h ambulatory blood pressure monitoring in haemodialysis patients: a study by the European Cardiovascular and Renal Medicine (EURECA-m) working group of the ERA-EDTA. AB - Background: Population-specific consensus documents recommend that the diagnosis of hypertension in haemodialysis patients be based on 48-h ambulatory blood pressure (ABP) monitoring. However, until now there is just one study in the USA on the prevalence of hypertension in haemodialysis patients by 44-h recordings. Since there is a knowledge gap on the problem in European countries, we reassessed the problem in the European Cardiovascular and Renal Medicine working group Registry of the European Renal Association-European Dialysis and Transplant Association. Methods: A total of 396 haemodialysis patients underwent 48-h ABP monitoring during a regular haemodialysis session and the subsequent interdialytic interval. Hypertension was defined as (i) pre-haemodialysis blood pressure (BP) >=140/90 mmHg or use of antihypertensive agents and (ii) ABP >=130/80 mmHg or use of antihypertensive agents. Results: The prevalence of hypertension by 48-h ABP monitoring was very high (84.3%) and close to that by pre-haemodialysis BP (89.4%) but the agreement of the two techniques was not of the same magnitude (kappa statistics = 0.648; P <0.001). In all, 290 participants were receiving antihypertensive treatment. In all, 9.1% of haemodialysis patients were categorized as normotensives, 12.6% had controlled hypertension confirmed by the two BP techniques, while 46.0% had uncontrolled hypertension with both techniques. The prevalence of white coat hypertension was 18.2% and that of masked hypertension 14.1%. Of note, hypertension was confined only to night-time in 22.2% of patients while just 1% of patients had only daytime hypertension. Pre dialysis BP >=140/90 mmHg had 76% sensitivity and 54% specificity for the diagnosis of BP >=130/80 mmHg by 48-h ABP monitoring. Conclusions: The prevalence of hypertension in haemodialysis patients assessed by 48-h ABP monitoring is very high. Pre-haemodialysis BP poorly reflects the 48 h-ABP burden. About a third of the haemodialysis population has white coat or masked hypertension. These findings add weight to consensus documents supporting the use of ABP monitoring for proper hypertension diagnosis and treatment in this population. PMID- 30007296 TI - Risk of progressive chronic kidney disease in individuals with early-onset type 2 diabetes: a prospective cohort study. AB - Background: The progression trajectory of renal filtration function has not been well characterized in patients with early-onset type 2 diabetes mellitus (T2DM) although albuminuria is often reported in this population. We aim to study the risk of progressive chronic kidney disease (CKD) in individuals with early-onset T2DM. Methods: In total, 1189 T2DM participants were followed for 3.9 (interquartile range 3.2-4.7) years. Progressive CKD was defined as estimated glomerular filtration rate (eGFR) decline of >=5 mL/min/1.73 m2 per year. Early onset T2DM was defined as age at T2DM diagnosis between 18 and 30 years. Results: Compared with later-onset counterparts (N = 1032), participants with early-onset T2DM (N = 157) were more obese and had poorer glycaemic control at baseline. In the follow-up, 24.2% and 15.6% experienced progressive CKD in early-onset and later-onset participants, respectively (P = 0.007). Logistic regression suggested that participants with early-onset T2DM had 2.63-fold [95% confidence interval (CI) 1.46-4.75] higher risk of progressive CKD after accounting for multiple traditional risk factors. Furthermore, the excess risk of progressive CKD associated with early-onset T2DM mainly occurred in participants with preserved renal function [eGFR >=60 mL/min/1.73 m2, odds ratio (OR) 2.85, 95% CI 1.50-5.42] and was more pronounced in those with diabetes duration <10 years (OR 3.67, 95% CI 1.51-8.90). Conclusions: Individuals with early-onset T2DM have a higher risk of progressive CKD. The excess risk mainly exhibits in early stage of CKD and cannot be solely attributed to traditional risk factors and a longer diabetes duration. PMID- 30007297 TI - The trehalose protective mechanism during thermal stress in Saccharomyces cerevisiae: the roles of Ath1 and Agt1. AB - Trehalose on both sides of the bilayer is a requirement for full protection of membranes against stress. It was not known yet how trehalose, synthesized in the cytosol when dividing Saccharomyces cerevisiae cells are shifted from 28 degrees C to 40 degrees C, is transported to the outside and degraded when cells return to 28 degrees C. According to our results, the lack of Agt1, a trehalose transporter, although had not affected trehalose synthesis, reduced cell tolerance to 51 degrees C and increased lipid peroxidation. The damage was reversed when external trehalose was added during 40 degrees C adaptation, confirming that the reason for the agt1Delta sensitivity is the absence of trehalose at the outside of the lipid bilayer. The 40-28 degrees C condition caused cytosolic trehalase (Nth1) activation, reducing intracellular trehalose and, consequently, the survival rates after 51 degrees C. Although lower than nth1Delta strain, cells deficient in acid trehalase (ath1Delta) maintained increased trehalose levels after 40 degrees C-28 degrees C shift, which conferred protection against 51 degrees C. Both Ath1 and Agt1 were found into vesicles near to plasma membrane in response to stress. This suggests that Agt1 containing vesicles would fuse with the membrane under 40 degrees C to transport part of the cytosolic trehalose to the outside. By a similar mechanism, Ath1 would reach the cell surface to hydrolyze the external trehalose but only when the stress would be over. Corroborating this conclusion, Ath1 activity in soluble cell-free extracts increased after 40 degrees C adaptation but decreased when cells returned to 28 degrees C. During 40 degrees C, Ath1 is confined into vesicles, avoiding the cleavage of the outside trehalose. PMID- 30007299 TI - Responsibility, prudence and health promotion. AB - This article considers the role of responsibility in public health promotion. Efforts to tackle non-communicable diseases which focus on changing individual behaviour and reducing risk factor exposure sometimes invoke individual responsibility for adopting healthy lifestyles. We provide a critical discussion of this tendency. First, we outline some key distinctions in the philosophical literature on responsibility, and indicate how responsibility is incorporated into health promotion policies in the UK. We argue that the use of some forms of responsibility in health promotion is inappropriate. We present an alternative approach to understanding how individuals can 'take responsibility' for their health, based on the concept of prudence (i.e. acting in one's interests). In this discussion, we do not prescribe or proscribe specific health promotion policies. Rather, we encourage public health professionals to consider how underlying assumptions (in this case, relating to responsibility) can shape health promotion policy, and how alternative framings (such as a shift from encouraging individual responsibility to facilitating prudence) may justify different kinds of action, for instance, shaping environments to make healthy behaviours easier, rather than using education as a tool to encourage responsible behaviour. PMID- 30007300 TI - A randomized clinical trial of the effectiveness of 0.018-inch and 0.022-inch slot orthodontic bracket systems: part 1-duration of treatment. AB - Objective: To compare treatment duration between 0.018-inch and 0.022-inch slot systems and determine factors influencing treatment duration. Subjects and methods: Eligible participants aged 12 years or over were allocated to the 0.018 inch or 0.022-inch slot MBT appliance (3M-Unitek, Monrovia, California, USA) using block randomization in groups of 10. Outcome measures included duration of: 1. overall treatment, 2. levelling and alignment, 3. working and finishing, and 4. appointment numbers and other treatment-related factors. Parametric tests (independent samples t-test) and non-parametric tests (chi-square with Fisher's exact tests and Mann-Whitney U-test) assessed differences between groups. A multiple linear regression analysis identified factors influencing treatment duration (P < 0.05). Results: Of the 187 participants randomized (1:1 ratio), 34 withdrew or were excluded (protocol deviations or poor cooperation). There were 77 patients in the 0.018-inch slot group and 76 patients in the 0.022-inch slot group (overall mean age: 19.1 years). Baseline characteristics were similar between groups (P > 0.05). The mean duration of treatment for the 0.018-inch and 0.022-inch slot groups was 29.3 and 31.2 months, respectively. There were no statistically significant differences between the two treatment groups in terms of treatment duration, duration of the key stages of treatment, and number of appointments (P > 0.05). The regression analysis revealed 33.0 per cent of variance in treatment duration was explained by age at bonding, Class II division 2 malocclusion, number of failed appointments, number of emergency appointments, and transfer to another clinician. There were no adverse events. Limitations: It was impossible to blind clinicians or patients to allocation and oral hygiene and periodontal outcomes were not assessed. Conclusions: There was no statistically or clinically significant difference in treatment duration between 0.018-inch and 0.022-inch slot bracket systems. Increasing patient age, Class II division 2 malocclusion, number of failed and emergency appointments, and multi-operator treatment all increase orthodontic treatment duration. Registration: The trial was registered with ClinicalTrials.gov on 5 March 2014, registration number: NCT02080338. Protocol: The protocol was published at DOI: 10.1186/1745-6215-15 389. PMID- 30007301 TI - A centralized automated-dispensing system in a French teaching hospital: return on investment and quality improvement. AB - Objectives: To evaluate the return on investment (ROI) and quality improvement after implementation of a centralized automated-dispensing system after 8 years of use. Design: Prospective evaluation of ROI; before and after study to evaluate dispensing errors; user satisfaction questionnaire after 8 years of use. Setting: The study was conducted at a French teaching hospital in the pharmacy department, which is equipped with decentralized automated medication cabinets in the wards. Participants: Pharmacy staff (technicians and residents). Intervention(s): Implementation of a centralized automated-dispensing robot. Main Outcome Measure(s): The true ROI was prospectively and annually compared to estimated returns calculated after implementation and upgrade of the robot; dispensing errors determined by observation of global deliveries and the satisfaction of users based on a validated questionnaire were evaluated. Results: Following the upgrade, we found little difference for the ROI (+1.86%). The payback period increased by almost 3 years. There was a significant reduction of dispensing errors, from 2.9% to 1.7% (P < 0.001). User satisfaction of the robot by the pharmacy staff was reported (score of 5.52 +/- 1.20 out of 7). Conclusions: These systems are worthwhile investments and largely contribute to improving the quality and safety of the medication process. PMID- 30007302 TI - Multiple-Lure Surveillance Trapping for Ips Bark Beetles, Monochamus Longhorn Beetles, and Halyomorpha halys (Hemiptera: Pentatomidae). AB - Invasions by insects introduced via international trade continue to cause worldwide impacts. Surveillance programs using traps baited with host volatiles and pheromones can detect incursions of nonnative species. We report on two experiments executed to determine if attractants for several insect species can be combined without compromising trap catches and detection ability of target species. In the first experiment, we tested the effect of bark beetle pheromones (plus alpha-pinene) and trap contact with foliage on trap catches of the brown marmorated stink bug Halyomorpha halys Stal (Hemiptera: Pentatomidae) in traps baited with a mixture of bisabolenes and methyl (E,E,Z)-2,4,6-decatrienoate. Trap capture of H. halys adults was greater in traps not in contact with foliage, and the bark beetle pheromones ipsenol and ipsdienol did not affect trap capture of H. halys. In the second experiment, we tested the effects of multi-lure interactions among the primary host attractants alpha-pinene and ethanol, and the pheromones monochamol, ipsenol, ipsdienol, lanierone, and the H. halys compounds, on trap captures of various forest and agricultural insect pests. Specifically, we targeted Monochamus spp. (Coleoptera: Cerambycidae), Ips spp. (Coleoptera: Scolytinae) and H. halys. We found that a combination of all lures did not catch significantly lower numbers of Monochamus carolinensis Olivier, Monochamus scutellatus Say (Coleoptera: Cerambycidae), and Ips pini Say (Coleoptera: Scolytidae) than lure combinations missing components although removal of both lanierone and ipsdienol somewhat increased catches of Ips grandicollis Eichhoff (Coleoptera: Curculionidae). Our results support the use of traps baited with a full combination of these attractants in surveillance programs. This should reduce costs and increase detection rates of a wider range of conifer forest pests and H. halys. PMID- 30007303 TI - Chikungunya chronic disease: a systematic review and meta-analysis. AB - Background: Chikungunya is a mosquito-borne disease caused by an arthritogenic alphavirus, with four genotypes: East Central South African (ECSA), West African, ECSA-diverged or Indian Ocean Lineage (IOL) and Asian lineage. Overall, the disease is self-limited; however, in some patients, joint pain and other non specific symptoms can last for months or years. This systematic review and meta analysis aims to estimate the proportion of people that self-report chikungunya related chronic non-specific symptoms. Methods: Medline, EMBASE, Global Health Library and Scopus were searched for articles published before March 2017. Case control, cohort, cross-sectional, clinical trials studies and outcome-independent case series were eligible. It was estimated that the proportion of patients who did not recover, by virus genotype, and by the time between disease onset and assessment of chronic symptoms. Results: A total of 38 studies were included in the review and 34 in the meta-analysis. Of 6532 chikungunya patients, 3157 did not recover fully after 3 months. The overall no recovery rate associated with chikungunya was 43% (95% CI, 35-52%); Inter-genotype group heterogeneity was observed, the highest prevalence in the ECSA-diverged genotype: 50% (95% CI; 40 60%), followed by the Asian lineage genotype: 36% (95% CI; 20-52%). After 12 months follow-up, the overall no-recovery rate was 21% (95% CI; 19-22%). Conclusion: The evidence suggests that the prevalence of chronic discomfort associated with chikungunya illness varies by virus lineage. The proportion of people that do not fully recovered after chikungunya was high and, therefore, health authorities must prepare to treat patients with symptoms of long-lasting chikungunya adequately addressing the physical, psychological and social needs. PMID- 30007305 TI - A Balance of Burdens: Pain, Opioids, and the Cost of Prescription Drug Monitoring. PMID- 30007304 TI - Serial measures of circulating biomarkers of dairy fat and total and cause specific mortality in older adults: the Cardiovascular Health Study. AB - Background: Controversy has emerged about the benefits compared with harms of dairy fat, including concerns over long-term effects. Previous observational studies have assessed self-reported estimates of consumption or a single biomarker measure at baseline, which may lead to suboptimal estimation of true risk. Objective: The aim of this study was to investigate prospective associations of serial measures of plasma phospholipid fatty acids pentadecanoic (15:0), heptadecanoic (17:0), and trans-palmitoleic (trans-16:1n-7) acids with total mortality, cause-specific mortality, and cardiovascular disease (CVD) risk among older adults. Design: Among 2907 US adults aged >=65 y and free of CVD at baseline, circulating fatty acid concentrations were measured serially at baseline, 6 y, and 13 y. Deaths and CVD events were assessed and adjudicated centrally. Prospective associations were assessed by multivariate-adjusted Cox models incorporating time-dependent exposures and covariates. Results: During 22 y of follow-up, 2428 deaths occurred, including 833 from CVD, 1595 from non-CVD causes, and 1301 incident CVD events. In multivariable models, circulating pentadecanoic, heptadecanoic, and trans-palmitoleic acids were not significantly associated with total mortality, with extreme-quintile HRs of 1.05 for pentadecanoic (95% CI: 0.91, 1.22), 1.07 for heptadecanoic (95% CI: 0.93, 1.23), and 1.05 for trans-palmitoleic (95% CI: 0.91, 1.20) acids. Circulating heptadecanoic acid was associated with lower CVD mortality (extreme-quintile HR: 0.77; 95% CI: 0.61, 0.98), especially stroke mortality, with a 42% lower risk when comparing extreme quintiles of heptadecanoic acid concentrations (HR: 0.58; 95% CI: 0.35, 0.97). In contrast, heptadecanoic acid was associated with a higher risk of non-CVD mortality (HR: 1.27; 95% CI: 1.07, 1.52), which was not clearly related to any single subtype of non-CVD death. No significant associations of pentadecanoic, heptadecanoic, or trans-palmitoleic acids were seen for total incident CVD, coronary heart disease, or stroke. Conclusions: Long-term exposure to circulating phospholipid pentadecanoic, heptadecanoic, or trans-palmitoleic acids was not significantly associated with total mortality or incident CVD among older adults. High circulating heptadecanoic acid was inversely associated with CVD and stroke mortality and potentially associated with higher risk of non-CVD death. PMID- 30007306 TI - A copy number variation generated by complicated organization of PCDHA gene cluster is associated with egg performance traits in Xinhua E-strain. AB - In recent years, a mass of duplicated and deleted DNA sequences have been found in human and animal genomes following the prevalence of employing high-throughput sequencing and SNP array. However, few copy number variation (CNV) studies have been performed on egg performance traits of chicken. In this study, 17 loci reported in previous studies were selected for CNV detection in the Xinhua E strain by using the CNVplex kit, and the detection results showed that locus14 exhibited CNV. Further association analysis indicated the copies of locus14 could be significantly associated with age at first egg (AFE; P < 0.0086) and egg number at 250 d (250EN; P < 0.036). DNA sequence amplification showed the loss of a 260-bp-long fragment in the upstream of locus14, which mainly occurred in normal or copy-gain individuals. The qPCR results showed that subjects with gain of copies could promote the total expression level of the PCDHA gene cluster in the pituitary gland of adult individuals. Additionally, PCR amplification with randomly combined primers revealed a larger number of chicken variable exons than that previously reported, indicating the complexity of the organization of the PCDHA gene cluster. Those variable exons are divergent in their distribution among the populations of Xinhua E-strain, Chahua, Tibetan, and Tulufan Game Chicken, and most individuals only possess part of variable exons. Overall, the copies of locus14 reflect the variable exon dosage effects on the total expression level of the PCDHA gene cluster, which may regulate the layer egg production by affecting the development of the neural system. PMID- 30007307 TI - Energy Beverage Use Among U.S. Service Members. AB - Introduction: The use of energy drinks (ED) or shots (ES) is becoming increasingly popular in U.S. beverage market. In addition, young, physically active males, such as active-duty enlistees represent a prime target for the advertising of ED/ES; however, the exact mechanisms and safety of these products have come under scrutiny. This cross-sectional, exploratory, web-based survey among U.S. service members describes the prevalence of ED/ES use as well as common side effects and safety of these products among self-reported users. Materials and Methods: A convenience sample of U.S. military members (n = 1,706; response rate = 7%) was used to conduct a cross-sectional, exploratory, web-based survey of ED/ES usage among U.S. military members. Main outcome measures included: (1) prevalence of ED/ES use, (2) perceived effects associated with use, and (3) differences among subgroups. Results: Among all respondents, 50% reported consuming ED and 16% reported consuming ES at least once a month. Young, male, enlisted and members of operational military units were significantly more likely to indicate use of ED/ES at least once within the past 30 days than other groups, and were more likely to co-ingest ED and alcohol. Self-reported reasons for using ED included needing an energy boost (77%) and increasing mental alertness (52%). Perceived increases in mental alertness, heart rate, and mental endurance were the most commonly reported effects of ED/ES consumption. About a third (36%) perceived energy beverages and dietary supplements to be safe; while more than half (53%) reported not discussing ED, ES, vitamins/minerals, DS, caffeine, or alcohol use with their healthcare provider(s). Conclusion: Military Service members fit the targeted age and gender demographic of many marketing campaigns for ED/ES products, and many perceive these beverages as safe to use. The possible problems associated with overuse/reliance on ED/ES products, particularly relating to operational force readiness, merit further investigation. PMID- 30007308 TI - STEPS: an efficient prospective likelihood approach to genetic association analyses of secondary traits in extreme phenotype sequencing. AB - It has been well acknowledged that methods for secondary trait (ST) association analyses under a case-control design (ST$_{?text{CC}}$) should carefully consider the sampling process to avoid biased risk estimates. A similar situation also exists in the extreme phenotype sequencing (EPS) designs, which is to select subjects with extreme values of continuous primary phenotype for sequencing. EPS designs are commonly used in modern epidemiological and clinical studies such as the well-known National Heart, Lung, and Blood Institute Exome Sequencing Project. Although naive generalized regression or ST$_{?text{CC}}$ method could be applied, their validity is questionable due to difference in statistical designs. Herein, we propose a general prospective likelihood framework to perform association testing for binary and continuous STs under EPS designs (STEPS), which can also incorporate covariates and interaction terms. We provide a computationally efficient and robust algorithm to obtain the maximum likelihood estimates. We also present two empirical mathematical formulas for power/sample size calculations to facilitate planning of binary/continuous STs association analyses under EPS designs. Extensive simulations and application to a genome wide association study of benign ethnic neutropenia under an EPS design demonstrate the superiority of STEPS over all its alternatives above. PMID- 30007310 TI - Defining the limits of detection for chromosome rearrangements in the preimplantation embryo using next generation sequencing. AB - STUDY QUESTION: Is next generation sequencing (NGS) capable of detecting smaller sub-chromosomal rearrangements in human embryos than the manufacturer's quoted resolution suggests? SUMMARY ANSWER: NGS was able to detect unbalanced chromosome segments smaller than the manufacturer's resolution. WHAT IS KNOWN ALREADY: Array Comparative Genomic Hybridization (array-CGH) has been the gold standard platform used for PGD of chromosome rearrangements. NGS is a viable alternative to array CGH for PGD of chromosome arrangements given that the manufacturer's guidelines quote a resolution of >=20 Mb. However, as many patients carry a chromosome rearrangement <20 Mb, the detection limits of NGS warrant further investigation. STUDY DESIGN, SIZE, DURATION: This study involved a retrospective assessment of stored DNA samples from embryos that had previously been diagnosed as unbalanced by array-CGH as part of routine PGD in two separate IVF clinics between November 2013 and April 2017. SurePlex whole genome amplification (WGA) products derived from DNA extracted from an embryo biopsy sample known to carry an unbalanced form of a chromosome rearrangement were subjected to a specific NGS workflow (VeriSeq PGS). The results from the two technologies were compared for each sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: WGA products from 200 embryos known to carry unbalanced rearrangements were sequenced and analysed. These embryos had been created by 75 patients known to carry a chromosome rearrangement (68 reciprocal translocations, 3 pericentric inversions, 1 paracentric inversion, 2 insertions and 1 dual reciprocal and inversion). Each sample was assessed for the size of the segmental gain/loss (Mb), copy number for each segment and chromosome, segregation pattern, the number of bins in the analysis software used and concordance with array-CGH results. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 294 unbalanced chromosome segments were assessed. NGS was capable of detecting 285/294 (97%) unbalanced segments previously identified using array CGH. The final PGD diagnosis was concordant for 200/200 (100%) embryos. In total, 44/75 (59%) patients contained an unbalanced chromosome segment below the quoted 20 Mb manufacturer's stated resolution. Of these, 35/44 (80%) patients had segments that were able to be detected using NGS, whilst maintaining clinical outcome concordance. LIMITATIONS, REASONS FOR CAUTION: Our study subset did not include any rearrangements involving the Y chromosome. NGS has less available bins per chromosome compared to the array-CGH platform used, thus it remains possible that chromosome rearrangements predicted to be small but still detectable by array-CGH may not be feasible for testing using NGS. This should be considered when undertaking a theoretical feasibility assessment for detecting the chromosome rearrangement in question. Only one specific workflow for WGA and NGS was investigated in this study. WIDER IMPLICATIONS OF THE FINDINGS: This study has shown that NGS is available for the detection of unbalanced chromosome rearrangements >=10 Mb. STUDY FUNDING/COMPETING INTEREST(S): Part sponsorship of the VeriSeq PGS kits used was provided by Illumina. The remainder of the kits were provided by two commercial IVF clinics. None of the authors has any conflicting interests to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 30007311 TI - Blunt traumatic injury to the thoracic aorta treated with thoracic endovascular aortic repair: a single-centre 20-year experience. AB - OBJECTIVES: Blunt thoracic aortic injury can be treated with thoracic endovascular aortic repair (TEVAR) with excellent short and mid-term outcomes. However, few data are available about the long-term results. Our goal was to report our single-centre, 20-year experience using TEVAR to treat blunt thoracic aortic injury. METHODS: We retrospectively reviewed our institutional database to identify all patients treated with TEVAR for traumatic lesions of the aortic isthmus. We identified 35 patients since 1998. Patients' charts were analysed for preoperative characteristics, intraoperative variables and short-term outcomes. Information about the long-term follow-up was collected by analysing cross sectional images and via phone calls. Follow-up was 100% complete. Rates of survival and of freedom from aortic redo were estimated using Kaplan-Meier methods. RESULTS: Twenty-nine patients were men (82%). The median age was 42 years (range 22-79 years) and the mean injury severity score was 38 (+/-13). The endovascular procedure was successfully carried out in all patients. The left subclavian artery was intentionally overstented in 11 patients (31%). Two patients died perioperatively (5.7%). The estimated survival was 92% and 87% at 5 and 10 years, respectively, with no aorta-related deaths. The estimated freedom from aortic redo was 96% and 91% at 5 and 10 years, respectively. CONCLUSIONS: Our data corroborate the excellent results of the endovascular treatment of blunt thoracic aortic injury when follow-up is extended to 20 years. New-generation devices, which are more comfortable and have smaller diameters, may further improve the results of TEVAR in treating traumatic aortic injury. Surveillance with cross-sectional imaging remains mandatory. PMID- 30007312 TI - Internationalisation of Gold Standards Framework use in Primary Health Care. PMID- 30007309 TI - Motor neuron-derived microRNAs cause astrocyte dysfunction in amyotrophic lateral sclerosis. AB - We recently demonstrated that microRNA-218 (miR-218) is greatly enriched in motor neurons and is released extracellularly in amyotrophic lateral sclerosis model rats. To determine if the released, motor neuron-derived miR-218 may have a functional role in amyotrophic lateral sclerosis, we examined the effect of miR 218 on neighbouring astrocytes. Surprisingly, we found that extracellular, motor neuron-derived miR-218 can be taken up by astrocytes and is sufficient to downregulate an important glutamate transporter in astrocytes [excitatory amino acid transporter 2 (EAAT2)]. The effect of miR-218 on astrocytes extends beyond EAAT2 since miR-218 binding sites are enriched in mRNAs translationally downregulated in amyotrophic lateral sclerosis astrocytes. Inhibiting miR-218 with antisense oligonucleotides in amyotrophic lateral sclerosis model mice mitigates the loss of EAAT2 and other miR-218-mediated changes, providing an important in vivo demonstration of the relevance of microRNA-mediated communication between neurons and astrocytes. These data define a novel mechanism in neurodegeneration whereby microRNAs derived from dying neurons can directly modify the glial phenotype and cause astrocyte dysfunction. PMID- 30007313 TI - VpsR and cyclic di-GMP together drive transcription initiation to activate biofilm formation in Vibrio cholerae. AB - The small molecule cyclic di-GMP (c-di-GMP) is known to affect bacterial gene expression in myriad ways. In Vibrio cholerae in vivo, the presence of c-di-GMP together with the response regulator VpsR results in transcription from PvpsL, a promoter of biofilm biosynthesis genes. VpsR shares homology with enhancer binding proteins that activate sigma54-RNA polymerase (RNAP), but it lacks conserved residues needed to bind to sigma54-RNAP and to hydrolyze adenosine triphosphate, and PvpsL transcription does not require sigma54 in vivo. Consequently, the mechanism of this activation has not been clear. Using an in vitro transcription system, we demonstrate activation of PvspL in the presence of VpsR, c-di-GMP and sigma70-RNAP. c-di-GMP does not significantly change the affinity of VpsR for PvpsL DNA or the DNase I footprint of VpsR on the DNA, and it is not required for VpsR to dimerize. However, DNase I and KMnO4 footprints reveal that the sigma70-RNAP/VpsR/c-di-GMP complex on PvpsL adopts a different conformation from that formed by sigma70-RNAP alone, with c-di-GMP or with VpsR. Our results suggest that c-di-GMP is required for VpsR to generate the specific protein-DNA architecture needed for activated transcription, a previously unrecognized role for c-di-GMP in gene expression. PMID- 30007314 TI - Effects of erythropoietin on fibroblast growth factor 23 in mice and humans. AB - Background: Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models. Methods: We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose. Results: Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models. Conclusion: EPO affects FGF23 production and metabolism, which may have important implications for CKD patients. PMID- 30007315 TI - Left ventricular remodelling patterns after MitraClip implantation in patients with severe mitral valve regurgitation: mechanistic insights and prognostic implications. AB - Aims: The effect of MitraClip implantation on left ventricular (LV) remodelling has been shown to be highly variable. The present study wants to assess patterns of LV remodelling and its relationship with outcome. Methods and results: Serial echocardiography before, 1 and 6 months after MitraClip implantation was performed in 79 pts with severe mitral regurgitation (MR) (age 74 +/- 10 years, New York Heart Association III/IV 80%, LV ejection fraction 38 +/- 13%, logistic EuroSCORE 21 +/- 15, and functional MR 81%). LV reverse/adverse remodelling was defined as a >15% decrease/>10% increase in LV end-diastolic volume (LVEDV), respectively. Patients were followed over a period of 32 +/- 16 months with all cause mortality as the primary endpoint. A sustained (6 month) reduction of MR <= 2 post-MitraClip implantation was observed in 83% of patients. The average decrease in LVEDV 6 months after intervention was 13% +/- 16%. Reverse remodelling at 6 months occurred in 40 patients (51%), and adverse remodelling occurred in 6 patients (8%). Patients with adverse remodelling showed a 38% increase of LVEDV at 1 month vs. no early change in LVEDV in patients with reverse remodelling. During follow-up, a total of 25 patients (32%) died. Patients with adverse remodelling died more frequently than patients with reverse remodelling [67% vs. 27%, adjusted odds ratio of 5.6 (95% CI 1.5-21)]. Conclusion: The majority of patients undergoing MitraClip implantation for severe MR showed LV reverse remodelling. However, there was a small group in whom afterload mismatch resulted in sustained adverse remodelling with subsequent high mortality. PMID- 30007317 TI - Upper Eyelid Blepharoplasty: A Novel Method to Predict and Improve Outcomes. AB - Background: In some upper eyelid blepharoplasties, maximal skin removal may not result in desired outcomes; raising crease height can therefore be considered. Currently, there is no method to determine the amount of skin to be excised and/or crease elevation required to achieve a specific outcome. Objective: This study extrapolated an equation to determine amount of skin excision and/or lid crease elevation needed to achieve a specific eyelid margin to fold distance (MFD). Methods: This institutional review board-approved, HIPAA-compliant study was a prospective, nonrandomized clinical trial. Patients were included if aged 30 to 100 years old and underwent upper eyelid blepharoplasty with one surgeon between 2012 and 2014. Exclusion criteria were thyroid eye disease, myasthenia gravis, myotonic dystrophy, pregnancy, blepharoptosis, prior eyelid surgery or trauma, concurrent brow surgery, and topical alpha-agonists. The following data were collected preoperatively and at postoperative months 1 and 6: age, gender, BMI, brow position, MFD, margin to crease distance (distance between eyelid margin and crease, MCD), and vertical skin distance (distance between eyelid margin and brow, VSD). Results: A total 322 eyelids of 164 patients underwent 208 skin excisions, 26 crease elevations, and 88 combined skin excision and crease elevation. Age, gender, and BMI category were all nonsignificant and excluded from the final model. This equation was extrapolated with regression analysis: Change in MFD = -0.40 + (-0.28 * Change VSD) + (0.53 * Change MCD) with |R| = 0.28. Conclusion: To better predict and obtain desired upper eyelid blepharoplasty outcomes, the authors created an equation. Level of Evidence 4: PMID- 30007316 TI - GlnR positive transcriptional regulation of the phosphate-specific transport system pstSCAB in Amycolatopsis mediterranei U32. AB - Amycolatopsis mediterranei U32 is an important industrial strain for the production of rifamycin SV. Rifampicin, a derivative of rifamycin SV, is commonly used to treat mycobacterial infections. Although phosphate has long been known to affect rifamycin biosynthesis, phosphate transport, metabolism, and regulation are poorly understood in A. mediterranei. In this study, the functional phosphate transport system pstSCAB was isolated by RNA sequencing and inactivated by insertion mutation in A. mediterranei U32. The mycelium morphology changed from a filamentous shape in the wild-type and pstS1+ strains to irregular swollen shape at the end of filamentous in the DeltapstS1 strain. RT-PCR assay revealed that pstSCAB genes are co-transcribed as a polycistronic messenger. The pstSCAB transcription was significantly activated by nitrate supplementation and positively regulated by GlnR which is a global regulator of nitrogen metabolism in actinomycetes. At the same time, the yield of rifamycin SV decreased after mutation (DeltapstS1) compared with wild-type U32, which indicated a strong connection among phosphate metabolism, nitrogen metabolism, and rifamycin production in actinomycetes. PMID- 30007318 TI - Socioeconomic inequalities in psychosocial problems of children: mediating role of maternal depressive symptoms. AB - Background: Socioeconomically disadvantaged children often have psychosocial problems. This study examined the mediating role of maternal depressive symptoms during pregnancy, infancy and early childhood in the association between maternal education, as indicator of socioeconomic status (SES), and child's psychosocial problems. Methods: Included were 3410 children from the Amsterdam Born Children and their Development (ABCD) study. To assess the child's psychosocial problems at age 5-6 years, mothers and teachers completed the Strengths and Difficulties Questionnaire (SDQ). Maternal depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and the Depressive Anxiety and Stress Scale 21. Mediation analysis was performed to calculate the direct effect of maternal education on SDQ score and indirect effects through maternal depressive symptoms. Results: The mean mother-reported SDQ total score was significantly higher (P < 0.001) for children of low-educated mothers (6.74 +/- 4.41) compared with children of highly educated mothers (4.47 +/- 3.73). Levels of maternal depressive symptoms were also higher in low-educated mothers during pregnancy, infancy and early childhood. Maternal depressive symptoms explained 27.5% of the association between maternal education and mother-reported SDQ scores and 22.9% for combined mother/teacher SDQ scores. Maternal depressive symptoms during pregnancy had the strongest indirect effect. Conclusion: Maternal depressive symptoms during pregnancy mediate the association between low maternal education and child's psychosocial problems. Early recognition and treatment of maternal depressive symptoms is important to prevent psychosocial problems in children, especially in those with low education. PMID- 30007319 TI - Microfluidic sorting selects sperm for clinical use with reduced DNA damage compared to density gradient centrifugation with swim-up in split semen samples. AB - STUDY QUESTION: Does microfluidic sorting improve the selection of sperm with lower DNA fragmentation over standard density-gradient centrifugation? SUMMARY ANSWER: Microfluidic sorting of unprocessed semen allows for the selection of clinically usable, highly motile sperm with nearly undetectable levels of DNA fragmentation. WHAT IS KNOWN ALREADY: Microfluidic devices have been explored to sort motile and morphologically normal sperm from a raw sample without centrifugation; however, it is uncertain whether DNA damage is reduced in this process. STUDY DESIGN, SIZE, DURATION: This is a blinded, controlled laboratory study of differences in standard semen analysis parameters and the DNA fragmentation index (DFI) in split samples from infertile men (n = 70) that were discarded after routine semen analysis at an academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm concentration, progressive motility and forward progression were assessed by microscopic examination. For each sample, the unprocessed semen was tested for DNA fragmentation and split for processing by density-gradient centrifugation with swim-up or sorting by a microfluidic chip. DNA fragmentation was assessed in unprocessed and processed samples by sperm chromatin dispersion assay. The DFI was calculated, from up to 300 cells per slide, as the number of cells with fragmented DNA divided by the number of cells counted per slide. MAIN RESULTS AND THE ROLE OF CHANCE: The median DFI in unprocessed samples was 21% (interquartile range (IQR): 14-30). In paired analyses of all samples, those processed by the microfluidic chip demonstrated significantly decreased DFI compared to those processed by density gradient centrifugation (P = 0.0029) and unprocessed samples (P < 0.0001). The median DFI for chip specimens was 0% (IQR: 0-2.4) while those processed by density-gradient centrifugation had a median DFI of 6% (IQR: 2-11). Unprocessed samples in the highest DFI quartile (DFI range: 31-40%) had a median DFI of 15% (IQR: 11-19%) after density-gradient centrifugation and DFI of 0% (IQR: 0-1.9%) after processing with the microfluidic chip (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: While a high DFI has been associated with poor outcomes with IVF/ICSI, there are limited data illustrating improvements in clinical outcomes with a reduction in DFI. As this study utilized discarded, non-clinical samples, clinical outcomes data are not available. WIDER IMPLICATIONS OF THE FINDINGS: While microfluidic sorting of unprocessed semen allowed for the selection of clinically usable, highly motile sperm with nearly undetectable levels of DNA fragmentation, standard processing by density-gradient centrifugation with swim up did not increase DNA fragmentation in an infertile population. The proposed microfluidic technology offers a flow-free approach to sort sperm, requiring no peripheral equipment or filtration step, while minimizing hands-on time. STUDY FUNDING/COMPETING INTEREST(S): No external funding to declare. Utkan Demirci, PhD is the Co-founder and Scientific Advisor for DxNow Inc., LevitasBio Inc. and Koek Biotech. Mitchell Rosen, MD is a member of the Clinical Advisory Board for DxNow Inc. PMID- 30007320 TI - Alternative strategies for lignocellulose fermentation through lactic acid bacteria: the state of the art and perspectives. AB - Lactic acid bacteria (LAB) have a long history in industrial processes as food starters and biocontrol agents, and also as producers of high-value compounds. Lactic acid, their main product, is among the most requested chemicals because of its multiple applications, including the synthesis of biodegradable plastic polymers. Moreover, LAB are attractive candidates for the production of ethanol, polyhydroalkanoates, sweeteners and exopolysaccharides. LAB generally have complex nutritional requirements. Furthermore, they cannot directly ferment inexpensive feedstocks such as lignocellulose. This significantly increases the cost of LAB fermentation and hinders its application in the production of high volumes of low-cost chemicals. Different strategies have been explored to extend LAB fermentation to lignocellulosic biomass. Fermentation of lignocellulose hydrolysates by LAB has been frequently reported and is the most mature technology. However, current economic constraints of this strategy have driven research for alternative approaches. Co-cultivation of LAB with native cellulolytic microorganisms may reduce the high cost of exogenous cellulase supplementation. Special attention is given in this review to the construction of recombinant cellulolytic LAB by metabolic engineering, which may generate strains able to directly ferment plant biomass. The state of the art of these strategies is illustrated along with perspectives of their applications to industrial second generation biorefinery processes. PMID- 30007321 TI - SecA inhibitors as potential antimicrobial agents: differential actions on SecA only and SecA-SecYEG protein-conducting channels. AB - Sec-dependent protein translocation is an essential process in bacteria. SecA is a key component of the translocation machinery and has multiple domains that interact with various ligands. SecA acts as an ATPase motor to drive the precursor protein/peptide through the SecYEG protein translocation channels. As SecA is unique to bacteria and there is no mammalian counterpart, it is an ideal target for the development of new antimicrobials. Several reviews detail the assays for ATPase and protein translocation, as well as the search for SecA inhibitors. Recent studies have shown that, in addition to the SecA-SecYEG translocation channels, there are SecA-only channels in the lipid bilayers, which function independently from the SecYEG machinery. This mini-review focuses on recent advances on the newly developed SecA inhibitors that allow the evaluation of their potential as antimicrobial agents, as well as a fundamental understanding of mechanisms of SecA function(s). These SecA inhibitors abrogate the effects of efflux pumps in both Gram-positive and Gram-negative bacteria. We also discuss recent findings that SecA binds to ribosomes and nascent peptides, which suggest other roles of SecA. A model for the multiple roles of SecA is presented. PMID- 30007322 TI - Shaping Escherichia coli for recombinant membrane protein production. AB - The bacterium Escherichia coli has been widely used for the production of both pro- and eukaryotic membrane proteins. Usually, a set of standard strains as well as different culture setups and induction regimes are screened for to enhance production yields. However, on a limited scale, E. coli strains have been isolated for recombinant helical bundle membrane protein production using both selection- and engineering-based approaches. Here, we discuss how such approaches have been used so far to shape E. coli for the production of these recombinant membrane proteins and may be used in the future to further enhance production yields. PMID- 30007323 TI - The Dangerous Pattern of Concurrent Use of Alcohol and Cocaine Among Drunk Drivers of Northeast Italy. AB - Aim: To estimate the prevalence of drug and polydrug use among drunk-drivers during the driving license regranting program, in order to assess the inclusion of toxicological tests on hair and urine samples in the systematic methodology in this category of subjects. Short summary: A total of 2160 drunk-drivers were tested for alcohol and drugs during driving license regranting. Thirty-one subjects showed alcohol use, 212 illicit drug use and, among these, 131 were polydrug users. Nineteen different patterns of drug and polydrug use were found. Cocaine was detected in 165 subjects. Methods: The study was performed on 2160 drunk-drivers examined at Legal Medicine and Toxicology Unit of the University of Padova, in a 3-year-period (2014-2017). The positivity for one or more illicit drugs in hair or urine samples was confirmed by LC/MS and GC/MS methods. Chi square test, Fischer's exact test and Cochran-Armitage Trend test were used to study the correlation between general characteristics of the examined sample and the presence of drug/polydrug use. Results: Thirty-one subjects showed alcohol use, 212 illicit drug use and, among these, 131 were polydrug users. Nineteen different patterns of drug and polydrug use were found. Cocaine was detected in 165 subjects in whom 122 showed a concurrent use of alcohol and cocaine, identified through the detection of cocaethylene in hair samples. No significant association and/or trends between drug/polydrug use and the general characteristics of the sample were detected. Conclusions: The results show that drug and polydrug use among drunk-drivers should be subjected to toxicological as well as alcohological monitoring, especially in the regranting procedure. The implementation of this procedure could improve the knowledge of dimensions of the issue, providing a powerful means for the reduction of phenomenon of driving under the influence of alcohol and drugs. PMID- 30007324 TI - Introduction to the Special Issue on Neural Processes and Pediatric Health: Creating a Pediatric Health Neuroscience Research Agenda. PMID- 30007325 TI - DNA binding with a minimal scaffold: structure-function analysis of Lig E DNA ligases. AB - DNA ligases join breaks in the phosphodiester backbone of DNA by catalysing the formation of bonds between opposing 5'P and 3'OH ends in an adenylation-dependent manner. Catalysis is accompanied by reorientation of two core domains to provide access to the active site for cofactor utilization and enable substrate binding and product release. The general paradigm is that DNA ligases engage their DNA substrate through complete encirclement of the duplex, completed by inter-domain kissing contacts via loops or additional domains. The recent structure of a minimal Lig E-type DNA ligase, however, implies it must use a different mechanism, as it lacks any domains or loops appending the catalytic core which could complete encirclement. In the present study, we have used a structure guided mutagenesis approach to investigate the role of conserved regions in the Lig E proteins with respect to DNA binding. We report the structure of a Lig-E type DNA ligase bound to the nicked DNA-adenylate reaction intermediate, confirming that complete encirclement is unnecessary for substrate engagement. Biochemical and biophysical measurements of point mutants to residues implicated in binding highlight the importance of basic residues in the OB domain, and inter domain contacts to the linker. PMID- 30007326 TI - Distribution of arabinogalactan proteins and pectins in the cells of apple (Malus * domestica) fruit during post-harvest storage. AB - Background and Aims: Changes in the arrangement of cell wall components determine cell wall properties (integrity, stiffness), thereby affecting the macro-scale properties of fruits, which are important for consumers and industry. Arabinogalactan proteins (AGPs) are ubiquitous components of the plant cell, in which they have various functions. Currently, AGPs are considered to be one of the less well-known, enigmatic proteoglycans, a consequence of their heterogeneous structure and unclear mechanism of activity. Methods: An immunocytochemical study was conducted to elucidate the distribution of AGPs and pectic polysaccharides contained in apple (Malus * domestica) fruit during senescence. De-esterified homogalacturonan (LM19), methyl-esterified homogalacturonan (LM20), processed arabinan (LM16) and three AGP epitopes (JIM13, JIM15, MAC207) were identified in the fruit at three stages: fresh fruit, and fruit at 1 and 3 months of post-harvest storage. Key Results: Microscopy revealed spatio-temporal changes in the localization of all examined epitopes. Changes of fruit cell wall assembly and its degradation were confirmed by determination of the galacturonic acid content in the WSP (water soluble pectins), CSP (chelator soluble pectins) and DASP (dilute alkali soluble pectins) fractions. Conclusions: The results revealed dependencies between AGPs, arabinan and homogalacturonan distribution in apple fruit, which are correlated with changes in microstructure during senescence. We propose that AGPs are involved in establishment of the cell wall - plasma membrane continuum. PMID- 30007328 TI - Commentary on: Reduced Pain and Accelerated Recovery Following Primary Breast Augmentation With Lightweight Breast Implants. PMID- 30007327 TI - Atrial arrhythmias in Takotsubo cardiomyopathy: incidence, predictive factors, and prognosis. AB - Aims: Takotsubo cardiomyopathy (TTC) is a stress-related transient cardiomyopathy. It is unclear whether TTC is associated with poorer prognosis when atrial arrhythmia (AA), atrial fibrillation or flutter, occurs. The purpose of this study was to assess the incidence of AA in patients with TTC, predictive factors of AA, and its association with mortality. Methods and results: We studied 214 consecutive cases of TTC over 8 years. The study cohort was divided into two groups-those with newly diagnosed AA (AA-group) and those without (non AA group). AA occurred in 24.8% of the patients. The AA group presented with lower left ventricular ejection fraction (LVEF) on admission and higher cardiac arrest rate. Admission and peak levels of troponin, B-type natriuretic peptide (BNP), C-reactive protein (CRP), and leucocytes were higher in the AA group. In hospital, 30-day, cardiovascular, and all-cause mortality were significantly higher in the AA group. Independent predictors of newly diagnosed AA were troponin peak [odds ratio (OR) 1.03 (1.003-1.06); P = 0.029], CRP peak [OR 1.006 (1.001-1.01); P = 0.026], and LVEF on admission [OR 0.96 (0.93-0.99); P = 0.01]. Newly diagnosed AA was not predictive of mortality. The BNP peak [OR 1.00 (1.000 1.001); P = 0.022] and leucocytes peak [OR 1.095 (1.034-1.16); P = 0.002] were predictive factors of in-hospital mortality. LVEF upon discharge [OR 0.935 (0.899 0.972); P = 0.001] and leucocytes peak [OR 1.068 (1.000-1.139); P = 0.049] were predictive of cardiovascular death. Conclusion: Newly diagnosed AA is frequently observed in patients presenting with TTC and is associated with poorer short- and long-term prognosis. Inflammation, myocardial damage, and LVEF are predictors of AA onset and cardiovascular mortality. PMID- 30007330 TI - A randomized clinical trial of the effectiveness of 0.018-inch and 0.022-inch slot orthodontic bracket systems: part 3-biological side-effects of treatment. AB - Objective: To compare orthodontically induced inflammatory root resorption (OIIRR) and patient perception of pain during orthodontic treatment between 0.018 inch and 0.022-inch slot bracket systems. Subjects and methods: Eligible participants aged 12 years or above were allocated to treatment with the 0.018 inch or 0.022-inch slot MBT appliance (3M Unitek, Monrovia, California, USA) using block randomization in groups of 10. OIIRR was assessed radiographically using standardized periapical radiographs before and after 9 months from the start of treatment. Patient perception of pain was assessed using a validated patient questionnaire at 6 months from the start of treatment. Parametric tests (t-test) and non-parametric tests (chi-square with Fisher's exact tests and Kruskal-Wallis test) assessed differences between the groups (P < 0.05). The correlation between severity of OIIRR and abnormal root morphology, history of dental trauma, and pain during treatment was assessed. Results: Of the 187 participants randomized (1:1 ratio), 34 withdrew or were excluded (protocol deviations or poor cooperation). There were 77 patients in the 0.018-inch slot group and 76 patients in the 0.022-inch slot group (overall mean age: 19.1 years). Baseline characteristics were similar between groups (P > 0.05). There was no significant difference in the severity of the OIIRR nor patient perception of pain between the two study groups (P = 0.115 and P = 0.08 respectively). The correlation between the severity of OIIRR and abnormal root morphology or history of dental trauma was not statistically significant (P = 0.086 and P = 0.313). Moreover, there was no significant correlation between the severity of OIIRR and pain during treatment (R = 0.045, P = 0.617). Limitations: It was impossible to blind clinicians or patients to allocation, and oral hygiene and periodontal outcomes were not assessed. Conclusions: The effect of bracket slot size on the severity of OIIRR and patient perception of pain are not significant. Trial registration: The trial was registered with ClinicalTrials.gov on 5 March 2014, registration number: NCT02080338. PMID- 30007329 TI - Treatment of Neonatal Chlamydial Conjunctivitis: A Systematic Review and Meta analysis. AB - Background: With the continued high prevalence of chlamydia worldwide and high risk of transfer from mothers to their infant during delivery, a need for safe and effective therapies for infants who acquire a chlamydial infection remains. We conducted a systematic review and meta-analysis of antibiotic treatments, including oral erythromycin, azithromycin, and trimethoprim, for neonatal chlamydial conjunctivitis. Methods: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from their inception to July 14, 2017. We included randomized and nonrandomized studies that evaluated the effects of erythromycin, azithromycin, or trimethoprim in neonates with chlamydial conjunctivitis. A meta-analysis using a random-effects generic inverse-variance method was performed, and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: We found 12 studies (n = 292 neonates) and were able to meta analyze 7 studies that used erythromycin at a dose of 50 mg/kg body weight per day for 14 days. The clinical and microbiological cure were 96% (95% confidence interval [CI], 94%-100%) and 97% (95% CI, 95%-99%), respectively, and adverse gastrointestinal effects occurred in 14% (95% CI, 1%-28%) of the neonates. The microbiological cure in the study that assessed azithromycin at 20 mg/kg per day were 60% (95% CI, 27%-93%) when it was given in a single dose and 86% (95% CI, 61%-100%) when given in a 3-day course. Two studies reported compliance with treatments, and 1 study reported no pyloric stenosis events. Because of the risk of bias and the few neonates included across the studies, the certainty of evidence is low to very low. No studies assessed trimethoprim. Conclusions: Although evidence suggests that erythromycin at 50 mg/kg per day for 14 days results in higher numbers of cure than does azithromycin, compliance and risk of pyloric stenosis related to their use for other infections in neonates will factor into treatment recommendations. More data are needed to compare these treatments directly. PMID- 30007331 TI - Determination of Cyanide by Microdiffusion Technique Coupled to Spectrophotometry and GC/NPD and Propofol by Fast GC/MS-TOF in a Case of Poisoning. AB - A man was found dead in a hotel located near Rome (Italy). The man was still holding a syringe attached to a butterfly needle inserted in his left forearm vein. The syringe contained a cloudy pinkish fluid. In the hotel room the Police found a broken propofol glass vial plus four sealed ones, an opened NaCl plastic vial and six more still sealed, and a number of packed smaller disposable syringes and needles. An opened plastic bottle containing a white crystalline powder labeled as potassium cyanide was also found. Systematic toxicological analysis (STA), carried out on blood, urine and bile, evidenced only the presence of propofol in blood and bile. So the validated L-L extraction protocol and the GC/MS-TOF method for the confirmation of propofol in the biological fluids optimized in our laboratory was applied to blood, urine and bile. The concentration of propofol resulted to be 0.432 MUg/mL in blood and 0.786 MUg/mL in bile. The quantitative determination of cyanide in blood was carried out by microdiffusion technique coupled to spectrophotometric detection obtaining a cyanide concentration of 5.3 MUg/mL. The quantitative determination was then confirmed by GC/NPD and the concentration of cyanide resulted to be 5.5 MUg/mL in blood and 1.7 MUg/mL in bile. Data emerging from autopsy findings, histopathological exams and the concentrations of cyanide suggested that death might be due to poisoning caused by cyanide, however, respiratory depression caused by propofol could not be excluded. PMID- 30007332 TI - The impact of educational intervention based on the health belief model on observing standard precautions among emergency center nurses in Sirjan, Iran. AB - Providing health care services has always been considered as a hazardous job due to a number of reasons. The risk of blood-borne viruses and the importance of their prevention has led to the formulation of principles called standard precautions (SPs). The goal of this study was to investigate the impact of an educational intervention based on the Health Belief Model constructs on the behavior of nurses in emergency centers regarding observing SPs in Sirjan, Iran. This was a quasi-experimental study. The study population included 100 emergency personnel working in health centers in Sirjan city (of Iran), who were randomly divided into two intervention (n = 50) and control (n = 50) groups. The educational intervention was conducted over two sessions each lasting for 60 min. Information was collected by a questionnaire (with 64 questions), completed in an interview conducted directly before the intervention and 3 months later. Data were analyzed using the chi2 test, t-test and paired t-test.The results showed nurses did not have enough information about SPs, but after the intervention, knowledge scores increased in both groups. In the Health Belief Model (HBM) constructs, significant differences were observed in perceived susceptibility, perceived severity, perceived benefits and barriers, cues to action and self efficacy, after the intervention, in the intervention group (P < 0.001), but not in the control group (P > 0.05). HBM was effective in educating SPs among emergency personnel. PMID- 30007333 TI - A randomized clinical trial of the effectiveness of 0.018-inch and 0.022-inch slot orthodontic bracket systems: part 2-quality of treatment. AB - Objective: To compare the quality of orthodontic treatment between 0.018-inch and 0.022-inch slot bracket systems. Subjects and methods: Eligible participants aged 12 years or over were allocated to the 0.018-inch or 0.022-inch slot MBT appliance (3M-Unitek, Monrovia, California, USA) using block randomization in groups of 10. Outcome measures included: 1. ABO cast-radiograph evaluation (CR EVAL), 2. peer assessment rating (PAR) scores, 3. incisor inclination, and 4. patient perception using the Index of Orthodontic Treatment Need aesthetic component (IOTN AC) and three validated questionnaires before, during and after treatment. Parametric tests [independent samples t-test and two-way analysis of variance (ANOVA)] and non-parametric tests (chi-square with Fisher's exact tests and Mann-Whitney U-test) assessed differences between groups (P < 0.05). Results: Of the 187 participants randomized (1:1 ratio), 34 withdrew or were excluded (protocol deviations or poor cooperation). There were 77 patients in the 0.018 inch slot group and 76 patients in the 0.022-inch slot group (overall mean age: 19.1 years). Baseline characteristics were similar between groups (P > 0.05). The mean total ABO CR-EVAL scores were 34.7 and 34.5; mean percentage PAR score reduction 74.1 per cent and 77.1 per cent; mean change for maxillary incisor inclination 2.9 degrees and 1.6 degrees and for mandibular incisor inclination 2.7 degrees and 1.4 degrees for the 0.018-inch and 0.022-inch groups, respectively. Improvement in patient perception of aesthetics after treatment was statistically significant for both groups (P < 0.05). However, there were no statistically significant differences between the two treatment groups for ABO CR EVAL, percentage PAR score reduction, incisor inclination, and patient perception of treatment (P > 0.05). No adverse events were observed during treatment. Limitations: It was impossible to blind clinicians or patients to allocation and oral hygiene and periodontal outcomes were not assessed. Conclusions: There were no statistically or clinically significant differences in the quality of occlusal outcomes, incisor inclination and patient perception of treatment between 0.018 inch and 0.022-inch slot bracket systems. Registration: The trial was registered with ClinicalTrials.gov on 5 March 2014, registration number: NCT02080338. Protocol: The protocol was published at DOI: 10.1186/1745-6215-15-389. PMID- 30007334 TI - Diagnostic Accuracy, Item Analysis and Age Effects of the UPSIT Spanish Version in Parkinson's Disease. AB - Objective: The University of Pennsylvania Smell Identification Test (UPSIT) is the most commonly used test to detect olfactory impairment in Parkinson's disease (PD), but the cut-off score for clinical purposes is often difficult to establish because of age and sex effects. The current work aims to study the sensitivity and specificity of the UPSIT Spanish version and its accuracy in discriminating PD patients at different age groups from healthy controls (HC), and to perform an item analysis. Method: Ninety-seven non-demented PD patients and 65 HC were assessed with the UPSIT Spanish version. Sensitivity, specificity, and diagnostic accuracy for PD were calculated. Multiple regression analysis was used to define predictors of UPSIT scores. Results: Using the normative cut-off score for anosmia (<=18), the UPSIT showed a sensitivity of 54.6% with a specificity of 100.0% for PD. We found that, using the UPSIT cut-off score of <=25, sensitivity was 81.4% and specificity 84.6% (area under the receiver operating characteristic curve = 0.908). Diagnosis and age were good predictors of UPSIT scores (B = 10.948; p < .001; B = -0.203; p < .001). When optimal cut-off scores were considered according to age ranges (<=60, 61-70, and >=71), sensitivity and specificity values were >80.0% for all age groups. Conclusions: In the Spanish UPSIT version, sensitivity and specificity are improved when specific cut-off scores for different age groups are computed. PMID- 30007335 TI - Society of Behavioral Medicine position statement: Society of Behavioral Medicine supports oral cancer early detection by all healthcare providers. AB - In response to the increasing incidence of certain oral and oropharyngeal cancers, the Society of Behavioral Medicine (SBM) calls on healthcare providers and legislators to expand awareness of oral and oropharyngeal cancer risk factors, increase early detection, and support policies that increase utilization of dental services. SBM supports the American Dental Association's 2017 guideline for evaluating potentially malignant oral cavity disorders and makes the following recommendations to healthcare providers and legislators. We encourage healthcare providers and healthcare systems to treat oral exams as a routine part of patient examination; communicate to patients about oral/oropharyngeal cancers and risk factors; encourage HPV vaccination for appropriate patients based on recommendations from the Advisory Committee on Immunization Practices; support avoidance of tobacco use and reduction of alcohol consumption; and follow the current recommendations for evaluating potentially malignant oral cavity lesions. Because greater evidence is needed to inform practice guidelines in the primary care setting, we call for more research in collaborative health and dental services. We encourage legislators to support policies that expand Medicaid to cover adult dental services, increase Medicaid reimbursement for dental services, and require dental care under any modification of, or replacement of, the Affordable Care Act. PMID- 30007336 TI - COL18A1 is a candidate eye iridocorneal angle-closure gene in humans. AB - Primary angle-closure glaucoma (PACG) is a common form of glaucoma in the Far East. Its defining feature is iridocorneal angle closure. In addition to PACG, indications of angle closure are included in the diagnostic criteria of related conditions primary angle-closure suspect (PACS) and primary angle closure (PAC). To the best of our knowledge, a causative gene for iridocorneal angle closure in humans has not been identified. This study aimed to identify the genetic cause of iridocorneal angle closure in a pedigree with at least 10 individuals diagnosed with PACS, PAC or PACG. Results of linkage analysis, segregation analysis of 44 novel variations, whole exome sequencing of 10 individuals, screenings of controls and bioinformatics predictions identified a mutation in COL18A1 that encodes collagen type XVIII as the most likely cause of angle closure in the pedigree. The role of COL18A1 in the etiology of Knobloch syndrome (KS) that is consistently accompanied by optic anomalies, available functional data on the encoded protein and the recognized role of collagens and the extracellular matrix in glaucoma pathogenesis supported the proposed role of the COL18A1 mutation in the pedigree. Subsequent identification of other COL18A1 mutations in PACS affected individuals of two unrelated families further supported that COL18A1 may affect angle closure. These PACS individuals were parents and grandparents of KS affected children. In conclusion, a gene that affects angle closure in humans, a critical feature of PACG, has been identified. The findings also reinforce the importance of collagens in eye features and functions. PMID- 30007337 TI - Spontaneously Ruptured Spleen Samples in Patients With Infectious Mononucleosis: Analysis of Histology and Lymphoid Subpopulations. AB - Objectives: Spontaneous rupture of the spleen is occasionally seen as the presenting event in infectious mononucleosis (IM). Diagnosis of these cases can be very challenging. Methods: We describe the morphologic and immunohistochemical findings in a series of seven splenectomy specimens removed after spontaneous rupture in patients with IM. Most cases were submitted for a second opinion since the histology of the cases suggested malignant lymphoma. Results: All the cases showed similar findings, with red pulp expansion occupied by activated T and B cells, including scattered large lymphocytes with both T- and B-cell markers, together with a polymorphic background rich in cytotoxic T cells. Clonality analysis revealed T-cell receptor clonal patterns in four of the six cases evaluated. Conclusions: IM should be considered a possible diagnosis in any case of splenic rupture whose histology suggests possible aggressive lymphoma. PMID- 30007338 TI - Prostate cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 30007340 TI - Commentary on: Intra-Areolar Pexy: The "Compass Rose" Suture Technique for Small and Moderate Areola Herniation. PMID- 30007339 TI - PIN1 is a new therapeutic target of craniosynostosis. AB - Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases. PMID- 30007341 TI - Quantification of Torque Teno Virus Viremia as a Prospective Biomarker for Infectious Disease in Kidney Allograft Recipients. AB - Background: Drug-induced immunosuppression following kidney transplantation is crucial to prevent allograft rejection, but increases risk for infectious disease. Tailoring of drug dosing to prevent both rejection and infection is greatly desirable. The apathogenic and ubiquitous torque teno virus (TTV) reflects immunocompetence of the host and might be a potential candidate for immunologic monitoring. Methods: To assess TTV as an infection biomarker, virus load was prospectively quantified in peripheral blood of 169 consecutive renal allograft recipients at the Medical University Vienna. Results: Patients with infection showed higher TTV levels compared to patients without infection (4.2 * 108 copies/mL [interquartile range, IQR, 2.7 * 107-1.9 * 109] vs 2.9 * 107 [IQR 1.0 * 106-7.2 * 108]; P = .006). Differences in TTV load became evident almost 3 months before infection (median 77 days, IQR 19-98). Each log level of TTV copies/mL increased the odds ratio for infection by 23% (95% confidence interval 1.04-1.45; P = .014). TTV >3.1 * 109 copies/mL corresponded to 90% sensitivity to predict infections. Logistic regression demonstrated independent association between TTV levels and infection. Conclusions: TTV quantification predicts infection after kidney transplantation and might be a potential tool to tailor immunosuppressive drug therapy. PMID- 30007342 TI - Performances of the IDEIA HpStAR Stool Antigen Test in Detection of Helicobacter pylori Infection Before and After Eradication Treatment in Algerian Children. AB - We aimed to evaluate in an Algerian pediatric population the diagnostic performances of the IDEIA HpStAR noninvasive stool antigen test (Oxoid, Cambridge, UK) to detect Helicobacter pylori infection before and after eradication therapy. A prospective study including 158 symptomatic Algerian children was conducted. Patients were initially diagnosed with invasive (culture, histology, and rapid urease test) and noninvasive tests (urea breath test and IDEIA HpStAR test). Infected patients were treated, and 101 were controlled after treatment with two invasive (culture and histology) and two noninvasive tests (urea breath test and IDEIA HpStAR test). In Algerian children, the IDEIA HpStAR test showed good performances for initial detection of H. pylori infection and also for subsequent control of eradication treatment. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of IDEIA HpStAR test before treatment were 93.6%, 100%, 100%, 87.3%, and 96%, respectively, and those after treatment were 100, 92.8, 78.6, 100, and 94.2%, respectively. PMID- 30007343 TI - A Mediterranean-like dietary pattern with vitamin D3 (10 ug/d) supplements reduced the rate of bone loss in older Europeans with osteoporosis at baseline: results of a 1-y randomized controlled trial. AB - Background: The Mediterranean diet (MD) is widely recommended for the prevention of chronic disease, but evidence for a beneficial effect on bone health is lacking. Objective: The aim of this study was to examine the effect of a Mediterranean-like dietary pattern [NU-AGE (New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe)] on indexes of inflammation with a number of secondary endpoints, including bone mineral density (BMD) and biomarkers of bone and collagen degradation in a 1-y multicenter randomized controlled trial (RCT; NU-AGE) in elderly Europeans. Design: An RCT was undertaken across 5 European centers. Subjects in the intervention group consumed the NU-AGE diet for 1 y by receiving individually tailored dietary advice, coupled with supplies of foods including whole-grain pasta, olive oil, and a vitamin D3 supplement (10 ug/d). Participants in the control group were provided with leaflets on healthy eating available in their country. Results: A total of 1294 participants (mean +/- SD age: 70.9 +/-4.0 y; 44% male) were recruited to the study and 1142 completed the 1-y trial. The Mediterranean-like dietary pattern had no effect on BMD (site-specific or whole body); the inclusion of compliance to the intervention in the statistical model did not change the findings. There was also no effect of the intervention on the urinary biomarkers free pyridinoline or free deoxypyridinoline. Serum 25 hydroxyvitamin D significantly increased and parathyroid hormone decreased (P < 0.001) in the MD compared with the control group. Subgroup analysis of individuals with osteoporosis at baseline (site-specific BMD T-score <= -2.5 SDs) showed that the MD attenuated the expected decline in femoral neck BMD (n = 24 and 30 in MD and control groups, respectively; P = 0.04) but had no effect on lumbar spine or whole-body BMD. Conclusions: A 1-y intervention of the Mediterranean-like diet together with vitamin D3 supplements (10 ug/d) had no effect on BMD in the normal age-related range, but it significantly reduced the rate of loss of bone at the femoral neck in individuals with osteoporosis. The NU AGE trial is registered at clinicaltrials.gov as NCT01754012. PMID- 30007344 TI - Natural History of a Sit-and-Wait Dipteran Predator That Uses Extrafloral Nectar as Prey Attractant. AB - Sit-and-wait predators use different strategies to encounter potential prey. Rhinoleucophenga myrmecophaga Vidal et (Vidal et Vilela; Diptera: Drosophilidae) larvae build sticky shelters on top of extrafloral nectaries (EFNs) of Qualea grandiflora Mart (Vochysiaceae), a common plant in the Brazilian cerrado savanna. Although larval shelters block the EFNs, nectar production is not obstructed and is used by the larvae to attract and trap nectar-gathering ants that are eventually eaten by the dipteran. Here we describe the natural history of R. myrmecophaga, its infestation pattern in Q. grandiflora, the ant assemblage at EFNs, and the insects used as prey. We use stable isotope composition (delta13C and delta15N) of R. myrmecophaga and potential food sources to infer its diet, and perform chemical analyses of the droplets found at shelter openings to determine whether nectar is used as a prey attractant. We found that Rhinoleucophenga larvae occur on the majority of Qualea plants and occupy active EFNs mainly in the rainy season. The two most frequent visiting species were also the most common insects found trapped at larval shelters. The stable isotope analyses confirmed that ants are the main food sources of R. myrmecophaga. Chemical analyses and field observations revealed that Rhinoleucophenga larvae use extrafloral nectar to attract prey to their shelters by pushing this liquid to the shelter opening where it forms a droplet. This is a rare case of sit-and wait predator exploiting an ant-plant mutualism through the use of the very food reward produced by the plant to attract and capture potential ant mutualists. PMID- 30007345 TI - Quality characterization of eggs from Romagnola hens, an Italian local breed. AB - In the past years, consumers' concerns about sustainability and animal welfare have increased, strengthening the demand for eggs and meat produced through alternative and extensive farming methods. In addition, producers have also become increasingly interested in the recovery and exploitation of local breeds due to their adaptability to local environmental conditions, to valorize the biodiversity and to provide added value to typical products. Among the Italian local breeds, Romagnola has almost risked extinction and currently is reared in small-scale farms for eggs and meat production. The aim of this study was to characterize the egg quality traits of Romagnola chicken breed (RMG) compared to those obtained by a commercial hybrid (CONV). Ten laying hens of both Romagnola breed and Hy-Line Brown at 40 wk of age were housed in the same outdoor pen and fed the same commercial feed (ME 2,830 kcal/kg, CP 17.2%) for 10 wk. At 5 and 10 wk after housing, all the eggs laid in 4 consecutive days were collected and used for the determination of egg and eggshell characteristics as well as proximate composition and fatty acid profile of egg yolk. As expected, some important productive traits such as egg weight and production resulted higher in CONV chickens. However, eggs from RMG hens presented a higher yolk/egg ratio (31.1 vs. 24.9%; P < 0.01) as well as carotenoids (36.8 vs. 20.2 ppm; P < 0.01) and cholesterol content (12.8 vs. 11.7 mg/g of yolk; P < 0.01) than those laid by the conventional genotype. Moreover, yolks from RMG eggs were characterized by lower polyunsaturated fatty acid (PUFA) n-6 content (22.6 vs. 28.4%; P < 0.01) and PUFA n-6/n-3 ratio (11.3 vs. 13.5; P < 0.01) showing a healthier fatty acids profile than conventional eggs. These results highlighted several valuable egg quality traits of Romagnola chicken breed that might be exploited for the conservation and the development of this underutilized Italian pure breed. PMID- 30007346 TI - What is "Non-Binary" and What Do I Need to Know? A Primer for Surgeons Providing Chest Surgery for Transgender Patients. AB - Background: The majority of transgender research focuses on patients who fall within the gender binary of either trans-male or trans-female. This largely omits understanding of the "non-binary" gender identity, as it pertains to surgical care. Objective: To describe a single-institution experience performing chest affirming procedures in non-binary patients, including patient characteristics, surgical techniques, practice pearls, and outcomes. Methods: This is an observational study of non-binary patients undergoing a "chest affirming surgery" from 2012 to 2017. Demographic and surgical data were collected. A postoperative questionnaire assessing quality of life and body image outcomes was administered. Results: A total of 458 patients with gender dysphoria underwent chest surgery; fifty-eight (13%) patients were non-binary. All non-binary patients indicated they had a female sex assigned at birth (100%). The most commonly performed procedure was the double incision technique with nipple grafts (72%), followed by the double incision technique without nipples grafts (19%). Patients reported improved quality of life (4.88, SD +/- 0.34), comfort with exercise (4.07, SD +/- 0.98), sex life (4.02, SD +/- 0.92), and comfort in physical appearance with (4.97, SD +/- 0.18) and without clothes (4.69, SD +/- 0.47) on a Likert scale. Conclusion: Chest surgery for non-binary patients comprises a significant proportion of our transgender surgery practice, and surgeons providing affirming care should be familiar with the unique characteristics and treatment options for this patient population. PMID- 30007347 TI - Applying Lean Principles to Reduce Wait Times in a VA Emergency Department. AB - Introduction: We describe the use of Lean quality improvement methodologies at a Veterans Affairs (VA) medical facility to redesign Emergency Department (ED) front-end operations and improve ED flow, specifically to reduce time from Veteran arrival to provider evaluation. Materials and Methods: The intervention, a Rapid Process Improvement Workshop (RPIW), took place during January 2014 at the VA Palo Alto Health Care System (VAPAHCS). Key changes made as a result of the RPIW included standardizing and streamlining evaluation and hand-off processes, better-delineating roles for RNs and MDs, more efficiently utilizing beds and improving team communication. We collected 13 months of pre-intervention and 13 months of post-intervention data. The primary outcome was the change in "Door to Doctor" time between the pre-intervention and post-intervention periods at VAPAHCS compared with contemporaneous national control facility sites. Secondary outcomes included the change in "Door to Triage" time and the rate at which patients left without being seen (LWBS). Data analyses were performed using a regression-adjusted difference-in-differences approach. This was a quality improvement project and the institutional review board determined that this project does not meet the definition of human subject research. Results: Overall, "Door to Doctor" time at VAPAHCS decreased 12.6 minutes after the intervention, compared to 3.7 minutes in the control sites. Regression-adjusted difference-in differences estimates for "Door to Doctor" time and "Door to Triage" time showed a significant reduction at VAPAHCS compared with control sites (8.9 minutes and 5.0 minutes, respectively), during the same time period (standard error = 3.5 min; p = 0.01 and standard error = 1.7 min; p = 0.004, respectively). Regression adjusted difference-in-differences estimates for LWBS rates showed that LWBS did not significantly change at VAPAHCS compared with control sites (0.1% vs. 0.3%, p = 0.8). Conclusions: Using Lean principles, VAPAHCS was able to improve Veteran flow in the ED. Use of Lean methods foster interdisciplinary teams and problem solving across departments and are one approach VA EDs can use to address systemic factors and contributors to ED crowding and improve care for Veterans. Future study should incorporate additional measures of quality to determine the effect of Lean on Veteran outcomes and should evaluate the long-term sustainability of the improvement. PMID- 30007348 TI - PAREsnip2: a tool for high-throughput prediction of small RNA targets from degradome sequencing data using configurable targeting rules. AB - Small RNAs (sRNAs) are short, non-coding RNAs that play critical roles in many important biological pathways. They suppress the translation of messenger RNAs (mRNAs) by directing the RNA-induced silencing complex to their sequence-specific mRNA target(s). In plants, this typically results in mRNA cleavage and subsequent degradation of the mRNA. The resulting mRNA fragments, or degradome, provide evidence for these interactions, and thus degradome analysis has become an important tool for sRNA target prediction. Even so, with the continuing advances in sequencing technologies, not only are larger and more complex genomes being sequenced, but also degradome and associated datasets are growing both in number and read count. As a result, existing degradome analysis tools are unable to process the volume of data being produced without imposing huge resource and time requirements. Moreover, these tools use stringent, non-configurable targeting rules, which reduces their flexibility. Here, we present a new and user configurable software tool for degradome analysis, which employs a novel search algorithm and sequence encoding technique to reduce the search space during analysis. The tool significantly reduces the time and resources required to perform degradome analysis, in some cases providing more than two orders of magnitude speed-up over current methods. PMID- 30007349 TI - KIAA1199 expression and hyaluronan degradation colocalize in multiple sclerosis lesions. AB - Modification of hyaluronan (HA) accumulation has been shown to play a key role in regulating inflammatory processes linked to the progression of multiple sclerosis (MS). The aim of this study was to characterize the enzymatic activity involved in HA degradation observed within focal demyelinating lesions in the experimental autoimmune encephalomyelitis (EAE) animal model. EAE was induced in 3-month-old female C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein 33 35 (MOG33-35) peptide. The mice were monitored for 21 days. Formalin-fixed paraffin-embedded tissue from control and EAE mice were labeled with an immunoadhesin against HA, antibodies against KIAA1199 and glial fibrillary acidic protein, a marker for astrocytes. In situ hybridization was conducted using a KIAA1199 nucleic acid probe. In histologic sections of spinal cord from EAE mice, abnormal HA accumulation was observed in the close vicinity of the affected areas, whereas HA was totally degraded within the focal loci of damaged tissue. KIAA1199 immunoreactivity was exclusively associated with focal loci in damaged white columns of the spinal cord. KIAA1199 was mainly expressed by activated astrocytes that invaded damaged tissue. Similar findings were observed in tissue from an MS patient. Here, we show that KIAA1199, a protein that plays a role in a HA degradation pathway independent of the canonical hyaluronidases such as PH20, is specifically expressed in tissue lesions in which HA is degraded. KIAA1199 expression by activated astrocytes may explain the focal HA degradation observed during progression of MS and could represent a possible new therapeutic target. PMID- 30007350 TI - Establishing average values for actigraphy or normal ones? PMID- 30007352 TI - AN EMPIRICAL STUDY: THE IMPACT OF THE NUMBER OF USERS ON ELECTRIC FIELD STRENGTH OF WIRELESS COMMUNICATIONS. AB - As a result of the drastic increase in the number of mobile device users, there is considerable public debate about possible health hazards especially due to base stations and Wi-Fi access points. For this reason, in this study the effects of the number of users in a base station and wireless fidelity (Wi-Fi) access point on electric field strength (E) levels were investigated using real-time measurements. Two-stage E measurements were performed on Ondokuz Mayis University's (OMU) Kurupelit Campus with a PMM-8053 and SRM-3006 electromagnetic field (EMF) meter. In the first stage, 24-h measurements were performed with PMM 8053 at the location where the maximum E was measured and from which the busiest times of the day were then determined. The relationship among band selective E values was assessed using the number of users per minute provided by three cellular system operators for the location. Upper and lower bounds of E according to the number of users were calculated, and then an empirical model that helps calculate the E of medium with 86% accuracy was proposed. In the second stage, the effect of the number of users in a Wi-Fi access point on E level was investigated. For this purpose, the measurement environment was set as including one Wi-Fi access point with needed measurement devices. The number of users was increased as per user per minute. The number of users was validated with the data obtained from OMU IT Department. Using the measurement result, a model with a 96% accuracy between the E value in the environment and the number of users accessing the Wi-Fi system is proposed. With the use of these models, E level in the medium can be determined without using any EMF meters, thus precautions can be taken to stay within regulatory limits. PMID- 30007353 TI - Performance of prognostic modelling of high and low ovarian response to ovarian stimulation for IVF. AB - STUDY QUESTION: What is the performance of previously established regression models in predicting low and high ovarian response to 150 MUg corifollitropin alfa/GnRH-antagonist ovarian stimulation in an independent dataset? SUMMARY ANSWER: The outcome of ovarian stimulation with 150 MUg corifollitropin alfa in a fixed, multiple dose GnRH-antagonist protocol can be validly predicted using logistic regression models with AMH being of paramount importance. WHAT IS KNOWN ALREADY: Predictors of ovarian response have been identified in FSH/GnRH agonist protocols as well as ovarian stimulation with corifollitropin alfa/GnRH antagonist. Multivariable response models have been established already, however, external validation of model performance has so far been lacking. STUDY DESIGN, SIZE, DURATION: Data from a prospective, multi-centre (n = 5), multi-national, investigator-initiated, observational cohort study were analysed. Infertile women (n = 211), body weight >60 kg, were undergoing ovarian stimulation with 150 MUg corifollitropin alfa in a GnRH-antagonist multiple dose protocol for transvaginal oocyte retrieval for IVF. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle Day 2 or 3 of spontaneous menstruation before ovarian stimulation. Main outcomes were low (<6 oocytes) and high (>18 oocytes) ovarian response. PARTICIPANTS/MATERIALS, SETTING, METHODS: Firstly, previously established prediction models for low ovarian response (LOR) and high ovarian response (HOR) were tested using the original parameters. Secondly, re-estimated parameters generated from the present data were tested on the established models. Thirdly, for the development of new predictive models of both LOR and HOR, several logistic regression models were estimated. Resulting prediction models were compared by means of the area under the receiver operating characteristic curve (AUC) and bias-corrected Akaike's Information Criterion (AICc) to identify the most reasonable model for each scenario. MAIN RESULTS AND THE ROLE OF CHANCE: The previously established prediction models for low and high response performed remarkably well on this dataset (low response AUC 0.8879 (95% CI: 0.8185-0.9573) and high response AUC 0.8909 (95% CI: 0.8251-0.9568)). A newly developed simplified model for LOR with log-transformed AMH values and only age as another covariate showed an AUC of 0.8920 (95% CI: 0.8237-0.9603) with the lowest AICc of all models compared. For predicting HOR, we suggest a simplified model using AMH, FSH and AFC (AUC of 0.8976, 95% CI: 0.8206-0.9746). LIMITATIONS, REASONS FOR CAUTION: All analyses were done on data from women with a body weight >60 kg. The newly developed simplified models may suffer from overfitting and need to be tested in further independent data sets. WIDER IMPLICATIONS OF THE FINDINGS: Patient selection for ovarian stimulation with corifollitropin alfa should utilize established response prediction models. The clinical impact of this needs to be evaluated in future studies. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by university funds. M.O.S., T.L. and I.R.K. have nothing to declare. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott, Marckryl Pharma, VitroLife, NMC Healthcare, ReprodWissen, ZIVA and BioSilu. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30007354 TI - An Attention Assessment for Informing Older Drivers' Crash Risks in Various Hazardous Situations. AB - Background and Objectives : Mobility is a critical factor that influences older adults' independence and well-being. Older drivers may experience increased crash risks due to age-related cognitive declines. Ensuring safe driving practices among older drivers is important to maintain their mobility without sacrificing safety. Investigations for an effective assessment technology that can inform older drivers' risks associated with cognitive declines are warranted. This study aims to identify attentional deteriorations that may underlie crashes in various situations. Research Design and Methods : This study employed driving simulation to examine associations between attentional functions of older drivers and crash risks in various hazardous situations. Using the Attention Network Test (ANT), a computerized assessment that measures efficiencies of the three distinct attentional functions (i.e., alerting, orienting, and executive), we examined specific attentional functions that underlie older drivers' crash risks in particular driving situations. Results : Findings from this study revealed significant associations between executive attentional efficiency and crash risks in situations that demand a driver quickly resolving conflicts among multiple competing tasks or information. These situations include turning while a pedestrian is crossing from an opposite direction, merging, and multitasking while driving. Discussion and Implications: The present findings expand our understanding of unique involvements of attentional functions in particular driving situations at an old age. Future driver assessment technologies for informing older drivers about their crash risks may aim to address more fundamental cognitive mechanisms that lead to elevated risks in particular driving situations rather than merely focusing on the situations themselves. PMID- 30007351 TI - Conditional accumulation of toxic tRNAs to cause amino acid misincorporation. AB - To develop a system for conditional amino acid misincorporation, we engineered tRNAs in the yeast Saccharomyces cerevisiae to be substrates of the rapid tRNA decay (RTD) pathway, such that they accumulate when RTD is turned off. We used this system to test the effects on growth of a library of tRNASer variants with all possible anticodons, and show that many are lethal when RTD is inhibited and the tRNA accumulates. Using mass spectrometry, we measured serine misincorporation in yeast containing each of six tRNA variants, and for five of them identified hundreds of peptides with serine substitutions at the targeted amino acid sites. Unexpectedly, we found that there is not a simple correlation between toxicity and the level of serine misincorporation; in particular, high levels of serine misincorporation can occur at cysteine residues without obvious growth defects. We also showed that toxic tRNAs can be used as a tool to identify sequence variants that reduce tRNA function. Finally, we generalized this method to another tRNA species, and generated conditionally toxic tRNATyr variants in a similar manner. This method should facilitate the study of tRNA biology and provide a tool to probe the effects of amino acid misincorporation on cellular physiology. PMID- 30007355 TI - Bifenthrin Fatality in a Canine: A Case Report with Postmortem Concentrations. AB - A case of canine intoxication and fatality with the pyrethroid insecticide bifenthrin is described. A 5-year-old female spayed Pit Bull Terrier was off leash and unsupervised at home for 15-20 min prior to discovery by her owner. The patient was in lateral recumbency, having what the owner described as a seizure. The patient was transported to an emergency veterinary hospital where she presented with tachycardia, tachypnea and intractable tremors/seizures. Despite aggressive medical intervention, the patient went into respiratory and cardiac arrest and died at 28 h after presentation. A postmortem liver sample screened positive for bifenthrin by gas chromatography-mass spectrometry (GC-MS). During the screening procedure, four additional bifenthrin-metabolic products were also observed. Concentrations for bifenthrin were determined for fat, kidney, liver and urine by GC-MS-MS. This is the first reported case of a canine fatality resulting from bifenthrin. PMID- 30007356 TI - A new AMPK activator, GSK773, corrects fatty acid oxidation and differentiation defect in CPT2-deficient myotubes. AB - Carnitine palmitoyl transferase 2 (CPT2) deficiency is one of the most common inherited fatty acid oxidation (FAO) defects and represents a prototypical mitochondrial metabolic myopathy. Recent studies have suggested a pivotal role of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle plasticity and mitochondrial homeostasis. Thus, we tested the potential of GSK773, a novel direct AMPK activator, to improve or correct FAO capacities in muscle cells from patients harboring various mutations. We used controls' and patients' myotubes and studied the parameters of FAO metabolism, of mitochondrial quantity and quality and of differentiation. We found that AMPK is constitutively activated in patients' myotubes, which exhibit both reduced FAO and impaired differentiation. GSK773 improves or corrects several metabolic hallmarks of CPT2 deficiency (deficient FAO flux and C16-acylcarnitine accumulation) by upregulating the expression of CPT2 protein. Beneficial effects of GSK773 are also likely due to stimulation of mitochondrial biogenesis and induction of mitochondrial fusion, by decreasing dynamin-related protein 1 and increasing mitofusin 2. GSK773 also induces a shift in myosin heavy chain isoforms toward the slow oxidative type and, therefore, fully corrects the differentiation process. We establish, through small interfering RNA knockdowns and pharmacological approaches, that these GSK773 effects are mediated through peroxisome proliferator-activated receptor gamma co-activator 1-alpha, reactive oxygen species and p38 mitogen-activated protein kinase, all key players of skeletal muscle plasticity. GSK773 recapitulates several important features of skeletal muscle adaptation to exercise. The results show that AMPK activation by GSK773 evokes the slow, oxidative myogenic program and triggers beneficial phenotypic adaptations in FAO-deficient myotubes. Thus, GSK773 might have therapeutic potential for correction of CPT2 deficiency. PMID- 30007357 TI - Pioneer Paper: Pioneers in Pediatric Psychology: "Doing Pediatrics". PMID- 30007358 TI - Evaluation of a Novel Fibrin Sealant Patch in Hemorrhage Control After Vascular or Hepatic Injury. AB - Introduction: Acute hemorrhage remains the leading cause of death in potentially survivable injuries. The use of topical hemostatic agents has increased over the last two decades with the evolution of damage control surgery. By 2008, the military widely adopted Combat Gauze as the hemostatic dressing of choice for compressible hemorrhage. The goal of this study was to compare the performance of a novel fibrin sealant patch to Combat Gauze in two clinically relevant models of hemorrhage. Materials and Methods: Yorkshire swine underwent unilateral femoral artery puncture or a grade V liver laceration with timed free bleeding then received either the fibrin patch or Combat Gauze packing with 3 minutes of standardized pressure. Animals were then resuscitated to maintain a mean arterial pressure of 60 mmHg for 4 hours. Hemostasis, blood loss, resuscitation volume, survival, vessel patency, and hematologic parameters were evaluated. Results: Hemostasis was equivalent in both groups after hepatic and vascular injury. Survival was 80% in the fibrin patch vascular injury group and 100% in all other groups. Hematologic parameters were not significantly different between treatment groups. Femoral artery patency was 80% in both groups after vascular injury. With simulated ambulation after vessel injury, 60% of the Combat Gauze group and 80% of the fibrin patch group remained hemostatic (p > 0.05). In simulated re exploration with packing removal, all animals rebled after hemostatic product removal. Conclusion: There was no significant difference in hemostasis between a novel fibrin patch and Combat Gauze after extremity arterial or hepatic injury. This novel fibrin patch may have a clinical advantage over the Combat Gauze, as it can be left in the body, thereby limiting the potential need for reoperation. PMID- 30007359 TI - Loneliness as a risk factor for care home admission in the English Longitudinal Study of Ageing. AB - Background: loneliness has an adverse effect on health and well-being, and is common at older ages. Evidence that it is a risk factor for care home admission is sparse. Objective: to investigate the association between loneliness and care home admission. Setting: English Longitudinal Study of Ageing (ELSA). Participants: two-hundred fifty-four individuals across seven waves (2002-15) of ELSA who moved into care homes were age, sex matched to four randomly selected individuals who remained in the community. Methods: logistic regression models examined associations between loneliness, socio-demographic factors, functional status and health on moving into care homes. Results: loneliness (measured by the University of California, Los Angeles (UCLA) Loneliness Scale and a single-item question from the Center for Epidemiological Studies Depression Scale (CES-D)) was associated with moving into a care home (CES-D OR 2.13, 95% CI 1.43-3.17, P = 0.0002, UCLA OR 1.81, 95% CI 1.01-3.27, P = 0.05). The association persisted after adjusting for established predictors (age, sex, social isolation, depression, memory problems including diagnosis of Alzheimer's disease, disability, long-term physical health and wealth). The impact of loneliness (measured by CES-D) on admission accounted for a population attributable fraction of 19.9% (95% CI 7.8-30.4%). Conclusions: loneliness conveys an independent risk of care home admission that, unlike other risk factors, may be amenable to modification. Tackling loneliness amongst older adults may be a way of enhancing wellbeing and delaying or reducing the demand for institutional care. PMID- 30007361 TI - Extracellular vesicles: a missing component in plant cell wall remodeling. PMID- 30007360 TI - The interplay between H2A.Z and H3K9 methylation in regulating HP1alpha binding to linker histone-containing chromatin. AB - One of the most intensively studied chromatin binding factors is HP1alpha. HP1alpha is associated with silenced, heterochromatic regions of the genome and binds to H3K9me3. While H3K9me3 is necessary for HP1alpha recruitment to heterochromatin, it is becoming apparent that it is not sufficient suggesting that additional factors are involved. One candidate proposed as a potential regulator of HP1alpha recruitment is the linker histone H1.4. Changes to the underlying make-up of chromatin, such as the incorporation of the histone variant H2A.Z, has also been linked with regulating HP1 binding to chromatin. Here, we rigorously dissected the effects of H1.4, H2A.Z and H3K9me3 on the nucleosome binding activity of HP1alpha in vitro employing arrays, mononucleosomes and nucleosome core particles. Unexpectedly, histone H1.4 impedes the binding of HP1alpha but strikingly, this inhibition is partially relieved by the incorporation of both H2A.Z and H3K9me3 but only in the context of arrays or nucleosome core particles. Our data suggests that there are two modes of interaction of HP1alpha with nucleosomes. The first primary mode is through interactions with linker DNA. However, when linker DNA is missing or occluded by linker histones, HP1alpha directly interacts with the nucleosome core and this interaction is enhanced by H2A.Z with H3K9me3. PMID- 30007362 TI - Method using a co-culture system with high-purity intramuscular preadipocytes and satellite cells from chicken pectoralis major muscle. AB - Intramuscular fat is important in improving meat quality; however, the lack of high-purity intramuscular preadipocyte (IMP) in vitro has severely limited the in depth research on the mutual regulation of myocytes and adipocytes in chicken. In this study, we establish a new method by combining the mature adipocyte ceiling method and the transwell co-culture system. Mature intramuscular adipocyte (MIA) and muscle satellite cell (MSC) were obtained from digested pectoralis major, and MIAs were transformed into IMPs by dedifferentiation with ceiling culture. MSCs were then purified by differential adhesion for 2 h. The results by inverted microscope observation, MTT assay, Oil Red O staining, and q-PCR revealed that the de-differentiated cells from MIA were identified as the IMPs, and had the same the cellular morphology, the capacity on differentiation, proliferation and passage with the abdominal fat preadipocytes (P > 0.05). The applicability of the obtained IMPs in co-cultured experiment with the MSC revealed that it could meet the requirements of the experimental study. Finally, a co-culture system of IMPs and MSCs was established using a transwell chamber. The co-cultured results indicated that MSCs in the proliferative stage tend to accelerate the differentiation of IMPs to induce more fat content in co-cultured IMPs than in single-culture IMPs (P < 0.05), in the non-proliferative stage, the results tend to show the opposite (P < 0.05). The mRNA levels of related genes significantly changed in accordance with the fat content in cells. The results strongly supported the view that the established co-culture system was effective and feasible. In summary, we successfully found a new method to explore the interaction between myocytes and adipocytes of chicken. Our findings can deepen research on the regulation of chicken myocytes and adipocytes. PMID- 30007363 TI - Machine Learning of Toxicological Big Data Enables Read-Across Structure Activity Relationships (RASAR) Outperforming Animal Test Reproducibility. AB - Earlier we created a chemical hazard database via natural language processing of dossiers submitted to the European Chemical Agency with approximately 10 000 chemicals. We identified repeat OECD guideline tests to establish reproducibility of acute oral and dermal toxicity, eye and skin irritation, mutagenicity and skin sensitization. Based on 350-700+ chemicals each, the probability that an OECD guideline animal test would output the same result in a repeat test was 78%-96% (sensitivity 50%-87%). An expanded database with more than 866 000 chemical properties/hazards was used as training data and to model health hazards and chemical properties. The constructed models automate and extend the read-across method of chemical classification. The novel models called RASARs (read-across structure activity relationship) use binary fingerprints and Jaccard distance to define chemical similarity. A large chemical similarity adjacency matrix is constructed from this similarity metric and is used to derive feature vectors for supervised learning. We show results on 9 health hazards from 2 kinds of RASARs "Simple" and "Data Fusion". The "Simple" RASAR seeks to duplicate the traditional read-across method, predicting hazard from chemical analogs with known hazard data. The "Data Fusion" RASAR extends this concept by creating large feature vectors from all available property data rather than only the modeled hazard. Simple RASAR models tested in cross-validation achieve 70%-80% balanced accuracies with constraints on tested compounds. Cross validation of data fusion RASARs show balanced accuracies in the 80%-95% range across 9 health hazards with no constraints on tested compounds. PMID- 30007365 TI - Differential expression of intestinal nutrient transporters and host defense peptides in Eimeria maxima-infected Fayoumi and Ross chickens. AB - Fayoumi chickens are believed to be more disease resistant compared to commercial broiler chickens. The objective of this study was to compare mRNA expression of intestinal nutrient transporters, digestive enzymes, and host defense peptides (HDP) between Eimeria maxima-challenged Fayoumi and Ross broiler chickens. At 21 d of age, Ross broilers and Fayoumi lines M5.1 and M15.2 were challenged with 1,000 E. maxima oocysts. Control birds were not challenged. Duodenum, jejunum, and ileum were sampled (n = 6) at 7 d post challenge. Gene expression was analyzed using relative quantification PCR. Data were analyzed by ANOVA and significance level was set at P < 0.05. There was numerical, but not statistically significant, differential weight gain depression for Ross (15%) and Fayoumi lines M5.1 (21%) and M15.2 (22%) and significant line-specific changes in gene expression. For nutrient transporters, there was downregulation of mRNA for the brush border membrane, amino acid transporters b0,+AT/rBAT, BoAT, and EAAT3 in different segments of the small intestine of Ross and both lines of Fayoumi chickens, indicating that E. maxima challenge likely caused a decrease in nutrient uptake. For HDP, there was downregulation of avian beta defensin (AvBD) 1, 6, 10, 12, and 13 mRNA in the jejunum of the 2 Fayoumi lines, but no change in the Ross broilers. In the duodenum, there was upregulation of AvBD10 mRNA in the Ross and both Fayoumi lines and additionally upregulation of AvBD11, 12, and 13 mRNA in only Fayoumi line M15.2. Liver expressed antimicrobial peptide 2 (LEAP2) mRNA was downregulated in the duodenum and jejunum of Ross and Fayoumi line M5.1 but not in Fayoumi line M15.2. The homeostatic, non-challenged levels of AvBD mRNA were greater in Fayoumi line M15.2 than Ross and Fayoumi line M5.1 in the duodenum and ileum. This study demonstrates tissue- and genetic line-specific transcriptional responses to E. maxima, highlights novel potential candidate genes for response to coccidiosis, and confirms a role for several previously reported genes in response to coccidiosis. PMID- 30007366 TI - Shared Decision Making About Housing Transitions for Persons With Dementia: A Four-Case Care Network Perspective. AB - Background: Persons with dementia (PWDs) and their caregivers often face difficult housing decisions, that is, decisions about their living arrangements, in which the perspectives of all members of the care network should be involved. Objective: We performed a qualitative data analysis to assess the extent to which housing decisions for PWDs with their formal and informal caregivers correspond to an interprofessional shared decision making (IP-SDM) approach, and what light this approach sheds on their experiences with decision making. Research Design and Methods: We used the IP-SDM model to content-code and analyze data from 4 care networks, each consisting of a PWD, 2 informal and 2 formal caregivers. Results: Decision making in all networks corresponded to most IP-SDM elements, but never included all network members. Decision making was guided by the wishes of the PWD, but their actual involvement decreased over time. Discussion: Results show that while the IP-SDM model was helpful, the options change with cognitive decline and moving to a nursing home can become inevitable in spite of preferences. Implications: Timely and honest communication helps to mitigate the distress of deciding against patient preferences, as could advance care planning about future housing transitions. PMID- 30007364 TI - Trypanosoma brucei UMSBP2 is a single-stranded telomeric DNA binding protein essential for chromosome end protection. AB - Universal minicircle sequence binding proteins (UMSBPs) are CCHC-type zinc-finger proteins that bind a single-stranded G-rich sequence, UMS, conserved at the replication origins of the mitochondrial (kinetoplast) DNA of trypanosomatids. Here, we report that Trypanosoma brucei TbUMSBP2, which has been previously proposed to function in the replication and segregation of the mitochondrial DNA, colocalizes with telomeres at the nucleus and is essential for their structure, protection and function. Knockdown of TbUMSBP2 resulted in telomere clustering in one or few foci, phosphorylation of histone H2A at the vicinity of the telomeres, impaired nuclear division, endoreduplication and cell growth arrest. Furthermore, TbUMSBP2 depletion caused rapid reduction in the G-rich telomeric overhang, and an increase in C-rich single-stranded telomeric DNA and in extrachromosomal telomeric circles. These results indicate that TbUMSBP2 is essential for the integrity and function of telomeres. The sequence similarity between the mitochondrial UMS and the telomeric overhang and the finding that UMSBPs bind both sequences suggest a common origin and/or function of these interactions in the replication and maintenance of the genomes in the two organelles. This feature could have converged or preserved during the evolution of the nuclear and mitochondrial genomes from their ancestral (likely circular) genome in early diverged protists. PMID- 30007367 TI - Increased burden of suicidality among young street-involved sex workers who use drugs in Vancouver, Canada. AB - Background: The risks of suicidality among street-involved youth who use drugs and engage in sex work are not well described. This study sought to evaluate if street-involved youth who engage in sex work were at an elevated risk for attempting suicide. Methods: Data were derived from the At-Risk Youth Study, a prospective cohort of street-involved youth who use drugs in Vancouver, Canada. Multivariable generalized estimating equation analyses were employed to examine whether youth who engaged in sex work were at elevated risk of attempting suicide, controlling for possible confounders. Results: Between September 2005 and May 2015, 1210 youth were recruited into the cohort, of whom, 173 (14.3%) reported recently attempting suicide at some point during the study period. In multivariable analysis, youth who engaged in sex work were significantly more likely to report a recent suicide attempt (adjusted odds ratio = 1.93; 95% confidence interval: 1.28-2.91). Conclusions: Street-involved youth who engage in sex work were observed to be at a significantly higher risk for suicidality. Systematic discrimination and unaddressed trauma may contribute to the observed increased burden of suicidality among this population. Interventions that support the mental health and well-being of street-involved youth who engage in sex work are urgently needed. PMID- 30007368 TI - Torque Teno Virus: Predictor of Infection After Solid Organ Transplant? PMID- 30007369 TI - Motor Impairment and Developmental Psychotic Risk: Connecting the Dots and Narrowing the Pathophysiological Gap. AB - The motor system in its manifold articulations is receiving increasing clinical and research attention. This is because motor impairments constitute a central, expressive component of the mental state examination and a key transdiagnostic feature indexing disease severity. Furthermore, within the schizophrenia spectrum, the integration of neurophysiological, developmental, and phenomenological perspectives suggests that motor impairment is not simply a generic, extrinsic proxy of an altered neurodevelopment, but might be more intimately related to psychotic risk. Therefore, an increased understanding, conceptualization, and knowledge of such motor system and its anomalies could empower contemporary risk prediction and diagnostic procedures. PMID- 30007370 TI - Seed mass diversity along resource gradients: the role of allometric growth rate and size-asymmetric competition. AB - The large variation in seed mass among species inspired a vast array of theoretical and empirical research attempting to explain this variation. So far, seed mass variation was investigated by two classes of studies. One class focuses on species varying in seed mass within communities, while the second focuses on variation between communities, most often with respect to resource gradients. Here, we develop a model capable of simultaneously explaining variation in seed mass within and between communities. The model describes resource competition (for both soil and light resources) in annual communities and incorporates two fundamental aspects: light asymmetry (higher light acquisition per unit biomass for larger individuals) and growth allometry (negative dependency of relative growth rate on plant biomass). Results show that both factors are critical in determining patterns of seed mass variation. In general, growth allometry increases the reproductive success of small-seeded species while light asymmetry increases the reproductive success of large-seeded species. Increasing availability of soil resources increases light competition, thereby increasing the reproductive success of large-seeded species and ultimately the community (weighted) mean seed mass. An unexpected prediction of the model is that maximum variation in community seed mass (a measure of functional diversity) occurs under intermediate levels of soil resources. Extensions of the model incorporating size dependent seed survival and disturbance also show patterns consistent with empirical observations. These overall results suggest that the mechanisms captured by the model are important in determining patterns of species and functional diversity. PMID- 30007371 TI - Laser-induced fluorescence detection of the elusive SiCF free radical. AB - The SiCF free radical has been spectroscopically identified for the first time. The radical was produced in an electric discharge jet using CF3Si(CH3)3 or CF3SiH3 vapor in high pressure argon as the precursor. The laser-induced fluorescence spectrum of the A?+2-X?2 band system in the 610 - 550 nm region was recorded and the ?3/22 spin component of the 0-0 band was studied at high resolution. Rotational analysis gave the B values for the combining states, and by fixing the CF bond lengths at ab initio values we obtained r"Si-C=1.6921A and r'Si-C=1.594(1)A. The bond lengths correspond to a silicon-carbon double bond in the ground state and an unusual Si-C triple bond in the excited state. Single vibronic level emission spectra yielded the ground state bending and stretching energy levels. These were fitted to a Renner-Teller model that included spin orbit and limited vibrational anharmonicity effects. PMID- 30007372 TI - Unraveling electronic absorption spectra using nuclear quantum effects: Photoactive yellow protein and green fluorescent protein chromophores in water. AB - Many physical phenomena must be accounted for to accurately model solution-phase optical spectral line shapes, from the sampling of chromophore-solvent configurations to the electronic-vibrational transitions leading to vibronic fine structure. Here we thoroughly explore the role of nuclear quantum effects, direct and indirect solvent effects, and vibronic effects in the computation of the optical spectrum of the aqueously solvated anionic chromophores of green fluorescent protein and photoactive yellow protein. By analyzing the chromophore and solvent configurations, the distributions of vertical excitation energies, the absorption spectra computed within the ensemble approach, and the absorption spectra computed within the ensemble plus zero-temperature Franck-Condon approach, we show how solvent, nuclear quantum effects, and vibronic transitions alter the optical absorption spectra. We find that including nuclear quantum effects in the sampling of chromophore-solvent configurations using ab initio path integral molecular dynamics simulations leads to improved spectral shapes through three mechanisms. The three mechanisms that lead to line shape broadening and a better description of the high-energy tail are softening of heavy atom bonds in the chromophore that couple to the optically bright state, widening the distribution of vertical excitation energies from more diverse solvation environments, and redistributing spectral weight from the 0-0 vibronic transition to higher energy vibronic transitions when computing the Franck-Condon spectrum in a frozen solvent pocket. The absorption spectra computed using the combined ensemble plus zero-temperature Franck-Condon approach yield significant improvements in spectral shape and width compared to the spectra computed with the ensemble approach. Using the combined approach with configurations sampled from path integral molecular dynamics trajectories presents a significant step forward in accurately modeling the absorption spectra of aqueously solvated chromophores. PMID- 30007373 TI - Adaptive resolution molecular dynamics technique: Down to the essential. AB - We investigate the role of the thermodynamic (TD) force as an essential and sufficient technical ingredient for an efficient and accurate adaptive resolution algorithm. Such a force applied in the coupling region of an adaptive resolution molecular dynamics setup assures thermodynamic equilibrium between atomistically resolved and coarse-grained regions, allowing the proper exchange of molecules. We numerically prove that indeed for systems as relevant as liquid water and 1,3 dimethylimidazolium chloride ionic liquid, the combined action of the TD force and thermostat allows for computationally efficient and numerically accurate simulations, beyond the current capabilities of adaptive resolution setups, which employ switching functions in the coupling region. PMID- 30007374 TI - Molecular model of J-aggregated pseudoisocyanine fibers. AB - Aggregated cyanines form ordered supramolecular structures with the potential to transport energy efficiently over long distances, a hallmark of photosynthetic light-harvesting complexes. In concentrated aqueous solution, pseudoisocyanine (PIC) spontaneously forms fibers with a chiral J-band red-shifted 1600 cm-1 from the monomeric 0-0 transition. A cryogenic transmission electron microscopy analysis of these fibers show an average fiber width of 2.89 nm, although the molecular-level structure of the aggregate is currently unknown. To determine a molecular model for these PIC fibers, the calculated spectra and dynamics using a Frenkel exciton model are compared to experiment. A chiral aggregate model in which the PIC monomers are neither parallel nor orthogonal to the long axis of the fiber is shown to replicate the experimental spectra most closely. This model can be physically realized by the sequential binding of PIC dimers and monomers to the ends of the fiber. These insights into the molecular aggregation model for aqueous PIC can also be applied to other similar cyanine-based supramolecular complexes with the potential for long-range energy transport, a key building block for the rational design of novel excitonic systems. PMID- 30007375 TI - Possible universal relation between short time beta-relaxation and long time alpha-relaxation in glass-forming liquids. AB - Relaxation processes in supercooled liquids are known to exhibit interesting complex behavior. One of the hallmarks of this relaxation process observed in the measured auto correlation function is the occurrence of multiple steps of relaxations. The shorter time relaxation is known as the beta-relaxation which is believed to be due to the motion of particles in the cage formed by their neighbors. The longer time relaxation is called the alpha-relaxation. The time scales of these two relaxations processes dramatically separate out with supercooling. In spite of decades of research, it is still not clearly known how these relaxation processes are related to each other. In this work, we show that there is a possible universal relation between short time beta-relaxation and long time alpha-relaxation. We also show that the proposed relation can be rationalized within random first order transition theory of glass transition if power law relation is assumed between static and dynamic length scales. PMID- 30007376 TI - Theory of curvature-dependent kinetics of diffusion-limited reactions and its application to ligand binding to a sphere with multiple receptors. AB - We present a simple theory that explains how surface curvature affects the reaction kinetics of diffusion-limited reactions on spherically curved surfaces. In this theory, we derive a quadratic equation under the conditions that the rate constant satisfies the Hill and Smoluchowski rate constants at the lowest and highest curvatures, respectively, and that at a certain intermediate curvature, there should be a maximum value of the rate constant, which was recently found in our previous work. We find that the result obtained from our theory is in good agreement with the corresponding one obtained from numerical calculation. In addition, we show that our theory can be directly applied to the Solc-Stockmayer model of axially symmetric reactants, which can be considered as a spherical reactant with a single reaction site. Furthermore, we discuss using our theory to improve the formula for the rate constant in the Berg-Purcell ligand-binding model of a cell membrane covered by multiple receptors. Our simple theory yields insight into the effect of curvature on diffusion-influenced reactions and provides a useful formula for easily and quantitatively evaluating the curvature effect. PMID- 30007377 TI - Communication: Adiabatic quantum trajectory capture for cold and ultra-cold chemical reactions. AB - The Langevin capture model is often used to describe barrierless reactive collisions. At very low temperatures, quantum effects may alter this simple capture image and dramatically affect the reaction probability. In this paper, we use the trajectory-ensemble reformulation of quantum mechanics, as recently proposed by one of the authors (Poirier) to compute adiabatic-channel capture probabilities and cross-sections for the highly exothermic reaction Li + CaH(v = 0, j = 0) -> LiH + Ca, at low and ultra-low temperatures. Each captured quantum trajectory takes full account of tunneling and quantum reflection along the radial collision coordinate. Our approach is found to be very fast and accurate, down to extremely low temperatures. Moreover, it provides an intuitive and practical procedure for determining the capture distance (i.e., where the capture probability is evaluated), which would otherwise be arbitrary. PMID- 30007378 TI - Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation. AB - Amyloid aggregates of human islet amyloid polypeptide (hIAPP or human amylin) have long been implicated in the development of type II diabetes. While hIAPP is known to aggregate into amyloid fibrils, it is the early-stage prefibrillar species that have been proposed to be cytotoxic. A detailed picture of the early stage aggregation process and relevant intermediates would be valuable in the development of effective therapeutics. Here, we use atomistic molecular dynamics simulations with a combination of enhanced sampling methods to examine the formation of the hIAPP dimer in water. Bias-exchange metadynamics calculations reveal relative conformational stabilities of the hIAPP dimer. Finite temperature string method calculations identify pathways for dimer formation, along with relevant free energy barriers and intermediate structures. We show that the initial stages of dimerization involve crossing a substantial free energy barrier to form an intermediate structure exhibiting transient beta-sheet character, before proceeding to form an entropically stabilized dimer structure. PMID- 30007379 TI - Precipitation strengthening in Cu-Ni-Si alloys modeled with ab initio based interatomic potentials. AB - Effective interaction potentials suitable for Cu/delta-Ni2Si and Cu/beta-Ni3Si are developed. We optimise the potential parameters of an embedded atom method potential to reproduce forces, energies, and stresses obtained from ab initio calculations. Details of the potential generation are given, and its validation is demonstrated. The potentials are used in molecular dynamics simulations of shear tests to study the interactions of edge dislocations with coherent delta Ni2Si and beta-Ni3Si precipitates embedded in a copper matrix. In spite of significantly different crystallographic structures of copper and delta-Ni2Si which usually result in circumvention of dislocations, we also observed cutting processes in our simulations. Dislocations cut for a specific orientation of the delta-Ni2Si precipitate and in some cases where dislocation loops originating from previous circumvention processes are present in the glide plane. It is found that beta-Ni3Si precipitates have a similar effect on precipitation strengthening as delta-Ni2Si. Dislocations usually cut beta-Ni3Si but increased coherency strain can lead to circumvention processes. PMID- 30007380 TI - Saltwater transport through pristine and positively charged graphene membranes. AB - Transport of saltwater through pristine and positively charged single-layer graphene nanoporous membranes is investigated using molecular dynamics simulations. Pressure-driven flows are induced by motion of specular reflecting boundaries at feed and permeate sides with constant speed. Unlike previous studies in the literature, this method induces a desired flow rate and calculates the resulting pressure difference in the reservoirs. Due to the hexagonal structure of graphene, the hydraulic diameters of nano-pores are used to correlate flow rate and pressure drop data. Simulations are performed for three different pore sizes and flow rates for the pristine and charged membrane cases. In order to create better statistical averages for salt rejection rates, ten different initial conditions of Na+ and Cl- distribution in the feed side are used for each simulation case. Using data from 180 distinct simulation cases and utilizing the Buckingham Pi theorem, we develop a functional relationship between the volumetric flow rate, pressure drop, pore diameter, and the dynamic viscosity of saltwater. A linear relationship between the volumetric flow rate and pressure drop is observed. For the same flow rate and pore size, charged membranes exhibit larger pressure drops. Graphene membranes with 9.90 A pore diameter results in 100% salt rejection with 163.2 l/h cm2 water flux, requiring a pressure drop of 35.02 MPa. PMID- 30007381 TI - Theoretical study on the polymer translocation into an attractive sphere. AB - We report a non-sampling model, combining the blob method with the standard lattice-based approximation, to calculate the free energy for the polymer translocation into an attractive sphere (i.e., spherical confined trans side) through a small pore. The translocation time is then calculated by the Fokker Planck equation based on the free energy profile. There is a competition between the confinement effect of the sphere and the polymer-sphere attraction. The translocation time is increased due to the confinement effect of the sphere, whereas it is reduced by the polymer-sphere attraction. The two effects offset each other at a special polymer-sphere attraction which is dependent on the sphere size, the polymer length, and the driving force. Moreover, the entire translocation process can be divided into an uncrowded stage where the polymer does not experience the confinement effect of the sphere and a crowded stage where the polymer is confined by the sphere. At the critical sphere radius, the durations of the two (uncrowded and crowded) stages are the same. The critical sphere radius R* has a scaling relation with the polymer length N as R* ~ Nbeta. The calculation results show that the current model can effectively treat the translocation of a three-dimensional self-avoiding polymer into the spherical confined trans side. PMID- 30007382 TI - Influence of hydrodynamic interactions on stratification in drying mixtures. AB - Nonequilibrium molecular dynamics simulations are used to investigate the influence of hydrodynamic interactions on vertical segregation (stratification) in drying mixtures of long and short polymer chains. In agreement with previous computer simulations and theoretical modeling, the short polymers stratify above the long polymers at the top of the drying film when hydrodynamic interactions between polymers are neglected. However, no stratification occurs under the same drying conditions when hydrodynamic interactions are incorporated through an explicit solvent model. Our analysis demonstrates that models lacking hydrodynamic interactions do not faithfully represent stratification in drying mixtures, in agreement with the recent analysis of an idealized model for diffusiophoresis. Hydrodynamic interactions must be incorporated into such models for drying mixtures in future. PMID- 30007383 TI - Electronic response of aluminum-bearing minerals. AB - Aluminum-bearing minerals show different hydrogen evolution and dissolution properties when subjected to radiation, but the complicated sequence of events following interaction with high-energy radiation is not understood. To gain insight into the possible mechanisms of hydrogen production in nanoparticulate minerals, we study the electronic response and determine the bandgap energies of three common aluminum-bearing minerals with varying hydrogen content: gibbsite (Al(OH)3), boehmite (AlOOH), and alumina (Al2O3) using electron energy loss spectroscopy, X-ray photoelectron spectroscopy, and first-principles electronic structure calculations employing hybrid density functionals. We find that the amount of hydrogen has only a small effect on the number and spectrum of photoexcitations in this class of materials. Electronic structure calculations demonstrate that low energy electrons are isotropically mobile, while holes in the valence band are likely constrained to move in layers. Furthermore, holes in the valence band of boehmite are found to be significantly more mobile than those in gibbsite, suggesting that the differences in radiolytic and dissolution behavior are related to hole transport. PMID- 30007384 TI - Linear response time-dependent density functional theory without unoccupied states: The Kohn-Sham-Sternheimer scheme revisited. AB - The Sternheimer approach to time-dependent density functional theory in the linear response regime is attractive because of its computational efficiency. The latter results from avoiding the explicit calculation of unoccupied orbitals and from the basic structure of the Sternheimer equations, which naturally lend themselves to far-reaching parallelization. In this article, we take a fresh look at the frequency-dependent Sternheimer equations. We first give a complete, self contained derivation of the equations that complements previous derivations. We then discuss several aspects of an efficient numerical realization. As a worked example, we compute the photoabsorption spectra of small hydrogenated silicon clusters and confirm that for these the quality of the Kohn-Sham eigenvalues is more important than the effects of the exchange-correlation kernel. Finally, we demonstrate how triplet excitations can readily be computed from the Sternheimer approach. PMID- 30007385 TI - Relation between image charge and potential alignment corrections for charged defects in periodic boundary conditions. AB - Charged defects are often studied within the periodic density functional theory (DFT), but this introduces strong finite-size artifacts. In this work, we develop an electrostatic image interaction correction (IIC) method based on the direct solution of the Poisson equation for charge models constructed directly from DFT calculations. These IICs are found to be detail-insensitive, depending almost entirely on bulk dielectric properties. As these IICs are not able to fully explain the observed finite-size scaling, we explore potential alignment in detail and introduce a novel decomposition to separate out different contributions. We find that the two main sources of potential alignment are defect image interactions and changes in the number of atoms present in the supercell. This first effect is accurately predicted by the periodic part of our IIC. The second contribution is unrelated to the IIC and justifies the common observation that the magnitude of finite-size dependence can strongly vary between vacancy and interstitial defects. It can be approximately predicted using atomic radius, but is strongly sensitive to the pseudopotential employed. Combined, these developments provide a new justification for known finite-size scaling rules. Our results suggest that for cubic supercells, the Lany-Zunger IIC, combined with simplified potential alignment between neutral systems, can yield accurate corrections in spite of the simplicity of the approach. PMID- 30007386 TI - Pore diameter dependence of catalytic activity: p-nitrobenzaldehyde conversion to an aldol product in amine-functionalized mesoporous silica. AB - The reaction yield for conversion of p-nitrobenzaldehyde (PNB) to an aldol product in amine-functionalized mesoporous silica nanoparticles (MSN) exhibits a 20-fold enhancement for a modest increase in pore diameter, d. This enhanced catalytic activity is shown to reflect a strong increase in the "passing propensity," P, of reactant and product species inside the pores. We find that P ~ 0, corresponding to single-file diffusion, applies for the smallest d which still significantly exceeds the linear dimensions of PNB and the aldol product. However, in this regime of narrow pores, these elongated species must align with each other and with the pore axis in order to pass. Thus, P reflects both translational and rotational diffusion. Langevin simulation accounting for these features is used to determine P versus d. The results are also augmented by analytic theory for small and large d where simulation is inefficient. The connection with the catalytic activity and yield is achieved by the incorporation of results for P into a multi-scale modeling framework. Specifically, we apply a spatially coarse-grained (CG) stochastic model for the overall catalytic reaction diffusion process in MSN. Pores are treated as linear arrays of cells from the ends of which species adsorb and desorb, and between which species hop and exchange, with the exchange rate reflecting P. CG model predictions including yield are assessed by Kinetic Monte Carlo simulation. PMID- 30007387 TI - Accurate rovibrational energies of ozone isotopologues up to J = 10 utilizing artificial neural networks. AB - In recent years, ozone and its isotopologues have been a topic of interest in many fields of research, due to its importance in atmospheric chemistry and its anomalous isotopic enrichment-or the so-called "mass-independent fractionation." In the field of potential energy surface (PES) creation, debate over the existence of a potential barrier just under the dissociation threshold (referred to as a "potential reef") has plagued research for some years. Recently, Dawes and co-workers [Dawes, Lolur, Li, Jiang, and Guo (DLLJG) J. Chem. Phys. 139, 201103 (2013)] created a highly accurate global PES, for which the reef is found to be replaced with a (monotonic) "plateau." Subsequent dynamical calculations on this "DLLJG" PES have shown improved agreement with experiment, particularly the vibrational spectrum. However, it is well known that reaction dynamics is also highly influenced by the rovibrational states, especially in cases like ozone that assume a Lindemann-type mechanism. Accordingly, we present the first significant step toward a complete characterization of the rovibrational spectrum for various isotopologues of ozone, computed using the DLLJG PES together with the ScalIT suite of parallel codes. Additionally, artificial neural networks are used in an innovative fashion-not to construct the PES function per se but rather to greatly speed up its evaluation. PMID- 30007388 TI - Perspective: Basic understanding of condensed phases of matter via packing models. AB - Packing problems have been a source of fascination for millennia and their study has produced a rich literature that spans numerous disciplines. Investigations of hard-particle packing models have provided basic insights into the structure and bulk properties of condensed phases of matter, including low-temperature states (e.g., molecular and colloidal liquids, crystals, and glasses), multiphase heterogeneous media, granular media, and biological systems. The densest packings are of great interest in pure mathematics, including discrete geometry and number theory. This perspective reviews pertinent theoretical and computational literature concerning the equilibrium, metastable, and nonequilibrium packings of hard-particle packings in various Euclidean space dimensions. In the case of jammed packings, emphasis will be placed on the "geometric-structure" approach, which provides a powerful and unified means to quantitatively characterize individual packings via jamming categories and "order" maps. It incorporates extremal jammed states, including the densest packings, maximally random jammed states, and lowest-density jammed structures. Packings of identical spheres, spheres with a size distribution, and nonspherical particles are also surveyed. We close this review by identifying challenges and open questions for future research. PMID- 30007389 TI - Using reduced density matrix techniques to capture static and dynamic correlation in the energy landscape for the decomposition of the CH2CH2ONO radical and support a non-IRC pathway. AB - The unexpected abundance of HNO in the photodecomposition of the radical 2 nitrosooxy ethyl (CH2CH2ONO) is investigated through calculations of the potential energy surface by the anti-Hermitian contracted Schrodinger equation (ACSE) method, which directly generates the 2-electron reduced density matrix. The ACSE, which is able to balance single-reference (dynamic) and multi-reference (static) correlation effects, reveals some subtle correlation effects along the intrinsic reaction coordinate (IRC) en route to NO + oxirane, an IRC which offers a potential bifurcation to the HNO + vinoxy product channel. These effects were not fully captured by either single-reference techniques, such as coupled cluster, or multi-reference techniques, such as second-order multi-reference perturbation theory. These correlation effects reveal small to moderate energy changes in key transition states, which have implications for the reaction mechanism as related to the production of HNO. PMID- 30007390 TI - State-interaction pair-density functional theory. AB - The accurate description of ground- and excited-state potential energy surfaces poses a challenge for many electronic structure methods, especially in regions where strong electronic state interaction occurs. Here we introduce a new methodology, state-interaction pair-density functional theory (SI-PDFT), to target molecular systems exhibiting strong interaction of electronic states. SI PDFT is an extension of multiconfiguration pair-density functional theory in which a set of N electronic states is generated through the diagonalization of an N * N effective Hamiltonian. We demonstrate the accuracy of the method by performing calculations on the ionic-neutral avoided crossing in lithium fluoride and the 1pipi-1pisigma* avoided crossing in the H-O bond photodissociation in phenol. We show that SI-PDFT can be a useful tool in the study of photochemistry and nonadiabatic dynamics. PMID- 30007391 TI - Dynamics of Janus motors with microscopically reversible kinetics. AB - Janus motors with chemically active and inactive hemispheres can operate only under nonequilibrium conditions where detailed balance is broken by fluxes of chemical species that establish a nonequilibrium state. A microscopic model for reversible reactive collisions on a Janus motor surface is constructed and shown to satisfy detailed balance. The model is used to study Janus particle reactive dynamics in systems at equilibrium where generalized chemical rate laws that include time-dependent rate coefficients with power-law behavior are shown to describe reaction rates. While maintaining reversible reactions on the Janus catalytic hemisphere, the system is then driven into a nonequilibrium steady state by fluxes of chemical species that control the chemical affinity. The statistical properties of the self-propelled Janus motor in this nonequilibrium steady state are investigated and compared with the predictions of a fluctuating thermodynamics theory. The model has utility beyond the examples presented here, since it allows one to explore various aspects of nonequilibrium fluctuations in systems with self-diffusiophoretic motors from a microscopic perspective. PMID- 30007392 TI - Analysis of fluctuations in the first return times of random walks on regular branched networks. AB - The first return time (FRT) is the time it takes a random walker to first return to its original site, and the global first passage time (GFPT) is the first passage time for a random walker to move from a randomly selected site to a given site. We find that in finite networks, the variance of FRT, Var(FRT), can be expressed as Var(FRT) = 2?FRT??GFPT? - ?FRT?2 - ?FRT?, where ?.? is the mean of the random variable. Therefore a method of calculating the variance of FRT on general finite networks is presented. We then calculate Var(FRT) and analyze the fluctuation of FRT on regular branched networks (i.e., Cayley tree) by using Var(FRT) and its variant as the metric. We find that the results differ from those in such other networks as Sierpinski gaskets, Vicsek fractals, T-graphs, pseudofractal scale-free webs, (u, v) flowers, and fractal and non-fractal scale free trees. PMID- 30007393 TI - Structures and spectroscopy of the ammonia eicosamer, (NH3)n=20. AB - In this work, we reported structures and relative stabilities of the neutral ammonia eicosamer at the APFD/6-31++g(d,p) level of theory. Furthermore, we have examined the temperature dependence isomer distribution and reported the relative population of the ammonia eicosamer for temperatures ranging from 20 to 400 K. Moreover, a theoretical infrared (IR) spectroscopic study is performed to confirm our results. As a result, several stable structures have been identified as isomers of the ammonia eicosamer. The most stable structure is a cage-like isomer with two central solvated ammonia molecules. It is found that cage-like isomers with central solvated ammonia molecules are more stable than other types of structures. Besides, two fused tetrameric cyclic structures belonging to the C2 symmetry point group are also located. Moreover, other reported isomers exhibit an amorphous behavior with no definite symmetry. When considering the temperature dependence isomer distribution, we found that only cage-like isomers contribute to the population of the ammonia eicosamer. The most stable isomer dominates the population of the cluster for all the investigated temperatures. Our analysis shows that only the IR spectra of isomers that contribute to the relative population have their peaks in agreement with the experiment. This agreement could be an indication of the reliability of our proposed structures of the ammonia eicosamer and their relative stability. PMID- 30007394 TI - Rovibrational analysis of c-SiC2H2: Further evidence for out-of-plane bending issues in correlated methods. AB - While the issue of properly describing the out-of-plane bends (OPBs) in sp2 hybridized carbon atoms has reappeared for c-SiC2H2, the present quantum chemical study provides a new characterization of this molecule in order to aid in its potential detection in astrophysically relevant studies. Combining the previous, high-level approach with MP2-F12/aug-cc-pVDZ gives exceptionally accurate results for the comparison of experimental rotational constants and seemingly reliable vibrational frequencies. Most notably, the brightest fundamental vibrational frequency in c-SiC2H2, the b1 OPB, is predicted to lie at 673.4 cm-1, within 4.0 cm-1 of the previous matrix isolation experiment. As with c-C3H2, CCSD(T)-F12/aug cc-pVTZ appears to be quite susceptible to over estimating the OPB anharmonic correction in c-SiC2H2 and may also do such for in-plane bends, as well. MP2 F12/aug-cc-pVDZ is less susceptible to these errors, and increasing the step size reduces this positive anharmonicity issue in both the cases. The OPB underestimation, however, likely still remains. Finally, estimates for some anharmonic vibrational frequencies are provided for the methylated form, c SiC2HCH3, which is likely also a product of gas phase reactions of .SiH with various alkynes. PMID- 30007395 TI - Nonlinear-response properties in a simplified time-dependent density functional theory (sTD-DFT) framework: Evaluation of the first hyperpolarizability. AB - Recent developments in nonlinear imaging microscopy show the need to implement new theoretical tools, which are able to characterize nonlinear optical properties in an efficient way. For second-harmonic imaging microscopy (SHIM), quantum chemistry could play an important role to design new exogenous dyes with enhanced first hyperpolarizabilities or to characterize the response origin in large endogenous biological systems. Such methods should be able to screen a large number of compounds while reproducing their trends and to treat large systems in reasonable computation times. To fulfill these requirements, we present a new simplified time-dependent density functional theory (sTD-DFT) implementation to evaluate the first hyperpolarizability where the Coulomb and exchange integrals are approximated by short-range damped Coulomb interactions of transition density monopoles. For an ultra-fast computation of the first hyperpolarizability, a tight-binding version (sTD-DFT-xTB) is also proposed. In our implementation, a sTD-DFT calculation is more than 600 time faster with respect to a regular TD-DFT treatment, while the xTB version speeds up the entire calculation further by at least two orders of magnitude. We challenge our implementation on three test cases: typical push-pull pi-conjugated compounds, fluorescent proteins, and a collagen model, which were selected to model requirements for SHIM applications. PMID- 30007396 TI - Molecular mechanism of charge inversion revealed by polar orientation of interfacial water molecules: A heterodyne-detected vibrational sum frequency generation study. AB - "Charge inversion" is a phenomenon in which multivalent counterions overcompensate for interfacial charges and invert the sign of the net charge near a surface. This phenomenon is believed to be relevant to biologically important processes such as DNA condensation, and hence it has attracted much attention. We investigated the polar orientation of interfacial water molecules at two different negatively charged interfaces in the absence and presence of La3+ using heterodyne-detected vibrational sum frequency generation spectroscopy, which can directly determine the up/down orientation of interfacial molecules. It was found that the orientations of water molecules at a bio-relevant phospholipid interface change from the hydrogen-up to the hydrogen-down with the addition of 10 uM La3+. This change of water orientation indicates that the net charge at the phospholipid interface is inverted by adsorption of La3+ to the phosphate headgroup. By contrast, at an alkylsulfate interface, the majority of the interfacial water molecules remain hydrogen-up orientated even in the presence of 25 mM La3+, indicating that the sulfate headgroup is still solvated by up oriented water. The observed headgroup specificity suggests that charge inversion at the phospholipid interface originates primarily from the chemical interaction between the phosphate and La3+ ion. PMID- 30007397 TI - The race within supercooled liquids-Relaxation versus crystallization. AB - Can any liquid be cooled down below its melting point to an isentropic (Kauzmann) temperature without vitrifying or crystallizing? This long-standing question concerning the ultimate fate of supercooled liquids is one of the key problems in condensed matter physics and materials science. In this article, we used a plethora of thermodynamic and kinetic data and well established theoretical models to estimate the kinetic spinodal temperature, TKS (the temperature where the average time for the first critical crystalline nucleus to appear becomes equal to the average relaxation time of a supercooled liquid), and the Kauzmann temperature, TK, for two substances. We focused our attention on selected compositions of the two most important oxide glass-forming systems: a borate and a silicate-which show measurable homogeneous crystal nucleation in laboratory time scales-as proxies of these families of glass-formers. For both materials, we found that the TKS are significantly higher than the predicted TK. Therefore, at ambient pressure, at deep supercoolings before approaching TK, crystallization wins the race over structural relaxation. Hence, the temperature of entropy catastrophe predicted by Kauzmann cannot be reached for the studied substances; it is averted by incipient crystal nucleation. Our finding that TKS > TK for two real glasses corroborate the results of computer simulations for a pressurized silica glass. PMID- 30007398 TI - Spectroscopy of gold atoms and gold oligomers in helium nanodroplets. AB - The 6p 2P1/2 <- 6s 2S1/2 and 6p 2P3/2 <- 6s 2S1/2 transitions (D lines) of gold atoms embedded in superfluid helium nanodroplets have been investigated using resonant two-photon ionization spectroscopy. Both transitions are strongly blue shifted and broadened due to the repulsive interaction between the Au valence electron and the surrounding helium. The in-droplet D lines are superimposed by the spectral signature of Au atoms relaxed into the metastable 2D states. These features are narrower than the in-droplet D lines and exhibit sharp rising edges that coincide with bare atom transitions. It is concluded that they originate from metastable 2D state AuHen exciplexes that have been ejected from the helium droplets during a relaxation process. Interestingly, the mechanism that leads to the formation of these complexes is suppressed for very large helium droplets consisting of about 2 * 106 He atoms, corresponding to a droplet diameter on the order of 50 nm. The assignment of the observed spectral features is supported by ab initio calculations employing a multiconfigurational self-consistent field method and a multi-reference configuration interaction calculation. For large helium droplets doped with Au oligomers, excitation spectra for mass channels corresponding to Aun with n = 2, 3, 4, 5, 7, and 9 are presented. The mass spectrum reveals even-odd oscillations in the number of Au atoms that constitute the oligomer, which is characteristic for coinage metal clusters. Resonances are observed close by the in-droplet D1 and D2 transitions, and the corresponding peak forms are very similar for different oligomer sizes. PMID- 30007399 TI - Structures of lithium-zinc compounds at high pressures. AB - Intermetallic lithium compounds have found a wide range of applications owing to their light mass and desirable electronic and mechanical properties. Here, by compressing pure lithium and zinc mixtures in a diamond-anvil cell, we observe a direct reaction forming the stoichiometric compound LiZn, at pressures below 1 GPa. On further compression above 10 GPa, we observe the formation of Li2Zn, which is the highest lithium content compound to be discovered in the Li-Zn system. Our results constrain the structures of these compounds and their evolution with pressure, furthering our understanding of potentially useful light volume-efficient energy storage materials. PMID- 30007400 TI - Two-dimensional Au-1,3,5 triethynylbenzene organometallic lattice: Structure, half-metallicity, and gas sensing. AB - On the basis of first-principles calculations, we investigated the structural and electronic properties of the two-dimensional (2D) Au-1,3,5 triethynylbenzene (Au TEB) framework, which has been recently synthesized by homocoupling reactions in experiments. Featured by the C-Au-C linkage, the 2D Au-TEB network has a kagome lattice by Au atoms and a hexagonal lattice by organic molecules within the same metal-organic framework (MOF), which exhibits intrinsic half-metallicity with one spin channel metallic and the other spin channel fully insulating with a large energy gap of 2.8 eV. Two branches of kagome bands are located near the Fermi level, with each branch including one flat band and two Dirac bands, which originates from the out-of-plane dxz and dyz orbitals of Au and may lead to many exotic topological quantum phases. We further studied the adsorption of F atoms, Cl atoms, and small gas molecules including O2, CO, NO2, and NH3 on the Au-TEB network, aiming to exploit its potential applications in gas sensors. Detailed analyses on adsorption geometry, energy, molecular orbital interaction, and electronic structure modification suggest the great potential of Au-TEP as a promising alternative for gas sensing. We expect these results to expand the universe of low-dimensional half-metallic MOF structures and shed new light on their practical applications in nanoelectronics/spintronics. PMID- 30007401 TI - A cluster randomized web-based intervention trial to reduce food neophobia and promote healthy diets among one-year-old children in kindergarten: study protocol. AB - BACKGROUND: A child's first years of life are crucial for cognitive development and future health. Studies show that a varied diet with a high intake of vegetables is positive for both weight and cognitive development. The present low intake of vegetables in children's diets is therefore a concern. Food neophobia can be a barrier for vegetable intake in children. Our hypothesis is that interventions that can increase children's intake of vegetables should be introduced early in life to overcome children's neophobia. This study aims to develop, measure and compare the effect of two different interventions among one year-old children in kindergartens to reduce food neophobia and promote healthy diets. METHODS: The kindergartens are randomized to one of three groups: two different intervention groups and one control group. We aimed to include a total of 210 children in the study. The first intervention group will be served a warm lunch meal with a variety of vegetables, 3 days a week during the intervention period of 3 months. The second intervention group will be served the same meals and, in addition, kindergarten staff will be asked to implement pedagogical tools including sensory lessons, adapted from the Sapere method, and advices on meal practice and feeding practices. The control group continues their usual meal practices. Parents and kindergarten staff will complete questionnaires regarding food neophobia, food habits and cognitive development at baseline and post intervention. A similar intervention among 2-year-old children in kindergarten has been implemented and evaluated earlier. We will investigate whether a digital version of this intervention has an effect, because digital interventions can be easily implemented nationwide. We will also investigate whether there are benefits of conducting such interventions in younger children, before the onset of food neophobia. Questionnaires, information videos and recipes will be digitally distributed. DISCUSSION: Results of this study will provide new knowledge about whether a sensory education and a healthy meal intervention targeting children, kindergarten staff and parents will reduce levels of food neophobia in children, improve parental and kindergarten feeding practices, improve children's dietary variety, improve children's cognitive development and reduce childhood overweight. TRIAL REGISTRATION: ISRCTN98064772 . PMID- 30007402 TI - Survival benefit of pure dose-dense chemotherapy in breast cancer: a meta analysis of randomized controlled trials. AB - BACKGROUND: Dose-dense chemotherapy is a widely accepted regimen for high-risk breast cancer patients. However, conflicting survival benefits of pure dose-dense chemotherapy have been reported in different randomized controlled trials (RCTs). This meta-analysis aimed to further assess the efficacy and safety of pure dose dense chemotherapy in breast cancer. METHODS: A literature search of electronic databases and websites was performed to identify phase III RCTs reporting the efficacy and toxicity of pure dose-dense chemotherapy. The endpoints of interest were overall survival (OS), disease-free survival (DFS), and toxicities. The hazard ratios (HRs) of death and recurrence and the odds ratios (ORs) of adverse events were estimated and pooled. RESULTS: Seven studies (five trials) were eligible, encompassing a total of 9851 patients. Patients treated with dose-dense chemotherapy obtained better DFS (HR = 0.83; 95% CI 0.75-0.91; p = 0.0001) than those treated with the conventional schedule, while OS benefit of dose-dense chemotherapy was less impressive (HR = 0.86; 95% CI 0.73-1.02; p = 0.08). However, significant OS benefit was observed in node-positive patients (HR = 0.77; 95% CI 0.66-0.90; p = 0.001). The incidence of anemia, pain, and transaminase elevation was higher in the dose-dense chemotherapy arm. CONCLUSIONS: Dose-dense chemotherapy leads to better prognosis; these findings suggest that it may be a potentially preferred treatment for breast cancer patients, particularly for women with lymph node involvement. However, more RCTs are warranted to better define the best candidates for dose-dense chemotherapy. PMID- 30007404 TI - Therapeutic and prophylactic gastrectomy in a family with hereditary diffuse gastric cancer secondary to a CDH1 mutation: a case series. AB - BACKGROUND: Gastric cancer is the fifth most prevalent and the third most lethal cancer worldwide, causing approximately 720,000 deaths annually. Although most cases of gastric cancers are sporadic, one of its inherited forms, hereditary diffuse gastric cancer (HDGC), constitutes about 1-3% of cases. Interestingly, females in families with HDGC are also predisposed to developing lobular breast cancer (LBC). Recent analyses have identified loss-of-function germline mutations in cadherein-1 (CDH1) as a culprit in HDGC and LBC. This discovery fueled several sequencing analyses and case series reports analyzing the pattern of inheritance of CDH1 and its propensity to induce HDGC. In 2015, a multinational and multidisciplinary task force updated the guidelines and criteria for screening, diagnosing, and managing HDGC. CASE PRESENTATION: Here, we present a case series of three siblings with family history of HDGC who tested positive for the CDH1 mutation and describe their surgical treatment course, post-operative management, and follow-up as they pertain to the updated guidelines. CONCLUSIONS: Despite recent updates in guidelines in the diagnosis and management of HDGC, the disease remains challenging to address with patients given the high level of uncertainty and the comorbidities associated with prophylactic intervention. We strongly recommend that an interdisciplinary team inclusive of clinical and surgical oncologists, along with geneticists, social work, and psychological support, should follow the patients in a longitudinal and comprehensive manner in order to achieve full recovery and return to normalcy, as with our patients. PMID- 30007405 TI - Urea cycle disorder presenting as bilateral mesial temporal sclerosis - an unusual cause of seizures: a case report and review of the literature. AB - BACKGROUND: Urea cycle disorders are secondary to defects in the system converting ammonia into urea, causing accumulation of ammonia and other byproducts which are neurotoxic. Ornithine transcarbamylase deficiency is the most common of the urea cycle disorders and frequently presents with coma or seizures during hyperammonemia. However, seizures can also occur without metabolic decompensation. CASE PRESENTATION: We describe a 23-year-old Chinese woman with urea cycle disorder who presented with confusion due to focal seizures arising from the left frontotemporal region. Interestingly, her ammonia levels remained normal during the seizures. Neuroimaging showed bilateral mesial temporal sclerosis. Her seizures were successfully controlled with two anti epileptic medications. CONCLUSIONS: This case adds evidence of the predisposition of the temporal lobe to injury in urea cycle disorder. Urea cycle disorder can lead to mesial temporal sclerosis which leads to increased susceptibility of patients to seizures regardless of their metabolic state. PMID- 30007403 TI - Therapeutic landscape in mutational triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scarce. Very few recurrent mutations, including TP53 and PI3KCA mutations, together with a long tail of individually rare mutations occur in TNBC. These combined effects of genomic alterations drive TNBC progression. Given the complexity and heterogeneity of TNBC, clinical interpretation of the genomic alterations in TNBC may pave a new way for the treatment of TNBC. In this review, we summarized the germline and somatic mutation profiles of TNBC and discussed the current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics. PMID- 30007407 TI - Triglyceride-mediated influence of serum angiopoietin-like protein 8 on subclinical atherosclerosis in type 2 diabetic patients: results from the GDMD study in China. AB - BACKGROUND: Hypertriglyceridemia, insulin resistance and hyperglycemia are risk factors for atherosclerosis in type 2 diabetes. Angiopoietin-like protein 8 (ANGPTL8) is a newly identified liver-derived hormone related to these risk factors. Hence, we aimed to explore the correlations between serum levels of ANGPTL8 and subclinical atherosclerosis in type 2 diabetes. METHODS: We measured serum ANGPTL8, blood lipids, blood glucose, common carotid artery Intima-Media Thickness (c-IMT) and calculated homeostasis model assessment of insulin resistance in (1) control subjects (n = 100), (2) type 2 diabetic patients without subclinical atherosclerosis (n = 100), and (3) type 2 diabetic patients with subclinical atherosclerosis (n = 100). RESULTS: Serum levels of ANGPTL8 and triglyceride (TG) were significantly increased in type 2 diabetic patients with subclinical atherosclerosis as compared with type 2 diabetic patients without subclinical atherosclerosis and control subjects (P < 0.001). ANGPTL8 was positively associated with age, TG, diabetes duration, and c-IMT in type 2 diabetes. Logistic regression analysis revealed that ANGPTL8 had higher odds of having subclinical atherosclerosis [odds ratio (OR) 2.90, 95% confidence interval (CI) 1.48-5.70, P = 0.002] in type 2 diabetes. Mediation analysis indicated that TG acted as a partial mediator in the relationship between ANGPTL8 and c-IMT. CONCLUSIONS: TG partially mediates the positive relationship between ANGPTL8 and c-IMT. Our data provide the first evidence for a strong link between ANGPTL8 and subclinical atherosclerosis, suggesting ANGPTL8 to be a new biomarker for subclinical atherosclerosis in type 2 diabetes. PMID- 30007406 TI - Treatment options for PNET liver metastases: a systematic review. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare pancreatic neoplasms. About 40-80% of patients with PNET are metastatic at presentation, usually involving the liver (40-93%). Liver metastasis represents the most significant prognostic factor. The aim of this study is to present an up-to-date review of treatment options for patients with liver metastases from PNETs. METHODS: A systematic literature search was performed using the PubMed database to identify all pertinent studies published up to May 2018. RESULTS: The literature search evaluated all the therapeutic options for patients with liver metastases of PNETs, including surgical treatment, loco-regional therapies, and pharmacological treatment. All the different treatment options showed particular indications in different presentations of liver metastases of PNET. Surgery remains the only potentially curative therapeutic option in patients with PNETs and resectable liver metastases, even if relapse rates are high. Efficacy of medical treatment has increased with advances in targeted therapies, such as everolimus and sunitinib, and the introduction of radiolabeled somatostatin analogs. Several techniques for loco-regional control of metastases are available, including chemo- or radioembolization. CONCLUSIONS: Treatment of patients with PNET metastases should be multidisciplinary and must be personalized according to the features of individual patients and tumors. PMID- 30007409 TI - Neoadjuvant vs definitive concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma patients. AB - BACKGROUND: The optimal treatment for locally advanced esophageal squamous cell carcinoma remains unclear. We compared the clinical outcomes of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy [the surgery group] and CCRT without surgery [the CCRT group] in patients with squamous cell carcinoma from an Asian population. METHODS: Eligible patients diagnosed from 2008 to 2015 were identified through the Taiwan Cancer Registry. To balance observable potential confounders, we constructed a 1:1 propensity score-matched cohort [surgery vs CCRT]. We compared the hazard ratios between the surgery and CCRT groups for death using a robust variance estimator. We also evaluated the outcomes of patients for freedom from local regional recurrence (FFLRR) and esophageal cancer-specific survival (ECSS). Extensive supplementary analyses were performed to examine the robustness of our findings. RESULTS: Our study population included 298 patients balanced with respect to the observed covariables. The hazard ratio of death was 0.56 [95% confidence interval 0.42~0.75] when surgery was compared to CCRT. The results remained significant in the FFLRR and ECSS outcomes. In the supplementary analyses, our results also remained significant when additional covariables were taken into consideration or when the definition of the index date was changed. CONCLUSIONS: When compared to definitive CCRT, neoadjuvant CCRT followed by esophagectomy was associated with improved overall survival for locally advanced esophageal squamous cell carcinoma. However, given the nonrandomized nature of the study and the sensitivity to potentially unmeasured confounders, our results should be interpreted cautiously. PMID- 30007408 TI - Age-related morphometrical peculiarities of Lithuanian women's primordial ovarian follicles. AB - BACKGROUND: For the first time, thorough morphometrical measurements of primordial ovarian follicles were performed and their age-related changes were investigated in Lithuanian women of the reproductive age. METHODS: Ovaries of dead women (n = 30) were divided into six age groups: 15-20 years old, 21-25 years old, 26-30 years old, 31-35 years old, 36-40 years old and 41-46 years old. Histological slides of left and right ovaries were stained using haematoxylin eosin and periodic acid-Schiff (PAS) staining methods. The morphometrical measurements of 10 primordial ovarian follicles of the left and right ovary of each woman were made from microphotographs. RESULTS: The diameter of primordial ovarian follicles increased in groups of women from 15 years old to 35 years old and decreased in the groups from 36 years old to 46 years old. The area of primordial ovarian follicles increased in the groups of women until 35 years old. It decreased in the groups of women older than 36 years. The follicular basement membrane thickened from 1.29 +/- 0.11 MUm to 1.43 +/- 0.18 MUm with increasing age of women. The diameter of primary oocytes enlarged until 35 years and then began to decrease. The area of primary oocytes increased in women until 35 years. It decreased in groups of women aged 36-40 and 41-46 years old. The diameter and the area of primary oocytes nuclei increased in women aged 15-30 years old; later, it began to decrease. The length of follicular cells varied from 8.56 +/- 0.43 MUm to 8.72 +/- 0.27 MUm (p > 0.05). The height of follicular cells varied from 2.59 +/- 0.27 MUm to 2.7 +/- 0.21 MUm (p > 0.05). The diameter, the area and the basement membrane thickness of primordial ovarian follicles and the diameter and the area of primary oocytes and their nuclei differed insignificantly in left and right ovaries in all age groups of women (p > 0.5). The length and height of follicular cells were similar in left and right ovaries of the same age group (p > 0.5). CONCLUSIONS: The age decreasing of morphometrical parameters begins in primordial ovarian follicles and their primary oocytes in Lithuanian women older than 35 years. The thickness of the follicular basement membrane increased with increasing age of women. No significant differences were found in the morphometrical parameters in primordial follicles of left and right ovaries in the same age group of women. PMID- 30007412 TI - Finding Genetic Regulators, Forecasting Function. PMID- 30007410 TI - Tuberculosis outbreak in a nursing home involving undocumented migrants and Israeli citizens. AB - ABSTRACK: OBJECTIVES: Israel has absorbed > 60,000 migrant from the horn of Africa (MHOA) since 2006. No cross-transmission of Mycobacterium tuberculosis from MOHA to Israeli citizens has yet been reported. This study describes the results of contact investigation and laboratory work-out of a unique mixed cluster which included both MOHA and Israeli citizens. METHODS: Description of the results of epidemiological investigation including laboratory confirmation. RESULTS: This unique Mycobacterium tuberculosis strain included 29 patients: 26 were MOHA and three citizens who immigrated to Israel from the former Soviet Union. This is the first mixed cluster described in Israel, which has not been represented in the SITVIT international database of genotyping markers. The transmission from non-citizens to citizens occurred in a nursing institution, when MOHA infected three other contacts- two of whom were retarded residents, one of them died. The index case was screened before employment, and was permitted to return to wok although his chest X-ray demonstrated radiological findings compatible with tuberculosis. Epidemiological links were found in other 12 MOHA members of the cluster. CONCLUSION: This report describes cross-transmission of Mycobacterium tuberculosis from non-citizens MOHA to Israeli citizens who were residents of a nursing home, which may be the first sign for an epidemiological shift. Although cross-ethnical transmission is still rare in Israel, medical settings should employ efficient infection control measures to protect both patients and staff from Mycobacterium tuberculosis. PMID- 30007413 TI - The Tuft Cell-ILC2 Circuit Integrates Intestinal Defense and Homeostasis. AB - The intestinal response to helminth infection is mediated by a recently established type 2 immune circuit that consists of intestinal tuft cells and type 2 innate lymphoid cells (ILC2s). Schneider et al. have discovered that tuft cells sense succinate fermented by Tritrichomonas via GPR91 to drive the IL-25-ILC2-IL 13-dependent immune circuit and intestinal remodeling. PMID- 30007411 TI - Brain 18F-FDG PET of SIV-infected macaques after treatment interruption or initiation. AB - BACKGROUND: Although rates of severe HIV-associated neurocognitive disorders have declined in the post-antiretroviral treatment (ART) era, subtle deficits persist, possibly exacerbated by treatment non-adherence. The actual effects of ART interruption/initiation on brain glucose metabolism as a reflection of viral replication and neuroinflammation remain unclear. Our study investigates how treatment initiation and interruption alter brain glucose metabolism in SIV infected macaques, using 18F-FDG PET in correlation with plasma and CSF viral loads (VL) and cytokine levels. METHODS: SIV-infected macaques (n = 7) underwent ART initiation only, ART interruption only, or both. Five uninfected animals served as controls. 18F-FDG PET imaging was performed at baseline and 1, 3, and 6 months after treatment modification. Mean and maximum standardized uptake values (SUV) for the whole-brain and subregions were calculated. Plasma and CSF VL and cytokine levels were measured. Paired t tests evaluated acute changes in whole brain SUV from baseline to 1 month, while mixed-effect linear regression models evaluated changes over multiple timepoints and correlated SUV values with disease markers. RESULTS: ART interruption was associated with increased SUVmean and SUVmax acutely, after 1 month (SUVmean 95% CI [0.044-0.786 g/ml], p = 0.037; SUVmax 95% CI [0.122-3.167 g/ml], p = 0.041). The correlation between SUV and time, however, was not significant when evaluated across all timepoints. Increased SUVmean and SUVmax correlated with decreased CD4+ and CD8+ T-cell counts and increased plasma VL. SUVmax was positively associated with increases in CSF VL, and there were borderline positive associations between SUVmax and IL 2, and between SUVmean and IL-15. The treatment initiation group showed no associations between imaging and disease biomarkers despite viral suppression, reduced cytokine levels, and increased CD4+ and CD8+ T-cell counts. CONCLUSIONS: ART interruption is associated with increased brain glucose metabolism within 1 month of treatment cessation, which, in concert with increased levels of pro inflammatory cytokines in the CSF, may reflect neuroinflammation in the setting of viral rebound. Although we cannot assert neurologic damage in association with cerebral hypermetabolism, it is a concerning outcome of ART non-adherence. Treatment initiation, meanwhile, did not result in significant changes in brain metabolism. HIV-induced neuroinflammation may require a longer period to abate than our follow-up period allowed. PMID- 30007414 TI - Translating the Physical Code of Life. AB - The cytoplasm is a highly crowded and complex environment, and the regulation of its physical properties has only recently begun to be revealed. In this issue of Cell, Delarue et al. demonstrate that the control of ribosome concentration through mTORC1 sets limits on the diffusion of large particles and controls phase separation in eukaryotic cells. PMID- 30007415 TI - An Algal Greening of Land. AB - Photosynthetic eukaryotes arose ~1.5 billion years ago by endosymbiosis with a cyanobacterium. Algae then evolved for a billion years before one lineage finally colonized land. Why the wait? The Chara braunii genome details a decisive step linking plant origins with Earth's history. PMID- 30007416 TI - Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance. AB - Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS-DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS-DNA complex to enable structure-guided design of cGAS therapeutics. PMID- 30007417 TI - The Chara Genome: Secondary Complexity and Implications for Plant Terrestrialization. AB - Land plants evolved from charophytic algae, among which Charophyceae possess the most complex body plans. We present the genome of Chara braunii; comparison of the genome to those of land plants identified evolutionary novelties for plant terrestrialization and land plant heritage genes. C. braunii employs unique xylan synthases for cell wall biosynthesis, a phragmoplast (cell separation) mechanism similar to that of land plants, and many phytohormones. C. braunii plastids are controlled via land-plant-like retrograde signaling, and transcriptional regulation is more elaborate than in other algae. The morphological complexity of this organism may result from expanded gene families, with three cases of particular note: genes effecting tolerance to reactive oxygen species (ROS), LysM receptor-like kinases, and transcription factors (TFs). Transcriptomic analysis of sexual reproductive structures reveals intricate control by TFs, activity of the ROS gene network, and the ancestral use of plant-like storage and stress protection proteins in the zygote. PMID- 30007420 TI - The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. PMID- 30007418 TI - A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell Type Targeting and Functionality. AB - Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain. PMID- 30007421 TI - SnapShot: Messenger RNA Modifications. AB - mRNA modifications are defining a novel layer of complexity that is becoming widely appreciated as the epitranscriptome. This SnapShot summarizes the major breakthroughs in the burgeoning field of mRNA modifications to provide an overview of the molecular players involved and insights gained into the functional consequences of the growing number of modifications occurring within mRNA transcripts. PMID- 30007423 TI - Ethics of research methodology requires a methodology of research ethics. PMID- 30007422 TI - Response of distal nitric oxide to bronchodilators sheds light on airway injury in COPD. PMID- 30007419 TI - A Genetically Encoded Fluorescent Sensor Enables Rapid and Specific Detection of Dopamine in Flies, Fish, and Mice. AB - Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here, we report the development of genetically encoded GPCR-activation-based-DA (GRABDA) sensors that enable these measurements. In response to extracellular DA, GRABDA sensors exhibit large fluorescence increases (DeltaF/F0 ~90%) with subcellular resolution, subsecond kinetics, nanomolar to submicromolar affinities, and excellent molecular specificity. GRABDA sensors can resolve a single-electrical stimulus-evoked DA release in mouse brain slices and detect endogenous DA release in living flies, fish, and mice. In freely behaving mice, GRABDA sensors readily report optogenetically elicited nigrostriatal DA release and depict dynamic mesoaccumbens DA signaling during Pavlovian conditioning or during sexual behaviors. Thus, GRABDA sensors enable spatiotemporally precise measurements of DA dynamics in a variety of model organisms while exhibiting complex behaviors. PMID- 30007424 TI - Unconstrained gene flow between populations of a widespread epiphytic lichen Usnea subfloridana (Parmeliaceae, Ascomycota) in Estonia. AB - Few studies have investigated the genetic diversity of populations of common and widespread lichenized fungi using microsatellite markers, especially the relationships between different measures of genetic diversity and environmental heterogeneity. The main aim of our study was to investigate the population genetics of a widespread and mainly clonally reproducing Usnea subfloridana at the landscape scale, focusing on the comparison of lichen populations within hemiboreal forest stands. Particular attention has been paid to the genetic differentiation of lichen populations in two geographically distinct regions in Estonia and the relationships between forest characteristics and measures of genetic diversity. We genotyped 578 Usnea thalli from eleven lichen populations using seven specific fungal microsatellite markers. Measures of genetic diversity (allelic richness, Shannon's information index, Nei's unbiased genetic diversity, clonal diversity, the number of multilocus genotypes, the number of private alleles, and the minimum number of colonization events) were calculated and compared between Usnea populations. Shared haplotypes, gene flow and AMOVA analyses suggest that unconstrained gene flow and exchange of multilocus genotypes exist between the two geographically remote regions in Estonia. Stand age, mean circumference of the host tree, size of forest site and tree species composition did not show any significant influence on allelic richness, Shannon's information index, Nei's unbiased genetic diversity, clonal diversity, the number of private alleles, and the minimum number of colonization events of U. subfloridana populations. Therefore it was concluded that other factors of habitat heterogeneity could probably have a more significant effect on population genetics of U. subfloridana populations. PMID- 30007425 TI - Characterization of extracellular proteins in members of the Paracoccidioides complex. AB - Paracoccidioides is a thermodimorphic fungus that causes Paracoccidioidomycosis (PCM) - an endemic systemic mycosis in Latin America. The genus comprises several phylogenetic species which present some genetic and serological differences. The diversity presented among isolates of the same genus has been explored in several microorganisms. There have also been attempts to clarify differences that might be related to virulence existing in isolates that cause the same disease. In this work, we analyzed the secretome of two isolates in the Paracoccidioides genus, isolates Pb01 and PbEpm83, and performed infection assays in macrophages to evaluate the influence of the secretomes of those isolates upon an in vitro model of infection. The use of a label-free proteomics approach (LC-MSE) allowed us to identify 92 proteins that are secreted by those strains. Of those proteins, 35 were differentially secreted in Pb01, and 36 in PbEpm83. According to the functional annotation, most of the identified proteins are related to adhesion and virulence processes. These results provide evidence that different members of the Paracoccidioides complex can quantitatively secrete different proteins, which may influence the characteristics of virulence, as well as host-related processes. PMID- 30007426 TI - Biotransformation of geranylated- and acetylated-phloroglucinols by Gibberella fujikuroi into molecules with increased antifungal activity against Botrytis cinerea. AB - Terpenylated phenols possess interesting biological activities. These properties vary mainly according to the type of terpene associated and the degree of oxidation of the molecule. The search for new active molecules for application in different areas of knowledge includes the structural modification of these through ecological methodologies, such as biotransformation. The aims of this study were the biotransformation of geranylated- and acetylated-phloroglucinol by the fungus Gibberella fujikuroi and the evaluation of the antifungal activity of the derivatives. Five major derivatives were identified after biotransformation, highlighting the formation of specific monoacetylated products. In vitro antifungal activity assays against the phytopathogenic fungus Botrytis cinerea indicated that deacetylated derivatives possess higher activity compared to the precursor molecule. In other biotransformation reactions, a relationship between the release of the alkyl chain from the aromatic ring with a decrease of the antifungal activity, was observed. The in vivo tests in infected tomato plants with B. cinerea confirmed the antifungal activity of the derivatives observed in in vitro experiments. PMID- 30007427 TI - Clarireedia: A new fungal genus comprising four pathogenic species responsible for dollar spot disease of turfgrass. AB - Dollar spot is one of the most destructive and economically important fungal diseases of amenity turfgrasses. The causal agent was first described in 1937 as the ascomycete Sclerotinia homoeocarpa. However, the genus-level taxonomic placement of this fungus has been the subject of an ongoing debate for over 75 y. Existing morphological and rDNA sequence evidence indicates that this organism is more appropriately placed in the family Rutstroemiaceae rather than the Sclerotiniaceae. Here we use DNA sequence data from samples of the dollar spot fungus and other members of the Rutstroemiaceae (e.g. Rutstroemia, Lanzia, Lambertella) collected throughout the world to determine the generic identity of the turfgrass dollar spot pathogen. Phylogenetic evidence from three nucleotide sequence markers (CaM, ITS and Mcm7; 1810-bp) confirmed that S. homoeocarpa is not a species of Sclerotinia; nor is it a member of any known genus in the Rutstroemiaceae. These data support the establishment of a new genus, which we describe here as Clarireedia gen. nov. The type species for the genus, Clarireedia homoeocarpa comb. nov., is described to accommodate the dollar spot fungus, and a neotype is designated. Three new species in this clade, Clarireedia bennettii sp. nov., Clarireedia jacksonii sp. nov., and Clarireedia monteithiana sp. nov. that also cause dollar spot disease are described. Clarireedia homoeocarpa and C. bennettii occur primarily on Festuca rubra (C3 grass) hosts and appear to be restricted to the United Kingdom. Clarireedia jacksonii and C. monteithiana occur on a variety of C3 and C4 grass hosts, respectively, and appear to be globally distributed. This resolved taxonomy puts to rest a major controversy amongst plant pathologists and provides a foundation for better understanding the nature and biology of these destructive pathogens. PMID- 30007428 TI - Label-free differentially proteomic analysis of interspecific interaction between white-rot fungi highlights oxidative stress response and high metabolic activity. AB - The laccase production by mycelial antagonistic interaction among white-rot fungi is a very important pathway for lignin degradation research. To gain a better understanding of competitive mechanisms under mycelial antagonistic interaction among three lignin-degrading white-rot basidiomycetes of Trametesversicolor (Tv), Pleurotusostreatus (Po) and Dichomitussqualens (Ds), mycelial morphology and proteins in three co-culture combinations TvPo (Tv cocultivated with Po), PoDs (Po cocultivated with Ds), TvDs (Tv cocultivated with Ds) were compared with corresponding each two mono-cultures. In this study, scanning electron microscopy detection of co-cultures indicated a highly close attachment of fungal hyphae with each other and conidiation could be inhibited under fungal interaction. In addition, a label-free proteomic analysis revealed changes on fungal proteomes existed in their counterpart competitors of co-culture. The maximum number of 1020 differentially expressed proteins (DEPs) were identified in PoDs relative to Po while the minimum number of 367 DEPs were identified in PoDs relative to Ds. Notably, we also found a large number of overexpressed proteins were oxidative stress-related proteins, followed by carbohydrate metabolism-related proteins and energy production-related proteins in all three co-culture combinations compared with control. These results were important for the future exploration of molecular mechanisms underlying lignin-degrading fungal interaction. PMID- 30007429 TI - Endophytic yeast diversity in leaf tissue of rice, corn and sugarcane cultivated in Thailand assessed by a culture-dependent approach. AB - Endophytic yeasts are yeast that can colonize healthy plant tissues without causing any damage to the host plant. This work aimed to explore the diversity of endophytic yeasts in leaf tissue of main agricultural crops (rice, corn and sugarcane) in Thailand, by a culture-dependent approach. A total of 311 leaf samples, consisting of rice (n = 100), corn (n = 109) and sugarcane (n = 102). From the tissue of rice (n = 92), corn (n = 76) and sugarcane (n = 78) leaf samples, 117, 118 and 123 yeast strains were respectively isolated and identified based on the D1/D2 region of the large subunit (LSU) rRNA gene sequence analysis to be yeast species in both the phyla Basidiomycota and Ascomycota. Higher numbers of basidiomycetous yeast than ascomycetous yeast were detected in the leaf tissue of the three crops. Pseudozyma (Dirkmeia) churashimaensis (Ustilaginales) was the most prevalent yeast species in the rice and corn leaves with relative frequencies (RF) of 35.9 % and 17.8 %, respectively. Whereas the predominant species in the sugarcane leaves was Meyerozyma caribbica (Saccharomycetales) with an RF of 14.6 %. In addition, six new yeast species and one new yeast genus were proposed. Our findings suggest that these plant species are good sources from which new yeast species may be isolated. PMID- 30007430 TI - The species of Coleosporium (Pucciniales) on Solidago in North America. AB - Species of Coleosporium (Pucciniales) are rust fungi that typically alternate between pines and angiosperms. In North America, species of Coleosporium often infect Solidago (goldenrods), although their taxonomy on these hosts is unresolved. Joseph. C. Arthur and George B. Cummins regarded these as a single species, Coleosporium solidaginis (fide Arthur) or C. asterum (fide Cummins), but later inoculation studies demonstrated the presence of more than one species, distinguishable by their aecial hosts. A more recent taxonomic study of Coleosporium found that specimens on Solidago identified as C. asterum in North America were not conspecific with the type, which is from Japan, prompting the present study. Herein, we conducted a systematic study on ca. 60 collections of Coleosporium infecting species of Asteraceae from North America using regions of ribosomal DNA and morphology of teliospores and basidia. Our data indicate at least three species of Coleosporium occur on Solidago in North America, C. solidaginis, C. montanum comb. nov., which is proposed for the taxon that has commonly been identified as C. asterum in North America, and C. delicatulum, all of which can be differentiated by morphology of their basidia. In addition, the challenges of marker selection for molecular barcoding of rust fungi is discussed. PMID- 30007431 TI - Diversity of mucoralean fungi in soils of papaya (Carica papaya L.) producing regions in Mexico. AB - Mexico is the fifth largest producer of papaya worldwide and has recently reported problems with mucoralean fungi in this crop. These fungi are considered saprophytes in the soil and are ubiquitous in nature. In this work, they were isolated from soil in regions of intensive papaya cultivation in Mexico. Collections were made in the states of Colima, Oaxaca and Veracruz in Apr 2016. A total of 72 mucorales fungal isolates was obtained and morphologically characterized and then molecular characterization (28S ribosomal region) of 25 representative isolates was carried out. Phylogenetic analysis of the sequences confirmed the presence of the species Gilbertella persicaria, Rhizopus oryzae, Rhizopus stolonifer, Mucor circinelloides and Mucor hiemalis, which cause soft rot in papaya fruits, therefore, spores of these fungi found in the orchard soils can be considered as a constant source of contamination that affects healthy fruits. Additionally, Choanephora cucurbitarum, Mucor ellipsoideus, Rhizopus homothallicus, Rhizopus microsporus, Rhizopus schipperae, Lichteimia ramosa, Gongronella butleri, Cunninghamella bertholletiae and Cunninghamella blakesleeana were identified which are considered to have agricultural, biotechnological and medical importance. PMID- 30007432 TI - Hidden diversity uncovered in Hygrophorus sect. Aurei (Hygrophoraceae), including the Mediterranean H. meridionalis and the North American H. boyeri, spp. nov. AB - For many years, the binomial Hygrophorus hypothejus was widely applied to collections from various geographical regions in different continents, assuming a circum-boreal and circum-mediterranean distribution for this species. This hypothesis, however, had never been put to the test. To assess the diversity and species-limits within this complex of yellow-coloured waxcaps, a phylogenetic, morphological and taxonomical investigation into Hygrophorus sect. Aurei and similar species in sect. Olivaceoumbrini was carried out, including material of pan-European origin, as well as the east and west coasts of North America. Following sequencing of the ITS rDNA locus, nine lineages are confirmed in sect. Aurei, most of them highly continentalised. Of these, two are new to science, introduced here as Hygrophorus boyeri sp. nov., from Pinus banksiana and P. rigida forests in eastern North America and from P. muricata and P. contorta forests in western North America, and Hygrophorus meridionalis sp. nov., from Pinus brutia and Pinus halepensis forests in the island of Cyprus and mainland Greece. H. hypothejus is lectotypified and epitypified, and here resolved as a strictly European species, with the old forgotten taxon Hygrophorus siccipes revived as its North American vicariant. The placement of Hygrophorus fuligineus in sect. Aurei is phylogenetically confirmed and detailed comparisons between morphologically similar and phylogenetically affiliated taxa in sect. Aurei and sect. Olivaceoumbrini are provided. The chronic confusion associated with Hygrophorus fuscoalbus, a highly controversial taxon described from Germany nearly two centuries ago and variously interpreted since, is discussed, concluding that this name is too ambiguous to be applied to any currently recognized species. PMID- 30007433 TI - Inhale and move, move; again, move! PMID- 30007434 TI - Current state and evolution of the tobacco epidemic in Portuguese and European school-aged adolescents by sex, between the years 1998 and 2014. PMID- 30007435 TI - Neurofibromatosis type I with lung involvement in a cancer patient. PMID- 30007436 TI - Lichen ketosynthase domains are not responsible for inoperative polyketide synthases in Ascomycota hosts. AB - Efforts by lichenologists to characterize lichen polyketide synthases (PKS) through heterologous expression experiments have so far proved unfruitful. A determination of systematic causes of failure is therefore required. Three hypotheses involving the ketosynthase (KS) domain of lichen polyketide synthases (PKS) from Cladonia uncialis are tested: (1) Horizontal versus vertical gene transfer; (2) Typical versus atypical active site residues; (3) Typical versus atypical tertiary protein structure and active site architecture. Phylogenetics, amino acid sequence alignment, and protein modelling indicate that C. uncialis PKS evolved through vertical transfer from Ascomycota fungi, possess Cys-His-His catalytic triads typical of KS from most organisms, and possess protein and catalytic site architecture identical to well-characterized KS from non-lichen organisms. Though the reason for lack of functional activity in heterologous hosts remains unknown, complications involving the KS are ruled out as a likely explanation. Heterologous translation of lichen PKS (or parts thereof) have not been reported. We demonstrate heterologous translation of two lichen KS domains in E. coli. PMID- 30007437 TI - Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts. AB - Long-term treatment with the potent immunosuppressive drug cyclosporine A (CsA) results in chronic nephrotoxicity. Its immunosuppressive properties are due to the inhibition of the calcium- and calmodulin-dependent phosphatase protein calcineurin A (CnA) which has three catalytic isoforms. Of those, the CnAalpha and beta isoforms are ubiquitously expressed, particularly in the kidney. Additionally, chronic nephrotoxicity has been associated with an imbalance of extracellular matrix (ECM) synthesis and degradation resulting in an accumulation of ECM molecules. This study evaluates whether the expressions of matrix metalloproteinases (MMP-2 and MMP-9) induced by CsA are calcineurin isoform specific. Wild-type (WT), CnAalpha knockout (CnAalpha-/-) and CnAbeta knockout (CnAbeta-/-) kidney fibroblast cell lines (an in vitro innovative tool that was previously created in our lab) were treated with CsA at 10 ng/ml for 48 h. ELISA analysis demonstrated that the CsA-induced secretion profile of MMP-9 was highest in CnAalpha-/- cells and lowest in CnAbeta-/- cells vs. WT cells. In contrast, CsA did not induce an increase in MMP-2 protein levels in WT, CnAalpha-/- nor CnAbeta-/- renal fibroblasts. These results indicate that MMP-9 secretion is CnA isoform specific, i.e. the CnAbeta isoform contributes to the CsA-induced upregulation of MMP-9 while the CnAalpha does not. As such, understanding the role of calcineurin A isoforms in the regulation of the homeostasis of ECM degradation in the kidney after long-term CsA treatment needs to be further investigated. PMID- 30007438 TI - TLR4 mediates high-fat diet induced physiological changes in mice via attenuating PPARgamma/ABCG1 signaling pathway. AB - High-fat diet (HFD) is known to promote atherosclerosis which accelerates the development of atherosclerotic cardiovascular diseases. Vascular dysfunction characterized by inflammation and lipid accumulation is common in atherosclerosis caused by HFD. The specific effects of HFD on blood vessels and the underlying mechanisms need to be further clarified. Toll-like receptor 4 (TLR4) is a key contributing factor in atherosclerosis and TLR4 deficiency protects vascular smooth muscle cells against inflammatory responses and lipid accumulation in vitro. However, the physiological significance of TLR4 signaling in HFD-induced changes is unknown. In this study, we observed that HFD feeding increased body weight, circulating inflammatory cytokines and lipid accumulation in the aorta of wild-type mice but apart from increasing body weight, did not affect the TLR4 knockout mice. TLR4 expression increased significantly in the arterial walls after receiving HFD treatment, while that of the co-localizing PPARgamma and ABCG1 markedly decreased. TLR4 deficiency reversed the HFD-induced attenuation of PPARgamma and ABCG1. In conclusion, TLR4 mediates HFD induced increase in body weight, inflammation and aortic lipid accumulation through, at least partly, the PPARgamma/ABCG1 signaling pathway. Therefore, interfering with TLR4 signaling is a viable therapeutic option in diet induced atherosclerosis. PMID- 30007439 TI - Strong TCR stimulation promotes the stabilization of Foxp3 expression in regulatory T cells induced in vitro through increasing the demethylation of Foxp3 CNS2. AB - Foxp3 is the master transcriptional regulator of regulatory T cells (Tregs), and the stabilization of Foxp3 expression is regulated by the demethylation of conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Recent studies have shown that TCR stimulation is required for the demethylation of Foxp3 CNS2 during Treg development. However, the relationship between the strength of TCR stimulation and the demethylation of Foxp3 CNS2 remains unclear. To address this issue, we compared the frequency of demethylation of the Foxp3 CNS2 among in vitro-induced Tregs (iTreg) that had received a range of TCR stimulation during their development. We found that the frequency of demethylation of the Foxp3 CNS2 was increased with increased TCR stimulation strength, whereas CD28 stimulation had only a limited effect. Mechanistically, the binding of Tet2, a member of the TET family of enzymes involved in DNA demethylation, on the Foxp3 CNS2 was increased by strong TCR stimulation. Furthermore, compared with iTreg induced by weak TCR stimulation, iTreg induced by strong TCR stimulation maintained Foxp3 expression both in vitro and in vivo. These data indicate that the strength of TCR stimulation is a key factor for induction of the demethylation of Foxp3 CNS2 and the generation of stable Tregs. PMID- 30007440 TI - LncRNA NKILA upregulation mediates oxygen glucose deprivation/re-oxygenation induced neuronal cell death by inhibiting NF-kappaB signaling. AB - Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces severe injury to neuronal cells. The expression and potential function of NKILA (NF-kappaB Interacting LncRNA) in OGDR-treated neuronal cells were tested in this study. We show that OGDR induced NKILA upregulation to in-activate NF-kappaB signaling in SH-SY5Y cells and primary murine hippocampal neurons. Conversely, shRNA-mediated NKILA silencing almost reversed OGDR-induced NF-kappaB inhibition. OGDR-induced neuronal cell viability reduction, apoptosis and necrosis were largely attenuated by NKILA shRNA as well. Conversely, ectopic overexpression of NKILA by a lentiviral vector enhanced OGDR-induced SH-SY5Y cell death. For the mechanism study, we show that OGDR downregulated miR-103 and miR-107 to induce NKILA upregulation in neuronal cells. Transfection of miR-103 mimic or miR-107 mimic almost reversed OGDR-induced NKILA upregulation, NF-kappaB in-activation and SH SY5Y cell death. Taken together, OGDR induces NKILA upregulation to in-activate NF-kappaB signaling, which mediates subsequent neuronal cell death. NKILA could be a novel therapeutic target of ischemic neuronal injury. PMID- 30007441 TI - Administration of plasmacytoid dendritic cell-stimulative lactic acid bacteria enhances antigen-specific immune responses. AB - Lactic acid bacteria (LAB) have been reported to have beneficial effects on protective immunity against viruses and pathogenic bacteria by activating innate immune cells such as dendritic cells (DC) or macrophages. However, little is known about whether LAB contributes to antigen-specific immune responses. Because plasmacytoid DC (pDC) links innate and acquired immunity, here we investigated whether the pDC-stimulative LAB, Lactococcus lactis strain Plasma (LC-Plasma), influences antigen-specific immune responses. In in vitro co-culture experiments, LC-Plasma enhanced the expression of MHC class I and II, and CD80 and CD86 on both pDC and conventional DC, and this enhancement was abolished by treatment with a Toll-like receptor 9 antagonist. A subsequent in vitro study showed that LC-Plasma increased antigen-specific T cell responses via DC activation. In mice, oral administration of LC-Plasma in combination with intraperitoneal antigen administration enhanced the percentage of antigen-specific CD8+ T cells and the amount of antigen-specific IgG. Furthermore, continuous intake of LC-Plasma increased T helper 1 responses, which contribute to antigen-specific cellular and humoral immune responses. Taken together, these results reveal that the oral intake of pDC-stimulative LAB enhances antigen-specific immune responses. PMID- 30007442 TI - Reflections on Regenerative Medicine. PMID- 30007444 TI - Joint statement by the Surgery Journal Editors Group. PMID- 30007443 TI - Treatment Outcomes and Health Care Resource Utilization in Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide-only Maintenance, Any Maintenance, or No Maintenance: Results from the Connect MM Registry. AB - PURPOSE: Maintenance therapy after autologous stem cell transplantation (ASCT) improves clinical outcomes in multiple myeloma (MM), but the effect of continued treatment with lenalidomide-only maintenance, or any maintenance, on health care resource utilization (HCRU) is largely unknown. METHODS: Here we present an analysis of HCRU and clinical outcomes in a cohort of patients from the Connect MM registry, the largest, ongoing, observational, prospective US registry of patients with symptomatic newly diagnosed MM. In this study, patients with newly diagnosed MM who completed induction and single ASCT without subsequent consolidation received lenalidomide-only maintenance (n = 180), any maintenance (n = 256), or no maintenance (n = 165). HCRU (hospitalization, surgery/procedures, and concurrent medications [growth factors, bisphosphonates, or neuropathic pain medication]) was assessed starting from 100 days post-ASCT for up to 2 years. FINDINGS: Although the rates of hospitalization per 100 person years were similar across groups at the end of years 1 and 2, the median duration of hospitalization was numerically longer with no maintenance. The rates of use of growth factors, bisphosphonates, and neuropathic pain medication were generally similar in all 3 groups. The receipt of any maintenance was associated with significantly reduced use of neuropathic pain medications during year 1. Of note, lenalidomide-only maintenance was associated with significantly longer progression-free survival (54.5 vs 30.4 months; hazard ratio [HR] = 0.58; 95% CI, 0.43-0.79; P = 0.0005) and overall survival (OS) (median OS not reached in either group; HR = 0.45; 95% CI, 0.28-0.73; P = 0.001) compared with no maintenance. Likewise, the group treated with any maintenance had significantly longer median progression-free survival (44.7 vs 30.4 months; HR = 0.62; 95% CI, 0.47-0.82; P = 0.0008) and OS (median OS not reached in either group; HR = 0.50; 95% CI, 0.33 0.76; P = 0.001) than did the group that did not receive maintenance. IMPLICATIONS: These findings suggest that in this largely community-based study population, post-ASCT maintenance therapy, including lenalidomide-only maintenance, improves clinical outcomes without negatively affecting HCRU. ClinicalTrials.gov identifier: NCT01081028. PMID- 30007446 TI - Lameness Evaluation of the Athletic Horse. AB - Lameness examination is commonly performed in the athletic horse. A skilled lameness diagnostician must have keen clinical and observational skills. Evaluation starts with a detailed history and thorough physical examination. Next, gait evaluation in the moving horse is performed. Lame horses have asymmetrical body movement due to unconscious shift of body weight. Recognition of the resultant head nod and pelvic hike is the basis for lameness diagnosis. Lameness identification is enhanced by circling, limb flexions, and riding. Most lame horses do not exhibit pathognomonic gait characteristics, and therefore, diagnostic analgesia is the best way to authenticate underlying sites of pain. PMID- 30007447 TI - Diagnosis of Skeletal Injury in the Sport Horse. AB - This article discusses the basis of image formation of radiography, scintigraphy, PET, computed tomography (fan beam and cone beam), and magnetic resonance as it relates to imaging of musculoskeletal injury in the sport horse. The benefits and drawbacks of each modality are discussed with particular emphasis on sensitivity, specificity, and accuracy of identification of subchondral bone injury. Examples of straightforward as well as confounding lesions are provided, emphasizing the need for appropriate clinical workup and diagnostic analgesia, where appropriate. PMID- 30007448 TI - Neurologic Conditions Affecting the Equine Athlete. AB - EPM, CVSM, and EDM are currently recognized as the 3 most common neurologic diseases in US horses, with the latter 2 conditions being most prevalent in young animals. Moreover, horses competing at shows and performance events are at greater risk for exposure to highly contagious, neurologic EHV-1 outbreaks. A clinical diagnosis of any neurologic disease should be based on a careful history, complete neurologic examination, and appropriate diagnostic testing and interpretation. However, mild or early neurologic signs can often mimic or be mistaken for an orthopedic condition when horses present for performance-related concerns. PMID- 30007449 TI - Borreliosis in Sport Horse Practice. AB - Given the variable clinical signs attributed to Borrelia burgdorferi, including infectious arthritis, neurologic disease, and behavioral changes, B burgdorferi is an important differential for decreased performance in sport horses. The primary vectors (Ixodes tick species) are expanding their range and thus Borrelia species are located in a wider area, making exposure more likely. Due to regionally high seroprevalence and vague clinical signs, diagnosis of Lyme disease in the horse is believed overestimated. Antibiotics are first-line treatment of confirmed Lyme disease. A single positive serologic test, by itself, is not conformation of Lyme disease but is evidence of current or past infection. PMID- 30007450 TI - Understanding the Basic Principles of Podiatry. AB - Foot-related lameness is one of the most frequently encountered problems in the equine industry. Therapeutic shoeing is a frequently used preventative discipline for the treatment of many causes of lameness. The primary goal for therapeutic applications is to offset the mechanical limitations and enhance the healing environment. Equine podiatry is a blend of the 2 highly respected professions each contributing to the task at hand, but neither formally educated and trained as collaborative team members with a common thread of podiatry principles. PMID- 30007451 TI - Cardiac/Cardiovascular Conditions Affecting Sport Horses. AB - Cardiac murmurs are not uncommonly detected in the equine athlete. Although most are benign in nature, differentiation and quantification of murmurs due to valvular regurgitation are important for prognosis and recommendations. Arrhythmias can be associated with structural disease or occur independently and may range in severity from minimal clinical effect to poor performance to presenting a safety risk to rider and horse. This article discusses commonly encountered cardiac conditions in the sport horse. Physical examination, diagnostic approach, valvular disease, and arrhythmias with an impact on performance or ridden safety are discussed. PMID- 30007452 TI - Lower Airway Disease in the Athletic Horse. AB - The airways are the first part of the pathway in the oxygen transport chain that is critical to excellent athletic performance, and the lower airways are considered the final gatekeeper before oxygen enters the blood and carbon dioxide exits. Horses are blessed with large airways and lungs that allow them to be superb athletes, but the down side of this largesse on the part of evolution is that unless they are truly elite athletes they may withstand noninfectious disease of the lower respiratory tract for months to years before the owner or trainer notices. The two conditions of the lower respiratory tract that affect the athletic horse during exercise are exercise-induced pulmonary hemorrhage and inflammatory airway disease. The former may be considered, at least at the onset, as a problem of physiology rather than a disease, and the latter is a disease primarily of domestication: both are widespread among the athletic horse population and account for an impressive number of horses that fail to perform to their potential. Because of the high demands for oxygen in the athletic horse, even minor insults to the oxygen-carrying capacity of the body can affect performance, so it is of critical importance to keep the lungs as healthy as possible. PMID- 30007453 TI - Equine Sports Medicine: Our Daily Challenge. PMID- 30007454 TI - Enamel remineralization therapies for treating postorthodontic white-spot lesions: A systematic review. AB - BACKGROUND: One of the adverse effects of orthodontic treatment is the appearance of white-spot lesions (WSLs) resulting from enamel demineralization. The objective of this systematic review was to investigate the effectiveness of remineralization therapies on WSLs after orthodontic treatment. TYPES OF STUDIES REVIEWED: In this systematic review, the authors identified relevant articles listed in 5 databases-PubMed, the Cochrane Library, Scopus, Embase, and Web of Science-by using a combination of search terms referring to orthodontics, demineralization, and treatment. Ten articles on the efficacy of WSL remineralization therapies met the inclusion criteria. RESULTS: Among the studies of remineralizing therapy, neither fluoride mouthrinses nor phosphopeptide toothpastes with or without fluoride had any positive effect in addition to oral hygiene maintenance with fluoride toothpaste. A 5% sodium fluoride varnish was the only therapy to show a statistically significant improvement compared with results in the control group. The authors found large variations in results among the studies reviewed because of the different methods used. CONCLUSIONS AND PRACTICAL IMPLICATIONS: None of the treatments was capable of remineralizing WSLs. A 5% sodium fluoride varnish could improve remineralization of WSLs. PMID- 30007455 TI - New Insights into Clonal Mast Cell Disorders Including Mastocytosis. AB - Mastocytosis is a heterogeneous group of neoplasms that involve the clonal expansion of mast cells into one or more organ systems, which typically involves the skin and hematopoietic systems. Systemic mastocytosis consists of a multifocal infiltration of mast cells into various noncutaneous tissue sites, especially the bone marrow. Diagnosis requires tissue confirmation, and algorithms have been developed to assist clinicians in this process. The current classification system focuses on delineating prognostic categories. Therapeutic approaches include symptomatic management, prevention of complications, and, in advanced disease, cytoreductive therapy. PMID- 30007456 TI - Cutaneous Mastocytosis in Adults and Children: New Classification and Prognostic Factors. AB - The skin is one of the most frequent tissues affected in patients with mastocytosis, but cutaneous lesions are highly heterogeneous in shape, size, color, number, localization, and distribution. The World Health Organization recognizes 3 subtypes of cutaneous mastocytosis (CM): maculopapular CM (MPCM), diffuse CM, and mastocytoma of skin. An international task force of experts in mastocytosis has recently proposed subdividing MPCM into monomorphic and polymorphic, which could predict the duration of the disease in children. More research is warranted to develop an improved classification of CM that ideally should incorporate robust factors with prognostic impact on disease behavior. PMID- 30007457 TI - Pediatric Expression of Mast Cell Activation Disorders. AB - Mast cell activation disorders is a term proposed to cover diseases and conditions related to activation of mast cells and effects of mast cell mediators. In its broadest sense, the term encompasses a wide range of diseases from allergic asthma to rhinoconjunctivitis, urticaria, food allergy, anaphylaxis, mastocytosis, and other conditions where MC activation is contributing to the pathogenesis. This article focuses on clinical presentations, challenges, and controversies in pediatric mastocytosis and gives an overview of current knowledge and areas in need of further research. PMID- 30007458 TI - Bone Marrow Expression of Mast Cell Disorders. AB - Mast cell disorders comprise a heterogeneous group of rare diseases, the diagnosis of which still remains a challenge. Bone marrow analysis constitutes the most appropriate site for screening systemic involvement in mastocytosis. Morphologic, immunohistochemical, flow cytometric immunophenotyping, and molecular studies should be routinely performed for diagnostic/prognostic purposes in experienced reference centers during the diagnostic workup in suspected systemic mastocytosis. The authors review the most relevant characteristics of bone marrow expression of mast cell disorders as well as the different methodological approaches to be applied to perform an objective and reproducible diagnosis and classification of mastocytosis and other mast cell disorders. PMID- 30007459 TI - Mast Cell Mediators of Significance in Clinical Practice in Mastocytosis. AB - Mast cells leave evidence, a "fingerprint," of their participation in acute and chronic clinical events. That fingerprint is an elevation, either chronic or acute, in levels of their secreted mediators or their metabolites. Of these, only serum tryptase is currently one of the diagnostic criteria for systemic mastocytosis or mast cell activation. Combinations of easily obtained and quantified urinary mast cell mediator metabolite levels correlate well with bone marrow findings of systemic mastocytosis. By inhibiting synthesis of or blockading receptors to the elevated mast cell mediator, relief of clinical symptoms can often be achieved. PMID- 30007460 TI - Kit Mutations: New Insights and Diagnostic Value. AB - Mastocytosis is a World Health Organization-defined clonal mast cell disorder characterized by significant clinicopathologic heterogeneity. Despite this diversity, a mutation of the KIT gene, most commonly D816V, is found in almost all cases and believed a driver lesion. Peripheral blood allele-specific oligonucleotide polymerase chain reaction can reliably detect KIT D816V and is used for the initial screening of adults with suspected systemic mastocytosis. The discovery of KIT mutations as central to the pathobiology of mastocytosis has prompted development of KIT-targeted agents, including imatinib and midostaurin (approved medications for patients with advanced systemic mastocytosis), and drugs in development, like KIT D816V-specific inhibitor avapritinib. PMID- 30007461 TI - Gastrointestinal Involvement in Mast Cell Activation Disorders. AB - Gastrointestinal (GI) symptoms are commonly reported in patients with mast cell disease. GI involvement in systemic mastocytosis is heterogeneous and symptoms may be caused by infiltration of abnormal mast cells in the GI tract and/or by the downstream effect of mast cell mediators on GI tissues. GI symptoms described the monoclonal mast cell activation syndrome are best characterized in the context of acute anaphylaxis. The presence of GI symptoms and a subjective response of symptoms to anti-mast cell mediator therapy are considered qualifying criteria in the diagnosis of the idiopathic mast cell activation syndrome. Antimediator therapy may help alleviate GI symptoms in mast cell disease. PMID- 30007462 TI - Bone Disease in Mastocytosis. AB - Systemic mastocytosis can give very different bone pictures: from osteosclerosis to osteoporosis. Osteoporosis is one of the most frequent manifestations particularly in adults and the most clinical relevant. It is often complicated by a high recurrence of mainly vertebral fragility fractures. The main factor of bone loss is the osteoclast with a relative or absolute predominance of bone resorption. The RANK-RANKL pathway seems of key importance, but histamine and other cytokines also play a significant role in the process. The predominance of resorption made bisphosphonates, as anti-resorptive drugs, the most rational treatment of bone involvement in systemic mastocytosis. PMID- 30007463 TI - Hymenoptera Anaphylaxis as a Clonal Mast Cell Disorder. AB - Up to 7% of adult patients with Hymenoptera venom allergy may suffer from a clonal mast cell disease. Patients with clonal mast cell disease and Hymenoptera venom anaphylaxis are commonly males, without skin lesions, and anaphylaxis is characterized by hypotension and syncope in the absence of urticaria and angioedema. A normal value of tryptase does not exclude a mastocytosis. The diagnosis of a mast cell disease leads to several therapeutic consequences concerning the treatment of Hymenoptera venom allergy as matter of fact these patients have to undergo long-life venom immunotherapy, to prevent further, potentially fatal severe reactions. PMID- 30007465 TI - Hereditary Alpha Tryptasemia: Genotyping and Associated Clinical Features. AB - Hereditary alpha tryptasemia is an autosomal dominant genetic trait caused by increased germline copies of TPSAB1 encoding alpha-tryptase. Individuals with this trait have elevated basal serum tryptase, and may present with associated multisystem complaints. Both basal serum tryptase levels and severity of clinical symptoms display a gene-dose relationship with TPSAB1, whereby higher tryptase levels and greater symptom severity are correlated with increasing numbers of alpha-encoding TPSAB1. As the functional effects of increased basal serum tryptase and/or altered tryptase gene expression are elucidated, greater insights will be gained into the symptoms associated with hereditary alpha tryptasemia and their potential therapy. PMID- 30007464 TI - Nonclonal Mast Cell Activation Syndrome: A Growing Body of Evidence. AB - Patients who present with typical features of mast cell activation with laboratory confirmation and without evidence of a clonal mast cell disorder or other medical condition should be initiated on medical treatment to block mast cells and their mediators. If a major response is achieved, a diagnosis of nonclonal mast cell activation syndrome (NC-MCAS) is likely and treatment should be optimized, including management of any associated conditions. In this review, the latest evidence with regard to the diagnosis and treatment of NC-MCAS is presented. PMID- 30007466 TI - Association of Postural Tachycardia Syndrome and Ehlers-Danlos Syndrome with Mast Cell Activation Disorders. AB - Mast cell activation disorders (MCADs) consist of episodic systemic symptoms due to mast cell mediator release. Diagnosis is based on clinical presentation and determination of high levels of tryptase or histamine. Ehlers-Danlos syndrome (EDS) and postural tachycardia syndrome (POTS) frequently coexist. It has been described that individuals with these syndromes can even present symptoms compatible to MCADs, which could represent a new specific phenotype. Preliminary genetic data suggest a role for tryptase in the pathogenesis of MCADs, EDS, and POTS association. Studies with larger samples evaluating clinics, genetics, and histopathology are required to define the real correlation between these 3 clinical entities. PMID- 30007467 TI - Patient Perceptions in Mast Cell Disorders. AB - Understanding experiences, perceptions, and perspectives of patients with a mast cell disorder (MCD), including cutaneous mastocytosis, systemic mastocytosis, mast cell activation syndromes, and hereditary alpha-tryptasemia, is an important aspect of successful care, treatment, and informed development of novel therapies. This article reviews existing studies and presents new data on MCD patient perceptions regarding medical care, symptoms, allergies/sensitivities, triggers, future health/disease progression, treatment, impact on daily living, quality of life, support needs, and concerns regarding possible familial disease. Discussion includes aspects affecting the MCD community that require further consideration and development. PMID- 30007468 TI - Tyrosine Kinase Inhibition in Mastocytosis: KIT and Beyond KIT. AB - Mastocytosis is a group of rare disorders characterized by abnormal accumulation of mast cells in one or several organs. Mastocytosis can be seen at any age; but, in adults, the disease is usually systemic and chronic. Patients with indolent systemic mastocytosis (SM) are usually treated symptomatically, but cytoreductive treatments are needed in more advanced SM. In most patients with SM, an activating KIT D816V mutation is found. Thus, patients with advanced SM benefit from treatment with KIT-targeting tyrosine kinase inhibitors. However, none of these drugs are curative; new targeted drugs or combinations are still needed to improve patients' outcome. PMID- 30007469 TI - The Many Faces of Mast Cell Disorders. PMID- 30007470 TI - Mastocytosis: Moving the Field to Precision and Personalized Medicine. PMID- 30007471 TI - Pretargeting in nuclear imaging and radionuclide therapy: Improving efficacy of theranostics and nanomedicines. AB - Pretargeted nuclear imaging and radiotherapy have recently attracted increasing attention for diagnosis and treatment of cancer with nanomedicines. This is because it conceptually offers better imaging contrast and therapeutic efficiency while reducing the dose to radiosensitive tissues compared to conventional strategies. In conventional imaging and radiotherapy, a directly radiolabeled nano-sized vector is administered and allowed to accumulate in the tumor, typically on a timescale of several days. In contrast, pretargeting is based on a two-step approach. First, a tumor-accumulating vector carrying a tag is administered followed by injection of a fast clearing radiolabeled agent that rapidly recognizes the tag of the tumor-bound vector in vivo. Therefore, pretargeting circumvents the use of long-lived radionuclides that is a necessity for sufficient tumor accumulation and target-to-background ratios using conventional approaches. In this review, we give an overview of recent advances in pretargeted imaging strategies. We will critically reflect on the advantages and disadvantages of current state-of-the-art conventional imaging approaches and compare them to pretargeted strategies. We will discuss the pretargeted imaging concept and the involved chemistry. Finally, we will discuss the steps forward in respect to clinical translation, and how pretargeted strategies could be applied to improve state-of-the-art radiotherapeutic approaches. PMID- 30007472 TI - Engineered microenvironments and microdevices for modeling the pathophysiology of type 1 diabetes. AB - The pathophysiology of type 1 diabetes is a complex process involving tightly controlled microenvironments, a number of highly specific immune cell - islet cell interactions, and the eventual breaking of immune tolerance leading to beta cell death. Modeling this process can provide researchers with powerful insights into how and when to best provide treatment, but has proven difficult to accurately model due to its complex nature and differences between animal models and humans. Much progress has been made in determining the genetic, molecular, and cellular mechanisms of type 1 diabetes, yet translating that knowledge to clinical treatments remains challenging. Thus, there exists a capabilities gap between understanding the disease pathophysiology and engineering effective clinical treatment strategies. Biomimetic modeling of human type 1 diabetes is a valuable tool to study and manipulate islet function and can be employed to address immunological aspects of type 1 diabetes. This article will review recent advances in this field, and will suggest ways to synergize systems to model and observe the pathophysiology of autoimmune diabetes with bioengineered therapeutic strategies. PMID- 30007473 TI - Editorial: 64th International Congress of Meat Science and Technology, Melbourne, Australia 12-17th August 2018. PMID- 30007474 TI - Sirtuin 1 and Alzheimer's disease: An up-to-date review. AB - Sirtuins are NAD+-dependent enzymes that regulate a large number of cellular pathways and are related to aging and age-associated diseases. In recent years, the role of sirtuins in Alzheimer's disease (AD) has become increasingly apparent. Growing evidence demonstrates that sirtuin 1 (SIRT1) regulates many processes that go amiss in AD, such as: APP processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. Here we review how SIRT1 affects AD and cognition, the main mechanisms in which SIRT1 is related to AD pathology, and its importance for the prevention and possible diagnosis of AD. PMID- 30007476 TI - IL-27 regulates HIF-1alpha-mediated VEGFA response in macrophages of diabetic retinopathy patients and healthy individuals. AB - Human macrophages produce vascular endothelial growth factor A (VEGFA) for angiogenesis in diabetic retinopathy (DR). The regulatory function of IL-27 on human macrophages is not well understood. In particular, the effect of IL-27 on VEGFA response in human macrophages has not been investigated. We find that IL-27 suppresses VEGFA mRNA expression as well as protein secretion by human macrophages. The synergistic action of purinergic signaling and activation of hypoxia-inducible factor 1 alpha (HIF-1alpha) induces VEGFA production in a positive feedback loop. IL-27 signaling in human macrophages disrupts this positive feedback loop thus suppresses VEGFA production. Blockade of IL-27 signaling with a JAK2 antagonist reverses this downregulatory effect on HIF 1alpha and partially blocks the inhibitory effect on VEGFA production. Lastly, DR patient macrophages have a higher propensity to produce VEGFA and this is amplified by an in vitro challenge with the pro-inflammatory cytokine IL-1beta. IL-27 suppresses VEGFA production by DR patient macrophages even in the presence of IL-1beta challenge indicating a potential therapeutic use of IL-27 in the clinic. PMID- 30007475 TI - A systematic analysis highlighting deficiencies in reported outcomes for patients with stage IV colorectal cancer undergoing palliative resection of the primary tumour. AB - BACKGROUND: Management of the primary tumour in the presence of unresectable metastatic colorectal cancer (mCRC) is controversial. The role of primary tumour resection (PTR) has been investigated by a number of retrospective cohort studies, with a number on going randomised controlled trials. The aim of this study was to identify the clinical and patient-reported outcomes currently reported in studies that evaluate the role of PTR in mCRC. METHODS: Literature searches were performed in MEDLINE (via OvidSP) (1966-June 2017), EMBASE (via OvidSP) and the Cochrane Library using terms related to colorectal cancer and primary tumour resection. All studies documenting outcomes following palliative PTR were included. Eligible articles were assessed using the Risk of Bias In Non Randomised Studies of Intervention (ROBINS-I) tool. RESULTS: Of 11,209 studies screened, 59 non-randomised studies reporting outcomes on 331,157 patients were included. Patient characteristics regarding performance status and co-morbidity were recorded in 26 (44.1%) and 17 (28.8%) studies. The chemotherapy regime used was reported in 27 (45.8%) studies. The operative setting and the operative approach was reported in 42 (71%) and 14 (23.7%) studies. Post-operative mortality and morbidity were reported in 33 (55.9%) and 35 (59.3%) studies. Overall survival was reported in 49 (83.1%) studies, with 5 different definitions identified. Quality of life was only reported in 1 (1.7%) study. CONCLUSION: This study demonstrates significant heterogeneity in the selection and definition of outcomes reported following PTR in mCRC. There is significant heterogeneity with a significant under-reporting of important outcomes such as treatment related adverse events and patient reported outcomes. PMID- 30007477 TI - Classification of Tendon Matrix Change Using Ultrasound Imaging: A Systematic Review and Meta-analysis. AB - Ultrasound imaging (US) is an accurate and reliable method used to diagnose tendinopathy. This systematic review was aimed at identifying common criteria and parameters used to diagnose tendinopathy, the methodological quality of studies and the predictive value of US. Nineteen studies met the inclusion criteria, with the Achilles, quadriceps and patella tendons being investigated. Overall, there was significant heterogeneity between the criteria used to diagnose tendinopathy utilising US. The methodological quality of included studies was "good." Additionally, meta-analysis revealed that US-identified abnormalities were predictive of future symptoms, and classification of tendinopathy using three US defined parameters indicated a higher relative risk of developing clinical tendinopathy compared with the use of two US-defined parameters. Further research into the development of a standardised US criterion that incorporates both clinical and US findings is required to allow for greater consistency in the diagnosis of tendinopathy. PMID- 30007478 TI - Midwifery education of the future: A perspective from Germany. PMID- 30007479 TI - Effect of anthocyanin supplementation on cardio-metabolic biomarkers: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Several studies have shown effects of anthocyanin on blood pressure, blood glucose, and lipid profile in different conditions, but the results of these studies are controversial. We summarized evidence from randomized clinical trials (RCTs) that investigated the effects of anthocyanin supplementation on cardio-metabolic biomarkers in adults. METHODS: The literature searches of MEDLINE and EMBASE for published studies in English was performed up to August 2017. Results were summarized as mean differences (MD) with 95% confidence intervals (CI). Effect sizes of eligible studies were pooled using random-effects models (the DerSimonian-Laird estimator). Heterogeneity among studies was evaluated by the Cochrane Q test. RESULTS: Of 5370 papers, 19 RCTs met inclusion criteria. There was no significant effect of anthocyanin supplementation on weight, waist circumference (WC), body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP). Our results indicated that anthocyanin supplementation had no significant effects on HbA1c (MD: -0.32; 95% CI = -0.64, 0.00; p = 0.050) with no heterogeneity (I2 = 0.0%, p = 0.966, no significant heterogeneity), however anthocyanin supplementation had significant effect on HOMA-IR (MD: -0.21; 95% CI = -0.36, -0.07; p = 0.004) (I2 = 37.9%, p = 0.200, no significant heterogeneity) in adults. Intake of anthocyanin had no significant effects on FBS (MD: 0.25; 95% CI = -5.70, 6.21; p = 0.933) and serum insulin (MD: 0.09; 95% CI = -0.92, 1.11; p = 0.860) with high heterogeneity for these variables (p = 0.000, and I2 = 83.5%) and (p = 0.098, and I2 = 52.4%), respectively. Anthocyanin supplementation had significant effects on total cholesterol (TC) and low density lipoprotein (LDL) for more than 300 mg/day intervention for more than 12 weeks. The dose and duration of supplementation were the potential sources of heterogeneity among most of the trials. CONCLUSION: The results demonstrate that supplementation with anthocyanin have beneficial effect on HOMA-IR in adults. PMID- 30007481 TI - Down-regulation of pyruvate decarboxylase gene of white-rot fungus Phlebia sp. MG 60 modify the metabolism of sugars and productivity of extracellular peroxidase activity. AB - Ethanologenic white-rot fungus Phlebia sp. MG-60-P2 produces ethanol directly from several lignocelluloses. Efficient gene silencing methods are needed for metabolic engineering of this fungus for biorefinery use. In this study, we evaluated the effectiveness of RNAi-mediated silencing of the pyruvate decarboxylase gene of Phlebia sp. MG-60-P2 (MGpdc1). The RNAi lines generated showed a variety of suppression levels of ethanol production and MGpdc1 expression, and two selected strains led to different metabolic fluxes, resulting in rapid accumulation of xylitol from xylose. Knockdown lines KD2 and KD10 showed different strength of silencing. The moderate-inhibition line (KD10) showed faster xylitol accumulation from xylose than the severe-inhibition line (KD2). KD2, KD10 and knockout line KO77 showed higher extracellular peroxidase activity than the wild-type. Gene silencing using RNAi for MGpdc1 in the ethanologenic white-rot fungus Phlebia sp. MG-60-P2 is an effective first step in metabolic engineering to produce other chemicals besides ethanol. This high efficiency of transformation and silencing effect will make it possible to cotransform with multiple expression vectors which enhance the minor metabolic pathway or introduce exogenous metabolic reaction in Phlebia sp. MG-60-P2. PMID- 30007480 TI - Prognostic value of energy expenditure and respiratory quotient measuring in patients with liver cirrhosis. AB - BACKGROUND & AIMS: Resting energy expenditure (REE) and respiratory quotient (RQ) as measured by indirect calorimetry (IC) may correlate with muscle mass and represent prognostic indicators in treating patients with liver cirrhosis. We aimed to assess the correlation of IC-measured REE and RQ with skeletal muscle mass (SM), mortality, and REE values as estimated by Harris-Benedict, European guidelines (EG), and Brazilian guidelines-DITEN (BG) equations in patients with liver cirrhosis. METHODS: In this prospectively designed study, REE was measured in 126 male patients with liver cirrhosis by IC and predicted by Harris-Benedict, EG (35 kcal/kg current weight), and BG (30 kcal/kg current weight) guidelines. Measurements were obtained at the time of admission to the study. Body composition was determined by whole-body dual-energy X-ray absorptiometry. The association between REE and 3-year survival was investigated. RESULTS: Cirrhosis etiology was classified as alcohol related (59.0%), viral (20.1%), cryptogenic (11.8%), or other (9.0%). Mean Child-Pugh and MELD indexes were 8.30 +/- 2.0 and 14.38 +/- 6.12, respectively. RQ showed a moderate correlation with SM (r = 0.64), while IC-measured REE was inversely associated with mortality (multivariate Cox Regression, HR = 0.88, 95% CI: 0.78; 1, p = 0.04). Among the predictive equations for REE, only Harris-Benedict yielded values close to the IC, with a positive Pearson correlation (r = 0.77), excellent accuracy (Cb = 0.98), and positive Lin's concordance correlation (CCC = 0.75). However, a large standard deviation was observed; HB-measured REE did not correlate with mortality. CONCLUSIONS: RQ and REE, as measured by IC, may be valuable tools for evaluating the severity of cirrhosis, by reflecting SM and predicting mortality, respectively. The predictive equations for REE included in this study cannot replace IC for this purpose. REGISTERED AT: www.clinicalTrials.gov (NCT02421848). PMID- 30007482 TI - Lowering the risk of stroke prevention: Managing bleeding complications. PMID- 30007483 TI - Corrigendum to 'Sirtuin 5 as a novel target to blunt blood-brain barrier damage induced by cerebral ischemia/reperfusion injury' [Int. J. Cardiol. 260 (2018) 148 155]. PMID- 30007484 TI - Addressing health inequities in cardiovascular health in Indigenous communities: Implementation process matters as much as the intervention itself. PMID- 30007485 TI - Evolving concepts in atrial fibrillation epidemiology: Advancing knowledge about cardiovascular health in sub-Saharan Africa. PMID- 30007486 TI - Guideline recommended treatment to targets of cardiovascular risk is inadequate in patients with inflammatory joint diseases. AB - OBJECTIVES: Patients with inflammatory joint diseases (IJD) have an increased risk of cardiovascular disease (CVD). Our goal was to examine indications for, and use of, lipid-lowering therapy (LLT) and antihypertensive treatment (AntiHT) in patients with IJD. Furthermore, to investigate the frequency of low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) goal attainment among IJD patients. METHODS: The cohort was derived from the NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR). Indications for AntiHT were: systolic/diastolic BP >= 140/90 mm Hg, self-reported hypertension or AntiHT. CVD risk was estimated by the systematic coronary risk evaluation (SCORE) algorithm. LDL-c goals were <2.6 mmol/L in case of diabetes, total cholesterol > 8 mmol/L or a SCORE estimate >= 5%, and <1.8 mmol/L for those with established CVD or SCORE >= 10%. Comparisons across IJD entities were performed using age and sex adjusted logistic regression. RESULTS: In total, 2277 patients (rheumatoid arthritis: 1376, axial spondyloarthritis: 474, psoriatic arthritis: 427) were included. LLT and AntiHT were indicated in 36.1% and 52.6% of the patients, of whom 37.6% and 47.0% were untreated, respectively. LDL-c and BP targets were obtained in 26.2% and 26.3%, respectively. Guideline recommended treatment and/or corresponding treatment targets were not initiated or obtained in approximately 50%. Rheumatoid arthritis patients were particularly likely to be undertreated with LLT, whereas hypertension undertreatment was most common in psoriatic arthritis. CONCLUSIONS: Inadequate CVD prevention encompasses all the three major IJD entities. The unmet need for CVD preventive measures is not only prevalent in RA, but exists across all the major IJD entities. PMID- 30007488 TI - Socioeconomic status and cardiovascular disease. PMID- 30007487 TI - [18F]-Fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: Comparison to immunohistology and relationship to acuity of events. AB - BACKGROUND: [18F]-fluorodeoxyglucose (18FDG) uptake imaged with positron emission tomography (PET) and computed tomography (CT) may serve as a biomarker of plaque inflammation. This study evaluated the relationship between carotid plaque 18FDG uptake and a) intraplaque expression of macrophage and macrophage-like cellular CD68 immunohistology; b) intraplaque inflammatory burden using leukocyte sensitive CD45 immunohistology; c) symptomatic patient presentation; d) time from last cerebrovascular event. METHODS: 54 patients scheduled for carotid endarterectomy underwent 18FDG PET/CT imaging. Maximum 18FDG uptake (SUVmax) and tissue-to-blood ratio (TBRmax) was measured for carotid plaques. Quantitative immunohistological analysis of macrophage-like cell expression (CD68) and leukocyte content (CD45) was performed. RESULTS: 18FDG uptake was related to CD68 macrophage expression (TBRmax: r = 0.51, p < 0.001), and total-plaque leukocyte CD45 expression (TBRmax: r = 0.632, p = 0.009, p < 0.001). 18FDG TBRmax uptake in carotid plaque associated with patient symptoms was greater than asymptomatic plaque (3.58 +/- 1.01 vs. 3.13 +/- 1.10, p = 0.008). 18FDG uptake differed between an acuity threshold of <90 days and >90 days (SUVmax:3.15 +/- 0.87 vs. 2.52 +/- 0.45, p = 0.015). CONCLUSIONS: In this CAIN cohort, 18FDG uptake imaged with PET/CT serves a surrogate marker of intraplaque inflammatory macrophage, macrophage-like cell and leukocyte burden. 18FDG uptake is greater in plaque associated with patient symptoms and those with recent cerebrovascular events. Future studies are needed to relate 18FDG uptake and disease progression. PMID- 30007489 TI - Non-specific effects of vaccines: Current evidence and potential implications. AB - Besides protection against specific microorganisms, vaccines can induce heterologous or non-specific effects (NSE). Epidemiological data suggest that vaccination with live-attenuated vaccines such as Bacillus Calmette-Guerin (BCG), measles vaccine, and oral polio vaccine results in increased overall childhood survival, and several of these observations have been confirmed in randomized trials. Immunological mechanisms mediating NSE include heterologous lymphocyte effects and induction of innate immune memory (trained immunity). Trained immunity induces long-term functional upregulation of innate immune cells through epigenetic and metabolic reprogramming. An overview of the epidemiological evidence of non-specific effects of vaccines and the latest insights regarding the biological mechanisms behind this phenomenon is presented, and future research priorities and potential implications are discussed. PMID- 30007495 TI - Liposarcoma: Clinico-pathological analysis, prognostic factors and survival in a series of 307 patients treated at a single institution. AB - BACKGROUND AND OBJECTIVES: Liposarcoma (LPS) is a malignant mesenchymal tumor and the most common soft tissue sarcoma. Four different subtypes are described: well differentiated (WD) LPS or atypical lipomatous tumor (ALT), dedifferentiated (DD) LPS, myxoid LPS, and pleomorphic LPS (PLS). The objective of the study was to investigate prognostic factors and clinical outcome of liposarcoma. METHODS: We retrospectively examined the clinico-pathological features of a series of 307 patients affected by Liposarcoma at a mean follow-up of 69 months (range 6-257). ALT/WD LPS were analyzed separately. The influence of site, size, type of presentation, grading, histotype and local recurrence on local and systemic control and survival was assessed. RESULTS: The statistical analysis indicated that only surgical margins represented a significant prognostic factor for local recurrence in ALT/WD LPS (P = 0.0007) and other subtypes of LPS (P = 0.0055). In myxoid, PLS and DD LPS, significant prognostic factors for metastasis free survival (MFS) were surgical margins (P = 0.0009), size of the tumor (P = 0.0358), histology (P = 0.0117) and local recurrence (P = 0.0015). In multivariate analysis, surgical margins (0.0180), size (0.0432) and local recurrence (0.0288) correlated independently with MFS. Margins (P = 0.0315), local recurrence (P = 0.0482) and metastases (P < 0.0001) were prognostic factors for overall survival (OS). CONCLUSION: Marginal surgery can be an accepted treatment for ALT/WD LPS. In other liposarcoma subtypes (Myxoid, DD, PLS) wide or radical surgery is recommended as the margins significantly influence local recurrence-free survival (LRFS), metastasis-free survival (MFS) and overall survival (OS). Local recurrence and metastases were significant prognostic factors for OS. PMID- 30007496 TI - Molar crenulation trait definition and variation in modern human populations. AB - Crenulated molars have been used extensively in biological anthropology. However, the trait has not been formally defined, nor have population frequencies been thoroughly outlined. This study provides a formal definition of molar crenulations and data on their presence in a large sample. Data were collected on maxillary and mandibular molars of modern dental material from various populations: South African, Hispanic, Japanese, American White, and American Black (n = 750). Molar crenulations were defined and a rank-scale created. Statistical analyses include chi-squared, correspondence analysis, and trait correlations. Significant statistical differences were found between populations in all molars. Minimal sexual dimorphism was noted, and is most pronounced among the American Black sample. Generally, American White and Japanese samples showed lower frequencies of molar crenulations, the highest frequencies were seen in the American Black and South African samples, and the Hispanic sample was intermediate. Correspondence analysis showed that American Black samples tended towards grade 2, and South African samples were more often a grade 1. American White and Japanese samples were most often grade 0, and Hispanic samples were intermediate. Correlations were noted across the molars. Population differences exist in the presence of molar crenulations, which were likely shaped by evolution. Based on these results molar crenulations can be added to the suite of traits currently used to study population differences. PMID- 30007497 TI - Discrepancies between reported and cadaveric body size measurements associated with a modern donated skeletal collection. AB - Body mass and stature estimation methods used in biological anthropology require materials with known body size information. There are several types of body size data that can be associated with skeletal collections. However, discussion regarding the reliability and suitability of these types of information for anthropological research is scarce. This paper focuses on differences between reported and recorded cadaver weights and heights associated with a modern donated skeletal collection, similar to these commonly used in anthropological research. In addition, the study identifies factors that may influence these discrepancies. The results show statistically significant differences between reported and cadaver body size information. Generally, reported weights, statures and body mass indices (BMI) were greater compared to the cadaver information in this sample. However, potential effects on these discrepancies varied depending on sex and information type. Age was found to influence stature discrepancy in females, and donation type had an effect on the female weight discrepancy. The results also show that body size range (weight, stature and BMI) can contribute to these discrepancies. Even though the differences between reported and cadaver data may not be significant at the population level, the individual variation can cause misclassifications of individuals depending on the data used. This study encourages researchers using modern documented collections and their body size information to openly acknowledge the types of weight and stature data used and to discuss potential problems associated with them. PMID- 30007498 TI - Ultracentral Tumors Treated With Stereotactic Body Radiotherapy: Single Institution Experience. AB - INTRODUCTION: Patients with ultracentral lung tumors, whose planning target volume directly contacts or overlaps the proximal bronchial tree, trachea, esophagus, pulmonary vein, or pulmonary artery, may be at higher risk of toxicity when treated with stereotactic body radiotherapy (SBRT). We reviewed the outcomes and toxicities of ultracentral lung tumors and compared the results with central lung tumors. PATIENTS AND METHODS: A review of our institutional prospective database of patients treated with lung SBRT from January 2006 to December 2015 was conducted. Patients with central tumors (RTOG 0813 definition) and ultracentral tumors were included. RESULTS: In total, 180 central and 26 ultracentral tumors were analyzed. The majority of patients received 60 Gy in 8 fractions (53.9%) or 48 Gy in 4 fractions (29.1%). The rates of any grade 2 or higher toxicity were 8.4% (n = 16) in the central group and 7.9% (n = 2) in the ultracentral group (P = .88). There were no observed grade 4 or 5 toxicities. In the nonmetastatic primary lung cancer cohort (n = 182), the median overall survival was 39.4 months versus 23.8 months (P = .40) and cause-specific survival was 55.5 months versus 28.2 months (P = .34) for central and ultracentral tumors, respectively. The 2-year cumulative local, regional, and distant failure rates were 3.3% versus 0 (P = .36), 9.1% versus 5.0% (P = .5), and 17.7% versus 18.7% (P = .63) in the central and ultracentral groups, respectively. CONCLUSION: In our experience, with strict adherence to planning parameters, SBRT to ultracentral tumors resulted in effective local control and no excessive risk of toxicity compared to central tumors. PMID- 30007499 TI - Robot-assisted laparoscopic common sheath ureteral reimplantation in duplex ureters: LUAA technique tips for optimal outcomes. AB - OBJECTIVE: To describe surgical tips for robot-assisted laparoscopic (RAL) common sheath ureteral reimplantation using the previously reported LUAA technique in patients with duplex renal collecting systems, and to assess the efficacy of this technique by reviewing operative outcomes in a single-institution case series. METHODS: We retrospectively reviewed a consecutive series of patients with duplicated collecting systems and vesicoureteral reflux (VUR) who underwent RAL extravesical common sheath ureteral reimplantation at a single medical center from 2010 to 2017. We included all duplex ureters requiring antireflux surgery. A standardized technique (LUAA) was used in each case, with additional tips used as described herein: a) careful common sheath ureteral mobilization, b) wide detrusorotomy with adequate detrusor flap elevation from the mucosa, and c) appropriate tension during tunnel detrusorraphy. Patient demographics, perioperative data, and follow-up imaging were reviewed. Radiographic resolution was defined as absence of VUR on voiding cystourethrogram (VCUG) performed 4 months postoperatively. Only patients undergoing ureteral reimplantation for VUR were included. Those with ureterovesical junction obstruction were excluded. RESULTS: A total of 13 patients underwent RAL common sheath ureteral reimplantation, with three bilateral cases for a total of 16 duplicated ureters reimplanted. Mean age at surgery was 3.64 +/- 1.04 years. Mean operative time was 125.1 +/- 30.73 min in unilateral cases and 200 +/- 51.18 in bilateral cases. Complete resolution of VUR was achieved in 14 of 16 ureters (87.50%). There were no high-grade complications (IIIV on the Clavien-Dindo scale). There were two grade II complications in our cohort, with a mean follow-up of 17.18 +/- 18.41 months. CONCLUSIONS: We report a radiographic success rate of 87.50% for RAL common sheath ureteral reimplantation in children with duplicated ureters, using the LUAA technique with several additional technical considerations. In our experience, careful mobilization of the ureter to preserve vascularity, a wide detrusorotomy to adequately elevate the detrusor flaps, and appropriate tension during detrusorraphy are essential components to optimize outcomes and prevent complications. PMID- 30007500 TI - Does the use of 5 mm instruments affect the outcomes of robot-assisted laparoscopic pyeloplasty in smaller working spaces? A comparative analysis of infants and older children. AB - INTRODUCTION: Pediatric robot-assisted laparoscopic (RAL) pyeloplasty has become a viable minimally invasive surgical option for ureteropelvic junction obstruction (UPJO) based on its efficacy and safety. However, RAL pyeloplasty in infants can be a challenging procedure because of the smaller working spaces. The use of the larger 8 mm instruments for these patients instead of the 5 mm instruments is common because of the shorter wrist lengths. OBJECTIVE: We hypothesized that the use of 5 mm instruments for RAL pyeloplasty in infants with smaller working spaces will have comparable perioperative parameters and surgical outcomes in comparison with older children with larger working spaces. STUDY DESIGN: We compared the perioperative parameters and surgical outcomes of RAL pyeloplasties performed by a single surgeon in infants and non-infant pediatric patients over a 2 year period. All of the procedures were performed using an 8.5 mm camera and 5 mm robotic instruments. Patient demographics, operative times, perioperative complications, hospital pain medication usage, hospital length of stay, and treatment success rates were compared between the two groups. RESULTS: A total of 65 pediatric RAL pyeloplasties were included in the study (16 infants and 49 non-infants, Table). There were no significant differences in gender, laterality, proportion of re-do pyeloplasty, or preoperative hydronephrosis grade between the two groups. All procedures were performed without conversion to open surgery or significant perioperative complications. There were no differences in segmental operative times (total operative time, console time, port placement time, time for dissection to UPJO, and anastomosis time), hospital pain medication usage, and hospital length of stay between the two groups (p > 0.05 for all comparisons). The treatment success rates were 93.8% (15/16) and 100% (49/49), respectively (p = 0.08). DISCUSSION: We present the first comparative study of infant and non-infant pediatric RAL pyeloplasty using 5 mm robotic instruments. An advantage of the current study is the use of a single surgeon's experience to compare RAL pyeloplasty outcomes in infants with those of older children, a group in which RAL pyeloplasty has already been shown to be efficacious and safe. Operative tips for infant RAL pyeloplasty are also provided. CONCLUSIONS: RAL pyeloplasty is a safe and effective surgical modality even in infants, with comparable perioperative parameters and outcomes as those in older children. The use of 5 mm instruments in infants does not affect outcomes and offers the potential for improved cosmesis. PMID- 30007501 TI - Nephroureterectomy with inferior vena-caval thrombectomy in post-chemotherapy Wilms' tumour in a child - From the eyes of the surgeon! AB - INTRODUCTION: Intracaval extension is present in 4-11% of all Wilms' tumour (WT). We present the open surgical nuances of inferior vena cava (IVC) thrombectomy with nephroureterectomy in post-chemotherapy WT. METHODS: A 10-year-old girl with right WT and intracaval tumour thrombus presented for surgical resection after six cycles of chemotherapy (vincristine, actinomycin D). A preoperative assessment plan of the vascular anatomy of the tumour was done. Meticulous intraoperative handling of the tumour mass, overcoming chemotherapy-induced fibrosis during inter-aortocaval groove dissection, optimal hemodynamic control during venotomy, en bloc resection of tumour with intracaval thrombus, and repair of the IVC are detailed. RESULTS: A 70 * 65 * 30 mm right renal mass with 20 * 10 * 4 mm level II IVC thrombus was excised en bloc. The intraoperative blood loss was 250 mL, operative time was 220 min, and total hospital stay was 7 days. The child completed post-surgical chemotherapy as per protocol. CONCLUSIONS: There is a paucity of literature regarding techniques for resection of WT with IVC extension in post-chemotherapy patients. With erudite preoperative planning and fine intraoperative dissection, complete resection of WT with intracaval thrombus is feasible with minimal blood loss and rapid postoperative recovery. PMID- 30007502 TI - Transmission of the relapsing fever spirochete, Borrelia miyamotoi, by single transovarially-infected larval Ixodes scapularis ticks. AB - The relapsing fever spirochete, Borrelia miyamotoi, is increasingly recognized as a cause of human illness (hard tick-borne relapsing fever) in the United States. We previously demonstrated that single nymphs of the blacklegged tick, Ixodes scapularis, can transmit B. miyamotoi to experimental hosts. However, two recent epidemiological studies from the Northeastern United States indicate that human cases of hard tick-borne relapsing fever peak during late summer, after the spring peak for nymphal tick activity but coincident with the peak seasonal activity period of larval ticks in the Northeast. These epidemiological findings, together with evidence that B. miyamotoi can be passed from infected I. scapularis females to their offspring, suggest that bites by transovarially infected larval ticks can be an important source of human infection. To demonstrate experimentally that transovarially-infected larval I. scapularis ticks can transmit B. miyamotoi, outbred Mus musculus CD1 mice were exposed to 1 or 2 potentially infected larvae. Individual fed larvae and mouse blood taken 10 d after larvae attached were tested for presence of B. miyamotoi DNA, and mice also were examined for seroreactivity to B. miyamotoi 8 wk after tick feeding. We documented B. miyamotoi DNA in blood from 13 (57%) of 23 mice exposed to a single transovarially-infected larva and in 5 (83%) of 6 mice exposed to two infected larvae feeding simultaneously. All 18 positive mice also demonstrated seroreactivity to B. miyamotoi. Of the 11 remaining mice without detectable B. miyamotoi DNA in their blood 10 d after infected larvae attached, 7 (64%) had evidence of spirochete exposure by serology 8 wk later. Because public health messaging for risk of exposure to Lyme disease spirochetes focuses on nymphal and female I. scapularis ticks, our finding that transovarially-infected larvae effectively transmit B. miyamotoi should lead to refined tick-bite prevention messages. PMID- 30007503 TI - Distribution and risk factors associated with Babesia spp. infection in hunting dogs from Southern Italy. AB - Canine babesiosis is caused by haemoprotozoan organisms of the genus Babesia which are transmitted by the bite of a hard tick. The aim of this survey was to determine the prevalence and risk factors associated with Babesia species infections in hunting dogs from Southern Italy. Blood samples were collected from 1311 healthy dogs in the Napoli, Avellino and Salerno provinces of the Campania region of Southern Italy. Serological testing was performed using two enzyme linked immunosorbent assays (ELISA), with one designed to detect B. canis and B. vogeli antibodies, and the other designed to detect B. gibsoni antibodies. Blood samples were also tested by quantitative real-time polymerase chain reaction (qPCR) assays for amplification of B. canis, B. vogeli and B. gibsoni DNA. The overall seroprevalence for B. canis/B. vogeli was 14.0%, compared to 0.2% for B. gibsoni. B. canis and B. vogeli PCR positive rates were 0.15% and 1.1%, respectively. B. gibsoni DNA was not amplified by qPCR. Male gender (OR 1.85), increased age (OR 1.01), long hair coat (OR 1.61) and living in Salerno province (OR 1.71) represented risk factors for B. canis/B. vogeli seroreactivity. Hunting dogs in Southern Italy are often exposed to B. canis/B. vogeli, however Babesia spp. infection was infrequently detected using qPCR. Further studies are needed to determine the extent to which Babesia spp. cause clinical disease in hunting dogs, and to evaluate the potential epidemiological relationships between hunting dogs and wild animal populations sharing the same area. PMID- 30007505 TI - Preimplantation Genetic Diagnosis of Autosomal Dominant Polycystic Kidney Disease Applied in China. PMID- 30007504 TI - Cognitive Changes in Peritoneal Dialysis Patients: A Multicenter Prospective Cohort Study. AB - RATIONALE & OBJECTIVE: Cognitive impairment is an independent predictor of technique failure and mortality in patients on peritoneal dialysis (PD) therapy. We investigated changes in cognitive function and factors associated with it in this population. STUDY DESIGN: Multicenter prospective cohort study. SETTING & PARTICIPANTS: 458 PD patients were enrolled and followed up for 2 years. PREDICTORS: Global and specific domains of cognitive function were measured at baseline and after 2 years. The Modified Mini-Mental State Examination (3MS) was used for assessment of global cognitive function; Trail-Making Tests A and B, for executive function; and subtests of the Battery for the Assessment of Neuropsychological Status, for immediate and delayed memory, visuospatial skill, and language ability. OUTCOMES: The primary outcome was change in cognitive function. Secondary outcomes included all-cause mortality, cardiovascular mortality, hospitalization, and transition to hemodialysis therapy. ANALYTICAL APPROACH: Multivariable linear regression models. RESULTS: The prevalence of cognitive impairment increased from 19.8% to 23.9%. 3MS scores significantly decreased (84.8 to 83.1), although executive function, immediate memory, and visuospatial skill improved over time. Delayed memory capacity and language ability were unchanged. Lower serum albumin level was associated with deteriorated delayed memory, visuospatial skill, and language ability, as well as with the decline in general cognitive function (beta values of 0.64, 0.90, 0.80, and 0.44, respectively). Advanced age, lower education, and depression were also correlated with deterioration in general and specific cognitive function. After multivariable adjustment, both global and specific cognitive impairment at baseline were associated with a greater rate of hospitalization, and memory dysfunction was associated with a lower dialysis modality survival rate. LIMITATIONS: A relatively short observation period, small number of deaths, and potential selection bias due to patients unavailable for the second assessment. CONCLUSIONS: In a PD population, global cognitive function declined over 2 years, though some specific cognitive domains improved. Besides well-recognized factors, hypoalbuminemia and depression were also risk factors for cognitive impairment. PMID- 30007506 TI - Associations Between Kidney Disease Measures and Regional Pulse Wave Velocity in a Large Community-Based Cohort: The Atherosclerosis Risk in Communities (ARIC) Study. AB - RATIONALE & OBJECTIVE: Arterial stiffness is suggested as a mediator of cardiorenal interaction. However, previous studies reported inconsistent associations between chronic kidney disease (CKD) and arterial stiffness and were limited by using either estimated glomerular filtration rate (eGFR) or albumin creatinine ratio (ACR) and examining arterial stiffness at limited segments. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 3,424 Atherosclerosis in Communities (ARIC) Study participants aged 66 to 90 years during 2011 to 2013. PREDICTORS: eGFR and ACR. OUTCOME: Pulse wave velocity (PWV) at 6 segments: carotid-femoral (cfPWV), heart-carotid (hcPWV), and heart-femoral (hfPWV), reflecting central stiffness; heart-ankle (haPWV) and brachial-ankle (baPWV), representing both central and peripheral stiffness; and femoral-ankle (faPWV), indicating peripheral stiffness. ANALYTICAL APPROACH: Multiple linear and logistic regression models to quantify the associations of eGFR and ACR with continuous PWV and elevated PWV (in the highest quartile), respectively. RESULTS: After adjusting for age, sex, and race, higher cfPWV and hfPWV were consistently associated with lower eGFR and higher ACR. Higher haPWV and baPWV were also observed with higher ACR. The independent association of both CKD measures with elevated cfPWV remained consistent after adjusting for additional confounders (ORs of elevated cfPWV were 1.09 [95% CI, 1.01-1.18] per 15-mL/min/1.73m2 lower eGFR and 1.20 [95% CI, 1.07-1.33] per 4-fold higher ACR). Higher ACR was also associated with elevated hfPWV and haPWV (ORs per 4-fold higher ACR were 1.25 [95% CI, 1.12-1.39] for elevated hfPWV and 1.19 [95% CI, 1.06-1.33] for elevated haPWV). Lower eGFR was associated with lower odds of elevated baPWV and faPWV (ORs per 15-mL/min/1.73m2 lower eGFR were 0.92 [95% CI, 0.84-0.99] and 0.91 [95% CI, 0.85-0.99], respectively). LIMITATION: Unable to address temporality between CKD measures and arterial stiffness. CONCLUSIONS: Both lower eGFR and higher ACR are independently associated with measures of central arterial stiffness, with stronger associations for ACR over eGFR. Our findings suggest that central arterial stiffness may be an important pathophysiologic phenotype of vascular disease in CKD. PMID- 30007507 TI - Predicting treatment eligibility for hepatitis B in low income regions: Can treatment scores without HBV DNA testing serve the purpose? PMID- 30007508 TI - The essential role of pharmacists in antibiotic stewardship in outpatient care: An official position statement of the Society of Infectious Diseases Pharmacists. AB - OBJECTIVES: The objective of this position statement is to describe the essential role of pharmacists in antimicrobial stewardship in outpatient care. DATA SOURCES: N/A. SUMMARY: The majority of antibiotic prescribing occurs in outpatient care settings highlighting the need for antibiotic stewardship in the community. Given their expertise on medication management, pharmacists are essential to any antibiotic stewardship effort. CONCLUSION: As the regulations for antibiotic stewardship in outpatient settings continue to evolve and optimal stewardship strategies are defined, pharmacists must be leaders in the implementation of these programs. PMID- 30007509 TI - Factors associated with dream enacting behaviors among US farmers. AB - INTRODUCTION: Dream enacting behavior (DEB) during REM sleep is a characteristic feature of REM sleep behavior disorder (RBD), the most specific prodromal symptom for Parkinson's disease (PD) and related synucleinopathies. METHODS: We screened for DEB among 20,591 male farmers in 2013-2015 using a validated question, and examined its association with pesticide uses and other potential risk factors reported about twenty years ago in 1993-1997. We reported odds ratios (OR) and 95% confidence intervals (CI) from multivariable logistic regression models. RESULTS: A total of 1623 (7.9%) farmers reported having had DEB. Farmers with DEB were more likely to report other nonmotor and motor symptoms of PD with age adjusted ORs ranging from 1.9 to 3.0. DEB prevalence varied little by age, but was significantly associated with current smoking (adjusted OR: 1.4, 95%CI: 1.2, 1.6), daily alcohol drinking (OR: 1.4, 95%CI: 1.1, 1.6), a history of head injury (OR: 1.3, 95%CI: 1.2, 1.5), and being married (OR: 1.4, 95%CI: 1.1, 1.7). We identified significant associations for several pesticides, especially cyclodiene organochlorines and pyrethroids, with adjusted ORs ranging from 1.2 to 1.5. The results were similar after excluding PD cases or when farmers with at least three DEB episodes in life were considered as DEB cases. CONCLUSIONS: This study suggests that DEB are not rare among male farmers. Findings on potential risk factors for DEB are intriguing, and given the close link between RBD and PD, these associations should be further investigated. PMID- 30007510 TI - Life-threatening DBS withdrawal syndrome in Parkinson's disease can be treated with early reimplantation. AB - INTRODUCTION: The deep brain stimulation (DBS) withdrawal syndrome (DBS-WDS) is a rare, life-threatening complication in Parkinson's disease (PD) patients with long disease duration and stimulation when stimulation is terminated for extended periods mostly due to infection of the DBS-hardware. METHODS, RESULTS: In five patients explantation became necessary because of infection after a mean of 11.4 years (range 4-15 years) of DBS and a mean disease duration of 24.6 years (range 3-22 years). Mean UPDRS motor-score pre-explantation was 38 points (range 24-55 points) which increased to a mean of 78.4 points (range 58-90 points) after explantation, despite optimal Levodopa dosing. Reimplantation of the hardware after 23 days (range 3-45 days) under antibiotic treatment led to an improvement to a mean of 40 points (range 25-73 points) and a complication free survival. CONCLUSION: Early reimplantation of the DBS-hardware is a treatment option of the DBS-WDS when the life-threatening urgency overrides surgical standards. Observation of the syndrome indicates pharmacological unresponsiveness of the dopaminergic system in advanced PD and long-term DBS. PMID- 30007511 TI - Three cases of adult-onset atopic dermatitis after hematopoietic stem cell transplantation. PMID- 30007512 TI - Darier's sign in urticaria pigmentosa-significance of perivascular eosinophilic infiltration. PMID- 30007513 TI - Spanish Cardiovascular Imaging Registry. First Official Report of the Spanish Society of Cardiology Working Group on Cardiovascular Imaging (2017). PMID- 30007514 TI - Recurrent Dislocation of the Tibialis Posterior Tendon Treated With Suture Tape: A Case Report of an Innovative Operative Procedure. AB - Dislocation of the tibialis posterior tendon (PTT) is a rare traumatic injury, and treatment is often delayed. Conservative treatment is ineffective for recurrent dislocation of the PTT; however, a reference standard procedure has not yet been established. In the present case report, we describe an innovative pseudo-pouch closing procedure with suture tape and a suture anchor for recurrent PTT dislocation. The patient returned to preoperative levels of activity at 21 weeks postoperatively and was asymptomatic at the 1-year follow-up examination. PMID- 30007515 TI - Pancreatic disorders in children: New clues on the horizon. AB - Pancreatic disorders in children represent a growing health problem in pediatric patients. In the past two decades, several advances have been made in the knowledge of pediatric pancreatic disorders, with better understanding of different etiologies and clinical manifestations of these disorders. Moreover, many efforts have been made in pancreatology, aiming to define guidelines in the management of pancreatitis in children, initially based on the available information in adults. A multidisciplinary and multicenter approach is necessary to better determine pancreatic disease pathways and treatment options in children. PMID- 30007517 TI - Does zoledronate therapy make mandibular bone susceptible to fracture? A radiographical and biomechanical study in rats. AB - INTRODUCTION: The aim of this study was to evaluate the effect of zoledronate therapy on susceptibility of mandibular bone to fracture in rats. METHODS: Fifty rats were randomly allocated to two groups of 25 animals. The rats in group Z received monthly intravenous infusion of 0.06 mg/kg zoledronate for 6 months. The rats in the group C were injected with an equal volume of saline in the same manner. A month after the last zoledronate/saline administration, all 50 rats were euthanized. Using a cone beam computed tomography, the cortical thickness of inferior border of mandible and the mandibular bone mineral density were calculated, and using a three-point bending test, the peak load failure and the ultimate stress of mandibular bone were determined. RESULTS: The mean mandibular inferior cortical bone thickness and the mean bone mineral density were significantly larger in zoledronate-treated rats (0.30 +/- 0.02 mm and 1045.00 +/ 185.79, respectively) compared to control rats (0.21 +/- 0.01 mm and 878.66 +/- 166.53, respectively). The peak load and the ultimate stress were lower in the zoledronate-treated hemimandibles (84.61 +/- 33.62 N and 1.76 +/- 0.72 MPa, respectively) compared to the control hemimandibles (98.36 +/- 16.5 9 N and 2.03 +/- 0.44 MPa, respectively). CONCLUSION: Zoledronate therapy reduced the mechanical strength of the mandibles, implying an increased risk of mandibular fracture in rats. PMID- 30007516 TI - A real life comparison of the effectiveness of adalimumab and golimumab in moderate-to-severe ulcerative colitis, supported by propensity score analysis. AB - BACKGROUND: Adalimumab and golimumab are effective in the treatment of moderate to severe ulcerative colitis. AIMS: We reported the comparative effectiveness of adalimumab and golimumab in ulcerative colitis. METHODS: 118 patients treated with adalimumab and 79 treated with golimumab were included and evaluated at 8 weeks and at the end of follow up. RESULTS: Overall clinical benefit was 72.6% at 8 weeks and 58.9% at the end of follow up. Patients with longer disease duration and those treated with adalimumab had a better outcome. Clinical benefit was 78.8% in adalimumab patients and 63.3% in golimumab patients (p = 0.026) after 8 weeks; it was 66.9% in adalimumab patients and 46.8% in golimumab patients (p = 0.008) at the end of follow up. These data were confirmed by propensity score analysis. A further analysis considering adalimumab optimization as treatment failure showed that the difference between adalimumab and golimumab was not significant. CONCLUSION: Adalimumab and golimumab are effective in the treatment of ulcerative colitis. Adalimumab seems to be more effective than golimumab. This difference is probably affected by the impossibility of golimumab to be optimized in Italy while adalimumab is. PMID- 30007518 TI - Increasing access to psychological treatments for mental illness. PMID- 30007519 TI - Automated psychological therapy using immersive virtual reality for treatment of fear of heights: a single-blind, parallel-group, randomised controlled trial. AB - BACKGROUND: Engaging, interactive, and automated virtual reality (VR) treatments might help solve the unmet needs of individuals with mental health disorders. We tested the efficacy of an automated cognitive intervention for fear of heights guided by an avatar virtual coach (animated using motion and voice capture of an actor) in VR and delivered with the latest consumer equipment. METHODS: We did a randomised trial of automated VR versus usual care. We recruited adults aged older than 18 years with a fear of heights by radio advertisements in Oxfordshire, UK. We diagnosed fear of heights if participants scored more than 29 on the Heights Interpretation Questionnaire (HIQ). We randomly allocated participants by computer in a 1:1 ratio to either automated VR delivered in roughly six 30-min sessions administered about two to three times a week over a 2 week period (intervention group) or to usual care (control group). Randomisation was stratified by severity of fear of heights. The research team, who were unaware of the random allocation, administered three fear-of-height assessments, at baseline (0 weeks), at the end of treatment (2 weeks), and at follow-up (4 weeks). The primary outcome measure was HIQ score (range 16-80, with higher scores indicating greater severity). This trial is registered with the ISRCTN registry, number ISRCTN11898283. FINDINGS: Between Nov 25, 2017, and Feb 27, 2018, 100 individuals were enrolled and underwent randomisation, of whom 49 were assigned to the VR treatment group and 51 to the control group. All participants completed the 4-week follow-up. The mean total treatment time in VR was 124.43 min (SD 34.23). Compared with participants in the control group, the VR treatment reduced fear of heights at the end of treatment (mean change score -24.5 [SD 13.1] in the VR group vs -1.2 [7.3] in the control group; adjusted difference 24.0, 95% CI -27.7 to -20.3; Cohen's d=2.0; p<0.0001). The benefit was maintained at follow-up (mean change score -25.1 [SD 13.9] in the VR group vs -1.5 [7.8] in the control group; adjusted difference -24.3, 95% CI -27.9 to -20.6; Cohen's d=2.0; p<0.0001). The number needed to treat to at least halve the fear of heights was 1.3. No adverse events were reported. INTERPRETATION: Psychological therapy delivered automatically by a VR coach can produce large clinical benefits. Evidence-based VR treatments have the potential to greatly increase treatment provision for mental health disorders. FUNDING: Oxford VR, and the National Institute of Health Research Oxford Health Biomedical Research Centre. PMID- 30007520 TI - The diabetes self-management educational programs and their integration in the usual care: A systematic literature review. AB - The increasing prevalence of type 2 diabetes has highlighted the importance of evidence-based guidelines for effective prevention, management and treatment. Diabetes self-management education (SME) produces positive effects on patient behaviours and health status. We analyzed the literature to identify (i) the level of integration between usual care and SME programs and (ii) any possible differences across them in terms of outcomes. Searches were made on three databases - PubMed, Scopus and Web of Science - to identify relevant publications on diabetes SME to 2015, which also describe the provider of usual care. In total, 49 studies met the inclusion criteria. We identified three levels of integration (high, medium and low) between usual care and SME programs based on the level of involvement of usual care professionals within the SME programs. In most cases, the primary care physician was responsible for the diabetes patients. Patient health behaviors and/or outcomes improve in most of the studies, independently from the level of integration. However, findings suggest that when patients/participants could perceive that usual care provider is highly involved in SME delivery, educational programs produced results that appear to be more positive. PMID- 30007521 TI - Understanding factors that influence the demand for dialysis among elderly in a multi-ethnic Asian society. AB - BACKGROUND: Despite literature suggesting conservative management (CM) is a viable option for elderly comorbid ESRD patients, the vast majority in Singapore receive dialysis. We hypothesized that the high demand for dialysis is driven by 1) lack of knowledge of CM and relative benefits of dialysis to CM, 2) adherence to physician recommendations which favour dialysis, and 3) high subsidies for haemodialysis (HD). METHODS: We tested these hypotheses via a survey, including a discrete choice experiment (DCE), administered to 151 elderly pre-dialysis kidney patients and their family caregivers. RESULTS: Results are consistent with the hypotheses: 40% (95% Confidence Interval (CI) 32-48) of patients and 46% (CI 38 55) of caregivers reported not being aware of CM, and 43% (CI 35-51) of patients and 24% (CI 17-31) of caregivers could not provide information on expected survival for dialysis or CM. Yet, once aware of CM as an option, 54% of patients and 42% of caregivers chose CM. However, if their physician recommended dialysis, 49% (CI 40-58) of patients and 68% (CI 59-77) of caregivers switched their choice. Subsidies on HD further reduced demand for CM by 6 percentage points. CONCLUSIONS: These results reveal that the high demand for dialysis is driven mostly by lack of awareness of CM as an option and by physician recommendations for dialysis over CM. PMID- 30007522 TI - Threshold and distribution of afterdischarges with electrical cortical stimulation. AB - OBJECTIVE: The present study aimed to investigate the threshold and distribution of afterdischarges (ADs) with cortical electrical stimulation for functional brain mapping. METHOD: We retrospectively analyzed data from 11 patients with medically intractable epilepsy who underwent 50-Hz cortical electrical stimulation for functional mapping followed by resection. These patients became seizure free for more than six months. The threshold and distribution of ADs induced by the stimulation were evaluated. RESULTS: The median threshold was 6 mA (range: 2-15 mA) for the frontal lobe, 8 mA (3-15 mA) for the temporal lobe, 6 mA (2-15 mA) for the parietal lobe, and 6 mA (4-12 mA) for the occipital lobe. No significant interlobar differences were observed in AD thresholds. No significant differences were noted between within and outside epileptogenic zones. The distribution of ADs, remote spread was observed in all patients, reflecting fronto-parieto-temporal connections, as well as contiguous spread. The stimulation of premotor areas, the inferior parietal lobule, supplementary motor area, and basal temporal areas appeared to induce ADs in remote cortices. CONCLUSION: While no locational differences were observed in AD thresholds, each brain region showed a characteristic pattern for AD spread. Remote AD spread needs to be considered for safe functional mapping. PMID- 30007523 TI - The application of RNFL thickness detection in early differential diagnosis among various types of idiopathic optic neuritis. AB - In this study, we attempted to investigate the application of RNFL thickness detection in the early differential diagnosis among various types of idiopathic optic neuritis (ION). In comparison with 19 healthy controls (HC), retrospective analysis of quadrant RNFL thickness in 83 patients with ION was performed, including eighteen multiple sclerosis (MS), forty-five neuromyelitis optica spectrum disorder (NMOSD), twenty patients with other idiopathic optic neuritis (O-ION). Our results showed that mean and every quadrant RNFL thickness of MS, NMOSD and O-ION were thinner than those of HC (P < 0.05). In comparison with MS and O-ION, NMOSD group had thinner RNFL thickness in nasal quadrant (P < 0.05). No significant difference in each quadrant RNFL thickness between MS-ON and O-ION was suggested (P > 0.05). Mean and every quadrant RNFL thickness of unaffected eyes of MS-ON were not different from those of HC (P > 0.05). We concluded that for patients only with simple optic neuritis, NMOSD has a significantly thinner RNFL thickness in nasal quadrant than MS and O-ION, which may contribute to the clinical differentiation and therapy among various types of idiopathic optic neuritis. PMID- 30007524 TI - Frameless stereotactic dual lead placement through single burr hole: A technical report. AB - Deep Brain Stimulation (DBS) surgery is a neurosurgical procedure involving the placement of stimulatory leads in subcortical structures. Rarely, DBS requires placement of dual ipsilateral leads. Previously, techniques for placing dual ipsilateral leads through a single burr hole were reported using a traditional stereotactic frame. Here, we demonstrate that dual ipsilateral leads can be safely and effectively placed through a single burr hole using a frameless stereotactic DBS system (NexFrame(r)) with only simple modifications to existing equipment. PMID- 30007525 TI - Improved Outcomes for Ruptured Abdominal Aortic Aneurysm Through Centralisation. PMID- 30007526 TI - Is There a Claudicating Elephant in the Room? PMID- 30007527 TI - Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC. AB - Uromodulin, the most abundant protein in normal urine, is essentially produced by the cells lining the thick ascending limb. There it regulates the activity of the cotransporter NKCC2 and is involved in sodium chloride handling and blood pressure regulation. Conflicting reports suggested that uromodulin may also be expressed in the distal convoluted tubule (DCT) where its role remains unknown. Using microdissection studies combined with fluorescent in situ hybridization and co-immunostaining analyses, we found a significant expression of uromodulin in mouse and human DCT at approximately 10% of thick ascending limb expression levels, but restricted to the early part of the DCT (DCT1). Genetic deletion of Umod in mouse was reflected by a major shift in NCC activity from the DCT1 to the downstream DCT2 segment, paralleled by a compensatory expansion of DCT2. By increasing the distal sodium chloride and calcium ion load with chronic furosemide administration, an intrinsic compensatory defect in the DCT from Umod /- compared to wild type mice was found manifested as sodium wasting and hypercalciuria. In line, co-expression studies in HEK cells suggested a facilitating role for uromodulin in NCC phosphorylation, possibly via SPAK-OSR1 modulation. These experiments demonstrate a significant expression of uromodulin in the early part of mouse and human DCT. Thus, biosynthesis of uromodulin in the DCT1 is critical for its function, structure and plasticity, suggesting novel links between uromodulin, blood pressure control and risk of kidney stones. PMID- 30007528 TI - Body representation does not lag behind in updating for the pubertal growth spurt. AB - Both making perceptual judgments about your own body and successfully moving your body through the world depend on a mental representation of the body. However, there are indications that moving might be challenging when your body is changing. For instance, the pubertal growth spurt has been reported to be negatively correlated to motor competence. A possible explanation for this clumsiness would be that when the body is growing fast, updating the body representation may lag behind, resulting in a mismatch between internal body representation and actual body size. The current study investigated this hypothesis by testing participants ranging from aged 6 to 50 years on both a tactile body image task and a motor body schema task. Separate groups of participants, including those in the age range when pubertal growth spurt occurs, were asked to estimate the distance between two simultaneously applied tactile stimuli on the arm and to move their hand through apertures of different widths. Tactile distance estimations were equal between participants before, during, and after the age range where the pubertal growth spurt is expected. Similarly, Bayesian evaluation of informative hypotheses showed that participants in the age range of the growth spurt did not move through the apertures as if their representation of the hand was smaller than its physical size. These results suggest that body representations do not lag behind in updating for the pubertal growth spurt. PMID- 30007529 TI - Young children in different linguistic environments: A multimodal neuroimaging study of the inferior frontal gyrus. AB - Magnetic resonance imaging (MRI) studies show that bilingual adults display structural and functional brain alterations, especially in the inferior frontal gyrus (IFG), dependent on when they learned their second language. However, it is unclear whether these differences are due to early exposure to another language, or to lifelong adaptation. We studied 22 children aged 3-5 years growing up in a multilingual environment and 22 age- and sex-matched controls exposed to an English-only environment. Resting-state functional MRI and T1-weighted MRI were used to assess functional connectivity and structure of the IFG. Children in a multilingual environment had higher functional connectivity between the left IFG and dorsal language and attention areas compared to children from a monolingual environment. Children in a multilingual environment also displayed decreased functional connectivity to temporal, anterior cingulate, and prefrontal areas. No significant group differences in IFG structure were observed. Our results suggest a more integrated functional language network, which is more segregated from other networks, in children who grow up in a multilingual environment. These findings suggest that functional alterations to the IFG due to second language learning occur early, while structural changes may not be apparent until later. PMID- 30007530 TI - Factors associated with how often community pharmacists offer and dispense naloxone. AB - BACKGROUND: A recent Surgeon General's report encourages people to ask pharmacists about naloxone, but whether pharmacists are well-prepared to respond to these requests is unclear. OBJECTIVES: Determine factors that are associated with how often pharmacists offer and dispense naloxone. METHODS: A convenience sample of 457 community pharmacists in North Carolina completed a 5-min online survey. Linear regressions were conducted to identify factors that are associated with how often pharmacists offer and dispense naloxone. Pharmacists' self reported barriers to teaching naloxone administration were identified. RESULTS: Most pharmacists (81.2%) worked in pharmacies that stocked naloxone, but many never offered (36.6%) or dispensed (19.4%) naloxone. Pharmacists offered (beta = 0.15, p < 0.01) and dispensed (beta = 0.15, p < 0.01) naloxone more often when their pharmacy stocked more naloxone formulations. Pharmacists who were more comfortable discussing naloxone offered it more often (beta = 0.26, p = 0.001). Pharmacists who worked in regional/local/grocery chain pharmacies dispensed and offered naloxone less often than other pharmacy types. Barriers to teaching naloxone administration included: time constraints, inadequate training, and perceived lack of patient comprehension. CONCLUSIONS: Many community pharmacists do not offer or dispense naloxone. Pharmacists who are uncomfortable discussing naloxone or work at smaller chain pharmacies may benefit from targeted naloxone training. PMID- 30007531 TI - Present and future options for treatment of infrainguinal deep vein disease. AB - OBJECTIVE: Management of chronic deep vein disease focuses on the alleviation of reflux and obstruction. For the suprainguinal veins, the main underlying pathologic process is obstruction, which has been recognized as a significant contributor to chronic venous insufficiency. This is currently being addressed with venous stenting and the development of dedicated stents designed for this segment of the venous system. Treatment of the femoropopliteal vein (FPV) is far more challenging because of the idiosyncratic anatomy, the hemodynamic physiology, and the technical aspects of size mismatch and valve flow dynamics in managing deep venous reflux. This review article discusses traditional and emerging technologies to treat infrainguinal disease. METHODS: Previous and current articles addressing this issue were reviewed. Emphasis was placed on emerging techniques and technologies. RESULTS: Significant bench work, in vitro and in vivo studies, have been conducted over the last 40 years addressing the issue of infrainguinal reflux and obstruction. Historically, open procedures to address FPV reflux and obstruction have had variable success in a few centers around the world. The significant increase of emerging endovascular therapies may allow more appropriate, reproducible, widespread treatment of infrainguinal deep venous disease. CONCLUSIONS: Adequate and durable therapies for infrainguinal venous disease represent one of the greatest challenges for a vein specialist. Recently, a cluster of interest and techniques/technologies have been developed. The endovascular management of arterial disease is mature. The endovenous management of infrainguinal disease is on the cusp of meaningful innovation. The purpose of this evidence summary is to describe the options for the management of chronic FPV disease, with emphasis on emerging technologies and techniques. PMID- 30007532 TI - Developmental dysplasia of the hip: A special pathology. AB - Developmental dysplasia of the hip (DDH) is one of the most common congenital disorders in childhood. Its diverse pathological changes require different treatments and result in different outcomes. Although many studies have been conducted on DDH, some special pathology is still unrecognized. We here presented a rare case of a one-year and eleven-month old girl with DDH; a half-free intra articular osteocartilaginous tissue was found in her right hip joint. X-ray, computer assisted tomography (CT) and magnetic resonance imaging (MRI) were performed to evaluate the pathological changes. MRI revealed some positive findings. The patient experienced open reduction and histopathological examination of the small tissue. Through gross anatomy it is a half-free intra articular osteocartilaginous tissue, which can fully match a fossa observed at the femoral head. Histopathological examination found that the tissue was composed of collagenous fiber and cartilage-like tissue. Interestingly, we found the expression of type I collagen according to immunohistochemical analysis, which indicated that the cartilage-like tissue was formed due to laceration of the articular cartilage. This kind of disorder should be included as one of the pathologies of DDH. The most possible origin of this tissue is the femoral head which we speculate may have been fractured before. PMID- 30007533 TI - Non-microsurgical skin flaps for reconstruction of difficult wounds in distal leg and foot. AB - PURPOSE: To express the versatility of a variety of non-microsurgical skin flaps used for coverage of difficult wounds in the lower third of the leg and the foot over 4 years period. Five kinds of flaps were used. Each flap was presented with detailed information regarding indication, blood supply, skin territory and technique. METHODS: Altogether 26 patients underwent lower leg reconstruction were included in this study. The reconstructive procedures applied five flaps, respectively distally based posterior tibial artery perforator flap (n = 8), distally based peroneal artery perforator flap (n = 4), distally based sural flap (n = 6), medial planter artery flap (n = 2) and cross leg flaps (n = 6). RESULTS: In all cases, there were no signs of osteomyelitis of underlying bones or discharge from the undersurface of the flaps. Fat necrosis occurred at the distal end of posterior tibial artery perforator flap in one female patient. The two cases of medial planter artery flap showed excellent healing with closure of donor site primarily. One cross leg flap had distal necrosis. CONCLUSION: Would at lower third of leg can be efficiently covered by posterior tibial, peroneal artery and sural flaps. Heel can be best covered by nearby tissues such as medial planter flap. In presence of vascular compromise of the affected limb or exposure of dorsum of foot, cross leg flap can be used. PMID- 30007534 TI - Parenchyma-sparing liver resection for hepatocellular carcinoma in left lateral section is associated with better liver volume recovery. AB - BACKGROUND: Left lateral sectionectomy (LLS) is frequently performed for surgical treatment of hepatocellular carcinoma (HCC) located in the left lateral section. However, no reports have described liver resection for such HCCs using a parenchyma-sparing strategy involving anatomic resection (AR) of segment II (S2 AR) or segment III (S3 AR). METHODS: From 1994 to 2014, patients who underwent LLS and S2 AR or S3 AR for HCC were included in the analysis. Short- and long term outcomes and pre- and postoperative LV were assessed. RESULTS: Of the 89 patients selected, 49 underwent LLS (LLS group) and 40 underwent S2 AR and S3 AR (S2/S3 AR group). The postoperative LV was not significantly smaller than the preoperative LV in the S2/S3 AR group (p = 0.114), whereas the postoperative LV was significantly smaller in the LLS group (p = 0.019). The overall survival (OS) and recurrence free survival (RFS) rates were not significantly different between the groups (OS, p = 0.056; RFS, p = 0.102). CONCLUSIONS: Parenchyma-sparing liver resection for HCC in the left lateral section is associated with better postoperative LV recovery than LLS with similar oncological outcomes. S2/S3 AR can be a reasonable therapeutic option when LLS results in the removal of more parenchyma than necessary. PMID- 30007535 TI - Comparison of a Patient-Centered Weight Loss Program starting before versus after knee replacement: A pilot study. AB - BACKGROUND: Most patients risk gaining weight in the years after knee replacement, adding further concern to a population that is mostly overweight/obese prior to surgery. OBJECTIVE: Via a randomised pilot study, we assessed changes in weight during a Patient Centered Weight Loss Program (PACE) initiated either before or after knee replacement, while simultaneously examining the feasibility of recruiting and retaining participants over 26 weeks. METHODS: Recruitment outreach was made to 133 patients scheduled for knee replacement. Sixteen participants were randomised to a 14-session weight loss program that started either <=6 weeks before surgery (PACE) or at 12 weeks post-op (Delayed PACE). Repeated measures ANOVAs were used to examine preliminary changes in weight, function, patient-reported outcomes, and physical activity across time (baseline/pre-op, 12 and 26 weeks after surgery) and group. RESULTS: Retention was 75% and 69% at 12 and 26 weeks after surgery, respectively. Weight significantly decreased across the 26 weeks (P<0.001). A group by time interaction (P=0.03) demonstrated Delayed PACE [-7.6+/-5.9kg (-7.9+/-5.9%)] lost significantly more weight than PACE [-2.5+/-2.7kg (-2.6+/-2.6%)] participants at 26 weeks. Significant improvements across time were seen for all function and patient reported outcomes, however activity did not change. CONCLUSION: Conducting a behavioural intervention was challenging but feasible in a knee replacement population, with preliminary evidence suggesting that initiating a program 12 weeks after surgery produces greater weight losses at 26 weeks compared to a program starting before knee replacement. PMID- 30007536 TI - Septal chondromucosal grafts in paralytic lagophthalmos. AB - OBJECTIVE: The risk of sight-threatening complications related to facial paralysis makes palpebral fissure management a priority. Surgery must take account of and adapt to the clinical signs of paralytic lagophthalmos. This therefore presupposes that a sufficient therapeutic arsenal is available. In this report, we propose a technique for palpebral lengthening (lower and/or upper), reconstructing the posterior lamella using a chondromucosal graft harvested from the nasal septum, combined with anterior lamellar repositioning. PATIENTS AND METHOD: A 5-year single center retrospective study was conducted, including sixteen patients for a total of nineteen septal chondromucosal grafts. The only inclusion criterion was paralytic lagophthalmos. Functional ophthalmic deficits were recorded (main outcome measure), first preoperatively, then postoperatively. Additionally, the degree of lagophthalmos was measured in order to infer palpebral fissure elongation gain. Surgical consequences and complications were recorded. RESULTS: A rapid regression in functional ophthalmic deficits was observed in 87% of patients, improving in stability over time (mean follow-up interval of 34 months). Mean palpebral fissure elongation gain was 3 mm. 53% of patients suffered from complete occlusion of the palpebral fissure. Surgical consequences were uncomplicated. 38% of patients eventually underwent revision surgery. CONCLUSION: Palpebral fissure lengthening using septal chondromucosal grafts serves as an alternative to existing treatment methods for paralytic lagophthalmos. Robust functional and cosmetic results, combined with very low morbidity, make this a simple and efficient technique whose indications may be extended. PMID- 30007537 TI - 'The silicone siphon' - A safe and simple method of removing silicone implant and content from the breast. PMID- 30007538 TI - Assessment of MRI safety issues for stainless steel sutures used for microtia reconstruction. AB - INTRODUCTION: Potential magnetic resonance imaging issues for stainless steel sutures used for microtia reconstruction could be clinically significant for safety and diagnostic yield considerations. Therefore, the purpose of this investigation was to assess magnetic resonance issues (magnetic field interactions, heating, and artifacts) for different types of stainless steel sutures used for microtia reconstruction. METHODS: Small gauge, commonly used stainless steel sutures from four different manufacturers (5/0 Steelex, Aesculap/B, Braun Medical, Inc.; Nagata 38 Gauge Microtia Wire, Bear Medical Corporation; Auricular Reco Wire, Medicon Surgical Inc.; and 5-0 B&S 35 Surgical Steel Suture, Ethicon, Inc.) were tested using standardized ex vivo techniques to assess magnetic field interactions, heating, and artifacts at 3 Tesla. Before testing, the stainless steel sutures were configured in a manner same as that for cartilage reconstruction used to treat microtia. RESULTS: Each stainless steel suture exhibited minor magnetic field interactions at 3 Tesla (translational attraction, deflection angle <10 degrees , and no torque). Heating associated with a whole-body averaged specific absorption rate of 2.9 W/kg was not excessive (highest temperature changes, <=1.8 degrees C). Artifacts were relatively minor in relation to the size and shape of each stainless steel suture (artifact size in relation to the size and shape of each stainless steel suture extending <=5 mm). CONCLUSIONS: The stainless steel sutures that underwent testing do not present additional risks to patients in a 3-Tesla or less magnetic field setting (i.e., magnetic resonance conditional). Artifacts for these sutures may only be an issue within close proximity to the reconstructed ear. PMID- 30007539 TI - Combinatorial Targeting by MicroRNAs Co-ordinates Post-transcriptional Control of EMT. AB - MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, functioning in part by facilitating the degradation of target mRNAs. They have an established role in controlling epithelial-mesenchymal transition (EMT), a reversible phenotypic program underlying normal and pathological processes. Many studies demonstrate the role of individual miRNAs using overexpression at levels greatly exceeding physiological abundance. This can influence transcripts with relatively poor targeting and may in part explain why over 130 different miRNAs are directly implicated as EMT regulators. Analyzing a human mammary cell model of EMT we found evidence that a set of miRNAs, including the miR-200 and miR-182/183 family members, co-operate in post-transcriptional regulation, both reinforcing and buffering transcriptional output. Investigating this, we demonstrate that combinatorial treatment altered cellular phenotype with miRNA concentrations much closer to endogenous levels and with less off-target effects. This suggests that co-operative targeting by miRNAs is important for their physiological function and future work classifying miRNAs should consider such combinatorial effects. PMID- 30007541 TI - Penile Paraffinoma. AB - : Penile paraffinoma is a rare cause of penile mass that can occur following injection of liquid paraffin, performed illicitly for penile augmentation. Over the past 2 yr, we have observed an increasing number of cases presenting with the complications of penile paraffinoma; three patients of central European origin have required inpatient treatment at our institution and posed a significant management dilemma. This mini-review aims to review the literature on the aetiopathogenesis, clinical features, diagnosis, and management of penile paraffinoma. A systematic search of PubMed and Scopus was performed with 10 case series and 26 case reports identified between 1956 and 2017. A total of 124 cases, with a mean age of 36.29 yr, were identified. The majority originated in Korea, and the most common injected material was liquid paraffin (80.6%). Patients presented with pain/swelling, ulceration/fistulae, and penile deformity. The majority required surgical excision of paraffinoma followed by reconstruction with a variety of procedures including split skin grafting, scrotal skin flap reconstruction, and prepuce grafting. Mean duration of follow-up was 15.8 mo. Penile paraffinoma remains a rare presentation; however, it can present management difficulties. We have had an increase in cases, with three patients presenting with complications following injection of paraffin in our unit in the past 2 yr. Definitive management includes surgical excision and reconstruction as required with early involvement of plastic surgeons. There may be a role for conservative management; however, long-term outcomes are unclear. There may be a need for targeted preventative measures through public health agencies in communities where the practice is more prevalent. PATIENT SUMMARY: Penile paraffinoma can occur following injection of liquid paraffin or similar substances, generally used by non-healthcare personnel for the purpose of penile augmentations, and can cause significant pain, ulceration, and penile deformity. Definitive management includes surgical excision with reconstruction as required. Prevention of its use through awareness and education may be required in communities where the practice is more common. PMID- 30007543 TI - Novel Devices for Adolescent and Adult Male Circumcision. AB - There is an abundance of devices for adolescent and adult male circumcision (MC). It has been shown that the safety and efficacy of device-assisted MC are equal to or better than those for MC via conventional surgery. MC devices have the potential to simplify the procedure and increase the acceptability of circumcision among patients. PMID- 30007542 TI - Complication Rate After Antibiotic Prophylaxis with Fosfomycin Versus Fluorochinolones or beta-lactam Antibiotics in Patients Undergoing Prostate Biopsy: A Propensity Score-adjusted Analysis. AB - BACKGROUND: Transrectal ultrasound-guided prostate biopsy (TRBx) or transperineal Bx (TPBx) are considered alternative approaches for the diagnosis of prostate cancer (PCa). However, urinary tract infection (UTI) or other complications could be more frequent in the TRBx approach. OBJECTIVE: To determine the complication rate following different antimicrobial prophylaxis (AMP; fosfomycin trometamol [FT] vs beta-lactame or fluorochinolones [FQ]) in patients undergoing TRBx or TPBx. DESIGN, SETTING, AND PARTICIPANTS: The analyses were based on prospectively collected data of a cohort of patients who underwent TRBx or TPBx for elevated prostate-specific antigen (PSA; >=4ng/ml) or clinical suspicion of PCa, between September 2016 and March 2017. Patients received a single dose of 3g oral FT (group A) or, alternatively, FQ or beta-lactame (group B). INTERVENTION: TRBx versus TPBx. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjustment variables consisted of age, PSA, biopsy technique (TPBx vs TRBx), and antibiotic prophylaxis (FT vs beta-lactame or FQ) using 1:1 propensity-score matching. Overall, 526 patients were considered, of whom 258 received FT (group A) and the other 258 received beta-lactame or FQ (group B). RESULTS AND LIMITATIONS: Overall complications occurred in 390 (75.58%) and major complications in 67/516 (12.98%). Lower prevalence of UTIs was detected in group A (34.1%) compared with that in group B (43.4%; p=0.03), while similar rates of haematuria (54.7% vs 55.4%), haemospermia (39.5% vs 33.0%), and acute urinary retention (11.6% vs 9.3%) were detected in groups A and B. We found that group B (odds ratio [OR]: 1.54; p=0.03), I grade haematuria (OR: 6.17; p<0.01), and II grade haematuria (OR: 5.13; p<0.01) were significantly associated with increased risk of UTIs. CONCLUSIONS: AMP with fluoroquinoles or beta-lactam antibiotics increased the rate of UTIs, when compared with FT, in patients undergoing TRBx or TPBx. The appearance of haematuria or haemospermia is associated with UTIs, suggesting the possibility of tailoring the strategy for prophylaxis in this category of patients. PATIENT SUMMARY: In this study, comparing complications after transrectal ultrasound-guided prostate biopsy versus transperineal biopsy, prophylaxis with fluoroquinoles or beta-lactam antibiotics increased the rate of urinary tract infections when compared with fosfomycin trometamol, regardless of the type of biopsy approach. PMID- 30007540 TI - Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. AB - Clinically used RAF inhibitors are ineffective in RAS mutant tumors because they enhance homo- and heterodimerization of RAF kinases, leading to paradoxical activation of ERK signaling. Overcoming enhanced RAF dimerization and the resulting resistance is a challenge for drug design. Combining multiple inhibitors could be more effective, but it is unclear how the best combinations can be chosen. We built a next-generation mechanistic dynamic model to analyze combinations of structurally different RAF inhibitors, which can efficiently suppress MEK/ERK signaling. This rule-based model of the RAS/ERK pathway integrates thermodynamics and kinetics of drug-protein interactions, structural elements, posttranslational modifications, and cell mutational status as model rules to predict RAF inhibitor combinations for inhibiting ERK activity in oncogenic RAS and/or BRAFV600E backgrounds. Predicted synergistic inhibition of ERK signaling was corroborated by experiments in mutant NRAS, HRAS, and BRAFV600E cells, and inhibition of oncogenic RAS signaling was associated with reduced cell proliferation and colony formation. PMID- 30007544 TI - Off-target effects of tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel-pamoate, and albendazole plus oxantel-pamoate on the human gut microbiota. AB - Soil-transmitted helminths infect 1.5 billion people worldwide. Treatment with anthelminthics is the key intervention but interactions between anthelminthic agents and the gut microbiota have not yet been studied. In this study, the effects of four anthelminthic drugs and combinations (tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel-pamoate, and albendazole plus oxantel-pamoate) on the gut microbiota were assessed. From each hookworm infected adolescent, one stool sample was collected prior to treatment, 24 h post-treatment and 3 weeks post-treatment, and a total of 144 stool samples were analyzed. The gut bacterial composition was analyzed using 16S rRNA gene sequencing. Tribendimidine given alone or together with oxantel-pamoate, and the combination of albendazole and oxantel pamoate were not associated with any major changes in the taxonomic composition of the gut microbiota in this population, at both the short-term post-treatment (24 h) and long-term post-treatment (3 weeks) periods. A high abundance of the bacterial phylum Bacteroidetes was observed following administration of tribendimidine plus ivermectin 24 h after treatment, due predominantly to difference in abundance of the families Prevotellaceae and Candidatus homeothermaceae. This effect is transient and disappears three weeks after treatment. Higher abundance of Bacteroidetes predicts an increase in metabolic pathways involved in the synthesis of B vitamins. This study highlights a strong relationship between tribendimidine and ivermectin administration and the gut microbiota and additional studies assessing the functional aspects as well as potential health-associated outcomes of these interactions are required. PMID- 30007546 TI - Dendritic cells in sepsis: Potential immunoregulatory cells with therapeutic potential. AB - Sepsis is a disease of dysfunctional immune response against the pathogen causing a profound immune-mediated damage to the vital organs and death of the patient in most cases. However, when sepsis is described much attention is given to monocytes/macrophages, complement system, neutrophils, cytokine storm, and T cells. Dendritic cells (DCs) get less attention in this scenario despite comprising the major immune cell population. Therefore the present review is designed to highlight the importance of DCs in the pathogenesis of sepsis, sepsis associated immunosuppression, and organ damage. The article starts with an introduction of sepsis as a major medical problem needing an urgent therapeutic targeting. Thereafter it provides a brief information regarding classical and plasmacytoid DCs and their role in the maintenance of immune homeostasis. The subsequent sections describe the role of DCs in the immunopathogenesis of sepsis via immunoregulation, impact of sepsis on DCs including their immunometabolic changes, and their therapeutic targeting during sepsis. PMID- 30007545 TI - Associations between high ambient temperatures and heat waves with mental health outcomes: a systematic review. AB - OBJECTIVES: The objective of this study was to describe the mental health effects of high ambient temperatures and heat waves, determine whether heat-related morbidity and mortality are increased among people with known mental disorders and identify knowledge gaps to inform targeting of future research. STUDY DESIGN: Systematic literature review and narrative synthesis. METHODS: A systematic review of published literature using MEDLINE, Embase and PsycINFO without geographical or temporal limits was conducted. We included studies that explicitly linked high ambient temperatures and/or heat waves to mental health outcomes. Evidence was graded using a National Institute of Health framework. RESULTS: A total of 35 studies were included in the review, among which 34 were observational studies and one was a case-control study. Six broad mental health outcome categories were identified: suicide and heat; bipolar disorder, mania and depression and heat; schizophrenia and heat; organic mental health outcomes and heat including dementia; alcohol and substance misuse and heat; and multiple mental health outcomes/mental health service usage and heat. The studies included were heterogeneous in terms of study design, population, setting, exposure measures, outcomes and location making meta-analysis unfeasible. Fifteen studies showed an increased suicide risk with heat (relative risk [RR] 1.014-1.37 per 1 degrees C, P < 0.05; r = 0.10-0.64, P < 0.05). Increased risks of mental health related admissions and emergency department visits at higher temperatures were also found. No evidence of change in community care use was found. Evidence for the impact of heat on other mental health outcomes was mixed. CONCLUSIONS: High ambient temperatures have a range of mental health effects. The strongest evidence was found for increased suicide risk. Limited evidence was found for an increase in heat-related morbidity and mortality among people with known mental health problems. Knowledge gaps exist on the impact of high temperatures on many common mental health disorders. Mental health impacts should be incorporated into plans for the public health response to high temperatures, and as evidence evolves, psychological morbidity and mortality temperature thresholds should be incorporated into hot weather-warning systems. PMID- 30007547 TI - Blood-brain barrier (BBB) and the complement landscape. AB - The brain is an immune privileged organ, uniquely placed in the body. Two systems involved in maintaining brain homeostasis and in protecting the brain are the blood-brain barrier (BBB) and the complement system. The BBB is present in the vasculature of the brain and is the dynamic interface between brain and body that regulates what enters and leaves the brain, thereby maintaining the brain microenvironment optimal for brain function. The complement system is ubiquitous, being present systemically and in the brain, both membrane bound and in circulation. It is an important arm of the body's defense that helps maintain homeostasis by eliminating debris and damaged cells, participating in destroying pathogens, promoting inflammation and conveying 'danger signals'. Recent studies reveal that the complement system plays an important role in normal brain development. However, when the complement system is overwhelmed, complement activation could contribute to loss of BBB integrity resulting in brain pathology. Studies support an association between complement proteins and BBB dysfunction, with the mechanisms being slowly unraveled. This review will provide an overview of both these systems, how they intersect and interact with each other. PMID- 30007548 TI - Investigating motor planning in children with DCD: Evidence from simple and complex grip-selection tasks. AB - Several studies suggest that children with Developmental Coordination Disorder (DCD) may be able to plan simple movements as well as their peers, but experience increasing difficulties as the movements become complex. The present study aimed to clarify the nature of motor planning in DCD, including a putative deficit, by being the first to investigate motor planning using converging measures of simple and complex motor planning in a single sample of children with DCD. Boys aged between 8 and 12 years with (n = 10) and without DCD (n = 17) completed three commonly used 'simple' (bar grasping, sword, and bar transport tasks) measures and one 'complex' (octagon task) measure of end-state-comfort (ESC), a classic measurement of motor planning ability. To achieve ESC when manipulating an object, a person may choose to start with an uncomfortable grip in order to end the movement in a comfortable position. Results indicate that the participants with DCD planned for ESC as efficiently as their peers when performing the 'simple' measures of ESC but were significantly less likely to end their performances in ESC than those without DCD for the more 'complex' octagon task. Taken together, our data suggest that school-aged children with DCD may be able to plan simple movements as efficiently as their peers, but have more difficulty doing so for multi-movement or complex sequences. Based on the assumption that the efficiency of such motor planning is dependent on the integrity of internal modelling systems, we argue that our study provides indirect support for the internal modelling deficit hypothesis. PMID- 30007549 TI - Differentiating type 1 and 2 acute myocardial infarctions using the N-terminal pro B-type natriuretic peptide/cardiac troponin T ratio. AB - PURPOSE: Differentiation of type 1 (T1MI) from type 2 myocardial infarction (T2MI) is important as recommended treatments for each differ. Patients with T2MI may have more/earlier cardiac wall stress resulting in an increased N-terminal pro B-type natriuretic peptide (NT-proBNP)/cTnT generation 5 ratio (cTnT Gen 5). METHODS: Emergency Department (ED) patients presenting with symptoms suspicious for acute coronary syndrome (ACS) were enrolled from 2013 to 2015. Baseline blood samples were collected within 60 min of a triage ECG, with additional draws at 30, 60 and 180 min. NT-proBNP and cTnT Gen 5 levels were measured later in an independent laboratory. Acute myocardial infarction (AMI) was adjudicated using the Third Universal Definition of Myocardial Infarction. RESULTS: 575 patients were enrolled with 44 (7.7%) having AMI [25 T1MI (59.1%) and 18 T2MI (40.9%)]. Patient characteristics showed very few AMI type differences so accurate clinical differentiation was difficult. The median NT-proBNP/cTnT Gen 5 ratios were significantly higher in T2MI when compared to T2MI at baseline and 30, 60 and 180 min later [7.3 v 53.0 (p = 0.003), 5.8 v 49.5 (p = 0.002), 6.3 v 47.5 (p = 0.003) and 4.3 v 33.7 (p = 0.016) respectively]. CONCLUSIONS: The clinical determination of whether an AMI is type 1 or 2 is difficult as the ED patient characteristics of each are similar. The NT-proBNP/cTnT Gen 5 ratio can aid in making this differentiation. Additional multicenter trials are needed to validate our results. PMID- 30007551 TI - Optimizing One-Lung Ventilation: Moving Beyond Tidal Volume. PMID- 30007550 TI - Impella Placement Guided by Echocardiography Can Be Used as a Strategy to Unload the Left Ventricle During Peripheral Venoarterial Extracorporeal Membrane Oxygenation. AB - OBJECTIVE: At the authors' institution, before 2015, patients cannulated for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) did not undergo left ventricular (LV) decompression with the use of an LV vent. After 2015, the authors' institution began using the Impella device to vent the left ventricle in patients on VA-ECMO. The authors hypothesized that survival outcomes would improve in patients on VA-ECMO with the use of an Impella for LV venting. DESIGN: Retrospective, chart based review study. SETTING: Single center, university-based hospital. PARTICIPANTS: All adult patients at the authors' institution who required VA-ECMO between January 2015 and May 2017. INTERVENTION: An Impella (Abiomed, Danvers, MA) device was placed percutaneously in patients cannulated for VA-ECMO as a mechanism to provide LV venting and decompression, therefore unloading the heart. MEASUREMENTS AND MAIN RESULTS: Manual chart review was conducted, and a survival analysis was performed. It was observed that patients on VA-ECMO in whom an Impella was implanted had improved survival and an improvement in LV function as demonstrated by echocardiography compared with patients maintained on VA-ECMO alone. CONCLUSIONS: Patients on VA-ECMO plus Impella implantation demonstrated improved survival compared with patients treated with VA-ECMO alone. Key echocardiographic characteristics such as improved LV function after Impella placement and LV cavity size reduction during therapy may help predict those patients who may benefit most from this cannulation strategy. PMID- 30007552 TI - Of Probabilities and Uncertainties: Current Challenges of the Heart Failure Epidemic. PMID- 30007553 TI - Design Elements and Enrollment Patterns of Contemporary Trials in Heart Failure With Preserved Ejection Fraction: A Systematic Review. PMID- 30007555 TI - Ambulatory Inotrope Infusions: The Importance of Historical Perspective. PMID- 30007556 TI - Ambulatory Inotrope Infusions in Advanced Heart Failure: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This study sought to systematically review the available evidence of risks and benefits of ambulatory intravenous inotrope therapy in advanced heart failure (HF). BACKGROUND: Ambulatory inotrope infusions are sometimes offered to patients with advanced Stage D HF; however, an understanding of the relative risks and benefits is lacking. METHODS: On August 7, 2016, we searched SCOPUS, Web of Science, Ovid EMBASE, and Ovid MEDLINE for studies of long-term use of intravenous inotropes in outpatients with advanced HF. Meta-analysis was performed using random effects models. RESULTS: A total of 66 studies (13 randomized controlled trials and 53 observational studies) met inclusion criteria. Most studies were small and at high risk for bias. Pooled rates of death (41 studies), all-cause hospitalization (15 studies), central line infection (13 studies), and implantable cardioverter-defibrillator shocks (3 studies) of inotropes were 4.2, 22.2, 3.6, and 2.4 per 100 person-months follow up, respectively. Improvement in New York Heart Association (NYHA) functional class was greater in patients taking inotropes than in controls (mean difference of 0.60 NYHA functional classes; 95% confidence interval [CI]: 0.22 to 0.98; p = 0.001; 5 trials). There was no significant difference in mortality risk in those taking inotropes compared with controls (pooled risk ratio: 0.68; 95% CI: 0.40 to 1.17; p = 0.16; 9 trials). Data were too limited to pool for other outcomes or to stratify by indication (i.e., bridge-to-transplant or palliative). CONCLUSIONS: High-quality evidence for the risks and benefits of ambulatory inotrope infusions in advanced HF is limited, particularly when used for palliation. Available data suggest that inotrope therapy improves NYHA functional class and does not impact survival. PMID- 30007554 TI - The Association of Obesity and Cardiometabolic Traits With Incident HFpEF and HFrEF. AB - OBJECTIVES: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately. BACKGROUND: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear. METHODS: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction >=50% vs. <50%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models. RESULTS: The mean age was 60 +/- 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34). CONCLUSIONS: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes. PMID- 30007557 TI - Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial. AB - OBJECTIVES: This study assessed the relationship between atrial fibrillation (AF) and outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, to evaluate whether AF modified the treatment response to spironolactone and whether spironolactone influenced post randomization AF. BACKGROUND: AF is common in heart failure with preserved ejection fraction (HFpEF) and likely contributes to increased risk of adverse outcomes. METHODS: A total 1,765 patients enrolled in TOPCAT trial in North and South America were divided into 3 groups: no known AF, history of AF without AF at enrollment, and AF found on the electrocardiogram (ECG) at enrollment. We assessed outcomes and treatment response to spironolactone in all groups, and the association between post-randomization AF and outcomes in patients free of AF at baseline. The primary outcome of the TOPCAT trial was a composite of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. RESULTS: A total of 760 patients (43%) had a history of AF (18%) or AF on ECG at enrollment (25%). The highest adjusted risk was associated with AF at enrollment (primary outcome, hazard ratio: 1.34; 95% confidence interval: 1.09 to 1.65; p = 0.006; and an increased early risk of secondary outcomes). Neither history of AF nor AF at enrollment modified the beneficial treatment effect of spironolactone. Post-randomization AF, which occurred in 6.3% of patients, was not influenced by spironolactone treatment, but was associated with an increased early risk of the primary outcome (hazard ratio: 2.32; 95% confidence interval: 1.59 to 3.40; p < 0.0001) and secondary outcomes. CONCLUSIONS: AF at enrollment was associated with increased cardiovascular risk in HFpEF patients in the TOPCAT study. Post-randomization AF, which was associated with an increased risk of morbidity and mortality, was not influenced by spironolactone. (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302). PMID- 30007558 TI - Regional Adipose Distribution and its Relationship to Exercise Intolerance in Older Obese Patients Who Have Heart Failure With Preserved Ejection Fraction. AB - OBJECTIVES: This study sought to test the hypothesis that older obese patients with heart failure with preserved ejection fraction (HFpEF) have significantly greater abdominal, cardiac, and intermuscular fat than healthy, age-matched controls, out of proportion to total body fat, and that these abnormalities are associated with objective measurements of physical function. BACKGROUND: Recent studies indicate that excess total body adipose tissue contributes to exercise intolerance in patients with HFpEF. However, the impact of the pattern of regional (abdominal, cardiac, intermuscular) adipose deposition on exercise intolerance in patients with HFpEF is unknown. METHODS: We measured total body adiposity (using dual-energy x-ray absorptiometry) and regional adiposity (using cardiac magnetic resonance), peak oxygen uptake (Vo2), 6-min walk distance (6MWD), short physical performance battery (SPPB), and leg press power in 100 older obese patients with HFpEF and 61 healthy controls (HCs) and adjusted for age, sex, race, and body surface area. RESULTS: Peak Vo2 (15.7 +/- 0.4 ml/kg/min vs. 23.0 +/- 0.6 ml/kg/min, respectively; p < 0.001), 6MWD (427 +/- 7 m vs. 538 +/- 10 m, respectively; p < 0.001), SPPB (10.3 +/- 0.2 vs. 10.9 +/- 0.2, respectively; p < 0.05), and leg power (117 +/- 5 W vs. 152 +/- 9 W, respectively; p = 0.004) were significantly lower in patients with HFpEF than HCs. Total fat mass, total percent fat, abdominal subcutaneous fat, intra abdominal fat, and thigh intermuscular fat were significantly higher, whereas epicardial fat was significantly lower in patients with HFpEF than in HC. After we adjusted for total body fat, intra-abdominal fat remained significantly higher, while epicardial fat remained significantly lower in patients with HFpEF. Abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intermuscular fat:skeletal muscle ratio were inversely associated, whereas epicardial fat was directly associated with peak Vo2, 6MWD, SPPB, and leg power. Using multiple stepwise regression, we found intra-abdominal fat was the strongest independent predictor of peak Vo2 and 6MWD. CONCLUSIONS: In metabolic obese HFpEF, the pattern of regional adipose deposition may have important adverse consequences beyond total body adiposity. Interventions targeting intra-abdominal and intermuscular fat could potentially improve exercise intolerance. (Exercise Intolerance in Elderly Patients With Diastolic Heart Failure [SECRET]; NCT00959660). PMID- 30007559 TI - HVAD: The ENDURANCE Supplemental Trial. AB - OBJECTIVES: The aim of this study was to prospectively evaluate the impact of blood pressure management on stroke rates in patients receiving the HeartWare HVAD System. BACKGROUND: The ENDURANCE trial demonstrated noninferiority of the HeartWare HVAD System versus control (HeartMate II) in patients with advanced heart failure ineligible for heart transplantation. However, stroke was more common in HVAD subjects. Post hoc analyses demonstrated increased mean arterial blood pressure as a significant independent risk factor for stroke. METHODS: The ENDURANCE Supplemental Trial was a prospective, multicenter evaluation of 465 patients with advanced heart failure ineligible for transplantation, randomized 2:1 to HVAD (n = 308) or control (n = 157). The primary endpoint was the 12-month incidence of transient ischemic attack or stroke with residual deficit 24 weeks post-event. Secondary endpoints included the composite of freedom from death, disabling stroke, and need for device replacement or urgent transplantation, as well as comparisons of stroke or transient ischemic attack rates in HVAD cohorts in ENDURANCE Supplemental and ENDURANCE. RESULTS: The enhanced blood pressure protocol significantly reduced mean arterial blood pressure. The primary endpoint was not achieved (14.7% with HVAD vs. 12.1% with control, noninferiority [margin 6%] p = 0.14). However, the secondary composite endpoint demonstrated superiority of HVAD (76.1%) versus control (66.9%) (p = 0.04). The incidence of stroke in HVAD subjects was reduced 24.2% in ENDURANCE Supplemental compared with ENDURANCE (p = 0.10), and hemorrhagic cerebrovascular accident was reduced by 50.5% (p = 0.02). CONCLUSIONS: The ENDURANCE Supplemental Trial failed to demonstrate noninferiority of HVAD versus control regarding the pre-specified primary endpoint. However, the trial confirmed that BP management is associated with reduced stroke rates in HVAD subjects. HVAD subjects, relative to control subjects, more commonly achieved the composite endpoint (freedom from death, disabling stroke, and device replacement or urgent transplantation). (A Clinical Trial to Evaluate the HeartWareTM Ventricular Assist System [ENDURANCE SUPPLEMENTAL TRIAL] [DT2]; NCT01966458). PMID- 30007560 TI - Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. AB - OBJECTIVES: This study aimed to determine temporal trends in the incidence of and mortality associated with heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart rate with preserved ejection fraction [HFpEF]) in the community. BACKGROUND: Major shifts in cardiovascular disease risk factor prevalence and advances in therapies may have influenced HF incidence and mortality. METHODS: In the FHS (Framingham Heart Study) and CHS (Cardiovascular Health Study), for participants who were >=60 years of age and free of HF (n = 15,217; 60% women; 2,524 incident HF cases; 115,703 person-years of follow-up), we estimated adjusted incidence rate ratios of HF, HFrEF, and HFpEF from 1990 to 1999 and 2000 to 2009. We compared the cumulative incidence of and mortality associated with HFrEF versus HFpEF within and between decades. RESULTS: Across the 2 decades, HF incidence rate ratio was similar (p = 0.13). The incidence rate ratio of HFrEF declined (p = 0.0029), whereas HFpEF increased (p < 0.001). Although HFrEF incidence declined more in men than in women, men had a higher incidence of HFrEF than women in each decade (p < 0.001). The incidence of HFpEF significantly increased over time in both men and women (p < 0.001 and p = 0.02, respectively). During follow-up after HF, 1,701 individuals died (67.4%; HFrEF, n = 557 [33%]; HFpEF, n = 474 [29%]). There were no significant differences in mortality rates (overall, cardiovascular disease, and noncardiovascular disease) across decades within HF subtypes or between HFrEF and HFpEF within decade. CONCLUSIONS: In several U.S. community-based samples from 1990 to 2009, we observed divergent trends of decreasing HFrEF and increasing HFpEF incidence, with stable overall HF incidence and high risk for mortality. Our findings highlight the need to elucidate factors contributing to these observations. PMID- 30007563 TI - Design, synthesis and evaluation of novel sophoridinic imine derivatives containing conjugated planar structure as potent anticancer agents. AB - Based on our previous study and the binding mode of camptothecin with Topo I, a series of novel sophoridine imine derivatives containing conjugated planar structure were designed, synthesized and tested for their in vitro anticancer activity. The results showed that most of the derivatives displayed potent activity. In particular, compounds 10b exhibited excellent anti-proliferative activities with IC50 5.7 uM and 8.5 uM against HepG-2 and HeLa cell lines, respectively. Molecular docking studies revealed that the introduction of conjugated planar structure could form pi-pi stacking interaction with DNA, leading to the improvement of biological activity. Its mode of action was to inhibit the activity of DNA Topo I, followed by the G0/G1 phase arrest. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound and 10b could emerge as promising lead compounds for the development of novel Topo I inhibitors. PMID- 30007562 TI - All Eyes and Ears for Gene Therapy. PMID- 30007561 TI - AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington's Disease Minipig Model. AB - Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Previously, we showed strong huntingtin reduction and prevention of neuronal dysfunction in HD rodents using an engineered microRNA targeting human huntingtin, delivered via adeno associated virus (AAV) serotype 5 vector with a transgene encoding an engineered miRNA against HTT mRNA (AAV5-miHTT). One of the challenges of rodents as a model of neurodegenerative diseases is their relatively small brain, making successful translation to the HD patient difficult. This is particularly relevant for gene therapy approaches, where distribution achieved upon local administration into the parenchyma is likely dependent on brain size and structure. Here, we aimed to demonstrate the translation of huntingtin-lowering gene therapy to a large-animal brain. We investigated the feasibility, efficacy, and tolerability of one-time intracranial administration of AAV5-miHTT in the transgenic HD (tgHD) minipig model. We detected widespread dose-dependent distribution of AAV5-miHTT throughout the tgHD minipig brain that correlated with the engineered microRNA expression. Both human mutant huntingtin mRNA and protein were significantly reduced in all brain regions transduced by AAV5-miHTT. The combination of widespread vector distribution and extensive huntingtin lowering observed with AAV5-miHTT supports the translation of a huntingtin-lowering gene therapy for HD from preclinical studies into the clinic. PMID- 30007564 TI - Anti-acute myeloid leukemia activity of 2-chloro-3-alkyl-1,4-naphthoquinone derivatives through inducing mtDNA damage and GSH depletion. AB - 2-Chloro-3-alkyl-1,4-naphthoquinone derivatives were synthesized and tested as the anti-acute myeloid leukaemia agents. The compound 9b (2-chloro-3-ethyl-5,6,7 trimethoxy-1,4-naphthoquinone) was the most potent toward HL-60 leukaemia cells. In mechanistic study for 9b, the protein levels of mtDNA-specific DNA polymerase gamma (poly-gamma) and mtDNA transcription factor A (mt-TFA) were decreased after the 24 h treatment, showing the occurrence of mtDNA damage. And 9b triggered cell cycle arrest at S phase accompanied by a secondary block in G2/M phase which had a direct link to the process of mtDNA damage. The dissipations of mitochondrial membrane potential and ATP also proceeded. On the other hand, 9b promoted the generation of ROS and resulted in the oxidation of intracellular GSH to GSSG. This process was coupled to the formation of adduct between 9b and GSH, detected by the UV-Vis spectrum and HRMS analysis. Depletion of GSH by buthionine sulfoximine enhanced ROS level and produced higher cytotoxicity, suggesting GSH was involved in the anti-leukemic mechanism of 9b. Together, our results provide new insights on the molecular mechanism of the derivatives of 2-chloro-1,4 naphthoquinone and 9b might be useful for the further development into an anti leukemia agent. PMID- 30007565 TI - Activation studies with amines and amino acids of the alpha-carbonic anhydrase from the pathogenic protozoan Trypanosoma cruzi. AB - The activation of a alpha-class carbonic anhydrase (CAs, EC 4.2.1.1) from Trypanosoma cruzi (TcCA) was investigated with the best known classes of activators, the amino acids and aromatic/heterocyclic amines. The best TcCA activators were l-/d-DOPA and 4-amino-l-phenylalanine, which had activation constants in the range of 0.38-0.83 uM. Low micromolar activators were also l-/d Trp, l-/d-Tyr, l-Gln, histamine and serotonin (KAs of 1.79-4.92 uM), whereas l-/d His, l-/d-Phe and l-Asp were less effective activators (KAs of 6.39-18.7 uM). Amines such as dopamine, pyridyl-alkylamines, aminoethyl-piperazine or l adrenaline, were devoid of activating effects on TcCA. Since the role of autacoids as many of these compounds investigated here is not known for the life cycle of T. cruzi, our work provides new tools for further investigations of factors connected with this protozoan pathogen infection. PMID- 30007566 TI - Stereospecific reduction of the butenolide in strigolactones in plants. AB - Reductive metabolism of strigolactones (SLs) in several plants was investigated. Analysis of aquaculture filtrates of cowpea and sorghum each fed with four stereoisomers of GR24, the most widely used synthetic SL, revealed stereospecific reduction of the double bond at C-3' and C-4' in the butenolide D-ring with preference for an unnatural 2'S configuration. The cowpea metabolite converted from 2'-epi-GR24 and the sorghum metabolite converted from ent-GR24 had the methyl group at C-4' in the trans configuration with the substituent at C-2', different from the cis configuration of the synthetic H2-GR24 reduced with Pd/C catalyst. The plants also reduced the double bond in the D-ring of 5-deoxystrigol isomers with a similar preference. The metabolites and synthetic H2-GR24 stereoisomers were much less active than were the GR24 stereoisomers in inducing seed germination of the root parasitic weeds Striga hermonthica, Orobanche crenata, and O. minor. These results provide additional evidence of the importance of the D-ring for bioactivity of SLs. PMID- 30007567 TI - Design, synthesis and docking study of 4-arylpiperazine carboxamides as monoamine neurotransmitters reuptake inhibitors. AB - Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied. PMID- 30007568 TI - Activity of steroid 4 and derivatives 4a-4f as inhibitors of the enzyme 5alpha reductase 1. AB - It is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5alpha-reductase (5alpha-R1) activity than type 2 5alpha-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues. Thus, in order to potentially improve the prognosis of this disease, in this work, seven derivatives of 17-(1H-benzimidazol-1-yl)-16 formillandrosta-5,16-dien-3beta-yl benzoate (4a-f) and 17-(1H-benzimidazol-1-yl) 3-hydroxy-16-formylandrost-5,16-diene (4) were synthesized, characterized and identified as inhibitors of type 1 5alpha-reductase (5alphaR1). These derivatives having the advantage of improved plasma half-life. The inhibitory activity of the compounds towards 5alpha-R1 isoenzyme was determined by conversion of T into DHT in the presence or absence of compounds 4, 4a-f. Further, in vivo experiments were also carried out, treating gonadectomized hamsters with T and/or 4, 4a-f and evaluating their effect on the diameter of hamster flank organs and on the weight of the prostatic and seminal vesicles. Results indicated that compounds 4, 4b, 4c, served as in vitro inhibitors of the enzyme 5alpha-R1 and pharmacological experiments showed that 4 and derivatives 4a-f decreased the diameter of the flank glands, the weight of the prostate and seminal vesicles of treated hamsters without any appreciable toxicity during observation. Noteworthy the fact that compound 4 is the product, in all cases, of the hydrolysis of the series of esters 4a-f, thus they can serve as precursors (prodrugs) of the active form 4. PMID- 30007569 TI - Evidence for and Against Green Tea and Turmeric in the Management of Chronic Lymphocytic Leukemia. AB - Complementary and alternative medicine (CAM) is a diverse group of medical and health care systems, practices, and products that are not generally considered part of conventional medicine. Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in the western hemisphere, and 16.5% to 66% of patients have reported using CAM. Most patients use spiritual/mind-body techniques and high doses of vitamins and herbs (most commonly polyphenols, including teas). We have reviewed the reported data on green tea and turmeric use in CLL patients. PMID- 30007570 TI - Treatment of Older Patients With Newly Diagnosed AML Unfit for Traditional Therapy. AB - Older patients with acute myeloid leukemia represent at least one half of those with the disease for whom randomized clinical trials of new treatments are in development. These patients represent an appropriate population in which to evaluate new treatments against the current standards of care, which could be azacitidine, decitabine, or low-dose cytarabine. However, despite the identification of treatments that can deliver a worthwhile increase in remission, none has yet delivered a survival superiority when assessed in a randomized setting, although some recent efforts provide encouragement. PMID- 30007572 TI - Corrigendum to "Solid-phase synthesis of Biotin-S-Farnesyl-l-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)" [Bioorg. Med. Chem. Lett. 23 (2013) [5671-5673]. PMID- 30007573 TI - ? PMID- 30007571 TI - UV Chromosomes and Haploid Sexual Systems. AB - The evolution of sex determination continues to pose major questions in biology. Sex-determination mechanisms control reproductive cell differentiation and development of sexual characteristics in all organisms, from algae to animals and plants. While the underlying processes defining sex (meiosis and recombination) are conserved, sex-determination mechanisms are highly labile. In particular, a flow of new discoveries has highlighted several fascinating features of the previously understudied haploid UV sex determination and related mating systems found in diverse photosynthetic taxa including green algae, bryophytes, and brown algae. Analyses integrating information from these systems and contrasting them with classical XY and ZW systems are providing exciting insights into both the universality and the diversity of sex-determining chromosomes across eukaryotes. PMID- 30007574 TI - Effect of radiofrequency electromagnetic fields (RF-EMFS) from mobile phones on nickel release from orthodontic brackets: An in vitro study. AB - BACKGROUND: The worldwide dramatic increase in the use of cell phones has generated great concerns about their potential adverse health effects. OBJECTIVE: The aim of the present study was to evaluate the effects of radiofrequency electromagnetic fields (RF-EMFs) emitted from mobile phones on the level of nickel release from orthodontic brackets. METHODS: Twenty stainless steel brackets were divided randomly into experimental and control groups (n=10). Brackets were immersed in artificial saliva at 37 degrees C for 6 months. Experimental group were exposed to GSM 900MHz RF-EMFs emitted from a mobile phone stimulator for 4hours. The specific absorption rate (SAR) was 2.287W/kg. The concentration of nickel in the artificial saliva in both groups was evaluated by using the cold-vapour atomic absorption spectrometry. The Mann-Whitney test was used to assess significant differences in nickel release between the exposed and non-exposed groups. RESULTS: The mean nickel levels in the exposed and non exposed groups were 11.95 and 2.89MUg/l, respectively. This difference between the concentrations of nickel in the artificial saliva of these groups was statistically significant (P=0.001). CONCLUSION: Exposure to RF-EMFs emitted from mobile phones can lead to human exposure to higher levels of nickel in saliva in patients with orthodontic appliances. As nickel exposure can lead to allergic reaction in humans and considering this point that about 10-20% of the population can be hypersensitive to nickel, further studies are needed to evaluate the effects of radiofrequency electromagnetic fields (RF-EMFs) emitted from common devices such as mobile phones or Wi-Fi routers on the level of nickel release from orthodontic brackets. PMID- 30007576 TI - Detection of disbonds in multi-layer bonded structures using the laser ultrasonic pulse-echo mode. AB - The laser ultrasonic technique with a pulse-echo mode has been investigated to detect disbonds in a multi-layer bonded structure and a quantitative method has been proposed to evaluate the defect sizes. The simulations were carried out to analyze influences of spot sizes on the characteristics of laser ultrasonic reflected waves, the interaction of laser ultrasonic reflected waves with disbonds, and quantitative characterization on disbonds. A noncontact laser ultrasonic inspection system has been established to perform a series of experiments to verify the theoretical results. Laser ultrasonic C-scans based on reflected shear waves can clearly redraw appearances of disbonds in the adhesive bond. The proposed quantitative method can evaluate the sizes of disbonds within a reasonable error range. Moreover, the experimental data are in good agreement with the simulation results. Therefore, a combination of the laser ultrasonic pulse-echo mode and the proposed quantitative strategy is practical for accurate detection of disbonds in multi-layer bonded structures. PMID- 30007577 TI - One-step polymeric phononic crystal manufacture. AB - A versatile system to construct bulk polymeric phononic crystals by using acoustic waves is described. In order to fabricate this material, a customised cavity device fitted with a ~2 MHz acoustic transducer and an acoustic reflector is employed for the acoustic standing wave creation in the device chamber. The polymer crystal is formed when the standing waves are created during the polymerisation process. The resulting crystals are reproduced into the shape of the tunable device cavity with a unique periodic feature. The separation is related to the applied acoustic wave frequency during the fabrication process and each unit cell composition was found to be made up to two material phases. To assess the acoustic properties of the polymer crystals their average acoustic velocity is measured relative to monomer solutions of different concentrations. It is demonstrated that one of the signature characteristics of phononic crystal, the slow wave effect, was expressed by this polymer. Furthermore the thickness of a unit cell is analysed from images obtained with microscope. By knowing the thickness the average acoustic velocity is calculated to be 1538 m/s when the monomer/cross-linker concentration is 1.5 M. This numerical calculation closely agrees with the predicted value for this monomer/cross-linker concentration of 1536 m/s. This work provides a methodology for rapid accessing a new type of adaptable phononic crystal based on flexible polymers. PMID- 30007578 TI - Supernumerary breast cancer. PMID- 30007579 TI - Postherpetic pseudohernia. PMID- 30007575 TI - The Predictive Coding Account of Psychosis. AB - Fueled by developments in computational neuroscience, there has been increasing interest in the underlying neurocomputational mechanisms of psychosis. One successful approach involves predictive coding and Bayesian inference. Here, inferences regarding the current state of the world are made by combining prior beliefs with incoming sensory signals. Mismatches between prior beliefs and incoming signals constitute prediction errors that drive new learning. Psychosis has been suggested to result from a decreased precision in the encoding of prior beliefs relative to the sensory data, thereby garnering maladaptive inferences. Here, we review the current evidence for aberrant predictive coding and discuss challenges for this canonical predictive coding account of psychosis. For example, hallucinations and delusions may relate to distinct alterations in predictive coding, despite their common co-occurrence. More broadly, some studies implicate weakened prior beliefs in psychosis, and others find stronger priors. These challenges might be answered with a more nuanced view of predictive coding. Different priors may be specified for different sensory modalities and their integration, and deficits in each modality need not be uniform. Furthermore, hierarchical organization may be critical. Altered processes at lower levels of a hierarchy need not be linearly related to processes at higher levels (and vice versa). Finally, canonical theories do not highlight active inference-the process through which the effects of our actions on our sensations are anticipated and minimized. It is possible that conflicting findings might be reconciled by considering these complexities, portending a framework for psychosis more equipped to deal with its many manifestations. PMID- 30007580 TI - Autologous falciform ligament graft for vascular reconstruction in pancreatic cancer surgery. PMID- 30007581 TI - Asking different questions: A call to action for research to improve the quality of care for every woman, every child. PMID- 30007582 TI - [Infectious cellulitis of the penis and scrotum]. PMID- 30007585 TI - Effectiveness of primary healthcare educational interventions undertaken by nurses to improve chronic disease management in patients with diabetes mellitus, hypertension and hypercholesterolemia: A systematic review. AB - BACKGROUND: Diabetes, hypertension and hypercholesterolemia are important chronic health problems that are becoming increasingly frequent worldwide. Educational interventions are a challenge for health teams. Nurses play a major role in overall health by providing educational interventions to help improve self management outcomes. OBJECTIVES: To evaluate the effectiveness of primary health care educational interventions undertaken by nurses to improve metabolic control and/or chronic disease management in individuals with Type 2 diabetes mellitus, hypertension, and hypercholesterolemia. METHODS: The methodology drew on systematic review without meta-analyses, methods developed by the Cochrane Collaboration. Elements related to content were chosen following the PRISMA statement. The databases of Pubmed, Web of Science, CINAHL, PsycInfo, Cuiden, Enfispo, and the Cochrane Library were consulted. Reference lists from relevant articles were also examined for additional references. Three authors independently assessed eligibility of studies for inclusion. A review of randomised controlled trials published between 2000 and 2015 was undertaken. Furthermore, an analysis of selected studies was carried out, in which nurses actively participated in the implementation of educational interventions in primary health care centres in order to improve control and chronic disease management in Type 2 diabetes mellitus, hypertension and hypercholesterolemia. RESULTS: Out of the 20 studies included in the systematic review, one had a low risk of bias, 14 an uncertain risk of bias, and five a high risk of bias. Although several studies showed significant changes in the measured variables, few significant differences were maintained over time, observed only in metabolic indicators and clinical variables more than in lifestyle behaviour. In addition, although most of the studies dealt with issues related to lifestyle behaviours such as nutrition, physical activity, and tobacco and alcohol use, few measured changes after the intervention. Finally, the difficulty in comparing the studies included in the review laid in the heterogeneity in educational strategies, the evaluation methods used, and the disparity of assessment tools, which made it difficult to establish the characteristics of the most effective interventions during the time of treatment for diabetes, hypertension, and hypercholesterolemia. CONCLUSIONS: Although there are numerous interventions that aim to control diabetes, hypertension, and hypercholesterolemia, the observation was that the results obtained are difficult to maintain over time. Therefore, it is necessary to continue to create high-quality interventions, with a low risk of bias and based on solid theoretical frameworks, not only to treat current symptoms of the disease but also to help prevent cardiovascular disease. PMID- 30007583 TI - Dynamics of Dystrophin's Actin-Binding Domain. AB - We have used pulsed electron paramagnetic resonance, calorimetry, and molecular dynamics simulations to examine the structural mechanism of binding for dystrophin's N-terminal actin-binding domain (ABD1) and compare it to utrophin's ABD1. Like other members of the spectrin superfamily, dystrophin's ABD1 consists of two calponin-homology (CH) domains, CH1 and CH2. Several mutations within dystrophin's ABD1 are associated with the development of severe degenerative muscle disorders Duchenne and Becker muscular dystrophies, highlighting the importance of understanding its structural biology. To investigate structural changes within dystrophin ABD1 upon binding to actin, we labeled the protein with spin probes and measured changes in inter-CH domain distance using double electron electron resonance. Previous studies on the homologous protein utrophin showed that actin binding induces a complete structural opening of the CH domains, resulting in a highly ordered ABD1-actin complex. In this study, double electron electron resonance shows that dystrophin ABD1 also undergoes a conformational opening upon binding F-actin, but this change is less complete and significantly more structurally disordered than observed for utrophin. Using molecular dynamics simulations, we identified a hinge in the linker region between the two CH domains that grants conformational flexibility to ABD1. The conformational dynamics of both dystrophin's and utrophin's ABD1 showed that compact conformations driven by hydrophobic interactions are preferred and that extended conformations are energetically accessible through a flat free-energy surface. Considering that the binding free energy of ABD1 to actin is on the order of 6-7 kcal/mole, our data are compatible with a mechanism in which binding to actin is largely dictated by specific interactions with CH1, but fine tuning of the binding affinity is achieved by the overlap between conformational ensembles of ABD1 free and bound to actin. PMID- 30007586 TI - Retraction notice to "Sun exposure related methylation in malignant and non malignant skin lesions" [Cancer Letters 245/1-2 (2007) 112-120]. PMID- 30007587 TI - A novel method for imminent crash prediction and prevention. AB - A crash prediction and prevention method was proposed to detect imminent crash risk and help recommend traffic control strategies to prevent crashes. The method consists of two modules, the crash prediction module and the crash prevention module. The crash prediction module detects crash-prone conditions when the predicted crash probability exceeds a specified threshold. Then the crash prevention module would simulate the safety effect of traffic control alternatives and recommend the optimal one. The proposed method was demonstrated in a case study with variable speed limit (VSL). Results showed that the proposed crash prediction and prevention method could effectively detect crash-prone conditions and evaluate the safety and mobility impacts of various safety countermeasures. PMID- 30007584 TI - A Database of Predicted Binding Sites for Cholesterol on Membrane Proteins, Deep in the Membrane. AB - The outer membranes of animal cells contain high concentrations of cholesterol, of which a small proportion is located deep within the hydrophobic core of the membrane. An automated docking procedure is described that allows the characterization of binding sites for these deep cholesterol molecules on the membrane-spanning surfaces of membrane proteins and in protein cavities or pores, driven by hydrogen bond formation. A database of this class of predicted binding site is described, covering 397 high-resolution structures. The database includes sites on the transmembrane surfaces of many G-protein coupled receptors; within the fenestrations of two-pore K+ channels and ATP-gated P2X3 channels; in the central cavities of a number of transporters, including Glut1, Glut5, and P glycoprotein; and in deep clefts in mitochondrial complexes III and IV. PMID- 30007588 TI - Ictal nose wiping in childhood absence epilepsy: A case series. PMID- 30007589 TI - Spastic paraparesis as the first manifestation of Machado-Joseph disease: A case report and review of the literature. AB - Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3, is characterized by remarkable clinical heterogeneity. We present a MJD family in which variable phenotypes were noted in affected members, including one presenting predominantly with spastic paraparesis. A review of the literature revealed that MJD with the initial presentation of spastic paraparesis is more frequently observed in cases of eastern Asian origin who carry a greater CAG expansions in the ATXN3 gene. A greatly expanded allele in ATXN3 combined with an eastern Asian genetic background is associated with a phenotype of spastic paraparesis in MJD. PMID- 30007590 TI - Lower motor neuron syndrome in a patient with HER2-positive metastatic breast cancer: A case report and review of the literature. AB - Paraneoplastic neurological syndromes are very rare and often associated to breast, ovarian and small cells lung cancers. Paraneoplastic motor neuron diseases (MNDs) are even rarer, and frequently described in patients with breast cancer. We presented the first case of patient affected by HER2-positive breast tumor and possible paraneoplastic lower motor neuron disease. In literature, few cases are reported but no one highlights the tumor receptors' profile. Instead, HER2-positive breast cancers are prone to be related to anti-Yo-associated paraneoplastic cerebellar disorders. Anti-onconeural antibodies positivity can be rarely found, confirming that paraneoplastic MND have no specific biomarkers. The presence of CSF oligoclonal bands (OBs) suggests the presence of immune-mediated mechanism, in absence of other possible OBs causes. PMID- 30007592 TI - The Suicidal Outpatient: Balancing Autonomy, Trust, and Responsibilities. PMID- 30007593 TI - Molecular deformation of wood and cellulose studied by near infrared spectroscopy. AB - Wood (Eucalyptus regnans and Pinus radiata) and paper samples were stretched to different strain levels using a purpose-built tensile test device fitted into a near infrared (NIR) spectrometer while collecting transmission spectra. Consistent spectral changes caused by mechanical strain, assigned to OH stretching bands, were observed for all three sample types. Bands at 6286 +/- 5 cm-1 and 6470 +/- 10 cm-1 were tentatively assigned to the OH groups connected with the 2OH?6O and 3OH?5O intramolecular hydrogen bonds of crystalline cellulose Ibeta, respectively. Both bands shifted to higher wavenumbers indicating the elongation of the hydrogen bonds. A linear relationship was found between band shifts and mechanical strain. Band shift rates for the 3OH bond were more than twice that of the 2OH bond, consistent with bending of the glycosidic bond. Bending tests showed that the band at around 6286 cm-1 shifted in opposite direction when under tension or compression. PMID- 30007591 TI - Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. AB - In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma. PMID- 30007594 TI - Magnetic extraction and purification of DNA from whole human blood using a gamma Fe2O3@Chitosan@Polyaniline hybrid nanocomposite. AB - We examined the properties of the nanocomposite gamma-Fe2O3@Chi@Pani as an adsorbent of deoxyribonucleic acid (DNA). As a model system, we used an aqueous solution of salmon sperm DNA, whose decreasing concentration was followed by monitoring the 260 nm UV-vis absorption. After adjusting the data collected to a Langmuir isotherm curve, we estimated the adsorption capacity (qe) of the nanocomposite as 49.5 mg/g. We also observed that the kinetic model of the DNA capture presents a mixed character, with both chemical mechanisms and intraparticle diffusion processes involved. When the MNC was used to extract the DNA from complex samples (human blood), a capture rate of 80 ng/MUL was achieved, with the collected fraction exhibiting good quality, as evaluated by PCR analysis and electrophoresis assays. These results suggest that the gamma-Fe2O3@Chi@Pani nanocomposite is a promising adsorbent for use in protocols for purification of DNA from complex samples. PMID- 30007595 TI - Ionic coupling of hyaluronic acid with ethyl N-lauroyl l-arginate (LAE): Structure, properties and biocide activity of complexes. AB - Ethyl alphaN-lauroyl l-arginate hydrochloride (LAE) was coupled with hyaluronic acid (HyA) to form ionic complexes with LAE to HyA ratios of 1:1 and 1:2. The complexes were extensively characterized by FTIR and NMR spectroscopies and their thermal properties evaluated by thermogravimetry and calorimetry. Thin films prepared from these complexes by casting displayed a smectic-like structure based on an ordered arrangement of LAE and HyA layers with a nanometric periodicity of 3.8-3.9 nm. Films immersed in water at pH 7.4 and 5.5 dissociated to deliver free LAE to the environment and reaching the equilibrium in few hours. The biocide activity of these films against both Gram-positive and Gram-negative bacteria was preliminary assessed by the liquid medium method, and shown to be notable in both cases. The antibacterial property of the complexes was found to increase with the content of LAE and to be particularly efficient against Gram-negative S. enterica bacteria. PMID- 30007596 TI - Folic acid-conjugated chitosan oligosaccharide-magnetic halloysite nanotubes as a delivery system for camptothecin. AB - In this research, to achieve enhanced intracellular uptake of anticancer drug carriers for efficient chemotherapy, folic acid conjugated chitosan oligosaccharides assembled magnetic halloysite nanotubes (FA-COS/MHNTs) have been tailored as multitask drug delivery system towards camptothecin (CPT). Besides magnetic targeting, the nanocomposites have been reacted with folate complex in order to selectively target cancer cells over expressing the folic acid receptor. HNTs showed to have a high storage capacity of CPT. In vitro, the release results indicated that CPT outflow from the nanocarriers at pH 5 was much greater than that at both pH 6.8 and 7.4. MTT assays showed that the CPT-loaded nanocarriers exhibited stronger cell growth inhibitory against colon cancer cell. Furthermore, nanocarriers gained specificity to target cancer cells because of the enhanced cell uptake mediated by FA moiety and presence of COS. Therefore, the rational designed HNTs nanocarrier for chemotherapy drug showed great potential as tumor targeted drug delivery carrier. PMID- 30007597 TI - Preparation and properties of chitosan/guar gum/nanocrystalline cellulose nanocomposite films. AB - Nanocrystalline cellulose (NCC) has shown great potential for reinforcing nanocomposite systems, particularly in biopolymer-based nanocomposites. In the present work, transparent and biodegradable chitosan (CH)/guar gum (GG)/NCC nanocomposite films were designed and prepared. The effect of NCC loadings on the rheological behavior of the as-prepared nanocomposite suspensions was investigated, the overall properties of the resultant nanocomposite films as a function of various amounts of NCC were determined, and the surface morphology of various nanocomposite films was characterized by scanning electron microscopy (SEM). Results indicated that the increased NCC loadings increased the shear viscosity of the nanocomposite suspensions. Moreover, as expected, the obtained CH/GG/NCC nanocomposite films were found to exhibit improved tensile strength and reduced air permeability in comparison to pure CH/GG films. This work supported the conclusion that NCC was effective in reinforcing the CH/GG composite films, which may be a promising material for food packaging applications. PMID- 30007598 TI - A green approach of improving interface and performance of plant fibre composites using microcrystalline cellulose. AB - In contrast to the conventional methods of improving interface and performances of plant fibre composites through fibre surface modification, this paper reports a novel approach based on the dispersion of microcrystalline cellulose (MCC) in the composite's matrix. MCC was dispersed within the matrix of jute fibre reinforced epoxy composites to improve the fibre/matrix interface as well as mechanical, dynamic-mechanical and thermal performances. To develop these novel jute/epoxy/MCC hierarchical composites, MCC was first dispersed within an epoxy resin using a short ultrasonication process (1 h) and subsequently, the MCC/epoxy suspensions were infused through jute fabrics using the vacuum infusion technique and cured. Hierarchical composites by dispersing multi-walled carbon nanotubes (MWCNTs) within the epoxy resin were also fabricated to compare their performance with MCC based hierarchical composites. Interface (single fibre pull-out test), mechanical (tensile, flexural, izod impact), thermal (thermogravimetric analysis) and dynamic mechanical performances of the developed composites were thoroughly studied. It was observed that the addition of MCC to the epoxy matrix led to a significant increase in the interfacial shear strength (IFSS) between jute fibres and the epoxy matrix and consequently, resulted up to 18.4%, 21.5%, 28.3%, 67% and 49.5% improvements in the tensile strength, flexural strength, impact energy, storage and loss moduli, respectively as compared to the neat jute/epoxy composites. The above improvements achieved with MCC were significantly higher as compared to the MWCNT based hierarchical composites developed using the same technique. PMID- 30007599 TI - Structural characteristics and bioactive properties of a novel polysaccharide from Flammulina velutipes. AB - A new water-soluble polysaccharide (FVP1) was extracted from Flammulina velutipes by traditional method "water extraction and alcohol precipitation" and purified by column chromatography. Physicochemical characterization showed that FVP1 was a homogeneous polysaccharide with a relative molecular weight of 54.78 kDa. It is composed of mannose (7.74%), glucose (70.41%), and galactose (16.38%). FVP1 (1000 mg/mL) possessed significant immune activity by increasing the secretion of nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha) (3183 +/- 133.84 pg/mL), interleukin (IL)-6 (1133.21 +/- 39.05 pg/mL), and IL-12 (579.96 +/- 74.53 pg/mL) in macrophages. Furthermore, FVP1 showed significant hepatitis B surface antibody (anti-HBV) activity through reducing the expression of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA replication. These results suggest a novel role for FVP1 to be applied as an immunomodulators in dietary supplements to prevent HBV infection. PMID- 30007600 TI - Fabrication of acetylated carboxymethylcellulose coated hollow mesoporous silica hybrid nanoparticles for nucleolin targeted delivery to colon adenocarcinoma. AB - To efficiently deliver the chemotherapeutics to the tumor tissue and minimize the associated adverse effects, nucleolin targeted hybrid nanostructure based on hollow mesoporous silica nanoparticles (HMSNs) were fabricated. To provide the controlled, sustained drug release and enhance blood circulation, the surface of doxorubicin-encapsulated HMSNs were coated with acetylated carboxymethyl cellulose (Ac-CMC) and then covalently conjugated to AS1411 aptamer for guided drug delivery to nucleolin overexpressed cancerous cells. In vitro cellular uptake and cytotoxicity studies confirmed that AS1411 aptamer specifically targets nucleolin overexpressing MCF-7 and C26 cells. Moreover, the in vivo tumor inhibitory effect of AS1411 aptamer conjugated formulation demonstrated a superior therapeutic efficiency over non-targeted formulation and free doxorubicin. The current study might open a new insight to the development of targeted intelligent hybrid materials based on AcCMC-coated HMSNs with high loading capacity, smart characteristics and desirable anticancer potential. PMID- 30007601 TI - Eucalyptus xylan: An in-house-produced substrate for xylanase evaluation to substitute birchwood xylan. AB - Over the past decades, most studies with xylanases have used Birchwood xylan as the standard substrate for activity assays. However, recently, Birchwood xylan production was discontinued by major suppliers, creating an important demand for a substitute. Ongoing and future studies require a substrate with characteristics equivalent to the discontinued xylan, in order to enable the comparison of results. In this context, a protocol for the production of a substrate similar to the discontinued commercial Birchwood xylan is reported. Obtained from bleached Eucalyptus cellulose pulp, xylan was extracted using 4% w/v NaOH solution at 25 degrees C, precipitated with glacial acetic acid (HOAc), and freeze-dried. A thermal pretreatment in an autoclave for 15 min increased its solubility. The resulting xylan was characterized by infrared spectroscopy, thermogravimetry, and NMR. When assessing the activity of xylanases, the results were the same as those for commercial Birchwood xylan. PMID- 30007603 TI - Properties of pectin extracted from fermented and steeped hawthorn wine pomace: A comparison. AB - To investigate the characteristics of the pectins from fermented and steeped hawthorn wine pomace (FHP and SHP), they were acid-extracted, respectively, and compared detailedly. The results of esterification degree indicated that these two pectins were both defined as high methoxyl pectin, which was confirmed by Fourier transform infrared spectroscopy analysis. Molecular weight of SHP was higher than that of FHP. Differential scanning calorimetry analysis showed that the melt temperature of SHP was lower than that of FHP, and the molecular arrangement of SHP is more orderly than FHP. FHP and SHP solutions exhibited shear-thinning properties but SHP had a stronger anti-shear ability. FHP tended to be more elastic-solid as the concentration increased, which was not prominent in SHP. This study suggested that FHP and SHP powder could be new sources of pectin and both pectins could be potentially used as a thicker and stabilizer in food processing. PMID- 30007602 TI - Fenton-like nanocatalyst for photodegradation of methylene blue under visible light activated by hybrid green DNSA@Chitosan@MnFe2O4. AB - High efficient 3,5-Dinitrosalicylic acid/Chitosan/MnFe2O4 (DNSA@CS@MnFe2O4) nano photocatalyst was prepared to enrich both adsorption and photodecomposition under visible light. This paper focused on the importance of DNSA@CS as an excellent connector between methylene blue (MB) and MnFe2O4 for accelerating photodegradation with the encouragement of photo-Fenton catalytic reagent hydrogen peroxide (H2O2). The optimum conditions were: contact time, 30 min, H2O2 concentration, 0.16 M, pH factor 9 and dosage 0.06 g/l at R.T, allowing excellent catalytic achievements 98.9% degree of decolorization in 30 min. More interestingly, the hybrid DNSA@CS@MnFe2O4 mechanism explained on the basis of coexistence of Mn2+/Mn3+ and Fe3+/Fe2+ redox couples during the reaction. The photocatalytic decolorization experimentally affirmed the suitability of DNSA@CS@MnFe2O4 obeying Langmuir-Hinshelwood model. Also, the nano-catalytic system was stable even after five runs. The prepared nanostructured catalyst provides simple fabrication to promote deep understand criteria for the mechanistic role of MnFe2O4 catalyst for degradation of MB molecules. PMID- 30007604 TI - Fabrication of novel bioactive hydroxyapatite-chitosan-silica hybrid scaffolds: Combined the sol-gel method with 3D plotting technique. AB - Sol-gel derived organic/inorganic hybrids, in which organic and inorganic components form co-networks at the molecular level, have demonstrated great potential for providing improved mechanical properties and biological functions in tissue engineering applications. Here, a novel bioactive hydroxyapatite chitosan-silica hybrid (HA-CSH) scaffold was successfully fabricated by combining the sol-gel method and 3D plotting technique. Physiochemical characterization confirmed that chitosan was hybridized homogeneously with the inorganic phase on nanoscale. The obtained scaffolds possessed precisely controllable and interconnected porous structures. The nano-sized HA formed in situ and dispersed uniformly in the hybrid network, which reduced the water absorption and increased the mechanical strength of the hybrid scaffold under humidity condition as compared to chitosan-silica hybrid (CSH) scaffold. Compression tests showed that the 3D plotted hybrid scaffolds under wet conditions had compressive strengths of 10-13 MPa and elastic moduli of 21-27 MPa and thus met the mechanical requirements of human trabecular bone. Studies on the mineralization process under simulated body fluid (SBF) conditions confirmed that the introduction of HA obviously increased the biological activity of hybrid scaffolds. In vitro cell results indicated that the HA-CSH scaffold not only supported adhesion and proliferation of mouse bone mesenchymal stem cells (mBMSCs), but also improved the osteoinductivity. The alkaline phosphatase activity and mineral deposition on the HA-CSH scaffold were higher than those on the CSH scaffold. These results suggested that the 3D plotted HA-CSH scaffold may be a promising bioactive material for bone tissues regeneration. PMID- 30007605 TI - Multifunctional self-assembled micelles of galactosamine-hyaluronic acid-vitamin E succinate for targeting delivery of norcantharidin to hepatic carcinoma. AB - A polymer of Galactosamine-hyaluronic acid-Vitamin E succinate (Gal-HA-VES) was designed to prepare multifunctional self-assembled micelles for delivery of Norcantharidin (NCTD) to Hepatic carcinoma. NCTD/Gal-HA-VES showed higher cytotoxicity toward CD44-overexpressing MCF-7 cells, MCF-7/Adr cells and ASGP-R overexpressing HepG2 cells, consistent with the enhanced cellular uptake in the selected cell models, indicating Gal-HA-VES micelles were taken up in MCF-7 and HepG2 cells by CD44 and ASGPR receptor mediated endocytosis, respectively. Moreover, the accumulation of Rhodamine 123 demonstrated that Gal-HA-VES has the same action of TPGS as a P-glycoprotein inhibitor blocked drug efflux-related MDR mechanism in resistant MCF-7/Adr cells. The Cell apoptosis assays indicated that NCTD/Gal-HA-VES were more effective in triggering apoptosis, compared with free NCTD or NCTD/HA-VES groups. In vivo study demonstrated that NCTD/Gal-HA-VES group exhibited enhanced tumor targeting and antitumor activity with lower systemic toxicity. Hence NCTD/Gal-HA-VES micelles system can achieve significant tumor targeting and effective treatment of hepatic carcinoma. PMID- 30007606 TI - Green and facile surface modification of cellulose nanocrystal as the route to produce poly(lactic acid) nanocomposites with improved properties. AB - In this study, lactic acid monomer or dimer is grafted onto CNC by a simple esterification reaction. The quantitative solid-state 13C NMR spectrum suggests that more than 87% of all the available OH groups on the surface of CNC are substituted by lactic acid. Such modified CNC (CNC-g-LA) exhibits excellent thermostability and nano-sized dispersion in chloroform. Benefit from this character, fully biobased PLLA/CNC-g-LA nanocomposite could be prepared simply by a solution-casting method. The crystallization behavior of obtained nanocomposites has been systematically investigated by differential scanning calorimetry (DSC). The results show that the crystallization rate of PLLA is distinctly enhanced. Moreover, the mechanical properties of nanocomposites are also improved remarkably by the addition of CNC-g-LA because of its excellent dispersion and compatibility with PLLA matrix. This study provides a green and facile way to modify CNC for fabricating bio-nanocomposites with fast crystallization rate and improved mechanical properties. PMID- 30007607 TI - Characterization and hypoglycemic effect of a neutral polysaccharide extracted from the residue of Codonopsis Pilosula. AB - A neutral polysaccharide coded as CERP1 was extracted and purified from the residue of Codonopsis pilosula by ethanol precipitation and column chromatography. The structure of CERP1 was determined by HPAEC-PAD, HPLC, HPSEC MALLS, FT-IR, NMR, and TEM. The results showed that CERP1 was a heteropolysaccharide composed of Arabinose, Glucose, and Galactose in the ratio of 1.00:19.83:6.94. HPSEC-MALLS showed that CERP1 was homogeneous with an absolute molecular weight of 4.840 * 103 Da. The NMR results and the GC-MS result of methylation indicated that 1-linked beta-d-glucose, 1,3-linked beta-d-glucose, 1,6-linked beta-d-glucose and 1,3,6-linked beta-d-galactose were the main linkages in CERP1. TEM results indicated that CERP1 had a homogeneous particle size and good dispersibility both in purified water and 0.05 M sodium sulfate. Pre-treatment with CERP1 could result in a significant improvement of the insulin secretion of the INS-1 cells. While in vivo assays, CERP1 exhibited a potent hypoglycemic effect on T2DM mice for its ability to relieve oxidative stress, ameliorate lipid metabolism, increase glycolytic enzyme activity as well as decrease liver transaminase activity. This study gives a chance for exploring the residue of Codonopsis pilosula. PMID- 30007608 TI - Development of Ag/AgX (X = Cl, I) nanoparticles toward antimicrobial, UV protected and self-cleanable viscose fibers. AB - In situ synthesis of Ag/AgX nanoparticles (NPs) onto viscose fibers adds new functionalities and broadens their applications. In this study, Ag/AgX (X = Cl, I) NPs were in situ synthesized onto viscose fibers to impart brilliant colors, UV-protection, antimicrobial, self-cleaning, and photocatalytic properties. The AgX NPs were deposited on the fibers by ultrasonic irradiation, while Ag-NPs were formed by photoreduction of excess Ag+ ions under UV irradiation. The Ag/AgX NPs loaded onto viscose fibers endowed with pale yellow for Ag/AgI and pale purple/violet for Ag/AgCl. The colored viscose fibers showed excellent antimicrobial activity against Escherichia coli (gram-negative), Staphylococcus aureus (Gram positive), and Candida Albican. The Ag/AgX/viscose fiber also showed excellent photocatalytic and self-cleaning activity toward degradation of methylene blue. PMID- 30007610 TI - Physicochemical characterization of several types of naturally colored cotton fibers from Peru. AB - Elemental composition, physical dimensions (length and apparent diameter), and crystallinity of different types of naturally colored cotton (NCCs) fibers from Peru were investigated using a CHNS organic elemental analyzer, optical microscopy and X-Ray Diffraction (XRD). Spectroscopic studies involving Fourier Transform Infrared Spectroscopy and X-Ray photoelectron spectroscopy (XPS) were conducted; and the thermal stability of cotton samples were also investigated. Results from organic elemental analyzer and XPS showed that cotton samples contain mainly carbon, oxygen and hydrogen, but darker color samples also presented nitrogen. It was also found that the white cotton sample exhibited the longest fibers whereas the darker color samples showed the shortest values in length. Interestingly, the crystallinity seems also decrease with color intensity of NCCs. Finally, the thermal stability of white cotton fibers was similar to those obtained for the NCCs. PMID- 30007609 TI - Fabrication and biocompatibility of agarose acetate nanofibrous membrane by electrospinning. AB - In the present paper, agarose acetate (AGA) nanofibrous membranes containing different weight percentages of beta-tricalcium phosphate (beta-TCP) were successfully developed through electrospinning. The fibers in the nanofibrous membranes had a rough surface due to the beta-TCP particles which were uniformly dispersed within or on the surface of AGA fibers. Rat-bone marrow-derived mesenchymal stem cells (rBMSCs) were cultured on the AGA based nanofibrous membranes while showed a good adhesion and proliferation. It was found that more rBMSCs were differentiated to osteoblast-like cells on the beta-TCP containing nanofibrous membranes compared with the single AGA membrane, and more alkaline phosphatase (ALP) and mineralized matrix could be detected when rBMSCs were cultured on the beta-TCP containing nanofibrous membranes. The nanofibrous membranes were implanted into Sprague-Dawley (SD) rats for biocompatibility test. Gross examination and histological analysis of the AGA based nanofibrous membranes results showed that there was less inflammatory response. All of experimental results suggested that the AGA based nanofibrous membranes had the great potential application in bone tissue engineering. PMID- 30007611 TI - Silver nanoparticles incorporated konjac glucomannan-montmorillonite nacre-like composite films for antibacterial applications. AB - Artificial nacre-like konjac glucomannan-Montmorillonite (KGM-MTM) composite films with 'brick and mortar' microstructures have been fabricated based on using KGM-MTM hybrid nanosheets as building blocks. In the designed fabrication procedure, we assembled hybrid building blocks with a thin layer of KGM coating on the MTM nanosheets to form KGM-MTM composite film via vacuum filtration. The nacre-like microstructures enhanced the light transmission performance and mechanical properties (Tensile strength: 116 MPa) of KGM-MTM composite films. Additionally, Ag nanoparticles (Ag NPs) can be incorporated into the layered structures of KGM-MTM composite films via an in situ reduced method. It was found that KGM-MTM-Ag composite films significantly suppress bacterial growth, which makes them potentially applicable as antimicrobial films in the biomedical field. PMID- 30007612 TI - Molecular interactions between 3,4-dihydroxyphenylglycol and pectin and antioxidant capacity of this complex in vitro. AB - This study explored the interaction of pectin with 3,4-dihydroxyphenylglycol (DHPG), a potent phenolic antioxidant naturally found in olive fruit, via encapsulation into pectinate beads. MALDI TOF-TOF analysis supported the formation of complexes between DHPG and pectin. A combination of covalent bonds (ester bonds) and non-covalent interactions, mostly hydrogen bonding, were suggested as the cause of DHPG-pectin complex formation. Free radical scavenging assays confirmed that DHPG maintained its antioxidant activity after complexation and after a digestion simulated in vitro with gastric and intestinal fluids. Therefore, DHPG-pectin beads could reach the large intestine and contribute to a healthy antioxidant environment. PMID- 30007613 TI - Characterisation of pectin-xylan complexes in tomato primary plant cell walls. AB - The primary plant cell wall is composed of a complex network of pectin, hemicellulose and cellulose. Potential interactions between these polysaccharides were studied for carrot, tomato and strawberry, with a focus on the role of pectin. The Chelating agent Unextractable Solids (ChUS), the residue after water- and EDTA extraction, was ball milled and subsequently water extracted. For tomato and strawberry, pectin and substantial amounts of hemicellulose were solubilised. Anion exchange chromatography (AEC) showed co-elution of pectin and acetylated glucuronoxylan in tomato, representing 18% of solubilised uronic acid and 48% of solubilised xylose by ball milling from ChUS. The existence of a covalently linked pectin-xylan complex was proposed since xylan co-precipitated with pectin under mild alkali conditions. It was proposed that pectin links with xylan through the RG-I region since degradation of HG did not alter AEC elution patterns for RG-I and xylan, suggesting RG-I - xylan interactions. PMID- 30007614 TI - High-strength and morphology-controlled aerogel based on carboxymethyl cellulose and graphene oxide. AB - Composite aerogels with excellent mechanical properties were prepared by using carboxymethyl cellulose (CMC) as raw materials, 2D graphene oxide (GO) nanosheets as reinforcement, boric acid (BA) as cross-linker. By controlling the heat transfer rate, composite aerogels with isotropy and anisotropy structure were prepared, the mechanical and heat insulation properties were studied. The isotropy composite aerogel had compression strength of 110 kPa at 60% compression, which was 5 times of the axial and 14 times of the radial of anisotropy structure composite aerogels, and thermal conductivity was also lower than those of two directions of anisotropy composite aerogel. Besides, the mechanical properties of isotropy composite aerogels increased with the increase of GO content. When GO content was up to 5 wt%, the compressive strength and Young's modulus of composite aerogels reached 349 kPa and 1029 kPa, which were 1.6 and 4.5 times that of CMC aerogels, respectively. PMID- 30007615 TI - Thermal conductivity, structure and mechanical properties of konjac glucomannan/starch based aerogel strengthened by wheat straw. AB - This study presents the preparation and property characterization of a konjac glucomannan (KGM)/starch based aerogel as a thermal insulation material. Wheat straw powders (a kind of agricultural waste) and starch are used to enhance aerogel physical properties such as mechanical strength and pore size distribution. Aerogel samples were made using environmentally friendly sol-gel and freeze drying methods. Results show that starch addition could strengthen the mechanical strength of aerogel significantly, and wheat straw addition could decrease aerogel pore size due to its special micron-cavity structure, with appropriate gelatin addition as the stabilizer. The aerogel formula was optimized to achieve lowest thermal conductivity and good thermal stability. Within the experimental range, aerogel with the optimized formula had a thermal conductivity 0.04641 Wm-1 K-1, a compression modulus 67.5 kPa and an elasticity 0.27. The results demonstrate the high potential of KGM/starch based aerogels enhanced with wheat straw for application in thermal insulation. PMID- 30007616 TI - Biosynthesized AgNP capped on novel nanocomposite 2-hydroxypropyl-beta cyclodextrin/alginate as a catalyst for degradation of pollutants. AB - This study presents an efficient and facile method for the trapping of Ag+ ions on hybrid nanocomposite based on 2-hydroxypropyl-beta-cyclodextrin (HPCD) and alginate (Alg) in aqueous medium through ionotropic gelation mechanism and followed by in situ assembly of silver nanoparticles (AgNPs) using aqueous extract of Jasminum subtriplinerve leaves as a reducing agent. The nanocomposite AgNPs/HPCD/Alg was characterized by UV-vis, EDX, TEM, HR-TEM analysis. The AgNPs were found to be spherical shape and uniform size with an average diameter of 13.5 nm. EDX data showed about 4.0% (w/w) of AgNPs capped on the nanocomposite HPCD/Alg. The role of HPCD and Alg in the nanocomposites was observed from FTIR and thermal studies. The stability and distribution of the nanoparticles in the aqueous solution were determined by zeta potential and DLS measurements. The nanocomposites showed excellent catalytic performance for degradation of pollutants within industrial effluents including 4-nitrophenol, methyl orange and rhodamine B. PMID- 30007618 TI - Thermoplastic starch foamed composites reinforced with cellulose nanofibers: Thermal and mechanical properties. AB - The present work reports the effect of cellulose nanofibers (CNFs) on the thermal, dynamic mechanical analysis (DMA), density and water uptake of thermoplastic starch (TPS) foamed composites. The obtained thermal and DMA results illustrate that thermal stability, storage modulus (E'), loss modulus (E") and damping factor (tan delta) increase for all TPS/CNF samples compared to the pure TPS foamed composite. The results showed that the incorporation of CNFs caused an increase in the glass transition temperature (Tg) of the TPS foamed composites. Additionally, thermal results revealed that 1.5 wt% CNF offers superior resistance or stability towards heat compared to its counterparts. Addition of the CNF filler into the TPS matrix decreased the apparent density and water absorption. Interestingly, SEM images illustrate that when a small content of rigid nano particles (1.0 or 1.5 wt%) was added in the foamed composites, the cell size decreased while the cell density increased. PMID- 30007617 TI - Influence of different divalent ions cross-linking sodium alginate-polyacrylamide hydrogels on antibacterial properties and wound healing. AB - Hydrogels are widely used as debriding agents on account of providing a moist environment for wound healing, however the lack of mechanical strength, angiogenesis and antibacterial property limits their applications. In this study, we synthesized novel divalent ion cross-liking hydrogels (copper, zinc, strontium and calcium) and compared the mechanical performance, swelling ratio, antibacterial properties and biocompatibility in vitro and vivo. Thereinto, among the four divalent ions cross-linked hydrogels, copper ion crosslinking exhibited the maximum breaking strength, while strontium and zinc ion cross-linked hydrogels exhibited an excellent mechanical strength. In addition, the swelling ratio and pore size of no-ion cross-linked hydrogels was larger than ion cross kinked hydrogels. In vitro, the improvements on wound healing after hydrogel application were evaluated by histological and molecular assays by detecting VEGF and TGF-beta expression. In vitro and in vivo study results showed that zinc cross-kinked hydrogel had a spectrum of antibacterial activities, cell viability, mechanical strength and the ability of wound closure by promoting fibroblasts migration, vascularization, collagen deposition and the formation of granulation tissue. PMID- 30007620 TI - Molecular weight impact on the mechanical forces between hyaluronan and its receptor. AB - Hyaluronan (HA) possesses manifold mechanical and signaling properties in the body. Most of these activities are largely regulated by its molecular weight, which often triggers opposing functions. However the molecular basis for such function distinction between HA size categories remains unclear. Using a combination of biophysical techniques, we measured the physical forces between HA ligand and its specific receptor CD44 in both normal and lateral directions, at different HA molecular weights and bound states. It was found that the impact of HA multivalency is more than just the sum of separate monovalent bindings. The HA CD44 specific interaction enhances with HA molecular weight and the maximum binding occurs at ~1000 kD, possibly due to the balance between multivalent HA zipping effect and conformational entropy. High friction patches, probably from CD44 protein clustering, was observed in friction force microscopy (FFM) upon HA shearing, which is also dependent on HA molecular weight. These results could help to understand the biophysical mechanism of HA in regulating CD44-induced physiological activities and thus facilitate the new design of HA-based material in fine tuning the receptor responses. PMID- 30007619 TI - Flexible starch-polyurethane films: Effect of mixed macrodiol polyurethane ionomers on physicochemical characteristics and hydrophobicity. AB - One of the most critical limitations in synthesizing starch-polyurethane (PU) hybrid materials is their microphase separation caused by physical incompatibility. This paper reports that the physical incompatibility and microphase separation between starch and PU can be overcome by using specifically designed anionic poly(ether-ester) polyurethane (AEEPU). The AEEPU was synthesised by preparing isocyanate (NCO)-terminated prepolymer using Isophorone diisocyanate (IPDI), 2,2-bis(hydroxymethyl)propionic acid (BMPA), poly (ethylene glycol) (PEG) and polycaprolactone (PCL). This AEEPU was physically mixed with glycerol plasticized high amylose starch (HAGS) at HAGS to AEEPU mass ratios of 90/10, 80/20, 70/30, 60/40, 50/50. Higher AEEPU content in HAGS-AEEPU increased surface hydrophobicity and elasticity while the Young's modulus remained unaffected. HAGS-AEEPU film at 50:50 ratio was comparable to LDPE film in terms of elongation at break (187%), Young's modulus (383 MPa), and contact angle (112 degrees ) and good transparency. These starch-PU films are expected to find increased application as biodegradable packaging materials. PMID- 30007621 TI - Dehydration-induced physical strains of cellulose microfibrils in plant cell walls. AB - The effect of dehydration of plant cell walls on the physical status of cellulose microfibrils (CMFs) interspersed in pectin matrices was studied. Vibrational sum frequency generation (SFG) spectroscopy analysis of cellulose revealed reversible changes in spectral features upon dehydration and rehydration of onion epidermal walls used as a model primary cell wall (PCW). Combined with microscopic imaging and indentation modulus data, such changes could be attributed to local strains in CMFs due to the collapse of the pectin matrix upon dehydration. X-ray diffraction (XRD) showed that the (200) spacing of cellulose in dried PCWs is larger than that of cellulose Ibeta obtained from tunicates. Thus, the modulus of CMFs in PCWs would be lower than those of highly-crystalline cellulose Ibeta and inhomogeneous local bending or strain of CMFs could occur readily during the physical collapse of pectin matrix due to dehydration. PMID- 30007622 TI - Effect of isolation methods of chitin nanocrystals on the properties of chitin silver hybrid nanoparticles. AB - Chitin nanocrystal (ChNC) was isolated using sulfuric acid hydrolysis (ChNCH2SO4), TEMPO-oxidation (ChNCTEMPO), and ammonium persulfate (ChNCAPS) methods, and used for the preparation of hybrid nanoparticles of ChNC/silver nanoparticles (AgNP). The ChNC exhibited a needle-shaped structure with a sulfate group content of 135 MUmol/g for ChNCH2SO4 and carboxyl content of 0.71 and 1.42 mmol/g for ChNCTEMPO and ChNCAPS, respectively. ChNC worked as a reducing and stabilizing agent for the production of AgNP and reduced the size of AgNP from 23.9 nm to 6.3 nm in the ChNC/AgNP hybrid. The carboxyl content of ChNC played a significant role for the nucleation, size distribution, and antibacterial activity of ChNC/AgNP. ChNC/AgNP hybrid, especially ChNCAPS/AgNP, exhibited strong antibacterial activity against food-borne pathogenic Gram-negative (E. coli) and Gram-positive (L. monocytogenes) bacteria. The prepared ChNC/AgNP hybrid nanomaterials have a high potential for the application to be used as a nanofiller to improve the properties of food packaging materials to extend the shelf-life of packaged food. PMID- 30007623 TI - Optimizing electric corona treatment for hydroxypropylated starch-based coatings. AB - The aim of this investigation was to determine the role of negative direct current and alternating current (plasma) corona treatments in modification of bio based dispersion barrier coatings and the response of replacing fossil-based binder with a thermoplastic bio-based binder (starch). The study emphasizes the importance of understanding and optimizing electric corona discharge in order to obtain high oxidation level without harming the substrate and causing unintentional treatment of the reverse side. The coatings were exposed to different corona treatment conditions using a novel developed sheet-fed laboratory-scale device. Corona-induced topographical, mechanical and surface chemical changes were observed from atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and contact angle and surface energy measurements. XPS results indicated further that partial starch decomposition occurred after plasma treatment. Coated surfaces became substantially smoother after both treatments suggesting that nanoparticle migration and re-orientation effects occurred. Additionally, reverse side effects and strike through were also discussed. PMID- 30007624 TI - Ultra sensitive detection of Cd (II) using reduced graphene oxide/carboxymethyl cellulose/glutathione modified electrode. AB - The present work describes the electrochemical detection of Cd2+ using reduced graphene oxide (rGO), carboxymethyl cellulose (CMC) and glutathione (GSH) modified glassy carbon electrode (GCE) by Square Wave Anodic Stripping Voltammetry (SWASV). The prepared nanocomposite was characterized by X-ray diffraction (XRD), RAMAN, Scanning Electron Microscopy (SEM), Fourier Transform Infrared (FTIR) and X-ray photoelectron spectroscopy (XPS), Cyclic Voltammetry (CV) and Electrochemical Impedance Spectroscopy (EIS). The influence of experimental parameters such as effect of pH, choice of supporting electrolyte, deposition time and deposition potential, were optimized. Under the optimized conditions, the linear relationship between the current intensity and Cd2+ concentration (2-20 nM) was I (MUA) = -6.78 (c/nM) + 4.547 (R2 = 0.996). The detection limit and sensitivity achieved for the modified electrode were 0.05 nM and 4.5 MUA/nM respectively. Finally, rGO/CMC/GSH/GCE was successfully demonstrated for the detection of Cd2+ in real samples, and the results were compared with AAS analysis. PMID- 30007625 TI - Effect of deacetylation degree on controlled pilocarpine release from injectable chitosan-g-poly(N-isopropylacrylamide) carriers. AB - Development of biodegradable thermogels as intracameral injectable carriers for ocular delivery of antiglaucoma medications can provide a better treatment modality with low dosing frequency than eye drop formulations. For the first time, this study investigates the effect of deacetylation degree (DD) of the polysaccharide component in chitosan-g-poly(N-isopropylacrylamide) (CN) carriers on controlled release of pilocarpine in the management of glaucoma. Our results showed that increasing the chitosan DD from 60.7% to 98.5% leads to enhanced biodegradation resistance of carrier and prolonged release profile of the drug. Significant DNA damage and caspase-3 activation could be detected in lens epithelial cell cultures exposed to CN made from highly deacetylated polysaccharides, indicating apoptosis-related cytotoxicity due to relatively high positive charge density of the graft copolymers. Postoperative outcomes demonstrated that long-term therapeutic efficacy in glaucomatous rabbits is governed by intraocular pressure changes in response to intracamerally administered pilocarpine-loaded CN, strongly suggesting the usefulness of deacetylation in this injectable drug delivery carrier. PMID- 30007626 TI - Spectroscopic investigation of a hyperbranched cationic amylopectin derivative as a multi-guest molecular host for targeted delivery of a photosensitizer to pancreatic cancer cells. AB - To increase pancreatic tumor-targeted phototoxicity of photosensitizers, a hyperbranched cationic amylopectin derivative conjugated with 3-(dimethylamino)-1 propylamine (DMAPA-Amp) was invevstigated as a multi-guest molecular host for the targeted delivery of a photosensitizer to human pancreatic cancer (Panc-1) cells. We selected protoporphyrin IX (PpIX) and folic acid as a photosensitizer and a tumor-targeting factor, respectively. The complexation mechanism of DMAPA-Amp with PpIX and folic acid was characterized using NMR spectroscopy including 1H NMR, two-dimensional diffusion ordered spectroscopy (2D DOSY) NMR, fluorescence and UV-vis spectroscopy. The results indicated that the DMAPA-Amp derivative could serve as a host for the encapsulation of two guests, PpIX and folic acid, through intermolecular interactions. The complex showed high phototoxicity against Panc-1 cells, and its folic-acid-mediated cancer-cell-targeting property was confirmed by laser confocal microscopy and flow cytometry analysis. We provide a method to study hyperbranched cationic polymer-based complexes containing multiple guests, which could facilitate the design of multi-functional complexes in the drug delivery field. PMID- 30007628 TI - Characterization of cell wall polysaccharides from Sicana odorifera fruit and structural analysis of a galactan-rich fraction pectins as side chains. AB - Sicana odorifera is a Brazilian native fruit. In this work, cell wall polysaccharides from S. odorifera pulp were isolated by sequential extraction with water, citric acid, and sodium hydroxide solutions. The monosaccharide composition of crude polysaccharide fractions was determined. The aqueous fractions displayed the highest yields and they were constituted by pectins, having mainly galactans as side chains. The citric acid fraction (SCA) had galactose as the main component. The hemicellulosic fractions consisted mainly of xylose, mannose, galactose, and glucose, suggesting the presence of xyloglucans, xylans and mannans. The SCA fraction was further purified, resulting in a linear galactan (SCAI2). NMR and methylation analysis showed that SCAI2 was a beta-(1 >4) d-galactan with molar mass of 17,560 g/mol, determined by light scattering. The presence of a linear galactan in free form in fruits is unusual because these polymers usually occur as side chains of type I rhamnogalacturonans. PMID- 30007627 TI - Polyurethane elastomer composites reinforced with waste natural cellulosic fibers from office paper in thermal properties. AB - Polyurethane elastomer (PUE) composites were synthesized with a low additive content of waste natural cellulosic fibers from office paper. A new technology combining prepolymer method with physical blending and modification was adopted. The results showed that cellulosic fibers were covalently bonded to polyurethane molecular chains and served as a cross-linking agent making the degree of phase separation decrease. Even so, the lowest additive content of cellulosic fibers (1 wt%) in this work could make polyurethane still hold a certain degree of phase separation. Besides, thermal stability of polyurethane was improved from 288 to around 300 degrees C even at the low cellulosic fibers content. PUE with 3% cellulosic fibers had the better interfacial compatibility between cellulosic fibers and polyurethane causing the greater thermal reinforcement. PUE with 4% and 5% cellulosic fibers had the worse interfacial compatibility generating the better damping capacity indicating that cellulosic fibers could improve damping performance of polyurethane, especially polyurethane with 5 wt% fibers. It meant that cellulosic fibers had a potential application in damping materials. PMID- 30007630 TI - Revealing the importance of non-thermal effect to strengthen hydrolysis of cellulose by synchronous cooling assisted microwave driving. AB - Non-thermal effect of microwave is precisely revealed as an important factor to strengthen the hydrolysis of cellulose to sugar by a new method of synchronous cooling assisted microwave driving. Using this particular method, the thermal effect is mandatorily removed from the hydrolysis of cellulose. After systematic analysis of the hydrolysis of low crystalline regenerated cellulose (RC), the non thermal effect of microwave is proved to strengthen hydrolysis. The enhancement of non-thermal effect effectively weaken the interaction between the hydroxyl groups of -O(2)H and -O(6)H, as well as strengthen interaction between the hydroxyl groups of -O(3)H and -O(5)H within one single molecular chain. It leads to the reduction of regularity of molecular chain and thus inhibits the recrystallization of RC. As a result, the efficiency of hydrolysis is greatly improved. This research provides an important theoretical support and technical guidance to construct new microwave driven hydrolysis with high efficiency in the future. PMID- 30007629 TI - Genipin-crosslinked carboxymethyl chitosan nanogel for lung-targeted delivery of isoniazid and rifampin. AB - Lung-targeted genipin-crosslinked deacetylated chitosan (GEN-CS)/isoniazid (INH)/rifampin (RMP) nanogel particles (NGPs) were prepared as a treatment for tuberculosis caused by multidrug-resistant Mycobacterium tuberculosis (MTB) to surmount the undesirable side effects and decrease the cytotoxicity of INH and RMP when being against MTB. The size, morphology, in vitro release property, long term antibacterial performance, stability, in vitro cytotoxicity, in vivo toxicity, and in vivo release property of GEN-CS/INH/RMP NGPs inhalation powder were investigated. The results showed that the GEN-CS/INH/RMP NGPs inhalation powder exhibited extended antibacterial activity because of its long-term release of INH and RMP. A simplex GEN-CS/INH/RMP NGPs pulmonary dose led to the therapeutic drug concentration of 40%-60% in lung and other organs (<5%) for 24 h. Furthermore, this GEN-CS/INH/RMP NGPs lyophilized inhalation powder displayed lung-targeted property and lower in vivo toxicity. These results suggested that this GEN-CS/INH/RMP NGPs inhalation powder would be a more useful dosage form than separate dose of INH or RMP for MTB. PMID- 30007631 TI - Hyaluronate-alginate hybrid hydrogels modified with biomimetic peptides for controlling the chondrocyte phenotype. AB - Hyaluronate-based hydrogels have been widely exploited as synthetic extracellular matrices in many tissue engineering applications, including cartilage tissue engineering. Hyaluronate-based hydrogels are typically prepared by chemical cross linking reactions, in which chemical reagents may induce side effects, unless they are completely removed after the cross-linking reaction. We thus suggest the utilization of hybrid materials composed of hyaluronate as a main chain and alginate for physical cross-linking to simply form hydrogels in the presence of calcium ions under physiological conditions. In this study, we hypothesized that the introduction of biomimetic peptides to hyaluronate-alginate hybrid (HAH) hydrogels could be useful to regulate the chondrocyte phenotype, including chondrogenic differentiation. HAH was modified with the arginine-glycine aspartate (RGD) peptide as a cell-matrix interaction motif and/or histidine alanine-valine (HAV) as a cell-cell interaction motif. The HAV peptide is known to bind to cadherin, which is a key factor involved in homophilic cell-cell interactions as well as chondrogenesis. The viability and growth of mouse chondrocytes (ATDC5 cells) increased significantly when cultured on RGD-modified HAH hydrogels. Cell aggregates formed on HAV-modified HAH hydrogels, resulting in enhanced chondrogenic differentiation via enhanced cell-cell interactions by HAV modification. Interestingly, a synergistic effect of HAV and RGD peptides within HAH hydrogels on chondrogenesis was found in 3-D experiments in vitro. This approach to utilizing physically cross-linkable hyaluronate-based hydrogels presenting biomimetic peptides has potential applications in tissue engineering, including cartilage regeneration. PMID- 30007632 TI - Thermodynamic analysis for assessing the physical stability of core materials microencapsulated in taro starch spherical aggregates. AB - Taro starch has the ability of producing spherical aggregates under spray-drying without the addition of binding agents. This property makes taro starch suitable for microencapsulation of dietary compounds. This study addressed the physical stability of hydrophilic and hydrophobic core materials microencapsulated by spray-drying into taro starch spherical aggregates determined from a thermodynamic standpoint via vapor adsorption isotherms. Ascorbic acid and almond oil were used as compound models. Encapsulation efficiency, GAB sorption parameters, differential and integral thermodynamic properties, Gibb's free energy, entropy-enthalpy compensation, spreading pressure, effective diffusion rate, activation energy and critical water activity were determined. The encapsulation efficiency of ascorbic acid and almond oil was 99% and 56%, respectively. Monolayer moisture content was relatively low for ascorbic acid microcapsules. The adsorption process was driven by entropic mechanisms. The physical stability of taro starch spherical aggregates microcapsules with different core material was guaranteed for a range of water activities and temperatures. PMID- 30007633 TI - Rice straw cellulose nanofibrils reinforced poly(vinyl alcohol) composite films. AB - In this study, cellulose nanofibrils (CNFs), obtained from the chemical treatment of steam exploded rice straw fibers and the following oxidation by 2,2,6,6 tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated system, were utilized to prepare the reinforced polyvinyl alcohol (PVA) composite films by solution casting method, and the morphology, transparency, thermal stability, mechanical properties and water absorption of these rice straw CNFs/PVA composite films were also investigated compared with the rice straw cellulose microfibrils (CMFs) reinforced PVA composite films. As compared with the rice straw CMFs/PVA composite films, the rice straw CNFs/PVA composite films exhibited more uniform fiber dispersion, better mechanical properties and transparency, and similar thermal stability. However, the rice straw CNFs/PVA composite films showed weaker water resistance than the rice straw CMFs/PVA composite films due to the existence of more polar groups in rice straw CNFs. PMID- 30007634 TI - Isolation, Purification and Structural Characterestics of Chondroitin Sulfate from Smooth hound Cartilage: In vitro Anticoagulant and Antiproliferative Properties. AB - Chondroitin sulfate was extracted from the cartilage of smooth hound (CSSH) and then purified by anion exchange chromatography. The structual characteristic of CSSH was evaluated by acetate cellulose electrophoresis, FTIR, 13C NMR and SAX HPLC. Molecular weight of CSSH was average 68.78 KDa. Disaccharide analysis indicated that CSSH was predominately composed of monosulfated disaccharides in position 6 and 4 of the N-acetylgalactosamine (45.34% and 32.49%, respectively). CSSH was tested for in vitro anticoagulant activity using the three classical coagulation assays (activated partial thromboplastin time (aPTT), prothrombine time (TT) and thrombin time (PT) tests). The finding showed that CSSH prolonged significatively (p < 0.05), aPTT, TT and PT about 1.4, 3.44 and 1.21 fold, respectively, greater than that of the negative control at a concentration of 100 MUg/ml. The CSSH caused a significant antiproliferative activity against HCT116 cell, which was 79% of cell proliferation inhibition at the concentration of 1000 MUg/ml. Further, CSSH presented no toxicity against the normal cells and no hemolysis towards bovine erythrocytes for all concentrations tested. CSSH demonstrated hopeful antiproliferative and anticoagulant potential, which may be used as a novel and effective drug. PMID- 30007635 TI - Isothermal titration calorimetry to study the influence of citrus pectin degree and pattern of methylesterification on Zn2+ interaction. AB - This work explored the influence of the citrus pectin degree and pattern of methylesterification on its interaction with Zn2+ using isothermal titration calorimetry (ITC). Pectin samples with a comparable degree of methylesterification (DM) but distinct distribution patterns of non methylesterified carboxylic groups (absolute degree of blockiness, DBabs) were produced through enzymatic (blockwise pattern) or alkaline (random pattern) demethylesterification. The pectin-Zn2+ interaction was found to be endothermic, in which a positive entropy change compensated for the unfavorable endothermic enthalpy change, driving the interaction between pectin and Zn2+. Decreasing pectin DM or increasing DBabs promoted Zn2+ binding, with the estimated binding capacity (mol Zn2+/mol GalA) and binding constant (mM-1) being mainly determined by pectin DBabs, rather than DM. ITC was found to be a useful technique to study the pectin-cation interaction, however, low DM pectin samples are sensitive to gelling and therefore more difficult to study. PMID- 30007636 TI - Injectable chitosan-hydroxyapatite hydrogels promote the osteogenic differentiation of mesenchymal stem cells. AB - Injectable hydrogels have emerged as promising biomaterials for tissue engineering applications. The goal of this study was to evaluate the potential of a pH-responsive chitosan-hydroxyapatite hydrogel to be used as a three dimensional support for encapsulated mesenchymal stem cells (MSCs) osteogenic differentiation. In vitro enzymatic degradation of the hydrogel, during 28 days of incubation, in simulated physiological condiditons, was characterized by swelling measurements, molecular weight determination and SEM analysis of hydrogel microstructure. Osteogenic differentiation of encapsulated MSCs was confirmed by osteogenic Runx2, collagen type I and osteocalcin immunostaining and alkaline phosphatase quantification. The deposition of late osteogenic markers (calcium phosphates) detected by Alizarin red and von Kossa staining indicated an extracellular matrix mineralization. PMID- 30007637 TI - Pectin-chitosan membrane scaffold imparts controlled stem cell adhesion and proliferation. AB - Processing stable polysaccharide membranes with suitable mechanical properties has been challenging for applications in wound healing and tissue engineering. Here we expand the characterization of pectin/chitosan (PT/CS) membranes (without covalent crosslinking), which we recently reported. Membranes containing pectin (PT) excess were formed, and PT/CS ratio can be tuned to enhance the mechanical strength, and to modulate hydrophilicity and cytocompatibility. The surface wettability and swelling properties of the polyelectrolyte complexes (PECs) played an important role to promote the attachment of stem cells. These PECs membranes have ultimate tensile strength similar to that of human skin, which is on the order of ten times higher than similar previously reported polysaccharide materials. We show for the first time that these new PT/CS membranes may promote anchorage, adhesion and support human stem cell growth, making them candidate materials for tissue engineering purposes. PMID- 30007638 TI - Hyaluronic acid decorated tacrolimus-loaded nanoparticles: Efficient approach to maximize dermal targeting and anti-dermatitis efficacy. AB - Nano-delivery systems have gained remarkable recognition for targeted delivery of therapeutic payload, reduced off-target effects, and improved biopharmaceutical profiles of drugs. Therefore, we aimed to fabricate polymeric nanoparticles (NPs) to deliver tacrolimus (TCS) to deeper layers of the skin in order to alleviate its systemic toxicity and improved therapeutic efficacy against atopic dermatitis (AD). To further optimize the targeting efficiency, TCS-loaded NPs were coated with hyaluronic acid (HA). Following the various physicochemical optimizations, the prepared HA-TCS-CS-NPs were tested for in vitro drug release kinetics, drug permeation across the stratum corneum, percentage of drug retained in the epidermis and dermis, and anti-AD efficacy. Results revealed that HA-TCS-CS-NPs exhibit sustained release profile, promising drug permeation ability, improved skin retention, and pronounced anti-AD efficacy. Conclusively, we anticipated that HA-based modification of TCS-CS-NPs could be a promising therapeutic approach for rationalized management of AD, particularly in children as well as in adults having steroid phobia. PMID- 30007639 TI - A one-step inkjet printing technology with reactive dye ink and cationic compound ink for cotton fabrics. AB - In the paper, a one-step inkjet printing technology with reactive dye ink and cationic compound ink for cotton fabric was reported. Cationic ink of 3-chloro-2 hydroxypropyltrimethyl ammonium chloride (CHPTAC) and reactive dye ink were printed simultaneously on the sized cotton fabric, and then the sample was steamed. Response surface methodology (RSM) was used to investigate the influences of steam conditions on the K/S value and dye fixation rate. The K/S value, dye fixation rate, staining of the white ground and colorfastness of cotton fabrics treated with different inkjet printing methods were compared. X ray photoelectron spectrometer (XPS) analysis and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum confirmed the reaction of CHPTAC to cotton treated by one-step inkjet printing technology. And a suggested reaction process of the one-step inkjet printing method was proposed through Gaussian calculation. PMID- 30007640 TI - Tough, resilient and pH-sensitive interpenetrating polyacrylamide/alginate/montmorillonite nanocomposite hydrogels. AB - Alginate, a naturally abundant and environmentally friendly carbohydrate polymer, can form ionically crosslinked hydrogels with Ca2+. Therefore, a novel design of interpenetrating nanocomposite hydrogels (PMACa) is proposed, which is synthesized by in situ polymerization of acrylamide in the presence of montmorillonite platelets and sodium alginate at an elevated temperature, followed by secondary crosslinking of the hydrogel using a CaCl2 solution. PMACa displays superior tensile strength and strain at break under the fully swollen state, as well as rapid shape recovery and insignificant residual strain upon the release of an external load. Furthermore, PMACa also shows remarkable reversible pH-dependent swelling/deswelling behaviors due to the pH-sensitivities of alginate network and montmorillonite platelets. These new high-performance interpenetrating alginate-containing nanocomposite hydrogels may find potential applications as aquatic load-bearing materials for artificial tissues, actuators, agriculture, etc. PMID- 30007642 TI - Chemical structure and anti-inflammatory effect of polysaccharide extracted from Morinda citrifolia Linn (Noni). AB - Polysaccharides extracted from plants are very promising molecules in the field of pharmacotherapy. Knowing this, the aim of this study was to extract, characterize and evaluate the action of the polysaccharide of Morinda citrifolia Linn (Noni-PLS) in biological models of inflammatory processes. The characterization tests shown that sample refers to a heteropolysaccharide composed mainly of homogalacturonan and rhamnogalacturonan. This polysaccharide at dose of 10 mg/kg, when tested in our models of inflammation, showed significant activity in reducing carrageenan-induced paw oedema as well as all mediators edemas. This polysaccharide was able to inhibit the migration of leukocytes to the site of inflammation, and still reduced inflammatory nociception tests. This results, allows us to conclude that the polysaccharide extracted from Morinda citrifolia linn has anti-inflammatory potential since it reversed inflammatory parameters such as edema, leukocyte migration and nociception. PMID- 30007641 TI - Effects of Bush Sophora Root polysaccharide and its sulfate on DHAV-1 replication. AB - Duck hepatitis A virus type 1 (DHAV-1) is a mortal virus to ducklings under three weeks old. Bush sophora root polysaccharide (BSRPS) and its sulfate, sulfated BSRPS (sBSRPS), inhibited the replication of DHAV-1. However the detailed mechanisms were still unknown. The protein translation and RNA synthesis are two most important steps of the replication. Additionally, DHAV-1 3D protein, cellular Hsp70 protein, and DHAV-1 IRES were the important regulatory factors. Therefore, the influence of BSRPS and sBSRPS on DHAV-1 protein translation and RNA synthesis were studied. RT-qPCR, western blot, and dual-luciferase reporter system were used to study the inhibition mechanisms of BSRPS and sBSRPS on DHAV 1. The results showed both BSRPS and sBSRPS significantly inhibited the DHAV-1 protein translation and RNA synthesis, and the effect of sBSRPS was stronger. Furthermore, they dropped the protein translation via suppressing DHAV-1 IRES activity and dropped the DHAV-1 synthesis via suppressing cellular Hsp70 expression. PMID- 30007643 TI - Water vapor sorption properties of TEMPO oxidized and sulfuric acid treated cellulose nanocrystal films. AB - For cellulose nanocrystal film, water adsorption is extremely important for its product performance. For gaining a deeper understanding of hygroscopic behavior, two cellulose nanocrystal films, such as TEMPO oxidized cellulose nanocrystal film (TOCNF) and sulfuric acid treated cellulose nanocrystal film (SACNF) were investigated using dynamic water vapor sorption apparatus. During the water vapor sorption process, the running time, real-time sample mass, target relative humidity (RH), actual RH and real-time temperature were all collected. Through the comparison of these collected data, significant differences in the equilibrium moisture content, sorption hysteresis and sorption kinetics were confirmed. It was important to note that TOCNF and SACNF had equilibrium moisture contents of 28.2% and 22.8, respectively, at a RH of 95%. Then, using parallel exponential kinetics (PEK) model, sorption kinetics data were accurately fitted. Furthermore, two Kelvin-Voigt elements were introduced to interpret the fitting results and calculate the modulus of TOCNF and SACNF. PMID- 30007644 TI - Slowly digestible starch in fully gelatinized material is structurally driven by molecular size and A and B1 chain lengths. AB - The objective of this study was to obtain structure-digestion relationships of fully gelatinized starch. Twelve starch samples with marked fine structural differences (HPLC-SEC) were studied for their retrogradation behavior (thermal and rheological properties of starch gels) and in vitro digestibility. A reduction in the digestion rate during storage for 7 days was observed in all samples and, interestingly, this reduction was particularly evident in sago (64.7%), potato (57.3%), pea (55.1%) and acid-converted maize (ACM, 51.6-51.8 %) starches. Results indicated two potential interactions that may result in slowly digestible supramolecular structures: 1) double helices between external A and B1 chains of DP at peak maximum >= 15.5 Glucose Units (perhaps involving internal long chains) that also are prone to forming intermolecular associations [high relative drop in the storage modulus (G') during heating of 7 days-stored gels] and; 2) interactions of small molecular size acid-hydrolyzed starch molecules that may be more mobile and easily aligned. PMID- 30007646 TI - Plasticizing of chitosan films with deep eutectic mixture of malonic acid and choline chloride. AB - Chitosan (CS) films containing deep eutectic solvent (DES) based on malonic acid (MA) and choline chloride (ChCl) were successfully prepared by solution casting method by using DES content ranging from 0 to 82 wt%. A strong interaction of CS with the components of DES was demonstrated by analyses of water sorption isotherms, atomic force microscopy and FTIR results. The plasticizing effect of the MA and ChCl mixture on the CS matrix was shown by static bulk mechanical measurements, thermal analysis and quantitative nanomechanical mapping (QNM). Elongation at break increased from 3 to 62% at increase of DES content from 0 to 67 wt%, while further increase of DES content led to the decreasing of maximal elongation. Introduction of DES into CS films led to the appearance of glass transition temperature in the region +2 - -2.3 degrees C. QNM results indicated homogeneity of the films containing up to 75 wt% of DES. PMID- 30007645 TI - Discovery of a polysaccharide from the fruiting bodies of Lepista sordida as potent inhibitors of indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells via blocking of STAT1-mediated JAK-PKC-delta signaling pathways. AB - The present study examined the role of a polysaccharide (LSP, 25 and 100 MUg/ml) from the fruiting bodies of Lepista sordid on the immunosuppressive enzyme indoleamine 2, 3-dioxygenase (IDO) in HepG2 cells, and the possible mechanism of action. IDO expression and kynurenine production from LSP-treated HepG2 cells following IFN-gamma stimulation were dramatically inhibited by LSP treatment. In line with this, the medium of HepG2 cells pretreated with LSP improved the survival rate of primary CD4+ and CD8+ T cells as compared with IFN-gamma-treated control cells. Moreover, tyrosine 701 and serine 727 phosphorylation of STAT1 were dramatically reduced by LSP pretreatment in IFN-gamma-stimulated HepG2 cells. Furthermore phosphorylation of JAK-1 and JAK-2 was also inhibited by LSP. Additionally, two IDO promoters (GAS and ISRE) were inhibited in cells pretreated with LSP prior to IFN-gamma exposure. These findings suggest that LSP exerts antitumor effects on HepG2 cells by inhibiting IDO via JAK-PKC-delta-STAT1 signaling pathway. PMID- 30007647 TI - Thermal stabilization of probiotics by adsorption onto porous starches. AB - Industrial processing factors, such as temperature, compromise the viability of probiotic cells. Objective was to develop a system to thermally stabilize probiotic bacteria based on porous starches and using biopolymers as coating materials (gelatinized starch, guar gum and xanthan gum). Porous starches from corn and rice starches, having controlled number and size of porous were used as supporting material. Scanning electron microscopy confirmed the adsorption of the microorganism, leading microcapsules with corn starch but aggregates with rice starch. Surface pores of rice starch increased the encapsulation yield of rice starch around 10%, but that effect was not observed in porous corn starch. The highest encapsulation yield was obtained with porous starches coated with gelatinized starch, which ranged from 92 to 100%. Microencapsulates made with porous starches with small pores, like the ones obtained with alpha-amylase, and coated with gelatinized starch resulted in the highest thermal resistance at 55 degrees C. PMID- 30007648 TI - Eco-friendly superabsorbent polymers based on carboxymethyl cellulose strengthened by TEMPO-mediated oxidation wheat straw cellulose nanofiber. AB - Superabsorbent Polymers (SAPs) have found widespread uses into the disposable personal hygiene, the medical-care and agricultural sections. The purpose of the current study is to produce green SAPs based on different cellulose derivatives and to explore the wheat straw cellulose nanofiber strengthening capabilities as an emerging bionanomaterial. Sodium carboxymethyl cellulose with varying amount of hydroxyethyl cellulose and TEMPO-mediated Cellulose Nanofibers (TCNFs) were used for the SAPs preparation. The results showed that increasing the citric acid as a crosslinking agent yielded decreasing the swelling capacity of the SAPs. The best swelling capacity was found to be 200 gr/gr along with addition of 10% TCNF. The ionic sensitivity of the SAPs was varied from 0.73-0.98 and also decreased with increasing TCNF content. Owning to biodegradable and non-toxic properties, the produced SAPs with appropriate swelling capacity are promising for potential applications in hygienic and horticultural sectors and can be replaced with synthetic ones. PMID- 30007649 TI - Nonabsorbable polysaccharide-functionalized polyethylenimine for inhibiting lipid absorption. AB - Overweight and obesity, which contribute to various chronic diseases, are increasingly common conditions around the world. For the purpose of weight loss in patients with overweight and obesity, we developed a series of beta cyclodextrin functionalized cationic branched polyethylenimine as oral pharmaceutical agents to inhibit digestion and absorption of dietary lipids in vivo. Tuning the structural configuration, molecular weight, and side-chain length of the cationic polymers provided the polymer with effective inhibition of lipid absorption. Importantly, the cationic polymer significantly increased fecal elimination of bile acids, triglycerides and cholesterol by 6.3-, 4.8- and 5.0 fold higher than those of the control with high fat diet, respectively. Moreover, the polymer could reduce the plasma lipids and liver lipid level in mice. The cationic polymer exhibited low cytotoxicity and did not cause observable histological changes for normal tissue. Therefore, the cationic polymer showed effective and safe characteristics as an oral pharmaceutical agent for inhibiting lipid absorption. This work offers a new promising venue to control weight for patients with overweight and obesity. PMID- 30007650 TI - Evaluation of the super disintegrant functionnalities of alginic acid and calcium alginate for the design of orodispersible mini tablets. AB - This study explores the influence of different synthesis methods and drying conditions in the preparation of sodium alginate-derivate xerogels presenting interesting disintegrant functionalities. Xerogels containing alginic acid (AA) or calcium alginate (CaA) and a mixture of both, AA/CaA, were isolated using two different drying methods oven and rotary evaporation. AA showed the best wettability behavior, in contrast to the rigid crosslinked CaA structure which showed a limited rate of water penetration. Interestingly, xerogel containing AA dried in the oven showed an enhanced maximum water uptake. Oven drying seems to favor the isolation of materials presenting good tabletability. Compression parameters of the formulations (tensile strength, elastic energy and porosity) were not affected by their presence (5%) in the design of OroDispersible Mini Tablets. In vitro disintegration results highlighted the water wicking as the key factor leading the disintegration mechanism of these materials. These results show promise of potential properties for the development of super disintegrant excipients. PMID- 30007651 TI - Partially carboxymethylated and partially cross-linked surface of chitosan versus the adsorptive removal of dyes and divalent metal ions. AB - Industrial wastes and their effluents containing dyes and heavy metals are a tremendous threat to the environment, and to treat these toxic waste streams, effective and environmentally benign methods are needed. In this study, NaCS-GL was used as an effective adsorbent, for the removal of dyes and metal ions from their aqueous solution. The presence of carboxylate groups on the NaCS-GL surface has altered the protonation of amino groups. The adsorption kinetics of dyes on NaCS-GL was initially controlled by the film diffusion or chemical reaction after which the intra-particle or pore diffusion started to govern the rate. Leaching of sodium ion confirmed the crosslinking of two carboxylate groups of NaCS-GL with the metal ions. Modeling of the adsorption isotherms revealed that the different active surface sites of NaCS-GL were involved in the adsorption of dyes and metals, suggesting the simultaneous removal of these components from the wastewater. PMID- 30007653 TI - Preparation and properties of gum arabic cross-link binding nisin microparticles. AB - Nisin is a small cationic peptide composed of 34 amino acid residues, it exhibits a wide spectrum antimicrobial activity against Gram-positive bacteria, but nisin has the disadvantages of poor stability and short duration of antibacterial activity. In order to improve the stability of nisin during food processing and storage period, the gum arabic (GA) is used to get GA-nisin microparticles. The analysis of zeta potential, SEM and FT-IR were used to characterize the combination of GA and nisin, test the antibacterial activity on Staphylococcus aureus and Escherichia coli, the bactericidal effect of GA-nisin microparticles decreased within 24 h compare to free nisin, however, GA-nisin microparticles after 121 degrees C treatment for 10 min, the activity loss rate is less than free nisin and has better sustained antibacterial effect at 25 degrees C. The results shown GA-nisin microparticles have better high-temperature stability and sustained bactericidal ability than the free nisin. PMID- 30007654 TI - Synthesis and characterization of nano fibrillated cellulose/Cu2O films; micro and nano particle nucleation effects. AB - Cubic, truncated cubic and spherical nano and micro particles of Cu2O, can be selectively deposited onto nano fibrilated cellulose gels by the modulated alkaline reduction of Cu2+ ions aided by the cellulose's reducing end groups. The role of the cellulose's reducing end groups and that of externally added carbohydrate reducing agents, towards inducing various Cu2O morphologies, is discussed with respect to the detailed nucleation effects leading to micro and nano Cu2O particle deposition on NFC. When the reducing end groups are provided only by the cellulose's chain ends, supersaturation effects seem to be affecting the Cu2O nucleation mechanism. However, the Cu2O nucleation considerations were altered when mobile reducing end groups were provided by adding dextrose in the system, promoting additional particle nucleation sites. Furthermore, the effort offered the possibility to quantitatively determine the number of accessible reducing end groups (-CHO) present in NFC, expressed in mmol/g. The optical properties of the created NFC/Cu2O films were examined by UV-vis absorption measurements, revealing band gaps ranging between 2.02-2.25 eV. The accumulated understanding expands the utility window and opens new directions for the novel utilization of nano-fibrillated cellulose, and more specifically toward semiconductor applications. PMID- 30007652 TI - Neuroprotective properties of Cantharellus cibarius polysaccharide fractions in different in vitro models of neurodegeneration. AB - The percentage of people suffering from neurodegenerative diseases is constantly increasing, because of that searching for substances able to prevent or inhibit neuronal death sseems to be reasonable. Because of the high popularity the search of new neuroprotective agents we started from Cantharellus cibarius. Neuroprotective properties of C. cibarius polysaccharides fractions was investigated in different models of neurodegeneration including trophic stress, excitotoxicity and andoxidative stress. Fractions influence on neurons viability was examined using Neurite Outgrowth Staining, MTT and LDH tests, while antioxidant capacity was determined by commercial antioxidant assays. Performed studies revealed beneficial effect of C. cibarius fractions (CC2a, CC3) on neurons viability and neurite outgrowth in normal and different stress conditions. Both tested fractions have shown antioxidant capacity and effectively neutralize the negative changes induced by glutamatergic system activators. Discovered neuroprotective properties of investigated compounds suggested the their use for developing effective and safety therapeutic strategy for neurodegenerative diseases. PMID- 30007655 TI - Engineering of chitosan-derived nanoparticles to enhance antimicrobial activity against foodborne pathogen Escherichia coli O157:H7. AB - Chitosan is an abundant and natural polymer derived from chitin, which presents a wide variety of properties, including antimicrobial activity. The raising of antibiotic resistant bacteria has increased the interest in finding alternatives to traditional antibiotics. Many studies have assessed the antimicrobial activity of chitosan itself, but a few have performed comparisons among different chitosan nanoparticle synthesis, which will be of particular interest for further applications. In this study, the effects of two types of cross-linking agents, sodium sulfate vs. tripolyphosphate, along with molecular weight (Mw) of chitosan, low vs. high Mw, and different sonication treatments, time and power, were assessed to determine the optimal conditions to enhance antimicrobial activity against bacterial pathogens. Physiochemical characteristics of the engineered chitosan nanoparticles were determined. It was observed that 20 min sonication time, low Mw of chitosan, Sodium sulfate as cross-linker, and particle size smaller than <300 nm, showed the greatest antimicrobial activity. Chitosan nanoparticles generated at this condition completely killed pathogenic E. coli O157:H7 without raising resistant bacteria, providing great insights into potential use as alternative antimicrobial agents. PMID- 30007656 TI - Modification of ulvans via periodate-chlorite oxidation: Chemical characterization and anticoagulant activity. AB - Native (F2) and carboxyl-reduced (R) ulvans from Ulva fasciata were sequentially oxidized with periodate-chlorite affording the polycarboxyl ulvans C1, C2 and C3 (1.20, 1.41 and 1.81 mmol g-1 of COOH, respectively; 19.7, 21.3 and 21.0% of NaSO3, respectively) and R-C3 (1.86 mmol g-1 of COOH; NaSO3 = 22.7%), respectively. APTT assay (polysaccharide fractions at 150 MUg mL-1) showed clotting time of 45.6 s for F2 fraction. For polycarboxyl ulvans C1, C2, C3 and R C3 the clotting times were 101.0, 122.2, 222.0 and 227.0 s, respectively. Comparison of the APTT assay results using ulvans chemically modified by carboxyl reduction, desulfation, periodate oxidation and/or chlorite oxidation showed the anticoagulant activity of polycarboxyl ulvans is dependent of the sulfate groups present in the native polymer. In addition, the increase of the anticoagulant activity was accompanied by the increasing of the carboxyl groups and the content of this acidic substituent seems to be more important than its positioning. PMID- 30007657 TI - Injectable hyaluronic acid hydrogels with the capacity for magnetic resonance imaging. AB - Monitoring hydrogel degradation in real time using noninvasive imaging techniques is of great interest for designing a scaffold in tissue engineering. We report the preparation of gadolinium (Gd)-labeled and injectable hyaluronic acid (HA) hydrogels that can be visualized using T1- and T2-weighted magnetic resonance imaging (MRI). An HA derivative functionalized with thiol and hydrazide was labeled using a diethylenetriaminepentaacetate complex modified with "clickable" dithiopyridyl functionalities (degree of modification was 3.77% with respect to HA repeat units). The HA derivative modified with cross-linkable groups and Gd complex exhibited relaxivities r1 = 3.78 mM-1s-1 and r2 = 56.3 mM-1s-1. A hydrazone hydrogel network was obtained by mixing Gd-labeled HA-hydrazide and HA aldehyde derivatives. Enzymatic hydrogel degradation could be followed using MRI because the MR images showed great correlation with the hydrogel mass loss. Ex vivo MRI of injected Gd-labeled hydrogels demonstrated that they show a significant contrast difference (SNRcoronal = 456; SNRaxial = 459) from the surrounding tissues. These results indicate that our Gd-labeled HA hydrogel has great potential as an injectable biocompatible hydrogel that can be used for longitudinal tracking in vivo using MRI. PMID- 30007658 TI - Rheological, structural and functional properties of high-pressure treated quinoa starch in dispersions. AB - The impact of high-pressure treatment on the gelatinization of quinoa starch (QS) dispersions was investigated as a function of pressure (300, 450 and 600 MPa for 15 min) and starch to water (S/W) ratio (1:3 and 1:4 w/w). The structural changes of QS were characterized by rheological, DSC, SEM, XRD, and FTIR spectroscopy. The water holding capacity and granules particle size increased significantly with the intensity of pressure. The G' of the QS gradually improved as a function of pressure and S/W ratio. A complete gelatinization of QS occurred at 600 MPa by breaking down of amylopectin crystallites and transformation to the amorphous state, which was confirmed by rheometry, XRD, and DSC. Additional heat-treatment to pressure-treated samples greatly improved the gel rigidity except for the sample treated at 600 MPa. It can be inferred that the functional properties of QS could be significantly modified/improved with the application a pressure treatment of 600 MPa. PMID- 30007659 TI - Molecular structure and properties of kappa-carrageenan-gelatin gels. AB - Rheological studies, FTIR spectroscopy and a molecular docking approach were used to explore the structural basis of the peculiar physicochemical properties of gelatin gels modified with a kappa-carrageenan admixture. Mixed gel properties are affected by the polysaccharide-to-gelatin ratio, Z, and can be divided into two categories. At low ratios, the strength of mixed gels varies insignificantly compared to gelatin due to the similar structures of the gels. Above the threshold content of kappa-carrageenan (Z > 0.1), the storage modulus and yield stress of mixed gels are significantly enhanced. The nonadditivity and threshold character of the rheological properties could be the result of conformational ordering of both gelatin and kappa-carrageenan, leading to the formation of additional junction zones in the gel network. According to molecular docking studies, the junctions could be formed as a result of complementary interactions between the gelatin triple helix and the kappa-carrageenan double helix. The stack formation increases the interaction energy, which explains the strengthening of the gel network. PMID- 30007660 TI - Fabrication of superhydrophobic cotton fabric with fluorinated TiO2 sol by a green and one-step sol-gel process. AB - The purpose of this paper is to propose a facile, green and low-cost approach of the preparation of superhydrophobic cotton textiles, which can be fabricated with fluorinated TiO2 sols via a sol-gel method. The coating was prepared with TiO2 sols catalyzed with acetic acid, then modified by poly(Hexafluorobutyl methacrylate) (PHFBMA) which was synthesized by free radical polymerization. The wettability, surface morphology and chemical composition of pristine and modified cotton fabrics were investigated. The modified fabric presents a high contact angle reached up to 152.5 degrees . The successful incorporation of fluorinated TiO2 nanoparticles into cotton fabric was verified by the above measurements results. Additionally, the chemical stability of the coated fabric has been tested by immersing in different pH solutions and organic solvents, demonstrating the outstanding water repellency of the fabric. Furthermore, the treated cotton fabric shows excellent self-cleaning properties, which makes it an ideal material for large-scaled industrial applications in various conditions. PMID- 30007661 TI - Preparation of low molecular weight heparins from bovine and ovine heparins using nitrous acid degradation. AB - Low molecular weight heparins (LMWHs) are important anticoagulant drugs. Nitrous acid degradation is a major approach to produce LMWHs, such as dalteparin. Due to the foreseeable shortage of porcine intestinal mucosa heparin and other potential risks, expansion of other animal tissues for heparin preparation is necessary. Heparins from different tissues differ in structure and bioactivity potency, and these variations may be carried over to the LMWH products. Sophisticated analytical techniques have been applied to compare various versions of dalteparins produced from porcine intestinal, bovine lung and ovine intestinal heparins to elucidate the effects of different animal tissues starting materials and processing conditions on the properties of final dalteparin products. With adjusted depolymerization conditions, versions of dalteparins that qualify under the European Pharmacopeia (EP) specifications were manufactured using non-porcine heparins. Dissimilarities among the three interspecies animal tissue heparin derived dalteparins regarding fine structures are also disclosed, and their origins are discussed. PMID- 30007663 TI - Sonication-assisted surface modification method to expedite the water removal from cellulose nanofibers for use in nanopapers and paper making. AB - This paper addresses the issue of high water retention by cellulose nanofibers (CNFs) that lead to exorbitant time consumption in the dewatering of CNF suspensions. This has been a bottleneck, which is restricting the commercialization of CNF derived products such as nanopapers and CNF reinforced paper sheets. As a remedy, we suggest an eco-friendly water-based approach that involves the use of sonication energy and lactic acid (LA) to modify the surface of CNFs. The suggested modification resulted in rapid water drainage, and dewatering was completed in 10 min; with unmodified CNFs, it took around 45 min. We have also compared the draining characteristics of LA modification of CNF suspensions with a common draining agent (NaCl); LA modification drains water 56% faster than the use of NaCl, and produced mechanically superior dimensionally stable nanopaper. Additionally, LA modification allows the addition of 10 wt.% CNF in paper sheets, with dewatering done in 2 min (while the unmodified CNFs took 23 min). PMID- 30007662 TI - Characterization and immunoregulatory activity of two polysaccharides from the root of Ilex asprella. AB - The polysaccharides obtained from the root of Ilex asprella, namely IAPS-1 and IAPS-2, with immunoregulatory activity were studied. Two polysaccharides were isolated and purified by Cellulose DEAE-52 and Sephadex columns. The structure of IAPS-1 was elucidated as 1,6-linked alpha-d-glucopyranosyl main chain with branch chain substituted at C-2 and/or C-4 position. For IAPS-2, the backbone is composed of 1, 4-linked alpha-d-glucose, galactose and rhamnose, and branched chains consists of arabinose, rhamnose and galacturonic acid, as confirmed by partial acid hydrolysis and NMR study. Further, the immunoregulatory activity of IAPS-1 and IAPS-2 was tested with the murine macrophages. Particularly, IAPS-2 polysaccharide can more effectively enhance the secretion of major inflammatory cytokines in macrophages, such as TNF-alpha, IL-1beta, IL-12, compared with IAPS 1. PMID- 30007664 TI - Bulk industrial fruit fibres. Characterization and prevalence of the original fruit metabolites. AB - Here we analysed the content of primary and secondary metabolites in nine types of industrially processed fibres derived from the juice industry. Specifically, we examined fibre from: apple, peach, and pear, as non-citrus fruits; the peel and flesh of orange and tangerine, and lemon flesh, as citrus fruits; and carrot, as vegetable. Regarding primary metabolites, the sugar content ranged from 21.6 mg/g in lemon to 290 mg/g in orange peel and lower mass organic acid content ranged from 25.0 mg/g in pear to 250 mg/g in lemon. The content of fatty acids were constant during fibre processing, ranging from 0.5 to 1.46%. Furthermore, the fatty acid profile was not affect for the processing. Concerning secondary metabolites, industrial processing did not decrease the sterols content, which ranged from 0.51 to 1.66 MUg/g. Regarding carotenoids, of note was the presence of epoxycarotenoids, which may reflect the quality of the industrial process, thus giving added value to the by-product. PMID- 30007665 TI - Mapping the risk of evaporated milk spoilage in the Mediterranean region based on the effect of temperature conditions on Geobacillus stearothermophilus growth. AB - A predictive model for the effect of storage temperature on the growth of Geobacillus stearothermophilus was applied in order to assess the risk of evaporated milk spoilage in the markets of the Mediterranean region. The growth of G. stearothermophilus in evaporated milk was evaluated during a shelf life of one year based on historical temperature profiles (hourly) covering 23 Mediterranean capitals for five years over the period 2012-2016 obtained from the Weather Underground database (http://www.wunderground.com/). In total, 115 scenarios were tested simulating the distribution and storage conditions of evaporated milk in the Mediterranean region. The highest growth of G. stearothermophilus was predicted for Marrakech, Damascus and Cairo over the period 2012-2016 with mean values of 7.2, 7.4 and 5.5 log CFU/ml, respectively, followed by Tunis, Podgorica and Tripoli with mean growth of 2.8, 2.4 and 2.3 log CFU/ml, respectively. For the rest 17 capitals the mean growth of the spoiler was <1.5 log CFU/ml. The capitals Podgorica, Cairo, Tunis and Ankara showed the highest variability in the growth during the 5 years examined with standard deviation values for growth of 2.01, 1.79, 1.77 and 1.25 log CFU/ml, respectively. The predicted extent and the variability of growth during the shelf life were used to assess the risk of spoilage which was visualised in a geographical risk map. The growth model of G. stearothermophilus was also used to evaluate adjustments of the evaporated milk expiration date which can reduce the risk of spoilage. The quantitative data provided in the present study can assist the food industry to effectively evaluate the microbiological stability of these products throughout distribution and storage at a reduced cost (by reducing sampling quality control) and assess whether and under which conditions (e.g. expiration date) will be able to export a product to a country without spoilage problems. This decision support may lead to a significant benefit for both the competitiveness of the food industry and the consumer. PMID- 30007666 TI - Effects of methyl jasmonate and carotenogenic inhibitors on gene expression and carotenoid accumulation in coriander (Coriandrum sativum L.) foliage. AB - Coriander (Coriandrum sativum L.), a commonly used annual herb that accumulates carotenoids upon methyl jasmonate (MeJA) treatment, provides an excellent model to investigate carotenogenesis and gene regulation. To explore key mechanisms involved in enhancing carotenoids, transcriptional expression profile of ten carotenogenic genes in the presence of MeJA and various gene specific inhibitors were investigated. Foliar application of MeJA (10 MUM) increased expression levels of CsPDS (phytoene desaturase), CsZDS (sigma-carotene desaturase), CsCHYE (carotene epsilon - hydroxylase) and CsLCYE (lycopene beta-cyclase) genes, and their transcript levels were strongly associated with carotenoid content, where, three days after treatment, 3.9 & 6.1 fold increase was observed for beta carotene and lutein respectively. The regulatory effect of key genes, CsPDS, CsZDS, CsLCYE and LCYB were further confirmed by using gene-specific inhibitors fosmidomycin, norflurazon and amitrol. Norflurazon- the phytoene desaturation inhibitor leads to a decrease in beta-carotene and lutein content correlated with CsPDS, CsZDS gene induction. Our results clearly demonstrate that MeJA induced signalling network evokes carotenogenic genes, leading to the accumulation of carotenoids. This knowledge may help to develop precise strategies for remodelling carotenoid pathway so that desired levels of a particular carotenoid in leafy vegetables is achievable. PMID- 30007667 TI - Quantitative evaluation of the risk of Vibrio parahaemolyticus through consumption of raw oysters (Crassostrea corteziensis) in Tepic, Mexico, under the RCP2.6 and RCP8.5 climate scenarios at different time horizons. PMID- 30007668 TI - Milk fat as a structuring agent of plastic lipid bases. AB - The global legislation regarding the elimination of trans fat in foods has led to the need for technological solutions to produce plastic fats. Currently, the industrial method used to obtain lipid bases with different physical properties is the chemical interesterification of blends from hardfats and vegetable oils. Milk fat can be an alternative to this process, which is natural plastic fat, as a structurant to obtain plastic lipid bases containing vegetable oils. This study aimed to evaluate the ability of the anhydrous milk fat (AMF) to structure lipid bases made from AMF and high oleic sunflower oil (HOSO) (~80% oleic acid) blends. The blends were prepared in the following AMF:HOSO proportions (% w/w): 100:00 (control); 90:10; 80:20; 70:30; 60:40; and 50:50, and characterized for fatty acid and triacylglycerol composition, solid fat content, compatibility, melting point, thermal behavior of crystallization and melting, crystallization kinetics, microstructure, polymorphism and hardness. All blends showed compatibility between the constituents, which is fundamental for the stability of plastic fats. The anhydrous milk fat governed the crystallization of these lipid bases, presenting crystals of <30 MUm of diameter, crystallized in polymorphic form beta'. The blends 70:30, 60:40 and 50:50 AMF:HOSO exhibited suitable profile for technological applications in the food industry, characterized by a solid fat content lower than 32% at 10 degrees C, and higher than 10% at 21 degrees C, and melting point near the body temperature. PMID- 30007669 TI - Evaluating the microbial ecology and metabolite profile in Kazak artisanal cheeses from Xinjiang, China. AB - Kazak artisanal cheese is one of the famous fermented food in Uighur Autonomy Region of Xinjiang, China. However, the microbial ecology in Kazak artisanal cheeses across different regions is unclear. In this study, we determined the microbial community composition through amplicon sequencing and measured the flavor profile of 10 cheese samples from different regions of Xinjiang. The associations between microbial communities, flavors and environmental factors were examined by redundancy analysis and Monte Carlo permutation test. Cheeses from different regions had different microbial communities, which was mainly reflected in the relative abundance of Lactobacillus, Streptococcus, Issatchenkia, Debaryomyces and Kluyveromyces. In addition, Pichia and Torulaspora were also the key microbial groups, according to the high relative abundance and large co-occurrence incidence in the correlation network. Using the microbe metabolites correlation analysis, the major flavor-producing taxa were identified as Kluyveromyces, Anoxybacillus, Torulaspora, Lactobacillus, Streptococcus and Dipodascus. Environmental factors accounted for the majority of the microbial community variations, 88.54% for bacteria and 75.71% for fungi. Compared to physico-chemical factors (temperature, moisture, and pH), geographical factors (longitude, latitude and elevation) had a stronger effect on microbial communities in cheese samples from different regions of Xinjiang. PMID- 30007670 TI - Origin and varietal based proteomic and peptidomic fingerprinting of Theobroma cacao in non-fermented and fermented cocoa beans. AB - It is well known that the development of chocolate flavor is initiated during cocoa bean fermentation. Storage proteins undergo the most intensive breakdown yielding peptides and free amino acids, which both serve as flavor precursors. A comprehensive analysis of cocoa proteins and oligopeptides of non-fermented and fermented beans from various geographic origins allows the assessment of systematic differences with respect to their origin as well as fermentation status. Protein quantities as well as their profiles derived from two-dimensional gel electrophoresis, showed striking differences for non-fermented beans depending on their geographical origin. From fermented beans, oligopeptides were relatively quantified by utilizing UHPLC-ESI-Q-q-TOF and annotated based on their characteristic fragmentation pattern in the positive-ion mode. With >800 unique oligopeptides, excluding di- and tri-peptides, across 25 different samples, we are herein reporting on the largest collection of cocoa oligopeptides ever observed and identified. The detected diversity of peptides could not be correlated to the geographical origin but rather to the degree of fermentation. Our findings suggest that the variability in peptide patterns depends on the fermentation method applied in the country of origin ultimately indicating diversified proteolytic activities. Furthermore, our results showed that well fermented and fair-fermented beans can be differentiated from partially fermented and under-fermented ones by higher numbers and total amounts of oligopeptides. PMID- 30007671 TI - Fruit peels as sources of non-extractable polyphenols or macromolecular antioxidants: Analysis and nutritional implications. AB - Despite increasing interest in the relevance of non-extractable polyphenols (NEPP) or macromolecular antioxidants as food bioactive compounds, most studies on their presence in foods focus mainly on the edible part of specific fruits, but their potential presence in fruit peels is usually ignored. The aim of this study was to evaluate NEPP content in the peels from ten common fruits. The results showed that NEPP made up more than half of the total polyphenol contents in half of the studied samples. HPLC analysis showed that NEPP were constituted by phenolic acids, flavanols and flavonols. Also, it was found that peels accounted for >40% of total NEPP in the fruit in four of the samples analysed. These results should encourage both the use of fruit peels in the fruit industry as ingredients and the consumption of whole fruits given the significant presence of NEPP in fruit peels. PMID- 30007672 TI - Characterization, identification, and quantification of phenolic compounds using UPLC-Q-TOF-MS and evaluation of antioxidant activity of 73 Perilla frutescens accessions. PMID- 30007673 TI - Lecithin and phytosterols-based mixtures as hybrid structuring agents in different organic phases. AB - In this study the effect of lecithin (L) addition and solvent quality in a well established oleogel system formed by beta-sitosterol and gamma-oryzanol (BG) was investigated. Medium chain triglycerides (MCT) and sunflower oil (SFO) were used as triglycerides and hexadecane (HEX) as a model of linear hydrocarbon. Lecithin was proposed due to its natural and versatile properties, showing different functionalities such as emulsifier and co-oleogelator. A study based on hierarchical organization of structured oil was performed applying techniques for bulk, meso and nanoscale. Self-sustained structures could no longer be observed after 40 wt% of BG replacement by lecithin. Small-angle X-ray scattering showed that the formed nanostructures (building blocks) were dependent on type of solvent and BG:L ratio in the mixture of oleogelators. Differential scanning calorimetry showed that stability against temperature was improved decreasing the polarity of the oil, and a time-dependent self-assembly of hybrid systems was observed from thermal and rheological measurements. Microscopy images exhibited changes on typical fibril aggregation of BG as lecithin was added, which promoted to a certain extent the suppression of ribbons. Oscillatory shear and uniaxial compression measurements were influenced by BG:L ratio and solvent mainly at higher lecithin amount. The combination of BG and MCT appeared to be the most affected by lecithin incorporation whereas SFO rendered harder oleogels. These results could contribute to understand the role of both lecithin and solvent type influencing the host oleogelator structure. It was hypothesized that intermolecular BG complex formation is hindered by lecithin, besides this phospholipid also might coexist as a different phase, causing structural changes in the gel network. Addressing the role of co-oleogelator it can provide the opportunity to tune soft materials with adjusted properties. PMID- 30007674 TI - Stability of curcumin in oil-in-water emulsions: Impact of emulsifier type and concentration on chemical degradation. AB - Oral ingestion of curcumin is claimed to be effective against several diseases, including inflammation and cancer. However, its utilization in food, supplement, and pharmaceutical products is often challenging due to its poor water solubility, high chemical instability, and limited oral bioavailability. Emulsion based delivery systems can be designed to overcome these challenges, but their composition and structure must be optimized to ensure they function appropriately. This study examined the impact of emulsifier type on the formation and stability of curcumin-loaded oil-in-water emulsions: sodium caseinate; Tween 80; quillaja saponin; gum arabic. The effectiveness of these food-grade emulsifiers at forming emulsions by microfluidization was characterized in terms of their surface load, i.e., the mass of emulsifier per unit surface area. The surface loads decreased in the following order: gum arabic (55.3 mg/m2) > > saponins (2.0 mg/m2) > Tween 80 (1.6 mg/m2) > caseinate (1.5 mg/m2), which indicated that much more gum arabic was required to form emulsions than the other emulsifiers. Curcumin-loaded emulsions were then prepared under conditions where there was just enough emulsifier to cover the droplet surfaces ("critical"), and under conditions where there was an excess of emulsifier in the aqueous phase ("excess"). Initially, both critical and excess emulsions were physically stable and had similar appearances. In all emulsions, curcumin degradation during storage occurred more rapidly at pH 7 than at pH 3, and was faster at 55 degrees C than at 37 degrees C. The physical and chemical stability of the curcumin loaded emulsions also depended on emulsifier type. After storage at 55 degrees C for 15 days, the extent of curcumin degradation decreased in the following order: saponins > > gum arabic ~ casinate ~ Tween 80. Moreover, droplet creaming was observed in the critical Tween 80 and saponin emulsions, but not in the other emulsions. These results suggest that saponin accelerated curcumin degradation, possibly due to its ability to promote peroxidation reactions. Emulsifier concentration did not significantly affect curcumin degradation. These results suggest that the physical and chemical stability of curcumin-loaded emulsions is influenced by emulsifier type and level. This information may be useful for formulating emulsion-based delivery systems for curcumin with improved physicochemical and functional properties. PMID- 30007675 TI - Combination of probiotic yeast and lactic acid bacteria as starter culture to produce maize-based beverages. AB - Cereal-based fermented beverages are non-dairy products which are considered possible carriers for probiotic strains and alternatives for use by vegans and lactose-intolerant consumers. In the present work, the commercial probiotic, Lactobacillus paracasei LBC-81, was used singly and in co-culture with potential probiotic yeasts, Saccharomyces cerevisiae CCMA 0731, S. cerevisiae CCMA 0732, and Pichia kluyveri CCMA 0615, to ferment a maize-based substrate. All tested strains showed viability higher than 6 log CFU/mL, as recommended for food probiotic products, except for the yeast P. kluyveri which decreased during fermentation and storage time. A reduction in pH value, from approximately 7 to 4, was observed. This decrease was due organic acid production, which did not affect the microbial viability. Lactic and acetic acids were the main organic acids produced during fermentation, and they decreased over 28 days of storage (<0.5 and 0.1 g/L for lactic and acetic acids, respectively). Ethanol was detected in the S. cerevisiae assays; however, the content was <5 g/L in a non alcoholic beverage. Seventy volatile compounds were detected, including acids, alcohols, aldehydes, esters, ketones, and other compounds. Sensory analysis showed score of 5.93-4.57, respectively for appearance and taste. This is an important result, considering that the beverage had no flavoring additive and lacked a sweet taste. Therefore, probiotic beverages were successfully obtained by maize fermentation inoculated with co-culture of S. cerevisiae (CCMA 0731 or CCMA 0732) and L. paracasei LBC-81. PMID- 30007676 TI - Study on the effect of citric acid adaptation toward the subsequent survival of Lactobacillus plantarum NCIMB 8826 in low pH fruit juices during refrigerated storage. AB - Pre-treatment of stationary phase cells of Lactobacillus plantarum NCMIB 8826 with citric acid (pH 3 to 6) for a short period of time significantly improved subsequent cell survival in several highly acidic fruit juices namely cranberry (pH 2.7), pomegranate (pH 3.5), and lemon & lime juices (pH 2.8). Although the mechanism for this adaptation is still unclear, the analysis of the cellular fatty acid content of acid adapted cells and the reverse transcription polymerase chain reaction (RT-PCR) showed a significant increase (by ~1.7 fold) of the cellular cyclopropane fatty acid, cis-11,12-methylene octadecanoic acid (C19:0cyclow7c) and a significant upregulation (~12 fold) of cyclopropane synthase (cfa) were observed, respectively, during acid adaptation. It is likely that these changes led to a decrease in membrane fluidity and to lower membrane permeability, which prevents the cells from proton influx during storage in these low pH fruit juices. PMID- 30007677 TI - Metabotyping of rice (Oryza sativa L.) for understanding its intrinsic physiology and potential eating quality. AB - Rice (Oryza sativa L.), the major staple food in many countries, has genetic diversity adapted to different environmental conditions. However, metabolic traits about diverse rice plants are rarely discovered. In the present study, rice leaves and grains were collected at whole growth stages from late (LMC) and early (EMC) maturing cultivars. Metabolic dependences of rice plants on both growth and cultivar were investigated in their leaves and grains through NMR based metabolomics approach. Rice leaf metabolome were differently regulated between two rice cultivars, thereby affecting variations of rice grain metabolome. Sucrose levels in leaves of EMC were markedly decreased compared to those in LMC, and more accumulations of sucrose, amino acids and free fatty acids were found in grains of EMC. These distinct metabolisms between EMC and LMC rice cultivars were associated with temperature during their growing seasons and might affect the eating quality of rice. The current study highlights that metabolomic approach of rice leaves and grains could lead to better understanding of the relationship between their distinct metabolisms and environmental conditions, and provide novel insights to metabolic qualities of rice grains. PMID- 30007678 TI - Untargeted metabolomics reveals predominant alterations in primary metabolites of broccoli sprouts in response to pre-harvest selenium treatment. AB - Broccoli sprouts have attracted considerable attention because of their abundant phytochemicals and high selenium accumulation capacity, which reportedly reduce the risks of different cancers and cardiovascular diseases. In this study, an untargeted metabolomics approach was developed to investigate the effect of 5 days of treatment with 100 MUmol/L selenate on the metabolome of broccoli sprouts. Results showed that the total sulfur content was slightly lower and the total selenium content was significantly higher in the selenate-treated sprouts. The multivariate statistical analyses showed that serine, d-erythronolactone, melezitose and tyrosine were obviously up-regulated, but d-glyceric acid, succinic acid and citric acid were down-regulated after selenate treatment. Moreover, metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that cannot be observed with conventional approaches. Selenate treatment influenced the metabolism of beta-alanine and glutathione, as well as the biosynthesis of plant metabolite related to the precursors of glucosinolate. These results could explain why the total glucosinolate decreased after selenate treatment. PMID- 30007679 TI - Characterization of Spanish powdered seaweeds: Composition, antioxidant capacity and technological properties. AB - This work aimed to characterise four seaweed species: nori (Phorphyra), kombu (Laminaria), wakame (Undaria) and sea spaghetti (Himanthalia elongata). Their nutritional composition, total phenolic compounds (TPC), antioxidant capacity, oil and water holding capacity (OHC and WHC), and swelling capacity (SC) were determined. Wakame and nori exhibited the highest proteins contents, rich in essential amino acids and in those related to umami flavour. All the samples had a low lipid content and high ash content values. High fibre levels were observed, especially in kombu. The TPC content and antioxidant capacity of sea spaghetti was significantly higher than in the other samples. The OHC, WHC and SC of the seaweeds demonstrated their potential influence on texture of food products. The incorporation of these seaweeds into different foodstuffs could entail an improvement of the nutritional quality and texture properties, and could also reduce the use of Na and synthetic additives. PMID- 30007680 TI - "Biosynthesis of volatile compounds by hydroperoxide lyase enzymatic activity during virgin olive oil extraction process". AB - The approach of this research was to describe the biochemical transformations of minor components of virgin olive oil with high impact on its sensory quality, specifically "volatile compounds" during its extraction process. For this purpose 'Picual', 'Arbequina' and 'Hojiblanca' cultivars were processed at three different harvesting times. Their volatile profiles and levels of enzymatic activity of "hydroperoxide lyase", responsible for the biosynthesis of C6 aldehydes related to "green and fruity notes", were monitored and identified in mesocarp, paste before kneading and paste after kneading based on the catalytic action of crude enzyme extracts. Both of them, volatiles and HPL, were analyzed by incubating with their corresponding substrates and reaction products formed were analyzed by Solid Phase Microextraction-Gas Chromatography and Mass Spectrometry. The results obtained in the present research can be useful in order to develop new markers biochemical whereby improved aroma quality in olive breeding programs or in the design of new protocol of VOO extraction. PMID- 30007681 TI - Fast analysis of polyphenols and alkaloids in cocoa-based products by ultra-high performance liquid chromatography and Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS). AB - The cocoa varieties Criollo, Forastero and Trinitario, which have different organoleptic properties, quite often are mixed together in cocoa-based products. The objective of this work was to develop a rapid method for the simultaneous determination of polyphenols (n = 35) and alkaloids (n = 2) in cocoa-based products by using the high throughput advantages provided by the Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer (HRMS). The proposed procedure was optimized and validated in terms of selectivity and specificity (mass accuracy <5 ppm), sensitivity (instrumental limit of detection from 15 to 30 fg), linearity (r2 > 0.990), accuracy (recovery range from 89.1 to 112.4%) and precision (relative standard deviation <10%). The method was applied to 80 cocoa-based samples. Alkaloids represented on average the 57.7% of assayed compounds. Flavanols and procyanidins were the most abundant polyphenols being quantified in a range between 261 and 668 mg/kg and from 127 to 405 mg/g, respectively. Mass equivalents but structural isomers bioflavonoids were characterized by using the HRMS-Orbitrap methodology here developed. PMID- 30007682 TI - Preparation and characterization of dialdehyde beta-cyclodextrin with broad spectrum antibacterial activity. AB - Consumers demand more alternatives of riskless antibacterial agents to prevent microbial contamination in food industry. Oxidized carbohydrate may be a potential option as new antibacterial agent. However, the relatively weak antibacterial property of oxidized carbohydrate is not satisfactory. In this paper, dialdehyde beta-cyclodextrins with different oxidation degree were prepared by periodate oxidation and their antibacterial properties were systematically studied. The results showed that multi-aldehyde groups were successfully introduced into beta-cyclodextrin molecules by periodate oxidation. The aqueous solubility and stability of dialdehyde beta-cyclodextrins were improved as expected. It is interesting that dialdehyde beta-cyclodextrins possessed outstanding antibacterial activity against both Gram-positive and Gram negative bacteria. The minimal inhibitory concentrations against E. coli, S. aureus and B. subtilis reached 0.63, 1.25 and 0.63 mg/mL, respectively. Moreover, dialdehyde beta-cyclodextrins effectively inhibited bacterial growth on the surface of apples. The results demonstrated that oxidized oligosaccharide with multi-aldehyde groups and good dispersibility in aqueous solution possessed satisfactory antibacterial activity, which can be used as new antibacterial agent in food industry. PMID- 30007683 TI - Structuring new alginate network aimed for delivery of dandelion (Taraxacum officinale L.) polyphenols using ionic gelation and new filler materials. AB - Alginate hydrogels are often used for immobilization of plant-derived bioactive compounds by fast and simple ionic gelation technique. However, the structure of alginate gel network is very porous and mostly result with high-diffusion rates of encapsulated compound, what limits its application as delivery vehicle. In order to prevent losses of bioactives and prepare efficient encapsulation systems, the aim of this study was to evaluate a potential of new natural fillers, cocoa powder (CP) and carob (C) for structuring alginate network aimed for encapsulation of aqueous dandelion (Taraxacum officinale L.) leaf extract using ionic gelation. Whey protein isolates served as a standard filler. The influence of different concentrations of gelling medium (2% and 3% calcium chloride) on encapsulation properties of alginate systems was also evaluated. Calcium concentration affected morphological properties (more acceptable when using 3% CaCl2), while textural properties and encapsulation efficiency of polyphenols and retained antioxidant capacity were more influenced by selected delivery materials. Alginate-whey protein isolates beads were scored with the highest loading capacity of polyphenols (>93%), while newly formulated binary mixtures (alginate-cocoa powder and alginate-carob) also enabled highly efficient entrapment of polyphenols (>88%). The slowest release of polyphenols in simulated gastrointestinal fluids were obtained when alginate was combined with CP and C, where system alginate-cocoa powder prepared with lower concentration of calcium chloride (2% CaCl2) enabled the most extended release of total polyphenols and hydroxycinnamic acids. Obtained results strongly justified implementation of new plant-derived functional fillers (cocoa powder and carob) for encapsulation purposes and opened new directions for designing of binary carrier's. PMID- 30007684 TI - Antioxidant activity and protective effects of Alcalase-hydrolyzed soybean hydrolysate in human intestinal epithelial Caco-2 cells. AB - Soybeans are known as a promising source of bioactive peptides. However, knowledge on the antioxidant behaviors of soybean protein hydrolysate (SPH) in the human intestinal epithelium is limited. In this study, SPH was prepared with Alcalase and subsequently ultrafiltered into four peptide fractions as SPH-I (<3 kDa), SPH-II (3-5 kDa), SPH-III (5-10 kDa) and SPH-IV (>10 kDa). The antioxidant properties of SPH and membrane fractions were investigated using different chemical assays and their protective effects against oxidative stress were evaluated using H2O2-stressed human intestinal Caco-2 cells. Results showed that SPH-I exhibited the strongest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC50 = 2.56 mg/mL) and reducing capacity while SPH-III had the best metal ion-chelating activity (IC50 = 0.29 mg/mL). Both SPH and the peptide fractions dose-dependently suppressed intracellular reactive oxygen species (ROS) accumulation induced by H2O2 in Caco-2 cells, but the strongest inhibitory effect was observed for SPH-I. Amino acid (AA) results revealed that SPH-I was rich in hydrophobic and antioxidant AAs, which could contribute to its stronger antioxidant properties. Additionally, SPH-I protected Caco-2 cells from H2O2-induced oxidative stress via inhibiting lipid peroxidation and stimulating antioxidant enzyme activities. These results suggest that SPH-I and constitutive peptides can be beneficial ingredients with antioxidant properties and protective effects against ROS-mediated intestinal injury. PMID- 30007685 TI - Photodynamic inactivation of Burkholderia cepacia by curcumin in combination with EDTA. AB - Burkholderia cepacia (B. cepacia) is an aerobic Gram-negative bacillus found in various aquatic environments and can cause food contamination. We investigated the photodynamic antibacterial effects of food additive curcumin combined with EDTA on B. cepacia. We found a ~4-log reduction in B. cepacia viability when photo-irradiated with curcumin at 50 MUM by blue LED light (16 mW/cm2) for 30 min with 0.4% (w/v) EDTA. Moreover, the bacterial morphological alterations and the leakage of intracellular contents were observed after photodynamic treatment. There were also obvious genomic DNA cleavage and a general loss of bacterial proteins assigned to large-scale protein degradation after photodynamic inactivation treatment. Collectively, curcumin in combination with EDTA illuminated by blue LED is a potential candidate for photodynamic inactivation of B. cepacia. PMID- 30007687 TI - Digestion fates of different edible oils vary with their composition specificities and interactions with bile salts. AB - The digestion fates of different edible oils are different. The objective of this study was to understand the influences of lipid composition on their digestion fates, and investigate the roles of bile salts (BS) played in emulsified lipid system (whey protein isolate as emulsifier) in the in-vitro small intestine digestion stage. Three typical oils (palm oil (PO), rapeseed oil (RO) and linseed oil (LINO)) were chosen. Results showed that with the BS addition increased from 0.0 to 2.0 mg/mL, the increasing magnitude of the different fatty acid (FA) apparent release rate constants were: PO > RO ~ LINO. Although the maximum FA release extent changed with BS addition, the order were: PO > RO > LINO. These may probably be attributed to palmitic acids, the most abundant FA in PO, was mostly located on the Sn-1, 3 positions of triacylglycerol (TAG) molecules, which contributed to the pancreatic lipase hydrolysis action. The relatively short chain length and the lower hydrophobicity also favored this process. However, Sn 1, 3 positions of TAGs in RO and LINO were mainly long chain mono- or poly unsaturated FAs, which restricted the continuous lipid hydrolysis. Furthermore, the lipid composition may also affect the BS behavior on the O/W emulsion droplet surface, thus modulating lipase hydrolysis reaction. These findings can provide some basic understandings of the digestion differences of different oils. PMID- 30007686 TI - Evaluation of gamma-irradiated aromatic herbs: Chemometric study of samples submitted to extended storage periods. AB - The preserving capacity of gamma radiation (10 kGy) on the chemical, nutritional and antioxidant components of Aloysia citrodora Palau, Melissa officinalis L., Melittis melissophyllum L. and Mentha piperita L., stored for 12 and 18 months, was evaluated. Despite the maintenance of the main characteristics during the first 12 months of storage, the additional 6 months induced several significant changes in individual compounds. In general, the analyzed species reacted dissimilarly throughout time, but it was possible to verify that the fatty acids, tocopherols and antioxidant capacity presented the most significant changes after 18 months of storage, inclusively in samples submitted to gamma radiation. In fact, the applied treatment (10 kGy) did not seem to be effective to prevent the decrease of free sugars, organic acids and tocopherols, especially considering the 18 months period. On the other hand, the evolution in color parameters indicated a greener color (yet slightly more yellow) among irradiated samples. Likewise, gamma radiation had a positive effect on oleic acid, beta-carotene bleaching inhibition (in infusions), DPPH scavenging activity and reducing power (in methanolic extracts). Nevertheless, it might be generally concluded that gamma radiation is less suitable than electron-beam to maintain the characteristics of dried herbs during extended storage periods. PMID- 30007688 TI - Enzyme-assisted extraction of polyphenol from edible lotus (Nelumbo nucifera) rhizome knot: Ultra-filtration performance and HPLC-MS2 profile. AB - Rhizome knot is always wasted as useless and inedible part of lotus root, despite its abundance of polyphenols. In this work, enzyme-assisted extraction followed by ultra-filtration was investigated to recover polyphenols from rhizome knot. Cellulase and pectinase treatment enhanced the polyphenols extraction. The 100 kDa membrane resulted in better filtration yield than 50 kDa membrane, 3.84% and 3.37%, respectively. With 100 kDa membrane, the highest filtration yield (4.08%) was achieved with a rotational speed of 600 rpm, TMP of 0.3 MPa and pH of 5. Satisfied permeate turbidity (<3 NTU) and polyphenol transmission (>90%) were obtained under these conditions. The main polyphenols identified in both rhizome knot extract and permeate were: chlorogenic acid, B-type procyanidin dimer.H2O, (+)-Catechin, B-type procyanidin dimer, (-)-Epicatechin, propyl gallate.H2O, caffeic acid, (-)-Epicatechin-3-gallate, and rutin. Membrane fouling led to the most important resistance (58% of total resistance). Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) evidenced that protein accumulation was the main fouling cause. PMID- 30007689 TI - Bioavailability, composition and functional characterization of extracts from Oryza sativa L. bran. AB - The aim of this study has been to assess the composition and antioxidant activities of rice bran extracts submitted to a human simulated digestion, which extraction process was previously optimized. In order to adjust the optimum values for the extraction, D-optimal experimental design and response surface methodology have been applied. Phenolic compounds and gamma-oryzanol contents have been used as response parameters. In this way, two different extracts have been obtained. The first one, was obtained with 100% water as solvent, and it was mainly composed by phenolic acids. Ferulic acid was the majority compound found with a concentration of 1.00 +/- 0.03 mg/g extract, followed by p-coumaric acid (0.19 +/- 0.02 mg/g), The second extract, extracted with ethanol as solvent, was a gamma-oryzanol enriched fraction with a content of 14.41 +/- 0.26 mg/g extract. The optimized rice bran extracts thus obtained were subjected to a process of human in-vitro digestion. In the first extract, with high polyphenol content, the phenolic content was oscillating during the digestion, like antioxidant activity. The oryzanol content found in this fraction (0.079 +/- 0.002 mg/g) has not been detected in any phase of digestion. In the second extract, with a high oryzanol content at the beginning, oryzanol content was not detected in any of digestion steps. However, phenolic composition was stable in all phases of simulation (ranging from 0.117 and 0.094 mg/g in the case of ferulic acid). This fact evidence that oryzanol is not a bioavailability fraction, while phenolic compounds support to some extent, the conditions of digestion. PMID- 30007690 TI - The production of yeast cell wall using an agroindustrial waste influences the wall thickness and is implicated on the aflatoxin B1 adsorption process. AB - The objectives of this study were: to evaluate the use of dry distillery grain soluble extract - DDGse to produce yeast biomass and to obtain cell wall (CW), to use the CW as an aflatoxin B1 (AFB1) adsorbent, to study the variation in the composition and thickness of the CW under the influence of DDGse to evaluate their implication on the adsorption process using transmission electron microscopy (TEM) and fourier-transform infrared spectroscopy (FITR). The production of biomass and CW were variable. The CW thickness values showed that S. boulardii strain grown in yeast extract peptone dextrose (YPD) or DDGse medium, with no significant differences observed. The thickness of the CW for S. cerevisiae (RC012 and VM014) were increased when the cells were grown in DDGse medium, the thickness was almost double compared to the values obtained in YPD medium. The spectra IR of each CW in the two culture media shown regions corresponding to polysaccharides, proteins and lipids. Cells grown in DDGse medium adsorbed more AFB1 than those grown in YPD. The CW adsorbed more AFB1 than the same amount of whole cell. Future studies should be done to determine the type of carbohydrates and the relationship between chitin - beta glucans responsible for mycotoxin adsorption. PMID- 30007691 TI - Bolus quality and food comfortability of model cheeses for the elderly as influenced by their texture. AB - The aim of this study was to examine the influence of the texture of dairy products on bolus properties and food comfortability as perceived by elderly persons. Four cheese models identical in terms of their nutritional composition but different by the type of texture (Soft, Hard, Processed and Whipped) were developed to resemble market cheese. Study was performed with a panel of 38 elderly persons without dental impairment but with variable rate of saliva flow. The time of chewing required to form the bolus was measured. The rheological properties of the bolus obtained were studied as well as the quantity of saliva incorporated. Food comfortability was assessed by means of a questionnaire asking about in-mouth comfort, bolus formation, pain, and perceived texture and flavor. Results showed that food comfortability was positively correlated to the ease of forming the bolus which depended on the food texture. Thus, the bolus formed with the Whipped product which required more saliva, was harder than the other three products and so judged the least comfortable. This product was characterized by a dry and sticky texture. On the other hand, the Soft and Processed products led to a softer food bolus that was more easily formed, and thus were judged as more comfortable. Their textures were perceived as soft, fatty and melting. This work highlights the importance of considering food bolus formation and related properties when looking for the link between food product characteristics and the enjoyment of eating in the case of the elderly population. PMID- 30007692 TI - Influence of polyphenol rich seabuckthorn berries juice on release of polyphenols and colonic microbiota on exposure to simulated human digestion model. AB - The present study investigated the effect of polyphenol rich Sea buckthorn berries juice (SBJ) on colonic microbial composition and diversity using in vitro simulated gut model. The release of polyphenols, their antioxidant activity and impact on microbial diversity was evaluated under long term fermentation for 21 days. The treatment of colonic reactors with basal feed supplemented with SBJ resulted in an increase in population and diversity of beneficial bacteria as revealed by viable cell count and PCR-DGGE. A higher release of phenolics was observed, which resulted in higher antioxidant activity in the colonic reactors throughout the treatment period (p < 0.05). Higher content of resveratrol, rutin and chlorogenic acid were observed in ascendens colon whereas quercetin, ferulic and caeffic acid level were higher in descendens colon due to biotransformation of polyphenols in the later part of colon. The Principal Component Analysis also indicated the stimulatory effect of SBJ on the beneficial microbial population of Lactobacilli, Bacteroides/Prevotella and Bifidobacteria in all the three reactors. It also confirmed higher release of polyphenolic compounds and associated antioxidant activities in descendens colon. PMID- 30007693 TI - The effect of repeated versus continuous annealing on structural, physicochemical, and digestive properties of potato starch. AB - Native potato starch was suspended in distilled water at starch: water ratio of 1:3 (w/v). The starch-water suspensions were then subjected to repeated annealing treatments (RANN) at 55 degrees C for 12 h, repeated for 8 cycles or continuous annealing treatments (CANN) at 55 degrees C for 24, 48, 72 and 96 h. The structural, physiochemical and digestive properties of the annealed starch samples were studied and compared with those of the native starch. The scanning electron microscopy and light microscopy analysis showed that the repeated and continuous annealing treatments could keep the integrity and surface perfection of the starch granules. The growth rings of the annealed starch granules were more distinct than those of the native starch granules as revealed by confocal laser scanning microscopy. The crystallinity degree increased and the crystalline retained the B-type pattern after the annealing treatments. There were no chemical bonds and functional groups produced or disappeared during the applied annealing treatments. Infrared absorption peak intensity of starch decreased and short-range ordered structures increased after treatments. The swelling power and solubility decreased at low temperature (50 to 60 degrees C) and increased at relatively high temperature (70 to 90 degrees C). The rapid visco-analyzer and differential scanning calorimeter analysis revealed an increase in the setback, final viscosity, pasting temperature and gelatinization transition temperature, and a decrease in breakdown value of the starch after the annealing treatments. On the other hand, the repeated and continuous annealing treatments resulted in starch with low in vitro digestibility degree, indicating formation of resistant starch. Generally, the repeated annealing treatment resulted in starch with high improved properties compared with the starch resulted from the continuous annealing treatments. Therefore, the repeated annealing treatments can be suggested as an effective method for producing of modified starch for food industrial applications. PMID- 30007694 TI - Understanding the crystal structure of lotus seed amylose-long-chain fatty acid complexes prepared by high hydrostatic pressure. AB - This paper presents an innovative approach using high hydrostatic pressure to prepare lotus seed amylose-long-chain fatty acid (stearic acid, oleic acid, and linoleic acid) complexes. The aim of this work was to investigate the spherocrystal structure and distribution of fatty acid within complexes. Wide angle X-ray diffraction diffractograms indicated the presence of typical V6-type polymorphs and B-type non-complexed amylose. The V6-type complexes were further confirmed as V6III polymorph from nuclear magnetic resonance. The degree of crystallinity and the complex index value decreased as the preparation pressure of the complexes increased, and the amylose-oleic acid complexes exhibited the highest relative crystallinity and complex index value in all of the conditions. Small-angle X-ray scattering indicated a larger proportion of crystalline and more compact structure within complexes than that of lotus seed amylose. The morphology of complexes with the spherulite form was determined from scanning electron microscopy images, and the distribution of fatty acid molecules within the spherulites of complexes was estimated using nuclear magnetic resonance, confocal laser scanning microscopy, and small-angle X-ray scattering. The results demonstrated that the fatty acids were within and between the amylose helix, and they were also trapped inside the amorphous lamellae of the complexes. This work provides an in-depth study of the spherocrystal structure within lotus seed amylose-long-chain fatty acid complexes and proposes a new model for spherulites. PMID- 30007695 TI - Assessment of the antioxidant effect of astaxanthin in fresh, frozen and cooked lamb patties. AB - Astaxanthin is a natural red carotene exerting a strong antioxidant action. The effect of this carotene on the oxidative stability of raw and cooked lamb patties was evaluated. Seven experimental treatments were included in this study depending on the antioxidants added, which are: no antioxidant added (control), 450 mg/kg of sodium metabisulphite, 500 mg/kg of sodium ascorbate, and 20 mg/kg, 40 mg/kg, 60 mg/kg and 80 mg/kg of astaxanthin. The raw patties were either refrigerated for up to 11 days or frozen for 3 months under aerobic conditions. Changes in thiobarbituric reactive substances (TBARS), instrumental colour, pH and Eh were determined in the refrigerated patties and TBARS in the frozen patties. Volatile compounds were determined in cooked patties and cholesterol oxides in both cooked and after cooking microwave reheated patties. The changes in TBARS of cooked patties during a four-day refrigerated storage were also studied. Compared to the control patties, the use of astaxanthin reduced the TBARS generation in a manner depending on the dose for both raw and cooked patties during storage (P < 0.05). Astaxanthin added at levels of 60 and/or 80 mg/kg showed a greater antioxidant effect than ascorbate and metabisulphite. The presence of astaxanthin, like that of ascorbate, decreased the oxysterols levels of cooked patties with regard to controls. The amount of volatiles released from the cooked patties was also reduced by astaxanthin. This effect was not observed for ascorbate or metabisulphite. Astaxanthin in lamb patties at levels of 60-80 mg/kg could improve raw and cooked lamb patty oxidative stability during refrigerated aerobic storage, protect their lipids against thermal degradation more than ascorbate and metabisulphite, and reduce oxysterols formation during cooking in a similar way to ascorbate. PMID- 30007696 TI - The simultaneous loading of catechin and quercetin on chitosan-based nanoparticles as effective antioxidant and antibacterial agent. AB - A novel chitosan-based nanoparticle (G-C-Q NPs), which simultaneously loaded catechin and quercetin, was synthesized through ionic gelation reaction between chitosan and sodium tripolyphosphate and subsequent modification by genipin. Chemical structure, size distribution, morphology, entrapment efficiency, in vitro release behavior, antioxidant and antibacterial effects of G-C-Q NPs were investigated. Results showed that G-C-Q NPs were dispersed as an ellipsoidal shape with an average diameter of 180.4 nm and a zeta potential of 31.79 +/- 1.28 mV. Entrapment efficiency of catechin and quercetin reached 76.35 +/- 1.37% and 52.23 +/- 2.45%, respectively. In vitro release study showed that both catechin and quercetin had a sustainable release from the G-C-Q NPs. G-C-Q NPs had higher or comparable potency in scavenging DPPH, ABTS+, OH and O2- radicals and in suppressing growing of Escherichia coli, Bacillus subtilis Staphylococcus aureus as compared to native drugs (single or combination). These results contribute some basis to the design and fabrication of polymeric nanoparticle delivery systems for multiple bioactive compounds with beneficial properties. PMID- 30007697 TI - Variation of triacylglycerol profiles in unfermented and dried fermented cocoa beans of different origins. AB - Fermentation and drying are the two crucial processing steps required to produce cocoa beans with desired properties, especially taste and flavor. To understand their impact on the lipid profile of cocoa, the lipid composition of unfermented raw and fermented dried beans from six different origins was investigated using high-performance liquid chromatography-mass spectrometry methods. While the comparison of triacylglycerol profiles across the different origins showed only small variations in individual compound concentrations, the comparison along the fermentation status showed major differences regarding the occurrence of polar lipids. These compounds may serve as biomarkers for the fermentation status of the beans and a simple analytical method suitable for field trials is proposed. Finally, a hypothesis identifying key unsaturated triacylglycerols contributing to the hardness and softness of cocoa butter is presented. PMID- 30007698 TI - Comparison of different clustering methods for investigating individual differences using choice experiments. AB - Different strategies for investigating individual differences among consumers using choice experiments are compared. The paper is based on a consumer study of iced coffee in Norway. Consumers (n = 102) performed a choice task of twenty different iced coffee profiles varying in coffee type, production origin, calorie content and price following an orthogonal design. Consumer factors, such as socio demographics, attitudes and habits, were also collected. Choice data will be analysed using two different clustering strategies. Strategy one is the most classical approach called Latent Class Logit (LCL) model, while Strategy two uses Mixed Logit (ML) model combined with Principal Component Analysis (PCA) for visual segmentation or with automatic clustering detection using Fuzzy C Means clustering (FCM). The clusters obtained can be interpreted using external consumer factors by using the Partial Least Square - Discrimination Analysis (PLS DA) model. The different approaches are compared in terms of data analysis methodologies, modelling, outcomes, interpretation, flexibility, practical issues and user friendliness. PMID- 30007699 TI - Natural antioxidants in processing and storage stability of sheep and goat meat products. AB - Oxidative damage is one of the main reasons for loss of quality in sheep and goat meat and meat products. Synthetic antioxidants are the current solution to stabilize oxidative process and extend the shelf life of such products; however, the negative impact on health may impose a risk to consumers. Natural antioxidants, extracted from several vegetable sources, have been considered an attractive alternative for this conflicting situation. Phenolic compounds are minor components in herbs, spices, tea and fruits that display potential application against the progression of lipid and protein oxidation and their consequences for meat quality, which can even overcome the protective effect of synthetic compounds. This review aims to discuss the mechanisms associated to lipid and protein oxidation and their implications on meat quality attributes and provides recent data regarding the application of natural antioxidants in sheep and goat meat products, which have a high susceptibility to oxidative processes compared to other red meats. PMID- 30007700 TI - Sensory evaluation of dark origin and non-origin chocolates applying Temporal Dominance of Sensations (TDS). AB - Dark chocolates are rich sources of polyphenols, widely acknowledged for eliciting several beneficial health effects. However, these compounds are key inducers of bitter taste and astringency, potentially limiting consumers' acceptance of chocolates with higher cocoa contents. In order to gain better insight in consumers' choices, the present study investigated the temporal profile of bitterness and astringency as well as sweet taste as covering agent, during the testing period in 5 dark origin (OR) (66.8-80.1% cocoa) and 6 non origin (N-OR) (54.5-80.0% cocoa) chocolates with different cocoa contents, applying Temporal Dominance of Sensations (TDS). The temporal profile of the evaluated OR chocolates was characterized by the dominance of bitterness independent of cocoa contents (%cc), reaching maximum dominance rates (DR%) between 60.0 and 80.0% over approximately 75.0% of the testing period, i.e. prior to swallowing. After swallowing, astringency dominated, mostly not significantly. DR (%) of sweetness reached the level of significance only in one sample (OR 67.4%cc). N-OR chocolates with 54.5-60.0%cc were characterized by significant dominances of sweet taste along the entire evaluation period, reaching maximum DR% between 90 and 95%. The increase of cocoa contents was combined with higher DR% of bitter taste. Astringency dominated in N-OR samples at the end of the evaluation period presumably after swallowing. Finally, in N-OR chocolates, cc% highly affected the dominance of the evaluated attributes. This impact was found to be rather minor or absent in OR chocolates. Thus, the TDS-parameters showed variations in attribute's dominance in OR and N-OR chocolates indicating a strong influence of cocoa bean variety and local conditions (environmental and farming conditions as well as post-harvest treatment practices) in addition to cocoa contents. PMID- 30007701 TI - Extraction of carotenoids from cantaloupe waste and determination of its mineral composition. AB - The carotenoid and mineral levels as well as the in vitro antioxidant capacity, using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, of waste from cantaloupe was assessed. Then the matrix was subjected to ultrasound assisted extraction (UAE) and response surface methodology (RSM) was used for the optimization of the extraction of carotenoids. The effect of the extraction procedure on the microstructure of the powder was assessed by scanning electron microscopy (SEM) analysis. The major carotenoids identified were lutein (63.24 +/ 0.73 MUg betaCE/g dw) and beta-carotene (56.43 +/- 0.11 MUg betaCE/g dw). Several mineral elements (K, Na, P, Mg, Ca, Fe, Cu, Mn and Zn) were identified, potassium being the major one.The extract exhibited in vitro antioxidant activity (IC50 = 7.33 +/- 0.22 MUg/mL). The RSM results showed that an amplitude of 100%, extraction time of 10 min, hexane percentage of 80% in hexane/acetone solvent, and solvent-to-solid ratio of 55 mL/g were the optimal conditions for the extraction of carotenoids. Under these conditions, the carotenoid content of the extract was 124.61 +/- 3.82 MUg/g.The microscopic analysis revealed the effectiveness of the ultrasound treatment that results in noticeable physical changes, like microscopic perforations and breakages. PMID- 30007702 TI - The role of edible oils in low molecular weight organogels rheology and structure. AB - In this paper, the role of solvent characteristics on the rheological and physicochemical properties of organogels was investigated using different techniques. Vegetable oils, such as rice, sunflower and castor oil were used as solvents, for producing organogels with monoglycerides of fatty acids or a mixture of fatty alcohols (policosanol) as gelators. Moreover, two non-edible oils (silicon and paraffin oil) were also used for analysing the properties of solvents completely different in nature with respect to the edible ones, for a better interpretation of the given results. Organogels were investigated from a rheological point of view and through a microscopic analysis, given by polarised light (POM) and atomic force (AFM) microscopy, and X-rays to study the crystallinity of the system. The IR technique was used to analyse the intermolecular interactions, resulting in interesting information about the effect of oil polarity on the driving forces promoting structuration. This investigation showed that when solvents of a similar chemical nature are used, their physical properties, mainly oil polarity, are strictly related to the properties of the organogel, such as the onset of crystallisation temperature, the stiffness of the final material and its crystallinity. Anyway, these physical parameters seem insufficient to describe properly the role of solvents when oils of a different chemical nature are compared. PMID- 30007703 TI - Acai (Euterpe oleracea Mart.) seed flour prevents obesity-induced hepatic steatosis regulating lipid metabolism by increasing cholesterol excretion in high fat diet-fed mice. PMID- 30007704 TI - Rhizobium and Phyllobacterium bacterial inoculants increase bioactive compounds and quality of strawberries cultivated in field conditions. AB - Strawberries (Fragaria * ananassa Duch.) are widely demanded by the consumers because they contain several bioactive compounds, mainly vitamin C and anthocyanins, which may be increased by biofertilization with some plant growth promoting bacteria. In this work we have analysed two bacterial strains, PEPV15 and PEPV16, from genera Phyllobacterium and Rhizobium, respectively, which under microcosms conditions were able to promote the strawberry growth, increasing the content of some bioactive compounds, such as vitamin C or organic acids. Here we have analysed the effect on bioactive compounds in strawberries from plants biofertilized with the strains PEPV15 and PEPV16 in field conditions. Under these conditions, the anthocyanin content was increased when plants were biofertilized with the strain PEPV15 and the pelargonidin-3-O-rutinoside content significantly increased. Besides, citric acid, vitamin C and epicatechin contents were significantly higher when either of the two strains was used as biofertilizer. Our results showed that the inoculation with Phyllobacterium and Rhizobium strains is a good agronomical practice, which improve the content of several bioactive compounds of strawberries increasing the beneficial effects on human health. PMID- 30007705 TI - Encapsulation of cactus (Opuntia megacantha) betaxanthins by ionic gelation and spray drying: A comparative study. AB - The encapsulation of betaxanthins from orange Opuntia megacantha fruits was performed as a stabilisation strategy for these natural pigments. Betaxanthin rich extract (BE) was encapsulated by two methodologies, spray drying (SD) and ionic gelation (IG). Encapsulates were obtained by using two encapsulating agents (EA), a mixture of maltodextrin-cactus cladode mucilage and sodium alginate (SA) for SD and IG, respectively. Their properties were compared with the freeze-dried cactus fruit pulp (CP) as control. Total betaxanthin content, moisture content, water activity (aw), particle size, morphology by SEM, colour parameters (CIELab), and thermogravimetric properties were analysed in the encapsulates. Additionally, the antioxidant activity, total dietary fibre content, and pigment stability of encapsulates under two relative humidity conditions were also evaluated. The results showed that the encapsulation technique, EA concentration, and the BE/EA ratio affected the particle size and morphology, the glass transition temperature, and the mass loss of encapsulated materials. The best pigment stabilisation was obtained for the SD capsules, although both encapsulation techniques allowed improving the pigment stability in comparison with the CP taken as control. These results provided evidence that betaxanthins from Opuntia megacantha have the potential to be used as natural pigments, soluble in water, with functional properties for the food industry. PMID- 30007706 TI - Bacterial and fungal microbiota in traditional Bangladeshi fermented milk products analysed by culture-dependent and culture-independent methods. AB - Dahi, chanar-misti, paneer, and borhani are traditional fermented milk products in Bangladesh. We evaluated the microbial properties of these products by analysing their bacterial and fungal microbiota using classical culture-dependent and culture-independent methods, including 16S rDNA (V4) and internal transcribed spacer (ITS) region pyrosequencing. The viable lactic acid bacteria (LAB) count was 6 and 8 log colony-forming units (CFU)/g. The yeast count was about 3 to 8 log CFU/g. The counts of aerobic gram-positive and gram-negative bacteria in paneer and borhani samples were similar to that of the LAB count. Pyrosequencing results revealed a high abundance of gram-negative bacteria (Acinetobacter, Enterobacteriaceae, and Aeromonadaceae) in chanar-misti, and of Moraxellaceae in paneer. Various bacteria and fungi, including intestinal and mastitis-related microorganisms such as Bifidobacterium, Clostridium, Veillonella, and Clavispora lusitaniae, were found in chanar-misti. These results indicate that more safety processes are necessary for the preparation and manufacture of ready-to-eat (RTE) foods. PMID- 30007707 TI - Moringa plants: Bioactive compounds and promising applications in food products. AB - Moringa plants have an extensive range of bioactive compounds that can be obtained from different vegetative structures, such as leaves, seeds, stems and pod husks. These bioactive molecules include carbohydrates, phenolic compounds, oils and fatty acids, proteins and functional peptides and have great potential to be used in several formulations of food products. This report collects recent information concerning bioactive molecules in other species of the Moringaceae family, different from Moringa oleifera. Thus, this document aims to describe these bioactive compounds and their functional properties on foodstuffs. In addition, more suitable methodologies applied for their extraction and characterization are reviewed. Finally, an overview of patents required to protect Moringa-derived products and processes is provided. PMID- 30007708 TI - Zein-polysaccharide nanoparticles as matrices for antioxidant compounds: A strategy for prevention of chronic degenerative diseases. AB - Oxidative Stress (OS) produces the formation of free radicals and other reactive oxygen and nitrogen species that are intimately involved in many diseases, especially Chronic Degenerative Diseases (CDD) such as cancer, diabetes, cardiovascular diseases, and obesity, among others. Thus, reactive compounds need to be quenched by antioxidants. The problems of these compounds include that they are susceptible to degradation, have low bioavailability, and can lose their bioactivity in the gastroIntestinal tract. Therefore, an alternative is encapsulation. Zein is a protein used in nanotechnology as a polymer matrix because it can encapsulate different compounds such as antioxidants to provide stability and control of the release. The disadvantage of zein as a delivery vehicle is that it is limited by the low stability of aggregation when suspended in water, in addition to the conditions of acid pH or that higher ionic strength tends to destabilize. To reduce these limitations, the incorporation of polysaccharides as a second polymer matrix can provide stability in zein nanoparticles. In this review, we discuss OS as a source of CDD, the role of antioxidants in the prevention of these diseases, and the preparation, characterization, and application of antioxidant-zein-polysaccharide particles as delivery systems as well as possible mechanisms to control CDD. PMID- 30007709 TI - Experimental approach for a possible integrated protocol to determine sanitizer activity against both planktonic bacteria and related biofilms. AB - The persistence of pathogenic bacteria in industrial settings is linked to biofilm embedded bacteria resistance to antimicrobial and disinfectant methods effective against planktonic cells. We proposed an experimental approach to evaluate sanitizers effectiveness against both planktonic microorganisms and related biofilms as possible integration of the official EN 1276 procedure. Firstly, the efficacy of three chemicals sanitizers was tested on planktonic cells of Escherichia coli O157:H7 ATCC 35150, Staphylococcus aureus ATCC 43387, Pseudomonas aeruginosa ATCC 9027, Enterococcus faecalis ATCC 29212 and Candida albicans ATCC 14053 using the suspension test indicated by EN 1276 in both dirty and clear simulated conditions (0.3% or 0.03% of bovine serum albumen). The sanitizers were tested against the related biofilms developed on stainless steel for 48 h at room temperature. The sanitizers (SANI 626, SUPERIG, IGIEN 155) reached 5-logarithmic reduction at the manufacture's recommended concentrations after 30 s and 5 min against planktonic microorganisms but, sometimes, the organic load interfered with their activity. The same concentrations tested with the proposed protocol weren't effective against biofilms and a log reduction >3 was reached using higher concentrations of the sanitizers and 15 min of contact, with the exception of IGIEN 155. The efficacy of a disinfectant/sanitizer is assessed against planktonic microorganisms and bacteria adhered to surface, while those embedded in biofilms are not taken into consideration. The proposed protocol could be used to evaluate the effectiveness of a sanitizer also against microorganisms organized in biofilms, in order to give to the users more detailed information on its activity. PMID- 30007710 TI - Effect of coffee roasting on in vitro alpha-glucosidase activity: Inhibition and mechanism of action. AB - In vitro alpha-glucosidase inhibitory activity of unroasted, and medium, dark and very dark roasted robusta coffee was studied. Coffee extracts significantly inhibited the enzyme activity in a dose-dependent way. The inhibitory activity was well correlated with the degree of roast. Coffee components were separated by gel permeation chromatography into low (1 < MW < 6 kDa), intermediate (15 < MW < 60 kDa) and high (MW > 100 kDa) molecular weight fractions, which were analyzed for the alpha-glucosidase inhibitory capacity. Only fractions obtained from dark and very dark roasted coffee exhibited inhibitory effect. When the same fraction was obtained from coffee presenting different roasting degree, changes in alpha glucosidase inhibition extent were observed. This was attributed to compositional changes within each fraction as induced by roasting. Coffee extracts and their fractions exerted a mixed-type to competitive inhibition against alpha glucosidase and these mechanisms are consistent with the complexity of coffee composition. PMID- 30007711 TI - Effect of mitochondrial cytochrome c release and its redox state on the mitochondrial-dependent apoptotic cascade reaction and tenderization of yak meat during postmortem aging. AB - We aim to investigate the effect of mitochondrial cytochrome c release and its redox state on the mitochondrial-dependent apoptotic pathway and yak meat tenderization during postmortem aging. Results indicated that the internal environment factors considerably decreased, whereas mitochondrial dysfunction increased in the early stage (0-72 h). Moreover, the release of mitochondrial cytochrome c into the cytosol, which was an apoptotic early event and the apoptosome elements in the cytoplasm changed remarkably with the increase of aging time. Meanwhile, N,N,N',N'-tetramethylphenylene-1, 4-diamine (TMPD) inhibited the mitochondrial apoptotic process and postmortem meat tenderization by influencing the redox state of cytochrome c and apoptotic factors. These findings confirmed that the internal environment factors in the muscles provided essential conditions for mitochondrial cytochrome c, which activated the mitochondrial apoptotic pathway by forming apoptosome complexes. The reduction state of cytochrome c produced by TMPD plays a negative role in the activation of the mitochondrial apoptotic cascade reaction and meat tenderization during postmortem aging. We conclude that mitochondrial cytochrome c release and oxidized cytochrome c plays a significant role in yak meat tenderization by regulating the mitochondrial apoptotic pathway. PMID- 30007712 TI - The use of indigenous Saccharomyces cerevisiae and Starmerella bacillaris strains as a tool to create chemical complexity in local wines. AB - The performance of two vineyard strains, Saccharomyces cerevisiae SacPK7 and Starmerella bacillaris StbPK9, was evaluated in laboratory and pilot scale fermentations of Cretan grape must under the following inoculation schemes: single inoculation of SacPK7 (IS), simultaneous inoculation of StbPK9 and SacPK7 (SM), and sequential inoculation of StbPK9 followed by SacPK7 (SQ). Un-inoculated (spontaneous) fermentations (SP) and fermentations inoculated with control S. cerevisiae strains (CS) were also conducted as reference. Star. bacillaris not only did not restrict but also slightly promoted the growth of S. cerevisiae when the two strains were co-inoculated at equal quantities. On the contrary, the SQ inoculation scheme conferred a competitive advantage to Star. bacillaris over S. cerevisiae, which maximum population was reduced, while increased levels of Star. bacillaris were recorded. The fermentation kinetics were also affected, accordingly. The completion of fermentation was faster in SM, IS and CS ferments than in SQ and SP. Ethanol accumulation had a predominant role in the early death of Star. bacillaris, since its growth was similarly arrested irrespective of the dominating yeast species, the magnitude of yeast population or the availability of energy sources. Interestingly, the inoculation scheme applied significantly affected the chemical profiles of the resulting wines. SQ produced the most divergent chemical profile in sterile must, with glycerol, acetic acid, acetaldehyde, residual glucose, malic acid, ethyl acetate and higher alcohols being the key compounds affected by the prolonged activity of StbPK9. In pilot scale ferments, the indigenous S. cerevisiae produced twice as high levels of esters and higher alcohols compared to the commercial starter. Star. bacillaris further increased the levels of ethyl esters in the respective ferments. The use of a mixed S. cerevisiae/Star. bacillaris starter culture instead of S. cerevisiae alone enhanced the chemical complexity of Cretan local wine. The magnitude of differentiation was even higher when the addition of Star. bacillaris preceded that of S. cerevisiae. The highest divergence in analytical profiles was recorded between wines produced by native strain combinations and commercial S. cerevisiae. Present results show that the use of indigenous yeast formulations provides significant diversification to local wines, in line with the microbial terroir concept and recent observations that indigenous yeast strains may confer regional characters to wines. PMID- 30007713 TI - Analyses of microbial community of naturally homemade soybean pastes in Liaoning Province of China by Illumina Miseq Sequencing. AB - Traditional Chinese soybean pastes are homemade using natural fermentation and are quite common and popular in Liaoning Province. In this study, we investigated microbial diversity by collecting 23 samples from 10 cities and sequenced them using 2 * 300 bp Illumina Miseq Sequencing. 16S and ITS primers were used to amplify the V3-V4 region of the bacterial 16S rRNA gene and the ITS1 region of the fungal ITS rDNA gene, respectively. In total, 687,888 filtered bacterial sequences were obtained from nineteen samples and 1,091,649 filtered fungal sequences were obtained from twenty samples. Among the bacterial sequences, Firmicutes (74.77%), Proteobacteria (22.61%), and Actinobacteria (2.55%) were the predominant phyla, with Staphylococcus making up most of the Firmicutes. Among the fungal sequences, Ascomycota, Basidiomycota and Zygomycota accounted for 94.88%, 3.29% and 1.77%, respectively, while Glomeromycota and Chytridiomycota accounted for the remaining 0.06%. Most of the species from Ascomycota were unclassified Trichocomaceae and Debaryomyces, including 404578 and 187827 sequences, respectively. The microbial community in each sample was unique, most likely due to the geographical differences and external factors including the environment and manufacturing process during the fermentation. Soybean paste is the result of fermentation involving a great diversity of microorganisms, which include not only bacteria but also fungi. PMID- 30007714 TI - Essential oil based nanoemulsions to improve the microbial quality of minimally processed fruits and vegetables: A review. AB - Due to the convenience and nutritional value, minimally processed fruits and vegetables (MPFV) are one of the rapid growing sectors in the food industry. However, their microbiological safety is a cause of great concern. Essential oils (EOs), known for potent antimicrobial efficacy have been shown to reduce microbial load in MPFV, but their low water solubility, high volatility and strong organoleptic properties limit their wide use. Encapsulating EOs to nanoemulsion offers a viable remedy for such limitations. Due to the unique properties of the EOs nanoemulsion, there has been an increasing interest in their fabrication and use in food system. The present review article encompasses the overview of the prominent microflora present in MPFV, the recent developments on the fabrication and stability of EOs based nanoemulsion, their in vitro antimicrobial activity and their application in MPFV. This review also discusses the EOs based nanoemulsions antimicrobial mechanism of action and their regulatory issues related to their use. Application of EOs based nanoemulsion either as washing disinfectant or with incorporation into edible coatings have been shown to considerably improve the microbial quality and safety of MPFV. This efficacy has been further shown to increase when combined with other hurdles. However, further studies are required on the toxicity of EOs based nanoemulsion to assure its commercial exploitation. PMID- 30007715 TI - Oak wood extracts as natural antioxidants to increase shelf life of raw pork patties in modified atmosphere packaging. AB - The use of antioxidants and refrigeration storage in modified atmosphere packaging, MAP, are the main strategies to slow down the oxidative and microbial deterioration of fresh meat. Synthetic antioxidants are commonly used for this purpose, however due to their controversial health effects, natural alternatives for their replacement are being looked for. The main aim of this work is the evaluation of pressurised aqueous extracts from oak wood as natural preservative of pork patties. The effect of different amounts of oak wood extracts (0.05, 0.5 and 1.0%) on the self-life of pork patties packed in MAP in refrigeration during 12 days were studied in comparison with the use of sodium ascorbate as synthetic preservative. Samples treated with oak wood extracts showed lower lipid oxidation, higher antioxidant capacity and an inhibitory effect on the enterobacteria growth. Furthermore, the addition of oak wood extracts resulted in a dramatically decrease of the volatile compounds coming from the lipid oxidation reactions. On the other hand, it is noteworthy that the use of oak wood extracts modified sensorial characteristics. Intensity colour was higher and new sensorial features such as oak wood and sweet spices appeared which were well appreciated. PMID- 30007716 TI - Creation of internal structure of mashed potato construct by 3D printing and its textural properties. AB - 3D printing was used for printing mashed potatoes (MP) constructs with variable internal structures. The dimensional properties, textural and structural qualities of the printed objects were investigated as a function of infill levels (10, 40 and 70%), infill patterns (rectilinear, honeycomb and hibert curve), and number of shell perimeters (3, 5 and 7). The printed samples significantly matched the designed geometries. Hardness and gumminess were strongly related to infill levels and perimeters, but the printing paths being performed to fill the samples showed no effect on them. Firmness and Young's modulus were only affected by infill percentage but not by perimeters and printing paths. Further, comparative assessment of 3D printed and cast samples were also conducted on the textural properties and microstructure features. Microstructure analysis indicated a uniform internal structure was obtained for cast sample. In comparison, an obvious layered structure was observed in longitudinal-sectional direction while a porous structure was obtained in cross-sectional view of 3D printed samples regardless of infill levels. 3D printed samples, even at 100% infill, were significantly (p < .05) less hard, by up to 26.75% and 28.36% in terms of hardness and gumminess, compared to cast samples. The results suggest that 3D printing considerably changes the properties of printed samples, possibly offering a new way for tailoring textural properties of printed samples through creating their internal structure. PMID- 30007717 TI - Combined effect of xanthan gum and water content on physicochemical and textural properties of gluten-free batter and bread. AB - The objective of this study was to evaluate the combined effect of xanthan gum (XG) on physicochemical, rheological and textural properties of gluten-free batter and bread. To prepare gluten-free batter, different levels of XG (1.5, 2.5 and 3.5%) and water (90, 100 and 110%) were added to a base formula of rice (50%), maize (30%) and quinoa flours (20%); and the batters were evaluated in a factorial design. Several properties on both batter (stickiness and back extrusion) and its corresponding bread (loaf specific volume, baking loss, water activity and pH, texture profile, mean cell area, mean cell density, cell size uniformity, void fraction, mean cell compactness and mean cell aspect ratio) were then evaluated. Higher XG doses (p < .001) tended to produce batters of lower stickiness, adhesion and cohesive-strength, yet, of higher firmness, consistency, cohesiveness and viscosity index. After baking, these loaves presented lower specific volume; lower crumb aw, pH, hardness, springiness, mean cell area and void fraction; and higher (p < .001) chewiness, resilience, mean cell density, cell size uniformity and mean cell compactness. The sticker and less consistent batters produced with higher WC rendered larger bread loaves of softer and more springy/resilient crumbs with greater mean cell size and void fraction. Gluten free loaves of good appearance in terms of higher specific volume, lower crumb hardness, higher crumb springiness, and open grain visual texture were obtained in formulations with 110% WC and XG doses between 1.5 and 2.5%. PMID- 30007718 TI - Comparative experiments of fibril formation from whey protein concentrate with homogeneous and secondary nuclei. AB - Two types of special structures, homogeneous and secondary nuclei, form during fibril formation. The structural and functional properties of amyloid fibrils in whey protein concentrate (WPC) with different ratios of added homogeneous nuclei to secondary nuclei were investigated. Thioflavin T fluorescence analysis and kinetic equations indicated that two types of nuclei could accelerate WPC fibrillation compared with WPC self-assembling into amyloid fibrils, thereby reducing the lag time and increasing the number of fibrils. However, there were considerable differences in the nucleation-inducing capability of WPC fibrillation between homogeneous and secondary nuclei. The number of fibrils formed by adding homogeneous nuclei was higher than that obtained with secondary nuclei, the increase in the Th T fluorescence intensity induced by homogeneous nuclei was 1.83-fold much than secondary nuclei. Meanwhile, secondary nuclei yielded a 2.71-fold faster aggregation rate of WPC than homogeneous nuclei, particularly during the first hour of thermal treatment (protein mass ratio of nuclei to WPC 1:1). The gelation time of WPC after secondary nuclei addition was shorter, from 10 h (WPC (2.0/6.5)) to 4 h (WPC + HN) to 2 h (WPC + SN); however, the gel microstructure of WPC after the addition of homogeneous nuclei was denser, yielding a preferred water holding capacity. PMID- 30007720 TI - Hydrolysis of food-derived opioids by dipeptidyl peptidase IV from Lactococcus lactis spp. lactis. AB - Food-derived opioid peptides that are released from proteins by digestion, fermentation, or food production processes lead to several health problems. The opioids are generally resistant to hydrolyze by proteases, except the dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme, because of proline amino acid. beta casomorphin (BCM) from milk casein, gluteomorphin (GM) from wheat gluten, and soymorphin (SM) from the soybean beta-conglycinin beta-subunit are natural substrates of DPPIV because of their amino acid sequences and proline location. In the present study, DPPIV from Lactococcus lactis spp. lactis was purified and characterized by mass spectrometry. Purified DPPIV was added to standard BCM, GM, and SM, and hydrolysis percentages of morphins were measured by HPLC analysis. The results indicated that DPPIV enzyme hydrolyzed food-derived opioids (from 0.1 mM to 2 mM), BCM (33.42% for 2 mM), SM (83.81% for 2 mM), and GM (45.73% for 2 mM) in vitro. Hydrolysis percentages of SM were considerably higher than the same concentrations with BCM and GM. For dietary supplements to be promising for reducing the adverse effects of food derived opioids, this must be supported by in vivo studies of DPPIV use in the human body. PMID- 30007719 TI - Dynamics and diversity of microbial community succession during fermentation of Suan yu, a Chinese traditional fermented fish, determined by high throughput sequencing. AB - The main goal of this study was to investigate the dynamics, diversity and succession of microbial community present during the preparation of Suan yu (fermented fish), with and without starter cultures by high-throughput sequencing of 16S rRNA and ITS1 genes. Firmicutes and Ascomycota were the predominant phyla of bacteria and fungi, respectively, in all samples. At the genus level, Lactobacillus, Macrococcus and Staphylococcus were the predominating bacteria throughout the fermentation process, regardless of the inclusion of starter cultures. Saccharomyces was the predominating fungal genus in the early fermentation stage of samples that inoculated starter cultures (MS), while the final product was dominated by Candida and Wickerhamomyces. Compared with naturally-fermented samples (NS; no starter cultures), Lactococcus, Leuconostoc, Enterococcus, Vibrio, Fusicolla and Torulaspora were inhibited and Aureobasidium emerged in samples inoculated with starter cultures (P < .05). Unweighted pair group and principal component analyses of bacterial and fungal compositions revealed that microbiota structures differed between NS and MS samples. Redundancy analysis indicated that water content and pH might be important factors influencing the dominant bacterial and fungal community. Results indicated that microbial community were dynamic during fermentation process and the inoculation of mixed starter culture inhibited the growth of many organisms associated with food spoilage and contributed to the improvement of the quality of Suan yu products. PMID- 30007721 TI - Proteomic analysis of Lactobacillus pentosus for the identification of potential markers of adhesion and other probiotic features. AB - We analyzed the adhesion capacity to mucus of 31 Lactobacillus pentosus strains isolated from naturally fermented Alorena green table olives using an immobilized mucin model. On the basis of their adhesive capacity to mucin, three phenotypes were selected for cell-wall protein proteomic analysis to pinpoint proteins involved in the adhesion process: the highly adhesive L. pentosus CF1-43 N (73.49% of adhesion ability), the moderately adhesive L. pentosus CF1-37 N (49.56% of adhesion ability) and the poorly adhesive L. pentosus CF2-20P (32.79% of adhesion ability). The results revealed four moonlighting proteins over produced in the highly adhesive L. pentosus CF1-43 N, which were under/not produced in the other two L. pentosus strains (CF1-37 N and CF2-20P). These proteins were involved in glycolytic pathway (phosphoglycerate mutase and glucosamine-6-phosphate deaminase), stress response (small heat shock protein) and transcription (transcription elongation factor GreA). Furthermore, the relative fold change in gene expression analysis showed significant up-regulation of the genes coding for these four moonlighting proteins in the highly adhesive L. pentosus CF1-43 N versus the poorly adhesive L. pentosus CF2-20P and also in response to mucin for 20 h which clearly indicate the significant role of these genes in the adhesion capacity of L. pentosus. Thus, these proteins could be used as biomarkers for mucus adhesion in L. pentosus. On the other hand, mucin exposure induced other probiotic effects in L. pentosus strains, enhancing their co-aggregation ability with pathogens and possible inactivation. PMID- 30007722 TI - Evaluation of PTR-ToF-MS as a tool to track the behavior of hop-derived compounds during the fermentation of beer. AB - Hop-derived volatile organic compounds (VOCs) play an important role in the flavor and aroma of beer, despite making up a small percentage of the overall profile. To understand the changes happening during fermentation, proton transfer reaction-time of flight-mass spectrometry (PTR-ToF-MS) was applied for the first time in brewing science to directly measure the changes in hop-derived VOCs during the fermentation of four different worts containing one of two aroma hops in combination with one of two yeast biotypes. PTR-ToF-MS successfully detected and tracked mass-to-charge ratios (m/z) arising from interactions between the different yeast strains and the hop cultivars. Differences were observed in the dynamic VOC profiles between different beer treatments for m/z such as m/z 145.121 (ethyl hexanoate) and m/z 173.153 (isoamyl isovalerate or ethyl octanoate). The ability to monitor changes in VOCs during fermentation provides valuable information on the priority of production and transformation reactions by yeast. PMID- 30007723 TI - Modification of the digestibility of extruded rice starch by enzyme treatment (beta-amylolysis): An in vitro study. AB - The rate and extent of starch hydrolysis in the digestive tract impacts blood glucose levels, which may influence an individual's susceptibility to diabetes and obesity. Strategies for decreasing starch digestibility are therefore useful for developing healthier foods. beta-amylase is an exo-hydrolase that specifically cleaves alpha-1,4 glycosidic linkages of gelatinized starches. In this study, starch granules were disrupted by extrusion under different feed moisture conditions, and then subjected to beta-amylolysis. The degree of starch gelatinization increased with increasing feed moisture content during extrusion, leading to faster beta-amylolysis. The hydrolysis of in vitro starch digestion study was reduced for extruded samples treated with beta-amylase, which was attributed to an increase in resistant starch (RS) after beta-amylase treatment. Indeed, X-ray diffraction (XRD) indicated that the crystalline structure in the extruded starch was either partially or fully lost after beta-amylase treatment. Similarly, Fourier transform infrared (FTIR) analysis indicated there was a higher level of amorphous regions in the starch after beta-amylase treatment. Overall, our results suggest that enzymatic treatment of extruded starch with beta-amylolysis reduces the ratio of crystalline-to-amorphous regions, which increases the level of resistant starch, thereby slowing down digestion. These results have important implications for the development of healthier starch-based foods. PMID- 30007724 TI - High content analysis of sea buckthorn, black chokeberry, red and white currants microbiota - A pilot study. AB - The high potential of sea buckthorn, black chokeberry, red and white currants in healthy food industry boosted interest in the plant cultivation. The present study is the first work providing comprehensive information on microbial populations of these berries. Next Generation Sequencing allowed identification of eukaryotic and prokaryotic microorganisms prevalent on specific berries, including uncultivable microorganisms. Our study revealed the broad diversity of berries-associated bacterial and fungal microorganisms. Analysis of representative microbial OTUs showed a clear separation among inhabitants of sea buckthorn, black chokeberry and both currants, indicating plant-defined differences in the composition of the bacterial and fungal microbiota. Among the microorganisms distributed on tested berries, we documented potentially beneficial fungi and bacteria along with potential phytopathogens or those harmful for humans. Thus, plant microbiota appears to be highly relevant for the evaluation of the microbiota impact on food quality and human health. PMID- 30007725 TI - Assessing the influence of pod storage on sugar and free amino acid profiles and the implications on some Maillard reaction related flavor volatiles in Forastero cocoa beans. AB - The practice of pod storage (PS) has been applied in many cocoa producing countries, especially by Ghanaian farmers over the years. However, the study of PS has not received much attention, hence, until now, its potential impact on specific flavor precursor development and implications on the flavor of cocoa beans still remains uncovered. The study was therefore aimed at exploring this possibility through physico-chemical and flavor precursor analyses, carried out on equally fermented and dried pod stored (0, 3 and 7 days) Ghanaian cocoa beans. Flavor analysis was also conducted on equally roasted pod stored cocoa beans. Through visual assessment of the pods, pulp and beans, the compelling impact of PS on fermentation index (FI) and nib acidity could be demonstrated by the various biochemical and physical changes such as respiration, moisture reduction, and cellular degradation, occurring during the process. Whereas the entire reaction of sugar degradation may be deemed complex, a clear relationship between the FI, nib acidity and the glucose content was observed. Also, PS was found to increase with marginal increase in total reducing sugars (glucose and fructose). Although the concentration of free amino acids was directly proportional to the duration of PS, within the framework of this study, a significant difference (p < .05) was only observed in the case of extended duration (7 days). Overall, 7 PS seemed to have enhanced the formation of more volatiles. This was followed by 0 PS and finally 3 PS. Suggestively, these findings could provide some indications in explaining the typical flavor profiles of the Ghanaian cocoa beans, considering the fact that 87.8% of Ghanaian farmers adhere to this practice. Meanwhile, for the chocolate industry, the surging demand for cocoa/chocolate products exhibiting unique flavors, could be partly addressed by adopting PS as a tool for varietizing the flavor capacity of "bulk" cocoa through the expression or suppression of specific flavor precursors in the raw material on the farm level, which comes with almost no additional cost. PMID- 30007726 TI - Selenium species determination in foods harvested in Seleniferous soils by HPLC ICP-MS after enzymatic hydrolysis assisted by pressurization and microwave energy. AB - Fast, green, automated, highly efficient and accurate methodology for extracting selenium species in foods samples (Brazil nut, golden berries and heart of palm) harvested in seleniferous soils by using pressurized-assisted enzymatic hydrolysis (PAEH) and microwave-assisted enzymatic hydrolysis (MAEH) were optimized. After foods defatting or drying, selenium species were released using protease XIV and enzyme activator in 7 and 12 min for PAEH and MAEHmethods, respectively. Inductively coupled plasma - mass spectrometry (ICP-MS) and high performance liquid chromatography (HPLC) coupled with ICP-MS detection were used to assess total selenium and selenium species contents in the enzymatic extracts. Analytical performances, such as limits of quantification (0.032-0.599 MUg g-1 and 0.014-0.240 MUg g-1 for PAEH and MAEH, respectively), repeatability (11 14.5%) and accuracy of the over-all procedures were established. Selenomethionine (SeMet) were detected in all analyzed samples and selenocystine (SeCys2) in Brazil nut; however, SeMet and SeCys2 levels were only quantified in Brazil nut. Inorganic selenium species were not detected in any sample. The presence of SeMet and SeCys2 and the absence of oxidized selenium methionine (SeOMet) in the enzymatic extracts were confirmed by Orbitrap mass spectrometry. PMID- 30007727 TI - Isolation, characterization, and application of a novel specific Salmonella bacteriophage in different food matrices. AB - Application of bacteriophages to eliminate foodborne pathogens in food matrices is an emerging research field. In this study, a promising phage candidate specific for Salmonella strains was screened and its ability to decrease Salmonella counts in some food, such as milk, sausage, and lettuce, was investigated. A total of 58 Salmonella phages were isolated from a wastewater treatment plant, sewage near a river, farm ditch near a lake, and poultry house. Among them, phages LPST10, LPST18, and LPST23 were highly efficient in infecting Salmonella Typhimurium ATCC 14028. In particular, phage LPST10 could infect all the tested Salmonella Typhimurium and Salmonella Enteritidis strains with high efficiency. Bacterial challenge tests revealed that phage LPST10 and its combination with phages LPST18 and LPST23 could consistently inhibit the growth of multiple strains. Phage LPST10 presented a lysis time of about 50 min with a burst size of 101 PFU/CFU, exhibited two distinct phases in the one-step growth curve, and was stable at a pH range of 3-13 that corresponds to the pH of most of the foods (pH 3.5-7.5) and at temperatures between 30 degrees C and 60 degrees C. Transmission electron microscopy demonstrated that phage LPST10 belongs to the Siphoviridae family, with an icosahedral head with a diameter of 83.26 nm and tail length and width of approximately 144.89 nm and 10.9 nm, respectively. A significant decrease in the bacterial counts (0.92-5.12 log10 CFU/sample) and an increase in phage titers (0-2.96 log10 PFU/sample) were observed in different food matrices tested. These results demonstrated that phage LPST10 is a promising candidate for controlling Salmonella contamination in foods owing to its safety and effectiveness. PMID- 30007728 TI - Designing food packaging for the Spanish market: Do motivations differ between involved and non-involved adolescents? AB - This paper investigates the relationships among food choice motivations and the relevance of packaging elements (visual and informative elements) in the adolescent market. In addition, these relationships are re-tested in two different frameworks: high-involved consumers and low-involved consumers. 590 young consumers between 13 and 17 years were interviewed at the door of their public or private schools. Structural Modelling was used to test our hypotheses. The first analysis was done considering the global sample. The second one split off the sample into two groups: 351 high-involved adolescents and 239 low involved adolescents. Our results showed, on one side, that weight control and familiarity motivations do significantly affect the relevance of visual packaging cues. On another side, price motivations and weight control motivations do affect the relevance of informative packaging cues. The rest of food choice motivations are not linked to packaging cues. Second, regarding involvement, our results could not demonstrate that high-involved adolescents will also be higher food choice motivated consumers with a greater concern with the packaging decisions. PMID- 30007729 TI - Structural Equation Modelling (SEM) applied to sensory profile of Vinho Verde monovarietal wines. AB - Vinho Verde is the biggest DOC of Portugal, and it produces wines distinguished by their high acidity and flavor. In this Portuguese wine-region, three grape varieties, Alvarinho, Loureiro, and Arinto, are used to produce monovarietal wines of great quality. Sensory characterization of wines has the aim of detecting unique qualities in wines, and the most common measurement for the sensory aspects of wines sensory profile is descriptive sensory analysis, typically performed by trained sensory panels. To a list of attributes that can characterize a wine, we call a "sensory lexicon" that can be used by marketers allowing the articulation of flavor perceptions to consumers. So, the aim of this work was to recruit and train a sensory panel able to describe the sensory aspects associated with the monovarietal wines from Loureiro, Arinto and Alvarinho grape-varieties. Furthermore, a second order factor analysis statistical model was developed for each grape-variety wine, based on the data set of sensory attributes, allowing a new perspective in the sensory characterization of these wines. We discover that there are some similarities between the sensory lexicons that can be used to better describe the wines. However, there are descriptors that specify each monovarietal wine. Loureiro wines present "Loureiro and mineral aromas"; Alvarinho wines are described by having "citrus" aroma and freshness in the mouth and Arinto wines possess a distinctive fruity aroma (peach and pineapple) with an alcoholic, acid and fresh flavor. Additionally, it was also shown that Structural Equation Modelling (SEM) is a worthy statistical tool to be used in sensory analysis data treatment. PMID- 30007730 TI - Brown propolis-metabolomic innovative approach to determine compounds capable of killing Staphylococcus aureus biofilm and Trichomonas vaginalis. AB - Propolis, a resin produced by bees, is widely used in industrial products, including food, cosmetics, supplements, and pharmaceuticals. Extracts (ethanolic and hydroethanolic) and fractions, yielded by accelerated solvent extraction methodology, were obtained from different samples of Brazilian brown propolis (BBP). They were evaluated for antioxidant capacity, antibacterial, antibiofilm, and anti-Trichomonas vaginalis activities. The metabolomics profiling was determined by LC-DAD-MS and an innovative application of statistical analyses (univariate and chemometrics) was applied to correlate chemical compounds with biological activities. Eighty-six compounds were identified, including phenylpropanoic acids, flavonoids, chlorogenic acids, and prenylated phenylpropanoic acids. Propolis-fractions killed about 93% of Staphylococcus aureus in biofilm (at concentration of 125 MUg/mL), showed activity against T. vaginalis with MIC at 400 MUg/mL and significative antioxidant capacity (IC50 2.32-3.80 MUg/mL). Propolis extracts and fractions did not show antibacterial and antibiofilm activities against Pseudomonas aeruginosa. The prenylated phenylpropanoic acids positively correlated with both the antibiofilm (S. aureus) and anti-T. vaginalis activities, such as the metabolites artepillin C, drupanin, and baccharin. PMID- 30007731 TI - Enhanced and green extraction of bioactive compounds from Lippia citriodora by tailor-made natural deep eutectic solvents. AB - Natural deep eutectic solvents (NADESs) have been postulated as alternative green solvents for the isolation of valuable bioactive compounds from Lippia citriodora. Thus, 11 different NADESs, based on choline chloride (ChCl) as the hydrogen bond acceptor in combination with different hydrogen bond donors (organic acids, polyalcohols, sugars, and urea) were tested. According to the results obtained, ChCl-lactic acid exhibited the highest extraction yield for iridoids, 7.25 mg g-1, phenylpropanoids, 17.23 mg g-1, and flavonoids, 9.02 mg g 1 being significantly greater than phenylpropanoid and flavonoid yields, 15.63 and 5.43 mg g-1 respectively, extracted with methanol as conventional solvent. Subsequently, in order to optimise the most influential microwave assisted extraction (MAE) parameters, a Box-Behnken design paired with a response surface methodology were implemented. Temperature and water content showed a strong effect on the extraction of polyphenol sub-classes, while the effect of irradiation time was less noticeable on extraction yields. Temperature of 63.68 degrees C, a water content of 32.19% and a microwave irrdiation time of 17.08 min were the optimum conditions provided by the statistical program. The use of NADESs showed potential to facilitate the design and customisation of green tailor-made solvents which have greater extraction capacity than conventional organic solvents. PMID- 30007732 TI - Structural modelling of food allergen knowledge, attitude and practices among consumers in Malaysia. AB - The aim of this study was to assess food allergen knowledge, attitude and self reported practices among consumers in Malaysia. An online survey was conducted and data were analysed using descriptive statistics and exploratory factor analysis. A model linking food allergen knowledge and attitude and their direct effects on practices were confirmed using structural equation modelling (SEM). Consumers demonstrated moderate food allergen knowledge in this study but scored highly in their attitude towards food allergens. Although participants scored moderately in food allergen knowledge, this does not necessarily translate into practices. There is a possibility that an increase in food allergen knowledge can increase optimistic bias or a sense of over-confidence to manage allergen risks. Consumers' attitude towards food allergens has a positive and significant influence on practices. A positive attitude represents personal beliefs and reflects the level of motivation and care required to manage food allergens effectively. There was insignificant relationship between food allergen knowledge and attitude. This demonstrates a need to tailor targeted risk communication and learning strategies to influence consumers' practices. PMID- 30007733 TI - Genetically modified food versus knowledge and fear: A Noumenic approach for consumer behaviour. AB - The theme of genetically modified organisms is very important for modern consumers, especially when they approach novel foods. In this paper, we have attempted to assess the impact of genetically modified foods on the consumers' preferences, considering a new vision of ours: however, the conclusions also form a topic for further discussion. We conducted an investigation on a sample size survey. The analysis was carried out in a representative sample of more than 900 Italian families, selected based on a functional relationship to the objectives of the work. The aims of the present study were: firstly, investigating consumers' preferences regarding genetically modified food consumption and developing a quantitative model to formalize the origins of behaviours regarding consumers' preferences toward genetically modified food consumption; secondly, detecting the drivers of their purchase, underlining that only by reasoning it is possible to ensure that specific variables do not condition purchasing behaviour. PMID- 30007734 TI - Analysis of bacterial diversity and biogenic amines content during the fermentation processing of stinky tofu. AB - Fermented foods may confer several benefits to human health and play an important role in a healthy and balanced diet. Stinky tofu is an important traditional fermented soy product in Asia. In this study, a comprehensive analysis of bacterial diversity in terms of rarefaction abundance, rank abundance, alpha diversity, and principal coordinates analysis was conducted using next-generation sequencing. The results obtained were further verified by culture-dependent methods. In addition, eight biogenic amines were also quantified to determine their levels in stinky tofu during conventional production. Our study revealed that lactobacillus was the major lactic acid bacteria throughout the fermentation process. Further, some potentially harmful bacterial belonging to the genera Halomonas and Solobacterium, were also found existing in the stinky tofu. In case of biogenic amines, the concentration of putrescine, cadaverine and histamine finally increased to high levels while spermine disappeared after the fermentation was completed. After the soaking step, putrescine, tryptamine and beta-phenethylamine increased sharply. This work provided an improved understanding of microbes and biogenic amines content associated with the traditionally consumed fermented food. However, there is a need to understand microbial interactions related to biogenic amines during the fermentation, and the origin and survival strategies of two important pathogens detected in our study. PMID- 30007735 TI - Dietary supplementation of different parts of Andrographis paniculata affects the fatty acids, lipid oxidation, microbiota, and quality attributes of longissimus muscle in goats. AB - The effects of dietary supplementation of different parts of Andrographis paniculata on fatty acids, lipid oxidation, microbiota and quality attributes of Longissimus thoracis et lumborum (LTL) muscle in goats were assessed. Twenty four, entire Boer bucks (4 months old; 20.18 +/- 0.19 kg BW) were randomly allotted to either a basal diet without additive (AP0), a basal diet + 1.5% Andrographis paniculata leaves (APL) or a basal diet + 1.5% Andrographis paniculata whole plant (APW). The bucks were fed the diets for 100 d and slaughtered. The LTL muscle was subjected to a 7 d chill storage. The AP0 meat had higher (p < .05) concentration of C16:0 and C18:0 than the APW and APL meat. The concentrations of total C18:1trans, total CLA, C18:1n-9, C18:2n-6, C18:3n-3 and C20:5n-3 were higher (p < .05) in APL and APW meat than the AP0 meat. Diets had no effect (p > .05) on muscle glycogen, pH, drip loss, chemical composition and lactic acid bacteria count. Cooking loss, shear force, and TBARS values were lower (p < .05) in APL (23.98%, 0.76 kg, 0.12 mg MDA/kg) and APW (24.53%, 0.80 kg, 0.15 mg MDA/kg) meat compared with AP0 (26.49%, 1.13 kg, 0.23 mg MDA/kg) meat. Meat redness was higher (p < .05) in APL (13.49) and APW (12.98) than AP0 (10.86). Sensory scores for juiciness, tenderness, and overall acceptability of APL (7.92, 7.88, 7.89) and APW (7.90, 7.08, 7.77) meat were higher (p < .05) than that of the AP0 (5.38, 5.95, 5.41) meat. Total viable counts and populations of Pseudomonas spp, Escherichia coli and Enterobacteriacea were higher (p < .05) in AP0 meat than in APL and APW meat. The APL exhibited higher (p < .05) antimicrobial potential than the APW. Chill storage affected (p < .05) the physicochemical properties, lipid oxidation and microbial counts in chevon. Dietary APL and APW enhanced the beneficial fatty acids, quality attributes and oxidative stability, and reduced microbial counts in chevon. PMID- 30007736 TI - Carotenoids and xanthophyll esters of yellow and red nance fruits (Byrsonima crassifolia (L.) Kunth) from Costa Rica. AB - Carotenoid profiles, by means of HPLC-PDA-MSn, and CIE-L*C*h degrees colour values of yellow and red nance fruits from Costa Rica were elucidated. Among 16 carotenoids detected, (all-E)-lutein was the most abundant accounting for >80% of the total carotenoids, followed by (all-E)-zeaxanthin (9-11%) and (all-E)-beta carotene (2-9%). Minor constituents were (Z)-isomers of lutein and beta-carotene, as well as diverse lutein diesters. Among the esters, lutein dimyristate was the most abundant as substantiated by the comparison with a marigold flower extract. Total carotenoids in the peel (616.2 MUg/100 g of FW in yellow nance and 174.2 MUg/100 g of FW in red nance) were higher than in the pulp (39.4 MUg/100 g of FW in yellow nance and 31.4 MUg/100 g of FW in red nance). Since carotenoid profiles of yellow and red varieties were qualitatively similar, although the colour values showed significant differences (77.2 and 88.6 h degrees in peel and pulp of yellow nance, versus 32.7 and 67.3 h degrees in peel and pulp of red nance, respectively), pigments other than carotenoids may impart the colour of red nance. High lutein content renders nance fruit as a nutritionally relevant source of this micronutrient. PMID- 30007737 TI - Influence of supplementary irrigation on the amino acid and volatile composition of Godello wines from the Ribeiro Designation of Origin. AB - Concentrations of amino acids and volatile compounds of a given grapevine cultivar might be altered by inter-annual climate variability and management practices such as irrigation. These compounds determine, in part, aroma and sensory characteristics of wines. The current study aimed at assessing the amino acid profile of musts and wines and the volatile composition of wines from Vitis vinifera (L.) cultivar 'Godello' grown in the Ribeiro Designation of Origin (NW Spain) under rain-fed and supplementary irrigation (SI) conditions over three years (2012-2014). Supplementary irrigation increased must titratable acidity. However, must amino acid concentrations were not significantly altered by SI. In contrast, the concentrations of ethyl lactate and geraniol were greater in wines from the SI treatment. Significant correlations between amino acids in musts and volatiles in wines were observed. Our results highlight the low impact of SI on must and wine composition, likely due to the low level of water stress experienced by Godello vines. Understanding the effects of SI on wine properties could aid to adapt management practices in the future. PMID- 30007738 TI - The phytochemical and bioactivity profiles of wild Calluna vulgaris L. flowers. AB - The nutritional composition of Calluna vulgaris flowers as well as the phytochemical profile, antioxidant (DPPH and FRAP assays), antimicrobial and cytotoxic (in human immortalized non-tumorigenic keratinocyte and fibroblasts) activities of aqueous, hydroalcoholic and ethanolic extracts were evaluated. A high content of fiber and carbohydrates (75%) and the prevalence of alpha tocopherol as vitamer deserves attention. Linolenic (35%), linoleic (27%) and palmitic (21%) acids were the most abundant fatty acids. Qualitative and quantitative analysis by LC-MS and 1NMR indicated high levels of quercetin, kaempferol and myricetin derivatives as well as procyanidins. The hydro-alcoholic extract displayed the highest antioxidant activity and total phenolics (TPC) and flavonoid contents (TFC). No adverse effects on cells were observed until a concentration of 100 MUg/mL and a good antimicrobial activity was reported against S. epidermidis and S. aureus with the hydro-alcoholic extract. The data obtained demonstrated that wild plants like heather, although not being a common nutritional reference, can be used in an alimentary base as a source of bioactive compounds, namely antioxidants. PMID- 30007739 TI - Measuring consumers' product associations with emoji and emotion word questionnaires: case studies with tasted foods and written stimuli. AB - Measurement of emotional associations to food/beverage stimuli and consumption situations provide consumer insights that extend beyond hedonic responses. The aim of this research was to compare emoji, a novel approach in product-focused emotion research, with emotion words, an established approach. Focus was directed to questionnaires, which are popular in this field of research. The questionnaires were overall comparable in the meanings conveyed by the emoji/emotion words, and matched for length. Eight studies with a total of 1121 consumers in New Zealand and China were conducted with tasted foods and written stimuli. The studies were diverse and compatible with an explorative research strategy. While emoji, overall, were more discriminative than emotion words, the findings were highly study specific. When tasted foods with medium/large sample differences were used, emoji and emotion words showed similar performance overall, although emotion words better discriminated between the most liked samples and emoji better discriminated between the lesser liked samples. When samples were more similar, emoji generally were more discriminative, although emotion words still discriminated well for the pairs of most liked samples. Among Chinese consumers, there was some evidence to suggest less suitability of emotion words to characterise and discriminate written stimuli that elicited negative emotions. Emoji profiles, on the other hand, fitted expectations, and this difference could be linked to the influence of national culture. Taken together, the results from this research suggest that emoji questionnaires can have some advantages. However, their multiple meanings can be an obstacle. Overall, practitioners are advised to not select emotion questionnaire method independently from other experimental factors, but make an informed study specific decision as to the choice of emoji or emotion word questionnaires. Additional research that eliminate some of the differences between the studies in this research are recommended to corroborate the present conclusions. PMID- 30007740 TI - Isolation and identification by high resolution liquid chromatography tandem mass spectrometry of novel peptides with multifunctional lipid-lowering capacity. AB - This work describes the isolation, characterization, and identification by RP HPLC-ESI-Q-TOF of novel peptides that interfere in the fat digestion and absorption mechanisms by multiple pathways. Peptides were ultrafiltrated and peptides in the most active fraction were further separated by semipreparative RP HPLC. Nine different subfractions were obtained observing a high amount of peptides in subfraction F3. Peptides in subfraction F3 could simultaneously reduce the solubility of cholesterol in micelles and inhibit pancreatic cholesterol esterase and pancreatic lipase, even after a simulated gastrointestinal digestion. The identification of lipid-lowering peptides has been scarcely performed and when done, low selectivity or sensitivity of employed identification techniques or conditions did not yield reliable results. Separation and detection of peptides by RP-HPLC-ESI-Q-TOF-MS was optimized and most favorable conditions were employed for the identification of peptides using de novo sequencing. Ten different peptides with 4-9 amino acids were identified. Main feature of identified peptides was the high acidity derived from a high presence of amino acids glutamic acid and aspartic acid in their sequences. PMID- 30007741 TI - Phospholipid molecular species composition of Chinese traditional low-salt fermented fish inoculated with different starter cultures. AB - Phospholipid molecular species composition of Chinese traditional low-salt fermented fish (Suan yu) inoculated with different starter cultures was investigated. Fifty-six molecular species of phospholipid including 20 species of phosphatidylcholine (PC), 15 species of phosphatidylethanolamine (PE), 6 species of phosphatidylserine (PS), 9 species of lysophosphatidylcholine (LPC), and 6 species of lysophosphatidylethanolamine (LPE) were identified using ultra performance liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). PC (C16:0-C18:1), PE (C16:0-C22:6), PS (C15:0 C22:6), LPC (C22:6) and LPE (C22:5) were the predominant species. Bioactive polyene phospholipids mainly existed in PE. Furthermore, starter cultures exhibited different influence on phospholipid molecular species. Compared to naturally fermented Suan yu, more molecular species of PE and PS as well as polyene phospholipids were detected in the samples inoculated with Saccharomyces cerevisiae 31 and mixed starter cultures. PMID- 30007742 TI - Biogenic amines and other polar compounds in long aged oxidized Vernaccia di Oristano white wines. AB - Oxidized white wines are produced by techniques that provide a barrel ageing which can range from a few years to some decades. This step, characterized by the metabolic activity of peculiar strains of Saccharomyces cerevisiae yeast, can affect the chemical composition of these wines and the production of unwanted substances such as biogenic amines. In this study, Vernaccia di Oristano wines from different vintages have been analysed for the first time regarding the content of biogenic amines and amino acids (by HPLC-FLD), and polar compounds (by HPLC-DAD and LC-MS). Furthermore, colour and technological parameters (contents of alcohol, reducing sugars, total and volatile acidities, pH and organic acids) of the wines were also evaluated. Older samples showed dark shades, which may have derived from polyphenols' oxidation while ageing. Some typical ageing products, such as 5-(hydroxymethyl)furfural and hydroxycinnamic acid derivatives were found in larger quantities in these samples, as well as the purinic compound xanthine, which was also detected in relevant concentrations. Additionally, as expected, the average of the main biogenic amines quantified in Vernaccia di Oristano was higher compared to non-oxidized white wines, especially in the older samples. Thus, though this content does not exceed values which spoil the quality of the wine, the monitoring of the winemaking conditions is suggested, to further limit the presence of these undesirable compounds. PMID- 30007743 TI - A Path Analysis of the Effects of Biopsychosocial Factors on the Onset of Nonspecific Low Back Pain in Office Workers. AB - OBJECTIVE: The purpose of this study was to develop a conceptual model for the association between various biopsychosocial factors and nonspecific low back pain (LBP) in a sample of office workers. METHODS: A 1-year prospective cohort study of 669 healthy office workers was conducted. At baseline, a self-administered questionnaire and standardized physical examination were employed to gather biopsychosocial data. Follow-up data were collected every month for the incidence of LBP. A regression model was built to analyze factors predicting the onset of LBP. Path analysis was performed to examine direct and indirect associations between identified risk factors and LBP. RESULTS: The onset of LBP was predicted by history of LBP, frequency of rest breaks, and psychological demand, measured by the Job Content Questionnaire. All 3 factors directly related to LBP; history of LBP was the strongest effector on the onset of LBP. History of LBP and frequency of rest breaks had indirect effects on LBP that were mediated through psychological demand, and frequency of rest breaks was the most influential effector on psychological demand. CONCLUSIONS: Three risk factors were identified to predict onset LBP, including history of LBP, frequency of rest breaks, and psychological demand. Each factor had direct effects on the development of LBP. Also, history of LBP and frequency of rest breaks had indirect effects on LBP that were mediated through psychological demand. PMID- 30007744 TI - Increased incidence of Bell's palsy with worse outcomes in pregnancy. PMID- 30007745 TI - To admit or not to admit? Experience with outpatient thyroidectomy for Graves' disease in a high-volume tertiary care center. AB - BACKGROUND: Outpatient thyroidectomy is increasingly performed. Thyroidectomy for Graves' disease, however, has greater risk of periprocedural complications, limiting use of same-day procedures. We sought to demonstrate that these patients may be managed with ambulatory surgery. METHODS: The experience of one endocrine surgeon with thyroidectomy for Graves' was examined from January 2016-November 2017. Forty-one patients met criteria. Patient demographics, perioperative parameters, and postoperative outcomes including emergency department utilization and readmission were recorded. RESULTS: Mean age was 31.5 +/- 17.0 years, with 80% females. Mode ASA score was 3, and median operative time was 77 minutes (43 132). Complications included transient hypocalcaemia in 12%, and temporary laryngeal nerve palsy in 9.7%, with no permanent complications. Two patients were admitted immediately postoperatively for non-medical reasons. Thirty-day emergency rdepartment visits were noted in 9.7%, with subsequent readmission of 7%. CONCLUSIONS: Outpatient total thyroidectomy is safe and effective with acceptable morbidity in the Graves' patient. PMID- 30007747 TI - A new mutation of the SCGA gene is the cause of a late onset mild phenotype limb girdle muscular dystrophy type 2D with axial involvement. AB - Mutations in the SGCA gene cause limb girdle muscular dystrophy type 2D (LGMD2D). We report a family with three affected siblings with a mild phenotype consisting of late onset glutei and axial muscle weakness produced by a new mutation in the SGCA gene leading to a partial expression of the alpha-sarcoglycan protein. The MRI showed muscle atrophy involving paraspinal, pelvic and thigh muscles and a dystrophic pattern was observed in the muscle biopsy. Exome sequencing revealed a homozygous intronic deletion of SGCA and mRNA analysis showed the presence of three different transcripts. The presence, though in a lower proportion, of wild type transcript leads to a milder presentation of the disease. Although clinical symptoms did not entirely correspond with a sarcoglycanopathy, a compatible muscle MRI drove us to look for changes in the sarcoglycan genes. These cases are an example of how clinical, radiological and pathological data enriches the interpretation of exome analysis. PMID- 30007748 TI - The Adult Patient with Acute Neurologic Deficit: An Update on Imaging Trends. AB - Stroke is the clinical syndrome of abrupt onset of acute neurologic deficit owing to decreased oxygen delivery to the brain, resulting in ischemia or infarction. Approximately 87% of strokes are ischemic and 13% are hemorrhagic. Improved awareness of the neuroimaging findings highlighted in recent stroke clinical trials, as well as of their role in patient selection for novel treatment options including "late window" (8-24 hours post-ictus!) intraarterial thrombectomy-has become increasingly important. This article focuses on the role of neuroimaging in the assessment and management of patients with acute ischemic stroke. PMID- 30007749 TI - The Patient with Thunderclap Headache. AB - Thunderclap headache is a common presentation in the emergency department and, although multiple causes have been described, subarachnoid hemorrhage (SAH) is the primary concern and early diagnosis is critical. CT is highly sensitive if performed within 6 hours of onset. Patients with aneurysmal or perimesencephalic SAH should be evaluated with CT angiography. Further work-up should be guided by the pattern of blood. Patients with negative CT angiography may be further evaluated with MR imaging, especially patients with peripheral convexity SAH. PMID- 30007750 TI - Approach to Imaging in Patients with Spontaneous Intracranial Hemorrhage. AB - Spontaneous intracranial hemorrhage is a commonly encountered neurologic emergency. Imaging plays important roles in both guiding the emergent stabilization of patients with ICH and in elucidating the etiology of the hemorrhage to prevent rebleeding. A thorough understanding of the factors that have an impact on immediate management, the causes of hemorrhage, and the strengths of various imaging techniques in addressing these 2 concerns is vital to crafting a patient-centered approach to this condition. PMID- 30007746 TI - Bridging Neural and Computational Viewpoints on Perceptual Decision-Making. AB - Sequential sampling models have provided a dominant theoretical framework guiding computational and neurophysiological investigations of perceptual decision making. While these models share the basic principle that decisions are formed by accumulating sensory evidence to a bound, they come in many forms that can make similar predictions of choice behaviour despite invoking fundamentally different mechanisms. The identification of neural signals that reflect some of the core computations underpinning decision formation offers new avenues for empirically testing and refining key model assumptions. Here, we highlight recent efforts to explore these avenues and, in so doing, consider the conceptual and methodological challenges that arise when seeking to infer decision computations from complex neural data. PMID- 30007751 TI - Acute Neurologic Syndromes Beyond Stroke: The Role of Emergent MR Imaging. AB - MR imaging with diffusion-weighted imaging has been essential in the evaluation of acute stroke but is also crucial for the diagnosis, treatment, and follow-up in patients with various nonischemic disorders, including infectious processes, trauma, toxic/metabolic disorders, and other abnormalities. This article reviews various disorders with diffusion abnormality that can be commonly seen in the emergency setting. PMID- 30007752 TI - Emergent Neuroimaging in the Oncologic and Immunosuppressed Patient. AB - Neuroimaging in the emergency department increasingly involves patients at increased risk for acute neurologic complications from malignancy and immunosuppression, including patients with organ transplantation, diabetes mellitus, treatment of chronic disease, and HIV positivity. These patients are susceptible to the same infections and emergencies as immunocompetent patients, but may present differently with common illnesses and are susceptible to a variety of other diseases. This article reviews important patient risk factors, emergent central nervous system abnormalities, and their imaging findings. Detailed knowledge of risk factors and specific complications in these complex patients is essential for optimal image acquisition, interpretation, diagnosis, and treatment. PMID- 30007753 TI - Emergent Neuroimaging During Pregnancy and the Postpartum Period. AB - Acute neurologic emergencies in pregnancy often require neuroimaging to guide diagnosis and treatment. Implementation of a patient-centered care model in radiology can alleviate a patient's stress, reinforce appropriate imaging workup, improve patient satisfaction, and lead to improved outcomes. The authors present the evaluation, differential diagnosis, and recommended imaging protocols for the three most common acute neurologic symptoms in pregnancy and the postpartum period: headache, seizure, and focal neurologic deficits. With the patient's symptoms as a reference point, the referring physician in consultation with the radiologist can effectively implement the optimal imaging procedures. PMID- 30007754 TI - Imaging the Unconscious "Found Down" Patient in the Emergency Department. AB - Unconsciousness may be due to severe brain damage or to potentially reversible causes. Noncontrast head computed tomography (CT) helps identify acute ischemic and hemorrhagic lesions as well as certain patterns of toxic encephalopathy. MR imaging plays an important role in the assessment of acutely encephalopathic patients who may show no significant abnormality on CT. This review describes some of the common and infrequent entities that can lead to unconsciousness, including epilepsy and vascular, traumatic, metabolic, and toxic disorders. PMID- 30007755 TI - Neurologic Emergencies in Pediatric Patients Including Accidental and Nonaccidental Trauma. AB - This article summarizes common neurologic emergencies presenting in pediatric patients. Imaging techniques and appearances of specific conditions are detailed, including pearls and pitfalls for each presentation. Specific attention is given to differential diagnoses that can serve as mimickers of pediatric neurologic emergencies. PMID- 30007756 TI - Head and Neck Injuries: Special Considerations in the Elderly Patient. AB - Traumatic injuries to the head and neck are common in the elderly, which is a rapidly growing sector of the American population. Most injuries result from low energy falls and therefore might be at risk for delayed presentation and undertriage. Imaging, particularly with computed tomography, plays a vital role in the evaluation of traumatic head and neck injuries in geriatric patients. A thorough understanding of the differing patterns of trauma in the elderly patient and the factors that are associated with poorer outcomes is essential. PMID- 30007757 TI - Current Challenges in the Use of Computed Tomography and MR Imaging in Suspected Cervical Spine Trauma. AB - There is controversy regarding the optimal imaging strategy in adult blunt trauma patients for suspected cervical spine trauma. Some investigators recommend negative computed tomography (CT) alone to clear the cervical spine in adult blunt trauma patients, while others insist that MR imaging is necessary, especially among obtunded adult blunt trauma patients. CT is an excellent imaging modality for bony cervical spine injury; however, there is a nonzero rate of clinically significant cervical spine injuries missed on CT. MR imaging has high sensitivity for soft tissue cervical spine injuries, but low specificity for the rare isolated unstable ligamentous cervical spine injury. PMID- 30007758 TI - Blunt Craniocervical Trauma: Does the Patient Have a Cerebral Vascular Injury? AB - Blunt cerebrovascular injury involves injury to the carotid and/or vertebral arteries sustained via generalized multitrauma or directed blunt craniocervical trauma. Stroke remains the most consequential outcome. Timely diagnosis and initiation of treatment before the development of neurologic complications has a well-established role in decreasing morbidity and mortality. This article presents evidence and controversies surrounding the optimization of diagnostic imaging for suspected blunt cerebrovascular injury. Discussion centers on the increasing reliance on multidetector computed tomography angiography for screening, considering relevant clinical criteria for determining screening. Imaging protocols, imaging findings, injury grading, pearls, and pitfalls are discussed. PMID- 30007759 TI - The Imaging of Maxillofacial Trauma 2017. AB - Maxillofacial injuries account for a large portion of emergency department visits and often result in surgical consultation. Although many of the principles of fracture detection and repair are basic, the evolution of technology and therapeutic strategies has led to improved patient outcomes. This article aims to provide a clinical review of imaging aspects involved in maxillofacial trauma and to delineate its relevance to patient management. PMID- 30007760 TI - Radiation Dose Considerations in Emergent Neuroimaging. AB - Computed tomography is often the first-line diagnostic imaging modality in the evaluation of patients with neurologic emergencies. A patient-centered approach to radiation dose management in emergent neuroimaging thus revolves around the appropriate use of computed tomography, including clinical decision support for ordering providers, thoughtful protocol design, the use of available technological advances in computed tomography, and radiation exposure monitoring at a population level. A multifaceted approach can help to minimize radiation exposure to individual patients while preserving diagnostic quality imaging. PMID- 30007761 TI - Emergent Neuroimaging: A Patient-Focused Approach. PMID- 30007762 TI - Emergent Neuroimaging: A Patient-Focused Approach. PMID- 30007763 TI - Creating space to discuss end-of-life issues in cancer care. AB - OBJECTIVES: Analyze entire oncology clinical visits and examine instances in which oncologists have to break the bad news that patients' treatments are no longer effective. METHODS: Using conversation analysis we examine 128 audio recorded conversations between terminal cancer patients, their caregivers, and oncologists. RESULTS: When oncologists break the bad news that a patient's treatment is no longer effective, they often use a conversational device we call an "exhausted current treatment" (ECT) statement, which avoids discussing prognosis in favor of further discussing treatment options. Analysis suggests that improving and prioritizing patient-centered care and shared decision making is possible if we first understand the social organization of clinical visits. CONCLUSIONS: ECT statements and their movement towards discussing treatment options means that opportunities are bypassed for patients and caregivers to process or discuss scan results, and their prognostic implications. PRACTICE IMPLICATIONS: When oncologists and patients, by fixating on treatment options, bypass opportunities to discuss the meaning of scan results, they fail to realize other goals associated with prognostic awareness. Talking about what scans mean may add minutes to that part of the clinic visit, but can create efficiencies that conserve overall time. We recommend that oncologists, after delivering scan news, ask, "Would you like discuss what this means?". PMID- 30007764 TI - Impact of a brief faculty training to improve patient-centered communication while using electronic health records. AB - OBJECTIVE: Despite rapid EHR adoption, few faculty receive training in how to implement patient-centered communication skills while using computers in exam rooms. We piloted a patient-centered EHR use training to address this issue. METHODS: Faculty received four hours of training at Cleveland Clinic and a condensed 90-minute version at the University of Chicago. Both included a lecture and a Group-Objective Structured Clinical Exam (GOSCE) experience. Direct observations of 10 faculty in their clinical practices were performed pre- and post-workshop. RESULTS: Thirty participants (94%) completed a post-workshop evaluation assessing knowledge, attitude, and skills. Faculty reported that training was important, relevant, and should be required for all providers; no differences were found between longer versus shorter training. Participants in the longer training reported higher GOSCE efficacy, however shorter workshop participants agreed more with the statement that they had gained new knowledge. Faculty improved their patient-centered EHR use skills in clinical practice on post- versus pre-workshop ratings using a validated direct-observation rating tool. CONCLUSION: A brief lecture and GOSCE can be effective in training busy faculty on patient-centered EHR use skills. PRACTICE IMPLICATIONS: Faculty training on patient-centered EHR skills can enhance patient-doctor communication and promotes positive role modeling of these skills to learners. PMID- 30007765 TI - An integrated experiential training programme with coaching to promote physical activity, and reduce fatigue among children with cancer: A randomised controlled trial. AB - OBJECTIVE: This study examined the effectiveness of an integrated programme in promoting physical activity, reducing fatigue, enhancing physical activity self efficacy, muscle strength and quality of life among Chinese children with cancer. METHODS: A randomised controlled trial was conducted in a Hong Kong public hospital. Seventy eligible children were randomly assigned to an experimental group (n = 37) or a control group (n = 33). The experimental group received an integrated programme with 28 home visits from coaches over a 6-month period. The control group received a placebo intervention. The primary outcome was fatigue at 9 months (3 months after intervention completion). Secondary outcomes were physical activity levels, physical activity self-efficacy, muscle strength and quality of life at 9 months, assessed at baseline, and 6 and 9 months after starting the intervention. RESULTS: The experimental group reported significantly lower levels of cancer-related fatigue, higher levels of physical activity and physical activity self-efficacy, greater right- and left-hand grip strength and better quality of life than the control group at 9 months. CONCLUSION: The programme is effective and feasible to implement among children with cancer and offers an alternative means of ameliorating the healthcare burden. PRACTICE IMPLICATIONS: Healthcare professionals should build multidisciplinary partnerships to sustain such programmes. PMID- 30007766 TI - Men with implantable cardioverter defibrillators: A qualitative study of gender and age. AB - OBJECTIVE: The purpose of this study was to examine men's adjustment to living with an implantable cardioverter defibrillator (ICD) as influenced by gender and age. BACKGROUND: Living with an ICD requires psychological and social adjustments throughout the lifespan. Approximately 60-70% of the ICD population are men, yet little is known about men's gender-specific issues related to living with ICDs. METHOD: Ethnographic methods were used with 12 men, 26-85 years of age. Data were analyzed using constructs of gender, chronic illness, and Life Course theory. RESULTS: Themes were identified: Maintaining a masculine image, Sudden cardiac death and social implications through time, and Self-image influenced by chronic illness. DISCUSSION: Gender and location in the life-course may influence adjustment to living with an ICD. Understanding where an individual is within place and time, as well as where they are at the present may account for many aspects of their acceptance, adjustment, and recovery. PMID- 30007767 TI - Optimal Glycated Hemoglobin Cutoff Point for Diagnosis of Type 2 Diabetes in Iranian Adults. AB - OBJECTIVES: The aim of this study was to evaluate the capability of glycated hemoglobin (A1C) levels to be a tool for identifying Iranian adults with diabetes and prediabetes. METHODS: In a cross-sectional population-based study, 1,813 adults, men and women 35 to 75 years of age and without a history of diabetes and hemoglobinopathies, were included. Fasting blood glucose and A1C levels were obtained. According to the criteria of the American Diabetes Association, participants were categorized into 3 groups: newly diagnosed diabetes, prediabetes and healthy subjects. The optimal cutoff point for A1C in diabetes and prediabetes diagnosis was determined by studying the sensitivity and specificity of different cutoff points for A1C, while using different levels of fasting blood glucose as the gold standard. RESULTS: Participants with newly diagnosed diabetes were significantly older than subjects with prediabetes and healthy subjects (mean [+/- SD] 47.3+/-12.9, 44.6+/-13.0 and 39.2+/-14.1 years, respectively) and also had higher body mass indexes. As expected, the levels of fasting blood glucose (8.79+/-2.24, 6.01+/-0.38 and 4.97+/-0.4 mmol/L) and A1C (6.55+/-1.4%, 5.61+/-0.61% and 5.28+/-0.59%) were significantly different in the groups (p<0.001). The optimal cutoff point for A1C to predict prediabetes was 5.5% (sensitivity of 60.5% and specificity of 63.1%) and for diabetes was 5.9% (sensitivity of 66.7% and specificity of 81.2%). ADA cutoff points for prediabetes and diabetes detection yielded a sensitivity of 45.2% and 39.8%, respectively. CONCLUSIONS: The findings suggest the necessity of determining the A1C cutoffs for detecting diabetes or prediabetes in each region's population. They also suggest that the combination of these A1C cutoffs with fasting blood glucose levels are required to determine diabetes and prediabetes more accurately. PMID- 30007768 TI - Imaging of vasa vasorum neovascularization: Opportunities and limitations. PMID- 30007769 TI - Narrative Training as a Method to Promote Nursing Empathy Within a Pediatric Rehabilitation Setting. AB - PURPOSE: Empathy is deemed essential to nursing, yet interventions that promote and sustain empathy in practicing nurses within healthcare organizations are limited. We tested the feasibility and perceived impact of an arts-based narrative training intervention involving pediatric rehabilitation nurses for the purpose of promoting nursing empathy. DESIGN AND METHODS: One-group qualitative repeated-measures design at an urban Canadian pediatric rehabilitation hospital. Eight nurse participants attended six 90-minute weekly group narrative training sessions and two in-depth interviews pre- and post-intervention. RESULTS: The intervention positively impacted participants in three primary domains: Empathy for Patients and Families, Empathy Within Nursing Team, and Empathy for the Self. Major findings included: increased value placed on patients' and families' backstory, identification of "moral empathic distress" (MED), enhanced sense of collaborative nursing community, and renewal of professional purpose. CONCLUSIONS: This study is the first of its kind conducted in the pediatric rehabilitation nursing context. Results indicate that arts-based narrative training enhances nursing empathy and contributes to a supportive nursing culture. PRACTICE IMPLICATIONS: In addition to enhancing empathy in clinical domains, nurses who participated in narrative training reported improved team collaboration, self-care practices, and renewed professional purpose. The results from the intervention are encouraging and future research needs to explore its utility in other settings with larger and more diverse sample. PMID- 30007770 TI - [Morbidity and mortality conferences in Lower Saxony: Implementation status and further development needs]. AB - BACKGROUND: Morbidity and mortality conferences (M&MC) are a tool to foster individual and organizational learning in hospitals, and they are important to improve patient safety. So far, no data has been available about the implementation of M&MC in Lower Saxony and the characteristics of M&MCs. The aim of this study was to assess the status quo of M&MC in Lower Saxony and to identify the potential for improvement. METHODS: A cross-sectional survey study was conducted among chief physicians in surgery, internal medicine, anesthesiology/intensive care, gynecology/obstetrics and pediatrics (response rate: 50 %). RESULTS: Apart from technical topics (37 %), the main issues addressed are process (92 %) and teamwork (64 %) issues. The results also show a strong heterogeneity in terms of structures and processes of implemented M&MC in Lower Saxony. Despite a high level of satisfaction (85 %) and perceived effectiveness (93 %), most participants see potential for improvement of "their" M&MC (58 %). CONCLUSION: Chief physicians in Lower Saxony report both a high level of acceptance and the need for further improvement of the M&MCs, which represents good preconditions for further development towards effective M&MCs. PMID- 30007772 TI - Greater Breastfeeding in Early Infancy Is Associated with Slower Weight Gain among High Birth Weight Infants. AB - OBJECTIVE: To examine whether feeding patterns from birth to age 6 months modify the association between birth weight and weight at 7-12 months of age. STUDY DESIGN: Longitudinal mixed models were used to examine feeding trajectories across categories of birth weight and weight at 7-12 months of age in 1799 mother infant dyads enrolled in the Infant Feeding Practices Study II. The percentage of breast milk received and the average daily formula consumption were calculated from birth to 6 months of age. Birth weights were classified as high (>=4000 g) and normal (>=2500 g and <4000 g). Weights at 7-12 months of age were categorized as high (z score >1) or normal (z score <=1). A secondary analysis was performed using categories defined by birth weight adjusted for gestational age percentiles (>90% and 10th-90th percentile). RESULTS: High birth weight (HBW) infants with high weights at 7-12 months of age demonstrated a rapid decline in the percentage of breast milk feedings compared with HBW infants with normal weights at 7-12 months of age. Normal birth weight infants with high weights at 7-12 months of age received a lower percentage of breast milk and had greater absolute intakes of formula than those with normal weights at 7-12 months of age; these associations did not vary over time. Results were similar when infants were categorized by birth weight percentiles. CONCLUSIONS: A lower proportion of breast milk feedings was associated with excess weight at 7-12 months of age in HBW infants. These findings suggest an initial target for obesity prevention programs focusing on the first 6 months after birth. PMID- 30007771 TI - Minding the Gap: Setting Research Priorities Related to HIV Testing, Treatment, and Service Delivery Among Adolescents. PMID- 30007774 TI - First case of sitosterolemia caused by double heterozygous mutations in ABCG5 and ABCG8 genes. AB - We present the first case of sitosterolemia caused by double heterozygous mutations in adenosine triphosphate-binding cassette subfamily G members 5 and 8 (ABCG5 and ABCG8) genes. A 1-year-old girl was admitted to Kanazawa University Hospital due to her hyper low-density lipoprotein (LDL)-cholesterolemia (453 mg/dL) as well as intertriginous xanthomas associated with breastfeeding. Initially, she was suspected as familial hypercholesterolemia (FH). However, her LDL cholesterol level significantly reduced after her weaning from breastfeeding. In addition, cascade screening did not show any evidence supporting dominant inheritance pattern as FH. Genetic analyses were performed using custom panel focusing on exome regions of 21 lipid-associated genes, including FH-causing genes (LDL receptor, proprotein convertase subtilisin/kexin type 9, apolipoprotein B), and ABCG5 and ABCG8 genes. In addition to a single deleterious mutation in ABCG5 gene (NM_022436.2:c.1166G>A or NP_071881.1:p.Arg389His), single deleterious mutation in ABCG8 gene (NM_022437.2:c.1285A>C or NP_071882.1:p.Met429Leu) was also identified. Segregations of those mutations from her parents were confirmed. Her serum sitosterol level was significantly elevated to 15.9 MUg/mL, leading to her definite diagnosis as sitosterolemia. The ABCG5 and ABCG8 proteins form heterodimers and act as a complex. To the best of our knowledge, this is the first case exhibiting sitosterolemia caused by both ABCG5 and ABCG8 gene mutations. PMID- 30007773 TI - Subsyndromal Manifestations of Depression in Children Predict the Development of Major Depression. AB - OBJECTIVE: To evaluate the utility of assessing subsyndromal symptoms of major depressive disorder in childhood, indexed through the Child Behavior Checklist (CBCL) anxiety/depression scale, in predicting risk of developing major depressive disorder in adolescent and young adult years. STUDY DESIGN: The sample consisted of 537 children, 6-17 years of age, originally ascertained for a longitudinal family genetic study of youth with and without attention-deficit hyperactivity disorder and their first-degree relatives who were followed prospectively and blindly for 10 years from childhood into young adult years. Children with full diagnosis major depressive disorder at baseline were excluded. For analysis, the sample was stratified into 4 groups based on the presence or absence of parental mood disorders and by the presence or absence of subsyndromal scores on the CBCL anxiety/depression scale at baseline assessment in childhood. RESULTS: Children of parents with mood disorders plus subsyndromal scores on the CBCL anxiety/depression scale at baseline (n = 22) had the highest risk for developing major depressive disorder and anxiety disorders at the 10-year follow up when compared with the other groups. Children with either subsyndromal scores on the CBCL anxiety/depression scale at baseline alone (n = 22) or parental mood disorders alone (n = 172) had intermediate outcomes. CONCLUSION: The CBCL anxiety/depression scale was useful in identifying children at high risk for the development of major depressive disorder and anxiety disorders at the 10-year prospective follow-up. Furthermore, our results emphasized the importance of familial psychiatric history in youth with subthreshold symptoms of depression. Parental mood disorder and subthreshold anxiety/depressive symptoms were predictive of developing depression. PMID- 30007775 TI - Pediatric lipid reference values in the general population: The Dutch lifelines cohort study. AB - BACKGROUND: Atherosclerosis starts in childhood and its progression is influenced by lifelong low-density lipoprotein cholesterol (LDL-c) exposure, the so-called cholesterol burden. Early identification of children and adolescents with severely elevated LDL-c is thus of major clinical significance. This is especially true for children with familial hypercholesterolemia (FH), a frequent but undertreated genetic disorder. To identify children with possible FH, insight in the distribution of lipid levels in children is a prerequisite. OBJECTIVE: To provide health care professionals with contemporary age- and gender-based pediatric reference values for lipid and lipoprotein levels to help the identification of children with dyslipidemia, especially FH. METHODS: Lifelines is a large prospective population-based Dutch cohort study. Children from 8 till 18 years of age were included and fasting lipid levels were measured. Smoothed reference curves and percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) were generated using the Generalized Additive Models for Location, Scale and Shape package in the statistical software R. RESULTS: A total of 8071 children (3823 boys and 4248 girls) were included. In the total cohort we noted marked dynamic changes in lipid and lipoprotein levels over age, which were in part gender specific. Our data highlight a high and unexpected prevalence of severely elevated LDL-c (>190 mg/dL) in both boys and girls. CONCLUSION: Our cross sectional data provide contemporary reference ranges for plasma lipids that can assist physicians in identifying children at increased risk of premature atherosclerosis, especially FH. PMID- 30007776 TI - Type 1 diabetes is associated with T-wave morphology changes. The Thousand & 1 Study. AB - BACKGROUND: Repolarization is impaired in patients with type 1 diabetes mellitus (T1DM), and repolarization disturbances are associated with an increased mortality. To study cardiac repolarization, we assessed T-wave morphology in patients with T1DM without known heart disease. METHODS: 855 T1DM patients without known heart disease were matched 1:2 with 1710 people from a background population. Rate-corrected T-wave morphology markers were obtained. Patients were stratified by albuminuria. Results are mean +/- standard deviation. RESULTS: T waves were flatter (0.398 +/- 0.059 vs. 0.382 +/- 0.062, p < 0.001) and more asymmetric (0.082 +/- 0.068 vs. 0.071 +/- 0.084, p = 0.001) in T1DM. Patients with albuminuria had an increased heart rate (normoalbuminuria: 71 +/- 13 bpm, microalbuminuria: 75 +/- 12 bpm, p < 0.001, macroalbuminuria: 78 +/- 12 bpm, p < 0.001) and more asymmetric T-waves (normoalbuminuria: 0.079 +/- 0.060, microalbuminuria: 0.094 +/- 0.085, p < 0.01, macroalbuminuria: 0.101 +/- 0.080, p < 0.01), but the QTc interval remained unchanged. CONCLUSIONS: T1DM is associated with changes in T-wave morphology. T-wave asymmetry but not QTc interval is associated with albuminuria in T1DM and may be used for stratification. PMID- 30007777 TI - Sample size and the establishment of safety in perioperative medicine. PMID- 30007778 TI - Genetic studies of gestational duration and preterm birth. AB - The fine control of birth timing is important to human survival and evolution. A key challenge in studying the mechanisms underlying the regulation of human birth timing is that human parturition is a unique to human event - animal models provide only limited information. The duration of gestation or the risk of preterm birth is a complex human trait under genetic control from both maternal and fetal genomes. Genomic discoveries through genome-wide association (GWA) studies would implicate relevant genes and pathways. Similar to other complex human traits, gestational duration is likely to be influenced by numerous genetic variants of small effect size. The detection of these small-effect genetic variants requires very large sample sizes. In addition, several practical and analytical challenges, in particular the involvement of both maternal and fetal genomes, further complicate the genetic studies of gestational duration and other pregnancy phenotypes. Despite these challenges, large-scale GWA studies have already identified several genomic loci associated with gestational duration or the risk of preterm birth. These genomic discoveries have revealed novel insights about the biology of human birth timing. Expanding genomic discoveries in larger datasets by more refined analytical approaches, together with the functional analysis of the identified genomic loci, will collectively elucidate the biological processes underlying the control of human birth timing. PMID- 30007779 TI - Navigating the lung for hidden treasure. PMID- 30007780 TI - Late oral acetaminophen versus immediate surgical ligation in preterm infants with persistent large patent ductus arteriosus. AB - OBJECTIVE: The study objective was to evaluate the association of oral acetaminophen therapy versus immediate surgical ligation with neonatal outcomes in infants with persistent patent ductus arteriosus. METHODS: We performed a retrospective cohort study of preterm infants born 28+6 weeks or less gestational age with persistent large patent ductus arteriosus being considered for surgical ligation after unsuccessful medical therapy. Infants in epoch 1 (July 2009 to June 2012) were immediately referred for ligation, and infants in epoch 2 (July 2012 to June 2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death or chronic lung disease. RESULTS: A total of 92 infants with median (interquartile range) gestational age 25.2 weeks (24.4-26.3) had persistent large patent ductus arteriosus (43 in epoch 1, 49 in epoch 2). Infants in epoch 2 had decreased surgical ligation (26 [53%] vs 31 [72%]; adjusted odds ratio [aOR], 0.32; 95% confidence interval [CI], 0.12-0.89) but increased chronic lung disease (36 [73%] vs 25 [58%]; aOR, 3.34; 95% CI, 1.05-10.58) and increased death/chronic lung disease of borderline significance (39 [80%] vs 29 [67%]; aOR, 3.09; 95% CI, 0.99 9.63). Infants in epoch 2 took longer to wean off of positive pressure ventilation (28.5 vs 24 days after enrollment; aOR, 0.52; 95% CI, 0.31-0.85). CONCLUSIONS: Late oral acetaminophen therapy for infants with persistent patent ductus arteriosus is associated with reduced surgical ligation but increased chronic lung disease. In light of a lack of improvement in clinical outcomes, the individual contributory effects of acetaminophen, surgical ligation, and prolonged exposure to patent ductus arteriosus require further study to define the optimal approach. PMID- 30007781 TI - Are uncomplicated type B aortic dissections truly uncomplicated? PMID- 30007782 TI - The rest of the story: Long-term, patient-reported outcomes in cardiac surgery. PMID- 30007783 TI - "Not in my brain": The use of embolic protection devices to prevent brain embolization during cardiovascular procedures. PMID- 30007784 TI - (What's so funny 'bout) peace, love, and thyroid hormone. PMID- 30007785 TI - SUDEP and seizure safety communication: Assessing if people hear and act. AB - BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death among people with chronic epilepsy. People with intellectual disability (ID) are overrepresented in this population. The SUDEP and Seizure Safety Checklist ("Checklist") is a tool to discuss risk factors influencing seizures and the risk of SUDEP. It includes questions about the availability of nocturnal monitoring. In Cornwall UK, people with epilepsy and ID and their relatives and carers are routinely advised to consider nocturnal surveillance to reduce harm from potential nocturnal seizures. We assessed the retention of advice provided on nocturnal monitoring and if there were differences between those in residential care and those living with their families. METHODS: A postal questionnaire was sent to carers of all people with epilepsy and ID in Cornwall followed by the adult specialist ID epilepsy service. All those who were contacted had received the same advice on SUDEP and nocturnal monitoring at least once in the past year. Each person was categorized into living in a residential setting or with their family group. Intergroup differences were compared using Fisher's exact test. RESULTS: Carers for 170 people were contacted and 121 responded (71%). The family group had statistically more nocturnal seizures than the residential group. While there was no difference in the awareness of SUDEP, the groups differed in their recollection of the person-centered discussion of risk with carers in residential setting being less aware. Where nocturnal monitoring advice was given, it was followed, and previously unknown seizures were identified in 75%. CONCLUSIONS: Carers in residential settings are less likely to recall specific person-centered discussion of risks to the individual they support as compared with those living with families although general awareness of SUDEP and implementing advice such as nocturnal monitoring is present equally in both groups. In improving detection of nocturnal seizures, audio monitoring may be a useful strategy to reduce risk of harm for people with ID. PMID- 30007786 TI - Cytomegalovirus associated with gastric ulcer: case report and literature review. PMID- 30007787 TI - Reviewing the therapeutic role of budesonide in Crohn's disease. AB - Oral budesonide is a glucocorticoid of primarily local action. In the field of digestive diseases, it is used mainly in inflammatory bowel disease, but also in other indications. This review addresses the pharmacology, pharmacodynamics and therapeutic use of budesonide. Its approved indications are reviewed, as well as other clinical scenarios in which it could play a role, in order to facilitate its use and improve the accuracy of its prescription. PMID- 30007788 TI - Modeling the connections of brain regions in children with autism using cellular neural networks and electroencephalography analysis. AB - The brain connections in the different regions demonstrate the characteristics of brain activities. In addition, in various conditions and with neuropsychological disorders, the brain has special patterns in different regions. This paper presents a model to show and compare the connection patterns in different brain regions of children with autism (53 boys and 36 girls) and control children (61 boys and 33 girls). The model is designed by cellular neural networks and it uses the proper features of electroencephalography. The results show that there are significant differences and abnormalities in the left hemisphere, (p < 0.05) at the electrodes AF3, F3, P7, T7, and O1 in the children with autism compared with the control group. Also, the evaluation of the obtained connections values between brain regions demonstrated that there are more abnormalities in the connectivity of frontal and parietal lobes and the relations of the neighboring regions in children with autism. It is observed that the proposed model is able to distinguish the autistic children from the control subjects with an accuracy rate of 95.1% based on the obtained values of CNN using the SVM method. PMID- 30007789 TI - The Efficacy of Tranexamic Acid in Total Hip Arthroplasty: A Network Meta analysis. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent commonly used to reduce blood loss in total hip arthroplasty (THA). The purpose of our study was to evaluate the efficacy of TXA in primary THA to support the combined clinical practice guidelines of the American Association of Hip and Knee Surgeons, American Academy of Orthopaedic Surgeons, Hip Society, Knee Society, and American Society of Regional Anesthesia and Pain Medicine on the use of TXA in primary total joint arthroplasty. METHODS: A search was performed using Ovid-MEDLINE, Embase, Cochrane Reviews, Scopus, and Web of Science databases to identify all publications before July 2017 on TXA in primary THA. We completed qualitative and quantitative homogeneity testing of all included studies. Direct and indirect comparisons were analyzed using a network meta-analysis followed by consistency testing of the results. RESULTS: Two thousand one hundred thirteen publications underwent critical appraisal with 34 publications identified as representing the best available evidence for inclusion in the analysis. Topical, intravenous, and oral TXA formulations provided reduced blood loss and risk of transfusion compared to placebo, but no formulation was clearly superior. Use of repeat doses, higher doses, or variation in timing of administration did not significantly reduce blood loss or risk of transfusion. CONCLUSIONS: Strong evidence supports the use of TXA to reduce blood loss and risk of transfusion after primary THA. No specific routes of administration, dosage, dosing regimen, or time of administration provides clearly superior blood-sparing properties. PMID- 30007790 TI - Impact of Atrial Fibrillation on Postoperative Adverse Outcomes of Surgical Patients With Knee Endoprosthetic Surgery. AB - BACKGROUND: Atrial fibrillation/flutter (AF) is associated with increased mortality, thromboembolism, heart failure, and adverse perioperative outcomes. We aimed to investigate the impact of AF on adverse in-hospital outcomes of hospitalized patients who underwent knee endoprosthetic surgery (KES). METHODS: The nationwide German inpatient sample of the years 2005-2015 was used for this analysis. Patients who underwent KES were identified based on the surgical and interventional procedural codes (surgery and procedure code [Operationen-und Prozedurenschlussel] 5-822), and patients were further stratified by AF (International Classification of Diseases and Related Health Problems code I48). We compared patients with and without AF who underwent KES as well as survivors vs nonsurvivors among patients with AF. Logistic regression models were used to investigate the impact of AF as a predictor for adverse in-hospital outcomes. RESULTS: Overall, 1,642,875 hospitalized surgical patients (65.4% females, 49.5% aged >70 years) were included in the analysis. Of these, 93,748 patients (5.7%) were diagnosed with AF. Overall, 0.1% of the patients who underwent KES and 0.6% of the patients who underwent KES with additional AF died during in-hospital stay. All-cause death (risk ratio 5.97 [95% confidence interval {CI} 5.41-6.58], P < .001) and adverse in-hospital events (risk ratio 2.62 [95% CI 2.50-2.74], P < .001) occurred both more often in patients with AF compared to those without. AF was an important predictor for in-hospital death (odds ratio 2.09 [95% CI 1.88 2.32], P < .001) and adverse in-hospital events (odds ratio 1.76 [95% CI 1.68 1.85], P < .001) in patients who underwent KES independent of age, sex, and comorbidities. CONCLUSION: In patients who underwent KES, AF is associated with increased in-hospital mortality and adverse in-hospital outcomes. Pneumonia, pulmonary embolism, shock, myocardial infarction, intracerebral bleeding, and stroke were the key complications promoting in-hospital death. PMID- 30007791 TI - Quantification of run order effect on chromatography - mass spectrometry profiling data. AB - Chromatographic systems coupled with mass spectrometry detection are widely used in biological studies investigating how levels of biomolecules respond to different internal and external stimuli. Such changes are normally expected to be of low magnitude and therefore all experimental factors that can influence the analysis need to be understood and minimized. Run order effect is commonly observed and constitutes a major challenge in chromatography-mass spectrometry based profiling studies that needs to be addressed before the biological evaluation of measured data is made. So far there is no established consensus, metric or method that quickly estimates the size of this effect. In this paper we demonstrate how orthogonal projections to latent structures (OPLS(r)) can be used for objective quantification of the run order effect in profiling studies. The quantification metric is expressed as the amount of variation in the experimental data that is correlated to the run order. One of the primary advantages with this approach is that it provides a fast way of quantifying run-order effect for all detected features, not only internal standards. Results obtained from quantification of run order effect as provided by the OPLS can be used in the evaluation of data normalization, support the optimization of analytical protocols and identification of compounds highly influenced by instrumental drift. The application of OPLS for quantification of run order is demonstrated on experimental data from plasma profiling performed on three analytical platforms: GCMS metabolomics, LCMS metabolomics and LCMS lipidomics. PMID- 30007792 TI - Multi-residue enantiomeric analysis of 18 chiral pesticides in water, soil and river sediment using magnetic solid-phase extraction based on amino modified multiwalled carbon nanotubes and chiral liquid chromatography coupled with tandem mass spectrometry. AB - This manuscript describes, for the first time, the multi-residue analysis of 18 chiral pesticides at enantiomeric levels in both environmental liquid (river water, influent and effluent wastewater) and solid matrices (agricultural soil, forestal soil and river sediment) based on magnetic solid-phase extraction (MSPE) and chiral liquid chromatography coupled with tandem mass spectrometry (LC MS/MS). Magnetic amino modified multiwalled carbon nanotubes (m-MWCNTs-NH2) were prepared and firstly applied to adsorb pesticides from complex matrices. Response surface methodology (RSM) was applied to assist the multivariable optimization. The simultaneous enantioseparation of the chiral pesticides was performed on a Chiralpak IG column. Under the optimum conditions, the mean recoveries for pesticides enantiomers from the water matrices ranged from 81.1 to 106.3% with intra-day RSD of 2.1-11.9% and inter-day RSD of 2.6-12.7%; the mean recoveries for all enantiomers from the solid matrices ranged from 80.3 to 105.9% with intra day RSD of 2.3-10.9% and inter-day RSD of 4.0-13.4%. Good linearity was achieved for all enantiomers with determination coefficients (r2) greater than 0.9912. Method quantification limits were below 2.04ng L-1 in liquid matrices and below 0.50ng g-1 in solid matrices. The developed method offered some advantages, such as simple operation, rapidity and high concentration factor. Therefore, it is suitable for monitoring the enantiomeric compositions of chiral pesticides in different environmental matrices. PMID- 30007793 TI - Lipidomic alterations in lipoproteins of patients with mild cognitive impairment and Alzheimer's disease by asymmetrical flow field-flow fractionation and nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with the clinical symptom of the progressive loss of cognitive function and mild cognitive impairment (MCI) is a translational state between cognitive changes of normal aging and AD. Lipid metabolism and pathogenesis of Alzheimer's disease (AD) are closely linked. Despite obviously discrete lipidome constitutions across lipoproteins, lipidomic approaches of AD has been mostly conducted without considering lipoprotein-dependent alterations. This study introduces a combination of asymmetrical flow field-flow fractionation (AF4) and nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry (nUHPLC-ESI MS/MS) for a comprehensive lipid profiling in different lipoprotein level of patients plasma with AD and amnestic MCI in comparison to age-matched healthy controls. Lipoproteins in plasma samples were size-sorted by a semi-preparative scale AF4, followed by non-targeted lipid identification and high speed targeted quantitation with nUHPLC-ESI-MS/MS. It shows 14 significantly altered high abundance lipids in AD, exhibiting >2-fold increases (p < 0.01) in LDL/VLDL including triacylglycerol, ceramide, phosphatidylethanolamine, and diacylglycerol. Three lipid species (triacylglycerol 50:1, diacylglycerol 18:1_18:1, and phosphatidylethanolamine 36:2) showing a strong correlation with the degree of brain atrophy were found as candidate species which can be utilized to differentiate the early stage of MCI when simple Mini-Mental State Examination results were statistically incorporated. The present study elucidated lipoprotein dependent alterations of lipids in progression of MCI and further to AD which can be utilized for the future development of lipid biomarkers to enhance the predictability of disease progress. PMID- 30007794 TI - Removal of bias in C37 alkenone-based sea surface temperature measurements by high-performance liquid chromatography fractionation. AB - Sea surface temperature determinations based on marine sedimentary C37 alkenone distributions have provided a wealth of data for paleoclimatic studies, including those performed at high resolution. The success of this approach results from several characteristics of alkenone compounds, e.g. their geochemical properties (such as unequivocal synthesis by certain widespread haptophyte algae, plus chemical stability/preservation of the original alkenone distributions during sedimentation), and their analytical properties (such as fast clean up procedures using alkaline hydrolysis of sediment extracts, followed by robust instrumental methods allowing large scale sample processing). Here we show that, in sediments under the influence of continental inputs, coelution of these compounds with cholest-5-enyl 3beta-undecenyl ether and 24-methylcholesta-5,22-dienyl 3beta undecenyl ether deviate the SST measurements despite alkaline hydrolysis. Here, we report a new high performance liquid chromatrography fractionation method which eliminates these interfering compounds and gathers all the alkenones into a single fraction. These fractions can then be analysed by gas chromatography as in the initial approach, providing large amounts of data as required in high resolution studies. PMID- 30007795 TI - Vitamin B12 deficiency - detection and treatment considerations. PMID- 30007796 TI - De-implementation of care practices and interventions. PMID- 30007797 TI - A Retrospective Study Identifying Breast Milk Feeding Disparities in Infants with Cleft Palate. AB - BACKGROUND: Breast milk represents the optimal substrate for all infants, including those with a cleft palate for whom growth may be compromised. OBJECTIVES: Frequency of breast milk feeding at the breast and per feeder (bottle, cup, enteral tube) in infants with cleft palate was determined and compared with rates reported by the Centers for Disease Control and Prevention. A secondary aim was to review growth status of the infants. DESIGN: This study represents a 5-year retrospective review using the electronic medical record. PARTICIPANTS AND SETTING: Patients were <=12 months old at the time of the initial, presurgical encounter after a diagnosis of cleft palate had been made and were treated at one of two pediatric cleft palate and craniofacial centers in Ohio between September 30, 2010, and September 30, 2015. MAIN OUTCOME MEASURES: Outcomes measured were breast milk use, reported by mothers and documented in patients' electronic medical records, chronological body weight, as well as weight for length and weight-for-age z scores and percentiles. STATISTICAL ANALYSES PERFORMED: Descriptive statistics included median with interquartile range and frequency with percentages. World Health Organization z scores were estimated using the Centers for Disease Control and Prevention programs for weight, weight for length, and weight for age at first visit. Comparisons of infants treated at the two hospitals were done using the Wilcoxon rank-sum test or the chi2 test. RESULTS: Breast milk consumption (26 infants were breastfed and 84 received human breast milk administered with a device) was 29.5%, markedly below the 2016 Centers for Disease Control and Prevention national statistics for ever receiving breast milk (81%). Anthropometric findings included z scores of 0.95 and -0.42 for weight for age and weight for length, respectively. CONCLUSIONS: Infants with cleft palate were seldom breastfed, nor was breast milk frequently used. In addition, median weight-for-age and weight-for-length z scores suggest that growth of infants with cleft palate was below normative standards. PMID- 30007798 TI - Arteriovenous Malformation Following Conservative Management of Cervical Pregnancy. AB - BACKGROUND: Medical management using potassium chloride feticide and methotrexate is often the first-line approach to cervical pregnancies. CASE: A 25-year-old woman presenting with a cervical ectopic pregnancy was unsuccessfully managed with conservative therapy, resulting in an arteriovenous malformation requiring a laparoscopic hysterectomy. CONCLUSION: Conservative management of ectopic pregnancies is the treatment of choice for young women looking to preserve fertility. However, medical management is not without risk, and this case illustrates one such complication. PMID- 30007799 TI - Early Discharge after Laparoscopic Hysterectomy: a Prospective Study. AB - OBJECTIVE: To evaluate the feasibility of same-day discharge after laparoscopic hysterectomy without excluding patients with complex surgical pathology and medical comorbidities. These factors are often considered potential barriers to early discharge, and the literature is lacking prospective trials addressing the feasibility of same-day discharge after laparoscopic hysterectomy in this patient population. METHODS: All women undergoing laparoscopic hysterectomy by a member of the minimally invasive gynaecology team at The Ottawa Hospital, a tertiary academic referral centre, from May 2013 to February 2015 were eligible to participate regardless of patient comorbidities or surgical complexity. Strict perioperative protocols are presented. Factors associated with decreased success of same-day discharge and baseline and postoperative quality of life surveys were analyzed. RESULTS: Fifty-three patients were included. Overall success of same day discharge was 83.0%. Average age and BMI were 44.4 years and 29.8 kg/m2, respectively. Thirty-four patients (63.0%) had at least one prior abdominal surgery. Those who had their surgery as first case of the day had a 91.7% same day discharge rate versus 64.7% if they did not (relative risk = 1.4 [range 1.0 2.0]; P = 0.02). Ninety-eight percent of participants would recommend same-day discharge. Clinically significant improvement in quality of life from baseline was observed in 5 of 8 of the Short Form 36 domains at 6 months. CONCLUSION: Same day discharge from hospital is reasonable and well accepted for patients undergoing laparoscopic hysterectomy, even with complex surgical pathology. The implementation of a successful same-day discharge program would mean greater efficiency, economic benefits, and improved access to surgical care for women. PMID- 30007800 TI - The Third Stage of Labour in the Extremely Obese Parturient. AB - BACKGROUND: Maternal obesity has been associated with an increased risk for an abnormal progression of labour; however, less is known about the length of the third stage of labour and its relation to maternal obesity. OBJECTIVE: To determine if the length of the third stage of labour is increased in extremely obese women and its possible correlation with an increased risk for postpartum hemorrhage. STUDY DESIGN: This was a retrospective cohort study of deliveries from January 2008 to December 2015 at our university hospital. Women with a BMI >=40 and a vaginal delivery were compared with the next vaginal delivery of a woman with a BMI <30. There were 147 women with a BMI >=40 compared with 157 with a BMI <30. Outcomes evaluated the length of the third stage of labour and the risk for postpartum hemorrhage and included antepartum, intrapartum, and perinatal complications. RESULTS: Subjects in the extreme obese group were more likely to be African American, older, diabetic (pregestational and gestational), hypertensive, pre-eclamptic, had a preterm delivery, and underwent an induction of labour. The overall length of the third stage of labour was significantly longer in the extreme obese group, 5 minutes (3, 8 [25th and 75th percentiles]) compared with 4 minutes (3,7) (P = 0.0374) in the non-obese group. Postpartum hemorrhage occurred more often in the extreme obese group (N = 16/147; 11%) compared with the non-obese group (N = 5/157; 3%) (P = 0.01). There were no differences between groups in respect to the following: gravidity, parity, length of the second stage of labour, birth weight, GA at delivery, Apgar score, cord blood gases, hematocrit change, need for postpartum transfusion, operative delivery, and development of chorioamnionitis. After an adjustment for ethnicity, maternal age, diabetes, preeclampsia, preterm labour, hypertension, and induction/augmentation, the analysis failed to show a significant difference in estimated blood loss and postpartum hemorrhage between the groups. CONCLUSIONS: The length of the third stage of labour is longer in the extreme obese parturient. Postpartum hemorrhage also occurs more often, but after adjustments for confounding variables, it is no longer significant. PMID- 30007801 TI - A Case of Epidural Lipomatosis in Pregnancy: Management during Labour and Caesarean Section. AB - BACKGROUND: Spinal epidural lipomatosis (SEL) is a rare condition of adipose tissue accumulation in the epidural space. As a result of excess adipose tissue, neuraxial anaesthesia has been reported to behave unpredictably in patients with this condition. CASE: A 36-year-old woman had worsening postural headaches during pregnancy. MRI revealed SEL involving the thecal sac between L3/L4 and L5/S1. She had induction of labour but ultimately required a CS for delivery. Her anaesthesia was managed with an epidural inserted at L3/4. She developed a high block with relative sacral sparing. CONCLUSION: Although neuraxial anaesthesia was thought to be contraindicated in patients with SEL, it can be done safely. Care must be taken to provide slow epidural titration to avoid high sensory block in patients with this condition. PMID- 30007802 TI - Influence of Resident Involvement in Obstetrics and Gynaecology Surgery on Surgical Outcomes: Systematic Review and Meta-Analysis. AB - OBJECTIVE: The effect of resident involvement during obstetrics and gynaecology (OB/GYN) surgery on surgical outcomes is unclear. This study sought to review the evidence systematically for the influence of resident participation in OB/GYN surgery on (1) operative time, (2) estimated blood loss, and (3) perioperative complications. METHOD: Published studies were identified via searches of PubMed, Embase, Cochrane Central Register, Web of Science, and ClinicalTrials.gov databases. The study included randomized or observational studies that compared outcomes for OB/GYN surgery performed by attending surgeons alone or with residents. Risk ratios or mean differences were extracted from the studies. A random effect model was performed for each outcome, with subgroup analysis by type of surgery and study quality. RESULTS: A total of 13 studies were included in the meta-analysis, comprising 40 968 patients in seven countries. Surgical procedures performed only by attending surgeons had shorter operative times (mean difference 18.20 minutes; 95% CI 13.58-22.82), whereas surgical procedures with resident involvement were associated with an increased risk of blood transfusion (risk ratio 1.23; 95% CI 1.08-1.41). There were no observable differences in risk of estimated blood loss, wound infection, urologic injury, viscus injury, or return to the operating room. Significant heterogeneity (I2 >50%) was present in one of seven outcomes. CONCLUSION: Resident participation in OB/GYN surgery is associated with longer operative times and increased risk of blood transfusion; however, other perioperative complications are not increased. PMID- 30007803 TI - Guideline for the Initial Management of Small Cell Lung Cancer (Limited and Extensive Stage) and the Role of Thoracic Radiotherapy and First-line Chemotherapy. AB - AIMS: We investigated the efficacy of adding radiotherapy to chemotherapy in patients with extensive stage small cell lung cancer (ES-SCLC) and the appropriate timing, dose and schedule of treatment for patients with ES-SCLC or limited stage SCLC (LS-SCLC). MATERIALS AND METHODS: The guideline was developed by Cancer Care Ontario's Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of randomised controlled trials. KEY RECOMMENDATIONS: In patients with LS-SCLC (stage I, II and III), the addition of thoracic radiotherapy to standard chemotherapy is recommended. However, there is no clear evidence to inform definitive recommendations for optimal timing, sequential versus concurrent therapies and optimal dose or regimen. In patients with LS-SCLC, etoposide-cisplatin is the preferred regimen for adults who are being treated with combined modality therapy with curative intent. In patients with ES-SCLC (stage IV), there is insufficient evidence to recommend the addition of thoracic radiotherapy to standard chemotherapy as a standard practice for survival benefit; however, it could be considered on a case-by-case basis to reduce local recurrence. In patients with ES-SCLC, a platinum agent plus etoposide is the preferred regimen for adult patients who are being treated with combined modality therapy. Cisplatin and irinotecan represents an alternative treatment option to this, but is associated with increased rates of adverse events such as diarrhoea. PMID- 30007804 TI - Short communication: Occurrence of methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci in dairy goat herds in Ohio, United States. AB - In light of the scarcity of information about the occurrence and epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MRCNS) in small ruminants in general, and particularly dairy goats, we launched this limited-scope study. The findings reported here show the detection of MRSA and MRCNS in goat milk and teat skin samples from dairy goat herds in the state of Ohio. A total of 120 milk samples and 120 teat-swab samples were collected from 5 farms. After conventional isolation and phenotypic characterization of the staphylococci colonies, bacterial isolates were tested by PCR assay targeting the genes nuc to identify Staphylococcus aureus and mecA to detect MRSA and MRCNS. The clonal complexes of MRSA isolates was also determined by multiloccus sequence typing. Fifteen (6.2%) positive S. aureus samples were found in this study: 9 from milk and 6 from teat skin samples. Four (2%) MRSA isolates were detected and, using multiloccus sequence typing genotyping, these were designated to clonal complexes CC133 (n = 2; milk samples) and CC5 (n = 2; teat skin). Three (1.25%) coagulase-negative staphylococci isolates from the teat skin also harbored the mecA gene. Although, the MRSA isolated from milk samples is not a typical human-associated lineage, the CC5 clone isolated from teat skin is a common and widespread clonal complex associated with humans, suggesting that this extramammary niche could be a relevant reservoir of methicillin-resistant staphylococci. Furthermore, the fact that 75% of MRSA were recovered from 1 farm showing poor hygiene practices strengthens the hypothesis that good hygiene practices could be useful to prevent persistence and spread of MRSA at a farm level. PMID- 30007805 TI - Genomic heritability and genome-wide association analysis of anti-Mullerian hormone in Holstein dairy heifers. AB - Anti-Mullerian hormone (AMH) is an ovarian growth factor that plays an important role in regulation of ovarian follicle growth. The objectives of this study were to estimate the genomic heritability of AMH and identify genomic regions associated with AMH production in a genome-wide association (GWA) analysis. Concentrations of AMH were determined in 2,905 dairy Holstein heifers genotyped using the Zoetis medium density panel (Zoetis Inclusions, Kalamazoo, MI) with 54,519 single nucleotide polymorphism (SNP) markers remaining after standard genotype quality control edits. A linear mixed model was used to model the random effects of sampling day and genomics on the logarithm of AMH. The genomic heritability (+/- standard error of the mean) of AMH was estimated to be 0.36 +/- 0.03. Our GWA analysis inferred significant associations between AMH and 11 SNP markers on chromosome 11 and 1 SNP marker on chromosome 20. Annotated genes with significant associations were identified using the Ensembl genome database (version 88) of the cow genome (version UMD 3.1; https://www.ensembl.org/biomart). Gene set enrichment analysis revealed that 2 gene ontology (GO) terms were significantly enriched in the list of candidate genes: G-protein coupled receptor signaling pathway (GO:0007186) and the detection of chemical stimulus involved in sensory perception (GO:0050907). The estimated high heritability and previously established associations between AMH and ovarian follicular reserve, fertility, longevity, and superovulatory response in cattle implies that AMH could be used as a biomarker for genetic improvement of reproductive potential. PMID- 30007806 TI - Technical note: Methodological and feed factors affecting measurement of protein A, B, and C fractions, degradation rate, and intestinal digestibility of rumen undegraded protein. AB - When formulating dairy cow rations, characterization of protein in feeds requires estimation of protein degradation in the rumen and digestion in the intestine. The objective of this work was to evaluate experimental and feed-related factors that affect characterization using in situ, in vitro, or mobile bag techniques, of 0-h washout (A), potentially degradable (B), and undegradable (C) protein fractions, protein degradation rate (Kd), and digestibility of rumen undegradable protein (dRUP). Data sets of 136 studies on A, B, C, and Kd and 113 studies on dRUP were amassed from the literature. Mixed-effect linear models were used to relate these variables to methodological and feed factors while accounting for random differences among studies. Predictions of A, B, and C protein fractions were significantly influenced by crude protein and neutral detergent fiber interactions with bag pore size, incubation time, bag area, and sample-to-bag area ratio. For example, a 20.0% decrease in crude protein of a theoretical legume silage sample would increase A fraction prediction by 20.1%, but 34.7% with bag incubation time -1 standard deviation below the mean. Similarly, reported Kd values were significantly influenced by crude protein interactions with bag area and sample-to-bag area ratio and by neutral detergent fiber interaction with pore size. Feed variables and measurement variables influencing protein digestibility measures suggest that these analytical factors are likely associated with variance among differing methodologies and within unique samples of the same feed. When predicting dRUP, the use of mobile bag method produced significantly different estimates compared with the in vitro 3-step method. The use of mobile bag resulted in an 8.9% (+/-3.8%) higher estimate of dRUP compared with the in situ technique. In 618 and 977 samples, sample variation to sample mean ratio for acid detergent fiber and pepsin-acid incubation time was 63.0 and 58.0%, respectively. Variation in feedstuff content and lack of standardization of methods used to measure protein disappearance led to a lack of robustness in the measurements commonly employed. PMID- 30007807 TI - Validating intrinsic markers and optimizing spot sampling frequency to estimate fecal outputs. AB - Indirect methods of spot sampling with intrinsic markers to estimate fecal output and nutrient digestibility often have been used in dairy nutrition research as alternatives to total collection of feces (TC) because of labor and expense. However, fecal output and nutrient digestibility estimated from the indirect method must be accurate regardless of altering dietary conditions. This experiment was designed to validate the accuracy of using indigestible neutral detergent fiber (iNDF) or acid-insoluble ash (AIA) as intrinsic markers to estimate fecal outputs and nutrient digestibility compared with TC and to determine the optimal number of spot sampling events to accurately determine fecal output and then nutrient excretion. The experiment used 12 multiparous lactating Holstein cows in a randomized complete block design. Cows were blocked by days in milk and milk yield and randomly assigned to 1 of 2 diets: a diet containing about 49% corn silage on a dry matter basis and a diet containing about 48% alfalfa silage with high by-product (soyhulls) and supplemental K. During the final 3 d of 21-d periods, TC was performed, and 12 spot samples were collected for the same 3 d to represent every 2 h in a 24-h cycle. Fecal outputs and nutrient digestibility of dry matter, organic matter, or nitrogen estimated with iNDF or AIA as an intrinsic marker were compared with TC. Overall, fecal outputs and digestibility estimated with iNDF were similar to that estimated with TC, whereas AIA overestimated fecal output by 44 to 61% and underestimated nutrient digestibilities by 16 to 32%. However, potential differences in statistical inference of dietary effects between iNDF and TC were found. Data from individual spot samples were aggregated to represent spot sampling frequencies of 12 (SP12), 6 (SP6), 4 (SP4), or 2 (SP2) evenly spaced events starting at feeding time. Compared with TC, SP12 produced similar fecal content of iNDF, organic matter, and nitrogen, but fecal AIA content was greater. Furthermore, compared with SP12, SP6 produced similar fecal content of all nutrients, whereas marker and nutrient concentrations in SP4 and SP2 were different. In this experiment, iNDF was a better fecal marker than AIA, and a spot sampling frequency of at least 6 events was necessary. However, interpretation of dietary effects could be confounded when iNDF was used to estimate fecal outputs. PMID- 30007808 TI - Short communication: Association analysis of diacylglycerol acyltransferase (DGAT1) mutation on chromosome 14 for milk yield and composition traits, somatic cell score, and coagulation properties in Holstein bulls. AB - The aim of the present study was to determine the allele frequencies of the diacylglycerol acyltransferase (DGAT1) K232A mutation in Italian Holstein bulls and to estimate the effect of the mutation on milk yield, composition, somatic cell score, and coagulation traits (rennet coagulation time and curd firmness). For this purpose, 349 Italian Holstein bulls were genotyped for the DGAT1 mutation on chromosome 14. Association analysis was performed by regressing the number of copies for the K allele on the deregressed estimated breeding value of the individual. Breeding values were calculated using field data routinely collected in Northeast Italy. The frequencies of the AA, KA, and KK genotypes were 59.6, 32.1, and 8.3%, respectively, and the minor allele frequency (K variant) was 24.7%. The K allele was significantly associated with greater fat yield and fat, protein, and casein percentages and with reduced protein:fat ratio. The association between the DGAT1 mutation and somatic cell score was not significant, whereas a favorable association between presence of the K allele and milk coagulation properties was found. Results from the present study confirmed the effect of the diallelic DGAT1 polymorphism K232A on milk production traits and, for the first time, provided evidence that this mutation also affects milk coagulation properties in the Italian Holstein breed. PMID- 30007809 TI - Evaluation of applying statistical process control techniques to daily average feeding behaviors to detect disease in automatically fed group-housed preweaned dairy calves. AB - Group housing and computerized feeding of preweaned dairy calves are gaining in popularity among dairy producers, yet disease detection remains a challenge for this management system. The aim of this study was to investigate the application of statistical process control charting techniques to daily average feeding behavior to predict and detect illness and to describe the diagnostic test characteristics of using this technique to find a sick calf compared with detection by calf personnel. This prospective cross-sectional study was conducted on 10 farms in Minnesota (n = 4) and Virginia (n = 6) utilizing group housing and computerized feeding from February until October 2014. Calves were enrolled upon entrance to the group pen. Calf personnel recorded morbidity and mortality events. Farms were visited either every week (MN) or every other week (VA) to collect calf enrollment data, computer-derived feeding behavior data, and calf personnel-recorded calf morbidity and mortality. Standardized self-starting cumulative sum (CUSUM) charts were generated for each calf for each daily average feeding behavior, including drinking speed (mL/min), milk consumption (L/d), and visits to the feeder without a milk meal (no.). A testing subset of 352 calves (176 treated, 176 healthy) was first used to find CUSUM chart parameters that provided the highest diagnostic test sensitivity and best signal timing, which were then applied to all calves (n = 1,052). Generalized estimating equations were used to estimate the diagnostic test characteristics of a single negative mean CUSUM chart signal to detect a sick calf for a single feeding behavior. Combinations of feeding behavior signals were also explored. Single signals and combinations of signals that included drinking speed provided the most sensitive and timely signal, finding a sick calf up to an average (+/-SE) of 3.1 +/- 8.8 d before calf personnel. However, there was no clear advantage to using CUSUM charting over calf observation for any one feeding behavior or combination of feeding behaviors when predictive values were considered. The results of this study suggest that, for the feeding behaviors monitored, the use of CUSUM control charts does not provide sufficient sensitivity or predictive values to detect a sick calf in a timely manner compared with calf personnel. This approach to examining daily average feeding behaviors cannot take the place of careful daily observation. PMID- 30007810 TI - Short communication: Relationship between body condition score and plasma adipokines in early-lactating Holstein dairy cows. AB - We hypothesized that plasma adipokine concentrations of early-lactation dairy cows are related to body condition score (BCS) at calving and to markers of metabolic status of the cow. As part of a larger study with 117 multiparous Holstein dairy cows, which had high BCS (BCS >4.0) or normal BCS (3.25-3.5) at calving, 22 cows were randomly selected (n = 11 per group) to be enrolled in this study. Cows were divided into 2 groups based on their BCS at calving: (1) normal BCS with BCS of 3.35 +/- 0.13 (mean +/- SD) and (2) high BCS cows with BCS of 4.14 +/- 0.17. The 22 selected animals did not have a clinically diagnosed health problem after calving. Blood samples were taken right after calving (d 1) and before morning feeding on d 8, 15, and 21 postpartum concurrently with body condition scoring for all cows. Blood samples were analyzed for plasma adiponectin, leptin, tumor necrosis factor-alpha, and IL-6. The mean BCS remained highest in high-BCS cows during the first 21 d in milk. Leptin concentrations decreased progressively for all cows after calving. However, differences in BCS at calving were not related to leptin concentrations. Adiponectin, IL-6, and tumor necrosis factor-alpha concentrations were neither influenced by days in milk nor BCS after calving. Leptin and the leptin-to-adiponectin ratio did not show any correlation at any time point during the first 21 d in milk with plasma concentrations of nonesterified fatty acids or beta-hydroxybutyrate, which are considered as markers of metabolic status. Only for IL-6 at d 8 did we find a strong correlation with metabolic status indicators. In conclusion, plasma adipokine concentrations during the first 3 wk postpartum were not related to BCS in lactating Holstein cows that were clinically healthy at calving. PMID- 30007811 TI - Feed and nitrogen efficiency are affected differently but milk lactose production is stimulated equally when isoenergetic protein and fat is supplemented in lactating dairy cow diets. AB - Fifty-six Holstein-Friesian cows were used in a randomized complete block design to test the effects of supplemental energy from protein (PT) and fat (FT) on lactation performance and nutrient digestibility in a 2 * 2 factorial arrangement. During the control period, cows were adapted for 28 d to a basal total mixed ration consisting of 34% grass silage, 33% corn silage, 5% grass hay, and 28% concentrate on a dry matter (DM) basis. Experimental rations were fed for 28 d immediately following the control period and consisted of (1) low protein, low fat (LP/LF), (2) high protein, low fat (HP/LF), (3) low protein, high fat (LP/HF), or (4) high protein and high fat (HP/HF). To obtain the HP and HF diets, intake of the basal ration was restricted and supplemented isoenergetically (net energy basis) with 2.0 kg/d of rumen-protected protein (soybean + rapeseed, 50:50 mixture on DM basis) and 0.68 kg/d of hydrogenated palm fatty acids (FA) on a DM basis. Milk production and composition, nutrient intake, and apparent digestibility were measured during the final 7 d of the control and experimental periods. No interaction was found between PT and FT on milk production and composition. Yields of milk, fat- and protein-corrected milk, and lactose increased in response to PT and FT and lactose concentration was unaffected by treatment. Milk protein concentration and yield increased in response to PT, and protein yield tended to increase in response to FT. Milk fat concentration and yield increased in response to FT and were unaffected by PT. Milk urea concentration increased and nitrogen efficiency decreased in response to PT. Feed and nitrogen efficiency were highest on the LP/HF diet and both parameters increased in response to FT, whereas milk urea concentration was not affected by FT. Energy from fat increased the concentration and yield of >=16-carbon FA in milk and decreased the concentration of FA synthesized de novo, but had no effect on their yield. Concentration and yield of de novo-synthesized FA increased in response to PT. Concentration and yield of polyunsaturated FA increased and decreased in response to PT and FT, respectively. Apparent total-tract digestibility of crude fat decreased in response to PT, and FT increased crude protein digestibility. Energy supplementation through rumen-inert hydrogenated palm FA appears to be an efficient feeding strategy to stimulate milk production with regard to feed and nitrogen efficiency compared with supplementing an isoenergetic level of rumen-protected protein. PMID- 30007812 TI - Short communication: Parapoxvirus and Orthopoxvirus coinfection in milk of naturally infected cows. AB - Several studies have shown the occurrence of poxvirus infections associated with exanthematic lesions in cattle from many Brazilian states. Coinfection between viruses belonging to 2 genera, Orthopoxvirus (OPXV) and Parapoxvirus (PPV), was already identified from the lesions of affected cows and humans. The DNA and infectious viral particles of Vaccinia virus, an OPXV, have been detected in milk of naturally and experimentally infected cows. However, to date no reports have described the detection of Pseudocowpox virus, a PPV, in milk. Thus, we investigated the presence of PPV and OPXV in milk samples obtained from dairy cows from a Brazilian region with exanthematic disease outbreaks. From 2011 to 2014, 6 dairy farms with exanthematic disease outbreaks involving dairy cows, calves, and humans were visited. Twelve crusts of cows' teat lesions and 60 milk samples were collected. The crusts and milk samples were analyzed by PCR to detect OPXV or PPV DNA. According to the analyzed crusts, we detected PPV infection in 4 of the 6 visited farms, from which we investigated the PPV contamination in milk. From the 40 milk samples tested, PPV DNA was detected in 12 samples. Of these milk samples, 8 were positive for both PPV and OPXV. This is the first report of PPV DNA detection in milk samples from affected cows, indicating that the virus may be present in milk and potentially contaminating dairy products associated or not with OPXV. In addition to the lesions caused by direct contact, the presence of 2 or more poxvirus species in milk showed that the effect of zoonotic exanthematic diseases on public health and animal husbandry is relevant and cannot be overlooked. PMID- 30007813 TI - Microbial analysis of commercially available US Queso Fresco. AB - Queso Fresco (QF), a fresh Hispanic-style cheese, is often associated with Listeria monocytogenes outbreaks and recalls. Queso Fresco's susceptibility to bacterial contamination is partially due to its high pH and moisture content as well as Listeria's tolerance for the salt content typical for QF. Nine different brands of US QF, 2 packages from 4 different lots (to account for temporal variability), were sampled. The pH, salt content, and moisture content were analyzed in addition to microbial testing including yeasts and molds, coliforms, lactic acid bacteria enumeration, and L. monocytogenes counts. The cheeses were also inoculated with a cocktail of 5 food and human isolates of food-borne outbreak-associated Listeria monocytogenes strains to evaluate how the differences between brands influenced Listeria growth. Three of the cheeses underwent additional genus-level microbial analysis using extracted 16S rDNA, allowing for phylogenetic analysis between bacterial taxa including diversity and relative abundance. We found little variation between the sampled QF pH (range = 6.62-6.86), salt content (1.53-2.01%), and moisture content (43.90-54.50%). Yeasts and molds were below the detection limit of enumeration in all of the cheeses and coliforms were below the detection limit across the first 3 lots, but were detected at varying levels in the fourth lot (>3.0 most probable number/g) for 3 of the brands. Listeria monocytogenes was not isolated after enrichment in any of the samples. All cheeses tested positive for the presence of lactic acid bacteria, with only 1 of the cheeses being labeled as produced with added cultures having substantial counts. Fourteen days after inoculation with L. monocytogenes, at least 2.5 log10 cfu/g of growth was found for all QF brands stored at 4 degrees C. Microbial genus analysis showed that, among the 3 brands, the microbial community was more similar within brand than when compared with the other 2 brands. Thermus, Anoxybacillus, and Streptococcus accounted for the dominant genera of brands A, B, and C, respectively. These variations within the microbial community may account for sensory differences and help manufacturers determine quality control consistency more readily than culture-based methods. PMID- 30007814 TI - Effect of dietary supplements of biotin, intramuscular injections of vitamin B12, or both on postpartum lactation performance in multiparous dairy cows. AB - The current study was conducted to investigate the effects of dietary supplementation of biotin, intramuscular injections of vitamin B12 (VB12), or both beginning at the prepartum period on feed intake and lactation performance in postpartum dairy cows. Forty-eight dairy cows were allocated into 12 blocks, based on parity and milk yield of the previous lactation cycle, and randomly assigned to 1 of 4 treatments. Supplementation of VB12 (weekly intramuscular injections of 0 or 10 mg) and biotin (dietary supplements of 0 or 30 mg/d) were used in a 2 * 2 factorial arrangement in a randomized complete block design of 12 blocks with repeated measures. The study started at 3 wk before the expected calving date and ended at 8 wk after calving. Feed intake and lactation performance (milk yield and composition) were recorded weekly after calving. Blood variables were measured on d -10, 0, 8, 15, 29, 43, and 57 relative to calving. When VB12 was given, the cows had greater feed intake, better lactation performance and lower body weight loss in the postpartum period compared with animals without injection of VB12. The VB12-injected cows had lower plasma nonesterified fatty acids and beta-hydroxybutyrate concentrations but higher plasma superoxide dismutase activity compared with cows without VB12. Cows fed a biotin supplement had higher milk protein yield (6 and 8 wk) and lactose yield (6 8 wk), compared with animals without biotin. However, under the present experimental conditions, we found no additive effect of a combined supplement of biotin and vitamin B12 on lactation performance of dairy cows. PMID- 30007815 TI - Ruminal biohydrogenation and abomasal flow of fatty acids in lactating cows fed diets supplemented with soybean oil, whole soybeans, or calcium salts of fatty acids. AB - Ruminants have a unique metabolism and digestion of unsaturated fatty acids (UFA). Unlike monogastric animals, the fatty acid (FA) profile ingested by ruminants is not the same as that reaching the small intestine. The objective of this study was to evaluate whole raw soybeans (WS) in diets as a replacer for calcium salts of fatty acids (CSFA) in terms of UFA profile in the abomasal digesta of early- to mid-lactation cows. Eight Holstein cows (80 +/- 20 d in milk, 22.9 +/- 0.69 kg/d of milk yield, and 580 +/- 20 kg of body weight; mean +/ standard deviation) with ruminal and abomasal cannulas were used in a 4 * 4 Latin square experiment with 22-d periods. The experiment evaluated different fat sources rich in linoleic acid on ruminal kinetics, ruminal fermentation, FA abomasal flow, and milk FA profile of cows assigned to treatment sequences containing a control (CON), with no fat source; soybean oil, added at 2.68% of diet dry matter (DM); WS, addition of WS at 14.3% of diet DM; and CSFA, addition of CSFA at 2.68% of diet DM. Dietary fat supplementation had no effect on nutrient intake and digestibility, with the exception of ether extract. Cows fed fat sources tended to have lower milk fat concentration than those fed CON. In general, diets containing fat sources tended to decrease ruminal neutral detergent fiber digestibility in relation to CON. Cows fed WS had lower ruminal digestibility of DM and higher abomasal flow of DM in comparison to cows fed CSFA. As expected, diets containing fat supplements increased FA abomasal flow of C18:0 and total FA. Cows fed WS tended to present a higher concentration of UFA in milk when compared with those fed CSFA. This study suggests that under some circumstances, abomasal flow of UFA in early lactation cows can be increased by supplementing their diet with fat supplements rich in linoleic acid, regardless of rumen protection, with small effects on ruminal DM digestibility. PMID- 30007817 TI - Having Found Meaningful Intermediate Prostate Cancer Clinical Endpoints Associated with Overall Survival, What Next? PMID- 30007816 TI - Evolution of PD-1 and PD-L1 Gene and Protein Expression in Primary Tumors and Corresponding Liver Metastases of Metastatic Bladder Cancer. PMID- 30007818 TI - Getting the Balance Right-The Benefits and Uncertainties of Focal Therapy for Significant Prostate Cancer. PMID- 30007819 TI - Metabolic Biosynthesis Pathways Identified from Fecal Microbiome Associated with Prostate Cancer. AB - BACKGROUND: The fecal microbiome is associated with prostate cancer risk factors (obesity, inflammation) and can metabolize and produce various products that may influence cancer but have yet to be defined in prostate cancer. OBJECTIVE: To investigate gut bacterial diversity, identify specific metabolic pathways associated with disease, and develop a microbiome risk profile for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: After prospective collection of 133 rectal swab samples 2 wk before the transrectal prostate biopsy, we perform 16S rRNA amplicon sequencing on 105 samples (64 with cancer, 41 without cancer). Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. The p values were adjusted using the false discovery rate. The alpha and beta-diversity analyses were performed using QIIME. The Mann-Whitney U test was employed to evaluate the statistical significance of beta-diversity distances within and between groups of interest, and least absolute shrinkage and selection operator (LASSO) regression analysis was used to determine pathway significance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The detection of prostate cancer on transrectal prostate needle biopsy and 16s microbiome profile. RESULTS AND LIMITATIONS: We identified significant associations between total community composition and cancer/non-cancer status (Bray-Curtis distance metric, p<0.01). We identified significant differences in enrichments of Bacteroides and Streptococcus species in cancer (all p<0.04). Folate (LDA 3.8) and arginine (LDA 4.1) were the most significantly altered pathways. We formed a novel microbiome derived risk factor for prostate cancer based on 10 aberrant metabolic pathways (area under curve=0.64, p=0.02). CONCLUSIONS: Microbiome analyses on men undergoing prostate biopsy noted mostly similar bacterial species diversity among men diagnosed with and without prostate cancer. The microbiome may have subtle influences on prostate cancer but are likely patient-specific and would require paired analysis and precise manipulation, such as improvement of natural bacterial folate production. PATIENT SUMMARY: Microbiome evaluation may provide patients with personalized data regarding the presence or absence of particular bacteria that have metabolic functions and implications regarding prostate cancer risk. The study provides a basis to investigate the manipulation of aberrant microbiomes to reduce prostate cancer risk. PMID- 30007820 TI - Reply to Riccardo Bertolo's Letter to the Editor re: Giorgio Gandaglia, Carlo Andrea Bravi, Paolo Dell'Oglio, et al. The Impact of Implementation of the European Association of Urology Guidelines Panel Recommendations on Reporting and Grading Complications on Perioperative Outcomes after Robot-assisted Radical Prostatectomy. Eur Urol 2018;74:4-7. PMID- 30007821 TI - Effect of radiocapitellar Achilles disc arthroplasty on coronoid and capitellar contact pressures after radial head excision. AB - BACKGROUND: Long-term radiographic arthritis has been commonly reported after radial head excision. Concern over radial head arthroplasty may arise in certain situations including capitellar arthritis, radiocapitellar malalignment, and in young and active patients. We hypothesized that radial head excision increases coronoid contact pressures, which may at least be partially reduced by radiocapitellar Achilles tendon disc arthroplasty. METHODS: Coronoid and capitellar contact pressure was measured on 6 human cadaveric elbows on a custom designed gravity-valgus simulator under passive flexion from 0 degrees to 90 degrees . Sequential testing, starting with the intact specimen, resection of the radial head, and finally, radiocapitellar Achilles tendon disc arthroplasty were performed on each specimen. RESULTS: Mean contact pressure of the coronoid significantly increased after radial head excision (P < .0001) and significantly improved after Achilles disc arthroplasty (P < .0001). The pressure difference was most pronounced on the lateral coronoid. From 15 degrees to 85 degrees of elbow flexion, mean contact pressures on the lateral coronoid were 291 kPa and 476 kPa before and after radial head excision, respectively (P < .0001). Achilles disc arthroplasty significantly lowered coronoid contact pressures to 385 kPa (P = .002); however, they remained significantly higher than those in the intact radial head group (P = .0009). CONCLUSIONS: Radial head resection increases contact pressure in the coronoid, especially the lateral coronoid. This study showed that radiocapitellar Achilles disc arthroplasty significantly improves contact pressures on the coronoid after radial head resection. Achilles disc arthroplasty could be considered in patients who are not candidates for radial head arthroplasty. PMID- 30007822 TI - Human keratinocyte cultures (HaCaT) can be infected by DENV, triggering innate immune responses that include IFNlambda and LL37. AB - The skin is the first anatomical region that dengue virus (DENV) encounters during the natural infection. Although the role of some skin resident cells like dendritic cells and fibroblasts has been demonstrated to be crucial to elucidate the role of resident cells and molecules participating during the early events of the innate immune response, the participation of keratinocytes during DENV infection has not been fully elucidated. In this paper we aimed to evaluate the use of the HaCaT cell line as a model to study the immune responses of skin keratinocytes to DENV infection. We demonstrated productive DENV-2 infection of HaCaT cells and their capability to establish an antiviral response through production of type I and type III interferons (IFN-beta and IFN-lambda). The production of these cytokines by HaCaT cells correlated with upregulation of IFN inducible transmembrane protein-3 (IFITM3) and viperin in bystander, uninfected cells. We also observed an increase in secretion of IL-6 and IL-8. Skin keratinocytes are known to secrete antimicrobial peptides (AMPs) during viral infections. In our model, DENV-2 infected HaCaT cells upregulate the production of cytoplasmic LL-37. We evaluated the dual role of LL-37, HBD2, and HBD3 antiviral activity and immunoregulation during DENV-2 infection of HaCaT cells and found that LL-37 significantly reduced DENV-2 replication. This indicates that the HaCaT cell line can be used as a model for studying the innate response of keratinocytes to DENV infection. Our results also suggest that skin keratinocytes play an important role in the skin microenvironment after DENV infection by secreting molecules like type I and type III IFNs, pro-inflammatory molecules, and LL-37, which may contribute to the protection against arboviral infections. PMID- 30007823 TI - Inspiratory muscle training for intensive care patients: A multidisciplinary practical guide for clinicians. AB - OBJECTIVES: To describe a multidisciplinary approach to inspiratory muscle training (IMT) for patients in the intensive care unit (ICU). BACKGROUND: Inspiratory muscle weakness is a known consequence of prolonged mechanical ventilation, and there is emerging evidence that specific IMT can ameliorate this weakness. However, IMT is not yet standard practice in many ICUs, possibly because of the wide variety of methods reported and a lack of published practical guidelines. While the optimal parameters for IMT are yet to be established, we share our detailed methodology which has been shown to be safe in selected ventilator-dependent patients and is the only approach which has been shown to increase quality of life in ICU patients. METHODS: Patients who have experienced invasive mechanical ventilation for at least 7 days can commence IMT in either the ventilator-dependent phase or when weaned from mechanical ventilation. Intensity should be prescribed based on maximum inspiratory pressure, which is measurable through the tracheostomy or endotracheal tube via the ventilator or a respiratory pressure meter. Using a removable threshold device, we recommend high intensity training (5 sets of 6 breaths at a minimum of 50% of maximum inspiratory pressure) performed once per day, supervised by the physiotherapist, with intensity increased daily such that patients can only just complete the 6th breath in each set. RESULTS: Using this high-intensity approach, IMT is likely to improve not only inspiratory muscle strength but also quality of life in patients recently weaned from mechanical ventilation of 7 days' duration or longer. Effective IMT requires a multidisciplinary approach to maximise feasibility, with doctors, nurses, and therapists working closely to optimise conditions for successful IMT. CONCLUSIONS: This multidisciplinary approach to implement IMT in ICU patients should assist clinicians in translating best-available evidence into practice, with the potential to enhance patient recovery. PMID- 30007824 TI - Visual Vaccinology: Changing public perception. PMID- 30007826 TI - Effects of geographic and economic heterogeneity on the burden of rotavirus diarrhea and the impact and cost-effectiveness of vaccination in Pakistan. AB - Globally, rotavirus is a leading cause of childhood diarrhea and related mortality. Although rotavirus vaccination has been introduced in many countries worldwide, there are numerous low- to middle-income countries that have not yet introduced. Pakistan is one of the countries with the highest number of rotavirus deaths in children under five years. Although rotavirus infection is almost universal among children, mortality is often a result of poor nutrition and lack of access to health care and other aspects of poverty. We assess the impact and cost-effectiveness of introducing childhood rotavirus vaccination in Pakistan. We use household data from the 2012-2013 Demographic Health survey in Pakistan to estimate heterogeneity in rotavirus mortality risk, vaccination benefits, and cost-effectiveness across geographic and economic groups. We estimate two-dose rotavirus vaccination coverage that would be distributed through a routine vaccination program. In addition, we estimate rotavirus mortality (burden), and other measures of vaccine cost-effectiveness and impact by subpopulations of children aggregated by region and economic status. Results indicate that the highest estimated regional rotavirus burden is in Sindh (3.3 rotavirus deaths/1000 births) and Balochistan (3.1 rotavirus deaths/1000 births), which also have the lowest estimated vaccination coverage, particularly for children living in the poorest households. In Pakistan, introduction could prevent 3061 deaths per year with current routine immunization patterns at an estimated $279/DALY averted. Increases in coverage to match the region with highest coverage (Islamabad) could prevent an additional 1648 deaths per year. Vaccination of children in the highest risk regions could result in a fourfold mortality reduction as compared to low risk children, and children in the poorest households have a three to four times greater mortality reduction benefit than the richest. Based on the analysis presented here, the benefits and cost effectiveness of rotavirus vaccination can be maximized by reaching economically and geographically vulnerable children. PMID- 30007825 TI - Novel influenza vaccine M2SR protects against drifted H1N1 and H3N2 influenza virus challenge in ferrets with pre-existing immunity. AB - Current influenza vaccines do not provide effective protection against heterologous influenza viruses. The ability of the novel M2SR influenza vaccine to protect against drifted influenza viruses was evaluated in naive ferrets and in ferrets with pre-existing immunity to influenza. In naive ferrets, M2SR provided similar protection against drifted challenge viruses as the comparator vaccine, FluMist(r). However, in ferrets with pre-existing immunity, M2SR provided superior protection than FluMist in two model systems. In the first model, ferrets were infected with influenza A H1N1pdm and influenza B viruses to mimic the diverse influenza exposure in humans. The pre-infected ferrets, seropositive to H1N1pdm and influenza B but seronegative to H3N2, were then vaccinated with H3N2 M2SR or monovalent H3N2 FluMist virus (A/Brisbane/10/2007, clade 1) and challenged 6 weeks later with a drifted H3N2 virus (clade 3C.2a). Antibody titers to Brisbane/10/2007 were higher in M2SR vaccinated ferrets than in FluMist vaccinated ferrets in the pre-infected ferrets whereas the opposite was observed in naive ferrets. After challenge with drifted H3N2 virus, M2SR provided superior protection than FluMist monovalent vaccine. In the second model, the impact of homologous pre-existing immunity upon vaccine-induced protection was evaluated. Ferrets, pre-infected with H1N1pdm virus, were vaccinated 90 days later with H1N1pdm M2SR or FluMist monovalent vaccine and challenged 6 weeks later with a pre-pandemic seasonal H1N1 virus, A/Brisbane/59/2007 (Bris59). While cross-reactive serum IgG antibodies against the Bris59 HA were detected after vaccination, anti-Bris59 hemagglutination inhibition antibodies were only detected post-challenge. M2SR provided better protection against Bris59 challenge than FluMist suggesting that homologous pre existing immunity affected FluMist virus to a greater degree than M2SR. These results suggest that the single replication intranasal M2SR vaccine provides effective protection against drifted influenza A viruses not only in naive ferrets but also in those with pre-existing immunity in contrast to FluMist viruses. PMID- 30007827 TI - Effects of geographic and economic heterogeneity on rotavirus diarrhea burden and vaccination impact and cost-effectiveness in the Lao People's Democratic Republic. AB - Rotavirus enteritis is responsible for nearly 200,000 child deaths worldwide in 2015. Globally, many low- and middle-income countries have introduced rotavirus vaccine, resulting in documented reductions in hospitalizations and child mortality. We examined the potential impact and cost-effectiveness of introducing rotavirus vaccination in Lao People's Democratic Republic using an Excel-based spreadsheet model. We estimated mortality risk factors, patterns of care seeking, and vaccination access to predict outcomes for regional, provincial, and socioeconomic subpopulations for one birth cohort through their first five years of life and life course in Disability-Adjusted Life Years estimates. Socioeconomic status was defined by categorizing households into regional wealth quintiles based on a national asset index. We modeled a two-dose ROTARIX vaccine under current Gavi pricing and efficacy estimates from Bangladesh and Vietnam. DPT1 and DPT2 coverages were used to estimate rotavirus vaccination coverage. Probabilistic sensitivity analysis was used to assess the impact of uncertainty on model parameters on predicted incremental cost-effectiveness ratios (ICERs), including scenarios of increases in vaccination coverage. Rotavirus vaccination would prevent 143 child deaths/year, or 28% of annual rotavirus burden. The estimated national level ICER for rotavirus vaccination was $140/DALY, with regional socioeconomic subpopulation estimates ranging from $72/DALY for the poorest in the Central region to $353/DALY for the richest in the North region, indicating high cost-effectiveness. Within regions, ICERs are most favorable for children in the poorer and poorest quintiles. However, the full benefits of rotavirus vaccination will only be realized by reducing disparities in vaccination coverage, access to treatment, and environmental health. Improving vaccination coverage to equitable levels alone would prevent 87 additional child deaths per year. PMID- 30007828 TI - Acupuncture for migraine without aura: a systematic review and meta-analysis. AB - BACKGROUND: Migraine without aura (MWoA), the most common type of migraine, has great impacts on quality of life for migraineurs. Acupuncture is used in the treatment and prevention of migraine for its analgesic effects. OBJECTIVE: The aim of this systematic review and meta-analysis is to systematically assess the therapeutic and preventive effect of acupuncture treatment and its safety for MWoA. SEARCH STRATEGY: Nine electronic databases (PubMed, MEDLINE, Cochrane Library, Lilacs, Embase, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data and Chinese Clinical Trial Registry (ChiCTR)) were systematically searched from their beginning through June 2017 using MeSH terms such as "acupuncture, acupuncture therapy, electro-acupuncture, ear acupuncture, acupuncture points, acupuncture analgesia," and "migraine disorders, cluster headache." Manual searching included other conference abstracts and reference lists. INCLUSION CRITERIA: Randomized controlled trials (RCTs) with a clinical diagnosis of MWoA, which were treated with acupuncture versus oral medication or sham acupuncture treatment. DATA EXTRACTION AND ANALYSIS: Two evaluators screened and collected literature independently; they extracted information on participants, study design, interventions, follow-up, withdrawal and adverse events and assessed risk of bias and quality of the acupuncture intervention. The primary outcomes were frequency of migraine (FM) and number of migraine days (NM). Secondary outcomes included the visual analogue scale (VAS) score, effective rate (ER) and adverse events. Pooled estimates were calculated as mean difference (MD) with 95% confidence interval (CI) for continuous data and relative risk (RR) with 95% CI for dichotomous data. RESULTS: Overall, 14 RCTs including 1155 participants were identified. The analysis found that acupuncture had a significant advantage over medication in reducing FM (MD = -1.50; 95% CI: 2.32 to -0.68; P < 0.001) and VAS score (MD = 0.97; 95% CI: 0.63-1.31; P < 0.00001) and had a higher ER (RR = 1.30; 95% CI: 1.16-1.45; P < 0.00001). Acupuncture also had a significant advantage over sham acupuncture in the decrease of FM (MD = -1.05; 95% CI: -1.75 to -0.34; P = 0.004) and VAS score (MD = -1.19; 95% CI: -1.75 to -0.63; P < 0.0001). Meanwhile, acupuncture was more tolerated than medication because of less side effect reports (RR = 0.29; 95% CI: 0.17-0.51; P < 0.0001). However, the quality of evidence in the included studies was mainly low (to very low), making confidence in the FM and VAS score results low. CONCLUSION: Our meta-analysis shows that the effectiveness of acupuncture is still uncertain, but it might be relatively safer than medication therapy in the treatment and prophylaxis of MWoA. Further proof is needed. PMID- 30007829 TI - Evaluation of acute and subacute toxicity of whole-plant aqueous extract of Vernonia mespilifolia Less. in Wistar rats. AB - OBJECTIVE: This study investigated the acute and subacute toxicity of whole-plant aqueous extract of Vernonia mespilifolia Less. (AEVM) in rats for evaluating its safety profile. METHODS: AEVM for the acute (2000 and 5000 mg/kg) and subacute (200, 400 and 600 mg/kg) toxicity studies was administered orally to rats according the guidelines 425 and 407 of Organization for Economic Cooperation and Development, respectively. Food and water intake as well as body and organ weight of animals were recorded. Signs of toxicity were assessed, and hematological, biochemical and histopathological analyses were performed. RESULTS: In the acute toxicity study, a single dose of the aqueous extract at 2000 or 5000 mg/kg caused no mortality in the animals, suggesting that the median lethal dose is greater than 5000 mg/kg. In the subacute toxicity study, administration of the extract for 28 d, at all doses, caused no significant changes in the body weights or organ weights of rats in the treated groups when compared with the control group. In addition, hematological and biochemical parameters also revealed no toxic effects of the extract on rats. Histological sections of the heart, liver and kidney from test animals showed no signs of degeneration. CONCLUSION: These results showed that AEVM at dosage levels up to 600 mg/kg is nontoxic and could also offer protection on some body tissues. AEVM could, therefore, be considered safe. PMID- 30007830 TI - Ethnomedicinal, phytochemical and pharmacological updates on Hygrophila auriculata (Schum.) Hiene: an overview. AB - This article explores the most recent evidence-based information on ethnomedicinal, phytochemical and pharmacological understanding of Hygrophila auriculata for the treatment of various diseases and health conditions. Various ethnomedicinal writings suggest the use of the plant or its parts for the treatment of jaundice, oedema, gastrointestinal ailments, diarrhoea, dysentery, urinogenital disorder, gall stones, urinary calculi, kidney stone, leucorrhoea, rheumatism, tuberculosis, anaemia, body pain, constipation, skin disease, and as an aphrodisiac. The plant has been reported to contain flavonoids (apigenin, luteolin, ellagic acid, gallic acid and quercetin), alkaloids (asteracanthine and asteracanthicine), triterpenes (lupeol, lupenone, hentricontane and betulin), sterols (stigmasterol and asterol), minerals, amino acids, fatty acids, aliphatic esters and essential oils. Extracts and bioactive compounds from the plant have been found to possess antimicrobial, anthelmintic, antitermite, nephroprotective, hepatoprotective, central nervous system protective, antitumour, antidiabetic, anticataract, antioxidant, haematopoietic, diuretic, antinociceptive, anti inflammatory, antipyretic, antimotility, aphrodisiac, neuroprotection, anti endotoxin and anti-urolithiatic activities. For this paper, we reviewed patents, clinical studies, analytical studies and marketed formulations from the earliest found examples from 1887 to the end of 2017. PMID- 30007831 TI - Differentiating malignant and benign lymph nodes using endobronchial ultrasound elastography. AB - BACKGROUND/PURPOSE: Endobronchial ultrasound (EBUS) elastography is a new technique that provides information on tissue compressibility during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The purposes of this study were to evaluate the utility of EBUS elastography in differentiating malignant and benign mediastinal lymph nodes (LNs) and to explore the factors that influence its accuracy. METHODS: A retrospective chart review of patients who underwent EBUS-TBNA from October 2016 to July 2017 was performed. EBUS with conventional B-mode features and elastographic patterns were compared with the final pathology results or clinical follow-up. We used the following EBUS elastographic patterns for classification: type 1, predominantly non-blue (green, yellow and red); type 2, part blue, part non-blue; type 3, predominantly blue. The potential impacts of the characteristics of LNs, the underlying lung diseases and obtaining fibrotic components from EBUS-TBNA specimens were evaluated relative to the accuracy of EBUS elastography. RESULTS: A total of 206 LNs from 94 patients were retrospectively evaluated. In classifying type 1 as 'benign' and type 3 as 'malignant,' the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy rate were 90.6, 82.6, 71.6, 94.7 and 85.2%, respectively. The EBUS elastographic patterns had higher diagnostic yields and negative predictive values than conventional B mode features. Logistic regression analysis revealed that central necrosis was a factor that influenced the accuracy of elastography in malignant LNs. The fibrotic component within benign LNs could cause an incorrect elastographic pattern. CONCLUSION: EBUS elastography is a valuable tool in discriminating benign and malignant mediastinal LNs. PMID- 30007832 TI - Corrigendum to "Sinomenine inhibits fibroblast-like synoviocyte proliferation by regulating alpha7nAChR expression via ERK/Egr-1 pathway" [Int. Immunopharmacol. 56 (2018) 65-70]. PMID- 30007834 TI - Male Breast Cancer: An Updated Surveillance, Epidemiology, and End Results Data Analysis. AB - BACKGROUND: Male breast cancer is rare and understudied compared with female breast cancer. A current comparison with female breast cancer could assist in bridging this gap. Although conflicting data have been reported on male and female survival outcomes, data from 1973 through 2005 in the Surveillance, Epidemiology, and End Results (SEER) program have demonstrated that the improvement in breast cancer survival in men has fallen behind that of women. As treatment for breast cancer has improved significantly, an updated analysis using a contemporary population is necessary. MATERIALS AND METHODS: An analysis of SEER data from patients with a diagnosis of primary breast cancer from 2005 to 2010 were included. A Cox regression model was used to examine the association between sex and breast cancer mortality after controlling for prognostic factors, including age, race, marital status, disease stage, estrogen and progesterone receptor status, lymph node involvement, tumor grade, surgery, and geography. Subgroup analyses were performed by race and stage. RESULTS: We included a total of 289,673 breast cancer cases (2054 men) with a diagnosis from 2005 to 2010. The 5-year survival rate for male patients was lower than that for female patients (82.8% vs. 88.5%). After controlling for other factors, the risk of death in men was 43% greater than that in women during the follow-up period (hazard ratio, 1.43; 95% confidence interval, 1.26-1.61). Similar results were noted in the race and stage subgroup analyses. CONCLUSION: In recent years, male breast cancer patients have had worse survival outcomes compared with those of female patients. PMID- 30007835 TI - Condylar changes after orthognathic surgery for class III dentofacial deformity: a systematic review. AB - After orthognathic surgery for class II dentofacial deformity, remodelling of the mandibular condyle will take place. In a number of cases, this may evolve towards a phenomenon of condylar resorption. Yet, studies on the occurrence of this complication after the correction of a class III deformity are scarce. A systematic review of the literature was performed with the aim of identifying reports on condylar resorption or remodelling after orthognathic surgery for class III dentofacial deformity. A search of the international databases yielded 12 eligible studies. Eight studies reported some degree of postoperative condylar remodelling, while symptoms of condylar resorption were only described in a limited group of patients. Thus, the literature may show evidence of condylar remodelling after orthognathic treatment of class III patients, and anecdotal reports of condylar resorption exist. The small sample sizes, heterogeneity in methods and outcomes, and use of two-dimensional radiographs indicate the need for updated long-term research. In the future, the use of cone beam computed tomography data for volumetric and morphological condylar analysis in combination with three-dimensional cephalometry may provide the opportunity to further elucidate this phenomenon and better characterize its aetiology. PMID- 30007836 TI - Baseline Rehospitalization Rates of Nursing Homes in Bundled Payments for Care Improvement. PMID- 30007833 TI - Single-Cell Multi-omics: An Engine for New Quantitative Models of Gene Regulation. AB - Cells in a multicellular organism fulfill specific functions by enacting cell type-specific programs of gene regulation. Single-cell RNA sequencing technologies have provided a transformative view of cell-type-specific gene expression, the output of cell-type-specific gene regulatory programs. This review discusses new single-cell genomic technologies that complement single-cell RNA sequencing by providing additional readouts of cellular state beyond the transcriptome. We highlight regression models as a simple yet powerful approach to relate gene expression to other aspects of cellular state, and in doing so, gain insights into the biochemical mechanisms that are necessary to produce a given gene expression output. PMID- 30007837 TI - Four novel RECQL4 mutations in four Chinese patients with Rothmund-Thomson syndrome and analysis of RECQL4 mRNA expression level in one typical patient. PMID- 30007838 TI - The influence of centre thickness on miniscleral lens flexure. AB - PURPOSE: To examine the influence of centre thickness upon miniscleral lens flexure and the association between the magnitude of in-vivo lens flexure and scleral toricity. METHODS: In-vivo lens flexure was measured using a videokeratoscope in 9 healthy young participants (25 +/- 4 years) with normal corneae fitted with ICD 16.5 miniscleral lenses (hexafocon B material) with centre thicknesses of 150, 250, and 350 MUm. Scleral toricity was determined from sagittal height data over a 15 mm chord obtained from a corneo-scleral topographer. RESULTS: On average, lens flexure increased with decreasing centre thickness, but remained <0.50 D (mean increase <0.25 D, p = 0.63). Scleral toricity was positively correlated with in-vivo flexure for the 150 MUm (r = 0.77, p = 0.02) and 250 MUm (r = 0.72, p = 0.03) lenses. Using a group mean split, eyes with >200 MUm scleral toricity exhibited greater in-vivo flexure than eyes with <200 MUm (0.40 D more, averaged across all lenses, p = 0.02), and this effect was greatest for the 150 MUm lens (0.61 D more, p = 0.04). CONCLUSIONS: Decreasing the centre thickness from 350 MUm to 150 MUm resulted in <0.25 D increase in lens flexure for a high Dk and low modulus material. Scleral toricity >200 MUm was associated with more in-vivo lens flexure. When intentionally reducing scleral lens centre thickness to enhance oxygen transmissibility, customised back surface designs may be required to minimise in-vivo flexure in eyes with >200 MUm scleral toricity at a 15 mm chord. PMID- 30007839 TI - A one-year risk score to predict all-cause mortality in hypertensive inpatients. AB - The aim of this study was to construct and internally validate a scoring system to estimate the probability of death in hypertensive inpatients. Existing predictive models do not meet all the indications for clinical application because they were constructed in patients enrolled in clinical trials and did not use the recommended statistical methodology. This cohort study comprised 302 hypertensive patients hospitalized between 2015 and 2017 in Spain. The main variable was time-to-death (all-cause mortality). Secondary variables (potential predictors of the model) were: age, gender, smoking, blood pressure, Charlson Comorbidity Index (CCI), physical activity, diet and quality of life. A Cox model was constructed and adapted to a points system to predict mortality one year from admission. The model was internally validated by bootstrapping, assessing both discrimination and calibration. The system was integrated into a mobile application for Android. During the study, 63 patients died (20.9%). The points system prognostic variables were: gender, CCI, personal care and daily activities. Internal validation showed good discrimination (mean C statistic of 0.76) and calibration (observed probabilities adjusted to predicted probabilities). In conclusion, a points system was developed to determine the one year mortality risk for hypertensive inpatients. This system is very simple to use and has been internally validated. Clinically, we could monitor more closely those patients with a higher risk of mortality to improve their prognosis and quality of life. However, the system must be externally validated to be applied in other geographic areas. PMID- 30007840 TI - Prediabetes and macrovascular disease: Review of the association, influence on outcome and effect of treatment. PMID- 30007841 TI - Quantum versus classical Monte Carlo simulation of low-energy electron transport in condensed amorphous media. AB - PURPOSE: Classical trajectory Monte Carlo (MC) simulations modelling radiation induced damage on subcellular length scales ignore quantum effects that may be non-negligible as electron energy decreases below 1 keV. This work investigates quantum mechanical (QM) treatments of low-energy electron transport in condensed media, comparing with classical MC. METHODS: QM calculations involve a simplified model of electron transport in water with a plane wave incident on a cylinder ("droplet") consisting of a cluster of point scatterers (positioned randomly but constrained by a minimum separation, dmin). The system of coupled equations for the electron wavefield incident on each scatterer is solved numerically and results are averaged over many clusters with different point scatterer positions. Average QM cluster cross sections and scattering event densities are compared with analogues computed within the corresponding classical MC model, and relative errors on MC results are calculated. RESULTS: Differences between QM and MC results for both cluster cross section and scattering event density are sensitive to electron energy (wavelength), structure (dmin), and single-scatterer elastic/inelastic cross sections. Relative errors on cluster cross sections generally differ from errors on scattering event densities. The introduction of inelastic scatter generally increases relative errors (compared to calculations with the same single-scatterer elastic cross section) with some exceptions. Accounting for structure (dmin?0) enhances differences between QM and MC results. CONCLUSIONS: The quantum wave nature of electrons is non-negligible for simulations of low-energy electron transport within small-scale biological targets. The development of more realistic models of electron transport in condensed media is motivated for future work. PMID- 30007843 TI - Funder Restrictions on Application Numbers Lead to Chaos. AB - Restricting application rates is an attractive way for funders to reduce time and money wasted evaluating uncompetitive applications. However, mathematical models show that this could induce chaotic cycles in total application numbers, increasing uncertainty in the funding process. One emergent property is that smaller institutions spend disproportionally more time unfunded. PMID- 30007842 TI - Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis. AB - Autoreactive lymphocytes that escape central immune tolerance may be silenced via an endogenous peripheral tolerance mechanism known as anergy. Antigen-specific therapies capable of inducing anergy may restore patients with autoimmune diseases to a healthy phenotype while avoiding deleterious side effects associated with global immunosuppression. Inducing anergy in B cells may be a particularly potent intervention, as B cells can contribute to autoimmune diseases through multiple mechanisms and offer the potential for direct antigen specific targeting through the B cell receptor (BCR). Our previous results suggested autoreactive B cells may be silenced by multivalent 'soluble antigen arrays' (SAgAs), which are polymer conjugates displaying multiple copies of autoantigen with or without a secondary peptide that blocks intracellular cell adhesion molecule-1 (ICAM-1). Here, key therapeutic molecular properties of SAgAs were identified and linked to the immunological mechanism through comprehensive cellular and in vivo analyses. We determined non-hydrolyzable 'cSAgAs' displaying multivalent 'click'-conjugated antigen more potently suppressed experimental autoimmune encephalomyelitis (EAE) compared to hydrolyzable SAgAs capable of releasing conjugated antigen. cSAgAs restored a healthy phenotype in disease specific antigen presenting cells (APCs) by inducing an anergic response in B cells and a subset of B cells called autoimmune-associated B cells (ABCs) that act as potent APCs in autoimmune disease. Accompanied by a cytokine response skewed towards a Th2/regulatory phenotype, this generated an environment of autoantigenic tolerance. By identifying key therapeutic molecular properties and an immunological mechanism that drives SAgA efficacy, this work guides the design of antigen-specific immunotherapies capable of inducing anergy. PMID- 30007844 TI - Ediacaran Extinction and Cambrian Explosion. AB - The Ediacaran-Cambrian (E-C) transition marks the most important geobiological revolution of the past billion years, including the Earth's first crisis of macroscopic eukaryotic life, and its most spectacular evolutionary diversification. Here, we describe competing models for late Ediacaran extinction, summarize evidence for these models, and outline key questions which will drive research on this interval. We argue that the paleontological data suggest two pulses of extinction - one at the White Sea-Nama transition, which ushers in a recognizably metazoan fauna (the 'Wormworld'), and a second pulse at the E-C boundary itself. We argue that this latest Ediacaran fauna has more in common with the Cambrian than the earlier Ediacaran, and thus may represent the earliest phase of the Cambrian Explosion. PMID- 30007845 TI - Overcoming the Data Crisis in Biodiversity Conservation. AB - How can we track population trends when monitoring data are sparse? Population declines can go undetected, despite ongoing threats. For example, only one of every 200 harvested species are monitored. This gap leads to uncertainty about the seriousness of declines and hampers effective conservation. Collecting more data is important, but we can also make better use of existing information. Prior knowledge of physiology, life history, and community ecology can be used to inform population models. Additionally, in multispecies models, information can be shared among taxa based on phylogenetic, spatial, or temporal proximity. By exploiting generalities across species that share evolutionary or ecological characteristics within Bayesian hierarchical models, we can fill crucial gaps in the assessment of species' status with unparalleled quantitative rigor. PMID- 30007847 TI - Exploring the limits of modelling thrombus formation: Comment on "Modeling thrombosis in silico: Frontiers, challenges, unresolved problems and milestones" by A.V. Belyaev et al. PMID- 30007848 TI - Low caregiver health literacy among pediatric food-allergic patients is associated with poorer food allergy management knowledge. PMID- 30007846 TI - Did Our Species Evolve in Subdivided Populations across Africa, and Why Does It Matter? AB - We challenge the view that our species, Homo sapiens, evolved within a single population and/or region of Africa. The chronology and physical diversity of Pleistocene human fossils suggest that morphologically varied populations pertaining to the H. sapiens clade lived throughout Africa. Similarly, the African archaeological record demonstrates the polycentric origin and persistence of regionally distinct Pleistocene material culture in a variety of paleoecological settings. Genetic studies also indicate that present-day population structure within Africa extends to deep times, paralleling a paleoenvironmental record of shifting and fractured habitable zones. We argue that these fields support an emerging view of a highly structured African prehistory that should be considered in human evolutionary inferences, prompting new interpretations, questions, and interdisciplinary research directions. PMID- 30007850 TI - Sarcoidosis: is cryobiopsy not cool enough? - Authors' reply. PMID- 30007851 TI - Sarcoidosis: is cryobiopsy not cool enough? PMID- 30007849 TI - Advancing the knowledge, skills and attitudes of mental health nurses working with families and caregivers: A critical review of the literature. AB - Involving and supporting the family members and caregivers of people with mental illness is essential to high-quality mental health services. However, literature suggests that there is a lack of engagement between family members and mental health nurses (MHNs). Lack of knowledge among MHNs is often cited as one of the main reasons for this lack of engagement. The aim of this review was to explore the knowledge, skills and attitudes that are required by MHNs to enable to them to work more effectively with families affected by mental illness. A literature based critical review was used to access and review 35 papers in order to extract concepts that could inform the design of eLearning materials to assist MHNs advance their knowledge in this area. Two overarching themes were identified; 'Mental health problems and the family' and 'Working with the family'. From these themes, the knowledge, skills and attitudes required to work more effectively with families are described. The findings from this review provide a descriptive account of the knowledge skills and attitudes that are required for effective family work. In addition, the review provides an empirical foundation for education programmes in the area. PMID- 30007852 TI - Are CT findings of pulmonary sarcoidosis ever sufficient for a presumptive diagnosis? PMID- 30007853 TI - Effect of the use of a national information brochure about foetal movements on patient delay. AB - BACKGROUND: Perinatal audits in the Netherlands showed that stillbirth was nearly always preceded by a period of reduced foetal movements. Patient or caregiver delay was identified as a substandard care factor. AIM: To determine whether the use of a new information brochure for pregnant women on foetal movements results in less patient delay in contacting their maternity caregiver. METHODS: A pre- and post-survey cohort study in the Netherlands, including 140 women in maternity care with a singleton pregnancy, expecting their first child. All participating women filled out a baseline questionnaire, Cambridge Worry Scale and pre-test questionnaire at the gestational age of 22-24 weeks. Subsequently, the intervention group received a newly developed information brochure on foetal movements. At a gestational age of 28 weeks, all women received the post-test questionnaire. Multiple regression analyses were used. FINDINGS: Per-protocol analysis showed less patient delay in the intervention group compared to the control group (Odds Ratio 0.43; 95% Confidence Interval 0.17-0.86, p=0.02). A significant linear relation was observed between reading the information brochure and an increase of knowledge about foetal movements (B=1.2, 95% Confidence Interval 1.0-1.4, p<0.001). Maternal concerns did not affect patient delay to report reduced foetal movements. CONCLUSION: Use of an information brochure regarding foetal movements has the potential to reduce patient delay and increase knowledge about reduced foetal movements. A national survey to determine the effect of an information brochure about reduced foetal movements on patient delay and stillbirth rates is needed. PMID- 30007854 TI - The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU COBESO study. AB - The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts. Adolescents aged 12-15 years showed poorer HRQoL in the domain "cognitive functioning" compared to controls. For adults >=16 years, poorer age-controlled HRQoL was found for the domains cognition, depressive moods, and anger, with a further trend for the domain "pain". With respect to metabolic control, only for adult PKU-patients robust associations were observed, indicating poorer functioning, most notably in the domains cognition, sleep, pain, sexuality and anger, with higher historical and concurrent Phe-levels. With respect to BH4-use, effects on HRQoL were again only observed for adult PKU-patients. After controlling for age and historical Phe-levels, small but significant differences in favor of adult BH4-users compared to non-users were observed for HRQoL categories happiness, anger, and social functioning. Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning. PMID- 30007856 TI - ACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis. AB - The production of anti-citrullinated peptide antibodies (ACPAs) requires the participation of both innate immunity and adaptive immunity. On the one hand, activated innate immunity is able to produce citrullinated auto-antigens that fuel autoimmunity and provide an inflammatory environment that facilitates the breach of self-tolerance, proliferation of self-reactive T/B cells and the production of ACPAs. On the other hand, after their production by plasma B cells, ACPAs are also able to interact with innate immunity to exacerbate the manifestation and chronicity of rheumatoid arthritis (RA). This article discusses the roles of citrullinated peptides and ACPA played in innate immunity and autoimmunity. In addition, we emphasise the relationships between environmental factors and innate immunity, as well as the pathogenic function of ACPAs per se. In doing so, we hope to provide fundamental knowledge of RA pathogenesis and reveal potential therapeutic targets in RA treatment. PMID- 30007857 TI - Histochemistry, immunohistochemistry and cytochemistry of the anterior midgut region of the stingless bee Melipona quadrifasciata and honey bee Apis mellifera (Hymenoptera: Apidae). AB - The anterior midgut region of stingless bees is anatomically differentiated with tall and narrow cells, whereas in other social and solitary bees this anatomical gut region is lacking. The objective of the present study was to describe the histochemistry, immunohistochemistry and cytochemistry of the anterior midgut region of the stingless bee Melipona quadrifasciata in comparison with the honey bee Apis mellifera. The anterior midgut region of both species was evaluated for identification of the enzymes beta- galactosidase, glucose-6-phosphatase, acid phosphatase, and alkaline phosphatase, the membrane transporter aquaporin, the hormone FMRF-amide, and lysosomes. Histology of the anterior midgut region showed that this region in M. quadrifasciata workers did not present external folds of the wall, whereas the following midgut wall presented many. In A. mellifera, folds in the midgut wall occur starting from the fore- midgut transition region. Despite these morphological differences, the tests evaluated were similar in both species. beta-galactosidase was not found in the anterior midgut cells. Glucose-6 phosphatase and acid phosphatase occurred in the apical region of the gut epithelium. Alkaline phosphatase occurred in vesicles in apical cytoplasm and in the basal plasma membrane infoldings of the epithelial cells. Aquaporin was found in the basal region of the midgut epithelium and in the associated visceral muscles. FMRF-amide was found only in nerve endings in the anterior midgut region. All cells in the anterior midgut region were rich in lysosomes. These results suggest that in both bee species, although they have anatomically different anterior midgut regions, these regions present high metabolic activity and function in cellular homeostasis, lipid absorption and are under neurohormone control. PMID- 30007858 TI - A ray tracing method for predicting contrast in neutral atom beam imaging. AB - A ray tracing method for predicting contrast in atom beam imaging is presented. Bespoke computational tools have been developed to simulate the classical trajectories of atoms through the key elements of an atom beam microscope, as described using a triangulated surface mesh, using a combination of MATLAB and C code. These tools enable simulated images to be constructed that are directly analogous to the experimental images formed in a real microscope. It is then possible to understand which mechanisms contribute to contrast in images, with only a small number of base assumptions about the physics of the instrument. In particular, a key benefit of ray tracing is that multiple scattering effects can be included, which cannot be incorporated easily in analytic integral models. The approach has been applied to model the sample environment of the Cambridge scanning helium microscope (SHeM), a recently developed neutral atom pinhole microscope. We describe two applications; (i) understanding contrast and shadowing in images; and (ii) investigation of changes in image formation with pinhole-to-sample working distance. More generally the method has a broad range of potential applications with similar instruments, including understanding imaging from different sample topographies, refinement of a particular microscope geometry to enhance specific forms of contrast, and relating scattered intensity distributions to experimental measurements. PMID- 30007855 TI - In-depth phenotypic characterization of reticulocyte maturation using mass cytometry. AB - Progress towards an in-depth understanding of the final steps of the erythroid lineage development is paramount for many hematological diseases. We have characterized the final stages of reticulocyte maturation from bone marrow to peripheral blood using for the first time single-cell Mass Cytometry (CyTOF). We were able to measure the expression of 31 surface markers within a single red blood cell (RBC). We demonstrate the validity of CyTOF for RBC phenotyping by confirming the progressive reduction of transferrin receptor 1 (CD71) during reticulocyte maturation to mature RBC. We highlight the high-dimensional nature of mass cytometry data by correlating the expression of multiple proteins on individual RBCs. We further describe a more drastic reduction pattern for a component of the alpha4/beta1 integrin CD49d at the very early steps of reticulocyte maturation in bone marrow and directly linked with the mitochondria remnants clearance pattern. The enhanced and accurate RBC phenotyping potential of CyTOF described herein could be beneficial to decipher RBC preferences, as well as still not well understood receptor-ligand interaction of some hemotropic parasites such as the malaria causing agent Plasmodium vivax. PMID- 30007859 TI - Determining EDS and EELS partial cross-sections from multiple calibration standards to accurately quantify bi-metallic nanoparticles using STEM. AB - Spectroscopic signals such as EDS and EELS provide an effective way of characterising multi-element samples such as Pt-Co nanoparticles in STEM. The advantage of spectroscopy over imaging is the ability to decouple composition and mass-thickness effects for thin samples, into the number of various types of atoms in a sample. This is currently not possible for multi element samples using conventional ADF quantification techniques alone. With recent developments in microscope hardware and software, it is now possible to acquire the ADF, EDS and EELS signals simultaneously and at high speed. However, the methods of quantifying the signals emitted from the sample vary greatly. Most approaches use pure-element standards in the form of needles, nanoparticles and wedges to quantify the spectroscopic signal into either partial scattering cross-sections, zeta-factors or k-factors. But self-consistency between the different methods has not been verified and the units of the quantification are not standardised. We present a robust approach for measuring and combining ADF, EDS and EELS signals using needle and nanoparticle standards in units of the partial scattering cross section. The partial scattering cross-section allows an easy interpretation of the signals emitted from the sample and enables accurate atom-counting of the sample. PMID- 30007860 TI - A comparative study of defect formation in GaAs nanocrystals selectively grown on nanopatterned and flat Si(001) substrates. AB - Crystal defects present in GaAs nanocrystals ~15-50 nm in diameter and grown by metal organic vapor phase epitaxy on top of two different nanopatterned Si(001) substrates (nanopillars and nanotips with ~40-80 nm openings embedded in a SiO2 matrix) and on a planar substrate, have been investigated by means of atomic resolution aberration-corrected scanning transmission electron microscopy. Conditions of their formation are discussed. The defect analysis of the three GaAs/Si systems reveals a higher defect density in the GaAs crystals grown on nanopillars as compared to those grown on nanotips and the planar substrate, possibly concomitant to the atomic-scale irregularities identified at the patterned Si(001) nanopillars. It is concluded that the misfit strain in the GaAs nanocrystals is fully plastically relaxed while no noticeable substrate compliance effects are observed on any of the studied substrates. PMID- 30007861 TI - The importance of pathophysiology to the understanding of functional limitations in the bioarchaeology of care approach. AB - This article presents a partial bioarchaeology of care case study of a mummified adult female with chronic obstructive pulmonary disease (COPD) from late historic period United States. It examines likely clinical and functional impacts of disease and corresponding need for provision of care, stopping short of Stage 4 Interpretation/analysis. The case study illustrates and argues for the importance of an interdisciplinary research team for achieving a comprehensive understanding of disability and care. The article highlights the necessity of knowledge of pathophysiology for identifying the potential interventions (supports) dictated by the associated functional limitations. inter alia, this case is a powerful illustration of the way analysis of preserved soft tissue can provide insights into disease and likely care that are inaccessible using skeletal analysis alone. The article represents an interesting contribution to the theory and methodology of both the bioarchaeology of care approach and mummy studies. PMID- 30007862 TI - Sexual Disorders of Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Antiangiogenic Therapies. AB - BACKGROUND: Targeted therapies, in particular antiangiogenic therapies (AATs), have become the standard of treatment for metastatic renal cell carcinoma (mRCC). Although common adverse effects like fatigue have been well-established, sexual disorders induced by these treatments, although often reported, have been poorly evaluated. The aim of this study was to evaluate the impact of AATs on the sexual life of patients with mRCC and the relationships with quality of life (QoL), fatigue, and biologic parameters. PATIENTS AND METHODS: This longitudinal study included patients with mRCC on first- or second-line AATs. Sexuality was evaluated by the French version of Changes in Sexual Functioning Questionnaire short-Form (CSFQ); QoL and fatigue were measured by the Functional Assessment of Cancer Therapy General (FACT-G) and the Multidimensional Fatigue Inventory (MFI 20), respectively. Biologic parameters were also assessed. RESULTS: Among 75 patients included in the study, 39 agreed to respond to the sexual functioning questionnaire (CSFQ). At baseline, all patients had at least 1 sexual dysfunction. No relationship with QoL, fatigue, and biologic parameters was shown. After 3 months of treatment, a decrease in at least 1 sexual dimension was observed in 69% of patients. The most affected sexual dimensions were pleasure (34%) and desire/interest (38%). No significant relationship between sexual dysfunctions and biologic parameters was found. The percentage of non participants (50%) and the absence of a control arm are the main limitations. DISCUSSION: Patients with mRCC exhibit sexual dysfunction that could be increased by AATs independently of the impact on fatigue and QoL. Further studies aiming to define the role of biologic parameters like inflammatory markers and thyroid parameters are warranted. CONCLUSION: Sexual disorders induced or degraded by AAT are an independent side effect that should be taken into account in oncology supportive care departments. PMID- 30007863 TI - Building words and phrases in the left temporal lobe. AB - A central part of knowing a language is the ability to combine basic linguistic units to form complex representations. While our neurobiological understanding of how words combine into larger structures has significantly advanced in recent years, the combinatory operations that build words themselves remain unknown. Are complex words such as tombstone and starlet built with the same mechanisms that construct phrases from words, such as grey stone or bright star? Here we addressed this with two magnetoencephalography (MEG) experiments, which simultaneously varied demands associated with phrasal composition, and the processing of morphological complexity in compound and suffixed nouns. Replicating previous findings, we show that portions of the left anterior temporal lobe (LATL) are engaged in the combination of modifiers and monomorphemic nouns in phrases (e.g., brown rabbit). As regards compounding, we show that semantically transparent compounds (e.g., tombstone) also engage left anterior temporal cortex, though the spatiotemporal details of this effect differed from phrasal composition. Further, when a phrase was constructed from a modifier and a transparent compound (e.g., granite tombstone), the typical LATL phrasal composition response appeared at a delayed latency, which follows if an initial within-word operation (tomb + stone) must take place before the combination of the compound with the preceding modifier (granite + tombstone). In contrast to compounding, suffixation (i.e., star + let) did not engage the LATL in any consistent way, suggesting a distinct processing route. Finally, our results suggest an intriguing generalization that morpho-orthographic complexity that does not recruit the LATL may block the engagement of the LATL in subsequent phrase building. In sum, our findings offer a detailed spatiotemporal characterization of the lowest level combinatory operations that ultimately feed the composition of full sentences. PMID- 30007864 TI - An outbreak of respiratory tract infection due to Respiratory Syncytial Virus-B in a postpartum center. AB - BACKGROUND: An outbreak of respiratory tract infection due to Respiratory Syncytial Virus (RSV) type B in a postpartum center was reported on February 1, 2017. Investigation was conducted to identify the magnitude, possible source of infection and risk factors for this outbreak on February 2, 2017. METHODS: A retrospective cohort study was conducted. A case was defined as a neonate having respiratory symptoms with or without fever and stayed at the postpartum center between January 1, 2017 and February 3, 2017. Daily records of neonates were reviewed, and all parents who stayed at the postpartum center were interviewed. Virological testing of real-time polymerase chain reaction was conducted for the neonates having respiratory illness, the parents and all staff members in the facility. RESULTS: This outbreak occurred between January 17, 2017 and February 7, 2017 in a postpartum center. Thirty-five (58.3%) neonates among 59 neonates were identified as cases and 12 neonates were confirmed to be RSV-B positive. The longer length of stay in the postpartum center is the only risk factor (Relative Risk = 8.10, 95% Confidence Interval:1.84-35.62, p < 0.01) in this outbreak. Two nursing staffs and eight parents were confirmed as RSV-B positive. CONCLUSIONS: Longer periods of stay in the postpartum center had an increased chance of becoming infected with RSV during this outbreak. Isolation of cases and temporary closure with environmental cleaning were recommended to the postpartum center. PMID- 30007865 TI - The role of granulocyte macrophage colony stimulating factor in hospitalized children with Mycoplasma pneumoniae pneumonia. AB - BACKGROUND: Inappropriate inflammatory response in children with M. pneumoniae infection might be associated with disease severity. The role of Granulocyte macrophage colony stimulating factor (GM-CSF) in hospitalized children with Mycoplasma pneumoniae pneumonia (MPP) has not been fully discussed. METHODS: Clinical and laboratory data of a total 40 children with MPP were collected. GM CSF and myeloperoxidase (MPO) were detected by ELISAs. Meanwhile, normal human bronchial epithelium was infected by M. pneumoniae and neutrophils were stimulated by GM-CSF to explore GM-CSF and MPO release in supernatant, respectively. RESULTS: Compared to control group, a significant increased percentage of neutrophils and decreased percentage of macrophages in bronchoalveolar lavage fluid of children with MPP was observed (P < 0.05). Children with MPP had significantly higher levels of GM-CSF (P = 0.0047) and MPO (P = 0.0002) in BALF compared to the controls. Level of GM-CSF in BALF was associated with duration of fever (r = 0.42, P = 0.007) and strongly correlated with level of MPO (r = 0.075, P = 0.0005). Levels of GM-CSF and MPO significantly decreased (both P < 0.05) after treatment. In vitro, M. pneumoniae induced GM-CSF expression in a time-dependent manner during a 72-h period (P < 0.05) and MPO secretion significantly increased by recombinant human GM-CSF stimulation at 24h (P < 0.05). CONCLUSION: GM-CSF could be induced by M. pneumoniae infection in vivo and vitro. Childen with high level GM-CSF had longer duration of fever. GM CSF probably plays a vital role in neutrophil inflammation in M. pneumoniae infection. PMID- 30007866 TI - First case of a bloodstream infection caused by the genus Brachybacterium. AB - An 83-year-old previously self-sufficient man was referred to our hospital for a fever, severe tenderness over the lumbar spine, and elevated C-reactive protein levels. Computed tomography revealed fluid collection in the intervertebral space of L3/4. Gram-positive, short rod-shaped bacteria were isolated from two sets of blood cultures. A 16S rRNA sequence analysis of an isolate showed a similarity of 98.1% to the nearest type strain Brachybacterium squillarum JCM 16464T. Biochemical characteristics of the presently isolated strain differed from those of the most closely related species of the genus Brachybacterium. The patient was successfully discharged on day 73 of admission with antimicrobial therapies and showed no recurrence during outpatient visits. Brachybacterium spp. have mainly been isolated from the environment, and human Brachybacterium infections have rarely been documented to date. To our knowledge, this is the first clinical isolation of Brachybacterium sp. as a causative pathogen of bloodstream infection. PMID- 30007867 TI - Olfactory deficits and psychosis-spectrum symptoms in 22q11.2 deletion syndrome. AB - Olfactory functioning is a promising biomarker for psychosis in 22q11.2 deletion syndrome (22q11DS) but has not been well studied to date. This is a pilot effort to evaluate the potential for tests of olfactory functioning to contribute to risk and resilience prediction in 22q11DS, and is the first study to evaluate relationships among olfactory deficits, cognition and psychosis-spectrum symptoms. Odor identification and discrimination were evaluated in 32 individuals with 22q11DS and 110 healthy comparison subjects (HC). Individuals with 22q11DS also underwent cognitive testing with the Penn Computerized Neurocognitive Battery, which evaluates executive functioning, episodic memory, complex cognition, and social cognition. Positive, negative, disorganized and general psychosis-spectrum symptoms were rated according to the Scale of Prodromal Symptoms. Age-normalized scores were calculated for odor identification and discrimination based on normative data. Both odor identification (p < 0.001, Cohen's d = -2.15, 95% CI [-2.62, -1.68]) and discrimination (p < 0.001, Cohen's d = -1.81, 95% CI [-2.26, -1.35]) were significantly impaired in 22q11DS relative to HC. There were no sex differences in either group. Neither odor identification nor discrimination was correlated with overall cognition or any specific cognitive domain in 22q11DS. Impairment in odor discrimination was correlated with higher negative and overall psychosis-spectrum symptoms. There was no significant effect of catechol-O-methyltransferase Val(158)Met genotype or presence of velopharyngeal insufficiency on olfactory functioning. Olfactory deficits, particularly olfactory discrimination, are robust in 22q11DS and appear to be independent of cognitive deficits. They are also clinically relevant and related to psychosis-spectrum symptoms. Olfactory functioning appears to be a promising biomarker for psychosis in 22q11DS. PMID- 30007868 TI - Exploring the relationship between the anticipation and experience of pleasure in people with schizophrenia: An experience sampling study. AB - BACKGROUND: It has been hypothesised that a reduction in anticipatory pleasure contributes to reduced levels of functioning in people with schizophrenia. Previous research on anticipatory pleasure, however, reports mixed findings and has not yet examined the link between anticipatory pleasure and activity. The aim of this study is to examine how pleasure anticipation is related to difficulties engaging in activity in people with schizophrenia. METHOD: A healthy control group (n = 44) and a group of individuals with schizophrenia (n = 36) completed an experience sampling study using portable devices. Participants rated motivation, mood, functional, leisure and social activity levels; anticipatory and consummatory pleasure seven times a day for six consecutive days. Multi-level regression models were constructed to examine the role of anticipatory pleasure and/or motivation in predicting future activities. RESULTS: The findings showed no evidence for a motivation or pleasure deficit in people with schizophrenia. Yet, people with schizophrenia did fewer functional activities and spent more time "resting" or "doing nothing". In the control group, expectation was the only significant predictor of future activity. In contrast, none of the parameters assessed could predict experiences occurring in people with schizophrenia. CONCLUSIONS: In contrast with controls people with schizophrenia did not show a link between their predictions and the activities they engaged in. This appears to be an important process influencing functioning in people with psychosis. Future interventions targeting reduced functioning should focus on reinforcing the link between pleasure anticipation and goal-directed behaviour. PMID- 30007869 TI - Stability in basic self-disturbances and diagnosis in a first treated psychosis: A seven year follow-up study. AB - BACKGROUND: Basic self-disturbances (BSDs) are considered core features of schizophrenia spectrum disorders, and are present in the prodromal, early psychotic and chronic phases. Considerable levels of BSDs are also present at first treatment in some patients with psychotic disorders outside the schizophrenia spectrum. There is limited knowledge about the stability of self disturbances over time. AIM: To explore the stability of BSDs in a seven-year follow-up of first treatment patients, and the association between baseline levels and changes in BSDs and diagnostic changes at follow-up. METHOD: Longitudinal study of 56 patients (35 schizophrenia and 21 non-schizophrenia) recruited at their first treatment for a psychotic disorder. BSDs were assessed using the Examination of Anomalous Self-Experience (EASE), while diagnostic categories, clinical symptom severity, and functioning were assessed with standard clinical instruments. RESULTS: The schizophrenia group had significantly lower levels of BSDs at follow-up compared to baseline. The EASE domain "Cognition and stream of consciousness" was the most stable. There were no diagnostic changes into or out of schizophrenia spectrum. Patients with schizophrenia had significantly higher levels of BSDs both at baseline and at follow up than patients with psychotic disorders outside the schizophrenia spectrum, who showed stable low levels. CONCLUSION: We found a decrease and thus less stability in BSDs in schizophrenia than expected. This might indicate that BSDs tent to weaken over time, and that unknown individual characteristics may influence the development of BSDs. Diagnostic stability from baseline to follow up may be due to long DUP before service entry. PMID- 30007870 TI - Exclusion of a giant saphenous vein graft pseudo-aneurysm with a "double-layer bridging" technique. AB - We report the case of a 72-year-old man admitted to our hospital for chest pain. He had undergone coronary artery bypass graft surgery 23 years before. Contrast enhanced computer tomography revealed a severe double-lobed dilatation of the saphenous vein graft for the obtuse marginal branch. Coronary angiography did not opacify completely the saphenous vein graft for the huge turbulence in the dilatation. Severe saphenous vein graft dilatation have a significant mortality and it has been generally treated by surgical repair, such as resection with or without bypass of the affected territory. We described an interventional technique, named "double-layer bridging" that combines metallic DES and covered stent used in a double layer. This percutaneous technique, relatively simple and virtually usable for any type of severe dilatation independently of length, can be a reasonable and safe option to exclude giant aneurysm and maintaining distal flow. PMID- 30007871 TI - Usefulness of rescue ultrasound guidance for transradial cardiac catheterization. AB - INTRODUCTION AND OBJECTIVES: Transradial cardiac catheterization reduces access site complications and is more comfortable for patients than the transfemoral approach. However, failure of the transradial approach is more common than the transfemoral approach. This study aimed to investigate whether ultrasound-guided rescue could facilitate transradial cardiac catheterization. METHODS: We retrospectively analyzed 592 consecutive patients who underwent coronary angiography and/or percutaneous coronary intervention. Patients were divided into 2 groups: the palpation technique (PT) (n = 280) and the ultrasound guidance (UG) available group (n = 312). The application and the timing of introduction of ultrasound guidance in the UG group were at the discretion of the individual operators. RESULTS: Real-time ultrasound guidance was used in 98 patients (31.4%) in the UG group. No statistically significant intergroup differences were observed in the incidence of hematoma (6.8% vs. 5.8%, p = 0.62). Although the procedural time in the UG group was longer than that in the PT group (303 s vs. 357 s, p < 0.01), the success rate of sheath insertion was significantly higher in the UG group (97% vs. 92%, p < 0.01). Multivariate analysis revealed that the availability of UG was the only independent predictor of success of sheath insertion (odds ratio 2.79, 95% confidence interval 1.24-6.31, p = 0.01). CONCLUSIONS: Although UG maneuvers require additional procedural time for setting up systems, UG rescue was effective for successful transradial cardiac catheterization. PMID- 30007872 TI - An acute exposure to ozone impairs human olfactory functioning. AB - INTRODUCTION: Ozone is a ubiquitous and irritant gas. We questioned whether an acute exposure to 0.2 ppm ozone impaired olfactory functioning. METHODS: Healthy, normosmic subjects were exposed according to a parallel group design either to 0.2 ppm ozone (n = 15) or to sham (n = 13) in an exposure chamber for two hours. Possible irritating effects were assessed by questionnaire (range 0-5). The detection threshold of n-butanol was measured with the Sniffin' Sticks test before and after exposure. Olfactory thresholds were logarithmized and a two-way analysis of variance (ANOVA) with repeated measurements was carried out to test the effects of exposure (ozone vs. sham) and time (before vs. after exposure). Additionally, nasal secretions were taken at a preliminary examination and after exposure to determine interleukins 1beta and 8. RESULTS: No irritating effects to the upper airways were observed. In the ozone group, the median score for cough increased from 0 to 2 at the end of exposure (sham group 0 and 0, respectively, p < 0.001). The ANOVA showed a main effect for ozone exposure (F (1, 26) = 27.6, p = 0.0002), indicating higher olfactory thresholds in the ozone group. Concentrations of interleukins in nasal secretions did not increase following ozone exposure. CONCLUSIONS: This study shows a clear impairment of olfactory functioning following an acute exposure to 0.2 ppm ozone. PMID- 30007873 TI - Change of cell growth and mitochondrial membrane polarization in the progeny of cells surviving low-dose high-LET irradiation from Ra-226. AB - In order to test the delayed effect of radiation on the progeny of irradiated survivors, the human keratinocyte cell line HaCaT and the fish common bluegill embryonic cell line CHSE/F were exposed to low-dose high-LET alpha-radiation from Ra-226 or gamma-rays. The clonogenic survival fraction, mitochondrial membrane polarization (MMP) and reproductive ability of the descendants of the surviving cells were measured. For progeny of irradiated HaCaT survivors, no delayed cell death occurred. On the contrary, progeny at about 47 cell doublings after Ra-226 irradiation and progeny at about 14 cell doublings after gamma-irradiation showed increased clonogenic survival. However the total cell number was reduced for progeny of Ra-226-treated cells up to about 47 cell doublings after irradiation and for progeny of gamma-irradiated cells up to about 28 doublings after irradiation, which means low reproductive ability had appeared. In addition, alpha-radiation from Ra-226 had greater impact on the MMP of the HaCaT progeny than gamma-rays. MMP of progeny of Ra-226-treated cells decreased at 5 cell doublings after irradiation and increased dose-dependently at 19 cell doublings after treatment, and then decreased dose-dependently at 47 cell doublings, while there was no significant effect on MMP in progeny of gamma irradiated cells. The progeny of Ra-226-irradiated CHSE/F survivors showed more serious damage than the offspring of gamma-irradiated CHSE/F cells. Significant, dose-dependent delayed cell death occurred in progeny of surviving cells up to about 61 cell doublings after Ra-226 treatment, and the reproductive ability was also significantly reduced. But the MMP increased, which might be because of the increased removal of dead cells. For progeny of CHSE/F cells surviving gamma-rays radiation, no significant change in clonogenic survival occurred, except for offspring of cells surviving low dose (0.1 Gy and 0.5 Gy) irradiation, which had higher survival than control up to about 28 cell doublings after irradiation. But the number of cells which were the progeny of gamma-irradiated survivors decreased dose dependently up to about 28 cell doublings after gamma-irradiation. PMID- 30007874 TI - Airborne manganese exposure and neurobehavior in school-aged children living near a ferro-manganese alloy plant. AB - Excessive exposure to Mn can lead to its accumulation in the brain with neurotoxic consequences. In children, elevated Mn has been associated with deficits in certain neuropsychological domains such as cognition, motor function, memory and attention, and in some instances, hyperactivity and behavioral problems. The aim of this study was to evaluate behavioral effects in school-aged children living near a ferro-manganese alloy plant and examine their association with Mn exposure. Occipital hair, toenails and blood samples were collected from 225 children (7-12 years old) enrolled in four elementary schools with different levels of exposure to Mn, based on dust Mn deposition rates. Full data set collection was completed and run from 165 children. Mn in hair (MnH), toenails (MnTn), blood (MnB) and blood lead levels (PbB) were determined by graphite furnace atomic absorption spectrometry. Children's behavior was assessed with the Child Behavior Check List (CBCL) reported by parents. Median levels and range of MnH, MnT and MnB were, respectively, 0.73 ug/g (0.16-8.79), 0.84 ug/g (0.15-9.29) and 8.98 MUg/L (1.51-40.43). Median and range of PbB were 1.2 ug/dL (0.2-15.6). MnH and MnB were not associated with any scale of the CBCL behavior scores. We found a positive association between logMnTn and raw total CBCL score (beta = 10.17, p = 0.034), adjusting for sex, age, maternal IQ and logPbB. Analyses using Generalized Additive Model showed non-linear associations between MnTn and externalizing behavior (p = 0.035), as well as with the related subscales: aggressive behavior (p = 0.045) and rule-breaking behavior (p = 0.024). Further positive associations were observed between MnTn and thought problems (p = 0.031) and social problems (p = 0.027). These findings corroborate previous studies showing an association between Mn exposures and externalizing behavior. Our results suggest that toenail Mn, as a biomarker of environmental exposure, is associated with disruptive behavior in children living near a ferro-manganese alloy plant. PMID- 30007875 TI - [Harlequin syndrome secondary to a neuroblastoma]. PMID- 30007876 TI - [Not all scoliosis are what they seem]. PMID- 30007877 TI - Corrigendum to 'Atrial natriuretic peptide inhibits lipopolysaccharide-induced acute lung injury' [Pulm. Pharmacol. Therapeut. 29/1 (2014) 24-30]. PMID- 30007878 TI - Meaning before order: Cardinal principle knowledge predicts improvement in understanding the successor principle and exact ordering. AB - Learning the cardinal principle (the last word reached when counting a set represents the size of the whole set) is a major milestone in early mathematics. But researchers disagree about the relationship between cardinal principle knowledge and other concepts, including how counting implements the successor function (for each number word N representing a cardinal value, the next word in the count list represents the cardinal value N + 1) and exact ordering (cardinal values can be ordered such that each is one more than the value before it and one less than the value after it). No studies have investigated acquisition of the successor principle and exact ordering over time, and in relation to cardinal principle knowledge. An open question thus remains: Is the cardinal principle a "gatekeeper" concept children must acquire before learning about succession and exact ordering, or can these concepts develop separately? Preschoolers (N = 127) who knew the cardinal principle (CP-knowers) or who knew the cardinal meanings of number words up to "three" or "four" (3-4-knowers) completed succession and exact ordering tasks at pretest and posttest. In between, children completed one of two trainings: counting only versus counting, cardinal labeling, and comparison. CP knowers started out better than 3-4-knowers on succession and exact ordering. Controlling for this disparity, we found that CP-knowers improved over time on succession and exact ordering; 3-4-knowers did not. Improvement did not differ between the two training conditions. We conclude that children can learn the cardinal principle without understanding succession or exact ordering and hypothesize that children must understand the cardinal principle before learning these concepts. PMID- 30007879 TI - Adaptation to other people's eye gaze reflects habituation of high-level perceptual representations. AB - Our sense of where another person is looking depends upon multiple features of their face, relating to both the deviation of their eyes and the angle of their head. In this way, gaze direction is a higher-level perceptual property that is dependent on holistic processing of lower-level visual cues. A key paradigm in social perception research is sensory adaptation, which has been used to probe how properties like gaze direction are encoded in the visual system. Here we test whether sensory adaptation acts on higher-level, perceptual representations of gaze direction, or occurs to lower-level visual features of the face alone. To this end, participants were adapted on faces that evoke the Wollaston illusion, in which the direction that the face appears to look differs from its veridical eye direction. We compared across sets of images that were exactly matched in the lower-level features of the face image, but perceptually distinct due to differences in the conjunction of head and eye direction. The changes in participants' perception of gaze direction following adaptation were consistent with habituation having occurred to the perceived gaze direction of the Wollaston faces, where this is dependent on integration of eye direction and head direction, rather than to lower-level sensory features of the face alone. This constitutes strong evidence for adaptable representations of other people's gaze direction in the visual system that are abstracted from lower-level facial cues. PMID- 30007880 TI - Cognitive development attenuates audiovisual distraction and promotes the selection of task-relevant perceptual saliency during visual search on complex scenes. AB - Searching for a target while avoiding distraction is a core function of selective attention involving both voluntary and reflexive mechanisms. Here, for the first time, we investigated the development of the interplay between voluntary and reflexive mechanisms of selective attention from childhood to early adulthood. We asked 6-, 10-, and 20-year-old participants to search for a target presented in one hemifield of a complex scene, preceded by a task-irrelevant auditory cue on either the target side (valid), the opposite side (invalid), or both sides (neutral). For each scene we computed the number of salient locations (NSL) and the target saliency (TgS). All age groups showed comparable orienting effects ("valid minus neutral" trials), indicating a similar capture of spatial attention by valid cues which was independent of age. However, only adults demonstrated a suppression of the reorienting effect ("invalid minus neutral" trials), indicating late developments in the reallocation of spatial attention toward a target following auditory distraction. The searching performance of the children (both 6- and 10-year-olds), but not of the adults, was predicted by the NSL, indicating an attraction of processing resources to salient but task-irrelevant locations in childhood; conversely, only adults showed greater performance with increased TgS in valid trials, indicating late development in the use of task related saliency. These findings highlight qualitatively different mechanisms of selective attention operating at different ages, demonstrating important developmental changes in the interplay between voluntary and reflexive mechanisms of selective attention during visual search in complex scenes. PMID- 30007881 TI - Binding interaction of sheep alpha-2-macroglobulin and tannic acid: A spectroscopic and thermodynamic study. AB - Tannic acid is a polyphenol found in plant species commonly consumed by ruminants. It works as an important molecule in plant defense system to fight against environmental stressors. Tannic acid has number of effects on animals and humans. An attempt has been made to study the interaction of tannic acid with alpha-2-macroglobulin (alpha2M). alpha2M is a large tetrameric glycoprotein which function as a key serum anti-proteinase under physiological conditions. In the present study we explored the tannic acid-alpha2M interaction by number of spectroscopic techniques such as UV, fluorescence, CD and FTIR along with isothermal titration calorimetry. CD and FT-IR spectroscopy were mainly used to study the secondary structural change induced in the antiproteinase. Analysis of activity shows the antiproteolytic potential of protein was compromised. Data of UV spectroscopy shows formation of alpha2M-tannic acid complex. The thermodynamic signatures of this interaction reveals hydrogen bonding played a major role in the binding of alpha2M-tannic acid. Analysis of CD and FTIR results suggest a minor conformational change in alpha2M on tannic acid binding. Overall, tannic acid induces subtle conformation change in alpha2M structure resulting the loss of its proteinase inhibitory activity. PMID- 30007882 TI - SERS detection of 4-Aminobenzenethiol based on triangular Au-AuAg hierarchical multishell nanostructure. AB - The surface-enhanced Raman signals of 4-Aminobenzenethiol (4-ABT) adsorbed on the surface of triangular Au-AuAg hierarchical-multishell nanostructure have been investigated. Here, the approach to produce core-cavity-shell sandwich nanostructures presented as Au-AuAg is the same as preparing metal nanoparticles with hollow morphology, in which the galvanic replacement reaction takes place between silver and chloroauric acid. In this paper, we directly mix 4-ABT with gold nanoparticles and drop it on glass slides to study the effect of nanoparticles on signal enhancement of Raman spectrum, avoiding the cumbersome process of preparing metal-molecular-metal three-layer structure as reported. A significant increase in the SERS intensity of b2 mode around 1140 cm-1 was observed, which could quantify the concentration of 4-ABT indirectly. In a certain range, the Raman intensity gradually increases with the increasing intermediate gap, which has a strong relationship with dipole plasmon hybridization of core-dielectric-shell sandwich nanostructure. Moreover, Raman spectrum results show that the Au-AuAg substrate can produce signal intensity about 3.8 * 102 times stronger than that of 4-ABT alone and the detection limit was as low as 0.1 MUM in solution. PMID- 30007883 TI - The hyperfine structure branching ratios and ab initio study on low-lying electronic states for 24Mg19F molecule. AB - The potential energy curves (PECs) of the fourteen low-lying Lambda-S electronic states, spectroscopic constants, transition properties for the 24Mg19F molecule are calculated at the multi-reference configuration interaction level of theory. The spin-orbit coupling effects are also taken into account in the electronic structure calculations. Spectroscopic constants agree well with previously obtained theoretical and experimental values. Based on the potential energy curves and transition dipole moments, the highly diagonally distributed Franck Condon factors (f00 = 0.975, f11 = 0.926) for the A2Pi (v' = 0, 1) -> X2Sigma+ (v" = 0, 1) transition are determined. Moreover, it is important to note that the dissociation energy (2.68 eV) of the B2Sigma+ state is achieved for the first time. Then, employing a quantum effective Hamiltonian approach, we investigate the hyperfine structure branching ratios between the A2Pi1/2 state and the X2Sigma1/2+ state. And the numerically analyze is obtained for a simple one dimension (1D) case on 24Mg19F molecular MOT. We hope that these data can provide a helpful reference for the assignment and analysis of guiding further experimental spectroscopic measurements and laser cooling in experimental on the 24Mg19F molecule. PMID- 30007884 TI - Endoplasmic reticulum-targeted two-photon turn-on fluorescent probe for nitroreductase in tumor cells and tissues. AB - Hypoxia conditions could increase the activity of intracellular nitroreductase (NTR) and lead to many malignant diseases. Therefore, monitoring the activity of NTR is of great significance to study the related diseases. Organelles play crucial roles in the metabolism of living cells. In these organelles, the endoplasmic reticulum (ER) possesses single membrane structure, and it is the largest organelle in the cell. ER performs the synthesis, processing and modification of proteins and lipid, stabilizing the intracellular Ca2+ concentration and other physiological functions in living cells. Therefore, it is of great significance to develop ER-target probes in living system. Toward this goal, a new endoplasmic reticulum-targeted two-photon fluorescence turn-on NTR probe Na-NTR-ER is designed and synthesized. Probe Na-NTR-ER has been proved to display high sensitivity (36 ng/mL) and selectivity to NTR. Particularly, probe Na-NTR-ER has been successfully applied for the monitoring of NTR in ER with a high the Pearson's colocalization coefficient as 0.90 in HeLa cells and cancerous mouse tissues up to the depth of 100 MUm with significant fluorescence signals. PMID- 30007885 TI - A targetable fluorescent probe for real-time monitoring of fluoride ions in mitochondria. AB - Fluorion are pivotal anions in biology because they play an important role in dental care, treating osteoporosis, preventing tooth decay and promoting the healthy growth of bone. Studies have shown that high levels of fluoride will lead to the inactivation of the mitochondria. Therefore, it is urgent to develop a method to detect the fluoride anions in the mitochondria. Herein, we have developed a novel mitochondrial-target fluorescent probe for detecting F- in living cells. The probe exhibited excellent sensitivity and high selectivity for F- over the other relative species. With changing fluoride ions, the fluorescence spectrum of the probe changed significantly with a large turn-on fluorescence signal. Cell imaging indicated that the probe can penetrate viable cell membranes and rapidly detects and images fluorion over other anions in the mitochondria. PMID- 30007886 TI - TGF-beta/SMAD4 mediated UCP2 downregulation contributes to Aspergillus protease induced inflammation in primary bronchial epithelial cells. AB - Elevated levels of mitochondrial reactive oxygen species (ROS) can lead to the development of airway inflammation. In this study, we investigated the role of Aspergillus proteases-which contribute to the pathogenesis of Aspergillus-induced diseases such as allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and atopic asthma-and their mechanisms of action in airway inflammation using primary human bronchial epithelial cells, and evaluated the inflammatory responses mediated by mitochondrial ROS. We found that Aspergillus proteases regulated the expression of multifunctional inflammatory cytokines such as interleukin (IL)- 1beta, - 6, and - 8, and transforming growth factor (TGF) beta, which stimulated cytokine production and chemokines involved in leukocyte migration and activated an inflammatory cascade. Expression of these factors and activator protein (AP)- 1 were decreased by treatment with the mitochondrial ROS scavenger Mito-TEMPO, suggesting that mitochondria are important sources of ROS in the context of inflammatory response by Aspergillus protease. The regulation of mitochondrial ROS influenced the production of proinflammatory mediators by preventing mitochondrial ROS-induced AP-1 activation in airway epithelial cells. In addition, Aspergillus protease-mediated mitochondrial ROS production was associated with downregulation of uncoupling protein (UCP)- 2 expression by TGF beta-SMAD4 signaling, which may play a regulatory role in mitochondrial ROS formation during fungal protease-mediated epithelial inflammation. This improved understanding of the allergenic fungal protease-induced inflammatory mechanism in the bronchial epithelium will help in developing intervention strategies for the regulation of inflammatory response in allergic airway diseases. PMID- 30007887 TI - A thiol-reactive Ru(II) ion, not CO release, underlies the potent antimicrobial and cytotoxic properties of CO-releasing molecule-3. AB - Carbon monoxide (CO)-releasing molecules (CORMs), mostly metal carbonyl compounds, are extensively used as experimental tools to deliver CO, a biological 'gasotransmitter', in mammalian systems. CORMs are also explored as potential novel antimicrobial drugs, effectively and rapidly killing bacteria in vitro and in animal models, but are reportedly benign towards mammalian cells. Ru-carbonyl CORMs, exemplified by CORM-3 (Ru(CO)3Cl(glycinate)), exhibit the most potent antimicrobial effects against Escherichia coli. We demonstrate that CORM-3 releases little CO in buffers and cell culture media and that the active antimicrobial agent is Ru(II), which binds tightly to thiols. Thus, thiols and amino acids in complex growth media - such as histidine, methionine and oxidised glutathione, but most pertinently cysteine and reduced glutathione (GSH) - protect both bacterial and mammalian cells against CORM-3 by binding and sequestering Ru(II). No other amino acids exert significant protective effects. NMR reveals that CORM-3 binds cysteine and GSH in a 1:1 stoichiometry with dissociation constants, Kd, of about 5 MUM, while histidine, GSSG and methionine are bound less tightly, with Kd values ranging between 800 and 9000 MUM. There is a direct positive correlation between protection and amino acid affinity for CORM 3. Intracellular targets of CORM-3 in both bacterial and mammalian cells are therefore expected to include GSH, free Cys, His and Met residues and any molecules that contain these surface-exposed amino acids. These results necessitate a major reappraisal of the biological effects of CORM-3 and related CORMs. PMID- 30007889 TI - Reduction of adsorbed dyes content in the discharged sludge coming from an industrial textile wastewater treatment plant using aerobic activated sludge process. AB - Dye mass balance study at full-scale industrial textile wastewater (ITW) treatment plant showed that 1.5 ton of excess waste sludge, containing 304.5 Kg of dyes, are daily produced and discharged in landfills. Therefore, this by product of activated sludge process (ASP) presents a serious environmental problem. In this work, a laboratory and pilot scale investigations were carried out to optimize aerobic biodegradation efficiency to reduce the amount of residual adsorbed dye that will be found in the waste sludge. The resistance of acclimated biomass to the toxicity of ITW was studied in 2.5 L batch reactors using different dye to biomass (D/B) ratios of 0.102, 0.25 and 0.72 g CODS/g VSS. Results of respirometric analyses showed that acclimated activated sludge (AS) biomass is able to treat ITW at high D/B ratio of 0.72 g CODS/g VSS. Moreover, biodegradation kinetic study using Monod law showed that COD and color removal were better for the highest D/B ratio. The half saturation coefficient of heterotrophs for indigo dye (KSind) of 20.01 g/m3 showed high affinity between biomass and dye molecules. Optimization of the process at pilot-scale with different hydraulic retention time (HRT) of 2-5 days, and different sludge recycling rates (SRR) of 220-680 m3/d, showed that high HRT of 5 days and a SRR of 0.22 allowed the best dye biodegradation efficiency (95%). Application of the best conditions at full-scale reduced significantly (89%) the amount of the discharged dyes from 304.5 Kg/d to 33 Kg/d. Results were numerically validated using a mathematical model based on the activated sludge model 1 (ASM1). PMID- 30007888 TI - Carbon monoxide releasing molecule-2 attenuates Pseudomonas aeruginosa-induced ROS-dependent ICAM-1 expression in human pulmonary alveolar epithelial cells. AB - Pseudomonas aeruginosa (P. aeruginosa) infection in the lung is common in patients with cystic fibrosis (CF). Intercellular adhesion molecule-1 (ICAM-1) is known to play a key role in lung inflammation. Acute inflammation and its timely resolution are important to ensure bacterial clearance and limit tissue damage. Carbon monoxide (CO) has been shown to exert anti-inflammatory effects in various tissues and organ systems. Here, we explored the protective effects and mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on P. aeruginosa induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs). We showed that P. aeruginosa induced prostaglandin E2 (PGE2)/interleukin-6 (IL-6)/ICAM-1 expression and monocyte adherence to HPAEpiCs. Moreover, P. aeruginosa-induced inflammatory responses were inhibited by transfection with siRNA of Toll-like receptor 4 (TLR4), PKCalpha, p47phox, JNK2, p42, p50, or p65. P. aeruginosa also induced PKCalpha, JNK, ERK1/2, and NF-kappaB activation. We further demonstrated that P. aeruginosa increased intracellular ROS generation via NADPH oxidase activation. On the other hand, P. aeruginosa induced inflammation was inhibited by pretreatment with CORM-2. Preincubation with CORM-2 had no effects on TLR4 mRNA levels in response to P. aeruginosa. However, CORM-2 inhibits P. aeruginosa-induced inflammation by decreasing intracellular ROS generation. P. aeruginosa-induced PKCalpha, JNK, ERK1/2, and NF kappaB activation was inhibited by CORM-2. Finally, we showed that P. aeruginosa induced levels of the biomarkers of inflammation in respiratory diseases, which were inhibited by pretreatment with CORM-2. Taken together, these data suggest that CORM-2 inhibits P. aeruginosa-induced PGE2/IL-6/ICAM-1 expression and lung inflammatory responses by reducing the ROS generation and the inflammatory pathways. PMID- 30007890 TI - Environmental benign synthesis, characterization and mechanism studies of green calcium hydroxide nano-plates derived from waste oyster shells. AB - Continuous dumping of oyster shells in open fields has been a global issue, causing serious problems in the water and human health. The conversion of those wastes into value-added products is highly desirable. Here, Green Calcium Hydroxide Nano-plates (GCHNPs) were first synthesized from waste oyster shells by a chemical precipitation method in an aqueous medium at 90 degrees C without using any additives. The crystal structure with a hexagonal portlandite (Ca(OH)2) was observed by both X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). The crystal size of around 350-450 nm and specific surface area with 4.96 m2g-1 were confirmed by field emission scanning electron microscopy (FE-SEM) and Brunauer-Emmett-Teller (BET), respectively. In addition, a schematically organized new qualitative model for a mechanism was proposed to explain the genesis and evolution of GCHNPs from raw oyster shells. PMID- 30007891 TI - Optimization of hydrogen and organic acids productions with autochthonous and allochthonous bacteria from sugarcane bagasse in batch reactors. AB - The individual and mutual effects of substrate concentration (from 0.8 to 9.2 g/L) and pH (from 4.6 to 7.4) on hydrogen and volatile fatty acids production from sugarcane bagasse (SCB) were investigated in batch reactors, using a response surface methodology (RSM) and central composite design (CCD). The maximum of 23.10 mmoL H2/L was obtained under optimized conditions of 7.0 g SCB/L and pH 7.2, at 37 degrees C through the acetic acid pathway (1.57 g/L). Butyric and succinic acids were the major volatile fatty acids (VFA) produced in the fermentation process (from 0.66 to 1.88 g/L and from 1.06 to 1.65 g/L, respectively). According to the results, the RSM and CCD were useful tools to achieve high hydrogen production rates using Clostridium, Bacillus and Enterobacter, identified by Illumina sequencing (16S RNAr) in the fermentative consortium, and Clostridium and Paenibacillus, autochthonous bacteria from SCB. Significant changes were observed in the microbial community according to the changes in the independent variables, since the genera in the central point condition (5.0 g SCB/L and pH 6.0) were Lactobacillus, Escherichia and Clostridium, and Bacteroides and Enterobacter, which were identified in the optimized condition (7.0 g SCB/L and pH 7.2). PMID- 30007892 TI - Diagnostic accuracy of quantitative EEG to detect delayed cerebral ischemia after subarachnoid hemorrhage: A preliminary study. AB - OBJECTIVE: Delayed cerebral ischemia (DCI) is the most important and preventable morbidity cause after subarachnoid hemorrhage (SAH). Therefore, DCI early detection is a major challenge. Yet, neurological examination can be unreliable in poor grade SAH patients. EEG provides information from most superficial cortical area, with ischemia-related changes. This study aims at defining an alpha-theta/delta (AT/D) ratio decrease thresholds to detect DCI. METHODS: We used EEG with a montage matching vascular territories (right and left anterior central and posterior) and compared them to follow-up brain imaging. RESULTS: 15 SAH patients (Fischer >= 3, World Federation of Neurological Surgeons scale >=4, 9 DCI) were monitored during 6.4 [4-8] days (min = 2d, max = 13d). AT/D changes could follow three different patterns: (1) prolonged or (2) transient decrease and (3) no decrease or progressive increase. A regional 30% decrease outlasting 3.7 h reached 100% sensitivity and 88.9% specificity to detect DCI. Only 22.6% were in a zone of uncertain diagnosis (3.7-8.04 h). These prolonged decreases, with a loss of transient changes, started in cortical areas evolving toward DCI, and preceded intracranial changes when available. CONCLUSION: Although this study has a small sample size, prolonged AT/D decrease seems to be a reliable biomarker of DCI. SIGNIFICANCE: cEEG changes are likely to precede cerebral infarction and could be useful at the bedside to detect DCI before irreversible damage. PMID- 30007893 TI - Electrophysiological evidence of an attentional bias towards appetitive and aversive words in adults with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Emotional dysregulation has emerged as a core symptom domain in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the pathophysiological underpinnings remain poorly understood. This study investigated attentional biases to positive and negative emotional words as possible contributing mechanisms. METHODS: Event-related potentials (ERPSs) and behavioral attention bias indices were recorded from 39 adult patients with ADHD and 41 healthy controls during a verbal dot-probe task with positive-neutral, negative-neutral, and neutral-neutral word pairs. RESULTS: Cue-locked N2pc amplitudes indicated a significant attentional bias towards emotional words in patients with ADHD and healthy controls. In healthy controls, the bias was only significant in positive trials. In patients, the bias was associated with ADHD severity and self-reported poor emotion regulation skills. ADHD patients also exhibited reduced target-locked P1 amplitudes and inferior behavioral performance compared with healthy controls. CONCLUSIONS: Our findings provide evidence of an attention bias to positive and negative emotional stimuli in adult patients with ADHD and adverse effects of emotional stimuli on task performance. SIGNIFICANCE: An attentional bias to emotional stimuli might contribute to emotional reactivity and dysregulation in adult patients with ADHD. PMID- 30007895 TI - Krebs von den Lungen-6 associated with chest high-resolution CT score in evaluation severity of patients with interstitial lung disease. AB - AIMS: The purpose of this prospective, single-center study was to measure the value of Krebs von den Lungen-6 (KL-6), a kind of transmembrane mucoprotein, in diagnosing interstitial lung disease (ILD) and in assessing the severity of ILD. METHODS: We enrolled 184 patients and 30 healthy controls. Ninety-eight patients were diagnosed with ILD, 47 with pneumonia, 19 with non-small cell lung cancer without ILD (NSCLC/non-ILD) and 20 with other lung diseases. Serum KL-6 levels, CT scores of high-resolution computerised tomography (HRCT) and pulmonary function in ILD patients were assessed. RESULTS: The mean value of serum KL-6 in patients with ILD, pneumonia, NSCLC/non-ILD, other lung diseases and healthy controls were 1000.67+/-882.73U/ml, 234.11+/-91.02U/ml, 269.95+/-149.23U/ml, 234.85+/-83.51U/ml and 189.03+/-55.50U/ml, respectively. Serum KL-6 levels of patients with ILD were significantly higher than that of other groups (P<0.000). The level of serum KL-6 in patients with pneumonia, NSCLC/non-ILD and other lung diseases was also statistically higher than healthy controls (P<0.05). When the cut-off value was 312U/ml, the sensitivity and specificity of KL-6 for the diagnosis of ILD was 84.7% and 85.3% respectively (AUC: 0.936, 95% CI: 0.906 0.965). The serum KL-6 levels in patients with ILD were significantly positively correlated with the CT scores (r=0.539, P=0.000) and negatively correlated with DLCO (r=-0.513, P=0.000). CONCLUSION: Serum KL-6 might be useful in the diagnosis of ILD, especially in the hard-to-diagnose cases, with high sensitivity and specificity. Furthermore, KL-6 might be a valuable marker for evaluation of ILD severity. PMID- 30007894 TI - A phase IIA trial of acupuncture to reduce chemotherapy-induced peripheral neuropathy severity during neoadjuvant or adjuvant weekly paclitaxel chemotherapy in breast cancer patients. AB - PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side-effect of neurotoxic chemotherapy for cancer patients. We evaluated the preliminary efficacy of acupuncture in preventing worsening CIPN in patients receiving paclitaxel. METHODS: In this phase IIA single-arm clinical trial, we screened stage I-III breast cancer patients receiving neoadjuvant/adjuvant weekly paclitaxel for development of CIPN. The primary objective was to assess acupuncture's efficacy in preventing the escalation of National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0, grade II CIPN to higher grades. Acupuncture was deemed worthy of further study if 23 or more of the 27 enrolled patients did not develop grade III CIPN. Outcome measures (NCI-CTCAE CIPN grade, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG Ntx], Neuropathic Pain Scale [NPS]) were obtained weekly during the intervention. RESULTS: Of 104 patients screened, 37 developed grade II CIPN (36%), and 28 (27%) enrolled into the intervention phase; one was removed due to protocol violation. Of the 27 patients receiving acupuncture, 26 completed paclitaxel treatment without developing grade III CIPN, meeting our prespecified success criteria for declaring acupuncture worthy of further study. FACT/GOG-Ntx and NPS scores remained stable during the intervention while continuing weekly paclitaxel. Acupuncture treatment was well tolerated; 4 of 27 (15%) patients reported grade I bruising. CONCLUSIONS: Acupuncture was safe and showed preliminary evidence of effectiveness in reducing the incidence of high grade CIPN during chemotherapy. A follow-up randomised controlled trial is needed to establish definitive efficacy in CIPN prevention for patients at risk. PMID- 30007896 TI - Effect of substituent position on aggregation-induced emission, customized self assembly, and amine detection of donor-acceptor isomers: Implication for meat spoilage monitoring. AB - We synthesized a class of positional isomers by attaching electron donor and acceptor units in different sites of a conjugated core. These isomers exhibit both aggregation-induced emission (AIE) and intramolecular charge transfer (ICT) effects, which are proved by adequate spectroscopic analysis. Their structure property relationships were systematically studied. We found that relocation of the D/A units would have remarkable impact on the intermolecular dipole-dipole interaction, further controlling the shape and color of the self-assembled architectures. With D/A units shifting to different sites, four types of the structures appear sequentially, including quadrate microsheets, microrods, nanofilaments and nanowires. Furthermore, the A unit (benzoic acid moiety) of the AIE isomers is easy to adsorb amines, leading to changes in both emission wavelength and intensity. Then a portable sensor is prepared on solid support based on the self-assembled architecture of HMBA-4, which has been proved to be the most sensitive to amines. It affords fast spectral responses as well as a low detection limit of 186 Pa (vapour pressure). The sensing mechanism was revealed by density functional theory (DFT) calculation, which indicates that the spectral responses stem from the weakened ICT effect. The sensor is able to detect amine vapours generated by meat, and thus succeeds in detecting the spoiled pork samples, offering high potential for meat spoilage monitoring in real-world applications. PMID- 30007897 TI - Fluorescent carbon dots synthesized by microwave-assisted pyrolysis for chromium(VI) and ascorbic acid sensing and logic gate operation. AB - Herein, nitrogen, sulfur co-doped fluorescent carbon dots (N,SCDs) were synthesized by simple and facile microwave-assisted pyrolysis using ammonium citrate and cysteamine hydrochloride as precursors. The obtained N,SCDs exhibited outstanding photostability, excitation-wavelength independence, excellent fluorescence properties with fluorescence quantum yield (FLQY) up to 54.8%. Significantly, the fluorescence of N,SCDs was effectively quenched by Cr(VI) based on inner filter effect (IFE). Subsequently, the fluorescence of the N,SCDs Cr(VI) system successfully recovered with addition of ascorbic acid (AA) owing to redox reaction between Cr(VI) and AA. Therefore, N,SCDs could be employed as an efficient fluorescent "turn-off" probe for highly sensitive detection of Cr(VI), with a liner detection range from 0.35 to 126.0 MUmol L-1 and a detection limit of 0.11 MUmol L-1. Meanwhile, the N,SCDs-Cr(VI) system could be used as an fluorescent "turn-on" sensor for detection of AA with a detection limit of 0.17 MUmol L-1 and a liner detection range of 0.57-264.0 MUmol L-1. Interestingly, a molecular logic gate was constructed based on the fluorescence recover of the N,SCDs-Cr(VI) system in the presence of AA. Most importantly, this fluorescent probe has been applied for determination of Cr(VI) and AA in environmental and biological fields with satisfactory results. PMID- 30007898 TI - A highly sensitive fluorescent sensor for Zn2+ based on diarylethene with an imidazole unit. AB - A new sensitive sensor for Zn2+ based on diarylethene with an imidazole unit has been synthesized. Its photochromic and fluorescent behaviors have been systematically investigated by the stimulation of UV/vis lights and Zn2+ ion in THF solution. It displayed a dual-mode with a "turn on" fluorescence and color response to Zn2+. With the addition of Zn2+, the emission intensity enhanced 26 fold, accompanied by the fluorescent color changed from dark red to bright yellow. The 1:1 stoichiometry between the sensor and Zn2+ was verified by Job's plot and MS. The LOD for Zn2+ was determined to be 6.12 * 10-9 mol L-1. Furthermore, a logic circuit was designed by using the fluorescence at 578 nm as output and the combinational stimuli of UV/vis and Zn2+/EDTA as inputs. PMID- 30007899 TI - Click chemistry inspired copper sulphide nanoparticle-based fluorescence assay of kanamycin using DNA aptamer. AB - A highly selective and sensitive fluorescence assay for kanamycin has been developed that depends on complementation of two splits of DNA aptamer. One DNA split was labeled with CuS nanoparticle and the other was decorated with biotin, which enabled coupling with streptavidin magnesphere paramagnetic particles (PMPs). Complementation of the two-aptamer splits happened only in the presence of kanamycin and the subsequent sandwich was separated via a magnet. The released Cu(II) was reduced to Cu(I) by sodium ascorbate and finally catalyzed the click reaction between fluorogenic 3-azido-7-hydroxycoumarin and propargyl alcohol to afford the corresponding fluorescent 1,4-disubstituted-1,2,3-triazole. The fluorescence signal produced (lambdaex. = 365 nm, lambdaem. = 470 nm) was dependent on kanamycin concentration. Fluorescence signal amplification was found to be in good linear relationship with the logarithm of kanamycin concentration in the range of 0.04-20 nM. Furthermore, the proposed assay showed a good reproducibility, high selectivity and low detection limits for kanamycin determination. In addition, the capability of the proposed method to detect kanamycin in biological samples with satisfactory results was demonstrated. PMID- 30007900 TI - Buchi's model based analysis of local anesthetic action in procaine hydrochloride: Vibrational spectroscopic approach. AB - The drug action of ester type local anesthetic (LA) procaine hydrochloride (PRC HCl) is activated by blocking Na+ ion flow when it binds to the ion channel in the ligand gated sodium ion channel protein. Buchi's model, explains binding action of ester type LA drug with receptor in terms of charge transfer, dipole dipole, hydrogen bonding and van der Waals interactions through lipophilic, ester and hydrophilic moieties. The present work investigates molecular structural and vibrational spectral features of para amino benzoate group, ester part and tertiary amino group respectively belonging to lipophilic, ester and hydrophilic moieties, accountable for the binding of drug to sodium channel. The electron transport mechanism through the ring responsible for structural deviation from benzenoid to quinonoid form and consequent dipolar nature of carbonyl group have been investigated, based on the analysis of XRD, DFT computed molecular structure, 8a ring mode and NBO charges. The characteristic UV absorption peaks and vibrational marker bands of LA drugs have been identified and the charge transfer interaction responsible for lipophilic binding has been investigated. The blocking of Na+ in the ion channel has been probed using attractive and repulsive energy profile. The molecular polarizability has been computed to substantiate the correlation between the structure activity relationship of LA drug molecule and molecular polarizability. The low toxicity of PRC HCl was evaluated using in vitro cytotoxicity study, confirming it as a potential short acting local anesthetic. PMID- 30007901 TI - A lysosome targetable fluorescent probe for palladium species detection base on an ESIPT phthalimide derivative. AB - A novel lysosome-targetable phthalimide fluorescent probe was designed for detecting palladium based on ESIPT for signal transduction. The fluorescent probe conjugating with allylcarbamate displayed weak fluorescent due to the ESIPT process hinder by allylcarbamate. But with the addition of palladium, the ESIPT emission was recovery though the palladium-catalyzed deallylation reaction and the fluorescence intensity exhibited 40-fold enhancement at 511 nm. In addition, the probe showed excellent selectivity, high sensitivity, fast responds and low limit detection for palladium with a larger Stoke-shift. Moreover, the targetable probe was also successfully applied for detecting palladium in lysosomes of living cells. Hence, the probe though ESIPT modulation is a promising for monitoring palladium in practical samples. PMID- 30007902 TI - Silver nanoparticles for the visual detection of lomefloxacin in the presence of cystine. AB - A novel optical sensors for lomefloxacin based on the plasma resonance properties of silver nanoparticles (AgNPs) for the first time. The hydrogen bonds and electrostatic force between the lomefloxacin and AgNPs could induce the change in color and absorption spectra of AgNPs suspension, which provided a theoretical basis for the optical detection of lomefloxacin. In addition, we made the AgNPs lomefloxacin detection system reach the critical point of discoloration by adding cystine to improve the sensitivity. Furthermore, the influence of some factors such as temperature, reaction time and pH on the AgNPs-lomefloxacin detection system was investigated. The results of UV-vis spectra showed that the absorption ratio (A520/A395) was linear with the concentration of lomefloxacin in the range from 0.2 to 5 MUmol/L with linear coefficients of 0.991. The proposed method can be applied to detecting lomefloxacin with an ultralow detection limit of 0.6 MUmol/L without any complicated instruments and complex pretreatment. The selectivity of AgNPs-lomefloxacin detection system is proved excellent by comparing with other ions and analytes in urine. The method in our study is appropriate to be used to monitor quantitatively entecavir in human urine owing to its rapid response rate, visible color changes, wide linear range and excellent selectivity. PMID- 30007903 TI - Down to Earth: The Emerging Field of Planetary Health. PMID- 30007904 TI - Erratum: "Climate Change and Future Pollen Allergy in Europe". AB - [This corrects the article DOI: 10.1289/EHP173.]. PMID- 30007905 TI - Epidemiology and socioeconomic impact of the rheumatic diseases on indigenous people: an invisible syndemic public health problem. AB - : Epidemiological studies in Latin America suggest indigenous people lack proper healthcare for musculoskeletal (MSK) and rheumatic diseases. OBJECTIVES: This study aimed to estimate the prevalence of MSK disorders and rheumatic diseases in eight Latin American indigenous communities, and to identify which factors influence such prevalence using network analysis and syndemic approach. METHODS: This is a cross-sectional, community-based census study according to Community Oriented Program for the Control of Rheumatic Diseases methodology. Individuals with MSK pain, stiffness or swelling in the past and/or during the last 7 days were evaluated by participating physicians. A descriptive, univariable and multivariable analysis was performed, followed by a network analysis. RESULTS: We surveyed 6155 indigenous individuals with a mean age of 41.2 years (SD 17.6; range 18-105); 3757 (61.0%) were women. Point prevalence in rank order was: low back pain in 821 (13.3%); osteoarthritis in 598 (9.7%); rheumatic regional pain syndromes in 368 (5.9%); rheumatoid arthritis in 85 (1.3%); undifferentiated arthritis in 13 (0.2%); and spondyloarthritis in 12 (0.1%). There were marked variations in the prevalence of each rheumatic disease among the communities. Multivariate models and network analysis revealed a complex relationship between rheumatic diseases, comorbidities and socioeconomic conditions. CONCLUSIONS: The overall prevalence of MSK disorders in Latin American indigenous communities was 34.5%. Although low back pain and osteoarthritis were the most prevalent rheumatic diseases, wide variations according to population groups occurred. The relationship between rheumatic diseases, comorbidities and socioeconomic conditions allows taking a syndemic approach to the study. PMID- 30007906 TI - Recurrent inflammatory myofibroblastic tumour of the lung: FDG PET/CT scan findings. AB - Inflammatory myofibroblastic tumour (IMT) is a rare neoplasm, occurring most often in children and young adults. IMTs have intermediate biological behaviour with the chance of local invasion, recurrence and even distant metastasis. Wide range of clinical presentations makes the precise diagnosis of IMT more challenging. The best method for definitive diagnosis is tissue biopsy and newer imaging modalities including fleurodeoxyglucose (FDG) positron emission tomography (PET)/CT are useful tools in detection of disease recurrence or distant metastasis. Complete surgical resection is the best-known treatment for this tumour. Here we are presenting an IMT case in a 12-year-old girl in which her recurrent pulmonary IMT was diagnosed based on FDG PET/CT findings and referred for further salvage treatment. Overall imaging modalities are not specific, but PET/CT scan can be useful tool for evaluation of IMT regarding initial staging and restaging to assess treatment response and recurrence. PMID- 30007907 TI - Two cases of high-output heart failure as initial presentation of iliac arteriovenous fistula. AB - We present two cases of females in their 40s presenting with biventricular heart failure being the consequence of a large arteriovenous fistula. Both patients had undergone abdominal surgery several years prior to the heart failure event with the initial finding of moderate pulmonary hypertension and high-output heart failure. CT revealed a large arteriovenous fistula between the common iliac artery and vein which subsequently was closed percutaneously. PMID- 30007908 TI - Port-wine stain as a clue for two rare coexisting entities. AB - Phakomatosis pigmentovascularis (PPV) is an uncommon dermatosis characterised by the presence of both pigmentary and vascular abnormalities.1 Its pathogenesis is not elucidated, and the prognosis is mainly determined by the presence of extracutaneous manifestations, such as Klippel-Trenaunay syndrome (KTS), that is defined by the triad of a port-wine stain (PWS), anomalous veins and progressive overgrowth of the affected extremity. Herein, we report a case of an adult patient, who presented with a large PWS, nevus of Ota, ocular melanosis, and limb hypertrophy and varicosities. These findings represented a rare association of PPV type IIb and KTS. PMID- 30007909 TI - Adult supraglottitis: a life-threatening disease and potential airway emergency. PMID- 30007910 TI - Impact of a case management programme for women seeking later second-trimester abortion: the case of the Massachusetts Access Program. AB - OBJECTIVE: The Massachusetts Access Program is a statewide, centralised referral and case management program created to address barriers to later second-trimester abortions. This study outlines the scope of, describes provider experiences with, and evaluates provider acceptability of the Program. STUDY DESIGN: We invited physicians, nurses and staff working in hospitals within the later abortion provider referral network to participate in a mixed-methods study that included a web-based quantitative survey and/or a semi-structured qualitative interview. We used descriptive statistics to analyse survey data and inductive coding methods to analyse interview data. RESULTS: From 2007-2012, 15-28% of abortions performed in Massachusetts at 19 weeks or greater gestational age annually were scheduled through the Access Program. We received 16 completed surveys and conducted seven interviews with providers who routinely receive referrals for later abortions through the Program. Providers overall reported positive experiences with the Program and found it highly acceptable. They described that the transportation, accommodation and financial assistance enabled patients access to care. The specialised and updated knowledge of the Access Coordinator in regards to abortion care also allowed her to act as a resource for providers. CONCLUSIONS: The Access Program, through its referral and case management network, was a valuable resource both to patients seeking later second-trimester abortions and providers involved in abortion care. It acts as one example of an effective, highly acceptable and potentially replicable intervention to reduce barriers to obtaining later second-trimester abortions. PMID- 30007912 TI - Hormone therapy should not be prescribed for primary prevention of chronic medical conditions in asymptomatic postmenopausal women. PMID- 30007913 TI - The times they are a-changin'. PMID- 30007911 TI - Dynamics of the Pollen Sequestrome Defined by Subcellular Coupled Omics. AB - Reproduction success in angiosperm plants depends on robust pollen tube growth through the female pistil tissues to ensure successful fertilization. Accordingly, there is an apparent evolutionary trend to accumulate significant reserves during pollen maturation, including a population of stored mRNAs, that are utilized later for a massive translation of various proteins in growing pollen tubes. Here, we performed a thorough transcriptomic and proteomic analysis of stored and translated transcripts in three subcellular compartments of tobacco (Nicotiana tabacum), long-term storage EDTA/puromycin-resistant particles, translating polysomes, and free ribonuclear particles, throughout tobacco pollen development and in in vitro-growing pollen tubes. We demonstrated that the composition of the aforementioned complexes is not rigid and that numerous transcripts were redistributed among these complexes during pollen development, which may represent an important mechanism of translational regulation. Therefore, we defined the pollen sequestrome as a distinct and highly dynamic compartment for the storage of stable, translationally repressed transcripts and demonstrated its dynamics. We propose that EDTA/puromycin-resistant particle complexes represent aggregated nontranslating monosomes as the primary mediators of messenger RNA sequestration. Such organization is extremely useful in fast tip growing pollen tubes, where rapid and orchestrated protein synthesis must take place in specific regions. PMID- 30007916 TI - Beyond barriers and facilitators: the central role of practical knowledge and informal networks in implementing infection prevention interventions. PMID- 30007915 TI - Formative evaluation of the video reflexive ethnography method, as applied to the physician-nurse dyad. AB - BACKGROUND: Despite decades of research and interventions, poor communication between physicians and nurses continues to be a primary contributor to adverse events in the hospital setting and a major challenge to improving patient safety. The lack of progress suggests that it is time to consider alternative approaches with greater potential to identify and improve communication than those used to date. We conducted a formative evaluation to assess the feasibility, acceptability and utility of using video reflexive ethnography (VRE) to examine, and potentially improve, communication between nurses and physicians. METHODS: We begin with a brief description of the institutional review boardapproval process and recruitment activities, then explain how we conducted the formative evaluation by describing (1) the VRE process itself; (2) our assessment of the exposure to the VRE process; and (3) challenges encountered and lessons learnt as a result of the process, along with suggestions for change. RESULTS: Our formative evaluation demonstrates that it is feasible and acceptable to video record communication between physicians and nurses during patient care rounds across many units at a large, academic medical centre. The lessons that we learnt helped to identify procedural changes for future projects. We also discuss the broader application of this methodology as a possible strategy for improving other important quality and safety practices in healthcare settings. CONCLUSIONS: The VRE process did generate increased reflection in both nurse and physician participants. Moreover, VRE has utility in assessing communication and, based on the comments of our participants, can serve as an intervention to possibly improve communication, with implications for patient safety. PMID- 30007914 TI - A Novel Differential Ion Mobility Device Expands the Depth of Proteome Coverage and the Sensitivity of Multiplex Proteomic Measurements. AB - The depth of proteomic analyses is often limited by the overwhelming proportion of confounding background ions that compromise the identification and quantification of low abundance peptides. To alleviate these limitations, we present a new high field asymmetric waveform ion mobility spectrometry (FAIMS) interface that can be coupled to the Orbitrap Tribrid mass spectrometers. The interface provides several advantages over previous generations of FAIMS devices, including ease of operation, robustness, and high ion transmission. Replicate LC FAIMS-MS/MS analyses (n = 100) of HEK293 protein digests showed stable ion current over extended time periods with uniform peptide identification on more than 10,000 distinct peptides. For complex tryptic digest analyses, the coupling of FAIMS to LC-MS/MS enabled a 30% gain in unique peptide identification compared with non-FAIMS experiments. Improvement in sensitivity facilitated the identification of low abundance peptides, and extended the limit of detection by almost an order of magnitude. The reduction in chimeric MS/MS spectra using FAIMS also improved the precision and the number of quantifiable peptides when using isobaric labeling with tandem mass tag (TMT) 10-plex reagent. We compared quantitative proteomic measurements for LC-MS/MS analyses performed using synchronous precursor selection (SPS) and LC-FAIMS-MS/MS to profile the temporal changes in protein abundance of HEK293 cells following heat shock for periods up to 9 h. FAIMS provided 2.5-fold increase in the number of quantifiable peptides compared with non-FAIMS experiments (30,848 peptides from 2,646 proteins for FAIMS versus 12,400 peptides from 1,229 proteins with SPS). Altogether, the enhancement in ion transmission and duty cycle of the new FAIMS interface extended the depth and comprehensiveness of proteomic analyses and improved the precision of quantitative measurements. PMID- 30007917 TI - Intestinal de novo phosphatidylcholine synthesis is required for dietary lipid absorption and metabolic homeostasis. AB - De novo phosphatidylcholine (PC) synthesis via CTP:phosphocholine cytidylyltransferase-alpha (CTalpha) is required for VLDL secretion. To determine the precise role of de novo PC synthesis in intestinal lipid metabolism, we deleted CTalpha exclusively in the intestinal epithelium of mice (CTalphaIKO mice). When fed a chow diet, CTalphaIKO mice showed normal fat absorption despite a ~30% decrease in intestinal PC concentrations relative to control mice, suggesting that biliary PC can fully support chylomicron secretion under these conditions. However, when fed a high-fat diet, CTalphaIKO mice showed impaired passage of FAs and cholesterol from the intestinal lumen into enterocytes. Impaired intestinal lipid uptake in CTalphaIKO mice was associated with lower plasma triglyceride concentrations, higher plasma glucagon-like peptide 1 and peptide YY, and disruption of intestinal membrane lipid transporters after a high fat meal relative to control mice. Unexpectedly, biliary bile acid and PC secretion was enhanced in CTalphaIKO mice due to a shift in expression of bile acid transporters to the proximal intestine, indicative of accelerated enterohepatic cycling. These data show that intestinal de novo PC synthesis is required for dietary lipid absorption during high-fat feeding and that the reacylation of biliary lyso-PC cannot compensate for loss of CTalpha under these conditions. PMID- 30007919 TI - TREM-1, the ideal predictive biomarker for endoscopic healing in anti-TNF-treated Crohn's disease patients? PMID- 30007920 TI - Messy autonomy: Commentary on Patient preference predictors and the problem of naked statistical evidence. PMID- 30007921 TI - Medical student research: it is necessary and beneficial! PMID- 30007918 TI - Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti obesity effects of polysaccharides isolated from Hirsutella sinensis. AB - OBJECTIVE: The medicinal fungus Ophiocordyceps sinensis and its anamorph Hirsutella sinensis have a long history of use in traditional Chinese medicine for their immunomodulatory properties. Alterations of the gut microbiota have been described in obesity and type 2 diabetes. We examined the possibility that H. sinensis mycelium (HSM) and isolated fractions containing polysaccharides may prevent diet-induced obesity and type 2 diabetes by modulating the composition of the gut microbiota. DESIGN: High-fat diet (HFD)-fed mice were treated with HSM or fractions containing polysaccharides of different molecular weights. The effects of HSM and polysaccharides on the gut microbiota were assessed by horizontal faecal microbiota transplantation (FMT), antibiotic treatment and 16S rDNA-based microbiota analysis. RESULTS: Fraction H1 containing high-molecular weight polysaccharides (>300 kDa) considerably reduced body weight gain (~50% reduction) and metabolic disorders in HFD-fed mice. These effects were associated with increased expression of thermogenesis protein markers in adipose tissues, enhanced gut integrity, reduced intestinal and systemic inflammation and improved insulin sensitivity and lipid metabolism. Gut microbiota analysis revealed that H1 polysaccharides selectively promoted the growth of Parabacteroides goldsteinii, a commensal bacterium whose level was reduced in HFD-fed mice. FMT combined with antibiotic treatment showed that neomycin-sensitive gut bacteria negatively correlated with obesity traits and were required for H1's anti obesogenic effects. Notably, oral treatment of HFD-fed mice with live P. goldsteinii reduced obesity and was associated with increased adipose tissue thermogenesis, enhanced intestinal integrity and reduced levels of inflammation and insulin resistance. CONCLUSIONS: HSM polysaccharides and the gut bacterium P. goldsteinii represent novel prebiotics and probiotics that may be used to treat obesity and type 2 diabetes. PMID- 30007922 TI - Sophistry in American medicine? Platonic reflections on expertise, influence and the public's health in the democratic context. AB - Without question, the American medical craft-the physicians, clinicians and healthcare organisations that comprise the American healthcare sector-provides immense value to patients and contributes expertise on matters relevant to the public's health. However, several conspicuous realities about healthcare in America should give the reader pause. Most problematic are the comparative measures of access to care, quality of care, life expectancy, racial health disparity and cost, all of which demonstrate how many Americans experience relatively lower value public health than other Western liberal democratic states. Since the early 1900s, American medical craft behaviour contributed to suboptimal social investment in public health, successfully influencing greater medical investment and higher healthcare expenditure relative to social welfare investments. Today, American policymakers seek the 'holy grail', a mythical panacea that purports to restrict spending and improve care quality and value, leading the USA to chase 'technocratic solutions to political problems'. This paper explores the claim that the USA is hampered by suboptimal public health decision making. Public health decision making has been historically impacted by the overextended reach of medical craft expertise-techne in Platonic terms of art as permitted by the American democratic political system. American policymakers must not forget that the debate over techne, episteme, sophistry and who should have authority in public affairs is not new. Rather, it is an ancient debate, and now as then, the ancient arguments remain relevant in a democratic context. For particularly helpful insight, one ought to look no further than the lessons of Plato's dialogues. Platonic lessons on expertise and decision making can enlighten our understanding of modern public health decision making, specifically regarding the appropriation, allocation and distribution of health-related resources in the state. PMID- 30007923 TI - Patient-rated importance of key information on screening colonoscopy in Germany: a survey of statutory health insurance members. AB - BACKGROUND: Primary colonoscopic screening is considered to be of great benefit but also has the potential to cause severe harm. Thus, eligible subjects should be supported in making an informed choice whether to participate. OBJECTIVES: To identify information on screening colonoscopy that colonoscopy-naive subjects rate as particularly important for decision making. DESIGN: Survey of German statutory health insurance members using a written questionnaire in November 2015. STUDY POPULATION: Colonoscopy-naive individuals aged 50 to 65 years. MAIN OUTCOME MEASURES: Importance of key information about screening colonoscopy, including potential risks and benefits, baseline risk of colorectal cancer/polyps and practical aspects of the procedure, as well as associations between participants' characteristics and their judgement of information as to being 'very important'. RESULTS: Of 1871 respondents (overall response rate: 31%), a subgroup of 370 colonoscopy-naive subjects was eligible for inclusion (average age: 55 years, 47% male). Information on the risks was rated as very important by most respondents, unimportant by 6%. Information on the benefits was considered unimportant by 26%. Regression analysis showed that less educated persons regarded most items to be more often relevant than highly educated subjects. A greater proportion of women than men rated details regarding pain and practical aspects as very important. Subjects with a low educational level living alone were identified as the group with the least interest in information on risks. CONCLUSION: Cultivating awareness around the central meaning of the (quantitative) benefits of screening in informed decision making should be focused on more in future information materials. The high requirement of less educated people to become more informed provides a strong motivation for further efforts to develop evidence-based information that adequately informs this group. Tailoring information according to gender-specific needs may be warranted in light of the observed differences in information preferences between women and men. PMID- 30007924 TI - Evaluating the impact of a community health worker programme on non-communicable disease, malnutrition, tuberculosis, family planning and antenatal care in Neno, Malawi: protocol for a stepped-wedge, cluster randomised controlled trial. AB - INTRODUCTION: This protocol concerns the implementation and evaluation of an intervention designed to realign the existing cadre of community health workers (CHWs) in Neno district, Malawi to better support the care needs of the clients they serve. The proposed intervention is a 'Household Model' where CHWs will be reassigned to households, rather than to specific patients with HIV and/or tuberculosis (TB). METHODS AND ANALYSIS: Using a stepped-wedge, cluster randomised design, this study investigates whether high HIV retention rates can be replicated for non-communicable diseases (NCDs), and the model's impact on TB and paediatric malnutrition case finding, as well as the uptake of family planning and antenatal care. Eleven sites (health centres and hospitals) were arranged into six clusters (average cluster population 21 800). Primary outcomes include retention in care for HIV and chronic NCDs, TB case finding, paediatric malnutrition case finding, and utilisation of early and complete antenatal care. Clinical outcomes are based on routinely collected data from the Ministry of Health's District Health Information System 2 and an OpenMRS electronic medical record supported by Partners In Health. Additionally, semistructured qualitative interviews with various stakeholders will assess community perceptions and context of the Household Model. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Malawian National Health Science Research Committee (#16/11/1694) in Lilongwe, Malawi; Partners Healthcare Human Research Committee (#2017P000548/PHS) in Somerville, Massachusetts; and the Biomedical and Scientific Research Ethics Sub-Committee (REGO-2017-2060) at the University of Warwick in Coventry, UK. Dissemination will include manuscripts for peer-reviewed publication as well as a full report detailing the findings of the intervention for the Malawian Ministry of Health. TRIAL REGISTRATION NUMBER: NCT03106727. PRIMARY SPONSOR: Partners In Health | Abwenzi Pa Za Umoyo P.O. Box 56, Neno, Malawi. Protocol Version 4, March 2018. PMID- 30007925 TI - Importance of clinical educators to research use and suggestions for better efficiency and effectiveness: results of a cross-sectional survey of care aides in Canadian long-term care facilities. AB - OBJECTIVE: This study explored the effect of clinical educators as facilitators of research use and how it may be modified by organisational context in the settings. DESIGN: Cross-sectional observational study. SETTING: A representative sample of 91 residential long-term care (LTC) facilities across Western Canada. PARTICIPANTS: We used surveys to collect data from the frontline care aides and information about the organisational context of the care units. OUTCOME MEASURE AND EXPLANATORY VARIABLES: We assessed research use (the outcome) with the Conceptual Research Utilization (CRU) scale. Explanatory variables in the multiple regression analysis were facilitation, organisational context and the interaction terms. Facilitation was measured by the frequency of contacts between care aides and clinical educator or person who brings new ideas about resident care. Three core organisational context variables were measured using the Alberta Context Tool. RESULTS: We included data of 3873 care aides from 294 care units in the LTC facilities. We found significant associations between CRU and facilitation, leadership, culture and evaluation. Interactions of facilitation x leadership and facilitation x culture were negative. The coefficient of the facilitation x evaluation term in the regression model was positive (0.019, 95% CI 0.012 to 0.026), suggesting synergistic effects between facilitation and a well-developed process to evaluate care quality using relevant data. CONCLUSIONS: Findings indicate clinical educators are effective facilitators of research use among the care aides, but the effect is modified by organisational context. For greatest impact, managers can direct efforts of the clinical educators to care units where leadership and culture ratings are lowest, but a proficient feedback and evaluation process is in place. This understanding enables managers to deploy clinical educators (a scarce resource in LTC settings) most efficiently. PMID- 30007926 TI - Health-related quality of life, participation, and physical and cognitive function of patients with intensive care unit-acquired muscle weakness 1 year after rehabilitation in Germany: the GymNAST cohort study. AB - OBJECTIVE: To describe predictors for health-related quality of life, participation, physical activity and cognitive function in patients with intensive care unit (ICU)-acquired muscle weakness 1 year after discharge from rehabilitation. DESIGN: This is a cohort study. PARTICIPANTS: We included 150 chronic critically ill individuals with ICU-acquired muscle weakness. SETTING: Postacute ICU and rehabilitation units in Germany. MEASURES: We measured health related quality of life using the EQ-5D, participation using the Reintegration of Normal Living Index, physical activity using the Physical Activity Scale for Individuals With Physical Disabilities, and basal cognitive function using the Montreal Cognitive Assessment (MoCA) at 6 months, and the Clock Drawing Test 6 and 12 months after discharge from postacute treatment. We described the predictors of the results at 12 months. RESULTS: The best predictors for good health-related quality of life 1 year after discharge were the time until regaining walking ability (OR=0.96, OR per day, 95% CI 0.93 to 0.99) and the mean MoCA score on admission to our postacute ICU and rehabilitation units (OR=1.25,95% CI 1.02 to 1.52).The best predictor for good participation 1 year after discharge was the MoCA sum score on admission to our postacute ICU and rehabilitation units (OR=0.85,95% CI 0.72 to 1.00). The best predictor for good physical activity 1 year after discharge was the Apache sum score on admission to our postacute ICU and rehabilitation units (OR=1.68,95% CI 0.89 to 3.13). The best predictor for normal cognitive function 1 year after discharge was regaining walking function in rehabilitation (OR=8.0,95% CI 0.49 to 13.69). CONCLUSION: Recovery of health-related quality of life, participation, physical activity and basal cognitive function was still not complete 12 months after discharge from postacute treatment. We described the predictors for these important outcomes in participants with ICU-acquired muscle weakness 1 year after discharge from rehabilitation. TRIAL REGISTRATION NUMBER: DRKS00007181. PMID- 30007927 TI - Smartphone application for preventing depression: study protocol for a workplace randomised controlled trial. AB - INTRODUCTION: Depression is the leading cause of life years lost due to disability. Appropriate prevention has the potential to reduce the incidence of new cases of depression, however, traditional prevention approaches face significant scalability issues. Prevention programmes delivered by via smartphone applications provide a potential solution. The workplace is an ideal setting to roll out this form of intervention, particularly among industries that are unlikely to access traditional health initiatives and whose workplace characteristics create accessibility and portability issues. The study aims to evaluate the effectiveness of a smartphone application designed to prevent depression and improve well-being. The effectiveness of the app as a universal, selective and indicated prevention tool will also be evaluated. METHODS AND ANALYSIS: A multicentre randomised controlled trial, to determine the effectiveness of the intervention compared with an active mood monitoring control in reducing depressive symptoms (primary outcome) and the prevalence of depression at 3 months, with secondary outcomes assessing well-being and work performance. Employees from a range of industries will be invited to participate. Participants with likely current depression at baseline will be excluded. Following baseline assessment, participants, blinded to their allocation, will be randomised to receive one of two versions of the application: headgear (a 30-day mental health intervention) or a control application (mood monitoring for 30 days). Both versions of the app contain a risk calculator to provide a measure of future risk. Analyses will be conducted within an intention-to-treat framework using mixed modelling, with additional analyses conducted to compare the moderating effect of baseline risk level and depression symptom severity on the intervention's effectiveness. ETHICS AND DISSEMINATION: The current trial has received ethics approval from the University of New South Wales Human Research Ethics Committee (HC17021). Study results will be disseminated through peer reviewed journals and conferences. TRIAL REGISTRATION NUMBER: ACTRN12617000548336; Results. PMID- 30007928 TI - Different predictors of pain severity across age and gender of a Chinese rural population: a cross-sectional survey. AB - OBJECTIVES: To investigate a 4-week period of pain prevalence and the risk factors of experiencing pain among a rural Chinese population sample. To explore the psychosocial and health condition predictors of pain severity and the interactions of age and gender with these factors in real-life situations among the general adult population in China. METHODS: Data were collected from a random multistage sample of 2052 participants (response rate=95%) in the rural areas of Liuyang, China. Visual analogue scale was used to assess participants' pain experienced and a series of internationally validated instruments to assess their sociodemographic characteristics, self-reported health status, depression symptoms, anxiety symptoms, sleep quality, self-efficacy and perceived stress. RESULTS: The pain prevalence over the 4-week period in rural China was 66.18% (62.84% for men and 68.82% for women). A logistic regression model revealed that being female (adjusted OR=1.58, 95% CI 1.24 to 2.02), age (adjusted OR=1.03, 95% CI 1.02 to 1.05), depressive symptoms (adjusted OR=1.07, 95% CI 1.02 to 1.13) and medium-quality sleep (adjusted OR=2.14, 95% CI 1.26 to 3.64) were significant risk factors for experiencing pain. General linear model analyses revealed that (1) pain severity of rural Chinese was related to self-rated physical health and social health; (2) the interactions of age, gender with employment status, depression symptoms, perceived stress and physical health were significant. Simple effect testing revealed that in different age groups, gender interacted with employment status, depression symptoms, perceived stress and physical health differently. CONCLUSIONS: Improving physical and social health could be effective in reducing the severity of pain and the treatment of pain should be designed specifically for different ages and genders among the general population. PMID- 30007929 TI - Out-of-hospital endotracheal intubation experience, confidence and confidence associated factors among Northern Japanese emergency life-saving technicians: a population-based cross-sectional study. AB - OBJECTIVE: Clinical procedural experience and confidence are both important when performing complex medical procedures. Since out-of-hospital endotracheal intubation (ETI) is a complex intervention, we sought to clarify clinical ETI experience among prehospital rescuers as well as their confidence in performing ETI and confidence-associated factors. DESIGN: Population-based cross-sectional study conducted from January to September 2017. SETTING: Northern Japan, including eight prefectures. PARTICIPANTS: Emergency life-saving technicians (ELSTs) authorised to perform ETI. OUTCOME MEASURES: Annual ETI exposure and confidence in performing ETI, according to a five-point Likert scale. To determine factors associated with ETI confidence, differences between confident ELSTs (those scoring 4 or 5 on the Likert scale) and non-confident ELSTs were evaluated. RESULTS: Questionnaires were sent to 149 fire departments (FDs); 140 agreed to participate. Among the 2821 ELSTs working at responding FDs, 2620 returned the questionnaire (response rate, 92.9%); complete data sets were available for 2567 ELSTs (complete response rate, 91.0%). Of those 2567 respondents, 95.7% performed two or fewer ETI annually; 46.6% reported lack of confidence in performing ETI. Multivariable logistic regression analysis showed that years of clinical experience (adjusted OR (AOR) 1.09; 95% CI 1.05 to 1.13), annual ETI exposure (AOR 1.79; 95% CI 1.59 to 2.03) and the availability of ETI skill retention programmes including regular simulation training (AOR 1.31; 95% CI 1.02 to 1.68) and operating room training (AOR 1.44; 95% CI 1.14 to 1.83) were independently associated with confidence in performing ETI. CONCLUSIONS: ETI is an uncommon event for most ELSTs, and nearly half of respondents did not have confidence in performing this procedure. Since confidence in ETI was independently associated with availability of regular simulation and operating room training, standardisation of ETI re-education that incorporates such methods may be useful for prehospital rescuers. PMID- 30007930 TI - Associations between sleep quality and its domains and insufficient physical activity in a large sample of Croatian young adults: a cross-sectional study. AB - OBJECTIVES: The main purpose of the present study was to explore the associations between sleep quality and insufficient physical activity. DESIGN: Cross sectional. SETTING: Faculties in Croatia. PARTICIPANTS: 2100 university students (1049 men and 1051 women) aged 18-24 years were recruited. PRIMARY OUTCOME: To assess the domains of sleep quality (independent variables) and 'insufficient' physical activity (dependent variable), we used previously validated Pittsburgh Sleep Quality Index and International Physical Activity questionnaires. Logistic regressions were used to calculate the associations between the sleep quality and 'insufficient' physical activity. RESULTS: When sleep quality domains were entered separately into the model, very bad subjective sleep quality (OR 3.09; 95% CI 1.50 to 6.56), >60 min of sleep latency (OR 2.17; 95% CI 1.39 to 3.39), <7 hours of sleep (OR 1.56; 95% CI 1.24 to 1.96), <65% of habitual sleep efficiency (OR 2.26; 95% CI 1.26 to 4.05), sleep disturbances >1/week (OR 1.61; 95% CI 1.03 to 2.52), use of sleep medication >1/week (OR 3.35; 95% CI 1.83 to 6.10), very big daytime dysfunction problem (OR 2.78; 95% CI 1.57 to 4.93) and poor sleep quality (1.53; 95% CI 1.23 to 1.91) were associated with 'insufficient' physical activity. When all sleep quality domains were entered simultaneously into the model, the same significant associations remained, except for sleep disturbances. Both models were adjusted for gender, body mass index, self-rated health, life satisfaction, socioeconomic status, presence or absence of chronic diseases, smoking status, binge drinking and psychological distress. CONCLUSIONS: Our results show that 'poor' sleep quality is associated with 'insufficient' physical activity in young adults. In order to improve, special strategies and policies that leverage 'good sleep' quality are warranted. PMID- 30007931 TI - Evaluating the validity of the selection measures used for the UK's foundation medical training programme: a national cohort study. AB - OBJECTIVES: Currently relative performance at medical school (educational performance measure (EPM) decile), additional educational achievements and the score on a situational judgement test (SJT) are used to rank applicants to the UK Foundation Years postgraduate medical training programme. We sought to evaluate whether these three measures were predictive of subsequent successful completion of the programme, and thus were valid selection criteria. METHODS: Data were obtained from the UK Medical Education Database (UKMED) on 14 131 UK applicants to the foundation programme starting in 2013 and 2014. These data included training outcomes in the form of Annual Reviews of Competency Progression (ARCPs), which indicated whether the programme was successfully completed. The relationship between applicants' performance on the three selection measures to the odds of successful programme completion were modelled. RESULTS: On univariable analyses, all three measures were associated with the odds of successful completion of the programme. Converting the SJT score to deciles to compare the effect sizes suggested that one decile increase in the EPM increased the odds of completing the programme by approximately 15%, whereas the equivalent value was 8% for the SJT scores. On multivariable analyses (with all three measures included in the model), these effects were only independently and statistically significant for EPM decile (OR 1.14, 95% CI 1.10 to 1.18, p<0.001) and SJT z-score decile (OR 1.05, 95% CI 1.01 to 1.09, p=0.02). CONCLUSIONS: The EPM decile and SJT scores may be effective selection measures for the foundation programme. However, educational achievements does not add value to the other two measures when predicting programme completion. Thus, its usefulness in this context is less clear. Moreover, our findings suggest that the weighting for the EPM decile score, relative to SJT performance, should be increased. PMID- 30007932 TI - Which type of tobacco product warning imagery is more effective and sustainable over time? A longitudinal assessment of smokers in Canada, Australia and Mexico. AB - OBJECTIVE: This study examined smokers' responses to pictorial health warnings (PHWs) with different types of imagery under natural exposure conditions. METHODS: Adult smokers from online panels in Canada (n=2357), Australia (n=1671) and Mexico (n=2537) were surveyed every 4 months from 2012 to 2013. Participants were shown PHWs on packs in their respective countries and asked about: (1) noticing PHWs; (2) negative affects towards PHWs; (3) believability of PHWs; (4) PHW-stimulated discussions; and (5) quit motivation due to PHWs. Country-specific generalised estimating equation models regressed these outcomes on time (ie, survey wave), PHW imagery type (ie, symbolic representations of risk, suffering from smoking and graphic depictions of bodily harm) and interactions between them. RESULTS: In all countries, PHW responses did not significantly change over time, except for increased noticing PHWs in Canada and Mexico, increased negative affect in Australia and decreased negative affect in Mexico. For all outcomes, symbolic PHWs were rated lower than suffering and graphic PHWs in Canada (the only country with symbolic PHWs). Graphic PHWs were rated higher than suffering PHWs for negative affect (all countries), discussions (Canada) and quit motivation (Australia). Suffering PHWs were rated higher than graphic PHWs for noticing PHWs (Canada), believability (all countries), discussions (AustraliaandMexico) and quit motivation (Mexico). Changes in noticing, believability and discussions varied somewhat by imagery type across countries. CONCLUSIONS: The different PHW imagery appears to have different pathways of influence on adult smokers. Reactions to specific PHWs are similar over 1-2 years, suggesting that wear-out of PHW effects is due to decreased attention rather than the diminishing effectiveness of content. PMID- 30007933 TI - Confirmation of Mycoplasma hyopneumoniae in a breeding herd through tracheobronchial swab sampling and PCR. PMID- 30007935 TI - Another Article About E-Cigarettes: Why Should I Care? PMID- 30007934 TI - Electronic Cigarette Use Prevalence, Associated Factors, and Pattern by Cigarette Smoking Status in the United States From NHANES (National Health and Nutrition Examination Survey) 2013-2014. AB - BACKGROUND: To examine the prevalence and patterns of recent electronic cigarette (e-cigarette) use in a nationally representative sample of US adults and adolescents. METHODS AND RESULTS: Using tobacco information from NHANES (National Health and Nutrition Examination Survey) 2013-2014, 5423 adults and 895 adolescents (aged 13-17 years) were included in this analysis. Demographic, tobacco use, and drug use information were self-reported. Recent e-cigarette use (within the previous 5 days) was stratified by smoking status. Of 125 e-cigarette users, 116 participants were aged >=18 years, corresponding to 2.6% (95% confidence interval [CI], 2.0-3.1) and 1.21% (95% CI, 0.3-2.1) prevalence of e cigarette use among US adults and adolescents, respectively. E-cigarette adult users were current smokers (68.1%), former smokers (23.7%), and never smokers (8.2%). The highest prevalence of e-cigarette use was among current smokers (8.2%; 95% CI, 6.3-10.1), followed by former smokers (2.7%; 95% CI, 1.4-4.1), and then never smokers (0.4%; 95% CI, 0.2-0.6). After adjusting for age, sex, and ethnicity, e-cigarette users had higher odds of being exposed to secondhand smoke (odds ratio: 6.3; 95% CI, 3.6-11.1) and drinking alcohol (odds ratio: 4.2; 95% CI, 1.8-10.0) and lower odds of having at least a college education or a higher income, compared with tobacco nonusers. CONCLUSIONS: Between 2013 and 2014, e cigarette use in the United States was more common among younger people, those with low socioeconomic status, and current and former smokers. These findings will help inform future research as well as public policy and regulatory actions. PMID- 30007936 TI - Phenotypes of Pregnant Women Who Subsequently Develop Hypertension in Pregnancy. AB - BACKGROUND: Hypertensive disorders complicating pregnancy are a major cause of maternal death. Our objective was to evaluate maternal clinical, hemodynamic, and placental prognostic indicators in a consolidated manner to identify women who develop hypertension in pregnancy. METHODS AND RESULTS: Twenty-six normotensive pregnant women from a specialized Placenta Clinic at increased risk of developing de novo hypertension and 20 normotensive healthy pregnant controls were recruited at 22 to 26 weeks' gestation. Fourteen maternal clinical, hemodynamic, and placental characteristics were assessed in the second trimester and aggregated. Principal component analysis of this combined data set determined that 3 dimensions accounted for 56% of the cohort variability. The first dimension accounted for 31% of the cohort variability, with significant contributions from total peripheral resistance, endoglin, and cardiac output. The second dimension was predominantly influenced by body mass index and mean arterial pressure, while uric acid and myeloperoxidase mainly contributed to the third dimension. Unsupervised clustering identified 3 groups within this combined data set. Total peripheral resistance was the most significant distinguishing parameter between these groups (P<0.0001), followed by placental growth factor, endoglin, and cardiac output (P<0.0001). Using these 4 parameters, a receiver operating curve was constructed with an area under the curve of 0.975 (95% confidence interval 0.93-1) for the prediction of developing hypertension in pregnancy. CONCLUSIONS: Consolidated assessment of prognostic indicators in the second trimester of pregnancy may be useful to characterize and distinguish pathways by which women may develop hypertension in pregnancy. This approach could contribute to the development of pathway-specific preventative and antihypertensive treatment strategies. PMID- 30007937 TI - Defining Hypertension by Blood Pressure 130/80 mm Hg Leads to an Impressive Burden of Hypertension in Young and Middle-Aged Black Adults: Follow-Up in the CARDIA Study. PMID- 30007938 TI - Hemodynamic Prediction and Stratification of Hypertensive Disorders of Pregnancy: A Dream That Is Coming True? PMID- 30007939 TI - Impact of breast milk intake on body composition at term in very preterm babies: secondary analysis of the Nutritional Evaluation and Optimisation in Neonates randomised controlled trial. AB - OBJECTIVE: To investigate the impact of breast milk (BM) intake on body composition at term in very preterm infants. DESIGN: Preplanned secondary analysis of the Nutritional Evaluation and Optimisation in Neonates Study, a 2-by 2 factorial randomised controlled trial of preterm parenteral nutrition (PN). SETTING: Four National Health Service hospitals in London and South-East England. PATIENTS: Infants born at <31 weeks of gestation; infants with life-threatening congenital abnormalities and those unable to receive trial PN within 24 hours of birth were ineligible. 133 infants survived and underwent whole-body MRI at term (37-44 weeks postmenstrual age). MAIN OUTCOME MEASURES: Non-adipose tissue mass (non-ATM), ATM and ATM as a percentage of body weight (% ATM) at term. RESULTS: Compared with the exclusively BM group (proportion of BM=100% milk, n=56), predominantly formula-fed infants (BM <=50%, n=38) weighed 283.6 g (95% CI 121.6 to 445.6) more, had 257.4 g (139.1-375.7) more non-ATM and a greater positive weight Z-score change between birth and term. There were no significant differences in weight, non-ATM and weight Z-score change between the exclusively and predominantly BM (BM 51%-99%, n=39) groups. Compared with the exclusively BM group no significant differences were observed in ATM and %ATM in the predominantly BM and predominantly formula-fed groups. CONCLUSIONS: The slower weight gain of preterm infants fed BM appears to be due to a deficit in non-ATM and may reflect lower protein intake. Whether this pattern persists into childhood, is altered by BM fortification or later diet, or relates to functional outcomes, are important research questions. CLINICAL TRIAL REGISTRATION: ISRCTN29665319, post results. PMID- 30007941 TI - Antenatal ultrasound and autism. PMID- 30007940 TI - Paternal uniparental disomy of chromosome 19 in a pair of monochorionic diamniotic twins with dysmorphic features and developmental delay. AB - BACKGROUND: We report here clinical, cytogenetic and molecular data for a pair of monochorionic diamniotic twins with paternal isodisomy for chromosome 19. Both twins presented with dysmorphic features and global developmental delay. This represents, to our knowledge, the first individual human case of paternal uniparental disomy for chromosome 19 (UPD19). METHODS: Whole-exome sequencing, together with conventional karyotype and SNP array analysis were performed along with genome-wide DNA methylation array for delineation of the underlying molecular defects. RESULTS: Conventional karyotyping on amniocytes and lymphocytes showed normal karyotypes for both twins. Whole-exome sequencing did not identify any pathogenic sequence variants but >5000 homozygous exonic variants on chromosome 19, suggestive of UPD19. SNP arrays on blood and buccal DNA both showed paternal isodisomy for chromosome 19. Losses of imprinting for known imprinted genes on chromosome 19 were identified, including ZNF331, PEG3, ZIM2 and MIMT1. In addition, imprinting defects were also identified in genes located on other chromosomes, including GPR1-AS, JAKMP1 and NHP2L1. CONCLUSION: Imprinting defects are the most likely cause for the dysmorphism and developmental delay in this first report of monozygotic twins with UPD19. However, epigenotype-phenotype correlation will require identification of additional individuals with UPD19 and further molecular analysis. PMID- 30007942 TI - Two-thumb-encircling advantageous for lay responder infant CPR: a randomised manikin study. AB - OBJECTIVE: Paediatric health providers and educators influence infant mortality through advocacy and training within families and communities. This research sought to establish the efficacy and training of two-finger versus two-thumb encircling techniques for lone responder infant chest compressions with ventilations in initially trained infant caregivers. DESIGN: This is a randomised, cross-over educational intervention assessed on instrumented manikins using the 2015 guideline measures of quality infant cardiopulmonary resuscitation (CPR). Additional subjective data on the experience were collected through self reporting. SETTING: Non-healthcare community organisations and secondary school classrooms. PARTICIPANTS: Fourteen years or older, fluent in English and had not taken infant CPR in the last 5 years. INTERVENTIONS: Groups of eight participants were randomised to learn one technique, practised and then tested for 8 min. After a 30 min rest, the group repeated the process using the other technique. MAIN OUTCOME MEASURES: Mean chest compression depth and rate, compression fraction, and correct hand position; tiredness and pain as reported by the caregiver. RESULTS: The two-thumb-encircling technique achieved a deeper mean compression depth over the 8 min period (2.0 mm, p<0.01), closer to the minimum recommendation of 40 mm; the two-finger technique achieved higher percentages of compression fraction and complete recoil. Caregivers preferred the two-thumb technique (64%), and of these 70% had long fingernails. CONCLUSIONS: The two thumb-encircling technique improved compression depth, over an 8 min scenario, and was preferred by caregivers. This adds to the existing literature on the advantages of two-thumb-encircling as a technique for lone and team infant CPR, which counters current guidelines. PMID- 30007943 TI - Question 1: In infant botulism, is equine-derived botulinum antitoxin (EqBA) an effective alternative therapy to human-derived botulinum immune globulin (BIG)? PMID- 30007944 TI - Hypoventilation disproportionate to OSAS severity in children with Prader-Willi syndrome. AB - OBJECTIVE: To test the hypothesis that children with Prader-Willi syndrome (PWS) and obstructive sleep apnoea syndrome (OSAS) have hypercapnia for higher proportion of total sleep time (TST) than non-syndromic children with similar obstructive apnoea-hypopnoea index (OAHI). DESIGN: Cross-sectional study. SETTING: Two tertiary care hospitals. PATIENTS: Patients with PWS and non syndromic children with snoring who underwent polygraphy and were of similar age, body mass index (BMI) z-score and OAHI. MAIN OUTCOME MEASURE: The two groups were compared regarding %TST with transcutaneous CO2 (PtcCO2) >50 mm Hg. The interaction between PWS diagnosis and OSAS severity (OAHI <1 episode/h vs 1-5 episodes/h vs >5 episodes/h) regarding %TST with PtcCO2 >50 mm Hg was tested using multiple linear regression. RESULTS: 48 children with PWS and 92 controls were included (median age 2.3 (range 0.2-14.1) years vs 2.2 (0.3-15.1) years; BMI z-score 0.7+/-1.9 vs 0.8+/-1.7; median OAHI 0.5 (0-29.5) episodes/h vs 0.5 (0 33.9) episodes/h; p>0.05). The two groups did not differ in %TST with PtcCO2 >50 mm Hg (median 0% (0-100%) vs 0% (0-81.3%), respectively; p>0.05). However, the interaction between PWS and OSAS severity with respect to duration of hypoventilation was significant (p<0.01); the estimated mean differences of %TST with PtcCO2 >50 mm Hg between children with PWS and controls for OAHI <1 episode/h, 1-5 episodes/h and >5 episodes/h were +0.2%, +1% and +33%, respectively. CONCLUSION: Increasing severity of upper airway obstruction during sleep in children with PWS is accompanied by disproportionately longer periods of hypoventilation when compared with non-syndromic children with similar frequency of obstructive events. PMID- 30007946 TI - Fluid regimes for DKA. PMID- 30007945 TI - Avoidable mortality from respiratory tract infection and sudden unexplained death in children with chronic conditions: a data linkage study. AB - OBJECTIVE: To determine the risk of death from two potentially avoidable causes with different aetiologies: respiratory tract infection (RTI) and sudden unexplained death (SUD) in children with and without chronic conditions. DESIGN: Whole-country, birth cohort study using linked administrative health databases from Scotland. SETTING AND PARTICIPANTS: Children aged 2 months to less than 5 years in Scotland between 2000 and 2014. MAIN OUTCOME MEASURES: Relative risk of death (expressed as the HR) related to RTIs or SUD, in children with and without chronic conditions. We separately analysed deaths at ages 2-11 months and at 1-4 years and adjusted for birth characteristics, socioeconomic status and vaccination uptake using Cox regression. RESULTS: The cohort comprised 761 172 children. Chronic conditions were recorded in 9.6% (n=72 901) of live births, 82.4% (n=173) of RTI-related deaths and 17.4% (n=49) of SUDs. Chronic conditions were very strongly associated with RTI mortality (2-11 months: HR 68.48, 95% CI (40.57 to 115.60), 1-4 years: HR 38.32, 95% CI (23.26 to 63.14)) and strongly associated with SUD (2-11 months: HR 2.42, 95% CI (1.67 to 3.63), 1-4 years: HR 2.53, 95% CI (1.36 to 4.71)). CONCLUSIONS: The very strong association with chronic conditions suggests that RTI-related mortality may sometimes be a consequence of a terminal decline and not possible to defer or prevent in all cases. Recording whether death was expected on death certificates could indicate which RTI-related deaths might be avoidable through healthcare and public health measures. PMID- 30007948 TI - Question 2: Does heavy metal chelation therapy improve the symptoms of autism spectrum disorder. PMID- 30007947 TI - Research priority setting by young people with rheumatic musculoskeletal disease. PMID- 30007949 TI - Risk factors for refractory anastomotic strictures after oesophageal atresia repair: a multicentre study. AB - OBJECTIVE: To determine the incidence of refractory anastomotic strictures after oesophageal atresia (OA) repair and to identify risk factors associated with refractory strictures. METHODS: Retrospective national multicentre study in patients with OA born between 1999 and 2013. Exclusion criteria were isolated fistula, inability to obtain oesophageal continuity, death prior to discharge and follow-up <6 months. A refractory oesophageal stricture was defined as an anastomotic stricture requiring >=5 dilations at maximally 4-week intervals. Risk factors for development of refractory anastomotic strictures after OA repair were identified with multivariable logistic regression analysis. RESULTS: We included 454 children (61% male, 7% isolated OA (Gross type A)). End-to-end anastomosis was performed in 436 (96%) children. Anastomotic leakage occurred in 13%. Fifty eight per cent of children with an end-to-end anastomosis developed an anastomotic stricture, requiring a median of 3 (range 1-34) dilations. Refractory strictures were found in 32/436 (7%) children and required a median of 10 (range 5-34) dilations. Isolated OA (OR 5.7; p=0.012), anastomotic leakage (OR 5.0; p=0.001) and the need for oesophageal dilation <=28 days after anastomosis (OR 15.9; p<0.001) were risk factors for development of a refractory stricture. CONCLUSIONS: The incidence of refractory strictures of the end-to-end anastomosis in children treated for OA was 7%. Risk factors were isolated OA, anastomotic leakage and the need for oesophageal dilation less than 1 month after OA repair. PMID- 30007950 TI - Self-regulated learning and critical reflection in an e-learning on patient safety for third-year medical students. AB - Objectives: To explore the influence of critical thinking, self-regulated learning and system usability on the acceptance of e-learning on patient safety. Methods: A cross-sectional study was conducted, using a 32-question online survey. One hundred ninety-three (n=193 medical students participated in the study and were asked to rate levels of reflective thinking, self-regulated learning and attitudes towards patient safety using scales from the Questionnaire for Reflective Thinking, the Attitudes to Patient Safety Questionnaire and the System Usability Scale. Differences between reflection levels were calculated using paired t-tests, associations between critical thinking and self-regulated learning were calculated using linear correlations. We performed linear multiple regression analysis to identify predictors for student acceptance of the e learning. Results: Students (n=193) engaged in intermediate levels of reflection (5-point Likert, M=3.62, SD=0.73) and significantly (t(143)=15.15, p<0.001, d=1.57) lower levels (M=2.35, SD=0.87) of critical reflection. Most students showed high (>= 4; 44.1%) or intermediate (<4 level > 2; 29.4 %) levels of self regulated learning. A regression model indicated that 5 predictors (Reflection, critical reflection, self-regulated learning, relevance, usability) explained 65.3% of the variance (R2=0.653, F(5, 96)=39.02, p<0.01) of perceived total quality. Conclusions: This study shows that reflection and learning skills are important factors for e-learning acceptance, but perceived relevance and system usability play a more important role. From a didactic perspective, it is indispensable to provide the students with sufficient examples and links to professional practice to enhance the perception of relevance and to improve system usability permanently. PMID- 30007952 TI - Antigenicity of tissues and organs from GGTA1/CMAH/beta4GalNT2 triple gene knockout pigs. AB - Clinical xenotransplantations have been hampered by human preformed antibody mediated damage of the xenografts. To overcome biological incompatibility between pigs and humans, one strategy is to remove the major antigens [Gal, Neu5Gc, and Sd(a)] present on pig cells and tissues. Triple gene (GGTA1, CMAH, and beta 4GalNT2) knockout (TKO) pigs were produced in our laboratory by CRISPR-Cas9 targeting. To investigate the antigenicity reduction in the TKO pigs, the expression levels of these three xenoantigens in the cornea, heart, liver, spleen, lung, kidney, and pancreas tissues were examined. The level of human IgG/IgM binding to those tissues was also investigated, with wildtype pig tissues as control. The results showed that alphaGal, Neu5Gc, and Sd(a) were markedly positive in all the examined tissues in wildtype pigs but barely detected in TKO pigs. Compared to wildtype pigs, the liver, spleen, and pancreas of TKO pigs showed comparable levels of human IgG and IgM binding, whereas corneas, heart, lung, and kidney of TKO pigs exhibited significantly reduced human IgG and IgM binding. These results indicate that the antigenicity of TKO pig is significantly reduced and the remaining xenoantigens on porcine tissues can be eliminated via a gene targeting approach. PMID- 30007953 TI - Bone regeneration with adipose derived stem cells in a rabbit model. AB - It has been shown that stem cells are able to calcify both in vitro and in vivo once implanted under the skin, if conveniently differentiated. Nowadays, however, a study on their efficiency in osseous regeneration does not exist in scientific literature and this very task is the real aim of the present experimentation. Five different defects of 6 mm in diameter and 2 mm in depth were created in the calvaria of 8 white New Zealand rabbits. Four defects were regenerated using 2 different conveniently modified scaffolds (Bio-Oss(r) Block and Bio-Oss Collagen(r), Geistlich), with and without the aid of stem cells. After the insertion, the part was covered with a collagen membrane fixed by 5 modified titan pins (Altapin(r)). The defect in the front was left empty on purpose as an internal control to each animal. Two animals were sacrificed respectively after 2, 4, 6, 10 weeks. The samples were evaluated with micro-CT and histological analysis. Micro-CT analysis revealed that the quantity of new bone for samples with Bio-Oss(r) Block and stem cells was higher than for samples with Bio-Oss(r) Block alone. Histological analysis showed that regeneration occurred in an optimal way in every sample treated with scaffolds. The findings indicated that the use of adult stem cells combined with scaffolds accelerated some steps in normal osseous regeneration. PMID- 30007951 TI - The decline of clinical skills: a challenge for medical schools. PMID- 30007954 TI - Identification of a LMNA (c.646C>T) variant by whole-exome sequencing in combination with a dilated cardiomyopathy (DCM) related gene filter in a family with familiar DCM. PMID- 30007955 TI - Delayed Graft Function: The AKI of Kidney Transplantation. AB - With the growing wait list of individuals waiting for kidney transplantation, there has been renewed interest in the quality and function of donor organs. In particular, concern about the development of delayed allograft function (DGF) after transplantation continues to lead to the avoidance of donor organs offered to a transplant center. DGF is associated with worse short-and long-term outcomes and associated with higher rejection rates. There are no FDA-approved therapies to mitigate the ischemic injury that occurs. Risk factors include both donor and recipient characteristics, although their prediction is not precise. With new understanding about mechanisms of injury and new focus on the function of the deceased donor, there is opportunity to identify not only novel therapies to improve allograft function but to identify potential biomarkers of DGF. DGF remains a significant factor in impacting kidney transplant outcome, and finding biomarkers will assist in the development and approval of novel agents to ameliorate early and later injury. This mini-review highlights our presentation at the 23rd International Conference on Advances in Critical Care Nephrology and UAB/UCSD O'Brien Center Acute Kidney Injury (AKI) Pre-Meeting. PMID- 30007956 TI - Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells. AB - BACKGROUND/AIMS: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs. METHODS: Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development. RESULTS: Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner. CONCLUSIONS: PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer. PMID- 30007958 TI - Transarterial Chemoembolization (TACE) Using Mitomycin with or without Irinotecan for Hepatocellular Carcinoma in European Patients. AB - BACKGROUND: We evaluated survival data and local tumor control in 2 groups of patients with hepatocellular carcinoma (HCC) treated with different chemotherapeutic agents for transarterial chemoembolization (TACE). METHODS: 28 patients (median age 63 years) with HCC were repeatedly treated with chemoembolization at 4-week intervals. 20 patients had Barcelona Clinic Liver Cancer (BCLC) stage B, while 8 patients obtained chemoembolization for bridging purposes (BCLC stage A). In total, 98 chemoembolizations were performed (median 3.0 treatments/patient). The administered chemotherapeutic agent comprised either mitomycin only (n = 14; 50%) or mitomycin in combination with irinotecan (n = 14; 50%). Lipiodol plus degradable starch microspheres was used for all embolizations. Local tumor response was assessed by magnetic resonance imaging using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Progression-free survival (PFS) was evaluated. RESULTS: In the mitomycin irinotecan group, complete response (CR) was observed in 21.4%, partial response (PR) in 42.9%, stable disease (SD) in 28.6%, and progressive disease (PD) in 7.1%. In the mitomycin group, PR was observed in 57.2% of patients, SD in 21.4%, and PD in 21.4% (p = 0.043). The PFS of patients after chemoembolization with mitomycin was 4 months compared to the significantly longer PFS of 12 months in the mitomycin-irinotecan group (p = 0.003). CONCLUSION: Chemoembolization of HCC with mitomycin and irinotecan is the preferred treatment option for achieving local control and better PFS. PMID- 30007957 TI - Effect of the LncRNA GAS5-MiR-23a-ATG3 Axis in Regulating Autophagy in Patients with Breast Cancer. AB - BACKGROUND/AIMS: An increasing body of evidence shows that long noncoding RNAs (lncRNAs) are involved in many different cancers. In this study, we aimed to investigate the competing endogenous RNA (ceRNA)-dependent mechanism by which the lncRNA GAS5 contributes to the development of breast cancer. METHODS: A total of 68 breast cancer patients were enrolled, and breast cancer and adjacent normal tissues were collected. The human breast cancer cell lines MDA-MB-231, MDA-MB 453, BT549, SK-BR-3 and MCF-7 and human breast cell line MCF10A were utilized in this study. Quantitative reverse transcription-polymerase chain reaction (qRT PCR) and western blotting were performed to detect expression of relative factors. RNA immunoprecipitation (RIP) was used to evaluate the relationship between GAS5 and miR-23a, and a dual luciferase reporter gene assay was employed to assess the relationship between ATG3 and miR-23a. A subcutaneous xenograft nude mouse model was generated to examine the role of GAS5 and its regulatory pathway in autophagy. RESULTS: GAS5 levels were frequently decreased in breast cancer tissues and cell lines, and its relatively low expression was closely related to a larger tumour size, advanced tumour-node-metastasis (TNM) stage and estrogen receptor-negative (ER-) breast cancer tissues. More importantly, we found that GAS5 promoted autophagy, with enhanced autophagosome formation after GAS5 overexpression. GAS5 was found to act as a microRNA sponge in a pathway that included miR-23a and its target gene ATG3. The GAS5-miR-23a-ATG3 axis significantly regulated autophagy in vivo and in vitro. CONCLUSIONS: In summary, we report that the GAS5-miR-23a-ATG3 axis can be regarded as a key regulator of autophagy pathways in breast cancer; it may constitute a promising biomarker and therapeutic target in the future. PMID- 30007959 TI - Curious Residents of the Thyroid Gland: Two Case Reports of Colorectal Carcinoma Metastasis by Fine-Needle Aspiration Diagnosis. AB - BACKGROUND: The most frequent metastases to the thyroid originate in the kidney, lung or breast. Colorectal adenocarcinoma represents less than 4% of metastases to the thyroid gland. Solitary metastases of colorectal cancer with no other manifestation of disseminated cancer disease are exceedingly rare. Within the Bethesda Classification for Reporting -Thyroid Cytopathology, metastases are included in Diagnostic Categories "Suspicious for Malignancy" and "Malignant." CASES: We present 2 cases of colorectal adenocarcinoma metastatic to the thyroid gland, diagnosed by fine-needle aspiration (FNA). One metastasis occurred in normal thyroid parenchyma; the other was a tumour-to-tumour metastasis into a follicular carcinoma of the thyroid. The latter is the first published tumour-to tumour metastasis of a colorectal carcinoma in the thyroid from which both components were diagnosed by FNA. CONCLUSION: Diagnosing a metastasis to the thyroid is challenging. On FNA, a dual cell population should raise suspicion. Immunocytochemical and molecular analysis may be helpful. Clinical information is essential in guiding specific ancillary technique panels in scant cellular material. PMID- 30007960 TI - Heat-Induced Epithelial Barrier Dysfunction Occurs via C-Src Kinase and P120ctn Expression Regulation in the Lungs. AB - BACKGROUND/AIMS: Thermal injury causes pulmonary edema and can lead to death. Intercellular junctions are composed of adhesive (p120ctn, E-cadherin, alpha catenin and beta-catenin) and compact (occludin and ZO-1) junctions. Heat deteriorates intercellular junctions and increases cell gaps to ultimately induce pulmonary edema, but the underlying mechanism remains elusive. METHODS: Mouse lung epithelial (MLE-12) cells pre-treated with the c-Src inhibitor PP2, p120ctn catenin (p120ctn) small interfering RNA and p120ctn catenin (p120ctn) complementary DNA were subjected to heat treatment. Western blotting and real time polymerase chain reaction assays were used to evaluate junction protein expression changes after heat treatment, and co-immunoprecipitation was used to test the binding state of junction proteins. In addition, hematoxylin and eosin staining and immunohistochemistry were used to evaluate changes in junction protein expression and lung injury in a Wistar rat model of thermal inhalation injury. RESULTS: Heat increased cell permeability; induced ZO-1, occludin, alpha catenin and beta-catenin degradation; and decreased E-cadherin distribution in cell membranes. Heat also activated c-Src and decreased both p120ctn expression levels and occludin and ZO-1 association. c-Src inhibitor (PP2) treatment and p120ctn overexpression reversed these effects and attenuated lung injury in vivo. CONCLUSION: Heat induces junction protein degradation and dissociation to increase membrane permeability and cause lung edema via c-Src kinase activation and p120ctn expression downregulation. PMID- 30007962 TI - Correlation between Anatomical Segments of the Pudendal Nerve and Clinical Findings of the Patient with Pudendal Neuralgia. AB - BACKGROUND: The objective was to describe clinical findings and outcomes of patients with pudendal neuralgia in relation with the anatomical segment affected. METHODS: Fifty-one consecutive patients with chronic perineal pain (CPP) located in the areas supplied by the pudendal nerve (PN), from January 2011 to June 2012, were analyzed. RESULTS: The distribution of pain at perineal, dorsal clitoris and inferior anal nerves was 92.2, 31.4 and 25.5% respectively. The duration of pain was longer when the dorsal clitoris nerve (DCN) was affected (p < 0,003). The pain in the pudendal canal was frequently associated with the radiation of pain to the inferior members (p < 0.043). CONCLUSION: CPP and radiation of pain to lower limbs suggest a disorder at the second segment of PN. A positive Tinel sign in the third segment indicates a nerve entrapment. In terminal branches, pain was more frequent at the perineal nerve and more persistent at the DCN. PMID- 30007961 TI - Methodological Recommendations for Trials of Psychological Interventions. AB - Recent years have seen major developments in psychotherapy research that suggest the need to address critical methodological issues. These recommendations, developed by an international group of researchers, do not replace those for randomized controlled trials, but rather supplement strategies that need to be taken into account when considering psychological treatments. The limitations of traditional taxonomy and assessment methods are outlined, with suggestions for consideration of staging methods. Active psychotherapy control groups are recommended, and adaptive and dismantling study designs offer important opportunities. The treatments that are used, and particularly their specific ingredients, need to be described in detail for both the experimental and the control groups. Assessment should be performed blind before and after treatment and at long-term follow-up. A combination of observer- and self-rated measures is recommended. Side effects of psychotherapy should be evaluated using appropriate methods. Finally, the number of participants who deteriorate after treatment should be noted according to the methods that were used to define response or remission. PMID- 30007963 TI - Apocynin Attenuates Cobalt Chloride-Induced Pheochromocytoma Cell Apoptosis by Inhibiting P38-MAPK/Caspase-3 Pathway. AB - BACKGROUND/AIMS: Apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been identified as a potential neuroprotectant. In this study, we aimed to investigate the protective effect of apocynin against cobalt chloride (CoCl2)-induced pheochromocytoma (PC12) cell apoptosis. METHODS: The PC12 cell culture was pretreated with apocynin and/or SB203580 (p38 mitogen activated protein kinase [p38-MAPK] inhibitor) at different time points prior to CoCl2 incubation. The cell viability, apoptosis rate, DAN damage, and antioxidant activity were detected using cell counting kit-8 (CCK-8), flow cytometry, enzyme linked immunosorbent assay (ELISA), and comet assay respectively. The protein and mRNA expressions of p38-MAPK and caspase-3 in the cells were measured by qRT-PCR and Western blotting. RESULTS: Apocynin inhibited CoCl2-mediated apoptosis, reduced oxidative stress, and down-regulated the expression of p38-MAPK and caspase-3. CONCLUSIONS: Our findings show that apocynin attenuated CoCl2-induced apoptosis by potently restraining p38-MAPK-caspase-3 signaling pathway in PC12 cells, suggesting that apocynin may be a potent prophylactic reagent against CoCl2-mediated PC12 cell apoptosis. PMID- 30007964 TI - Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells. AB - BACKGROUND/AIMS: Mechanical stimulation and WNT signalling have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding the regulation of WNT signalling molecule expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. METHODS: Microarrays of BMSCs from elderly individuals or patients with osteoporosis (GSE35959) from the GEO database were analysed using GeneSight-Lite 4.1.6 (BioDiscovery) and C2 curated gene sets downloaded from Molecular Signatures Database (MSigDB). Realtime PCR and western blotting were used to measure the expression of the indicated genes. ALP and Alizarin red staining were used to evaluate the osteogenesis of BMSCs. RESULTS: In this study, we investigated whether mechanical loading directly regulates the expression of WNT signalling molecules and examined the role of WNT signalling in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found downregulation of the GPCR ligand binding gene set in the BMSCs of patients with osteoporosis. Then, we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. FZD4 was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, and the JNK signalling pathway was activated. FZD4 knockdown inhibited the mechanical stimuli-induced osteogenesis and JNK activity. More importantly, we found an activating effect of WNT5A and FZD4 that regulated bone formation in response to hindlimb unloading in mice, and pretreatment with WNT5A or activation of the expression of FZD4 partly rescued the osteoporosis caused by mechanical unloading. CONCLUSIONS: Our results demonstrate, for the first time, that mechanical stimulation alters the expression of genes involved in the osteogenic differentiation of BMSCs via the direct regulation of FZD4 and that therapeutic WNT5A and FZD saRNA may be an efficient strategy for enhancing bone formation under mechanical stimulation. PMID- 30007965 TI - Chronic Sleep Restriction Impairs the Antitumor Immune Response in Mice. AB - OBJECTIVES: Sleep regulates immune function reciprocally and can affect the parameters that are directly involved in the immune response. Sleep deprivation is considered to be a stress-causing factor and is associated with impaired immune activity. It causes increased glucocorticoid concentrations by activating the hypothalamic-pituitary-adrenal axis; this can lead to a series of disorders that are associated with the prolonged or increased secretion of these hormones. The aim of this study was to evaluate the effects of sleep restriction (SR) on the development of pulmonary experimental metastasis and the modulation of the tumor immune response. METHODS: The SR protocol was accomplished by depriving C57BL/6 male mice of sleep for 18 h/day for 2, 7, 14, and 21 days. The modified multiple-platforms method was used for SR. RESULTS: The results showed that cytotoxic cells (i.e., natural killer [NK] and CD8+ T cells) were reduced in number and regulatory T cells were predominant in the tumor microenvironment. Sleep-restricted mice also exhibited a reduced number of dendritic cells in their lymph nodes, which may have contributed to the ineffective activation of tumor specific T cells. Peripheral CD4+ and CD8+ T cells were also reduced in the sleep restricted mice, thus indicating an immunosuppressive status. CONCLUSIONS: Sleep dep-rivation induces failure in the activity of cells that are im-portant to the tumor immune response, both in the tumor microenvironment and on the periphery. This leads to the early onset and increased growth rate of lung metastasis. PMID- 30007966 TI - A Rationale for Timing of Luteal Support Post Gonadotropin-Releasing Hormone Agonist Trigger. AB - Gonadotropin-releasing hormone (GnRH) antagonist-based ovarian stimulation protocol is gaining popularity. This protocol allows for the use of GnRH agonist as a trigger of final oocyte maturation, instead of the "gold standard" human chorionic gonadotropin (hCG) trigger. GnRH agonist trigger causes quick luteolysis, hence its widespread use in the context of ovarian hyperstimulation syndrome (OHSS) prevention. To secure pregnancy post GnRH agonist trigger, the luteal phase must be supplemented to counteract the luteolysis. Several luteal phase protocols post GnRH agonist trigger have been suggested, most notably based on increasing luteal luteinizing hormone (LH) activity (by adding LH or hCG). The current review aims at delineating a rationale for timing luteal support with a single hCG bolus post GnRH agonist trigger. The review also suggests a set of simple rules that must be followed when designing luteal phase support post GnRH agonist trigger. PMID- 30007967 TI - Total Dorsal Pancreatectomy, an Alternative to Total Pancreatectomy: Report of a New Case and Literature Review. AB - BACKGROUND: Total dorsal pancreatectomy (TDP) is a conservative pancreatic resection that should be considered in cases of benign or low malignant tumors confined to the dorsal pancreas to preserve the viability of both digestive and biliary tracts, and to avoid the endocrine and metabolic consequences of total pancreatectomy. We report a new case of TDP and provide a literature review of this procedure. METHODS: The case reported was a 35-year-old female patient with a solid pseudopapillary tumor. We resected the dorsal segment of the pancreas while preserving the common bile duct, gastroduodenal artery, and pancreaticoduodenal arcades, and the spleen and splenic vessels. The MEDLINE(r) and Embase(r) databases were searched for English language studies, case series, or case reports published through August 31, 2017. RESULTS: The postoperative course was uneventful and patient was discharged on postoperative day 11. The patient was alive and in good condition at the 10-year follow-up. To date in English literature, there are only 3 reported cases of TDP, and all cases were patients with intraductal papillary mucinous neoplasia and pancreas divisum. There was no postoperative mortality, and 2 grade B pancreatic fistulas healed 1 month postoperatively. CONCLUSIONS: TDP is a feasible and safe operation for benign or low grade malignant pancreatic tumors involving the dorsal pancreas, as an alternative to total pancreatectomy. PMID- 30007968 TI - ZFX Promotes Proliferation and Metastasis of Pancreatic Cancer Cells via the MAPK Pathway. AB - BACKGROUND/AIMS: The role of ZFX in tumourigenesis is unclear. We aimed to study ZFX expression, regulation, and function and the clinical implications of this protein in human pancreatic cancer (PCa). METHODS: One hundred and twenty patients with histologically confirmed PCa who underwent surgery were recruited for this study. Tumour samples and PCa cell lines were used to examine ZFX. Various cell functions related to tumourigenesis were assessed. In vivo mouse tumour xenografts were used to confirm the in vitro results. RESULTS: Patients with ZFX-positive tumours had worse overall survival than patients with ZFX negative tumours. The depletion of ZFX using lentiviral shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in G0/G1 phase and resulted in increased cell apoptosis and invasive repression. In vivo studies confirmed that ZFX promoted tumour growth. Mechanistically, MAPK pathway activation was involved in the oncogenic functions of ZFX. CONCLUSIONS: ZFX acts as a putative oncogene in PCa and could be a novel therapeutic target for this disease. PMID- 30007969 TI - Imatinib Ameliorated Retinal Neovascularization by Suppressing PDGFR-alpha and PDGFR-beta. AB - BACKGROUND/AIMS: Platelet-derived growth factors (PDGFs) have emerged as pivotal in pathological angiogenesis, which is a hallmark of various tumors and retinal diseases. Here we evaluated the anti-angiogenic effect of imatinib, an inhibitor of PDGF receptors alpha and beta (PDGFR-alpha and -beta), in retinal neovascularization using an oxygen-induced retinopathy (OIR) model. METHODS: The OIR model was established and given imatinib or vehicle treatments daily from P12 to P16. At the peak of angiogenesis at P17, the neovascularization area was quantified on retinal whole-mounts with isolectin B4 staining. Immunofluorescence staining and western blots were used to determine the effect of imatinib on different vascular cells and the pathway molecules involved. RESULTS: Imatinib effectively suppressed pathological angiogenesis in OIR mice and reduced the number of all three types of vascular cells, including endothelial cells, pericytes, and smooth muscle cells. Moreover, the expression and activation of PDGFR-alpha and -beta were inhibited by imatinib. The imatinib-treated OIR mice presented with reduced expression of other potent pro-angiogenic factors such as VEGF and FGF2. No obvious retinal or systemic side effects were observed in the imatinib treatment group. CONCLUSIONS: Imatinib appears to be safe and effective in suppressing retinal neovascularization. Targeting PDGFs/PDGFRs may also be important for anti-angiogenic treatment and offer a viable alternative treatment for retinal angiogenic diseases. PMID- 30007970 TI - Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation. AB - BACKGROUND/AIMS: Fibronectin type III domain-containing 5 (FNDC5) protein is involved in the beneficial effects of exercise on metabolism. FNDC5 attenuates hepatic steatosis induced by high fat diet (HFD). Here, we examined the effects of FNDC5 on liver fibrosis and underline mechanisms. METHODS: Experiments were carried out on wild-type and FNDC5-/- mice, primary mouse hepatic stellate cells (HSCs) and human hepatic stellate cell line (LX-2). The mice were fed with HFD for 6 months to induce liver fibrosis. Oxidized low density lipoprotein (oxLDL) were used to induce the activation of hepatic stellate cells and fibrosis in mouse HSCs and human LX-2 cells. H&E, Masson's trichrome staining and Sirius red staining were used for liver sections. Protein and mRNA expressions were evaluated with Western blot and RT-PCR, respectively. RESULTS: FNDC5 deficiency aggravated the HFD-induced liver fibrosis and HSCs activation in mice. It exacerbated the HFD-induced inhibition of AMPK phosphorylation, upregulation of connective tissue growth factor (CTGF) and transforming growth factor-beta (TGF beta), and deposition of extracellular matrix (ECM) in liver of mice. Administration of FNDC5 attenuated oxLDL-induced AMPK deactivation, HSCs activation, CTGF and TGF-beta upregulation and ECM deposition in mouse HSCs. The beneficial effects of FNDC5 on oxLDL-induced AMPK dephosphorylation, HSCs activation and ECM deposition were prevented by the inhibition of AMPK with compound C in human LX-2 cells. However, the effects of FNDC5 on hepatic fibrosis in vivo in this study cannot be distinguished from its effects on adiposity and hepatic steatosis. CONCLUSIONS: FNDC5 deficiency aggravates HFD-induced liver fibrosis in mice. FNDC5 plays beneficial roles in attenuating liver fibrosis via AMPK phosphorylation-mediated inhibition of HSCs activation. PMID- 30007971 TI - Spectrum of Clinical, Neuroimaging, and Cerebrospinal Fluid Features of Adult Neurocutaneous Melanocytosis. AB - BACKGROUND: Neurocutaneous melanocytosis (NCM) is a poorly understood disease due to its rarity. This study aimed to summarize the characteristics of adult NCM and improve the awareness of this disease. METHODS: The clinical data of 13 adult patients with NCM were retrospectively reviewed, including neuroimages, cerebrospinal fluid (CSF), and histological features. RESULTS: There were 9 males and 4 females. The mean age at symptom onset was 36.5 years. The initial symptoms included intracranial hypertension in 8 patients and seizure in 4 patients. Ten patients had large and/or multiple congenital melanocytic nevi. MRI revealed hydrocephalus and diffuse thickening of the leptomeninges with T1 shortening in all patients. Post-contrast T1-weighted images showed diffuse linear enhancement of the leptomeninges. Lumbar punctures showed increased open pressure, and elevated protein levels and decreased glucose concentrations in CSF. Cells with intracytoplasmic coarse black granules were found in the CSF and were positive for S100, HMB45, and vimentin. Histopathology of the cutaneous lesions and meninges showed melanocytes but no evidence of malignant melanoma. CONCLUSION: Adult NCM patients present a diversity of clinical manifestations. Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing NCM. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases. PMID- 30007972 TI - Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia. AB - OBJECTIVE: To evaluate the placental and decidual gene expression and maternal and umbilical serum concentrations of tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, IL-10, IL-1 receptor antagonist (IL-1RA), intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1), along with the proinflammatory/anti-inflammatory cytokine ratios in women with preeclampsia (PE) vs. women with normal pregnancy (NP), and to analyze PE classified as early- (EO) and late-onset (LO). METHODS: This cross-sectional study was performed with 50 women with PE (EO n = 30, LO n = 20) and 50 women with NP. Tissue gene expression levels were measured by real-time RT-PCR. Cytokines and adhesion molecules serum concentrations were measured by immunoassays. RESULTS: In PE, placental expression of IL-10 and IL-1RA was lower, while placental IL-8/IL-1RA ratio and maternal concentrations of VCAM-1 were higher vs. NP. In EO, placental expression of IL-10 was lower, while placental IL-8/IL-10 and IL-8/IL-1RA ratios were higher than LO and NP. Maternal concentrations of IL-6 were higher in LO than EO and NP. Throughout PE, maternal VCAM-1 concentrations were higher vs. NP. No significant differences were observed in the decidual expression and umbilical concentrations of the markers between the groups. CONCLUSION: PE associates with a proinflammatory placental state; however, EO associates with a proinflammatory placental state, while LO associates with systemic maternal inflammation. Both subtypes associated with maternal endothelial dysfunction. PMID- 30007973 TI - Intra-Amniotic Pressure of Twin-to-Twin Transfusion Syndrome. PMID- 30007974 TI - Effect of Exercise on Physical Recovery of People with Locked-In Syndrome after Stroke: What Do We Know from the Current Evidence? A Systematic Review. AB - INTRODUCTION: Locked-in syndrome (LIS) results from a brainstem lesion in the pons. Ischemic stroke is the most common etiology of LIS. People with LIS have poor mobility with serious complications due to immobilization. Benefits of exercise after stroke have been widely reported. However, little is known about what and how much exercise should be prescribed for these patients. OBJECTIVES: To explore and evaluate the effect of exercise on the physical recovery of people with LIS after stroke. METHODS: We searched the following databases (last searched August 2017): EMBASE, MEDLINE, PubMed, CINAHL, AMED, PEDro, Cochrane Central Register of Controlled Trials, REHABDATA, Google Scholar, WANFANG, CNKI, and CQVIP. Handsearching of relevant journals and reference lists was also performed. The Oxford Centre for Evidence-Based Medicine was used to assess the evidence level of the included studies. RESULTS: We identified 5 papers from 207 papers involving 35 cases; 26 cases had various degrees of improvement in physical performance after exercise; 9 cases had no change. Five types of exercises and prescriptions were adopted. Study designs and interventions were heterogeneous. All studies contained mixed rehabilitation interventions. A total of 8 different outcome measurement tools have been reported in the studies. CONCLUSION: Studies indicate a positive trend of effect of exercise for physical recovery of people with LIS after stroke including the improvement of muscle strength, tone, walking ability, and activity in daily living. Mixed physical exercises were used. The effects were not significant. No adverse event has been reported. The quality of the existing evidence is relatively low since the papers were either case series or case studies. Further studies are needed on exercise types and dosages for better prescriptions for people with LIS after stroke. This may help to extend their lives with better control of the complications and to improve their quality of life. PMID- 30007976 TI - Sensitization to Aeroallergens in Patients with Primary Immunodeficiencies. AB - BACKGROUND: Primary immunodeficiencies (PID) are a heterogeneous group of diseases that cause alterations in the immune system, leading to the increased susceptibility to infections, autoimmune diseases, and malignancies. The aim was to evaluate the presence of clinical manifestations and diagnoses of asthma, rhinitis, and atopic dermatitis in patients diagnosed with PID, and correlate these with allergen sensitization verified by skin prick testing (SPT). MATERIAL AND METHODS: This cross-sectional, descriptive, and observational study was conducted from February 2015 to February 2016. We performed a medical report analysis and SPT for aeroallergens in patients with a PID diagnosis. RESULTS: Thirty-one patients with a PID diagnosis were included. The mean age of the participants was 15.41 years. From the 31 patients, 28 had symptoms suggestive of allergic disease (asthma, rhinitis, and atopic dermatitis) and only 7 presented positive SPT for at least 1 aeroallergen. CONCLUSION: The frequency of allergenic sensitization in the group of patients with PID and symptoms suggestive of asthma, rhinitis, or atopic dermatitis is lower than that found in the general population, probably due the impairment of IgE formation secondary to their immunologic alterations. PMID- 30007975 TI - Identification of a Panel of MiRNAs as Positive Regulators of Insulin Release in Pancreatic Beta-Cells. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) are a novel class of small RNAs that participate in a variety of biological processes. Although miRNAs have been linked to insulin synthesis and glucose homeostasis, their role in the targeting of mitochondrial uncoupling protein 2 (UCP2), a negative modulator of insulin secretion, remains unclear. METHODS: miRNA levels were determined by real-time quantitative PCR analysis using TaqMan probes, and insulin secretion from isolated islets was quantified by ELISA. Effects of miRNAs on UCP2 expression were checked with a luciferase assay and western blotting analysis. RESULTS: An overall change in a set of miRNAs was discovered, with miR-15a, miR-424, miR-497, and miR-185 coinciding with insulin levels in islets maintained under high glucose conditions. Moreover, experiments in MIN6 cells illustrated that miR-15a, miR-424, miR-497, and miR-185 positively regulated insulin biosynthesis by co inhibiting UCP2 expression. Furthermore, the four miRNAs were found to post transcriptionally repress UCP2 expression by directly targeting the 3'UTR of UCP2 mRNA. CONCLUSIONS: Thus, our results shed further light on the regulatory network in beta-cells consisting of miRNAs, UCP2, and insulin and provide novel therapeutic targets for diabetes. PMID- 30007977 TI - Organization of the Orexin/Hypocretin System in the Brain of Holostean Fishes: Assessment of Possible Relationships with Monoamines and Neuropeptide Y. AB - Holosteans form a small group of actinopterygian fishes considered the sister group of teleosts. Despite this proximity to the biggest group of vertebrates, relatively few studies have been conducted to investigate the organization of the central nervous system of this group of fishes. In this study, the neuroanatomical distribution of orexin/hypocretin-like immunoreactive (OX-ir) cell bodies and fibers was analyzed in the brain of 3 representative species of the 2 orders of extant holosteans, the spotted gar Lepisosteus oculatus, the Florida gar Lepisosteus platyrhincus, and the bowfin Amia calva. Antibodies against orexin-A (OXA) and orexin-B (OXB) were used, which labeled the same cells and fibers throughout the brain. In addition, double immunohistofluorescence was performed for the simultaneous detection of OXA and OXB with tyrosine hydroxylase, serotonin, and neuropeptide Y (NPY), in an attempt to localize the orexinergic structures precisely and study the possible interactions between these neuroactive substances. The pattern of distribution of OX-ir cells in the 3 species was largely similar, showing labeled cells in the preoptic area (POA), and the tuberal and retrotuberal hypothalamic regions, with only subtle differences between species in the density of labeled cells. OX-ir fibers were found in all main brain subdivisions of the 3 species, mostly in the ventral subpallial areas, POA, hypothalamus, posterior tubercle, thalamus, and mesencephalic tectum. Different densities of orexinergic fibers were observed in relation to catecholaminergic and serotoninergic cell groups, as well as an absence of colocalization between orexins and NPY in the same hypothalamic neurons. The comparison of these results with those obtained in other vertebrates highlights a constant pattern of distribution of this system of neurotransmission among different groups of actinopterygian fishes, especially in teleosts. Conserved features shared by all vertebrates studied were also observed, such as the presence of OX-ir cells in the basal hypothalamus, reflecting the preserved functions of these neuropeptides over the course of evolution. PMID- 30007978 TI - Cupping Therapy for Knee Osteoarthritis: A Synthesis of Evidence. AB - BACKGROUND: This systematic review was aimed to evaluate the efficacy and safety of cupping therapy for treating patients with knee osteoarthritis (KOA). METHODS: The following databases were searched from their inception until June 2017: the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and 4 Chinese databases (Wan Fang Data, Chinese Biomedical Literature Database (CBM), VeiPu, and China National Knowledge Infrastructure (CNKI)). Randomized controlled trials (RCTs) assessing the effects of cupping therapy on KOA were included in this systematic review. A quantitative synthesis of the RCTs was conducted using RevMan 5.3 software. Study selection and data extraction and validation were performed independently by 2 reviewers. Cochrane criteria for risk of bias were used to assess the methodological quality of the trials. RESULTS: A total of 5 studies met our inclusion criteria. We analyzed the data from these 5 RCTs involving 535 participants. All included studies were judged to be at high risk for bias. Dry cupping therapy plus Western medicine therapy was more effective than Western therapy alone in reducing the pain scores (mean difference (MD) = 1.79, 95% confidence interval (CI) -2.40 to -1.18; p < 0.01). In addition, the study participants in the dry cupping therapy plus Western medicine therapy group showed significantly greater improvements in the pain (MD = -0.73, 95% CI -1.61 to -0.41; p < 0.01), stiffness (MD = -0.94, 95% CI -1.30 to -0.58; p < 0.01), and physical function (MD = -10.07, 95% CI -13.45 to -6.69; p < 0.01) domains of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) compared to participants in the Western medicine therapy group. Moreover, when compared with Western medicine therapy alone, a meta-analysis of 4 RCTs suggested statistically significant favorable effects of wet cupping therapy plus Western medicine on the Lequesne Algofunctional Index (LAI) (MD = -3.44, 95% CI -4.21 to 2.68; p < 0.01). CONCLUSION: There is weak evidence to support the hypothesis that cupping therapy has beneficial effects on reducing the pain intensity and improving the physical function in patients with KOA. PMID- 30007979 TI - High-Risk Types of Human Papilloma Virus DNA Testing in Women with False Negative Cytology. AB - OBJECTIVE: To determine whether high-risk types of human papilloma virus (hrHPV) DNA testing is reliable for selection patients in need of further investigation with colposcopy in women with increased risk of high-grade cervical lesions as a result of false negative cytology. The secondary objective was to compare the sensitivity of hrHPV testing on self-collected versus physician-collected samples for the detection of histological high-grade cervical intraepithelial neoplasia (CIN2+). METHODS: Sixty-three patients identified with a missed abnormality following the re-evaluation of benign cervical cytology were included. A patient collected and a physician-collected sample for HPV, colposcopy and cervical specimen collection for histology and cytology were performed. RESULTS: The sensitivity of hrHPV testing of physician-collected samples for CIN2+ was 100% (95% CI 82.7-100), and the negative predictive value (NPV) was 100% (95% CI 93.3 100). The sensitivity of the self-sampling device to identify CIN2+ was 84.6% (95% CI 59.1-96.7), and the NPV was 94.4% (95% CI 83.4-98.8). The differences in the sensitivity and NPV between the 2 methods were non-significant. The agreement between the 2 methods regarding the HPV results was good, with a kappa value of 0.74 (95% CI 0.57-0.91). CONCLUSION: The current findings indicate that physician collected samples for hrHPV DNA testing may be used as triage for the colposcopy of women with false negative cytology. PMID- 30007981 TI - Psychometric Properties of a Modified KINDL-R Questionnaire for Adolescents and Adults, and Construction of a Brief Version, the KINDL-A(dult)B(rief) Questionnaire, KINDL-AB. AB - BACKGROUND/AIMS: The generic quality of life KINDL-R -questionnaire is validated for use in children/adolescents <=16 years. The aim of this cross-sectional investigation was to modify the KINDL-R questionnaire for use in adults and to validate its psychometric properties. METHODS: Five items of the KINDL-R questionnaire were adapted and the newly developed KINDL-A(dult) questionnaire administered to 255 patients with hereditary and acquired bleeding disorders (mean age 53 years). Its internal consistency and convergent and divergent construct validity were investigated and confirmatory factor analysis was used to evaluate the latent factor structure. RESULTS: The KINDL-A questionnaire showed satisfactory reliability, varying construct validity, but inconclusive factor structure. The KINDL-AB(rief) was developed by removing half of the items and combining 2 sub-axes. This led to factor loadings between 0.62 and 0.91 and increased overall fit (Goodness of fit > 0.8 and Root Mean Square Error of Approximation, RMSEA, < 0.08). Results were validated in 966 healthy blood donors (mean age 38 years). In this group, the KINDL-AB questionnaire showed factor loadings between 0.43 and 0.77, Goodness of fit > 0.95 and RMSEA < 0.05. CONCLUSIONS: The new KINDL-AB suggests sufficient to good psychometric properties in adult patients with hereditary and acquired bleeding disorders. PMID- 30007980 TI - Is Perfusion MRI without Deconvolution Reliable for Mismatch Detection in Acute Stroke? Validation with 15O-Positron Emission Tomography. AB - BACKGROUND: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions. METHODS: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the -upper PF threshold as defined by PET cerebral blood flow <20 mL/100 g/min. RESULTS: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85-0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84-0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87-0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET. CONCLUSIONS: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e.g., Tmax) to guide treatment decisions in acute stroke. PMID- 30007982 TI - Predictive Value of LINC01133 for Unfavorable Prognosis was Impacted by Alcohol in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND/AIMS: Considerable evidence indicates that long noncoding RNAs (lncRNAs) exert importantly regulatory functions during human cancer initiation and progression and are promising biotargets in the flight against cancer. METHODS: In this study, we evaluated the role of the lncRNA LINC01133 in esophageal squamous cell carcinoma (ESCC). LINC01133 expression in ESCC was examined by quantitative real-time PCR. The correlations between LINC01133 expression and clinicopathological variables and survival were examined by the chi2 test, Kaplan-Meier method, log-rank test, and univariate Cox regression analysis. RESULTS: LINC01133 expression levels were frequently lower in ESCC tissues and cell lines than in paired normal tissues and an immortalized esophageal epithelial cell line, respectively. The expression of LINC01133 decreased in a TNM stage- and lifestyle-independent manner. LINC01133 was an independent protective factor and had an anti-tumor effect in the early stage of ESCC development. More importantly, we discovered that drinking status in our cohort impaired the predictive accuracy of LINC01133 for patients with ESCC. Furthermore, a new risk model combining LINC01133 expression, drinking status, and TNM stage provided better survival discrimination compared with three other predictors. CONCLUSIONS: Our data indicate that a loss of LINC01133 expression is a potential poor prognostic biomarker and therapeutic target for ESCC and provide additional prognostic information to improve the outcomes of ESCC patients. PMID- 30007983 TI - Home-Based Care Evolution in Chronic Respiratory Failure between 2001 and 2015 (Antadir Federation Observatory). AB - BACKGROUND: The aetiologies of chronic respiratory failure (CRF) are moving in many western countries. Obesity-Hypoventilation syndrome (OHS) has become one of the most common indications of non-invasive ventilation (NIV) with Chronic Obstructive Pulmonary Diseases (COPD). Long-Term Oxygen Therapy (LTOT) technology is the treatment plan for CRF patients in the new era. OBJECTIVES: This study aimed to assess home-based care evolution in CRF patients on LTOT (LTOT) and/or NIV from the ANTADIR observatory. METHODS: A computerized database from 14 regional facilities was analysed (30% of French home-treated patients). Patient age, sex, aetiology, home respiratory devices were recorded between 2001 and 2015. RESULTS: By the end of 2015, 12,147 CRF patients received LTOT (40%), NIV (24%), LTOT + NIV (23%), continuous positive airway pressure (CPAP; 11%) or LTOT + CPAP (3%). Between 2001 and 2015, we observed a decrease of LTOT (63-40%) in the benefit of NVI +/- LTOT (25-47%). Regarding the aetiology, we note a slight decrease in obstructive disease and a significant increase in restrictive disease, mainly due to OHS. The 10-year survival was better on NIV +/- LTOT than on LTOT, for overall patients and for both obstructive and restrictive patients. The 10-year survival was better on NIV +/- LTOT than on LTOT (35 vs. 10%, p < 0.05). In COPD patients on LTOT, a switch from conventional to new home devices was observed. Stationary LTOT systems were less prescribed, while portable/transportable -system, liquid oxygen and self-filling oxygen were increasingly prescribed. CONCLUSION: Our study confirmed changes in CRF aetiologies and home devices. OHS is now an important indication of NIV. Using new LTOT technologies changed home prescriptions in COPD patients. PMID- 30007984 TI - Sorafenib for Advanced Hepatocellular Carcinoma: A Real-Life Experience. AB - INTRODUCTION: Sorafenib (SOR) has proved to be effective in patients with advanced hepatocellular carcinoma (HCC), since overall survival was higher in phase III clinical trials; however, disease progression can occur. OBJECTIVES: The study aimed to describe real-life experience in advanced HCC treatment with SOR at a university hospital in Brazil and to estimate the number of patients with indication of second-line therapy. METHODS: This is a retrospective study that included cases of HCC with prescription of SOR based on real-life practice between 2011 and 2016. Demographic, clinical, and laboratory data were collected. RESULTS: From 572 patients with HCC, SOR was prescribed in 103 cases. From them, 62.1% were classified as Child-Pugh (CP)-A, 54.4% as Barcelona Clinic Liver Cancer (BCLC)-C, and 74 (71.8%) started treatment. Overall survival was 25.5 (95% CI 17.0-34.1) months and 1-year survival was greater in patients who received SOR than in non-treated (88.7 vs. 44.4%, p < 0.001). There was no difference in survival between BCLC-B and C (p = 0.405), as well as CP-A and B (p = 0.919). In 21.6% of the patients, a second-line therapy with regorafenib was indicated. CONCLUSION: In this real-life study, SOR significantly increased the survival rate by 1 year in patients with advanced HCC regardless of BCLC staging and CP score. Second-line therapy would be indicated in 21.6% of cases. PMID- 30007985 TI - A Comprehensive Diagnostic Algorithm for Direct Antiglobulin Test-Negative Autoimmune Hemolytic Anemia Reveals the Relative Ratio of Three Mechanisms in a Single Laboratory. AB - BACKGROUND: Direct antiglobulin test (DAT)-negative warm autoimmune hemolytic anemia (AIHA) is mainly caused by three mechanisms: red blood cell (RBC)-bound immunoglobulin (Ig)G below the detection limit of routine DAT; RBC-bound IgA or IgM; or low-affinity autoantibodies. Although most cases of DAT-negative AIHA are thought to be caused by RBC-bound IgG, and combinatory serological analyses are recommended, the relative ratios of each mechanism have not been clarified. METHODS: Two groups of patients with undiagnosed hemolytic anemia and negative conventional tube method-DAT (TM-DAT) were investigated using anti-IgA and anti IgM sera, or column agglutination method-DAT (CM-DAT), respectively, in addition to radioimmunological quantitation of RBC-bound IgG. RESULTS: Three of 73 patients with DAT-negative AIHA showed positive RBC-bound IgA and normal amounts of RBC-bound IgG. Another group of 3 patients were RBC-bound IgM-positive, but only one of these showed normal amounts of RBC-bound IgG. In another group of patients with DAT-negative AIHA, 4 of the 20 showed positive CM-DAT and negative CM-DAT after washing RBCs. Three of these patients had normal amounts of RBC bound IgG. Five patients with positive CM-DAT both before and after washing RBCs had high amounts of RBC-bound IgG. CONCLUSION: Relative ratios of patients with DAT-negative AIHA resulting from RBC-bound IgG, RBC-bound IgA, RBC-bound IgM, and low-affinity IgG were estimated as 80, 4, 1 and 15%, respectively. A new classification and diagnostic algorithm for DAT-negative AIHA were proposed. PMID- 30007986 TI - CircRNA8924 Promotes Cervical Cancer Cell Proliferation, Migration and Invasion by Competitively Binding to MiR-518d-5p /519-5p Family and Modulating the Expression of CBX8. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) play a significant role in the development and progression of various human cancers. However, the expression and function of circRNAs in cervical cancer (CC) have rarely been explored. The aim of this study was to investigate the biological function of circRNA8924 in CC and elucidate the possible molecular mechanism involved. METHODS: Quantitative polymerase chain reaction was used to determine mRNA expression of circRNA8924, miR-518d-5p/519-5p and CBX8 in CC tissues and cells. CBX8 protein expression was measured by Western blotting. The CCK-8 assay was used to evaluate cell proliferation, and the transwell assay to determine cell migration and invasion. The luciferase reporter assay was used to determine the direct regulation of miR 518d-5p/519-5p and circRNA8924 or CBX8 Results: The study demonstrated that the expression level of circRNA8924 in CC was significantly higher than that in the adjacent normal tissues (P < 0.001), and that it was also associated with tumor size, FIGO staging and myometrial invasion. The knockdown of circRNA8924 significantly inhibited the proliferation, migration and invasion of CC cells SiHa and HeLa. The expression level of miR-518d-5p/519-5p was negatively correlated with circRNA8924, and circRNA8924 regulated CBX8 by competitively binding to miR-518d-5p/519-5p. CONCLUSIONS: CircRNA8924 is highly expressed in CC tissue and can be considered a competitive endogenous RNA of the miR-518d-5p/519 5p family to promote the malignant biological behavior of CC cells. It is suggested that it may serve as a new biomarker for CC diagnosis and disease progression and provide potential targets for targeted therapy. PMID- 30007988 TI - Direct Antiglobulin Test-Negative Autoimmune Hemolytic Anemia. PMID- 30007987 TI - Metformin in Idiopathic Pulmonary Fibrosis "Seeking the Holy-Grail through Drug Repositioning". PMID- 30007989 TI - Clinical and Cytogenetic Study of Egyptian Patients with Sex Chromosome Disorders of Sex Development. AB - Disorders of sex development (DSD) are conditions with an abnormal development of chromosomal, gonadal, or anatomical sex. Sex chromosome DSD involve conditions associated with either numerical or structural abnormalities of the sex chromosomes. This study included patients comprising a wide spectrum of presenting features suggestive of DSD and aimed at studying the frequency of sex chromosome abnormalities among 108 Egyptian DSD patients who presented to the Clinical Genetics and Endocrinology Clinics, National Research Centre (NRC) over the 2-year period of 2013 and 2014. The age of the studied patients ranged from 2 months to 39 years. The patients exhibited various presentations, including ambiguous genitalia, undescended testis, hypogonadism, short stature with Turner manifestations, primary or secondary amenorrhea, primary infertility, edema of the dorsum of the hands and feet, and dysmorphic features. The patients were subjected to detailed clinical examination, pubertal staging, and cytogenetic analysis. Our study reported a wide karyotypic diversity and a high frequency of sex chromosome DSD, reaching 44.44% (48/108). In conclusion, we showed a high incidence of sex chromosome DSD among Egyptian DSD patients with wide karyotype/phenotype diversity. The most frequent sex chromosome DSD detected among patients of the present study was Turner syndrome and variants (52.08%; 25/48) followed by Klinefelter syndrome and variants (43.75%; 21/48). Further long term studies are necessary for accurate detection of frequencies of different types of sex chromosomal anomalies and associated phenotypes. PMID- 30007990 TI - Intra-Operative Frozen Section Histology of the Pancreatic Resection Margins and Clinical Outcome of Patients with Adenocarcinoma of the Head of the Pancreas Undergoing Pancreaticoduodenectomy. AB - BACKGROUND The aim of this study was to compare the clinical outcome in patients with pancreatic ductal adenocarcinoma who underwent frozen section and paraffin section histology of the surgical resection margins during pancreaticoduodenectomy. MATERIAL AND METHODS Frozen section and routine paraffin section histopathology were performed using the following categories: R0 (no tumor cells at the surgical resection margin), R1 (tumor cells at, or within 1 mm, of the surgical resection margin), and R2 (tumor seen macroscopically at the surgical resection margin). R1 and R2 patients underwent additional resection to achieve R0. RESULTS Of 346 patients who underwent pancreaticoduodenectomy, frozen section histology showed positive resection margins in 22 patients (9.2%) and paraffin section histology was positive in 20 patients (8.4%). The OS was nine months in frozen section-positive patients and 20 months in frozen section negative patients (p=0.001). The OS rates were significantly different between the paraffin section-positive and paraffin section-negative patients (11 months vs. 21 months) (p=0.001). Univariate and multivariate analysis showed that increased tumor size, high tumor grade, lymph node metastases, a positive superior mesenteric artery and retroperitoneal margin, and a positive resection margin on frozen section were significantly correlated with reduced OS (p<0.05). Twenty-two patients with positive resection margins on frozen section histology underwent further resection; R0 was achieved in 14 patients, with no significant difference in OS. CONCLUSIONS For patients who underwent pancreaticoduodenectomy for pancreatic carcinoma with positive resection margins on frozen section, further surgical resection to achieve R0 had no significant positive impact on OS. PMID- 30007991 TI - Investigation of miR-490-3p Expression in Hepatocellular Carcinoma Based on Reverse Transcription-Polymerase Chain Reaction (RT-qPCR) and a Meta-Analysis of 749 Cases. AB - BACKGROUND miR-490-3p could play vital roles in multiple cancers. However, the role of miR-490-3p in hepatocellular carcinoma (HCC) remains uncertain. In this study, we sought to explore the underlying role of miR-490-3p in HCC. MATERIAL AND METHODS In this study, we explored the clinical role of miR-490-3p in HCC via quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and The Cancer Genome Atlas (TCGA) database. Then, a meta-analysis was performed to evaluate the expression trend and diagnostic value of miR-490-3p in HCC. Furthermore, 12 miRNA prediction algorithms were applied to predict the potential target genes of miR-490-3p. The differentially expressed genes in HCC in the Gene Expression Profiling Interactive Analysis (GEPIA) database were also selected. Additionally, bioinformatics analyses were utilized to investigate the possible functions and pathways of the target genes. RESULTS miR-490-3p was clearly down regulated in HCC based on RT-qPCR (P=0.002). Consistent with the results of RT qPCR, miR-490 was more highly expressed in normal liver tissue than in HCC (P<0.001). Additionally, the meta-analysis confirmed the results from RT-qPCR and TCGA. Furthermore, based on the prediction algorithms and GEPIA, a total of 113 genes were selected. According to the bioinformatics analyses, we found that the most remarkably enriched functional terms included protein transport, poly(A) RNA binding, and intracellular organelle part. Additionally, the miR-490-3p target genes were significantly related to the pathways in cancer. CONCLUSIONS We found that miR-490-3p is down-regulated in HCC and is related to genes that have potential tumoral functions. However, the exact mechanism should be confirmed by functional experiments. PMID- 30007993 TI - Epilepsy in pregnancy. A comprehensive literature review and suggestions for saudi practitioners. AB - In the context of local culture and misconceptions regarding epilepsy, Saudi practitioners need a careful management plan for women with epilepsy that satisfies all the patients' needs and ensures their spouses' understanding. Such a management strategy needs to incorporate careful selection and monitoring of anti-epileptic drugs and regular counseling of patients. Female epileptic patients in the reproductive age group, no matter whether they are pregnant or not, should be managed by safest drugs from the earliest with folic acid supplementation along with adequate pre-marriage/conception counseling. All antiepileptic drugs are potentially teratogenic. However, valproic acid, phenytoin, phenobarbitone, and topiramate are least favored for use. Monotherapy is preferred over polytherapy, and the least possible dose should be used. During pregnancy, many epileptic women may need monthly drug level monitoring and dose readjustments. Normal vaginal delivery is safe in epileptic women. Post-partum follow-up with anti-epileptic drug titration may be required. PMID- 30007994 TI - Abnormal admission kidney function predicts higher mortality in stroke patients. AB - OBJECTIVE: To investigate the impact of abnormal kidney function on stroke outcome. METHODS: This was a retrospective cohort of stroke patients admitted to King Abdulaziz University Hospital in Kingdom of Saudi Arabia between 2010 and 2014. Serum creatinine and urine protein were collected at admis-sion. We defined proteinuria as urine protein dipstick >/=+1. Estimated glomerular filtration (eGFR) rate was calculated by Modification of Diet in Renal Disease Study equation in mL/min/1.73m2. Abnormal kidney disease was defined as Creatinine>126 mg/dl or eGFR<60. Clinical characteristics and outcomes including one-year mortality and 30-day readmission were compared between patients with versus (vs.) without abnormal kidney function and/or proteinuria. RESULTS: Out of 548 patients, 507 had creatinine measurement at admission and 193 patients had ab normal kidney function. These patients tended to be older (median age 67 years vs. 60.5 for those with normal kidney function), men (66.7% vs. 54.3%), and hypertensive (96% vs. 88%). Diabetes prevalence did not differ between the 2 groups. Proteinuria was not associ-ated with future mortality. Abnormal kidney function was a significant predictor of post-stroke one-year mortality (adjusted OR=2.5, 95% CI=1.4 to 4.6; p-value=0.003). CONCLUSION: Abnormal kidney function doubled the risk of one-year mortality post stroke in our cohort. High-risk groups, including older hypertensive men, could be targeted for aggressive moni toring and early treatment of risk factors. PMID- 30007992 TI - miR-145-5p Inhibits Vascular Smooth Muscle Cells (VSMCs) Proliferation and Migration by Dysregulating the Transforming Growth Factor-b Signaling Cascade. AB - BACKGROUND There is accumulating evidence demonstrating that microRNAs (miRNA) play essential roles in proliferation, migration, and invasion of vascular smooth muscle cells (VSMCs). However, the exact function of these molecules and the mechanisms involved are not fully understood. In this study, we defined the role of miR-145-5p in VSMCs. MATERIAL AND METHODS This study used the PDGF-bb-induced VSMCs proliferation model. Expression of miR-145-5p and its target, Smad4, were detected and measured by real-time PCR and Western blot analysis. The luciferase reporter of miR-145-5p was used to elucidate miRNA-target interactions. The functions of miR-145-5p in proliferation and migration were detected by CCK-8 assay, Transwell assay, and scratch test. RESULTS This study demonstrates that miR-145-5p is downregulated in PDGF-mediated VSMCs in both time- and dose dependent manners. The in vitro results suggest that overexpression of miR-145-5p results in a reduction in SMAD4 and an increase in SMAD2, Smad3, and TGF-beta at the mRNA and protein levels. Overexpression of miR-145-5p inhibited PDGF-induced VSMCs proliferation and migration. Moreover, SMAD4 was identified as a direct target of miR-145-5p and is involved in PDGF-mediated VSMC proliferation. Downstream factors such as Smad2, Smad3, and TGF-beta were also influenced by miR 145-5p. CONCLUSIONS We identify miR-145-5p as a novel regulator of VSMC. Moreover, miR-145-5p inhibits VSMCs proliferation and migration by directly targeting Smad4 and dysregulating the transforming growth factor-beta signaling cascade, including Smad2, Smad3, and TGF-beta. PMID- 30007995 TI - Tolerability and discontinuation rates in teriflunomide-treated patients. A real world clinical experience. AB - OBJECTIVE: To assess the real-world tolerability of teriflunomide in multiple sclerosis (MS) patients from a large Canadian MS Centre of Care to determine whether previously treated (PT) patients have different tolerability thresholds than treatment-naive (TN) patients, leading to differing discontinuation rates. METHODS: This non-interventional, single-center, retrospective chart review examined all patients who were prescribed commercial teriflunomide between July 2014 and May 2015 at the MS Clinic in the Ottawa General Hospital and Research Institute, Ottawa, Canada. RESULTS: A total of 119 patient charts were reviewed (29 TN and 90 PT). Overall, 19 (15.9%) patients discontinued teriflunomide after a mean treatment duration of 35 weeks. The most common reason for discontinuation was side effects in 8 patients (42%).Discontinuation due to intolerability alone occurred in 13 patients. The number of discontinuations was not sufficient to demonstrate a statistically significant difference between TN and PT patients (p=0.1). CONCLUSION: This retrospective chart review provides some evidence about the real-world tolerability of teriflunomide. Discontinuations were low overall and consistent with previously reported clinical trial data. There was no significant difference in discontinuation rates between patients in the TN and PT groups. We believe that teriflunomide is a safe and well-tolerated oral alternative to injectable therapies. PMID- 30007996 TI - Sensorimotor integration training in Parkinson's disease. AB - OBJECTIVE: To determine the effects of sensorimotor integration training on postural control in Parkinson's disease. METHODS: This prospective, randomized controlled trial was conducted at Hacettepe University (Ankara, Turkey). The study was carried out from August 2012 until March 2015 and included 24 Parkinson's patients with stage 2-3 according to the Modified Hoehn&Yahr Rating Scale. The patients were divided into 2 groups (control and study). The control group received conventional physiotherapy; the study group received sensorimotor integration training combined with conventional physiotherapy, 2 times per week for 6 weeks. We assessed the patients with clinical balance tests and computerized dynamic posturography. Assessments were performed at baseline, 7- and 12-weeks follow-up. RESULTS: Computerized dynamic posturography posturography values (5th and 6th positions, composite balance, and vestibular system scores) were higher in the study group than in the control group. The improvements were maintained at the 12-week follow up except 6th positions scores (p<0.05). CONCLUSION: Sensorimotor integration training combined with conventional physiotherapy approach ameliorated postural control by improving vestibular system in patients with Parkinson's disease by improving sensory processes. PMID- 30007997 TI - Personal, family and societal educational needs assessment of individuals with spinal cord injury in Iran. AB - OBJECTIVE: To explore individuals' perception of the personal, family and societal educational needs following a spinal cord injury (SCI). METHODS: Sixty one patients who sustained a traumatic SCI between March 2015 and June 2016 referred to Brain and Spinal Cord Injury Research Center (BASIR) were included in a cross sectional study and completed an online survey containing open-and closed ended questions, in Iran. Participants' responses were analyzed using a qualitative approach with a thematic analysis. RESULTS: Following a thematic analysis of the patient's perceived educational needs, 3 themes and 14 subthemes were identified. The 3 themes included personal, family, and societal educational perceived needs. Within personal educational needs, there were 7 subthemes which included personal independence and transportation, financial independence, life skills modification, knowledge about SCI, prevention of SCI complications, relationships and sexual function, and psychological adjustments. Among family educational needs, the 3 subthemes were caregiver skills and communication, first aid and emergency skills, and emotional and psychological support. For societal educational needs, the 4 subthemes described were social integration, interpersonal communication skills, SCI awareness and injury prevention, sympathize while avoiding pity. CONCLUSION: According to our findings, people with SCI have various needs that need to be addressed. Educational support should be a part of a comprehensive rehabilitation program and geared towards addressing the patients' personal and family needs, while educating the community about SCI in order to allow for reintegration into society. PMID- 30007998 TI - Epidemiological study of epilepsy from a tertiary care hospital in kingdom of Saudi Arabia. AB - OBJECTIVE: To identify the types of seizures and describe the clinical features, EEG and radiological findings among patients with epilepsy. METHODS: In this retrospective epidemiological study, we analyzed the medical records of the patients with the diagnosis of epilepsy during the study period (January 1st 2016 December 2016) RESULTS: The study included 184 patients, 91 (49.5%) were males and 93 (50.5%) females. Age ranged between 12 and 85 years (mean 35.4+/-19.5 SD years). Most of the patients 150 (82%) had Generalized tonic clonic seizures followed by focal onset in 27 (14%) of the patients. Main EEG abnormality was focal to bilateral was recorded in 53 (41%), idiopathic/ cryptogenic epilepsy was diagnosed in 61% of the patients. The most common abnormalities on brain imaging were temporal/hippocampal atrophy/stroke. The most common cause of symptomatic epilepsy was stroke found in 20(11%) followed by post infectious epilepsy and head trauma. CONCLUSION: Seizure types, EEG characteristics and etiologies of symptomatic epilepsy in our cohort of patients are in accordance with the current literature. Slight discrepancy observed in gender distribution and etiologies for symptomatic epilepsy compared with other studies from Saudi Arabia need to be studied further by prospective and population base studies. PMID- 30008000 TI - Prevalence of mental disorders among patients attending primary health care centers in the capital of Saudi Arabia. AB - OBJECTIVE: To assess the prevalence of common mental disorders at primary health care (PHC) centers in Saudi Arabia using the Self-Reporting Questionnaire. METHODS: This was a cross-sectional study carried out at a single PHC center in Riyadh city, Kingdom of Saudi Arabia. A self-medication questionnaire was utilized to collect the data. The prevalence of mental disorders has assessed by the Self-Reporting Questionnaire that consists of 20 items with binary answers (Yes/No). RESULTS: This study reports that the prevalence of mental disorders among patients attended primary health care center was 28.5%. Moreover, prevalence did not significant differ by sociodemographic (p>0.05). CONCLUSION: The prevalence of mental disorders was slight high. The rates of untreated mental disorders necessitate the healthcare makers in Kingdom of Saudi Arabia to implement efficient strategies to halt the progression of untreated mental disorders. PMID- 30007999 TI - Public awareness of central nervous system tumors in the Kingdom of Saudi Arabia. AB - OBJECTIVE: To investigate individuals' knowledge about central nervous system tumors (CNST) signs and symptoms and risk factors, as well as their readiness to seek medical advice. The signs and symptoms associated with CNSTs are often vague, and failure to recognize them could lead to delays in seeking help and possibly fatal results. METHODS: This was a cross-sectional survey that utilized 2 delivery methods. A total of 1,500 personally delivered and 1,500 online self administered questionnaires were completed in parallel between June 2015 and June 2016 for the occupants of the Kingdom of Saudi Arabia. RESULTS: Significant differences were observed for the sociodemographic characteristics of participants recruited via the 2 methods. The most recognized symptom was "Headaches" (45.2%), and the most recognized risk factor was "Radioactive location/occupation" (84.1%). Overall knowledge scores were low, significantly predicted by employment and cancer contact (p<0.05), while the scores significantly higher for participants who were willing to see their doctors within a week (p<0.005). The most recognized barrier to seeking help was "Worry about what the doctor might find" (74.0%). CONCLUSION: The level of awareness of CNSTs was low. Using a questionnaire delivered in 2 different ways enabled the recruitment of sample pools with different sociodemographic characteristics. PMID- 30008001 TI - Epilepsy monitoring units in Saudi Arabia: Where do we stand compared to developed countries? AB - OBJECTIVE: To descriptively assess Epilepsy Monitoring Units (EMUs) and the provided services in Saudi Arabia and compare them based on the geographic region. METHODS: In this cross-sectional study, an electronic questionnaire was emailed to all directors of EMUs in Saudi Arabia from July 2013 to January 2016, with constant updates being made by all respondents throughout the period of data collection. RESULTS: All EMU directors participated. There were 11 EMUs in KSA operating in 8 hospitals; 8 (54.5%) EMUs in Riyadh, 2 (18.2%) in Dammam, 2 (18.2%) in Makkah and 1 (9.1%) in Jeddah. Five (54.5%) EMUs were shared for adults and pediatrics, 3 (27.3%) were devoted to adult patients, and 3 (27.3%) to pediatric patients. The average waiting time was 11 weeks (range: 2-52 weeks). The mean percentage of patients coming from an outside region was 30.6%. The average length of stay was 7 days. Less than 100 patients were monitored annually in 54.5% of the EMUs. Seven EMUs (63.6%) admitted less than 100 patients for seizure characterization. Intracranial monitoring was available in all EMUs. Most EMUs (54.5%) admitted less than 100 patients for pre-surgical workup while 36.4% admitted 100-199, and 9.1% admitted more than 300 patients per year. Epilepsy surgeries were performed for less than 50 patients annually in 81.8% of the hospitals. CONCLUSION: There are 11 EMUs in Saudi Arabia fully equipped to serve epileptic patients. However, they are underutilized considering the number of admitted patient and the number of epilepsy surgeries per year. Also, they are unequally distributed throughout the kingdom. PMID- 30008002 TI - Salmonella brain abscess in an infant. AB - Brain abscess is a potentially life-threatening condition requiring rapid diagnosis and prompt medical and surgical intervention. Various etiological agents associated with different epidemiological backgrounds are implicated, including Gram-positive and Gram- negative bacterial agents as well as anaerobes. Salmonella is rarely reported to be the cause of this medical condition despite being known to cause invasive infections at extremes of age and the fact that this organism is a common cause of other clinical infectious diseases encountered in immunocompromised and immunocompetent individuals. A case of Salmonella brain abscess involving the right posterior parietal region of the brain is described in a 6-month-old infant. The clinical, microbiological, and radiological features, as well as the clinical management and outcome, are presented. This case highlights the slow-progression nature of brain abscess caused by Salmonella species and the challenge in achieving optimal resolution despite initial surgical intervention. PMID- 30008003 TI - An unusual presentation of Dyke-Davidoff Masson syndrome. AB - Dyke Davidoff- Masson syndrome is a rare disorder of hemiatrophy of the cerebral hemisphere and clinically manifests as hemiparesis, seizures disorder, mental retardation and facial asymmetry and has various perinatal or post natal etiologies and has characteristic radiological appearance on brain imaging. It is important to recognize the clinical and radiological features of this condition for the neurologists as well as the radiologists. We are discussing our case as this patient presented very late although his symptoms seem to present since his birth which is very unusual with this disorder. PMID- 30008004 TI - Post-partum headache caused by dual pathology: A message to the anesthetist. PMID- 30008005 TI - The role of neuronavigation and intraoperative ultrasonography in distal middle cerebral artery aneurysm. PMID- 30008006 TI - Treatment of infantile spasms in Saudi Arabia. AB - OBJECTIVE: To evaluate the treatment approach and compliance of pediatric neurologists with evidence-based guidelines across Kingdom of Saudi Arabia (KSA). These guidelines that clarify the optimal management of infantile spasms (IS) are not widely followed for various practical reasons. METHODS: Physicians practicing in the field of pediatric neurology in KSA were contacted from the database of national societies. A cross-sectional study was conducted using a structured 20 item on-line survey designed to examine their clinical experience with IS and their treatment choices. RESULTS: A total of 52 pediatric neurologists completed the survey (69% estimated capture rate). They received their formal training within KSA (40%), North America (33%), or Europe (14%). The majority practiced in 2 major cities, Riyadh (46%) or Jeddah (19%). Vigabatrin was favored over adrenocorticotropic hormone (ACTH) as first line drug for patients without tuberous sclerosis complex (48% vs. 21%). Several factors correlated with correctly selecting ACTH as first line including western training (33% vs. 5%, p=0.001), practicing in the city of Riyadh (25% vs. 14%, p=0.001), or having >10 years of clinical experience (25% vs. 5%, p=0.017). Reasons for not complying with the recommended treatment guidelines included lack of availability of ACTH (42%), side effect profile of steroids (29%), and personal preferences (14%). Only 4% admitted lack of awareness of the currently published management guidelines. CONCLUSION: Many pediatric neurologists in KSA are not following the published IS management guidelines. Using ACTH as first line correlated with their training, practice location, and years of experience. Lack of drug availability and side effect profile were common reasons for not complying with the management guidelines. PMID- 30008007 TI - Endovascular management for tandem occlusions of anterior cerebral circulation. AB - OBJECTIVE: To compare the endovascular approaches and techniques used to treat tandem occlusions of anterior cerebral circulation. METHODS: A literature review was carried out using PubMed to review the studies that described endovascular therapies for patients with tandem cerebral occlusions. RESULTS: A total of 106 patients (median age: 64 years; range: 18-90 years) were identified. The median National Institutes of Health Stroke scale score at the time of admission for 104 patients was 16.5 (standard deviation [SD] +/-5.7). The mean times and ranges from symptom onset to recanalization were 396.85 minutes (range: 120-1,574 minutes) and from groin puncture to recanalization were 80.3 minutes (range: 14 180 minutes). The mean outcome modified Rankin scale (mRS) score was 2.31 (SD +/ 2.2), and 61.3% of patients had an outcome mRS score 99% Hg complexed with thiol groups in DOM. The modelled concentrations of Hg-DOM complexes from low-T (low-temperature, 300 degrees C) biochars were greater than from high-T (600 degrees C) biochars. The concentrations of Hg-DOM complexes were lower in wood-based than in agricultural residue- and manure-based biochars. Hg-DOM complexes may affect Hg speciation, bioavailability, transport, and methylation processes. This research describes a method to evaluate Hg-DOM interactions, and the results indicate extra caution regarding Hg-DOM complex formation is required in the selection of biochar for Hg remediation. PMID- 30008040 TI - "We Don't Really Do Anything Unless it's Really Bad": Understanding Adolescent Sun Protective Knowledge, Attitudes and Behaviors in the U.S. AB - Risk factors for melanoma, the deadliest form of skin cancer, include lifetime sun exposure and a history of sunburns. However, a minority of adolescents report consistent engagement in sun protective behaviors. The few sun protection interventions that have targeted adolescents have had little effect on behavior change, which suggests that a better understanding of the issue, especially from the adolescents' perspective, is needed. Although efforts to qualitatively examine adolescent sun protection have been carried out in a handful of countries, no studies to date have focused on U.S. adolescents. We conducted focus groups with 44 6th-8th grade students in Colorado to explore their sun protection knowledge, attitudes and behaviors. Results supported previous findings that adolescents do not engage in regular skin protection but have experienced the negative consequences of sun exposure (e.g., severe sun burns, and blistering). In addition, participants demonstrated limited and sometimes inaccurate knowledge about the long-term risks of sun exposure, as well as effective methods of sun protection. Barriers to engaging in sun protective behaviors included a desire to tan, inconvenience, and physical discomfort. Facilitators included peer and family encouragement, previous experience with sunburns and/or skin cancer, and knowledge of potential consequences. These findings provide valuable insights that can inform future intervention and research related to sun protection among U.S. adolescents. PMID- 30008038 TI - The acute effects of walking exercise intensity on systemic cytokines and oxidative stress. AB - PURPOSE: Oxidative stress is associated with tissue cytokine secretion although the precise mechanism(s) underpinning this relationship during high intensity intermittent exercise remains unclear. This study investigates the acute response to a bout of high intensity intermittent walking (HIIW), compared to continuous moderate intensity walking (CMW), on various cytokines and biomarkers of oxidative stress. METHODS: Seventeen (n = 17) apparently healthy male participants (aged 22.6 +/- 4.6 years; [Formula: see text]: 53.7 +/- 7.1 ml kg-1 min-1) undertook a randomised crossover study consisting of two exercise trials: (1) HIIW requiring 3 * 5 min bursts at 80% [Formula: see text] (each separated by 5 min of walking at 30% [Formula: see text]) and (2) CMW (60% [Formula: see text] for 30 min). Each trial was separated by 7 days. Venous blood samples were obtained pre-exercise, post-exercise and at 2, 4, 24 and 48 h post-exercise for determination of systemic inflammation (IL-6 and TNF-alpha), lipid soluble antioxidants and oxidative stress (LOOH, H2O2 and the ascorbyl free radical). RESULTS: Both IL-6 and TNF-alpha increased immediately post exercise, regardless of intensity and remained elevated until at least 4 h (main effect for time; p < 0.05). While there was no change in either lipid peroxidation or free radical metabolism (Asc. and H2O2), alpha-tocopherol increased (pooled HIIW and CMW, p < 0.05), whereas lycopene decreased at 2 h post HIIW (p < 0.05). CONCLUSION: Bouts of both HIIW and CMW promote cytokine secretion post exercise, and this seems to be independent of oxidative stress. Further investigation is required to assess how such changes may underpin some of the transient health benefits of exercise. PMID- 30008041 TI - Examining Patient Perspectives on Weight Management Support in the Primary Care Setting. AB - Obesity affects more than one-third of Americans and is a leading cause of preventable death. Integrating patient perspectives into obesity treatment can help primary care providers (PCPs) intervene more effectively. In this study, we describe patients' experiences with PCPs concerning the diagnosis and treatment of obesity and offer suggestions for patient-centered care in weight management. We conducted four focus groups with patients of a university medical system associated family practice who had a BMI >= 30. Interview questions addressed general weight management perceptions and preferences for weight management support in a primary care setting. Patients completed a brief demographic survey at the conclusion of the group. Four authors independently coded focus group notes to identify themes and determine saturation using qualitative thematic analysis. We resolved discrepancies by team discussion. Thirty primary care patients participated, of whom 23 were female and whose average age was 50. Twenty-four had attempted to lose weight in the past 12 months and had discussed management with their providers. Analyses identified four themes regarding weight management in a primary care setting: motivation and weight management, the provider-patient relationship, desire for concrete weight loss plans, and limitations of the primary care setting. Motivation was named as a weight management obstacle. Participants felt that PCPs need to be partners in weight management efforts and also recognized limitations of PCP time and expertise. They endorsed an integrated behavioral approach that includes physical activity and nutrition support. Improving PCP delivery of evidence-based treatment for obesity will lead to increased patient attempts to lose weight. Incorporating patients' desires for concrete plans, ongoing support, and referral to integrated service (e.g., nutritionists, care managers, behavioral health providers) programs can increase patient engagement and success. The chronic disease care and Patient Centered Medical Home models offer guidance for ensuring sustainability of weight management services. PMID- 30008042 TI - The Intersection Between Women's Reproductive Desires and HIV Care Providers' Reproductive Health Practices: A Mixed Methods Analysis. AB - Background HIV-positive women in the United States can have healthy pregnancies and avoid transmitting HIV to their children. Yet, little is known about the extent to which HIV care providers' reproductive health practices match women's pregnancy desires. Accordingly, we explored young HIV-positive women's pregnancy desires and reproductive health behaviors and examined reproductive health information offered by HIV care clinics. Methods A mixed-method analysis was conducted using data from a 14-site Adolescent Medicine Trials Network (ATN) study. We conducted descriptive statistics on data from 25 HIV-positive women (e.g., demographics, pregnancy desires, and sexual- and health-related behaviors). Qualitative interviews with 58 adolescent and adult clinic providers were analyzed using the constant comparative method. Results About half of the women reported using reproductive health care services (i.e., contraception and pregnancy tests) (n = 12) and wanted a future pregnancy (n = 13). Among women who did not desire a future pregnancy (n = 5), three used dual methods and two used condoms at last sexual encounter. Qualitative themes related to clinics' approaches to reproductive health (e.g., "the emphasis...is to encourage use of contraceptives") and the complexity of merging HIV and reproductive care (e.g., "We [adolescent clinic] transition pregnant moms from our care back and forth to adult care"). Discussion Despite regular HIV-related medical appointments, HIV positive women may have unaddressed reproductive health needs (e.g., pregnancy desire with providers focused on contraceptive use). Findings from this study suggest that increased support for young HIV-positive women's reproductive health is needed, including supporting pregnancy desires (to choose when, how, and if, to have children). PMID- 30008043 TI - Comparison of High and Normal Birth Weight Infants on Eating, Feeding Practices, and Subsequent Weight. AB - Objectives High birth weight (HBW >= 4000 g) infants are at increased risk for obesity, but research has yet to identify the mechanism for this increased risk and whether certain subsets of HBW infants are at greater risk. Methods This exploratory study examined child eating behaviors and maternal feeding practices and beliefs across 21 HBW and 20 normal birth weight (NBW, 2500-3999 g) infants at 7-8 months of age using maternal-report measures (n = 41) and a bottle feeding task (n = 16). Results HBW infants were at increased risk for high weight-for length at 7-8 months (F (2, 38) = 6.03, p = .02) compared to NBW infants, but no statistically significance differences on weight gained per day since birth, child eating behaviors, or most maternal feeding practices and beliefs were found between HBW and NBW infants. However, HBW infants who maintained a high weight for-length (>= 85th percentile) at 7-8 months had a higher birth weight, gained more weight per day, and had lower maternal-reported satiety responsiveness and maternal social interactions during feedings than their HBW counterparts who were currently below the 85th percentile. Conclusions for Practice HBW infants did not differ from NBW infants on eating behaviors and feeding practices, but children born at HBW who maintain excess weight during infancy do differ from those infants who fall below the 85th percentile for weight-for-length. Future research should identify risk factors that longitudinally differentiate HBW infants at greatest risk for maintaining excess weight and develop early screening and intervention efforts for this subset of at-risk infants. PMID- 30008044 TI - Color postprocessing of conventional CT images: preliminary results in assessment of nondisplaced proximal femoral fractures. AB - PURPOSE: The purpose of this study was to demonstrate the diagnostic performance and effect on reader confidence of a custom computed tomography (CT) color postprocessing algorithm for assessment of nondisplaced proximal femoral fractures. MATERIALS AND METHODS: Four radiologists, including two PGY-3 radiology residents and two emergency radiologists, independently interpreted 30 CT examinations of the hip and/or pelvis performed for trauma, consisting of a total of 15 cases positive for nondisplaced hip fracture and 15 age and sex matched controls. Images were reviewed first with conventional CT images and after at least 8 weeks, all images were reviewed again with the addition of coronal color postprocessed images. Sensitivity and specificity were compared with McNemar's test, and diagnostic confidence was compared with paired t tests. RESULTS: There was no significant difference in diagnostic performance between conventional and postprocessed images, although there was nominally increased sensitivity and decreased specificity with the postprocessed images: for all readers, the sensitivity and specificity for conventional images was 88.3 and 95.0%, compared to 93.3% (p = 0.25) and 88.3% (p = 0.14) for postprocessed images. Three of four readers (including both attending radiologists) reported an increase in confidence with postprocessed images for cases negative for fracture (10-point confidence scale of 7.25 for conventional images, compared to 8.2 for postprocessed images for all readers, p = 0.0053). There was no difference in diagnostic confidence for cases positive for fracture. CONCLUSIONS: A custom color CT postprocessing algorithm did not demonstrate a significant difference in diagnostic performance for assessment of nondisplaced proximal femoral fractures within the limitations of a relatively small sample size; however, postprocessing increases confidence of experienced readers in cases negative for fracture. PMID- 30008045 TI - Musculoskeletal health of Indigenous Australians. AB - INTRODUCTION: Research on non-communicable diseases (NCD) in Indigenous Australians has mostly focused on diabetes mellitus and chronic kidney or cardiovascular disease. Osteoporosis, characterised by low bone mass and structural deterioration of bone tissue, and sarcopenia, the age-related loss of muscle mass and strength, often co-exist with these common NCDs-the combination of which will disproportionately increase bone fragility and fracture risk and negatively influence cortical and trabecular bone. Furthermore, the social gradient of NCDs, including osteoporosis and fracture, is well-documented, meaning that specific population groups are likely to be at greater risk of poorer health outcomes: Indigenous Australians are one such group. PURPOSE: This review summarises the findings reported in the literature regarding the muscle and bone health of Indigenous Australians. FINDINGS: There are limited data regarding the musculoskeletal health of Indigenous Australians; however, areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) is reported to be greater at the hip compared to non-Indigenous Australians. Falls are the leading cause of injury-related hospitalisations in older Australians, particularly Indigenous Australians, with a great proportion suffering from fall related fractures. Despite sparse data, it appears that Indigenous men and women have a substantially higher risk of hip fracture at a much younger age compared to non-Indigenous Australians. CONCLUSION: Data on more detailed musculoskeletal health outcomes are required in Indigenous Australians to better understand fracture risk and to formulate evidence-based strategies for fracture prevention and to minimise the risk of falls. PMID- 30008047 TI - Exploring the Effect of Endoplasmic Reticulum Stress Inhibition by 4 Phenylbutyric Acid on AMPA-Induced Hippocampal Excitotoxicity in Rat Brain. AB - Excessive stimulation of ionotropic glutamate receptor is associated with glutamate-mediated excitotoxicity, thereby causing oxidative imbalance and mitochondrial dysfunction, resulting in the excitotoxic death of neurons. Eminent role of endoplasmic reticulum under glutamate-induced excitotoxicity has been highlighted in numerous literatures which have been observed to trigger endoplasmic reticulum stress (ER stress) as well as regulating oxidative stress. However, combating ER stress in excitotoxic neurons can provide a novel approach to alleviate the mitochondrial dysfunctioning and ROS generation. Therefore, we propose to investigate the cross-communication of alpha-amino-3-hydroxy-5-methyl 4-isoxzole-propionate (AMPA) excitotoxicity-induced oxidative injury with ER stress by employing ER stress inhibitor-4-phenlybutyric acid (4-PBA). Male SD rats were divided into four groups viz sham group (group 1), AMPA (10 mM)-induced excitotoxic group (group 2), curative group of AMPA-induced excitotoxic animals given 4-PBA at a dose of 100 mg/kg body weight (group 3), and alone 4-PBA treatment group (100 mg/kg body weight) (group 4). Animals were sacrificed after 15 days of treatment, and hippocampi were analyzed for histopathological examination, ROS, inflammatory markers, mitochondrial dysfunction, and ER stress markers. AMPA-induced excitotoxicity exhibited a significant increase in the levels of ROS, upregulated ER stress markers, inflammation markers, and compromised mitochondrial functioning in the hippocampus. However, 4-PBA administration significantly curtailed the AMPA-induced excitotoxic insult. This study suggests that targeting ER stress with a chemical chaperone can provide a better therapeutic intervention for neurological disorders involving excitotoxicity, and thus, it opens a new avenue to screen chemical chaperones for the therapeutic modalities. PMID- 30008046 TI - Feasibility of directional percutaneous epicardial ablation with a partially insulated catheter. AB - PURPOSE: To demonstrate the feasibility of directional percutaneous epicardial ablation using a partially insulated catheter. METHODS: Partially insulated catheter prototypes were tested in 12 (6 canine, 6 porcine) animal studies in two centers. Prototypes had interspersed windows to enable visualization of epicardial structures with ultrasound. Epicardial unipolar ablation and ablation between two electrodes was performed according to protocol (5-60 W power, 0-60 mls/min irrigation, 78 s mean duration). RESULTS: Of 96 epicardial ablation attempts, unipolar ablation was delivered in 53.1%. Electrogram evidence of ablation, when analyzable, occurred in 75 of 79 (94.9%) therapies. Paired pre/post-ablation pacing threshold (N = 74) showed significant increase in pacing threshold post-ablation (0.9 to 2.6 mA, P < .0001). Arrhythmias occurred in 18 (18.8%) therapies (11 ventricular fibrillation, 7 ventricular tachycardia), mainly in pigs (72.2%). Coronary artery visualization was variably successful. No phrenic nerve injury was noted during or after ablation. Furthermore, there were minimal pericardial changes with ablation. CONCLUSIONS: Epicardial ablation using a partially insulated catheter to confer epicardial directionality and protect the phrenic nerve seems feasible. Iterations with ultrasound windows may enable real-time epicardial surface visualization thus identifying coronary arteries at ablation sites. Further improvements, however, are necessary. PMID- 30008048 TI - Two-stage oxygen supply strategy based on energy metabolism analysis for improving acetic acid production by Acetobacter pasteurianus. AB - Oxygen acts as the electron acceptor to oxidize ethanol by acetic acid bacteria during acetic acid fermentation. In this study, the energy release rate from ethanol and glucose under different aerate rate were compared, and the relationship between energy metabolism and acetic acid fermentation was analyzed. The results imply that proper oxygen supply can maintain the reasonable energy metabolism and cell tolerance to improve the acetic acid fermentation. Further, the transcriptions of genes that involve in the ethanol oxidation, TCA cycle, ATP synthesis and tolerance protein expression were analyzed to outline the effect of oxygen supply on cell metabolism of Acetobacter pasteurianus. Under the direction of energy metabolism framework a rational two-stage oxygen supply strategy was established to release the power consumption and substrates volatilization during acetic acid fermentation. As a result, the acetic acid production rate of 1.86 g/L/h was obtained, which were 20.78% higher than that of 0.1 vvm one-stage aerate rate. And the final acetic acid concentration and the stoichiometric yield were 88.5 g/L and 94.1%, respectively, which were 84.6 g/L and 89.5% for 0.15 vvm one-stage aerate rate. PMID- 30008050 TI - Timing and Predictors of Initiation on Antiretroviral Therapy Among Newly Diagnosed HIV-Infected Persons in South Africa. AB - Despite a decade of advancing HIV/AIDS treatment policy in South Africa, 20% of people living with HIV (PLHIV) eligible for antiretroviral treatment (ART) remain untreated. To inform universal test and treat (UTT) implementation in South Africa, this analysis describes the rate, timeliness and determinants of ART initiation among newly diagnosed PLHIV. This analysis used routine data from 35 purposively selected primary clinics in three high HIV-burden districts of South Africa from June 1, 2014 to March 31, 2015. Kaplan-Meier survival curves estimated the rate of ART initiation. We identified predictors of ART initiation rate and timely initiation (within 14 days of eligibility determination) using Cox proportional hazards and multivariable logistic regression models in Stata 14.1. Based on national guidelines, 6826 patients were eligible for ART initiation. Under half of men and non-pregnant women were initiated on ART within 14 days (men: 39.7.0%, 95% CI 37.7-41.9; women: 39.9%, 95% CI 38.1-41.7). Pregnant women initiated at a faster rate (within 14 days: 87.6%, 86.1-89.0). ART initiation and timeliness varied significantly by district, facility location, and age, with little to no variation by World Health Organization stage, or CD4 count. Men and non-pregnant women newly diagnosed with HIV who are eligible for ART in South Africa show suboptimal timeliness of ART initiation. If treatment initiation performance is not improved, UTT implementation will be challenging among men and non-pregnant women. UTT programming should be tailored to district and location categories to address contextual differences influencing treatment initiation. PMID- 30008051 TI - Validation of the AIDS Prevention Questionnaire: A Brief Self-Report Instrument to Assess Risk of HIV Infection and Guide Behavioral Change. AB - This paper describes the process of building and validating the AIDS Prevention Questionnaire (CPS), a brief HIV risk assessment measure. An initial 64-items bank was filled out by 466 young people (192 men and 274 women), aged between 17 and 26 years (M = 20.62; SD = 2.15). The exploratory factor analysis revealed five components: Knowledge about HIV, Condom Attitudes, Intentions of Condom Use, Safe sexual behavior and Stigma and discrimination towards people living with HIV. This structure was confirmed by confirmatory factor analysis. The internal consistency for the different components ranged from .67 to .74. Moreover, CPS has a classification system that allows determining the level of risk. These results support the AIDS Prevention Questionnaire as a valid and reliable measure to detect earlier the risk for HIV infection and to design adjusted preventive interventions. PMID- 30008049 TI - Nonlinear optical properties of aluminum nitride nanotubes doped by excess electron: a first principle study. AB - Aluminum nitride nanotubes (AlNNTs) doped by the excess electron, e@AlNNT and M@N AlNNT (M = Li, Na, K), have been designed and their geometrical, electronic, and nonlinear optical (NLO) properties have been explored theoretically. The results showed that the excess electron narrows the energy gap between HOMO and LUMO values (EH-L) of the doped systems in the range of 3.42-5.37 eV, which is due to a new energy level HOMO formed for the doped excess electron, with higher energy than the original HOMO of AlNNT. Importantly, the doped excess electron considerably increases the first hyperpolarizability (beta0) from 130 a.u. of the undoped AlNNT to 646 a.u. for e@AlNNT, 2606 a.u. for Li@N-AlNNT, while 1.14 * 105 a.u. for Na@N-AlNNT, and 1.37 * 106 a.u. for K@N-AlNNT. The enormous beta0 values for Na@N-AlNNT and K@N-AlNNT are attributed to the low transition energy. These results demonstrate that AlNNTs are a promising material in high-performance NLO nanomaterials for electronic devices. PMID- 30008054 TI - Discussion of "Survival models and health sequences" by Walter Dempsey and Peter McCullagh. AB - This is a discussion of the paper by Dempsey and McCullagh. PMID- 30008052 TI - The Effect of Food on Tramadol and Celecoxib Bioavailability Following Oral Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open Label, Single-Dose, Crossover Study in Healthy Volunteers. AB - BACKGROUND AND OBJECTIVE: Co-Crystal of Tramadol-Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol.HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions. METHODS: Healthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol.HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O desmethyltramadol and celecoxib plasma concentrations were measured pre- and post dose up to 48 h. Pharmacokinetic parameters were calculated using non compartmental analysis. Safety was also assessed. RESULTS: Thirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration (Cmax) and extrapolated area under the plasma concentration-time curve to infinity (AUCinfinity) were within the pre-defined range for comparative bioavailability (80-125%). For celecoxib, Cmax and AUCinfinity fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98-146.49) and 129.34% (121.78-137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions. CONCLUSIONS: As reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O-desmethyltramadol bioavailability. CLINICAL TRIAL REGISTRATION NUMBER: 152052 (registered with the Therapeutic Products Directorate of Health Canada). PMID- 30008055 TI - Analysis of the effects of mesoporous silica particles SBA-15 and SBA-16 in Streptococcus pneumoniae transformation process. AB - Streptococcus pneumoniae are natural competent bacteria which requires the presence of a pheromone-like molecule to do the transformation process. This study verified the influence of mesoporous silica (SBA-15 and SBA-16) on the transformation process in S. pneumoniae using a donor DNA obtained from a mutant strain of this microorganism (Sp360?luxS). The results showed that mesoporous silica SBA-15 and SBA-16 particles doubled the transformation ratio frequency compared with negative control (without nanoparticles) in using SBA-15 (ratio 1.81 +/- 0.04) and SBA-16 (ratio 2.18 +/- 0.22). We demonstrated the how mesoporous silica nanoparticles were able to increase the pneumococcus transformations, which could possibly lead to the acquisition of virulence factor genes and resistance of antibiotics. PMID- 30008053 TI - Recombinant helical plant virus-based nanoparticles for vaccination and immunotherapy. AB - Plant virus-based nanoparticles (PVNs) are self-assembled capsid proteins of plant viruses, and can be virus-like nanoparticles (VLPs) or virus nanoparticles (VNPs). Plant viruses showing helical capsid symmetry are used as a versatile platform for the presentation of multiple copies of well-arrayed immunogenic antigens of various disease pathogens. Helical PVNs are non-infectious, biocompatible, and naturally immunogenic, and thus, they are suitable antigen carriers for vaccine production and can trigger humoral and/or cellular immune responses. Furthermore, recombinant PVNs as vaccines and adjuvants can be expressed in prokaryotic and eukaryotic systems, and plant expression systems can be used to produce cost-effective antigenic peptides on the surfaces of recombinant helical PVNs. This review discusses various recombinant helical PVNs based on different plant viral capsid shells that have been developed as prophylactic and/or therapeutic vaccines against bacterial, viral, and protozoal diseases, and cancer. PMID- 30008056 TI - Incidence of second-time lateral patellar dislocation is associated with anatomic factors, age and injury patterns of medial patellofemoral ligament in first-time lateral patellar dislocation: a prospective magnetic resonance imaging study with 5-year follow-up. AB - PURPOSE: To examine the predictors of the second-time lateral patellar dislocation (LPD) in patients after acute first-time LPD in a 5-year follow-up. METHODS: Data were collected prospectively from patients after acute first-time LPD with conservative treatment. Factors included sex, age at the first-time LPD, anatomical variants [trochlear dysplasia, patellar height, tibial tuberosity trochlear groove (TT-TG) distance], and injury patterns of medial patellofemoral ligament (MPFL) in acute first-time LPD. Logistic regression was carried out to identify the independent risk factors for the incidence of the second-time LPD. RESULTS: The incidence rate of a second-time LPD was 35.5% (59 of 166) in the 5 year follow-up. Univariate analysis revealed significant differences in the incidence rate of the second-time LPD among age at the first-time LPD (P = 0.04), trochlear dysplasia (P = 0.003), patella height (P = 0.017) and the TT-TG distance (P = 0.027). Risk factors for the second-time LPD were age < 18 years at the first-time LPD [odds ratio (OR) 4.088], low-grade trochlear dysplasia (OR 7.214), high-grade trochlear dysplasia (OR 18.945), patella alta (OR 8.416), elevated TT-TG distance (OR 12.742), complete MPFL tear at its isolated femoral side (OR 6.04) and complete combined MPFL tear (OR 5.851). CONCLUSIONS: Trochlear dysplasia, elevated TT-TG distance, patella alta, age < 18 years at the first time LPD, complete MPFL tear at its isolated femoral-side and complete combined MPFL tear in the first-time LPD are independently associated with a higher incidence rate of the second-time LPD. LEVEL OF EVIDENCE: III. PMID- 30008057 TI - Hamstring tendon autografts do not show complete graft maturity 6 months postoperatively after anterior cruciate ligament reconstruction. AB - PURPOSE: In this prospective, double-center cohort study, we aim to assess how the anterior cruciate ligament (ACL) signal intensity on magnetic resonance imaging (MRI) potentially varies between a group of patients with anatomic ACL reconstruction using autogenous hamstring grafts 6 months postoperatively and a healthy ACL control group, and how MRI-based graft signal intensity is related to knee laxity. METHODS: Sixty-two consecutive patients who underwent ACL reconstruction using quadrupled hamstring tendon autograft were prospectively invited to participate in this study, and they were evaluated with MRI after 6 months of follow-up. 50 patients with an MRI of their healthy ACL (Clinica Luganese, Lugano, Switzerland) and 12 patients of their contralateral healthy knee (Department of Orthopaedic and Trauma Surgery, Medical University of Vienna, Austria) served as the control group. To evaluate graft maturity, the signal-to noise quotient (SNQ) was measured in three regions of interest (ROIs) of the proximal, mid-substance and distal ACL graft and the healthy ACL. KT-1000 findings were obtained 6 months postoperatively in the ACL reconstruction group. Statistical analysis was independently performed to outline the differences in the two groups regarding ACL intensity and the correlation between SNQ and KT 1000 values. RESULTS: There was a significant difference in the mean SNQ between the reconstructed ACL grafts and the healthy ACLs in the proximal and mid substance regions (p = 0.001 and p = 0.004). The distal region of the reconstructed ACL showed a mean SNQ similar to the native ACL (n.s). Patients with a KT-1000 between 0 and 1 mm showed a mean SNQ of 0.1; however, a poor correlation was found between the mean SNQ and KT-1000 findings, probably due to the small sample size of patients with higher laxity. CONCLUSION: After 6 months of follow-up, hamstring tendon autografts for anatomic ACL reconstruction do not show equal MRI signal intensity compared to a healthy ACL and should therefore be considered immature or at least not completely healed even if clinical laxity measurement provides good results. However, in the case of a competitive athlete, who is clinically stable and wants to return to sports at 6 months, performing an MRI to confirm the stage of graft healing might be an option. LEVEL OF EVIDENCE: Prospective, comparative study II. PMID- 30008058 TI - Development of a modeling pipeline for the prediction of hemodynamic outcome after virtual mitral valve repair using image-based CFD. AB - PURPOSE: Severe mitral valve regurgitation can either be treated by a replacement or a repair of the valve. The latter is recommended due to lower perioperative mortality and better long-term survival. On the other hand, recurrence rates after mitral valve repair are high compared to those after replacements and the repair intervention can cause induced mitral valve stenosis. So far, there are no methods to predict the hemodynamic outcome of a chosen treatment or to compare different treatment options in advance. To overcome this, diastolic mitral valve hemodynamics are simulated using computational fluid dynamics after different virtual treatments of the valve. METHODS: The left ventricular geometry of one patient was reconstructed using trans-esophageal echocardiography and computed tomography data. Pre-op hemodynamics are simulated using a referenced wall model to avoid expansive modeling of wall motion. Subsequently, the flow structures are compared to in vivo measurements. After manipulating the patient-specific geometry in order to mimic a restrictive mitral annuloplasty as well as a MitraClip intervention, hemodynamics results are calculated. RESULTS: Good agreements exist between calculated pre-op hemodynamics and in vivo measurements. The virtual annuloplasty did not result in any remarkable change of hemodynamics. Neither the pressure drop nor the velocity field showed strong differences. In contrast, the virtual MitraClip intervention led to a complete change in blood flow structures as well as an elevated pressure drop across the valve. CONCLUSION: The presented approach allows fast simulation of the diastolic hemodynamic situation before and after treatment of a mitral valve insufficiency. However, this approach is limited to the early diastolic phase of the cardiac cycle and needs to be validated using a larger sample size. PMID- 30008060 TI - Lipid Bilayer Interactions of Amyloidogenic N-Terminal Fragment of Apolipoprotein A-I Probed by Forster Resonance Energy Transfer and Molecular Dynamics Simulations. AB - The effects of one of the amyloidogenic mutations of apolipoprotein A-I (apoA-I), G26R, on the thermal stability, structural dynamics and lipid-associating properties of the 1-83 N-terminal fragment of apoA-I (A83) have been investigated using the Forster resonance energy transfer (FRET) and molecular dynamics (MD) simulation. The measurements of FRET between the tryptophan residues of the single Trp variants of A83 as donors and the membrane-incorporated fluorescent probe 4-dimethylaminochalcone as an acceptor provided evidence for a less depth of A83/G26R penetration into phosphatidylcholine (PC) bilayer compared to WT counterpart. The unfolding MD simulations showed that G26R mutation destabilizes the overall structure of A83, with individual alpha-helices differing in their thermal stability. The MD simulations performed at physiological temperature revealed that A83 and A83/G26R differ in their conformational behavior in an aqueous solution, PC and PC/Cholesterol bilayers. These findings may prove of importance for deeper understanding of the key determinants of apoA-I amyloidogenesis. PMID- 30008061 TI - The Effect of the Bariatric Surgery Type on the Levothyroxine Dose of Morbidly Obese Hypothyroid Patients. AB - BACKGROUND: Doubts exist about the effect of different bariatric surgery (BS) types on levothyroxine (Lt4) absorption. We compared Lt4 doses and their variation (DeltaLt4) in patients with hypothyroidism that underwent malabsorptive (MS) or restrictive (RS) surgery and studied predictors of Lt4 dose change. METHODS: Retrospective study of morbidly obese hypothyroid patients submitted to BS. We compared RS ("sleeve" gastrectomy or adjustable gastric banding) with MS (Roux-en-Y gastric bypass) patients. We built a multivariable logistic regression and a linear regression model to study predictors of Lt4 dose changes and DeltaLt4, respectively. RESULTS: Fifty-seven patients: 35 MS and 22 RS. Mean age 47 years; 7% men. Patients submitted to MS had lower BMI at 1 year than those submitted to RS. Lt4 dose remained unchanged in 61.4%, increased in 12.3%, and decreased in 26.3% of patients. Initial and 1-year Lt4 dose were not different between surgical groups. Relative Lt4 dose, but not absolute (p = 0.07), increased at 1 year (p < 0.001). Neither BS nor BMI variation were predictors of Lt4 dose variation. BMI variation was associated with relative Lt4 dose change independently of initial BMI and BS type: beta (95%CI) - 0.03 (- 0.05; 0.00); p = 0.03. CONCLUSIONS: There were no differences in Lt4 dose and its variation between restrictive and malabsorptive techniques 1 year after surgery. Malabsorptive procedures may not affect Lt4 absorption differently from restrictive ones. Bariatric surgery type was not predictive of Lt4 dose changes. BMI variation is associated with relative Lt4 dose (dose per weight) variation and its association was independent of bariatric surgery type. PMID- 30008059 TI - Review on Recent Advances in Metal Ions Sensing Using Different Fluorescent Probes. AB - Fluorescence probes serves as unique detection methods for its simplicity and low detection limit (LOD) and especially bioimaging ability. Research on the probes has already sprouted during the last decade with the help of its molecular recognition properties. This review spotlights recent progress in sensing and bioimaging biologically, environmentally and industrially important metal ions e.g. Zn2+, Cu2+, Hg2+, Ag+ etc. using suitable fluorescent chemosensors including carbon quantum dots (CQD). PMID- 30008064 TI - Late onset necrotizing autoimmune myopathy 1 year after cessation of statin treatment. PMID- 30008062 TI - Associations of maternal type 1 diabetes with childhood adiposity and metabolic health in the offspring: a prospective cohort study. AB - AIMS/HYPOTHESIS: Exposure to an intrauterine hyperglycaemic environment has been suggested to increase the offspring's later risk for being overweight or having metabolic abnormalities, but conclusive evidence for pregnancies affected by maternal type 1 diabetes is still lacking. This study aims to analyse the relationship between maternal type 1 diabetes and the offspring's metabolic health and investigate whether birthweight and/or changes in the offspring's metabolome are in the potential pathway. METHODS: We analysed data from 610 and 2169 offspring having a first-degree relative with type 1 diabetes from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Anthropometric and metabolic outcomes, assessed longitudinally at 0.3-18 years of age, were compared between offspring of mothers with type 1 diabetes and offspring of non-diabetic mothers but with fathers or siblings with type 1 diabetes using mixed regression models. Non-targeted metabolomic measurements were carried out in 500 individuals from TEENDIAB and analysed with maternal type 1 diabetes and offspring overweight status. RESULTS: The offspring of mothers with type 1 diabetes had a higher BMI SD score (SDS) and an increased risk for being overweight than the offspring of non-diabetic mothers (e.g. OR for overweight status in TEENDIAB 2.40 [95% CI 1.41, 4.06]). Further, waist circumference SDS, fasting levels of glucose, insulin and C-peptide, and insulin resistance and abdominal obesity were significantly increased in the offspring of mothers with type 1 diabetes, even when adjusted for potential confounders and birthweight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring's overweight status, but no significant associations were observed between maternal type 1 diabetes and metabolite concentrations in the offspring. CONCLUSIONS/INTERPRETATION: Maternal type 1 diabetes is associated with offspring's overweight status and metabolic health in later life, but this is unlikely to be caused by alterations in the offspring's metabolome. PMID- 30008063 TI - Lupeol against high-glucose-induced apoptosis via enhancing the anti-oxidative stress in rabbit nucleus pulposus cells. AB - PURPOSE: This study aimed to investigate the potential mechanism and value of lupeol in inhibiting high-glucose-induced apoptosis in rabbit nucleus pulposus cells (NPCs). METHODS: NPCs were divided into four groups: control (CON), high glucose (HG), LUP, and HG + LUP. Viability, reactive oxygen species (ROS) levels, and apoptosis were examined in NPCs. The protein expression levels of Bax, Bcl-2, cytochrome C, and caspase 9/3 were measured using reverse transcription polymerase chain reaction and Western blot assay. RESULTS: The apoptotic rate and total ROS level of the HG group significantly increased compared with the CON group (P < 0.01). The total ROS level in the HG + LUP group significantly decreased compared with the HG group(P < 0.05). The mRNA expression of Bcl-2 was significantly upregulated, whereas the expression of Bax, cytochrome C, and caspase 9/3 was downregulated in the HG + LUP group compared with those in the HG group(P < 0.05).The Western blot assay showed that the expression of Bcl-2 was upregulated, but the expression of Bax, cytochrome C, and caspase 9/3 was significantly downregulated in the HG + LUP group compared with the HG group (P < 0.05). CONCLUSIONS: Lupeol inhibited high-glucose-induced apoptosis in NPCs by enhancing the anti-oxidative stress in the mitochondria. This study suggested lupeol as a potential therapeutic drug for treating intervertebral disc degeneration under hyperglycaemic conditions. These slides can be retrieved under Electronic Supplementary Material. PMID- 30008066 TI - Tumor-Associated T-Lymphocytes and Macrophages are Decreased in Endometrioid Endometrial Carcinoma with MELF-Pattern Stromal Changes. AB - Microcystic, elongated, fragmented (MELF)-pattern is an unusual morphology of myometrial invasive front in endometrioid endometrial carcinoma (EA). The aim of the study was to investigate potential correlation between MELF-pattern and peritumoral inflammatory immune response. A total of 96 out of 368 patients were included in this study. CD3, CD20, CD57. CD68 and S100 markers were used for the detection of tumor-associated T-lymphocytes (TAT), tumor-associated B-lymphocytes (TAB), tumor-associated NK-lymphocytes (NK), tumor-associated macrophages and dendritic cells respectively. Mann-Whitney tests, receiver operating characteristic (ROC) curve analysis, and Spearman correlation were used as methods for statistical analyses. Odds ratio with 95% confidence interval (95% CI) was determined with the use of a logistic regression model. A p < 0.05 was considered statistically significant. Our results suggested that the number of CD3 and CD68 cells were significantly lower (p < 0.001) in cases of endometrioid carcinoma with MELF-pattern. A significant correlation between the presence of MELF-pattern and decrease of CD3 positive T-lymphocytes (r = 0.691; p < 0.001) was also observed. Additionally, we found an inverse correlation between the presence of MELF-pattern and TAM (r = 0.568; p = 0.001). Therefore, our data suggest that MELF-pattern may be associated with EA stroma fibrosis that contains immune cells infiltration and demonstrated a decrease in the number of TAT and TAM cells. This may indicate the poor clinical prognosis of this disease. PMID- 30008067 TI - Abstracts from the 11th International Symposium on Minimal Residual Disease, 3-5 May 2018, Montpellier, France. PMID- 30008068 TI - Single versus double pass technique for preparation of ultrathin Descemet's stripping automated endothelial keratoplasty tissues from donated whole eyes. AB - This study was conducted to analyze the preoperative thickness profile and endothelial rating of ultrathin Descemet's stripping automated endothelial keratoplasty (UT-DSAEK) tissues prepared with a single versus double microkeratome pass from donated whole eyes and corresponding eye bank postoperative results. Microkeratome-assisted UT-DSAEK tissues were prepared from freshly donated whole eyes with single-pass (SP) and double-pass (DP) technique in the Central Eye Bank of Iran. Preoperative thickness profiles and endothelial cell densities of UT-DSAEK tissues were obtained from optical coherence tomography and specular microscopy, respectively, and compared between groups. Corneal perforation rates during the eye bank preparation and postoperative reports of transplanted UT-DSAEK tissues were also compared. Over a 15-month period, 342 UT-DSAEK tissues were prepared: 248 via SP and 94 with DP technique. Mean donor corneal central thickness was 610 +/- 58 um with SP and 790 +/- 100 um with DP technique. Mean central thickness of UT-DSAEK tissues was not statistically different between the groups (84.8 +/- 11.0 um with SP and 85.1 +/- 10.5 um with DP technique, P = 0.857). Mean increase of UT-DSAEK thickness from central to pericentral and peripheral cornea was not significantly different with both techniques. Mean differences between thicknesses of 2 pericentral locations and between those of 2 peripheral locations were not statistically different in the study groups. Corneal perforation of 1.6 and 1.1% occurred in SP and DP groups, respectively. Failed graft was reported 6 months postoperatively in 4 (1.6%) cases with SP and in 1 (1.1%) case with DP technique. Preoperative thickness profiles of UT-DSAEK tissues prepared from donated whole eyes via SP technique were not significantly different from those prepared with DP, showing a symmetric increase of thickness towards peripheral locations. PMID- 30008069 TI - Genome dimensions control biological and toxicological functions; myth or reality? AB - The multidimensional genome offers a new perspective to understand molecular mechanisms of genotoxicity and provide deeper knowledge of how genome organization and reorganization in dimensions can alter cell sensitivity, tolerance, resistance, or toxicity to drugs, whether drugs per se can influence the 3D architecture of the genome directly or indirectly through transcriptional factors, and how we can improve cell sensitivity to drugs through the reorganization of genome and regulation of gene expression. We address roles of 3D genome organization and reorganization in the pathogenesis and progression of disease by evaluating various methodologies of studying the 3D genome, and in the genome integrity and stability susceptible to chemicals as mechanisms of genotoxicity. We discuss the value of imaging, visualizing, and nuclear proximity ligation-based methods of 3D genome organization to measure spatial proximity and visualize spatial distances between genomic loci. We also list a number of dynamic genome changes during genome function and call for further investigations on the interaction of drugs with genome-specific regulators, key enzymes, or spliceosome. PMID- 30008065 TI - A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers. AB - The evolutionary and biological bases of the Central African "pygmy" phenotype, a characteristic of rainforest hunter-gatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations. PMID- 30008070 TI - Morphological Neuron Classification Based on Dendritic Tree Hierarchy. AB - The shape of a neuron can reveal interesting properties about its function. Therefore, morphological neuron characterization can contribute to a better understanding of how the brain works. However, one of the great challenges of neuroanatomy is the definition of morphological properties that can be used for categorizing neurons. This paper proposes a new methodology for neuron morphological analysis by considering different hierarchies of the dendritic tree for characterizing and categorizing neuronal cells. The methodology consists in using different strategies for decomposing the dendritic tree along its hierarchies, allowing the identification of relevant parts (possibly related to specific neuronal functions) for classification tasks. A set of more than 5000 neurons corresponding to 10 classes were examined with supervised classification algorithms based on this strategy. It was found that classification accuracies similar to those obtained by using whole neurons can be achieved by considering only parts of the neurons. Branches close to the soma were found to be particularly relevant for classification. PMID- 30008071 TI - Chemotherapy-Induced Cognitive Impairment Is Associated with Cytokine Dysregulation and Disruptions in Neuroplasticity. AB - Chemotherapy-induced cognitive impairment, often referred to as "chemobrain," is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-alpha levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain. PMID- 30008072 TI - Pharmacological Sequestration of Mitochondrial Calcium Uptake Protects Neurons Against Glutamate Excitotoxicity. AB - Neuronal excitotoxicity which is induced by exposure to excessive extracellular glutamate is shown to be involved in neuronal cell death in acute brain injury and a number of neurological diseases. High concentration of glutamate induces calcium deregulation which results in mitochondrial calcium overload and mitochondrial depolarization that triggers the mechanism of cell death. Inhibition of mitochondrial calcium uptake could be potentially neuroprotective but complete inhibition of mitochondrial calcium uniporter could result in the loss of some physiological processes linked to Ca2+ in mitochondria. Here, we found that a novel compound, TG-2112x, can inhibit only the lower concentrations mitochondrial calcium uptake (induced by 100 nM-5 MUM) but not the uptake induced by higher concentrations of calcium (10 MUM and higher). This effect was not associated with changes in mitochondrial membrane potential and cellular respiration. However, a pre-treatment of neurons with TG-2112x protected the neurons against calcium overload upon application of toxic concentrations of glutamate. Thus, sequestration of mitochondrial calcium uptake protected the neurons against glutamate-induced mitochondrial depolarization and cell death. In our hands, TG-2112x was also protective against ionomycin-induced cell death. Hence, low rate mitochondrial calcium uptake plays an underestimated role in mitochondrial function, and its inhibition could protect neurons against calcium overload and cell death in glutamate excitotoxicity. PMID- 30008073 TI - Peripheral Biomarkers for Early Detection of Alzheimer's and Parkinson's Diseases. AB - Neurological disorders are found to be influencing the peripheral tissues outside CNS. Recent developments in biomarkers for CNS have emerged with various diagnostic and therapeutic shortcomings. The role of central biomarkers including CSF-based and molecular imaging-based probes are still unclear for early diagnosis of major neurological diseases. Current trends show that early detection of neurodegenerative diseases with non-invasive methods is a major focus of researchers, and the development of biomarkers aiming peripheral tissues is in demand. Alzheimer's and Parkinson's diseases are known for the progressive loss in neural structures or functions, including the neural death. Various dysfunctions of metabolic and biochemical pathways are associated with early occurrence of neuro-disorders in peripheral tissues including skin, blood cells, and eyes. This article reviews the peripheral biomarkers explored for early detection of Alzheimer's and Parkinson's diseases including blood cells, skin fibroblast, proteomics, saliva, olfactory, stomach and colon, heart and peripheral nervous system, and others. Graphical Abstract ?. PMID- 30008075 TI - A systematic review of 3251 emergency department thoracotomies: is it time for a national database? AB - PURPOSE: Emergency department thoracotomy (EDT) is a potentially life-saving procedure, performed on patients suffering traumatic cardiac arrest. Multiple indications have been reported, but overall survival remains unclear for each indication. The objective of this systematic review is to determine overall survival, survival stratified by indication, and survival stratified by geographical location for patients undergoing EDT across the world. METHODS: Articles published between 2000 and 2016 were identified which detailed outcomes from EDT. All articles referring to pre-hospital, delayed, or operating room thoracotomy were excluded. Pooled odds ratios (OR) were calculated comparing differing indications. RESULTS: Thirty-seven articles, containing 3251 patients who underwent EDT, were identified. There were 277 (8.5%) survivors. OR demonstrate improved survival for; penetrating vs blunt trauma (OR 2.10; p 0.0028); stab vs gun-shot (OR 5.45; p < 0.0001); signs of life (SOL) on admission vs no SOL (OR 5.36; p < 0.0001); and SOL in the field vs no SOL (OR 19.39; p < 0.0001). Equivalence of survival was demonstrated between cardiothoracic vs non cardiothoracic injury (OR 1.038; p 1.000). Survival was worse for USA vs non-USA cohorts (OR 1.59; p 0.0012). CONCLUSIONS: Penetrating injury remains a robust indication for EDT. Non-cardiothoracic cause of cardiac arrest should not preclude EDT. In the absence of on scene SOL, survival following EDT is extremely unlikely. Survival is significantly higher in the non-USA publications; reasons for this are highly complex. A UK multicentre prospective study which collects standardised data on all EDTs could provide robust evidence for better patient stratification. PMID- 30008074 TI - Lysosomal Cathepsin Protease Gene Expression Profiles in the Human Brain During Normal Development. AB - Cathepsin protease genes are necessary for protein homeostasis in normal brain development and function. The diversity of the 15 cathepsin protease activities raises the question of what are the human brain expression profiles of the cathepsin genes during development from prenatal and infancy to childhood, adolescence, and young adult stages. This study, therefore, evaluated the cathepsin gene expression profiles in 16 human brain regions during development by quantitative RNA-sequencing data obtained from the Allen Brain Atlas resource. Total expression of all cathepsin genes was the lowest at the early prenatal stage which became increased at the infancy stage. During infancy to young adult phases, total gene expression was similar. Interestingly, the rank ordering of gene expression among the cathepsins was similar throughout the brain at the age periods examined, showing (a) high expression of cathepsins B, D, and F; (b) moderate expression of cathepsins A, L, and Z; (c) low expression of cathepsins C, H, K, O, S, and V; and (d) very low expression of cathepsins E, G, and W. Results show that the human brain utilizes well-defined, balanced patterns of cathepsin gene expression throughout the different stages of human brain development. Knowledge gained by this study of the gene expression profiles of lysosomal cathepsin proteases among human brain regions during normal development is important for advancing future investigations of how these cathepsins are dysregulated in lysosomal-related brain disorders that affect infants, children, adolescents, and young adults. PMID- 30008076 TI - Preliminary experience with tigecycline treatment for severe infection in children. AB - : Severe infection is a primary cause of mortality in children facing challenges from multidrug-resistant (MDR) pathogens, particularly MDR Acinetobacter baumannii. Tigecycline has an expanded spectrum of antibacterial activity, and some successful instances of its use in children have been reported. We conducted a retrospective chart review of children treated at a tertiary hospital between May 1, 2012 and May 1, 2017 to examine the efficacy and safety of tigecycline in children with severe infection. A total of 110 patients (69 males) were enrolled in this study, including 46 MDR A. baumannii infection patients, encompassing 51 A. baumannii strains. Totally, the median duration of tigecycline therapy was 10 days (range, 2-47 days), with a clinical improvement rate of 47.27% (52/110). In A. baumannii infection group, the clinical improvement rate was 50% (23/46) and the microbiology eradication rate was 50.98% (26/51). No adverse events were reported during therapy; however, in one case, a 9-year-old boy with hematologic disease developed tooth discoloration. CONCLUSION: Although some patients benefited from tigecycline, the efficacy and safety of tigecycline should not be overvalued. Additional data from randomized controlled trials are required to assess the administration of tigecycline. What is Known: * Severe infection is a primary cause of mortality in pediatric patients and its treatment is facing challenges from an increasing number of multidrug-resistant (MDR) pathogens. * Tigecycline has an expanded spectrum of antibacterial activity. * Several case reports have indicated that tigecycline could be used as a salvage therapy in children when options are limited or non-existent. What is New: * We found that rate of clinical improvement was different in various groups of different infection. The efficacy of tigecycline should not be overvalued. * Six dosage models and different infection types were observed in our series, with different improvement and eradication rate, indicating that more data are required to identify a proper tigecycline dosage. PMID- 30008077 TI - Transcriptomic analysis of porcine PBMCs in response to Actinobacillus pleuropneumoniae reveals the dynamic changes of differentially expressed genes related to immuno-inflammatory responses. AB - Actinobacillus pleuropneumoniae is the cause of porcine pleuropneumonia, for which the mortality rate is high. Host peripheral blood is a body site for the immune clearance of pathogens mediated by release of inflammatory factors. However, "out of control" inflammatory factor release can contribute to host death. To further understand the changes in the transcription level of immune related effectors, samples of peripheral blood mononuclear cells (PBMCs) collected from piglets at different stages of infection (0, 24 and 120 h) were sequenced on an Illumina HiSeqTM 4000 platform. We found 3818 differentially expressed genes (DEGs) in the 24 h-infection group compared to the 0 h-infection group (Pb24-Vs-Pb0). DEGs mainly involved in the Gene ontology and KEGG pathways that included nucleic acid metabolism regulation, cell growth, cell differentiation, and organ morphological maintenance were not significantly enriched (P > 0.05). However, DEGs associated with protein kinase activity, receptor activation, metabolism, local adhesion and immune inflammatory responses were significantly enriched in Pb120-Vs-Pb24 (P < 0.05), as were those related to the T cell receptor signalling pathway, with most being down-regulated compared to the preceding stage (Pb24-Vs-Pb0). In PBMCs there were some changes in glucose metabolism, local adhesion and the immune inflammatory response (Pb120-Vs-Pb0). In addition, up-regulated DEGs, such as IL8, IL1beta, and CCL2, and were significantly enriched in immune-inflammatory related pathways compared to the uninfected stage, although they began to decline after 24 h. PMID- 30008078 TI - Anterior-apical single-incision mesh surgery (uphold): 1-year outcomes on lower urinary tract symptoms, anatomy and ultrasonography. AB - INTRODUCTION AND HYPOTHESIS: Our primary objective is to determine the presence of SUI at 6-12 months after surgery. The secondary objective is to determine the objective and subjective outcomes of POP. METHODS: A retrospective study conducted between February 2015 and July 2016 at Chang Gung Memorial Hospital. The subjects had had symptomatic anterior or apical prolapse with stage III or IV and undergone pelvic reconstructive surgery using UpholdTM LITE. Patients completed a 3-day voiding diary, urodynamic study, real-time ultrasonography and validated quality-of-life questionnaires at baseline and 12-month follow-up. Primary outcome was the absence of USI. Secondary outcomes included the objective cure rate of POP, <= stage 1 at the anterior/apical vaginal wall, and the subjective cure rate, negative feedback to POPDI-6. RESULTS: Ninety-five women were eligible. Six were excluded because of incomplete data. The postoperative de novo USI and SUI were 22.7 and 19.7%, respectively. There was significant improvement of USI in patients who had MUS insertion (93.8%) and bladder outlet obstruction (96.7%). The objective and subjective cure rate for prolapse was 95.5 and 94.3%, respectively. POP-Q measurements pre- and postoperatively were significantly improved at all points except for Gh and Pb. There was a significant difference in the distance between the bladder neck to the distal end of the mesh during straining both at both the postoperative 3rd month and 1 year. CONCLUSIONS: UpholdTM mesh has a 20% incidence of de novo USI with acceptable objective and subjective cure rates at 1 year postoperatively. The de novo USI rate was high but not bothersome enough to require surgery. PMID- 30008079 TI - Dutch translation and validation of the pelvic organ prolapse/incontinence sexual questionnaire-IUGA revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: Condition-specific sexual questionnaires are important patient-reported outcome measures. The aim of this study was to translate and validate the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire-International Urogynecology Association Revised (PISQ-IR) into Dutch. METHODS: The translated PISQ-IR was linguistically validated, followed by psychometrical validation among women presenting with symptoms of pelvic floor dysfunction in urogynecology clinics. For analysis of the criterion validity, the Pelvic Floor Dysfunction Inventory-20 (PFDI-20) and Female Sexual Function Index (FSFI) were used. Descriptive statistics, floor and ceiling effects, internal consistency using Cronbach's alpha coefficient and Pearson's and Spearman's correlations were calculated for all PISQ-IR subscales. RESULTS: The PISQ-IR was completed by 220 women, of whom 61 (27.7%) considered themselves not sexually active (NSA) and 159 (72.3%) sexually active (SA). The mean age of participating women was 57 years; 49.5% reported symptoms of pelvic organ prolapse (POP), 66.8% urinary incontinence and 2.3% anal incontinence. The PISQ-IR subscales were analyzed separately for SA and NSA women with Cronbach's alpha coefficient ranging from 0.61 to 0.87. Moderate to high correlations were observed between PISQ-IR subscales and corresponding FSFI subscales and a moderate correlation between urinary distress and the condition impact (CI) subscale among NSA subjects. CONCLUSIONS: The Dutch PISQ-IR demonstrated a good internal consistency and criterion validity compared with the FSFI, but criterion validity compared with the PFDI-20 was poor except for urinary distress in NSA women and needs further attention. PMID- 30008080 TI - Impact of animated instruction on tablets and hands-on training in applying bimanual perineal support on episiotomy rates: an intervention study. AB - INTRODUCTION AND HYPOTHESIS: In Palestine, episiotomy is frequently used among primiparous women.This study assesses the effect of training birth attendants in applying bimanual perineal support during delivery by either animated instruction on tablets or hands-on training on episiotomy rates among primiparous women. METHODS: An interventional cohort study was performed from 15 October 2015 to 31 January 2017, including all primiparous women with singletons and noninstrumental vaginal deliveries at six Palestinian hospitals. Intervention 1 (animated instructions on tablets) was conducted in Hospitals 1, 2, 3, and 4. Intervention 2 (bedside hands-on training) was applied in Hospitals 1 and 2 only. Hospitals 5 and 6 did not receive interventions. Differences in episiotomy rates in intervention and nonintervention hospitals were assessed before and after the interventions and presented as p values using chi-square test, and odds ratios (OR) with 95% confidence intervals (CI). Differences in the demographic and obstetric characteristics were presented as p values using the Kruskal-Wallis test. RESULTS: Of 46,709 women, 12,841 were included. The overall episiotomy rate in the intervention hospitals did not change significantly after intervention 1, from 63.1 to 62.1% (OR = 0.96, 95% CI 0.84-1.08), but did so after intervention 2, from 61.1 to 38.1% (OR = 0.39, 95% CI 0.33-0.47). Rates after Intervention 2 changed from 65.0 to 47.3% (OR = 0.52, 95% CI 0.40-0.67) in Hospital 1 and from 39.4 to 25.1% (OR = 0.49, 95% CI 0.35-0.68) in Hospital 2. CONCLUSIONS: Hands-on training of bimanual perineal support during delivery of primiparous women was significantly more effective in reducing episiotomy rates than animated instruction videos alone. PMID- 30008081 TI - Pharmacy quality improvement project to enhance the medication management process in pediatric patients. AB - BACKGROUND: Improvement in the quality of the medication management process is a crucial component of twenty-first-century medicine. AIM: To improve the quality of medication management process within pediatric specialty through designing a quality improvement project for the pharmaceutical care services in a children' hospital to solve the drug-related problems during drug prescribing, administration, and monitoring. METHODS: A total of 900 medical files were evaluated (100 file/month) from the pediatric medical ward to detect any medication errors during prescribing, administration, or monitoring of the drugs. Three pharmacy quality indicators were designed to detect any medication errors during prescribing, administration, or monitoring of the drugs, then a collective datasheet was designed to record any defect in the system during drug management process within the hospital. A quality improvement project was designed using many quality improvement techniques to decrease the rates of medication errors in each drug handling stage. Brainstorming, fishbone chart, questionnaire, and voting were the main quality tools used to detect the causes of medication errors problem in pediatric patients. Certain actions were implemented which included educational program, implementation of clinical pharmacy, intravenous admixture, and drug information services. RESULTS: The quality improvement interventions succeeded in decreasing the rates of medication errors in each stage. These interventions succeeded in decreasing the rates of medication errors in prescribing, administration, and monitoring stages from 47, 60, and 56% respectively to <= 15% within 9 months. CONCLUSION: Pharmacists can have a key role in improving the health-care system's quality in developing countries' health-care systems. PMID- 30008084 TI - Is depression more likely following childbirth? A population-based study. AB - Postpartum depression (PPD) is characterized as a depressive episode conditional on childbirth. We examined whether the risk of depression is higher following childbirth than that at a randomly generated time unrelated to childbirth. In a prospective cohort of all women with live singleton births in Sweden, 1997-2008, we first calculated the relative risk (RR) of PPD for mothers with a history of depression compared to mothers without such a history. Next, we repeated the calculations, but now for depression following a computer-generated arbitrary "phantom delivery" date, unrelated to the true date of delivery. For this phantom delivery date, we used the average expected date of delivery for all women of the same age. For the analyses of each group, women were followed for a full calendar year. We fitted Poisson regression and calculated RR and two-sided 95% confidence intervals (CI). Among a total of 707,701 deliveries, there were 4397 PPD cases and 4687 control depression cases. The RR of PPD was 21.0 (CI 19.7-22.4). The RR of depression in the control group was 26.2 (CI 24.7-27.9). We provide evidence that the risk for PPD is no greater following childbirth than following a random date unrelated to childbirth. This finding suggests that the postpartum period may not necessarily represent a time of heightened vulnerability for clinically significant depression and that the well-established observation of depression covarying with childbirth does not necessarily equate to causation, but rather may be a secondary effect of postpartum women representing a medically captured population. PMID- 30008083 TI - Supraspinal interaction between HIV-1-gp120 and cannabinoid analgesic effectiveness. AB - The growing therapeutic use (self-medication) of cannabinoids by HIV-1 infected people and the recent interest in the possible medicinal use of cannabinoids, particularly in pain management, create an urgent need to identify their potential interactions with HIV-1. The goal here is to determine any interaction between proteins of HIV-1 and the analgesic effectiveness of cannabinoid at supraspinal level. Young adult male rats (Sprague-Dawley) were stereotaxically pretreated with HIV-1 envelope glycoprotein 120 (gp120) into the periaqueductal gray (PAG) area, the primary control center of pain modulation. Then, we examined its effect on cannabinoid receptor agonist WIN55,212-2-induced analgesia. Our results demonstrated that gp120 in PAG diminished the analgesic effectiveness of this cannabinoid agonist. These results suggest that gp120 may interact with the cannabinoid system through the descending modulatory pain pathways centered in the PAG to impair the analgesic effectiveness of cannabinoids. PMID- 30008085 TI - Brain plasticity in pregnancy and the postpartum period: links to maternal caregiving and mental health. AB - Pregnancy and the postpartum period involve numerous physiological adaptations that enable the development and survival of the offspring. A distinct neural plasticity characterizes the female brain during this period, and dynamic structural and functional changes take place that accompany fundamental behavioral adaptations, stimulating the female to progress from an individual with self-directed needs to being responsible for the care of another life. While many animal studies detail these modifications, an emerging body of research reveals the existence of reproduction-related brain plasticity in human mothers too. Additionally, associations with aspects of maternal caregiving point to adaptive changes that benefit a woman's transition to motherhood. However, the dynamic changes that affect a woman's brain are not merely adaptive, and they likely confer a vulnerability for the development of mental disorders. Here, we review the changes in brain structure and function that a woman undergoes during the peripartum period, outlining associations between these neural alterations and different aspects of maternal care. We additionally discuss peripartum mood disorders and postpartum psychosis, and review the neuroimaging studies that investigate the neural bases of these conditions. PMID- 30008082 TI - Cardiovascular pharmacology of K2P17.1 (TASK-4, TALK-2) two-pore-domain K+ channels. AB - K2P17.1 (TASK-4, TALK-2) potassium channels are expressed in the heart and represent potential targets for pharmacological management of atrial and ventricular arrhythmias. Reduced K2P17.1 expression was found in atria and ventricles of heart failure (HF) patients. Modulation of K2P17.1 currents by antiarrhythmic compounds has not been comprehensively studied to date. The objective of this study was to investigate acute effects of clinically relevant antiarrhythmic drugs on human K2P17.1 channels to provide a more complete picture of K2P17.1 electropharmacology. Whole-cell patch clamp and two-electrode voltage clamp electrophysiology was employed to study human K2P17.1 channel pharmacology. K2P17.1 channels expressed in Xenopus laevis oocytes were screened for sensitivity to antiarrhythmic drugs, revealing significant activation by propafenone (+ 296%; 100 MUM), quinidine (+ 58%; 100 MUM), mexiletine (+ 21%; 100 MUM), propranolol (+ 139%; 100 MUM), and metoprolol (+ 17%; 100 MUM) within 60 min. In addition, the currents were inhibited by amiodarone (- 13%; 100 MUM), sotalol (- 10%; 100 MUM), verapamil (- 21%; 100 MUM), and ranolazine (- 8%; 100 MUM). K2P17.1 channels were not significantly affected by ajmaline and carvedilol. Concentration-dependent K2P17.1 activation by propafenone was characterized in more detail. The onset of activation was fast, and current voltage relationships were not modulated by propafenone. K2P17.1 activation was confirmed in mammalian Chinese hamster ovary cells, revealing 7.8-fold current increase by 100 MUM propafenone. Human K2P17.1 channels were sensitive to multiple antiarrhythmic drugs. Differential pharmacological regulation of repolarizing K2P17.1 background K+ channels may be employed for personalized antiarrhythmic therapy. PMID- 30008088 TI - Compromise of alpha-Defensin Function in Liver Cirrhosis Facilitates the Toxic Relationship Between Gut Permeability and Endotoxemia. PMID- 30008086 TI - The neural gamma2alpha1beta2alpha1beta2 gamma amino butyric acid ion channel receptor: structural analysis of the effects of the ivermectin molecule and disulfide bridges. AB - While ~30% of the human genome encodes membrane proteins, only a handful of structures of membrane proteins have been resolved to high resolution. Here, we studied the structure of a member of the Cys-loop ligand gated ion channel protein superfamily of receptors, human type A gamma2alpha1beta2alpha1beta2 gamma amino butyric acid receptor complex in a lipid bilayer environment. Studying the correlation between the structure and function of the gamma amino butyric acid receptor may enhance our understanding of the molecular basis of ion channel dysfunctions linked with epilepsy, ataxia, migraine, schizophrenia and other neurodegenerative diseases. The structure of human gamma2alpha1beta2alpha1beta2 has been modeled based on the X-ray structure of the Caenorhabditis elegans glutamate-gated chloride channel via homology modeling. The template provided the first inhibitory channel structure for the Cys-loop superfamily of ligand-gated ion channels. The only available template structure before this glutamate-gated chloride channel was a cation selective channel which had very low sequence identity with gamma aminobutyric acid receptor. Here, our aim was to study the effect of structural corrections originating from modeling on a more reliable template structure. The homology model was analyzed for structural properties via a 100 ns molecular dynamics (MD) study. Due to the structural shifts and the removal of an open channel potentiator molecule, ivermectin, from the template structure, helical packing changes were observed in the transmembrane segment. Namely removal of ivermectin molecule caused a closure around the Leu 9 position along the ion channel. In terms of the structural shifts, there are three potential disulfide bridges between the M1 and M3 helices of the gamma2 and 2 alpha1 subunits in the model. The effect of these disulfide bridges was investigated via monitoring the differences in root mean square fluctuations (RMSF) of individual amino acids and principal component analysis of the MD trajectory of the two homology models-one with the disulfide bridge and one with protonated Cys residues. In all subunit types, RMSF of the transmembrane domain helices are reduced in the presence of disulfide bridges. Additionally, loop A, loop F and loop C fluctuations were affected in the extracellular domain. In cross-correlation analysis of the trajectory, the two model structures displayed different coupling in between the M2-M3 linker region, protruding from the membrane, and the beta1-beta2/D loop and cys-loop regions in the extracellular domain. Correlations of the C loop, which collapses directly over the bound ligand molecule, were also affected by differences in the packing of transmembrane helices. Finally, more localized correlations were observed in the transmembrane helices when disulfide bridges were present in the model. The differences observed in this study suggest that dynamic coupling at the interface of extracellular and ion channel domains differs from the coupling introduced by disulfide bridges in the transmembrane region. We hope that this hypothesis will be tested experimentally in the near future. PMID- 30008087 TI - RNase H meets molecular beacons: an ultrasensitive fluorometric assay for nucleic acids. AB - An innovative signal amplification strategy assisted by RNase H is described here for the detection of DNA targets in a universal fashion. A tailor-made RNA molecular beacon (RMB) conjugated with a fluorescence resonance energy transfer (FRET) pair (fluorophore and quencher) was designed, characterized, and combined with the employment of RNase H. Its performance is compared to that of other nucleases including Exonuclease III and T7 exonuclease. Fluorometry, performed best at excitation/emission wavelengths of 490/520 nm, gives an amazingly low detection limit of 23 fM for target DNA. The method was verified by the determination of human hemochromatosis (HFE) gene. It is perceived that the method represents a versatile tool for the detection of a wide range of targets. Graphical Abstract An RNase H-assisted signal amplification (RASA) method for the fluorometric assay of nucleic acids has been developed by using a unique RNA molecular beacon (RNA MB) conjugated with a fluorophore (F) and quencher (Q) pair for signal generation. PMID- 30008089 TI - The importance of sensor contacting force for predicting fluid responsiveness in children using respiratory variations in pulse oximetry plethysmographic waveform. AB - Predicting fluid responsiveness is crucial for adequate fluid management. Respiratory variations in pulse oximetry plethysmographic waveform amplitude (DeltaPOP) are used to predict fluid responsiveness, but show inconsistent results when used for children. Contacting force between the measurement site and sensor can affect the DeltaPOP value, thereby hindering its reliability as an indicator. We studied the influence of contacting force on the efficacy of DeltaPOP as a fluid responsiveness indicator in children. In total, 43 mechanically ventilated children aged 1 month-5 years were studied. After anesthetic induction, mechanical ventilation began with a tidal volume of 10 ml/kg. DeltaPOP was calculated for five different contacting force groups (0 0.3N, 0.3-0.6N, 0.6-0.9N, 0.9-1.2N, and 1.2-1.5N) and individually adjusted contacting force. Pulse pressure variation (PPV), and DeltaVpeak were recorded before and after volume expansion. Subjects were considered as fluid responders if volume expansion increased the stroke volume index (SVI) by > 15%. Data from 38 patients were finally analyzed. A significant difference between the responders and non-responders was found only in DeltaPOPs at 0.9-1.2N contacting force (P = 0.002) and individually adjusted contacting force (P < 0.000), while other contacting force groups did not show significant differences. DeltaVpeak predicted a 15% increase in SVI (P = 0.008), whereas PPV did not. The ability of DeltaPOP to predict fluid responsiveness depends on the contacting force in mechanically ventilated children. When contacting force is controlled to an adequate degree, the ability of DeltaPOP to predict fluid responsiveness can be improved. PMID- 30008090 TI - Is There Causal Relationship of Smoking and Alcohol Consumption with Bone Mineral Density? A Mendelian Randomization Study. AB - Observational studies examining associations of smoking and alcohol consumption with bone mineral density (BMD) have generated inconsistent results and suffer from several methodological limitations. We aim to evaluate whether there are causal associations between smoking, alcohol consumption, and BMD using a Mendelian randomization (MR) design. Genetic variants associated with smoking status (n = 142), no. of cigarettes smoked per day (CPD) (n = 3), smoking initiation (n = 1), and alcohol consumption (n = 6) identified in published genome-wide association studies (GWAS) were used as instruments. Summary statistics data of 32735, 28498, 8143, and 445921 European subjects included in The GEnetic Factors for Osteoporosis Consortium or UK Biobank were used to generate associations of genetically predicted smoking or alcohol consumption with femoral neck (FN-BMD), lumbar spine (LS-BMD), forearm (FA-BMD), and heel BMD, respectively, by using the inverse-variance weighted method. The BMD was measured using either ultrasound (for heel) or Dual-energy X-ray Absorptiometry (for others). In our analyses, smoking status tended to be negatively associated with several types of BMD (heel BMD: beta = - 0.053, p = 0.003; FN-BMD: beta = - 0.139, p = 0.053; FA-BMD: beta = - 0.264, p = 0.077), although the association with LS-BMD was null. Smoking initiation was significantly inversely associated with heel BMD (beta = - 0.201, p = 3.60 * 10-8). CPD was associated with a lower FN-BMD (beta = - 0.014, p = 0.047) only. There was no clear association of genetically predicted alcohol consumption with BMD. Our study provided some evidence of a potential association between genetically predicted smoking and lower BMD, especially for heel BMD, but not for alcohol consumption. Considering the inconsistent findings with the different types of BMD and limitations of the current work, further studies are needed to better characterize the exact relationship between smoking, alcohol consumption, and BMD. PMID- 30008091 TI - Ultrastructure of Bone: Hierarchical Features from Nanometer to Micrometer Scale Revealed in Focused Ion Beam Sections in the TEM. AB - The ultrastructure of bone has been widely debated, in part due to limitations in visualizing nanostructural features over relevant micrometer length scales. Here, we employ the high resolving power and compositional contrast of high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) to investigate new features in human bone with nanometer resolution over microscale areas. Using focused ion beam (FIB)-milled sections that span an area of 50 MUm2, we have shown how most of the mineral of cortical human osteonal bone occurs in the form of long, thin polycrystalline plates (mineral lamellae, MLs) which are either flat or curved to wrap closely around collagen fibrils. Close to the collagen fibril (< 20 nm), the radius of curvature matches that of the fibril diameter, while at greater distances, MLs form arcs with much larger radii of curvature. In addition, stacks of closely packed planar (uncurved) MLs occur between fibrils. The curving of mineral lamellae both around and between the fibrils would contribute to the strength of bone. At a larger scale, rosette-like clusters of fibrils are noted for the first time, arranged in quasi-circular arrays that define tube-like structures in alternating osteonal lamellae. At the boundary between adjacent osteonal lamellae, the orientation of fibrils and surrounding mineral lamellae changes abruptly, resembling the "orthogonal" patterns identified by others (Reznikov et al. in Acta Biomater 10:3815-3826, 2014). These features spanning nanometer to micrometer scale have implications for our understanding of bone structure and mechanical integrity. PMID- 30008092 TI - Influence of Sodium Selenite on the mRNA Expression of the Mammalian Selenocysteine-Containing Protein Genes in Testicle and Prostate Cancer Cells. AB - The sodium selenite concentration that reduces the viability of Du-145 human prostate adenocarcinoma cells and F-9 mouse testicular teratocarcinoma cells was determined. We investigated the effect of sodium selenite on the mRNA expression level of the genes encoding mammalian selenocysteine-containing glutathione peroxidases and thioredoxin reductases (key antioxidant enzymes involved in the regulation of intracellular thiol redox balance), endoplasmic reticulum selenoproteins, and selenoproteins located in the testes and prostate. PMID- 30008093 TI - Creation of Bifunctional Indicating Complex Based on Nanodiamonds and Extracellular Oxidases of Luminous Fungus Neonothopanus nambi. AB - A bifunctional indicating complex was created by immobilization of extracellular oxidases (glucose oxidase and peroxidases) of luminous fungus Neonothopanus nambi onto modified nanodiamonds (MNDs) synthesized by detonation. It was found that the enzymes firmly adsorb onto MND particles and exhibit their catalytic activity. Model in vitro experiments showed that the created MND-enzymes complex is suitable for repeated use for analyte (glucose and phenol) testing and retains its activity after storage at 4 degrees C in deionized water for 1 month. The data obtained offer the prospects for developing a new class of reusable multifunctional indicating and diagnostic test systems on the basis of MNDs and higher fungal enzymes for medical and ecological analytics. PMID- 30008094 TI - Antimicrobial Activity of Geometric Isomers of Etherolenic Acid-the Products of Plant Lipoxygenase Cascade. AB - Data on the influence of the double bond geometry on the antimicrobial properties of different isomers of etherolenic acid against phytopathogenic bacteria are presented. (omega5Z)-Etherolenic acid possesses bactericidal properties against Xanthomonas campestris ssp. vesicatoria, Pseudomonas syringae ssp. tomato, Pectobacterium atrosepticum SCRI1043; the etherolenic and (11Z)-etherolenic acids possess only bacteriostatic properties. PMID- 30008095 TI - Effect of Glutamine Synthetase Gene Overexpression in Birch (Betula pubescens) Plants on Auxin Content and Rooting in vitro. AB - The effects of transformation of downy birch (Betula pubescens Ehrh.) with the GS1 gene encoding the cytosolic form of glutamine synthetase on the rooting of plants in vitro was studied. The transgenic plants had an elevated content of glutamine as well as glutamic and aspartic acids and rooted more rapidly than the control plants. Rooting on a medium containing the glutamine synthetase inhibitor phosphinothricin prevented the accumulation of auxin in birch plants carrying the GS1 gene, indicating the involvement of this enzyme in raising the level of auxins in the transgenic plants. The correlation between the increase in the auxin levels in the transgenic plants carrying the glutamine synthetase gene and the increase in the rooting rate is shown for the first time. PMID- 30008096 TI - Study of Human Fibrinogen Oxidative Modification using Differential Scanning Calorimetry. AB - For the first time, with the aid of differential scanning calorimetry, the thermal denaturation of fibrinogen under induced oxidation was studied. All fibrinogen structural elements detected by DSC (D region, alphaC-domain, and E region) are subjected to oxidation. Structural changes in fibrinogen molecule were characterized by the denaturation temperature, denaturation enthalpy, and van't Hoff enthalpy. PMID- 30008097 TI - The Principle of Competitive Exception in a Two-Species Community with One Metabolic Regulation Factor. AB - The validity of the competitive exclusion principle (the Gause's principle) at one metabolic regulation factor is demonstrated for a general model of two species community. The competitive exclusion principle postulates that a long term coexistence of species is impossible if their number exceeds the number of density-dependent growth-regulating factors. Previously, this principle was proved for the stationary states in a general model of a community with any number of factors. In the dynamic modes, the number of species in a community may exceed the number of regulating factors. However, under the influence of one factor, only one species survives. PMID- 30008098 TI - Epoxygenase Inhibitors Attenuate the Stimulatory Effect of Glutoxim on Na+ Transport in Frog Skin. AB - Using voltage-clamp technique, the involvement of epoxygenases in immunomodulatory drug glutoxim regulation of Na+ transport in frog skin was investigated. We have shown for the first time that preincubation of the frog skin with epoxygenase inhibitors econazole or proadifen almost completely inhibits the stimulatory effect of glutoxim on Na+ transport. The data suggest the involvement of the enzymes and/or products of epoxygenase oxidation pathway of arachidonic acid metabolism in glutoxim effect on Na+ transport in frog skin epithelium. PMID- 30008100 TI - A Universal Tumor-Specific Promoter for Cancer Gene Therapy. AB - An artificial double tandem tumor-specific promoter based on survivin and human telomerase reverse transcriptase gene promoters was constructed. Studies in in vitro and ex vivo therapeutic systems showed that the designed promoter exhibits a high activity in tumor cells, which is comparable to the activity of the CMV constitutive promoter. PMID- 30008099 TI - Identification of the ORC Complex Subunits That Can Interact with the ENY2 Protein of Drosophila melanogaster. AB - The interaction of the Drosophila ENY2 protein with the ORC complex subunits was investigated. It is found that ORC4 and ORC6 subunits directly interact with ENY2. PMID- 30008101 TI - Sigma-1 Receptor Antagonist Haloperidol Attenuates Store-Dependent Ca2+ Entry in Macrophages. AB - Using Fura-2AM microfluorimetry, we have shown for the first time that preincubation of macrophages with sigma-1 receptor antagonist haloperidol leads to a significant inhibition of the store-dependent Ca2+ entry induced by endoplasmic Ca2+-ATPase inhibitors thapsigargin or cyclopiazonic acid in rat peritoneal macrophages. The results suggest the involvement of the sigma-1 receptor in the regulation of storedependent Ca2+ entry in macrophages. PMID- 30008102 TI - Study of the Ability of the gypsy Insulator to Stabilize Amplification of the chorion Replication Origin of Drosophila melanogaster. AB - The role of the gypsy insulator in the replication origin (RO) activity in the presence and absence of one and two copies of this insulator in several genomic sites was studied. Due to the fact that the prepared model system makes it possible to study the activity of this element in a given genomic site, it was shown that the RO stabilization, indeed, is determined by the activity of the insulator rather than by the construct integration site into the genome. The role of the Su(Hw) protein in this process was also studied in detail. PMID- 30008103 TI - The Sensitivity of Resting Eggs of the Cladoceran Moina macrocopa to the Effect of Ionizing Radiation during the Reactivation of the Eggs. AB - We investigated the sensitivity of resting eggs of the cladoceran Moina macrocopa to the effect of ionizing radiation during the reactivation of the eggs. The study showed that the resting eggs during reactivation are more vulnerable to irradiation than the resting eggs in a stage of deep dormancy. The decrease in the efficiency of egg reactivation was observed at high doses, the growth rate of juveniles, fecundity, and the number of produced clutches by females strongly decreased when resting eggs at the reactivation stage absorbed doses of 64 Gy and higher. PMID- 30008104 TI - Detection of Hispidin by a Luminescent System from Basidiomycete Armillaria borealis. AB - In in vitro experiments, the possibility of using a luminescent system extracted from the luminous fungus Armillaria borealis has been shown to detect and determine the concentration of hispidin. A linear dependence of the luminescent response on the content of hispidin in solutions in the concentration range of 5.4 * 10-5-1.4 * 10-2 uM was detected. The stability of the enzyme system and the high sensitivity of the bioluminescent reaction allows carrying out multiple measurements with the analyte detection limit of 1.3 * 10-11 g. The obtained results show the prospects of creating a rapid bioluminescent method for the analysis of medical substances or extracts from various biological objects for the presence of hispidin. PMID- 30008106 TI - The insulinotropic effect of a high-protein nutrient preload is mediated by the increase of plasma amino acids in type 2 diabetes. AB - AIMS: Eating protein before carbohydrate reduces postprandial glucose excursions by enhancing insulin and glucagon-like peptide-1 (GLP-1) secretion in type 2 diabetes (T2D). We tested the hypothesis that this insulinotropic effect depends on the elevation of plasma amino acids (AA) after the digestion of food protein. METHODS: In 16 T2D patients, we measured plasma AA levels through the course of two 75-g oral glucose tolerance tests (OGTT) preceded by either 500-ml water or a high-protein nutrient preload (50-g Parmesan cheese, one boiled egg, and 300-ml water). Changes in beta cell function were evaluated by measuring and modelling plasma glucose, insulin, and C-peptide through the OGTT. Changes in incretin hormone secretion were assessed by measuring plasma GLP-1. RESULTS: Plasma AA levels were 24% higher after the nutrient preload (p < 0.0001). This increment was directly proportional to both the enhancement of beta cell function (r = 0.58, p = 0.02) and the plasma GLP-1 gradients (r = 0.57, p = 0.02) produced by the nutrient preload. Among single AA, glutamine showed the strongest correlation with changes in beta cell function (r = 0.61, p = 0.01), while leucine showed the strongest correlation with GLP-1 responses (r = 0.74, p = 0.001). CONCLUSIONS: The elevation of circulating AA that occurs after a high-protein nutrient preload is associated with an enhancement of beta cell function and GLP-1 secretion in T2D. Manipulating the meal sequence of nutrient ingestion may reduce postprandial hyperglycaemia through a direct and GLP-1-mediated stimulation of insulin secretion by plasma AA. TRIAL REGISTRATION NUMBER: NCT02342834. PMID- 30008107 TI - Oral Potentially Malignant Disorder Based Customized Epithelial Dysplasia Grading: a Need of the Hour. PMID- 30008105 TI - Isolation and Purification of Fungal Luciferase from Neonothopanus nimbi. AB - This is the first study to obtain a high-purity luciferase from the fungus Neonothopanus nambi biomass that is suitable for subsequent sequencing. PMID- 30008109 TI - Comparison of combined posterior and anterior spondylodesis versus hybrid stabilization in unstable burst fractures at the thoracolumbar spine in patients between 60 and 70 years of age. AB - INTRODUCTION: Surgical treatment of unstable burst fractures of the thoracolumbar spine in the elderly population is highly variable with combined posterior and anterior stabilization (CPAS) and posterior augmented stabilization with cementation of the vertebral body (hybrid) being two commonly used techniques. The aim of this study was to compare the clinical and radiographic outcomes of CPAS versus hybrid stabilization for the treatment of unstable burst fractures of the thoracolumbar spine in patients aged between 60 and 70 years. MATERIALS AND METHODS: A retrospective analysis was performed of all thoracolumbar burst fractures treated surgically in a single level I trauma center between June 2013 and February 2015. Two commonly used strategies of surgical stabilization were compared; the first consisted of initial posterior reduction and bisegmental stabilization, followed by additional anterior spondylodesis (CPAS); the second method comprised a hybrid technique with a posterior cement augmented bisegmental minimally invasive stabilization and kyphoplasty of the fractured vertebral body. Patients were evaluated clinically after a minimum follow-up of 18 months. The primary endpoint was the Oswestry Disability Index (ODI) at the latest follow-up. Secondary parameters of interest were length of in-hospital stay (LIHS), duration of surgery (DS), surgical revisions (SR), pain level (P-VAS), satisfaction level and the SF-36 score (PSC, MSC), the bisegmental postoperative Cobb angle, the reduction loss (RL), and all alignment parameters (pelvic tilt, pelvic incidence, sacral slope, lumbar lordosis, C7 plumb line). RESULTS: A total of 29 patients were included (17 females, 12 males, mean age 65.6 years +/- 3.4 years). The following vertebral bodies were fractured: thoracic level (T) 12: n = 6; lumbar (L) 1: n = 14; L 2: n = 6; L 3: n = 3. CPAS was performed in 10 patients (34%), whereas the hybrid was carried out in 19 patients (66%). There were no statistical significant differences between both study groups regarding age, gender, trauma energy, fracture level, and fracture morphology. The latest follow up was performed after a mean of 27 months (range 18-53 months). The LIHS between the treatment methods was statistically significant (p < 0.01); CPAS-mean 24 days versus hybrid-mean 12 days. DS was also significantly longer in patients treated with CPAS, 254 versus 95 min for the hybrid group (p < 0.01). No SR were necessary in either group. No significant differences were found regarding the clinical and radiological outcomes between the groups. The mean ODI score was 13.6 in the CPAS patients compared to 10.8 in the hybrid patients without significant differences between the groups. The majority of patients had no (80%) or minor (13%) limitations according to the ODI score. The P-VAS was 2.8 in CPAS and 2.9 in the hybrid group. RL was 7.1 degrees in CPAS and 4.2 degrees in the hybrid group. CONCLUSIONS: CPAS and hybrid stabilization provide safe and promising short- and middle-term results in patients between 60 and 70 years of age. The majority of patients demonstrated no disability or minimal limitations with either technique. CPAS resulted in prolonged inpatient hospital stays, longer duration of surgery compared to hybrid stabilization without significant differences in clinical and radiological outcome. PMID- 30008108 TI - BrFLC5: a weak regulator of flowering time in Brassica rapa. AB - KEY MESSAGE: A splicing site mutation in BrFLC5, a non-syntenic paralogue of FLOWERING LOCUS C, was demonstrated to be related to flowering time variation in Brassica rapa. Flowering time regulation in Brassica rapa is more complex than in Arabidopsis, as there are multiple paralogues of flowering time genes in B. rapa. Brassica rapa contains four FLOWERING LOCUS C (FLC) genes, three of which are syntenic orthologues of AtFLC, while BrFLC5 is not. BrFLC1, BrFLC2, and BrFLC3 have been reported to be involved in flowering time regulation. However, BrFLC5 has thus far been deemed a pseudogene. We detected two alternative splicing patterns of BrFLC5 resulting from a nucleotide mutation (G/A) at the first nucleotide of intron 3 (named as Pi3+1(G/A)). Genotyping of BrFLC5Pi3 + 1(G/A) for 301 B. rapa accessions showed that this single nucleotide polymorphism was significantly related to flowering time variation (p < 0.001). In the collection, the frequency of the functional G allele (35.2%) was much lower than that of the nonfunctional A allele (59.1%); however, the frequency of the G allele was very high among the turnips (83.6%). An F2 population segregating at this locus was developed to analyze the genetic effect of BrFLC5. The result showed that the G allele individuals began to bolt two days later than the A allele individuals, indicating that BrFLC5 is a weak regulator of flowering time. BrFLC5 was expressed at the lowest level among the three analyzed BrFLCs. The late allele (G allele) was dominant to the early allele (A allele) at the BrFLC5 locus, which was in contrast to that of BrFLC1 and BrFLC2. This characteristic suggests that BrFLC5 would be more efficient for breeding premature bolting resistance in B. rapa. PMID- 30008110 TI - Reply to the Letter to the Editor from Peters et al: On the use of the liver as a reference organ for Deauville scoring in lymphoma patients and how it may be affected by liver steatosis. PMID- 30008111 TI - Hypermetabolism in the cerebellum and brainstem and cortical hypometabolism are independently associated with cognitive impairment in Parkinson's disease. AB - PURPOSE: Cognitive impairment (CI) in Parkinson's disease (PD) is associated with a widespread reduction in cortical glucose metabolism and relative increases in the cerebellum and brainstem as measured using 18F-fluorodesoxyglucose (FDG) PET. We separately analysed CI-related hypermetabolism and hypometabolism in comparison with neuropsychological test performance and investigated whether increased FDG uptake is a true feature of the disease or a normalization effect. METHODS: The study included 29 subjects (12 patients with PD, 10 patients with PD dementia and 7 healthy controls") who underwent FDG PET and comprehensive neuropsychological testing. Test performance across various cognitive domains was summarized in a cognitive staging score. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism (rCGM) were calculated: index(-) for CI-related hypometabolism, and index(+) for CI-related hypermetabolism. We tested whether index(+) offered additional value in predicting the severity of CI in multiple regression analysis. RESULTS: At higher stages of CI, increased rCGM was found in the posterior cerebellar vermis and pons, associated with impaired attention, executive function and memory. Reduced rCGM was found in various cortical regions in agreement with the literature. In multiple regression analysis, both indices independently predicted the severity of CI with a whole model R2 of 0.68 (index(-), p = 0.0006; index(+), p = 0.013), confirmed by alternative analyses combining different reference tissues in the multiple regression. CONCLUSION: We found CI-related hypermetabolism in cerebellar regions that are known to be involved in several cognitive functions and in the pons. These alterations may represent compensatory activation of cognitive networks including cerebropontocerebellar tracts. PMID- 30008112 TI - The gut microbiota of critically ill patients: first steps in an unexplored world. PMID- 30008114 TI - The better outcomes of diffuse large B-cell lymphoma in adolescents and young adults. PMID- 30008113 TI - Characterization of the interactions between coumarin-derivatives and acetylcholinesterase: Examination by NMR and docking simulations. AB - Alzheimer's disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (KD) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with KD = 30 MUM ,even greater than tacrine (KD = 140 MUM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future. PMID- 30008116 TI - Highlights of Issue 8, 2018. PMID- 30008117 TI - Lyme borreliosis as a trigger for NMDA receptor encephalitis? PMID- 30008118 TI - Amygdala response and functional connectivity during cognitive emotion regulation of aversive image sequences. AB - Emotion regulation (ER) is crucial in terms of mental health and social functioning. Attention deployment (AD) and cognitive reappraisal (CR) are both efficient cognitive ER strategies, which are based on partially dissociated neural effects. Our understanding of the neural underpinnings of ER is based on laboratory paradigms that study changes of the brain activation related to isolated emotional stimuli. To track the neural response to ER in the changing and dynamic environment of daily life, we extended the common existing paradigms by applying a sequence of emotionally provocative stimuli involving three aversive images. Eighteen participants completed an ER paradigm, in which they had to either shift their attention away from the emotionally negative images by counting backwards (AD strategy) or reinterpret the meaning of stimuli (CR strategy) to attain a down-regulation of affective responses. An increased recruitment of left-sided lateral and medial PFC was shown upon regulation of negative emotions with CR as compared to AD. Remarkably, the amygdala activation showed an increasing pattern of activation during CR. The inverse relationship between PFC and amygdala was compromised during elongated blocks of reappraisal, reflecting a reduction in engagement of the top-down prefrontal regulatory circuitry upon repeated exposure to negative stimuli. These results highlight that temporal dynamic of amygdala response and its functional connectivity differentiates AD and CR strategies in regulating emotions. Findings of the current study underscore the importance of adopting temporally variant approaches for investigating the neural effects of ER. Identifying neural systems that subserve down-regulation of negative emotions is of importance in developing treatment strategies for various forms of psychopathology. PMID- 30008115 TI - The dark side of laparoscopic surgery for colorectal cancer patients aged 75 years or older. AB - PURPOSE: The rate of postoperative morbidity and mortality is reportedly high in patients aged >= 75 years with colorectal cancer (CRC). In such patients, a comparison of the short-term outcome between open method and laparoscopy has not been clearly defined in Taiwan. We aimed to compare postoperative morbidity and mortality parameters after open method and laparoscopy in CRC patients aged >= 75 years. METHODS: We retrospectively analyzed patients who underwent surgery for CRC from February 2009 to September 2015 at the Linkou Chang Gung Memorial Hospital in Taiwan and analyzed their clinicopathological factors. Postoperative morbidity and mortality were analyzed for evaluating if laparoscopic surgery offers more favorable outcomes than open surgery in the elderly. RESULTS: A total of 1133 patients were enrolled and analyzed in this study; they were divided into two groups (open method vs. laparoscopy = 797 vs. 336). The anastomotic leakage rate was significantly higher in the laparoscopy group than in the open method group (3.3 vs. 0.9%, p = 0.003). Overall postoperative morbidity and mortality rates showed no significant difference between these two groups. Postoperative hospital stay was significantly shorter in the laparoscopy group than in the open method group (10.4 +/- 8.7 vs. 13.8 +/- 13.5 days, p < 0.001). CONCLUSIONS: Our results suggest that laparoscopy in patients aged >= 75 years with CRC had higher anastomosis leakage rate compared with open surgery but is acceptable and offers the benefit of a shorter hospital stay over open surgery. PMID- 30008119 TI - Is (S)-norketamine an alternative antidepressant for esketamine? PMID- 30008120 TI - Reconsidering clinical pharmacology frameworks as a necessary strategy for improving the health care of patients: a systematic review. PMID- 30008121 TI - Dexmedetomidine as a sedative and analgesic adjuvant in spine surgery: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: This systematic review and meta-analysis appraise the clinical evidence on efficacy and safety of dexmedetomidine (DEX), as a sedative and analgesic adjunct in adult patients undergoing spine surgery. METHODS: A database search was conducted to identify randomized clinical trials (RCTs) pertinent to the perioperative use of DEX in spine surgery. Sedative and analgesic efficacy of DEX constituted the primary outcomes, whilst the incidence of hemodynamic changes, quality of recovery and occurrence of adverse events served as secondary ones. RESULTS: Fifteen studies enrolling a total of 913 patients were selected for qualitative analysis, among which eight RCTs incorporating a placebo comparison group were included in the meta-analysis. Most of the retrieved studies were of moderate to good quality and demonstrated an acceptable risk of bias. DEX-treated patients showed a significant reduction of both propofol [mean difference (MD), 214.47 mg; 95%CI, -253.16 to -175.78; P < 0.001] and morphine equivalents consumption both intraoperatively and postoperatively (MD, -2.69; 95% CI, -3.05 to -2.33; P < 0.001 and MD, -4.36 mg; 95%CI, -6.93 to -1.79; P < 0.001, respectively) compared to those assigned to placebo. Postoperative nausea and vomiting incidence were comparable between DEX and placebo groups, whilst other adverse events were not consistently reported. CONCLUSIONS: DEX emerges as an attractive alternative to standard sedative and analgesic modalities applied in spine surgery, by attaining a notable sedative and opioid-sparing effect, which goes with an enhanced safety profile. Yet, no definite conclusion can be drawn due to the considerable heterogeneity of available data. TRIAL REGISTRATION: PROSPERO CRD42015029537. PMID- 30008122 TI - A novel mutation KCNQ1p.Thr312del is responsible for long QT syndrome type 1. AB - Patients with high-risk long QT syndrome (LQTS) mutations may experience life threatening cardiac events. The present study sought to characterize a novel pathogenic mutation, KCNQ1p.Thr312del, in a Chinese LQT1 family. Clinical and genetic analyses were performed to identify this novel causative gene mutation in this LQTS family. Autosomal dominant inheritance of KCNQ1p.T312del was demonstrated in the three-generation pedigree. All mutation carriers presented with prolonged QT intervals and experienced recurrent syncope during exercise or emotional stress. The functional consequences of the mutant channel were investigated by computer homology modeling as well as whole-cell patch-clamp, western-blot and co-immunoprecipitation techniques using transfected mammalian cells. T312 is in the selectivity filter (SF) of the pore region of the KCNQ1 encoded channel. Homology modeling suggested that secondary structure was altered in the mutant SF compared with the wild-type (WT) SF. There were no significant differences in Kv7.1 expression, membrane trafficking or physical interactions with KCNE1-encoded subunits between the WT and mutant transfected channels. However, the KCNQ1p.T312del channels expressed in transfected cells were non functional in the absence or presence of auxiliary KCNE1-subunits. Dominant negative suppression of current density and decelerated activation kinetics were observed in cells expressing KCNQ1WT and KCNQ1p.T312del combined with KCNE1 (KCNQ1WT/p.T312del + KCNE1 channels). Those electrophysiological characteristics underlie the pathogenesis of this novel mutation and also suggest a high risk of cardiac events in patients carrying KCNQ1p.T312del. Although protein kinase A dependent current increase was preserved, a significant suppression of rate dependent current facilitation was noted in the KCNQ1WT/p.T312del + KCNE1 channels compared to the WT channels during 1- and 2-Hz stimulation, which was consistent with the patients' phenotype being triggered by exercise. Overall, KCNQ1p.Thr312del induces a loss of function in channel electrophysiology, and it is a high-risk mutation responsible for LQT1. PMID- 30008123 TI - Follow-up tests and outcomes for patients undergoing percutaneous coronary intervention: analysis of a Japanese administrative database. AB - Follow-up tests after percutaneous coronary intervention (PCI) are considered inappropriate for asymptomatic patients. Despite this perception, many cardiologists conduct follow-up tests as routine practice. The objective of this study was to investigate the survival benefits of follow-up testing after PCI in a real-world setting in Japan. A nationwide Japanese administrative database was used to identify unselected patients who underwent PCI with stent implantation between January 2010 and December 2013. We used time-dependent Cox proportional hazards models to evaluate the association between follow-up testing and outcomes. The primary outcome was the composite of all-cause death and acute myocardial infarction (AMI). Among a total of 21,409 patients, 15,095 (70.5%) completed follow-up testing, of whom 9814 (45.0%) underwent coronary angiography. During a median of 2.7 years of observation, the primary outcome occurred less frequently for patients who underwent follow-up testing (1.21 vs. 4.51% per year; adjusted hazard ratio, 0.59; 95% CI 0.52-0.67; p < 0.001). Individual rates of all-cause death and AMI were also lower for the patients who underwent follow-up testing. Follow-up testing was associated with a lower risk of all-cause death and/or AMI. However, because of the unexpectedly large effect and many limitations of the administrative data, our findings should be further investigated to assess the net benefit of follow-up tests. In addition, we do not intend to encourage routine follow-up tests for patients without clear clinical indications. Follow-up tests should be conducted in accordance with clinical indications. PMID- 30008125 TI - Evaluation of IVD 3.0 Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of Mycobacterium tuberculosis and nontuberculous mycobacteria and its use in routine diagnostics. PMID- 30008124 TI - Viral Hypothesis and Antiviral Treatment in Alzheimer's Disease. AB - PURPOSE OF REVIEW: Viruses, particularly herpes simplex virus (HSV), may be a cause of Alzheimer's disease (AD). The evidence supporting the viral hypothesis suggests that antiviral treatment trials, which have not been conducted, are warranted. RECENT FINDINGS: HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid aggregation, and their DNA is common in amyloid plaques. HSV1 reactivation is associated with tau hyperphosphorylation and possibly tau propagation. Anti-HSV drugs reduce Abeta and p-tau accumulation in infected mouse brains. Clinically, after the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and recurrent reactivation may produce neuronal damage and AD pathology. Clinical studies show cognitive impairment in HSV seropositive patients, and antiviral drugs show strong efficacy against HSV. An antiviral treatment trial in AD is clearly warranted. A phase II treatment trial with valacyclovir, an anti-HSV drug, recently began with evaluation of clinical and biomarker outcomes. PMID- 30008126 TI - Early detection of M. leprae by qPCR in untreated patients and their contacts: results for nasal swab and palate mucosa scraping. AB - To verify if the hard palate mucosa can be a site of relevance in the early molecular detection of Mycobacterium leprae in leprosy cases and their household contacts and if there is a correlation of results in nasal swab with those of the scraping of the palate mucosa. The quantitative polymerase chain reaction technique was used. Sample included 78 patients with untreated leprosy (G1), their 54 household contacts (G2), and 80 healthy individuals for the negative control (G3). The presence of M. leprae in both G1 and G2 was observed with the nasal swab and the palate mucosa scrapings methods, and it was shown that the sensitivity between the qPCR exams for RLEP and 85B genes is equivalent, with no statistically significant differences (G1 positivity of 35% in the hard palate mucosa and 44% for the nasal one, p = 0.3731 and for G2 of 31 and 38%, respectively, p = 0.6774). Results support the fact that the buccal mucosa and nasal mucosa may be important sites of primary infection of leprosy with repercussion in the transmission chain and that asymptomatic household contacts are heavily harbored by the causative agent of leprosy, which has a critical significance in the prevention and control action of this disease, since the evaluation of these sites arises as of importance in the early detection of M. leprae. Close monitoring and chemoprophylaxis of household contacts appear to be critical to attain interruption of the transmission of leprosy in endemic countries. PMID- 30008127 TI - Foot function in rheumatoid arthritis patients: a cross-sectional study. AB - Rheumatoid arthritis (RA) is a chronic disease that affects mainly small joints from hands and feet. The aims of this study were to analyze the prevalence of foot involvement in a sample of Brazilian RA patients and to explore the influence of disease variables such as inflammatory activity, serological, and epidemiological profile in this type of involvement. One hundred RA patients and 100 healthy controls paired for gender, age, and body mass index answered the FFI BR (Foot Functional Index-Brazilian version) that evaluates foot function. RA patients had epidemiological and clinical data collection upon direct questioning and chart review. C-reactive protein (CRP), ESR (erythrocyte sedimentation rate), and DAS28-ESR were used to measure disease activity. In the RA sample, 98% had foot pain versus 76% in the controls (p < 0.0001; OR = 15.4; 95% CI = 3.4-67.5); 96% had some difficulty in function versus 66% of controls (p < 0.0001; OR = 12.3; 95% CI = 4.1-36.5); and 73% had some incapacity versus 20% of controls (p < 0.0001; OR = 10.8; 95% CI = 5.5-20.9). Values of FFI-BR showed correlation with ESR (p = 0.006), CRP (p = 0.01), and DAS28-ESR (p < 0.0001). No association between FFI-BR total score and gender, ethnic background, positive rheumatoid factor, tobacco exposure, and any of used medications was found (all p = ns). The majority of RA patients suffers from foot problems and was associated with inflammatory biomarkers. The control of inflammatory activity may help in the treatment of this problem. PMID- 30008128 TI - Bisphosphonates in the treatment of complex regional pain syndrome: is bone the main player at early stage of the disease? AB - Complex Regional Pain Syndrome type 1 (CRPS-1) is a disabling painful disease whose hallmark is pain disproportionate to inciting event. CRPS is also characterized by symptoms and signs, such as vasomotor, sudomotor, trophic and motor changes. Therapeutic approach of CRPS-1 still remains a challenge for clinicians treating a disease with potential heavy consequences on patient prognosis. In the past years, the treatment with bisphosphonates (BPs) has gained some success as confirmed by the results of a number of meta-analyses. The aim of this paper is to point out the pivotal role of bone in CRPS pathogenesis. The efficacy of BPs is likely to be related to bone tissue involvement in the early pathophysiological steps of the disease, as demonstrated by evidences highlighting the central role of bone in the initial phases. Bone can become a source of inflammatory cytokines when triggered by a direct injury. Moreover, peptidergic fibers that innervate both mineralized bone and bone marrow can play a role in triggering or maintaining the microvascular disturbance at bone level. Indeed, bone involvement is consistent with the mineralization disturbance as well as the results of instrumental investigations (e.g., MRI, bone scan). In this regard, an intriguing issue relies on the excellent therapeutic response to BPs treatment of other diseases (e.g., Transient Osteoporosis of the Hip and Regional Migratory Osteoporosis) that share with CRPS-1 some clinical and instrumental features. PMID- 30008130 TI - Life Expectancy of Olympic Wrestling Champions in Comparison to the General Population. AB - Although it was presumed that moderate exercise is a healthy practice but long term high intensity exercise is not, studies observed a life expectancy benefit for both high-intensity endurance and fast power sports athlets, but the data for contact sports are conflicting. Therefore, the author aimed to investigate the life expectancy of Olympic wrestling champions in comparison to the general population. Characteristics, vital status and life-span of the male Olympic wrestling champions was collected (1896-2016). The life expectancy of Olympic champions was compared with matched individuals of the general population (by country, age, and year of birth) obtained from the human mortality database ( http://www.mortality.org ). Overall, 341 male Olympic wrestling champions with median age of 25 (IQR 24-28) years at their Olympic victory were included in this analysis. In total, 142 (41.6%) came of rich countries. The survival was not affected by weight class and country of origin. A significant life expectancy benefit for Olympic champions in comparison to the general population was observed. Male Olympic wrestling champions lived in mean 19.1 +/- 19.1 years longer than the matched individuals of the general population (respectively of their country of origin). A substantially lower mortality in male Olympic wrestling champions, compared with the general male population was observed. However, the results do not allow us to draw conclusions about the causes of this survival benefit. PMID- 30008129 TI - Vitamin D insufficiency, hemoglobin, and anemia in children with chronic kidney disease. AB - BACKGROUND: 25-Hydroxyvitamin D (25OHD) deficiency is common in children with chronic kidney disease (CKD). It has been associated with an increased risk for anemia in both healthy US children and in adults with CKD. This association has not been explored in children with CKD. METHODS: Children aged 1-16 enrolled in the Chronic Kidney Disease in Children (CKiD) study with mild to moderate kidney dysfunction, and with 25OHD measured at baseline (n = 580), were included in the analysis. The cross-sectional associations between 25OHD and hemoglobin (g/dL) and anemia were assessed. Anemia was defined as hemoglobin < 5th percentile for age and sex. RESULTS: Overall 334 (57.59%) children were vitamin D insufficient/deficient and 137 (23.62%) were anemic. Of those who were vitamin D insufficient/deficient, 95 (28.44%) were anemic. In the overall cohort, the odds of being anemic was 1.9 times higher (95% CI, 1.22-3.04, p < 0.01) in vitamin D insufficient/deficient vs sufficient children, when adjusting for covariates (age, sex, race [black, white, or other], body mass index (BMI), iohexol GFR (iGFR), erythropoietin stimulation agent (ESA) use, iron supplementation use, and underlying cause of CKD). Stratified by race, the odds of being anemic was 2.39 times higher (95% CI, 1.41-4.05, p = 0.001) in vitamin D insufficient/deficient vs vitamin D sufficient white children. The association between vitamin D status and anemia was not significant in black children. CONCLUSIONS: The data support our hypothesis that vitamin D insufficiency/deficiency increases the odds of anemia in children with CKD. The effect was strong and significant among white, but not black, children. PMID- 30008131 TI - Effect of heat stress on the behavioral and physiological patterns of Small-tail Han sheep housed indoors. AB - This study was conducted to investigate the effects of heat stress on the behavioral and physiological patterns in Small-tail Han sheep housed indoors in summer without climate control. Sixteen adult animals were allocated into two groups of eight animals, based on sex: one group of eight rams and one group of eight ewes. Temperature-humidity index (THI) was used to assess the degree of heat stress. All sheep were subjected to a 10-day pre-experimental period of habituation to the experimental feed and environment. Physiological parameters monitored were respiratory rate (RR), rectal temperature (RT), and heart rate (HR). Blood chemistry parameters were also recorded, including plasma minerals and blood metabolites, from jugular vein blood samples. Behavioral parameters were lying, standing, excreting, drinking, foraging, walking, and ruminating. The research findings showed that there were some significant differences of behavior (standing, P = 0.001; walking, P = 0.049; ruminating, P = 0.010), physiology (RR, P = 0.0001; HR, P = 0.002; RT, P = 0.03;) and plasma minerals and blood metabolites (sodium, P = 0.047; phosphorus, P = 0.002; T4, P = 0.041; cortisol, P = 0.0047; triglyceride, P = 0.009) between ram and ewe and that heat stress also significantly affected (P < 0.05) standing, lying, foraging and drinking behavior, all of the physiological parameters and some of the blood chemistry parameters (chlorides, sodium, phosphorus, total protein, tetraiodothyronine, cholesterol, triglyceride, creatinine, cortisol, and glucose). These results indicate that ewe has better high-temperature tolerance than ram, and heat stress can alter behavioral and physiological patterns in Small-tail Han sheep housed indoors. These changes may allow the sheep to adapt better to the ambient temperature. PMID- 30008132 TI - Pleurotus ostreatus extract inhibits Eimeria species development in naturally infected broiler chickens. AB - Coccidian organisms of poultry have proved very hard to control due to their abilities to resist most anticoccidial drugs. Pleurotus ostreatus (Fr.) Jacq. ex (Pleurotaceae), a medicinal mushroom, was investigated in vivo against Eimeria spp. Ninety-six broilers (day-old) naturally infected with Eimeria spp. were divided into eight groups (12 birds per group). Group A was infected untreated (negative control) and group B was treated with toltrazuril (positive control) while groups C-H were gavaged with graded doses of P. ostreatus extract at 100, 200, 300, 400, 500, and 600 mg/kg, respectively. The phytochemical analysis of the aqueous extract of P. ostreatus which revealed saponins, flavonoids, anthraquinones, and alkaloids was evaluated for anticoccidial activity by assessing the inhibition of oocyst output, lesion score, faecal score, weight differences, haematological parameters, and leucocyte differential counts. The acute toxicity study showed extract of P. ostreatus to be non-toxic at 600 mg/kg. The weight of the groups treated with the extracts and toltrazuril increased significantly (P < 0.05) compared with the untreated control. Treated groups significantly (P < 0.05) reduced oocyst output except groups C and D. The therapeutic best-fit ED50 value for the extract was 448 mg/kg. The post-treatment mean packed cell volume and red blood cell count were significantly higher (P < 0.05) than the untreated group, while the WBC count was significantly higher (P < 0.05) in the untreated group. Pleurotus ostreatus therefore could be a potential source of new anticoccidial medicine which could find application in the control of avian coccidiosis. PMID- 30008133 TI - Nutrient deficiency promotes male-biased apparent sex ratios at the ramet level in the dioecious plant Myrica gale var. tomentosa in oligotrophic environments in bogs. AB - In populations of dioecious plants, the differences in the cost of reproduction between male and female plants can promote a male-biased sex ratio. In this study, we examine the macronutrient levels in tissues of the dioecious wetland shrub Myrica gale to identify the cost of reproduction for male and female plants and to examine the effect of nutrients on the apparent sex ratio at the ramet level. We examined plants across 12 populations of M. gale inhabiting bogs and fens in Japan. For each population, we used line transects to estimate the apparent sex ratio and measured the concentrations of nitrogen (N), phosphorus (P), and potassium (K) in the leaves sampled from male and female plants and in the fruits from female plants. For five of the populations, we calculated the flowering frequency, mortality, and the recruitment rate (as the rate of clonal propagation). We found that the proportion of females was positively affected, and the male bias of sex ratios reduced, by increases in P concentration in leaves sampled from female plants. Neither mortality nor recruitment was affected by sex or by the nutrient concentration (P, K). The flowering frequency was not affected by sex or by K concentration, but decreased with decreases in the P concentration measured in leaves. This study confirmed that reproduction in M. gale is P-limited. We found no distinct differences in the flowering frequency, mortality, or recruitment rate between the male and female plants. PMID- 30008134 TI - Molecular characterisation and risk factor analysis of Cryptosporidium spp. in calves from Italy. AB - To provide up-to-date information on the occurrence of Cryptosporidium in pre weaned calves from Sardinia (Italy), the species implicated and their zoonotic potential, 147 faecal samples from 22 cattle herds were microscopically examined for Cryptosporidium oocysts; positive isolates were molecularly characterised. A questionnaire was developed to identify risk factors for Cryptosporidium infection. Overall, the percentage of positive calves and farms was 38.8 and 68.2%, respectively. The SSU rRNA-based PCR identified two Cryptosporidium species, Cryptosporidium parvum (95.8%) and C. bovis (4.2%). Sequence analyses of the glycoprotein (gp60) gene revealed that all C. parvum isolates belonged to the subtype family IIa (IIaA15G2R1 and IIaA16G3R1), with the exception of three isolates that belonged to the subtype family IId (IIdA20G1b and IIdA20). Mixed logistic regression results indicated that calves aged 15-21 days were more likely to be Cryptosporidium-positive. The risk of being positive was also significantly higher in herds from Central Sardinia and in farms using non slatted flooring. In addition, the application of disinfectants and milk replacers was significantly associated with higher Cryptosporidium prevalence. In contrast, the risk of being positive was significantly reduced in halofuginone treated calves. Our results reveal that a significant percentage of suckling calves are carriers of zoonotic subtypes of C. parvum. Thus, both healthy and diarrhoeic calves younger than 1 month may represent a risk for the transmission of cryptosporidiosis in humans and animals. PMID- 30008136 TI - Species-specific low plasma glucose in fish is associated with relatively high tissue glucose content and is inversely correlated with cardiac glycogen content. AB - The relationship between plasma glucose concentration and intracellular glucose (liver, heart, brain, gill, gonad, intestine, kidney, spleen, white muscle) was determined in fish species with a range in plasma glucose (Atlantic cod, 5.06 mM; cunner, 3.8 mM; rainbow trout, 3.7 mM; lumpfish, 0.9 mM; short-horned sculpin, 0.6 mM; and winter flounder, 0.6 mM). The ratio of intracellular glucose/plasma glucose was always higher than one in liver for all species consistent with a diffusion gradient from the tissue to the plasma. In all other tissues in Atlantic cod, cunner, and rainbow trout the diffusion gradient was from the plasma to the intracellular space. In short-horned sculpin, the mean ratio in heart and white muscle exceeded one and in winter flounder the ratio was significantly greater than one at 5.97 and 2.92 for heart and muscle, respectively. The presence of an active glucose 6-phosphatase in white muscle could account for elevated amounts of free glucose. The white muscle of all species displayed phosphoenolpyruvate carboxykinase and in winter flounder the activity was as high in white muscle as in liver suggesting that gluconeogenesis may be associated with a relatively high-muscle glucose content. The glycogen content was highest in liver followed by heart with lower amounts in all other tissues. There was an inverse correlation between heart glycogen content and plasma glucose concentration when all species were included. It is contended that in species with low plasma glucose, heart glycogen is accumulated at a slow rate under normoxia, to be called upon under hypoxic conditions when the gradient for inward diffusion is unfavourable for high rates of glucose metabolism. PMID- 30008137 TI - Savanna elephants maintain homeothermy under African heat. AB - To conserve body water, mammals may reduce evaporative water loss by storing heat, allowing core body temperature to rise more than usual during the day, and to fall more than usual during the cooler night, so demonstrating heterothermy. It has been proposed that elephants are heterothermic, but body temperature never has been measured in elephants over 24 h at environmental temperatures higher than body temperature, where elephants would have to rely on evaporative cooling to maintain homeothermy. We used ingested temperature data loggers to record core temperature of four partly free-ranging savanna elephants exposed to high solar radiation and environmental temperatures that exceeded core temperature (> 36 degrees C) in their natural habitat. The elephants maintained core temperature at an average 36.6 degrees C within narrow daily limits of about 1.3 degrees C. While mean 24-h core temperature increased with maximum air temperature, it did not increase with mean air temperature. Maximum and minimum daily core temperatures also did not change with maximum air temperatures. As a result, core temperature range remained constant despite large variations in daily air temperatures. Contrary to the view that elephants exhibit heterothermy to cope with heat, savanna elephants in their natural habitat with access to adequate resources of food and water, and able to use thermoregulatory behaviour, maintained homeothermy. PMID- 30008135 TI - Review on medicinal plants and natural compounds as anti-Onchocerca agents. AB - Onchocerciasis is a filarial vector borne disease which affects several million people mostly in Africa. The therapeutic approach of its control was based on a succession of drugs which always showed limits. The last one: ivermectin is not the least. It was shown to be only microfilaricidal and induced resistance to the human parasite Onchocerca volvulus. The approach using medicinal plants used in traditional medicine is a possible alternative method to cure onchocerciasis. Onchocerca ochengi and Onchocerca gutturosa are the parasite models used to assess anthelmintic activity of potentially anthelmintic plants. Numerous studies assessed the in vitro and/or in vivo anthelmintic activity of medicinal plants. Online electronic databases were consulted to gather publications on in vitro and in vivo studies of anti-Onchocerca activity of plants from 1990 to 2017. Globally, 13 plant families were investigated for anti-Onchocerca activity in 13 studies. The most active species were Anacardium occidentale, Euphorbia hirta and Acacia nilotica each with an LC50 value of 2.76, 6.25 and 1.2 MUg/mL, respectively. Polycarpol, voacamine, voacangine, ellagic acid, gallic acid, gentisic acid, 3-O-acetyl aleuritolic acid and (-)-epigallocatechin 3-O-gallate were the isolated plant compounds with anti-Onchocerca activity. Most of the assessed extract/compounds showed a good safety after in vivo acute toxicity assays and/or in vitro cytotoxicity test. The exception was the ethanol extract of Trichilia emetica, which killed completely and drastically mice at a dose of 3000 mg/kg. Several plant groups of compounds were shown active against Onchocerca sp. such as tannins, alkaloids, triterpenoids and essential oils. Nevertheless, none of the active compounds was subjected to clinical trial, to assessment of its diffusibility through nodular wall or its capability to induce genetic resistance of Onchocerca sp. PMID- 30008138 TI - Ocean acidification: effects of pH on 45Ca uptake by lobster branchiostegites. AB - Gill chambers of the Atlantic lobster, Homarus americanus, possess three structures that are involved with respiration and ion regulation: gill filaments, epipodites, and branchiostegites. This paper describes ion transport mechanisms present in the plasma membranes of branchiostegite epithelial cells and the effects of pH on the uptake of 45Ca by these processes. Partially purified membrane vesicles (PPMV) of branchiostegite cells were produced by a homogenization/centrifugation method that has previously been used to define ion transport processes in both crab and lobster gill tissues. In the present study, lobster branchiostegite PPMV 45Ca uptake was highest at pH 8.5 and lowest at pH values between 6.0 and 7.0 (p < 0.02). At pH 8.0, 45Ca uptake was a biphasic process consisting of a saturable process at low [Ca] and a linear process at higher [Ca]. At pH 6.0, 45Ca uptake was only a linear process and paralleled linear uptake at pH 8.0. A valinomycin/K+-induced membrane potential (PD, inside negative) doubled 45Ca uptake at pH 7.0 above that in the absence of a PD (p < 0.05). An induced PD at pH 8.0 did not significantly (p > 0.05) affect 45Ca uptake observed in the absence of a PD, but was threefold greater than uptake at pH 7.0 in the absence of a PD (p < 0.05). Amiloride (2 mM) did not affect 45Ca uptake at pH 8.0, but 2 mM amiloride + 100 uM verapamil reduced uptake by approximately 50%. In the presence of both 2 mM amiloride + 100 uM verapamil, 15 s 45Ca influx at pH 8.5 was a hyperbolic function of [Ca] (0.1-5 mM) (Km = 4.2 +/ 0.3 mM; Jmax = 9792 +/- 439 pmol/mg protein * 15 s). 45Ca influxes at pH 7.5 under the same conditions were also hyperbolic with Km = 8.3 +/- 1.4 mM; Jmax = 10732 +/- 1250 pmol/mg protein * 15 s. Km values were significantly different (p < 0.05), but Jmax values were not (p > 0.05). These results suggest that 45Ca uptake by lobster branchiostegites may have occurred by the combination of diffusion through a verapamil-inhibited calcium channel and carrier-mediated transport by amiloride-insensitive, electroneutral, 1Ca2+/2H+ antiporters. Decreased pH, as might occur during ocean acidification, did not appear to modify calcium diffusion through the channels, but protons acted as competitive inhibitors of calcium transport by carrier-mediated antiport. Decreased calcium uptake with continued ocean acidification may significantly affect calcification processes during periodic molting, potentially influencing mortality. PMID- 30008139 TI - Seasonality of total fatty acid profiles in acid mine drainage impaired streams. AB - Pre-regulation coal mining and subsequent acid mine drainage (AMD) have drastically altered stream quality in the Appalachian region of the USA. Streams impaired by AMD often times demonstrate lowered pH, increases in specific conductance, and increase in dissolved metal concentrations. These changes in the chemical environment are reflected in the biotic community with drastic reductions in diversity and biomass. Recently, there has been an increase in applying traditional measures of food quality to understand how the biofilm community is altered by environmental condition and use for stream quality monitoring. The purpose of this study was two-fold: (1) to use fatty acid profiles to distinguish between biofilm communities in AMD impaired and unimpaired streams and (2) to determine the consistency of biofilm fatty acid profiles throughout the summer sampling period. Impaired streams showed significantly lower pH and increased specific conductance. Biofilm samples from the AMD impaired streams had lower fatty acid content with a decreased proportion of polyunsaturated fatty acids. Fatty acid profiles easily and rapidly separated biofilm communities into their respective categories, either as being impaired by AMD or unimpaired by AMD, using multivariate statistical approaches. Fatty acid profiles were similar within stream type throughout the summer sampling season, and the profiles were correlated to pH and specific conductance. The results of this study suggest that fatty acid profiles can rapidly and accurately categorize the biofilm community responses to environmental impairment. PMID- 30008140 TI - Impact of balloon laryngoplasty on management of acute subglottic stenosis. AB - PURPOSE: To assess the impact of balloon laryngoplasty on clinical and surgical outcomes in pediatric patients with acute subglottic stenosis. METHODS: Two case series were included and compared. The first group included patients treated initially either with tracheostomy (if severe symptoms) or with close follow-up (if mild symptoms). Those children underwent re-evaluation and specific treatment of their stenosis with laser incisions or open surgeries some weeks later. The other group included children treated initially with balloon laryngoplasty, reflecting a shift in surgical practice after 2009. Data as success of the procedure, mean hospital stay, mean pediatric intensive care unit (PICU) stay, post-procedure fever, need of antibiotics, procedure-related complications, and deaths were assessed and compared between both cohorts. RESULTS: The sample comprised 38 pediatric patients aged 0-5 years. Fifteen children were treated before 2009, of who 10 (66.7%) required tracheostomy soon after the diagnosis. Ultimately, 13 (86.6%) underwent laryngotracheal reconstruction. Twenty-three children were treated after 2009 and the success rate in these patients treated primarily with balloon laryngoplasty was 82.6%. Of these, only 3 (13%) required tracheostomy and 1 (4.3%) required further open laryngotracheal reconstruction. Patients treated by balloon laryngoplasty underwent fewer procedures under general anesthesia and had a lower burden of treatment-related morbidity, as denoted by shorter PICU stay, less antibiotic use, earlier postoperative resumption of oral feeding, and a lower incidence of postoperative complications and fever. CONCLUSION: When used for management of acute laryngeal stenosis, balloon laryngoplasty is associated with a high success rate, presenting lower morbidity than open surgery. PMID- 30008142 TI - Genome size estimation of brackishwater fishes and penaeid shrimps by flow cytometry. AB - Flow cytometry was used for estimating the genome size of five brackishwater finfish and four shrimp species. The genome size for Lutjanus argentimaculatus was 0.95 +/- 0.10 and 0.79 +/- 0.01 pg for Scatophagus argus. The genome sizes for Chanos chanos (0.72 +/- 0.01 pg), Etroplus suratensis (1.71 +/- 0.16 pg) and Liza macrolepis (0.87 +/- 0.02 pg) which are important aquaculture species are reported for the first time in this study. The phylogenetic tree constructed using sixty-seven sequence accessions of cytochrome c oxidase subunit 1 (COI) gene of Lates calcarifer revealed two separate clades. The Indian Lates calcarifer species with estimated genome size of 0.44 +/- 0.02 pg belonged to a clade different than that of South East Asia and Australia reported to have larger genome size. The genome size for the four major species of genus Penaeus (Penaeus monodon, Penaeus indicus, Penaeus vannamei and Penaeus japonicus) were found in similar range. The genome size of female shrimps ranged from 2.91 +/- 0.03 pg (P. monodon) to 2.14 +/- 0.02 pg (P. japonicus). In male shrimps, the genome size ranged from 2.86 +/- 0.06 pg (P. monodon) to 2.19 +/- 0.02 pg (P. indicus). Significant difference was observed in the genome size between male and female shrimp of all species except in P. monodon. The highest relative difference of 12.78% was observed in the genome size between the either sex in P. indicus. The interspecific relative difference of 30.59% in genome size was highest between the male shrimps of P. monodon and P. indicus and 35.98% between the female shrimps of P. monodon and P. japonicus. The stored gills and pleopod tissues could be successfully used up to 3 weeks to estimate the genome size in shrimps. PMID- 30008141 TI - The genetic background of antibiotic resistance among clinical uropathogenic Escherichia coli strains. AB - The spreading mechanisms of antibiotic resistance are related to many bacterial and environment factors. The overuse of antibiotics is leading to an unceasing emergence of new multidrug resistant strains. This problem also concerns uropathogenic Escherichia coli strains, which is the most common pathogen causing urinary tract infections. The aim of this study was the genetic analysis of antibiotic resistance in comparison to the phenotypic background of E. coli strains. The characterized collection of E. coli strains isolated 10 years ago from the urine samples of patients with urinary tract infections was used for antimicrobial susceptibility testing (the disc diffusion method) and analysis of antibiotic resistance genes (PCR reaction, sequencing). Additionally, the presence of ESBL strains was analyzed. Fourteen genes were associated with resistance to beta-lactams, aminoglycosides, sulfonamides and quinolones. The genetic analysis revealed that blaTEM-1 and sul2 were present in almost all of the studied strains. Other drug-resistance genes were very rare or non-existent. Otherwise, the phenotypic resistance to fluoroquinolones was well correlated with the genotypic background of the studied bacteria. The presence of particular genes and specific mutations indicate a high bacterial potential to multidrug resistance. On the other hand, it needs to be emphasized that the standard disk diffusion test for the routine antimicrobial susceptibility analysis is still the best way to estimate the current situation of bacterial drug-resistance. PMID- 30008144 TI - The impact of overweight in the efficiency and complications of midurethral sling in patients with stress urinary incontinence: a systematic review and meta analysis. AB - AIMS: To compare the efficiency and complications of normal weight and overweight women with stress urinary incontinence (SUI) after surgery. METHODS: We searched the PubMed, Embase, and Cochrane Library Databases to identify all compared results, including those involving the terms normal weight, overweight, body mass index (BMI), and SUI. After treatment with surgery, the efficiency (subjective cure rate, objective cure rate, UDI-6, and IIQ-7) and complications were compared between the normal weight and overweight groups. RESULTS: The study inclusion criteria were met by 20 studies involving 3829 patients. The data synthesized from these studies indicated that the subjective and objective cure rates in the normal weight group were significantly more effective than those in the overweight group (RR 1.07; 95% CI 1.04-1.10; P < 0.00001; RR 1.24; 95% CI 1.18 1.30; P < 0.00001), while the IIQ-7 and UDI-6 were no different between the two groups (MD 0.07; 95% CI - 1.44 to 1.58; P = 0.93; MD 0.18; 95% CI - 1.24 to 1.60; P = 0.81). For the data of complications, only the urgency was more in the overweight group (RR 0.68, 95% CI 0.55-0.84, P = 0.0003). CONCLUSIONS: The objective success rate and subjective success rate of the surgery were higher in normal weight patients than those in overweight patients. Also, the side effects between the two groups were not significantly different. PMID- 30008145 TI - Heritability of the aged glutathione phenotype is dependent on tissue of origin. AB - Glutathione is a ubiquitous antioxidant that protects cells against reactive oxygen species and other chemical stressors. Despite its functional importance, the impact of genetics on the glutathione system has yet to be fully appreciated. Here, we investigated the heritability of glutathione levels and redox status in a disease-relevant condition: advanced age. We assembled a panel of 18-21-month old mice representing 19 inbred strains and quantified the levels of reduced and oxidized glutathione, and their sums and ratios, in liver, kidney, heart, pancreas, cerebral cortex, and striatum. Heritability values were calculated for each phenotype and the results varied by tissue of origin. Cardiac glutathione phenotypes exhibited the highest heritabilities (G2 = 0.44-0.67), while striatal glutathione was least heritable (G2 = 0.11-0.29). Statistical relationships between tissues were evaluated, and the emergence of significant correlations suggested that despite tissue-specific heritabilities, at least some shared regulatory mechanisms may exist. Overall, these data highlight another mechanism by which genetic background determines antioxidant protection and stress resistance. PMID- 30008146 TI - Non-sarcomeric causes of heart failure. PMID- 30008143 TI - Nicotinic Acetylcholine Receptors in HIV: Possible Roles During HAND and Inflammation. AB - Infection with the human immunodeficiency virus (HIV) remains a threat to global health. Since its discovery, many efforts have been directed at understanding the mechanisms and consequences of infection. Although there have been substantial advances since the advent of antiretroviral therapy, there are still complications that significantly compromise the health of infected patients, particularly, chronic inflammation and HIV-associated neurocognitive disorders (HAND). In this review, a new perspective is addressed in the field of HIV, where the alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) is the protagonist. We comprehensively discuss the available evidence implicating alpha7-nAChRs in the context of HIV and provide possible explanations about its role in HAND and inflammation in both the central nervous system and the periphery. PMID- 30008148 TI - Number of ischemic strokes potentially eligible for revascularization treatments in an Italian Comprehensive Stroke Center: a modeling study. AB - To rationally plan acute services, the proportion of ischemic strokes that may be eligible for revascularization treatments should be estimated. We aimed to estimate the proportion of patients directly admitted to an Italian Comprehensive Stroke Center who may be eligible for intravenous thrombolysis (IVT), combined IVT and endovascular thrombectomy (ET), or direct ET according to the current guidelines. We conducted a retrospective analysis based on data prospectively collected from 876 consecutive adult ischemic stroke patients who were directly admitted to the Stroke Unit of the University Hospital of Verona within 12 h of stroke onset. A theoretical model was created to calculate the proportion of patients potentially eligible for revascularization treatments. In our cohort, 289 (33%) patients would be eligible for IVT alone, 193 (22%) for combined IVT and ET, and 39 (4%) for direct ET with level of evidence IA according to the current guidelines. According to our theoretical model, more than half of the ischemic stroke patients directly admitted to Verona Stroke Unit within 12 h of stroke onset would be eligible for IVT and more than a quarter for ET. Systems of care should promptly organize to offer each patient the best treatment. PMID- 30008147 TI - Sensory Sensitivity in TBI: Implications for Chronic Disability. AB - PURPOSE OF REVIEW: This review investigates the relationship between sensory sensitivity and traumatic brain injury (TBI), and the role sensory sensitivity plays in chronic disability. RECENT FINDINGS: TBI is a significant cause of disability with a range of physical, cognitive, and mental health consequences. Sensory sensitivities (e.g., noise and light) are among the most frequently reported, yet least outwardly recognizable symptoms following TBI. Clinicians and scientists alike have yet to identify consistent nomenclature for defining noise and light sensitivity, making it difficult to accurately and reliably assess their influence. Noise and light sensitivity can profoundly affect critical aspects of independent function including communication, productivity, socialization, cognition, sleep, and mental health. Research examining the prevalence of sensory sensitivity and evidence for the association of sensory sensitivity with TBI is inconclusive. Evidence-based interventions for sensory sensitivity, particularly following TBI, are lacking. PMID- 30008149 TI - Myocardial deformation and volume of exercise: a new overlap between pathology and athlete's heart? AB - Regular physical exercise induces cardiac adaptations that can overlap pathological conditions. Controversy still persists about the variability of myocardial deformation in different types and intensity of exercise. The aim of this study was to assess myocardial longitudinal deformation in athletes with different level of exercise. Two groups of young athletes involved in endurance sports characterized by high intensity dynamic component were enrolled. According to the level and the number of exercise training hours/week, two groups were defined: Group 1-high level (national/international and >= 20 training hours/week; N = 60); Group 2-low level (recreational/regional and < 10 training hours/week; N = 48). A comprehensive transthoracic echocardiogram including evaluation of global longitudinal strain (GLS) assessed by 2D speckle-tracking was performed. Athletes in Group 1 showed more pronounced cardiac remodeling and enhanced diastolic function. No significant differences were evident in left ventricle ejection fraction (LVEF) between groups. Overall, GLS (absolute values) was 18.0 +/- 2.5%, but significantly lower in Group 1 compared to Group 2 (17.3 +/- 2.6% vs. 18.9 +/- 2.1%; p = 0.001). Thirty-three (31%) athletes had GLS below 17%, more frequently in Group 1 (79% vs. 45%; p = 0.001), with higher LV and left atrium volumes, lower E wave and A wave peak velocities and E/e' ratio. In a multivariate analysis to belong to Group 1 was the only independent variable associated with GLS < 17% (OR 6.5; 95% CI 2.4-17.4; p < 0.001). The athletes with a GLS < 17% were all men, more frequently involved in high level exercise, with higher chamber volumes and lower E/e' ratio. Left ventricular global myocardial longitudinal deformation evaluated by GLS was significantly lower in athletes with higher level of exercise. Although GLS in athletes overlap several pathological conditions, these lower values are associated with an enhanced diastolic performance that allows discrimination between physiologic adaptations and pathology. PMID- 30008150 TI - Identification and Functional Analysis of Novel Bradykinin-Related Peptides (BRPs) from Skin Secretions of Five Asian Frogs. AB - In recent decades, various types of bioactive substances have been identified from amphibian skin and its secretions. Bradykinin-related peptides (BRPs) are among these compounds that make up the host defence system of amphibians. In the present study, we identified six novel BRPs, amolopkinin-GN1, amolopkinin-RK1, amolopkinin-TR1, amolopkinin-LF1, ranakinin-MS1, and ranakinin-MS2, from five East Asian amphibians, Amolops granulosus, Amolops ricketti, Amolops torrentis, Amolops lifanensis, and Hylarana maosonensis. This is the first report on BRPs in the skin of these species. Physiological assays reveal that these peptides have a contractive effect on the smooth muscle of rat ileum. PMID- 30008152 TI - Occult isolated fracture of the trapezoid diagnosed by ultrasonography. AB - PURPOSE: To describe a patient with an occult isolated trapezoid fracture of the wrist. Isolated trapezoid fractures are very difficult to detect without advanced radiological imaging, since the fragment displacement does not occur in the sagittal plane. A discussion regarding the investigation of trapezoid fractures utilizing multiple imaging modalities includes the first demonstration of its detection via ultrasonography (US). METHODS: A 26-year-old male presented to a chiropractic teaching clinic with pain involving the left wrist, after vaulting over the handlebars of his bicycle 2 days prior. The mechanism of injury was hyperflexion of the left wrist. Left wrist pain, reduced range of motion, and dorsal soft tissue edematous changes were identified at examination. Although the initial radiographic examination was negative, elevated clinical suspicion triggered an US examination 4 days later. The US exam demonstrated an isolated 1.8 mm dorsal trapezoid fracture, which was minimally displaced by 0.7 mm. RESULTS: Following the US diagnosis of an isolated trapezoid fracture, the wrist was immobilized. The patient elected to not pursue an orthopedic consultation. Conservative care included ice and Class IV therapeutic laser therapy. The patient reported complete alleviation of clinical symptoms after approximately 2 weeks of splinting and treatment. CONCLUSION: We emphasize the limitations of radiography in the diagnosis of this fracture. To our knowledge, this is the first case to describe the use of US in the diagnosis of an isolated trapezoid fracture. PMID- 30008151 TI - Cell adhesion molecules and plasminogen activator inhibitor type-1 (PAI-1) in patients with rheumatoid arthritis: influence of metabolic syndrome. AB - Rheumatoid arthritis (RA) is a chronic inflammatory and systemic disease characterized by endothelial activation. The main objective of this study was to verify the profile of cell adhesion molecules (CAM) in RA patients, and the influence of metabolic syndrome (MetS) and drugs used in the treatment of RA in this profile. A second objective was to propose models of prediction of activity in RA using these biomarkers. A total of 115 healthy individuals and 144 RA patients were enrolled. Disease activity was determined by DAS28 (disease activity score 28) based on erythrocyte sedimentation rate (DAS28-ESR) or C reactive protein (DAS28-CRP). Serum CAM and plasminogen activator inhibitor type 1 (PAI-1), anthropometric and immunological parameters were measured. Vascular cell adhesion molecule-1 (VCAM-1) was significantly decreased, and PAI-1 was significantly higher in RA patients as compared to controls. Binary logistic regression analysis showed that VCAM-1, CRP, and tumor necrosis factor-alpha (TNF alpha) predicted RA with a sensitivity of 95.9% and a specificity of 89.5%. 42.9% of the variance in DAS28-ESR and 49.2% of the variance in DAS28-CRP are explained by increased PAI-1, TNF-alpha, body mass index (BMI) and decreased platelet endothelial cell adhesion molecule 1 (PECAM-1). Our data show that lower levels of VCAM-1 are associated with RA independently of MetS, while increased PAI-1 levels were associated with both RA and MetS and increased selectins (E-selectin and P-selectin) were exclusively associated with MetS and not with RA. A model to predict disease activity based on PECAM-1, PAI-1, TNF-alpha, age and BMI is proposed. PMID- 30008153 TI - Proteomics in Chronic Arthritis-Will We Finally Have Useful Biomarkers? AB - PURPOSE OF REVIEW: Current technical advances enable the assessment of the complex changes in body fluid proteomes and thus allow for the discovery of biomarker signatures rather than just following differences of a single marker. In this review, we aim to summarize current approaches to discover and evaluate multi-biomarker panels for improved monitoring of chronic arthritis disease activity. RECENT FINDINGS: Mass spectrometry and affinity proteomic methodologies have been used to identify biomarker panels in synovial fluid, serum, plasma, or urine of pediatric and adult chronic arthritis patients. Notably, despite the numerous efforts to develop new and better biomarker panels, very few have undergone extensive analytical and clinical validation and been adopted into routine use for patient benefit. There remains a significant gap between discovery of chronic arthritis biomarker signatures and their validation for clinical use. PMID- 30008154 TI - Temporal muscle thickness is an independent prognostic marker in melanoma patients with newly diagnosed brain metastases. AB - OBJECTIVES: The purpose of this study was to evaluate the prognostic relevance of temporal muscle thickness (TMT) in melanoma patients with newly diagnosed brain metastases. METHODS: TMT was retrospectively assessed in 146 melanoma patients with newly diagnosed brain metastases on cranial magnetic resonance images. Chart review was used to retrieve clinical parameters, including disease-specific graded prognostic assessment (DS-GPA) and survival times. RESULTS: Patients with a TMT > median showed a statistically significant increase in survival time (13 months) compared to patients with a TMT < median (5 months; p < 0.001; log rank test). A Cox regression model revealed that the risk of death was increased by 27.9% with every millimeter reduction in TMT. In the multivariate analysis, TMT (HR 0.724; 95% 0.642-0.816; < 0.001) and DS-GPA (HR 1.214; 95% CI 1.023-1.439; p = 0.026) showed a statistically significant correlation with overall survival. CONCLUSION: TMT is an independent predictor of survival in melanoma patients with brain metastases. This parameter may aid in patient selection for clinical trials or to the choice of different treatment options based on the determination of frail patient populations. PMID- 30008156 TI - Implications of detection of foramen ovale patent after cryptogenic ischemic stroke. AB - BACKGROUND: Therapeutic uncertainty is inherent in decisions in patients with patent foramen ovale (PFO) and cryptogenic stroke. We aimed to determine clinical implications of PFO identification in transesophageal echocardiography (TEE) after a cryptogenic ischemic stroke. METHODS: Consecutive TEE done between 2011 and 2015 in patients with previous cryptogenic stroke was evaluated. Clinical implications of PFO identification (closure and/or medical therapy) were retrieved from the medical records and discharge summaries. Adverse events related to therapy, stroke recurrence and death were analyzed during follow-up. RESULTS: Three-hundred one patients (mean age 59 +/- 11 years; 61% male) underwent a TEE, of which 77 (26%) patients had a diagnosis of PFO. Patients with PFO were younger (56 +/- 13 versus 60 +/- 14, p = 0.03). Of those with PFO, 23 (30%) underwent percutaneous closure of PFO and these patients had more frequently complex or large PFO (p < 0.001 and p = 0.004, respectively). The remaining 54 (70%) were treated with medical therapy: 30 (39%) with antiplatelet therapy and 24 (31%) with oral anticoagulation. During follow-up (44 +/- 17 months), only two patients had another stroke (both referred for PFO closure, while they were waiting for the procedure) and two patients, on whom PFO closure was not performed, died (not for cardiovascular causes). CONCLUSION: PFO's (size and complexity) and patients' characteristics influenced clinical decision when PFO was detected on TEE. The risk for recurrent stroke was not increased in patients who did not undergo PFO closure; although two patients waiting for PFO closure had recurrent stroke, demonstrating its importance. PMID- 30008155 TI - Rapid regulation of excitation energy in two pennate diatoms from contrasting light climates. AB - Non-photochemical quenching (NPQ) is a fast acting photoprotective response to high light stress triggered by over excitation of photosystem II. The mechanism for NPQ in the globally important diatom algae has been principally attributed to a xanthophyll cycle, analogous to the well-described qE quenching of higher plants. This study compared the short-term NPQ responses in two pennate, benthic diatom species cultured under identical conditions but which originate from unique light climates. Variable chlorophyll fluorescence was used to monitor photochemical and non-photochemical excitation energy dissipation during high light transitions; whereas whole cell steady state 77 K absorption and emission were used to measure high light elicited changes in the excited state landscapes of the thylakoid. The marine shoreline species Nitzschia curvilineata was found to have an antenna system capable of entering a deeply quenched, yet reversible state in response to high light, with NPQ being highly sensitive to dithiothreitol (a known inhibitor of the xanthophyll cycle). Conversely, the salt flat species Navicula sp. 110-1 exhibited a less robust NPQ that remained largely locked-in after the light stress was removed; however, a lower amplitude, but now highly reversible NPQ persisted in cells treated with dithiothreitol. Furthermore, dithiothreitol inhibition of NPQ had no functional effect on the ability of Navicula cells to balance PSII excitation/de-excitation. These different approaches for non-photochemical excitation energy dissipation are discussed in the context of native light climate. PMID- 30008157 TI - Modelling a preference-based index for EQ-5D using a non-parametric Bayesian method. AB - BACKGROUND: Conventionally, models used for health state valuation data have been parametric. Recently, a number of researchers have investigated the use of non parametric Bayesian methods in this area. OBJECTIVES: In this paper, we present a non-parametric Bayesian model to estimate a preference-based index for a five dimensional health state classification, namely EQ-5D. METHODS: A sample of 2997 members of the UK general population valued 43 health states selected from a total of 243 health states defined by the EQ-5D using time trade-off technique. Findings from non-parametric modelling are reported in this paper and compared to previously used parametric estimations. The impact of respondent characteristics on health state valuations is also reported. RESULTS: The non-parametric models were found to be better at predicting scores in populations with different distributions of characteristics than observed in the survey sample. Additionally, non-parametric models were found to be better at allowing for the impact of respondent characteristics to vary by health state. The results show an important age effect with sex having some effect. CONCLUSION: The non-parametric Bayesian models provide more realistic and better utility estimates from the EQ 5D than previously used parametric models have done. Furthermore, the model is more flexible in estimating the impact of covariates. PMID- 30008159 TI - Vestibular rehabilitation in elderly patients with postural instability: reducing the number of falls-a randomized clinical trial. AB - BACKGROUND: Our previous study had shown the effectiveness of vestibular rehabilitation (VR) in improving balance in elderly patients, assessed immediately afterwards. AIMS: The main goal of the present study is to consider whether this improvement in balance assessment turns out in a reduction of the number of falls. METHODS: 139 elderly patients with high risk of falls were included and randomized to one of the following study arms: computerized dynamic posturography (CDP) training, optokinetic stimulus, exercises at home or control group. Patients were assessed with objective outcome measures (sensorial organization test and limits of stability of CDP, number of falls and number of hospital admissions due to falls) and subjective outcome measures (dizziness handicap inventory and short falls efficacy scale-international) during a 12 month follow-up period. RESULTS: Average number of falls significantly declined from 10.96 (before VR) to 3.03 (12-month follow-up) in the intervention group (p < 0.001); meanwhile, in the control group, the average number of falls changed from 3.36 to 2.61 during a 12-month follow-up period (p = 0.166). DISCUSSION: The present study provides evidence that VR can decisively improve balance in elderly patients with instability, which can lead in turn to a significant reduction of falls. CONCLUSION: We recommend performing VR in any older person with high risk of falls. PMID- 30008158 TI - Isolated adrenocorticotropic hormone deficiency as a form of paraneoplastic syndrome. AB - PURPOSE: In isolated adrenocorticoropic hormone (ACTH) deficiency (IAD), autoimmunity against corticotrophs has been suggested; however, the pathogenesis remains largely unknown. Large cell neuroendocrine carcinoma (LCNEC) of the lung is a pulmonary tumor of high-grade malignant neuroendocrine tumor and it reportedly caused paraneoplastic syndrome by autoimmunity in several cases. METHODS: A 42-year-old woman with isolated adrenocorticotropic (ACTH) hormone deficiency (IAD) was diagnosed with large cell neuroendocrine carcinoma (LCNEC) 3 years after being diagnosed with IAD. We hypothesized that the LCNEC played a causal role in the development of IAD as a paraneoplastic syndrome and analyzed the autoimmunity. We also analyzed another case of ectopic ACTH syndrome to prove this hypothesis. RESULTS: The LCNEC tissue revealed an ectopic ACTH expression and lymphocyte infiltration. Interestingly, autoantibody against the proopiomelanocortin (POMC) protein was detected in the peripheral blood. Although, patient's serum did not show any effects on cell viability, proliferation, nor pomc expression in a corticotroph cell line, AtT20 cells, patient's lymphocytes in the peripheral blood specifically reacted toward POMC protein, indicating a presence of cytotoxic T lymphocytes (CTLs). In addition, the analysis of another case of ectopic ACTH syndrome showed lymphocyte infiltration not only in the metastatic liver tumors but also in the pituitary. Moreover, most CD8-positive cells resided adjacent to corticotrophs. CONCLUSIONS: These data indicate that the ectopic ACTH expression in the tumor evoked the autoimmunity to corticotrophs and caused IAD as a form of paraneoplastic syndrome. PMID- 30008160 TI - Diesel oil removal by Serratia sp. W4-01 immobilized in chitosan-activated carbon beads. AB - Serratia sp. W4-01 was immobilized in chitosan-activated carbon beads and used for diesel oil removal. The type and concentration of chitosan, activated carbon content, and bead diameter were investigated as factors affecting diesel oil removal. The results showed that 2% (w/v) squid pen chitosan beads modified with 1% activated carbon (w/v) and with a 3-mm diameter had a good spherical shape and strength as well as diesel oil removal capability. The immobilized W4-01 cells removed more than 40% of diesel oil after 7 days when the initial diesel oil concentration was 100 to 400 mg L-1, whereas 29-36% of diesel oil was removed after 14 days when the initial concentration was 800 to 1000 mg L-1. Additionally, the immobilized cells maintained the ability to remove diesel oil over a pH range of 5-11. The addition of a biosurfactant increased the diesel oil removal from 62 to 75%. The reusability tests revealed that the ability of immobilized cells to remove diesel oil was enhanced after reuse, and 50-90% of diesel oil was removed during 2 to 12 reuse cycles. The stability and survival of W4-01 cells was confirmed by scanning electron microscopy and confocal laser scanning microscopy. The results of this study showed the potential use of W4-01 cells immobilized in chitosan-activated carbon beads for future applications in remediating diesel contamination. PMID- 30008161 TI - Effects of phosphorus on absorption and transport of selenium in rice seedlings. AB - The effects of different concentrations of phosphorus (P) on absorption and transfer of selenium (Se) in rice seedlings were studied by hydroponics experiment. The interaction between iron plaque and phosphorus on absorption and transport of selenium were studied by adding a large amount of iron-induced iron plaque, to provide a theoretical basis for rational application of phosphate fertilizer in the selenium bio-strengthening process of rice. The results showed that phosphorus deficiency may result in the formation of reddish brown iron oxide coating on the root surface of rice. The formation of root iron plaque of rice is related to concentration of phosphorus, and low concentration of phosphorus (0-1.5 mmol L-1) can increase the amount of root iron plaque. Compared P deficiency culture and 2 mmol L-1 P culture, Se content in the shoots and roots decreased by 76 and 47%, respectively. Addition of Fe2+ significantly reduced biomass of shoot and had no significant effect on the roots; when the P concentration increased from 0.1 to 0.3 mmol L-1, transfer coefficient of Se decreased. Therefore, both root iron plaques induced by phosphorus deficiency and iron addition have a strong adsorption effect on selenium, which reduces the transport of selenium from the rice roots to the shoots. In the lower range of phosphorus concentration, low phosphorus can promote selenium content of rice shoot, while higher on the contrary. In the practice of rice production, proper management of phosphorus nutrient is of great significance to control selenium content in rice grain. PMID- 30008162 TI - Assessment of seafood contamination under the marine strategy framework directive: contributions of the German environmental specimen bank. AB - Descriptor 9 (D9) of the European Union Marine Strategy Framework Directive refers to the compliance of contaminant levels in fish and other seafood of a defined marine region or subregion with human health threshold values. This requires georeferenced samples that are often difficult to obtain when relying on commercial fisheries or programs designed for monitoring human exposure. The present study examines whether georeferenced samples of blue mussel (Mytilus edulis) and eelpout (Zoarces viviparus) fillet of the German environmental specimen bank (ESB) can be used in this context. The suitability of the ESB samples, procedures, and analytical methods is evaluated with respect to D9 requirements. Based on ESB data for the D9 relevant contaminants Pb, Cd, Hg, ?4 PAHs, PCDD/Fs, dioxin-like (dl)-PCBs, and indicator non-dl-PCBs and the potentially relevant substances TBT, PFOS, PBDE, and HBCDD, the Good Environmental Status for D9 is assessed at the ESB sites in the North and Baltic Seas. The overall evaluation indicates that ESB samples are suitable for D9 assessment with the limitation that only coastal areas of the North and Baltic Seas are covered. Over a period of up to 30 years, concentrations of the D9 relevant contaminants were well below the maximum levels allowed for human consumption. PMID- 30008164 TI - Testing environmental Kuznets curve hypothesis in G7 countries: the role of renewable energy consumption and trade. AB - This study has been conducted to examine the impact of trade, economic growth, and renewable energy on environmental degradation in G7 countries. The data consist of the years 1991-2016. We employed the panel unit root test and co integration test, along with cross-sectional dependence and cross-sectionally augmented IPS unit root test by Pesaran (J Appl Econ 22:265-312, 2007). We also employed dynamic ordinary least squares, fully modified ordinary least squares, and fixed effect ordinary least squares regression. The result concluded that all the variables are co-integrated in the long run and all the variables create a significant effect on CO2 emission. This study implies that economic growth and trade increases the CO2 emission in the long run whereas the renewable energy consumption reduces the CO2 emission in the long run. The result also provides support for the Environmental Kuznets curve hypothesis in G7 countries. PMID- 30008165 TI - Organic carbon content and humus composition after application aluminum sulfate and rice straw to soda saline-alkaline soil. AB - The soil organic carbon accumulation in soda saline-alkaline soil and the humus composition changes with application of aluminum sulfate and rice straw were investigated by the controlled simulative experiments in laboratory. For evaluating the amelioration effect, organic carbon content and humus composition in soda saline-alkaline soil were investigated with different application amounts of rice straw and aluminum sulfate. Potassium dichromate oxidation titration (exogenous heat) method and Kumada method were used to analyze the contents of organic carbon and humus composition, respectively. The transformation of soil organic matter in the saline-alkali soil during the amelioration has been clarified in this paper. The results demonstrated that the contents of soil organic carbon were significantly increased (13-92%) with different application amounts of rice straw and aluminum sulfate. The contents of free fraction and combined fraction of humus and their compositions (humic acid and fulvic acid) were increased with different application amounts of rice straw. The free fraction of humus was increased more dramatically. Due to aluminum sulfate application, free fraction of humus and humic acid (HA) was transformed to combined fraction partially. Free HA was changed to be P type with rice straw application. With aluminum sulfate application, free form of HA was changed from type P to type Rp. For rice straw application, combined HA only was transferred within the area of type A. Aluminum sulfate addition had no significant effect on the type of combined form of HA. With the same amount of rice straw application, the contents of soil organic carbon were increased by increasing the amount of aluminum sulfate application. Both rice straw and aluminum sulfate applications could reduce the humification degree of free and combined fraction of HA. According to the types of HA, it could be concluded that humus became younger and renewed due to the application of rice straw and aluminum sulfate. PMID- 30008163 TI - Effects on Eichhornia crassipes under Zn stress. AB - Eichhornia crassipes is a macrophyte widely used in phytoremediation, demonstrating a high ability to remove metals from water. The aim of this work was to evaluate its enzymatic detoxification strategies and metal accumulation when it is exposed to different Zn concentrations (0, 2, 4, 6, and 9 ppm) for periods of 24, 48, and 72 h. Zn concentration in roots was significantly higher than in aerial parts. Independently of the treatment, in the first 48 h, concentrations of photosynthetic pigments were not affected. However, a significant increase (between 19 and 34%) in Chl-b concentrations for all treatments was observed at 72 h. Carotenoid concentration was not affected during the first 48 h, while at 72 h, there was a significant increase regarding the control (between 11 and 24%) for all treatments. Malondialdehyde concentration in aerial parts and roots was not affected during the experiment. Nonetheless, a significant increase in the enzymatic activity of the antioxidant system was observed. Results suggest that Zn could have potential antioxidant properties, which may result in the activation of different antioxidant enzymes involved in the protection against metal stress. PMID- 30008166 TI - Application of Escherichia coli antibiotic resistance patterns for contamination source identification in watershed. AB - Spatial correlation of pollution of the water resource in Taipei, Taiwan, were examined by analyzing the antibiotic resistance patterns (ARPs) of 96 Escherichia coli colonies, which were isolated from 7 sampling sites in 3 river sections. The ARPs were the growth patterns of isolated E. coli colonies in the medium with seven kinds of antibiotics, including ampicillin, chlortetracycline, erythromycin, oxytetracycline, streptomycin, tetracycline, and salinomycin of different concentrations. The results showed that the survival rate of E. coli decreased with increasing concentration of antibiotics; however, various ARPs under different antibiotics of different concentrations significantly increased both the useful information and complexities. Hierarchical cluster analysis (HCA) and two-stage principal component analysis (PCA) were applied to analyze the spatial correlations and interrelations of distinct ARPs among sampling sites in this study. It was found that the seven sampling sites can be categorized into three groups which may represent three possible pollution characteristics. PMID- 30008167 TI - Seed priming with Se mitigates As-induced phytotoxicity in rice seedlings by enhancing essential micronutrient uptake and translocation and reducing As translocation. AB - We laid down this investigation to explore the promotive and antagonistic aspect of selenium (Se) when supplemented through seed priming technology in rice before sowing into arsenic (As) free and As spiked soil. Findings suggest that As stress inhibits germination (35.38%), seedling growth (38.19%), chlorophyll content by 42.31%, and reduced translocation of iron, zinc, manganese by 19.40, 17.33, and 18.40% respectively, in the seedlings of unprimed seeds. Seedlings of unprimed seeds also had greater As translocation into the aerial part beside repressing micronutrient translocation, significantly. On the contrary, Se-primed seeds had higher germination (27.82%), longer root length (20.14%), greater chlorophyll content beside having greater translocation of iron, zinc, manganese in shoots along with restricting As translocation in rice seedlings by confining more As in the root, in a significant manner (p < 0.05 level) than the unprimed seedlings grown in identical stress. On the other hand, seedlings of Se-primed seeds grown alike the control also had higher germination % (7.08%), root and shoot length with significantly less proline, and hydrogen peroxide content in root and shoot. Findings indicate that seed priming with Se executes dual role, a growth promoting and antagonism in a more practical and farmer-friendly way to mitigate As-induced toxicity and enhance growth in rice seedlings. PMID- 30008168 TI - Assessment of chromium hyper-accumulative behaviour using biochemical analytical techniques of greenhouse cultivated Sonchus asper on tannery waste dump site soils. AB - Keeping the sources of pollution such as chromium (Cr) under a safe limit is a daunting challenge due to the negative impact of heavy metal bioaccumulation in vegetation and the concomitant human health exposure. We took a closer look at Sonchus asper by cultivating in the green house. It resulted in 80% germination when cultivated over nine different soils collected from the tannery dump site. The biochemical analytical techniques such as mass spectrometry indicated significant bioaccumulation of Cr in the plant tissue. As per the ICP-MS analysis, this annual herb resulted in the accumulation of 601 mg kg-1 of total Cr with 212 mg kg-1 in its shoot from soil samples containing up to 41 mg kg-1 of hexavalent Cr. The energy dispersive X-ray (EDX) spectroscopy of S. asper revealed a higher level of S element indicating a sulfate-Cr binding relation. Elevated content of Cr in soil (73,721 +/- 65 mg kg-1) caused biochemical changes in the shoot of S. asper as indicated by the disappearance of Fourier transform infrared spectroscopy (FTIR) bands at 935 and 872 cm-1 and further revealing aliphatic -CH2 appearing as anti-symmetry nua(CH2) and symmetric vibration nus(CH2) at the band of 2920 and 2850 cm-1, respectively. PMID- 30008170 TI - An Electronic Questionnaire for Liver Assessment in Congenital Disorders of Glycosylation (LeQCDG): A Patient-Centered Study. AB - Congenital disorders of glycosylation (CDG) are ultra-rare diseases showing a great phenotypic diversity ranging from mono- to multi-organ/multisystem involvement. Liver involvement, mostly nonprogressive, is often reported in CDG patients. The main objectives of this work were (1) to better understand liver involvement in CDG patients through a liver electronic questionnaire targeting CDG families (LeQCDG) and (2) to compare responses from LeQCDG participants with literature review regarding the prevalence of liver disease and the occurrence of liver symptoms in CDG patients. The network of patient advocacy groups, families and professionals (CDG & Allies - PPAIN) developed the LeQCDG by adapting validated published questionnaires. The LeQCDG was approved by an ethics committee, and the recruitment of patients and caregivers proceeded through social media platforms. Participants were asked to report past or present liver related symptoms (e.g. hepatomegaly, liver fibrosis and cirrhosis) and laboratory results (e.g. biochemical and/or radiological). From 11 December 2016 to 22 January 2017, 155 questionnaires were completed. Liver disease was present in 29.9% of CDG patients. Main symptoms reported included hepatomegaly, increased levels of serum transaminases, fibrosis, steatosis and cirrhosis. The data obtained in this online survey confirm findings from a recent literature review of 25 years of published evidence (r = 0.927, P = 0.02). Our questionnaire collected large amounts of meaningful, clinical and patient-oriented data in a short period of time without geographic limitations. Internet-based approaches are especially relevant in the context of ultra-rare diseases such as CDG. PMID- 30008169 TI - Hydrogel applications for adsorption of contaminants in water and wastewater treatment. AB - During the last decade, hydrogels have been used as potential adsorbents for removal of contaminants from aqueous solution. To improve the adsorption efficiency, there are numerous different particles that can be chosen to encapsulate into hydrogels and each particle has their respective advantages. Depending on the type of pollutants and approaching method, the particles will be used to prepare hydrogels. The hydrogels commonly applied in water/wastewater treatment was mainly classified into three classes according to their shape included hydrogel beads, hydrogel films, and hydrogel nanocomposites. In review of many recently research papers, we take a closer look at hydrogels and their applications for removal of contaminants, such as heavy metal ion, dyes, and radionuclides from water/wastewater in order to elucidate the reactions between contaminants and particles and potential for recycling and regeneration of the post-treatment hydrogels. Graphical abstract ?. PMID- 30008172 TI - Biologics and stem cell-based therapies for rotator cuff repair. AB - The rotator cuff is composed of several distinct muscles and tendons that function in concert to coordinate shoulder motion. Injuries to these tendons frequently result in permanent dysfunction and persistent pain. Despite considerable advances in operation techniques, surgical repair alone still does not fully restore rotator cuff function. This review focuses on recent research in the use of biologics and stem cell-based therapies to augment repair, highlighting promising avenues for future work and remaining challenges. While a number of animal models are used for rotator cuff studies, the anatomy of the rotator cuff varies dramatically between species. Since the rodent rotator cuff shares the most anatomical features with the human, this review will focus primarily on rodent models to enable consistent interpretation of outcome measures. PMID- 30008173 TI - Targeting tumor necrosis factor receptors in ankylosing spondylitis. AB - Over the past two decades, considerable advances in our understanding of inflammatory and immune pathways have allowed for the growing use of targeted biologic therapy. Most notably, the introduction of tumor necrosis factor (TNF) inhibitors has dramatically changed the management of autoimmune inflammatory disorders, including ankylosing spondylitis (AS). Despite the efficacy of TNF inhibitors documented in multiple clinical trials, anti-TNF therapy in AS is far from foolproof; it is associated with serious adverse effects and limited response to therapy in some patients. Moreover, specific questions regarding the role of TNF as a mediator of AS remain unanswered. Therefore, additional efforts are needed in order to better understand the role of TNF in the pathogenesis of AS and to develop safer and more effective treatment strategies. The purpose of this review is to better the understanding of the physiologic and pathogenic roles of TNF signaling in the course of AS. Relevant TNF biology and novel approaches to TNF blockade in AS are discussed. PMID- 30008171 TI - The Effects of Air Pollution on the Brain: a Review of Studies Interfacing Environmental Epidemiology and Neuroimaging. AB - PURPOSE OF REVIEW: An emerging body of evidence has raised concern regarding the potentially harmful effects of inhaled pollutants on the central nervous system during the last decade. In the general population, traffic-related air pollution (TRAP) exposure has been associated with adverse effects on cognitive, behavior, and psychomotor development in children, and with cognitive decline and higher risk of dementia in the elderly. Recently, studies have interfaced environmental epidemiology with magnetic resonance imaging to investigate in vivo the effects of TRAP on the human brain. The aim of this systematic review was to describe and synthesize the findings from these studies. The bibliographic search was carried out in PubMed with ad hoc keywords. RECENT FINDINGS: The selected studies revealed that cerebral white matter, cortical gray matter, and basal ganglia might be the targets of TRAP. The detected brain damages could be involved in cognition changes. The effect of TRAP on cognition appears to be biologically plausible. Interfacing environmental epidemiology and neuroimaging is an emerging field with room for improvement. Future studies, together with inputs from experimental findings, should provide more relevant and detailed knowledge about the nature of the relationship between TRAP exposure and cognitive, behavior, and psychomotor disorders observed in the general population. PMID- 30008174 TI - The need for improving access to emergency care through community involvement in low- and middle-income countries: A case study of cardiac arrest in Hanoi, Vietnam. AB - Out-of-hospital cardiac arrest patients require immediate interventions by bystanders and emergency medical services (EMS). However, in many low- and middle income countries (LMIC), bystanders witnessing a cardiac arrest rarely perform chest compressions and contact EMS. This paper attempts to draw lessons from a case of a patient with a cardiac arrest who could have survived with immediate interventions. A 40 year old man collapsed following electrocution at a construction site. His colleagues immediately transferred him to hospital via taxi, without performing chest compressions. At the hospital he showed ventricular fibrillation; resuscitation attempts failed and he died. Ventricular fibrillation due to electrocution is a benign type of cardiac arrest. The chance of survival increases with immediate chest compressions and prompt defibrillation. We discuss the reasons why the bystanders did not perform resuscitation or contact EMS and identify approaches for the improvement of pre hospital care in LMICs. PMID- 30008176 TI - Survey of Aboriginal smokers' and ex-smokers' knowledge, attitudes and behaviours in Central Australia 2016-2017. AB - OBJECTIVE: To examine tobacco knowledge, attitudes and behaviours of community members in Central Australia and to compare these by participant's location (town or remote community). DESIGN: Community-based survey of 165 smokers and recent ex smokers. OUTCOME MEASURES: Knowledge was assessed using responses to questions on the health risk of smoking (e.g. lung cancer) and knowledge of quit support services. Attitudes towards smoking were assessed using statements that asked participant whether they agreed or disagreed. Smoking behaviours were assessed by asking participants about quit attempts, cigarettes per day and time to first cigarette (used to calculate the heaviness of smoking index). RESULTS: There were high levels of knowledge about most common diseases associated with smoking, including cancer (93%) and heart disease (89%). There was less knowledge about quit support services that are available through telephone (69%), online (27%) and apps (32%). Responses to attitude statements were suggestive of the normalised practices towards smoking in town and remote participants, with remote participants more likely to disagree that 'ok to smoke close to a building' and to disagree 'if I had my time over again I would not have started'. Over 75% of the participants had attempted to quit smoking and 55% had a sustained quit attempt (>1 month). CONCLUSION: There are greater challenges to reduce smoking in remote areas due to the social and communal practices of smoking and in providing service needs that encourage quit attempts. This supports the need for continued and increased investment for targeted tobacco control by remote health services. PMID- 30008177 TI - An overview of offshore wind energy resources in Europe under present and future climate. AB - Long-term sustainable development of European offshore wind energy requires knowledge of the best places for installing offshore wind farms. To achieve this, a good knowledge of wind resources is needed, as well as knowledge of international, European, and national regulations regarding conflict management, marine environment conservation, biodiversity protection, licensing processes, and support regimes. Such a multidisciplinary approach could help to identify areas where wind resources are abundant and where conflicts with other interests are scarce, support measures are greater, and licensing processes are streamlined. An overview of offshore wind power studies at present, and of their future projections for the 21st century, allows for determining the optimal European locations to install or maintain offshore wind farms. Only northern Europe, the northwest portion of the Iberian Peninsula, the Gulf of Lyon, the Strait of Gibraltar, and the northwest coast of Turkey show no change or increase in wind power, revealing these locations as the most suitable for installing and maintaining offshore wind farms in the future. The installation of wind farms is subject to restrictions established under international law, European law, and the domestic legal framework of each EU member state. Europe is moving toward streamlining of licensing procedures, reducing subsidies, and implementing auction systems. PMID- 30008175 TI - Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior. AB - BACKGROUND: Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams Beuren syndrome (WS). Of particular interest is the unusual social-cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD-like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified. METHOD: Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale. RESULTS: We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect. CONCLUSIONS: Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains. PMID- 30008179 TI - Subtropical cyclones over the oceanic basins: a review. AB - Subtropical cyclones are hybrid systems presenting a warm core at low levels, as tropical cyclones, and a cold core at upper levels, as extratropical cyclones. Their genesis can be as proper subtropical system or from the transitions (extratropical to subtropical or tropical to subtropical). Subtropical cyclones occur mostly over the sea and generate intense near surface winds with great impacts on human activities and ecosystems. We present a review of the main features, as obtained from observations and numerical simulations, for subtropical cyclone development over the major oceanic basins. PMID- 30008178 TI - Induction chemotherapy in the treatment of nasopharyngeal carcinoma: Clinical outcomes and patterns of care. AB - The role of induction chemotherapy in nasopharyngeal carcinoma (NPC) remains controversial. The primary aim of this study was to use the National Cancer Database to evaluate the patterns of care of induction chemotherapy in NPC and its impact on overall survival (OS). Patients with NPC from 2004 to 2014 were obtained from the NCDB. Patients were considered to have received induction chemotherapy if it was started >=43 days before the start of RT and concurrent CRT if chemotherapy started within 21 days after the start of RT. Propensity score matching was used to control for selection bias. Cox proportional hazards model was used to determine significant predictors of OS. Logistic regression model was used to determine predictors of the use of induction chemotherapy. Significance was defined as a P value <.05. A total of 4857 patients were identified: 4041 patients (87.2%) received concurrent CRT and 816 patients (16.8%) received induction chemotherapy. The use of induction therapy remained stable between 2004 and 2014. Younger patients and those with higher T- and N stage had a higher likelihood of being treated with induction chemotherapy. The 5 year OS in patients treated with induction chemotherapy and CRT was 66.3% vs 69.1%, respectively (P = .25). There was no difference in OS when these two groups were analyzed after propensity score matching. No differences in OS existed between these treatment groups in patients with T3-T4N1 or TanyN2-3 disease (P = .76). Propensity score matching also did not reveal any difference in OS in patients with T3-T4N1 or TanyN2-3 disease. The use of induction chemotherapy has remained stable in the last decade. In this study of patients with NPC, induction chemotherapy was not associated with improved OS compared to CRT alone. PMID- 30008180 TI - Role of increasing leukocyturia for detecting the transition from asymptomatic bacteriuria to symptomatic infection in women with recurrent urinary tract infections: A new tool for improving antibiotic stewardship. AB - OBJECTIVES: To evaluate the importance of leukocyturia in detecting the transition from asymptomatic bacteriuria to symptomatic infection in women with recurrent urinary tract infections. METHODS: In this cross-sectional study, we evaluated all women with recurrent urinary tract infection and asymptomatic bacteriuria who had been enrolled in two previous studies. Data from urological visits, urine analyses and microbiological evaluations were collected. Patients were divided into two groups: patients with symptomatic recurrence (group A) and patients without recurrence (group B), with a mean follow-up period of 38.8 months. Data on leukocyturia and clinical data were compared. Logistic regression analyses were carried out and areas under the receiver operating characteristic curves were calculated. RESULTS: A total of 301 women with symptomatic urinary tract infection were included in group A, whereas 249 women without clinical infection were included in group B. Group A showed a higher level of leukocytes in the urinary analysis taken at the moment of recurrence when compared with the baseline value (mean leukocytes per high power field 54 +/- 5 vs 19 +/- 6 at baseline; P < 0.0001). When an increase of leukocytes/mm3 of >150% from baseline was used for logistic regression, the area under the receiver operating characteristic of the model was 0.82 (95% CI 0.78-0.94; P = 0.01). An increase of leukocytes/mm3 of >150% from baseline had a sensitivity of 90.1% and a specificity of 91.2% for symptomatic urinary tract infection. CONCLUSIONS: This study shows that an increase of leukocyturia of >150% from baseline has a predictive role for the transition from asymptomatic bacteriuria to symptomatic urinary tract infection in women with recurrent urinary tract infections. PMID- 30008181 TI - Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy. AB - Articular chondrocytes are quiescent, fully differentiated cells responsible for the homeostasis of adult articular cartilage by maintaining cellular survival functions and the fine-tuned balance between anabolic and catabolic functions. This balance requires phenotypic stability that is lost in osteoarthritis (OA), a disease that affects and involves all joint tissues and especially impacts articular cartilage structural integrity. In OA, articular chondrocytes respond to the accumulation of injurious biochemical and biomechanical insults by shifting toward a degradative and hypertrophy-like state, involving abnormal matrix production and increased aggrecanase and collagenase activities. Hypertrophy is a necessary, transient developmental stage in growth plate chondrocytes that culminates in bone formation; in OA, however, chondrocyte hypertrophy is catastrophic and it is believed to initiate and perpetuate a cascade of events that ultimately result in permanent cartilage damage. Emphasizing changes in DNA methylation status and alterations in NF-kappaB signaling in OA, this review summarizes the data from the literature highlighting the loss of phenotypic stability and the hypertrophic differentiation of OA chondrocytes as central contributing factors to OA pathogenesis. PMID- 30008182 TI - Confronting ageism: The potential of intergenerational contemporary art events to increase understandings of older adults and ageing. AB - OBJECTIVE: To explore the impact of an innovative intergenerational art event showcasing retirement village life on attendees' understandings of older adults and ageing. METHODS: A survey of 93 art event attendees was conducted immediately after 16 sessions of the event (78% response rate). Respondents reported on their event experience and its impact on their understandings of older adults and attitudes towards ageing. Analysis of Variance (ANOVA) used to test for differences between age groups (18-34, 35-64 and 65+ years). RESULTS: Over 90% of attendees reported the art event helped them develop an understanding of the lives of older people, with the greatest impact on young and middle-aged adults. The majority of young and middle-aged adults, however, expressed concern about their own ageing. CONCLUSION: Results suggest that intergenerational art events have the potential to increase understandings of older adults and their lives, but this may not translate into personalised comfort with ageing. PMID- 30008183 TI - Aboriginal and Torres Strait Islander health-care delivery: The views of health care professionals in Sydney's tertiary paediatric hospitals. AB - AIM: To determine the cultural competency training, knowledge and attitudes of health professionals about Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) health-care delivery. METHODS: Survey of medical (n = 200), nursing (n = 200) and other health professionals (n = 210) working in two tertiary paediatric hospitals in December 2013. The main outcome measures were training in Aboriginal health-care delivery, knowledge of Aboriginal health and services, attitudes to identification of Aboriginal patients and suggested ways to improve health-care delivery to Aboriginal patients. RESULTS: We received responses from 286 of 572 (50.0%) staff with valid emails: 75 medical, 88 nursing and 123 other health professionals. A minority reported receiving specific Aboriginal health training (126/286, 44.8%) and Aboriginal cultural competency training (106/286, 37.1%). Medical staff were less likely than others to report Aboriginal health-care training (P = 0.01), cultural competency training (P < 0.001) and that their training equipped them to manage Aboriginal patients (P = 0.04). Few medical staff reported a good/very good knowledge of the services provided by the Aboriginal Community Controlled Health Services (20.0%), the Federal Government Closing the Gap initiative (14.7%) or the Royal Australasian College of Physicians' Reconciliation Action Plan (8.0%). Only 62 of 286 (21.7%) staff agreed that they usually asked patients/parents whether they identified as Aboriginal. Although 256 of 286 (89.5%) agreed that Aboriginal staff were an important resource, only 125 of 286 (43.7%) had referred Aboriginal patients to one. CONCLUSION: The opportunities we have identified to improve health-care delivery to Aboriginal patients include: increasing Aboriginal cultural competency training, correct identification of Aboriginal patients, referring Aboriginal patients to Aboriginal health-care services and increased awareness of Aboriginal Community Controlled Health Services. PMID- 30008186 TI - Effect of a clinical flowchart incorporating Wells score, PERC rule and age adjusted D-dimer on pulmonary embolism diagnosis, scan rates and diagnostic yield. AB - OBJECTIVE: To assess the association between the use of a flowchart incorporating Wells score, PERC rule and age-adjusted D-dimer and subsequent imaging and yield rates of computed tomography pulmonary angiogram and nuclear medicine ventilation perfusion scans being ordered in the ED for the assessment of pulmonary embolism. METHODS: A flowchart governing ED pulmonary embolism investigation was introduced across three EDs in Melbourne, Australia for a 12 month period. Comparison of pulmonary embolism imaging rates and yield with the preceding 12 months was performed. RESULTS: A total of 1815 pre-implementation scans were performed compared with 1116 scans post-implementation. Because of growth in patient attendances over this time, this equated to an imaging rate of 14.5 per 1000 presentations pre-implementation and 8.6 per 1000 presentations post implementation (P < 0.001). Overall pulmonary embolism imaging yield rates rose from 9.9% to 16.5% (P < 0.001). A total of 179 pre-implementation pulmonary embolisms were identified, with an incidence of 1.4 per 1000 presentations. This compared to 184 pulmonary embolisms post-implementation, with an incidence of 1.4 per 1000 presentations (P = 0.994). CONCLUSION: The introduction of a clinical flowchart incorporating Wells score, PERC rule and age-adjusted D-dimer was associated with an increase in ED computed tomography pulmonary angiogram and nuclear medicine ventilation perfusion yield rate from 9.9% to 16.5% across the three enrolment hospitals when investigating possible pulmonary embolism. This corresponded to a 40% relative reduction in pulmonary embolism imaging. Diagnosis rates remained unchanged and no cases of missed pulmonary embolism attributable to the flowchart were identified. PMID- 30008185 TI - Value of emergency department triage data to describe and understand patterns and mechanisms of cycling injuries. AB - OBJECTIVE: To characterise patients presenting to EDs for a bicycle-related injury, identify contributing factors to the injuries and describe the data gaps. METHODS: A retrospective study of bicycle-related injury presentations over the 5 year period 2010-2014 to two major metropolitan EDs. Data collected from the emergency presentation database consisted of patient demographics, presenting complaint, discharge diagnosis and details about the circumstances and mechanism of the accident. RESULTS: Bicycle injuries (n = 4144) increased from 20.0 to 25.2 per 1000 injury presentations over 5 years. Patients were 80% male across all age groups and 35% of presentations occurred at the weekend. Fractures accounted for one-third (34%) of all injuries, while injuries to the upper extremities and head resulted in 36% and 19% of cases, respectively. Admission rate was 17%. The number of falls exceeded collisions (1611 vs 937), and in the 13.3% of the fall cases where documentation was present for which how the fall occurred, over half were attributed to bike handling errors. Information related to type of bicycle, accident location, type of activity, protective clothing worn (including helmets) and visibility aids was not recorded for over 95% of the cases. CONCLUSION: Bicycle injuries carry a considerable burden to the ED and the incidence of presentations appears to be rising. The current triage data, designed to provide a rapid assessment for medical urgency, are limited to describing broad demographics, trends and causes. PMID- 30008187 TI - Editorial Comment to Role of increasing leukocyturia for detecting the transition from asymptomatic bacteriuria to symptomatic infection in women with recurrent urinary tract infections: A new tool for improving antibiotic stewardship. PMID- 30008184 TI - Pre- and early postnatal nicotine exposure exacerbates autoresuscitation failure in serotonin-deficient rat neonates. AB - KEY POINTS: Sudden infant death syndrome (SIDS) is one of the leading causes of death during the first year of life and abnormalities linked to serotonin (5-HT) have been identified in many SIDS cases. Cigarette smoking and associated exogenous stressors, e.g. developmental nicotine exposure, may compound these serotonergic defects and any associated defects in cardiorespiratory function. Using neonatal rodent pups subjected to medullary 5-HT deficiency and perinatal nicotine exposure, we examined the impact of this interplay of factors on the neonates' ability to autoresuscitate at specific ages. In perinatal nicotine exposed 5-HT deficient pups, impaired autoresuscitation along with significantly delayed post-anoxic recovery of normal breathing and heart rate was observed at postnatal day 10 (P10). We found that the interaction between 5-HT deficiency and perinatal nicotine exposure can significantly increase pups' vulnerability to environmental stressors and exacerbate defects in cardiorespiratory protective reflexes to repetitive anoxia during the development period. ABSTRACT: Cigarette smoking during pregnancy increases the risk of sudden infant death syndrome (SIDS), and nicotine replacements, a key ingredient of cigarettes, have been recently prescribed to women who wish to quit smoking during their pregnancy. Serotonin (5-HT) abnormalities have been consistently identified in many SIDS cases. Here we investigated the effects of perinatal nicotine exposure in mild 5 HT deficiency rat neonates on autoresuscitation, a protective cardiorespiratory reflex. The mild 5-HT deficiency was induced by a maternal tryptophan-deficient diet, and nicotine was delivered from embryonic day (E) 4 to postnatal day (P) 10 at 6 mg kg-1 day-1 through an osmotic pump. In P10 rats, nicotine exposure exacerbates autoresuscitation failure (mortality) in mildly 5-HT-deficient rats to a greater extent than in controls (P = 0.029). The recovery of eupnoea and heart rate to baseline values following repetitive anoxic events (which elicit an apnoea accompanied by a bradycardia) is significantly delayed in 5-HT-deficient rats treated with nicotine, making them more susceptible to failure of autoresuscitation (eupnoea recovery: P = 0.0053; heart rate recovery: P = < 0.0001). Neither 5-HT deficiency nor nicotine exposure alone appears to affect the ability to autoresuscitate significantly when compared among the four treatments. The increased vulnerability to environmental stressors, e.g. severe hypoxia, asphyxia, or anoxia, in these nicotine-exposed 5-HT-deficient neonates during postnatal developmental period is evident. PMID- 30008188 TI - Combination of solifenacin with tamsulosin reduces prostate volume and vascularity as opposed to tamsulosin monotherapy in patients with benign prostate enlargement and overactive bladder symptoms: Results from a randomized pilot study. AB - OBJECTIVES: To identify the potential influence of antimuscarinics on morphometric parameters of the prostate in patients with benign prostatic enlargement and overactive bladder. METHODS: Non-neurological patients with prostate volume >30 mL, predominately storage lower urinary tract symptoms, three or more urgency episodes per 24 h, maximum flow rate >=10 mL/s and post-void residual <=100 mL were recruited for this study. They were randomized to receive either tamsulosin or tamsulosin + solifenacin. Patients were submitted to transrectal and transvesical ultrasonography, pressure-flow study and prostate specific antigen test, and completed the International Prostate Symptom Score, bladder diary and overactive bladder questionnaire at induction and at 6 months. End-study changes in morphometric prostate parameters (total prostate and adenoma volumes, prostate vascularity), as measured by transrectal ultrasound, were the principal outcomes. RESULTS: A reduction in total prostate volume (mean -9.5%) was noted in the combination group, as opposed to an increase in the monotherapy group (+9.2%; P < 0.001). Similar changes were reflected in adenoma volume (monotherapy +17.4% vs combination -12.5%, P = 0.001) and in prostate vascularity (monotherapy +149.3% vs combination -19.8%, P = 0.001). Both treatment regimens improved the International Prostate Symptom Score (P = 0.001); monotherapy improved the voiding subscale (P = 0.01) more, whereas combination therapy improved the storage subscale (P = 0.024). Cystometric capacity improved in the combination group (P < 0.001). Post-void residual was increased in the combination group (+34.79%), as opposed to a decrease in the monotherapy group ( 17.05%; P = 0.001). CONCLUSIONS: The results of this pilot study suggest that solifenacin might affect morphometric properties of the prostate, decreasing total prostate and adenoma volume, as well as vascularity. A molecular effect of antimuscarinics on the prostate, in parallel with their expected bladder effect, warrants further investigation. PMID- 30008189 TI - Gordon Research Conference on Ca2+ Signalling 2017 Editorial. PMID- 30008191 TI - Overview: neuroplasticity and synaptic function in neuropsychiatric disorders. PMID- 30008192 TI - Leber Hereditary Optic Neuropathy-Light at the End of the Tunnel? AB - Leber hereditary optic neuropathy (LHON) is an important cause of mitochondrial blindness. The majority of patients harbor one of three mitochondrial DNA (mtDNA) point mutations, m.3460G>A, m.11778G>A, and m.14484T>C, which all affect complex I subunits of the mitochondrial respiratory chain. The loss of retinal ganglion cells in LHON is thought to arise from a combination of impaired mitochondrial oxidative phosphorylation resulting in decreased adenosine triphosphate (ATP) production and increased levels of reactive oxygen species. Treatment options for LHON remain limited, but major advances in mitochondrial neuroprotection, gene therapy, and the prevention of transmission of pathogenic mtDNA mutations will hopefully translate into tangible benefits for patients affected by this condition and their families. PMID- 30008193 TI - Wide field of view optical coherence tomography for structural and functional diagnoses in dentistry. AB - We report herein the fabrication and performance response of a three-dimensional (3-D) intraoral scan probe based on optical coherence tomography (OCT) that enables 3-D structural and functional diagnoses of the human teeth. The OCT system was configured using a swept-source OCT (SS-OCT) with a center wavelength of 1310 nm. The scan probe was built using an MEMS mirror and an optical collimator. The implemented SS-OCT equipped with the MEMS-based scan probe yielded an axial resolution of 10 MUm and a scan range of 8 * 8 mm2. Two dimensional (2-D) cross-sectional images of the teeth were acquired by the scan probe based on the OCT. The 3-D volume image was acquired by combining a series of 2-D images, which includes internal and structural information of the human teeth. To utilize the OCT system as an intraoral scanner, partially overlapped 3 D volume images were sequentially acquired and stitched. The 3-D stitching was implemented based on an iterative closest point algorithm. The feasibility of the intraoral scan probe is demonstrated based on its ability to image and characterize the structure and function of the human teeth. PMID- 30008194 TI - Is CO2 insufflation an amelioration of routine colonoscopy? AB - BACKGROUND: The insufflation of gas during colonoscopy leads to distention of the colon with abdominal discomfort and pain for the patients. Use of CO2 during endoscopy is reported to minimize abdominal discomfort during and after endoscopy. Aim of this study was to find out whether this improvement leads to decreased dosage of sedation drugs in order to improve patient's safety and satisfaction. METHODS: In this double-blind, randomized and controlled study 150 Patients referred to colonoscopy were assigned to either CO2 or air insufflation. We recorded basic characteristics of colonoscopy and the amount of drugs used for sedation. Patients and investigators filled out questionnaires to record pain, abdominal bloating and flatulence. RESULTS: Seventy-two patients were randomized for examination with room air, 78 patients for use of CO2. We found no difference in basic characteristics of colonoscopy (cecal intubation time and procedure time). Both groups were administered the same amount of drugs for sedation. We found only slight improvement of pain, abdominal bloating and flatulence. CONCLUSIONS: The study revealed only moderate positive effects for use of CO2 during colonoscopy. We found only modest improvement of patient's comfort during and after colonoscopy. No reduced doses of drugs for sedation could be recorded. PMID- 30008190 TI - Mechanisms underlying the role of DISC1 in synaptic plasticity. AB - Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self-association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity. It concentrates on DISC1's role in interacting with synaptic proteins, controlling dendritic structure and cellular trafficking of mRNA, synaptic vesicles and mitochondria. N-terminal directed mutations appear to impair synaptic plasticity through interactions with phosphodiesterase 4B (PDE4B) and hence protein kinase A (PKA)/GluA1 and PKA/cAMP response element-binding protein (CREB) signalling pathways, and affect spine structure through interactions with kalirin 7 (Kal-7) and Rac1. C-terminal directed mutations also impair plasticity possibly through altered interactions with lissencephaly protein 1 (LIS1) and nuclear distribution protein nudE-like 1 (NDEL1), thereby affecting developmental processes such as dendritic structure and spine maturation. Many of the same molecules involved in DISC1's cytoskeletal interactions are also involved in intracellular trafficking, raising the possibility that impairments in intracellular trafficking affect cytoskeletal development and vice versa. While the multiplicity of DISC1 protein interactions makes it difficult to pinpoint a single causal signalling pathway, we suggest that the immediate-term effects of N-terminal influences on GluA1, Rac1 and CREB, coupled with the developmental effects of C-terminal influences on trafficking and the cytoskeleton make up the two main branches of DISC1's effect on synaptic plasticity and dendritic spine stability. PMID- 30008195 TI - Chronic Placental Inflammation as a Risk Factor of Severe Retinopathy of Prematurity. AB - BACKGROUND: Chronic placental inflammation (CPI) has been implicated in the pathogenesis of diseases in premature infants, whereas retinopathy of prematurity (ROP) is a major complication primarily affecting preterm and very low-birth weight (VLBW) infants. This study aims to investigate the association between CPI and ROP in VLBW infants. METHODS: We performed a retrospective review of clinical records of VLBW infants born between 2013 and 2016. Placental pathology findings including CPI cases were analyzed using logistic regression to study infants' morbidities and other clinical characteristics. RESULTS: A total of 402 infants with a mean (standard deviation) gestational age of 28.5 (2.8) weeks and birth weight of 1,027.2 (304.4) g were included. The incidence of ROP was 24.1%. CPI was found in 90 infants (22.4%), among which 28.9% (26 of 90) developed ROP, and 21.1% (19 of 90) underwent laser photocoagulation. Lower gestational age, lower birth weight, longer duration of oxygen supply, and presence of CPI were associated with the development of ROP. After adjustment for gestational age, birth weight, sex, duration of oxygen supply, and other overlapping placental pathology, CPI was associated with the odds for type 1 ROP that required laser photocoagulation (adjusted odds ratio, 2.739; 95% confidence interval, 1.112 to 6.749; p = .029). CONCLUSIONS: CPI was associated with severe ROP requiring treatment with laser photocoagulation in VLBW infants. PMID- 30008196 TI - WITHDRAWN:A Clinicopathologic Study of 220 Cases of Pulmonary Sclerosing Pneumocytoma in Korea: A Nationwide Survey. AB - Ahead of Print article withdrawn by publisher. PMID- 30008197 TI - Bile Granuloma Mimicking Peritoneal Seeding: A Case Report. AB - Laparoscopic cholecystectomy is a widely used treatment method for most cholelithiasis and is a relatively safe procedure. Foreign body granulomatous reaction to bile or gallstone spillage during laparoscopic cholecystectomy has rarely been reported. We report a case of bile granuloma after laparoscopic cholecystectomy, which mimicked peritoneal seeding. A 59-year-old Korean man presented with right upper quadrant pain. He underwent laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis. Pathologic examination revealed an incidental adenocarcinoma invading the lamina propria with acute cholecystitis and cholelithiasis. After 3 months, follow-up abdominal computed tomography revealed a subhepatic nodule, which showed hypermetabolism on positron emission tomography-computed tomography. Suspecting localized peritoneal seeding, wedge resection of the liver, wedge resection of the transverse colon, and omentectomy were performed. Pathologic examination of the resected specimens revealed multiple bile granulomas. Awareness of bile granuloma mimicking malignancy is noteworthy for patient management to reduce unnecessary procedure during postoperative surveillance. PMID- 30008198 TI - Follicular T-Cell Lymphoma with Concomitant Lennert Lymphoma. PMID- 30008199 TI - Comparison of the Marginal Utility and Disease Burden of Hearing Loss and Other Chronic Diseases. AB - BACKGROUND: Compared with other chronic diseases, hearing loss is generally overlooked from the perspective of disease burden. However, hearing loss is emerging as an important issue in the current society. The objective of this study was to investigate disease burdens and marginal utilities associated with hearing loss and other chronic diseases. METHODS: This study analyzed the cross sectional data of 32,986 participants aged 19 years and older who completed the Korea National Health and Nutrition Examination Surveys between 2009 and 2013. Additionally, this study used the pure tone audiometric test, European Quality of Life-Five Dimensions Questionnaire, and chronic disease status. The data were analyzed using a multiple linear regression method. RESULTS: The data of 23,297 people who underwent a pure tone audiogram and completed the European Quality of Life-Five Dimensions Questionnaire were used in this analysis. The marginal utility of hearing loss ranked fifth among nine chronic diseases. The estimated loss of quality-adjusted life years associated with hearing loss was -93.69 years per 100,000 people, which is similar to other chronic diseases. CONCLUSION: This study assessed the marginal utilities and public burdens of hearing loss and eight chronic diseases in a South Korean population. Although the values may vary depending on country and race, this study may provide an indispensable foundation for more detailed studies on hearing loss. PMID- 30008200 TI - CTCF Regulates Otic Neurogenesis via Histone Modification in the Neurog1 Locus. AB - The inner ear is a complex sensory organ responsible for hearing and balance. Formation of the inner ear is dependent on tight regulation of spatial and temporal expression of genes that direct a series of developmental processes. Recently, epigenetic regulation has emerged as a crucial regulator of the development of various organs. However, what roles higher-order chromatin organization and its regulator molecules play in inner ear development are unclear. CCCTC-binding factor (CTCF) is a highly conserved 11-zinc finger protein that regulates the three-dimensional architecture of chromatin, and is involved in various gene regulation processes. To delineate the role of CTCF in inner ear development, the present study investigated inner ear-specific Ctcf knockout mouse embryos (Pax2-Cre; Ctcffl/fl ). The loss of Ctcf resulted in multiple defects of inner ear development and severely compromised otic neurogenesis, which was partly due to a loss of Neurog1 expression. Furthermore, reduced Neurog1 gene expression by CTCF knockdown was found to be associated with changes in histone modification at the gene's promoter, as well as its upstream enhancer. The results of the present study demonstrate that CTCF plays an essential role in otic neurogenesis by modulating histone modification in the Neurog1 locus. PMID- 30008202 TI - Scalable Synthesis of Cyclocitrinol. AB - A 10-step synthesis of the C25 steroid natural product cyclocitrinol from inexpensive, commercially available pregnenolone is reported. This synthesis features a biomimetic cascade rearrangement to efficiently construct the challenging bicyclo[4.4.1] A/B ring system, which enabled a gram-scale synthesis of the bicyclo[4.4.1] enone intermediate 18 in only nine steps. This work also provides experimental support for the biosynthetic origin of cyclocitrinol. PMID- 30008203 TI - Zinc Isotope Fractionation during Sorption onto Al Oxides: Atomic Level Understanding from EXAFS. AB - Interactions between aqueous Zn and mineral surfaces can lead to notable Zn isotope fractionation that affects Zn source fingerprinting, which needs an atomic-level understanding. In this study, we demonstrate that Zn isotope fractionation (Delta66Znsorbed-aqueous) during Zn sorption onto gamma-Al2O3 depends on both pH and Zn concentration and ultimately correlates to surface coverage (Gamma). At pH values of 6.0-6.5 and/or Zn concentrations of 0.1-0.2 mM, where Gamma < 0.8 MUmol m-2, Delta66Znsorbed-solution is 0.47 +/- 0.030/00, whereas Delta66Znsorbed-aqueous decreases to 0.02 +/- 0.070/00 at pH values of 7.0-8.0 and Zn concentrations of 0.4-0.8 mM, with a high Gamma ranging from 1.5 to 3.2 MUmol m-2. Using extended X-ray absorption fine structure (EXAFS) spectroscopy, we elucidated that a Zn-Al layered double hydroxide (LDH) with a Zn O bond length of 2.06 A forms at high surface coverage (1.5 < Gamma < 3.2 MUmol m 2). In contrast, at low surface coverage (Gamma < 0.8 MUmol m-2), the sorbed Zn occurs as a tetrahedrally coordinated inner-sphere surface complex with an average Zn-O interatomic distance of 1.98 A. Such contrasts lead to an atomic level understanding of the strong links between isotope fractionation, local bonding structures (i.e., coordination and bond distances), and solution chemistry, which is crucial for more effective applications of stable metal isotopes as environmental tracers. PMID- 30008201 TI - Structural Basis for LAR-RPTP-Mediated Synaptogenesis. AB - Leukocyte common antigen-related protein tyrosine phosphatases (LAR-RPTPs) are cellular receptors of heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans that regulate neurite outgrowth and neuronal regeneration. LAR RPTPs have also received particular attention as the major presynaptic hubs for synapse organization through selective binding to numerous postsynaptic adhesion partners. Recent structural studies on LAR-RPTP-mediated trans-synaptic adhesion complexes have provided significant insight into the molecular basis of their specific interactions, the key codes for their selective binding, as well as the higher-order clustering of LAR-RPTPs necessary for synaptogenic activity. In this review, we summarize the structures of LAR-RPTPs in complex with various postsynaptic adhesion partners and discuss the molecular mechanisms underlying LAR-RPTP-mediated synaptogenesis. PMID- 30008204 TI - Effect of Surface Chemistry on Confined Phase Behavior in Nanoporous Media: An Experimental and Molecular Modeling Study. AB - It is well accepted that nanopore size is a controlling parameter in determining the phase behavior of confined adsorbate molecules. Despite this knowledge, the quantitative effect of surface chemistry on the confined phase behavior is a factor that remains obfuscated. Obtaining a complete understanding of the variables controlling confined phase behavior is a critical step in developing more complete equations of state for predictive modeling. To this end, a combined experimental and molecular modeling study was conducted to investigate the effects of surface chemistry and wetting on the confined phase behavior of propane and n-butane in modified and unmodified silica MCM-41. Isotherms were measured in four types of silica MCM-41 modified with varying sizes of alkyl groups to determine the effects of increasing surface modification. Results showed that increased pore surface coverage of carbon resulted in a notable change in the capillary condensation pressures, adsorption enthalpy, and confined critical temperature of the adsorbate. Correlations between the surface coverage of carbon and the confined critical temperature were presented and supported by thermodynamic arguments. The primary conclusions were partially supported by hybrid molecular dynamics-Monte Carlo simulations of propane adsorption in models of the four types of experimental adsorbents. Several differences were noted and explained between the experimental and modeling results. Energetic heterogeneity on the surface of the modified MCM-41 adsorbents as well as differences in adsorbate entropy induced by surface features and chemistry were suggested as primary driving factors for the observed trends. The results of this work have direct implications for improving understanding of confined phase behavior in materials of varying surface chemistries. PMID- 30008206 TI - Non-Target and Suspect Screening of Per- and Polyfluoroalkyl Substances in Airborne Particulate Matter in China. AB - Airborne particulate matter (APM) has an important role in inhalation exposure, especially in China. The environmental occurrence of conventional and unknown per and polyfluoroalkyl substances (PFASs) in APM remains unclear. Therefore, in this study, a two-stage experiment was designed to identify potential PFASs and to investigate their distribution in APM. Indoor and outdoor APM samples were collected from five selected cities in China. Through PFAS homologue analysis and suspect screening, 50 peaks were identified with different confidence levels (levels 1-3). Among the identified PFASs, 34 emerging PFASs including p perfluorous nonenoxybenzenesulfonate, 6:2 polyfluoroalkyl phosphate diester, n:2 fluorotelomer sulfonates, n:2 fluorinated telomer acids, n:2 chlorinated polyfluoroalkyl ether sulfonic acids, 1:n polyfluoroalkyl ether carboxylic acids (1:n PFECAs), perfluoroalkyl dioic acids (PFdiOAs), hydro-substituted perfluoroalkyl dioic acids (H-PFdiOAs), and unsaturated perfluorinated alcohols (UPFAs) were identified in APM. In particular, 1:n PFECAs, PFdiOAs, H-PFdiOAs, and UPFAs were first detected in APM. Although human exposure to perfluorooctanoic acid via inhaled APM was noted to not be a risk (hazard quotient <0.1) in this study, the expansion of the PFASs screened in APM implies that human exposure to PFASs might be much more serious and should be considered in future risk assessments in China. PMID- 30008205 TI - Catalytic, Computational, and Evolutionary Analysis of the d-Lactate Dehydrogenases Responsible for d-Lactic Acid Production in Lactic Acid Bacteria. AB - d-Lactate dehydrogenase (d-LDH) catalyzes the reversible reaction pyruvate + NADH + H+ <-> lactate + NAD+, which is a principal step in the production of d-lactate in lactic acid bacteria. In this study, we identified and characterized the major d-LDH (d-LDH1) from three d-LDHs in Leuconostoc mesenteroides, which has been extensively used in food processing. A molecular simulation study of d-LDH1 showed that the conformation changes during substrate binding. During catalysis, Tyr101 and Arg235 bind the substrates by hydrogen bonds and His296 acts as a general acid/base for proton transfer. These residues are also highly conserved and have coevolved. Point mutations proved that the substrate binding sites and catalytic site are crucial for enzyme activity. Network and phylogenetic analyses indicated that d-LDH1 and the homologues are widely distributed but are most abundant in bacteria and fungi. This study expands the understanding of the functions, catalytic mechanism, and evolution of d-LDH. PMID- 30008207 TI - Tuning the Surface Ordering of Self-Assembled Ionic Surfactants on Semiconducting Single-Walled Carbon Nanotubes: Concentration, Tube Diameter, and Counterions. AB - We report direct spectroscopic measurements of the macromolecular organization of ionic surfactants on the surface of semiconducting single-walled carbon nanotubes (SWCNTs) within solution-processed thin films. By using vibrational sum frequency generation (VSFG) spectroscopy, sensitive measurements of interfacial surfactant ordering were obtained as a function of surfactant concentration for sodium dodecyl sulfate (SDS)-encapsulated (6,5) and (7,6) SWCNTs with and without excess electrolytes. Anionic surfactants are known to effectively stabilize SWCNTs. The current models suggest a strong influence of the dispersion conditions on the surfactant interfacial macromolecular organization and self-assembly. Direct experimental probes of such an organization using nanotubes of specific chirality are needed to validate the existing models. We found that as the bulk SDS concentration increases near the surfactant critical micelle concentration, the interfacial ordering increased, approaching the formation of cylindrical-like micelles with the nanotube at the core. At the higher surfactant concentrations measured here, the (6,5) SWCNTs produced more ordered structures relative to those with the (7,6) SWCNTs. The relatively larger-diameter (7,6) chiral tubes support enhanced van der Waals (vdW) interactions between the tube carbon surface and the surfactant methylene chain groups that likely increase the density of gauche defects. A new effect arises when the precursor solution is exposed to a small concentration of divalent Ca2+ counterions. We postulate that a salt bridging configuration on such highly curved surfaces decreases the ordering of interfacial surfactant molecules, resulting in compact, disordered structures. However, this phenomenon was not observed with excess Na+ ions at the same ionic strength. Instead, a modest increase in surfactant ordering was observed with the excess monovalent electrolyte. These results provide new insights for thin film solution processing of vdW nanomaterials and demonstrate that VSFG is a sensitive probe of surfactant organization on nanostructures. PMID- 30008208 TI - Immune Profiling of Polysaccharide Submicron Vesicles. AB - Alginate (ALG) and chitosan (CS) have been extensively used for biomedical applications; however, data relative to immune responses exerted by them are scarce. We synthesized a submicron vesicle system (SV) displaying a CS shell over an ALG core. Intravenous injection of these promising carriers could be a possible route of delivery; therefore, we evaluated their impact on human peripheral blood mononuclear cells (PBMCs). By this ex vivo approach, we established how SV chemical-physical characteristics affected the immune cells in terms of cellular uptake, viability, and state of activation. By flow cytometry, we demonstrated that SVs were internalized by PBMCs with differential trends. No substantial necrotic and apoptotic signals were recorded, and SVs weakly affected activation status of PBMCs (concerning the markers CD69, CD25, CD80, and the cytokines TNF-alpha and IL-6), showing high immune biocompatibility and low immunomodulating properties. Our findings gain particular value toward the biomedical applications of SVs and make these polymer-based structures more attractive for translation into clinical uses. PMID- 30008209 TI - Operando Evolution of the Structure and Oxidation State of Size-Controlled Zn Nanoparticles during CO2 Electroreduction. AB - We explored the size-dependent activity and selectivity of Zn nanoparticles (NPs) for the electrochemical CO2 reduction reaction (CO2RR). Zn NPs ranging from 3 to 5 nm showed high activity and selectivity (~70%) for CO production, whereas those above 5 nm exhibited bulk-like catalytic properties. In addition, a drastic increase in hydrogen production was observed for the Zn NPs below 3 nm, which is associated with the enhanced content of low-coordinated sites on small NPs. The presence of residual cationic Zn species in the catalysts was also revealed during CO2RR via operando X-ray absorption fine-structure spectroscopy measurements. Such species are expected to play a role in the selectivity trends obtained. Our findings can serve as guidance for the development of highly active and CO-selective Zn-based catalysts for CO2RR. PMID- 30008210 TI - Long-Lived, Non-Geminate, Radiative Recombination of Photogenerated Charges in a Polymer/Small-Molecule Acceptor Photovoltaic Blend. AB - Minimization of open-circuit-voltage ( VOC) loss is required to transcend the efficiency limitations on the performance of organic photovoltaics (OPV). We study charge recombination in an OPV blend comprising a polymer donor with a small molecule nonfullerene acceptor that exhibits both high photovoltaic internal quantum efficiency and relatively high external electroluminescence quantum efficiency. Notably, this donor/acceptor blend, consisting of the donor polymer commonly referred to as PCE10 with a pseudoplanar small molecule acceptor (referred to as FIDTT-2PDI) exhibits relatively bright delayed photoluminescence on the microsecond time scale beyond that observed in the neat material. We study the photoluminescence decay kinetics of the blend in detail and conclude that this long-lived photoluminescence arises from radiative nongeminate recombination of charge carriers, which we propose occurs via a donor/acceptor CT state located close in energy to the singlet state of the polymer donor. Additionally, crystallographic and spectroscopic studies point toward low subgap disorder, which could be beneficial for low radiative and nonradiative losses. These results provide an important demonstration of photoluminescence due to nongeminate charge recombination in an efficient OPV blend, a key step in identifying new OPV materials and materials-screening criteria if OPV is to approach the theoretical limits to efficiency. PMID- 30008211 TI - Contribution to Accurate Spherical Gold Nanoparticle Size Determination by Single Particle Inductively Coupled Mass Spectrometry: A Comparison with Small-Angle X ray Scattering. AB - Small-angle X-ray scattering spectroscopy (SAXS) is the method of choice for nanoparticle diameter and concentration determination. On the one hand, it is metrologically traceable for spherical nanoparticle mean diameter determination and does not require any sample preparation or calibration. On the other hand, single-particle inductively coupled mass spectrometry (SPICPMS) is still under development and requires involved process clarification and accuracy improvement. The strategy of this study is the comparison of the two techniques to study comprehensively SPICPMS performance and observe phenomena otherwise hidden. Six spherical gold nanoparticle suspensions distributed over a large size range (30, 50, 60, 80,100, and 150 nm) are studied as calibration points. Potential matrix effects are eliminated by stabilizing nanoparticles with chitosan in HCl. Chitosan encapsulates nanoparticles, stabilizes their dispersion, and protects them from dissolution. Detection counting/analogue threshold and timeout appear as the relevant parameters for transient signals. They show an influence not only on mean signal but also on signal distribution. The detection tuning proposed allows to linearly calibrate the nanoparticle distribution signal to cubed diameter over the entire range studied with no sensitivity diminution. Comparing the three classical transport efficiency methods, size transport efficiency is shown as the most accurate. The new procedure is validated analyzing three gold nanoparticle suspensions (135, 40, and 50 nm). The results are consistent with SAXS measurements. PMID- 30008212 TI - Highly Ordered and Field-Free 3D DNA Nanostructure: The Next Generation of DNA Nanomachine for Rapid Single-Step Sensing. AB - Herein, by directly using Watson-Crick base pairing, a highly ordered and field free three-dimensional (3D) DNA nanostructure is self-assembled by azobenzene (azo)-functionalized DNA nippers in a few minutes, which was applied as a 3D DNA nanomachine with an improved movement efficiency compared to traditional Au-based 3D nanomachines due to the organized and high local concentration of nippers on homogeneous DNA nanostructure. Once microRNA (miRNA) interacts with the 3D nanomachine, the nippers "open" to hybridize with the miRNA. Impressively, photoisomerization of the azo group induces dehybridization/hybridization of the nippers and miRNA under irradiation at different wavelengths, which easily solves one main technical challenge of DNA nanotechnology and biosensing: reversible locomotion in one step within 10 min. As a proof of concept, the described 3D machine is successfully applied in the rapid single-step detection of a biomarker, which gives impetus to the design of new generations of mechanical devices beyond the traditional ones with ultimate applications in sensing analysis and diagnostic technologies. PMID- 30008213 TI - Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth. AB - Epstein-Barr virus (EBV) establishes latent infection and is associated with several types of lymphomas and carcinomas. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV-positive tumor cells. EBNA1 binds to the origin of virus plasmid replication (OriP) on the EBV episome to initiate virus DNA replication and regulates virus gene expression as a transcriptional activator. In this study, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst 33258 conjugate named EIP-2 (2), which specifically binds to the OriP region with high affinity, to interrupt EBNA1-OriP binding in vitro and in vivo. By eradicating the EBV episome in EBV-positive cells, compound 2 selectively inhibited EBV positive cell proliferation. Moreover, the injection of 2 significantly suppressed tumor growth in the mice xenograft tumor model. These findings demonstrate that compound 2 is a potential therapeutic candidate for the treatment of EBV-associated tumors. PMID- 30008214 TI - Ultrahigh Performance All Solid-State Lithium Sulfur Batteries: Salt Anion's Chemistry-Induced Anomalous Synergistic Effect. AB - With a remarkably higher theoretical energy density compared to lithium-ion batteries (LIBs) and abundance of elemental sulfur, lithium sulfur (Li-S) batteries have emerged as one of the most promising alternatives among all the post LIB technologies. In particular, the coupling of solid polymer electrolytes (SPEs) with the cell chemistry of Li-S batteries enables a safe and high-capacity electrochemical energy storage system, due to the better processability and less flammability of SPEs compared to liquid electrolytes. However, the practical deployment of all solid-state Li-S batteries (ASSLSBs) containing SPEs is largely hindered by the low accessibility of active materials and side reactions of soluble polysulfide species, resulting in a poor specific capacity and cyclability. In the present work, an ultrahigh performance of ASSLSBs is obtained via an anomalous synergistic effect between (fluorosulfonyl)(trifluoromethanesulfonyl)imide anions inherited from the design of lithium salts in SPEs and the polysulfide species formed during the cycling. The corresponding Li-S cells deliver high specific/areal capacity (1394 mAh gsulfur-1, 1.2 mAh cm-2), good Coulombic efficiency, and superior rate capability (~800 mAh gsulfur-1 after 60 cycles). These results imply the importance of the molecular structure of lithium salts in ASSLSBs and pave a way for future development of safe and cost-effective Li-S batteries. PMID- 30008215 TI - Biomineralized Metal-Organic Framework Nanoparticles Enable Intracellular Delivery and Endo-Lysosomal Release of Native Active Proteins. AB - Efficient delivery and endo-lysosomal release of active proteins in living cells remain a challenge in protein-based theranostics. We report a novel protein delivery platform using protein-encapsulating biomineralized metal-organic framework (MOF) nanoparticles (NPs). This platform introduces an adapted biomimetic mineralization method for facile synthesis of MOF NPs with high protein encapsulation efficiency and a new polymer coating strategy to confer the NPs with long-term stability. In vitro results show that protein-encapsulating MOF NPs have the advantages of preserving protein activity for months and protecting proteins from enzyme-mediated degradation. Live cell studies reveal that MOF NPs enable rapid cellular uptake, efficient release and escape of proteins from endo-lysosomes, and preservation of protein activity in living cells. Moreover, the developed platform is demonstrated to enable easy encapsulation of multiple proteins in single MOF NPs for efficient protein co delivery. To our knowledge, it is the first time that protein-encapsulating MOF NPs have been developed as a generally applicable strategy for intracellular delivery of native active proteins. The developed protein-encapsulating biomineralized MOF NPs can provide a valuable platform for protein-based theranostic applications. PMID- 30008217 TI - Sulfide Protects [FeFe] Hydrogenases From O2. AB - [FeFe] hydrogenases catalyze proton reduction and hydrogen oxidation with high rates and efficiency under physiological conditions, but are highly oxygen sensitive. The [FeFe] hydrogenase from Desulfovibrio desulfuricans ( DdHydAB) can be purified under air in an oxygen stable inactive state Hoxair. The formation of the Hoxair state in vitro allows the handling of hydrogenases in air, making their implementation in biotechnological applications more feasible. Here, we report a simple and robust protocol for the formation of the Hoxair state in DdHydAB and the [FeFe] hydrogenase from Chlamydomonas reinhardtii, which is based on high potential inactivation in the presence of sulfide. PMID- 30008216 TI - Highly Conjugated Three-Dimensional Covalent Organic Frameworks Based on Spirobifluorene for Perovskite Solar Cell Enhancement. AB - Highly conjugated three-dimensional covalent organic frameworks (3D COFs) were constructed based on spirobifluorene cores linked via imine bonds (SP-3D-COFs) with novel interlacing conjugation systems. The crystalline structures were confirmed by powder X-ray diffraction and detailed structural simulation. A 6- or 7-fold interpenetration was formed depending on the structure of the linking units. The obtained SP-3D-COFs showed permanent porosity and high thermal stability. In application for solar cells, simple bulk doping of SP-3D-COFs to the perovskite solar cells (PSCs) substantially improved the average power conversion efficiency by 15.9% for SP-3D-COF 1 and 18.0% for SP-3D-COF 2 as compared to the reference undoped PSC, while offering excellent leakage prevention in the meantime. By aid of both experimental and computational studies, a possible photoresponsive perovskite-SP-3D-COFs interaction mechanism was proposed to explain the improvement of PSC performance after SP-3D-COFs doping. PMID- 30008218 TI - Doping-Enhanced Short-Range Order of Perovskite Nanocrystals for Near-Unity Violet Luminescence Quantum Yield. AB - All-inorganic perovskite nanocrystals (NCs) have emerged as a new generation of low-cost semiconducting luminescent system for optoelectronic applications. The room-temperature photoluminescence quantum yields (PLQYs) of these NCs in the green and red spectral range approach unity. However, their PLQYs in the violet are much lower, and an insightful understanding of such poor performance remains missing. We report a general strategy for the synthesis of all-inorganic violet emitting perovskite NCs with near-unity PLQYs through engineering local order of the lattice by nickel ion doping. A broad range of experimental characterizations, including steady-state and time-resolved luminescence spectroscopy, X-ray absorption spectra, and magic angle spinning nuclear magnetic resonance spectra, reveal that the low PLQY in undoped NCs is associated with short-range disorder of the lattice induced by intrinsic defects such as halide vacancies and that Ni doping can substantially eliminate these defects and result in increased short-range order of the lattice. Density functional theory calculations reveal that Ni doping of perovskites causes an increase of defect formation energy and does not introduce deep trap states in the band gap, which is suggested to be the main reason for the improved local structural order and near-unity PLQY. Our ability to obtain violet-emitting perovskite NCs with near perfect properties opens the door for a range of applications in violet-emitting perovskite-based devices such as light-emitting diodes, single-photon sources, lasers, and beyond. PMID- 30008220 TI - Discerning the Contribution of Morphology and Chemistry in Wettability Studies. AB - The wetting behavior of homogeneous systems is now well understood at the macroscopic scale. However, this understanding offers little predictive power regarding wettability when mesoscopic chemical and morphological heterogeneities come into play. The fundamental interest in the effect of heterogeneity on wettability is derived from its high technological relevance in several industries, including the petroleum industry where wettability is recognized as a key determinant of the overall efficiency of the water-flooding-based enhanced oil recovery process. Here, we demonstrate the use of the atomic force microscopy force curve measurements to distinguish the roles of chemistry and morphology in the wetting properties of rock formations, thus providing a clear interpretation and deeper insight into the wetting behavior of heterogeneous formations. Density functional theory calculations further prove the versatility of our approach by establishing benchmarks on ideal surfaces that differ in chemistry and morphology in a predefined manner. PMID- 30008219 TI - Sodium Butyrate Improves High-Concentrate-Diet-Induced Impairment of Ruminal Epithelium Barrier Function in Goats. AB - We investigated the effect of sodium butyrate feeding on the disruption of ruminal epithelium barrier function in goats fed a high-concentrate diet. A total of 18 male Boer goats (live weight of 31.75 +/- 1.35 kg, aged 1 year) were randomly assigned to three groups, which were fed a low-concentrate diet (LC), a high-concentrate diet (HC), or a high-concentrate diet with 1% sodium butyrate by weight (SH) for 9 weeks. We found that the pH of rumen fluid in the SH and LC groups was higher than that in the HC group. The activity of protein kinase C (PKC) kinase in the rumen epithelium was higher in the HC group than that in the LC and SH groups. The mRNA expression and phosphorylated protein levels of mitogen-activated protein kinases (MAPKs) in the rumen epithelium were lower in the SH and LC groups than those in the HC group. The DNA methylation rate of occludin was higher in the HC group than that in the SH and LC groups. The mRNA and protein expression of claudin-1, claudin-4, occludin, and zona occludin-1 was greater in the SH and LC groups than that in the HC group. In addition, sodium butyrate mitigated damage to the rumen epithelium caused by the HC diet. Together, our results suggest that the supply of sodium butyrate reverses the damage of rumen epithelium tight junction by inhibiting PKC and MAPK signaling pathways and is protective to the rumen epithelium during subacute rumen acidosis. PMID- 30008221 TI - Activity Coefficients of Aqueous Sodium, Calcium, and Europium Nitrate Solutions from Osmotic Equilibrium MD Simulations. AB - Osmotic and activity coefficients of three aqueous electrolyte solutions with cations of similar ionic radius, but different charges, are described by molecular dynamics with the help of the osmotic equilibrium method using polarizable force fields up to high concentration. Simulations of vapor-liquid interfaces of aqueous solutions of NaNO3, Ca(NO3)2, and Eu(NO3)3 at different concentrations and at 298.15 K provide time-averaged number density profiles and consequently the quantity of solvent molecules in the vapor phase. These three cations of similar ionic radii exhibit an increasing amount of water in their first coordination sphere due to their increasing charge. The solvent activity is directly determined by the vapor phase density at different salt concentrations with respect to the vapor phase density of the pure solvent. The obtained densities of the liquid bulk and the osmotic and activity coefficients for the three different nitrate salts are in good agreement with the experimental results. Time-averaged concentration profiles and the interpretation of radial distribution functions are used to explain the role of coordination on the thermodynamic properties of aqueous electrolyte solutions. PMID- 30008223 TI - Chemical and Biochemical Mechanisms of Redox-Mediated Toxicology. PMID- 30008222 TI - Heating-Induced Transformations of Atmospheric Particles: Environmental Transmission Electron Microscopy Study. AB - Environmental transmission electron microscopy was employed to probe transformations in the size, morphology, and composition of individual atmospheric particles as a function of temperature. Two different heating devices were used and calibrated in this work: a furnace heater and a Micro Electro Mechanical System heater. The temperature calibration used sublimation temperatures of NaCl, glucose, and ammonium sulfate particles, and the melting temperature of tin. Volatilization of Suwanee River Fulvic Acid was further used to validate the calibration up to 800 degrees C. The calibrated furnace holder was used to examine both laboratory-generated secondary organic aerosol particles and field-collected atmospheric particles. Chemical analysis by scanning transmission X-ray microscopy and near-edge fine-structure spectroscopy of the organic particles at different heating steps showed that above 300 degrees C particle volatilization was accompanied by charring. These methods were then applied to ambient particles collected in the central Amazon region. Distinct categories of particles differed in their volatilization response to heating. Spherical, more-viscous particles lost less volume during heating than particles that spread on the imaging substrate during impaction, due to either being liquid upon impaction or lower viscosity. This methodology illustrates a new analytical approach to accurately measure the volume fraction remaining for individually tracked atmospheric particles at elevated temperatures. PMID- 30008224 TI - In vivo tracking of intravenously injected mesenchymal stem cells in an Alzheimer's animal model. AB - PURPOSE: The purpose of this study was to investigate how intravenously injected bone marrow-derived mesenchymal stem cells (BMSCs) are distributed in the body of an Alzheimer's disease (AD) animal model. METHODS: Stem cells were collected from bone marrow of mice and labeled with Indium-111 (111In). The 111In-labeled BMSCs were infused intravenously into 3*Tg-AD mice in the AD group and non-transgenic mice (B6129SF2/J) as controls. Biodistribution was evaluated with a gamma counter and gamma camera 24 and 48 h after injecting the stem cells. RESULTS: A gamma count of the brain showed a higher distribution of labeled cells in the AD model than in the control group at 24 (p = .0004) and 48 h (p = .0016) after injection of the BMSCs. Similar results were observed by gamma camera imaging (i.e., brain uptake in the AD model was significantly higher than that in the control group). Among the other organs, uptake by the spleen was the highest in both groups. More BMSCs were found in the lungs of the control group than in those of the AD group. CONCLUSIONS: These results suggest that more intravenously infused BMSCs reached the brain in the AD model than in the control group, but the numbers of stem cells reaching the brain was very small. PMID- 30008225 TI - Perceptions of Health Care Executives on Leadership Development Skills for Residents After Participating in a Longitudinal Mentorship Program. AB - Despite the fact that physicians are being asked to lead and enact change to improve a myriad of quality of care measures, there is little focus on leadership skills development during their training. One strategy to address this gap is to focus on trainees during graduate medical education, specifically those residents aspiring to careers as physician leaders in quality. The authors designed a leadership curriculum for self-selected residents who are pursuing a certificate in health care leadership in quality. Residents were surveyed and focus groups were conducted with health system executives who participated in the curriculum as part of an evaluation designed to inform improvements in the program and to provide guidance to others who direct physician leadership training programs. The findings support the need to invest in young physician leaders who are focused on quality with the ultimate goal of improving population health in the ever changing health care environment. PMID- 30008226 TI - Noninvasive Determination of Firmness and Dry Matter Content of Stored Onion Bulbs Using Shortwave Infrared Imaging with Whole Spectra and Selected Wavelengths. AB - A firm texture of dry onions is important for consumer acceptance. Both the texture and dry matter content decline during storage, influencing the market value of onions. The main goal of this study was to develop predictive models that in future might form the basis for automated sorting of onions for firmness and dry matter content in the industry. Hyperspectral scanning was conducted in reflectance mode for six commercial batches of onions that were monitored three times during storage. Mean spectra from the region of interest were extracted and partial least squares regression (PLSR) models were constructed. Feature wavelengths were identified using variable selection techniques resulting from interval partial least squares and recursive partial least squares analyses. The PLSR model for firmness gave a root mean square error of cross-validation (RMSECV) of 0.84 N, and a root mean square error of prediction (RMSEP) of 0.73 N, with coefficients of determination ( R2) of 0.72 and 0.83, respectively. The RMSECV and RMSEP of the PLSR model for dry matter content were 0.10% and 0.08%, respectively, with a R2 of 0.58 and 0.79, respectively. The whole wavelength range and selected wavelengths showed nearly similar results for both dry matter content and firmness. The results obtained from this study clearly reveal that hyperspectral imaging of onion bulbs with selected wavelengths, coupled with chemometric modeling, can be used for the noninvasive determination of the firmness and dry matter content of stored onion bulbs. PMID- 30008228 TI - Nusinersen: A Treatment for Spinal Muscular Atrophy. AB - OBJECTIVE: To review the efficacy and safety of nusinersen (Spinraza) in the treatment of spinal muscular atrophy (SMA). DATA SOURCES: An English-language literature search of PubMed and MEDLINE (1946 to June 2018) was performed using the terms nusinersen, ISIS-SMN (Rx), and spinal muscular atrophy. Manufacturer prescribing information, abstracts, article bibliographies, and clinicaltrials.gov data were incorporated for additional materials. STUDY SELECTION/DATA EXTRACTION: All clinical trials of nusinersen were identified and analyzed in the review. DATA SYNTHESIS: Nusinersen is the first drug therapy approved for the treatment of SMA. It is a novel modified antisense oligonucleotide designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron protein deficiency. Nusinersen has been studied for safety, pharmacokinetics, and efficacy in both open-label and randomized controlled trials. The studies show improvement in motor function across SMA of all types. The most common adverse effects were respiratory tract infections, headache, back pain, constipation, and post-lumbar puncture syndrome. Relevance to Patient Care and Clinical Practice: Based on phase III trial data, nusinersen produced positive changes in the clinical course of patients with SMA. The acquisition and administration of nusinersen present a number of challenges in clinical practice. Its intrathecal delivery and costly price tag must be recognized. CONCLUSION: Nusinersen is safe and effective in patients with SMA. It was well tolerated across all studied age groups. PMID- 30008227 TI - Design and Implementation of a Depression Registry for Primary Care. AB - Registries are fundamental to the success of population health initiatives to improve care and outcomes for patients, including those with depression. The purpose of this article is to describe the design and clinical implementation of a depression registry as part of a collaborative care for depression intervention at 2 large academic outpatient internal medicine practices. The primary objective of the registry was to identify and track patients with depression and monitor antidepressant therapy. Secondary objectives of the registry were to assist in addressing pay-for-performance and value-based reimbursement metrics for depression screening and remission. The registry design and variables for inclusion in the registry were defined with input from clinicians, institutional leadership, and data analysts. For implementation, specific clinical workflows were established and responsible team roles were designated. PMID- 30008229 TI - Resveratrol Treatment in Different Time-Attenuated Neuronal Apoptosis After Oxygen and Glucose Deprivation/Reoxygenation via Enhancing the Activation of Nrf 2 Signaling Pathway In Vitro. AB - Recent studies have indicated that resveratrol has protective effects against cerebral ischemia/reperfusion injury. However, the best therapeutic time for resveratrol treatment after acute ischemic stroke remains unknown. We aim to investigate whether resveratrol, administrated at different times after neuronal oxygen and glucose deprivation/reoxygenation (OGD/R) reduced neuronal injury in vitro. There were six experimental groups: normal, model, resveratrol pretreatment, resveratrol post-treatment, resveratrol OGD-treatment, and resveratrol whole-processing group. We found that resveratrol in a concentration dependent manner decreased the activity of lactate dehydrogenase (LDH) and increased the activity of superoxide dismutase (SOD). Moreover, resveratrol, administrated at different times, increased neuronal viability, reduced neuronal apoptosis, upregulated the protein expressions of Nuclear factor erythroid 2 related factor 2 (Nrf-2), NAD(P)H: quinone oxidoreductase 1 (NQO-1), heme oxygenase 1 (HO-1), and Bcl-2, downregulated the protein expression of Caspase-3, and promoted Nrf-2 to transfer into the nuclei from the cytoplasm. The most effective treatment group was the whole-processing treatment group. These results suggest that resveratrol treatment at different times increased neuronal viability and inhibited neuronal apoptosis in vitro, at least in part, via enhancing the activation of the Nrf-2 signaling pathway. PMID- 30008230 TI - Trop2 Guarantees Cardioprotective Effects of Cortical Bone-Derived Stem Cells on Myocardial Ischemia/Reperfusion Injury. AB - Stem cell transplantation represents a promising therapeutic approach for myocardial ischemia/reperfusion (I/R) injury, where cortical bone-derived stem cells (CBSCs) stand out and hold superior cardioprotective effects on myocardial infarction than other types of stem cells. However, the molecular mechanism underlying CBSCs function on myocardial I/R injury is poorly understood. In a previous study, we reported that Trop2 (trophoblast cell-surface antigen 2) is expressed exclusively on the CBSCs membrane, and is involved in regulation of proliferation and differentiation of CBSCs. In this study, we found that the Trop2 is essential for the ameliorative effects of CBSCs on myocardial I/R induced heart damage via promoting angiogenesis and inhibiting cardiomyocytes apoptosis in a paracrine manner. Trop2 is required for the colonization of CBSCs in recipient hearts. When Trop2 was knocked out, CBSCs largely lost their functions in lowering myocardial infarction size, improving heart function, enhancing capillary density, and suppressing myocardial cell death. Mechanistically, activating the AKT/GSK3beta/beta-Catenin signaling axis contributes to the essential role of Trop2 in CBSCs-rendered cardioprotective effects on myocardial I/R injury. In conclusion, maintaining the expression and/or activation of Trop2 in CBSCs might be a promising strategy for treating myocardial infarction, I/R injury, and other related heart diseases. PMID- 30008231 TI - Vascularization of Natural and Synthetic Bone Scaffolds. AB - Vascularization of engineered bone tissue is critical for ensuring its survival after implantation. In vitro pre-vascularization of bone grafts with endothelial cells is a promising strategy to improve implant survival. In this study, we pre cultured human smooth muscle cells (hSMCs) on bone scaffolds for 3 weeks followed by seeding of human umbilical vein endothelial cells (HUVECs), which produced a desirable environment for microvasculature formation. The sequential cell-seeding protocol was successfully applied to both natural (decellularized native bone, or DB) and synthetic (3D-printed Hyperelastic "Bone" scaffolds, or HB) scaffolds, demonstrating a comprehensive platform for developing natural and synthetic-based in vitro vascularized bone grafts. Using this sequential cell-seeding process, the HUVECs formed lumen structures throughout the DB scaffolds as well as vascular tissue bridging 3D-printed fibers within the HB. The pre-cultured hSMCs were essential for endothelial cell (EC) lumen formation within DB scaffolds, as well as for upregulating EC-specific gene expression of HUVECs grown on HB scaffolds. We further applied this co-culture protocol to DB scaffolds using a perfusion bioreactor, to overcome the limitations of diffusive mass transport into the interiors of the scaffolds. Compared with static culture, panoramic histological sections of DB scaffolds cultured in bioreactors showed improved cellular density, as well as a nominal increase in the number of lumen structures formed by ECs in the interior regions of the scaffolds. In conclusion, we have demonstrated that the sequential seeding of hSMCs and HUVECs can serve to generate early microvascular networks that could further support the in vitro tissue engineering of naturally or synthetically derived bone grafts and in both random (DB) and ordered (HB) pore networks. Combined with the preliminary bioreactor study, this process also shows potential to generate clinically sized, vascularized bone scaffolds for tissue and regenerative engineering. PMID- 30008232 TI - [Improvement in the glycaemic control of patients after switching from human insulin to insulin glargine-based basal-bolus regimen]. AB - INTRODUCTION: The effectiveness of human and analogue insulins is similar but the latter have more advantageous pharmacokinetic features, leading to an improvement in hypoglycaemia and come closer to achieving the physiologic insulin profile. AIM: To demonstrate that switching from a human basal-bolus insulin treatment to an insulin glargine-based basal-bolus regimen can achieve a better glycaemic control. METHOD: This 3-month prospective, non-interventional study, including a 12-month retrospective data collection phase, enrolled patients who were switched to the insulin glargine- - 100 U/mL - based basal-bolus treatment at the time of enrolment if they were inadequately controlled and had at least one additional HbA1c result in the 12 months before the switch. Of 1513 patients 1181 had the data that were needed for the efficacy analysis. RESULTS: The mean age of the efficacy population was 58.3 years and 48.1% were male. Their mean HbA1c levels remained unchanged in the year before the switch: it was 8.8 +/- 1.4% at 12 months prior to the switch and 8.8 +/- 1.2% at the switch, but decreased significantly to 7.7 +/- 1.0% (p<0.001) after 3 months. Between the baseline and 3 months, the fasting blood glucose and the postprandial blood glucose improved significantly (from 10.0 +/- 3.2 mmol/L to 7.4 +/- 1.9 mmol/L, p<0.001 and from 11.1 +/- 2.8 mmol/L to 8.8 +/- 1.7 mmol/L, p<0.001, respectively). Insulin doses were increased both before and after the switch. CONCLUSIONS: Switch to an insulin glargine-based basal-bolus regimen could achieve a significant improvement in the glycaemic control in patients who were inadequately controlled prior to the switch. Orv Hetil. 2018; 159(29): 1201-1207. PMID- 30008233 TI - [Setup margin for head-and-neck cancer patients receiving 2D-2D and 3D image guided intensity-modulated radiation therapy]. AB - INTRODUCTION: Image-guided intensity-modulated radiation therapy is essential for oncology treatment of head-and-neck cancer patients. AIM: MV-kV and CBCT modalities were compared in case of IGRT treatment for head-and-neck cancer patients. Setup error, setup margin (SM), imaging and evaluation times and imaging doses were analyzed. METHOD: Eight patients' elective treatment was evaluated, 66 orthogonal MV-kV images and 66 CBCT series were acquired. Setup error measurement was based on bony manual image registration in three translational directions. Normality test and F-test were performed followed by the comparison with independent-samples T-test (p<0,05). The necessary target volume setup margin was calculated based on Van Herk's equation. Imaging time and setup error determination time were measured. Imaging doses were estimated based on the literature. RESULTS: No statistically significant difference was found between setup errors determined by MV-kV and CBCT (VRT: 0.5 mm, SD = 1.9 vs. 0.4 mm, SD = 2.1, p = 0.371; LNG: 0.2 mm, SD = 2.2 vs. -0.1 mm, SD = 2.2, p = 0.188; LAT: 0.2 mm, SD = 2.2 vs. 0.3 mm, SD = 2.1, p = 0.41). SM values were: VRT: 2.7 mm vs. 2.5 mm; LNG: 2.1 mm vs. 1.3 mm; LAT: 2.2 mm vs. 2.3 mm. Mean imaging time was 0.65 min (MV-kV) vs. 2.29 min (CBCT). Mean setup error determination time was 2.41 min for both modalities. Estimated imaging doses were 6.88 mGy (MV-kV) vs. 17.2 mGy (CBCT) per fraction. CONCLUSION: The bony anatomy derived image registration based translational setup error determination results in similar values either by MV-kV or by CBCT. Using 3 mm setup margin in all the directions might be adequate. Imaging time is less by MV-kV, significant difference in imaging doses did not appear. Using CBCT is generally suggested. MV-kV might be an alternative in case of need for shortened imaging time. Orv Hetil. 2018; 159(29): 1193-1200. PMID- 30008234 TI - [Neuroendocrine mechanisms controlling the development in puberty. A literature overview]. AB - Puberty is the stage of development in human life, when the hypothalamus hypophysis-gonad axis is re-activated after quiescence. Humanity has long been concerned with the idea of exogenous and endogenous factors and mechanisms that influence the temporal course of puberty neuroendocrine events. Recent discoveries have helped to understand the functioning of the neuroendocrine system. It has been clarified that kisspeptin plays a key role in puberty and regulation of fertility. However, in the function of the gonadotropin-releasing hormone (GnRH) pulse secretion, besides kisspeptin, neurokinin B, dynorphin neurons other positive and negative signals are involved, guiding the release of hormones of hypophysis gonadotropin. The knowledge of these nerves further enhanced the understanding of GnRH pulsation modulation by endocrine, metabolic and environmental impacts. The authors point out the risk of endocrine disruptors in the physiological course of puberty. The aim of the review is to provide a comprehensive picture of the research results of the physiology of kisspeptin, as the manipulation of kisspeptin signaling has the potential for novel therapies in patients with pathologically low or high luteinizing hormone (LH) pulsatility. Orv Hetil. 2018; 159(29): 1175-1182. PMID- 30008236 TI - [Phoniatric outcomes of endoscopic arytenoid abduction lateropexy in patients with transient bilateral vocal cord paralysis]. AB - INTRODUCTION: Dyspnea caused by bilateral vocal cord paralysis often requires surgical intervention to prevent acute asphyxiation. The regeneration of the laryngeal nerves may last weeks or months and it is difficult to predict the outcome. In the past decades, several open and endoscopic surgical techniques have been introduced for treatment to avoid tracheostomy, however, these procedures with resection of the glottis resulted in irreversible changes in the laryngeal structure, thus the voice quality decreased over a long-term period. AIM: Endoscopic arytenoid abduction lateropexy is an accepted reversible, minimally invasive technique that provides an immediate patent airway by the lateralisation of the arytenoid cartilage with a suture. The aim of our study was to analyze the phonatory and respiratory outcomes of this treatment concept. METHOD: Two patients suffering from bilateral vocal cord palsy were treated with endoscopic arytenoid abduction lateropexy. After recovery of the vocal cord movements, the sutures were removed. Spirometric and phoniatric results of the two patients were analysed after suture removal. RESULTS: Good spirometric parameters and normal voice quality were detected in both cases. CONCLUSIONS: These results prove the high reversibility of the minimally invasive endoscopic arytenoid abduction lateropexy. Lateralization suture can be removed in the case of vocal cord movement recovery, and phonation may be physiological. Orv Hetil. 2018; 159(29): 1188-1192. PMID- 30008237 TI - [Proper oral health can protect from developing gingival hyperplasia induced by calcium channel blockers]. AB - Cardiovascular diseases including hypertension affect 40% of the adult population in Hungary. Calcium channel blockers are frequently prescribed for the treatment of hypertension either in monotherapy or in fixed-combination therapy. Their main effect is vasodilatation with gingival hyperplasia as a side effect. Our aim is to draw our colleagues' attention to the practical importance of the fact that calcium channel blocker-induced gingival hyperplasia correlates closely with the dental status and the quantity of plaque on the surface of teeth and dental implants. Once established, gingival hyperplasia makes it more difficult for the patient to maintain individual tooth cleaning and increases plaque formation. Thus proliferation of Gram-negative bacteria is enabled in the plaque which promotes gingival overgrowth and can pose a risk factor for further cardiovascular diseases. If proper individual oral hygiene and professional interventions are carried out, healthy and hyperplasia-free gingival state can be sustained in the long term in most cases, even with calcium channel blocker therapy. In order to protect patients' oral health, a closer cooperation of internists and dentists would be desirable. Orv Hetil. 2018; 159(29): 1183-1187. PMID- 30008238 TI - [ECG pearl: transient Q-waves in myocardial infarction]. AB - A case of ST-segment elevation myocardial infarction (STEMI) is presented with pathologic transient Q-waves in the precordial leads disappearing after percutaneous coronary intervention (PCI). Orv Hetil. 2018; 159(29): 1208-1209. PMID- 30008239 TI - Chunking, Conscious Processing, and EEG During Sequence Acquisition and Performance Pressure: A Comprehensive Test of Reinvestment Theory. AB - This study was designed to test the theorized link between reinvestment, motor chunks, and conscious processing, to provide a thorough examination of reinvestment theory. The authors measured electroencephalographic power and connectivity alongside self-reported conscious processing and behavioral indices of chunking in a 2 (group) * 5 (block) mixed-model design. A total of 55 individuals acquired a motor sequence (blocks A1, A2, A3, and A4) by relatively explicit (errorful) or implicit (errorless) paradigms. Then they performed in a pressure condition (block T). Results confirmed that chunking characterizes both modes of acquisition. However, explicit acquisition resulted in quicker chunking, reduced conscious processing, and increased cortical efficiency (left-temporal high-alpha power). In support of reinvestment theory, self-reported conscious processing tended to increase under pressure among explicit trainees only. In contrast to reinvestment theory, this had no adverse effect on performance. The results endorse explicit acquisition as an effective mode of training and provide a new neurophysiological explanation of this phenomenon. PMID- 30008240 TI - Endocrine Effects of Relative Energy Deficiency in Sport. AB - The term Relative Energy Deficiency in Sport was introduced by the International Olympic Committee in 2014. It refers to the potential health and performance consequences of inadequate energy for sport, emphasizing that there are consequences of low energy availability (EA; typically defined as <30 kcal.kg-1 fat-free mass.day-1) beyond the important and well-established female athlete triad, and that low EA affects populations other than women. As the prevalence and consequences of Relative Energy Deficiency in Sport become more apparent, it is important to understand the current knowledge of the hormonal changes that occur with decreased EA. This paper highlights endocrine changes that have been observed in female and male athletes with low EA. Where studies are not available in athletes, results of studies in low EA states, such as anorexia nervosa, are included. Dietary intake/appetite-regulating hormones, insulin and other glucose regulating hormones, growth hormone and insulin-like growth factor 1, thyroid hormones, cortisol, and gonadal hormones are all discussed. The effects of low EA on body composition, metabolic rate, and bone in female and male athletes are presented, and we identify future directions to address knowledge gaps specific to athletes. PMID- 30008241 TI - Goalkeepers' Reputations Bias Shot Placement in Soccer Penalties. AB - Research has demonstrated that in addition to minor changes in goalkeepers' position or height, goalkeeper reputation seems to influence penalty takers' shot placement. However, this evidence is based on correlative designs. Here, the authors experimentally manipulated both height and reputation to examine their causal impact on actual shot placement. Penalty takers performed kicks facing goalkeepers of different height (tall vs. short) and reputation (high vs. low) projected on a life-size screen. Results showed that tall goalkeepers were judged as taller than short goalkeepers. Likewise, high-reputation goalkeepers were judged as taller than low-reputation goalkeepers. An important finding was that reputation also influenced shot placement. When facing high-reputation goalkeepers, penalty takers aimed farther away from the goalkeeper and missed the goal more often. It follows that reputation affects both height estimates of goalkeepers and, most important, shot placement. Consequently, manipulating perceived reputation of goalkeepers provides an avenue for sport professionals to subtly influence shot placement of penalty takers. PMID- 30008242 TI - Effects of Tai Chi Chuan and Brisk Walking Exercise on Balance Ability in Elderly Women: A Randomized Controlled Trial. AB - This study aims to investigate the effects of Tai Chi Chuan (TCC) and brisk walking (BW) on balance and training duration for the two exercises to significantly improve balance. A total of 48 elderly women were randomly divided into three groups. The TCC and BW groups completed a 60-min intervention training program with five sessions weekly for 16 weeks. Single-leg standing balance was tested every 4 weeks. Results showed that all the variables with eyes open improved on the eighth week (p < .05) in the TCC group and on the 12th week (p < .01) in the BW group. All variables with eyes closed improved on the 12th week (p < .01) in the TCC group and on the 16th week (p < .05) in the BW group. The results showed that 12 and 16 weeks of TCC and BW, respectively were essential to improve balance with eyes closed among the women aged 60-70 years. PMID- 30008243 TI - Within-Person Relationships Between Recreational Running and Psychological Well Being. AB - Participants in the study were recreational runners (N = 244) who maintained online diaries. Once a week for approximately 3 months they indicated how far they had run each day that week, and at the end of the week, they provided measures of their psychological well-being. A series of multilevel modeling analyses (weeks nested within persons) found that well-being, measured in terms of self-esteem, life satisfaction, self-efficacy, meaning in life, and affect, was positively related to how many days people ran each week and how far they ran each week. Satisfaction with one's progress mediated relationships between well being and the amount of running, suggesting that increases in running lead to increases in satisfaction with progress, which lead to increased well-being. These results complement and extend existing research on the psychological benefits of exercise. PMID- 30008244 TI - Associations of Eczema Severity and Parent Knowledge With Child Quality of Life in a Pediatric Primary Care Population. AB - We investigated factors associated with quality of life (QOL) in children with eczema. We conducted a cross-sectional analysis of survey data from 224 parents of children with eczema attending a large, hospital-based pediatric clinic. Parents completed a validated eczema severity scale (Patient-Oriented Eczema Measure), a QOL scale (Infants' Dermatitis QOL Index or Children's Dermatology Life Quality Index), and a knowledge and understanding questionnaire. In adjusted multivariate analyses, worse eczema severity was associated with worse overall QOL (beta = 0.5; 95% confidence interval [CI] = [0.5, 0.6]), while a higher knowledge score was associated with better QOL (beta = -3.4; 95% CI = [-6.6, 0.2]). Similarly, even after adjustment for eczema severity, greater understanding of a child's individual treatment plan was associated with better QOL (beta = -0.7; 95% CI = [-1.4, -0.08]), while increased frequency of worrying about a child's eczema was associated with worse QOL (beta = 0.7; 95% CI = [0.03, 1.1]). These results suggest primary care providers may be able to influence QOL through optimal eczema management and family education. PMID- 30008245 TI - Visual-Vestibular Interaction for Postural Control During Sit-to-Stand: Effects of Aging. AB - During sit-to-stand (STS), the vestibular system is highly stimulated in response to linear acceleration of the head and may play an important role, in addition to vision, for postural control. We examined the effects of aging on visual vestibular interaction for postural control during STS in 15 young (22.5 +/- 1.1 years) and 15 older (73.9 +/- 5.3 years) participants. Vestibular information was manipulated using galvanic vestibular stimulation. Vision conditions involved normal (eyes open), suboptimal (blurring goggles), and no (eyes closed) vision. Older participants had significantly greater mediolateral peak-to-peak trunk roll (p = .025) and center of mass displacements (p < .001) than young participants. However, despite having greater mediolateral instability, older participants utilized similar strategies as young participants to overcome sensory perturbations during STS. Overall visual inputs were more dominantly used for mediolateral trunk control during STS than vestibular inputs. PMID- 30008246 TI - Mediating Effects of Parents' Coping Strategies on the Relationship Between Parents' Emotional Intelligence and Sideline Verbal Behaviors in Youth Soccer. AB - The overall purpose of this study was to examine the mediating effects of parents' coping strategies on the relationship between parents' emotional intelligence and sideline verbal behaviors during their children's soccer games. Participants were 232 parents (120 mothers and 110 fathers) of youth soccer players age 9-13 years. Observations in situ were carried out at 30 soccer games during a soccer tournament. At the end of the game, parents were approached and asked to complete the Emotional Intelligence Scale and the Brief COPE scale. Structural-equation-modeling analyses revealed that adaptive and maladaptive coping mediated the relationship between regulation of emotion and parents' praise/encouragement, and negative and derogatory comments during the game. In addition, game result moderated the relationships between emotional intelligence, coping strategies, and parent behaviors. Emotional regulation and adaptive coping may promote desirable parent sideline behaviors and reduce undesirable behaviors. PMID- 30008247 TI - Heterogeneity in Male Adolescents With Illegal Sexual Behavior: A Latent Profile Approach to Classification. AB - Current research has established that male adolescents with illegal sexual behavior (AISB) are a heterogeneous population. We aimed to explore this within group heterogeneity to derive clinically relevant groups of AISB using the Millon Adolescent Clinical Inventory (MACI). We then compared these groups on selected covariates (age at intake, minority status, and child maltreatment history) and distal outcomes (general, nonviolent, violent, drug, and sexual recidivism 5 years after release) to identify any differences. The sample consisted of 698 male AISB (age = 11-20 years) referred to a secure juvenile facility for assessment and treatment. A latent profile analysis (LPA) was conducted using the clinical and personality scales of the MACI to identify AISB groups and examine group differences. Four unique AISB groups emerged: Anxious, Depressed/Anxious, Dysthymic/Disorganized, and Antisocial. Groups differed on age at intake and child maltreatment history, but not minority status. At 5-year follow up, groups differed in their rates of general, nonsexual, and violent recidivism but not in their rates of sexual or drug recidivism. Clinically relevant AISB groups can be identified using personality and psychopathology indicators from the MACI. Implications for the assessment and treatment of AISB, as well as directions for future research are discussed. PMID- 30008248 TI - The Connection Between Testicular Cancer, Minority Males, and Planned Parenthood. AB - Testicular cancer (TCa) is the most prevalent neoplasm diagnosed in males aged 15 40 years. Lack of access to care is a key impediment to early-stage TCa diagnosis. Health equity concerns arise, however, as poor access largely manifests within underserved male populations, therefore, placing them at a higher risk to develop late-stage TCa. Planned Parenthood Federation of America (PPFA) offers a myriad of male reproductive/sexual health care options, including TCa screening and referral services. Therefore, expanding these amenities in traditionally underserved communities may address the concern of TCa screening opportunities. An ecological analysis was performed using data from the United States Cancer Statistics, American Community Survey, and PPFA databases to assess the impact of TCa upon minority males, identify associations between PPFA services and minority males, and provide future implications on the role PPFA may play in bridging health-care access gaps pertaining to TCa screenings. Results indicate that states with higher rates of poverty and uninsured individuals, as well as specifically Black/African American males, have lower TCa incidence and limited access to screening services. PPFA service presence and Black/African American, as well as uninsured, males had a negative association but revealed positive correlations with TCa incidence. Considering the emerging TCa outcome disparities among minority males, expanding PPFA men's health services is crucial in providing affordable options to help identify testicular abnormalities that are early stage or carcinoma in situ. Many at-risk males have limited means to obtain TCa screening services. Expanding this discussion could provide a foundation for future advocacy. PMID- 30008249 TI - Sex hormones and venous thromboembolism - from contraception to hormone replacement therapy. AB - The use of sex hormones such as combined oral contraceptives (COC) or hormone replacement therapy (HRT) increases the risk for venous thromboembolism (VTE) considerably, especially in patients with an increased intrinsic risk for thromboembolic complications. Despite public and media attention and increasing scientific evidence, prescription patterns seem to be hard to change. It is well recognized that the patient's baseline risk is the most relevant factor in the absolute risk for developing VTE. The relative risk increase associated with sex hormones, depends on the type and dosage of hormones, the route of application (oral, vaginal, transdermal), and for COC, on the specific combination of oestrogen and gestagen components. Consequently, a careful decision for or against any specific type of hormone treatment needs to be based on an assessment of the patient's risk profile (disposition) as well as on the treatment associated risks and benefits (exposition). This review discusses the most common sex hormone treatments in contraception and HRT, the relevance for VTE risk patients, and strategies to counsel patients with regard to hormone use according to their risk profiles. Keywords: Oral contraceptives, hormonal contraception, hormone replacement therapy, venous thromboembolism. PMID- 30008250 TI - Acute Onset of Unilateral Edema of Leg Followed by Hemiplegia in an Adolescent: A Case Report. PMID- 30008251 TI - Human placental membrane as a wound cover for chronic diabetic foot ulcers: a prospective, postmarket, CLOSURE study. AB - OBJECTIVE: To evaluate the safety and efficacy of a chorioamniotic allograft, used as a wound cover for chronic foot ulcers, in patients with diabetes. METHODS: A multicentre, prospective, postmarket study where eligible patients received up to 11 weekly wound cover applications. Computerised planimetry was used to calculate the diabetic foot ulcer (DFU) area each week. The primary endpoint of the study was wound closure assessment. Secondary endpoints included DFU recurrence and morbidity. RESULTS: A total of 63 patients with 64 ulcers were enrolled, after successful completion of a two-week run-in period. Patients were predominantly male and had risk factors for delayed healing. Mean baseline DFU area was 3.8cm2 (standard deviation (SD): 4.8). After 12 weeks, a total of 19 (40%) DFUs had closed. Results varied by size category, 'small' (<=2.0cm2), 'medium' (>2.0-4.0 cm2), and 'large' (>4.0-25.0 cm2), with higher percentage closure in the 'small' DFU group, compared with the 'medium' and 'large' DFUs (57%, 33%, and 10%, respectively). Of those DFUs that closed, the average closure time was 6.5 weeks. There were no unanticipated adverse events. CONCLUSION: Known risk factors for healing, including DFU size, location and duration, affected the outcomes. However, the results are in line with the literature and support the use of the chorioamniotic allograft in chronic and complex cases. PMID- 30008252 TI - Factors in facilitating an organisational culture to prevent pressure ulcers among older adults in health-care facilities. AB - OBJECTIVE: Despite the availability of high-quality clinical practice guidelines, pressure ulcers (PU) continue to develop among older adults in acute and long term health-care facilities. Except during acute medical crisis or near end-of life, most PUs are preventable and their development is a health-care quality indicator. The aim of this study was to understand which factors facilitate pressure ulcer prevention among adults over 65 years-of-age receiving care in health-care facilities. METHOD: A critical literature review from three scholarly databases examined components of organisational culture associated with PU prevention. Research papers involving adults >65 years-of-age who were admitted to acute and long-term health-care facilities with PU prevention programmes between 2010 and 2017 were included. A secondary manual search included literature discussing health-care organisational culture, with a total of 41 articles reviewed. RESULTS: Based on a synthesis of this literature, the Factors Facilitating Pressure Ulcer Prevention Model was developed to depict five multilevel factors for PU prevention among older adults in health-care facilities. These five factors are: senior leadership, education, ongoing quality improvement, clinical practice, and unit level champions. CONCLUSION: Ongoing prioritisation of these factors sustains PU prevention and assists health-care facilities to redefine their culture, expand education programmes, and promote accountability to improve health outcomes of older adults receiving care. PMID- 30008253 TI - Efficacy of a nitric oxide dressing in decreasing bacterial counts on human skin. AB - OBJECTIVE: Inhibiting the proliferation of skin bacteria, using nitric oxide (NO), is a potential strategy to prevent infections. This study evaluated the efficacy of using a new NO releasing film dressing to decrease resident human bacterial skin flora compared with the measured microbial activity underneath control sterile Tegaderm transparent dressings. METHODS: A within-subjects design using a sample of convenience compared the bacterial counts under the skin of experimental dressings to those under control dressings. NO releasing film dressings (three) and control dressings (three) were applied without antiseptic preparation to the intact skin on the backs of 67 healthy volunteers. Subsequent skin cultures were obtained from underneath dressing pairs (one experimental and one control) on days three, five, and seven after application. Baseline microflora bacterial counts from uncovered skin was obtained on day three of the study. Comparisons of bacterial counts were analysed. RESULTS: On days three, five and seven, the experimental NO releasing film dressings demonstrated a statistically significant reduction in bacterial count compared with the control dressings. CONCLUSION: The NO releasing film dressings resulted in significantly lower bacterial colony counts as compared to the control dressings at all time points. Incorporating a NO compound into a dressing has an antibacterial effect lasting a minimum of seven days. PMID- 30008254 TI - Sharing international innovations. PMID- 30008255 TI - Use of a novel chitosan-based dressing on split-thickness skin graft donor sites: a pilot study. AB - OBJECTIVE: Split-thickness skin graft (STSG) donor site dressings can play an integral role in reducing donor site morbidity. This study tested a novel, chitosan-based wound dressing, Opticell Ag, as an STSG donor site dressing for wounds <10% total body surface area (TBSA). METHOD: Between January and December 2016, the chitosan-based dressing was placed on participating patients' donor sites immediately following graft harvest and covered with a transparent occlusive dressing. Pain was evaluated on postoperative day one, before dressing change between days 5-7, and before and after dressing removal between days 10-14 using the Visual Analog Scale (VAS). The extent of re-epithelialisation was determined between day 10-14 and at one month, and healing quality was also evaluated at one month post-operatively using the Vancouver Scar Scale (VSS). RESULTS: A total of 19 patients were recruited, of which 16 completed the study. Patients experienced mild-to-moderate pain in their donor sites when the chitosan based dressing was used. Pain decreased significantly between postoperative day one and days 10-14, as well as between days 5-7 and 10-14. The mean percentage of re-epithelialisation on days 10-14 was 92% and by one month was 99%. The mean VSS at one month was 3.2+/-1.4. There were no statistically significant differences between patients' re-epithelialisation rates or VSS scores. There were unplanned dressing changes in four patients. No donor site infections or other adverse events were identified. CONCLUSION: The chitosan-based dressing tested in this study is safe, effective, and associated with reasonable pain control and acceptable healing quality. The results suggest that it is a promising STSG donor site dressing. PMID- 30008256 TI - Loss of heterozygosity of key tumor suppressor genes in advanced renal cancer patients treated with nivolumab. AB - AIM: We studied the possible clinical significance of loss of heterozygosity (LOH) at key tumor suppressor genes loci in advanced renal cancer patients treated with nivolumab. METHODS: LOH study was performed on 3p14.2 (FHIT gene); 3p21.3-21.2; 9p21 (BDMF gene); 9p22 (SH3GL2 gene). RESULTS: Of 12 patients, 8 (67%) had LOH. The most affected gene was FHIT. All five patients with LOH at FHIT locus had good outcome, mean progression free survival of 6.8 months. The patients LOH negative at FHIT locus had mean progression free survival of 4 months, 67% were treatment refractory. Overall, 75% of patients with LOH of at least one gene had benefit; 75% of LOH negative cases were refractory. CONCLUSION: LOH at key tumor suppressor genes should be further investigated as predictive for immunotherapy. PMID- 30008257 TI - Survivin-peptide vaccination elicits immune response after allogeneic nonmyeloablative transplantation: a safe strategy to enhance the graft versus tumor effect. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) is an adoptive immunotherapy strategy whose effectiveness relies on graft-versus-tumor (GVT) effect. We explored the feasibility of enhancing GVT after allo-HCT by peptide vaccination. Two myeloma patients were transplanted with a fludarabine-total body irradiation conditioning regimen and vaccinated with an HLA-A*0201-restricted modified survivin nonapeptide, plus montanide as adjuvant. At time of first vaccination, one patient had just attained serological remission despite documented relapse after transplant, while the other patient was in stable disease. Both patients had an immune response to vaccination: the frequency of survivin-specific CD8+ T cells increased between second and sixth vaccination and accounted for 0.5-0.8% of CD8+ cells; CD8+ cells were functional in ELISPOT assay. The first patient persists in complete remission with a follow-up of >5 years, while the second patient did not have a clinical response and vaccination was halted. We analyzed the T-cell receptor (TCR) repertoire of the first patient by spectratyping and found that vaccination did not affect the diversity of TCR profile, indicating that survivin clonotypes were probably spread in multiple TCR families. We generated a limited number (n = 4) of survivin-specific T cell clones: three were reactive only against the modified peptide, whereas one clone recognized also the naive peptide. Peptide vaccination is safe and applicable after allo-HCT and elicits an efficient antigen-specific T cell response without causing graft-versus-host disease. PMID- 30008258 TI - Antithymocyte globulin-induced hemolytic anemia and thrombocytopenia after kidney transplantation. AB - Antithymocyte globulin is the most widely used lymphocyte-depleting treatment in kidney transplantation. In spite of the frequency of side effects, including anemia and thrombocytopenia, their pathophysiological mechanisms are not clearly established. Here, we report the case of a 21-year-old patient who had a first kidney transplantation and received induction immunosuppressive therapy by thymoglobulin. Immediately after kidney transplantation, he developed a severe hemolytic anemia and thrombocytopenia with a subsequent perirenal hematoma, which lead to a second surgical procedure and a transfer to the intensive care unit. Our patients' anemia and thrombocytopenia had heteroimmune characteristics, and thymoglobulin therapy was suspected to be the cause, via an interaction with a common Fc-receptor epitope in the different cell lines. PMID- 30008260 TI - STING signaling: a key to therapeutic tumor immunity. PMID- 30008259 TI - Oncolytic herpes simplex virus immunovirotherapy in combination with immune checkpoint blockade to treat glioblastoma. AB - Oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are a new class of cancer therapeutic, which selectively replicate and kill cancer cells, while inducing an inflammatory microenvironment, immunovirotherapy. Recently, an oHSV (talimogene laherparepvec) has been approved for the treatment of advanced melanoma. Glioblastoma (GBM) is an almost always lethal primary tumor in the brain that is highly immunosuppressive, and posited to contain GBM stem-like cells (GSCs). Immune checkpoint blockade has revolutionized therapy for some cancers, but not GBM. We have used a syngeneic GSC-derived orthotopic GBM model (005) to develop immunotherapeutic strategies. Curative therapy required oHSV expressing IL-12 in combination with two checkpoint inhibitors, anti-PD-1 and anti-CTLA-4. This response required CD4+ and CD8+ T cells, and macrophages in a complex interplay. PMID- 30008261 TI - Do immune checkpoint inhibitors perform identically in patients with weight extremes? AB - The interaction between the two recent hallmarks of carcinogenesis, the immune system and energetic metabolism, has not been well investigated. The limited literature available on this topic describes a correlation between the efficacy and safety of immune checkpoint inhibitors with body mass index. A key knowledge gap is the understanding of this correlation as outcomes are strongly affected highlighting the need to prospective studies in this regard. This paper evaluates the rationale to these correlations at weight extremes and suggests the evaluation patient's weights and associated inflammatory profile before the initiation of immune checkpoint inhibition in cancer patients. PMID- 30008262 TI - Immunotherapy in non-small-cell lung cancer: potential predictors of response and new strategies to assess activity. AB - The treatment algorithm of advanced non-small-cell lung cancer is rapidly evolving. This result is mostly related to the availability in clinical practice of checkpoint inhibitors targeting the programmed death-1 (PD-1) and its ligands (PD-Ls) immunosuppressive pathway. Although patient's selection in the first-line setting relies essentially on high levels of PD-L1 tumor expression, treatment choice in pretreated patients is more challenging and, although clinical and biological characteristics might be of help, there is an urgent need for novel tools to better identify sensitive and resistant patients. In this context, the integration of molecular markers and immune-PET imaging might represent a potentially effective strategy to refine patient selection. PMID- 30008263 TI - IAPT under the microscope. AB - England's flagship 'Improving Access to Psychological Therapies' (IAPT) service has cost around L1 billion yet Scott's (2018a) study suggests that only 9.2% of IAPT patients recover. This leaves an enormous gap of 40.8% between the observed recovery rate and IAPT's claimed recovery rate of 50.0%. The spotlight is on patients with 'medically unexplained symptoms' (MUS) and 'long-term conditions' (LTCs) such as 'diabetes, COPD and ME/CFS, yet there is no way of knowing whether IAPT is capable of yielding the promised rewards or English patients are being sold an expensive pup. An urgent independent expert review of IAPT recovery rates is necessary to answer this question. PMID- 30008264 TI - Attempting to reconcile large differences in Improving Access to Psychological Therapies recovery rates. AB - The Improving Access to Psychological Therapies initiative has a reported 50 percent recovery rate. Recently, Scott published a scathing report asserting that 9.2 percent is the correct rate. This alarming assertion requires a closer look and further scrutiny of the Improving Access to Psychological Therapies. Scott's study is fundamentally flawed in many ways; chiefly, the small ( n = 87), forensically involved, convenience sample is not representative of the Improving Access to Psychological Therapies population. Scott's study is more a limited scope non-representative-sampled audit (or pilot study audit) of the Improving Access to Psychological Therapies. Given the large amount of public funds involved in the project, further research and a high degree of transparency is warranted. PMID- 30008265 TI - Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation. AB - BACKGROUND: Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells. METHODS: Here, we characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines. RESULTS: In recipient HNOK cells, we found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). We have also identified CEP55 as a potential cancer exosomal marker. CONCLUSIONS: In conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies. PMID- 30008266 TI - Overexpression of eis without a mutation in promoter region of amikacin- and kanamycin-resistant Mycobacterium tuberculosis clinical strain. AB - BACKGROUND: Aminoglycosides such as amikacin and kanamycin are effective injectable second-line drugs for treatment of multidrug-resistant tuberculosis. Molecular mechanisms underlying aminoglycoside resistance are not well understood. We have previously identified the amikacin- and kanamycin-resistant M. tuberculosis MT433 clinical strain, of which all known mutations related to resistance have not been found. Drug efflux pump is one of reported resistance mechanisms that might play a role in aminoglycoside resistance. METHODS: The expression levels of sixteen putative efflux pump genes, including eis and one regulator gene, whiB7, of MT433 in the presence of kanamycin were determined using the reverse transcription-quantitative PCR method. The effects of upregulated genes on amikacin and kanamycin resistance were investigated by overexpression in M. tuberculosis H37Ra strain. RESULTS: Upon kanamycin exposure, other than whiB7 and eis that were found extremely overexpressed, two drug efflux pump genes, namely Rv1877 and Rv2846c, showed specifically high-level of expression in M. tuberculosis MT433 strain. However, direct effect of overexpressed Rv1877 and Rv2846c on amikacin and kanamycin resistance could not be demonstrated in M. tuberculosis H37Ra overexpressed strain. CONCLUSIONS: Our finding demonstrated that overexpression of eis could occur without any mutations in the promoter region and be detectable in clinical isolate. This might be a consequence of overexpressed whiB7, resulting in amikacin and kanamycin resistance in M. tuberculosis MT433 strain. PMID- 30008268 TI - Distinctive vasculopathy with systemic involvement due to levamisole long-term therapy: a case report. AB - BACKGROUND: Levamisole belongs to the antihelminthic class of drugs that are sometimes administered to patients with frequently relapsing or steroid-dependent nephrotic syndrome, owing to its steroid-sparing effects. Neutropenia and skin lesions, compatible with vasculitis, have been reported as drug complications, but they are rarely associated with any systemic involvement. CASE PRESENTATION: We report a case of a 9-year-old Arab boy with steroid-dependent nephrotic syndrome who was treated with levamisole after his third relapse. The drug was initially well tolerated, but mild isolated neutropenia occurred 6 months after levamisole administration. This was followed by cutaneous vasculitis of both ears and the left cheek. The patient also developed hepatosplenomegaly and anemia. Levamisole was discontinued, and his disease remained in remission. All the systemic manifestations disappeared gradually over the course of 1 month. The patient remained in remission until 1 year after levamisole withdrawal, when clinical nephrosis recurred. CONCLUSIONS: Despite levamisole's being a useful drug for maintaining remission in steroid-dependent nephrotic syndrome, patients on long-term levamisole therapy should be monitored closely to prevent serious complications that can easily be resolved by simple drug withdrawal. PMID- 30008267 TI - Changes in HbA1c and weight, and treatment persistence, over the 18 months following initiation of second-line therapy in patients with type 2 diabetes: results from the United Kingdom Clinical Practice Research Datalink. AB - BACKGROUND: Intensification of metformin monotherapy with additional glucose lowering drugs is often required in patients with type 2 diabetes (T2D). This study evaluated changes in HbA1c and weight, as well as treatment persistence, associated with different second-line therapies used in UK clinical practice. METHODS: The UK Clinical Practice Research Datalink was used to identify patients with T2D who initiated second-line therapy after metformin monotherapy between 1 August 2013 and 14 June 2016. Treatment persistence and changes in HbA1c and weight were assessed at 6-month intervals up to 18 months. RESULTS: In total, 9097 patients (mean age 61.2 years, 57.2% men, mean [standard deviation] HbA1c 9.0% [1.8]/ 75 mmol/mol [19.7]) were included in the analysis, with a median 2.3 years between initiating metformin monotherapy and initiating second-line therapy. Patients were stratified according to second-line therapy: metformin in combination with sulfonylurea (SU; n = 4655 [51.2%]), a dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor; n = 2899 [31.9%]), or a sodium-glucose cotransporter 2 inhibitor (SGLT-2 inhibitor; n = 441 [4.9%]) or other therapies (all other second-line treatments; n = 1102 [12.1%]). At 18 months, the cumulative proportion of patients changing treatment was lowest for those who received metformin plus an SGLT-2 inhibitor (42.3%), followed by patients on metformin plus SU or metformin plus a DPP-4 inhibitor (46.8%). HbA1c reductions were seen with all second-line therapies, with an overall mean (standard error) reduction of -1.23% (0.05)/-13.4 mmol/mol (0.5). Changes were directly, but not linearly, related to baseline HbA1c and were greater in those with higher HbA1c at baseline. Weight loss from baseline was greatest in patients treated with metformin plus either an SGLT-2 inhibitor (-4.2 kg) or a DPP-4 inhibitor (-1.5 kg). The highest proportion of patients who achieved the composite outcome of HbA1c reduction >= 0.5%, body weight loss >= 2.0 kg and treatment persistence for 18 months was observed in those receiving metformin plus an SGLT-2 inhibitor (36.5%). CONCLUSIONS: In this population-based cohort, all second-line therapies added to metformin monotherapy improved glycaemic control, but the lowest treatment change/discontinuation rate and most sustained weight loss was seen with patients receiving metformin plus an SGLT-2 inhibitor. PMID- 30008269 TI - The Dengue virus in Nepal: gaps in diagnosis and surveillance. AB - BACKGROUND: The introduction of the dengue virus (DENV) in Nepal is recent, first reports date back to 2004 from a Japanese traveller and limited information is available about DENV infection in the Nepali population. Within a decade after the first DENV detection, it is now endemic in multiple districts of Nepal with approximately 11.2 million people residing in the Terai belt being at risk of DENV infection. Sporadic cases of DENV infection have been reported every year for the past decade during the monsoon season, mainly in the Terai region. METHODS: Medline/Embase/Cochrane databases were reviewed for reports on the burden of dengue infection, diagnostic methods, and national surveillance. RESULTS: Four outbreaks were reported since 2004 including the diagnosis of all serotypes in 2006 and predominance of a single serotype in 2010 (DENV-1), 2013 (DENV-2), and 2016 (DENV-1). The clinical diagnoses showed a predominance of dengue fever while 4/917 (0.4%), 8/642 (1.2%) and 8/1615 (0.4%) dengue haemorrhagic fever/dengue shock syndrome cases were identified during the outbreaks in 2010, 2013 and 2016, respectively. The number of cases reported in males was significantly higher (67.4%) than in females. Disease occurrence was primarily found in the Terai region until 2010 and was increasingly detected in the Hilly region in 2016. CONCLUSION: In Nepal currently weak diagnostic facilities, very limited research on mosquitoes vectors, and poor surveillance of dengue leading to inappropriate detection and control of DENV. We surmise that improved basic research and epidemiological training courses for local scientists and laboratory personal at national and international level will help better understand the evolution and distribution of DENV transmission and its eventual control. PMID- 30008270 TI - Determinants of viral load rebound on HIV/AIDS patients receiving antiretroviral therapy: results from South Africa. AB - BACKGROUND: Antiretroviral therapy (ART) has become the standard of care for patients with HIV infection in South Africa and has led to the reduction in AIDS related morbidity and mortality. In developing countries, the nucleosides reverse transcriptase inhibitors (NRTIs) class are widely used because of their low production costs. However patients treated with NRTIs develop varying degree of toxicity after long-term therapy. For this study patients are administered with a triple therapy of two NRTIs and one non-nucleoside reverse transcriptase inhibitor (NNRTI). METHOD: In this study the progression of HIV in vivo is divided into some viral load states and a continuous time-homogeneous model is fitted to assess the effects of covariates namely gender, age, CD4 baseline, viral load baseline, lactic acidosis, peripheral neuropathy, non-adherence and resistance to treatment on transition intensities between the states. Effects of different drug combinations on transition intensities are also assessed. RESULTS: The results show no gender differences on transition intensities. The likelihood ratio test shows that the continuous time Markov model for the effects of the covariates including combination give a significantly better fit to the observed data. From almost all states, rates of viral suppression were higher than rates of viral rebound except for patients in state 2 (viral load between 50 and 10,000 copies/mL) where rates of viral rebound to state 3 (viral load between 10,000 and 100,000 copies/mL) were higher than rates of viral suppression to undetectable levels. For this transition, confidence intervals were very small. This was quite notable for patients who were administered with AZT-3TC-LPV/r and FTC-TDF-EFV. Although patients on d4T-3TC-EFV also had higher rates of viral rebound from state 2 than suppression, the difference was not significant. CONCLUSION: From these findings, we can conclude that administering of any HIV drug regimen is better when based on the viral load level of an HIV+ patient. Before initiation of treatment, patients should be well equipped on how antiretroviral drugs operate including possibilities of toxicity in order to reduce chances of non adherence to treatment. There should also be a good relationship between patient and health-care-giver to ensure proper adherence to treatment. Uptake of therapy by young patients should be closely monitored by adopting pill counting every time they come for review. PMID- 30008271 TI - Diaphanocephalus galeatus (Nematoda: Diaphanocephalidae), a poorly known parasite of lizards: redescription, first genetic characterization and a revision of its congeners from Brazil. AB - Diaphanocephalus galeatus collected from the small intestine of the lizard Dracaena paraguayensis in the Pantanal wetlands, State of Mato Grosso do Sul, Brazil, is redescribed. Genetic characterization and observations using scanning electron microscopy (SEM) were performed for the first time. The vouchers of D. galeatus and the type specimens of its congeners, deposited in the Colecao Helmintologica do Instituto Oswaldo Cruz (CHIOC), were consulted. Light and SEM observations revealed several undescribed features of D. galeatus, i.e. structure of the cephalic end and of the buccal capsule, position and morphology of deirids, presence of phasmids in females and presence of unpaired papilla on the membranous projection that covers the genital cone in males. After observation of the specimens deposited in the helminthological collection, D. jacuruxi is considered a synonym of D. galeatus, and D. diesingi, despite its incomplete description, is tentatively retained as valid due to the poor condition of the type material. The results also indicated low host specificity of D. galeatus, contradicting previous assertions. Genetic comparisons using patristic distances and phylogenetic trees generated from sequences of the 28S rRNA nuclear gene indicated that D. galeatus is closer to the taxa within Ancylostomatoidea and Strongyloidea than any lineage of Metastrongyloidea or Trichostrongyloidea. However, most of the nodal supports were low. Based on the genetic and morphological characterization, the validity of D. galeatus was confirmed. These data may serve for further comparative approaches for different populations of the parasite, from different hosts in different geographical areas, mitigating taxonomic confusions. PMID- 30008272 TI - Evaluation of enzyme-linked immunoelectrotransfer blot for diagnosis of cysticercosis in swine from North India. AB - Taenia solium cysticercosis is a major public health problem in developing countries. Swine cysticercosis results in economic losses for pig farmers in disease endemic areas. Consumption of cysticercotic pork leads to taeniasis in humans. Eggs excreted in the faeces of T. solium carriers disseminate to humans and pigs through the faecal-oral route, thus maintaining the life cycle in endemic areas. An enzyme-linked immunoelectrotransfer blot (EITB) assay was developed using whole crude T. solium cysticercus antigens (WCA) for the diagnosis of swine cysticercosis. Sera from 30 swine with cysticercosis confirmed by magnetic resonance imaging were subjected to EITB assay. Sera from 50 swine that were raised in a government farm and not allowed to roam freely were included as negative controls. Two or more bands of 8, 11, 14, 24, 26 and 29 kDa were immunoreactive on blot with sera from all infected swine except two, and none from swine raised on the government farm. The overall sensitivity and specificity of EITB assay for diagnosis of swine cysticercosis were 93.3% and 100%, respectively. Hence, EITB assay based on WCA may be a suitable diagnostic tool for swine cysticercosis in endemic areas. PMID- 30008273 TI - Endoscopic cricoid split in a tertiary referral paediatric centre. AB - BACKGROUND: Anterior cricoid split is performed for grade 2 and 3 subglottic stenosis, which can be a cause of extubation failure. It can be performed endoscopically or as an open procedure. This paper describes a case series of endoscopic cricoid split procedures performed using a bespoke sickle knife. METHOD: Nine patients (six pre-term infants) underwent endoscopic cricoid split in a tertiary referral paediatric unit between August 2012 and March 2015. RESULTS: Six patients (67 per cent; four pre-term and two term infants) were on oxygen pre-operatively. Mean age at operation was 30 weeks (range, 11-104 weeks). Mean number of days' intubation was 5.6 days (range, 4-9 days). All five patients intubated pre-operatively were extubated. Seven patients required repeat dilatations. One patient required tracheostomy. CONCLUSION: The extubation rates for endoscopic cricoid split are comparable to the open procedure. It is a safe and efficient method for managing subglottic stenosis, whether acquired or congenital. The main advantage is the shorter operative time, in addition to the avoidance of an external scar and drain. PMID- 30008274 TI - Effects of a commercial broiler enrichment programme with or without natural light on behaviour and other welfare indicators. AB - Commercial broiler production systems based on market initiatives to improve animal welfare beyond minimum legal requirements have emerged in several European countries. A common factor in the 'higher welfare' indoor systems is the application of environmental enrichment, with or without natural light, to promote locomotor activity and natural behaviours of the broiler chickens. In the current study, we evaluated the effects of a commercial enrichment programme for fast-growing indoor-housed broiler chickens, with or without natural light entering the broiler house. Enrichment materials were selected in relation to perceived minimal hygiene risk and ease of cleaning in between production cycles. Selected enrichments were a combination of wood shavings bales (1.5 bale/1000 chickens), round metal perches (2.7 m/1000 chickens) and metal chains as pecking objects (1/1000 chickens). Three treatments were studied: control (C) without enrichment and natural light, enriched (E) with enrichments as previously defined but without natural light and enriched plus natural light (EL) with enrichments as previously defined and natural light entrance. The experiment was carried out during five subsequent production cycles on one commercial broiler farm with three identical houses. EL could only be assigned to the middle house that was equipped with roof windows (light entrance area: 3% of floor space). C and E were in the two outer houses (alternated in between production cycles). Behaviour was observed during daytime at days 25 and 39 of age by scan sampling. Lameness, footpad dermatitis, hock burn, cleanliness and injuries were scored at the same ages, in addition to the response of the chickens to a novel object. Results showed that the treatments only affected broiler behaviour. E flocks showed significantly more resting as compared with EL and C. EL flocks showed significantly more walking, exploration and foraging behaviour as compared with E and C. Thus, broiler activity was highest in the EL treatment and lowest in the E treatment, with the C treatment in between. No treatment effects were found on the other welfare indicators and only a few tendencies for treatment effects were found for the novel object test, with E birds tending to be more reluctant to approach the object as compared with EL and C birds. We concluded that providing environmental enrichment and natural light-stimulated activity and natural behaviours in broiler chickens, whereas providing enrichment only seemed to have the opposite effect as compared with control flocks without enrichment. PMID- 30008275 TI - Commit, hide and escape: the story of Plasmodium gametocytes. AB - Malaria is the major cause of mortality and morbidity in tropical countries. The causative agent, Plasmodium sp., has a complex life cycle and is armed with various mechanisms which ensure its continuous transmission. Gametocytes represent the sexual stage of the parasite and are indispensable for the transmission of the parasite from the human host to the mosquito. Despite its vital role in the parasite's success, it is the least understood stage in the parasite's life cycle. The presence of gametocytes in asymptomatic populations and induction of gametocytogenesis by most antimalarial drugs warrants further investigation into its biology. With a renewed focus on malaria elimination and advent of modern technology available to biologists today, the field of gametocyte biology has developed swiftly, providing crucial insights into the molecular mechanisms driving sexual commitment. This review will summarise key current findings in the field of gametocyte biology and address the associated challenges faced in malaria detection, control and elimination. PMID- 30008276 TI - Bonebridge transcutaneous bone conduction implant in children with congenital aural atresia: surgical and audiological outcomes. AB - OBJECTIVES: To investigate the surgical and audiological outcomes of the Bonebridge transcutaneous bone conduction hearing implant among children with congenital aural atresia. METHODS: Six children were recruited and underwent Bonebridge transcutaneous bone conduction implant surgery. The patients' audiometric thresholds for air conduction, bone conduction and sound-field tests were assessed pre-operatively and at six months post-operatively. Patients' satisfaction was assessed at six months post-operatively with the Hearing Device Satisfaction Scale. RESULTS: No major complications were reported. Mean aided sound-field thresholds improved post-operatively by more than 30 dB for 0.5-4 kHz (p 0.05). All patients were satisfied (scores were over 90 per cent) with the implant in terms of functional outcome and cosmetic appearance. CONCLUSION: Bonebridge transcutaneous bone conduction implant surgery is safe and effective among children with congenital aural atresia with conductive hearing loss. PMID- 30008277 TI - Developmental changes in articulation rate and phonic groups during narration in French children aged four to eleven years. AB - This paper reports on an original study designed to investigate age-related change in the way French children produce speech during oral narrative, considering both prosodic parameters - speaking rate and duration of the prosodic speech unit - and linguistic structure. Eighty-five French children aged four to eleven years were asked to tell a story after they were shown an excerpt from an animated film. All their remarks were transcribed and coded using ELAN as an annotation tool. Each narrative was analyzed for duration, articulation rate, and linguistic components (i.e., number of phonic groups, syllables, words, clauses). All measures were found to increase with age, with the duration of the phonic group and its linguistic structure showing the stronger differences. Results contribute to providing reference data on speech production during childhood, and they suggest the existence of two distinct developmental patterns in narrative production. PMID- 30008278 TI - The role of meta-analyses and umbrella reviews in assessing the harms of psychotropic medications: beyond qualitative synthesis. AB - ?phiepsilonlambdaepsilonepsiloniotanu, ? MU? betalambdaalphapitauepsiloniotanu (Primum non nocere) - Hiotappocrates' principle should still guide daily medical prescribing. Therefore, assessing evidence of psychopharmacologic agents' safety and harms is essential. Randomised controlled trials (RCTs) and observational studies may provide complementary information about harms of psychopharmacologic medications from both experimental and real-world settings. It is considered that RCTs provide a better control of confounding variables, while observational studies provide evidence from larger samples, longer follow-ups, in more representative samples, which may be more reflective of real-life clinical scenarios. However, this may not always hold true. Moreover, in observational studies, safety data are poorly or inconsistently reported, precluding reliable quantitative synthesis in meta-analyses. Beyond individual studies, meta analyses, which represent the highest level of 'evidence', can be misleading, redundant and of low methodological quality. Overlapping meta-analyses sometimes even reach different conclusions on the same topic. Meta-analyses should be assessed systematically. Descriptive reviews of reviews can be poorly informative. Conversely, 'umbrella reviews' can use a quantitative approach to grade evidence. In this editorial, we present the main factors involved in the assessment of psychopharmacologic agents' harms from individual studies, meta analyses and umbrella reviews. Study design features, sample size, number of the events of interest, summary effect sizes, p-values, heterogeneity, 95% prediction intervals, confounding factor adjustment and tests of bias (e.g., small-study effects and excess significance) can be combined with other assessment tools, such as AMSTAR and GRADE to create a framework for assessing the credibility of evidence. PMID- 30008279 TI - Foraging choices balanced between resource abundance and handling concerns: how the honeybee, Apis mellifera, select the flowers of Robinia pseudoacacia. AB - Nectar is a main resource harvested by foraging honeybees: their ability in selecting among flowers is the key to optimize resource collection. This ability is expected to be the result of co-evolutionary traits between the plant and the pollinator visiting it; notwithstanding, novel interactions may occur between native and invasive species. Analysing foraging efforts, flexibility and individual constrains has to be taken into account. The foraging pattern of the ubiquitous honeybee on Robinia pseudoacacia, a North-American species widely naturalized in European countries, grounds a perfect case study. The plant shows papilionate flowers especially reach in nectar, but their tripping mechanism is difficult for the small/light-weight honeybee. Yet Apis mellifera is known to pay frequent and constant visits to them: in fact, one of the most appreciated unifloral honey is produced out of R. pseudoacacia. The aim of this study was to understand when and how the bees overcome physical constraints to succeed in flower visits, and to what extent this flexibility extend from the individual to the species. Data were collected in Italy, through focal observations of foraging individuals, nectar content measurements and experiments with manipulated inflorescences. Results clearly indicate that nectar content changes accordingly to the state of flowers (visited or unvisited), which also show slight changes in appearance. Foraging individuals, able to detect these differences, perform active choices preferentially selecting already-visited flowers: lower in nectar content but easier to manipulate. Even if the choice is primarily driven by handling constraints, individual experience and strength of stimuli are prompting visits also to unvisited flowers, notwithstanding a higher risk of failure in resource collection. Behavioural plasticity matching a satisfactory compromise grounds the decision that maximizes the intake of resource balanced with the effort to gain it. PMID- 30008281 TI - Association of direct and indirect aggression and victimization with self-harm in young adolescents: A person-oriented approach. AB - We sought to determine which patterns of direct and indirect aggression and victimization are most clearly associated with self-harm in adolescent girls and boys cross-sectionally at two time points, as well as prospectively over one year. A cluster analysis using the LICUR procedure (Bergman, 1998) was employed to identify stable patterns of aggression and victimization in a community cohort of 883 Swedish adolescents (51% girls; mean age 14.5). The results showed that a pattern combining high aggression with high victimization was consistently associated with high levels of self-harm in both genders, both cross-sectionally and prospectively. Additionally, this pattern of aggressive victims was a clear risk factor for the development of repetitive self-harm over a one-year period in both girls (odds ratio 13.58) and boys (odds ratio 5.72). We also found several gender differences: In girls, subgroups characterized by high victimization (aggressive victims and non-aggressive victims) had the highest levels of self harm, whereas in boys the patterns characterized by high aggression (aggressive victims and aggressive non-victims) seemed more relevant. The findings concerning the aggressive victim cluster are clear warning signs of severe psychopathology and possible psychiatric diagnosis in this subgroup of girls and boys. PMID- 30008280 TI - Mediator effects of parameters of inflammation and neurogenesis from a N-acetyl cysteine clinical-trial for bipolar depression. AB - OBJECTIVE: This study aimed to explore effects of adjunctive treatment with N acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression. METHODS: This is a secondary analysis of a placebo-controlled randomised trial. Serum samples were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF alpha), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers. RESULTS: Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters. CONCLUSION: The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression. PMID- 30008286 TI - Platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3) is required for the formation of the meiotic spindle during invitro oocyte maturation. AB - Platelet-activating factor (PAF) is a well-described autocrine growth factor involved in several reproductive processes and is tightly regulated by its hydrolysing enzyme, PAF acetylhydrolase 1B (PAFAH1B). This intracellular enzyme consists of three subunits: one regulatory, 1B1, and two catalytic, 1B2 and 1B3. PAFAH1B3 has remained uncharacterised until now. Here, we report that PAFAH1B3 is present during the different stages of the first meiotic division in bovine, murine and human oocytes. In these species, the PAFAH1B3 subunit was clearly present in the germinal vesicle, while at metaphase I and II, it localised primarily at the meiotic spindle structure. In cattle, manipulation of the microtubules of the spindle by nocodazole, taxol or cryopreservation revealed a close association with PAFAH1B3. On the other hand, disruption of the enzyme activity either by P11, a selective inhibitor of PAFAH1B3, or by PAFAH1B3 antibody microinjection, caused arrest at the MI stage with defective spindle morphology and consequent failure of first polar body extrusion. In conclusion, our results show that one of the catalytic subunits of PAFAH1B, namely PAFAH1B3, is present in bovine, murine and human oocytes and that it plays a functional role in spindle formation and meiotic progression during bovine oocyte maturation. PMID- 30008287 TI - Use of single-question screening for erectile dysfunction: a study of at-risk Asian men in primary health care. AB - This study assesses the validity of a single-question screener for erectile dysfunction (ED) in men at risk in comparison to a standard validated tool - the five-item version of the International Index of Erectile Function (IIEF-5). A total of 174 men with at least one risk factor for ED were studied, with 58.0% and 10.9% of the study respondents meeting the criteria for their erectile impairment by IIEF-5 and single-question screener respectively. Our results suggest that in spite of high feasibility, a simplified, single-question screener has low sensitivity in capturing ED prevalence, even in an at-risk population, within the Asian context. PMID- 30008288 TI - Changing pattern of sexually transmissible infections and HIV diagnosed in public sexual health services compared with other locations in New South Wales, 2010?14. AB - Background: In Australia, testing and treatment for HIV and other sexually transmissible infections (STIs) is usually managed in general practice, while publicly funded sexual health clinics (PFSHC) attract people at higher risk for infection. The proportion of HIV and STI diagnoses in New South Wales (NSW) occurring in PFSHC stratified by priority population was investigated. Methods: From 2010 to 2014, NSW notification frequencies for chlamydia, gonorrhoea, infectious syphilis, and HIV were compared with the number of diagnoses in PFSHC. The annual proportion of diagnoses at PFSHC was calculated and Wilcoxon rank-sum tests assessed trends. Diagnoses from PFSHC were also organised by priority population, including gay and bisexual men (GBM), people living with HIV, Aboriginal and Torres Strait Islander people, people who use injecting drugs, sex workers and young people. Results: The annual proportion of HIV and STIs diagnosed at PFSHC increased (all P<0.001): chlamydia from 12% to 15%, gonorrhoea 23% to 38%, infectious syphilis 21% to 40% and HIV 22% to 30%. Overall, the majority of all infections diagnosed at PFSHC were among GBM, with the proportional distribution of chlamydia increasing from 32% to 46% among GBM (P<0.001) and decreasing among young people (50% to 40%; P<0.001). There were no other significant changes by population or infection at PFSHC. Conclusions: Increasing proportions of STI and HIV are being diagnosed at NSW PFSHC, mostly among GBM. PFSHC reorientation to priority populations continues to make a large and increasing contribution to STI and HIV control efforts in NSW. PMID- 30008289 TI - 23rd and 24th Meetings of the French society of toxinology (SFET): Special issue on "Toxins: Immunity, inflammation and pain". PMID- 30008290 TI - Bacterial Adaptation to the Host's Diet Is a Key Evolutionary Force Shaping Drosophila-Lactobacillus Symbiosis. AB - Animal-microbe facultative symbioses play a fundamental role in ecosystem and organismal health. Yet, due to the flexible nature of their association, the selection pressures that act on animals and their facultative symbionts remain elusive. Here we apply experimental evolution to Drosophila melanogaster associated with its growth-promoting symbiont Lactobacillus plantarum, representing a well-established model of facultative symbiosis. We find that the diet of the host, rather than the host itself, is a predominant driving force in the evolution of this symbiosis. Furthermore, we identify a mechanism resulting from the bacterium's adaptation to the diet, which confers growth benefits to the colonized host. Our study reveals that bacterial adaptation to the host's diet may be the foremost step in determining the evolutionary course of a facultative animal-microbe symbiosis. PMID- 30008291 TI - Zika Virus Vaccine: Progress and Challenges. AB - The explosive emergence of Zika virus has inspired a global effort to develop vaccines. Zika virus, which is a flavivirus primarily transmitted by mosquitoes, can cause devastating congenital syndrome in fetuses of pregnant women, including microcephaly, craniofacial disproportion, spasticity, ocular abnormalities, and miscarriage. In adults, Zika infection has been linked to the autoimmune disorder Guillain-Barre syndrome. Thus, despite the current waning in newly reported Zika infections, an efficacious vaccine is urgently needed to help limit the emergence of another detrimental epidemic. Here we summarize the current status of the Zika vaccine pipeline and highlight the challenges for clinical efficacy trials. PMID- 30008293 TI - Toxoplasma Parasite Twisting Motion Mechanically Induces Host Cell Membrane Fission to Complete Invasion within a Protective Vacuole. AB - To invade cells, the parasite Toxoplasma gondii injects a multi-unit nanodevice into the target cell plasma membrane (PM). The core nanodevice, which is composed of the RhOptry Neck (RON) protein complex, connects Toxoplasma and host cell through a circular tight junction (TJ). We now report that this RON nanodevice mechanically promotes membrane scission at the TJ-PM interface, directing a physical rotation driven by the parasite twisting motion that enables the budding parasitophorous vacuole (PV) to seal and separate from the host cell PM as a bona fide subcellular Toxoplasma-loaded PV. Mechanically impairing the process induces swelling of the budding PV and death of the parasite but not host cell. Moreover, this study reveals that the parasite nanodevice functions as a molecular trigger to promote PV membrane remodeling and rapid onset of T. gondii to intracellular lifestyle. PMID- 30008292 TI - The Stringent Response Determines the Ability of a Commensal Bacterium to Survive Starvation and to Persist in the Gut. AB - In the mammalian gut, bacteria compete for resources to maintain their populations, but the factors determining their success are poorly understood. We report that the human gut bacterium Bacteroides thetaiotaomicron relies on the stringent response, an intracellular signaling pathway that allocates resources away from growth, to survive carbon starvation and persist in the gut. Genome scale transcriptomics, 13C-labeling, and metabolomics analyses reveal that B. thetaiotaomicron uses the alarmone (p)ppGpp to repress multiple biosynthetic pathways and upregulate tricarboxylic acid (TCA) cycle genes in these conditions. During carbon starvation, (p)ppGpp triggers accumulation of the metabolite alpha ketoglutarate, which itself acts as a metabolic regulator; alpha-ketoglutarate supplementation restores viability to a (p)ppGpp-deficient strain. These studies uncover how commensal bacteria adapt to the gut by modulating central metabolism and reveal that halting rather than accelerating growth can be a determining factor for membership in the gut microbiome. PMID- 30008294 TI - Diffuse panbronchiolitis research in MEDLINE (1969-2017): Report of a bibliometric analysis. AB - BACKGROUND: Given the well documented and undesired impact of diffuse panbronchiolitis (DPB), there is a need to create a statistical inventory of research output on DPB. The aim of this study was to identify and analyze different trends in publication over time, with technological additions. METHODS: Articles indexed in MEDLINE regarding DPB were retrieved using PubMed. Citation results were categorized by article type, year of publication, language, and country. RESULTS: A total of 657 publications, published between 1969 and 2017 were retrieved from PubMed; the year with the highest number of articles published was 1992 (n = 32). Japan accounted for 68.34% (n = 449) publications, followed by the United States of America (USA; 6.70%, n = 44) and China (5.48%, n = 36). English (n = 401) was the most commonly used language in the publications, followed by Japanese (n = 223) and Chinese (n = 16). Articles were published in 218 different journals; The Japanese Journal of Thoracic Diseases published the maximum number of articles, accounting for 13.7% (n = 90) citations. Sugiyama Y was the most productive author and contributed to 12 publications. CONCLUSIONS: This was the first bibliometric analysis of DPB. Between 1991 and 2000, the number of publications on DPB literature reached a peak, and although the frequency of publication has decreased recently, the quantity of DPB research during the past 48 years is adequate and satisfactory. Overall, the publications on DPB have undergone exponential growth over the last 30 years. PMID- 30008295 TI - Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: A systematic review. AB - BACKGROUND: Balloon pulmonary angioplasty (BPA) has been performed for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or residual pulmonary hypertension after pulmonary endarterectomy (PEA). We performed a systematic review to assess the efficacy and safety of BPA, especially compared to medical treatment or PEA. METHODS: We reviewed all studies investigating pre- and post treatment pulmonary hemodynamics, mortality, or complications from three electronic databases (PubMed, Cochrane Library, Japan Medical Abstracts Society) prior to February 2017. From 26 studies retrieved, we selected 13 studies (493 patients): the 10 most recent ones including complete data from each institution, one study of residual pulmonary hypertension, and two studies comparing BPA with medical treatment or PEA. RESULTS: No randomized controlled or prospective controlled studies comparing BPA with medical treatment or PEA were reported. The early mortality of BPA ranged from 0% to 14.3%; lung injury occurred in 7.0% to 31.4% (average sessions, 2.5-6.6). Mean pulmonary arterial pressure decreased from 39.4-56 to 20.9-36 mm Hg, and the 6-min walk distance increased from 191-405 to 359-501 m. The 2-year mortality of 80 patients undergoing BPA was significantly lower compared to 68 patients receiving medical treatment (1.3% vs. 13.2%); the risk ratio was 0.14 (95% confidence interval: 0.03-0.76). No significant difference was observed in the 2-year mortality between BPA (n=97) and PEA (n=63) patients. CONCLUSIONS: This systematic review suggests that BPA improves hemodynamics, has acceptable early mortality, and may improve long-term survival compared with medical treatment in inoperable CTEPH patients. PMID- 30008296 TI - A successful pembrolizumab treatment case of lung adenocarcinoma after becoming resistant to ALK-TKI treatment due to G1202R mutation. AB - BACKGROUND: In current guidelines, the role of immune checkpoint inhibitors is not yet determined in the treatment strategy for NSCLC harboring ALK translocations. CASE: A 51-year-old woman with lung adenocarcinoma harboring ALK translocation was treated with alectinib until PD. After the second (CDDP/PEM) and third (crizotinib) line treatment, a second biopsy was performed, revealing PD-L1 tumor proportion score of 70-80% and G1202R mutation of ALK. Pembrolizumab was selected for the fourth line, leading to PR for more than 6 months. CONCLUSIONS: While alectinib might induce resistance to ALK-TKI, it could increase PD-L1 positive cells to become sensitive to PD-1/PD-L1 inhibitors. PMID- 30008297 TI - A Dedicated Population for Reward Coding in the Hippocampus. AB - The hippocampus plays a critical role in goal-directed navigation. Across different environments, however, hippocampal maps are randomized, making it unclear how goal locations could be encoded consistently. To address this question, we developed a virtual reality task with shifting reward contingencies to distinguish place versus reward encoding. In mice performing the task, large scale recordings in CA1 and subiculum revealed a small, specialized cell population that was only active near reward yet whose activity could not be explained by sensory cues or stereotyped reward anticipation behavior. Across different virtual environments, most cells remapped randomly, but reward encoding consistently arose from a single pool of cells, suggesting that they formed a dedicated channel for reward. These observations represent a significant departure from the current understanding of CA1 as a relatively homogeneous ensemble without fixed coding properties and provide a new candidate for the cellular basis of goal memory in the hippocampus. PMID- 30008300 TI - The moderating effects of ethnicity on key predictors of trauma in child welfare involved adolescents. AB - Key predictors of trauma were examined using a multi-group analysis of a nationally representative sample of 716 child welfare involved youth ages 11-17. Results indicate that co-occurring clinical depression was associated with trauma across all racial/ethnic groups. Results also support that youth's ethnicity moderates the relationship between gender, history of sexual abuse and sexual orientation and the development of trauma. Contrary to prior research, trauma was not significantly associated with substance abuse or having experienced out of home placement for all ethnic groups. Implications for policy, practice with child welfare involved adolescents and future research in this area are discussed. PMID- 30008299 TI - Microclimate evaluation of strap-based wheelchair seating systems for persons with spinal cord injury: A pilot study. AB - STUDY PURPOSE: The purpose of this pilot study was to assess microclimate characteristics of two versions of a strap-based wheelchair seating system (perforated and solid straps) and to conduct preliminary microclimate comparisons of subjects' current wheelchair seating systems. MATERIALS AND METHODS: In this pilot study, the microclimate properties of two variations (solid and perforated) of a strap-based seating system were compared with two commonly used seating systems. Six subjects sat on three different seating systems each for 100-min test periods, while temperature and relative humidity were measured with a single sensor adjacent to the skin-seat interface. Additionally, thermal images of the seat interface were collected before and after each test period. RESULTS: The thermal images revealed that the maximum surface temperature of the solid-strap based seating system was significantly lower than the other seating systems, 1.21 degrees C. (95% CI -2.11 to -0.30, p = 0.02), immediately following transfer out of the seat. Five minutes after transferring out of the seat, the perforated-strap seat was significantly cooler than the other seats -0.94 degrees C. (95% CI -1.59 to -0.30), p = 0.01, as was the solid-strap-based seat, 1.66 degrees C. (95% CI -2.69 to -0.63), p = 0.01. There were no significant differences in interface temperature or relative humidity measured with the single sensor near the skin-seat interface. CONCLUSION: This pilot study offers preliminary evidence regarding the microclimate of the strap-based seating systems compared with other common seating systems. Clinically, the strap-based seating system may offer another option for those who struggle with microclimate management. PMID- 30008298 TI - Rapid Cue-Specific Remodeling of the Nascent Axonal Proteome. AB - Axonal protein synthesis and degradation are rapidly regulated by extrinsic signals during neural wiring, but the full landscape of proteomic changes remains unknown due to limitations in axon sampling and sensitivity. By combining pulsed stable isotope labeling of amino acids in cell culture with single-pot solid phase-enhanced sample preparation, we characterized the nascent proteome of isolated retinal axons on an unparalleled rapid timescale (5 min). Our analysis detects 350 basally translated axonal proteins on average, including several linked to neurological disease. Axons stimulated by different cues (Netrin-1, BDNF, Sema3A) show distinct signatures with more than 100 different nascent protein species up- or downregulated within the first 5 min followed by further dynamic remodeling. Switching repulsion to attraction triggers opposite regulation of a subset of common nascent proteins. Our findings thus reveal the rapid remodeling of the axonal proteomic landscape by extrinsic cues and uncover a logic underlying attraction versus repulsion. PMID- 30008301 TI - Night sleep duration trajectories and associated factors among preschool children from the EDEN cohort. AB - OBJECTIVE: Sleep duration may vary both interindividually and intraindividually over time. We aimed to identify night-sleep duration (NSD) trajectories among preschoolers and to study associated factors. METHODS: NSD was collected within the French birth-cohort study EDEN at ages 2, 3, and 5-6 years through parental questionnaires, and were used to model NSD trajectories among 1205 children. Familial socioeconomic factors, maternal sociodemographic, health and lifestyle characteristics, as well as child health, lifestyle, and sleep characteristics at birth and/or at age two years were investigated in association with NSD using multinomial logistic regressions. RESULTS: Five distinct NSD trajectories were identified: short (SS, <10 h, 4.9%), medium-low (MLS, <11 h, 47.8%), medium-high (MHS, ~11.5 h, 37.2%), long (LS, >=11.5 h, 4.5%) and changing (CS, ie, >=11.5 h then <11 h, 5.6%) NSD trajectories. Multivariable analyses showed in particular that compared to the MHS trajectory factors associated with increased risk for the SS trajectory were male gender, first child, maternal age and working status, night-waking, parental presence when falling asleep, television-viewing duration, as well as both "Processed and fast foods" and the "Baby food" dietary patterns at age two years. Factors positively associated with the CS trajectory were maternal smoking, feeding at night, and the Processed and fast foods dietary pattern at age two years, whereas child's activity and emotionality scores at age one year were negatively associated. CONCLUSION: We identified distinct NSD trajectories among preschoolers and associated early life factors. Some of them may reflect less healthy lifestyles, providing cues for early multi-behavioral prevention interventions. PMID- 30008302 TI - Serum metabonomics study on antidiabetic effects of fenugreek flavonoids in streptozotocin-induced rats. AB - Fenugreek is a well-known medicinal plant used for treatment of diabetes. In this study, the antidiabetic effect of fenugreek flavonoids was investigated by metabonomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Fenugreek flavonoids were purified using polyamide resin and D101 macroporous adsorption resin, characterized by UPLC-Q-TOF-MS, and administered to streptozotocin (STZ)-induced diabetic rats for 28 days. Pharmacological study results indicated that fenugreek flavonoids exerted a strong antidiabetic effect characterized by significant reduction of fasting blood glucose (P < 0.01), increase in serum insulin level (P < 0.01) and liver glycogen content (P < 0.01), attenuation of weight loss, and improvement of pancreatic islet and kidney conditions. The antidiabetic effect of fenugreek flavonoids was further analyzed by metabonomics. Serum samples of health and diabetic rats treated or not with fenugreek flavonoids were evaluated by UPLC-Q-TOF-MS, followed by principal component analysis (PCA) and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA). The PCA model revealed significant differences among the animal groups, and OPLS-DA identified fenugreek flavonoids-induced changes of 11 potential biomarkers involved in lipid metabolism (docosahexaenoic acid, arachidonic acid, sphinganine, sphingosine-1-phosphate, and lysophosphatidylcholines 20:4, 18:2, 16:0, and 20:2), amino acid metabolism (hippuric acid and tryptophan), and kidney function-related metabolism (2-phenylethanol glucuronide). Our study demonstrates that flavonoids are bioactive components of fenugreek with potent antidiabetic activity, which exert their therapeutic effects by multiple mechanisms, including reducing insulin resistance, improving gluconeogenesis, and protecting islet cells and kidneys from damage. PMID- 30008303 TI - Analysis of terephthalate metabolites in human urine by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). AB - Owing to their toxicity, phthalate plasticizers are currently being replaced with terephthalates in many consumer products. Nevertheless, data on human exposure to and toxicity of terephthalates are still scarce. In this study, we developed a robust analytical method for the measurement of six terephthalate metabolites (TPhMs) in human urine through their successful separation from phthalate metabolites (PhMs). Target analytes were identified, using commercially available standards, and quantified with isotopically labeled internal standards (IS). The limits of quantification (LOQ) of TPhMs were in the range of 0.12 to 0.4 ng/mL, with the exception of 2.8 ng/mL for terephthalic acid (TPA) and 3.75 ng/mL for mono-(2-ethylhexyl) terephthalate (mEHTP), which were found in procedural blanks at notable levels. The method developed in this study showed excellent accuracy (recoveries: 86-117%) and precision (RSD: 0.6-12.2%) for TPhMs. The method was successfully applied for the analysis of 30 human urine samples collected from individuals with no known history of occupational exposure. The detection frequencies (df %) of TPhMs in urine ranged between 26.6 and 100%. This is one of the first studies that report a method for the analysis of emerging class of environmental chemicals in human specimens. PMID- 30008304 TI - Determination of three tetracyclines in bovine milk using magnetic solid phase extraction in tandem with dispersive liquid-liquid microextraction coupled with HPLC. AB - A novel analytical method namely magnetic solid phase extraction in tandem with dispersive liquid-liquid microextraction was developed and used for the extraction/preconcentration of tetracycline (TCN), oxytetracycline (OTC) and doxycycline (DC) from bovine milk sample before HPLC-UV analysis. The beta cyclodextrin functionalized silica-coated magnetic graphene oxide (Fe3O4@SiO2@GO beta-CD) was used as an adsorbent. The adsorbent was fully characterized using FT IR, SEM, EDX and Zeta potential techniques. The effective parameters on the performance of the method such as extraction solvent type and volume, adsorbent amount, desorption solvent type and volume, disperser solvent type, desorption time, ionic strength and pH value were investigated. The limit of detection (LOD) and limit of quantification (LOQ) were obtained in the ranges of 1.8-2.9 MUg L-1 and 6.1-9.7 MUg L-1, respectively. The linearity was in the range of 10.0-200.0 MUg L-1 with satisfactory determination coefficients (R2) higher than 0.9929 and a good precision (RSD < 8.8%). The recovery percentages for the analytes in real samples (bovine milk and water) were achieved in a range from 70.6 to 121.5%. PMID- 30008305 TI - Determination of voriconazole and co-administered drugs in plasma of pediatric cancer patients using UPLC-MS/MS: A key step towards personalized therapeutics. AB - Untreated invasive aspergillosis results in high mortality rate in pediatric cancer patients. Voriconazole (VORI), the first line of treatment, requires strict dose monitoring because of its narrow therapeutic index and individual variation in plasma concentration levels. Commonly co-administered drugs; either Esomeprazole (ESO) or Ondansetron (OND) have reported drug-drug interaction with VORI that should adversely alter therapeutic outcomes of the latter. Although VORI, ESO and OND are co-administered to pediatric cancer patients, the combined effect of ESO and OND on the plasma concentration levels of VORI has not been fully explored. In this study, an accurate, reliable and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for simultaneous determination of VORI, ESO, and OND in ultra-low sample volumes (25 MUL) of plasma of pediatric cancer patients. Based on the physicochemical properties of the studied drugs and internal standard, liquid liquid extraction was successfully adopted with methyl t-butyl ether. Consistent and reproducible recovery of the three drugs and the internal standard were calculated using plasma and matrix matched samples (RE% > 72.97%, RSD < 8.29%). Chromatographic separation was carried out using UPLC with C18 column and a mobile phase of acetonitrile:water:methanol (70:25:5 V/V/V) at 0.3 mL/min. Mass spectrometric determination at positive electrospray ionization in the MRM mode was employed. The analysis was achieved within 4 min over a linear concentration range of 1.00-200.00 ng/mL for the three drugs. The assay validity was assessed as per the Food and Drug Administration guidelines for bioanalytical method validation, and satisfactory results were obtained. The accuracy and precision were within the acceptable limits for the three drugs in both quality control and incurred plasma samples. Matrix effect and process efficiency were investigated in neat solvent, post-extraction matrix, and plasma. Correlation of the plasma concentration levels of the three drugs revealed differences from the reported drug-drug interactions. This confirmed the need for simultaneous determination of VORI and co-administered drugs in order to achieve optimal therapeutic outcomes. To achieve this, analysis results of this study, genetic polymorphisms in CYP2C19 and clinical data will be used to establish one model incorporating all possible factors that might lead to variation in therapeutic outcomes. PMID- 30008306 TI - Supercritical fluid chromatography coupled to mass spectrometry - A metabolomics perspective. AB - Metabolomics as a global analysis of a large number of cellular metabolites relies heavily on the new developments in separation science and technology. None of the existing analytical techniques can simultaneously separate and measure all the cellular metabolites due to complexity of cellular metabolome and, therefore, a combination of analytical techniques must be used. Currently NMR, GC-MS and LC MS are most often used in metabolomics. Novel separation methods such as supercritical fluid chromatography (SFC), which can increase metabolome coverage while decreasing cost and analysis time, can provide alternative to other analytical techniques. As a result of major improvements in instrumentation and development of a new diverse column chemistries SFC-MS is increasingly used in a variety of biomedical applications and is becoming an attractive compliment to other major analytical platforms in metabolomics. Despite its potential and advantages, SFC-MS application in metabolomics is limited. Here we provide a brief overview of the latest developments of SFC-MS for metabolomics applications. PMID- 30008307 TI - Simultaneous analysis of olanzapine, fluoxetine, and norfluoxetine in human plasma using liquid chromatography-mass spectrometry and its application to a pharmacokinetic study. AB - Adjunctive therapy with olanzapine and fluoxetine has been shown to be beneficial in treatment-resistant depression and the depressive phase of bipolar disorder. Consensus guidelines issued by the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie strongly recommend that patients taking olanzapine undergo therapeutic drug monitoring (TDM), and suggest that TDM is useful for patients taking fluoxetine. The aim of the current study was to develop and validate a sensitive, practical, and robust liquid chromatography tandem mass spectrometry method (LC-MS/MS) for simultaneous determination of olanzapine, fluoxetine, and norfluoxetine in human plasma for routine TDM. Simple liquid-liquid extraction using ethyl acetate was used to extract olanzapine, fluoxetine, and norfluoxetine from 200 MUL of pre-basified human plasma. Analytes were separated on an Agilent Eclipse Plus C18 column (4.6 * 100 mm, 5 MUm) eluted with a mobile phase consisting of methanol:20 mM ammonium formate buffer (82.5:17.5, v/v), and then quantified using an electrospray ionization source operated in positive ion multiple reaction monitoring mode. The linear range for the analytes was 0.2-25 ng/mL, covering the vast majority of levels encountered in real-life samples. A weighting factor of 1/x2 best fit the calibration curves. The mean internal standard-normalized matrix effects for all analytes were 99.5% 110%. The extraction recoveries were 75%-85% for olanzapine and olanzapine-d3, and 58%-69% for fluoxetine, norfluoxetine, and their deuterated internal standards. Accuracy and precision values also met the acceptance criteria. The stability assessments showed that QC samples containing the three analytes were stable for at least 1 d at room temperature, 21 d at -70 degrees C, and through three freeze-thaw cycles. Post-preparation storage for 2 d in the autosampler did not cause obvious degradation of the investigated compounds. This validated high performance LC-MS/MS method was successfully applied to a pharmacokinetic study in healthy male volunteers. PMID- 30008308 TI - Development of a novel conjugatable sunitinib analogue validated through in vitro and in vivo preclinical settings. AB - Sunitinib is an oral FDA/EMEA approved multi-targeted tyrosine kinase inhibitor. It possesses anti-angiogenic and antitumor activity against a variety of advanced solid tumors. However, its chemical core does not allow a potential linkage to tumor-homing elements that could eventually enhance its potency. Therefore, a novel linkable sunitinib derivative, designated SB1, was rationally designed and synthesized. The pharmaceutical profile of SB1 was explored both in vitro and in vivo. Mass spectrometry and NMR spectroscopy were utilized for characterization, while MTT assays and LC-MS/MS validated protocols were used to explore its antiproliferative effect and stability, respectively. Cytotoxicity evaluation in three glioma cells showed that SB1 preserved the antiproliferative effect of sunitinib. SB1 was stable in vitro after 24 h incubation in mouse plasma, while both agents exhibited bioequivalent pharmacokinetic characteristics after i.v. administration in Balb/c mice. To evaluate the levels of SB1 in mouse plasma, a novel analytical method was developed and validated in accordance to the US FDA and the EU EMA guidelines. We formulated a novel linkable sunitinib analog exhibiting similar antiproliferative and apoptotic properties with native sunitinib in glioma cell lines. Both SB1 and native sunitinib showed identical in vitro stability in mouse plasma and pharmacokinetics after i.v. administration in Balb/c mice. PMID- 30008309 TI - WDC15 Basic and Clinical Stream to offer extensive coverage on treatment advances. PMID- 30008310 TI - Aortic dilatation after tetralogy of Fallot repair: A ghost from the past or a problem in the future? AB - INTRODUCTION AND AIMS: Intrinsic aortopathy can lead to dilatation late after tetralogy of Fallot (TOF) repair. Its extent and prevalence are not known. We aimed to assess aortic dimensions and elasticity and to find predictors of aortic dilatation. METHODS: A total of 126 adults were prospectively included after TOF repair and compared to 63 gender- and age-matched controls. Transthoracic echocardiography was used to assess aortic diameters at the level of the sinuses of Valsalva and ascending aorta and aortic dilatation was defined as z-score >+2. M-mode parameters of the ascending aorta were used to calculate strain, distensibility and stiffness index. RESULTS: TOF patients (mean age 30+/-9 years; 52% male) had a complete repair at a median age of five (2-49) years; mean follow up time since repair was 23+/-7 years. The prevalence of aortic dilatation at the sinuses of Valsalva and ascending aorta was 29% and 24%, respectively. Compared to controls, TOF patients had a higher ascending aorta z-score, lower strain (6.4% [0.0-61.5] vs. 15.2% [0.0-45.0], p<0.01) and higher stiffness index (7.3 [0.8-23.6] vs. 3.1 [0.9-14.1], p<0.01). On multivariate analysis male gender was strongly associated with sinuses of Valsalva dilatation (odds ratio 6.3, 95% confidence interval 1.5-26.3, p=0.01). CONCLUSIONS: The prevalence of aortic dilatation late after TOF repair is significant, with a larger and stiffer ascending aorta. Male gender appears to influence aortic root dilatation. This aortopathy requires careful follow-up in order to prevent future complications. PMID- 30008311 TI - Aortic dilatation in repaired tetralogy of Fallot: Can an old problem be solved? PMID- 30008312 TI - Portuguese Registry of Acute Coronary Syndromes (ProACS): 15 years of a continuous and prospective registry. AB - The Portuguese Registry of Acute Coronary Syndromes (ProACS) has completed 15 years of continuous and prospective activity. We present an overall picture of the data from this powerful tool. Up to 2016, 45 141 records were included, mostly male (71%), and with a mean age of 66 years. Baseline characteristics remained stable over the years. Of the overall population, 44% of cases were ST elevation myocardial infarction (STEMI). Over the years there was a significant improvement in compliance with international guidelines, in terms of both diagnostic and therapeutic procedures, as well as for medication. In particular, the rate of reperfusion in STEMI increased to 84%, mainly by primary percutaneous coronary intervention (only 5.2% were treated by thrombolysis in 2016). By contrast, timings in STEMI did not change significantly. Improvements in treatment were accompanied by a reduction in in-hospital mortality from 6.7% in 2002 to 2.5% in 2016 in the overall population. This registry enables analysis of the management and results of acute coronary syndromes over time in Portugal, and hence assessment of improvements in quality of care. PMID- 30008313 TI - Confirming the value of continuous registries of clinical activity. PMID- 30008314 TI - Comparison of multiparametric risk scores for predicting early mortality after transcatheter aortic valve implantation. AB - INTRODUCTION: Surgical risk scores are widely used to identify patients at high surgical risk who may benefit from transcatheter aortic valve implantation (TAVI). A multiparametric TAVI mortality risk score based on a French registry (FRANCE-2) has recently been developed. The aim of our study was to compare the 30-day mortality prediction performance of the FRANCE-2, EuroSCORE II and STS scores. METHODS: We retrospectively studied 240 patients from a single-center prospective registry who underwent TAVI between January 2008 and December 2015. All scores were assessed for calibration and discrimination using calibration-in the-large and ROC curve analysis, respectively. RESULTS: The observed mortality was 5.8% (n=14). The median EuroSCORE II, STS and FRANCE-2 scores were 5.0 (IQR 3.2-8.3), 5.1 (IQR 3.6-7.1) and 2.0 (IQR 1.0-3.0), respectively. Discriminative power was greater for EuroSCORE II (C-statistic 0.67) and STS (C-statistic 0.67) than for FRANCE-2 (C-statistic 0.53), but this was not statistically significant (p=0.26). All scores showed adequate calibration. CONCLUSIONS: All scores showed modest performance in early mortality prediction after TAVI. Despite being derived from a TAVI population, FRANCE-2 was no better than surgical risk scores in our population. PMID- 30008315 TI - ["Addictive substances": A new thematic series]. PMID- 30008316 TI - Targeted Enhancer Activation by a Subunit of the Integrator Complex. AB - The control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor. Integrator is a general activator of transcription at coding genes and is required for eRNA maturation. Here, we show that INTS13 functions as an independent sub-module and targets enhancers through Early Growth Response (EGR1/2) TFs and their co-factor NAB2. INTS13 binds poised monocytic enhancers eliciting chromatin looping and activation. Independent depletion of INTS13, EGR1, or NAB2 impairs monocytic differentiation of cell lines and primary human progenitors. Our data demonstrate that Integrator is not functionally homogeneous and has TF-specific regulatory potential, revealing a new enhancer regulatory axis that controls myeloid differentiation. PMID- 30008317 TI - DNA Replication Determines Timing of Mitosis by Restricting CDK1 and PLK1 Activation. AB - To maintain genome stability, cells need to replicate their DNA before dividing. Upon completion of bulk DNA synthesis, the mitotic kinases CDK1 and PLK1 become active and drive entry into mitosis. Here, we have tested the hypothesis that DNA replication determines the timing of mitotic kinase activation. Using an optimized double-degron system, together with kinase inhibitors to enforce tight inhibition of key proteins, we find that human cells unable to initiate DNA replication prematurely enter mitosis. Preventing DNA replication licensing and/or firing causes prompt activation of CDK1 and PLK1 in S phase. In the presence of DNA replication, inhibition of CHK1 and p38 leads to premature activation of mitotic kinases, which induces severe replication stress. Our results demonstrate that, rather than merely a cell cycle output, DNA replication is an integral signaling component that restricts activation of mitotic kinases. DNA replication thus functions as a brake that determines cell cycle duration. PMID- 30008318 TI - S-Nitrosylation Targets GSNO Reductase for Selective Autophagy during Hypoxia Responses in Plants. AB - Nitric oxide (NO) regulates diverse cellular signaling through S-nitrosylation of specific Cys residues of target proteins. The intracellular level of S nitrosoglutathione (GSNO), a major bioactive NO species, is regulated by GSNO reductase (GSNOR), a highly conserved master regulator of NO signaling. However, little is known about how the activity of GSNOR is regulated. Here, we show that S-nitrosylation induces selective autophagy of Arabidopsis GSNOR1 during hypoxia responses. S-nitrosylation of GSNOR1 at Cys-10 induces conformational changes, exposing its AUTOPHAGY-RELATED8 (ATG8)-interacting motif (AIM) accessible by autophagy machinery. Upon binding by ATG8, GSNOR1 is recruited into the autophagosome and degraded in an AIM-dependent manner. Physiologically, the S nitrosylation-induced selective autophagy of GSNOR1 is relevant to hypoxia responses. Our discovery reveals a unique mechanism by which S-nitrosylation mediates selective autophagy of GSNOR1, thereby establishing a molecular link between NO signaling and autophagy. PMID- 30008320 TI - Polycomb-Dependent Chromatin Looping Contributes to Gene Silencing during Drosophila Development. AB - Interphase chromatin is organized into topologically associating domains (TADs). Within TADs, chromatin looping interactions are formed between DNA regulatory elements, but their functional importance for the establishment of the 3D genome organization and gene regulation during development is unclear. Using high resolution Hi-C experiments, we analyze higher order 3D chromatin organization during Drosophila embryogenesis and identify active and repressive chromatin loops that are established with different kinetics and depend on distinct factors: Zelda-dependent active loops are formed before the midblastula transition between transcribed genes over long distances. Repressive loops within polycomb domains are formed after the midblastula transition between polycomb response elements by the action of GAGA factor and polycomb proteins. Perturbation of PRE function by CRISPR/Cas9 genome engineering affects polycomb domain formation and destabilizes polycomb-mediated silencing. Preventing loop formation without removal of polycomb components also decreases silencing efficiency, suggesting that chromatin architecture can play instructive roles in gene regulation during development. VIDEO ABSTRACT. PMID- 30008319 TI - The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression. AB - Chromatin remodeling complexes play essential roles in metazoan development through widespread control of gene expression, but the precise molecular mechanisms by which they do this in vivo remain ill defined. Using an inducible system with fine temporal resolution, we show that the nucleosome remodeling and deacetylation (NuRD) complex controls chromatin architecture and the protein binding repertoire at regulatory regions during cell state transitions. This is primarily exerted through its nucleosome remodeling activity while deacetylation at H3K27 follows changes in gene expression. Additionally, NuRD activity influences association of RNA polymerase II at transcription start sites and subsequent nascent transcript production, thereby guiding the establishment of lineage-appropriate transcriptional programs. These findings provide a detailed molecular picture of genome-wide modulation of lineage-specific transcription by an essential chromatin remodeling complex as well as insight into the orchestration of molecular events involved in transcriptional transitions in vivo. VIDEO ABSTRACT. PMID- 30008322 TI - SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis. AB - YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis. PMID- 30008323 TI - EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation. AB - Human melanomas frequently harbor amplifications of EZH2. However, the contribution of EZH2 to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we show that EZH2 drives tumorigenesis from benign BrafV600E- or NrasQ61K-expressing melanocytes by silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma. Finally, we demonstrate that loss of cilia enhances pro-tumorigenic WNT/beta catenin signaling, and is itself sufficient to drive metastatic melanoma in benign cells. Thus, primary cilia deconstruction is a key process in EZH2-driven melanomagenesis. PMID- 30008324 TI - Low Cell-Matrix Adhesion Reveals Two Subtypes of Human Pluripotent Stem Cells. AB - We show that a human pluripotent stem cell (hPSC) population cultured on a low adhesion substrate developed two hPSC subtypes with different colony morphologies: flat and domed. Notably, the dome-like cells showed higher active proliferation capacity and increased several pluripotent genes' expression compared with the flat monolayer cells. We further demonstrated that cell-matrix adhesion mediates the interaction between cell morphology and expression of KLF4 and KLF5 through a serum response factor (SRF)-based regulatory double loop. Our results provide a mechanistic view on the coupling among adhesion, stem cell morphology, and pluripotency, shedding light on the critical role of cell-matrix adhesion in the induction and maintenance of hPSC. PMID- 30008325 TI - Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis. AB - The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) regulates cellular function in various cell types. Although the role of mTORC1 in skeletogenesis has been investigated previously, here we show a critical role of mTORC1/4E-BPs/SOX9 axis in regulating skeletogenesis through its expression in undifferentiated mesenchymal cells. Inactivation of Raptor, a component of mTORC1, in limb buds before mesenchymal condensations resulted in a marked loss of both cartilage and bone. Mechanistically, we demonstrated that mTORC1 selectively controls the RNA translation of Sox9, which harbors a 5' terminal oligopyrimidine tract motif, via inhibition of the 4E-BPs. Indeed, introduction of Sox9 or a knockdown of 4E-BP1/2 in undifferentiated mesenchymal cells markedly rescued the deficiency of the condensation observed in Raptor-deficient mice. Furthermore, introduction of the Sox9 transgene rescued phenotypes of deficient skeletal growth in Raptor-deficient mice. These findings highlight a critical role of mTORC1 in mammalian skeletogenesis, at least in part, through translational control of Sox9 RNA. PMID- 30008326 TI - CD90 Identifies Adventitial Mesenchymal Progenitor Cells in Adult Human Medium- and Large-Sized Arteries. AB - Mesenchymal stem cells (MSCs) reportedly exist in a vascular niche occupying the outer adventitial layer. However, these cells have not been well characterized in vivo in medium- and large-sized arteries in humans, and their potential pathological role is unknown. To address this, healthy and diseased arterial tissues were obtained as surplus surgical specimens and freshly processed. We identified that CD90 marks a rare adventitial population that co-expresses MSC markers including PDGFRalpha, CD44, CD73, and CD105. However, unlike CD90, these additional markers were widely expressed by other cells. Human adventitial CD90+ cells fulfilled standard MSC criteria, including plastic adherence, spindle morphology, passage ability, colony formation, and differentiation into adipocytes, osteoblasts, and chondrocytes. Phenotypic and transcriptomic profiling, as well as adoptive transfer experiments, revealed a potential role in vascular disease pathogenesis, with the transcriptomic disease signature of these cells being represented in an aortic regulatory gene network that is operative in atherosclerosis. PMID- 30008327 TI - A sisRNA/miRNA Axis Prevents Loss of Germline Stem Cells during Starvation in Drosophila. AB - Animal reproduction responds to nutritional status. During starvation, Drosophila and Caenorhabditis elegans enter a period of reproductive diapause with increase apoptosis, while maintaining a stable pool of germline stem cells (GSCs). How GSCs are protected is not understood. Here, we show that a sisRNA/miRNA axis maintains ovarian GSCs during starvation in Drosophila. Starvation induces the expression of an ovary-enriched sisRNA sisR-2, which negatively regulates GSC maintenance via a fatty acid metabolism gene dFAR1. sisR-2 promotes the expression of bantam, which in turn inhibits the activity of sisR-2, forming a negative feedback loop. Therefore, bantam acts as a buffer to counteract sisR-2 activity to prevent GSC loss during starvation. We propose that the sisR-2/bantam axis confers robustness to GSCs in Drosophila. PMID- 30008329 TI - Cheating on Cheaters Stabilizes Cooperation in Pseudomonas aeruginosa. AB - Bacterial cooperation can be disrupted by non-producers that can profit from public goods without paying their production cost. A cheater can increase in frequency, exhausting the public good and causing a population collapse. Here, we investigate how interactions among two cheaters for distinct social traits influence the short- and long-term dynamics of polymorphic populations. Using as a model Pseudomonas aeruginosa and its extensively studied social traits, production of the siderophore pyoverdine, and the quorum-sensing regulated elastase, we analyzed the social dynamics of polymorphic populations under conditions where the two traits are required for optimal growth. We show that cheaters for either trait compete with both the wild-type and each other and that mutants for pyoverdine production can prevent a drastic population collapse caused by quorum-sensing cheaters. A simple mathematical model suggests that the observed social dynamics are determined by the ratio of the costs of each social trait, such that the mutant, which avoids paying the highest cost, dominates the population; in contrast, mean fitness of the population is determined by the difference between the benefits and the costs of the social traits. Finally, we demonstrate how quorum-sensing regulation can avoid the full loss of cooperation. PMID- 30008328 TI - Suppressing Nodal Signaling Activity Predisposes Ectodermal Differentiation of Epiblast Stem Cells. AB - The molecular mechanism underpinning the specification of the ectoderm, a transient germ-layer tissue, during mouse gastrulation was examined here in a stem cell-based model. We captured a self-renewing cell population with enhanced ectoderm potency from mouse epiblast stem cells (EpiSCs) by suppressing Nodal signaling activity. The transcriptome of the Nodal-inhibited EpiSCs resembles that of the anterior epiblast of embryonic day (E)7.0 and E7.5 mouse embryo, which is accompanied by chromatin modifications that reflect the priming of ectoderm lineage-related genes for expression. Nodal-inhibited EpiSCs show enhanced ectoderm differentiation in vitro and contribute to the neuroectoderm and the surface ectoderm in postimplantation chimeras but lose the propensity for mesendoderm differentiation in vitro and in chimeras. Our findings show that specification of the ectoderm progenitors is enhanced by the repression of Nodal signaling activity, and the ectoderm-like stem cells provide an experimental model to investigate the molecular characters of the epiblast-derived ectoderm. PMID- 30008330 TI - Marked Diversity of Unique Cortical Enhancers Enables Neuron-Specific Tools by Enhancer-Driven Gene Expression. AB - Understanding neural circuit function requires individually addressing their component parts: specific neuronal cell types. However, not only do the precise genetic mechanisms specifying neuronal cell types remain obscure, access to these neuronal cell types by transgenic techniques also remains elusive. Whereas most genes are expressed in the brain, the vast majority are expressed in many different kinds of neurons, suggesting that promoters alone are not sufficiently specific to distinguish cell types. However, there are orders of magnitude more distal genetic cis-regulatory elements controlling transcription (i.e., enhancers), so we screened for enhancer activity in microdissected samples of mouse cortical subregions. This identified thousands of novel putative enhancers, many unique to particular cortical subregions. Pronuclear injection of expression constructs containing such region-specific enhancers resulted in transgenic lines driving expression in distinct sets of cells specifically in the targeted cortical subregions, even though the parent gene's promoter was relatively non specific. These data showcase the promise of utilizing the genetic mechanisms underlying the specification of diverse neuronal cell types for the development of genetic tools potentially capable of targeting any neuronal circuit of interest, an approach we call enhancer-driven gene expression (EDGE). PMID- 30008331 TI - Baculovirus Actin-Based Motility Drives Nuclear Envelope Disruption and Nuclear Egress. AB - Viruses that replicate in the host cell nucleus face challenges in usurping cellular pathways to enable passage through the nuclear envelope [1]. Baculoviruses are enveloped, double-stranded DNA viruses that infect lepidopteran insects and are tools for protein expression, cell transduction, and pest management [2-4]. The type species Autographa californica M nucleopolyhedrovirus (AcMNPV) shares with other pathogens an ability to assemble host actin monomers (G-actin) into actin filaments (F-actin) to drive motility [5]. During early infection, actin-based motility in the cytoplasm speeds AcMNPV transit to the nucleus and passage through nuclear pores, enabling nuclear ingress [6, 7]. During late infection, AcMNPV assembles F-actin within the nucleus [8], which is essential for virus production [9, 10]. However, the function of nuclear F-actin is poorly understood [11], and its mechanistic role in AcMNPV infection was unknown. We show that AcMNPV mobilizes actin within the nucleus to promote egress. AcMNPV nucleocapsids exhibit intranuclear actin-based motility, mediated by the viral protein P78/83 and the host Arp2/3 complex. Viral motility drives transit to the nuclear periphery and is required for viruses to enter protrusions of the nuclear envelope. Moreover, actin polymerization is necessary for viral disruption of nuclear envelope integrity during egress. In the cytoplasm, viruses use actin-based motility to reach the plasma membrane to enable budding. Our results demonstrate that pathogens can harness actin polymerization to disrupt the nuclear envelope. Employing actin for nuclear envelope disruption may reflect viral appropriation of normal functions of nuclear actin in nuclear envelope integrity, stability, and remodeling. PMID- 30008332 TI - Early African Fossils Elucidate the Origin of Embrithopod Mammals. AB - Modern mammals rapidly evolved in the early Cenozoic in all continental provinces, including in Africa, with one of the first placental branches, the Afrotheria [1, 2]. Afrotherian evolution is at the origin of the major radiation of African ungulate-like mammals, including extant hyrax, elephant, and sea cow orders, which all belong to the Paenungulata. The paenungulate radiation also includes the extinct order Embrithopoda of uncertain interordinal relationships, which is best known for the giant and strangely specialized Oligocene genus Arsinoitherium. The Ouled Abdoun basin, Morocco, yielded exceptional Paleocene Eocene fossils documenting the early paenungulate evolution [3-8]. Here we report two new small Ypresian species, Stylolophus minor n.g., n.sp. and cf. Stylolophus sp., which are the earliest and most primitive embrithopods. The cladistic analysis relates the Embrithopoda to crown paenungulates as the stem-group of the Tethytheria, which makes crown tethytherians restricted to extant elephant and sea cow orders. The Embrithopoda is therefore an early tethytherian offshoot predating the elephant and sea cow divergence. The resulting phylogeny supports a strictly African early radiation of the paenungulates excluding the Phenacolophidae and Anthracobunia. It sustains an at least early Paleocene African origin of the Embrithopoda. The unique tooth pattern of the embrithopods (hyperdilambdodont and pseudolophodont molars) is resolved as evolving early and directly from the dilambdodont (W-shaped labial molar crests) ancestral paenungulate morphotype. The specialized upper molar morphology with two transverse crests is convergent and non-homologous in embrithopods and crown Tethytheria. These convergences for specialized folivorous diet were driven by free herbivorous African niches in the early Paleogene. PMID- 30008334 TI - Tau Does Not Stabilize Axonal Microtubules but Rather Enables Them to Have Long Labile Domains. AB - It is widely believed that tau stabilizes microtubules in the axon [1-3] and, hence, that disease-induced loss of tau from axonal microtubules leads to their destabilization [3-5]. An individual microtubule in the axon has a stable domain and a labile domain [6-8]. We found that tau is more abundant on the labile domain, which is inconsistent with tau's proposed role as a microtubule stabilizer. When tau is experimentally depleted from cultured rat neurons, the labile microtubule mass of the axon drops considerably, the remaining labile microtubule mass becomes less labile, and the stable microtubule mass increases. MAP6 (also called stable tubule-only polypeptide), which is normally enriched on the stable domain [9], acquires a broader distribution across the microtubule when tau is depleted, providing a potential explanation for the increase in stable microtubule mass. When MAP6 is depleted, the labile microtubule mass becomes even more labile, indicating that, unlike tau, MAP6 is a genuine stabilizer of axonal microtubules. We conclude that tau is not a stabilizer of axonal microtubules but is enriched on the labile domain of the microtubule to promote its assembly while limiting the binding to it of genuine stabilizers, such as MAP6. This enables the labile domain to achieve great lengths without being stabilized. These conclusions are contrary to tau dogma. PMID- 30008333 TI - The Value of Ecosystem Services from Giant Panda Reserves. AB - Ecosystem services (the benefits to humans from ecosystems) are estimated globally at $125 trillion/year [1, 2]. Similar assessments at national and regional scales show how these services support our lives [3]. All valuations recognize the role of biodiversity, which continues to decrease around the world in maintaining these services [4, 5]. The giant panda epitomizes the flagship species [6]. Its unrivalled public appeal translates into support for conservation funding and policy, including a tax on foreign visitors to support its conservation [7]. The Chinese government has established a panda reserve system, which today numbers 67 reserves [8, 9]. The biodiversity of these reserves is among the highest in the temperate world [10], covering many of China's endemic species [11]. The panda is thus also an umbrella species [12] protecting panda habitat also protects other species. Despite the benefits derived from pandas, some journalists have suggested that it would be best to let the panda go extinct. With the recent downlisting of the panda from Endangered to Vulnerable, it is clear that society's investment has started to pay off in terms of panda population recovery [13, 14]. Here, we estimate the value of ecosystem services of the panda and its reserves at between US$2.6 and US$6.9 billion/year in 2010. Protecting the panda as an umbrella species and the habitat that supports it yields roughly 10-27 times the cost of maintaining the current reserves, potentially further motivating expansion of the reserves and other investments in natural capital in China. PMID- 30008335 TI - Benefits and costs of home pedometer assisted physical activity in patients with COPD. A preliminary randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: There are barriers to providing pulmonary rehabilitation for chronic obstructive pulmonary disease (COPD) such as the high number of patients, difficult access to health facilities and high costs of programs. Pedometers can monitor and improve physical activity (PA). The aim of this study was to evaluate benefits and costs of home pedometer assisted PA, as compared to a standard outpatient supervised exercise training program in patients with COPD. METHODS: Patients were randomly assigned either to home pedometer assisted PA (Group 1), or to a six-week outpatient standard supervised exercise training program (Group 2). Patients of Group 1 had to walk at home for 6 weeks, at least 30min daily at the fastest step pace as possible, to achieve a weekly 10% increase in their average daily steps up to more than 6500. Pre and post programs we assessed: the six minute walking distance (6MWT: primary outcome), daily steps count, the Medical Research Council scale (MRC), the COPD assessment test score, and the BODE index (body-mass index, airflow obstruction, dyspnea, exercise capacity). Costs of programs were also evaluated. RESULTS: Out of 40 patients, 18 in both groups (mean (standard deviation)) age: 68.3 (6.7) and 61.2 (6.7) years; FEV1: 1.1 (0.5) and 0.9 (0.4) liters in Group 1 and 2 respectively completed the study. At the end of the program 44.5% patients of Group 1 had reached the target daily steps, in 26.6 (9.5) days. Following the programs, both groups showed significant improvements in all outcome measures, except BODE. The home program was cheaper (p=0.0001), with a mean 76.3 euros saving per patient. CONCLUSION: Home pedometer assisted PA may be a useful and cheaper alternative to outpatient supervised exercise training programs in patients with COPD. PMID- 30008336 TI - Novel techniques to understand consumer responses towards food products: A review with a focus on meat. AB - Consumer evaluation has been used extensively over the past decades to evaluate acceptability and quality of food products. New methods have been developed to overcome some biases of traditional techniques. Testing with meat is challenging due to the high variability of the meat samples. This review outlines (a) the traditional consumer-based techniques for assessing food, and available methods to link consumer responses to sensory properties (b) qualitative measurements, (c) past and current methods for evaluating meat sensory characteristics and the development of the Meat Standard Australia (MSA) protocol, and (d) psychological and physiological factors affecting consumers. Conclusions from this review are: (1) Traditional consumer testing provides important information regarding acceptability but may miss important unconscious responses of consumers (2) Qualitative methods can obtain more holistic responses from consumers, (3) The Meat Standard Australia (MSA) protocol delivers consistent scores of meat's juiciness/tenderness/flavour and overall acceptability from consumers, and (4) Physiological responses may help to understand the unbiased emotions of consumers. PMID- 30008337 TI - Factors affecting lamb eating quality and the potential for their integration into an MSA sheepmeat grading model. AB - Major efforts in the sheep industry to control eating quality have resulted in reduced product variability. Yet inconsistent eating quality for consumers remains, due to a degree of inaccurate representation of cut quality. Eating quality defined through a complex interplay of different factors can be predicted for individual cuts, and Meat Standards Australia (MSA) grading schemes have been developed to achieve these defined quality outcomes. This review outlines the justifications to refine the current sheepmeat MSA pathways system to transition into a cuts-based prediction model and details some of the factors affecting sheepmeat eating quality as key factors under consideration into the new model. The development of the new sheepmeat MSA prediction model will allow for more efficient carcass sorting to underpin a value based payment system throughout the supply chain. However it requires the inclusion of individual carcass yield and eating quality measurements (i.e. IMF). Furthermore, the adoption challenges internationally of an MSA like model are discussed. PMID- 30008338 TI - Calibration of an on-line dual energy X-ray absorptiometer for estimating carcase composition in lamb at abattoir chain-speed. AB - This experiment assessed the ability of an on-line dual energy x-ray absorptiometer (DEXA) installed at a commercial abattoir to determine carcase composition at abattoir chain-speed. 607 lamb carcases from 7 slaughter groups were DEXA scanned and then scanned using computed tomography to determine the proportions of fat (CT fat%), lean (CT lean%), and bone (CT bone%). Data between slaughter groups were standardised relative to a synthetic phantom consisting of Nylon-6. Models were then trained within each dataset using hot carcase weight and DEXA value to predict CT composition, and then validated in the remaining datasets. Results from across-dataset validation tests demonstrated excellent precision for predicting CT fat%, with RMSE and R2 values of 1.32 and 0.89, compared to values of 1.69 and 0.69 for CT lean%, and 0.81 and 0.68 for CT bone% which had less precision. Accuracy across datasets was also robust, with average bias values of 0.66, 0.83, and 0.51 for CT fat%, lean%, and bone%. PMID- 30008339 TI - Why seemingly more difficult test conditions produce more accurate recognition of semantic prototype words: A recognition memory paradox? AB - Subjects studied Deese-Roediger-McDermott semantic-associate lists and took a recognition test. The makeup and number of test probes were manipulated. In Experiments 1 and 2A, one of three or all three distractors were semantically related to the list theme. In Experiment 2B, 6 or 30 related probes were used at test. Results showed that semantically related distractors and a longer list of test words both had a beneficial effect on the accurate discrimination of the prototype lures from the studied semantic associates and on the discrimination of studied from unstudied prototype words. These findings are inconsistent with predictions of memory interference and activation theories. We propose that the counterintuitive findings can be explained by the notion of old/new recognition as categorization learning and that relatedness and a larger number of test probes provide more accurate information about the prototype lure as a distractor, thereby improving its classification as a distractor. PMID- 30008340 TI - The Efficacy of Pharmacologic Treatment of Temporomandibular Disorders. AB - This is not a pharmacopeia offering directions for choosing the proper pain medication for treating temporomandibular disorders. Rather, the appropriate decision depends on proper diagnosis, an understanding of the pain mechanisms involved, and the different targets for analgesic action. This article discusses these issues and evaluates the various drugs involved. It also describes potential reasons for therapeutic failure. PMID- 30008341 TI - The Use of Botulinum Toxin for the Treatment of Myofascial Pain in the Masticatory Muscles. AB - Although the use of botulinum toxin has been recommended for the management of myofascial pain and dysfunction, the precise mechanism of its action remains undetermined and studies on its effectiveness are equivocal. Moreover, even if such treatment may temporarily relieve the symptoms, it does not address the cause of the problem. Also, its use is not free of potential complications. On this basis, botulinum toxin does not seem to be a logical treatment of myofascial pain and dysfunction. PMID- 30008342 TI - Surgical Versus Nonsurgical Management of Degenerative Joint Disease. AB - As knowledge of the complexity of myofascial pain and its interaction with temporomandibular joint disorders has increased, the use of surgical procedures to treat degenerative joint disease has decreased. The focus has moved from a "surgery-first" approach toward a more cautious one that involves nonsurgical treatment as the primary modality, then minimally invasive treatments, followed by open surgical modalities, when indicated. This article examines the current literature regarding the effectiveness of nonsurgical and surgical treatments for the management of degenerative joint disease. PMID- 30008343 TI - Costochondral Graft Versus Total Alloplastic Joint for Temporomandibular Joint Reconstruction. AB - Presently, there are 2 options for the replacement of the temporomandibular joint for end-stage pathology: autogenous bone grafting or alloplastic joint replacement. This article presents evidence-based advantages and disadvantages for each of these management options to assist both surgeons and their patients in making that choice. PMID- 30008344 TI - Surgical Management of Idiopathic Condylar Resorption: Orthognathic Surgery Versus Temporomandibular Total Joint Replacement. AB - Young females with retruded and hyperdivergent mandibles, class II openbite malocclusions, and steep occlusal planes with or without TMJ symptoms are at higher risk for Idiopathic Condylar Resorption (ICR). Such patients undergoing orthodontic and /or surgical treatment should be informed of possible relapse due to ICR. Orthognathic Surgery with Total joint replacement or Orthognathic surgery alone may both be acceptable options for management of the facial deformity and the malocclusion that ensues from ICR. Proper patient selection is key to achieving a successful outcome. Current trends and the evidence in the literature suggest that orthognathic surgery with alloplastic joint replacement may be the preferred approach. PMID- 30008345 TI - Introduction. PMID- 30008346 TI - Current Controversies in the Management of Temporomandibular Disorders. PMID- 30008347 TI - PAMAM dendrimer - cell membrane interactions. AB - PAMAM dendrimers have been conjectured for a wide range of biomedical applications due to their tuneable physicochemical properties. However, their application has been hindered by uncertainties in their cytotoxicity, which is influenced by dendrimer generation (i.e. size and surface group density), surface chemistry, and dosage, as well as cell specificity. In this review, biomedical applications of polyamidoamine (PAMAM) dendrimers and some related cytotoxicity studies are first outlined. Alongside these in vitro experiments, lipid membranes such as supported lipid bilayers (SLBs), liposomes, and Langmuir monolayers have been used as cell membrane models to study PAMAM dendrimer-membrane interactions. Related experimental and theoretical studies are summarized, and the physical insights from these studies are discussed to shed light on the fundamental understanding of PAMAM dendrimer-cell membrane interactions. We conclude with a summary of some questions that call for further investigations. PMID- 30008348 TI - ADRIFT in the North Pacific: The movement, surveillance, and impact of Japanese tsunami debris. PMID- 30008349 TI - An Interview with Thomas H. Gallagher. PMID- 30008350 TI - We Will Not Compete on Safety: How Children's Hospitals Have Come Together to Hasten Harm Reduction. AB - BACKGROUND: Launched in 2012, the Children's Hospitals' Solutions for Patient Safety (SPS) Network is a collaborative of children's hospitals in the United States and Canada working together to eliminate patient and employee/staff harm across all children's hospitals. METHODS: The SPS Network, which has grown from 8 to 137 hospitals, has a foundation of leadership engagement, noncompetition, data driven learning, attention to safety culture, family engagement, and transparency. The SPS Leadership Group, which consists of more than 150 leaders from participating hospitals, forms condition-specific teams to promote the reduction of hospital-acquired harm in a phased design that includes an ongoing focus on both process improvement and safety culture enhancements. Hospital leaders are engaged through monthly reports, executive webinars, in-person meetings, and biannual training opportunities for boards of trustees. SPS has developed extensive opportunities for learning collaboration, including in-person networkwide learning sessions, regional meetings, general and condition-specific webinars, communications, and a shared website. RESULTS: Over time, the portfolio has expanded as SPS has achieved harm reduction targets for some conditions and begun work to reduce harm in other, previously unaddressed areas. In 2017 SPS reported a 9%-71% reduction in eight harm conditions by an initial cohort of 33 hospitals. SPS estimates that more than 9,000 children have been spared harm since 2012, with $148.5 million in health care spending avoided. CONCLUSION: Participation in the SPS Network has been associated with improved safety in children's hospitals. Widespread participation in this or similar collaborations has the potential to dramatically decrease harm to patients, employees, and staff. PMID- 30008351 TI - National Quality Program Achieves Improvements in Safety Culture and Reduction in Preventable Harms in Community Hospitals. AB - BACKGROUND: Through an innovative affiliation, Duke University Health System (DUHS), a large and complex academic health system, and LifePoint Health(r) (LifePoint [LP]) collaborated to create a joint venture, DLP Healthcare (DLP) to measurably improve culture and quality and patient safety metrics in community hospitals across the United States. A structured approach to quality was developed in DLP hospitals and later refined and spread to all LP hospitals through the National Quality Program (NQP). METHODS: The NQP was designed to drive organizationwide performance improvement through use of a framework of leadership, performance improvement, and culture. A comprehensive quality assessment of each DLP and LP hospital led to the creation of a customized improvement plan that was specific to the performance level of individual hospitals and aligned with strategic organizational goals. The improvement process was data driven, managed with defined improvement methodologies and practices, and implemented in a culture that honors teamwork, mutual respect, accountability and provider well-being. RESULTS: Implementation of the NQP has led to significant improvements in patient safety metrics and in safety culture, which have now been sustained for more than seven years. Aggregate harm, as measured by administrative claims data-based harms per 1,000 inpatient-days, was reduced by 62.5% between January 2011 and December 2017, as compared to 2010 baseline data. CONCLUSION: The LP and Duke journey to achieve high reliability in community hospitals has yielded significant improvement in measures of patient safety and culture. The results are consistent with literature supporting the link between culture and overall performance. PMID- 30008352 TI - A Lean Six Sigma Quality Improvement Project Improves Timeliness of Discharge from the Hospital. AB - BACKGROUND: Hospital overcrowding has become a widespread problem, with constrained bed capacity and admission bottlenecks having far-reaching negative impacts on quality and safety. Focus on timing of discharge may be the least disruptive and most effective way to address constrained bed capacity, yet there may be significant institution-specific barriers to implementation. METHODS: With the creation of a "Value Team," a 627-bed, tertiary care academic medical center embarked on a quality improvement (QI) project using Lean Six Sigma process improvement methodology. After defining the problems around timeliness of discharge, the team went through the steps in the Define, Measure, Analyze, Improve, Control (DMAIC) framework. Interventions, which were implemented on the basis of an in-depth analysis of barriers to the discharge process, included geographic cohorts of internal medicine physicians on specific hospital units and multidisciplinary huddles one day before anticipated discharge. RESULTS: After accounting for the concurrent trends in the control group, the percentage of discharge orders released by 10:00 a.m. increased by 21.3 points (p < 0.001; adjusted odds ratio [OR] = 2.62; 95% confidence interval [CI] = 1.91-3.59), and the percentage of patients discharged by noon increased by 7.5 points (p = 0.001; adjusted OR = 1.70; 95% CI 1.15-2.51). There were no significant changes in the 30-day readmission rate or length of stay. CONCLUSION: A QI program shaped by Lean Six Sigma principles and reinforced by clinician huddles and geographic cohorting was associated with earlier posting of discharge orders and physical discharge by noon. PMID- 30008353 TI - A Conceptual Framework to Reduce Inpatient Preventable Deaths. AB - BACKGROUND: Efforts to reduce preventable deaths in the in-hospital setting should target both cardiopulmonary arrest (CPA) prevention and optimal resuscitation. This requires consideration of a broad range of clinical issues and processes. A comprehensive, integrated system of care (SOC) that links data collection with a modular education program to reduce preventable deaths has not been defined. METHODS: This study was conducted in two urban university hospitals from 2005 to 2009. The Advanced Resuscitation Training (ART) program was implemented in 2007, incorporating hands-on resuscitative skills and in-hospital specific training with an institutional resuscitation database. Linkage between the database and training modules occurs via the ART Matrix, which classifies all CPA events into the following etiologies: sepsis, hemorrhage, pulmonary embolus, heart failure, tachyarrhythmias, bradyarrhythmias, acute respiratory distress syndrome, non-intubated pulmonary disease, obstructive apnea, traumatic brain injury, ischemic brain injury, and intracranial mass lesions. This taxonomy was validated using descriptive statistics, before-and-after analysis evaluating CPA incidence, and multivariate logistic regression to predict CPA survival. RESULTS: A total of 336 inpatients suffered a cardiopulmonary arrest during the study period-187 in the pre-ART period and 149 in the post-ART period. The vast majority of CPA events were categorized using the ART Matrix with high inter observer reliability. As anticipated, changes in CPA incidence and survival were observed for some Matrix categories but not others following ART implementation. In addition, multivariate logistic regression revealed strong independent associations between taxonomy classifications and outcome. CONCLUSION: A novel SOC using a unique taxonomy for arrest classification appears to be effective at reducing inpatient CPA incidence and outcome. PMID- 30008354 TI - Emotional Harm Following Incidents in Health Care: What Can Researchers Do? PMID- 30008356 TI - ? PMID- 30008355 TI - A Multi-Stakeholder Consensus-Driven Research Agenda for Better Understanding and Supporting the Emotional Impact of Harmful Events on Patients and Families. AB - BACKGROUND: The nature and consequences of patient and family emotional harm stemming from preventable medical error, such as losing a loved one or surviving serious medical injury, is poorly understood. Patients and families, clinicians, social scientists, lawyers, and foundation/policy leaders were brought together to establish research priorities for this issue. METHODS: A one-day conference of diverse stakeholder groups to establish a consensus-driven research agenda focused on (1) priorities for research on the short-term and long-term emotional impact of harmful events on patients and families, (2) barriers and enablers to conducting such research, and (3) actionable steps toward better supporting harmed patients and families now. RESULTS: Stakeholders discussed patient and family experiences after serious harmful events, including profound isolation, psychological distress, damaging aspects of medical culture, health care aversion, and negative effects on communities. Stakeholder groups reached consensus, defining four research priorities: (1) Establish conceptual framework and patient-centered taxonomy of harm and healing; (2) Describe epidemiology of emotional harm; (3) Determine how to make emotional harm and long-term impacts visible to health care organizations and society at large; and (4) Develop and implement best practices for emotional support of patients and families. The group also created a strategy for overcoming research barriers and actionable "Do Now" approaches to improve the patient and family experience while research is ongoing. CONCLUSION: Emotional and other long-term impacts of harmful events can have profound consequences for patients and families. Stakeholders designed a path forward to inform approaches that better support harmed patients and families, with both immediately actionable and longer-term research strategies. PMID- 30008357 TI - [Factors in the occurrence of medication errors and the use of order sets]. AB - The packaging of the medication and the writing on the label can be the cause of medication errors. Errors in the intake of sodium chloride and potassium chloride have notably been due to the fact that the label of the infusion solute did not explicitly indicate the quantities present in the 500 mL and 1 000 mL bottles. Moreover, the meaning of the description comprising the term 'q.s.p. 1 000 mL' was not known by some of the nursing staff. These two factors, combined with the possibility of prescribing predefined order sets, have led to medication errors which have given rise to a study of how practices can be improved. PMID- 30008358 TI - ? PMID- 30008359 TI - [Post-colonial countertransference, a Brazilian experience]. AB - A team of caregivers travelled to the favelas of a Brazilian province. They were subjected to emotionally charged situations, working with people faced with extreme poverty and poor health. They highlight a cultural countertransference requiring an objective approach to the psychological and political repercussions of these situations. PMID- 30008360 TI - [Psychological vulnerability of teams working with displaced Syrians in Lebanon]. AB - In the context of the humanitarian crisis of Syrian refugees in Lebanon, a team of young Lebanese social workers attempted to identify the most economically vulnerable people. These professionals have themselves sometimes been exposed to social and economic difficulties, having in their own past experienced war and deprivation. They were confronted with experiences of war, poverty, inter community conflicts, the recollection of their own family trauma or guilt. Support in the form of psychological care was provided to them. PMID- 30008361 TI - [Countertransference with mother-baby dyads in a context of multiple traumas]. AB - The encounter of mother-baby dyads in a context of a traumatic narrative renders the areas of transference and countertransference more complex, with multiple identification processes. What are the implications regarding the transmission of trauma to the child and how does it occur? The clinical case of a mother, with a past fraught with challenges and traumas, illustrates a way of accessing a child's experience of trauma via the clinician's countertransference. PMID- 30008362 TI - [Impact of trauma on suicide prevention helpline operators]. AB - Based on the clinical experience acquired with suicide prevention helplines, it is possible to examine how the clinician experiences the interaction. Taking into account certain aspects of the caller-operator relationship is indeed essential for the improvement of this psychological support. PMID- 30008363 TI - [Countertransference reactions faced with traumatised mothers and their babies in Central Africa]. AB - In Central Africa, a team of psychosocial workers provides psychological support to traumatised mothers and their babies. They experience significant countertransferences, particularly when patients' accounts remind them of traumatic events they themselves have lived through. The emotions and the intensity felt by the team demonstrate the need for specific supervision in this context. PMID- 30008364 TI - [Benefit of the group for supporting a traumatised mother-baby dyad]. AB - Research has been carried out to explore the countertransference reactions of a group of therapists faced with a mother having experienced traumatic events and her baby. The study highlights the potential advantages of a group setting for supporting these dyads. PMID- 30008367 TI - Woman and Birth (June 2018). PMID- 30008365 TI - [Impact of the trauma of refugees of war on mental health workers]. AB - As part of a research project aiming to measure the psychological impact of humanitarian intervention in the wars affecting the Middle East, 28 humanitarian players working with refugees and displaced people took part in semi-structured qualitative interviews. The material was analysed using the interpretative phenomenological approach. The results show indications of transmission of the trauma when issues of identity and a sense of belonging are involved, psychosomatic manifestations as well as complex transference-countertransference relationships. PMID- 30008366 TI - ? PMID- 30008368 TI - Reduced axonal surface expression and phosphoinositide sensitivity in Kv7 channels disrupts their function to inhibit neuronal excitability in Kcnq2 epileptic encephalopathy. AB - Neuronal Kv7/KCNQ channels are voltage-gated potassium channels composed of Kv7.2/KCNQ2 and Kv7.3/KCNQ3 subunits. Enriched at the axonal membrane, they potently suppress neuronal excitability. De novo and inherited dominant mutations in Kv7.2 cause early onset epileptic encephalopathy characterized by drug resistant seizures and profound psychomotor delay. However, their precise pathogenic mechanisms remain elusive. Here, we investigated selected epileptic encephalopathy causing mutations in calmodulin (CaM)-binding helices A and B of Kv7.2. We discovered that R333W, K526N, and R532W mutations located peripheral to CaM contact sites decreased axonal surface expression of heteromeric channels although only R333W mutation reduced CaM binding to Kv7.2. These mutations also altered gating modulation by phosphatidylinositol 4,5-bisphosphate (PIP2), revealing novel PIP2 binding residues. While these mutations disrupted Kv7 function to suppress excitability, hyperexcitability was observed in neurons expressing Kv7.2-R532W that displayed severe impairment in voltage-dependent activation. The M518 V mutation at the CaM contact site in helix B caused most defects in Kv7 channels by severely reducing their CaM binding, K+ currents, and axonal surface expression. Interestingly, the M518 V mutation induced ubiquitination and accelerated proteasome-dependent degradation of Kv7.2, whereas the presence of Kv7.3 blocked this degradation. Furthermore, expression of Kv7.2 M518V increased neuronal death. Together, our results demonstrate that epileptic encephalopathy mutations in helices A and B of Kv7.2 cause abnormal Kv7 expression and function by disrupting Kv7.2 binding to CaM and/or modulation by PIP2. We propose that such multiple Kv7 channel defects could exert more severe impacts on neuronal excitability and health, and thus serve as pathogenic mechanisms underlying Kcnq2 epileptic encephalopathy. PMID- 30008369 TI - Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer. AB - Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit efficient anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for injections or clinician intervention. In this study, the NDES was used to deliver immunotherapeutics intratumorally in the 4 T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti tumor immune response and inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors. PMID- 30008370 TI - A gel system for single instillation of non-muscle-invasive bladder Cancer: A "divide-and-rule" strategy. AB - Single instillation (SI) reduces recurrence of non-muscle-invasive bladder cancer by chemoresecting floating tumor cells and residual tumor lesions (RTLs) after transurethral resection of the bladder, but with limited efficacy. Current studies improved this by prolonging retention time and increasing penetration to bladder wall, ignoring that the two separate factors should be treated in different ways. Here, we introduced a smart gel system-based SI to prevent re implantation of tumor cells (RTCs) and ablate RTLs in a "divide-and-rule" approach. The gel system was synthesized by PEG-PAMAM and dextran aldehyde and composed of gold nanorods and gemcitabine for photothermal therapy and chemotherapy, respectively. It was developed to provide dextran aldehyde selective adhesion with tissue amines. Since tumor surface expressed high levels of collagen, the exposed amines could act as adhesion points for the gel system. Thus, the gel presented more affinity to tumor tissues. When being instilled, it could form a protective layer on the inner face of the entire bladder wall immediately, preventing RTCs in early time. And it persisted long at the tumor site, ablating RTLs. Our data proved the gel system improved intravesical treatment efficacy in a "divide-and-rule" approach and might be a promising treatment strategy for SI. PMID- 30008371 TI - Combinatory therapy adopting nanoparticle-based cancer vaccination with immune checkpoint blockade for treatment of post-surgical tumor recurrences. AB - Cancer immunotherapy is emerging as a candidate treatment modality for treating post-surgical metastasis and recurrences. Despite the great promises with therapeutic cancer vaccines and checkpoint blocking antibodies in pre-clinical studies, response rates in the clinic still remain unsatisfactory. The evaluation of immunotherapy after surgery in patients could confront significant unexpected hurdles. Surgery itself tends to cause immune suppression, while wound healing factors also stimulate tumor cell outgrowth and metastasis. Regarding the marked changes in the post-surgical tumor microenvironment, one can anticipate that better tumor growth control is attainable by combining cancer vaccines with immune checkpoint blockade. However, it is important that vaccines and checkpoint blocking antibodies are delivered efficiently to their target cells, are released sustained and locally and do not induce cytotoxic effects. The generation of effective anti-tumor immunity and durable response rates could largely depend on these parameters. In the last decade, researchers spend tremendous effort in optimizing the delivery of immunotherapeutic compounds with the use of nanomedicine. Biocompatible nanoparticle based delivery systems demonstrated intriguing results with regard to specific immune cell activation, improved drug delivery, cell targeting, limiting off target toxicity and improving treatment outcome. It therefore makes sense, to speculate on the promises of combined cancer vaccination and immune checkpoint blocking immunotherapy with the aid of nanomedicine. A powerful nanoparticle combination immunotherapy conferring durable therapeutic benefit whilst leaving healthy tissue untouched represents the base for more efficient post-surgical cancer treatment. PMID- 30008372 TI - Targeting of drug-loaded nanoparticles to tumor sites increases cell death and release of danger signals. PMID- 30008373 TI - Potential use of polymers and their complexes as media for storage and delivery of fragrances. AB - The use of fragrances is often essential to create an elegant, welcoming, or exhilarating environment. Through encapsulation, the release and delivery of fragrances are customized in many consumer products. For such purposes, cost effective techniques have been developed and employed with the use of various polymers and porous organic materials to efficiently impart fragrances to foods and various other consumer products. After entrapment or uptake/storage of fragrant molecules within a polymeric complex, the properties can be investigated by automated thermal desorption (ATD) analysis. For efficient delivery, fragrances are adsorbed (or entrapped) in some media (e.g., fabric or paper). The release of such entrapped fragrances usually is achieved by spraying. Fragrances can be also loaded in a media by purging aroma gases or by adding fragrance essence directly into a liquid medium. Porous materials, such as zeolites, have been traditionally used for air purification as well as in cosmetics and similar applications. Similarly, other polymeric porous complexes have also been used in fragrance delivery as a templating agent for aromatherapy textiles. Such polymeric materials offer an advantage in terms of development of new hybrid blends via homogenous mixing of two or more matrices. Such blends may possess different desirable physical properties as encapsulants. This review article is aimed at presenting an overview of polymers and their complexes as the main media of fragrance encapsulation. This study also discusses the expansion and future application of porous materials as host matrices for fragrances. PMID- 30008375 TI - Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats. AB - Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves. PMID- 30008374 TI - In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-beta. AB - Fibrosis is a pathophysiological state characterized by the excessive formation/deposition of fibrous extracellular matrix. Transforming growth factor beta (TGF-beta) is a central profibrotic mediator, and targeting TGF-beta is a promising strategy in the development of drugs for the treatment of fibrosis. Therefore, the effect of LY2109761, a small molecule inhibitor against TGF-beta with targets beyond TGF-beta signaling, on fibrogenesis was elucidated in vitro (HepG2 cells and LX-2 cells) and ex vivo (human and rat precision-cut liver slices). Our results displayed an anti-fibrotic effect of LY2109761, as it markedly down-regulated gene and protein expression of collagen type 1, as well as gene expression of the inhibitor of metalloproteinases 1. This effect on fibrosis markers was partially mediated by targeting TGF-beta signaling, seeing that LY2109761 inhibited TGF-beta1 gene expression and SMAD2 protein phosphorylation. Interestingly, particularly at a high concentration, LY2109761 decreased SMAD1 protein phosphorylation and gene expression of the inhibitor of DNA binding 1, which appeared to be TGF-beta-independent effects. In conclusion, LY2109761 exhibited preclinical anti-fibrotic effects via both TGF-beta-dependent and -independent pathways. These results illustrate that small molecule inhibitors directed against TGF-beta could possibly influence numerous signaling pathways and thereby mitigate fibrogenesis. PMID- 30008376 TI - Stabilization of the hypoxia-inducible transcription Factor-1 alpha (HIF-1alpha) in thiamine deficiency is mediated by pyruvate accumulation. AB - Vitamin B1, or thiamine is a critical enzyme cofactor required for metabolic function and energy production. Thiamine deficiency (TD) is common in various diseases, and results in severe neurological complications due to diminished mitochondrial function, oxidative stress, excitotoxicity and inflammation. These pathological sequelae result in apoptotic cell death in both neurons and astrocytes in distinct regions, in particular the thalamus and mammillary bodies. Comparable histological injuries in patients with hypoxia/ischemia (H/I) have also been described, suggesting a congruency between the cellular responses to these stresses. Analogous to H/I, TD stabilizes and activates Hypoxia Inducible Factor-1alpha (HIF-1alpha) even without changes in physiological oxygen levels. However, the mechanism of HIF-1alpha stabilization in TD is currently unknown. Using a pyruvate assay, we have demonstrated that TD induces pyruvate accumulation in mouse primary astrocytes which correlates to an increase in HIF 1alpha expression. Additionally, we utilized an enzymatic assay for pyruvate dehydrogenase to demonstrate a reduction in catalytic activity during TD due to lack of available thiamine pyrophosphate cofactor, resulting in the observed pyruvate accumulation. Finally, a pyruvate kinase inhibitor which limited pyruvate accumulation was utilized to demonstrate the role of pyruvate accumulation in HIF-1alpha stabilization during TD. These results reveal that stabilization of HIF-1alpha protein in TD centralizes on pyruvate accumulation in mouse primary astrocytes due to metabolic disruption of PDH. PMID- 30008377 TI - Microbiome-related metabolite changes in gut tissue, cecum content and feces of rats treated with antibiotics. AB - The metabolic functionality of the gut microbiota contributes to the metabolism and well-being of its host, although detailed insight in the microbiota's metabolism is lacking. Omics technologies could facilitate unraveling metabolism by the gut microbiota. In this study, we performed metabolite profiling of different matrices of the gut, after antibiotic treatment of rats in order to evaluate metabolite changes observed at different dose levels and in different sexes, and to identify the best tissue matrix for further investigations regarding an assessment of metabolic effects of new compounds with antibiotic activity. Three different antibiotics (vancomycin, streptomycin and roxithromycin) were administered orally to rats for 28 days according to the OECD 407 guideline with a subsequent metabolic profiling in feces, cecum content and gut tissue (jejunum, ileum, cecum, colon and rectum). The data were analyzed in the MetaMap(r)Tox database. Treatment-related effects could be observed in the metabolite profile of feces and cecum content, but not of the different gut tissues. The metabolite profile showed compound specific effects on the microbiome. In line with the activity spectra of the antibiotics tested, vancomycin showed the largest effects, followed by roxithromycin and then by streptomycin for which changes were modest. In general, for all antibiotics the largest changes were observed for the classes of lipids (increase up to 94-fold), bile acids (increase up to 33-fold), amino acids (increase up to 200-fold) and amino acid related (increase up to 348-fold). The most relevant changes in metabolite values were similar in feces and cecum content and among sexes. The results of this targeted analysis indicate that the metabolic profiles of male and female animals in the gut microbiome are comparable. Concluding, taking other samples than feces does not add any extra information. Thus, as a non-invasive sampling method, feces provide a suitable matrix for studies on metabolism by the gut microbiota. PMID- 30008378 TI - Investigation on the relationship between critical body residue and bioconcentration in zebrafish based on bio-uptake kinetics for five nitro aromatics. AB - It is well known that the critical body residue (CBR) can be estimated via bioconcentration factor (BCF). However, the relationship between CBR and BCF in zebrafish has not been carried out based on bio-uptake kinetics for nitro aromatics. In this paper, the time-variable concentrations and CBRs in zebrafish were determined for five nitro substituted benzenes. The result shows that CBR values can well be calculated from the BCF and external critical concentrations (LC50). Although CBRs measured from 5 h exposure period are greater than the CBRs obtained from 96 h for the five nitro-aromatics, no significant difference was observed, indicating that the CBR approach is a truer measure of chemical levels in exposed organisms and an ideal indicator to reflect the toxicity of a chemical. The bio-uptake can well be described by first-order kinetics and reach steady-state within 48 h. Almost same BCF values are obtained from the ratio of concentration in the fish (Cf) and in the water (Cw) at apparent steady-state and the ratio of the rate constants of uptake (k1) and depuration (k2) assuming first order kinetics. The toxicity ratio (TR) can reflect the difference of internal critical concentrations and be used to identify mode of action. PMID- 30008379 TI - Determination of chidamide in rat plasma and cerebrospinal fluid. AB - Chidamide is a new subtype-selective histone deacetylase inhibitor (HDACi), which has been approved for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in China. However, there are few studies about the application of chidamide in PTCL with central nervous system (CNS) involvement. It is essential to investigate the penetration of chidamide in the blood brain barrier (BBB). LC MS methods were established firstly to determine the concentration of chidamide in rat plasma and CSF. Then five rats were anaesthetized and the plasma and CSF samples were collected at the time of 5, 15, 30, 60, 120, 180, 240, 360 and 480 min after being administered 1 mg/kg chidamide by intravenous injection, respectively. All samples were analyzed with the established LC-MS method by using the precursor/product transitions (m/z) of 391.1/265.1 for chidamide and 441.1/138.2 for internal standard (IS). The PK parameters were calculated after both of the concentrations of chidamide in plasma and CSF were determined. The penetration ratio of chidamide in BBB ranged from 0.19% to 0.67%. Result indicated chidamide could pass through the BBB, enter into the CNS and have the potential to be utilized in PTCL with CNS involvement. PMID- 30008381 TI - Bilaterally prolonged latencies of pain-related evoked potentials in peripheral nerve injuries. AB - OBJECTIVE: Cross-sectional study to test the applicability of pain-related evoked potentials (PREP) for the diagnosis of peripheral nerve injuries (PNI). INTRODUCTION: Patients with generalized polyneuropathies show prolonged latencies and decreased amplitudes of PREP indicating an impairment of A-delta fibers. Although these fibers are frequently affected in PNI, it is unclear, if PREP testing detects PNI comparable to Nerve Conduction Studies (NCS). METHODS: 23 patients with PNI of one upper limb underwent bilateral PREP-testing (using concentric surface electrodes) and NCS. 41 healthy controls underwent PREP testing only. We determined pain thresholds, N1-latencies and N1P1-amplitudes of PREP and analyzed them for group and side-to-side differences. Small-fiber function was evaluated using thermal detection thresholds of Quantitative Sensory Testing (QST). N1-latencies above a cut-off calculated by ROC-analysis were defined as abnormal in order to compare detection rates of PREP and NCS. RESULTS: Patients with PNI showed bilaterally prolonged N1-latencies (ipsilateral: 167.0 +/- 40.7 ms vs. 141.2 +/- 20.5 ms / contralateral: 160.0 +/- 41.0 ms vs. 140.2 +/ 23.9 ms) without a significant side-to-side difference. Pain thresholds were increased on the affected side only (4.6 +/- 5.2 mA vs. 2.4 +/- 1.4 mA (controls)). N1P1-amplitudes did not differ between patients and controls. 7 (32%) patients showed prolonged N1-latencies (>176 ms) of PREP. NCS were abnormal in 16 (73%) cases. 13 (59%) patients showed thermal hypoesthesia in QST. CONCLUSION: Contrary to our expectations, we found bilaterally prolonged N1 latencies and normal N1P1-amplitudes in patients with PNI. Our findings support the hypothesis of a bilateral generation of PREP and indicate that PREP are not suitable for the diagnosis of PNI. PMID- 30008380 TI - The effect of bilateral low-frequency rTMS over dorsolateral prefrontal cortex on serum brain-derived neurotropic factor and serotonin in patients with generalized anxiety disorder. AB - To investigate the effect of bilateral low-frequency repetitive transcranial magnetic stimulation (rTMS) over dorsolateral prefrontal cortex on serum brain derived neurotropic factor (BDNF) and serotonin (5-HT) in patients with generalized anxiety disorders (GAD). As compared with before treatment, the HARS score in patients markedly decreased after treatment, and the levels of serum BDNF and 5-HT were significantly higher. Pearson correlation analysis revealed that the increase in the level of serum 5-HT was positively associated with the increase of the level of serum BDNF, and the change of anxiety score was negatively associated with the change of the level of serum BDNF and 5-HT. The results suggested that alleviation of GAD by bilateral low-frequency rTMS may be involved in the increase of the level of BDNF and the release of 5-HT in the brain. PMID- 30008382 TI - Enhanced biodegradation of sediment-bound heavily weathered crude oil with ligninolytic enzymes encapsulated in calcium-alginate beads. AB - The degradation of crude and weathered crude oil following the application of crude and calcium-alginate encapsulated ligninolytic enzymes was studied using in situ microcosms. Changes in the chemical composition of the oil were monitored in crude enzyme extracts, as well as a sediment matrix, for as long as 70 days. Compound-specific effects of ligninolytic enzymes applied to the sediments were observed over time through changes in concentration of total petroleum hydrocarbons (TPH), polycyclic aromatic hydrocarbons (PAHs) and fractions of saturates, aromatics, resins and asphaltenes (SARA). As the oil weathered, most TPH and PAH fractions showed a rapid decrease in concentration. As sediment oil concentrations decreased following treatment with ligninolytic enzymes, the microbial population was enriched with hydrocarbon-degrading species. This trend demonstrates that the oil fractions initially not bioavailable for microbial degradation, were subsequently released to the sediment via catalytic conversion with laccase and manganese peroxidase, and the oil continues to be biodegraded by microbial populations. PMID- 30008384 TI - The role of neuropeptides and neurotransmitters on kisspeptin/kiss1r-signaling in female reproduction. AB - Reproductive function is regulated by the hypothalamic-pituitary-gonads (HPG) axis. Hypothalamic neurons synthesizing kisspeptin play a fundamental role in the central regulation of the timing of puberty onset and reproduction in mammals. Kisspeptin is a regulator of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH). In female rodent, the kisspeptin (encoded by kiss1 gene), neurokinin B (Tac3) and dynorphin neurons form the basis for the "KNDy neurons" in the arcuate nucleus and play a fundamental role in the regulation of GnRH/LH release. Furthermore, various factors including neurotransmitters and neuropeptides may cooperate with kisspeptin signaling to modulate GnRH function. Many neuropeptides including proopiomelanocortin, neuropeptide Y, agouti-related protein, and other neuropeptides, as well as neurotransmitters, dopamine, norepinephrine and gamma-aminobutyric acid are suggested to control feeding and HPG axis, the underlying mechanisms are not well known. Nonetheless, to date, information about the neurochemical factors of kisspeptin neurons remains incomplete in rodent. This review is intended to provide an overview of KNDy neurons; major neuropeptides and neurotransmitters interfere in kisspeptin signaling to modulate GnRH function for regulation of puberty onset and reproduction, with a focus on the female rodent. PMID- 30008383 TI - Oxidative removal of brilliant green by UV/S2O82-, UV/HSO5- and UV/H2O2 processes in aqueous media: A comparative study. AB - The removal of brilliant green (BG), a toxic organic and cationic dye, has been examined by UV/S2O82- (PS), UV/HSO5- (PMS) and UV/H2O2 processes. BG showed insignificant direct photolysis at 254 nm (i.e., 8.6% after 30 min). However, enhanced BG degradation was observed in UV/PS, UV/PMS and UV/H2O2 systems as revealed from 63.1, 47.0 and 34.8% BG degradation, respectively, at 30 min of reaction time, using 0.05 mM BG and 1.0 mM oxidant initial concentration. The bimolecular rate constants of OH and SO4- with BG were determined to be 2.35 * 109 and 2.21 * 109 M-1 s-1, respectively. Electrical energy per order (EE/O) values for UV/PS, UV/PMS and UV/H2O2 processes were calculated to be 5.4, 6.8, and 7.8 KWh/m3/order, respectively. The addition of humic acid (HA) and inorganic anions inhibited the degradation of BG by UV/PS in the order of NO2- > HA > HCO3- > Cl- > NO3- ~ SO42-. The results of frontier electron densities (FEDs) showed that C-atom holding the three rings (C7), and C-atoms at para positions to N alkyl groups of the two rings (C4 and C14) are the predominant sites for radical addition. Furthermore, nine degradation products (DPs) of BG were detected experimentally using LC/MS/MS. PMID- 30008386 TI - Delivery of MGMT mRNA to glioma cells by reactive astrocyte-derived exosomes confers a temozolomide resistance phenotype. AB - The glioma-astrocyte interaction plays an important role in tumor microenvironment remodeling; however, the underlying mechanism has not been completely clarified. In this study, we show that glioma cells stimulate normal human astrocyte (NHA) into reactive astrocyte (RAS) in a non-contact manner. Additionally, the amount of O6-alkylguanine DNA alkyltransferase (MGMT) mRNA in exosomes (EXOs) released by RAS was significantly increased compared with that in non-reactive NHA. Importantly, MGMT-negative glioma cells can take up RAS-EXOs and acquire a temozolomide (TMZ)-resistant phenotype via the translation of exogenous exosomal MGMT mRNA both in vitro and in vivo. Our findings illuminate a novel phenomenon that may be a potent mechanism underlying glioma recurrence in which glioma-associated NHAs protect MGMT-negative glioma cells from TMZ-induced apoptosis by the functional intercellular transfer of exosomal MGMT mRNA. PMID- 30008385 TI - Corrigendum to "Association of burnout with emotional intelligence and personality in surgical residents: Can we predict who is most at risk?" [J Surg Educ (2017) e22-e30]. PMID- 30008387 TI - Molecular cloning and tissue distribution of fatty acid binding protein-3 in goldfish (Carassius auratus) and its mRNA expression in response to cadmium and PAMPs. AB - Fatty acid binding proteins (FABPs) are members of the conserved, multigene family of intracellular lipid binding proteins. In this study, the full-length cDNA of goldfish (Carassius auratus) FABP-3 (gfFABP-3) was successfully cloned. gfFABP-3 had an open reading frame of 402 bp and encoded a 133 amino acid polypeptide. The predicted gfFABP-3 protein included a lipocalin domain and displayed typical conserved FABP tertiary structures. Reverse transcription-PCR (RT-PCR) revealed that the gfFABP-3 gene was expressed in all tested tissues, with higher levels of expression in the testis, liver, heart, fat and kidney. After 24 h of cadmium exposure, gfFABP-3 was significantly upregulated in the gill, liver and spleen, but downregulated in the intestine, as compared to unexposed controls. gfFABP-3 expression was significantly downregulated in the spleen in goldfish challenged with LPS and Poly I:C. Our study provides a molecular characterization of goldfish FABP-3 and indicated that gfFABP-3 was potentially associated with the toxic effects of cadmium on lipid metabolism, and with the immune response to pathogenic infection. PMID- 30008388 TI - Retinal nerve fiber bundle trajectories in Chinese myopic eyes: Comparison with a Caucasian based mathematical model. AB - Previously we developed a mathematical model for describing the retinal nerve fiber bundle (RNFB) trajectories in the human retina. The model was based on Caucasian eyes that were not selected regarding refraction. The aim of this study was to determine the characteristics of the RNFB trajectories in Chinese myopic eyes. We collected high quality red free fundus images from 80 eyes of 80 Chinese myopic subjects (median [interquartile range/range] refraction -3.9 [-6.0 to 2.5/-10 to -1] D). We traced all visible RNFBs (n = 1460) and evaluated their trajectories using the previously published mathematical model. In the superior temporal region, the RNFB trajectories of the Chinese myopic eyes were similar to that of the Caucasian eyes (86% of trajectories within the 95% central range of the Caucasian model). In the inferior-temporal region, the trajectories of the Chinese low to moderate myopic eyes were also similar to that of the Caucasian eyes (85%); trajectories of the high myopic eyes (spherical equivalent beyond 6.00 D) were clearly less curved (75%). Associations between individual deviations from the model and axial length, retinal vessel course, and optic disc anatomy were studied with multiple linear regression analysis. In the superior temporal region, the trajectories were associated with retinal vessel course (P = 0.008) and optic disc size (P = 0.016). In the inferior-temporal region, there was a significant association with axial length (P < 0.001), retinal vessel course (P = 0.006), and disc torsion (P = 0.009). PMID- 30008389 TI - TLR4-MyD88 pathway promotes the imbalanced activation of NLRP3/NLRP6 via caspase 8 stimulation after alkali burn injury. AB - Alkali burn (AB) is one of the most serious ocular traumas in the world, characterized by extreme ocular surface disorders, critical secondary dry eye and irreversible vision loss. The exact mechanisms involved are unknown. Innate immunity, including the involvement of Toll-like receptors (TLRs) and NOD-like receptors (NLRs), is believed to participate in the pathogenesis of the epithelia, but the exact mechanisms by which TLRs transduce signals to NLRs and downstream molecules to initiate innate immunity remain poorly defined. In this present study, we used murine models of AB and AB concomitant desiccating stress (DS) to investigate the potential functions and mechanisms of TLR4 in regulating NLRP3 and NLRP6 during AB injury and secondary dry eye. We demonstrated that AB injury induced activation of the TLR4-MyD88 pathway, leading to imbalanced NLRP3 and NLRP6 via the activation of caspase-8 signaling. DS worsened ocular surface disorders post-AB injury by magnifying this phenomenon. Caspase-8 signaling promoted NLRP3 upregulation via the nuclear factor (NF)-kappaB pathway, while NLRP6 suppressed NF-kappaB activation. Our findings also revealed that TLR4-MyD88 knockout can alleviate AB-induced or DS-worsened ocular surface disorders, shedding light on the potential therapeutic strategies in the future for AB injury. Taken together, our findings demonstrate that AB promotes the TLR4-MyD88 caspase-8 axis to cause imbalanced NLRP3/NLRP6, and DS exacerbates ocular surface damage via magnifying this imbalance. PMID- 30008390 TI - Molecular and functional characterization of circulating extracellular vesicles from diabetic patients with and without retinopathy and healthy subjects. AB - Diabetic retinopathy is a sight-threatening complication of diabetes, characterized by loss of retinal pericytes and abnormal angiogenesis. We previously demonstrated that extracellular vesicles (EVs) derived from mesenchymal stem cells cultured in diabetic-like conditions are able to enter the pericytes, causing their detachment and migration, and stimulating angiogenesis in vitro. The purpose of this work was the molecular and functional characterization of EVs derived from diabetic subjects with or without diabetic retinopathy, compared with healthy controls. Characterization of EVs extracted from serum/plasma of diabetic patients with or without retinopathy, and healthy controls, was performed by FACS and microarray analysis of microRNA (miRNA) content. Relevant miRNA expression was validated through qRT-PCR. EV influence on pericyte detachment, angiogenesis and permeability of the blood-retinal barrier was also investigated. Diabetic subjects had a 2.5 fold higher EV concentration than controls, while expression of surface molecules was unchanged. Microarray analysis revealed 11 differentially expressed miRNAs. Three of them (miR-150-5p, miR-21-3p and miR-30b-5p) were confirmed by qRT-PCR. Plasma EVs from subjects with diabetic retinopathy induced pericyte detachment and pericyte/endothelial cell migration, increased the permeability of pericyte/endothelial cell bilayers and the formation of vessel-like structures, when compared with EVs from controls. In conclusion, circulating EVs show differences between diabetic patients and healthy subjects. EVs extracted from plasma of diabetic retinopathy patients are able to induce features of retinopathy in in vitro models of retinal microvasculature. Our data suggest a role for miR-150-5p, miR-21-3p and miR-30b 5p as potential biomarkers of the onset of diabetic retinopathy. PMID- 30008391 TI - Mechanism of fibrosis inhibition in laser induced choroidal neovascularization by doxycycline. AB - To explore the mechanisms underlying doxycycline suppression of fibrosis in laser induced choroidal neovascularization (LCNV), C57BL/6J male mice (aged from 6 to 8 weeks) received intraperitoneal injections of PBS/doxycycline solution from one day before laser injury until they were sacrificed. Leakage was assessed by FA, and CNV (stained by IB4) or fibrosis (stained by collagen type I) size was measured. The percentage of Pan-keratin+alpha-SMA+ cells was counted in the eyes' cryostat sections by immunohistochemistry. qPCR was used to measure the mRNA of markers of pan-macrophages, M1 and M2-type macrophages (M1 and M2), markers of EMT, and markers in the downstream of STAT6 signaling. Western blotting was used to analyze the expression of Arg-1, alpha-SMA, E-cadherin, pSTAT6 and STAT6. Our data showed that doxycycline inhibited leakage from CNV, areas of CNV on day 7 and day 14, and suppressed fibrosis, and the ratio of fibrotic/angiogenic areas during day 7 to day 35. We also showed attenuation of EMT in the doxycycline group. The percentage of Pan-keratin+alpha-SMA+ cells was lower in the doxycycline group than in the control group. The mRNA and protein levels of mesenchymal markers were downregulated in the doxycycline group, while the epithelial marker was upregulated. In addition, our data showed that the protein expression of Arg-1, the mRNA expression of M1 and M2-markers, were both inhibited by doxycycline, while the level of pan-macrophages (f4/80) showed no significant difference in two groups. Finally, our results showed that doxycycline was able to modulate the STAT6 signaling in transcript and protein levels. Accordingly, we suggested that the mechanism of doxycycline-mediated inhibition of fibrosis in CNV occurs through the STAT6 pathway. PMID- 30008392 TI - Goal-setting and volitional behavioural change: Results from a school meals intervention with vitamin-A biofortified sweetpotato in Nigeria. AB - Malnutrition, particularly vitamin A deficiency, is a major public health problem in many developing countries. This study investigated whether priming or self generation of goals, or whether attention to instrumental or experiential goals together with use of a reminder condition or not, promotes dietary behaviour intentions and change. A set of 556 randomly selected children aged 7-12 in Osun state, Nigeria, participated in an four-week intervention and field experiment in which a meal based on orange-fleshed sweetpotato, rich in pro-vitamin A, was introduced on five occasions as a complement to the existing school meal. Baseline intentions, anticipated feelings and repeated measures of post consumption and experience were assessed. The analyses included a generalised linear mixed model for consumption and a linear mixed model for feelings and experience. The results confirmed that attention to instrumental goals undermines goal pursuit, while a focus on experiential goals increases the persistence of pursuit. Priming of experiential goals should be recommended, especially because this approach evokes positive feelings after eating. There was no evidence of an effect from repeated pairing of goals with the school meal, but use of planning by stating intentions increased the amount eaten. These results have implications for how school meals programmes should be designed to better align personal motivation with behavioural change in relation to dietary health. PMID- 30008393 TI - Suspected quinine resistant P. falciparum severe malaria possibly acquired in Ivory Coast. AB - An expatriate to Ivory Coast (supposedly allergic to artemether-lumefantrine) was diagnosed with severe malaria in Spain. Parasitemia increased from 2% up to 21% within 24 h under quinine (10 mg/kg) and clindamycin (450 mg/8 h) combination treatment. Molecular profiling of the patient revealed the presence of molecular markers of quinine and other antimalarials resistance. Additionally, multiple copies of pfpm2 gene were also noticed in the patient sample, despite the absence of piperaquine drug pressure in Ivory Coast. Parasitemia was cleared with artesunate (2.4 mg/kg) under a desensitization protocol. Nevertheless, detection of early treatment failure is needed mainly in cases of suspected antimalarial resistance. PMID- 30008394 TI - Anti-aging properties of Curcuma heyneana Valeton & Zipj: A scientific approach to its use in Javanese tradition. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Temu giring, the rhizome of Curcuma heyneana Valeton & Zipj (C. heyneana), is native to tropical regions, especially in Indonesia. It is traditionally used as a skin care, for cosmetic and body freshness, in Javanese and Balinese women, and has many other bioactivities such as antioxidant, anticancer and antiinflammatory. AIM OF THE STUDY: The purpose of this study was to determine the antiaging activity of C. heyneana to prove its traditional use. MATERIALS AND METHODS: The antioxidant activity was determined using the DPPH free radical method, and anti-aging activity was examined using in vitro assays such as tyrosinase inhibitor and collagenase inhibitor. In vivo tests were performed by observing histomorphologic changes in rat skin exposed to Ultraviolet (UV) rays. The total curcuminoid contents and chromatographic profiles were determined by Thin Layer Chromatography (TLC) - densitometry. RESULTS: In all in vitro assays, all of the extracts showed a dose-dependent manner in the final concentration range from 62.5 to 500 ug/mL for DPPH assay and 31.25 to 250 ug/mL for tyrosinase inhibition and collagenase inhibition assay. Curcuminoid (CUR), the active principle of Curcuma genus shows antioxidant, tyrosinase inhibitor and collagenase inhibitor activity greater than all C. heyneana extracts. The in vivo assay results showed that the topical application of the crude extract of C. heyneana produced significant improvement effects on the UV-induced skin structure damage. The total CUR content was correlated with the anti-aging activity of Curcuma heyneana. CONCLUSIONS: The results show that C. heyneana contains antioxidant compounds and has potent anti-aging activity, indicating that it can be used as an anti-aging drug candidate or as a phyto cosmeceutical. PMID- 30008395 TI - Oral administration of Aristolochia manshuriensis Kom in rats induces tumors in multiple organs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochia manshuriensis Kom (AMK), belonging to the Aristolochia family, is traditionally used in China to remove heart fire, promote dieresis, restore menstruation, and enhance milk secretion. The active constitutes of AMK are aristolochic acids (AAs, I and II) that are reported to cause serious side effects including nephrotoxicity and carcinogenicity. AIM OF THE STUDY: The tumorigenic role of AMK is far to be understood. We analyzed the toxicity reactions after long-term exposure of AMK in rats. MATERIALS AND METHODS: Sprague-Dawley rats underwent gavage with AMK doses of 51 mg/kg (AMK-1), 253 mg/kg (AMK-2), 508 mg/kg (AMK-3), 1029 mg/kg (AMK-4) or AAs of 15 mg/kg (AAs), and then sacrificed at the 6th, 10th, 14th, 18th, 22th, 26th and 30th weeks. Endpoint measurements included clinical observations, body weights, blood biochemistry, haematology and histomorphological observations. RESULTS: Body weight decreased after AMK or AAs treatment in rats. AMK destroyed renal function, and induced anemia in rats. AMK caused kidney, stomach, bladder and subcutaneous tumors in rats. In addition, primary hepatic carcinoma was not observed in rats. CONCLUSIONS: AMK had significant toxic effects in rats with regard to decreased body weight, diminished renal function, increased anemia and tumor incidence. Kidney, stomach, bladder and subcutaneous tissue are carcinogenic target organs of AMK or AAs, however liver is no- carcinogenic target organ of AMK or AAs in rats. AMK is carcinogenic in rats, and not be safe for humans. PMID- 30008396 TI - The diagnostic threshold for osteoporosis impedes fracture prevention in women at high risk for fracture: A registry-based cohort study. AB - The diagnostic threshold for osteoporosis, a bone mineral density (BMD) T-score <= -2.5, signals an increased risk for fracture. However, most fragility fractures arise among the majority of women with 'osteopenia' or 'normal' BMD. We hypothesized that a BMD T-score of -2.5, even if not intended as a treatment threshold, paradoxically may create disincentive to initiating treatment of women with osteopenia or normal BMD at high risk for fracture. From a population-based BMD registry covering the Province of Manitoba, Canada, we identified 3735 untreated women aged >= 50 years undergoing BMD screening in 2006-2015 found to qualify for Osteoporosis Canada guidelines-based treatment. The main outcome was prescription of an approved osteoporosis medications in the year after BMD testing ascertained from a population-based pharmacy database. We estimated adjusted odds ratios (OR, 95% confidence interval [CI]) for treatment initiation based on BMD, major fracture history (non-traumatic vertebral, hip or multiple fractures), age, and calendar year (to examine the impact of treatment guidelines published in 2010). Among these women, 50% (1853) initiated treatment: 71% with osteoporosis, 21% with osteopenia, and 5% with normal BMD with similar values in those with a prior major fracture (71%, 19%, 5%, respectively). Compared to women with osteoporosis, adjusted ORs for treatment of high risk women with osteopenia or normal BMD alone were 0.10 (95% CI 0.09-0.12) and 0.02 (95% CI 0.01-0.04), respectively, and no higher in women with a prior major fracture (OR 1.00, 95% CI 0.84-1.19) or following introduction of treatment guidelines (p = 0.294). In summary, we found evidence that the diagnostic threshold for osteoporosis may serve as a disincentive to initiation of treatment in many women at high risk for incident fracture. PMID- 30008397 TI - Models for the bystander effect in gradient radiation fields: Range and signalling type. AB - Bystander responses to radiation are responsible for a significant fraction of cell death, but are not included in the conventional linear-quadratic (LQ) radiobiological model. Strong dose gradients in radiation fields affect the distribution of bystander signals and can be used to decrease the survival of cancer cells. Predictive models incorporating bystander effects are needed to design the dose gradients in modulated fields to improve cancer treatments. Fundamental questions concern the nature and range of bystander signalling. Some authors propose bystander signals are carried by diffusing molecular factors expressed into the extracellular medium and that strong dose gradients drive their diffusion. Others propose bystander effects occur between neighbouring cells through gap-junctions, leaving no universal agreement. Here we test three assumptions concerning the effective range of bystander signals using both average and local measures of survival. Model 1 assumes short range signalling (e.g. gap-junction mediated) proportional to the local dose gradient, without relying on diffusion across the extracellular medium; Model 2 assumes metabolite diffusion governed by Fick's second law with either negative or both signs of bystander effect; Model 3 assumes that the extent of signal production is dependent on the average of the dose gradient over the field and that the signals have long range distribution. A single bystander parameter for each model was fitted to observed average survival of cancer cells in uniform and modulated fields. All models gave better fits than the classical LQ model. Model 2 fitted best with one sign of bystander effect on survival. Model 3 gave the best overall fit of average survival. The models were then used to predict local survival and survival as a function of dose in modulated fields, using independent datasets, without changing the bystander parameter. Model 3 gave the best overall prediction. This study demonstrates that the bystander effect can be controlled by design of the radiation field modulation. PMID- 30008398 TI - Somatosensory Inputs Induced by Passive Movement Facilitate Primary Motor Cortex Excitability Depending on the Interstimulus Interval, Movement Velocity, and Joint Angle. AB - Somatosensory inputs affect primary motor cortex (M1) excitability; however, the effect of movement-induced somatosensory inputs on M1 excitability is unknown. This study examined whether M1 excitability is modulated by somatosensory inputs with passive movement in 29 healthy subjects. Motor-evoked potentials (MEPs), elicited by transcranial magnetic stimulation (TMS) were recorded from the first dorsal interosseous (FDI) muscle (Experiment 1). M- and F-waves were measured from the FDI muscle (Experiment 2). Passive movements of the index finger were performed in the adduction direction. TMS pulses were preceded by starting passive movements with interstimulus intervals (ISIs) of 30, 60, 90, 120, 150, 180, and 210 ms. TMS or electrical stimulation was performed in the midrange of the metacarpophalangeal joint during passive movements. MEPs were significantly facilitated at 90, 120, and 150 ms (p < 0.05). No M- or F-wave changes were observed for any ISI. In addition, we investigated whether MEP changes were dependent on passive movement velocity and joint angle. Passive movement was performed at two movement velocities (Experiment 3) or joint angles (Experiment 4). MEP facilitation was observed depending on the movement velocities or joint angles. These experiments demonstrated that somatosensory inputs induced by passive movements facilitated M1 excitability depending on the ISIs, passive movement velocity, and joint angle. PMID- 30008399 TI - Gallium arsenide (GaAs) leaching behavior and surface chemistry changes in response to pH and O2. AB - Gallium arsenide (GaAs) is a material widely used in electronic devices. Disposal of electronic waste containing GaAs in municipal solid waste landfills raises concerns about the public health and ecological risks associated with the potential release of toxic arsenic (As) species. In this study, different tests were performed to investigate the leaching behavior of particulate GaAs in aqueous solutions. In the U.S. Toxicity Characteristic Leaching Procedure (TCLP) and California Waste Extraction Test (WET), the concentrations of As released from the GaAs particles were about 2.6-2.8-fold higher than the regulatory limit (5 mg/L). A much higher As concentration (72 mg/L), accounting for as much as 15.4% of the initial As in GaAs, was solubilized in a pH-7.6 synthetic landfill leachate under ambient atmosphere after 120 days. Additional tests performed to evaluate the dissolution of GaAs under a range of redox conditions, pH levels, ionic strength, and presence of organic constituents commonly found in landfills revealed that oxic environments and mildly alkaline conditions (pH 8.1-8.5) promote release of As (chiefly arsenite) and gallium species to the surrounding aqueous environment. The rate of As release in long-term exposure experiments was initially constant but later progressively diminished, likely due to the formation of a passivating layer on the surface of GaAs consisting of corrosion products rich in poorly soluble gallium oxides (Ga2O3 and Ga(OH)3). This hypothesis was confirmed by surface analysis of GaAs particles subjected to leaching using X-ray photoelectron spectroscopy (XPS). These findings suggest that further research is needed to assess the potential release of toxic As from electronic waste in municipal landfills. PMID- 30008400 TI - Solar pyrolysis of waste rubber tires using photoactive catalysts. AB - The solar pyrolysis of waste tire rubber was investigated with the application of heterogeneous photocatalysts including TiO2, Pd/TiO2, Pt/TiO2, Pd-Pt/TiO2, and Bi2O3/SiO2/TiO2. Experiments were performed at temperatures ranging between 550 and 570 degrees C under solar irradiations of 950-1050 W/m2. The gas yield from non-catalytic solar pyrolysis was at 20% while the use of TiO2 catalyst increased the gas yield to 27%. Doping of TiO2 with noble metals and Bi2O3/SiO2 metal oxides enhanced further the cracking ability of the catalyst. Bi2O3/SiO2/TiO2 gave a 32% gas yield. The highest gas yields of 40% and 41% were achieved over Pd Pt/TiO2 and Pd/TiO2 catalysts, respectively. Catalyst characterization by BET, SEM, EDX and XRD showed the role of metal doping in altering the morphology of TiO2, resulting in nanocrystallites, larger pore volume and higher surface area. Both, Pd and Bi influenced the photocatalytic properties of TiO2 improving cracking activity during pyrolysis of waste rubber. PMID- 30008401 TI - Production of benzene/toluene/ethyl benzene/xylene (BTEX) via multiphase catalytic pyrolysis of hazardous waste polyethylene using low cost fly ash synthesized natural catalyst. AB - The valuable aromatics benzene, toluene, ethyl benzene and xylene (BTEX) were effectively produced from waste polyethylene (PE) using fly ash synthesized catalyst. The BTEX yield was enhanced significantly using multiphase catalytic pyrolysis of polyethylene. Low cost natural catalyst was synthesized from fly ash (FA) in 5 different synthesized form i.e., fly ash in natural form (FAN), fly ash calcined at 600 degrees C (FA-600), 700 degrees C (FA-700), 800 degrees C (FA 800) and 900 degrees C (FA-900). The thermal and catalytic pyrolysis both were conducted in a specially designed semi-batch reactor at the temperature range of 500-800 degrees C. Catalytic pyrolysis were performed in two different phases within the reactor batch by batch systematically, keeping the catalyst in a liquid phase (A-Type) and liquid and vapor phase/multiphase (B-Type), respectively. The maximum liquid yield of 78.20 wt% was obtained at a temperature of 700 degrees C using FA-800 catalyst in A-type arrangement. Total aromatics (BTEX) of 10.92 wt% was obtained for thermal pyrolysis at a temperature of 700 degrees C. In contrary, the aromatic (BTEX) contents were significantly increased for the catalytic pyrolysis in both reactor arrangement A and B types, nearly doubled from 10.92 wt% (thermal pyrolysis) to 21.34 wt% for A-type and 22.12 wt% for B type/multiphase. The pyrolysis oil was characterized using GC-FID, carbon residue test and other fuel testing methods to evaluate the suitability of its end use and aromatic content. PMID- 30008402 TI - Study on the effects of catalysts on the immobilization efficiency and mechanism of heavy metals during the microwave pyrolysis of sludge. AB - In order to enhance the immobilization of heavy metals in the bio-char during microwave pyrolysis, the immobilization efficiency and mechanism of heavy metals in the microwave pyrolysis of sludge with different alkaline catalysts were explored. Results showed that the leaching concentrations of heavy metals reduced greatly after pyrolysis, which were lower when catalyzed by CaO than those of Fe2O3. CaO was more favorable for the immobilization of Cr, Cu, Zn, Pb and Ni while Fe2O3 was more favorable for Cd. Different species distributions of heavy metals in the bio-char affected the leaching concentrations. Adding catalyst could significantly reduce the ecological risks of heavy metals in the bio-char, and CaO (RI = 15.17-20.43) had a better performance than Fe2O3 (RI = 16.88 21.79). When catalyzed by CaO, the formation of pores and co-crystal compounds in the bio-char determined the immobilization efficiencies of heavy metals. PMID- 30008403 TI - Biological stability of multi-component agri-food digestates and post-digestates. AB - The use of digestate in agriculture has been an efficient way to mitigate greenhouse gas emissions through the recycling of organic materials. However, harmful effects can arise if the organic matter is unstable. The goal of this study was to determine the biological stability (4-day oxygen demand for degradation of readily biodegradable organic matter (AT4), 21-day anaerobic biogas potential (GP21), and organic matter (VS) content) of six digestates after mesophilic digestion, and that of the corresponding post-digestates after psychrophilic post-digestion. Moreover, the kinetics of the changes in biological stability during post-digestion were determined. Mesophilic digestion of six multi-component agri-food feedstocks consisting of maize silage, bovine manure, mallow silage, pig slurry, glycerin, and spent wash from distillation was carried out at an organic loading rate of 2-3 kg VS/(m3.d), and at a hydraulic retention time of 45-60 days. Digestates were left in stirred reactors, imitating storage digesters, and kept for the next 120 d under anaerobic psychrophilic conditions (20 +/- 1 degrees C) for further stabilization. The additional biogas yields during post-digestion (50.9-114.9 dm3/kg TS) accounted for 8.5-27.4% of the biogas productivity of the feedstocks and 40-80% of that of the digestates. The efficiency of the loss of organic matter content was 22.5-40.2%. The decrease in the values of AT4, GP21 and VS content made the post-digestates more biologically stable than the digestates (digestates: AT4 = 13.7-67.0 mg O2/g TS, GP21 = 71.5 130.1 dm3/kg TS; post-digestates: AT4 = 6.6-37.4 mg O2/g TS, GP21 = 15.7-79.2 dm3/kg TS). For digestates and post-digestates, AT4 values strongly correlated with GP21 values. PMID- 30008404 TI - Role of plastics in decoupling municipal solid waste and economic growth in the U.S. AB - Analysis of data from the US Environmental Protection Agency (EPA) on municipal solid waste (MSW) generation rates correlated to personal consumption expenditure (PCE) uncovers a decoupling event occurring between 1997 and 2000. A comparison of waste generation rates for each material category found in MSW reveals that plastics increased by nearly 84 times from 1960 to 2013 while total MSW increased only 2.9 times. The increase in plastic waste generation coincides with a decrease in glass and metal found in the MSW stream. In addition, calculating the material substitution rates for glass, metal and other materials with plastics in packaging and containers demonstrates an overall reduction by weight and by volume in MSW generation of approximately 58% over the same time period. A quantitative calculation of a scenario where plastics were not used in packaging and containers to replace glass, metal, and other materials demonstrates that MSW generation rate rises equally with PCE. Therefore, this study has determined that the increase of plastic use is a contributing factor to the decoupling of MSW generation from PCE. PMID- 30008405 TI - How can the role of leachate on nitrate concentration and groundwater quality be clarified? An approach for landfills in operation (Southern Italy). AB - Where the unique natural water resource is groundwater, the attention and the susceptibility of local communities and authorities to groundwater quality degradation risks can be so high to determine relevant problems to waste management, especially for landfills in operation or to be realised. A multi methodological approach was suggested with the purpose to clarify the role of landfill leakage on groundwater quality degradation. The selected study area (SSA) hosts some landfills in a narrow portion of a wide and deep coastal karstic aquifer, for these characteristics to be considered a case of high hydrogeological complexity and vulnerability. News concerning nitrate and secondly iron groundwater concentration anomalously high caused concern in the population and strong local opposition to landfills. The multi-methodological approach includes: the hydrogeological site characterization; the chemical study and the multi-isotope characterization of groundwater and leachate; the land use analysis and the estimation of nitrogen contributions deriving from fertilizers; the mineralogical study of groundwater suspended particles to define the role of natural soil substances. The hydrogeological site characterisation highlighted the local peculiarities of the aquifer. The chemical study was used to define geochemical features, groundwater and leachate characteristics and their macroscopic mixing. The environmental isotopes of hydrogen, carbon, nitrogen, and oxygen were used to investigate the groundwater origin, the most relevant geochemical reactions, the existence of groundwater-leachate mixing, and the sources of anthropogenic NO3-. The land use analysis highlighted quantity and type of used fertilizers permitting to compare these with groundwater in terms of isotopic signature. The mineralogical study demonstrated the role of suspend natural particles due the presence of terre rosse (red or residual soils) in groundwater. The approach confirmed that there are not the groundwater quality degradation effects of landfills, contributing to reassure population and institutions, simplifying the waste management. PMID- 30008406 TI - Fertilizer potential of liquid product from hydrothermal treatment of swine manure. AB - Compared with composting, hydrothermal treatment (HTT) technology can dramatically shorten the duration for manure waste treatment. This study firstly investigated the effect of HTT on solubilization of N, P and organics from swine manure, and then evaluated the phytotoxicity of liquid product from hydrothermally treated manure by seed germination test. Results show that 98% of N in manure could be converted into soluble form after HTT at 200 degrees C for 60 min. Soluble P in hydrothermally treated manure (at 150 degrees C for 60 min) was 2.7 times that in raw manure. The germination indices (GI) were all greater than 100% when the liquid product (from HTT at 150 degrees C for 60 min) or its diluted samples being used. Results from this study suggest that HTT could be a promising technology for producing safe and value-added liquid fertilizers from swine manure. PMID- 30008407 TI - Identification and modelling of risk factors for food waste generation in school and pre-school catering units. AB - Public sector food service is a major contributor to food waste generation in Sweden, with schools, pre-schools, elderly care homes, hospitals etc., producing approximately 70,000 tons of food waste each year. Sweden has appropriate infrastructure for handling food waste in place, recycling nutrients and energy, but there is still great potential to move upwards in the waste hierarchy and prevent waste. An important step in designing waste reduction measures is to identify and quantify the importance of different risk factors, in order to start by solving the problems with the greatest potential benefit and the lowest cost. This study sought to identify and quantify risk factors for food waste generation in public sector canteens by correlation analyses and statistical modelling. The empirical material comprised food waste quantification data for 177 kitchens in the Swedish municipalities of Falun, Malmo, Sala, Uppsala and Orebro, supplemented with quantifiable information about the kitchens obtained using a questionnaire. According to the findings, plate waste in schools and pre-schools increases with children's age. Schools with older children could potentially reduce plate waste by introducing more structured lunch breaks. Plate waste also increases with dining hall capacity, potentially due to rising stress and noise levels. Both plate waste and serving waste increase with greater overproduction, as indicated by calculated portion size, and could be reduced by schools and pre schools estimating their daily number of diners and their diners' food intake more accurately. As serving waste was significantly higher in satellite units (which bring in cooked food), due to lack of cooling and storage possibilities, than in production units (which cook, serve and sometimes deliver hot food), satellite units in particular would benefit from more accurate quantification of the food required on a daily basis. These findings were confirmed by multiple linear regression models, which explained >85% of the variation in plate, serving and total waste per portion. When used for quantification after changing the value of different factors, these models confirmed that the main factors influencing serving waste and total waste per portion were type of kitchen and rate of overproduction, while plate waste was mainly influenced by children's age and factors indicating a stressful dining environment. PMID- 30008408 TI - Production of fuel pellets via hydrothermal carbonization of food waste using molasses as a binder. AB - Hydrochar was produced from food waste under varying hydrothermal carbonization (HTC) conditions, and was pelletized using molasses and molasses/lime binders for fuel pellet production. The physico-chemical properties, density, mechanical properties, and water resistance, and combustion characteristics of the hydrochar pellets were investigated. The results indicated that molasses pellets and molasses/lime pellets exhibited increased compressive strength, density, and impact resistance due tothe "solid bridge" that formed from molasses recrystallization and agglomeration by lime. The hydrochar samples prepared at 230 degrees C and 260 degrees C, with long residence times of 8 h, showed excellent compressive strength and impact resistance index (IRI). Both molasses pellets and molasses/lime pellets exhibited slightly increased equilibrium moisture content (EMC), with the former showing a high water-resistance index (WRI) in the immersion test. Thermogravimetric analyses indicated that the molasses pellets had a lower ignition temperature and higher combustion interval than those of the molasses/lime pellets. PMID- 30008409 TI - Gold recovery from shredder light fraction of E-waste recycling plant by flotation-ammonium thiosulfate leaching. AB - This paper describes the recovery of gold (Au) from shredder light fraction (SLF) of a recycling plant by flotation and leaching. SLF is typically sent to landfills as waste, but it still contains substantial amounts of Au, and other metals like Cu and Fe. The SLF sample used in this study contains 0.003% of Au, 12% of Cu, and 10% of Fe. Flotation results showed that over 99% of Au and 50% of combustibles were recovered in froth while most of the base metals were recovered in tailing. SEM-EDX of froth products indicates that Au floated via two mechanisms: (1) flotation of Au-plated plastic particles, and (2) agglomeration of fine Au particles together with plastic particles due to kerosene-induced hydrophobic-hydrophobic interactions followed by the flotation of these agglomerated particles. Combustibles in froth/tailing were analyzed by ATR-FTIR, and the results showed that plastics in the froth were mostly sulfonated polystyrene (PS) and acrylonitrile butadiene styrene (ABS) while those in tailing were polyurethane (PU) and polyethylene terephthalate (PET). Contact angle measurements of plastic particles suggest that PS and ABS are more hydrophobic than PU and PET. Most of the base metals in the tailing had either bent or twisted shapes because they were mostly made up of wires. In flotation, these large and heavy particles are unaffected by bubbles and simply sink. Leaching results using ammonium thiosulfate solutions showed that Au extraction increased from 33 to 51% after flotation. PMID- 30008410 TI - From sewage sludge and agri-food waste to VFA: Individual acid production potential and up-scaling. AB - Volatile fatty acid (VFA) production through anaerobic fermentation may constitute an innovative solution for organic waste management within the context of circular economy. In the present study, the evolution of individual VFA during laboratory-scale fermentation of sewage sludge (SS), winery wastewater (Www) and meat and bone meal (MBM) was assessed, focusing on the effect of pH (5.5 and 10) and temperature (35 and 55 degrees C). Up-scaling of the fermentation process was evaluated in batch operation. The latter showed that specific VFA could be produced, giving similar individual evolution to lab-scale testing. To be precise, acetic acid percentage ranged within 30-65% and increased up to 5900 mg O2 L-1 during SS fermentation at 55 degrees C and pH 9. In addition, 60% butyric acid was reached during Www acid fermentation at 55 degrees C, which corresponded to 6670 mg O2 L-1 concentration in the fermentation broth. Regarding valeric acid, over 20% proportion and 2700 mg O2 L-1 were reached in MBM acid fermentation at 35 degrees C. Finally, iso-valeric maximum level ranged within 15-17% in SS alkaline fermentation at 55 degrees C, which represented a concentration close to 2000 mg O2 L-1. Interestingly, co-fermentation of agri food waste and SS at thermophilic temperature and alkaline pH, boosted the VFA concentration 1.7-2 fold, which suggests that anaerobic co-fermentation of substrates from different nature could give promising outcomes in full-scale operation. PMID- 30008411 TI - Clarifying configurations of reaction rate constant for first-order and Monod type kinetics: A comparative manner and a pursuit of parametric definition. AB - The mechanisms of first-order and Monod-type kinetics describes degradation in distinct manner and yet too little attention is paid on the fact that first-order kinetic was derived from pure elementary reaction while Monod-type degradation was based on microbial uptake. Both mechanisms are basic theories in developing sophisticated degradation models and there are needs to give more guidance on selection of kinetics. The objective of this study was to compare the two kinetics when used for modeling degradation and biodegradability during composting. With both experimental data, from reactor composting of swine manure/wheat straw, and simulated results, it was found that Monod-type kinetic was more capable of modeling the lag phase, while first-order kinetic could explain the fast oxygen uptake rate for the oxidation of soluble substrate. Comparison of growth rate constants, based on Monod-type equation, with maximum degradation rate constants, based on first-order kinetic, showed that the former was generally one magnitude greater, which could be explained with the fact that part of growth of cell weight was from water consumption. PMID- 30008412 TI - Characterization of odor emissions and microbial community structure during degradation of pig carcasses using the soil burial-composting method. AB - A soil burial-composting method was proposed as a hybrid disposal method for infected carcasses. This is a modified soil burial technique that involves covering carcasses with compost to achieve a final compost bed of 1.0-1.2 m during the soil burial process. To evaluate the feasibility and applicability of the soil burial-composting method, a pilot-scale system was constructed to dispose of pig carcasses and monitored its performance for 346 days. Temperature around the pig carcasses in the compost bed increased gradually, and was in the range of 35-45 degrees C after 200 days. Mesophilic (Sporosarcina and Steroidobacter) and thermophilic (Truepera) bacteria were dominant in the compost bed. Based on odor gas profiling and the morphological properties of the carcasses excavated after 346 days, it was estimated that an advanced decay stage was reached after 243 days. Considering the results of previous studies, the carcass degradation rate achieved by soil burial-composting was faster than that of soil burial, but slower than that of the composting method. Sum of odor quotient (SOQ) in the upper soil bed was lower than the SOQ in the compost bed where the carcasses were buried. This result demonstrated that the upper soil bed functioned as a biofilter to mitigate odor gases emitted during degradation of the carcasses. The soil burial-composting disposal method is preferred over soil burial because the degradation of carcasses is faster, and over composting because odor complaints and compost usage can be minimized. PMID- 30008413 TI - Eddy current evaluation of recovered conductive waste purity. AB - The main goal of this paper is to present a new approach to evaluate the recovered conductive granular waste purity. For this purpose, the eddy current approach which is commonly applied in nondestructive evaluation has been used. The experimental tests consist of several samples composed of copper particles mixed with sand inserted in a cylindrical container with solenoidal coil. The impedance of the coil is measured, using precision LRC-meter, for several frequencies per sample and used according to the Experiment Design Methodology (EDM) to determinate the relationship between input and output of experiments, to have a quadratic model that will be used for inversion. The input and output are successively impedance and percentage of copper particles contained in the container. The results show the capability of the proposed approach to evaluate the conductive recovered waste purity. PMID- 30008414 TI - Influence of the expansion of the selective collection in the sorting infrastructure of waste pickers' organizations: A case study of 16 Brazilian cities. AB - Although recycling is a viable alternative to minimizing the impacts of the Municipal Solid Waste (MSW), identification of the local recycling market is a requirement for its empowerment. This paper aims to assess the recyclable solid waste market in 16 cities of Brazil. Through the application of interviews, field research and secondary data collection this research observed that while relying on poor infrastructure and on Government subsidies, the 12 pickers organizations surveyed can deliver 18.53% of recyclable waste to recycling with an average sorting productivity of 109 kg/picker/day and average earnings of US$ 293.40/picker/month. Based on the validated methods, 17% of these organizations were classified as having average efficiency, whereas 82% of them operated with very low efficiency. The investment required for the adequacy and expansion of the sorting capacity of waste pickers' organizations has been estimated at US$ 2.5 M, which could be counterbalanced by the savings with the current US$ 2 M/year spent with the disposal of recyclable waste into landfills. We also estimate new 189 job openings in the pickers' organizations to meet the requirements of the proposed scenario, contrasting with the current 93 cooperative members currently formalized. Regarding the consumer market, only few recycling companies were identified in the region, which may justify the low price paid for waste. The market for recyclables is mostly composed of micro and small companies that generally carry out the collection, transportation, sorting, and commercialization. PMID- 30008415 TI - Emission characteristics of a pyrolysis-combustion system for the co-production of biochar and bioenergy from agricultural wastes. AB - The co-production of biochar and bioenergy using pyrolysis-combustion processes can potentially minimize the emission problems associated with conventional methods of agricultural by-product disposal. This approach also provides significant added-value potential through biochar application to soil. Despite these advantages, variations in biomass composition, including sulfur, nitrogen, ash, and volatile matter (VM) content, may significantly influence both the biochar quality and the emissions of harmful particulate matter (PM) and gaseous pollutants (SO2, H2S, NO2, NO). Using a laboratory-scale continuous pyrolysis combustion facility, the influence of biomass composition (rice husk and grape pruning) and volatile production (pyrolysis) temperature (400-800 degrees C) on the biochar properties and emissions during combustion of the raw pyrolysis volatiles were evaluated. Utilization of grape pruning resulted in higher energy based yields of PM10 than the rice husk, the majority of which consisted of the PM1.1 fraction due to the elevated pyrogas content of the volatiles. The PM emissions were found to be independent of the feedstock ash content due to its retainment in the biochar. Greater volatilization of biomass sulfur and nitrogen during pyrolysis at higher temperatures resulted in higher yields of sulfurous and nitrogenous gaseous pollutants. The energy-based yields of NO and NO2 were found to increase by 16% and 50% for rice husk and 21% and 189% for grape pruning respectively between 400 and 800 degrees C. The same trend was also observed for the emissions of H2S and SO2 for both feedstocks. PMID- 30008416 TI - Message in a bottle - The story of floating plastic in the eastern Mediterranean sea. AB - The Mediterranean Sea is a closed basin with limited water exchange through the Strait of Gibraltar, and sites along its shores show the greatest densities of marine debris in the world. Plastic bottles, which are a growing concern due to high consumption of soft drinks and bottled water, constitute most of the floating marine debris. In this paper we present the transport mechanisms of floating marine debris to and from the Israeli coast using an experimental offshore release and recovery of plastic bottles, with the participation of citizens. Many bottles released near the beach in the south part of Israel, returned to the beach at a short distance and time from the release point. Some release locations had no bottle returns. Ten bottles, released from three locations, were recovered many dozens to hundreds of kilometers from the release point. Since most of the westward water flow in the eastern Mediterranean is subsurface, it was not surprising to find our floating debris only in the east. That makes the Levant basin in the eastern Mediterranean a collection area for floating debris. PMID- 30008417 TI - Exploring temple floral refuse for biochar production as a closed loop perspective for environmental management. AB - Religious faith and ritual activities lead to significant floral offerings production and its disposal as waste to the nearby open lands and water bodies. These activities result into various social and environmental nuisances because of their high organic content. Alternatively, it can be used as valuable resources for various biochemical and thermo-chemical processes. Floral refuse has been utilized in natural dye extraction, however, the residual solid refuse is of significant environmental concern due to its nutrient rich nature. This study explores the potential utilization of solid residue of temple floral refuse after natural dye extraction by thermo-chemical decomposition of it. The slow pyrolysis of solid residue was performed at 350 degrees C and 500 degrees C, and the biochar yield of 42 and 36% was obtained, respectively. TGA-DTG analysis was performed to observe the thermo-chemical behaviour of floral refuse. The biochar products were further characterized by FTIR, SEM, EDX, BET, XRD, and RAMAN spectroscopy to observe the impact of pyrolysis temperature (PT) on the resulting material, i.e. biochar and its possible application measures. EDX results revealed the presence of various macro-nutrients such as C, N, P, K Ca and Mg in different proportions which showed its soil amelioration potential. Moreover, based on the SEM and BET results, biochar prepared at 500 degrees C was further explored for adsorption of methylene blue dye at various dose and pH conditions. Based on Langmuir (R2 = 0.98) and Freundlich (R2 = 0.97) isotherms, it is found as a potential adsorbent material for removal of methylene blue dye. The results revealed that biochar conversion of colour extracted floral refuse can be a vital option for quick and efficient management of it in a closed loop approach. PMID- 30008418 TI - Agronomic effectiveness of urban biochar aged through co-composting with food waste. AB - Terra preta soils have been shown to develop after considerable modification of soil through char addition and over time natural ageing has led to increase in fertility of those soils. A co-composting experiment was conducted to accelerate the artificial ageing of urban biochar (UB) with the aim of achieving similar terra preta effect. UB was produced through the pyrolysis of 2:1 ratio of biosolids and green waste and then composted with food waste (10% v/v) until compost maturity at around 75 days. A portion of the UB was placed in litterbags within the composting biomass in order to examine the effects of co-composting more closely. Addition of 10% UB to food waste accelerated the composting process. As measured from the litter bags, co-composting UB with foodwaste increased CEC, pH, EC and nitrogen loading of composted UB relative to the un composted UB. However, the composting process reduced BET surface area and porosity of UB most probably due to clogging of pores by the organics released during composting. The agronomic value of UB, UB co-composted with foodwaste and foodwaste compost was evaluated in a greenhouse pot experiment with sorghum plants on a sandy acidic topsoil. Results of the pot experiment showed higher plant growth, lower emissions of N2O and higher nitrogen use efficiency in soil amended with UB than the soil amended with compost and co-composted UB. PMID- 30008419 TI - Environmental impacts of food waste in Europe. AB - Approximately 88 Million tonnes (Mt) of food is wasted in the European Union each year and the environmental impacts of these losses throughout the food supply chain are widely recognised. This study illustrates the impacts of food waste in relation to the total food utilised, including the impact from food waste management based on available data at the European level. The impacts are calculated for the Global Warming Potential, the Acidification Potential and the Eutrophication Potential using a bottom-up approach using more than 134 existing LCA studies on nine representative products (apple, tomato, potato, bread, milk, beef, pork, chicken, white fish). Results show that 186 Mt CO2-eq, 1.7 Mt SO2-eq. and 0.7 Mt PO4-eq can be attributed to food waste in Europe. This is 15 to 16% of the total impact of the entire food supply chain. In general, the study confirmed that most of the environmental impacts are derived from the primary production step of the chain. That is why animal-containing food shows most of the food waste related impacts when it is extrapolated to total food waste even if cereals are higher in mass. Nearly three quarters of all food waste-related impacts for Global Warming originate from greenhouse gas emissions during the production step. Emissions by food processing activities contribute 6%, retail and distribution 7%, food consumption, 8% and food disposal, 6% to food waste related impacts. Even though the results are subject to certain data and scenario uncertainties, the study serves as a baseline assessment, based on current food waste data, and can be expanded as more knowledge on the type and amount of food waste becomes available. Nevertheless, the importance of food waste prevention is underlined by the results of this study, as most of the impacts originate from the production step. Through food waste prevention, those impacts can be avoided as less food needs to be produced. PMID- 30008421 TI - Anti-acidogenic and anti-biofilm activity of 5,6,8-trihydroxy-7-methoxy-2-(4 methoxyphenyl)-4H-chromen-4-one. AB - OBJECTIVES: Crude extracts of Dodonaea viscosa var. angustifolia (DVA), has shown to have anticariogenic property. However the compound responsible for this activity has not been identified. The aim of this study was to investigate anti acidogenic and anti-biofilm activity of a flavone 5,6,8-Trihydroxy-7-methoxy-2-(4 methoxyphenyl)-4H-chromen-4-one isolated from D. viscosa var. angustifolia (DVA) in cariogenic bacteria Streptococcus mutans. METHODS: The crude extract from DVA leaves was fractionated into six fractions (F1-F6) using chromatography. The Minimum Inhibitory Concentrations (MIC) and Minimum Bactericidal Concentration (MBC) were determined. The effect of the six fractions on biofilm formation and acid production were investigated. The most active fraction (F5) was further fractionated, purified, identified and elucidated using GC-MS and NMR. The anticariogenic property of this purified compound was established. Results were analyzed using Wilcoxon rank-sum test (Mann-Whitney). RESULTS: The MIC and MBC of the fractions (F1-F6) and crude extract ranged from 0.39 to 12.5 mg/ml. F5 showed the lowest MBC. At 0.2 mg/ml, F5 reduced biofilm formation by 93.3% and reduced acid production in S. mutans. Subfraction F5.1 showed higher antimicrobial activity compared to the crude extract and F5. Purified F5.1 was identified as 5,6,8-Trihydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (TMMC). TMMC inhibited biofilm formation at both 6 h (94% reduction) and 24 h (99% reduction), which was higher compared to the crude extract (87% reduction at 0.78 mg/ml after 6 h). TMMC also exhibited a higher inhibitory effect on acid production compared to the crude extract. CONCLUSION: Flavone 5,6,8-Trihydroxy-7-methoxy-2-(4 methoxyphenyl)-4H-chromen-4-one derived from DVA has anti-S. mutans, anti-biofilm and anti-acidogenic activity therefore it has a potential for use in the oral cavity to prevent dental caries. PMID- 30008422 TI - The association of human papillomavirus type 16 E2 variations with cervical cancer in a Han Chinese population. AB - Human papillomavirus type 16 (HPV16) is considered to be the primary pathogen related to cervical cancer. The HPV16 E2 protein plays an important role in tumourigenicity of cervical carcinoma. In the current study, we enrolled 121 HPV16-positive cervical cancer patients in the case group and 130 HPV16-positive asymptomatic individuals in the control group, and we investigated the association between HPV16 E2 gene variations and cervical cancer. The HPV16 E2 DNA was amplified and sequenced. We identified two HPV variants (EUR and As) in the control group; the As variant was predominant (68.5%), followed by the EUR variant (31.5%). In the case group, three HPV variants (EUR, As and AA) were observed; the As variant was predominant (72.7%), followed by the EUR variant (22.3%) and the AA variant (5.0%). Our results showed a significant difference in the distribution of the HPV16 variants between the case and control groups (P < 0.05). Moreover, in the HPV16 E2 gene variation analysis, the distribution of sixteen variations was significantly different between the case and control groups (P < 0.05), and all of these variations were present in the AA variant. In the subgroup analysis, the frequency of the T3575G (S274A) variation in the EUR variant was significantly different between the case and control groups (P = 0.029); however, there was no significant difference in the frequency of the variations in the As variant between the case and control groups. Our findings in the current study could provide a better understanding of the relationship between HPV16 variants, E2 gene variations and cervical cancer. PMID- 30008423 TI - Effect of drug incorporation technique and polymer combination on the performance of biopolymeric antifungal buccal films. AB - Numerous films with a dissolved or dispersed active principle within a polymeric matrix have been described in literature. However, the incorporation of solid crystals into the films may influence several relevant properties. Additionally, it has been reported that different polymeric matrices lead to films presenting a different performance. The aim of this work was to evaluate the effect of the combination of chitosan with carrageenan (kappa-, lambda-, and iota-) as matrices, and of the miconazole nitrate incorporation method, on the films behavior. Mechanical properties, drug release and antifungal activity were evaluated. The state of the drug in the films was analyzed by different techniques. Films showed a homogeneous surface and a thermal protective effect on the drug. The combination of chitosan and lambda-carrageenan leads to films with the highest values of tensile and mucoadhesive strength. Films with solubilized drug displayed slightly higher elongation at break, tensile and mucoadhesive strength and faster drug release than those with suspended miconazole nitrate. However, no differences were found regarding the antifungal activity of the different formulations including time-to-kill curves. PMID- 30008424 TI - Injury type-dependent differentiation of NG2 glia into heterogeneous astrocytes. AB - The glial scar is comprised of a heterogeneous population of reactive astrocytes. NG2 glial cells (also known as oligodendrocyte progenitor cells or polydendrocytes) may contribute to this heterogeneity by differentiating into astrocytes in the injured CNS, but there have been conflicting reports about whether astrocytes comprise a significant portion of the NG2 cell lineage. By using genetic fate mapping after spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE) in mice, the goal of this study was to confirm and extend upon previous findings, which have shown that NG2 cell plasticity varies across CNS injuries. We generated mice that express tdTomato in NG2 lineage cells and express GFP under the Aldh1l1 or Glt1 promoter so that NG2 glia derived astrocytes can be detected by their expression of GFAP and/or GFP. We found that astrocytes comprise approximately 25% of the total NG2 cell lineage in the glial scar by 4 weeks after mid-thoracic contusive SCI, but only 9% by the peak of functional deficit after EAE. Interestingly, a subpopulation of astrocytes expressed only GFP without co-expression of GFAP, uncovering their heterogeneity and the possibility of an underestimation of NG2 glia-derived astrocytes in previous studies. Additionally, we used high performance liquid chromatography to measure the level of tamoxifen and its metabolites in the spinal cord and show that genetic labeling of NG2 glia-derived astrocytes is not an artifact of residual tamoxifen. Overall, our data demonstrate that a heterogeneous population of astrocytes are derived from NG2 glia in an injury type-dependent manner. PMID- 30008425 TI - Integrated constraints based analysis of an engineered violacein pathway in Escherichia coli. AB - Strategies towards optimal violacein biosynthesis, a potential drug molecule, need systems level coordination of enzymatic activities of individual genes in a multigene operon vioABCDE. Constraints-based flux balance analysis of an extended iAF1260 model (iAF1260vio) with a reconstructed violacein module predicted growth and violacein yields in Escherichia coli accurately. Shadow price (SP) analysis identified tryptophan metabolism and NADPH as limiting. Increased tryptophan levels in Deltapgi & DeltapheA were validated using in silico gene deletion analysis. Phenotypic phase plane (PhPP) analysis highlighted sensitivity between tryptophan and NADPH for violacein synthesis at molar growth yields. A synthetic VioABCDE operon (SYNO) sequence was designed to maximize Codon Adaptive Index (CAI: 0.9) and tune translation initiation rates (TIR: 2-50 fold higher) in E. coli. All pSYN E. coli transformants produced higher violacein, with a maximum six-fold increase in yields. The rational design E. coli: DeltapheA SYN: gave the highest violacein titers (33.8 mg/l). Such integrated approaches targeting multiple molecular hierarchies in the cell can be extended further to increase violacein yields. PMID- 30008426 TI - Urine metabolome analysis by gas chromatography-mass spectrometry (GC-MS): Standardization and optimization of protocols for urea removal and short-term sample storage. AB - BACKGROUND: Before derivatization, urine analyzed by gas chromatography-mass spectrometry (GC-MS) requires the complete removal of urea to avoid interferences. We aimed at establishing the most effective sample pretreatment for urea removing; moreover, we explored the impact of two short-term sample storage conditions on urine metabolome. METHODS: 92 aliquots were obtained from a single sample collected from a healthy adult; they were divided into 6 groups. Group 1 consisted of untreated aliquots while groups 2-6 differed from each other for the addition of various defined urease solution volumes combined with either 30 min or 1-hour sonication time. Urine sample storage was tested by comparing 20 fresh aliquots analyzed after collection with 20 aliquots frozen at -80 degrees C for 72 h. RESULTS: the most effective protocol consisted of the combination between 200 MUL urease solution with 1-h sonication time; urease solution volumes >200 MUL increase the risk to underestimate metabolite peaks because of sample dilution. Short-term storage of samples at -80 degrees C pointed out significant changes in the urine metabolic profile compared with that of fresh samples. CONCLUSIONS: our study confirms the importance of urea removal for a reliable recognition and quantitation of metabolites; urine short-term storage at -80 degrees C should be carefully reconsidered. PMID- 30008427 TI - Long non-coding RNA CRNDE in cancer prognosis: Review and meta-analysis. AB - BACKGROUND: Colorectal neoplasia differentially expressed (CRNDE), a 1910-nt lncRNA encoded on human chromosome 16, has been found to be involved in various cancers. Nevertheless, the clinical and diagnostic values of CRNDE in tumors still need to be explored. In this review, we aimed to elucidate the clinical role of CRNDE in cancer by searching all correlative literature, and we sequentially explored the association between CRNDE levels and overall survival (OS) or clinicopathological characteristics of cancer. METHODS: We conducted a database search of PubMed, Wanfang Data, Ovid, SinoMed, China National Knowledge Infrastructure, Cochrane Library, and Web of Science (up to January 1, 2018). The pooled odds ratio (OR) and hazard ratio (HR) were used to assess extents of correlation between CRNDE and cancer prognosis. After identification of the inclusion and exclusion criteria, 12 articles including 1361 patients were selected for this review. RESULTS: The results suggested that high levels of CRNDE were highly related to poor OS in tumor patients, with pooled HRs of 2.314 (1.894-2.826, P < .001, fixed-effects model). Likewise, we also found that high CRNDE expression was correlated with high tumor stage [OR: 3.340, 95% confidence interval (CI): 2.417-4.616, P < .001, random-effects model] and lymph node metastasis (OR: 3.027, 95% CI: 2.071-4.425, P = .004, random-effects model). CONCLUSIONS: Our findings demonstrated that CRNDE may modify susceptibility for various cancers and may serve as a new predictive factor for prognosis and diagnosis in different types of cancers. PMID- 30008428 TI - Initial Risk Assessment as part of the Quality by Design in peptide drug containing formulation development. AB - Risk Assessment (RA) is the key element of the Quality by Design (QbD) approach recommended by the pharmaceutical regulatory bodies. This research paper aimed to implement the regulatory requirements, the QbD thinking and the RA from the first steps of the oral peptide formulation development. The authors intended to give a general recommendation about the application possibilities of this methodology, to demonstrate the risk factors and the required decision points. Later, this paper presents a concrete development in practice. This case study shows the QbD and RA based early phase development of the GLP 1 analog, Liraglutide, an antidiabetic peptide drug mainly used in the treatment of type 2 Diabetes Mellitus. The objective here was to design Liraglutide encapsulated polymeric nanoparticles for oral delivery and the progress of their RA based development is presented. In this case, the particle size, the encapsulation efficiency, and the drug loading were found as the most critical quality attributes, the polymer concentration, the drug concentration, the w2/o ratio, the stabilizer concentration and polymer type were identified by the criticality rating as having the greatest impact on the product quality among the critical material attributes, finally the sonication time and sonication power were selected as the most critical elements of the production process. The results showed the importance of the risk factor-focused development in the oral peptide pharmaceutical formulations, and underlined the importance of the profound planning phase even in such cases. The formulation of an oral peptide delivery system is associated with several risks, but their priority ranking helps to focus on the resources (human, financial, time) related to the final product quality aimed at. PMID- 30008429 TI - Fast dissolving drug delivery membrane based on the ultra-thin shell of electrospun core-shell nanofibers. AB - Structural nanocomposites that provide fast dissolving drug release profiles are highly in demand in pharmaceutics. In this study, a poorly water-soluble drug such as quercetin or tamoxifen citrate (TC) was selected as a model active pharmaceutical ingredient. Core-shell nanofibers with ultra-thin shells were designed and prepared using modified coaxial electrospinning. Polyvinylpyrrolidone (PVP) K90 or Polycaprolactone (PCL) was selected as core. The drugs and PVP K10 were selected as shell. All types of solutions can be used as the shell fluids in modified coaxial process regardless of their electrospinnability, which means the increasing functional ingredients and unspinnable matrix can be processed. Evaluations via SEM and TEM demonstrated that the core-shell nanofibers had linear morphology with a shell thickness smaller than 100 nm. XRD and FTIR results showed that the model drug was distributed in the polymeric matrix amorphously and that PVP K10 had good compatibility with quercetin or TC. In vitro dissolution tests suggested that the core-shell nanofibers with ultra-thin shells released the loaded cargoes in the dissolution media within 1 min. The present investigation paved a new way for implementing the modified coaxial processes, which can be utilized to fabricate structural nanocomposites with ultra-thin shells for enhancing the fast dissolution of poorly water-soluble drugs. PMID- 30008430 TI - Brain mechanisms for perceiving illusory lines in humans. AB - Illusory contours (ICs) are perceptions of visual borders despite absent contrast gradients. The psychophysical and neurobiological mechanisms of IC processes have been studied across species and diverse brain imaging/mapping techniques. Nonetheless, debate continues regarding whether IC sensitivity results from a (presumably) feedforward process within low-level visual cortices (V1/V2) or instead are processed first within higher-order brain regions, such as lateral occipital cortices (LOC). Studies in animal models, which generally favour a feedforward mechanism within V1/V2, have typically involved stimuli inducing IC lines. By contrast, studies in humans generally favour a mechanism where IC sensitivity is mediated by LOC and have typically involved stimuli inducing IC forms or shapes. Thus, the particular stimulus features used may strongly contribute to the model of IC sensitivity supported. To address this, we recorded visual evoked potentials (VEPs) while presenting human observers with an array of 10 inducers within the central 5 degrees , two of which could be oriented to induce an IC line on a given trial. VEPs were analysed using an electrical neuroimaging framework. Sensitivity to the presence vs. absence of centrally presented IC lines was first apparent at ~200 ms post-stimulus onset and was evident as topographic differences across conditions. We also localized these differences to the LOC. The timing and localization of these effects are consistent with a model of IC sensitivity commencing within higher-level visual cortices. We propose that prior observations of effects within lower-tier cortices (V1/V2) are the result of feedback from IC sensitivity that originates instead within higher-tier cortices (LOC). PMID- 30008431 TI - Investigations into the therapeutic potential of Asphodeline liburnica roots: In vitro and in silico biochemical and toxicological perspectives. AB - This study aims to establish the biological and chemical profile of Asphodeline liburnica (Scop.) Rchb. root. The antioxidant, antimicrobial, enzyme inhibitory, DNA protection, apoptotic DNA ladder fragmentation analysis, and anti proliferative of A. liburnica were established using standard assays. In silico study was also performed to understand interactions between quantified anthraquinones and key enzymes of clinical relevance. Total phenolic and flavonoid contents were found to be 9.67 mgGAE/g and 1.48 mgRE/g extract, respectively. Chrysophanol was detected as a major anthraquinone. The extract exhibited radical scavenging ability against DPPH and ABTS with values of 13.23 and 66.99 mgTE/g extract, respectively. Good inhibitory activity against tyrosinase was recorded. In silico experiments showed that the anthraquinones were able to establish coordinative bonds with the copper atoms present in the enzymatic cavity of tyrosinase. MTT cell viability test on MDA-MB-231 cells showed that at 0.1 and 1 MUg of extracts induced anti-proliferative effect. Apoptotic DNA fragmentation analysis indicated nuclear condensation resulting in DNA fragmentation, which exhibited apoptotic cell death in the presence of A. liburnica. This study has provided insights on the potential usage of A. liburnica which could open new avenues for research and stimulate future interest for the development of safe novel biopharmaceuticals. PMID- 30008434 TI - When winning is losing: A randomized controlled trial testing a video game to train food-specific inhibitory control. AB - Overweight and obesity are major causes of worldwide morbidity and mortality. A two-armed randomized controlled trial (n = 104) examined the effectiveness of Hit n Run, a video game based on the principles of Go/No-Go inhibition training, in young adults who reported disinhibited eating. Adults (aged 18 to 30) were randomly assigned to play Hit n Run or received an informative brochure (Healthy Eating Step by Step; HESbS). Prior to and directly following the intervention week general and food-specific inhibitory control, caloric intake, and perceived attractiveness of food pictures were assessed. Results revealed no improvements in food-specific inhibitory control or caloric intake in either intervention group. Similar improvements for general inhibitory control and similar decreases in perceived attractiveness of food-related stimuli were observed for both Hit n Run and HESbS. Future research should aim to clarify how video game design can implement working mechanisms of cognitive training tasks to facilitate the development of effective game-based interventions. PMID- 30008432 TI - Ammonia role in glial dysfunction in methylmalonic acidemia. AB - Hyperammonemia is a common finding in patients with methylmalonic acidemia. However, its contribution to methylmalonate (MMA)-induced neurotoxicity is poorly understood. The aim of this study was evaluate whether an acute metabolic damage to brain during the neonatal period may disrupt cerebral development, leading to neurodevelopmental disorders, as memory deficit. Mice received a single intracerebroventricular dose of MMA and/or NH4Cl, administered 12 hs after birth. The maze tests showed that MMA and NH4Cl injected animals (21 and 40 days old) exhibited deficit in the working memory test, but not in the reference memory test. Furthermore, MMA and NH4Cl increased the levels of 2',7' dichlorofluorescein-diacetate (DCF), TNF-alpha, IL-1beta in the cortex, hippocampus and striatum of mice. MMA and NH4Cl also increased glial proliferation in all structures. Since the treatment of MMA and ammonia increased cytokines levels, we suggested that it might be a consequence of the glial activation induced by the acid and ammonia, leading to delay in the developing brain and contributing to behavioral alterations. However, this hypothesis is speculative in nature and more studies are needed to clarify this possibility. PMID- 30008433 TI - Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation. AB - Antibiotic combination therapy is promising for the treatment of lower respiratory tract infections caused by multi-drug resistant Gram-negative pathogens. Inhaled antibiotic therapy offers the advantage of direct delivery of the drugs to the site of infection, as compared to the parenteral administrations. In this study, we developed composite particle formulations of colistin and meropenem. The formulations were characterized for particle size, morphology, specific surface area, surface chemical composition, in-vitro aerosolization performance and in-vitro antibacterial activity. The combinations demonstrated enhanced antibacterial activity against clinical isolates of Acinetobacter baumannii N16870 and Pseudomonas aeruginosa 19147, when compared with antibiotic monotherapy. Spray-dried meropenem alone showed a poor aerosolization performance as indicated by a low fine particle fraction (FPF) of 32.5 +/- 3.3%. Co-spraying with colistin improved the aerosolization of meropenem with up to a two-fold increase in the FPF. Such improvements in aerosolization can be attributed to the enrichment of colistin on the surface of composite particles as indicated by X-ray photoelectron spectroscopy (XPS) and time-of flight secondary ion mass spectrometry (ToF-SIMS), and the increases in particle porosity. Intermolecular interactions between colistin and meropenem were observed for the combination formulations as measured by FT-IR. In conclusion, our results show that co-spray drying with colistin improves the antibacterial activity and aerosol performance of meropenem and produces a formulation with synergistic bacterial killing. PMID- 30008436 TI - 4D flow MRI for the analysis of celiac trunk and mesenteric artery stenoses. AB - PURPOSE: This study aims to assess the feasibility of 4D flow MRI measurements in complex vascular territories; namely, the celiac artery (CA) and superior mesenteric artery (SMA). MATERIALS AND METHODS: In this prospective study, 22 healthy volunteers and 10 patients were scanned at 3 T. Blood flow parameters were compared between healthy volunteers and patients with stenosis of the CA and/or SMA as a function of stenosis grade characterized by prior contrast enhanced computed tomography (CE-CT). The 4D flow MRI acquisition covered the CA, SMA and adjusting parts of the abdominal aorta (AO). Measurements of velocity- (peak velocity [PV], average velocity [AV]) and volume-related parameters (peak flow [PF], stroke volume [SV]) were conducted. Further, stenosis grade and wall shear stress in the CA, SMA and AO were evaluated. RESULTS: In patients, prior evaluation by CE-CT revealed 11 low- and 5 mid-grade stenoses of the CA and/or SMA. PV and AV were significantly higher in patients than in healthy volunteers [PV: p < 0.0001; AV: p = 0.03, p < 0.001]. PF and SV did not differ significantly between healthy volunteers and patients; however, a trend towards lower PF and SV could be detected in patients with mid-grade stenoses. Comparison of 4D flow MRI with CE-CT revealed a strong positive correlation in estimated degree of stenosis (CA: r = 0.86, SMA: r = 0.98). Patients with mid-grade stenoses had a significantly higher average WSS magnitude (AWM) than healthy volunteers (p = 0.02). CONCLUSION: This feasibility study suggests that 4D flow MRI is a viable technique for the evaluation of complex flow characteristics in small vessels such as the CA and SMA. 4D flow MRI approves comparable to the morphologic assessment of complex vascular territories using CE-CT but, in addition, offers the functional evaluation of flow parameters that goes beyond the morphology. PMID- 30008435 TI - Targeted overexpression of catalase to mitochondria does not prevent cardioskeletal myopathy in Barth syndrome. AB - Barth Syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy and muscle weakness. The underlying cause of BTHS is a mutation in the tafazzin (TAZ) gene, a key enzyme of cardiolipin biosynthesis. The lack of CL arising from loss of TAZ function results in destabilization of the electron transport system, promoting oxidative stress that is thought to contribute to development of cardioskeletal myopathy. Indeed, in vitro studies demonstrate that mitochondria-targeted antioxidants improve contractile capacity in TAZ-deficient cardiomyocytes. The purpose of the present study was to determine if resolving mitochondrial oxidative stress would be sufficient to prevent cardiomyopathy and skeletal myopathy in vivo using a mouse model of BTHS. To this end we crossed mice that overexpress catalase in the mitochondria (MCAT mice) with TAZ-deficient mice (TAZKD) to produce TAZKD mice that selectively overexpress catalase in the mitochondria (TAZKD+MCAT mice). TAZKD+MCAT mice exhibited decreased mitochondrial H2O2 emission and lipid peroxidation compared to TAZKD littermates, indicating decreased oxidative stress. Despite the improvements in oxidative stress, TAZKD+MCAT mice developed cardiomyopathy and mild muscle weakness similar to TAZKD littermates. These findings indicate that resolving oxidative stress is not sufficient to suppress cardioskeletal myopathy associated with BTHS. PMID- 30008437 TI - Dopamine D2 receptor polymorphism (C957T) is associated with sugar consumption and triglyceride levels in West Mexicans. AB - Genetic variations in the dopamine receptor D2 (DRD2) may alter dopamine signaling and modify the rewarding effects of food. This study aimed to analyze the association of the C957T DRD2 polymorphism with sugar consumption in West Mexican subjects. In a cross-sectional and analytical study, a total of 215 Mexican subjects were enrolled. DRD2 genotyping was performed by an allelic discrimination assay. Habitual dietary intake and the biochemical profile were evaluated. Genotype frequencies of the C957T DRD2 polymorphism were CC (12.1%), CT (40.9%) and TT (47.0%). Carriers of the CC genotype had a higher intake of sugar (g/day) than heterozygotes (67.4 g vs. 41.3 g, p = 0.001) and TT homozygotes (67.4 g vs. 45.2 g, p = 0.004). Also, the habitual consumption of soda (daily or at least 3 times per week) was more frequent among CC genotype carriers compared with heterozygotes (81% vs. 51%, p = 7.5 * 10-6) and TT homozygotes (81% vs. 57%, p = 2.4 * 10-4). Furthermore, the CC genotype was associated with elevated serum triglyceride levels (>150 mg/dL) than the CT genotype (OR = 2.80, 95% CI 1.08-7.24, p = 0.034). In conclusion, our results suggest a genetic background associated with sugar consumption among West Mexicans, which may contribute to increases in serum triglyceride levels. PMID- 30008438 TI - PTEN/FLJ10540/PI3K/Akt cascade in experimental brain stem death: A newfound role for a classical tumorigenic signaling pathway. AB - Despite great advances in contemporary medicine, brain death still remains enigmatic and its cellular and molecular mechanisms unsettled. This review summarizes recent findings that substantiate the notion that PTEN/FLJ10540/PI3K/Akt cascade, the classical tumorigenic signaling pathway, is actively engaged in experimental brain stem death. These results were based on a clinically relevant animal model that employs the pesticide mevinphos as the experimental insult in Sprague-Dawley rats to mimic brain stem death in patients died of organophosphate poisoning. The neural substrate investigated is the rostral ventrolateral medulla (RVLM), a brain stem site classically known to maintain arterial pressure (AP) and is established to be the origin of a "life and-death" signal detected from AP, which reflects brain stem cardiovascular dysregulation that precedes death. Activation of PI3K/Akt signaling pathway in the RVLM upregulates the nuclear factor-kappaB/nitric oxide synthase II/peroxynitrite cascade, resulting in impairment of brain stem cardiovascular regulation that leads to the loss of the "life-and-death" signal in experimental brain stem death. This process is reinforced by FLJ10540, a PI3K-association protein; and is counteracted by PTEN, a negative regulator of PI3K/Akt signaling. The concept that a classical signaling pathway in tumorigenesis is also an active player in cardiovascular dysregulation in brain stem death provides new ramifications for translational medicine. It promulgates the concept that rather than focusing on a particular disease condition, a new vista for future therapeutic strategy against both fatal eventualities should target at this common cellular cascade. PMID- 30008439 TI - WITHDRAWN: Basic Properties of ATP-Induced Myosin Head Movement in Hydrated Myosin Filaments, Studied Using the Gas Environmental Chamber. PMID- 30008442 TI - What role for metformin in type 1 diabetes? AB - Tight glycaemic control is key to reducing the risk of cardiovascular and microvascular complications in people with type 1 diabetes.1 Standard treatment involves optimising insulin therapy to achieve an HbA1c level of 48mmol/mol (6.5%) or lower. Although not licensed for use in type 1 diabetes, metformin is included in some clinical guidelines as adjuvant therapy for people with type 1 diabetes who are overweight and wish to improve glycaemic control while minimising the dose of insulin.1,2 The REMOVAL study is the largest trial to date that has investigated the longer-term effects of metformin in people with type 1 diabetes.3 Here, we consider the role of metformin in individuals with type 1 diabetes in light of these results and other study findings. PMID- 30008440 TI - New insights on the pathogenesis of endometriosis and novel non-surgical therapies AB - Endometriosis is a disease of theories, but none has succeeded to explain the whole picture. Most widely available drugs for endometriosis aim to relieve symptoms and improve fertility. Unfortunately, many short and long-term side effects are associated with the treatments. To overcome this problem, researchers have developed many novel therapeutic agents, including non-invasive technique. We aim to provide new insights on pathogenesis model and novel non-surgical treatments for endometriosis, including drugs already available in the market and also drugs which are still under research. Seven novel treatment modalities are recognized, namely dienogest, aromatase inhibitor (AI), gonadotrophine-releasing hormone (GnRH) antagonist, anti tumor necrosing factor (TNF)-alpha, selective estrogen receptor modulator (SERM), selective progesterone receptor modulator (SPRM), and high-intensity focused ultrasound (HIFU). Dienogest, AI, and GnRH antagonists are effective novel treatments with good tolerance and safety. SERM and SPRM show inconsistent results, while anti-TNF-alpha is still in the animal experimental stage. HIFU is a potential futuristic treatment. However, it is still a long way until this technology is truly applicable. PMID- 30008441 TI - Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr-/- mice. AB - Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in Ldlr-/- mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in Ldlr-/- mice with diet induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease. PMID- 30008443 TI - Ocrelizumab for multiple sclerosis. AB - ?Ocrelizumab (Ocrevus - Roche Registration GmbH) has received marketing authorisation approval from the European Medicines Agency (EMA) for the treatment of adults with multiple sclerosis.1,2 It is the first drug to be licensed for use in early primary progressive multiple sclerosis and relapsing forms of multiple sclerosis. Here, we review the evidence for the safety and effectiveness of ocrelizumab. PMID- 30008444 TI - Sport and dance interventions for healthy young people (15-24 years) to promote subjective well-being: a systematic review. AB - OBJECTIVE: To review and assess effectiveness of sport and dance participation on subjective well-being outcomes among healthy young people aged 15-24 years. DESIGN: Systematic review. METHODS: We searched for studies published in any language between January 2006 and September 2016 on PsychINFO, Ovid MEDLINE, Eric, Web of Science (Arts and Humanities Citation Index, Social Science and Science Citation Index), Scopus, PILOTS, CINAHL, SPORTDiscus and International Index to Performing Arts. Additionally, we searched for unpublished (grey) literature via an online call for evidence, expert contribution, searches of key organisation websites and the British Library EThOS database, and a keyword Google search. Published studies of sport or dance interventions for healthy young people aged 15-24 years where subjective well-being was measured were included. Studies were excluded if participants were paid professionals or elite athletes, or if the intervention was clinical sport/dance therapy. Two researchers extracted data and assessed strength and quality of evidence using criteria in the What Works Centre for Wellbeing methods guide and GRADE, and using standardised reporting forms. Due to clinical heterogeneity between studies, meta-analysis was not appropriate. Grey literature in the form of final evaluation reports on empirical data relating to sport or dance interventions were included. RESULTS: Eleven out of 6587 articles were included (7 randomised controlled trials and 1 cohort study, and 3 unpublished grey evaluation reports). Published literature suggests meditative physical activity (yoga and Baduanjin Qigong) and group-based or peer-supported sport and dance has some potential to improve subjective well-being. Grey literature suggests sport and dance improve subjective well-being but identify negative feelings of competency and capability. The amount and quality of published evidence on sport and dance interventions to enhance subjective well-being is low. CONCLUSIONS: Meditative activities, group and peer-supported sport and dance may promote subjective well being enhancement in youth. Evidence is limited. Better designed studies are needed. TRIAL REGISTRATION NUMBER: CRD42016048745; Results. PMID- 30008446 TI - CORRECTION: Vol. 175: 746-757, 2017. PMID- 30008445 TI - The Interaction between DELLA and ARF/IAA Mediates Crosstalk between Gibberellin and Auxin Signaling to Control Fruit Initiation in Tomato. AB - Fruit initiation following fertilization in angiosperms is strictly regulated by phytohormones. In tomato (Solanum lycopersicum), auxin and gibberellin (GA) play central roles in promoting fruit initiation. Without fertilization, elevated GA or auxin signaling can induce parthenocarpy (seedless fruit production). The GA signaling repressor SlDELLA and auxin-signaling components SlIAA9 and SlARF7 repress parthenocarpy, but the underlying mechanism is unknown. Here, we show that SlDELLA and the SlARF7/SlIAA9 complex mediate crosstalk between GA and auxin pathways to regulate fruit initiation. Yeast-two-hybrid and coimmunoprecipitation assays showed that SlARF7 and additional activator SlARFs interact with SlDELLA and SlIAA9 through distinct domains. SlARF7/SlIAA9 and SlDELLA antagonistically modulate the expression of feedback-regulated genes involved in GA and auxin metabolism, whereas SlARF7/SlIAA9 and SlDELLA coregulate the expression of fruit growth-related genes. Analysis of procera (della), SlARF7 RNAi (with downregulated expression of multiple activator SlARFs), and entire (iaa9) single and double mutants indicated that these genes additively affect parthenocarpy, supporting the notion that the SlARFs/SlIAA9 and SlDELLA interaction plays an important role in regulating fruit initiation. Analysis of the GA-deficient mutant gib1 showed that active GA biosynthesis and signaling are required for auxin-induced fruit initiation. Our study reveals how direct crosstalk between auxin- and GA-signaling components is critical for tomato fruit initiation. PMID- 30008448 TI - Epidemiology and Survival of Systemic Sclerosis-Systemic Lupus Erythematosus Overlap Syndrome. AB - OBJECTIVE: Systemic sclerosis (SSc) may overlap with systemic lupus erythematous (SLE). Little is known about the epidemiology, clinical characteristics, and survival of SSc-SLE overlap. We evaluated the prevalence of SSc-SLE overlap and differences in SSc characteristics, and compared survival with SSc without SLE. METHODS: A cohort study was conducted including subjects who fulfilled the American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for SSc and/or the ACR criteria for SLE. The primary outcome was time from diagnosis to all-cause mortality. Survival was evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: We identified 1252 subjects (SSc: n = 1166, SSc-SLE: n = 86) with an SSc-SLE prevalence of 6.8%. Those with SSc-SLE were younger at diagnosis (37.9 yrs vs 47.9 yrs, p < 0.001), more frequently East Asian (5.5% vs 20%) or South Asian (5.1% vs 12%), had lupus anticoagulant (6% vs 0.3%, p < 0.001), anticardiolipin antibody (6% vs 0.9%, p < 0.001), and pulmonary arterial hypertension (PAH; 52% vs 31%, p < 0.001). Those with SSc-SLE less frequently had calcinosis (13% vs 27%, p = 0.007), telangiectasia (49% vs 75%, p < 0.001), and diffuse subtype (12% vs 35%, p < 0.001). There were no significant differences in the occurrence of renal crisis (7% vs 7%), interstitial lung disease (ILD; 41% vs 34%), and digital ulcers (38% vs 32%). Those with SSc-SLE had better median survival time (26.1 vs 22.4 yrs), but this was not statistically significant (log-rank p = 0.06). Female sex and diffuse subtype attenuated survival differences between groups (HR 1.07, 95% CI 0.67-1.67). CONCLUSION: Patients with SSc-SLE are younger at diagnosis, more frequently have PAH, and less frequently have cutaneous manifestations of SSc. They should be monitored for ILD, renal crisis, and digital ulcers. PMID- 30008449 TI - Preconceptional Cardiovascular Health and Pregnancy Outcomes in Women with Systemic Lupus Erythematosus. AB - OBJECTIVE: To estimate the effects of preconceptional cardiovascular (CV) health, measured by American Heart Association (AHA) guidelines, on pregnancy outcomes in women with systemic lupus erythematosus (SLE). METHODS: The study included patients in the Hopkins Lupus Pregnancy Cohort. Body mass index (BMI), total cholesterol, and blood pressure (BP) in the most recent clinic visit prior to conception or first trimester were used to determine CV health (ideal, intermediate, or poor health) based on AHA definitions. Outcomes included preterm birth, gestational age at birth, and small for gestational age (SGA). Multivariable linear and logistic regression models with generalized estimating equations estimated the association of each CV health factor and outcome. RESULTS: The analysis included 309 live births. There were 95 preterm births (31%), and of the 293 pregnancies with birth weights, 18% were SGA. Ideal BMI, total cholesterol, and BP were reported in 56%, 85%, and 51% of pregnancies, respectively. Intermediate BMI was associated with decreased odds of SGA (OR 0.26, 95% CI 0.11-0.63), adjusted for race and prednisone use. Intermediate/poor total cholesterol was associated with increased odds of preterm birth (OR 2.21, 95% CI 1.06-4.62). Intermediate/poor BP was associated with decreased gestational age at birth (beta -0.96, 95% CI -1.62 to -0.29). CONCLUSION: Poor/intermediate preconception CV health affects pregnancy outcomes of preterm birth and SGA infants among women with SLE. Efforts to maintain BMI, total cholesterol, and BP within the recommended ideal range prior to pregnancy is important to improve pregnancy outcomes in women with SLE. PMID- 30008447 TI - Functional Diversity of Diterpene Synthases in the Biofuel Crop Switchgrass. AB - Diterpenoids constitute a diverse class of metabolites with critical functions in plant development, defense, and ecological adaptation. Major monocot crops, such as maize (Zea mays) and rice (Oryza sativa), deploy diverse blends of specialized diterpenoids as core components of biotic and abiotic stress resilience. Here, we describe the genome-wide identification and functional characterization of stress related diterpene synthases (diTPSs) in the dedicated bioenergy crop switchgrass (Panicum virgatum). Mining of the allotetraploid switchgrass genome identified an expansive diTPS family of 31 members, and biochemical analysis of 11 diTPSs revealed a modular metabolic network producing a diverse array of diterpenoid metabolites. In addition to ent-copalyl diphosphate (CPP) and ent-kaurene synthases predictably involved in gibberellin biosynthesis, we identified syn-CPP and ent-labda-13-en-8-ol diphosphate (LPP) synthases as well as two diTPSs forming (+)-labda-8,13E-dienyl diphosphate (8,13-CPP) and ent-neo-cis-trans clerodienyl diphosphate (CT-CLPP) scaffolds not observed previously in plants. Structure-guided mutagenesis of the (+)-8,13-CPP and ent-neo-CT-CLPP synthases revealed residue substitutions in the active sites that altered product outcome, representing potential neofunctionalization events that occurred during diversification of the switchgrass diTPS family. The conversion of ent-CPP, ent LPP, syn-CPP, and ent-neo-CT-CLPP by promiscuous diTPSs further yielded distinct labdane-type diterpene olefins and alcohols. Of these metabolites, the formation of 9beta-hydroxy-syn-pimar-15-ene and the expression of the corresponding genes were induced in roots and leaves in response to oxidative stress and ultraviolet irradiation, indicating their possible roles in abiotic stress adaptation. Together, these findings expand the known chemical space of diterpenoid metabolism in monocot crops toward systematically investigating and ultimately improving stress resilience traits in crop species. PMID- 30008450 TI - Monitoring of Systemic Lupus Erythematosus Pregnancies: A Systematic Literature Review. AB - OBJECTIVE: Few data exist to guide the frequency and type of monitoring in systemic lupus erythematosus (SLE) pregnancies. A systematic literature review was performed to address this gap in the literature. METHODS: A systematic review of original articles (1975-2015) was performed using Medline, Embase, and Cochrane Library. We included search terms for SLE, pregnancy, and monitoring. We also hand-searched reference lists, review articles, and grey literature for additional relevant articles. RESULTS: The search yielded a total of 1106 articles. After removing 117 duplicates, 929 articles that were evidently unrelated to our topic based on title and/or abstract, and 7 that were in a language other than English or French, 53 articles were included for full-text review. Following a more in-depth review, 15 were excluded: 6 did not use any measure of SLE activity and 6 did not specifically address SLE monitoring in pregnancy; 1 case series, 1 review, and 1 metaanalysis were removed. Among the 38 included studies, presence of active disease, antiphospholipid (aPL) antibodies positivity, and abnormal uterine and umbilical artery Doppler studies predicted poor pregnancy outcomes. No studies evaluated an evidence-based approach to the frequency of monitoring. CONCLUSION: Few existing studies address monitoring for optimal care during SLE pregnancies. The available data imply roles for aPL antibodies measurement (prior to pregnancy and/or during the first trimester), uterine and umbilical artery Doppler studies in the second trimester, and following disease activity. Optimal frequency of monitoring is not addressed in the existing literature. PMID- 30008451 TI - Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE. METHODS: We enrolled 7 SLE cases (from different families) with disease onset <= 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons of C1QA, C1QB, and C1QC were screened with Sanger sequencing. RESULTS: We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in C1QA in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in C1QC in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in C1QC in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in C1S in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. Further, in 1 patient, we determined a strong candidate variant in HDAC7 (histone decetylase 7). CONCLUSION: Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had DNASE1L3 variant, which functions in the clearance of self antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE. PMID- 30008452 TI - Antiphosphatidylserine/prothrombin Antibodies in Antiphospholipid Syndrome with Intrauterine Growth Restriction and Preeclampsia. AB - OBJECTIVE: Antibodies that recognize the phosphatidylserine/prothrombin complex (antiphosphatidylserine/prothrombin antibodies; aPS/PT) might reveal enhanced thrombotic risk in patients with systemic lupus erythematosus. Little is known about their association with pregnancy complications in the antiphospholipid syndrome (APS). METHODS: We enrolled 55 patients with APS who were seeking pregnancy in 2 Italian hospitals. Antiphospholipid antibodies (aPL), including anticardiolipin antibodies, anti-beta2-glycoprotein I antibodies, lupus-like anticoagulant, and aPS/PT antibodies were assessed, and the patients were prospectively followed for 24 months. RESULTS: There were 65% (36/55) of the APS patients who had aPS/PT antibodies. Forty-seven pregnancies were followed, including 33 of aPS/PT+ patients. Forty-one of the 47 patients (87%) who initiated a pregnancy eventually gave birth to a child. The pregnancy duration and the mean newborn weight at delivery were significantly lower in aPS/PT+ than in aPS/PT- patients (33.1 +/- 4.7 vs 36.2 +/- 3.4 wks of gestation, respectively, and 2058 +/- 964 g vs 2784 +/- 746 g, respectively, p < 0.05). Late pregnancy complications, including intrauterine fetal death, preterm delivery, preeclampsia, and intrauterine growth restriction (IUGR), were more frequent in aPS/PT+ patients, independent of the therapy. Titers of aPS/PT IgG were significantly inversely correlated with the neonatal weight at delivery. Vascular injury, as reflected by thrombosis, fibrinoid necrosis, ischemic and hemorrhagic areas, and presence of chorangiomas characterized the IUGR placentas in the presence of aPS/PT. CONCLUSION: The aPS/PT antibodies might represent markers of aPL-related pregnancy complications, IUGR/preeclampsia in particular, and could help identify beforehand patients who may require additional treatment. PMID- 30008453 TI - Gout and the Risk of Incident Erectile Dysfunction: A Body Mass Index-matched Population-based Study. AB - OBJECTIVE: Gout is the most common inflammatory arthritis. Erectile dysfunction (ED) is common in the general population; however, evidence regarding ED among patients with gout is limited. Our purpose was to study the association between incident gout and the risk of incident ED in the general population. METHODS: We conducted a cohort study using The Health Improvement Network, an electronic medical record database in the United Kingdom. Up to 5 individuals without gout were matched to each case of incident gout by age, enrollment time, and body mass index (BMI). Multivariate HR for ED were calculated after adjusting for smoking, alcohol consumption, comorbidities, and medication use. RESULTS: We identified 2290 new cases of ED among 38,438 patients with gout (mean age 63.6 yrs) and 8447 cases among 154,332 individuals in the comparison cohort over a 5-year median followup (11.9 vs 10.5 per 1000 person-years, respectively). Univariate (matched for age, entry time, and BMI) and multivariate HR for ED among patients with gout were 1.13 (95% CI 1.08-1.19) and 1.15 (95% CI 1.09-1.21), respectively. In our sensitivity analysis, by restricting gout cases to those receiving anti-gout treatment (n = 27,718), the magnitude of relative risk was stronger than the primary analysis (multivariate HR 1.31, 95% CI 1.23-1.39). CONCLUSION: This population-based study suggests that gout is associated with an increased risk of developing ED, supporting a possible role for hyperuricemia and inflammation as independent risk factors for ED. PMID- 30008454 TI - Tongue Atrophy in Sjogren Syndrome Patients with Mucosa-associated Lymphoid Tissue Lymphoma: Autoimmune Epithelitis beyond the Epithelial Cells of Salivary Glands? AB - OBJECTIVE: Primary Sjogren syndrome (pSS), an autoimmune epithelitis, bears the risk of evolving to non-Hodgkin lymphoma and most frequently to the mucosa associated lymphoid tissue (MALT) subtype. Based on the observation that pSS patients with MALT present a more atrophic and more intensely fissured tongue, we aimed to semiquantify severity of tongue atrophy and clinically assess lingual appearance in pSS patients with and without MALT, and investigate whether tongue atrophy and fissured appearance could serve as clinical indicators/signs of MALT. METHODS: A blinded complete oral examination was performed in pSS patients with and without MALT. Tongue atrophy was scored using a semiquantified atrophy score. Clinical and laboratory variables were recorded for all patients. RESULTS: After excluding pSS patients with oral candidiasis, iron deficiency, and megaloblastic anemia, 19 pSS patients with salivary MALT were matched 1:3 for age, sex, and disease duration with 57 pSS patients without MALT. The pSS-MALT patients had increased prevalence of salivary gland enlargement, lymphadenopathy, monoclonal gammopathy, rheumatoid factor positivity, higher focus and Tarpley scores in the minor salivary gland biopsy, and hyposalivation, compared to the pSS non-MALT patients. A significantly higher prevalence of tongue atrophy (68% vs 30%, p = 0.006) and fissured tongue (89% vs 33%, p < 0.001) was observed in the former group. Multivariate analysis showed that fissured tongue appearance, hyposalivation, and lymphadenopathy associate independently with salivary MALT in pSS. CONCLUSION: These results suggest that pSS patients with lymphoid malignancy exhibit a more atrophic and more fissured tongue. This particular clinical tongue appearance can serve as an additional clinical sign for salivary MALT lymphoma in pSS patients. PMID- 30008455 TI - Clinical and Laboratory Characteristics and Mortality in Korean Patients with Systemic Sclerosis: A Nationwide Multicenter Retrospective Cohort Study. AB - OBJECTIVE: We aimed to investigate demographic and clinical features and predictors of mortality in Korean patients with systemic sclerosis (SSc). METHODS: We performed a retrospective multicenter medical chart review in Korean patients diagnosed with SSc from 1986 to 2016 at 11 university hospitals representing each geographic area of Korea. SSc patients were defined according to the American College of Rheumatology preliminary classification criteria and subtyped as limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) SSc. RESULTS: We enrolled 751 patients (female, 86.7%; mean age at diagnosis, 48.9 yrs). The most common organ involvement was interstitial lung disease (52.7%), followed by gastroesophageal reflux disease (32.9%) and pulmonary arterial hypertension (13.6%). Patients with lcSSc were more common than those with dcSSc (64.8 vs 35.2%), whereas anti-Scl-70 and anticentromere antibody positivity were identified in 302 (42.5%) and 175 (25.5%) patients, respectively. In the 46 (6.1%) patients who developed a malignancy, lung cancer (23.9%) was the most common diagnosis, followed by gastric (13%) and breast cancer (13%). During the study period, 57 (7.6%) patients died, and the 5- and 10-year survival rates were 94% and 87%, respectively. Increased age at diagnosis, cardiovascular involvement, and anti-Scl-70 antibody positivity were significant predictors of death. CONCLUSION: Clinical manifestations and survival rates in Korean SSc patients are similar to those of other populations. However, the prevalence of anti-Scl-70 antibody is higher in Korean SSc patients compared with whites, while the prevalence of anticentromere antibody is lower. PMID- 30008456 TI - Risk Factors for Future Scleroderma Renal Crisis at Systemic Sclerosis Diagnosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a disease of autoimmunity, fibrosis, and vasculopathy. Scleroderma renal crisis (SRC) is one of the most severe complications. Corticosteroid exposure, presence of anti-RNA polymerase III antibodies (ARA), skin thickness, and significant tendon friction rubs are among the known risk factors at SSc diagnosis for developing future SRC. Identification of additional clinical characteristics and laboratory findings could expand and improve the risk profile for future SRC at SSc diagnosis. METHODS: In this retrospective cohort study of the entire military electronic medical record between 2005 and 2016, we compared the demographics, clinical characteristics, and laboratory results at SSc diagnosis for 31 cases who developed SRC after SSc diagnosis to 322 SSc without SRC disease controls. RESULTS: After adjustment for potential confounding variables, at SSc diagnosis these conditions were all associated with future SRC: proteinuria (p < 0.001; OR 183, 95% CI 19.1-1750), anemia (p = 0.001; OR 9.9, 95% CI 2.7-36.2), hypertension (p < 0.001; OR 13.1, 95% CI 4.7-36.6), chronic kidney disease (p = 0.008; OR 20.7, 95% CI 2.2-190.7), elevated erythrocyte sedimentation rate (p < 0.001; OR 14.3, 95% CI 4.8-43.0), thrombocytopenia (p = 0.03; OR 7.0, 95% CI 1.2-42.7), hypothyroidism (p = 0.01; OR 2.8, 95% CI 1.2-6.7), Anti-Ro antibody seropositivity (p = 0.003; OR 3.9, 95% CI 1.6-9.8), and ARA (p = 0.02; OR 4.1, 95% CI 1.2-13.8). Three or more of these risk factors present at SSc diagnosis was sensitive (77%) and highly specific (97%) for future SRC. No SSc without SRC disease controls had >= 4 risk factors. CONCLUSION: In this SSc cohort, we present a panel of risk factors for future SRC. These patients may benefit from close observation of blood pressure, proteinuria, and estimated glomerular filtration rate, for earlier SRC identification and intervention. Future prospective therapeutic studies could focus specifically on this high-risk population. PMID- 30008457 TI - Cardiovascular Disease Prevention in Rheumatoid Arthritis: Compliance with Diabetes Screening Guidelines. AB - OBJECTIVE: To evaluate compliance with diabetes screening guidelines for cardiovascular disease (CVD) prevention in rheumatoid arthritis (RA) compared to the general population. METHODS: We conducted the first longitudinal study of a population-based RA cohort including all prevalent RA cases in British Columbia between 1996 and 2006 and followed until 2010, with matched general population comparators. Using administrative data, we measured compliance with general population guidelines [i.e., testing plasma glucose (PG) at least once every 3 years after age 45] after excluding individuals with previous diabetes. Followup was divided into 3-year eligibility periods. Compliance was measured as the proportion of periods with >= 1 PG test performed. OR (95% CI) of compliance in RA (vs general population) was calculated using generalized estimating equation models, adjusting for age and sex. Mean compliance rate per patient was also calculated and compared using the Mann-Whitney U test. RESULTS: Analysis included 22,624 individuals with RA, contributing 48,724 three-year eligibility periods; and 22,579 people in a general population group, contributing 51,081 three-year eligibility periods. PG was measured in 72.3% (SD 37%) of the eligible time periods in the RA sample and in 70.4% (SD 38%) for the general population (OR 1.05, 95% CI 1.02-1.09, p < 0.0001). RA individuals met recommended screening guidelines in 71.4% of their eligible periods, compared to 70.6% (p < 0.001). Screening improved over time in RA relative to the general population. Family physicians ordered nearly all the PG tests. CONCLUSION: Compliance with general population guidelines for diabetes screening in RA was suboptimal, with little difference relative to the general population, despite a higher risk of CVD and diabetes. PMID- 30008458 TI - Psoriatic Arthritis Sonographic Enthesitis Instruments: A Systematic Review of the Literature. AB - OBJECTIVE: As part of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) ultrasound working group, we performed a systematic review of the literature to assess the evidence and knowledge gaps in scoring instruments of enthesitis in psoriatic arthritis (PsA). METHODS: A systematic search of PubMed, EMBase, and Cochrane databases was performed. The search strategy was constructed to find original publications containing terms related to ultrasound, enthesitis, spondyloarthritis (SpA) or PsA. Data extraction focused on the properties of the sonographic enthesitis instruments used in each study following components of the Outcome Measures in Rheumatology (OMERACT) filter: feasibility, test-retest reliability, construct validity as related to clinical assessment of enthesitis, biomarkers of inflammation and imaging of enthesitis by other modalities, discriminative validity, and responsiveness to treatment. RESULTS: Fifty-one of 310 identified manuscripts were included. Only 1 scoring instrument of enthesitis was specifically developed and validated in patients with PsA. Only 18 (35%) of the studies involved patients with PsA, while the remaining studies focused on SpA. In PsA, construct validity was assessed using biomarkers and clinical examination in 1 (2%) and 11 (21.5%) of the studies, respectively, whereas no studies used imaging for the same purpose. Only 2 (4%) of the studies assessed discriminative validity in PsA. Responsiveness to treatment was assessed in 7 studies, none of which included patients with PsA. CONCLUSION: Although sonographic enthesitis scoring instruments have been developed for SpA, only a few have been validated in PsA. None of them passed the OMERACT filter in patients with PsA. Additional research is required before endorsing a specific instrument for the assessment of enthesitis in patients with PsA. PMID- 30008459 TI - Primary and Secondary Fibromyalgia Are The Same: The Universality of Polysymptomatic Distress. AB - OBJECTIVE: Polysymptomatic distress (PSD) is the underlying metric of fibromyalgia (FM), and levels of PSD can identify criteria-positive FM with > 90% accuracy. We used levels of the PSD scale to test whether symptom levels in primary FM (PFM) and secondary FM (SFM) were the same and whether symptoms were equivalent in persons not meeting FM criteria. METHODS: We studied 1525 patients with a clinical diagnosis of FM and 12,037 patients with rheumatoid arthritis (RA). We used regression models to compare patients with potential and actual PFM to RA patients with potential and actual SFM for 17 key clinical variables. RESULTS: When controlled for PSD values, the widespread pain index, symptom severity scale, and pain, global, quality of life, and physical and mental component scores were essentially the same or only slightly different in PFM and SFM. Health Assessment Questionnaire-Disability Index scores were slightly higher in SFM (0.21 units), as was the painful joint count (1.6 joints). Overall, higher PSD scores were associated with more severe symptoms or abnormal status. PSD scores in patients not satisfying FM criteria and in patients satisfying criteria operated similarly. CONCLUSION: PFM and SFM are equivalent regarding symptom burden. PSD scores are more informative about severity and severity within diagnosis than dichotomization into FM/non-FM. Studies of FM versus "healthy individuals," or FM versus other diseases, are inherently defective, while studies of FM and PSD in RA offer the opportunity to have meaningful comparison groups, because there are no readily available unbiased appropriate controls for PFM. PMID- 30008460 TI - Characteristics and Outcomes of Patients with Systemic Lupus Erythematosus associated Thrombotic Microangiopathy, and Their Acquired ADAMTS13 Inhibitor Profiles. AB - OBJECTIVE: To investigate the characteristics and outcomes of patients with systemic lupus erythematosus (SLE)-associated thrombotic microangiopathy (TMA) based on their ADAMTS13 inhibitor profiles. METHODS: The medical data of 31 SLE patients with clinically diagnosed TMA were analyzed. ADAMTS13 activity and ADAMTS13 inhibitor were measured in all patients. RESULTS: TMA was attributable to active SLE in 19 patients. ADAMTS13 inhibitor and severe ADAMTS13 deficiency were detected in 6 of them. Patients with ADAMTS13 inhibitor (n = 6) exhibited a lower platelet count (7.3 +/- 5.1 vs 25.0 +/- 17.8 * 109/l, p = 0.005) and more prevalent central nervous system (CNS) involvement (100.0% vs 23.1%, p = 0.003) than patients without ADAMTS13 inhibitor (n = 13). Patients with ADAMTS13 inhibitor also had mild renal involvement characterized by a higher estimated glomerular filtration rate (112.7 +/- 18.0 vs 21.6 +/- 12.0, p < 0.001), lower proteinuria level [0.6 (0.2-2.5) vs 8.1 (5.2-14.0) g/d, p = 0.011], and lower mean arterial pressure (95.3 +/- 13.6 vs 117.5 +/- 13.1 mmHg, p = 0.008) than was observed in patients without ADAMTS13 inhibitor. All patients with ADAMTS13 inhibitor achieved complete remission within 18.6 +/- 8.7 days, while 3 patients (23.1%) without ADAMTS13 inhibitor achieved complete remission during a median followup of 5.0 months, even though more patients in this group received therapeutic apheresis (100.0% vs 50.0%, p = 0.021). The chance of complete remission increased by 10.8-fold (HR 10.8, 95% CI 1.8-65.5, p < 0.001) when ADAMTS13 inhibitor was present in SLE-associated TMA. CONCLUSION: Acquired ADAMTS13 deficiency is associated with more severe thrombocytopenia and CNS involvement, mild renal involvement, rapid resolution, and relatively good treatment response in SLE-associated TMA. PMID- 30008462 TI - Miniaturization of breath sampling with silicon chip: application to volatile tobacco markers tracking. AB - This work presents the performances of silicon micro-preconcentrators chips for breath sampling. The silicon chips were coupled to a handheld battery powered system for breath sampling and direct injection in a laboratory gas chromatography mass spectrometry system through thermal desorption (TD). Performances of micro-preconcentrators were first compared to commercial TD for benzene trapping. Similar chromatographic peaks after gas chromatographic separation were observed while the volume of sample needed was reduced by a factor of 5. Repeatability and day to day variability of the micro preconcentrators were then studied for a 500 ppb synthetic model mixture injected three times a day four days in a row: 8% and 12% were measured respectively. Micro-preconcentrator to micro-preconcentrator variability was not significant compared to day to day variability. In addition, micro-preconcentrators were tested for breath samples collected in Tedlar(r) bags. Three analyses of the same breath sample displayed relative standard deviations values below 16% for eight of the ten most intense peaks. Finally, the performances of micro preconcentrators for breath sampling on a single expiration were illustrated with the example of volatile tobacco markers tracking. The signals of three smoking markers in breath, benzene, 2,5-dimethylfuran, and toluene were studied. Concentrations of benzene and toluene were found to be 10 to 100 higher in the breath of smokers. 2,5-dimethylfuran was only found in the breath of smokers. The elimination kinetics of the markers were followed as well during 4 h: a fast decrease of the signal of the three markers in breath was observed 20 min after smoking in good agreement with what is described in the literature. Those results demonstrate the efficiency of silicon chips for breath sampling, compared to the state of the art techniques. Thanks to miniaturization and lower sample volumes needed, micro-preconcentrators could be in the future a key technology towards portable breath sampling and analysis. PMID- 30008463 TI - Dietary vitamin D intake and vitamin D related genetic polymorphisms are not associated with gastric cancer in a hospital-based case-control study in Korea. AB - There have been few studies on the association between vitamin D levels and gastric cancer in Asian populations, but no studies have been performed on the interactions between vitamin D intake and polymorphisms in the vitamin D pathway. The effects of vitamin D intake, vitamin D related genetic polymorphisms, and their association with the incidence of gastric cancer were investigated in a hospital case-control study, including 715 pairs of newly diagnosed gastric cancer patients and controls matched for age and sex. Correlations between vitamin D intake and plasma vitamin D concentrations were also assessed in a subset of subjects. No statistically significant difference was observed in the dietary intake of vitamin D between the patients and controls, nor were there any evident associations between vitamin D intake and risk of gastric cancer in multivariate analyses. Vitamin D intake significantly correlated with the circulating 25-hydroxyvitamin D levels, but not with the active form of the vitamin, 1,25-dihydroxyvitamin D. There were no statistically significant interactions between vitamin D intake, and VDR or TXNIP polymorphisms. This study suggests that dietary vitamin D intake is not associated with gastric cancer risk, and the genetic polymorphisms of vitamin D-related genes do not modulate the effect of vitamin D with respect to gastric carcinogenesis. PMID- 30008461 TI - Zoster after Cyclophosphamide for Systemic Lupus Erythematosus or Vasculitis: Incidence, Risk Factors, and Effect of Antiviral Prophylaxis. AB - OBJECTIVE: To assess the incidence and the risk factors for zoster in patients exposed to intravenous cyclophosphamide (CYC) for systemic vasculitis or systemic lupus erythematosus (SLE), as well as the protective effect of prophylaxis by valacyclovir (VCV). METHODS: This retrospective study included all adults treated by intravenous CYC for SLE or systemic vasculitis between 2011 and 2015 at Toulouse University Hospital, France. Zoster occurrence was recorded using medical chart review, laboratory data, and patient interviews. Univariate Cox models were computed to assess the risk factors for zoster and the protective effect of prophylaxis by VCV. RESULTS: The cohort consisted of 110 patients (81 systemic vasculitis and 29 SLE). During a mean followup of 3.4 years after CYC initiation, 10 cases of zoster occurred, leading to an overall incidence of 27.9/1000 patient-years (95% CI 15.2-50.6); it was 59.4/1000 patients (95% CI 27.5-123.6) during the year after CYC initiation. Four patients experienced persistent postherpetic neuralgia. Probable risk factors were lymphopenia < 500/ul at CYC initiation (HR 5.11, 95% CI 0.94-27.93) and female sex (HR 4.36, 95% CI 0.51-37.31). The incidence was higher in patients with SLE (HR as compared with systemic vasculitis patients = 2.68, 95% CI 0.54-13.26). None of the 19 patients exposed to VCV during the followup developed zoster. CONCLUSION: The incidence of zoster is high in systemic vasculitis and in patients with SLE exposed to intravenous CYC. CYC may favor postherpetic neuralgia. Prophylaxis by VCV should be considered, particularly in cases of lymphopenia < 500/ul at CYC initiation and during the year after. PMID- 30008464 TI - Pravastatin alleviates lipopolysaccharide-induced placental TLR4 over-activation and promotes uterine arteriole remodeling without impairing rat fetal development. AB - Preeclampsia is associated with over-activation of the innate immune system in the placenta, in which toll-like receptor 4 (TLR4) plays an essential part. With their potent anti-inflammatory effects, statins have been suggested as potential prevention or treatment of preeclampsia, although evidence remains inadequate. Herewith, we investigated whether pravastatin could ameliorate preeclampsia-like phenotypes in a previously established lipopolysaccharide (LPS)-induced rat preeclampsia model, through targeting the TLR4/NF-kappaB pathway. The results showed that pravastatin reduced the blood pressure [maximum decline on gestational day (GD) 12, (101.33+/-2.49) mmHg vs. (118.3+/-1.37) mmHg, P<0.05] and urine protein level [maximum decline on GD9, (3,726.23+/-1,572.86) MUg vs. (1,991.03+/-609.37) MUg, P<0.05], which were elevated following LPS administration. Pravastatin also significantly reduced the rate of fetal growth restriction in LPS-treated rats (34.10% vs. 8.99%, P<0.05). Further pathological analyses suggested a restoration of normal spiral artery remodeling in preeclampsia rats by pravastatin treatment. These effects of pravastatin were associated with decreased TLR4/NF-kappaB protein levels in the placenta and IL 6/MCP-1 levels in serum. Additionally, no obvious abnormalities in fetal liver, brain, and kidney were found after administration of pravastatin. These results provide supportive evidence for use of pravastatin in preventing preeclampsia. PMID- 30008465 TI - 2-Methyl-5H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine, an edaravone analog, exerts neuroprotective effects against acute ischemic injury via inhibiting oxidative stress. AB - Oxidative stress plays an indispensable role in the pathogenesis of cerebral ischemia. Inhibiting oxidative stress has been considered as an effective approach for stroke treatment. Edaravone, a free radical scavenger, has been shown to prevent cerebral ischemic injury. However, the clinical efficacy of edaravone is limited because it has a low scavenging activity for superoxide anions (O2.-). Here, we report that 2-methyl-5H-benzo[d]pyrazolo[5,1 b][1,3]oxazin-5-imine, a novel small-molecule compound structurally related to edaravone, showed a stronger inhibitory effect on oxidative stress in vitro. In vivo, 2-methyl-5H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine reversed transient middle cerebral artery occlusion-induced dysfunctions of superoxide dismutases and malondialdehyde, two proteins crucial for oxidative stress, suggesting a strengthened antioxidant system. Moreover, 2-methyl-5H-benzo[d]pyrazolo[5,1 b][1,3]oxazin-5-imine decreased blood brain barrier permeability. Then, we found that 2-methyl-5H-benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine had a stronger neuroprotective effect than edaravone. More importantly, 2-methyl-5H benzo[d]pyrazolo[5,1-b][1,3]oxazin-5-imine decreased not only infarct size and neurological deficits in the acute phase but also modified neurological severity score and escape latency in Morris water maze task in the delayed period, indicating enhanced neuroprotection, sensorimotor function and spatial memory. Together, these findings suggest that 2-methyl-5H-benzo[d]pyrazolo[5,1 b][1,3]oxazin-5-imine could be a preferable option for stroke treatment. PMID- 30008466 TI - The Effects of Ludartin on Cell Proliferation, Cell Migration, Cell Cycle Arrest and Apoptosis Are Associated with Upregulation of p21WAF1 in Saos-2 Osteosarcoma Cells In Vitro. AB - BACKGROUND The aim of this study was investigate the effects of the sesquiterpene lactone, ludartin, on cell proliferation, cell migration, apoptosis, and the cell cycle in osteosarcoma cell lines, compared with a normal osteoblast cell line. MATERIAL AND METHODS Osteosarcoma cell lines, MG-63 Saos-2 U-2OS, T1-73 143B, and HOS, and normal hFOB 1.19 osteoblasts, were cultured and treated with increasing doses of ludartin, The MTT colorimetric assay was used to measure cell metabolic activity and viability. Apoptosis was studied by fluorescence-activated cell sorting (FACS) using 4',6-diamidino-2-phenylindole (DAPI) nuclear staining and Annexin-V/propidium iodide (PI) staining. Cell cycle was studied using flow cytometry. Cell migration and invasion were studied using wound healing and Boyden chamber assays. Protein expression was measured by Western blotting. RESULTS Ludartin inhibited cell viability, cell migration, cell proliferation, and increased cell apoptosis, in all osteosarcoma cell lines, with an IC50 dose ranging from 15-30 uM. The greatest effects were on the Saso-2 osteosarcoma cells, with an IC50 of 15 uM. However, ludartin showed minor cytotoxic effects of the normal hFOB 1.19 osteoblasts (IC50 >100 uM). Ludartin exerted its anti proliferative effects on Saos-2 cells via induction of apoptosis and cell cycle arrest at the G2/M checkpoint, associated with reduced expression of Cdc25c (Ser216), Cdc25c, pCdc2 (Tyr15), and Cdc2 and increased expression of p21WAF1. Ludartin inhibited cell migration and invasion of the Saos-2 cells. CONCLUSIONS The dose-dependent effects of ludartin on cell proliferation, migration, apoptosis, cell cycle arrest at the G2/M checkpoint involved p21WAFI in Saos-2 osteosarcoma cells. PMID- 30008467 TI - Serotonin Syndrome in the Perioperative Setting. AB - BACKGROUND Serotonin syndrome is a life-threatening condition that can lead to neurologic complications and is associated with the use of serotonergic medications. As the use of antidepressant medications has increased, the incidence of perioperative serotonin syndrome has transitioned from a rare diagnosis to one that should be considered as a differential diagnosis for any patient displaying signs of neuroexcitation. CASE REPORT A 70-year-old man (ASA 2) with a history of vestibular migraines (treated with venlafaxine), gastroesophageal reflux disease, and benign prostatic hyperplasia presented to our institution for photoselective vaporization of the prostate. Upon review of prior anesthetic records, his medical chart was found to list a propofol allergy. In discussion with the patient, he stated the reaction was rigidity. The anesthesiologist and patient agreed this was not an allergy. Thus, the patient was induced with propofol and given ketamine and fentanyl boluses throughout the procedure. During emergence, the patient exhibited myoclonic jerks in the upper and lower extremities. He was given intravenous meperidine for postoperative shivering; minutes after administration, the myoclonic jerks and rigidity worsened. The anesthesia team raised concern about serotonin syndrome. Intravenous midazolam improved the patient's myoclonic jerks and rigidity. CONCLUSIONS Patients with a history of rigidity/movement disorders during the perioperative period may have experienced serotonin toxicity. It is possible, as in our case, for this history to have been labelled as an allergy to a perioperative medication. Clinicians should remain vigilant for patients at risk of developing serotonin syndrome, such as those taking outpatient medications that increase neuronal serotonin. PMID- 30008468 TI - Bacterial adhesion at the single-cell level. AB - The formation of multicellular microbial communities, called biofilms, starts from the adhesion of a few planktonic cells to the surface. The transition from a free-living planktonic lifestyle to a sessile, attached state is a multifactorial process that is determined by biological, chemical and physical properties of the environment, the surface and the bacterial cell. The initial weak, reversible interactions between a bacterium and a surface strengthen to yield irreversible adhesion. In this Review, we summarize our understanding of the mechanisms governing bacterial adhesion at the single-cell level, including the physical forces experienced by a cell before reaching the surface, the first contact with a surface and the transition from reversible to permanent adhesion. PMID- 30008469 TI - Structural insights into the signalling mechanisms of two-component systems. AB - Two-component systems reprogramme diverse aspects of microbial physiology in response to environmental cues. Canonical systems are composed of a transmembrane sensor histidine kinase and its cognate response regulator. They catalyse three reactions: autophosphorylation of the histidine kinase, transfer of the phosphoryl group to the regulator and dephosphorylation of the phosphoregulator. Elucidating signal transduction between sensor and output domains is highly challenging given the size, flexibility and dynamics of histidine kinases. However, recent structural work has provided snapshots of the catalytic mechanisms of the three enzymatic reactions and described the conformation and dynamics of the enzymatic moiety in the kinase-competent and phosphatase competent states. Insight into signalling mechanisms across the membrane is also starting to emerge from new crystal structures encompassing both sensor and transducer domains of sensor histidine kinases. In this Progress article, we highlight such important advances towards understanding at the molecular level the signal transduction mechanisms mediated by these fascinating molecular machines. PMID- 30008470 TI - Activity-dependent neuroprotective protein (ADNP) is an alcohol-responsive gene and negative regulator of alcohol consumption in female mice. AB - Neuroadaptations in the brain reward system caused by excessive alcohol intake, lead to drinking escalation and alcohol use disorder phenotypes. Activity dependent neuroprotective protein (ADNP) is crucial for brain development, and is implicated in neural plasticity in adulthood. Here, we discovered that alcohol exposure regulates Adnp expression in the mesolimbic system, and that Adnp keeps alcohol drinking in moderation, in a sex-dependent manner. Specifically, Sub chronic alcohol treatment (2.5 g/kg/day for 7 days) increased Adnp mRNA levels in the dorsal hippocampus in both sexes, and in the nucleus accumbens of female mice, 24 h after the last alcohol injection. Long-term voluntary consumption of excessive alcohol quantities (~10-15 g/kg/24 h, 5 weeks) increased Adnp mRNA in the hippocampus of male mice immediately after an alcohol-drinking session, but the level returned to baseline after 24 h of withdrawal. In contrast, excessive alcohol consumption in females led to long-lasting reduction in hippocampal Adnp expression. We further tested the regulatory role of Adnp in alcohol consumption, using the Adnp haploinsufficient mouse model. We found that Adnp haploinsufficient female mice showed higher alcohol consumption and preference, compared to Adnp intact females, whereas no genotype difference was observed in males. Importantly, daily intranasal administration of the ADNP-snippet drug candidate NAP normalized alcohol consumption in Adnp haploinsufficient females. Finally, female Adnp haploinsufficient mice showed a sharp increase in alcohol intake after abstinence, suggesting that Adnp protects against relapse in females. The current data suggest that ADNP is a potential novel biomarker and negative regulator of alcohol-drinking behaviors. PMID- 30008471 TI - Legal Risks and Considerations Associated with Inflammatory Bowel Disease: A Primer. PMID- 30008472 TI - Rectal Cancer in 2018: A Primer for the Gastroenterologist. AB - The rectum has distinctive anatomic and physiologic features, which increase the risk of local spread and recurrence among rectal cancers as compared to colon cancers. Essential to the management of rectal cancers is accurate endoscopic localization as well as preoperative imaging assessment of local and distant disease. Successful oncologic care is multidisciplinary including input from Gastroenterologists, Surgeons, Medical and Radiation Oncologists, Radiologists, and Pathologists. Extensive planning of curative intent is mandatory as failures of upfront treatment present great long-term difficulty for patients and caregivers. Local recurrences are frequently associated with major morbidity including bowel and urinary obstruction, severe pain, and significantly diminished quality of life. Distant recurrence is associated with lower survival. Over the last two decades, there have been many advances in diagnostic imaging techniques as well as surgical techniques including transanal endoscopic microsurgery for very early stage cancers. Progress in curative management paradigms includes shorter courses of preoperative radiotherapy and chemotherapy doublet paradigms for perioperative treatment. This review describes the diagnosis, workup, and multimodality curative intent treatment of rectal cancers. It is emphasized that success begins in the hands and eyes of the gastroenterologist. PMID- 30008473 TI - Granulomatosis With Angiitis and the Expunging of a Medical Eponym. PMID- 30008474 TI - Choosing the Right Central Venous Catheter for Parenteral Nutrition. PMID- 30008475 TI - Clinical genome sequencing in an unbiased pediatric cohort. AB - PURPOSE: We report for the first time, the use of clinical genome sequencing (GS) in an unbiased pediatric cohort. We describe the clinical validation, patient metrics, ordering patterns, results, reimbursement, and physician retrieval of results for the first consecutive 80 cases. METHODS: Clinical GS was performed for both inpatients and outpatients undergoing etiologic evaluations. Results were reported in the electronic medical record. Evidence of report retrieval by clinicians and whether interpretation was concordant with laboratory report was obtained through retrospective chart review. RESULTS: Twenty definitive diagnoses were made in 19 patients (24%; n = 80). Except for two partial gene deletions, all diagnostic variants would have been detectable by our exome methods. Surprisingly, there was no documentation of communication of results to the family in the medical record for 17.5% of patients, and in 7.5%, physician and laboratory interpretations were discordant. Average insurance reimbursement was 30.2%, with yield for commercial payers significantly higher, at 54.1%. CONCLUSIONS: The detection rate of GS is equivalent and potentially superior to exome sequencing (ES). Reimbursement rates were variable but overall satisfactory for commercial insurers, and poor for government entities. In addition, we identify opportunities for improvement in the communication of results to families, likely translatable to other tests and other institutions. PMID- 30008477 TI - The MCL1-specific inhibitor S63845 acts synergistically with venetoclax/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells. PMID- 30008476 TI - Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients. AB - PURPOSE: MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype. METHODS: Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach. RESULTS: Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL. CONCLUSION: This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes. PMID- 30008478 TI - [Musculoskeletal, hearing and skin problems related to playing the instrument]. AB - BACKGROUND: Physical demands, exposure to noise and intense contact of skin with musical instruments - inevitable in musicians' job - influence the development of musculoskeletal, hearing and skin problems. This paper aims at identifying playing-related health problems among Polish musicians and potential differences in this regard between students and professional musicians. MATERIAL AND METHODS: This questionnaire study involved 255 musicians who volunteered to participate - 104 students and 151 professional musicians having music education. The study sample included 61% of women. Mean age of the participants equaled 31 years old, mean playing experience - 23 years old. RESULTS: From 10% to 79% (depending on the affected body part) of the studied musicians experienced musculoskeletal problems. Hearing (41% - tinnitus; 43% - hearing impairment and 52% - hyperacusis) and skin problems (69% - callosities, 58% - abrasions and 26% - allergic reactions) were reported less frequently and were assessed as less severe than musculoskeletal symptoms. The studied professionals assessed their hearing problems (hyperacusis, hearing impairment and tinnitus) as significantly more severe than reported by students. Young musicians, in turn, experienced more severe abrasions than the studied professional musicians. We found no significant differences between students and professionals as regards their musculoskeletal problems. CONCLUSIONS: Playing-related health risks translate into relatively high prevalence of musculoskeletal as well as hearing and skin problems among musicians. Hence, it is essential for future studies to search for risk factors for these health problems as well as effective corrective and therapeutic measures. Med Pr 2018;69(4):383-394. PMID- 30008479 TI - Families at the Intersection of the Criminal Justice and Child Protective Services Systems. AB - In this article, we first describe the incidence and prevalence of incarceration and CPS involvement in the United States. Second, we outline the reasons that the same individuals and families may be at risk for involvement in both systems and review the limited existing research examining links between incarceration and CPS involvement. Third, we use unique longitudinal data from Wisconsin, spanning from 2004 to 2012, to describe intergenerational and intragenerational overlap in the two systems. Specifically, we calculate (1) the proportion of all CPS involved children who have an incarcerated parent; (2) the proportion of incarcerated adults who have a CPS-involved child; (3) the proportion of incarcerated young men and women who were involved in the CPS system as adolescents; and (4) the proportion of CPS-involved adolescents who subsequently became incarcerated. We conclude with a discussion of potential directions for future research as well as implications for practice and policy. PMID- 30008480 TI - Immigration Restrictions as Active Labor Market Policy: Evidence from the Mexican Bracero Exclusion. AB - An important class of active labor market policy has received little impact evaluation: immigration barriers intended to raise wages and employment by shrinking labor supply. Theories of endogenous technical advance raise the possibility of limited or even perverse impact. We study a natural policy experiment: the exclusion of almost half a million Mexican 'bracero' farm workers from the United States to improve farm labor market conditions. With novel archival data we measure state-level exposure to exclusion, and model the labor market effect in the absence of technical change. We reject such an effect and fail to reject a null effect. PMID- 30008481 TI - So, how much of the Earth's surface is covered by rain gauges? AB - The measurement of global precipitation, both rainfall and snowfall, is critical to a wide range of users and applications. Rain gauges are indispensable in the measurement of precipitation, remaining the de facto standard for precipitation information across the Earth's surface for hydro-meteorological purposes. However, their distribution across the globe is limited: over land their distribution and density is variable, while over oceans very few gauges exist and where measurements are made, they may not adequately reflect the rainfall amounts of the broader area. Critically, the number of gauges available, or appropriate for a particular study, varies greatly across the Earth due to temporal sampling resolutions, periods of operation, data latency and data access. Numbers of gauges range from a few thousand available in near real time, to about a hundred thousand for all 'official' gauges, and to possibly hundreds of thousands if all possible gauges are included. Gauges routinely used in the generation of global precipitation products cover an equivalent area of between about 250 m2 and 3,000 m2. For comparison, the center circle of a soccer pitch or tennis court is about 260 m2. Although each gauge should represent more than just the gauge orifice, auto-correlation distances of precipitation vary greatly with regime and the integration period. Assuming each Global Precipitation Climatology Centre (GPCC) available gauge is independent and represents a surrounding area of 5 km radius, this represents only about 1% of the Earth's surface. The situation is further confounded for snowfall which has a greater measurement uncertainty. PMID- 30008482 TI - Prediction and attenuation of seasonal spillover of parasites between wild and domestic ungulates in an arid mixed-use system. AB - Transmission of parasites between host species affects host population dynamics, interspecific competition, and ecosystem structure and function. In areas where wild and domestic herbivores share grazing land, management of parasites in livestock may affect or be affected by sympatric wildlife due to cross-species transmission.We develop a novel method for simulating transmission potential based on both biotic and abiotic factors in a semi-arid system in Botswana. Optimal timing of antiparasitic treatment in livestock is then compared under a variety of alternative host scenarios, including seasonally migrating wild hosts.In this region, rainfall is the primary driver of seasonality of transmission, but wildlife migration leads to spatial differences in the effectiveness of treatment in domestic animals. Additionally, competent migratory wildlife hosts move parasites across the landscape.Simulated transmission potential matches observed patterns of clinical disease in livestock in the study area. Increased wildlife contact is correlated with a decrease in disease, suggesting that non-competent wild hosts may attenuate transmission by removing infective parasite larvae from livestock pasture.Optimising the timing of treatment according to within-year rainfall patterns was considerably more effective than treating at a standard time of year. By targeting treatment in this way, efficient control can be achieved, mitigating parasite spillover from wildlife where it does occur. Synthesis and applications. This model of parasite transmission potential enables evidence-based management of parasite spillover between wild and domestic species in a spatio-temporally dynamic system. It can be applied in other mixed-use systems to mitigate parasite transmission under altered climate scenarios or changes in host ranges. PMID- 30008484 TI - The Relationship between the School Breakfast Program and Food Insecurity. AB - Food insecurity rates have risen significantly in the United States beginning with the recent recession and remained high. The implications of these high rates are severe in that food insecurity has been associated with a wide range of health, behavioral, social and cognitive difficulties. This paper examines the relationship between the School Breakfast Program (SBP) and food insecurity outcomes. The SBP has the potential to reduce food insecurity because of the direct provision of breakfast to students and the implied income transfer to households. We use state-level cutoffs tied to school-level poverty rates that mandate the provision of the SBP to compare the food security outcomes of students in similar schools, but with different requirements to provide breakfast. Our estimates suggest that state policies requiring schools to offer the SBP have reduced food insecurity for young children. PMID- 30008483 TI - Geostatistical models using remotely-sensed data predict savanna tsetse decline across the interface between protected and unprotected areas in Serengeti, Tanzania. AB - Monitoring abundance is essential for vector management, but it is often only possible in a fraction of managed areas. For vector control programmes, sampling to estimate abundance is usually carried out at a local-scale (10s km2), while interventions often extend across 100s km2. Geostatistical models have been used to interpolate between points where data are available, but this still requires costly sampling across the entire area of interest. Instead, we used geostatistical models to predict local-scale spatial variation in the abundance of tsetse-vectors of human and animal African trypanosomes-beyond the spatial extent of data to which models were fitted, in Serengeti, Tanzania.We sampled Glossina swynnertoni and Glossina pallidipes >10 km inside the Serengeti National Park (SNP) and along four transects extending into areas where humans and livestock live. We fitted geostatistical models to data >10 km inside the SNP to produce maps of abundance for the entire region, including unprotected areas.Inside the SNP, the mean number of G. pallidipes caught per trap per day in dense woodland was 166 (+/- 24 SE), compared to 3 (+/-1) in grassland. Glossina swynnertoni was more homogenous with respective means of 15 (+/-3) and 15 (+/-8). In general, models predicted a decline in abundance from protected to unprotected areas, related to anthropogenic changes to vegetation, which was confirmed during field survey. Synthesis and applications. Our approach allows vector control managers to identify sites predicted to have relatively high tsetse abundance, and therefore to design and implement improved surveillance strategies. In East and Southern Africa, trypanosomiasis is associated with wilderness areas. Our study identified pockets of vegetation which could sustain tsetse populations in farming areas outside the Serengeti National Park. Our method will assist countries in identifying, monitoring and, if necessary, controlling tsetse in trypanosomiasis foci. This has specific application to tsetse, but the approach could also be developed for vectors of other pathogens. PMID- 30008485 TI - Europe's Culture(s): Negotiating Cultural Meanings, Values, and Identities in the European Context. AB - The intent of this Special Issue is to be a starting point for a broadly-defined European cultural psychology. Across seven research articles, the authors of this Special Issue explore what European culture(s) and European identity entail, how acculturation within the European cultural contexts takes place and under what conditions a multicultural Europe might be possible. The Special Issue also discusses what is currently missing from the research agenda. Therein, the findings of this Special Issue constitute an important starting point for future psychological research that accompanies Europe along its journey into the 21st century. PMID- 30008486 TI - Investigation of the influence of a large steel plate on the magnetic field distribution of a magnetic proximity detection system. AB - A magnetic proximity detection system is mounted on a mobile mining machine to prevent underground workers from being pinned or struck by machine motion. The system generates magnetic fields around the machine to determine safe working distances. The miner-worn component measures the magnetic field in order to approximate location. Large masses of steel, such as those from mining equipment, can alter the magnetic field distribution. This affects the locational accuracy of the system, thus adversely impacting worker safety. To examine this problem, U.S. National Institute for Occupational Safety and Health researchers developed a method and test system to study the influence of a steel mass on the magnetic field distribution. The results show that a steel plate can strengthen the magnetic field perpendicular to the generator by up to 40 percent. Furthermore, they show that the degree of the influence on the field distribution is a function of distance. The results from this study can be used to further develop and improve the performance and reliability of electromagnetic proximity detection systems used in underground mining applications. PMID- 30008487 TI - Maximally rotating supermassive stars at the onset of collapse: the perturbative effects of gas pressure, magnetic fields, dark matter, and dark energy. AB - The discovery of quasars at increasingly large cosmological redshifts may favour 'direct collapse' as the most promising evolutionary route to the formation of supermassive black holes. In this scenario, supermassive black holes form when their progenitors - supermassive stars - become unstable to gravitational collapse. For uniformly rotating stars supported by pure radiation pressure and spinning at the mass-shedding limit, the critical configuration at the onset of collapse is characterized by universal values of the dimensionless spin and radius parameters J/M2 and R/M, independent of mass M. We consider perturbative effects of gas pressure, magnetic fields, dark matter, and dark energy on these parameters, and thereby determine the domain of validity of this universality. We obtain leading-order corrections for the critical parameters and establish their scaling with the relevant physical parameters. We compare two different approaches to approximate the effects of gas pressure, which plays the most important role, find identical results for the above dimensionless parameters, and also find good agreement with recent numerical results. PMID- 30008488 TI - Michelson Interferometer for Global High-resolution Thermospheric Imaging (MIGHTI): Instrument Design and Calibration. AB - The Michelson Interferometer for Global High-resolution imaging of the Thermosphere and Ionosphere (MIGHTI) instrument was built for launch and operation on the NASA Ionospheric Connection Explorer (ICON) mission. The instrument was designed to measure thermospheric horizontal wind velocity profiles and thermospheric temperature in altitude regions between 90km and 300km, during day and night. For the wind measurements it uses two perpendicular fields of view pointed at the Earth's limb, observing the Doppler shift of the atomic oxygen red and green lines at 630.0nm and 557.7nm wavelength. The wavelength shift is measured using field-widened, temperature compensated Doppler Asymmetric Spatial Heterodyne (DASH) spectrometers, employing low order echelle gratings operating at two different orders for the different atmospheric lines. The temperature measurement is accomplished by a multichannel photometric measurement of the spectral shape of the molecular oxygen A-band around 762nm wavelength. For each field of view, the signals of the two oxygen lines and the A band are detected on different regions of a single, cooled, frame transfer charge coupled device (CCD) detector. On-board calibration sources are used to periodically quantify thermal drifts, simultaneously with observing the atmosphere. The MIGHTI requirements, the resulting instrument design and the calibration are described. PMID- 30008489 TI - Addiction medicine and addiction psychiatry in America: The impact of physicians in recovery on the medical treatment of addiction. AB - Two distinct medical disciplines treat addiction in the United States: Addiction medicine and addiction psychiatry. This article argues that physicians recovering from alcoholism or drug abuse played a key role in creating the field of addiction medicine, and that the development of addiction medicine inadvertently contributed to the formation of addiction psychiatry. Addiction medicine's undercurrent of recovery, specifically questions about the knowledge that recovering physicians call on to treat addiction, remains central to an ongoing professional conflict between addiction medicine and addiction psychiatry. PMID- 30008490 TI - Writing Alone or Together: Police Officers' Collaborative Reports of an Incident. AB - After witnessing an incident, police officers may write their report collaboratively. We examined how collaboration influences the amount and accuracy of information in police reports. Eighty-six police officers participated, in pairs, in a live training scenario. Officers wrote a report about the incident, either with their partner or individually. Reports by two officers working together (collaborative performance) contained less information than reports by two officers working individually (nominal performance), with no difference in accuracy. After the first report, officers who had worked individually wrote a collaborative report. Police officers who recorded their own memories prior to collaboration included less incorrect information in the collaborative report than police officers who wrote a collaborative report immediately after the incident. Finally, content-focused retrieval strategies (acknowledge, repeat, rephrase, elaborate) during the officers' discussion positively predicted the amount of information in collaborative reports. Practical recommendations for the police and suggestions for further research are provided. PMID- 30008492 TI - Recovering The Principles of Humane Experimental Technique: The 3Rs and the Human Essence of Animal Research. AB - The 3Rs, or the replacement, reduction, and refinement of animal research, are widely accepted as the best approach to maximizing high-quality science while ensuring the highest standard of ethical consideration is applied in regulating the use of animals in scientific procedures. This contrasts with the muted scientific interest in the 3Rs when they were first proposed in The Principles of Humane Experimental Technique (1959). Indeed, the relative success of the 3Rs has done little to encourage engagement with their original text, which remains little read and out of print. By adopting a historical perspective, this article argues that one explanation for this disjunction may be found in another, more celebrated, event of 1959: C. P. Snow's Rede lecture on The Two Cultures. The moral outlook of The Principles of Humane Experimental Technique derived from an earlier ethos wherein humanistic and scientific values occupied a shared culture. While the synthetic style of The Principles has hindered its readership, this article concludes that there is value to recovering the notion that the humanities and social sciences can contribute to the improvement of animal research. PMID- 30008491 TI - Modeling the Influence of Social Ties and Transportation Choice on Access to Oral Healthcare for Older Adults. AB - The current U.S. demographic shift toward an older population and the importance of intervening before conditions become severe warrant a concerted effort to ease the burden of access to healthcare for older adults. With regard to oral healthcare, more integrated services for older adults are needed to effectively serve their complex medical and dental needs. Using an agent-based simulation model, this paper examines the influence of social ties and transportation mode choices on opportunities for older adults to participate in community-based preventive screening events and access needed oral healthcare. This approach accounts for the heterogeneity of behavior that arises for a population exhibiting diversity in terms of social factors, including socioeconomic means and social support. In the context of older adults living in urban environments, the availability of different transportation modes ought to be taken into consideration. To explore alternative scenarios for the accessibility of preventive screening events offered at senior centers in northern Manhattan, an agent-based model (ABM) was created with a geographic information system (GIS) to simulate the influence of social ties and transportation choices on older adults seeking preventive screening services and oral healthcare. Results of simulation experiments indicate preferences for public transportation and inequities in accessibility that may be mitigated with social support. This simulation model offers a way to explore social support as an important factor in making transportation mode choices that mediate oral healthcare accessibility and thus oral health outcomes for older adults. PMID- 30008493 TI - Societal Sentience: Constructions of the Public in Animal Research Policy and Practice. AB - The use of nonhuman animals as models in research and drug testing is a key route through which contemporary scientific knowledge is certified. Given ethical concerns, regulation of animal research promotes the use of less "sentient" animals. This paper draws on a documentary analysis of legal documents and qualitative interviews with Named Veterinary Surgeons and others at a commercial laboratory in the UK. Its key claim is that the concept of animal sentience is entangled with a particular imaginary of how the general public or wider society views animals. We call this imaginary societal sentience. Against a backdrop of increasing ethnographic work on care encounters in the laboratory, this concept helps to stress the wider context within which such encounters take place. We conclude that societal sentience has potential purchase beyond the animal research field, in helping to highlight the affective dimension of public imaginaries and their ethical consequences. Researching and critiquing societal sentience, we argue, may ultimately have more impact on the fate of humans and nonhumans in the laboratory than focusing wholly on ethics as situated practice. PMID- 30008494 TI - Exploring the Role of Animal Technologists in Implementing the 3Rs: An Ethnographic Investigation of the UK University Sector. AB - The biomedical industry relies on the skills of animal technologists (ATs) to put laboratory animal welfare into practice. This is the first study to explore how this is achieved in relation to their participation in implementing refinement and reduction, two of the three key guiding ethical principles--the "3Rs"--of what is deemed to be humane animal experimentation. The interpretative approach contributes to emerging work within the social sciences and humanities exploring care and ethics in practice. Based on qualitative analysis of participant observation within animal research facilities in UK universities, in-depth interviews with ATs, facility managers, and other stakeholders, and analysis of regulatory guidelines, we draw a contrast between the minimum required of ATs by law and how their care work not only meets but often exceeds these requirements. We outline how ATs constitute a key source of innovation and insight into the refinement of animal care and the reduction of animal use, hitherto not formally acknowledged. Exploring AT care work as an example of ethics in practice makes an original contribution to broader debates within health care and animal welfare about how technology, regulation, and behavior can foster and sustain a "culture of care". PMID- 30008495 TI - Responsibility and Laboratory Animal Research Governance. AB - The use of animals in experiments and research remains highly contentious. Laboratory animal research governance provides guidance and regulatory frameworks to oversee the use and welfare of laboratory animals and relies heavily on the replacement, reduction, and refinement (3Rs) principles to demonstrate responsibility. However, the application of the 3Rs is criticized for being too narrow in focus and closing down societal concerns and political questions about the purpose of animal laboratory research. These critiques challenge the legitimacy of responsibility in laboratory animal research governance and call for new approaches. With the advent of the "Responsible Research and Innovation" (RRI) agenda, we investigate whether the notion of responsibility in the controversial area of animal research governance could be enhanced by examining the 3Rs through RRI. Our analysis reveals RRI has the potential to helpfully augment the 3Rs in three key ways: recognizing the need to include a broader range of experts and publics in animal research governance; emphasizing the importance for animal research scientists of taking societal, and not just role, responsibilities into account; and acknowledging the political questions animal research raises. PMID- 30008496 TI - Seasonal patterns of bole water content in old growth Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco). AB - Large conifer trees in the Pacific Northwest, USA (PNW) use stored water to extend photosynthesis, both diurnally and seasonally. This is particularly important during the summer drought, which is characteristic of the region. In the PNW, climate change is predicted to result in hotter, drier summers and warmer, wetter winters with decreased snowpack by mid-century. Understanding seasonal bole water dynamics in relation to climate factors will enhance our ability to determine the vulnerability of forests to climate change. Seasonal patterns of bole water content in old-growth Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) trees were studied in the Cascade Mountains of western Oregon, USA. Relative water content (RWC) was monitored hourly in three 400+ and three ~150 years-old trees using permanently mounted dielectric devices for 10 years. RWC increased during the late spring and early summer to maximum levels in August then decreased into fall and remained low over winter. The difference between minimum RWC in the winter and maximum in mid-summer averaged 4.5 and 2.3% for the older and younger trees, respectively, across all years. RWC closely followed growth and was positively correlated with air and soil temperature, vapor pressure deficit and photosynthetically active radiation, but lagged plant available soil water. The progressive decrease in RWC seen each year from mid summer through fall was attributed to net daily loss of water during the summer drought. The marked increase in RWC observed from spring to mid-summer each year was hypothesized to be the period of embolism repair and water recharge in elastic tissues. We conclude that bole water content is an integral part of tree water dynamics enabling trees to extend carbon assimilation into drought periods and during periods when cold soil inhibits water uptake by roots, an adaptation that could benefit the survival of large PNW trees under climate change. PMID- 30008497 TI - Maternal Repartnering: Does Father Involvement Matter? Evidence from United Kingdom. AB - Maternal repartnering may have benefits for mothers and children. Yet, mothers with coresident children face more difficulty repartnering than other adults. Despite that shared physical custody and father involvement have increased over time, few studies have examined whether nonresidential father involvement and financial support are associated with subsequent maternal repartnering. Using data from the UK Millennium Cohort Study, we found a negative relationship between nonresident father involvement and subsequent maternal repartnering among mothers who were neither married nor cohabiting at childbirth. A potential explanation is that these parents may be engaged in fluid and uncertain relationships, and that the ambiguity thereof may discourage maternal repartnering. We found no association between father involvement and maternal repartnering for mothers who were cohabiting with or married to the father at the time of birth. Finally, we found no association between child support (maintenance) receipt and maternal repartnering, regardless of parental relationship status at the birth. PMID- 30008498 TI - Tolerance Versus Support: Perceptions of Residential Community Climate Among LGB Parents. AB - Objective: To understand which aspects of residential communities are most salient for determining whether sexual minority parents classify their residential community climates as tolerant versus supportive. Background: Metropolitan hubs for lesbian, gay, and bisexual (LGB) parents are well established, but less is known about nonmetropolitan community climates for LGB parents. Residential community climate toward nonmetropolitan LGB persons may be particularly important to LGB parents because of the potential influences on child and family well-being. Method: Open- and closed-ended survey data from a sample of 55 LGB parents were collected along with publically available data regarding their residential communities. Self-reported residential community climate (tolerant vs. supportive) and community involvement, as well as objective county and municipal climate were analyzed. Results: Compared with LGB parents who perceived their communities to be tolerant (n = 38), parents who considered their residential communities to be supportive (n = 17) were more likely to live in counties characterized by legal support and broad social acceptance, were personally more likely to participate in LGB-focused social and political activities, had children with more exposure to other LGB families, and attended church less frequently. Conclusion: Having basic features of equity such as city ordinances and LGB organizations provides a foundation for tolerance in a community; however, individuals in a community must access personal and social supports and activities beyond work and church to feel truly supported. Implications: LGB parents' perceptions of climate reveal specific community features that need to be strengthened to promote family well-being. PMID- 30008499 TI - Multi-scale relief model (MSRM): a new algorithm for the visualization of subtle topographic change of variable size in digital elevation models. AB - Morphological analysis of landforms has traditionally relied on the interpretation of imagery. Although imagery provides a natural view of an area of interest (AOI) images are largely hindered by the environmental conditions at the time of image acquisition, the quality of the image and, mainly, the lack of topographical information, which is an essential factor for a correct understanding of the AOI's geomorphology. More recently digital surface models (DSMs) have been incorporated into the analytical toolbox of geomorphologists. These are usually high-resolution models derived from digital photogrammetric processes or LiDAR data. However, these are restricted to relatively small areas and are expensive or complex to acquire, which limits widespread implementation. In this paper, we present the multi-scale relief model (MSRM), which is a new algorithm for the visual interpretation of landforms using DSMs. The significance of this new method lies in its capacity to extract landform morphology from both high- and low-resolution DSMs independently of the shape or scale of the landform under study. This method thus provides important advantages compared to previous approaches as it: (1) allows the use of worldwide medium resolution models, such as SRTM, ASTER GDEM, ALOS, and TanDEM-X; (2) offers an alternative to traditional photograph interpretation that does not rely on the quality of the imagery employed nor on the environmental conditions and time of its acquisition; and (3) can be easily implemented for large areas using traditional GIS/RS software. The algorithm is tested in the Sutlej-Yamuna interfluve, which is a very large low relief alluvial plain in northwest India where 10 000 km of palaeoriver channels have been mapped using MSRM. The code, written in Google Earth Engine's implementation of JavaScript, is provided as Supporting Information for its use in any other AOI without particular technical knowledge or access to topographical data. (c) 2017 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd. PMID- 30008500 TI - How well can we simulate complex hydro-geomorphic process chains? The 2012 multi lake outburst flood in the Santa Cruz Valley (Cordillera Blanca, Peru). AB - Changing high-mountain environments are characterized by destabilizing ice, rock or debris slopes connected to evolving glacial lakes. Such configurations may lead to potentially devastating sequences of mass movements (process chains or cascades). Computer simulations are supposed to assist in anticipating the possible consequences of such phenomena in order to reduce the losses. The present study explores the potential of the novel computational tool r.avaflow for simulating complex process chains. r.avaflow employs an enhanced version of the Pudasaini (2012) general two-phase mass flow model, allowing consideration of the interactions between solid and fluid components of the flow. We back calculate an event that occurred in 2012 when a landslide from a moraine slope triggered a multi-lake outburst flood in the Artizon and Santa Cruz valleys, Cordillera Blanca, Peru, involving four lakes and a substantial amount of entrained debris along the path. The documented and reconstructed flow patterns are reproduced in a largely satisfactory way in the sense of empirical adequacy. However, small variations in the uncertain parameters can fundamentally influence the behaviour of the process chain through threshold effects and positive feedbacks. Forward simulations of possible future cascading events will rely on more comprehensive case and parameter studies, but particularly on the development of appropriate strategies for decision-making based on uncertain simulation results. (c) 2017 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd. PMID- 30008501 TI - The epistemic innocence of clinical memory distortions. AB - In some neuropsychological disorders, distorted reports seem to fill gaps in people's memory of their past, where people's self-image, history, and prospects are often enhanced. False beliefs about the past compromise both people's capacity to construct a reliable autobiography and their trustworthiness as communicators. However, such beliefs contribute to people's sense of competence and self-confidence, increasing psychological well-being. Here, we consider both the psychological benefits and epistemic costs and argue that distorting the past is likely to also have epistemic benefits that cannot be obtained otherwise, such as enabling people to exchange information, receive feedback, and retain key beliefs about themselves. PMID- 30008502 TI - Mathematical modelling of expanded bed adsorption - a perspective on in silico process design. AB - Expanded bed adsorption (EBA) emerged in the early 1990s in an attempt to integrate the clarification, capture and initial product concentration/purification process. Several mathematical models have been put forward to describe its operation. However, none of the models developed specifically for EBA allows simultaneous prediction of bed hydrodynamics, mass transfer/adsorption and (unwanted) interactions and fouling. This currently limits the development and early optimization of EBA-based separation processes. In multiphase reactor engineering, the use of multiphase computational fluid dynamics has been shown to improve fundamental understanding of fluidized beds. To advance EBA technology, a combination of particle, equipment and process scale models should be used. By employing a cascade of multiscale simulations, the various challenges EBA currently faces can be addressed. This allows for optimal design and selection of equipment, materials and process conditions, and reduces risks and development times of downstream processes involving EBA. (c) 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 30008503 TI - Continuous cell flocculation for recombinant antibody harvesting. AB - BACKGROUND: Integrated continuous production technology is of great interest in biopharmaceutical industry. Efficient, flexible and cost effective methods for continuous cell removal have to be developed, before a fully continuous and integrated product train can be realized. The paper describes the development and testing of such an integrated continuous and disposable set-up for cell separation by flocculation combined with depth filtration. RESULTS: Screening of multiple flocculation agents, depth filters, and conditions demonstrated that the best performance was obtained with 0.0375% polydiallyldimethylammonium chloride (pDADMAC; a polycationic flocculation agent) in combination with Clarisolve(r) depth filters. Using this set-up, a 4-fold decrease of filtration area was achieved relative to standard filtration without flocculation, with yields of >=97% and DNA depletion of up to 99%. Continuous operation was accomplished using a simple tubular reactor design with parallelization of the filtration. The reactor length was selected to allow a 13.2-min residence time, which was sufficient to complete flocculation in batch experiments. Continuous flocculation performance was monitored on-line using focused beam reflectance measurement. Filter switch cycles based on upstream pressure were controlled by in-line pressure sensors, and were stable from one filter to the next. CONCLUSION: It was demonstrated that stable and efficient continuous flocculation associated with depth filtration can be easily accomplished using tubular reactors and parallelization. Continuous cell separation is essential for the development of fully continuous integrated process trains. This cost-efficient disposable design run in continuous mode significantly reduces facility foot print, process costs and enables great flexbility. (c) 2017 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 30008504 TI - Magnetic hydrophobic-charge induction adsorbents for the recovery of immunoglobulins from antiserum feedstocks by high-gradient magnetic fishing. AB - BACKGROUND: The extraction of biopharmaceuticals from plasma and serum often employs overly complicated antiquated procedures that can inflict serious damage on especially prone protein targets and which afford low purification power and overall yields. This paper describes systematic development of a high-gradient magnetic fishing process for recovery of immunoglobulins from unclarified antiserum. RESULTS: Non-porous superparamagnetic particles were transformed into hydrophobic-charge induction adsorbents and then used to recover immunoglobulins from rabbit antiserum feedstocks. Comprehensive characterisation tests conducted with variously diluted clarified antiserum on a magnetic rack revealed that immunoglobulin binding was rapid (equilibrium reached in <45 s), strong (Kd < 0.1 mg mL-1), of high capacity (Qmax = 214 mg g-1), and pH and ionic strength dependent. In a high-gradient magnetic fishing process conducted with the same adsorbent, and a conventional 'magnetic filter + recycle loop' arrangement, >72% of the immunoglobulin present in an unclarified antiserum feed was recovered in 0.5 h in >3-fold purified form. CONCLUSIONS: Fast magnetic particle based capture of antibodies from an unclarified high-titre feed has been demonstrated. Efficient product recovery from ultra-high titre bioprocess liquors by high gradient magnetic fishing requires that improved magnetic adsorbents displaying high selectivity, ultra-high capacity and operational robustness are used with 'state-of-the-art' rotor-stator magnetic separators. (c) 2018 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 30008505 TI - Effects of bed compression on protein separation on gel filtration chromatography at bench and pilot scale. AB - BACKGROUND: Poorly packed chromatography columns are known to reduce drastically the column efficiency and produce broader peaks. Controlled bed compression has been suggested to be a useful approach for solving this problem. Here the relationship between column efficiency and resolution of protein separation are examined when preparative chromatography media were compressed using mechanical and hydrodynamic methods. Sepharose CL-6B, an agarose based size exclusion media was examined at bench and pilot scale. The asymmetry and height equivalent of a theoretical plate (HETP) was determined by using 2% v/v acetone, whereas the void volume and intraparticle porosity (epsilon p) were estimated by using blue dextran. A protein mixture of ovalbumin (chicken), bovine serum albumin (BSA) and gamma'- globulin (bovine) with molecular weights of 44, 67 and 158 kDa, respectively, were used as a 'model' separation challenge. RESULTS: Mechanical compression achieved a reduction in plate height for the column with a concomitant improvement in asymmetry. Furthermore, the theoretical plate height decreased significantly with mechanical compression resulting in a 40% improvement in purity compared with uncompressed columns at the most extreme conditions of compression used. CONCLUSION: The results suggest that the mechanical bed compression of Sepharose CL-6B can be used to improve the resolution of protein separation. (c) 2017 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 30008507 TI - Preferential crystallization for the purification of similar hydrophobic polyphenols. AB - BACKGROUND: Preferential crystallization is a common technique used in the purification of enantiomers, proving that crystallization may also be applied to the purification of very similar molecules by seeding the solution with the desired compound. Nonetheless, its application to other organic molecules is less widely documented in the literature. Knowing that chemically related polyphenols are generally co-produced by fermentation and their purification can be too expensive for their market value, this technique may contribute to developing a downstream process with less expensive steps. The goal of this work is to show the applicability of the preferential crystallization concept to the purification of similar polyphenols - naringenin and trans-resveratrol - with either single or coupled crystallizers. RESULTS: After developing the required crystallization kinetic models, an experiment using two coupled vessels was devised, where a 63% yield of naringenin and 44% yield of trans-resveratrol was obtained, with >=98% purity in both cases. When the vessels were working independently, 81% of pure trans-resveratrol (started 60% pure) and 70% of pure naringenin (started 68% pure) were recovered. CONCLUSION: The experiments performed show the possibility of separately purifying two similar molecules (from 60% to roughly 100%) with promising yields, despite their similar solubility. This method, which can be significantly improved, might provide an economically attractive way for the production of low added value products. (c) 2017 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 30008506 TI - Purification of influenza virus-like particles using sulfated cellulose membrane adsorbers. AB - BACKGROUND: Vaccines based on virus-like particles (VLPs) are an alternative to inactivated viral vaccines that combine good safety profiles with strong immunogenicity. In order to be economically competitive, efficient manufacturing is required, in particular downstream processing, which often accounts for major production costs. This study describes the optimization and establishment of a chromatography capturing technique using sulfated cellulose membrane adsorbers (SCMA) for purification of influenza VLPs. RESULTS: Using a design of experiments approach, the critical factors for SCMA performance were described and optimized. For optimal conditions (membrane ligand density: 15.4 umol cm-2, salt concentration of the loading buffer: 24 mmol L-1 NaCl, and elution buffer: 920 mmol L-1 NaCl, as well as the corresponding flow rates: 0.24 and 1.4 mL min-1), a yield of 80% in the product fraction was obtained. No loss of VLPs was detected in the flowthrough fraction. Removal of total protein and DNA impurities were higher than 89% and 80%, respectively. CONCLUSION: Use of SCMA represents a significant improvement compared with conventional ion exchanger membrane adsorbers. As the method proposed is easily scalable and reduces the number of steps required compared with conventional purification methods, SCMA could qualify as a generic platform for purification of VLP-based influenza vaccines. (c) 2017 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 30008508 TI - The importance of family income in the formation and evolution of non-cognitive skills in childhood. AB - Little is known about the relationship between family income and children's non cognitive (or socio-emotional) skill formation. This is an important gap, as these skills have been hypothesized to be a critical link between early outcomes and adult socioeconomic status. This paper presents new evidence of the importance of family income in the formation and evolution of children's non cognitive skills using a recent US panel dataset that tracks children between grades K-5. Findings suggest an important divergence in non-cognitive skills based on family income that accumulates over time and does not seem to be explained by children's health status differences. PMID- 30008509 TI - Nonparametric Two-Sample Tests of the Marginal Mark Distribution with Censored Marks. AB - Occasionally, investigators collect auxiliary marks at the time of failure in a clinical study. Because the failure event may be censored at the end of the follow-up period, these marked endpoints are subject to induced censoring. We propose two new families of two-sample tests for the null hypothesis of no difference in mark-scale distribution that allows for arbitrary associations between mark and time. One family of proposed tests is a nonparametric extension of an existing semi-parametric linear test of the same null hypothesis while a second family of tests is based on novel marked rank processes. Simulation studies indicate that the proposed tests have the desired size and possess adequate statistical power to reject the null hypothesis under a simple change of location in the marginal mark distribution. When the marginal mark distribution has heavy tails, the proposed rank-based tests can be nearly twice as powerful as linear tests. PMID- 30008510 TI - High level of self-control ability in a small passerine bird. AB - Abstract: Cognitively advanced animals are usually assumed to possess better self control, or ability to decline immediate rewards in favour of delayed ones, than less cognitively advanced animals. It has been claimed that the best predictor of high such ability is absolute brain volume meaning that large-brained animals should perform better than small-brained ones. We tested self-control ability in the great tit, a small passerine. In the common test of this ability, the animal is presented with a transparent cylinder that contains a piece of food. If the animal tries to take the reward through the transparent wall of the cylinder, this is considered an impulsive act and it fails the test. If it moves to an opening and takes the reward this way, it passes the test. The average performance of our great tits was 80%, higher than most animals that have been tested and almost in level with the performance in corvids and apes. This is remarkable considering that the brain volume of a great tit is 3% of that of a raven and 0.1% of that of a chimpanzee. Significance statement: The transparent cylinder test is the most common way to test the ability of self-control in animals. If an animal understands that it only can take food in the cylinder from the cylinder's opening and controls its impulsivity, it passes the test. A high level of self-control has been demonstrated only in cognitively advanced animals such as apes and corvids. Here, we demonstrate that the great tit, a small song bird that is very good at learning, performs almost in level with chimpanzees and ravens in this test. PMID- 30008511 TI - Intraspecific variation in the petal epidermal cell morphology of Vicia faba L. (Fabaceae). AB - At a microscopic scale, the shape and fine cell relief of the petal epidermal cells of a flower play a key role in its interaction with pollinators. In particular, conical shaped petal epidermal cells have been shown to have an important function in providing grip on the surface of bee-pollinated flowers and can influence bee visitation rates. Previous studies have explored interspecific variation in this trait within genera and families, but naturally-occurring intraspecific variation has not yet been comprehensively studied. Here, we investigate petal epidermal cell morphology in 32 genotypes of the crop Vicia faba, which has a yield highly dependent on pollinators. We hypothesise that conical cells may have been lost in some genotypes as a consequence of selective sweeps or genetic drift during breeding programmes. We find that 13% of our lines have a distribution of conical petal epidermal cells that deviates from that normally seen in V. faba flowers. These abnormal phenotypes were specific to the ad/abaxial side of petals, suggesting that these changes are the result of altered gene expression patterns rather than loss of gene function. PMID- 30008512 TI - Comparison of thiaminase activity in fish using the radiometric and 4 nitrothiophenol colorimetric methods. AB - Thiaminase induced thiamine deficiency occurs in fish, humans, livestock and wild animals. A non-radioactive thiaminase assay was described in 2007, but a direct comparison with the radioactive 14C-thiamine method which has been in use for more than 30 years has not been reported. The objective was to measure thiaminase activity in forage fish (alewife Alosa pseudoharengus, rainbow smelt Osmerus mordax, and slimy sculpin Cottus cognatus) consumed by predators that manifest thiamine deficiency using both methods. Modifications were made to the colorimetric assay to improve repeatability. Modification included a change in assay pH, enhanced sample clean-up, constant assay temperature (37 degrees C), increase in the concentration of 4-nitrothiophenol (4NTP) and use of a spectrophotometer fitted with a 0.2 cm cell. A strong relationship between the two assays was found for 51 alewife (R2=0.85), 36 smelt (R2=0.87) and 20 sculpin (R2=0.82). Thiaminase activity in the colorimetric assay was about 1000 times higher than activity measured by the radioactive method. Application of the assay to fish species from which no thiaminase activity has previously been reported resulted in no 4NTP thiaminase activity being found in bloater Coregonus hoyi, lake trout Salvelinus namaycusch, steelhead trout Oncorhynchus mykiss or Chinook salmon Oncorhynchus tshawytscha. In species previously reported to contain thiaminase, 4NTP thiaminase activity was measured in bacteria Paenibacillus thiaminolyticus, gizzard shad Dorosoma cepedianum, bracken fern Pteridium aquilinum, quagga mussel Dreissena bugensis and zebra mussels D. polymorpha. PMID- 30008513 TI - Toward Father-friendly Parenting Interventions: A Qualitative Study. AB - Levels of father participation in parenting interventions are often very low, yet little is known about the factors which influence father engagement. We aimed to qualitatively explore perceived barriers to, and preferences for, parenting interventions in a community sample of fathers. Forty-one fathers across nine focus groups were interviewed using a semi-structured interview. Data were analysed using inductive thematic analysis. Key barriers to father participation identified included: the perception that interventions are mother-focused; beliefs about gender roles regarding parenting and help-seeking; mothers' role as 'gatekeeper'; lack of knowledge and awareness of parenting interventions; and lack of relevance of interventions. Fathers reported preferences for specific content and intervention features, facilitator characteristics, practical factors, and highlighted the need for father-targeted recruitment and advertising. Many of the barriers and preferences identified are consistent with previous research; however, fathers' beliefs and attitudes around gender roles and help-seeking, as well as the perception that interventions are predominantly mother-focused, may be key barriers for community fathers. Strategies to overcome these barriers and better meet the needs of fathers in promoting and delivering parenting interventions are discussed. PMID- 30008514 TI - Suffering a Loss Is Good Fortune: Myth or Reality? AB - We sometimes decide to take an offered option that results in apparent loss (e.g., unpaid overtime). Mainstream decision theory does not predict or explain this as a choice we want to make, whereas such a choice has long been described and highly regarded by the traditional Chinese dogma "" (suffering a loss is good fortune). To explore what makes the dogma work, we developed a celebrity anecdote based scale to measure "Chikui" (suffering a loss) likelihood and found that:(i) people with higher scores on the Chikui Likelihood Scale (CLS) were more likely to report higher scores on subjective well-being and the Socioeconomic Index for the present and (ii) the current Socioeconomic Index could be positively predicted not only by current CLS scores but also by retrospective CLS scores recalled for the past, and the predictive effect was enhanced with increasing time intervals. Our findings suggest that "suffering a loss is good fortune" is not a myth but a certain reality. PMID- 30008515 TI - Relating Decision-Making Styles to Social Orientation and Time Approach. AB - Research on decision-making styles has shown that stylistic differences matter for real-life outcomes, but less research has explored how styles relate to other differences between individuals. Heeding a call for a more systematic and theoretically sound understanding of decision-making styles, we investigated the relation between decision-making styles and specific aspects of social orientation and approach to time in two samples (students, n = 118, and police investigators, n = 90). The results of regression analyses showed that decision making styles are related to specific differences in social orientation and time approach. Furthermore, results of structural equation model analyses suggested possible adjustments to the proposed two-factor model for decision-making styles (Dewberry, Juanchich, & Narendran, 2013a). PMID- 30008516 TI - The Effects of Source Water Quality on Drinking Water Treatment Costs: A Review and Synthesis of Empirical Literature. AB - Watershed protection, and associated in situ water quality improvements, has received considerable attention as a means for mitigating health risks and avoiding expenditures at drinking water treatment plants (DWTPs). This study reviews the literature linking source water quality to DWTP expenditures. For each study, we report information on the modeling approach, data structure, definition of treatment costs and water quality, and statistical methods. We then extract elasticities indicating the percentage change in drinking water treatment costs resulting from a 1% change in water quality. Forty-six elasticities are obtained for various water quality parameters, such as turbidity, total organic carbon (TOC), nitrogen, sediment loading, and phosphorus loading. An additional 29 elasticities are obtained for land use classification (e.g., forest, agricultural, urban), which often proxy source water quality. Findings indicate relatively large ranges in the estimated elasticities of most parameters and land use classifications. However, average elasticities are smaller and ranges typically narrower for studies that incorporated control variables consistent with economic theory in their models. We discuss the implications of these findings for a DWTP's incentive to engage in source water protection and highlight gaps in the literature. PMID- 30008518 TI - Integrability and Linear Stability of Nonlinear Waves. AB - It is well known that the linear stability of solutions of 1+1 partial differential equations which are integrable can be very efficiently investigated by means of spectral methods. We present here a direct construction of the eigenmodes of the linearized equation which makes use only of the associated Lax pair with no reference to spectral data and boundary conditions. This local construction is given in the general N*N matrix scheme so as to be applicable to a large class of integrable equations, including the multicomponent nonlinear Schrodinger system and the multiwave resonant interaction system. The analytical and numerical computations involved in this general approach are detailed as an example for N=3 for the particular system of two coupled nonlinear Schrodinger equations in the defocusing, focusing and mixed regimes. The instabilities of the continuous wave solutions are fully discussed in the entire parameter space of their amplitudes and wave numbers. By defining and computing the spectrum in the complex plane of the spectral variable, the eigenfrequencies are explicitly expressed. According to their topological properties, the complete classification of these spectra in the parameter space is presented and graphically displayed. The continuous wave solutions are linearly unstable for a generic choice of the coupling constants. PMID- 30008517 TI - Mn Doped AZIS/ZnS Nanocrystals (NCs): Effects of Ag and Mn Levels on NC Optical Properties. AB - In this work, Mn-doped AZIS/ZnS NCs were prepared using a nucleation doping approach with the tuning of Mn and Ag levels in their synthesis. The optical properties of Mn:AZIS/ZnS NCs are found to be significantly affected by Ag and Mn levels. Specifically, more Ag and Mn atoms in Mn:AZIS/ZnS NCs cause their fluorescence red-shift, and as the Ag or Mn level reaches a high threshold, the fluorescence lifetime of Mn:AZIS/ZnS NC has a significant drop. The reasons for the effects of Mn and Ag levels on NC optical properties were explored and discussed. Through this study, it is also found that with certain Ag and Mn levels in synthesis, some Mn:AZIS/ZnS NCs present optimal optical properties including high brightness (QY > 40%), long fluorescence lifetime (> 1.2 ms), low energy for excitation (excitable at 405 nm), and no reabsorption. The feasibility of the optimized NCs for time-gated fluorescence measurement using a portable/compact instrument was further demonstrated, which indicates the application potential of the NCs in time-gated biosensing including point-of-care testing. Notably, this study also discloses that Mn:AZIS/ZnS NCs with different lifetimes can be achieved by tuning Mn and Ag levels in synthesis, which may further broaden the applications of Mn:AZIS/ZnS NCs in multiplexing detection/measurement. PMID- 30008519 TI - Identification of Stochastically Perturbed Autonomous Systems from Temporal Sequences of Probability Density Functions. AB - The paper introduces a method for reconstructing one-dimensional iterated maps that are driven by an external control input and subjected to an additive stochastic perturbation, from sequences of probability density functions that are generated by the stochastic dynamical systems and observed experimentally. PMID- 30008520 TI - Intra-Sectoral Differences in Climate Change Strategies: Evidence from the Global Automotive Industry. AB - Companies are increasingly challenged for action on climate change. Most studies on business responses to climate change focus on cross-sector comparisons and neglect intra-sectoral dynamics. This paper investigates the influence of supply chain position and regional affiliation on climate change strategies within a particular industry. We present a generic framework integrating both market and non-market responses to climate change. We argue that climate change strategies comprise several corporate activities that have different foci of interaction and four main objectives: governance, innovation, compensation and legitimation. Using a global sample of 116 automotive companies, we conduct a cluster analysis and identify four types of strategy. We find that the sophistication of automobile manufacturers' strategies significantly differs from that of suppliers. Regional affiliation and firm size prove to be determinants of the strategy type pursued. We cannot find evidence for a relationship between financial performance and a company's strategic approach to climate change. (c) 2017 The Authors. Business Strategy and the Environment published by ERP Environment and John Wiley & Sons Ltd. PMID- 30008521 TI - Cycling in Warsaw, Poland - Perceived enablers and barriers according to cyclists and non-cyclists. AB - Cycling in urban environments provides many benefits to people. However, planning of cycling infrastructures in large cities faces numerous challenges and requires better understanding of both the factors enabling cycling as well as barriers to it, determined by particular local context. While there is a growing body of research that tackle the bike transport related questions in Western Europe and the USA, there is relatively little research on that in Central Eastern Europe (CEE), in post-communist countries. In this study we used qualitative and quantitative methods to explore urban cyclists and non-cyclists opinions about the cycling, the perceived problems and obstacles, and perception of the on-going changes in bicycle transportation system in Warsaw, Poland. Although many people see potential advantages of cycling, it is mostly perceived as a leisure time activity. Those who do utilitarian cycling are more acutely aware of the benefits, such as rapidity and flexibility of this mean of transport. The main perceived barriers are linked to lack of good cycling infrastructure in the city, the feeling of insecurity linked to the behaviour of drivers, and to maintenance during winter. In conclusion, our research highlights both the opportunities and challenges linked to the development of improved cycle transportation system, suggesting the need for a range of policies, from the infrastructure improvements and comprehensive planning of the whole transportation system, to improving the driving culture that would support feeling of security of the cyclists. PMID- 30008522 TI - Adaptive Optimization of Visual Sensitivity. AB - Sensory systems adapt to environmental change. It has been argued that adaptation should have the effect of optimizing sensitivity to the new environment. Here we consider a framework in which this premise is made concrete using an economic normative theory of visual motion perception. In this framework, visual systems adapt to the environment by reallocating their limited neural resources. The allocation is optimal when uncertainties about different aspects of stimulation are balanced. This theory makes predictions about visual sensitivity as a function of environmental statistics. Adaptive optimization of the visual system should be manifested as a change in sensitivity for an observer and for the underlying motion-sensitive neurons. We review evidence supporting these predictions and examine effects of adaptation on the neuronal representation of visual motion. PMID- 30008523 TI - Is the symptom of cervical or lumbar radiculopathy an evidence of spinal instability? PMID- 30008524 TI - Interlaminar lumbar device implantation in treatment of Baastrup disease (kissing spine). AB - Background: Baastrup disease (BD) is characterized by the degenerative changes of spinous processes and interspinous soft tissues. It is more common among aged persons. This disorder is a relatively common cause of low back pain. Its incidence is underestimated. A few studies have investigated BD epidemiology and proposed treatment efficacy. The aim of this paper is to establish impact and outcome evaluations of managing the patients with Baastrup disease who have been treated by implementing of floating interlaminar device (FID). Materials and Methods: Between January 2015 and September 2017, 47 patients have been operated by implementing of FID for BD in our Department of Neurosurgery. Results: Of the 47 patients, 20 were female and 27 were male with an average age of 51.78. On average, we followed the cases up to 11 months. The most frequent level of disorder was L4"L5 followed by L3"L4 level. The condition of 45 patients improved after surgery according to Oswestry low back pain score and 39 patients could return to their work. Conclusion: The results from our study corroborate that implementing of FID is a good alternative treatment for patient chronic low back pain due to BD This technique contributes to improving a better living situation for the patients given the correct indications. PMID- 30008525 TI - Long-term clinical and radiological outcomes following anterior cervical discectomy and fusion by zero-profile anchored cage. AB - Objectives: The purpose of this study was to extend the results of our previous study providing a minimum of 4-year follow-up results of a prospective study following implantation of a cervical cage with an integrated fixation system. Summary of Background Data: The use of cervical intersomatic cages with an integrated fixation system for anterior cervical discectomy and fusion (ACDF) has increased rapidly in this last decade. In addition to immediate stabilization, these implants allow avoidance of anterior plating and iliac crest bone-grafting. Methods: Patients were studied prospectively, and data were collected and analyzed. Intersomatic cages with an integrated fixation system were used in consecutive 100 patients operated on for ACDF. Intraoperative parameters, clinical, and outcome scores were recorded. Radiographs were taken to evaluate implant positioning and fusion rate, disc height (DH), and changes in adjacent disc spaces. All the patients had a minimum 4-year follow-up. Results: A total of 127 cages were implanted in the 100 patients. Compared to preoperatively, the visual analog scale, 36-item short-form health survey, the Japanese Orthopedic Association, and the Neck Disability Index scores were significantly improved at 1-year follow-up without change during subsequent follow-up. At 4 years, the fusion rate was 97%. Two patients complained about minor dysphagia-related symptoms, which resolved rapidly. DH index and cervical Cobb angle were significantly restored after surgery, and the results were maintained during the whole follow-up. Conclusions: This is a prospective, independently conducted study on cages with an integrated fixation system with 4-year long follow-up. Findings of this study seem to be interesting regarding outcomes and low complications rates compared to recent series using other implants with integrated fixation system. Larger, randomized controlled trials are warranted. PMID- 30008526 TI - Late appearance of low back pain relating to Modic change after lumbar discectomy. AB - Background: In practice of neurosurgery, we find that a wide number of patients referred for refractory low back pain have a history of lumbar discectomy. In a large number of them, magnetic resonance imaging (MRI) studies detect Modic changes (MCs). The aim of this study is to determine the relationship between emergence of MC and low back after lumbar discectomy. Materials and Methods: Three hundred and fifty-eight patients with a medical history of discectomy had a MC at the level of the operated disc without any other discopathy. They have been selected from among the 1154 patients operated for lumbar disc herniation over 5 years. Results: Two hundred and fourteen patients (67.30%) had not presented MCs on preoperative MRI. Conclusion: Our study awakens a strong presumption about the relationship between emergence of MC after lumbar discectomy. PMID- 30008527 TI - Application and use of subcutaneous stay sutures in anterior cervical spine surgeries with a transverse neck incision: A technical report. AB - Objective/Purpose: The objective of this study is to describe our experience with the use of stay sutures and transverse neck incision for anterior cervical spine surgeries involving multiple levels. Summary of Background Data: Transverse incisions on neck usually heal with minimal fibrosis resulting in cosmetically acceptable scars whereas vertical incision, although provides greater exposure, heals with extensive fibrosis resulting in ugly scars. Transverse incision is thus highly recommended. However, the fear of nonextensibility of transverse incision for multilevel fusion has led to the preference of vertical incision, development of techniques for identifying the optimal level of the incision, or has suggested the usage of two transverse incisions. Materials and Methods: Seventy-six patients underwent anterior cervical spine surgeries using a transverse neck incision for single or multilevel discectomy/corpectomy and fusion. Having divided the platysma, dissection was carried down to the anterior surface of the cervical spine between the carotid sheath laterally and the trachea and esophagus medially. Stay sutures were taken through the platysma and subcutaneous tissue, converting the transverse incision into a quadrilateral window providing access for as much as three-level corpectomy or five levels of fixation. Results: All the wounds healed with no evidence of wound-related complications, leaving a cosmetically acceptable scar. Conclusion: Using appropriately placed stay sutures, a transverse neck incision taken in the middle of the field of work can provide enough of a surgical window to perform multilevel fusion surgeries. Its simplicity and cost-effectiveness make it easily implementable, addressing the underlying pathology adequately with best possible cosmetic results. PMID- 30008528 TI - Lumbar fusion for lytic spondylolisthesis: Is an interbody cage necessary? AB - Study Design: This study was a retrospective observational study. Purpose: The purpose of the study was to determine the radiological and clinical outcome of using locally sourced autologous bone graft in the surgical management of single level lumbar lytic spondylolisthesis. Background: Many spinal surgeons supplement pedicle screw fixation of lumbar spondylolisthesis with cages. In developing countries, the high cost of interbody cages has precluded their use, with surgeons resorting to filling the interbody space with different types of bone graft instead. This study reports on the clinical and radiological outcome of posterior lumbar interbody fusions for low-grade lytic spondylolisthesis using locally sourced autologous bone graft. Material and Methods: Posterior interbody fusion was performed in 22 consecutive patients over 18-month period, using (BRAND) pedicle screw system and locally sourced bone graft, i.e., bone removed during neural decompression. There were no postoperative restrictions, and all patients underwent clinical outcome measurements using Oswestry Disability Index (ODI), visual analogue pain score (VAS) at a minimum follow-up of 12 months, and computed tomography (CT) assessment of fusion with intraobserver validation by radiology consultant blinded, at 6 and12 months. Nearly 50% of the population were smokers. Results: There was significant clinical improvement in ODI, VAS back pain, and VAS leg pain (P < 0.001). By contrast, the radiologic fusion rate measured by CT at 12 months was less satisfactory at 64%. There was no difference in clinical outcome between the fused group and nonfused population. Conclusions: These results indicate that the use of locally sourced bone graft in single-level lumbar lytic low-grade spondylolisthesis. Interbody fusion provides good clinical outcomes. The use of an interbody cage may not be clinically necessary. Our radiologic outcome, however, shows inferior fusion rates compared with published data. Future research will focus on long-term outcomes. PMID- 30008529 TI - Navigated minimally invasive unilateral laminotomy with crossover for intraoperative prediction of outcome in degenerative lumbar stenosis. AB - Background: Different surgical techniques have been described for treatment of degenerative lumbar stenosis (DLS). Only postoperative measures have been identified as predictors of efficacy of decompression. The objective of this study is to assess the role of navigated unilateral laminotomy with crossover to achieve and predict a satisfying decompression and outcome in DLS. Materials and Methods: We enrolled patients with DLS who underwent navigation-assisted unilateral laminotomy with crossover. The extent of decompression was evaluated during surgery using neuronavigation. The outcome was assessed through the Oswestry disability index (ODI) and visual analog scale (VAS) for leg pain. Outcome correlation with the extent of the intraoperative bone decompression was analyzed. Finally, the outcome, surgical time, and in-hospital length-of-stay were compared with a control group treated through standard unilateral laminotomy. Results: Twenty-five patients were treated using the navigated technique (Group A), 25 using the standard unilateral laminotomy (Group B). In Group A, a cut-off value >=0.9 cm for bone decompression revealed to be an intraoperative predictor of good outcome, both regarding the ODI and VAS scores (P = 0.0005; P = 0.002). As compared with Group B, patients operated using the navigated technique showed similar operative times, in-hospital length-of-stay, ODI scores, but improved VAS scores for leg pain (P = 0.04). Conclusions: The intraoperative navigated evaluation of the bone decompression could predict the outcome allowing satisfactory results in unilateral laminotomy for DLS. The navigated technique also could lead to an improved decompression of lateral recesses resulting in better control of leg pain as compared to standard unilateral laminotomy. PMID- 30008532 TI - De novo syrinx formation in a patient with type I Chiari malformation: Case report and review of the literature. AB - This report highlights the case of a 56-year-old woman with an incidental type I Chiari malformation who on initial presentation had no associated cervical syrinx on magnetic resonance imaging (MRI), but who on subsequent MRI 8 years later was found to have developed a de novo upper cervical cord syrinx. PMID- 30008530 TI - Cadaveric device-injected very high-viscosity cement during vertebroplasty. AB - Introduction: Cement extravasation during vertebroplasty (VP) is the most commonly reported complication. Cement viscosity is considered the single most important predictor of the risk of extravasation. Certainly, injecting high viscosity cement (HVC) is difficult to utilize in real practice. We invented a new device capable of injecting high-viscosity with ease and at a distance to avoid radiation. The aim of this study is to confirm the efficacy and safety of the new device on cadaveric vertebrae. Methodology: A 126 osteoporotic vertebral bodies were harvested from cadavers. Eighty vertebrae were included in the study. Computer-randomization software was used to allocate specimens over two main groups, Conventional VP and New Device. Both groups were further subdivided into two subgroups; high-viscosity and low-viscosity. A custom device was used on each vertebra to induce a compression fracture. Results: Injecting HVC was associated with a lower leakage volume compared with low-viscosity cement. HVC was associated with no leakage into the spinal canal. It was also associated with a low incidence of vascular extravasation (P < 0.001). The mean volume of cement leakage in the low-viscosity group was 0.23 and 0.15 cc, for the Conventional VP and New Device, respectively. In both groups, the most common site for leakage was the vertebral end plate, which was exhibited more in the low-viscosity group (71.5%) compared with the high-viscosity group (42.5%). The preset target amount of cement to be injected was reached in 99% of the time when injecting HVC with the New Device, compared with 62% using the Conventional VP. In both groups, there was no correlation between the amount of cement injected and the amount of leakage. Conclusion: The new device is capable of injecting HVC easily, with a lower incidence of cement leakage. It also minimized the risk of radiation exposure to the surgeon. PMID- 30008531 TI - Technical pearls and surgical outcome of early transitional period experience in minimally invasive lumbar discectomy: A prospective study. AB - Background: There is growing indications of minimally invasive spine surgery. The inherent attitude and institutive learning curve limit transition from standard open surgery to minimally invasive surgery demanding understanding of new instruments and correlative anatomy. Materials and Methods: In this prospective study, 80 patients operated for lumbar disc prolapse were included in the study (between January 2016 and March 2018). Fifty patients (Group A) operated by various minimally invasive spine surgery (MISS) techniques for herniated disc disease were compared with randomly selected 30 patients (Group B) operated between the same time interval by standard open approach. Surgical outcome with Oswestry Disability Index (ODI) and patient satisfaction score was calculated in pre- and postoperative periods. Results: Mean preoperative ODI score in Group A was 31.52 +/- 7.5 standard deviation (SD) (range: 6"46; interquartile range [IQR]: 8; median: 32.11) and postoperative ODI score was 9.20 +/- 87.8 SD (range: 0"38; IQR: 11; median: 6.67). Mean preoperative ODI score in Group B was 26.47 +/ 4.9 SD (range: 18"38; IQR: 4; median: 25) and postoperative ODI score was 12.27 +/- 8.4 SD (range: 3"34; IQR: 12; median: 10.0). None of the patients was unsatisfied in either group. On comparing the patient satisfaction score among two groups, no significant difference (P = 0.27) was found. Discussion: On comparing the change in ODI and preoperative ODI among both groups, we found a significant difference between the groups. It is worth shifting from open to MISS accepting small learning curve. The satisfaction score of MISS in early transition period is similar to open procedure. Conclusion: The MISS is safe and effective procedure even in transition period for the central and paracentral prolapsed lumbar intervertebral disc treatment. The results are comparable, and patient satisfaction and symptomatic relief are not compromised. PMID- 30008533 TI - Some generalizations of the new SOR-like method for solving symmetric saddle point problems. AB - Saddle-point problems arise in many areas of scientific computing and engineering applications. Research on the efficient numerical methods of these problems has become a hot topic in recent years. In this paper, we propose some generalizations of the new SOR-like method based on the original method. Convergence of these methods is discussed under suitable restrictions on iteration parameters. Numerical experiments are given to show that these methods are effective and efficient. PMID- 30008534 TI - Some majorization integral inequalities for functions defined on rectangles. AB - In this paper, we first prove an integral majorization theorem related to integral inequalities for functions defined on rectangles. We then apply the result to establish some new integral inequalities for functions defined on rectangles. The results obtained are generalizations of weighted Favard's inequality, which also provide a generalization of the results given by Maligranda et al. (J. Math. Anal. Appl. 190:248-262, 1995) in an earlier paper. PMID- 30008535 TI - Inequalities and asymptotic expansions related to the generalized Somos quadratic recurrence constant. AB - In this paper, we give asymptotic expansions and inequalities related to the generalized Somos quadratic recurrence constant, using its relation with the generalized Euler constant. PMID- 30008536 TI - Sums of finite products of Chebyshev polynomials of the second kind and of Fibonacci polynomials. AB - In this paper, we consider sums of finite products of Chebyshev polynomials of the second kind and of Fibonacci polynomials and derive Fourier series expansions of functions associated with them. From these Fourier series expansions, we can express those sums of finite products in terms of Bernoulli polynomials and obtain some identities by using those expressions. PMID- 30008537 TI - Refining trigonometric inequalities by using Pade approximant. AB - A two-point Pade approximant method is presented for refining some remarkable trigonometric inequalities including the Jordan inequality, Kober inequality, Becker-Stark inequality, and Wu-Srivastava inequality. Simple proofs are provided. It shows to achieve better approximation results than those of prevailing methods. PMID- 30008538 TI - Assessment of Irrigation Physics in a Land Surface Modeling Framework using Non Traditional and Human-Practice Datasets. AB - Irrigation increases soil moisture, which in turn controls water and energy fluxes from the land surface to the planetary boundary layer and determines plant stress and productivity. Therefore, developing a realistic representation of irrigation is critical to understanding land-atmosphere interactions in agricultural areas. Irrigation parameterizations are becoming more common in land surface models and are growing in sophistication, but there is difficulty in assessing the realism of these schemes, due to limited observations (e.g., soil moisture, evapotranspiration) and scant reporting of irrigation timing and quantity. This study uses the Noah land surface model run at high resolution within NASA's Land Information System to assess the physics of a sprinkler irrigation simulation scheme and model sensitivity to choice of irrigation intensity and greenness fraction datasets over a small, high resolution domain in Nebraska. Differences between experiments are small at the interannual scale but become more apparent at seasonal and daily time scales. In addition, this study uses point and gridded soil moisture observations from fixed and roving Cosmic Ray Neutron Probes and co-located human practice data to evaluate the realism of irrigation amounts and soil moisture impacts simulated by the model. Results show that field-scale heterogeneity resulting from the individual actions of farmers is not captured by the model and the amount of irrigation applied by the model exceeds that applied at the two irrigated fields. However, the seasonal timing of irrigation and soil moisture contrasts between irrigated and non-irrigated areas are simulated well by the model. Overall, the results underscore the necessity of both high-quality meteorological forcing data and proper representation of irrigation for accurate simulation of water and energy states and fluxes over cropland. PMID- 30008539 TI - Inertial forward-backward methods for solving vector optimization problems. AB - We propose two forward-backward proximal point type algorithms with inertial/memory effects for determining weakly efficient solutions to a vector optimization problem consisting in vector-minimizing with respect to a given closed convex pointed cone the sum of a proper cone-convex vector function with a cone-convex differentiable one, both mapping from a Hilbert space to a Banach one. Inexact versions of the algorithms, more suitable for implementation, are provided as well, while as a byproduct one can also derive a forward-backward method for solving the mentioned problem. Numerical experiments with the proposed methods are carried out in the context of solving a portfolio optimization problem. PMID- 30008540 TI - Pediatric Neurology Briefs: Year in Review. AB - In 2018, the mission of Pediatric Neurology Briefs (PNB) remains the same: "PNB is a continuing education service designed to expedite and facilitate the review of current scientific research and advances in child neurology and related subjects." PMID- 30008541 TI - Inadequate Regulation Contributes to Mislabeled Online Cannabidiol Products. AB - Researchers from the University of Pennsylvania, Veterans Affairs San Diego, RTI international, Americans for Safe Access, Palo Alto University and Johns Hopkins University analyzed the content of 84 cannabidiol (CBD) products purchased on the internet and compared the results to their advertised concentrations. PMID- 30008542 TI - When Leadership Powers Team Learning: A Meta-Analysis. AB - Team learning behavior is found to be one of the most effective team processes, as learning behavior at the team level (e.g., sharing, discussing, and reflecting on knowledge and actions) enables teams to adapt existing or develop new knowledge. Team leadership behavior is considered a critical accelerant for creating conditions that are essential to engage in team learning behavior, such as a safe environment. Yet despite the growing amount of research in team learning, this relationship remains unclear. Meta-analytic techniques were used to examine when team leadership behaviors support team learning behavior and how the task type moderates that relationship. Forty-three empirical studies reporting 92 effect sizes were synthesized. Analyses show that team leadership behavior explains 18% of the variance in team learning behavior. Furthermore, results indicate that person-focused leaders foster team learning for both adaptive and developmental tasks, whereas task-focused leaders influence team learning for adaptive tasks only. PMID- 30008543 TI - Size diversity in Swiss Bronze Age cattle. AB - To date, osteometric data for Swiss Bronze Age cattle, particularly from Alpine sites, are scarce. In the present study, using a large dataset generated by combining preexisting data with recent data obtained from a large Alpine site, cattle size from the Late Neolithic to the Late Bronze Age (LBA) in populations from different sites and regions was evaluated using the logarithmic size index and other statistical analysis. Additionally, the finite mixture model and a meta analytic technique were used to observe possible effects of sex ratios on cattle size. Results indicated that sex ratios did not affect size distribution. Cattle populations did not differ over time, but the Alpine cattle were smaller than the Central Plateau cattle. There were two distinct sizes in the Alpine cattle populations. It is suggested that the different economic interrelationships between Alpine and other geographically related communities might have led to the emergence of size diversity in Swiss Bronze Age cattle. Further interdisciplinary studies with larger sample sizes are required to confirm these possibilities. PMID- 30008544 TI - Incorporating Health into Studies of Political Behavior: Evidence for Turnout and Partisanship. AB - We argue that research on political behavior, including political participation, public opinion, policy responsiveness, and political inequality will be strengthened by studying the role of health. We then provide evidence that health matters for voter turnout and partisanship. Using the General Social Survey (GSS) and The National Longitudinal Study of Adolescent Health (Add Health), we find that people who report poor health are less likely to vote and identify with the Republican Party. Moreover, the effects of health on voter turnout and partisanship appear to have both developmental and contemporaneous components. Taken together, our findings suggest that health inequalities may have significant political consequences. PMID- 30008545 TI - Where Did Informed Consent for Research Come From? PMID- 30008548 TI - "Equipping Practitioners": Linking Neglected Tropical Diseases and Human Rights. PMID- 30008546 TI - Pragmatic Tools for Sharing Genomic Research Results with the Relatives of Living and Deceased Research Participants. PMID- 30008549 TI - Addressing Inequity: Neglected Tropical Diseases and Human Rights. AB - Twenty neglected tropical diseases (NTDs) are currently recognized by the World Health Organization. They affect over one billion people globally and are responsible for significant morbidity, mortality, poverty, and social stigmatization. In May 2013, the World Health Assembly adopted a resolution calling on member states to intensify efforts to address NTDs, with the goal of reaching previously established targets for the elimination or eradication of 11 NTDs. The resolution also called for the integration of NTD efforts into primary health services. NTDs were subsequently included in Sustainable Development Goal (SDG) 3, which calls for an end to the "epidemics of AIDS, tuberculosis, malaria and NTDs" by 2030. While both the World Health Assembly resolution and SDG 3 provide a strong framework for action, neither explicitly references the human right to the highest attainable standard of health or describes a rights-based approach to NTDs' elimination. This article identifies key human rights relevant to NTD control and elimination efforts and describes rights-based interventions that address (1) inequity in access to preventive chemotherapy and morbidity management; (2) stigma and discrimination; and (3) patients' rights and non discrimination in health care settings. In addition, the article describes how human rights mechanisms at the global, regional, and national levels can help accelerate the response to NTDs and promote accountability for access to universal health care. PMID- 30008550 TI - Emotional Difficulties and Experiences of Stigma among Persons with Lymphatic Filariasis in Plateau State, Nigeria. AB - Lymphatic filariasis (LF) is a chronic and often disfiguring condition that predominantly affects the rural poor and leads to social exclusion, stigma, and discrimination. Little is currently known about the emotional difficulties and stigma experiences among persons living with LF in Nigeria. Our study evaluated the emotional difficulties and stigma experienced by persons with LF in Plateau State, Nigeria. We utilized a combination of qualitative data instruments comprising focus group discussions, McGill's Illness Narrative Interviews, and key informant interviews. We transcribed and analyzed the data using a combination of inductive and deductive coding approaches. Sixty-nine respondents were interviewed: 37 females and 32 males. The prevalent community perception of LF was the belief that it was a spiritual problem. Emotional reactions included feelings of sadness, hopelessness, anger, frustration, worry, and suicidal ideation. These experiences, including those of stigma, discrimination, and social exclusion, culminated in difficulties with occupational functioning, marital life, and community participation. Our findings highlight the value of a rights-based approach that emphasizes state and non-state actors' need to provide access to the highest attainable standard of health, including mental health, and to protect persons with LF from stigma, discrimination, and social exclusion. PMID- 30008551 TI - Building Trust through Lymphatic Filariasis Elimination: A Platform to Address Social Exclusion and Human Rights in the Dominican Republic. AB - Hispaniola, the Caribbean island that includes the countries of Haiti and the Dominican Republic (DR), accounts for 90% of lymphatic filariasis (LF) in the Americas. Both countries have committed to LF elimination by 2020. In the DR, LF occurs mainly in bateyes, or company towns that historically hosted migrant laborers from Haiti. A legacy of anti-Haitian discrimination as well as the 2013 Sentencia, which stripped generations of Haitian-descended Dominicans of their citizenship, ensure that this population remains legally, economically, and socially marginalized. Despite this context, the country's LF elimination program (PELF) has worked in bateyes to eliminate LF through health education and annual drug treatment to interrupt parasite transmission. Based on interviews with batey residents and observations of PELF activities from February-April 2016, this study describes local understandings of social exclusion alongside the PELF community-based approach. The Sentencia reinforced a common perception shared by batey residents: that their lives were unimportant, even unrecognized, in Dominican society. At the same time, the government-run PELF has generated trust in government health activities and partially counteracts some of the effects of social exclusion. These findings suggest that neglected tropical disease (NTD) programs can not only improve the health of marginalized populations, but also create a platform for improving human rights. PMID- 30008553 TI - Health in the Courts of Latin America. PMID- 30008552 TI - A Human Right to Shoes? Establishing Rights and Duties in the Prevention and Treatment of Podoconiosis. AB - Podoconiosis is a debilitating chronic swelling of the foot and lower leg caused by long-term exposure to irritant red volcanic clay soil in the highland regions of Africa, Central America, and India. In this paper, we consider the human rights violations that cause, and are caused by, podoconiosis in Ethiopia. Specifically, we discuss the way in which the right to an adequate basic standard of living is not met in endemic regions, where the following basic necessities are not readily available: appropriate footwear, health education, and affordable, accessible health care. Those living with podoconiosis experience disablement, stigma and discrimination, and mental distress, contributing to greater impoverishment and a reduced quality of life. We suggest that while identifying rights violations is key to characterizing the scale and nature of the problem, identifying duties is critical to eliminating podoconiosis. To this end, we describe the duties of the Ethiopian government, the international community, and those sourcing Ethiopian agricultural products in relation to promoting shoe-wearing, providing adequate health care, and improving health literacy. PMID- 30008554 TI - Revisiting Health Rights Litigation and Access to Medications in Costa Rica: Preliminary Evidence from the Cochrane Collaboration Reform. AB - In response to the incremental creation of an expansive constitutional right to health in Costa Rica, the country's rights-friendly constitutional chamber of the Supreme Court (known as the Sala IV) unleashed a flood of litigation for medications, treatments, and other health care issues. This development was met by widespread criticism from within the health sector, which complained that the court's jurisprudence routinely elevated the right to health above financial considerations, thus posing a threat to the financial well-being of the state-run health care system.1 Further, a 2014 study by Ole Frithjof Norheim and Bruce Wilson examining successful health rights litigation revealed that more than 70% of favorable rulings were for low-priority medications, suggesting a lack of fairness in access to medications in Costa Rica.2 To address some of these criticisms, the Sala IV initiated a partnership in 2014 with the Cochrane Collaboration to incorporate medical expert evaluations into its decision-making process for claims seeking access to medications. This article examines the court's reformed decision-making process to determine whether the increased reliance on medical expertise has changed health rights jurisprudence. We reviewed all medication claims from 2016 and classified the successful cases into four groups using standard priority-setting criteria. We then compared these results with rulings issued in 2008, prior to the court's reform (and the year analyzed in Norheim and Wilson's study). Our analysis reveals that under the court's new rules, the probability of winning a medication lawsuit has increased significantly; moreover, the percentage of rulings granting experimental medications has declined while the percentage granting high-priority medications has increased. Based on these results, in comparison to the court's pre-reform jurisprudence, we can tentatively conclude that the new process has led to some minor gains in fairness. PMID- 30008555 TI - How the Uruguayan Judiciary Shapes Access to High-Priced Medicines: A Critique through the Right to Health Lens. AB - Uruguay has witnessed an ever-increasing number of domestic court claims for high priced medicines despite its comprehensive universal coverage of pharmaceuticals. In response to the current national debate and development of domestic legislation concerning high-priced medicines, we review whether Uruguayan courts adequately interpret the state's core obligations to provide essential medicines and ensure non-discriminatory access in line with the right to health in the International Covenant on Economic, Social and Cultural Rights. Using a sample of 42 amparo claims for the reimbursement of medicines in 2015, we found that the circuits of appeal fail to offer predictable legal argumentation, including for nearly identical cases. Moreover, the judiciary does not provide an interpretation of state obligations that is consistently aligned with the right to health in the International Covenant on Economic, Social and Cultural Rights. These findings illustrate that medicines litigation in Uruguay offers relief for some individual claims but may exacerbate systemic inequalities by failing to address the structural problems behind high medicines prices. We recommend that the judiciary adopt a consistent standard for assessing state action to realize the right to health within its available resources. Moreover, the legislature should address the need for medicines price control and offer a harmonized interpretation of the right to health. These transformations can increase the transparency and predictability of Uruguay's health and legal systems for patients and communities. PMID- 30008556 TI - Can Judges Ration with Compassion? A Priority-Setting Rights Matrix. AB - How should courts supervise health service resource allocation? Although practice varies widely, four broad approaches can be represented on a matrix comparing, on two axes, (a) individual-community rights and (b) substantive-procedural remedies. Examples from each compartment of the matrix are discussed and, although the community-procedural approach is recommended as a general rule, a range of other responses within the matrix may also be desirable. PMID- 30008557 TI - Evolving the Right to Health: Rethinking the Normative Response to Problems of Judicialization. AB - Judicial readings of the right to health-and related rights-frequently possess something of an "all or nothing" quality, exhibiting either straightforward deference to allocative choices or conceptualizing the right as absolute, with consequent disruption to health systems, as witnessed in Latin America. This article seeks to identify pathways through which a normatively intermediate approach might be developed that would accord weight to rights claims without overlooking the scarcity of health resources. It is argued that such development is most likely both to accompany and support a role for courts as institutions functioning within a society that is characterized by a deliberative conception of democracy. PMID- 30008558 TI - Realizing the Fundamental Right to Health through Litigation: The Colombian Case. AB - Colombia has made significant progress in the recognition and protection of the right to health. Using litigation-a structural element of the democratic Colombian design-many people have had to fight in order to enjoy effective access to health care. Such litigation has proven a pacific and democratic way to protect a constitutional principle: health as a fundamental and justiciable right. In 2008, in the wake of thousands of individual rulings on the right to health, Colombia's Constitutional Court issued a structural decision, T-760 of 2008, ordering government entities to identify flaws that made the country's health system outdated and inequitable and to take correctional measures. In the years following this decision, Congress and the executive branch have increasingly included a rights-oriented perspective in public policies. The Colombian case reveals judicial intervention as a legitimate way to extend pressure on the government to act according to constitutional boundaries. Although there is still a long road ahead, public institutions responsible for health care are now on a constitutionally acceptable track. PMID- 30008559 TI - Individual Health Care Litigation in Brazil through a Different Lens: Strengthening Health Technology Assessment and New Models of Health Care Governance. AB - This article investigates policy and bureaucracy changes provoked by individual litigation for health care rights in Brazil, especially the one regarding access to medicines, looking at the effects it produced in relation to health technology assessment (HTA) and health care governance. The article first contextualizes the social, legal, and political conditions for the development of individual litigation for health care rights in Brazil. Then it points out the changes brought about by this litigation model and discusses their potential to contribute to efficiency and fairness in the health care system by the improvement of the HTA decision-making process and health care governance. PMID- 30008560 TI - Expanding the Debate: Citizen Participation for the Implementation of the Right to Health in Brazil. AB - Brazil has established a well-known constitutional right to health. Legal scholars have focused largely on one aspect of this right: the role of the courts in enforcing health care access. Less attention has been paid to another aspect: citizens' right to participate in health planning. Participation is a constituent component of Brazil's right to health that is intended to guarantee accountability and fair resource distribution for improved population health. In this paper, drawing on constitutional analysis and interviews carried out for my doctoral research, I discuss Brazil's national-level participatory body, the National Health Council, and its potential for fostering accountability and balancing individual and societal interests in health policy. Effective participation, I contend, is a way to strengthen Brazil's health system to the benefit of the entire population, rather than only those who have access to the courts. This paper seeks to underline the constitutional requirement of participation as a core element of the realization of the right to health in Brazil and to invite other legal scholars to critically engage with the way in which Brazil's right to health is implemented. PMID- 30008561 TI - Challenges in Priority Setting from a Legal Perspective in Brazil, Costa Rica, Chile, and Mexico. AB - Priority setting is the process through which a country's health system establishes the drugs, interventions, and treatments it will provide to its population. Our study evaluated the priority-setting legal instruments of Brazil, Costa Rica, Chile, and Mexico to determine the extent to which each reflected the following elements: transparency, relevance, review and revision, and oversight and supervision, according to Norman Daniels's accountability for reasonableness framework and Sarah Clark and Albert Wale's social values framework. The elements were analyzed to determine whether priority setting, as established in each country's legal instruments, is fair and justifiable. While all four countries fulfilled these elements to some degree, there was important variability in how they did so. This paper aims to help these countries analyze their priority setting legal frameworks to determine which elements need to be improved to make priority setting fair and justifiable. PMID- 30008562 TI - Access to Justice in Health Matters: An Analysis Based on the Monitoring Mechanisms of the Inter-American System. AB - This article analyzes how states are complying with their periodic reporting obligations under the Protocol of San Salvador (PSS) in one specific area: access to justice as a key component of the right to health. The sources of information for this analysis are seven reports submitted by the States parties, together with the observations and final recommendations made by the experts of the monitoring mechanism of the PSS. The reports are based on progress indicators, a group of indicators that the states must use to measure progress in compliance with its rights obligations. This system of indicators presents the cross-cutting category "access to justice," which allows the identification of each branch of government's involvement in the design of a health system and the guarantees of judicial protection of the right to health. The analysis focuses on the articulation of the empirical evidence presented by the States in the context of protection and fulfillment of the right to health, identifying progress made or limitations faced in the compliance with state responsibilities. The main findings reveal the weakness of the current mechanisms of access to justice in health and the reticence of the judiciary to take an active role towards accountability. PMID- 30008563 TI - A Comparison of Health Achievements in Rwanda and Burundi. AB - Strong primary health care systems are essential for implementing universal health coverage and fulfilling health rights entitlements, but disagreement exists over how best to create them. Comparing countries with similar histories, lifestyle practices, and geography but divergent health outcomes can yield insights into possible mechanisms for improvement. Rwanda and Burundi are two such countries. Both faced protracted periods of violence in the 1990s, leading to significant societal upheaval. In subsequent years, Rwanda's improvement in health has been far greater than Burundi's. To understand how this divergence occurred, we studied trends in life expectancy following the periods of instability in both countries, as well as the health policies implemented after these conflicts. We used the World Bank's World Development Indicators to assess trends in life expectancy in the two countries and then evaluated health policy reforms using Walt and Gilson's framework. Following both countries' implementation of health sector policies in 2005, we found a statistically significant increase in life expectancy in Rwanda after adjusting for GDP per capita (14.7 years, 95% CI: 11.4-18.0), relative to Burundi (4.6 years, 95% CI: 1.8-7.5). Strong public sector leadership, investments in health information systems, equity-driven policies, and the use of foreign aid to invest in local capacity helped Rwanda achieve greater health gains compared to Burundi. PMID- 30008564 TI - Health, Human Rights, and the Transformation of Punishment: South African Litigation to Address HIV and Tuberculosis in Prisons. AB - South Africa experiences the world's highest HIV burden and one of the highest burdens for tuberculosis (TB). People in prison are particularly vulnerable to these diseases. Globally, and internally in South Africa, increased attention is being paid to HIV and TB treatment and prevention in prisons, with the public health community arguing for reforms that improve respect for the human rights of incarcerated people, for example, by calling for the reduction of overcrowding and unnecessary incarceration. Despite the retributive rhetoric that is popular among politicians and the public, the constitution mandates and recognizes the right of people in prison to humane and dignified conditions of detention. These values are diffused through law and policy, supported by an independent judiciary, and monitored by a small but vigilant prisons-focused human rights community. These factors enable the courts to make decisions that facilitate systemic improvements in prison conditions-counter to popular sentiment favoring punitive measures-and increase access to HIV and TB services in detention. This article examines a series of strategic litigation cases that illustrate this process of change to remedy disease-inducing and rights-violating conditions in South African prisons. PMID- 30008565 TI - Political Priority for Abortion Law Reform in Malawi: Transnational and National Influences. AB - In July 2015, Malawi's Special Law Commission on the Review of the Law on Abortion released a draft Termination of Pregnancy bill. If approved by Parliament, it will liberalize Malawi's strict abortion law, expanding the grounds for safe abortion and representing an important step toward safer abortion in Malawi. Drawing on prospective policy analysis (2013-2017), we identify factors that helped generate political will to address unsafe abortion. Notably, we show that transnational influences and domestic advocacy converged to make unsafe abortion a political issue in Malawi and to make abortion law reform a possibility. Since the 1980s, international actors have promoted global norms and provided financial and technical resources to advance ideas about women's reproductive health and rights and to support research on unsafe abortion. Meanwhile, domestic coalitions of actors and policy champions have mobilized new national evidence on the magnitude, costs, and public health impacts of unsafe abortion, framing action on unsafe abortion as part of a broader imperative to address Malawi's high level of maternal mortality. Although these efforts have generated substantial support for abortion law reform, an ongoing backlash from the international anti-choice movement has gained momentum by appealing to religious and nationalist values. Passage of the bill also antagonizes the United States' development work in Malawi due to US policies prohibiting the funding of safe abortion. This threatens existing political will and renders the outcome of the legal review uncertain. PMID- 30008566 TI - Access to Medicines in Times of Conflict: Overlapping Compliance and Accountability Frameworks for Syria. AB - Syria is currently experiencing the world's largest humanitarian crisis since World War II, and access to medicines for emergency care, pain control, and palliative care remains shockingly restricted in the country. Addressing the dire need for improved access to medicines in Syria from an international law compliance and accountability perspective, this article highlights four complementary legal frameworks: international human rights law, international drug control law, international humanitarian law, and international criminal law. It arrives at two central conclusions. First, all four bodies of law hold clear potential in terms of regulatory-hence compliance-and accountability mechanisms for improving access to medicines in times of conflict, but they are too weak on their own account. Second, the potential for on-the-ground change lies in the mutual reinforcement of these four legal frameworks. This reinforcement, however, remains rhetorical and far from practical. Finally, within this complex picture of complementary international legal frameworks, the article proposes concrete recommendations for a more integrated and mutually reinforcing interpretation and implementation of these areas of law to foster better access to medicines in Syria and elsewhere. PMID- 30008567 TI - Missing: Where Are the Migrants in Pandemic Influenza Preparedness Plans? PMID- 30008568 TI - Case Study: Degree of Integration of Disability Rights Into Allied Health Professional Education. AB - Persons with disabilities are vulnerable to rights violations when accessing health care, including allied health care. However, the commitment of allied health professional education to disability rights has not been researched. This study is the first to investigate the extent to which disability rights principles are integrated into allied health competencies and education. Specifically, this paper explores the extent to which disability rights principles are integrated into the competencies and education of the six allied health professions taught by the University of Sydney's Faculty of Health Sciences. The study brings to light facilitators and barriers to professional curriculum renewal, and recommendations for future health professional education. This case study reveals that three allied health professions-exercise physiology, physiotherapy, and radiography-incorporate a rights-based approach to a lesser degree than the other three-speech pathology, occupational therapy, and rehabilitation counseling. We refer to this as an "allied health continuum." The paper concludes that there is considerable scope for the allied health professions to strengthen human rights-based education and care provision through ethical codes of conduct, competencies, curriculum renewal, accreditation, and registration requirements, with the aim of reducing rights violations experienced by persons with disabilities when accessing allied health care. PMID- 30008569 TI - Inequitable Physical Illness and Premature Mortality for People with Severe Mental Illness in Australia: A Social Analysis. AB - Australians with severe mental illness experience inequitably high rates of physical illness and shortened life expectancy compared to the general population. A social analysis of this phenomenon incorporating a precis of historical and contemporary public health approaches reveals persistent discrimination and entrenched social disadvantage influencing access to appropriate physical health care. People with severe mental illness in Australia are among the most vulnerable and marginalized populations in society, with fragmented and inadequate health and social services materially influencing their physical health status and longevity. Enhanced multi-sectoral collaboration, integrated physical and mental health care models, empowerment strategies, and privileging of a lay perspective within program design are critical to challenging this enduring infringement on the human right to health. PMID- 30008570 TI - Cultural Rights and First Nations Health Care in Canada. AB - In this paper, I apply Kymlicka's theory of cultural rights to the health care of Canada's First Nations, within the framework of human rights and the rights of indigenous peoples, as formulated by the United Nations. I extend Kymlicka's concept of cultural rights into a specific right to culturally appropriate health care, and I consider how this right can be categorized. I also explore how far the Canadian state recognizes a right to health care in general and to culturally appropriate health care in particular; and whether it has instituted a statutory or constitutional right in these areas. Finally, I consider the same questions with regard to First Nations health care in British Columbia. My conclusions are that the right to culturally appropriate health care is not recognized nationally, or in British Columbia, and that the potential exists to establish such a right politically. PMID- 30008571 TI - Adolescent Rights and the "First 1,000 days" Global Nutrition Movement: A View from Guatemala. PMID- 30008572 TI - Pirfenidone tablets in idiopathic pulmonary fibrosis: a profile of their use. AB - Pirfenidone (Esbriet(r)) is available as capsules containing 267 mg of pirfenidone and, more recently, as bioequivalent tablets containing 267, 534 or 801 mg of pirfenidone. Both formulations are indicated to treat idiopathic pulmonary fibrosis (IPF), with pirfenidone being shown to generally reduce the rate of decline in forced vital capacity in patients with mild to moderate IPF, while prolonging progression-free survival and reducing the risk of IPF-related and all-cause mortality. The availability of the tablet formulation reduces the daily pill burden of pirfenidone, as the recommended daily divided maintenance dose of 2403 mg/day may be administered as one 801 mg tablet three times daily instead of three 267 mg capsules three times daily. Pirfenidone is associated with gastrointestinal and skin-related events, with such events generally being manageable. PMID- 30008573 TI - Species check-list for Tintinnids of the Philippines Archipelago (Protozoa, Ciliophora). AB - Tintinnids are an essential link between nano- and macro- planktons in the food webs of the marine environment. It is also known that tintinnids are one of themajor components of marine planktonic ciliates and has a cosmopolitan character. In the Philippine archipelago, which is recognized as a center of marine biodiversity, tintinnids checklist has not been done or published. Therefore, a checklist is presented in this study based on a compilation of previous tintinnids studies conducted at the Philippines waters. As a result of the studies done since 1941 up to present, a total of 114 taxa belonging to 14 families and 37 genera were listed. The Philippines coastal waters record a total of 50 species while the open seas document 72 species to date. PMID- 30008574 TI - Echinoderes pterus sp. n. showing a geographically and bathymetrically wide distribution pattern on seamounts and on the deep-sea floor in the Arctic Ocean, Atlantic Ocean, and the Mediterranean Sea (Kinorhyncha, Cyclorhagida). AB - Kinorhynchs rarely show a wide distribution pattern, due to their putatively low dispersal capabilities and/or limited sampling efforts. In this study, a new kinorhynch species is described, Echinoderes pterussp. n., which shows a geographically and bathymetrically wide distribution, occurring on the Karasik Seamount and off the Svalbard Islands (Arctic Ocean), on the Sedlo Seamount (northeast Atlantic Ocean), and on the deep-sea floor off Crete and on the Anaximenes Seamount (Mediterranean Sea), at a depth range of 675-4,403 m. The new species is characterized by a combination of middorsal acicular spines on segments 4-8, laterodorsal tubes on segment 10, lateroventral tubes on segment 5, lateroventral acicular spines on segments 6-9, tufts of long hairs rising from slits in a laterodorsal position on segment 9, truncated tergal extensions on segment 11, and the absence of any type-2 gland cell outlet. The specimens belonging to the populations from the Arctic Ocean, the Sedlo Seamount, and the Mediterranean Sea show morphological variation in the thickness and length of the spines as well as in the presence/absence of ventromedial sensory spots on segment 7. The different populations are regarded as belonging to a single species because of their overlapping variable characters. PMID- 30008575 TI - Two new species of the genus Trilacuna from Chongqing, China (Araneae, Oonopidae). AB - Two new species of the genus Trilacuna Tong & Li, 2007, T. simianshan Tong & Li, sp. n. and T. songyuae Tong & Li, sp. n., are described from Simianshan Natural Reserve, Chongqing, China. PMID- 30008576 TI - Comments on the genus Diplura C. L. Koch, 1850, with description of two new species (Araneae, Mygalomorphae, Dipluridae). AB - Two new species of Diplura C. L. Koch 1850 are described from Brazil: Diplura mapinguarisp. n., from the state of Rondonia in southeastern Amazonia, northern Brazil, and Diplura rodrigoisp. n., known from southeastern and central west regions of Brazil. Diplura rodrigoisp. n. is morphologically similar to D. lineata (Lucas, 1857), D. sanguinea (F. O. Pickard-Cambridge, 1896), and D. mapinguarisp. n. Comments on diagnostic characters of Diplura are included. The synonymy of D. maculata (Mello-Leitao, 1927) with D. catharinensis (Mello-Leitao, 1923) is corroborated. A classification of color pattern of the dorsum of the abdomen is given. PMID- 30008577 TI - The Dromiusina Bonelli, 1810 of southwestern Saudi Arabia with description of a new species (Coleoptera, Carabidae, Lebiini). AB - In this paper, species of the subtribe Dromiusina Bonelli, 1810 from southwestern Saudi Arabia are revised. Eleven species in six genera (Calodromius, Dromius, Mesolestes, Metadromius, Microlestes, and Zolotarevskyella) are recognized. Dromius saudiarabicus Rasool, Abdel-Dayem and Felix, sp. n. is newly described species from Rayda Nature Reserve Asir province. The presence of Metadromius ephippiatus in Saudi Arabia is doubtful. A key is also provided to genera and species level for Dromiusina of Saudi Arabia. PMID- 30008578 TI - Revision of the Palaearctic species of the Merodon desuturinus group (Diptera, Syrphidae). AB - This revision of material belonging to the Merodon desuturinus group from the Palaearctic Region resulted in the delimitation of four species: Merodon cabanerensis Marcos-Garcia, Vujic & Mengual, 2007; Merodon desuturinus Vujic, Simic & Radenkovic, 1995; Merodon neolydicus Vujic, nom. n.; and Merodon murorum Fabricius, 1794. Merodon murorum is redescribed. A neotype for Merodon auripilus Meigen, 1830 is designated, which is a new junior synonym of Merodon murorum. The related Afrotropical species Merodon cuthbertsoni Curran, 1939 is re-evaluated and compared to its sibling Palaearctic taxon Merodon desuturinus. An identification key for the Merodon desuturinus group is provided. PMID- 30008579 TI - A review of the Japanese Cryptochironomus Kieffer, 1918 (Diptera, Chironomidae). AB - The genus Cryptochironomus Kieffer, 1918 from Japan is reviewed based on material composed of male adults. New combinations of three species are established and they are re-described based on male adult of: C. misumaiprimus (Sasa & Suzuki, 1998), comb. n., C. tokaraefeus (Sasa & Suzuki, 1995), comb. n. and C. tonewabeus (Sasa & Tanaka, 2002), comb. n. Additional taxonomic notes are also provided: C. albofasciatus (Staeger, 1839), which is a senior synonym of Parachironomus inafegeus Sasa, Kitami & Suzuki, 2001 and C. rostratus (Kieffer, 1921) as the senior synonym of Paracladopelma inaheia Sasa, Kitami & Suzuki, 2001. A key to the known adult males of the genus from Japan is given. PMID- 30008580 TI - Safety and Accuracy of Core Needle Biopsy for Soft Tissue Masses in an Ambulatory Setting. AB - Background: Percutaneous needle biopsy has been found to be a safe and accurate method for the initial investigation of soft tissue masses. The notion exists that needle biopsies should be performed in specialized sarcoma centers, which can place a financial burden on patients without a sarcoma center near their place of residence. There is no consensus in the current literature regarding the diagnostic accuracy and clinical utility of clinic-based percutaneous core needle biopsy performed by community orthopedic surgeons with fellowship training in musculoskeletal oncology. Questions/Purposes: Our primary goal was to determine if office-based core needle biopsy of soft tissue masses could safely yield accurate diagnoses when performed by a community orthopedic surgeon with fellowship training in musculoskeletal oncology. Patients and Methods: We retrospectively reviewed the charts of 105 patients who underwent percutaneous core needle biopsy of soft tissue masses in a community clinic. All procedures were performed by one fellowship-trained musculoskeletal oncologist. Accuracy of the initial clinic-based needle biopsy was determined through comparison to the results of pathological analysis of the surgically excised masses. Final data analysis included 69 patients who underwent both clinic-based biopsy and subsequent surgical excision of their masses. Results: We found clinic-based biopsies to be 87.0% accurate for exact diagnosis and 94.2% accurate in determining whether the mass was benign or malignant (p < 0.0001). Minor complications related to the clinic-based biopsy occurred in 5.80% of cases, with no documentation of major complications. Conclusions: Our results provide evidence that office-based percutaneous biopsy can be administered safely and yield accurate, clinically useful results when performed by a fellowship-trained musculoskeletal oncologist. PMID- 30008582 TI - Population-based survey regarding factors contributing to expectation for death at home. AB - Background: In 2015 in Japan 12.7% of people die at home. Since the government has no policy to increase the number of hospital beds, at-home deaths should inevitably increase in the near future. Previous researches regarding expected place of death have focused on end-of-life patients. The aim of this study is to clarify the percentage and factors of senior people who expect at-home deaths whether they are end-of-life or not. Methods: Using cross-sectional questionnaire survey data which had been taken by a research group with the support from Tama City Medical Association (Tokyo) in 2014, univariable and multivariable logistic regression analyses were conducted to identify associations among factors. The dependent variable was the expected site of death and other factors were set as independent variables. Results: Of 1781 respondents, 46.5% expected at-home deaths. Data from 1133 people were analyzed and 46.5% of those wanted at-home deaths. Factors significantly associated with expectation of at-home death were men, stand-alone houses for dwelling, expectation to continue life in Tama city, twosome life with the spouse, healthiness, and economic challenge. Conclusion: Percentage of those who expected at-home deaths was much higher than the latest percentage of at-home deaths. Some factors associated with expectation of at-home deaths in this study have never been discussed. PMID- 30008581 TI - Inferring transient dynamics of human populations from matrix non-normality. AB - In our increasingly unstable and unpredictable world, population dynamics rarely settle uniformly to long-term behaviour. However, projecting period-by-period through the preceding fluctuations is more data-intensive and analytically involved than evaluating at equilibrium. To efficiently model populations and best inform policy, we require pragmatic suggestions as to when it is necessary to incorporate short-term transient dynamics and their effect on eventual projected population size. To estimate this need for matrix population modelling, we adopt a linear algebraic quantity known as non-normality. Matrix non-normality is distinct from normality in the Gaussian sense, and indicates the amplificatory potential of the population projection matrix given a particular population vector. In this paper, we compare and contrast three well-regarded metrics of non normality, which were calculated for over 1000 age-structured human population projection matrices from 42 European countries in the period 1960 to 2014. Non normality increased over time, mirroring the indices of transient dynamics that peaked around the millennium. By standardising the matrices to focus on transient dynamics and not changes in the asymptotic growth rate, we show that the damping ratio is an uninformative predictor of whether a population is prone to transient booms or busts in its size. These analyses suggest that population ecology approaches to inferring transient dynamics have too often relied on suboptimal analytical tools focussed on an initial population vector rather than the capacity of the life cycle to amplify or dampen transient fluctuations. Finally, we introduce the engineering technique of pseudospectra analysis to population ecology, which, like matrix non-normality, provides a more complete description of the transient fluctuations than the damping ratio. Pseudospectra analysis could further support non-normality assessment to enable a greater understanding of when we might expect transient phases to impact eventual population dynamics. PMID- 30008583 TI - The Role of Bone Marrow-Derived Cells during Ectopic Bone Formation of Mouse Femoral Muscle in GFP Mouse Bone Marrow Transplantation Model. AB - Multipotential ability of bone marrow-derived cells has been clarified, and their involvement in repair and maintenance of various tissues has been reported. However, the role of bone marrow-derived cells in osteogenesis remains unknown. In the present study, bone marrow-derived cells during ectopic bone formation of mouse femoral muscle were traced using a GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) mice were transplanted into C57BL/6 J wild type mice. After transplantation, insoluble bone matrix (IBM) was implanted into mouse muscle. Ectopic bone formation was histologically assessed at postoperative days 7, 14, and 28. Immunohistochemistry for GFP single staining and GFP-osteocalcin double staining was then performed. Bone marrow transplantation successfully replaced hematopoietic cells with GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts and osteocytes involved in ectopic bone formation were GFP-negative, whereas osteoclasts and hematopoietic cells involved in bone formation were GFP-positive. These results indicate that bone marrow-derived cells might not differentiate into osteoblasts. Thus, the main role of bone marrow-derived cells in ectopic osteogenesis may not be to induce bone regeneration by differentiation into osteoblasts, but rather to contribute to microenvironment formation for bone formation by differentiating tissue stem cells into osteoblasts. PMID- 30008584 TI - Anti-inflammatory Effects of Sinomenium Acutum Extract On Endotoxin-induced Uveitis in Lewis Rats. AB - PURPOSE: Recent studies have reported the anti-inflammatory effect of Sinomenium acutum. We investigated the anti-inflammatory effect of sinomenine on endotoxin induced uveitis in a rat model. METHODS: Endotoxin-induced uveitis was induced in rat by lipopolysaccharide (LPS) immunization. Sinomenine (50mg/kg and 100mg/kg) was administered at 30 minutes before, 6 hours and 12 hours after LPS immunization. Clinical and histological severity was evaluated. Protein concentration and levels of tumor necrosis factor (TNF)-alpha and prostaglandin (PG)-E2 in aqueous humor were measured. Expression of activated Nuclear factor (NF)-kappaB p65 in ciliary body was also observed. RESULTS: Clinical and histological severities were significantly milder in sinomenine-treated rat than in controls (P < 0.001). Sinomenine suppressed protein leakage and down-regulated the production of TNF-alpha and PG-E2 in a dose-dependent manner. Sinomenine treatment suppressed the translocation of the NF-kappaB p65 subunit into the nuclei. CONCLUSION: Systemic administration of sinomenine suppressed the inflammation of ocular tissues. These findings suggest that sinomenine could be a novel therapeutic agent for the control of endogenous ocular inflammatory disease. PMID- 30008585 TI - Correlation of E-cadherin gene polymorphisms and epidermal growth factor receptor mutation in lung adenocarcinoma. AB - Epithelial-mesenchymal transition (EMT) was recently discovered related to the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) in NSCLC patients and cell lines. In this study, we aimed to explore the association among the E-cadherin gene (CDH1) genetic variants, TK-domain mutations of EGFR, and clinicopathologic characteristics in patients with lung adenocarcinoma. A total of 280 patients with lung adenocarcinoma were recruited between years 2012 and 2015. All subjects underwent the analysis of CDH1 genetic variants (rs16260 and rs9929218) by real-time polymerase chain reaction (PCR) genotyping. The results showed that CA and CA + AA genotypes of CDH1 single nucleotide polymorphism (SNP) rs16260 were significantly reverse associated with EGFR mutation type (Adjusted odds ratio (AOR) = 0.43, 95% CI = 0.20-0.92 and AOR = 0.46, 95% CI = 0.22-0.96, respectively) in female lung adenocarcinoma patients. Moreover, the significantly reverse associations between CA and CA + AA genotypes of CDH1 rs16260 and EGFR hotspot mutations, namely L858R mutation and exon 19 in frame deletion, were also demonstrated among female patients. Besides, CA + AA genotype of CDH1 rs16260 was noted significantly reverse associated with the tumor sizes (OR = 0.31, 95% CI = 0.12-0.80; p = 0.012). In conclusion, our results suggested that CDH1 variants are significantly reverse associated with mutation of EGFR tyrosine kinase, especially among the female patients with lung adenocarcinoma. The CDH1 variants might contribute to pathological development in lung adenocarcinoma. PMID- 30008586 TI - The replicative senescent mesenchymal stem / stromal cells defect in DNA damage response and anti-oxidative capacity. AB - Replicative senescence and potential malignant transformation are great limitations in the clinical application of bone marrow-derived mesenchymal stem / stromal cells (MSCs). An abnormal DNA damage response may result in genomic instability, which is an integral component of aging and tumorigenesis. However, the effect of aging on the DNA damage response in MSCs is currently unknown. In the present study, we evaluated the DNA damage response induced by oxidative stress and DNA double-strand breaks in human bone marrow-derived MSCs. After long term cell culture, replicative senescent MSCs (sMSCs) were characterized by a poor proliferation rate, high senescence-associated beta-galactosidase activity, and enhanced expression of P53 and P16. Features of the DNA damage response in these sMSCs were then compared with those from early-passage MSCs. The sMSCs were more sensitive to hydrogen peroxide and bleomycin treatment with respect to cell viability and apoptosis induction. Combined with the comet assay, gammaH2AX foci characterization and reactive oxygen species detection were used to demonstrate that the antioxidant and DNA repair ability of sMSCs are attenuated. This result could be explained, at least in part, by the downregulation of anti-oxidation and DNA repair genes, including Cu/Zn-SOD, GPX, CAT, OGG1, XRCC1, Ku70, BRCA2 and XRCC4. In conclusion, MSCs aging is associated with a reduction in the DNA repair and anti-oxidative capacity. PMID- 30008587 TI - Hyperbaric Oxygen Therapy in Liver Diseases. AB - Hyperbaric oxygen therapy (HBOT) is an efficient therapeutic option to improve progress of lots of diseases especially hypoxia-related injuries, and has been clinically established as a wide-used therapy for patients with carbon monoxide poisoning, decompression sickness, arterial gas embolism, problematic wound, and so on. In the liver, most studies positively evaluated HBOT as a potential therapeutic option for liver transplantation, acute liver injury, nonalcoholic steatohepatitis, fibrosis and cancer, especially for hepatic artery thrombosis. This might mainly attribute to the anti-oxidation and anti-inflammation of HBOT. However, some controversies are existed, possibly due to hyperbaric oxygen toxicity. This review summarizes the current understandings of the role of HBOT in liver diseases and hepatic regeneration. Future understanding of HBOT in clinical trials and its in-depth mechanisms may contribute to the development of this novel adjuvant strategy for clinical therapy of liver diseases. PMID- 30008588 TI - Effects of Tranexamic Acid Based on its Population Pharmacokinetics in Pediatric Patients Undergoing Distraction Osteogenesis for Craniosynostosis: Rotational Thromboelastometry (ROTEMTM) Analysis. AB - Background: Distraction osteogenesis for craniosynostosis is associated with significant hemorrhage. Additionally, patients usually require several transfusions. Tranexamic acid (TXA) is effective for reducing blood loss and the need for transfusions during surgeries. However, the significance of TXA infusion has not been thoroughly described yet. Methods: Forty-eight children undergoing distraction osteogenesis for craniosynostosis were administered intraoperative TXA infusion (loading dose of 10 mg/kg for 15 min, followed by continuous infusion at 5 mg/kg/h throughout surgery; n = 23) or normal saline (control, n = 25). Rotational thromboelastometry (ROTEMTM) was conducted to monitor changes in coagulation perioperatively. Results: Blood loss during surgery was significantly lower in the TXA-treated group than it was in the control group (81 vs. 116 mL/kg, P = 0.003). Furthermore, significantly fewer transfusions of red blood cells and fresh frozen plasma were required in the TXA group. In the control group, clotting time during the postoperative period was longer than it was during the preoperative period. Similarly, clot strength was weaker during the postoperative period. D-dimer levels dramatically increased in the control group compared with the TXA group after surgery. The duration of mechanical ventilation and the number of postoperative respiratory-related complications were significantly greater in the control group than they were in the TXA group. Conclusions: TXA infusion based on population pharmacokinetic analysis is effective in reducing blood loss and the need for transfusions during the surgical treatment of craniosynostosis. It can also prevent the increase in D dimer levels without affecting systemic hemostasis. PMID- 30008589 TI - Efficacy and safety of nucleos(t)ide analogues to prevent hepatitis B virus mother-to-child transmission in pregnant women with high viremia: real life practice from China. AB - Purpose: To evaluate the efficacy and safety of nucleos(t)ide analogues, especially telbivudine (LdT) for the prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in women with high viremia. Methods: We conducted a prospective, open-label, multicenter study of LdT for treating pregnant women having high viral loads of hepatitis B virus (HBV DNA>5 log10 IU/mL) but normal levels of alanine aminotransferase (ALT). Maternal HBV DNA, HBV serologic status and ALT were measured at baseline, 4 weeks after therapy, before delivery, 4 weeks after delivery, and 12 weeks after delivery. Infant HBV serologic status and HBV DNA levels were measured at 7 months. We calculated the MTCT rate of LdT-treated and LdT-untreated groups and analyzed the efficacy and safety of LdT. Results: Ninety-one women (the treatment group) were treated with LdT, and twenty-one patients (the observation group) did not undergo antiviral therapy. The baseline HBV DNA levels were 8.15+/-0.82 log10 IU/mL in the treatment group, and 8.09+/-1.04 log10 IU/mL in the observation group. The MTCT rate was 0% in the treatment group, and 9.5% in the observation group (p=0.042). In the treatment group, HBV DNA levels were 5.02+/-0.74 log10 IU/mL at one month after therapy, and 3.95+/-0.94 log10 IU/mL before delivery. Both groups had significant differences from baseline levels in HBV DNA levels (p<0.001). In total, five patients had elevated ALT levels but without evidence of decompensate liver function. No severe adverse events or complications were observed in women or infants. Conclusions: For pregnant women with HBV DNA greater than 5 log10IU/mL, LdT therapy was effective in reducing HBV MTCT. If serum HBV DNA was detectable at delivery, discontinuation of LdT immediately was found to be safe and rarely induced off-treatment hepatitis flare. PMID- 30008590 TI - Effect of Muscle Strength by Trichinella spiralis Infection during Chronic Phase. AB - Introduction:Trichinella spiralis establishes a chronic infection in skeletal muscle by developing nurse cells within muscle fibers. During symbiosis in host, changes in the muscle fibers and inflammation may affect muscle function. Methods: We investigated muscle strength and inflammation in T. spiralis-infected mice during 1 to 48 weeks after infection. Results: Muscle strength decreased compared to that in uninfected control mice during the late infection stage. Additionally, inflammatory related cytokines increased significantly during early stage of infection and then rapidly decreased. In pathological study, nuclear infiltration maintained from the early infection stage to chronic infection stage. Moreover, vacuoles and eosinophil infiltration were observed in infected muscle in chronic stage. Conclusion: These results suggest that infection by T. spiralis significantly affects muscle function was continuously being weakness because vacuoles formation and maintained nucleus and eosinophil infiltration during chronic phase of T. spiralis infection. PMID- 30008591 TI - Iroquois Homeodomain transcription factors in ventricular conduction system and arrhythmia. AB - Iroquois homeobox genes, Irx, encode cardiac transcription factors, Irx1-6 in most mammals. These six transcription factors are expressed in different patterns mainly in the ventricular part of the heart. Existing researches show that Irx genes play key roles in the differentiation and development of ventricular conduction system and the establishment and maintenance of gradient expression of potassium channels, Kv4.2. Our main focus of this review is on the recent advances in the discovery of above-mentioned genes and the function of the encoding products, how Irx genes establish ventricular conduction system and regulate ventricular repolarization, how the individual and complementary functions can be verified to complement our cognition and leads to novel therapeutic approaches. PMID- 30008592 TI - Intestinal dysbiosis activates renal renin-angiotensin system contributing to incipient diabetic nephropathy. AB - Considerable interest nowadays has focused on gut microbiota owing to their pleiotropic roles in human health and diseases. This intestinal community can arouse a variety of activities in the host and function as "a microbial organ" by generating bioactive metabolites and participating in a series of metabolism dependent pathways. Alternations in the composition of gut microbiota, referred to as intestinal dysbiosis, are reportedly associated with several diseases, especially diabetes mellitus and its complications. Here we focus on the relationship between gut microbiota and diabetic nephropathy (DN), as the latter is one of the major causes of chronic kidney diseases. The activation of renin angiotensin system (RAS) is a critical factor to the onset of DN, and emerging data has demonstrated a provoking and mediating role of gut microbiota for this system in the context of metabolic diseases. The purpose of the current review is to highlight some research updates about the underlying interplay between gut microbiota, their metabolites, and the development and progression of DN, along with exploring innovative approaches to targeting this intestinal community as a therapeutic perspective in clinical management of DN patients. PMID- 30008594 TI - Proscillaridin A induces apoptosis, inhibits STAT3 activation and augments doxorubicin toxicity in prostate cancer cells. AB - Cardiac glycosides are natural compounds used for the treatment of congestive heart failure and cardiac arrhythmias. Recently, they have been reported to exhibit anticancer activity. Proscillaridin A (PSN-A), a cardiac glycoside constituent of Urginea maritima has been shown to exhibit anticancer activity. However, the cellular targets and anticancer mechanism of PSN-A in various cancers including prostate cancer remain largely unexplored. In the present study, we have shown that PSN-A inhibits proliferation and induces apoptosis in prostate cancer cells in a dose-dependent manner. Further mechanistic study have shown that anticancer activity of PSN-A in prostate cancer cells is associated with ROS generation, Bcl-2 family proteins modulation, mitochondrial membrane potential disruption and ultimately activation of caspase-3 and cleavage of PARP. Moreover, we found that PSN-A inhibits JAK2/STAT3 signaling and augments doxorubicin toxicity in prostate cancer cells. Of note, LNCaP cells were found to be more sensitive to PSN-A treatment as compared to DU145 cells. Taken together, the data provided first evidence of the anticancer activity and possible molecular mechanism of PSN-A in prostate cancer. Further study is needed to develop PSN-A into a potential lead compound for the treatment of prostate cancer. PMID- 30008593 TI - Compliance with Saliva Collection Protocol in Healthy Volunteers: Strategies for Managing Risk and Errors. AB - Salivary bioscience technologies such as electrophoresis are widely applied for diagnosing systemic health status. Diagnosis using a saliva sample has emerged as a preferred technique since the sample is easy to collect and the method is inexpensive and non-invasive. Salivary diagnostics have even been identified as potential substitutes for serum protein biomarkers. However, the optimal protocol for collecting saliva has not yet been established. In many scientific settings, such as randomized controlled trials, sampling and statistical errors often occur when handling samples from healthy volunteers. These errors can be due to the psychological behavior of the volunteers, subject nonadherence, questionnaire characteristics, collection methods, and/or sample processing. The purpose of the review presented here is to outline the strategies for managing the risk factors and to minimize the sampling errors during saliva collection in healthy volunteers. PMID- 30008595 TI - A human origin strain Lactobacillus acidophilus DDS-1 exhibits superior in vitro probiotic efficacy in comparison to plant or dairy origin probiotics. AB - Background: The health benefits of probiotics are well established and known to be strain-specific. However, the role of probiotics obtained from different origins and their efficacy largely remains unexplored. The aim of this study is to investigate the in vitro efficacy of probiotics from different origins. Methods: Probiotic strains utilized in this study include Lactobacillus acidophilus DDS-1 (human origin), Bifidobacterium animalis ssp. lactis UABla-12 (human origin), L. plantarum UALp-05 (plant origin) and Streptococcus thermophilus UASt-09 (dairy origin). Screening assays such as in vitro digestion simulation, adhesion, cell viability and cytokine release were used to evaluate the probiotic potential. Results: All strains showed good resistance in the digestion simulation process, especially DDS-1 and UALp-05, which survived up to a range of 107 to 108 CFU/mL from an initial concentration of 109 CFU/mL. Two human colonic mucus-secreting cells, HT-29 and LS174T, were used to assess the adhesion capacity, cytotoxicity/viability, and cytokine quantification. All strains exhibited good adhesion capacity. No significant cellular cytotoxicity or loss in cell viability was observed. DDS-1 and UALp-05 significantly upregulated anti-inflammatory IL-10 and downregulated pro-inflammatory TNF-alpha cytokine production. All the strains were able to downregulate IL-8 cytokine levels. Conclusion: Of the 4 strains tested, DDS-1 demonstrated superior survival rates, good adhesion capacity and strong immunomodulatory effect under different experimental conditions. PMID- 30008596 TI - Chewing during prenatal stress prevents prenatal stress-induced suppression of neurogenesis, anxiety-like behavior and learning deficits in mouse offspring. AB - Prenatal stress (PS) induces learning deficits and anxiety-like behavior in mouse pups by increasing corticosterone levels in the dam. We examined the effects of maternal chewing during PS on arginine vasopressin (AVP) mRNA expression in the dams and on neurogenesis, brain-derived neurotrophic factor (BDNF) mRNA expression, learning deficits and anxiety-like behavior in the offspring. Mice were divided into control, stress and stress/chewing groups. Pregnant mice were exposed to restraint stress beginning on day 12 of pregnancy and continuing until delivery. Mice in the stress/chewing group were given a wooden stick to chew during restraint stress. PS significantly increased AVP mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus in the dams. PS also impaired learning ability, suppressed neurogenesis and BDNF mRNA expression in the hippocampus, and induced anxiety-like behavior in the offspring. Chewing during PS prevented the PS-induced increase in AVP mRNA expression of the PVN in the dams. Chewing during PS significantly attenuated the PS-induced learning deficits, anxiety-like behavior, and suppression of neurogenesis and BDNF mRNA expression in the hippocampus of the offspring. Chewing during PS prevented the increase in plasma corticosterone in the dam by inhibiting the hypothalamic pituitary-adrenal axis activity, and attenuated the attenuated the PS-induced suppression of neurogenesis and BDNF expression in the hippocampus of the pups, thereby ameliorating the PS-induced learning deficits and anxiety-like behavior. Chewing during PS is an effective stress-coping method for the dam to prevent PS induced deficits in learning ability and anxiety-like behavior in the offspring. PMID- 30008597 TI - Myokines related to leukocyte recruitment are down-regulated in osteosarcoma. AB - Myokines are cytokines that are secreted by muscle cells during exercises, muscle development and pathology. Studies have shown that expression of some individual myokines was altered in tumors. However, comprehensive analyses of myokines' expression in osteosarcoma (OS), the most common malignant tumor in musculoskeletal system, have not been performed. In this study, we analyzed the expression of 35 myokines in osteosarcoma, peritumoral skeletal muscle, and cancellous bone by qRT-PCR. Heatmap analysis based on the expression pattern of these myokines revealed that OS is more likely derived from cancellous bone than peritumoral skeletal muscle. Thus, we compared the expression of myokines between OS and cancellous bone to reveal a potential role of myokines in OS development. Our results showed that expression of 19 myokines in OS was significantly lower than that in cancellous bone. KEGG signaling pathway analysis showed that these 19 myokines are involved in several important signaling pathways, one of which was associated with leukocyte recruitment in TNF-alpha signaling. We verified that expression of these leukocyte recruitment-related myokines were down regulated in OS cell line MNNG compared to those in human BMSC. Downregulation of the myokines related to leukocyte recruitment suggests that escaping from host immune system may help the occurrence of osteosarcoma. PMID- 30008598 TI - Outcome and Prospective Factor Analysis of High-dose Therapy Combined with Autologous Peripheral Blood Stem Cell Transplantation in Patients with Peripheral T-cell Lymphomas. AB - Background: For peripheral T-cell lymphomas (PTCLs) patients, high-dose therapy combined with autologous peripheral blood stem cell transplantation (HDT/ASCT) has been an alternative treatment option, due to the lack of efficacy from conventional chemotherapy. While not all PTCLs could have benefit in survival from HDT/ASCT. The aim of this study was to evaluate the value of high-dose therapy combined with autologous peripheral blood stem cell transplantation (HDT/ASCT) in Chinese patients with Peripheral T-cell Lymphomas (PTCLs), in order to determine the cohort most suitable to receive HDT/ASCT. Methods: A total of 79 patients with PTCLs who received HDT/ASCT in Peking University Cancer Hospital & Institute from January 2001 to august 2016 were retrospectively analyzed. Results: At a median follow-up time of 23.6 months, the 2-year progression-free survival (PFS) and 2-year overall survival (OS) of the entire cohort were 75.2% and 83.6% respectively. Patients with first complete remission (CR1) (2-year PFS 85.8%, 2-year OS 94.2%) were superior to others in survival. Patients with second complete remission (CR2) had no advantage in survival compared with those with first partial remission (PR1) (2-year PFS: 43.8% vs. 76.2%, p=0.128; 2-year OS: 72.9% vs. 77.1%, p=0.842). In multivariate analysis, response before HDT/ASCT (p=0.001) and LDH before HDT/ASCT (p=0.047) were highly predictive for PFS, while no factors could independently predict OS. Subgroup analysis revealed that HDT/ASCT could improve the survival of patients with angioimmunoblastic T-cell lymphoma (AITL), especially in patients with chemosensitivity. Patients with natural killer / T-cell lymphoma (NKTCL) who received HDT/ASCT with CR1 also had benefit in survival from HDT/ASCT, while nearly 90% of non-CR1 patients appeared bone marrow involvement after HDT/ASCT. Conclusion: Patients who achieved complete remission after first-line therapy, especially with AITL and NKTCL, should strongly be recommended to receive HDT/ASCT. The future prospective trial is warranted. PMID- 30008599 TI - Morphine Induces Fibroblast Activation through Up-regulation of Connexin 43 Expression: Implication of Fibrosis in Wound Healing. AB - Morphine is the most effective drugs for attenuating various types of severe pain, but morphine abuse carries a high risk of systemic fibrosis. Our previous have indicated that systemic administration of morphine hinders angiogenesis and delays wound healing. Here we have explained the pathological mechanism underlying the effect of morphine on wound healing. To determine how morphine affects wound healing, we first created a wound in mice treated them with a combination of a low doses (5 mg/kg/day) and high doses (20 or 30 mg/kg/day) of morphine. An In vivo study revealed that high-dose morphine-induced abnormal myofibroblasts persist after the end of wound healing because of connexin 43 (Cx43) upregulation. High-dose morphine-induced Cx43 increased the expression levels of focal adhesion molecules, namely fibronectin and alpha-smooth muscle actin (alpha-SMA) through the activation of transforming growth factor (TGF) beta1 signaling. In addition, we found that Cx43 contributed to TGF-betaRII/ Smad2/3 signaling for regulating the differentiation of fibroblasts into myofibroblasts during high-dose morphine exposure. In conclusion, the abnormal regulation of Cx43 by morphine may induce systemic fibrosis because of abnormal myofibroblast function. PMID- 30008600 TI - Biomarkers for Predicting Malignant Pleural Mesothelioma in a Mexican Population. AB - Background: Diagnosis of malignant pleural mesothelioma (MPM) remains a challenge, especially when resources in pathology are limited. The study aimed to evaluate cost-effective tumor markers to predict the probability of MPM in plasma samples in order to accelerate the diagnostic workup of the tissue of potential cases. Methods: We conducted a case-control study stratified by gender, which included 75 incident cases with MPM from three Mexican hospitals and 240 controls frequency-matched by age and year of blood drawing. Plasma samples were obtained to determine mesothelin, calretinin, and thrombomodulin using enzyme-linked immunosorbent assays (ELISAs). We estimated the performance of the markers based on the area under the curve (AUC) and predicted the probability of an MPM diagnosis of a potential case based on the marker concentrations. Results: Mesothelin and calretinin, but not thrombomodulin were significant predictors of a diagnosis of MPM with AUCs of 0.90 (95% CI: 0.85-0.95), 0.88 (95% CI: 0.82 0.94), and 0.51 (95% CI: 0.41-0.61) in males, respectively. For MPM diagnosis in men we estimated a true positive rate of 0.79 and a false positive rate of 0.11 for mesothelin. The corresponding figures for calretinin were 0.81 and 0.18, and for both markers combined 0.84 and 0.11, respectively. Conclusions: We developed prediction models based on plasma concentrations of mesothelin and calretinin to estimate the probability of an MPM diagnosis. Both markers showed a good performance and could be used to accelerate the diagnostic workup of tissue samples in Mexico. PMID- 30008601 TI - A high frequency of CD8+CD28- T-suppressor cells contributes to maintaining stable graft function and reducing immunosuppressant dosage after liver transplantation. AB - CD8+CD28-T cells (CD8Ts) exert immunosuppressive effects in various autoimmune diseases. The current study was designed to investigate the role of defects in CD8Ts in liver transplantation (LT). The proportion of CD8Ts in peripheral blood was determined by flow cytometry. The mean proportion of CD8Ts was 23.39% in recipients with stable graft function and 16.64% in those with graft dysfunction following LT compared with 19.86% in the healthy cohort. After receiving enhanced immunosuppressive therapy, patients in the rejection group who achieved recovery of graft function showed an increase in the proportion of CD8Ts (from 17.39% to 25.55%), but those in the group with refractory graft dysfunction showed no significant change (12.49% to 10.30%). Furthermore, in the first year after LT, recipients longer removed in time from the LT date exhibited a higher proportion of CD8Ts. Patients benefited most from tacrolimus concentrations of 5-10 ng/ml in the first year after LT and 0-5 ng/ml thereafter. Moreover, the change in the proportion of CD8Ts (DeltaCD8Ts) was significantly higher in recipients with stable graft function than in those with graft dysfunction. These results suggest that a high frequency of CD8Ts prevents rejection and contributes to reduce immunosuppressant dosage and even induces tolerance. PMID- 30008602 TI - Assessment of a combination of Serum Proteins as potential biomarkers to clinically predict Schizophrenia. AB - Schizophrenia (SZ) is a devastating psychiatric disorder. Validation of potential serum biomarkers during first-episode psychosis (FEP) is especially helpful to understand the onset and prognosis of this disorder. To address this question, we examined multiple blood biomarkers and assessed the efficacy to diagnose SZ. The expression levels of Neuregulin1 (NRG1), ErbB4, brain-derived neurotrophic factor (BDNF), DNA methyltransferases 1 (DNMT1) and ten-eleven translocation 1 (TET1) proteins in peripheral blood of 53 FEP patients and 57 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression including biomarker concentration as covariates was used to predict SZ. Differentiating performance of these five serum protein levels was analyzed by Receiver Operating Characteristic (ROC) curve analysis. We found that patients with SZ present a higher concentration of DNMT1, and TET1 in peripheral blood, but a lower concentration of NRG1, ErbB4 and BDNF than controls. Multivariable logistic regression showed that ErbB4, BDNF and TET1 were independent predictors of SZ, and when combined, provided high diagnostic accuracy for SZ. Together, our findings highlight that altered expression of NRG1, ErbB4, BDNF, DNMT1 and TET1 are involved in schizophrenia development and they may serve as potential biomarkers for the diagnosis of the schizophrenia. Therefore, our study provides evidence that combination of ErbB4, BDNF and TET1 biomarkers could greatly improve the diagnostic performance. PMID- 30008603 TI - Rehabilitative ultrasound imaging of the bilateral intrinsic plantar muscles and fascia in post-stroke survivors with hemiparesis: A case-control study. AB - Purpose: The study main aim was to compare the cross-sectional area (CSA) and thickness of the plantar muscles and fascia in the hemiparesis and contralateral feet of poststroke survivors with respect to healthy feet of matched controls. Methods: A case-control observational study was performed using B-mode rehabilitative ultrasound imaging. A convenience sampling method was used to select 60 feet. The sample was divided into 20 feet ipsilateral and 20 feet contralateral to the hemiparesis lower limb from poststroke survivors, as well as 20 healthy feet from matched controls. The CSA and thickness of the abductor hallucis, flexor digitorum brevis and flexor hallucis brevis, as well as the thickness for the posterior, middle and anterior plantar fascia portions were measured. Comparisons and multivariate predictive analyses were carried out for ultrasound measurements. In all analyses, a P-value<.01 with a 99% confidence interval was considered as statistically significant. Results: Statistically significant differences (P<.01) were shown for a flexor hallucis brevis thickness increase as well as middle and anterior plantar fascia thickness decrease of the hemiparesis feet and contralateral feet with respect to the healthy matched control feet. The rest of measurements did not show any statistically significant difference (P>.01). Conclusions: The thickness of the flexor hallucis brevis muscle as well as the middle and anterior plantar fascia portions of the hemiparesis and contralateral feet from poststroke survivors presented morphology changes with respect to the healthy matched control feet. PMID- 30008604 TI - Co-infection Of Ureaplasma urealyticum And Human Papilloma Virus In Asymptomatic Sexually Active Individuals. AB - This study aimed to determine the role of asymptomatic bacterial sexually transmitted infections (STIs), such as Chlamydia trachomatis (Ct), Mycoplasma genitalium (Mg), Mycoplasma hominis (Mh), and Ureaplasma urealyticum (Uu) in human papillomavirus (HPV) infection. In total, 264 asymptomatic outpatients aged between 21 and 80 years were prospectively enrolled in this study during routine gynecological screening tests. Specimens collected with a Cervex Brush were routinely analyzed with the Hybrid Capture 2 assay for HPV. Simultaneously, a specimen obtained with an endocervical swab was used to detect Ct and Mg with a monoplex real-time polymerase chain reaction (PCR) and to confirm Mh and Uu with a Mycoplasma IST 2 kit. The detection rates (%) of HPV, Ct, Mg, Mh, and Uu were 82/264 (31.1), 6/264 (2.3), 5/264 (1.9), 16/264 (6.1), and 95/264 (36.0), respectively. Of 95 Uu, 32 (33.7%) showed high density colonization (HDC, >=104 color-changing units/mL). HDC-Uu was significantly associated with HPV infection (p=0.014, chi-square test). Mg infection and Mh infection were not associated with HPV infection (p=0.981 and p=0.931, chi-square test). Age was not associated with HPV infection or bacterial infection. Our data suggested that asymptomatic HDC-Uu was closely associated with HPV infection. Therefore, simultaneous evaluation for Uu and HPV should be performed during gynecological screening, even in asymptomatic individuals. PMID- 30008605 TI - Recovery effect of pre-germinated brown rice on the changes of sperm quality, testicular structure and androgen receptor expression in a rat model of drug addiction. AB - Drug addiction is reported to have adverse effects in male reproduction. Dextromethorphan (DXM) administration was used in this study as a model of addiction in rats, and various treatments including the use of pre-germinated brown rice (PGBR) were investigated for their effects on the changes of sperm quality, testicular structure and androgen receptor (AR) expressions in rats receiving DXM. The results demonstrated that these animals showed significant reduction in all parameters of sperm quality, an increase in abnormal testicular structure and decreased androgen receptor expression in spermatogenic, Sertoli and Leydig cells. However, different effects of the treatments applied in this study were observed with the greatest recovery effect from treatment with PGBR. Sperm motility and sperm concentration reverted to normal after treatment with PGBR for 60 days. Moreover, all parameters of testicular structure also returned to normal after 60 days of PGBR treatment, as well as AR expression in Sertoli and Leydig cells. Therefore, we have demonstrated that PGBR treatment can reverse the changes in sperm quality, testicular structure and AR expression in addicted animals and PGBR may be a novel therapeutic strategy for the treatment of drug addiction. PMID- 30008606 TI - Anti-inflammation and Anti-Cancer Activity of Ethanol Extract of Antarctic Freshwater Microalga, Micractinium sp. AB - Inflammation mediated by the innate immune system is an organism's protective mechanism against infectious environmental risk factors. It is also a driver of the pathogeneses of various human diseases, including cancer development and progression. Microalgae are increasingly being focused on as sources of bioactive molecules with therapeutic potential against various diseases. Furthermore, the antioxidant, anti-inflammatory, and anticancer potentials of microalgae and their secondary metabolites have been widely reported. However, the underlying mechanisms remain to be elucidated. Therefore, in this study, we investigated the molecular mechanisms underlying the anti-inflammatory and anticancer activities of the ethanol extract of the Antarctic freshwater microalga Micractinium sp. (ETMI) by several in vitro assays using RAW 264.7 macrophages and HCT116 human colon cancer cells. ETMI exerted its anti-inflammatory activity by modulating the main inflammatory indicators such as cyclooxygenase (COX)-2, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-alpha, and nitric oxide (NO) in a dose-dependent manner. In addition, ETMI exerted cytotoxic activity against HCT116 cells in a dose-dependent manner, leading to significantly reduced cancer cell proliferation. Further, it induced cell cycle arrest in the G1 phase through the regulation of hallmark genes of the G1/S phase transition, including CDKN1A, and cyclin-dependent kinase 4 and 6 (CDK4 and CDK6, respectively). At the transcriptional level, the expression of CDKN1A gradually increased in response to ETMI treatment while that of CDK4 and CDK6 decreased. Taken together, our findings suggest that the anti-inflammatory and anticancer activities of the Antarctic freshwater microalga, Micractinium sp., and ETMI may provide a new clue for understanding the molecular link between inflammation and cancer and that ETMI may be a potential anticancer agent for targeted therapy of colorectal cancer. PMID- 30008607 TI - Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors. AB - Objectives: In Japan, sodium-glucose co-transporter type 2 (SGLT2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders. A post-marketing surveillance (PMS) study suggested that the association was specific for ipragliflozin and, to a lesser extent for dapagliflozin. These studies were performed to confirm the association of 6 SGLT2 inhibitors with serious skin disorders in a clinical setting, to elucidate the role of melanin in serious skin disorders and to understand the underlying mechanisms. Methods: The latest PMS records were retrieved from the Japanese Adverse Drug Event Report (JADER) database, and the associations were analyzed by data mining techniques. In silico 3-D docking simulation of SGLT2 inhibitors with melanin was performed using the MOE software. The skin tissue distribution of SGLT2 inhibitors was evaluated using albino rats after oral administration at clinical doses. Results: The adjusted reporting odds ratio (95% confidential limit) was 1.667 (1.415, 1.963) for ipragliflozin, 0.514 (0.317, 0.835) for dapagliflozin, 0.149 (0.048, 0.465) for tofogliflozin, 0.624 (0.331, 1.177) for luseogliflozin, 0.590 (0.277, 1.257) for canagliflozin and 0.293 (0.073, 1.187) for empagliflozin, when drugs other than the SGLT2 inhibitors were referred, and the association was detected only for ipragliflozin in clinical use. In silico 3 D docking simulation suggested the influence of melanin in ipragliflozin-specific serious skin disorders. The skin tissue-to-plasma concentration ratio of ipragliflozin was 0.45 +/- 0.20 (+/-SD) at 1 hr after administration and increased in a time-dependent manner to 5.82 +/- 3.66 at 24 hr (p<0.05), but not in case of other SGLT2 inhibitors. Conclusions: Serious skin disorders were suggested to be specific for ipragliflozin. Interaction with melanin might be implicated in ipragliflozin-specific serious skin disorders. Ipragliflozin was retained in the skin tissue, which suggested its interaction with the skin tissue in serious skin disorders. PMID- 30008608 TI - Polydatin, Natural Precursor of Resveratrol, Promotes Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Bone loss and fractures are consequences of aging, diseases or traumas. Furthermore the increased number of aged people, due to the rise of life expectancy, needs more strategies to limit the bone loss and regenerate the lost tissue, ameliorating the life quality of patients. A great interest for non pharmacological therapies based on natural compounds is emerging and focusing on the oligostilbene Polydatin, present in many kinds of fruits and vegetables, when resveratrol particularly in red wines. These molecules have been extensively studied due to their antioxidant and anti-inflammatory effects, showing more recently Resveratrol the ability to enhance osteogenic differentiation and bone formation. However, the clinical applications of Resveratrol are limited due to its low bioavailability and rapid metabolism, while its natural glycosilated precursor Polydatin shows better metabolic stability and major abundance in fresh fruits and vegetables. Nevertheless the role of Polydatin on osteogenic differentiation is still unexplored. Mesenchymal stem cells (MSCs) from dental tissues, such as dental bud stem cells (DBSCs), are able to differentiate toward osteogenic lineage: thus we investigated how Resveratrol and Polydatin influence the differentiation of DBSCs, eventually affecting bone formation. Our results showed that Polydatin increases MSCs osteogenic differentiation sharing similar properties with Resveratrol. These results encourage to deepen the effects of this molecule on bone health and its associated mechanisms of action, wishing for the future a successful use in bone loss prevention and therapy. PMID- 30008609 TI - Manual acupuncture relieves bile acid-induced itch in mice: the role of microglia and TNF-alpha. AB - Pruritus, or itch, is a frequent complaint amongst patients with cholestatic hepatobiliary disease and is difficult to manage, with many patients refractory to currently available antipruritic treatments. In this study, we examined whether manual acupuncture (MA) at particular acupoints represses deoxycholic acid (DCA)-induced scratching behavior and microglial activation and compared these effects with those induced by another pruritogen, 5'-guanidinonaltrindole (GNTI, a kappa opioid receptor antagonist). MA at Hegu (LI4) and Quchi (LI11) acupoints significantly attenuated DCA- and GNTI-induced scratching, whereas no such effects were observed at the bilateral Zusanli acupoints (ST36). Interestingly, GNTI-induced scratching was reduced similarly by both MA and electroacupuncture (EA) at the LI4 and LI11 acupoints. MA at non-acupoints did not affect scratching behavior. Intraperitoneal injection of minocycline (a microglial inhibitor) reduced GNTI- and DCA-induced scratching behavior. In Western blot analysis, subcutaneous DCA injection to the back of the neck increased spinal cord expression of ionized calcium-binding adapter molecule 1 (Iba1) and tumor necrosis factor-alpha (TNF-alpha) as compared with saline injection, while MA at LI4 and LI11 reduced these DCA-induced changes. Immunofluorescence confocal microcopy revealed that DCA-induced Iba1-positive cells with thicker processes emanated from the enlarged cell bodies, while this effect was attenuated by pretreatment with MA. It is concluded that microglia and TNF-alpha play important roles in the itching sensation and MA reduces DCA induced scratching behavior by alleviating spinal microglial activation. MA may be an effective treatment for cholestatic pruritus. PMID- 30008610 TI - Falling down a flight of stairs: The impact of age and intoxication on injury pattern and severity. AB - Background: Falling down a flight of stairs is a common injury mechanism in major trauma patients, but little research has been undertaken into the impact of age and alcohol intoxication on the injury patterns of these patients. The aim of this study was to compare the impact of age and alcohol intoxication on injury pattern and severity in patients who fell down a flight of stairs. Methods: This was a retrospective observational study of prospectively collected trauma registry data from a major trauma centre in the United Kingdom comparing older and younger adult patients admitted to the Emergency Department following a fall down a flight of stairs between July 2012 and March 2015. Results: Older patients were more likely to suffer injuries to all body regions and sustained more severe injuries to the spine; they were also more likely to suffer polytrauma (23.6% versus 10.6%; p < 0.001). Intoxicated patients were more likely to suffer injuries to the head and neck (42.9% versus 30.5%; p = 0.006) and were significantly younger than sober patients (53 versus 69 years; p < 0.001). Conclusion: Older patients who fall down a flight of stairs are significantly different from their younger counterparts, with a different injury pattern and a greater likelihood of polytrauma. In addition, alcohol intoxication also affects injury pattern in people who have fallen down a flight of stairs, increasing the risk of traumatic brain injury. Both age and intoxication should be considered when managing these patients. PMID- 30008611 TI - Predictive Value of Combined LIPS and ANG-2 Level in Critically Ill Patients with ARDS Risk Factors. AB - To investigate the predictive value of the acute physiology and chronic health evaluation 2 (APACHE2) score and lung injury prediction score (LIPS) for acute respiratory distress syndrome (ARDS) when combined with biomarkers for this condition in patients with ARDS risk factors. In total, 158 Han Chinese patients with ARDS risk factors were recruited from the Respiratory and Emergency Intensive Care Units. The LIPS, APACHE2 score, primary diagnosis at admission, and ARDS risk factors were determined within 6 h of admission, and PaO2/FiO2 was determined on the day of admission. Blood was collected within 24 h of admission for the measurement of angiopoietin-2 (ANG-2), sE-selectin, interleukin-6 (IL-6), and interleukin-8 (IL-8) levels. ARDS was monitored for the next 7 days. Univariate and multivariate analyses and receiver operating characteristic (ROC) analyses were employed to construct a model for ARDS prediction. Forty-eight patients developed ARDS within 7 days of admission. Plasma ANG-2 level, sE selectin level, LIPS, and APACHE2 score in ARDS patients were significantly higher than those in non-ARDS patients. ANG-2 level, LIPS, and APACHE2 score were correlated with ARDS (P < 0.001, P < 0.006, and P < 0.042, resp.). When the APACHE2 score was used in combination with the LIPS and ANG-2 level to predict ARDS, the area under the ROC curve (AUC) was not significantly increased. Compared to LIPS or ANG-2 alone, LIPS in combination with ANG-2 had significantly increased positive predictive value (PPV) and AUC for the prediction of ARDS. In conclusion, plasma ANG-2 level, LIPS, and APACHE2 score are correlated with ARDS. Combined LIPS and ANG-2 level displays favorable sensitivity, specificity, and AUC for the prediction of ARDS. PMID- 30008612 TI - Immune Regulatory Cells in Inflammation, Infection, Tumor, Metabolism, and Other Diseases. PMID- 30008613 TI - Single Bout Exercise in Children with Juvenile Idiopathic Arthritis: Impact on Inflammatory Markers. AB - Objective: In a context of inflammatory disease such as juvenile idiopathic arthritis (JIA), we do not know what impact physical activity may have on a deregulated immune system. The objective is to measure the impact of a single bout of exercise on plasma inflammatory markers such as calprotectin, IL-6, sIL 6R, sgp130, and the hypothalamic-pituitary-adrenal axis in children with juvenile idiopathic arthritis. Methods: Twelve children with JIA performed a nonexercise control day and a consecutive day that included a 20 min exercise bout at 70% of max-HR at 08:30 am. Venous blood samples were taken at 08:30, 08:50, 09:30, 10:30 am, and 12:00 pm to measure plasma concentrations of calprotectin, IL-6, sIL-6R, sgp130, cortisol, and ACTH. Pain was evaluated at 08:30, 08:50 am, and 06:00 pm. Results: There was a transient twofold increase in postexercise self-evaluated pain (p = 0.03) that disappeared in the evening. A single bout of exercise resulted in a 1.7-fold increase in plasma calprotectin (p < 0.001) but not IL-6 and its soluble receptors. Calprotectin levels returned to baseline within 3 hours after cessation of exercise. Conclusion: Acute exercise in children with JIA induced slightly musculoskeletal leg pain and transient increased plasma calprotectin levels but not IL-6 levels. Trial registration in ClinicalTrials.gov, reference number NCT 02502539, registered on 29 May 2015. PMID- 30008614 TI - Spontaneous preterm birth prevention in multiple pregnancy. AB - Key content: Twin pregnancies are associated with a three-fold greater perinatal mortality than singleton pregnancies. Prematurity is a main contributor, with 50% of twin pregnancies delivering before 37 weeks and 10% delivering before 32 weeks of gestation.The aetiology of preterm delivery in twin pregnancies is likely multifactorial and different from that of singletons.Cervical cerclage reduces preterm birth rates in singletons but has mixed results in twins with some studies showing harm.The use of progesterone to prevent preterm birth in singletons has conflicting results and has not been proven to prevent preterm birth in twins. Studies continue to determine whether the cervical pessary is effective in preventing preterm birth in multiple pregnancies.There is a paucity of data available on the prevention of preterm birth in triplets/higher order multiples but similar principles to twin pregnancy apply. Learning objectives: To review the burden of preterm birth in multiple pregnancy.To understand the methods available for preventing preterm birth in multiple pregnancies and the evidence surrounding the use of each one.To be aware of the use of the Arabin pessary. PMID- 30008615 TI - Long noncoding RNA PVT1 modulates hepatocellular carcinoma cell proliferation and apoptosis by recruiting EZH2. AB - Background: We aimed to figure out the molecular network of PVT1 and EZH2 on hepatocellular carcinoma (HCC) cells growth. We also explored the interaction between PVT1, EZH2, MDM2 and P53. Methods: Microarray analysis was performed to screen for abnormally expressed genes in HCC tissues and PVT1 was identified as one gene significantly upregulated in HCC. CCK-8 assay, colony formation assay, and flow cytometry detected cell vitality, proliferation and apoptosis, respectively. RIP and RNA pull-down assays were employed to examine the connection between PVT1 and EZH2. The effect of PVT1 on the stability of EZH2 protein and the impact of EZH2 on MDM2 were detected by ELISA. Co immunoprecipitation assay was used to evaluate the relationship between MDM2 and EZH2. Western blot detected the expression of EZH2, MDM2 and P53. Results: Up regulated PVT1 was detected in HCC. Knockdown of PVT1 inhibited HCC cell propagation and promoted apoptotic cells. PVT1 could improve EZH2 protein stability by binding to EZH2 protein but have no significant impact on EZH2 mRNA expression. EZH2 protein stabilized MDM2 protein expression by binding to MDM2 protein. PVT1 enhanced the protein expression of EZH2 and MDM2 as well as inhibited P53 protein expression. Conclusions: PVT1 promoted HCC cell propagation and inhibited apoptotic cells by recruiting EZH2, stabilizing MDM2 protein expression and restraining P53 expression. PMID- 30008617 TI - B7-H4 overexpression contributes to poor prognosis and drug-resistance in triple negative breast cancer. AB - Background: The expression of the immunoregulatory protein B7-H4 has been reported in many types of cancer, including breast cancer. However, its role in triple-negative breast cancer (TNBC), especially its correlation with patients' prognosis and chemoresistance remains unclear. Methods: The expression of B7-H4 in TNBC tissues and cell lines were measured with Real-Time PCR and western blotting. 65 cases of TNBC tissue samples and adjacent non-tumor tissue samples were analyzed by immunochemistry to demonstrate the correlation between the B7-H4 expression and clinicopathological characteristics. In vitro studies assessed mAb MIH43 alone and in combination with transfecting B7-H4 siRNA on the growth of chemosensitive and chemoresistant TNBC cell lines by CCK-8 and apoptotic enzyme linked immunosorbent assay (ELISA). Results: B7-H4 expression was detected positive in 59 of 65 (90.8%) different stage TNBC patients, especially in the samples of recurrence TNBC patients after receiving neoadjuvant chemotherapy treatment. Survival curves showed that patients with B7-H4 overexpression had significantly shorter survival and recurrence time than those with low B7-H4 expression (p < 0.005). Univariate and multivariate COX regression analysis demonstrated that B7-H4 was an independent predictor for advanced tumor stage. The monoclonal antibody of B7-H4 has the potential anti-proliferative effects on inhibiting the chemoresistant TNBC cell lines and increasing the sensitivity of TNBC cell lines to doxorubicin, paclitaxel or carboplatin. RNAi-mediated silencing of B7-H4 in TNBC cells enhanced drug-induced apoptosis via inhibiting PTEN/PI3K/AKT pathway, whereas reexpression of B7-H4 in B7-H4 knockdown and low B7-H4 expressing cells increased the phosphorylation of PI3K and AKT along with restoration of PETN expression. Conclusions: Our data show that B7-H4 is a biomarker indicative of a poor prognosis in TNBC patients and at least partially downregulated in chemoresistance via PTEN/PI3K/AKT pathway. Targeting B7-H4 might provide an attractive therapeutic approach specifically for TNBC patients. PMID- 30008616 TI - Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. AB - Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue. PMID- 30008618 TI - Nanostructured lipid carriers for MicroRNA delivery in tumor gene therapy. AB - MicroRNAs (miRNAs), which are endogenous about 20-23 nucleotides non-coding RNAs, have been acted as post-transcriptional regulators of gene expression. Current studies demonstrated that miRNAs are promising candidates for tumor gene therapy because of their important biological functions in tumor cell proliferation, metastasis, apoptosis, and drug resistance. As an important delivery system, nanostructured lipid carriers (NLCs) have great potential in tumor gene therapy, particularly for miRNA delivery, due to low toxicity, low immunogenicity, long metabolic cycles, and easy modification. This article reviews recent research progress on NLCs for miRNA delivery in tumor gene therapy and prospective applications. PMID- 30008619 TI - Caspase recruitment domain (CARD) family (CARD9, CARD10, CARD11, CARD14 and CARD15) are increased during active inflammation in patients with inflammatory bowel disease. AB - Background: The CARD family plays an important role in innate immune response by the activation of NF-kappaB. The aim of this study was to determine the gene expression and to enumerate the protein-expressing cells of some members of the CARD family (CARD9, CARD10, CARD11, CARD14 and CARD15) in patients with IBD and normal controls without colonic inflammation. Methods: We included 48 UC patients, 10 Crohn's disease (CD) patients and 18 non-inflamed controls. Gene expression was performed by RT-PCR and protein expression by immunohistochemistry. CARD-expressing cells were assessed by estimating the positively staining cells and reported as the percentage. Results: The CARD9 and CARD10 gene expression was significantly higher in UC groups compared with CD (P < 0.001). CARD11 had lower gene expression in UC than in CD patients (P < 0.001). CARD14 gene expression was higher in the group with active UC compared to non inflamed controls (P < 0.001). The low expression of CARD14 gene was associated with a benign clinical course of UC, characterized by initial activity followed by long-term remission longer than 5 years (P = 0.01, OR = 0.07, 95%CI:0.007 0.70). CARD15 gene expression was lower in UC patients versus CD (P = 0.004). CARD9 protein expression was detected in inflammatory infiltrates; CARD14 in parenchymal cells, while CARD15 in inflammatory and parenchymal cells. CARD9-, CARD14- and CARD15 - expressing cells were significantly higher in patients with active UC versus non-inflamed controls (P < 0.05). Conclusion: The CARD family is involved in the inflammatory process and might be involved in the IBD pathophysiology. PMID- 30008620 TI - Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. AB - Introduction: Both disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) cause microvascular thrombosis associated with thrombocytopenia, bleeding tendency and organ failure. Reports and discussion: The frequency of DIC is higher than that of thrombotic thrombocytopenic purpura (TTP). Many patients with TMA are diagnosed with DIC, but only about 15% of DIC patients are diagnosed with TMA. Hyperfibrinolysis is observed in most patients with DIC, and microangiopathic hemolytic anemia is observed in most patients with TMA. Markedly decreased ADAMTS13 activity, the presence of Shiga-toxin-producing Escherichia coli (STEC) and abnormality of the complement system are useful for the diagnosis of TTP, STEC-hemolytic uremic syndrome (HUS)and atypical HUS, respectively. However, there are no specific biomarkers for the diagnosis of DIC. Conclusion: Although DIC and TMA are similar appearances, all coagulation, fibrinolysis and platelet systems are activated in DIC, and only platelets are markedly activated in TMA. PMID- 30008621 TI - Effects of Matricaria Recutita (L.) in the Treatment of Oral Mucositis. AB - Objective: The objective of this study was to review the effects of the Matricaria recutita (L.) in the treatment of oral mucositis. Methodology: The online search was performed in the period from June 2016 to April 2018 by means of databases LILACS (Latin American and Caribbean Center on Health Sciences Information), SciELO (Scientific Electronic Library Online), and MEDLINE (Medical Literature Analysis and Retrieval System Online). The consultation was restricted to the years 1991 to 2018 with the aim of elucidating the effects of Matricaria recutita in the treatment of oral mucositis. Results: The final sample consisted of 21 studies, of which 10 were developed in animals and 11 in humans, published from 1991 to 2017, with a total sample of 644 patients. The total number of patients treated with Matricaria included in 11 studies was 364, while in the control groups the total number was 280. In experimental studies, animal models used were rats and the sample size ranged between 36 and 105 animals submitted to the induction of oral mucositis, where 4 studies used an intraperitoneal injection of 5-fluorouracil, while 7 induced lesion in the mucosa. From the data collected, it should be noted that both studies with humans and with animals showed significant effects. In this way, there is strong evidence for the discussion on the therapy; however, it should be noted that more studies are developed in order to clarify the most appropriate protocol for the prevention and treatment of injuries. Conclusion: According to the results found in this study, Matricaria recutita appeared to be a promising alternative for the treatment of oral mucositis. However, due to the great variability in the various types of intervention, more controlled double-blind randomized clinical studies are necessary to ensure the best protocol for treating oral mucositis. PMID- 30008622 TI - Digital Models as an Alternative to Plaster Casts in Assessment of Orthodontic Treatment Outcomes. AB - Objective: This study aimed to compare the use of digital models and plaster casts in assessing the improvement in occlusion following orthodontic treatment. Materials and Methods: Digital models and plaster casts of 39 consecutive patients at pre- and posttreatment stages were obtained and assessed using the Peer Assessment Rating (PAR) index and the Index of Complexity and Treatment Need (ICON). PAR and ICON scores were compared at individual and group levels. Categorization of improvement level was compared using Kappa (kappa) statistics. Results: There was no significant difference in neither PAR scores (p > 0.05) nor ICON scores (p > 0.05) between digital and plaster cast assessments. The Intraclass Correlation Coefficient (ICC) values for changes in PAR and ICON scores were excellent (ICC > 0.80). Agreement of ratings of occlusal improvement level between digital and plaster model assessments was 0.83 (kappa) for PAR and 0.59 (kappa) for ICON, respectively. Conclusion: The study supported the use of digital models as an alternative to plaster casts when assessing changes in occlusion at the 'individual patient' level using ICON or PAR. However, it could not fully support digital models as an alternate to plaster casts at 'the group level' (as in the case of clinical audit/research). PMID- 30008623 TI - Continuous-Phase Control of a Powered Knee-Ankle Prosthesis: Amputee Experiments Across Speeds and Inclines. AB - Control systems for powered prosthetic legs typically divide the gait cycle into several periods with distinct controllers, resulting in dozens of control parameters that must be tuned across users and activities. To address this challenge, this paper presents a control approach that unifies the gait cycle of a powered knee-ankle prosthesis using a continuous, user-synchronized sense of phase. Virtual constraints characterize the desired periodic joint trajectories as functions of a phase variable across the entire stride. The phase variable is computed from residual thigh motion, giving the amputee control over the timing of the prosthetic joint patterns. This continuous sense of phase enabled three transfemoral amputee subjects to walk at speeds from 0.67 to 1.21 m/s and slopes from -2.5 to +9.0 deg. Virtual constraints based on task-specific kinematics facilitated normative adjustments in joint work across walking speeds. A fixed set of control gains generalized across these activities and users, which minimized the configuration time of the prosthesis. PMID- 30008625 TI - Pinnipeds and PTSD: An Analysis of a Human-Animal Interaction Case Study Program for a Veteran. AB - The objective of this study was to examine the impact of a pinniped (grey and harbor seals) facilitated human-animal interaction pilot program on the self reported PTSD-like symptoms of a veteran. This study analyzed preexisting, deidentified data that represented the participant's scores on the Post-Traumatic Stress Disorder Checklist (PCL-5). The PCL-5 was completed as part of a pilot program operated in partnership between the Veteran and Military Affiliated Research Center (VMARC) and a local aquarium. Scores on the PCL-5 were collected prior to (T1), midway (T2), and immediately after (T3) completion of the Project Seal to Heal program. Changes in the scores of each item were reported for the participant, for aggregated items that represented different clusters of PTSD symptoms, and for overall scores. Results revealed decreased scores in 11 of the 20 PTSD symptom-related items, improvement in the sum scores for each criteria symptom cluster, and a 15-point decrease in the overall PCL-5 score, indicating clinical significance. These results serve as a call to motivate future research investigating pinniped interactions with veterans who have PTSD in order to determine therapeutic clinical application and outcomes. PMID- 30008626 TI - Contrasting decadal-scale changes in elevation and vegetation in two Long Island Sound salt marshes. AB - Northeastern US salt marshes face multiple co-stressors, including accelerating rates of relative sea level rise (RSLR), elevated nutrient inputs, and low sediment supplies. In order to evaluate how marsh surface elevations respond to such factors, we used surface elevation tables (SETs) and surface elevation pins to measure changes in marsh surface elevation in two eastern Long Island Sound salt marshes, Barn Island and Mamacoke Marsh. We compare marsh elevation change at these two systems with recent rates of RSLR and find evidence of differences between the two sites; Barn Island is maintaining its historic rate of elevation gain (2.3+/- 0.24 mm yr-1 from 2003 to 2013) and is no longer keeping pace with RSLR, while Mamacoke shows evidence of a recent increase in rates (4.2 +/- 0.52 mm yr-1 from 1994 to 2014) to maintain its elevation relative to sea level. In addition to data on short-term elevation responses at these marshes, both sites have unusually long and detailed data on historic vegetation species composition extending back more than half a century. Over this study period, vegetation patterns track elevation change relative to sea levels, with the Barn Island plant community shifting towards those plants that are found at lower elevations and the Mamacoke vegetation patterns showing little change in plant composition. We hypothesize that the apparent contrasting trend in marsh elevation at the sites is due to differences in sediment availability, salinity, and elevation capital. Together these two systems provide critical insight into the relationships between marsh elevation, high marsh plant community, and changing hydroperiods. Our results highlight that not all marshes in southern New England may be responding to accelerated rates of RSLR in the same manner. PMID- 30008624 TI - In Vivo and In Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents. AB - The vesicular acetylcholine transporter (VAChT), a presynaptic cholinergic neuron marker, is a potential internal molecular target for the development of an imaging agent for early diagnosis of neurodegenerative disorders with cognitive decline such as Alzheimer's disease (AD). Since vesamicol has been reported to bind to VAChT with high affinity, many vesamicol analogs have been studied as VAChT imaging agents for the diagnosis of cholinergic neurodeficit disorder. However, because many vesamicol analogs, as well as vesamicol, bound to sigma receptors (sigma1 and sigma2) besides VAChT, almost all the vesamicol analogs have been shown to be unsuitable for clinical trials. In this report, the relationships between the chemical structure and the biological characteristics of these developed vesamicol analogs were investigated, especially the in vitro binding profile and the in vivo regional brain accumulation. PMID- 30008627 TI - Wetland loss patterns and inundation-productivity relationships prognosticate widespread salt for southern New England. AB - Tidal salt marsh is a key defense against, yet is especially vulnerable to, the effects of accelerated sea level rise. To determine whether salt marshes in southern New England will be stable given increasing inundation over the coming decades, we examined current loss patterns, inundation-productivity feedbacks, and sustaining processes. A multi-decadal analysis of salt marsh aerial extent using historic imagery and maps revealed that salt marsh vegetation loss is both widespread, and accelerating, with vegetation loss rates over the past four decades summing to 17.3%. Seaward retreat of the marsh edge, widening and headward expansion of tidal channel networks, loss of marsh islands, and the development and enlargement of interior depressions found on the marsh platform contributed to vegetation loss. Inundation due to sea level rise is strongly suggested as a primary driver: vegetation loss rates were significantly negatively correlated with marsh elevation (r2=0.96; p=0.0038), with marshes situated below mean high water (MHW) experiencing greater declines than marshes sitting well above MHW. Growth experiments with Spartina alterniflora, the Atlantic salt marsh ecosystem dominant, across a range of elevations and inundation regimes further established that greater inundation decreases belowground biomass production of Spartina alterniflora and thus negatively impacts organic matter accumulation. These results suggest that southern New England salt marshes are already experiencing deterioration and fragmentation in response to sea level rise, and may not be stable as tidal flooding increases in the future. PMID- 30008629 TI - Surrogate Measures of Insulin Resistance in an Apparently Healthy Population: a Simpler and Easier, yet Reliable Index. PMID- 30008628 TI - Metabolomics reveals immunomodulation as a possible mechanism for the antibiotic effect of Persicaria capitata (Buch.-Ham. ex D. Don) H.Gross. AB - Introduction: In spite of advances in antibiotics, urinary tract infection (UTI) is still among the most common reasons for antibiotic medication worldwide. Persicaria capitata (Buch.-Ham. ex D. Don) H.Gross (P. capitata) is a herbal medicine used by the Miao people in China to treat UTI. However studies of its mechanism are challenging, owing to the complexity of P. capitata with multiple constituents acting on multiple metabolic pathways. Objective: The objective of this study was to explore the working mechanism of P. capitata on urinary tract infection. Methods: Relinqing(r) granule, which is solely made from aqueous extracts of the whole P. capitata plant, was used in this study. Urine metabolomics based on gas chromatography-mass spectroscopy was employed to assess the metabolic changes caused by administration of Relinqing(r) granule in a UTI mouse model. Female specific-pathogen-free Kunming mice were divided into control group (mock infection, saline treatment), model group (E.coli infection, saline treatment), Relinqing(r) group (E.coli infection, Relinqing(r) granule treatment), ciprofloxacin group (E.coli infection, ciprofloxacin treatment), and sham-Relinqing(r) group (no surgery, Relinqing(r) granule treatment). Results: The results showed that after the treatments, urine levels of itaconic acid in Relinqing(r) group increased by 4.9 fold and 11.3 fold compared with model and ciprofloxacin groups respectively. Itaconic acid is an endogenous antibacterial metabolite produced by macrophages, which also functions as a checkpoint for metabolic reprogramming of macrophage. Conclusion: Our findings suggest that this herbal medicine can cure urinary tract infection through modulation of immune system. PMID- 30008632 TI - Radon and Lung Cancer: Disease Burden and High-risk Populations in Korea. PMID- 30008631 TI - Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers. AB - Background: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking. After smoking, radon exposure is the second leading cause and the primary risk factor of lung cancer among never smokers. Exposure to radon can lead to genetic and epigenetic alterations in tumor genomes affecting genes and pathways involved in lung cancer development. The present study sought to explore genetic alterations associated with LCINS exposed to radon gas indoors. Methods: Genetic associations were assessed via a case-control study of LCINS (39 cases and 30 controls) using next generation sequencing. Associations between genetic mutations and high exposure to radon were investigated by OncoPrint and heatmap graphs. Bioinformatic analysis was conducted using various tools. According radon exposure levels, we divided subjects in two groups of cases and controls. Results: We found that ABL2 rs117218074, SMARCA4 rs2288845, PIK3R2 rs142933317, MAPK1 rs1803545, and androgen receptor (AR) rs66766400 were associated with LCINS exposed to high radon levels. Among these, Chromodomain helicase DNA-binding protein 4 (CHD4) rs74790047, TSC2 rs2121870, and AR rs66766408 were identified as common exonic mutations in both lung cancer patients and normal individuals exposed to high levels of radon indoor. Conclusion: We identified that CHD4 rs74790047, TSC2 rs2121870, and AR rs66766408 are found to be common exonic mutations in both lung cancer patients and normal individuals exposed to radon indoors. Further analysis is needed to determine whether these genes are completely responsible for LCINS exposed to residential radon. PMID- 30008630 TI - The Cut-off Values of Surrogate Measures for Insulin Sensitivity in a Healthy Population in Korea according to the Korean National Health and Nutrition Examination Survey (KNHANES) 2007-2010. AB - Background: This study aimed to identify the gender-specific characteristics of the surrogate measures of insulin resistance and to establish valid cut-off values for metabolic abnormalities in a representative sample in Korea. Methods: Data were collected from the datasets of the Korean National Health and Nutrition Examination Survey between 2007 and 2010. The total number of eligible participants was 10,997. We used three measures of insulin resistance: the homeostasis model assessment-insulin resistance (HOMA-IR), McAuley index, and triglyceride and glucose (TyG) index. The estimated cut-off values were determined using the highest score of the Youden index. Results: The area under the curve (AUC) of the HOMA-IR, McAuley index, and TyG index were 0.737 (95% confidence interval [CI], 0.725-0.750), 0.861 (95% CI, 0.853-0.870), and 0.877 (95% CI, 0.868-0.885), respectively. The cut-off values of the HOMA-IR were 2.20 in men, 2.55 in premenopausal women, and 2.03 in postmenopausal women, and those of the McAuley index were 6.4 in men and 6.6 in premenopausal and postmenopausal women. For the TyG index, the cut-off values were 4.76 in men and 4.71 in premenopausal and postmenopausal women. Conclusion: In conclusion, the present study provides the valid cut-off values of the indirect surrogate measures of insulin sensitivity. These values may be used as reference for insulin sensitivity in a clinical setting and may provide a simple and supplementary method for identifying populations at risk of insulin resistance. PMID- 30008633 TI - Estimation of Cancer Incidence and Mortality Risks Attributed to Diagnostic Medical Radiation Exposure in Korea, 2013. AB - Background: Radiation exposure from medical procedures has been rapidly increasing. We purposed to estimate the fraction of cancer incidence and mortality attributed to diagnostic medical radiation exposure in Korea. Methods: Using information on diagnostic medical radiation exposure from various sources including national health examination (National Health Insurance Service), private health examination, and conscription health examination; the annual mean exposed organ dose (mGy) from all diagnostic medical radiation use, grouped by sex and 5-year age ranges up to 80 years, was calculated. Cancer incidence and mortality lifetime attributable risks (LARs) up to 85 years using estimated exposed organ doses and biological effects of ionizing radiation (BEIR) VII model (excess relative risk and excess absolute risk) were estimated. Using background cancer incidence and mortality risk based on the national database, along with estimated LARs, we finally estimated population attributable fraction (PAF) of cancer incidence and mortality. Results: The PAF for diagnostic medical radiation exposure among all cancers of Koreans was 0.9% for incidence and mortality, resulting 1,915 cancer cases and 637 cancer deaths a year. The PAF in females was higher than those in males: 1.2% and 1.7% (incidence and mortality) versus 0.6% (same in incidence and mortality), respectively. Conclusion: The estimated PAF for diagnostic medical radiation in Korea in 2013 was higher than those reported in the UK in 2004. Optimized management of diagnostic medical radiation use is important in Korea. PMID- 30008634 TI - The Disease Burden of Lung Cancer Attributable to Residential Radon Exposure in Korean Homes. AB - Background: Residential radon exposure is known to be an important risk factor for the development of lung cancer. The objective of this study was to calculate the disease burden of lung cancer attributable to residential radon exposure in Korea. Methods: We calculated the national exposure level using Korean national radon survey data from 2011 to 2014, and house structure distribution data from each administrative region. Using the exposure-risk function, the population attributable fraction (PAF) was calculated and applied to calculate the disease burden for lung cancer attributable to residential radon exposure. Results: Residential radon exposure levels were the highest, at 116.4 +/- 50.4 Bq/m3 (annual mean radon concentration +/- standard deviation) in detached houses, followed by 74.1 +/- 30.0 Bq/m3 in the multi-family dwellings, and 55.9 +/- 21.1 Bq/m3 in apartments. The PAF for lung cancer, due to long-term radon exposure in Korean homes, was 6.6% and 4.7% in men and women, respectively. The total disease burden of lung cancer attributable to residential radon exposure was 14,866 years of life lost (YLL) and 1,586 years lost due to disability (YLD) in 2013. Overall, 1,039 deaths occurred due to residential radon exposure, of which 828 were in men and 211 in women. Conclusion: The smoking rate of men in Korea exceeded 70% in the 1990s, and is still near 40%. Although the size of the effect varies depending on the estimation method, it is a critical aspect as a risk factor of lung cancer because of the synergistic relationship between smoking and radon exposure. Because the Korean society is rapidly aging, population who were formerly heavy-smokers are entering a high-risk age of lung cancer. Therefore, it is necessary to inform the public about the health benefits of reduced radon exposure and to strengthen the risk communication. PMID- 30008635 TI - NAD(P)H-Dependent Dehydrogenases for the Asymmetric Reductive Amination of Ketones: Structure, Mechanism, Evolution and Application. AB - Asymmetric reductive aminations are some of the most important reactions in the preparation of active pharmaceuticals, as chiral amines feature in many of the world's most important drugs. Although many enzymes have been applied to the synthesis of chiral amines, the development of reductive amination reactions that use enzymes is attractive, as it would permit the one-step transformation of readily available prochiral ketones into chiral amines of high optical purity. However, as most natural "reductive aminase" activities operate on keto acids, and many are able to use only ammonia as the amine donor, there is considerable scope for the engineering of natural enzymes for the reductive amination of ketones, and also for the preparation of secondary amines using alkylamines as donors. This review summarises research into the development of NAD(P)H-dependent dehydrogenases for the reductive amination of ketones, including amino acid dehydrogenases (AADHs), natural amine dehydrogenases (AmDHs), opine dehydrogenases (OpDHs) and imine reductases (IREDs). In each case knowledge of the structure and mechanism of the enzyme class is addressed, with a further description of the engineering of those enzymes for the reductive amination of ketones towards primary and also secondary amine products. PMID- 30008636 TI - BIO (6-bromoindirubin-3'-oxime) GSK3 inhibitor induces dopaminergic differentiation of human immortalized RenVm cells. AB - Parkinson's disease (PD) is one of the most neurodegenerative disorders which can lead to severe neural disability and neurological defects. Cell-based therapy using fully differentiated cells is a new method for the treatment of this abnormal condition. In the present study, we investigated the effects of 6 bromoindirubin-3'-oxime (BIO) on dopaminergic differentiation of human immortalized RenVm cells in order to obtain a set of fully differentiated cells for transplantation in Parkinson's disease. To this end, the immortalized RenVm cells were induced to dopaminergic differentiation using a neuro basal medium supplemented with N2 and different concentrations (75, 150, 300, 600, and 1200 nM) of BIO for 4, 8, and 12 days. The efficiency of dopaminergic differentiation was determined using immunocytochemistry for tyrosine hydroxylase expressions. In addition, the expression of a beta-catenin marker was measured using the western blot technique. The results of immunocytochemistry revealed that the mean percentage of Tuj1- and TH-positive sells in 150- and 300-nM-BIO-treated groups was significantly increased compared to that of other groups (p <= 0.01). In addition, the expression of the beta-catenin marker was higher in these groups as compared with that of other groups. Overall, BIO through its effect on the Wnt Frizzled signaling pathway can promote dopaminergic differentiation of RenVm cells in a dose-dependent manner. PMID- 30008637 TI - Methanolic extract of Celosia argentea var. crista leaves modulates glucose homeostasis and abates oxidative hepatic injury in diabetic rats. AB - Celosia argentea commonly known as cockscomb plant is widely used in folkloric medicine in the treatment and management of diabetes mellitus. The effect of methanolic extract of Celosia argentea var. cristata L. (CAVCL) leaves on blood glucose level, superoxide dismutase (SOD), catalase (CAT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities, and malondialdehyde (MDA) level were evaluated in diabetic rats. Five groups of male albino rats consisting of 5 animals each were used for the present study. They were grouped as normal control, diabetic control, diabetic administered with 250 and 750 mg/kg b.w C. argentea, and 5 mg/kg b.w glibenclamide. Diabetes was induced with alloxan monohydrate intraperitoneally at 120 mg/kg b.w. The control and diabetic groups were given distilled water and rat chow for 21 days. Blood glucose level of each group was estimated every week, and at the end of the experiment, SOD, CAT, MDA and serum ALP, and AST and ALT activities were assayed in the liver and serum respectively of the experimental animals. The results showed a significant increase (p < 0.05) in serum AST, ALP, and ALT activities and reduction in SOD and CAT activities compared with normal control groups. The extract at both doses significantly lowered the high levels of the serum enzymes and increased the level of CAT and SOD. These results indicate an anti-hyperglycemia and antioxidative protective effect of C. argentea leaves. PMID- 30008638 TI - Quo vadis, biological treatment for psoriasis and psoriatic arthritis? AB - Psoriasis is a chronic autoimmune disease that affects approximately 2-3% of the world's population. Although the cutaneous manifestations of the disease are the most prevalent, psoriasis is also associated with a systemic inflammation and various co-morbidities linked with autoinflammatory processes. One of those processes is psoriatic arthritis, an inflammatory, seronegative spondyloarthropathy that develops in 13.8-30% of psoriatic patients at some point of their lives. Over the past 15 years the therapeutic options for severe and generalized psoriasis have broadened immensely with the introduction of biological agents to everyday practice. We present a quick overview of current biological therapies in the treatment of psoriasis and prospects for forthcoming advancements in biological treatment. PMID- 30008639 TI - Skin melanoma imaging using ultrasonography: a literature review. AB - Melanoma is one of the most unpredictable tumours, as regards both morphology and the course of disease. It may have different clinical forms making it very difficult to diagnose. Therefore, it often surprises even the most experienced dermatologists. Despite numerous attempts, no efficient treatment of advanced stages have been elaborated, and early detection and removal of a skin lesion currently constitutes the most efficient treatment method. Diagnostics uses different types of dermoscopic techniques characterised by considerable sensitivity and specificity in detecting melanoma at an early developmental stage. A continuous development of medical technologies leads to improving many methods of skin lesion imaging. Ultrasonography is one of these methods, enabling evaluation of the thickness of melanoma in vivo with high precision. Change thickness is the decisive factor influencing 5-year survival. The paper evaluates the usefulness of high-frequency ultrasonography (HFUS) in pre-operative melanoma imaging on the basis of literature review. Additionally, the use, role and placement of HFUS in skin melanoma diagnostics is determined. PMID- 30008640 TI - Dilemmas associated with local allergic rhinitis. AB - Local allergic rhinitis (LAR) in patients with no systemic markers of atopy is a very interesting phenomenon due to the lack of any definitive explanation for the mechanism of this IgE-dependent reaction. Some of the recent attempts to explain this phenomenon consider LAR to be closely associated with an allergic reaction, some suggest that this phenomenon is a spontaneous process in the nasal mucosa. Future attempts to elucidate the complexity of inflammatory reactions will undoubtedly establish a clear differential diagnostics algorithm for rhinitis. PMID- 30008641 TI - Overlap syndromes in systemic sclerosis. AB - Introduction: It is known, that course of the disease differs between overlap syndromes (OS) and systemic sclerosis (SSc) group. Aim: To compare the prevalence of OS in limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous SSc (dcSSc) and to analyze the presence of different manifestations in the SSc and OS group. Material and methods: The study included 126 European Caucasian SSc patients (99 females and 27 males) hospitalized consecutively in the Department of Rheumatology and Connective Tissue Diseases. Patients fulfilled the American College of Rheumatology (ACR) classification criteria of SSc (57 - dcSSc and 69 - lcSSc). The study groups were determined according to the subtype of SSc, coexistence of other connective tissue diseases (CTDs), and incidence of clinical and serological manifestations. Results: In our SSc study group, 28/126 patients (22%) were affected by more than one CTD. The prevalence of OS was significantly higher in the lcSSc group - 33% (23/69) compared to the dcSSc group - 8% (5/57). We found that mortality and digital ulcers were significantly higher, whereas kidney involvement and arthritis were significantly lower in the SSc group compared to the OS group. The prevalence of anti-topoisomerase I (a-Scl-70) was significantly higher, and prevalence of anti-PM/Scl, anti-Ro-52 antibodies was significantly lower in the SSc group compared to the OS group. Conclusions: Overlap syndromes were more common in lcSSc than in dcSSc. The course of the disorder and internal organ involvement were different in OS compared to SSc patients. PMID- 30008642 TI - Dermoscopy as a first step in the diagnosis of onychomycosis. AB - Introduction: Over the years, clinical studies have provided new knowledge about the dermoscopic features of the diseases of cutaneous annexes. It seems that dermoscopy has opened a new morphological dimension in the diagnosis and management of hair disorders and onychopathies. Aim: To identify and describe dermoscopic features of onychomycosis. Material and methods: A total of 81 consecutive patients with onychomycosis (55 men and 26 women) were prospectively enrolled in the present study. For each patient, all fingernails and toenails were evaluated in clinical and dermoscopic examinations. Mycological tests were performed by potassium hydroxide (KOH) preparation. Mann-Whitney U and chi2 tests were used for the statistical analysis, with a significance threshold of p < 0.05. Results: Dermoscopic examination of the patients' nails revealed the following: jagged proximal edge with spikes of the onycholytic area (51.9%), longitudinal streaks and patches (44.4%), subungual hyperkeratosis (27.2%), brown black pigmentation (9.9%) and leukonychia (1.2%). Jagged proximal edge, subungual hyperkeratosis and leukonychia were positively associated with the onychomycosis type. Conclusions: Onychomycosis accounts for up to 50% of all consultations for onychopathies. Fast and effective diagnostic approaches are needed in everyday clinical practice. Dermoscopy can provide immediate and accurate information in the diagnosis of onychomycosis. We suggest that dermoscopy should be taken as a first step toward the diagnosis of onychomycosis. PMID- 30008643 TI - Demographic and medical factors affecting short-term changes in subjective evaluation of asthma control in adolescents. AB - Introduction: Asthma control is an important measure of disease stabilization, which is linked to the treatment and lifestyle recommendations. Aim: To assess the impact of selected factors on asthma control in adolescents, as assessed using the Asthma Control Test (ACTTM). Material and methods: The prospective study included 100 asthma patients aged between 12 and 19. Asthma was assessed in three consecutive follow-up visits spaced 3 months apart, using the standardized ACTTM questionnaire. Results: Asthma was fully controlled (ACT score = 25 points) in more than half of the patients in all follow-up visits (53.0%, 54.0%, and 56.0%, respectively). More than one third of the participants scored between 20 and 24 points (37.0% vs. 39.0% vs. 40.0%). A minority of patients had uncontrolled asthma (scores below 20), and the group consistently diminished in subsequent visits (10% vs. 7% vs. 4%). Uncontrolled asthma was found significantly more often in female patients (33.33%; p < 0.001) and those living in rural areas (20.59%; p < 0.01). Treatment with a combination of inhaled corticosteroids (ICS) and LABAs was associated with worse asthma control (14.81%; p < 0.05). Better asthma control was found in patients with a family history of allergies (73.85% vs. 75.38% vs. 78.46%; p < 0.001) and in those with concurrent allergies (66.67% vs. 68.00% vs. 70.67%; p < 0.001). Conclusions: Asthma control in adolescents differs by sex and residence. Concurrent allergies and family history of allergies improve asthma self-control in adolescents. PMID- 30008644 TI - The effect of selected risk factors, including the mode of delivery, on the development of allergic rhinitis and bronchial asthma. AB - Introduction: Cesarean section affects the process of colonization by bacteria transferred from the mother's skin and hospital bacteria, which in turn contributes to development of allergic conditions. Aim: To assess selected risk factors, including the mode of delivery, parity, and the role of genetic factors for the development of allergic rhinitis and bronchial asthma. Material and methods: The study was conducted in 18,617 respondents aged 6-7, 13-14, and 20-44 years who completed the ECRHS II and ISSAC questionnaires. Thirty percent of the study population underwent complementary assessments in the form of skin-prick tests, serum IgE levels, lung function tests, and peak nasal inspiratory flow (PNIF). The study is a part of the Epidemiology of Allergic Disorders in Poland (ECAP) study conducted in 8 areas in Poland (Warsaw, Lublin, Bialystok, Gdansk, Poznan, Wroclaw, Katowice, Krakow, and two rural areas - Zamosc and Krasnystaw counties). Results: Respondents diagnosed with allergic rhinitis were at a significantly higher risk of inheriting the allergic condition if their mother (OR = 2.17; 95% CI: 1.98-2.39, p = 2.00 * 10-16) or father (OR = 2.20; 95% CI: 1.96-2.47; p = 2.00 * 10-16) suffers from this allergy. Conversely, in the group diagnosed with bronchial asthma, the highest risk of an inherited allergy was observed in situations where maternal (OR = 2.00; 95% CI: 1.57-2.55; p = 1.69 * 10-5) or paternal (OR = 1.94; 95% CI: 1.42-2.66; p = 3.61 * 10-5) grandparent was affected. Moreover, the risk of developing allergic rhinitis depended on the mode of delivery: i.e. it was higher for a Cesarean section (OR = 1.20; 95% CI: 1.01 1.43; p = 0.04) than vaginal delivery (OR = 0.88; 95% CI: 0.78-0.99; p = 0.03). The higher the number of siblings, the lower the risk of allergic rhinitis. Conclusions: Allergy risk factors, especially those predisposing to allergic rhinitis, include not only genetic factors but also the mode of delivery: vaginal delivery or Cesarean section. PMID- 30008645 TI - Presence of Chlamydophila pneumoniae DNA in blood cells is a frequent event in patients with the late stage of primary cutaneous lymphomas and with atopic dermatitis. AB - Introduction: Microbial infection and associated super antigens have been implicated in the pathogenesis of cutaneous T-cell lymphoma (CTCL), and many patients die from complicating bacterial infections. It has been postulated that Chlamydophila pneumoniae (C. pneumoniae) infection may be involved in the pathogenesis of Mycosis fungoides (MF) but published data are limited and controversial. Aim: To analyze the frequency of (C. pneumoniae) DNA presence in blood samples of lymphoma cases. Material and methods: Using Q-PCR method we analyzed the presence of DNA in the blood samples obtained from 57 patients with CTCL (55 - mycosis fungoides (MF)/Sezary syndrome (SS), one primary cutaneous anaplastic large cell lymphoma (CD30+) and one NKT cell lymphoma) and 3 patients with cutaneous B-cell lymphomas, and 120 individuals from control groups (40 patients with psoriasis, 40 patients with atopic dermatitis and 40 healthy controls). Results: Chlamydophila pneumoniae DNA was identified in 13 of 55 cases in the MF/SS group (23.6%), in 1 patient with CD30+ large cell lymphoma and in 1 of 3 patients with B-cell lymphoma. The presence of C. pneumoniae was confirmed in 1 of 40 psoriatic patients (2.5%), in 5 of 40 patients with atopic dermatitis (12.5%) and in none of 40 healthy individuals. Presence of C. pneumoniae DNA in MF patients was strongly associated with disease progression; rs = 0.756; p = 0.0123 for groups IA -> IVB, and was noted more frequently in advanced (III + IV) stages than in early (I-II) stages (p = 0.0139). There are no differences in the mean age of MF/SS patients with and without infection. Conclusions: The presence of C. pneumoniae DNA in the blood cells is a frequent event in late stages of MF/SS and may be explained by Th2 shift and suppression of the immune system during the course of the disease. PMID- 30008646 TI - Association of PTPN22 gene polymorphism with non-segmental vitiligo in South Indian Tamils. AB - Introduction: Non-segmental vitiligo (NSV) is a depigmentation skin disease with loss of melanocytes in the skin. Aim: To evaluate whether the protein tyrosine phosphatase non-receptor type (PTPN22) single nucleotide polymorphism at +1858C/T had any association with non-segmental vitiligo in South Indian Tamils. Material and methods: Genomic DNA was extracted using the phenol-chloroform method, and PTPN22 +1858C/T polymorphism was assayed by Taqman 5'allele discrimination assay. Protein levels were quantified by ELISA. Results: We found that the allelic frequency of variants of PTPN22 (rs2476601) were significantly different between controls and cases showing a vitiligo risk in the South Indian Tamil population. PTPN22 levels were higher in the heterozygous CT genotype in NSV, when compared with that of the major variant CC genotype of rs2476601. Conclusions: This study suggests that the heterozygous CT genotype, of the PTPN22 SNP rs2476601, has a strong risk association with non-segmental vitiligo in South Indian Tamils. PMID- 30008648 TI - Scalp involvement in pemphigus: a prognostic marker. AB - Introduction: Scalp involvement in the course of pemphigus is observed in 16-60% of patients. Aim: To determine the prognostic significance of scalp involvement in pemphigus vulgaris and pemphigus foliaceus. Material and methods: A total of 75 patients (46 with pemphigus vulgaris, 29 with pemphigus foliaceus) were included into this prospective study. The following clinical data were analyzed: Pemphigus Disease Area Index, time to complete clinical remission and duration of complete clinical remission. Indirect immunofluorescence and enzyme-linked immunosorbent assay were performed to monitor serum pemphigus antibodies. Results: Scalp involvement was observed in 30/46 (65.2%) patients with pemphigus vulgaris and 28/29 (96.6%) patients with pemphigus foliaceus. A positive correlation was found between scalp involvement and general disease severity as measured by the Pemphigus Disease Area Index (r = 0.7, p < 0.05). The time required to achieve a complete clinical remission in patients with and without scalp involvement was 39.1 +/-47.1 and 9.1 +/-7.8 months, respectively. The duration of complete clinical remission was 14.1 +/-17.4 and 105.7 +/-108.8 months, respectively. The respective time required to achieve serological remission was 37.7 +/-58.5 and 15.5 +/-18.8 months, whereas the duration of serological remission was 9.2 +/-18.8 and 39.1 +/-60.1 months, respectively. The average concentration of anti-desmoglein 1 autoantibodies was significantly higher in patients with scalp involvement compared to patients without scalp involvement (109.9 +/-68.0 U/ml and 21.3 +/-39.4 U/ml). Conclusions: Scalp involvement in pemphigus is associated with a higher disease severity, longer time required to achieve complete clinical and serological remission and may indicate the need for a more aggressive therapeutical approach. PMID- 30008647 TI - ERAP1 and HLA-C*06 are strongly associated with the risk of psoriasis in the population of northern Poland. AB - Introduction: HLA-C*06 is a major psoriasis genetic risk marker. Recent reports have been focused on the role of different polymorphisms within genes involved in the functioning of the epidermal barrier and antigen processing in the pathogenesis of psoriasis. Data on the association between genetic variants of LCE3B_LCE3C, CSTA, ERAP1, ZAP70 and this dermatosis in the population from Eastern Europe are lacking. Aim: To compare the association between known genetic risk markers and psoriasis in a cohort of northern Polish patients with psoriasis and healthy controls. Material and methods: Based on previous studies' results, five susceptibility loci: HLA-C, LCE3C_LCE3B, ERAP1, ZAP70 and CSTA were selected for genotyping in 148 patients with chronic plaque psoriasis and 146 healthy controls. Each patient with this disease was clinically assessed with the Psoriasis Area and Severity Index. Results: The study population showed a significant association of psoriasis and a single nucleotide polymorphism in the ERAP1 - rs26653 (p = 3.11 * 10-5) and HLA-C*06 allele (p = 1.02 * 10-11) when compared with the control group. The presence of HLA-C*06 or rs26653 G allele significantly increased the risk of psoriasis by 2.4 times or twice, respectively. Carrying rs26653 C allele considerably decreased the risk of psoriasis by 1.5 times. Conclusions: In the context of pathogenesis of psoriasis, our findings might give the evidence on disturbances in the proteolytic processing of N-terminal fragments of antigens presented via major histocompatibility complex class I to T cells. PMID- 30008649 TI - The effect of tinea versicolor on thiol/disulphide homeostasis. AB - Introduction: Tinea versicolor is a superficial fungal infection caused by Malassezia spp. Malassezia spp. is a member of the normal human skin flora. It becomes a pathogen by transforming from the yeast form to the mycelium form. The oxidant/antioxidant homeostasis may be responsible for this. Thiol/disulphide homeostasis is a new marker indicating oxidative stress. This homeostasis is affected in many illnesses. Aim: To investigate the thiol/disulphide homeostasis in patients with tinea versicolor. Material and methods: Forty-two patients with tinea versicolor (median age: 36 years, min.-max.: 19-58) and 36 healthy controls (median age: 32 years, min.-max.: 18-60) were included in the trial. The levels of native thiol, disulphide, and total thiol were measured by an automated method in the patient and control groups. Disulphide/total thiol, disulphide/native thiol and native thiol/total thiol rates were calculated as percentage. Results: For the patient group and the control group, the native thiol levels were found to be 464.32 +/-51.48 mmol/l and 465.18 +/-51.32 mmol/l, disulphide levels - 19.80 +/-7.08 mmol/l and 21.27 +/-8.90 mmol/l, total thiol levels - 503.92 +/ 53.65 mmol/l and 508.07 +/-56.59 mmol/l, respectively. No statistical difference was detected between the two groups. Conclusions: Thiol/disulphide homeostasis was not affected in tinea versicolor. According to our findings, oxidative stress seems to have no role in the pathogenesis of tinea versicolor. PMID- 30008650 TI - Advanced oxidation protein products and serum total oxidant/antioxidant status levels in rosacea. AB - Introduction: Rosacea is a chronic, inflammatory dermatosis which develops due to the effect of genetic and environmental factors. Aim: To evaluate the oxidative stress in rosacea patients by measuring serum total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) and advanced oxidation protein products (AOPP) levels in our study. Material and methods: Our study included rosacea patients and healthy volunteers aged between 18 and 65 years. Total antioxidant status, TOS and AOPP levels were measured and OSI was calculated. Results: The study included 70 rosacea patients and 30 healthy volunteers as a control group. When TAS, TOS, OSI and AOPP levels were compared between rosacea and control groups, there was no difference for OSI levels; while TAS, TOS and AOPP levels were significantly higher in the rosacea group (p = 0.151, p = 0.013, p = 0.034, p = 0.017, respectively). In the rosacea group, there was no correlation between TAS, TOS, OSI and AOPP levels and disease duration. Besides there was no difference between family history, rosacea type, symptom frequency and ocular involvement and TAS, TOS, OSI and AOPP levels in the rosacea group. Conclusions: We observed that serum TAS, TOS and AOPP levels were significantly higher in rosacea patients, but there was no significant difference among the disease activity parameters. These results can support the role of oxidative stress in the pathogenesis of rosacea. PMID- 30008651 TI - The prevalence and etiological factors of onychomycosis in psoriatic patients. AB - Introduction: The role of a number of inherited, acquired and environmental factors has been identified to increase the risk of onychomycosis. The literature data on psoriasis as a risk factor are contradictory. The potential relationship between these pathologies is very important as it influences the patient management. Aim: To evaluate the frequency of onychomycosis and etiological factors in patients with psoriasis compared to controls. Material and methods: The studied group (n = 2427) included 2325 patients with nail abnormalities raising a clinical suspicion of nail onychomycosis (with no history of psoriasis) and 102 psoriatic inpatients. The control group included 100 patients with clinically normal nails. The assessment of psoriasis severity using Nail Psoriasis Severity Index (NAPSI) and Psoriasis Area and Severity Index (PASI) was performed in all psoriatic patients. The presence of fungi was confirmed in direct microscopy and culture. Results: A significantly higher incidence of onychomycosis was observed in psoriatic patients as well as in non-psoriatic patients with clinically abnormal nails compared to controls. The prevalence of onychomycosis did not differ significantly between psoriatic patients and non psoriatic patients with nail alterations. The characteristics of isolated fungi differed significantly between psoriatic and non-psoriatic patients. NAPSI >= 40 and receiving systemic treatment increased the risk of onychomycosis in psoriatic patients. Conclusions: The presented study showed a relatively high prevalence of onychomycosis in patients with psoriasis, what confirms the accuracy of performing screening mycological examination in this group. Further studies are warranted to evaluate the role of specific risk factors, explain the differences observed in previous studies and to determine optimal patient management. PMID- 30008652 TI - Comparison of spirometric results obtained from the sitting and standing position in children participating in an epidemiological study. AB - Introduction: It is recommended that spirometric testing in children be completed while sitting. Our experience indicates that children prefer standing during spirometry. Aim: We sought to compare spirometric results obtained from the sitting (SIP) and standing (STP) positions. Material and methods: Two testing sessions were performed in random order (SIP vs. STP: 30-45 min apart) in 118 children (7-13 years), attending one, randomly selected, primary school (response rate: 92%). Results: Acceptable quality was found in 77.9% of STP and 77.1% of SIP maneuvers. Higher values of spirometric variables on STP, compared to SIP, were obtained for forced vital capacity (FVC) (2.12 +/-0.41 l vs. 2.11 +/-0.39 l) and forced expiratory volume in 1 s (FEV1) (1.78 +/-0.36 l vs. 1.77 +/-0.35 l) but the differences were not statistically significant. Relative between-position differences (RBPD) <= 5% were found with the following frequencies: FVC: 56.4%, FEV1: 69.2%, PEF: 21.7%, and FEF25-75: 24.3%. Similar patterns were found for FEF25, FEF50, and FEF75. Relative between-position differences were related to age in the case of FEV1 (p = 0.005), FEF25 (p = 0.02), and FEF25-75 (p = 0.01) where older children had smaller RBPD. Forced vital capacity RBPD was lower (p = 0.01) in subjects with current wheeze; PEF RBPD were lower (p = 0.02) in children with asthma. Conclusions: In epidemiological studies, the position of spirometric testing does not affect the results of lung function assessment. PMID- 30008653 TI - Folliculitis decalvans and orofacial granulomatosis. PMID- 30008654 TI - Wheat desensitization treatment in patients with gluten sensitivity. PMID- 30008655 TI - A case of leukocytoclastic vasculitis associated with anti-tumor necrosis factor therapy. PMID- 30008656 TI - Intramedullary spinal cord metastasis from malignant melanoma: a case report of a central nervous system secondary lesion occurred 15 years after the primary skin lesion resection. PMID- 30008657 TI - Nail dermoscopy (onychoscopy) is useful in diagnosis and treatment follow-up of the nail mixed infection caused by Pseudomonas aeruginosa and Candida albicans. PMID- 30008658 TI - Random Forests Based Group Importance Scores and Their Statistical Interpretation: Application for Alzheimer's Disease. AB - Machine learning approaches have been increasingly used in the neuroimaging field for the design of computer-aided diagnosis systems. In this paper, we focus on the ability of these methods to provide interpretable information about the brain regions that are the most informative about the disease or condition of interest. In particular, we investigate the benefit of group-based, instead of voxel-based, analyses in the context of Random Forests. Assuming a prior division of the voxels into non overlapping groups (defined by an atlas), we propose several procedures to derive group importances from individual voxel importances derived from Random Forests models. We then adapt several permutation schemes to turn group importance scores into more interpretable statistical scores that allow to determine the truly relevant groups in the importance rankings. The good behaviour of these methods is first assessed on artificial datasets. Then, they are applied on our own dataset of FDG-PET scans to identify the brain regions involved in the prognosis of Alzheimer's disease. PMID- 30008659 TI - Assessing Command-Following and Communication With Vibro-Tactile P300 Brain Computer Interface Tools in Patients With Unresponsive Wakefulness Syndrome. AB - Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor disablities, and thus assessing their spared cognitive abilities can be difficult. Recent research from several groups has shown that non-invasive brain computer interface (BCI) technology can provide assessments of these patients' cognitive function that can supplement information provided through conventional behavioral assessment methods. In rare cases, BCIs may provide a binary communication mechanism. Here, we present results from a vibrotactile BCI assessment aiming at detecting command-following and communication in 12 unresponsive wakefulness syndrome (UWS) patients. Two different paradigms were administered at least once for every patient: (i) VT2 with two vibro-tactile stimulators fixed on the patient's left and right wrists and (ii) VT3 with three vibro-tactile stimulators fixed on both wrists and on the back. The patients were instructed to mentally count either the stimuli on the left or right wrist, which may elicit a robust P300 for the target wrist only. The EEG data from -100 to +600 ms around each stimulus were extracted and sub-divided into 8 data segments. This data was classified with linear discriminant analysis (using a 10 * 10 cross validation) and used to calibrate a BCI to assess command following and YES/NO communication abilities. The grand average VT2 accuracy across all patients was 38.3%, and the VT3 accuracy was 26.3%. Two patients achieved VT3 accuracy >=80% and went through communication testing. One of these patients answered 4 out of 5 questions correctly in session 1, whereas the other patient answered 6/10 and 7/10 questions correctly in sessions 2 and 4. In 6 other patients, the VT2 or VT3 accuracy was above the significance threshold of 23% for at least one run, while in 4 patients, the accuracy was always below this threshold. The study highlights the importance of repeating EEG assessments to increase the chance of detecting command-following in patients with severe brain injury. Furthermore, the study shows that BCI technology can test command following in chronic UWS patients and can allow some of these patients to answer YES/NO questions. PMID- 30008660 TI - Investigation of Gal-3 Expression Pattern in Serum and Cerebrospinal Fluid of Patients Suffering From Neurodegenerative Disorders. AB - We performed this study to investigate the possibility of a definitive pattern of Galectin-3 (Gal-3) expression in the cerebrospinal fluid (CSF) and serum of Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS) patients. In our study, we collected the CSF and serum samples of 31 AD patients, 19 ALS patients and 50 normal healthy subjects (controls). Quantitative ELISA measured Gal-3 concentrations in CSF and serum samples. A comparative analysis was performed to analyze and understand the Gal-3 expression pattern. A number of neuropsychological assessments and statistical analyses were carried out to validate our findings. Recent researches have established the role of galectins in various neurodegenerative disorders (NDDs), but a definitive pattern of galectin expression is still elusive. A significant difference was observed in serum and CSF Gal-3 concentrations between AD patients and healthy controls. The difference in serum and CSF Gal-3 concentrations between ALS patients vs. controls was lesser as compared to AD patients vs. controls. The difference in serum and CSF Gal-3 concentrations of AD vs. ALS patients was not significant. The MMSE score and serum and CSF Gal-3 concentrations in AD and ALS patients, and controls exhibited a significant positive correlation. The findings of the present study are expected to provide an insight into the definitive pattern of Gal-3 expression in AD and ALS patients, and might thus establish Gal-3 as a strong biomarker. This in turn will open up new and promising research avenues targeting the expression of galectins to modulate the progression of NDDs, and pave the way for novel therapeutic options. PMID- 30008662 TI - Editorial: From Ecology to Brain Development: Bridging Separate Evolutionary Paradigms. PMID- 30008661 TI - Non-invasive Neuromodulation of Spinal Cord Restores Lower Urinary Tract Function After Paralysis. AB - It is commonly assumed that restoration of locomotion is the ultimate goal after spinal cord injury (SCI). However, lower urinary tract (LUT) dysfunction is universal among SCI patients and significantly impacts their health and quality of life. Micturition is a neurologically complex behavior that depends on intact sensory and motor innervation. SCI disrupts both motor and sensory function and leads to marked abnormalities in urine storage and emptying. Current therapies for LUT dysfunction after SCI focus on preventing complications and managing symptoms rather than restoring function. In this study, we demonstrate that Transcutaneous Electrical Spinal Stimulation for LUT functional Augmentation (TESSLA), a non-invasive neuromodulatory technique, can reengage the spinal circuits' active in LUT function and normalize bladder and urethral sphincter function in individuals with SCI. Specifically, TESSLA reduced detrusor overactivity (DO), decreased detrusor-sphincter dyssynergia (DSD), increased bladder capacity and enabled voiding. TESSLA may represent a novel approach to transform the intrinsic spinal networks to a more functionally physiological state. Each of these features has significant clinical implications. Improvement and restoration of LUT function after SCI stand to significantly benefit patients by improving their quality of life and reducing the risk of incontinence, kidney injury and urinary tract infection, all the while lowering healthcare costs. PMID- 30008663 TI - Human Cortical Pyramidal Neurons: From Spines to Spikes via Models. AB - We present detailed models of pyramidal cells from human neocortex, including models on their excitatory synapses, dendritic spines, dendritic NMDA- and somatic/axonal Na+ spikes that provided new insights into signal processing and computational capabilities of these principal cells. Six human layer 2 and layer 3 pyramidal cells (HL2/L3 PCs) were modeled, integrating detailed anatomical and physiological data from both fresh and postmortem tissues from human temporal cortex. The models predicted particularly large AMPA- and NMDA-conductances per synaptic contact (0.88 and 1.31 nS, respectively) and a steep dependence of the NMDA-conductance on voltage. These estimates were based on intracellular recordings from synaptically-connected HL2/L3 pairs, combined with extra-cellular current injections and use of synaptic blockers, and the assumption of five contacts per synaptic connection. A large dataset of high-resolution reconstructed HL2/L3 dendritic spines provided estimates for the EPSPs at the spine head (12.7 +/- 4.6 mV), spine base (9.7 +/- 5.0 mV), and soma (0.3 +/- 0.1 mV), and for the spine neck resistance (50-80 MOmega). Matching the shape and firing pattern of experimental somatic Na+-spikes provided estimates for the density of the somatic/axonal excitable membrane ion channels, predicting that 134 +/- 28 simultaneously activated HL2/L3-HL2/L3 synapses are required for generating (with 50% probability) a somatic Na+ spike. Dendritic NMDA spikes were triggered in the model when 20 +/- 10 excitatory spinous synapses were simultaneously activated on individual dendritic branches. The particularly large number of basal dendrites in HL2/L3 PCs and the distinctive cable elongation of their terminals imply that ~25 NMDA-spikes could be generated independently and simultaneously in these cells, as compared to ~14 in L2/3 PCs from the rat somatosensory cortex. These multi-sites non-linear signals, together with the large (~30,000) excitatory synapses/cell, equip human L2/L3 PCs with enhanced computational capabilities. Our study provides the most comprehensive model of any human neuron to-date demonstrating the biophysical and computational distinctiveness of human cortical neurons. PMID- 30008664 TI - Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid Induced Epilepsy Mouse Model. AB - Epilepsy is one of the most common neurological disorders affecting millions of people. Due to the complicated and unclear mechanisms of epilepsy, still a significant proportion of epilepsy patients remain poorly controlled. Epilepsy is characterized by convulsive seizures that are caused by increased excitability. In this study, by using kainic acid (KA)-induced epilepsy mice, we investigated the neuronal activities and revealed the neuronal compensatory mechanisms after KA-induced toxic hyperexcitability. The results indicate that both phasic inhibition induced by enhanced inhibitory synaptic activity and tonic inhibition mediated by activated astrocytes participate in the compensatory mechanisms. Compensatory mechanisms were already found in various neuronal disorders and were considered important in protecting nervous system from toxic hyperexcitability. This study hopefully will provide valuable clues in understanding the complex neuronal mechanisms of epilepsy, and exploring potential clinical treatment of the disease. PMID- 30008666 TI - Pharmacological Manipulation of DNA Methylation in Adult Female Rats Normalizes Behavioral Consequences of Early-Life Maltreatment. AB - Exposure to adversity early in development alters brain and behavioral trajectories. Data continue to accumulate that epigenetic mechanisms are a mediating factor between early-life adversity and adult behavioral phenotypes. Previous work from our laboratory has shown that female Long-Evans rats exposed to maltreatment during infancy display both aberrant forced swim behavior and patterns of brain DNA methylation in adulthood. Therefore, we examined the possibility of rescuing the aberrant forced swim behavior in maltreated-adult females by administering an epigenome-modifying drug (zebularine) at a dose previously shown to normalize DNA methylation. We found that zebularine normalized behavior in the forced swim test in maltreated females such that they performed at the levels of controls (females that had been exposed to only nurturing care during infancy). These data help link DNA methylation to an adult phenotype in our maltreatment model, and more broadly provide additional evidence that non-targeted epigenetic manipulations can change behavior associated with early-life adversity. PMID- 30008667 TI - Evidence for a Supraspinal Contribution to the Human Crossed Reflex Response During Human Walking. AB - In humans, an ipsilateral tibial nerve (iTN) stimulation elicits short-latency crossed-responses (SLCR) comprised of two bursts in the contralateral gastrocnemius lateralis (cGL) muscle. The average onset latency has been reported to be 57-69 ms with a duration of 30.4 +/- 6.6 ms. The aim of this study was to elucidate if a transcortical pathway contributes to the SLCR. In Experiment 1 (n = 9), single pulse supra-threshold transcranial magnetic stimulation (supraTMS) was applied alone or in combination with iTN stimulation (85% of the maximum M wave) while participants walked on a treadmill (delay between the SLCR and the motor evoked potentials (MEP) varied between -30 and 200 ms). In Experiment 2 (n = 6), single pulse sub-threshold TMS (subTMS) was performed and the interstimulus interval (ISI) varied between 0-30 ms. In Experiment 3, somatosensory evoked potentials (SEPs) were recorded during the iTN stimulation to quantify the latency of the resulting afferent volley at the cortical level. SLCRs and MEPs in cGL occurred at 63 +/- 6 ms and 29 +/- 2 ms, respectively. The mean SEP latency was 30 +/- 3 ms. Thus, a transcortical pathway could contribute no earlier than 62-69 ms (SEP+MEP+central-processing-delay) after iTN stimulation. Combined iTN stimulation and supraTMS resulted in a significant MEP extra-facilitation when supraTMS was timed so that the MEP would coincide with the late component of the SLCR, while subTMS significantly depressed this component. This is the first study that demonstrates the existence of a strong cortical control on spinal pathways mediating the SLCR. This likely serves to enhance flexibility, ensuring that the appropriate output is produced in accord with the functional demand. PMID- 30008665 TI - Retinal Vascular Degeneration in the Transgenic P23H Rat Model of Retinitis Pigmentosa. AB - Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases involving a progressive degeneration of photoreceptor cells. Following the loss of photoreceptors, retinal vascularization tends to decrease, which seems to play a role in the degenerative process of retinal cells. This study reports changes in retinal vascular network architecture in the P23H rat model of RP at different stages of retinal degeneration. Homozygous P23H line-3 rats of ages ranging from 18 days to 16 months were used in this study. Age-matched Sprague-Dawley (SD) rats were used as control animals. Vertical sections and wholemount retinas were immunolabeled for type IV collagen or stained using NADPH diaphorase histochemistry, and retinal vascular networks were drawn using a camera lucida. The superficial and deep capillary plexus (DCP) were fully developed at P18 in P23H rat retinas and showed no differences from the control animals. In 4-month old P23H rat retinas, the superficial and intermediate capillary plexus were similar to those observed in age-matched SD rats, but a reduction in the DCP could be observed in these animals, with a significant decrease in both capillary density and capillary loops. At 16 months, the DCP was completely lost, and only vessels exhibiting an abnormal, tortuous dead-end could be observed. The middle capillary plexus had virtually disappeared at this age. Only perpendicular vessels connecting the superficial and DCP were found. The superficial plexus showed no changes in the vascular surface with age. In RP, photoreceptor loss is accompanied by degenerative changes in the retinal vascular network. The disruption of the capillary plexus, with loss of capillary density and capillary loops, can hamper the normal supply of oxygen and nutrients to retinal cells, thus accelerating retinal degeneration. Therefore, changes in retinal vascularization must be taken into account in the design of therapies targeting retinal degenerative diseases. PMID- 30008668 TI - Corrigendum: Extremely Scalable Spiking Neuronal Network Simulation Code: From Laptops to Exascale Computers. AB - [This corrects the article DOI: 10.3389/fninf.2018.00002.]. PMID- 30008669 TI - Screening for CCNF Mutations in a Chinese Amyotrophic Lateral Sclerosis Cohort. AB - Previous research has identified CCNF mutations in familial (FALS) and sporadic amyotrophic lateral sclerosis (SALS), as well as in frontotemporal dementia (FTD). The aim of our study was to measure the frequency of CCNF mutations in a Chinese population. In total, 78 FALS patients, 581 SALS patients and 584 controls were included. We found 19 missense mutations, nine synonymous mutations and two intron variants. According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, eight variants were judged to be pathogenic or likely pathogenic variants. The frequency of such variants was 2.56% in FALS and 1.03% in SALS. In conclusion, CCNF mutations are common in FALS and SALS patients of Chinese origin, and further study is still needed. PMID- 30008670 TI - Patient-Specific iPSC-Based Models of Huntington's Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting. AB - Neurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lack of adequate models for screening markedly impairs the development of relevant drugs. A potential breakthrough in this field is offered by the models of hereditary neurodegenerative pathologies based on endogenous expression of mutant proteins in neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs). Here, we study specific features of store-operated calcium entry (SOCE) using an iPSCs-based model of Huntington's disease (HD) and analyze the pharmacological effects of a specific drug targeted to the calcium channels. We show that SOCE in gamma aminobutyric acid-ergic striatal medium spiny neurons (GABA MSNs) was mediated by currents through at least two different channel groups, ICRAC and ISOC. Both of these groups were upregulated in HD neurons compared with the wild-type neurons. Thapsigargin-induced intracellular calcium store depletion in GABA MSNs resulted in predominant activation of either ICRAC or ISOC. The potential anti-HD drug EVP4593, which was previously shown to have neuroprotective activity in different HD models, affected both ICRAC and ISOC. PMID- 30008671 TI - Chronic Use of Statins and Their Effect on Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis. AB - Background and Aims: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is one of the major complications of ERCP. Thus, several non invasive as well as invasive strategies have been investigated as preventative therapies for PEP with various efficacy. Methods: We enrolled any patients who underwent ERCP both at the Shaare Zedek Medical Center in Jerusalem and EMMS Nazareth hospital. Association between use of statins and different variables were assessed with univariate tests (chi-squared for categorical variables). Predictors of incidence of PEP and severity of pancreatitis were computed using conditional logistic regression, correcting for potential confounding factors. Results: 958 subjects were analyzed. Average age was 62.04 +/- 21.18 years (median 68 years). Most of the patients were female (n = 558, 58.2%), Jewish (n = 827, 86.3%), and inpatients (n = 631, 65.9%). Only few ERCPs were performed emergently (n = 40, 4.2%). Twenty-Seven patients repeated the exam. Overall incidence of PEP/hyperamylasemia was 16.8% (n = 161); with a 5.6% (n = 54) incidence of hyperamylasemia and a 11.2% (n = 107) incidence of pancreatitis. Overall, 6 cases of severe pancreatitis were identified. The logistic regression analysis demonstrated that chronic use of statins is a protective factor in preventing development of PEP/hyperamylasemia [OR 0.436 [95%CI 0.303-0.627], p < 0.001]; Particularly, the PEP OR was of 0.318 [95%CI 0.169-0.597], p < 0.001 and the hyperamylasemia OR was of 0.565 [95%CI 0.372-0.859], p = 0.008. No significant predictor could be found for the risk of developing severe PEP. Conclusions: Our data support the possibility of exploiting statins as preventive agents for PEP. However, further studies, mainly RCTs, are warranted in order to replicate our findings. PMID- 30008672 TI - Genetic Variation in Acid Ceramidase Predicts Non-completion of an Exercise Intervention. AB - Genetic variation is associated with a number of lifestyle behaviours; it may be associated with adherence and individual responses to exercise training. We tested single nucleotide polymorphisms (SNPs) in the acid ceramidase gene (ASAH1) for association with subject adherence and physiologic benefit with exercise training in two well-characterised randomised, controlled 8-month exercise interventions: STRRIDE I (n = 239) and STRRIDE II (n = 246). Three ASAH1 non coding SNPs in a linkage disequilibrium block were associated with non completion: rs2898458(G/T), rs7508(A/G), and rs3810(A/G) were associated with non completion in both additive (OR = 1.8, 1.8, 2.0; P < 0.05 all) and dominant (OR = 2.5, 2.6, 3.5; P < 0.05 all) models; with less skeletal muscle ASAH expression (p < 0.01) in a subset (N = 60); and poorer training response in cardiorespiratory fitness (peak VO2 change rs3810 r2 = 0.29, P = 0.04; rs2898458 r2 = 0.29, P = 0.08; rs7508 r2 = 0.28, p = 0.09); and similar in direction and magnitude in both independent exploratory and replication studies. Adherence to exercise may be partly biologically and genetically moderated through metabolic regulatory pathways participating in skeletal muscle adaptation to exercise training. PMID- 30008673 TI - Bid Expression Network Controls Neuronal Cell Fate During Avian Ciliary Ganglion Development. AB - Avian ciliary ganglion (CG) development involves a transient execution phase of apoptosis controlling the final number of neurons, but the time-dependent molecular mechanisms for neuronal cell fate are largely unknown. To elucidate the molecular networks regulating important aspects of parasympathetic neuronal development, a genome-wide expression analysis was performed during multiple stages of avian CG development between embryonic days E6 and E14. The transcriptome data showed a well-defined sequence of events, starting from neuronal migration via neuronal fate cell determination, synaptic transmission, and regulation of synaptic plasticity to growth factor associated signaling. In particular, we extracted a neuronal apoptosis network that characterized the cell death execution phase at E8/E9 and apoptotic cell clearance at E14 by combining the gene time series analysis with network synthesis from the chicken interactome. Network analysis identified TP53 as key regulator and predicted involvement of the BH3 interacting domain death agonist (BID). A virus-based RNAi knockdown approach in vivo showed a crucial impact of BID expression on the execution of ontogenetic programmed cell death (PCD). In contrast, Bcl-XL expression did not impact PCD. Therefore, BID-mediated apoptosis represents a novel cue essential for timing within CG maturation. PMID- 30008675 TI - AFM Monitoring the Influence of Selected Cryoprotectants on Regeneration of Cryopreserved Cells Mechanical Properties. AB - Cryopreservation of cells (mouse embryonic fibroblasts) is a fundamental task for wide range of applications. In practice, cells are protected against damage during freezing by applications of specific cryoprotectants and freezing/melting protocols. In this study by using AFM and fluorescence microscopy we showed how selected cryoprotectants (dimethyl sulfoxide and polyethylene glycol) affected the cryopreserved cells mechanical properties (stiffness) and how these parameters are correlated with cytoskeleton damage and reconstruction. We showed how cryopreserved (frozen and thawed) cells' stiffness change according to type of applied cryoprotectant and its functionality in extracellular or intracellular space. We showed that AFM can be used as technique for investigation of cryopreserved cells surfaces state and development ex vivo. Our results offer a new perspective on the monitoring and characterization of frozen cells recovery by measuring changes in elastic properties by nanoindentation technique. This may lead to a new and detailed way of investigating the post-thaw development of cryopreserved cells which allows to distinguish between different cell parts. PMID- 30008674 TI - Melatonin Relations With Respiratory Quotient Weaken on Acute Exposure to High Altitude. AB - High altitude (HA) exposure may affect human health and performance by involving the body timing system. Daily variations of melatonin may disrupt by HA exposure, thereby possibly affecting its relations with a metabolic parameter like the respiratory quotient (RQ). Sea level (SL) volunteers (7 women and 7 men, 21.0 +/- 2.04 y) were examined for daily changes in salivary melatonin concentration (SMC). Sampling was successively done at SL (Antofagasta, Chile) and, on acute HA exposure, at nearby Caspana (3,270 m asl). Saliva was collected in special vials (Salimetrics Oral Swab, United Kingdom) at sunny noon (SMCD) and in the absence of blue light at midnight (SMCN). The samples were obtained after rinsing the mouth with tap water and were analyzed for SMC by immunoassay (ELISA kit; IBL International, Germany). RQ measurements (n = 12) were realized with a portable breath to breath metabolic system (OxiconTM Mobile, Germany), between 8:00 PM and 10:00 PM, once at either location. At SL, SMCD, and SMCN values (mean +/- SD) were, respectively, 2.14 +/- 1.30 and 11.6 +/- 13.9 pg/ml (p < 0.05). Corresponding values at HA were 8.83 +/- 12.6 and 13.7 +/- 16.7 pg/ml (n.s.). RQ was 0.78 +/- 0.07 and 0.89 +/- 0.08, respectively, at SL and HA (p < 0.05). Differences between SMCN and SMCD (SMCN-SMCD) strongly correlate with the corresponding RQ values at SL (r = -0.74) and less tight at HA (r = -0.37). Similarly, mean daily SMC values (SMC) tightly correlate with RQ at SL (r = 0.79) and weaker at HA (r = -0.31). SMCN-SMCD, as well as, SMC values at SL, on the other hand, respectively, correlate with the corresponding values at HA (r = 0.71 and r = 0.85). Acute exposure to HA appears to loosen relations of SMC with RQ. A personal profile in daily SMC variation, on the other hand, tends to be conserved at HA. PMID- 30008676 TI - Laterality Influences Agility Performance in Elite Soccer Players. AB - Introduction: Laterality (i.e., handedness, footedness, and eyedness) could have an impact on highly repeated soccer movements and thus, could influence performance. The purpose of this study was to examine the laterality of high level football players and its effects on 180 degrees left and right U-turn movements. Materials and Methods: Handedness, footedness, and eyedness were determined in 72 elite football players (EFP, 18.2 +/- 2.2 years) from the Stade Rennais Football Club (French League 1) and 9 amateur football players (AFP, 19.6 +/- 2.1 years). Players performed a visual-motor task on a synthetic pitch consisting of 180 degrees left and right rotations as fast as possible in response to a visual light on a computer screen. Movement times and reactive times for each left and right rotation were recorded with an accelerometer and video display. Results: Laterality profiles showed a majority (chi2 = 9.42, df = 2, p = 0.031) of crossed formulas (i.e., dominant leg or hand is controlateral to the dominant eye) for EFP (53 +/- 7%) and a majority of non-crossed formulas for AFP (63 +/- 9%). Reaction times were significantly faster (p = 0.028, effect size = 0.148, trivial) in EFP right-eyed (568.2 +/- 55.5 ms) than in AFP (610.0 +/- 43.9 ms). For the left rotation and for right-footed players, movement times were significantly different (p = 0.043, effect size = 0.413, small) between EFP (1.15 +/- 0.07 s) and AFP (1.17 +/- 0.07 s). A significant difference (p < 0.033) was observed between footedness and rotation movement times in the EFP. Conclusion: Our results showed that laterality profiles differed between EFP and AFP. Hence, in EFP, reaction times depended on the side of the visual stimulus. Moreover, leg laterality of EFP influenced 180 degrees left or right rotation speed. Our results indicate the importance of determining laterality in soccer players and identifying deficits in performance when turning. PMID- 30008677 TI - Corrigendum: Comparison of Peak Oxygen Uptake and Test-Retest Reliability of Physiological Parameters between Closed-End and Incremental Upper-Body Poling Tests. AB - [This corrects the article DOI: 10.3389/fphys.2017.00857.]. PMID- 30008678 TI - Resilience and Cognitive Function in Patients With Schizophrenia and Bipolar Disorder, and Healthy Controls. AB - Background: This study compared adaptive resilience among patients with schizophrenia, bipolar disorder, and healthy controls, and examined the relationship of resilience to cognitive function. Methods: A sample of 81 patients diagnosed with schizophrenia, 34 with bipolar disorder, and 52 healthy controls completed the Connor-Davidson Resilience Scale (CD-RISC) and cognitive tests of verbal comprehension, executive functioning, and working memory. Paired comparison of diagnostic groups on CD-RISC and cognitive tests was conducted. Linear regression was used to identify the independent association of clinical diagnoses and neurocognition with resilience deficits. Results: Both patient groups showed significantly lower CD-RISC scores and poorer cognitive function than healthy controls and the schizophrenia group scored lower than bipolar group on these measures as well. CD-RISC scores were positively correlated with all three cognitive measures in the entire sample but not within the diagnostic subgroups. Multiple regression analysis showed differences in CD-RISC between diagnostic groups were not mediated by differences in these three measures of neurocognition. Discussion: Schizophrenia and bipolar disorder are associated with impairments in both resilience and cognitive function but the impairment in resilience appears to be independent of deficits in cognitive function measured here and may reflect unmeasured dimensions of cognitive function, other impairments or environmental factors. PMID- 30008680 TI - Using Affective Cognition to Enhance Precision Psychiatry. PMID- 30008679 TI - Impaired Antisaccades in Obsessive-Compulsive Disorder: Evidence From Meta Analysis and a Large Empirical Study. AB - Increasing evidence indicates that patients with obsessive-compulsive disorder (OCD) exhibit alterations in fronto-striatal circuitry. Performance deficits in the antisaccade task would support this model, but results from previous small scale studies have been inconclusive as either increased error rates, prolonged antisaccade latencies, both or neither have been reported in OCD patients. In order to address this issue, we investigated antisaccade performance in a large sample of OCD patients (n = 169) and matched control subjects (n = 183). As impaired antisaccade performance constitutes a potential endophenotype of OCD, unaffected first-degree relatives of OCD patients (n = 100) were assessed, as well. Furthermore, we conducted a quantitative meta-analysis to integrate our data with previous findings. In the empirical study, OCD patients exhibited significantly increased antisaccade latencies, intra-subject variability (ISV) of antisaccade latencies, and antisaccade error rates. The latter effect was driven by errors with express latency (80-130 ms), as patients did not differ significantly from controls with regards to regular errors (>130 ms). Notably, unaffected relatives of OCD patients showed elevated antisaccade express error rates and increased ISV of antisaccade latencies, as well. Antisaccade performance was not associated with state anxiety within groups. Among relatives, however, we observed a significant correlation between antisaccade error rate and harm avoidance. Medication status of OCD patients, symptom severity, depressive comorbidity, comorbid anxiety disorders and OCD symptom dimensions did not significantly affect antisaccade performance. Meta-analysis of 10 previous and the present empirical study yielded a medium-sized effect (SMD = 0.48, p < 0.001) for higher error rates in OCD patients, while the effect for latencies did not reach significance owing to strong heterogeneity (SMD = 0.51, p = 0.069). Our results support the assumption of impaired antisaccade performance in OCD, although effects sizes were only moderately large. Furthermore, we provide the first evidence that increased antisaccade express error rates and ISV of antisaccade latencies may constitute endophenotypes of OCD. Findings regarding these more detailed antisaccade parameters point to potentially underlying mechanisms, such as early pre-stimulus inhibition of the superior colliculus. PMID- 30008681 TI - Discriminating Pathological and Non-pathological Internet Gamers Using Sparse Neuroanatomical Features. AB - Internet gaming disorder (IGD) is often diagnosed on the basis of nine underlying criteria from the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Here, we examined whether such symptom-based categorization could be translated into computation-based classification. Structural MRI (sMRI) and diffusion-weighted MRI (dMRI) data were acquired in 38 gamers diagnosed with IGD, 68 normal gamers diagnosed as not having IGD, and 37 healthy non-gamers. We generated 108 features of gray matter (GM) and white matter (WM) structure from the MRI data. When regularized logistic regression was applied to the 108 neuroanatomical features to select important ones for the distinction between the groups, the disordered and normal gamers were represented in terms of 43 and 21 features, respectively, in relation to the healthy non gamers, whereas the disordered gamers were represented in terms of 11 features in relation to the normal gamers. In support vector machines (SVM) using the sparse neuroanatomical features as predictors, the disordered and normal gamers were discriminated successfully, with accuracy exceeding 98%, from the healthy non gamers, but the classification between the disordered and normal gamers was relatively challenging. These findings suggest that pathological and non pathological gamers as categorized with the criteria from the DSM-5 could be represented by sparse neuroanatomical features, especially in the context of discriminating those from non-gaming healthy individuals. PMID- 30008682 TI - Dimming the "Halo" Around Monogamy: Re-assessing Stigma Surrounding Consensually Non-monogamous Romantic Relationships as a Function of Personal Relationship Orientation. AB - Previous research suggests that both monogamous and consensually non-monogamous (CNM) participants rate monogamous targets more positively. However, this pattern of stigma toward CNM relationships and the "halo effect" surrounding monogamy is at odds with the view that people typically favor members from their own groups over members of other groups. In the current research, we sought to re-examine the halo effect, using a more direct measure of stigma (i.e., desired social distance), in a methodological context that differentiates between the three most common types of CNM relationships. A convenience sample (N = 641) of individuals who self-identified as monogamous (n = 447), open (n = 80), polyamorous (n = 62), or swinger (n = 52) provided social distance ratings in response to these same relationship orientations in a counterbalanced order. Congruent with prior findings, CNM participants favored monogamous targets over CNM targets as a broad category (replicating the halo effect). However, results indicated this effect dissipated when participants were asked to differentiate between relationships they identify with, and other CNM relationships. Furthermore, supplementary findings suggest that monogamous targets were perceived to be the least promiscuous and were associated with the lowest perceived sexually transmitted infection (STI) rates, while swinger targets were perceived as the most promiscuous and were associated with the highest perceived STI rates. Consequently, our results imply social distance is partly attributable to the perception of STI risk, but not perceptions of promiscuity. PMID- 30008683 TI - Misophonia and Potential Underlying Mechanisms: A Perspective. AB - There is a growing research interest in the diagnosis rate of misophonia, a condition characterized by a negative emotional/autonomic reaction to specific everyday sounds. Diagnosis of misophonia requires a thorough case history and audiological test procedures. Associative and non-associative learning models for understanding the underlying mechanisms of misophonia have been presented. Currently, there is no cure or pharmaceutical agent for misophonia; however, therapy programs addressing misophonia and its characteristics do exist. Investigation of comorbid conditions and other psychological therapy strategies might help to reveal more about the underlying mechanisms and potentially lead to a successful treatment method. PMID- 30008684 TI - Personality Traits and Vitamin D3 Supplementation Affect Mood State 12 h Before 100 km Ultramarathon Run. AB - Background: Participation in extreme endurance sports is becoming an increasingly popular activity, and thus more and more people are getting involved in it. Taking part in a 100 km run is associated with great physiological and psychological stress, which can affect one's mood state. Thus, the goal of this study was to determine if personality, experience, and motives for participation are related to a runner's mood and its changes as well as to investigate whether vitamin D3 supplementation influences mood 12 h before and 12 h after the run. Method: The study group consisted of 20 experienced marathon and ultramarathon runners taking part in a 100 km track run. All participants were males aged between 31 and 50 (M = 40.75, SD = 7.15). The group was divided in two equal subgroups: the placebo group and the group supplemented with vitamin D3. Personality traits were assessed using the Polish version of Eysenck's EPQ-R 106 and mood states were measured twice (12 h before and after the run) using the Polish version of the UMACL by Mathews, Chamberlain, and Jones. Motives for participation in ultramarathons were measured with the IPAO by Lipowski and Zaleski. Results: Levels of vitamin D3 correlated very strongly with energetic arousal (EA) (rs = 0.80; p < 0.05) and strongly hedonic tone (HT) (rs = 0.74; p < 0.05) 12 h before the run. There were no significant correlations between levels of vitamin D3 and mood states after the run. Moreover, extraversion correlated moderately with tense arousal (TA) (rs = -0.48; p < 0.05) and EA (rs = 0.47; p < 0.05) while neuroticism correlated moderately with TA (rs = 0.53; p < 0.05) and HT (rs = -0.57; p < 0.05). Conclusion: Both personality and vitamin D3 supplementation are related to runners' pre-run mood. These effects are nullified when it comes to post-run mood states. PMID- 30008685 TI - Similarity and Positivity of Personality Profiles Consistently Predict Relationship Satisfaction in Dyads. AB - The effect of similarities in the personality traits of romantic partners on their relationship satisfaction (RS) has often been studied, albeit with mixed results. Beyond the main effects of personality traits, incremental validity was often completely missing, or at least very low. In contrast, our five studies, three cross-sectional - including one study on leader-follower dyads to secure generalizability - and two longitudinal, show that, in predicting RS, the beta coefficients of distance (where distance is defined as the average across items of absolute differences between the two partners' self-ratings) or positivity (where positivity is defined as the frequency of extremely positive self-ratings) increase when either the positivity of the profiles or the distance between the profiles is added as second predictor. Thus, positivity and distance seem to function as reciprocal suppressor variables that allow controlling for irrelevant components of the predictors. Consequently, when combined with positivity, distance proved to be a consistently better predictor of RS than has been reported in most previous studies. Combining profile distance with profile positivity appears to be promising well beyond research on RS, in that an individual profile of traits can be matched with a profile of a specific environment's offers and demands when person-environment fit is the focus of interest. PMID- 30008686 TI - Character Strengths, Strengths Use, Future Self-Continuity and Subjective Well Being Among Chinese University Students. AB - The study was designed to explore the relationships among character strengths, strengths use, future self-continuity and subjective well-being. A total of 225 undergraduates completed paper-and-pencil questionnaires assessing character strengths, strengths use, future self-continuity, and subjective well-being. Results suggested several character strengths were correlated with subjective well-being and the strongest correlations were found for hope, curiosity, zest, perseverance and love. All character strengths were significantly correlated with strengths use. Strengths use and future self-continuity were robustly correlated with subjective well-being. The mediation analysis showed that strengths use mediates the relationship between character strengths and subjective well-being, and specifically, the indirect effects of strengths use varies from different character strengths. The moderated mediator suggested that future self-continuity moderated the mediation of strengths use because future self-continuity moderates the effect of strengths use on subjective well-being. Furthermore, the indirect effect of strengths use was stronger with high level of future self-continuity than those with low level of future self-continuity. The present findings make a contribution to understand the underlying mechanisms involving in character strengths are associated with higher level of well-being. Additionally, the findings expand knowledge about future self-continuity and its relation to strengths use and subjective well-being among undergraduates, having significant implications in the educational context. PMID- 30008687 TI - Service Members Prefer a Psychotherapist Who Is a Veteran. AB - The military is experiencing high rates of mental illness, yet service members and veterans with mental health problems often choose not to seek treatment. Based on clinical-psychology models of client-therapist matching and cultural competency, we hypothesized that willingness to seek treatment among military personnel is higher when the potential psychotherapist is a discharged veteran. Seventy-seven military personnel (73% men, 70% White, Mage = 34.2) took part in the study. As hypothesized, the majority of participants indicated that they would prefer to see a psychologist who is a veteran. When responding to vignettes, ratings of the psychotherapist's ability to understand the client (a soldier post-deployment), of his ability to help such a client, and of whether the client should seek treatment from this psychotherapist were higher when the psychotherapist was a veteran compared to when he had no military experience. There were no between-group differences in age, years of service, deployment history, or attitudes toward psychotherapy in general. Similarly, gender and education level had no effect on the results. These findings imply that having the opportunity to receive treatment by a psychotherapist who is a veteran may remove barriers for treatment and encourage more service members and veterans to seek and obtain the help that they need. This can be done by communicating these findings to the military population and by encouraging therapists who have military experience to make this fact known to their potential clients. PMID- 30008688 TI - Sex Differences in Emotion Recognition and Working Memory Tasks. AB - It is proposed that emotional and cognitive functions may be differentiated based on sex. However, it is still unknown whether this assumption could be generalized for all emotional faces and working memory (WM) functions. To examine this, 50 females, and 60 males performed an emotion recognition task, consisting of a series of emotional faces as well as three working memory tasks from Cambridge Neuropsychological test battery (CANTAB); namely, spatial working memory (SWM), stocking of Cambridge (SOC), and intra/extradimensional shifts tasks (IED). The results found that females had faster response times in recognition of both positive and negative faces as compared to males. Furthermore, it was observed that while females were better on SWM task processing, males performed better on IED and four move SOC tasks, illustrating that processing of WM components may differentiate by sex. It has been concluded that emotional and cognitive functions are indeed sensitive to sex differences. PMID- 30008689 TI - Neuropsychological Assessment of Older Adults With Virtual Reality: Association of Age, Schooling, and General Cognitive Status. AB - The development of neuropsychological assessment methods using virtual reality (VR) is a valid and promising option for the detection of cognitive impairment in the older people, focusing on activities composed of tasks of multiple demands. This study verified the association of age, schooling, and general cognitive status on the performance of neurologically healthy older adults in ECO-VR, a VR task of multiple demands for neuropsychological assessment. A total of 111 older adults answered a sociodemographic questionnaire, the Mini Mental State Examination, the Vocabulary subtest of the Wechsler Intelligence Scale for Adults (third edition), and the ECO-VR. Correlation analyses, multiple linear regression, and comparisons between groups (effects by age and schooling groups) were used to evaluate the results. The ECO-VR total score was significantly associated with age, years of education, MMSE, and Vocabulary subtest. The linear regression models identified that age was the main predictor for total score and rule breaking of ECO-VR. According to the univariate analysis, it was identified the main effect of age group and schooling group in the total ECO-VR score, but there was no interaction effect. The results are discussed in order to understand the role of sociodemographic characteristics in the performance of older adults in a VR task of multiple demands. It was also verified the possibility use of VR for neuropsychological assessment of older adults. PMID- 30008690 TI - A Multidimensional PERMA-H Positive Education Model, General Satisfaction of School Life, and Character Strengths Use in Hong Kong Senior Primary School Students: Confirmatory Factor Analysis and Path Analysis Using the APASO-II. AB - The multidimensional PERMA-H positive education model provided evaluation and education framework for the theoretical and practice development of positive psychology in schools. Character strengths use mediates the association of strength knowledge and well-being. Using the Assessment Program for Affective and Social Outcomes (2nd Version) (APASO-II), the Subjective Happiness Scale, and the Physical Health Subscale of the PERMA-profiler, a multidimensional measure of PERMA-H was validated using confirmatory factor analysis in the context of a positive education program evaluation in senior primary school students. The association of PERMA-H measurements with school well-being as measured by general satisfaction of school life, and levels of depression and anxiety, and the mediation mechanism of character strengths use in such association were studied using path analysis. A cross-sectional sample of 726 senior primary school students (i.e., grade 4-6) aged 8-13 from the two primary schools completed a baseline evaluation questionnaire of a positive education program. Satisfactory internal reliability of the scales was obtained with Cronbach's alpha coefficients < 0.70. The scales were generally positively and moderately inter correlated, except for level of anxiety and depression symptoms which was negative. Good psychometric properties of APASO-II were evidenced from the factor structure of sub-scale scores conforming to six factors of the PERMA-H model by confirmatory factor analysis. Path analyses showed that the APASO-II factors together with measures of subject happiness and positive health as the multidimensional PERMA-H model of positive education differentially predicted general satisfaction of school life, level of anxiety and depression, and character strengths use. Character strengths use mediated the relationship of Positive Engagement with general satisfaction of school life. Positive education utilizes knowledge and research findings from positive psychology in schools to produce intended positive outcomes like enhanced well-being and reduced level of depression in students. This study provided a solid foundation for related scientific research and the understanding of the multidimensional framework of positive psychology concepts. Systematic promotion and longitudinal evaluation of positive education at the institutional level in Hong Kong can be achieved with the use of APASO-II and the positive education scales of subjective happiness and physical health. PMID- 30008691 TI - Group Motivation-Focused Interventions for Patients With Obesity and Binge Eating Disorder. PMID- 30008692 TI - Corrigendum: Hypernatural Monitoring: A Social Rehearsal Account of Smartphone Addiction. AB - [This corrects the article DOI: 10.3389/fpsyg.2018.00141.]. PMID- 30008693 TI - Do We Need to Rethink the Epidemiology and Healthcare Utilization of Parkinson's Disease in Germany? AB - Epidemiological aspects of Parkinson's disease (PD), co-occurring diseases and medical healthcare utilization of PD patients are still largely elusive. Based on claims data of 3.7 million statutory insurance members in Germany in 2015 the prevalence and incidence of PD was determined. PD cases had at least one main hospital discharge diagnosis of PD, or one physician diagnosis confirmed by a subsequent or independent diagnosis or by PD medication in 2015. Prevalence of (co-)occurring diseases, mortality, and healthcare measures in PD cases and matched controls were compared. In 2015, 21,714 prevalent PD cases (standardized prevalence: 511.4/100,000 persons) and 3,541 incident PD cases (standardized incidence: 84.1/100,000 persons) were identified. Prevalence of several (co )occurring diseases/complications, e.g., dementia (PD/controls: 39/13%), depression (45/22%), bladder dysfunction (46/22%), and diabetes (35/31%), as well as mortality (10.7/5.8%) differed between PD cases and controls. The annual healthcare utilization was increased in PD cases compared to controls, e.g., regarding mean +/- SD physician contacts (15.2 +/- 7.6/12.2 +/- 7.3), hospitalizations (1.3 +/- 1.8/0.7 +/- 1.4), drug prescriptions (overall: 37.7 +/- 24.2/21.7 +/- 19.6; anti-PD medication: 7.4 +/- 7.4/0.1 +/- 0.7), assistive/therapeutic devices (47/30%), and therapeutic remedies (57/16%). The standardized prevalence and incidence of PD in Germany as well as mortality in PD may be substantially higher than reported previously. While frequently diagnosed with co-occurring diseases/complications, such as dementia, depression, bladder dysfunction and diabetes, the degree of healthcare utilization shows large variability between PD patients. These findings encourage a rethinking of the epidemiology and healthcare utilization in PD, at least in Germany. Longitudinal studies of insurance claims data should further investigate the individual and epidemiological progression and healthcare demands in PD. PMID- 30008694 TI - Importance of Angiogenin and Endothelial Progenitor Cells After Rehabilitation Both in Ischemic Stroke Patients and in a Mouse Model of Cerebral Ischemia. AB - Background: Rehabilitation therapy is the only available treatment for stroke survivors presenting neurological deficits; however, the underlying molecules and mechanisms associated with functional/motor improvement during rehabilitation are poorly understood. Objective: Our aim is to study the modulation of angiogenin and endothelial progenitor cells (EPCs) as repair-associated factors in a cohort of stroke patients and mouse models of rehabilitation after cerebral ischemia. Methods: The clinical study included 18 ischemic strokes admitted to an intensive rehabilitation therapy (IRT) unit, 18 non-ischemic controls and brain samples from three deceased patients. Angiogenin and EPCs were measured in blood obtained before and up to 6 months after IRT together with an extensive evaluation of the motor/functional status. In parallel, C57BL/6 mice underwent middle cerebral artery occlusion, and the pasta matrix reaching-task or treadmill exercises were used as rehabilitation models. Angiogenin RNA expression was measured after 2 or 12 days of treatment together with cell counts from EPCs cultures. Results: Brain angiogenin was identified in both human and mouse tissue, whereas serum levels increased after 1 month of IRT in association with motor/functional improvement. EPC populations were increased after stroke and remained elevated during follow up after IRT. The mouse model of rehabilitation by the task-specific pasta matrix exercise increased the number of EPCs at 2 days and increased angiogenin expression after 12 days of rehabilitation. Conclusions: Angiogenin and EPCs are modulated by rehabilitation after cerebral ischemia, suggesting that both angiogenin and EPCs could serve as biomarkers of improvement during rehabilitation or future therapeutic targets. PMID- 30008695 TI - Juvenile Myoclonic Epilepsy Shows Potential Structural White Matter Abnormalities: A TBSS Study. AB - Background: Several studies on patients with juvenile myoclonic epilepsy (JME) showed widespread white matter (WM) abnormalities in the brain. The aim of this study was to investigate potential structural abnormalities in JME patients (1) compared to healthy controls, (2) among JME subgroups with or without photoparoxysmal responses (PPR), and (3) in correlation with clinical variables. Methods: A selection of 31 patients with JME (12 PPR positive) and 27 age and gender matched healthy controls (HC) were studied at a tertiary epilepsy center. Fractional anisotropy (FA) was calculated and intergroup differences analyzed using Tract Based Spatial Statistics (TBSS). Results: Compared to HC the JME group showed reduced FA widespread and bilateral in the longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, anterior and posterior thalamic radiation, corona radiata, corpus callosum, cingulate gyrus and external capsule (p < 0.01). Subgroup analysis revealed no significant differences of WM alterations between PPR positive and negative patients and with clinical and epilepsy-related factors. Conclusions: Widespread microstructural abnormalities among patients with JME have been identified.Prior findings of frontal and thalamofrontal microstructural abnormalities have been confirmed. Additionally, microstructural abnormalities were found in widespread extra-frontal regions that may help to validate pathophysiological concepts of JME. PMID- 30008696 TI - Impact of Maternal Age on Oocyte and Embryo Competence. AB - The overall success of human reproduction, either spontaneously or after IVF, is highly dependent upon maternal age. The main reasons for age-related infertility include reduced ovarian reserve and decreased oocyte/embryo competence due to aging insults, especially concerning an increased incidence of aneuploidies and possibly decreased mitochondrial activity. Age-related chromosomal abnormalities mainly arise because of meiotic impairments during oogenesis, following flawed chromosome segregation patterns such as non-disjunction, premature separation of sister chromatids, or the recent reverse segregation. In this review, we briefly discuss the main mechanisms putatively impaired by aging in the oocytes and the deriving embryos. We also report the main strategies proposed to improve the management of advanced maternal age women in IVF: fertility preservation through oocyte cryopreservation to prevent aging; optimization of the ovarian stimulation and enhancement of embryo selection to limit its effects; and oocyte donation to circumvent its consequences. PMID- 30008697 TI - XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression. AB - Multiple myeloma bone disease (MMBD) is characterized by non-healing lytic bone lesions that persist even after a patient has achieved a hematologic remission. We previously reported that p62 (sequestosome-1) in bone marrow stromal cells (BMSC) is critical for the formation of MM-induced signaling complexes that mediate OB suppression. Importantly, XRK3F2, an inhibitor of the p62-ZZ domain, blunted MM-induced Runx2 suppression in vitro, and induced new bone formation and remodeling in the presence of tumor in vivo. Additionally, we reported that MM cells induce the formation of repressive chromatin on the Runx2 gene in BMSC via direct binding of the transcriptional repressor GFI1, which recruits the histone modifiers, histone deacetylase 1 (HDAC1) and Enhancer of zeste homolog 2 (EZH2). In this study we investigated the mechanism by which blocking p62-ZZ domain dependent signaling prevents MM-induced suppression of Runx2 in BMSC. XRK3F2 prevented MM-induced upregulation of Gfi1 and repression of the Runx2 gene when present in MM-preOB co-cultures. We also show that p62-ZZ-domain blocking by XRK3F2 also prevented MM conditioned media and TNF plus IL7-mediated Gfi1 mRNA upregulation and the concomitant Runx2 repression, indicating that XRK3F2's prevention of p62-ZZ domain signaling within preOB is involved in the response. Chromatin immunoprecipitation (ChIP) analyses revealed that XRK3F2 decreased MM induced GFI1 occupancy at the Runx2-P1 promoter and prevented recruitment of HDAC1, thus preserving the transcriptionally permissive chromatin mark H3K9ac on Runx2 and allowing osteogenic differentiation. Furthermore, treatment of MM exposed preOB with XRK3F2 after MM removal decreased GFI1 enrichment at Runx2-P1 and rescued MM-induced suppression of Runx2 mRNA and its downstream osteogenic gene targets together with increased osteogenic differentiation. Further, primary BMSC (hBMSC) from MM patients (MM-hBMSC) had little ability to increase H3K9ac on the Runx2 promoter in osteogenic conditions when compared to hBMSC from healthy donors (HD). XRK3F2 treatment enriched Runx2 gene H3K9ac levels in MM-hBMSC to the level observed in HD-hBMSC, but did not alter HD-hBMSC H3K9ac. Importantly, XRK3F2 treatment of long-term MM-hBMSC cultures rescued osteogenic differentiation and mineralization. Our data show that blocking p62-ZZ domain dependent signaling with XRK3F2 can reverse epigenetic-based mechanisms of MM induced Runx2 suppression and promote osteogenic differentiation. PMID- 30008699 TI - A Broad Spectrum Racemase in Pseudomonas putida KT2440 Plays a Key Role in Amino Acid Catabolism. AB - The broad-spectrum amino acid racemase (Alr) of Pseudomonas putida KT2440 preferentially interconverts the l- and d-stereoisomers of Lys and Arg. Despite conservation of broad-spectrum racemases among bacteria, little is known regarding their physiological role. Here we explore potential functional roles for Alr in P. putida KT2440. We demonstrate through cellular fractionation that Alr enzymatic activity is found in the periplasm, consistent with its putative periplasm targeting sequence. Specific activity of Alr is highest during exponential growth, and this activity corresponds with an increased accumulation of d-Lys in the growth medium. An alr gene knockout strain (Deltaalr) was generated and used to assess potential roles for the alr gene in peptidoglycan structure, producing soluble signaling compounds, and amino acid metabolism. The stationary phase peptidoglycan structure did not differ between wild-type and Deltaalr strains, indicating that products resulting from Alr activity are not incorporated into peptidoglycan under these conditions. RNA-seq was used to assess differences in the transcriptome between the wild-type and Deltaalr strains. Genes undergoing differential expression were limited to those involved in amino acid metabolism. The Deltaalr strain exhibited a limited capacity for catabolism of l-Lys and l-Arg as the sole source of carbon and nitrogen. This is consistent with a predicted role for Alr in catabolism of l-Lys by virtue of its ability to convert l-Lys to d-Lys, which is further catabolized through the l pipecolate pathway. The metabolic profiles here also implicate Alr in catabolism of l-Arg, although the pathway by which d-Arg is further catabolized is not clear at this time. Overall, data presented here describe the primary role of Alr as important for basic amino acid metabolism. PMID- 30008698 TI - Neuropeptide G Protein-Coupled Receptors as Oncotargets. AB - Neuropeptide G protein-coupled receptors (GPCRs) are overexpressed on numerous cancer cells. In a number of tumors, such as small cell lung cancer (SCLC), bombesin (BB) like peptides and neurotensin (NTS) function as autocrine growth factors whereby they are secreted from tumor cells, bind to cell surface receptors and stimulate growth. BB-drug conjugates and BB receptor antagonists inhibit the growth of a number of cancers. Vasoactive intestinal peptide (VIP) increases the secretion rate of BB-like peptide and NTS from SCLC leading to increased proliferation. In contrast, somatostatin (SST) inhibits the secretion of autocrine growth factors from neuroendocrine tumors (NETs) and decreases proliferation. SST analogs such as radiolabeled octreotide can be used to localize tumors, is therapeutic for certain cancer patients and has been approved for four different indications in the diagnosis/treatment of NETs. The review will focus on how BB, NTS, VIP, and SST receptors can facilitate the early detection and treatment of cancer. PMID- 30008700 TI - Fonsecaea pedrosoi Sclerotic Cells: Secretion of Aspartic-Type Peptidase and Susceptibility to Peptidase Inhibitors. AB - Fonsecaea pedrosoi is a dematiaceous fungus and the main causative agent of chromoblastomycosis that is a chronic disease usually affecting the human skin and subcutaneous tissues, which causes deformations and incapacities, being frequently refractory to available therapies. A typical globe-shaped, multiseptated and pigmented cells, known as sclerotic cells, are found in the lesions of infected individuals. In the present work, we have investigated the production of aspartic-type peptidase in F. pedrosoi sclerotic cells as well as the effect of peptidase inhibitors (PIs) on its enzymatic activity and viability. Our data showed that sclerotic cells are able to secrete pepstatin A-sensible aspartic peptidase when grown under chemically defined conditions. In addition, aspartic PIs (ritonavir, nelfinavir, indinavir, and saquinavir), which are clinically used in the HIV chemotherapy, significantly decreased the fungal peptidase activity, varying from 55 to 99%. Moreover, sclerotic cell-derived aspartic peptidase hydrolyzed human albumin, an important serum protein, as well as laminin, an extracellular matrix component, but not immunoglobulin G and fibronectin. It is well-known that aspartic peptidases play important physiological roles in fungal cells. With this task in mind, the effect of pepstatin A, a classical aspartic peptidase inhibitor, on the F. pedrosoi proliferation was evaluated. Pepstatin A inhibited the fungal viability in both cellular density- and drug-concentration manners. Moreover, HIV-PIs at 10 MUM powerfully inhibited the viability (>65%) of F. pedrosoi sclerotic cells. The detection of aspartic peptidase produced by sclerotic cells, the parasitic form of F. pedrosoi, may contribute to reveal new virulence markers and potential targets for chromoblastomycosis therapy. PMID- 30008701 TI - Cultivation of Drought-Tolerant and Insect-Resistant Rice Affects Soil Bacterial, but Not Fungal, Abundances and Community Structures. AB - The impacts of rice varieties with stacked drought tolerance and insect resistance on soil microbiomes are poorly understood. Hence, the objective of this study was to investigate the effects resulting from the cultivation of the drought-tolerant and insect-resistant rice cultivar, Hanhui3T, on soil physical chemical properties, and bacterial and fungal community composition. Soil samples of Hanhui3T and conventional rice varieties (Hanhui3 and Zhonghua11) were collected in triplicate at the booting stage, and bacterial and fungal population sizes and community structures were assessed using qPCR and Illumina MiSeq sequencing, respectively. The Bt protein concentration of Hanhui3T was significantly higher than that of Hanhui3 and Zhonghua11, while the pH of Hanhui3T was significantly lower. Bacterial population sizes and community composition were significantly different between Hanhui3T and Hanhui3 (or Zhonghua11), while no similar effects were observed for fungal communities. These differences suggest that the effect of Hanhui3T cultivation on bacterial community composition is stronger than the effect on fungal communities. Moreover, bacterial abundance was positively correlated to soil pH, while bacterial community structure variations were mainly driven by soil pH and Bt protein concentration differences. In conclusion, the abundances and structure of bacterial communities were altered in rhizosphere with Hanhui3T cultivation that changed soil pH and Bt protein concentrations, while fungal communities displayed no such responsiveness. PMID- 30008702 TI - Antarctic Cryptoendolithic Fungal Communities Are Highly Adapted and Dominated by Lecanoromycetes and Dothideomycetes. AB - Endolithic growth is one of the most spectacular microbial adaptations to extreme environmental constraints and the predominant life-form in the ice-free areas of Continental Antarctica. Although Antarctic endolithic microbial communities are known to host among the most resistant and extreme-adapted organisms, our knowledge on microbial diversity and composition in this peculiar niche is still limited. In this study, we investigated the diversity and structure of the fungal assemblage in the cryptoendolithic communities inhabiting sandstone using a meta barcoding approach targeting the fungal Internal Transcribed Sequence region 1 (ITS1). Samples were collected from 14 sites in the Victoria Land, along an altitudinal gradient ranging from 1,000 to 3,300 m a.s.l. and from 29 to 96 km distance to coast. Our study revealed a clear dominance of a 'core' group of fungal taxa consistently present across all the samples, mainly composed of lichen-forming and Dothideomycetous fungi. Pareto-Lorenz curves indicated a very high degree of specialization (F0 approximately 95%), suggesting these communities are highly adapted but have limited ability to recover after perturbations. Overall, both fungal community biodiversity and composition did not show any correlation with the considered abiotic parameters, potentially due to strong fluctuations of environmental conditions at local scales. PMID- 30008703 TI - Organic Peroxide-Sensing Repressor OhrR Regulates Organic Hydroperoxide Stress Resistance and Avermectin Production in Streptomyces avermitilis. AB - The bacterium Streptomyces avermitilis is an industrial-scale producer of avermectins, which are important anthelmintic agents widely used in agriculture, veterinary medicine, and human medicine. During the avermectin fermentation process, S. avermitilis is exposed to organic peroxides generated by aerobic respiration. We investigated the role of MarR-family transcriptional regulator OhrR in oxidative stress response and avermectin production in S. avermitilis. The S. avermitilis genome encodes two organic hydroperoxide resistance proteins: OhrB1 and OhrB2. OhrB2 is the major resistance protein in organic peroxide stress responses. In the absence of organic peroxide, the reduced form of OhrR represses the expression of ohrB2 gene by binding to the OhrR box in the promoter region. In the presence of organic peroxide, the oxidized form of OhrR dissociates from the OhrR box and the expression of ohrB2 is increased by derepression. OhrR also acts as a repressor to regulate its own expression. An ohrR-deletion mutant (termed DohrR) displayed enhanced avermectin production. Our findings demonstrate that OhrR in S. avermitilis represses avermectin production by regulating the expression of pathway-specific regulatory gene aveR. OhrR also plays a regulatory role in glycolysis and the pentose phosphate (PP) pathway by negatively controlling the expression of pykA2 and ctaB/tkt2-tal2-zwf2-opcA2-pgl. PMID- 30008704 TI - Presence of Segmented Filamentous Bacteria in Human Children and Its Potential Role in the Modulation of Human Gut Immunity. AB - Segmented filamentous bacteria (SFB) are commensal organisms that grow by anchoring a specialized holdfast structure to the intestinal walls of a variety of animals. Interaction of SFB with Peyer's patches in mice promotes the post natal maturation of the immune system. We previously reported that the colonization of SFB in humans mainly occurs by 36 months of age, and is difficult to be detected afterward. In this study, we measured the level of SFB in intestinal fluids of human children. SFB were found via qPCR to represent a small fraction of the whole SFB-positive microbiota (105 SFB in 1011 total bacteria). Bacteria with filamentous segmented morphology were observed in intestinal fluids via fluorescent in situ hybridization, and from gut biopsies via scanning electron microscopy. SFB-specific DNA and peptide fragments were also identified via multiple displacement amplification PCR and mass spectrometry. There was an overall positive correlation between the presence of SFB and the titer of total secretory immunoglobulin A (sIgA), which is more apparent in intestinal fluids of the age group of 8-36 months. Afterward there was a decline of SFB in numbers correlated with a reduction of total sIgA. RT-qPCR analysis of the terminal ileal biopsies revealed that the expression of Th17 pathway genes were induced in SFB positive samples, while the markers of T and B cell receptor signaling pathways were also upregulated. Collectively, these data suggest that SFB is a rare member of microbiota, and may play an important role in the development of human gut immunity. PMID- 30008705 TI - Lab to Field Assessment of the Ecotoxicological Impact of Chlorpyrifos, Isoproturon, or Tebuconazole on the Diversity and Composition of the Soil Bacterial Community. AB - Pesticides are intentionally applied to agricultural fields for crop protection. They can harm non-target organisms such as soil microorganisms involved in important ecosystem functions with impacts at the global scale. Within the frame of the pesticide registration process, the ecotoxicological impact of pesticides on soil microorganisms is still based on carbon and nitrogen mineralization tests, despite the availability of more extensive approaches analyzing the abundance, activity or diversity of soil microorganisms. In this study, we used a high-density DNA microarray (PhyloChip) and 16S rDNA amplicon next-generation sequencing (NGS) to analyze the impact of the organophosphate insecticide chlorpyrifos (CHL), the phenyl-urea herbicide isoproturon (IPU), or the triazole fungicide tebuconazole (TCZ) on the diversity and composition of the soil bacterial community. To our knowledge, it is the first time that the combination of these approaches are applied to assess the impact of these three pesticides in a lab-to-field experimental design. The PhyloChip analysis revealed that although no significant changes in the composition of the bacterial community were observed in soil microcosms exposed to the pesticides, significant differences in detected operational taxonomic units (OTUs) were observed in the field experiment between pesticide treatments and control for all three tested pesticides after 70 days of exposure. NGS revealed that the bacterial diversity and composition varied over time. This trend was more marked in the microcosm than in the field study. Only slight but significant transient effects of CHL or TCZ were observed in the microcosm and the field study, respectively. IPU was not found to significantly modify the soil bacterial diversity or composition. Our results are in accordance with conclusions of the Environmental Food Safety Authority (EFSA), which concluded that these three pesticides may have a low risk toward soil microorganisms. PMID- 30008706 TI - Comparative Transcriptome Profiling Reveals a Potential Role of Type VI Secretion System and Fimbriae in Virulence of Non-O157 Shiga Toxin-Producing Escherichia coli. AB - Shiga toxin-producing Escherichia coli (STEC) cause both sporadic infections and outbreaks of enteric disease in humans, with symptoms ranging from asymptomatic carriage to severe disease like haemolytic uremic syndrome (HUS). Bacterial virulence factors like subtypes of the Shiga toxin (Stx) and the locus of enterocyte effacement (LEE) pathogenicity island, as well as host factors like young age, are strongly associated with development of HUS. However, these factors alone do not accurately differentiate between strains that cause HUS and those that do not cause severe disease, which is important in the context of diagnosis, treatment, as well as infection control. We have used RNA sequencing to compare transcriptomes of 30 stx2a and eae positive STEC strains of non-O157 serogroups isolated from children <5 years of age. The strains were from children with HUS (HUS group, n = 15), and children with asymptomatic or mild disease (non HUS group, n = 15), either induced with mitomycin C or non-induced, to reveal potential differences in gene expression levels between groups. When the HUS and non-HUS group were compared for differential expression of protein-encoding gene families, 399 of 6,119 gene families were differentially expressed (log2 fold change >= 1, FDR < 0.05) in the non-induced condition, whereas only one gene family was differentially expressed in the induced condition. Gene ontology and cluster analysis showed that several fimbrial operons, as well as a putative type VI secretion system (T6SS) were more highly expressed in the HUS group than in the non-HUS group, indicating a role of these in the virulence of STEC strains causing severe disease. PMID- 30008708 TI - Transmission Characteristics of Barley Yellow Striate Mosaic Virus in Its Planthopper Vector Laodelphax striatellus. AB - The most economically important plant viruses are specifically transmitted by phytophagous insects that significantly affect viral epidemiology. Barley yellow striate mosaic virus (BYSMV), a member of the genus Cytorhabdovirus, is transmitted by the small brown planthopper (SBPH, Laodelphax striatellus) in a persistent-propagative manner. However, the infection route of BYSMV in SBPHs is poorly understood. In this study, immunofluorescence confocal laser scanning microscopy (iCLSM) was performed to investigate the route of BYSMV in SBPHs. We unexpectedly found that BYSMV initially infected the hindgut epithelium of SBPHs, instead of the midgut epithelium initially infected by other persistent propagative viruses. Subsequently, BYSMV disseminated to the hindgut visceral muscles and spread to other parts of alimentary canals, hemolymph, and salivary glands. Comparative analysis of gene expression on viral mRNAs and the BYSMV nucleoprotein by using different molecular detection and immunohistochemistry further demonstrated that BYSMV initially infected and replicated in the hindgut epithelial cells of SBPHs. Collectively, our study provides the first insight into that hindgut is initial infection site of BYSMV that represents a new dissemination route of persistent-propagative viruses. PMID- 30008707 TI - Counting the Countless: Bacterial Quantification by Targeting rRNA Molecules to Explore the Human Gut Microbiota in Health and Disease. AB - Over the past decade, the advent of next-generation-sequencing tools has revolutionized our approach to understanding the human gut microbiota. However, numerical data on the gut bacterial groups-particularly low-cell-count microbiota, such as indigenous pathobionts, that are otherwise important components of the microbiota-are relatively limited and disparate. As a result, the comprehensive quantitative structure of the human gut microbiota still needs to be fully defined and standardized. With the aim of filling this knowledge gap, we have established a highly sensitive quantitative analytical system that is based on reverse transcription-quantitative PCR and targets microbial rRNA molecules. The system has already been validated in the precise, sensitive, and absolute quantification of more than 70 target bacterial groups belonging to various human gut bacterial clades, including predominant obligate and facultative anaerobes. The system demonstrates sensitivity several hundred times greater than that of other rRNA-gene-targeting methods. It is thus an efficient and valuable tool for exhaustive analysis of gut microbiota over a wide dynamic range. Using this system, we have to date quantified the gut microbiota of about 2,000 healthy Japanese subjects ranging in age from 1 day to over 80 years. By integrating and analyzing this large database, we came across several novel and interesting features of the gut microbiota, which we discuss here. For instance, we demonstrated for the first time that the fecal counts of not only the predominant bacterial groups but also those at lower cell counts conform to a logarithmically normal distribution. In addition, we revealed several interesting quantitative differences in the gut microbiota of people from different age groups and countries and with different diseases. Because of its high analytic sensitivity, the system has also been applied successfully to other body niches, such as in characterizing the vaginal microbiota, detecting septicemia, and monitoring bacterial translocation. Here, we present a quantitative perspective on the human gut microbiota and review some of the novel microbial insights revealed by employing this promising analytical approach. PMID- 30008709 TI - Interplay Between Membrane Permeability and Enzymatic Barrier Leads to Antibiotic Dependent Resistance in Klebsiella Pneumoniae. AB - The interplay between membrane permeability alterations and the enzymatic barrier contributes to Klebsiella pneumoniae multidrug resistance. We assessed the specific effect of the efflux levels of the main efflux pumps (AcrAB and OqxAB), alone and associated with the loss of the main porins (OmpK35 and OMPK36), on the activity of various antibiotics by constructing a set of K. pneumoniae isogenic strains, including strains with plasmid-mediated beta-lactamases (DHA-1, CTX-M 15, and OXA-48). The two pumps contributed to intrinsic chloramphenicol resistance and AcrAB to that of nalidixic acid and cefoxitin, whereas they had no impact on the activity of the other 11 antibiotics tested. We confirmed the expulsion of these three antibiotics by the two overproduced pumps and that of tigecycline by overproduced AcrAB, and showed that overproduced AcrAB also expelled ertapenem, piperacillin, ceftolozane, and ceftazidime. The sole loss of porins did not significantly affect the activity of the tested antibiotics, except ertapenem. The effect of efflux increases and porin loss on beta-lactam activity was the highest in plasmid-mediated beta-lactamase-producing strains. Thus, DHA-1-producing strains became non-susceptible (NS) to (i) ertapenem when there was an increase in efflux or porin loss, (ii) imipenem and ceftazidime+avibactam when the two mechanisms were associated, and (iii) temocillin when AcrAB was overproduced. The CTX-M-15-producing strains became NS to (i) ertapenem when there was no porin, (ii) ceftolozane+tazobactam when there was either overproduced OqxAB or porin loss, and (iii) temocillin when AcrAB was overproduced. OXA-48-producing strains known to be NS to temocillin were also NS to ceftolozane and they became NS to imipenem when the two pumps were overproduced or there was porin loss. Overall, this study shows that the balance between influx and efflux differentially modulates the activity of the tested antibiotics, an important point for evaluating the activity of future antibiotics or new combinations. PMID- 30008710 TI - Phage Therapy in Prostatitis: Recent Prospects. AB - Prostatitis has various etiology including bacterial infection and dysregulated immunity; some of its forms remain a serious therapeutic challenge. Inflammation occurs in all forms of this disorder and is proposed to predispose to the development of prostate cancer (PC). There are reports that phage therapy is effective in chronic bacterial prostatitis. Recent findings suggest that phages not only eliminate bacteria, but also mediate immunomodulating (for example, anti inflammatory) functions. The immunomodulating effects of phages could be beneficial in treating all forms of prostatitis and play some role in the prevention of the development of PC. As the etiological factors contributing to the majority of prostatitis cases remains largely unknown, and management options are often likewise limited, phage therapy merits further research as an attractive therapeutic option given its immunomodulating effects irrespective of the underlying causative factor(s). PMID- 30008711 TI - Laboratory-Based and Point-of-Care Testing for MSSA/MRSA Detection in the Age of Whole Genome Sequencing. AB - Staphylococcus aureus is an opportunistic pathogen of animals and humans that is capable of both colonizing and infecting its eukaryotic host. It is frequently detected in the clinical microbiology routine laboratory. S. aureus is capable of acquiring antibiotic resistance traits with ease and, given its rapid global dissemination, resistance to meticillin in S. aureus has received extensive coverage in the popular and medical press. The detection of meticillin-resistant versus meticillin-susceptible S. aureus (MRSA and MSSA) is of significant clinical importance. Detection of meticillin resistance is relatively straightforward since it is defined by a single determinant, penicillin-binding protein 2a', which exists in a limited number of genetic variants carried on various Staphylococcal Cassette Chromosomes mec. Diagnosis of MRSA and MSSA has evolved significantly over the past decades and there has been a strong shift from culture-based, phenotypic methods toward molecular detection, especially given the close correlation between the presence of the mec genes and phenotypic resistance. This brief review summarizes the current state of affairs concerning the mostly polymerase chain reaction-mediated detection of MRSA and MSSA in either the classical laboratory setting or at the point of care. The potential diagnostic impact of the currently emerging whole genome sequencing (WGS) technology will be discussed against a background of diagnostic, surveillance, and infection control parameters. Adequate detection of MSSA and MRSA is at the basis of any subsequent, more generic antibiotic susceptibility testing, epidemiological characterization, and detection of virulence factors, whether performed with classical technology or WGS analyses. PMID- 30008712 TI - Strain-Specific Contribution of Eukaryotic Elongation Factor 1 Gamma to the Translation of Influenza A Virus Proteins. AB - Influenza A virus exploits multiple host proteins during infection. To define the virus-host interactome, our group conducted a proteomics-based screen and identified 299 genes that contributed to virus replication and 24 genes that were antiviral. Of these genes, we focused on the role during virus replication of eukaryotic elongation factor 1 gamma (eEF1G), which is a subunit of the eukaryotic elongation factor-1 complex and known to be a pro-viral host protein. Using the CRISPR/Cas9 system, we obtained two clones that were defective in eEF1G expression. In both of these clones, A/WSN/33 (H1N1) virus growth and protein expression were significantly suppressed, but viral mRNA, vRNA, and cRNA expression were not reduced. However, the replication and protein expression of A/California/04/2009 (H1N1pdm) virus in both clones were similar to those in parental cells. We found that the PB2 and PA proteins of WSN virus were responsible for the eEF1G-dependent replication. Our data show that eEF1G plays a role in the translation of virus proteins in a strain-specific manner. Additional analyses may be needed to further understand the role of strain-specific host proteins during virus replication. PMID- 30008713 TI - Corrigendum: ComX-Induced Exoproteases Degrade ComX in Bacillus subtilis PS-216. AB - [This corrects the article DOI: 10.3389/fmicb.2018.00105.]. PMID- 30008714 TI - Optimized Peptide-MHC Multimer Protocols for Detection and Isolation of Autoimmune T-Cells. AB - Peptide-MHC (pMHC) multimers have become the "gold standard" for the detection and isolation of antigen-specific T-cells but recent evidence shows that normal use of these reagents can miss fully functional T-cells that bear T-cell receptors (TCRs) with low affinity for cognate antigen. This issue is particularly pronounced for anticancer and autoimmune T-cells as self-reactive T cell populations are enriched for low-affinity TCRs due to the removal of cells with higher affinity receptors by immune tolerance mechanisms. Here, we stained a wide variety of self-reactive human T-cells using regular pMHC staining and an optimized technique that included: (i) protein kinase inhibitor (PKI), to prevent TCR triggering and internalization, and (ii) anti-fluorochrome antibody, to reduce reagent dissociation during washing steps. Lymphocytes derived from the peripheral blood of type 1 diabetes patients were stained with pMHC multimers made with epitopes from preproinsulin (PPI), insulin-beta chain, glutamic acid decarboxylase 65 (GAD65), or glucose-6-phospate catalytic subunit-related protein (IGRP) presented by disease-risk allelles HLA A*02:01 or HLA*24:02. Samples from ankylosing spondylitis patients were stained with a multimerized epitope from vasoactive intestinal polypeptide receptor 1 (VIPR1) presented by HLA B*27:05. Optimized procedures stained an average of 40.5-fold (p = 0.01, range between 1.4 and 198) more cells than could be detected without the inclusion of PKI and cross linking anti-fluorochrome antibody. Higher order pMHC dextramers recovered more cells than pMHC tetramers in parallel assays, and standard staining protocols with pMHC tetramers routinely recovered less cells than functional assays. HLA A*02:01-restricted PPI-specific and HLA B*27:05-restricted VIPR1-specific T-cell clones generated using the optimized procedure could not be stained by standard pMHC tetramer staining. However, these clones responded well to exogenously supplied peptide and endogenously processed and presented epitopes. We also showed that anti-fluorochrome antibody-conjugated magnetic beads enhanced staining of self-reactive T-cells that could not be stained using standard protocols, thus enabling rapid ex vivo isolation of autoimmune T-cells. We, therefore, conclude that regular pMHC tetramer staining is generally unsuitable for recovering self-reactive T-cells from clinical samples and recommend the use of the optimized protocols described herein. PMID- 30008715 TI - Computational Evaluation of B-Cell Clone Sizes in Bulk Populations. AB - B cell clones expand and contract during adaptive immune responses and can persist or grow uncontrollably in lymphoproliferative disorders. One way to monitor and track B cell clones is to perform large-scale sampling of bulk cell populations, amplifying, and sequencing antibody gene rearrangements by next generation sequencing (NGS). Here, we describe a series of computational approaches for estimating B cell clone size in NGS immune repertoire profiling data of antibody heavy chain gene rearrangements. We define three different measures of B cell clone size-copy numbers, instances, and unique sequences-and show how these measures can be used to rank clones, analyze their diversity, and study their distribution within and between individuals. We provide a detailed, step-by-step procedure for performing these analyses using two different data sets of spleen samples from human organ donors. In the first data set, 19 independently generated biological replicates from a single individual are analyzed for B cell clone size, diversity and sampling sufficiency for clonal overlap analysis. In the second data set, B cell clones are compared in eight different organ donors. We comment upon frequently encountered pitfalls and offer practical advice with alternative approaches. Overall, we provide a series of pragmatic analytical approaches and show how different clone size measures can be used to study the clonal landscape in bulk B cell immune repertoire profiling data. PMID- 30008716 TI - B Cell-Related Circulating MicroRNAs With the Potential Value of Biomarkers in the Differential Diagnosis, and Distinguishment Between the Disease Activity and Lupus Nephritis for Systemic Lupus Erythematosus. AB - Our understanding of circulating microRNAs (miRNAs) related to systemic lupus erythematosus (SLE) remains very limited. In this study, we screened SLE-specific miRNAs in plasma from 42 B cell-related miRNAs by using miRNA PCR Array. The selected miRNAs were first confirmed in plasma samples from 50 SLE patients, 16 rheumatoid arthritis (RA) patients, and 20 healthy donors using qRT-PCR. We then investigated the relationship between expressions of the selected miRNAs and SLE clinical indicators. As a result, 14 miRNAs (miR-103, miR-150, miR-20a, miR-223, miR-27a, miR-15b, miR-16, miR-181a, miR-19b, miR-22, miR-23a, miR-25, miR-92a, and miR-93) were significantly decreased in the plasma of SLE patients compared with healthy controls (P < 0.05) and could act as the diagnostic signature to distinguish SLE patients from healthy donors. Six miRNAs (miR-92a, miR-27a, miR 19b, miR-23a, miR-223, and miR-16) expressed in plasma were significantly lower in SLE patients than in RA patients (P < 0.05), revealing the potentially diagnostic signature to distinguish SLE patients from RA patients. Furthermore, the downregulated expression of miR-19b, miR-25, miR-93, and miR-15b was associated with SLE disease activity (P < 0.05) while miR-15b and miR-22 expressions were significantly lower in SLE patients with low estimate glomerular filtration rate (eGFR < 60 ml/min/1.73 m2) (P < 0.05). The diagnostic potential of miR-15b for SLE disease activity and lupus nephritis (LN) with low eGFR was validated on an independent validation set with 69 SLE patients and a cross validation set with 80 SLE patients. In summary, the signature of circulating miRNAs will provide novel biomarkers for the diagnosis of SLE and evaluation of disease activity and LN. PMID- 30008717 TI - It Takes "Guts" to Cause Joint Inflammation: Role of Innate-Like T Cells. AB - Innate-like T cells such as invariant natural killer T (iNKT) cells and mucosal associated T (MAIT) cells, characterized by a semi-invariant T cell receptor and restriction toward MHC-like molecules (CD1 and MR1 respectively), are a unique unconventional immune subset acting at the interface of innate and adaptive immunity. Highly represented at barrier sites and capable of rapidly producing substantial amounts of cytokines, they serve a pivotal role as first-line responders against microbial infections. In contrast, it was demonstrated that innate-like T cells can be skewed toward a predominant pro-inflammatory state and are consequently involved in a number of autoimmune and inflammatory diseases like inflammatory bowel diseases and rheumatic disorders, such as spondyloarthritis (SpA) and rheumatoid arthritis. Interestingly, there is link between gut and joint disease as they often co-incide and share certain aspects of the pathogenesis such as established genetic risk factors, a critical role for pro-inflammatory cytokines, such as TNF-alpha, IL-23, and IL-17 and therapeutic susceptibility. In this regard dysregulated IL-23/IL-17 responses appear to be crucial in both debilitating pathologies and innate-like T cells likely act as key player. In this review, we will explore the remarkable features of iNKT cells and MAIT cells, and discuss their contribution to immunity and combined gut-joint disease. PMID- 30008718 TI - Pre-Activation of Toll-Like Receptor 2 Enhances CD8+ T-Cell Responses and Accelerates Hepatitis B Virus Clearance in the Mouse Models. AB - Toll-like receptors (TLRs) play a crucial role in activation of innate immunity, which is essential for inducing effective adaptive immune responses. Our previous studies have shown that toll-like receptor 2 (TLR2) is required to induce effective virus-specific T-cell responses against hepatitis B virus (HBV) in vivo. However, the contribution of TLR2 activation to adaptive immunity and HBV clearance remains to be clarified. In this study, we explored the hydrodynamic injection (HI) mouse models for HBV infection and examined how the TLR2 agonist Pam3CSK (P3C) influences HBV control and modulates HBV-specific T-cell response if applied in vivo. We found that TLR2 activation by P3C injection leads to the rapid but transient production of serum proinflammatory factors interleukin-6 and tumor necrosis factor-alpha and activation of CD8+ T cells in vivo. Then, the anti-HBV effect and HBV-specific T-cell immunity were investigated by TLR2 activation in the mouse models for persistent or acute HBV infections using HBV plasmids pAAV-HBV1.2 and pSM2, respectively. Both P3C application at early stage and pre-activation promoted HBV clearance, while only TLR2 pre-activation enhanced HBV-specific T-cell response in the liver. In the mouse model for acute HBV infection, P3C application had no significant effect on HBV clearance though P3C significantly enhanced the HBV-specific T-cell response. Collectively, TLR2 pre-activation enhances HBV-specific T-cell responses and accelerates HBV clearance in HI mouse models. Thus, the modulation of host immune status by TLR2 agonists may be explored for immunotherapeutic strategies to control HBV infection. PMID- 30008719 TI - Interaction of Mannose-Binding Lectin With Lipopolysaccharide Outer Core Region and Its Biological Consequences. AB - Lipopolysaccharide (LPS, endotoxin), the main surface antigen and virulence factor of Gram-negative bacteria, is composed of lipid A, core oligosaccharide, and O-specific polysaccharide (O-PS) regions. Each LPS region is capable of complement activation. We have demonstrated that LPS of Hafnia alvei, an opportunistic human pathogen, reacts strongly with human and murine mannose binding lectins (MBLs). Moreover, MBL-LPS interactions were detected for the majority of other Gram-negative species investigated. H. alvei was used as a model pathogen to investigate the biological consequences of these interactions. The core oligosaccharide region of H. alvei LPS was identified as the main target for human and murine MBL, especially l-glycero-d-manno-heptose (Hep) and N-acetyl d-glucosamine (GlcNAc) residues within the outer core region. MBL-binding motifs of LPS are accessible to MBL on the surface of bacterial cells and LPS aggregates. Generally, the accessibility of outer core structures for interaction with MBL is highest during the lag phase of bacterial growth. The LPS core oligosaccharide-MBL interactions led to complement activation and also induced an anaphylactoid shock in mice. Unlike Klebsiella pneumoniae O3 LPS, robust lectin pathway activation of H. alvei LPS in vivo was mainly the result of outer core recognition by MBL; involvement of the O-PS is not necessary for anaphylactoid shock induction. Our results contribute to a better understanding of MBL-LPS interaction and may support development of therapeutic strategies against sepsis based on complement inhibition. PMID- 30008720 TI - Elevated Expression of Serum Amyloid A 3 Protects Colon Epithelium Against Acute Injury Through TLR2-Dependent Induction of Neutrophil IL-22 Expression in a Mouse Model of Colitis. AB - Induced expression of serum amyloid A (SAA) is a hallmark of many inflammatory diseases, but whether SAA exacerbates inflammation or protects tissues against injury remains unclear. In dextran sulfate sodium (DSS)-induced colitis, SAA3 is the predominant isoform of inducible SAA proteins that also include SAA1 and SAA2, and mice with genetic deletion of Saa3 exhibits increased production of proinflammatory cytokines, decreased expression of IL-22 along with aggravated epithelium disruption, and reduced colon length compared with wild-type littermates. Colonic neutrophils have been identified as a major source of IL-22 in these mice. Administration of exogenous SAA3 as recombinant protein to Saa3-/- mice improves neutrophil IL-22 production, colonic epithelial integrity, and secretion of the antimicrobial peptides Reg3beta and Reg3gamma. Stimulation of mouse bone marrow neutrophils with mouse SAA3 or human SAA1 leads to expansion of IL-22-producing neutrophils. Unlike previously reported IL-22 induction through IL-23, the SAA3-induced neutrophil IL-22 expression utilizes a TLR2-dependent mechanism that does not depend on IL-23. Adoptive transfer of the SAA3-treated neutrophils to Saa3-/- mice ameliorates DSS-induced colitis and improves colonic epithelial integrity. These findings suggest that in the DSS-induced mouse colitis model, SAA isoforms are expressed to different extent in colon and deletion of Saa3 renders these mice more susceptible to DSS-induced injury. The presence of SAA3 in the inflamed colon mucosal serves to protect epithelial barrier in part through expansion of IL-22-producing neutrophils. It is speculated that SAA3 stimulation of autologous neutrophils may have therapeutic potential for inflammatory bowel disease. PMID- 30008721 TI - Immunization With a DNA Vaccine Cocktail Encoding TgPF, TgROP16, TgROP18, TgMIC6, and TgCDPK3 Genes Protects Mice Against Chronic Toxoplasmosis. AB - Toxoplasmosis is a zoonotic disease caused by the intracellular protozoan Toxoplasma gondii; and a major source of infection in humans is via ingestion of T. gondii tissue cysts. Ultimately, the goal of anti-toxoplasmosis vaccines is to elicit a sustainable immune response, capable of preventing formation of the parasite tissue cysts-or, at least, to restrain its growth. In this study, we formulated a cocktail DNA vaccine and investigated its immunologic efficacy as a protection against the establishment of T. gondii cysts in the mouse brain. This multicomponent DNA vaccine, encoded the TgPF, TgROP16, TgROP18, TgMIC6, and TgCDPK3 genes, which play key roles in the pathogenesis of T. gondii infection. Results showed that mice immunized via intramuscular injection three times, at 2 week intervals with this multicomponent DNA vaccine, mounted a strong humoral and cellular immune response, indicated by significantly high levels of total IgG, CD4+ and CD8+ T lymphocytes, and antigen-specific lymphocyte proliferation when compared with non-immunized mice. Immunization also induced a mixed Th1/Th2 response, with a slightly elevated IgG2a to IgG1 ratio. The increased production of proinflammatory cytokines gamma-interferon, interleukin-2, and interleukin-12 (p < 0.0001) correlated with increased expression of p65/RelA and T-bet genes of the NF-kappaB pathway. However, no significant difference was detected in level of interleukin-4 (p > 0.05). The number of brain cysts in immunized mice was significantly less than those in non-immunized mice (643.33 +/- 89.63 versus 3,244.33 +/- 96.42, p < 0.0001), resulting in an 80.22% reduction in the parasite cyst burden. These findings indicate that a multicomponent DNA vaccine, encoding TgPF, TgROP16, TgROP18, TgMIC6, and TgCDPK3 genes, shows promise as an immunization strategy against chronic toxoplasmosis in mice, and calls for a further evaluation in food-producing animals. PMID- 30008723 TI - In Vitro Exposure to Prostratin but Not Bryostatin-1 Improves Natural Killer Cell Functions Including Killing of CD4+ T Cells Harboring Reactivated Human Immunodeficiency Virus. AB - In the attempt of purging the HIV-1 reservoir through the "shock-and-kill" strategy, it is important to select latency-reversing agents (LRAs) devoid of deleterious effects on the antiviral function of immune effector cells. Here, we investigated two LRAs with PKC agonist activity, prostratin (PRO) and bryostatin 1 (BRY), for their impact on the function of natural killer (NK) cells, the major effectors of innate immunity whose potential in HIV-1 eradication has emerged in recent clinical trials. Using NK cells of healthy donors, we found that exposure to either PRO or BRY potently activated NK cells, resulting in upmodulation of NKG2D and NKp44 activating receptors and matrix metalloprotease-mediated shedding of CD16 receptor. Despite PRO and BRY affected NK cell phenotype in the same manner, their impact on NK cell function was diverse and showed considerable donor-to-donor variation. Altogether, in most tested donors, the natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of NK cells were either improved or maintained by PRO, while both activities were impaired by BRY. Moreover, we analyzed the effect of these drugs on the capacity of treated NK cells to kill autologous latently infected CD4+ T cells reactivated via the same treatment. First, we found that PRO but not BRY increased upmodulation of the ULBP2 ligand for NKG2D on reactivated p24+ cells. Importantly, we showed that clearance of reactivated p24+ cells by NK cells was enhanced when both targets and effectors were exposed to PRO but not to BRY. Overall, PRO had a superior potential compared with BRY as to the impact on key NK cell functions and on NK cell-mediated clearance of the HIV-1 reservoir. Our results emphasize the importance of considering the effects on NK cells of candidate "shock-and-kill" interventions. With respect to combinative approaches, the impact on NK cells of each LRA should be re-evaluated upon combination with a second LRA, which may have analogous or opposite effects, or with immunotherapy targeting NK cells. In addition, avoiding co-administration of LRAs that negatively impact ADCC activity by NK cells might be essential for successful application of antibodies or vaccination to "shock-and-kill" strategies. PMID- 30008724 TI - Cis-Effects Condition the Induction of a Major Unfolded Protein Response Factor, ZmbZIP60, in Response to Heat Stress in Maize. AB - Adverse environmental conditions such as heat and salt stress create endoplasmic reticulum (ER) stress in maize and set off the unfolded protein response (UPR). A key feature of the UPR is the upregulation of ZmbZIP60 and the splicing of its messenger RNA. We conducted an association analysis of a recombinant inbred line (RIL) derived from a cross of a tropical founder line, CML52 with a standard temperate line, B73. We found a major QTL conditioning heat-induced ZmbZIP60 expression located cis to the gene. Based on the premise that the QTL might be associated with the ZmbZIP60 promoter, we evaluated various maize inbred lines for their ability to upregulate the expression of ZmbZIP60 in response to heat stress. In general, tropical lines with promoter regions similar to CML52 were more robust in upregulating ZmbZIP60 in response to heat stress. This finding was confirmed by comparing the strength of the B73 and CML52 ZmbZIP60 promoters in transient maize protoplast assays. We concluded that the upstream region of ZmbZIP60 is important in conditioning the response to heat stress and was under selection in maize when adapted to different environments. Summary: Heat stress has large negative effects on maize grain yield. Heat stress creates ER stress in maize and sets off the UPR. We searched for factors conditioning heat induction of the UPR in maize seedlings by conducting an association analysis based on the upregulation of unspliced and spliced forms of ZmbZIP60 mRNA (ZmbZIP60u and ZmbZIP60s, respectively). ZmbZIP60u was upregulated more robustly by heat stress in the tropical maize line, CML52, than in B73, and a major QTL derived from the analysis of RILs from a cross of these two lines mapped in the vicinity of ZmbZIP60. We conducted a cis/trans test to determine whether the QTL was acting as a cis regulatory element or in trans, as might be expected for a transcription factor. We found that the QTL was acting in cis, likely involving the ZmbZIP60 promoter. ZmbZIP60 promoters in other temperate and tropical lines similar to CML52 showed enhanced expression of ZmbZIP60u by heat. The contribution of the CML52 promoter to heat induction of ZmbZIP60 was confirmed by analyzing the CML52 and B73 promoters linked to a luciferase reporter and assayed in heat-treated maize protoplasts. PMID- 30008725 TI - Sex-Dependent Variation of Pumpkin (Cucurbita maxima cv. Big Max) Nectar and Nectaries as Determined by Proteomics and Metabolomics. AB - Nectar is a floral reward that sustains mutualisms with pollinators, which in turn, improves fruit set. While it is known that nectar is a chemically complex solution, extensive identification and quantification of this complexity has been lacking. Cucurbita maxima cv. Big Max, like many cucurbits, is monoecious with separate male and female flowers. Attraction of bees to the flowers through the reward of nectar is essential for reproductive success in this economically valuable crop. In this study, the sex-dependent variation in composition of male and female nectar and the nectaries were defined using a combination of GC-MS based metabolomics and LC-MS/MS based proteomics. Metabolomics analysis of nectar detected 88 metabolites, of which 40 were positively identified, and includes sugars, sugar alcohols, aromatics, diols, organic acids, and amino acids. There are differences in 29 metabolites between male and female nectar. The nectar proteome consists of 45 proteins, of which 70% overlap between nectar types. Only two proteins are unique to female nectar, and 10 are specific to male nectar. The nectary proteome data, accessible at ProteomeXchange with identifier PXD009810, contained 339 identifiable proteins, 71% of which were descriptively annotatable by homology to Plantae. The abundance of 45 proteins differs significantly between male and female nectaries, as determined by iTRAQ labeling. This rich dataset significantly expands the known complexity of nectar composition, supports the hypothesis of H+-driven nectar solute export, and provides genetic and chemical targets to understand plant-pollinator interactions. PMID- 30008722 TI - Interferon-Gamma-Mediated Osteoimmunology. AB - Osteoimmunology is the interdiscipline that focuses on the relationship between the skeletal and immune systems. They are interconnected by shared signal pathways and cytokines. Interferon-gamma (IFN-gamma) plays important roles in immune responses and bone metabolism. IFN-gamma enhances macrophage activation and antigen presentation. It regulates antiviral and antibacterial immunity as well as signal transduction. IFN-gamma can promote osteoblast differentiation and inhibit bone marrow adipocyte formation. IFN-gamma plays dual role in osteoclasts depending on its stage. Furthermore, IFN-gamma is an important pathogenetic factor in some immune-mediated bone diseases including rheumatoid arthritis, postmenopausal osteoporosis, and acquired immunodeficiency syndrome. This review will discuss the contradictory findings of IFN-gamma in osteoimmunology and its clinical application potential. PMID- 30008726 TI - Genome-Wide Identification and Characterization of Four Gene Families Putatively Involved in Cadmium Uptake, Translocation and Sequestration in Mulberry. AB - The zinc-regulated transporters, iron-regulated transporter-like proteins (ZIPs), the natural resistance and macrophage proteins (NRAMP), the heavy metal ATPases (HMAs) and the metal tolerance or transporter proteins (MTPs) families are involved in cadmium (Cd) uptake, translocation and sequestration in plants. Mulberry (Morus L.), one of the most ecologically and economically important (as a food plant for silkworm production) genera of perennial trees, exhibits excellent potential for remediating Cd-contaminated soils. However, there is no detailed information about the genes involved in Cd2+ transport in mulberry. In this study, we identified 31 genes based on a genome-wide analysis of the Morus notabilis genome database. According to bioinformatics analysis, the four transporter gene families in Morus were distributed in each group of the phylogenetic tree, and the gene exon/intron structure and protein motif structure were similar among members of the same group. Subcellular localization software predicted that these transporters were mainly distributed in the plasma membrane and the vacuolar membrane, with members of the same group exhibiting similar subcellular locations. Most of the gene promoters contained abiotic stress related cis-elements. The expression patterns of these genes in different organs were determined, and the patterns identified, allowing the categorization of these genes into four groups. Under low or high-Cd2+ concentrations (30 MUM or 100 MUM, respectively), the transcriptional regulation of the 31 genes in root, stem and leaf tissues of M. alba seedlings differed with regard to tissue and time of peak expression. Heterologous expression of MaNRAMP1, MaHMA3, MaZIP4, and MaIRT1 in Saccharomyces cerevisiae increased the sensitivity of yeast to Cd, suggested that these transporters had Cd transport activity. Subcellular localization experiment showed that the four transporters were localized to the plasma membrane of yeast and tobacco. These results provide the basis for further understanding of the Cd tolerance mechanism in Morus, which can be exploited in Cd phytoremediation. PMID- 30008728 TI - Highly Disturbed Populations of Seagrass Show Increased Resilience but Lower Genotypic Diversity. AB - The response of seagrass systems to a severe disturbance provides an opportunity to quantify the degree of resilience in different meadows, and subsequently to test whether there is a genetic basis to resilience. We used existing data on levels of long-standing disturbance from poor water quality, and the responses of seagrass (Zostera muelleri) after an extreme flood event in Moreton Bay, Queensland, Australia. Sites were grouped into high and low disturbance categories, in which seagrass showed high and low resilience, respectively, as determined by measuring rates of key feedback processes (nutrient removal, suppression of sediment resuspension, and algal grazing), and physiological and morphological traits. Theoretically, meadows with higher genotypic diversity would be expected to have greater resilience. However, because the more resilient meadows occur in areas historically exposed to high disturbance, the alternative is also possible, that selection will have resulted in a narrower, less diverse subset of genotypes than in less disturbed meadows. Levels of genotypic and genetic diversity (allelic richness) based on 11 microsatellite loci, were positively related (R2 = 0.58). Genotypic diversity was significantly lower at highly disturbed sites (R = 0.49) than at less disturbed sites (R = 0.61). Genotypic diversity also showed a negative trend with two morphological characteristics known to confer resilience on seagrass in Moreton Bay, leaf chlorophyll concentrations and seagrass biomass. Genetic diversity did not differ between disturbed and undisturbed sites. We postulate that the explanation for these results is historical selection for genotypes that confer protection against disturbance, reducing diversity in meadows that contemporarily show greater resilience. PMID- 30008727 TI - Effect of Ppd-A1 and Ppd-B1 Allelic Variants on Grain Number and Thousand Kernel Weight of Durum Wheat and Their Impact on Final Grain Yield. AB - The main yield components in durum wheat are grain number per unit area (GN) and thousand kernel weight (TKW), both of which are affected by environmental conditions. The most critical developmental stage for their determination is flowering time, which partly depends on photoperiod sensitivity genes at Ppd-1 loci. Fifteen field experiments, involving 23 spring durum wheat genotypes containing all known allelic variants at the PHOTOPERIOD RESPONSE LOCUS (Ppd-A1 and Ppd-B1) were carried out at three sites at latitudes ranging from 41 degrees to 27 degrees N (Spain, Mexico-north, and Mexico-south, the latter in spring planting). Allele GS100 at Ppd-A1, which causes photoperiod insensitivity and results in early-flowering genotypes, tended to increase TKW and yield, albeit not substantially. Allele Ppd-B1a, also causing photoperiod insensitivity, did not affect flowering time or grain yield. Genotypes carrying the Ppd-B1b allele conferring photoperiod sensitivity had consistently higher GN, which did not translate into higher yield due to under-compensation in TKW. This increased GN was due to a greater number of grains spike-1 as a result of a higher number of spikelets spike-1. Daylength from double ridge to terminal spikelet stage was strongly and positively associated with the number of spikelets spike-1 in Spain. This association was not found in the Mexico sites, thereby indicating that Ppd B1b had an intrinsic effect on spikelets spike-1 independently of environmental cues. Our results suggest that, in environments where yield is limited by the incapacity to produce a high GN, selecting for Ppd-B1b may be advisable. PMID- 30008731 TI - Editorial: Protein Quality Controlling Systems in Plant Responses to Environmental Stresses. PMID- 30008729 TI - Arbuscular Mycorrhizal Symbiosis as a Promising Resource for Improving Berry Quality in Grapevines Under Changing Environments. AB - Climate change and their resulting impacts are becoming a concern for winegrowers due to the high socioeconomic relevance of the winemaking sector worldwide. In fact, the projected climate change is expected to have detrimental impacts on the yield of grapevines, as well as on the quality and properties of grapes and wine. It is well known that arbuscular mycorrhizal fungi (AMF) can improve the nutritional quality of edible parts of crops and play essential roles in the maintenance of host plant fitness under stressed environments, including grapevines. The future scenarios of climate change may also modify the diversity and the growth of AMF in soils as well as the functionality of the mycorrhizal symbiosis. In this review, we summarize recent research progress on the effects of climate change on grapevine metabolism, paying special attention to the secondary compounds involved in the organoleptic properties of grapes and wines and to the levels of the phytohormones implied in the control of berry development and fruit ripening. In this context, the potential role of AMF for maintaining fruit quality in future climate change scenarios is discussed. PMID- 30008732 TI - Corrigendum: Physcomitrella Patens Dehydrins (PpDHNA and PpDHNC) Confer Salinity and Drought Tolerance to Transgenic Arabidopsis Plants. AB - [This corrects the article on p. 1316 in vol. 8, PMID: 28798765.]. PMID- 30008730 TI - Functional Microbial Features Driving Community Assembly During Seed Germination and Emergence. AB - Microbial interactions occurring on and around seeds are especially important for plant fitness since seed-borne microorganisms are the initial source of inoculum for the plant microbiota. In this study, we analyze structural and functional changes occurring within the plant microbiota at these early stages of the plant cycle, namely germination and emergence. To this purpose, we performed shotgun DNA sequencing of microbial assemblages associated to seeds, germinating seeds and seedlings of two plant species: bean and radish. We observed an enrichment of Enterobacteriales and Pseudomonadales during emergence and a set of functional traits linked to copiotrophy that could be responsible for this selection as a result of an increase of nutrient availability after germination. Representative bacterial isolates of taxa that are selected in seedlings showed indeed faster bacterial growth rate in comparison to seed-associated bacteria isolates. Finally, binning of metagenomics contigs results in the reconstruction of population genomes of the major bacterial taxa associated to the samples. Together, our results demonstrate that, although seed microbiota varied across plant species, nutrient availability during germination elicits changes of the composition of microbial communities by potentially selecting microbial groups with functional traits linked to copiotrophy. The data presented here represents the first attempts to empirically assess changes in the microbial community during plant emergence and moves us toward a more holistic understanding of the plant microbiome. PMID- 30008734 TI - Fast-Growing Engineered Microbes: New Concerns for Gain-of-Function Research? AB - Research on fast-growing microbes holds promise for many industrial applications, including shortening test and trial times in research and development stages and reducing the operation costs for production. Such microbes can be obtained either by selecting naturally occurring variants or via metabolic engineering approaches, either eliminating 'unnecessary' or adding necessary pathways affecting growth speed in the cell. Here, we review recent research and development of engineered fast-growing strains in industrial biotechology, with a special focus on vaccine production using (synthetic biology) engineered pathogenic strains. We will discuss whether this represents a security concern and whether the industrial biotech sector needs to pay more attention to issues of Gain-of-Function (GoF) while developing and harnessing these fast-growing microbes. We will also shed a light on the use of in-built biosafety circuits as a way to control the propagation of fast-growing strains, including their capacity to survive in the environment. Other possible GoF concerns raised by the publication of research results in this field will be also addressed. In conclusion, judging from the current development from the field, assessing the potential GoF risks on engineered fast-growing microbes does not lead to a clear generalized outcome. We argue that fast growing strains need to be evaluated in combination with their wild type and engineered characteristics, and require always a case-by-case assessment. Monitoring the progress of the field and proactively raising awareness on the GoF issues among the scientists are important for the further development of the field. PMID- 30008735 TI - Tree Wave Migration Across an Elevation Gradient in the Altai Mountains, Siberia. AB - The phenomenon of "tree waves" (hedges and ribbons) formation within the alpine ecotone in Altai Mountains and its response to observed air temperature increase was considered. At the upper limit of tree growth Siberian pine (Pinus sibirica) forms hedges on windward slopes and ribbons on the leeward ones. Hedges were formed by prevailing winds and oriented along winds direction. Ribbons were formed by snow blowing and accumulating on the leeward slope and perpendicular to the prevailing winds, as well as to the elevation gradient. Hedges were always linked with microtopography features, whereas ribbons were not. Trees are migrating upward by waves and new ribbons and hedges are forming at or near tree line, whereas at lower elevations ribbons and hedges are being transformed into closed forests. Time series of high-resolution satellite scenes (from 1968 to 2010) indicated an upslope shift in the position ribbons averaged 155+/-26 m (or 3.7 m yr-1) and crown closure increased (about 35-90%). The hedges advance was limited by poor regeneration establishment and was negligible. Regeneration within the "ribbon zone" was approximately 2.5 times (5060 vs 2120 ha-1) higher then within the "hedges zone". During the last four decades, Siberian pine in both hedges and ribbons strongly increased its growth increment and recent tree growth rate for 50 year old trees was about twice higher than recorded for similarly aged trees at the beginning of the 20th century. Hedges and ribbons are phenomena that are widespread within the southern and northern Siberian Mountains. PMID- 30008736 TI - Nonlinear response of tropical lower stratospheric temperature and water vapor to ENSO. AB - A series of simulations using the NASA Goddard Earth Observing System Chemistry Climate Model are analyzed in order to assess interannual and sub-decadal variability in the tropical lower stratosphere over the past 35 years. The impact of El Nino-Southern Oscillation on temperature and water vapor in this region is nonlinear in boreal spring. While moderate El Nino events lead to cooling in this region, strong El Nino events lead to warming, even as the response of the large scale Brewer Dobson Circulation appears to scale nearly linearly with El Nino. This nonlinearity is shown to arise from the response in the Indo-West Pacific to El Nino: strong El Nino events lead to tropospheric warming extending into the tropical tropopause layer and up to the cold point in this region, where it allows for more water vapor to enter the stratosphere. The net effect is that both strong La Nina and strong El Nino events lead to enhanced entry water vapor and stratospheric moistening in boreal spring and early summer. These results lead to the following interpretation of the contribution of sea surface temperatures to the decline in water vapor from the late 1990s to the early 2000s: the very strong El Nino event in 1997/1998, followed by more than two consecutive years of La Nina, led to enhanced lower stratospheric water vapor. As this period ended in early 2001, entry water vapor concentrations declined. This effect accounts for approximately one-quarter of the observed drop. PMID- 30008737 TI - An extension of the RiMAX multipath estimation algorithm for ultra-wideband channel modeling. AB - This work presents an extension of the high-resolution RiMAX multipath estimation algorithm, enabling the analysis of frequency-dependent propagation parameters for ultra-wideband (UWB) channel modeling. Since RiMAX is a narrowband algorithm, it does not account for the frequency-dependency of the radio channel or the environment. As such, the impact of certain materials in which these systems operate can no longer be considered constant with respect to frequency, preventing an accurate estimation of multipath parameters for UWB communication. In order to track both the specular and dense multipath components (SMC and DMC) over frequency, an extension to the RiMAX algorithm was developed that can process UWB measurement data. The advantage of our approach is that geometrical propagation parameters do not appear or disappear from one sub-band onto the next. The UWB-RiMAX algorithm makes it possible to re-evaluate common radio channel parameters for DMC in the wideband scenario, and to extend the well-known deterministic propagation model comprising of SMC alone, towards a more hybrid model containing the stochastic contributions from the DMC's distributed diffuse scattering as well. Our algorithm was tested with synthetic radio channel models in an indoor environment, which show that our algorithm can match up to 99% of the SMC parameters according to the multipath component distance (MCD) metric and that the DMC reverberation time known from the theory of room electromagnetics can be estimated on average with an error margin of less than 2 ns throughout the UWB frequency band. We also present some preliminary results in an indoor environment, which indicate a strong presence of DMC and thus diffuse scattering. The DMC power represents up to 50% of the total measured power for the lower UWB frequencies and reduces to around 30% for the higher UWB frequencies. PMID- 30008733 TI - Applications of New Breeding Technologies for Potato Improvement. AB - The first decade of genetic engineering primarily focused on quantitative crop improvement. With the advances in technology, the focus of agricultural biotechnology has shifted toward both quantitative and qualitative crop improvement, to deal with the challenges of food security and nutrition. Potato (Solanum tuberosum L.) is a solanaceous food crop having potential to feed the populating world. It can provide more carbohydrates, proteins, minerals, and vitamins per unit area of land as compared to other potential food crops, and is the major staple food in many developing countries. These aspects have driven the scientific attention to engineer potato for nutrition improvement, keeping the yield unaffected. Several studies have shown the improved nutritional value of potato tubers, for example by enhancing Amaranth Albumin-1 seed protein content, vitamin C content, beta-carotene level, triacylglycerol, tuber methionine content, and amylose content, etc. Removal of anti-nutritional compounds like steroidal glycoalkaloids, acrylamide and food toxins is another research priority for scientists and breeders to improve potato tuber quality. Trait improvement using genetic engineering mostly involved the generation of transgenic products. The commercialization of these engineered products has been a challenge due to consumer preference and regulatory/ethical restrictions. In this context, new breeding technolgies like TALEN (transcription activator-like effector nucleases) and CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR associated 9) have been employed to generate transgene-free products in a more precise, prompt and effective way. Moreover, the availability of potato genome sequence and efficient potato transformation systems have remarkably facilitated potato genetic engineering. Here we summarize the potato trait improvement and potential application of new breeding technologies (NBTs) to genetically improve the overall agronomic profile of potato. PMID- 30008738 TI - Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice. AB - Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid beta-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARgamma and phosphorylated PPARgamma at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARalpha and diminished levels of PPARgamma phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARalpha and posttranslational modification of PPARgamma in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD. PMID- 30008739 TI - An Approach to Linguistic Multiple Attribute Decision-Making Based on Unbalanced Linguistic Generalized Heronian Mean Aggregation Operator. AB - This paper proposes an approach to linguistic multiple attribute decision-making problems with interactive unbalanced linguistic assessment information by unbalanced linguistic generalized Heronian mean aggregation operators. First, some generalized Heronian mean aggregation operators with unbalanced linguistic information are proposed, involving the unbalanced linguistic generalized arithmetic Heronian mean operator and the unbalanced linguistic generalized geometric Heronian mean operator. For the situation that the input arguments have different degrees of importance, the unbalanced linguistic generalized weighted arithmetic Heronian mean operator and the unbalanced linguistic generalized weighted geometric Heronian mean operator are developed. Then we investigate their properties and some particular cases. Finally, the effectiveness and universality of the developed approach are illustrated by a low-carbon tourist instance and comparison analysis. A sensitivity analysis is performed as well to test the robustness of proposed methods. PMID- 30008740 TI - String Grammar Unsupervised Possibilistic Fuzzy C-Medians for Gait Pattern Classification in Patients with Neurodegenerative Diseases. AB - Neurodegenerative diseases that affect serious gait abnormalities include Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington disease (HD). These diseases lead to gait rhythm distortion that can be determined by stride time interval of footfall contact times. In this paper, we present a new method for gait classification of neurodegenerative diseases. In particular, we utilize a symbolic aggregate approximation algorithm to convert left-foot stride-stride interval into a sequence of symbols using a symbolic aggregate approximation. We then find string prototypes of each class using the newly proposed string grammar unsupervised possibilistic fuzzy C-medians. Then in the testing process the fuzzy k-nearest neighbor is used. We implement the system on three 2-class problems, i.e., the classification of ALS against healthy patients, that of HD against healthy patients , and that of PD against healthy patients. The system is also implemented on one 4-class problem (the classification of ALS, HD, PD, and healthy patients altogether) called NDDs versus healthy. We found that our system yields a very good detection result. The average correct classification for ALS versus healthy is 96.88%, and that for HD versus healthy is 97.22%, whereas that for PD versus healthy is 96.43%. When the system is implemented on 4-class problem, the average accuracy is approximately 98.44%. It can provide prototypes of gait signals that are more understandable to human. PMID- 30008742 TI - Impact of Global Mean Normalization on Regional Glucose Metabolism in the Human Brain. AB - Because the human brain consumes a disproportionate fraction of the resting body's energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease. PMID- 30008741 TI - Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System. AB - Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress changes LC neuronal physiology, function, and morphology from a genetic, cellular, and neuronal circuitry/transmission perspective. Specifically, we describe morphological changes of LC neurons in response to stressful stimuli and signal transduction pathways underlying them. Also, we will review changes in excitatory glutamatergic synaptic transmission in LC neurons and possible stress-induced modifications of AMPA receptors. This review will also address stress-related behavioral adaptations and specific noradrenergic receptors responsible for them. Finally, we summarize the results of several human studies which suggest a link between stress, altered LC function, and pathogenesis of posttraumatic stress disorder. PMID- 30008743 TI - The Role of Autoimmunity in the Pathogenesis of Sudden Sensorineural Hearing Loss. AB - Sudden sensorineural hearing loss (SSHL) is a clinically common acute symptom in otolaryngology. Although the incidence of SSHL has increased around the world in recent years, the etiology of the disease is still unclear. It has been reported that infections, ototoxic drugs, membrane labyrinth rupture, carcinomas, circulatory system diseases, autoimmune diseases, brain lesions, mental diseases, congenital or inherited diseases, and so on, are all risk factors for SSHL. Here, we discuss the autoimmune mechanisms behind SSHL, which might be induced by type II-IV allergic reactions. We also introduce the main immunosuppressive medications that have been used to treat SSHL, which will help us to identify potential targets for immune therapy. PMID- 30008745 TI - Diagnosis of Superficial Gastric Lesions Together with Six Gastric Lymphoma Cases via Probe-Based Confocal Laser Endomicroscopy: A Retrospective Observational Study. AB - Objective: To evaluate the performance of probe-based confocal laser endomicroscopy (pCLE) in diagnosis of gastric lesions. Methods: An outpatient department- (OPD-) based retrospective study was conducted for patients with suspected upper gastrointestinal (GI) tract lesions who underwent pCLE between 2014 and 2016 at a tertiary hospital in China. Final diagnosis was based on the histopathological reports. CLE reports were compared to histopathological reports to evaluate the diagnostic ability, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy. Results: 322 of 380 patients were diagnosed with gastric lesions via pCLE, including inflammation and benign ulcers (n = 110), atrophy and intestinal metaplasia (n = 152), intraepithelial neoplasia (n = 27), adenocarcinoma (n = 27), and lymphoma (n = 6). In total, the diagnostic ability of CLE in evaluation of gastric lesions showed sensitivity 72.4% (95% confidence interval (CI): 67.1 77.2%); specificity 93.1% (95% CI: 5.6-8.4%); PPV 72.4% (95% CI: 67.1-77.2%); NPV 93.1% (95% CI: 5.6-8.4%); and accuracy 88.9% (95% CI: 87.3-90.4%), respectively. We further observed the capability of pCLE in diagnosing six gastric lymphoma showing those affected mucosa densely infiltrated with identical and round-shaped abnormal cells. Immunohistochemistry analysis confirmed one patient with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) and five with mucosa-associated lymphoid tissue (MALT) lymphoma. Conclusion: pCLE is an accurate tool for the detection of gastric lesions and shows optimal values of sensitivity and negative predictivity. Moreover, combining pCLE with white light endoscopy (WLE) may be a promising adjunct to conventional biopsy sampling in evaluating GI tract with suspected lymphoma. PMID- 30008747 TI - Improvement of Physicomechanical Properties of Pineapple Leaf Fiber Reinforced Composite. AB - Pineapple leaf fiber (PALF) reinforced polypropylene (PP) composites were prepared by compression molding. The fiber content varied from 25% to 45% by weight. Water uptake percentages of the composites containing various wt% of fiber were measured. All the composites demonstrated lower water uptake percentages and maximum of 1.93% for 45 wt% PALF/PP composite treated with 7(w/v)% NaOH. Tensile Strength (TS), Tensile Modulus (TM), Elongation at Break (Eb %), Bending Strength (BS), Bending Modulus (BM), and Impact Strength (IS) were evaluated for various fiber content. The 45 wt% PALF/PP composite exhibited an increase of 210% TS, 412% TM, 155% BS, 265% BM, and 140% IS compared to PP matrix. Moreover, with the increasing of fiber content, all the mechanical properties increase significantly; for example, 45 wt% fiber loading exhibited the best mechanical property. Fibers were also treated with different concentration of NaOH and the effects of alkali concentrations were observed. The composite treated with 7 (w/v)% NaOH exhibited an increase of 25.35% TS, 43.45% TM, 15.78% BS, and 52% BM but 23.11% decrease of IS compared to untreated composite. Alkali treatment improved the adhesive characteristics of fiber surface by removing natural impurities, hence improving the mechanical properties. However, over 7% NaOH concentration of the tensile strength of the composite reduced slightly due to overexposure of fibers to NaOH. PMID- 30008746 TI - Reaching 100 in the Countryside: Health Profile and Living Circumstances of Portuguese Centenarians from the Beira Interior Region. AB - The interest in studying a specific population of centenarians who lives in the country's interior region (PT100-BI) emerged during the first Portuguese systematic study about centenarians (PT100 Oporto Centenarian Study). This region of Portugal is predominantly rural and is one of the regions with the largest number of aged people. The aim of this study is to provide information on the centenarians who live in the Beira Interior region, specifically in terms of their health status and the health services they use. A total of 101 centenarians (mean age: 101.1 years; SD = 1.5 years), 14 males and 87 females, were considered. Most centenarians lived in the community, and 47.6% lived in nursing homes. Nearly half (47.5%) presented cognitive functioning without deficits. A noteworthy percentage presented conditioned mobility and sensory problems. The most common self-reported diseases include urinary incontinence (31.7%), high blood pressure (23.8%), and heart conditions (19.8%). Despite these health and functional characteristics, formal support services and technical assistance were found to be scarcely used. Further research is needed to understand how the role of contextual variables and the countryside environment contribute to the centenarians' adaptation to advanced longevity. PMID- 30008748 TI - Modification of Medium Composition for Enhancing the Production of Antifungal Activity from Xenorhabdus stockiae PB09 by Using Response Surface Methodology. AB - Xenorhabdus stockiae PB09 bacterium has been shown to exhibit antifungal activity against several plant pathogens. To improve its efficacy, the optimization of the nutritional components in culture media was performed. The medium components that have significant effects on antifungal activity of X. stockiae PB09 were initially identified using a fractional factorial design. Response surface methodology and central composite design were then used to create a model for optimizing the levels of carbon, nitrogen, and mineral sources that maximize antifungal activity of X. stockiae PB09. After that, the suitable carbon, nitrogen, and mineral sources were selected and adjusted by the second-order polynomial regression model, which predicted that 98.62% of antifungal activity could be obtained when the medium contained sucrose, yeast extract, NaCl, and K2HPO4 at 3.24, 23.71, 5.46, and 2.73 g/L, respectively. Laboratory verification of this recipe resulted in the antifungal activity at 97.95% in the shake flask experiment after 48-hour cultivation, which was significantly 27.22% higher than that obtained by using the TSB medium. In addition, X. stockiae PB09 cultured in the verified recipe by using 5 L fermenter could effectively inhibit the mycelial growth of Phytophthora sp., Rhizoctonia solani, Pythium sp., and Fusarium oxysporum. This study demonstrated that the RSM and CCD were shown to be valuable tools for optimizing the culture medium that maximize the antifungal activity of X. stockiae PB09. PMID- 30008749 TI - A Rapidly Fatal Case of Low-Dose Methotrexate Toxicity. AB - An 82-year-old female presented with multiple oral ulcers and malena for 1 week. Her laboratory tests revealed pancytopenia and acute renal failure. She had history of rheumatoid arthritis for which she was taking 7.5 mg methotrexate weekly and stage 4 chronic kidney disease from diabetic nephropathy. During the hospital stay, she developed pneumonia and septic shock requiring norepinephrine and vasopressin. She underwent continuous venovenous hemodiafiltration. Leucovorin, filgrastim, and multiple packed red blood cell and platelet transfusions were given. She remained hypotensive and pancytopenic despite all interventions. She died on day 6 of hospital stay from acute hypoxic respiratory failure due to septic shock. PMID- 30008750 TI - Atypical Presentation of IgA Nephropathy Mimicking Acute Pyelonephritis. AB - Background: IgA glomerulonephritis may present with hematuria, flank pain, and fever. This clinical presentation may be easily confused with acute pyelonephritis. Case Report: We present the case of a 25-year-old female with a typical clinical presentation for acute pyelonephritis (high fever, left flank pain, left costovertebral angle tenderness, hematuria, elevated inflammatory markers, and a hypoenhancing region in the left kidney on contrast-enhanced computed tomography). However, urine and blood cultures were both negative, the serum creatinine was elevated, and the urinalysis revealed significant proteinuria and dysmorphic red blood cells. A kidney biopsy confirmed a diagnosis of IgA nephropathy. She was treated with a combination of lisinopril and methylprednisolone, with good response. Conclusion: Gross hematuria, especially in the absence of pyuria or bacteriuria, should raise the suspicion for underlying IgA nephropathy, even if the rest of the clinical presentation is typical for a urinary tract infection. The presence of significant proteinuria, red blood cell casts, and dysmorphic red blood cells are useful clues suggesting glomerular disease. PMID- 30008744 TI - Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives. AB - Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC. PMID- 30008751 TI - Use of Self-Assembling Peptides to Enhance Stem Cell Function for Therapeutic Angiogenesis. AB - The use of nanomaterials for biomedical applications has become a promising field in regenerative medicine. Self-assembling peptides (SAPs) have been proposed as a good candidate because they are able to self-assemble into stable hydrogels and interact with cells or molecules when combined together. This in turn can lead to the improved survival or action of cells or molecules to obtain the desired effects. In this study, we investigated whether the combination of mesenchymal stem cells (MSCs) with SAPs could improve angiogenesis in ischemic hindlimbs of rats compared to MSC or SAP treatment alone. The combination of MSCs and SAPs showed an overall higher expression of angiogenesis markers on fluorescent immunohistochemical analysis and a lower degree of fibrosis and cell apoptosis, which in turn led to an overall tendency for improved perfusion of the ischemic hindlimbs. Finally, SAPs also showed the ability to recruit endogenous host MSCs into the site of action, especially when modified to incorporate substance P as a functional motif, which when injected with exogenous MSCs, allowed for the dual presence of MSCs at the site of action. Overall, these results suggest that SAPs can be applied with stem cells to potentiate angiogenesis, with potential therapeutic application in vascular diseases. PMID- 30008752 TI - Generation of Retinal Organoids with Mature Rods and Cones from Urine-Derived Human Induced Pluripotent Stem Cells. AB - Urine cells, a body trash, have been successfully reprogrammed into human induced pluripotent stem cells (U-hiPSCs) which hold a huge promise in regenerative medicine. However, it is unknown whether or to what extent U-hiPSCs can generate retinal cells so far. With a modified retinal differentiation protocol without addition of retinoic acid (RA), our study revealed that U-hiPSCs were able to differentiate towards retinal fates and form 3D retinal organoids containing laminated neural retina with all retinal cell types located in proper layer as in vivo. More importantly, U-hiPSCs generated highly mature photoreceptors with all subtypes, even red/green cone-rich photoreceptors. Our data indicated that a supplement of RA to culture medium was not necessary for maturation and specification of U-hiPSC-derived photoreceptors at least in the niche of retinal organoids. The success of retinal differentiation with U-hiPSCs provides many opportunities in cell therapy, disease modeling, and drug screening, especially in personalized medicine of retinal diseases since urine cells can be noninvasively collected from patients and their relatives. PMID- 30008753 TI - Therapeutic Use of Extraembryonic-Derived Tissues. PMID- 30008754 TI - LAMP3 plays an oncogenic role in osteosarcoma cells partially by inhibiting TP53. AB - Background: Osteosarcoma (OS) is a common malignant tumor that predominantly occurs in adolescents. Its most common metastasis is to the lungs. As shown in our earlier study, lysosome-associated membrane glycoprotein 3 (LAMP3) is highly upregulated in metastatic OS. However, its role in the regulation of OS cell viability and apoptosis remains unknown. Methods: We knocked down and overexpressed LAMP3 in OS cells and assessed the cell viability and apoptosis. Then, we investigated the expression of apoptosis-associated genes to identify the downstream gene(s) of LAMP3. Results: Knockdown of LAMP3 significantly inhibited OS cell viability and promoted apoptosis. TP53, which is involved in the apoptosis pathway, was found to be highly upregulated after knockdown of LAMP3. Overexpression of LAMP3 significantly increased cell viability and abrogated apoptosis. Importantly, subsequent knockdown of TP53 partially suppressed the increased OS cell apoptosis induced by the inhibition of LAMP3, suggesting that TP53 is a key functional downstream gene of LAMP3. Conclusions: Our findings suggest that LAMP3 promotes OS cell viability and survival by regulating TP53 expression. PMID- 30008756 TI - Identifying Factors Associated with Functional Limitation Among Diabetic Patients in Northwest of Iran: Application of the Generalized Additive Model. AB - Background: Functional limitation is one of the most important health - related concerns of diabetic patients. This study aimed to identify the factors associated with functional limitation among diabetic patients using generalized additive model (GAM) as a flexible technique to reveal the non - linear and non - monotonic association between the response and a set of independent variables. Methods: The source data belonged to two cross - sectional studies conducted in 2014. A total of 694 people with type 2 diabetes in the age range of 31 - 70 years were selected via convenience sampling from diabetes clinics in Ardabil and Tabriz. The data were collected by interviewers using structured questionnaires and checklists. The functional capacity was measured using the physical functioning subscale of the Medical Outcomes Study Short Form 36 - Item Health Survey (SF36). Participants with a total functional capacity of less than 90 were considered to have "moderate or high level of functional limitation." To identify the factors associated with functional limitation and reveal the shape of associations, the GAM procedure with "logit" link function was applied to the dataset of 378 diabetic patients without any missing data by smoothening of the effect of underlying factors. The Akaike information criterion (AIC) as the relative quality of the model's criterion was computed for GAM and compared with AIC of the simple logistic regression. Results: Sex (P = 0.029), age (P < 0.001), BMI (P = 0.029), and SBP (P = 0.04) were significant in the GAM. Moreover, age with a linear function (df = 0.98), BMI with quadratic function (df = 1.75), and SBP with the degree 1.33 were significantly related to functional capacity. AIC of the GAM was lower than that of the logistic model. Conclusions: In our sample, GAM could identify some linear and nonlinear associations between underlying factors and functional limitation in diabetic patients. These complex associations could relatively increase the fit quality of the GAM when compared to logistic regression. PMID- 30008755 TI - The Polycystic Ovary Syndrome Health-Related Quality-of-Life Questionnaire: Confirmatory Factor Analysis. AB - Background: The health related quality-of-life (HRQoL) among females with polycystic ovary syndrome (PCOS) is reduced due to emotional, psychosocial, infertility, marital, and hirsutism problems. Objectives: The current study aimed at analyzing exploratory and confirmatory factor structures of HRQoL questionnaire for polycystic ovary syndrome (PCOSQ-50) in females with PCOS in order to verify the validity of the developed instrument. Methods: The current cross validation study was conducted on females with PCOS using the PCOSQ-50. The PCOSQ-50 was developed based on a qualitative study. The exploratory factor analysis (EFA) and the confirmatory factor analysis (CFA) were conducted to examine the factor structure of PCOSQ-50. After the CFA, the reliability of the new instrument was also evaluated using Cronbach's alpha coefficient. Results: Totally, 350 females with PCOS were entered into the study. The mean age of the subjects was 26.9 +/- 5.1 years. Based on the results of CFA, data were fit to the 43-item model: the comparative fit index (CFI) = 0.91; the normal fit index (NFI) = 0.90; the goodness of fit index (GFI) = 0.60; incremental fit index (IFI) = 0.91; the root mean square error of approximation (RMSEA) = 0.09; standardized root mean square residual (SRMR) = 0.09 and the relative chi-square (x2/df) = 2.20, P < 0.05. The intraclass correlation coefficient ranged 0.91 to 0.94 indicating a satisfactory finding. Conclusion: The 43-item PCOSQ showed appropriate validity and reliability and its psychometric quality was superior to that of the original version. However, further longitudinal studies should be conducted to evaluate its predictive efficacy. PMID- 30008757 TI - Factor Analysis of Metabolic Syndrome Components in an Iranian Non-Diabetic Adult Population: A Population-Based Study from the North of Iran. AB - Objectives: The aim of this study was to explore the underlying latent factors that can explain the observed variation of components of metabolic syndrome (MetS) in Iranian non-diabetic adult population. Methods: The researchers performed an exploratory factor analysis (EFA) of metabolic syndrome components, including body mass index (BMI), waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), triglyceride (TG), high density lipoprotein (HDL), and Fasting blood sugar (FBS). These observed variables were measured from a representative sample of 841 non-diabetic participants in a cross-sectional population-based study of adults aged 20 to 70 years in the North of Iran. Results: Three factors were extracted by EFA in both genders. In males, the 3 generated factors were, 1) blood pressure factor underlying systolic and diastolic blood pressure, 2) obesity factor manifested by BMI and WC, 3) lipid/glucose factor underlying TG, HDL and FBS that explained 23.9%, 23.0% and 18.4% of variance in the observed data, respectively, in males. However, in females, BMI and WC were revealed as obesity factors, and systolic and diastolic blood pressure were characterized as hypertension factor, and TG, HDL and FBS appeared to be loaded on lipid/glucose factor, similar to males, and designated 25.6%, 25.4%, and 15.8% of the variance, respectively. Triglyceride and FBS were positively loaded, whereas HDL was loaded negatively with similar loading pattern in both genders. Overall, these 3 underlying latent factors explained 65.3% of the variance of observed clinical data sets in males and 66.8% in females. When TG and HDL were replaced by TG to HDL ratio and also SBP and DBP by mean arterial pressure (MAP), the two-factor model was generated in both genders. Conclusions: The 2-and 3-factor models were characterized indicating a single pathogenesis that could not explain the unified clustering of MetS in non-diabetic adults. PMID- 30008758 TI - The Association Between Empirical Dietary Inflammatory Pattern and Metabolic Phenotypes in Overweight/Obese Adults. AB - Objectives: The study aimed to investigate whether diet-induced inflammation assessed by Empirical Dietary Inflammatory Pattern (EDIP) is associated with odds of unhealthy metabolic phenotype and components of metabolic syndrome (MetS). Methods: This cross-sectional study included 403 overweight/obese individuals recruited from employees of two pharmaceutical companies in Iran. The weighted intake of 15 food groups was summed to construct EDIP and metabolic phenotypes were defined based on MetS criteria. Results: After adjusting for age, sex, BMI, and marital status, the odds of unhealthy phenotype increased significantly from quartile 1 to quartile 4 (P-trend = 0.013). However, the association became non significant after adjusting for energy intake. Compared to those in the lowest quartile, individuals with higher EDIP scores had higher odds of high fasting blood sugar (FBS) (P-trend = 0.031) and low HDL-C (P-trend = 0.036) after adjusting for all covariates. By adding energy intake into the model, an inverse association was observed between EDIP, waist circumference (WC), and odds of high WC. Conclusions: A higher pro-inflammatory diet was associated with higher odds of unhealthy phenotype, high FBS, and low-HDL-C in overweight/obese individuals. However, the association with unhealthy phenotype seems to be dependent on the energy intake. PMID- 30008759 TI - Contractions in the Isolated Uterus of a Rat Model of Polycystic Ovary Syndrome Compared to Controls in Adulthood. AB - Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women during the reproductive age. Considering disorders reported in women with PCOS, e.g. infertility, pregnancy complications (premature delivery, caesarean section and spontaneous miscarriages), and hormonal disorders, we hypothesized that uterine contractions in PCOS rats may be different from controls. We aimed to compare uterine contractions in PCOS rats with controls. Methods: Rats in the experimental group were subcutaneously injected with 5 mg of free testosterone on gestational day 20, while controls received solvent. The contractions of isolated uterus in offspring of both groups were recorded by the power lab system, after exposure to carbachol and oxytocin. Two-way analysis of variance was used to compare results between 2 groups. Results: PCOS rats showed more irregular uterine contractions compared to controls. After exposure to carbachol, frequency, and resting tone in the PCOS rats were significantly increased compared to controls (P = 0.004, P = 0.02, respectively). After exposure to oxytocin, the frequency, resting tone and amplitude of rhythmic contractions did not differ between the 2 groups. Conclusions: Our study indicates irregular uterine contractions and different mechanical responses of isolated uterus in PCOS rats compared to controls. PMID- 30008761 TI - Severely calcified coronary stenoses: novel challenges, old remedy. PMID- 30008760 TI - Insulin Monotherapy Versus Insulin Combined with Other Glucose-Lowering Agents in Type 2 Diabetes: A Narrative Review. AB - Context: Insulin can be prescribed as a monotherapy or a combined therapy with other anti-diabetic medications. In this narrative review, the authors aimed to gather data related to comparison of insulin monotherapy versus combination of insulin and other anti-diabetic treatments with regards to different outcome measures in type 2 diabetes. Evidence Acquisition: This study searched and focused on the most recently published systematic reviews and their references investigating issues related to the primary aim. Results: The current data available on this topic is heterogeneous and suffers from low quality with respect to most combination treatments. Considering the efficacy and safety of combination therapy of insulin with older hypoglycemic agents, in general metformin and pioglitazone have the best and worst profiles, respectively. Compared to insulin monotherapy, combination of insulin and metformin is associated with better glycemic control, reduced daily insulin dose, less hypoglycemia, and weight gain; combination of insulin and pioglitazone results in greater hypoglycemia and weight gain and is associated with increased risk of edema and heart failure. Regarding sulphonylurea, there is some concern regarding hypoglycemia and weight gain. Addition of dipeptidyl peptidase-4 inhibitors to insulin seems to be beneficial with respect to glycemic control without any significant adverse effects. New drugs, including glucagon-like peptide-1 agonists and sodium glucose co-transporter 2 inhibitors, have acceptable profiles with significant benefits regarding weight reduction when added on insulin therapy. Conclusions: Considering the quality and longevity of evidence, compared to insulin monotherapy, insulin combined with metformin and pioglitazone has the best and worst profiles, respectively. New anti-diabetic medications have acceptable profiles yet are expensive. It is important for clinicians to meticulously weigh the advantages of combination therapy against the possible adverse effects with each drug class in every patient, individually. PMID- 30008762 TI - Bioresorbable vascular scaffold: a step back thinking of the future. PMID- 30008763 TI - Left atrial compliance: an overlooked predictor of clinical outcome in patients with mitral stenosis or atrial fibrillation undergoing invasive management. AB - In the assessment of cardiovascular disease, the clinical significance of left atrial (LA) pressure-volume relations has largely been overlooked in contrast to left ventricular (LV) compliance. However, LA compliance has recently gained more attention. Net atrioventricular compliance (Cn), a joint measure of LA and LV compliance, can be calculated non-invasively by a previously validated method using parameters from standard echocardiography. Compliance measurement may be of relevance in selected clinical settings. First, subjects with low Cn are more likely to have their mitral valve area overestimated by the traditional mitral pressure half-time method. Consequently, low Cn in mitral stenosis, usually resulting from reduced LA compliance, can be mistaken for mild mitral stenosis. Second, low Cn independently predicted pulmonary hypertension and disease progression in medically treated mitral stenosis, and late cardiovascular complications after successful percutaneous mitral valvuloplasty. Decreased LA compliance also accounts for stiff LA syndrome, a rare complication of radiofrequency catheter ablation for atrial fibrillation, manifesting as otherwise unexplained heart failure with elevated LA pressure and pulmonary hypertension. Finally, depressed pre-ablation LA stiffness index, i.e. the ratio of the change in LA pressure to the corresponding change in LA volume during passive LA filling, was an independent predictor of arrhythmia recurrence. Thus, LA stiffening translates into adverse clinical outcomes in patients with mitral stenosis or atrial fibrillation undergoing interventional procedures. Whether reduced LA compliance after LA appendage occlusion can result in the LA stiff syndrome, has not been reported so far. PMID- 30008764 TI - Comparison of outcomes in patients undergoing rotational atherectomy after unsuccessful coronary angioplasty versus elective rotational atherectomy. AB - Introduction: Revascularization of patients with heavily calcified coronary arteries can be a challenge for interventional cardiologists. The procedural success rate in these patients can be improved by using rotational atherectomy (RA). Aim: To compare in-hospital outcomes and those at 12-month follow-up between patients who underwent RA as a bailout procedure secondary to failed conventional angioplasty or as an elective procedure. Material and methods: This is a retrospective analysis of 156 consecutive patients hospitalized at a high volume percutaneous coronary intervention (PCI) center who underwent RA. In 43 (27.6%) patients, RA was performed on an elective basis (group 1). In 113 (72.4%) patients RA was carried out after unsuccessful traditional angioplasty (group 2). Results: Patients in group 1 more often had a history of peripheral vascular disease (32.6% vs. 15.9%; p = 0.03). Group 1 was dominated by patients with multivessel disease (62.8% vs. 33.6%; p < 0.001). The left main coronary artery was more often treated in group 1 (25.6% vs. 2.7%; p < 0.001). Success rates in the two groups were similar: 93.0% for group 1 and 91.2% for group 2 (p = 0.71). The rate of in-hospital complications did not significantly differ between the groups. Twelve-month MI, TLR, and TVR rates were similar in both groups. There was no difference in the 12-month survival rate (86.1% vs. 92.0% in group 2; p = 0.27) or MACE (16.3% vs. 15.0%; p = 0.8). Conclusions: Rotational atherectomy is associated with high efficacy and a relatively low risk of complications, with no significant differences in outcomes between patients treated with primary and secondary RA procedures. PMID- 30008765 TI - Bailout rotational atherectomy in patients with myocardial infarction is not associated with an increased periprocedural complication rate or poorer angiographic outcomes in comparison to elective procedures (from the ORPKI Polish National Registry 2015-2016). AB - Introduction: Many years of experience and refinement of existing rotational atherectomy (RA) techniques have resulted in improved clinical outcomes and a tendency to broaden the spectrum of RA usage. Aim: To compare the angiographic effectiveness and periprocedural complications in patients with stable angina (SA) and acute myocardial infarction (AMI) treated using RA. Material and methods: Data were prospectively collected using the Polish Cardiovascular Intervention Society national registry (ORPKI) on all percutaneous coronary interventions (PCIs) performed in Poland in 2015 and 2016. In total, 975 RA procedures were recorded out of 221,187 PCI procedures. Results: We compared angiographic effectiveness and periprocedural complications in 530 patients with SA and 245 with AMI in the RA group of patients, and 60,522 patients with SA and 91,985 with AMI in the non-RA group. The overall rate of periprocedural complications did not differ between SA and AMI patients in the RA group (2.3% vs. 2.0%; p = 0.84), while it was lower in AMI patients from the RA group compared to those from the non-RA group (2.0% vs. 3.0%; p = 0.34). The percentage of patients with angiographic success in the RA group was similar to the non-RA group in SA patients (97.3% vs. 97.1%; p = 0.75), whereas in the AMI group it was significantly higher compared to the non-RA group (96.7% vs. 92.6%; p < 0.001). Conclusions: The angiographic effectiveness of PCI with RA in patients with AMI was not worse than in patients with SA. PMID- 30008766 TI - Two-year clinical outcomes after implantation of an everolimus-eluting bioresorbable scaffold (Absorb) in stable angina and acute coronary syndrome patients. Single-centre real-life registry data. AB - Aim: The aim of this long-term registry data was to evaluate 2-year clinical and angiographic outcomes after implantation of everolimus-eluting bioresorbable scaffolds (Absorb) from the Latvian Centre of Cardiology Real-life Registry. Material and methods: Between November 2012 and December 2014 in the Centre of Cardiology Real-life Bioresorbable Vascular Scaffold Registry, 187 patients with stable angina or acute coronary syndrome and available 2-year follow-up were selected. All patients had percutaneous coronary intervention (PCI) following bioresorbable scaffold (Absorb) implantation. At 2 years, clinical parameters were analysed in stable angina and acute coronary syndrome subgroups: all-cause death, cardiac death, non-cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), scaffold thrombosis (ST), cerebral infarction, in-scaffold restenosis and bleeding. Results: The clinical follow-up rate at 2 years was 96.2%. In-hospital death occurred in 2 (1.1%) patients, and 1 (0.5%) patient had in-hospital MI. At 2 years, the rate of all-cause death was 3.9% (n = 7), MI 1.6% (n = 3), TLR 3.9% (n = 7), and TVR 8.4% (n = 15). Between hospital discharge and 2-year follow-up scaffold thrombosis occurred in 2 (1.1%) patients. In-hospital scaffold thrombosis occurred in 1 (0.5%) patient due to clopidogrel resistance, and 1 additional case of scaffold thrombosis occurred at 5 days after implantation (0.5%). Conclusions: Bioresorbable scaffolds showed acceptable efficacy (target lesion revascularization) and safety (cardiac death, myocardial infarction, and scaffold thrombosis) results at mid-term follow-up in stable angina and acute coronary syndrome patients. PMID- 30008767 TI - Comparison of the Absorb bioresorbable vascular scaffold to the Xience durable polymer everolimus-eluting metallic stent in routine clinical practice: a propensity score-matched analysis from a multicenter registry. AB - Introduction: Most clinical trials related to bioresorbable vascular scaffold (BVS) technology are limited to a highly selected patient population. Aim: To evaluate early and long-term clinical outcomes of the Absorb everolimus-eluting BVS compared to the everolimus-eluting metallic XIENCE V stent in routine clinical practice. Material and methods: This is a multicenter, retrospective propensity score-matched comparative study, comprising 76 patients treated with a bare metal stents (BMS) and 501 with a XIENCE stent. Patients included in the study had stable and unstable angina and both types of myocardial infarction (STEMI and NSTEMI) as an indication for intervention and at least one significant de novo lesion in native coronary arteries. The primary endpoint was major adverse cardiovascular event (MACE), defined as death, myocardial infarction (MI), or target vessel revascularization (TVR). Results: Median follow-up was 400 days in both groups. After propensity score matching for patient baseline characteristics, only higher rate of predilatation, predominantly treated left anterior descending artery (LAD) and lower number of used stents in the BVS group remained statistically significant. After adjustment there was no difference in type of treated lesions. The MACE rate did not differ between BVS and drug eluting stents (DES) groups (7.2% vs. 11.15%, respectively; p = 0.17). The TVR was 2.9% in both groups. Except in the periprocedural period, there were no deaths or MI in the BVS group. There was no stent thrombosis in either studied group. Conclusions: In routine clinical practice throughout long-term follow-up, clinical outcomes of patients who successfully received the Absorb BVS did not differ from those of patients who received the Xience stent. Longer follow-up data are required to determine whether these findings will persist beyond one year. PMID- 30008768 TI - Saphenous graft atherosclerosis as assessed by optical coherence tomography data for stenotic and non-stenotic lesions from the OCTOPUS registry. AB - Introduction: Coronary artery bypass grafting (CABG), although widely used for a long time in diffuse coronary artery disease (CAD), has serious limitations associated with graft aging and its degeneration. Aim: The relationship between saphenous vein graft (SVG) plaque morphology assessed by optical coherence tomography (OCT) and clinical findings has not been elucidated yet. Material and methods: We compared the morphology of SVG in stenotic vs. non-stenotic lesions using OCT imaging in 29 patients hospitalized in our center within the OCTOPUS registry. Results: Stenotic lesions were characterized by higher incidence of thin-cap fibroatheroma (TCFA) (33% vs. 0%, p = 0.0048), thrombus (28% vs. 0%, p = 0.0008), lipid-rich plaque (LRP) (75% vs. 35%, p = 0.0013) and plaque within the SVG valve (19% vs. 0%, p = 0.0114) as compared to non-stenotic lesions. Patients with intimal tearing or rupture (ITR) were older (75.8% vs. 68.9 years, p = 0.047) and had lower left ventricular ejection fraction (LVEF) (32.0% vs. 49.7%, p = 0.001) and glomerular filtration rate (GFR) (36.0 vs. 73.6 ml/min/1.73 m2, p = 0.010). Patients with calcified lesions vs. those without had lower high density lipoprotein (HDL) cholesterol (33.2 vs. 44.1 mg/dl, p = 0.018), similarly to those with ruptured plaque vs. those without (28.3 vs. 41.7 mg/dl, p = 0.047). Conclusions: Presence of ITR was associated with advanced age, decreased LVEF and renal insufficiency. Decreased concentration of HDL was associated with higher occurrence of calcified and ruptured plaque. PMID- 30008769 TI - Retrospective analysis of single-center early and midterm results of transapical catheter-based mitral paravalvular leak closure with a purpose-specific device. AB - Introduction: Due to the recent lack of definitions to establish the severity of paravalvular leak (PVL) and endpoints for its treatment, the effectiveness and safety of a new device for PVL closure have not been comprehensively analyzed. Aim: To analyze a single center's experience of mitral PVL closure in a surgical transapical catheter-based fashion with a purpose-specific device. Material and methods: This is a retrospective cohort study of patients following transapical catheter-based mitral PVL closure with a purpose-specific device. Data were analyzed at baseline, perioperatively, at discharge, at six months and annually after the procedure. Results: Nineteen patients underwent surgical transapical catheter-based mitral PVL closure with the Occlutech PLD Occluder. Mean follow-up time was 20 +/-7 (range: 9-33) months. The patients' mean age was 64 +/-7 years, and 11 (58%) were male. Technical, device and individual patient success at follow-up was achieved in 18 (95%), 16 (84%) and 16 (84%) patients respectively. Median intensive therapy unit stay was one day (1-4) and mean hospital stay was 11 +/-4 days. A reduction of paravalvular regurgitation to a mild or lesser degree was achieved in 18 (95%) patients. There were no strokes or myocardial infarctions at follow-up. There were no deaths at 30 days after the procedure. One (5%) patient expired due to progression of heart failure 12 months after surgery. None of the patients required immediate conversion to full sternotomy. Conclusions: Surgical transapical catheter-based mitral PVL closure with the Occlutech PLD Occluder is a safe and clinically effective treatment. PMID- 30008770 TI - Midterm outcomes of transmyocardial laser revascularization with intramyocardial injection of adipose derived stromal cells for severe refractory angina. AB - Introduction: Refractory angina has limited effective therapeutic options and often contributes to frequent hospitalizations, morbidity and impaired quality of life. Aim: We sought to examine midterm results of a bio-interventional therapy combining transmyocardial laser revascularization (TMLR) and intramyocardial injection of adipose derived stem cells (ADSC) in patients with refractory angina not amenable to percutaneous or surgical revascularization. Material and methods: We included 15 patients with severe refractory angina and anterior wall ischemia who were ineligible for revascularization strategies. Adipose tissue was harvested and purified, giving the stem cell concentrate. All patients underwent left anterior thoracotomy and TMLR using a low-powered holmium : yttrium-aluminum garnet laser and intramyocardial injection of ADSC using a combined delivery system. Results: No deaths or major adverse cardiovascular or cerebrovascular events were observed in the 6-month follow-up. Mean ejection fraction increased from 35% to 38%, and mean Canadian Cardiovascular Society Angina Score decreased from 3.2 to 1.4, with decreased necessity of nitrate usage. Seventy-three percent of patients reported health improvement particularly regarding general health and bodily pain. Improvement in endocardial movement, myocardial thickening and stroke volume index (35.26 to 46.23 ml/m2) on cardiac magnetic resonance imaging (MRI) was observed in 3 patients who had repeat CMR imaging after 6 months. Conclusions: Our study suggested that interventional therapy combining TMLR with intramyocardial implantation of ADSC may reduce symptoms and improve quality of life in patients with refractory angina. These early findings need further validation in large scale randomized controlled trials. PMID- 30008771 TI - Safety of a simplified electrophysiological method of transseptal puncture. A single center's experience. PMID- 30008772 TI - Supra-annular sizing for transcatheter valve implantation in bicuspid aortic stenosis. PMID- 30008773 TI - Atorvastatin facilitates protection against contrast-induced nephropathy in patients undergoing coronary angiography via humoral mediators rather than altered renal hemodynamics. PMID- 30008774 TI - Painful and painless myocardial ischemia detected by elevated level of high sensitive troponin in patients with hypertrophic cardiomyopathy. PMID- 30008775 TI - Optical coherence tomography guided successful fibrinolytic treatment without the need for percutaneous coronary intervention in a patient with acute ST-segment elevation myocardial infarction. PMID- 30008776 TI - Recurrent myocardial infarction with non-obstructive coronary arteries in the course of an angiographically non-obstructive, but physiologically significant, proximal left artery descending lesion recognized with fractional flow reserve. PMID- 30008777 TI - Marking wire technique for zero-contrast percutaneous coronary interventions. PMID- 30008778 TI - Staged percutaneous angioplasty of a long calcified left anterior descending artery with rotablation in a patient with stable angina. PMID- 30008779 TI - Coronary compression by supposed cardiac hydatid cyst: an unusual cardiac mass. PMID- 30008780 TI - Melody valve implantation pre-procedural planning using custom-made 3D printed model of the region of interest. PMID- 30008781 TI - Rare coexistence: type A aortic interruption and left ventricular non-compaction. PMID- 30008782 TI - Isolated carotid artery fibromuscular dysplasia unifocal type diagnosed in the postpartum period. PMID- 30008783 TI - Endovascular retrieval of ruptured and dislocated vascular catheter. PMID- 30008784 TI - Effect of Aqueous Extract from Descurainia sophia (L.) Webb ex Prantl on Ventricular Remodeling in Chronic Heart Failure Rats. AB - Objective: Descurainia sophia (L.) Webb ex Prantl (DS) is a traditional Chinese medicine. Our current study was to evaluate the effect of DS on ventricular remodeling in chronic heart failure (HF) rats and its underlying mechanism. Methods: The rat chronic heart failure model induced by suprarenal abdominal aortic coarctation surgery. The survival rats were randomly divided into 3 groups: the sham group (n=6), the HF group (n=6), and the HF+DS group (n=6). After 3 months of drug intervention, we examined the effects of DS by Sirius Red staining, electron microscopy, echocardiography, hemodynamic measurement, and TUNEL and explored the underlying mechanism by Western blotting. Results: We found that rats treated with DS showed improved cardiac function and less tissue damage compared to untreated group. Additionally, DS could reduce the cardiomyocytes apoptosis, decrease the ratio of Bax/bcl-2 and Caspase-3 expression, and enhance the phosphorylation of Akt protein expression. Conclusion: Our study suggested that rats treated with DS after suprarenal abdominal aortic coarctation surgery showed attenuated cardiac fibrosis and apoptosis, and the protective effect may be correlated with the activation of PI3k/Akt/mTOR dependent manner. PMID- 30008785 TI - In Vitro and In Vivo Immunomodulator Activities of Allium sativum L. AB - Allium Sativum L. (garlic), which is a species of the onion family, Alliaceae, is one of the most used plants in traditional medicine worldwide. More than 200 chemicals with diverse properties have been found in garlic extracts. Several garlic compounds were suggested to be efficient in improving various pathologies including certain types of cancer. This paper is an overview of data about garlic biological activities in vitro and/or in vivo on immune cells, on the development of certain inflammatory diseases, and on different types of carcinomas and sarcomas. Garlic and its compounds were found to have notable antioxidant properties. Garlic therapeutic potential has also been studied in several inflammatory diseases such as allergic-airway inflammation, inflammatory bowel disease, arthritic rheumatism, and atherosclerosis. Furthermore, garlic was found to be able to maintain the immune system homeostasis and to exhibit beneficial effects on immune cells especially through regulation of proliferation and cytokine gene expression. Finally, we will show how major garlic components such as sulfur compounds and polyphenols might be responsible for the garlic biological activities revealed in different situations. If identified, specific compounds present in garlic could potentially be used in therapy. PMID- 30008786 TI - Herb Formula ZhenRongDan Balances Sex Hormones, Modulates Organ Atrophy, and Restores ERalpha and ERbeta Expressions in Ovariectomized Rats. AB - Herb mixtures are widely used for treatment of the menopausal syndrome long before the hormonal therapy. However, there is insufficient data for herb remedies in treating menopausal syndromes. Here we aim to investigate the effect of ZhenRongDan (ZRD) in balancing female hormones, regulating expression of estrogen receptors (ERs), and preventing organ atrophy in menopausal rats. Rats that underwent bilateral ovariectomy were used in the experiments; the effects of ZRD on serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and estradiol (E2) levels were observed. Histology of vagina and ERs expression in vagina, uterus, and adrenal gland were also examined. ELISAs were used to analyze the changes of FSH, LH, PRL, and E2 in serum, and the morphological changes of the cervical epithelium cells were observed by Hematoxylin & Eosin (H&E) staining. Immunohistochemistry and western blot were applied to detect estrogen receptors subtypes alpha (ERalpha) and beta (ERbeta) expression in vagina, uterus, and adrenal gland. We found that ZRD could significantly reduce the weight of the adrenal gland and increase the weight of the uterus. It could decrease the release of FSH and LH as well as increasing E2 and PRL levels. Furthermore, ZRD could improve the number of cervical vaginal epithelial cells and increase the thickness of the vaginal wall. And the altered expressions of ERalpha and ERbeta are also restored by ZRD. ZRD could obviously relieve the endocrine disorders, modulate organ atrophy, and restore ERalpha and ERbeta expression in the ovariectomized rat model. PMID- 30008787 TI - The Effects of Fermented Laminaria japonica on Short-Term Working Memory and Physical Fitness in the Elderly. AB - Considering the neuroprotective and antioxidant potential of fermented Laminaria japonica A. (FST), the purpose of the present study is to establish whether FST may be considered a viable, efficacious supplement that can be administered in later life to offset neurodegenerative conditions associated with aging. Forty senior subjects participated in a randomized, double-blind, and placebo controlled study. Two groups were formed, one FST group (n = 32, 72.35 +/- 5.54 yrs) and one placebo (CON) (n = 28, 74.57 +/- 5.69 yrs), which received 1.5 g/day of FST for 6 weeks. Subjects were asked to abstain from any regular exercise. In order to analyze short-term memory, a variety of neuropsychological tests were implemented. Body composition, physical fitness evaluations, antioxidant function, and inflammatory markers were also included in the analyses pre- and posttest. We demonstrated that FST significantly improved neuropsychological test scores, including higher scores in the K-MMSE, numerical memory test, Raven test, and iconic memory, compared to the CON group. Shorter test trial times in the 6 minute walk test were observed in the FST group (p<0.001 and p<0.05, trials 1 and 2, respectively). FST also significantly increased antioxidant activity of GPx, GSR, and SOD, reduced the production of TBARS, and lowered 8-oxoDG levels. The present study highlights the potential widespread application of FST in protecting against the degenerative effects of aging on short-term memory and physical function. Neuropsychological evaluation indicates that FST may provide a protective mechanism against cognitive impairment associated with dementia. Neuromuscular integrity and physical function are typically compromised in aging and dementia patients; thus, whether by stimulation of muscle-related growth factors or an increase in serum BDNF, FST supplementation may act to preserve physical function in the elderly. The bioactive constituents of FST such as GABA and fucoidan acting to provide improvements in antioxidant activity following FST supplementation may protect against progressive degeneration purportedly caused by reactive oxygen species. PMID- 30008788 TI - In Vivo Antimalarial Activity of the 80% Methanolic Root Bark Extract and Solvent Fractions of Gardenia ternifolia Schumach. & Thonn. (Rubiaceae) against Plasmodium berghei. AB - Background: Evolution of antimalarial drug resistance makes the development of new drugs a necessity. Important source in search of such drugs is medicinal plants. Gardenia ternifolia plant is used in Ethiopian traditional medicine for the treatment of malaria and is endowed with in vitro antimalarial activity. Herein, the in vivo antimalarial activity of the plant was investigated. Methods: Acute toxicity was carried out using a standard procedure. A 4-day suppressive test was employed to evaluate the antimalarial effect of methanolic crude extract and solvent fractions of the plant. The curative and prophylactic effect of crude extract was further tested by Ranes's test and residual infection procedure, respectively, using Plasmodium berghei (ANKA strain) in Swiss albino mice. Results: The chemosuppressive effect exerted by the crude extract and fractions ranged between 30-59% and 14-51%, respectively. Curative and prophylactic effects of the crude extract were in the range of 36-63% and 24-37%, respectively. All dose levels of the crude extract prevented loss of weight, reduction in temperature, and anemia on early and established infection. Butanol and chloroform fractions also did reverse reduction in temperature, body weight, and packed cell volume. Conclusions: The results indicated that the plant has a promising antiplasmodial activity and it could be considered as a potential source to develop new antimalarial agents. PMID- 30008790 TI - Impact of 3-year changes in lipid parameters and their ratios on incident type 2 diabetes: Tehran lipid and glucose study. AB - Background: To examine the impact of changes in all lipid measures including total cholesterol (TC), log-transformed triglycerides (Ln-TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), non HDL-C, TC/HDL-C and Ln TG/HDL-C, over an approximate 3 year duration, on incident type 2 diabetes (T2DM). Methods: A total of 5474 participants, mean age 41.3 years, without prevalent diabetes at baseline or the first follow-up were entered into the study. The association of lipid changes between baseline and the first follow-up i.e., between 1999-2002 and 2002-2005 for those entered in the first phase (n = 4406) and between 2002-2005 and 2005-2008 for participants recruited in the second phase (n = 1068) with incident T2DM over the follow-up period was assessed, using multivariate Cox proportional hazard analysis. Results: During a median follow-up of 8.9 years after the second lipid measurements, 577 incident cases of T2DM occurred. After adjustment for a wide variety of confounders and body mass index (BMI) change, each 1-SD increase in TC, Ln-TG, HDL-C, LDL-C, non HDL-C, Ln-TG/HDL-C and TC/HDL-C was associated with 12, 14, 0.86, 12, 16, 15 and 13% risk for T2DM, respectively (all p-values < 0.05). However, after further adjustment for fasting plasma glucose (FPG) change, the risk disappeared for all lipid measures, excluding HDL-C [hazard ratio (HR): 0.84 (0.76-0.93)], Ln-TG/HDL C [1.14 (1.04-1.25)] and TC/HDL-C [1.12 (1.04-1.21)]. Conclusions: Three year changes in all lipid parameters, after adjustment for known risk factors of T2DM and BMI changes, were associated with incident T2DM. The independent risk of HDL C and its ratios remained even after adjustment for FPG changes. PMID- 30008791 TI - Variation in admission rates between psychiatrists on call in a university teaching hospital. AB - Background: Hospital-based physicians must routinely decide whether patients receiving care in the emergency room require admission to an acute care bed. We endeavoured to understand clinician-related factors that influence the decision to admit. Methods: We retrospectively examined data collected between August 1, 2013 and July 31, 2015 for patients triaged as mental health assessments in the emergency department of a university teaching hospital. We identified 1530 unique cases who had been reviewed by the staff psychiatrist for a decision on whether to admit to an acute care bed. Patient and physician characteristics were analyzed by standard descriptive methods, comparative statistics (Chi square and analysis of variance) and regression analyses using SPSS version 24.0 (IBM Corp. Armonk, NY, USA). Results: There were no differences in patient characteristics in the clinical encounters reviewed by different staff psychiatrists. The physician factor found significant in deciding whether to admit the patient was assignment to PES (psychiatric emergency services). This appeared to be the only physician variable impacting the decision to admit a patient with PES psychiatrists admitting less often than their colleagues (p = 0.018, Table 3). The effect size of the variable in terms of odds ratio was 0.592. Interpretation: Training and practice in emergency psychiatry lead to lower admission rates when these clinicians are on call. Training in emergency psychiatry for all psychiatrists participating in a call pool may result in lowered admission rates. PMID- 30008792 TI - Epworth sleepiness scale in medical residents: quality of sleep and its relationship to quality of life. AB - Background: Resident doctors are continuously exposed to prolonged working hours and night shifts, making them susceptible to the many physical, psychological, and cognitive side effects of sleep deprivation, which may affect their quality of life. Therefore, this study aimed to determine the prevalence of sleep penury in resident doctors and to assess the association between self-apprehended sleepiness and quality of life. Methods: A cross-sectional study was carried out in the governmental hospitals in the North of the West Bank between May 2017 and September 2017. Doctors enrolled in residency programmes completed questionnaires about general, sociodemographic, and sleep characteristics. The doctors completed the Arabic Version of the Epworth Sleepiness Scale (ArESS) to assess subjective daytime sleepiness and the RAND 36-item short-form health survey (SF-36) to determine quality of life. Results: A total of 101 participants were enrolled. Daytime sleepiness was observed in 37.6% (n = 38) of the participants with an ESS score of >=10. There was a notable negative correlation between the ESS and quality of health index in the physical composition (r = - 0.351, p < 0.001) demonstrated in the following four subscales: the physical functioning (p < 0.001), role limitations due to physical health (p = 0.045), body pain (p = 0.036), and general health (p < 0.001) components of the SF-36 scale. Females and residents of the centre region had poorer mental quality (p = 0.006 and 0.020, respectively). Conclusions: More than one third of the resident doctors suffer from daytime sleepiness according to the ESS. This was proven to significantly affect several aspects of their quality of life, including physical function and health, body pain, and general health. Sleep deprivation and improvement of quality of life require health promotion actions among medical residents. PMID- 30008789 TI - alpha-Tocopherol influences glycaemic control and miR-9-3 DNA methylation in overweight and obese women under an energy-restricted diet: a randomized, double blind, exploratory, controlled clinical trial. AB - Background: Excess weight is a strong risk factor for the development of dysglycaemia. It has been suggested that changes in the metabolism microRNAs, small non-coding RNAs that regulate gene expression, could precede late glycaemic changes. Vitamin E in turn may exert important functions in methylation and gene expression processes. This study aimed to determine the effect of alpha tocopherol on glycaemic variables and miR-9-1 and miR-9-3 promoter DNA methylation in overweight women. Methods: A randomized, double-blind, exploratory, placebo-controlled study was conducted in overweight and obese adult women (n = 44) who ingested synthetic vitamin E (all-rac-alpha-tocopherol), natural source vitamin E (RRR-rac-alpha-tocopherol) or placebo capsules and were followed up for a period of 8 weeks. Supplemented groups also received dietary guidance for an energy-restricted diet. An additional group that received no supplementation and did not follow an energy-restricted diet was also followed up. The intervention effect was evaluated by DNA methylation levels (quantitative real-time PCR assay) and anthropometric and biochemical variables (fasting plasma glucose, haemoglobin A1C, insulin, and vitamin E). Results: Increased methylation levels of the miR-9-3 promoter region (P < 0.001) and reduced haemoglobin A1C (P < 0.05) were observed in the natural source vitamin E group after intervention. Increased fasting plasma glucose was observed in the synthetic vitamin E group, despite the significant reduction of anthropometric variables compared to the other groups. Conclusions: alpha-Tocopherol from natural sources increased methylation levels of the miR-9-3 promoter region and reduced haemoglobin A1C in overweight women following an energy-restricted diet. These results provide novel information about the influence of vitamin E on DNA methylation. Trial registration: ClinicalTrials.gov, NCT02922491. Registered 4 October, 2016. PMID- 30008793 TI - Pilot testing of the Becoming Breastfeeding Friendly toolbox in Ghana. AB - Background: Ghana has achieved significant progress in breastfeeding practices in the past two decades. Further progress is, however, limited by insufficient government funding and declining donor support for breastfeeding programs. The current study pretested feasibility of the Becoming Breastfeeding Friendly (BBF) toolbox in Ghana, to assess the existing enabling environment and gaps for scaling-up effective actions. Methods: Between June 2016 and April 2017, a 15 person expert country committee drawn from government and non-government agencies was established to implement the BBF toolbox. The committee used the BBF index (BBFI), comprising of 54 benchmarks and eight gears of the Breastfeeding Gear Model (advocacy; political will; legislation and policy; funding and resources; training and program delivery; promotion; research and evaluation; and coordination, goals and monitoring). Available evidence (document reviews, and key informant interviews) was used to arrive at consensus-scoring of benchmarks. Benchmark scores ranged between 0 (no progress) and 3 (major progress). Scores for each gear were averaged to estimate the Gear Total Score (GTS), ranging from 0 (least) to 3.0 (strong). GTS's were aggregated as a weighted average to estimate the BBFI which ranged from 0 (weak) to 3.0 (outstanding). Gaps in policy and program implementation and recommendations were proposed for decision-making. Results: The BBFI score was 2.0, indicating a moderate scaling-up environment for breastfeeding in Ghana. Four gears recorded strong gear strength: advocacy (2.3); political will (2.3); legislation and policy (2.3); and coordination, goals and monitoring (2.7). The remaining four gears had moderate gear strength: funding and resources (1.3); training and program delivery (1.9); promotion (2.0); and research and evaluation (1.3). Key policy and program gaps identified by the committee included sub-optimal coordination across partners, inadequate coverage and quality of services, insufficient government funding, sub-optimal enforcement of policies, and inadequate monitoring of existing initiatives. Prioritized recommendations from the process were: 1) strengthen advocacy and empower breastfeeding champions, 2) strengthen breastfeeding regulations, including maternity protection, 3) strengthen capacity for providing breastfeeding services, and 4) expand and sustain breastfeeding awareness initiatives. Conclusions: The moderate environment for scaling-up breastfeeding in Ghana can be further strengthened by addressing identified gaps in policy and programs. PMID- 30008795 TI - High throughput phenotyping of morpho-anatomical stem properties using X-ray computed tomography in sorghum. AB - Background: In bioenergy/forage sorghum, morpho-anatomical stem properties are major components affecting standability and juice yield. However, phenotyping these traits is low-throughput, and has been restricted by the lack of a high throughput phenotyping platforms that can collect both morphological and anatomical stem properties. X-ray computed tomography (CT) offers a potential solution, but studies using this technology in plants have evaluated limited numbers of genotypes with limited throughput. Here we suggest that using a medical CT might overcome sample size limitations when higher resolution is not needed. Thus, the aim of this study was to develop a practical high-throughput phenotyping and image data processing pipeline that extracts stem morpho anatomical traits faster, more efficiently and on a larger number of samples. Results: A medical CT was used to image morpho-anatomical stem properties in sorghum. The platform and image analysis pipeline revealed extensive phenotypic variation for important morpho-anatomical traits in well-characterized sorghum genotypes at suitable repeatability rates. CT estimates were highly predictive of morphological traits and moderately predictive of anatomical traits. The image analysis pipeline also identified genotypes with superior morpho-anatomical traits that were consistent with ground-truth based classification in previous studies. In addition, stem cross section intensity measured by the CT was highly correlated with stem dry-weight density, and can potentially serve as a high throughput approach to measure stem density in grass stems. Conclusions: The use of CT on a diverse set of sorghum genotypes with a defined platform and image analysis pipeline was effective at predicting traits such as stem length, diameter, and pithiness ratio at the internode level. High-throughput phenotyping of stem traits using CT appears to be useful and feasible for use in an applied breeding program. PMID- 30008794 TI - Label-free visualization of fruit lignification: Raman molecular imaging of loquat lignified cells. AB - Background: Flesh lignification, leading to increased fruit firmness, has been reported in several kinds of fruit. Understanding the mechanisms underlying fruit lignification is important to optimize the postharvest storage strategies and reduce the quality deterioration of postharvest fruit. Especially cellular level investigation of lignin deposition in fruits provides novel insight for deciphering the mechanisms underlying fruit lignification. The primary objective of this study was to establish a procedure of using Raman microspectroscopy technique to depict fruit lignification at the cell level. Results: Lignified cells, a special kind of cells contained high lignin content, were found abundantly scattered in red-fleshed 'Luoyangqing' loquat. Whereas these special lignified cells were barely detected in 'Baisha' loquat flesh. Dominant Raman bands of lignified cells were found primarily attributed to lignin (1664, 1628, 1603, 1467, and 1272 cm-1), cellulose (1383, 1124 and 1098 cm-1) and pectin (852 and 1740 cm-1). The band intensity correlation analysis indicated the peak at 1335 cm-1 assigned to either lignin or cellulose in previous works was related to lignin for the lignified cells. Multi-peaks Gaussian fitting successfully resolved the overlapped fingerprint peaks of lignin in 1550-1700 cm-1 into three independent peaks, which were assigned to different functional groups of lignin. Furthermore, the spatially resolved Raman images of lignified cells were generated, indicating that lignin and cellulose saturated the whole lignified cells, pectin mainly located in the cell corner, and the parenchyma cells contained little lignin. In addition, both phloroglucinol-HCl staining and autofluorescence analysis confirmed the results of lignin distribution of Raman microscopic analysis. Conclusions: A procedure for the simultaneous visualization of the main components of the flesh cells without labeling by high-resolution Raman microspectroscopy has been established. With Raman microscopic imaging technique, we can add a microscopic level to cell compositions, essential for a detailed molecular understanding of loquat lignification. Such method can be further used to chemically monitor the textural changes during the ripening process or postharvest storage of other fruits and vegetables. PMID- 30008796 TI - Sample Entropy Analysis of Noisy Atrial Electrograms during Atrial Fibrillation. AB - Most cardiac arrhythmias can be classified as atrial flutter, focal atrial tachycardia, or atrial fibrillation. They have been usually treated using drugs, but catheter ablation has proven more effective. This is an invasive method devised to destroy the heart tissue that disturbs correct heart rhythm. In order to accurately localise the focus of this disturbance, the acquisition and processing of atrial electrograms form the usual mapping technique. They can be single potentials, double potentials, or complex fractionated atrial electrogram (CFAE) potentials, and last ones are the most effective targets for ablation. The electrophysiological substrate is then localised by a suitable signal processing method. Sample Entropy is a statistic scarcely applied to electrograms but can arguably become a powerful tool to analyse these time series, supported by its results in other similar biomedical applications. However, the lack of an analysis of its dependence on the perturbations usually found in electrogram data, such as missing samples or spikes, is even more marked. This paper applied SampEn to the segmentation between non-CFAE and CFAE records and assessed its class segmentation power loss at different levels of these perturbations. The results confirmed that SampEn was able to significantly distinguish between non CFAE and CFAE records, even under very unfavourable conditions, such as 50% of missing data or 10% of spikes. PMID- 30008797 TI - Wall Shear Stress Estimation of Thoracic Aortic Aneurysm Using Computational Fluid Dynamics. AB - An attempt has been made to evaluate the effects of wall shear stress (WSS) on thoracic aortic aneurysm (TAA) using Computational Fluid Dynamics (CFD). Aneurysm is an excessive localized swelling of the arterial wall due to many physiological factors and it may rupture causing shock or sudden death. The existing imaging modalities such as MRI and CT assist in the visualization of anomalies in internal organs. However, the expected dynamic behaviour of arterial bulge under stressed condition can only be effectively evaluated through mathematical modelling. In this work, a 3D aneurysm model is reconstructed from the CT scan slices and eventually the model is imported to Star CCM+ (Siemens, USA) for intensive CFD analysis. The domain is discretized using polyhedral mesh with prism layers to capture the weakening boundary more accurately. When there is flow reversal in TAA as seen in the velocity vector plot, there is a chance of cell damage causing clots. This is because of the shear created in the system due to the flow pattern. It is observed from the proposed mathematical modelling that the deteriorating WSS is an indicator for possible rupture and its value oscillates over a cardiac cycle as well as over different stress conditions. In this model, the vortex formation pattern and flow reversals are also captured. The non-Newtonian model, including a pulsatile flow instead of a steady average flow, does not overpredict the WSS (15.29 Pa compared to 16 Pa for the Newtonian model). Although in a cycle the flow behaviour is laminar-turbulent-laminar (LTL), utilizing the non-Newtonian model along with LTL model also overpredicted the WSS with a value of 20.1 Pa. The numerical study presented here provides good insight of TAA using a systematic approach to numerical modelling and analysis. PMID- 30008798 TI - Information-Based Medicine in Glioma Patients: A Clinical Perspective. AB - Glioma constitutes the most common type of primary brain tumor with a dismal survival, often measured in terms of months or years. The thin line between treatment effectiveness and patient harm underpins the importance of tailoring clinical management to the individual patient. Randomized trials have laid the foundation for many neuro-oncological guidelines. Despite this, their findings focus on group-level estimates. Given our current tools, we are limited in our ability to guide patients on what therapy is best for them as individuals, or even how long they should expect to survive. Machine learning, however, promises to provide the analytical support for personalizing treatment decisions, and deep learning allows clinicians to unlock insight from the vast amount of unstructured data that is collected on glioma patients. Although these novel techniques have achieved astonishing results across a variety of clinical applications, significant hurdles remain associated with the implementation of them in clinical practice. Future challenges include the assembly of well-curated cross institutional datasets, improvement of the interpretability of machine learning models, and balancing novel evidence-based decision-making with the associated liability of automated inference. Although artificial intelligence already exceeds clinical expertise in a variety of applications, clinicians remain responsible for interpreting the implications of, and acting upon, each prediction. PMID- 30008799 TI - Ischemic colitis caused increased early and delayed mortality. AB - Background: Ischemic colitis remains a challenge for the surgeon, both in its diagnosis and treatment. Data from a single tertiary center, of patients diagnosed with ischemic colitis, was collected. An attempt was made to delineate the patients requiring surgical intervention. Methods: A retrospective study was undertaken in patients diagnosed with ischemic colitis admitted to Rambam Health Care Campus between 2011 and 2016. The primary outcome was defined as mortality. Secondary outcomes were defined as complications during conservative treatment and postoperative course. Results: Sixty-three patients were diagnosed with ischemic colitis during the study period. The mean age at presentation was 72.5 years, with a female predominance (62%). The overall mortality rate was 29% (18/63). Six patients (50%) of those operated died. An older age, comorbidities and higher lactate levels present risk factors for a worse outcome. Conclusions: Ischemic colitis continues to present a challenge in its management. A better understanding of the disease process is required. And one needs to adhere to sound surgical principles for a timely diagnosis and treatment, especially in older patients with worrisome clinical, laboratory, and imaging features. PMID- 30008800 TI - Prevalence of non-communicable diseases and access to care among non-camp Syrian refugees in northern Jordan. AB - Background: Tackling the high non-communicable disease (NCD) burden among Syrian refugees poses a challenge to humanitarian actors and host countries. Current response priorities are the identification and integration of key interventions for NCD care into humanitarian programs as well as sustainable financing. To provide evidence for effective NCD intervention planning, we conducted a cross sectional survey among non-camp Syrian refugees in northern Jordan to investigate the burden and determinants for high NCDs prevalence and NCD multi-morbidities and assess the access to NCD care. Methods: We used a two-stage cluster design with 329 randomly selected clusters and eight households identified through snowball sampling. Consenting households were interviewed about self-reported NCDs, NCD service utilization, and barriers to care.We estimated the adult prevalence of hypertension, diabetes type I/II, cardiovascular- and chronic respiratory conditions, thyroid disease and cancer and analysed the pattern of NCD multi-morbidities. We used the Cox proportional hazard model to calculate the prevalence ratios (PR) to analyse determinants for NCD prevalence and logistic regression to determine risk factors for NCD multi-morbidities by calculating odds ratios (ORs). Results: Among 8041 adults, 21.8%, (95% CI: 20.9-22.8) suffered from at least one NCD; hypertension (14.0, 95% CI: 13.2-14.8) and diabetes (9.2, 95% CI: 8.5-9.9) were the most prevalent NCDs. NCD multi morbidities were reported by 44.7% (95% CI: 42.4-47.0) of patients. Higher age was associated with higher NCD prevalence and the risk for NCD-multi-morbidities; education was inversely associated.Of those patients who needed NCD care, 23.0% (95% CI: 20.5-25.6) did not seek it; 61.5% (95% CI: 54.7-67.9) cited provider cost as the main barrier. An NCD medication interruption was reported by 23.1% (95% CI: 20-4-26.1) of patients with regular medication needs; predominant reason was unaffordability (63.4, 95% CI: 56.7-69.6). Conclusion: The burden of NCDs and multi-morbidities is high among Syrian refugees in northern Jordan. Elderly and those with a lower education are key target groups for NCD prevention and care, which informs NCD service planning and developing patient-centred approaches.Important unmet needs for NCD care exist; removing the main barriers to care could include cost-reduction for medications through humanitarian pricing models. Nevertheless, it is still essential that international donors agencies and countries fulfill their commitment to support the Syrian-crisis response. PMID- 30008801 TI - Assessment of patients' satisfaction and associated factors among outpatients received mental health services at public hospitals of Mekelle Town, northern Ethiopia. AB - Background: Satisfaction is the psychological state that results from confirmation or disconfirmation of expectations with reality. Patients' satisfaction is a healthcare recipient's reaction to salient aspect of the contexts, process and result of their service experience. The aim of this study was to assess patient satisfaction and associated factors among outpatients receiving mental health services at public hospitals in Mekelle town. Objectives: To assess patient satisfaction and associated factors among outpatients receiving mental health services at public hospitals in Mekelle town, northern Ethiopia. Methods: An institution based cross-sectional study was conducted among 415 outpatients receiving mental health services at public hospitals in Mekelle town from September 2013 to August 2014. The data were collected using standardized, structured pre-tested questionnaire. Participants were selected by systematic random sampling technique. Satisfaction rate was examined with the client satisfaction questionnaire (CSQ-8), having four responses ranging from poor to very good. Descriptive summary using percentages, frequency and graph were used to present study results. Multivariate logistic regressions with 95% confidence interval (CI) were used to assess the strength and p-value < 0.05 was used to indicate the significance of the association. Results: A total of 415 respondents were enrolled, with a response rate of 100% and magnitude of satisfaction of 72%. The predictors associated with patient satisfaction were higher education (AOR = 0.34; 95% CI 0.24, 0.97), longer waiting time (AOR = 0.01; 95% CI 0.002, 0.07), having a diagnosis of psychosis (AOR = 2.36; 95% CI 1.41, 5.72) were significantly associated with satisfaction. Conclusion and recommendation: More than one-four of patients receiving mental health services were dissatisfied with the service they received. Improvement in accessibility and availability of drugs, minimizing consultation time (< 45 min) or increasing number of OPD units are important to improve satisfaction. PMID- 30008802 TI - Children's Perceived Competence Scale: reevaluation in a population of Japanese elementary and junior high school students. AB - Background: It is important for children to maintain high self-perceived competence and self-esteem, and there are few measures to evaluate them through elementary to junior high school days in Japan. To evaluate psychometric properties of the Children's Perceived Competence Scale (CPCS). Methods: Data were collected from 697 elementary school and 956 junior high school students. Some of these students completed measures for construct validity, whereas others repeated the CPCS. Results: The results demonstrated the three-factor structure of the CPCS: cognitive (nine items), social (eight items) and physical (nine items). Factorial invariance was confirmed between elementary and junior high school students, as well as between boys and girls. Construct validity was excellent. Scores on the cognitive, physical and general self-worth domains declined with increasing age. Boys scored significantly higher than girls on physical and general self-worth domains. Conclusions: The CPCS is a valid and reliable measure of perceived competence in Japanese children aged 6-15 years. The CPCS may be applied to students from elementary through junior high school days as a measure of self-perceived and psychological state in Japan. PMID- 30008803 TI - Comparison of Modular Control during Smash Shot between Advanced and Beginner Badminton Players. AB - This study investigated muscle synergy during smash shot in badminton and compared synergies of advanced players (more than 7 years experience) and beginner players (less than 3 years experience). The dominant hand of all players was the right side. Muscle activities were recorded on both sides of the rectus abdominis, external oblique (EO), internal oblique/transversus abdominis (IO/TrA), and erector spinae. Additionally, the right side of the biceps brachii, triceps brachii, flexor carpi radialis, flexor carpi ulnaris, and flexor digitorum profundus muscle activities were recorded. All data was obtained using surface electromyography. Synergy was extracted from electromyography signals using nonnegative matrix factorization. Extracted synergies in each group were compared using scalar product (SP) which is the similarity index. As a result, two synergies were extracted in the beginner players and three synergies were extracted in advanced players. Beginner and advanced players had one synergy in common (SP = 0.86) that was mainly on the left side of the EO. It activated in the early stroke and had a role of side bending from the left to hit the shuttlecock at a higher point. Another synergy that had coactivation of the IO/TrA and forearm muscles at impact was extracted only for advanced players and it may enhance the smash shot performance in badminton. PMID- 30008804 TI - Cellulose modification by recyclable swelling solvents. AB - Background: The invention of efficient systems for lignocellulose conversion is essential for economically feasible production of bio-based chemicals and biofuels. One limiting step is highly selective processes to quickly decrystallize the compact cellulose structure for efficient hydrolysis. We evaluated the impact of trifluoroacetic acid (TFA) and phosphorous acid (PA) induced swelling of crystalline cellulose on enhancement of enzymatic digestion. Results: In this study, two swelling agents, TFA and PA, are compared and found to be highly efficient for cellulose decrystallization at low temperatures within 1 h. After treatment, the microfibril structure of swollen celluloses was observed to develop distinct microscopic morphology and subsequent enzymatic hydrolysis resulted over 90% cellulose conversion within 24 h. The crystalline cellulose change was determined by reduction of loss of X-ray diffractability, and loss of resistance to enzymatic hydrolysis. NMR results suggest that both TFA and PA efficiently converted most of the crystalline cellulose regions to amorphous regions through cellulose chain relocation that inhibits recrystallization. It was found that the swelling mechanism is different between TFA and PA. To the best of our knowledge, it is the first time to compare and quantify the cellulose regions transformation by swelling agents. Conclusion: This study shows the low-temperature swelling of different celluloses in TFA and PA reduces recalcitrance of crystalline cellulose to enzymatic hydrolysis. TFA and PA are both ideal candidate swelling agents for a closed system for ease of solvent recovery by either simple distillation or filtration. This study provides potentially useful agents in large-scale deconstruction of biomass. PMID- 30008805 TI - An uncommon t(9;11)(p24;q22) with monoallelic loss of ATM and KMT2A genes in a child with myelodysplastic syndrome/acute myeloid leukemia who evolved from Fanconi anemia. AB - Background: Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, characterized by congenital malformations and progressive BMF. Patients with FA usually present chromosomal aberrations when evolving to MDS or acute myeloid leukemia (AML). Thus, the cytogenetic studies in the bone marrow (BM) of these patients have an important role in the therapeutic decision, mainly in the indication for hematopoietic stem cell transplantation (HSCT). The most frequent chromosomal alterations in the BM of FA patients are gains of the chromosomal regions 1q and 3q, and partial or complete loss of chromosome 7. However, the significance and the predictive value of such clonal alterations, with respect to malignant progress, are not fully understood and data from molecular cytogenetic studies are very limited. Case presentation: A five-year-old boy presented recurrent infections and persistent anemia. The BM biopsy revealed hypocellularity. G banding was performed on BM cells and showed a normal karyotype. The physical examination showed to be characteristic of FA, being the diagnosis confirmed by DEB test. Five years later, even with supportive treatment, the patient presented severe hypocellularity and BM evolution revealing megakaryocyte dysplasia, intense dyserythropoiesis, and 11% myeloblasts. G-banded analysis showed an abnormal karyotype involving a der(9)t(9;11)(p24;q?22). The FISH analysis showed the monoallelic loss of ATM and KMT2A genes. At this moment the diagnosis was MDS, refractory anemia with excess of blasts (RAEB). Allogeneic HSCT was indicated early in the diagnosis, but no donor was found. Decitabine treatment was initiated and well tolerated, although progression to AML occurred 3 months later. Chemotherapy induction was initiated, but there was no response. The patient died due to disease progression and infection complications. Conclusions: Molecular cytogenetic analysis showed a yet unreported der(9)t(9;11)(p24;q?22),der(11)t(9;11)(p24;q?22) during the evolution from FA to MDS/AML. The FISH technique was important allowing the identification at the molecular level of the monoallelic deletion involving the KMT2A and ATM genes. Our results suggest that this chromosomal alteration conferred a poor prognosis, being associated with a rapid leukemic transformation and a poor treatment response. PMID- 30008806 TI - Theoretical Extensions of Minority Stress Theory for Sexual Minority Individuals in the Workplace: A Cross-Contextual Understanding of Minority Stress Processes. AB - Minority stress theory posits that stress processes specific to a sexual minority orientation can affect the psychological health and well-being of lesbian, gay, bisexual, or queer-identified (LGBQ) individuals. In the workplace, LGBQ employees experiencing minority stress report poor mental health outcomes and decreased job satisfaction and commitment. However, few scholars have examined the cross-contextual effects minority stressors that individuals experience in the workplace may have on couples. That is, given the literature highlighting the work-family interface, how do minority stressors at work affect the sexual minority employee within the family dynamics of same-sex couples at home? The purpose of this article is to propose a multi-theoretical approach which includes elements of minority stress theory and work-family border theory to guide future research in examining the cross-contextual effects of minority stress for couple- and family-level outcomes. PMID- 30008807 TI - Implementing a podiatry prescribing mentoring program in a public health service: a cost-description study. AB - Background: In the management of diabetes and high-risk patients, timely treatment with scheduled medicines is critical to prevent severe infections and reduce the risk of lower extremity amputation. However, in Australia, few podiatrists have attained endorsement to prescribe. The aims of this study were to identify the costs associated with developing and implementing a podiatry prescribing mentoring program; and to compare the cost of this program against potential healthcare savings produced. Methods: This was a cost-description analysis, involving the calculation of costs associated with the development and implementation of a mentoring program to train podiatrists to become endorsed prescribers. Costs were calculated using the Ingredients Method and examined from the perspective of a public health service provider, and the individual learner podiatrist. Breakeven analysis compared the cost of training a podiatry prescriber for endorsement against the potential benefit (savings) made by averting complications of an infected foot ulcer. A sensitivity analysis was conducted to allow for uncertainty in the results of an economic evaluation. Results: Total start-up cost for the podiatry prescriber mentoring program was $13, 251. The total cost to train one learner podiatrist was $30, 087, distributed between the hospital $17, 046 and the individual learner $13, 041. In the setting studied, a podiatry prescriber must avert 0.40 major amputations arising from an infected foot ulcer through prescribing to recover the cost of training. If in-kind training costs are included, total cost increases to $50, 654, and the breakeven point shifts to 0.68 major amputations averted. Conclusion: The economic benefits (savings) created by an endorsed prescribing podiatrist over their career in a public health service are likely to outweigh the costs to train a podiatrist to attain endorsement. Further research is required to help understand the effectiveness of podiatry prescribing in reducing diabetic foot related complications and the potential economic impact of podiatry prescribers on this health condition. PMID- 30008808 TI - Identification of Schizosaccharomyces pombe in the guts of healthy individuals and patients with colorectal cancer: preliminary evidence from a gut microbiome secretome study. AB - Over the years, genetic profiling of the gut microbiome of patients with colorectal cancer (CRC) using genome sequencing has suggested over-representation of several bacterial taxa. However, little is known about the protein or metabolite secretions from the microbiota that could lead to CRC pathology. Proteomic studies on the role of microbial secretome in CRC are relatively rare. Here, we report the identification of proteins from Schizosaccharomyces pombe found in the stool samples of both healthy individuals and patients with CRC. We found that distinctive sets of S. pombe proteins were present exclusively and in high intensities in each group. Our finding may trigger a new interest in the role of gut mycobiota in carcinogenesis. PMID- 30008810 TI - The early 20th century warming: Anomalies, causes, and consequences. AB - The most pronounced warming in the historical global climate record prior to the recent warming occurred over the first half of the 20th century and is known as the Early Twentieth Century Warming (ETCW). Understanding this period and the subsequent slowdown of warming is key to disentangling the relationship between decadal variability and the response to human influences in the present and future climate. This review discusses the observed changes during the ETCW and hypotheses for the underlying causes and mechanisms. Attribution studies estimate that about a half (40-54%; p > .8) of the global warming from 1901 to 1950 was forced by a combination of increasing greenhouse gases and natural forcing, offset to some extent by aerosols. Natural variability also made a large contribution, particularly to regional anomalies like the Arctic warming in the 1920s and 1930s. The ETCW period also encompassed exceptional events, several of which are touched upon: Indian monsoon failures during the turn of the century, the "Dust Bowl" droughts and extreme heat waves in North America in the 1930s, the World War II period drought in Australia between 1937 and 1945; and the European droughts and heat waves of the late 1940s and early 1950s. Understanding the mechanisms involved in these events, and their links to large scale forcing is an important test for our understanding of modern climate change and for predicting impacts of future change. This article is categorized under:Paleoclimates and Current Trends > Modern Climate Change. PMID- 30008809 TI - Identification of a new alanine racemase in Salmonella Enteritidis and its contribution to pathogenesis. AB - Background: Non-typhoidal Salmonella (NTS) infections caused primarily by S. Enteritidis and S. Typhimurium particularly in immunocompromised hosts have accounted for a large percentage of fatalities in developed nations. Antibiotics have revolutionized the cure of enteric infections but have also led to the rapid emergence of pathogen resistance. New powerful therapeutics involving metabolic enzymes are expected to be potential targets for combating microbial infections and ensuring effective health management. Therefore, the need for new antimicrobials to fight such health emergencies is paramount. Enteric bacteria successfully evade the gut and colonize their hosts through specialized virulence strategies. An important player, alanine racemase is a key enzyme facilitating bacterial survival. Results: This study aims at understanding the contribution of alanine racemase genes alr, dadX and SEN3897 to Salmonella survival in vitro and in vivo. We have shown SEN3897 to function as a unique alanine racemase in S. Enteritidis which displayed essential alanine racemase activity. Interestingly, the sole presence of this gene in alr dadX double mutant showed a strict dependence on d-alanine supplementation both in vitro and in vivo. However, Alr complementation in d-alanine auxotrophic strain restored the alanine racemase deficiency. The Km and Vmax of SEN3897 was 89.15 +/- 10.2 mM, 400 +/- 25.6 umol/(min mg) for l-alanine and 35 +/- 6 mM, 132.5 +/- 11.3 umol/(min mg) for d alanine, respectively. In vitro assays for invasion and survival as well as in vivo virulence assays involving SEN3897 mutant showed attenuated phenotypes. Further, this study also showed attenuation of d-alanine auxotrophic strain in vivo for the development of potential targets against Salmonella that can be investigated further. Conclusion: This study identified a third alanine racemase gene unique in S. Enteritidis which had a potential effect on survival and pathogenesis in vitro and in vivo. Our results also confirmed that SEN3897 by itself wasn't able to rescue d-alanine auxotrophy in S. Enteritidis which further contributed to its virulence properties. PMID- 30008811 TI - Baseline and changes in serum uric acid independently predict glucose control among community-dwelling women. AB - Background: Elevated serum uric acid (SUA) levels are associated with glucose control. However, whether baseline and changes in SUA predict long-term follow-up glucose control [e.g., glycated hemoglobin (HbA1c)] remains unclear. Methods: The subjects comprised 393 women aged 71 +/- 8 years and 279 men aged 71 +/- 10 years from a rural village. We have identified participants who underwent a similar examination 11 years prior, and subjects were divided into four groups based on the tertiles of baseline and changes in SUA, and examined the relationship between baseline and changes in SUA, and glucose control evaluated by follow-up HbA1c after 11-years. Results: In both genders, follow-up SUA were significantly higher in Group 4 (i.e., women: Group 4, baseline SUA >= 4.0 mg/dL and changes in SUA >= 0.8 mg/dL; men: Group 4, >= 5.3 mg/dL and >= 0.4 mg/dL) than in the other Groups, but eGFR was significantly lower. Only in women, there were significant differences among the four groups regarding follow-up HbA1c, and follow-up HbA1c was highest in Group 4. In addition, the interaction between baseline and changes in SUA (F = 5.391, p = 0.021) as well as baseline low-density lipoprotein cholesterol (LDL-C) (F = 13.793, p < 0.001), estimated glomerular filtration ratio (F = 10.715, p = 0.001), HbA1c (F = 118.285, p < 0.001), SUA (F = 9.457, p = 0.002), and changes in SUA (F = 7.757, p = 0.006) was a significant and independent determinant of follow-up HbA1c. Multivariate-adjusted follow-up HbA1c (p = 0.002) were significantly higher in Group 4 than the other groups. Conclusions: These results suggested that combined assessment of baseline and changes in SUA provides increased information for long-term predictive glucose control, independent of other confounding factors in community-dwelling women. PMID- 30008812 TI - On flexible force fields for metal-organic frameworks: Recent developments and future prospects. AB - Classical force field simulations can be used to study structural, diffusion, and adsorption properties of metal-organic frameworks (MOFs). To account for the dynamic behavior of the material, parameterization schemes have been developed to derive force constants and the associated reference values by fitting on ab initio energies, vibrational frequencies, and elastic constants. Here, we review recent developments in flexible force field models for MOFs. Existing flexible force field models are generally able to reproduce the majority of experimentally observed structural and dynamic properties of MOFs. The lack of efficient sampling schemes for capturing stimuli-driven phase transitions, however, currently limits the full predictive potential of existing flexible force fields from being realized. This article is categorized under: Structure and Mechanism > Computational Materials ScienceMolecular and Statistical Mechanics > Molecular Mechanics. PMID- 30008813 TI - alpha7 nicotinic acetylcholine receptors in lung cancer. AB - Lung cancer has one of the highest mortality rates among malignancies globally, and smoking has been documented as the main cause of lung cancer. Nicotinic acetylcholine receptors (nAChRs) were initially identified as notable regulators of the nervous system. In addition to their function in the brain, accumulating evidence indicates that nAChRs perform a host of diverse functions in almost all non-neuronal mammalian cells. The homomeric alpha7nAChR, a subtype of nAChRs, is responsible for the proliferative, pro-angiogenic and pro-metastatic effects of nicotine in lung cancer. Provided the association of cigarette smoking with several disease types such as cardiovascular disease, the alpha7nAChR-mediated signaling pathway has been implicated in the pathophysiology of lung cancer. Currently, strategies that target the alpha7nAChR including alpha7nAChR antagonists are considered to be potentially useful anticancer drugs for therapeutic purposes. Thus, the present review assesses current understanding of the function and underlying molecular mechanisms of alpha7nAChR in lung cancer and evaluates how targeting alpha7nAChR may result in novel therapeutic methods. PMID- 30008815 TI - Fatty acid activation in carcinogenesis and cancer development: Essential roles of long-chain acyl-CoA synthetases. AB - The significance of fatty acid metabolism in cancer initiation and development is increasingly accepted by scientists and the public due to the high prevalence of overweight and obese individuals. Fatty acids have different turnovers in the body: Either breakdown into acetyl-CoA to aid ATP generation through catabolic metabolism or incorporation into triacylglycerol and phospholipid through anabolic metabolism. However, these two distinct pathways require a common initial step known as fatty acid activation. Long-chain acyl-CoA synthetases (ACSLs), which are responsible for activation of the most abundant long-chain fatty acids, are commonly deregulated in cancer. This deregulation is also associated with poor survival in patients with cancer. Fatty acids physiologically regulate ACSL expression, but cancer cells could hijack certain involved regulatory mechanisms to deregulate ACSLs. Among the five family isoforms, ACSL1 and ACSL4 are able to promote ungoverned cell growth, facilitate tumor invasion and evade programmed cell death, while ACSL3 may have relatively complex functions in different types of cancer. Notably, ACSL4 is also essential for the induction of ferroptosis (another form of programmed cell death) by facilitating arachidonic acid oxidation, which makes the enzyme a desirable cancer target. The present review thus evaluates the functions of deregulated ACSLs in cancer, the possible molecular mechanisms involved and the chemotherapeutic potentials to target ACSLs. A better understanding of the pathological effects of ACSLs in cancer and the involved molecular mechanisms will aid in delineating the exact role of fatty acid metabolism in cancer and designing precise cancer prevention and treatment strategies. PMID- 30008814 TI - Role of the SOX18 protein in neoplastic processes. AB - There is a high demand for anticancer drugs due to the fact that the chemotherapeutics currently used have numerous side effects, which lowers the patient's quality of life. However, the latest antibody therapies are extremely expensive, hence the requirement to identify novel, equally effective but low toxic treatments that have limited side effects. As a result of this, a number of research centres around the world are attempting to identify novel molecular markers that could be effective targets for anticancer therapy in the future. The SOX18 protein has been suggested to be a significant diagnostic and prognostic marker in various types of cancer. SRY-related HMG-box 18 (SOX18) is an important transcription factor involved in the development of cardiovascular and lymphatic vessels during embryonic development. In addition, it is involved in the progression of atherosclerosis and wound-healing processes. It has been observed that its level is higher in a number of cancer types, including melanoma, pancreas, stomach, liver, breast, lung, ovarian and cervical cancer. Furthermore, an association between a high expression of SOX18 in gastric cancer stromal cells and a poor prognosis has been demonstrated. The literature indicates how complex the pathogenesis of cancer is. Knowing the molecular basis of the pathogenesis of the tumor will allow for the effective use of targeted therapy, which may result in a higher success in treating patients. It is therefore important to identify novel and effective therapies as well as new proteins that could be potential markers. The SOX18 family, represented by the SOX18 protein, seems to be in this respect a promising element in modern anticancer therapy. PMID- 30008816 TI - Lily extracts inhibit the proliferation of gastric carcinoma SGC-7901 cells by affecting cell cycle progression and apoptosis via the upregulation of caspase-3 and Fas proteins, and the downregulation of FasL protein. AB - The present study aimed to investigate the effect of alkaloids and carbinol extracts from lily on the proliferation of SGC-7901 cells, as well as the underlying mechanism. SGC-7901 cells were incubated with different concentrations of alkaloid or carbinol extracts for 24, 48 or 72 h. MTT assays were used to measure the inhibition rate of SGC-7901 cell proliferation. Inverted phase contrast and fluorescence microscopy was used to observe morphological changes of SGC-7901 cells. Flow cytometry was employed to detect cell cycle progression and apoptosis rates of SGC-7901 cells. Western blotting was performed to measure the expression of caspase-3, Fas and Fas ligand (FasL) proteins in SGC-7901 cells. The inhibition rate of SGC-7901 cell proliferation was significantly enhanced with increasing drug concentrations and time elapsed. Treatment with alkaloid or carbinol extracts deteriorated the morphology of SGC-7901 cells in a dose dependent manner. Alkaloid and carbinol extracts arrested SGC-7901 cells in the G2/M phase, and induced apoptosis in a dose-dependent manner. Alkaloid and carbinol extracts enhanced caspase-3, and Fas expression, but reduced FasL expression in SGC-7901 cells. The present study demonstrated that alkaloids and carbinol extracts from lily inhibited the proliferation of gastric carcinoma SGC 7901 cells by arresting cells in the G2/M phase. The upregulation of caspase-3 and Fas proteins, and the downregulation of FasL protein may be an important mechanism for the induction of SGC-7901 cell apoptosis. PMID- 30008817 TI - Inhibitory effect of icariin on osteosarcoma cell proliferation via the Wnt/beta catenin signaling pathway. AB - Osteosarcoma, is a kind of malignant tumor derived from malignant interstitial cells. The pathogenesis of osteosarcoma remains unclear and despite use of chemotherapy drugs, resistance to these drugs affects the success of treatment. The present study was conducted to investigate the effects of icariin (ICA) on osteosarcoma cell proliferation and to investigate the role of the Wnt/beta catenin signaling pathway in the inhibition process of ICA on osteosarcoma cell proliferation. Different concentrations of ICA were selected to treat the osteosarcoma cell line 143B for 24 h, and then the onset concentration of ICA when it inhibited the growth of osteosarcoma cancer cell line 143B was detected via an MTT assay. The effect of ICA on the apoptosis of colon cancer cell line 143B under this concentration was detected using a flow cytometer. RNA in osteosarcoma cell line 143B was extracted, followed by reverse transcription. The expression levels of related and apoptotic proteins in the Wnt/beta-catenin signaling pathway using ICA were detected by semi-quantitative PCR and western blot analysis, respectively. The expression quantities of vascular endothelial growth factor (VEGF) and MMP-9 were detected by ELISA. MTT assay showed that ICA inhibited the growth of 143B when its concentration was 5 uM (p<0.01). Flow cytometry showed that the number of apoptotic cells after ICA treatment was significantly higher than that in control group (p<0.01). RNA in osteosarcoma cell line 143B was extracted, followed by reverse transcription. Semi quantitative PCR and western blot analysis revealed that the expression levels of p-GSK3beta, beta-catenin, c-Myc and cyclin D1 in cells after ICA treatment were significantly downregulated (p<0.01), while the expression level of caspase-3 was significantly increased (p<0.01). ELISA showed that the expression quantities of VEGF and MMP-9 were significantly decreased (p<0.01). Thus, ICA can significantly inhibit osteosarcoma cell proliferation and promote osteosarcoma cell apoptosis, which may be realized by affecting the expression of the Wnt/beta-catenin signaling pathway and blocking the expression of related proteins. PMID- 30008818 TI - Metabolic tumor volume changes assessed by interval 18fluorodeoxyglucose positron emission tomography-computed tomography for the prediction of complete response and survival in patients with diffuse large B-cell lymphoma. AB - An early discrimination of survival probability is required for patients with diffuse large B cell lymphoma (DLBCL), which may identify patients that require other treatment options, for example clinical trials. To the best of our knowledge, the impact of interim evaluation with 18fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) has not yet been determined in this type of neoplasia. The aim of the present study was to determine the role of changes in metabolic tumor volume (MTV) between baseline and interim 18F-FDG PET/CT scans, following three courses of chemotherapy in order to predict complete response (CR) and overall survival (OS) in patients with DLBCL. Patients with previously untreated DLBCL who had received the standard 6-8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone were included in the present study. A predictive model was constructed using changes in MTV and other clinical factors including age, gender, East Cooperative Oncology Group (ECOG) status, clinical stage, B symptoms, the presence of bulky disease and elevated lactate dehydrogenase levels, and data were analyzed using logistic regression analysis. In total, 50 patients with DLBCL were included in the present study. The majority of patients presented with stage III/IV disease (64%), B symptoms (72%) and bulky disease (58%). According to the International Prognostic Index score, 44% of patients were in the intermediate-high or high-risk categories for risk of relapse, and therefore considered to have poor prognosis. In total, >=94% of patients achieving a decrease in total MTV had a 2-year OS rate of 95%, compared with the 58% OS rate of those with a suboptimal response. A multivariate model, including a change in MTV (a decrease of >=94%), the ECOG performance status >=2, a change in leukocyte counts and age, was used to predict CR. This model was used to define two groups according to the predicted probability of recurrence (cutoff, 0.69). The 2-year survival rates of the two groups were 95 and 59%, respectively. Analysis of changes in MTV in the interim 18F-FDG PET/CT revealed significant prognostic value for the prediction of CR and OS in patients with DLBCL. PMID- 30008819 TI - Colonic granular cell tumor: Report of 11 cases and management with review of the literature. AB - Colonic granular cell tumors (GCTs) are rare and benign, but have malignant potential. The recent progress in endoscopic procedures and technology facilitate the diagnosis and treatment of GCTs. The present study described 11 cases of colonic GCTs diagnosed between March 2010 and April 2015, including patient clinical and histopathological features. Patients were generally asymptomatic. The most common symptoms were hematoquezia and abdominal pain. The male/female ratio was 7:4; age range was 40-67 years. Colonoscopy revealed a yellowish or white, solid and well-circumscribed tumor covered by normal mucosa. Endoscopic ultrasonography (EUS) showed a homogenous, or granular-type heterogeneous, hypoechoic solid tumor originating from the submucosal layer (8 cases) or muscularis mucosae (3 cases), with maximum diameters 0.3-3.0 cm. All patients underwent endoscopic submucosal dissection or endoscopic submucosal excavation without complication. All tumors were block removed. The mean operative time was 38 min (range, 31-50 min). Immunohistochemical analysis of all specimens confirmed the diagnosis of GCT by positive staining of S-100 protein. No recurrence or metastasis was observed during follow-up periods of 11 months to 5 years. In conclusion, colonoscopy, EUS and immunohistological examination increase the accuracy of diagnosis of GCTs. Endoscopic management is feasible and safe for GCT treatment. PMID- 30008820 TI - Growth inhibition of human hepatocellular carcinoma cells by antagonism of the beta2 adrenergic receptor. AB - Previous studies have shown that the activation of the beta2 adrenergic receptor (ADRB2) can stimulate several signaling pathways that promote tumor growth and metastasis. beta-adrenergic antagonism may have a beneficial role in cancer treatment; however, little is known about the effect of ADRB2 inhibition on the growth of human hepatocellular carcinoma (HCC) cells. The present study revealed that ADRB2 was highly expressed in HCC cell lines compared with that in a normal liver cell line. Treatment with the ADRB2 antagonists ICI118,551 and metoprolol significantly inhibited the growth of human HCC cells. Annexin V/propidium iodide apoptosis and Hoechst staining assays revealed that treatment with ADRB2 antagonists induced apoptosis in HCC cells. Additionally, cell cycle analysis using propidium iodide staining demonstrated that growth suppression was associated with G2/M phase cell cycle arrest by ADRB2 antagonism in HCC cells. Treatment with the ADRB2 antagonists suppressed HCC growth, possibly through inhibiting expression of B-cell lymphoma-2 (Bcl-2) and upregulating that of caspase-9 and Bcl-2-associated X, as well as downregulating the expression levels of the G2/M phase-associated proteins cyclin B1 and cyclin-dependent kinase 1. Therefore, the observations of the present study indicate that ADRB2 blockade inhibited HCC growth, potentially mediated by inducing apoptosis and G2/M phase cell cycle arrest. ADRB2 antagonists may therefore be a promising therapeutic strategy for HCC. PMID- 30008821 TI - ADME/toxicity prediction and antitumor activity of novel nitrogenous heterocyclic compounds designed by computer targeting of alkylglycerone phosphate synthase. AB - Alkylglycerone phosphate synthase (AGPS) is an oncogene and can be considered as an antitumor drug target. The aim of the present study was to design novel nitrogenous heterocyclic compound improving targetability by computer-aided drug design technology targeting AGPS. A total of 12 nitrogenous heterocyclic compounds were designed and predicted the absorption, distribution, metabolism and excretion parameters/toxicity. Their activity in terms of proliferation inhibition, cell cycle arrest and apoptosis induction was then measured using an MTS assay and a high-content screening system in U251 cells. The results showed that anti-glioma activity was present in compounds N4, N5, N6, N7, N8 and N12, which was in accordance with the computer prediction. Therefore, these compounds may be suitable for the development of a novel glioma therapeutic drug. PMID- 30008823 TI - Bilateral breast fibromatosis after silicone prosthetics in a patient with classic familial adenomatous polyposis: A case report. AB - Breast fibromatosis is a benign fibroblastic proliferation accounting for less than 0.2% of breast tumors. It presents sporadically or as a manifestation of familial adenomatous polyposis (FAP). Fibromatosis in FAP may develop in patients with adenomatous polyposis coli (APC) gene mutations at any location through the gene. Notably, there is an increased risk if mutation is downstream codon 1400. The present case report described a 33-year-old woman with recurrent bilateral breast fibromatosis after breast implants in a context of classic FAP. APC mutation (codon-935) was detected at the age of 16. In the same year, a thyroidectomy for a cribriform-morular papillary thyroid carcinoma (pT1) was performed. Seven years later, a prophylactic total colectomy with >100 adenomas without invasive carcinoma was performed and the patient was kept under surveillance. At the age of 30 years old, she underwent breast silicone implantation for cosmetic reasons. One year later, bilateral breast tumors were diagnosed in core biopsy as fibromatosis (nuclear beta-catenin+, estrogen receptors-). After no success with medical treatment with tamoxifen, bilateral mastectomy was performed. The patient relapsed one year later and a fibromatosis lesion in the right thoracic wall was excised again. The patient demonstrated no signs of relapse 24 months after the surgery. This rare case illustrates that the increased risk of developing fibromatosis in patients with FAP, even in the classic form, should be considered before deciding to place breast implants. PMID- 30008822 TI - miR-204 functions as a tumor suppressor gene, at least partly by suppressing CYP27A1 in glioblastoma. AB - Gliomas are the most common type of malignant primary brain tumors in adults and exhibit a spectrum of aberrantly aggressive phenotypes. Despite advances in treatments during past decades, prognosis of the disease remains poor, with a median survival time of 12-14 months. Future studies on the molecular mechanism of the disease may provide the theoretical basis to identify new targets for effective therapies. The present study revealed that in glioblastoma cells, the overexpression of cytochrome P450, family 27, subfamily A, polypeptide 1 (CYP27A1) promoted proliferation, while silencing of CYP27A1 inhibited proliferation, without affecting migration and invasion. CYP27A1 protein was upregulated in glioblastoma tissues, indicating that CYP27A1 is an oncogene. The downregulation of specific microRNAs (miRNA) may contribute to the upregulation of oncogenes in glioblastoma. A common strategy was used to predict target miRNAs of CPY27A1 using the miRanda algorithm. miR-211 and miR-204 could target the 3'untranslated region of CPY27A1 mRNA. Additional studies confirmed that the overexpression of miR-204 inhibited CPY27A1 expression in glioblastoma cells. Finally, it was identified that miR-204 was downregulated in glioblastoma and that its overexpression inhibited proliferation, migration and invasion in glioblastoma cells. Thus, it was concluded that miR-204 functions as a tumor suppressor gene, at least partly by suppressing CYP27A1 in glioblastoma. PMID- 30008824 TI - 12-Lipoxygenase promotes invasion and metastasis of human gastric cancer cells via epithelial-mesenchymal transition. AB - The role of 12-lipoxygenase (12-LOX) in tumorigenesis has been well established in several types of human cancer, including gastric cancer. It was reported that epithelial-mesenchymal transition (EMT) contributes to tumor invasion and metastasis. However, whether 12-LOX promotes the invasion and metastasis of human gastric cancer cells via EMT remains to be elucidated. In the present study, the expression of 12-LOX and EMT markers, N-cadherin and E-cadherin, was evaluated in gastric cancer and adjacent normal mucosa samples by immunohistochemical analysis. 12-LOX-overexpressing gastric cancer cells were established via lentiviral transfection of SCG-7901 cells. Wound-healing and Transwell assays were performed to examine the regulation of cell metastasis and invasion by 12 LOX. Furthermore, the regulation of N-cadherin expression by 12-LOX was evaluated using reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that the expression of 12-LOX and N-cadherin was significantly higher in gastric cancer compared with that in adjacent normal mucosa tissues (P<0.05). By contrast, the expression of E-cadherin was significantly decreased in gastric cancer compared with that in adjacent normal mucosa tissues (P<0.05). Furthermore, the expression of 12-LOX was positively associated with N-cadherin expression in gastric cancer tissues. 12-LOX overexpressing gastric cancer cells exhibited significantly increased invasion and migration abilities compared with the empty vector and control groups. The expression of N-cadherin in 12-LOX-overexpressing gastric cancer cells was increased compared with that in the empty vector and control groups. The present study suggests that EMT may be involved in the promotion of the invasion and metastasis of human gastric cancer cells by 12-LOX. PMID- 30008825 TI - Neuroradiological features of lymphomatosis cerebri: A systematic review of the English literature with a new case report. AB - Lymphomatosis cerebri is a rare form of diffusely infiltrating primary central nervous system (CNS) lymphoma (PCNSL). The neuroradiological findings of lymphomatosis cerebri have not been adequately characterized, as the relevant literature consists only of case reports and small case series. The present study describes an unusual presentation of lymphomatosis cerebri in a 56-year-old immunocompetent woman who presented with diffusely infiltrating lesions with perivascular curvilinear enhancement on initial magnetic resonance imaging (MRI) and multiple nodules on the later follow-up computed tomography (CT) scan. A systematic review of the literature is also performed searching PubMed between January 1996 and December 2016 to collect all pertinent case reports and series written in the English language with pathologically confirmed lymphomatosis cerebri and diffuse infiltrative PCNSL without cohesive masses on initial MRI. A total of 45 cases were identified from 39 articles and the present case report. The patient ages ranged from 28 to 85 years (mean, 57.3 years). Only 3 patients (6.7%) were immunosuppressed (acquired immune deficiency syndrome patients). The most common clinical presentation was cognitive changes or dementia (46.7%). Cerebrospinal fluid analysis in all cases was non-specific. Diffuse and asymmetric abnormal T2-hyperintensity in deep and subcortical white matter was observed in all cases. Gray matter involvement (17.8%), spreading along the corticospinal tract (35.6%) and a slight mass effect (51.1%) also were observed. Contrast-enhanced patterns on MRI could be divided into three forms of non enhancement (64.4%) and non-mass-like enhancement (35.6%) on initial MRI, as well as nodular or mass-like enhancement on the later follow-up MRI (15.6%). There were non-specific findings on magnetic resonance spectroscopy for 4 patients, on positron emission tomography/CT for 12 patients and on single-photon emission CT for 1 patient. Diagnosis was established by brain biopsy in 35 cases (77.8%) and autopsy in 9 cases (20%), involving B-cell lymphoma in 40 cases (88.9%) and T cell lymphoma in 4 cases (8.9%). In conclusion, lymphomatosis cerebri, namely diffuse PCNSL or diffuse lymphoma of the CNS, is characterized by rapidly progressive dementia in the elderly, diffusely infiltrated CNS white matter along the corticospinal tract, possible involvement of the gray matter, a slight mass effect and varied contrast-enhancement patterns on MRI. Non-enhancement or non mass-like enhancement on MRI may be a special form of diffuse PCNL during disease development and progression. PMID- 30008826 TI - RNA binding protein HuR promotes osteosarcoma cell progression via suppressing the miR-142-3p/HMGA1 axis. AB - The present study aimed to study the roles and underlying mechanisms of human antigen R (HuR) in osteosarcoma (OS) cell progression. It was determined that the HuR mRNA and protein levels were significantly upregulated in OS tissues, compared with that in normal adjacent tissues. HuR expression was negatively associated with miR-142-3p expression, but positively with High Mobility Group AT Hook 1 (HMGA1). Additionally, knockdown of HuR inhibited OS cells viability, epithelial-mesenchymal transition and promoted cell apoptosis. HuR was determined to harbor binding sites on HMGA1, directly binding to HMGA1, increasing HMGA1 mRNA stability and expression. Notably, the promotion of HuR on HMGA1 expression was attenuated via miR-142-3p overexpression, and miR-142-3p could directly bind to HMGA1 3'untranslated region (UTR). Furthermore, HMGA1 3'UTR with a mutated miR 142-3p binding site did not respond to HuR alterations. Finally, the inhibition of HuR knockdown was attenuated or even reversed via HMGA1 overexpression; therefore, the results of the present study indicated that RNA binding protein HuR may facilitate OS cell progression via competitively binding to HMGA1 with miR-142-3p. PMID- 30008827 TI - Clinical significance of ADAM29 promoting the invasion and growth of gastric cancer cells in vitro. AB - ADAM metallopeptidase domain 29 (ADAM29) belongs to the ADAM family, is a type I integral membrane protein and secrets a glycoprotein that mediates cell-cell and cell-matrix interaction. Aberrant expression of ADAM29 is involved in a number of physiological processes diversification. The purpose of the present study was to investigate the expression and biological effect of ADAM29 in human gastric cancer (GC) specimens and cell lines in vitro. The expression of ADAM29 was examined in 83 GC samples and 25 adjacent normal gastric tissues using quantitative reverse transcriptase-quantitative polymerase chain reaction and immunohistochemistry. The association between ADAM29 expression and cellular function of GC cells was assessed in vitro. The ADAM29 mRNA levels were significantly elevated in GC tissues compared with paracancerous tissues. Increased levels of ADAM29 were associated with high-grade staging and high Tumor Node-Metastasis stages. Kaplan-Meier survival curves demonstrated that patients with GC and low ADAM29 transcript levels exhibited longer overall survival (OS) (P<0.01) and progression-free survival (PFS) time (P<0.01) compared with patients with high ADAM29 expression levels. ADAM29 significantly promoted the proliferation, migration and invasion of GC cells in vitro when overexpressed in MGC803 cells and knocked down in AGS cells. ADAM29 was increased in GC and the elevated expression of ADAM29 was associated with a poor survival rate of patients. ADAM29 may become a prognostic factor and therapeutic candidate for human GC. PMID- 30008828 TI - Long noncoding RNA UPAT promoted cell proliferation via increasing UHRF1 expression in non-small cell lung cancer. AB - Evidence indicates that long non-coding RNAs (lncRNAs) serve a critical role in the regulation of non-small cell lung cancer (NSCLC) progression. LncRNA Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) protein associated transcript (UPAT) has been identified to be overexpressed in a variety of types of cancer. The present study demonstrated that lncRNA UPAT expression was upregulated in NSCLC tissues and significantly associated with tumor size and Tumor-Node-Metastasis stage. Additionally, UPAT promoted NSCLC cell proliferation and G1-S phase transition in vitro. Furthermore, UPAT promoted NSCLC cell proliferation, partly via increasing UHRF1 expression and consequently epigenetically silencing RASSF1 and CDH13 transcription. In addition, the knockdown of UHRF1 partially decreased the promotion of cell growth and G1-S phase transition caused by UPAT overexpression. In conclusion, these data suggest that the lncRNA UPAT promotes the NSCLC cell proliferation and may be a potential therapeutic target of NSCLC. PMID- 30008829 TI - REV-ERBalpha reduction is associated with clinicopathological features and prognosis in human gastric cancer. AB - Gastric cancer is a serious threat to human health. Nuclear receptor subfamily 1 group D member 1 (REV-ERBalpha) is a member of the nuclear hormone receptor family that regulates lipid metabolism, inflammatory responses and circadian rhythms. However, the role of REV-ERBalpha in the pathogenesis of human gastric cancer is unclear. The present study employed gastric cancer tissues from 74 patients and determined the association between REV-ERBalpha expression with clinicopathological variables and prognosis. Furthermore, the association between REV-ERBalpha and apoptosis in undifferentiated and moderately differentiated human gastric cancer cells was determined. It was identified that REV-ERBalpha expression was decreased in gastric cancer, which was positively associated with poor differentiation (P=0.009), T stage (P=0.001), Tumor-Node-Metastasis (TMN) stage (P=0.001) and lymph node metastasis (P=0.007). In the survival analysis, the 3- and 5-year survival times of patients were significantly associated with REV-ERBalpha expression (P=0.009 and P=0.002, respectively). Low REV-ERBalpha expression was associated with poor prognosis (P<0.05). Concurrently, cleaved caspase-3 expression was downregulated, whereas expression levels of Bcl-2 and the Bcl-2/Bax ratio were upregulated in gastric cancer tissues compared with normal tissues. REV-ERBalpha activator GSK4112 caused apoptosis in SGC-7901 and BGC-823 cell lines. REV-ERBalpha levels were decreased in human gastric cancer, which was associated with poor differentiation, TMN stages and poor prognosis. REV-ERBalpha is a potential biomarker for tumor development and prognosis, and a potential therapeutic target for gastric cancer. PMID- 30008830 TI - Expression of WNT1 in ameloblastoma and its significance. AB - The present study aimed to measure the expression of WNT1 in ameloblastoma (AB). Immunohistochemistry was used to observe changes in WNT1 expression in 80 AB samples, 10 keratocystic odontogenic tumor (KCOT) samples and 10 normal oral mucosa (NOM) samples. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to measure WNT1 protein and mRNA expression, respectively, in 30 AB samples, 5 KCOT samples, 5 NOM samples and 3 tooth germ samples. Ectopic cytoplasmic expression of WNT1 was detected in AB; 88.8% (71/80) of the samples were WNT1-positive. The western blotting results demonstrated that compared with NOM (0.57+/-0.05), WNT1 expression was significantly higher in AB tissue (1.74+/-0.36, P<0.05), whereas it was not significantly different between AB and KCOT samples (0.80+/-0.06, P>0.05). RT qPCR revealed that the level of WNT1 gene expression in AB was increased 2.43 fold compared with normal mucosa, and 1.77-fold compared with tooth germ tissue. In conclusion, WNT1 protein and mRNA expression were increased in AB, and there was ectopic cytoplasmic expression. This indicates that WNT1 may serve an important role in AB occurrence and development. PMID- 30008831 TI - Tryptase promotes breast cancer angiogenesis through PAR-2 mediated endothelial progenitor cell activation. AB - Mast cells have been demonstrated to accumulate around and within solid tumors of numerous types, and express a number of pro-angiogenic compounds, including tryptase. They may serve an early role in angiogenesis within developing tumors. In the present study, the role and mechanism of tryptase in the activation of endothelial progenitor cells (EPCs) in breast cancer angiogenesis were evaluated. Human umbilical cord blood EPCs were isolated and cultured. MB-MDA-231 breast cancer cells were then pretreated with tryptase, and the conditioned medium was collected. The effects of tryptase on the migratory and angiogenesis abilities of EPCs were determined using wound-healing and tube formation assays, respectively. The effect of tryptase on the proliferation of EPCs was detected using a Cell Counting Kit-8 assay. Alterations in proteinase activated receptor (PAR)-2, phosphorylated (p)-protein kinase B (AKT), p-extracellular signal-regulated kinase (p-ERK) and vascular endothelial growth factor receptor (VEGFR)-2 expression were analyzed, in tryptase or conditioned medium-treated EPCs, by western blot analysis and reverse transcription-quantitative polymerase chain reaction. It was confirmed that the EPCs expressed PAR-2; and that tryptase treatment promoted the migration and tube formation of EPCs. Treatment with a PAR 2 agonist had a similar effect to tryptase, whereas treatment with a tryptase inhibitor, APC366, or a PAR-2 inhibitor, SAM 11, inhibited the effect of tryptase treatment. Tryptase and PAR-2 agonists did not affect the rate of EPC proliferation. MB-MDA-231 cells also expressed PAR-2. Treatment with tryptase or conditioned medium increased the expression of PAR-2, p-AKT, p-ERK and VEGFR-2 in EPCs. In conclusion, tryptase activated EPCs via PAR-2-mediated AKT and ERK signaling pathway activation, thereby enhancing angiogenesis in breast cancer. PMID- 30008832 TI - Discrimination of malignant and benign breast masses using automatic segmentation and features extracted from dynamic contrast-enhanced and diffusion-weighted MRI. AB - Magnetic resonance imaging exhibits high sensitivity but low specificity for breast cancer. The present study aimed to investigate whether combining morphology, texture features and kinetic features with diffusion-weighted imaging using quantitative analysis improves the accuracy of discriminating malignant from benign breast masses. In total, 104 and 171 malignant lesions in 205 women were included. Additionally, 13 texture and 11 morphology features were computed from each lesion using a semi-automated segmentation method. To increase prediction accuracy, a newly designed classification model, difference-weighted local hyperplane, was used for statistical analysis of the combined effects of the features for predicting lesion type. The mean apparent diffusion coefficient (ADC) value for each lesion was calculated. Diagnostic performances of morphology and texture features, kinetic features and ADC alone and the combination of them were evaluated using receiver operating characteristics analysis. Malignant lesions had lower mean ADCs than benign lesions. By using 10-fold cross validation scheme, combined morphological and kinetic features achieved a diagnostic average accuracy of 0.87. Adding an ADC threshold of 1.37*10-3 mm2/sec increased the overall averaged accuracy to 0.90. A multivariate model combining ADC values with 6 morphological and kinetic parameters best discriminated malignant from benign lesions. Incorporating morphology and texture features, kinetic features and ADC into a multivariable diagnostic model improves the discriminatory power of breast lesions. PMID- 30008833 TI - Decreased argininosuccinate synthetase expression in Thai patients with cholangiocarcinoma and the effects of ADI-PEG20 treatment in CCA cell lines. AB - Cholangiocarcinoma (CCA) is a severe cancer with poor prognosis. The aim of the present study was to explore the expression of argininosuccinate synthetase (ASS), as well as the possibility of using pegylated arginine deiminase (ADI PEG20) for the treatment of CCA. ASS expression was determined in CCA specimens from 40 patients in Thailand. Immunohistochemical detection of ASS and determination of the proliferative index, Ki-67, were carried out in paraffin embedded sections of these specimens, as well as in two CCA cell lines, HuCCA and RmCCA-1, derived from CCA samples from patients in Thailand. In total, ~45% of the CCA specimens had low ASS expression, and the level of expression was significantly negatively associated with cell differentiation (P<0.05) and Ki-67 expression (P<0.05). The level of ASS expression in tumor cells was significantly lower than that in non-tumor cells (1.3-fold, P<0.05). The HuCCA cell line had significantly lower levels (P<0.05) of ASS expression at the mRNA and protein levels relative to those of normal human immortalized fibroblast cells (BJ-1). By contrast, the RmCCA-1 cell line showed no significant difference. In addition, the effects of ADI-PEG20 on growth inhibition, apoptosis and cell cycle arrest were determined in HuCCA and RmCCA-1 cells. ADI-PEG20 treatment reduced cell viability and cell proliferation in the two CCA cell lines, though it had no effect in immortalized BJ-1 cells. Furthermore, ADI-PEG20 treatment significantly increased G0/G1 cell cycle arrest in HuCCA, though not in RmCCA-1 cells. ASS silencing in the RmCCA-1 cell line significantly enhanced its sensitivity to ADI PEG20 treatment. Results from the in vitro study demonstrated that ADI-PEG20 has antitumor activity against CCA with low ASS expression. PMID- 30008834 TI - Dyspnea caused by a giant retroperitoneal liposarcoma: A case report. AB - Liposarcomas are the most common soft tissue tumors with various histological subtypes. They usually appear in the retroperitoneal region of the abdomen, but their symptomatology remains unclear and their diagnosis, as well as treatment challenging. A case of a 55-year-old female patient with dyspnea and light diffuse abdominal pain caused by a giant retroperitoneal liposarcoma is presented. The patient had an unremarkable medical history, while the computed tomography scan revealed a large mass at the right portion of the abdomen, with its upper limits to the lower edge and the gate portion of the liver. The mass was in contact with the right kidney, the inferior vena cava and the right renal vein, causing mild dilation of the right kidney pelvis. Without any evidence of intra-abdominal metastases, the tumor was surgically resected. The histological analysis of the tumor revealed a well-differentiated liposarcoma. The patient had an uneventful recovery and was discharged on the 10th postoperative day. Until today (4 years later) she remains asymptomatic, without any signs of recurrence. The retroperitoneal liposarcoma is a clinical entity with unclear clinical symptoms and the physician should consider including it in the differential diagnosis of a majority of symptoms, such as dyspnea. PMID- 30008835 TI - MicroRNA-29c restores cisplatin sensitivity in liver cancer through direct inhibition of sirtuin 1 expression. AB - Liver cancer is one of the most prevalent human tumors in the world. Despite recent advances regarding the understanding of the molecular basis of liver cancer and the introduction of novel chemotherapeutic approaches, liver cancer remains associated with a poor prognosis. Sirtuin 1 (SIRT1) was identified to be abnormally upregulated in liver cancer. Dysregulation of microRNAs (miRs/miRNAs) is associated with a variety of types of cancer, and miRNAs may also serve a role in tumorigenesis and progression. The present study demonstrated that following the selection of the cisplatin chemoresistant HepG2 cell line, miR-29c is downregulated using reverse transcription-quantitative polymerase chain reaction. Furthermore, overexpression of miR-29c in cisplatin-resistant cancer cells was demonstrated to inhibit tumor cell proliferation and to promote apoptosis in vitro and in vivo, as well as restoring cisplatin chemosensitivity by using a cell counting assay, colony formation assay, Annexin V-fluorescein isothocyanate/propidium iodide apoptosis analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling and xenograft tumors in nude mice. Mechanistically, according to bioinformatics analysis and a luciferase assay, miR 29c may directly target SIRT1 mRNA and repress SIRT1 expression, which is positively associated with the chemoresistance of liver cancer and may ultimately provide a novel therapeutic method. PMID- 30008836 TI - Value of combined detection of serum carcino-embryonic antigen, carbohydrate antigen 19-9 and cyclooxygenase-2 in the diagnosis of colorectal cancer. AB - The aim of the present study was to investigate the value of combined detection of serum carcino-embryonic antigen (CEA), carbohydrate antigen (CA) 19-9 and cyclooxygenase-2 (COX-2) in the diagnosis of colorectal cancer. A total of 50 patients with colorectal cancer were selected as Group A and 50 healthy subjects as the control group. A sample of 2 ml fasting venous blood was drawn from patients in each group, and serum CEA, CA19-9 and COX-2 were detected using electrochemiluminescence analyzer and ELISA. Receiver operating characteristic curve analysis was performed on analyze the sensitivity and specificity of diagnostic methods for colorectal cancer patients at different stages. The expression levels of CEA, CA199 and COX-2 in the cancer patients group were significantly higher than those in the healthy group (P<0.05). The coincidence rates of CEA, CA199, COX-2 and combined detection were 56.0, 64.0, 62.0 and 88.0%, respectively. The coincidence rate of combined detection was significantly higher than that of diagnosis using a single factor (P<0.05). Sensitivity of combined detection of colorectal cancer patients with stage I, II, III and IV were 82.9, 85.3, 86.4 and 88.7%, respectively. The specificities were 65.3, 68.7, 57.8 and 58.6%, respectively. Thus, CEA, CA199 and COX-2 in serum are highly expressed in colorectal cancer patients, and may useful as effective indicators for the early diagnosis of colorectal cancer. PMID- 30008837 TI - Assessment of pancreatic colloid carcinoma using 18F-FDG PET/CT compared with MRI and enhanced CT. AB - Pancreatic colloid carcinoma (CC) is a rare sub-type of pancreatic adenocarcinoma which has an improved prognosis compared with pancreatic ductal carcinoma. Consequently, the early detection of CC by imaging may be of great significance in guiding patient management and therapeutic decisions. The present study aimed to analyze 18F-FDG PET/CT findings of CC in comparison to MRI and CT. PET/CT findings in 5 patients with CC were retrospectively reviewed based on visual interpretation and semi-quantitative index of SUVmax and TNR. Four patients received dual-time-point PET/CT scans. Additionally, one patient underwent contrast-enhanced CT scan, one MRI, and three received both. A total of five lesions were detected in five patients. Visually, two cases presented with mild FDG uptake, two with moderate and one with high. The mean of SUVmax and TNR was 5.1+/-2.2 and 2.8+/-0.7, respectively. Compared with CCs with low SUVmax, CCs with high SUVmax were more aggressive. No distant metastases were observed in five cases. Among four patients with dual-time-point PET/CT imaging, SUVmax increased in three cases and decreased in one case. The mean early and delayed SUVmax were 4.2+/-1.1 and 4.7+/-1.9, respectively (P>0.05). Radiological findings mainly included septated cystic components, internal sponge-like contrast enhancement, calcification and 'salt-and-pepper sign' on MRI T2-weighted imaging. Thus, PET/CT provided additional information on metabolic tumor activity as well as locoregional and distant staging, which are important prognostic markers and may improve further patient management. However, PET/CT did not show any findings in addition to MRI and contrast-enhanced CT that were unique to CC and allowed a clear differentiation from other pancreatic malignancies. PMID- 30008838 TI - EPCR promotes MGC803 human gastric cancer cell tumor angiogenesis in vitro through activating ERK1/2 and AKT in a PAR1-dependent manner. AB - The endothelial cell protein C receptor (EPCR) serves a key role in activated protein C (APC)-mediated cytoprotective effects in endothelial cells, and is involved in the development of certain types of human cancer. To the best of our knowledge, the present study is the first to demonstrate that EPCR may exert effects on gastric cancer angiogenesis in vitro. To detect microvessel density (MVD), the microvascular endothelial cells were stained for cluster of differentiation (CD)31 and CD34 in 61 cases of surgical resection of gastric carcinoma tissues, and the association between the expression of EPCR protein and MVD was analyzed. In addition, to analyze the effect of EPCR expressed by gastric cancer cells on the proliferation, migration and angiogenic abilities of endothelial cells, human umbilical vein endothelial cells (HUVECs) were cultured with tumor-conditioned medium derived from EPCR knockdown or protease-activated receptor 1 (PAR1)-blocked MGC803 gastric cancer cells. A CCK-8 assay was used to assess the proliferation ability of the HUVECs. A Transwell assay was performed to assess the migration ability of the HUVECs and a Matrigel-based tube formation assay was used to assess the angiogenic activity of the HUVECs. The results demonstrated that the expression of EPCR was correlated with the MVD of gastric cancer tissues. When cultured with tumor-conditioned medium derived from EPCR knockdown or PAR1-blocked MGC803 cells, the proliferation, migration and tubules formation abilities of HUVECs were markedly inhibited markedly. The expression of phosphorylated (p)-extracellular signal regulated kinase 1/2, p-protein kinase B (AKT; s473) and p-AKT (T308) in the HUVECs was decreased. In addition, EPCR knockdown inhibited PAR1 activation in the MGC803 cells. These results indicated that the expression of EPCR in gastric cancer cell line MGC803 contributes to tumor angiogenesis in vitro by activating ERK1/2 and AKT, and that this effect of EPCR is dependent on PAR1 activation. PMID- 30008839 TI - Detection of human papillomavirus in branchial cleft cysts. AB - High-risk human papillomavirus (HPV) DNA has been reported to be present in branchial cleft cysts, but further information is required to clarify the role of HPV infection in branchial cleft cysts. The presence of HPV, the viral load and the physical statuses in samples from six patients with branchial cleft cysts were investigated using the polymerase chain reaction (PCR), quantitative PCR, in situ hybridization (ISH) using HPV DNA probes and p16INK4a immunohistochemical analysis. High-risk type HPV-16 DNA was identified in four of the six branchial cleft cysts analyzed. Of the HPV-positive branchial cleft cysts, three exhibited mixed-type integration of HPV. HPV DNA was distributed among the basal-to granular layers of the cystic wall in ISH analysis, and p16INK4a was weakly expressed in the nuclei and cytoplasm of the same layers in patients with integration. ISH revealed that one patient with episomal-type infection exhibited HPV DNA in the cyst wall and did not express p16INK4a. Two patients without evidence of HPV infection exhibited weak p16INK4a expression in the superficial cyst-lining cells of branchial cleft cysts. These results indicate that infection with high-risk HPV types may be common in branchial cleft cysts. In addition, p16INK4a is not a reliable surrogate marker for HPV infection in branchial cleft cysts. PMID- 30008840 TI - Resveratrol inhibits the growth of gastric cancer via the Wnt/beta-catenin pathway. AB - The inhibitory effect of resveratrol on the growth of gastric cancer cells through downregulation of the Wnt/beta-catenin signaling pathway were studied. First we determined the effective concentration of resveratrol on the growth and proliferation of MGC-803 gastric cancer cells. Methylthiazolyl tetrazolium assay showed that resveratrol significantly inhibited the proliferation of MGC-803 cells in a dose-dependent manner. Resveratrol induced apoptotic morphological changes in MGC-803 cells. Reverse transcription-polymerase chain reaction and western blot analysis showed that resveratrol downregulated the expression of three important components of the Wnt signaling pathway, beta-catenin, c-myc, and cyclin D1, at the mRNA and protein levels. Overall, resveratrol inhibits the growth of MGC-803 cells by inhibiting the Wnt signaling pathway. This study provides a new idea and direction for the antitumor mechanism of resveratrol. PMID- 30008841 TI - Association of the characteristics of B- and T-cell repertoires with papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Complementarity-determining region 3 (CDR3) of B-cell receptors (BCRs) and T-cell receptors are the major site of antigen recognition, which determines a unique clone type, and are considered to be the representative of the disease. In the present study, high-throughput sequencing was used to analyze the association of characteristics of the BCR immunoglobulin heavy chain (IGH) and the T-cell receptor beta chain (TRB) CDR3 genes in PTC and corresponding pericarcinous tissues from patients. A difference of CDR3 length distributions of total IGH CDR3 sequences between the two groups was revealed. IGHV3-11/IGHJ6, TRBV2/TRBJ1-2 and TRBV2/TRBJ1-1 may be biomarkers for the development of PTC. Furthermore, it was revealed that the extent of the common clonotype expressions at the amino acid level was slightly higher compared with the nucleotide level. The Shannon entropy demonstrated a diversity reduction in PTC compared with the pericarcinous group, and the highly expended clone (HEC) expression of PTC was higher compared with that of the corresponding pericarcinous group. Additionally, the highest clone frequency percentage of IGH and TRB was at 0.1-1.0% degree of expansion, as HEC expression was higher in PTC compared with the matched group. There was no shared clone of HECs in the two groups either at the amino acid level or at the nucleotide expression level. The differential expression of CDR3 sequences of PTC have been identified in the present study. Further research is required for assessing the immune repertoire size, diversity, cloning tracking and finding public clones of T-cell and B-cell populations in the development of PTC. PMID- 30008842 TI - Serum long noncoding RNA LRB1 as a potential biomarker for predicting the diagnosis and prognosis of human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a type of malignant tumor with a high mortality rate. Long non-coding RNAs (lncRNAs) serve important roles in cellular processes and gene regulation. Identifying novel prognostic biomarkers is important for the monitoring and treatment of HCC. However, only a limited number of biomarkers with high sensitivity and specificity have been determined and are used in clinical practice. The aim of the present study was to investigate the use of serum lncRNA uc007biz.1 (LRB1) expression levels as a novel non-invasive biomarker for the monitoring and diagnosis of HCC. The expression levels of LRB1 were detected in 326 patients with HCC and 73 healthy volunteers by using lncRNA expression microarrays and reverse transcription quantitative polymerase chain reaction analysis, and the associations between LRB1 expression and clinical parameters were analyzed. The results indicated that the serum LRB1 levels in patients with HCC were significantly increased compared with healthy volunteers. The serum LRB1 levels were positively associated with alpha-fetoprotein (AFP) expression, large tumor sizes, tumor stage (tumor-node metastasis or Barcelona Clinic Liver Cancer stage) and venous invasion, and were negatively associated with overall survival. Additionally, the use of a combination of LRB1, AFP and des-gamma-carboxy prothrombin (DCP) markers for the diagnosis of HCC, the diagnostic accuracy was increased compared with using LRB1 alone. LRB1 may act as an important regulator in the progression of HCC, and LRB1 may be considered as a novel biomarker for diagnosis and prediction of prognosis of HCC, additionally complementing the accuracy of AFP and DCP. PMID- 30008843 TI - Primary extra-nodal diffuse large B-cell lymphoma: A prognostic analysis of 141 patients. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma. Approximately 40% of DBLCL originates from extra-nodal sites, but the diversity of clinical presentations and the genetic and molecular alterations indicate that extra-nodal DLBCLs may be distinct disease entities. The aim of the present study was to highlight the various aspects of primary extra-nodal DLBCL (PE-DLBCL) based on a single center cohort. The data from 141 patients with PE-DLBCL treated at Peking Union Medical College Hospital were retrospectively evaluated. The primary extra-nodal sites involved were the gastrointestinal tract (n=42), central nervous system (CNS; n=38), breast (n=19), adrenal gland (n=15), female genital system (FGS; n=12), thyroid (n=8) and bone (n=7). The median overall survival rate was 28 months (range, 1-116). Multivariate analysis demonstrated that an International Prognostic Index (IPI) <=2 (P=0.049), complete remission (CR) achieved following first-line therapy (P=0.001) and chemotherapy combined with rituximab (P<0.001) were positive prognostic factors. Patients with DLBCL with primary adrenal gland or female genital system (FGS) involvement exhibited a significantly higher risk of CNS recurrence (P<0.05). Rituximab treatment may have reduced the likelihood of CNS recurrence (P=0.005), whereas prophylaxis with intrathecal injection alone was not sufficient for prevention (P>0.05). In conclusion, IPI >2 and the lack of a CR following first-line therapy were independent prognostic risk factors for PE-DLBCL. Patients with primary adrenal gland or FGS involvement exhibited a higher risk of CNS relapse. Rituximab had a positive impact on the survival of patients with PE-DLBCL, also reducing the likelihood of CNS relapse. PMID- 30008845 TI - Effect of CEACAM-1 knockdown in human colorectal cancer cells. AB - Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is the major antigen of the CD66 cluster of granulocyte differentiation antigens. The present study aimed to assess the biological function of CEACAM-1 on the growth of human colorectal cancer (CRC) cells in vitro. Treatment of cultured CRC HCT-8 cells with CEACAM-1-specific siRNA successfully downregulated CEACAM-1 expression by 61% compared with control cells. The effects of CEACAM-1 downregulation on HCT-8 cell proliferation and apoptosis were then assessed via Cell Counting kit-8 assay and flow cytometry, respectively. The results demonstrated that siRNA-induced CEACAM-1 downregulation significantly inhibited proliferation and increased apoptosis, but had no significant effect on cell cycle progression in HCT-8 cells. Together, these results suggest that CEACAM-1 activity is critical to CRC growth, and thus, CEACAM-1 may be a promising therapeutic target for the treatment of CRC. PMID- 30008844 TI - A novel RFLP-ARMS TaqMan PCR-based method for detecting the BRAF V600E mutation in melanoma. AB - To enable the rapid and sensitive screening of the BRAF V600E mutation in clinical samples, a novel method combining restriction fragment length polymorphism (RFLP) analysis with the popular amplification refractory mutation system (ARMS) TaqMan quantitative (qPCR) genotyping method in a single reaction tube was developed. A total of 2 primer pairs were designed to enrich for and genotype the BRAF mutational hotspot (RFLP primers and ARMS primers) and a restriction enzyme was used to remove the wild-type alleles. The analysis revealed that this method detected mutant alleles in mixed samples containing >0.1% mutant sequences. In a survey of 53 melanoma samples, this method detected 21 mutation-positive samples. This novel RFLP-ARMS TaqMan qPCR protocol may prove useful for detecting mutations in clinical samples containing only a small proportion of mutant alleles. PMID- 30008846 TI - Inhibitory effect of NVP-BKM120 on cholangiocarcinoma cell growth. AB - Abnormal activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been demonstrated in certain types of cancer, including cholangiocarcinoma (CCA). This pathway may therefore be a promising target for CCA treatment. The present study assessed the inhibitory effect of NVP-BKM120, a pan-class I PI3K inhibitor, on CCA cell growth. This inhibitory effect was determined using CCA cell lines and in CCA-inoculated mice. The result from sulforhodamine B (SRB) assay demonstrated that NVP-BKM120 treatment inhibited CCA cell growth in a dose-dependent manner, even at the lowest tested concentration. The in vivo study revealed that oral administration of NVP-BKM120 (10 or 30 mg/kg) to CCA-inoculated nude mice led to a reduction in tumor growth when compared with controls, which was indicated by an immunohistochemical assay for Ki67 expression. In addition, the result from TUNEL assay demonstrated that NVP-BKM120 induced cancer cell death without any signs of toxicity, which indicated by the body weight of mice (data not shown). Western blot analysis demonstrated that NVP-BKM120 inhibited CCA cell growth by suppressing RAC serine/threonine protein kinase/mechanistic target of rapamycin activation and inhibiting the phosphorylation of phosphatase and tensin homolog, which is the inactivation form of the negative regulator of this pathway. Therefore, the results of the present study indicated that NVP-BKM120 should be considered as a therapeutic agent against CCA that could be used to improve treatment. PMID- 30008847 TI - Inhibitor of DNA binding 3 reverses cisplatin resistance in human lung adenocarcinoma cells by regulating the PI3K/Akt pathway. AB - Inhibitor of DNA-binding 3 (ID3) is a helix-loop-helix transcription factor that is associated with cell proliferation, differentiation and drug resistance in human cancer, and with anticancer effects in certain types of cancer cells. The present study investigated whether and how ID3 was involved in multidrug resistance (MDR) in human cisplatin (DDP)-resistant A549/DDP lung adenocarcinoma cells. The underlying mechanism of action was investigated in vitro. Cell Counting Kit-8 (CCK-8) and flow cytometry assays demonstrated that overexpression of ID3 enhanced chemosensitivity and decreased drug efflux in A549/DDP cells. Reverse transcription-quantitative polymerase chain reaction revealed that the expression of anti-apoptotic gene B-cell lymphoma-2 was significantly downregulated in cells expressing exogenous ID3 (P<0.05). These results indicated that ID3 may synergize with DDP to increase apoptosis in A549/DDP cells. ID3 overexpression modulated the activity of phosphoinositide 3-kinase/RAC serine/threonine-protein kinase signaling and downregulated the expression of multi-drug resistance protein-1, indicating that ID3 expression can reverse multi drug resistance in A549/DDP cells. Collectively, these results indicate that ID3 is a potential effective chemotherapeutic target for the treatment of human DDP resistant A549 lung adenocarcinoma therapy. PMID- 30008848 TI - The dog as an animal model for bladder and urethral urothelial carcinoma: Comparative epidemiology and histology. AB - Despite the recent approval of several novel agents for patients with metastatic urothelial carcinoma (UC), survival in this setting remains poor. As such, continued investigation into novel therapeutic options remains warranted. Pre clinical development of novel treatments requires an animal model that accurately simulates the disease in humans. The aim of the present study was to evaluate the dog as an animal model for human UC. A total of 260 cases of spontaneous, untreated canine primary urethral and urinary bladder UC, were epidemiologically and histologically assessed and classified based on the current 2016 World Health Organization (WHO) tumor classification system. Canine data was compared with human data available from scientific literature. The mean age of dogs diagnosed with UC was 10.22 years (range, 4-15 years), which is equivalent to 60-70 human years. The results revealed a high association between UC diagnosis with the female sex [odds ratio (OR) 3.51; 95% confidence interval (CI) 2.57-4.79; P<0.001], surgical neutering (OR 4.57; 95% CI 1.87-11.12; P<0.001) and breed (OR 15.11 for Scottish terriers; 95% CI 8.99-25.41; P<0.001). Based on the 2016 WHO tumor (T), node and metastasis staging system, the primary tumors were characterized as T1 (38%), T2a (28%), T2b (13%) and T3 (22%). Non-papillary, flat subgross tumor growth was strongly associated with muscle invasion (OR 31.00; P<0.001). Irrespective of subgross growth pattern, all assessable tumors were invading beyond the basement membrane compatible with infiltrating UC. Conventional, not further classifiable infiltrating UC was the most common type of tumor (90%), followed by UC with divergent, squamous and/or glandular differentiation (6%). Seven out of the 260 (2.8%) cases were classified as non urothelial based on their histological morphology. These cases included 5 (2%) squamous cell carcinomas, 1 (0.4%) adenocarcinoma and 1 (0.4%) neuroendocrine tumor. The 2 most striking common features of canine and human UC included high sex predilection and histological tumor appearance. The results support the suitability of the dog as an animal model for UC and confirm that dogs also spontaneously develop rare UC subtypes and bladder tumors, including plasmacytoid UC and neuroendocrine tumor, which are herein described for the first time in a non-experimental animal species. PMID- 30008849 TI - Effects of Helicobacter pylori on the expression levels of GATA-3 and connexin 32 and the GJIC function in gastric epithelial cells and their association by promoter analysis. AB - The present study aimed to explore the effects of Helicobacter pylori (H. pylori) infection on the expression of transcription factor GATA binding protein 3 (GATA 3) and connexin 32 (Cx32) in cultured gastric mucosa cells, and their association with each other. GES-1 cells were co-cultured with East Asian type cytotoxin associated gene A+ H. pylori in the H. pylori group, and without H. pylori culture in the control group. Additionally, Mongolian gerbils were gavaged with H. pylori, and later the gastric antrum tissues were collected. The GATA-3 and Cx32 mRNA and protein expression levels were detected by a reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. The scratch labeling fluorescent dye tracer (SLDT) technique was used to detect the gap junctional intercellular communication (GJIC) function. GATA-3 small interfering RNA (siRNA) was transfected into BGC823 cells and its effect on Cx32 expression levels was detected. The impact of GATA-3 on Cx32 promoter transcriptional activity was detected using a dual luciferase reporter assay. The results revealed that H. pylori infection increased GATA-3 expression and decreased Cx32 expression in GES-1 cells and in animal gastric tissues compared with their respective controls, whilst in BGC823 cells, GATA-3 siRNA increased Cx32 expression compared with the control. In the SLDT experiment of GES-1 cells with H. pylori infection, the fluorescent dye was primarily limited to a single cell row close to the scratch, and only a limited amount of dye passing to the second cell row, indicating that the GJIC function was substantially reduced or absent compared with the control group, where the fluorescence dye transferred to the neighboring cells of 3-4 rows, indicating a stronger GJIC function comparatively. GATA-3 inhibited the expression of the luciferase reporter gene, compared with the controls, suggesting that GATA-3 inhibited the expression of Cx32 by binding to Cx32 promoter sites. These results indicated that H. pylori increased GATA-3 expression, which downregulated Cx32 expression, may serve an important function in gastric carcinogenesis, and GATA-3 siRNA may serve a function in the prevention and treatment of gastric cancer. PMID- 30008850 TI - Significance and prognosis of epithelial-cadherin expression in invasive breast carcinoma. AB - The objective of the present study was to investigate and analyze the epithelial cadherin (E-cadherin) expression in invasive ductal carcinoma of the breast, and to analyze the associations between the expression and clinicopathological characteristics of lymph node metastasis and the prognosis of breast cancer. The immunohistochemical streptavidin-peroxidase method was used to detect the E cadherin expression in 30 cases of breast fibroadenoma and in 450 cases of invasive breast cancer, and then the chi2test and Kaplan-Meier method were used to analyze the data. The 30 cases of breast fibroadenoma showed positive expression of E-cadherin. Specifically, results found that E-cadherin was highly expressed in 49.04% (77/157) of patients with non-metastatic breast cancer, while low expression was found in 50.96% (80/157). Additionally, E-cadherin was highly expressed in 29.69% (87/293) of patients with lymph node metastasis of breast cancer, with low expression in 70.31% (206/293); these differences were significantly different (chi2=16.53; P<0.001). E-cadherin was expressed in 35.48% (22/62), 33.73% (84/249), 63.83% (30/47) and 30.43% (28/92) of patients with luminal A type, luminal B type, human epidermal growth factor receptor-2positive and triple-negative breast cancer (TNBC), respectively. It was found that patients with high expression of E-cadherin had a better prognosis than the low expression group with regards to TNBC, and this result was significantly different (chi2=4.48; P=0.034). In conclusion, low E-cadherin expression was associated with lymph node metastasis in invasive breast cancer, and the patients with low expression also had a poor prognosis compared with those in the high expression group. The present results suggested that E-cadherin could be used in a prognostic index for patients with lymph node metastasis and TNBC. PMID- 30008851 TI - miR-224/miR-141 ratio as a novel diagnostic biomarker in renal cell carcinoma. AB - Biomarkers to guide the clinical treatment of patients with renal cell carcinoma (RCC) are not yet routinely available. MicroRNAs (miRNAs) have been demonstrated to serve as biomarkers for a number of types of cancer. Based on a previous study by this group, we hypothesize that several highly differentially expressed miRNAs may serve as tissue and plasma biomarkers in patients with RCC. The expression levels of miR-210, miR-224 and miR-141 were analyzed in tissue samples from the same cohort of 78 patients with RCC, in paired pre- and post-operative plasma samples from 66 patients with clear cell RCC (ccRCC) and in 67 healthy controls by reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic (ROC) was used to evaluate the diagnostic accuracy associated with the expression of miR-210, miR-224 and miR-141. ROC curves revealed that the diagnostic accuracy (area under the curve) of tissue miR-210, miR-224, the ratio of miR-210/miR-141 (miR210/141), miR-224/miR-141 (miR224/141) and miR-210* miR-224/miR-141 (miR210*224/141) in ccRCC was 0.8329, 0.8511, 0.9412, 0.9898 and 0.9771, respectively. Notably, miR224/141 demonstrated the highest accuracy among these miRNAs for discriminating ccRCC tissues from normal tissues, with a sensitivity of 97.06% and a specificity of 98.53%. The expression levels of plasma miR-210 and miR-224 were significantly increased in patients compared with healthy control patients, and were reduced postoperatively (P<0.05). The diagnostic accuracy of plasma miR-210 and miR-224 were 0.6775 (89.55% sensitivity and 48.48% specificity) and 0.6056 (88.06% sensitivity and 40.91% specificity), respectively. The present study indicated that the tissue miR-224/miR-141 ratio is a potentially powerful tool for detecting ccRCC. However, plasma miR-210 and miR-224 may not be associated with diagnosis of ccRCC. PMID- 30008852 TI - Knockout of SIRT4 decreases chemosensitivity to 5-FU in colorectal cancer cells. AB - Previous studies demonstrated that sirtuin (SIRT) 4 is aberrantly expressed in human malignant tumors and is associated with poor prognosis in patients with colorectal cancer. However, the role of SIRT4 in the progression of human colorectal cancer (CRC) and in chemotherapy remains unclear. In the present study, the expression of SIRT4 in CRC tissues and the effect of SIRT4 on colorectal cancer proliferation, migration and invasion was investigated. Additionally, the effects of SIRT4 on the chemosensitivity in colorectal cancer cells and the underlying molecular mechanisms were also explored. The results demonstrated that SIRT4 expression is significantly downregulated in CRC tissues and cell lines. Downregulation of SIRT4 significantly increased tumor proliferation, migration and invasion. Additionally, downregulation of SIRT4 decreased the chemosensitivity of CRC cells by inhibiting cell apoptosis. Thus, these results suggest that SIRT4 may be a promising therapeutic target in CRC. PMID- 30008853 TI - FBP1 promotes ovarian cancer development through the acceleration of cell cycle transition and metastasis. AB - Epithelial ovarian cancer (EOC) is the fifth most common malignancy in women, with a 5-year mortality of >70% in North America. As the symptoms are often not observed until the cancer has spread extensively, few women are diagnosed at an early stage of disease. Large-scale gene expression analyses have identified molecular subtypes within high-grade ovarian cancer with variable survival rates and drug resistance. The understanding of gene expression, the mechanisms underlying cancer processes and drug resistances have facilitated the development of targeted therapies. The far-upstream element (Fuse)-binding protein 1 (FBP1) is overexpressed in a number of malignancies such as hepatocellular carcinoma, and has been identified as an oncoprotein. In our early studies, FBP1 was demonstrated to physically interact with p53 and suppresses p53 transcription activity. In the present study, FBP1 expression increased as ovarian cancer developed. Among ovarian normal, adenoma and carcinoma tissues, the highest FBP1 expression was identified in carcinoma tissues. Furthermore FBP1 did not influence the apoptosis of ovarian carcinoma cells, yet enhanced cell cycle transition and metastasis. Therefore, it was hypothesized that FBP1 promotes ovarian cancer development through the acceleration of cell cycle transition and metastasis, and FBP1 is a novel potential biological marker for epithelial ovarian cancer diagnosis. PMID- 30008854 TI - Functional cardiac Na+ channels are expressed in human melanoma cells. AB - Resting membrane potential (RMP) and intracellular Ca2+ concentration [(Ca2+)i] are involved in tumorigenesis and metastasis. The present study investigated whether functional cardiac Na+ channels are expressed in human melanoma cells (WM 266-4) and its nonmalignant human melanocytes (HMC), as well as whether they participate in RMP maintenance and Ca2+ homeostasis. Confocal microscopy and western blot analysis were used to detect Na+ channels. The patch-clamp technique was employed to record Na+ currents and action potentials. Cytoplasmic Ca2+ was measured by loading Fluo-4. Cardiac (Nav1.5) Na+ channels were expressed in HMCs and WM 266-4 cells. Tetrodotoxin (TTX) dose-dependently blocked Na+ currents in WM 266-4 while HMCs had no Na+ currents. Ultraviolet light induced similar action potentials in HMCs and WM 266-4 cells, which were abolished by transient receptor potential A1 channel-specific blocker, HC-030031. Compared with HMCs, RMP was substantially depolarized in WM 266-4. TTX hyperpolarized RMP in WM 266-4 cells at a concentration of 30 uM, which facilitated Ca2+ influx. Compared with HMCs, (Ca2+)i was significantly higher in WM 266-4 cells and was elevated by 30 uM TTX. Collectively, Cardiac Na+ channels depolarize RMP and inhibit Ca2+ uptake in melanoma cells possibly contributing to tumorigenesis and metastasis. Na+ channel agonists may be developed to treat melanoma such as WM 266-4. PMID- 30008855 TI - Effects of zoledronic acid and ibandronate in the treatment of cancer pain in rats with lung cancer combined with bone metastases. AB - The aim of the study was to investigate the efficiency and safety of zoledronic acid and ibandronate in the treatment of rats with lung cancer combined with bone metastases. A total of 124 rats with lung cancer bone metastasis were established. Rats were randomly divided into A, B and C groups (n=30). Rats in group A were treated with ibandronate combined with zoledronic acid, rats in group B were treated with zoledronic acid monotherapy, and rats in group C were treated with ibandronate monotherapy. Rats in group A were injected subcutaneously with zoledronic acid 0.1 mg/kg and ibandronate 10 ug/kg, once per week for 12 weeks; rats in group B were injected subcutaneously with zoledronic acid, and rats in group C were injected subcutaneously with ibandronate, the same method as the treatment group. The remaining 34 SD rats were not treated to serve as the control group. Treatment efficacy and physical improvement in 8 weeks were observed, and improvement of pain behavior in rats was evaluated to reflect the effect of drug treatment. Of the 30 rats in group A, 25 showed different degrees of remission, 5 rats showed no improvement and the effective rate was 83.3%. Of the 30 rats in group B, 21 showed different degrees of remission, 9 rats showed no improvement and the effective rate was 70%. Of the 30 rats in group C, 20 showed different degrees of remission, 10 rats showed no improvement and the effective rate was 66.7%. Statistically significant differences in total effective rate were found among three groups, and the combined method showed the highest effective rate (P<0.05). Ibandronate combined with zoledronic acid has a good therapeutic effect on cancer pain caused by bone metastases from lung cancer. PMID- 30008856 TI - Correlation between ultrasonic features and expression levels of C-erbB-2, VEGF and nm23 in breast cancer. AB - Breast cancer is one of the most common female malignancies in clinical practice, which ranks number one in terms of its high incidence. We investigated the relevance of ultrasonic features of breast cancer and expression levels of C-erbB 2, vascular endothelial growth factor (VEGF) and nm23 and its clinical significance. A total of 76 patients with breast cancer were recruited who were admitted to The Affiliated Hospital of Qingdao University from January, 2016 to August, 2017. All patients underwent color Doppler ultrasonic imaging, and expression levels of C-erbB-2, VEGF and nm23 in their tumor tissues were measured by immunohistochemistry. The ultrasonic features were evaluated and compared with the expression levels of C-erbB-2, VEGF and nm23 for each patient. Ultrasonography showed a tumor mass with spiculated margins, abnormal vasculature, and a diameter no less than 3 cm, as well as lymph node metastasis. The above signs were associated with high expression of C-erbB-2, VEGF and nm23 (p<0.05), but calcification was not associated with high expression of these biomarkers (p>0.05). For patients with highly expressed C-erbB-2 and VEGF, the time to peak (TTP) of the time-intensity curve obtained by contrast enhanced ultrasound was shorter, while the peak intensity (PI) was higher. On the contrary, for patients with highly expressed nm23, the TTP was apparently longer, while the PI was lower (p<0.05). The ultrasonic features of breast cancer were relevant to the expression levels of C-erbB-2, VEGF and nm23. Thus, the expression levels of C-erbB-2, VEGF and nm23 were predictable indirectly according to the ultrasonic features of the patient, which can be used as a reference for breast cancer treatment and prognosis prediction. PMID- 30008857 TI - MiR-1256 suppresses proliferation and migration of non-small cell lung cancer via regulating TCTN1. AB - Mounting evidence has shown that miRNA expression is abnormal in various human cancers. Here, we mainly explored the biological function and the potential mechanisms of miR-1256 in non-small cell lung cancer (NSCLC). The miR-1256 mRNA expression was detected by quantitative real-time PCR and tectonic family member 1 (TCTN1) mRNA expression was detected by immunoblotting. The TCTN1 was identified to be the direct and specific target gene of miR-1256 by luciferase reporter assay. Cell proliferation was examined by methyl thiazolyl tetrazolium assay and migration was detected by transwell assay. MiR-1256 expression was downregulated in NSCLC tissues, whereas the expression of TCTN1 was upregulated, compared with normal tissues. We also found that overexpression of miR-1256 in these NSCLC cell lines inhibited cell proliferation and migration. Furthermore, TCTN1 was identified as a direct target of miR-1256 by luciferase reporter assays. Collectively, these data stated that the inhibitory effect of miR-1256 in NSCLC was realized by upregulating TCTN1, suggesting that miR-1256/TCTN1 axis may play a critical role as NSCLC therapeutic target. PMID- 30008858 TI - miR-205-5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1. AB - Many studies have demonstrated that miRNAs have influence on tumorigenesis and progression of human cancers, including invasion and migration. Thus, the role of miR-205/ZEB1 axis for the migration and invasion of prostate cancer cells was explored in the present study. The miR-205-5p and zinc finger E-box binding homeobox 1 (ZEB1) mRNA expression levels were observed in prostate cancer tissues or cell lines via reverse transcription-quantitative PCR (RT-qPCR), and the protein level of ZEB1 was measured by western blotting. Dual-Luciferase Reporter Assay was used to verify the relationship between miR-205-5p and ZEB1. In addition, cell migration and invasion was measured by Transwell assay. The results revealed that, compared with the control, downregulation of miR-205-5p was detected in prostate cancer tissues and cell lines, and miR-205-5p overexpression was found to inhibit cell migration and invasion. Moreover, miR 205-5p was confirmed to directly target ZEB1 in prostate cancer. Importantly, ZEB1 was identified to weaken the inhibitory effect of miR-205-5p in prostate cancer. In conclusion, miR-205-5p inhibited cell migration and invasion in prostatic carcinoma by targeting ZEB1 and miR-205-5p/ZEB1 axis shows potential to be developed in therapeutic strategies for prostate cancer. PMID- 30008859 TI - Correlation between miR-222 and uterine cancer and its prognostic value. AB - Relationship between the expression of miR-222 and uterine cancer was investigated to explore its prognostic value. A total of 66 patients with uterine cancer diagnosed by pathological examination in Dongying People's Hospital were enrolled from March 2014 to October 2016. Uterine cancer and adjacent tissues were collected, and the expression of miR-222 in the tissues was detected by stem loop RT-PCR. The relationship between miR-222 expression and various clinicopathological features of uterine cancer was analyzed. All the patients were followed up to record the survival conditions. The results revealed that stem-loop RT-PCR method could specifically amplify miR-222. The expression of miR 222 in uterine cancer tissues was significantly upregulated compared with that in adjacent tissues (p<0.05). The expression level of miR-222 was significantly increased with the increase of degree of tumor differentiation (p<0.05). The expression of miR-222 in uterine cancer tissue was not significantly correlated with patients age, tumor size, gross tumor type, pathological type and FIGO stage (p>0.05). There was a significant negative correlation between the expression of miR-222 and the survival of patients with uterine cancer. In conclusion, the expression of miR-222 in uterine cancer tissues was significantly upregulated in uterine cancer and negatively correlated with prognosis. miR-222 may play a pivotal role in the development and progression of uterine cancer. It is expected that miR-222 will be an indicator and target for the treatment and prognosis of uterine cancer. PMID- 30008860 TI - Combination of procalcitonin, C-reaction protein and carcinoembryonic antigens for discriminating between benign and malignant pleural effusions. AB - Pleural effusion (PE) is a common manifestation associated with certain chest diseases. However, there is no effective diagnostic marker with high sensitivity and specificity. The aim of the present study was to evaluate the diagnostic performance of several biomarkers in the use of detecting malignant pleural disorder. One hundred and fifty patients with a specific diagnosis of exudative PE were enrolled in this study and were divided into the benign PE group (n=93) and the malignant PE group (n=57). Thoracoscopy was conducted to identify the reasons for the PE. Biomarkers in pleural fluid and in sera were determined either by microparticle enzyme immunoassay [carcinoembryonic antigen (CEA)], fluorescence immunoassay [procalcitonin (PCT)] or light-scattering turbidimetric immunoassay [C-reaction protein (CRP)]. Then, correlation analysis and receiver operating characteristic (ROC) curve analysis individually or in combination were performed. The CRP and PCT levels were higher in benign PE than they were in malignant PE (PCT: P=0.017, P=0.032; CRP: P=0.001, P<0.001, respectively), while CEA levels were lower in benign PE than in malignant PE (CEA: P=0.001, P=0.001, respectively). During the ROC curve analysis, an optimal discrimination was identified by combining pleural CRP, pleural CEA and serum (s)PCT with an area under the curve of 0.973 (sensitivity, 98.9%; specificity, 89.5%). In the diagnosis of PE, there was no single biomarker that appeared to be adequately accurate. The combination of pleural CRP, pleural CEA and sPCT may represent an efficient diagnostic procedure for guiding the patient towards follow-up clinical treatment. PMID- 30008861 TI - Cross talk of chromosome instability, CpG island methylator phenotype and mismatch repair in colorectal cancer. AB - Colorectal cancer is a severe cancer associated with a high prevalence and fatality rate. There are three major mechanisms for colorectal cancer: (1) Chromosome instability (CIN), (2) CpG island methylator phenotype (CIMP) and (3) mismatch repair (MMR), of which CIN is the most common type. However, these subtypes are not exclusive and overlap. To investigate their biological mechanisms and cross talk, the gene expression profiles of 585 colorectal cancer patients with CIN, CIMP and MMR status records were collected. By comparing the CIN+ and CIN-samples, CIMP+ and CIMP-samples, MMR+ and MMR-samples with minimal redundancy maximal relevance (mRMR) and incremental feature selection (IFS) methods, the CIN, CIMP and MMR associated genes were selected. Unfortunately, there was little direct overlap among them. To investigate their indirect interactions, downstream genes of CIN, CIMP and MMR were identified using the random walk with restart (RWR) method and a greater overlap of downstream genes was indicated. The common downstream genes were involved in biosynthetic and metabolic pathways. These findings were consistent with the clinical observation of wide range metabolite aberrations in colorectal cancer. To conclude, the present study gave a gene level explanation of CIN, CIMP and MMR, but also showed the network level cross talk of CIN, CIMP and MMR. The common genes of CIN, CIMP and MMR may be useful for cross-subtype general colorectal cancer drug development. PMID- 30008863 TI - Expression of ZEBs in gliomas is associated with invasive properties and histopathological grade. AB - The invasiveness of glioma cells is the predominant clinical problem associated with this tumor type, and is correlated with pathological malignant grade. ZEB1 is highly expressed in glioma cells and associated with the aggressiveness of various types of cancer. In the present study, the expression of ZEB1 and ZEB2 was examined with the aim of determining the role of ZEBs in glioma. ZEB1 and ZEB2 were highly expressed in all glioma cells used in this study. Double knockdown of ZEB1 and ZEB2 suppressed tumor invasiveness more effectively than knockdown of either alone, in both in vitro and in vivo experiments. ZEB1 and ZEB2 were marginally expressed in grade II, but expressed at higher levels in grade IV. Importantly, ZEB-positive cells were more abundant in recurrent glioma with malignant transformation than in initial grade II tissue from the same case. These results indicate that the levels of ZEB1 and ZEB2 are positively correlated with histopathological grade and invasiveness of glioma, suggesting that deltaEF1 family proteins (ZEB1 and ZEB2) could be useful as prognostic markers and therapeutic targets in patients with glioma. PMID- 30008862 TI - Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma. AB - The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC. PMID- 30008864 TI - Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis. AB - Oxidative stress, demonstrated by an accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), results in DNA damage, which is normally repaired by base excision repair enzymes including 8-OHdG DNA glycosylase (OGG1) and human MutY homolog (MUTYH), in addition to nucleotide pool sanitizing enzymes including MutT Homolog 1 (MTH1). Abnormalities of this repair system are present in various cancer types. The present study aimed to elucidate the clinicopathological significance of altered expression levels of inducible nitric oxide synthase (iNOS), 8-OHdG, OGG1, MTH1 and MUTYH in ulcerative colitis (UC) and UC-associated neoplasms. Immunohistochemical staining for these markers and p53 in 23 cases of UC associated neoplasm (Group A, 14 carcinomas and nine dysplasias), 16 cases of UC without neoplasm (Group B) and 17 cases of normal colon specimens (Group C) was performed. Mutation analyses was conducted for KRAS proto-oncogene, GTPase (K ras), tumor protein P53 (TP53) and isocitrate dehydrogenase (NADP (+)) 1, cytosolic (IDH1) genes. Immunohistochemically, the iNOS, 8-OHdG, OGG1 and MTH1 expression levels were increased in Groups A and B compared with Group C. The OGG1 and MTH1 expression levels in Group A were also increased compared with Group B. Group A and Group B exhibited increased cytoplasmic expression and decreased nuclear expression of MUTYH compared with Group C. Mutations of K-ras and TP53 were detected in 2/21 (9.5%) and 10/22 (45.5%) cases of Group A, respectively. IDH1 mutation was not detected in any cases. These findings suggest that, as a response to oxidative damage, OGG1 and MTH1 may be upregulated in UC through an inflammatory condition that progresses to cancer formation. Persisting oxidative damage stress may play a role in the pathogenesis of UC-associated tumors. PMID- 30008865 TI - Influence of YKL-40 gene RNA interference on the biological behaviors of endometrial cancer HEC-1A cells. AB - The present study aimed to investigate the effects of chitinase-3-like protein 1 (YKL-40) gene RNA interference on the biological behaviors and enhanced chemosensitivity of endometrial cancer (EC) HEC-1A cells. YKL-40 small interfering (si)RNA was transduced into EC HEC-1A cells using a lentivirus. The experiment was divided into three groups: The experimental group was transfected with YKL-40 siRNA (si-YKL-40); the mock-treatment group was transfected with transfection reagent only; and the blank control group was left untreated. A reverse transcription-quantitative polymerase chain reaction was performed to investigate the mRNA expression levels of YKL-40. The biological behaviors, including cell proliferation, migration, invasion and apoptosis, were detected by MTT and Transwell assays, and flow cytometry (FCM) analysis, respectively. The results of the present study demonstrated that the mRNA expression levels of YKL 40 were downregulated within HEC-1A cells upon transfection with si-YKL-40 (P<0.05). The proliferative, migratory and invasive abilities of HEC-1A cells were inhibited by si-YKL-40 (P<0.05). The mRNA expression levels of YKL-40 were upregulated within HEC-1A cells following treatment with cisplatin (P<0.05). FCM analysis revealed that the average cellular apoptosis rate increased following the inhibition of YKL-40 gene expression via siRNA (P<0.05). Therefore, the YKL 40 gene may be associated with the proliferative, migratory, invasive and anti apoptotic ability of HEC-1A cells. YKL-40 downregulation may enhance the sensitivity of human EC HEC-1A cells to chemotherapy. PMID- 30008866 TI - Loss of Raf kinase inhibitor protein expression is associated with human papillomavirus 16 infection in anal tumors. AB - There has been an increase in the incidence of anal cancer in the past two decades, with squamous cell carcinoma (SCC) being the most frequent histological type identified. Among the risk factors, high-risk human papillomavirus (HPV) infection is the most pervasive. Raf kinase inhibitor protein (RKIP) is expressed in a number of normal human tissues and previous studies have demonstrated the prognostic value of the loss of RKIP expression in several gastrointestinal tumors. Therefore, the present study aimed to evaluate the clinical implications of RKIP expression in a series of neoplastic lesions of the anal canal. The resected tumors of 48 patients [8 high-grade intraepithelial lesions (HSILs), 14 adenocarcinomas and 26 squamous cell carcinomas (SCCs)] were immunohistochemically evaluated for RKIP expression, and the results were correlated with clinicopathological data. The results identified a decreased 5 year overall survival rate in patients with adenocarcinoma (40.8%) compared with patients with SCC (76.7%), and a decreased 5-year disease-free survival rate in patients at clinical stages III/IV (37.3 vs. 62.5 and 82.6% for clinical stages 0 and I/II, respectively). Low RKIP expression was revealed in 62.5% of HSILs, 88.5% of SCCs and 100.0% of the adenocarcinomas. High RKIP expression was associated with patient ethnicity (37.5% in non-Caucasians vs. 7.5% in Caucasians) and patient age (33.3% in younger patients vs. 0.0% in older patients). Finally, high RKIP expression was correlated with HPV16 infection status (40% in HPV- vs. 5.3% in HPV+ patients). A correlation was identified between high RKIP expression and lesions with a generally improved prognosis, such as those diagnosed in younger patients, in situ lesions and lesions of lower clinical grades; there was also a negative correlation between high RKIP expression and HPV16 positivity in patients. PMID- 30008867 TI - Elevated FUS/TLS expression is negatively associated with E-cadherin expression and prognosis of patients with non-small cell lung cancer. AB - Fused in sarcoma/translocated in liposarcoma (FUS/TLS), a ubiquitous and multifunctional DNA and RNA-binding protein, contributes an important function in cancer and neurodegenerative disease; however, its role in lung cancer remains unclear. In the present study, the expression of FUS/TLS in non-small cell lung cancer (NSCLC) and the significance of FUS/TLS for predicting the clinical outcome of patients with NSCLC, was examined. FUS/TLS expression was investigated in NSCLC tissues and their matched adjacent non-tumorous tissues by reverse transcription-quantitative polymerase chain reaction, western blotting, and immunohistochemistry. Tissue microarrays representing 208 patients with NSCLC were used to determine the expression pattern and associations with FUS/TLS using immunohistochemistry. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Data revealed that FUS/TLS expression was elevated in NSCLC tissues compared with corresponding normal tissue mRNA (9.27+/ 0.73 vs. 6.15+/-0.60) and protein (3.32+/-0.75 vs. 0.30+/-0.07) levels. In tissue microarrays, FUS/TLS was highly expressed in 103 (49.5%, 103/208) NSCLC tissues compared with adjacent normal lung tissues (28.4%, 59/208). Overexpression of FUS/TLS was associated with higher tumor node metastasis stage (P=0.016), poorer differentiation (P=0.008), large tumor size (P=0.019) and predicted poor prognosis (P=0.005) in patients with NSCLC. Notably, correlation analysis revealed a significant inverse association between the expression of FUS/TLS and E-cadherin (r2=0.51; P=0.036). Furthermore, patients with NSCLC with high FUS/TLS and impaired E-cadherin expression had a notably poor prognosis (P=4.01*10-4). Thus, the results from the present study indicate that elevated FUS/TLS expression promotes NSCLC progression. FUS/TLS, alone or in combination with E cadherin, is a novel prognostic predictor for patients with NSCLC. PMID- 30008868 TI - Downregulation of long non-coding RNA GAS5 promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma. AB - The present study aimed to investigate the potential role of long non-coding RNA growth arrest-specific transcript 5 (lncRNA GAS5) in the progression of esophageal squamous cell carcinoma (ESCC) and to reveal its possible regulatory mechanism. The expression of lncRNA GAS5 in ESCC tissues and cell lines was analyzed using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The overexpression vector pc-GAS5 and control vector pc negative control (NC), containing no GAS5 sequence, were transfected into ESCC cells. The effects of lncRNA GAS5 overexpression on cell proliferation, cell cycle distribution, cell migration and invasion were then analyzed. Besides, the expression levels of ATM-CHK2 pathway-associated proteins and epithelial mesenchymal transition (EMT)-associated proteins were measured. Expression of lncRNA GAS5 was downregulated in the ESCC tissues compared with adjacent normal tissues, and was also downregulated in ESCC Kyse450 cells compared with the human esophageal epithelial HET-1A cell line. Additionally, lncRNA GAS5 was successfully overexpressed in ESCC cells following transfection with pc-GAS5. Overexpression of lncRNA GAS5 significantly inhibited cell proliferation, induced cell cycle arrest at G2/M phase and suppressed cellular migration and invasion. When cells were transfected with pc-GAS5, the levels of phosphorylated (p)-ATM serine/threonine protein kinase, p-checkpoint kinase 2 (CHK2), p-cell division cycle 25C, p-cyclin-dependent kinase 1, N-cadherin, vimentin and Snail were significantly increased, whereas that of E-cadherin were markedly decreased. The results of the present study indicate that overexpression of lncRNA GAS5 may inhibit cell proliferation, migration and invasion in ESCC. lncRNA GAS5 overexpression may induce cell cycle arrest at G2/M stage by activating the ATM CHK2 pathway. The results of the current study further indicate that lncRNA GAS5 overexpression may suppress cell migration and invasion via EMT-associated proteins. lncRNA GAS5 could therefore serve as a potential target for ESCC therapy. PMID- 30008869 TI - Overexpression of the long noncoding RNA CCAT1 promotes metastasis via epithelial to-mesenchymal transition in lung adenocarcinoma. AB - The long noncoding RNA (lncRNA) colon cancer-associated transcript 1 (CCAT1) has been identified as an oncogene in multiple types of human malignancy, and the aberrant expression of CCAT1 has been associated with the tumorigenesis and progression of cancer. However, the underlying mechanism of how CCAT1 affects malignant behaviors in lung adenocarcinoma cells remains unknown. In the current study, the expression of CCAT1 was identified to be increased in lung adenocarcinoma tissues (n=96) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and its expression level was associated with epidermal growth factor receptor (EGFR) expression (P=0.011), lymphatic metastasis (P=0.003) and tumor node metastasis (TNM) stage (P=0.003). In vitro, by using Transwell assays, the overexpression of CCAT1 was demonstrated to promote the migration and invasion of H358 lung adenocarcinoma cells; while downregulation of CCAT1 expression inhibited H1650 cell migration and invasion. Furthermore, western blot analysis indicated that aberrant CCAT1 expression may induce epithelial-to-mesenchymal transition (EMT) by regulating the expression levels of EMT markers (E-cadherin, N-cadherin and vimentin). In conclusion, these results indicate that CCAT1 is able to promote the metastasis of lung adenocarcinoma cells by inducing EMT. PMID- 30008870 TI - Effect of cytokine-induced killer cells combined with dendritic cells on the survival rate and expression of 14-3-3zeta and p-Bad proteins in Lewis lung cancer cell lines. AB - In the present study, the function and mechanism of cytokine-induced killer cells (CIK) combined with dendritic cells (DC-CIK) were examined in Lewis lung cancer (LLC) cells. Co-culture of CIK dendritic cells (DC) in vitro was used to investigate their proliferation and the antitumor effects on LLC cells. DC and CIK cells were collected from healthy human peripheral blood mononuclear cells and co-cultured as an experimental group, while LLC cells were cultured alone as a control group. Cell morphology was observed by an inverted microscope and an MTT assay was utilized to detect the proliferation of LLC cells. Expression of 14 3-3zeta and p-Bad were measured by western blot analysis. Compared with the control group, treatment of LLC cells with DC-CIK resulted in decreased cell adherence, reduced cell proliferation and abnormal morphological changes. Additionally, DC-CIK treatment of LLC cells resulted in the decreased expression of 14-3-3zeta and p-Bad protein in LLC cells, which may provide important information pertaining to the possible mechanism of DC-CIK-induced antitumor activity against LLC cells. The present study provides a theoretical and experimental basis for the clinical treatment of DC-CIK cell co-culture. PMID- 30008871 TI - MicroRNA-218 inhibits the migration, epithelial-mesenchymal transition and cancer stem cell properties of prostate cancer cells. AB - MicroRNA (miRNA) is a class of non-coding single-stranded RNA, able to regulate tumor-associated genes via binding the 3'-UTR of the target gene mRNA. Previous publications have demonstrated that miRNA-218 (miR-218) acts as a tumor suppressive miRNA in various types of human cancer, including prostate cancer (PCa). However, the role of miR-218 in regulating PCa cell stemness and epithelial-mesenchymal transition remains unknown and requires further research. In the present study, it is demonstrated that miR-218 was downregulated in 2 PCa cell lines and could suppress cell migration, EMT and the exhibition of cancer stem cell-like properties. The expression of GLI family zinc finger 1 (Gli1) was inhibited by miR-218 overexpression, suggesting miR-218-suppression of Gli1 as a potential mechanism for the tumor-suppressive effect of miR-218. Overall, the results indicate that miR-218 served a critical role in the inhibition of PCa development. This may provide new insight for elucidating the mechanisms of PCa oncogenesis and suggests that miR-218 may be a novel therapeutic target for PCa. PMID- 30008872 TI - The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer. AB - The expression levels of one-carbon metabolic enzymes were investigated and observed to be correlated with clinicopathological parameters in patients with pancreatic cancer. Mitochondrial one-carbon metabolism comprises a network of biological reactions that integrate nutrient status with nucleotide synthesis, amino acid metabolism, antioxidant reduced nicotinamide adenine dinucleotide phosphate production and epigenetic methylation processes. Previous studies have reported that the hyper-activation of mitochondrial one-carbon metabolism serves a significant role in malignant cancer phenotypes. A total of 103 patients underwent surgical resection of pancreatic ductal adenocarcinomas (PDAC) at Osaka University Hospital between April 2007 and December 2013 and were enrolled in this study. Subsequently, the expression of the one-carbon metabolic enzymes methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), and serine hydroxymethyltransferase (SHMT2) was examined using immunohistochemical analysis. The immunohistochemical analyses demonstrated that patients with high expression levels of MTHFD2, ALDH1L2 or SHMT2 had significantly poor overall survival (OS) and disease-free survival (DFS) rates, as compared with patients with low expression levels. Furthermore, multivariate Cox proportional hazards analysis indicated that MTHFD2 and ALDH1L2 were independent prognostic factors for OS and DFS, whereas SHMT2 was not predictive of DFS. However, high and low expression levels of all three folate metabolic enzymes were significantly associated with improved OS and DFS, compared with the high expression of one or two folate metabolic enzymes. The expression levels of mitochondrial one-carbon metabolic enzymes are independent prognostic factors and potential therapeutic targets for future pancreatic cancer treatments. PMID- 30008873 TI - Prognostic significance of ANLN in lung adenocarcinoma. AB - Anillin actin binding protein (ANLN) is a biomarker of cancer progression and is overexpressed in lung adenocarcinoma. The aim of the present study was to investigate the role of ANLN protein and RNA in the development of lung adenocarcinoma. The ANLN protein sequence was downloaded from The National Centre for Biotechnology information, RNA sequencing (RNA-seq) data was obtained from The Cancer Genome Atlas database. All immunohistochemical staining pictures were adapted from the Human Protein Atlas. PyMOL software was employed to predict protein functional changes in response to mutations. Gene Set Enrichments Analysis was employed for pathway analysis. The results indicated that ANLN experiences genetic change and overexpression at the RNA and protein levels in patients with lung adenocarcinoma. Kaplan-Meier survival curve analysis revealed significant differences between high and low RNA-seq expression levels in ANLN, and patients exhibiting higher expression of ANLN had a relatively poor prognosis. Pathway analysis demonstrated that ANLN was involved in developmental processes via the regulation of nuclear division' pathway. In conclusion, ANLN has potential for use as a diagnostic and prognostic biomarker to diagnoseand predict the outcome of lung adenocarcinoma. PMID- 30008874 TI - Inhibiting the proliferation and metastasis of hilar cholangiocarcinoma cells by blocking the expression of vascular endothelial growth factor with small interfering RNA. AB - The aim of the present study was to investigate whether the proliferation and metastasis of hilar cholangiocarcinoma cells can be suppressed and whether apoptosis can be induced by small interfering RNA (siRNA) repression of vascular endothelial growth factor (VEGF). siRNA sequences targeting the VEGF gene were designed and the human hilar cholangiocarcinoma QBC939, HCCC-9810 and RBE cell lines were transfected with VEGF-siRNA plasmids for 48 h. Reverse transcription quantitative polymerase chain reaction and western blotting measured the levels of VEGF-A, VEGF-C and matrix metalloproteinase 2 (MMP2) mRNA expression and protein content. The cell invasion potential was evaluated using the Transwell invasion and migration assay and the MTT assay was employed to detect the proliferation of hilar cholangiocarcinoma cells. Flow cytometry was used to quantify cell apoptosis and necrosis. Following the transfection of VEGF-siRNA, a significant reduction of mRNA and protein levels of VEGF-A, VEGF-C and MMP2 was observed in the hilar cholangiocarcinoma cells. The invasion, migration and proliferation of tumor cells were also notably decreased. The rate of tumor cell apoptosis was increased in the VEGF-siRNA group (15.42%) compared with the non siRNA control (2.22%) and the negative control (2.71%) groups. It was concluded that blocking the expression of VEGF via VEGF-siRNA effectively inhibited the invasion, migration and proliferation, and induced apoptosis in hilar cholangiocarcinoma cells. These observations suggested that targeting VEGF with RNAi may be an effective therapeutic strategy for treating hilar cholangiocarcinoma. PMID- 30008875 TI - Knockdown of FBXO39 inhibits proliferation and promotes apoptosis of human osteosarcoma U-2OS cells. AB - F-box proteins are essential components of the Skp-cullin-F-box complex (a type of E3 ubiquitin ligase), and participate in cell cycle and immune responses through the ubiquitin proteasome system. F-box protein 39 (FBXO39) belongs to the F-box family, which has been reported to be associated with cancer oncogenesis and progression. The present study aimed to investigate the role of FBXO39 in osteosarcoma (OS) cell proliferation and apoptosis in vitro. It was demonstrated that U-2OS cells exhibited high expression of FBXO39 compared with HOS and SaOS-2 osteosarcoma cells. Thus, knockdown of FBXO39 was performed using lentivirus mediated short hairpin RNA (shRNA) transfection to validate the effect of FBXO39 in U-2OS cells. Western blotting and RT-qPCR analysis were used to confirm the efficiency of infection by analyzing the expression level of FBXO39. Using Celigo based cell counting and MTT assays, it was demonstrated that FBXO39 knockdown significantly reduced the rate of cell proliferation compared with control. Caspase 3/7 activity assays and fluorescence-activated cell sorting confirmed the induction of apoptosis in U-2OS cells following FBXO39 knockdown. In conclusion, it was demonstrated that FBXO39 knockdown may significantly inhibit proliferation and promote apoptosis of U-2OS cells. Thus, FBXO39 may serve an important role in OS progression. PMID- 30008876 TI - Dermatofibrosarcoma protuberans: A clinical analysis. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor with a high incidence of misdiagnosis. DFSP has a high rate of recurrence but a low rate of metastasis. In the present study, retrospective analyses were performed on the clinical features, differential diagnosis and treatment of patients with DFSP to improve our understanding of the disease and allow more effective treatment measures to be implemented. The present study investigated the clinicopathological features of 70 pathologically confirmed cases of DFSP at the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between March 2012 and 2017. The primary endpoint was recurrence rate. Three cases were analyzed in detail. The results revealed that 7 of the 41 primary patients (follow-up at 2.7 years) had recurrence (17.1%), compared with 11 (37.9%) of the 29 recurrent patients (follow-up at 2.0 years, P=0.049). Of the 59 patients with DFSP (follow-up at 2.6 years), 12 had recurrence (20.3%) compared with 6 (54.6%) of the 11 patients with fibrosarcomatous DFSP (FS-DFSP; follow-up at 2.1 years, P=0.045). DFSP requires diagnosis by pathological examination, and surgical resection is the main treatment. DFSP demonstrated a high recurrence rate, with the degree of malignancy increasing following multiple recurrences. FS-DFSP had a higher risk of local recurrence and distant metastasis, and a higher degree of malignancy than classic DFSP. These data may be useful to guide clinicians to improve decisions in the treatment of patients with DFSP. PMID- 30008877 TI - Aneuploidy of chromosome 8 and mutation of circulating tumor cells predict pathologic complete response in the treatment of locally advanced rectal cancer. AB - Identifying patients who may or may not achieve pathologic complete response (pathCR) allows for treatment with alternative approaches in the preoperative setting. The aim of the current study was to investigate whether aneuploidy of chromosome 8 and mutations of circulating tumor cells (CTCs) could predict the response of patients with rectal cancer to preoperative chemoradiotherapy. A total of 33 patients with locally advanced rectal cancer (cT3-T4 and/or cN+) treated with neoadjuvant chemoradiotherapy between September 2014 and March 2015 were recruited. Blood samples were collected from 33 patients with pre chemoradiotherapy rectal cancer. It was demonstrated that >=5 copies of chromosome 8 was associated with pathCR (univariate logistic regression, P=0.042). Of the 6 patients whose CTCs had <5 copies of chromosome 8, 3 achieved pathCR (3/6, 50%), and of the 27 patients whose CTCs had >=5 copies of chromosome 8 obtained 3 pathCR (3/27, 11.1%; Chi-square test, P=0.0255). Of the 33 patients with mutations assessed, 8 significant nonsynonymous mutations in CTCs were identified as associated with pathCR (Chi-square test, P-values range, 0.0004 0.0298; mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 and AR). These results suggest that >=5 copies of chromosome 8 and 8 nonsynonymous mutations in ARID1A, HDAC1, APC, ERBB3, TP53, AMER1 AR in CTCs were associated with pathCR. This conclusion should be validated further in larger prospective studies and the long-term follow-up survival data of this study will also be reported in the future. PMID- 30008878 TI - DUSP1 enhances the chemoresistance of gallbladder cancer via the modulation of the p38 pathway and DNA damage/repair system. AB - Cisplatin (CDDP) is a commonly used drug for gallbladder cancer (GBC) chemotherapy. However, resistance to CDDP treatment results in relapse. Therefore, there is a need for the development of more effective treatment strategies to overcome chemoresistance. Dual-specificity phosphatase 1 (DUSP1) was reported to be involved in the resistance of a number of chemotherapeutic agents and was revealed to be highly expressed in CDDP-resistant GBC cells and CDDP-treated tumor types compared with normal cells or tissues in the present study. DUSP1 was revealed to inhibit the cytotoxicity of CDDP in two GBC cell lines, SGC996 and GBC-SD. P38 mitogen-activated protein kinases may be involved in the mechanism of chemoresistance. Furthermore, the number of DNA double-strand breaks in SGC996 OE cells was reduced compared with SGC996 vector cells indicating DUSP1 may attenuate the chemotherapeutic efficiency. Due to its potency against CDDP treatment, DUSP1 may be a promising target to overcome chemoresistance in GBC therapy. PMID- 30008879 TI - MicroRNA-137-regulated AKT serine/threonine kinase 2 inhibits tumor growth and sensitizes cisplatin in patients with non-small cell lung cancer. AB - The present study investigated the role of microRNA-137-regulated AKT serine/threonine kinase 2 (AKT2) on tumor growth and cisplatin sensitivity in patients with non-small cell lung cancer (NSCLC). The results demonstrated that the expression of microRNA-137 in cisplatin-treated NSCLC patient tissue samples was markedly lower than that in healthy tissue samples. The disease-free survival and overall survival rates of patients with NSCLC exhibiting a high microRNA-137 expression were higher than the survival rates of patients with NSCLC exhibiting a low expression of microRNA-137. Overexpression of microRNA-137 inhibited the proliferation of A549 and H520 cells treated with cisplatin. Overexpression of miR-137 suppressed the protein expression of AKT2, increased caspase-3 activity, increased Bax protein expression and suppressed Cyclin D1 protein expression in A549 and H520 cells treated with cisplatin. MK2206, an AKT2 inhibitor, inhibited AKT2 protein expression and suppressed the proliferation of A549 and H520 cells treated with cisplatin following overexpression of miR-137. The inhibition of AKT2 also increased caspase-3 activity and Bax protein expression, and suppressed Cyclin D1 protein expression in A549 and H520 cells treated with cisplatin following overexpression of miR-137. Taken together, the results of the present study suggested that microRNA-137-regulated AKT2 inhibits tumor growth and sensitizes cisplatin in patients with NSCLC. PMID- 30008880 TI - Notch-regulated ankyrin-repeat protein is a novel tissue biomarker that predicts poor prognosis in non-small cell lung cancer. AB - Notch-regulated ankyrin-repeat protein (NRARP) has recently been reported to be involved in a number of malignant cancers; however, its role in non-small lung cancer (NSCLC) remains unclear. The present study aimed to identify whether NRARP could be applied as a novel prognostic marker for NSCLC. A total of 108 NSCLC patients were enrolled in the present study and their lung tissues were collected. Reverse-transcription quantitative polymerase chain reaction and immunohistochemical staining were used to assess the mRNA and protein levels of NRARP. Appropriate statistical tests were performed to evaluate the associations between NRARP protein expression and clinicopathological features and prognosis in NSCLC patients. The results revealed that NRARP expression was significantly associated with tumor differentiation (P=0.001), Tumor-Node-Metastasis stage (P=0.004) and cigarette smoking (P<0.001). Furthermore, patients with higher NRARP protein expression had significantly shorter overall survival times (P<0.001). Multivariate analysis indicated that overexpression of NRARP protein could be applied as an independent prognostic biomarker for NSCLC. In summary, the present study demonstrated that NRARP protein is overexpressed in NSCLC and that high NRARP expression is correlated with tumor progression and overall survival time. These data indicated the potential value of NRARP as a novel therapeutic target for the treatment of NSCLC. PMID- 30008881 TI - c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. AB - Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer. PMID- 30008883 TI - Intrarenal urothelial cancers confused as infiltrative renal masses: Report of 22 cases and literature review. AB - Distinguishing infiltrative renal masses (IRMs) from intrarenal urothelial cancers (IUCs) is critically important, but may be challenging for any radiologist or urologist. The present study aimed to summarize the clinical, imaging and pathological characteristics of IRM, which were postoperatively confirmed as IUC. The analysis was performed using the records of 22 patients who were preoperatively diagnosed with IRM but the results of percutaneous biopsies or postoperative pathological analyses led to diagnoses of urothelial cancers (UCs) from January 2011 to December 2017. The demographic data, computed tomography (CT) imaging features and pathological characteristics were evaluated. The present study also reviewed the literature concerning the IRM and IUC. The mean age of patients was 62 years and 86.4% of them were >55 years. The sex and tumor side distributions were equal. Hematuria and/or flank pain were observed in 86.4% of patients. All patients exhibited endophytic solid renal masses with unclear tumor boundaries on CT images. The kidneys of 81.8% of patients maintained their normal shape while mild alternations were observed in 18.2% of cases. A total of 81.8% of patients maintained the reniform shape and 18.2% exhibited mild contour change. Of all patients, all tumors exhibited less or equal attenuation on unenhanced CT images and they were mildlyimproved on enhanced CT. A total of 6 cases were confirmed by biopsy, when patients underwent laparoscopic nephroureterectomy instead of radical nephrectomy. The remaining 16 patients underwent laparoscopic nephrectomy but the postoperative pathological diagnoses revealed the presence of UCs. All postoperatively confirmed cancers were stages T3 and T4 (62.5 and 37.5%, respectively). UCs should be suspected in middle aged or elderly middle-elderly patients presenting renal masses with endophytic solid unclear tumor boundary on unenhanced and slightly enhanced CT images, accompanied with hematuria and/or flank pain. Preoperative biopsy is preferred for complicated cases. PMID- 30008882 TI - A meta-analysis of transcriptome datasets characterizes malignant transformation from melanocytes and nevi to melanoma. AB - Melanoma represents one of the most aggressive malignancies and has a high tendency to metastasize. The present study aims to investigate the molecular mechanisms of two pathways to cancer transformation with the purpose of identifying potential biomarkers. Our approach is based on a meta-analysis of gene expression profiling contrasting two scenarios: A model that describes a transformation pathway from melanocyte to melanoma and a second model where transformation occurs through an intermediary nevus. Data consists of three independent, publicly available microarray datasets from the Gene Expression Omnibus (GEO) database comprising samples from melanocytes, nevi and melanoma. The present analysis identified 808 differentially expressed genes (528 upregulated and 360 downregulated) in melanoma compared with nevi, and 2,331 differentially expressed genes (946 upregulated and 1,385 downregulated) in melanoma compared with melanocytes. Further analysis narrowed down this list, since 682 differentially expressed genes were found in both models (417 upregulated and 265 downregulated). Enrichment analysis identified relevant dysregulated pathways. This article also presented a discussion on significant genes including ADAM like decysin 1, neudesin neurotrophic factor, MMP19, apolipoprotein L6, C-X-C motif chemokine ligand (CXCL)8, basic, immunoglobulin like variable motif containing and CXCL16. These are of particular interest because they encode secreted proteins hence represent potential blood biomarkers for the early detection of malignant transformation in both scenarios. Cytotoxic T-lymphocyte associated protein 4, an important therapeutic target in melanoma treatment, was also upregulated in both comparisons indicating a potential involvement in immune tolerance, not only at advanced stages but also during the early transformation to melanoma. The results of the present study may provide a research direction for studying the mechanisms underlying the development of melanoma, depending on its origin. PMID- 30008884 TI - Knockdown of collagen alpha-1(III) inhibits glioma cell proliferation and migration and is regulated by miR128-3p. AB - As a member of the collagen family, collagen alpha-1(III) (COL3A1) is an important protein in the development and progression of several tumors. However, the role of COL3A1 in glioma is not yet clear. The present study examined the expression and function of COL3A1 in glioma cell behavior and identified microRNA (miRNA) regulators. It was demonstrated that COL3A1 expression was upregulated in glioma and directly correlated with the tumor grade. Analysis of the GSE4290 and GSE7696 profiles acquired from the Gene Expression Omnibus database also revealed an increased COL3A1 expression in malignant gliomas compared with the lower grade gliomas and non-tumor brain tissue, which was directly correlated with glioma grade. To explore the functional role of COL3A1 in glioma cell growth, small interfering RNA interference was applied to inhibit COL3A1 expression in Hs683 and U251 cells. The relative COL3A1 mRNA and protein expression levels were significantly reduced in the knockdown cells as determined by western blot analysis. In addition, decreased COL3A1 expression in Hs683 and U251 glioma cells resulted in a delay in cell growth and colony disruption as determined by MTS and colony formation assays. Wound healing analysis indicated that cells with suppressed expression of COL3A1 had a reduced ability to migrate. COL3A1 mRNA levels were inversely correlated with the miR128-3p level in glioma, suggesting that miR128-3p expression is associated with COL3A1 inhibition as verified by reverse transcription-quantified polymerase chain reaction. These results suggest that COL3A1 may be a novel regulator of glioblastoma cell behavior and may represent a novel target for gene therapies against glioma. PMID- 30008885 TI - Stereotactic image-based histological analysis reveals a correlation between 11C methionine uptake and MGMT promoter methylation in non-enhancing gliomas. AB - Gliomas are genetically and histopathologically heterogeneous. Intratumoral heterogeneity in the MGMT promoter methylation status is an important clinical biomarker of glioblastoma. A higher uptake of 11C-methionine in positron-emission tomography (PET) reportedly reflects increased MGMT promoter methylation; however, non-stereotactic comparison of MGMT methylation and 11C-methionine PET images may not be accurate. The present study examined the correlation between 11C-methionine uptake and MGMT promoter methylation in non-enhancing gliomas using stereotactic image-based histological analysis. Data were collected from 9 patients with newly diagnosed non-enhancing glioma who underwent magnetic resonance imaging and 11C-methionine PET during pre-surgical examination. Clinical data were also collected from 3 patients during repeat surgery. The correlation between 11C-methionine uptake and MGMT methylation or cell density was analyzed using histological specimens obtained by multiple stereotactic sampling and an exact local comparison of 11C-methionine PET images and histological specimens was made. A total of 31 stereotactic sample sites were identified. In newly diagnosed cases, the tumor to normal uptake (T/N) ratio revealed a significant positive correlation with MGMT methylation (R=0.54, P=0.009) and a marginal correlation with cell density (R=0.42, P=0.05). In recurrent cases, the T/N ratio demonstrated no correlation with MGMT methylation (R=0.01, P=0.97) or cell density (R=0.15, P=0.70). An increased uptake of 11C methionine in PET may reflect increased MGMT promoter methylation according to stereotactic image-based histological analysis. 11C-methionine PET could therefore be a useful tool for detecting regional MGMT promoter methylation in non-enhancing primary glioma. PMID- 30008886 TI - DNA methylation contributes to silencing the expression of linc00086 in gastric cancer. AB - Previous evidence has revealed that long non-coding RNAs serve important functions in numerous types of cancer when dysregulated, including in gastric cancer (GC). In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was used to detect the expression of small integral membrane protein 10 like 2A (linc00086) in GC tissues and non-cancerous tissues, and the expression of linc00086 in GC cell lines was analyzed. A RT-qPCR assay was used to assess linc00086 expression levels in GC cell lines following treatment with 5-Aza-2'-deoxycytidine (5-aza-dC), which is a DNA methyltransferase inhibitor. Small interfering RNA was used to silence the expression of methyl-CpG binding protein 2 (MeCP2), and then the expression of linc00086 was detected. Linc00086 expression was revealed to be downregulated in GC tissues and GC cell lines. Furthermore, it was revealed that 5-aza-dC induced linc00086 expression in SGC-7901 and MKN45 cells, and analysis of CpG methylation by bisulfite sequencing-polymerase chain reaction demonstrated that DNA methylation may regulate the expression of linc00086. MeCP2 is involved in gene regulation by binding to methylated promoters, and it was revealed that the knockdown of the expression of MeCP2 resulted in a higher expression of linc00086. The present study revealed that DNA methylation regulate the expression of linc00086 in human GC cell lines. PMID- 30008887 TI - Anticancer effect of HOTTIP regulates human pancreatic cancer via the metabotropic glutamate receptor 1 pathway. AB - The present study aimed to determine how the expression and function of HOTTIP modifies, and regulates the metabotropic glutamate receptor 1 (mGluR1) to affect human pancreatic cancer cell viability. HOTTIP expression was higher in human pancreatic cancer tissue compared with in para-carcinoma tissue. However, downregulation of HOTTIP expression was revealed to significantly reduce cell viability, induce apoptosis, promote caspase-3 and caspase-8 activities and increase Bax expression in pancreatic cancer cells. Additionally, downregulation of HOTTIP expression significantly suppressed mGluR1 and mitigated activation of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in pancreatic cancer cells. To the best of our knowledge, the present study is the first to identify that the anticancer effect of HOTTIP against human pancreatic cancer functions the mGluR1 pathway. PMID- 30008888 TI - Inhibitory effects of XAV939 on the proliferation of small-cell lung cancer H446 cells and Wnt/beta-catenin signaling pathway in vitro. AB - Lung cancer, including small-cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are the most common tumor types, which represent 13% of newly diagnosed cancer cases worldwide. SCLC represents 15% of all lung cancer cases. Although an increasing number of novel targeted drugs are employed for the treatment of NSCLC, including Iressa, Tarceva and Conmana, there have been almost no major breakthroughs in SCLC over the last 30 years. Therefore, new drug targets are required to treat or prevent SCLC. Aberrant Wnt signaling is associated with numerous types of tumors, and it plays a key role in cell proliferation and survival. Recent preclinical studies suggested that XAV939 is a small-molecule inhibitor of the Wnt signaling pathway. In the present study, whether XAV939 is able to inhibit the proliferation of SCLC cells and the underlying mechanism were investigated. The inhibition of cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay. The mRNA expression of beta catenin and cyclin D1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the protein expression of beta-catenin and cyclin D1 was determined by western blotting. The results from the CCK-8 cell viability assay confirmed that XAV939 is able to inhibit the proliferation of SCLC cells in a dose-dependent manner. However, the effects of XAV939 were not time-dependent. By contrast, the effect of DDP treatment was time- and dose dependent. Furthermore, the effect of combination treatment with XAV939 and DDP was antagonistic at low doses and synergistic at high doses. It was also observed that the mRNA and protein expression of beta-catenin and cyclin D1 was significantly in SCLC cells following XAV939 treatment compared with the control group. These findings suggested that XAV939 is able to inhibit the proliferation of H446 cells, at least partially, through downregulating the Wnt/beta-catenin signaling pathway. All of these results may provide potential therapeutic approaches for the treatment of SCLC. PMID- 30008889 TI - Migration and invasion in B16-F10 mouse melanoma cells are regulated by Nrf2 inhibition during treatment with ionizing radiation. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) serves a critical role in carcinogenesis. The present study examined the effect of Nrf2 on the proliferation and invasion of melanoma cells that were treated with ionizing radiation. B16-F10 mouse melanoma cells were exposed to various doses of ionizing radiation for different time periods. Small interfering (si)RNAs targeting Nrf2 were transfected into B16-F10 cells, and cell proliferation, invasion and apoptosis were detected by Transwell, MTT or western blot assays. The expression of Nrf2 and its downstream heme oxygenase 1 (HO-1) was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. HO-1 activity was also examined. Ionizing radiation stimulated Nrf2 expression, increased caspase-3 expression, and reduced the viability, migration and invasion of B16-F10 mouse melanoma cells. Transfection with Nrf2 siRNA was able to inhibit Nrf2 and HO-1 expression in B16-F10 mouse melanoma cells that were treated by ionizing radiation. Inhibition of Nrf2 further reduced cell viability, invasion and migration, and elevated caspase-3 expression in B16-F10 mice melanoma cells that were treated by ionizing radiation. In summary, treatment with ionizing radiation was able to stimulate Nrf2 expression and regulate cell viability, invasion and migration of B16-F10 cells. A combination of Nrf2 knockdown and ionizing radiation treatment exerted a synergistic effect on migration, invasion and apoptosis in B16-F10 murine melanoma cells. PMID- 30008890 TI - Histone deacetylase inhibitor AR-42 inhibits breast cancer cell growth and demonstrates a synergistic effect in combination with 5-FU. AB - AR-42 is a member of a novelly discovered class of phenylbutyrate-derived histone deacetylase inhibitors, and has a number of antitumor effects in a variety of tumor types; however, the role of AR-42 and its possible mechanisms have not been reported in the treatment of breast cancer. The aim of the present study was to investigate the antitumor effects of AR-42 and its associated mechanisms in breast cancer. MTT assays and colony formation assays were conducted to measure the proliferation of MCF-7 cells, and flow cytometry was used to analyze cell apoptosis. The results revealed that AR-42 induced cell apoptosis and suppressed cell growth in a dose- and time-dependent manner. Mechanistically, AR-42 treatment increased the acetylation of the p53 protein and prolonged the half life of the p53 protein; furthermore, AR-42 treatment upregulated p21 and PUMA expression. Notably, AR-42 had a synergistic effect on MCF-7 cells in combination with fluorouracil, which is one of the most commonly used chemotherapeutic agents. In conclusion, the results indicated that AR-42 inhibits breast cancer cell proliferation and induces apoptosis, indicating that AR-42 is a potential therapeutic agent. PMID- 30008891 TI - Thapsigargin induces apoptosis of prostate cancer through cofilin-1 and paxillin. AB - It is widely considered that endoplasmic reticulum stress may rapidly induce apoptosis. The aim of the present study was to investigate the effect of thapsigargin on the induction of apoptosis in prostate cancer cells, and to explore its possible mechanism. A Cell Counting Kit-8 was selected to determine the effect of thapsigargin (0, 1, 10 and 100 nM) on the proliferation of PC3 cells. Cell proliferation of the prostate cancer cells was effectively inhibited by treatment with thapsigargin, and thapsigargin significantly increased the rate of apoptosis and caspase-3/9 activities in prostate cancer cells. The protein expression of phosphorylated (p)-RAC-alpha serine threonine-protein kinase, p mechanistic target of rapamycin, F-actin and paxillin were significantly decreased, and cofilin-1 protein expression was significantly increased by treatment with thapsigargin in prostate cancer cells. Overall, the data of the present study revealed that thapsigargin induced apoptosis in prostate cancer cells through cofilin-1 and paxillin. PMID- 30008892 TI - Histone deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells. AB - Period circadian regulator (Per)1 and Per2 genes are involved in the molecular mechanism of the circadian clock, and exhibit tumor suppressor properties. Several studies have reported a decreased expression of Per1, Per2 and Per3 genes in different types of cancer and cancer cell lines. Promoter methylation downregulates Per1, Per2 or Per3 expression in myeloid leukemia, breast, lung, and other cancer cells; whereas histone deacetylase inhibitors (HDACi) upregulate Per1 or Per3 expression in certain cancer cell lines. However, the transcriptional regulation of Per1 and Per2 in cancer cells by chromatin modifications is not fully understood. The present study aimed to determine whether HDACi regulate Per1 and Per2 expression in gastric cancer cell lines, and to investigate changes in chromatin modifications in response to HDACi. Treatment of KATO III and NCI-N87 human gastric cancer cells with sodium butyrate (NaB) or Trichostatin A (TSA) induced Per1 and Per2 mRNA expression in a dose-dependent manner. Chromatin immunoprecipitaion assays revealed that NaB and TSA decreased lysine 9 trimethylation on histone H3 (H3K9me3) at the Per1 promoter. TSA, but not NaB increased H3K9 acetylation at the Per2 promoter. It was also observed that binding of Sp1 and Sp3 to the Per1 promoter decreased following NaB treatment, whereas Sp1 binding increased at the Per2 promoter of NaB- and TSA treated cells. In addition, Per1 promoter is not methylated in KATO III cells, while Per2 promoter was methylated, although NaB, TSA, and 5-Azacytidine do not change the methylated CpGs analyzed. In conclusion, HDACi induce Per1 and Per2 expression, in part, through mechanisms involving chromatin remodeling at the proximal promoter of these genes; however, other indirect mechanisms triggered by these HDACi cannot be ruled out. These findings reveal a previously unappreciated regulatory pathway between silencing of Per1 gene by H3K9me3 and upregulation of Per2 by HDACi in cancer cells. PMID- 30008893 TI - Impact of hemodialysis on the prognosis of multiple myeloma: A nationwide population-based study and single-institute analysis. AB - Myeloma-associated kidney disease (MRKD) occurs in <=40% patients with multiple myeloma (MM). The impact of hemodialysis (HD) on patients with MM was investigated. Between 2000 and 2010, a total of 1,610 patients in Taiwan were enrolled from the National Health Institute Research Database. MM was an independent risk factor for HD following adjustment via multivariate logistic regression analysis (adjusted hazard ratio, 7.347; 95% confidence interval, 6.156 8.768; log-rank test, P<0.001). In addition, a notable decrease in survival rate was determined in patients with MM who underwent HD in the first year since diagnosis of MM. A total of 198 (61.49%) patients received HD in the first year. Patients with MM with a lower frequency of HD in the first year had a relatively good prognosis. The present study confirmed that MM was a risk factor for HD. Significant early mortality in the first year was determined in patients with MM who underwent HD; however, renal recovery following therapeutic management was a prognostic factor. In addition to anti-myeloma therapy, early initiation of HD was beneficial following risk stratification of MRKD; however, an increased probability of recovery of renal function and discontinuation of dialysis, was demonstrated in patients with MM following HD, compared with patients with MM without HD. PMID- 30008894 TI - Prediction and identification of human leukocyte antigen-A2-restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein. AB - Persistent infection with high-risk human papilloma virus (HPV) is the primary cause of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. HPV58 is the third most common HPV genotype in China after HPV16 and HPV18. HPV E6 and E7 are oncoproteins and are constitutively expressed in HPV-associated cancer cells, therefore they are considered to be ideal target antigens for immunotherapy, including HPV therapeutic vaccine. In the present study, human leukocyte antigen (HLA)-A2-restricted cytotoxic T lymphocyte (CTL) epitope peptides were predicted and screened from HPV58 E7 antigen and their immunogenicity was subsequently determined. A total of 6 HLA-A2-binding peptides derived from HPV58 E7 were predicted and selected using 3 different prediction programs. A negative control peptide and PBS were used as two negative controls. Peripheral blood mononuclear cells (PBMCs) with HLA-A2(+) allele were used to detect the specific cellular immune response among the 6 predicted peptides by enzyme-linked immunospot assay (ELISOPT). Following preliminary screening for the predicted peptides, the antigenicity of the peptide HPV58 E772-80 was further assessed by an immunoassay to a vaccine contained HPV58 E7 antigen. Specific humoral and cellular immunity were detected using the peptide HPV58 E772-80 as the specific antigen. A total of 6 peptides from HPV58 E7 protein were predicted and subsequently named P1 (E77-15: TLREYILDL), P2 (E714-22: DLHPEPTDL), P3 (E769 77: CINSTTTDV), and P4 (E772-80: STTTDVRTL), P5 (E779-87: TLQQLLMGT) and P6 (E783 91: LLMGTCTIV). In the ELISPOT assay on HLA-A2 (+) human PBMCs, interferon (IFN) gamma-production was evident in the P2 and P4 groups. The average numbers of IFN gamma associated spots in the P2 and P4 groups was 50.61+/-5.37 spot-forming cells (SFC)/1*105 and 266+/-34.42 SFC/1*105, respectively. The numbers of spots in the two peptides were significantly increased compared with the other 4 peptides and the control groups (P<0.05). In the further antigenicity verification of P4 (HPV58 E772-80), the peptide only stimulated the humoral immune response of the AD-HPV16/18/58 mE6E7 vaccine containing HPV58 E7 antigen. Compared with the 2 negative control groups (1:400), the antibody titers of the vaccine group (1:25,600) were significantly increased (P<0.05). In cellular immunoassays the average number of IFN-gamma associated spots was 143.3+/-32.13 SFC/1*105 in the vaccine group, which was significantly enhanced compared with the PBS group (8+/-5.29 SFC/1*105; P<0.01) and the AD-NC group (28+/-5.13 SFC/1*105; P<0.01). The peptide HPV58 E772-80 (STTTDVRTL) displayed sufficient antigenicity to a vaccine contained HPV58 E7 antigen. Therefore, HPV58 E772-80 peptide may be considered as a candidate epitope peptide for the construction of HPV58 peptide vaccines. PMID- 30008895 TI - Alteration of microRNA profiling in sphere-cultured ovarian carcinoma cells. AB - Ovarian cancer is an aggressive and lethal cancer, which in part, can be attributed to complications in the effective detection of this disease during early stages of progression. Frequently, epithelial ovarian cancer is disseminated to the abdominal cavity and forms multicellular aggregates. This unique early metastatic event, and formation of the multicellular aggregate is implicated to provide a basis for understanding the underlying molecular mechanisms of metastasis in ovarian cancer. Therefore, a 3-dimensional (3D) sphere culture system was established in the present study to mimic the later stages of ovarian cancer. The aim of the present study was to investigate whether microRNAs (miRNAs), which have functions in metastasis and chemoresistance in various cancer models, are altered in ovarian cancer cells by 3-dimensional (3D) culture. A multicellular aggregate of SKOV3ip1 ovarian carcinoma cells was generated using a 3D sphere culture system. Cell viability analysis demonstrated that the sphere-cultured SKOV3ip1 cells exhibited chemoresistance compared with those in a conventional 2-dimensional (2D) monolayer cultured SKOV3ip1 system. Under the same experimental conditions, 71 upregulated miRNAs and 63 downregulated miRNAs were identified in the 3D sphere-cultured SKOV3ip1 cells. The predicted targets of the 3D sphere-culture specific miRNAs were further identified using PITA, microRNAorg and TargetScan. Compared with the target gene pool and Kyoto Encyclopedia of Genes and Genomes pathway, the present study provides evidence that the 3D sphere culture-specific miRNAs regulated sphere formation and chemoresistance in 3D sphere-cultured SKOV3ip1 cells. Overall, the results of the present study demonstrated that miRNA-mediated regulation is implicated to provoke features of SKOV3ip1 multicellular aggregation, including sphere formation and chemoresistance. PMID- 30008896 TI - Use of Clavien-Dindo classification in evaluating complications following pancreaticoduodenectomy in 1,056 cases: A retrospective analysis from one single institution. AB - The Clavien-Dindo (C-D) classification is a simple and feasible grading system of postoperative complications. The aim of the present study was to apply this system to retrospectively classify all types of post-pancreaticoduodenectomy (PD) complications (PPCs) and to systematically identify associated risk factors. Between January 2009 and December 2014, the C-D classification was applied to retrospectively classify PPCs for 1,056 patients who had undergone PD at the West China Hospital. Univariate and multivariate analyses were performed to link perioperative parameters and mortality with the severity of PPCs, which were subdivided into overall PPCs (Grade I-V), severe PPCs (Grade III-V) and mortality (Grade V). The number of patients with Clavien-Dindo grade I, II, IIIa, IIIb, IVa, IVb and V complications was 185 (17.5%), 128 (12.1%), 50 (4.7%), 25 (2.4%), 35 (3.3%), 19 (1.8%) and 33 (3.1%), respectively. A total of 475 (45.0%) patients experienced overall PPCs; 168 (15.9%) patients experienced severe PPCs; and 33 patients succumbed to mortality following PD. The following risk factors were identified following PD: Preoperative hypoproteinemia was correlated with all three subdivisions; obstructive jaundice was associated with severe PPCs and mortality; and older age was revealed to be an independent risk factor of mortality. A large retrospective study was performed in the present study and PD was correlated with a high occurrence of PPCs. The Clavien-Dindo system represents a broad applicable and feasible approach to evaluating PPCs in patients following PD. The independent risk factors of PPCs that were identified in the present study require further validation using the Clavien-Dindo classification in additional prospective studies. PMID- 30008897 TI - Metformin-induced apoptosis facilitates degradation of the cellular caspase 8 (FLICE)-like inhibitory protein through a caspase-dependent pathway in human renal cell carcinoma A498 cells. AB - Renal cell carcinoma (RCC) is one of the most common types of cancer in adults. Previous studies have reported that the survival rate was significantly lower for renal cancer patients with diabetes than for those without diabetes. Metformin is a well-known anti-diabetic agent used for the treatment of type 2 diabetes mellitus (T2DM). It also inhibits cell proliferation and angiogenesis and is known to possess antitumor effects. However, the molecular mechanism for metformin-induced apoptosis in renal cell carcinoma is not understood. In the present study, treatment with metformin induced apoptosis in A498 cells in a dose dependent manner. It was revealed that degradation of cellular caspase 8 (FLICE) like inhibitory protein (c-FLIP) and activation of procaspase-8 were associated with metformin-mediated apoptosis. By contrast, treatment with metformin did not affect the mRNA level of c-FLIPL in A498 cells. Treatment with benzyloxycarbonyl Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk, a pan-caspase inhibitor) almost completely blocked metformin-induced apoptosis and degradation of c-FLIPL protein. However, N-acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) scavenger, did not inhibit metformin-mediated apoptosis in A498 cells. Taken together, the results of the present study demonstrated that metformin-induced apoptosis involved degradation of the c-FLIPL protein and activation of caspase-8 in human renal cell carcinoma A498 cells and suggested that metformin could be potentially used for the treatment of renal cancer. PMID- 30008898 TI - Caspase-10, matrix metalloproteinase-9 and total laminin are correlated with the tumor malignancy of clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is a common malignant kidney tumor, the pathogenesis of which remains unclear. The aim of the present study was to investigate whether caspase-10, matrix metalloproteinase-9 (MMP-9) and total laminin (LM) were involved into the pathogenesis of ccRCC. The levels of caspase 10, MMP-9 and total LM were analyzed by ELISA in tumor tissues and adjacent non malignant tissues of 27 patients with ccRCC. The results revealed that caspase-10 levels in the tumor tissues were significantly higher than those in the adjacent non-malignant tissues (P<0.05). The MMP-9 levels in the tumor tissues were significantly lower than those in adjacent non-malignant tissues (P<0.01). The total LM levels in tumor tissues revealed no statistical difference with those in the adjacent non-malignant tissues (P=0.757). Additionally, caspase-10 levels were positively correlated with MMP-9 levels (P<0.001), but negatively correlated with total LM levels (P<0.05) in tumor tissues. Correlation analyses with clinical data of patients with ccRCC, revealed that caspase-10 levels (P<0.05) and MMP-9 levels (P<0.001) in tumor tissues were positively correlated with tumor grades of ccRCC, whereas total LM levels were positively correlated with tumor size (P<0.05). The results of the present study suggested that interactions between caspase-10, MMP-9 and LM are likely involved in the pathogenesis of ccRCC. A deeper understanding of the correlation between caspase-10, MMP-9 and LM would aid the clarification of pathogenesis of ccRCC. PMID- 30008899 TI - Antioxidant activity and leukemia initiation prevention in vitro and in vivo by N acetyl-L-cysteine. AB - N-acetyl-L-cysteine (NAC) is the most abundant water-soluble component of garlic. No study to date has studied the leukemia prevention ability of NAC in mouse systemic leukemia model. The current study aimed to investigate the leukemia initiation prevention potential of NAC in a mouse model. The cytotoxic concentration of NAC was determined first in HL-60 cells, and its in vivo activity was studied in a mouse acute myelocytic leukemia model with WEHI-3 leukemia cells. The results showed that a non-toxic concentration of NAC efficiently scavenged free-radicals, lowered lipid peroxidation and reduced DNA damage induced by hydrogen peroxide in a cultured HL-60 leukemia cell line. NAC also elevated the cellular antioxidant enzyme activity significantly. Furthermore, NAC prevented mouse death induced by injection of murine WEHI-3 leukemia cells and reduced organ damage, as well as activated antioxidant mechanisms. The results of this study provided strong evidence that NAC may have potential benefits in terms of elevating antioxidant activity and preventing leukemia initiation. PMID- 30008900 TI - Correlation between CT features of adrenocortical and adrenal medullary tumors and expression of miR-96 in serum. AB - Correlation between CT features of adrenocortical and adrenal medullary tumors and the expression of miR-96 in serum were investigated. A total of 230 patients with adrenocortical tumors and 194 patients with adrenal medullary tumors were selected in Dongying People's Hospital from August 2013 to August 2017. The two groups of patients underwent CT examination, and the signs and symptoms were recorded. The expression of miR-96 in the serum of the two groups was detected by RT-PCR, and the correlation between the expression of serum miR-96 and CT features was analyzed. In patients with adrenocortical tumor, serum miR-96 expression levels were significantly higher in patients with tumor diameter >=5 cm than those with tumor diameter <5 cm (p<0.001). In patients with adrenal medullary tumor, serum miR-96 expression levels were significantly higher in patients with tumor diameter >=3 cm than those with tumor diameter <3 cm (p<0.001). In patients with adrenocortical or adrenal medullary tumor, serum miR 96 expression levels were significantly higher in patients with peripheral infiltration than those without peripheral infiltration (p<0.001), and serum miR 96 expression levels were also significantly higher in patients with distant metastasis than those without distant metastasis (p<0.001). Serum levels of miR 96 in patients with benign adrenocortical and adrenal medullary tumors were significantly lower than those with malignant tumors in the same group (p<0.001). miR-96 may have oncogenic functions in patients with adrenocortical or adrenal medullary tumors. Increased expression level of miR-96 may promote proliferation, invasion and metastasis of tumors, and serum levels of miR-96 provide references for the diagnosis of adrenocortical and adrenal medullary tumors. PMID- 30008901 TI - Combination therapy: A feasibility strategy for CAR-T cell therapy in the treatment of solid tumors. AB - Chimeric antigen receptor (CAR) T-cell therapies have been demonstrated to have durable and potentially curative therapeutic efficacies in patients with hematological malignancies. Currently, multiple clinical trials in CAR-T cell therapy have been evaluated for the treatment of patients with solid malignancies, but have had less marked therapeutic effects when the agents are used as monotherapies. When summarizing relevant studies, the present study found that combination therapy strategies for solid tumors based on CAR-T cell therapies might be more effective. This review will focus on various aspects of treating solid tumors with CAR-T cell therapy: i) The therapeutic efficacy of CAR T cell monotherapy, ii) the feasibility of the CAR-T cell therapy in conjunction with chemotherapy, iii) the feasibility of CAR-T cell therapy with radiotherapy, iv) the feasibility of CAR-T cell therapy with chemoradiotherapy, and v) the feasibility of the combination of CAR-T cell therapy with other strategies. PMID- 30008903 TI - Effects of TONS504-photodynamic therapy on mouse mammary tumor cells. AB - In the present study, TONS504 (C51H58N8O5I2; molecular weight, 1,116.9), a novel cationic hydrophilic photosensitizer, was synthesized from protoporphyrin IX dimethyl ester through a five-step process according to a patented method for use in photodynamic therapy (PDT). The subcellular localization of TONS504 and the cytotoxic effects of TONS504-mediated PDT in the mouse mammary tumor EMT6 cell line were investigated. TONS504 was localized primarily in the lysosomes and partially in the mitochondria. The cytotoxic effects of TONS504-mediated PDT in the mouse mammary tumor EMT6 cell line were investigated using a WST8 assay and an Oxidative Stress kit. The cell viability values following treatment with 10 ug/ml TONS504 at light energies of 0, 1, 5 and 10 J/cm2 were 92.5, 101.8, 27.7 and 1.8%, respectively. The percentages of reactive oxygen species (ROS)(+) cells following the same treatment were 8.6, 8.5, 29.2 and 70.1%, respectively, whereas the percentages of apoptotic cells were 7.1, 5.6, 24.8 and 48.7%, respectively. The percentages of ROS(+) and apoptotic cells in the group subjected to TONS504 mediated PDT increased in a manner dependent on the TONS504 concentration and light energy. Further studies are required to evaluate the in vivo pharmacokinetics, tissue distribution and photodynamic effects of TONS504. PMID- 30008902 TI - The role of chemokine receptor 9/chemokine ligand 25 signaling: From immune cells to cancer cells. AB - Chemokine ligand 25 (CCL25) and chemokine receptor 9 (CCR9) are important regulators of migration, proliferation and apoptosis in leukocytes and cancer cells. Blocking of the CCR9/CCL25 signal has been demonstrated to be a potential novel cancer therapy. Research into CCR9 and CCL25 has revealed their associated upstream and downstream signaling pathways; CCR9 is regulated by several immunological factors, including NOTCH, interleukin 2, interleukin 4 and retinoic acid. NOTCH in particular, has been revealed to be a crucial upstream regulator of CCR9. Furthermore, proteins including matrix metalloproteinases, P glycoprotein, Ezrin/Radixin/Moesin and Livin are regulated via phosphatidylinositol-3 kinase/protein kinase B, which are in turn stimulated by CCR9/CCL25. This is a review of the current literature on the functions and signaling pathways of CCR9/CCL25. PMID- 30008904 TI - Conversion therapy for advanced gastric cancer with trastuzumab combined with chemotherapy: A case report. AB - Gastric cancer is a common cancer of the gastrointestinal tract and the second most prevalent cause of cancer-associated mortality globally. Gastric cancer associated mortality is increased in China compared with that in other countries. Key contributors to the poor prognosis of gastric cancer include late clinical presentation and genetic heterogeneity. Treatment based on the subtype of gastric cancer is important for effective therapy. The overexpression of the erb-b2 receptor tyrosine kinase 2 (ERBB2) gene and protein is associated with gastric cancer in humans. Chemotherapy and targeted therapy may control tumor growth and recurrence, which is an important function of conversion surgery. The present study reported a patient diagnosed with gastric cancer with multiple abdominal cavity and retroperitoneal lymph node metastases. ERBB2 amplification and overexpression were identified in both case reports presented. The patients were treated with four cycles of oxaliplatin, capecitabine and trastuzumab. Computed tomography revealed the lymph node metastases decreased in size following treatment, and surgical resection was performed. The four cycles of oxaliplatin, capecitabine and trastuzumab were continued subsequent to surgical resection at the administered dose. No recurrence was observed for >1 year after surgery. Trastuzumab combined with oxaliplatin and capecitabine as a conversion therapy regime for ERBB2-overexpressing advanced gastric adenocarcinoma increased the likelihood of successful surgical resection, and prolonged progression-free survival. PMID- 30008905 TI - A risk score staging system based on the expression of seven genes predicts the outcome of bladder cancer. AB - Bladder cancer (BLCA) is among the most malignant types of cancer. At present, the prognostic tools available for this disease are insufficient. In the present study, the transcriptome of 1,049 BLCA samples from four datasets from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) were analyzed. By utilizing the RNA-seq data provided by TCGA, a risk score staging system model was built to predict the outcome of patients with BLCA using random forest variable hunting and Cox multivariate regression. A total of 7 genes, including zinc finger protein 230, Bcl2-like 14, AHNAK, transmembrane protein 109, apolipoprotein L2, advanced glycation end-product specific receptor and amine oxidase, copper containing 2 were identified as predicting the survival time of patients with BLCA. The patients with a low risk score had a significantly higher survival rate than those with a high-risk score both in the training and validation datasets. Association analyses between risk score and other clinical information were additionally performed; it was demonstrated that the risk score was significantly associated with pathological stage. A nomogram was plotted to compare risk score and other clinical information. The risk score spanned the greatest range of points, indicating the relative accuracy of risk score. In summary, the risk staging model based on the expression of 7 genes is robust and performs more effectively than other clinical information in predicting a prognosis. PMID- 30008906 TI - Enhanced motility and proliferation by miR-10b/FUT8/p-AKT axis in breast cancer cells. AB - Upregulation of microRNA (miR)-10b has been confirmed in multiple types of cancer, however, the role of miR-10b in glycosylation remains unclear. Protein core-fucosylation is an important N-linked glycosylation modification and serves important roles in cancer progression. In a previous study, a glycogene array was applied to profile the alterations of glycogene expression in miR-10b overexpressed MCF10A cells. Notably, fucosyltranferase 8 (FUT8), which is responsible for the addition of core-fucose to N-glycan, was significantly upregulated by miR-10b. In the present study, increased motility and proliferation were observed in miR-10b-overexpressed MCF10A cells. To assess the mechanism involved, the role of FUT8 in MCF10A cells was studied and it was confirmed that miR-10b promotes motility and proliferation by regulating FUT8 and activating the protein kinase B (AKT) signaling pathway. Consistent with the aforementioned result, decreased motility and proliferation were detected when miR-10b expression was inhibited in MDA-MB-231 cells, transforming growth factor beta-induced and Twist-overexpressed MCF10A cells. To conclude, the findings from the present study indicate that miR-10b promotes motility and proliferation by increasing FUT8 and activating AKT in breast cancer cells. PMID- 30008907 TI - Association between EGFR/KRAS mutation and expression of VEGFA, VEGFR and VEGFR2 in lung adenocarcinoma. AB - Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) are two of the most notable driver genes in lung cancer, whilst vascular endothelial growth factor (VEGF) signaling serves a critical function in tumor angiogenesis. However, few studies have focused on the potential connection between EGFR/KRAS mutational status, and VEGFA, VEGF receptor (VEGFR)1 and VEGFR2 expression in lung adenocarcinoma. EGFR (exon 19, 20 and 21) and KRAS (exon 2) mutations were detected using an amplification refractory mutation system technique, and the expression of VEGFA, VEGFR1 and VEGFR2 was analyzed using immunohistochemistry in 204 patients with lung adenocarcinoma. Associations between EGFR/KRAS mutational status and VEGFA, VEGFR1, and VEGFR2 expression was analyzed using Pearson chi2 tests. It was revealed that EGFR 21 exon (P=0.033) and EGFR 20 exon (P=0.002) mutated tumors exhibited a significantly higher level of expression of VEGFA. EGFR 21 exon mutant tumors additionally demonstrated a significantly higher level of co-expression of VEGFA and VEGFR1 (P<0.001). EGFR 19 exon mutation was significantly associated with low levels of VEGFR1 (P=0.008). KRAS mutation was significantly associated with a high level of co expression of VEGFA, VEGFR1 and VEGFR2 (P=0.035), but no such association with the individual expression of VEGFA, VEGFR1 or VEGFR2 was identified. However, neither KRAS or EGFR mutations exhibited an association with the expression of VEGFR2. The present study may help in the treatment of various patients with KRAS or subtype of EGFR mutation with anti-angiogenesis therapy. PMID- 30008908 TI - Decreased BMP-7 and p-Smad1/5/8 expression, and increased levels of gremlin in hepatocellular carcinoma. AB - The aim of the present study was to investigate the expression of bone morphogenetic protein-7 (BMP-7), gremlin, and p-Smad/1/5/8 in carcinomatous and para-carcinoma tissue specimens from patients with hepatocellular carcinoma (HCC). The association of serum BMP-7 levels with clinicopathological parameters was examined to assess its relevance as a clinical biomarker for HCC. A total of 27 patients with HCC and 7 healthy subjects were included. Gene expression levels of BMP-7 and p-Smad1/5/8 were examined by reverse transcription-quantitative polymerase chain reaction. Immunohistochemical and western blot analysis were performed to determine the protein expression of target genes. The serum levels of BMP-7 were assessed by enzyme linked immunosorbent assay. The mRNA and protein expression of BMP-7 and gremlin were significantly down- and upregulated in HCC tumor tissues, respectively, compared with para-carcinoma tissues (P<0.05). The association of BMP-7 and gremlin expression with the differentiation status of HCC was also analyzed. There was a relatively higher level of BMP-7 and a lower level of gremlin expression in tumor tissues from patients with highly differentiated HCC when compared with poorly or moderately differentiated HCC (BMP-7, F=42.29, P<0.01; gremlin, F=37.93, P<0.01). Furthermore, the level of BMP 7 and p-Smad1/5/8 was decreased in patients with advanced stages of HCC, when compared with stage I HCC. The findings from the present study suggest that the BMP-7/p-Smad signaling pathway may be involved in the pathogenesis of HCC. The serum levels of BMP-7 may serve as a potential biomarker for HCC. PMID- 30008909 TI - Long non-coding RNA LINC00857 promotes gastric cancer cell proliferation and predicts poor patient survival. AB - Gastric cancer (GC) is a common malignancy worldwide and its pathogenesis remains unclear. Long non-coding RNAs (lncRNAs) serve an important function in cancer development, therefore identification of functional lncRNAs in GC is required. The results of the present study demonstrate that an lncRNA, LINC00857, was increased in GC tissues compared with adjacent non-tumor tissues. Overexpression of LINC00857 was positively associated with poor survival rate, as well as with the tumor size of patients with GC. LINC00857 knockdown induced by specific small interfering RNAs significantly inhibited GC cell proliferation in vitro. Genome wide analysis revealed that LINC00857 knockdown deregulated the cell cycle. Western blot analysis confirmed that LINC00857 knockdown decreased protein expression of cyclin D1 and cyclin E1 in GC cells. Taken together, the results indicated that LINC00857 knockdown suppressed GC cell proliferation through deregulating the cell cycle, resulting in the downregulation of cyclin D1 and cyclin E1. Therefore, LINC00857 expression may be an independent biomarker for the diagnosis and prognosis of GC. PMID- 30008910 TI - H3K4me3 and Wdr82 are associated with tumor progression and a favorable prognosis in human colorectal cancer. AB - Histone methylation is closely associated with the occurrence of cancer. Histone H3 trimethylation at lysine 4 (H3K4me3) has been reported to modulate the expression of tumor-associated expression and be altered during the progression of several human cancers. WD Repeat Domain 82 (Wdr82), a key epigenetics associated factor, is a component of the H3K4me3 methyltransferase complex. An aim of the present study was to determine H3K4me3 and Wdr82 expression and their clinical significances in colorectal cancer (CRC). Immunohistochemistry results demonstrated that the expression level of the H3K4me3 and Wdr82 were significantly decreased in CRC tissues compared with paired noncancerous tissues from 123 patients with CRC. Furthermore, the negative expression of H3K4me3 and Wdr82 expression were significantly associated with lymph node (n=33, P=0.0001) and liver metastasis (n=30, P=0.0001). Additionally, multivariate Cox regression analysis indicated that the low expression level of H3K4me3 or Wdr82 was associated with reduced overall survival (OS, P<0.05), and patients with a low H3K4me3 and Wdr82 expression had a significantly poorer outcome compared with patients with a high expression of H3K4me3 and Wdr82 (P=0.0001), suggesting that H3K4me3 and Wdr82 expression were independent factors for OS in patients with CRC. In conclusion, the decreased expressions of H3K4me3 and Wdr82 were associated with a poor prognosis in CRC. The combined expression of H3K4me3 and Wdr82 may serve as a novel prognostic marker for CRC. PMID- 30008911 TI - Hint1 expression inhibits proliferation and promotes radiosensitivity of human SGC7901 gastric cancer cells. AB - Gastric cancer is a prevalent, malignant tumor that frequently escapes treatment. Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene which contributes to intercellular communication, helps to regulate cell proliferation and survival, and is frequently underexpressed in gastric cancer. To examine the involvement of Hint1 in gastric cancer, small interfering RNA was used to knock down Hint1 expression in the human gastric cancer cell line SGC-7901. The data revealed that Hint1 inhibited cell proliferation, reduced radiation-induced DNA damage repair and caused G1 phase arrest, which increased the radiosensitivity of gastric cancer cells. Further mechanistic studies revealed a novel function of Hint1, whereby it acted as a negative regulator of extracellular signal-regulated kinase. These results demonstrated the critical function of Hint1 in the biology of human gastric cancer. Acting as a tumor growth suppressor and a radiosensitive agent, this protein is a potential biomarker and may be an attractive target for specific therapeutic interventions against gastric cancer. PMID- 30008912 TI - beta-elemene enhances anticancer bone neoplasms efficacy of paclitaxel through regulation of GPR124 in bone neoplasms cells. AB - The purpose of the present study was to investigate the anticancer effects of beta-elemene and paclitaxel for bone neoplasms. MTT assay, reverse transcription quantitative polymerase chain reaction, western blotting, flow cytometry and immunostaining were used to analyze the combined effects of beta-elemene and paclitaxel both in vitro and in vivo. The results demonstrated that combined treatment of beta-elemene and paclitaxel (beta-elemene-paclitaxel) significantly inhibited growth and aggressiveness of U-2OS cells compared with either beta elemene or paclitaxel treatment alone. It was demonstrated that beta-elemene promoted paclitaxel-induced apoptosis of U-2OS cells. Anti-apoptosis B-cell lymphoma (Bcl)-2 and Bcl-w genes were downregulated and pro-apoptotic Bcl-2 associated agonist of cell death and caspase-3 genes were upregulated in U-2OS cells following treatment with beta-elemene-paclitaxel. Treatment of beta-elemene paclitaxel arrested the cell cycle and decreased cyclin-dependent kinase, cyclin B1, P21 and P27 expression levels and decreased resistant genes alterations of ATP binding cassette subfamily B member 1, LDL receptor related protein and TS in U-2OS cells. Results demonstrated that beta-elemene-paclitaxel decreased G protein coupled receptor 124 (GPR124), vascular endothelial growth factor receptor, matrix metallopeptidase (MMP)-3, MMP-9 expression levels and increased endostatin, TIMP metallopeptidase inhibitor (TIMP)-1, TIMP-2 expression in U-2OS cells. In vivo assay demonstrated that beta-elemene-paclitaxel treatment inhibited tumor growth of BALB/c-nu/nu nude mice and prolonged survival rate of tumor-bearing mice. Immunostaining demonstrated that beta-elemene-paclitaxel treatment increased apoptotic bodies, GPR124 and increased endostatin, TIMP-1 and TIMP-2 expression in tumor tissues. In conclusion, these results suggest that the combined treatment of beta-elemene-paclitaxel is more effective at inhibiting bone neoplasm growth than beta-elemene or paclitaxel single treatment GPR124. PMID- 30008913 TI - Knockdown of RAC1 and VASP gene expression inhibits breast cancer cell migration. AB - The ability of tumor cells to migrate is biologically fundamental for tumorigenesis, growth, metastasis and invasion. The present study examined the role of Ras-related C3 botulinum toxin substrate (RAC1) and vasodilator stimulated phosphoprotein (VASP) in breast cancer cell migration. According to data in Kaplan, Oncomine and The Cancer Genome Atlas, increased expression levels of RAC1 and VASP in breast cancer are associated with decreased cancer cell differentiation, advanced pathological stage and more aggressive tumor subtypes, while increased VASP mRNA expression levels are positively correlated with a poor prognosis in patients with breast cancer. The short hairpin (sh)RNA technique was employed to knock down the expression of RAC1 or VASP. Stable interference with the expression of RAC1 or VASP using RAC1-shRNA or VASP-shRNA, respectively, was established in MCF-7 breast cancer cells. In RAC1-shRNA or VASP-shRNA cells, the protein expression levels of RAC1 or VASP were significantly downregulated compared with control cells. The proliferation and migration rates of the RAC1 shRNA or VASP-shRNA cells were significantly lower compared with control cells. It was observed that the protein expression levels of VASP also decreased in RAC1 shRNA cells compared with control cells. The results revealed that RAC1 and VASP may serve important roles in promoting the migration of MCF-7 breast cancer cells, and that VASP may among the downstream signaling molecules associated with RAC1. PMID- 30008914 TI - Arginine methyltransferase inhibitor-1 inhibits sarcoma viability in vitro and in vivo. AB - Protein arginine methyltransferases (PRMTs) are a class of epigenetic modified enzymes that are overexpressed in a various types of cancer and serve pivotal functions in malignant transformation. Arginine methyltransferase inhibitor-1 (AMI-1) is a symmetrical sulfonated urea that inhibits the activity of type I PRMT in vitro. However, previous studies demonstrated that AMI-1 may also inhibit the activity of type II PRMT5 in vitro. To the best of our knowledge, the present study provides the first evidence that AMI-1 may significantly inhibit the viability of mouse sarcoma 180 (S180) and human osteosarcoma U2OS cells. Additionally, the results demonstrated that AMI-1 downregulated the activities of PRMT5, the symmetric dimethylation of histone 4 and histone 3 (a PRMT5-specific epigenetic mark) in a mouse xenograft model of S180 and induced apoptosis in S180 cells. Taken together, the results suggest that AMI-1 may exhibit antitumor effects against sarcoma cells by targeting PRMT5. PMID- 30008915 TI - PO2-based biodosimetry evaluation using an EPR technique acts as a sensitive index for chemotherapy. AB - The partial pressure of oxygen (PO2) in the tumor microenvironment directly affects tumor sensitivity to chemotherapy. In the present study, a lithium phthalocyanine probe was implanted into MCF-7 human breast cancer cells, followed by transplant of the cells into nude mice. The present study used an electron paramagnetic resonance (EPR) oximetry measuring technique to dynamically monitor PO2 in the tumor microenvironment prior to and following chemotherapy, and aimed to determine the precise time window in which the microenvironmental PO2 peaked following chemotherapy. The results indicated that PO2 was significantly higher in breast cancer compared with control (P<0.05). Following four cycles of chemotherapy, the activity of NADH dehydrogenase, succinate-cytochrome c reductase and cytochrome c oxidase in the mitochondria of cells was significantly reduced when compared with their activity prior to chemotherapy (P<0.05). Regional blood flow in tumor tissues undergoing chemotherapy was significantly lower than that prior to chemotherapy (P<0.05). The rate of cellular apoptosis in the PO2 peak-based chemotherapy group was significantly greater than that in the conventional chemotherapy group after two and four cycles of chemotherapy (P<0.05). Tumor volume in the PO2 peak-based chemotherapy group was significantly reduced compared with that in the 0.9% NaCl solution control and the conventional chemotherapy groups after four cycles of chemotherapy (P<0.05). The tumor inhibitory rate of the experimental group was significantly higher than that of the conventional chemotherapy group (P<0.01). In conclusion, the present study may provide guidance for the development of effective strategies depending on tumor-maximal response to chemotherapy in an oxygen-rich environment. Additionally, the present study aimed to establish a foundation for a clinical noninvasive assessment intended to guide treatment and formulate individual regimens, in order to improve cancer therapeutics, sensitivity monitoring and curative effect estimation. PMID- 30008917 TI - Prognostic significance of the expression of HER family members in primary osteosarcoma. AB - The prognosis of patients with metastatic osteosarcoma is poor and has shown no significant improvement in nearly 20 years. The human epidermal growth factor (EGF) receptor (HER) family is frequently overexpressed in the majority of human carcinomas, and is involved in promoting the proliferation and survival of cancer cells. However, the role of EGFR and HER-2 expression in osteosarcoma survival remains controversial and no previous study has simultaneously investigated the association of the expression of all the four HER family members with the prognostic significance of osteosarcoma. Therefore, the present study investigated the expression levels of the complete members of the HER family in osteosarcoma specimens, as well as their associations with the clinicopathological parameters, progression-free survival (PFS) and overall survival (OS) time of patients with osteosarcoma. The expression of HER family members was detected in osteosarcoma tumor specimens from 60 patients using immunohistochemistry. The association of the expression of HER receptors in osteosarcoma with clinicopathological parameters was analyzed using chi2 test and Fishers exact test. Survival analyses were evaluated by Kaplan-Meier method and Cox proportional hazards regression model. Overall, 18 (30%), 13 (22%), 23 (38%) and 19 (32%) patients presented with high expression of EGFR, HER-2, HER-3 and HER-4, respectively, and the co-expression of 2, 3 and all 4 members of the HER family was observed. High expression of EGFR and HER-4 was associated with distant metastasis. High HER-3 expression was significantly associated with an advanced Enneking stage and distant metastasis. Multivariate analysis demonstrated that the expression of EGFR, HER-3, HER-4, EGFR/HER-3, EGFR/HER-4 and HER-3/HER-4 was an independent predictor of poor PFS and OS time in osteosarcoma patients with stage I-IIB disease. In patients with stage IIB osteosarcoma, the expression of HER-4 and EGFR/HER-4 demonstrated a more significant effect on PFS and OS time. In conclusion, therapies targeting EGFR, HER-3 and HER-4 may provide promising strategies for primary osteosarcoma. PMID- 30008916 TI - Oncogenic miR-425-5p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. AB - An increasing number of studies have demonstrated the function of microRNAs (miRNAs) in the initiation and development of various types of cancer. Among them, miR-425-5p is proven to serve an important function in several types of cancer, including gastric, cervical cancer, and hepatocellular carcinoma. However, the function of miR-425-5p in renal cell carcinoma (RCC) remains unclear. In the present study, it was demonstrated that the expression level of miR-425-5p was upregulated in RCC tissues and cell lines compared with normal tissues and cell lines (P<0.05). Additionally, Cell Counting kit-8 and MTT assays were employed to assess cell viability and proliferation, whereas wound healing and Transwell assays were employed to examine migration and invasion. The results demonstrated that upregulation of miR-425-5p promoted cell viability and the invasion and migration of ACHN and 786O cells (P<0.05). Flow cytometric analysis confirmed that upregulation of miR-425-5p inhibited apoptosis of ACHN and 786O cells (P<0.05). Downregulation of miR-425-5p inhibited the viability and invasion and migration of ACHN and 786O cells (P<0.05). In the present study, upregulation of miR-425-5p inhibited apoptosis of ACHN and 786O cells whereas no differences in early apoptotic rate were observed between the inhibitor and inhibitor NC groups for 786O and ACHN cells. These results indicate that miR-425-5p may act as an oncogene in RCC. PMID- 30008919 TI - Association between EGFR mutation and expression of BRCA1 and RAP80 in non-small cell lung cancer. AB - Association between the epithelial growth factor receptor (EGFR) mutation and the expression of breast cancer 1 (BRCA1) and receptor-associated protein 80 (RAP80) in non-small cell lung cancer (NSCLC) was studied. From September 2014 to September 2016, 51 patients with NSCLC who were hospitalized in Department of Thoracic Surgery in The Affiliated Jiangyin Hospital of Southeast University Medical College and underwent biopsy or operation were selected. The pathological changes of lung tissue were detected by hematoxylin and eosin histopathological staining. The fluorescent expression of BRCA1 and RAP80 protein in the two groups was determined by immunofluorescence staining. Reverse transcriptase polymerase chain reaction method and western blot analysis were used to detect BRCA1 and RAP80 mRNA and protein expression. Then the EGFR gene mutation was detected and analyzed. The results show that non-small cell lung cancer has an association with smoking. Compared with the control, the lung tissue structure of the NSCLC group was damaged. The protein fluorescence expression of BRCA1 and RAP80 in non small cell lung cancer group was significantly increased. The expression of BRCA1 and RAP80 mRNA and protein in NSCLC group was significantly increased. The difference in expression of BRCA1 and RAP80 in the control and the non-small cell lung cancer group was statistically significant (P<0.05). EGFR gene mutations detected 14 of the 51 patients with genetic mutations. Non-small cell lung cancer and smoking have certain relevance, and BRCA1 and RAP80 expression in the development and progression of NSCLC has a close relationship. EGFR mutation in non-small cell lung cancer significantly related to the mutation of EGFR and BRCA1 and RAP80 gene expression plays an important role in the diagnosis and treatment of NSCLC. PMID- 30008918 TI - The tumor suppressor role of microRNA-338-3p in renal cell carcinoma. AB - Human renal cell carcinoma (RCC) is the most common type of kidney malignancy in adults accounting for 2-3% of all adult malignancies. In China, RCC accounts for ~0.5% of all cancer-associated mortalities, ranking 16th among all cancer types. For early-stage RCC, surgery is the recommended treatment. Molecularly targeted therapy is the preferred first-line treatment for clear-cell RCC. However, more potential targets are required. MicroRNA-338-3p (miR-338-3p) functions as a tumor suppressor in various cancers, but has not been studied in RCC. Accordingly, the present study investigated the role of miR-338-3p of RCC. It was demonstrated that miR-338-3p was present at low levels in RCC tissues. Also, overexpression of miR-338-3p inhibited cell proliferation and promoted cell apoptosis, and downregulation of miR-338-3p promoted cell proliferation. The 3' untranslated region of AKT serine/threonine kinase 3 was targeted by miR-338-3p. In conclusion, the data of the present study revealed the inhibitory function of miR 338-3p in RCC and suggested that miR-338-3p is novel therapeutic target for RCC, but further investigation is needed. PMID- 30008920 TI - MicroRNA-205 is downregulated in hepatocellular carcinoma and inhibits cell growth and metastasis via directly targeting vascular endothelial growth factor A. AB - MicroRNAs (miRs) are an emerging class of non-coding, endogenous and small RNA molecules that serve important functions in tumorigenesis and development. The present study investigated the expression, functions and molecular mechanism underlying miR-205 in hepatocellular carcinoma. miR-205 was downregulated in hepatocellular carcinoma tissues and cell lines. Ectopic miR-205 expression suppressed hepatocellular carcinoma cell proliferation, migration and invasion in vitro. In addition, vascular endothelial growth factor A (VEGFA) was identified as a functional downstream target of miR-205 in hepatocellular carcinoma. Furthermore, knockdown of VEGFA revealed the same functions with miR-205 overexpression in hepatocellular carcinoma cells. These results provided evidence that miR-205 served important functions in the inhibition of hepatocellular carcinoma cells growth and metastasis via directly targeting VEGFA, which indicated that miR-205 may have therapeutic value for hepatocellular carcinoma. PMID- 30008921 TI - Color Doppler ultrasound and contrast-enhanced ultrasound in the diagnosis of lacrimal apparatus tumors. AB - Color Doppler ultrasound and contrast-enhanced ultrasound (CEUS) in the diagnosis of lacrimal apparatus tumors were investigated. In total, 48 patients undergoing preoperative two-dimensional and color Doppler ultrasound and CEUS examinations were included in this study. Conventional ultrasound and CEUS characteristics of 48 patients pathologically and clinically diagnosed with lacrimal apparatus tumors were retrospectively analyzed. Results of conventional ultrasound of 29 cases with pleomorphic adenoma of lacrimal gland showed moderate-hypoechogenic solid masses in lacrimal gland; CEUS displayed two enhancement modes: High, fast developed slow-extinct and overall uniform enhancement (20/29, 68.97%) and high, fast-developed slow-extinct, centripetal, uniform or non-uniform enhancement (9/29, 31.03%); after enhancement, the mass edge was clear without changes in size. Results of conventional ultrasound of 6 cases with adenoid cystic carcinoma of lacrimal gland showed hypoechogenic solid masses with unclear edge, irregular form, non-uniform echo, and abundant blood flow signals; the CEUS displayed high, fast-developed fast-extinct and overall uniform enhancement; after enhancement, mass edge was unclear and masses were larger than that in two-dimensional ultrasound. Results of conventional ultrasound of 10 cases with lacrimal sac cyst showed non-uniform, hypoechogenic masses, or cystic solid mixed masses with clear edge but no blood flow signal; the CEUS displayed peripheral circular enhancement and no enhancement inside. Results of conventional ultrasound of 3 cases with adenocarcinoma of lacrimal sac showed hypoechogenic solid masses with unclear edge, irregular form, non-uniform echo inside, and abundant blood flow signals in lacrimal sac; CEUS displayed high, fast-developed fast-extinct and overall uniform enhancement; after enhancement, masses with irregular shapes were obviously larger than that in two-dimensional ultrasound. CEUS shows the microcirculation of tumors and surrounding tissues. Combination of two dimensional and color Doppler ultrasound can improve the preoperative qualitative diagnosis of tumors and provide references for the selection of operation methods and determination of tumor resection scope. PMID- 30008922 TI - miR-184 promotes cell proliferation in tongue squamous cell carcinoma by targeting SOX7. AB - The aim of this study was to investigate whether the miR-184 could regulate the proliferation of the tongue squamous cell carcinoma (TSCC) through sex determining region Y-box 7 (SOX7) gene. miR-184 expression was upregulated in TSCC cell lines and tissues. MTT assay revealed that overexpression of miR-184 significantly promoted the proliferation of the TSCC cells in vitro. SOX7 was the direct target of miR-184 and luciferase reporter assay confirmed that miR-184 downregulated the expression of SOX7. MTT assay verified that knockdown of SOX7 remarkably promoted the proliferation of TSCC cells in vitro. miR-184 promoted the proliferation of TSCC by targeting SOX7. Taken together, our results provided a new potential therapeutic target for TSCC treatment. PMID- 30008924 TI - High MMP-26 expression in glioma is correlated with poor clinical outcome of patients. AB - To date the management of glioma remains a great challenge in cancer therapy worldwide. The identification of novel diagnostic and therapeutic methods is required. Although there is data indicating that matrix metalloproteinase (MMP) 26 serves an important role in many human cancer types, its clinical significance in glioma remains uncertain. The present study aimed to evaluate MMP-26 expression in human astrocytic glioma specimens, and investigate its role and significance in the progression of astrocytic glioma. Immunohistochemistry was performed to assess MMP-26 expression in astrocytic glioma tissues. The levels of MMP-26 expression and its relevance to the clinicopathological features and prognostic factors in patients with astrocytic glioma patients were then investigated. The results demonstrated that MMP-26 expression was significantly assocaited with the World Health Organization grade (P<0.05). Additionally, it was identified that MMP-26 expression was an effective predictor of the overall survival of patients with astrocytic glioma (P<0.05). Analyses of univariate and multivariate Cox regression confirmed that MMP-26 expression was an independent factor for evaluating the prognosis of astrocytic glioma patients (P<0.05). The current results support that MMP-26 may be a novel indicator of diagnosis and an independent factor for evaluating prognosis in patients with glioma. PMID- 30008923 TI - miR-210 promotes human osteosarcoma cell migration and invasion by targeting FGFRL1. AB - Osteosarcoma is a common bone tumor and a frequently occuring cancer-associated threat to children. Notably, the prognosis of osteosarcoma is very poor when it is diagnosed with metastasis. A growing number of studies have indicated that various microRNAs (miRs) serve important regulatory roles in the pathogeny of different types of cancer. However, the functions of miR-210 in osteosarcoma need to be elucidated comprehensively. The aim of the present study was to investigate the potential roles of miR-210 in osteosarcoma by targeting fibroblast growth factor receptor-like 1 (FGFRL1). Reverse transcription-quantitative polymerase chain reaction results revealed that the expression of miR-210 was highly elevated while FGFRL1 expression was reduced inversely in osteosarcoma tissues compared with matched normal tissues. The results of Transwell assays showed that miR-210 promoted osteosarcoma cell migration and invasion. Furthermore, the luciferase reporter assay results suggested that miR-210 could directly bind to FGFRL1 in osteosarcoma cells. In addition, the present findings demonstrated that miR-210 could negatively regulate FGFRL1 expression by targeting the 3'untranslated region. In conclusion, the findings of the present study suggested that miR-210 exerted tumor carcinogenic functions in osteosarcoma by targeting FGFRL1. The findings of this study demonstrated that FGFRL1 was a direct target of miR-210 in osteosarcoma involved in the promoting functions mediated by miR 210 in the invasion and migration of osteosarcoma, suggesting that miR-210/FGFRL1 may be promising for discovering diagnostic and prognostic biomarkers for the therapies of osteosarcoma. PMID- 30008925 TI - MicroRNA-1294 inhibited oral squamous cell carcinoma growth by targeting c-Myc. AB - Oral squamous cell carcinoma (OSCC) is the predominant histological type of oral cancer. The 5-year survival rate of OSCC is only ~50%. c-Myc is a known oncogene and target gene in various cancer types, including OSCC. The presnet study revealed that c-Myc is one of the target genes of miR-1294. Results indicated lower levels of miR-1294 in OSCC tissues samples collected from 24 patients with OSCC. Notably, overexpression of miR-1294 inhibited proliferation and migration in OSCC cell lines and inhibition of miR-1294 promoted cell growth and migration in OSCC cell lines. Moreover, miR-1294 can target the 3'UTR of c-Myc, as we identified a negative correlation between c-Myc mRNA expression and miR-1294 expression in 24 OSCC tissues. In conclusion, the data demonstrate the tumor suppressive role of miR-1294 in OSCC. PMID- 30008926 TI - Expression of miR-106 in endometrial carcinoma RL95-2 cells and effect on proliferation and invasion of cancer cells. AB - Expression of miR-106 in endometrial carcinoma RL95-2 cell line and its effect on proliferation and invasion of cancer cells was investigated. miR-106 expression vector was constructed and transiently transfected into in vitro cultured RL95-2 cells of human endometrial carcinoma. Cells were divided into three groups including blank control cells (MOCK group), miR-106 transfection group (miR-106 group) and negative control group (siNC group). Reverse-transcription quantitative PCR (RT-qPCR) was used to detect the expression of miR-106. Proliferation and in vitro migration of RL95-2 cells were detected by MTT and scratch assay, and cell apoptosis was detected by flow cytometry. Compared with MOCK and siNC group, cell apoptosis rate was significantly decreased but cell proliferation rate was significantly increased in miR-106 group (p<0.05). In addition, cell migration and invasion ability was significantly increased in miR 106 group (p<0.05). Overexpression of miR-106 can promote proliferation and inhibit apoptosis of endometrial cancer RL95-2 cells, and miR-106 may serve as a new target for the treatment of endometrial cancer in the future. PMID- 30008928 TI - Identification and validation of a Hedgehog pathway-based 3-gene prognostic signature for gastric cancers. AB - Developing prognostic factors for patients with gastric cancer (GC) is crucial for the accurate identification of subgroups with distinct clinical outcomes and the development of effective treatment strategies. The aim of this study was to determine novel gene expression signatures from the hedgehog (Hh) signaling pathway as predictors of risk with biological significance. The Cancer Genome Atlas (TCGA) GC (STAD) cohort was used as the training dataset to select for significant prognostic Hh genes. Three Hh genes, indian hedgehog (IHH), patched 1 (PTCH1) and smoothened frizzled class receptor (SMO), were identified to be significant prognostic factors. On this basis, a 3-Hh-gene set was constructed and the high-risk patients of the training cohort were distinguished against low risk cases [hazard ratio (HR)=1.73, 95% confidence interval (CI)=1.26-2.39, P=0.00069]. Then the gene signature was externally validated in a combined dataset from Gene Expression Omnibus (n=631), and experimentally confirmed in an independent cohort of 126 clinical GC samples by immunohistochemistry (IHC). Validation in the combined GEO dataset yielded consistent results (HR=1.45, 95% CI=1.17-1.81, P=0.00068), and remained significant for stages I-III, HER2 positive and surgery alone subgroups. Subsequently, we further demonstrated that this mRNA-based gene set could be successfully transferred to an IHC-based signature in our local cohort (HR=2.04, 95% CI=1.09-3.82, P=0.02). In addition, this signature served as an independent prognostic indicator for overall survival in the multivariate Cox analysis (HR=2.133, 95% CI=1.110-4.099, P=0.02). In conclusion, we successfully generated a stable III-Hh-gene model with the ability to separate patients into prognostic subgroups, which may have notable biological importance and be easily utilized clinically. PMID- 30008927 TI - Kadsurenone is a useful and promising treatment strategy for breast cancer bone metastases by blocking the PAF/PTAFR signaling pathway. AB - Breast cancer (BC) is characterized by high incidences of bone metastases. Current treatment strategies for BC bone metastases primarily focused on breaking the 'vicious osteolytic cycle'. Platelet-activating factor (PAF) is a potent phospholipid mediator, which has previously reported biological activities in BC progression and osteoclast differentiation by activating its receptor PAF receptor (PTAFR). However, the role of PAF in the mediation of BC bone metastases remains elusive. In the present study, it was revealed that the upregulation of PTAFR was associated with an increased incidence of bone metastases. It was also revealed that PAF significantly enhanced the processes of BC cell migration and BC mediated osteoclastogenesis. These results suggest that PAF serves a promotion role in BC bone metastases. It was further demonstrated that the natural PAF antagonist Kadsurenone may effectively attenuate each process by partially blocking the PAF/PTAFR signaling pathway. Therefore, targeting PAF/PTAFR by Kadsurenone may be a promising treatment strategy for BC bone metastases. PMID- 30008929 TI - Suppressed epithelial-mesenchymal transition and cancer stem cell properties mediate the anti-cancer effects of ethyl pyruvate via regulation of the AKT/nuclear factor-kappaB pathway in prostate cancer cells. AB - Castration-resistant prostate cancer (CRPC) is a leading cause of mortality among cases of prostate cancer (PCa). Current treatment options for CRPC are limited. Ethyl pyruvate (EP), a lipophilic derivative of pyruvic acid, has been reported to have antitumor activities. In the present study, the efficacy of EP against PCa was investigated using two human PCa cell lines and a mouse xenograft tumor model. PC3 and CWR22RV1 cells were treated with EP, and cytotoxicity was evaluated via Cell Counting Kit-8 and colony formation assays, while cell cycle distribution was assessed by flow cytometry. Changes in cell migration and invasion caused by EP treatment were also evaluated with Transwell and wound healing assays, and changes in the expression of intracellular signaling pathway components were detected by western blotting. EP treatment reduced cell viability, induced G1 arrest, and activated the intrinsic apoptosis pathway. Additionally, the in vivo experiments revealed that EP administration markedly inhibited tumor growth. EP also reversed epithelial-mesenchymal transition and suppressed cancer stem cell properties in part through negative regulation of AKT/nuclear factor-kappaB signaling. These results indicate that EP has anticancer activity in vitro and in vivo, and is therefore a promising therapeutic agent for the treatment of PCa. PMID- 30008930 TI - Monitoring immunoglobulin heavy chain and T-cell receptor gene rearrangement in cfDNA as minimal residual disease detection for patients with acute myeloid leukemia. AB - The present study aimed to examine whether monoclonal immunoglobulin heavy chain (IGH) or T-cell receptor (TCR) gene rearrangement in cell-free DNA (cfDNA) may be used for minimal residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML). Monoclonal IGH and TCR rearrangement in cfDNA were monitored in patients with AML. A total of 94 (40%) patients had monoclonal IGH or TCR rearrangements in cfDNA at diagnosis; 84% of these patients (79 cases) achieved complete remission following 1-3 courses of induction chemotherapy. Among these cases, 89.9% were negative for monoclonal IGH or TCR rearrangement in cfDNA following consolidation chemotherapies. A total of 8 patients with consistently positive monoclonal IGH or TCR rearrangement in cfDNA relapsed within 6-10 months. During follow up, 39 patients demonstrated positive monoclonal IGH or TCR rearrangement in cfDNA and relapsed. Recurrence of monoclonal IGH or TCR rearrangement in cfDNA was observed 1-3 months earlier than bone marrow relapse and 11 patients with solitary extramedullary relapse demonstrated positive monoclonal IGH or TCR rearrangement recurrence in cfDNA. In conclusion, the detection of monoclonal IGH and TCR rearrangement in cfDNA may represent a useful tool for MRD monitoring in patients with AML. PMID- 30008931 TI - Oridonin inhibits VEGF-A-associated angiogenesis and epithelial-mesenchymal transition of breast cancer in vitro and in vivo. AB - Metastasis is the primary cause of mortality in patients with breast cancer and lacks effective therapeutic agents. Oridonin, an active diterpenoid compound isolated from Rabdosia rubescens, was identified to be the most potent anti-tumor ingredient. However, the molecular mechanisms responsible for its anti-metastatic effects remain unclear. In the present study, oridonin significantly suppressed the migration, invasion and adhesion of MDA-MB-231 and 4T1 breast cancer cells, and inhibited tube formation of human umbilical vein endothelial cells in a dose dependent manner. The expression levels of epithelial-mesenchymal transition (EMT)-associated marker and the hypoxia inducible factor 1alpha (HIF 1alpha)/vascular endothelium growth factor (VEGF) signaling pathway mRNA and proteins were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively in vitro. The results demonstrated that oridonin effectively inhibited EMT as demonstrated by the significant increases in the expression levels of E-cadherin, and decreased expression of N cadherin, Vimentin and Snail. In addition, oridonin exerted its anti-angiogenesis activity through significantly decreasing HIF-1alpha, VEGF-A and VEGF receptor-2 protein expression. Furthermore, oridonin was demonstrated to decrease the micro vessel density as evidenced by the decreased expression of cluster of differentiation 31, a marker for neovasculature. In brief, oridonin inhibits tumor cell migration, invasion and adhesion, as well as tumor angiogenesis, which are mediated by suppressing EMT and the HIF-1alpha/VEGF signaling pathway. The results of the present study suggest that oridonin may be a promising anti metastatic agent in breast cancer treatment. PMID- 30008932 TI - An improved biopsy technique for rabbits with VX2 bone tumors. AB - The present study aimed to investigate the efficacy of an improved biopsy method for reducing local exudation and metastasis. After resecting the VX2 tumor in cancer-bearing VX2 rabbits, a tumor cell suspension was prepared. Tumor cells were transplanted into the tibias of 20 rabbits in order to establish a bone tumor model. These adult rabbits underwent a puncture procedure after 2 weeks. All the left tibias were punctured using the improved biopsy method (the experimental group), where bolt closures were implanted into puncture holes through the metallic casing following biopsy. All the right tibias were punctured using a traditional biopsy technique (the control group). Color Doppler ultrasonography was used to assess the exudation of each puncture hole after 1 h. After 7 days, a pathological study was performed on the soft tissue near each puncture hole. The success rate of the bone model was 100% for the 20 rabbits. The exudation rate in the experimental group was lower than that in the control group (25 vs. 80%, respectively; chi2=12.13; P<0.05). The tumor-spreading rate in the experimental group was lower than that in the control group (35 vs. 85%, respectively; chi2=10.41; P<0.05). Overall, it was shown that the improved biopsy method can prevent local bleeding and tumor metastasis. PMID- 30008933 TI - Effects of connective tissue growth factor on prostate cancer bone metastasis and osteoblast differentiation. AB - Previous studies have demonstrated that connective tissue growth factor (CTGF) is expressed at increased levels in prostate cancer bone metastasis mouse models and patients with prostate cancer which metastasizes to the bone; however, the underlying molecular mechanism(s) remain unknown. The present study investigated the function of CTGF in osteoblast differentiation and its effect on prostate cancer bone metastasis by analyzing CTGF gene expression and transcription at different levels of invasion, metastasis of prostate cancer cells, and the influence of CTGF on proliferation and xenotransplantation. A mouse model demonstrating bone metastasis was used to investigate the function(s) of CTGF in bone metastasis and osteoblast differentiation. Results demonstrated that CTGF expression was increased in association with high bone metastasis in prostate cancer cells, and its expression was significantly decreased in whole cell lysates. CTGF expression in prostate cancer cells with high levels of bone metastasis was increased 1.9-fold compared with prostate cancer cells with low levels of bone metastasis. The expression of CTGF in mesenchymal cells was markedly increased compared with epithelial cells. Results indicated that the increased expression of CTGF does not affect the proliferation of tumor cells and possesses no influence on tumor volume. Control and CTGF plasmids were transfected into RM1 cells and led to 4 and 17% bone lesions, respectively. Increased expression of CTGF significantly enlarged the tumor area in the bone metastatic position compared with the control. Positive areas of alkaline phosphatase were significantly decreased as the concentration of CTGF increased. The results of the present study demonstrated that CTGF promotes prostate carcinoma to metastasize in the bone by dysregulating osteoblast differentiation. PMID- 30008934 TI - Ubiquitin E3 Ligase MARCH7 promotes proliferation and invasion of cervical cancer cells through VAV2-RAC1-CDC42 pathway. AB - Ubiquitin E3 Ligase MARCH7 is involved in T cell proliferation and neuronal development. In our previous study, we demonstrated MARCH7 promoted malignant behavior of ovarian cancer via the nuclear factor (NF)-kappaB and Wnt/beta catenin signaling pathway. However, the expression and function of MARCH7 in cervical cancer remains unknown. The present study aimed to unravel the expression and function of MARCH7 in cervical cancer to elucidate its potential role in the diagnosis and pathogenesis of cervical cancer. Results indicated that the expression of MARCH7 was abnormally high in cervical cancer tissues than normal cervical tissues. However, silencing the expression of MARCH7 in HeLa cells resulted in decreased cell proliferation and invasion. Mechanistic investigations revealed that MARCH7 interacted with VAV2. Silencing the expression of MARCH7 in HeLa cells inhibited the VAV2-RAC1-CDC42 signaling pathway. Overall, the results of the present study identified MARCH7 as a candidate oncogene in cervical cancer, and a potential target for cervical cancer therapy. PMID- 30008935 TI - MicroRNA-23a/27a/24-2 cluster promotes gastric cancer cell proliferation synergistically. AB - Previous studies have indicated that certain microRNAs (miRNAs/miRs) function as either tumor suppressors or oncogenes in human cancer. The present study identified the miR-23a/27a/24-2 cluster, containing miR-23, miR-27a and miR-24, as an oncogene in gastric cancer. The expression of the miR-23a/27a/24-2 cluster was upregulated in clinical gastric cancer tissues. Transfection with inhibitors of miR-23a, miR-27a, or miR-24, either independently or together, repressed in vitro colony formation and in vivo tumor formation. The miR23a/27a/24-2 cluster inhibitors repressed the growth of gastric cancer cells in a synergistic manner. In addition, treatment with lower doses of the miRNA inhibitor mixture induced the formation of apoptotic bodies. According to computational predictions using TargetScan, suppressor of cytokine-induced signaling 6 (SOCS6) was identified as one of the downstream target genes of the miR-23a/27a/24-2 cluster. The expression of SOCS6 was significantly lower in tumor tissues than in matched normal tissues (P<0.01) and was associated with poor survival (P<0.00001). Taken together, these results strongly suggested that the miR-23a/27a/24-2 cluster may mediate the progression of gastric cancer through the suppression of SOCS6 expression. The present study also provides a novel molecular target for the development of an anti-gastric cancer agent. PMID- 30008936 TI - MicroRNA-650 targets inhibitor of growth 4 to promote colorectal cancer progression via mitogen activated protein kinase signaling. AB - Colorectal cancer (CRC) is the third most common malignant disease globally and causes numerous cancer-associated mortalities; however, the underlying molecular mechanisms remain unresolved. MicroRNAs (miRs) are endogenous noncoding RNAs that regulate post-transcriptional gene silencing by annealing to partially complementary sequences in the 3'-untranslated regions of target mRNAs. In the present study, expression of the tumor suppressor gene inhibitor of growth protein 4 (ING4) in cell lines was investigated using reverse transcription quantitative polymerase chain reaction and western blotting. miR-650 overexpression promoted CRC cell proliferation and migration by targeting ING4 when the cells were transfected with the miR-650 mimics. Additionally, overexpression of miR-650 increased the epithelial-mesenchymal transition and activation of the Ras homolog gene family member A/Ras-related C3 botulinum toxin GTPase. Extracellular signal-regulated kinases and p38 mitogen-activated protein kinase signaling were markedly activated when miR-650 was increased in CRC cells. Combined, the results indicate the mechanism underlying the miR-650 promotion of CRC progression, and provide promising potential biomarkers for the prognosis and treatment of CRC. PMID- 30008937 TI - Effect of the degree of gastric filling on the measured thickness of advanced gastric cancer by computed tomography. AB - Imaging of gastric cancer thickness is closely associated with the depth of tumor invasion, which provides guidance for clinical staging and assists the evaluation of the effects of adjuvant therapy. However, it is unclear whether the measurement of thickness is affected by the degree of gastric filling, and its accuracy and reliability are under-reported. The present study aimed to investigate the influence of the degree of gastric filling on the measurement of gastric cancer thickness. A total of 38 patients with advanced gastric cancer who underwent enhanced abdominal computed tomography (CT) scanning at the Department of CT and MR in The Fourth Hospital of Hebei Medical University (Shijiazhuang, China) between July and September 2016 were recruited, consisting of 21 newly diagnosed cases and 17 follow-up cases following non-surgical treatments. Plain scanning (prior to filling) and enhanced scanning in venous phase (following filling) were performed. Axial CT images prior to and following filling of the normal part of gastric wall and the lesions were compared. The same procedure was repeated on these participants 1 month later by the same radiologist, and the results were compared with those obtained previously. Normal gastric wall thickness prior to and following gastric filling was significantly different (all P<0.001) with the most substantial changes observed at the greater curvature. Lesion thickness prior to and following filling was similar in newly diagnosed patients, but significantly different in patients for re-examination (P<0.05). The two thickness measurements in the same patients were consistent. The measured thickness of gastric cancer in newly diagnosed patients was relatively stable, and could be used as an indicator in baseline CT examination. Maintaining a similar degree of gastric filling during re-examination could aid the accurate evaluation of treatment efficacy. PMID- 30008938 TI - Hub genes and key pathways of non-small lung cancer identified using bioinformatics. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for ~80% of all lung cancer cases. The aim of the present study was to identify key genes and pathways in NSCLC, in order to improve understanding of the mechanism of lung cancer. The GSE33532 gene expression dataset, containing 20 normal and 80 NSCLC samples, was used. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to obtain the enrichment data of differently expressed genes (DEGs). Disease modules within NSCLC were constructed by Cytoscape, using protein-protein interaction (PPI) from the Search Tool for the Retrieval of Interacting Genes database. In addition, the Kaplan Meier plotter KMplot was used to assess the top hub genes in the PPI network. As a result, 1,795 genes were identified in NSCLC; 729 were upregulated and 1,066 were downregulated. The results of the GO analysis indicated that the upregulated DEGs were significantly enriched in 'biological processes' (BP), including 'cell cycle and nuclear division'; the downregulated DEGs were also significantly enriched in BP, including 'response to wounding', 'anatomical structure morphogenesis' and 'response to stimulus'. Upregulated DEGs were also enriched in 'cell cycle', 'DNA replication' and the 'tumor protein 53 signaling pathway', while the downregulated DEGs were also enriched in 'complement and coagulation cascades', 'malaria' and 'cell adhesion molecules'. The top 9 hub genes were cyclin-dependent kinase 9 (CDK1), polo-like kinase 1, aurora kinase B, cell division cycle 20, baculoviral initiator of apoptosis repeat containing 5, mitotic checkpoint serine/threonine kinase B, proliferating cell nuclear antigen (PCNA), centromere protein A and MAD2 mitotic arrest deficient-like 1, and the KMplot results revealed that the high expression levels of these genes resulted in significantly low survival rates, compared with low expression samples (P<0.05), with the exception of PCNA and CDK1. In the pathway crosstalk analysis, 26 nodes and 41 interactions were divided into two groups: One module of the two groups primarily included 'metabolism of amino acid' and the other primarily contained 'tumor necrosis signaling' pathways. In conclusion, the present study assisted in improving the understanding of the molecular mechanisms underlying NSCLC development, and the results may help the understanding of the biological mechanism of NSCLC. PMID- 30008939 TI - Identification of differentially expressed proteins in the gastric mucosal atypical hyperplasia tissue microenvironment. AB - In the present study, the interaction of proteins in the microenvironment of gastric mucosal atypical hyperplasia was analyzed. The stromata of normal gastric mucosa (NGM) and gastric mucosal atypical hyperplasia (GMAH) tissues were purified with laser capture microdissection (LCM). The differentially expressed GMAH proteins of the NGM and GMAH tissues were identified by quantitative proteomic techniques with isotope labeling. The cross-talk between differentially expressed proteins in NGM and GMAH tissues was then analyzed by bioinformatics. There were 165 differentially expressed proteins identified from the stromata of NGM and GMAH tissues. Among them, 99 proteins were upregulated and 66 were downregulated in GMAH tissue. The present study demonstrated that these proteins in gastric mucosal atypical hyperplasia were involved in cancer-associated signaling pathways, including the p53, mitogen-activated protein kinase (MAPK), cell cycle and apoptosis signaling pathways, and were involved in cellular growth, cellular proliferation, apoptosis and the humoral immune response. The results of the present study suggest that the 165 differentially expressed proteins, including S100 calcium-binding protein A6 (S100A6) and superoxide dismutase 3 (SOD3) in the microenvironment of gastric mucosal atypical hyperplasia, are involved in the p53, MAPK, cell cycle and apoptosis signaling pathways, and serve a function in the pathogenesis of gastric cancer. PMID- 30008940 TI - Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels. AB - Resistance to oxaliplatin (L-OHP) is a major obstacle to successful chemotherapy in colorectal cancer (CRC). In the present study, the ability of gambogic acid (GA) to reverse L-OHP resistance in CRC LoVo cells was investigated. L-OHP resistant LoVo/L-OHP cells were established by exposing them to increasing concentrations of L-OHP. GA-reversed L-OHP-sensitive LoVo/L-OHP/GA cells were established by exposure to 0.5 umol/l GA for 2 weeks. A Cell Counting Kit-8 assay was used to assess levels of proliferation. Flow cytometry was applied to detect apoptosis rates. Transwell assays were used to analyse invasion. Inductively coupled plasma mass spectrometry was used to determine intracellular platinum (Pt) content. Western blot analysis was used to reveal the protein levels of Human copper transporter 1 (hCTR1), Copper-transporting p-type adenosine triphosphatases 1 (ATP7A) and Copper-transporting p-type adenosine triphosphatases 2 (ATP7B). LoVo/L-OHP and LoVo/L-OHP/GA cell lines were successfully established, and it was identified that L-OHP inhibited the proliferation of LoVo, LoVo/L-OHP and LoVo/L-OHP/GA cells in a dose-dependent manner. Compared with the parent LoVo cells, the anti-apoptosis and invasion properties of LoVo/L-OHP cells were enhanced, and were reversed by GA treatment. Intracellular Pt content was highest in the LoVo cells, followed by LoVo/L-OHP/GA cells, and then lowest in the LoVo/L-OHP cells. Downregulated hCTP1 and upregulated ATP7A and ATP7B were associated with L-OHP resistance, and GA reversed the resistance by increasing levels of hCTR1 and decreasing levels of ATP7A and ATP7B. In conclusion, GA has the potential ability to reverse L-OHP resistance in CRC cells by increasing intracellular Pt content, which it achieves by increasing hCTR1 levels and decreasing ATP7A and ATP7B levels. GA may represent a promising treatment agent for L-OHP resistance. PMID- 30008941 TI - Programmed death-ligand 1 positivity can predict improved survival and a lower risk of brain metastasis in patients with resectable small cell lung cancer. AB - The present study aimed to investigate the expression of programmed death-ligand 1 (PD-L1) in resectable small cell lung cancer (SCLC) and investigate its predictive value for survival and brain metastasis (BM). Postoperative SCLC specimens were immunostained with the SP142 antibody against PD-L1. Positive PD L1 expression was defined as PD-L1 expression in >=5% of tumor cells. A total of 80 patients were recruited between January 2010 and December 2012. PD-L1 was expressed in 65.0% (52/80) of all patients and 59.3% (16/27) of patients with BM. The median survival time (MST) was longer in the PD-L1(+) group (46.4 vs. 28.5 months, P=0.002). There was no significant difference in the MST between patients with PD-L1(+) or (-) BM (P=0.55). The 3-year risk of BM in the PD-L1(+) group was lower than that in the PD-L1(-) group (24.1 vs. 48.4%, P=0.046). PD-L1 was an independent factor for overall survival (OS) [hazard ratio (HR)=0.485, P=0.011] and BM (HR=0.335, P=0.024). The present study concludes that PD-L1 is commonly expressed in SCLC and is associated with OS and BM. PMID- 30008942 TI - Overexpression of Napsin A resensitizes drug-resistant lung cancer A549 cells to gefitinib by inhibiting EMT. AB - Lung cancer is one of the most common malignant tumors and also the leading cause of cancer-related deaths in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib, have been used in the therapy of lung cancer. However, the acquisition of drug resistance is a major limitation in the clinical efficiency of EGFR-TKIs. Epithelial-mesenchymal transition (EMT) has been demonstrated to be an underlying mechanism of acquired resistance. A previous study has reported that Napsin A expression can inhibit EMT in lung cancer cells. The present study therefore investigated the effect of Napsin A on the sensitivity of EGFR-TKI-resistant lung cancer cells. First, a drug-resistant lung cancer cell line was generated using the EGFR-TKI gefitinib on A549 cells (termed here A549-GFT). EMT was demonstrated to be induced in the drug resistant A549-GFT cells, evidenced by reduced E-cadherin expression and increased Vimentin expression compared with control A549 cells. Next, Napsin A was overexpressed in the cells by transfection of the Napsin A-expression vector, PLJM1-Napsin A. Western blot analysis confirmed that the protein expression levels of Napsin A were significantly elevated in the Napsin A-overexpressing cells. Cell proliferation and apoptosis assays were performed to evaluate the effect of Napsin A overexpression on resistant A549 cells. The results of MTT assay demonstrated that Napsin A overexpression inhibited the proliferation of A549 and drug-resistant A549-GFT cells and that the proliferation of Napsin A overexpressing A549-GFT cells was significantly inhibited by gefitinib treatment compared with control A549-GFT cells. The results from the Annexin V/propidium iodide double staining apoptosis assay indicated that Napsin A overexpression enhanced gefitinib-induced apoptosis in A549-GFT cells. Additionally, EMT was reversed following Napsin A expression in A549-GFT cells, as evidenced by the restoration of E-cadherin and downregulation of Vimentin expression. Further investigation demonstrated that Napsin A overexpression resulted in inhibition of focal adhesion kinase, a critical factor in integrin signaling, in the resistant A549-GFT cells. These data suggested that Napsin A resensitized the drug resistant A549-GFT cells to gefitinib, possibly by reversing EMT via integrin signaling inhibition. Therefore, Napsin A combined with a TKI may be a more effective treatment strategy for lung cancer. PMID- 30008943 TI - Ursodeoxycholic acid attenuates 5-fluorouracil-induced mucositis in a rat model. AB - Intestinal mucositis is a commonly encountered complication of chemotherapy. However, there are few effective treatments or preventive methods. Ursodeoxycholic acid (UDCA) stabilizes cell membranes, acts as an antioxidant and inhibits apoptosis, thereby exerting cytoprotective effects. The aim of the present study was to examine the ability of UDCA to protecting against chemotherapy-associated mucositis. Sprague-Dawley rats were randomly assigned to five groups: Control, vehicle + 5-fluorouracil (5-FU), 5-FU + UDCA (10 mg/kg/day), 5-FU + UDCA (100 mg/kg/day) and 5-FU + UDCA (500 mg/kg/day). Following randomization, a single dose of 5-FU was injected and varying amounts of UDCA was administered to each group. UDCA was administered orally to rats for 6 days, beginning 1 day prior to 5-FU administration. The rats were sacrificed 1 day following the last UDCA administration and intestinal tissue specimens were prepared for analysis. UDCA administration attenuated body weight loss, decreased inflammatory cytokine levels and curbed intestinal villus damage in the 10 and 100 mg/kg/day groups. When compared with the jejunal villi lengths in the vehicle+5-FU group (212.8+/-58.0 um), those in the 5-FU + UDCA (10 mg/kg/day) and 5-FU + UDCA (100 mg/kg/day) groups were significantly greater [331.3+/-18.0 um (P=0.001) and 310.0+/-112.6 um (P=0.046), respectively]. Tumor necrosis factor alpha and interleukin-6 levels were reduced in the 10 and 100 mg/kg/day UDCA groups (P<0.05). UDCA considerably attenuated the elevation in inflammatory cytokines and intestinal villus damage. The results of the study suggest that UDCA may be used as a protective agent against chemotherapy-associated intestinal mucositis. PMID- 30008944 TI - Prognostic significance of Wilms' tumor 1 expression in patients with pancreatic ductal adenocarcinoma. AB - The only current curative treatment for patients with pancreatic ductal adenocarcinoma (PDA) is surgical resection, and certain patients still succumb to disease shortly after complete surgical resection. Wilms' tumor 1 (WT1) serves an oncogenic role in various types of tumors; therefore, in the present study, WT1 protein expression in patients with PDA was analyzed and the association with overall survival (OS) and disease-free survival (DFS) time in patients with PDA was assessed following surgical resection. A total of 50 consecutive patients with PDA who received surgical resection between January 2005 and December 2015 at the Jikei University Kashiwa Hospital (Kashiwa, Chiba, Japan) were enrolled. WT1 protein expression in PDA tissue was measured using immunohistochemical staining. Furthermore, laboratory parameters were measured within 2 weeks of surgery, and systemic inflammatory response markers were evaluated. WT1 protein expression was detected in the nucleus and cytoplasm of all PDA cells and in tumor vessels. WT1 exhibited weak staining in the nuclei of all PDA cells; however, the cytoplasmic expression of WT1 levels was classified into four groups: Negative (n=0), weak (n=19), moderate (n=23) and strong (n=8). In patients with PDA, it was demonstrated that the OS and DFS times of patients with weak cytoplasmic WT1 expression were significantly prolonged compared with those of patients with moderate-to-strong cytoplasmic WT1 expression, as determined by log-rank test (P=0.0005 and P=0.0001, respectively). Furthermore, an association between the density of WT1-expressing tumor vessels and worse OS/DFS times was detected. Multivariate analysis also indicated a significant association between the overexpression of WT1 in PDA tissue and worse OS/DFS times. To the best of our knowledge, the present study is the first to demonstrate that moderate-to strong overexpression of WT1 in the cytoplasm of PDA cells is significantly associated with worse OS/DFS times. Therefore, overexpression of WT1 in the cytoplasm of PDA cells may impact the recurrence and prognosis of patients with PDA following surgical resection. The results further support the development of WT1-targeted therapies to prolong survival in all patients with PDA. PMID- 30008945 TI - The tumor suppressor role of miR-155-5p in gastric cancer. AB - Gastric cancer (GC) is the fifth most common type of malignant tumor worldwide and the most common cause of cancer-associated mortality in China. Recent studies revealed that microRNAs (miRNAs) function in the pathogenesis of GC, and that miR 155-5p expression is downregulated in GC tissues. However, the function of miR 155-5p has not been fully identified. In the present study, it was demonstrated that overexpression of miR-155-5p inhibited GC-cell proliferation and promoted apoptosis, while downregulation of miR-155-5p promoted GC-cell proliferation and decreased the cisplatin sensitivity of GC cells. Mitogen-activated protein kinase kinase kinase 10 was demonstrated to be a potential target gene of miR-155-5p. In conclusion, an antitumor role of miR-155-5p in gastric cancer was suggested. PMID- 30008947 TI - The Flow of Learning. PMID- 30008946 TI - Performance of Gd-EOB-DTPA-enhanced MRI for the diagnosis of LI-RADS 4 category hepatocellular carcinoma nodules with different diameters. AB - In 2011, the American College of Radiology released a standardized reporting and data collection system, named Liver Imaging Reporting and Data System (LI-RADS), to improve the consistency of diagnostic imaging examinations of hepatocellular carcinoma (HCC). When the LI-RADS guideline was updated in 2014, hepatobiliary contrast agents, including gadoxetate acid (Gd-EOB-DTPA), were incorporated into the system. However, the diagnostic performance of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) for nodules of different diameters has not been addressed. In the present study, a total of 263 LI-RADS 4 category hepatic nodules were examined blindly and independently by two radiologists. All nodules were divided into two datasets: Set 1 (n=86) that included nodules with iso/hypo intensity in the arterial phase (HCC, n=42; non-HCC, n=44) and set 2 (n=177) that included nodules with hyper-intensity in the arterial phase (HCC, n=131; non-HCC, n=46). The diagnostic performance of Gd-EOB-DTPA-enhanced MRI for evaluation of nodules with different diameters was evaluated. The present study revealed that the diagnostic performance of Gd-EOB-enhanced MRI of larger nodules (>2 cm) was higher compared with (<2 cm) smaller nodules. The FPR of large nodules (>2 cm) with a hypervascular pattern was lower compared with smaller nodules (<2 cm) with hypovascular pattern. In conclusion, Gd-EOB-enhanced MRI is useful for the diagnosis of HCC where hypervascular LI-RADS 4 nodules are >2 cm in diameter. However, Gd-EOB-enhanced MRI may be of limited use for the assessment of nodules that <20 mm due to low diagnostic performance and high FPR. PMID- 30008948 TI - Addiction, Passion, or Confusion? New Theoretical Insights on Exercise Addiction Research From the Case Study of a Female Body Builder. AB - Exercise addiction is widely studied in sport science and psychology, but at this time it is not recognized as an independently diagnosable mental or psychiatric disorder. Indeed, studies on exercise addiction assess a level of risk for disordered exercise behaviour, characterized by lack of control and negative personal consequences. It is argued that commitment and passion are two overlapping features of high exercise involvement which obscure the fine line between healthy and unhealthy exercise. The present case study examined a successful female body builder who initially claimed that she was addicted to exercise. During an interview she also completed three questionnaires and her appraisal of well-being in eight life domains were assessed at present, as well as retrospectively before her intensive involvement with exercise. She was screened under the Non-Substance Related Disorders category of Substance-Related and Addictive Disorders classification of DSM-5 for gambling, by replacing the word "gambling" with "exercise". Although she was susceptible to exercise addiction, attained high scores on obsessive passion, exhibited more than four symptoms on the DSM list, she exhibited no signs of loss of control and she mainly reported positive experiences associated with her exercise behaviour. She has obtained a nearly maximum score on commitment to exercise and high score on harmonious passion. Almost all aspects of her life have changed in positive direction after getting intensely involved in exercise. This case illustrates that the current scholastic path to the study of exercise addiction may be obscured by ambiguous assumptions and unilateral quantitative focus. PMID- 30008949 TI - The Illusion of Knowing in Metacognitive Monitoring: Effects of the Type of Information and of Personal, Cognitive, Metacognitive, and Individual Psychological Characteristics. AB - The aim of the paper is to analyse the illusion of knowing in metacognitive monitoring of the learning activity of university students (n = 262). The analysis focuses on the effects of the different types of information proposed and of personal, cognitive, metacognitive, and individual psychological characteristics of the participants. The research has shown that the illusion of knowing can occur in all types of metacognitive judgments, but is more evident in prospective judgments and depends on the type of information, its length and style, task type, etc. There are empirically established correlations between the selected personal, cognitive, and metacognitive characteristics. Gender and age differences in the manifestation of the illusion of knowing are not observed, although it is found that women tend towards overconfidence. The results also showed that the illusion of knowing is more typical for younger students, especially for those with lower levels of academic achievements. PMID- 30008951 TI - The Centrality of Events Scale for Italian Adolescents: Integrating Traumatic Experience Into One's Identity and Its Relation to Posttraumatic Stress Disorder Symptomatology. AB - Adolescents could develop areas of vulnerability, especially if they have had to deal with highly stressful and traumatic life events. Stressful experiences can work as traumatic memories that become central to one's life and core topics for one's identity and for the attribution of meaning to life experience. The present work evaluates (a) the internal structures of the 20-item Centrality of Event Scale in the Italian context and (b) the impact of stressful and traumatic experience during adolescence. The present work includes a convenience sample of 872 Italian adolescents -528 males, 344 females- aged between 11 and 21 years (M = 15.85; SD = 2.09). We performed a confirmatory factor analysis that confirmed a three-factor solution. Moreover, the perception of stressful event as central in the participants' lives was significantly correlated with the presence of PTSD symptomatology, as measured by the Impact of Event Scale Revised. We found that participants with PTSD symptoms had significantly higher CES scores. These data show the validity of the CES with adolescent samples, emphasizing the sensitivity of this instrument in detecting the impact of negative life experiences even in a sample of adolescents. PMID- 30008950 TI - Freeze or Forget? Virtual Attack Effects in an Emotional Sternberg Task. AB - Emotionally salient stimuli have the ability to disrupt cognitive processing. This kind of disruption involves effects on working memory and may be related to mental health problems. To explore the nature of such emotional interference on working memory, a Virtual Attack Emotional Sternberg Task (VAEST) was used. Neutral faces were presented as distractors and warning signals, which were sometimes followed by a virtual attack, created by having the neutral face turn angry while the image was enlarged. The attack was hypothesized to have one of two effects: to disrupt cognitive processing and thereby increase interference effects, or to terminate a state of freezing and thereby reduce interference effects. The task was successfully completed online by a sample of 59 students. Results clearly show that the virtual attack caused a reduction of interference relative to no-attack trials. The apparent cognitive disruption caused by emotional distractors may thus reflect freezing, which can be reversed by a freeze-terminating stimulus. PMID- 30008952 TI - Sickness Absence due to Chronic Musculoskeletal Pain: The Exploration of a Predictive Psychological Model Including Negative Moods, Subjective Health and Work Efficacy in an Adult County Population (The HUNT Study). AB - The relation between musculoskeletal pain and sickness absence was tested in an adult county population. Maximal explained variance in absence from work due to chronic musculoskeletal pain (sickness absence) was tested in a model in which subjective health was expected to mediate the associations between such pain and dysphoria, respectively, and work efficacy. In turn, work efficacy was expected to mediate the link between subjective health and sickness absence. All the residents in the County of Nord-Trondelag, Norway, aged 20 and older, were invited to take part in a public health survey during 1995-97 (HUNT-2), and 66,140 (71.2%) participated. Prevalence of musculoskeletal pain, dysphoria, subjective health and work efficacy were assessed, as well as sickness absence last year due to musculoskeletal pain. The model test was performed by use of the LISREL procedure based upon data from 30,158 employees reporting chronic musculoskeletal pain last year. The measurement model fitted the data well: chi2 = 9075, df = 52, p < .0004, Critical N = 1041, RMSEA = 0.038, CFI = 0.99, SRMR = 0.020. The structural model fitted the data equally well, and the best prediction of sickness absence was obtained with lower back pain, upper and lower extremity pain, as well as dysphoria as the primary variables affecting subjective health that, in turn, was the convergent predictor of work efficacy that, finally, best explained the variance in sickness absence (56%). The data supported an indirect sequence of complaint-health-efficacy (CHE-model) as the best predictor of sickness absence due to musculoskeletal pain. PMID- 30008953 TI - Cross-Cultural Adaptation of Research Tools: A Study on the Cultural Intelligence Scale Adaptation in Slovenian. AB - The article examines the cross-cultural transferability of a widely accepted cross-cultural assessment tool - the Cultural Intelligence Scale (CQS) - using research conducted in Slovenia and insights from the American and Slovenian researchers who translated the tool into Slovene and adapted it for use in Slovenia. In the context of a qualitative focus group based study, the researchers look at the specific characteristics of CQS perceptions within the Slovenian sample (two focus groups - one in the capital and the other in the south of the country) and identify barriers to these perceptions and the specific characteristics of the perceptions of Slovenian citizens regarding cross-cultural interaction. PMID- 30008954 TI - (Dis)Obedience in U.S. American Young Adults: A New Way to Describe Authority Relationships. AB - The present research aims to investigate the psychosocial phenomena of obedience and disobedience in young adults residing in the United States, as a replication of a previous study by Pozzi, Fattori, Bocchiaro, and Alfieri (2014). We utilize social representation theory as a means to better understand and define (dis)obedience, a behavioral dimension of the concept of authority. The analysis was conducted using a concurrent mixed methods design. One hundred and fifty-one participants completed a self-report online questionnaire. The results indicate that participants see both obedience and disobedience as related to an authority. Obedience was mostly perceived as an ability to be responsive to laws, social norms, or physical authorities, as well as a positive social object. Disobedience, instead, was defined as a failure of a negative line of conduct. These results differ from previous research, contributing meaningfully and pragmatically to the theoretical debate on (dis)obedience. Theoretical and practical implications of these findings are discussed. PMID- 30008955 TI - The Role of Autobiographical Story-Telling During Rehabilitation Among Hip Fracture Geriatric Patients. AB - Hip fracture is one of the most common health care problems among elderly people. Literature shows that high self-efficacy expectations and positive affect are some of the key issues in functional recovery after hip fracture. The present investigation tested whether self-narration of such life-breaking event influences self-efficacy and depression during the process of rehabilitation. We designed a Self-Narration Journey (SNJ) to be administered during the in-hospital rehabilitation. In Study 1, we investigated the influence of SNJ on depression and perceived self-efficacy. Study 2 aimed to explore the effect of SNJ, depression, and self-efficacy on functional recovery of independence to perform daily activities during the rehabilitation process. The data showed that the Self Narration Journey proved effective in increasing the perceived self-efficacy and in lowering the level of depression. The present work highlights a significant effect of the SNJ on the functional recovery process. PMID- 30008956 TI - Group Psychodynamic Counselling as a Clinical Training Device to Enhance Metacognitive Skills and Agency in Future Clinical Psychologists. AB - Metacognitive skills and agency are among the main psychological abilities a clinical psychologist should have. This study aimed to assess the efficacy of group psychodynamic counselling as a clinical training device able to enhance metacognitive skills and agency in final-year undergraduates in clinical psychology within an educational context. Thirty-three final-year students of clinical psychology participated in an experiential laboratory lasting two months. Participants completed measures regarding metacognitive skills and agency at pre-, post-treatment, and 3-month follow-up assessment. The results suggested that group psychodynamic counselling made students feel more capable of recognizing emotional states, understanding causal relationships, inferring mental states of others in terms of beliefs, desires, intentions, and expectations, and thinking critically. Furthermore, the group psychodynamic counselling helped students to feel more able to derive pathways to desired goals and to motivate themselves via agency thinking to use those pathways. Thus, the study confirmed the efficacy of group psychodynamic counselling as a clinical training device able to enhance metacognitive skills and agency in future clinical psychologists. PMID- 30008958 TI - Singleness, Religiosity, and the Implications for Counselors: The Indonesian Case. AB - This paper explores the unique role of religiosity in assisting Indonesian singles (extensively refer to those who are never married) and how it relates to the counseling and therapeutic practices with never-married clients. Whereas the role of religiosity has been drawn into scholarly attention for its effectiveness in dealing with many situations that are particularly related to social stigma, little is known regarding its role in assisting singles to overcoming stigma due to their singleness. Indonesian society regards marriage as a social achievement and this perception places singles in an undervalued position. On the contrary, the society regards positively those who demonstrate religious attributes. Therefore, religiosity is a potential factor that mediates social perception of singles who attach themselves to religious attributes (such as: religious symbols and rituals). Using database search methodology, this paper presents an overview of how religiosity assists singles in overcoming their challenges and discusses the implications of those dynamics in counseling settings. PMID- 30008957 TI - Testing Intergroup Threat Theory: Realistic and Symbolic Threats, Religiosity and Gender as Predictors of Prejudice. AB - The complex phenomenon of prejudice has been the focus of interest among social psychologists since the mid-20th century. The Intergroup Threat Theory (ITT) is one of the most efficient theoretical frameworks to identify the triggers of prejudice. In this study, using experimental design, we examined the effects of symbolic and realistic threats on prejudice that was measured by means of a modified social distance scale. The study participants were 611 undergraduate students from the country of Georgia. In addition to providing further support for ITT, the study showed that the level of religiosity moderated the effects between both types of threats and prejudice, although it had different indications for realistic and symbolic threats, while gender interacted only with symbolic threat. Implications of the findings are discussed. PMID- 30008959 TI - Therapists' Experiences in Their Work With Sex Offenders and People With Pedophilia: A Literature Review. AB - This article presents a review of the literature that pertains to the experiences of therapists who work directly with child sex offenders and/or people with pedophilia. We draw together results from studies that attempted to identify how therapists experience such work and how they were personally impacted by it. Usually, such studies are embedded within one of the following theoretical frameworks: Secondary traumatic stress, compassion fatigue, vicarious traumatization and burnout. Most literature on the topic has therefore sought to determine to what extent and why, work-related stress responses may occur among these therapists. The aim of this paper is therefore to provide insight into this, arguably, important line of research, while evaluating the current knowledge as well as providing recommendations for future research efforts. PMID- 30008960 TI - Optimal vitamin D spurs serotonin: 1,25-dihydroxyvitamin D represses serotonin reuptake transport (SERT) and degradation (MAO-A) gene expression in cultured rat serotonergic neuronal cell lines. AB - Background: Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5 HT; serotonin) and 1,25-dihydroxyvitamin D3 (1,25D; active vitamin D metabolite), are proposed to play a role in the atypical social behaviors associated with psychological conditions including autism spectrum disorders and depression. We reported previously that 1,25D induces expression of tryptophan hydroxylase-2 (TPH2), the initial and rate-limiting enzyme in the biosynthetic pathway to 5-HT, in cultured rat serotonergic neuronal cells. However, other enzymes and transporters in the pathway of tryptophan metabolism had yet to be examined with respect to the actions of vitamin D. Herein, we probed the response of neuronal cells to 1,25D by quantifying mRNA expression of serotonin synthesis isozymes, TPH1 and TPH2, as well as expression of the serotonin reuptake transporter (SERT), and the enzyme responsible for serotonin catabolism, monoamine oxidase-A (MAO-A). We also assessed the direct production of serotonin in cell culture in response to 1,25D. Results: Employing quantitative real-time PCR, we demonstrate that TPH-1/-2 mRNAs are 28- to 33-fold induced by 10 nM 1,25D treatment of cultured rat serotonergic neuronal cells (RN46A-B14), and the enhancement of TPH2 mRNA by 1,25D is dependent on the degree of neuron-like character of the cells. In contrast, examination of SERT, the gene product of which is a target for the SSRI-class of antidepressants, and MAO-A, which encodes the predominant catabolic enzyme in the serotonin pathway, reveals that their mRNAs are 51-59% repressed by 10 nM 1,25D treatment of RN46A-B14 cells. Finally, serotonin concentrations are significantly enhanced (2.9-fold) by 10 nM 1,25D in this system. Conclusions: These results are consistent with the concept that vitamin D maintains extracellular fluid serotonin concentrations in the brain, thereby offering an explanation for how vitamin D could influence the trajectory and development of neuropsychiatric disorders. Given the profile of gene regulation in cultured RN46A-B14 serotonergic neurons, we conclude that 1,25D acts not only to induce serotonin synthesis, but also functions at an indirect, molecular-genomic stage to mimic SSRIs and MAO inhibitors, likely elevating serotonin in the CNS. These data suggest that optimal vitamin D status may contribute to improving behavioral pathophysiologies resulting from dysregulation of serotonergic neurotransmission. PMID- 30008961 TI - Genetic polymorphism in selenoprotein P modifies the response to selenium-rich foods on blood levels of selenium and selenoprotein P in a randomized dietary intervention study in Danes. AB - Background: Selenium is an essential trace element and is suggested to play a role in the etiology of a number of chronic diseases. Genetic variation in genes encoding selenoproteins, such as selenoprotein P and the glutathione peroxidases, may affect selenium status and, thus, individual susceptibility to some chronic diseases. In the present study, we aimed to (1) investigate the effect of mussel and fish intake on glutathione peroxidase enzyme activity and (2) examine whether single nucleotide polymorphisms in the GPX1, GPX4, and SELENOP genes modify the effect of mussel and fish intake for 26 weeks on whole blood selenium, plasma selenoprotein P concentrations, and erythrocyte GPX enzyme activity in a randomized intervention trial in Denmark. Results: CC homozygotes of the SELENOP/rs3877899 polymorphism who consumed 1000 g fish and mussels per week for 26 consecutive weeks had higher levels of both selenoprotein P (difference between means - 4.68 ng/mL (95% CI - 8.49, - 0.871)) and whole blood selenium (difference between means - 5.76 (95% CI - 12.5, 1.01)) compared to fish and mussel consuming T-allele carriers although the effect in whole blood selenium concentration was not statistically significant. Conclusions: Our study indicates that genetically determined variation in SELENOP leads to different responses in expression of selenoproteins following consumption of selenium-rich foods. This study also emphasizes the importance of taking individual aspects such as genotypes into consideration when assessing risk in public health recommendations. PMID- 30008962 TI - Cytotoxic, DNA Cleavage and Pharmacokinetic Parameter Study of Substituted Novel Furan C-2 Quinoline Coupled 1, 2, 4-Triazole and Its Analogs. AB - Background: Furan, quinoline and triazoles are known for their wide spectrum biologically active molecules. A series of novel furan C-2 quinoline and 1, 2, 4 triazole (FQT) coupled hybrids were designed and synthesized to evaluate for their DNA cleavage and cytotoxic studies. Objectives: In this work we describe the synthesis and biological evaluation of furan C-2 quinoline coupled triazoles exposed for cytotoxic and DNA cleavage study. Methods: The electrophoretic DNA cleavage studies on lambda-DNA (Eco-RI/Hinda-III double digest) using agarose gelelectrophoresis and the cytotoxic activity were carried out by MTT assay method. Results: The results revealed that, the molecules 7(a-o) did cleave the DNA completely with no trace of fragments at 100 ug concentration, on the other hand, cytotoxic assay was achieved by two different human cancer cell lines (melanoma cell line-A375 and breast cancer cell line MDA-MB 231). Among the synthesized compounds 7a, 7b, 7c and 7k exhibited potent cytotoxic activity with IC50 values ranging from 2.9, 4.0, 7.8 and 5.1 ug/ml against A375 and 6.2, 9.5, 11.3 and 7.3 ug/ml against, MDA-MB 231, respectively. Conclusion: In synthesized compounds 7(a-o) exhibited complete DNA cleavage at 100 ug/ml and the compounds 7a, 7b, 7c and 7k showed very less cytotoxic in nature. The structure activity relationship revealed that, the presence of halogen group/atoms at para position of phenyl ring remarkably enhanced the DNA cleavage and cytotoxic activities among the synthesized compounds. PMID- 30008963 TI - Cytotoxic, DNA Cleavage and Pharmacokinetic Parameter Study of Substituted Novel Furan C-2 Quinoline Coupled 1, 2, 4-Triazole and Its Analogs. PMID- 30008965 TI - Dystonia in Patients with Spinocerebellar Ataxia 3 - Machado-Joseph disease: An Underestimated Diagnosis? AB - Background: Spinocerebellar Ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is characterized by cerebellar, central and peripheral symptoms, including movement disorders. Dystonia can be classified as hereditary and neurodegenerative when present in SCA3. Objective: The objective of this study was to evaluate the dystonia characteristics in patients with MJD. Method: We identified all SCA3 patients with dystonia from the SCA3 HC-UFPR database, between December 2015 and December 2016.Their medical records were reviewed to verify the diagnosis of dystonia and obtain demographic and clinical data. Standardized evaluation was carried out through the classification of Movement Disorders Society of 2013 and Burke Fahn-Marsden scale (BFM). Results: Amongst the presenting some common characteristics, 381 patients with SCA3, 14 (3.7%) subjects presented dystonia: 5 blepharospasm, 1 cervical dystonia, 3 oromandibular, 3 multifocal and 2 generalized dystonia. Regarding dystonia's subtypes, 71.4% had SCA3 subtype I and 28.6% SCA3 subtype II. The average age of the disease onset was 40+/-10.7 years; the SCA3 disease duration was 11.86+/- 6.13 years; the CAG repeat lengths ranged from 75 to 78, and the BFM scores ranged from 1.0 to 40. There was no correlation between the dystonia severity and CAG repeat lengths or the SCA3 clinical evolution. Conclusion: Dystonia in SCA3 is frequent and displays highly variable clinical profiles and severity grades. Dystonia is therefore a present symptom in SCA3, which may precede the SCA3 classic symptoms. Dystonia diagnosis is yet to be properly recognized within SCA3 patient. PMID- 30008964 TI - The Rationale for Monitoring Cognitive Function in Multiple Sclerosis: Practical Issues for Clinicians. AB - About half of patients with multiple sclerosis exhibit cognitive impairment which negatively affects their quality of life. The assessment of cognitive function in routine clinical practice is still undervalued, although various tools have been proposed for this reason. In this article, we describe the potential benefits of implementing cognitive assessment tools in routine follow -ups of MS patients. Early detection of changes in cognitive performance may provide evidence of disease activity, could unmask depression or medication side-effects and provide suitable candidates for cognitive rehabilitation. Since apathy and cognitive deficiencies are common presenting symptoms in Progressive Multifocal Leukoencephalopathy, we discuss the utility of frequent monitoring of mental status in multiple sclerosis patients at increased risk. In addition, we propose a relevant algorithm aiming to incorporate a systematic evaluation of cognitive function in every day clinical practice in multiple sclerosis. PMID- 30008966 TI - Type of Treatment Supporters in Successful Completion of Tuberculosis Treatment: A Retrospective Cohort Study in Pakistan. AB - Background: The World Health Organization has recommended a patient-centered approach to tuberculosis drug administration. A central element of the patient centered strategy is the use of treatment supporters to evaluate and elevate adherence to the treatment regimen and to address poor adherence when it occurs. This study was led to determine the part of various treatment supporters in the successful completion of treatment. Method: This study was conducted in two locales of Sindh, Hyderabad and Mirpurkhas. Information gathered included age, gender, regions, sort of treatment supporters (relatives, community and health facility workers) and treatment outcomes. Results: Of the 773 patients incorporated into the study, 86.8% picked a family supporter, 7.63% selected community worker and 5.56% chose health facility worker as their treatment supporter. Women and younger patients were more likely to prefer that family members supervise their treatment. Treatment achievement rates among the patients regulated by the three kinds of treatment supporters, were not altogether unique in relation to each other (p=0.23 Chi square). Conclusion: The study demonstrates that TB patients ought to be urged to pick the supporter of their inclination as selection of treatment supporter outside the health system does not adversely affect TB treatment outcomes in limited resource settings. PMID- 30008967 TI - Characteristics and Outcomes of Children with Clinical History of Atopic Versus Non-atopic Asthma Admitted to a Tertiary Pediatric Intensive Care Unit. AB - Background: Children admitted to the Pediatric Intensive Care Unit (PICU) with status asthmaticus have variable clinical courses, and predicting their outcomes is challenging. Identifying characteristics in these patients that may require more intense intervention is important for clinical decision-making. Objective: This study sought to determine the characteristics and outcomes, specifically length of stay and mortality, of atopic versus non-atopic asthmatics admitted to a PICU with status asthmaticus. Methods: A retrospective study was conducted at a children's hospital from November 1, 2008 to October 31, 2013. A total of 90 children admitted to the PICU were included in the analysis. Patients were divided into two groups based on the presence of specific historical data indicative of a clinical history of atopy. Children were considered to be atopic if they had a parental history of asthma, a personal history of eczema, or a combined history of wheezing (apart from colds) and allergic rhinitis (diagnosed by a medical provider). The median hospital Length Of Stay (LOS), PICU LOS, cardiopulmonary arrest, and mortality were compared between atopic and non-atopic asthma groups. Regression models were used to estimate the LOS stratified by atopic or non-atopic and by history of intubation in present hospitalization. Results: Median hospital LOS for atopic children was 5.9 days (IQR of 3.8-8.7) and 3.5 days (IQR of 2.2-5.5) for non-atopic asthmatics (z = 2.9, p = 0.0042). The median PICU LOS was 2.5 days (IQR 1.4-6.1) for atopic asthmatics and 1.6 days (IQR 1.1-2.4) for non-atopic asthmatics (z = 2.5, p = 0.0141). The median LOS was significantly higher for atopic intubated patients compared to non-atopic intubated patients (p=0.021). Although there was an increased tendency towards intubation in the atopic group, the difference was not significant. There was no significant difference in cardiopulmonary arrest or mortality. Conclusion: A clinical history of atopic asthma in children admitted to the PICU with status asthmaticus was associated with longer length of stays The longest LOS was observed when atopic patients required intubation. PMID- 30008968 TI - Midterm Results of Cementless Total Knee Arthroplasty: A Retrospective Case Series. AB - Background: There is an ongoing debate about whether to use cementless or cemented fixation for Total Knee Arthroplasty (TKA). Objective: The study aimed to assess midterm survivorship of the Vanguard cementless system, and to demonstrate the utility of the Bone Hardness Test (BHT) for the selection of cementless fixation TKA. Methods: From September 2009 through November 2014, 123 total knee arthroplasties were completed, with cementless Vanguard Cruciate Retaining TKA in 110 knees (102 patients) and cemented Vanguard in 13 cases (12 patients). Implant fixation was based on intraoperative assessment of posterior cruciate ligament stability, bone quality, and BHT. All patients with a cementless Vanguard implant were eligible for this retrospective study. Preoperative and postoperative Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index were obtained. Standardized standing anteroposterior and lateral radiographs were taken. Results: Three patients (4 TKAs) were lost to follow-up. The mean follow-up time was 5.5 +/- 1.4 years. All scores significantly improved postoperatively. No radiographic failures were observed. Five-year implant survival, with revision of any component for any reason as an endpoint, was 97.2% (95% confidence interval, 91.7 - 99.1%). Five year survival with revision for aseptic loosening was 100%. Only one knee required revision due to an isolated unrelated bearing exchange, and two additional knees required secondary resurfacing of the patella for retropatellar pain. Conclusion: Good midterm results were obtained with the cementless Vanguard Cruciate Retaining TKA for the treatment of osteoarthritis. The Bone Hardness Test appears to be an effective way to determine the selection of cementless TKA. PMID- 30008969 TI - Retained Foreign Body in a Diabetic Patient's Hand. AB - Background: Diabetic peripheral neuropathy puts patients at increased risk of acute injury by foreign bodies and also contributes to delayed presentation and diagnosis. Case report: We describe a 57-year-old patient with poorly controlled type 1 diabetes who presented with a three-week history of worsening swelling and erythema in the metacarpophalangeal joint of his left thumb. He denied any previous trauma or injury and was initially treated with intravenous antibiotics. Subsequent imaging revealed septic arthritis and osteomyelitis secondary to a retained foreign body, which was surgically removed in theatre. Conclusion: This is the first reported case of a retained foreign body in the hand of a diabetic patient, and demonstrates the importance of early radiological imaging of peripheral limb injuries in high-risk patients. PMID- 30008970 TI - Comparison of Total Hip Arthroplasty Outcomes after Failed Femoral Wedge or Curved Varus Osteotomy. AB - Background: Differences in clinical and radiographic results following total hip arthroplasty between failed wedge and curved varus osteotomy are unclear. Objective: To investigate differences in clinical and radiographic results following total hip arthroplasty in patients who exhibited failed wedge or curved varus osteotomy. Method: We performed 18 total hip arthroplasties after failed femoral varus osteotomy. Hips were divided into two groups: 14 had failed wedge varus osteotomy and four had failed curved varus osteotomy. Average ages at osteotomy and total hip arthroplasty were 27 years old (range, 10-46 years old) and 56 years old (range, 25-74 years old), respectively. The average duration of follow-up monitoring was 72.2 months (range, 54-91 months). Clinical and radiographic evaluations were completed for each group. Results: The Japanese Orthopaedic Association hip score of total hip arthroplasty after failed varus osteotomy significantly improved at the last follow-up in both groups. However, hip score at the last follow-up was significantly higher after failed curved varus osteotomy than after failed wedge varus osteotomy (p<0.01). Four hips that failed wedge varus osteotomy underwent subtrochanteric corrective osteotomy with total hip arthroplasty. Radiographic evaluation showed that three stems for total hip arthroplasty after failed wedge varus osteotomy were inserted in malposition, and all stems in total hip arthroplasty after failed curved varus osteotomy were inserted in the normal position. Conclusion: Surgeons performing femoral varus osteotomy should consider possible future conversion to total hip arthroplasty. Curved varus osteotomy is more suitable than wedge varus osteotomy for future conversion to total hip arthroplasty. PMID- 30008971 TI - Evaluation of Preloaded IOL Delivery System and Hydrophobic Acrylic Intraocular Lens in Cataract Surgery. AB - Background: Advancements in cataract surgery have necessitated the availability of intraocular lens preloaded delivery systems that can safely, effectively and predictably deliver IOLs in the eye. Preloaded delivery systems simplify and reduce procedural variability during surgery preparation. Objective: The objective of this study was to evaluate clinical acceptability, delivery characteristics and clinical outcomes in patients implanted with new generation hydrophobic acrylic Intraocular Lens with Preloaded delivery system. Methods: This was a single centre retrospective study. Total 41 patients were enrolled in the study to get at least 38 patients for evaluation. All patients were assessed on day1 and 1, 3 and 6 months after surgery. Results: EYECRYL-SERT showed 'excellent' ease of insertion and handling in all 41(100%) patients. Corrected Distance Visual Acuity (CDVA) improved from 0.74+/-0.58 logMAR during screening to 0.03+/-0.04 logMAR 6 months after surgery. The Corrected Intermediate Visual Acuity (CIVA) and Corrected Near Visual Acuity (CNVA) were 0.10+/-0.04 and 0.01+/ 0.02 logMAR post 6 months surgery, respectively. The refractive spherical equivalence was -1.94+/-2.51 D during screening, which improved significantly (p=0.0018) to -0.21+/-0.47 D post 6 months surgery. The low and high contrast sensitivity was 0.06+/-0.06 and -0.05+/-0.06 logMAR after 6 months surgery, respectively. The endothelial cell loss was 5.67%, 7.22% and 9.75% at 1, 3, and 6 months after surgery, respectively, as compared to screening. None of the subjects reported any adverse event during the study period. Conclusion: The IOL delivery system (EYECRYL_SERT) provided desired delivery characteristics during cataract surgery and was effective in improving clinical outcomes in cataract patients. PMID- 30008972 TI - Comparison of Dynamic Contour Tonometry and Non-contact Tonometry in Older Patients Presenting with Headache or Vision Loss. AB - Background: Dynamic Contour Tonometry (DCT) is touted to be the most accurate tonometer for Intraocular Pressure (IOP) measurement. Non-Contact "air puff" Tonometry (NCT) may be the most commonly used tonometer for screening of IOP. Elevated IOP is important to exclude in patients presenting with headache or vision loss. Objective: To determine the agreement between DCT and NCT. Methods: The IOP of adult patients 50 years of age or older presenting with headache or vision loss for possible temporal artery biopsy were prospectively recorded. NCT and DCT measurements were obtained within thirty minutes. The right eye IOP measurements were compared with paired t-test, and Bland- Altman plot analysis. The left eye IOP measurements were subsequently analyzed for confirmation of results. Results: There were 106 subjects with complete right eye data, and 104 subjects with complete left eye data. The average age was 72 years, and 70% were female. The NCT IOP was on average 3.9 mm Hg lower in the right eye, and 3.5 mm Hg lower in the left eye compared with DCT. (p<.001) In the right eye the Bland Altman analysis showed the 95% agreement interval between the two tonometers was 2.5 to 10.4 mmHg and in the left eye -3.0 to 9.9 mmHg. Conclusion: The IOP from NCT and DCT should not be used interchangeably because their level of disagreement includes clinically important discrepancies of up to 10 mm Hg. PMID- 30008973 TI - Treatment Outcome and Adverse Events of Tenofovir Disoproxil Fumarate Based Regimens as Compared to Zidovudine Based Regimens Among People Living with HIV/AIDS: A Systematic Review and Meta-Analysis of Observational Studies. AB - Background: Findings from different studies report inferior clinical and virologic efficacy with TDF/3TC/NVP. But, some studies show that, there was no statistically significant difference in mortality among ZDV and TDF based regimens. The objective of this review was to systematically identify, appraise and synthesize the best available evidence on efficacy and safety of TDF based regimen as compared to ZDV based regimens. Methods: A three-step search strategy was used to locate published and unpublished studies. First, an initial limited search of google was undertaken followed by analysis of text words. A second extensive search was undertaken. We searched the PubMed, EMBASE, Google Scholar, Medline, and CINHAL. We did the initial search for articles on July 11-18, 2016, and updated the results on May 13, 2017.Third, the reference lists of all identified articles was searched for additional studies. Results: ZDV based regimens had better outcome on prevention of mortality (OR=1.31, 95%CI (1.14, 1.50), I2 = 0%, Chi2 = 2.51), and lower virologic failure (OR = 1.44, 95% CI [1.18, 1.76], chi2 = 5.91, P= 0.003, I2 =83%) while, TDF based regimens were more tolerable (OR=0.15, 95%CI (0.08, 0.30), I2 = 40%, Chi2 = 3.31). The difference in incidence of opportunistic infection is not significant (OR = 0.83, 95% CI [0.52, 1.32], chi2 = 0.11, P= 0.42, I2 =0%). Conclusion: There is lower mortality and lower virologic failure in ZDV group, but better safety profile among TDF based regimens. PMID- 30008974 TI - Association of Thrombomodulin Gene C1418T Polymorphism with Susceptibility to Kawasaki Disease in Chinese Children. AB - Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects children and can result in coronary artery lesions (CALs). Thrombomodulin (TM) is a critical cofactor in the protein C anticoagulant system. The TM C1418T (rs1042579) polymorphism is associated with a high risk of cardiac-cerebral vascular diseases. But the association of the TM C1418T polymorphism with susceptibility to KD, CAL formation, and intravenous immunoglobulin (IVIG) resistance is still unclear. In our study, we examined the TM C1418T polymorphism in 122 children with KD and 126 healthy children and revealed the correlation between the TM C1418T polymorphism and KD, CAL formation, and IVIG resistance. PMID- 30008975 TI - Urinary Biochemistry in the Diagnosis of Acute Kidney Injury. AB - Acute kidney injury (AKI) is a common complication, impacting short- and long term patient outcomes. Although the application of the classification systems for AKI has improved diagnosis, early clinical recognition of AKI is still challenging, as increments in serum creatinine may be late and low urine output is not always present. The role of urinary biochemistry has remained unclear, especially in critically ill patients. Differentiating between a transient and persistent acute kidney injury is of great need in clinical practice, and despite studies questioning their application in clinical practice, biochemistry indices continue to be used while we wait for a novel early injury biomarker. An ideal marker would provide more detailed information about the type, intensity, and location of the injury. In this review, we will discuss factors affecting the fractional excretion of sodium (FeNa) and fractional excretion of urea (FeU). We believe that the frequent assessment of urinary biochemistry and microscopy can be useful in evaluating the likelihood of AKI reversibility. The availability of early injury biomarkers could help guide clinical interventions. PMID- 30008977 TI - Impact of Nasopharyngeal FilmArray Respiratory Panel Results on Antimicrobial Decisions in Hospitalized Patients. AB - Objective: To determine whether results of the nasopharyngeal FilmArray respiratory panel (NP-FARP) influenced antibiotic decisions. Methods: We reviewed the medical records of nonintensive care unit (ICU) inpatients that had an NP FARP performed at our institution between June 2013 and June 2014. The inpatient records were reviewed 48 hours after the NP-FARP for the following data: demographic information; NP-FARP, serum procalcitonin, and methicillin-resistant Staphylococcus aureus nasal swab (MRSA NS) results; antibiotics prior and post-48 hours of the NP-FARP result; and the current immunosuppression status. Clinical outcome data were not obtained. Patients were categorized into those who had a positive (+) or a negative (-) NP-FARP. We further subdivided these two categories into groups A, B, and C based on the antibiotic modifications 48 hours after their NP-FARP result. Group A included patients who were never initiated on antimicrobial therapy. Patients whose antibiotics were discontinued or deescalated were placed in group B. Patients with antibiotic escalation or continuation without change constituted group C. We compared and analyzed groups A, B, and C in the (+) and (-) NP-FARP cohorts. Results: A total of 545 patients were included. There were 143 (26%) patients with positive and 402 (74%) patients with negative NP-FARPs. Comparison of groups A, B, and C between those with a (+) and (-) NP-FARP were as follows: (+) A and (-) A, 28/143 (20%) and 84/402 (21%); (+) B and (-) B, 59/143 (41%) and 147/402 (37%); and (+) C and (-) C, 56/143 (39%) and 171/402 (43%), respectively. We found no statistically significant differences between groups (+) A versus (-) A, (+) B versus (-) B, and (+) C versus (-) C with respect to age, gender, MRSA NS result, procalcitonin result, or concurrent immunosuppression. Conclusion: In non-ICU inpatients, NP-FARP alone or in combination with procalcitonin or MRSA NS did not influence antibiotic decisions during the study period. PMID- 30008976 TI - Moderate Fluid Shear Stress Could Regulate the Cytoskeleton of Nucleus Pulposus and Surrounding Inflammatory Mediators by Activating the FAK-MEK5-ERK5-cFos-AP1 Signaling Pathway. AB - We first applied moderate fluid shear stress to nucleus pulposus cells. The correlation of AP-1 with type II collagen, proteoglycan, Cytokeratin 8 protein, MAP-1, MAP-2, and MAP-4 and the correlation of AP-1 with IL-1beta, TNF-alpha, IL 6, IL-8, MIP-1, MCP-1, and NO were detected. Our results document that moderate fluid shear stress could activate the FAK-MEK5-ERK5-cFos-AP1 signaling pathway. AP1 could downregulate the construct factors of cytoskeleton such as type II collagen, proteoglycan, Cytokeratin 8 protein, MAP-1, MAP-2, and MAP-4 in nucleus pulposus cell after the fluid shear stress was loaded. AP1 could upregulate the inflammatory factors such as IL-1beta, TNF-alpha, IL-6, IL-8, MIP-1, MCP-1, and NO in nucleus pulposus cell after the fluid shear stress was loaded. Taken together, our data suggested that moderate fluid shear stress may play an important role in the cytoskeleton of nucleus pulposus and surrounding inflammatory mediators by activating the FAK-MEK5-ERK5-cFos-AP1 signaling pathway, thereby affecting cell degeneration. PMID- 30008978 TI - Computed tomography diagnosis of omental infarction presenting as an acute abdomen. AB - Omental infarction is a rare cause of acute abdominal pain. Without the support of radiological evidence, diagnosis is difficult to attain owing to its infrequent incidence, low awareness among clinicians, and its nonspecific presentation that mimics other causes of acute abdomen, namely, acute appendicitis and cholecystitis. Incorrect diagnosis may lead to unnecessary invasive surgery in patients with omental infarction, a disorder that is typically managed conservatively without exposing the patient to intraoperative risks and postoperative morbidity. We report a case of a 61-year-old man who presented to the emergency department with signs of peritonitis. He was eventually diagnosed with omental infarction through computed tomography of the abdomen. He was successfully managed medically with nonsteroidal anti inflammatory and antiemetic medications, with complete resolution of his symptoms within 2 weeks. PMID- 30008979 TI - Bilateral mammary Paget disease in a young adult female. AB - Mammary Paget disease is an uncommon malignancy of the breast that presents with ulceration or eczema of the nipple and is almost always associated with an underlying breast carcinoma. This disease is most commonly seen in the fifth and sixth decades of life and is almost always unilateral. The diagnosis of mammary Paget disease is generally based on clinical findings, confirmed by histopathologic examination. Mammographic and ultrasonographic findings may be nonspecific for malignancy, with 50% of cases showing negative findings. Magnetic resonance imaging can be used as a diagnostic tool to detect clinically occult cancer with nonspecific findings on mammogram and ultrasonogram. In this article, we are presenting a rare case of a young woman with biopsy-proven bilateral mammary Paget disease, for which bilateral modified radical mastectomy was done, followed by adjuvant chemotherapy and radiotherapy. PMID- 30008980 TI - Incidentally detected ectopic thyroid in juxta cardiac location-Imaging and pathology. AB - Ectopic thyroid gland is a developmental anomaly that results from the arrest of thyroid tissue along its path of descent from the floor of mouth to the pre tracheal position in the lower neck. It is typically found along the thyroglossal duct with the base of the tongue being the most common site. Apart from mediastinal extension of goiter, the incidence of true intrathoracic ectopic thyroid tissue is rare. Presence of ectopic thyroid has been reported not only in the chest but also in the abdomen and pelvis. Pericardial and intracardiac locations are extremely uncommon and right ventricle location is predominant among the described cases. We describe a case of incidentally detected ectopic thyroid tissue in a rarer location-adjacent to the left atrium. The patient, who had undergone a nephrectomy for renal oncocytoma 5 years ago, presented with unintentional weight loss and left sided flank pain, prompting a workup to rule out abdominal malignancy. Findings on the computed tomography (CT) scan of the abdomen and pelvis prompted further investigation including a chest CT which showed a heterogeneously enhancing mass near the left atrium. Given its location, further radiological investigations played an important role in eliminating the differential diagnosis of paraganglioma. The mass was surgically resected and discovered to be a hyperplastic thyroid nodule on histologic examination. PMID- 30008982 TI - EMDB Web Resources. AB - The Electron Microscopy Data Bank (EMDB; http://emdb-empiar.org) is a global openly-accessible archive of biomolecular and cellular 3D reconstructions derived from electron microscopy (EM) data. EMBL-EBI develops web-based resources to facilitate the reuse of EMDB data. Here we provide protocols for how these resources can be used for searching EMDB, visualising EMDB structures, statistically analysing EMDB content and checking the validity of EMDB structures. Protocols for searching include quick link categories from the main page, links to latest entries released during the weekly cycle, filtered browsing of the entire archive and a form-based search. For visualisation, the 'Volume Slicer' enables slices of EMDB entries to be visualised interactively and in three orthogonal directions. The EMstats web service (https://emdb empiar.org/emstats) provides up-to-date interactive statistical charts analysing EMDB. All EMDB entries have 'visual analysis' pages that provide basic validation information for the entry. PMID- 30008983 TI - Meningeal whole mount preparation and characterization of neural cells by flow cytometry. AB - Neuroimmunologists aim to understand the interactions between the central nervous system and the immune system under both homeostatic and pathological conditions. The meninges, contrary to the brain parenchyma, are populated by numerous immune cells. Soluble factors produced by these cells are capable to diffuse into the brain parenchyma and influence the brain cells within the parenchyma, including neurons. In this unit, we will describe two protocols: analysis the meningeal compartment of rodents and the use flow cytometry to study the cells of the brain parenchyma (particularly neurons). PMID- 30008984 TI - Gnotobiotic and Conventional Mouse Systems to Support Microbiota Based Studies. AB - Animal models are essential to dissect host-microbiota interactions that impact health and the development of disease. In addition to providing pre-clinical models for the development of novel therapeutics and diagnostic biomarkers, mouse systems actively support microbiome studies by defining microbial contributions to normal development and homeostasis, and as well as their role in promoting diseases such as inflammatory auto-immune diseases, diabetes, metabolic syndromes, and susceptibilities to infectious agents. Mice provide a genetically tenable host that can be reared under gnotobiotic (germfree) conditions, allowing colonization studies with human or mouse-origin defined or complex microbial communities to define specific in vivo effects. The protocols and background information detail key aspects to consider in designing host-microbiome experiments with mouse models, and to develop robust systems that leverage gnotobiotic mice, microbial consortia, and specific environmental perturbations to identify causal effects in vivo. PMID- 30008981 TI - Scanning Techniques for Nanobioconjugates of Carbon Nanotubes. AB - Nanobioconjugates using carbon nanotubes (CNTs) are attractive and promising hybrid materials. Various biological applications using the CNT nanobioconjugates, for example, drug delivery systems and nanobiosensors, have been proposed by many authors. Scanning techniques such as scanning electron microscopy (SEM) and scanning probe microscopy (SPM) have advantages to characterize the CNT nanobioconjugates under various conditions, for example, isolated conjugates, conjugates in thin films, and conjugates in living cells. In this review article, almost 300 papers are categorized based on types of CNT applications, and various scanning data are introduced to illuminate merits of scanning techniques. PMID- 30008985 TI - How Could We Influence Systemic Inflammation in Allergic Rhinitis? The Role of H1 Antihistamines. AB - The aim of the study was the analysis of adhesion molecules' profile (ICAM-1, VCAM-1, and E-selectin) in patients with allergic rhinitis and the influence of H1 antihistamines on those markers. Seventy-nine patients with persistent allergic rhinitis (PAR) and 30 healthy volunteers were included in the study. The patients with PAR were treated with desloratadine 5 mg/day or levocetirizine 5 mg/day for 4 weeks. The clinical (rhinitis symptoms and total symptoms score (TSS), type of sensitization) and biological evaluation (total IgE, eosinophils, ICAM-1, VCAM-1, and E-selectin) as well as fractionate nitric oxide in exhaled air (FeNO) measurement was performed before and after treatment. The plasmatic levels of ICAM-1, VCAM-1, total IgE, and eosinophils and FeNO were significantly increased in patients with PAR compared to healthy volunteers. H1 antihistamines significantly improved TSS, with no differences between the investigated drugs. There was a significant decrease of eosinophils, total IgE, and FeNO after treatment. H1 antihistamines significantly decreased the plasmatic levels of ICAM 1 and E-selectin but not VCAM-1 compared to basal values. There is no difference between levocetirizine and desloratadine in the reduction of CAMs. A systemic inflammation characterized by increased levels of CAMs is present in patients with PAR. H1 antihistamines improve symptoms and reduce CAMs and FeNO levels after 1 month of treatment. H1 antihistamines might reduce the systemic inflammation which could be responsible to asthma occurrence in patients with PAR. PMID- 30008987 TI - Oxidative Stress and Membrane Transport Systems. PMID- 30008989 TI - alpha-Ketoglutarate-A New Currency of Longevity. PMID- 30008988 TI - A standardized workflow for submitting data to the Minimum Information about a Biosynthetic Gene cluster (MIBiG) repository: prospects for research-based educational experiences. AB - Microorganisms utilize complex enzymatic pathways to biosynthesize structurally complex and pharmacologically relevant molecules. These pathways are encoded by gene clusters and are found in a diverse set of organisms. The Minimum Information about a Biosynthetic Gene cluster repository facilitates standardized and centralized storage of experimental data on these gene clusters and their molecular products, by utilizing user-submitted data to translate scientific discoveries into a format that can be analyzed computationally. This accelerates the processes of connecting genes to chemical structures, understanding biosynthetic gene clusters in the context of environmental diversity, and performing computer-assisted design of synthetic gene clusters. Here, we present a Standard Operating Procedure, Excel templates, a tutorial video, and a collection of relevant review literature to support scientists in their efforts to submit data into MiBIG. Further, we provide tools to integrate gene cluster annotation projects into the classroom environment, including workflows and assessment materials. PMID- 30008990 TI - Medical Signal Processing in Biomedical and Clinical Applications. PMID- 30008986 TI - High Cholesterol Diet-Induced Changes in Oxysterol and Scavenger Receptor Levels in Heart Tissue. AB - Involvement of high cholesterol and oxidative stress in cardiovascular diseases is well studied, as it can be hypothesized that various products originated from lipid peroxidation, such as oxysterols, or affected protein expression might lead to cardiomyocyte damage followed by the pathological modifications. Although oxidation of excessive cholesterol to oxysterols in elevated stress conditions is identified by a number of studies, the role of a high cholesterol diet in regulating fatty acid and oxysterol accumulation, together with scavenger receptor mRNA levels, in the heart remains little investigated. Our study provides a detailed analysis of the changes in fatty acid, oxysterol, and scavenger receptor profiles and its relation with histological alterations in the heart tissue. We evaluated alterations of fatty acid composition, by the GC-MS method, while 4beta-, 25-, and 27-hydroxycholesterol and 7-ketocholesterol levels by means of LC-MS/MS in high cholesterol diet-fed rabbits. Additionally, a number of proteins related to lipid metabolism and scavenger receptor mRNA expressions were evaluated by Western blotting and RT-PCR. According to our in vivo results, a high cholesterol diet enhances a number of unsaturated fatty acids, oxysterols, and LXRalpha, in addition to CD36, CD68, CD204, and SR-F1 expressions while alpha tocopherol supplementation decreases LXRalpha and SR expressions together with an increase in 27-hydroxycholesterol and ABCA1 levels. Our results indicated that the high cholesterol diet modulates proteins related to lipid metabolism, which might result in the malfunction of the heart and alpha-tocopherol shows its beneficial effects. We believe that this work will lead the generation of different theories in the development of heart diseases. PMID- 30008991 TI - Application of Operational Research Techniques in Operating Room Scheduling Problems: Literature Overview. AB - Increased healthcare costs are pushing hospitals to reduce costs and increase the quality of care. Operating rooms are the most important source of income and expense for hospitals. Therefore, the hospital management focuses on the effectiveness of schedules and plans. This study includes analyses of recent research on operating room scheduling and planning. Most studies in the literature, from 2000 to the present day, were evaluated according to patient characteristics, performance measures, solution techniques used in the research, the uncertainty of the problem, applicability of the research, and the planning strategy to be dealt within the solution. One hundred seventy studies were examined in detail, after scanning the Emerald, Science Direct, JSTOR, Springer, Taylor and Francis, and Google Scholar databases. To facilitate the identification of these studies, they are grouped according to the different criteria of concern and then, a detailed overview is presented. PMID- 30008992 TI - 3D Shape-Weighted Level Set Method for Breast MRI 3D Tumor Segmentation. AB - Three-dimensional (3D) medical image segmentation is used to segment the target (a lesion or an organ) in 3D medical images. Through this process, 3D target information is obtained; hence, this technology is an important auxiliary tool for medical diagnosis. Although some methods have proved to be successful for two dimensional (2D) image segmentation, their direct use in the 3D case has been unsatisfactory. To obtain more precise tumor segmentation results from 3D MR images, in this paper, we propose a method known as the 3D shape-weighted level set method (3D-SLSM). The proposed method first converts the LSM, which is superior with respect to 2D image segmentation, into a 3D algorithm that is suitable for overall calculations in 3D image models, and which improves the efficiency and accuracy of calculations. A 3D shape-weighted value is then added for each 3D-SLSM iterative process according to the changes in volume. Besides increasing the convergence rate and eliminating background noise, this shape weighted value also brings the segmented contour closer to the actual tumor margins. To perform a quantitative analysis of 3D-SLSM and to examine its feasibility in clinical applications, we have divided our experiments into computer-simulated sequence images and actual breast MRI cases. Subsequently, we simultaneously compared various existing 3D segmentation methods. The experimental results demonstrated that 3D-SLSM exhibited precise segmentation results for both types of experimental images. In addition, 3D-SLSM showed better results for quantitative data compared with existing 3D segmentation methods. PMID- 30008993 TI - Field testing a novel high residence positioning system for monitoring the fine scale movements of aquatic organisms. AB - Acoustic telemetry is an important tool for studying the behaviour of aquatic organisms in the wild.VEMCO high residence (HR) tags and receivers are a recent introduction in the field of acoustic telemetry and can be paired with existing algorithms (e.g. VEMCO positioning system [VPS]) to obtain high-resolution two dimensional positioning data.Here, we present results of the first documented field test of a VPS composed of HR receivers (hereafter, HR-VPS). We performed a series of stationary and moving trials with HR tags (mean HR transmission period = 1.5 s) to evaluate the precision, accuracy and temporal capabilities of this positioning technology. In addition, we present a sample of data obtained for five European perch Perca fluviatilis implanted with HR tags (mean HR transmission period = 4 s) to illustrate how this technology can estimate the fine-scale behaviour of aquatic animals.Accuracy and precision estimates (median [5th-95th percentile]) of HR-VPS positions for all stationary trials were 5.6 m (4.2-10.8 m) and 0.1 m (0.02-0.07 m), respectively, and depended on the location of tags within the receiver array. In moving tests, tracks generated by HR-VPS closely mimicked those produced by a handheld GPS held over the tag, but these differed in location by an average of ~9 m.We found that estimates of animal speed and distance travelled for perch declined when positional data for acoustically tagged perch were thinned to mimic longer transmission periods. These data also revealed a trade-off between capturing real nonlinear animal movements and the inclusion of positioning error.Our results suggested that HR VPS can provide more representative estimates of movement metrics and offer an advancement for studying fine-scale movements of aquatic organisms, but high precision survey techniques may be needed to test these systems. PMID- 30008994 TI - Atomistic picture of conformational exchange in a T4 lysozyme cavity mutant: an experiment-guided molecular dynamics study. AB - Despite the importance of dynamics to protein function there is little information about the states that are formed as the protein explores its conformational landscape or about the mechanism by which transitions between the different states occur. Here we used a combined NMR spin relaxation and unbiased molecular dynamics (MD) approach to investigate the exchange process by which a cavity in an L99A mutant of T4 lysozyme (T4L 99A) interconverts between an empty and occupied form that involves repositioning of an aromatic residue, Phe114. Although structures of the end-states of the exchange process are available, insight into the mechanism by which the transition takes place cannot be obtained from experiment and the timescales involved are too slow to address using brute force MD. Using spin relaxation NMR methods, we have identified a triple-mutant of T4L that undergoes the same exchange process as T4L L99A but where the minor state lifetime has decreased significantly so that the spontaneous conformational transition to the major state can be studied using all-atom MD simulations. The simulation trajectories were analyzed using Markov state models and the energy landscape so obtained is in good agreement with expectations based on NMR studies. Notably there is no large-scale perturbation of the structure during the transition, multiple intermediates are formed between the two similar exchanging conformations and the free energy barrier between these two well-folded, compact forms is small (6kBT), only slightly larger than for processes considered to be barrierless. PMID- 30008995 TI - Cis-trans isomerism modulates the magnetic relaxation of dysprosium single molecule magnets. AB - Geometry and magnetic relaxation modulations in a series of mononuclear dysprosium complexes, [DyLz2(o-vanilin)2].X.solvent (Lz = 6-pyridin-2-yl [1,3,5]triazine-2,4-diamine; X = Br- (1), NO3- (2), CF3SO3- (3)), were realized by changing the nature of the counter-anion. The DyIII ions in all complexes are eight-coordinate and in approximate D4d symmetry environments. The magnetic relaxation and anisotropy of these complexes were systematically investigated, both experimentally and from ab initio calculations. All complexes exhibit excellent single-molecule magnetic behavior. Remarkably, magneto-structural studies show that the rotation of the coordinating plane of the square antiprismatic environment in complex 2 induces a magnetic relaxation path through higher excited states, yielding a high anisotropy barrier of 615 K (696 K for a diluted sample). Additionally, obvious opening of the hysteresis loop is observed up to 7 K, which is the highest blocking temperature ever reported for dysprosium single-molecule magnets. PMID- 30008996 TI - [NiIII(OMe)]-mediated reductive activation of CO2 affording a Ni(kappa1-OCO) complex. AB - Carbon dioxide is expected to be employed as an inexpensive and potential feedstock of C1 sources for the mass production of valuable chemicals and fuel. Versatile chemical transformations of CO2, i.e. insertion of CO2 producing bicarbonate/acetate/formate, cleavage of CO2 yielding MU-CO/MU-oxo transition metal complexes, and electrocatalytic reduction of CO2 affording CO/HCOOH/CH3OH/CH4/C2H4/oxalate were well documented. Herein, we report a novel pathway for the reductive activation of CO2 by the [NiIII(OMe)(P(C6H3-3-SiMe3-2 S)3)]- complex, yielding the [NiIII(kappa1-OCO-)(P(C6H3-3-SiMe3-2-S)3)]- complex. The formation of this unusual NiIII(kappa1-OCO-) complex was characterized by single-crystal X-ray diffraction, EPR, IR, SQUID, Ni/S K-edge X-ray absorption spectroscopy, and Ni valence-to-core X-ray emission spectroscopy. The inertness of the analogous complexes [NiIII(SPh)], [NiII(CO)], and [NiII(N2H4)] toward CO2, in contrast, demonstrates that the ionic [NiIII(OMe)] core attracts the binding of weak sigma-donor CO2 and triggers the subsequent reduction of CO2 by the nucleophilic [OMe]- in the immediate vicinity. This metal-ligand cooperative activation of CO2 may open a novel pathway promoting the subsequent incorporation of CO2 in the buildup of functionalized products. PMID- 30008997 TI - Efficient metal-free photochemical borylation of aryl halides under batch and continuous-flow conditions. AB - A rapid, chemoselective and metal-free C-B bond-forming reaction of aryl iodides and bromides in aqueous solution at low temperatures was discovered. This reaction is amenable to batch and continuous-flow conditions and shows exceptional functional group tolerance and broad substrate scope regarding both the aryl halide and the borylating reagent. Initial mechanistic experiments indicated a photolytically generated aryl radical as the key intermediate. PMID- 30008998 TI - Supramolecular reactions of metallo-architectures: Ag2-double-helicate/Zn4-grid, Pb4-grid/Zn4-grid interconversions, and Ag2-double-helicate fusion. AB - Supramolecular reactions are of importance in many fields. We report herein three examples where complexes of hydrazone-based ligands are involved. A Ag2-double helicate was converted, by treatment with Zn(OTf)2, into a Zn4-grid (exchange of metal ions and change of the nature of the initial complex). A Pb4-grid was converted, upon reaction with ZnCl2 or ZnBr2, into a Zn4-grid (exchange of metal ions, but conservation of the nature of the initial complex). The reverse conversions were also achieved. The fusion of a Ag2-double-helicate with another Ag2-double-helicate was performed (exchange of ligands, but conservation of the nature of the complexes) and resulted in a mixture of three helicates (two homostranded ones and one heterostranded one). PMID- 30008999 TI - A carboxylesterase-selective ratiometric fluorescent two-photon probe and its application to hepatocytes and liver tissues. AB - Carboxylesterases (CEs) are widely distributed enzymes in the human body that catalyze hydrolysis of various endogenous and exogenous substrates. They are directly linked to hepatic drug metabolisms and steatosis, and their regulations are important issues in pharmacological and clinical applications. In this work, we have developed an emission ratiometric two-photon probe (SE1) for quantitatively detecting CE in situ. This probe is based on a translation of intramolecular charge transfer character upon reaction with CE. It shows a sensitive blue-to-yellow emission change in response to human CE activity, easy loading into cells, insensitivity to pH and other metabolites including ROS and RNS, high photostability, and low cytotoxicity. Using live hepatocytes and liver tissues, we found that ratiometric two-photon microscopic imaging with SE1 is an effective tool for monitoring CE activities at the subcellular level in live tissues. This probe will find useful applications in biomedical research, including studies of hepatic steatosis and drug developments. PMID- 30009000 TI - Cyanide-bridged iron complexes as biomimetics of tri-iron arrangements in maturases of the H cluster of the di-iron hydrogenase. AB - Developing from certain catalytic processes required for ancient life forms, the H2 processing enzymes [NiFe]- and [FeFe]-hydrogenase (H2ase) have active sites that are organometallic in composition, possessing carbon monoxide and cyanide as ligands. Simple synthetic analogues of the 2Fe portion of the active site of [FeFe]-H2ase have been shown to dock into the empty carrier (maturation) protein, apo-Hyd-F, via the bridging ability of a terminal cyanide ligand from a low valent FeIFeI unit to the iron of a 4Fe4S cluster of Hyd-F, with spectral evidence indicating CN isomerization during the coupling process (Berggren, et al., Nature, 2013, 499, 66-70). To probe the requirements for such cyanide couplings, we have prepared and characterized four cyanide-bridged analogues of 3 Fe systems with features related to the organoiron moiety within the loaded HydF protein. As in classical organometallic chemistry, the orientation of the CN bridge in the biomimetics is determined by the precursor reagents; no cyanide flipping or linkage isomerization was observed. Density functional theory computations evaluated the energetics of cyanide isomerization in such [FeFe]-CN Fe ? [FeFe]-NC-Fe units, and found excessively high barriers account for the failure to observe the alternative isomers. These results highlight roles for cyanide as an unusual ligand in biology that may stabilize low spin iron in [FeFe]-hydrogenase, and can act as a bridge connecting multi-iron units during bioassembly of the active site. PMID- 30009002 TI - Well-structured bimetallic surface capable of molecular recognition for chemoselective nitroarene hydrogenation. AB - Unprecedented molecular recognition ability governed by a simple bimetallic surface is reported. A series of Rh-based ordered alloys supported on silica gel (Rh x M y /SiO2, where M is Bi, Fe, Ga, Ge, In, Ni, Pb, Sb, Sn, or Zn) were tested in the hydrogenation of nitrostyrene to form aminostyrene. RhIn/SiO2 showed remarkably high catalytic activity and good selectivity under 1 atm H2 at room temperature. Moreover, various other nitroarenes containing carbonyl, cyano, or halo moieties were selectively hydrogenated into the corresponding amino derivatives using RhIn/SiO2. Kinetic study and density functional theory (DFT) calculations revealed that the high selectivity originates from RhIn/SiO2 adsorbing nitro groups much more favorably than vinyl groups. In addition, the DFT calculations indicated that the RhIn ordered alloy presents concave Rh rows and convex In rows on its surface, which are able to capture the nitro group with end-on geometry while effectively minimizing vinyl-pi adsorption. Thus, the specific and highly ordered surface structure of RhIn enables the chemoselective molecular recognition of nitro groups over vinyl groups through geometric and chemical effects. PMID- 30009001 TI - Multivalence cooperativity leading to "all-or-nothing" assembly: the case of nucleation-growth in supramolecular polymers. AB - All-or-nothing molecular assembly events, essential for the efficient regulation of living systems at the molecular level, are emerging properties of complex chemical systems that are largely attributed to the cooperativity of weak interactions. The link between the self-assembly and the interactions responsible for the assembly is however often poorly defined. In this work we demonstrate how the chelate effect (multivalence cooperativity) can play a central role in the regulation of the all-or-nothing assembly of structures (supramolecular polymers here), even if the building blocks are not multivalent. We have studied the formation of double-stranded supramolecular polymers formed from Co metalloporphyrin and bi-pyridine building blocks. Their cooperative nucleation elongation assembly can be summarized as a thermodynamic cycle, where the monomer weakly oligomerizes linearly or weakly dimerizes laterally. But thanks to the chelate effect, the lateral dimer readily oligomerizes linearly and the oligomer readily dimerizes laterally, leading to long double stranded polymers. A model based on this simple thermodynamic cycle can be applied to the assembly of polymers with any number of strands, and allows for the determination of the length of the polymer and the all-or-nothing switching concentration from the pairwise binding constants. The model, which is consistent with the behaviour of supramolecular polymers such as microtubules and gelators, clearly shows that all or-nothing assembly is triggered by a change in the mode of assembly, from non multivalent to multivalent, when a critical concentration is reached. We believe this model is applicable to many molecular assembly processes, ranging from the formation of cell-cell focal adhesion points to crystallization. PMID- 30009004 TI - Catalysis by design: development of a bifunctional water splitting catalyst through an operando measurement directed optimization cycle. AB - A critical challenge in energy research is the development of earth abundant and cost-effective materials that catalyze the electrochemical splitting of water into hydrogen and oxygen at high rates and low overpotentials. Key to addressing this issue lies not only in the synthesis of new materials, but also in the elucidation of their active sites, their structure under operating conditions and ultimately, extraction of the structure-function relationships used to spearhead the next generation of catalyst development. In this work, we present a complete cycle of synthesis, operando characterization, and redesign of an amorphous cobalt phosphide (CoP x ) bifunctional catalyst. The research was driven by integrated electrochemical analysis, Raman spectroscopy and gravimetric measurements utilizing a novel quartz crystal microbalance spectroelectrochemical cell to uncover the catalytically active species of amorphous CoP x and subsequently modify the material to enhance the activity of the elucidated catalytic phases. Illustrating the power of our approach, the second generation cobalt-iron phosphide (CoFePx) catalyst, developed through an iteration of the operando measurement directed optimization cycle, is superior in both hydrogen and oxygen evolution reactivity over the previous material and is capable of overall water electrolysis at a current density of 10 mA cm-2 with 1.5 V applied bias in 1 M KOH electrolyte solution. PMID- 30009003 TI - Product-oriented chemical surface modification of a levansucrase (SacB) via an ene-type reaction. AB - Carbohydrate processing enzymes are sophisticated tools of living systems that have evolved to execute specific reactions on sugars. Here we present for the first time the site-selective chemical modification of exposed tyrosine residues in SacB, a levansucrase from Bacillus megaterium (Bm-LS) for enzyme engineering purposes via an ene-type reaction. Bm-LS is unable to sustain the synthesis of high molecular weight (HMW) levan (a fructose polymer) due to protein oligosaccharide dissociation events occurring at an early stage during polymer elongation. We switched the catalyst from levan-like oligosaccharide synthesis to the efficient production of a HMW fructan polymer through the covalent addition of a flexible chemical side-chain that fluctuates over the central binding cavity of the enzyme preventing premature oligosaccharide disengagement. PMID- 30009005 TI - Engineering of a near-infrared fluorescent probe for real-time simultaneous visualization of intracellular hypoxia and induced mitophagy. AB - Mitophagy induced by hypoxia plays an important role in regulating cellular homeostasis via the removal of dysfunctional mitochondria in the lysosomal degradation pathway, which results in physiological changes in the mitochondria, such as the pH, polarity and viscosity. However, the lack of an effective method for imaging of both the hypoxic microenvironment and the resulting variable mitochondria limits the visualization of hypoxia-induced mitophagy. Based on the specific mitochondrial pH changes during the hypoxia-induced mitophagy process, we have reported a near-infrared fluorescent probe (NIR-HMA) for real-time simultaneous visualization of the hypoxic microenvironment and the subsequent mitophagy process in live cells. NIR-HMA selectively accumulated in the hypoxic mitochondria in the NIR-MAO form, emitting at 710 nm, and then transformed into NIR-MAOH, emitting at 675 nm, in the acidified mitochondria-containing autolysosomes. Importantly, by smartly tethering the hypoxia-responsive group to the hydroxyl group of the NIR-fluorochrome, which shows ratiometric pH changes, NIR-HMA can differentiate between different levels of the hypoxic microenvironment and mitophagy. Furthermore, using NIR-HMA, we could track the complete mitophagy process from the mitochondria to the autolysosomes and visualize mitophagy caused only by hypoxia both in cancer cells and normal cells. Finally, NIR-HMA was applied to investigate the role that mitophagy plays in the hypoxic microenvironment via the cycling hypoxia-reoxygenation model. We observed a decreased fluorescence ratio after reoxygenation and a further increased mitophagy level after hypoxia was induced again, suggesting that mitophagy might be a self-protective process that allows cells to adapt to hypoxia. Our work may provide an attractive way for real-time visualization of relevant physiological processes in hypoxic microenvironments. PMID- 30009006 TI - Single and double activation of acetone by isolobal B[triple bond, length as m dash]N and B[triple bond, length as m-dash]B triple bonds. AB - B[triple bond, length as m-dash]N and B[triple bond, length as m-dash]B triple bonds induce C-H activation of acetone to yield a (2-propenyloxy)aminoborane and an unsymmetrical 1-(2-propenyloxy)-2-hydrodiborene, respectively. DFT calculations showed that, despite their stark electronic differences, both the B[triple bond, length as m-dash]N and B[triple bond, length as m-dash]B triple bonds activate acetone via a similar coordination-deprotonation mechanism. In contrast, the reaction of acetone with a cAAC-supported diboracumulene yielded a unique 1,2,3-oxadiborole, which according to DFT calculations also proceeds via an unsymmetrical diborene, followed by intramolecular hydride migration and a second C-H activation of the enolate ligand. PMID- 30009008 TI - An N-heterocyclic carbene ligand promotes highly selective alkyne semihydrogenation with copper nanoparticles supported on passivated silica. AB - We report a surface organometallic route that generates copper nanoparticles (NPs) on a silica support while simultaneously passivating the silica surface with trimethylsiloxy groups. The material is active for the catalytic semihydrogenation of phenylalkyl-, dialkyl- and diaryl-alkynes and displays high chemo- and stereoselectivity at full alkyne conversion to corresponding (Z) olefins in the presence of an N-heterocyclic carbene (NHC) ligand. Solid-state NMR spectroscopy using the NHC ligand 13C-labeled at the carbenic carbon reveals a genuine coordination of the carbene to Cu NPs. The presence of distinct Cu surface environments and the coordination of the NHC to specific Cu sites likely account for the increased selectivity. PMID- 30009007 TI - Reagent-dictated site selectivity in intermolecular aliphatic C-H functionalizations using nitrogen-centered radicals. AB - The site selectivities of intermolecular, aliphatic C-H bond functionalizations are central to the value of these transformations. While the scope of these reactions continues to expand, the site selectivities remain largely dictated by the inherent reactivity of the substrate C-H bonds. Herein, we introduce reagent dictated site selectivity to intermolecular aliphatic C-H functionalizations using nitrogen-centered amidyl radicals. Simple modifications of the amide lead to high levels of site selectivity in intermolecular C-H functionalizations across a range of simple and complex substrates. DFT calculations demonstrate that the steric demand of the reacting nitrogen-centered radical is heavily affected by the substitution pattern of the starting amide. Optimization of transition state structures consistently indicated higher reagent-dictated steric selectivities using more hindered amides, consistent with experimental results. PMID- 30009009 TI - An ultrasensitive polydopamine bi-functionalized SERS immunoassay for exosome based diagnosis and classification of pancreatic cancer. AB - Early diagnosis and metastasis monitoring for pancreatic cancer are extremely difficult due to a lack of sensitive liquid biopsy methods and reliable biomarkers. Herein, we developed easy-to-prepare and effective polydopamine modified immunocapture substrates and an ultrathin polydopamine-encapsulated antibody-reporter-Ag(shell)-Au(core) multilayer (PEARL) Surface-Enhanced Raman Scattering (SERS) nano-tag with a quantitative signal of the Raman reporter at 1072 cm-1, which achieved ultrasensitive and specific detection of pancreatic cancer-derived exosomes with a detection limit of only one exosome in 2 MUL of sample solution (approximately 9 * 10-19 mol L-1). Furthermore, by analyzing a 2 MUL clinical serum sample, the migration inhibitory factor (MIF) antibody-based SERS immunoassay could not only discriminate pancreatic cancer patients (n = 71) from healthy individuals (n = 32), but also distinguish metastasized tumors from metastasis-free tumors, and Tumor Node Metastasis (TNM) P1-2 stages from the P3 stage (the discriminatory sensitivity was 95.7%). Thus, this novel immunoassay provides a powerful tool for the early diagnosis, classification and metastasis monitoring of pancreatic cancer patients. PMID- 30009010 TI - Modular access to functionalized 5-8-5 fused ring systems via a photoinduced cycloisomerization reaction. AB - A 5-8-5 carbocyclic ring system forms the core of over 30 distinct natural products. Several members of this family have gained attention for their diverse activity in cell culture. In these cases, biological function is mediated by the arrangement of substituents around a conserved 5-8-5 nucleus. Despite the potential applications of this privileged substructure in medicinal chemistry, modular strategies for its assembly are underdeveloped. Herein, we describe a cycloisomerization reaction that forms the 5-8-5 framework directly. This strategy uniquely allows access to gram quantities of this valuable scaffold in four steps. PMID- 30009012 TI - Sustainable p-type copper selenide solar material with ultra-large absorption coefficient. AB - Earth-abundant solar absorber materials with large optical absorption coefficients in the visible enable the fabrication of low-cost high-efficiency single and multi-junction thin-film solar cells. Here, we report a new p-type semiconductor, Cu4TiSe4 (CTSe), featuring indirect (1.15 eV) and direct (1.34 eV) band gaps in the optimal range for solar absorber materials. CTSe crystallizes in a new noncentrosymmetric cubic structure (space group F4[combining macron]3c) in which CuSe4 tetrahedra share edges and corners to form octahedral anionic clusters, [Cu4Se4]4-, which in turn share corners to build the three-dimensional framework, with Ti4+ ions located at tetrahedral interstices within the channels. The unique crystal structure and the Ti 3d orbital character of the conduction band of CTSe give rise to near-optimal band gap values and ultra-large absorption coefficients (larger than 105 cm-1) throughout the visible range, which are promising for scalable low-cost high-efficiency CTSe-based thin-film solar cells. PMID- 30009013 TI - Reversible mechanofluorochromism of aniline-terminated phenylene ethynylenes. AB - Seven three-ring phenylene-ethynylene (PE) structural analogs, differing only in the lengths of alkyl chains on terminal aniline substituents, show 50-62 nm bathochromic shifts in emission maxima in response to mechanical force (mechanofluorochromism, MC). These shifts are fully reversible with heat or solvent fuming. Shearing of these solids yields a transition from green-emitting crystalline phases to orange-emitting amorphous phases as established by differential scanning calorimetry and X-ray diffraction. Molecules with shorter alkyl chain lengths required higher temperatures to recover the hypsochromically shifted crystalline phases after grinding, while the recovery with chain lengths longer than butyl occurred at room temperature. In addition to this structure dependent thermochromism, these compounds retain their MC properties in polymer hosts to various extents. The crystalline phases of these materials have PE chromophores that are twisted due to non-covalent perfluoroarene-arene (ArF-ArH) interactions involving perfluorophenyl pendants and the terminal rings of the PE chromophore, resulting in interrupted conjugation and an absence of chromophore aggregation. The MC behavior of an analog without the perfluoroarene rings is severely attenuated. This work demonstrates the general utility of twisted PEs as stimuli-responsive moieties and reveals clear structure-property relationships regarding the effects of alkyl chain length on these materials. PMID- 30009011 TI - Core-shell patterning of synthetic hydrogels via interfacial bioorthogonal chemistry for spatial control of stem cell behavior. AB - A new technique is described for the patterning of cell-guidance cues in synthetic extracellular matrices (ECM) for tissue engineering applications. Using s-tetrazine modified hyaluronic acid (HA), bis-trans-cyclooctene (TCO) crosslinkers and monofunctional TCO conjugates, interfacial bioorthogonal crosslinking was used to covalently functionalize hydrogels as they were synthesized at the liquid-gel interface. Through temporally controlled introduction of TCO conjugates during the crosslinking process, the enzymatic degradability, cell adhesivity, and mechanical properties of the synthetic microenvironment can be tuned with spatial precision. Using human mesenchymal stem cells (hMSCs) and hydrogels with a core-shell structure, we demonstrated the ability of the synthetic ECM with spatially defined guidance cues to modulate cell morphology in a biomimetic fashion. This new method for the spatially resolved introduction of cell-guidance cues for the establishment of functional tissue constructs complements existing methods that require UV-light or specialized equipment. PMID- 30009014 TI - Versatile in situ synthesis of MnO2 nanolayers on upconversion nanoparticles and their application in activatable fluorescence and MRI imaging. AB - We have developed a simple and versatile strategy for in situ growth of MnO2 on the surfaces of oleic acid-capped hydrophobic upconversion nanoparticles (UCNPs) by optimizing the component concentrations in the Lemieux-von Rudloff reagent. The oxidation time was shortened by a factor of two compared to that of the reported method. This oxidation process has no obvious adverse effects on the phases of UCNPs. STEM, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) and energy-dispersive X-ray analysis (EDX) characterization demonstrated the successful growth of MnO2 on the surfaces of UCNPs. Furthermore, when the weight ratio of MnO2/UCNPs reached (147.61 +/- 17.63) MUg mg-1, 50% of the initial upconversion luminescence of UCNPs was quenched, as revealed by fluorescence and inductively coupled plasma optical emission spectrometry (ICP OES) results. The presence of the surface MnO2 precipitate not only confers high dispersity of UCNPs in water, but also allows further activatable magnetic resonance imaging (MRI) and fluorescence multimodal imaging after reduction to Mn2+ by intracellular glutathione (GSH). A novel targeted drug carrier nanosystem was prepared to protect MnO2 from early decomposition in blood circulation by coating with mesoporous silica and capping with a gelatin nanolayer. Aptamer sgc8 was then attached to the surface of the gelatin nanolayer by covalent crosslinking to achieve targeted drug delivery. The results suggest that this nanosystem shows promise for further applications in cancer cell imaging and therapy. PMID- 30009015 TI - Highly stable and porous porphyrin-based zirconium and hafnium phosphonates - electron crystallography as an important tool for structure elucidation. AB - The Ni-metallated porphyrin-based tetraphosphonic acid (Ni-tetra(4 phosphonophenyl)porphyrin, Ni-H8TPPP) was used for the synthesis of highly porous metal phosphonates containing the tetravalent cations Zr4+ and Hf4+. The compounds were thoroughly characterized regarding their sorption properties towards N2 and H2O as well as thermal and chemical stability. During the synthesis optimization the reaction time could be substantially decreased under stirring from 24 to 3 h in glass vials. M-CAU-30, [M2(Ni-H2TPPP)(OH/F)2].H2O (M = Zr, Hf) shows exceptionally high specific surface areas for metal phosphonates of aBET = 1070 and 1030 m2 g-1 for Zr- and Hf-CAU-30, respectively, which are very close/correspond to the theoretical values of 1180 and 1030 m2 g-1. CAU-30 is always obtained as mixtures with one mol ZrO2/HfO2 per formula unit as proven by TEM, electron diffraction, TG and elemental analysis. Hence experimentally derived specific surface areas are 970 and 910 m2 g-1, respectively. M-CAU-30 is chemically stable in the pH range 0 to 12 in HCl/NaOH and thermally up to 420 degrees C in air as determined by variable-temperature powder X-ray diffraction (VT-PXRD). The crystal structure of M-CAU-30 was determined by combining electron diffraction tomography for structure solution and powder X-ray diffraction data for the structure refinement. The crystal structure consists of chains of corner sharing MO6 octahedra interconnected by the partly deprotonated linker molecules Ni-H2TPPP6-. Thus 1D channels with pore diameters of 1.3 * 2.0 nm are formed. The redox activity of Zr-CAU-30 was investigated by cyclic voltammetry resulting in a reversible redox process at a half-wave potential of E1/2 = -0.649 V. PMID- 30009016 TI - Annulation cascade of arylnitriles with alkynes to stable delocalized PAH carbocations via intramolecular rhodium migration. AB - Herein, we propose the conception of heteroatom-promoted delocalization of the positive charge of an oxonium ion and thus develop a highly efficient rhodium(iii)-catalyzed hydration and three fold C-H activation/annulation cascade of arylnitriles with alkynes, affording a structurally diverse family of delocalized polycyclic aromatic hydrocarbon (PAH) carbocations. DFT calculations demonstrate that the positive charge mostly locates around the C1 atom and is partly delocalized by ambient N, O1 and C5 atoms. A mechanistic study indicates that the hydration of the arylnitrile and three fold insertion of the alkyne is a successive process rather than a step by step process, wherein a unique intramolecular rhodium migration is probably involved. These novel carbeniums show tunable fluorescence emission, low cytotoxicity and the ability to specifically target lysosomes. PMID- 30009017 TI - Enhanced Upper Extremity Functions with a Single Session of Action-Observation Execution and Accelerated Skill Acquisition Program in Subacute Stroke. AB - Background: Action-observation-execution (AOE) primes physical training. We examined the immediate effect of AOE with accelerated skill acquisition program (ASAP) on dexterity in subacute stroke. Methods: Twelve individuals from 1 to 6 months after stroke were allocated into two groups by matching age and side of stroke. After AOE of 30 minutes, the experimental group received ASAP for 60 minutes whereas the control group received dose-equivalent usual care. The movement time (MT) and functional ability (FA) of hand items of the Wolf motor function test (WMFT), hand functions and global recovery of stroke impact scale (SIS), and intrinsic motivation items of stroke rehabilitation motivation scale were assessed at baseline, after training, and during one-week follow-up. Data were analyzed within and between the groups. Results: AOE significantly decreased MT of flipping cards of WMFT and hand functions of SIS. Total MT was markedly reduced. AOE with ASAP demonstrated significant group-by-time interactions on MT of lifting pencil of WMFT, total MT, and global recovery. Grip strength, FA, and hand functions were significantly improved only in the experimental group. Both groups improved motivation significantly. Conclusions: The AOE with ASAP enhanced dexterity, which persisted for at least a week. This intervention might improve dexterity in subacute stroke. Trial Registration Number: This trial is registered with TCTR20161007001. PMID- 30009018 TI - In vitro combinations of inert phenolato Ti(iv) complexes with clinically employed anticancer chemotherapy: synergy with oxaliplatin on colon cells. AB - Advanced anticancer phenolato titanium(iv) complexes were combined with known chemotherapeutic anticancer drugs applied in the clinic and were analyzed in vitro on cell lines most sensitive to the Ti(iv) complex and relevant to the clinical application of the known drugs. Combination of the Ti(iv) complex with cisplatin on ovarian cells showed mostly an additive behavior, also on a line resistant to cisplatin. Combination of the Ti(iv) complex with fluorouracil on colon cells gave near additive behavior, and that with oxaliplatin gave a synergistic behavior at a wide range of Ti : Pt ratios, but only when the drugs were administered together. Increasing the time intervals between the administration of Ti and of Pt turned the behavior to antagonistic, suggesting some deactivation of Pt by the Ti agent. For combinations where the drugs were applied together, the behavior depended on the effect level, and higher effects gave greater synergism, implying that technical aspects such as solubility are influential. Nevertheless, more complex patterns recorded for combinations where the drugs had been applied separately suggested multiple mechanisms with different concentration dependence. Overall the results point to high medicinal potential for the tested compounds for anticancer combination treatments. PMID- 30009019 TI - Facile production of nanocomposites of carbon nanotubes and polycaprolactone with high aspect ratios with potential applications in drug delivery. AB - The geometries and surface properties of nanocarriers greatly influence the interaction between nanomaterials and living cells. In this work we combine multiwalled carbon nanotubes (CNTs) with poly-epsilon-caprolactone (PCL) to produce non-spherical nanocomposites with high aspect ratios by using a facile emulsion solvent evaporation method. Particles were characterised by dynamic light scattering (DLS), scanning electron microscopy (SEM), atomic force microscopy (AFM) and asymmetric flow field flow fractionation (AF4). Different sizes and morphologies of nanoparticles were produced depending on the concentration of the sodium dodecyl sulphate (SDS), CNTs and PCL. Rod-like PCL CNT nanostructures with low polydispersity were obtained with 1.5 mg mL-1 of SDS, 0.9 mg mL-1 of CNTs and 10 mg mL-1 PCL. AFM analysis revealed that the PCL and PCL-CNT nanocomposite had comparatively similar moduli of 770 and 560 MPa respectively, indicating that all the CNTs have been coated with at least 2 nm of PCL. Thermogravimetric analysis of the PCL-CNT nanocomposite indicated that they contained 9.6% CNTs by mass. The asymmetric flow field flow fractionation of the samples revealed that the PCL-CNT had larger hydrodynamic diameters than PCL alone. Finally, the drug loading properties of the nanocomposites were assessed using docetaxel as the active substance. The nanocomposites showed comparable entrapment efficiencies of docetaxel (89%) to the CNTs alone (95%) and the PCL nanoparticles alone (81%). This is a facile method for obtaining non-spherical nanocomposites that combines the properties of PCL and CNTs such as the high aspect ratio, modulus. The high drug entrapment efficiency of these nanocomposites may have promising applications in drug delivery. PMID- 30009020 TI - In situ monitoring of SI-ATRP throughout multiple reinitiations under flow by means of a quartz crystal microbalance. AB - An investigation of the polymerisation of 2-hydroxyethyl methacrylate (HEMA) by means of surface-initiated atom transfer radical polymerisation (SI-ATRP) has been carried out in situ using a quartz crystal microbalance, with multiple reinitiations under continuous flow of the reaction mixture. The SI-ATRP kinetics of HEMA were studied continuously by means of changes in the frequency, varying conditions including temperature and solvent composition, as well as monomer and catalyst concentrations, showing the influence of key reaction parameters on SI ATRP kinetics. Such experiments enabled the design of a polymerisation protocol that leads to a reasonably fast but well-controlled growth of poly(HEMA) brushes. Furthermore, only a minor change in growth rate was observed when the polymerisation was stopped and reinitiated multiple times (essential for block synthesis), demonstrating the living nature of the SI-ATRP reaction under such conditions. The clean switching of reaction mixtures in the flow-based QCM has been shown to be a powerful tool for real-time in situ studies of surface initiated polymerisation reactions, and a promising approach for the precise fabrication of block-containing brush structures. PMID- 30009021 TI - Impact of alcohol disorder and the use of illicit drugs on tuberculosis treatment outcomes: a retrospective cohort study. AB - Background: Alcohol and illicit drugs are associated with the discontinuation of tuberculosis (TB) treatment and can compromise the immune system. We estimated the impact of alcohol disorder and the use of illicit drug on TB treatment outcomes, considering the interaction of both substances in patients from Sao Paulo state, Brazil. Methods: This is a retrospective cohort of patients diagnosed with TB from 2011 to 2015. We estimated the relative risk (RR) of an unsuccessful outcome associated with alcohol disorder, use of illicit drugs and their interaction using a multiple regression model. We used the adjusted RR to estimate the population attributable fraction. Results: Out of a total 77,212 TB patients, 22.2% used at least one of the substances of interest during treatment, while 17% presented an unsuccessful outcome of TB treatment. Compared with no exposure to any substance, alcohol disorder alone (adjusted RR: 1.48; 95% CI: 1.4 1.56), drug use alone (adjusted RR: 2.1; 95% CI: 1.98-2.21) and exposure to both substances (adjusted RR: 2.09; 95% CI: 1.97-2.21) were all associated with a higher risk of an unsuccessful outcome. The adjusted RR of an unsuccessful outcome for people exposed to both substances was 32.7% (95% CI: 26.8-38.2%) and 15.8% (95% CI: 11.5-20.1%) lower than expected on the multiplicative and additive scales respectively. Among all TB patients, 15.8% (95% CI: 15-16.5%) of unsuccessful outcomes was attributable to those exposures. Conclusions: We identified a negative interaction between alcohol disorder and the use of illicit drugs on TB treatment outcomes. Despite this, interventions to reduce substance use in TB patients could have a meaningful contribution to preventing unsuccessful treatment outcomes. PMID- 30009022 TI - Do adolescents understand the items of the European Health Literacy Survey Questionnaire (HLS-EU-Q47) - German version? Findings from cognitive interviews of the project "Measurement of Health Literacy Among Adolescents" (MOHLAA) in Germany. AB - Background: In Germany, there are no measurement tools to assess the general health literacy of adolescents. The aim of the study "Measurement of Health Literacy Among Adolescents" (MOHLAA) is to develop such a tool for use among adolescents aged 14-17. The German version of the European Health Literacy Survey Questionnaire (HLS-EU-Q47-GER) served as a blueprint for the development of the tool. The present study examined the extent to which the HLS-EU-Q47-GER can be applied to the measurement of general health literacy in adolescents. Methods: The applicability of the HLS-EU-Q47-GER for adolescents was tested qualitatively using cognitive interviewing (CI). Purposive sampling was used to achieve an equal distribution of participants regarding age groups, educational backgrounds and gender. CI was standardized on the basis of an interview guide. Verbal probing and the retrospective think-aloud technique were applied. The interviews were audio-recorded, transcribed and analyzed using the criteria of theory-based analysis, which were derived from the model of cognitive processes. The analysis focused on identifying terms and questions that were difficult to understand and on scrutinizing the extent to which the content of the items is appropriate for assessing adolescents' health literacy. Results: Adolescent respondents were unfamiliar with some terms of the HLS-EU-Q47-GER or provided heterogeneous interpretations of the terms. They had limited or no experience regarding some health-related tasks in health care and disease prevention that are addressed by HLS-EU-Q-items. A few items seemed to be too "difficult" to answer due to a high abstraction level or because they lacked any reference to the everyday lives of youth. Despite comprehension problems with some of the HLS-EU items, the respondents assessed the covered health-related tasks as "very easy" or "fairly easy". CI stressed the importance of interpersonal agents, especially parents, in helping adolescents understand and judge the reliability of health information. Conclusions: The results of CI indicated that the applicability of the HLS-EU-Q47 GER to the measurement of general health literacy among adolescents aged 14-17 is limited. In order to prevent biased data, some items of the questionnaire should be adjusted to adolescents' state of development and experiences with health care and disease prevention. PMID- 30009023 TI - A full monolayer of superoxide: oxygen activation on the unmodified Ca3Ru2O7(001) surface. AB - Activating the O2 molecule is at the heart of a variety of technological applications, most prominently in energy conversion schemes including solid oxide fuel cells, electrolysis, and catalysis. Perovskite oxides, both traditionally used and novel formulations, are the prime candidates in established and emerging energy devices. This work shows that the as-cleaved and unmodified CaO-terminated (001) surface of Ca3Ru2O7, a Ruddlesden-Popper perovskite, supports a full monolayer of superoxide ions, O2-, when exposed to molecular O2. The electrons for activating the molecule are transferred from the subsurface RuO2 layer. Theoretical calculations using both, density functional theory (DFT) and more accurate methods (RPA), predict the adsorption of O2- with Eads = 0.72 eV and provide a thorough analysis of the charge transfer. Non-contact atomic force microscopy (nc-AFM) and scanning tunnelling microscopy (STM) are used to resolve single molecules and confirm the predicted adsorption structures. Local contact potential difference (LCPD) and X-ray photoelectron spectroscopy (XPS) measurements on the full monolayer of O2- confirm the negative charge state of the molecules. The present study reports the rare case of an oxide surface without dopants, defects, or low-coordinated sites readily activating molecular O2. PMID- 30009024 TI - Computer simulations of 4240 MOF membranes for H2/CH4 separations: insights into structure-performance relations. AB - Design of new membranes having high H2/CH4 selectivity and high H2 permeability is strongly desired to reduce the energy demand for H2 production. Metal organic frameworks (MOFs) offer a great promise for membrane-based gas separations due to their tunable physical and chemical properties. We performed a high-throughput computational screening study to examine membrane-based H2/CH4 separation potentials of 4240 MOFs. Grand canonical Monte Carlo (GCMC) and molecular dynamics (MD) simulations were used to compute adsorption and diffusion of H2 and CH4 in MOFs. Simulation results were then used to predict adsorption selectivity, diffusion selectivity, gas permeability and membrane selectivity of MOFs. A large number of MOF membranes was found to outperform traditional polymer and zeolite membranes by exceeding the Robeson's upper bound for selective separation of H2 from CH4. Structure-performance analysis was carried out to understand the relations between MOF membranes' selectivities and their pore sizes, surface areas, porosities, densities, lattice systems, and metal types. Results showed that MOFs with pore limiting diameters between 3.8 and 6 A, the largest cavity diameters between 6 and 12 A, surface areas less than 1000 m2 g-1, porosities between 0.5 and 0.75, and densities between 1 and 1.5 g cm-3 are the most promising membranes leading to H2 selectivities >10 and H2 permeabilities >104 Barrer. Our results suggest that monoclinic MOFs having copper metals are the best membrane candidates for H2/CH4 separations. This study represents the first high-throughput computational screening of the most recent MOF database for membrane-based H2/CH4 separation and microscopic insight provided from molecular simulations will be highly useful for the future design of new MOFs having extraordinarily high H2 selectivities. PMID- 30009025 TI - The effect of oxygen on the efficiency of planar p-i-n metal halide perovskite solar cells with a PEDOT:PSS hole transport layer. AB - Poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) is frequently used as hole transport layer in planar p-i-n perovskite solar cells. Here we show that processing of a metal halide perovskite layer on top of PEDOT:PSS via spin coating of a precursor solution chemically reduces the oxidation state of PEDOT:PSS. This reduction leads to a lowering of the work function of the PEDOT:PSS and the perovskite layer on top of it. As a consequence, the solar cells display inferior performance with a reduced open-circuit voltage and a reduced short-circuit current density, which increases sublinearly with light intensity. The reduced PEDOT:PSS can be re-oxidized by thermal annealing of the PEDOT:PSS/perovskite layer stack in the presence of oxygen. As a consequence, thermal annealing of the perovskite layer in air provides solar cells with increased open-circuit voltage, short-circuit current density and high efficiency. PMID- 30009026 TI - Vacancy defect configurations in the metal-organic framework UiO-66: energetics and electronic structure. AB - Vacancy lattice sites in the metal-organic framework UiO-66 are known to have a profound effect on the material properties. Here we use density functional theory to compare the energies of defect arrangements containing missing linkers and missing metal clusters for different choices of charge compensation. Our results show that the preference for missing metal clusters or missing linker defects depends on the charge compensation as well as the overall concentration of defects in the crystal. Both regimes can be experimentally accessible depending on the synthesis conditions. We investigate the electronic structure of the different types of defects, showing that, despite some changes in the localisation of the frontier orbitals, the electronic energy levels are only weakly affected by the presence of point defects. PMID- 30009027 TI - Red green blue emissive lead sulfide quantum dots: heterogeneous synthesis and applications. AB - Visible emission colloidal quantum dots (QDs) have shown promise in optical and optoelectronic applications. These QDs are typically composed of relatively expensive elements in the form of indium, cadmium, and gallium since alternative candidate materials exhibiting similar properties are yet to be realized. Herein, for the first time, we report red green blue (RGB) photoluminescences with quantum yields of 18% from earth-abundant lead sulfide (PbS) QDs. The visible emissive property is mainly attributed to a high degree of crystallinity even for the extremely small QD sizes (1-3 nm), which is realized by employing a heterogeneous reaction methodology at high growth temperatures (>170 degrees C). We demonstrate that the proposed heterogeneous synthetic method can be extended to the synthesis of other metal chalcogenide QDs, such as zinc sulfide and zinc selenide, which are promising for future industrial applications. More importantly, benefiting from the enlarged band gaps, the as-prepared PbS solar cells show an impressive open circuit voltage (~0.8 V) beyond that reported to date. PMID- 30009028 TI - Cation, magnetic, and charge ordering in MnFe3O5. AB - The recently-discovered high pressure material MnFe3O5 displays a rich variety of magnetically ordered states on cooling. Fe spins order antiferromagnetically below a Neel transition at 350 K. A second transition at 150 K marks Mn spin order that leads to spin canting of some of the Fe spins and ferrimagnetism. A further transition at 60 K is driven by charge ordering of Fe2+ and Fe3+ over two inequivalent Fe sites, with further canting of all spins. Electrical resistivity measurements reveal semiconducting behaviour in MnFe3O5 with a change in activation energy at 285 K. PMID- 30009029 TI - Fibronectin protein expression in renal cell carcinoma in correlation with clinical stage of tumour. AB - Background: Carcinogenesis is a multistep process which involves interplay between the tumour cells and the matrix proteins. This occurs by adherence between the tumour cells and proteins in the extracellular matrix. VHL mutation affects through the hypoxia inducible factor (HIF) and causes changes in various tissue proteins like VEGF, PDGF, TGF, Fibronectin and others. As not much literature is available, we aim to quantify the changes of fibronectin protein in renal cell carcinoma (RCC) tissue. Methods: This Prospective unbalanced case control study was conducted over a period of 18 months from April 2016 to September 2017. The patients undergoing nephrectomy for the diagnosis of RCC were included in the study after obtaining written informed consent. Patients were excluded from study, if normal renal tissue could not be identified in the resected kidney and if the artery clamp time to retrieval of tissue was more than 30 min. Fibronectin protein is estimated in the tumour tissue by gel electrophoresis and western blotting which is compared with that of normal kidney tissue of the same kidney. Results have been expressed as absolute values with standard deviation and relative expression (RE). Results: Of the 21 patients analysed 15 showed an increase in fibronectin expression in the renal tumour tissue while 6 did not. The mean expression of Fibronectin protein has increased 1.5 times in the tumour tissue when compared with the normal tissue. The increase was 1.54 times in early tumours compared to 1.37 times in advanced tumours of RCC. Conclusions: Fibronectin showed a 1.5 times increase in the tumour compared to normal. This increase is more in Stage 1&2 tumours when compared to the Stage 3&4 tumours. PMID- 30009030 TI - Tracheobronchial involvement of mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a rare type of B-cell non-Hodgkin's lymphoma that commonly affects extranodal sites; however, tracheobronchial involvement is rare. We report the case of a 65-year-old male who presented with cough and dyspnoea. A chest computed tomography (CT) revealed irregular wall thickening of the trachea and bilateral bronchi and bilateral bronchiectasis. A bronchoscopy revealed a diffuse irregular surface of the tracheal and bilateral bronchial mucosa and polyposis-like lesions. He was diagnosed with MCL based on an endobronchial biopsy, and then, the diagnosis was confirmed with a biopsy of the fluorodeoxyglucose (FDG)-avid nasal mucosal soft tissue. PMID- 30009031 TI - Use of low-cost three-dimensional printer to simulate grasping of bronchial foreign body. AB - An 89-year-old man was hospitalized with severe pneumonia. Chest computed tomography showed a foreign body in the left main bronchus. We moulded a three dimensional (3D) model of the foreign body with a low-cost 3D printer and found it had the shape of a tooth. We simulated grasping the model with several forceps and succeeded in grasping it with a retrieval net and shark-tooth forceps. Bronchoscopy was performed after his respiratory condition improved. We found a dental foreign body that had accidentally moved and become stuck in the right upper bronchus. We scraped it out with a retrieval net and grasped the recess site of the foreign body with a shark-tooth forceps as performed in the simulation. Removal was successful, and the total bronchoscopy time was 9 min. The bronchial foreign body was safely grasped and removed in a short time after simulation with several forceps using a low-cost 3D printer. PMID- 30009032 TI - Commentary to: a cross-validation-based approach for delimiting reliable home range estimates. AB - Background: Continued exploration of the performance of the recently proposed cross-validation-based approach for delimiting home ranges using the Time Local Convex Hull (T-LoCoH) method has revealed a number of issues with the original formulation. Main text: Here we replace the ad hoc cross-validation score with a new formulation based on the total log probability of out-of-sample predictions. To obtain these probabilities, we interpret the normalized LoCoH hulls as a probability density. The application of the approach described here results in optimal parameter sets that differ dramatically from those selected using the original formulation. The derived metrics of home range size, mean revisitation rate, and mean duration of visit are also altered using the corrected formulation. Conclusion: Despite these differences, we encourage the use of the cross-validation-based approach, as it provides a unifying framework governed by the statistical properties of the home ranges rather than subjective selections by the user. PMID- 30009033 TI - Comparison of extracorporeal membrane oxygenation outcome for influenza associated acute respiratory failure in Japan between 2009 and 2016. AB - Background: Since the 2009 pandemic influenza, we have nationally established a committee of the extracorporeal membrane oxygenation (ECMO) project. This project involves adequate respiratory management for severe respiratory failure using ECMO. This study aimed to investigate the correlations between changes in respiratory management using ECMO in Japan and outcomes of patients with influenza-associated acute respiratory failure between 2009 and 2016. Methods: We investigated the incidence, severity, characteristics, and prognosis of influenza associated acute respiratory failure in 2016 by web-based surveillance. The correlations between clinical characteristics, ventilator settings, ECMO settings, and prognosis were evaluated. Results: A total of 14 patients were managed with ECMO in 2016. There were no significant differences in age, sex, and the acute physiology and chronic health evaluation II score between 2009 and 2016. The maximum sequential organ failure assessment score and highest positive end-expiratory pressure were lower in 2016 than in 2009 (p = 0.03 and p = 0.015, respectively). Baseline and lowest partial pressure of arterial oxygen (PaO2)/fraction of inspiratory oxygen (FIO2) ratios were higher in 2016 than in 2009 (p = 0.009 and p = 0.002, respectively). The types of consoles, circuits, oxygenators, centrifugal pumps, and cannulas were significantly changed between 2016 and 2009 (p = 0.006, p = 0.003, p = 0.004, p < 0.001, respectively). Duration of the use of each circuit was significantly longer in 2016 than in 2009 (8.5 vs. 4.0 days; p = 0.0001). Multivariate analysis showed that the use of ECMO in 2016 was an independent predictor of better overall survival in patients with influenza-associated acute respiratory failure (hazard ratio, 7.25; 95% confidence interval, 1.35-33.3; p = 0.021). Conclusions: Respiratory management for influenza-associated acute respiratory failure using ECMO was significantly changed in 2016 compared with 2009 in Japan. The outcome of ECMO use had improved in 2016 compared with the outcome in 2009 in patients with influenza-associated acute respiratory failure. PMID- 30009034 TI - Screening of anticancer drugs to detect drug-induced interstitial pneumonia using the accumulated data in the electronic medical record. AB - Because drug-induced interstitial pneumonia (DIP) is a serious adverse drug reaction, its quantitative risk with individual medications should be taken into due consideration when selecting a medicine. We developed an algorithm to detect DIP using medical record data accumulated in a hospital. Chest computed tomography (CT) is mainly used for the diagnosis of IP, and chest X-ray reports, KL-6, and SP-D values are used to support the diagnosis. The presence of IP in the reports was assessed by a method using natural language-processing, in which IP was estimated according to the product of the likelihood ratio of characteristic keywords in each report. The sensitivity and the specificity of the method for chest CT reports were 0.92 and 0.97, while those for chest X-ray reports were 0.83 and 1, respectively. The occurrence of DIP was estimated by the patterns of presence of IP before, during, and after the administration of the target medicine. The occurrence rate of DIP in cases administered Gefitinib; Methotrexate (MTX); Tegafur, Gimeracil, and Oteracil potassium (TS-1); and Tegafur and Uracil (UTF) was 6.0%, 2.3%, 1.4%, and 0.7%, respectively. The estimated DIP cases were checked by having the medical records independently reviewed by medical doctors. By chart review, the positive predictive values of DIP against Gefitinib, MTX, TS-1, and UFT were 69.2%, 44.4%, 58.6%, and 77.8%, respectively. Although the cases extracted by this method included some that did not have DIP, this method can estimate the relative risk of DIP between medicines. PMID- 30009035 TI - The characteristics of asbestos-related disease claims made to the Korea Workers' Compensation and Welfare Service (KCOMWEL) from 2011 to 2015. AB - Background: This study aimed to enhance understanding of the epidemiologic characteristics of asbestos-related diseases, and to provide information that could inform policy-making aimed at prevention and compensation for occupational asbestos exposure, through analyzing asbestos-related occupational disease claims to Korea Workers' Compensation and Welfare Service from 2011 to 2015. Methods: We analyzed 113 workers who filed medical care claims or survivor benefits for asbestos exposure and occupational-related disease from 2011 to 2015. Among these claims, we selected approved workers' compensation claims relating to malignant mesothelioma and lung cancer, and analyzed the general characteristics, exposure characteristics, pathological characteristics, and occupation and industry distribution. Results: Malignant mesothelioma and lung cancer occurred predominantly in males at 89.7 and 94%, respectively. The mean age at the time of diagnosis for malignant mesothelioma and lung cancer was 59.5 and 59.7 years, respectively, while the latency period for malignant mesothelioma and lung cancer was 34.1 and 33.1 years, respectively. The companies involving exposed workers were most commonly situated within the Busan-Ulsan-Gyeongnam region. Histology results for lung cancer indicated adenocarcinoma as the most common form, accounting for approximately one half of all claims, followed by squamous cell carcinoma, and small cell lung cancer. The most common occupation type was construction in respect of malignant mesothelioma, and shipbuilding in respect of lung cancer. Conclusions: Considering the long latency period of asbestos and that the peak period of asbestos use in Korea was throughout the mid-1990s, damage due to asbestos-related diseases is expected to show a continued long-term increase. Few studies providing an epidemiologic analysis of asbestos-related diseases are available; therefore, this study may provide baseline data to assist in predicting and preparing for future harm due to asbestos exposure. Trial registration: DUIH 2018-02-004-001. Registered 28 Februrary 2018. PMID- 30009036 TI - Working hours and depressive symptoms: the role of job stress factors. AB - Background: South Korea is one of the countries with the longest working hours in the OECD countries. The aim of this study was to evaluate the effect of working hours on depressive symptoms and the role of job stress factors between the two variables among employees in South Korea. Methods: This study used data from the Korea Working Conditions Survey in 2014. Study subjects included 23,197 employees aged 19 years or older who work more than 35 h per week. Working hours were categorized into 35-39, 40, 41-52, 53-68, and more than 68 h per week. Depressive symptoms were assessed using the WHO's Well-Being Index with a cut-off score of 13. We calculated prevalence ratios of depressive symptoms according to working hours using log-binomial regression. Through the percentage change in prevalence ratios, we identified the extent of the role of job stress factors that explain depressive symptoms. Results: The risks of depressive symptoms were significantly higher in people who worked 35-39 h per week (PR: 1.09, CI: 1.01-1.18), 53-68 h/week (PR: 1.21, CI: 1.16-1.25), and more than 68 h/week (PR: 1.14, CI: 1.07 1.21) than 40 h/week, after adjusting for confounding variables. Job stress explained the effects of long working hours on depressive symptoms in about 20 40% of the groups working more than 40 h/week. Among the factors of job stress, social support was 10-30%, which showed the highest explanatory power in all working hours. Reward explained 15-30% in the more than 52 h working group, and reward was the most important factor in the working group that exceeded 68 h. Conclusions: We showed the working hours could be an independent risk factor for depressive symptoms in employees. To improve workers' mental health, it is important to strengthen social support in the workplace, to provide adequate rewards as they work, and ultimately to regulate the appropriate amount of working hours. PMID- 30009037 TI - Residency and career satisfaction among Anglo-American model emergency medicine residents in Japan. AB - Aim: The number of institutions providing Anglo-American model emergency medicine has increased with the rise in its social demand in Japan. The ER Committee of the Japanese Association for Acute Medicine has introduced a residency model for use in Japanese hospitals that have adopted the Anglo-American emergency medicine model. Despite the critical importance of its quality, no studies have examined Japanese emergency medicine residents' level of satisfaction with their training. This study investigated their residency and career satisfaction, and factors associated with satisfaction. Methods: We developed a cross-sectional, anonymous survey. Data were obtained from 67 Anglo-American model emergency medicine residents in Japan in February 2010. Data were analyzed with factor analysis and multivariable analysis with a logistic regression model. Results: Response rate was 100% (n = 67). Overall, 50.7% and 67.2% of residents reported high residency and career satisfaction, respectively. Factor analysis derived four factors: working conditions; stress reduction; training systems; education. Logistic regression analysis revealed that the training system factor was significantly associated with high residency satisfaction (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.2-8.4) and the stress reduction factor was significantly associated with high career satisfaction (OR, 3.0; 95%CI, 1.2-8.4). A total of 28.8% reported intentions to switch specialties. The intention was not significantly associated with low residency satisfaction (OR, 1.7; 95%CI, 0.6 5.0), but was associated with low career satisfaction (OR, 5.1; 95%CI, 1.6-16.0). Conclusion: Improvements in training systems and stress reduction may increase residency and career satisfaction of emergency medicine residents, respectively. This study suggested that high career satisfaction was required to secure future emergency physicians. PMID- 30009038 TI - The utility of patient reported data in a gynecologic oncology clinic. AB - Background: Measuring QoL is essential to the field of gynecologic oncology but there seems to be limited standardized data regarding collecting QoL assessments throughout a patient's cancer treatment especially in non-clinical trial patients. The aim of this study is to explore patient characteristics that may be associated with poor quality of life (QoL) in women with gynecologic cancers at two University of Arizona Cancer Center (UACC) sites. Methods: A cross-sectional survey was conducted among English speaking women with gynecologic malignancies at the University of Arizona Cancer Centers in Phoenix and Tucson from April 2012 to July 2015. The survey was a paper packet of questions that was distributed to cancer patients at the time of their clinic visit. The packet contained questions on demographic information, treatment, lifestyle characteristics, pelvic pain and Health-related quality of life (HRQoL). Measures included the generic and cancer specific scores on the Functional Assessment of Cancer Therapy-General (FACT-G) and the Female Genitourinary Pain Index (GUPI). The total scores and subdomains were compared with descriptive variables (age, body mass index (BMI), diet, exercise, disease status, treatment and support group attendance) using Cronbach alpha (alpha), Spearman rank correlations (rho), and Holm's Bonferroni method. Results: One-hundred and forty-nine women completed the survey; 55% (N = 81) were older than 60 years, 38% (N = 45) were obese (BMI > 30), 46% (N = 66) exercised daily, and 84% (N = 111) ate one or more daily serving of fruit and vegetables. Women in remission, those who exercised daily and ate fruits/vegetables were less likely to have their symptoms impact their QoL. Younger women were more likely to report genitourinary issues (p = - 0.22) and overall problems with QoL (p = - 0.29) than older women. Among FACT-G support group responses, we found those that did not attend support groups had a significantly higher emotional wellbeing (p = 0.05). Conclusions: This study identified potential areas of clinical focus, which aid in understanding our approach to caring for gynecologic cancer patients and improvement of their HRQoL. We identified that age, pelvic pain, and lifestyle characteristics have indicators to poor QoL in women with gynecologic cancers. In this population, younger women and those with pelvic pain complaints, poor diet and exercise habits should be targeted early for supportive care interventions to improve QoL throughout both treatment and survivorship. PMID- 30009039 TI - Examination of the xanthosine response on gene expression of mammary epithelial cells using RNA-seq technology. AB - Background: Xanthosine treatment has been previously reported to increase mammary stem cell population and milk production in cattle and goats. However, the underlying molecular mechanisms associated with the increase in stem cell population and milk production remain unclear. Methods: Primiparous Beetal goats were assigned to the study. Five days post-partum, one mammary gland of each goat was infused with xanthosine (TRT) twice daily (2*) for 3 days consecutively, and the other gland served as a control (CON). Milk samples from the TRT and CON glands were collected on the 10th day after the last xanthosine infusion and the total RNA was isolated from milk fat globules (MEGs). Total RNA in MFGs was mainly derived from the milk epithelial cells (MECs) as evidenced by expression of milk synthesis genes. Significant differentially expressed genes (DEGs) were subjected to Gene Ontology (GO) terms using PANTHER and gene networks were generated using STRING db. Results: Preliminary analysis indicated that each individual goat responded to xanthosine treatment differently, with this trend being correlated with specific DEGs within the same animal's mammary gland. Several pathways are impacted by these DEGs, including cell communication, cell proliferation and anti-microbials. Conclusions: This study provides valuable insights into transcriptomic changes in milk producing epithelial cells in response to xanthosine treatment. Further characterization of DEGs identified in this study is likely to delineate the molecular mechanisms of increased milk production and stem or progenitor cell population by the xanthosine treatment. PMID- 30009040 TI - On the Road to Recovery psychological therapy versus treatment as usual for forensic mental health patients: study protocol for a randomized controlled feasibility trial. AB - Background: On the Road to Recovery (OTRTR) is a brief low intensity group psychological therapy that aims to improve patients' insight into their mental disorder and develop adaptive coping skills to help manage distress. OTRTR is currently delivered in forensic mental health services in Scotland. However, to date, this therapy has not been evaluated as to its effectiveness or safety for forensic patients. Methods: This is a parallel-group feasibility randomized controlled trial with single-blind assessments comparing OTRTR therapy to treatment as usual (TAU) for forensic mental health patients. Fifty participants will be recruited from high, medium, and low secure forensic mental health services in Scotland. Participants will receive OTRTR for approximately 12 weeks or continue treatment as usual for 12 weeks. The trial's primary aims relate to testing the acceptability and feasibility of key trial procedures that would be necessary for a definitive RCT of OTRTR. The secondary aims include estimating therapeutic effect sizes on clinical outcomes including insight and coping skills. The study design also features an adverse event monitoring plan to estimate the safety of OTRTR for participants, as well as use of intensive longitudinal methods to identify "key ingredients" to the OTRTR therapy protocol. Discussion: This study will inform the design and sample size for a future full scale randomized controlled trial (RCT), which will be conducted to determine the effectiveness of the On the Road to Recovery intervention in improving forensic mental health patients' clinical insight and coping skills. Trial registration: ISRCTN Registry, ISRCTN75126867 registered 27 July 2017. PMID- 30009042 TI - Social determinants of household wealth and income in urban China. AB - Using data from a nationwide household survey-the China Family Panel Studies (CFPS)-we study how social determinants-political and market factors-are associated with wealth and income among urban households in China. Results indicate that both political and market factors contribute significantly to a household's economic wellbeing, but the political premium is substantially greater in wealth than in income. Further, political capital has a larger effect on the accumulation of housing assets, while market factors are more influential on the accumulation of non-housing assets. We propose explanations for these findings. PMID- 30009041 TI - Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). AB - Background: Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP NETs). The only treatment that offers a cure is surgery, however most patients are diagnosed with metastatic disease, and curative surgery is usually not an option.Since the majority of patients are not candidate for curative surgery, they can be offered long-term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence based treatment options include somatostatin analogues, everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), peptide receptor radionuclide therapy (PRRT), chemotherapy, etc., alone or combined with cytoreductive procedures (surgery or liver directed procedures). However, there is an increasing need for novel therapies. Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. Following first line therapy with somatostatin analogues, there is no clear information to date indicating a preferred treatment sequence, and therefore the treatment approach should be individualized based on each NET patient characteristics. Conclusions: NET patients are increasingly diagnosed throughout the world, usually with metastatic disease and requiring systemic therapy. We believe that each patient should be therefore thoroughly evaluated and individually discussed by a multidisciplinary and dedicated NET-expert team, updated with all treatment options including ongoing clinical trials, and before selecting the proper treatment sequence. PMID- 30009043 TI - Recruiting and retaining service agencies and public health providers in longitudinal studies: Implications for community-engaged implementation research. AB - This article addresses a lack of attention in the implementation science literature regarding how to overcome recruitment and retention challenges in longitudinal studies involving large samples of service agencies and health service providers ("providers"). Herein, we provide a case-illustration of procedures that improved recruitment and retention in a longitudinal, mixed method study-Project Interprofessional Collaboration Implementation-funded by the US National Institute of Mental Health. Project Interprofessional Collaboration Implementation included counselors, program workers, educators, and supervisors. We present a research-engagement model to overcome barriers that included developing a low-burden study, social gatherings to engage stakeholders, protocols to recruit agencies and providers, comprehensive record-keeping, research procedures as incentives to participation, a plan to retain hard-to reach participants, and strategies for modifying incentives over time. Using our model, we retained 36 agencies over the life of the project. Between baseline (N = 379) and 12-month follow-up (N = 285), we retained 75% of the sample and between the 12- (N = 285) and 24-month follow-ups (N = 256), we retained 90%. For qualitative interviews (between baseline and 12-month follow-up and between 12- and 24-month follow-ups), we retained 100% of the sample (N = 20). We provide a summary of frequency of contacts required to initiate data collection and time required for data collection. The model responded to environmental changes in policy and priorities that would not have been achievable without the expertise of community partners. To recruit and retain large samples longitudinally, researchers must strategically engage community partners. The strategies imbedded in our model can be performed with moderate levels of effort and human resources. Creating opportunities for research partners to participate in all phases of the research cycle is recommended, which can help build research capacity for future research. PMID- 30009044 TI - Freeze-cast Porous Chitosan Conduit for Peripheral Nerve Repair. AB - A novel freeze-cast porous chitosan conduit for peripheral nerve repair with highly-aligned, double layered porosity, which provides the ideal mechanical and chemical properties was designed, manufactured, and assessed in vivo. Efficacies of the conduit and the control inverted nerve autograft were evaluated in bridging 10-mm Lewis rat sciatic nerve gap at 12 weeks post-implantation. Biocompatibility and regenerative efficacy of the porous chitosan conduit were evaluated through the histomorphometric analysis of longitudinal and transverse sections. The porous chitosan conduit was found to have promising regenerative characteristics, promoting the desired neovascularization, and axonal ingrowth and alignment through a combination of structural, mechanical and chemical cues. PMID- 30009045 TI - Can OCT Angiography Be Made a Quantitative Blood Measurement Tool? AB - Optical Coherence Tomography Angiography (OCTA) refers to a powerful class of OCT scanning protocols and algorithms that selectively enhance the imaging of blood vessel lumens, based mainly on the motion and scattering of red blood cells (RBCs). Though OCTA is widely used in clinical and basic science applications for visualization of perfused blood vessels, OCTA is still primarily a qualitative tool. However, more quantitative hemodynamic information would better delineate disease mechanisms, and potentially improve the sensitivity for detecting early stages of disease. Here, we take a broader view of OCTA in the context of microvascular hemodynamics and light scattering. Paying particular attention to the unique challenges presented by capillaries versus larger supplying and draining vessels, we critically assess opportunities and challenges in making OCTA a quantitative tool. PMID- 30009046 TI - Synergetic Effects of Plasmodium, Hookworm, and Schistosoma mansoni Infections on Hemoglobin Level among Febrile School Age Children in Jawe Worda, Northwest Ethiopia. AB - Plasmodium coinfection with hookworm and/or Schistosoma mansoni has detrimental effects on human's hemoglobin level. This study aimed to determine the effects of plasmodium, hookworm, and S. mansoni infections on hemoglobin level among febrile school age children in Northwest Ethiopia. A cross-sectional study was conducted from April 2016 to August 2016. Plasmodium and helminths infections were detected using Giemsa stain and formol-ether concentration techniques, respectively. Hemoglobin level was determined using Hemocue method. Among 333 children, 143 (42.9%), 49 (14.75%), and 22 (6.6%) had Plasmodium, hookworm, and Schistosoma mansoni infections, respectively. The prevalence of Plasmodium-hookworm and Plasmodium-Schistosoma mansoni coinfections was 18 (12.6%) and 4 (2.8%) in children, respectively. The overall prevalence of anaemia in children was 41.4%. Effect of Plasmodium, hookworm, and Schistosoma mansoni on hemoglobin level was high. Therefore, febrile children should be screened for Plasmodium, hookworm, Schistosoma mansoni, and anaemia simultaneously in malaria endemic areas. PMID- 30009048 TI - SERPINA1 mRNA as a Treatment for Alpha-1 Antitrypsin Deficiency. AB - Alpha-1-antitrypsin (AAT) deficiency is a genetic disorder that produces inactive/defective AAT due to mutations in the SERPINA1 gene encoding AAT. This disease is associated with decreased activity of AAT in the lungs and deposition of excessive defective AAT protein in the liver. Currently there is no specific treatment for liver disease associated with AAT deficiency. AAT lung disease is often treated with one of several serum protein replacement products; however, long-term studies of the effectiveness of SerpinA1 replacement therapy are not available, and it does not reduce liver damage in AAT deficiency. mRNA therapy could potentially target both the liver and lungs of AAT deficient patients. AAT patient fibroblasts and AAT patient fibroblast-derived hepatocytes were transfected with SERPINA1-encoding mRNA and cell culture media were tested for SerpinA1 expression. Our data demonstrates increased SerpinA1 protein in culture media from treated AAT patient fibroblasts and AAT patient fibroblast-derived hepatocytes. In vivo studies in wild type mice demonstrate SERPINA1 mRNA biodistribution in liver and lungs, as well as SerpinA1 protein expression in these two target organs which are critically affected in AAT deficiency. Taken together, our data suggests that SerpinA1 mRNA therapy has the potential to benefit patients suffering from AAT deficiency. PMID- 30009047 TI - The Effect of Steep Trendelenburg Positioning on Retinal Structure and Function during Robotic-Assisted Laparoscopic Procedures. AB - Purpose: Robotic-assisted laparoscopic radical prostatectomy (RALP) has become a standard treatment choice for localized prostate cancer. RALP requires a steep Trendelenburg position, which leads to a significant increase in intraocular pressure (IOP). This study evaluated the effect on the retinal structure and function in patients undergoing RALP. Methods: Standard automated perimetry (SAP) and optical coherence tomography (OCT) were performed in 20 males scheduled for RALP at 1 month and 1 day before the operation and at 1 and 3 months after the operation. IOP measurements were made in the supine position at 5 min after intubation under general anesthesia (T1), at 6 discrete time points (5, 30, 60, 120, 180, and 240 min; T2-7), and at 5 min after returning to a horizontal supine position (T8). Serial retinal nerve fiber layer (RNFL) thicknesses and visual field progression were assessed using the guided progression analysis software program. RNFL thickness progression and visual field progression were evaluated by event analysis. Results: Average IOP (mmHg) for each time point was as follows: T1 = 12.3 +/- 2.6, T2 = 20.4 +/- 4.2, T3 = 23.3 +/- 3.8, T4 = 24.0 +/- 3.2, T5 = 24.3 +/- 3.4, T6 = 27.1 +/- 7.2, T7 = 29.8 +/- 8.7, and T8 = 20.1 +/- 4.4. During RALP, IOP significantly increased. There was no progression of the visual field and RNFL thickness after surgery or any other ocular complications found. Conclusions: Although IOP significantly increased during RALP, there were no significant changes in the retinal structure and function between the pre- and postoperation observations. PMID- 30009049 TI - Thiol/Disulfide Balance in Patients with Familial Hypercholesterolemia. AB - Objective: Herein, we investigated the balance of thiol/disulfide, with the hypothesis that the balance between disulfides and thiols, which are natural antioxidants, might be disrupted in patients with familial hypercholesterolemia, which eventually leads to endothelial damage. Methods: In this study, we evaluated 51 patients diagnosed with familial hypercholesterolemia and 81 healthy subjects. Blood samples were taken from the patients after a minimum of 12 hours of fasting; samples were immediately centrifuged, stored in Eppendorf tubes, and preserved at -80 degrees C. Results: This study found that thiol levels are significantly lower in patients with familial hypercholesterolemia, whereas disulfide levels are higher (independent of age, gender, and body mass index). This means that in such patients, the thiol/disulfide balance changes in favour of disulfide. Conclusions: In this study, we found that the thiol/disulfide balance in patients with familial hypercholesterolemia is disrupted in favour of disulfide. PMID- 30009050 TI - Dyslipidemia and Fatty Liver Disease in Overweight and Obese Children. AB - Introduction: Obesity is a worldwide concern. It is associated with morbidity such as dyslipidemia and liver disease. Childhood obesity has dramatically increased, particularly in the Gulf region. We aim to assess the prevalence of dyslipidemia and fatty liver disease (FLD) in overweight and obese children and analyze the association between different anthropometric measures with dyslipidemia and fatty liver disease. Methods: A descriptive, cross-sectional study conducted on children referred with obesity. BMI percentiles were plotted and standardized waist circumference (WC) was generated. Family history of metabolic syndrome was recorded. Fasting lipid, liver transaminases, and ultrasound scans (US) for those with elevated enzymes were performed. Descriptive statistics were used for quantitative parameters. Results: 216 participants were recruited. Mean +/- SD age was 10.58 +/- 2.996 years. 55.3% had dyslipidemia; 11.7% had high cholesterol, 28.6% high triglyceride, 32.7% high LDL, and 18.0% low HDL. 51 (84%) had either elevated transaminases. All had liver US, and 43 had FLD. WC was strongly associated with dyslipidemia and FLD (P=0.04 and 0.003). Conclusion: Dyslipidemia is common in overweight, obese children. FLD is prevalent in those with elevated liver transaminases. WC is an easy tool that can be utilized to screen for dyslipidemia and FLD in overweight and obese children. PMID- 30009052 TI - Simulation-based estimation of an automotive magnetorheological brake system performance. AB - Magnetorheological (MR) brakes, owing to their quick response, are being investigated as a possible candidate for substitution for the conventional hydraulic brakes of road vehicles. The MR brake system for a two-wheeler application was envisaged in this article. Based on analytical equations, the system was modelled in the MATLAB Simulink environment. The braking performance of the system in terms of the stopping distance was estimated with the help of the model. The output from the model was compared with the Indian Standard (IS) automotive brake standard requirement for two-wheelers. A single-disc MR brake system did not seem to satisfy this requirement. It took six or more MR disc brakes to meet the stopping distance requirement of the IS standard. Moreover, weight and space constraints may not allow these brakes to be used for automotive applications. With the current state of the technology, MR brakes do not fulfil the requirements of an automotive brake system. PMID- 30009051 TI - Phenotypic characterization of rhizobia nodulating legumes Genista microcephala and Argyrolobium uniflorum growing under arid conditions. AB - A phenotypic characterization of thirteen root nodule bacteria recovered from wild legumes (Genista microcephala and Argyrolobium uniflorum) growing in arid eco-climate zones (Northeastern Algeria) was conducted using analysis of sixty six phenotypic traits (carbohydrate and nitrogen assimilation, vitamin requirements, growth temperature, salinity/pH tolerance and enzyme production). Furthermore, SDS-PAGE profiles of total cell protein, antibiotic susceptibility and heavy metal resistance were performed. The results showed that the isolates can grow at pH 4 to 10, salt concentration (0-5%) and temperature up to 45 degrees C. The rhizobia associated with Genista microcephala and Argyrolobium uniflorum were able to produce different hydrolytic enzymes including cellulose, pectinase and urease, with remarkable tolerance to toxic metals such as zinc, lead, copper, and mercury. Numerical analysis of the phenotypic characteristics revealed that the rhizobial isolates formed four main distinct groups showing high levels of similarity with Gammaproteobacteria. The salt tolerant and heavy metals resistance patterns found among the indigenous rhizobial strains are reflecting the environmental stresses pressure and make the strains good candidates for plant successful inoculation in arid areas. PMID- 30009054 TI - Comment on "Evaluation of Complication Rates after Breast Surgery Using Acellular Dermal Matrix: Median Follow-Up of Three Years". PMID- 30009055 TI - Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates. AB - The design, synthesis, and development of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are respectable area of research. Novel Diclofenac Schiff's bases (M1, M2, M4, M7, and M8) were designed and synthesized, and their respective chemical structures were deduced using various spectral tools (IR, 1H NMR, 13C NMR, and MS). The compounds were synthesized via Schiff's condensation reaction and their anti-inflammatory activity was investigated applying the Carrageenan-induced paw edema model against Diclofenac as positive control. Percentage inhibition of edema indicated that all compounds were exhibiting a comparable anti-inflammatory activity as Diclofenac. Moreover, the anti-inflammatory activity was supported via virtual screening using molecular docking study. Interestingly compound M2 showed the highest in vivo activity (61.32% inhibition) when compared to standard Diclofenac (51.36% inhibition) as well as the best binding energy score (-10.765) and the virtual screening docking score (-12.142). PMID- 30009053 TI - Butenafine and analogues: An expeditious synthesis and cytotoxicity and antifungal activities. AB - The incidence of fungal infections is considered a serious public health problem worldwide. The limited number of antimycotic drugs available to treat human and animal mycosis, the undesirable side effects and toxicities of the currently available drugs, and the emergence of fungal resistance emphasizes the urgent need for more effective antimycotic medicines. In this paper, we describe a rapid, simple, and efficient synthetic route for preparation of the antifungal agent butenafine on a multigram scale. This novel synthetic route also facilitated the preparation of 17 butenafine analogues using Schiff bases as precursors in three steps or less. All the synthesized compounds were evaluated against the yeast, Cryptococcus neoformans/C. gattii species complexes and the filamentous fungi Trichophyton rubrum and Microsporum gypseum. Amine 4bd, a demethylated analogue of butenafine, and its corresponding hydrochloride salt showed low toxicity in vitro and in vivo while maintaining inhibitory activity against filamentous fungi. PMID- 30009056 TI - Evaluation of Skin and Soft Tissue Infection Outcomes and Admission Decisions in Emergency Department Patients. AB - Background: Skin and soft tissue infections are common presenting complaints for Emergency Department (ED) patients. Although they are common, there remain no definitive guidelines on decisions of admission for these patients. Objectives: To determine the influence of demographic and clinical information of those presenting with skin and soft tissue infection(s) (SSTI) on both disposition and treatment failure. Methods: We prospectively enrolled adults with SSTI seen at a large urban ED. Secondary outcome was treatment failure. Statistics utilized t tests and multivariate logistic regression. Results: We enrolled 125 subjects and 32 were admitted. 15.2% of patients failed treatment with both increasing age and infection area correlating with admission. IV drug use (IVDU) (OR: 10.2; 95% confidence interval [CI]: 1.9 to 50.0) and recent antibiotic use (OR: 2.9; 95% CI 1.003 to 8.333) independently predicted admission. Age and recent surgery in the area of infection (OR: 6.4; 95% CI 1.3 to 30.8) showed positive association with treatment failure. IV antibiotics (OR: 22.3; 95% CI 2.8 to 179.4) and admission (OR: 12.1; 95% CI 2.9 to 50.4) strongly predicted treatment failure. Conclusions: Age, infection size, IVDU, and recent antibiotics predicted admission. Age, recent surgery at infection site, IV antibiotics, and admission correlated with treatment failure. PMID- 30009057 TI - Concordance between Immunohistochemistry and Microarray Gene Expression Profiling for Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Statuses in Breast Cancer Patients in Lebanon. AB - Introduction: Accurate evaluation of estrogen and progesterone receptors and HER2 is critical when diagnosing invasive breast cancer for optimal treatment. The current evaluation method is via immunohistochemistry (IHC). In this paper, we compared results of ER, PR, and HER2 from microarray gene expression to IHC in 81 fresh breast cancer specimens. Methods: Gene expression profiling was performed using the GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix Inc). Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 status was performed using standard methods at a CAP-accredited pathology laboratory. Concordance rates, agreement measures, and kappa scores were calculated for both methods. Results: For ER, Kappa score was 0.918 (95% CI, 0.77.3-1.000) and concordance rate was 97.5% (95% CI, 91.4%-99.7%). For PR, Kappa score was 0.652 (95% CI, 0.405-0.849) and concordance rate was 86.4% (95% CI, 77% 93%). For HER2, Kappa score was 0.709 (95% CI, 0.428-0.916) and concordance rate was 97.5% (95% CI, 91.4%-99.7%). Conclusion: Our results are in line with the available evidence with the concordance rate being the lowest for the progesterone receptor. In general, microarray gene expression and IHC proved to have high concordance rates. Several factors can increase the discordance rate such as differences in sample processing. PMID- 30009058 TI - Feasibility of Ideal Cardiovascular Health Evaluation in a Pediatric Clinic Setting. AB - The feasibility of "point-of-care" screening for ideal cardiovascular health was explored in a pediatric specialty clinic setting. Children and adolescents aged 9 18 years (n=91) with treated and stabilized diseases were recruited at a pediatric endocrinology clinic. A table-top device was used to assay fingerstick samples for non-HDL cholesterol (non-HDL-C), which was used to divide participants into two groups based on the non-HDL-C threshold for comparison of the remaining metrics between groups. A significant number of children had low scores, and score frequency distribution was similar to larger retrospective studies, with few participants achieving none or all of the health metrics. Healthy diet was the metric least often achieved. Those with a non-HDL-C above the ideal threshold of 3.1 mmol/L (120 mg/dl) had a higher BMI percentile (p<0.01) and diastolic blood pressure percentile (p<0.05). We conclude that pediatric risk factor screening and scoring can be performed in a specialty clinic with meaningful cardiovascular health scores for patients and providers. Association of abnormal "point-of care" non-HDL-C levels with elevated BMI and blood pressure supports evidence for risk factor clustering and use of the ideal health construct in pediatric clinic settings. PMID- 30009059 TI - Fat Embolism Syndrome in Duchenne Muscular Dystrophy Patients: Early Recognition and Aggressive Therapy. AB - We describe two pediatric patients with Duchenne muscular dystrophy that presented with acute neurologic deterioration and hypoxic respiratory failure requiring mechanical ventilation. These cases fulfill the clinical criteria for Fat Embolism Syndrome. Early recognition and aggressive supportive therapy with mechanical ventilation, right ventricular afterload reduction, and blood transfusion led to survival without any residual effects from the event. Fat Embolism Syndrome needs to be considered early in the course of patients with Duchenne muscular dystrophy who present with respiratory and neurological symptoms. PMID- 30009060 TI - Pediatric Acute Promyelocytic Leukemia Presenting to the Emergency Department as Refusal to Ambulate. AB - A previously healthy 10-year-old girl presented to the emergency department (ED) with a headache and vomiting which resolved with oral NSAIDs. The patient returned two days later unable to ambulate with mental slowing and lower extremity bruising. Labs demonstrated marked leukocytosis, severe anemia and thrombocytopenia, and disseminated intravascular coagulation (DIC). Brain MRI showed multiple intracranial hemorrhages. A peripheral blood smear demonstrated blasts with many Auer rods. A diagnosis of acute promyelocytic leukemia (APL) was made and therapy including all-transretinoic acid (ATRA) was initiated. Neurologic status returned to baseline within 1 week in the pediatric intensive care unit. PMID- 30009061 TI - A Case of Euthyroid Graves' Ophthalmopathy in a Patient Sero-Negative for TSH Receptor Autoantibody. AB - We report of a case of Graves' ophthalmopathy presented solely with symptoms of the eyes with normal thyroid function tests and negative immunoreactive TSH receptor autoantibody. 40-year-old male was referred to our hospital due to 2 month history of ocular focusing deficit without any signs or symptoms of hyper- or hypothyroidism. Serum thyroid function tests and 99mTc uptake were both within the normal range. Anti-thyroid autoantibodies were all negative except for the cell-based assay for serum TSH receptor stimulating activity. Since orbital CT scan and MRI gave typical results compatible with Graves' ophthalmopathy, we treated the patients with corticosteroid pulse therapy and orbital radiation therapy, leading to a partial improvement of the symptoms. This case gives insights into the potential pathophysiologic mechanism underlying Graves' ophthalmopathy and casts light upon the difficulties of establishing the diagnosis in a euthyroid case with minimal positive results for anti-thyroid autoantibodies. PMID- 30009062 TI - Treatment of Bleeding Diathesis Associated with a Heparin-Like Anticoagulant in Plasma Cell Neoplasia Using Protamine. AB - The development of a heparin-like anticoagulant (HLAC) in plasma cell neoplasia has previously been described in clinical literature. Testing of this HLAC, primarily in vitro, has demonstrated that neutralization may be achieved with protamine sulfate, owing to antithrombin III cofactor activity. We report a case in which intravenous protamine sulfate was administered to a patient with IgG kappa monotypic multiple myeloma, which resulted in resolution of bleeding and coagulopathy, confirmed via objective laboratory data. Our case is intended to demonstrate that intravenous protamine sulfate should be considered in acute bleeding with plasma cell neoplasia. We review the literature to observe past experiences about this phenomenon. We postulate that chemotherapy, targeted therapies, and immunotherapies may also disrupt production of a HLAC. With further investigation, this strategy could be applicable in other hematological malignancies with bleeding diathesis, chiefly if the pathophysiology of the HLAC is precisely defined. PMID- 30009063 TI - Efficacy of Nivolumab in a Patient with Metastatic Renal Cell Carcinoma and End Stage Renal Disease on Dialysis: Case Report and Literature Review. AB - Treatment of patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease (ESRD) on dialysis poses a therapeutic challenge, particularly as this patient group was excluded from the pivotal clinical trials. In addition, there is uncertainty regarding drug dosing/pharmacokinetics, lack of safety and efficacy data, and potential for increased toxicity when using targeted therapy or immunotherapy for the management of patients with mRCC on dialysis. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor antibody, is indicated for the treatment of patients with mRCC who have received prior antiangiogenic therapy. Given the above-mentioned uncertainties, clinicians may be reluctant to use nivolumab for this patient population, leading to potential denial of life prolonging medications. We report the case of a 72-year-old gentleman with mRCC and ESRD on dialysis who received second-line nivolumab therapy and achieved an excellent symptomatic and radiological response, remaining progression-free for over 22 months. In addition, we have reviewed the pharmacokinetic data and published retrospective case studies to review the management options for patients with mRCC and ESRD on dialysis. PMID- 30009064 TI - Isolated Sporothrix schenckii Monoarthritis. AB - Sporothrix schenkii sensu lato is a rare cause of arthritis. Its course is indolent with lack of constitutional symptoms resulting in delayed presentation and diagnosis. It is a dimorphic fungus found ubiquitously in sphagnum moss, decaying vegetation, soil, and hay. Inoculation of dirt into the skin and soft tissues and, in rare instances, inhalation of aerosolized conidia from soil and plants can lead to infection. Subacute and chronic involvement of skin and subcutaneous tissues is the most common manifestation of sporotrichosis in immunocompetent hosts. In patients with underlying risk factors (HIV, alcoholism, diabetes mellitus, organ transplant patients, immunosuppressive medications, steroids, and malignancies), it can often have disseminated visceral, osteoarticular, meningeal, and pulmonary involvement. Sporothrical arthritis most commonly infects knee joint followed by hand and wrist joints. A culture of Sporothrix schenkii sensu lato is the gold standard for the diagnosis of sporotrichosis. Itraconazole is the drug of choice for osteoarticular sporotrichosis. We present a case of sporotrichal arthritis in a patient without skin or lymph node involvement who underwent treatment with itraconazole resulting in resolution of his symptoms. PMID- 30009065 TI - Retained Glass Fragment in the Cervical Spinal Canal in a Patient with Acute Transverse Myelitis: A Case Report and Literature Review. AB - A 50-year-old male presented with a one-day history of right leg weakness, numbness, and urinary retention. Weakness was present for two weeks but worsened significantly during the last 24 hours. On the right there was sensory loss in the leg and below the Th8 dermatome. On the left there was sensory loss below the Th10 dermatome and distal loss of temperature sensation. Past medical history revealed a cervical trauma 30 years ago when a glass chip lodged into the left side of the neck. The patient did not seek medical attention after removing it himself. No neurological symptoms followed the incident. No cervical manipulation or other physical trauma occurred before current symptom onset. Magnetic resonance (MR) imaging showed features consistent with myelitis at the level of C4-Th3. At the level of C6-C7, a T1 and T2 hypointense lesion was noted. On computed tomography, this lesion was hyperdense and occupied the spinal canal and the left intervertebral foramen. It was deemed to be a glass fragment. Surgical removal was withheld because the fragment was clinically silent for 30 years, the risk of surgical removal would outweigh the benefits and the patient did not prefer surgical treatment. Acute demyelinating transverse myelitis was diagnosed and treated with methylprednisolone. 10 months later MR features of myelitis resolved and the patient's neurological condition improved. Our case shows that foreign bodies in the cervical spinal canal can remain asymptomatic for up to 30 years. In the case of a long asymptomatic retention period the need for surgical removal of a foreign body must be carefully evaluated, taking into account the probability that a foreign body is the cause of current symptoms, risk of a foreign body causing damage in the future, risk of damage to the spinal cord during removal, and probability of therapeutic success. PMID- 30009066 TI - Absent Ductus Venosus Associated with Partial Liver Defect. AB - Absent ductus venosus (ADV) is a rare vascular anomaly. We describe a fetus/neonate with ADV with a partial liver defect. A 41-year-old woman was referred to our institute because of fetal cardiomegaly detected by routine prenatal ultrasound, which revealed absence of ductus venosus with an umbilical vein directly draining into the right atrium, consistent with extrahepatic drainage type of ADV. She vaginally gave birth to a 3,096-gram male infant at 38 weeks of gestation. Detailed ultrasound examination revealed a defect of the hepatic rectangular leaf at half a month postnatally. He showed normal development at 1.5 years of age with the liver abnormality and a Morgagni hernia. Liver morphological abnormality should also be considered as a complication of ADV. PMID- 30009067 TI - Endoscopic Surgery under Fluoroscopic Guidance Is Useful for Diagnosing and Treating Epiphyseal Osteomyelitis Caused by Mycobacterium Species. AB - Osteomyelitis caused by Mycobacterium species may be difficult to diagnose and treat. We report a case of treatment for osteomyelitis caused by Mycobacterium species in the epiphysis of the right proximal tibia. A 28-month-old boy presented to a hospital with symptoms of fever and right knee pain. He had been vaccinated with Mycobacterium bovis Bacille Calmette-Guerin (BCG) at five months of age. The epiphyseal radiolucent lesion had increased in size and extended to the metaphysis through the physis on a plain radiograph of the right proximal tibia. Surgical drainage and curettage of the lesion were performed with an endoscope under C-arm fluoroscopy. The intraoperative histopathological examination revealed granulation tissue composed of caseous necrosis and Langerhans giant cells, revealing Mycobacterium species to be the causative pathogen. Because of suspected osteomyelitis caused by BCG, the antituberculosis drugs were administered orally from an early postoperative stage. A plain radiograph taken eight months postoperatively showed bone regeneration in the area of curettage and a slight physeal bridge, in addition to normalization of the inflammatory response on blood sampling. It was possible to perform accurate diagnosis and rapid treatment for epiphyseal osteomyelitis caused by Mycobacterium species using endoscopic surgery under fluoroscopic guidance. PMID- 30009069 TI - A Rare Case of Large Schwannoma of the Parapharyngeal Space. AB - Schwannoma originating from the peripheral nerves is a rare lesion of the parapharyngeal space. The special traits of the presented case included the following: the patient presented with slowly progressing dysphagia, speech difficulties, jaw numbness, and taste dysfunction. A dislocated lateral pharyngeal wall with mild inflammatory changes of the oropharyngeal mucosa was observed during pharyngoscopy. The radiological and histological characteristics of the neoplasm are consequently presented. Special emphasis is placed on the surgical treatment of the tumor. PMID- 30009068 TI - A Case of Osteomyelitis after Calcaneal Fracture Treated by Antibiotic-Containing Calcium Phosphate Cements. AB - Calcaneal osteomyelitis (CO) is considered to be difficult to cure when it turned into a chronic phase. We report one case of calcaneal osteomyelitis which arises after the operation of calcaneal fracture. Remission was obtained by performing curettage of the infected cancellous bone of the calcaneal body and filling antibiotic-containing calcium phosphate cements (CPC) within its bone defect. This one-stage surgery is useful to treat calcaneal osteomyelitis. PMID- 30009070 TI - Rapidly Growing Pancreatic Adenocarcinoma Presenting as an Irreducible Umbilical Hernia. AB - Hernia sacs are a common anatomic pathology specimen, which rarely contain malignancy. We present a case of rapidly growing pancreatic adenocarcinoma, which initially presented as metastasis to an umbilical hernia sac. The patient was a 55-year-old male with a two-year history of umbilical hernia. Two months prior to herniorrhaphy, the hernia became painful and the patient experienced nausea and weight loss. The gross examination did not reveal distinct lesions. Microscopically, the hernia sac was diffusely infiltrated by moderately differentiated adenocarcinoma, which was positive for CK7 and pancytokeratin and negative for TTF-1, CK20, PSA, and CDX2. Clinical laboratory tests found elevated levels of CA 19-9 and CEA. Computed tomography scan with intravenous contrast showed a 5 cm ill-defined and hypoattenuating mass involving the pancreatic tail and body, as well as numerous ill-defined lesions in the liver and peritoneal carcinomatosis. The patient had an earlier noncontrast computed tomography scan four months prior to the surgery, which did not detect any lesions in the abdomen. This case highlights the importance of intravenous contrast with computed tomography for the evaluation of pancreatic lesions and also emphasizes the importance of thorough histologic evaluation of hernia sacs for the detection of occult malignancy. PMID- 30009071 TI - Incontinentia Pigmenti Misdiagnosed as Neonatal Herpes Simplex Virus Infection. AB - Incontinentia pigmenti (IP) is an X-linked dominant neurocutaneous syndrome with ophthalmologic, neurologic, cutaneous, and dental manifestations and in most cases antenatally lethal in boys. Occasionally, typical IP may occur in boys due to Klinefelter syndrome or a genomic mosaicism. Skin lesions are observed in 4 stages: blistering, verrucous linear plaques, swirling macular hyperpigmentation, followed by linear hypopigmentation that develop during adolescence and early adulthood. Neonatal herpes simplex virus (HSV) infection can be manifested in 3 forms: localized, disseminated, and central nervous system (CNS) involvement. Timely diagnosis and treatment of neonatal HSV infection is critical. In this case report, we present a 12-day female newborn with a history of maternal genital HSV in second trimester and vesicular lesions on the upper and lower limbs that was appeared at first hours of life. She was admitted in the maternity hospital that was born and was treated by antibiotic and acyclovir for 11 days. Then, she readmitted for her distributed vesicular lesions. The results of blood and CSF for HSV PCR were negative. Eventually the diagnosis for incontinentia pigmenti was made by consultation with a dermatologist, and skin biopsy confirmed the diagnosis. PMID- 30009072 TI - Stenotrophomonas maltophilia Meningitis in a Term Healthy Neonate: A Case Report and Literature Review. AB - Stenotrophomonas maltophilia is an environmental bacterium of growing concern due to its multidrug resistance and pathogenic potential. It is considered an opportunistic pathogen of nosocomial origin most of the time, targeting a specific patients' population. We describe a case of a previously healthy full term neonate who was found to have S. maltophilia meningitis and was successfully treated with a combination of Trimethoprim-Sulfamethoxazole and Ciprofloxacin. PMID- 30009073 TI - Intramural Bowel Hematoma Presenting as Small Bowel Obstruction in a Patient on Low-Molecular-Weight Heparin. AB - There is increasing use of low-molecular-weight heparin (LMWH) for treatment of pediatric thromboembolic disease as it has been shown to be safe and effective. It has several advantages over unfractionated heparin, such as reduced need for monitoring, easier route of administration, decreased risk of heparin-induced thrombocytopenia, and lack of drug-drug interactions. Nevertheless, LMWH still poses a bleeding risk as with any anticoagulant therapy. We present the case of a 4-year-old boy who was placed on LMWH for a catheter-related deep venous thrombosis in the setting of intractable seizures and subsequently developed a small bowel obstruction secondary to a suspected intussusception. He underwent exploratory laparotomy and was found to have an intramural bowel hematoma. Prior to this bleed, the patient had been monitored daily, and his anti-Xa levels were found to be in the therapeutic range. This case highlights the need for a high index of suspicion for spontaneous bleeding even in the setting of therapeutic anti-Xa levels. PMID- 30009074 TI - Nontyphi Salmonella Empyema with Bronchopleural Fistula in a Patient with Human Immunodeficiency Virus. AB - Patients with human immunodeficiency virus (HIV) have an increased risk of inoculation with nontyphoid Salmonella compared to the general population. While nontyphoid Salmonella commonly manifests as gastroenteritis, Salmonella bacteremia can be seen in patients with HIV. We present a case of disseminated Salmonellosis in a patient with HIV complicated by bronchopleural fistula and secondary empyema. Case Presentation. A 40-year-old African American male with HIV noncompliant with HAART therapy presented with complaints of generalized weakness, weight loss, cough, night sweats, and nonbloody, watery diarrhea of four weeks' duration. A computed tomography (CT) scan demonstrated a bilobed large, thick-walled cavitary lesion in the right upper lobe communicating with the pleural space to form a bronchopleural fistula. Thoracentesis yielded growth of nontyphi Salmonella species consistent with empyema; he was treated with intravenous Ceftriaxone and underwent placement of chest tube for drainage of empyema with instillation of alteplase/dornase twice daily for three days. Repeat CT chest showed a hydropneumothorax. The patient subsequently underwent video assisted thoracoscopy with decortication. The patient continued to improve and follow-up CT chest demonstrated improved loculated right pneumothorax with resolution of the right bronchopleural fistula and resolution of the cavitary lesions. Discussion. We describe one of the few cases of development of bronchopulmonary fistula and the formation of empyema in the setting of disseminated Salmonella. Empyema complicated by bronchopulmonary fistula likely led to failure of intrapleural fibrinolytic therapy and the patient ultimately required decortication in addition to antibiotics. While Salmonella bacteremia can be seen in immunocompromised patients, extraintestinal manifestations of Salmonella infection such as empyema and bronchopleural fistulas are uncommon. Bronchopleural fistulas most commonly occur as a postoperative complication of pulmonary resection. Conclusions. This case highlights the unusual pulmonary manifestations that can occur due to disseminated Salmonella in an immunocompromised patient as well as complex management decisions related to these complications. PMID- 30009075 TI - Mandibular Osteitis Leading to the Diagnosis of SAPHO Syndrome. AB - Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a disorder characterized by pustular skin lesions and osteoarticular lesions. Mandibular involvement of SAPHO syndrome is clinically rare, and it is difficult to reach a diagnosis of SAPHO syndrome from only mandibular manifestations. This report describes the case of a 26-year-old woman who presented with mandibular osteitis. Orthopantomogram and computed tomography showed sclerotic change of the right body of the mandible with periosteal reaction without odontogenic infection, which suggested the possibility of SAPHO syndrome. Detailed medical interview found that she had a history of palmoplantar pustulosis treated at a local dermatology clinic and additional bone scintigraphy showed diffuse increased uptake in the right mandible, as well as in the sternum and the sternocostoclavicular joints. She was eventually diagnosed as having SAPHO syndrome. We should consider SAPHO syndrome when we encounter a patient with mandibular osteitis of unknown etiology. PMID- 30009076 TI - Large Bowel Obstruction Subsequent to Resected Lobular Breast Carcinoma: An Unconventional Etiology of Malignant Obstruction. AB - Introduction: Breast cancer metastasis to the gastrointestinal tract is rare and mostly limited to case reports which recommend consideration of metastasis when breast cancer patients particularly those with invasive lobular carcinoma present with new gastrointestinal complaints. Presentation of case: We report a 50-year old female who presented with gastrointestinal symptoms of nausea and vomiting determined to be the result of large bowel obstruction secondary to rectosigmoid metastasis and carcinomatosis of breast invasive lobular carcinoma. She was treated with diverting loop sigmoid colostomy for her large bowel obstruction. Discussion: Our case reflects the importance of gastrointestinal surveillance of patients with a history of breast cancer. Current National Comprehensive Cancer Network (NCCN) guidelines for stage I-II breast cancer suggest posttreatment lab and imaging evaluation for metastasis only if new symptoms present. Conclusion: We observed an unusually rapid disease progression, requiring evaluation of new gastrointestinal symptoms. Assessment for GI tract metastatic involvement should be done as early as progression to symptomatic disease can result in need for further invasive surgery in advanced stages of cancer. PMID- 30009077 TI - Novel Approach for Endoscopic Management of Duodenal Injury during Perirenal Infected Haematoma Drainage after Shock-Wave Lithotripsy. AB - Background. Gaining percutaneous access during percutaneous nephrolithotomy (PNL) can be complicated with the bowel injury. We report a novel approach of management of duodenal injury complicating percutaneous drainage of infected haematoma after Shock-Wave Lithotripsy (SWL). Case Presentation. A 57-year-old patient with the 15 mm right pelvic kidney stone underwent uneventful SWL. Patient visited emergency department 3 days later with high fever and chills with severe right flank pain. CT urography revealed lower pole kidney injury with signs of infected hematoma due to low attenuation areas but without signs of obstruction or urine leakage. Infected haematoma was drained percutaneously under ultrasound and X-ray control and a pigtail catheter 10 Fr was left beneath the lower pole of the right kidney. Postoperatively duodenal injury was suspected due to amber color, low creatinine, and high bilirubin level in the drainage output. CT demonstrated that the pigtail of the drain had entered the second part of the duodenum. Catheter was withdrawn and defect of the duodenal wall was stapled with four staples endoscopically. After 2 days of fasting patient was allowed to start oral food intake and was discharged on the 5th day. Conclusion. Injury of the duodenum during percutaneous kidney manipulation is an extremely rare complication. Conservative management consisting of endoscopic stapling of the duodenal wall defect is a safe and feasible approach to expediting the recovery of the patient. PMID- 30009078 TI - A Rare Case of Human Diphallia Associated with Hypospadias. AB - Diphallia or penile duplication is a rare congenital variant with an estimated frequency of 1 per 5 to 6 million live births. The extent of duplication varies widely and typically occurs with other malformations including urogenital, gastrointestinal, and musculoskeletal anomalies. Here we present a case of human diphallia that was detected during routine dissection of an 84-year-old cadaver. Upon thorough examination, this case was characterized as a complete bifid penis which was accompanied by hypospadias with no other anatomical abnormalities detected. To gain insights into the etiology of this case, we analyzed DNA procured from the body for putative genetic variants using Next Generation Sequencing (NGS) technology. Our results support clinical observations consistent with human diphallia being a polygenic syndrome and identify new genetic variants that might underlie its etiology. PMID- 30009079 TI - Urachal Carcinoma with Peritoneal Dissemination Treated with Chemotherapy and Surgical Resection Leading to Prolonged Survival with No Recurrence. AB - A 56-year-old man was admitted to our hospital for urachal carcinoma with peritoneal dissemination. He received first-line chemotherapy with gemcitabine and cisplatin. After the fifth cycle, a computed tomography (CT) scan revealed abdominal fluid, and his serum tumor marker levels were increased. The patient was started on second-line therapy with FOLFIRI. After 11 cycles, his tumor decreased in size and no new metastatic lesions were detected. The patient underwent complete tumor resection with partial cystectomy and pelvic lymph node dissection. The tumor was removed, along with adhering surrounding organs, including the omentum, peritoneum, abdominal rectus muscle, and vermiform appendix. Although pathological examination confirmed peritoneal dissemination, his tumor markers normalized soon after surgery. The patient has survived 62 months after surgery without any adjuvant therapy and with no evidence of recurrence. To our knowledge, this is the longest duration of survival without recurrence of a patient with urachal carcinoma with peritoneal dissemination who received multimodal therapy. PMID- 30009080 TI - Tobacco Use and Associated Factors in Patients Presenting to a Psychiatric Emergency Room. AB - Background: Rates of cigarette smoking among the public and individuals with mental illness have been well documented. Studies have demonstrated that prevalence of smoking among individuals with mental illness remains elevated compared to the general population and as a distinct subgroup, individuals with mental illness consume more than a third of cigarettes sold in the U.S. However, information on rates of smoking among patients presenting to a psychiatric emergency room (ER) is lacking. This study assesses this understudied population for smoking prevalence and associated factors. Methods: A retrospective chart review of 203 distinct psychiatric ER patients was conducted. Demographics, tobacco use, substance use, psychiatric diagnoses, and family history were noted and analyzed with SPSS. Result: Tobacco use rates were noted to be nearly fifty percent and significant associations were found with active suicidal ideation, alcohol use disorders, illicit drug use disorders, and history of prior psychiatric hospitalization. Conclusion: Tobacco use among psychiatric ER patients is much higher than that of the general population and associated with active suicidal ideations, alcohol use disorders, and illicit substance use disorders. These findings should be considered in the evaluation and expectant management of these patients by their clinicians and healthcare providers. PMID- 30009082 TI - Erratum: Utility of magnetic resonance cisternography with intrathecal gadolinium in detection of cerebrospinal fluid fistula associated with Mondini dysplasia in a patient with recurrent meningitis: Case report and literature review. AB - [This corrects the article on p. 92 in vol. 9, PMID: 29770252.]. PMID- 30009083 TI - Posterior longitudinal ligament and its implications in intradural cervical disc herniation: Case report and review of the literature. AB - Background: Intradural disc herniations (IDH) are rare, particularly in the cervical spine, where they account for less than 5% of all discs. Adhesions between the ossified/calcified posterior longitudinal ligament (OPLL), dura, and ossified/calcified disc herniations increase the complexity of resecting these cervical lesions. Case Description: A 42-year-old male presented with a rapidly progressive cervical myelopathy over a 2-month period. This was attributed to an ossified/calcified intradural cervical disc herniation in conjunction with OPLL. The anterior cervical discectomy and fusion (ACDF) resulted in a dural defect but there was no cerebrospinal fluid (CSF) fistula as the arachnoid membrane remained intact. Had there been a CSF leak, it would have warranted both wound-peritoneal (WP) and lumbo-peritoneal shunts (LP). The surgeons should have anticipated that a CSF leak would likely occur prior to performing the ACDF, and should have prophylactically prepared and draped the abdomen for a potential WP, followed by a LP shunt. Three months postoperatively, the patient's proprioceptive deficit improved, and he almost completely recovered motor function. Conclusion: Performing an ACDF for resection of an intradural calcified/ossified disc with OPLL often results in both a dural defect and CSF fistula. As the arachnoid membrane rarely remains intact, the spine surgeon should be prepared to immediately perform both a WP shunt, and subsequently, an LP. In this case, following an ACDF, resection of an intradural ossified disc with OPLL resulted in an isolated dural defect without a CSF fistula and did not require no dural repair or shunting procedures. PMID- 30009081 TI - Assessing the value of screening tools: reviewing the challenges and opportunities of cost-effectiveness analysis. AB - Background: Screening is an important part of preventive medicine. Ideally, screening tools identify patients early enough to provide treatment and avoid or reduce symptoms and other consequences, improving health outcomes of the population at a reasonable cost. Cost-effectiveness analyses combine the expected benefits and costs of interventions and can be used to assess the value of screening tools. Objective: This review seeks to evaluate the latest cost effectiveness analyses on screening tools to identify the current challenges encountered and potential methods to overcome them. Methods: A systematic literature search of EMBASE and MEDLINE identified cost-effectiveness analyses of screening tools published in 2017. Data extracted included the population, disease, screening tools, comparators, perspective, time horizon, discounting, and outcomes. Challenges and methodological suggestions were narratively synthesized. Results: Four key categories were identified: screening pathways, pre-symptomatic disease, treatment outcomes, and non-health benefits. Not all studies included treatment outcomes; 15 studies (22%) did not include treatment following diagnosis. Quality-adjusted life years were used by 35 (51.4%) as the main outcome. Studies that undertook a societal perspective did not report non health benefits and costs consistently. Two important challenges identified were (i) estimating the sojourn time, i.e., the time between when a patient can be identified by screening tests and when they would have been identified due to symptoms, and (ii) estimating the treatment effect and progression rates of patients identified early. Conclusions: To capture all important costs and outcomes of a screening tool, screening pathways should be modeled including patient treatment. Also, false positive and false negative patients are likely to have important costs and consequences and should be included in the analysis. As these patients are difficult to identify in regular data sources, common treatment patterns should be used to determine how these patients are likely to be treated. It is important that assumptions are clearly indicated and that the consequences of these assumptions are tested in sensitivity analyses, particularly the assumptions of independence of consecutive tests and the level of patient and provider compliance to guidelines and sojourn times. As data is rarely available regarding the progression of undiagnosed patients, extrapolation from diagnosed patients may be necessary. PMID- 30009084 TI - Microsurgical clipping for anterior communicating artery aneurysm associated with the accessory anterior cerebral artery via the pterional approach. AB - Background: Accessory anterior cerebral artery (ACA), a type of median artery of anomalous triplicate ACA, is not rare, but aneurysms of the anterior communicating artery (ACoA) associated with accessory ACA can be a considerable challenge to treat surgically based on the morphological features of the ACoA complex. Case Description: A 35-year-old man was admitted to our hospital with severe headache and subsequent loss of consciousness. Initial computed tomography (CT) showed typical findings of subarachnoid hemorrhage in the basal cistern and three-dimensional CT angiography revealed an ACoA aneurysm arising from the trifurcation of the accessory ACA, the branching point of the ACoA, and the right A1 or A2 segment of the ACA. The aneurysmal fundus projected superolaterally to the right, and was treated via a right-sided pterional approach. The aneurysm was behind the ipsilateral A2 segment of the ACA and the accessory ACA was hidden behind the aneurysm. The aneurysm was successfully obliterated with clipping using a straight fenestrated Yasargil titanium clip. Complete aneurysm occlusion and patency of both the A2 segment of the ACA and the accessory ACA were confirmed intraoperatively by indocyanine green angiography. Conclusion: In treating this aneurysm via the pterional approach, selection of approach side it is critical to preserve prevent the patency of the accessory ACA and to simultaneously perform aneurysm clipping without leaving a neck remnant. Selecting the optimal approach based on preoperative neuroimaging of which side will allow both these actions is important. PMID- 30009085 TI - Use of intraoperative X-ray to differentiate between reducible versus irreducible atlantoaxial dislocation. AB - Background: The treatment and classification of atlantoaxial dislocations (AADs) remain controversial. Here, we utilized intraoperative X-ray to differentiate between reducible and irreducible AADs. Methods: Five patients were diagnosed as having irreducible AAD on dynamic and post-traction X-rays. Under general anesthesia, they were placed prone in a neutral position utilizing skeletal traction. The X-rays and motor evoked potential (MEP), were then monitored before, during, and after placing a thumb on the C2 spinous process and pushing it anteriorly to attain reduction. Results: The intraoperative X-ray confirmed reducibility of AAD in four patients; they subsequently underwent a C1-C2 posterior fusion, which maintained that reduction. For the one patient with an irreducible AAD (despite thumb maneuver), an anterior release was required first to attain reduction, followed by posterior C1-C2 fusion. Conclusion: Here, we divided irreducible AAD into two categories: a) reducible-utilizing a thumb maneuver to compress/push the C2 spinous process forward with the patient positioned prone and b) irreducible-those who cannot be reduced with this technique. A posterior only approach was sufficient for those with "reducible" AAD, whereas those who could not be reduced required an anterior release followed by posterior fusion. PMID- 30009086 TI - Adult intramedullary epidermoid cyst without spinal dysraphism: A case report. AB - Background: Intramedullary epidermoid cyst (IEC), typically associated with spinal dysraphism, is rare, with fewer than 80 such cases reported in the literature. Here we present an adult with an IEC without spinal dysraphism. Case Description: A 41-year-old female presented with the gradual onset of a progressive spastic paraparesis attributed to a magnetic resonance imaging (MRI) documented D8-9 intramedullary lesion. Following microsurgical excision of the IEC, she fully recovered. Conclusion: IECs are rare lesions, typically found in conjunction with spinal dysraphism. Utilizing MRI studies to document the lesion location, gross total microsurgical excision is the procedure of choice. Early excision of these benign lesions maximizes functional recovery. PMID- 30009087 TI - Retained distal protection device during carotid artery stenting necessitating carotid endarterectomy: A complication and management considerations. AB - Background: Neuroendovascular techniques have significantly altered the treatment paradigm of cerebrovascular diseases. Since the introduction of distal cerebral protection devices (DCPD), the incidence of embolic strokes during carotid artery stenting (CAS) has been significantly reduced. Treatment guidelines for retained foreign bodies in the cerebral vasculature do not exist. Case Description: Here, we present the case of an 88-year-old male who, during carotid artery angioplasty and stenting for symptomatic carotid artery stenosis, suffered from a retained distal protection device ultimately requiring open surgical carotid endarterectomy including removal of the retained device and stent. Conclusions: Carotid artery angioplasty and stenting utilizing distal protection devices is a commonly employed technique that may rarely result in retained devices. Knowledge of how to retrieve foreign bodies and the salvage techniques are essential to prevent complications from CAS. PMID- 30009088 TI - Catalytic Asymmetric Intermolecular Allylic Functionalization of Unactivated Internal Alkenes. AB - The asymmetric allylic functionalization of unactivated internal alkenes is an emerging strategy for the conversion of simple unsaturated starting materials into a diverse range of enantioenriched products. This Perspective summarizes the development of reactions wherein a chiral catalyst facilitates the intermolecular stereoselective reaction between an achiral unactivated internal alkene and a reagent. PMID- 30009089 TI - The Effects of Preeclampsia on Perinatal Risks and Infant Temperaments Among Mothers With Antenatal Depression. AB - Importance: Preeclampsia and depression are two most prevalent disorders known to affect pregnant women and unborn infant. However, few studies have prospectively examined the adverse influence of the in-utero exposures to the two disorders on the optimal development in their offspring, including mortality, adverse birth outcomes, and infant temperament styles. Objectives: (1) To examine whether exposures to preeclampsia and antenatal depression were associated with developmental indices of offspring at birth and temperament at 3 months; and (2) To evaluate how preeclampsia and antenatal depression associated with offspring temperamental style. Design: Prospective cohort study with regular assessment of mother's blood pressure at each prenatal visit: offspring were followed till 3 months. Setting: Two prenatal clinics, New York City, USA. Participants: A cohort of 233 pregnant women was followed throughout pregnancy. Of those, 141 provided ratings of infant temperament at three months. Exposures: Diagnostic outcome of maternal depression by clinical interviewers blind to preeclampsia status, were ascertained using the Structured Clinical Interview for DSM-IV Axis I Disorders. The development of preeclampsia, defined by the onset of hypertension (> 140/90 mm HG) after 20 weeks' gestation, accompanied by 300 mg of protein, monitored via electronic medical records. Main Outcome Measures: Birth outcomes were assessed via standardized ratings at delivery. Infant temperament was reported by the mother at three months, using 91-item IBQ-R (Infant Behavioral Questionnaire Revised). Results: Preeclampsia was associated with an over 5-fold increased risk for fetal/infant mortality, a 3- to 7-fold increased risk for poorer birth outcomes, and flatter affect and distress in infants. Furthermore, infants born to preeclamptic mothers with co-occurring depression displayed lower levels of smile/laughter, high-intensity pleasure seeking behavior, perceptual sensitivity, and approach behavior. Conclusion: Preeclampsia was associated with a few difficult temperament styles in the first three months after birth. Moreover, its negative impact was amplified by mother's antenatal depression. Our findings regarding additive risk for negative infant outcomes in babies exposed to preeclampsia and antenatal depression suggests that the development of early detection programs to identify and monitor women who are at heightened risk for these conditions can potentially have a positive influence on long-term infant neurobehavioral development. PMID- 30009090 TI - Parafoveal Nonperfusion Analysis in Diabetic Retinopathy Using Optical Coherence Tomography Angiography. AB - Purpose: To describe a new technique for mapping parafoveal intercapillary areas (PICAs) using optical coherence tomography angiography (OCTA), and demonstrate its utility for quantifying parafoveal nonperfusion in diabetic retinopathy (DR). Methods: Nineteen controls, 15 diabetics with no retinopathy (noDR), 15 with nonproliferative diabetic retinopathy (NPDR), and 15 with proliferative diabetic retinopathy (PDR) were imaged with 10 macular OCTA scans. PICAs were automatically delineated on the averaged superficial OCTA images. Following creation of an eccentricity-specific reference database from the controls, all PICAs greater than 2 SD above the reference means for PICA area and minor axis length were identified as nonperfused areas. Regions of interest (ROI) at 300 MUm and 1000 MUm from the foveal avascular zone (FAZ) margin were analyzed. Percent nonperfused area was defined as summed nonperfused areas divided by ROI area. Values were compared using Kruskal-Wallis and post-hoc Mann-Whitney U tests. Results: Median values for total percent nonperfused area at the 300-MUm ROI were 2.09, 2.44, 18.08, and 27.55 in the control, noDR, NPDR, and PDR groups, respectively. Median values at the 1000-MUm ROI were 3.10, 3.31, 13.42, and 23.00. While there were no significant differences between the control and noDR groups, significant differences were observed between all other groups at both ROIs. Conclusions: Percent nonperfused area can quantify parafoveal nonperfusion in DR and can be calculated through automatic delineation of PICAs in an eccentricity-specific manner using a standard deviation mapping approach. Translational Relevance: Percent nonperfused area shows promise as a metric to measure disease severity in diabetic retinopathy. PMID- 30009091 TI - Impact of Dry Eye Disease on Vision Quality: An Optical Quality Analysis System Study. AB - Purpose: We evaluated the relationship between ocular surface clinical tests and quality of vision in patients with dry eye disease (DED). Methods: In this study, 136 eyes of 72 dry eye patients were evaluated retrospectively using the ocular surface disease index (OSDI), measurement of tear film break-up time (TBUT), the Oxford score, Van Bijsterveld score, and Schirmer I test. Quality of vision was assessed with the optical quality analysis system (OQAS) using the objective scatter index (OSI) recorded over 20 seconds without blinking. Correlations between dry eye symptoms and signs, and OSI measurements were evaluated. Results: The OSI and OSI standard deviation (OSI SD) were correlated with TBUT (r = -0.21, P = 0.013 and r = -0.18, P = 0.038, respectively), Oxford score (r = 0.31, P = 0.0002 and r = 0.18, P = 0.032, respectively), and the Van Bijsterveld score (r = 0.33, P = 0.0001 and r = 0.25, P = 0.003, respectively). The OSI also was correlated with the Schirmer test (r = -0.19, P = 0.025), OSDI (r = 0.17, P = 0.04), and the ocular symptoms subscale of the OSDI (r = 0.21, P = 0.01). OSI SD was correlated with the environmental triggers subscale of the OSDI (r = 0.21, P = 0.016). Conclusions: Quality of vision measured with the OQAS was correlated with dry eye symptoms and signs. The OQAS could be a useful tool to better evaluate visual function in patients with DED. Translational Relevance: The OQAS provides a better understanding of patient complaints about alteration of vision quality. It might be useful to integrate this objective system in severity assessments and follow-up of DED, especially for treatment evaluations. PMID- 30009092 TI - The impact of an emotionally expressive writing intervention on eating pathology in female students. AB - Introduction: Previous research demonstrating emotional influences on eating and weight suggest that emotionally expressive writing may have a significant impact on reducing risk of eating pathology. This study examined the effects of writing about Intensely Positive Experiences on weight and disordered eating during a naturalistic stressor. Method: Seventy-one female students completed an expressive or a control writing task before a period of exams. Both groups were compared on BMI (kg/m2) and the Eating Disorder Examination - Questionnaire (EDE Q) before the writing task and at 8-week follow-up. A number of secondary analyses were also examined (to identify potential mediators) including measures of attachment, social rank, self-criticism and self-reassurance, stress and mood. Results: There was a significant effect of intervention on changes in the subscales of the EDE-Q (p = .03). Specifically, expressive writers significantly reduced their dietary restraint while those in the control group did not. There was no significant effect of the intervention on changes in BMI or the other subscales of the EDE-Q (Eating, Weight and Shape Concern). There was also no effect of writing on any of the potential mediators in the secondary analyses. Discussion: Emotionally expressive writing may reduce the risk of dietary restraint in women but these findings should be accepted with caution. It is a simple and light touch intervention that has the potential to be widely applied. However, it remains for future research to replicate these results and to identify the mechanisms of action. PMID- 30009093 TI - 2017 Writing Contest Undergraduate Winner: Pathways to Preventable Hospitalizations for Filipino Patients with Diabetes and Heart Disease in Hawai'i. AB - Filipinos are one of the fastest growing Asian ethnic groups in the United States, yet little is known about how to specifically address the varying health needs of the Filipino community with diabetes and heart disease. This is a problem because rates of potentially preventable hospitalizations (PPH) are high for Filipinos with these conditions. A PPH is a hospitalization that could potentially have been avoided with better access to quality primary care. Patients over 21 years of age with heart disease or diabetes and who were hospitalized at the Queen's Medical Center with a PPH were recruited to complete a face-to-face interview eliciting the patients' perspectives on key factors leading to this hospitalization (n=102). This study focused on a subset of Filipino patients (n=21). Two independent coders reviewed interviews to identify factors leading to their PPH. A majority of the Filipino respondents identified social vulnerabilities as the most common factor that led to their hospitalization, including financial challenges, limited social support, and life instability. Many respondents also noted challenges with the healthcare system as precipitating their hospitalization, including poor communication/coordination, management plan issues, and bad experience with their healthcare providers. Cultural and language barriers were also identified by Filipino patients as challenges leading to their hospitalizations. These findings emphasize the importance of considering patients' perspectives of the barriers they face inside and outside of healthcare facilities. PMID- 30009094 TI - The Effect of a Targeted Educational Activity on Obstetrics and Gynecology Resident In-Training Examination Scores. AB - The objective of this study was to compare the examination scores before and after implementation of a study program based on high yield topics on the Council of Resident Education in Obstetrics and Gynecology (CREOG) In-Training Examination. This prospective cohort study compared scores from academic years 2012 to 2014 of University of Hawai'i obstetrics and gynecology residents who participated in a directed study program based on selected high yield topics from the CREOG Test Item Summary Booklet. Topics were considered high yield if more than 75% of the program residents answered the topic questions incorrectly during the immediately preceding CREOG In-Training Examination administration. Residents were assigned topics to research and present at monthly teaching sessions. The presentations were made accessible in a wiki website. The intervention was initiated in 2012 and discontinued in 2013. The primary outcome was the difference among CREOG In-Training Examination scores before the study program, during the study program, and after the study program was discontinued. Only scores of residents who sat for all three exams were included. Eleven residents were present during the duration of the study period and sat for all three CREOG examinations. During the year of the educational activity, paired individual resident CREOG exams scores increased significantly from the 2012 CREOG administration (mean = 194.7) to the 2013 CREOG administration (mean = 208.2). These findings demonstrate that the CREOG Test Item Summary Booklet and the wiki platform can be used to effectively direct educational efforts resulting in improvements in CREOG examination performance. PMID- 30009095 TI - Medical School Hotline: Continuing Medical Education at the John A. Burns School of Medicine. PMID- 30009096 TI - Insights in Public Health: Equitable Access to Abortion Care in Hawai'i: Identifying Gaps and Solutions. AB - Despite a progressive legislative landscape, some women in Hawai'i lack access to abortion care. Those in the military, undocumented immigrants, and people living in rural areas and on neighbor islands face significant barriers to timely and affordable abortion care. Evaluating these gaps in access can help identify key areas for policy improvement to ensure health equity in Hawai'i. PMID- 30009098 TI - Ranolazine for Prevention of Atrial Fibrillation after Cardiac Surgery: A Systematic Review. AB - Postoperative atrial fibrillation (POAF) remains a major risk after cardiac surgery and is associated with an increased risk of stroke, length of stay, mortality, and cost. Ranolazine, an anti-anginal drug, also has anti-arrhythmic properties. The present study is to evaluate the effectiveness of ranolazine in preventing POAF after cardiac surgery. We searched the literature for clinical studies published up to August 2017 with a pre-defined inclusion and exclusion criteria. We identified four studies with a total of 754 patients of which 300 patients received ranolazine; there was a 14% decrease in POAF occurrence following cardiac surgery compared to 32% in the control group. Although ranolazine is an effective therapy in prevention of POAF, larger, multi-center, randomized trials are warranted. PMID- 30009099 TI - Simultaneous Clinical Presentation of Renal Cell Carcinoma and Immunoglobulin Light Chain Amyloidosis. AB - A 77-year-old female was admitted to the hospital for an evaluation of congestive heart failure. She gave a history of progressive peripheral edema over eight to 10 months, extending up to the knees bilaterally. Admitting creatinine was 148 mmol/L, serum albumin was 15g/L, and urine protein on quantification was 9.09 g/day. Her immunoglobulin G (IgG) level was 18.4g/L and serum-free kappa level was 92.3 mg/L. The immunofixation of urine revealed monoclonal IgG kappa (1.97 g/d). Her kidney biopsy subsequently confirmed the diagnosis of immunoglobulin light chain (AL) amyloidosis. During the course of investigations, it was incidentally noted that she had a mass on her right kidney, which on biopsy was identified as renal cell carcinoma (RCC). This case deals with the rare situation of AL amyloidosis existing with a solid organ carcinoma and the therapeutic dilemma of treating two unrelated conditions involving the kidneys. PMID- 30009100 TI - The Use of Dehydrated Amniotic Membrane Allograft for the Augmentation of Dural Repair in Craniotomies. AB - BACKGROUND: In cranial neurosurgery, primary watertight dural closure is the standard method of post-craniotomy dural repair. However, cerebrospinal fluid (CSF) leaks, pseudomeningoceles, postoperative infections, and dural scarring are possible complications, even when a meticulous technique is implemented. For this reason, materials that enhance the dura's ability to create a watertight seal, inhibit the inflammatory response, and prevent disease transmission are sought. Dehydrated amniotic membrane (DAM) allograft appears to facilitate these properties, as studies have shown that it improves wound healing, prevents scar tissue formation, promotes epithelialization, and inhibits bacterial growth. We detail the use of a DAM allograft to augment dural closures for craniotomies. METHODS: We conducted a pilot study, retrospectively reviewing our institution's database of craniotomies that utilized DAM to supplement dural closure. RESULTS: A total of 122 cases, including 18 initial craniotomies for infratentorial lesions, 102 initial craniotomies for supratentorial lesions, one re-do craniotomy for supratentorial recurrent glioma, and one craniotomy for an anterior skull base schwannoma used a DAM allograft to augment dural closure. Only one complication occurred (0.8% complication rate), which was a superficial wound infection requiring washout without craniectomy. No CSF leaks occurred. CONCLUSIONS: This pilot study demonstrates that dehydrated amniotic membrane allograft can be safely utilized as an adjunct during dural closures for craniotomies. PMID- 30009101 TI - Nearly Missed: Painless Aortic Dissection Masquerading as Infective Endocarditis. AB - Aortic dissection is a life-threatening emergency associated with significant mortality rate. Early diagnosis is essential to improve the survival. Although the most common presentation is severe chest pain, it can be variable leading to delay in the diagnosis especially if it is painless. Painless aortic dissection is a rare entity with sparse data available based on case reports. We present a case of a young male with an atypical presentation where the presumptive diagnosis of infective endocarditis was made based on initial presentation but was eventually diagnosed as painless aortic dissection. PMID- 30009103 TI - An Unusual Case of an Acquired Esophageal-pulmonary Fistula Caused by Hodgkin Lymphoma. AB - Bronchoesophageal and tracheoesophageal fistulas are an uncommon but well documented complication of Hodgkin lymphoma (HL). To our knowledge, a fistula directly connecting the esophagus with the lung (esophageal-pulmonary fistula) and resulting from HL has not been reported in the literature. We present a case of HL complicated with an esophageal-pulmonary fistula. The early recognition and treatment of an esophageal-pulmonary fistula in patients with HL are imperative since, with appropriate treatment, HL complicated with an aero-esophageal fistula has the same prognosis as those without one, unlike the dismal prognosis in esophageal and lung cancer. Endoscopic esophageal stenting followed by chemotherapy is the preferred treatment approach. This leads to the healing of the fistula and the prolongation of patient survival. PMID- 30009102 TI - Colonic Obstruction from an Unusual Cause: A Rare Case of Metastatic Invasive Ductal Carcinoma to the Colon. AB - Colon metastasis from breast cancer is rare. Gastrointestinal (GI) metastasis is more frequently seen in patients with invasive lobular carcinoma of the breast compared to invasive ductal carcinoma; however, the most common sites of metastasis still remain the lymph nodes, lungs, liver, and bones. We describe a 68-year-old female with a remote history of invasive ductal carcinoma of the breast who presented with abdominal pain and a palpable mass. On imaging, she was found to have a colonic obstruction and underwent a right hemicolectomy that proved to be metastatic invasive ductal carcinoma of the breast. PMID- 30009104 TI - Stereotactic Body Radiation Therapy for Prostate Cancer: An Institutional Experience Using MRI-guided Treatment Planning. AB - With 222,500 new cases estimated for 2017, prostate cancer makes up approximately 10% of all new cancer diagnoses in the United States and is the third most common cancer after breast and lung cancer. In 2013, the American Society of Radiation Oncology (ASTRO) policy model recognized that stereotactic body radiation therapy (SBRT) may be used as an alternative to standard treatment modalities, i.e. intensity modulated radiation therapy (IMRT), to treat prostate cancer. In this study, we report outcomes for a cohort of 30 patients with prostate cancer treated with SBRT at our institution. We also describe, in detail, the technical aspects of SBRT planning and delivery for these patients, specifically the use of MRI in determining treatment volumes and detecting gross lesions. After institutional review board (IRB) approval, a retrospective analysis was done of 30 males with the diagnosis of prostate cancer treated in the Department of Radiation Oncology at the Baylor College of Medicine between January 2011 and June 2016. All patients received image-guided SBRT. Treatment planning was performed using a non-contrast computed tomography (CT) scan as well as a contrast thin-slice open MRI with the patient in the treatment position. Patient comparisons were done using the Mann-Whitney U, Fishers Exact, and Kaplan-Meier tests. Thirty patients were treated between January 2011 and June 2016. Twenty six had follow-up data available and were included in the analysis. Median follow up was 32 months (range 2-72 months). Mean and median ages at diagnosis were both 68.5 years. A total of 64% of the patients had foci on magnetic resonance imaging (MRI) or a palpable nodule on an exam. The median prostate-specific antigen (PSA) at diagnosis was 7.35 ng/mL (range 2.8-13), and the median PSA nadir after treatment was 0.4 ng/mL (range 0.01-4.5). The biochemical disease-free recurrence rate per Phoenix definition was 96%, with only one patient experiencing a biochemical recurrence four years after treatment. The patient with a recurrence was T2c, high-intermediate risk with a Gleason score of 7(3+4). He had a focus visible on MRI. Overall survival was 96%, with the only patient death unrelated to his prostate cancer. There was no statistical significance associated with recurrence and nodule on MRI (p=0.318), T-stage (p=0.222), Gleason score (p=0.890), risk group (p=0.654), age (p=0.692), or race (p=0.509). There were no grade three or four acute or long-term toxicities. SBRT of the prostate is an effective method for treating prostate cancer. We saw excellent PSA control and minimal acute or long-term toxicities after a median of three years of follow-up. PMID- 30009105 TI - The Impact of Bariatric Surgery on Sleep Disordered Breathing Parameters From Overnight Polysomnography and Home Sleep Apnea Test. AB - Background Obstructive sleep apnea (OSA) is a common sleep disorder, especially in patients with obesity. Bariatric surgery is an effective tool to reduce weight and treat co-morbid diseases in patients with morbid obesity. One of these disorders is OSA. The most common bariatric procedures currently performed are Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG). Objectives Our study demonstrates that bariatric surgery is a very effective tool to reduce the severity of OSA, if not resolve it. Methods The medical charts of nine patients who had OSA and underwent bariatric surgery (LSG or RYGB) were reviewed and the apnea-hypopnea index (AHI) was compared before and after surgery. The study was conducted at the Sanford sleep center which is affiliated with the University of North Dakota School of Medicine. Results One patient was excluded from the statistical analysis since he was the only male patient, the remaining nine female patients had a significant reduction in AHI after surgery. The mean AHI before surgery was 40 events per hour and seven events per hour after surgery (P 0.004). The mean follow-up with sleep study after surgery was 16 months. The mean reduction in AHI was 80%. There was also an improvement in oxygen saturation (SpO2) before and after surgery (90% and 94% respectively, P 0.008). Conclusion The study confirms the significant reduction in AHI after bariatric surgery in female patients with OSA especially short term (one to two years postoperatively). PMID- 30009106 TI - Comparative Analysis of Junior and Senior Clinician Educator Evaluation of Relevant Articles Within Medical Education. AB - Introduction It may be difficult for junior clinician educators (JCEs) to get a grasp of pertinent literature and determine which are most relevant to their learning, due to limited experience and lack of formalized system to rank all available resources with respect to their value for JCEs. Our study aimed to identify whether senior clinician educators (SCEs) and JCEs differ in their selection of what they perceive as key medical education articles. Methods As a part of the Academic Life in Emergency Medicine (ALiEM) Faculty Incubator program, we developed a series of primer articles for JCEs by identifying and discussing key articles within specific medical education arenas, which were designed to enhance the reader's educational growth. Each set of articles within the primer series were selected based on data collected from JCEs and SCEs, who ranked the specific articles with respect to their perceived relevancy to the JCEs. ANOVA analysis was performed for each of the series to determine whether there was a statistically significant difference between JCE and SCE rating of articles. Results Two-hundred-and-sixteen total articles were evaluated within the nine primer topics. No statistically significant difference was found between the rankings of papers by JCEs and SCEs (effect size: 0.06; 95% CI: -0.27 to 0.40). However, a subgroup analysis of the data found that three of the nine primers showed statistically significant divergence based on seniority (p < 0.05). Conclusions Based on the data, the involvement of JCEs in the consensus building process was important in identifying divergence in views between JCEs and SCEs in one-third of cases. Our findings suggest that it is important to involve JCEs in selecting articles that are worthwhile for their learning, since SCEs may not fully understand their needs. PMID- 30009107 TI - A Vascular-appearing Spindle Cell Xanthogranuloma in a Child. AB - Spindle cell xanthogranuloma is a rare variant of juvenile xanthogranuloma that most commonly presents in adults as papulonodules. We describe a vascular appearing case of spindle cell xanthogranuloma on the nose of a 10-year-old boy. The lesion was a dark red, well-demarcated, dome-shaped papule. Histopathology revealed spindle-shaped histiocytes in a storiform pattern that stained positive for cluster of differentiation 68 (CD68) and the nuclear antigen Ki-67. No vascular features were found. To our knowledge, this is the first reported spindle cell xanthogranuloma to mimic an angiomatous lesion. PMID- 30009108 TI - Impact of Clinical Information on the Turnaround Time in Surgical Histopathology: A Retrospective Study. AB - Introduction Clinical information (CI) is a key requisite to diagnose and report a specimen in histopathology. A timely dispatched report can help a clinician to confirm a diagnosis and initiate a prompt treatment plan while an unnecessary delay in reporting time can compromise patient's healthcare. The aim of this study was to ascertain the impact of the adequacy of CI provided by clinicians on the turnaround time (TAT) and to investigate factors pertinent to specimens, their handling, and diagnosis. Methods This retrospective study reviewed a total of 803 surgical specimens reported in a duration of four months (from December 2015 till March 2016) by the Department of Histopathology, FMH College of Medicine & Dentistry, Lahore, Pakistan. Frozen section and cytology specimens were excluded. CI was classified into three categories: short and focused, long and detailed, and deficient CI. Deficient CI was designated where the pathologist had to seek more information from the requesting clinicians. Total time taken by the histopathologist to complete a report was calculated after excluding weekends and holidays. Other factors like type of specimen, special staining, diagnosis of malignancy and source of referral were also studied. The data were entered and analyzed on SPSS 22.0 (IBM, Armonk, NY). Shapiro-Wilk test was used to measure the distribution. Results Most of the specimens (46.2%, n = 371) were reported within three days. Of these, most of the specimens (46.9%, n = 174) had a short and focused CI (p < 0.001). Majority of the specimens which were reported within four to five days (42.1%, n = 114) and after five days (62.1%, n = 100) were found to have a long and detailed CI in their requisition forms. Median TAT extended to six (4.00-7.00) days with the use of special stains (p < 0.001). One hundred and sixty-three (20.29%) of the total cases were diagnosed as malignant in which the median TAT significantly prolonged to five days (p < 0.001). Most of the specimens (80%, n = 60) received from the outside laboratories had a long and detailed CI in requisition forms. Endometrial tissue specimen was the predominant type received by the department (24.3%, n = 90). Conclusion Adequate CI is necessary for timely and error-free reporting of a specimen in surgical histopathology. A short, focused and concise CI is associated with a shorter TAT. Long and detailed CI is often seen with a complex surgical specimen that requires a longer time to report. Factors like specimen type, special staining, number of special stains and diagnosis of a malignancy also affect TAT. PMID- 30009110 TI - Growth Patterns of Residual Tumor in Preoperatively Growing Vestibular Schwannomas. AB - Objectives To analyze growth of residual vestibular schwannoma (VS) following incomplete tumor resection and determine the influence of residual location and size. Design Retrospective case note and scan review. Setting Tertiary skull base unit. Participants Patients with residual tumor following primary surgery for medium and large unilateral growing vestibular schwanomas between 2006 and 2009. Main Outcome Measures Location of residual VS and post-operative growth, comparing those with more (>5%) or less than 5% of tumor residual (<5%). Results Fifty-two patients had visible residual tumor left behind at surgery. Twenty had < 5% and 32 had > 5% residual. The residual growth rates were 38% overall, 20% in < 5%, and 50% in > 5% residuals. There was no significant difference in growth rates at different residual locations. Median follow-up was 6.4 years. Conclusions There is a greater risk of regrowth of residuals > 5%. All positions of residual tumor can regrow, and the preoperative tumor size plays a role in this. Further data is needed to confirm if residual tumor in the fundus is less likely to grow. PMID- 30009111 TI - Endoscopic Endonasal Landmarks to the Greater Palatine Canal: A Radiographic Study. AB - Background The palatine neurovascular bundle is at risk during endoscopic surgery. Injury may result in significant blood loss and anesthesia of the ipsilateral hard palate. Nonetheless, its endoscopic anatomy has not been described previously. This article strives to establish landmarks to identify the greater palatine canal; thus, avoiding injury to its contents. Methodology This study comprised 50 deidentified computed tomographic angiograms using landmarks that are immediately visible during endoscopic medial maxillectomy to calculate: the angle of the greater palatine canal to the vertical, the distance from the anteroinferior aspect of the greater palatine canal to the orifice of the nasolacrimal duct, the distance from the anteroinferior aspect of the greater palatine canal to the posterolateral free edge of the hard palate, and the distance from the anterior aspect of the greater palatine canal as it enters the hard palate to the posterior wall of the maxillary sinus. Results The mean angle of the greater palatine canal to the vertical was 23.01 degrees. The mean distance from the anteroinferior aspect of the greater palatine canal to the nasolacrimal duct was 31.52 mm. The mean distance from the anterior aspect of the greater palatine canal to the posterolateral free edge of the hard palate was 7.71 mm and the mean distance from the anterior aspect of the greater palatine canal to the posterior wall of the maxillary sinus was 7.07 mm. Conclusion Accessible anatomical landmarks help ascertain the location of the greater palatine canal intraoperatively; thus, avoiding injury to its contents. PMID- 30009109 TI - In vitro or not in vitro: a short journey through a long history. AB - The aim of ecotoxicology is to study toxic effects on constituents of ecosystems, with the protection goal being populations and communities rather than individual organisms. In this ecosystem perspective, the use of in vitro methodologies measuring cellular and subcellular endpoints at a first glance appears to be odd. Nevertheless, more recently in vitro approaches gained momentum in ecotoxicology. In this article, we will discuss important application domains of in vitro methods in ecotoxicology. One area is the use of in vitro assays to replace, reduce, and refine (3R) in vivo tests. Research in this field has focused mainly on the use of in vitro cytotoxicity assays with fish cells as non-animal alternative to the in vivo lethality test with fish and on in vitro biotransformation assays as part of an alternative testing strategy for bioaccumulation testing with fish. Lessons learned from this research include the importance of a critical evaluation of the sensitivity, specificity and exposure conditions of in vitro assays, as well as the availability of appropriate in vitro-in vivo extrapolation models. In addition to this classical 3R application, other application domains of in vitro assays in ecotoxicology include the screening and prioritization of chemical hazards, the categorization of chemicals according to their modes of action and the provision of mechanistic information for the pathway-based prediction of adverse outcomes. The applications discussed in this essay may highlight the potential of in vitro technologies to enhance the environmental hazard assessment of single chemicals and complex mixtures at a reduced need of animal testing. PMID- 30009112 TI - Primary Dural Closure for Retrosigmoid Approaches. AB - Object Primary closure of posterior fossa dura can be challenging, and postoperative cerebrospinal fluid (CSF) leaks continue to represent a common complication of the retrosigmoid approach. We describe a simple technique to allow for primary closure of the dura following retrosigmoid approaches. The incidence of CSF leaks using this method is reported. Methods A retrospective chart review was conducted on all cases of retrosigmoid craniotomies performed by the senior surgeon from February 2009 to February 2015. The primary outcome was development of postoperative CSF leak or pseudomeningocele. Length of stay, lesion type, and other surgical complications were also reported. Results Eighty six patients underwent a retrosigmoid craniotomy during the study period. The most common indications for retrosigmoid craniotomy were microvascular decompression (58%) and tumor resection (36%). No allo- or autografts to repair the dural defect were needed, and no lumbar drains were used. No patients developed CSF otorrhea, rhinorrhea, or incisional leak postoperatively. Conclusion Primary dural closure is possible in retrosigmoid approaches without the use of allo- or autografts and may prevent postoperative CSF leaks when combined with other posterior fossa closure techniques. Careful attention to the handling of the dural flap is necessary to achieve this. PMID- 30009114 TI - Postoperative Cochlear Obliteration after Retrosigmoid Approach in Patients with Vestibular Schwannoma. AB - Objective Vestibular schwannomas (VSNs) account for the vast majority of lesions located in the cerebellopontine angle (CPA). The goals of VSN surgery are possible total tumor removal, intact facial nerve function, and preservation of cochlear nerve function. In cases of pre- or postoperative deafness, restoration of hearing with auditory brainstem implant (ABI) or cochlear implant (CI) is a promising treatment option with normally better results in CI than in ABI. The aim of this retrospective study is to evaluate cochlear ossification or obliteration secondary to a retrosigmoid approach, which is important for later CI, especially in single-sided deafness. Materials and Methods We retrospectively reviewed data from our suboccipital retrosigmoid operation database for the period from January 2008 to February 2015. A total of 65 patients with VSN could be analyzed retrospectively. The patient's data (age, gender, side of operation, tumor entities, and the duration of follow-up) were evaluated. The most recent T2-weigted MRI exams were taken into account for the evaluation of cochlea. To compare left and right sides, the coronal reformatted images were reconstructed in a symmetrical way. Results Twenty-two out of 65 (33%) patients had cochlear obliteration in our survey. The cochlear obliteration was more common in females (44 vs. 20% in males). The median follow-up was 28 months. The size and the intrameatal extension of tumors could not be considered as factors influencing the cochlear obliteration rate. According to our survey, 33% of suboccipital approaches manifested cochlear obliteration to some extent. It was more common in females. The intrameatal extension of tumors played statistically no role in the occurrence of postoperative cochlear obliteration. Whether the prohibition of cochlear ossification can be best achieved by retrosigmoid approaches, compared to other approaches to the CPA, or not could be a subject of future studies. PMID- 30009113 TI - Impact of Cochlear Dose on Hearing Preservation following Stereotactic Radiosurgery and Fractionated Stereotactic Radiotherapy for the Treatment of Vestibular Schwannoma. AB - Objective The objective of this study was to examine the effect of cochlear dose on hearing preservation in stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) for vestibular schwannoma (VS). Design This is a retrospective case-control study. Setting This study was completed at the Ronald Reagan UCLA Medical Center, a university-affiliated tertiary care center. Participants Patients who underwent SRS (marginal dose of 12 Gy) or fSRT (marginal dose of 50.4 Gy) procedures for VS were included in the study. Main Outcome Measures The main outcome measure was hearing preservation. Audiometric data, when available, were used to determine the level of hearing according to the Gardner Robertson scale. Results A total of 38 patients (14 SRS and 24 fSRT) were analyzed. SRS patients with decreased hearing received a significantly higher minimum cochlear dose (7.41 vs. 4.24 Gy, p = 0.02) as compared with those with stable hearing. In fSRT patients, there were no significant differences in cochlear dose for patients with decreased hearing as compared with those with stable hearing. For SRS patients, who received a minimum cochlear dose above 6 Gy, there was a significant risk of decreased hearing preservation (odds ratio: 32, p = 0.02). Conclusion Higher minimum cochlear dose was predictive of decreased hearing preservation following SRS. Though the study is low powered, the radiation dose to the cochlea should be a parameter that is considered when planning SRS or fSRT therapies for patients with VS. PMID- 30009115 TI - Vastus Lateralis Muscle Free Flap for Skull Base Osteoradionecrosis in Nasopharyngeal Carcinoma. AB - Objectives To describe the first experience with a free vastus lateralis muscle only flap to be used to cover and protect the exposed skull base and carotid artery from radiotherapy-induced skull base osteoradionecrosis (ORN). Design Retrospective review of a case series. Setting Tertiary academic medical center. Participants Post treatment nasopharyngeal carcinoma patients with skull base ORN. Main Outcome Measures Coverage of the internal carotid artery (ICA). Results Four patients underwent the procedure. Following the procedure, all patients were documented to have adequate viable soft tissue covering their ICA. Topical nasal steroids were prescribed to all patients as florid granulation tissue was noted to occur overlying the muscle flap in the early postoperative period. There were no flap failures. All patients noted an improvement in speech, cacosmia, and nasal crusting. No significant epistaxis occurred following surgery. Choanal stenosis was noted in three patients. Conclusion For skull base ORN resulting from the treatment of nasopharyngeal carcinoma (NPC) with radiotherapy that fails conservative management, an open approach to the nasopharynx, that allows debridement then placement of a vastus lateralis muscle only free flap for coverage, offers a unique and viable approach to the management of this challenging condition. PMID- 30009117 TI - Finding the Petroclival Carotid Artery: The Vidian-Eustachian Junction as a Reliable Landmark. AB - Introduction Identifying the internal carotid artery (ICA) when managing petroclival and infratemporal fossa pathology is essential for the skull base surgeon. The vidian nerve and eustachian tube (ET) cartilage come together at the foramen lacerum, the vidian-eustachian junction (VEJ). The ICA position, relative to the VEJ is described. Methods Endoscopic dissection of adult fresh-frozen cadaver ICAs and a case series of patients with petroclival pathology were performed. The relationship of the VEJ to the ICA horizontal segment, vertical segment, and second genu was assessed. The distance of the ICA second genu to VEJ was determined in coronal, axial, and sagittal planes. The length of the vidian nerve and ET was measured from the pterygopalatine fossa (PPF) and nasopharyngeal orifice to the VEJ. Results In this study, 10 cadaver dissections (82.3 +/- 6.7 years, 40% female) were performed. The horizontal petrous ICA was at or behind VEJ in 100%, above VEJ in 100%, and lateral to VEJ in 80%. The vertical paraclival segment was at or behind VEJ in 100%, above in 100%, and medial in 100%. The second genu was at or behind VEJ in 100% (3.3 +/- 2.4 mm), at or above in 100% (2.5 +/- 1.6 mm), and medial in 100% (3.4 +/- 2.0 mm). The VEJ was successfully used to locate the ICA in nine consecutive patients (53.3 +/- 13.6 years, 55.6% female) where pathology was also present. The VEJ was 15.0 +/- 6.0 mm from the ET and 17.4 +/- 4.1 mm from the PPF. Conclusion The VEJ is an excellent landmark as it defines both superior and posterior limits when isolating the ICA in skull base surgery. PMID- 30009116 TI - Management and Outcome in Patients with Advanced Juvenile Nasopharyngeal Angiofibroma. AB - Objective To report the management outcome in a series of patients with advanced juvenile nasopharyngeal angiofibroma (JNA). Design Retrospective study. Setting Tertiary care teaching hospital. Participants Forty-five patients classified as Radkowski stage IIIA or IIIB who presented to us over the past 10 years. Main Outcome Measures Surgical approaches used and disease free outcomes in patients with advanced JNA. Results Surgical access for the extracranial component included open (41.9%) and expanded endonasal approaches (58.1%). Craniotomy (16.3%), endoscopy-assisted open approach (7%), or expanded endonasal approach (20.9%) was performed to excise the skull base or intracranial component. Follow up ranged from 4 to 96 months (mean, 20.3 months). Of 35 patients who underwent imaging at the first postoperative follow up, 25 (71.4%) had negative scans. Three symptomatic patients with residual disease underwent endoscopic excision and had negative scans thereafter. Of two others who had radiation therapy, one was disease free and the other lost to follow up. Five others had stable, residual disease. Three patients (8.6%) with recurrent disease underwent surgical excision, of whom two had minimal, stable residual disease. At the last follow up, 27 (77.1%) patients had negative scans, and 7 (20%) had stable residual disease with one (2.9%) patient lost to follow-up. Conclusions Advanced JNA may be successfully treated in most cases with expanded endonasal/endoscopy assisted +/- craniotomy approach after appropriate preoperative evaluation. At follow-up, only symptomatic patients or those with enlarging residue require treatment; periodic imaging surveillance is adequate for those with stable disease. PMID- 30009119 TI - Importance of Frontal Horn Ratio and Optimal CSF Drainage in the Treatment of Very Low-Pressure Hydrocephalus. AB - Introduction Unlike low-pressure hydrocephalus, very low pressure hydrocephalus (VLPH) is a rarely reported clinical entity previously described to be associated with poor outcomes and to be possibly refractory to treatment with continued cerebrospinal fluid (CSF) drainage at subatmospheric pressures. 1, 2 We present four cases of VLPH following resection of suprasellar lesions and hypothesize that untreatable patients can be identified early, thereby avoiding futile prolonged external ventricular drainage in ICU. Methods We performed a retrospective chart review of four cases of VLPH encountered between 2007 and 2015 in two different institutions and practices and tried to identify factors contributing to successful treatment. We hypothesized that normalization of frontal horn ratio (FHR), optimization of volume of CSF drained, and avoidance of fluid shifts would contribute to improved Glasgow Coma Score (GCS). We examined fluid shifts by studying net fluids shifts and serum levels of sodium, urea, and creatinine. We used Pearson and Spearman correlations to identify measures that would correlate with improved GCS. Results Our study reveals that improving GCS is positively correlated with decreased FHR and increased CSF drainage within an optimal range. The most important determinant of good outcome is retention of brain viscoelasticity as evidenced by restoration and maintenance of good GCS score despite fluctuations in FHR. Conclusion Futile prolonged subatmospheric drainage can be avoided by declining to continue treatment in patients who have permanently altered brain compliance secondary to unsealed CSF leaks, irremediable ventriculitis, and who are therefore unable to sustain an improved neurologic examination. PMID- 30009118 TI - Petroclival Meningiomas: Factors Determining the Choice of Approach. AB - Objectives To review a surgical series of petroclival meningiomas and the factors considered in the choice of approach. Design Retrospective review. Setting The study was conducted in a university hospital in southern Brazil. Participants Twenty-two patients with petroclival meningioma originating from the upper two-thirds of the clivus medial to the fifth cranial nerve. Main Outcome Measures Gross-total resection, mortality, major morbidity, new cranial nerve deficits and tumor progression or recurrence. Results Retrosigmoid approach was used in tumors <3 cm and in those at or below the internal auditory meatus. Posterior petrosectomy was performed for tumors extending into the middle fossa. Gross-total resection was performed in 11 patients (50%). The mean follow up time was 32 months (6-75 months). There were four cases of tumor progression or recurrence, which were treated with radiosurgery. Conclusions Resection of petroclival meningiomas remains challenging. In most cases, the retrosigmoid approach was sufficient, without affecting the degree of tumor resection. Petrosal approaches were reserved for patients with tumor extension into the middle fossa. PMID- 30009120 TI - Orbital Apex Lesions: A Diagnostic and Therapeutic Challenge. AB - Objective To analyze the clinical characteristics of and treatment outcomes for orbital apex lesions according to their pathological diagnosis and identify clinical characteristics that could aid in their differential diagnosis. Design Retrospective analysis design was used for this study. Setting The study was conducted in a single tertiary institution. Participants Patients with pathologically confirmed lesions centered in the orbital apex who were admitted between January 2011 and December 2015. Main Outcome Measures Clinical characteristics, including demographics, predisposing factors, presenting symptoms, radiological findings, intraoperative findings, biopsy results, and treatment outcomes. Results Nine patients with invasive fungal sinusitis, six with inflammatory pseudotumor, and six with neoplastic or tumorous lesions were enrolled. The most common presenting symptom was orbital pain or headache, followed by ophthalmoplegia and vision loss, which exhibited overall recovery rates of 62.5% and 33.3%, respectively, after definitive treatment. The prognosis was worse for patients with invasive fungal sinusitis. There was no significant difference in age, underlying medical conditions, absolute neutrophil count, C reactive protein level, and radiological findings among the three groups. Grossly necrotic tissues around the orbital apex area at biopsy were more frequently found in patients with invasive fungal sinusitis than in the other patients. In most cases, pain ameliorated after surgical intervention. There were no surgery related morbidities. Conclusions Lesions centered in the orbital apex included invasive fungal sinusitis, inflammatory pseudotumor, and tumorous lesions. However, clinical features that clearly differentiated chronic invasive fungal sinusitis from inflammatory pseudotumor could not be identified. Our findings suggest that prompt biopsy is warranted for timely diagnosis, symptom relief, and early implementation of definitive treatment. PMID- 30009121 TI - Comparison of Male and Female Prolactinoma Patients Requiring Surgical Intervention. AB - Objectives Prolactinomas are the most common functional pituitary adenoma. Symptoms of a prolactinoma stem from hormonal causes (menstrual irregularities, galactorrhea, and reduced libido) or from tumor mass effect (visual changes and headache). Gender differences have been noted in prolactinomas, with males presenting with larger tumors and sequelae of mass effect, while females present commonly with hormonal symptoms. The purpose of this study is to evaluate differences in patient and disease characteristics, and outcomes between male and female prolactinoma patients undergoing surgery. Design This was a retrospective chart review. Setting This was done at the tertiary medical center. Participants The medical records of prolactinomas patients who underwent endoscopic endonasal surgery between March 2008 and August 2016 were reviewed. Main Outcome Measures Demographic information, tumor characteristics, and treatment characteristics and outcomes were collected. Statistical analysis was performed using chi-squared test or Student's t -test as applicable. Results Seventy-nine patients were identified, 22 males and 57 females. The average age for males was 38 years and for females was 35 years. Males were more likely to present with decreased libido ( p < 0.0001), whereas females more often presented with galactorrhea ( p < 0.0001) and menstrual irregularities. Tumor size was larger in males ( p = 0.0044) with higher likelihood of suprasellar extension ( p = 0.0409) and cavernous sinus invasion ( p = 0.0026). Males were more likely to have a subtotal resection rather than gross total resection ( p = 0.0086) and less likely to have normalization of prolactin levels following surgery ( p = 0.0019) Conclusion Male prolactinoma patients tend to have larger tumors with more aggressive features. This may have a role in the differences in outcomes noted in this study. PMID- 30009122 TI - Radiological "Teddy Bear" Sign on CT Imaging to Aid Internal Carotid Artery Localization in Transsphenoidal Pituitary and Anterior Skull Base Surgery. AB - Objectives Internal carotid artery (ICA) injury remains a rare but potentially fatal complication of transsphenoidal pituitary or anterior skull base surgery. Preoperative imaging must be scrutinized to minimize risk. On axial computed tomography (CT), the protrusions of the ICAs into the sphenoid resemble a "teddy bear." This article aims to describe the sign, its grading system (0-2) and quantify its presence. Design Retrospective review of preoperative CT imaging. Setting Tertiary referral center in the United Kingdom. Participants One hundred patients who underwent endoscopic transsphenoidal surgery for pituitary disease were enrolled. Main Outcome Measure The presence and grading of the "teddy bear" sign were assessed on preoperative CT imaging. Results A grade 2 (strongly positive) "teddy bear" sign was identified in 40% at the level of the superior pituitary fossa, 78% at the inferior pituitary fossa, and 59% at the clivus. A grade 1 (intermediate) sign was seen in 23.5, 7.5, and 10% of cases, respectively. In 5% of cases, the sign was grade 0 at all levels-indicating poor intraoperative localization of the ICA. Conclusion The "teddy bear" sign is a useful preoperative tool for identification of anatomy predisposing patients to a higher risk of ICA injury. Those patients who have an absent or grade 0 "teddy bear" sign require extra care to ensure intraoperative localization of the ICAs which may include the use of neuronavigation or a Doppler probe. A grade 2 sign predicts good intraoperative localization of the ICA intraoperatively to inform the safe lateral limit of sellar bone resection. PMID- 30009123 TI - Orbital Paraganglioma: A Systematic Review. AB - Purpose The purpose of this study was to perform a systematic review of the literature on orbital paragangliomas, evaluating clinical presentation, diagnosis, management patterns, and prognosis. Methods The systematic review was conducted based on the principles described in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. PubMed, Cochrane databases, Embase, and Web of Science were searched for articles related to orbital paragangliomas. Inclusion criteria included English language articles with original reports on human subjects. Data on clinical presentation, diagnosis, treatment, and prognosis were collected. Results Twenty-seven articles met inclusion criteria (28 total patients). The mean patient age was 37.1 years (range, 3-75 years); 13 (46.4%) patients were male. The most common presenting symptoms were proptosis (89.2%), visual acuity changes (67.9%), and extraocular muscle restriction (64.2%). Lesions were most commonly intraconal (92.9%). Single modality therapy was employed in 19 patients (67.9%), including excision in 12 patients (42.9%) and exenteration in 5 patients (17.9%). Ten patients (35.7%) developed recurrence, and there was a 92.9% survival rate (mean follow-up, 29 months). Conclusion Orbital paragangliomas are rare tumors with an excellent prognosis. These lesions commonly present with proptosis, and are primarily managed surgically with simple excision, although exenteration and adjuvant radiation may be necessary for invasive tumors. This series is the largest and most comprehensive systematic review of orbital paragangliomas conducted to date. PMID- 30009125 TI - Successful rituximab treatment of TAFRO syndrome with pathological findings of glomerular endothelial damage. AB - Thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly constitute TAFRO syndrome, a variant of Castleman disease. We describe a patient with TAFRO syndrome who underwent renal biopsy. A 79-year-old woman was referred to us with fever and leg edema. She also had thrombocytopenia, pleural effusion, ascites, and acute kidney injury, and was admitted to our hospital. Her response to initial therapy with corticosteroid and cyclosporine was poor. Therefore, she received 4 doses of rituximab per week, which resulted in clinical improvement, including recovery of thrombocytopenia. A kidney biopsy thereafter showed diffuse, global glomerular endothelial injury indicating thrombotic microangiopathy (TMA). These findings suggested that TMA is associated with the thrombocytopenia and renal insufficiency of TAFRO syndrome. PMID- 30009124 TI - Developing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Treatment Tool for Cocaine Use Disorder: a Series of Six Translational Studies. AB - Purpose of the Review: Cocaine dependence is a chronic and relapsing disorder which is particularly resistant to behavioral or pharmacologic treatment, and likely involves multiple dysfunctional frontal-striatal circuits. Through advances in preclinical research in the last decade, we now have an unprecedented understanding of the neural control of drug-taking behavior. In both rodent models and human clinical neuroimaging studies, it is apparent that medial frontal-striatal limbic circuits regulate drug cue-triggered behavior. While non human preclinical studies can use invasive stimulation techniques to inhibit drug cue-evoked behavior, in human clinical neuroscience, we are pursuing non-invasive theta burst stimulation (TBS) as a novel therapeutic tool to inhibit drug cue associated behavior. Recent Findings: Our laboratory and others have spent the last 7 years systematically and empirically developing a non-invasive, neural circuit-based intervention for cocaine use disorder. Utilizing a multimodal approach of functional brain imaging and brain stimulation, we have attempted to design and optimize a repetitive transcranial magnetic stimulation treatment protocol for cocaine use disorder. This manuscript will briefly review the data largely from our own lab that motivated our selection of candidate neural circuits, and then summarize the results of six studies, culminating in the first double-blinded, sham-controlled clinical trial of TMS as a treatment adjuvant for treatment-engaged cocaine users (10 sessions, medial prefrontal cortex, 110% resting motor threshold, continuous theta burst stimulation, 3600 pulses/session). Summary: The intent of this review is to highlight one example of a systematic path for TMS treatment development in patients. This path is not necessarily optimal, exclusive, or appropriate for every neurologic or psychiatric disease. Rather, it is one example of a reasoned, empirically derived pathway which we hope will serve as scaffolding for future investigators seeking to develop TMS treatment protocols. PMID- 30009126 TI - Respiratory Syncytial Virus Vaccine Approaches: a Current Overview. AB - Purpose of Review: Respiratory syncytial virus (RSV) is a global human pathogen responsible for lower respiratory tract infections (LRTI). While RSV infection is innocuous in healthy adults, it is the leading cause of infant hospitalization for respiratory tract infection. Nearly everyone shows evidence of an RSV infection by the age of 3. However, there is still not a vaccine commercially available. This review will provide an update on the clinical and preclinical vaccine studies and different approaches to prevent RSV infection. Recent Findings: Novel vaccine approaches that induce protection against RSV without enhancement of respiratory tract disease. Summary: Recent technological approaches have led to generation of different strategies to prevent RSV infection, including live attenuated, chimeric, and subunit vaccines, virus-like particles, and nanoparticles. These vaccine approaches represent promising candidates towards an efficient RSV vaccine that effectively protects infants, children, and adults. PMID- 30009127 TI - The effect of tDCS on functional connectivity in primary progressive aphasia. AB - Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network. We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming). Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy. These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions. PMID- 30009129 TI - Virtual localization of the seizure onset zone: Using non-invasive MEG virtual electrodes at stereo-EEG electrode locations in refractory epilepsy patients. AB - In some patients with medically refractory epilepsy, EEG with intracerebrally placed electrodes (stereo-electroencephalography, SEEG) is needed to locate the seizure onset zone (SOZ) for successful epilepsy surgery. SEEG has limitations and entails risk of complications because of its invasive character. Non-invasive magnetoencephalography virtual electrodes (MEG-VEs) may overcome SEEG limitations and optimize electrode placement making SOZ localization safer. Our purpose was to assess whether interictal activity measured by MEG-VEs and SEEG at identical anatomical locations were comparable, and whether MEG-VEs activity properties could determine the location of a later resected brain area (RA) as an approximation of the SOZ. We analyzed data from nine patients who underwent MEG and SEEG evaluation, and surgery for medically refractory epilepsy. MEG activity was retrospectively reconstructed using beamforming to obtain VEs at the anatomical locations corresponding to those of SEEG electrodes. Spectral, functional connectivity and functional network properties were obtained for both, MEG-VEs and SEEG time series, and their correlation and reliability were established. Based on these properties, the approximation of the SOZ was characterized by the differences between RA and non-RA (NRA). We found significant positive correlation and reliability between MEG-VEs and SEEG spectral measures (particularly in delta [0.5-4 Hz], alpha2 [10-13 Hz], and beta [13-30 Hz] bands) and broadband functional connectivity. Both modalities showed significantly slower activity and a tendency towards increased broadband functional connectivity in the RA compared to the NRA. Our findings show that spectral and functional connectivity properties of non-invasively obtained MEG VEs match those of invasive SEEG recordings, and can characterize the SOZ. This suggests that MEG-VEs might be used for optimal SEEG planning and fewer depth electrode implantations, making the localization of the SOZ safer and more successful. PMID- 30009128 TI - Amyloid pathology fingerprint differentiates post-traumatic stress disorder and traumatic brain injury. AB - Introduction: Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for early onset of Alzheimer's disease (AD) and may accelerate the progression rate of AD pathology. As amyloid-beta (Abeta) plaques are a hallmark of AD pathology, we hypothesized that TBI and PTSD might increase Abeta accumulation in the brain. Methods: We examined PET and neuropsychological data from Vietnam War veterans compiled by the US Department of Defense Alzheimer's Disease Neuroimaging Initiative, to examine the spatial distribution of Abeta in male veterans' who had experienced a TBI and/or developed PTSD. Subjects were classified into controls, TBI only, PTSD only, and TBI with PTSD (TBI_PTSD) groups and data were analyzed using both voxel-based and ROI-based approaches. Results: Compared to controls, all three clinical groups showed a pattern of mainly increased referenced standard uptake values (SUVR) for the amyloid tracer [18F]-AV45 PET, with rank order PTSD > TBI_PTSD > TBI > Control, and same rank order was seen in the deficits of cognitive functions. SUVR increase was observed in widespread cortical regions of the PTSD group; in white matter of the TBI_PTSD group; and cerebellum and precuneus area of the TBI group, in contrast with controls. The [18F]-AV45 SUVR correlated negatively with cerebrospinal fluid (CSF) amyloid levels and positively with the CSF tau concentrations. Conclusion: These results suggest that both TBI and PTSD are substantial risk factors for cognition decline and increased Abeta deposition resembling that in AD. In addition, both PTSD and TBI_PTSD have a different pathways of Abeta accumulation. PMID- 30009130 TI - The neuropsychological profiles and semantic-critical regions of right semantic dementia. AB - Introduction: Previous literature has revealed that the anterior temporal lobe (ATL) is the semantic hub of left-sided or mixed semantic dementia (SD), whilst the semantic hub of right-sided SD has not been examined. Methods: Seventeen patients with right-sided SD, 18 patients with left-sided SD and 20 normal controls (NC) underwent neuropsychological assessments and magnetic resonance imaging scans. We investigated the relationship between the degree of cerebral atrophy in the whole brain and the severity of semantic deficits in left and right-sided SD samples, respectively. Results: We found the semantic deficits of right-sided SD patients were related to bilateral fusiform gyri and left temporal pole, whilst the left fusiform gyrus correlated with the semantic performance of left-sided SD patients. Moreover, all the findings couldn't be accounted for by total gray matter volume (GMV) or general cognitive degradation of patients. Discussion: These results provide novel evidence for the current semantic theory, that the important regions for semantic processing include both anterior and posterior temporal lobes. PMID- 30009131 TI - Engineering redox-balanced ethanol production in the cellulolytic and extremely thermophilic bacterium, Caldicellulosiruptor bescii. AB - Caldicellulosiruptor bescii is an extremely thermophilic cellulolytic bacterium with great potential for consolidated bioprocessing of renewable plant biomass. Since it does not natively produce ethanol, metabolic engineering is required to create strains with this capability. Previous efforts involved the heterologous expression of the gene encoding a bifunctional alcohol dehydrogenase, AdhE, which uses NADH as the electron donor to reduce acetyl-CoA to ethanol. Acetyl-CoA produced from sugar oxidation also generates reduced ferredoxin but there is no known pathway for the transfer of electrons from reduced ferredoxin to NAD in C. bescii. Herein, we engineered a strain of C. bescii using a more stable genetic background than previously reported and heterologously-expressed adhE from Clostridium thermocellum (which grows optimally (Topt) at 60 degrees C) with and without co-expression of the membrane-bound Rnf complex from Thermoanaerobacter sp. X514 (Topt 60 degrees C). Rnf is an energy-conserving, reduced ferredoxin NAD oxidoreductase encoded by six genes (rnfCDGEAB). It was produced in a catalytically active form in C. bescii that utilized the largest DNA construct to be expressed in this organism. The new genetic lineage containing AdhE resulted in increased ethanol production compared to previous reports. Ethanol production was further enhanced by the presence of Rnf, which also resulted in decreased production of pyruvate, acetoin and an uncharacterized compound as unwanted side products. Using crystalline cellulose as the growth substrate for the Rnf containing strain, 75 mM (3.5 g/L) ethanol was produced at 60 degrees C, which is 5-fold higher than that reported previously. This underlines the importance of redox balancing and paves the way for achieving even higher ethanol titers in C. bescii. PMID- 30009133 TI - Gastric neuroendocrine carcinoma with positive staining for prostate cancer markers including prostate-specific antigen and alpha-methylacyl-CoA racemase. AB - We report a case with prostate cancer and gastric neuroendocrine carcinoma. A 72 year old male presented with a gastric lesion 5 months after radical prostatectomy. The lesion was immunohistochemically positive for PSA, alpha methylacyl-CoA racemase, synaptophysin, and chromogranin A, but negative for androgen receptor (AR). Differentiating gastric neuroendocrine carcinoma from gastric metastasis of prostate cancer is difficult, as both lesions exhibit similar acinar cell proliferation with prominent nucleoli.1 We discuss the diagnostic process of this case and how AR was a useful specific marker for diagnosing primary gastric neuroendocrine carcinoma. PMID- 30009134 TI - Rupture of pheochromocytoma caused by phenoxybenzamine - A case report. PMID- 30009132 TI - Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia. AB - Objective: Reaching a genetic diagnosis of mitochondrial disorders (MDs) is challenging due to their broad phenotypic and genotypic heterogeneity. However, there is growing evidence that the use of whole exome sequencing (WES) for diagnosing patients with a clinical suspicion of an MD is effective (39-60%). We aimed to study the effectiveness of WES in clinical practice in Estonia, in patients with an unsolved, but suspected MD. We also show our first results of mtDNA analysis obtained from standard WES reads. Methods: Retrospective cases were selected from a database of 181 patients whose fibroblast cell cultures had been stored from 2003 to 2013. Prospective cases were selected during the period of 2014-2016 from patients referred to a clinical geneticist in whom an MD was suspected. We scored each patient according to the mitochondrial disease criteria (MDC) (Morava et al., 2006) after re-evaluation of their clinical data, and then performed WES analysis. Results: A total of 28 patients were selected to the study group. A disease-causing variant was found in 16 patients (57%) using WES. An MD was diagnosed in four patients (14%), with variants in the SLC25A4, POLG, SPATA5, and NDUFB11 genes. Other variants found were associated with a neuromuscular disease (SMN1, MYH2, and LMNA genes), neurodegenerative disorder (TSPOAP1, CACNA1A, ALS2, and SCN2A genes), multisystemic disease (EPG5, NKX1-2, ATRX, and ABCC6 genes), and one in an isolated cardiomyopathy causing gene (MYBPC3). The mtDNA point mutation was found in the MT-ATP6 gene of one patient upon mtDNA analysis. Conclusions: The diagnostic yield of WES in our cohort was 57%, proving to be a very good effectiveness. However, MDs were found in only 14% of the patients. We suggest WES analysis as a first-tier method in clinical genetic practice for children with any multisystem, neurological, and/or neuromuscular problem, as nuclear DNA variants are more common in children with MDs; a large number of patients harbor disease-causing variants in genes other than the mitochondria-related ones, and the clinical presentation might not always point towards an MD. We have also successfully conducted analysis of mtDNA from standard WES reads, providing further evidence that this method could be routinely used in the future. PMID- 30009136 TI - Non-gallstone acute pancreatitis and pre-eclampsia: A case report. AB - Acute pancreatitis is rare but well documented in pregnancy and most cases are attributable to biliary disease. We present a case of acute non-gallstone pancreatitis in a patient with acute and severe pre-eclampsia. A 39-year-old primigravida woman at 33 + 4 weeks' dichorionic diamniotic gestation presented with severe bilateral lower-limb oedema and underwent an emergency caesarean section due to the development of acute severe pre-eclampsia. Postpartum, the woman developed out-of-proportion generalised upper abdominal tenderness with worsening liver function and markedly raised lipase and amylase levels. Imaging confirmed oedema and inflammatory changes in keeping with acute non-gallstone pancreatitis. The patient improved with conservative management and was eventually discharged home on day 13 postpartum. The development of abdominal pain out of proportion to expected clinical progression should prompt the physician to consider other causes, including acute pancreatitis, in order to provide effective and timely clinical care. The clinical presentation of this woman suggests that pre-eclampsia may be associated with the development of acute pancreatitis. Further prospective study would be needed to establish any association. PMID- 30009135 TI - Occurrence of Aflatoxin M1 in cow milk in El Salvador: Results from a two-year survey. AB - Aflatoxin M1 (AFM1) is a metabolite of Aflatoxin B1 (AFB1) and is excreted through cow's milk. AFM1 contamination of milk is extended geographically and there might be seasons-related variations for both prevalence and contents, with higher than average values in regions with long periods of drought like El Salvador. Therefore, this project quantified AFM1 levels in raw cow milk and AFs in cattle feedstuffs, during the transitional dry-rainy seasons of two consecutive years and it determined the variation of occurrence and contents associated to drought. Significant variations were shown from year to year in the prevalence of contamination (30% vs. 20%) and in the average levels of AFM1 in milk (0.056 vs 0.039 MUg/kg), associated with drought and increased temperature. The AFs median levels raised significantly with the drought period (from 22.5 to 10.3 MUg/kg). A significant relationship was demonstrated between AFs levels and those of AFM1, both in the year with drought and without that condition. AFM1 positive cases and its levels in milk increase in drought and hot conditions, AFs levels in the cattle feed tend to be higher with the same, as well. Both relationship between AFs and AFM1 levels and their association with drought were demonstrated. So that, heat and drought stress conditions can evoke raising effects on both Aflatoxins level and occurrence due to AFM1 in milk is a carryover from AFs contaminated feedstuffs ingested by dairy cows. PMID- 30009137 TI - Helsinki VideoMEG Project: Augmenting magnetoencephalography with synchronized video recordings. AB - The primary goal of the Helsinki VideoMEG Project is to enable magnetoencephalography (MEG) practitioners to record and analyze the video of the subject during an MEG experiment jointly with the MEG data. The project provides: *Hardware assembly instructions and software for setting up video and audio recordings of the participant synchronized to MEG data acquisition.*Basic software tools for analyzing video and audio together with the MEG data. The resulting setup allows reliable recording of video and audio from the subject in various real-world usage scenarios. The Helsinki VideoMEG Project allowed successful establishment of video-MEG facilities in four different MEG laboratories in Finland, Sweden and the United States. PMID- 30009138 TI - Expression of soluble native protein in Escherichia coli using a cold-shock SUMO tag-fused expression vector. AB - At present, approximately 30% of eukaryotic proteins can be expressed in a soluble form in Escherichia coli. In this study, a pCold-SUMOa plasmid was constructed in order to express heterologous proteins fused with SUMO by a cold shock expression vector. The human cysteine desulfurase NFS1 and a chimeric cysteine desulfurase namely, EH-IscS were successfully expressed in E. coli. The proteins were particularly difficult to be produced functionally, due to their readily sequestered nature. The recombinant cysteine desulfurases that were generated by pCold-SUMOa exhibited higher activity, solubility and stability compared with the well-known plasmid pCold I. In contrast to the pCold TF plasmid, the SUMO tag conferred no biological activity with regard to the conformation of the cysteine desulfurases. Furthermore, the SUMO protease 1 can efficiently recognize the tertiary structure of SUMO and cleave it. The data indicate that the pCold-SUMOa vector is a promising tool for native eukaryotic protein production. PMID- 30009139 TI - The 40th Anniversary of IVF: Has ART's Success Reached Its Peak? PMID- 30009141 TI - Review of Trichomonas vaginalis in Iran, Based on Epidemiological Situation. AB - Trichomoniasis, which is caused by Trichomonas vaginalis, is the most common non viral sexually transmitted infection (STI) in the world including Iran. There were roughly 250 million new cases all over the world in a year. T. vaginalis as an important disease has been associated with HIV (in terms of exposure to sexually transmitted infection, STI) which increases the number of high-risk members, and thus it is an important public health problem. Additionally, this pathogen has been associated with serious health consequences. For instance, it may cause a woman to deliver a low-birth-weight or premature infant, and increase chances of cervical cancer. Because little information is available about the prevalence of T. vaginalis infection in Iranian population, this review was carried out to determine the prevalence of T. vaginalis among Iranian population. For this systematic review, data about epidemiology of T. vaginalis in different parts of Iran with different populations were systematically collected from 1992 to 2017 through the international databases such as PubMed, Scirus, ISI Web of Science, Scopus, EMBASE, Science Direct and Google Scholar and Islamic World Science Citation Center (ISC). National database searching included Iran Medex, Iran Doc, Magiran and Scientific Information Database (SID). A total of 39 clinical and laboratory investigations about the prevalence of Trichomoniasis from different regions of Iran were analyzed. The overall prevalence rate of T. vaginalis infection in Iranian population was estimated to be minimally 0.4% and maximally 42%. The present review showed that T. vaginalis infection rate is relatively high among the Iranian population. The control strategies, including personal hygienic education, simultaneous couple treatment, the sensitivity of diagnostic methods, appropriate preventive tool (condom) in sexual contacts could lead to the disruption of transmission. PMID- 30009140 TI - Zinc is an Essential Element for Male Fertility: A Review of Zn Roles in Men's Health, Germination, Sperm Quality, and Fertilization. AB - Zinc (Zn) is the second most abundant trace element in human, which can't be stored in the body, thus regular dietary intake is required. This review explained the physiological and pathogenesis roles of zinc in men's health and its potentials in germination, quality of sperm, and fertilization. Our investigation showed that Zn contained many unique properties in human, especially males. The antioxidant quality is one of them. Also, the increased reactive oxygen species levels in the seminal plasma of men who are both infertile and smokers influence the Zn content of seminal plasma in a way that physiology of spermatozoa can be affected as well. Moreover, Zn acts as a toxic repercussionagainst heavy metals and cigarette inflammatory agents. Zinc as a hormone balancer helps hormones such as testosterone, prostate and sexual healthand functions as an antibacterial agent in men's urea system. It plays a role in epithelial integrity, showing that Zn is essential for maintaining the lining of the reproductive organs and may have a regulative role in the progress of capacitation and acrosome reaction. In contrast, Zn deficiency impedes spermatogenesis and is a reason for sperm abnormalities and has a negative effect on serum testosterone concentration. Based on these findings, Zn microelement is very essential for male fertility. It could be considered as a nutrient marker with many potentials in prevention, diagnosis, and treatment of male infertility. PMID- 30009142 TI - Assessment of PGC1alpha-FNDC5 Axis in Granulosa Cells of PCOS Mouse Model. AB - Background: Polycystic ovarian syndrome (PCOS) is a metabolic and endocrine disorder which is characterized by hyperandrogenism, anovulation or oligomenorrhea and polycystic ovarian morphology. It is believed that modulation in metabolism of granulosa cells of PCOS patients may lead to infertility. One of the metabolic modulators is FNDC5 and its cleaved form, irisin. The axis of PGC1alpha-FNDC5 pathway is one of the main factors affecting cellular energy balance the purpose of this study was to evaluate this pathway in granulosa cells derived from PCOS mice model in comparison with control group. Methods: In the present study, PCOS mouse model was developed by injection of dehydroepiandrosterone (DHEA) hormone in 20 mice for a period of 20 days. Also, 20 uninjected mice were used as the control. Meanwhile, a vehicle group consisted of mice which received daily subcutaneous sesame oil injection (n=20). Relative expressions of PGC1alpha and FNDC5 in granulosa cells were evaluated by RT-qPCR. Analysis of gene expressions was calculated by the DeltaDeltaCT method and the relative levels of mRNA were normalized to GAPDH transcript levels. Differences in genes expression among three groups were assessed using one-way ANOVA, Tukey's Post Hoc test. Results: Our results showed that expression of FNDC5 was significantly reduced in granulosa cells of DHEA-induced PCOS mice compared with control and vehicle groups (p<0.05), while there was no significant differences in PGC1alpha expression among different groups. Conclusion: Down regulation of FNDC5 transcript level may contribute in metabolic disturbance of granulosa cells derived from PCOS ovary apart from PGC1alpha levels which remained unchanged. PMID- 30009143 TI - Angiotensin Type 2 Receptor Gene Polymorphisms and Susceptibility to Preeclampsia. AB - Background: The purpose of the study was to determine the relationship between angiotensin II type 1 receptor at position+1166 (AT1R+1166A/C; rs5186) and angiotensin II type 2 receptor at position+1675 (AT2R+1675A/G; rs5194) gene polymorphisms with preeclampsia in an Iranian women population. Methods: 430 women were recruited in this study including 212 preeclamptics and 218 healthy women. PCR-RFLP method was used for genotyping the polymorphisms. Chi square and Fisher exact test were used for comparing case and control groups. The p<0.05 was considered statistically significant. Results: The frequency of genotypes of the AT1R gene and AT2R gene was similar in preeclampsia and normal pregnancy. There were no significant differences in genotype and also allele frequencies between preeclamptics and healthy women regarding the two studied polymorphisms. AT1R/AT2R genotypes combination study indicated that there was a statistically significant difference between preeclamptics and healthy women. AC/AG combination was significantly decreased, while CC/AA combination showed significant increase in patients compared with the healthy women (p<0.01). Conclusion: The present study showed that the genetic polymorphisms within AT1R and AT2R genes may be associated with susceptibility to preeclampsia in Iranian women. PMID- 30009144 TI - Decreased Expression of CDC25A in Azoospermia as the Etiology of Spermatogenesis Failure. AB - Background: Spermatogenesis is a tightly regulated developmental process of male germ cells. The stages in spermatogenesis are mitosis, meiosis and spermiogenesis. One of the genes playing a role in meiosis is Cell Division Cycle 25A (CDC25A). Decreased expression of CDC25A is associated with failure of spermatogenesis and sperm retrieval. Infertility examination for azoospermia has been limited on histological examination. Hence, molecular research to find marker genes for infertility will improve the examination of testis biopsies. Methods: This research is a cross sectional study of 50 testicular biopsies with Johnsen scoring categories from scoring 2 to 8. Analysis of mRNA expression used qPCR and protein expression using immunohistochemistry. Statistical analysis with Spearman correlation was considered significant at p<0.05. Results: The result showed that transcript level and protein expression of CDC25A decreased in score 5 of Johnsen scoring categories. Moderate Spearman rho correlation (r=0.546) between mRNA relative expression and protein expression of CDC25A was significant at p<0.01. Conclusion: Decreased expression of CDC25A is associated with meiotic arrest as the etiology of spermatogenic failure in many azoospermic men. PMID- 30009145 TI - Metabolic Fingerprinting of Seminal Plasma from Non-obstructive Azoospermia Patients: Positive Versus Negative Sperm Retrieval. AB - Background: Non-obstructive azoospermia (NOA) occurs in approximately 10% of infertile men. Retrieval of the spermatozoa from the testicle of NOA patients is an invasive approach. Seminal plasma is an excellent source for exploring to find the biomarkers for presence of spermatozoa in testicular tissue. The present discovery phase study aimed to use metabolic fingerprinting to detect spermatogenesis from seminal plasma in NOA patients as a non-invasive method. Methods: In this study, 20 men with NOA were identified based on histological analysis who had their first testicular biopsy in 2015 at Avicenna Fertility Center, Tehran, Iran. They were divided into two groups, a positive testicular sperm extraction (TESE(+)) and a negative testicular sperm extraction (TESE(-)). Seminal plasma of NOA patients was collected before they underwent testicular sperm extraction (TESE) operation. The metabolomic fingerprinting was evaluated by Raman spectrometer. Principal component analysis (PCA) and an unsupervised statistical method, was used to detect outliers and find the structure of the data. The PCA was analyzed by MATLAB software. Results: Metabolic fingerprinting of seminal plasma from NOA showed that TESE (+) versus TESE(-) patients were classified by PCA. Furthermore, a possible subdivision of TESE(-) group was observed. Additionally, TESE(-) patients were in extreme oxidative imbalance compared to TESE(+) patients. Conclusion: Metabolic fingerprinting of seminal plasma can be considered as a breakthrough, an easy and cheap method for prediction presence of spermatogenesis in NOA. PMID- 30009146 TI - To What Extent Are Cryopreserved Sperm and Testicular Biopsy Samples Used in Assisted Reproduction? AB - Background: Testicular biopsies and ejaculated spermatozoa are routinely cryopreserved in many units but the fate of these samples has not provoked large interest. This prompted us to review our data accumulated during a period of 20 years (1997 to 2016). Methods: For patients with biopsies (group 1) or ejaculated spermatozoa (group 2), an attempt was made to evaluate whether the samples stored, had been discarded with the patient's consent or because the patient had died, or whether they had been transported to another laboratory. In each of these categories, a previous use in our program of assisted reproduction was assessed. Results: The total utilization rate in group 1 (n=95) was 53.7% and only 5.48% in group 2 (n=365). In both groups, deceased patients had not previously used their cryopreserved samples. In detail, the utilization rates for still banked, discarded and transferred samples were 84.2%, 50% and 27.3%, respectively in group 1 and 2.88%, 10.4% and 10%, respectively in group 2. Conclusion: The exact reasons for the low utilization rates of cryopreserved male gametes remain to be explored. A closer contact between sperm banking units and patients might be useful to discuss the need for further storage of the probes, their possible disposal or the prospects when a specific use for assisted reproduction is intended. PMID- 30009147 TI - Ebstein Anomaly with Pregnancy: A Rare Case. AB - Background: Ebstein anomaly is an uncommon, complex congenital malformation of the heart with prevalence of 0.3-0.5%. It occurs in 1% of congenital heart disease cases. It is characterized by dysplastic abnormalities of tricuspid valve which involves both basal and free attachments of the tricuspid valve leaflets, with downward displacement and elongation of the septal and anterior cusp which resulting in tricuspid regurgitation, the proximal part of the right ventricle is "atrialised", becoming thin walled and poorly contractile, along with an enlarged right atrium. With this anomaly, fertility is usually unaffected, even in women with cyanosis. The average life expectancy at birth of patients with Ebstein anomaly is 25-30 years. Due to its rarity and varied clinical presentations associated with Ebstein anomaly during pregnancy, this case was presented in this paper. Case Presentation: A 24 year old G2A1 at 39 weeks 6 days gestation with a known case of Ebstein anomaly was referred to NEIGRIHMS in April 2017 for further management as our institute is having well equipped cardiac facilities. Her antepartum period was uneventful. Elective LSCS was done at 40 weeks 3 days and a healthy baby weighing 2.5 kg was delivered. Intra and postpartum period was uneventful. Conclusion: Due to varied clinical presentations associated with Ebstein anomaly during pregnancy, such women should undergo close surveillance with multidisciplinary approach during the antenatal period to be diagnosed in terms of complications and hence be treated accordingly. PMID- 30009148 TI - A Comparison of Continuous Thoracic Epidural Analgesia with Bupivacaine Versus Bupivacaine and Dexmedetomidine for Pain Control in Patients with Multiple Rib Fractures. AB - Background: The control of pain in traumatic patients with chest injury leading to rib fracture is one of the primary goals in traumatic patients. The efficacy of the thoracic epidural approach in comparison with other approaches for relieving post-thoracotomy pain is unknown. The goal of the present study was to compare thoracic epidural analgesia with bupivacaine alone and in combination with dexmedetomidine in patients with multiple rib fractures. Methods: 64 traumatic patients with multiple rib fractures were selected and randomly assigned to two similar groups. For pain relief, a thoracic epidural catheter was inserted to infuse bupivacaine alone or the combination of bupivacaine and dexmedetomidine. Then, we recorded and analyzed pain scores and ABG changes. Results: Based on the results, the two approaches could result in proper analgesia, but analgesia with the combination of bupivacaine and dexmedetomidine was significantly improved compared to bupivacaine alone (P < 0.05). In addition, ABG of patients significantly changed when the combination of bupivacaine and dexmedetomidine was used within 2 to 4 days (P < 0.05). Conclusions: The results of the present study showed that epidural infusion of a combination of bupivacaine and dexmedetomidine could provide better control of rib fracture pain in traumatic patients, and is a proper alternative for bupivacaine alone. PMID- 30009149 TI - The Effect of Dexmedetomidine Prescription on Shivering during Operation in the Spinal Anesthesia Procedures of Selective Orthopedic Surgery of the Lower Limb in Addicted Patients. AB - Background: Shivering during a surgery is common. Recently, Alpha-D-agonist dexmedetomidine has been used to control and prevent shivering during and after surgery. However, the anti-shivering effects of this drug in people are unknown with substance abuse. The purpose of this study was to investigate the anti shivering effect of this drug in addicted individuals. Methods: After obtaining the required criteria, the criteria were randomized in 2 groups, dexmedetomidine and normal saline (each group n = 30), and were matched in age and sex. The dexmedetomidine 0.5 mg/kg/h was given to one group and normal saline infusion was given to the other group as a placebo immediately after induction of anesthesia and before surgery for lower limb lesions. During the operation, patients were monitored for shivering as well as vital signs and arterial oxygen saturation. In addition, after surgery, patients were evaluated for clinical side effects. Results: The results showed that systolic blood pressure was significantly lower in the dexmedetomidine group at 30 minutes to 150 minutes after injection during the operation (P < 0.01). There was no significant difference between the 2 groups at the other times. In intra-group comparisons in both groups, diastolic pressure drop was significantly decreased to 90 minutes after surgery. In general, at other times in each group, diastolic pressure changes were not significant compared to preoperative. In between group comparisons, the mean heart rate was significantly lower in the dexmedetomidine group at 30 minutes and 60 minutes compared to the control group. In addition, at other times, its lower values were not significantly different with the control group. The 2 groups did not show significant differences in the number of breaths per minute or as the intra-group (P > 0.05), although, the average respiratory rate per minute in the dexmedetomidine group was lower. Decreased temperature of the tympanic curvature was significantly lower in the DEX group at 10 and 60 minutes after surgery than the control group (P < 0.001). Arterial oxygen saturation was more than 97% in both groups before and after operation, and no difference was observed between the 2 groups. Conclusions: Prescribing dexmedetomidine during spinal anesthesia in patients with substance abuse can significantly decrease the incidence of shivering during surgery while not having adverse effects on hemodynamics of patients and can be used as a safe and effective drug for this purpose. PMID- 30009150 TI - Effect of Perioperative Intravenous Lignocaine Infusion on Haemodynamic Responses and postoperative Analgesia in Laparoscopic Cholecystectomy Surgeries. AB - Background: During general anaesthesia, intubation of trachea and extubation of trachea are often associated with increase in haemodynamic response. Laparoscopic cholecystectomy is a minimal access surgery; postoperatively patients may experience moderate to severe pain. It is well known that lignocaine is useful in attenuating haemodynamic response to intubation and extubation. Previous studies also state that perioperative lignocaine infusion provides postoperative analgesia as well. We hypothesize that perioperative intravenous lignocaine infusion can both attenuate haemodynamic responses to intubation and extubation of trachea and also provide good postoperative analgesia in laparoscopic cholecystectomy surgeries. Methods: Double blinded randomized controlled trial was undertaken at the department of anesthesia, Sri Siddartha medical college. In group A, 0.9% normal saline was used as placebo for perioperative intravenous infusion. In group B, preservative free 1.5 mg/kg 2 % lignocaine (Loxicard) diluted with normal saline to 1% given at 10 minutes to induction as bolus, followed by an infusion of 1.5 mg/kg/h. till 1 hour postoperatively. Results: In Group B there was a statistically less rise in heart rate [HR] and mean blood pressure [MBP] during intubation and extubation of trachea compared to group A. In group B there was a statistically significant increase in the mean pain free period postoperatively compared to group A. Conclusions: Perioperative intravenous infusion of lignocaine attenuates haemodynamic response during the intubation and extubation of the trachea. In addition, it also increases the mean pain free period postoperatively. PMID- 30009151 TI - Comparison of Oral Melatonin and Midazolam as Premedication in Children Undergoing General Anesthesia for Dental Treatment. AB - Background: Dental anxiety is prevalent in children. This condition may cause uncooperative behavior and need a treatment under general anesthesia. The perioperative period, especially for children, is a stressing event. Premedication is commonly used to reduce perioperative anxiety and facilitate the induction of anesthesia. Methods: 132 children candidates for dental treatment under GA were enrolled in this study and randomly divided into 3 groups. Oral melatonin, midazolam, and normal saline were administered as premedication. Patient's sedation score before GA, the ease of intravenous line establishment, patient's need for painkillers, and duration of recovery were evaluated and compared. Results: Regarding the sedation score and response to IV access establishment, comparisons showed statistically significant differences between melatonin and midazolam groups (P < 0.05) as well as between midazolam and placebo groups (P < 0.001). The difference between melatonin and placebo groups was not significant (P > 0.05). The need for painkiller administration was statistically different between midazolam and placebo, melatonin and placebo, and midazolam and melatonin groups (P < 0.05). A statistically significant difference was also found between melatonin and midazolam as well as between melatonin and placebo groups (P < 0.05) with regard to the recovery duration while no significant difference was observed between midazolam and placebo groups (P > 0.05). Conclusion: Midazolam is superior to melatonin for premedication regarding the patients' sedation score before anesthesia and the ease of IV access establishment. Premedication with midazolam decreases the need for painkillers and increases the rate of recovery in children undergoing GA for dental treatment. PMID- 30009152 TI - The Determination of an Appropriate Time for Placement of the Classic Laryngeal Mask Airway in Patients Undergoing General Anesthesia. AB - Background: The management of the airways is an essential component of anesthesia planning. Laryngeal mask airway (LMA) plays an important role in modern anesthesia, however, intubation by LMA has some complications. It may cause inadequate anesthesia depth, which can lead to adverse events. The aim of this study was to evaluate the optimal time for intubation by LMA under general anesthesia. Methods: This study was conducted on 96 patients, who underwent operation and were appropriate candidates for intubation with appropriate LMA. The participants were divided to four groups, each with 24 cases, based on the time interval between anesthetic agent administration and intubation with LMA; 15 seconds for the first group, 16 to 30 seconds for the second group, 31 to 45 seconds for the third group, and 45 to 60 seconds for the fourth group. The patients involved in these groups were selected based on the following prerequisites, patients' age, gender, easy intubation, need for additional drug administration, basic blood pressure before drug administration, within the time intervals one, three, and five minutes after placement of LMA, duration of LMA, SaO2 before and after placement of LMA, coughing, patient's movement, laryngospasm, gag reflex after intubation, allowing appropriate ventilation, presence of sore throat after surgery, number of attempts, extent of mouth opening and leak in peri-LMA space. Results: Overall, 72 males and 24 females participated in this study with a mean age of 40.64. Intubation by LMA was performed easily during the first attempt in 58% of the participants, with minimal resistance in 28.6% and with some problems during the second attempt in 10.5% of the cases. Throat pain after the operation was significantly lower. Systolic and diastolic pressure and heart rate had no statistically significant difference. Conclusions: The results showed that in the first 15 seconds after the drug (e.g. propofol) administration, there were lower complications, rapid placement, and optimized time for the placement of LMA. The rate of success and its quality were reduced during the first attempt of insertion and termination of the effect of propofol. PMID- 30009153 TI - A Comparative Study of the Amount of Bleeding and Hemodynamic Changes between Dexmedetomidine Infusion and Remifentanil Infusion for Controlled Hypotensive Anesthesia in Lumbar Discopathy Surgery: A Double-Blind, Randomized, Clinical Trial. AB - Background: The aim of this study was to compare the volume of blood loss and hemodynamic changes in patients undergoing lumbar discopathy, after continuous infusions of dexmedetomidine versus remifentanil during anesthesia with controlled low blood pressure. Methods: In this randomized double-blind clinical trial, 60 patients aged 20 to 65 years were randomly assigned to control and intervention groups. The intervention group received a continuous infusion of dexmedetomidine at 0.3 - 0.7 ug/kg/hour plus propofol at 50 - 100 ug/kg/minute. The control group was given a continuous infusion of remifentanil at 0.1 to 1 ug/kg/minute plus the same dose of propofol as above. The primary outcome was the amount of patient's bleeding during surgery, and secondary outcomes were changes in the patient's systolic blood pressure, diastolic blood pressure, mean arterial pressure, and urinary output. Results: Univariate and multivariate analyses of the main outcome in the control and intervention groups showed that there was no significant difference between the two drugs with regards to the volume of blood loss, mean arterial pressure, and systolic and diastolic blood pressure. Postoperative side effects were significantly lower in the intervention group (P = 0.002). Conclusions: Administration of dexmedetomidine plus propofol in comparison with remifentanil plus propofol did not show any significant difference regarding blood loss and hemodynamic changes; however, it reduced some side effects after surgery and decreased analgesic requirement in the postoperative period. Taken together, the findings of this study do not support strong recommendations for dexmedetomidine infusion for all patients and the decision should be taken with caution on basis of the anesthesiologist's expert opinion and the patient's condition during surgery. PMID- 30009154 TI - A Non Platinum Regimen for the Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Region. Results From an Extended Phase II Study With Paclitaxel and Capecitabine. AB - Background: This study presents the results of an extended phase II study originally published in 2007, regarding the antitumor activity and toxicity of a non-platinum containing regimen with paclitaxel and capecitabine for the treatment of recurrent or disseminated squamous cell carcinoma of the head and neck region. Fifty patients were included in the original study. Materials and methods: A total of 183 patients with recurrent or disseminated squamous cell carcinoma were eventually included in the extended study. There were 37 women and 146 men. The mean age was 56 years. Performance status (WHO) was as follows: WHO 0:31, WHO 1:107, and WHO 2:45 patients. The treatment consisted of paclitaxel 175 mg/m2, once every third week and capecitabine 825 mg/m2 p.o. b.i.d for 2 weeks. Results: The overall response rate (complete response and partial response) according to the WHO criteria was: 33% (CI 26-40). The median progression-free survival was 4.8 (CI 4.2-5.4) months. The median overall survival (OS) was 8.9 (CI 7.6-9.5) months. Compliance was good. Of the 1,131 cycles, only 13% had to be administered with a reduced dose and/or postponed to a later date. Toxicity was mild and grades 3 and 4 toxicities were uncommon. Two toxic deaths were registered though. Conclusion: The response rate and the OS for this low toxicity regimen makes it a feasible alternative for not cisplatin eligible patients. PMID- 30009155 TI - Genomic Deletion at 10q23 in Prostate Cancer: More Than PTEN Loss? AB - The PTEN gene encodes for the phosphatase and tensin homolog; it is a tumor suppressor gene that is among the most frequently inactivated genes throughout the human cancer spectrum. The most recent sequencing approaches have allowed the identification of PTEN genomic alterations, including deletion, mutation, or rearrangement in about 50% of prostate cancer (PCa) cases. It appears that mechanisms leading to PTEN inactivation are cancer-specific, comprising gene mutations, small insertions/deletions, copy number alterations (CNAs), promoter hypermethylation, and RNA interference. The examination of publicly available results from deep-sequencing studies of various cancers showed that PCa appears to be the only cancer in which PTEN is lost mostly through CNA. Instead of inactivating mutations, which are seen in other cancers, deletion of the 10q23 locus is the most common form of PTEN inactivation in PCa. By investigating the minimal deleted region at 10q23, several other genes appear to be lost simultaneously with PTEN. Expression data indicate that, like PTEN, these genes are also downregulated upon loss of 10q23. These analyses raise the possibility that 10q23 is lost upon selective pressure not only to inactivate PTEN but also to impair the expression of surrounding genes. As such, several genes from this deleted region, which represents about 500 kb, may also act as tumor suppressors in PCa, requiring further studies on their respective functions in that context. PMID- 30009156 TI - Macroscopic Portal Vein Thrombosis in HCC Patients. AB - Macroscopic portal vein invasion (PVT) by hepatocellular carcinoma (HCC) in the liver is one of the most important negative prognostic factors for HCC patients. The characteristics of a large cohort of such patients were examined. We found that the percent of patients with PVT significantly increased with increasing maximum tumor diameter (MTD), from 13.7% with tumors of MTD <5cm to 56.4% with tumors of MTD >10cm. There were similar numbers of HCC patients with very large tumors with and without PVT. Thus, MTD alone was insufficient to explain the presence of PVT, as were high AFP levels, since less than 50% of high AFP patients had PVT. However, the percent of patients with PVT was also found to significantly increase with increasing blood alpha-fetoprotein (AFP) levels and tumor multifocality. A logistic regression model that included these 3 factors together showed an odds ratio of 17.9 for the combination of MTD>5.0cm plus tumor multifocality plus elevated AFP, compared to low levels of these 3 parameters. The presence or absence of macroscopic PVT may therefore represent different HCC aggressiveness phenotypes, as judged by a significant increase in tumor multifocality and AFP levels in the PVT positive patients. Factors in addition to MTD and AFP must also contribute to PVT development. PMID- 30009157 TI - The Continental Divide: Anti-TNF Use in Pediatric IBD Is Different in North America Compared to Other Parts of the World. AB - Background and Aims: Use of anti-TNF therapies varies internationally. As an initiative of the international Pediatric IBD Network (PIBDNet), we compared global pediatric IBD anti-TNF practice patterns. Methods: Physicians were surveyed about anti-TNF use in Crohn's disease (CD) and ulcerative colitis (UC). Chi-squared, independent samples Mann-Whitney U, or related samples Wilcoxon signed rank tests were used to compare groups. Results: 344 physicians treating pediatric IBD responded from 43 countries (54% North America, 29% Europe, 6% Oceania, 6% Asia, 3% Africa, and 2% South America). Respondents treated a median 40 IBD patients. CD was more commonly treated with anti-TNF than UC (40% vs. 10%, p<0.001). North Americans more often used anti-TNF (median 50% vs. 30%, p<0.001) and before immunomodulator (80% vs. 35% CD, p<0.001; 76% vs. 43% steroid dependent UC, p<0.001). Anti-TNF monotherapy was more common in North America. Anti-TNF in combination with methotrexate, instead of thiopurine, characterized North American practices. North Americans more often continued immunomodulator indefinitely and less often adhered to standard infliximab induction dosing. Access limitations were more common outside North America and Europe for both CD (67% vs. 31%, p<0.001) and UC (62% vs. 33%, p<0.001). Conclusions: Anti-TNF use in North America varies significantly from elsewhere. PMID- 30009159 TI - Multisensor Systems by Electrochemical Nanowire Assembly for the Analysis of Aqueous Solutions. AB - The development of electrochemical multisensor systems is driven by the need for fast, miniature, inexpensive, analytical devices, and advanced interdisciplinary based on both chemometric and (nano)material approaches. A multicomponent analysis of complex mixtures in environmental and technological monitoring, biological samples, and cell culture requires chip-based multisensor systems with high-stability sensors. In this paper, we describe the development, characterization, and applications of chip-based nanoelectrochemical sensor arrays prepared by the directed electrochemical nanowire assembly (DENA) of noble metals and metal alloys to analyze aqueous solutions. A synergic action of the electrode transducer function and electrocatalytic activity of the nanostructured surface toward analytes is achieved in the assembled metal nanowire (NW) sensors. Various sensor nanomaterials (Pd, Ni, Au, and their multicomponent compositions) can be electrochemically assembled on a single chip without employing multiple cycles of photolithography process to realize multi-analyte sensing applications as well as spatial resolution of sensor analysis by this single-chip multisensor system. For multi-analyte electrochemical sensing, individual amperometric signals of two or more nanowires can be acquired, making use of the specific electrocatalytic surface properties of the individual nanowire sensors of the array toward analytes. To demonstrate the application of a new electrochemical multisensor platform, Pd-Au, Pd-Ni, Pd, and Au NW electrode arrays on a single chip were employed for the non-enzymatic analysis of hydrogen peroxide, glucose, and ethanol. The analytes are determined at low absolute values of the detection potentials with linear concentration ranges of 1.0 * 10-6 - 1.0 * 10-3 M (H2O2), 1.5 * 10-7 - 2.0 * 10-3 M (glucose), and 0.7 * 10-3 - 3.0 * 10-2 M (ethanol), detection limits of 2 * 10-7 M (H2O2), 4 * 10-8 M (glucose), and 5.2 * 10-4 M (ethanol), and sensitivities of 18 MUA M-1 (H2O2), 178 MUA M-1 (glucose), and 28 MUA M-1 (ethanol), respectively. The sensors demonstrate a high level of stability due to the non-enzymatic detection mode. Based on the DENA-assembled nanowire electrodes of a compositional diversity, we propose a novel single-chip electrochemical multisensor platform, which is promising for acquiring complex analytical signals for advanced data processing with chemometric techniques aimed at the development of electronic tongue-type multisensor systems for flexible multi-analyte monitoring and healthcare applications. PMID- 30009160 TI - Comparative Anatomy of Mitral and Tricuspid Valve: What Can the Interventionlist Learn From the Surgeon. AB - : Transcatheter valve interventions on the mitral and tricuspid valves entail increasing complexity. Part of the knowledge that has been generated during the development of mitral devices can be transferred to the tricuspid valve (TV). However, a deeper understanding of the peculiar anatomy of the TV and of the right heart chambers, together with differences and similarities between the two valves, is fundamental. This report compares the anatomy of the mitral and tricuspid valves, and its inferences with regard to transcatheter treatments. Condensed abstract: This report explores anatomical similarities and differences between the mitral and the tricuspid valves, and their implications with regard to transcatheter treatments. PMID- 30009158 TI - Economic Evaluations of Treatments for Inflammatory Bowel Diseases: A Literature Review. AB - Objective: The objective of this literature review was to evaluate the existing evidence regarding the cost-effectiveness of treatment options in IBD. Methods: A systematic review of the literature was conducted to identify economic evaluations of IBD therapy. The literature search was performed using electronic databases MEDLINE and EMBASE. Searches were limited to full economic evaluations published in English or French between 2004 and 2016. Results: A total of 5,403 potentially relevant studies were identified. After screening titles and abstracts, 48 studies were included, according to the eligibility criteria. A total of 56% and 42% of the studies were assessing treatments of UC or CD, respectively. Treatment options under evaluation included biological agents, mesalamine, immunosuppressants, and surgery. The majority of studies evaluated the cost-effectiveness of biological treatments. Biological therapies were dominant in 23% of the analyses and were cost-effective according to a $CAD50,000/QALY and $CAD100,000/QALY threshold in 41% and 62% of the analyses, respectively. Conclusion: This literature review provided a comprehensive overview of the economic evaluations for the different treatment options for IBD over the past 12 years and represents a helpful reference for future economic evaluations. PMID- 30009161 TI - Comparative Effects of Different Dosages of hCG on Follicular Development in Postpartum Dairy Cows With Cystic Ovarian Follicles. AB - The objective of this study was to determine the effects of different intramuscular dosages of human chorionic gonadotropin (hCG) on ovarian follicular development of dairy cows diagnosed with refractory cystic ovarian follicles (COFs). Cows diagnosed with COFs (>=25 mm in diameter) were allocated to four treatment groups: hCG-1 (n = 3), a single dose of 4,500 IU on day 1; hCG-2 (n = 3), 2,250 IU on days 1 and 3; hCG-3 (n = 3), 1,500 IU on days 1, 3, and 5; and hCG-C (n = 3) received saline on day 1. Blood sampling and ovarian ultrasonographic (US) examinations were performed on days 1, 3, 5, 7, and 14. A progesterone (P4) value < 1 ng/ml was used as an indicator of absence of a functional CL. A significant increase (P < 0.05) in the number of follicles < 4 mm in diameter was observed in the hCG-2 group on day 5. Additionally, there was a significant difference in the number of follicles < 4 mm (P < 0.05) between both the hCG-2 and hCG-3 groups compared to the hCG-C group on day 5, and a tendency (P = 0.08) toward a difference in the number of 5-9 mm follicles in groups hCG-3, hCG-2, and hCG-1, compared with the hCG-C group on day 7. The proportion of cows on days 7 and 14 with P4 > 1 ng/ml was 100% (3/3) and 100% (3/3) in group hCG-1; 100% (3/3) and 67% (2/3) in group hCG-2; 67% (2/3) and 100% (3/3) in group hCG-3; and 33% (1/3) and 33% (1/3) in group hCG-C, respectively. Strong tendencies of P4 increases in group hCG-1 (P = 0.054) and hCG-2 (P = 0.051) were measured after hCG administration. Additionally, P4 values tended to be higher (P = 0.07) for group hCG-1 compared to group hCG-C on day 5. The preliminary findings of this study suggest that multiple smaller doses of hCG might be equally effective as a single large dose of hCG in modulating ovarian follicular development in dairy cows with COFs. PMID- 30009162 TI - Topological Characterization of Human and Mouse m5C Epitranscriptome Revealed by Bisulfite Sequencing. AB - Background: Compared with the well-studied 5-methylcytosine (m5C) in DNA, the role and topology of epitranscriptome m5C remain insufficiently characterized. Results: Through analyzing transcriptome-wide m5C distribution in human and mouse, we show that the m5C modification is significantly enriched at 5' untranslated regions (5'UTRs) of mRNA in human and mouse. With a comparative analysis of the mRNA and DNA methylome, we demonstrate that, like DNA methylation, transcriptome m5C methylation exhibits a strong clustering effect. Surprisingly, an inverse correlation between mRNA and DNA m5C methylation is observed at CpG sites. Further analysis reveals that RNA m5C methylation level is positively correlated with both RNA expression and RNA half-life. We also observed that the methylation level of mitochondrial RNAs is significantly higher than RNAs transcribed from the nuclear genome. Conclusions: This study provides an in-depth topological characterization of transcriptome-wide m5C modification by associating RNA m5C methylation patterns with transcriptional expression, DNA methylations, RNA stabilities, and mitochondrial genome. PMID- 30009163 TI - Mesenchymal Stem Cells Attenuate Radiation-Induced Brain Injury by Inhibiting Microglia Pyroptosis. AB - Radiation-induced brain injury (RI) commonly occurs in patients who received head and neck radiotherapy. However, the mechanism of RI remains unclear. We aimed to evaluate whether pyroptosis was involved in RI and the impact of mesenchymal stem cells (MSCs) on it. BALB/c male mice (6-8 weeks) were cranially irradiated (15 Gy), and MSCs were transplanted into the bilateral cortex 2 days later; then mice were sacrificed 1 month later. Meanwhile, irradiated BV-2 microglia cells (10 Gy) were cocultured with MSCs for 24 hours. We observed that irradiated mice brains presented NLRP3 and caspase-1 activation. RT-PCR then indicated that it mainly occurred in microglia cells but not in neurons. Further, irradiated BV-2 cells showed pyroptosis and increased production of IL-18 and IL-1beta. RT-PCR also demonstrated an increased expression of several inflammasome genes in irradiated BV-2 cells, including NLRP3 and AIM2. Particularly, NLRP3 was activated. Knockdown of NLRP3 resulted in decreased LDH release. Noteworthily, in vivo, MSCs transplantation alleviated radiation-induced NLRP3 and caspase-1 activation. Moreover, in vitro, MSCs could decrease caspase-1 dependent pyroptosis, NLRP3 inflammasome activation, and ROS production induced by radiation. Thus, our findings proved that microglia pyroptosis occurred in RI. MSCs may act as a potent therapeutic tool in attenuating pyroptosis. PMID- 30009164 TI - Numerical Evaluation and Prediction of Porous Implant Design and Flow Performance. AB - Porous structure has been widely acknowledged as important factor for mass transfer and tissue regeneration. This study investigates effect of aimed-control design on mass transfer and tissue regeneration of porous implant with regular unit cell. Two shapes of unit cells (Octet truss, and Rhombic dodecahedron) were selected, which have similar symmetrical structure and are commonly used in practice. Through parametric design, porous scaffolds with the strut sizes of phi 0.5, 0.7, 0.9, and 1.1mm were created, respectively. Then using fluid flow simulation method, flow velocity, permeability, and shear stress which could reflect the properties of mass transfer and tissue regeneration were compared and evaluated, and the relationships between porous structure's physical parameters and flow performance were studied. Results demonstrated that unit cell shape and strut size greatly determine and influence other physical parameters and flow performances of porous implant. With the increasing of strut size, pore size and porosity linearly decrease, but the volume, surface area, and specific surface area increased. Importantly, implant with smaller strut size resulted in smaller flow velocity directly but greater permeability and more appropriate shear stress, which should be beneficial to cell attachment and proliferation. This study confirmed that porous implant with different unit cell shows different performances of mass transfer and tissue regeneration, and unit cell shape and strut size play vital roles in the control design. These findings could facilitate the quantitative assessment and optimization of the porous implant. PMID- 30009165 TI - Reliability and Concurrent Validity of a Chinese Version of the Alberta Infant Motor Scale Administered to High-Risk Infants in China. AB - The Alberta Infant Motor Scale (AIMS) is widely used to screen for delays in motor development in high-risk infants, but its reliability and validity in Chinese infants have not been investigated. To examine the reliability and concurrent validity of AIMS in high-risk infants aged 0-9 months in China, this single-center study enrolled 50 high-risk infants aged 0-9 months (range, 0.17 9.27; average, 4.14+/-2.02), who were divided into two groups: 0-3 months (n=23) and 4-9 months (n=27). A physical therapist evaluated the infants with AIMS, with each evaluation video-recorded. To examine interrater reliability, two other evaluators calculated AIMS scores by observing the videos. To measure intrarater reliability, the two evaluators rescored AIMS after >1 month, using the videos. Concurrent validity was assessed by comparing results between AIMS and the Peabody Developmental Motor Scale-2 (PDMS-2). For all age groups analyzed (0-3, 4 9, and 0-9 months), intraclass correlation coefficients (ICCs) for AIMS total score were high for both intrarater comparisons (0.811-0.995) and interrater comparisons (0.982-0.997). AIMS total scores were well correlated with all PDMS-2 subtest scores (ICC=0.751-0.977 for reflexes, stationary, locomotion, grasping, and visual-motor integration subsets). However, the fifth percentile of AIMS total score was only moderately correlated with the gross motor quotient, fine motor quotient, and total motor quotient subtests of PDMS-2 (kappa=0.580, 0.601, and 0.724, respectively). AIMS has acceptable reliability and concurrent validity for screening of motor developmental delay in high-risk infants in China. PMID- 30009166 TI - Could Prolonged Usage of GPS Navigation Implemented in Augmented Reality Smart Glasses Affect Hippocampal Functional Connectivity? AB - Background: Augmented reality (AR) glasses with GPS navigation represent the rapidly evolving technology which spares (and externalizes) navigational capacities. Regarding the expected everyday usage of this device, its impact on neuroplastic brain changes and navigation abilities should be evaluated. Aims: This study aimed to assess possible changes in functional connectivity (FC) of hippocampus and other brain regions involved in spatial navigation. Methods: Thirty-three healthy participants completed two resting state functional magnetic resonance imaging (rsfMRI) measurements at the baseline and after 3 months. For this period, the experimental group (n = 17) has had used AR device (Vuzix M100) with incorporated GPS guidance system during navigation in real world. Participants from the control group (n = 16) have not used any GPS device while navigating during walking. The rsfMRI FC of right and left hippocampi was analyzed using a seed-driven approach. Virtual city task was used to test navigational abilities both before and after the usage of AR device. Results: We identified strong functional coupling of right and left hippocampi at the baseline (p < 0.05, FDR corrected). Mild changes in bilateral hippocampal FC (p < 0.05, FDR uncorrected) were observed in both assessed groups mainly between the bilateral hippocampi and between each hippocampus and temporal regions and cerebellum. However, the experimental group showed FC decrease after three months of using GPS navigation implemented in AR glasses in contrast to FC increase in the control group without such intervention. Importantly, no effect of intervention on navigational abilities was observed. Discussion: Our observation supports the assumption that externalization of spatial navigation to technological device (GPS in AR glasses) can decrease the functional coupling between hippocampus and associated brain regions. Considering some limitations of the present study, further studies should elucidate the mechanism of the observed changes and their impact on cognitive abilities. PMID- 30009167 TI - Identification of Feline Interferon Regulatory Factor 1 as an Efficient Antiviral Factor against the Replication of Feline Calicivirus and Other Feline Viruses. AB - Interferons (IFNs) can inhibit most, if not all, viral infections by eliciting the transcription of hundreds of interferon-stimulated genes (ISGs). Feline calicivirus (FCV) is a highly contagious pathogen of cats and a surrogate for Norwalk virus. Interferon efficiently inhibits the replication of FCV, but the mechanism of the antiviral activity is poorly understood. Here, we evaluated the anti-FCV activity of ten ISGs, whose antiviral activities were previously reported. The results showed that interferon regulatory factor 1 (IRF1) can significantly inhibit the replication of FCV, whereas the other ISGs tested in this study failed. Further, we found that IRF1 was localized in the nucleus and efficiently activated IFN-beta and the ISRE promoter. IRF1 can trigger the production of endogenous interferon and the expression of ISGs, suggesting that IRF1 can positively regulate IFN signalling. Importantly, the mRNA and protein levels of IRF1 were reduced upon FCV infection, which may be a new strategy for FCV to evade the innate immune system. Finally, the antiviral activity of IRF1 against feline panleukopenia virus, feline herpesvirus, and feline infectious peritonitis virus was demonstrated. These data indicate that feline IRF1 plays an important role in regulating the host type I IFN response and inhibiting feline viral infections. PMID- 30009168 TI - CD4+CD45RA-FOXP3low Regulatory T Cells as Potential Biomarkers of Disease Activity in Systemic Lupus Erythematosus Brazilian Patients. AB - Heren, we analyzed Treg cells as potential biomarkers of disease activity in systemic lupus erythematosus (SLE) patients. Peripheral blood mononuclear cells from 30 SLE patients (15 active: SLEDAI > 6/15 SLE remission: SLEDAI< 6) and 15 healthy volunteers were purified. Treg immunophenotyping was performed using CD4, CD25, CD45, CD127, and FOXP3 markers. CD4+FOXP3+ Treg activation state was investigated based on CD45RA and FOXP3 expression. To increase the accuracy of our findings, a multivariate linear regression was performed. We showed a significant increase in the frequency of CD4+FOXP3+ Treg cells in SLE patients. However, unlike all other Treg cells phenotypes analyzed, only eTreg (CD4+FOXP3highCD45RA-) (p=0.01) subtype was inversely correlated with disease activity while Foxp3+nontreg (CD4+FOXP3lowCD45RA-) (p=0.003) exerted a direct influence in the outcome of the disease. Foxp3+nontreg cells were the most consistent SLE active indicator, confirmed by multiple linear regression analyses. In summary, our results demonstrate Foxp3+nontreg cells as new biomarkers in the search of an effective therapeutic strategy in SLE. PMID- 30009169 TI - Prevalence and Risk Factors of MRI Abnormality Which Was Suspected as Sinusitis in Japanese Middle-Aged and Elderly Community Dwellers. AB - The aims of this study were to determine the prevalence of MRI abnormalities which were suspected as sinusitis in community-dwelling middle-aged and elderly Japanese and to identify risk factors for the MRI abnormality. Brain magnetic resonance imaging (MRI) data from the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA) were used for the analysis. Among the 2330 subjects in the NILS-LSA, 1933 participants were categorized as having no MRI abnormality or MRI abnormality using the Lund-Mackay (LM) score. The mean LM score of the participants was 0.88+/-1.92, and 144 (7.4%) participants had MRI abnormalities which were suspected as sinusitis when it was classified as an LM score greater than or equal to 4. The prevalence of MRI abnormality was significantly higher in participants of older age and the male sex, in participants with obesity, hypertension, bronchial asthma, chronic bronchitis, gout, or hyperuricemia and in ex- or current smokers. A multivariate logistic regression revealed that older age (odds ratio [OR] = 1.17), obesity (OR = 1.54), a smoking habit (OR = 1.71), history of asthma (OR = 3.77), and chronic bronchitis (OR = 2.66) were significant risk factors for MRI abnormality. PMID- 30009171 TI - Synovial Fluid Aspiration Should Not Be Routinely Performed during the Two-Stage Exchange of the Knee. AB - Purpose: Detection of infection persistence during the two-stage exchange of the knee for periprosthetic joint infection is challenging. Synovial fluid culture (SFC) and synovial white blood cell count (SWBCC) before joint reimplantation are widespread diagnostic means for this indication. The sensitivity and specificity of SFC and of SWBCC for infection persistence before planned reimplantation were evaluated. Methods: 94 two-stage exchanges of the knee with synovial fluid aspiration performed after a drug holiday of at least 14 days and before reimplantation or spacer exchange (planned reimplantation) were retrospectively analyzed. Only cases with at least 3 intraoperative samples at planned reimplantation were included. SFC and SWBCC were compared to pathogen detection (SFC(culture)/SWBCC(culture)) and to histopathological signs of infection persistence (SFC(histo)/SWBCC(histo)) from intraoperative samples at planned reimplantation. For SFC, the sensitivity and specificity were calculated. For SWBCC, the optimal cut-off value with its sensitivity and specificity was calculated with the Youden-Index. Results: Sensitivity and specificity of SFC(culture) were 0.0% and 98.9%. Sensitivity and specificity of SFC(histo) were 3.4% and 100%. The optimal cut-off value for SWBCC(culture) was 4450 cells/MUl with a sensitivity of 50.0% and a specificity of 86.5%. The optimal cut-off value for SWBCC(histo) was 3250 cells/MUl with a sensitivity of 35.7% and a specificity of 92.9%. Conclusion: The detection of infection persistence remains challenging and a consented approach is lacking. The results do not warrant the routine performance of SFC during the two-stage exchange at the knee. SWBCC can be used to confirm infection persistence at high cut-offs, but they only occur in few patients and are therefore inappropriate for the routine use. PMID- 30009172 TI - Use of a Radiomics Model to Predict Tumor Invasiveness of Pulmonary Adenocarcinomas Appearing as Pulmonary Ground-Glass Nodules. AB - Background: It is important to distinguish the classification of lung adenocarcinoma. A radiomics model was developed to predict tumor invasiveness using quantitative and qualitative features of pulmonary ground-glass nodules (GGNs) on chest CT. Materials and Methods: A total of 599 GGNs [including 202 preinvasive lesions and 397 minimally invasive and invasive pulmonary adenocarcinomas (IPAs)] were evaluated using univariate, multivariate, and logistic regression analyses to construct a radiomics model that predicted invasiveness of GGNs. In primary cohort (comprised of patients scanned from August 2012 to July 2016), preinvasive lesions were distinguished from IPAs based on pure or mixed density (PM), lesion shape, lobulated border, and pleural retraction and 35 other quantitative parameters (P <0.05) using univariate analysis. Multivariate analysis showed that PM, lobulated border, pleural retraction, age, and fractal dimension (FD) were significantly different between preinvasive lesions and IPAs. After logistic regression analysis, PM and FD were used to develop a prediction nomogram. The validation cohort was comprised of patients scanned after Jan 2016. Results: The model showed good discrimination between preinvasive lesions and IPAs with an area under curve (AUC) of 0.76 [95% CI: 0.71 to 0.80] in ROC curve for the primary cohort. The nomogram also demonstrated good discrimination in the validation cohort with an AUC of 0.79 [95% CI: 0.71 to 0.88]. Conclusions: For GGNs, PM, lobulated border, pleural retraction, age, and FD were features discriminating preinvasive lesions from IPAs. The radiomics model based upon PM and FD may predict the invasiveness of pulmonary adenocarcinomas appearing as GGNs. PMID- 30009170 TI - The Signaling Pathways Involved in the Antiatherosclerotic Effects Produced by Chinese Herbal Medicines. AB - Cardiovascular diseases (CVDs) are considered to be the predominant cause of death in the world. Chinese herb medicines (CHMs) have been widely used for the treatment of CVDs in Asian countries for thousands of years. One reason of high efficacy of CHMs in treating CVDs is attributed to their inhibition in atherosclerosis (AS) development, a critical contributor to CVDs occurrence. Cumulative studies have demonstrated that CHMs alleviate atherogenesis via mediating pathophysiologic events involved in AS. However, there is deficiency in the summaries regarding antiatherogenic signal pathways regulated by CHMs. In this review, we focus on the signal cascades by which herb medicines and relevant extractives, derivatives, and patents improve proatherogenic processes including endothelium dysfunction, lipid accumulation, and inflammation. We mainly elaborate the CHMs-mediated signaling pathways in endothelial cells, macrophages, and vascular smooth muscle cells of each pathogenic event. Moreover, we briefly describe the other AS-related factors such as thrombosis, autophagy, immune response, and noncoding RNAs and effects of CHMs on them in the way of cascade regulation, which is helpful to further illustrate the molecular mechanisms of AS initiation and progression and discover newly effective agents for AS management. PMID- 30009173 TI - Association between HLA-DP Gene Polymorphisms and Cervical Cancer Risk: A Meta Analysis. AB - Objective. We aimed to derive a more precise estimation of the associations between human leukocyte antigens DP (HLA-DP) gene polymorphisms and cervical cancer risk by meta-analysis. Methods. PubMed, EMBASE, ScienceDirect, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were systematically searched to identify studies investigating the relationship between HLA-DP gene polymorphisms and cervical cancer. The associations between them were evaluated by pooled OR and 95% CI. Results. A total of 11 studies including 5008 cases and 9322 controls with 11 HLA-DP alleles were included in the current meta-analysis. Results. The results showed that HLA-DPB1*03:01 was significantly associated with an increased risk of cervical cancer (OR=1.252, 95%CI: 1.116-1.403, Pz=0.001), while HLA-DPB1*04:02 and HLA-DP rs3117027 G allele were significantly associated with a decreased risk of cervical cancer (OR=0.744, 95%CI: 0.652-0.848, Pz=0.001; OR=0.790, 95%CI: 0.745-0.837, Pz=0.001), and HLA-DP rs9277535 G allele was significantly associated with a decreased risk of cervical cancer in Asia (OR=0.802, 95%CI: 0.753-0.855, Pz=0.001). Subgroup analyses based on race system showed that HLA-DPB1*13:01 was significantly associated with an increased risk of cervical cancer in Asia (OR=1.834, 95%CI: 1.107-3.039, Pz=0.019). No significant association was established for the HLA-DP following alleles: DPB1*02:01, DPB1*02:02, DPB1*04:01, DPB1*05:01, rs4282438, and rs3077. Conclusion. HLA-DP gene polymorphisms (HLA-DPB1*03:01, DPB1*04:02, DPB1*13:01, rs9277535, and rs3117027) were significantly associated with cervical cancer. PMID- 30009174 TI - Indicators of Data Quality at the Cancer Registry Zurich and Zug in Switzerland. AB - Data quality is an important issue in cancer registration. This paper provides a comprehensive overview of the four main data quality indicators (comparability, validity, timeliness, and completeness) for the Cancer Registry Zurich and Zug (Switzerland). We extracted all malignant cancer cases (excluding non-melanoma skin cancer) diagnosed between 1980 and 2014 in the canton of Zurich. Methods included the proportion of morphologically verified cases (MV%), the proportion of DCN and DCO cases (2009-2014), cases with primary site uncertain (PSU%), the stability of incidence rates over time, age-specific incidence rates for childhood cancer, and mortality:incidence (MI) ratios. The DCO rate decreased from 6.4% in 1997 to 0.8% in 2014 and was <5% since 2000. MV% was 95.5% in 2014. PSU% was <3% over the whole period. The incidence rate of all tumours increased over time with site-specific fluctuations. The overall M:I ratio decreased from 0.58 in 1980 to 0.37 in 2014. Overall, data quality of the Cancer Registry Zurich and Zug was acceptable according to the methods presented in this review. Most indicators improved over time with low DCO rates, high MV%, low PSU%, relatively low M:I ratios and age-specific incidence of childhood cancer within reference ranges. PMID- 30009175 TI - Potential of Gene and Cell Therapy for Inner Ear Hair Cells. AB - Sensorineural hearing loss is caused by the loss of sensory hair cells (HCs) or a damaged afferent nerve pathway to the auditory cortex. The most common option for the treatment of sensorineural hearing loss is hearing rehabilitation using hearing devices. Various kinds of hearing devices are available but, despite recent advancements, their perceived sound quality does not mimic that of the "naive" cochlea. Damage to crucial cochlear structures is mostly irreversible and results in permanent hearing loss. Cochlear HC regeneration has long been an important goal in the field of hearing research. However, it remains challenging because, thus far, no medical treatment has successfully regenerated cochlear HCs. Recent advances in genetic modulation and developmental techniques have led to novel approaches to generating HCs or protecting against HC loss, to preserve hearing. In this review, we present and review the current status of two different approaches to restoring or protecting hearing, gene therapy, including the newly introduced CRISPR/Cas9 genome editing, and stem cell therapy, and suggest the future direction. PMID- 30009176 TI - Chitosan Tubes Enriched with Fresh Skeletal Muscle Fibers for Primary Nerve Repair. AB - Muscle-in-vein conduit is successfully employed for repairing nerve injuries: the vein prevents muscle fiber dispersion, while the muscle prevents the vein collapse and creates a favorable environment for Schwann cell migration and axon regrowth. However, it requires microsurgical skills. In this study we show a simple strategy to improve the performance of a chitosan hollow tube by the introduction of fresh skeletal muscle fibers. The hypothesis is to overcome the technical issue of the muscle-in-vein preparation and to take advantage of fiber muscle properties to create an easy and effective conduit for nerve regeneration. Rat median nerve gaps were repaired with chitosan tubes filled with skeletal muscle fibers (muscle-in-tube graft), hollow chitosan tubes, or autologous nerve grafts. Our results demonstrate that the fresh skeletal muscle inside the conduit is an endogenous source of soluble Neuregulin 1, a key factor for Schwann cell survival and dedifferentiation, absent in the hollow tube during the early phase of regeneration. However, nerve regeneration assessed at late time point was similar to that obtained with the hollow tube. To conclude, the muscle-in-tube graft is surgically easy to perform and we suggest that it might be a promising strategy to repair longer nerve gap or for secondary nerve repair, situations in which Schwann cell atrophy is a limiting factor for recovery. PMID- 30009177 TI - Bone Response to Titanium Implants Coated with Double- or Single-Stranded DNA. AB - We aimed to evaluate in vivo bone response and in vitro apatite formation to titanium (Ti) implants, coated with double-stranded DNA (DNA-d) or single stranded DNA (DNA-s), and to compare the influence in different structure of DNA, double strand and single strand on bone response and apatite formation. The bone responses to multilayered DNA-d/protamine or DNA-s/protamine coating implants were evaluated after implantation into the extracted sockets of rat maxillary molars. Apatite formation on either coating surface after immersion in simulated body fluid (SBF) was evaluated using the quartz crystal microbalance (QCM) method. DNA-d/protamine and DNA-s/protamine coatings produced more roughened and hydrophilic surfaces than untreated Ti. Animal experiments showed that higher bone-to-implant ratios were achieved 3 and 6 weeks after implantation using DNA d/protamine and DNA-s/protamine coatings compared with Ti. QCM measurements revealed that each coating contributed to significant earlier apatite formation in SBF. We conclude that both DNA-d/protamine and DNA-s/protamine coatings enhanced early bone formation. We suggest that a DNA-multilayer coating is useful for the surface modification of a Ti implant. PMID- 30009179 TI - Students' Motivation for Sport Activity and Participation in University Sports: A Mixed-Methods Study. AB - Background: Physical activity among students is essential for complimenting sedentary behavior and for individuals' future health. This study investigates reasons for sport engagement among students and addresses the utilization of university sports programs (USP) by employing a mixed-methods approach. Methods: The NuPhA-Study consists of a quantitative online survey (n=689) followed by qualitative interviews (n=20). In the survey, we assessed reasons for sport activity using a 24-item battery and USP utilization. Quantitative results were further explored using qualitative data to check for completeness of the predefined items (content validity) and to identify opportunities to improve participating in USP. Results: A factor analysis grouped the 24 items into five factors (life balance/fitness/body image/contact with others/fun). Our qualitative study explained these in more detail and revealed missing aspects. 47.6% of students participated in USP. Potential improvements for USP include program maintenance during the semester break and temporal harmonization with the classes. Discussion: The qualitative component identified additional reasons for sport activity that were not addressed by the item battery, which provides critical implications for developing item batteries for future research. Our results may help to generate a more target-group-oriented approach to increase physical activity among students, which will reduce sedentary behavior and future disease burden. PMID- 30009180 TI - Gender Dysphoria: Bioethical Aspects of Medical Treatment. AB - Gender affirmation surgery remains one of the greatest challenges in transgender medicine. In recent years, there have been continuous discussions on bioethical aspects in the treatment of persons with gender dysphoria. Gender reassignment is a difficult process, including not only hormonal treatment with possible surgery but also social discrimination and stigma. There is a great variety between countries in specified tasks involved in gender reassignment, and a complex combination of medical treatment and legal paperwork is required in most cases. The most frequent bioethical questions in transgender medicine pertain to the optimal treatment of adolescents, sterilization as a requirement for legal recognition, role of fertility and parenthood, and regret after gender reassignment. We review the recent literature with respect to any new information on bioethical aspects related to medical treatment of people with gender dysphoria. PMID- 30009178 TI - Resistant Gram-Negative Bacteria and Diagnostic Point-of-Care Options for the Field Setting during Military Operations. AB - The spread of multidrug-resistant bacteria in resource-poor settings affects the military medical service in case of deployments of soldiers to war and crisis zones. Patients with war injuries are prone to colonization or infection with multidrug-resistant bacteria. Resistant Gram-negative bacteria play a dominant role in military wound infections. Problematic hygiene conditions on deployment facilitate exposition of soldiers with subsequent colonization. Although colonizing strains are frequently cleared from their hosts after returning from deployment, transmission to close contacts of the soldiers in the home country cannot be excluded and therapeutic options are reduced if colonization progresses to invasive infection. Since sophisticated culture-based diagnostic approaches are typically not available in the field setting on deployment, molecular rapid diagnostic test systems are an option for transmission control if the locally prevalent molecular resistance mechanisms are known. Efforts for global resistance surveillance can contribute to better understanding of resistance distribution and spread at deployment sites. This review summarizes experience of the military medical services with multidrug resistance on deployment and with the influx of resistant strains to the home country and discusses potential use of available molecular rapid test systems as an option for the field setting. PMID- 30009181 TI - Direct Intrahepatic Portocaval Shunt for Sinusoidal Obstruction Syndrome Associated with Hepatotoxicity of Pyrrolizidine Alkaloids. AB - We retrospectively identified 89 consecutive patients from January 2004 to January 2012 to investigate efficacy of direct intrahepatic portocaval shunt (DIPS) combined with inferior vena cava (IVC) stenting for sinusoidal obstruction syndrome (SOS) associated with hepatotoxicity of pyrrolizidine alkaloids. Indications for treatment were variceal hemorrhage and/or refractory ascites. Patients were treated with DIPS plus IVC stenting (group A, n=68) or DIPS alone (group B, n=21). A technical success rate of 100% was obtained in all 89 patients, and there were no early procedure-related adverse events or 30-day mortality. Mean portosystemic gradient decreased in both groups. Changes in aspartate and alanine aminotransferases and total bilirubin did not differ between the groups. Ascites disappeared in group A but was not obvious in group B until IVC stenting. During follow-up, recurrent bleeding and ascites and incidence of hepatic encephalopathy did not differ between the groups. The 1-, 3 , and 5-year survival rate was 98, 89.59, and 80%, respectively. Satisfactory clinical results were obtained for combined DIPS and IVC stenting for SOS associated with pyrrolizidine-alkaloid-related decompensated cirrhosis. PMID- 30009183 TI - The Effects of Momordica balsamina Methanolic Extract on Kidney Function in STZ Induced Diabetic Rats: Effects on Selected Metabolic Markers. AB - Background: Studies suggest that Momordica balsamina (intshungu) possesses hypoglycaemic effects. The effects of Momordica balsamina on diabetic complications such as DN, however, have not been established. Accordingly, this study seeks to investigate the effects of M. balsamina on kidney function in STZ induced diabetic rats. Methods: Methanolic extracts (ME) of M. balsamina's leaves were used in this study. Short-term effects of M. balsamina methanolic extract on kidney function and MAP were studied in STZ-induced diabetic rats treated twice daily with M. balsamina methanolic extract (250 mg/kg), insulin (175 MUg/kg, s.c.), and metformin (500 mg/kg) for 5 weeks. Results: M. balsamina methanolic extract significantly increased Na+ excretion outputs in STZ-induced diabetic rats by comparison to STZ-diabetic control rats. M. balsamina methanolic extract significantly increased GFR in STZ-diabetic rats with a concomitant decrease in creatinine concentration and also reduced kidney-to-body ratio, albumin excretion rate (AER), and albumin creatinine ratio (ACR). M. balsamina methanolic extract significantly reduced MAP in STZ-diabetic animals by comparison with STZ-diabetic control animals. These results suggest that M. balsamina methanolic extract not only lowers blood glucose but also has beneficial effects on kidney function and blood pressure. Conclusion: These findings suggest that M. balsamina may have beneficial effects on some processes that are associated with renal derangement in STZ-induced diabetic rats. PMID- 30009182 TI - Prevalence, Risk Factors, and Pathophysiology of Dysglycemia among People Living with HIV in Sub-Saharan Africa. AB - Objective: To review available literature on the prevalence, risk factors, pathophysiology, and clinical outcomes of dysglycemia among people living with HIV (PLHIV) in sub-Saharan Africa (SSA). Methods: Database search on PUBMED for eligible studies describing the prevalence, risk factors, pathophysiology, or clinical outcomes of dysglycemia in SSA PLHIV. Results: Prevalence of diabetes mellitus (DM) and pre-DM among SSA PLHIV ranged from 1% to 26% and 19% to 47%, respectively, in 15 identified studies. Older age and an elevated body mass index (BMI) were common risk factors for dysglycemia. Risk factors potentially more specific to PLHIV in SSA included exposure to older-generation thymidine analogues or protease inhibitors, malnutrition at ART initiation, a failure to gain fat mass on treatment, and elevated serum lipids. There is evidence of higher nephropathy and neuropathy rates among PLHIV in SSA with comorbid DM compared to HIV-negative individuals with DM. Conclusion: There is a need for longitudinal studies to enhance understanding of the risk factors for dysglycemia among PLHIV in SSA, further research into optimal therapies to reduce pre-DM progression to DM among SSA PLHIV, and studies of the burden and phenotype of diabetic complications and other health outcomes among PLHIV with comorbid DM in SSA. PMID- 30009184 TI - HbA1c Cutoff Point of 5.9% Better Identifies High Risk of Progression to Diabetes among Chinese Adults: Results from a Retrospective Cohort Study. AB - Aims: This article performed a retrospective cohort study to estimate the annual incidence rates of diabetes and to assess the utility of HbA1c as a predictor for progression to diabetes in Chinese community adults aged 40 years or older. Methods: In all, 2778 nondiabetic subjects (including 1901 women) underwent HbA1c testing and oral glucose tolerance test (OGTT) measurements at baseline and after 3 years. Diabetes and prediabetes were defined using the WHO criteria. The HbA1c cutoff points were evaluated to predict the future risks of diabetes. Relative risk (RR) was calculated using the chi-square test. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive efficiency of fasting plasma glucose (FPG), 2 hr postprandial plasma glucose (2hPG), and HbA1c for progression to diabetes. A superior cutoff point was defined as the point on the ROC curve with a larger Youden index. Results: Overall, 7.5% (210/2778) of the subjects progressed to diabetes, yielding an annual 2.5% diabetes incidence rate. Additionally, 4.5% (100/2227) of the subjects with normal glucose tolerance (NGT) and 19.6% (110/561) of the subjects with prediabetes progressed to diabetes, and the relative risk of progression to diabetes was 5.188 times higher in subjects with prediabetes than in subjects with NGT (p < 0.001). Compared to subjects with HbA1c values <= 5.6%, the RRs of progression to diabetes in subjects whose HbA1c ranged from 5.7 to 5.8%, 5.9 to 6.2%, 6.3 to 6.4%, and >=6.5% were 1.165, 2.582, 5.732, and 16.619, respectively. However, the RRs for subjects with HbA1c ranging from 5.7 to 5.8% and those with HbA1c <= 5.6% did not differ significantly (p = 0.615). The AUCs for predicting diabetes after 3 years by FPG, 2hPG, and HbA1c were 0.752 (95% confidence interval 0.718-0.787), 0.710 (95% confidence interval 0.671-0.748), and 0.756 (95% confidence interval 0.720-0.793), respectively. The HbA1c cutoff point of 5.9% (sensitivity of 0.771 and specificity of 0.580) may better identify individuals at high risk of progression to diabetes than the 5.7% value (sensitivity of 0.862 and specificity of 0.371) due to the former's larger Youden index of 0.351, which exceeded the indices for FPG and 2hPG. Conclusions: The use of HbA1c values >= 5.9% may provide greater accuracy in evaluating the risk of progression to diabetes and identify individuals with prediabetes with greater reliability among Chinese adults. PMID- 30009187 TI - Immune Responses to RNA Viruses. PMID- 30009188 TI - Immunotherapy and Vaccine Development. PMID- 30009185 TI - Intralymphatic Glutamic Acid Decarboxylase-Alum Administration Induced Th2-Like Specific Immunomodulation in Responder Patients: A Pilot Clinical Trial in Type 1 Diabetes. AB - GAD-alum given into lymph nodes to type 1 diabetes patients participating in an open-label pilot trial resulted in preservation of C-peptide similar to promising results from other trials. Here, we compared the immunomodulatory effect of giving GAD-alum directly into lymph nodes versus that induced by subcutaneous administration. Samples from T1D patients (n = 6) who received 4 MUg GAD-alum into lymph nodes (LNs), followed by two booster injections one month apart, and from patients (n = 6) who received two subcutaneous injections (SC) (20 MUg) given one month apart were compared. GADA, IA-2A, GADA subclasses, IgE, GAD65 induced cytokines, PBMC proliferation, and T cell markers were analyzed. Lower doses of GAD-alum into LN induced higher GADA levels than SC injections and reduced proliferation and IgG1 GADA subclass, while enhancing IgG2, IgG3, and IgG4. The cytokine profile was dominated by the Th2-associated cytokine IL-13, and GAD65 stimulation induced activated CD4 T cells. Patients responding clinically best account for most of the immunological changes. In contrast, SC treatment resulted in predominant IgG1, predominant IFN-gamma, higher proliferation, and activated CD4 and CD8 cells. Patients from the LN group with best metabolic outcome seemed to have common immune correlates related to the treatment. This trial is registered with DIAGNODE (NCT02352974, clinicaltrials.gov) and DIABGAD (NCT01785108, clinicaltrials.gov). PMID- 30009186 TI - Immunotherapy with Native Molecule rather than Hypoallergenic Variant of Pru p 3, the Major Peach Allergen, Shows Beneficial Effects in Mice. AB - Background: The use of hypoallergenic derivatives is considered beneficial to promote the safety and efficacy of allergen-specific immunotherapy. We aimed to assess the efficacy of reduced and alkylated (R/A) Pru p 3, a hypoallergenic folding variant of the major peach allergen, in subcutaneous immunotherapy (SCIT) using a murine model of peach allergy. Methods and Results: After sensitization with Pru p 3, BALB/c mice received SCIT with Pru p 3 or R/A Pru p 3 and were challenged with Pru p 3. SCIT with Pru p 3, but not with R/A Pru p 3, suppressed anaphylaxis upon the challenge significantly. SCIT with Pru p 3 did not suppress Pru p 3-specific IgE and IgG1 production, but enhanced IgG2a production. In contrast, SCIT with R/A Pru p 3 suppressed IgE and IgG1 production, but enhanced IgG2a production only moderately. The therapeutic efficacy of SCIT with Pru p 3 was associated with induction of IL-10 and IFN-gamma. Conclusion: Hypoallergenic folding variant of Pru p 3 is not likely an efficacious therapeutic component in SCIT of peach allergy. The lower efficacy of R/A Pru p 3 might be attributed to poor antigenicity and/or weak stability due to its unfolded conformation. PMID- 30009189 TI - Medical Plants and Immunological Regulation. PMID- 30009190 TI - Free-style puzzle flap as a cross-leg pedicled flap: the concept of re-using a flap in acute burns, a case report. AB - Background: In well-selected cases, flaps can play a pivotal role in optimizing outcomes in the acute phase of burns. A previous redundant flap could be reused or recycled as a donor site from which a new flap could be raised. Case presentation: We report the case of a patient with full thickness burns on both legs, leading to the exposure of joints of the right ankle and the right foot and left patellar tendon. The right lower extremity was covered with a free musculo cutaneous latissimus dorsi flap. Then, a musculo-cutaneous cross-leg flap pedicled on the anterior branch and centered on a perforator was harvested from the previous redundant flap to cover the controlateral knee. Conclusion: Sequential flap coverage can be considered in cases of extensive soft tissue defects and particularly in burns. This case illustrates that re-using a redundant part of a previous flap to cover another defect is a safe and interesting alternative in the event of a lack of donor sites or to save donor sites for later reconstruction of contracted burn scars. PMID- 30009191 TI - An objective measure for the assessment and management of fluid shifts in acute major burns. AB - Background: Major burns are life threatening. Fluid resuscitation is required for survival to maintain intravascular volumes and prevent hypovolemic shock. Bioimpedance spectroscopy (BIS) has been recognised as a potential method of monitoring fluid shifts after burn and in other disease states. The aims of this study were to examine the reliability of BIS across different dressing conditions and electrode positions, establish the influence of ActicoatTM on BIS variable measures and determine the validity of whole-body BIS to assess net fluid shift in the presence of moderate to major burns. Methods: An observational longitudinal cohort study was conducted from December 2014 to February 2016. Patients with over 15% total body surface area (TBSA) burns and injury less than 48 h were enrolled in the study. BIS triplicate measures were collected in an open wound and with an ActicoatTM dressing (at 5 half hour intervals). Standard and alternate electrode placements were utilised for the reliability analysis and standard placement only for determining the validity of BIS in moderate to major burns. The ImpediMde SFB7 was used to collect whole-body and segmental BIS measures. Stata statistical software, release 14 was utilised to analyse all results. Descriptive analyses were performed and were reported using the means and standard deviations (SD). Results: BIS-repeated measures established BIS raw resistance (R), and predicted volume variables were reliable in any condition (intra-class correlation coefficient (ICC) 0.996-0.999, 95% confidence intervals (CI) 0.996-0.999) without a systematic difference. ActicoatTM dressings significantly influenced all BIS-predicted volumes (p <= 0.01) as determined by multilevel mixed effects (MLME) linear regression analysis. Validity of BIS was demonstrated by resistance variables significantly decreasing with increasing net ionic fluid shift and increased TBSA (severity of injury) and calculated fluid volumes increasing with increasing net fluid shift and TBSA. BIS resistance also decreased with time as oedema reduced. For clinical use, a calculator was developed to adjust BIS variables when an ActicoatTM dressing is in situ, thus facilitating BIS variable change estimates in real time, with dressings intact. Conclusion: BIS may be used clinically to monitor fluid volume change in major acute burns. PMID- 30009193 TI - Post-traumatic stress disorder and resilience among adult burn patients in Pakistan: a cross-sectional study. AB - Background: Post-traumatic stress disorder (PTSD) is one of the major psychological disorders developed after burn injuries, though this subject of burn injuries and their destructive chronic psychological impact are not considered as thoughtfully in developing countries like Pakistan. Hence, the current study investigated the relationship between PTSD symptoms and resilience among burn patients in Pakistan, exploring the variance occurrence of the two variables concerning male burn patients and female burn patients. Methods: Seventy burn patients from three burn units of Rawalpindi and Islamabad, Pakistan, during January 2015 to September 2015 were recruited. Patients with psychiatric disorder which would restrict the study procedures were excluded from the study. PTSD symptoms of burn patients were measured by PTSD CheckList Civilian Version (PCL-C) and resilience was measured by Connor-Davidson Resilience scale (CD-RISC). Spearman's Rank-Order correlation was used to analyze the relationship between symptoms of PTSD and resilience in burn patients, and analysis of covariance (ANCOVA) was applied to analyze the gender difference in symptoms of PTSD and level of resilience. Results: Negative correlation between PTSD and resilience among burn patients was found (r = - 0.72, p < 0.001). Moreover, significant gender differences were observed on PTSD symptoms and resilience between male and female burn patients when demographic variables such as age, socioeconomic status, marital status, and educational background were controlled. Female burn patients showed more PTSD symptoms (eta2 = 0.18, p < 0.001) and less resilience (eta2 = 0.25, p < 0.001) when compared to male burn patients. Conclusions: PTSD and resilience were negatively correlated in burn patients. Female burn patients have more PTSD symptoms and lower resilience compared to male burn patients. PMID- 30009194 TI - Acute Effect of Extreme Sports on Serum Lipids. AB - Purpose: The aim of this study is to determine the effect of rafting and paragliding exercises by sedentary males on serum lipids. Material and Methods: 17 male rafters and 10 male paragliders volunteers (non-smoker, no known history of cardiovascular disease, body mass index <25 kg/m2, and no intake of prescription medications) participated in the study. Participants had blood samples taken a day before and after rafting and paragliding practices. Data were analyzed by Wilcoxon and Mann-Whitney U tests. Results: Significant decreases occurred for the low-density lipoprotein (LDL)/very low-density lipoprotein (VLDL) ratio in the rafting group after the exercise; though, there was no significant difference in serum lipids parameters of the paraglide group after the exercise. Conclusion: While acute rafting and paragliding exercises have similar effects on TG and HDL, effect on LDL/VLDL ratio is different. PMID- 30009195 TI - Comparison of cross sectional optical coherence tomography images of elevated optic nerve heads across acquisition devices and scan protocols. AB - Background: Optic nerve head measurements extracted from optical coherence tomography (OCT) show promise for monitoring clinical conditions with elevated optic nerve heads. The aim of this study is to compare reliability within and between raters and between image acquisition devices of optic nerve measurements derived from OCT scans in eyes with varying degrees of optic nerve elevation. Methods: Wide angle line scans and narrow angle radial scans through optic nerve heads were obtained using three spectral domain(SD) OCT devices on 5 subjects (6 swollen optic nerves, 4 normal optic nerves). Three raters independently semi manually segmented the internal limiting membrane(ILM) and Bruch's membrane(BM) on each scan using customized software. One rater segmented each scan twice. Segmentations were qualitatively and quantitatively compared. Inter-rater, intra rater and inter-device reliability was assessed for the optic nerve cross sectional area calculated from the ILM and BM segmentations using intraclass correlation coefficients and graphical comparison. Results: Line scans from all devices were qualitatively similar. Radial scans for which frame rate could not be adjusted were of lower quality. Intra-rater reliability for segmentation and optic nerve cross sectional area was better than inter-rater reliability, which was better than inter-device reliability, though all ICC exceeded 0.95. Reliability was not impacted by the degree of optic nerve elevation. Conclusions: SD-OCT devices acquired similar quality scans of the optic nerve head, with choice of scan protocol affecting the quality. For image derived markers, variability between devices was greater than that attributable to inter and intra rater differences. PMID- 30009192 TI - Tissue engineering of skin and regenerative medicine for wound care. AB - Engineering of biologic skin substitutes has progressed over time from individual applications of skin cells, or biopolymer scaffolds, to combinations of cells and scaffolds for treatment, healing, and closure of acute and chronic skin wounds. Skin substitutes may be categorized into three groups: acellular scaffolds, temporary substitutes containing allogeneic skin cells, and permanent substitutes containing autologous skin cells. Combined use of acellular dermal substitutes with permanent skin substitutes containing autologous cells has been shown to provide definitive wound closure in burns involving greater than 90% of the total body surface area. These advances have contributed to reduced morbidity and mortality from both acute and chronic wounds but, to date, have failed to replace all of the structures and functions of the skin. Among the remaining deficiencies in cellular or biologic skin substitutes are hypopigmentation, absence of stable vascular and lymphatic networks, absence of hair follicles, sebaceous and sweat glands, and incomplete innervation. Correction of these deficiencies depends on regulation of biologic pathways of embryonic and fetal development to restore the full anatomy and physiology of uninjured skin. Elucidation and integration of developmental biology into future models of biologic skin substitutes promises to restore complete anatomy and physiology, and further reduce morbidity from skin wounds and scar. This article offers a review of recent advances in skin cell thrapies and discusses the future prospects in cutaneous regeneration. PMID- 30009196 TI - Characteristics of Primary Care Physicians Associated With High Outpatient Antibiotic Prescribing Volume. AB - Our objective was to identify characteristics associated with high-volume antibiotic prescribing among office-based primary care physicians to target antibiotic stewardship efforts. Physicians aged 40 years and older who were male, located in the South, and in solo or 2-physician practices prescribed higher volumes of antibiotics than their peers by specialty. PMID- 30009197 TI - Altered dynamics of neurovascular coupling in CADASIL. AB - Background and Objective: Neurovascular coupling is the complex biological process that underlies use-dependent increases in blood flow in response to neural activation. Neurovascular coupling was investigated at the early stage of CADASIL, a genetic paradigm of ischemic small vessel disease. Methods: Functional hyperemia and evoked potentials during 20- and 40-sec visual and motor stimulations were monitored simultaneously using arterial spin labeling functional magnetic resonance imaging (ASL-fMRI) and electroencephalography. Results: Cortical functional hyperemia differed significantly between 19 patients and 19 healthy individuals, whereas evoked potentials were unaltered. Functional hyperemia dynamics, assessed using the difference in the slope of the response curve between 15 and 30 sec, showed a time-shifted decrease in the response to 40 sec neural stimulations in CADASIL patients. These results were replicated in a second cohort of 10 patients and 10 controls and confirmed in the whole population. Interpretation: Alterations of neurovascular coupling occur early in CADASIL and can be assessed by ASL-fMRI using a simple marker of vascular dysfunction. PMID- 30009198 TI - Apathy and brain alterations in Parkinson's disease: a multimodal imaging study. AB - Objective: Apathy is a common nonmotor symptom in Parkinson's disease (PD) affecting 40% of patients. The aim of the study was to investigate brain changes and correlates of frontal, striatal, and limbic pathways related to subclinical symptoms of apathy in PD patients. Methods: Thirty-two PD patients divided into low-subclinical symptoms of apathy (LSA) (n = 18) and high-subclinical symptoms of apathy (HSA) (n = 14) and 25 healthy controls (HC) underwent a T1-weighted, diffusion-weighted, and resting-state functional MRI. Apathy was evaluated with the Lille Apathy Rating Scale. Voxel-based morphometry, tract-based spatial statistics, and resting-state functional connectivity (FC) analyses were performed with a region-of-interest approach. Results: HSA-PD showed increased white matter axial and mean diffusivity compared with HC and increased white matter axial diffusivity compared with LSA-PD. HSA-PD showed decreased fronto striatal and fronto-limbic FC compared with HC and decreased fronto-striatal FC compared with LSA-PD. LSA-PD showed decreased fronto-limbic but increased fronto striatal FC (hyperconnectivity) compared with HC. No significant differences in grey matter were found. Fronto-striatal FC and white matter axial and mean diffusivity were associated with symptoms of apathy in HSA-PD. The fronto striatal hyperconnectivity was associated with lower symptoms of apathy in LSA PD. Interpretation: Findings suggest distinct brain alterations in PD groups with subclinical symptoms of apathy. The increased pattern of activation in LSA-PD, accompanied with lower apathetic symptomatology, might be the initial manifestation of compensatory mechanisms for dysfunctional limbic pathway. The same pattern of hyperconnectivity has been found in other pathologies and the implication of these abnormalities as a cross-disease model for initial apathy symptomatology is further discussed. PMID- 30009199 TI - Modified amyloid variants in pathological subgroups of beta-amyloidosis. AB - Objective: Amyloid beta (Abeta) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified Abeta in plaques characterizes distinct biochemical stages of Abeta maturation. However, the molecular composition of vascular Abeta deposits in CAA and its relation to plaques remain enigmatic. Methods: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Abeta in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. Results: Sequential deposition of Abeta in CAA resembled Abeta maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of Abeta in the absence of pyroglutaminated AbetaN3pE and phosphorylated AbetapS8. B CAA stage 2 showed additional AbetaN3pE and B-CAA stage 3 additional AbetapS8. Based on the Abeta maturation staging in CAA and plaques, three case groups for Abeta pathology could be distinguished: group 1 with advanced Abeta maturation in CAA; group 2 with equal Abeta maturation in CAA and plaques; group 3 with advanced Abeta maturation in plaques. All symptomatic AD cases presented with end stage plaque maturation, whereas CAA could exhibit immature Abeta deposits. Notably, Abeta pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. Interpretation: Balance of Abeta maturation in CAA and plaques defines distinct pathological subgroups of beta amyloidosis. The association of CAA-related Abeta maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Abeta pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention. PMID- 30009201 TI - Association of severity between carotid and intracranial artery atherosclerosis. AB - Objective: This study sought to investigate the relationship of atherosclerosis between intracranial and extracranial carotid arteries using three-dimensional multicontrast magnetic resonance (MR) vessel wall imaging. Methods: Patients with recent cerebrovascular symptoms in anterior circulation were recruited and underwent MR vessel wall imaging for intracranial and extracranial carotid arteries. The plaque burden, including maximum wall thickness (Max WT) and stenosis, and presence of intraplaque hemorrhage (IPH) were assessed. The correlation of the plaque characteristics between intracranial and extracranial carotid arteries was determined. Results: In total, 107 patients (mean age: 57.0 +/- 11.1 years, 69 males) were recruited. In discriminating intracranial severe stenosis (>=50% stenosis), the odds ratio (OR) of Max WT of extracranial carotid arteries was 1.41 (95% confidence interval [CI], 0.94-2.11, P = 0.095) and 1.72 (95% CI, 1.04-2.83, P = 0.034) before and after adjusting for confounding factors, respectively. The OR of stenosis of extracranial carotid arteries with increment of 10% was 1.26 (95% CI, 0.99-1.60, P = 0.054) and 1.37 (95% CI, 1.03 1.82, P = 0.033) before and after adjusting for confounding factors, in discriminating intracranial severe stenosis respectively. Receiver operating characteristic analysis revealed that the area under the curve (AUC) of Max WT, stenosis, and IPH of extracranial carotid artery plaques was 0.641, 0.605, and 0.603 in discriminating intracranial severe stenosis, respectively. After adjusting for confounding factors, the AUC of Max WT, stenosis, and presence of IPH in extracranial carotid artery plaques increased to 0.812, 0.817 and 0.781, respectively. Interpretation: Carotid artery plaque burden is significantly associated with severe intracranial artery stenosis, suggesting that extracranial carotid plaque burden might be an independent indicator for severity of intracranial artery atherosclerosis. PMID- 30009200 TI - Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. AB - Objective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals. Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University. Results: We identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (P = 2.17 * 10-8; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with SORL1 qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP,WDR76 and GRN, were among candidates for follow-up studies. Interpretation: This study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimer's disease in a large whole-exome study of unrelated cases and controls. PMID- 30009203 TI - Combined transcranial magnetic stimulation in the treatment of chronic tinnitus. AB - Objective: Repetitive transcranial magnetic stimulation (rTMS) is currently being tested for suppressing the symptoms of subjective chronic primary tinnitus, although its effect is controversial. The aim of this randomized double-blinded controlled trial was to determine the effect of rTMS with unique settings for tinnitus treatment. Methods: Fifty-three adult patients suffering from chronic subjective unilateral or bilateral nonpulsatile primary tinnitus for at least 6 months were randomly assigned to rTMS (group 1, n = 20), sham stimulation (group 2, n = 12), or medicament therapy only (group 3, n = 21). The dorsolateral prefrontal cortex (frequency 25 Hz, 300 pulses, and 80% resting motor threshold [RMT]) on the left side and primary auditory cortex (1 Hz, 1000 pulses, 110% RMT) were stimulated on both sides in patients in group 1 for 5 consecutive days. The Tinnitus Reaction Questionnaire (TRQ), Tinnitus Handicap Questionnaire (THQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), pure-tone audiometry with Fowler scoring of hearing loss, and tinnitus analysis were used to evaluate tinnitus in all patients. Data were recorded the day the patient was included in the study and at 1- and 6-month follow-up. Results: The study groups were homogenous. No significant effect of rTMS was found at 1 or 6 months based on the BDI, THQ, and TRQ scores or tinnitus masking. There was a significant but clinically irrelevant effect on the THI score after 1 and 6 months. Interpretation: No significant effect of bilateral low-frequency rTMS of the primary auditory cortex and high-frequency stimulation of the left dorsolateral prefrontal cortex was demonstrated. PMID- 30009204 TI - Pallidal deep brain stimulation and intraoperative neurophysiology for treatment of poststroke hemiballism. AB - Deep brain stimulation is a recognized and effective treatment for several movement disorders. Nevertheless, the efficacy of this intervention on abnormal movements secondary to structural brain pathologies is less consistent. In this report, we describe a case of hemiballism-hemichorea due to a peripartum ischemic stroke-treated with deep brain stimulation of the globus pallidus internus. Patient observed marked improvement in her symptoms at long-term follow-up. Neurophysiologic data revealed lower globus pallidus internus firing rates compared to other hyperkinetic disorders. Pallidal deep brain stimulation is a plausible option for medically refractory hemiballism-hemichorea and cumulative data from multiple centers may be used to fully evaluate its efficacy. PMID- 30009202 TI - Remote ischemic conditioning for acute stroke patients treated with thrombectomy. AB - Objective: Remote ischemic conditioning (RIC) has been demonstrated to be safe and feasible for patients with acute ischemic stroke (AIS), as well as for those receiving intravenous thrombolysis. We assessed the safety and feasibility of RIC for AIS patients undergoing endovascular treatment (ET). Methods: We conducted a pilot study with patients with AIS who were suspected of having an emergent large vessel occlusion in the anterior circulation and who were scheduled for ET within 6 hours of ictus. Four cycles of RIC were performed before recanalization, immediately following recanalization, and once daily for the subsequent 7 days. The primary outcome was any serious RIC-related adverse events. Results: Twenty subjects, aged 66.1 +/- 12.1 years, were recruited. No subject experienced serious RIC-related adverse events. The intracranial pressure, cranial perfusion pressure, mean arterial pressure, heart rate, middle cerebral artery peak systolic flow velocity, and pulsatility index did not change significantly before, during, or after the limb ischemia (P > 0.1 for all). Of 80 cycles, 71 (89%) were completed before recanalization and 80 (100%) were completed immediately after recanalization; 444 of 560 cycles (78%) were completed within 7 days posttreatment. No patients had to stop RIC because it affected routine clinical managements. Six subjects (30%) experienced intracerebral hemorrhage, which was symptomatic in one case (5%). At the 3-month follow-up, 11 subjects (55%) had achieved functional independence, and two subjects (10%) died. Interpretation: RIC appears to be safe and feasible for patients with AIS undergoing ET. Investigations are urgently needed to determine the efficacy of RIC in this patient population. PMID- 30009205 TI - Immunosuppressants and risk of Parkinson disease. AB - We performed a population-based case-control study of United States Medicare beneficiaries age 60-90 in 2009 with prescription data (48,295 incident Parkinson disease cases and 52,324 controls) to examine the risk of Parkinson disease in relation to use of immunosuppressants. Inosine monophosphate dehydrogenase inhibitors (relative risk = 0.64; 95% confidence interval 0.51-0.79) and corticosteroids (relative risk = 0.80; 95% confidence interval 0.77-0.83) were both associated with a lower risk of Parkinson disease. Inverse associations for both remained after applying a 12-month exposure lag. Overall, this study provides evidence that use of corticosteroids and inosine monophosphate dehydrogenase inhibitors might lower the risk of Parkinson disease. PMID- 30009206 TI - Serum neurofilament light chain is increased in hereditary spastic paraplegias. AB - Blood biomarkers are still largely missing in hereditary spastic paraplegias (HSPs). We here explored Neurofilament light chain (NfL) as a biomarker in HSP. Serum NfL was assessed in 96 HSP (63 genetically confirmed), 96 healthy control, and 33 ALS subjects by single molecule array (Simoa). Compared to controls, NfL was increased in HSP (P < 0.001), correlating with cross-sectional disease progression (rho = 0.28). Levels were lower than in ALS (P < 0.001), allowing to differentiate HSP from ALS (AUC = 0.91). Serum NfL might serve as a biomarker in HSP indicating neuronal damage and, if confirmed longitudinally, disease progression. It might also support differentiating HSP from ALS. PMID- 30009207 TI - CSF nonphosphorylated Tau as a biomarker for the discrimination of AD from CJD. AB - Creutzfeldt-Jakob disease and Alzheimer's disease are characterized by the presence of elevated total-Tau cerebrospinal fluid concentrations while the presence of hyperphosphorylated Tau forms in the cerebrospinal fluid is rather a hallmark of Alzheimer's disease. Here we aimed to investigate potential contribution of nonphospho-Tau epitopes (non-P-Tau) in the discrimination between both diseases. Non-P-Tau cerebrospinal fluid concentration was highly increased in Creutzfeldt-Jakob disease (n = 57, 3683 +/- 3599 pg/mL) compared to Alzheimer's disease (n = 41, 148 +/- 219 pg/mL) and neurological controls (n = 56, 62 +/- 40 pg/mL), and significantly improved the proportion of correctly classified patients (99%) compared to that achieved by total-Tau (90%), P-Tau (62%) and 14-3-3 (91%). PMID- 30009209 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/acn3.533.]. PMID- 30009208 TI - Using automated electrode localization to guide stimulation management in DBS. AB - Deep Brain Stimulation requires extensive postoperative testing of stimulation parameters to achieve optimal outcomes. Testing is typically not guided by neuroanatomical information on electrode contact locations. To address this, we present an automated reconstruction of electrode locations relative to the treatment target, the subthalamic nucleus, comparing different targeting methods: atlas-, manual-, or tractography-based subthalamic nucleus segmentation. We found that most electrode contacts chosen to deliver stimulation were closest or second closest to the atlas-based subthalamic nucleus target. We suggest that information on each electrode contact's location, which can be obtained using atlas-based methods, might guide clinicians during postoperative stimulation testing. PMID- 30009210 TI - GABAergic Neurons as Putative Neurochemical Substrate Mediating Aversive Effects of Nicotine. AB - Nicotine, the main addictive component of tobacco smoke, has both rewarding and aversive properties. Recent studies have suggested that GABAergic neurons, one of the main neurochemical components of the reward-addiction circuitry, may also play a role in the aversive responses to nicotine. In the present study of transgenic mice expressing Green Fluorescent Protein (GFP) in Glutamate Decarboxylase 67 (GAD67) neurons, we hypothesized that a subpopulation of GABAergic neurons in the Ventral Tegmental Area (VTA) are the targets of aversive doses of nicotine in the CNS. We tested this hypothesis using c-Fos immunohistochemical techniques to identify GAD67-GFP positive cells within the VTA, that are activated by a single intraperitoneal (i.p.) injection of a low (40 ug/kg) or a high (2 mg/kg) dose of nicotine. We also assessed the anatomical location of GAD67-GFP positive cells with respect to tyrosine hydroxylase (TH) Immunoreactive (IR) dopaminergic cells in VTA. Consistent with our previous studies low- and high-dose nicotine both induced c-Fos activation of various intensities at multiple sites in VTA. Double labeling of c-Fos activated cells with GAD67-GFP positive cells identified a subpopulation of GABAergic neurons in Substantia Nigra Compact part Medial tier (SNCM) that were activated by high- but not by low-dose nicotine. Of 217 GABAergic cells counted at this site, 48.9% exhibited nicotine induced c-fos immunoreactivity. GAD67-GFP positive cells in other regions of VTA were not activated by the nicotine doses tested. Double labeling of GAD67-GFP positive cells with TH IR cells showed that the GABAergic neurons that were activated by high-dose nicotine were located in close proximity to the dopaminergic neurons of substantia nigra compact part and VTA. Dose dependent activation of GAD67-GFP positive neurons in SNCM, by a nicotine dose known to produce aversive responses, implies that GABAergic neurons at these sites may be an important component of the nicotine aversive circuitry. PMID- 30009211 TI - The REM Sleep Behavior Disorder Screening Questionnaire is not Valid in De Novo Parkinson's Disease. AB - Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is one of the most specific prodromal indicators for Parkinson's disease (PD). Objectives: To test the validity of the RBD-Screening Questionnaire (RBDSQ) in assessing RBD in early PD. Methods: The RBDSQ was completed before video-supported polysomnography (vPSG) by 134 de novo PD patients, 109 matched controls without neurological disorder (CTR) and 30 subjects with idiopathic RBD (iRBD) without clinical signs of PD; results were compared with vPSG-confirmed RBD diagnosis. Results and Conclusions: Sensitivity/specificity of the RBDSQ for the PD cohort were 0.44/0.84 at the previously published cut-off score of 6 for PD patients, and the area under the curve (AUC) 0.68 (95% CI, 0.56-0.79). By contrast, in the iRBD/CTR cohort the RBDSQ (cut-off = 5) had a sensitivity/specificity of 0.97/0.84 and an AUC of 0.95 (95% CI, 0.90-1.00). Subanalysis of question 6 only (4 subitems asking for dream enactment) at a cut-off score of 1 revealed a sensitivity of 0.74 and a specificity of 0.70 for the de novo PD cohort, AUC was 0.74 (95% CI, 0.63-0.84). RBDSQ is an insufficient screening tool for RBD in de novo PD. New screening tools for RBD assessment need to be developed. PMID- 30009213 TI - Injectable DaxibotulinumtoxinA in Cervical Dystonia: A Phase 2 Dose-Escalation Multicenter Study. AB - Background: Injectable daxibotulinumtoxinA (an investigational botulinum toxin, RT002) may offer a more prolonged duration of response-and therefore less frequent dosing-than onabotulinumtoxinA. Objectives: To perform a phase 2, open label, dose-escalation study to assess the efficacy and safety of daxibotulinumtoxinA in cervical dystonia. Methods: Subjects with moderate-to severe isolated cervical dystonia were enrolled in sequential cohorts to receive a single open-label, intramuscular dose of injectable daxibotulinumtoxinA of up to 200 U (n = 12), 200-300 U (n = 12), or 300-450 U (n = 13; https://clinicaltrials.gov identifier NCT02706795). Results: Overall, 33/37 enrollees completed the trial. DaxibotulinumtoxinA was associated with mean reductions in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score of 16.8 (38%) at week 4, 21.3 (50%) at week 6, and 12.8 (30%) at week 24. The proportion of subjects who were responders (achieved >= 20% reduction in TWSTRS-Total score) was 94% at week 6 and 68% at week 24. The median duration of response (time until > 20% of the improvement in TWSTRS-Total score achieved at week 4 was no longer retained or re-treatment was needed) was 25.3 weeks (95% CI, 20.14-26.14 weeks). There were no serious adverse events and there was no apparent dose-related increase in the incidence of adverse events. The most common treatment-related adverse events were dysphagia (14%) and injection site erythema (8%). Conclusions: Preliminary assessments suggest that injectable daxibotulinumtoxinA at doses up to 450 U is well tolerated and may offer prolonged efficacy in the treatment of cervical dystonia. Further studies involving larger numbers of patients are now warranted. PMID- 30009215 TI - Expansion of Airway Basal Cells and Generation of Polarized Epithelium. AB - Airway basal stem cells are the progenitor cells within the airway that exhibit the capacity to self-renew and give rise to multiple types of differentiated airway epithelial cells. This stem cell-derived epithelium displays organized architecture with functional attributes of the airway mucosa. A protocol has been developed to culture and expand human airway basal stem cells while preserving their stem cell properties and capacity for subsequent mucociliary differentiation. This achievement presents a previously unrealized opportunity to maintain a durable supply of progenitor cells derived from healthy donors to differentiate into human primary airway epithelium for cellular and molecular based studies. Further, basal stem cells can be harvested from patients with a specific airway disease, such as cystic fibrosis, enabling investigation of potentially altered behavior of disease-specific cells in the appropriate context of the airway mucosa. Here we describe, in detail, a protocol for the serial expansion of airway basal stem cells to enable the generation of nearly unlimited airway basal cells that can be stored and readily available for subsequent culturing and differentiation. In addition, we describe culturing and differentiation of airway basal stem cells on permeable transwell filters at air liquid interface to create functional mucociliary pseudostratified polarized airway epithelial mucosa. PMID- 30009212 TI - Systematic Review of Rehabilitation in Focal Dystonias: Classification and Recommendations. AB - Background: Rehabilitation interventions are rarely utilized as an alternative or adjunct therapy for focal dystonias. Reasons for limited utilization are unknown, but lack of conclusive evidence of effectiveness is likely a crucial factor. Methods and Findings: The purpose of this systematic review was to determine the level of evidence for rehabilitation interventions in focal dystonias. Rehabilitation interventions were classified based upon the underlying theoretical basis of different approaches, and the strength of evidence for each category was evaluated to identify gaps in the field. Prospective studies using rehabilitation methods in cervical, hand, and foot dystonia were reviewed. The key elements of treatments tested were identified and studies were grouped into six categories based on the theoretical basis of the intervention: (1) movement practice, (2) training with constraint, (3) sensory reorganization, (4) normalization of muscle activity with external techniques, (5) neuromodulation with training, and (6) compensatory strategies. Quality of the body of evidence ranged from very low-to-low according to the grades of recommendation, assessment, development, and evaluation (GRADE). Despite inconclusive evidence for these rehabilitation approaches, data suggest that intensive movement practice and neuromodulation combined with motor training should be further explored. Conclusions: This systematic review presents a novel approach to classify studies of rehabilitation in focal dystonias based on the theoretical basis of intervention. The proposed classification system will move toward a unified theoretical understanding of rehabilitation interventions in dystonia. Moreover, it will help provide recommendations for clinical applications and future investigations. PMID- 30009214 TI - Multiple Microelectrode Recordings in STN-DBS Surgery for Parkinson's Disease: A Randomized Study. AB - Background: Subthalamic nucleus deep brain stimulation improves motor symptoms and fluctuations in advanced Parkinson's disease, but the degree of clinical improvement depends on accurate anatomical electrode placement. Methods used to localize the sensory-motor part of the nucleus vary substantially. Using microelectrode recordings, at least three inserted microelectrodes are needed to obtain a three-dimensional map. Therefore, multiple simultaneously inserted microelectrodes should provide better guidance than single sequential microelectrodes. We aimed to compare the use of multiple simultaneous versus single sequential microelectrode recordings on efficacy and safety of subthalamic nucleus stimulation. Methods: Sixty patients were included in this double-blind, randomized study, 30 in each group. Primary outcome measures were the difference from baseline to 12 months in the MDS-UPDRS motor score (part III) in the off medication state and quality of life using the Parkinson's Disease Questionnaire 39 (PDQ-39) scores. Results: The mean reduction of the MDS-UPDRS III off score was 35 (SD 12) in the group investigated with multiple simultaneous microelectrodes compared to 26 (SD 10) in the single sequential microelectrode group (p = 0.004). The PDQ-39 Summary Index did not differ between the groups, but the domain scores activities of daily living and bodily discomfort improved significantly more in the multiple microelectrodes group. The frequency of serious adverse events did not differ significantly. Conclusions: After 12 months of subthalamic nucleus stimulation, the multiple microelectrodes group had a significantly greater improvement both in MDS-UPDRS III off score and in two PDQ 39 domains. Our results may support the use of multiple simultaneous microelectrode recordings. Trial registration: http://ClinicalTrials.gov Identifier: NCT00855621 (first received March 3, 2009). PMID- 30009216 TI - Small Molecule-Based Retinal Differentiation of Human Embryonic Stem Cells and Induced Pluripotent Stem Cells. AB - Retinal degeneration leads to loss of light-sensing photoreceptors eventually resulting in vision impairment and impose a heavy burden on both patients and the society. Currently available treatment options are very limited and mainly palliative. Ever since the discovery of human pluripotent stem cell technologies, cell replacement therapy has become a promising therapeutic strategy for these patients and may help restore visual function. Reproducibly generating enriched retinal cells including retinal progenitors and differentiated retinal neurons such as photoreceptors using human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in a dish is an essential first step for developing stem cell-based therapies. In addition, this will provide a reliable and sufficient supply of human retinal cells for studying the mechanisms of diseases. Here we describe a small molecule-based retinal induction protocol that has been used to generate retinal progenitors and differentiated retinal neurons including photoreceptors from several human ES and iPS cell lines. The retinal cells generated by this protocol can survive and functionally integrate into normal and diseased mouse retinas for several months following subretinal transplantation. PMID- 30009217 TI - Warning Size Affects What Adolescents Recall From Tobacco Advertisements. AB - Objectives: In the U.S., print advertisements for smokeless tobacco (SLT) feature a large black-and-white text warning covering 20% of the advertisement space. Cigarette and e-cigarette advertisements feature a small warning covering approximately 4% of advertisement space. We explored how warning size affects adolescent boys' spontaneous recollection of the warning, brand-relevant advertisement features, and product risks. Methods: 1,220 adolescent males (ages 11-16) viewed SLT, cigarette, and e-cigarette advertisements. After each advertisement, boys were asked to recall what they remembered most. Coders identified recalls of the warning label, brand-relevant advertisement features, and risks associated with the product in responses. Results: Participants were less likely to recall warnings in the cigarette vs. SLT (OR=0.30, p<0.001) and e cigarette vs. SLT (OR=0.15, p<0.001) ads. Separate GEEs revealed that boys who recalled warnings were less likely to mention brand-relevant advertisement features (OR's<0.32, p's<0.001). Logistic regressions revealed that boys who recalled the warnings were more likely to mention risks associated with the products (OR's>3.50, p's<0.001). Conclusions: Youth are more likely to recall large SLT warnings than small cigarette and e-cigarette warnings. Warning recall is associated with lower likelihood of recalling brand-relevant advertisement features and greater likelihood of mentioning product risks. PMID- 30009218 TI - Sudden Death Following Oral Intake of Metal Objects (Acuphagia): a Case Report. AB - According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), pica is described as eating one or more non-nutritive, non-food substances over a period of at least 1 month that is severe enough to warrant clinical attention. The present case is a 44-year-old man who was brought to emergency department following severe abdominal pain, but died before admission or receiving any treatments. On the autopsy, 64 bolts and metal fittings (3700 grams) were found in the esophagus, stomach, small intestine, and large intestine of the patient. PMID- 30009220 TI - Prevalence of Mycoplasma Pneumoniae Infection in Patients with COPD Exacerbation; a Letter to the Editor. PMID- 30009219 TI - Loss of Guide Wire as an Important Complication of Central Venous Catheterization; a Case Report. AB - Many critically ill patients need aggressive procedures, such as central venous catheterization. The complication rate of central venous line placement is estimated to be 15%. Common complications include arterial puncture, hematoma, pneumothorax, hemothorax, arrhythmia, thoracic duct injury, infection, and thrombosis. Cardiac tamponade, pericardial effusions, pleural effusions, air or guidewire embolisms, and lost guide wires are rare but severe complications. Here we report a case of lost guide wire following central venous line insertion. PMID- 30009221 TI - Emergency Medicine Resident versus Radiologist in Detecting the Ultrasonographic Signs of Acute Cholecystitis; a Diagnostic Accuracy Study. AB - Introduction: Dependence of ultrasonography on the operator's skill plays a major role in the differences between various studies in reporting its diagnostic accuracy. Therefore, the present study was done with the aim of comparing the ultrasonography findings performed by emergency medicine resident and radiologist in evaluation of acute cholecystitis. Methods: The present diagnostic accuracy study has been carried out on patients presenting to the emergency department with complaint of pain in the right upper quadrant of abdomen suspected with acute cholecystitis. All the patients underwent gallbladder ultrasonography by a trained emergency medicine resident and a radiologist and their findings were compared with surgical and pathology findings regarding gallstone and increased gallbladder wall thickness. Results: 51 patients with the mean age of 42.3+/-15.8 (17-81) years were analyzed (82.4% female). The overall agreement between emergency medicine resident and radiologist in ultrasonographic diagnosis of cholecystitis was 0.421 (95% CI: 0.118-0.724). Based on the pathology and surgical findings, acute cholecystitis was confirmed for all 51 (100%) patients. Meanwhile, based on the ultrasonographic report of radiologist and emergency medicine resident only 45 (88.2%) and 34 (66.7%) patients, respectively, were diagnosed with cholecystitis. Screening performance characteristics of ultrasonography by radiologist for detection of gallbladder stone (p = 0.010) and gallbladder wall thickness (p < 0.0001) were significantly better than emergency medicine resident. Conclusion: The screening performance characteristics of ultrasonography by radiologist in detection of gallstones and increased wall thickness of gallbladder were significantly better. PMID- 30009222 TI - Sudden Death due to Hydatid Cyst Emboli; a Case Report. AB - Echinococcosis is an infection caused in human by complex parasites that causes cystic hydatid disease. These infections are prevalent in most areas where livestock is raised in association with dogs. These parasites are found in all continents. Slowly enlarging cysts generally remain asymptomatic until their size has expanded. Here we present a case of sudden death following cyst emboli to the large veins and right heart of a young adult female. PMID- 30009223 TI - The Effect of Low-Dose Ketamine in Treating Acute Asthma Attack; a Randomized Clinical Trial. AB - Introduction: Efficient treatment of asthma can play an important role in controlling asthma attacks, rapid recovery and decrease of patient mortality. Therefore, in the present study the therapeutic effect of low-dose ketamine is evaluated in patients with acute asthma attack. Methods: In the present single blind, randomized clinical trial with placebo control, the effect of low-dose intravenous ketamine in treating 18 to 85 year-old asthmatic patients who presented to the emergency department was evaluated. Peak expiratory flow rate (PEFR) and the patients' response to treatment were measured before and 1 hour after treatment. Additionally, using SPSS 22.0, effectiveness of ketamine with 0.3, 0.4, and 0.5 mg/kg doses followed by infusion of the same dose during 30 minutes were compared with placebo. Results: 92 patients were enrolled (59.8% female, mean age 48.5 +/- 13.9 years). 15 (16.3%) patients were treated with 0.3 mg/kg ketamine, 14 (15.2%) with 0.4 mg/kg, and 16 (17.4%) with 0.5 mg/kg doses. Mean PEFR was 336.2 +/- 101.5 liters in the placebo group and 345.8 +/- 84.7 liters in the ketamine group before intervention (p = 0.6), while after intervention, they were 352.1 +/- 101.2 and 415.8 +/- 76.2 liters, respectively (p = 0.001). Ketamine treatment with 0.4 and 0.5 mg/kg doses led to a higher increase in PEFR compared to 0.3mg/kg dose (df: 3, 88; F = 23.8; p < 0.001). Conclusion: It seems that administration of 0.4 - 0.5 mg/kg doses of intravenous ketamine followed by infusion of the same dose during 30 minutes can be effective for rapid recovery of PEFR in patients with mild to moderate asthma. PMID- 30009224 TI - A Simple Device to Control Valsalva Manoeuvre Strain Pressure; a Letter to Editor. PMID- 30009225 TI - Hopkins Syndrome in a 14 Year Old Boy; a Case Report. AB - Hopkins syndrome (HS) is a flaccid paralysis resembling poliomyelitis that has been seen in some children who are recovering from an acute episode of asthma. This syndrome should be suspected based on clinical findings even before the occurrence of characteristic breathing patterns and epilepsy. We report a 14-year old boy who had experienced an episode of HS. PMID- 30009226 TI - Lidocaine-Midazolam-Fentanyl Combination in Controlling Pain for Reduction of Anterior Shoulder Dislocation; a Randomized Clinical Trial. AB - Introduction: Finding a fast-acting compound with minimal side-effects to induce a safe and efficient analgesia with short or medium duration of action is of great interest in the emergency department. The present study has been designed with the aim of comparing the effect of midazolam + fentanyl + lidocaine combination with midazolam + fentanyl + placebo in pain management of anterior shoulder dislocation reduction. Methods: The present two-arm parallel double blind randomized controlled trial was performed on patients who presented to emergency department with anterior shoulder dislocation. Patients were randomly allocated to the 2 treatment groups of midazolam + fentanyl + placebo (double drug group) and midazolam + fentanyl + intravenous (IV) lidocaine (triple-drug group). Then outcomes such as treatment success rate and side-effects following prescription of drugs were compared between the 2 groups. Results: 100 patients were included in the present study (50 patients in each group; mean age of the studied patients 27.3+/-8.9 years; 93.0% male). Using the double-drug regimen led to 35 (70%) cases of complete analgesia, while this rate in the triple-drug group was 41 (82%) cases (p=0.16). The calculated number needed to treat was 9 cases. This means that about one in every 9 patients in treatment arm will benefit from the treatment. The most important side-effects observed included dysrhythmia (1 patient in double drug and 1 patient in triple-drug group), apnea (2 patients in each group) and SPO2<90% (2 patients in triple-drug group) (p=0.78). Number needed to harm was 25 cases. In other words, for each 25 patients treated with the triple drug regimen, 1 case of SPO2<90% is observed. Conclusion: Findings of the present study showed that adding IV lidocaine to IV midazolam + fentanyl drug combination does not provide additional analgesia in sedation for anterior shoulder reduction. PMID- 30009227 TI - Systemic Fibrinolytic Therapy in the Presence of Absolute Contraindication; a Case Series. AB - In massive pulmonary embolism (PE), fibrinolytic therapy is a potential lifesaving treatment; therefore, if other treatments are not available, the physicians encounter this question: can we accept the risk of complications from fibrinolytic therapy, especially intracranial hemorrhage, in the presence of absolute contraindication, in order to save the patient's life? Here, we describe three cases of massive PE with absolute contraindication for fibrinolytic therapy who presented to emergency department following dyspnea. Since, surgical or catheter embolectomy were not available and patients were very high risk for transferring to another hospital, systemic fibrinolytic was administered. The patients improved clinically and were discharged from hospital. It seems that, if no other acceptable treatments are available, physicians could consider fibrinolytic therapy, even at the presence of contraindication, to save the patient's life. PMID- 30009228 TI - Prehospital Emergency Medical Services Challenges in Disaster; a Qualitative Study. AB - Introduction: Prehospital Emergency Medical Care (EMC) is a critical service in disaster management. The aim of this study was to explore the challenges of prehospital Emergency Medical Services (EMS) during disaster response in Iran. Methods: A qualitative study was conducted from April 2015 to March 2017. Data were collected through in-depth, semi-structured interviews with 23 experienced individuals in the field of disaster that were selected using purposeful sampling. Data were analyzed using content analysis approach. Results: Fifteen sub-themes and the following six themes emerged in the analysis: challenges related to people, challenges related to infrastructure, challenges related to information management systems, challenges related to staff, challenges related to managerial issues and challenges related to medical care. Conclusions: Iran's prehospital EMS has been chaotic in past disasters. Improvement of this process needs infrastructure reform, planning, staff training and public education. PMID- 30009229 TI - Vagus Nerve Stimulation and External Defibrillation during Resuscitation; a Letter to Editor. PMID- 30009230 TI - Rectus Muscle Hematoma as a Rare Differential Diagnosis of Acute Abdomen; a Case Report. AB - Rectus sheath hematoma is a rare but well-known problem. Exercise, pregnancy, subcutaneous injection of insulin, abdominal surgery and severe coughs can be predisposing factors of hemorrhage in the mentioned muscle sheath. Here, we will discuss a case of rectus sheath hematoma in a 28 year-old female patient who presented to emergency department with complaint of abdominal pain and improved in 1 week with palliative care. PMID- 30009231 TI - Post-Traumatic Pulmonary Pseudocyst following Blunt Chest Trauma; a Case Report. AB - Traumatic pulmonary pseudocyst is a rare complication of chest trauma that has been poorly documented and usually resolves without specific treatment. Here, we present a case of pulmonary pseudocyst in a child with chest trauma without obvious symptoms. It is important to consider this diagnosis in patients with chest trauma to avoid unnecessary invasive procedures. PMID- 30009232 TI - Epidemiology and Outcome of Patients with Acute Kidney Injury in Emergency Department; a Cross-Sectional Study. AB - Introduction: Elimination of preventable deaths due to acute kidney injury (AKI) in low-income countries by 2025 is an important healthcare goal at the international level. The present study was designed with the aim of evaluating the prevalence and outcome of AKI in patients presenting to emergency department. Methods: The present cross-sectional, retrospective study was performed on patients that presented to the emergency departments of 3 major teaching hospitals, Tehran, Iran, between 2005 and 2015 and were diagnosed with AKI. Patient selection was done using consecutive sampling and required data for this study was extracted by referring to the medical profiles of the patients and filling out a checklist designed for the study. Results: 770 AKI patients with the mean age of 62.72 +/- 19.79 (1 - 99) years were evaluation (59.1% male). 690 (89.61%) cases of AKI causes were pre-renal or renal. Among the pre-renal causes, 74 (73.3%) cases were due to different types of shock (p < 0.001). The most common etiologic causes of AKI in pre-renal group were hypotension (57.3%) and renal vascular insufficiency (31.6%). In addition, regarding the renal types, rhabdomyolysis (35.0%), medication (17.5%) and chemotherapy (15.3%) and in post renal types, kidney stone (34.5%) were the most common etiologic causes. 327 (42.5%) patients needed dialysis and 169 (21.9%) patients died. Sex (p = 0.001), age over 60 years (p = 0.001), blood urea nitrogen level (p < 0.001), hyperkalemia (p < 0.001), metabolic acidosis (p < 0.001), cause of failure (p = 0.001), and type of failure (p = 0.009) were independent risk factors of mortality. Conclusion: The total prevalence of AKI in emergency department was 315 for each 1000000 population and preventable mortality rate due to AKI was estimated to be 28.2 cases in each 1000000 population. The most important preventable AKI causes in the pre-renal group included shock, sepsis, and dehydration; in the renal group they included rhabdomyolysis and intoxication; and stones in the post-renal group. PMID- 30009233 TI - Full and Modified Glasgow-Blatchford Bleeding Score in Predicting the Outcome of Patients with Acute Upper Gastrointestinal Bleeding; a Diagnostic Accuracy Study. AB - Introduction: Screening of high risk patients and accelerating their treatment measures can reduce the burden of the disease caused by acute upper gastrointestinal (GI) bleeding. This study aimed to compare the full and modified Glasgow-Blatchford Bleeding Score (GBS and mGBS) in prediction of in-hospital outcomes of upper GI bleeding. Methods: In the present retrospective cross sectional study, the accuracy of GBS and mGBS models were compared in predicting the outcome of patients over 18 years of age with acute upper GI bleeding confirmed via endoscopy, presenting to the emergency departments of 3 teaching hospitals during 4 years. Results: 330 cases with the mean age of 59.07 +/- 19.00 years entered the study (63.60% male). Area under the curve of GBS and mGBS scoring systems were 0.691 and 0.703, respectively, in prediction of re-bleeding (p = 0.219), 0.562 and 0.563 regarding need for surgery (p = 0.978), 0.549 and 0.542 for endoscopic intervention (p = 0.505), and 0.767 and 0.770 regarding blood transfusion (p = 0.753). Area under the ROC curve of GBS scoring system regarding need for hospitalization in intensive care unit (0.589 vs. 0.563; p = 0.035) and mortality (0.597 vs. 0.564; p = 0.011) was better but the superiority was not clinically significant. Conclusion: GBS and mGBS scoring systems have similar accuracy in prediction of the probability of re-bleeding, need for blood transfusion, surgery and endoscopic intervention, hospitalization in intensive care unit, and mortality of patients with acute upper GI bleeding. PMID- 30009234 TI - Introducing a Device for Measuring Pain Intensity; a Letter to Editor. PMID- 30009235 TI - Medical Errors in Emergency Department; a Letter to Editor. PMID- 30009237 TI - Performance of Local Anesthesia with Lidocaine among Opium Addicts and Non Addicts; a Case Control Study. AB - Introduction: Compared to ordinary people, addicts usually have a lower pain threshold. The current work attempts to compare the performance of local analgesia with lidocaine among opium addicts and non-addicts. Methods: In this case-control study, opium addicts and healthy patients with skin laceration referring to emergency departments of two educational hospitals were compared regarding the response to local anesthesia with lidocaine, as well as side effects. Results: 197 cases with the mean age of 43.44 +/- 20.12 years were studied (72.1% male). 98 (49.8%) cases were addicts and 99 (50.2%) were healthy people. Two groups were similar regarding age (p = 0.281), sex (p = 0.666), and wound size (p = 0.272). The amount of pain reduction 5 (df =1.5, F=0.38, p = 0.88) and 10 (df =1.5, F=0.58, p = 0.72) minutes after lidocaine injection was not different between the groups. Subgroup analysis based on sex and age of patient did not show any differences between the groups (p > 0.1 for all analysis). The mean duration of analgesia was 16.4 +/- 5.37 minutes in addicts and 16.95+/-1.79 in control group (p = 0.334). Conclusion: Lidocaine, as a commonly used local anesthetic agents, does not show different effects in addicts and non-addicts in repairing skin laceration. PMID- 30009236 TI - Anaphylaxis as a Rare Side Effect of Pantoprazole; a Case Report. AB - Anaphylaxis is a serious life-threatening allergic reaction. Any medication may potentially trigger anaphylaxis, but reaction to pantoprazole is rare. Our case is a 21 year-old girl with anaphylactic reaction to pantoprazole a short time after prescription. PMID- 30009238 TI - Awareness of Basic Life Support among Egyptian Medical Students; a Cross Sectional Study. AB - Introduction: It is important for all medical and paramedical staff to be aware of basic life support (BLS) maneuvers. In this study, we aimed to evaluate the level of BLS awareness among Egyptian medical students. Methods: The level of BLS knowledge was assessed using a validated questionnaire and the results were analyzed using an answer key, prepared from the Advanced Cardiac Life Support (ACLS) manual. We used the Student's t-test to analyze the association between awareness level and year of study, previous BLS training and practical experience. Results: A total of 823 medical students with the mean age of 20.3 +/ 2.7 years, from Al-Azhar medical schools completed the questionnaire (463 and 360 in academic and clinical years, respectively). About 72% and 84% of students failed to recognize the proper point of chest compression in adults and infants, respectively. Moreover, the majority (80%) did not know how to give rescue breathing in infants. Only 18% of students correctly identified early signs of shock and only 22% knew how to help patients with myocardial infarction. Being in clinical years, previous BLS training or practical experience were significantly associated with higher BLS knowledge scores (p < 0.001). Conclusion: The level of BLS awareness among Egyptian medical students is generally poor. Introduction of regular BLS courses into the undergraduate curriculum is a must to increase the level of BLS knowledge among Egyptian future physicians. PMID- 30009239 TI - Examination of References in Rosen's Emergency Medicine Text Book, 8th Edition; an Observational Study. AB - Introduction: This study aims to analyze the references that the authors and editors used during the writing of Rosen's Emergency Medicine, 8th edition. Methods: 15,209 references, which were used in 197 chapters of Rosen's Emergency Medicine, 8th edition, were examined regarding the distribution of countries, journals, publication year, and the department of the affiliation of the first author. Results: A total of 63.1% (n = 9591) of the references were led by authors from the United States (US). US-based journals were mostly used, and Annals of Emergency Medicine was the journal from which the references were most frequently extracted, with a percentage of 5.2% (n = 756). The studies conducted by emergency physicians have increased in recent years, and emergency physicians, with a percentage of 17.8% (n = 351), were the leading authors of studies conducted between 2010 and 2013, which were cited in the references of Rosen's Emergency Medicine, 8th edition. Conclusion: US-based studies make up a significantly bigger portion of the references used in Rosen's Emergency Medicine, 8th edition. If Europe and other countries give due importance to emergency medicine, they will have the capability to produce studies that can be used as references in textbooks as much as the US. PMID- 30009240 TI - Acute Lidocaine Toxicity; a Case Series. AB - Introduction: Parenteral form of lidocaine is the best-known source of lidocaine poisoning. This study aimed to evaluate the characteristics of acute lidocaine toxicity . Methods: In this retrospective cross-sectional study, demographics, clinical presentation, laboratory findings, and outcome of patients intoxicated with lidocaine (based on ICD10 codes) admitted to Loghman Hakim Hospital, during April 2007 to March 2014 were analyzed. Results: 30 cases with the mean age of 21.83 +/- 6.57 year were studied (60% male). All subjects had used either 6.5% lidocaine spray or 2% topical formulations of lidocaine. The mean consumed dose of lidocaine was 465 +/- 318.17 milligrams. The most frequent clinical presentations were nausea and vomiting (50%), seizure (33.3%), and loss of consciousness (16.7%). 22 (73.3%) cases had normal sinus rhythm, 4 (13.3%) bradycardia, 2 (6.7%) ventricular tachycardia, and 2 (6.7%) had left axis deviation. 11 (36.6%) cases were intubated and admitted to intensive care unit (ICU) for 6.91 +/- 7.16 days. Three patients experienced status epilepticus that led to cardiac arrest, and death (all cases with suicidal intention). Conclusion: Based on the results of this study, most cases of topical lidocaine toxicity were among < 40-year-old patients with a male to female ratio of 1.2, with suicidal attempt in 90%, need for intensive care in 36.6%, and mortality rate of 10%. PMID- 30009241 TI - Candidemia in Febrile Neutropenic Patients; a Brief Report. AB - Introduction: Febrile neutropenic patients are at risk of serious infections. The aim of the present study is to identify the frequency, species, and susceptibility patterns of candidemia in febrile neutropenic patients. Methods: This cross-sectional study was conducted on febrile neutropenic patients suspected with candidemia who had been referred to 3 educational hospitals during 9 months. Results: The blood samples of 80 febrile neutropenic patients with the mean age of 48+/-16.6 years were studied (60% female). Five (6.25%) episodes of candidemia were identified. The underlying disease was acute myeloid leukemia in 4 (80%) cases and all 5(100%) cases had central venous catheter and were receiving prophylactic ciprofloxacin and acyclovir. 100% of isolates were found to be susceptible to Voriconazole, 80% to Caspofungin, 60% to Amphotericin B, and 40% to Fluconazole. Conclusion: The frequency of candidemia among the studied febrile neutropenia patients was 6.25%, with 80% mortality rate, and the most frequently identified yeast was Candida albicans (100% susceptible to Voriconazole). PMID- 30009242 TI - Trimester specific reference ranges for serum TSH and Free T4 among United Arab Emirates pregnant women. AB - Background: The American Thyroid Association (ATA) recommended the establishment of population specific reference ranges for thyroid hormones during pregnancy. Initial studies conducted in the United Arab Emirates (UAE) in 2003 and 2004 on pregnant women published a considerably higher upper limit for thyroid stimulating hormone (TSH) than that proposed by ATA. The UAE was classified as a country with mild iodine deficiency at the time of this initial study. After the implementation of aggressive strategies to address iodine deficiency over the last decade, the UAE was recently declared as iodine sufficient. The current study re-evaluates the reference intervals for thyroid hormones for pregnant women in the UAE after the declaration of iodine sufficiency status. Methods: TSH and free thyroxin (FT4) from 414 UAE national pregnant females were analyzed to determine trimester specific reference ranges. Results: The upper limits of the TSH reference ranges were found to be significantly lower than previously reported, but still higher than those recommended by ATA in 2011.FT4 reference ranges were found to be slightly lower than previously reported. Conclusion: TSH trimester specific reference ranges in UAE national pregnant women are higher than those recommended by ATA in 2011 but in keeping with the latest guidelines published in 2017. This should be considered while interpreting thyroid function tests in this population. Further studies including urinary iodine measurement, body mass index and larger numbers per partition in this population are recommended. PMID- 30009243 TI - A cold scare: Formation of cold reactive anti-A1 coinciding with gross hemolysis. AB - Anti-A1 antibodies can be found as a usually clinically insignificant naturally occurring cold IgM antibody in A-subgroup patients. It is known from multiple prior case reports that warm-reactive anti-A1 that reacts at 37 degrees C can be clinically significant, and it has been previously reported that it could form after alloimmunization with donor A1 red blood cell (RBC) transfusion. In addition, the development of anti-A1, often as an autoantibody, have been described in the setting of various malignancies, perhaps due to expressed subtle alterations of the ABO antigens provoking an immune response. Here, we report a rare case of a cold-reactive anti-A1 alloantibody (after multiple transfusions with group A1 RBC units) in a 76 year old male patient (A2) with history of myelodysplastic syndrome and metastatic carcinoma who presented with hemolytic anemia and dark urine. The patient had previously typed as blood type A without reverse typing reaction for anti-A1; as a result, the patient had been transfused with group A1 RBCs. Four days prior to discovery of the ABO discrepancy, the patient had a febrile transfusion reaction associated with his A1 RBC transfusion. On admission, his immunohematology workup demonstrated an alloantibody to anti-A1 that coincidentally appeared during a new onset of hemolytic anemia. Case reports of patients with hemolytic anemia with a newly developed anti-A1 alloantibody are sparse in the literature, and this case is particularly interesting as the cold reactive anti-A1 (without demonstrable wide thermal amplitude) appeared to form after alloimmunization and in the setting of an underlying malignancy. PMID- 30009244 TI - Rapid diagnosis of mixed phenotype acute leukemia after identifying a blood histogram abnormality. AB - A 38-year-old woman was suffering from back, right arm, and ankle joint pain, and visited our emergency department. Upon admission, the white blood cell (WBC) count was high (11,700/uL), and low numbers of red blood cells (2.21 * 106/uL) and platelets (PLTs) (42,000/uL) were observed. A PLT histogram showed an abnormally shaped peak at around 20-30 fL, suggesting the presence of giant PLTs or PLT aggregation. The WBC histogram showed abnormal elevation at 35 fL and around 100 fL, suggesting abnormal cells including nucleated red blood cells. A peripheral blood smear was prepared, and morphology was examined. As a result, blasts (4%) including many orthochromatic erythroblasts (48/100 WBCs) were observed. Acute leukemia was suspected, and the patient was transferred the next day to a hospital with a hematology department. Bone marrow aspiration revealed that 99% of cells were blasts positive for B lymphoid lineage markers and myeloperoxidase. The patient was diagnosed with mixed phenotype lineage acute leukemia, treated immediately, and achieved remission. Thus, careful observation of histogram abnormalities of an automatic blood cell analyzer is important for rapid diagnosis of acute leukemia. PMID- 30009245 TI - Rapid detection of four non-fermenting Gram-negative bacteria directly from cystic fibrosis patient's respiratory samples on the BD MAXTM system. AB - The aim of this study was to develop a multiplex PCR test to detect Achromobacter xylosoxidans (AX), Burkholderia cepacia (BC), Pseudomonas aeruginosa (PSA) and Stenotrophomonas maltophilia (SM) directly from CF patient's respiratory samples using the open mode of the BD MAXTM System. A total of 402 CF respiratory samples were evaluated by culture and PCR. Specific sets of primers and probes for each target were designed in-house. Out of 402 samples tested, 196 were identified as negative and 206 as positive by culture for AX, PSA, BC and SM. Among culture positive samples, PCR detected 21/27 AX, 4/5 BC, 138/140 PSA and 29/34 SM. In addition, PCR assay identified 35 samples as positive that were initially negative by culture for those 4 targets. The CF BDM test proved to be an excellent tool to detect AX, BC, PSA and SM by real-time PCR on an automated platform. PMID- 30009247 TI - Nicotine and cotinine in oral fluid: Passive exposure vs active smoking. AB - Scheidweiler and colleagues have clinically tested and identified a reporting cutoff (10 ng/mL) of nicotine and cotinine in oral fluid that could reliably determine active smoking in patients. The results from that study were reevaluated using a large data set of oral fluid nicotine and cotinine results available from pain medication monitoring. Additionally, test results from patients using a nicotine transdermal patch delivery device are compared with those from smokers. Finally, oral fluid test results collected over a 2-year period were normalized and transformed to yield a near Gaussian distribution for nicotine. The normalized and transformed data reveal the presence of two independent populations: a larger population consistent with active smokers and a smaller population consistent with those passively exposed to smoke. Furthermore, application of this model to patients prescribed transdermal nicotine reveals oral fluid levels consistent with those of active smokers. The clinical delineation of smokers from non-smokers reported earlier is supported by the oral fluid nicotine data modelling presented herein. These data indicate that oral fluid is an acceptable sample matrix for determining the smoking status of patients. Further, these data indicate that oral fluid test results are indistinguishable between patients prescribed transdermal patches and active smokers; however, oral fluid testing can determine absence of patches or smoking. PMID- 30009246 TI - Method validation studies and an inter-laboratory cross validation study of lenvatinib assay in human plasma using LC-MS/MS. AB - Cross validation studies for bioanalytical methods are important to ensure that assay data from all study sites where sample analysis is performed can be compared throughout clinical trials. To support global clinical studies of lenvatinib, a novel multi-targeted tyrosine kinase inhibitor, seven bioanalytical methods by liquid chromatography with tandem mass spectrometry (LC-MS/MS) were developed at five laboratories. In this study, methods were initially validated at each laboratory according to bioanalytical guidelines. For subsequent inter laboratory cross validation, quality control (QC) samples and clinical study samples with blinded lenvatinib concentrations were assayed to confirm comparable assay data. Lenvatinib and an internal standard were extracted by protein precipitation, liquid-liquid extraction, or solid phase extraction and then detected in positive ion electrospray mode by multiple reaction monitoring using LC-MS/MS. The assay method developed at each laboratory was successfully validated with parameters within the acceptance criteria recommended by the guidelines. In the cross validation study, accuracy of QC samples was within+/- 15.3% and percentage bias for clinical study samples was within+/- 11.6%. These findings suggest that lenvatinib concentrations in human plasma can be compared across laboratories and clinical studies. PMID- 30009248 TI - Individual differences in face perception and person recognition. PMID- 30009249 TI - Photo ID verification remains challenging despite years of practice. AB - Background: Matching unfamiliar faces to photographic identification (ID) documents occurs across many domains, including financial transactions (e.g., mortgage documents), controlling the purchase of age-restricted goods (e.g., alcohol sales), and airport security. Laboratory research has repeatedly documented the fallibility of this process in novice observers, but little research has assessed individual differences based on occupational expertise (cf. White et al., PLoS One 9:e103510, 2014; White et al., Proceedings of the Royal Society B 282(1814):20151292, 2015). In the present study, over 800 professional notaries (who routinely verify identity prior to witnessing signatures on legal documents), 70 bank tellers, and 35 undergraduate students completed an online unfamiliar face-matching test. In this test, observers made match/nonmatch decisions to 30 face ID pairs (half of which were matches), with no time constraints and no trial-by-trial feedback. Results: Results showed that all groups performed similarly, although age was negatively correlated with accuracy. Critically, weekly and yearly experience with unfamiliar face matching did not impact performance. Conclusions: These results suggest that accumulated occupational experience has no bearing on unfamiliar face ID abilities and that cognitive declines associated with aging also manifest in unfamiliar face matching. PMID- 30009250 TI - Individual differences in the detection, matching and memory of faces. AB - Previous research has explored relationships between individual performance in the detection, matching and memory of faces, but under limiting conditions. The current study sought to extend previous findings with a different measure of face detection, and a more challenging face matching task, in combination with an established test of face memory. Experiment 1 tested face detection ability under conditions designed to maximise individual differences in accuracy but did not find evidence for relationships between measures. In addition, in Experiments 2 and 3, which utilised response times as the primary performance measure for face detection, but accuracy for face matching and face memory, no correlations were observed between performance on face detection and the other tasks. However, there was a correlation between accuracy in face matching and face memory, consistent with other research. Together, these experiments provide further evidence for a dissociation between face detection, and face matching and face memory, but suggest that these latter tasks share some common mechanisms. PMID- 30009251 TI - Individual differences in face identity processing. AB - We investigated the relationships between individual differences in different aspects of face-identity processing, using the Glasgow Face Matching Test (GFMT) as a measure of unfamiliar face perception, the Cambridge Face Memory Test (CFMT) as a measure of new face learning, and the Before They Were Famous task (BTWF) as a measure of familiar face recognition. These measures were integrated into two separate studies examining the relationship between face processing and other tasks. For Study 1 we gathered participants' subjective ratings of their own face perception abilities. In Study 2 we used additional measures of perceptual and cognitive abilities, and personality factors to place individual differences in a broader context. Performance was significantly correlated across the three face identity tasks in both studies, suggesting some degree of commonality of underlying mechanisms. For Study 1 the participants' self-ratings correlated poorly with performance, reaching significance only for judgements of familiar face recognition. In Study 2 there were few associations between face tasks and other measures, with task-level influences seeming to account for the small number of associations present. In general, face tasks correlated with each other, but did not show an overall relation with other perceptual, cognitive or personality tests. Our findings are consistent with the existence of a general face-perception factor, able to account for around 25% of the variance in scores. However, other relatively task-specific influences are also clearly operating. PMID- 30009254 TI - Individual differences in hyper-realistic mask detection. AB - Hyper-realistic masks present a new challenge to security and crime prevention. We have recently shown that people's ability to differentiate these masks from real faces is extremely limited. Here we consider individual differences as a means to improve mask detection. Participants categorized single images as masks or real faces in a computer-based task. Experiment 1 revealed poor accuracy (40%) and large individual differences (5-100%) for high-realism masks among low realism masks and real faces. Individual differences in mask categorization accuracy remained large when the Low-realism condition was eliminated (Experiment 2). Accuracy for mask images was not correlated with accuracy for real face images or with prior knowledge of hyper-realistic face masks. Image analysis revealed that mask and face stimuli were most strongly differentiated in the region below the eyes. Moreover, high-performing participants tracked the differential information in this area, but low-performing participants did not. Like other face tasks (e.g. identification), hyper-realistic mask detection gives rise to large individual differences in performance. Unlike many other face tasks, performance may be localized to a specific image cue. PMID- 30009253 TI - Face recognition ability does not predict person identification performance: using individual data in the interpretation of group results. AB - There are large individual differences in people's face recognition ability. These individual differences provide an opportunity to recruit the best face recognisers into jobs that require accurate person identification, through the implementation of ability-screening tasks. To date, screening has focused exclusively on face recognition ability; however real-world identifications can involve the use of other person-recognition cues. Here we incorporate body and biological motion recognition as relevant skills for person identification. We test whether performance on a standardised face-matching task (the Glasgow Face Matching Test) predicts performance on three other identity-matching tasks, based on faces, bodies, and biological motion. We examine the results from group versus individual analyses. We found stark differences between the conclusions one would make from group analyses versus analyses that retain information about individual differences. Specifically, tests of correlation and analysis of variance suggested that face recognition ability was related to performance for all person identification tasks. These analyses were strikingly inconsistent with the individual differences data, which suggested that the screening task was related only to performance on the face task. This study highlights the importance of individual data in the interpretation of results of person identification ability. PMID- 30009252 TI - Applied screening tests for the detection of superior face recognition. AB - In recent years there has been growing interest in the identification of people with superior face recognition skills, for both theoretical and applied investigations. These individuals have mostly been identified via their performance on a single attempt at a tightly controlled test of face memory-the long form of the Cambridge Face Memory Test (CFMT+). The consistency of their skills over a range of tests, particularly those replicating more applied policing scenarios, has yet to be examined systematically. The current investigation screened 200 people who believed they have superior face recognition skills, using the CFMT+ and three new, more applied tests (measuring face memory, face matching and composite-face identification in a crowd). Of the sample, 59.5% showed at least some consistency in superior face recognition performance, although only five individuals outperformed controls on overall indices of target-present and target-absent trials. Only one participant outperformed controls on the Crowds test, suggesting that some applied face recognition tasks require very specific skills. In conclusion, future screening protocols need to be suitably thorough to test for consistency in performance, and to allow different types of superior performer to be detected from the outset. Screening for optimal performers may sometimes need to directly replicate the task in question, taking into account target-present and target-absent performance. Self-selection alone is not a reliable means of identifying those at the top end of the face recognition spectrum. PMID- 30009255 TI - Accelerating rates of Arctic carbon cycling revealed by long-term atmospheric CO2 measurements. AB - The contemporary Arctic carbon balance is uncertain, and the potential for a permafrost carbon feedback of anywhere from 50 to 200 petagrams of carbon (Schuur et al., 2015) compromises accurate 21st-century global climate system projections. The 42-year record of atmospheric CO2 measurements at Barrow, Alaska (71.29 N, 156.79 W), reveals significant trends in regional land-surface CO2 anomalies (DeltaCO2), indicating long-term changes in seasonal carbon uptake and respiration. Using a carbon balance model constrained by DeltaCO2, we find a 13.4% decrease in mean carbon residence time (50% confidence range = 9.2 to 17.6%) in North Slope tundra ecosystems during the past four decades, suggesting a transition toward a boreal carbon cycling regime. Temperature dependencies of respiration and carbon uptake suggest that increases in cold season Arctic labile carbon release will likely continue to exceed increases in net growing season carbon uptake under continued warming trends. PMID- 30009256 TI - Chondrules as direct thermochemical sensors of solar protoplanetary disk gas. AB - Chondrules, millimeter-sized igneous spherules comprising the major component of most chondritic meteorites, formed during the first 4 million to 5 million years of the evolution of the solar protoplanetary disk and, therefore, can potentially offer important constraints on the conditions in the disk, provided that the processes that led to their formation can be understood. High-resolution cathodoluminescence (CL) survey of chondrules from various chondrite groups revealed changes of CL activator concentrations of magnesium-rich olivines. We show that these overlooked internal zoning structures provide evidence for high temperature gas-assisted near-equilibrium epitaxial growth of olivines during chondrule formation. We argue that this interaction with the surrounding gas, rather than various cooling histories, defined chondrule composition and texture. Chondrules are thus direct thermochemical sensors of their high-temperature gaseous environment, and high partial pressures of gaseous Mg and SiO are required in their solar protoplanetary disk-forming region to maintain olivine saturation in chondrules. The inferred crystallization of olivines, from stable melts approaching equilibrium with the surrounding gas, provides an explanation for the notable absence of large and systematic isotopic fractionations in chondrules. PMID- 30009257 TI - Evidence of an early projectile point technology in North America at the Gault Site, Texas, USA. AB - American archeology has long been polarized over the issue of a human presence in the Western Hemisphere earlier than Clovis. As evidence of early sites across North and South America continues to emerge, stone tool assemblages appear more geographically and temporally diverse than traditionally assumed. Within this new framework, the prevailing models of Clovis origins and the peopling of the Americas are being reevaluated. This paper presents age estimates from a series of alluvial sedimentary samples from the earliest cultural assemblage at the Gault Site, Central Texas. The optically stimulated luminescence age estimates (~16 to 20 thousand years ago) indicate an early human occupation in North America before at least ~16 thousand years ago. Significantly, this assemblage exhibits a previously unknown, early projectile point technology unrelated to Clovis. Within a wider context, this evidence suggests that Clovis technology spread across an already regionalized, indigenous population. PMID- 30009258 TI - Neurite architecture of the planum temporale predicts neurophysiological processing of auditory speech. AB - The left hemispheric advantage in speech perception is reflected in faster neurophysiological processing. On the basis of postmortem data, it has been suggested that asymmetries in the organization of the intrinsic microcircuitry of the posterior temporal lobe may produce this leftward timing advantage. However, whether this hypothetical structure-function relationship exists in vivo has never been empirically validated. To test this assumption, we used in vivo neurite orientation dispersion and density imaging to quantify microcircuitry in terms of axon and dendrite complexity of the left and right planum temporale in 98 individuals. We found that a higher density of dendrites and axons in the temporal speech area is associated with faster neurophysiological processing of auditory speech, as reflected by electroencephalography. Our results imply that a higher density and higher number of synaptic contacts in the left posterior temporal lobe increase temporal precision and decrease latency of neurophysiological processes in this brain region. PMID- 30009259 TI - Barium isotope evidence for pervasive sediment recycling in the upper mantle. AB - The upper mantle, as sampled by mid-ocean ridge basalts (MORBs), exhibits significant chemical variability unrelated to mechanisms of melt extraction at ridges. We show that barium isotope variations in global MORBs vary systematically with radiogenic isotopes and trace element ratios, which reflects mixing between depleted and enriched MORB melts. In addition, modern sediments and enriched MORBs share similar Ba isotope signatures. Using modeling, we show that addition of ~0.1% by weight of sediment components into the depleted mantle in subduction zones must impart a sedimentary Ba signature to the overlying mantle and induce low-degree melting that produces the enriched MORB reservoir. Subsequently, these enriched domains convect toward mid-ocean ridges and produce radiogenic isotope variation typical of enriched MORBs. This mechanism can explain the chemical and isotopic features of enriched MORBs and provide strong evidence for pervasive sediment recycling in the upper mantle. PMID- 30009260 TI - Phosphorylation of human TRM9L integrates multiple stress-signaling pathways for tumor growth suppression. AB - The human transfer RNA methyltransferase 9-like gene (TRM9L, also known as KIAA1456) encodes a negative regulator of tumor growth that is frequently silenced in many forms of cancer. While TRM9L can inhibit tumor cell growth in vivo, the molecular mechanisms underlying the tumor inhibition activity of TRM9L are unknown. We show that oxidative stress induces the rapid and dose-dependent phosphorylation of TRM9L within an intrinsically disordered domain that is necessary for tumor growth suppression. Multiple serine residues are hyperphosphorylated in response to oxidative stress. Using a chemical genetic approach, we identified a key serine residue in TRM9L that undergoes hyperphosphorylation downstream of the oxidative stress-activated MEK (mitogen activated protein kinase kinase)-ERK (extracellular signal-regulated kinase)-RSK (ribosomal protein S6 kinase) signaling cascade. Moreover, we found that phosphorylated TRM9L interacts with the 14-3-3 family of proteins, providing a link between oxidative stress and downstream cellular events involved in cell cycle control and proliferation. Mutation of the serine residues required for TRM9L hyperphosphorylation and 14-3-3 binding abolished the tumor inhibition activity of TRM9L. Our results uncover TRM9L as a key downstream effector of the ERK signaling pathway and elucidate a phospho-signaling regulatory mechanism underlying the tumor inhibition activity of TRM9L. PMID- 30009261 TI - BAFF inhibition attenuates fibrosis in scleroderma by modulating the regulatory and effector B cell balance. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. More than 90% of patients with SSc are positive for autoantibodies. In addition, serum B cell activating factor (BAFF) level is correlated with SSc severity and activity. Thus, B cells are considered to play a pathogenic role in SSc. However, there are two opposing subsets: regulatory B cells (Bregs) and effector B cells (Beffs). Interleukin-10 (IL-10)-producing Bregs negatively regulate the immune response, while IL-6-producing Beffs positively regulate it. Therefore, a protocol that selectively depletes Beffs would represent a potent therapy for SSc. The aims of this study were to investigate the roles of Bregs and Beffs in SSc and to provide a scientific basis for developing a new treatment strategy targeting B cells. A bleomycin-induced scleroderma model was induced in mice with a B cell-specific deficiency in IL-6 or IL-10. We also examined whether BAFF regulates cytokine-producing B cells and its effects on the scleroderma model. IL-6-producing Beffs increased in number and infiltrated the inflamed skin in the scleroderma model. The skin and lung fibrosis was attenuated in B cell specific IL-6-deficient mice, whereas B cell-specific IL-10-deficient mice showed more severe fibrosis. In addition, BAFF increased Beffs but suppressed Bregs. Furthermore, BAFF antagonist attenuated skin and lung fibrosis in the scleroderma model with reduction of Beffs but not of Bregs. The current study indicates that Beffs play a pathogenic role in the scleroderma model, while Bregs play a protective role. BAFF inhibition is a potential therapeutic strategy for SSc via alteration of B cell balance. PMID- 30009262 TI - Establishment of environmentally sensitive DNA methylation states in the very early human embryo. AB - The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype. PMID- 30009263 TI - Acceleration of Two Point Correlation Function Calculation for Pathology Image Segmentation. AB - The segmentation of tissue regions in high-resolution microscopy is a challenging problem due to both the size and appearance of digitized pathology sections. The two point correlation function (TPCF) has proved to be an effective feature to address the textural appearance of tissues. However the calculation of the TPCF functions is computationally burdensome and often intractable in the gigapixel images produced by slide scanning devices for pathology application. In this paper we present several approaches for accelerating deterministic calculation of point correlation functions using theory to reduce computation, parallelization on distributed systems, and parallelization on graphics processors. Previously we show that the correlation updating method of calculation offers an 8-35* speedup over frequency domain methods and decouples efficient computation from the select scales of Fourier methods. In this paper, using distributed computation on 64 compute nodes provides a further 42* speedup. Finally, parallelization on graphics processors (GPU) results in an additional 11-16* speedup using an implementation capable of running on a single desktop machine. PMID- 30009264 TI - Bile Duct Injury in Children: Is There a Role for Early Endoscopic Retrograde Cholangiopancreatography? AB - Introduction Liver injury is common among pediatric abdominal trauma. Nonoperative management is the standard of care in isolated stable liver injuries. Bile leak is not an uncommon complication in moderate- and high-grade injuries. Case series Three pediatric patients (age: 10-15 years) suffered grade IV liver injuries secondary to blunt abdominal trauma. All developed significant bile leak treated nonoperatively with endoscopic retrograde cholangiopancreatography (ERCP), and patients 1 and 2 were treated with bile duct stent alone. Patient 3 required laparotomy for bile peritonitis and abdominal compartment syndrome followed by interval ERCP and bile duct stent. Conclusion Traumatic bile leaks if not recognized and managed early can result in significant morbidity. This paper describes the presentation and treatment of three pediatric patients with blunt liver trauma complicated by significant bile leaks that were managed successfully with ERCP and bile duct stent. This paper demonstrates the importance of early detection of bile leak to prevent bile peritonitis. Abdominal imaging 4 to 5 days postinjury can help in detecting bile accumulation. We believe that ERCP and bile duct stent are becoming the standard of care in diagnosing and treating traumatic bile leak. This paper confirms the safety and feasibility of this technique in the pediatric population. PMID- 30009265 TI - Caesarean Section Does Not Increase the Risk of Caries in Swedish Children. AB - Caesarean section has been shown to affect the health of the child. Only a few studies have investigated whether the mode of delivery is associated with dental caries, and they present conflicting results. Our study investigated whether dental caries was associated with delivery method in Swedish preschool children. This retrospective register-based cohort study included all children born from 2000 to 2003 who were residing in Stockholm County, Sweden, at 3 y of age (n = 83,147). The study followed the cohort until individuals were 7 y of age. Children examined at 3 and 7 y constituted the final study cohort (n = 65,259). We dichotomized the key exposure "delivery starts by caesarean section" and analyzed it in univariate analyses as well as in multivariate analyses. The multivariate analyses used 3 outcomes: caries experience at age 3 (deft >0 [decayed, extracted, and filled teeth]), caries increment between 3 and 7 y of age (Deltadeft > 0), and caries experience at age 7 (deft > 0). Of the final cohort, 15% (n = 9,587) were delivered by caesarean section. At 3 y of age, the results showed no statistically significant association between caesarean section and caries experience (odds ratio = 0.92, 95% confidence interval [CI] = 0.82 to 1.04). Between 3 and 7 y of age, the association of caesarean section on caries increment was 0.88 (95% CI = 0.83 to 0.94) and at 7 y of age, 0.88 (caries experience; 95% CI = 0.82 to 0.94). Higher mean values for caries experience and caries increment were observed in vaginally delivered children. We found that preschool children who were delivered by caesarean section do not represent a group with an excess risk of developing dental caries. Furthermore, the statistically significant associations with caries increment and caries experience at age 7 were negative. Knowledge Transfer Statement: Children born by caesarean section are at greater risk of developing asthma and obesity. The proportion of elective caesarean sections without a medical indication has increased over the years; therefore, it is important to know how this mode of delivery affects oral health of the child. The results show that children who are delivered by caesarean section are not at greater risk of developing dental caries, and clinicians can use these findings in their risk assessment. PMID- 30009266 TI - Dependency and health utilities in stroke: Data to inform cost-effectiveness analyses. AB - Introduction: Health utilities (HU) assign preference weights to specific health states and are required for cost-effectiveness analyses. Existing HU for stroke inadequately reflect the spectrum of post-stroke disability. Using international stroke trial data, we calculated HU stratified by disability to improve precision in future cost-effectiveness analyses. Materials and methods: We used European Quality of Life Score (EQ-5D-3L) data from the Virtual International Stroke Trials Archive (VISTA) to calculate HU, stratified by modified Rankin Scale scores (mRS) at 3 months. We applied published value sets to generate HU, and validated these using ordinary least squares regression, adjusting for age and baseline National Institutes of Health Stroke Scale (NIHSS) scores. Results: We included 3858 patients with acute ischemic stroke in our analysis (mean age: 67.5 +/- 12.5, baseline NIHSS: 12 +/- 5). We derived HU using value sets from 13 countries and observed significant international variation in HU distributions (Wilcoxon signed-rank test p < 0.0001, compared with UK values). For mRS = 0, mean HU ranged from 0.88 to 0.95; for mRS = 5, mean HU ranged from -0.48 to 0.22. OLS regression generated comparable HU (for mRS = 0, HU ranged from 0.9 to 0.95; for mRS = 5, HU ranged from -0.33 to 0.15). Patients' mRS scores at 3 months accounted for 65-71% of variation in the generated HU. Conclusion: We have generated HU stratified by dependency level, using a common trial endpoint, and describing expected variability when applying diverse value sets to an international population. These will improve future cost-effectiveness analyses. However, care should be taken to select appropriate value sets. PMID- 30009267 TI - Impact of detecting potentially serious incidental findings during multi-modal imaging. AB - Background: There are limited data on the impact of feedback of incidental findings (IFs) from research imaging. We evaluated the impact of UK Biobank's protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer 'flagging' with radiologist confirmation of potentially serious IFs) compared with systematic radiologist review of all images. Methods: Brain, cardiac and body magnetic resonance, and dual-energy x ray absorptiometry scans from the first 1000 imaged UK Biobank participants were independently assessed for potentially serious IFs using both protocols. We surveyed participants with potentially serious IFs and their GPs up to six months after imaging to determine subsequent clinical assessments, final diagnoses, emotional, financial and work or activity impacts. Results: Compared to systematic radiologist review, radiographer flagging resulted in substantially fewer participants with potentially serious IFs (179/1000 [17.9%] versus 18/1000 [1.8%]) and a higher proportion with serious final diagnoses (21/179 [11.7%] versus 5/18 [27.8%]). Radiographer flagging missed 16/21 serious final diagnoses (i.e., false negatives), while systematic radiologist review generated large numbers of non-serious final diagnoses (158/179) (i.e., false positives). Almost all (90%) participants had further clinical assessment (including invasive procedures in similar numbers with serious and non-serious final diagnoses [11 and 12 respectively]), with additional impact on emotional wellbeing (16.9%), finances (8.9%), and work or activities (5.6%). Conclusions: Compared with systematic radiologist review, radiographer flagging missed some serious diagnoses, but avoided adverse impacts for many participants with non-serious diagnoses. While systematic radiologist review may benefit some participants, UK Biobank's responsibility to avoid both unnecessary harm to larger numbers of participants and burdening of publicly-funded health services suggests that radiographer flagging is a justifiable approach in the UK Biobank imaging study. The potential scale of non-serious final diagnoses raises questions relating to handling IFs in other settings, such as commercial and public health screening. PMID- 30009268 TI - The Effects of a Comprehensive Psychosocial Intervention on Secondary Stressors and Social Support for Adult Child Caregivers of Persons With Dementia. AB - Background and Objectives: Many evaluations of nonpharmacologic interventions for family members of persons with Alzheimer's disease or related dementias (ADRDs) exist, but few consider effects on outcomes that are pertinent to caregivers' roles and relationships. The current study evaluated the efficacy of the New York University Caregiver Intervention-Adult Child (NYUCI-AC) on perceptions of family conflict, role conflict (effects of family caregiving and time, family, and social life), and perceived social support for adult child caregivers of relatives with ADRD over a 3-year period. Research Design and Methods: A single blinded randomized controlled trial design was used. One-hundred and seven adult child caregivers were enrolled in the NYUCI-AC and randomly assigned to a treatment or contact control group. Assessments were scheduled to be completed every 4 months during the first year of participation and every 6 months thereafter for up to 3 years. Individual growth curve models were utilized to ascertain the effects of the NYUCI-AC on change in family conflict, role conflict, and perceptions of social support. Results: Among the entire sample, role conflict significantly (p < .05) declined and satisfaction with instrumental assistance increased over the course of the study, whereas family conflict slightly increased over the initial study period and then declined slightly. The findings indicated that the NYUCI-AC did not exert statistically significant effects on changes in family conflict, role conflict, or perceptions of social support over the 3-year study period. Discussion and Implications: Although the clinical content of some dementia caregiver interventions is tailored to the specific needs of each caregiver and family, the outcomes selected to judge the efficacy of these interventions might not follow similar principles. Incorporating clinical content and evaluation outcomes that are family-centered will help to advance the state of the art of dementia caregiving interventions. PMID- 30009270 TI - Production and partial characterization of dehairing alkaline protease from Bacillus subtilis AKAL7 and Exiguobacterium indicum AKAL11 by using organic municipal solid wastes. AB - Alkaline proteases have applications in numerous industries. In this study, we have isolated and screened proteolytic bacteria from poultry wastes mixed soil and identified two bacterial isolates as Bacillus subtilis AKAL7 and Exiguobacterium indicum AKAL11 based on 16S rDNA sequencing. Maximum level of protease production was achieved after 24 h of fermentation in a basal medium. The optimal temperature, initial pH of the media and agitation for alkaline protease production by these two isolates were 30 degrees C, pH 9.0 and 120 rpm, respectively. The both bacterial isolates produced maximum level of protease with 3.0% organic municipal solid wastes (OMSW) as the sole source of carbon and nitrogen under previously optimized fermentation conditions. In comparison with the shake flask, protease production increased about 2.5-fold in the bioreactor with reduction in fermentation period. The partial purification of protease resulted in a final 45.67 and 34.86-fold purified protease with a specific activity of 8335.34 and 9918.91 U/mg protein and a typical yield of 9.75 and 9.41% from B. subtilis and E. indicum, respectively. The optimum temperature and pH of the partially purified protease from the both sources was 40 degrees C and pH 9.0, respectively. Protease from the both isolates was stable at pH 7.0-12.0 and at temperatures up to 50 degrees C. The effects of protease inhibitors indicated that the protease from B. subtilis might be serine and cysteine type and from E. indicum might be cysteine type. Mg2+, K+ and Ca2+ stimulated but Zn2+, Hg2+, Co2+ and Fe3+ strongly inhibited the protease activity. The partially purified protease from B. subtilis substantially dehaired cow skin and decomposed gelatinous compound from X-ray film. Our study revealed that OMSW can be used as raw material for production of bacterial extracellular protease and alkaline protease from B. subtilis might be potential for industrial and biotechnological applications. PMID- 30009269 TI - Overexpression of miR-221 in sudden death with cardiac hypertrophy patients. AB - Background: Cardiac hypertrophy is a well-known risk factor for heart failure and sudden cardiac death (SCD). On the other hand, physiological cardiac hypertrophy is often observed in young healthy men, and it is difficult to predict SCD in cardiac hypertrophy subjects who do not show symptoms of heart failure. MicroRNAs (miRNAs) widely regulate biological activity and play pivotal roles in heart failure progression. In this study, we investigated whether miRNA expression is altered in SCD with cardiac hypertrophy (SCH). Methods: Cardiac tissues were sampled at autopsy from SCH patients, compensated cardiac hypertrophy (CCH) subjects who died of causes other than heart failure, and control cases without cardiac hypertrophy or heart failure. After histopathological examination, we performed deep sequencing and quantitative PCR of cardiac miRNAs. Results and discussion: Although SCH and CCH showed indistinguishable histological features, their miRNA expression signatures were distinct. Among the 240 miRNAs stably detected in the heart, 8 were differentially expressed between SCH and CCH. Specifically, miR-221 increased in SCH compared to CCH and control cases. The significant elevation of cardiac miR-221 in SCH patients is correlated with lethal outcomes. Thus, our results indicate that an elevated miR-221 level is potentially associated with an increased risk of SCD in subjects with cardiac hypertrophy. PMID- 30009271 TI - Lactobacillus kefiranofaciens, the sole dominant and stable bacterial species, exhibits distinct morphotypes upon colonization in Tibetan kefir grains. AB - Tibetan kefir grains (TKGs), natural starters for milk fermentation, are believed to comprise diverse microflora of lactic acid and acetic acid bacteria. In order to better understand the bacterial community in TKGs, TKGs that had been cultured continuously either naturally or aseptically for 10 months were subject to analysis using both culture-dependent and various culture-independent methods. Results of DGGE, metagenomics, FISH, qPCR and isolation all demonstrated that Lactobacillus kefiranofaciens is the only dominant and stable bacterial species in TKGs regardless of culture conditions and time. FISH and SEM showed that L. kefiranofaciens exhibited two distinct morphotypes of short rod (3.0 MUm in length) and long rod (10.0 MUm in length) upon colonization of either the outer surface or inner component of TKGs, providing evidence for its trophic adaptation to the hollow globular grain structure of TKGs. These findings pave ways for further study of the specific symbiotic interaction between L. kefiranofaciens and the dominant Saccharomyces cerevisiae yeast in TKGs in vivo. PMID- 30009272 TI - Embedding hexanuclear tantalum bromide cluster {Ta6Br12} into SiO2 nanoparticles by reverse microemulsion method. AB - Hexanuclear tantalum bromide cluster units [{Ta6Bri12}La6] (i = inner, a = apical, L = ligand OH or H2O) are embedded into SiO2 nanoparticles by a reverse microemulsion (RM) based method. [{Ta6Bri12}Bra2 (H2O)a4].nH2O (noted TBH) and tetraethyl orthosilicate (TEOS) are used as the starting cluster compound and the precursor of SiO2, respectively. The RM system in this study consists of the n heptane (oil phase), Brij L4 (surfactants), ethanol, TEOS, ammonia solution and TBH aqueous sol. The size and morphology of the product namely {Ta6Br12}@SiO2 nanoparticles are analyzed by HAADF-STEM and EDS mappings. The presence and integrity of {Ta6Br12} in the SiO2 nanoparticles are evidenced by EDS mapping, ICP-OES/IC and XPS analysis. The optical properties of {Ta6Br12}@SiO2 nanoparticles are analyzed by diffuse reflectance UV-vis spectroscopy, further evidencing the integrity of the embedded {Ta6Br12} and revealing their oxidation state. Both {Ta6Br12}2+ and {Ta6Br12}3+ are found in SiO2 nanoparticles, but the latter is much more stable than the former. The by-products in this RM-based synthesis, as well as their related factors, are also discussed. PMID- 30009273 TI - Development stage, storage temperature and storage duration influence phytonutrient content in cowpea (Vigna unguiculata L. Walp.). AB - Cowpea (Vigna unguiculata) plays an important role in sustainable food security and livelihood improvement in Sub-Saharan Africa (SSA). The crop is rich in phytonutrients and minerals, which are key in solving malnutrition and hunger crisis, a major challenge in SSA. However, physiological status, storage temperature and duration affect phytonutrient levels and postharvest life of the leafy vegetable. Despite the significant importance of cowpeas, the maturity and postharvest storage effects on quality of the leafy vegetable remains unrevealed. The aim of this study was to analyze the dynamics of phytonutrients in cowpea leaves during development under field conditions in Kenya and in storage. The total carbohydrates (glucose, fructose, sucrose and starch) were highest at 90 d after planting (105.9 +/- 2.5 g kg-1) compared to 30, 60 and 120 d. The total Phenolics (Gallic acid equivalents) increased gradually with age up to 12.0 +/- 0.2 g kg-1 by 120 d. Catechin equivalent flavonoids, trolox equivalent antioxidants (TEA) and chlorophyll were highest in concentrations at 60 d after planting with 8.0 +/- 0.5 g kg-1, 26.19 +/- 0.5 g kg-1 and 5.7 +/- 0.4 g kg-1, respectively. Quercetin equivalent flavonoids and total carotenoids did not show significant changes with age, while mineral concentration dynamics were specific for each element. Storage of cowpea leaves at room temperature (50-55 % relative humidity) led to a stronger decline of phytonutrients after 4 d, but mostly they remained stable at cold storage (5 degrees C). Results of this study highlight the importance of developmental stage at harvest, storage conditions and duration for the optimal availability of phytonutrients in freshly consumed leaves and for postharvest management strategies. PMID- 30009274 TI - Optimizing the Magnetic Dipole-Field Source for Magnetically Guided Cochlear Implant Electrode-Array Insertions. AB - Magnetic guidance of cochlear-implant electrode arrays during insertion has been demonstrated in vitro to reduce insertion forces, which is believed to be correlated to a reduction in trauma. In those prior studies, the magnetic dipole field source (MDS) was configured to travel on a path that would be coincident with the cochlea's modiolar axis, which was an unnecessary constraint that was useful to demonstrate feasibility. In this paper, we determine the optimal configuration (size and location) of a spherical-permanent-magnet MDS needed to accomplish guided insertions with a 100 mT field strength required at the cochlea, and we provide a methodology to perform such an optimization more generally. Based on computed-tomography scans of 30 human subjects, the MDS should be lateral-to and slightly anterior-to the cochlea with an approximate radius (mean and standard deviation across subjects) of 64 mm and 4.5 mm, respectively. We compare these results to the modiolar configuration and find that the volume of the MDS can be reduced by a factor of five with a 43% reduction in its radius by moving it to the optimal location. We conservatively estimate that the magnetic forces generated by the optimal configuration are two orders of magnitude below the threshold needed to puncture the basilar membrane. Although subject-specific optimal configurations are computed in this paper, a one-size-fits-all version with a radius of approximately 75 mm is more robust to registration error and likely more practical. Finally, we explain how to translate the results obtained to an electromagnetic MDS. PMID- 30009275 TI - A randomized preference trial of cognitive-behavioral therapy and yoga for the treatment of worry in anxious older adults. AB - Background: Worry is a common problem among older adults. Cognitive-behavioral therapy is the most studied nonpharmacological intervention and it has demonstrated efficacy in reducing late-life worry and anxiety. Although the evidence-base is smaller, yoga has been shown to reduce anxiety and stress. However, little is known about the relative effectiveness of these two nonpharmacological interventions. Further, the impact of patient preference on outcomes is unknown.Purpose: The purpose to this study is to compare the effectiveness of cognitive-behavioral therapy (CBT) with yoga for improving late life worry, anxiety, and sleep. We will also examine the effects of preference and selection on outcomes, adherence, and attrition. Methods: We are conducting a two-stage randomized preference trial comparing CBT and yoga for the reduction of worry in a sample of anxious older adults. Five hundred participants will be randomized to either the preference trial (participants choose the intervention; N = 250) or to the randomized trial (participants are randomized to one of the two interventions; N = 250) with equal probability. CBT consists of 10 telephone based sessions with an accompanying workbook. Yoga consists of 10 weeks of group yoga classes (twice a week) that is modified for use with older adults. Conclusions: The study design is based on feedback from anxious older adults who wanted more nonpharmacological options for intervention as well as more input into the intervention they receive. It is the first head-to-head comparison of CBT and yoga for reducing late-life worry and anxiety. It will also provide information about how intervention preference affects outcomes. Trial registration: ClinicalTrials.gov NCT02968238. PMID- 30009277 TI - PALINA: A phase II safety study of palbociclib in combination with letrozole or fulvestrant in African American women with hormone receptor positive HER2 negative advanced breast cancer. AB - Palbociclib has been shown to be a highly effective therapy in hormone receptor positive metastatic breast cancer when used in combination with letrozole or fulvestrant. Grade 3/4 neutropenia is a common side effect although febrile neutropenia is relatively uncommon. Insufficient data exist to describe the hematological safety of palbociclib in African American women (AAW) known to have a high incidence of benign ethnic neutropenia (BEN). PALOMA 1, 2 and 3, the initial phase II/III studies that led to the U.S. Food and Drug Administration (FDA) approval of palbociclib in metastatic breast cancer, only included participants with baseline absolute neutrophil count (ANC) of 1500/mm3 or higher. African American women (AAW) were underrepresented in the PALOMA trials and this may be partially explained by strict requirements for minimal ANC >=1500/mm3. The ANC of 1500/mm3 for initiation of treatment in those with BEN has been previously challenged. In this study, we propose to lower the ANC cutoff for enrollment to 1000/mm3. PALINA (NCT02692755) is a phase II, single arm, multicenter clinical trial that will enroll 35 patients. The primary endpoint is to assess the proportion of patients who complete therapy without the development of febrile neutropenia or treatment discontinuation due to neutropenia. The secondary endpoints include number of patients who required dose delays or dose reductions in palbociclib attributed to neutropenia, rate of grade 3/4 neutropenia, clinical benefit rate at 24 weeks, the association between metabolite and exosomal signature with disease response and the association between baseline ANC prior to cancer diagnosis and the Duffy Null polymorphism (SNP rs2814778) with hematological safety. PALINA will provide important information about the hematologic safety of palbociclib in AAW with advanced breast cancer. PMID- 30009276 TI - Meal-exercise challenge and physical activity reduction impact on immunity and inflammation (MERIIT trial). AB - Background: The effect of a pre-exercise meal as countermeasure to exercise induced immunodepression is poorly known. Also, sedentary behavior is associated with increased cardiometabolic risk but studies on immune changes are lacking. Therefore, we aimed to assess: 1) the impact of a pre-exercise Mediterranean meal (MdM) compared with a fast-food type meal (FFM) on exercise-induced immunological changes and 2) the impact of an induced acute period of sedentary behavior on neuro-immune-endocrine status. Methods: /Design: This is a two steps clinical trial including: (a) randomized crossover clinical trial, comparing the effect a high-fat/low-nutrient dense meal, FFM, with an isoenergetic similar high-nutrient dense meal, MdM, in the immune response to an exercise challenge (EC) and (b) a pilot trial assessing the neuro-immune-endocrine change induced by acute decreasing by half the usual physical activity level. Results: A total of 46 participants (26 females), median aged 25 years were included. Of those 39 completed protocol, including overweight, physical active and inactive and participants with asthma. There were no differences in the EC between interventions. Dietary factors and physical activity were closely monitored during interventions and kept similar. During physical inactivity induction, 31% reached the target of 50% reduction in mean step number and 77% reached a 30% reduction. Conclusion: The use of a pre-exercise meal to modulate immune response and the understanding of the immunological impact of physical inactivity might help to establish future recommendations on how to practice exercise in a safer way and to recognize the potential impact of inactivity. PMID- 30009280 TI - 'Humanizing' healthcare environments: architecture, art and design in modern hospitals. AB - In recent decades, hospital design literature has paid increasing attention to an apparent need to 'humanize' hospital environments. Despite the prevalence of this design goal, the concept of 'humanizing' a space has rarely been defined or interrogated in depth. This article focuses on the meaning of humanization, as a necessary step towards understanding its implementation in practice. It explores the recent history of humanistic design as a goal in healthcare contexts, focusing on the UK in the late twentieth century. It shows that many features of humanistic design were not revolutionary, but that they were thought to serve a new purpose in counterbalancing high-technology, scientific and institutional medical practice. The humanistic hospital, as an ideal, operated as a symbol for wider social concerns about the loss - or decentring - of patients in modern medical practice. Overall, this article indicates a need to interrogate further the language of 'humanization' and its history. The term is not value free; it carries with it assumptions about the dehumanization of modern medicine, and has often been built on implicit binaries between the human and the technological. PMID- 30009278 TI - AGE-RELATED DETERIORATION OF BONE TOUGHNESS IS RELATED TO DIMINISHING AMOUNT OF MATRIX GLYCOSAMINOGLYCANS (GAGS). AB - Hydration status significantly affects the toughness of bone. In addition to the collagen phase, recent evidence shows that glycosaminoglycans (GAGs) of proteoglycans (PGs) in the extracellular matrix also play a pivotal role in regulating the tissue-level hydration status of bone, thereby affecting the tissue-level toughness of bone. In this study, we hypothesized that the amount of GAGs in bone matrix decreased with age and such changes would lead to reduction in bound water and subsequently result in a decrease in the tissue-level toughness of bone. To test the hypothesis, nanoscratch tests were conducted to measure the tissue-level toughness of human cadaveric bone specimens, which were procured only from male donors in three different age groups: young (26 +/- 6 years old), mid-aged (52 +/- 5 years old) and elderly (73 +/- 5 years old), with six donors in each group. Biochemical and histochemical assays were performed to determine the amount and major subtypes of GAGs and proteoglycans in bone matrix. In addition, low-field NMR measurements were implemented to determine bound water content in bone matrix. The results demonstrated that aging resulted in a statistically significant reduction (17%) of GAGs in bone matrix. Concurrently, a significant deterioration (20%) of tissue-level toughness of bone with age was observed. Most importantly, the deteriorated tissue-level toughness of bone was associated significantly with the age-related reduction (40%) of bound water, which was partially induced by the decrease of GAGs in bone matrix. Furthermore, we identified that chondroitin sulfate (CS) was a major subtype of GAGs and the amount of CS decreased with aging in accompany with a decrease of biglycan that is a major subtype of PGs in bone. The findings of this study suggests that reduction of GAGs in bone matrix is likely one of the molecular origins for age related deterioration of bone quality. PMID- 30009281 TI - Joint Reconstruction and Segmentation of 7T-like MR Images from 3T MRI Based on Cascaded Convolutional Neural Networks. AB - 7T MRI scanner provides MR images with higher resolution and better contrast than 3T MR scanners. This helps many medical analysis tasks, including tissue segmentation. However, currently there is a very limited number of 7T MRI scanners worldwide. This motivates us to propose a novel image post-processing framework that can jointly generate high-resolution 7T-like images and their corresponding high-quality 7T-like tissue segmentation maps, solely from the routine 3T MR images. Our proposed framework comprises two parallel components, namely (1) reconstruction and (2) segmentation. The reconstruction component includes the multi-step cascaded convolutional neural networks (CNNs) that map the input 3T MR image to a 7T-like MR image, in terms of both resolution and contrast. Similarly, the segmentation component involves another paralleled cascaded CNNs, with a different architecture, to generate high-quality segmentation maps. These cascaded feedbacks between the two designed paralleled CNNs allow both tasks to mutually benefit from each another when learning the respective reconstruction and segmentation mappings. For evaluation, we have tested our framework on 15 subjects (with paired 3T and 7T images) using a leave one-out cross-validation. The experimental results show that our estimated 7T like images have richer anatomical details and better segmentation results, compared to the 3T MRI. Furthermore, our method also achieved better results in both reconstruction and segmentation tasks, compared to the state-of-the-art methods. PMID- 30009279 TI - Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel-Hypermutated Cancer Genome and Comutation of POLD1 and MLH1. AB - Purpose: A73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods: Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results: The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion: POLD1 mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy. PMID- 30009282 TI - Personalized Diagnosis for Alzheimer's Disease. AB - Current learning-based methods for the diagnosis of Alzheimer's Disease (AD) rely on training a general classifier aiming to recognize abnormal structural alternations from homogenously distributed dataset deriving from a large population. However, due to diverse disease pathology, the real imaging data in routine clinic practices is highly complex and heterogeneous. Hence, prototype methods commonly performing well in the laboratory cannot achieve expected outcome when applied under the real clinic setting. To address this issue, herein we propose a novel personalized model for AD diagnosis. We customize a subject specific AD classifier for the new testing data by iteratively reweighting the training data to reveal the latent testing data distribution and refining the classifier based on the weighted training data. Furthermore, to improve estimation of diagnosis result and clinical scores at the individual level, we extend our personalized AD diagnosis model to a joint classification and regression scenario. Our model shows improved performance on classification and regression accuracy when applied on Magnetic Resonance Imaging (MRI) selected from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our work pin points the clinical potential of personalized diagnosis framework in AD. PMID- 30009283 TI - Medical Image Synthesis with Context-Aware Generative Adversarial Networks. AB - Computed tomography (CT) is critical for various clinical applications, e.g., radiation treatment planning and also PET attenuation correction in MRI/PET scanner. However, CT exposes radiation during acquisition, which may cause side effects to patients. Compared to CT, magnetic resonance imaging (MRI) is much safer and does not involve radiations. Therefore, recently researchers are greatly motivated to estimate CT image from its corresponding MR image of the same subject for the case of radiation planning. In this paper, we propose a data driven approach to address this challenging problem. Specifically, we train a fully convolutional network (FCN) to generate CT given the MR image. To better model the nonlinear mapping from MRI to CT and produce more realistic images, we propose to use the adversarial training strategy to train the FCN. Moreover, we propose an image-gradient-difference based loss function to alleviate the blurriness of the generated CT. We further apply Auto-Context Model (ACM) to implement a context-aware generative adversarial network. Experimental results show that our method is accurate and robust for predicting CT images from MR images, and also outperforms three state-of-the-art methods under comparison. PMID- 30009285 TI - Specific ion effects for polyelectrolytes in aqueous and non-aqueous media: the importance of the ion solvation behavior. AB - We present the results of atomistic molecular dynamics simulations with regard to specific ion effects in water, methanol and N,N-dimethylacetamide (DMAc). As a reference system, we introduce rigid and rod-like models of polyanions and polycations in combination with alkali metal cations and halide anions as counterions. Pronounced specific ion effects can be observed in terms of the individual anion and cation condensation behavior. The outcomes of our simulations thus reveal significant deviations from standard electrostatic mean field theories. A detailed investigation of the individual energy contributions shows that ion-dipole interactions play a pivotal role in rationalizing the findings. The corresponding deviations in terms of the cation and anion distribution can be brought into agreement with the donor and acceptor numbers of the solvents, which thus highlights the importance of solvent-ion interactions in addition to electrostatic attraction. PMID- 30009284 TI - Phenolics from Eugenia jambolana seeds with advanced glycation endproduct formation and alpha-glucosidase inhibitory activities. AB - Published data suggest that dietary-derived phenolics exert beneficial effects against hyperglycemia-mediated diseases, such as diabetes, through inhibiting the formation of advanced glycation endproducts (AGEs) and carbohydrate hydrolyzing enzyme activities. In the course of our investigation on the edible berry, Eugenia jambolana (known as Jamun), 21 phenolics (1-21) were isolated and identified from its seeds. Among these, one compound (1) is new and eleven compounds (3, 6, 9-13, 17, and 19-21) are being reported from E. jambolana for the first time. The anti-AGE activities of thirteen pure isolates (2-7, 9-12, 14, 15, and 20) were either comparable or superior to the synthetic anti-glycation agent, aminoguanidine, at three test concentrations (20, 50, and 100 MUM) in the BSA-fructose assay. Most of these phenolics with anti-AGE activity exhibited potent free radical scavenging activity in the DPPH assay, and attenuated intracellular levels of LPS-induced reactive oxygen species in RAW264.7 macrophage. In addition, compounds 2-6, and 14 showed superior alpha-glucosidase inhibitory activity (IC50 = 5.0-21.2 MUM) compared to the clinical alpha glucosidase inhibitor, acarbose (IC50 = 289.9 MUM). This is the first report of the anti-AGE effects of compounds 2-6 and 9-12, and alpha-glucosidase inhibitory activities of compounds 3-6, 9, 11 and 14. The current study supports the role of phenolics in the antidiabetic properties attributed to this edible berry, and warrants further animal studies to evaluate their potential as dietary agents for the prevention and/or therapy of hyperglycemia-mediated diseases. PMID- 30009286 TI - Macromolecular crowding and the importance of proper hydration for the structure and dynamics of protein solutions. AB - Recent experiments by Weingartner et al. have given a first hint that dielectric spectroscopy is able to yield a quantitative measure of inter-protein mutual orientation. Therefore, in this computational study, we investigate crowded multi protein solutions with a special focus on this mutual orientation and its context with dielectric spectroscopy. To the end, existing standard force fields had to be improved by re-scaling the dispersion interaction between protein and water. We find that proper hydration has a strong influence on inter-protein correlations as an enhancement of protein hydration by 10% has a great impact on orientational intermolecular structure. Altogether, the crowding behaviour is improved considerably. PMID- 30009287 TI - T-Nb2O5 nanoparticle enabled pseudocapacitance with fast Li-ion intercalation. AB - Orthorhombic Nb2O5 (T-Nb2O5) nanocrystallites are successfully fabricated through an evaporation induced self-assembly (EISA) method guided by a commercialised triblock copolymer - Pluronic F127. We demonstrate a morphology transition of T Nb2O5 from continuous porous nanofilms to monodisperse nanoparticles by changing the content of Pluronic F127. The electrochemical results show that the optimized monodisperse Nb-2 with a particle size of 20 nm achieves premier Li-ion intercalation kinetics and higher rate capability than mesoporous T-Nb2O5 nanofilms. Nb-2 presents an initial intercalation capacity of 528 and 451 C g-1 at current densities of 0.5 and 5 A g-1 and exhibited a stable capacity of 499 C g-1 after 300 charge/discharge cycles and 380 C g-1 after 1000 cycles, respectively. We would expect this copolymer guided monodispersion of T-Nb2O5 nanoparticles with high Li+ intercalation performance to open up a new window for novel EES technologies. PMID- 30009288 TI - Exploiting poly(alpha-hydroxy acids) for the acid-mediated release of doxorubicin and reversible inside-out nanoparticle self-assembly. AB - Biodegradable poly(alpha-hydroxy acid) copolyesters consisting of benzyl protected glutamic acid and carboxybenzyl-protected lysine derived blocks possess the capability to self-assemble to form stable nanoparticles in aqueous solution (pH 7.4), that are able to withhold doxorubicin, prior to its directed release in acidic solution. Such pH-responsive nanoparticles are non-toxic against a panel of human breast cancer cell lines, but demonstrated comparable toxicities to free doxorubicin when loaded with doxorubicin. Significantly, comparable efficacy to free doxorubicin was observed even against triple negative breast cancer cells, highlighting the potential of the materials generated as drug delivery vehicles for cancer treatment. Facile block copolymer deprotection resulted in a polymer that presents an altered self-assembly/disassembly profile; forming nanoparticles when stored in either acidic or alkaline solution, but undergoing self disassembly when added to aqueous solution of pH 7.4. This second polymer highlights the considerable versatility that poly(alpha-hydroxy acids) inherently possess. PMID- 30009289 TI - Construction of MOF-derived hollow Ni-Zn-Co-S nanosword arrays as binder-free electrodes for asymmetric supercapacitors with high energy density. AB - Mixed transition metal sulfides with hollow structures hold great promise for energy-related applications. However, most of them are in the powder form, which should be mixed with unwanted polymer binders and conductive agents. In this study, a facile two-step strategy has been developed to grow mesoporous and hollow Ni-Zn-Co-S nanosword arrays (NSAs) on a nickel foam (NF) substrate with robust adhesion, which involves the hydrothermal growth of bimetallic Zn-Co-ZIF NSAs on NF and subsequent transformation into hollow Ni-Zn-Co-S NSAs through the sulfurization process. Benefiting from the unique structural and compositional advantages as well as directly grown conductive substrate, the Ni-Zn-Co-S-0.33 NSAs/NF electrode exhibits the best electrochemical performance when investigated as a binder-free electrode for supercapacitors. Impressively, the Ni-Zn-Co-S-0.33 NSAs/NF electrode delivers a high areal capacity of 1.11 mA h cm-2 at the current density of 10 mA cm-2, and the corresponding specific capacity is as high as 358.1 mA h g-1. Moreover, an asymmetric supercapacitor (ASC) device based on the Ni-Zn-Co-S-0.33 NSAs/NF as the positive electrode and Bi2O3/NF as the negative electrode has been successfully fabricated, and can deliver a high energy density of 91.7 W h kg-1 at a power density of 458 W kg-1 and maintain the energy density of 66.9 W h kg-1 at a high power density of 6696 W kg-1. The electrochemical results suggest that the hollow Ni-Zn-Co-S NSAs would possess great potential for applications in high-performance supercapacitors. PMID- 30009290 TI - Simulated and experimental force spectroscopy of lysozyme on silica. AB - The force spectra of proteins detaching from oxide surfaces measured by atomic force microscopy (AFM) often present complex patterns of peaks, which are difficult to correlate with individual bond-breaking events at the atomic scale. In this work we rationalize experimental AFM force spectra of hen-egg-white lysozyme detaching from silica by means of all-atom steered molecular dynamics (SMD) simulations. In particular, we demonstrate that the native tertiary structure of lysozyme is preserved if, and only if, its four intramolecular disulfide bridges are intact. Otherwise, the protein pulled off the surface undergoes severe unfolding, which is well captured by SMD simulations in explicit solvent. Implicit solvent simulations, on the contrary, wrongly predict protein unfolding even in the presence of S-S bridges, due to the lack of additional structural stabilization provided by the water's hydrogen-bond network within and surrounding the protein. On the basis of our combined experimental and theoretical findings, we infer that the rugged force spectra characteristic of lysozyme/silica interfaces are not due to the successive breaking of internal disulfide bonds leading to partial unfolding events. Rather, they reflect the detachment of several molecules bound to the same AFM tip, each anchored to the surface via multiple hydrogen and ionic bonds. PMID- 30009291 TI - MXene nanoribbons as electrocatalysts for the hydrogen evolution reaction with fast kinetics. AB - MXenes, a new class of two-dimensional materials, arouse great interest due to their diverse chemistries, superior electrical conductivity and stability. Recently, the nanostructures of MXenes such as nanoribbons and nanodots have been synthesized in experiments, which show peculiar properties and expand the application spectrum of MXenes. Here we exploited MXene nanoribbons as potential electrocatalysts for the hydrogen evolution reaction (HER) by considering 12 kinds of MXene systems. Our first-principles calculations showed that the edges of the MXene nanoribbons can adsorb hydrogen species and serve as the reaction sites for hydrogen evolution. The binding strength of the ribbon edge is correlated with the d band center of metal atoms in MXenes. In particular, the nanoribbons of Ti3C2 and solid solution (Ti,Nb)C exhibit high activity for the HER with the adsorption free energy approaching zero and Tafel barrier below 0.42 and 0.17 eV, respectively. The low barrier is owing to the prominent charge transfer from the edge metal atoms to the H* reactants in the transition state. These theoretical results illuminate the principle for designing MXene nanostructures for electrocatalysts with fast kinetics, and shed light on the utilization of MXenes with more than one metal element for a broad range of electrochemical reactions. PMID- 30009292 TI - Dinuclear iminophenoxide copper complexes in rac-lactide polymerisation. AB - Dinuclear bis(R'-(R''-iminomethyl)phenoxide) copper complexes L2Cu2(MU-OR)2 were prepared from the reaction of copper methoxide with ROH and LH (ROH = dimethylaminoethanol or pyridylmethanol, R' = H, 4,6-tBu, 1,3-Cl, R'' = benzyl, cyclohexyl, diphenylmethyl and 2,6-dimethylphenyl). Preparation was complicated by formation of homoleptic L2Cu and only 9 of the 24 possible combinations could be prepared. All complexes were characterized by single crystal X-ray diffraction studies and crystallized as dinuclear penta-coordinated complexes. Homoleptic complexes L2Cu were inactive in lactide polymerization at room temperature. Most heteroleptic complexes showed modest to good activities with full conversion in less than 6 h at room temperature. Complexes with R' = H showed poor molecular weight control, complexes with R' = Cl were inactive in polymerization. In pyridylmethoxide-containing complexes, only one alkoxide initiated chain growth. All complexes produced atactic polymer. PMID- 30009293 TI - Collision-induced dissociation of sodiated glucose, galactose, and mannose, and the identification of anomeric configurations. AB - Collision-induced dissociation of sodiated alpha-glucose, beta-glucose, alpha galactose, beta-galactose, alpha-mannose, and beta-mannose was studied using electronic structure calculations and resonance excitation in a low-pressure linear ion trap. We made an extensive search of conformers and transition states in calculations to ensure the transition state with the lowest barrier height for each dissociation channel could be located. The major dissociation channels, in addition to desodiation, are cross-ring dissociation and dehydration. Cross-ring dissociation starts with H atom transfer from the O1 atom to the O0 atom, followed by the cleavage of the C1-O0 bond. Dehydration of the anomer with O1 and O2 atoms in the cis configuration involves the transfer of an H atom from the O2 atom to the O1 atom, followed by the cleavage of the C1-O1 bond. In contrast, dehydration of the anomer with O1 and O2 atoms in the trans configuration mainly occurs through H atom transfer from the O3 or O2 atom to the O1 atom for glucose, from the O3 or O4 atom to the O1 atom for galactose, and from the O4 or O2 atom to the O1 atom for mannose, followed by the cleavage of the C1-O1 bond. The dehydration barrier heights are lower than those of cross-ring dissociation for cis anomers, but higher than those of cross-ring dissociation for trans anomers. The relative barrier heights from calculations are consistent with the experimental measurements of branching ratios. Both computational and experimental results show that the branching ratio of dehydration can be generalized as a simple rule for rapidly identifying the anomeric configurations of these monosaccharides. PMID- 30009294 TI - Enhancement in RNase H activity of a DNA/RNA hybrid duplex using artificial cationic oligopeptides. AB - This study assessed the effects of artificial cationic oligopeptides on a DNA/RNA hybrid duplex. An oligopeptide containing the octamer of l-2,4-diaminobutyric acid (Dab8) was found to enhance both the RNase A resistance and RNase H activity of the DNA/RNA hybrid, which are important for developing nucleic acid drugs. PMID- 30009295 TI - Conformation-guided analogue design identifies potential antimalarial compounds through inhibition of mitochondrial respiration. AB - The synthesis of a 2-methyl-substituted analogue of the natural product, neopeltolide, is reported in an effort to analyze the importance of molecular conformation and ligand-target interactions in relation to biological activity. The methyl substitution was incorporated via highly diastereoselective ester enolate alkylation of a late-stage intermediate. Coupling of the oxazole sidechain provided 2-methyl-neopeltolide and synthetic neopeltolide via total synthesis. The substitution was shown to maintain the conformational preferences of its biologically active parent compound through computer modeling and NMR studies. Both compounds were shown to be potential antimalarial compounds through the inhibition of mitochondrial respiration in P. falciparum parasites. PMID- 30009296 TI - In situ infrared study of photo-generated electrons and adsorbed species on nitrogen-doped TiO2 in dye-sensitized solar cells. AB - Charge transfer between adsorbed dyes and the TiO2 surface plays a key role in controlling the efficiency of dye-sensitized solar cells (DSSCs). The lack of understanding of charge transfer steps has hindered further development of DSSCs and many solar energy conversion devices/processes. In this study, we used in situ infrared spectroscopy to investigate electron transfer and photo-electric energy conversion processes at the interface, i.e., surface hydroxyls, adsorbed species, as well as the dynamics of photo-generated electrons in TiO2 and N-TiO2 in DSSCs. Nitrogen (N-) doping of TiO2 blocked linear OH, giving more hydrophobic surface characteristics than undoped TiO2. N-Doping further increased the electron-hole separation caused by solar light on the working electrode and the current density in the DSSC. In situ infrared (IR) studies revealed that N-doping facilitated the electron transfer from the N719 dye (di-tetrabutylammonium cis bis(isothiocyanato)bis(2,2-bipyridyl-4,4-dicarboxylato)ruthenium(ii)) to the conduction band in TiO2, reducing the impedance in the DSSC. Probing N-TiO2 with adsorbed ethanol showed that shallow traps in N-TiO2 can be accessed by electrons from adsorbed ethanol. Electron transfer from the N719 dye is significantly faster than that from adsorbed ethanol which involves C-H bond breaking. PMID- 30009297 TI - Hollow nanoparticles as emerging electrocatalysts for renewable energy conversion reactions. AB - While the realization of clean and sustainable energy conversion systems primarily requires the development of highly efficient catalysts, one of the main issues had been designing the structure of the catalysts to fulfill minimum cost as well as maximum performance. Until now, noble metal-based nanocatalysts had shown outstanding performances toward the oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction (HER). However, the scarcity and high cost of them impeded their practical use. Recently, hollow nanostructures including nanocages and nanoframes had emerged as a burgeoning class of promising electrocatalysts. The hollow nanostructures could expose a high proportion of active surfaces while saving the amounts of expensive noble metals. In this review, we introduced recent advances in the synthetic methodologies for generating noble metal-based hollow nanostructures based on thermodynamic and kinetic approaches. We summarized electrocatalytic applications of hollow nanostructures toward the ORR, OER, and HER. We next provided strategies that could endow structural robustness to the flimsy structural nature of hollow structures. Finally, we concluded this review with perspectives to facilitate the development of hollow nanostructure-based catalysts for energy applications. PMID- 30009298 TI - Tunable thermal conductivity of pi-conjugated two-dimensional polymers. AB - Two-dimensional (2D) polymers are organic analogues of graphene. Compared to graphene, 2D polymers offer a higher degree of tunability in regards to structure, topology, and physical properties. The thermal transport properties of 2D polymers play a crucial role in their applications, yet remain largely unexplored. Using the equilibrium molecular dynamics method, we study the in plane thermal conductivity of dubbed porous graphene that is comprised of pi conjugated phenyl rings. In contrast to the conventional notion that pi conjugation leads to high thermal conductivity, we demonstrate, for the first time, that pi-conjugated 2D polymers can have either high or low thermal conductivity depending on their porosity and structural orientation. The underlying mechanisms that govern thermal conductivity were illustrated through phonon dispersion. The ability to achieve two orders of magnitude variance in thermal conductivity by altering porosity opens up exciting opportunities to tune the thermal transport properties of 2D polymers for a diverse array of applications. PMID- 30009299 TI - Room temperature carbon monoxide oxidation based on two-dimensional gold-loaded mesoporous iron oxide nanoflakes. AB - In this work, we fabricate a highly effective catalyst for carbon monoxide oxidation based on gold-loaded mesoporous maghemite nanoflakes which exhibit nearly 100% CO conversion and a very high specific activity of 8.41 molCO gAu-1 h 1 at room temperature. Such excellent catalytic activity is promoted by the synergistic cooperation of their high surface area, large pore volume, and mesoporous structure. PMID- 30009300 TI - Molecular structure of octadecylphosphonic acids during their self-assembly on alpha-Al2O3(0001). AB - The formation of octadecylphosphonic acid (ODPA) self-assembled monolayers (SAMs) from 2-propanol solutions on hydroxylated alpha-Al2O3(0001) surfaces was studied in situ and in real time at the solid/liquid interface. Time-resolved vibrational spectra from sum-frequency generation (SFG) of C-H stretching modes revealed contributions from ODPA's alkyl backbone and the terminal methyl group as well as vibrational bands that originated from the presence of 2-propanol molecules at the alpha-Al2O3 surface. 2-Propanol signatures in SFG spectra decreased during SAM formation. This is due to adsorption of ODPA molecules which trigger desorption of 2-propanol from the alpha-Al2O3(0001) surface, so that these sites can be occupied by ODPA molecules. SAM formation was studied for different bulk concentrations of ODPA which changed substantially both the quality and the coverage of the final SAM. At initial stages of SAM growth, SFG spectra are dominated by methylene contributions and are indicative for a low molecular order and coverage of ODPA molecules. For concentrations of ODPA <=2 mM this situation did not change within reasonable adsorption times (~16 h) while for 5 and 30 mM concentrations a dramatic increase in molecular order and coverage within the first 2 h of adsorption is observed. Thermodynamic analysis using Langmuir adsorption kinetics provided equilibrium constants and the Gibbs free energy of adsorption between -24 and -28 kJ mol-1. PMID- 30009301 TI - Metalloenzymes in natural product biosynthetic pathways. PMID- 30009302 TI - Molecular adaptation in supramolecular self-assembly: brickwall-type phases of indacene-tetrone on silver surfaces. AB - The supramolecular self-assembly of s-indacene-1,3,5,7(2H,6H)-tetrone (INDO4) on Ag(111), Ag(100) and Ag(110) surfaces was studied using scanning tunneling microscopy (STM). Four similar brickwall-type phases were found and in two of them the molecules appeared with distinct alternating contrast. The origin of this effect is discussed in terms of molecular adaptation. PMID- 30009303 TI - Red phosphorus in its two-dimensional limit: novel clathrates with varying band gaps and superior chemical stabilities. AB - First-principles calculations within density functional theory reveal the preferred structures of red phosphorus in the two-dimensional (2D) limit to be porous with intriguing structural, electronic, and chemical properties. These few atomic-layer structures are stabilized as novel 2D clathrates with tunable pore sizes and varying semiconducting band gaps, labelled as V-Hex, P-Monoclinic, P Hex, and V-Tetr in descending energetic stabilities. The cohesive energies of the 2D clathrates are all substantially higher than that of white phosphorus. More strikingly, the V-Hex structure is energetically as stable as black phosphorene, but possesses distinctly superior chemical stability when exposed to O2 due to the presence of a much higher activation barrier against chemisorption. We also exploit the salient properties of these 2D clathrates for their important application potentials, including serving as effective elemental photocatalysts for visible-light-driven water splitting, and as a new class of sieves for molecular separation and DNA sequencing. PMID- 30009304 TI - Porous cobalt sulfide hollow nanospheres with tunable optical property for magnetic resonance imaging-guided photothermal therapy. AB - Transition-metal chalcogenides with an imaging element and tunable optical property are strongly desired as ideal high-efficiency photothermal theranostic agents to diagnose and eliminate tumors. Herein, we report on a one-pot solvothermal strategy to synthesize various porous cobalt sulfide hollow nanospheres (PCSH NSs) and elucidate the relation between PCSH NSs and their optical absorption as a guide to obtain optimal photothermal therapy (PTT) agents. After PEG modification, PEG-PCSH NSs show superexcellent photothermal conversion efficiency (~70.1%) which is higher than that of binary transition metal chalcogenides materials reported to date. A low dose (100 MUL, 25 ppm) could completely ablate tumors under an 808 nm laser power of 0.7 W cm-2, reducing in vivo long-term residual agent content and thus lowering the possibility of side effects. Additionally, they also exhibit excellent biocompatibility, good photostability and utility for magnetic resonance imaging. Our results indicate that PCSH NSs can be considered as an outstanding PTT agent and give guidance towards the design of other photothermal theranostic agents. PMID- 30009305 TI - [RuII(tpy)(bpy)Cl]+-Catalyzed reduction of carbon dioxide. Mechanistic insights by carbon-13 kinetic isotope effects. AB - In this work, we examine the use of competitive 13C kinetic isotope effects (13C KIEs) on CO2 reduction reactions that produce CO and formic acid as a means to formulate reaction mechanisms. The findings reported here mark a further advancement in the combined 13C KIE measurements and theoretical calculations methodology for probing CO2 conversion reactions. PMID- 30009306 TI - Role of transition metals in a charge transfer mechanism and oxygen removal in Li1.17Ni0.17Mn0.5Co0.17O2: experimental and first-principles analysis. AB - Oxygen removal from high capacity Li-rich layered oxide Li1.17Ni0.17Mn0.5Co0.17O2 affects the charge transfer process during cycling. During de-lithiation, oxygen removal takes place with the reduction in oxygen binding energy. Co substitution affects oxygen removal by shifting the O-p orbital closer to the Fermi energy. A convex hull plot is used to analyse single-phase and two-phase reactions during de-lithiation in Li1.17Ni0.17Mn0.5Co0.17O2 and Li2MnO3. Experimentally, the single-phase and two-phase reactions are identified based on the characteristics of the charge curve. In the charge transfer process more than 80% of lithium charge is transferred to oxygen in both the compounds. Effective charge and cyclic voltammetry reveal the redox centers in the compounds which help to understand the role of oxygen and transition metals in de-lithiation. A detailed explanation of oxygen removal and the charge transfer mechanism of Li1.17Ni0.17Mn0.5Co0.17O2 and Li2MnO3 is provided in the current experimental and density functional theory based study. PMID- 30009307 TI - Principal component analysis for automatic extraction of solid-state kinetics from combined in situ experiments. AB - Solid-state reactivity is often studied by in situ experiments with a multi technique approach, where complementarity of different probes is exploited. In situ data are usually analysed using a complex protocol: first the reaction model most suited to describe the specific solid-state reaction is chosen, second the reaction coordinate is obtained from the data, the order of reaction is then calculated by applying a specific kinetic equation, and finally kinetic parameters are obtained with an Arrhenius plot. The approach is both time consuming and subject to errors due to the arbitrariness of extraction of the reaction coordinate, typically from individual peak intensity variations during the reaction. In addition, application of the different kinetic equations to obtain the best fitting one is tedious and no general method to select the best model with an unbiased approach is available. Here we propose a new procedure based on principal component analysis to get kinetic information from in situ data, which simplifies and speeds up the process of kinetic parameter calculation from a three- to a two- or even a one-step form, reaching a high degree of automation and the ability to manage the huge amount of data produced by in situ multi-technique experiments. The new approach treats data as a whole, without biases introduced by manual methods of obtaining the reaction coordinate by peak intensity evaluation from individual patterns typical of the traditional approach. The procedure is described in its theoretical framework and applied to the formation of a molecular complex, monitored by in situ X-ray powder diffraction and Raman measurements. PMID- 30009308 TI - Binary "island" shaped arrays with high-density hot spots for surface-enhanced Raman scattering substrates. AB - We have demonstrated a facile and low-cost approach for the fabrication of binary "island" shaped arrays (BISA) with high-density hot spots as reproducible surface enhanced Raman scattering (SERS) substrates by depositing a self-assembled monolayer Au nanoparticle (AuNP) film with small gaps onto a two-dimensional (2D) silica microsphere opal structure. By varying the size of silica spheres, the SERS performance of the BISA substrate with an enhancement factor (EF) of 3.74 * 1010 magnitude and the corresponding signal intensity deviation of below 8% using 770 nm silica sphere arrays were achieved. Compared with the assembled monolayer AuNP film on a planar substrate, the BISA enabled the installation of more AuNPs as a source of hot spots due to the undulation of morphology on the nanoscale within the designated laser-illumination area. In addition, a finite-difference time-domain (FDTD) simulation suggested that the BISA structure provided geometric conditions for increasing the intensity of the formed hot spots, and the strong periodic electric fields on the BISA are located not only in the gap between adjacent AuNPs, but also along the boundary of the neighboring island of silica spheres. Surface plasmon-decayed hot carriers (hot electrons and hot holes) from AuNPs can be applied in the field of energy conversion (i.e., photocatalysis), integrated with the SERS as a sensitive optical indicator to accurately monitor the catalytic reaction process. Furthermore, we examined the catalytic reaction process of the dimerization of 4-ATP into DMAB and found that photocatalytic activity could be tuned by changing the size of silica spheres. This study provides a new design route for the fabrication of the SERS platform with high sensitivity and reproducibility to detect molecules or improve catalyst efficiency. PMID- 30009309 TI - Probing the enhanced catalytic activity of carbon nanotube supported Ni-LaOx hybrids for the CO2 reduction reaction. AB - Oxygenated functionalized carbon nanotube (oCNT) supported LaOx-promoted Ni nanoparticles (10Ni-xLa/oCNT) were prepared by the co-impregnation method and tested for synthetic natural gas from the CO2 reduction reaction. Several advanced characterization methods, including atomic resolution scanning transmission electron microscopy (STEM), temperature programmed experiments (TPSR, CO2-TPD, and H2-TPR) and X-ray photoelectron spectroscopy (XPS), were applied to explore, for the first time, the origin of structure modulation of LaOx species on oCNT supported Ni-LaOx hybrids and the structure-activity relationship over the CO2 reduction reaction. The Z-contrast STEM-HAADF results revealed that the LaOx species are mostly in the size of the sub-nano scale and highly dispersed on the surface of Ni nanoparticles and oCNT, and consequently no diffraction peak of LaOx was observed from XRD results. TEM analysis showed that the Ni nanoparticle sizes were similar among all samples either after reduction or after reaction due to the relatively strong interaction between Ni and oxygenated groups on CNT supports, regardless of the influence of the La mass loading. It was suggested that the catalytic performance trend was due to the structural variation rather than the size effect. The LaOx modulation catalyst with 2 wt% of La metal loading not only presented low CO2 activation temperature at only 163 degrees C, but also resulted in extremely high CH4 selectivity (100%) compared with the initial supported Ni catalyst (52.7% of CH4 selectivity at 300 degrees C). PMID- 30009311 TI - ESIPT-based fluorescence probe for the rapid detection of hypochlorite (HOCl/ClO ). AB - ESIPT-based fluorescence probes are emerging as an attractive tool for the detection of biologically relevant analytes owing to their unique photophysical properties. In this work, we have developed an ESIPT-based fluorescence probe (TCBT-OMe) for the detection of HClO/ClO- through the attachment of a bioorthogonal dimethylthiocarbamate linker. TCBT-OMe was shown to rapidly detect HClO/ClO- (<10 s) at biologically relevant concentrations (LoD = 0.16 nM) and have an excellent selectivity towards others ROS/RNS and amino acids. Therefore, TCBT-OMe was tested in live cells and was successfully shown to be able to detect endogenous and exogenous HClO/ClO- in HeLa cells. Additionally, TCBT-OMe acts as a dual input logic gate for Hg2+ and H2O2. Interestingly, Hg2+ alone gradually causes a fluorescence response but requires >30 min to produce a fluorescence response. Test strips containing TCBT-OMe were prepared and were demonstrated as an effective way to detect HClO/ClO- in water. Furthermore, TCBT-OMe was shown to detect exogenously added HClO/ClO- in three different water samples with little interference thus demonstrating the effectiveness as a method for the detection of HClO/ClO- in drinking water samples. PMID- 30009310 TI - Nickel(ii)-promoted specific hydrolysis of zinc finger proteins. AB - In this work we demonstrate that the previously described reaction of sequence specific Ni(ii)-dependent hydrolytic peptide bond cleavage can be performed in complex metalloprotein molecules, such as the Cys2His2 zinc finger proteins. The cleavage within a zinc finger unit possessing a (Ser/Thr)-X-His sequence is not hindered by the presence of the Zn(ii) ions. It results in loss of the Zn(ii) ion, oxidation of the SH groups and thus, in a collapse of the functional structure. We show that such natural Ni(ii)-cleavage sites in zinc finger domains can be edited out without compromising the DNA binding specificity. Inserting a Ni(ii)-susceptible sequence between the edited zinc finger and an affinity tag allows for removal of the latter sequence by Ni(ii) ions after the protein purification. We have shown that this reaction can be executed even when a metal ion binding N-terminal His-tag is present. The cleavage product maintains the native zinc finger structure involving Zn(ii) ions. Mass spectra revealed that a Ni(ii) ion remains coordinated to the hydrolyzed protein product through the N terminal (Ser/Thr)-X-His tripeptide segment. The fact that the Ni(ii)-dependent protein hydrolysis is influenced by the Ni(ii) concentration, pH and temperature of the reaction provides a platform for novel regulated DNA effector design. PMID- 30009312 TI - Graphene oxide liquid crystals: a frontier 2D soft material for graphene-based functional materials. AB - Graphene, despite being the best known strong and electrical/thermal conductive material, has found limited success in practical applications, mostly due to difficulties in the formation of desired large-scale highly organized structures. Our discovery of a liquid crystalline phase formation in graphene oxide dispersion has enabled a broad spectrum of highly aligned graphene-based structures, including films, fibers, membranes, and mesoscale structures. In this review, the current understanding of the structure-property relationship of graphene oxide liquid crystals (GOLCs) is overviewed. Various synthetic methods and parameters that can be optimized for GOLC phase formation are highlighted. Along with the results from different characterization methods for the identification of the GOLC phases, the typical characteristics of different types of GOLC phases introduced so far, including nematic, lamellar and chiral phases, are carefully discussed. Finally, various interesting applications of GOLCs are outlined together with the future prospects for their further developments. PMID- 30009313 TI - Binding indirect greenhouse gases OCS and CS2 by nitrogen heterocyclic carbenes (NHCs). AB - Carbon disulfide (CS2) and carbonyl sulfide (OCS) are indirect greenhouse gases that can be effectively trapped by classical, abnormal and remote nitrogen heterocyclic carbenes (NHCs), according to high level ab initio calculations. The process is described through a reaction profile involving two minima, a non covalent complex and a covalently bound product, connected by a single transition state. Both CS2 and OCS react towards NHCs in a similar way, forming a new C-C bond and leading to very stable products with feasible barriers in many cases, although they vary significantly depending on the NHC structure. The barriers are larger than those reported for CO2, oscillating from barrierless processes up to a maximum of 57.9 kJ mol-1, whereas the products are more stabilized than those incorporating CO2. The lowest barriers for the CS2 + NHC reactions correspond to the largest C-C distances in the products, unlike the CO2 case. Remarkably, the most favored reactions, which are those involving a remote NHC, do not exhibit the highest interaction energies at the TS, but low distortion energy values of the OCS/CS2 moieties. The decomposition of the interaction energy allowed to confirmed that in fact the remote carbene is the less favored one in terms of the electrostatic and exchange terms. Substitution in CO2 of O by a more polarizable atom such as S have a great influence on the balance between the steric plus orbital interaction and the kinetic energy terms, thus making the products between NHCs and OCS/CS2 more stable. Both OCS and CS2 become better charge acceptors than CO2 on going from the starting complexes to the products. PMID- 30009314 TI - Single nanoparticle detection using a photonic nanojet. AB - A novel method of detecting single nanoparticles (NPs) in a microfluidic channel directly using a photonic nanojet (PNJ) was investigated. The theoretical model comprised a plane wave-illuminated, liquid-filled hollow-microcylinder (LFHM) and a single Au NP. Relevant studies were implemented and demonstrated with a finite element method (FEM)-based numerical simulation and explained physically through a ray-optics theoretical analysis with the assistance of energy flow line shifts. When depicting the optical-field distribution by gradually altered contour lines for LFHMs with or without a single Au NP, the outward distances of the specific points on the right end of each contour line, for a LFHM with a single Au NP relative to a LFHM without a NP, increased exponentially with decreasing contour levels. By dividing the contour levels into ten levels, the detectable NP of size of a few nanometers can be reflected through the outward distance of the contour points. The key parameters of the PNJ (the maximum light intensity, decay length and lateral beam waist), combined with the electric field distribution and focal point offset, can provide information on NP location. This work showed the PNJ itself to be a powerful and promising tool for the detection and identification of single NPs. PMID- 30009315 TI - Ligand-regulated oligomerisation of allosterically interacting proteins. AB - The binding of ligands to distinct sites at proteins or at protein clusters is often cooperative or anti-cooperative due to allosteric signalling between those sites. The allostery is usually attributed to a configurational change of the proteins from a relaxed to a configurationally different tense state. Alternatively, as originally proposed by Cooper and Dryden, a tense state may be achieved by merely restricting the thermal vibrations of the protein around its mean configuration. In this work, we provide theoretical tools to investigate fluctuation allostery using cooling and titration experiments in which ligands regulate dimerisation, or ring or chain formation. We discuss in detail how ligands may regulate the supramolecular (co)polymerisation of liganded and unliganded proteins. PMID- 30009316 TI - A randomised, controlled trial comparing adductor canal block and femoral nerve block for knee arthroplasty. AB - INTRODUCTION: Adductor canal block (ACB) is hypothesised to provide superior analgesia to femoral nerve block (FNB) for total knee arthroplasty (TKA) while preserving quadriceps strength. METHODS: 30 patients undergoing TKA were randomised to receive either ACB or FNB. Baseline tests of quadriceps strength were performed. Ultrasound-guided blocks with 30 mL of 0.5% ropivacaine were administered before induction of general anaesthesia. Patient-controlled analgesia (morphine) was prescribed for postoperative analgesia. The primary outcome of this prospective, double-blinded, randomised controlled trial was morphine consumption (mean +/- standard deviation) in the first 24 hours. Secondary outcomes were pain scores using a numeric rating scale (median and interquartile range [IQR]), quadriceps strength (% of baseline) and functional outcomes at 24 hours and 48 hours postoperatively. RESULTS: There was no statistically significant difference in morphine consumption at 24 hours between the ACB and FNB groups (21 +/- 11 mg vs. 20 +/- 12 mg; p = 0.85). No statistically significant differences were observed between the ACB and FNB groups in pain scores at 24 hours (at rest: 0 [IQR 0-2] vs. 0 [IQR 0-2]; on movement: 5 [IQR 4-8] vs. 5 [IQR 3-8]) and quadriceps strength (24 hours: 28.8% +/- 26.1% vs. 26.8% +/- 19.6% of baseline; 48 hours: 31.5 +/- 23.1% vs. 33.7% +/- 20.1% of baseline). There were also no statistically significant differences in functional outcomes and length of stay. CONCLUSION: We found no statistically significant differences in analgesic effects, quadriceps strength or functional recovery postoperatively between ACB and FNB. PMID- 30009318 TI - Improving telestroke treatment times through a quality improvement initiative in a Singapore emergency department. AB - INTRODUCTION: Telestroke allows for remote determination of suitability for treatment with thrombolysis in patients with acute ischaemic stroke. However, this approach is time-dependent and most centres have yet to achieve the recommended treatment times. We describe a quality improvement initiative aimed at improving the telestroke workflow and treatment times at our centre. METHODS: A multidisciplinary workgroup comprising clinicians, stroke case managers and radiology staff was formed to oversee the initiative. A phase-by-phase review of the existing workflow was done to identify the reasons for delay. Phase-specific measures were then introduced to address these delays, and a data-monitoring system was established to track the impact of these measures. The initiatives were implemented through four Plan-Do-Study-Act cycles. The door-to-needle (DTN) times for thrombolysis and clinical outcomes before and after the interventions were compared. RESULTS: A total of 104 patients were evaluated. The median DTN time improved from 96 minutes to 78 minutes post implementation of initiatives (p = 0.003). Fewer patients had symptomatic intracranial haemorrhages (8.5% vs. 24.2%, p = 0.03), and more patients had improvements in their National Institutes of Health Stroke Scale score (47.9% vs. 25.0%, p = 0.031) after the initiatives were introduced. CONCLUSION: The quality improvement initiative resulted in a reduction in median DTN time. Our approach allowed for a systematic method to resolve delays within the telestroke workflow. This initiative is part of an ongoing effort aimed at providing thrombolysis safely to eligible patients in the shortest possible time. PMID- 30009317 TI - Erythema and induration of the Bacillus Calmette-Guerin site for diagnosing Kawasaki disease. AB - INTRODUCTION: Kawasaki disease (KD) is a challenging diagnosis. Erythema and induration of the Bacillus Calmette-Guerin (BCG) site is increasingly recognised as a significant clinical clue. However, there is little data to support its specificity or KD as compared to other febrile illnesses. We aimed to evaluate BCG reaction or induration as a diagnostic tool for KD. METHODS: A retrospective case-controlled study of patients discharged with a diagnosis of KD from 2007 to 2010 was conducted. Another group of patients admitted over the same period for possible KD, but later found not to have KD, served as control. RESULTS: Significantly more infants with KD (69.7%) had BCG site changes than older children (27.8%; p < 0.001). It also presented earlier in the course of KD; < 5 days (53.3%) compared to >= 5 days of fever (30.0%; p < 0.001). Positive predictive value of BCG site reaction or induration for KD was 90.8% (95% confidence interval [CI] 0.819-0.962) for infants and 96.2% (95% CI 0.868-0.995) for older children. The prevalence rate of changes at the BCG site was 9.9% among patients with non-KD febrile illnesses and 42.6% among patients with KD. CONCLUSION: BCG site reaction or induration is a useful clinical clue for KD in both infants and older children, with a higher prevalence in infants. Physicians should consider KD in children with febrile illness and redness or crust formation at the BCG site, especially in view of low rates of BCG reaction or induration in non-KD febrile illnesses. PMID- 30009319 TI - An unusual presentation of ankylosing spondylitis. PMID- 30009320 TI - Fibreoptic intubation in airway management: a review article. AB - Since the first use of the flexible fibreoptic bronchoscope, a plethora of new airway equipment has become available. It is essential for clinicians to understand the role and limitations of the available equipment to make appropriate choices. The recent 4th National Audit Project conducted in the United Kingdom found that poor judgement with inappropriate choice of equipment was a contributory factor in airway morbidity and mortality. Given the many modern airway adjuncts that are available, we aimed to define the role of flexible fibreoptic intubation in decision-making and management of anticipated and unanticipated difficult airways. We also reviewed the recent literature regarding the role of flexible fibreoptic intubation in specific patient groups who may present with difficult intubation, and concluded that the flexible fibrescope maintains its important role in difficult airway management. PMID- 30009321 TI - Qualitative research essentials for medical education. AB - This paper offers a selective overview of the increasingly popular paradigm of qualitative research. We consider the nature of qualitative research questions, describe common methodologies, discuss data collection and analysis methods, highlight recent innovations and outline principles of rigour. Examples are provided from our own and other authors' published qualitative medical education research. Our aim is to provide both an introduction to some qualitative essentials for readers new to this research paradigm and a resource for more experienced readers, such as those who are currently engaged in a qualitative research project and would like a better sense of where their work sits within the broader paradigm. PMID- 30009322 TI - Antimicrobial additives for poly(lactic acid) materials and their applications: current state and perspectives. AB - Poly(lactic acid)-based antimicrobial materials received considerable attention as promising systems to control microbial growth. The remarkable physicochemical properties of PLA such as renewability, biodegradability, and US Food and Drug Administration (FDA) approval for clinical use open up interesting perspectives for application in food packaging and biomedical materials. Nowadays, there is an increasing consumer demands for fresh, high-quality, and natural foods packaged with environmentally friendly materials that prolong the shelf life. The incorporation of antimicrobial agents into PLA-based polymers is likely to lead to the next generation of packaging materials. The development of antimicrobial PLA materials as a delivery system or coating for biomedical devices is also advantageous in order to reduce possible dose-dependent side effects and limit the phenomena of antibiotic resistance. This mini-review summarizes the most recent advances made in antimicrobial PLA-based polymers including their preparation, biocidal action, and applications. It also highlights the potential of PLA systems as efficient stabilizers-carriers of various kinds of antimicrobial additives including essential oils and other natural compounds, active particles and nanoparticles, and conventional and synthetic molecules. PMID- 30009323 TI - Correction to: Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling. AB - In the original publication of the article, Table 1 was published with incorrect caption and values. The Table 1 with corrected caption and values is given in this Correction. PMID- 30009324 TI - High-salt diet affects amino acid metabolism in plasma and muscle of Dahl salt sensitive rats. AB - Genetic background and high-salt diet are considered key factors contributing to the development of hypertension and its associated metabolic disorders. Metabolomics is an emerging powerful tool to analyze the low-molecular weight metabolites in plasma and tissue. This study integrated metabolomics and correlation network analysis to investigate the metabolic profiles of plasma and muscle of Dahl salt-sensitive (SS) rats and SS.13BN rats (control) under normal and high-salt diet. The hub metabolites, which could play important roles in the metabolic changes, were identified by correlation network analysis. The results of the network analysis were further confirmed by pathway analysis and enzyme activity analysis. The results indicated a higher amino acid levels in both plasma and muscle of SS rats fed with high-salt diet. Alanine was found as a hub metabolite with the highest score of three centrality indices and also as the significant differential metabolite in plasma of SS rats after high-salt diet. Valine and lysine were found as hub metabolites and differential metabolites in muscle of SS rats after high-salt diet. Amino acid levels increased in both plasma and muscle of SS rats fed with a high salt diet. Moreover, alanine in plasma and valine and lysine in muscle as hub metabolites could play important roles in the response to high-salt diet. PMID- 30009325 TI - Enzymatic Degradation of Allergen Peptides from Bovine Casein by a Combination of Streptomyces Aminopeptidases. AB - Cow's milk is one of the most common allergenic foods. Cow's milk allergy is mainly an IgE-mediated hypersensitivity reaction, and the major allergens from cow's milk have been found to be caseins, beta-lactoglobulin, and alpha lactalbumin. Several peptides derived from bovine casein are known allergens in cow's milk. To reduce their allergenicity, these proteins can be degraded by food grade peptidases. We succeeded in detection of two peptides, VLPVPQK and FFVAPFPEVFGK, from bovine casein-derived allergen peptides by using an ion trap LC-MS apparatus. This study focuses on the synergistic effects of Streptomyces aminopeptidases belonging to the M1, M24, and M28 families on the degradation of the allergen peptides. From these results, we demonstrated that the combination of M1 and M24 aminopeptidases was the most effective for degrading the abovementioned allergenic peptides. PMID- 30009326 TI - Laccases from Marine Organisms and Their Applications in the Biodegradation of Toxic and Environmental Pollutants: a Review. AB - The discharge of industrial effluent creates environmental problems around the world and so necessitates the need for the economically expensive and sometimes technically problematic treatment of the wastewater. Laccases have enormous potential for the oxidative bioremediation of toxic xenobiotic compounds using only molecular oxygen as the sole cofactor for their reaction, and their application is regarded as environmentally friendly. Due to the low substrate specificity of laccases, they can oxidize a variety of substrates. Moreover, by using appropriate mediators, laccases can degrade a wide range of substrates, including those with structural complexity. Thus, laccases are an attractive alternative for wastewater treatment. Marine environments are rich in microorganisms that are exposed to extreme conditions, such as salinity, temperature, and pressure. Laccases from these microorganisms potentially have suitable properties that might be adaptive to bioremediation processes. This review provides the latest information on laccases from marine environments, their sources, biochemical properties, media composition for laccase production, and their applications in the bioremediation of industrial waste, especially focusing on dye decolorization. PMID- 30009327 TI - Choroid plexus cysts-antenatal course and postnatal outcome in a tertiary hospital in North India. AB - PURPOSE: To assess the gestational course and postnatal outcome of antenatally diagnosed choroid plexus cysts. METHODS: From January 2015 to October 2017, mothers carrying foetuses with choroid plexus cysts (CPCs) were followed up prospectively till delivery, and subsequent postnatal assessment of all the babies was done. Progress of the lesions was monitored during pregnancy with ultrasound (USG) scans and postnatally analysed with clinical assessment and USG examination of the cranium. RESULTS: A total of 67 mothers of antenatally diagnosed CPCs were referred to the Paediatric Surgery Unit for opinion. Mean gestational age at the time of diagnosis was 19 +/- 2.1 weeks (17-28 weeks) while mean age of the mothers at the time of referral was 26 +/- 3.3 years (19-35 years). Sixty four mothers have undergone repeat antenatal scans after the diagnosis, and the CPCs disappeared completely in 60 (93.8%) of them. The CPCs persisted but reduced in size in 2 (4.1%), and the other 2 have been lost to follow-up. Thirty eight patients (56.7%) have unilateral CPCs. Mean size of cysts is 6.08 +/- 3.0 mm (2.4-14.8 mm). One foetus, in which the CPC disappeared antenatally, developed it again on the postnatal scans, but is doing well on follow-up. Thirteen babies (19.4%) have other associated congenital malformations as well. CONCLUSIONS: CPCs may involve one or both ventricles and disappear in approximately 95% of the cases, mostly within 2 months from the diagnosis. The size of the cyst has no relation to its rate of disappearance. Postnatal persistence of CPCs is uncommon and the neurological sequel is unlikely; hence, prospective parents should be reassured accordingly. PMID- 30009328 TI - Preface: Pheromone-Mediation of Female Reproduction and Reproductive Dominance in Social Species. PMID- 30009329 TI - Ritualised Dung Kicking by White Rhino Males Amplifies Olfactory Signals but Reduces Odour Duration. AB - Many mammals enhance their olfactory signals visually by depositing them in conspicuous locations such as well-travelled paths. It is also possible to enhance the odour itself through behaviours aimed at modifying odour emission rates. White rhinos defecate in communal middens. While defecating, territorial males kick sharply with their back feet which disperses their dung. Despite being a ubiquitous trait of territorial male white rhinos, the reason behind this behaviour is unclear. We hypothesised that the purpose of dung kicking was for olfactory signal amplification (OSA) in terms of an increased emission of volatile compounds (i.e. increased signal strength). Using dung collected from non-territorial adult males (because it is not possible to collect whole dung from territorial males), we show that the dispersal of male white rhino dung causes OSA by increasing the emission of hydrocarbon acids. The dung odour of territorial and non-territorial males differs only quantitatively, hence it is likely that the same emission patterns occur for territorial male dung odours following dung dispersal. The volatile compound indicating age of intact dung was toluene, but for dispersed dung it was acetophenone (similar to territorial male dung). Despite the benefits of OSA, dung dispersal carried a cost of decreased odour longevity. Thus, signal detectability is temporally reduced. However, territorial males likely counteract this by defecating in middens both before and during peak visitation times by other individuals (15:00-23:00). As a result, we suggest that dung kicking by territorial males amplifies signal strength, such that their dung odours are the most prominent and easily detectable by individuals visiting the middens. This would then better signal territorial ownership to both potential rivals and potential mates. PMID- 30009330 TI - A positive correlation between blood glucose level and bone mineral density in Taiwan. AB - : This study was undertaken to assess the effect of blood glucose on BMD and interactions with age, sex, and BMI in a Taiwanese population. Both obese and non obese people with type 2 diabetes (T2DM) had higher BMD, at lumbar spine and femoral neck, compared with healthy subjects. In addition, the prevalence of osteoporosis significantly decreased with blood sugar and HbA1c. PURPOSE: This study was undertaken to assess the effect of blood glucose on BMD and possible interactions with age, sex, and BMI in a Taiwanese population. PATIENTS AND METHODS: This study was a retrospective cross-sectional study using data from the Health Examination Database of Changhua Christian Hospital. Data on BMD of the lumbar spine and femoral neck were obtained by dual X-ray absorptiometry (DXA), and other relevant clinical and laboratory data were recorded. RESULTS: The type 2 diabetes (T2DM) group had a higher BMD than the controls. When comparing the prevalence of osteoporosis between subjects by glucose and HbA1c level, the prevalence of osteoporosis significantly decreased with blood glucose and HbA1c. In addition, the BMD of the lumbar spine and femoral neck was higher in the T2DM group than in the controls. Osteoporosis was negatively associated with DM, BMI, and drinking, but positively associated with age, female gender, previous fracture history, and other diseases of the musculoskeletal system and connective tissue. The association between diabetes and osteoporosis remained statistically significant after adjusting for the above factors. T2DM was associated with lower odds of osteoporosis in both obese (OR = 0.77) and non-obese (OR = 0.63) (p for interaction = 0.555). CONCLUSIONS: Both obese and non-obese people with T2DM had higher BMD, at lumbar spine and femoral neck, compared with healthy subjects. In addition, the prevalence of osteoporosis significantly decreased with blood glucose and HbA1c. PMID- 30009331 TI - Strontium inhibits osteoclastogenesis by enhancing LRP6 and beta-catenin-mediated OPG targeted by miR-181d-5p. AB - Strontium is a drug with the bone formation and anti-resorption effects on bone. The underlying mechanisms for the dual effect of strontium on bone metabolism, especially for the anti-resorption effects remain unknown. Thus, we aim to investigate the mechanisms of effects of strontium on osteoclastogenesis. Firstly, we found that strontium decreased the levels of important biomarkers of receptor activator of nuclear factor kappa-B ligand (RANKL) which induced osteoclast differentiation, indicating that strontium might directly inhibit osteoclast differentiation. Next, we revealed that strontium enhanced Low Density Lipoprotein Receptor-Related Protein 6 (LRP6)/beta-catenin/osteoprotegerin (OPG) signaling pathway in MC3T3-E1 cells. The signaling pathway may negatively regulate osteoclastogenesis. Thus, strontium indirectly inhibited RANKL induced osteoclast differentiation. Finally, we revealed that OPG was targeted by miR 181d-5p as determined by luciferase reporter assay and downregulated by miR-181d 5p at both mRNA and protein levels as determined by western blot. PMID- 30009332 TI - Molecular Insights into Antimicrobial Resistance Traits of Commensal Human Gut Microbiota. AB - Antimicrobial resistance (AMR) among bacterial species that resides in complex ecosystems is a natural phenomenon. Indiscriminate use of antimicrobials in healthcare, livestock, and agriculture provides an evolutionary advantage to the resistant variants to dominate the ecosystem. Ascendency of resistant variants threatens the efficacy of most, if not all, of the antimicrobial drugs commonly used to prevent and/or cure microbial infections. Resistant phenotype is very common in enteric bacteria. The most common mechanisms of AMR are enzymatic modifications to the antimicrobials or their target molecules. In enteric bacteria, most of the resistance traits are acquired by horizontal gene transfer from closely or distantly related bacterial population. AMR traits are generally linked with mobile genetic elements (MGEs) and could rapidly disseminate to the bacterial species through horizontal gene transfer (HGT) from a pool of resistance genes. Although prevalence of AMR genes among pathogenic bacteria is widely studied in the interest of infectious disease management, the resistance profile and the genetic traits that encode resistance to the commensal microbiota residing in the gut of healthy humans are not well-studied. In the present study, we have characterized AMR phenotypes and genotypes of five dominant commensal enteric bacteria isolated from the gut of healthy Indians. Our study revealed that like pathogenic bacteria, enteric commensals are also multidrug-resistant. The genes encoding antibiotic resistance are physically linked with MGEs and could disseminate vertically to the progeny and laterally to the distantly related microbial species. Consequently, the AMR genes present in the chromosome of commensal gut bacteria could be a potential source of resistance functions for other enteric pathogens. PMID- 30009333 TI - The serum level of inflammatory markers in chronic and episodic migraine: a case control study. AB - The exact mechanism of the migraine pathophysiology remained unclear. Although there are some reports showing low-grade inflammation in migraineurs, further studies are needed in this field. Thus, we designed a study to evaluate the serum levels of two main proinflammatory markers in migraine patients. In this case control research, 43 migraine patients (23 chronic and 20 episodic migraineurs) and 40 age-sex-matched headache-free controls were studied. Demographic, dietary, and anthropometric data, headache characteristics, and serum C-reactive proteins (CRP) and tumor necrosis factor-alpha (TNF-alpha) assessments were collected. The mean +/- SD age of the case and control groups were 36.98 +/- 9.91 and 34.84 +/- 9.75 years respectively. Compared to control subjects, both episodic and chronic migraineurs had significantly higher median levels of TNF-alpha (0.24, 0.95, and 1.90 pg/ml, respectively; P value < 0.001). Also, we observed a positive association between the TNF-alpha levels and the odds of having migraine after considering gender, age, body mass index, and dietary intakes of energy, carbohydrate, protein, fat, and mono and poly unsaturated fatty acids in the multivariable regression models (OR = 2.15; 95% CI 1.31-3.52; P value < 0.001). However, no significant association was demonstrated between migraine and serum CRP (OR = 2.91; 95% CI 0.87-9.78; P value = 0.08). These findings supported that inflammatory state could be related to the pathogenesis of migraine and it can thus be suggested that this effect might be beyond migraine progression. Further detailed studies are needed to investigate the importance of these findings in the pathogenesis of migraine headache. PMID- 30009334 TI - National Institutes of Health Stroke Scale in patients with primary intracerebral hemorrhage. AB - BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) is able to predict mortality and functional outcome in patients with ischemic stroke. Its role in primary intracerebral hemorrhage (ICH) is not clear. The objective of our study was to investigate whether NIHSS is a reliable instrument of clinical monitoring and correlates with mortality and functional outcome in ICH. METHODS: One hundred fifty-six consecutive subjects with primary ICH were included. We evaluated NIHSS at admission. The functional state after a 30-day and a 3-month long follow-up was assessed by the modified Rankin Scale (mRS). Spearman's rank correlation coefficient analysis was used for statistics. Sensitivity, specificity, positive predictive value, negative predictive value, global accuracy, and ROC curve were computed using the median score 7 as NIHSS cutoff and the score 4 as mRS cutoff. RESULTS: Median NIHSS score at admission was 7 (16 4); the mean (+/- SD) was 10.82 (+/- 8.27). Thirty-two patients (20.5%) died within 30 days and other 22 (14.1%) within 3 months. The median mRS score at 3 months was 4 (6-1); the mean (+/- SD) was 3.38 (+/- 2.42). We found a statistically significant correlation between initial NIHSS score and mRS score after 30 days (0.74) and 3 months (0.66, p < 0.01). Sensitivity was 93.5 and 92.2%, specificity 82.3 and 69.6%, and GA 87.8 and 80.8%, respectively, at 1 and 3 months. The 1- and 3-month ROC curves comparing initial NIHSS and mRS showed a fitted area as 0.914 and 0.833, respectively. CONCLUSIONS: NIHSS is a reliable tool of clinical monitoring and correlates with 30-day and 3-month mortality and functional outcome in subjects with ICH. PMID- 30009335 TI - Does primary lactase deficiency reduce bone mineral density in postmenopausal women? A systematic review and meta-analysis. AB - : Postmenopausal osteoporosis is a significant cause of morbidity and mortality. The role of primary lactase deficiency (PLD) in its development is not clear. This meta-analysis showed that PLD is a risk factor for osteoporosis in postmenopausal women. These women need special attention in terms of screening for osteoporosis and its prevention. INTRODUCTION: Postmenopausal osteoporosis is an important predictor of bone fractures. The purpose of the study was to conduct a systematic review and meta-analysis of association of PLD and bone mineral density (BMD) in postmenopausal women. METHODS: The electronic databases PubMed, Scopus, and Web of Science were searched over the course of July 2017 for any date of publication without language limitation. Studies were included in the meta-analysis if the diagnosis of PLD was made by genetic testing or H-2 breath tests and the diagnosis of osteoporosis was made by a modern reliable method for BMD measurement. Two investigators conducted a comprehensive, independent review of all the papers. Five of the studies initially identified met the inclusion criteria. We used MOOSE guidelines for abstracting data and assessing data quality and validity. Meta-analysis was performed using the random effects model. RESULTS: Five case-control studies with 2223 participants and 763 lactase deficient cases fulfilled the inclusion criteria. Meta-analysis showed a significantly higher bone density Z-score in absorbers (mean difference 0.20, CI (0.14-0.27), P = 0.000), with no significant heterogeneity among the studies. Moreover, the Z-score in the vast majority of the measured sites (femoral head, femoral neck, lumbar spine, radius, and Ward's triangle) was significantly higher in absorbers. There was no significant overall difference in BMD in g/cm2 between absorbers and non-absorbers, but a significantly higher BMD using g/cm2 was observed in absorbers in the total hip site. CONCLUSIONS: Postmenopausal women with PLD had lower Z-scores at most anatomic sites compared to healthy controls. PMID- 30009336 TI - The therapeutic effects of percutaneous kyphoplasty on osteoporotic vertebral compression fractures with or without intravertebral cleft. AB - PURPOSE: The purpose of this study was to investigate the clinical effects of percutaneous kyphoplasty (PKP) on osteoporotic vertebral compression fractures (OVCFs) with or without intravertebral cleft (IVC). METHODS: From 2010 to 2016, 309 OVCFs patients (43 males, 266 females) treated with PKP were included in our study. All patients were divided into no intravertebral cleft (NIVC) group and intravertebral cleft (IVC) group according to pre-operative magnetic resonance imaging. Anterior wall height (AWH), posterior wall height (PWH), and kyphotic angle (KA) of the injured vertebral body were evaluated pre-operatively, post operatively, and at final follow-up. RESULTS: All patients were followed up for 12~34 months, with an average of 16.2 months. The incidence of IVC was associated with older age and lower bone mineral density (BMD). The anterior wall, posterior wall, and kyphotic angle of vertebral bodies of patients from both groups were significantly improved immediately after surgery. The visual analogue scale (VAS) and Oswestry Disability Index (ODI) also improved significantly without significant difference between the two groups. At the final follow-up, compared to that immediately after surgery, the anterior wall height decreased and kyphotic angle increased significantly in both groups. Compared to the NIVC group, the kyphotic angle in the IVC group increased more significantly within 1 year after surgery. The volume of bone cement injected in the IVC group was larger and consequent. The IVC group had higher incidence of bone cement leakage than the NIVC group, but there was no statistic difference between two groups. CONCLUSION: Our results suggested that unilateral PKP was a safe and reliable treatment for OVCFs with IVC. However, the IVC group had higher incidence of bone cement leakage during surgery and more severe KA rebound during the follow-up period. Therefore, to reduce the incidence of bone cement leakage, it is very important to evaluate the pre-operative imaging and inject the cement carefully and repetitiously. When cement leakages are found, injection should be stopped immediately. Longer rehabilitation interventions such as wearing suitable brace, doing exercise to strengthen low-back muscle, and replacing bending with squatting in ordinary living are essential to prevent KA rebound in patients with OVCFs with IVC. However, extended follow-up may be necessary for patients with OVCFs with IVC. PMID- 30009337 TI - Nuclear localization signal region in nuclear receptor PXR governs the receptor association with mitotic chromatin. AB - In recent years, some transcription factors have been observed to remain associated with mitotic chromatin. Based on these observations, it is suggested that these chromatin-bound transcription factors may serve as 'epigenetic marks' for transmission of pattern of gene expression from progenitor to progeny cells. In this context, our laboratory has reported that nuclear receptor PXR, a master regulator of xenobiotic metabolism, remains constitutively associated with mitotic chromatin. However, the region responsible for this interaction with chromatin remained unknown. In this study, we have shown, for the first time, that mitotic chromatin association of this factor is mediated by the combined action of two zinc fingers present in the DNA-binding domain of PXR. Overall, the nuclear localization signal (NLS) region appears to play a major role in this interaction with mitotic chromatin. Also, we have identified a sub-region of 11 amino acid residues within NLS region of PXR (R66-76R) essential for receptor interaction with the mitotic chromatin. Interestingly, this minimal region is sequence-specific and independent of its basic charge. We have termed this minimal sub-region as 'mitotic chromatin binding-determining region' (MCBR). It is suggested that this receptor region is essential for activation of its target genes. Additionally, we have shown that PXR remains associated with the everted repeat (ER6) region of its major target gene, CYP3A4 promoter during mitosis implying its suggested role in 'gene bookmarking'. PMID- 30009338 TI - Injuries in girls' soccer and basketball: a comparison of high schools with and without athletic trainers. AB - BACKGROUND: Sports injuries impose physical and economic burdens on high school athletes, yet only 37% of high schools have access to a fulltime certified athletic trainer (AT). Although intuitively there are multiple benefits of AT coverage, research demonstrating the measurable effect of AT coverage on rates and patterns of injury is limited. Our objective was to investigate the epidemiology of girls' basketball and soccer injuries in high schools with and without an AT. METHODS: We compared data captured by two similar sports injury surveillance systems during the 2006/07-2008/09 academic years. High School Reporting Information Online (RIO) included a national sample of schools with ATs, and the Sports Injury Surveillance System (SISS) included a sample of Chicago public high schools without ATs. RESULTS: Overall injury rates were higher in schools without ATs than schools with ATs in girls' soccer (RR: 1.73, 95% CI: 1.51-2.00) and basketball (RR: 1.22, 95% CI: 1.03-1.45). Recurrent injury rates were even higher in schools without ATs compared to schools with ATs in soccer (RR: 6.00 95% CI: 4.54-7.91) and basketball (RR: 2.99, 95% CI: 2.12-4.14). Conversely, concussion rates were higher in schools with ATs than schools without ATs in soccer (RR: 8.05, 95% CI: 2.00-32.51) and basketball (RR: 4.50, 95% CI: 1.43-14.16). Other injury patterns were similar between the two samples. CONCLUSIONS: This study demonstrated the effectiveness of AT coverage of high school girls' soccer and basketball, both in reducing overall and recurrent injury rates and in identifying athletes with concussions. Future studies should evaluate the effect of ATs on other high school sports and on youth sports to determine if these findings are generalizable across sports and age groups. PMID- 30009339 TI - Mechanisms and regulation of epithelial phosphate transport in ruminants: approaches in comparative physiology. AB - Ruminants have a unique utilization of phosphate (Pi) based on the so-called endogenous Pi recycling to guarantee adequate Pi supply for ruminal microbial growth and for buffering short-chain fatty acids. Large amounts of Pi enter the gastrointestinal tract by salivary secretion. The high saliva Pi concentrations are generated by active secretion of Pi from blood into primary saliva via basolateral sodium (Na+)-dependent Pi transporter type II. The following subsequent intestinal absorption of Pi is mainly carried out in the jejunum by the apical located secondary active Na+-dependent Pi transporters NaPi IIb (SLC34A2) and PiT1 (SLC20A1). A reduction in dietary Pi intake stimulates the intestinal Pi absorption by increasing the expression of NaPi IIb despite unchanged plasma 1,25-dihydroxyvitamin D3 concentrations, which modulate Pi homeostasis in monogastric species. Reabsorption of glomerular filtrated plasma Pi is mainly mediated by the Pi transporters NaPi IIa (SLC34A1) and NaPi IIc (SLC34A3) in proximal tubule apical cells. The expression of NaPi IIa and the corresponding renal Na+-dependent Pi capacity were modulated by high dietary phosphorus (P) intake in a parathyroid-dependent manner. In response to reduced dietary Pi intake, the expression of NaPi IIa was not adapted indicating that renal Pi reabsorption in ruminants runs at a high level allowing no further increase when P intake is diminished. In bones and in the mammary glands, Na+ dependent Pi transporters are able to contribute to maintaining Pi homeostasis. Overall, the regulation of Pi transporter activity and expression by hormonal modulators confirms substantial differences between ruminant and non-ruminant species. PMID- 30009340 TI - Early diagnosed impacted maxillary canines and the morphology of the maxilla: a three-dimensional study. AB - BACKGROUND: The aetiology of the canine displacement still remains controversial. Some authors implicated a deficiency in maxillary width as a local mechanical cause for impacted canines. The aim of the study was to examine whether there is a relationship between impacted maxillary canines, early diagnosed by using panoramic radiographs, and the morphology of the maxilla on 3D model casts. METHODS: The displaced maxillary canines (DMC) group consisted of 24 patients (mean age, 9.1 +/- 1.1 years), while the control group consisted of 25 subjects (mean age, 8.7 +/- 0.9 years). Seven measurements were calculated on the digital casts of each subject: intermolar width (IMW), arch length (AL), depth of the palatal vault (PVD), available arch space (AAS), the sum of the anterior segments (SAS), the right/affected (R-Af) and left/unaffected (L-Un) available spaces. RESULTS: Both IMW and AL in the DMC group were significantly decreased relative to the control group (P < 0.01), indicating that patients with displaced canines presented a shorter and narrower palate than subjects without eruption problems. Moreover, the values of the SAS and AAS were significantly decreased (P < 0.01) in the DMC group relative to the controls. CONCLUSIONS: The shape of the maxillary arch was narrower and shorter in the displaced maxillary canines group compared with the control group. PMID- 30009341 TI - Molecular remission at the end of treatment is a necessary goal for a good outcome in ELN favorable-risk acute myeloid leukemia: a real-life analysis on 201 patients by the Rete Ematologica Lombarda network. AB - Favorable acute myeloid leukemia (AML) patients (pts.) demonstrate a relatively good outcome with standard induction; thus, pts. are generally not addressed to allogeneic transplant in first remission. However, it is not clear if also in a real-life setting, the outcome is homogeneous in the different favorable molecular groups and which are the parameters significantly associated to an increased relapse risk, useful to suggest the need of an intensified approach. In order to clarify this point, we collected clinical data on consecutive unselected AML pts. assigned to favorable category (modified ELN 2010 due to the inclusion of double-mutated CEBPA-positive cases), diagnosed and treated in six centers of the Italian network Rete Ematologica Lombarda (REL) from 2007 to 2015. We assessed response (CR, mCR), relapse rate (CIR), and outcome (OS, DFS) after first-line treatment. A total of 201 pts. was studied and the analysis was performed globally and in each molecular group: t(8;21)(q22;q22)/RUNX1-RUNX1T1 (30 pts., 14.9%), inv. (16)(p13q22) or t(16;16)(p13q22)/CBFB-MIH11 (35 pts., 17.4%), normal karyotype and mutated NPM1 and negative FLT3-ITD (116 pts., 57.7%) or double-mutated CEBPA (CEBPAdm) (20 pts., 10%). Complete remission (CR) was obtained in 188 pts. (93.5%), molecular CR (mCR) in 114 (67.5%); After a median follow-up of 2.4 years, cumulative incidence of relapse (CIR) was documented in 78 of 188 responding pts. (41%) after a median time of 11.3 months. CIR was higher in the CBFB-MIH11 group, in pts. achieving only a hematological response without mCR (72.1 vs 28.1%, p < 0.001), in older pts. and it resulted independently associated with a lower median cytarabine cumulative dose (CCD). Median OS was not reached: after 5 years it was 66.3%, and median DFS was 5.3 years, both without difference among groups. Molecular CR reached at any time, during or after the end of first-line treatment, was significantly associated with better DFS, and in particular, mCR assessed at the end of treatment was confirmed in multivariate analysis as an independent prognostic factor both for DFS and OS. In conclusion, the present study confirms in a real-life context the overall good prognosis of favorable-risk AML; the achievement of any molecular negativity during first-line treatment, particularly when assessed at the end of treatment, is associated with lower relapse and better survival. Increasing age at diagnosis has a negative prognostic impact, while CCD higher than 18 g/sqm is associated with better outcome. PMID- 30009342 TI - Effects of fermented green-loofah and green-papaya on nitric oxide secretion from murine macrophage raw 264.7 cells. AB - To clarify the effect of lactic acid bacteria (LAB) fermentation on the immunomodulation capacity of green-loofah and green-papaya, aqueous suspensions prepared from the fresh and dry-powdered vegetables were fermented by Lactococcus lactis subsp. lactis Uruma-SU1 and Lactobacillus plantarum Uruma-SU4. Fermented and non-fermented suspensions were added to murine macrophage RAW264.7 culture with and without Escherichia coli O111 lipopolysaccharide (LPS). In the absence of LPS, nitric oxide (NO) secretion was elevated significantly in LAB fermented suspensions compared to that in non-fermented suspensions. NO production in fermented suspensions was observed even at low sample concentrations, but it was attenuated in the centrifuged supernatant. With LPS treatment, inhibition of NO secretion was shown with the high concentration of the non-fermented and also fermented samples. These results suggest that fermented green-loofah and green papaya suspensions can play both immunostimulatory and anti-inflammatory roles at low and high doses, respectively. PMID- 30009343 TI - The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy. AB - In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy. PMID- 30009344 TI - Discovery of the Late Changhsingian Bivalve Complex and Two Fauna Extinction Episodes in Northeastern Asia at the End of the Permian. AB - A late Changhsingian bivalve complex including species from the genera Palaeonucula, Dacryomya, Malletia ?, Sarepta ?, Myalina, Pteria, Maitaia, and Unionites is discovered in northeastern Asia for the first time. The transition from the Permian to the Triassic in high-boreal basins has been shown to include two extinction episodes similar to those observed in the low-boreal basins and apparently evoked by trap volcanism activation in Siberia. Changes in benthic foraminifera diversity and vertical distribution of ammonoidea of the genus Otoceras in transitional Permian-Triassic deposits also are considered. Images of bivalves from the most typical taxa are presented. PMID- 30009345 TI - First Finding of a Representative of Giant Mustelids of the Genus Eomellivora (Carnivora, Mustelidae) in Russia (Tuva, Upper Miocene). AB - In the late Miocene deposits in the Taralik-Cher locality (Tuva Republic), fossil remains of a giant mustelid of the genus Eomellivora Zdansky, 1924 have been found. This finding is the first reliable evidence of the Eomellivora inhabiting the modern Russia. Teeth of the Eomelliovra from Taralik-Cher are similar in size to those of E. wimani and E. piveteaui from the late Miocene in Eurasia. The morphology of teeth of the material from Tuva is most similar to that of E. ursogulo; therefore, it is considered a small form of Eomellivora ursogulo. The described finding expands the understanding of diversity, variability, and distribution of representatives of the genus Eomellivora in Asia during the late Miocene. PMID- 30009346 TI - Deuterium Oxide Enhances Escherichia coli SOS Response Induced by Genotoxicants. AB - It has been demonstrated that deuterium oxide enhances the SOS response of Escherichia coli cells induced by chemical genotoxicants and mutagens. This demonstrates that the heavy nonradioactive hydrogen isotope deuterium can be considered to be a comutagen. PMID- 30009347 TI - Phosphorus Budget of Lake Baikal and the Angara Cascade Water Reservoirs: Modeling, Reconstruction, and Prognosis. AB - A mass balance model of phosphorus flow in a system of connected water reservoirs has been developed and used for quantitative assessment of phosphorus budget elements in Lake Baikal and water reservoirs on the Angara River, the only river that drains Lake Baikal. PMID- 30009348 TI - Isotopic Composition of Blood of Polar Bears (Ursus maritimus) of the Kara Barents Sea Population. AB - The data on the content of carbon and nitrogen isotopes in the blood samples of polar bears obtained in the present study confirm that polar bears in the Taimyr region (and the Kara-Barents sea population in general) are partly dependent on the resources of terrestrial origin. However the "terrestrial carbon" evidently reaches bears' tissues indirectly, via marine food webs utilizing organic carbon brought into the polar basin by Siberian rivers. PMID- 30009349 TI - Structure and Ultrastructure of the Acrotrichis grandicollis (Coleoptera: Ptiliidae) Compound Eyes and the Eye Features Related to Miniaturisation. AB - Here is the first description of the visual organ of Acrotrichis grandicollis, a member of Ptiliidae family that includes the smallest free-living insects. The apposition eyes of A. grandicollis have the acone-type crystalline cone; a fused rhabdom is formed by eight retinula cells and surrounded by primary pigment cells. Secondary pigment cells are located only in the distal part of the ommatidium under the lens. The eye consists of about 50 facets about 12 MUm in diameter. The A. grandicollis ommatidium ultrastructure has been compared with that of large Coleoptera. The results obtained enabled us to emphasize the compound eye specific features associated with the small body size. PMID- 30009351 TI - The Impact of Winter Meteorological Parameters on Abundance of the Grey Partridge Perdix perdix in the Southern Ural Steppe. AB - In the winter periods from 1994 to 2017, the grey partridge average abundance in the steppe zone of the southern Urals was significantly negatively correlated with some meteorological parameters (the snow cover height, precipitations, snow density). At the same time, in the subsequent summer period, these winter parameters (including the mean air temperature) had no influence on the bird number. Indeed, the harsh and snowy winters did not affect the grey partridge abundance in the reproductive period. We believe that migrations from the breeding area or nomadic movements of these birds occurred in the most extreme winters. PMID- 30009350 TI - Viable Nematodes from Late Pleistocene Permafrost of the Kolyma River Lowland. AB - We have obtained the first data demonstrating the capability of multicellular organisms for longterm cryobiosis in permafrost deposits of the Arctic. The viable soil nematodes Panagrolaimus aff. detritophagus (Rhabditida) and Plectus aff. parvus (Plectida) were isolated from the samples of Pleistocene permafrost deposits of the Kolyma River Lowland. The duration of natural cryopreservation of the nematodes corresponds to the age of the deposits, 30 000-40 000 years. PMID- 30009352 TI - Ortho-Phthalic Acid Esters Suppress the Phytopathogen Capability for Biofilm Formation. AB - This is the first study demonstrating that ortho-phthalic acid esters, dibutylphthalate (DBP) and di-(2-ethylhexyl)-o-phthalate (DEHP), inhibit the ability to form biofilms of the biotrophic pathogen Clavibacter michiganensis ssp. sepedonicus and Pectobacterium carotovorum ssp. carotovorum necrotroph. Inhibition of biofilm formation depends on the DBP and DEHP concentrations. PMID- 30009353 TI - The Effect of Weather Conditions on Eutrophication in the Neva River Estuary. AB - Analysis of long-term data on chlorophyll a and total phosphorus concentrations, plankton primary production, organic matter mineralization, and weather conditions in the middle of summer in 2003-2017 revealed eutrophication processes in the Neva River estuary. Weather conditions in the region exerted a strong effect on organic matter prodaction and mineralization processes in the estuary. Rainy and cold summers of the recent years promoted massive development of algae due to increased washout of nutrients from the catchment area, but the rate of organic matter mineralization in the water column was reduced because of low water temperature. PMID- 30009354 TI - Distribution of Polychaeta Communities in the West Spitsbergen Area in Winter (December 2015). AB - Using the materials collected in 2015, modern data have been obtained on the polychaete species composition and quantitative distribution in the West Spitsbergen area in winter. Polychaete species complexes corresponding to different habitat conditions have been identified in the outer and inner parts of the bays. The distribution of the Polychaeta communities proved to be dependent on the bottom sediment composition, depth, and specific hydrological regime. PMID- 30009355 TI - Taxonomic Interpretation of Allopatric Mammalian Forms on the Example of Two Karyoforms of Microtus (Terricola) subterraneus (Rodentia, Arvicolinae) from Eastern Europe. AB - New European pine vole records from the Novgorod, Kaluga, Voronezh, and Belgorod oblasts were studied by sequencing of the mtDNA cytb gene (1143 bp) and by karyotyping (routine staining and G-banding techniques). The results enabled us to summarize chromosome variability of this species throughout Eastern Europe. In the sample studied, two geographically replacing chromosomal forms have been identified: northern, 2n = 54 (Novgorod and Kaluga oblasts), and southern, 2n = 52 (Voronezh and, presumably, Belgorod oblasts). Our data make the boundaries of these two karyoforms in Eastern Europe more precise and testify to intraspecific level of their taxonomic differentiation. PMID- 30009356 TI - Correction to: Regulation of SIRT1/AMPK axis is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in hepatocellular carcinoma cells. AB - This article contains an error. PMID- 30009358 TI - Task instructions modulate unit-decade binding in two-digit number representation. AB - Previous studies have found decomposed processes, as well as holistic processes, in the representation of two-digit numbers. The present study investigated the influence of task instruction on such processes. Participants completed both magnitude and parity tasks in one of three instructional conditions, where they were asked to either consider two-digit numbers as a whole or to focus on one specific digit. In two experiments, we found that when participants were asked to consider the two digits as an integrated number, they always exhibited a unit decade compatibility effect, indicating a failure of selective attention on the digit relevant to the given task. However, the mere presence of the neighboring digit is not a sufficient condition for the compatibility effect: when participants were explicitly asked to process a specific digit, their success/failure to selectively ignore the irrelevant digit depended on task requirements. Further, computer mouse tracking indicated that the locus of the compatibility effect was related to late response-related processing. The results signify the deep involvement of top-down processes in unit-decade binding for two digit number representation. PMID- 30009359 TI - Monitoring of methane emission from a landfill site in daily and hourly time scales using an automated gas sampling system. AB - Landfill sites are significant sources of methane gas globally. Understanding the temporal variabilities of methane emissions from landfill sites is necessary for estimating such emissions. In this study, an automated monitoring system was used to monitor methane emission flux and concentration on daily and hourly time scales at a landfill site. Measured methane emission fluxes were almost negligible in the studied area. However, methane concentration at landfill surface at nighttime was significantly higher than those in the daytime, which demonstrates the importance of investigating methane emissions at an hourly time scale, including during nighttime. The daily and hourly variations in methane concentration were well correlated with either soil temperature or volumetric water content near the surface. The obtained relations indicate that the automated monitoring system measurements can facilitate a more comprehensive understanding of the methane emission mechanisms at different time scales. PMID- 30009357 TI - Multiple Phases of Climbing Fiber Synapse Elimination in the Developing Cerebellum. AB - Functional neural circuits in the mature animals are shaped during postnatal development by elimination of unnecessary synapses and strengthening of necessary ones among redundant synaptic connections formed transiently around birth. In the cerebellum of neonatal rodents, excitatory synapses are formed on the somata of Purkinje cells (PCs) by climbing fibers (CFs) that originate from neurons in the contralateral inferior olive. Each PC receives inputs from multiple (~ five) CFs that have about equal synaptic strengths. Subsequently, a single CF selectively becomes stronger relative to the other CFs during the first postnatal week. Then, from around postnatal day 9 (P9), only the strongest CF ("winner" CF) extends its synaptic territory along PC dendrites. In contrast, synapses of the weaker CFs ("loser" CFs) remain on the soma and the most proximal portion of the dendrite together with somatic synapses of the "winner" CF. These perisomatic CF synapses are eliminated progressively during the second and the third postnatal weeks. From P6 to P11, the elimination proceeds independently of the formation of the synapses on PC dendrites by parallel fibers (PFs). From P12 and thereafter, the elimination requires normal PF-PC synapse formation and is presumably dependent on the PF synaptic inputs. Most PCs become mono-innervated by single strong CFs on their dendrites in the third postnatal week. In this review article, we will describe how adult-type CF mono-innervation of PC is established through these multiple phases of postnatal cerebellar development and make an overview of molecular/cellular mechanisms underlying them. PMID- 30009360 TI - Light and scanning electron microscopy of the tongue of the sand lizard (Lacerta agilis). AB - Despite the fact that numerous reptile species are widely studied by the researchers, information describing the detailed structure of particular organs in many reptiles is missing. The tongue of the sand lizard (Lacerta agilis) was examined under the light and scanning electron microscope. It is divided into bifurcated apex, corpus and bifurcated radix. The tip of the lingual apex is devoid of lingual papillae. The remaining dorsal surface of the tongue bears either fused papillae in the form of caudally directed ridges or individual papillae represented by mushroom like or semilunar prominences (lingual apex) or fish scale-like papillae (lingual corpus) and horizontally laid ridges extending in the form of lobulated prominences (lingual corpus, lingual radix). Regardless of the shape, lingual papillae contain numerous muscle fibers and they are all considered to be mechanical. The lingual epithelium changes from the simple squamous into stratified squamous in the caudal direction. No salivary glands or sensory structures were recognised. This description is to be used mainly for comparative studies. It could also help to understand how different lizards capture the pray. PMID- 30009361 TI - The differential effects of high-fat and high fructose diets on the liver of male albino rat and the proposed underlying mechanisms. AB - BACKGROUND: The western-style diet is characterized by the high intake of energy dense foods. Consumption of either high fructose diet or saturated fat resulted in the development of metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Many researchers studied the effect of high-fat diet (HFD), high fructose diet (HFruD) and high fructose high-fat diet (HFHF) on the liver. The missing data are the comparison effect of these groups i.e. are effects of the HFHF diet on the liver more pronounced? So, this study was designed to compare the metabolic and histopathological effect of the HFD, HFruD, and HFHF on the liver. The proposed underlying mechanisms involved in these changes were also studied. MATERIALS AND METHODS: 24 rats were divided into four groups: control, HFD, HFruD, and HFHF. Food was offered for 6 weeks. Biochemical, light microscopic, immunohistochemical { Inducible nitric oxide synthase (iNOS) and alpha-smooth muscle actin (alpha SMA)}, Real-time PCR (gene expression of TNF-alpha, IL-6, Bax, BCL2, and caspase 3), histomorphometric analysis and oxidative/antioxidative markers {thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA)/glutathione (GSH) and superoxide dismutase (SOD)} were done. RESULTS: The HFD, HFruD and HFHF groups developed a cluster of liver disorders; steatosis, necrosis, inflammation, apoptosis, ballooning degeneration and cytoplasmic vacuolations. Internal metabolic impairments include elevated the serum levels of glucose, triglycerides, LDL and decreased the serum levels of HDL and albumin. The immunoreaction of the alpha-SMA and iNOS was strong in these groups. The oxidant markers (MDA and TBARS) were elevated, while the antioxidant markers (SOD and GSH) were decreased. The area % of collagen, inflammatory markers, caspase 3 and Bax elevated, while the BCL-2/Bax ratio decreased. The decrease of PAS, antioxidant markers and the elevation of the alpha-SMA, iNOS, inflammatory and oxidant markers were obvious in the HFHF when compared to that of the other groups. CONCLUSIONS: HFD, HFruD, and HFHF developed morphologic hepatic changes ranging from steatosis to necrosis and inflammation, besides the development of internal metabolic impairments. The chief factors of hepatic injury were fat accumulation in the hepatocytes, oxidative stress and highly elevated iNOS. Compared to the other groups, HFHF's effect was more prominent. PMID- 30009363 TI - Analysis of corpus callosum size depending on age and sex. AB - BACKGROUND: The aim of the study was to analyse changes in the size of the corpus callosum (CC) depending on age and sex and to establish the reference values of the morphometric indices of the CC in the Polish population. MATERIAL AND METHODS: The results of MR studies of 1108 patients performed in the years 2010 2014 were analysed. Two independent radiologists evaluated cerebral images to exclude deviations from normal state. In patients divided according to sex and to 10 age groups, measurements of CC and brain dimensions were made and morphometric indices were calculated. RESULTS: The results of measurements related to the following parameters: lengths of longitudinal cross-section of CC (CD), CC thickness in the narrowest place - isthmus (EF), the largest linear dimension of the brain from the frontal pole to the occipital pole (AB), the longitudinal cross-section area of the CC (A1) and cerebral cross-section area (A2) as well as CD/AB and A1/A2 ratios are summarized in 7 figures and 3 tables. CONCLUSIONS: It was demonstrated, that in all age groups there are statistically significant differences in the values of the analysed parameters and ratios of CC size. It was indicated, that there are no statistically significant differences between men and women in the CD, EF, and A1 parameters related to CC size, and the profiles of variations of these parameters are very similar. It was proved that there are statistical differences between women and men in parameters/indicators concerning of the brain size. PMID- 30009362 TI - Anatomical evaluation of nasopalatine canal on cone-beam computed tomography images. AB - BACKGROUND: Nasopalatine canal (NPC) (incisive canal) morphology is important for oral surgery techniques carried out on the maxilla, in the treatment of nasopalatine cyst, palatal pathologies that require a surgical intervention. MATERIALS AND METHODS: The morphology of NPC was classified in sagittal, coronal and axial planes on the CBCT. The length of NPC was found by measuring the distance between the mid-points of nasopalatine foramen and incisive foramen. The numbers, shapes and diameters of incisive foramen and nasopalatine foramen were examined. Nasopalatine angle present between the NPC and the palate and anterior to the NPC was measured. RESULTS: In the sagittal plane, the shape of NPC was classified in six groups: 26.7% hourglass, 14.7% cone, 13.3% funnel, 16.0% banana, 28.7% cylindrical and 0.7% reverse-cone shaped. In the coronal plane, shape of NPC was classified in three groups: 63.3% Y shaped, 36.0% single canal, 0.7% double canal and external border of NPC was classified in four groups: 26.7% U, 28.7% Y, 44.0% V and 0.7% reverse-V shaped. In the axial plane, the shape of nasopalatine foramen, incisive foramen and NPC at the mid-level was evaluated. The shape of the canal was detected as four types at three evaluated levels: round, oval, heart and triangle shaped. It was seen in every three axial planes that the round group is more than the others. CONCLUSIONS: The morphological properties and variations of NPC should be considered with a correct radiological evaluation so as to prevent the complications and improper practices in local anesthesia, maxillary surgery and implant surgery practices. Especially dentists, otolaryngologist and plastic surgeons need to know the anatomy and variations of NPC. PMID- 30009364 TI - Evaluation of the anatomical measurements of the temporomandibular joint by cone beam computed tomography. AB - BACKGROUND: To examine the detailed anatomy of the normal temporomandibular joint in a large series of patients divided into different age groups. METHODS: Cone beam computed tomography (CBCT) images of 100 patients included the study. Morphometric analysis regarding mandibular condyle and mandibular fossa, articular tubercle and the zygomatic arch was done. The volumetric and surface measurements of mandibular condyles (total tissue volume (TV), total bone volume (BV), bone surface area (BS) and percentage of bony tissue of the mandibular condyle (BV/TV)) were also measured. RESULTS: Statistical analysis was performed, and statistically significant differences according to the side of the joint, sex, and age groups were reported. Additionally, correlations between aging and all of these parameters were also determined. CONCLUSIONS: TV, BV, BS and BV/TV parameters according to side, age, and sex groups were defined for normal TMJ which may help to understand the onset and progress of TMJ disorders. PMID- 30009365 TI - From thyroid cartilage to thyroid gland. AB - The ancient Greek physicians skipped the description of thyroid gland probably due to their difficultly to understand the anatomy and the existence of this organ. Although the ancient physicians had described the disease bronchocele (Greek: Betarhoomicrongammachiomicronkappaetalambdaeta), this disease did not correspond exactly to goiter. The first official description of this gland was made by Andreas Vesalius (1514-1564). Thomas Wharton (1614-1673) in his work Adenographia was the one who coined the term Glandulae thyreoidea. PMID- 30009366 TI - Morphological variations of the mandibular canal in digital panoramic radiographs: a retrospective study in a Chilean population. AB - BACKGROUND: Morphological variations of the mandibular canal (MC) have been described in literature, so the clinician must be able to recognise them and adapt their treatment accordingly. The aim of this study was to determine the prevalence of morphological variations of the MC using digital panoramic radiographs (DPR) of Chilean patients. MATERIALS AND METHODS: A retrospective study in which 1400 DPR were analysed to identify cases of bifid, trifid and retromolar MC. The radiographs were analysed independently by two examiners who had previously been trained by a specialist in oral and maxillofacial radiology. Inclusion and exclusion criteria were applied to reach a final sample. RESULTS: 925 radiographs were included (599 female, 326 male; mean age 36.1 +/- 15.54 years). The prevalence of bifid MC was 11% (n=102), with no significant differences by sex (p=0.069). Proportion of bifid MC was higher among younger patients (p=0.038). Prevalence of morphological variations of Type 1 bifid MC was 7.4% (n=69), Type 2 was 2.3% (n=23), Type 3 was 0% (n=0) and Type 4 was 1.1% (n=10). Prevalence of retromolar canal was 0.9% (n=8), with no significant differences by sex (p=0.893) or age (p=0.371); of these, 2 cases (0.2%) were forward type and 6 cases (0.6%) were retromolar type. No cases of trifid MC were found. CONCLUSIONS: DPR are useful for detecting morphological variations of the MC; we were able to identify three types of bifid MC as well as retromolar canals. Proper identification of these variations by an easily accessible examination is important for avoiding possible complications in clinical-surgical practice. PMID- 30009367 TI - The effect of nitro-oleic versus losartan in diabetic nephropathy: modulation of parathyroid hormone related protein. AB - BACKGROUND: Parathyroid hormone related protein (PTHrP) involvement in the mechanisms related to angiotensin II (Ang II)- induced renal injury has become an emerging concern. The current study was thus designed to compare the possible preventive and therapeutic effect of Ang II antagonists; losartan and nitro-oleic (NO2-OA) acid on diabetic nephropathy (DN), and evaluate their effect on PTHrP modulation as well as on the functional and histopathological parameters in the kidney of diabetic rats. METHODS: Forty eight adult male Sprague Dawley rats were divided into control group, DN group, pre-diabetic nephropathy (pre-DN) losartan group, pre-diabetic nephropathy nitro-oleic acid (pre-DN NO2-OA) group, post diabetic nephropathy (post-DN) losartan and post-diabetic nephropathy nitro-oleic acid (post DN-NO2-OA) groups. At the end of the study, systolic blood pressure (SBP), serum fasting glucose, glomerular filtration rate (GFR), urea, urea albumin excretion (UAE), serum angiotensin, renal PTHrP gene expression and correlations between PTHrP and SBP, serum glucose, Ang II and kidney functions were evaluated. Histological examination, Masson's trichrome, Periodic acid shift staining as well as morphometric analysis and histopathological scoring for tubular and glomerular parameters have been carried out. RESULTS: Prophylactic losartan and NO2-OA were associated with improvement in SBP, serum glucose, urea, GFR, UAE, with reduction in serum Ang II and PTHrP overexpression observed in diabetic kidney. Treatment with losartan and NO2-OA showed the same effect except that post-DN NO2-OA showed no significant effect regarding kidney function. Strong correlations were observed between PTHrP and SBP, serum glucose, Ang II and kidney functions. Histopathological results revealed obvious improvement in glomerulosclerosis, vascular and tubular injury parameters in prophylactic groups especially with losartan. CONCLUSIONS: Both pre and post-DN losartan, NO2-OA may have a potential role in protection and regression of DN through reduction of PTHrP overexpression. PMID- 30009368 TI - Bilateral anatomic variation in the relation of the upper trunk of the brachial plexus to the anterior scalene muscle. AB - The brachial plexus represents a field of many anatomical variations with important clinical implications, especially in the diagnosis and treatment of the thoracic outlet syndrome (TOS). The case described in this paper presented a novel bilateral variation in the relation of the upper trunk of the brachial plexus to the anterior scalene muscle. The ventral rami of the C5 and C6 spinal nerves perforated the anterior scalene muscle simultaneously through a common opening, and joined to form the upper trunk. Previous literature reports described variations of the brachial plexus and the scalene muscles, as well as the embryological basis for their presence. The case reported herein helps to improve the comprehension of the TOS, as well as the diagnostic and therapeutical approach to this syndrome. PMID- 30009369 TI - Osseointegration of hydroxyapatite coatings doped with silver nanoparticles: scanning electron microscopy studies on a rabbit model. AB - Modern joint arthroplasties rely on osseointegration of metal components through bone ingrowth into hydroxyapatite (HA) layers. However, such surfaces are prone to colonisation by bacteria and formation of biofilms. Application of silver nanoparticles (SN) to hydroxyapatite coatings could reduce the risk of infection, however little is known about how this would affect the process of bone ingrowth. This study examined osseointegration of conventional and SN doped HA coatings in a rabbit model. In this study, twelve cylindrical implants coated with conventional and SN doped HA were implanted into New Zealand white rabbit femora, with each animal receiving both types of implants. After 12 weeks, rabbits were sacrificed, their femora were harvested and implants removed during pull-out testing. Retrieved samples were dehydrated, sputter coated and observed using a scanning electron microscope (SEM) to verify bony ingrowth and retention of SNs. The percentage of implant in direct contact with bone was measured in cross sections of implants. The SEM analysis demonstrated that osseointegration of the SN doped coatings was similar to the conventional HA samples. A similar morphology of newly formed trabecular bone was observed in both implants, with silver doped HA-coated implants retaining multiple nanoparticles in areas which were not overgrown by bone. Analysis of the bone-implant contact area revealed comparable results for both types of coatings. These finding indicated that SN doped HA coatings are characterised by good osseointegrative properties. Since SNs were found in areas not covered by mineralised bone, it is assumed that the antimicrobial properties of the modified coating may be retained for 12 weeks after implantation. Additional studies are required to fine-tune the composition of HA coatings with silver nanoparticles, to ensure optimal osseointegrative and antimicrobial properties. PMID- 30009370 TI - Morphological characterization of the coronary arteries in African sheep (Ovis orientalis). Differential analysis with those of humans and other animal species. AB - BACKGROUND: Despite the importance of the coronary system in the African sheep as an possible experimental model, there is little information about this particular anatomical. The objective of this investigation was to characterize morphologically the coronary arteries and their branches in African sheep. MATERIALS AND METHODS: This descriptive cross-sectional study evaluated the coronary arteries and their branches of 62 hearts of short hair sheep. The right and left coronary ostia were perfused with a semi-synthetic resin (Palatal GP40L 85%; styrene 15%) dyed with mineral red. The morphological characteristics were evaluated using a digital calibrator and the biometrics of the coronary arteries and their branches were registered. RESULTS: The right coronary artery had a proximal caliber of 2.11+/-0.46 mm. The subsinusal interventricular branch ended at the middle third of the homonym sulcus in 19 specimens (30.6%).The left coronary artery had a diameter of 5.38+/-1.59 mm and a length of 4.67+/-3.32 mm. This artery bifurcated itself in the paraconal interventricular branch and the left circumflex branch in 57 hearts (91.9%) and trifurcated with an additional left diagonal branch in five specimens (8.1%). Left coronary artery dominance was observed in 51 specimens (82.3%), whereas in 11 cases (17.7%) the coronary circulation dominance was balanced. CONCLUSIONS: Due to the similitude in the features of the coronary arteries between African sheep and humans, this animal model can be proposed for procedural and hemodynamic activities. PMID- 30009371 TI - Examination of inclinations in spine at childhood and adolescence stage. AB - Spine is a column that consists of consecutively lined up vertebras. It includes medulla spinalis. It contributes the motions of head, neck and body. Spine is not a straight column. It figures a convexity towards the front of the spine (lordosis) at cervical and lumbal areas in adults. It also figures a convexity towards the back of the spine (kyfosis) at thoracic and sacral spine area. In this study, lateral MRI images of 731 children between 1-16 years old were examined and their cervical lordosis, thoracic kyfosis and lumbal lordosis angles were measured with Cobb method using ImageJ program for every age group. The mean calculated cervical lordosis angles in 1-16 years old children were found 20.51o+/-6.11 (minimum 17.96o+/-6.29, maximum 23.50o+/-4.14). It has been observed that cervical angle value decrease with age. The mean thoracic kyfosis angle measurement was found 28.71o+/-6.99 (minimum 24.55o+/-5.65, maximum 30.44o+/-4.68). Lumbal lordosis angle was measured 28.08o+/-7.39 (minimum 20.36o+/-6.59, maximum 32.68o+/-6.03). Thoracic kyfosis and lumbal lordosis angle values increase with age. In our study, a statistical difference was found in increasing thoracic kyfosis angle between 1 year old group and 14 years old group. Statistically difference was also found in decreasing cervical lordosis angle value between 1 year old group and 16 years old group. When we compare our study results with literature values, cervical lordosis values were similar but lumbal lordosis values were lower. In a result, we think that knowing sagittal plane inclinations developing in childhood and adolescence stages will contribute determination of pathologies earlier. We also hope that it will contribute clinical stages and other studies in this field. PMID- 30009372 TI - Branching patterns of the foetal popliteal artery. AB - BACKGROUND: The objective of the study is to evaluate the popliteal artery topography and the origin variability of its branches in human foetuses at the gestational age of from 4 to 9 months. The basis for the analysis are direct observations of classic anatomic dissections of the popliteal fossa. Possible dimorphic and bilateral differences, as well as the gestational age variability at the foetal period, were considered. Atypology of popliteal artery branches will be made on the basis of the studies. MATERIAL AND METHODS: The research material of this study comprises 231 foetuses (including 116 males and 115 females). The foetuses were divided into five 28-day age classes. The vessels of the lower extremity were injected with LBSK 5545 latex through the femoral artery. The bilateral dissection of the popliteal artery along with its branches was performed. No visible malformations were found in the research material, and the foetuses came from spontaneous abortions and premature births. RESULTS AND CONCLUSIONS: 10% of the cases featured the variations of popliteal artery terminal branches. Three most commonly seen variations are the trifurcation, anterior tibial-peroneal trunk, and high terminal division of the popliteal artery. The most common course of the superior muscular branches is that there are two large branches which are distributed from the popliteal artery at the height of the knee joint cavity and they do not distribute cutaneous branches. Sural branches are also present as two large vessels without cutaneous branches. The genicular anastomosis branches that run on their own are a typical topographic system of these branches. PMID- 30009373 TI - The effect of beta-blockers on mortality in patients with heart failure and atrial fibrillation: A meta-analysis of observational cohort and randomized controlled studies. AB - BACKGROUND: Beta-blockers (BB) are the cornerstone of therapy for heart failure (HF); however, the effects of these drugs on the prognosis of patients with concomitant atrial fibrillation (AF) remain controversial. The objective of this meta-analysis was to evaluate the efficacy of BB on mortality in HF coexisting with AF. METHODS: A systematic search of PubMed, EMBASE and the Cochrane Library databases was conducted. Observational cohort studies (OCSs) and randomized controlled studies (RCTs) reporting outcomes of mortality or HF hospitalizations for patients with HF and AF, being assigned to BB treatment and non-BB group were included. RESULTS: A total of 8 clinical studies (5 randomized controlled trials and 3 observational cohort studies) involving 34197 patients were included in the analysis. The pooled analysis demonstrated that BB treatment was associated with a 22% reduction in relative risk of all-cause mortality in patients with HF and AF (RR: 0.78; 95% CI 0.71-0.86; p < 0.00001; I2 = 27%). The pooled analysis of 5 studies reporting the outcome of HF hospitalization (2774 patients) showed that BB therapy was not associated with a reduction of HF hospitalizations (RR: 0.94; 95% CI 0.79-1.11; p = 0.46; I2 = 38%). CONCLUSION: Our meta-analysis suggests the potential mortality benefit of BB in patients with HF and AF. We conclude that it is premature to deny patients with AF and HF BB therapy considering current evidence. PMID- 30009374 TI - Schoolteachers as candidates to be basic life support trainers: A simulation trial. AB - BACKGROUND: The aim was to assess future schoolteachers' basic life support (BLS) knowledge and willingness to include this content in school lessons. The aim was also to determine the learning effect of a brief BLS hands-on training session, supported by real-time feedback. METHODS: A convenience sample of 98 University students of Educational Sciences and Sports were recruited. The training program consisted of brief theoretical and hands-on interactive sessions with a 2/10 instructor/participants ratio. Knowledge and willingness was assessed by means of a survey. Chest compressions (CC) and ventilation quality were registered in 47 cases during 1 min cardiopulmonary resuscitation (CPR) tests. RESULTS: Fifty eight percent of subjects declared to know how to perform CPR, 62% knew the correct chest compression/ventilation ratio but only one in four knew the CC quality standards. Eighty-eight percent knew what an automated external defibrillator (AED) was; willingness to use the device improved from 70% to 98% after training. Almost half of CCs were performed atan adequate rate. Men performed deeper compressions than women ( 56.1 +/- 4.03 mm vs. 52.17 +/- 5.51 mm, p = 0.007), but in both cases the mean value was within recommendations. Full chest recoil was better in women (72.2 +/- 32.8% vs. 45.4 +/- 32.9%, p = 0.009). All CCs were delivered with correct hand positions. CONCLUSIONS: Brief hands-on training supported by real-time feedback of CPR quality helps future schoolteachers improve their knowledge, self-confidence and CPR skills. BLS training should be implemented in University curricula for schoolteachers in order to promote their engagement in effective BLS training of schoolchildren. PMID- 30009375 TI - Effect of intracoronary adenosine on ergonovine-induced vasoconstricted coronary arteries. AB - BACKGROUND: This study aimed to evaluate the effect of adenosine on epicardial coronary artery diameter during ergonovine provocation testing. METHODS: A total of 158 patients who underwent an ergonovine provocation test with intracoronary adenosine injection between 2011 and 2014 were selected. Patients were divided into four groups based on the severity of percent diameter stenosis following intracoronary ergonovine administration: Group 1, induced spasm < 50%; Group 2, 50-89%; Group 3, 90-99%; and Group 4, total occlusion. RESULTS: Spasm positivity was observed in 44 (27.8%) cases in the study population (mean age, 57.4 +/- 10.7 years). Intracoronary adenosine increased the diameter of the ergonovine-induced epicardial artery by 0.51 +/- 0.31 mm, 0.73 +/- 0.39 mm, 0.44 +/- 0.59 mm, and 0.01 +/- 0.04 mm in Groups 1, 2, 3, and 4, respectively. Subsequent administration of nitroglycerin further increased vessel diameter by 0.49 +/- 0.28 mm, 0.93 +/- 0.68 mm, 2.11 +/- 1.25 mm, and 2.23 +/- 0.69 mm in Groups 1, 2, 3, and 4, respectively. The ratios of adenosine-induced diameter to reference diameter were significantly lower in patients with spasm positive results (0.68 [0.59-0.76] vs. 0.18 [0.00-0.41], p < 0.001 in the study population; 0.60 [0.54 0.67] vs. 0.40 [0.27-0.44], p < 0.001 in Group 2) with the best cut-off value of 0.505 (sensitivity 0.955, specificity 0.921). CONCLUSIONS: Intracoronary administration of adenosine dilated the ergonovine-induced vasoconstricted epicardial coronary artery. The ratio of adenosine-induced diameter to reference diameter was significantly lower in patients with spasm positive results. PMID- 30009376 TI - Two-year prognostic value of mean platelet volume in patients with diabetes and stable coronary artery disease undergoing elective percutaneous coronary intervention. AB - BACKGROUND: Mean platelet volume (MPV) is a marker of platelet size and activity, and is associated with a poor prognosis of cardiovascular disease. Studies have shown a relationship between diabetes mellitus (DM) and MPV. This study examined the relationship between admission MPV and 2-year cardiac mortality in patients with DM and stable coronary artery disease (SCAD) undergoing elective percutaneous coronary intervention (PCI). METHODS: A total of 1389 patients were enrolled and divided into two groups according to MPV as follows: lower MPV (n = 908, MPV <= 10.9 fL) and higher MPV (n = 481, MPV > 10.9 fL). RESULTS: Body mass index, platelet distribution width, MPV/platelet and glycated hemoglobin (HbA1c) levels were significantly higher in the higher MPV group compared with the lower MPV group (all p < 0.05). The platelet count was significantly lower in the higher MPV group compared with the lower MPV group (p < 0.05). MPV was positively associated with HbA1c and fasting plasma glucose levels (r = 0.073 and 0.061, p = 0.007 and 0.023, respectively) in bivariate correlation analysis. The 2-year cardiac mortality rate was 0.7%, and was significantly lower in the lower MPV group than in the higher MPV group in Kaplan-Meier analysis (p = 0.019). Receiver operating characteristic analysis showed a good diagnostic value for MPV at predicting long-term cardiac mortality (area under the curve: 0.735, 95% confidence interval [CI]: 0.590-0.880, p = 0.01). Elevated MPV was a significant risk factor for 2-year cardiac mortality (hazard ratio [HR]: 2.091, 95% CI: 1.075 4.070, p = 0.030) in multivariable Cox regression analysis. CONCLUSIONS: MPV is a strong, independent prognostic factor in PCI-treated patients with DM and SCAD. PMID- 30009377 TI - Fragmented endocardial signals and early afterdepolarizations during torsades de pointes tachycardia. AB - BACKGROUND: Bradycardia-induced torsade de pointes (TdP) tachycardia in patients with spontaneous high-degree atrioventricular block (AVB) is common. The aim of this study was to analyze endocardial recordings during TdP in spontaneous high degree AVB in humans to better understand the electrophysiological mechanisms underlying this phenomenon. METHODS: The study group consisted of 5 patients with typical episodes of TdP during spontaneous high-degree AVB. A standard (USCI) temporary bipolar endocardial catheter positioned at the apex of the right ventricle (RV) and bipolar chest leads from two precordial leads V1 and V4 were used to record the tracings during TdP. RESULTS: The presence of a wide spectrum of fragmentations was noted on endocardial electrograms (EGMs), which were invisible on the surface electrocardiogram (ECG) tracing. Endocardial signals indicated that TdP started in the proximity of the right ventricular apex, since the local EGM began prior to the QRS complex on the surface ECG. Early afterdepolarizations (EADs) were observed in 2 out of 5 cases confirming a common opinion about the mechanism of TdP. However, this phenomenon was not observed in 3 other patients suggesting that the arrhythmia was the result of a different mechanism originating in proximity to the RV apex. CONCLUSIONS: This work demonstrated early endocardial signals in the RV apex during TdP associated with high-degree AVB in humans, and exhibits a spectrum of fragmented signals in this area occurring on a single or multiple beats. These fragmentations indicate areas of poor conduction and various degrees of intramyocardial block, and therefore a new mechanism of TdP tachycardia in some patients with spontaneous high-degree AVB. PMID- 30009378 TI - Effect of moderate-intensity statin therapy on plaque inflammation in patients with acute coronary syndrome: A prospective interventional study evaluated by 18F FDG PET/CT of the carotid artery. AB - BACKGROUND: Asian patients with acute coronary syndrome (ACS) are frequently prescribed moderate-intensity statin in real practice, even during the early stage of ACS. Under assessment herein was the effect of moderate-intensity statin therapy on the resolution of plaque inflammation during the first month after ACS, a period with highest recurrent ischemic events, using dual time point 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). METHODS: This prospective study included statin-naive patients with ACS and non calcified carotid plaques (3 3 mm on ultrasound images). Baseline FDG PET/CT images of the carotid arteries of the patients were obtained. Then, all patients received atorvastatin (20 mg/day); follow-up FDG PET/CT images of the carotid arteries were then obtained after 1 month of therapy. The primary endpoint measurement was the change in the target-to-background ratio (TBR) of the carotid artery between the initial and follow-up FDG PET/CT scans. RESULTS: Thirteen ACS patients completed the initial and follow-up FDG PET/CT scans. Moderate-intensity statin therapy failed to reduce plaque inflammation at 1 month after ACS (TBR 1.60 +/- 0.20 at baseline vs. 1.50 +/- 0.40 after therapy; p = 0.422) but significantly reduced serum low-density lipoprotein cholesterol (LDL-C) levels (mean LDL-C 101.2 +/- 21.1 mg/dL at baseline vs. 70.7 +/- 12.4 mg/dL after therapy; p < 0.001). Changes in the TBR and serum LDL-C levels were not correlated (r = -0.27, p = 0.243). CONCLUSIONS: Dual time point FDG PET/CT imaging demonstrates that moderate-intensity statin therapy was insufficient in suppressed plaque inflammation within the first month after ACS in Asian patients, even though achieving target LDL levels. PMID- 30009379 TI - Aortic stenosis and anemia with an update on approaches to managing angiodysplasia in 2018. AB - Angiodyplasia and aortic stenosis are both conditions that are highly prevalent in elderly people and can often co-exist. Recent studies suggest that this association is related to subtle alterations in plasma coagulation factors. The Von Willebrand factor is the strongest link between aortic stenosis and bleeding associated with gastrointestinal angiodysplasia. With an ageing population, the disease burden of aortic stenosis and its association with angiodysplasia of the bowel makes this an incredibly underdiagnosed yet important condition. Clinicians should be aware of this association when dealing with elderly patients presenting either with unexplained anemia, gastrointestinal bleeding or with aortic stenosis. A high index of suspicion and appropriate diagnostic techniques followed by appropriate and prompt treatment could be life-saving. No clear guidelines exist on management but surgical aortic valve replacement is thought to offer the best hope for long-term resolution of bleeding. With a growing number of technological armamentarium in the management of such patients, especially with the advent of transcatheter aortic valve implantation, new options can be offered even to elderly patients with comorbidities for whom conventional surgery would have been impossible. PMID- 30009380 TI - Association of CTLA-4 polymorphisms with increased risks of myasthenia gravis. AB - Myasthenia gravis (MG) is considered to be a kind of autoimmune disorder resulting from dysfunction of neuromuscular transmission caused by autoantibodies against the nicotinic acetylcholine receptors. A number of studies have identified Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) as a candidate gene for MG. Several recent reports have indicated that single nucleotide polymorphisms (SNPs) of CTLA-4, including rs733618, rs4553808, rs5742909, rs231775, and rs3087243 were associated with the risks of MG; however, the results were not consistent. To assess the correlations between CTLA-4 SNPs and MG susceptibility, a meta-analysis was performed following a series of database searching. A total of 1460 cases and 1652 controls from 12 studies were enrolled in the analysis. Our results indicated that rs231775 and rs733618 were associated with higher risks of MG, providing potential references for future case-control studies. PMID- 30009381 TI - Altered circadian rhythms and oscillation of clock genes and sirtuin 1 in a model of sudden unexpected death in epilepsy. AB - OBJECTIVES: Circadian rhythms are affected in many neurological disorders. Although sleep disturbances are known in epilepsy, data on circadian rhythm disturbances in epilepsy are sparse. Here, we examined diurnal and circadian rest activity and sleep-wake patterns in Kcna1-null mice, which exhibit spontaneous recurrent seizures and are a model of sudden unexpected death in epilepsy. Furthermore, we sought to determine whether seizures or aberrant oscillation of core clock genes and a regulator, sirtuin 1 (Sirt1), is associated with disrupted rhythms. METHODS: We used passive infrared actigraphy to assess rest-activity patterns, electroencephalography for seizure and sleep analysis, and reverse transcription polymerase chain reaction and Western blotting to evaluate expression of clock genes and Sirt1 in Kcna1-null and wild-type mice. RESULTS: Epileptic Kcna1-null animals have disrupted diurnal and circadian rest-activity patterns, tending to exhibit prolonged circadian periods. Electroencephalographic analysis confirmed disturbances in sleep architecture, with more time spent awake and less asleep. Although all epileptic mice manifested disrupted diurnal and circadian rest-activity patterns, we found no correlation between actual seizure burden and degree of sleep disruption. However, we found attenuated oscillations of several clock genes (ie, Clock, Bmal1, Per1, and Per2) and diurnal Sirt1 mRNA in the anterior hypothalamus. SIGNIFICANCE: Attenuated oscillation of several core clock genes correlates with, and may underlie, aberrant diurnal and circadian rest-activity and sleep-wake patterns observed in Kcna1-null mice. This could contribute to late complications in epilepsy, such as sudden unexpected death in epilepsy. Sirt1 may represent a useful therapeutic target for rescuing circadian clock gene rhythmicity and sleep patterns in epilepsy. PMID- 30009383 TI - Regeneration in the enteropneust hemichordate, Ptychodera flava, and its evolutionary implications. AB - Hemichordates are marine invertebrates that are closely related to chordates, but while their body plans are comparable to those of chordates, they possess a remarkable capacity for regeneration, even as adults. A small fragment is sufficient to form a complete individual. Unlike echinoderms, their larvae transform directly into adults; therefore, hemichordate systems offer clear morphological and molecular parallels between regeneration and development. Morphological events in regeneration are generally similar to organogenesis in juveniles. Nonetheless, comparative analysis of gene expression in these two morphological phenomena suggests that hemichordate regeneration is regulated by regeneration-specific mechanisms, as well as by developmental mechanisms. Dependency upon resident pluripotent/multipotent stem cells is a significant difference in metazoan regeneration, and such stem cells are essential for regeneration in many lineages. Based on the present gene expression study, regeneration in acorn worms is more closely related to that in vertebrates, because it employs endogenous stem cell-independent transdifferentiation. PMID- 30009382 TI - Porphyromonas gingivalis in the tongue biofilm is associated with clinical outcome in rheumatoid arthritis patients. AB - Several studies have suggested a link between human microbiome and rheumatoid arthritis (RA) development. Porphyromonas gingivalis seems involved in RA initiation and progression, as supported by the high occurrence of periodontitis. In this case-control study, we analysed tongue P. gingivalis presence and quantification in a large healthy and RA cohort. We enrolled 143 RA patients [male/female (M/F) 32/111, mean +/- standard deviation (s.d.), age 57.5 +/- 19.8 years, mean +/- s.d. disease duration 155.9 +/- 114.7 months); 36 periodontitis patients (M/F 11/25, mean +/- s.d., age 56 +/- 9.9 years, mean +/- s.d. disease duration 25.5 +/- 20.9 months); and 57 patients (M/F 12/45, mean +/- s.d., age 61.4 +/- 10.9 years, mean +/- s.d. disease duration 62.3 +/- 66.9 months) with knee osteoarthritis or fibromyalgia. All subjects underwent a standard cytological swab to identify the rate of P. gingivalis/total bacteria by using quantitative real-time polymerase chain reaction. The prevalence of P. gingivalis resulted similarly in RA and periodontitis patients (48.9 versus 52.7%, P = not significant). Moreover, the prevalence of this pathogen was significantly higher in RA and periodontitis patients in comparison with control subjects (P = 0.01 and P = 0.003, respectively). We found a significant correlation between P. gingivalis rate in total bacteria genomes and disease activity score in 28 joints (DAS28) (erythrocyte sedimentation rate) (r = 0.4, P = 0.01). RA patients in remission showed a significantly lower prevalence of P. gingivalis in comparison with non-remission (P = 0.02). We demonstrated a significant association between the percentage of P. gingivalis on the total tongue biofilm and RA disease activity (DAS28), suggesting that the oral cavity microbiological status could play a role in the pathogenic mechanisms of inflammation, leading to more active disease. PMID- 30009384 TI - Enhancing lactational performance of Holstein dairy cows under commercial production: malic acid as an option. AB - BACKGROUND: In Experiment 1 we studied the effect of malic acid addition at 0, 1, 2 and 3 mg g-1 dry matter (DM) feed on in vitro ruminal fermentation. In Experiment 2, the effect of supplementing malic acid on feed intake, digestion and milk production and composition of lactating cows was studied. 200 multiparous lactating Holstein dairy cows were randomly assigned to two treatments: a basal diet containing concentrate and roughage at 58:42, respectively, with no additive (control treatment) or supplemented with malic acid at 30 g per cow daily (malic treatment). RESULTS: In Experiment 1, malic acid inclusion at 3 mg g-1 DM decreased in vitro methane production by 33%. In Experiment 2, malic acid decreased (P < 0.01) nutrient intake and increased nutrient digestibility. Greater (P < 0.05) milk yields, energy-corrected milk yields and milk component yields were observed in cows supplemented with malic acid. Greater milk (feed) efficiency was observed with malic acid treatment compared with the control treatment. CONCLUSION: The results show that the inclusion of malic acid at 30 g daily in the diet of lactating cows enhanced the nutrient digestibility and increased the milk production as well as feed efficiency. (c) 2018 Society of Chemical Industry. PMID- 30009385 TI - Biosynthesis of Oxylipins by Rhizoctonia solani with Allene Oxide and Oleate 8S,9S-Diol Synthase Activities. AB - Oxylipin biosynthesis by fungi is catalyzed by both the lipoxygenase (LOX) family and the linoleate diol synthase (LDS) family of the peroxidase-cyclooxygenase superfamily. Rhizoctonia solani, a pathogenic fungus, infects staple crops such as potato and rice. The genome predicts three genes with 9-13 introns, which code for tentative dioxygenase (DOX)-cytochrome P450 fusion enzymes of the LDS family, and one gene, which might code for a 13-LOX. The objective was to determine whether mycelia or nitrogen powder of mycelia oxidized unsaturated C18 fatty acids to LDS- or LOX-related metabolites. Mycelia converted 18:2n-6 to 8R-hydroxy 9Z,12Z-octadecadienoic acid and to an alpha-ketol, 9S-hydroxy-10-oxo-12Z octadecenoic acid. In addition to these metabolites, nitrogen powder of mycelia oxidized 18:2n-6 to 9S-hydroperoxy-10E, 12Z-octadecadienoic, and 13S-hydroperoxy 9Z,11E-octadecadienoic acids; the latter was likely formed by the predicted 13 LOX. 18:1n-9 was transformed into 8S-hydroperoxy-9Z-octadecenoic and into 8S,9S dihydroxy-10E-octadecenoic acids, indicating the expression of 8,9-diol synthase. The allene oxide, 9S(10)epoxy-10,12Z-octadecadienoic acid, is unstable and decomposes rapidly to the alpha-ketol above, indicating biosynthesis by 9S-DOX allene oxide synthase. This allene oxide and alpha-ketol are also formed by potato stolons, which illustrates catalytic similarities between the plant host and fungal pathogen. PMID- 30009386 TI - Drug reaction with eosinophilia and systemic symptoms caused by spironolactone: Case report. PMID- 30009387 TI - GC-MS study of changes in polar/mid-polar and volatile compounds in Persian lime (Citrus latifolia) during fruit growth. AB - BACKGROUND: Citrus fruits possess a high content of bioactive compounds whose changes during fruit maturation have not been studied in depth. Fruits were sampled from week 1, after fruit onset (7 days after flowering), to week 14. Volatile compounds isolated by headspace-solid-phase microextraction and polar extracts from all samples were analyzed by gas chromatography-mass spectrometry. RESULTS: The relative abundance of 107 identified metabolites allowed differences among samples at different stages of fruit growth to be established. Principal component analysis showed a clear discrimination among samples, and analysis of variance revealed significant differences in 94 out of the 107 metabolites. Among total volatiles, monoterpenes increased their relative abundance from 86% to 94% during fruit growth, d-limonene, gamma-terpinene and beta-pinene being the most abundant; conversely, sesquiterpenes decreased from 11.5% to 2.8%, beta bisabolene and alpha-bergamotene being the most concentrated. Sugars, in general, exhibited a gradual increase in abundance, reaching a maximum between weeks 9 and 12. Citric and malic acids, representing approximately 90% of the total identified carboxylic acids, reached a maximum concentration at commercial maturity (week 14). CONCLUSION: Of the 107 tentatively identified metabolites during Persian lime growth, sugars, carboxylic acids, and volatiles were those that experienced more significant changes and more clearly created differences among fruit growth stages. (c) 2018 Society of Chemical Industry. PMID- 30009388 TI - Changes and degradation kinetics of some bioactive compounds in dried Orthosiphon aristatus (Java tea) leaves during elevated temperature storage. AB - BACKGROUND: Orthosiphon aristatus is a traditional medicinal herb mostly used in Southeast Asia and which has many health benefits. Packaging types and storage temperatures were investigated in order to select the best conditions for producing high bioactive compounds (BC) from two kinds of dried O. aristatus leaves. RESULTS: Blanched leaves were vacuum packed in polypropylene (PP) and aluminum foil laminated with polyethylene terephthalate and polyethylene (PET/Al/PE) and dried in a freeze dryer (B_FD) or heat pump-assisted dehumidified dryer (B_HPD60) at 60 degrees C prior to storage at 15, 25 and 35 degrees C for 6 months. Leaves in PET/Al/PE bags had higher total phenolic content (TPC), antioxidant activity (AOA) and BC than in PP bags (P <= 0.05). Storage at 15 degrees C retained the highest TPC and AOA in PET/Al/PE bags (P <= 0.05). The degradation kinetics for BC, sinensetin and eupatorin followed first-order kinetics. Half-lives (t1/2 ) for BC in PET/Al/PE were higher than in PP and were the highest at 15 degrees C for both packaging types. CONCLUSIONS: Low temperature and PET/Al/PE bags provided the highest bioactive compound retention. The dried leaves from B_HPD60 and packed in PET/Al/PE bags had higher resistance to degradation of sinensetin than B_FD in PP bags. (c) 2018 Society of Chemical Industry. PMID- 30009389 TI - NRH:quinone oxidoreductase 2 (NQO2) and glutaminase (GLS) both play a role in large extracellular vesicles (LEV) formation in preclinical LNCaP-C4-2B prostate cancer model of progressive metastasis. AB - In the course of studies aimed at the role of oxidative stress in the development of metastatic potential in the LNCaP-C4-2B prostate cancer progression model system, we found a relative decrease in the level of expression of the cytoplasmic nicotinamide riboside: quinone oxidoreductase (NQO2) and an increase in the oxidative stress in C4-2B cells compared to that in LNCaP or its derivatives C4 and C4-2. It was also found that C4-2B cells specifically shed large extracellular vesicles (LEVs) suggesting that these LEVs and their cargo could participate in the establishment of the osseous metastases. The level of expression of caveolin-1 increased as the system progresses from LNCaP to C4-2B. Since NQO2 RNA levels were not changed in LNCaP, C4, C4-2, and C4-2B, we tested an altered cellular distribution hypothesis of NQO2 being compartmentalized in the membrane fractions of C4-2B cells which are rich in lipid rafts and caveolae. This was confirmed when the detergent resistant membrane fractions were probed on immunoblots. Moreover, when the LEVs were analyzed for membrane associated caveolin-1 as possible cargo, we noticed that the enzyme NQO2 was also a component of the cargo along with caveolin-1 as seen in double immunofluorescence studies. Molecular modeling studies showed that a caveolin-1 accessible site is present in NQO2. Specific interaction between NQO2 and caveolin-1 was confirmed using deletion constructs of caveolin-1 fused with glutathione S-transferase (GST). Interestingly, whole cell lysate and mitochondrial preparations of LNCaP, C4, C4-2, and C4-2B showed an increasing expression of glutaminase (GLS, kidney type). The extrusion of LEVs appears to be a specific property of the bone metastatic C4-2B cells and this process could be inhibited by a GLS specific inhibitor BPTES, suggesting the critical role of a functioning glutamine metabolism. Our results indicate that a high level of expression of caveolin-1 in C4-2B cells contributes to an interaction between caveolin-1 and NQO2 and to their packaging as cargo in the shed LEVs. These results suggest an important role of membrane associated oxidoreductases in the establishment of osseous metastases in prostate cancer. PMID- 30009390 TI - Transcatheter aortic valve-in-valve implantation in failed stentless bioprostheses. AB - OBJECTIVE: To compare the safety and efficacy of transcathether aortic valve-in valve implantation (ViV-TAVI) in degenerated stentless bioprostheses with failed stented valves and degenerated native aortic valves. INTRODUCTION: Little is known about ViV-TAVI in degenerated stentless valves. METHODS: Out of 45 ViV-TAVI procedures reported in the POL-TAVI registry, 20 failed stentless valves were compared with 25 stented prostheses and propensity-matched with 45 native TAVI cases. The mean follow-up was 633 (95% confidence interval [CI], 471-795) days and Valve Academic Research Consortium-2 (VARC-2) definitions were applied. RESULTS: Patients with degenerated stentless valves were younger (65.6, CI 58 73.1 years vs 75.6, CI 72.2-78 [stented] vs 80.1, CI 78.7-81.6 y. [native], P < 0.001). Implantation was required later after surgery (11.5, CI 8-14.9 years) in the stentless cohort as compared with the stented one (6.2, CI 4.7-7.6 years, P = 0.006). ViV-TAVI in the stentless group was also associated with larger amount of contrast (211, CI 157-266 mL vs 135, CI 104-167 mL [stented] vs 132 (119-145) mL [native], P = 0.022). Using VARC-2 composite endpoints, ViV-TAVI in stentless prostheses was characterized by a lower device success (50% vs 76% in stented vs 88.9% in native TAVI, P < 0.001), but comparable early safety up to 30 days (73.7% vs 84% vs 81.8%, respectively, log-rank P = 0.667) and long-term clinical efficacy beyond 30 days (72.2% vs 72% vs 73.8%, respectively, log-rank P = 0.963). CONCLUSIONS: Despite technical challenges and a lower device success, ViV TAVI in stentless aortic bioprostheses achieves similar safety, efficacy, and functional improvement as in stented or degenerated native valves. PMID- 30009391 TI - Chronic ghrelin administration restores hippocampal long-term potentiation and ameliorates memory impairment in rat model of Alzheimer's disease. AB - Alzheimer's disease (AD), as a common age-related dementia, is a progressive manifestation of cognitive decline following synaptic failure resulted majorly by senile plaques composed of deposits of amyloid beta (Abeta). Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Here, we investigated the neuroprotective and therapeutic effects of intracerebroventricular (icv) ghrelin infusion for 2 weeks on passive avoidance learning (PAL), memory retention, and synaptic plasticity in the hippocampal dentate gyrus (DG) and CA1 of both normal rats and Abeta1-42-induced neurotoxicity in AD model. Male Wistar rats were evaluated for their passive memory performance using a shuttle box while some groups had already received Abeta1-42 and/or chronic ghrelin. Using field potential recording, the induction of short- and long-term potentiation (STP and LTP) was studied in DG granule cells along with the LTP changes in CA1 pyramidal neurons through stimulation of the medial perforant path (mPP) and Schaffer collaterals (SCs), respectively. Our results demonstrated that chronic ghrelin treatment not only improved memory processing and retrieval in normal rats during the PAL task, but also promoted memory retention and alleviated memory loss by amelioration of Abeta1-42-induced synaptic plasticity impairment in AD subjects through augmentation of field excitatory postsynaptic potential (fEPSP) slope that led to LTP restitution in both the mPP-DG and the CA3-CA1 synapses. Meanwhile, STP was not significantly changed, meaning that although ghrelin enhanced postsynaptic excitability in DG, it did not change presynaptic transmitter release significantly. This suggests the involvement of postsynaptic mechanisms in long term ghrelin-enhanced memory. In conclusion, it can be inferred that chronic ghrelin administration has an auspicious therapeutic value for impaired cognitive performance and memory deficits in AD-like neuropathology. PMID- 30009392 TI - Spectroscopic Fingerprints of Intermolecular H-Bonding Interactions in Carbon Nitride Model Compounds. AB - The effect of intermolecular H-bonding interactions on the local electronic structure of N-containing functional groups (amino group and pyridine-like N) that are characteristic of polymeric carbon nitride materials p-CN(H), a new class of metal-free organophotocatalysts, was investigated. Specifically, the melamine molecule, a building block of p-CN(H), was characterized by X-ray photoelectron (XPS) and near edge X-ray absorption fine structure (NEXAFS) spectroscopy. The molecule was studied as a noninteracting system in the gas phase and in the solid state within a H-bonded network. With the support of DFT simulations of the spectra, it was found that the H-bonds mainly affect the N 1s level of the amino group, leaving the N 1s level of the pyridine-like N mostly unperturbed. This is responsible for a reduction of the chemical shift between the two XPS N 1s levels relative to free melamine. Consequently, N K-edge NEXAFS resonances involving the amino N 1s level also shift to lower photon energies. Moreover, the solid-state absorption spectra showed significant modification/quenching of resonances related to transitions from the amino N 1s level to sigma* orbitals involving the NH2 termini. PMID- 30009393 TI - Quantification of hydrolyzed peptides and proteins by amino acid fluorescence. AB - Reliable quantification of peptides and proteins is essential for drug discovery. We report the successful development and validation of an accurate and broadly applicable high performance liquid chromatography hyphenated to fluorescence detector procedure for the quantitative determination of the aromatic amino acids tyrosine, phenylalanine, and tryptophan, without relying on derivatization chemistry. Using ion-pair chromatography, fluorescent amino acids were clearly separated within 10 minutes. The hydrolysis of peptides was performed under acidic and heated conditions to yield the monomeric building blocks. Various protecting agents were tested to ensure tryptophan stability. The presented analytical method accurately (>95%) quantifies all fluorescent residues. The power of the method was confirmed by correct quantification of protein reference standard to 98.6% over all fluorescence traces. The method allowed us to identify pre-analytical differences between the nominal and actual concentrations of 12 peptide solutions. Salt formation, weighing errors, and other pre-analytical pitfalls resulted in noteworthy differences of up to 85% between the indicated and actual concentration of peptide solutions, subsequently leading to false positive or negative interpretation of activity data. Finally, only one solution is needed to perform quantification as well as UV-purity tests and can further be used as stock solution for activity testing. PMID- 30009394 TI - The evolution of GRADE (part 1): Is there a theoretical and/or empirical basis for the GRADE framework? AB - RATIONALE, AIMS, AND OBJECTIVES: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework has been presented as the best method available for developing clinical recommendations. GRADE has undergone a series of modifications. Here, we present the first part of a three article series examining the evolution of GRADE. Our purpose is to explore if (and if so, how) GRADE provides: (1) a justification (ie, theoretical and/or empirical) for why the criteria/components under consideration in the system are included (and other factors excluded), as well as why some criteria/components where added/modified in the evolution process, (2) clear and functional (ie, how to operationalize them) definitions of the included criteria/components, and (3) instruction and justification for how all the criteria/components are to be integrated when determining a recommendation. In part 1 of the series, we examine the first two versions of GRADE. METHODS: Narrative review. RESULTS: The justification scheme that sustains GRADE is not articulated in the first two versions of the framework. Why some criteria/components were included, and others excluded, is not justified theoretically nor is empirical support provided to suggest that the framework as presented includes that which is needed to produce valid recommendations. The first two versions of GRADE show a lack of clear instruction on how to operationalize the criteria for assessing the quality of evidence and the components for making a recommendation (including how to integrate the criteria/components at each step), which leaves substantial room for judgement on the part of the user of GRADE for guideline development. CONCLUSIONS: This article revealed an absence of a justification (theoretical and/or empirical) to support important aspects of the GRADE framework, as well as a lack of clear instruction on how to operationalize the criteria and components in the framework. These issues limit one's ability to scientifically assess the appropriateness of GRADE for determining clinical recommendations. PMID- 30009395 TI - Diversity and population density of methanogens in the large intestine of pigs fed diets of different energy levels. AB - Marker gene analysis was performed to assess the effect of energy level on the diversity and population density of methanogens in pig fecal material. Crossbred pigs were fed high or low energy level diets, a high-energy (HE) diet that satisfied daily gain at 1.2 kg, and a low-energy (LE) diet with amount of 0.6 times of the HE diet. Growth performance and short-chain fatty acid in feces were examined. Diversity of methanogen was analyzed by the alpha-subunit of methyl coenzyme-M reductase gene (mcrA) clone library from fecal DNA. The DNA copy numbers of mcrA were quantified by real-time PCR. There was no difference in the concentration and composition of short-chain fatty acid between treatments. Differences in the mcrA clone library were observed between HE and LE treatments (p < 0.05). Ninety-five percent of cloned sequence affiliated genus Methanobrevibacter in the feces of the pig regardless of treatments. During the experimental period, no significant difference in the proportion of copy numbers of mcrA against that of 16S rRNA gene of total bacteria was observed between treatments. In conclusion, feeding energy level affected composition of methanogens in the large intestine of the pig, while population density of methanogen was not affected. PMID- 30009396 TI - Communicating health-Optimising young adults' engagement with health messages using social media: Study protocol. AB - BACKGROUND: Obesity is a global health problem. Understanding how to utilise social media (SM) as a platform for intervention and engagement with young adults (YAs) will help the practitioners to harness this media more effectively for obesity prevention. AIM: Communicating health (CH) aims to understand the use of SM by YAs, including Aboriginal YAs, and in doing so will improve the effectiveness of SM strategies to motivate, engage and retain YAs in interventions to reduce the risk of obesity, and identify and disseminate effective ways for health professionals to deliver obesity prevention interventions via SM. METHODS: The present study describes the theoretical framework and methodologies for the CH study, which is organised into four interrelated phases, each building on the outcomes of preceding phases. Phase 1 is a mixed methods approach to understand how YAs use SM to navigate their health issues, including healthy eating. Phase 2 utilises co-creation workshops where YAs and public health practitioners collaboratively generate healthy eating messages and communication strategies. Phase 3 evaluates these messages in a real world setting. Phase 4 is the translation phase where public health practitioners use outcomes from CH to inform future strategies and to develop tools for SM for use by stakeholders and the research community. DISCUSSION: The outcomes will include a rich understanding of psychosocial drivers and behaviours associated with healthy eating and will provide insight into the use of SM to reach and influence the health and eating behaviours of YAs. PMID- 30009397 TI - How a growing organismal perspective is adding new depth to integrative studies of morphological evolution. AB - Over the past half century, the field of Evolutionary Developmental Biology, or Evo-devo, has integrated diverse fields of biology into a more synthetic understanding of morphological diversity. This has resulted in numerous insights into how development can evolve and reciprocally influence morphological evolution, as well as generated several novel theoretical areas. Although comparative by default, there remains a great gap in our understanding of adaptive morphological diversification and how developmental mechanisms influence the shape and pattern of phenotypic variation. Herein we highlight areas of research that are in the process of filling this void, and areas, if investigated more fully, that will add new insights into the diversification of morphology. At the centre of our discussion is an explicit awareness of organismal biology. Here we discuss an organismal framework that is supported by three distinct pillars. First, there is a need for Evo-devo to adopt a high-resolution phylogenetic approach in the study of morphological variation and its developmental underpinnings. Secondly, we propose that to understand the dynamic nature of morphological evolution, investigators need to give more explicit attention to the processes that generate evolutionarily relevant variation at the population level. Finally, we emphasize the need to address more thoroughly the processes that structure variation at micro- and macroevolutionary scales including modularity, morphological integration, constraint, and plasticity. We illustrate the power of these three pillars using numerous examples from both invertebrates and vertebrates to emphasize that many of these approaches are already present within the field, but have yet to be formally integrated into many research programs. We feel that the most exciting new insights will come where the traditional experimental approaches to Evo-devo are integrated more thoroughly with the principles of this organismal framework. PMID- 30009398 TI - WONOEP APPRAISAL: The many facets of epilepsy networks. AB - The brain is a complex system composed of networks of interacting elements, from genes to circuits, whose function (and dysfunction) is not derivable from the superposition of individual components. Epilepsy is frequently described as a network disease, but to date, there is no standardized framework within which network concepts applicable to all levels from genes to whole brain can be used to generate deeper insights into the pathogenesis of seizures or the associated morbidities. To address this shortcoming, the Neurobiology Commission of the International League Against Epilepsy dedicated a Workshop on Neurobiology of Epilepsy (XIV WONOEP 2017) with the aim of formalizing network concepts as they apply to epilepsy and to critically discuss whether and how such concepts could augment current research endeavors. Here, we review concepts and strategies derived by considering epilepsy as a disease of different network hierarchies that range from genes to clinical phenotypes. We propose that the concept of networks is important for understanding epilepsy and is critical for developing new study designs. These approaches could ultimately facilitate the development of novel diagnostic and therapeutic strategies. PMID- 30009400 TI - Effects of alpha-, beta- and maltosyl-beta-cyclodextrins use on the glucoraphanin sulforaphane system of broccoli juice. AB - Cyclodextrins (CDs) are macromolecules with several industrial applications, being particularly used in the food industry as health-promoting compounds protection agents, as flavour stabilizers, or to eliminate undesired tastes and browning reactions, among others. This study shows the effects of alpha- (10, 30 and 40 mmol L-1 ), beta- (3, 6 and 10 mmol L-1 ) and maltosyl-beta-CDs (30, 60 and 90 mmol L-1 ) use on the health-promoting glucoraphanin-sulforaphane system of a broccoli juice up to 24 h at 22 degrees C. Maltosyl-beta-CD (90 mmol L-1 ) highly retained glucoraphanin content after 24 h at 22 degrees C, showing better effectiveness than beta-CD (10 mmol L-1 ). Sulforaphane was efficiently encapsulated with beta-CD at just 3 mmol L-1 , and the sulforaphane formed was stable during 3 h at 22 degrees C. On the other hand, 40 mmol L-1 alpha-CD retained a high glucoraphanin content in broccoli juice. In contrast, glucoraphanin levels in juice without CDs decreased by 71% after 24 h. Consequently, CDs addition may potentially preserve glucoraphanin in this broccoli juice during industrial processing with the possibility to be later transformed by endogenous myrosinase after ingestion to the health-promoting sulforaphane. (c) 2018 Society of Chemical Industry. PMID- 30009399 TI - S100A10, a novel biomarker in pancreatic ductal adenocarcinoma. AB - Pancreatic cancer is arguably the deadliest cancer type. The efficacy of current therapies is often hindered by the inability to predict patient outcome. As such, the development of tools for early detection and risk prediction is key for improving outcome and quality of life. Here, we introduce the plasminogen receptor S100A10 as a novel predictive biomarker and a driver of pancreatic tumor growth and invasion. We demonstrated that S100A10 mRNA and protein are overexpressed in human pancreatic tumors compared to normal ducts and nonductal stroma. S100A10 mRNA and methylation status were predictive of overall survival and recurrence-free survival across multiple patient cohorts. S100A10 expression was driven by promoter methylation and the oncogene KRAS. S100A10 knockdown reduced surface plasminogen activation, invasiveness, and in vivo growth of pancreatic cancer cell lines. These findings delineate the clinical and functional contribution of S100A10 as a biomarker in pancreatic cancer. PMID- 30009401 TI - Wernicke-Korsakoff Syndrome in End-Stage Renal Disease: A Case Report. PMID- 30009402 TI - Catalytic Transformation of Lignocellulosic Biomass into Arenes, 5 Hydroxymethylfurfural, and Furfural. AB - The complete transformation of lignocellulosic biomass into valuable platform chemicals is of great significance. Herein, a catalytic process for the upgrading of lignocellulose to arenes, 5-hydroxymethylfurfural (HMF), and furfural is reported. Firstly, the lignin fraction in lignocellulosic biomass is selectively converted into lignin oil (82.9 mol % yield of lignin monomers from birch wood) over a Pd/C catalyst and then further hydrodeoxygenated to arenes in catalytic hydrogen-transfer reactions over a Ru/Nb2 O5 catalyst. High yields of C7 -C9 hydrocarbons (95.6 mol %) with 85.6 wt % selectivity to arenes based on lignin oil are achieved owing to the synergistic effect between Ru and Nb2 O5 , which enables direct hydrogenolysis of the Caromatic -OH bond in phenolics. Secondly, the cellulose and hemicellulose fractions in the Pd/C-containing solid residue, as well as methylated C5 sugars produced during the stripping of lignin, are converted into HMF and furfural with a total yield of up to 24.5 wt % (based on the amount of birch wood) in a THF/concentrated seawater (ca. 30 wt % salts) biphasic reaction system. Here, seawater played a key role in the conversion of cellulose and hemicellulose into HMF and furfural, respectively; more importantly, it made the separation and reuse of the Pd/C catalyst easier. With this catalytic process, the complete and efficient transformation of lignocellulose into highly value-added products with recycling of each catalyst and solvent has been realized. PMID- 30009403 TI - In Memoriam: Herbert Kaplan, MD, 1929-2018. PMID- 30009405 TI - Identifying New Clotting Factor XIa Inhibitors in Virtual High-Throughput Screens Using PCA-GA-SVM Models and Signature. AB - Blood Clotting Factor XI is an important actor in the clotting mechanism: it activates downstream zymogen involved in the clotting process. It can be targeted for activation or inhibition depending on treatment goals to enhance or inhibit clotting. In terms of antithrombosis treatment, Factor XI has emerged as a promising target to focus on. In this work, an iterative virtual high-throughput screening pipeline was proposed that can supplement current efforts to find inhibitors. The first iteration identified 11 compounds to test with 3 active for a hit-rate of 27.3%. The second iteration of the pipeline identified another 11 compounds to test with 7 active for a hit-rate of 63.6%. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30009404 TI - Interventricular differences in sodium current and its potential role in Brugada syndrome. AB - Brugada syndrome (BrS) is an inherited disease associated with ST elevation in the right precordial leads, polymorphic ventricular tachycardia (PVT), and sudden cardiac death in adults. Mutations in the cardiac sodium channel account for a large fraction of BrS cases. BrS manifests in the right ventricle (RV), which led us to examine the biophysical and molecular properties of sodium channel in myocytes isolated from the left (LV) and right ventricle. Patch clamp was used to record sodium current (INa ) in single canine RV and LV epicardial (epi) and endocardial (endo) myocytes. Action potentials were recorded from multicellular preparations and single cells. mRNA and proteins were determined using quantitative RT-PCR and Western blot. Although LV wedge preparations were thicker than RV wedges, transmural ECG recordings showed no difference in the width of the QRS complex or transmural conduction time. Action potential characteristics showed RV epi and endo had a lower Vmax compared with LV epi and endo cells. Peak INa density was significantly lower in epi and endo RV cells compared with epi and endo LV cells. Recovery from inactivation of INa in RV cells was slightly faster and half maximal steady-state inactivation was more positive. beta2 and beta4 mRNA was detected at very low levels in both ventricles, which was confirmed at the protein level. Our observations demonstrate that Vmax and Na+ current are smaller in RV, presumably due to differential Nav 1.5/beta subunit expression. These results provide a potential mechanism for the right ventricular manifestation of BrS. PMID- 30009408 TI - From Indium-Doped Ag2 S to AgInS2 Nanocrystals: Low-Temperature In Situ Conversion of Colloidal Ag2 S Nanoparticles and Their NIR Fluorescence. AB - Focusing on ternary I-III-VI2 colloidal nanocrystals (NCs) synthesized with precise control of the composition (from doping to ternary composition) and NIR fluorescence performance, monodisperse binary In3+ -doped Ag2 S NCs and ternary AgInS2 NCs have been achieved successfully by facile low-temperature in situ conversion of colloidal Ag2 S nanoparticles. In3+ ions were inserted into the crystal lattice of Ag2 S NCs at a relatively low temperature as dopant and ternary AgInS2 NCs were obtained at a higher temperature following a phase transition. These doped Ag2 S and AgInS2 NCs based on different indium precursor concentrations were explored with respect to the position and intensity of the near-infrared photoluminescent emission at different doping levels and crystal phase evolution. PMID- 30009409 TI - Evaluation of the performance of Illumina's ForenSeqTM system on serially degraded samples. AB - The use of next generation sequencing is increasing in the field of forensic genomics. This study assesses the performance of Illumina's MiSeq FGx System in the recovery of forensic genomic sequencing information from degraded and low template DNA. The analysis involved a sensitivity study where a range of 1 ng to 5 pg of 2800M DNA was utilized. DNA was artificially and systematically degraded by incubating 2800 M DNA at 98 degrees C for 10, 20, 30, 40, 50, 60, 70, 120 and 180 min (resulting in degradation index values ranging from 0.837 to 232.247). The results revealed the detected allele call frequencies were greater than 80% when the DNA input was > = 50 pg or the degradation index was lower than 72.28. The allele balance was lower than 0.6 when the samples were heated for more than 120 min or the input quantity was less than 25 pg. Our data also indicated that the stutter type and ratio depend on the specific locus, while the sequencing run was the most significant factor in noise occurrence. The results of this study will help laboratories to develop workflows for the analysis of challenging samples using the ForenSeq FGx system. PMID- 30009406 TI - Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia. AB - BACKGROUND: Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. METHODS: Nod SCID gamma mice (n = 6-10) were injected intraperitoneally with 1 * 107 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. RESULTS: In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (-12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 +/- 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour bearing mice (approximately -35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (-34%, P < 0.01) and muscle weakness (-50%, P < 0.001). Body composition assessment by dual energy X-ray absorptiometry revealed decreased bone mineral density (-8%, P < 0.01) and bone mineral content (-19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho AKT (-44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (-16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. CONCLUSIONS: Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC. PMID- 30009410 TI - The POMONA-ESP project methodology: Collecting data on health indicators for people with intellectual developmental disorders. AB - BACKGROUND: People with intellectual developmental disorders have significant health disparities and a lack of proper attention to their health needs. They have been underrepresented in scientific research, and very few studies have been carried out using a representative randomized sample. The aim of this study was to describe the methods used in the POMONA-ESP project to recruit a representative and randomized sample of participants with intellectual developmental disorders. METHODS: The POMONA-ESP project is an observational cross-sectional study. It aims to explore the health status of people with intellectual developmental disorders across Spain and the use they make of health services. RESULTS AND CONCLUSIONS: The results of the POMONA-ESP project may have a major impact on people with intellectual developmental disorders and society in general. It is the first study to obtain geographically representative epidemiological data from a large sample, information that is fundamental to improving care and healthcare planning for people with intellectual developmental disorders. PMID- 30009411 TI - Fatal correlation between YAP1 expression and glioma aggressiveness: clinical and molecular evidence. AB - During the last decade, large-scale genomic analyses have clarified the somatic alterations in gliomas, providing new molecular classification based on IDH1/2 mutations and 1p19q codeletion with more accurate patient prognostication. The Hippo pathway downstream effectors, YAP1 and TAZ, have recently emerged as major determinants of malignancy by inducing proliferation, chemoresistance, and metastasis in solid tumors. In this study, we investigated the expression of YAP1 in 117 clinical samples of glioma described according to the WHO 2016 classification. We showed for the first time that YAP1 was tightly associated with glioma molecular subtypes and patient outcome. We validated our results in an independent cohort from the TCGA database. More interestingly, we found that YAP1 may have prognostic significance for predicting patient survival, especially in low-grade gliomas. Using patient-derived glioblastoma stem cell cultures, we demonstrated that YAP1 was activated and that it controlled cell proliferation. Transcriptome analysis revealed lower expression of YAP1 in the proneural GBM subtype. Furthermore, we found that overexpression of YAP1 was sufficient to inhibit the OLIG2 proneural marker, suggesting its involvement in maintenance of the GBM phenotype. Taken together, our results showed that YAP1 could be a relevant prognostic biomarker and a potential therapeutic target in glioma. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30009412 TI - Older adults' dependence in activities of daily living: Implications for oral health. AB - OBJECTIVE: To assess the relationship between ADL and oral health status in older adults. DESIGN AND SAMPLE: Quantitative, analytical, cross-sectional research with 280 people aged >=60 in public primary health care centers in the city of Fortaleza, Northeastern Brazil. MEASURES: Collection of sociodemographic data, oral discomfort data, and general health data and application of the Community Oral Health Indicator-COHI and the activities of daily living scale. RESULTS: Significant differences in functional dependence were found between age groups (p < .001), incomes (p = .034), and levels of education (p = .003). Tooth loss (OR = 2.13; p = 0.025), having no teeth (OR = 2.97), difficulties in chewing and swallowing food (OR = 2.56; p = 0.003), problems with taste of food (OR = 2.06; p = .044), poor self-rated general health (OR = 3.7; p = .001), hearing problems (OR = 2.23; p = .009) and speech problems (OR = 3.15; p = .002) increased chances for functional dependence. Dependent individuals were less likely to use toothpaste, thereby increasing the potential for caries (p = .013). Age 80 or older (p < .001), ages 70-79 (p < .001), three or more visible dental cavities (p = .030) and difficulty chewing and swallowing food (p = .027) remained associated with dependence in ADL in the logistic regression model. CONCLUSION: Functional dependence in activities of daily living has implications for the oral health status of older people. PMID- 30009414 TI - Synaptic Device Network Architecture with Feature Extraction for Unsupervised Image Classification. AB - For the efficient recognition and classification of numerous images, neuroinspired deep learning algorithms have demonstrated their substantial performance. Nevertheless, current deep learning algorithms that are performed on von Neumann machines face significant limitations due to their inherent inefficient energy consumption. Thus, alternative approaches (i.e., neuromorphic systems) are expected to provide more energy-efficient computing units. However, the implementation of the neuromorphic system is still challenging due to the uncertain impacts of synaptic device specifications on system performance. Moreover, only few studies are reported how to implement feature extraction algorithms on the neuromorphic system. Here, a synaptic device network architecture with a feature extraction algorithm inspired by the convolutional neural network is demonstrated. Its pattern recognition efficacy is validated using a device-to-system level simulation. The network can classify handwritten digits at up to a 90% recognition rate despite using fewer synaptic devices than the architecture without feature extraction. PMID- 30009415 TI - Indirect and direct measures of striving for perfection moderate body mass index curves in the intensive treatment of anorexia nervosa. PMID- 30009413 TI - Piezotronics in Photo-Electrochemistry. AB - Photo-electrochemistry is the major trajectory for directly transforming solar energy into chemical compounds. The performance of a photo-electrochemical (PEC) system is directly related to the interfacial electrical band energy landscape. Recently, piezotronics has stood out as a promising strategy for tuning interfacial energetics. It applies intrinsic or deformation-induced ionic displacements (ferroelectric and piezoelectric polarizations) to engineer the interfacial charge distribution, and thereby the band structures of PEC electrodes. Here, contemporary research efforts of coupling piezotronics with photo-electrochemisty are reviewed. Quantitative band diagrams of a polarization tuned semiconductor-electrolyte junction are first introduced, with an emphasis on the impact of interface chemistry. Experimental advances of employing piezoelectric and ferroelectric polarizations to enhance the charge separation and transportation, and surface kinetics of PEC water splitting are discussed. Finally, critical challenges of applying piezotronics in PEC systems and promising solutions are presented. PMID- 30009416 TI - beta-hydroxy-beta-methyl butyrate promotes leucine metabolism and improves muscle fibre composition in growing pigs. AB - The aim of this study was to investigate the effects of excess leucine (Leu) vs. its metabolites alpha-ketoisocaproate (KIC) and beta-hydroxy-beta-methyl butyrate (HMB) on Leu metabolism, muscle fibre composition and muscle growth in growing pigs. Thirty-two pigs with a similar initial weight (9.55 +/- 0.19 kg) were fed 1 of 4 diets for 45 days: basal diet, basal diet + 1.25% L-Leu, basal diet + 1.25% KIC-Ca, basal diet + 0.62% HMB-Ca. Results indicated that relative to the basal diet and HMB groups, Leu and KIC groups exhibited increased Leu concentrations and decreased concentrations of isoleucine, valine and EAAs in selected muscle (p < 0.05) and had lower mRNA levels of MyHC I and higher expression of MyHC IIx/IIb (p < 0.05), and there was no significant difference between the basal and HMB supplemented groups. Moreover, the mRNA expression levels of AMPKalpha and UCP3 were higher but the myostatin mRNA levels were lower in the soleus muscle of the HMB group than those from other groups (p < 0.05). These findings demonstrated that doubling dietary Leu content exerted growth-depressing effects in growing pigs; dietary KIC supplementation induced muscular branched-chain amino acid imbalance and promoted muscle toward a more glycolytic phenotype; while dietary HMB supplementation promoted the generation of more oxidative muscle types and increased muscle growth specially in oxidative skeletal muscle, and these effects of HMB might be associated with the AMPKalpha-Sirt1-PGC-1alpha axis and mitochondrial biogenesis. PMID- 30009417 TI - Therapeutic Effects of a TANK-Binding Kinase 1 Inhibitor in Germinal Center Driven Collagen-Induced Arthritis. AB - OBJECTIVE: The production of class-switched high-affinity autoantibodies derived from organized germinal centers (GCs) is a hallmark of many autoimmune inflammatory diseases, including rheumatoid arthritis (RA). TANK-binding kinase 1 (TBK-1) is a serine/threonine kinase involved in the maturation of GC follicular helper T (Tfh) cells downstream of inducible costimulator signaling. We undertook this study to assess the therapeutic potential of TBK-1 inhibition using the small-molecule inhibitor WEHI-112 in antibody-dependent models of inflammatory arthritis. METHODS: Using the models of collagen-induced arthritis (CIA), antigen induced arthritis (AIA), and K/BxN serum-transfer-induced arthritis (STIA), we determined the effectiveness of WEHI-112 at inhibiting clinical and histologic features of arthritis in C57BL/6 and DBA/1 mice. We used immunohistochemistry to characterize GC populations during CIA development, and we used enzyme-linked immunosorbent assays to determine levels of Ig autoantibodies in WEHI-112-treated mice compared to vehicle-treated mice. RESULTS: WEHI-112, a tool compound that is semiselective for TBK-1 but that also has activity against IKKepsilon and JAK2, abolished TBK-1-dependent activation of interferon (IFN) regulatory factor 3 and inhibited type I IFN responses in vitro. In vivo, treatment with WEHI-112 selectively abrogated clinical and histologic features of established, antibody dependent CIA, but had minimal effects on an antibody-independent model of AIA or on K/BxN STIA. In keeping with these findings, WEHI-112 reduced arthritogenic type II collagen-specific IgG1 and IgG2b antibody production. Furthermore, WEHI 112 altered the GC Tfh cell phenotype and GC B cell function in CIA. CONCLUSION: We report that TBK-1 inhibition using WEHI-112 abrogated antibody-dependent CIA. As WEHI-112 failed to inhibit non-antibody-driven joint inflammation, we conclude that the major effect of this compound was most likely the targeting of TBK-1 mediated mechanisms in the GC reaction. This approach may have therapeutic potential in RA and in other GC-associated autoantibody-driven inflammatory diseases. PMID- 30009418 TI - Isoproterenol-induced cardiac ischemia and fibrosis: Plant-based approaches for intervention. AB - Heart is the most active and incumbent organ of the body, which maintains blood flow, but due to various pathological reasons, several acute and chronic cardiac complications arise out of which myocardial infarction is one of the teething problems. Isoproterenol (ISP)-induced myocardial ischemia is a classical model to screen the cardioprotective effects of various pharmacological interventions. Phytochemicals present a novel option for treating various human maladies including those of the heart. A large number of plant products and their active ingredients have been screened for efficacy in ameliorating ISP-induced myocardial ischemia including coriander, curcumin, Momordica, quercetin, and Withania somnifera. These phytochemicals constituents may play key role in preventing disease and help in cardiac remodeling. Reactive oxygen species scavenging, antiinflammatory, and modulation of various molecular pathways such as Nrf2, NFkB, p-21 activated kinase 1 (PAK1), and p-smad2/3 signaling modulation have been implicated behind the claimed protection. In this review, we have provided a focused overview on the utility of ISP-induced cardiotoxicity, myocardial ischemia, and cardiac fibrosis for preclinical research. In addition, we have also surveyed molecular mechanism of various plant-based interventions screened for cardioprotective effect in ISP-induced cardiotoxicity, and their probable mechanistic profile is summarized. PMID- 30009419 TI - Redefine the role of range shifter in treating bilateral head and neck cancer in the era of Intensity Modulated Proton Therapy. PMID- 30009420 TI - Highly concentrated omega-3 fatty acid ethyl esters by urea complexation and molecular distillation. AB - BACKGROUND: Raya liver deodorized oil contains high concentrations of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). The present study investigated the processes of urea complexation (UC) and molecular distillation (MD) to determine the most adequate operation conditions for each process, separately and together, aiming to obtain highly concentrated EPA, DPA and DHA ethyl esters with chemical indicator values permitted by the current legislation for edible oils. RESULTS: In the second stage of MD, a concentration of 820.27 g kg-1 in the distillate and 951.06 g kg-1 of omega-3 fatty acid ethyl esters in the residue was obtained. The distillate showed values of free fatty acids, peroxide and p-anisidine lower than the maximum allowed for edible oils in accordance with the current legislation. CONCLUSION: The use of UC and MD together has revealed a significant improvement in the total concentration of omega-3 fatty acid ethyl esters in the final product and good application prospects. (c) 2018 Society of Chemical Industry. PMID- 30009421 TI - Consequence of Elevated Fibroblast Growth Factor 23 Levels in Acute Kidney Injury, Renal Recovery and Overall Survival in Intensive Care Unit Patients After Major Surgery. AB - The main goal of our study was to investigate the role of increased fibroblast growth factor 23 (FGF23) levels on renal recovery and overall survival. We conducted a prospective case-control cohort study, which included 121 adult cases who developed AKI after major surgical procedures. The subjects were followed-up until the last enrolled patient survived 180 days or until the time of death. Higher FGF23 levels positively correlated with serum creatinine levels (P < 0.05). Significantly higher number of patients without diuresis and with FGF23 <= 709 RU/mL survived when compared to patients without diuresis and with FGF23 >= 709 RU/mL (P < 0.001). FGF23 levels >709 RU/mL were a good predictive tool for overall mortality in a 6-month period (P < 0.05). This is the first study to analyze the impact of FGF23 values on short-term renal recovery and survival of patients with AKI after major surgery. The FGF23 increase related to AKI especially in more severe stages and in patients without diuresis is an independent risk factor for mortality. PMID- 30009422 TI - A working definition of white-coat hypertension must include nocturnal blood pressure. PMID- 30009423 TI - Individual differences in the effectiveness of self-distancing for young children's emotion regulation. AB - Self-distancing has been shown to improve children's self-regulation in a variety of tasks. However, it is unknown whether this strategy is more effective for some children than others. This study investigated self-distancing in relation to individual differences in executive function (EF) and effortful control (EC). Typically developing 4- (n = 72) and 6-year-olds (n = 67) were randomly assigned to think about the self from one of four perspectives: self-immersed, control, third-person, or competent media character. Children participated in a frustrating task for up to 10 min and overt expressions of frustration were coded. Conceptually replicating prior research with adults, younger children, and children with lower EF and lower EC (independent of age) benefitted the most from self-distancing. This suggests self-distancing is especially effective during a frustrating task for children with less developed self-control, adding to a growing body of research showing self-distancing is especially effective for vulnerable individuals. Statement of contribution What is already known on this subject? Using third-person speech and pretending to be a media character improve children's self-regulation. Age and theory of mind skills are related to the effectiveness of self-distancing. What does this study add? Self-distancing can help children regulate their emotions during an emotionally charged task. Individual differences in executive function and effortful control are related to the efficacy of self-distancing. PMID- 30009424 TI - Rituximab maintenance improves overall survival in follicular lymphoma: A retrospective nationwide real-world analysis from Taiwan Cancer Registry Database. AB - Follicular lymphoma (FL) is the most frequent indolent lymphoma in Western countries, but it is less frequent in Asia. Several trials have demonstrated the progression-free benefit of rituximab maintenance for FL patients in Western countries. However, the overall survival (OS) benefits and effectiveness of rituximab maintenance in Asian FL patients remain uncertain. We utilized the Taiwan Cancer Registry Database and the National Health Insurance Research Database to investigate the roles of rituximab maintenance for newly diagnosed FL patients in Taiwan. Among 836 patients with newly diagnosed FL during 2009-2012, we enrolled patients with stage II-IV diseases receiving 4-8 cycles of rituximab containing induction chemotherapies (R-induction). We excluded those who died or received additional chemotherapy within 180 days after R-induction. Among the 396 enrolled patients, 260 underwent rituximab maintenance (R-maintenance group), and 136 served as the observation group. The R-maintenance group received less anthracycline and fewer cycles of R-induction than the observation group, but they exhibited a significantly better OS both in the univariate and multivariate analyses [hazard ratio, 0.42; 95% confidence interval, 0.19-0.91] after adjusting for age, sex, and Ann Arbor stages. Meanwhile, we also found more patients required further therapies in the first 6 months after the cease of rituximab maintenance. In the subgroup analysis, patients older than 60 years or with stage IV diseases benefited more from rituximab maintenance. Conclusively, our nationwide study is the first one to demonstrate the OS benefit of rituximab maintenance after induction therapies in newly diagnosed FL patients from Asian populations. PMID- 30009425 TI - The State of Sex Research in MFT and Family Studies Literature: A Seventeen-Year Content Analysis. AB - The ability to conceptualize and treat sexual problems has been widely accepted as a crucial skill to master the MFT training. However, clients' sexual relationships are often ignored by clinicians because of a lack of experience or training, or personal discomfort. In this content analysis, we review sex and sex therapy research within MFT and family studies journals since the turn of the century. Of the 13,919 articles published within the 15 journals, 137 focused on sexuality or sex therapy. The articles were divided into five themes: sexual and relational health, sexual diversity, treatment and contributors of sexual dysfunction, sex therapy practices, and sexual education and development. Implications for clinical practices, sex therapy integration, and future research are discussed. PMID- 30009426 TI - A PRRT2 variant in a Chinese family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures results in loss of interaction with STX1B. AB - OBJECTIVE: To identify the causative gene of autosomal dominant paroxysmal kinesigenic dyskinesia and benign familial infantile seizures (PKD/BFIS) in a large Chinese family and explore the potential pathogenic mechanism of a PRRT2 (proline-rich transmembrane protein 2) variant. METHODS: Genetic testing was performed via whole exome sequencing. Western blotting and immunofluorescence were used to analyze the protein expression level and subcellular localization of the PRRT2 mutant in HeLa cells and N2A cells. Coimmunoprecipitation was conducted to investigate the interaction of the PRRT2 mutant with syntaxin 1B (STX1B). RESULTS: In a large Chinese family with autosomal dominant PKD/BFIS showing wide phenotypic heterogeneity, including patients suffering from PKD, BFIS, or epilepsy and asymptomatic variant carriers, a c.621dupA variant in PRRT2 was identified in the proband and was shown to cosegregate with the phenotype in this family. This variant results in premature termination at codon 224, producing a truncated protein (p.Ser208Ilefs*17) in which the two conserved hydrophobic segments and the cytoplasmic loop are missing. Both the expression and subcellular localization of PRRT2 are strongly affected by the c.621dupA variant. In addition, we found that PRRT2 directly interacts with STX1B, a SNARE protein critical for neurotransmitter release, whereas the truncated variant p.Ser208Ilefs*17 lacking the helix-loop-helix domain fails to bind to STX1B. SIGNIFICANCE: Our findings identified a PRRT2 variant in a family with PKD/BFIS and confirmed STX1B as a new binding partner of PRRT2, which suggested that the loss of the interaction between PRRT2 and STX1B may contribute to the pathogenesis of PKD/BFIS. PMID- 30009427 TI - Effect of T1 relaxation on ventilation mapping using hyperpolarized 129 Xe multiple breath wash-out imaging. AB - PURPOSE: To investigate the effect of incorporating T1 as a function of wash-out breath number (T1 (n)) on estimation of fractional ventilation (r) using hyperpolarized 129 Xe multiple breath wash-out (MBWO) imaging in rats. METHODS: MBWO imaging was performed in 8 healthy mechanically ventilated rats at several inter-image delay times (tau) and tidal volumes (TV). r maps were calculated from the imaging data using a model of T1 (n) (assuming that the longitudinal relaxation rate of 129 Xe in the lung is directly proportional to pA O2 ) and compared to r maps obtained by assuming a fixed T1 measured before wash-out breaths (r'). RESULTS: Fractional ventilation was overestimated by up to 19.3% when T1 was fixed. An inverse relationship between bias (Deltar) and ventilation was observed at all tau and TV. Additionally, Deltar significantly increased when TV was decreased (F statistic F(2,7) = 48.97, P < 10-4 ). Histograms from r' maps were significantly more skewed toward lower values as compared to r histograms at all tau and TV (P < 0.05) except TV = Vdose - 1 mL. CONCLUSION: Analysis of hyperpolarized 129 Xe MBWO imaging using a model incorporating T1 (n) corrects for an overestimating bias in the mapping of fractional ventilation in mechanically ventilated rats introduced by assuming a fixed T1 . PMID- 30009428 TI - Enabling and Localizing Omnidirectional Nonlinear Deformation in Liquid Crystalline Elastomers. AB - Liquid crystalline elastomers (LCEs) are widely recognized for their exceptional promise as actuating materials. Here, the comparatively less celebrated but also compelling nonlinear response of these materials to mechanical load is examined. Prior examinations of planarly aligned LCEs exhibit unidirectional nonlinear deformation to mechanical loads. A methodology is presented to realize surface templated homeotropic orientation in LCEs and omnidirectional nonlinearity in mechanical deformation. Inkjet printing of the homeotropic alignment surface localizes regions of homeotropic and planar orientation within a monolithic LCE element. The local control of the self-assembly and orientation of the LCE, when subject to rational design, yield functional materials continuous in composition with discontinuous mechanical deformation. The variation in mechanical deformation in the film can enable the realization of nontrivial performance. For example, a patterned LCE is prepared and shown to exhibit a near-zero Poisson's ratio. Further, it is demonstrated that the local control of deformation can enable the fabrication of rugged, flexible electronic devices. An additively manufactured device withstands complex mechanical deformations that would normally cause catastrophic failure. PMID- 30009429 TI - Black Raspberry Seed Oil Improves Lipid Metabolism by Inhibiting Lipogenesis and Promoting Fatty-Acid Oxidation in High-Fat Diet-Induced Obese Mice and db/db Mice. AB - The objective of this study was to evaluate the beneficial effect of alpha linolenic acid-rich black raspberry seed (BRS) oil on lipid metabolism in high fat diet (HFD)-induced obese and db/db mice. Five-week-old C57BL/6 mice were fed diets consisting of 50% calories from lard, 5% from soybean, and 5% from corn oil (HFD), or 50% calories from lard and 10% from BRS oil (HFD + BRS oil diet) for 12 weeks. Six-week-old C57BL/KsJ-db/db mice were fed diets consisting of 16% calories from soybean oil (standard diet), 8% from soybean, and 8% from BRS oil, or 16% from BRS oil for 10 weeks. The BRS oil diets lowered the levels of triacylglycerol, nonesterified fatty acids, and total cholesterol in serum and liver of both of the obese and db/db mice as compared with the HFD and standard diet, respectively. mRNA levels of lipogenesis markers including cluster of differentiation 36, fatty-acid-binding protein 1, sterol regulatory element binding protein 1c, fatty-acid synthase, and solute carrier family 25 member 1 in the liver of the BRS oil groups were lower than those in the liver of the HFD and standard groups in the obese and db/db mice, respectively. On the other hand, fatty-acid oxidation markers including carnitine palmitoyltransferase 1A, acyl CoA dehydrogenase, hydroxylacyl-CoA dehydrogenase alpha, and acyl-CoA oxidase in the liver of the BRS oil groups were higher than those in the liver of the HFD and standard groups in the obese and db/db mice, respectively. Peroxisome proliferator-activated receptor alpha mRNA and protein levels increased in the liver and epididymal adipose tissue of the obese and db/db mice fed BRS oil compared with HFD and standard diet, respectively. BRS oil might improve lipid metabolism by inhibiting lipogenesis and promoting fatty-acid oxidation in HFD induced obese and db/db mice. PMID- 30009430 TI - Racemic crystal structures of peptide toxins, GsMTx4 prepared by protein total synthesis. AB - The Piezo channel is a versatile mechanosensitive cation channel that mediates tactile, vascular development, and proprioception. GsMTx4 is the only reported inhibitor specifically targeting Piezo channels. Although the sequence of GsMTx4 is reported, the crystal structure of GsMTx4 is still unknown. Here, we achieved the two-segment synthesis of GsMTx4 and its enantiomer, enGsMTx4, through hydrazide based Native Chemical Ligation, and analyzed the crystal structure of GsMTx4 through the racemic crystallization technology. By analyzing the structure, we found that there is a hydrophobic patch surrounded by aromatic residues and charged residues. PMID- 30009431 TI - The Design and Synthesis of Hollow Micro-/Nanostructures: Present and Future Trends. AB - Hollow micro-/nanostructures have attracted tremendous interest owing to their intriguing structure-induced physicochemical properties and great potential for widespread applications. With the development of modern synthetic methodology and analytical instruments, a rapid structural/compositional evolution of hollow structures from simple to complex has occurred in recent decades. Here, an updated overview of research progress made in the synthesis of hollow structures is provided. After an introduction of definition and classification, achievements in synthetic approaches for these delicate hollow architectures are presented in detail. According to formation mechanisms, these strategies can be categorized into four different types, including hard-templating, soft-templating, self templated, and template-free methods. In particular, the rationales and emerging innovations in conventional templating syntheses are in focus. The development of burgeoning self-templating strategies based on controlled etching, outward diffusion, and heterogeneous contraction is also summarized. In addition, a brief overview of template-free methods and recent advances on combined mechanisms is provided. Notably, the strengths and weaknesses of each category are discussed in detail. In conclusion, a perspective on future trends in the research of hollow micro-/nanostructures is given. PMID- 30009432 TI - Contamination of skin and surfaces by cobalt in the hard metal industry. AB - BACKGROUND: It is well known that hard metal workers have historically been affected by contact allergy to cobalt. Knowledge is sparse about occupational skin exposure to cobalt, in terms of skin doses and sources of exposure, which could be used to improve protection of workers. OBJECTIVES: To improve knowledge about skin doses and sources of skin exposure to cobalt within hard metal production, thereby facilitating better protection of workers. METHODS: Forty workers were sampled on the index finger by acid wipe sampling after 2 hours of work. The samples were analysed with inductively coupled plasma mass spectrometry. Cobalt spot testing was performed in the work environment. RESULTS: The highest skin doses were found among raw material workers. Skin doses among other production workers were also significant. Most office workers had low, but measurable, levels of cobalt on the skin. Glove use varied between workers. Cobalt was found on production equipment, on items in the canteen area, and on handles and buttons throughout the company. CONCLUSIONS: Cobalt skin doses were prominent, and originated from contact with raw materials, sintered materials, and contaminated surfaces. Cobalt was present on surfaces outside production areas. Companies need to identify and reduce skin exposure for protection of workers. PMID- 30009433 TI - Survey of nutritional practices in total gastrectomy and oesophagectomy procedures. AB - AIM: Total gastrectomy and Ivor Lewis oesophagectomy procedures are the mainstay of upper gastrointestinal cancer management. Maintenance of adequate nutritional intake is essential for positive patient outcomes. Although numerous nutritional support options exist, clear evidence-based guidelines on the optimal means and duration of nutritional support are lacking. The aim of this study is to establish preliminary data on the current perioperative nutritional practices of upper gastrointestinal surgeons performing these procedures across Australia and New Zealand. It is hoped this will help provide the platform for future research towards establishing evidence-based guidelines in upper gastrointestinal surgery. METHODS: A questionnaire exploring the nutritional practices and considerations of surgeons was developed and emailed to the members of the Australia & New Zealand Gastric & Oesophageal Surgery Association. RESULTS: A total of 27.4% of Australia & New Zealand Gastric & Oesophageal Surgery Association members completed the questionnaire. Surgeons reported inserting a jejunostomy feeding tube intraoperatively in Ivor Lewis oesophagectomy procedures 80-100% of the time, compared to only 20-39% of the time in total gastrectomy procedures. For both procedures, surgeons often refer their patients to a dietitian preoperatively, and always postoperatively. Preoperative immune-enhancing nutrition is rarely administered. Patient age and BMI are deemed to be of low importance when determining the means of nutritional support. CONCLUSIONS: This study has demonstrated the current nutritional practices employed in Australia and New Zealand for patients undergoing major upper gastrointestinal surgery. Questions remain regarding the noted differences between procedures as well as the optimal means and duration of perioperative nutritional support. PMID- 30009434 TI - Text messages as revision aids. PMID- 30009435 TI - Clinical education research: do numbers matter? PMID- 30009436 TI - Cost-effectiveness training at medical school. PMID- 30009437 TI - How to... get started with theory in education. AB - This paper, on using theory in health professions education research, is the second in a series that aims to support novice researchers within clinical education, particularly those undertaking their first qualitative study. Diving into the world of education theory can be challenging and uncomfortable for clinician-educators. Nonetheless, theory is an essential ingredient in high quality research, shaping everything from research questions to study design, analysis and, ultimately, the interpretation of findings. We hope that this paper, introducing different levels of theory and examples of how to use theory, will shed light on how theory can be used in research, and that it will help you in getting to grips with using theory in your own work. It will help you in getting to grips with using theory in your own work. PMID- 30009438 TI - Digital learning: the future of medical education? PMID- 30009439 TI - Widening participation: the value of diversity. PMID- 30009440 TI - Medical students' views of clinical environments. PMID- 30009441 TI - Giant fibroepithelial polyp of the vulva. PMID- 30009442 TI - Experimental and Theoretical Investigations of an Electrochromic Azobenzene and 3,4-Ethylenedioxythiophene-based Electrochemically Formed Polymeric Semiconductor. AB - An electrochromic material based on azobenzene and 3,4-ethylenedioxythiophene (EDOT) semiconducting layer was electrochemically deposited on an indium tin oxide coated glass electrode. Chemical synthesis of the azobenzene and EDOT-based chromophore (DAE) and electrochemical formation of its corresponding polymer (pDAE) are reported. The electrochromic properties of the synthesized polymer pDAE were investigated by electrochemical and spectroelectrochemical methods. pDAE exhibited an optical bandgap of 1.82 eV and three distinct colored states in its reduced, neutral, and oxidized forms. The pDAE polymer showed 44 % optical contrast at 710 nm between its reduced and oxidized states and a fast electrochromic switching time of 1.0 s. The frontier molecular orbitals, Raman shifts, and semiconducting properties of this electrochromic polymer were evaluated by density functional theory calculations. The optical absorption bands of the polymer charged states were assigned and investigated. PMID- 30009443 TI - Seizure duration and latency of hypermotor manifestations distinguish frontal from extrafrontal onset in sleep-related hypermotor epilepsy. AB - Sleep-related hypermotor epilepsy (SHE) is an epilepsy syndrome that is characterized by the occurrence of sleep-related hypermotor seizures of variable complexity and duration. Seizures usually arise in the frontal lobe, but extrafrontal seizure onset zones are well described. To identify clinically relevant ictal features of SHE that could distinguish a frontal from an extrafrontal onset zone, we conducted a retrospective analysis of seizure characteristics in 58 patients with drug-resistant SHE (43 frontal and 15 extrafrontal) who underwent video-stereo-electroencephalographic recordings and became seizure-free after epilepsy surgery. We found that the mean duration of electrographic seizures and clinically observable ictal manifestations were significantly shorter in frontal SHE compared to extrafrontal SHE. The mean latency between electrographic seizure onset and the onset of hypermotor manifestations was also shorter in frontal SHE. Accordingly, a latency > 5 seconds between the first video-detectable movement (eg, eye opening or a minor motor event) and the onset of hypermotor manifestations yielded a sensitivity of 75% and a specificity of 90% for an extrafrontal onset, thereby indicating that specific ictal features in SHE can provide clinically useful clues to increase diagnostic accuracy in this syndrome. PMID- 30009444 TI - Chemical and physicochemical characterization of orange by-products derived from industry. AB - BACKGROUND: Industrial extraction of orange juice produces a large amount of waste that affects the environment and gives rise to important economic losses; at the same time, information about the composition of the waste is still limited. The present study carried out an exhaustive chemical and physicochemical characterization of the residues in the waste, aiming to increase their potential application for the extraction of functional ingredients. RESULTS: Four different products (three solids and one liqueur) were provided by the industry. The overall characterization indicated that carbohydrates comprised the main components. During processing, carbohydrate derivatives were formed such as those corresponding to the initial steps of the Maillard reaction. In this sense, furosine was demonstrated to be a suitable indicator with respect to the control of the process. Although the phenolic content substantially decreased (by up to 57%) as the processing proceeded, the antioxidant capacity was affected to a much lesser extent (~10%). Dehydrated products were rich in galacturonic acid and hardly any change was detected during their elaboration. The liqueur by-product was found to have a much higher level of fructose than glucose and sucrose. CONCLUSION: Orange juice waste obtained industrially under the conditions described in the present study could be used as a source of pectic derivatives or fructose in the case of solid or liquid by-products, respectively. The results reported here could diversify the present application of these products as a source of food ingredients, contributing to an improvement in their utilization. (c) 2018 Society of Chemical Industry. PMID- 30009445 TI - Smoking cessation and associated dental factors in a cohort of smokers born in 1942: 5 year follow up. AB - INTRODUCTION: Tobacco usage is a serious threat to the health of a population and thus cessation of tobacco use is an important step in improving patients' quality of life. Cessation activities are essential also for middle aged and older people. Dental personnel have a unique role as they treat patients who might not otherwise have regular contact with general medical practitioners. OBJECTIVE: The aim of this study was to identify factors associated with smoking cessation in a cohort of smokers as they progressed from 65 to 70 years of age. MATERIAL AND METHODS: The base population was all inhabitants born in 1942 in two Swedish counties who had been followed by postal questionnaires every fifth year since 1992. Data had been collected and accumulated at the individual level. In this study, the 533 self-reported smokers in 2007 were selected and their smoking habits in 2012 were used as the outcome variable. Analyses used were bivariate associations and logistic regression. RESULTS: The total smoking-cessation rate was 28%. The logistic regression had a Nagelkerke R2 of 0.32 and showed that remembering information on tobacco cessation given in the dental office increased the reported chances of quitting smoking (odds ratio = 10, 95% confidence interval: 3.2-31.7). Also associated with smoking cessation was increased incidence of reporting bleeding gums. CONCLUSION: Information on smoking cessation given in dental clinics is effective for elderly people. PMID- 30009446 TI - o-Benzenediol-Functionalized Carbon Nanosheets as Low Self-Discharge Aqueous Supercapacitors. AB - Widening the voltage window is often proposed as a way to increase the energy density of aqueous supercapacitors. However, attempting to operate beyond the aqueous supercapacitor stability region can undermine the supercapacitor reliability due to pronounced electrolyte decomposition, which can lead to a significant self-discharge process. To minimize this challenge, charge injection by grafting o-benzenediol onto the carbon electrode is proposed through a simple electrochemical cycling technique. Due to charge injection from o-benzenediol into the carbon electrode, the equilibrium potential of the individual electrode can be reduced. In addition, due to its small molecular size, charge distribution, which is commonly faced by bulk pseudocapacitive materials, is also avoided. The assembled supercapacitor based on the o-benzenediol-grafted carbon demonstrated a maximum energy density of 24 Wh kg-1 and a maximum power density of 69 kW kg-1 , with a retention of 89 % after 10 000 cycles at 10 A g-1 . A low self-discharge of about 4 h was recorded; this could be attributed to the low driving force arising from the lower equilibrium potential. Thus, the proposed technique may provide insight towards the tuning of the equilibrium potential to attain reliable, high-performing supercapacitors with a low self-discharge process. PMID- 30009447 TI - Corrigendum. PMID- 30009448 TI - Screening and selection of Bifidobacterium strains isolated from human feces capable of utilizing resistant starch. AB - BACKGROUND: Resistant starch (RS) has been studied for its ability to serve as a substrate for the microbiota present in the human large intestine and for its beneficial physiological effects. The aim of this study was to screen and select novel strains of lactic acid bacteria (LAB) in the genus Bifidobacterium isolated from human fecal samples for further application as probiotics relying on their utilization of RS3, a prebiotic. RESULTS: LAB were isolated from human fecal samples, based on their ability to utilize RS3 as a carbon source. Consequently, two LAB were identified as Bifidobacterium adolescentis based on morphological, physiological and biochemical properties, and molecular biological analysis. The RS3-utilizing ability of these isolates was shown by the rapid decrease in pH of RS3-MRS media and by the pinhole traces on the surface of RS3 particles. Isolated B. adolescentis JSC2 was shown to be negative for beta-glucuronidase, suggesting that it would be safe for human use, and was found to be tolerant towards the acidic, bile-salt environment. CONCLUSION: This synbiotics approach of B. adolescentis JCS2, an RS-utilizing probiotics, coupled with RS utilization, is expected to enhance RS utilization in the food industry and be beneficial for the promotion of human health. (c) 2018 Society of Chemical Industry. PMID- 30009449 TI - Patient Safety Culture Associated With Patient Safety Competencies Among Registered Nurses. AB - PURPOSE: To investigate the relationships between registered nurses' (RNs') perceptions of the culture of patient safety in their workplace and their patient safety competency-attitudes, skills, and knowledge. DESIGN: A cross-sectional study design was used. Data were collected by using a self-reported survey from 343 RNs working in a university hospital in Seoul, South Korea. METHODS: Patient safety culture was measured using the Korean version of the Agency for Healthcare Research and Quality's Hospital Survey on Patient Safety Culture (Hospital SOPSTM). Patient safety competency was measured using the Patient Safety Competency Self-Evaluation tool. Multiple regression analysis was performed using Stata version 14 to examine the relationships between patient safety culture and RNs' patient safety competency, while adjusting for the RNs nested in their units. FINDINGS: Of the 10 specific aspects of patient safety culture, only teamwork within units was significantly related to overall safety competency. In relation to each of the three patient safety competencies, teamwork within and across units and supervisor or manager expectations were significantly related to attitudes, while teamwork within units and learning were significantly related to skills. Only organizational learning was significantly related to knowledge. CONCLUSIONS: Although teamwork, leadership, and continuous learning in the nursing unit were major factors influencing RNs' safety competency, the relationships of these factors to patient safety attitudes, skills, and knowledge among RNs were varied. CLINICAL RELEVANCE: Creating a unit-specific patient safety culture that is tailored to the competencies of the unit's RNs in patient safety practice would be essential to enhance and maintain high levels of patient safety attitudes, skills, and knowledge among the unit's RNs, which would ultimately affect patient safety. PMID- 30009450 TI - Corrigendum. PMID- 30009451 TI - Corrigendum. PMID- 30009452 TI - Suggestions to nurse authors from one manuscript reviewer. AB - Many others have written about how to prepare a manuscript for publication. Therefore the purpose of this article is to share the experiences of one reviewer and suggest the need for using a theory or conceptual framework to guide research, practice, and publications. Many times while reading a manuscript I feel I am on a journey of discovery without a road map. My sense is authors may be confused about when to include the conceptual framework or the "theory part" in a manuscript if the work being described was not a research study per se. The author shares recommendations from a recent publication on how to use theory or a conceptual framework in manuscript preparation. PMID- 30009453 TI - Arachidyl glucoside: Another cosmetic allergen. PMID- 30009454 TI - Effect of Neutral pH Icodextrin Peritoneal Dialysis Fluid on Mesothelial Cells. AB - Conventional acidic icodextrin peritoneal dialysate (CI) has low biocompatibility due to its low pH, and a neutral pH icodextrin dialysate (NI) was developed. The influence of NI on the peritoneum has not been clarified. The effects of the two dialysates on cultured rat mesothelial cells were examined. CI, but not NI, increased alpha-smooth muscle actin, collagen type 1 and 3, and P21 mRNA expressions. CI with neutralized pH did not improve these harmful effects. With NI+ glucose degradation products (GDPs: same concentration as CI), mRNA expressions were comparable to those with NI alone. However, if NI + GDPs was acidified, mRNA levels matched those with CI. The proportion in the G2/M phase of the cell cycle was lower with CI than with NI stimulation. From these results, CI stimulated epithelial-mesenchymal transition, fibrotic changes, inhibited cell growth, and induced cell senescence. These effects were attributed to the combined low pH and high GDPs. PMID- 30009455 TI - Guideline for the treatment of chronic lymphocytic leukaemia: A British Society for Haematology Guideline. PMID- 30009456 TI - Systematical characterization of physiochemical and rheological properties of thermal-induced polymerized whey protein. AB - BACKGROUND: Effects of pH (6-8), protein concentration (60-110, g kg-1 ), heating temperature (70-95 degrees C) and time (5-30 min) on physiochemical and rheological properties of thermal-induced polymerized whey protein isolate (PWP) were systematically investigated. Degree of denaturation, particle size, zeta potential, free sulfhydryl group content, surface hydrophobicity and apparent viscosity were determined. RESULTS: Heating whey protein above 75 degrees C at pH 7 or 8 resulted in denaturation of 80-90% whey protein. pH variation had a remarkable influence on particle size of samples (P < 0.05), whereas heating temperature and time did not generate significant changes. Zeta potential of PWP samples fell in the range of -30 to -40 mV. Free sulfhydryl group content of PWP samples decreased with increasing level regarding each factor. Surface hydrophobicity analysis showed that samples at higher pH or concentration became less hydrophobic, and increasing heating temperature or time resulted in higher hydrophobicity index. Time sweep test revealed that increasing protein concentration, heating temperature or time led to higher apparent viscosity. Flow behavior of PWP samples approached Newtonian character as protein concentration, heating temperature or time decreased. CONCLUSION: Systematic data may provide helpful information in designing a heating process for dairy products and application of PWP in the food industry. (c) 2018 Society of Chemical Industry. PMID- 30009457 TI - Persistent pruritic rash, fever, and joint pains in a young female. PMID- 30009458 TI - A New Theory of Aging Based on Energy Maintenance. PMID- 30009459 TI - Australasian bronchiolitis guideline. AB - AIM: Bronchiolitis is the most common lower respiratory tract disorder in infants aged less than 12 months, and research has demonstrated that there is substantial variation in practice patterns despite treatment being well defined. In order to align and improve the consistency of the management of bronchiolitis, an evidence based guideline was developed for the Australasian population. METHODS: The guideline development committee included representation from emergency and paediatric specialty medical and nursing personnel in addition to geographical representation across Australia and New Zealand - rural, remote and metropolitan. Formulation of the guideline included identification of population, intervention, comparator, outcomes and time questions and was associated with an extensive literature search from 2000 to 2015. Evidence was summarised and graded using the National Health and Medical Research Council and Grading of Recommendations Assessment, Development and Evaluation methodology, and consensus within the guideline group was sought using nominal group technique principles to formulate the clinical practice recommendations. The guideline was reviewed and endorsed by key paediatric health bodies. RESULTS: The guideline consists of a usable clinical interface for bedside functionality supported by evidence summary and tables. The Grading of Recommendations Assessment, Development and Evaluation and National Health and Medical Research Council processes provided a systematic and transparent process to review and assess the literature, resulting in a guideline that is relevant to the management of bronchiolitis in the Australasian setting. CONCLUSION: This is the first robust Australasian acute paediatric guideline and provides clear guidance for the management of the vast majority of patients seen in Australasian emergency departments and general paediatric wards with bronchiolitis. PMID- 30009460 TI - Allergic contact dermatitis caused by dexpanthenol-Probably a frequent allergen. AB - BACKGROUND: Panthenol (synonym: dexpanthenol), the alcohol analogue of panthothenic acid, is frequently included in moisturizers, wound-healing agents, and other cosmetics, and has been shown to be responsible for allergic contact dermatitis (ACD). OBJECTIVES: To evaluate the frequency of ACD caused by dexpanthenol, and to characterize reactive patients. METHODS: We retrospectively reviewed the files of patients patch tested between 2009 and 2017 in the Department of Dermatology of the Coimbra's University Hospital and describe patients who reacted to dexpanthenol 5% pet., tested initially in a cosmetic/vehicle series and in the last 3 years in consecutive patients. RESULTS: Among 2171 patients, 26 (1.2%) had positive patch test reactions to dexpanthenol, mostly patients tested for chronic eczema (88.5%, n = 23), either widespread (5), or localized to the hands (5), face (4), or legs (7). Relevance could be traced in 20 patients (76.9%), related to the use of Bepanthene cream (15), moisturizers (3), topical medications (1), and a shampoo (1). Twenty-five of 26 patients (96.2%) reacted to several other allergens, mostly ingredients of cosmetic or pharmaceutical products. CONCLUSIONS: Although ACD caused by dexpanthenol is considered to be rare, it may be frequently overlooked. As we found a relatively high frequency of relevant cases, in agreement with a previous study, the inclusion of dexpanthenol in patch test series, at least in cosmetic and topical drug series, is encouraged. PMID- 30009461 TI - Do we need a core outcome set for childbirth perineal trauma research? A systematic review of outcome reporting in randomised trials evaluating the management of childbirth trauma. AB - BACKGROUND: Selecting appropriate outcomes to reflect both beneficial and harmful effects is a critical step in designing childbirth trauma trials. OBJECTIVE: To evaluate the outcomes and outcome measures reported in randomised controlled trials evaluating interventions for childbirth trauma. SEARCH STRATEGY: Randomised trials were identified by searching bibliographical databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. SELECTION CRITERIA: Randomised trials evaluating the efficacy and safety of different techniques in the management of perineal lacerations. DATA COLLECTION AND ANALYSIS: Two researchers independently assessed studies for inclusion, evaluated methodological quality, and extracted the relevant data. Spearman's rho correlation and multivariate linear regression analysis using the backward stepwise model were used for analysis. MAIN RESULTS: Forty-eight randomised trials, reporting data from 20 308 women, were included. Seventeen different interventions were evaluated. Included trials reported 77 different outcomes and 50 different outcome measures. Commonly reported outcomes included pain (34 trials; 70%), wound healing (20 trials; 42%), and anorectal dysfunction (16 trials, 33%). In the multivariate analysis, no relationship was demonstrated between the quality of outcome reporting and year of publication (P = 0.31), journal impact factor (P = 0.49), and methodological quality (P = 0.13). CONCLUSION: Outcome reporting in childbirth trauma research is heterogeneous. Developing, disseminating, and implementing a core outcome set in future childbirth trauma research could help address these issues. TWEETABLE ABSTRACT: Developing @coreoutcomes for childbirth trauma research could help to reduce #research waste. PMID- 30009462 TI - Intraocular Pressure Changes During Hemodialysis or Hemodiafiltration in End Stage Renal Disease Patients. AB - The aim of this study was to evaluate the intraocular pressure during hemodialysis and hemodiafiltration. Fifteen patients were enrolled (seven treated with hemodialysis therapy and eight with hemodiafiltration). The intraocular pressure was measured before and after dialysis and every 30 min during dialysis. Before dialysis, both groups had similar dialysis prescription, blood pressure, and biochemical parameters. At the end of dialysis, potassium, and osmolarity decreased in both groups, while systolic blood pressure and sodium decreased in the hemodialysis group, and glucose decreased in the hemodiafiltration group. Mean intraocular pressure was similar between groups at all measured times and had no significant changes during hemodialysis. During minute 120 of hemodiafiltration, mean intraocular pressure in the left eye decreased significantly compared to minute 90. This suggests a high intra-individual variability of intraocular pressure during both types of dialysis, which could be relevant particularly among those with the risk of glaucoma. PMID- 30009463 TI - Exosomes derived from mesenchymal stem cells exert therapeutic effect in a rat model of cavernous nerves injury. AB - Postradical prostatectomy erectile dysfunction (pRP-ED) is a major health issue. There has been a shortage of an effective treatment method until now. In this study, a total of 48 adult male Sprague-Dawley (SD) rats were randomly equally divided into four groups, including group 1-sham surgery with cavernous nerve exposure plus vehicle, group 2-bilateral cavernous nerve injury (BCNI) plus vehicle, group 3-BCNI plus adipose-derived mesenchymal stem cells (ADSCs)-derived exosomes (ADSC-Exo), and group 4-BCNI plus bone marrow-derived mesenchymal stem cell (BMSCs)-derived exosomes (BMSC-Exo). Twenty-one days following surgery, erectile function was measured before tissue harvest. Histologic and Western blot analyses were then performed. Exosomes were capable of internalization into human umbilical vein endothelial cells (HUVEC) in vitro and could be detected in the corpus cavernosum in vivo. The nNOS expression in the penile dorsal nerves (DN) and major pelvic ganglion (MPG), protein level of neurofilament in the DN, endothelial markers vWF, alpha smooth muscle actin (alpha-SMA), the ratio of smooth muscle to collagen content were obviously lower in BCNI group compared with the sham group, while ADSC-Exo and BMSC-Exo groups resulted in significant restoration of the above histopathological changes. Moreover, BCNI treated with ADSC-Exo or BMSC-Exo had significantly higher mean intracavernous pressure/mean arterial pressure ratio compared with BCNI group. The results demonstrated that both ADSC-Exo and BMSC-Exo treatment could significantly alleviate pathological changes and improve the erectile function in BCNI-related rats. Exosomes derived from ADSCs and BMSCs may be a potential agent for pRP-ED treatment. PMID- 30009464 TI - Corinthian raisins (Vitis vinifera L., var. Apyrena) antioxidant and sugar content as affected by the drying process: a 3-year study. AB - BACKGROUND: Corinthian raisins or Corinthian currants are dried grape products that account for approximately 3% of dried vine fruit production worldwide. Greece is the major Corinthian raisin producer. In this study Corinthian raisins were produced by applying two traditional drying methods, i.e. sun and shade drying. The drying process effect on the raisin phytochemical and sugar content was assessed; samples obtained over three consecutive crops were evaluated to prevail over climatic condition variations. RESULTS: Total phenolic, flavanol, and anthocyanin content were higher in Corinthian raisins dried under shade as compared with the sun-dried ones; individual anthocyanidin-3-O-glucosides were also qualitatively and quantitatively higher under shade drying in most cases. Differences were observed in Corinthian raisin phytochemical content among the crop years evaluated. The drying process applied did not discriminatively affect the sugar content of Corinthian raisin. CONCLUSION: Drying under shade was proven superior to sun drying with respect to Corinthian raisin phytochemicals and could be considered as an appealing drying method for the production of dried raisins and perhaps other dried fruits. (c) 2018 Society of Chemical Industry. PMID- 30009465 TI - Black soldier fly (Hermetia illucens) pre-pupae meal as a dietary protein source for broiler production ensures a tasty chicken with standard meat quality for every pot. AB - BACKGROUND: Animal products (fishmeal etc.) are typically used in commercial broiler production systems. However, progressively more pressure is placed on the animal feed industry to find alternative protein sources that are more sustainable, ethical and green, such as insect meal, without having negative effects on the sensory and meat quality. Hence this study aimed to validate the commercial value of black soldier fly (BSF) pre-pupae meal for broiler production by determining the effects of different dietary levels (0%, 5%, 10% or 15%) on carcass, sensory and meat quality. RESULTS: There were no significant differences for the carcass characteristics, pH, colour, thaw loss and cooking loss of the broilers. Treatment had no influence on the sensory characteristics (aroma, flavour, juiciness and tenderness) of the breast muscle (P > 0.05). Mineral content was similar across treatments and no differences (P > 0.05) were observed for the long-chain fatty acid composition of the cooked broiler meat. None of the fatty acids was correlated with chicken flavour. CONCLUSION: BSF pre-pupae meal (up to 15%) can be included in broiler diets without influencing the carcass, sensory or meat quality characteristics. (c) 2018 Society of Chemical Industry. PMID- 30009466 TI - Chronic pelvic pain and prostate inflammation in rat experimental autoimmune prostatitis: Effect of a single treatment with phosphodiesterase 5 inhibitors on chronic pelvic pain. AB - BACKGROUND: Experimental autoimmune prostatitis (EAP) is most often used as a nonbacterial model of chronic prostatitis/chronic pelvic pain. We investigated the development of chronic pelvic pain and inflammatory changes in rat EAP and examined the effect of a single treatment with phosphodiesterase 5 (PDE5) inhibitors on the chronic pelvic pain. METHODS: EAP was induced in rats by intradermal injection of rat prostate antigen and complete Freund's adjuvant on days 0 and 28. On day 42, after antigen injection, prostatic inflammatory changes, including the mRNA and protein levels of cytokines/chemokines, were measured and histological analysis of the prostate was performed. Pelvic pain was measured by applying von Frey filaments to the lower abdomen. To confirm that this model is appropriate for evaluating pelvic pain, we tested two drugs, celecoxib and pregabalin, which are clinically used for the treatment of prostatitis-related pain. Subsequently, we examined the effects of single treatments with three phosphodiesterase 5 inhibitors, including tadalafil, on pelvic pain in this model. RESULTS: On day 42, after antigen injection, the mRNA levels of 44 of 84 kinds of cytokines/chemokines and their receptors increased significantly in EAP rats, as did the protein levels of seven of 23 kinds of cytokines/chemokines. Histological analysis revealed inflammation characterized by neutrophils and/or mononuclear cells in the glandular and stromal tissue of the ventral prostate from rats in the EAP group. Some animals in this group showed fibrosis and hemorrhage in the stromal tissue. Pelvic pain had developed in EAP rats, which was attenuated by a single treatment with celecoxib or pregabalin, suggesting that EAP is an appropriate model for prostatitis-related pain. A single treatment with any of the three PDE5 inhibitors tested attenuated the chronic pelvic pain. CONCLUSIONS: Prostatitis leads to inflammatory changes in the prostate, which may contribute to the development and maintenance of chronic pelvic pain. PDE5 inhibitors, including tadalafil, may have the ability to block chronic pelvic pain. PMID- 30009467 TI - In vivo quantification of glial activation in minipigs overexpressing human alpha synuclein. AB - Parkinson's disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (alpha-syn). The pathology of Parkinson's disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of alpha-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [11 C](R)PK11195, to image brain microglial activation and (+)-alpha-[11 C]dihydrotetrabenazine ([11 C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Gottingen minipigs following injection with recombinant adeno-associated virus (rAAV) vectors expressing either mutant A53T alpha-syn or green fluorescent protein (GFP) into the SN (4 rAAV-alpha-syn, 4 rAAV-GFP, 5 non injected control minipigs). We performed motor symptom assessment and immunohistochemical examination of tyrosine hydroxylase (TH) and transgene expression. Expression of GFP and alpha-syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [11 C]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [11 C](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the alpha-syn group than the control animals. We conclude that mutant alpha-syn expression in the SN resulted in microglial activation in multiple sub- and cortical regions, while it did not affect TH stains or VMAT2 availability. Our data suggest that microglial activation constitutes an early response to accumulation of alpha-syn in the absence of dopamine neuron degeneration. PMID- 30009468 TI - Graphene-Based Nanomaterials for Flexible and Wearable Supercapacitors. AB - Along with the quick development of flexible and wearable electronic devices, there is an ever-growing demand for light-weight, flexible, and wearable power sources. Because of the high power density, excellent cycling stability and easy fabrication, flexible supercapacitors are widely studied for this purpose. Graphene-based nanomaterials are attractive electrode materials for flexible and wearable supercapacitors owing to their high surface area, good mechanical and electrical properties, and excellent electrochemical stability. The 2D structure and high aspect ratio of graphene nanosheets make them easy to assemble into films or fibers with good mechanical properties. In recent years, enormous progress has been made in developing flexible and wearable graphene-based supercapacitors. Here, the material and structure design strategies for developing film-shaped and emerging fiber-shaped flexible supercapacitors based on graphene nanomaterials are summarized. PMID- 30009470 TI - Correction. PMID- 30009472 TI - Printable MoOx Anode Interlayers for Organic Solar Cells. AB - Currently, solution-processed MoOx anode interfacial layers (AILs) can only be fabricated by the spin-coating method in organic solar cells (OSCs), which severely limits their use in practical productions where large-area printing techniques are used. Herein, a facile method is demonstrated to prepare highly conductive MoOx (denoted EG:Mo) that can be processed by printing methods such as wire-bar and blade coatings. The EG:Mo films are prepared by depositing an aqueous solution containing ammonium heptamolybdate (VI) tetrahydrate (NMo) and ethylene glycol (EG) and annealing at 200 degrees C. UV-vis absorption and X-ray photoelectron spectroscopy measurements confirm that Mo (VI) can be reduced to Mo (V) by EG, resulting in the n-doped EG:Mo. Using the EG:Mo as AILs, an OSC based on a PB3T:IT-M active layer exhibits a power conversion efficiency (PCE) of 12.1%, which is comparable to that of the PEDOT:PSS modified devices. More importantly, EG:Mo AILs can be processed by wire-bar and blade-coating methods, and the corresponding devices show PCEs of 11.9% and 11.5%, respectively. Furthermore, the EG:Mo AIL is processed by wire-bar coating to fabricate a large area device (1.0 cm2 ), and a PCE of 10.1% is achieved. PMID- 30009471 TI - Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival. AB - BACKGROUND: Mutations or truncation of the ligand-binding domain (LBD) of androgen receptor (AR) underlie treatment resistance for prostate cancer (PCa). Thus, targeting the AR N-terminal domain (NTD) could overcome such resistance. METHODS: Luciferase reporter assays after transient transfection of various DNA constructs were used to assess effects of E1A proteins on AR-mediated transcription. Immunofluorescence microscopy and subcellular fractionation were applied to assess intracellular protein localization. Immunoprecipitation and mammalian two-hybrid assays were used to detect protein-protein interactions. qRT PCR was employed to determine RNA levels. Western blotting was used to detect protein expression in cells. Effects of adenoviruses on prostate cancer cell survival were evaluated with CellTiter-Glo assays. RESULTS: Adenovirus 12 E1A (E1A12) binds specifically to the AR. Interestingly, the full-length E1A12 (266 aa) preferentially binds to full-length AR, while the small E1A12 variant (235 aa) interacts more strongly with AR-V7. E1A12 promotes AR nuclear translocation, likely through mediating intramolecular AR NTD-LBD interactions. In the nucleus, AR and E1A12 co-expression in AR-null PCa cells results in E1A12 redistribution from nuclear foci containing CBX4 (also known as Pc2), suggesting a preferential AR-E1A12 interaction over other E1A12 interactors. E1A12 represses AR-mediated transcription in reporter gene assays and endogenous AR target genes such as ATAD2 and MYC in AR-expressing PCa cells. AR-expressing PCa cells are more sensitive to death induced by a recombinant adenovirus expressing E1A12 (Ad E1A12) than AR-deficient PCa cells, which could be attributed to the increased viral replication promoted by androgen stimulation. Targeting the AR by E1A12 promotes apoptosis in PCa cells that express the full-length AR or C-terminally truncated AR variants. Importantly, inhibition of mTOR signaling that blocks the expression of anti-apoptotic proteins markedly augments Ad-E1A12-induced apoptosis of AR-expressing cells. Mechanistically, Ad-E1A12 infection triggers apoptotic response while activating the PI3K-AKT-mTOR signaling axis; thus, mTOR inhibition enhances apoptosis in AR-expressing PCa cells infected by Ad-E1A12. CONCLUSION: Ad12 E1A inhibits AR-mediated transcription and suppresses PCa cell survival, suggesting that targeting the AR by E1A12 might have therapeutic potential for treating advanced PCa with heightened AR signaling. PMID- 30009473 TI - Proenkephalin for the early detection of acute kidney injury in hospitalized patients with chronic kidney disease. AB - BACKGROUND: The early detection of acute kidney injury (AKI) in patients with chronic kidney disease (CKD) is an unmet clinical need. Proenkephalin (PENK) might improve the early detection of AKI. METHODS: One hundred and eleven hospitalized CKD patients undergoing radiographic contrast procedures were enrolled. PENK was measured in a blinded fashion at baseline (before contrast media administration) and on day 1 (after contrast media administration). The potential of PENK levels to predict contrast-induced AKI was the primary endpoint. RESULTS: Baseline creatinine and baseline PENK were similar in AKI and no-AKI patients. In AKI patients, day 1 PENK (198 pmol/L vs 121 pmol/L, P < 0.01) was significantly higher compared to no-AKI patients. The area under the curve (AUC) for the prediction of AKI by day 1 PENK was 0.79, 95% CI: 0.70-0.87, similar to serum creatinine: 0.78, 95% CI: 0.61-0.95. Delta PENK was significantly higher in AKI compared to no-AKI patients (53 pmol/L vs 1 pmol/L, P < 0.01). The AUC for the prediction of AKI by delta PENK was high (0.92, 95%CI 0.82-1.00) and remained high for creatinine-blind AKI (0.94, 95% CI: 0.87-0.97). CONCLUSION: Delta PENK levels improve the early detection of contrast-induced AKI in CKD patients over serial creatinine sampling. Delta PENK accelerates the detection of creatinine-blind AKI by 24 hours. PMID- 30009474 TI - Treatment of secondary hyperparathyroidism: How do cinacalcet and etelcalcetide differ? AB - Secondary hyperparathyroidism (SHPT), commonly encountered in patients receiving maintenance dialysis, is associated with numerous adverse outcomes, including mortality. Calcimimetics, agents that act on the calcium sensing receptor (CaSR), were designed to overcome limitations in the use of vitamin D sterols to treat SHPT, and have demonstrated efficacy in reducing levels of PTH in randomized trials. Currently available calcimimetics include oral cinacalcet and the recently approved intravenously administered agent, etelcalcetide. While cinacalcet is an allosteric modulator of the CaSR, etelcalcetide acts as a direct CaSR agonist. Etelcalcetide's properties allow it to be administered intravenously thrice weekly at the end of a hemodialysis treatment session. Etelcalcetide has recently been shown to be more potent than cinacalcet in reducing PTH levels. However, etelcalcetide appears, like cinacalcet, to cause gastrointestinal intolerance. Additionally, etelcalcetide, which appears to reduce calcium substantially more than cinacalcet does, can prolong the QTc electrocardiographic interval. While etelcalcetide is very effective at reducing PTH levels, the current climate of dialysis cost containment in the United States may limit its widespread use. This review compares and contrasts the pharmacologic characteristics of cinacalcet and etelcalcetide, discusses the results of clinical trials involving these drugs, and posits implications for their use for clinical practice. PMID- 30009476 TI - Peri-implant tissue healing at implants with different designs and placement protocols: An experimental study in dogs. AB - OBJECTIVES: To compare the peri-implant tissue response to subcrestal or crestal placement of implants with or without "platform-switched" implant/abutment connections. MATERIAL AND METHODS: On each side of the mandible in six Labrador dogs, two "platform-switched" (PS) implants and two implants with matching implant/abutment diameters (PM) were placed in a crestal or a 1.5 mm subcrestal position. Sulcus formers/abutments were connected, baseline radiographs obtained and the distance between the abutment-fixture junction (A/F) and the marginal bone level (B) was determined. Five months later, radiographic and clinical examinations were repeated and biopsies were obtained and processed for histological analysis. RESULTS: The radiographic analysis showed that marginal bone level changes occurred during the first observation period (13 weeks). PS implants showed minor marginal bone level alterations during the full observation period (20 weeks), regardless of placement depth. For PM-implants, placement had a significant impact on bone level changes; crestal placement resulted in a mean bone loss of 0.4 mm and subcrestal placement in a 1.5 mm bone loss. The histometric measurements resulted in a distance A/F-B of 0.6 and 0.0 mm for PS implants, placed in a crestal or subcrestal position, respectively. The corresponding distance at PM-implants was 1.5 mm irrespective of placement protocol. The peri-implant mucosa was thicker at subcrestally placed implants as compared to a crestal placement. CONCLUSIONS: Bone remodeling occurred within the early healing phase. During the full 20 weeks of observation, PS-implants demonstrated significantly less crestal bone loss compared to PM-implants. PMID- 30009477 TI - Functional connectivity in category-selective brain networks after encoding predicts subsequent memory. AB - Activity in category selective regions of the temporal and parietal lobes during encoding has been associated with subsequent memory for face and scene stimuli. Reactivation theories of memory consolidation predict that after encoding connectivity between these category-selective regions and the hippocampus should be modulated and predict recognition memory. However, support for this proposal has been limited in humans. Here, participants completed a resting-state functional MRI (fMRI) scan, followed by face- and place-encoding tasks, followed by another resting-state fMRI scan during which they were asked to think about the stimuli they had previously encountered. Individual differences in face recognition memory were predicted by the degree to which connectivity between face-responsive regions of the fusiform gyrus and perirhinal cortex increased following the face-encoding task. In contrast, individual differences in scene recognition were predicted by connectivity between the hippocampus and a scene selective region of the retrosplenial cortex before and after the place-encoding task. Our results provide novel evidence for category specificity in the neural mechanisms supporting memory consolidation. PMID- 30009475 TI - Recurrent aphthous stomatitis may be a precursor or risk factor for specific cancers: A case-control frequency-matched study. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is considered a prophase symptom in patients with specific cancers. This study assessed the association between RAS and subsequent onset of cancer based on a nationwide population-based database in Taiwan. MATERIALS AND METHODS: We selected study participants from the National Health Insurance Research Database from January 2000 to December 2008. Patients in the non-RAS cohort were matched to case study patients at a 1:1 ratio through frequency matching. All participants were followed up for at least 5 years, and those who received cancer diagnoses during follow-up were identified. RESULTS: Among 52 307 patients with and 52 304 patients without RAS, the combined hazard ratio (HR) of all subsequent cancer cases was 1.3 (95% confidence interval [CI]: 1.25-1.35, P = 0). RAS diagnosis was associated with risk for cancers of the head and neck (aHR = 2, 95% CI: 1.8-2.3), colon (aHR = 1.2, 95% CI: 1.1-1.4), liver (aHR = 1.1, 95% CI: 1-1.3), pancreas (aHR = 1.4, 95% CI: 1.1-1.7), skin (aHR = 1.4, 95% CI: 1.2-1.7), breast (aHR = 1.2, 95% CI: 1.1 1.4), and prostate (aHR = 1.5, 95% CI: 1.3-1.8), as well as hematologic cancers (aHR = 1.6, 95% CI: 1.3-1.9). A higher risk was observed for male patients (aHR = 1.35, 95% CI: 1.28-1.42) than for female patients (aHR = 1.25, 95% CI: 1.18-1.31) with RAS. CONCLUSIONS: RAS was associated with specific cancers. Susceptible RAS patients should be screened for specific cancers. PMID- 30009478 TI - Further applications of classical amide coupling reagents: Microwave-assisted esterification on solid phase. AB - Ester linkage (s) is a key chemical connector in organic chemistry, including natural products, peptides, and synthetic polymers. We herein describe a straightforward method for the efficient formation of ester linkage (s) on solid phase. This method simply involves the use of amide coupling reagents under microwave irradiation. The robustness of this method relies on the use of classical solid-phase coupling reagents, heating by microwave irradiation, and a short time period, which results in high yields and the minimization of racemization. PMID- 30009479 TI - Use of ambiguous detections to improve estimates from species distribution models. AB - As large carnivores recover throughout Europe, their distribution needs to be studied to determine their conservation status and assess the potential for human carnivore conflicts. However, efficient monitoring of many large carnivore species is challenging due to their rarity, elusive behavior, and large home ranges. Their monitoring can include opportunistic sightings from citizens in addition to designed surveys. Two types of detection errors may occur in such monitoring schemes: false negatives and false positives. False-negative detections can be accounted for in species distribution models (SDMs) that deal with imperfect detection. False-positive detections, due to species misidentification, have rarely been accounted for in SDMs. Generally, researchers use ad hoc data-filtering methods to discard ambiguous observations prior to analysis. These practices may discard valuable ecological information on the distribution of a species. We investigated the costs and benefits of including data types that may include false positives rather than discarding them for SDMs of large carnivores. We used a dynamic occupancy model that simultaneously accounts for false negatives and positives to jointly analyze data that included both unambiguous detections and ambiguous detections. We used simulations to compare the performances of our model with a model fitted on unambiguous data only. We tested the 2 models in 4 scenarios in which parameters that control false-positive detections and true detections varied. We applied our model to data from the monitoring of the Eurasian lynx (Lynx lynx) in the European Alps. The addition of ambiguous detections increased the precision of parameter estimates. For the Eurasian lynx, incorporating ambiguous detections produced more precise estimates of the ecological parameters and revealed additional occupied sites in areas where the species is likely expanding. Overall, we found that ambiguous data should be considered when studying the distribution of large carnivores through the use of dynamic occupancy models that account for misidentification. PMID- 30009480 TI - Different associations between body composition and alcohol when assessed by exposure frequency or by quantitative estimates of consumption. AB - BACKGROUND: Alcohol intake is widely assumed to contribute to excess body fatness, especially among young men; however, the evidence is inconsistent. We have addressed this research question by investigating associations between reported alcohol consumption and body composition from large representative national surveys in a high alcohol-consuming country with a high obesity prevalence. METHODS: The present study comprised a secondary analysis of combined cross-sectional nationally representative Scottish Health Surveys (1995-2010). Reported alcohol-drinking frequency was divided into five groups: from 'nonfrequent drinking' (reference) to daily/'almost every day' among 35 837 representative adults [mean (SD) age: 42.7 (12.7) years (range 18-64 years)]. Quantitative alcohol consumption was categorised into seven groups: from '1-7 to >=50 10 g units per week'. Regression models against measured body mass index (BMI) and waist circumference (WC) were adjusted for age, physical activity, income, smoking, deprivation category and economic status. RESULTS: Among alcohol consuming men, heavier drinking (21-28 units per week) was associated with a higher BMI by +1.4 kg m-2 [95% confidence interval (CI) = 1.38-1.43] and higher WC by +3.4 cm (95% CI = 3.2-3.6) than drinking 1-7 units per week. However, those who reported daily drinking frequency were associated with a lower BMI by -2.45 kg m-2 (95% CI = -2.4 to -2.5) and lower WC by -3.7 cm (95% CI = -3.3 to -4.0) than those who reported less-frequent drinking. Similar associations were found for women. Most of these associations were restricted to subjects aged >30 years. Unexplained variances in BMI and WC are large. CONCLUSIONS: Quantitative alcohol consumption and frequency of consumption were positively and inversely associated, respectively, with both BMI and WC among alcohol-consuming adults. Surveys are needed that evaluate both the quantity and frequency of consumption. The lowest BMI and WC were associated with a 'Mediterranean' drinking style (i.e. relatively little, but more frequently). PMID- 30009481 TI - Development, commissioning, and evaluation of a new intensity modulated minibeam proton therapy system. AB - PURPOSE: To invent, design, construct, and commission an intensity modulated minibeam proton therapy system (IMMPT) without the need for physical collimation and to compare its resulting conformity to a conventional IMPT system. METHODS: A proton therapy system (Hitachi, Ltd, Hitachi City, Japan; Model: Probeat-V) was specially modified to produce scanned minibeams without collimation. We performed integral depth dose acquisitions and calibrations using a large diameter parallel plate ionization chamber in a scanning water phantom (PTW, Freiburg, Germany; Models: Bragg Peak ionization chamber, MP3-P). Spot size and shape was measured using radiochromic film (Ashland Advanced Materials, Bridgewater NJ; Type: EBT3), and a synthetic diamond diode type scanned point by point in air (PTW Models: MicroDiamond, MP3-P). The measured data were used as inputs to generate a Monte Carlo-based model for a commercial radiotherapy planning system (TPS) (Varian Medical Systems, Inc., Palo Alto, CA; Model: Eclipse v13.7.15). The regular ProBeat-V system (sigma ~2.5 mm) TPS model was available for comparison. A simulated base of skull case with small and medium targets proximal to brainstem was planned for both systems and compared. RESULTS: The spot sigma is determined to be 1.4 mm at 221 MeV at the isocenter and below 1 mm at proximal distances. Integral depth doses were indistinguishable from the standard spot commissioning data. The TPS fit the spot profiles closely, giving a residual error maximum of 2.5% in the spot penumbra tails (below 5% of maximum) from the commissioned energies 69.4 to 221.3 MeV. The resulting IMMPT plans were more conformal than the IMPT plans due to a sharper dose gradient (90-10%) 1.5 mm smaller for the small target, and 1.3 mm for the large target, at a representative central axial water equivalent depth of 7 cm. CONCLUSIONS: We developed, implemented, and tested a new IMMPT system. The initial results look promising in cases where treatments can benefit from additional dose sparing to neighboring sensitive structures. PMID- 30009482 TI - Prenatally diagnosed congenital lung malformations-A long-term outcome study. AB - AIM: To report the natural history of a cohort of children with prenatally diagnosed congenital lung malformations (CLM) which we set out to manage expectantly. METHODS: Retrospective review of children born between 1995 and 2013 with a CLM identified on prenatal ultrasound. Prenatal ultrasound data were analyzed along with patient medical records, radiology, and pathology. RESULTS: One hundred fifty-nine newborns with a fetal lung lesion were identified during the study period. All infants were live born. Twenty-eight (18%) newborns were symptomatic, 17 with transient symptoms, and 11 with persistent symptoms. The latter all underwent lobectomy in the neonatal period with two postoperative deaths. One hundred thirty-one asymptomatic newborns plus the 17 babies with transient symptoms (148 total) were followed during childhood for a median of 6.0 years (0.1-19.2 years). Twenty-one children (13% of the original cohort of 159) became symptomatic at a median age of 2.5 years (9 months-5 years 8 months) with infection and underwent CLM resection. No child became symptomatic after the age of 5 years 8 months. One hundred twenty-seven children remained symptom free during follow-up for a median of 5.75 years (1 month-19 years). We saw no instance of malignancy in the resected specimens. CONCLUSIONS: This study adds further evidence that most children born with CLM identified prenatally are asymptomatic at birth and the majority will remain asymptomatic during childhood. We recommend follow-up to the age of 10 years. PMID- 30009483 TI - Quantitative Proteomic Analysis of Biological Processes and Responses of the Bacterium Desulfovibrio desulfuricans ND132 upon Deletion of Its Mercury Methylation Genes. AB - Recent studies of microbial mercury (Hg) methylation revealed a key gene pair, hgcAB, which is essential for methylmercury (MeHg) production in the environment. However, many aspects of the mechanism and biological processes underlying Hg methylation, as well as any additional physiological functions of the hgcAB genes, remain unknown. Here, quantitative proteomics are used to identify changes in potential functional processes related to hgcAB gene deletion in the Hg methylating bacterium Desulfovibrio desulfuricans ND132. Global proteomics analyses indicate that the wild type and DeltahgcAB strains are similar with respect to the whole proteome and the identified number of proteins, but differ significantly in the abundance of specific proteins. The authors observe changes in the abundance of proteins related to the glycolysis pathway and one-carbon metabolism, suggesting that the hgcAB gene pair is linked to carbon metabolism. Unexpectedly, the authors find that the deletion of hgcAB significantly impacts a range of metal transport proteins, specifically membrane efflux pumps such as those associated with heavy metal copper (Cu) export, leading to decreased Cu uptake in the DeltahgcAB mutant. This observation indicates possible linkages between this set of proteins and metal homeostasis in the cell. However, hgcAB gene expression is not induced by Hg, as evidenced by similarly low abundance of HgcA and HgcB proteins in the absence or presence of Hg (500 nm). Taken together, these results suggest an apparent link between HgcAB, one-carbon metabolism, and metal homeostasis, thereby providing insights for further exploration of biochemical mechanisms and biological functions of microbial Hg methylation. PMID- 30009484 TI - Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]-gingerol in cancer: A comprehensive review. AB - Natural dietary agents have attracted considerable attention due to their role in promoting health and reducing the risk of diseases including cancer. Ginger, one of the most ancient known spices, contains bioactive compounds with several health benefits. [6]-Gingerol constitutes the most pharmacologically active among such compounds. The aim of the present work was to review the literature pertaining to the use of ginger extract and [6]-gingerol against tumorigenic and oxidative and inflammatory processes associated with cancer, along with the underlying mechanisms of action involved in signaling pathways. This will shed some light on the protective or therapeutic role of ginger derivatives in oxidative and inflammatory regulations during metabolic disturbance and on the antiproliferative and anticancer properties. Data collected from experimental (in vitro or in vivo) and clinical studies discussed in this review indicate that ginger extract and [6]-gingerol exert their action through important mediators and pathways of cell signaling, including Bax/Bcl2, p38/MAPK, Nrf2, p65/NF kappaB, TNF-alpha, ERK1/2, SAPK/JNK, ROS/NF-kappaB/COX-2, caspases-3, -9, and p53. This suggests that ginger derivatives, in the form of an extract or isolated compounds, exhibit relevant antiproliferative, antitumor, invasive, and anti inflammatory activities. PMID- 30009485 TI - Lactobacillus parafarraginis ZH1 producing anti-yeast substances to improve the aerobic stability of silage. AB - Enhancing the aerobic stability of silage is very important in silage production. The objective of this study was to compare the roles of a new bacterial strain Lactobacillus parafarraginis ZH1 with Lactobacillus plantarum Chikuso-1 (LP) and Lactobacillus buchneri NCIMB 40788 (LB) in improving the aerobic stability of oat silage and identify the anti-yeast substances produced by them. After ensiled for 45 days, either inoculated silages or control silage were of pH values lower than 4.2. The control and LP inoculated silage had poorer aerobic stability than LB and ZH1 inoculated ones (p < 0.05). ZH1 inoculated silage produced more acetic acid, benzoic acid and hexadecanoic acid than LB inoculated one and had the best aerobic stability (p < 0.05). In MRS medium, strain ZH1 produced more hexadecanoic acid than LP and LB strains, more benzoic acid than strain LP (p < 0.05), and the equal amount of benzoic acid to LB (p > 0.05). In addition, benzoic acid and hexadecanoic acid had low minimal inhibitory concentrations to target yeasts in the pure culture. In conclusion, L. parafarraginis ZH1 had stronger anti-yeast potential and more effectively improved the aerobic stability of silage than other strains used in this study. PMID- 30009486 TI - The complex drivers of thermal acclimation and breadth in ectotherms. AB - Thermal acclimation capacity, the degree to which organisms can alter their optimal performance temperature and critical thermal limits with changing temperatures, reflects their ability to respond to temperature variability and thus might be important for coping with global climate change. Here, we combine simulation modelling with analysis of published data on thermal acclimation and breadth (range of temperatures over which organisms perform well) to develop a framework for predicting thermal plasticity across taxa, latitudes, body sizes, traits, habitats and methodological factors. Our synthesis includes > 2000 measures of acclimation capacities from > 500 species of ectotherms spanning fungi, invertebrates, and vertebrates from freshwater, marine and terrestrial habitats. We find that body size, latitude, and methodological factors often interact to shape acclimation responses and that acclimation rate scales negatively with body size, contributing to a general negative association between body size and thermal breadth across species. Additionally, we reveal that acclimation capacity increases with body size, increases with latitude (to mid latitudinal zones) and seasonality for smaller but not larger organisms, decreases with thermal safety margin (upper lethal temperature minus maximum environmental temperatures), and is regularly underestimated because of experimental artefacts. We then demonstrate that our framework can predict the contribution of acclimation plasticity to the IUCN threat status of amphibians globally, suggesting that phenotypic plasticity is already buffering some species from climate change. PMID- 30009487 TI - Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy. AB - OBJECTIVE: With the exception of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDTs) are unknown. We aimed to determine whether common variation across the genome influences the response to KDT for epilepsy. METHODS: We genotyped individuals who were negative for glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Genotyping was performed with the Infinium HumanOmniExpressExome Beadchip. Hospital records were used to obtain demographic and clinical data. KDT response (>=50% seizure reduction) at 3-month follow-up was used to dissect out nonresponders and responders. We then performed a genome wide association study (GWAS) in nonresponders vs responders, using a linear mixed model and correcting for population stratification. Variants with minor allele frequency <0.05 and those that did not pass quality control filtering were excluded. RESULTS: After quality control filtering, the GWAS of 112 nonresponders vs 123 responders revealed an association locus at 6p25.1, 61 kb upstream of CDYL (rs12204701, P = 3.83 * 10-8 , odds ratio [A] = 13.5, 95% confidence interval [CI] 4.07-44.8). Although analysis of regional linkage disequilibrium around rs12204701 did not strengthen the likelihood of CDYL being the candidate gene, additional bioinformatic analyses suggest it is the most likely candidate. SIGNIFICANCE: CDYL deficiency has been shown to disrupt neuronal migration and to influence susceptibility to epilepsy in mice. Further exploration with a larger replication cohort is warranted to clarify whether CDYL is the causal gene underlying the association signal. PMID- 30009489 TI - Corrigendum. PMID- 30009488 TI - Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vgamma9gammadeltaT cells and Valpha24NKT cells in patients with glioblastoma multiforme and in healthy donors. AB - The finding that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs for developing more effective vaccines for DC therapy. The expression of cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) presents a unique opportunity to target these viral proteins for tumour immunotherapy. Here, we demonstrate that Vgamma9gammadeltaT cells, innate immune cells activated by zoledronate (Z) and Valpha24 natural killer (Valpha24NK) cells, innate/adaptive immune cells activated by alpha galactosylceramide (G) can link innate and adaptive immunities through cross-talk with interferon (IFN) DCs from patients with glioblastoma multiforme (GBM) and healthy donors in a manner that can amplify the activation and proliferation of CMVpp65-specific CD8+ T cells. The IFN DCs derived from patients with GBM used in this study express lower levels of programmed cell death ligand (PD)-L1 and PD-L2 and higher levels of C-C receptor 7 (CCR7) than the most commonly used mature interleukin (IL)-4 DCs. The expression level of programmed cell death 1 (PD-1) on CD8+ T cells, including CMVpp65-specific CD8+ T cells, expanded by IFN DCs pulsed with the CMVpp65-peptide and Z plus G (IFN DCs/P+Z+G), was lower than that expanded by IFN DCs pulsed with the peptide alone (IFN DCs/P). Multi-functional T cells, including human leucocyte antigen (HLA)-A*0201-restricted CMVpp65-specific CD8+ T cells, Vgamma9gammadeltaT cells and Valpha24NKT cells, efficiently kill the HLA-A*0201-positive GBM cell line expressing CMVpp65 protein (T98G). These findings indicate that DC therapy using IFN DCs/P+Z+G and/or CTL therapy using CMVpp65-specific CD8+ T cells expanded by IFN DCs/P+Z+G may lead to a good clinical outcome for patients with GBM. PMID- 30009490 TI - Evaluation of the efficacy of transdermal drug delivery of calcipotriol plus betamethasone versus tacrolimus in the treatment of vitiligo. AB - BACKGROUND: Vitiligo is a common pigmentary disorder affecting about 1% of the general population. There are numerous medical and surgical treatments. Microneedling is an evolving treatment technique for an expanding number of dermatologic conditions. It is used also to augment transdermal drug delivery through pores created in the stratum corneum. AIM: To evaluate the efficacy of microneedling with tacrolimus versus its efficacy with calcipotriol plus betamethasone in vitiligo treatment. METHODS: Twenty-five patients having vitiligo were selected and their symmetrical patches were divided into side A (right side) which received microneedling with dermapen and topical calcipotriol plus betamethasone and side B (left side) which received microneedling and topical tacrolimus. Every patient received a session every 2 weeks for a maximum 6 months (12 sessions) and follow-up for 3 months. Skin biopsies were taken before and after the treatment to evaluate the clinical results. RESULTS: On side A, 60% of the patients showed excellent improvement while 32% showed excellent response on side B. The mean percentage of improvement was significantly higher on side A than side B (P = 0.017* ). It was effective in the most resistant sites of vitiligo such as: elbows, knees, extremities, and acral area. Histopathological examination showed a significant expression of HMB45 on side A more than side B (P = 0.005* ). CONCLUSION: The combination of microneedling with calcipotriol plus betamethasone is more effective than its combination with tacrolimus. They are both effective in resistant sites. Both methods are safe, cheap, and good tolerated office techniques with minimal side effects. PMID- 30009491 TI - Remembering resiliency. PMID- 30009492 TI - SpheroidSim-Preliminary evaluation of a new computational tool to predict the influence of cell cycle time and phase fraction on spheroid growth. AB - BACKGROUND: There is a relative paucity of research that integrates materials science and bioengineering with computational simulations to decipher the intricate processes promoting cancer progression. Therefore, a first-generation computational model, SpheroidSim, was developed that includes a biological data set derived from a bioengineered spheroid model to obtain a quantitative description of cell kinetics. RESULTS: SpheroidSim is a 3D agent-based model simulating the growth of multicellular cancer spheroids. Cell cycle time and phases mathematically motivated the population growth. SpheroidSim simulated the growth dynamics of multiple spheroids by individually defining a collection of specific phenotypic traits and characteristics for each cell. Experimental data derived from a hydrogel-based spheroid model were fit to the predictions providing insight into the influence of cell cycle time (CCT) and cell phase fraction (CPF) on the cell population. A comparison of the number of active cells predicted for each analysis showed that the value and method used to define CCT had a greater effect on the predicted cell population than CPF. The model predictions were similar to the experimental results for the number of cells, with the predicted total number of cells varying by 8% and 12%, respectively, compared to the experimental data. CONCLUSIONS: SpheroidSim is a first step in developing a biologically based predictive tool capable of revealing fundamental elements in cancer cell physiology. This computational model may be applied to study the effect of the microenvironment on spheroid growth and other cancer cell types that demonstrate a similar multicellular clustering behavior as the population develops. PMID- 30009493 TI - Enhancement of Istrian Malvasia wine aroma and hydroxycinnamate composition by hand and mechanical leaf removal. AB - BACKGROUND: Leaf removal is a viticultural practice that promotes the biosynthesis of several important grape constituents by improving fruit zone microclimate. The purpose of this study was to assess the effects of hand and mechanical leaf removal, applied at the pea-size stage of berry development, on fruit zone microclimate, volatile aroma compounds, hydroxycinnamates and sensory characteristics of Istrian Malvasia (Vitis vinifera L.) wines. Three different sunlight exposure conditions were applied: hand leaf removal (HLR), mechanical leaf removal (MLR) and untreated control (UC). RESULTS: Both leaf removal treatments, and especially the more intense HLR, significantly increased the concentration of varietal thiol 3-sulfanylhexan-1-ol, monoterpenes, beta damascenone and esters. The higher concentration of these aromas contributed to the improvement of wine sensory quality, as expressed by more enhanced floral, fruity and tropical sensory attributes in leaf removal treatments. Hydroxycinnamates were increased only by HLR, a treatment with a greater degree of fruit exposure to sunlight than MLR. CONCLUSION: Leaf removal applied at the pea-size stage of berry development in a season characterized by abundant rainfall improves both the chemical composition and sensory quality of Istrian Malvasia wine, even when performed by machine, implying that this technique might be successfully applied in large-scale viticultural production. (c) 2018 Society of Chemical Industry. PMID- 30009494 TI - Computer-based training to detect antecedents and consequences of problem behavior. AB - Training teachers and paraprofessionals to detect and record putative antecedents and consequences of problem behavior in the classroom has a number of potential benefits. In this study, we evaluated the outcomes of a computer-based training program consisting of lectures, models, and practice. A total of 39 teachers and paraprofessionals participated. Participants scored videos of teacher-student interactions after completing components of the instruction. The study was designed to evaluate the incremental contribution of instruction focused on (a) single exemplars of antecedents and consequences, (b) multiple exemplars of antecedents and consequences, and (c) simultaneously occurring antecedents and consequences. Training to detect simultaneously occurring events was necessary for the majority of participants to reach high levels of performance. The findings support the efficacy of computer-based training and indicate the necessary and sufficient components of this training. PMID- 30009495 TI - Therapeutic Plasma Exchange Outcomes in Cairo University Hospitals: 6 Years Experience. AB - Therapeutic plasma exchange is used in treating different immunological and non immunological diseases. We analyzed the outcome of 308 patients treated by 1783 membrane plasma exchange sessions from January 2011 until January 2017 at Cairo University Hospital. Thrombotic microangiopathies were the commonest indication [73 (23.7%) patients] with response in 63/73 patients (86.3%), followed by systemic vasculitis with pulmonary-renal involvement [40(13%) patients] with recovery in 32/40 patients (80.0%), Guillain-Barre syndrome [39(12.7%) patients] with recovery in 30/39 patients (76.9%), myasthenia gravis [31(10.1%) patients] with response in 26/31 patients (83.9%), and catastrophic antiphospholipid syndrome [28(9.1%) patients] with recovery in only 6/28 patients (21.4%). Complications included hypotension [276/1783 (15.5%) sessions], hypocalcemia [26/308 (8.5%) patients], and 37/308 (12%) patients died. Sepsis caused mortality in 29/37 (78.4%) of patients. In conclusion, our therapeutic plasma exchange experience shows a favorable outcome for thrombotic microangiopathies, systemic vasculitis, myasthenia gravis, and Guillain-Barre syndrome. Sepsis was the leading mortality cause. PMID- 30009496 TI - Common garden experiments disentangle plant genetic and environmental contributions to ectomycorrhizal fungal community structure. AB - The interactions among climate change, plant genetic variation and fungal mutualists are poorly understood, but probably important to plant survival under drought. We examined these interactions by studying the ectomycorrhizal fungal (EMF) communities of pinyon pine seedlings (Pinus edulis) planted in a wildland ecosystem experiencing two decades of climate change-related drought. We established a common garden containing P. edulis seedlings of known maternal lineages (drought tolerant, DT; drought intolerant, DI), manipulated soil moisture and measured EMF community structure and seedling growth. Three findings emerged: EMF community composition differed at the phylum level between DT and DI seedlings, and diversity was two-fold greater in DT than in DI seedlings. EMF communities of DT seedlings did not shift with water treatment and were dominated by an ascomycete, Geopora sp. By contrast, DI seedlings shifted to basidiomycete dominance with increased moisture, demonstrating a lineage by environment interaction. DT seedlings grew larger than DI seedlings in high (28%) and low (50%) watering treatments. These results show that inherited plant traits strongly influence microbial communities, interacting with drought to affect seedling performance. These interactions and their potential feedback effects may influence the success of trees, such as P. edulis, in future climates. PMID- 30009497 TI - Diagnostic performance of CA 125, HE4, and risk of Ovarian Malignancy Algorithm for ovarian cancer. AB - OBJECTIVE: We evaluated the diagnostic performance of CA 125, HE4, and ROMA for ovarian cancer in Koreans and set optimal cutoffs. METHOD: Serum levels of HE4 and CA 125 and the ROMA score were determined in 762 patients with benign gynecological disease and 70 with ovarian cancer. Receiver operating characteristic curves were constructed to calculate the areas under the curve (AUC). CA 125, HE4, and ROMA exhibiting maximum Youden index were determined, respectively, as the optimal cutoffs, and sensitivity and specificity were evaluated by applying those cutoffs. RESULTS: In benign diseases, CA 125 significantly increased in patients with uterine myoma, adenomyosis, endometrial pathology, or endometriosis, but HE4 only increased in patients with adenomyosis. For the diagnosis of ovarian cancer, the combination of CA 125, HE4, and age showed the highest AUC value of 0.892 in the premenopausal group, and ROMA demonstrated the best diagnostic performance, with an AUC of 0.935 in postmenopausal patients. When the optimal cutoff values for CA 125 and HE4 were applied, the sensitivities of CA 125, HE4, and ROMA in premenopausal women were all the same at 0.714, while the specificities were 0.841, 0.974, and 0.972, respectively. In the postmenopausal group, the sensitivities of these markers were 0.857, 0.804, and 0.929, and the specificities were 0.836, 0.887, and 0.800, respectively. CONCLUSION: Although all markers demonstrated good diagnostic performance, they varied depending on the pathologic types of benign diseases and ovarian cancer. For accurate diagnosis of ovarian cancer, CA 125, HE4, and ROMA should be used complementarily. PMID- 30009498 TI - Phenolic composition and total antioxidant capacity of South African frozen concentrated orange juice as affected by varietal, seasonal and regional differences. AB - BACKGROUND: There is epidemiological evidence that fruits and vegetables promote general health due to their phenolic composition. The phenolic composition of three commercially important citrus varieties ('Mandarin', 'Navel' orange and 'Valencia' orange), used for frozen concentrated orange juice (FCOJ) production in South Africa, were evaluated based on variety, production season and geographical region (Western Cape (WC) and Eastern Cape (EC)). RESULTS: FCOJ from the WC had significantly (P < 0.05) lower titratable acidity (TA) and higher total soluble solids (TSS):TA ratio compared to FCOJ produced in the EC. The 'Navel' FCOJ, irrespective of season and region, had the highest (P < 0.05) phenolic content (sum of quantified compounds, TP). Regional effects were clear for the 'Mandarin' variety, the EC 'Mandarin' FCOJ had the highest TP and WC 'Mandarin' had the lowest. Seasonal differences were less evident. Variation that could be ascribed to regional differences were also found for individual phenolic compounds. CONCLUSION: Robust data regarding the phenolic profile of FCOJ produced in South Africa, suitable for inclusion in food composition databases, were collected. (c) 2018 Society of Chemical Industry. PMID- 30009499 TI - Hepatitis C viral infection and imprisonment among Aboriginal and Torres Strait Islander and non-Indigenous people who inject drugs. AB - INTRODUCTION AND AIMS: An understanding of the relationship between hepatitis C viral (HCV) infection and contextual factors such as imprisonment may contribute to the development of targeted treatment and prevention programs. We examine the associations of imprisonment and drug dependence with lifetime exposure to HCV, and whether these associations differ for Aboriginal and Torres Strait Islander and non-Indigenous people who inject drugs. DESIGN AND METHODS: Respondent-driven sampling was used in major cities and 'peer recruitment' in regional towns of Queensland to obtain a community sample of people who injected drugs, which comprised 243 Indigenous and 227 non-Indigenous participants who had ever been tested for HCV. Data are cross-sectional. Two binary Poisson models were developed to examine associations for variables relating to imprisonment, Indigeneity and drug use history. RESULTS: Sharing needles and syringes in prison (adjusted risk ratio 1.25, 95% confidence interval 1.02-1.53) remained significantly associated with HCV infection after adjustment for Indigeneity, injecting drug use history and drug dependence. Opioid dependence and concurrent dependence on opioids and methamphetamine was also independently associated with HCV infection. DISCUSSION AND CONCLUSIONS: Sharing needles and syringes in prison is linked with HCV infection, for both Aboriginal and Torres Strait Islander and non-Indigenous people who inject drugs. Further development of treatment and prevention programs in prisons is required, with consideration of the role of opioid and methamphetamine dependence in HCV exposure. PMID- 30009500 TI - Second-order calibration serves as a remedial measure for the simultaneous determination of andrographolide and dehydroandrographolide in Andrographis paniculata and its preparations by HPLC without complete baseline separation. AB - In this work, high-performance liquid chromatography with diode array detection was applied for the simultaneous determination of andrographolide and dehydroandrographolide in Andrographis paniculata and its preparations. As a result of the incomplete baseline separation caused by complex backgrounds, the classical univariate calibration method failed to determine accurate contents of the analytes. On this occasion, chemometric second-order calibration based on the well-known alternating trilinear decomposition algorithm was then explored to serve as a post-experimental remedial tool to solve this problem. By using the intelligent "mathematical separation" of alternating trilinear decomposition, the peak areas of the analytes do not need to be directly measured and the predictive results become accurate. The contents of andrographolide and dehydroandrographolide were determined to be (7.95 +/- 0.15) and (1.85 +/- 0.02) MUg/mL for Andrographis paniculata, (1.34 +/- 0.01) and (5.53 +/- 0.04) MUg/mL for its preparations, which was in agreement with those obtained by a reference liquid chromatography with mass spectrometry method. This study showed the superiority of second-order calibration method over classical univariate calibration method for simultaneous determination of multi-analytes in complex samples. It also proved that second-order calibration may be a good choice for remedying incomplete baseline separation problem, with the accompanied reduction of experimental burden and toxic organic solvents as well as analysis time and cost. PMID- 30009501 TI - Surveillance imaging for high-grade childhood brain tumors: What to do 10 years after completion of treatment? AB - Brain tumors are the second most common childhood cancer. Treatment protocols for high-grade pediatric brain tumors recommend regular follow-up imaging for up to 10 years. We review maximal time to recurrence and minimal time to radiologically detectable long-term sequelae such as secondary malignancies, vascular complications, and white matter disease. No tumors recurred after the 10-year point, but radiological long-term sequelae grew more common as the treatment completion date receded. We do not recommend regular imaging more than 10 years after treatment has ended, unless there are clinical symptoms. PMID- 30009502 TI - Polymorphisms of dopamine receptor genes DRD2 and DRD4 in African populations of Hadza and Datoga differing in the level of culturally permitted aggression. AB - The key regulator in the control of aggressive behavior is dopamine receptors. Association of variants in these genes with aggression has been shown in modern populations. However, these studies have not been conducted in traditional cultures. The aim of our study was to investigate population features in distributions of allele and genotype frequencies of DRD2 rs1800497, DRD4 120 bp Ins, and DRD4 exon III polymorphisms and their associations with aggressive behavior in the traditional African populations of Hadza and Datoga, which display a contrast in their culturally permitted aggression. Overall, 820 healthy unrelated Hadza and Datoga individuals were studied. Self-rated scores of aggression were collected using Buss and Perry's Aggression Questionnaire. Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotype of each individual. We show that the Hadza and the Datoga differed significantly in allele and genotype frequencies of all studied loci. Our association analysis detected that only ethnicity and sex of individuals significantly influenced their aggression rank, but we failed to identify any associations of DRD2 rs1800497, DRD4 120 bp Ins, or DRD4 exon III polymorphisms with aggression. Thus, our data have no strong evidence to support the involvement of polymorphisms of DRD2 and DRD4 in controlling aggressive behavior. PMID- 30009503 TI - Exendin-4 enhances radiation response of prostate cancer. AB - BACKGROUND: Exendin-4, one of the most widely used antidiabetic drugs, has recently been reported to have potential antitumor effects in cancers. Prostate cancer (PC) is one of the most common cancers in male patients with type 2 diabetes mellitus, and radiotherapy plays a vital role in the therapy of PC. Whether exendin-4 has the potential to enhance PC response to ionizing radiation (IR) remains unknown. We aimed to explore whether exendin-4 radiosensitizes PC cells. METHODS: GLP-1 receptor (GLP-1R) expression in PC tissue samples and cell lines were analyzed, Human prostate cancer cells (PC3 and LNCap) were treated with IR and exendin-4, and subjected to proliferation, clone formation, cell cycle, immunoblotting, and immunohistochemical analysis. An in situ prostate tumor of animal model was established. RESULTS: We found that GLP-1R was expressed in human PC tissues and cell lines. 1-100 nM exendin-4 promoted the anti-proliferation effects of IR in vitro and in vivo, and enhanced radiation induced G2/M cycle arrest in PC cells in a dose-dependent manner. Furthermore, Ex 4 increased AMPK phosphorylation, decrease the levels of p-mTOR, cyclin B, and p34cdc2 . CONCLUSIONS: Our study suggested exendin-4 radiosensitizes PC cells via activation of AMPK A and subsequent inhibition of p-mTOR, cyclin B, and p34cdc2 activation. PMID- 30009504 TI - Regulation of ELL2 stability and polyubiquitination by EAF2 in prostate cancer cells. AB - BACKGROUND: Elongation factor for RNA polymerase 2 (ELL2) and ELL associated factor 2 (EAF2) have been reported to have tumor suppressive properties in prostate epithelial cells. AIMS: We investigated ELL2 expression in human prostate cancer specimens, and ELL2 protein stability and ubiquitination in prostate cancer cells. MATERIALS AND METHODS: Immunostaining analysis of human prostate cancer specimens was used to determine ELL2 expression in tumor and normal tissues. ELL2 knockdown in prostate cancer cell lines LNCaP and C4-2 was used to compare proliferation and motility. Deletion and site-directed mutagenesis was used to identify amino acid residues in ELL2 that were important for degradation. RESULTS: ELL2 protein was downregulated in prostate cancer specimens and was up-regulated by androgens in prostate cancer cell lines LNCaP and C4-2. ELL2 knockdown enhanced prostate cancer cell proliferation and motility. ELL2 protein has a short half-life and was stabilized by proteasome inhibitor MG132. Amino acid residues K584 and K599 in ELL2 were important for ELL2 degradation. EAF2 could stabilize ELL2 and inhibited its polyubiquitination. CONCLUSION: Our findings provide further evidence that ELL2 is a potential tumor suppressor frequently down-regulated in clinical prostate cancer specimens and provides new insights into regulation of ELL2 protein level by polyubiquitination and EAF2 binding. PMID- 30009505 TI - Charged Si9 Clusters in Neat Solids and the Detection of [H2 Si9 ]2- in Solution: A Combined NMR, Raman, Mass Spectrometric, and Quantum Chemical Investigation. AB - Polyanionic silicon clusters are provided by the Zintl phases K4 Si4 , comprising [Si4 ]4- units, and K12 Si17 , consisting of [Si4 ]4- and [Si9 ]4- clusters. A combination of solid-state MAS-NMR, solution NMR, and Raman spectroscopy, electrospray ionization mass spectrometry, and quantum-chemical investigations was used to investigate four- and nine-atomic silicon Zintl clusters in neat solids and solution. The results were compared to 29 Si isotope-enriched samples. 29 Si-MAS NMR and Raman shifts of the phase-pure solids K4 Si4 and K12 Si17 were interpreted by quantum-chemical calculations. Extraction of [Si9 ]4- clusters from K12 Si17 with liquid ammonia/222crypt and their transfer to pyridine yields in a red solid containing Si9 clusters. This compound was characterized by elemental and EDX analyses and 29 Si-MAS NMR and Raman spectroscopy. Charged Si9 clusters were detected by 29 Si NMR in solution. 29 Si and 1 H NMR spectra reveal the presence of the [H2 Si9 ]2- cluster anion in solution. PMID- 30009506 TI - Quantitative depolarization measurements for fiber-based polarization-sensitive optical frequency domain imaging of the retinal pigment epithelium. AB - A full quantitative evaluation of the depolarization of light may serve to assess concentrations of depolarizing particles in the retinal pigment epithelium and to investigate their role in retinal diseases in the human eye. Optical coherence tomography and optical frequency domain imaging use spatial incoherent averaging to compute depolarization. Depolarization depends on accurate measurements of the polarization states at the receiver but also on the polarization state incident upon and within the tissue. Neglecting this dependence can result in artifacts and renders depolarization measurements vulnerable to birefringence in the system and in the sample. In this work, we discuss the challenges associated with using a single input polarization state and traditional depolarization metrics such as the degree-of-polarization and depolarization power. We demonstrate quantitative depolarization measurements based on Jones vector synthesis and polar decomposition using fiber-based polarization-sensitive optical frequency domain imaging of the retinal pigment epithelium in a human eye. PMID- 30009507 TI - Resistance exercise stimulates mixed muscle protein synthesis in lean and obese young adults. AB - Obese individuals exhibit a diminished muscle protein synthesis response to nutrient stimulation when compared with their lean counterparts. However, the effect of obesity on exercise-stimulated muscle protein synthesis remains unknown. Nine lean (23.5 +/- 0.6 kg/m2 ) and 8 obese (33.6 +/- 1.2 kg/m2 ) physically active young adults participated in a study that determined muscle protein synthesis and intracellular signaling at rest and following an acute bout of resistance exercise. Mixed muscle protein synthesis was determined by combining stable isotope tracer ([13 C6 ]phenylalanine) infusion with serial biopsies of the vastus lateralis. A unilateral leg resistance exercise model was adopted so that resting and postexercise measurements of muscle protein synthesis could be obtained simultaneously. Obesity was associated with higher basal levels of serum insulin (P < 0.05), plasma triacylglycerol (P < 0.01), plasma cholesterol (P < 0.01), and plasma CRP (P < 0.01), as well as increased insulin resistance determined by HOMA-IR (P < 0.05). However, resting and postexercise rates of muscle protein synthesis were not significantly different between lean and obese participants (P = 0.644). Furthermore, resistance exercise stimulated muscle protein synthesis (~50% increase) in both groups (P < 0.001), with no difference between lean and obese (P = 0.809). Temporal increases in the phosphorylation of intracellular signaling proteins (AKT/4EBP1/p70S6K) were observed within the exercised leg (P < 0.05), with no differences between lean and obese. These findings suggest a normal anabolic response to muscle loading in obese young adults. PMID- 30009508 TI - A prospective study of joint function and the quality of life of patients undergoing total joint replacement. AB - AIMS: To investigate joint functioning and the quality of life (QOL) before and after total knee and total hip replacement and the factors that influence the QOL. METHODS: A longitudinal study was conducted between August 2015 and January 2017. A questionnaire composed of the EQ-5D, Oxford Hip Score, and Oxford Knee Score was used to collect data before surgery and 6 weeks, 3 months, and 6 months after surgery. RESULTS: A repeated-measures analysis of variance revealed significant differences in the EQ-5D utility index between the preoperative and all 3 postoperative periods (F = 124.195, P < .05). There were significant differences in knee functioning (F = 133.859, P < .05) and hip functioning (F = 34.717, P < .05) between the preoperative and all 3 postoperative periods. The EQ 5D utility index was significantly higher among patients undergoing total knee replacement than those undergoing total hip replacement (F = 15.490, P < .05) and higher among female than male patients (F = 7.613, P < .05). A positive correlation between the QOL and the perceived convenience of living at home was observed (P < .05). CONCLUSIONS: The findings are expected to inform patient education for patients undergoing arthroplasty surgery. PMID- 30009509 TI - Using conservation science to advance corporate biodiversity accountability. AB - Biodiversity declines threaten the sustainability of global economies and societies. Acknowledging this, businesses are beginning to make commitments to account for and mitigate their influence on biodiversity and report this in sustainability reports. We assessed the top 100 of the 2016 Fortune 500 Global companies' (the Fortune 100) sustainability reports to gauge the current state of corporate biodiversity accountability. Almost half (49) of the Fortune 100 mentioned biodiversity in reports, and 31 made clear biodiversity commitments, of which only 5 were specific, measureable, and time bound. A variety of biodiversity-related activities were disclosed (e.g., managing impacts, restoring biodiversity, and investing in biodiversity), but only 9 companies provided quantitative indicators to verify the magnitude of their activities (e.g., area of habitat restored). No companies reported quantitative biodiversity outcomes, making it difficult to determine whether business actions were of sufficient magnitude to address impacts and were achieving positive outcomes for nature. Conservation science can advance approaches to corporate biodiversity accountability by helping businesses make science-based biodiversity commitments, develop meaningful indicators, and select more targeted activities to address business impacts. With the biodiversity policy super year of 2020 rapidly approaching, now is the time for conservation scientists to engage with and support businesses in playing a critical role in setting the new agenda for a sustainable future for the planet with biodiversity at its heart. PMID- 30009510 TI - Spiromesifen and spirotetramat resistance in field populations of Bemisia tabaci Gennadius in Spain. AB - BACKGROUND: Spiromesifen and spirotetramat are novel insecticides belonging to the chemical class of tetronic and tetramic acid derivatives. Both compounds have proven very effective against field populations of Bemisia tabaci around the world. However, several growers have recently reported control failures in Spain. Therefore, we studied the resistance level to these insecticides in field populations reporting control failures. In addition, we further selected a spiromesifen-resistant strain to study the mechanisms involved and the cross resistance pattern. RESULTS: All the new field populations collected were significantly more resistant to spiromesifen than the susceptible population, confirming the presence of resistance. Several populations showing high levels of resistance to spiromesifen (>10 000-fold), exhibited cross-resistance to spirotetramat, but resistance ratios were much lower (130-fold). The spiromesifen laboratory-selected strain was very resistant to spiromesifen (LC50 > 30 000 mg L 1 ) and spirotetramat (LC50 = 368.1 mg L-1 ), but lacks any cross-resistance to other insecticides, thus providing options for resistance management. None of the synergists tested significantly restored the susceptibility of B. tabaci to either spiromesifen or spirotetramat. CONCLUSION: This is the first report of resistance to spiromesifen and spirotetramat in B. tabaci, and such high levels of resistance have not been reported before in any field collected pest. Our results suggest that enhanced detoxification does not critically contribute to resistance to ketoenols in B. tabaci. The obvious lack of a metabolic resistance mechanism either suggests a target-site resistance mechanism or a metabolic mechanism insensitive to the synergists tested. (c) 2018 Society of Chemical Industry. PMID- 30009511 TI - Multipolydioxanone scaffold improves upper lip and forehead wrinkles: A 12-month outcome. AB - BACKGROUND: The safety and wrinkle-reducing effects of multipolydioxanone (PDO) scaffold have been confirmed in animal, and clinical tests for 3 months, but the 12-month outcomes, are unknown. OBJECTIVE: The safety and efficacy of multi-PDO scaffold were tested in animal models and in humans for 12 months. METHODS: In the animal study, a multi-PDO scaffold was implanted into the panniculus carnosus of rat dorsal skin (n = 18) and into the subcutaneous layer of minipig dorsal skin (n = 2) followed by histological staining and analysis. In a human study, a multi-PDO scaffold was implanted deep into the periosteal subcutaneous layer under the wrinkles on the upper lips and forehead, followed by evaluation of clinical changes using digital photography and PRIMOS. RESULTS: A multi-PDO scaffold was not observed after 6 months in rats and minipigs. However, the newly formed tissues within the hollow body of the scaffolds were maintained for up to 12 months. The enhanced effect on the upper lips and forehead wrinkles lasted up to 12 months without any side effects. CONCLUSION: A multi-PDO scaffold represents a new tool to improve upper lips and forehead wrinkles. PMID- 30009512 TI - Rapid creation system of morphologically and functionally communicative three dimensional cell-dense tissue by centrifugation. AB - This study reports a rapid fabrication system of a morphologically and functionally communicative three-dimensional (3D) cell-dense tissue without scaffolds by centrifugation. The tight adhesion between C2C12 myoblasts and culture surface was accelerated without significant cell damage by centrifugation (80 x g, 37 degrees C, 30 min). A thicker tissue created on a temperature responsive culture surface was harvested by decreasing temperature. The 3D myoblast tissues having approximately 200 MUm-thickness were created at 1.5 h [centrifugation (80 x g, 37 degrees C) for 30 min and tissue harvest for 1 h]. However, in the case of without centrifugation, the myoblast tissues had fragile parts even at 7.5 h after the incubation. Additionally, electrically/functionally communicative and thicker human induced pluripotent stem (iPS) cell-derived cardiac tissues were created rapidly by the centrifugation and cultivation at 37 degrees C. We report a centrifugation system that significantly shortens the creation time of 3D tissues. We envision that this procedure will contribute to the field of tissue engineering and regenerative medicine. PMID- 30009513 TI - When Does the Epigenome Become "Sexy"? PMID- 30009514 TI - Current strategies exploiting NK-cell therapy to treat haematologic malignancies. AB - Natural killer (NK) cells recognize targets that have been changed via malignant transformation or infection. Previously, NK cells were thought to be short-lived, but we now know that NK cells can be long-lived and remember past exposures in response to CMV. NK cells use a plethora of activating and inhibitory receptors to recognize these changes and attack targets, but tumour cells often evade NK cells. Therefore, major efforts are being made to hone in on NK cell antitumour properties in immunotherapy. In the clinical setting, haploidentical NK cells can be adoptively transferred to help treat cancer. To expand NK cells in vivo and enhance tumour targeting, IL-15 is being tested in combination with a glycogen synthase kinase (GSK) 3 inhibitor (CHIR99021), an inhibitor that has been shown to expand mature, highly functional NK cells capable of killing multiple tumour targets. One major limitation to NK cell therapy is lack of specificity. To address this concern, bispecific or trispecific engagers that target NK cells to the tumour and an ADAM17 inhibitor that prevents CD16 shedding after NK cell activation are being tested. Additionally, monoclonal antibodies are being designed to redirect the inhibitory signals that limit NK cell functionality. Further understanding of the biology of NK cells will inform strategies to exploit NK cells for therapeutic purposes. PMID- 30009515 TI - Keratinocyte-specific ablation of protease-activated receptor 2 prevents gingival inflammation and bone loss in a mouse model of periodontal disease. AB - Chronic periodontitis is characterised by gingival inflammation and alveolar bone loss. A major aetiological agent is Porphyromonas gingivalis, which secretes proteases that activate protease-activated receptor 2 (PAR2 ). PAR2 expressed on oral keratinocytes is activated by proteases released by P. gingivalis, inducing secretion of interleukin 6 (IL-6), and global knockout of PAR2 prevents bone loss and inflammation in a periodontal disease model in mice. To test the hypothesis that PAR2 expressed on gingival keratinocytes is required for periodontal disease pathology, keratinocyte-specific PAR2 -null mice were generated using K14-Cre targeted deletion of the PAR2 gene (F2rl1). These mice were subjected to a model of periodontitis involving placement of a ligature around a tooth, combined with P. gingivalis infection ("Lig + Inf"). The intervention caused a significant 44% decrease in alveolar bone volume (assessed by microcomputed tomography) in wildtype (K14-Cre:F2rl1wt/wt ), but not littermate keratinocyte-specific PAR2 null (K14-Cre:F2rl1fl/fl ) mice. Keratinocyte-specific ablation of PAR2 prevented the significant Lig + Inf-induced increase (2.8-fold) in the number of osteoclasts in alveolar bone and the significant up-regulation (2.4-4-fold) of the inflammatory markers IL-6, IL-1beta, interferon-gamma, myeloperoxidase, and CD11b in gingival tissue. These data suggest that PAR2 expressed on oral epithelial cells is a critical regulator of periodontitis-induced bone loss and will help in designing novel therapies with which to treat the disease. PMID- 30009517 TI - Structure of the CoI Intermediate of a Cobalt Pentapyridyl Catalyst for Hydrogen Evolution Revealed by Time-Resolved X-ray Spectroscopy. AB - Cobalt polypyridyls are highly efficient water-stable molecular catalysts for hydrogen evolution. The catalytic mechanism explaining their activity is under debate and the main question is the nature of the involvement of pyridyls in the proton transfer: the pentapyridyl ligand, acting as a pentadentate ligand, can provide stability to the catalyst or one of the pyridines can be involved in the proton transfer. Time-resolved Co K-edge X-ray absorption spectroscopy in the microsecond time range indicates that, for the [CoII (aPPy)] catalyst (aPPy=di([2,2'-bipyridin]-6-yl)(pyridin-2-yl)methanol), the pendant pyridine dissociates from the cobalt in the intermediate CoI state. This opens the possibility for pyridinium to act as an intramolecular proton donor. In the resting state, the catalyst returns to the original six-coordinate high-spin CoII state with a pentapyridyl and one water molecule coordinating to the metal center. Such a bifunctional role of the polypyridyl ligands can be exploited during further optimization of the catalyst. PMID- 30009516 TI - Disease-Triggered Drug Release Effectively Prevents Acute Inflammatory Flare-Ups, Achieving Reduced Dosing. AB - For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is first demonstrated from a pH responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares. PMID- 30009518 TI - An analysis of dysmenorrhoea and depressive symptoms in university students: A case-control study. AB - AIM: Dysmenorrhoea is a significant problem frequently observed in young women; it affects their daily life. The study aims were to describe and compare the presence of depressive symptoms in female university students with and without dysmenorrhoea and to infer which factors may influence dysmenorrhoea. METHODS: This case-control study included 942 students, 471 in each group. The case group consisted of university students in a large university hospital in Eastern Turkey who applied to the adult emergency service and were diagnosed with dysmenorrhoea. The control group consisted of randomly selected students in the same university who did not report painful menstruation. The data were collected between September 2015 and May 2016 using a questionnaire. RESULTS: Depressive symptoms were observed in 61.1% of the students with dysmenorrhoea and 38.9% of the students without dysmenorrhoea (P < .05). The logistic regression analysis showed that depressive symptoms (OR: 1.87) and family history of dysmenorrhoea (OR: 2.20) were found to be higher in the students with dysmenorrhoea than in the students without dysmenorrhoea. CONCLUSION: Students with dysmenorrhoea were more likely to have depressive symptoms and a family history of dysmenorrhoea; findings alert health care professionals to the psychological as well as physiological effects. PMID- 30009520 TI - Long-term outcome and recurrence of hepatitis B virus following liver transplantation from hepatitis B surface antigen-positive donors in a Chinese population. AB - Due to the severe shortage of the donor pool in China, a large number of patients are waiting for a suitable liver, or even worse lose the opportunity of transplantation. Reasonable use of hepatitis B surface antigen-positive (HBsAg positive) donors is one possible strategy to increase the donor pool but the long term outcome in a Chinese population is unknown. To evaluate the safety of using of HBsAg-positive donor for liver transplantation, we set up a multicentric retrospective study from 1 January 2007 to 31 December 2012. A total of 8632 patients underwent liver transplantation during the period and 282 (2.97%) received a liver from a HBsAg-positive donor. A total of 259 cases in both the case and control groups were matched. The incidence of postoperative liver dysfunction, early-stage and long-term complications and the 1-, 3- and 5-year patient survival (78.92% vs 85.65%, 60.41% vs 69.14%, 58.08% vs 69.14%, respectively) showed no difference between the two groups (P value > 0.05). However, the 1-, 3- and 5-year HBV recurrence for patients received the HBsAg positive donor was higher compared with controls (5.85% vs 1.97%, 11.63% vs 4.46%, 17.94% vs 4.46%, respectively, P value = 0.016). Our results showed the use of HBsAg-positive donors is feasible and postoperative antiviral therapy should be managed. PMID- 30009522 TI - The Atopic March. PMID- 30009519 TI - Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study. AB - BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for both insulin-dependent and non-insulin-dependent diabetes. We sought to clarify the pathophysiology of diabetes after abdRT by performing dynamic studies of insulin and glucose and testing for type 1 diabetes-associated autoantibodies. PROCEDURE: Cross-sectional analysis of 2-year childhood cancer survivors treated with abdRT at age <=21 years who underwent oral glucose tolerance testing and assessment of diabetes-related autoantibodies from December 2014 to September 2016. Prevalence of insulin/glucose derangements, indices of insulin sensitivity/secretion (homeostatic model assessment of insulin resistance [HOMA-IR], whole-body insulin sensitivity, insulinogenic index), autoantibody positivity, and treatment/demographic factors associated with adverse metabolic outcomes were assessed. RESULTS: Among 40 participants previously exposed to abdRT (57.5% male; median age at cancer diagnosis, 3.3 years [range, 0.5-20.1]; median age at study 14.3 years [range, 8.3-49.8]; none with obesity), 9 (22.5%) had glucose derangements (n = 4 with impaired fasting glucose [>=100 mg/dL]; n = 4 with impaired glucose tolerance [2-hour glucose 140-199 mg/dL]; n = 1 with previously unrecognized diabetes [2-hour glucose >=200 mg/dL]). Three of the four individuals with impaired fasting glucose also had insulin resistance, as measured by HOMA-IR; an additional four subjects with normal glucose tolerance were insulin resistant. The subject with diabetes had normal HOMA-IR. No participant had absolute insulinopenia or >1 positive diabetes-related autoantibody. CONCLUSIONS: This study suggests that radiation-induced damage to the insulin-producing beta-cells is an unlikely explanation for the early derangements in glucose metabolism observed after abdRT. Research into alternative pathways leading to diabetes after abdRT is needed. PMID- 30009521 TI - Response to "The Atopic March". PMID- 30009523 TI - On the pathogenicity of the plasminogen K330E mutation for hereditary angioedema. PMID- 30009524 TI - Chronic urticaria can be caused by cancer and resolves with its cure. PMID- 30009525 TI - Traumatic Experiences in Childhood and Adult Substance Use in a Nonclinical Sample: The Mediating Role of Arousal/Reactivity. AB - The vast majority of adults in the United States experience at least one traumatic event during childhood. According to the self-medication hypothesis of substance use disorders, adult survivors of childhood trauma may cope with trauma related symptoms via alcohol or drug use. The purpose of this study is to identify through which specific PTSD symptom clusters childhood trauma exposure are associated with adult substance use. Participants of this study (N = 627) were not recruited based on substance use or traumatic exposure. Results of this study demonstrate that arousal/reactivity partially mediates the association between childhood trauma and current substance use. Implications for treatment include recommendations for trauma-informed approaches that aim to decrease arousal/reactivity and subsequently substance use. PMID- 30009526 TI - A dosimetric evaluation of the IAEA-AAPM TRS483 code of practice for dosimetry of small static fields used in conventional linac beams and comparison with IAEA TRS 398, AAPM TG51, and TG51 Addendum protocols. AB - PURPOSE: The International Atomic Energy Agency (IAEA) and the American Association of Physicists in Medicine (AAPM) have jointly published a new code of practice (CoP), TRS483, for the dosimetry of small static photon fields used in external beam radiotherapy. It gave recommendations on how to perform reference dosimetry in nonstandard machine-specific reference (msr) fields and measure field output factors in small fields. The purpose of this work was to perform a dosimetric evaluation of the recommendations given in this CoP. METHODS: All measurements were done in a Varian TrueBeamTM STx linear accelerator. Five ionization chambers were used for beam quality measurements, four Farmer type ionization chambers for performing reference dosimetry and two diodes for performing field output factor measurements. Field output factor measurements were done for fourteen field sizes (ranging from 0.5 cm * 0.5 cm to 10 cm * 10 cm). Beam energies used were: 6 MV WFF, 6 MV FFF, 10 MV WFF, and 10 MV FFF. Where appropriate, results from this study were compared with those obtained from the recommendations given in the IAEA TRS398 CoP, AAPM TG51 and TG51 Addendum protocols. RESULTS: Beam quality measurements show that for all beam energies and for equivalent square msr field sizes ranging from 4 cm * 4 cm to 10 cm * 10 cm, agreement between calculated and measured values of TPR20,10 (10) was within 0.6%. When %dd(10,10)X was used as beam quality specifier, the agreement was found to be within 0.8%. Absorbed dose to water per unit monitor unit at the depth of maximum dose zmax in a beam of quality Q, Dw,Qzmax/MU, was determined using both %dd(10,10)X and TPR20,10 (10) as beam quality specifiers. Measured ratios of Dw,Q (zmax )/MU, determined using the two approaches, ranged between 0.999 and 1.000 for all the beam energies investigated. Comparison with TRS398, TG51 and TG51 addendum protocols show that depending on beam energy, the mean values of the ratios TRS398/TRS483, TG51/TRS483, and TG51 Addendum/TRS483 of Dw,Q (zmax )/MU determined using both approaches show excellent agreement with TRS398 CoP (to within 0.05%); agreement with TG51 and TG51 addendum was to within 0.3% for all four beam energies investigated. Field output factors, determined using the two methods recommended in the TRS483 CoP, showed excellent agreement between the two methods. For the 1 cm collimator field size, the mean value of the field output factor obtained from an average of the two detectors investigated was found to be 2% lower than the mean value of the uncorrected ratio of readings. CONCLUSION: For beams with and without flattening filters, the values of Dw,Q (zmax )/MU obtained following the new CoP are found to be consistent with those obtained using TRS398, TG51 and TG51 addendum protocols to within 0.3%. Field output factors for small beams can be improved when the correction factors for different detectors included in TRS483 are appropriately incorporated into their dosimetry. PMID- 30009527 TI - Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer. AB - Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32.9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy. PMID- 30009529 TI - Interdisciplinary approaches for neuropathology. PMID- 30009528 TI - Sporotrichosis in Southern Brazil, towards an epidemic? AB - Rio Grande do Sul (RS) is the second highest state with respect to sporotrichosis incidence in Brazil, with most cases occurring in the southern region. Given the importance of epidemiologic monitoring in hyperendemic areas, this study evaluated the spatial, geographical and annual sporotrichosis incidence over a period of 7 years in the southern region of RS, as well as the disease evolution over the last two decades. Data were collected from the Mycology Laboratory of the Federal University of Rio Grande (FAMED-FURG) and from the Centre for Zoonosis Control (CZC) of the Prefeitura Municipal of Pelotas city. All feline cases of sporotrichosis diagnosed between 2010 and 2016 were included and analysed. In addition, cases of human and canine sporotrichosis were accounted for. Over the 7-year period (2010-2016), 372 feline, 34 canine and 83 human cases of sporotrichosis were diagnosed, being the mean number of cases/year 18.33 in the first 3 years of the study and 116.33 in the last 3 years. Cases were distributed among 34 and 28 neighbourhoods in Rio Grande and Pelotas city, respectively. Socioeconomic features reinforced the result that the disease is already spreading across a major part of the southern region. In addition, the study demonstrated the intensification and expansion of the high endemicity areas. Therefore, given that the number of feline sporotrichosis cases in southern RS reached alarming proportions, we suggested that this region will promptly face an epidemic of sporotrichosis if no preventive or control measures are undertaken. PMID- 30009530 TI - Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex-Mediated Activation of the NLRP3 Inflammasome. AB - OBJECTIVE: High-expression alleles of macrophage migration inhibitory factor (MIF) are linked genetically to the severity of systemic lupus erythematosus (SLE). The U1 small nuclear RNP (snRNP) immune complex containing U1 snRNP and anti-U1 snRNP antibodies, which are found in patients with SLE, activates the NLRP3 inflammasome, comprising NLRP3, ASC, and procaspase 1, in human monocytes, leading to the production of interleukin-1beta (IL-1beta). This study was undertaken to investigate the role of the snRNP immune complex in up-regulating the expression of MIF and its interface with the NLRP3 inflammasome. METHODS: MIF, IL-1beta, NLRP3, caspase 1, ASC, and MIF receptors were analyzed by enzyme linked immunosorbent assay, Western blotting, quantitative polymerase chain reaction, and cytometry by time-of-flight mass spectrometry (CytoF) in human monocytes incubated with or without the snRNP immune complex. MIF pathway responses were probed with the novel small molecule antagonist MIF098. RESULTS: The snRNP immune complex induced the production of MIF and IL-1beta from human monocytes. High-dimensional, single-cell CytoF analysis established that MIF regulates activation of the NLRP3 inflammasome, including findings of a quantitative relationship between MIF and its receptors and IL-1beta levels in the monocytes. MIF098, which blocks MIF binding to its cognate receptor, suppressed the production of IL-1beta, the up-regulation of NLRP3, which is a rate-limiting step in NLRP3 inflammasome activation, and the activation of caspase 1 in snRNP immune complex-stimulated human monocytes. CONCLUSION: The U1 snRNP immune complex is a specific stimulus of MIF production in human monocytes, with MIF having an upstream role in defining the inflammatory characteristics of activated monocytes by regulating NLRP3 inflammasome activation and downstream IL 1beta production. These findings provide mechanistic insight and a therapeutic rationale for targeting MIF in subgroups of lupus patients, such as those classified as high genotypic MIF expressers or those with anti-snRNP antibodies. PMID- 30009531 TI - Accelerated MR parameter mapping with a union of local subspaces constraint. AB - PURPOSE: A new reconstruction method for multi-contrast imaging and parameter mapping based on a union of local subspaces constraint is presented. THEORY: Subspace constrained reconstructions use a predetermined subspace to explicitly constrain the relaxation signals. The choice of subspace size (K) impacts the approximation error vs noise-amplification tradeoff associated with these methods. A different approach is used in the model consistency constraint (MOCCO) framework to leverage the subspace model to enforce a softer penalty. Our proposed method, MOCCO-LS, augments the MOCCO model with a union of local subspaces (LS) approach. The union of local subspaces model is coupled with spatial support constraints and incorporated into the MOCCO framework to regularize the contrast signals in the scene. METHODS: The performance of the MOCCO-LS method was evaluated in vivo on T1 and T2 mapping of the human brain and with Monte-Carlo simulations and compared against MOCCO and the explicit subspace constrained models. RESULTS: The results demonstrate a clear improvement in the multi-contrast images and parameter maps. We sweep across the model order space (K) to compare the different reconstructions and demonstrate that the reconstructions have different preferential operating points. Experiments on T2 mapping show that the proposed method yields substantial improvements in performance even when operating at very high acceleration rates. CONCLUSIONS: The use of a union of local subspace constraints coupled with a sparsity promoting penalty leads to improved reconstruction quality of multi-contrast images and parameter maps. PMID- 30009532 TI - Changes in secondary metabolites, organic acids and soluble sugars during the development of plum fruit cv. 'Furongli' (Prunus salicina Lindl). AB - BACKGROUND: Organic acids, sugars and pigments are key components that determine the taste and flavor of plum fruit. However, metabolism of organic acid and sugar is not fully understood during the development of plum fruit cv. 'Furongli'. RESULTS: Mature fruit of 'Furongli' has the highest content of anthocyanins and the lowest content of total phenol compounds and flavonoids. Malate is the predominant organic acid anion in 'Furongli' fruit, followed by citrate and isocitrate. Glucose was the predominant sugar form, followed by fructose and sucrose. Correlation analysis indicated that malate content increased with increasing phosphoenolpyruvate carboxylase (PEPC) activity and decreasing nicotinamide adenine dinucleotide-malate dehydrogenase (NAD-MDH) activity. Citrate and isocitrate content increased with increasing PEPC and aconitase (ACO) activities, respectively. Both acid invertase and neutral invertase had higher activities at the early stage than later stage of fruit development. Fructose content decreased with increasing phosphoglucoisomerase (PGI) activity, whereas glucose content increased with decreasing hexokinase (HK) activity. CONCLUSION: Dynamics in organic acid anions were not solely controlled by a single enzyme but regulated by the integrated activity of enzymes such as nicotinamide adenine dinucleotide phosphate-malic enzyme (NADP-ME), NAD-ME, PEPC, ACO and NADP isocitrate dehydrogenase. Sugar metabolism enzymes such as PGI, invertase and HK may play vital roles in the regulation of individual sugar metabolic processes. (c) 2018 Society of Chemical Industry. PMID- 30009533 TI - Flow cytometry for assessment of the tumor microenvironment in pediatric Hodgkin lymphoma. AB - BACKGROUND: The role of flow cytometry in diagnosis and management of Hodgkin lymphoma (HL) remains limited. As knowledge emerges of the tumor microenvironment in this disease, various methods are being evaluated in its study. This study examines the microenvironment using flow cytometry to assess differences between subtypes and clinicopathologic correlates. PROCEDURE: A retrospective cross sectional study was performed analyzing the tumor immunophenotype, by flow cytometry, for 31 children with classical HL. Correlation was made with patient information, including outcome. RESULTS: The makeup of the tumor microenvironment varies across subtype of HL, with T cells predominating in nodular sclerosis (NS), and similar proportions of B and T cells in mixed cellularity (MC). CD4 cells predominate in NS, whereas CD8 more so in MC subtype. The rate of continuous complete remission is significantly higher in the MC subgroup. Last, the proportion of HLA-DR/CD38 copositive lymphocytes was an independent prognostic factor for relapse/refractoriness. CONCLUSIONS: This study indicates that flow cytometry can be used to examine the tumor microenvironment in HL and that percentage of HLA-DR/CD38 copositive lymphocytes may be a biomarker for relapse and refractoriness in pediatric HL. PMID- 30009534 TI - A Novel Mammalian Cell Line Development Platform Utilizing Nanofluidics and OptoElectro Positioning Technology. AB - Generating a highly productive cell line is resource intensive and typically involves long timelines because of the need to screen large numbers of candidates in protein production studies. This has led to miniaturization and automation strategies to allow for reductions in resources and higher throughput. Current approaches rely on the use of standard cell culture vessels and bulky liquid handling equipment. New nanofludic technologies offer novel solutions to surpass these limits, further miniaturizing cell culture volumes (105 times smaller) by growing cells on custom nanofluidic chips. Berkeley Lights' OptoElectro Positioning technology projects light patterns to activate photoconductors that gently repel cells to manipulate single cells on nanofluidic culturing chips. Using a fully integrated technology platform (Beacon), common cell culture tasks can be programmed through software, allowing maintenance and analysis of thousands of cell lines in parallel on a single chip. Here, we describe the ability to perform key cell line development work on the Beacon platform. We demonstrate that commercial production Chinese hamster ovary cell lines can be isolated, cultured, screened, and exported at high efficiency. We compare this process head to head with a FACS-enabled microtiter plate-based workflow and demonstrate generation of comparable clonal cell lines with reduced resources. PMID- 30009535 TI - Overload Effects in Reversed Phase Protein Separations using Capillary-Channeled Polymer Fiber Columns. AB - In preparative chromatography, overloading effects are a fact of life. However, peak distortion is problematic in analytical scale chromatography, especially in the case of bio-macromolecule separations. Capillary-channeled polymer fibers have been employed for fast protein separations in reversed phase, ion exchange, and hydrophobic interaction liquid chromatography. Although the primary advantage of the phase is operation at high linear velocities (~100 mm s-1 ) without van Deemter C-term limitations, the limited specific surface area (<5 m2 g-1 ) suggests that a thorough understanding of overloading effects is needed. We evaluate important factors (injected mass and volume) affecting overload in terms of peak height, width and shape (asymmetry). Overload conditions readily apparent as the peak shape changes from a Gaussian distribution to a left-triangle with slight tailing; more-or-less classical overload behavior. Three methods were used to compute column efficiency in terms of plate counts (N), including the area height, half-height, and the Dorsey-Foley approaches. The half-height method is best-suited for describing column overload, accounting for peak distortion and achieving high levels of consistency. The limiting plate count (N0 ) and the column sample loading capacity (omega0.5 ) were key metrics to characterize overall column performance. Peak capacity (P) was used to assess gradient elution separation performance. Increased flow rates and column length result in enhanced loading capacity. pH mismatch between the sample matrix and the mobile phase, a common cause of protein overload with other phases, was not responsible for distorted peak shapes unless the solvent pH is close to the pI of protein samples. PMID- 30009536 TI - DNA ladders can be used to size polyphosphate resolved by polyacrylamide gel electrophoresis. AB - PAGE is often used to resolve inorganic polyphosphates (polyP), but unfortunately polyP size ladders are not commercially available. Since several dyes that are commonly used to detect nucleic acids in gels also stain polyP, we examined the utility of commercially available DNA size ladders for estimating polyP polymer lengths by gel electrophoresis. Narrow size fractions of polyP were prepared and their polymer lengths were quantified using NMR. Commercially available DNA ladders and these polyP fractions were then subjected to PAGE to determine the relationship between migration of DNA vs polyP, which was found to be: log10 (dsDNA length in bp) = 1.66 * log10 (polyP length in phosphate units) - 1.97. This relationship between DNA and polyP size held for a variety of different polyacrylamide concentrations, indicating that DNA size ladders can readily be employed to estimate polyP polymer lengths by PAGE. PMID- 30009537 TI - Extended HLA-G haplotypes in patients with age-related macular degeneration. AB - The study aims to determine if genetic polymorphisms in the human leukocyte antigen (HLA)-G gene are associated with age-related macular degeneration (AMD). HLA-G is important for immunological tolerance, and it is also known to have angiogenic effects. Polymorphisms in the 5'-upstream regulatory region (URR) and 3'-untranslated region (UTR) of HLA-G have been associated with a number of diseases, especially with respect to a 14 bp insertion/deletion (ins/del) polymorphism in the 3'UTR. Full gene sequencing was performed on a cohort of 146 AMD patients and 63 healthy controls aged 60 years or older and HLA-G haplotypes were determined. Analyses were performed on a publicly available gene expression dataset from the NCBI GEO database (accession number GSE29801) from which expression data for HLA-G, -C and -A were extracted. Analysis of the GEO dataset showed that both HLA-G and -C was expressed in the back of the eye and that expression was upregulated in the macular area of AMD. No differences were observed between patients and controls when analysing the distribution of haplotypes in the HLA-G promoter, coding region, 3'UTR or the 14 bp ins/del polymorphism of the 3'UTR. The increased expression of HLA-G in the macula of AMD patients indicates a role of HLA-G in the micro environment as part of the AMD pathogenesis. This is supported by the expression of HLA-C, which has previously been shown to play a role in AMD. The HLA-G haplotype distribution did not display any differences between AMD patients and controls. This article is protected by copyright. All rights reserved. PMID- 30009539 TI - Peel meals as feed ingredients in poultry diets: Chemical composition, dietary recommendations and prospects. AB - The increase demand for poultry products has had direct effect on the supply and price of feed. This has increased research interest into the potential of locally available, less competed and low cost materials as feed ingredients. Several peels from roots/tubers and fruits have been evaluated in poultry diets but recommendations have not been consistent. High fibre, low nutrient density and likely presence of antinutritional factors limit the efficient utilisation of peel meal by poultry. Plant cultivar, age, agronomic practices, method of peel processing, breed and age of poultry all affect the inclusion level of peel meal in poultry diets. The increase interest in breeding crops for low antinutrients, knowledge in processing technologies and availability of several additives such as enzyme products, amino acids and antinutrients binding agents in the feed market could improve the usefulness of peel meal in on-farm poultry rations. This study reviews the potential of selected root/tuber and fruit peels as feed ingredients for poultry with regards their composition, dietary recommendation and prospects. PMID- 30009538 TI - Muscle Fn14 gene expression is associated with fat-free mass retention during energy deficit at high altitude. AB - Intramuscular factors that modulate fat-free mass (FFM) loss in lowlanders exposed to energy deficit during high-altitude (HA) sojourns remain unclear. Muscle inflammation may contribute to FFM loss at HA by inducing atrophy and inhibiting myogenesis via the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible protein 14 (Fn14). To explore whether muscle inflammation modulates FFM loss reportedly developing during HA sojourns, muscle inflammation, myogenesis, and proteolysis were assessed in 16 men at sea level (SL) and following 21 days of energy deficit (-1862 +/- 525 kcal/days) at high altitude (HA, 4300 m). Total body mass (TBM), FFM, and fat mass (FM) were assessed using DEXA. Gene expression and proteolytic enzymatic activities were assessed in muscle samples collected at rest at SL and HA. Participants lost 7.2 +/- 1.8 kg TBM (P < 0.05); 43 +/- 30% and 57 +/- 30% of the TBM lost was FFM and FM, respectively. Fn14, TWEAK, TNF alpha-receptor (TNFalpha-R), TNFalpha, MYOGENIN, and paired box protein-7 (PAX7) were upregulated (P < 0.05) at HA compared to SL. Stepwise linear regression identified that Fn14 explained the highest percentage of variance in FFM loss (r2 = 0.511, P < 0.05). Dichotomization of volunteers into HIGH and LOW Fn14 gene expression indicated HIGH lost less FFM and more FM (28 +/- 28% and 72 +/- 28%, respectively) as a proportion of TBM loss than LOW (58 +/- 26% and 42 +/- 26%; P < 0.05) at HA. MYOGENIN gene expression was also greater for HIGH versus LOW (P < 0.05). These data suggest that heightened Fn14 gene expression is not catabolic and may protect FFM during HA sojourns. PMID- 30009540 TI - Li2 S- or S-Based Lithium-Ion Batteries. AB - While members of the Li-S battery research community are becoming more conscious of the practical testing parameters, the widespread commercialization of S-based batteries is still far from realization. Particularly, the metallic Li used as the anode poses potential safety and cycle stability concerns. Alternatively, other S-battery configurations without a Li anode, i.e., lithium-ion, Li2 S, or S batteries, do not suffer from the same safety concerns and can possibly serve as better methods to bring room-temperature S-based battery technologies to industry. However, whether Li2 S or S will be used as the initiating cathode material remains unclear as each offers their own unique advantages and disadvantages. Here, both S and Li2 S as cathodes are briefly discussed and the key benefits of Li2 S are highlighted. PMID- 30009541 TI - Corpora amylacea in prostatectomy tissue and associations with molecular, histological, and lifestyle factors. AB - BACKGROUND: Corpora amylacea are amyloid bodies commonly found adjacent to damaged prostate epithelium. Little is known about their formation or function. The current study sought to characterize corpora amylacea in prostate tissue and to describe their relationship with clinical, histological, molecular, and lifestyle factors, especially with chronic inflammation which is associated with aggressive disease. METHODS: We studied a cohort of 355 men with prostate cancer and tissue specimens from the Health Professionals Follow-Up Study. Pathologists examined H&E slides and undertook a standardized review for histologic data and inflammation. Trained observers counted corpora amylacea within the benign and predominately tumor areas. Immunohistochemistry biomarkers were available from tissue microarrays. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) to assess associations of chronic inflammation, clinical, histological, molecular, and lifestyle factors with the presence of corpora amylacea. RESULTS: Corpora amylacea were present in benign tissue area for 298 men (84%). Specimens with moderate-to-severe chronic inflammation were more likely to have corpora amylacea in benign regions (OR = 5.4 95%CI 1.9, 15.6). Moreover, corpora amylacea were more common in men with higher body mass index (OR = 1.13 95%CI 1.01, 1.26). In contrast, Gleason grade (OR = 0.4 95%CI 0.2, 0.8), proliferation index (OR = 0.6 95%CI 0.3, 1.2) and the presence of the TMPRSS2:ERG fusion (OR = 0.4 95%CI 0.2, 0.8) were inversely associated with corpora amylacea presence. TURP specimens were less likely to have corpora amylacea than prostatectomy specimens (OR = 0.12 95%CI 0.03, 0.47). Age, PSA, stage, biomarkers of angiogenesis and PTEN, and vasectomy were not significantly associated with corpora amylacea. CONCLUSION: Corpora amylacea were common among men with prostate cancer and were associated with pro-inflammatory factors, some markers of less aggressive disease, and lack of the TMPRSS2:ERG fusion. PMID- 30009542 TI - Capture enrichment of aquatic environmental DNA: A first proof of concept. AB - Environmental DNA (eDNA) sampling-the detection of genetic material in the environment to infer species presence-has rapidly grown as a tool for sampling aquatic animal communities. A potentially powerful feature of environmental sampling is that all taxa within the habitat shed DNA and so may be detectable, creating opportunity for whole-community assessments. However, animal DNA in the environment tends to be comparatively rare, making it necessary to enrich for genetic targets from focal taxa prior to sequencing. Current metabarcoding approaches for enrichment rely on bulk amplification using conserved primer annealing sites, which can result in skewed relative sequence abundance and failure to detect some taxa because of PCR bias. Here, we test capture enrichment via hybridization as an alternative strategy for target enrichment using a series of experiments on environmental samples and laboratory-generated, known composition DNA mixtures. Capture enrichment resulted in detecting multiple species in both kinds of samples, and postcapture relative sequence abundance accurately reflected initial relative template abundance. However, further optimization is needed to permit reliable species detection at the very low-DNA quantities typical of environmental samples (<0.1 ng DNA). We estimate that our capture protocols are comparable to, but less sensitive than, current PCR-based eDNA analyses. PMID- 30009543 TI - Role of ACE inhibitors in anthracycline-induced cardiotoxicity: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Several measures including drugs have been tried to reduce anthracycline cardiotoxicity. The lack of randomized trials prompted this study to assess the role of an angiotensin converting enzyme (ACE) inhibitor (enalapril) in anthracycline-induced cardiotoxicity in children with hematological malignancies. METHODS: A randomized, double-blind, placebo controlled trial was conducted on 84 patients with leukemia (41) and lymphoma (43) who received anthracyclines (doxorubicin and/or daunorubicin) at cumulative dose >=200 mg/m2 . The patients were randomized to receive either enalapril [group A (n = 44)] or placebo [group B (n = 40)] for 6 months. Left ventricular ejection fraction (LVEF) and cardiac biomarkers (cardiac troponin I [cTnI], probrain natriuretic peptide [proBNP], and creatine kinase MB [CK-MB]) were assessed at baseline and 6 months. The primary outcome was a measured decrease in LVEF (>=20%). Secondary outcome measures were changes in cardiac biomarkers and the development of heart failure or arrhythmias. RESULTS: LVEF decreased in both groups at 6 months, more so in group B (62.25 +/- 5.49 vs 56.15 +/- 4.79, P < 0.001). A >=20% decrease was seen in 3 patients in group B but none in group A (P = 0.21). Cardiac biomarkers increased more in group B at 6 months, and the increase was significant for proBNP (49.60 +/- 35.97 vs 98.60 +/- 54.24, P < 0.001) and cTnI (0.01 +/- 0.00 vs 0.011 +/- 0.003, P = 0.035) but not significant for CK-MB (1.08 +/- 0.18 vs 1.21 +/- 0.44, P = 0.079). In group A, 9.1% of the patients showed an increase in proBNP level >=100 compared with 37.5% in group B (P < 0.001). No patient developed heart failure or arrhythmia. CONCLUSION: Enalapril has a role in reducing cardiac toxicity after anthracycline administration. PMID- 30009544 TI - Progress in the Development of Platelet-Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases. AB - Platelet-activating factor (PAF) and its receptor (PAFr) have been implicated in a wide range of diseases and disorders that originate from the activation of inflammatory pathways. Although the exact structure of the binding site on the PAFr remains unknown, the PAFr is a well-established therapeutic target, and an array of structurally diverse PAFr antagonists have been identified. These include compounds that are structurally similar to the natural PAF ligand, synthetic heterocycles, complex polycyclic natural products, and various metal complexes. This review provides an update on more than 20 years of progress in this area. The development and synthesis of new PAFr antagonists, structure activity relationship studies, the biological activity of these molecules, and their therapeutic potential are discussed. PMID- 30009545 TI - Managing protein-energy wasting in hemodialysis patients: A comparison of animal- and plant-based protein foods. AB - Protein-energy wasting (PEW) is a major diet-related complication in hemodialysis (HD) patients. Nutrient-based dietary guidelines emphasize animal-based protein foods for preventing and managing PEW in HD patients. Although dietary protein intake is important for protein anabolism, other dietary factors contribute to PEW. In this article, we examine the diet-related etiologies of PEW in HD patients, and discuss how they may be affected differently by animal- and plant based protein foods. In general, animal foods are superior sources of protein, but may contribute more to metabolic derangements that cause PEW. Given the potential mixed effects of animal-based protein foods on PEW, human research studies are needed to determine the impact of liberalizing the diet to allow plant-based protein foods on protein status. PMID- 30009547 TI - 'Nausicaa' compression suture: a simple and effective alternative to hysterectomy in placenta accreta spectrum and other causes of severe postpartum haemorrhage. AB - Postpartum haemorrhage (PPH), especially resulting from placenta accreta spectrum (PAS), has become a worldwide concern in maternity care. We describe a novel method of uterine compression sutures (the 'Nausicaa' technique) as an alternative to hysterectomy for patients who have suffered from major PPH. We applied this technique in 68 patients with major PPH during caesarean section (including 43 patients with PAS, 20 patients with placenta praevia totalis, and five patients with uterine atony), and none of these patients required further hysterectomy. We conclude that our Nausicaa suture is a simple and feasible alternative to hysterectomy in patients suffering from major PPH. PMID- 30009546 TI - Acute saccharin infusion has no effect on renal glucose handling in normal rats in vivo. AB - Artificial sweeteners are extensively used by the food industry to replace sugar in food and beverages and are widely considered to be a healthy alternative. However, recent data suggest that artificial sweeteners may impact intestinal glucose absorption and that they might lead to glucose intolerance. Moreover, chronic consumption of artificial sweeteners has also been linked to detrimental changes in renal function. Using an in vivo approach, our study aimed to determine if short-term infusion of the artificial sweetener saccharin can alter renal function and renal glucose absorption. We show that saccharin infusion does not induce any major change in GFR or urine flow rate at either the whole kidney or single nephron level, suggesting that any reported change in renal function with artificial sweeteners must depend on chronic consumption. As expected for a nondiabetic animal, glucose excretion was low; however, saccharin infusion caused a small, but significant, decrease in fractional glucose excretion. In contrast to the whole kidney data, our micropuncture results did not show any significant difference in fractional glucose reabsorption in either the proximal or distal tubules, indicating that saccharin does not influence renal glucose handling in vivo under euglycemic conditions. In keeping with this finding, protein levels of the renal glucose transporters SGLT1 and SGLT2 were also unchanged. In addition, saccharin infusion in rats undergoing a glucose tolerance test failed to induce a robust change in renal glucose excretion or renal glucose transporter expression. In conclusion, our results demonstrate that saccharin does not induce acute physiologically relevant changes in renal function or renal glucose handling. PMID- 30009548 TI - Molecular properties of gp100-reactive T-cell receptors drive the cytokine profile and antitumor efficacy of transgenic host T cells. AB - To study the contribution of T-cell receptors (TCR) to resulting T-cell responses, we studied three different human alphabeta TCRs, reactive to the same gp100-derived peptide presented in the context of HLA-A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen-induced IFN-gamma responses, which correlated with TCR affinity for peptide-MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL-17A release. Importantly, in vivo, SILv44-transgenic T cells mediated superior antitumor responses to 888-A2 + human melanoma tumor cells upon adoptive transfer into tumor-challenged mice while maintaining IL-17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T-cell receptor in defining host T-cell physiology than traditionally assumed, while parameters beyond IFN-gamma secretion and TCR affinity ultimately determine the reactivity of tumor-reactive T cells. PMID- 30009549 TI - Recent Advances in Mechanism Research and Methods for Electric-Field-Assisted Sintering of Ceramics. AB - Electric-field-assisted sintering of ceramic materials is under considerable attention during recent years. The current research is reviewed with a focus on mechanism research. Research of the mass transfer mechanisms in flash sintering (FS) is under debate during recent years. The research yields three main proposed mechanisms: nucleation due to movement of charged defects, Joule heating runaway, and electrochemical reactions. These are critically presented and discussed. Unlike FS, the mechanism of field-assisted sintering technologies (FAST) of ceramics is well agreed upon. However, recent studies challenge even this perception with new approaches, which are presented here. New technological and methodological developments in both FS and FAST/spark plasma sintering are also presented. PMID- 30009550 TI - Recent Progress in Isolation and Detection of Extracellular Vesicles for Cancer Diagnostics. AB - Extracellular vesicles (EVs) are emerging as one of the many new and promising biomarkers for liquid biopsy of cancer due to their loading capability of some specific proteins and nucleic acids that are closely associated with cancer states. As such, the isolation and detection of cancer-derived EVs offer important information in noninvasive diagnosis of early-stage cancer and real time monitoring of cancer development. In light of the importance of EVs, over the last decade, researchers have made remarkable innovations to advance the development of EV isolation and detection methods by taking advantage of microfluidics, biomolecule probes, nanomaterials, surface plasmon, optics, and so on. This review introduces the basic properties of EVs and common cancer-derived EV ingredients, and provides a comprehensive overview of EV isolation and detection strategies, with emphasis on liquid biopsies of EVs for cancer diagnostics. PMID- 30009551 TI - Detection of an HLA-C*03 variant, HLA-C*03:187, in a Taiwanese individual. AB - One nucleotide substitution at residue 527 of HLA-C*03:03:01:01 results in a novel allele, HLA-C*03:187. PMID- 30009552 TI - Controlling Interactions of Cyclic Oligosaccharides with Hetero-Oligomeric Nanopores: Kinetics of Binding and Release at the Single-Molecule Level. AB - Controlling the molecular interactions through protein nanopores is crucial for effectively detecting single molecules. Here, the development of a hetero oligomeric nanopore derived from Nocardia farcinica porin AB (NfpAB) is discussed for single-molecule sensing of biopolymers. Using single-channel recording, the interaction of cyclic oligosaccharides such as cationic cyclodextrins (CDs) of different symmetries and charges with NfpAB is measured. Studies of the transport kinetics of CDs reveal asymmetric geometry and charge distribution of NfpAB. The applied potential promotes the attachment of the cationic CDs to the negatively charged pore surface due to electrostatic interaction. Further, the attached CDs are released from the pore by reversing the applied potential in time-resolved blockages. Release of CDs from the pore depends on its charge, size, and magnitude of the applied potential. The kinetics of CD attachment and release is controlled by fine-tuning the applied potential demonstrating the successful molecular transport across these nanopores. It is suggested that such controlled molecular interactions with protein nanopores using organic templates can be useful for several applications in nanopore technology and single-molecule chemistry. PMID- 30009553 TI - Blood pressure control rates measured in specialty vs primary care practices within a large integrated health system. AB - Blood pressure measurement is a diagnostic test and a key component of assessing and managing hypertension, a major contributor to cardiovascular risk. Based on real-world clinical observations within a large, university-based, accountable care organization, we sought to assess whether blood pressure control results varied by the assessment setting, primary care versus specialty. We studied the most recent outpatient measurement for patients with hypertension during the 2016 calendar year and categorized each as being performed in a primary care or specialty setting, and as being controlled (<140/90 mm Hg) or uncontrolled. Among the 86 512 patients identified, the 43 364 whose most recent blood pressure measurement was in a specialty setting were significantly less likely to be controlled compared to the 43 148 whose most recent measurement was in primary care (63% vs 68%, respectively, OR = 0.83 [0.80-0.85]). For the 27 955 patients who had measurements performed in both settings during the year, the control rates based upon their most recent specialty and primary care measurements were 63% and 71%, respectively (OR = 0.62, 0.60-0.65). For the subsets of patients whose measurements in each setting were within 30 or within seven days of each other, the odds of control in the specialty versus primary care setting were 0.63 (0.58-0.75) and 0.65 (0.57-0.75), respectively. Health systems should weigh the value of performing blood pressure measurement in specialty settings that do not manage this condition, taking into consideration the resources required to perform it and the potential negative consequences of inaccurate measurements. PMID- 30009554 TI - The importance of body image disturbances for the outcome of outpatient psychotherapy in patients with anorexia nervosa: Results of the ANTOP-study. AB - This study investigates the role of body image self-appraisal in predicting the outcomes of outpatient psychotherapy in patients with anorexia nervosa (AN). Multiple linear regression analyses and a path-analysis model were applied to test the study hypotheses that body image at baseline predicts treatment outcomes of outpatient psychotherapy in patients with AN at follow-up measurement. The analyses were conducted as secondary analyses in a subgroup (n = 148) of the anorexia nervosa treatment of outpatient-cohort (ANTOP-study) (N = 242) of patients with AN. The results show that Negative Evaluation of the Body at baseline predicts perceived stress during psychotherapy, which in turn predicts depressive symptoms at the end of therapy which in turn predicts the outcomes body mass index and EDI-2 sum score at 12 months follow-up. The results underline the importance of body image disturbance in the course of AN and call for body image as a central target of psychotherapeutic interventions in patients with AN. PMID- 30009555 TI - Wrinkles, brown spots, and cancer: Relationship between appearance- and health based knowledge and sunscreen use. AB - BACKGROUND: There is increasing understanding that sunscreen use is associated with reduced photoaging and that appearance-based messages are more effective than health-based messages in promoting daily sunscreen use. We hypothesized that persons with greater awareness of the effects of photoaging use sunscreen more consistently. METHODS: Cross-sectional survey of adults in Dallas, TX, assessing sunscreen-related knowledge, behavior, and information source. RESULTS: Each respondent averaged 2.5 +/- 1.7 hours of self-reported sun exposure daily with the least reported time being 0.15 hours. Eighty-eight percent reported that sun exposure caused skin cancer "a lot." Eighty-nine percent "agreed" or "strongly agreed" that "sun exposure causes most signs of skin aging." Over 70% "agreed" or "strongly agreed" to an appearance-based reason for their sunscreen use. Sixty six percent reported they would consider using sunscreen if anticipating sun exposure lasting 2 hours or less. Only 30% reported using sunscreen daily. Greater photoaging knowledge was positively associated with sunscreen adherence (at least P < 0.05 with each knowledge item). Those with darker complexions or skin less likely to burn reported less knowledge of photoaging (rho = -0.219, P <= 0.001) and had lower sunscreen use (rho = 0.301, P < 0.001). CONCLUSION: Despite most respondents reporting knowledge of health and appearance risks of sun exposure and a motivation to prevent them with sunscreen, most do not use sunscreen adequately. This discrepancy could be due to people perceiving risks of sun exposure based on duration of continuous exposure. There may be misconceptions that short-interval sun exposure that does not result in sunburn is less harmful than extended exposure. PMID- 30009556 TI - Growth performance, apparent digestibility, and N balance in Mongolian lambs and hoggs fed diets supplemented with a Chinese traditional herbal medicine complex. AB - We evaluated the effects of dietary supplementation with Chinese traditional herbal medicine (CTHM) on the growth performance, apparent digestibility, and nitrogen balance in Mongolian lambs and hoggs. The CTHM used as a dietary supplement consisted of 30% pine needles, 20% mugwort, 40% garlic, and 10% Astragalus mongholicus on a dry matter (DM) basis. The basal diet was prepared from corn stover, corn grain, wheat bran, rapeseed meal, shell meal, dicalcium phosphate, salt, vitamin premix, and mineral premix. In total, 16 Mongolian lambs (20.75 kg initial body weight [BW]) and 16 hoggs (33.81 kg initial BW) were allocated randomly to one of two treatments, the basal diet without and with CTHM, with the group receiving CTHM fed 98.5% basal diet + 1.5% CTHM complex on a DM basis. Lamb and hogg growth trials showed that CTHM supplementation improved the final live weight, gain, and feed conversion ratio (p < 0.01). A digestibility trial showed that the diet with CTHM improved the digestibility of DM, organic matter (OM), crude protein (CP), and neutral detergent fiber in lambs and hoggs. Finally, CTHM supplementation decreased (p < 0.0001) fecal and urinary nitrogen and increased (p = 0.0004) nitrogen (N) retention. Overall, the addition of CTHM to the diets of lambs and hoggs has beneficial effects on growth. PMID- 30009557 TI - Dietetics workforce preparation and preparedness in Australia: A systematic mapping review to inform future dietetics education research. AB - AIM: The present study aimed to systematically map and summarise existing research regarding dietetics workforce preparation and preparedness that has been conducted in Australia. The secondary aim was to then identify gaps in the literature to inform future priority areas in Australian dietetics education research. METHODS: The databases MEDLINE, CINAHL, Embase, ERIC, Informit and PsycINFO were systematically searched from inception until July 2017 using key search terms to identify eligible studies. Extracted data were independently reviewed, and study quality was appraised by multiple researchers. Results were categorised by setting and primary focus/foci and then narratively summarised. RESULTS: Sixty-eight studies were included from 3779 records identified. Dietetics education research in Australia has spanned almost 30 years with more than half of studies (51%; 35/68) published in the last five years. The greatest proportion of research was conducted in the university setting (43%; 29/68), with students as participants (48%; 43/90) and was focused on the medical nutrition therapy area of dietetics practice (43%; 29/68). Published studies involving graduates (14%; 13/90); conducted in the workplace (12%; 8/68); and regarding emerging areas of dietetics practice (0%; 0/90) are lacking. Employment outcomes of dietetics graduates across Australia were last published over 25 years ago. CONCLUSIONS: This review provides a map for dietetics educators and researchers in Australia to guide future research regarding the preparation and preparedness of dietitians. Advancing the Australian dietetics workforce of the future will require a strategic, coordinated and collaborative approach to address the research gaps identified in this review. PMID- 30009558 TI - New Fellows Early Career Survey 2014-2017: Shift of trends in emergency medicine workforce. AB - OBJECTIVE: Within the complex and dynamic emergency medicine workforce setting, the Australasian College for Emergency Medicine (ACEM) New Fellows (FACEMs) Early Career Survey was established in 2014 to capture information on the work profiles, future career plans and challenges experienced among new FACEMs. METHODS: The voluntary online survey is distributed twice yearly to new FACEMs who gained their Fellowship the preceding 6-12 months. Eligible new FACEMs were contacted by email and invited to participate. RESULTS: A representative sample of 348 (53%) of 660 eligible new FACEMs responded to the survey from 2014 to 2017. New Fellows in the 2017 cohort were less likely to have secured a specialist position at attainment of Fellowship or 6-12 months later. Compared with new FACEMs in earlier cohorts, they were significantly more likely to be working in regional areas, across multiple workplaces and in more than one area of clinical/professional practice. The proportion of new FACEMs working part-time or in casual positions (42%) remained reasonably consistent across the 4 years. Finding a specialist position and securing a permanent position were among the main challenges experienced by new FACEMs after attaining their Fellowship. CONCLUSION: A shift in the employment profile of early career Fellows was observed between 2014 and 2017, with the potential push factor of limited specialist positions in metropolitan areas now starting to result in an increase in new FACEMs choosing to work in regional and rural areas and in the number working across multiple workplaces. PMID- 30009560 TI - Spontaneous Membrane Generation and Extension in a Dipeptide Single Crystal and Phospholipid Mixed System. AB - Self-reproduction is one of the most important characteristics of lipid vesicles for origin of life research. Most vesicle self-reproduction systems are based on fatty acid vesicles and spontaneous phospholipid vesicle production is difficult owing to the relatively high stability of these vesicles. Now, spontaneous phospholipid vesicle generation and extension in a dipeptide/phospholipid system is demonstrated. Dissolution of the dipeptide crystal provides both the driving force and phospholipid constituents for vesicle generation and extension. This study provides a new system to enhance the understanding of vesicle self reproduction mechanisms. PMID- 30009559 TI - Thermal stability of poly[1-(trimethylsilyl)-1-propyne] and the gas chromatographic stationary phase based on it. AB - The thermal stability of poly[1-(trimethylsilyl)-1-propyne] is investigated by heating the capillary column with this polymer as the stationary phase with the subsequent separation of the test mixture of light hydrocarbons. It is shown that heating of the column up to 130 degrees C does not cause a decrease in efficiency or in the retention time of solutes. A further increase in temperature results in both decrease in column efficiency and sorbate retention. However, a decrease in column retentivity goes in one way for all the tested hydrocarbons. At the same time, the efficiency of the column is changed to a lesser degree for methane and ethane up to the temperature of polymer degradation, while for propane, butane, and iso-butane the difference is rather sharp. The most expressed decrease in efficiency was found for iso-butane: the column efficiency for this sorbate versus temperature of heating had two stages. The diffusion coefficients for sorbates in the polymeric phase were also evaluated and the sharp decrease in their values was found after the column heating. PMID- 30009561 TI - Synthesis of Phlorin Analogues of Dithiacorrphycene and Their Use as Specific Chemodosimetric Sensors for Fe3+ Ions. AB - The first examples of stable phlorin analogues of dithiacorrphycene were synthesized by treating appropriate tetrapyrranes with two equivalents of trifluoroacetic acid in CH2 Cl2 followed by oxidation with p-chloranil. The oxidative coupling of tetrapyrrane resulted in the formation of two unexpected phlorin analogues of dithiacorrphycenes that differed from each other at the meso sp3 -carbon, and the two macrocycles were easily separated and isolated by column chromatography. The novel macrocycles were confirmed by X-ray crystallography and characterized by HRMS, 1D and 2D NMR spectroscopy, absorption spectroscopy, cyclic voltammetry, and time-dependent DFT studies. X-ray structure analysis revealed the highly strained and distorted nature of the macrocycles. The macrocycles showed one ill-defined absorption band at lambda~315 nm and a broad band at lambda~530 nm. Because both macrocycles possess two thiophene and two pyrrole rings with one ionizable inner NH, the cation-sensing properties of the phlorin analogues of dithiacorrphycenes have been investigated. The phlorin analogues of dithiacorrphycenes act as specific chemodosimetric sensors for Fe3+ ions by converting phlorin analogues of dithiacorrphycenes into dithiacorrphycene. PMID- 30009562 TI - Reply to: Use of ROTEM in correction of unexpected oozing in a child with a preexisting normal coagulation profile undergoing splenectomy. PMID- 30009563 TI - Profiling Analysis Reveals the Potential Contribution of Peptides to Human Adipocyte Differentiation. AB - PURPOSE: Peptide drugs provide promising regimes in anti-obesity treatment. In order to identify potential bioactive peptides involved in adipogenesis. EXPERIMENTAL DESIGN: The intracellular peptides between preadipocytes and adipocytes are compared by liquid chromatography/mass spectrometry. The underlying biological function of the identified peptides are evaluated by gene ontology (GO) and pathway analysis of their precursors. To find more potential bioactive peptides, 50 peptide sequences are identified located in the functional domains with the use of the SMART and UniProt databases. Finally, the Open Targets Platform database is used to investigate the precursors related to metabolic diseases. RESULTS: A total of 181 downregulated peptides and 89 upregulated peptides after differentiation (fold change > 1.5 and p-value < 0.05) are identified. The GO and pathway analysis indicate that these differentially expressed peptides play a role in adipogenesis. A total of 10 putative peptides 6 to 26 amino acids in length are identified that might have bioactive effects in adipogenesis and metabolic diseases. CONCLUSIONS AND CLINICAL RELEVANCE: On one hand, present preliminary research provides a better understanding of the intracellular peptides during adipocyte differentiation. On the other hand, it lays a foundation for discovering new peptide drugs in anti-obesity treatment. PMID- 30009564 TI - Practical application of Octavius(r) -4D: Characteristics and criticalities for IMRT and VMAT verification. AB - Octavius(r) -4D is a very effective device in radiotherapy treatment quality assurance (QA), due to its simple set-up and analysis package. However, even if it is widely used, its main characteristics and criticalities were only partially investigated. Taking start from its commissioning, the aim of this work was to study the main dependencies of the device response. The outcome dependence was studied comparing results by different delivery techniques [Intensity Modulated Radiation Therapy, IMRT (n = 29) and RapidArc, RA (n = 15)], anatomical regions [15 head/neck, 19 pelvis and 10 pancreas] and linear accelerators [DHX (n = 14) and Trilogy (n = 30)]. Moreover, the agreement dependency on the section of the phantom was assessed. Plan evaluations obtained by 2D, 3D, and volumetric gamma index (both local and global) were also compared. Generally, high dose gradient resulted critically managed by the assembly, with a smoother effect in RA technique. Worse agreements emerged in the 2D gamma-index vs those of 3D and volumetric (P < 0.001), that were instead statistically comparable in global metric (P > 0.300). Volumetric plan evaluation was coherent with the average of passing rates on the 3 phantom axes (r >= 0.9), but transversal section provided best agreements vs sagittal and coronal ones (P < 0.050). The three studied districts furnished comparable results (P > 0.050) while the two LINACs provided different agreements (P < 0.005). The study pointed out that the phantom transversal section better fits the planned dose distribution, so this should be accounted when a two-dimensional evaluation is needed. Moreover, the major reliability of the 3D metric with respect to the 2D one, as it better agrees with the dosimetric evaluation on the whole volume, suggests that it should be preferred in a two-dimensional evaluation. Better agreements, obtained with RA vs IMRT technique, confirm that Octavius(r) -4D is specifically conceived for rotational delivery. Lastly, the assembly resulted sensitive to different technology. PMID- 30009565 TI - Variable selection and parameter estimation of viral amplification in vero cell cultures dedicated to the production of a dengue vaccine. AB - In this study, a dynamic model of a Vero cell culture-based dengue vaccine production process is developed. The approach consists in describing the process dynamics as functions of the whole living (uninfected and infected) biomass whereas previous works are based on population balance approaches. Based on the assumption that infected biomass evolves faster than other variable, the model can be simplified using a slow-fast approximation. The structural identifiability of the model is analysed using differential algebra as implemented in the software DAISY. The model parameters are inferred from experimental datasets collected from an actual vaccine production process and the model predictive capability is confirmed both in direct and cross-validation. The model prediction shows the impact of the metabolism on virus yield and confirms observations reported in previous studies. Multi-modality and sensitivity analysis complement the parameter estimation, and allow to obtain confidence intervals on both parameters and state estimates. Finally, the model is used to compute the maximum infectious virus yield that can be obtained for different combinations of multiplicity of infection (MOI) and time of infection (TOI). (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30009566 TI - Parent-child communication surrounding genetic testing for Li-Fraumeni syndrome: Living under the cloud of cancer. AB - BACKGROUND: Advances in the application of genetic technologies reveal a growing number of heritable disorders associated with an increased risk to develop cancer during childhood. As genetic testing is increasingly employed in the clinical setting, it is essential to understand whether parents communicate with their children about test results and to elucidate the factors that influence the content and outcomes of these conversations. METHODS: Semistructured interviews were conducted with 14 parents whose children tested positive for Li-Fraumeni syndrome (LFS). Semantic content analysis was performed on transcribed interviews, focusing on questions related to parent-child conversations about the genetic testing process and disclosure of positive test results. RESULTS: All parents emphasized the importance of involving children in conversations about LFS. The majority (93%) identified as being part of "cancer families" in which prior experiences with cancer created opportunities for communication. While all had spoken with their children about cancer, only seven (50%) specifically disclosed to their children that they had tested positive for LFS. The most common reason cited for nondisclosure at the time of this study was the young age of the children. CONCLUSION: Parents of children with LFS desire open conversations about genetic testing and cancer risk. These conversations are challenging yet essential to enable child understanding of genetic risk status and enhance compliance with health-promoting and cancer surveillance measures. Development of age-appropriate educational materials and novel clinical models to facilitate parent-child conversations about genetic test results and risk status for cancer are needed. PMID- 30009567 TI - Review and in silico analysis of fermentation, bioenergy, fiber, and biopolymer genes of biotechnological interest in Agave L. for genetic improvement and biocatalysis. AB - Several of the over 200 known species of Agave L. are currently used for production of distilled beverages and biopolymers. The plants live in a wide range of stressful environments as a result of their resistance to abiotic stress (drought, salinity, and extreme temperature) and pathogens, which gives the genus potential for germplasm conservation and biotechnological applications that may minimize economic losses as a result of the global climate change. However, the limited knowledge in the genus of genome structure and organization hampers development of potential improved biotechnological applications by means of genetic manipulation and biocatalysis. We reviewed Agave and plant sequences in the GenBank NCBI database for identifying genes with biotechnological potential for fermentation, bioenergy, fiber improvement, and in vivo plant biopolymer production. Three-dimensional modeling of enzyme structures in plant accessions revealed structural differences in sucrose 1-fructosyltransferase, fructan 1 fructosyltransferase, fructan exohydrolase (1-FEH), cellulose synthase (CES), and glucanases (EGases) with possible effects in fructan, sugar, and biopolymer production. Although the coding genes of FEH and enzymes involved in biopolymer production (CES, sucrose synthase, and EGases) remain unidentified in Agave L., our results could aid isolation of such genes in Agave. By comparing nucleotide and amino acid sequences in accessions of Agave and other plants, knowledge may be gained about transcriptional regulation and enzymatic activity factors. Future study is needed of biotechnological application of Agave genes for crop breeding aided by genetic engineering and biocatalysis. PMID- 30009568 TI - TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population. AB - Tumour necrosis factor (TNF)-mediated signalling plays a key role in inflammatory and neurodegenerative processes leading to the development of multiple sclerosis (MS). Recent studies have highlighted the role of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene encoding the type 1 TNF receptor in the genetic predisposition to MS. This study aimed to validate the association of TNFRSF1A rs1800693 and rs4149584 polymorphisms with susceptibility to MS in the Slovak population and analyse their influence on age at disease onset, severity, and disability progression. Polymerase chain reaction-restriction fragment length polymorphism method was used to genotype both TNFRSF1A polymorphisms in 541 MS patients and 724 healthy controls. Logistic regression analysis revealed a significantly increased risk of developing MS for the carriers of rs1800693 C allele (TC + CC vs. TT: pcorr = 0.005; OR = 1.61; 95% CI = 1.23-2.12), irrespective of sex and carriage of the major MS risk allele HLA-DRB1*15:01. On the other hand, no association could be found between rs4149584 and MS risk (GA + AA vs. GG: pcorr = 1.00; OR = 1.25; 95% CI = 0.71-2.21). Moreover, neither polymorphism was significantly associated with age at disease onset, MS Severity Score (MSSS) or MS Progression Index (PI) in any of the inheritance models. In conclusion, our results provide support for a sex- and HLA-DRB1*15:01-independent association of TNFRSF1A rs1800693 SNP with MS susceptibility, but not with age at disease onset, severity or rate of disability accumulation. PMID- 30009569 TI - Patients receiving dialysis do not have increased energy needs compared with healthy adults. AB - BACKGROUND: Patients receiving dialysis are thought to have increased energy needs due to stress from the dialysis process or uraemic toxins. However, certain conditions may induce hypometabolic states potentially leading to unwanted weight gains when increased calorie intake is recommended. OBJECTIVES: Since there is conflicting research, this study aims to assess total energy expenditure (TEE) of patients receiving dialysis through analysis of resting energy expenditure (REE) and physical activity levels. DESIGN: Comprehensive review of the current literature on REE and physical activity levels. METHODS: Two electronic databases (PubMed and CINAHL) were searched using keywords to find papers published within the last 10 years for physical activity studies and within the last five years for REE. INCLUSION CRITERIA: Adults undergoing long-term dialysis treatments who do not have comorbidities that influence energy expenditure such as inflammation, hyperthyroidism or cancers. Participants were also required to ambulate without assistance. RESULTS: Only seven of the 325 studies found were included in this review. Most studies were controlled trials with one being a prospective study. Patients receiving dialysis had rest energy expenditures comparable to healthy adults. There was not a consensus between studies as to which predictive energy equation produced accurate energy recommendations. Overall, patients receiving dialysis were significantly less active compared with healthy adults and this related to muscle mass. CONCLUSION: Patients receiving dialysis tend to be sedentary or lightly active and do not have increased energy expenditure compared with healthy adults. Therefore, stable patients should not be prescribed increased calorie intake. PMID- 30009570 TI - Curcumin supplementation mitigates NASH development and progression in female Wistar rats. AB - Curcumin, a naturally occurring plant polyphenolic compound, may have beneficial effects in nonalcoholic steatohepatitis (NASH) development. We examined whether curcumin supplementation could be used in both prevention and treatment of NASH with fibrosis. Female Wistar rats were provided ad libitum access to a "western diet" (WD) high in fat (43% kcal), sucrose (29% kcal), and cholesterol (2% w/v), as well as 15% fructose drinking water. Intraperitoneal CC14 injections (0.5 mL/kg) were also administered at weeks 1, 2, 4, and 6 to accelerate development of a NASH with fibrosis phenotype. Rats were randomized to four groups (n = 9 12/group) and fed ad libitum: (1) WD for 8-weeks (8WD), (2) WD enriched with curcumin for 8-weeks (8WD+C; 0.2% curcumin, BCM-95, DolCas Biotech) to assess prevention, (3) WD for 12-weeks (12WD), (4) WD for 8-weeks followed by 4-weeks WD+C (12WD+C) to assess treatment. Curcumin prevention (8WD vs. 8WD+C) attenuated (P < 0.05) histological liver inflammation, molecular markers of fibrosis (Col1a1 mRNA) and a serum marker of liver injury (AST). Curcumin treatment (12WD vs. 12WD+C) reduced (P < 0.05) hepatocellular inflammation, steatosis, NAFLD Activity Scores, and serum markers of liver injury (AST, ALP). Moreover, curcumin treatment also increased hepatic pACC/ACC, ApoB100, and SOD1 protein, and decreased hepatic FGF-21 levels; whereas, curcumin prevention increased hepatic glutathione levels. Both curcumin prevention and treatment reduced molecular markers of hepatic fibrosis (Col1a1 mRNA) and inflammation (TNF-alpha, SPP1 mRNA). Curcumin supplementation beneficially altered the NASH phenotype in female Wistar rats, particularly the reversal of hepatocellular inflammation. PMID- 30009571 TI - An Industry-Driven Roadmap for Manufacturing in Regenerative Medicine. AB - Regenerative medicine is poised to become a significant industry within the medical field. As such, the development of strategies and technologies for standardized and automated regenerative medicine clinical manufacturing has become a priority. An industry-driven roadmap toward industrial scale clinical manufacturing was developed over a 3-year period by a consortium of companies with significant investment in the field of regenerative medicine. Additionally, this same group identified critical roadblocks that stand in the way of advanced, large-scale regenerative medicine clinical manufacturing. This perspective article details efforts to reach a consensus among industry stakeholders on the shortest pathway for providing access to regenerative medicine therapies for those in need, both within the United States and around the world. Stem Cells Translational Medicine 2018;7:564-568. PMID- 30009572 TI - Unilateral temporal interictal epileptiform discharges correctly predict the epileptogenic zone in lesional temporal lobe epilepsy. AB - OBJECTIVE: To evaluate the necessity of recording ictal electroencephalography (EEG) in patients with temporal lobe epilepsy (TLE) considered for resective surgery who have unilateral temporal interictal epileptiform discharges (IEDs) and concordant ipsitemporal magnetic resonance imaging (MRI) pathology. To calculate the necessary number of recorded EEG seizure patterns (ESPs) to achieve adequate lateralization probability. METHODS: In a retrospective analysis, the localization and lateralization of interictal and ictal EEG of 304 patients with lesional TLE were analyzed. The probability of further contralateral ESPs was calculated based on a total of 1967 recorded ESPs, using Bayes' theorem. RESULTS: Two hundred seventy-one patients had unilateral TLE, and in 98% of them (265 of 271), IEDs were recorded during video-EEG monitoring. Purely unilateral temporal IEDs were present in 61% (166 of 271 patients). Ipsilateral temporal MRI pathology was found in 83% (138 of 166). Ictal EEG was concordant with the clinical side of TLE in 99% (136 of 138) of these patients. Two patients had discordant ictal EEG with both ipsilateral and contralateral ESPs. Epilepsy surgery with resection in the lesioned temporal lobe was still performed, and both patients remain seizure-free. Probability calculations demonstrate that at least 6 recorded unilateral ESPs result in a >95% probability for a concordance of >0.9 of any further ESPs. SIGNIFICANCE: The combination of purely unilateral temporal IED with ipsitemporal MRI pathology is sufficient to identify the epileptogenic zone, and the recording of ictal ESP did not add any surgically relevant information in these 138 patients. Rarely, discordant ESPs might be recorded, but the surgical outcome remains excellent after surgery on the lesioned side. PMID- 30009573 TI - Hepatitis B Virus Infection Among Patients With Chronic Kidney Disease Who Attended an Educational Program in Japan. AB - The rate of hepatitis B infection among hemodialysis patients is high. However, it is not clear if this rate reflects the infection rate among patients with chronic kidney disease (CKD). Therefore, we evaluated the rate of hepatitis B infection among patients with CKD. This is an important clinical issue when considering the risk of infection to medical staff when performing invasive procedures in this clinical population. A retrospective, observational study was conducted among stable, non-dialysis patients with CKD who attended a CKD educational program at our hospital, between August 2012 and October 2017. We collected patients' background and markers of hepatitis infection (HBsAg, HBcAb and HBsAb, as well as HBV-DNA when available) from medical records. The data from 496 patients (373 men and 123 women, with a mean age of 69.3 +/- 13.0 years and mean level of creatinine of 3.15 +/- 1.72 mg/dL, AST of 21.6 +/- 10.5 IU/L, and ALT of 17.3 +/- 12.5 IU/L), were included in the analysis. The rate of positive testing for hepatitis B virus infection was as follows: HBsAg, 1.6%; HBsAb, 16.5%; and HBcAb, 21.4%. Of the patients with a negative HBsAg test, 20.1% tested positive for HBcAb. Of the 66 patients in whom HBV-DNA testing was performed, 10.6% tested positive. The rate of hepatitis B virus infection was specifically higher among patients >=71-years-old. In patients with CKD, the rate of HBsAg positivity is high. Rate of HBcAb positivity is higher particularly in older individuals. PMID- 30009574 TI - A brassinosteroid responsive miRNA-target module regulates gibberellin biosynthesis and plant development. AB - Plant growth and development are highly coordinated by hormones, including brassinosteroid (BR) and gibberellin (GA). Although much progress has been made in understanding the fundamental signaling transduction in BR and GA, their relationship remains elusive in rice. Here, we show that BR suppresses the level of OsmiR159d, which cleaves the target OsGAMYBL2 gene. The OsmiR159d-OsGAMYBL2 pair functions as an early BR-responsive module regulating the expression of BU1, a BR-regulated gene involved in BR signaling, and CPS1 and GA3ox2, two genes in GA biosynthesis, by binding to the promoters of these genes. Furthermore, OsGSK2, a key negative player in BR signaling, interacts with OsGAMYBL2 and prevents it from being degraded under 24-epibrassinolide treatment, whereas SLR1, a rice DELLA protein negatively regulating GA signaling, interacts with OsGAMYBL2 and prevents OsGAMYBL2 from binding to the target gene promoter. GA signaling induces degradation of OsGAMYBL2 and, consequently, enhances BR signaling. These results demonstrate that a BR-responsive module acts as a common component functioning in both BR and GA pathways, which connects BR signaling and GA biosynthesis, and thus coordinates the regulation of BR and GA in plant growth and development. PMID- 30009576 TI - Penile lymphoedema: approach to investigation and management. AB - BACKGROUND: Penile lymphoedema (with and without cellulitis) is a rare, often chronic, clinically heterogeneous entity with an uncertain pathogenesis and an important differential diagnosis. It creates significant physical and psychosexual morbidity, and presents considerable therapeutic challenges. The existing literature is limited. AIM: To describe and share our updated cumulative experience of a cohort of patients with penile lymphoedema. METHODS: This was a retrospective review of the case records of patients with chronic penile lymphoedema seen in two dedicated male genital dermatology clinics between January 2011 and July 2016. RESULTS: In total, 41 cases were identified. Over a third had Crohn disease (CD) (which was occult in one-third of these), and over a third had serological evidence of streptococcal infection. All patients responded to systemic antibiotics and specialized urological surgery circumcision and excision). CONCLUSIONS: Penile lymphoedema should be investigated to exclude underlying pathology especially CD and streptococcal infection. Treatment with antibiotics should be considered early and long term to try to preserve the foreskin: most patients are uncircumcised. Some patients may benefit from a course or courses of oral steroids. The development of gross dysfunction of the prepuce usually dictates circumcision and excision of lymphoedematous tissue once the situation is medically stabilized. PMID- 30009575 TI - Effect of marital status on survival in glioblastoma multiforme by demographics, education, economic factors, and insurance status. AB - The relationship between marital status and glioblastoma multiforme (GBM) has not been addressed in depth. Here, we aimed to investigate the association between marital status and survival in GBM. We searched the Surveillance, Epidemiology, and End Results (SEER) database and extracted the data of eligible patients diagnosed with GBM after 2004. Marital status was classified as married, divorced/separated, widowed, and single. A Kaplan-Meier test was conducted to compare the survival curves of different groups. Multivariate Cox regression was performed to evaluate overall survival (OS) and cause-specific survival (CSS) in different groups. Subgroup analysis was applied according to demographics, typical education and income levels in the locale, and insurance status. A total of 30 767 eligible patients were included. The median OS values were 9, 7, 3, 9 months in married, divorced/separated, widowed, and single patients, respectively. After adjustment for other covariates, married patients had better OS and CSS than other patients had. In addition to marital status, demographic factors, disease progression factors, local educational level, and insurance status were also associated with survival in GBM. Furthermore, subgroup analyses revealed the protective effect of marriage in most of the comparisons. Notably, the protective effect of marriage becomes more and more apparent as time goes on. The advantageous effect of marriage on GBM survival is especially prominent in patients who are male, older than 60 years of age, White, or living in middle income counties. In conclusion, marital status is an independent prognostic factor for GBM. PMID- 30009577 TI - (-)-Epigallocatechin gallate derivatives reduce the expression of both urokinase plasminogen activator and plasminogen activator inhibitor-1 to inhibit migration, adhesion, and invasion of MDA-MB-231 cells. AB - Urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) are established independent biomarkers for high metastasis risk in breast cancer. In this study, we investigated the regulatory activity of (-)-epigallocatechin-3-gallate (EGCG) and its derivatives on uPA and PAI-1 expression and thereby their anti-metastatic potential. EGCG showed only marginal effects on the uPA system and on the metastatic behavior of breast cancer cells (MDA-MB-231). However, the EGCG derivative 3e with a methyl-substituted carbonate substituent at the 4"-position showed potent inhibition of PAI-1 (62%) and uPA (50%) expression. The Ras-extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase (PI3K)/Akt/NF-kappaB pathways, which regulate uPA and PAI-1 expression, were also affected by 3e (25%, 45%, and 25% reduction, respectively). In line with these findings, substantial reduction in metastatic behavior of MDA-MB-231 cells, such as adhesion (40%), invasion (56%), and migration (40%), was observed in the presence of 3e. It is also noteworthy that, in MDA-MB-231 cells, 3e did not exert any beneficial effect on the expression of matric metalloprotein (MMP) 2 and 9, which indicates that the anti-metastatic activity of 3e in MDA-MB-231 cells is not related to its regulation of the expression of MMPs. Taken together, we have shown that the EGCG derivative 3e could suppress the metastatic behavior of MDA MB-231 cells through regulation of uPA and PAI-1. PMID- 30009578 TI - The challenge of psychiatric diagnosis: Looking beyond the symptoms to the company that they keep. PMID- 30009579 TI - Reproductive medicine: still more ART than science? PMID- 30009580 TI - Flexible Graphene-Wrapped Carbon Nanotube/Graphene@MnO2 3D Multilevel Porous Film for High-Performance Lithium-Ion Batteries. AB - The ingenious design of a freestanding flexible electrode brings the possibility for power sources in emerging wearable electronic devices. Here, reduced graphene oxide (rGO) wraps carbon nanotubes (CNTs) and rGO tightly surrounded by MnO2 nanosheets, forming a 3D multilevel porous conductive structure via vacuum freeze drying. The sandwich-like architecture possesses multiple functions as a flexible anode for lithium-ion batteries. Micrometer-sized pores among the continuously waved rGO layers could extraordinarily improve ion diffusion. Nano-sized pores among the MnO2 nanosheets and CNT/rGO@MnO2 particles could provide vast accessible active sites and alleviate volume change. The tight connection between MnO2 and carbon skeleton could facilitate electron transportation and enhance structural stability. Due to the special structure, the rGO-wrapped CNT/rGO@MnO2 porous film as an anode shows a high capacity, excellent rate performance, and superior cycling stability (1344.2 mAh g-1 over 630 cycles at 2 A g-1 , 608.5 mAh g-1 over 1000 cycles at 7.5 A g-1 ). Furthermore, the evolutions of microstructure and chemical valence occurring inside the electrode after cycling are investigated to illuminate the structural superiority for energy storage. The excellent electrochemical performance of this freestanding flexible electrode makes it an attractive candidate for practical application in flexible energy storage. PMID- 30009581 TI - Assembled Nanocomplex for Improving Photodynamic Therapy through Intraparticle Fluorescence Resonance Energy Transfer. AB - In recent years, one of main obstacles in a photodynamic therapy (PDT) process has been that most photosensitizers for PDT are excited by visible light with limited penetrating ability; thus most applications of PDT are for superficial treatments. One of the methods to increase the treatment depth is to introduce a two-photon-active technique into PDT, known as TP-PDT. The difficulty here is to obtain photosensitizers with a large enough two-photon absorption cross-section. In this work, an organic nanocomplex, composed of the two-photon nanoaggregate as the core and photosensitizer as the shell, has been constructed. Photosensitizers could be excited indirectly through a fluorescence resonance energy transfer (FRET) mechanism after the two-photon core was excited by a two-photon laser. The FRET efficiency was extremely high, owing to sufficient energy donors and stable energy acceptors. In this way, a photosensitizer could induce two-photon toxicity for improving the treatment depth in PDT. The nanocomplexes were prepared through a molecular assembly method, which avoided complicated reactions for synthesizing two-photon photosensitizers. The assembly method would expand the selection of photosensitizers and two-photon dyes, and endow traditional photosensitizers with a larger two-photon absorption cross-section for TP-PDT. PMID- 30009582 TI - Mathematical modeling of adsorption isotherms in mixed salt systems in hydrophobic interaction chromatography. AB - Hydrophobic interaction chromatography (HIC) is often used for purifying proteins. The prediction of the adsorption equilibria in such systems is a difficult task as they depend on the pH value and the influence of the salts, which are added for controlling the solvent properties. This is especially tedious when salt mixtures are used, which can have positive or negative cooperative effects on the adsorption. A mathematical model to describe these complex effects of the salts was recently introduced by our group. In that model, the influence of the salts is described by a Taylor series expansion in the individual ion molarities. However, in our previous work, only the loading of the adsorbent at a given constant protein concentration in the liquid phase cp = 0.01 mM was considered and correlated as a function of the salt composition at constant ionic strength. In the present study, that model is extended to other protein concentrations and it is shown that the Taylor series expansion works well for a wide range of cp . The model parameters are found to depend on cp , but only in a simple way. The dependence of the model parameters on cp was correlated using a new three parameter equation. From that correlation, the loading qp can be determined for any value of cp . Hence, the entire adsorption isotherm is known for any salt composition. The approach is illustrated using experimental data from previous studies of our group on the adsorption of bovine serum albumin, lysozyme, polyethylene glycol, and di-PEGylated lysozyme on the mildly hydrophobic resin Toyopearl PPG-600 M. The pH values are between 4.0 and 7.0. Binary and ternary mixtures of ammonium chloride, sodium chloride, ammonium sulfate, and sodium sulfate as well as the single salts are used at overall ionic strengths between 1,500 and 4,200 mM. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30009583 TI - Kheri (Acacia chundra, family: Mimosaceae) gum: Characterization using analytical, mathematical and pharmaceutical approaches. AB - BACKGROUND: Natural polymers have been used in medical, pharmaceutical, cosmetic and food industry. They should be characterized before their possible applications in different industries. OBJECTIVES: The objective of this study was to characterize Kheri (Acacia chundra, family: Mimosaceae) gum using analytical, mathematical and pharmaceutical approaches. MATERIAL AND METHODS: Crude Kheri gum (KG) was purified using distilled water as a solvent and ethanol as a precipitating agent. KG was characterized in terms of phytochemical screening, micromeritic properties, microbial load, ash value, rheological behavior, solid state 1H nuclear magnetic resonance (NMR), mass spectra and Fourier-transform infrared spectroscopy (FTIR) studies for their possible applications in food, cosmetics and pharmaceutical industry. RESULTS: Studies show that KG contains carbohydrates, while protein, fat, volatile oils, alkaloids and glycosides are absent. 1% aqueous solution of polysaccharide showed 25.58 * 103 kJ/kg activation energy and 1.39 Reynold's number. Viscosity average molecular weight of purified gum was found 1.73 * 105 D. Thermodynamic parameters, i.e., change in enthalpy DeltaHv and change in enthalpy DeltaHv, were found to be 12.26 * 103 kJ/mol and 24.47 kJ/mol, respectively. Mathematical approach also determined the rod shaped conformation of KG in aqueous solution. IR spectroscopic study shows the presence of free (COO-) and esterified (COO-R) carboxylic acid, ether (C-O stretching), galacturonic acid and mannose in polysaccharide 1H NMR study predicts presence of tetrahydropyran hydrogen in molecule. Furthermore, KG was also characterized as a suspending agent using paracetamol as a model drug. Flow rate, pH, particle size and settling behavior of suspensions were evaluated. Initial particle size of dispersed phase particles does not change significantly after 45 days. CONCLUSIONS: From the findings of the research it can be concluded that KG can be used as an excipient in cosmaceuticals and pharmaceuticals and its characteristic rheological behavior may attract rheologists. PMID- 30009584 TI - [Influence of electrochemical ageing on properties of chosen medical receptacles]. AB - BACKGROUND: Presently, most of receptacles used in medicine are made of polymeric materials. This is due to, e.g., low price, low weight, and aesthetic values of these materials. The important issue is to ensure long life of polymer in order to protect the medicines closed in the boxes. However, all materials during exploitation are exposed to many factors, which can cause degradation of polymer materials. Degradation processes lead to deterioration of thermomechanical properties of polymers. OBJECTIVES: The aim of this syudy was to examine the influence of electrochemical ageing on properties of polymeric materials used in production of receptacles for drugs and boxes for medical use. MATERIAL AND METHODS: We conducted comparative analysis of samples before and after electrochemical ageing, cut out of receptacles for drugs made from polyethylene, as well as from boxes for medical use and Eppendorf tube made from polypropylene. Investigating methods included differential scanning calorimetry (DSC) and imaging of microstructure *400 magnification. RESULTS: We noticed different value of the degree of crystallinity for the aged samples in comparison to not aged samples. The change in value of temperature of physical transformation was also detected. In the aged samples defragmentation of crystal structure was observed. CONCLUSIONS: Electrochemical ageing results in changes of properties of polymeric materials used in production of medical receptacles. PMID- 30009586 TI - Light-cured dimethacrylate dental restorative composites under a prism of annihilating positrons. AB - BACKGROUND: Breakthrough resolutions in current biopolymer engineering rely on reliable diagnostics of atomic-deficient spaces over the finest sub-nanometer length scales. One such diagnostic is positron annihilation lifetime spectroscopy, which probes space-time continuum relationships for the interaction between electrons and their antiparticle (positrons) in structural entities like free-volume defects, vacancies, vacancy-like clusters, interfacial voids and pores, etc. OBJECTIVES: This paper is intended to highlight the possibilities of positron annihilation lifetime spectroscopy as an informative instrumentation tool to parameterize free-volume evolution in light-cured dimethacrylate dental restorative composites exemplified by Charisma(r) (Heraeus Kulzer GmbH, Hanau, Germany) and Dipol(r) (Oksomat-AN Ltd, Kyiv, Ukraine). MATERIAL AND METHODS: The subjects of the study were the commercially available dimethacrylate-type dental restorative composites Charisma(r) and Dipol(r). The analysis used a fast-fast coincidence system of 230 ps resolution based on 2 photomultiplier tubes coupled to BaF2 scintillator detectors and ORTEC(r) (ORTEC, Oak Ridge, USA) electronics to register lifetime spectra in normal-measurement statistics evolving ~1 million coincidences. RESULTS: The annihilation process in both composites is identified as mixed positron-Ps (positronium) trapping, where ortho-Ps decaying is caused entirely by free-volume holes in the polymer matrix, and the 2nd component is defined mainly by interfacial free-volume holes between filler nanoparticles and the surrounding polymer. The most appropriate model-independent estimation of photopolymerization volumetric shrinkage in dental restorative composites can be done using averaged positron annihilation lifetime. Partiallyconstrained x4-term analysis of lifetime spectra is less efficient, giving greater scatter of variance with an additional artifact of fixed shortest lifetime allowing unresolved mixing in the 2nd component. A meaningful phenomenological description of transformations in Ps and positron-trapping sites under light curing, which occurs more efficiently in Charisma(r) than in Dipol(r) nanocomposites, can be developed at the basis of a semi-empirical model exploring a x3-x2-coupling decomposition algorithm. CONCLUSIONS: A deep understanding of void-evolution processes in dimethacrylate dental composites employing positron annihilation lifetime spectroscopy makes it possible to diagnose, characterize and engineer novel biomaterials for advanced use in medical practice. PMID- 30009585 TI - Improving the solubility of nevirapine using A hydrotropy and mixed hydrotropy based solid dispersion approach. AB - BACKGROUND: Nevirapine, an antiviral drug, is a potent reverse transcriptase inhibitor (NNRTI). It is used in combination with nucleoside analogues for treatment of HIV type-1 (HIV-1) infection and AIDS. Nevirapine is a BCS class II drug which shows dissolution rate limited absorption. OBJECTIVES: The aim of the present research was to provide a fast dissolving solid dispersion of nevirapine. MATERIAL AND METHODS: The solubility of nevirapine was initially determined individually in four hydrotropic agents - namely urea, lactose, citric acid and mannitol - at a concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. The highest solubility was obtained in the 40% citric acid solution. Then different combinations of 2 and 3 hydrotropic agents in different ratios were used to determine solubility, so that the total concentration of hydrotropic agents was always 40%. RESULTS: The highest solubility was obtained in a solution of lactose and citric acid at the optimum ratio of 15:25. This optimized combination was utilized in preparing solid dispersions by a common solvent technique using distilled water as a solvent. The solid dispersions were evaluated for XRD, DSC and FTIR to show no drug-hydrotrope interaction. CONCLUSIONS: It was concluded that the concept of mixed hydrotropic solid dispersion is a safe, novel and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs by dissolving the drug in a nonionized form. The enhancement in solubility of nevirapine using hydrotropy is a clear indication of its potential to be used in the future for other poorly water-soluble drugs in which low bioavailability is a major concern. PMID- 30009587 TI - Formulation and evaluation of controlled-release matrix systems of ciprofloxacin. AB - BACKGROUND: Ciprofloxacin is a broad-spectrum fluoroquinolone antibacterial drug to which most Gram-negative and many Gram-positive bacteria are highly susceptible. Fluoroquinolones are administered repeatedly, twice a day for 5 days, during the course of therapy. Hence, they require repeated administration. Ciprofloxacin qualifies as a drug candidate for a controlled-release drug delivery system. OBJECTIVES: The present work was aimed to develop ciprofloxacin hydrochloride-containing matrix tablets by the wet granulation method. MATERIAL AND METHODS: The tablets were prepared using EthocelTM 100 Premium and Eudragit(r) RS PO (Evonik Laboratory, Mumbai, India) as a rate-controlling polymer. Granular dioctyl phthalate (DCP) was used as a diluent. An isopropyl alcohol and dichloromethane (1:1) mixture was used as a granulating agent. The effect of the formulation variables on tablet performance was examined based on weight variation, hardness, friability, thickness, and drug release profiles. The results suggested that the tablets had good integrity. RESULTS: The tablets were stable for 18 months. Formulation F7 gave a linear release pattern up to 12 h. The release of ciprofloxacin from formulation F7 followed zero-order kinetics. The release mechanism was found to be diffusion-controlled as the Higuchi equation was obeyed. CONCLUSIONS: Ciprofloxacin hydrochloride-containing matrix tablets were prepared successfully. The tablets had good integrity and were found stable for 18 months. PMID- 30009588 TI - Impaired sports performance of athletes suffering from pollen-induced allergic rhinitis: a cross-sectional, observational survey in German athletes. AB - BACKGROUND: Allergic rhinitis has major impacts on sports performance of athletes. The present study aimed at determining the frequency of seasonal pollen allergy and analysing the impacts of pollen allergy, the choice of allergy treatments and their benefits for sports performance in a group of professional and recreational athletes. METHODS: The study was conducted as a self-reported questionnaire survey. Subjects were recruited from the German Sport University and the Cologne Marathon 2014 during the peak pollen season of 2014. RESULTS: Athletes returned 636 completed questionnaires, 42.6% of participants reported suffering from a pollen allergy and 30.2% also suffered from asthma. Performance impairments were reported in more than 80% of allergic subjects. In all, 82.2% of subjects used symptomatic medications, 32.3% alternative therapies, and 47.6% allergen immunotherapy. Subjects who used immunotherapy had fewer impaired training bouts than those who used symptomatic and alternative therapies. The majority of subjects had concerns about allergy treatment such as side effects, negative impacts on sports performance and lack of long-term effects. CONCLUSIONS: This study confirmed a high prevalence of pollen allergy among German athletes. The majority of allergic rhinitis athletes were undertreated and the reason could be their reservations about allergy treatments. Pollen allergy tremendously reduced sports performance of athletes during the pollen season. This impact can be lessened with proper treatment such as immunotherapy. Better understanding of available treatment modalities should be provided to patients and physicians to improve sports performance of athletes suffering from pollen allergy. PMID- 30009589 TI - Teamwork key to survival of Orlando shooting victims. PMID- 30009590 TI - Mixed-Valent Cyanoplatinates Featuring Neptunyl-Neptunyl Cation-Cation Interactions. AB - The tetracyanoplatinate ligand was employed in synthesizing the first neptunyl cyanoplatinate complexes. Results indicate in situ oxidation of Pt(II) by Np(V/VI) to form mixed-valent Pt-Pt stacked columnar chains linked by cation cation interaction induced chains of Np(V) polyhedra into a two-dimensional sheet structure. The Pt-Pt stacking distances of 3.04-3.05 A are the longest reported columnar platinophilic interactions among mixed-valent tetracyanoplatinate structures. These complexes further illustrate the marked chemical differences and structural diversity of solid-state Np(V) coordination complexes with regard to Np(VI) and U(VI). PMID- 30009591 TI - Flexible and Transparent Organic-Inorganic Hybrid Thermoelectric Modules. AB - Light-weight, mechanically flexible, transparent thermoelectric modules are promising as portable and easy-to-integrate energy sources. Here, we demonstrate flexible, transparent thermoelectric modules by using a conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as the p-type leg and indium tin oxide (ITO)-PEDOT:PSS as the n-type leg. Main observations include the following: (1) the bilayer combination of ITO-PEDOT:PSS (PEDOT:PSS coated on top of the ITO) displays a negative Seebeck coefficient ( S) and the value is similar to that of the ITO single layer; (2) the S value of the ITO PEDOT:PSS is almost not dependent on the area ratio of the stacked PEDOT:PSS and ITO; and (3) the conducting polymer PEDOT:PSS deposition on top of ITO helps the ITO not to generate cracks during bending, which enhances the mechanical flexibility of the ITO. On the basis of these observations, thermoelectric modules with eight pairs of junctions are fabricated and the thermoelectric modules' Delta V/Delta T (modules' generated thermovoltage per temperature difference) is nearly the addition of S values of all legs. Thermoelectric modules show good mechanical flexibility and air stability. Applications of thermoelectric modules have also been demonstrated to produce thermovoltage via the temperature difference produced by a human hand or warm water. PMID- 30009592 TI - Tailored Robust Hydrogel Composite Membranes for Continuous Protein Crystallization with Ultrahigh Morphology Selectivity. AB - The tailored and robust hydrogel composite membranes (HCMs) with diverse ion adsorption and interfacial nucleation property are prepared and successfully used in the continuous lysozyme crystallization. Beyond the heterogeneous supporter, the HCMs functioning as an interface ion concentration controller and nucleation generator are demonstrated. By constructing accurately controlled nucleation and growth circumstances in the HCM-equipped membrane crystallizer, the target desired morphology (hexagon cube) and brand-new morphology (multiple flower shape) that differ from the ones created in the conventional crystallizer are continuously and repetitively generated with ultrahigh morphology selectivity. These tailored robust HCMs show great potential for improving current approaches to continuous protein crystallization with specific crystal targets from laboratorial research to actual engineering applications. PMID- 30009593 TI - Aliphatic C-H Bond Halogenation by Iron(II)-alpha-Keto Acid Complexes and O2: Functional Mimicking of Nonheme Iron Halogenases. AB - alpha-Ketoglutarate-dependent nonheme halogenases catalyze the halogenation of aliphatic C-H bonds in the biosynthesis pathway of many natural products. An iron(IV)-oxo-halo species has been established as the active oxidant in the halogenation reactions. With an objective to emulate the function of the nonheme halogenases, two iron(II)-alpha-keto acid complexes, [(phdpa)Fe(BF)Cl] (1) and [(1,4-tpbd)Fe2(BF)2Cl2] (2) (where phdpa = N,N-bis(2-pyridylmethyl)aniline, 1,4 tpbd = N,N, N',N'-tetrakis(2-pyridylmethyl)benzene-1,4-diamine, and BF = benzoylformate), have been prepared. The iron complexes are capable of carrying out the oxidative halogenation of aliphatic C-H bonds using O2 as the terminal oxidant. Although the complexes are not selective toward C-H bond halogenation, they are the only examples of nonheme iron(II)-alpha-keto acid complexes mimicking the activity of nonheme halogenases. The dinuclear complex (2) exhibits enhanced reactivity toward C-H bond halogenation/hydroxylation. PMID- 30009594 TI - Syntheses and Crystal Structures of Phenyl-Lithium Derivatives. AB - Although organolithium compounds have been studied and applied for ~100 years, only few crystal structures of pure, unsolvated organolithium compounds have been reported so far. Therefore, several phenyl-lithium derivatives were synthesized by lithium-halogen exchange reactions, yielding fairly soluble polymers in the cases of 4- and 2-methylphenyl-lithium ( p-TolLi and o-TolLi). Their crystal structures have been determined by X-ray powder diffraction. Remarkably, o-TolLi crystallizes in the noncentrosymmetric space group P212121 with two independent monomers, whereas the crystal structure of p-TolLi is described in spacegroup P21/ a. In contrast, no polymer of 5- m-XyLi (3,5-dimethyl-phenyl-lithium) could be observed, but single crystals of a [(5- m-XyLi)3(MTBE)3LiBr] adduct were isolated (MTBE = methyl- tert-butylether). This gives hints on the nature of lithium-halogen exchange reactions. Steric and electronic effects of the phenyl lithium substitution are further discussed in conjunction with related compounds. PMID- 30009595 TI - Electrochemical CO Reduction Builds Solvent Water into Oxygenate Products. AB - Numerous studies have examined the electrochemical reduction of CO (COR) to oxygenates (e.g., ethanol). None have considered the possibility that oxygen in the product might arise from water rather than from CO. To test this assumption, C16O reduction was performed in H218O electrolyte. Surprisingly, we found that 60 70% of the ethanol contained 18O, which must have originated from the solvent. We extended our previous all-solvent density functional theory metadynamics calculations to consider the possibility of incorporating water, and indeed, we found a new mechanism involving a Grotthuss chain of six water molecules in a concerted reaction with the *C-CH intermediate to form *CH-CH(18OH), subsequently leading to (18O)ethanol. This competes with the formation of ethylene that also arises from *C-CH. These unforeseen results suggest that all previous studies of COR under aqueous conditions must be reexamined. PMID- 30009596 TI - Ring-Oxidized Zinc(II) Phthalocyanine Cations: Structure, Spectroscopy, and Decomposition Behavior. AB - A bromonium oxidizing agent was used to produce a ring-oxidized zinc phthalocyanine (PcZn), [PcZn(solvent)]*2[BArF4]2 (1.solvent), in good yield. This material is dimeric in the solid state with one axially coordinated solvent [tetrahydrofuran (THF) or 1,2-dimethoxyethane (DME)] and close intradimer ring ring distances of 3.18 and 3.136 A (THF and DME respectively); this proximity facilitates strong antiferromagnetic coupling to yield diamagnetic dimers. 1.THF is present in solution as a monomer and a dimer. In CH2Cl2, the dimer is favored above 0.1 mM, and it is almost exclusively present in solvents with a high dielectric constant such as acetonitrile. The material 1.THF/DME decomposes in DME to a meso-nitrogen-protonated species, [HPcZn(DME)2][BArF4] (2), which was isolated and represents the first example of such a structurally characterized, protonated, unsubstituted PcM complex. A partially oxidized dimer or "pimer" [(PcZn(DME))2]*[BArF4] (3) was also structurally characterized and has a intradimer ring-ring distance of 3.192 A, similar to 1.THF/DME. Dimer 3 also represents the first isolated PcM-based pimer. Electron paramagnetic resonance analysis of a 1.0 mM solution of 1.DME in DME showed the production of 3 over hours by the combination of 1.DME and 2 in solution. PMID- 30009597 TI - Physicochemical Analysis of DPPC and Photopolymerizable Liposomal Binary Mixture for Spatiotemporal Drug Release. AB - The development of a spatiotemporal drug delivery system with a long release profile, high loading efficiency, and robust therapeutic effects is still a challenge. Liposomal nanocarriers have secured a fortified position in the biomedical field over decades. Herein, liposomal binary mixtures of 1,2 dipalmitoyl- sn-glycero-3-phosphocholine (DPPC) and photopolymerizable 1,2 bis(10,12-tricosadiynoyl)- sn-glycero-3-phosphocholine (DC8,9PC) phospholipids were prepared for drug delivery applications. The diacetylenic groups of DC8,9PC produce intermolecular cross-linking following UV irradiation. Exposure of the liposomal mixture to 254 nm radiation induces a pore within the lipid bilayer, expediting the release of its entrapped 5,6-carboxyfluorescein dye. The dosage and rate of the released content are highly dependent on the number and size of the induced pore. Photochemical cross-linking studies at different exposure times were reported through the analysis of UV-visible spectrophotometry, nano differential scanning calorimetry, Fourier transform infrared spectroscopy, and Raman spectroscopy. The optimal irradiation time was established after 8 min of exposure, inducing lipid cross-linking with minimal oxidative degradation, which plays an essential role in the pathogenesis of numerous diseases due to the formation of primary and secondary oxidation products, accordingly reducing the encapsulated drug therapeutic level. PMID- 30009598 TI - Intergrain Diffusion of Carbon Radical for Wafer-Scale, Direct Growth of Graphene on Silicon-Based Dielectrics. AB - Graphene intrinsically hosts charge-carriers with ultrahigh mobility and possesses a high quantum capacitance, which are attractive attributes for nanoelectronic applications requiring graphene-on-substrate base architecture. Most of the current techniques for graphene production rely on the growth on metal catalyst surfaces, followed by a contamination-prone transfer process to put graphene on a desired dielectric substrate. Therefore, a direct graphene deposition process on dielectric surfaces is crucial to avoid polymer-adsorption related contamination from the transfer process. Here, we present a chemical diffusion mechanism of a process for transfer-free growth of graphene on silicon based gate-dielectric substrates via low-pressure chemical vapor deposition. The process relies on the diffusion of catalytically produced carbon radicals through polycrystalline copper (Cu) grain boundaries and their crystallization at the interface of Cu and underneath silicon-based gate-dielectric substrates. The graphene produced exhibits low-defect multilayer domains ( La ~ 140 nm) with turbostratic orientations as revealed by selected area electron diffraction. Further, graphene growth between Cu and the substrate was 2-fold faster on SiO2/Si(111) substrate than on SiO2/Si(100). The process parameters such as growth temperature and gas compositions (hydrogen (H2)/methane (CH4) flow rate ratio) play critical roles in the formation of high-quality graphene films. The low-temperature back-gating charge transport measurements of the interfacial graphene show density-independent mobility for holes and electrons. Consequently, the analysis of electronic transport at various temperatures reveals a dominant Coulombic scattering, a thermal activation energy (2.0 +/- 0.2 meV), and two dimensional hopping conduction in the graphene field-effect transistor. A band overlapping energy of 2.3 +/- 0.4 meV is estimated by employing the simple two band model. PMID- 30009599 TI - Metal-Binding Isosteres as New Scaffolds for Metalloenzyme Inhibitors. AB - The principle of isosteres or bioisosteres in medicinal chemistry is a central and essential concept in modern drug discovery. For example, carboxylic acids are often replaced by bioisosteres to mitigate issues related to lipophilicity or acidity while retaining acidic characteristics in addition to hydrogen bond donor/acceptor abilities. Separately, the development of metal-binding pharmacophores (MBPs) for binding to the active site metal ion in metalloenzymes of therapeutic interest is an emerging area in the realm of fragment-based drug discovery (FBDD). The direct application of the bioisostere concept to MBPs has not been well-described or systematically investigated. Herein, the picolinic acid MBP is used as a case study for the development of MBP isosteres (so-called MBIs). Many of these isosteres are novel compounds, and data on their physicochemical properties, metal binding capacity, and metalloenzyme inhibition characteristics are presented. The results show that MBIs of picolinic acid generally retain metal coordinating properties and exhibit predictable metalloenzyme inhibitory activity while possessing a broad range of physicochemical properties (e.g., p Ka, log P). These findings demonstrate the use of bioisosteres results in an untapped source of metal binding functional groups suitable for metalloenzyme FBDD. These MBIs provide a previously unexplored route for modulating the physicochemical properties of metalloenzyme inhibitors and improving their drug-likeness. PMID- 30009600 TI - Quaternary Chalcogenide Semiconductors with 2D Structures: Rb2ZnBi2Se5 and Cs6Cd2Bi8Te17. AB - Two new layered compounds Rb2ZnBi2Se5 and Cs6Cd2Bi8Te17 are described. Rb2ZnBi2Se5 crystallizes in the orthorhombic space group Pnma, with lattice parameters of a = 15.6509(17) A, b = 4.218(8) A, and c = 18.653(3) A. Cs6Cd2Bi8Te17 crystallizes in the monoclinic C2/ m space group, with a = 28.646(6) A, b = 4.4634(9) A, c = 21.164(4) A, and beta = 107.65(3) degrees . The two structures are different and composed of anionic layers which are formed by inter connecting of BiQ6 octahedra (Q = Se or Te) and MQ4 (M = Zn or Cd) tetrahedra. The space between the layers hosts alkali metal as counter cations. The rubidium atoms of Rb2ZnBi2Se5 structure can be exchanged with other cations (Cd2+, Pb2+ and Zn2+) in aqueous solutions forming new phases. Rb2ZnBi2Se5 is an n-type semiconductor and exhibits an indirect band gap energy of 1.0 eV. Rb2ZnBi2Se5 is a congruently melting compound (mp ~644 degrees C). The thermal conductivity of this semiconductor is very low with 0.38 W.m-1.K-1 at 873 K. Density functional theory (DFT) calculations suggest that the low lattice thermal conductivity of Rb2ZnBi2Se5 is attributed to heavy Bi atom induced slow phonon velocities and large Gruneisen parameters especially in the a and c directions. The thermoelectric properties of Rb2ZnBi2Se5 were characterized with the highest ZT value of ~0.25 at 839 K. PMID- 30009601 TI - Self-Adapting Hydrogel to Improve the Therapeutic Effect in Wound-Healing. AB - Smart materials that can respond to multistimuli have been broadly studied. However, the smart materials that can spontaneously answer the ever-changing inner environment of living bodies have not been reported. Here, we report a strategy based on the dynamic chemistry to develop possible self-adapting solid materials that can automatically change shape without external stimuli, as organisms do. The self-adapting property of a chitosan-based self-healing hydrogel has been rediscovered since its dynamic Schiff-base network confers the unique mobility to that solid gel. As a result, the hydrogel can move slowly, like an octopus climbing through a narrow channel, only following the natural forces of surface tension and gravity. The fascinating self-adapting feature enables this hydrogel as an excellent drug carrier for the in vivo wound treatment. In a healing process of the rat-liver laceration, this self-adapting hydrogel demonstrated remarkable superiority over traditional drug delivery methods, suggesting the great potential of this self-adapting hydrogel as a promising new material for biomedical applications. We believe the current research revealed a possible strategy to achieve self-adapting materials and may pave the way toward the further development, study, and application of new generation smart materials. PMID- 30009602 TI - NiFe2O4 Nanoparticles/NiFe Layered Double-Hydroxide Nanosheet Heterostructure Array for Efficient Overall Water Splitting at Large Current Densities. AB - Constructing catalysts with new and optimizational chemical components and structures, which can operate well for both the anodic oxygen evolution reaction (OER) and the cathodic hydrogen evolution reaction (HER) at large current densities, is of primary importance in practical water splitting technology. Herein, the NiFe2O4 nanoparticles/NiFe layered double hydroxide (LDH) nanosheet heterostructure array on Ni foam was prepared via a simple one-step solvothermal approach. The as-prepared heterostructure array displays high catalytic activity toward the OER with a small overpotential of 213 mV at 100 mA cm-2 and can afford a current density of 500 mA cm-2 at an overpotential of 242 mV and 1000 mA cm-2 at 265 mV. Moreover, it also presents outstanding HER activity, only needing a small overpotential of 101 mV at 10 mA cm-2, and can drive large current densities of 500 and 750 mA cm-2 at individual overpotentials of 297 and 314 mV. A two-electrode electrolyzer using NiFe2O4 nanoparticles/NiFe LDH nanosheets as both the anode and the cathode implements active overall water splitting, demanding a low voltage of 1.535 V to drive 10 mA cm-2, and can deliver 500 mA cm 2 at 1.932 V. The NiFe2O4 nanoparticles/NiFe LDH nanosheet array electrodes also show excellent stability against OER, HER, and overall water splitting at large current densities. Significantly, the overall water splitting with NiFe2O4 nanoparticles/NiFe LDH nanosheets as both the anode and the cathode can be continuously driven by a battery of only 1.5 V. The intrinsic advantages and strong coupling effects of NiFe2O4 nanoparticles and NiFe LDH nanosheets make NiFe2O4 nanoparticles/NiFe LDH nanosheet heterostructure array abundant catalytically active sites, high electronic conductivity, and high catalytic reactivity, which remarkably contributed to the catalytic activities for OER, HER, and overall water splitting. Our work can inspire the optimal design of the NiFe bimetallic heterostructure electrocatalyst for application in practical water electrolysis. PMID- 30009603 TI - Flexible and Broad-Spectral Hybrid Optical Modulation Transistor Based on a Polymer-Silver Nanoparticle Blend. AB - The light-matter interplay on a soft substrate is critically important for novel optoelectronic applications such as soft robotics, human-machine interfaces, and wearable devices. Here, we for the first time report a flexible and efficiency enhanced hybrid optical modulation transistor (h-OMT) in the ultraviolet-infrared spectral range by blending a polymer with silver nanoparticles (AgNPs). The h-OMT device exhibits a unipolar transport and an ultrahigh on-off ratio of ~4.8 * 106 in a small voltage range of ~2 V. Using charge modulation reflection spectroscopy, we demonstrate that the h-OMT device shows a broad-spectral response from 400 to 2000 nm and maximum optical modulation of ~15% at lambda = 785 nm, 6-fold higher magnitude than that of the device without AgNPs. Furthermore, the incorporation of AgNPs enhances the extinction ratio by 4-fold magnitude without any complex geometry designs. We find that the performance improvement relies on the AgNP-induced electron trap states and electrochemical dopings in the polymer. Importantly, the device exhibits pronounced mechanical flexibility, and the optical modulation is kept down to a bending radius of 0.5 mm. Our data provide the possibility of organic materials for constructing novel optoelectronic systems in the future. PMID- 30009604 TI - Synthesis of ( S)-3-Amino-4-(difluoromethylenyl)-cyclopent-1-ene-1-carboxylic Acid (OV329), a Potent Inactivator of gamma-Aminobutyric Acid Aminotransferase. AB - ( S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329, 1) is being developed for the treatment of epilepsy and addiction. The previous 14 step synthesis of OV329 was low yielding, involved an unselective alpha elimination to form the cyclopentene, required the use of tert-butyllithium, and produced toxic selenium byproducts in the penultimate step. A new synthesis, which avoids the aforementioned issues, was carried out on large scale, reducing the step count from 14 to 9 steps and increasing the overall yield from 3.7% to 8.1%. PMID- 30009605 TI - Pore-Scale Simulations of Porous Electrodes of Li-O2 Batteries at Different Saturation Levels. AB - This study reconstructs pore-scale structures of battery electrodes from scanning electron microscopy images, quantitatively studies the distribution of the electrolyte at various saturations, and simulates the discharge performance of Li O2 batteries. This research sheds lights on the critical role of liquid-gas two phase mass transfer within the porous electrode on the electrochemical performance of batteries. It is found that fully saturated electrodes (100% saturation) have high oxygen-transfer resistance, which will impede the battery performance at typical electrode thickness (~200 MUm). On the contrary, overdried battery (with <50% saturations) electrodes have poor electrochemical performance because dry pores are inactive for electrochemical reactions. In addition, the low electrolyte saturation level leads to low ionic conductivity and high mass transfer resistance of the lithium ion. Carefully designed electrodes with the mixture of lyophilic and lyophobic pores could achieve similar discharge capacity (>7 A h/g) at high current (20 A/m2) with lyophilic electrodes that are fully saturated by the electrolyte at low current (1 A/m2). The findings from this study enable further research to significantly increase (by orders of magnitude) the operating current and power of the Li-O2 battery and accelerate its deployment to transport and stationary applications. PMID- 30009606 TI - Right Heterogeneous Microstructure for Achieving Excellent Thermoelectric Performance in Ca0.9R0.1MnO3-delta (R = Dy, Yb) Ceramics. AB - Perovskite manganite Ca0.9R0.1MnO3-delta (R = Dy, Yb) ceramics have been synthesized by a traditional solid-state reaction with multicalcination processes. A heterogeneous microstructure including large and small micrometer sized grains, coherent interfaces, and oxygen defects has been formed with optimized calcination time. The carrier concentration of the third-calcined samples is enhanced approximately 3 times compared with those synthesized through conventional methods. Thus, the electrical resistivity of the third-calcined Ca0.9R0.1MnO3-delta (R = Dy, Yb) ceramic samples obviously decreases, leading to a higher power factor. Additionally, the thermal conductivity is also reduced by multiscale scattering of the heterogeneous structure. The lowest lattice thermal conductivities of Dy- or Yb-doped samples are 1.24 and 1.22 W m-1 K-1, respectively. Thus, the high thermoelectric performance for Ca0.9R0.1MnO3-delta (R = Dy, Yb) has been achieved by the multicalcination process. The highest figure of merit is almost 30% higher than that of the first-calcined samples. Therefore, a heterogeneous microstructure formed by optimized multicalcination can effectively optimize the thermoelectric performance of oxides. PMID- 30009607 TI - Correction to "Supramolecular Hydrogel Derived from a C3-Symmetric Boronic Acid Derivative for Stimuli Responsive Release of Insulin and Doxorubicin". PMID- 30009608 TI - Surfactant-Enriched ZnO Surface via Sol-Gel Process for the Efficient Inverted Polymer Solar Cell. AB - In this study, we demonstrate that the top surface is enriched by surfactants, tetraoctylammonium bromide, and cetylpyridinium bromide (CPB), in the sol-gel ZnO, being evidenced by the Br depth profile of electron spectroscopy for chemical analysis data. X-ray photoelectron spectroscopy results showed the formation of Zn-Br bonding due to the oxygen defects occupied by Br at the surfactant-enriched ZnO surface. The surfactant-enriched ZnO surface possessed a smoother surface and more hydrophobicity than the pristine ZnO from the experimental results of atomic force microscopy and contact angle, respectively. On the basis of ultraviolet photoelectron spectroscopy data, the work function slightly reduced due to the dipole built-up by the electrostatic force between Br and N+ to enhance the electron extraction ability. The improved properties benefited the power conversion efficiency (PCE) of bulk-heterojunction polymer solar cells (PSCs) by spin-coating the active layer on the surfactant-enriched ZnO surface. The inverted PSCs with the surfactant-enriched ZnO surface showed the highest PCE of 9.55% for the CPB case, in comparison with the pristine ZnO surface (8.08% PCE). This study discloses that turning the ZnO surface is easily achieved by the addition of surfactants with different molecular structures in the sol-gel ZnO for high performance polymer solar cells. PMID- 30009609 TI - One-Step Synthesis and Stealth Photochromism of Arylbutadienes. AB - The synthesis of thermally irreversible photochromic arylbutadienes has been demonstrated with a one-step reaction using commercially available ketones by McMurry cross-coupling. Although ( Z)-5-(1-([1,1'-bi(cyclopentylidene)]-2 ylidene)ethyl)-4-methyl-2-phenylthiazole, a 1-(4-methyl-2-phenyl-5 thiazolyl)butadiene, showed poor photochromism, ( Z)-5-(1-([1,1' bi(cyclopentylidene)]-2-ylidene)ethyl)-2,4-dimethylthiazole, a 1-(2,4-dimethyl-5 thiazolyl)butadiene, showed stealth photochromic transformations by 313 and 366 nm light irradiation between the moderate conversion ratios of the open and closed forms. PMID- 30009610 TI - Palladium-Catalyzed Cyclocarbonylation of Pyridinylated Vinylogous Amides and Ureas to Generate Ring-Fused Pyridopyrimidinones. AB - As part of a program aimed at generating new heterocyclic frameworks for medicinal chemistry exploration, an efficient approach to the assembly of novel ring-fused pyridopyrimidinones was undertaken. Specifically, a collection of 11 H pyrido[2,1- b]quinazoline-1,11(2 H)-diones and 2,3-dihydropyrido[1,2- a]pyrrolo[3,4- d]pyrimidine-1,10-diones was generated via a palladium-catalyzed, pyridine-directed, cyclocarbonylation of 2-pyridyl-linked vinylogous amides and ureas in yields of up to 90%. PMID- 30009611 TI - Manganese-Catalyzed ortho-C-H Amidation of Weakly Coordinating Aromatic Ketones. AB - An efficient manganese-catalyzed ortho-C-H amidation of weakly coordinating aromatic ketones using the readily available sulfonyl azide as the amination reagent is developed. The key step is the ketone directed aromatic metalation using the in situ generated reactive Mn intermediate, MnMe(CO)5. This method offers excellent chemical yields, high regioselectivities, and good functional group tolerance. PMID- 30009612 TI - Tetrahydrobenzochromene Synthesis Enabled by a Deconjugative Alkylation/Tsuji Saegusa-Ito Oxidation on Knoevenagel Adducts. AB - A modular and practical route to versatile cyano-1,3-dienes by a sequence involving deconjugative alkylation and "Tsuji-Saegusa-Ito oxidation" is reported. In this letter, the versatility of the products is also explored, including a route to benzochromene scaffolds common to many natural products. PMID- 30009613 TI - Subclinical Atherosclerosis in Patients With Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - Cardiovascular (CV) risk in type 1 diabetes mellitus (T1DM) is increased. In this study, we evaluated the differences in major markers of CV risk between patients with T1DM and healthy controls by a systematic review and meta-analysis. Literature from PubMed, EMBASE, and The Cochrane Library comparing CV risk markers between patients with T1DM and controls was obtained. The overall standard mean differences (SMDs) of carotid intima-media thickness (cIMT), endothelium-dependent flow-mediated dilation (FMD%), carotid-femoral pulse wave velocity (cf-PWV), and glyceryl trinitrate-mediated dilatation (GTN%) with its 95% confidence interval (CI) between patients with T1DM and control groups were calculated using fixed-effect or random-effect model. Heterogeneity was evaluated using the Cochran Q and I2 statistics. The results showed that patients with T1DM had a significantly greater cIMT (SMD: 0.89; 95% CI, 0.69-1.09; P < .001), significantly lower FMD% (SMD: -1.45%; 95% CI, -1.74 to -1.17; P < .001), significantly increased cf-PWV (SMD: 0.57; 95% CI, 0.03-1.11; P < .001), and significantly decreased GTN% (SMD: -1.11; 95% CI, -1.55 to -0.66; P < .001) than controls. Our results support the current evidence for an elevated CV burden in patients with T1DM and affirm the clinical utility of markers of subclinical atherosclerosis in the management of these patients. PMID- 30009614 TI - The Role of Hyperbaric Oxygen as Salvage Therapy for Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: We sought to evaluate hearing outcomes after salvage therapy with hyperbaric oxygen (HBO2) for the treatment of sudden sensorineural hearing loss (SSNHL). STUDY DESIGN: Matched control retrospective case series. SETTING: Tertiary neurotology referral center. PATIENTS: Thirty-six patients (>18 years) diagnosed with SSNHL. INTERVENTION: Patients received initial therapy with oral and/or intratympanic (IT) steroids with an incomplete response. Eighteen patients underwent salvage therapy with IT steroids and HBO2 (group 1). Eighteen matched controls underwent salvage therapy with IT steroids alone (group 2). MAIN OUTCOME MEASURES: The main outcome measure was improvement in pure tone average (PTA) and word recognition score (WRS). Complications as a result of therapy were also monitored. RESULTS: There were no significant differences in age, gender, or hearing between the 2 groups ( P > .05). There was no significant difference in mean post-treatment PTA between group 1 (60.3 dB) and group 2 (53.2 dB). There were no significant difference in mean post-treatment WRS between group 1 (42%) and group 2 (51%). Serviceable hearing was defined as a minimum WRS of 50%. Thirty-three percent in group 1 and 42% in group 2 went from nonserviceable hearing to serviceable hearing ( P > .05). PTA and WRS change scores were not significantly affected by age, gender, form of initial treatment, or pre treatment PTA and WRS. CONCLUSION: The present study demonstrated no significant difference in hearing outcomes between patients receiving salvage therapy with HBO2 and IT steroids compared to patients receiving IT steroids alone. Larger, prospective randomized trials are needed to better define the role of HBO2 as salvage therapy for SSNHL. PMID- 30009615 TI - Pediatricians' vaccine attitudes and practices before and after a major measles outbreak. AB - The objective of this study was to describe how a sample of pediatricians were impacted by and responded to the Disneyland measles outbreak in the United States. We conducted three repeated cross-sectional, online surveys in 2014 (before the outbreak), 2015, and 2016 (after the outbreak) among members of three state chapters of the American Academy of Pediatrics. We assessed pediatricians' level of willingness and length of time comfortable delaying the measles-mumps rubella (MMR) vaccine before and after the outbreak. Frequency of alternative immunization schedule requests and creation of office immunization policies due to the outbreak were measured. The sample included 304 pediatricians in 2014, 270 in 2015, and 221 in 2016. We found no significant changes in willingness or comfort delaying the MMR vaccine before and after the outbreak. In 2015, 38% of pediatricians reported fewer requests for alternative immunization schedules and 20% created stricter office immunization policies. A subsample of pediatricians reported administering the MMR vaccine earlier in the recommended time frame and taking extra precautions in waiting rooms due to the outbreak. Our results suggest that this measles outbreak did not lead to significant changes in attitudes or practices among this sample, but did modestly affect office immunization policies and practices. PMID- 30009616 TI - "It's very humbling": The Effect Experienced by Those Who Facilitate a Legacy Project Session Within Palliative Care. AB - OBJECTIVES: The creative arts can be utilized within palliative care to facilitate the creation of a legacy project, an object which will reflect the unique experiences and interests of the creator. This can be bestowed to a loved one, thereby providing an opportunity to leave something tangible behind. However, there is a paucity of evidence exploring the impact experienced by those who facilitate the legacy generation session. METHODS: "From The HEart" is a volunteer operated program that offers creative arts based legacy projects to palliative care patients. Five volunteers were interviewed to understand their personal experiences. Emphasis was placed on any perceived positive or negative impact from this work, and if a self-care program would be required. Interviews were transcribed verbatim into a textual document which was coded by the principal investigator using inductive content analysis to derive overarching themes. RESULTS: Five themes emerged from the data: "providing a benefit", "internal validation", "it's all been positive", "self-awareness", and "if you need support". All facilitators reported positive experiences, which provided internal validation or confirmation that this work was personally significant to this group. Self-care practises emerged as important, but group activities would only be warranted if requirements couldn't be meet through individual self-care practises. SIGNIFICANCE OF RESULTS: This study provides confirmation that facilitators do not report any negative experiences while assisting a palliative care client in creating a legacy project. These activities can provide meaning while working in the field of palliative care. PMID- 30009617 TI - Age, Disease, and Their Interaction Effects on Intrinsic Connectivity of Children and Adolescents in Autism Spectrum Disorder Using Functional Connectomics. AB - Brain connectivity analysis has provided crucial insights to pinpoint the differences between autistic and typically developing (TD) children during development. The aim of this study is to investigate the functional connectomics of autism spectrum disorder (ASD) versus TD and underpin the effects of development, disease, and their interactions on the observed atypical brain connectivity patterns. Resting-state functional magnetic resonance imaging (rs fMRI) from the Autism Brain Imaging Data Exchange (ABIDE) data set, which is stratified into two cohorts: children (9-12 years) and adolescents (13-16 years), is used for the analysis. Differences in various graph theoretical network measures are calculated between ASD and TD in each group. Furthermore, two-factor analysis of variance test is used to study the effect of age, disease, and their interaction on the network measures and the network edges. Furthermore, the differences in connection strength between TD and ASD subjects are assessed using network-based statistics. The results showed that ASD exhibits increased functional integration at the expense of decreased functional segregation. In ASD adolescents, there is a significant decrease in modularity suggesting a less robust modular organization, and an increase in participation coefficient suggesting more random integration and widely distributed connection edges. Furthermore, there is significant hypoconnectivity observed in the adolescent group especially in the default mode network, while the children group shows both hyper- and hypoconnectivity. This study lends support to a model of global atypical connections and further identifies functional networks and areas that are independently affected by age, disease, and their interaction. PMID- 30009618 TI - Development and Implementation of an End-of-Life Curriculum for Pediatric Residents. AB - BACKGROUND: Caring for a child near the end of life (EOL) can be a stressful experience. Resident physicians are often the frontline providers responsible for managing symptoms, communicating difficult information, and pronouncing death, yet they often receive minimal education on EOL care. OBJECTIVE: To develop and implement an EOL curriculum and to study its impact on resident comfort and attitudes surrounding EOL care. DESIGN: Kern's 6-step approach to curriculum development was used as a framework for curriculum design and implementation. SETTING/PARTICIPANTS: Categorical and combined pediatric residents at a large quaternary care children's hospital were exposed to the curriculum. MEASUREMENTS: A cross-sectional survey was distributed pre- and postimplementation of the curriculum to evaluate its impact on resident comfort and attitudes surrounding EOL care. RESULTS: One-hundred twenty-six (49%) of 258 residents completed the preimplementation survey, and 65 (32%) of 201 residents completed the postimplementation survey. Over 80% of residents reported caring for a dying patient, yet less than half the residents reported receiving prior education on EOL care. Following curriculum implementation, the percentage of residents dissatisfied with their EOL education fell from 36% to 14%, while the percentage of residents satisfied with their education increased from 14% to 29%. The postimplementation survey identified that resident comfort with communication based topics improved, and they sought additional training in symptom management. CONCLUSIONS: The implementation of a longitudinal targeted multimodal EOL curriculum improved resident satisfaction with EOL education and highlighted the need for additional EOL education. PMID- 30009619 TI - Catecholamine and Indolamine Pathway: A Case-Control Study in Fibromyalgia. AB - OBJECTIVES: Fibromyalgia (FM) is a complex syndrome characterized by widespread pain. Its etiology is unclear, and diagnosis is difficult. The aim of this study was to assess plasma levels of monoamine neurotransmitters (catecholamines, indolamines, and intermediate metabolites) in patients with FM and healthy controls to investigate possible alterations in the metabolism of these molecules in FM. We also examined potential relationships between monoamine neurotransmitters and clinical features of FM. The predictive value of these molecules in FM was determined by receiver operating characteristic analysis. METHOD: We measured plasma catecholamines (epinephrine, norepinephrine, and dopamine), as well as indolamines and intermediary metabolites (serotonin or 5 hydroxytryptamine [5-HT], 5-hydroxyindolacetic acid [5-HIAA], 5-hydroxytryptophan [5-HTP], and N-acetyl-5-hydroxytryptamine [Nac-5-HT]) in 35 women with FM and 12 age-matched healthy women. RESULTS: Higher levels of norepinephrine and lower levels of dopamine, 5-HT, 5-HIAA, and 5-HTP were found in women with FM in comparison with controls. Epinephrine and Nac-5-HT levels did not differ significantly between groups. Higher norepinephrine levels were associated with worse physical health status in FM patients. Also, plasma norepinephrine levels > 694.69 pg/ml might be an accurate predictor of FM. CONCLUSIONS: These findings show evidence of the dysregulation of the catecholamine and indolamine pathway in patients with FM, which may contribute to the physiopathology of this syndrome. In addition, the determination of plasma norepinephrine levels could help in the FM diagnosis. PMID- 30009620 TI - A model for the provision of integrated perinatal and infant mental health services in regional settings. AB - OBJECTIVE: This paper aims to describe current approaches in Victoria to the development of perinatal and infant mental health services in regional areas. METHOD: The paper outlines the significance of perinatal mental disorder for maternal wellbeing and impact on infant development, and describes the model of care at the Agnes Unit. RESULTS: The Agnes Unit has been established as a residential therapeutic unit offering short-term treatment that focusses on promoting parental mental health, parenting sensitivity and the parent-infant relationship. CONCLUSIONS: A coordinated and integrated approach with focus on early intervention is needed to deliver perinatal and infant mental health services. Services need to focus on the infant and parent-infant relationship in addition to parental mental health. PMID- 30009621 TI - Social Work Assessment and Outcomes Measurement in Hospice and Palliative Care. AB - While psychosocial assessment is required in hospice, no requirement exists for documentation of psychosocial outcomes. Social work research has identified the psychosocial and spiritual domains most often and appropriate for social workers to address, and standardized assessment tools have been developed by social workers based on this research. The aims of this study were to document the current use of standardized assessment measures for assessment and documenting outcomes and specifically the use of the Social Work Assessment Tool. A national sample of 203 hospice and palliative care social workers was recruited for this mixed methods study. Results indicated that most social workers used a form developed by a nonsocial worker in the agency for the initial assessment, and many palliative care social workers were not responsible for the assessment. Fewer conducted a follow-up assessment or documented outcomes. No common standardized measure was used. This study confirmed anecdotal evidence about lack of standardized social work assessment and outcomes measurement occurring in hospice and palliative care. As the Centers for Medicare and Medicaid Services is likely to select a standardized tool to measure psychosocial outcomes, social workers have an opportunity to contribute a quantitatively driven outcomes measure, developed by social workers, that will demonstrate effectiveness of social work intervention and lead to a better understanding of the social work role in hospice and palliative care. PMID- 30009622 TI - Incidence and demographics of 1751 surgically treated periprosthetic femoral fractures around a primary hip prosthesis. AB - INTRODUCTION: Periprosthetic femoral fractures (PPFF), treated surgically, have been recorded in the Swedish Hip Arthroplasty Register (SHAR) since 1979. It is postulated that fractures treated with other methods other than stem revision have a lower registration rate, which may lead to incomplete registry data and thus, inaccurate information. We collected all PPFFs surgically treated in Sweden between 2001 and 2011 with the purpose of studying the annual incidence, demographics and distribution of fracture types with regard to type of fixation. METHODS: Data was linked between the SHAR and the National Patient Register (NPR) in order to detect even those PPFFs not reported to the SHAR. Fractures were classified according to the Vancouver classification system, based on information collected from the medical charts. This procedure was validated with observer variation analysis compared to fracture classification based on radiographs. In total 1751 first-time PPFFs around primary conventional stems were included. RESULTS: The incidence of PPFF increased from about 1.0 per 1000 primary THRs to 1.4. Vancouver type C fractures (37% of all fractures) were more common than previously reported, and more common in cemented than in uncemented stems. The 3 most common stem designs involved were Exeter polished, Lubinus SPII, and Charnley (66.3% of all stems), partly reflecting their occurrence in the Swedish THR population. DISCUSSION: The incidence of PPFFs has increased in Sweden during the period 2001 to 2011. The improved reporting of type C fractures, after data linking, revealed an almost 4 times higher incidence compared to previous register studies in Sweden. PMID- 30009623 TI - Macular oedema due to immune reconstitution uveitis occurring in an HIV-negative patient without cytomegalovirus retinitis. AB - We describe a case of immune reconstitution uveitis occurring in an HIV-negative patient with bone-marrow transplant, not directly related to cytomegalovirus retinitis. PMID- 30009624 TI - Physicians' End-of-Life Conversations: Have We Arrived? PMID- 30009625 TI - Indirect Benefits in HIV Cure Clinical Research: A Qualitative Analysis. AB - Currently, much of early phase HIV cure research involves unknown and potentially serious risks, with little or no chance of direct health benefits. During informed consent, researchers emphasize this lack of personal medical benefit to minimize misconceptions that undermine genuine consent. We explored participants' and researchers' perspectives on HIV cure clinical research participation and its potential benefits. We conducted semistructured interviews with 17 HIV cure research participants and nine researchers in North Carolina, USA. We analyzed interviews to identify participant experience-related themes. We were particularly interested in indirect benefits, such as psychological support or improved care. We also assessed five consent documents for benefit/risk-related language. Research participants were male, with a median age of 50 (range: 28 62); most were non-Hispanic white (15/17) and men who have sex with men (13/17). All 17 trial participants found research participation meaningful and beneficial. Reported benefits included improved healthcare (16/17), HIV knowledge (13/17), intimate relationships (10/17), and positive behaviors (6/17). In addition, all participants described psychological benefits, including increased positive outlook, improved sense of purpose, emotional support, and enriched self-image. Participants reported risks such as quality of life concerns, uncomfortable procedures (e.g., leukapheresis), latency reversal, and HIV status disclosure. While the consent documents included discussion of these and other risks, they did not mention potential indirect benefits. Individuals involved in HIV clinical research have recognized participant psychological, social, and behavioral benefits. We recommend that researchers and institutional review boards consider these benefits for inclusion during risk/benefit assessments, consent procedures, and other discussions with prospective participants. PMID- 30009626 TI - Sustainability of Early Intensive Behavioral Intervention for Children With Autism Spectrum Disorder in a Community Setting. AB - This study examined whether outcomes in early intensive behavioral intervention (EIBI) during a university-led multisite project could be replicated by the same community agency independently of the project. Participants, age 18 to 75 months at onset of intervention, were 48 children with autism spectrum disorder (ASD) enrolled in 35 hr per week of publicly funded, community-based EIBI for 3 years and 46 children who were matched on baseline characteristics and received early childhood services as usual (SAU) through local early childhood special education providers. Linear mixed models indicated that EIBI participants improved significantly more than SAU participants on standardized tests of IQ, nonverbal IQ, adaptive behavior, and academic achievement, administered by independent evaluators. Although limited by the use of a matched comparison group rather than random assignment, the study provides evidence for the sustainability of effective EIBI in community settings for children with ASD who start intervention at varying ages throughout early childhood. PMID- 30009627 TI - Early Versus Late Motion Following Volar Plating of Distal Radius Fractures. AB - BACKGROUND: Distal radius fractures are common, and the trend in fixation has included the use of locked volar plating. The duration of splinting required after surgery and the effect splinting has upon outcome of the wrist are not clear. Our aim was to compare outcome of patients treated with early versus late motion protocol after volar plating. METHODS: Thirty-three patients with distal radius fractures were prospectively and randomly enrolled into an early versus late motion study including volar plating of the distal radius fracture. Early motion included an active and passive wrist motion protocol by 14 days after surgery and delayed motion was initiated at 5 weeks. Fractures were defined as intra-articular and extra-articular, and those with, and without, ulnar styloid fracture. Motion and outcome scores (Disabilities of the Arm, Shoulder and Hand [DASH]/patient-rated wrist evaluation [PRWE]), and strength were measured through 1 year. RESULTS: Wrist motion, DASH, and PRWE scores were only significantly different at 6 weeks with no significant differences at any later time points up to 1 year. One patient had complex regional pain syndrome (CRPS) and one had adhesive capsulitis in the late motion group. CONCLUSIONS: Following locked volar plating of distal radius fractures, early motion favored earlier return of motion along with lower DASH, PRWE, and pain scores within first 6 weeks. Although the late motion group had delayed recovery, there were no long-term significant differences in motion, strength, outcome, or pain scores. The 2 cases with complications (CRPS and adhesive capsulitis) did occur in the late motion group and may implicate late motion with these problems. PMID- 30009628 TI - Endovascular Treatment of Transplant Renal Artery Stenosis: Evaluation of Postoperative Outcomes and Risk Factors for Recurrence. AB - Angioplasty with or without stenting has become a well-established procedure to treat transplant renal artery stenosis (TRAS). We evaluated our experience on postoperative outcomes following the intervention and identified potential predictive factors of TRAS recurrence. Consecutive patients who underwent endovascular treatment of TRAS were retrospectively reviewed. The study end points were the technical success, 30-day postoperative complications, and the estimated glomerular filtration rate (eGFR). Thirty-two patients underwent endovascular treatment for TRAS. The technical success rate was 96.6%. Complications were observed for 7 (21.9%) patients: 4 had a dissection, 2 a pseudoaneurysm, and 1 (3.1%) patient developed an acute pulmonary edema. The mean eGFR significantly increased at 7 days, 3 months, and 6 months postintervention (43.1, 44.9, and 44.3 vs 33.9 mL/min/1.73 m2 preoperatively, P < .05). The TRAS recurrence was observed in 7 (21.9%) patients. These patients had significantly higher preoperative peak systolic velocity and systolic rise time (5 vs 4 m/s, P = .0383 and 103 vs 80 milliseconds, P = .0148, respectively). Endovascular treatment of TRAS is associated with high technical success and significant improvement in renal function. Further studies are required to confirm predictive factors of TRAS recurrence following endovascular treatment. PMID- 30009629 TI - Commentary of retinal vascularization speed in retinopathy of prematurity. PMID- 30009630 TI - Disruptive Mood Dysregulation Disorder: A Critical Perspective. PMID- 30009631 TI - Compound Motor Action Potential Measures Acute Changes in Laryngeal Innervation. AB - OBJECTIVE: Vocal fold paralysis is caused by injury to the recurrent laryngeal nerve (RLN). Current clinical measures of laryngeal innervation are often nonquantitative. Compound motor action potentials (CMAP) measure motor innervation. The goal of this study was to determine whether CMAP can quantify laryngeal innervation following acute nerve injury. STUDY DESIGN: Animal study. METHODS: Twelve canine hemilaryngeal preparations were used. The RLN was serially stimulated with increasing intensities until the nerve was maximally stimulated. The CMAP amplitude was measured for each intensity stimulation and correlated. Next, the RLN was incompletely transected, and the reduction in CMAP amplitude was correlated to the percentage of transected axons. The percentage of transected axons was determined using horseradish peroxidase (HRP) staining. RESULTS: Combining all hemilaryngeal preparations, the submaximal stimulation of the RLN linearly correlated with the resultant CMAP amplitude (r = 0.83; 95% CI, 0.76-0.88). Following partial RLN transection, the percentage of remaining axons linearly correlated with the CMAP amplitude (r = 0.87; 95% CI, 0.34-0.98). CONCLUSIONS: CMAP amplitude is a quantitative measure that may correlate with the degree of vocal fold innervation in canines. Following RLN injury, CMAP may help clinicians quantify the number of intact axons, assess the likelihood of recovery, and counsel patients on their prognosis. PMID- 30009632 TI - AF-CBT for Families Experiencing Physical Aggression or Abuse Served by the Mental Health or Child Welfare System: An Effectiveness Trial. AB - The Partnerships for Families project is a randomized clinical trial to evaluate the effectiveness of Alternatives for Families: A Cognitive Behavioral Therapy (AF-CBT), an evidence-based treatment (EBT) for families who are at risk of or have histories of child physical abuse. Across 10 agencies whose programs were supported by referrals from the mental health or child welfare system, individual providers were randomized to receive AF-CBT training ( n = 90) in a 6-month learning community or treatment as usual (TAU; n = 92) which provided trainings per agency routine. We recruited families served by providers in the AF-CBT ( n = 122) and TAU ( n = 73) conditions and collected multiple outcomes at up to four time points (0, 6, 12, and 18 months). Using univariate tests and growth curve models, the analyses revealed that AF-CBT (vs. TAU) showed improvements in both service systems (e.g., abuse risk, family dysfunction) or one service system (e.g., threats of force, child to parent minor assault), with some outcomes showing no improvement (e.g., parental anger). These findings are discussed in relation to AF-CBT, service system, provider, and family characteristics, and training/dissemination methods that affect the delivery of an EBT for this population in community settings. PMID- 30009633 TI - African born women living with HIV in the United States: unmet needs and opportunities for intervention. AB - Africa born (immigrant) women comprise a disproportionate number of Black women living with HIV in the United States. Though they are at risk for mental health disorders, including psychological distress and depression, little is known about their experience with these important predictors of quality of life, retention in care and adherence to antiretroviral therapy. In this qualitative study, we used constructivist grounded theory to explore the psychosocial and mental health challenges of African born women living with HIV in Boston and New York City. We conducted one-on-one semi-structured interviews with 45 women. Major themes contributing to psychological distress and depressive symptoms included (1) pre immigration HIV-related stigma; (2) persistent HIV-related stigma post immigration, (3) undocumented immigration status, (4) economic insecurity, and (5) intimate partner violence (IPV). Many participants described ongoing depressive symptoms or histories of depressive episodes. Yet, most had not been formally diagnosed or treated for depression. Prayer, consultation with faith leadership, and support groups were described most frequently as useful interventions. Future research should explore these thematic areas among a larger, more representative sample of African born women living with HIV to determine differences by country of origin across thematic areas. These data would be useful to inform development of innovative and culturally appropriate interventions. PMID- 30009634 TI - Positions of Ocular Geometrical and Visual Axes in Brazilian, Chinese and Italian Populations. AB - PURPOSE: To identify the relative positions of geometrical and visual axes of the eye and present a method to locate the visual center when the geometrical axis is taken as a reference. METHODS: Topography elevation data was collected using a Pentacam HR (r) topographer from 2040 normal eyes of 1020 healthy participants in Brazil, China and Italy. A three-dimensional, rotation algorithm, a first-order Zernike polynomial fit and a nonlinear least-squares error function was used within an optimization function to locate the geometrical axis and the visual center of each eye. RESULTS: The right eyes of participants were significantly more tilted than left eyes throughout the topography scanning process (p < 0.001). The visual centers were always located in the nasal-superior quadrant, although the visual centers of fellow eyes were not symmetrically located. Mean distances between the visual center and the geometrical center in right eyes were 0.8 +/- 0.29 mm, 0.56 +/- 0.18 mm and 0.91 +/- 0.34 mm among Brazilian, Chinese and Italian participants, respectively, and located at angular positions of 38.7 +/- 24.5 degrees , 23.0 +/- 29.8 degrees and 23.1 +/- 28.1 degrees from the nasal side. However, in left eyes, mean distances were 0.76 +/- 0.33 mm, 0.45 +/- 0.12 mm and 0.75 +/- 0.33 mm at polar angles from the nasal side of 59.3 +/- 29.0 degrees , 50.6 +/- 44.5 degrees and 61.8 +/- 34.1 degrees , respectively. CONCLUSIONS: Fellow eyes do not perform similarly during the fixation process, with right eyes tending to tilt more than left eyes, and the visual centers of the fellow eyes positioned differently relative to the geometrical centers. PMID- 30009635 TI - A Prospective Evaluation of Adverse Reactions to Single-Dose Intravenous Antibiotic Prophylaxis During Outpatient Hand Surgery. AB - BACKGROUND: While it is established that routine prophylactic antibiotics are not needed for all hand surgery, some cases do require it. The purpose of this study was to determine the rate of adverse reactions resulting from prophylactic antibiotic administration on patients undergoing outpatient hand and upper extremity surgical procedures. We hypothesize that the rate of complications resulting from the use of antibiotic prophylaxis is smaller than that reported in the currently referenced literature. METHODS: We prospectively evaluated 570 consecutive patients undergoing outpatient upper extremity surgery. Patients were excluded if they were on antibiotics prior to surgery, were discharged on antibiotics, or if they wished to be excluded. Nineteen patients were excluded, resulting in a study cohort of 551 patients. Patients were monitored perioperatively, 2 to 3 days postoperatively, during the first postoperative visit and 1 month postoperatively for adverse reactions. The type and timing of the adverse reaction was recorded. RESULTS: Five hundred fifty-one patients were included for evaluation and 8 patients (1.5%) developed an adverse reaction to antibiotics. Five patients (0.9%) reported a rash and 3 patients (0.5%) reported diarrhea within 3 days of surgery. There were no anaphylactic reactions or complications necessitating hospital transfer or admission in the postoperative period. CONCLUSION: This study represents a prospective investigation designed to determine the rate of adverse reactions to single-dose antibiotics given during outpatient hand surgery. We conclude that the use of intravenous, single-dose prophylactic antibiotic is safe in the outpatient setting for cases that require it. PMID- 30009636 TI - Effect of a Virtual Reality-Based Exercise Program on Fatigue in Hospitalized Taiwanese End-Stage Renal Disease Patients Undergoing Hemodialysis. AB - The purpose of this study was to evaluate the short-term effect of a virtual reality-based exercise program on fatigue in patients with end-stage renal disease (ESRD) who receive hemodialysis (HD). In this quasi-experimental study design, an experimental group ( n = 32) received virtual reality training that promoted exercise, and a control group ( n = 32) received routine care (advice on physical activities). Fatigue and physiologic parameters were assessed pretest (before intervention) as well as posttest (4 weeks after the onset of intervention). Our results showed that patients in the experimental group had significantly lower levels of overall fatigue, reduction in vigor and motivation, distress and loss of control in mood, and higher hemoglobin levels compared with the control group. ANCOVA revealed that there were no differences in overall fatigue and different domains of fatigue. Exercise only increased the blood urea nitrogen (BUN) and creatinine levels significantly in the intervention group. PMID- 30009637 TI - Disability and disasters: the role of self-efficacy in emergency preparedness. AB - Although individuals with physical disabilities have special needs regarding preparedness for a natural or human-made disaster, little is known about the factors involved in motivating members of this population to engage in behaviors which reduce the probability of negative health outcomes. This study proposes and empirically tests an integrated theory-based model for individuals with physical disabilities in which perceived self-efficacy for emergency preparedness moderates the relationship between perceived threat and emergency preparedness behaviors. A nationwide convenience cross-sectional sample of 294 adults self identifying as having a physical disability completed an online survey. The general linear model was used to assess the effects on preparedness of perceived threat, perceived self-efficacy, and their interaction. In addition to the hypothesized moderating effect of self-efficacy, it was found that minimal (if any) relationship exists between perceived threat and preparedness among those who reported low levels of self-efficacy. Results suggest that self-efficacy and perceived threat operate jointly to motivate individuals with physical disabilities to take precautionary steps to reduce the consequential adverse health effects of natural and human-made disasters. These findings have important implications for the design of effective interventions for individuals with disabilities. PMID- 30009638 TI - Development of a Structured Outcomes Assessment and Implementation Program in the Pediatric Intensive Care Unit. AB - This article reports on the Outcomes Program (OP) that the pediatric intensive care unit (PICU) developed to (1) monitor unit-based outcomes trends and safety data, (2) systematically identify targets for process improvement, and (3) implement new projects and care protocols with the aim of improving patient care. Following development of the OP structure in 2013, the authors have coordinated the components of outcomes data and reporting, clinical performance review, outcomes committee, knowledge translation, and implementation science programs to impact practice. Through routine provider updates, educational strategies, and prioritization of focused projects that include structured implementation plans, the model of PICU care has been improved. Described herein is the development of the process to evaluate intensive care unit outcomes and address the need for programmatic change through implementation science principles. Such a process may be of use in other PICUs. PMID- 30009639 TI - "I Can't Crack the Code": What Suicide Notes Teach Us about Experiences with Mental Illness and Mental Health Care. AB - OBJECTIVE: While mental illness is a risk factor for suicidal behaviour and many suicide decedents receive mental health care prior to death, there is a comparative lack of research that explores their experiences of mental illness and care. Suicide notes offer unique insight into these subjective experiences. Our study explores the following questions: "How are mental illness and mental health care experienced by suicide decedents who leave suicide notes?" and "What role do these experiences play in their paths to suicide?" METHOD: We used a constructivist grounded theory framework to select a focus of qualitative analysis and engage in line-by-line open coding, axial coding, and theorizing of the data. Our sample is a set of 36 suicide notes that explicitly make mention of mental illness and/or mental health care, purposefully selected from a larger sample of 252 notes. RESULTS: The primary themes from our sample were 1) negotiating personal agency in the context of mental illness, 2) conflict between self and illness, and 3) experiences of mental health treatment leading to hopelessness and self-blame. These experiences with mental illness and mental health care can give rise to exhaustion and a desire to exercise personal agency, contributing to suicidal behaviour. CONCLUSIONS AND RELEVANCE: This study highlights unique perspectives by suicide decedents, whose voices and experiences may not have been heard otherwise, addressing a critical deficit in existing literature. These insights can potentially enrich clinical care or strengthen existing suicide prevention programs. PMID- 30009640 TI - The Comparative Efficacy and Tolerability of Diclofenac 0.1% and Bromfenac 0.09% Ophthalmic Solutions after Cataract Surgery. AB - PURPOSE: To compare the efficacy and tolerability of diclofenac and bromfenac ophthalmic solutions as adjunctive therapy after cataract surgery. MATERIALS AND METHODS: This prospective randomized controlled study included 130 patients who underwent cataract surgery. One hundred patients were randomized to receive postoperatively diclofenac 0.1% (four times daily for 28 days, Group 1) or bromfenac 0.09% (twice daily for 14 days, Group 2) ophthalmic solutions in addition to steroid-antibiotic combination. Thirty patients instilled only steroid-antibiotic combination (Control Group 3). Laser flare-cell photometry and optical coherence tomography scans with central foveal thickness (CFT) measurement were performed before (V0) and 7 (V1), 14 (V2) and 28 days (V3) after surgery. Treatment tolerability was scored using the Ocular Comfort Grading Assessment. RESULTS: Laser flare-cell photometry values were significantly higher at V1, V2 and V3 compared to V0 in all the groups (respectively 13.3 +/- 1.0, 12.7 +/- 0.9 and 9.6 +/- 0.9 vs 8.4 +/- 0.6 ph/ms for Group 1; 13.4 +/- 1.0, 12.7 +/- 0.9 and 12.7 +/- 1.0 vs 8.1 +/- 0.6 for Group 2; 15.9 +/- 0.8, 15.4 +/- 0.7 and 14.5 +/- 0.7 vs 7.5 +/- 0.5 for Group 3) (p < 0.001); flare increase was significantly lower in Group 1 compared to Groups 2 and 3 (p < 0.001). CFT values were higher after surgery in all the three groups; the increase was significantly lower in Group 1 compared to Groups 2 and 3 (p < 0.0002). The percentage of symptoms-free patients after study treatment was significantly higher in Group 2 compared to Group 1 (respectively 74% vs 14% of the total; p < 0.001). CONCLUSION: The addition of diclofenac or bromfenac ophthalmic solutions contributed to further reduce both inflammation and cystoid macular edema after cataract surgery compared to steroid-antibiotic combination alone. Diclofenac appeared to be more effective in reducing postoperative intraocular inflammation with a more intense and prolonged regimen, while bromfenac more tolerated with lower daily dose and treatment duration. PMID- 30009641 TI - Thyroid-Stimulating Hormone Receptor Expression on Primary Cultured Human Extraocular Muscle Myoblasts. AB - PURPOSE: To isolate and culture human extraocular muscle (EOM) myoblasts and facilitate their differentiation to myotubes in vitro, and to determine whether these myoblasts express thyroid-stimulating hormone receptor (TSHR). MATERIALS AND METHODS: Human EOM myoblasts were isolated from EOM samples, and identified by immunostaining for PAX7 and MYOD1 (markers of human skeletal myoblasts), and western blot for desmin (muscle marker). In addition, we investigated the expressions of SHOX2 (a genetic marker of EOM myoblasts) and HOXC10 (an exclusive marker of hind-limb muscle-derived myoblasts) by RT-PCR. Fusion index and myotube area were measured to quantify myotube differentiation. TSHR immunostaining and western blot were used to determine the presence of TSHR on human EOM myoblasts and investigate its expression during myogenesis. RESULTS: Human EOM myoblasts were immunopositive for PAX7 and MYOD1 staining, and had desmin expression during myogenesis. The EOM-specific gene SHOX2 was detected by RT-PCR, but HOXC10 was not detected. The significant change in both fusion index and myotubes were shown at 8 days after induction of differentiation myotubes. Immunostaining revealed TSHR was expressed on human EOM myoblasts and western blot demonstrated the presence of TSHR protein and highest TSHR protein expression was shown at 10 days after myogenic differentiation. CONCLUSIONS: Human EOM myoblasts were cultured and underwent myogenic differentiation in vitro. TSHR protein was detected on human EOM myoblasts and increasing TSHR expression during myogenic differentiation. PMID- 30009642 TI - Removing Subjective Post-Mortem Grading from Posterior Capsular Opacification: A New Automated Detector Opacification Software, ADOS. AB - : Purpose/aim: Posterior capsular opacification (PCO) is the leading complication following cataract surgery. However, PCO grading methods vary between studies and rely on subjective scoring methods; hence, they are prone to error. Therefore, software that reduces subjectivity and enhances reproducibility is needed. The aim of the study was to evaluate the reproducibility and objectivity of a novel automated custom-designed PCO detection software. MATERIALS AND METHODS: In total, 165 fixed eyes with intraocular lenses were sectioned to obtain a Miyake Apple view (MAV) image. The capsular bag (CB) with the in situ IOL was removed and imaged using the Olympus DSX110 stereoscope. Central, peripheral, and Soemmering's ring area (SRA) and intensity (SRI) were graded by two ophthalmologists using a scale of 0-4. Software was developed to detect PCO, and these values were correlated with subjective scoring. RESULTS: Intra-observer agreement for MAV and CB images ranged from poor to moderate, with very good agreement for SRI (k = 0.88, 0.86, respectively). Agreement between graders was fair to good (k = 0.31-0.77). Miyake Apple view and capsular bag images showed good correlation; central PCO showed the least correlation for both evaluators (k = 0.29, 0.72). Subjective average grading versus software correlation demonstrated very good correlation for intensity and good for area (r = 0.85, 0.61). Reproducibility of the methodology resulted in good to very good correlation. CONCLUSIONS: Software correlates with previous scoring methods and is a reliable and reproducible system. Moreover, the capsular bag view, as opposed to the Miyake Apple view, allows visualization of the capsular bag directly and avoids overlapping structures (vitreous, cornea) that may interfere with proper PCO quantification. PMID- 30009643 TI - The mesentery: an ADME perspective on a 'new' organ. AB - With the inclusion of mesentery, the total number of human organs has recently increased by one. The mesentery was formerly construed to be a complex, discontinuous anatomical structure simply serving as a support for organs in abdominal cavity. However, recent research has established the mesentery to be a far more simple and unfragmented organ. Newly emerging information on the mesentery has challenged some older pathophysiological concepts. This review briefly discusses the anatomy of the mesentery, historical perspective on the mesentery, embryology, drug metabolizing enzymes and transporters of the mesentery, and the mesentery's role in diseases. The possible impact of the mesentery on absorption, distribution, metabolism, and excretion (ADME) is also discussed. PMID- 30009645 TI - Effects of anesthesia on cerebral blood flow, metabolism, and neuroprotection. AB - Administration of anesthetic agents fundamentally shifts the responsibility for maintenance of homeostasis from the patient and their intrinsic physiological regulatory mechanisms to the anesthesiologist. Continuous delivery of oxygen and nutrients to the brain is necessary to prevent irreversible injury and arises from a complex series of regulatory mechanisms that ensure uninterrupted cerebral blood flow. Our understanding of these regulatory mechanisms and the effects of anesthetics on them has been driven by the tireless work of pioneers in the field. It is of paramount importance that the anesthesiologist shares this understanding. Herein, we will review the physiological determinants of cerebral blood flow and how delivery of anesthesia impacts these processes. PMID- 30009646 TI - Height Growth Impairment in Children With Neurofibromatosis Type 1 Is Characterized by Decreased Pubertal Growth Velocity in Both Sexes. AB - Previous studies have suggested that children with neurofibromatosis type 1 are shorter than their unaffected counterparts as an effect of a germline NF1 gene mutation. The pathophysiology of this effect is still uncertain. The purpose of this study was to characterize longitudinal growth in children with neurofibromatosis type 1 in order to assess growth velocity and its influence on stature. Longitudinal height data were collected for 188 patients with a confirmed clinical diagnosis of neurofibromatosis type 1. Children with neurofibromatosis type 1 had population mean heights statistically different from the general population, with a reduced peak height velocity during pubertal growth. In addition, there were no significant differences in the timing of peak height velocity during puberty between the general population and those with neurofibromatosis type 1. These data demonstrate that short stature in neurofibromatosis type 1 is due in part to subnormal height acquisition during puberty. PMID- 30009647 TI - Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenib + trametinib versus nivolumab or pembrolizumab monotherapy. AB - OBJECTIVE: To compare healthcare resource utilization (HRU) between patients with metastatic melanoma (MM) initiated on first-line (1L) combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (D + T; oral) and those initiated on 1 L monotherapy with the anti-PD1 monoclonal antibodies nivolumab or pembrolizumab (N/P; intravenous). METHODS: Patients with melanoma initiated on D + T or N/P from Q1/2014 to Q2/2016 (defined as 1 L treatment for MM) were identified in the Truven MarketScan database. Entropy balancing was used to reweight the N/P cohort in order to make it comparable to the D + T cohort with respect to the mean and variance of baseline covariates. HRU outcomes during 1 L therapy, reported per patient-year (PPY), were described and compared between the two cohorts post-weighting (i.e. independently of baseline covariates). RESULTS: Of the 445 patients included, 202 and 243 were initiated on D + T and N/P, respectively. After weighting, patients initiated on N/P had more outpatient visits for drug administration during 1 L therapy than those initiated on D + T (difference = 18.6 visits PPY [95% CI = 16.0-21.1]). Patients initiated on N/P also had more outpatient office visits for reasons other than drug administration (difference = 8.1 visits PPY [95% CI = 1.9-13.7]). No significant differences were observed for other HRU parameters (i.e. inpatient admissions, inpatient days, and emergency department visits during 1 L therapy). CONCLUSIONS: HRU during 1 L therapy was generally similar between patients initiated on D + T and N/P. Nonetheless, patients initiated on N/P had more outpatient visits, including more outpatient visits for reasons unrelated to drug administration. PMID- 30009648 TI - Twelve tips for designing curricula that support the development of adaptive expertise. AB - An essential component of expertise is a clinician's ability to adapt to uncertain, complex, or novel situations while maintaining their competence in routine situations. Adaptive expertise provides a framework for understanding and developing experts who have the skills to effectively balance and support these dimensions of work using both procedural and conceptual knowledge. It is important for educators to understand that often the training which fosters adaptive expertise does not require new tools or approaches, but rather a reconceptualization of training using many of the same instruction and assessment formats already available. The twelve tips discussed in this paper showcase ways in which education can be transformed to support the development of adaptive expertise including the significance of instruction that combines various forms for knowledge, the value of productive struggle, and shifting the design of assessments to support learning and performance beyond retention and direct application. PMID- 30009649 TI - Effectiveness and safety of initiating adalimumab plus >=12 mg/week methotrexate with adjustable dosing in biologic-naive patients with early rheumatoid arthritis: HAWK study postmarketing surveillance in Japan. AB - OBJECTIVES: This real-world study assessed the effectiveness and safety outcomes of initiating adalimumab and methotrexate (>=12 mg/week) with adjustable dosing in Japanese patients with early rheumatoid arthritis (RA). METHODS: This single arm, prospective postmarketing observational study (conducted from September 2012 to March 2017 at 119 sites) enrolled biologic-naive patients with early RA (<=2 years duration) and a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) >3.2 who were treated with methotrexate for >=3 months and had initiated treatment with adalimumab and methotrexate (>=12 mg/week). This report presents 52-week data. The primary outcome was the proportion of patients who achieved DAS28-CRP scores <2.6 at week 52. RESULTS: Overall, 293 of 346 enrolled patients were included in the effectiveness population: women, 73%; mean (standard deviation) age, 54.3 (13.9) years; DAS28-CRP score, 4.51 (0.90); and modified total Sharp score (mTSS), 7.69 (9.98). At week 52, 77% of patients achieved clinical remission (DAS28-CRP <2.6), 92.3% achieved low disease activity (DAS28-CRP <=3.2), and 86% of evaluable patients experienced structural remission (DeltamTSS <=0.5). CONCLUSION: Adalimumab plus methotrexate (>=12 mg/week) with adjustable dosing was well tolerated, and could be a beneficial treatment option for Japanese patients with early RA. PMID- 30009650 TI - Pharmacotherapeutic strategies for treating epilepsy in patients with Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD)-related epileptic comorbidity is now well documented and appears to have been previously underestimated. Prescribing antiepileptic drugs (AEDs) in AD patients aims at preventing seizure-related morbi-mortality and the occurrence of deleterious status epilepticus. At the earlier stages of the disease, some clinicians even expect a disease-modifying effect. Areas covered: In this review, the author provides a brief overview of the epileptic comorbidity in AD, discusses the appropriate AEDs from a syndromic point of view, reviews the effectiveness and cognitive tolerability of the currently available drugs, and considers the influence of the comorbidities and the age of AD patients in the choice of an AED. Expert opinion: Given the paucity of current empirical data, much remains to be done to provide good evidence of the efficacy and tolerability of AEDs in the area of AD-related seizures and epilepsy. To our knowledge, lamotrigine and levetiracetam are currently the two best therapeutic options as low-dose monotherapies. PMID- 30009651 TI - Growth of infants and young children born small for gestational age: growth restriction accompanied by overweight. AB - Objectives To compare growth profiles of children born small for gestational age (SGA) with those born the appropriate size for gestational age (AGA), and examine expected growth patterns for SGA in early childhood. Methods A survey on 23,871 SGA children was conducted in Shanghai. Data were collected at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, and 60 months of age (+30 days). A check-up included assessments of weight, height, and head circumference. Results At 5 years old, weight, height, and head circumference were lower in SGA children compared with AGA children. The proportions of overweight and obesity of SGA children at 4 to 18 months after birth were significantly higher than those in AGA children, with higher proportions in boys than in girls. There was no correlation between overweight at 5 years old and overweight before 2 years old in SGA children. Conclusions Children born SGA remain shorter and lighter, with a smaller head circumference at 5 years old compared with AGA children. At 4 to 18 months after birth, there is a high incidence of overweight and obesity in SGA children. Overweight and obesity in SGA boys are more serious than those in SGA girls. PMID- 30009652 TI - Intradermal Acupuncture Along with Analgesics for Pain Control in Advanced Cancer Cases: A Pilot, Randomized, Patient-Assessor-Blinded, Controlled Trial. AB - PURPOSE: Ninety percent of patients with advanced cancer have moderate to severe pain, and up to 70% of patients with cancer pain do not receive adequate pain relief. This randomized controlled clinical trial was designed to determine the feasibility and evaluate the effects and safety of intradermal acupuncture (IA) in patients who were being administered analgesics for cancer pain. METHODS: Advanced cancer patients experiencing pain were randomly assigned to IA or sham IA treatment for 3 weeks (15 patients for each group), wherein the CV12, bilateral ST25, LI4, LR3, PC06, and Ashi points were selected and stimulated. Follow-up evaluations were conducted 3 weeks after the end of treatments. The grade and dosage of analgesics for cancer pain, pain intensity, quality of life, and safety were assessed. RESULTS: Twenty-seven patients (90%) completed 6-week trial, and no serious adverse events were associated with either IA or sham IA procedures except the transient side effect such as fatigue. Nine patients in the IA group (64.3%) and 5 in the sham IA group (38.5%) responded to the 3-week intervention. These patients were mostly in the nonopioid and the weak opioid levels of the World Health Organization analgesic ladder. Self-reported pain declined by -1.54 +/- 1.45 and -1.15 +/- 1.57 in the IA and sham IA groups, respectively, with improved quality of life reported. CONCLUSIONS: IA treatment appears feasible and safe for advanced cancer patients. It might reduce analgesic usage in the early World Health Organization analgesic ladder stage cancer patient, though it could not show significant outcome differences due to design limitation of sham IA. PMID- 30009653 TI - An Interdisciplinary Clinical Approach for Workplace Violence Prevention and Injury Reduction in the General Hospital Setting: S.A.F.E. Response. AB - BACKGROUND: Workplace violence is a major public health concern. According to the U.S. Bureau of Labor Statistics, from 2002 to 2013, incidents of serious workplace violence (those requiring days off) were four times more common in health care than in private industry. AIMS: An interprofessional committee developed, implemented, and evaluated a quality improvement project from 2012 to 2016 to reduce workplace violence and prevent staff injury. The initiative termed S.A.F.E. Response stands for Spot a threat, Assess the risk, Formulate a safe response, Evaluate the outcome. METHOD: An institutional review board-approved quality improvement survey was implemented and evaluated. The data were analyzed using descriptive statistics. An interprofessional committee developed and implemented a comprehensive program to prevent injury, which included (a) a mandatory eLearning educational training, (b) a S.A.F.E. Response with standardized interventions for the clinical conditions affecting safety, and (c) a clinical debriefing process. A reduction in nursing staff assault incidence rates was identified as a success. RESULTS: Nursing staff injury rates decreased an average of 40%. CONCLUSIONS: A reduction in nursing staff assault incidence rates was notable. Clinicians equipped with knowledge, skills, and resources can identify and defuse unsafe situations to prevent violence. This clinical approach shifts the focus from crisis intervention to crisis prevention, which reduces injury. PMID- 30009655 TI - They Know How to Work It, That's Their Focus in Life: The Complex Role of Industry Representatives in Surgical Innovation. AB - Relationships between health care providers and industry can generate conflicts of interest with their attendant harms. However, the types of relationships that involve conflicts of interest have often been understood narrowly as material ones between individual clinicians and industry. In research we undertook with surgical teams, we found the role of industry representatives has become normalized in the context of surgical innovation. In this article, we report the findings of our study and unpack the features of both surgery and innovation which contribute to the scope and normalization of industry involvement. We argue that these relationships generate significant ethical challenges and conclude by commenting on how our conceptualization of the situation might inform change. PMID- 30009654 TI - Renal dysfunctions/injury in adult epilepsy patients treated with carbamazepine or valproate. AB - OBJECTIVES: Clinical and subclinical laboratory evidence of renal proximal tubular dysfunction had been reported in children with epilepsy as an adverse effect of some antiepileptic drugs (AEDs). This study aimed to determine kidney function in adult patients with monosymptomatic epilepsy of unknown etiology and treated with valproate (VPA) or carbamazepine (CBZ). METHODS: This study included 60 patients [mean age of 33.97 +/- 6.70 years and treated with VPA (n = 24) or CBZ (n = 36) for mean duration of treatment of 6.03 +/- 2.81years. Measurements of serum creatinine (sCr), urinary creatinine, creatinine clearance (CrCl) and serum kidney injury molecule 1 (KIM-1), markers of renal dysfunction/injury were done. RESULTS: Compared to controls, patients had higher sCr, KIM-1 and lower CrCl levels. Compared to patients on VPA, those on CBZ had relatively higher KIM 1 and lower CrCl levels. We reported only significant correlations between KIM-1 with sCr (r = 0.324, p = 0.001) and duration of treatment with AEDs (r = 0.301, p = 0.02). CONCLUSION: Chronic VPA and CBZ therapy may be associated with subclinical renal glomerular and/or proximal tubular dysfunctions or injuries. The treating neurologist have to consider this while selection of AED on start treating patients or modifying the AED for patients at high risk of kidney injury. PMID- 30009656 TI - Intrathecal Baclofen Therapy-Practical Approach: Clinical Benefits and Complication Management. AB - Intrathecal baclofen is an expanding accepted treatment for children with cerebral palsy and other causes of spasticity and dystonia. The aims of this review are therefore to (1) delineate the clinical benefits of intrathecal baclofen therapy in pediatric spasticity and dystonia and (2) increase awareness of the potential complications and emergency management measures of intrathecal baclofen therapy. A current literature review demonstrates the benefits and complications of this minimally invasive device. Practical guides for recognizing acute conditions and management recommendations are included. Intrathecal baclofen is increasingly being used to help individuals attain realistic functional goals. Therefore, families and health care professionals should be aware of potential complications, symptoms, and emergency management. PMID- 30009657 TI - The Relationship Between Reported Pain and Depressive Symptoms Among Adolescents. AB - Pain and depressive symptoms are common reasons for adolescents to contact the school nurse. The aim was to describe the prevalence of pain (headache, abdominal pain, and back pain) and depressive symptoms among adolescents and to examine whether there is an association between pain and depressive symptoms. This cross sectional survey included students ( N = 639) in Sweden (median age: 16 years). Over half of the female participants (56%) and one third of male participants (33%) had weekly headaches, abdominal pain, or back pain. Almost every second girl (48%) and one in four boys (25%) had depressive symptoms (as measured by the Center for Epidemiological Studies Depression Scale, scores >= 16). There was a significant association between having pain (headache, abdominal pain, or back pain) and having depressive symptoms. It is of great importance for school nurses to adequately identify and treat the cause of pain and other factors contributing to depression. PMID- 30009658 TI - In vitro evaluation of loop design influencing the sliding of orthodontic wires: A preliminary study. AB - AIM: Resistance to sliding between bracket and wire is present, in a different magnitude, in most orthodontic treatments and it affects the biomechanics of the tooth movement. However, the influence of loop design on resistance to sliding is currently unknown. METHODS: In total, 12 stainless steel orthodontic wires of different sizes (0.016"*0.022"; 0.017"*0.025"), loop height (6mm, 8mm, 10mm), and loop type (open, close) were analyzed. Wires were tied with elastic ligatures to a bracket and tested during sliding at 0.5 mm/min. Straight wires were used as controls. Differences in the force to start the sliding ( N), force during the sliding ( N), and displacement to start the sliding (mm), were evaluated with Kruskal-Wallis one-way analysis of variance and Mann-Whitney tests (alpha=0.05). RESULTS: Open loops had a lower force to start the sliding compared to straight wires ( p<0.05), and some closed loops showed a similar trend. Open loops had lower force during the sliding compared to straight wires, but closed loops were less predictable. Displacement to start the sliding increased with loop height, and differences were present between loops and straight wires ( p<0.001). Force to start the sliding and force during the sliding changed relative to loop type ( p<0.05), and closed loops showed higher resistance to sliding. Differences were also found in force to start the sliding and force during the sliding between wire sizes, with larger wires associated with higher forces ( p<0.05). CONCLUSIONS: Loops should be considered as significant variables in the resistance to sliding, as they can influence both the amount of force and the onset of sliding. Compared to straight wires, rectangular wires with open loops may help clinicians reduce resistance to sliding. Further studies are necessary to confirm these preliminary findings. PMID- 30009659 TI - Primary Esophageal Mixed Sarcomatoid and Small Cell Neuroendocrine Carcinoma With Brain Metastasis: A Challenging Diagnosis on Biopsy. AB - Mixed carcinomas in the esophagus are highly uncommon neoplasms that represent a diagnostic challenge on small tissue biopsies. We present a case of a primary mixed sarcomatoid-small cell carcinoma of the esophagus that was diagnosed after repeat sampling of the lesion. The components were morphologically distinct and could be further classified by immunohistochemistry. Next-generation sequencing identified mutations in PIK3CA and CDKN2A. The small cell component morphology was also identified in brain metastasis. PMID- 30009660 TI - Empathic profile of nursing freshmen. AB - OBJECTIVE: To analyze the empathic profile and the empathy scores of freshmen of the nursing course. DESIGN AND PARTICIPANTS: Descriptive study involving 399 freshmen students of two modalities of nursing courses: Bachelor and Bachelor and Teaching Diploma, in the period from 2012 to 2015. A sociodemographic questionnaire and the Empathy Inventory were applied. Ethical considerations: The research received approval from the Research Ethics Committee of the University of Sao Paulo at Ribeirao Preto College of Nursing. The students registered their acceptance to participate in the research by signing the Free and Informed Consent Form and anonymity was guaranteed. FINDINGS: The mean age of the participants was 19 years, being 85.5% female. The students were grouped by course modality and all groups presented high empathy scores. A significant difference (p < 0.001) was found, which indicates that students of the Bachelor and Teaching Diploma program presented a higher degree of empathy for the General Score, Domain 2 (Interpersonal Flexibility), and Domain 3 (Altruism) in relation to students in the Bachelor program. CONCLUSION: Results show that nursing undergraduate freshmen are emphatic, with minimum differences between the two courses. This profile is relevant for the development of future professionals capable to demonstrate a balance between instrumental and expressive competences. PMID- 30009662 TI - MitraClip procedure as 'bridge to list', the ultimate therapeutic option for end stage heart failure patients not eligible for heart transplantation due to severe pulmonary hypertension. AB - Patients with end-stage heart failure (HF), pulmonary hypertension and elevated pulmonary vascular resistance (PVR) despite medical therapy are not eligible for heart transplantation (HTx). In this 'proof of concept' case series, we demonstrate the feasibility and efficacy of the MitraClip procedure as 'bridge to list' in end-stage HF patients not eligible for HTx. In fact, in the three patients reported, who were initially excluded from the HTx list because of elevated PVR, the MitraClip procedure was followed by a sustained improvement of PVR, allowing the patients' risk to be reclassified, and they were then considered eligible for HTx. PMID- 30009663 TI - Soybean-Macrophomina phaseolina-Specific Interactions and Identification of a Novel Source of Resistance. AB - Charcoal rot, caused by the fungus Macrophomina phaseolina, is an economically important disease of soybean (Glycine max) worldwide. Objectives of the present research were to (i) study the genetic and pathogenic diversity in a collection of M. phaseolina isolates from Argentina and Paraguay and (ii) develop an improved in vitro phenotyping method to evaluate disease response of soybean genotypes to M. phaseolina isolates. Cluster analysis showed no clear association among simple sequence repeat profiles, year of collection, pathogenicity, and geographical origin of the isolates from Argentina and Paraguay. Subsequently, the response of four soybean genotypes against seven M. phaseolina isolates was evaluated in the field and the results were confirmed using the in vitro assay developed. This assay, which is based on root disease development on soybean seedlings, allowed the detection of a differential level of aggressiveness among the isolates on four soybean genotypes. The results suggest the existence of specific interactions among soybean genotypes and M. phaseolina isolates. In addition, cultivar Munasqa RR showed a superior response against M. phaseolina compared with DT 97-4290 (moderately resistant), thus becoming a novel source of resistance to charcoal rot. PMID- 30009661 TI - Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease. AB - Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD. PMID- 30009664 TI - The phagophore in four dimensions-a study in wood. AB - : One of the key features of macroautophagy/autophagy is the dynamic nature of the membrane rearrangements that take place during expansion of the phagophore, the sequestering compartment that matures into an autophagosome. There are various ways to depict this process, but in most cases the method ultimately relies on a two-dimensional medium. Most people working in the field of autophagy realize that the typical 'C'-shaped drawing of a phagophore is meant to represent a cup- or bowl-like structure that exists in the cell in 3 dimensions. However, explaining this concept to a lay person often leads to confusion and misinterpretation. Accordingly, we decided to generate a four-dimensional version of the expanding phagophore as a wood sculpture, that depicts this transient compartment in 3 dimensions over time. ABBREVIATIONS: ER: endoplasmic reticulum. PMID- 30009665 TI - Accelerometry to measure physical activity in toddlers: Determination of wear time requirements for a reliable estimate of physical activity. AB - Accelerometry is widely used to evaluate physical activity in toddlers however recommendations regarding wear time are needed to understand physical activity behaviours in this age group. This study aimed to determine the minimum wear time to reliably evaluate physical activity in toddlers. Children from the 3D Birth Cohort (n = 255, 49.8% boys, 2.1 +/- 0.2 years) were asked to wear an accelerometer (GT3X+, ActiGraph) for 7 days. Physical activity was expressed in active time (min/day) and counts per minute (CPM). Single day intraclass correlation coefficients (ICCs) were calculated to assess the effect of varying minimal wear time on reliability estimates. The Spearman-Brown formula was used to determine wear time required to achieve reliability levels of 70%, 80% and 90%. For active time, a reliability of 72.1% was achieved with wearing the accelerometer for >= 4 days of >= 6 h, which comprised 85.9% of the sample. For CPM, >= 4 days of >= 6 h provided a reliability of 74.7% and comprised 85.9% of the children. Results differed slightly when girls and boys were analysed separately, but restricting analyses to children with a weekend day did not. In summary, a minimum of 4 days with >= 6 h of accelerometry data provides a reliable estimate of physical activity in 2-year toddlers. PMID- 30009667 TI - Neonatal onset familial Mediterranean fever. AB - OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent, self-limited attacks of fever with serositis. Recently, it was shown that FMF patients with early disease onset have more severe disease. The aim of this study was to describe the demographic, clinical and genetic features of FMF patients who had disease onset during the neonatal period. METHODS: Medical records of all patients diagnosed as FMF and had been seen in the outpatient clinic of Paediatric Rheumatology department between January 2013 and January 2014 were retrospectively evaluated. Patients with disease onset during the first month of life were included to the study. RESULTS: Among 317 patients; 19 (12 males) were included to the study. Approximately 60% of the patients had family history of FMF. Homozygous p.M694V mutation was detected in 42% of the cases. Thirteen patients present with attacks of fever and remaining had attacks in the form of restlessness, resembling infantile colic starting in the neonatal period. Majority of these patients developed classical abdominal attacks between the ages of 1 and 2.5 years. The diagnosis of FMF was significantly delayed; the median age at onset of therapy was 3.5 years (range 7 months-17 years). CONCLUSION: Patients with FMF could have complaints even in the neonatal period. Homozygous p.M694V mutation is a prominent mutation in this group of patients. In order to prevent diagnostic delay physicians dealing with these type of patients should be more vigilant. PMID- 30009668 TI - Long-Term Engraftment Promotes Differentiation of Alveolar Epithelial Cells from Human Embryonic Stem Cell Derived Lung Organoids. AB - Human embryonic stem cell (hESC) derived 3D human lung organoids (HLOs) provide a promising model to study human lung development and disease. HLOs containing proximal or/and immature distal airway epithelial cells have been successfully generated in vitro, such as early staged alveolar type 2 (AT2) cells (SPC+/SOX9+) and immature alveolar type 1 (AT1) cells (HOPX+/SOX9+). When HLOs were transplanted into immunocompromised mice for further differentiation in vivo, only few distal epithelial cells could be observed. In this study, we transplanted different stages of HLOs into immunocompromised mice to assess whether HLOs could expand and mature in vivo. We found that short-term transplanted HLOs contained lung progenitor cells (NKX2.1+, SOX9+, and P63+), but not SPC+ AT2 cells or AQP5+ AT1 cells. Meanwhile, long-term engrafted HLOs could differentiate into lung distal bipotent progenitor cells (PDPN+/SPC+/SOX9+), AT2 cells (SPC+, SPB+), and immature AT1 cells (PDPN+, AQP5-). However, HLOs at late in vitro stage turned into mature AT1-like cells (AQP5+/SPB-/SOX9-) in vivo. Immunofluorescence staining and transmission electron microscopy (TEM) results revealed that transplanted HLOs contained mesenchymal cells (collagen I+), vasculature (ACTA2+), neuroendocrine-like cells (PGP9.5+), and nerve fiber structures (myelin sheath structure). Together, these data reveal that hESC derived HLOs would be useful for human lung development modeling, and transplanted HLOs could mimic lung organ-like structures in vivo by possessing vascular network and neuronal network. PMID- 30009666 TI - "Keaping" a lid on lung cancer: the Keap1-Nrf2 pathway. AB - Lung cancer remains one of the world's deadliest cancers, with effective targeted treatment options available for only a small subset of patients. The rapid expansion of cancer genomics in recent years has provided insight into the genetic landscape of all major lung cancer subtypes and led to new discoveries on the heterogeneous biology underlying lung tumorigenesis. Interestingly, these studies have revealed a high frequency of alterations in the Kelch-like ECG associated protein 1 (KEAP1)-Nuclear factor erythoid-2-related factor 2 (NRF2) stress response pathway, for which no targeted treatments are currently available. In this review, we describe the molecular mechanisms underlying NRF2 pathway activation in lung cancer cells, with a focus on in vivo functional studies in genetically engineered mouse models. Importantly, potential avenues and implications for therapeutic targeting of KEAP1-NRF2 pathway vulnerabilities for lung cancer patients will be highlighted. PMID- 30009669 TI - Stimulating the Injured Spinal Cord: Plenty to Grasp. PMID- 30009670 TI - Extracorporeal membrane oxygenation in acute massive pulmonary embolism: a case series and review of the literature. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been used to stabilize patients with massive pulmonary embolism though few reports describe this approach. We describe the presentation, management and outcomes of patients who received ECMO for massive pulmonary embolism (PE) in our pulmonary embolism response team (PERT) registry. METHODS: We enrolled a consecutive cohort of patients with confirmed PE for whom PERT was activated and selected patients treated with ECMO. We prospectively captured clinical, therapeutic and outcome data at the time of PERT activation and during the follow-up period for up to 365 days. RESULTS: Thirteen patients who had PERT activation with confirmed PE diagnosis have undergone ECMO since the initiation of our PERT program in 2012. The mean age was 49 +/- 19 years. Six (46%) patients were female. All the patients had cardiac arrest, either as an initial presentation or in-hospital cardiac arrest after presentation. All the patients exhibited right ventricular (RV) dilation on echocardiogram with RV hypokinesis. Eight (62%) patients received systemic thrombolysis with intravenous tissue plasminogen activator (tPA) and three (23%) patients underwent catheter-directed thrombolysis therapy using the EKOS system (EKOS Corporation, Bothell, WA, USA). Four (31%) patients underwent surgical embolectomy. Mean ECMO duration was 5.5 days, ranging from 2 18 days. Thirty-day mortality was 31% and one-year mortality was 54%. CONCLUSIONS: Patients with massive pulmonary embolism who suffer a cardiac arrest have high morbidity and mortality. ECMO can be used in conjunction with systemic thrombolysis, catheter-directed therapy or as a bridge to surgical embolectomy. PMID- 30009672 TI - Effect of personalized wrist orthosis for wrist pain with three-dimensional scanning and printing technique: A preliminary, randomized, controlled, open label study. AB - BACKGROUND:: Three-dimensional printer technology can produce the personalized orthosis in various forms. OBJECTIVE:: To develop a personalized wrist orthosis using a three-dimensional scanner and three-dimensional printer for patients with wrist pain. STUDY DESIGN:: A preliminary, prospective, randomized, open-label study. METHODS:: A total of 22 patients with wrist pain were randomly assigned to the control and experimental groups. The control group wore a cock-up orthosis and the experimental group wore a three-dimensional-printed wrist orthosis for 1 week. The Patient-Rated Wrist Evaluation, Jebsen Hand Function Test, and Orthotics and Prosthetics Users' Survey were checked before and 1 week after the application. RESULTS:: The Patient-Rated Wrist Evaluation showed significant pain relief in both groups. Two items of the 28 Orthotics and Prosthetics Users' Survey questions, "Put toothpaste on brush and brush teeth" and "Dial a touch tone phone," showed high satisfaction scores, with statistically significant difference in the experimental group ( p = 0.036 and 0.004). CONCLUSION:: The three-dimensional-printed wrist orthosis was superior to the cock-up orthosis for two items of the Orthotics and Prosthetics Users' Survey. Wrist pain was reduced in the group wearing the three-dimensional-printed wrist orthosis as well as the group wearing the cock-up orthosis, so the three-dimensional-printed wrist orthosis could possibly play the same role as the cock-up orthosis. CLINICAL RELEVANCE: A three-dimensional-printed wrist orthosis can be a substitute for a conventional ready-made wrist orthosis for patients with wrist pain with more satisfaction. PMID- 30009671 TI - Combined treatment of human multiple myeloma cells with bortezomib and doxorubicin alters the interactome of 20S proteasomes. AB - : The proteasome is the key player in targeted degradation of cellular proteins and serves as a therapeutic target for treating several blood malignancies. Although in general, degradation of proteins via the proteasome requires their ubiquitination, a subset of proteins can be degraded independently of their ubiquitination by direct interaction with subunits of the 20S proteasome core. Thus, investigation of the proteasome-associated proteins may help identify novel targets of proteasome degradation and provide important insights into the mechanisms of malignant cell proteostasis. Here, using biochemical purification of proteasomes from multiple myeloma (MM) cells followed by mass-spectrometry we have uncovered 77 proteins in total that specifically interacted with the 20S proteasome via its PSMA3 subunit. Our GST pull-down assays followed by western blots validated the interactions identified by mass-spectrometry. Eleven proteins were confirmed to bind PSMA3 only upon apoptotic conditions induced by a combined treatment with the proteasome inhibitor, bortezomib, and genotoxic drug, doxorubicin. Nine of these eleven proteins contained bioinformatically predicted intrinsically disordered regions thus making them susceptible to ubiquitin independent degradation. Importantly, among those proteins five interacted with the ubiquitin binding affinity matrix suggesting that these proteins may also be ubiquitinylated and hence degraded via the ubiquitin-dependent pathway. Collectively, these PSMA3-interacting proteins represent novel potential substrates for 20S proteasomes upon apoptosis. Furthermore, these data may shed light on the molecular mechanisms of cellular response to chemotherapy. ABBREVIATIONS: BD: bortezomib/doxorubicin treatment; CDK: cyclin-dependent kinases; CHCA: alpha-cyanohydroxycinnamic acid; IDP: intrinsically disordered proteins; IDR: intrinsically disordered regions; IPG: immobilized pI gradient; MALDI TOF/TOF: matrix-assisted laser desorption/ionization time-of-flight tandem mass-spectrometry; MM: multiple myeloma; ODC: ornithine decarboxylase; PI: proteasomal inhibitors; PSMA: alpha-type 20S proteasome subunits; PTMs: post translational modifications; SDS-PAGE: sodium dodecylsulphate polyacrylamide gel electrophoresis; UIP: ubiquitin-independent proteasomal proteolysis. PMID- 30009673 TI - Influence of upright versus time trial cycling position on determination of critical power and W' in trained cyclists. AB - Body position is known to alter power production and affect cycling performance. The aim of this study was to compare mechanical power output in two riding positions, and to calculate the effects on critical power (CP) and W' estimates. Seven trained cyclists completed three peak power output efforts and three fixed duration trial (3-, 5- and 12-min) riding with their hands on the brake lever hoods (BLH), or in a time trial position (TTP). A repeated-measures analysis of variance showed that mean power output during the 5-min trial was significantly different between BLH and TTP positions, resulting in a significantly lower estimate of CP, but not W', for the TTP trial. In addition, TTP decreased the performance during each trial and increased the percentage difference between BLH and TTP with greater trial duration. There were no differences in pedal cadence or heart rate during the 3-min trial; however, TTP results for the 12-min trial showed a significant fall in pedal cadence and a significant rise in heart rate. The findings suggest that cycling position affects power output and influences consequent CP values. Therefore, cyclists and coaches should consider the cycling position used when calculating CP. PMID- 30009674 TI - An Improved, Chemically Modified RNA Encoding BMP-2 Enhances Osteogenesis In Vitro and In Vivo. AB - The first therapeutic application of messenger RNA (mRNA) was suggested more than two decades ago. However, its application was constrained by the ability of mRNA to activate the innate immune response, cytotoxicity, and poor potency. We and others recently demonstrated that these undesirable properties of mRNA may be overcome by alterating its structure. In this study, we developed a new chemically modified mRNA coding for BMP-2 with improved osteogenic features. To develop this new construct, we removed from the mRNA sequence the following undesirable elements: an upstream open reading frame in the 5'-untranslated region (UTR) and a polyadenylation element together with an AU-rich tract in the 3'UTR. In addition, a translation initiator of short UTRs (TISU) was introduced together with 5-iodo modified pyrimidine nucleotides. The new TISU BMP-2 chemically modified RNA (cmRNA) showed robust BMP-2 production in vitro in cell lines (HEK293 and MC3T3) and primary cells (muscle-derived mesenchymal stem cells). Stem cells additionally showed upregulation of osteogenic and angiogenic genes as a result of the TISU BMP-2 cmRNA transfection. The in vivo osteogenic properties of TISU BMP-2 cmRNA were explored in a critical-sized femoral defect in the rat. For this, the TISU BMP-2 cmRNA was loaded into collagen sponges to form transcript-activated matrices. Animals treated with TISU BMP-2 cmRNA showed superior bone formation that seemed to recapitulate endochondral ossification. The higher of the two doses examined in this model showed more robust new tissue formation. Finally, improved vascularization was detected in the healing area for animals treated with TISU BMP-2 cmRNA. PMID- 30009676 TI - Functional similarities and differences between the coding of positional information in verbal and spatial short-term order memory. AB - Temporal grouping effects in verbal and spatial serial recall suggest that the representation of serial order in verbal and spatial short-term memory (STM) incorporates positional information. However, not all effects of grouping are created equal in the verbal and spatial domains. Although grouping a sequence of verbal items engenders an increase in between-group transpositions that maintain their within-group position, grouping a sequence of spatial items does not engender an increase in these so-called interposition errors. Here I present experimental and computational modeling evidence which suggests that positional information is represented in subtly different ways in verbal and spatial STM. Specifically, the findings indicate that in verbal STM, groups are coded for their position in a sequence and items are coded for their position in a group. By contrast, in spatial STM groups are coded for their position in a sequence, but items are coded for their position in a sequence, rather than in a group. Findings support the notion that positional information in verbal and spatial STM is represented by modality-specific mechanisms rather than a domain-general system. PMID- 30009675 TI - Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation. AB - INTRODUCTION: Cytomegalovirus (CMV) is a common opportunistic infection that causes significant morbidity and preventable mortality after solid-organ and allogeneic hematopoietic stem cell transplantation. Areas covered: Current strategies of pharmacological treatment of CMV in solid-organ and hematologic stem cell transplantation are reviewed. The role of the newly approved drug, letermovir, and other novel investigational compounds is discussed. The complementary role of viral and immunologic monitoring in guiding the optimal role of pharmacologic agents on the management of CMV after transplantation is highlighted. Advances in immunotherapeutics are highlighted. Expert commentary: With advances in therapeutic and diagnostic modalities, the management of CMV infection and disease after transplantation continues to evolve. The authors provide a succinct yet comprehensive review of the current prevention and treatment for CMV infection and disease in transplant recipients. The role of the newly approved drug, letermovir, for CMV prevention is highlighted in the context of current prevention strategies after allogeneic hematopoietic stem cell transplantation. The emerging role of cell-mediated immunologic monitoring, which complements the established function of viral load testing, is emphasized. Finally, the integration of novel antiviral therapies, standardized molecular tests, immunologic assays, and immunotherapeutics are discussed. PMID- 30009677 TI - Generation of CD34 Fluorescent Reporter Human Induced Pluripotent Stem Cells for Monitoring Hematopoietic Differentiation. AB - Hematopoietic stem and progenitor cells (HSPCs) derived from human induced pluripotent stem cells (hiPSCs) hold great promise for disease modeling, drug screens, and eventually cell therapy approaches. During in vitro differentiation of hiPSCs into hematoendothelial progenitors, the emergence of CD34-positive cells indicates a critical step of lineage specification. To facilitate the monitoring of hematopoietic differentiation of hiPSCs, we established fluorescent reporter cells for the stem and progenitor cell marker CD34. An IRES-GFP (internal ribosome entry site green fluorescent protein) construct was introduced by CRISPR/Cas9 into the 3' untranslated region of one endogenous CD34 allele. Single-cell clones were generated after excision of the floxed puromycin resistance cassette by Cre recombination and correct insertion was confirmed by genotyping polymerase chain reaction and Southern blot. To validate their functionality, the reporter hiPSCs were in vitro differentiated toward CD34+ cells using the STEMdiff Hematopoietic Kit combined with short-term inhibition of GSK3 (glycogen synthase kinase 3). All cells expressing nuclear GFP were positive for cell surface CD34, thus allowing the direct monitoring of the differentiation of hiPSCs into CD34+ cells either by flow cytometry or confocal microscopy. After fluorescence-activated cell sorting, cells displaying high GFP expression exhibited increased colony-forming potential in the MethoCult colony-forming unit assays as compared with CD34+ cells obtained by magnetic-activated cell sorting. In summary, we have generated functional CD34 GFP reporter hiPSCs, which not only permit label-free separation of HSPCs, but also tracing of the emergence and fate of CD34+ progenitors at the single-cell level. PMID- 30009678 TI - Understanding the Effect of Information Presentation Order and Orientation on Information Search and Treatment Evaluation. AB - BACKGROUND: Past research finds that treatment evaluations are more negative when risks are presented after benefits. This study investigates this order effect: manipulating tabular orientation and order of risk-benefit information, and examining information search order and gaze duration via eye-tracking. DESIGN: 108 (Study 1) and 44 (Study 2) participants viewed information about treatment risks and benefits, in either a horizontal (left-right) or vertical (above-below) orientation, with the benefits or risks presented first (left side or at top). For 4 scenarios, participants answered 6 treatment evaluation questions (1-7 scales) that were combined into overall evaluation scores. In addition, Study 2 collected eye-tracking data during the benefit-risk presentation. RESULTS: Participants tended to read one set of information (i.e., all risks or all benefits) before transitioning to the other. Analysis of order of fixations showed this tendency was stronger in the vertical (standardized mean rank difference further from 0, M = +/- .88) than horizontal orientation ( M = +/- 0.71). Approximately 50% of the time was spent reading benefits when benefits were shown first, but this was reduced to ~40% when risks were presented first (regression coefficient: B = -4.52, p < .001). Eye-tracking measures did not strongly predict treatment evaluations, although time percentage reading benefits positively predicted evaluation when holding other variables constant ( B = 0.02, p = .023). CONCLUSION: These results highlight the impact of seemingly arbitrary design choices on inspection order. For instance, presenting risks where they will be seen first leads to relatively less time spent considering treatment benefits. Other research suggests these changes to inspection order can influence multi-option and multi-attribute choices, and represent an area for future research. PMID- 30009679 TI - Postsynaptic GluR2 Involved in Amelioration of Abeta-Induced Memory Dysfunction by KAIXIN-San Through Rescuing Hippocampal LTP in Mice. AB - Kaixin-San (KXS), a Chinese formula, was used to treat "amnesia," a senile dementia in the modern world. This formula was reported to improve behavioral performances in many animal models. This study was designed to explore how KXS has improved amyloid-beta (Abeta)-induced memory dysfunction in mice. The mouse models were achieved through unilateral ventricle injection with Abeta42. The effects of KXS on memory improvement were evaluated by the step-down test. The electrophysiological changes induced by KXS were measured by long-term potentiation (LTP) analysis in the hippocampus in vivo. The expression of glutamate receptor 2 (GluR2) was observed through immunohistochemical staining. Behavioral experiment outcome demonstrated reduced avoidance time and increased error time during the step-down test in the mice of Abeta group. This memory impairment, however, was reversed by KXS. Electrophysiological experiment showed no significant difference between Abeta group and KXS group either in the size or the shape of field excitatory postsynaptic potentiation recorded from perforant path to dentate gyrus pathway. However, LTP in this region was reduced by Abeta and recovered by KXS administration. Moreover, immunohistochemical staining showed increased postsynaptic GluR2 expression in DG area in KXS group. These findings suggest that Abeta results in impairment to memory function of the animals, and KXS protects the animal from memory loss by rescuing LTP through postsynaptic mechanism which refers to increasing GluR2 expression. PMID- 30009680 TI - The healthcare seeking rate of individuals with influenza like illness: a meta analysis. AB - BACKGROUND: Not all individuals with Influenza like illness (ILI) seek healthcare. Knowing the proportion that do is important to evaluate the actual burden and fatality rate of ILI-relevant diseases, such as seasonal influenza and human infection with avian influenza. A number of studies have investigated the healthcare seeking rate, but the results varied from 0.16 to 0.85. We conducted this analysis for better understanding the healthcare seeking rate for ILI, and providing fundamental data for researchers in relevant fields. METHODS: In this meta-analysis, a total of 799 articles, published as of 13 December 2016, were retrieved from Pubmed, Embase, Web of Science and Cochrane, and 11 of them were included after screening. The pooled estimates and factors which influence healthcare seeking rates were analysed. RESULTS: The overall pooled healthcare seeking rate was 0.52 (95% CI: 0.46-0.59). The rate was significantly higher during the H1N1 pandemic in 2009 (0.61, 95% CI: 0.51-0.74), in children (0.56, 95% CI: 0.55-0.57) and in patients with documented fever (0.62, 95% CI: 0.53 0.72) than during non-pandemic periods (0.39, 95% CI: 0.33-0.45), in adults (0.45, 95% CI: 0.42-0.48) and in patients without documented fever (0.44, 95% CI: 0.38-0.50). Meta-regression indicated that these three factors could jointly explain 70.1% of the total heterogeneity among published studies. CONCLUSION: The healthcare seeking rate of ILI patients is needed for estimation of the burden of ILI in the general population based on data from routine ILI sentinel surveillance systems. PMID- 30009681 TI - What affects gait performance during walking while texting? A comparison of motor, visual and cognitive factors. AB - Texting on a cell phone disrupts walkers' gait performance. The performance decrement has been attributed to increased motor demand, decreased visual information and increased cognitive load. However, relative contributions of motor, visual and cognitive factors are poorly understood. Here we quantitatively estimated the relative contributions of these factors by comparing multiple walking conditions. Thirty-two adults walked for 20 m, with or without a dual task on the phone. The dual task was either a cognitively demanding digit ordering task or a casual tapping task. Gait performance was assessed using gait speed, stride length, stride time and stride time variability. Results showed that texting negatively impacted gait performance. Importantly, we found that cognitive factor contributed the most, visual factor the least, and motor factor in between. Our findings resolve the inconsistency in the literature and unambiguously show that motor, visual and cognitive factors caused by simultaneous phone use all contribute to gait alterations. Practitioner Summary: Walking performance is typically worsened when a concurrent phone use task such as texting is performed. We found that visual, motor and cognitive factors contributed to this performance decrement with increasing importance. Besides resolving inconsistency among previous reports, we also raised theoretical and practical concerns for phone use during walking. PMID- 30009682 TI - On the Pitch Strength of Bandpass Noise in Normal-Hearing and Hearing-Impaired Listeners. AB - The psychoacoustic measure pitch strength describes the strength of the tonal sensation evoked by a sound on a scale from weak to strong. For normal-hearing listeners, it was shown in the literature that pitch strength of bandpass noise (relative to the pitch strength of a sinusoid at its center frequency) decreases with increasing bandwidth. This decrease also depends on the center frequency. These effects were often attributed to the frequency selectivity of the auditory system. The present study investigated the relative pitch strength of bandpass noise in hearing-impaired listeners and for comparison in a normal-hearing control group. For the normal-hearing listeners, pitch strength was measured at sound pressure levels of 30 and 70 dB SPL for bandwidths between 5 and 1620 Hz and center frequencies of 375, 750, and 1500 Hz. In addition, two ways of generating the stimuli (filtering in frequency or time domain) were used to compare the data with previous results. Apart from the known effect of center frequency on the change of relative pitch strength with increasing bandwidth, stimulus generation also had a significant influence on the results. Relative pitch strength of bandpass noise in hearing-impaired listeners was measured for bandwidths from 5 to 1620 Hz; the center frequency was 1500 Hz. Compared with the corresponding results of the normal hearing, relative pitch strength was altered in the hearing-impaired listeners. These alterations, however, could not be explained by altered spectral processing in the damaged cochlea alone. PMID- 30009683 TI - Alternative assessment of knee joint muscle balance of soccer players through total work-based hamstring: quadriceps ratios. AB - Isokinetic hamstring-to-quadriceps (H:Q) ratios are frequently used to assess knee muscle strength imbalances and risk of injuries/re-injuries. The use of peak torque (PT) or total work (TW) to estimate joint stability may lead to different results because of the differences between these two neuromuscular variables. Thus, the current study aimed to compare the conventional and functional H:Q ratios calculated by PT and TW. Ninety-three male professional soccer players from Brazilian first division teams performed isokinetic concentric and eccentric contractions of the quadriceps and the hamstrings at 60 degrees /s. Muscle strength balance was calculated using the conventional torque ratio (CTR) and conventional work ratio (CWR), functional torque ratio (FTR) and functional work ratio (FWR) were highly and moderately correlated between them (r = 0.83 and r = 0.73, respectively). The Wilcoxon statistical test revealed significant differences between CTR and CWR, as well as FTR and FWR (p < 0.05). T-test demonstrated significant differences in mean CTR-CWR and FTR-FWR, whereas Bland Altman plots showed non-consistent bias. In addition, the chi-square test demonstrated significant differences between players below the conventional reference values and functional reference values (p < 0.001). In conclusion, TW ratios seem to provide distinct and additional information regarding the H:Q strength balance in professional soccer players. Moreover, taking into account that TW captures torque information throughout the entire range of motion, it is possible that TW ratios represent a more comprehensive assessment of muscle strength imbalance. PMID- 30009684 TI - Perspectives of applied collaborative sport science research within professional team sports. AB - The purpose of the study was to examine the perspectives of both academics and practitioners in relation to forming applied collaborative sport science research within team sports. Ninety-three participants who had previously engaged in collaborative research partnerships within team sports completed an online survey which focused on motivations and barriers for forming collaborations using blinded sliding scale (0-100) and rank order list. Research collaborations were mainly formed to improve the team performance (Academic: 73.6 +/- 23.3; Practitioner: 84.3 +/- 16.0; effect size (ES = 0.54), small). Academics ranked journal articles' importance significantly higher than practitioners did (Academic: Mrank = 53.9; Practitioner: 36.0; z = -3.18, p = .001, p < q). However, practitioners rated one-to-one communication as more preferential (Academic: Mrank = 41.3; Practitioner 56.1; z = -2.62, p = .009, p < q). Some potential barriers were found in terms of staff buy in (Academic: 70.0 +/- 25.5; Practitioner: 56.8 +/- 27.3; ES = 0.50, small) and funding (Academic: 68.0 +/- 24.9; Practitioner: 67.5 +/- 28.0; ES = 0.02, trivial). Both groups revealed low motivation for invasive mechanistic research (Academic: 36.3 +/- 24.2; Practitioner: 36.4 +/- 27.5; ES = 0.01, trivial), with practitioners have a preference towards 'fast' type research. There was a general agreement between academics and practitioners for forming research collaborations. Some potential barriers still exist (e.g. staff buy in and funding), with practitioners preferring 'fast' informal research dissemination compared to the 'slow' quality control approach of academics. PMID- 30009685 TI - Consumer Numeracy and Insurance Design Decisions: An Examination of Inflation Protection Take-Up Among Private Long-Term Care Insurance Policy Holders. AB - Given the rising cost of long-term care (LTC) services, the selection of a private long-term care insurance (LTCi) policy with inflation protection has critical implications for the ability of this coverage to protect against potentially catastrophic LTC expenses. This study examines the effect of consumers' numeric abilities on the decision to add inflation protection to private LTCi policies. Over 40% of current LTCi policies lack inflation protection. Higher scores on a three-question numeracy scale are associated with increases in the probability of choosing inflation protection at the time of policy purchase, with households answering all three questions correctly being 12 percentage points more likely to have this benefit type relative to those with a numeracy score of 0 ( p = .002). Market reforms that simplify the task of evaluating LTCi plans and assessing the value of indexed benefits may be needed to ensure that LTCi policy purchasers are selecting adequate protection against future LTC costs. PMID- 30009686 TI - Toxicity and Toxicokinetic Study of Subcutaneously Administered RPh201 in Minipigs. AB - Mastic gum extracts are widely used as herbal remedies and are being tested for several clinical indications. Nevertheless, information on their safety is limited. RPh201 is an extract of the mastic gum, formulated and stabilized in a proprietary method, which is being developed as a novel drug candidate for neurological indications. The aim of this study was to assess the systemic toxic potential of RPh201, administered twice weekly by subcutaneous injections to minipigs, after 39 weeks of administration followed by a recovery period of 6 weeks. No clinical or dose-related signs were observed, but treatment-related findings were seen at the injection sites of the high-dose animals, composed of abscesses, chronic inflammation, and subcutaneous fibrosis. Abscesses >30 mm in size, graded as marked severity, were confined to the high-dose group and were considered as adverse. Minimal-slight subcutaneous and lymph nodes abscesses seen in control, low, and intermediate doses, related to the vehicle (cottonseed oil), were not considered as adverse. Additionally, minimal-to-slight cystic spaces or vacuolation related to the vehicle were observed in the skin, lymph nodes, kidney, and lungs. These findings were considered not to be adverse. The no observed-adverse-effect level was considered to be 12.5 mg/kg/occasion. PMID- 30009689 TI - Response to Walker et al. (doi: 10.1089/neu.2017.5359): Predicting Long-Term Global Outcome after Traumatic Brain Injury: Development of a Practical Prognostic Tool Using the Traumatic Brain Injury Model Systems National Database. AB - na. PMID- 30009688 TI - Feasibility of DriveFocusTM and Driving Simulation Interventions in Young Drivers. AB - Motor vehicle collisions are the leading cause of death among North American youth, with a high prevalence of distraction-related fatalities. Youth-focused interventions must address detecting (visual scanning) and responding (adjustment to stimuli) to critical roadway information. In this repeated measures study, we investigated the feasibility (i.e., recruitment and sample characteristics; data collection procedures; acceptability of the intervention; resources; and preliminary effects) of a DriveFocusTM app intervention on youth's driving performance. Thirty-four youth participated in a 9-week protocol (retention rate = 89.7%; adherence rate = 100%). No participants experienced simulator sickness. A preliminary nonparametric evaluation of the results ( n = 34) indicated a statistically significant decrease in the number of visual scanning, F(2, 68) = 3.769, p = .028, and adjustment to stimuli, F(2, 68) = 6.759, p = .002, errors between baseline, midpoint, and posttest. This study lays the foundation to support a targeted intervention trial to improve youth's attention to critical road information, building on their mobile technology preferences. PMID- 30009687 TI - Conflicts of CpG density and DNA methylation are proximally and distally involved in gene regulation in human and mouse tissues. AB - The relationship between CpG content and DNA methylation has attracted considerable interest in recent years. Direct or indirect methods have been developed to investigate their regulatory functions based on various hypotheses, large cohort studies, and meta-analyses. However, all of these analyses were performed at units of CpG blocks and, thus, the influence of finer genome structure has been neglected. Herein, we present a novel algorithm of base-pair resolution to systematically investigate the relationship between CpG contents and DNA methylation. By introducing the concept of 'complementary index' we examined the methylomes of 34 adult and 7 embryonic tissues and successfully fitted the relationship of DNA methylation and CpG density into a nonlinear mathematical model. A further algorithm was developed to locate the regions where CpG density does not match expectations from the model, termed 'conflict of gap' (COG) regions. Interestingly, COGs are highly concordant in human and mouse and their distributions display a tissue-specific pattern. Based on COG methylation patterns we correctly classified tissues according to their function or origin. We demonstrate that COGs based on our method can reveal more and deeper information than traditional differential methylation region (DMR) approaches. We also found that when COGs are located near to transcription start site (TSS), these regions can determine which promoters will be utilized for initiating gene transcription. Furthermore, COGs located far from the TSS perform as enhancers in terms of histone modification, sequence conservation, transcription factor binding, and DNase I-hypersensitivity. PMID- 30009691 TI - Effects of 900-MHz electromagnetic fields exposure throughout middle/late adolescence on the kidney morphology and biochemistry of the female rat. AB - The effect of the electromagnetic field (EMF) established when cell phones are in use on human health, and particularly the head, has been the subject of major scientific research. Phones are usually carried near the lumbar region when not in use, and the kidneys will also inevitably be affected by such fields. We investigated the effects on the kidneys of female rats exposed to a continuous 900-megahertz (MHz) EMF for 1 h daily in mid-late adolescence. Control, sham, and EMF groups were established. The EMF was applied to the application group rats daily on postnatal days 35-59. A pseudo-megahertz effect was applied to sham group rats. All animals were euthanized on postnatal day 60. Right kidney tissues were subjected to routine procedures. Malondialdehyde, total antioxidant status, and total oxidant status (TOS) were investigated in left kidneys, and the oxidative stress index (OSI) was also calculated from these. Histopathological analysis revealed no pathology in either the control or sham groups. However, findings including hemorrhage in glomerulus, vacuolization and irregularity in the proximal and distal tubular epithelium, diffuse glomerular degeneration and edema, occasional degeneration in Bowman capsules, hemorrhage in the medullary region, disturbed nucleus location and morphology, and tubular edema in the cortex were observed in the EMF groups. TOS and OSI values were lower in the EMF group (9.4316 +/- 1.0211 and 0.8461 +/- 0.0826, respectively) and the sham group (8.2171 +/- 0.6437 and 0.7358 +/- 0.0545, respectively) than in the control group (11.1522 +/- 1.3389 and 1.0085 +/- 0.1174, respectively) ( p < 0.05). In conclusion, exposure to a continuous 900-MHz EMF for 1 h daily during middle and late adolescence may cause various changes in the female rat kidney at postnatal day 60. PMID- 30009692 TI - Municipal solid waste management: Constraints and opportunities to improve capacity of local government authorities of Phnom Penh Capital. AB - Solid waste management is a challenge for Phnom Penh city owing to the increasing volume of waste produced and insufficient collection capacity. Sustainable management is required in response to continuing population growth and urbanisation. This article aims to examine the status and constraints of solid waste management in Phnom Penh and discuss the performance of local government authorities to propose possible mechanisms and strategies to improve the system. Data were collected through literature reviews, key informant interviews and focus group discussions with the local government authorities. Six performance measures were used as assessment variables, including technical, environmental, institutional and organisational, financial and economic, social and cultural, and policy and legal factors. Limited institutional capacity and performance are the consequence of insufficient decentralisation power and allocation of budget and workforce for promoting technological and environmentally sustainable practices. Lack of cooperation and coordination among relevant agencies led to their unwillingness to participate in management performance. A decentralisation and provision of management services in the public-private partnership would enable operational procedures that enhance accountability, transparency, efficiency, and productivity at the local level. PMID- 30009693 TI - Drug-Induced Nephrotoxicity and Drug Metabolism in Renal Failure. PMID- 30009694 TI - Sodium-glucose Co-transporters 2 Inhibitors: The Miraculous Route from Hypoglycemic to Cardiovascular Drugs. PMID- 30009695 TI - Synthetic Peptide Libraries. From random mixtures to in vivo testing. AB - Combinatorially generated molecular repertoires have been largely used to identify novel bioactive compounds. Ever more sophisticated technological solutions have been proposed to simplify and speed up such process, expanding the chemical diversity space and increasing the prospect to select new molecular entities with specific and potent activities against targets of therapeutic relevance. In this context, random mixtures of oligomeric peptides were originally used and since more than 25 years they represent a continuous source of bioactive molecules with potencies ranging from the subnM to microM concentration. Synthetic peptide libraries They are indeed still employed as starting "synthetic broths" of structurally and chemically diversified molecular fragments from which lead compounds can be extracted and further modified. Thousands of studies have been reported describing the application of combinatorial mixtures of synthetic peptides with different complexity and engrafted on diverse structural scaffolds for the identification of new compounds which have been further developed and also tested in in vivo models of relevant diseases. We briefly review some of the most used methodologies for library preparation and screening and the most recent case studies appeared in the literature where compounds have reached at least in vivo testing in animal or similar models. Recent technological advancements in biotechnology, engineering and computer science have suggested new options to facilitate the discovery of new bioactive peptides. In this instance, we anticipate here a new approach for the design of simple but focused tripeptide libraries against druggable cavities of therapeutic targets and its complementation with existing approaches. PMID- 30009696 TI - The role of matrix Gla protein (MGP) in vascular calcification. AB - Matrix Gla protein (MGP) is a vitamin K-dependent protein, which is synthesized in bone and many further mesenchymal cells, which is also highly expressed by vascular smooth 1muscle cells (VSMCs) and chondrocytes. Numerous studies have confirmed that MGP acts as a calcification-inhibitor although the mechanism of action is still not fully understood. The modulation of tissue calcification by MGP is potentially regulated in several ways including direct inhibition of calcium-phosphate precipitation, the formation of matrix vesicles (MVs), the formation of apoptotic bodies (ABs), and trans-differentiation of VSMCs. MGP occurs as four species, i.e. fully carboxylated (cMGP), under-carboxylated, i.e. poorly carboxylated (ucMGP), phosphorylated (pMGP), and non-phosphorylated (desphospho, dpMGP). ELISA methods are currently available that can detect the different species of MGP. The expression of the MGP gene can be regulated via various mechanisms that have the potential to become genomic biomarkers for the prediction of vascular calcification (VC) progression. VC is an established risk factor for cardiovascular disease and is particularly prevalent in those with chronic kidney disease (CKD). The specific action of MGP is not yet clearly understood but could be involved with the functional inhibition of BMP-2 and BMP 4, by blocking calcium crystal deposition and shielding the nidus from calcification. PMID- 30009697 TI - Methodological aspects of phytosterol measurements in biological samples. AB - Phytosterol measurement has gained a lot of interest during the last two decades after foods and supplements with added 4-desmethyl phytosterols were recognized and used as effective and safe non-pharmacologic hypocholesterolemic agents, and also after the mechanisms of intestinal absorption and hepatic excretion of sterols were unraveled. In addition, the wide use of serum phytosterols as biomarkers of cholesterol absorption has increased the interest in their measurement. In this review the basic methods are discussed without going into details in the practical operations. The analysis includes first lipid extraction and saponification from various biologic matrices such as serum/plasma, feces, or tissues, after which the individual sterols are separated by adsorption chromatography (gas-liquid or liquid or high performance liquid chromatography) based on the polarity of the various sterols. We also deal with some specific aspects of phytosterol measurements in biological samples such as the need of harmonization of their analysis in biological samples, the discrepancies in results of sitosterol and campesterol concentrations between different studies, and what is known about their biological day-to-day fluctuation. Phytosterols have a remarkable role in human health, so that their complicated and time consuming measurements call attention to routine ways of standardization between the sterol research laboratories. PMID- 30009698 TI - Drug Repurposing in the Development of Anticancer Agents. AB - BACKGROUND: Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established. OBJECTIVE: This review provides an overview of anti-cancer drug development strategies which is one of the important areas of drug re structuring. METHODS: Repurposed drugs for cancer treatments are classified by their pharmacological effects. The successes and failures of important repurposed drugs as anti-cancer agents are evaluated in this review. RESULTS AND CONCLUSION: Drugs could have many off-target effects, and can be intelligently repurposed if the off-target effects can be employed for therapeutic purposes. In cancer, due to the heterogeneity of the disease, often targets are quite diverse, hence a number of already known drugs that interfere with these targets could be deployed or repurposed with appropriate research and development. PMID- 30009699 TI - The role of adipokines in the establishment and progression of head and neck neoplasms. AB - Adipokines constitute a family of protein factors secreted by white adipose tissue (WAT), that regulate the functions of WAT and other sites. Leptin, adiponectin, resistin, are the main adipokines present in serum and saliva, targeting several tissues and organs, including vessels, muscles, liver and pancreas. Besides body mass regulation, adipokines affect glucose homeostasis, inflammation, angiogenesis, cell proliferation and apoptosis, and other crucial cell procedures. Their involvement in tumor formation and growth is well established and deregulation of adipokine and adipokine receptors' expression is observed in several malignancies including those located in the head and neck region. Intracellular effects of adipokines are mediated by a plethora of receptors that activate several signaling pathways including Janus kinase/ Signal transducer and activator of transcription (JAK/ STAT), Phospatidylinositol kinase (PI3/ Akt/ mTOR) and Peroxisome proliferator-activated receptor (PPAR). The present review summarizes the current knowledge on the role of adipokines family members in carcinogenesis of the head and neck region. The diagnostic and prognostic significance of adipokines and their potential role as serum and saliva biomarkers is also discussed. PMID- 30009700 TI - Quercetin and its Natural Sources in Wound Healing Management. AB - Giving a glance to the report Wound Care Market by Product up-to-date at 2017, we can see that wound care market is expected to reach USD 22.01 billion by 2022 from USD 18.35 billion at a CAGR of 3.7%. Numerous are the factors driving the growth of this market, including the increasing prevalence of chronic wounds and acute wounds, increasing aged population, rising R&D activities and advancement in the field of wound care research. Advanced wound management products are accounted for the largest market share in 2017. These evidences meaning that the wound care research represents a Clinical Emergency other than an interesting Marketing tool. Drugs therapies so far fight efficaciously the opportunistic pathologies derived from chronic wounds, although an unsolved challenge is still finding a useful remedy to correct the impaired wound healing process and overcome the chronic wound state, to avoid bacterial rising and severe pain. Traditional medicinal plants have been widely used in the management of wounds and different plant extracts have been evaluated for their wound healing properties through both in vitro and in vivo studies. Their phytochemical components in particular quercetin, which contributes to their remedial properties in wound repair. Quercetin has important biological activities related to the improvement of the wound healing process. The present review discusses and focuses on the latest findings of the wound healing properties of quercetin, alone or as a part of plant extract, and its role as a new frontier in wound repair. PMID- 30009701 TI - Calcium Channel Blockers in Restoration of Endothelial Function: Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Clinical evaluation of the endothelial function (EF) is becoming an essential step in the quality assessment of cardiovascular risk prevention and rational pharmacotherapy of cardiovascular disorders. The existing pieces of evidence suggested that calcium channel blockers (CCB) can induce positive effects on impaired EF. OBJECTIVE: To evaluate the effects of CCB on EF we have performed a meta-analysis of available data from randomized and placebo controlled or other treatment-controlled clinical studies encompassing effects of CCB on EF, as measured by flow-mediated dilation (FMD) of the brachial artery. METHODS: The relevant clinical studies were searched by the systematic exploration of the appropriate databases until November 30, 2017. A random-effect model was conducted. The primary outcome was the percentage change in FMD between the baseline and the final levels in response to investigated drugs. RESULTS: Fifteen randomized clinical studies with 33 arms were identified. CCB improved FMD more pronounced than thiazide diuretics - TD (3 studies, 157 participants, WMD=2.08%, 95% CI=0.35-3.80%; P=0.02). Oppositely, ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) notably improved FMD if compared to CCB (CCB vs. ACEI: 5 studies, 533 participants, WMD = -1.62%, 95% CI = -2.74% to -0.50%; P=0.005; and CCB vs. ARB: 9 studies, 669 participants, WMD = -1.52%, 95% CI = 2.22% to -0.81%; P=0.0001). CCB effects on EF were similar to those evoked by beta blockers or placebo. CONCLUSION: CCB improved EF to a more prominent extent only if paralleled to TD, while inversely; ACEI and ARB were more effective in augmenting FMD. PMID- 30009702 TI - Antimicrobial Peptides: Amphibian Host Defense Peptides. AB - Antimicrobial peptides (AMPs) are one of the most common components of the innate immune system that protect multicellular organisms against microbial invasion. The vast majority of AMPs are isolated from the frog skin. Anuran (frogs and toads) skin contains abundant AMPs that can be developed therapeutically. Such peptides are a unique but diverse group of molecules. In general, more than 50% of the amino acid residues form the hydrophobic part of the molecule. Normally, there are no conserved structural motifs responsible for activity, although the vast majority of the AMPs are cationic due to the presence of multiple lysine residues; this cationicity has a close relationship with antibacterial activity. Notably, recent evidence suggests that synthesis of AMPs in frog skin may confer an advantage on a particular species, although they are not essential for survival. Frog skin AMPs exert potent activity against antibiotic-resistant bacteria, protozoa, yeasts, and fungi by permeating and destroying the plasma membrane and inactivating intracellular targets. Importantly, since they do not bind to a specific receptor, AMPs are less likely to induce resistance mechanisms. Currently, the best known amphibian AMPs are esculentins, brevinins, ranacyclins, ranatuerins, nigrocin-2, magainins, dermaseptins, bombinins, temporins, and japonicins-1 and -2, and palustrin-2. This review focuses on these frog skin AMPs and the mechanisms underlying their antimicrobial activity. We hope that this review will provide further information that will facilitate further study of AMPs and cast new light on novel and safer microbicides. PMID- 30009703 TI - Cysteine-Targeted Irreversible Inhibitors of Tyrosine Kinases and Key Interactions. AB - Tyrosine kinases are a subgroup of the larger class of protein kinases that transfer phosphate groups from ATP to various amino acid residues. By phosphorylating the tyrosine residues, the tyrosine kinases are responsible for the activation of various proteins through signal transduction cascades, which serves as a ubiquitous mechanism of cell signaling. The frequent success of many tyrosine kinase inhibitors (TKIs) in clinical success and disease-causing mutations in protein kinases suggests that a large number of kinases may represent therapeutically relevant targets. To date, most of the clinical and preclinical TKIs are ATP-competitive non-covalent inhibitors, which achieve their selectivity by recognizing the unique features of specific protein kinases. Of growing interest now in the scientific community is the development of irreversible inhibitors that form covalent bonds with cysteines or other nucleophilic residues in the ATP binding pocket. Irreversible TKIs have many potential advantages including prolonged pharmacodynamics, reasonable compound design suitability, high potency, and the ability to validate pharmacological specificity by mutations in reactive cysteine residues. Here, we review recent efforts to develop cysteine-targeting irreversible TKIs and to discuss their patterns of configuration that identify adenosine triphosphate binding pockets and their biological activities. PMID- 30009704 TI - C-cinnamoyl glycosides: an emerging "tail" for the development of selective carbonic anhydrase inhibitors. AB - Attachment of different tails to the well-known carbonic anhydrase (CA) pharmacophores has led to the development of several new CA inhibitors (CAIs). A very good example of such "tails" is constituted by carbohydrates, which represent a wide range of chemotypes, leading thus to a high number of new CAIs. In the last years, several C-cinnamoyl glycosides containing different scaffolds have been prepared and investigated as carbonic anhydrase inhibitors, showing that some of them are very potent and selective CAIs. This article will review the latest developments in the synthesis and biological activity of these C glycosides. PMID- 30009705 TI - Synergistic Interplay of The Co-administration of Rifampin And Newly Developed Anti-TB Drug: Could It Be a Promising New Line of TB Therapy? AB - BACKGROUND: Rifampin resistance has dampened the existing efforts being made to control the global crisis of Tuberculosis and antimicrobial resistance in general. Previous studies that attempted to provide insights into the structural mechanism of Rifampin resistance did not utilize the X-ray crystal structure of Mycobacterium tuberculosis RNA polymerase due to its unavailability. METHODS/RESULTS: We provide an atomistic mechanism of Rifampin resistance in a single active site mutating Mycobacterium tuberculosis RNA polymerase, using a recently resolved crystal structure. We also unravel the structural interplay of this mutation upon co-binding of Rifampin with a novel inhibitor, D-AAP1. Mutation distorted the overall conformational landscape of Mycobacterium tuberculosis RNA polymerase, reduced binding affinity of Rifampin and shifted the overall residue interaction network of the enzyme upon binding of only Rifampin. Interestingly, co-binding with DAAP1, though impacted by the mutation, exhibited improved Rifampin binding interactions amidst a distorted residue interaction network. CONCLUSION: Findings offer vital conformational dynamics and structural mechanisms of mutant enzyme-single ligand and mutant enzyme-dual ligand interactions which could potentially shift the current therapeutic protocol of Tuberculosis infections. PMID- 30009707 TI - Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects. AB - Opioid analgesics, such as morphine, are widely employed in the treatment of moderate to severe pain. However, they are notorious for abuse liability and respiratory depression. Therefore circumventing the side effects, such as euphoria, addiction, respiratory depression and gastrointestinal adverse reactions, is of extensive importance. Recently, a large number of research results have revealed that such morphine-like side effects are not inevitable, and they focus on the novel approaches to disconnecting the analgesics from adverse effects. In this review, we mainly discuss the approaches including biasing the GPCRs over beta-arrestin2 recruitment (TRV130, PZM21, HS665), the positive allosteric modulators of the MOR (BMS-986122) and multiple agonists of opioid receptors subtypes (SNC80, DPI-125). Besides these, we also introduce the key protein sites of MOR and beta-arrestin2 recruitment briefly. PMID- 30009706 TI - Substituted Aminobenzothiazole Derivatives of Tacrine: Synthesis and Study on Learning and Memory Impairment in Scopolamine-Induced Model of Amnesia in Rat. AB - BACKGROUND: Currently, there is no conclusive cure for Alzheimer's disease (AD) and existing treatments mainly offer symptomatic relief. Dysfunction of the cholinergic system plays an important role in pathogenesis of AD. Tacrine (1, 2, 3, 4-tetrahydroacridin-9-amine, I) was the first approved agent for the palliative therapy of AD but its use is associated with some complications. Development of novel multi target derivatives of Tacrine with lower complications is strongly warranted. In this study, new aminobenzothiazole (1-5, with many useful biological and pharmacological properties) analogues (II-VI) were synthesized by changing of amine moiety of I. Then, the effects of these new compounds on learning and memory impairment in scopolamine-induced model of amnesia were studied and the outcomes were compared with control and Tacrine groups in rat. MATERIAL AND METHODS: The rats received Tacrine or its derivatives (II-VI) i.p. for two weeks at a dose of 10 mg/kg. For induction of amnesia, scopolamine at a dose of 1 mg/kg was daily administered i.p. started on day-8 till the end of the study. Behavioral experiments including Y-maze, novel object recognition (discrimination) and passive avoidance paradigms were conducted at week 2. RESULTS: Data analysis showed that some Tacrine derivatives, especially V with 2-amino, 6-nitrobenzothiazole moiety, could markedly and significantly improve alternation score, discrimination ratio and step through latency compared to control and Tacrine groups. CONCLUSION: These findings indicated that some of these derivatives (especially compounds IV and V) are capable to mitigate learning and memory deficits in scopolamine-induced model of amnesia in rats and may have potential benefit in management of patients with AD. PMID- 30009708 TI - Lipid Based Aqueous Core Nanocapsules (ACNs) for Encapsulating Hydrophillic Vinorelbine Bitartrate: Preparation, Optimization, Characterization and In vitro Safety Assessment for Intravenous Administration. AB - BACKGROUND: Vinorelbine bitartrate (VRL) is an antimitotic agent approved by FDA for breast cancer and non-small cell lung cancer (NSCLC) in many countries. However, high aqueous solubility and thermo degradable nature of VRL limited the availability of marketed dosage forms. OBJECTIVES: The current work is focused on the development of lipid based aqueous core nanocapsules which can encapsulate the hydrophilic VRL in the aqueous core of nanocapsules protected with a lipidic shell which will further provide a sustained release. METHODS: The ACNs were prepared by double emulsification technique followed by solvent evaporation. Box Behnken Design was utilized to optimize the formulation and process variables. Thirteen batches were generated utilizing lipid concentration, surfactant concentration and homogenizer speed as dependent variables (at three levels) and particle size and encapsulation efficiency as critical quality attributes. The ACNs were characterized for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, morphology by Transmission Electron Microscopy (TEM) and in vitro release. The ACNs were further evaluated for safety against intravenous administration by haemocompatibility studies. RESULTS: Results demonstrated that lipidic nanocapsules enhanced the entrapment efficiency of VRL up to 78%. Transmission Electron Microscopy revealed spherical shape of ACNs with core-shell structure. The GMS-VRL-ACNs showed that release followed Korsemeyer peppas kinetics suggesting Fickian diffusion. Moreover, the compliance towards haemocompatibility studies depicted the safety of prepared nanocapsules against intravenous administration. CONCLUSION: ACNs were found to be promising in encapsulating high aqueous soluble anticancer drugs with enhanced entrapment and safety towards intravenous administration. PMID- 30009709 TI - Treatment of Latent Autoimmune Diabetes in Adults: What Is Best? AB - Latent autoimmune diabetes in adults (LADA), although formally classified as type 1 diabetes (T1D), very often (at least in Western countries) appear clinically with type 2 diabetes (T2D)-like features as overweight and insulin resistance. LADA patients do not need exogenous insulin at the time they are diagnosed with diabetes, but a large percentage will within a few years develop need for such treatment. The decline in beta cell function progresses much faster in LADA than in T2D, presumably because of the ongoing autoimmune assault in LADA, and therefore necessitates insulin therapy much earlier in LADA than in T2D. Despite high prevalence of LADA (about 10% of the total diabetic population in many countries), the treatment of LADA patients is far less elucidated than is the case for T1D and T2D. Finding a treatment strategy for LADA from the time of diagnosis, that can reduce the decline of beta cell function, ensure adequate metabolic control and thereby reduce the risk of diabetic complications is this an important clinical challenge. Conclusions from randomized treatment studies do so far not indicate an optimal treatment strategy in LADA. This review aims to give an overview of current practices for the medical treatment of LADA as well as an update on results from recent studies on the treatment of the disease. PMID- 30009710 TI - Environmental (Lifestyle) Risk Factors For Lada. AB - Background To prevent diabetes it is important to identify common, modifiable risk factors in the population. Such knowledge is extensive for type 2 diabetes but limited for autoimmune forms of diabetes. Objective This review aims at summarizing the limited literature on potential environmental (lifestyle) risk factors for LADA. Method A pubmed search identified 15 papers that estimated the risk of LADA in relation to lifestyle. These were based on data from two population-based studies; a Swedish case-control study or a Norwegian cohort study. Results Studies published to date indicate that the risk of LADA is associated with factors promoting insulin resistance and type 2 diabetes such as overweight, physical inactivity, smoking, low birth weight, sweetened beverage intake and moderate alcohol consumption (protective). There is also some indication of potential effects on autoimmunity exerted by intake of coffee (harmful) and fatty fish (protective). This supports the concept of LADA as a hybrid form of diabetes with an etiology that includes both factors associated with insulin resistance and autoimmunity. Conclusion These findings indicate that LADA may in part be preventable through the same lifestyle modifications as type 2 diabetes including weight loss, physical activity and smoking cessation. Current knowledge is however hampered by the small number of studies and the fact that they exclusively based on Scandinavian populations. There is a great need for additional studies on the role of lifestyle factors in the development of LADA. PMID- 30009711 TI - LADA: a type of diabetes in its own right? AB - Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than "classical" type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive for LADA this form of diabetes displays phenotypic characteristics that distinguishes it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and life style factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA. PMID- 30009712 TI - A form of autoimmune diabetes in adults named LADA - an update on essential features and controversies. AB - Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than "classical" type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis has been challenged. Despite the absence of a genetic background that is exclusive for LADA this form of diabetes displays phenotypic characteristics that distinguishes it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and life style factors, something that poses problems as to therapy and follow-up perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA. PMID- 30009713 TI - Autoantibodies for Cardiac Channels and Sudden Cardiac Death and its Relationship to Autoimmune Disorders. AB - Sudden cardiac death (SCD) is an unexpected death caused by heart dysfunction. Autoantibodies against cardiac proteins may be potentially involved in the occurrence and progression of cardiac disease and SCD. The first report on the role of autoantibodies in idiopathic dilated cardiomyopathy appeared in the 1980s. In recent years new studies on the effects of the presence of specific autoantibodies and their relationship to ventricular arrhythmias and SCD were published. The purpose of the current mini-review is to analyze the results of the research studies focused on the relationship between anti-cardiomyocyte autoantibodies and SCD with respect to autoimmune disorders. According to our analysis, more research is needed to understand the role of these autoantibodies against cardiac proteins in the SCD pathogenesis, and potentially employ this knowledge for improving prognosis of SCD. PMID- 30009714 TI - Study of Adverse Drug Effects of Direct-Acting Antivirals for Chronic HCV Infection at Fayoum Governorate, Egypt - A Pharmacovigilance Study. AB - BACKGROUND: Different combinations of Direct Antiviral Agents (DAAs) have been used against different Hepatitis C Virus (HCV) genotypes and in different types of patients. Despite being effective and characterized by a very low rate of adverse effects in clinical trials, few data are available on adverse events in real life studies. OBJECTIVES: The aim of this study was to identify the incidence and pattern of Adverse Drug Reactions (ADRs) caused by DAAs; daclatasvir and sofosbuvir and their combination with ribavirin and to assess the causality and the severity of the reported ADRs. METHODS: A prospective observational study was conducted over six months at treatment HCV center of Health Insurance Hospital in Fayoum Governorate, Egypt. A pre-tested, interviewed structured questionnaire was used by authors to gather required data from 345 enrolled patients regarding demographics, co-morbidity and ADRs. Causality and severity of ADRs were assessed. RESULTS: According to our data. we have found that 75.7% (261out of 345) patients reported 36 different ADRs involving different systems, of these 1.2% experienced Serious Adverse Events (SAEs), including three deaths (0.9%). A majority of ADRs were more significantly reported with ribavirin-containing regimen. Out of 345 patients, 23.5% have comorbidities. Among them, 92.6% reported ADRs. Causality assessment of ADRs by WHO-UMC criteria revealed that 38.89% were probable while 61.11% were possible. CONCLUSION: New antiviral drugs require careful follow-up of any significant adverse event that may occur and can affect adherence. Special population as the elderly and those with comorbidities should always be managed with caution to avoid development of serious side effects. PMID- 30009715 TI - Real life Egyptian experience of Daclatasvir plus Sofosbuvir with Ribavirin in naive difficult to treat HCV patients. AB - Background Chronic infection with Hepatitis C virus (HCV) is considered as a major cause for developing liver cirrhosis and hepatocellular carcinoma. A new era in HCV treatment is ongoing using direct acting antiviral activity (DAA). The first approved DAA drug was Sofosbuvir which has a high tolerability and preferable pharmacokinetic profile. Another recently developed drug is Daclatasvir a first-in-class HCV NS5A replication complex inhibitor. Both drugs are administered orally once daily and have potent antiviral activity with wide genotypic coverage. Methods In the outpatient clinic, one hundred and fifty naive difficult to treat chronic HCV patients were recruited from Tropical Medicine Department at Fayoum public hospital. A combination of Daclatasvir (60 mg) and Sofosbuvir (400 mg) (DCV/SOF) has been administered for those patients once daily with Ribavirin (1200 mg or 1000 mg based on patients' weight on two divided doses) over a period of 12 weeks. All patients have been followed up for clinical, laboratory assessment and HCV PCR to detect the efficacy and safety of the therapy. Results Sustained Virologic Response rate (SVR12) was achieved in the vast majority of patients (90.67%). Cirrhotic patients showed lower SVR compared to non-cirrhotic patients (88.89% vs 90.91%, respectively). Around half of the patients (49.33%) developed adverse events (AEs) during treatment. The most common AEs were headache, fatigue and abdominal pain Conclusion The available evidence seems to suggest that combination therapy of (DCV/SOF with RBV) in the treatment of chronic HCV genotype IV naive difficult to treat patients either cirrhotic or non-cirrhotic is safe and effective. Monitoring for clinical and laboratory hepatic parameters was the basis for these findings. PMID- 30009716 TI - Overexpression of hepassocin in diabetic patients with nonalcoholic fatty liver disease may facilitate increased hepatic lipid accumulation. AB - BACKGROUND & AIMS: Insulin resistance is the real determinant of both Nonalcoholic fatty liver disease (NAFLD) and diabetes, and can facilitate the accumulation of triglycerides in the liver. Overexpression of hepassocin (HPS) increased the accumulation of hepatic fat and NAFLD activity scores (NAS) in mice. The aim of this study was to investigate the relationship between hepassocin and steatosis of the liver in diabetic patients with or without NAFLD in humans. METHODS: The study enrolled 60 patients plus 20 healthy controls that were divided into 4 groups: Group I: included 20 patients who were diagnosed as diabetes mellitus type 2, Group II: included 20 patients who were diagnosed as nonalcoholic fatty liver disease (NAFLD), Group III: included 20 patients who were diagnosed as diabetes type 2 and NAFLD, and Group IV (control group): included 20 healthy person or controls who were matched in age and sex with patients group. All patients and controls were subjected to full history taking, thorough clinical examination, laboratory investigations including: measurement of serum hepassocin in peripheral blood by ELISA technique. RESULTS: There was a significant overexpression of serum hepassocin in patients with type 2 diabetes and NAFLD patients (Group 3) mostly than diabetic patients (Group 1) and even than non-alcoholic fatty liver disease (Group 2). CONCLUSION: This study provides evidence that increased HPS may facilitate increased hepatic lipid accumulation with NAFLD and type 2 diabetes. PMID- 30009717 TI - Proopiomelanocortin (POMC) sequencing and developmental delay: Preliminary evidence for a SNP in the 3' UTR region of the POMC gene-Possible relevance for biological risk and self-injurious behavior. AB - The proopiomelanocortin (POMC) molecule has been implicated in models of self injurious behavior (SIB) in neurodevelopmental disorders, but it has never been specifically sequenced in search of base specific polymorphisms. The empirical focus of this preliminary study was to sequence the POMC gene in 11 children (mean age = 41.8 months, range = 12-60 months; 73% male) with clinical concerns regarding global developmental delay, 5 with reported self-injury. Genomic DNA was extracted from blood samples, and the POMC gene was amplified by specific oligonucleotide primers via polymerase chain reaction. The amplified gene products were sequenced by the University of Minnesota Genomic Center, and the results were analyzed using Sequencher software. A single nucleotide polymorphism (SNP), 1130 C>T, was found in the 3' untranslated region (UTR) of two samples (one of whom had SIB). The program TargetScanHuman was used to predict the function of this mutation. Variant c.1130 C= 2 mg/L, the difference was not statistically significant (chi2 = 1.129, P = 0.288). The effective rate was 72.92% (35/48) with trough levels < 10 mg/L vs. 82.93% (34/41) with trough levels >= 10 mg/L, the difference was not statistically significant (chi2 = 1.272, P = 0.259). There were 4 cases of vancomycin associated nephrotoxicity, the incidence of nephrotoxicity was 4.49%, and the vancomycin serum trough levels were 17.22-28.53 mg/L. There were 33 cases of liver dysfunction, and elevated gamma-glutamine transferase, alkaline phosphatase and aspartate aminotransferase were most common. There were 2 cases of neutropenia and 2 patients appeared rash during vancomycin period. CONCLUSIONS: Treatment outcomes were similar regardless of vancomycin MIC and serum trough level. The incidence of vancomycin associated nephrotoxicity rises apparently when serum trough level is over 15 mg/L. Clinical Trial Registry: Chinese Clinical Trail Registry, ChiCTR-OPC-16007920. PMID- 30009728 TI - [Evaluation value of the quick sequential organ failure assessment score on prognosis of intensive care unit adult patients with infection: a 17-year observation study from the real world]. AB - OBJECTIVE: To investigate the predictive value of quick sequential organ failure assessment (qSOFA) score on the prognosis of adult patients with infection in intensive care unit (ICU). METHODS: A retrospective analysis was conducted on the clinical data of the infected patients in the ICU of the 401st Hospital of the People's Liberation Army from August 1st, 2000 to December 31st, 2017. The clinical data included patients' gender, age, basic diseases, etc.; the worst values of vital signs and laboratory test results within 24 hours of admission were recorded, the scores of the qSOFA, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation II (APACHE II) were calculated separately; the outcome of ICU was recorded. The predictive values of three scoring systems were evaluated by receiver operating characteristic curve (ROC). RESULTS: Excluding patients with incomplete clinical data, cancer and immunosuppressive patients, a total number of 1 059 patients were enrolled in this study, with 679 males and 380 females, the average age was 72.57+/-16.06, the ICU mortality was 35.32% (374/1 059). The ROC curve analysis showed that the areas under ROC curve (AUC) of APACHE II, SOFA, qSOFA scores to predict the prognosis of infected patients were 0.713, 0.744 and 0.662, respectively. Although the AUC of qSOFA in predicting prognosis was significantly lower than that of other two scoring systems (both P < 0.05), but it still had some predictive ability. According to the Youden index, the best cut-off point for qSOFA was 2 to evaluate the prognosis of the infection, and the sensitivity was 71.65%, the specificity was 53.87%, the positive likelihood ratio was 1.55, the negative likelihood ratio was 0.53, the positive predictive value was 0.426, the negative predictive value was 0.799, and the accuracy was 59.62%. The mortality of the infected patients was increased with qSOFA score, and the mortality difference among patients with different qSOFA scores was statistically significant (chi2 = 84.605, P = 0.000). The patients were divided into two groups according to the cut-off value of qSOFA, and the mortality in qSOFA score >=2 group was higher than that in qSOFA score < 2 group [odds ratio (OR) = 2.767, 95% confidence interval (95%CI) = 2.116-3.617, P = 0.000]. CONCLUSIONS: qSOFA, SOFA and APACHE II scores have the capability of predicting the outcome for the infected patients. qSOFA score is expected to be a quick and simple tool to judge the prognosis of ICU infection patients because of its advantages of quick acquisition. PMID- 30009729 TI - [Comparison of neurologic outcome between active abdominal compression decompression cardiopulmonary resuscitation and standard cardiopulmonary resuscitation in asphyxia cardiac arrest]. AB - OBJECTIVE: To compare the neurologic outcome after the active abdominal compression-decompression cardiopulmonary resuscitation (AACD-CPR) and chest compression cardiopulmonary resuscitation (STD-CPR) in asphyxia cardiac arrest (CA). METHODS: A prospective multicenter randomized controlled trial (RCT) was conducted. Adult patients with CA because of asphyxia such as drowning, airway obstruction admitted to Zhengzhou People's Hospital and Sanmenxia Central Hospital from June 2014 to December 2017 were enrolled. With the informed consent of patients' families, patients were divided into AACD-CPR group and STD-CPR group according to random number table method. The blood from median cubital vein or basilic vein were extracted at 1, 6, 12, 24 and 48 hours after the return of spontaneous circulation (ROSC), and the levels of S100B protein and neuron specific enolase (NSE) were detected by enzyme linked immunosorbent assay. Neurological outcome was classified according to cerebral performance classification (CPC) after 3 months. RESULTS: A total of 183 patients were selected, including 78 ROSC patients after CPR. Patients with CA > 8 minutes and rescue time > 1 hour were excluded, 69 ROSC patients (36 in STD-CPR group and 33 in AACD-CPR group) were finally included. After ROSC, the levels of S100B protein and NSE in blood of two groups were increased gradually, reaching the peak at 6 hours, and then decreased gradually. The levels of S100B protein and NSE in AACD CPR group at different time points after ROSC were significantly lower than those in STD-CPR group [S100B protein (MUg/L): 1.62+/-0.52 vs. 1.88+/-0.46 at 1 hour, 1.71+/-0.41 vs. 2.02+/-0.58 at 6 hours, 1.24+/-0.37 vs. 1.52+/-0.59 at 12 hours, 1.05+/-0.23 vs. 1.28+/-0.37 at 24 hours, 0.82+/-0.29 vs. 1.05+/-0.36 at 48 hours; NSE (MUg/L): 24.76+/-3.02 vs. 26.78+/-4.29 at 1 hour, 58.78+/-5.58 vs. 61.68+/ 5.44 at 6 hours, 53.87+/-4.84 vs. 56.78+/-5.68 at 12 hours, 40.96+/-3.52 vs. 43.13+/-4.50 at 24 hours, 33.23+/-2.89 vs. 35.54+/-3.44 at 48 hours; all P < 0.05]. 3 months after ROSC, the CPC classification of AACD-CPR group was lower than that of the STD-CPR group (average rank: 28.86 vs. 42.46, Z = -3.375, P < 0.001). CONCLUSIONS: After suffering asphyxia CA, patients who accepted AACD-CPR had better neurologic outcome than STD-CPR. PMID- 30009730 TI - [Comparison of the accuracy of predicting poor outcome of coma after cardiopulmonary resuscitation with two kinds of electroencephalogram techniques]. AB - OBJECTIVE: To compare the accuracy of electroencephalography (EEG) grading scale with amplitude-integrated electroencephalography (aEEG) in predicting poor outcomes (3-month), who sustained coma after cardiopulmonary resuscitation (CPR) in adults. METHODS: A retrospective study was conducted. The patients with post anoxic coma admitted to intensive care unit (ICU) of Tongren Hospital, Capital Medical University from March 2010 to June 2017 were enrolled. EEG was registered and recorded at least once within 7 days of coma after CPR, while not being subjected to therapeutic hypothermia. General data, Glasgow coma scale (GCS), EEG grading and aEEG model were collected. According to Glasgow prognosis score (GOS) of 3-month outcome, patients were divided into poor prognosis group (GOS 1-2) and good prognosis group (GOS 3-5), and the differences of related indexes between the two groups were compared. The predictive ability of aEEG model and EEG grading for brain function prognosis was evaluated by receiver operating characteristic (ROC) curve. RESULTS: Fifty-four patients were included, with 31 males and 23 females, and age of (53.9+/-19.3) years. Among the EEG Young grades, 17 cases (31.5%) were grade 1, 4 cases (7.4%) were grade 2-5, and 33 cases (61.1%) were grade 6. Among the aEEG model grades, 26 cases (48.1%) had slow wave pattern grade 1, 23 cases (42.6%) had suppressed mode grade 4, 4 cases (7.4%) had status epilepticus mode grade 2, and 1 case (1.9%) had burst suppression mode grade 3. Thirty-six patients had poor prognosis 3-month after onset, 26 of them died and 10 had persistent vegetative state. The prognosis was good in 18 cases, including 16 cases with severe neurological disability and 2 cases with moderate neurological disability. There was no significant difference in gender, age, anoxic time between two groups with different prognosis, while the degree of consciousness disorder in poor prognosis group was more severe than that in good prognosis group (GCS score: 4.1+/-1.7 vs. 5.0+/-2.1, P < 0.05). The consistency test showed that different physicians had good consistency in EEG grading and aEEG model (Kappa values were 0.917 and 0.932, respectively). It was shown by ROC curve analysis that the area under ROC curve (AUC) of aEEG model and EEG grading for predicting poor prognosis of coma patients after CPR were 0.815 and 0.720, respectively (both P < 0.01); when the cut-off value of aEEG was 2.5, the sensitivity was 79.3%, the specificity was 77.4%, the positive likelihood ratios (PLR) was 3.508, and the negative likelihood ratios (NLR) was 0.267; when the cut off value of EEG grading was 4.5, the sensitivity was 82.8%, the specificity was 61.3%, the PLR was 2.140, and NLR was 0.281. CONCLUSIONS: aEEG model was more accurate in prognosticating poor outcomes (3-month) in patients with post-anoxic coma, when compared to EEG grading. Its operation was simple, so aEEG is very suitable in ICU. PMID- 30009731 TI - [Accuracy of sequential organ failure assessment score in emergency department physicians in Beijing: a multicenter investigation study]. AB - OBJECTIVE: To investigate the accuracy of sequential organ failure assessment (SOFA) scoring in emergency physicians in Beijing. METHODS: Emergency physicians from 8 hospitals in Beijing in January 2018 were demanded to complete a SOFA questionnaire which was developed on "wenjuanxing" website and submit via cell phone. All participants were divided into urban center group (UC group) and no urban center group (NUC group) based on the hospital's location. The accuracy rate of components and total score of SOFA along with the mistakes were evaluated, and the results of the two groups were compared. RESULTS: (1) The questionnaire was sent to 217 emergency physicians of the 8 hospitals, and 197 qualified questionnaires were received with 109 of NUC group and 88 of UC group, respectively, the total response rate was 90.8%. Compared with those from NUC group, UC physicians had older ages [years: 37 (32, 42) vs. 34 (29, 40), Z = 2.554, P = 0.011] and higher education level [postgraduate degree 76.1% (67/88) vs. 40.4% (44/109), chi2 = 25.327, P < 0.001], and more of them experienced SOFA scoring [62.5% (55/88) vs. 45.9% (50/109), chi2 = 5.409, P = 0.020]. Other baseline characteristics such as gender, working years, professional title and training experience were not different between the two groups. (2) The accuracy rate of total SOFA score was 62.4% (123/197) in the whole cohort, and UC group was lower than that of NUC group, but the difference was not significant [56.8% (50/88) vs. 67.0% (73/109), chi2 = 2.141, P = 0.143]. While comparing the accuracy of individual variable/system of SOFA, the accuracy rate of norepinephrine of UC group was much higher than NUC group [80.7% (71/88) vs. 66.1% (72/109), chi2 = 5.235, P = 0.022], but the accuracy of Glasgow coma scale (GCS) was much lower in NUC group [38.6% (27/70) vs. 81.6% (71/87), chi2 = 30.629, P < 0.001]. Other variables of SOFA were not different between the two groups. Based upon the results of all submitted questionnaires, 566 mistakes were identified. It was indicated that the mistakes per capital was 2.9 in the whole cohort and in the two groups. The first type mistakes which caused by carelessness (including calculating error, filling error, choosing error) were 233 times. The calculating error in norepinephrine from NUC physicians was higher than the UC group [33.9% (37/109) vs. 19.3% (17/88), chi2 = 5.235, P = 0.022], there was no significant difference in any other first type mistakes between the two groups. The total second type mistakes caused by misunderstanding of SOFA (including using wrong variables, not using the worst value within 24 hours, and incorrect GCS score) were 333 times in the whole cohort. GCS error [61.8% (42/88) vs. 16.9% (14/109), chi2 = 32.292, P < 0.001], and using urine output per hour instead of urine output per 24 hours [15.9% (14/88) vs. 4.6% (5/109), chi2 = 7.162, P = 0.007] were much higher in UC group than NUC group. CONCLUSIONS: The total accuracy of SOFA scoring in the investigated emergency physicians of 8 hospitals in Beijing was not good. Mistakes causing by carelessness or misunderstanding of score rules were similar. It is necessary to apply strict training in SOFA scoring. PMID- 30009732 TI - [Observation on therapeutic effect of combined acupuncture for stress gastric mucosal injury after traumatic brain injury]. AB - OBJECTIVE: To observe the therapeutic effect of combined acupuncture combined with omeprazole on patients with craniocerebral trauma complicated with stress gastric mucosal injury. METHODS: Patients with stress gastric mucosal injury after cerebral trauma admitted to neurology of Brain Hospital, Affiliated Hospital of Logistics University from June 2016 to July 2017 were enrolled, with the inclusion criteria within 24 hours after injury at admission, and Glasgow coma scale (GCS) less than 12. Patients were divided into omeprazole group, acupuncture group and acupuncture plus omeprazole combined treatment group according to random number table method. All patients in the three groups were given symptomatic treatment in time after admission. After diagnosis, omeprazole group was injected intravenously omeprazole, 40 mg each time, one dose in 12 hours for 7 days; acupuncture group was acupunctured at bilateral Zusanli point and Zhongwan point, 20 minutes for needle retention, once a day for 7 days; combined treatment group was given acupuncture and omeprazole at the same time. The GCS score and the occult stool test were performed at admission and treatment of 7 days; the pH of gastric juice, the levels of serum neurotensin (NT) and endothelin-1 (ET-1) were measured at admission and treatment 1, 3, 5, 7 days. At the same time, 10 healthy persons were selected as the control. RESULTS: Finally, 90 patients were selected, 30 in each group. GCS score at 7 days after treatment in omeprazole group, acupuncture group and combined treatment group were significantly higher than those at admission, but there was no statistical difference among the groups (9.46+/-2.81, 10.26+/-2.24, 10.52+/-2.50, F = 2.010, P = 0.141). For treatment of 7 days, the incidence of occult stool in the combined treatment group was significantly lower than that in the omeprazole group and acupuncture group (13.3% vs. 36.7%, 40.0%, both P < 0.05). The pH value of gastric excretion was increased gradually after treatment in the three groups. The pH value of gastric excretion in the combined treatment group was significantly higher than that in the omeprazole group and acupuncture group at 5 days of treatment (4.58+/-0.53 vs. 4.20+/-0.52, 4.28+/-0.43, both P < 0.05). The levels of serum NT in the three groups were both bi-directional: the level of NT at admission was significantly higher than that in the healthy control group, then decreased significantly, and the treatment of 3 days was significantly lower than that in the healthy control group and then rise gradually. The level of NT at treatment 5 days in the combined treatment group was significantly higher than that of the omeprazole group and the acupuncture group (ng/L: 45.88+/-8.03 vs. 36.15+/-11.54, 37.32+/-7.79, both P < 0.05), and had returned to normal level on the 7th day after treatment (ng/L: 56.88 +/-12.54). The level of serum ET-1 in the three groups showed a bimodal change: the level of ET-1 at admission was significantly higher than that of the healthy control group. The treatment of 1 day to the normal range was gradually increased, and the peak of 5 days appeared again and then decreased slowly. The level of ET-1 at treatment of 7 days in the combined treatment group was significantly lower than that of the omeprazole group and acupuncture group (ng/L: 53.25+/-7.60 vs. 63.74+/-9.05, 65.50+/-12.73, both P < 0.05), and had been restored to normal. CONCLUSIONS: Combined acupuncture at points of Zusanli and Zhongwan for the treatment of stress gastric mucosal injury after traumatic brain injury, can reduce gastric acid secretion, promote the level of NT in serum, reduce the secretion of ET-1 level, help to repair the gastric mucosa, and the effect of combined with omeprazole is more significant. PMID- 30009733 TI - [Effect of early rehabilitation physiotherapy on muscle quality and function in critically ill patients]. AB - OBJECTIVE: To investigate the effect of early rehabilitation physiotherapy on muscle quality and function in critical patients. METHODS: A prospective randomized controlled study was performed. Adult critically ill patients admitted to intensive care unit (ICU) of Anhui Provincial Hospital from October 1st, 2016 to August 31st, 2017 who had been hospitalized for more than 7 days and had acute physiology and chronic health evaluation II (APACHE II) > 8 were enrolled, and they were divided into treatment group and control group according to random number table method. All patients were given routine treatment, and on this basis, the treatment group was given rehabilitation therapy within 24 hours after admission, including limb active/passive activities, respiratory muscle function training and transcutaneous electrical nerve stimulation, etc. Bedside ultrasound was used to measure the area and cross sectional thickness of left rectus femoris muscle and the cross sectional thickness of middle thigh muscle of patients at 1, 4 and 7 days after treatment; at the same time, the muscle strength of sober patients was evaluated by medical research council (MRC) muscle strength evaluation method, and the mechanical ventilation time, ICU hospitalization time and ICU expenses were recorded. RESULTS: Forty patients were enrolled in this study, with 20 in each group. Compared with the control group, the difference of left rectus femoris muscle area between 1 day and 4 days, 4 days and 7 days, 1 day and 7 days (cm2: 0.19+/-0.02 vs. 0.31+/-0.19, 0.02+/-0.01 vs. 0.08+/-0.05, 0.04+/-0.02 vs. 0.38+/-0.23), and the difference in left rectus femoris thickness (cm: 0.01+/-0.01 vs. 0.14+/-0.13, 0.03+/-0.03 vs. 0.16+/-0.14) and the difference in middle thigh muscle thickness (cm: 0.02+/-0.02 vs. 0.11+/-0.09, 0.03+/-0.02 vs. 0.16+/-0.12) between 1 day and 4 days, 1 day and 7 days in the treatment group were significantly reduced (all P < 0.01). The MRC strength score in the treatment group was significantly higher than that of the control group at 7 days (52.06+/-3.52 vs. 47.94+/-3.96, P < 0.05). The mechanical ventilation time in the treatment group (n = 15) and the control group (n = 13) were (138.5+/-34.5) hours and (185.0+/-40.9) hours, respectively, and the difference between two groups were statistical significance (P < 0.05). Compared with the control group, the incidence rate of ICU acquired muscle weakness (ICUAW) in the treatment group was significantly decreased [5.0% (1/20) vs. 40.0% (8/20), P < 0.05], the length of ICU stay was significantly shortened (days: 17.67+/-4.91 vs. 22.06+/-5.94, P < 0.05), and the ICU expenses were significantly reduced (ten thousand yuan: 7.53+/ 2.09 vs. 9.55+/-1.73, P < 0.05). CONCLUSIONS: Early rehabilitation physiotherapy can improve the muscle quality and function in critical patients, and decrease the length of ICU stay. PMID- 30009734 TI - [Influence of enteral nutrition initiation timing on curative effect and prognosis of acute respiratory distress syndrome patients with mechanical ventilation]. AB - OBJECTIVE: To explore the effect of enteral nutrition (EN) initiation time on the treatment and prognosis of acute respiratory distress syndrome (ARDS) patients with mechanical ventilation. METHODS: A retrospective study was conducted. 116 adult ARDS patients with mechanical ventilation admitted to the intensive care unit (ICU) of the Sixth Division Hospital of Xinjiang from January 2016 to December 2017 were enrolled. There was no difference in gender, age, acute physiology and chronic health evaluation II (APACHE II) at admission. Patients were divided into early enteral nutrition group (E-EN group, 66 cases, starting EN within 48 hours) and late enteral nutrition group (L-EN group, 50 cases, starting EN after 7 days later) according to the EN initiation time. Both groups of patients achieved the standard nutrition after 3-5 days of EN. Nutritional indicators [albumin (ALB), pre-albumin (PA)], liver function [total bilirubin (TBIL)], infection index [procalcitonin (PCT)], insulin dosage, respiratory mechanics and pulmonary function [airway peak pressure (PIP), airway plateau pressure (Pplat), mean airway pressure (MPaw), effective static total compliance (Cst), oxygenation index (PaO2/FiO2)], critical scores [APACHE II, multiple organ dysfunction score (MODS), Murray lung injury score, and systemic inflammatory response syndrome (SIRS) score], duration of mechanical ventilation, the length of ICU stay, incidence of multiple organ dysfunction syndrome, 14-day mortality, and ICU hospitalization expenses were collected before treatment and 1, 3, 7, 10, 14 days after treatment. RESULTS: There was no difference in biochemical indicators, respiratory mechanics, pulmonary function, or critical scores between the two groups before ICU treatment. Compared with before treatment, ALB and PA were significantly increased, TBIL and MPaw were significantly decreased, insulin dosage was significantly decreased, PIP, Pplat, MPaw were significantly decreased, Cst and PaO2/FiO2 were significantly increased, and the critical scores were significantly decreased. Compared with L-EN group, E-EN group had lower TBIL and PCT after treatment [TBIL (MUmol/L): 13.21+/-1.03 vs. 29.02+/ 1.38, PCT (ng/L): 5.36+/-1.58 vs. 11.33+/-1.95], lower insulin dose (U: 16.37+/ 1.01 vs. 27.01+/-1.92), lower PIP, Pplat, MPaw [PIP (cmH2O, 1 cmH2O = 0.098 kPa): 17.7+/-3.5 vs. 22.5+/-4.3, Pplat (cmH2O): 10.5+/-1.4 vs. 15.6+/-1.2, MPaw (cmH2O): 5.5+/-0.7 vs. 8.2+/-0.8], higher Cst, PaO2/FiO2 [Cst (mL/cmH2O): 128.6+/ 16.5 vs. 93.7+/-11.9, PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 242.9+/-27.9 vs. 188.6+/-25.9, all P < 0.05], however, there was no significant difference in ALB, PA and critical care scores [ALB (g/L): 37.09+/-1.49 vs. 35.88+/-1.77, PA (mg/L): 387.29+/-10.93 vs. 369.27+/-11.44, APACHE II: 13.9+/-3.5 vs. 14.5+/-5.0, Murray: 5.6+/-0.9 vs. 5.2+/-1.4, MODS: 1.1+/-0.4 vs. 1.2+/-0.3, SIRS: 2.9+/-0.5 vs. 3.1+/ 0.9, all P > 0.05]. Compared with L-EN group, incidence of multiple organ dysfunction syndrome was significantly decreased in E-EN group [31.8% (21/66) vs. 48.0% (24/50), P < 0.05], duration of mechanical ventilation and the length of ICU stay were significantly shortened (days: 5.5+/-0.7 vs. 9.2+/-0.8, 8.6+/-1.5 vs. 18.3+/-1.9, both P < 0.05), ICU hospitalization expenses was significantly reduced (10 000 yuan: 6.324+/-0.009 vs. 11.419+/-0.010, P < 0.05), but there was no significantly difference in 14-day mortality between two groups [15.2% (10/66) vs. 16.0% (8/50), P > 0.05]. CONCLUSIONS: Early and reasonable application of EN supportive therapy can improve the clinical efficacy of ARDS patients, reduce the incidence of infection, make it easier to control blood sugar, improve lung function, shorten the duration of mechanical ventilation and the length of ICU stay, and reduce hospitalization expenses. However, no significant difference has been found in the prognosis of the recent 14 days. PMID- 30009735 TI - [Qingfeihuayutongfu prescription for intervening fibrosis in patients with sepsis associated acute respiratory distress syndrome: a prospective single blind randomized controlled clinical trial study]. AB - OBJECTIVE: To investigate the effect of Qingfeihuayutongfu prescription on oxygenation and pulmonary fibrosis in patients with sepsis-associated acute respiratory distress syndrome (ARDS). METHODS: A prospective randomized controlled trial was performed. Patients with moderate to severe ARDS admitted to intensive care unit (ICU) of Affiliated Hospital of Nanjing University of Chinese Medicine from July 2015 to February 2017 were enrolled, and randomly divided into Qingfeihuayutongfu prescription group (observation group, 200 mL of Qingfeihuayutongfu prescription was given through nasal feeding on the first day after admission, one dose per day for 7 days) and placebo control group. Routine treatment of ARDS in both groups was the same. The oxygenation index (PaO2/FiO2), levels of serum procollagen III (PC III) and prolidase (PLD) were measured at 1, 3, 7, 14 and 28 days after treatment, duration of mechanical ventilation, the length of ICU stay and 60-day survival rate were recorded. RESULTS: A total of 32 patients with ARDS were selected, with 16 in each group, and their baseline data were balanced and comparable. As time went on, PaO2/FiO2 in both groups was decreased gradually, and serum levels of PC III and PLD were increased gradually. Compared with placebo control group, PaO2/FiO2 was significantly increased at 14 days and 28 days after treatment in observation group [mmHg (1 mmHg = 0.133 kPa): 185.81+/-65.07 vs. 137.19+/-55.72, 250.56+/-102.72 vs. 178.25+/-80.97, both P < 0.05], the levels of serum PC III were significantly decreased at 14 days and 28 days after treatment (MUmol/L: 197.13+/-26.61 vs. 240.81+/-45.27, 169.06+/-36.34 vs. 234.75+/-46.30, both P < 0.01), the levels of serum PLD was significantly decreased at 28 days after treatment (U/L: 1 166.31+/-304.84 vs. 1 468.81+/ 387.65, P < 0.05), duration of mechanical ventilation (days: 18.20+/-5.20 vs. 23.38+/-7.57) and the length of ICU stay (days: 23.7+/-5.7 vs. 31.0+/-7.9 ) were significantly shortened (both P < 0.05). Kaplan-Meier survival curve analysis showed that there was no significant difference in the 60-day survival rate between the observation group and placebo control group [81.25% (13/16) vs. 68.75% (11/16), chi2 = 0.667, P = 0.505]. CONCLUSIONS: The Qingfeihuayutongfu prescription may improve oxygenation of ARDS patients, reduce the levels of serum PC III and PLD, and inhibit pulmonary fibrosis, thus improve prognosis. PMID- 30009736 TI - [FK866 protects polymicrobial sepsis-induced liver injury in mice]. AB - OBJECTIVE: To investigate the effects of nicotinamide phosphoribosyl transferase (NAMPT) inhibitor FK866 on polymicrobial sepsis-induced liver injury in mice. METHODS: Eighty-four healthy male C57BL/6J mice were divided into four groups by random number table method (n = 21): sham group, sepsis-induced liver injury model by cecal ligation and perforation group (CLP group), vehicle+CLP group and FK866+CLP group. FK866 (10 mg/kg) or same volume dimethyl sulfoxide were given intraperitoneally into mice 24, 12 and 0.5 hours prior to CLP in the FK866+CLP group or the vehicle+CLP group, respectively. Fifteen mice in each group were used to observe the 48-hour survival after operation. The remaining 6 mice were sacrificed 20 hours after operation to harvest venous blood and liver tissue samples for index detection. The levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured by colorimetry; the levels of serum NAMPT, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by enzyme linked immunosorbent assay (ELISA); the mRNA expressions of TNF-alpha and IL-6 were measured by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR); the protein expressions of hepatic NAMPT, cytoplasmic IkappaBalpha and nuclear factor-kappaB (NF-kappaB) were measured by Western Blot. RESULTS: Compared with the sham group, the 48-hour survival in the CLP group was significantly decreased; serum and liver NAMPT protein levels were significantly increased, serum ALT, AST, TNF-alpha, IL-6 levels and mRNA expressions of TNF-alpha, IL-6 in liver tissue were significantly increased; the expression of cytoplasmic IkappaBalpha protein was significantly decreased, and the expression of nuclear NF-kappaB protein was significantly increased; which indicated that CLP induced NF-kappaB activation, inflammation and liver injury. There was no significant difference between the vehicle+CLP group and the CLP group. Compared with the vehicle+CLP group, the 48-hour survival in FK866+CLP group was significantly increased (53.33% vs. 26.67%); serum ALT, AST, TNF-alpha, IL-6 levels and mRNA expressions of TNF-alpha, IL-6 in liver tissue were significantly decreased [serum ALT (U/L): 128.94+/-32.48 vs. 237.24+/-58.61, serum AST (U/L): 289.89+/-68.74 vs.468+/-82.17, serum TNF-alpha (pg/L): 65.17+/-18.74 vs.127.64+/-48.18, serum IL-6 (ng/L): 31.78+/-5.23 vs. 60.87+/-13.12, liver TNF-alpha mRNA (2-DeltaDeltaCt): 8.37+/-4.17 vs. 18.24+/ 6.12, liver IL-6 mRNA (2-DeltaDeltaCt): 18.58+/-7.12 vs.34.24+/-6.71], the expression of cytoplasmic IkappaBalpha protein was significantly increased (IkappaBalpha/GAPDH: 0.23+/-0.03 vs. 0.12+/-0.04), while expression of nuclear NF kappaB protein was significantly decreased (NF-kappaB/Lamin B1: 0.25+/-0.04 vs. 0.42+/-0.05), with statistically significant differences (all P < 0.05). CONCLUSIONS: NAMPT inhibitor FK866 protects polymicrobial sepsis-induced liver injury via the inhibition of NF-kappaB activation and inflammation. PMID- 30009737 TI - [Activation of A2b adenosine receptor decreases lipopolysaccharide-induced pulmonary microvascular permeability]. AB - OBJECTIVE: To explore the role of the A2b adenosine receptor (Adora2b) in lipopolysaccharide (LPS)-induced injury of human pulmonary microvascular endothelial cells (HPMECs), and its mechanism. METHODS: HPMECs were cultured in vitro. The LPS dose-effect experiment, time-effect experiment and the Adora2b agonist/antagonist intervention experiment were performed respectively. (1) Dose effect and time-effect experiments: HPMECs were stimulated with 1, 10, 100, 1 000 MUg/L LPS for 24 hours, or 100 MUg/L LPS for 4, 8, 12, 16, 24 hours. Cell viability was measured by cell counting kit-8 (CCK8). The protein and mRNA expressions of Adora2b were determined by Western Blot and real-time reverse transcription-polymerase chain reaction (RT-PCR) respectively. (2) Adora2b agonist/antagonist intervention experiment: serum-starved HPMECs were pretreated with Adora2b specific agonist BAY60-6583 (0.1, 1, 10 MUmol/L) or Adora2b specific antagonist PSB1115 (1 MUmol/L) for 1 hour, respectively, and then incubated with 100 MUg/L of LPS for 24 hours. The HPMECs without treatment were served as blank control group, and those treated with LPS, BAY60-6583 or PSB1115 alone were served as single challenge groups. The monolayer permeability of HPMECs was determined by fluorescein isothiocyanate (FITC)-dextran. Cell cycle was analyzed by flow cytometry. The mRNA expressions of VE-cadherin, occludin, vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANGPT1) were determined by RT-PCR. RESULTS: (1) Dose-effect and time-effect experiments: LPS induced the decreased cell viability of HPMECs in dose and time-dependent manner. Compared with the control group, the protein expression of Adora2b was sharply up regulated after 100 MUg/L or 1 000 MUg/L LPS stimulation. Meanwhile, LPS was shown to cause a dose and time-dependent induction of Adora2b transcript level. (2) Adora2b agonist/antagonist intervention experiments: compared with the control group, the monolayer permeability of HPMECs was rapidly enhanced after LPS treatment, and lower cell viability and proliferation, as well as the expression of cell junction and angiogenic factors were downregulated. Compared with LPS group, 0.1, 1, 10 MUmol/L BAY 60-6583 pretreatment could decrease the endothelial cell barrier leakage in a dose-dependent manner [Pd: (203.06+/ 15.24)%, (164.15+/-17.82)%, (125.69+/-10.38)% vs. (218.53+/-12.05)%], and promote cell proliferation of HPMECs [the proportion of S and G2 phases: (24.36+/-1.40)%, (32.37+/-0.95)%, (40.05+/-2.99)% vs. (18.83+/-0.73)%]. Pretreatment of 10 MUmol/L BAY60-6583 also upregulated the mRNA expressions of cell junction and angiogenic factors [VE-cadherin (2-DeltaDeltaCt): 2.17+/-0.23 vs. 0.56+/-0.10, occludin (2 DeltaDeltaCt): 5.32+/-0.28 vs. 0.48+/-0.11, VEGF (2-DeltaDeltaCt): 4.44+/-0.34 vs. 0.58+/-0.09, ANGPT-1 (2-DeltaDeltaCt): 5.98+/-0.73 vs. 0.66+/-0.10, all P < 0.01]. PSB1115 pretreatment aggravated injury of microvascular endothelial cells after LPS incubation, with lower cell viability, slower proliferation and less expression of VEGF and ANGPT1. There was no influence of BAY 60-6583 or PSB1115 single treatment on cell viability, cell cycle and the expression of angiogenic factors in HPMECs. CONCLUSIONS: In vitro studies of cultured HPMECs exposed to LPS are identified as dose and time-dependent induction of Adora2b transcript and corresponding protein induction. Activation of Adora2b attenuates LPS-induced pulmonary microvascular endothelial cell barrier enhancement by regulating intercellular junction and promoting angiogenesis, suggesting Adora2b as potential therapeutic target in the treatment of LPS-induced forms of acute lung injury. PMID- 30009738 TI - [Role of dendritic cells in lipopolysaccharide induced cardiac dysfunction in mice]. AB - OBJECTIVE: To observe the role of dendritic cells (DC) in lipopolysaccharide (LPS)-induced myocardial dysfunction in mice. METHODS: Eighty wild type male C57BL/6 mice were divided into four groups, according to random number table method: sham group, DC inhibitors in control group (VAG539-sham group), LPS sepsis model group (LPS group) and DC inhibitors pretreatment group (VAG539-LPS group), 20 in each group. The cardiac dysfunction model of sepsis mice was established by LPS intraperitoneal injection; the sham group was injected with the same dose of normal saline. VAG539-sham group and VAG539-LPS group were injected with the DC inhibitor VAG539 (30 mg/kg, twice per day, for 2 days) before injection with normal saline or LPS, respectively. Ten mice in each group were used to observe the 14-day survival rate. Mean arterial pressure (MAP) of the remaining 10 mice was measured through the small animal tail artery cannula; the cardiac function [including the heart rate (HR), left ventricular ejection fraction (LVEF) and short axial shortening rate (FS)] were evaluated by small animal echocardiography; the aggregation and maturation of myocardial DC were detected by flow cytometry; and serum inflammatory factors [including tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-12, IL-6)] were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with sham group, the 14-day cumulative survival rate in LPS group was significantly reduced, while HR, MAP, LVEF and FS were significantly decreased, and the number of DC in myocardial tissues was significantly increased, and the levels of serum inflammatory factors were increased significantly. The 14-day cumulative survival rate in VAG539-LPS group was significantly higher than that in the LPS group (55% vs. 15%, P < 0.05). Compared with LPS group, after pretreatment by VAG539, the HR, MAP, LVEF and FS were significantly increased [HR (bpm): 610+/-25 vs. 556+/-28, MAP (mmHg, 1 mmHg = 0.133 kPa): 68+/-6 vs. 42+/-2, LVEF: 0.48+/-0.02 vs. 0.30+/-0.03, FS: (34+/-3)% vs. (14+/-2)%, P < 0.05]; the number of DC in myocardial tissue was significantly decreased from 6.5% to 3.7%; the level of serum inflammatory factors were significantly decreased [TNF-alpha (ng/L): 192.00+/-25.45 vs. 291.34+/-23.12, IL-12 (ng/L): 58.44+/-12.37 vs. 78.43+/-11.24, IL-6 (ng/L): 46.97+/-8.12 vs. 149.12+/-15.45, all P < 0.05]. CONCLUSIONS: Sepsis can cause cardiac dysfunction, and it can play an important role by inhibiting the DC cell function of myocardium and reducing the expression of inflammatory factors. PMID- 30009739 TI - [Effect of heat acclimatization training on inflammatory reaction and multiple organ dysfunction syndrome in patients with exertional heat stroke]. AB - OBJECTIVE: To investigate the effects of heat acclimatization training on the inflammatory reaction and multiple organ dysfunction syndrome (MODS) in patients with exertional heat stroke (EHS). METHODS: 600 officers and soldiers from a special team who participated in 5 km armed wild training from June to July 2017 were selected as the research object, while 30 healthy officers and men who did not participate in armed wild training during the same period were selected as normal controls. The officers and soldiers who participated in 5 km armed wild training (ambient temperature > 35 centigrade, humidity > 65%, 2-3 times a week for 3 weeks) were divided into heat acclimatization group and non-acclimatization group, with 300 in each group. The heat acclimatization group first took part in the heat acclimatization training of wild or long distance running (the initial temperature was 30 centigrade, gradually transferred to the hot time of 37 centigrade), 2 hours each time, twice a day, and 5 days a week, for a total of 2 weeks. Venous blood was taken before and after heat acclimatization training, before armed wild training, and after the last training or EHS onset, and the contents of serum interleukin (IL-1beta, IL-10), tumor necrosis factor-alpha (TNF alpha) and gamma-interferon (IFN-gamma) were detected by enzyme linked immunosorbent assay (ELISA). The occurrence of EHS and MODS in EHS patients were recorded. RESULTS: There was no significant difference in serum inflammatory factors between the officers and soldiers who participated in the training and the healthy control group before heat training or cross-country training. Compared with those before heat training, IL-1beta, TNF-alpha, IFN-gamma were significantly increased in all participants of heat acclimatization training while IL-10 was significantly decreased. For those who experienced premonitory (6 cases) and mild (2 cases) heatstroke during training, they could return to normal without severe heatstroke or EHS within 10-30 minutes after being immediately put in a cool and ventilated place and given anti-heatstroke drugs and other interventions. Compared with those before wild training, the levels of inflammatory factors in the two groups of officers and soldiers also changed after wild training, but the increase or decrease of inflammatory indexes in the heat acclimatization group were significantly smaller than those in the non acclimatization group [IL-1beta (ng/L): 10.65+/-5.18 vs. 12.13+/-7.91, TNF-alpha (ng/L): 14.60+/-5.79 vs. 16.27+/-8.52, IFN-gamma (ng/L): 13.66+/-5.43 vs. 15.33+/ 8.71, IL-10 (ng/L): 8.22+/-2.68 vs. 7.13+/-2.63, all P < 0.05]. During armed wild training, a total of 27 cases of EHS occurred. The incidence of EHS in the heat acclimatization group was significantly lower than that in the non acclimatization group [2.67% (8/300) vs. 6.33% (19/300), chi2 = 4.693, P = 0.030]. In patients with EHS, IL-1beta, TNF-alpha, IFN-gamma after wild training in the heat acclimatization group were also significantly lower than those in the non-acclimatization group, and IL-10 was significantly higher [IL-1beta (ng/L): 34.50+/-3.74 vs. 39.53+/-4.51, TNF-alpha (ng/L): 43.75+/-2.87 vs. 46.79+/-2.66, IFN-gamma (ng/L): 40.25+/-1.75 vs. 46.58+/-1.92, IL-10 (ng/L): 7.50+/-2.45 vs. 5.42+/-1.80, all P < 0.01], and the incidence of MODS and organ involvement of EHS patients in the heat acclimation group were significantly lower than that in the non-acclimatization group [50.00% (4/8) vs. 89.47% (17/19), chi2= 5.075, P = 0.024; 28.13% (9/32) vs. 47.79% (65/136), chi2= 4.066, P = 0.044]. CONCLUSIONS: Heat acclimatization training before high strength training in high temperature and humidity environment can effectively reduce the degree of inflammation reaction of EHS, protect the physiological functions of EHS organs, and reduce the incidence of MODS. PMID- 30009740 TI - [Big data in emergency medcine and Datathon event]. AB - OBJECTIVE: A detailed, high-scale clinical data can be generated in the process of diagnosis and treatment of emergency critically ill patients. The integration and analysis and utilization of these data are of great value for improving the treatment level and efficiency and developing the data-driven clinical assistant decision support. China has large volume of health information resources, however, the construction of healthcare databases and subsequent secondary analysis has just started. With the effort of the Chinese PLA General Hospital in building an emergency database and promoting data sharing, the first emergency database was published in China and a health Datathon was organized utilizing this database, providing experience for clinical data integration, database construction, cross-disciplinary collaboration and data sharing. Referring to the development at home and abroad, this review discussed work in this area and further proposed establishing a big data cooperation for emergency medicine and building a learning healthcare system to integrate more clinical resources and form a closed loop of "clinical database construction-analysis-applications", and enhance the effectiveness of medical big data in reducing medical costs and improving healthcare delivery. PMID- 30009741 TI - [A cross-disciplinary collaborative "Datathon" model to promote the application of medical big data]. AB - OBJECTIVE: Medical practice generates and stores immense amounts of clinical process data, while integrating and utilization of these data requires interdisciplinary cooperation together with novel models and methods to further promote applications of medical big data and research of artificial intelligence. A "Datathon" model is a novel event of data analysis and is typically organized as intense, short-duration, competitions in which participants with various knowledge and skills cooperate to address clinical questions based on "real world" data. This article introduces the origin of Datathon, organization of the events and relevant practice. The Datathon approach provides innovative solutions to promote cross-disciplinary collaboration and new methods for conducting research of big data in healthcare. It also offers insight into teaming up multi expertise experts to investigate relevant clinical questions and further accelerate the application of medical big data. PMID- 30009742 TI - [Pilot research: construction of emergency rescue database]. AB - OBJECTIVE: To construct a database containing multiple kinds of diseases that can provide "real world" data for first-aid clinical research. METHODS: Structured or non-structured information from hospital information system, laboratory information system, emergency medical system, emergency nursing system and bedside monitoring instruments of patients who visited department of emergency in PLA General Hospital from January 2014 to January 2018 were extracted. Database was created by forms, code writing, and data process. RESULTS: Emergency Rescue Database is a single center database established by PLA General Hospital. The information was collected from the patients who had visited the emergency department in PLA General Hospital since January 2014 to January 2018. The database included 530 585 patients' information of triage and 22 941 patients' information of treatment in critical rescue room, including information related to human demography, triage, medical records, vital signs, lab tests, image and biological examinations and so on. There were 12 tables (PATIENTS, TRIAGE_PATIENTS, EMG_PATIENTS_VISIT, VITAL_SIGNS, CHARTEVENTS, MEDICAL_ORDER, MEDICAL_RECORD, NURSING_RECORD, LAB_TEST_MASTER, LAB_RESULT, MEDICAL_EXAMINATION, EMG_INOUT_RECORD) that containing different kinds of patients' information. CONCLUSIONS: The setup of high quality emergency databases lay solid ground for scientific researches based on data. The model of constructing Emergency Rescue Database could be the reference for other medical institutions to build multiple diseases databases. PMID- 30009743 TI - [Research and invention of sinus cavity flushing drainage tube and clinical application in the minimally invasive treatment of sinus cavity pressure ulcer]. AB - OBJECTIVE: To develop a washing tube for minimally invasive treatment of sinus cavity pressure ulcer, and to observe its clinical effect. METHODS: Using transparent non-toxic PU plastic to make sinus cavity flushing and drainage tube, and with rounded hemispherical blunt head for the entry of the sinus, the perforated tube in the sinus cavity was designed with perforated holes (3 rows, 5 for each row); the end of the tube is blocked with heparin cap. The invented sinus cavity flushing tube was used for clinical observation and its use effect was observed. When used, the sinus cavity flushing drainage tube must be placed in the deepest antrum. The wounds were covered with PU sponge. By the active aspiration drainage of the negative pressure with sterile isotonic flushing fluid, bacteria, liquefied necrotic tissue, purulent secretion, internal and external toxins produced by bacteria, and the harmful material such as exudate of inflammatory medium in the sinus cavity was thoroughly removed. RESULTS: When treating sinus cavity and mixed pressure ulcer, minimally invasive treatment using the developed sinus cavity flushing drainage tube for irrigation and negative pressure drainage can significantly reduce patients' iatrogenic trauma, observably reduce the pain of the patients, shorten the treatment cycle, improve the cure rate of sinus pressure ulcers, and achieve good clinical effect. The sinus cavity flushing drainage tube has no damage to soft tissue, with simple operation and easy tolerance of patients. It is low price and using disposable materials, which can avoid cross-infection; It can be used to treat oxygen negative pressure in sinus cavity, and it has therapeutic effect on the sinus cavity pressure sore infected by anaerobic bacteria. It can be made into different specifications, different models, and widely used in different professional fields. CONCLUSIONS: The sinus cavity flushing drainage tube combined with negative pressure treatment is a new technique of mild and undamaged cleansing wound, which makes up for the deficiency of flap surgery, and it is a very ideal method for minimally invasive treatment for sinus and cavity pressure ulcers. PMID- 30009744 TI - [Progress of therapeutic strategies for glucose metabolic disorders in sepsis]. AB - OBJECTIVE: Glucose metabolic disorder is a common issue in sepsis and it leads to an increase in mortality. However, the therapeutic methods of the glucose metabolic disorders in sepsis patients need to be improved. Studying the mechanism of glucose metabolism disorder, and adjusting the existing treatment measures are especially significant in curing the sepsis. This review summarizes recent animal experiments and clinical studies about glucose change after septic complications, focusing on the treatment of three disorders including hyperglycemia, hypoglycemia, and blood glucose variability. They definitely provide new ideas for the control of blood glucose in sepsis patients. PMID- 30009745 TI - Cognitive insight, neurocognition and life skills in patients with schizophrenia. AB - BACKGROUND: The concept of cognitive insight refers to the capacity for self reflectiveness as a mechanism for evaluating one's symptoms and self-certainty, understood as the ability to correct inappropriate interpretations and conclusions. There are no conclusive results regardingabout the clinical and neuropsychological variables involved and there are hardly any studies of their impact on functional outcomes. METHOD: The objectives were to analyze the neuropsychological and clinical cognitive insight in a sample of 22 stable patients diagnosed with schizophrenia, to assess its impact on life skills and to analyze whether it can be a mediating variable between cognitive deficits and daily functioning. A neuropsychological battery composed of tests of memory (TAVEC and WAIS-Digits), executive functioning (WCST and Stroop) and vocabulary, the BCIS, a measure of everyday functions (LSP) and the PANSS. RESULTS: We found significant negative correlations between the WAIS vocabulary test, self assurance, and life skills; although this is influenced to a greater extent by the negative symptomatology and the premorbid general cognitive level. CONCLUSIONS: A greater openness to corrective feedback of distorted thoughts, without specific cognitive capacities, improves the ability of patients with schizophrenia to adapt to the environment. PMID- 30009746 TI - Incidence, prevalence and risk factors related to anxiety symptoms during pregnancy. AB - : Symptoms of anxiety are one of the most prevalent emotional responses in women during their reproductive phase and especially during pregnancy. OBJECTIVE: Estimate the incidence and prevalence of anxiety throughout the three trimesters of pregnancy in addition to studying the possible risk factors associated with anxiety symptoms. METHOD: A sample of 385 pregnant women participated in a longitudinal study in which the GAD-7 questionnaire was used. RESULTS: Anxiety prevalence was 19.5% in the first trimester. In the second trimester, it was 16.8%, with an incidence of 0.048%. In the third trimester, it was 17.2%, with an incidence of 0.068%. The following predictive factors of anxiety symptoms were identified: being a smoker, presence of previous illness and changes in social relationships. CONCLUSIONS: High incidence and prevalence of anxiety symptoms occur during pregnancy; consequently, applicable preventive policies should be developed. PMID- 30009747 TI - Oppositional Defiant Disorder dimensions and aggression: The moderating role of hostile bias and sex. AB - BACKGROUND: Hostile Attributional Bias (HAB) has been related to conduct problems. The common and unique associations between the different dimensions of Oppositional Defiant Disorder (ODD) symptoms, specific components of HAB, sex and types of aggression (overt and relational) in a community sample of 491 7-year old children are investigated. METHOD: Teachers rated the children's ODD symptoms and aggression and the children self-reported about HAB. Multiple linear regressions showed that ODD dimensions were directly associated with both types of aggression. RESULTS: Boys were more overtly aggressive and girls more relational. Emotional distress was directly associated with relational aggression. The relational component of HAB uniquely moderated the influence of the oppositional dimension on relational aggressive behaviour. CONCLUSIONS: The assessment of social cognition variables is necessary to approach specific interventions in the presence of ODD symptoms, as this may help to identify a subset of children prone to aggressive reactions. PMID- 30009748 TI - Brain disease or biopsychosocial model in addiction? Remembering the Vietnam Veteran Study. AB - BACKGROUND: In recent years, we have repeatedly been told that addictions are a brain disease, leaving aside their classic biopsychosocial explanation. OBJECTIVE: To describe both models and discusses the weakness and reductionism of the brain disease model following the consumption of heroin by North American soldiers in the Vietnam war in the 1970s. METHOD: A literature review of the Vietnam Veteran Study in relation to drug consumption. RESULTS: The soldiers greatly increased their consumption of heroin in Vietnam, but almost all of them ceased using it upon returning home. The analysis of the environmental factors related to this self-healing is a critique of the brain disease model of addictions because it cannot explain this or other studies. CONCLUSION: The biopsychosocial model is still the best model to guide the field of addiction due to its utility, coherence, and efficacy in treatment. PMID- 30009749 TI - The contrastive value of lexical stress in visual word recognition: Evidence from Spanish. AB - BACKGROUND: Many pairs of words in Spanish, in particular many verbal forms, differ only in the syllable stressed, such as aNImo (I encourage) and aniMO (he encouraged). Consequently, word stress may acquire a lexical contrastive value that has been confirmed by Dupoux, Pallier, Sebastian, and Mehler (1997) for Spanish speakers though not for French speakers in auditory perception. METHOD: This study contrasts the priming effect produced by pairs of written words that differ only in their stress pattern with the priming effect in repetition priming, stress only priming (with no orthographic relation), and morphological priming, in visual word recognition. RESULTS: The results, using short and masked prime presentation, showed facilitation for different stress (orthographically identical) pairs (rasGÓ/RASgo) compared to totally unrelated pairs (rasGO/RASgo) but no facilitation compared to orthographically unrelated (but stress related) pairs (PERsa/RASgo). However, identity pairs (RASgo-RASgo) produced facilitation compared to both orthographically unrelated conditions. At long SOA, orthographically related (stress unrelated) pairs produced significant facilitation, as occurred with morphologically related pairs (RASga/RASgo), on the orthographically unrelated words (PERsa/RASgo). CONCLUSION: These results confirm the early and prelexical importance of word stress for lexical selection in Spanish, as is the case with orthographic and phonological features. PMID- 30009750 TI - Suicidal ideation and suicide attempts in persons with gender dysphoria. AB - BACKGROUND: The little research there is about suicidal behaviour in those with gender dysphoria indicates that they are at a much higher risk of death by suicide and suicidal behaviour than the general population. The objective of this research is to analyse the prevalence of suicidal ideation and suicide attempts reported by people who attended consultations at the Gender Identity Treatment Unit between 2007 and 2017 presenting complaints related to gender dysphoria. METHOD: An ex-post facto study with a sample of 151 people who were clients at the unit, 97 in the male to female trans group, 54 female to male. Clinical evaluations were carried out assessing variables of suicidal ideation and attempts, along with a possible psychiatric diagnosis. RESULTS: Almost half (48.3%) reported suicidal ideation, 23.8% had attempted suicide. CONCLUSIONS: There are higher levels of suicidal ideation and suicide attempts in people with gender dysphoria than in the general population. No differences were seen between groups in terms of gender/sex. Psychiatric morbidity was not an influential variable for suicidal behaviour. This suggests that suicidal ideation is one of the best indicators of the risk of suicidal behaviours. PMID- 30009751 TI - Moral reasoning in adolescent offenders: A meta-analytic review. AB - BACKGROUND: Moral reasoning and its association with various types of behavior have been the subject of many studies in Psychology. Specifically, moral reasoning has been widely related to juvenile delinquency in the research about the subject. OBJECTIVES: this review integrates more than 70 years of scientific research into the differences in moral reasoning between adolescent offenders and non-offenders with a view to elucidating the relationship between moral reasoning and juvenile delinquency with provision for the potential moderating effect of demographic and methodological variables. METHOD: We conducted a meta-analytic review whose target population was young offenders between 11 and 20 years old. RESULTS: A search for literature on the target topic retrieved a total of 72 studies with a moderated effect size (r = -.336). The most salient finding was that effect sizes were significant for all subgroups of moderating variables. CONCLUSIONS: This result suggests a powerful relationship between moral reasoning and officially recorded juvenile delinquency that cannot be exclusively ascribed to sociodemographic or methodological variables. There remain some unsolved challenges in this field, however, which are briefly commented on. PMID- 30009752 TI - Testing carer skill training programs in Spanish carers of patients with eating disorders. AB - BACKGROUND: The aim of this research was to conduct a pilot study to measure the effectiveness of the Collaborative Care Skills Training Workshops (CCSTW) on the outcomes of Spanish carers and to analyse the impact of this programme on the patient's wellbeing. We used psychoeducation as a comparison intervention in the study. METHOD: The study compared two forms of carer workshops. 64 carers and 37 eating disorder patients participated in this study. Carers were randomised to either the CCSTW or the Psycho-educational programme. This study used an experimental intervention design with evaluations before, after and at a 3-month follow-up. RESULTS: Carers receiving both intervention programmes showed an improvement in wellbeing indicating a benefit from the training. The course of burden, psychological distress, expressed emotion and illness perception was similar in the two groups. In patients whose caregivers had participated in CCSTW programme the levels of anxiety, depression and psychological distress decreased. CONCLUSIONS: These findings suggest that carer distress, burden, illness perception and expressed emotion can be alleviated if they are helped in this role. There appear to be secondary benefits of the CCSTW on patients' wellbeing. PMID- 30009754 TI - Trait emotional intelligence and subjective well-being in adolescents: The moderating role of feelings. AB - BACKGROUND: Trait emotional intelligence (EI) is a key concept related to different well-being indicators. These relationships, mediated by affective variables, have mainly been found in adults. However, little is known about these associations with moderating effects of feelings in adolescents and certain indicators of well-being. This study examined the moderating role of feelings in the relation between trait emotional intelligence and several indicators of well being (life satisfaction, self-perceived stress and somatic complaints) in adolescents. METHODS: The sample was composed of 1,273 pupils from 10 high schools, aged between 12 and 16 (M=13.63 years; SD=1.22) 666 (52.7%) were girls. RESULTS: The results supported different pathways between trait emotional intelligence (especially attention and clarity) and well-being indicators. CONCLUSIONS: No moderating role of feelings could be found in this relationship. This data supports the direct influence of EI on the improvement of adolescent well-being. PMID- 30009753 TI - Taste priming and cross-modal taste-olfactory priming in normal aging and in older adults with mild cognitive impairment. AB - BACKGROUND: Previous research has shown repetition priming for objects between vision and touch, environmental sounds and pictures in young and older adults. METHODS: This preliminary study investigated whether repetition priming exists for edible stimuli and if it is preserved in healthy older adults and older adults with mild cognitive impairment (MCI) (Experiment 1). Experiment 2 investigated whether cross-modal repetition priming between taste and olfaction is preserved with age and cognitive impairment. RESULTS: The results of Experiment 1 showed significant repetition priming effects for edible stimuli presented to taste, but there was a significant decrease in performance with age and cognitive decline. Experiment 2 showed cross-modal taste to olfactory priming in young adults and healthy older people, but the performance of older adults with MCI did not differ from zero. Again, identification decreased significantly in older adults and was absent in those with MCI. CONCLUSIONS: Implicit memory for stimuli presented to taste persists in healthy older adults and those with MCI, although their performance declined compared to young adults. The finding of cross-modal taste and olfactory priming suggests the connection between these two chemosensory perceptual modalities. PMID- 30009755 TI - Anomalies in the cognitive-executive functions in patients with Chiari Malformation Type I. AB - BACKGROUND: Over the last decade there has been growing evidence that neuropsychological deficits, principally in the executive functions, may be involved in the pathogenesis of Chiari Type I disease. The aim of this study is to compare changes in cognitive function in patients with Chiari Type I and healthy subjects. METHOD: The neuropsychological profile of these patients was compared with healthy controls. Three neuropsychological tests were administered to both Chiari Type I patients and healthy controls to assess the frontal executive functions of vigilance or selective attention, mental flexibility, planning and concept formation. RESULTS: The results suggest that Chiari Type I patients are affected in the processes of inhibition and self-control as well as in attention capacity and maintaining a course of thought and action. CONCLUSIONS: These results provide evidence of possible deficits or anomalies in the cognitive executive functions of patients with Chiari Type I. PMID- 30009756 TI - Discovering learning processes using Inductive Miner: A case study with Learning Management Systems (LMSs). AB - BACKGROUND: Process mining with educational data has made use of various algorithms for model discovery, principally Alpha Miner, Heuristic Miner, and Evolutionary Tree Miner. In this study we propose the implementation of a new algorithm for educational data called Inductive Miner. METHOD: We used data from the interactions of 101 university students in a course given over one semester on the Moodle 2.0 platform. Data was extracted from the platform's event logs; following preprocessing, the mining was carried out on 21,629 events to discover what models the various algorithms produced and to compare their fitness, precision, simplicity and generalization. RESULTS: The Inductive Miner algorithm produced the best results in the tests on this dataset, especially for fitness, which is the most important criterion in terms of model discovery. In addition, when we weighted the various metrics according to their importance, Inductive Miner continued to produce the best results. CONCLUSIONS: Inductive Miner is a new algorithm which, in addition to producing better results than other algorithms using our dataset, also provides valid models which can be interpreted in educational terms. PMID- 30009757 TI - Development and validation of the Monopoly on Truth Scale. A measure of political extremism. AB - BACKGROUND: Extreme political attitudes have been on the rise since the economic and political crisis of 2008. This surge of extremism constitutes a real threat, as attitudes like these are dangerous for the peaceful, democratic functioning of society. A new cognitive style, Monopoly on Truth has been proposed, based mainly on the concept of naive realism. METHOD: The development and validation of a scale for this new construct is the main objective of this study. A pilot study (N=209) was performed in order to gather the items that make up the final scale; and a main study (N=369) was conducted to test the validity and predictive power of the scale. RESULTS: The validation is successful as the scale shows good reliability scores, while also proving to be linked to extremism-related constructs. Additionally, the scale shows signs of not being ideologically biased. CONCLUSION: Results show the scale to be a very useful tool for studying extremism and other political trends. Future directions and other implications of the Monopoly on Truth are also discussed. PMID- 30009758 TI - Validity and reliability of the Parental Homework Management Scale. AB - BACKGROUND: Prior research has shown that parents help their children manage homework (i.e. environment, time, motivation and emotion management), especially in elementary school. However, researchers have not developed and validated a scale focused on those dimensions. METHOD: The purpose of the present study is to validate the Parental Homework Management Scale (PHMS) for parents of elementary school children in the domain of mathematics. A sample of 2,118 parent-child dyads was split randomly into two groups to conduct the analysis in two stages: (i) exploratory factor analysis on Group 1 and (ii) confirmatory factor analysis on Group 2. RESULTS: PHMS is comprised of two distinct but related factors (i.e. environment-time and motivation-emotion management). Results further indicated that the PHMS was positively related to homework self-regulation and positive emotions, and negatively related to math achievement. Contrary to expectations, no relationship was found between PHMS and amount of student homework completed. CONCLUSIONS: The scale revealed good psychometric quality. PMID- 30009759 TI - Validity evidence of the Organizational Justice Scale in Spain. AB - BACKGROUND: Interest in measuring the perception of organizational justice has been growing in recent years due to its proven ability to produce significant organizational outcomes such as well-being and emotional exhaustion. In Spain, the Organizational Justice Scale (OJS) can be highlighted as an instrument which has shown good psychometric properties in previous research in the hotel industry. This study provides further evidence of the characteristics of the OJS using a large multi-sectorial sample. METHOD: Participants comprised 849 employees from different occupational sectors. The structure of the OJS was studied by means of an exploratory and confirmatory factor analysis splitting the sample up into two random subsamples. The reliability and validity of each dimension was also analyzed. RESULTS: Results indicated a three-factorial structure: distributive, procedural, and interactional, offering adequate reliability and validity. As expected, positive correlations were found between perception of organizational justice and well-being, and negative correlations with respect to emotional exhaustion. CONCLUSIONS: OJS is an appropriate tool for use by researchers and practitioners in the study of the perception of organizational justice in Spain, additionally ensuring adequate validity and reliability. PMID- 30009760 TI - Accuracy of bone resection in total knee arthroplasty using CT assisted-3D printed patient specific cutting guides. AB - INTRODUCTION: We conducted this study to determine if the pre-surgical patient specific instrumented planning based on Computed Tomography (CT) scans can accurately predict each of the femoral and tibial resections performed through 3D printed cutting guides. The technique helps in optimization of component positioning determined by accurate bone resection and hence overall alignment thereby reducing errors. METHODS: Prophecy evolution medial pivot patient specific instrumented knee replacement systems were used for end stage arthrosis in all consecutive cases over a period of 20 months by a single surgeon. All resections (4 femoral and 2 tibial) were measured using a vernier callipers intraoperatively. These respective measurements were then compared with the preoperative CT predicted bone resection surgical plan to determine margins of errors that were categorized into 7 groups (0 mm to >=2.6 mm). RESULTS: A total of 3618 measurements (averaged to 1206) were performed in 201 knees (105 right and 96 left) in 188 patients (112 females and 76 males) with an average age of 67.72 years (44 to 90 years) and average BMI of 32.3 (25.1 to 42.3). 94% of all collected resection readings were below the error margin of <=1.5 mm of which 90% showed resection error of <=1 mm. Mean error of different resections were <=0.60 mm (P <= 0.0001). In 24% of measurements there were no errors or deviations from the templated resection (0.0 mm). CONCLUSION: The 3D printed cutting blocks with slots for jigs accurately predict bone resections in patient specific instrumentation total knee arthroplasty which would directly affect component positioning. PMID- 30009762 TI - Erratum. PMID- 30009761 TI - The proteasome as a target to combat malaria: hits and misses. AB - The proteasome plays a vital role throughout the life cycle as Plasmodium parasites quickly adapt to a new host and undergo a series of morphologic changes during asexual replication and sexual differentiation. Plasmodium carries 3 different types of protease complexes: typical eukaryotic proteasome (26S) that resides in the cytoplasm and the nucleus, a prokaryotic proteasome homolog ClpQ that resides in the mitochondria, and a caseinolytic protease complex ClpP that resides in the apicoplast. In silico prediction in conjunction with immunoprecipitation analysis of ubiquitin conjugates have suggested that over half of the Plasmodium falciparum proteome during asexual reproduction are potential targets for ubiquitination. The marked potency of multiple classes of proteasome inhibitors against all stages of the life cycle, synergy with the current frontline antimalarial, artemisinin, and recent advances identifying differences between Plasmodium and human proteasomes strongly support further drug development efforts. PMID- 30009763 TI - Erratum. PMID- 30009764 TI - Herd-level risk factors associated with Brucella sero-positivity in cattle, and perception and behaviours on the disease control among agro-pastoralists in Tanzania. AB - Brucellosis is endemic in Tanzania, particularly in agro-pastoral areas. This study investigated the herd-level sero-prevalence and risk factors for Brucella sero-positivity in cattle, and perception and behaviours associated with brucellosis control among agro-pastoralists in Morogoro Region, Tanzania. A cross sectional study involving herd milk diagnosis by indirect enzyme-linked immunosorbent assay and questionnaire survey was conducted in 124 farms. Questions included potential risk factors, knowledge of brucellosis, willingness to-pay for cattle vaccination, and item count technique (ICT) for selling behaviour of cows that experienced abortion. Risk factor analysis for Brucella sero-positivity in cattle and analysis of factors associated with willingness-to pay were conducted using classical tests and generalised linear models. Most farmers had little knowledge about brucellosis (disease name: 13.7%, symptoms: 3.2%, transmission from cattle to human: 2.4%, and Brucella vaccine: 2.4%). The proportion of Brucella sero-positive herd was 44.4% (55/124, 95%CI: 35.5-53.5). No risk factors for Brucella sero-positivity were identified; however, using a veterinary service was identified as a preventive factor (OR = 0.39, 95%CI: 0.18 0.84, p = 0.02). For scenarios of vaccinating all cattle and only calves, 59.7% and 89.5% of farmers were willing to pay for vaccination, respectively. Being a Maasai tribe member was a hesitating factor for vaccinating all cattle (OR = 0.39, 95%CI: 0.19-0.83, p = 0.01) and using a veterinary service was an encouraging factor for vaccinating calves (OR = 4.0, 95%CI: 1.2-13.0, p = 0.02). The ICT found that 45.1% of farmers sold cows that experienced abortion. This estimate was not statistically different from that obtained by direct questioning (34.1%, SE = 7.5%, binomial p value = 0.27, factor score = 1.32), suggesting that farmers did not hesitate to sell such cows. The Maasai conducted more risky behaviours for human infection such as drinking raw milk (p = 0.06) or blood (p < 0.01) and helping delivery with bare hands (p = 0.03) than other tribes. Community-based brucellosis control programmes with calf vaccination may be feasible in the study areas. A One Health approach including the promotion of health education and expansion of veterinary services is crucial for disease control. PMID- 30009765 TI - Composition and structure of glycosaminoglycans in DBS from 2-3-day-old newborns for the diagnosis of mucopolysaccharidosis. AB - Dried blood spot (DBS) technology is a cheap and easy method largely applied in newborn screening. Mucopolysaccharidoses (MPS) are characterized by the deficit of enzymes that degrade glycosaminoglycans (GAGs) characterized by progressive worsening of the conditions. For a possible early diagnosis of MPS, we developed a method of uronic acid (UA)-GAGs determination in DBS of 600 healthy newborns and from a small group of MPS subjects matched for age. Spotted blood UA-GAGs of the normal newborns are composed of 67.2% chondroitin sulfate (CS), 28.6% heparan sulfate (HS) and 4.4% hyaluronic acid with a CS/HS ratio of 2.35 and a total GAGs content of 0.43 MUg/DBS. A chemical evaluation of CS and HS structure was performed by measuring their disaccharide composition, sulfation and the overall charge density. The DBS of four different MPS types presented an increase of total or single UA-GAGs content and/or modifications of the CS and HS disaccharide composition as well as chemical signature also related to the MPS enzymatic defect. The modifications of the UA-GAGs composition, parameters and structure of healthy newborns determined in DBS would be useful for a possible early diagnosis of various MPS types. PMID- 30009766 TI - High-fat diet suppresses the astrocytic process arborization and downregulates the glial glutamate transporters in the hippocampus of mice. AB - Metabolic disorders induce adverse effects on brain functions. The hippocampus is one of the most vulnerable regions to metabolic disorders. Disrupted neuroplasticity is a major cause of hippocampus-related behavioral impairments, including memory loss, anxiety, and depression. Astrocytes support processes of neuroplasticity. However, whether metabolic disorders induce changes in astrocytes and their roles in affective disorders is relatively unclear. To answer this question, we fed 8-week-old male C57BL/6 mice with a high-fat diet (HFD) for 12 weeks to induce metabolic disruption and then examined their performance of hippocampus-related memory, and anxiety- and depression-like behaviors. The morphology of astrocytes and the expression of astrocytic neuroplasticity-related proteins in the hippocampus were also assessed. The results showed that HFD led to obesity, systemic insulin resistance and dysregulated lipid metabolism in mice. HFD induced depression-like behaviors, but not anxiety or memory impairment. Furthermore, HFD increased the expression of GFAP, shortened the processes of GFAP+ cells, and downregulated the expression of astrocytic neuroplasticity-related protein, GLAST, GLT-1, and connexin-43 in the hippocampi. In conclusion, HFD disturbs the function of hippocampal astrocytes and induces depression-like behaviors in mice. A decrease of hippocampal glutamate transporters may play a critical role in the pathogenesis of metabolic disorder-related depression. PMID- 30009767 TI - Stoichiometry dependent inhibition of rat alpha3beta4 nicotinic acetylcholine receptor by the ribbon isomer of alpha-conotoxin AuIB. AB - The ribbon isomer of alpha-conotoxin AuIB has 10-fold greater potency than the wild-type globular isomer at inhibiting nicotinic acetylcholine receptors (nAChRs) in rat parasympathetic neurons, and unlike its globular isoform, ribbon AuIB only targets a specific stoichiometry of the alpha3beta4 nAChR subtype. Previous electrophysiological recordings of AuIB indicated that ribbon AuIB binds to the alpha3(+)alpha3(-) interface within the nAChR extracellular domain, which is displayed by the (alpha3)3(beta4)2 stoichiometry but not by (alpha3)2(beta4)3. This specificity for a particular stoichiometry is remarkable and suggests that ribbon isoforms of alpha-conotoxins might have great potential in drug design. In this study, we investigated the binding mode and structure-activity relationships of ribbon AuIB using a combination of molecular modeling and electrophysiology recording to determine the features that underpin its selectivity. An alanine scan showed that positions 4 and 9 of ribbon AuIB are the main determinants of the interaction with (alpha3)3(beta4)2 nAChR. Our computational models indicate that the first loop of ribbon AuIB binds in the "aromatic box" of the acetylcholine orthosteric binding site, similar to that of globular AuIB. In contrast, the second loop and the termini of the ribbon isomer have different orientations and interactions in the binding sites to those of the globular isomer. The structure-activity relationships reported herein should be useful to design peptides displaying a ribbon alpha-conotoxin scaffold for inhibition of nAChR subtypes that have hitherto been difficult to selectively target. PMID- 30009768 TI - Resveratrol represses estrogen-induced mammary carcinogenesis through NRF2-UGT1A8 estrogen metabolic axis activation. AB - Estrogen plays a pivotal role in the pathological development of breast cancer. Resveratrol has chemo-preventive effects against breast cancer, whereas, the mechanism of antitumor activities of resveratrol remains unanswered. In this study, we showed that estrogen homeostasis profile was disturbed in both breast cancer patients and in experimental breast cancer model rats, with carcinogenic catechol estrogens significantly accumulated in the mammary tissues. UDP glucuronosyltransferase 1A8 (UGT1A8) is an important phase II drug-metabolizing enzymes which involved in the metabolism of catechol estrogens. Here we found that the mammary nuclear factor erythroid 2-related factor 2 (NRF2) - UGT1A8 signaling was down-regulated in breast cancer rats, whereas treatment with resveratrol could upregulate the expression of NRF2 and UGT1A8, accelerate metabolic elimination of catechol estrogens, inhibit estrogen-induced DNA damage and suppress the pathological development of breast cancer. In addition, luciferase reporter assay suggested that resveratrol activated the expression of UGT1A8 by up-regulating the transcriptional activity of NRF2. Small-interfering RNA-mediated silencing of NRF2 abolished resveratrol-mediated preventive effects indicated that the antitumor effect of resveratrol is based on NRF2-UGT1A8 estrogen metabolism axis. Taken together, we established the resveratrol regulating potential on estrogen homeostasis based on NRF2-UGT1A8 signaling pathway, and also provided a novel link between estrogen glucuronidation metabolism and breast cancer pathological development. PMID- 30009769 TI - Perspectives on Structural Molecular Biology Visualization: From Past to Present. AB - Visualization has been a key technology in the progress of structural molecular biology for as long as the field has existed. This perspective describes the nature of the visualization process in structural studies, how it has evolved over the years, and its relationship to the changes in technology that have supported and driven it. It focuses on how technical advances have changed the way we look at and interact with molecular structure, and how structural biology has fostered and challenged that technology. PMID- 30009770 TI - Modifying Chromatin by Histone Tail Clipping. AB - Post-translational modifications (PTMs) of histone proteins play a crucial role in the regulation of chromatin structure and functions. Studies in the last few decades have revealed the significance of histone PTMs in key cellular processes including DNA replication, repair, transcription, apoptosis and cell cycle regulation. The PTMs on histones are carried out by chromatin modifiers, which are reversible in nature. The dynamic activity of chromatin modifiers maintains the levels of different PTMs on histones. The modified histones are recognized by reader proteins, which recruit effector proteins to regulate the function. The interplay between histone PTMs and chromatin dynamics plays a major role in the regulation of most of the cellular processes. Importantly, the perturbations in the histone PTMs by various intrinsic or extrinsic factors can cause defects in fundamental cellular processes leading to a wide range of diseases. The proteolytic clipping of histone proteins has also been shown to regulate many biological processes. Histone clipping has been observed from yeast to mammals, suggesting that this mechanism is a conserved epigenetic phenomenon. In this review, we have summarized the significance of histone clipping and provided future directions to comprehend the mechanism of this distinct and poorly understood epigenetic event. PMID- 30009772 TI - Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH). AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths worldwide. Among others, non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the two major risk factors as both of them may develop cirrhosis and hepatocellular carcinoma (HCC) if left untreated. However, patients with NASH progress to HCC at a rate around 0.5% annually, while 3-10% ASH patients may progress to HCC annually. The present study is to demonstrate the molecular differences in oncogenesis pathway between NASH and ASH. By using immunofluorescence study and quantitating the fluorescence intensity morphometrically in liver biopsied specimens from NASH and ASH patients, the protein expression of candidate molecules within hepatocytes cytoplasm are studied, including two HCC-related molecules FAT10 and FOXO1, and one GPCR pathway related molecule ADRA2A. Compared with the control group patients, the expression levels of all the molecules were upregulated in the ASH group of patients (p < 0.001 in all molecules), while FAT10 and ADRA2A were upregulated, FOXO1 did not change in the NASH group of patients. The most important finding is that compared with the ASH group of patients, the expression levels of all three molecules were significantly lower than in the NASH group of patients (p < 0.001 in all molecules). These results confirmed our previous finding that there are significant differences of molecules change in ASH compared to NASH. Thus, we conclude that there are significantly different molecules and pathways involved during the pathogenesis of HCC development in ASH compared to NASH which could help explain why the tumorigenic rate is different in ASH and NASH. PMID- 30009773 TI - Immunohistochemistry is a feasible method to screen BRAF V600E mutation in colorectal and papillary thyroid carcinoma. AB - AIMS: To investigate whether immunohistochemistry (IHC) could be used to screen BRAF mutation status in formalin-fixed paraffin-embedded (FFPE) colorectal carcinoma (CRC) and papillary thyroid carcinoma (PTC) samples. METHODS: Eight surgical resected samples, including 2 CRCs with mutated BRAF V600E, 2 PTCs with mutated BRAF V600E, 2 CRCs with wild-type BRAF and 2 PTCs with wild-type BRAF, were selected to explore the optimized IHC conditions for BRAF V600E (VE1) immunostaining using BenchmarkXT automated immunostainer VENTANA Medical System. BRAF V600E status was tested by optimized IHC and ARMS-PCR methods in 255 samples (123 CRCs and 132 PTCs). Sanger sequencing was performed to validate the BRAF V600E status if discordant results were found between optimized IHC and ARMS-PCR methods. RESULTS: Antigen retrieval time in 32 min and 64 min showed satisfactory intensity and homogeneity of BRAF V600E staining in CRC and PTC samples, respectively. The concordance between IHC and ARMS/Sanger sequencing was 99.2% (122/123) in CRCs and 96.2% (127/132) in PTCs. In CRCs, the sensitivity of IHC staining for BRAF V600E was 100% (3/3) and the specificity was 99.1% (119/120). In PTCs, the sensitivity was 100% (106/106) and specificity was 80.8% (21/26). The overall concordance across all cases was 97.6% (249/255). CONCLUSION: The appropriate antigen retrieval protocol is critical for accurate analysis of BRAF V600E status by Benchmark XT automated immunostainer. IHC is a suitable method to screen BRAF V600E mutation in FFPE samples of CRCs and PTCs. PMID- 30009774 TI - Piecemeal necrosis is due to the immunologic synapse formation and internalization of intact TCR-MHC II complexes by CD4 T cells. AB - The nature of the immunologic synapse in autoimmune hepatitis is defined. This process involves the T cell receptor (TCR) which binds to the hepatocyte antigen presenting major histocompatibility complex (MHC) on the plasma membrane. This complex is quickly removed from the liver cell and taken into the T cell cytoplasm to be digested by the lysosome. The liver cell is gradually diminished to the point of its total removal by the lymphocytes binding to it. PMID- 30009775 TI - Proteasome mediated degradation of CDC25C and Cyclin B1 in Demethoxycurcumin treated human glioma U87 MG cells to trigger G2/M cell cycle arrest. AB - Recently, we have reported that Demethoxycurcumin induced Reactive oxygen species via inhibition of Mitochondrial Superoxide Dismutase is an initial event to trigger apoptosis through caspase-8 and 9 activation and to inhibit Akt/NF-kappaB survival signaling in human glioma U87 MG cells (Kumar et al., 2018). Although cell-cycle disruption had been suggested to be the possible mechanism for DMC inhibitory effect on human glioma U87 MG cells, comprehensive mechanisms of cell cycle arrest caused by DMC are not fully understood. The present study was designed to elucidate the DMC induced mechanism of cell cycle arrest in human glioma U87 MG cells. In this study, the results illustrated that DMC induced Reactive oxygen species (ROS) leads to reduced expression of CDC25C, Cyclin B1 and CDK1 (Thr161) triggers G2/M cell cycle arrest in U87 MG glioma cells. Moreover, the DMC induced ROS generation activates ubiquitination and proteasome degradation of CDC25C and Cyclin B1 in U87MG glioma cells. In addition, the immunoprecipitation results showed that significant dissociation of CDK1or CDC2 Cyclin B1 complex leads to G2/M cell cycle arrest. To explore the possibility of direct involvement of DMC in the dissociation of CDK1/Cyclin B1 complex, the molecular docking and MD simulation studies were carried. The results showed that DMC nicely fitted into the binding site of CDK1 and Cyclin B1 with minimum binding energy (DeltaG) of -9.46 kcal/mol (Ki = 0.11 MUM) and - 9.90 kcal/mol (Ki = 0.05 MUM) respectively. Therefore, this is the first study demonstrating CDC25C and Cyclin B1 proteins could be used as potential target for anticancer therapy and DMC may be explored as new therapeutic agent in the cure of Glioblastoma (GBM). PMID- 30009776 TI - Triptolide induces p53-dependent cardiotoxicity through mitochondrial membrane permeabilization in cardiomyocytes. AB - Triptolide (TP), a major active component of Tripterygium wilfordii Hook f., is widely used in the treatment of inflammation and autoimmune disorders. Its clinical application is limited by severe adverse effects, especially cardiotoxicity. Accumulative evidences indicate that TP induces DNA damage by inhibiting RNA polymerase. Considering the relationship among DNA damage, p53, and the role of p53 in mitochondria-dependent apoptosis, we speculate that TP induced cardiotoxicity results from p53 activation. In this study, the role of p53 in TP-induced cardiotoxicity was investigated in H9c2 cells, primary cardiomyocytes, and C57BL/6 genetic background p53-/- mice. p53 protein level was elevated by TP in vitro and in acute heart injury models. With TP administration (1.2 mg/kg), p53 deficiency prevented heart histology injury and decreased serum cardiac troponin I (cTn-I) and apoptotic proteins. Mechanistically, immunoblotting and immunofluorescence staining identified that TP-induced toxicity is dependent on p53 nuclear translocation and transactivation of Bcl2 family genes, leading to mitochondrial outer membrane permeabilization (MOMP) and mitochondria dysfunction. Consistently, p53 antagonist PFTalpha counteracted TP induced p53 overexpression and regulation of Bcl2 family transcription, which improved mitochondrial membrane integrity and prevented apoptosis. Moreover, Bax antagonist Bax inhibitor peptide (BIP) V5 ameliorated TP-induced apoptosis through suppressing membrane depolarization and ROS accumulation. These results suggest that TP-induced cardiotoxicity is p53-dependent by promoting Bax-induced mitochondria-mediated apoptosis. PMID- 30009777 TI - Restoration of cardiac function after anaemia-induced heart failure in zebrafish. AB - AIMS: New therapeutic approaches are needed to fight against the growing epidemic of heart failure. Unlike mammals, zebrafish possess the incredible ability to regenerate cardiac tissue after acute trauma such as apical resection. Yet, the ability of zebrafish to recover after a chronic stress leading to heart failure has not been reported. The aim of this study was to test whether zebrafish can recover a normal cardiac function after anaemia-induced heart failure. METHODS AND RESULTS: Eight- to ten-month-old zebrafish were treated with phenylhydrazine hydrochloride, an anaemia inducer, to generate heart failure. Treatment was stopped after 5 weeks and fish were followed-up for 3 weeks. Assessment of ventricular function by ultrasound at the end of the treatment revealed an increase in ventricle diameter (+47%) and a decrease in heart rate (-36%) and fractional shortening (-30%). A decrease in swim capacity was also observed ( 31%). Tissue staining showed a thickening of the ventricular wall (5-fold), cell apoptosis and proliferation but no fibrosis. Expression of foetal genes, angiogenic factor and inflammation markers was increased, and beta-adrenergic receptor-1 was decreased. Three weeks after phenylhydrazine hydrochloride withdrawal, all parameters returned to baseline and the fish recovered a normal cardiac function, tissue morphology and gene expression. CONCLUSIONS: Zebrafish are able to completely recover from anaemia-induced heart failure. This model represents a unique opportunity to investigate the mechanisms of cardiac repair and may lead to the discovery of novel therapeutic targets of heart failure. PMID- 30009771 TI - The Role of Functional Amyloids in Bacterial Virulence. AB - Amyloid fibrils are best known as a product of human and animal protein misfolding disorders, where amyloid formation is associated with cytotoxicity and disease. It is now evident that for some proteins, the amyloid state constitutes the native structure and serves a functional role. These functional amyloids are proving widespread in bacteria and fungi, fulfilling diverse functions as structural components in biofilms or spore coats, as toxins and surface-active fibers, as epigenetic material, peptide reservoirs or adhesins mediating binding to and internalization into host cells. In this review, we will focus on the role of functional amyloids in bacterial pathogenesis. The role of functional amyloids as virulence factor is diverse but mostly indirect. Nevertheless, functional amyloid pathways deserve consideration for the acute and long-term effects of the infectious disease process and may form valid antimicrobial targets. PMID- 30009778 TI - Quantitative temporal analysis of protein dynamics in cardiac remodeling. AB - Cardiac remodeling (CR) is a complex dynamic process common to many heart diseases. CR is characterized as a temporal progression of global adaptive and maladaptive perturbations. The complex nature of this process clouds a comprehensive understanding of CR, but greater insight into the processes and mechanisms has potential to identify new therapeutic targets. To provide a deeper understanding of this important cardiac process, we applied a new proteomic technique, PALM (Pulse Azidohomoalanine in Mammals), to quantitate the newly synthesized protein (NSP) changes during the progression of isoproterenol (ISO) induced CR in the mouse left ventricle. This analysis revealed a complex combination of adaptive and maladaptive alterations at acute and prolonged time points including the identification of proteins not previously associated with CR. We also combined the PALM dataset with our published protein turnover rate dataset to identify putative biochemical mechanisms underlying CR. The novel integration of analyzing NSPs together with their protein turnover rates demonstrated that alterations in specific biological pathways (e.g., inflammation and oxidative stress) are produced by differential regulation of protein synthesis and degradation. PMID- 30009779 TI - A global accounting of medically significant scorpions: Epidemiology, major toxins, and comparative resources in harmless counterparts. AB - Scorpions are an ancient and diverse venomous lineage, with over 2200 currently recognized species. Only a small fraction of scorpion species are considered harmful to humans, but the often life-threatening symptoms caused by a single sting are significant enough to recognize scorpionism as a global health problem. The continued discovery and classification of new species has led to a steady increase in the number of both harmful and harmless scorpion species. The purpose of this review is to update the global record of medically significant scorpion species, assigning each to a recognized sting class based on reported symptoms, and provide the major toxin classes identified in their venoms. We also aim to shed light on the harmless species that, although not a threat to human health, should still be considered medically relevant for their potential in therapeutic development. Included in our review is discussion of the many contributing factors that may cause error in epidemiological estimations and in the determination of medically significant scorpion species, and we provide suggestions for future scorpion research that will aid in overcoming these errors. PMID- 30009780 TI - Regulation of aldose reductase activity by tubulin and phenolic acid derivates. AB - In this work we demonstrate that aldose reductase (AR) interacts directly with tubulin and, was subjected to microtubule formation conditions, enzymatic AR activity increased more than sixfold. Since AR interacts mainly with tubulin that has 3-nitro-tyrosine in its carboxy-terminal, we evaluated whether tyrosine and other phenolic acid derivatives could prevent the interaction tubulin/AR and the enzymatic activation. The drugs evaluated have two characteristics in common: the presence of an aromatic ring and a carboxylic substituent. The 9 drugs tested were able to prevent both the interaction tubulin/AR and the enzymatic activation. In addition, we found that the induction of microtubule formation by high concentrations of glucose and the consequent activation of AR in cultured cells can be inhibited by phenolic acid derivates that prevent the interaction tubulin/AR. These results suggest that tubulin regulates the activation of AR through a direct interaction which can be controlled with phenolic derivates of carboxylic acids. PMID- 30009781 TI - The role of mitochondrial KATP channel in anti-inflammatory effects of uridine in endotoxemic mice. AB - In this study, we examined the effects of uridine on plasma cytokine levels, heat shock protein (HSP) 72 expression, and nuclear factor (NF)-kappaB signaling in spleen lymphocytes after exposure of male BALB/c mice to Escherichia coli lipopolysaccharide (LPS). Mice were treated with uridine (30 mg/kg body weight, intraperitoneal injection [i.p.]) or saline solution of LPS (2.5 mg/kg, i. p.). Endotoxin increased plasma levels of tumor necrosis factor-alpha, interferon gamma, interleukin (IL)-1, IL-2, and IL-6 by 2.1-, 1.9-, 1.7-, 1.6-, and 2.3 fold, respectively. Prior treatment with uridine prevented LPS-induced increases in all studied cytokines. In splenic lymphocytes, LPS treatment increased the expression of HSP 72 by 2.4-fold, whereas preliminary treatment with uridine completely prevented this effect. LPS also activated NF-kappaB signaling in splenic lymphocytes, and uridine decreased NF-kappaB pathway activity. Inhibitory analysis showed that the mechanism of uridine action was associated with the formation of the UDP-metabolic activator of the mitochondrial ATP-dependent potassium channel (mitoKATP) and the UTP-activator of glycogen synthesis in the tissues. A specific inhibitor of mitoKATP, 5-hydroxydecanoate (5 mg/kg), and an inhibitor of glycogen synthesis, galactosamine (110 mg/kg), prevented the effects of uridine. Thus, uridine itself or uridine phosphates, which increased after uridine treatment, appeared to inhibit pro-inflammatory responses induced by LPS application. Overall, these findings demonstrated that the mechanisms mediating the effects of uridine were regulated by activation of glycogen synthesis and opening of the mitoKATP, which in turn increased the energy potential of the cell and reduced oxidative stress. PMID- 30009782 TI - Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress in prostate cancer progression by regulating MAP3K12. AB - It has been reported that mircoRNAs (miRNAs) can act as tumor inhibitors in multiple malignant tumors. As a tumor suppressor, miR-150-5p has been reported in some cancers. However, the biological impacts of miR-150-5p in prostate cancer is not fully elaborated. This study aims to explore the biological role and mechanism of miR-150-5p in prostate cancer. The expression level of miR-150-5p was examined with Quantitative real time polymerase chain reaction (qRT-PCR). Moreover, Kaplan Meier analysis revealed that downregulation of miR-150-5p predicted unfavorable prognosis for patients with prostate cancer. To identify the inhibitory effects of miR-150-5p on the cellular processes of prostate cancer, gain-of function assay was conducted. Next, the inhibitory effects of Tetrachlorodibenzo-p-dioxin (TCDD) and 3,3'-Diindolylmethane (DIM) on the proliferation and invasion of prostate cancer cells were demonstrated. Knockdown of Ahr reversed the TCDD/DIM-mediated proliferation and invasion. The expression level of CYP1A1 also was measured to confirm that Ahr was activated by TCDD or DIM in prostate cancer cells. Mechanism experiments revealed that MAP3K12 is a target mRNA of miR-150-5p in prostate cancer cells. In conclusion, Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress cell proliferation and invasion in prostate cancer by regulating MAP3K12. PMID- 30009783 TI - Serum biomarkers to predict liver fibrosis in hepatitis B. PMID- 30009784 TI - Temporomandibular Joint Pain Presentation of Myocardial Ischemia. AB - Cardiovascular disease is a leading cause of death worldwide. We report a case of myocardial infarction for which temporomandibular joint (TMJ) pain was the sole presenting initial symptom. A 28-year-old man presented to a dental clinic reporting TMJ pain. He was an active duty infantry solider in the US Army who was otherwise healthy and in excellent physical condition. He reported a 3-week history of intense throbbing to his left TMJ, specifically during physical activities and weight lifting. On examination by his general dentist, his blood pressure, heart rate, respiratory rate, and temperature were unremarkable. His maximal incisal opening was more than 45 mm without pain and demonstrated deviation, crepitus, and a full range of excursive movements without restrictions or provocation of pain. A hard night guard appliance was fabricated, and muscular physical therapy instructions were given, because his symptoms were thought to be related to muscle-related pain, possibly related to bruxism. He was referred to the oral and maxillofacial surgery (OMS) department for further evaluation and a second opinion. Before his appointment, he collapsed during physical training in cardiac arrest. He was brought to the emergency department and successfully resuscitated. He was found to have an 80% occlusion of his left anterior descending artery that was treated with a 1-vessel coronary artery bypass graft. After his cardiac surgery, he was seen and evaluated by OMS, and his TMJ symptoms had completely resolved. During the differential diagnosis of orofacial pain, clinicians should consider nonfacial sources of pain, especially referred cardiac pain that can mimic TMJ, odontogenic, and myofascial pain. PMID- 30009785 TI - Oral and Maxillofacial Surgery Resident Perception of Personal Achievement and Anxiety: A Cross-Sectional Analysis. AB - PURPOSE: Anxiety is prevalent among medical residents and is associated with fatigue, psychological dysfunction, and burnout. A low personal achievement level is a characteristic of burnout, which-if unaddressed-may lead to medical error and decrease the quality of patient care. This study aimed to assess both personal achievement levels and anxiety levels in current oral and maxillofacial surgery (OMS) residents and to discern a relationship between anxiety severity and perceived personal achievement level among residents. MATERIALS AND METHODS: An anonymous 20-question cross-sectional online survey was developed using the anxiety component of the Hospital Anxiety and Depression Scale and the personal Maslach Burnout Inventory. The survey was sent to all the OMS residents enrolled in programs affiliated with the American Association of Oral and Maxillofacial Surgeons in 2017. Univariate and bivariate analyses were conducted to obtain summary measures of the predictor (anxiety) and the outcome (personal achievement) stratified by age, gender, marital status, program type (4- or 6 year program), and year of residency. Multinomial logistic regression models were obtained to evaluate the association between anxiety and personal achievement. A 2-sided P < .05 was considered statistically significant. RESULTS: We received 238 responses (20% response rate); 58% of respondents had moderate or severe levels of anxiety, and nearly half of respondents reported moderate or low levels of personal achievement. Women were more likely to have severe anxiety than men (60% vs 37%, P < .01). Residents with severe anxiety were 91% more likely to report low levels of personal achievement than residents with low anxiety (odds ratio, 0.09; 95% confidence interval, 0.03 to 0.22; P < .0001). The results suggest the presence of an inverse relationship between personal achievement level and anxiety. CONCLUSIONS: More than half of OMS residents in the United States report moderate to severe anxiety. Higher levels of anxiety are associated with lower personal achievement levels. It is important to understand the negative impact anxiety has on trainees, including the unintended consequences. PMID- 30009786 TI - Frontal Sinus Morphology: A Reliable Factor for Classification of Frontal Bone Fractures? AB - PURPOSE: The frontal sinus shows a wide range of morphologic variations. The aim of this study was to evaluate the influence of frontal sinus size on fracture characteristics in frontal bone trauma. MATERIALS AND METHODS: In this cross sectional study, data from patients with traumatic fractures of the frontal bone were retrospectively collected from the institution's database. Radiometric analysis of computed tomography and cone-beam computed tomography datasets was performed. Frontal sinus size was measured as variables of height, width, and depth. The secondary predictor was morphologic sinus type according to Guerram's classification: hyperplasia, medium size, hypoplasia, or aplasia of the frontal sinus. To determine outcomes, we classified fractures into the following categories: fracture isolated to the anterior table, combined fractures of the anterior and posterior tables, fracture isolated to the posterior table, and frontal bone fracture without sinus involvement. Further study variables were patients' demographic characteristics, combined midfacial fractures, orbital rim involvement, fracture displacement, and surgical approach. For statistical analysis, fracture types were assessed for frontal sinus metric size and morphologic type using bivariate tests with P < .05 defined as significant. RESULTS: We enrolled 53 consecutive patients with a mean age of 35 years; male patients comprised 91%. Fracture types differed significantly in sinus width and height (both P < .001), as well as depth (P = .002). Frontal sinus morphology was hyperplastic in 66%, medium in 30.2%, and hypoplastic in 3.8%. Patients with a hyperplastic frontal sinus had an increased likelihood of isolated anterior table fractures (odds ratio, 6.0; P = .007) compared with medium-sized types. Fractures without sinus involvement were more likely in hypoplastic and medium types (P < .001). CONCLUSIONS: The morphology of the frontal sinus determines the probability of fracture types from craniofacial trauma. Thus the frontal sinus size appears to be a major factor for frontal bone resistance to traumatic force impingement. PMID- 30009787 TI - Regarding "The Millimeter Mindset: The Dental Underpinnings of an Inborn Surgical Advantage". PMID- 30009788 TI - In Reply. PMID- 30009789 TI - Influence of Platelet-Poor Plasma on Angiogenesis and Maintenance of Volume in Autogenous Bone Grafts. AB - PURPOSE: The aim of this study was to evaluate the effect of different storage media on angiogenesis and maintaining autogenous bone graft volume in rabbits. MATERIAL AND METHODS: Two grafts were removed bilaterally from the calvaria of 18 rabbits. One graft was removed and immediately fixed in the right mandibular angle (control group). The other graft was stored for 30 minutes in 1 of the following storage media (n = 6): saline solution (saline group), air exposure (dry group), or platelet-poor plasma (PPP group) and then retained by a screw in the right mandibular angle in the same animal. Four weeks later the animals were euthanized, and the grafted areas were harvested, fixed in 10% phosphate buffered formaldehyde solution, and embedded in paraffin. The 5-MUm semi-serial sections were stained in hematoxylin and eosin and Mallory trichrome. RESULTS: Histologic analysis of all groups showed the bone graft was vascularized and well incorporated into the recipient site. The number of blood vessels decreased in the saline and dry groups compared with the control group (P < .03); in contrast, the number of blood vessels increased in the PPP group (P < .05). There were fewer osteoclasts in the saline group compared with the control group (P < .05). Furthermore, the saline group showed larger numbers of blood vessels than the dry group (P < .01). The PPP group showed larger bone graft volumes compared with the dry and saline groups (P < .01). In addition, the saline group showed larger bone graft volumes than the dry group (P < .01). CONCLUSIONS: PPP improved angiogenesis, maintained the volume of the autogenous bone graft, and was a better storage medium during the trans-surgical period than the dry and saline media. PMID- 30009790 TI - Experimental Study on Involvement of the Central Nervous System in Inferior Alveolar Nerve Damage-Associated Hyperalgesia of the Mental Region. AB - PURPOSE: Involvement of the central nervous system in sensory disturbances of the mental region occurring after inferior alveolar nerve damage was investigated using a rat model of inferior alveolar nerve damage. PATIENTS AND METHODS: The rat inferior alveolar nerve was damaged by ligation with thread, and the course of behavioral changes after surgery was observed for 42 days. In addition, activation of microglia and astroglia in the trigeminal spinal subnucleus caudalis (Vc) was analyzed using immunohistochemistry. c-Fos-positive cells were quantitatively evaluated to analyze the state of neuron excitement. RESULTS: The withdrawal threshold was significantly decreased 5 days after surgery in the inferior alveolar nerve-ligated (IANL) group compared with that in the sham group and subsequently recovered over time. In addition, microglia and astroglia were activated in the Vc region 5 days after surgery in the model group, and c-fos positive cells were also significantly more frequent in the IANL group. However, no significant difference in the withdrawal threshold was seen between the IANL and sham groups on day 42, nor were any significant differences seen in the amounts of microglia, astroglia, or c-fos-positive cells. CONCLUSIONS: Interactions among microglia, astroglia, and neurons in the central nervous system might be involved in the progression of inferior alveolar nerve damage associated mental hyperalgesia to a chronic state. PMID- 30009791 TI - TCEA1 regulates the proliferative potential of mouse myeloid cells. AB - Leukemia is a malignance with complex pathogenesis and poor prognosis. Discovery of noval regulators amenable to leukemia could be of value to gain insight into the pathogenesis, diagnosis and prognosis of leukemia. Here, we conducted a large scale shRNA library screening for functional regulators in the development of myeloid cells in primary cells. We identified eighteen candidate regulators in the primary screening. Those genes cover a wide range of cellular functions, including gene expression regulation, intracellular signaling transduction, nucleotide excision repair, cell cycle control and transcription regulation. In both primary screening and validation, shRNAs targeting Tcea1, encoding the transcription elongation factor A (SII) 1, exhibited the greatest influence on the proliferative potential of cells. Knocking down the expression of Tcea1 in the 32Dcl3 myeloid cell line led to enhanced proliferation of myeloid cells and blockage of myeloid differentiation induced by G-CSF. In addition, silence of Tcea1 inhibited apoptosis of myeloid cells. Thus, Tcea1 was identified as a gene which can influence the proliferative potential, survival and differentiation of myeloid cells. These findings have implications for how transcriptional elongation influences myeloid cell development and leukemic transformation. PMID- 30009792 TI - STING positively regulates human ORMDL3 expression through TBK1-IRF3-STAT6 complex mediation. AB - Orosomucoid 1-like protein 3 (ORMDL3) is an asthma candidate gene associated with virus-triggered recurrent wheeze. Stimulator of interferon gene (STING) controls TLR-independent cytosolic responses to viruses. However, the association of STING with ORMDL3 is unclear. Here, we have shown that ORMDL3 expression shows a linear correlation with STING in recurrent wheeze patients. In elucidating the molecular mechanisms of the ORMDL3-STING relationship, we found that STING promoted the transcriptional activity of ORMDL3, which was significantly associated with increased levels of interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 6 (STAT6). Further study showed that via activation of TANK binding kinase 1 (TBK1), STING enhanced the phosphorylation and binding of IRF3 and STAT6, which upregulated ORMDL3 by binding to the promoter. Our results showed that STING positively regulated ORMDL3 through the TBK1-IRF3-STAT6 complex. PMID- 30009793 TI - Why does hyperglycinemia exhibit so grave brain anomalies and so severe neurological symptoms? AB - Nonketotic-hyperglycinemia (NKH) is an autosomal recessive disorder associated with grave brain malformations and severe neurological symptoms, and also characterized by accumulation of a large amount of glycine in body fluids. NKH is caused by an inherited deficiency of the glycine cleavage system (GCS), which is the main system to degrade glycine in mammalians. These severe symptoms and grave bran malformations are not normally observed in the other amino acid metabolic disorders, suggesting that GCS should have unknown pivotal roles in brain development and function. Interestingly, GCS is indispensable in supplying proliferating cells with 5,10-methylenetetrahydrofolate as a one-carbon donor, which is essential for the synthesis of DNA in cell proliferation. Since GCS is expressed intensely and ubiquitously in the neuroepithelium, the lack of GCS might greatly impair the proliferation of neural stem cells. On the other hand, this system is also very important to regulate extracellular glycine concentrations. Since glycine is an important neurotransmitter, which binds to both glycine receptors and NMDA receptors, high glycine concentrations caused by the deficiency of GCS might cause the aberrant neurotransmission in the patient brains. Considering these unique two faces of GCS functions, proliferation disturbance and aberrant neurotransmission are intricately mixed in the developing brain, leading to the grave brain malformations and sever neurological symptoms. PMID- 30009794 TI - Inferring parameters of prey switching in a 1 predator-2 prey plankton system with a linear preference tradeoff. AB - We construct two ordinary-differential-equation models of a predator feeding adaptively on two prey types, and we evaluate the models' ability to fit data on freshwater plankton. We model the predator's switch from one prey to the other in two different ways: (i) smooth switching using a hyperbolic tangent function; and (ii) by incorporating a parameter that changes abruptly across the switching boundary as a system variable that is coupled to the population dynamics. We conduct linear stability analyses, use approximate Bayesian computation (ABC) combined with a population Monte Carlo (PMC) method to fit model parameters, and compare model results quantitatively to data for ciliate predators and their two algal prey groups collected from Lake Constance on the German-Swiss-Austrian border. We show that the two models fit the data well when the smooth transition is steep, supporting the simplifying assumption of a discontinuous prey-switching behavior for this scenario. We thus conclude that prey switching is a possible mechanistic explanation for the observed ciliate-algae dynamics in Lake Constance in spring, but that these data cannot distinguish between the details of prey switching that are encoded in these different models. PMID- 30009795 TI - A "Large-N" Content Uniformity Process Analytical Technology (PAT) Method for Phenytoin Sodium Tablets. AB - Accurate assessment of tablet content uniformity is critical for narrow therapeutic index drugs such as phenytoin sodium. This work presents a near infrared (NIR)-based analytical method for rapid prediction of content uniformity based on a large number of phenytoin sodium formulation tablets. Calibration tablets were generated through an integrated experimental design by varying formulation and process parameters, and scale of manufacturing. A partial least squares model for individual tablet content was developed based on tablet NIR spectra. The tablet content was obtained from a modified United States Pharmacopeia phenytoin sodium high-performance liquid chromatography assay method. The partial least squares model with 4 latent variables explained 92% of the composition variability and yielded a root mean square error of prediction of 0.48% w/w. The resultant NIR model successfully assayed the composition of tablets manufactured at the pilot scale. For one such batch, bootstrapping was applied to calculate the confidence intervals on the mean, acceptance value, and relative SD for different sample sizes, n = 10, 30, and 100. As the bootstrap sample size increased, the confidence interval on the mean, acceptance value, and relative SD became narrower and symmetric. Such a 'large N' NIR-based process analytical technology method can increase reliability of quality assessments in solid dosage manufacturing. PMID- 30009796 TI - Molecular Dynamic in Ethosuximide Glass Forming Pharmaceutical as Studied by Dielectric Relaxation Spectroscopy. AB - Polymorphism and molecular dynamics of ethosuximide with molecules of left- and right-handed chirality have been studied in detail using dielectric spectroscopy. Density functional theory calculations of molecular conformations and dimer formation were performed to aid the interpretation of measurements. Moving window correlation analysis of the imaginary part of dielectric permittivity spectra allowed us to complete the monotropic system of phases found by the differential scanning calorimetry method. Extra transition connected with freezing in/activation of slow molecular motions was identified in partially ordered crystal CrI phase. In high-temperature orientationally disordered CrIh and in low temperature conformationally disordered CrIl phases, 2 relaxation processes were detected at frequency range below 105 Hz. In glass of CONDIS CrIl, beta relaxation was identified. PMID- 30009797 TI - Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing. AB - The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20. PMID- 30009798 TI - Impact of Shear History on Powder Flow Characterization Using a Ring Shear Tester. AB - In this study, we have investigated the impact of repeated shear displacement on powder flow properties. We show that when multiple yield loci are obtained using the same bulk solid specimen by stepping through different stress levels (i.e., stress walk [SW]), the shear deformation of the powder in a rotational shear cell, that is, Schulze Ring Shear Tester, is maximized, reducing the powder shear strength. This approach is material and time sparing; however, it imprecisely predicts better powder flowability. The magnitude of the change in the unconfined yield strength, sigmac, due to this prolonged shear displacement appears to be material-dependent, being less impactful for free-flowing powders. Using the SW and the individual yield loci-generated flow properties, we have demonstrated that in hopper design, the shear displacement effect impacts the computed critical arching diameter more than the critical mass flow angle. This knowledge of powder flow properties highlights limitations associated with the SW. An exponential function was found to describe the relationship between the change in sigmac at the highest major principal stress and the density weighted flowability, ffrho, with an R2 of 0.98. Such a model could be a valuable tool for correcting shear strength results obtained from SW, saving time, and material. PMID- 30009799 TI - Tablet Compression Force as a Process Analytical Technology (PAT): 100% Inspection and Control of Tablet Weight Uniformity. AB - The modern rotary pharmaceutical tablet press is capable of accepting or rejecting individual tablets based on the measured compression force of the tablet. Because during steady operation, each tablet is compressed to the same thickness, a larger compression force implies a heavier tablet. Tablets that are too heavy likely contain more than the desired content of drug substance. The measured compression force thus becomes an important input to the overall control strategy, and variability in the compression force from one tablet to the next corresponds directly with the uniformity of dosage units. This provides an extraordinary opportunity to use the instantaneous compression force signal as a process analytical technology to make product collection decisions on every individual tablet. Only 1 question requires investigation: how to set the main compression force limits to achieve the desired tablet weights? In this work, a small-scale characterization method and associated mathematical model are developed to answer this question. PMID- 30009800 TI - Suprasternal and Left Axillary Transcatheter Aortic Valve Replacement in Morbidly Obese Patients. AB - In morbidly obese patients who cannot undergo transfemoral, transaortic, or transapical transcatheter aortic valve replacement (TAVR) due to body habitus, suprasternal (SS) and left subclavian/axillary artery (LSCLA) approaches may provide safe TAVR access. Nine morbidly obese patients with a body mass index of 35 or more underwent SS-TAVR (7 patients) or LSCLA-TAVR (2 patients) at two institutions from 2015 to 2017. Mean age was 69.4 +/- 7.3 years, and mean body mass index was 50.3 +/- 10.6. There were no deaths, valve reinterventions, or reoperations. Three patients required new pacemakers. In morbidly obese patients who are not candidates for the other approaches, SS-TAVR and LSCLA-TAVR allow easier vascular access and prevent the need for thoracotomy or sternotomy. PMID- 30009801 TI - Listing Low-Weight or Ill Infants for Heart Transplantation: Is It Prudent? AB - BACKGROUND: Infants awaiting heart transplantation (HTx) have the highest waitlist mortality than other HTx patients. This study analyzed the impact of weight and other factors on waitlist and post-HTx outcomes in infants. METHODS: All infants on the HTx waitlist in the United Network for Organ Sharing database from October 1987 to June 2016 were divided into the following weight groups: less than 2.5 kg, 2.5 to 3.9 kg, and more than 4 kg. Survival from listing regardless of transplantation was compared by using Kaplan-Meier analysis. RESULTS: Of 4,711 infants listed for HTx, 250 (5.3%) weighed less than 2.5 kg, 1,993 (42%) weighed 2.5 to 3.9 kg, and 2,468 (52%) weighed more than 4 kg. Median time on the waitlist was similar between the groups weighing less than 2.5 kg and 2.5 to 3.9 kg (28 days versus 31 days, p = 0.423), whereas the group weighing more than 4 kg waited longer (42 days; p = 0.027 and p < 0.001). Infants weighing less than 2.5 kg (1 year, 43%) had the worst survival from listing regardless of transplantation compared with other groups (versus weighing 2.5 to 3.9 kg: 1 year, 54%, p = 0.001; versus weighing >4 kg: 1 year, 66%, p < 0.001). For infants weighing less than 2.5 kg on ventilator support, the 1 year-survival was 35%, on extracorporeal membrane oxygenation (ECMO) it was 10%. For infants weighing 2.5 to 3.9 kg on ventilator support, the 1 year-survival was 45%, on ECMO it was 23%. An infant with congenital heart disease (CHD) on ventilator support awaiting transplantation has a 1 year-survival rate of 37% to 42% regardless of weight. Multivariate analysis found that weighing less than 2.5 kg and being on ventilator support, ECMO, or having CHD were associated with 1-year mortality. CONCLUSIONS: Survival of infants after being listed for HTx is substantially affected by weight but also by illness at listing. Therefore, going into a transplantation ill or too small, as seen in the present study, may not be prudent, given the limited resource of infant donors. PMID- 30009802 TI - Multimodal Treatment for Post-Pneumonectomy Bronchopleural Fistula Associated With Empyema. AB - Post-pneumonectomy bronchopleural fistula associated with empyema still remains a dreaded complication in thoracic surgery. A variety of surgical and endoscopic procedures have been proposed over the years, but none of these has been suitable for all patients. Herein, we report a new multimodal approach, including the insertion of tracheobronchial conical stent, the open pleural packing, and the closure of bronchial stump with omentoplasty. This procedure was successfully applied in 11 patients with post-pneumonectomy bronchopleural fistula with empyema. PMID- 30009803 TI - Midterm Echocardiographic Assessment of Right Ventricular Function After Midline Unifocalization. AB - BACKGROUND: Patients with an open ventricular septal defect (VSD) after repair of pulmonary atresia (PA), VSD, and major aortopulmonary collaterals (MAPCAs) are the most vulnerable subgroup. We analyzed the impact of concomitant versus delayed VSD closure on survival and intermediate-term right ventricular (RV) function. METHODS: Between October 1996 and February 2017, 96 patients underwent a pulmonary flow study-aided repair of PA/VSD/MAPCAs. For patients who underwent either concomitant or delayed intracardiac repair, echocardiographic RV systolic function was retrospectively calculated to assess (1) RV fractional area change (RVFAC) and (2) two-dimensional RV longitudinal strain (RVLS) of the free wall of the right ventricle. QLAB cardiac analysis software version 10.3 (Philips Medical Systems, Andover, MA) was used for analysis. RESULTS: A total of 64 patients underwent concomitant VSD closure at the time of unifocalization, and 16 patients underwent delayed VSD closure at a median of 2.3 years (range: 3 days to 7.4 years). At a median follow-up of 8.1 years (range: 0.1 to 19.5 years) for the concomitant repair group versus 7.4 years (range: 0.01 to 15.3 years) for the delayed repair group, no differences in RVFAC and RVLS were observed (RVFAC: 41.0% +/- 6.2% versus 41.2% +/- 7.6%, p = 0.91; RVLS: -18.7 +/- 4.3 versus -18.9 +/- 4.0, p = 0.87). CONCLUSIONS: Patients (83%) with PA/VSD/MAPCAs underwent complete repair at intermediate-term follow-up with preserved RV function. Delayed VSD closure was accomplished in 50% of the patients initially deemed unsuitable for repair. Delayed VSD closure did not affect survival and did not portend impaired RV systolic function. PMID- 30009804 TI - Type B Interrupted Right Aortic Arch: Diagnostic and Surgical Approaches. AB - Interrupted right aortic arch (IRAA) is a rare congenital cardiovascular anomaly typically associated with other forms of congenital heart disease. We report 2 cases of IRAA associated with isolated left pulmonary artery and bilateral ductus arteriosus in the first case and with truncus arteriosus (TA) in the second. Computed tomography was complimentary to echocardiography in delineating the anatomic details in both cases, informing surgical repair with reconstruction of a left aortic arch in first case and right arch in the second. PMID- 30009805 TI - Giant Rhabdomyoma Requiring Emergency Resection Early After Birth. PMID- 30009806 TI - Patient Reported Outcomes in Cardiothoracic Surgery. AB - BACKGROUND: Current studies in cardiothoracic clinical research frequently fail to use endpoints that are most meaningful to patients, including measures associated with quality of life. Patient- reported outcomes (PRO) represent an underutilized but important component of high quality patient-centered care. Our objective was to highlight important principles of PRO measurement, describe current use in cardiothoracic surgery, and discuss the potential for and challenges associated with integration of PROs into large clinical databases. METHODS: We performed a literature review using the PubMed/EMBASE databases. Clinical articles that focused on the use of PROs in cardiothoracic surgery outcomes measurement or clinical research were included in this review. RESULTS: PROs measure the outcomes that matter most to patients and facilitate the delivery of patient-centered care. When effectively used, PRO measures have provided detailed and nuanced quality of life data for comparative effectiveness research. However, further steps are needed to better integrate PRO into routine clinical care. CONCLUSIONS: Incorporation of PRO into routine clinical practice is essential for delivering high quality patient-centered care. Future integration of PRO into prospectively collected registries and databases, including that the Society of Thoracic Surgeons National Database, has the potential to enrich comparative effectiveness research in cardiothoracic surgery. PMID- 30009807 TI - Contemporary Outcomes After Repair of Isolated and Complex Complete Atrioventricular Septal Defect. AB - BACKGROUND: Contemporary outcomes of complete atrioventricular septal defect (CAVSD) repair, particularly for defects with associated abnormalities, is unclear. The goal of this study is to report an all-inclusive experience of CAVSD repair using a consistent surgical approach. METHODS: All patients undergoing CAVSD repair between 1995 and 2016 at our institution were included. Patients were divided into 2 groups: isolated and complex (tetralogy of Fallot, aortic arch repair, double outlet right ventricle, and total anomalous pulmonary venous return). Survival and reoperation were analyzed using log-rank test and Gray's test, respectively. Multivariable analysis was performed with Cox regression. RESULTS: Overall, 406 patients underwent repair: 350 (86%) isolated and 56 (14%) complex CAVSD (tetralogy of Fallot: 34, double outlet right ventricle: 7, aortic arch repair: 12, total anomalous pulmonary venous return: 3). Median age at repair was 5 months (range, 10 days to 16 years); 339 (84%) had trisomy 21. A 2 patch repair was used in 395 (97%) and the zone of apposition was completely closed in 305 (75%). Perioperative mortality was 2% and 4% in the isolated and complex groups, respectively. Perioperative mortality since 2006 was 0.9%. Median follow-up was 7 years. Overall 10-year survival and incidence of any reoperation were 92% and 11%, respectively. Complex anatomy was not a risk factor for mortality (p = 0.35), but it was for reoperation (hazard ratio [HR]: 2.6; p < 0.01). Risk factors for left atrioventricular valve reoperation were a second bypass run (HR: 2.7) and preoperative moderate or worse regurgitation (HR: 2.3). CONCLUSIONS: Mortality after CAVSD repair is low, yet reoperation remains a significant problem. Repair of complex CAVSD can be performed with similar mortality rates. PMID- 30009808 TI - Diffuse Alveolar Septal Amyloidosis with Wild-Type Transthyretin with Spontaneous Lung Hematoma. AB - We experienced a mass formation in the right lower lobe in a patient with cardiac amyloidosis and heart failure. Radiological findings of the chest showed no abnormality except a mass. The patient had non-valvular atrial fibrillation and taking edoxaban. Surgical resection of the mass revealed a hematoma. Further pathological evaluation revealed diffuse alveolar septal amyloidosis with transthyretin (ATTR). The genetic testing found no mutation in TTR gene. So, systemic wild-type TTR amyloidosis (ATTRwt) was confirmed. Alveolar septal ATTRwt is rare. And to our knowledge, this is the first case of alveolar septal ATTRwt with spontaneous lung hematoma. PMID- 30009809 TI - Arterial Switch Operation: Operative Approach and Outcomes. AB - The ASO has excellent early outcomes. While the majority of patients are growing into healthy adults, a small subset require reoperation for PS as well as neo-ARD and neo-AR especially as follow-up increases. Challenging subgroups include patients with anomalous coronary anatomy, concomitant AAO, TBA, VSD, low operative weight and patients with an intact IVS who present late. PMID- 30009811 TI - Simvastatin-dependent actin cytoskeleton rearrangement regulates differentiation via the extracellular signal-regulated kinase-1/2 and p38 kinase pathways in rabbit articular chondrocytes. AB - Alterations in cell morphology involve changes in the actin cytoskeleton and play crucial roles in determining chondrocyte phenotypes. Although the effects of simvastatin (SV) have been demonstrated in various cell types, the mechanisms and effects of SV on chondrocyte differentiation and actin cytoskeletal rearrangement are still unclear. Here, we investigated the roles of actin filament rearrangement on SV-induced differentiation of rabbit articular chondrocytes. Treatment with SV caused actin remodeling in comparison with that in untreated chondrocytes, as determined by immunofluorescence staining. Moreover, treatment with cytochalasin D (CD) and jasplakinolide (JAS), which modulate actin filament formation, resulted in reorganization of the actin cytoskeleton compared with that induced by SV in chondrocytes. In addition, CD synergistically enhanced the SV-induced increase in type II collagen expression, whereas JAS dramatically inhibited SV-induced differentiation. We also found that differentiation via SV dependent actin cytoskeleton changes was regulated by the extracellular signal regulated kinase (ERK)-1/2 and p38 kinase pathways. These results demonstrated that actin cytoskeletal rearrangement by SV regulated type II collagen expression and suggested that ERK-1/2 and p38 kinase pathways may play important roles in SV induced type II collagen expression by altering actin cytoskeletal reorganization in rabbit articular chondrocytes. PMID- 30009810 TI - Proteomic and immunomic analysis of Schistosoma mekongi egg proteins. AB - Schistosomiasis remains a global health problem. In the Mekong river basin, approximately 80,000 people are at risk of infection by Schistosoma mekongi. The parasite's eggs become entrapped in the host's organs and induce massive inflammation, contributing to the pathogenesis of schistosomiasis. In addition, egg antigens are important in circumoval precipitin tests (COPTs) and other diagnostic techniques. Little is known regarding the egg proteins of S. mekongi, and so we applied immunoblotting and mass spectrometry-based proteomic approaches to study these proteins and their antigenicity. A total of 360 unique proteins were identified in S. mekongi eggs using proteomic analyses. The major protein components of S. mekongi eggs were classified into several groups by functions, including proteins of unknown function, structural proteins, and regulators of transcription and translation. The most abundant proteins in S. mekongi eggs were antioxidant proteins, potentially reflecting the need to neutralize reactive oxidative species released from host immune cells. Immunomic analyses revealed that only DNA replication factor Cdt1 and heat shock protein 70 overlap between the proteins recognized by sera of infected mice and humans, illustrating the challenges of knowledge transfer from animal models to human patients. Forty-one immunoreactive protein bands were recognized by either mouse or patient sera. Phosphoglycerate kinase, fructose-1,6-bisphosphate aldolase and elongation factor 1 appeared to be interesting immunogens of S. mekongi eggs as these proteins were recognized by polyclonal IgMs and IgGs in patient sera. Our findings provide new information on the protein composition of S. mekongi eggs as well as the beginnings of a S. mekongi immunogen dataset. These data may help us better understand the pathology of schistosomiasis as well as natural antibody responses against S. mekongi egg proteins, both of which may be useful in including S. mekongi to other schistosoma diagnostic, vaccine and immunotherapy development. PMID- 30009812 TI - Evaluation of different classes of histamine H1 and H2 receptor antagonist effects on neuropathic nociceptive behavior following tibial nerve transection in rats. AB - It seems that histamine release in the site of neuronal injury could contribute to the neuropathic pain mechanism. In the present study, we investigated the anti allodynic effects of chronic administration of different classes of histamine H1 and H2 receptor antagonists on neuropathic nociceptive behavior following tibial nerve transection (TNT) in rats. Peripheral neuropathy was induced by TNT surgery. We performed acetone tests (AT) to record cold allodynia, Von Frey tests (VFT) to measure mechanical allodynia, double plate test (DPT) to evaluate thermal place preference/avoidance and open field test (OFT) for evaluation of animal activity. TNT rats showed a significant mechanical and cold allodynia compared to the sham group. Chlorpheniramine (5 and 15 mg/kg, i.p) significantly attenuated cold allodynia and prevented cold plate avoidance behavior and at the dose of 15 mg/kg remarkably decreased mechanical allodynia. Fexofenadine (10 and 30 mg/kg, p.o) significantly attenuated the mechanical allodynia and prevented cold plate avoidance. Ranitidine (5 and 15 mg/kg, i.p) significantly prevented cold plate avoidance behavior and at the dose of 15 mg/kg notably improved mechanical and cold allodynia. Famotidine (1 and 3 mg/kg, p.o) was ineffective on all nociceptive tests. Gabapantin (100 mg/kg, p.o) significantly improved all types of nociceptive behaviors. These results indicate that both blood brain barrier penetrating (chlorpheniramine) and poorly penetrating (fexofenadine) histamine H1 receptor antagonists could improve the neuropathic pain sign, but only the blood brain barrier penetrating histamine H2 receptor antagonist (ranitidine) could produce anti-allodynic effects in the TNT model of neuropathic pain in rats. PMID- 30009813 TI - Additive counteraction by alpha7 and alpha4beta2-nAChRs of the hypotension and cardiac sympathovagal imbalance evoked by endotoxemia in male rats. AB - The cholinergic antiinflammatory pathway favorably influences end organ damage induced by inflammatory conditions. Here, we hypothesized that alpha7 and/or alpha4beta2-nicotinic acetylcholine receptors (nAChRs) protect against cardiovascular and autonomic imbalances induced by endotoxemia in rats. We assessed dose-effect relationships of i.v. nicotine (25, 50, or 100 MUg/kg), PHA 543613 (alpha7-nAChR agonist; 0.2 or 2.0 mg/kg), or 5-iodo-A-85380 (5IA, alpha4beta2-nAChRs agonist; 0.01 or 0.1 mg/kg) on cardiovascular and inflammatory responses elicited by lipopolysaccharide (LPS, 10 mg/kg i.v.). The two lower doses of nicotine caused dose-dependent attenuation of hypotensive and tachycardic responses of LPS. Nicotine also reversed LPS-evoked reductions in time-domain indices of heart rate variability (HRV) and spectral measure of cardiac sympathovagal balance. Alternatively, hypotensive and tachycardic effects of LPS were (i) partly and dose-dependently reversed after selective activation of alpha7 (PHA) or alpha4beta2-nAChRs (5IA), and (ii) completely eliminated after co-treatment with the smaller doses of the two agonists. Further, PHA or 5IA abolished the reducing effect of LPS on time and spectral measures of HRV. Elevations in serum tumor necrosis factor-alpha (TNF-alpha) observed in LPS treated rats were compromised upon co-administration of nicotine, PHA, or 5IA. In conclusion, monomeric alpha7 or heteromeric alpha4beta2-nAChRs favorably and additively influence inflammatory and associated cardiovascular anomalies induced by endotoxemia. PMID- 30009814 TI - Evaluation of the antinociceptive and anti-inflammatory activities of piperic acid: Involvement of the cholinergic and vanilloid systems. AB - Piperin is the active compound of black pepper (Piper nigrum). From the piperine was obtained the molecule of the piperic acid (PAC). The objective of this study was to evaluate the antinociceptive and anti-inflammatory of the compound. The antinociceptive effects of PAC were evaluated by abdominal writhing, formalin, capsaicin and tail-flick tests; while the anti-inflammatory effects were evaluated by paw oedema and air pouch tests, and in vitro COX inhibition assay. The possible action mechanism of PAC was evaluated using naloxone, L-NAME, glibenclamide and atropine in tail flick test and by Cholinesterase activity assay and production of TNF-alpha and IL-1beta. PAC significantly reduced the nociceptive effects induced by acetic acid or formalin in mice. PAC also demonstrated an antinociceptive effect in the tail-flick model. The muscarinic receptor antagonist, atropine reduced the antinociceptive effect of PAC in the tail-flick model. PAC was able to inhibit capsaicin-induced nociception, showing involvement of TRPV1. The compound did not alter the motor capacity of the animals, not interfering in the nociceptive response. PAC also showed anti- inflammatory activity by inhibiting the formation of carrageenan-induced paw oedema, leukocyte migration, and cytokine production / release. Atropine reduced the activity of PAC on leukocyte migration, and cytokine production. The compound showed to be able to reduce the cytokine production stimulated by capsaicin. PAC inhibited the COX activity. The results presented suggest that the possible cholinomimetic action and vanilloid agonist of the piperic acid may be responsible by antinociceptive and anti- inflammatory effects; these effects are devoid of toxicity. PMID- 30009815 TI - Fermentable Sugar Ingestion, Gas Production, and Gastrointestinal and Central Nervous System Symptoms in Patients With Functional Disorders. AB - BACKGROUND & AIMS: Functional gastrointestinal disorders (FGID) are defined by broad phenotypic descriptions and exclusion of recognizable disease. FGIDs cause multi-organ symptoms and abnormal results in a wide range of laboratory tests, indicating broad mechanisms of pathogenesis. Many patients with FGID develop symptoms following ingestion of fermentable sugars; we investigated the associations between symptoms and intestinal gas production following sugar provocation tests to elucidate mechanisms of FGID. METHODS: We performed fructose and lactose breath tests in 2042 patients with a diagnosis of FGID (based on Rome III criteria), referred to a gastroenterology practice from January 2008 through December 2011. Medical and diet histories were collected from all subjects. Breath samples were collected before and each hour after, for 5 hours, subjects ingested fructose (35 g) and lactose (50 g) dissolved in 300 mL water. Hydrogen and methane gas concentrations were measured and GI and non-GI symptoms were registered for 5 hours following sugar ingestion. Symptom and gas time profiles were compared, treelet transforms were used to derive data-related symptom clusters, and the symptom severity of the clusters were analyzed for their association with breath gas characteristics. RESULTS: We identified 11 GI and central nervous system (CNS) symptom profiles and hydrogen and methane breath concentrations that changed significantly with time following sugar ingestion. Treelet transform analysis identified 2 distinct clusters, based on GI and CNS symptoms. The severity scores for the GI and CNS symptoms correlated following ingestion of sugars (all, P < .0001). However, only the GI symptoms associated with hydrogen and methane gas production (all, P < .0001). CONCLUSIONS: In an analysis of breath test results from more than 2000 patients with FGIDs, we identified clusters of GI and CNS symptoms in response to fructose of lactose ingestion. The association between specific symptoms and breath gas concentrations indicate distinct mechanisms of FGID pathogenesis, such as changes in the microbiome or mechanical and chemical sensitization. ClinicalTrials.gov ID: NCT02085889. PMID- 30009816 TI - Changing Trends in Etiology-Based Annual Mortality From Chronic Liver Disease, From 2007 Through 2016. AB - BACKGROUND & AIMS: Although treatment of hepatitis C virus (HCV) infection has improved, the prevalence of alcoholic liver disease (ALD) has been increasing, so we need an updated estimate of the burden and etiology-specific mortality of chronic liver diseases. We studied trends in age-standardized mortality of chronic liver diseases in adults at least 20 years old in the United States from 2007 through 2016. METHODS: We collected data from the US Census and National Center for Health Statistics mortality records and identified individuals with HCV infection, ALD, nonalcoholic fatty liver disease, or hepatitis B virus infection using ICD-10 codes. We obtained temporal mortality rate patterns using joinpoint trend analysis with estimates of annual percentage change (APC). RESULTS: Age-standardized HCV-related mortality increased from 7.17 per 100,000 persons in 2007 to 8.14 per 100,000 persons in 2013, followed by a marked decrease in the time period at which patients began receiving treatment with direct-acting antiviral agents (from 8.09 per 100,000 persons in 2014 to 7.15 per 100,000 persons in 2016). The APC in HCV mortality increased 2.0%/year from 2007 through 2014 but decreased 6.4%/year from 2014 through 2016. In contrast, age standardized mortality increased for ALD (APC 2.3% from 2007 through 2013 and APC 5.5% from 2013 through 2016) and nonalcoholic fatty liver disease (APC 6.1% from 2007 through 2013 and APC 11.3% from 2013 through 2016). Mortality related to hepatitis B virus decreased steadily from 2007 through 2016, with an average APC of -2.1% (95% CI -3.0 to -1.2). Etiology-based mortality in minority populations was higher. HCV-related mortality (per 100,000 persons) was highest in non Hispanic blacks (10.28) and whites (6.92), followed by Hispanics (5.94), and lowest in non-Hispanic Asians (2.33). Non-Hispanic Asians had higher mortality for hepatitis B virus infection (2.82 per 100,000 vs 1.02 for non-Hispanic blacks and 0.47 for non-Hispanic whites). CONCLUSION: In our population-based analysis of chronic liver disease mortality in the United States, the decrease in HCV related mortality coincided with the introduction of direct-acting antiviral therapies, whereas mortality from ALD and nonalcoholic fatty liver disease increased during the same period. Minorities in the United States have disproportionately higher mortality related to chronic liver disease. PMID- 30009817 TI - Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: The existence of postinfection irritable bowel syndrome (PI IBS) has been substantiated by epidemiology studies conducted in diverse geographic and clinical settings. However, the available evidence has not been well summarized, and there is little guidance for diagnosis and treatment of PI IBS. The ROME Foundation has produced a working team report to summarize the available evidence on the pathophysiology of PI-IBS and provide guidance for diagnosis and treatment, based on findings reported in the literature and clinical experience. METHODS: The working team conducted an evidence-based review of publication databases for articles describing the clinical features (diagnosis), pathophysiology (intestinal sensorimotor function, microbiota, immune dysregulation, barrier dysfunction, enteroendocrine pathways, and genetics), and animal models of PI-IBS. We used a Delphi-based consensus system to create guidelines for management of PI-IBS and a developed treatment algorithm based on published findings and experiences of team members. RESULTS: PI-IBS develops in about 10% of patients with infectious enteritis. Risk factors include female sex, younger age, psychological distress during or before acute gastroenteritis, and severity of the acute episode. The pathogenesis of PI-PBS appears to involve changes in the intestinal microbiome as well as epithelial, serotonergic, and immune system factors. However, these mechanisms are incompletely understood. There is no evidence-based, effective pharmacologic strategies for treatment of PI-IBS. We provide a consensus-based treatment algorithm, based on clinical presentation and potential disease mechanisms. CONCLUSIONS: Based on a systematic review of the literature and team experience, we summarize the clinical features, pathophysiology (from animal models and human studies), and progression of PI-IBS. Based on these findings, we present an algorithm for diagnosis and treatment of PI-IBS based on team consensus. We also propose areas for future investigation. PMID- 30009818 TI - CpG Island Methylation in Sessile Serrated Adenomas Increases With Age, Indicating Lower Risk of Malignancy in Young Patients. AB - Among sessile serrated adenomas (SSAs) with identical histologic features, some never progress, whereas others become dysplastic and develop into invasive cancers. Development of the CpG island methylator phenotype is a feature of SSA progression; we examined the CIMP status of 448 SSAs and examined the association with patient clinical data. Overall, 190 SSAs were CpG island methylator phenotype-positive. CpG island methylator phenotype positivity was associated with older patient age (P < .001) and proximal polyp site (P < .001), but not with patient sex (P = .94) or polyp size (P = .34). These results might be used to improve SSA surveillance guidelines. PMID- 30009821 TI - Altered expression of Aquaporin-2 in one-kidney, one-clip hypertension. AB - AIMS: The aim of the present study was to evaluate the regulation of Aquaporin-2 (AQP2) water channel in the kidney of one-kidney, one-clip rats (Goldblatt-1 model). In addition, some mechanisms that underlie the role of AQP2 in the Goldblatt-1 model were evaluated. MAIN METHODS: Sprague-Dawley rats were divided in three groups: control two-kidney, no clip (C, 2 K-NC); nephrectomized one kidney, no clip (N, 1 K-NC) and Goldblatt one-kidney, one-clip (G, 1 K-1C). AQP2 expression (by westernblot, real time PCR, immunohistochemistry and immunofluorescence), vasopressin V2 receptor expression (by real time PCR), cAMP concentration, NFkB and TonEBP (cytosol to nucleus ratio) were evaluated in the renal medulla. KEY FINDINGS: AQP2 expression, V2 receptor expression and cAMP concentration were decreased in the renal medulla of 1 K-1C rats, NFkB translocation was favoured towards the nucleus suggesting its activation while TonEBP translocation was not altered in this model of hypertension. SIGNIFICANCE: In this model of hypertension the decrease of AQP2 expression could be a mechanism that counteracts the high blood pressure promoting water excretion and this may be consequence of decreased vasopressin sensitivity and/or the increased activity of NFkB at renomedullary collecting duct level. Given that renovascular hypertension is among the most common causes of secondary hypertension, it is important to elucidate all the relevant mechanisms involved in the generation or in the compensation of the hypertensive state in order to improve the diagnoses and treatment of the patients. PMID- 30009820 TI - Overexpression of Rac GTPase Activating Protein 1 Contributes to Proliferation of Cancer Cells by Reducing Hippo Signaling to Promote Cytokinesis. AB - BACKGROUND & AIMS: Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth. METHODS: Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes. RESULTS: The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells. CONCLUSIONS: In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR. PMID- 30009822 TI - Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner. AB - Acute kidney injury (AKI) is a serious disorder that accompanies rhabdomyolysis (RM). The underlying mechanisms as well as protective approaches need to be investigated. This study was targeted to explore the prophylactic effect of agmatine (AGM), an endogenous metabolite of l-arginine against RM-induced AKI. A rat model was elucidated by 50% glycerol (10 ml/kg, im). Glycerol induced functional and structural alterations in the kidney. Pretreatment with AGM significantly ameliorated RM through decreasing total creatinine kinase (CK) and creatine kinase-MB (CK-MB) levels. AGM alleviated functional changes evidenced by decreased serum levels of creatinine (Cr), blood urea nitrogen (BUN) and decreased urinary levels of albumin and proteins. Moreover, AGM decreased renal levels of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta), neutrophil gelatinase-associated lipocalin (NGAL), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-kappaB) and myeloperoxidase (MPO). Furthermore, AGM significantly increased renal levels of reduced glutathione (GSH), superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Structural abnormalities confirmed by histopathological examination were also attenuated. AGM confers a dose-dependent protection against RM-induced AKI by preventing muscle degradation, alleviating oxidative stress and inhibiting production of cytokines and inflammation. PMID- 30009823 TI - Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-kappaB-mediated autophagy activation. AB - AIMS: It has been shown that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Meanwhile, activation of nuclear factor-kappaB (NF-kappaB) has been found to induce autophagy in several types of human diseases including cancer and cardiac diseases. However, it is still unknown whether NF-kappaB mediates autophagy activation in PAH, and whether activation of adenosine monophosphate-activated protein kinase (AMPK) benefits PAH by modulation of NF-kappaB and autophagy. MAIN METHODS: Rat models of PAH were established by intraperitoneally injection of monocrotaline (MCT). The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and percentage of medial wall thickness (%MT) were performed to evaluate the development of PAH. The translocation of NF-kappaB p65 from cytosol to nucleus, the protein levels of LC3A, LC3B, and RND3 were determined by immunoblotting. Metformin was used to activate AMPK. KEY FINDINGS: NF-kappaB and autophagy were significantly activated in MCT-induced PAH rats, this was accompanied with the reduction of RND3. Pharmacological inhibition of NF-kappaB suppressed MCT-induced activation of autophagy and down-regulation of RND3 expression and reduced RVSP, RVHI, and %MT in MCT-induced PAH rats. In addition, activation of AMPK by metformin suppressed NF-kappaB-mediated autophagy activation and down-regulation of RND3 and therefore reduced RVSP, RVHI, and %MT in MCT-induced PAH. SIGNIFICANCE: NF-kappaB-induced autophagy activation and consequent down regulation of RND3 contributes to the development of PAH in MCT-treated rats. Activation of AMPK prevents the development of PAH by targeting on NF-kappaB to suppress autophagy and vascular remodeling. PMID- 30009824 TI - BCL9 promotes epithelial mesenchymal transition and invasion in cisplatin resistant NSCLC cells via beta-catenin pathway. AB - AIMS: Bcell lymphoma 9 (BCL9)-Wnt/beta-catenin pathway, a key signaling pathway related to epithelial-mesenchymal transition (EMT), is widely considered to be involved in invasion in various malignant tumors. However, the dysregulation of BCL9/beta-catenin pathway in non-small cell lung cancer (NSCLC) has not been revealed. This study aimed to investigate the correlation between chemotherapy resistance and BCL9/Wnt/beta-catenin signaling dysfunction. MAIN METHODS: We performed BCL9 knockdown using a lentivirus-mediated sh-RNA interference in cisplatin-resistant (CR) lung cancer cells. Subsequently, the migration and invasion were determined by wound-healing and Transwell assays. Furthermore, EMT markers and beta-catenin were examined by Western blot. Immunofluorescence was used to investigate the subcellular localization of beta-catenin. The chemotherapeutic sensitivity to cisplatin in A549/DDP cell lines after treatment with BCL9 sh-RNA was estimated by MTT assay. KEY FINDINGS: The knockdown of BCL9 remarkably reduced the migration and invasion abilities of A549/DDP cells. Meanwhile, nuclear translocation of beta-catenin was reduced after BCL9 was knocked down. BCL9 silencing also resulted in the downregulation of EMT-related proteins. Additionally, the Wnt/beta-catenin agonist, CP21, significantly restored the expression of beta-catenin and abilities of migration and invasion in BCL9-knockdown A549/DDP cell lines. Finally, we proved that the inhibition of BCL9 could partially attenuate the stemness of cancer cells and recover the chemotherapeutic sensitivity. SIGNIFICANCE: These findings indicated BCL9 induced the occurrence of EMT and enhancement of stemness, which resulted in cisplatin resistance and promoted migration in NSCLC cells. Mechanically, Wnt/beta-catenin pathway is crucial in BCL9-induced migration, invasion, and chemotherapy resistance. PMID- 30009826 TI - Conditional loss of Kcnj13 in the retinal pigment epithelium causes photoreceptor degeneration. AB - The retina is the light sensing tissue of the eye which contains multiple layers of cells required for the detection and transmission of a visual signal. Loss of the light-sensing photoreceptors leads to defects in visual function and blindness. Previously, we found that mosaic deletion of Kcnj13, and subsequent loss of the potassium channel Kir7.1, in mice leads to photoreceptor degeneration and recapitulates the human retinal disease phenotype (Zhong et al., 2015). Kcnj13 expression in the retinal pigment epithelium (RPE) is essential for normal retinal electrophysiology, function, and survival. Mice with homozygous loss of Kcnj13 die at postnatal day 1 (P1), requiring a tissue-specific approach to study retinal degeneration phenotypes in adult mice. We used the CRISPR-Cas9 system to generate a floxed, conditional loss-of-function (cKO) Kcnj13flox allele to study the pathogenesis of Kcnj13 deficiency in the retina. To investigate if the Kcnj13 is required in the RPE for photoreceptor function and survival, we used Best1 cre, which is specifically expressed in the RPE. We observed complete loss of Kcnj13 expression in Cre-positive RPE cells. Furthermore, our findings show that widespread loss of Kcnj13 in the RPE leads to severe and progressive thinning of the outer nuclear layer and a reduced response to light. Finally, to detect Best1 cre expression in the RPE of live animals without sacrificing the animal for histology, we generated a Cre-reporter-containing Kcnj13 cKO mouse line (cKOR: Kcnj13flox/flox; Best1-cre; Ai9) which can be rapidly screened using retinal fluorescence microscopy. These findings provide new tools for studying the roles of Kcnj13 in retinal homeostasis. PMID- 30009819 TI - Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. AB - BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high power field (or approximately 60 eosinophils per mm2) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change. PMID- 30009825 TI - Retinal dysfunction parallels morphologic alterations and precede clinically detectable vascular alterations in Meriones shawi, a model of type 2 diabetes. AB - Diabetic retinopathy is a major cause of reduced visual acuity and acquired blindness. The aim of this work was to analyze functional and vascular changes in diabetic Meriones shawi (M.sh) an animal model of metabolic syndrome and type 2 diabetes. The animals were divided into four groups. Two groups were fed a high fat diet (HFD) for 3 and 7 months, two other groups served as age-matched controls. Retinal function was assessed using full field electroretinogram (Ff ERG). Retinal thickness and vasculature were examined by optical coherence tomography, eye fundus and fluorescein angiography. Immunohistochemistry was used to examine key proteins of glutamate metabolism and synaptic transmission. Diabetic animals exhibited significantly delayed scotopic and photopic ERG responses and decreases in scotopic and photopic a- and b-wave amplitudes at both time points. Furthermore, a decrease of the amplitude of the flicker response and variable changes in the scotopic and photopic oscillatory potentials was reported. A significant decrease in retinal thickness was observed. No evident change in the visual streak area and no sign of vascular abnormality was present; however, some exudates in the periphery were visible in 7 months diabetic animals. Imunohistochemistry detected a decrease in the expression of glutamate synthetase, vesicular glutamate transporter 1 and synaptophysin proteins. Results indicate that a significant retinal dysfunction was present in the HFD induced diabetes involving both rod and cone pathways and this dysfunction correlate well with the morphological abnormalities reported previously. Furthermore, neurodegeneration and abnormalities in retinal function occur before vascular alterations would be detectable in diabetic M.sh. PMID- 30009827 TI - Enamel Anomalies in a Pachyonychia Congenita Patient with a Mutation in KRT16. PMID- 30009828 TI - Cockayne Syndrome Type A Protein Protects Primary Human Keratinocytes from Senescence. AB - Defects in Cockayne syndrome type A (CSA), a gene involved in nucleotide excision repair, cause an autosomal recessive syndrome characterized by growth failure, progressive neurological dysfunction, premature aging, and skin photosensitivity and atrophy. Beyond its role in DNA repair, the CSA protein has additional functions in transcription and oxidative stress response, which are not yet fully elucidated. Here, we investigated the role of CSA protein in primary human keratinocyte senescence. Primary keratinocytes from three patients with CS-A displayed premature aging features, namely premature clonal conversion, high steady-state levels of reactive oxygen species and 8-OH-hydroxyguanine, and senescence-associated secretory phenotype. Stable transduction of CS-A keratinocytes with the wild-type CSA gene restored the normal cellular sensitivity to UV irradiation and normal 8-OH-hydroxyguanine levels. Gene correction was also characterized by proper restoration of keratinocyte clonogenic capacity and expression of clonal conversion key regulators (p16 and p63), decreased NF-kappaB activity and, in turn, the expression of its targets (NOX1 and MnSOD), and the secretion of senescence-associated secretory phenotype mediators. Overall, the CSA protein plays an important role in protecting cells from senescence by facilitating DNA damage processing, maintaining physiological redox status and keratinocyte clonogenic ability, and reducing the senescence associated secretory phenotype-mediated inflammatory phenotype. PMID- 30009829 TI - Keratinocyte Cytokine Networks Associated with Human Melanocytic Nevus Development. AB - Melanocytes can group together in nevi, commonly thought to form because of intrinsic somatic mutations involving MAPK pathway activation. However, the role of the microenvironment, in particular keratinocytes, in nevogenesis is rarely studied. Melanocytes proliferate during the hair follicle growth phase and in some basal cell carcinomas, allowing us to construct keratinocyte gene expression clusters correlated with melanocyte activation. We asked whether such correlations are evident in the more subtle context of regulation of melanocyte behavior in normal skin. We considered genes which, when mutated in keratinocytes in mice, lead to nevogenesis. Across the human GTEx normal skin database, their expression was correlated with that of keratinocyte cytokines KITLG, HGF, FGF2, EDN1, and melanocyte markers. These cytokines have pleiotropic effects on melanocyte-specific and pigmentation genes and also influence mast cell gene expression. We show five classes of keratinocyte genes that, via germline genetic variation, influence melanocyte activity. These include genes involved in SHH signaling, structural keratins, ribosomal biogenesis, and stem cell governance. In agreement with the finding of KITLG linked to nevogenesis in human genome-wide association studies, we provide evidence that specific keratinocyte cytokines are components of networks that may drive or exacerbate nevus development. PMID- 30009830 TI - Insights into Male Androgenetic Alopecia: Differential Gene Expression Profiling of Plucked Hair Follicles and Integration with Genetic Data. PMID- 30009831 TI - CXCL5 as Regulator of Neutrophil Function in Cutaneous Melanoma. AB - Chemokines mold the tumor microenvironment by recruiting distinct immune cell populations, thereby strongly influencing disease progression. Previously, we showed that CXCL5 expression is upregulated in advanced stages of primary melanomas, which correlates with the presence of neutrophils in the tumor. The analysis of neutrophil populations in various tissues revealed a distinct phenotype of tumor-associated neutrophils. Tumor-associated neutrophils expressed PD-L1, CXCR4, CCR5, Adam17, and Nos2 and were immunosuppressive in a T-cell proliferation assay. To investigate the impact of CXCL5 and neutrophils in vivo, we established a syngeneic mouse tumor transplantation model using CXCL5 overexpressing and control melanoma cell lines. Growth behavior or vascularization of primary tumors was not affected by CXCL5 expression and neutrophils alone. However, in combination with Poly(I:C), tumor-associated neutrophils were able to attenuate induced antitumoral T-cell responses. CXCL5 overexpressing tumors had reduced lung metastasis compared with control tumors. Neutrophil depletion reversed this effect. In vitro, unstimulated lung-derived neutrophils had higher levels of reactive oxygen species compared with tumor associated neutrophils, and CXCL5 stimulation further increased reactive oxygen species levels. In summary, in melanoma, neutrophils play a context-dependent role that is influenced by local or systemic factors, and interfere with therapies activating the acquired immune system. Actively switching neutrophils into antitumorigenic mode might be a new therapeutic strategy. PMID- 30009832 TI - Cornulin Is Induced in Psoriasis Lesions and Promotes Keratinocyte Proliferation via Phosphoinositide 3-Kinase/Akt Pathways. AB - Psoriasis is a chronic inflammatory skin disease characterized by abnormal proliferation of epidermal keratinocytes and infiltration of inflammatory cells. CRNN is a major component of the cornified cell envelope and implicated in several epithelial malignancies. Here, we show that CRNN expression was increased in the lesioned epidermis from the patients with psoriasis vulgaris and skin lesions from the imiquimod (IMQ)-treated mice. Expression of CRNN in cultured keratinocytes (HEKa and HaCaT) was also induced by M5, a mixture of five pro inflammatory cytokines (i.e., IL-17A, IL-22, IL-1alpha, oncostatin M, and TNF alpha). Lentiviral expression of CRNN increased cell proliferation by inducing cyclin D1. Conversely, knockdown of CRNN by small interfering RNA suppressed G1/S transition and attenuated the M5-induced proliferation. In addition, CRNN overexpression increased the phosphorylation and activation of phosphoinositide 3 kinase and Akt. Inactivation of the phosphoinositide 3-kinase and Akt pathways using small interfering RNA or selective inhibitors (LY294002 and MK2206) reduced the proliferative effects of CRNN. Furthermore, topical use of anti-psoriatic calcipotriol effectively decreased expression of CRNN, inhibited the Akt activation and improved the IMQ-stimulated psoriasis-like pathologies. Taken together, these results suggest that induced expression of CRNN may contribute to the pathogenesis of psoriasis. PMID- 30009833 TI - Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma. AB - Oral cancer is often painful and lethal. Oral cancer progression and pain may result from shared pathways that involve unresolved inflammation and elevated levels of pro-inflammatory cytokines. Resolvin D-series (RvDs) are endogenous lipid mediators derived from omega-3 fatty acids that exhibit pro-resolution and anti-inflammatory actions. These mediators have recently emerged as a novel class of therapeutics for diseases that involve inflammation; the specific roles of RvDs in oral cancer and associated pain are not defined. The present study investigated the potential of RvDs (RvD1 and RvD2) to treat oral cancer and alleviate oral cancer pain. We found down-regulated mRNA levels of GPR18 and GPR32 (which code for receptors RvD1 and RvD2) in oral cancer cells. Both RvD1 and RvD2 inhibited oral cancer proliferation in vitro. Using two validated mouse oral squamous cell carcinoma xenograft models, we found that RvD2, the more potent anti-inflammatory lipid mediator, significantly reduced tumor size. The mechanism of this action might involve suppression of IL-6, C-X-C motif chemokine 10 (CXCL10), and reduction of tumor necrosis. RvD2 generated short-lasting analgesia in xenograft cancer models, which coincided with decreased neutrophil infiltration and myeloperoxidase activity. Using a cancer supernatant model, we demonstrated that RvD2 reduced cancer-derived cytokines/chemokines (TNF-alpha, IL 6, CXCL10, and MCP-1), cancer mediator-induced CD11b+Ly6G- myeloid cells, and nociception. We infer from our results that manipulation of the endogenous pro resolution pathway might provide a novel approach to improve oral cancer and cancer pain treatment. PMID- 30009835 TI - Aiming for the target: Mitochondrial drug delivery in traumatic brain injury. AB - Mitochondria are a keystone of neuronal function, serving a dual role as sustainer of life and harbinger of death. While mitochondria are indispensable for energy production, a dysregulated mitochondrial network can spell doom for both neurons and the functions they provide. Traumatic brain injury (TBI) is a complex and biphasic injury, often affecting children and young adults. The primary pathological mechanism of TBI is mechanical, too rapid to be mitigated by anything but prevention. However, the secondary injury of TBI evolves over hours and days after the initial insult providing a window of opportunity for intervention. As a nexus point of both survival and death during this second phase, targeting mitochondrial pathology in TBI has long been an attractive strategy. Often these attempts are mired by efficacy-limiting unintended off target effects. Specific delivery to and enrichment of therapeutics at their submitochondrial site of action can reduce deleterious effects and increase potency. Mitochondrial drug localization is accomplished using (1) the mitochondrial membrane potential, (2) affinity of a carrier to mitochondria specific components (e.g. lipids), (3) piggybacking on the cells own mitochondria trafficking systems, or (4) nanoparticle-based approaches. In this review, we briefly consider the mitochondrial delivery strategies and drug targets that illustrate the promise of these mitochondria-specific approaches in the design of TBI pharmacotherapy. PMID- 30009834 TI - Identification by virtual screening and functional characterisation of novel positive and negative allosteric modulators of the alpha7 nicotinic acetylcholine receptor. AB - Several previous studies have demonstrated that the activity of neurotransmitters acting on ligand-gated ion channels such as the nicotinic acetylcholine receptor (nAChR) can be altered by compounds binding to allosteric modulatory sites. In the case of alpha7 nAChRs, both positive and negative allosteric modulators (PAMs and NAMs) have been identified and have attracted considerable interest. A recent study, employing revised structural models of the transmembrane domain of the alpha7 nAChR in closed and open conformations, has provided support for an inter subunit transmembrane allosteric binding site (Newcombe et al 2017). In the present study, we have performed virtual screening of the DrugBank database using pharmacophore queries that were based on the predicted binding mode of PAMs to alpha7 nAChR structural models. A total of 81 compounds were identified in the DrugBank database, of which the 25 highest-ranked hits corresponded to one of four previously-identified therapeutic compound groups (carbonic anhydrase inhibitors, cyclin-dependent kinase inhibitors, diuretics targeting the Na+-K+-Cl cotransporter, and fluoroquinolone antibiotics targeting DNA gyrase). The top ranked compound from each of these four groups (DB04763, DB08122, furosemide and pefloxacin, respectively) was tested for its effects on human alpha7 nAChR expressed in Xenopus oocytes using two-electrode voltage-clamp electrophysiology. These studies, conducted with wild-type, mutant and chimeric receptors, resulted in all four compounds exerting allosteric modulatory effects. While DB04763, DB08122 and pefloxacin were antagonists, furosemide potentiated ACh responses. Our findings, supported by docking studies, are consistent with these compounds acting as PAMs and NAMs of the alpha7 nAChR via interaction with a transmembrane site. PMID- 30009838 TI - Targeted training: Converging evidence against the transferable benefits of online brain training on cognitive function. AB - There is strong incentive to improve our cognitive abilities, and brain training has emerged as a promising approach for achieving this goal. While the idea that extensive 'training' on computerized tasks will improve general cognitive functioning is appealing, the evidence to support this remains contentious. This is, in part, because of poor criteria for selecting training tasks and outcome measures resulting in inconsistent definitions of what constitutes transferable improvement to cognition. The current study used a targeted training approach to investigate whether training on two different, but related, working memory tasks (across two experiments, with 72 participants) produced transferable benefits to similar (quantified based on cognitive and neural profiles) untrained test tasks. Despite significant improvement on both training tasks, participants did not improve on either test task. In fact, performance on the test tasks after training were nearly identical to a passive control group. These results indicate that, despite maximizing the likelihood of producing transferable benefits, brain training does not generalize, even to very similar tasks. Our study calls into question the benefit of cognitive training beyond practice effects, and provides a new framework for future investigations into the efficacy of brain training. PMID- 30009837 TI - A-type K+ channels impede supralinear summation of clustered glutamatergic inputs in layer 3 neocortical pyramidal neurons. AB - A-type K+ channels restrain the spread of incoming signals in tufted and apical dendrites of pyramidal neurons resulting in strong compartmentalization. However, the exact subunit composition and functional significance of K+ channels expressed in small diameter proximal dendrites remain poorly understood. We focus on A-type K+ channels expressed in basal and oblique dendrites of cortical layer 3 pyramidal neurons, in ex vivo brain slices from young adult mice. Blocking putative Kv4 subunits with phrixotoxin-2 enhances depolarizing potentials elicited by uncaging RuBi-glutamate at single dendritic spines. A concentration of 4-aminopyridine reported to block Kv1 has no effect on such responses. 4 aminopyridine and phrixotoxin-2 increase supralinear summation of glutamatergic potentials evoked by synchronous activation of clustered spines. The effect of 4 aminopyridine on glutamate responses is simulated in a computational model where the dendritic A-type conductance is distributed homogeneously or in a linear density gradient. Thus, putative Kv4-containing channels depress excitatory inputs at single synapses. The additional recruitment of Kv1 subunits might require the synchronous activation of multiple inputs to regulate the gain of signal integration. PMID- 30009836 TI - Contributions of medial prefrontal cortex to decision making involving risk of punishment. AB - The prefrontal cortex (PFC) plays an important role in several forms of cost benefit decision making. Its contributions to decision making under risk of explicit punishment, however, are not well understood. A rat model was used to investigate the role of the medial PFC (mPFC) and its monoaminergic innervation in a Risky Decision-making Task (RDT), in which rats chose between a small, "safe" food reward and a large, "risky" food reward accompanied by varying probabilities of mild footshock punishment. Inactivation of mPFC increased choice of the large, risky reward when the punishment probability increased across the session ("ascending RDT"), but decreased choice of the large, risky reward when the punishment probability decreased across the session ("descending RDT"). In contrast, enhancement of monoamine availability via intra-mPFC amphetamine reduced choice of the large, risky reward only in the descending RDT. Systemic administration of amphetamine reduced choice of the large, risky reward in both the ascending and descending RDT; however, this reduction was not attenuated by concurrent mPFC inactivation, indicating that mPFC is not a critical locus of amphetamine's effects on risk taking. These findings suggest that mPFC plays an important role in adapting choice behavior in response to shifting risk contingencies, but not necessarily in risk-taking behavior per se. PMID- 30009839 TI - The disappearing limb trick and the role of sensory suggestibility in illusion experience. AB - Body ownership (the feeling that my body belongs to me) can be easily perturbed in healthy individuals by inducing bodily illusions. For example, dis-integrating vision, touch, and proprioception can produce the feeling that your limb is 'lost', such as in "the disappearing hand trick" (DHT). Following this illusion, participants report that the hand feels as though it is no longer part of the body, that it does not belong to them anymore, and that they do not know its location. However, it remains unknown whether this illusion can also be applied to the feet. Lower body ownership is disturbed in some populations, such as in Body Integrity Identity Disorder (BIID), where people have a longstanding desire to paralyze or amputate a (disowned) part of their body (i.e. usually the legs), thus exploring the efficacy and utility of lower body illusions might be useful for populations like such. In the current study, we induced the disappearing hand and foot trick in two groups of healthy adults. As the illusion crucially relies on illusory sensory feedback, we also explored if one's level of sensory suggestibility influenced the experience of the illusion. Questionnaire data showed that the DHT can be applied to the feet, as there was no difference in experience between those who experienced the illusion for the hands and those who experienced the illusion for the feet. Moreover, one's level of sensory suggestibility correlated positively with the experience of illusory sensations (like warmth, numbness, or the presence of an extra limb) following the illusion. We discuss the implications of bodily illusions in clinical populations and emphasize the critical role that sensory signals (even illusory) play in creating the bodily experience. PMID- 30009840 TI - Common variation within the SETBP1 gene is associated with reading-related skills and patterns of functional neural activation. AB - Epidemiological population studies highlight the presence of substantial individual variability in reading skill, with approximately 5-10% of individuals characterized as having specific reading disability (SRD). Despite reported substantial heritability, typical for a complex trait, the specifics of the connections between reading and the genome are not understood. Recently, the SETBP1 gene has been implicated in several complex neurodevelopmental syndromes and disorders that impact language. Here, we examined the relationship between common polymorphisms in this gene, reading, and reading associated behaviors using data from an ongoing project on the genetic basis of SRD (n = 135). In addition, an exploratory analysis was conducted to examine the relationship between SETBP1 and brain activation using functional magnetic resonance imaging (fMRI; n = 73). Gene-based analyses revealed a significant association between SETBP1 and phonological working memory, with rs7230525 as the strongest associated single nucleotide polymorphism (SNP). fMRI analysis revealed that the rs7230525-T allele is associated with functional neural activation during reading and listening to words and pseudowords in the right inferior parietal lobule (IPL). These findings suggest that common genetic variation within SETBP1 is associated with reading behavior and reading-related brain activation patterns in the general population. PMID- 30009841 TI - A Case of Fatal Clostridial Necrotizing Fasciitis After Radical Prostatectomy. PMID- 30009842 TI - MOTOM toolbox: MOtion Tracking via Optotrak and Matlab. AB - We present a Matlab toolbox that allows the user to control and collect data using Northern Digital's Optotrak system. The Optotrak is a modular motion capture system, which tracks the positions of infrared markers. It also supports grouping markers together as a single body. The body's position, orientation as well as all the marker position data can be obtained simultaneously. The installation, set-up and alignment procedures are highly automated, and thus require minimal human interaction. We provide additional scripts, functions, documentation and examples to help experimenters integrate the Optotrak system into experiments using recent 64-bit computers and existing Matlab toolboxes. PMID- 30009843 TI - Allograft rejection is associated with development of functional IgE specific for donor MHC antigens. AB - BACKGROUND: Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss. OBJECTIVE: This study aimed to investigate whether MHC-specific antibodies of the IgE isotype are induced during allograft rejection. METHODS: Anti-MHC/HLA IgE levels were measured in sera of mice grafted with skin or heart transplants from various donor strains and in sera of kidney transplant patients with high levels of HLA IgG. Mediator release was triggered in vitro by stimulating basophils that were coated with murine or human IgE-positive serum, respectively, with specific recombinant MHC/HLA antigens. Kidney tissue samples obtained from organ donors were analyzed by using flow cytometry for cells expressing the high-affinity receptor for IgE (FcepsilonRI). RESULTS: Donor MHC class I- and MHC class II-specific IgE was found on acute rejection of skin and heart grafts in several murine strain combinations, as well as during chronic antibody-mediated heart graft rejection. Anti-HLA IgE, including donor HLA class I and II specificities, was identified in a group of sensitized transplant recipients. Murine and human anti-MHC/HLA IgE triggered mediator release in coated basophils on stimulation with specific MHC/HLA antigens. HLA-specific IgE was not linked to atopy, and allergen-specific IgE present in allergic patients did not cross-react with HLA antigens. FcepsilonRI+ cells were found in the human renal cortex and medulla and provide targets for HLA-specific IgE. CONCLUSION: These results demonstrate that MHC/HLA specific IgE develops during an alloresponse and is functional in mediating effector mechanisms. PMID- 30009844 TI - Optimisation of enzyme cascades for chiral amino alcohol synthesis in aid of host cell integration using a statistical experimental design approach. AB - Chiral amino alcohols are compounds of pharmaceutical interest as they are building blocks of sphingolipids, antibiotics, and antiviral glycosidase inhibitors. Due to the challenges of chemical synthesis we recently developed two TK-TAm reaction cascades using natural and low cost feedstocks as substrates: a recycling cascade comprising of 2 enzymes and a sequential 3-step enzyme cascade yielding 30% and 1% conversion, respectively. In order to improve the conversion yield and aid the future host strain engineering for whole cell biocatalysis, we used a combination of microscale experiments and statistical experimental design. For this we implemented a full factorial design to optimise pH, temperature and buffer type, followed by the application of Response Surface Methodology for the optimisation of substrates and enzymes concentrations. Using purified enzymes we achieved 60% conversion for the recycling cascade and 3-fold improvement using the sequential pathway. Based on the results, limiting steps and individual requirements for host cell metabolic integration were identified expanding the understanding of the cascades without implementing extensive optimisation modelling. Therefore, the approach described here is well suited for optimising reaction conditions as well as defining the relative enzyme expression levels required for construction of microbial cell factories. PMID- 30009845 TI - A touch-scaffolded model of human prosociality. AB - For centuries, scholars have been puzzled by the distinct human prosociality. A variety of explanations have been proposed to unveil the mystery of it and nearly all these explanations have focused on the role of complex cognitive processes. In this paper, we propose a novel hypothesis that human prosociality is touch scaffolded. We argue that early tactile stimulation such as maternal touch serves as the basic component that enables the emergence of nascent human prosociality. During this process, C-tactile afferents along with many neuropeptides, such as oxytocin and endogenous opioids, play pivotal roles in the touch - prosociality connection by facilitating the formation of an intimate caregiver-infant bond and the development of a positive social schema. Our model provides a different perspective on the development of human prosociality and builds a bridge between the human tactile system and high-level psychology - human prosociality. PMID- 30009846 TI - Relationship between exposure, body burden and target tissue concentration after oral administration of a low-dose mixture of pyrethroid insecticides in young adult rats. AB - Pyrethroids (PYRs) are synthetic insecticides increasingly used in agricultural and household pest control. Little is known on how the toxicity of highly effective bolus doses of single compounds compares to more realistic scenarios of low-level exposure to PYR mixtures. In this study, we examined a quaternary mixture of two noncyano (tefluthrin, TEF; bifenthrin, BIF) and two cyano (alpha cypermethrin, alpha-CPM; deltamethrin, DTM) PYRs in young adult rats. These compounds are mostly composed of PYR isomers ranking top ten in acute lethality in rats. Concurrently, we administered near-threshold levels of the four PYRs dissolved in corn oil by oral route. Six hours later blood was collected and the liver and cerebellum were dissected out to determine PYR concentrations in these tissues using Gas Chromatography with Electron Capture Detector (GC-ECD). The mixture caused mild-to-moderate changes in non-locomotor behaviors and subcutaneous body temperature (up to +1.2-1.5 degrees C increase at 2-4 h after dosing, respectively, compared to pre-dosing records). The most toxic PYRs BIF and TEF reached higher concentrations in the cerebellum than the cyano-compounds alpha-CPM and DTM. In addition, PYR concentrations in the cerebellum were correlated to single compound proportions in the dosing solution and changes in body temperature. Our results suggest that aggregate exposures resulting in a target tissue burden of ~10-1 nmoles PYR/g may be toxicologically relevant, expanding the evidence on exposure-dose-effect relationships for PYRs, and serving to design convenient pharmacokinetic models for environmentally relevant exposures to PYR mixtures. PMID- 30009847 TI - p300 promotes differentiation of Th17 cells via positive regulation of the nuclear transcription factor RORgammat in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) has been the major cause of acute respiratory failure in critical patients and one of the leading causes of death worldwide for several decades. Th17 cells are involved in the occurrence and progression of ARDS. Furthermore, histone acetyltransferase (HAT) p300 is a transcriptional coactivator, and its activity is closely related to cancer and inflammatory diseases. p300 and histone deacetylase 1 (HDAC1) interact with and stabilize the nuclear transcription factor retinoic acid-related orphan receptor gamma t (RORgammat) and participate in the regulation of RORgammat-mediated IL-17 transcription in T helper 17 (Th17) cell differentiation by acetylation and deacetylation. However, the effect of p300 on RORgammat and Th17 cells in ARDS is not well reported. Therefore, we aimed to investigate the clinical features of p300 and its effect on RORgammat and Th17 cells in patients with ARDS as well as in lipopolysaccharide-induced acute lung injury (ALI) mouse models. Overexpression of p300 and RORgammat mRNA was found in the peripheral blood mononuclear cells from patients with ARDS, especially among non-survivors, compared to that in healthy individuals (P < 0.05). Moreover, the decline of FOXP3 mRNA level correlated with survival and increased RORgammat mRNA levels corelated with infection (P < 0.05). Immunohistochemical analysis revealed high p300 and RORgammat expression in ALI mouse lung tissues. Inhibitor-mediated knockdown of p300 reduced lung tissue inflammation and lung injury score (P < 0.05). Western blotting and ELISA revealed that p300 inhibitor caused a decrease in the mRNA and protein levels of RORgammat as well as interleukin 17 (IL-17) production in ALI mouse lung tissues (P < 0.05). Thus, our findings suggest that p300 may play a key role in ARDS by positively regulating RORgammat transcription and is a potential new immunotherapy target for ARDS. PMID- 30009848 TI - Infectivity of okra enation leaf curl virus and the role of its V2 protein in pathogenicity. AB - Cotton crop has been severely affected by multiple begomoviruses in Pakistan and India. In our previous study, we found okra enation leaf curl virus (OELCuV), cotton leaf curl Multan betasatellite (CLCuMuB) and cotton leaf curl Multan alphasatellite (CLCuMuA) infecting cotton in Pakistan. The current study was designed to investigate the infectivity of OELCuV and its ability to trans replicate non-cognate CLCuMuB. Agro-infectious clones containing the partial tandem repeats of OELCuV and CLCuMuB were constructed and the infectivity assays were carried out through Agrobacterium mediated transformation in the model host species Nicotiana benthamiana under controlled conditions. The results showed that in the inoculated plants OELCuV alone can cause downward curling and yellowing of leaves with thickened veins. However, when co-inoculated with the non-cognate CLCuMuB it could functionally trans-replicate CLCuMuB resulting in a more severe phenotype. The expression of Pre-coat/V2 protein in the N. benthamiana plants through the potato virus X (PVX) system caused localized cell death after severe leaf curling in the infiltrated leaves. The tissue tropism of the virus was associated with the systemic development of a hypersensitive response (HR), which ultimately lead to the plant death. The results indicated the involvement of V2 protein in the pathogenicity of OELCuV and its ability to trigger the host defense machinery. This study also demonstrated the ability of OELCuV to trans-replicate CLCuMuB resulting in typical leaf curl disease symptoms in N. benthamiana. PMID- 30009849 TI - Analysis of complete genome and pathogenicity studies of the spring viremia of carp virus isolated from common carp (Cyprinus carpio carpio) and largemouth bass (Micropterus salmoides): An indication of SVC disease threat in Korea. AB - A batch of wild common carp and largemouth bass died in Andong, Gyeongsangbuk-do province, South Korea, in 2016. Moribund fish showed typical signs of spring viremia of carp (SVC) disease, which causes acute hemorrhage in the skin and ascites. Thus far, SVC disease has been detected in several regions of the world but never in South Korea. Suspecting the infectious agent to be the SCV virus (SVCV), the moribund fish were sampled and screened. The isolated virus developed a cytopathic effect in EPC cells. Both viral isolates from the common carp (ADC SVC2016-1) and largemouth bass (ADC-SVC2016-3) were identical in terms of their genome sequence, which were 11,034 bp nucleotides in length. Genome comparison exhibited greater sequence similarity with the Asian SVCV sequences available at NCBI. Phylogenetic analysis revealed that the Korean SVCV isolates were clustered within the Asian clade. More specifically, evolutionary analysis by using the P gene sequences showed that the Korean isolates were sub-cladded within the Iai genogroup but diverged from Chinese strains of SH150514 and SH160901. The Korean isolates shared more than 98% sequence similarity with the two Chinese SVCV isolates, suggesting that the spread of SVCV originated from China. The isolated virus had cytopathic effects on EPC cells. Virus transmission studies showed that the virus exhibited the highest virulence at 15 degrees C, which was also dependent on the method used, with the injection method being better than the immersion and cohabitation methods. This is the first study to document that Korean SVCV isolates may be epizootic in wild common carp and other susceptible animal populations in South Korea. PMID- 30009850 TI - Evaluation of an incubation instrument-free reverse transcription recombinase polymerase amplification assay for rapid and point-of-need detection of canine distemper virus. AB - Canine distemper, caused by Canine distemper virus (CDV), is a highly contagious and fatal systemic disease in free-living and captive carnivores worldwide. Accurate, rapid and simple detection of CDV is critical to improve disease management and prevent outbreaks. In this study, a visible and incubation instrument-free reverse-transcription recombinase polymerase amplification assay combined with lateral flow strip (LFS RT-RPA) was developed to detect CDV using primers and lateral flow (LF) probe specific for the nucleocapsid (N) protein gene. The CDV LFS RT-RPA assay was performed in a closed fist using body heat for 15 min, and the products were visible to the naked eyes on the LFS within 5 min. The assay could detect CDV, and there was no cross-reaction with the other viruses tested. Using the in vitro transcribed CDV RNA as template, the analytical sensitivity was 9.4 * 101 copies per reaction, which was the same result as that of a real-time RT-PCR. The assay performance was further evaluated by testing 32 nasal/oropharyngeal swab samples, and CDV RNA positive rate was 62.0% (20/32) by LFS RT-RPA, which was the same result as that of the real-time RT-PCR assay. The performance of the LFS RT-RPA was comparable to real-time RT PCR, while the LFS RT-RPA assay was much faster and easier to perform. The novel CDV LFS RT-RPA assay provides an attractive and promising tool for rapid and reliable detection of CDV in the underequipped laboratory and point-of-need facility, which is of great significance in CD control in low resource settings. PMID- 30009851 TI - Sanger-based sequencing technology for yellow fever vaccine genetic quality control. AB - Yellow Fever (YF) is an acute viral hemorrhagic disease prevalent mainly in Africa and Americas, with 20-60% fatality rate in severe forms. Currently, antiviral drugs for the infection are not available, reinforcing the importance of vaccination in resident populations and travelers. Manufactured in 7 different countries, the YF vaccine was first created in 1937 and two substrains are used for production, 17DD and 17D-204. The vaccine produced in Bio-Manguinhos/Brazil uses 17DD substrain and more than 160 million doses have been exported to over 74 countries. The World Health Organization (WHO) recommends that new seed- and working-lots should have the viral genome sequenced in order to check vaccine genetic stability. The aim of this study was to develop and standardize a Sanger based sequencing protocol for the genetic monitoring of the Brazilian 17DD vaccine. We designed 54 oligos to access the complete YF vaccine genome by RT-PCR and sequencing approach. After protocol standardization, we tested 45 vaccine lots and the corresponding secondary and working seed lots. All 45 lots presented 100% nucleotide identity to each other and to the seed lots. We also detected 2 heterogeneous positions at nucleotides 4523 (C/T) and 6673 (C/T) that may indicate a quasispecies diversity of YF 17DD strain. When compared to the Brazilian GenBank sequence YFU17066, the Brazilian 17DD vaccine presented 6 silent mutations. By applying the sequencing methodology to two YF 17D-204 strains, we showed that our method can also be used to sequence different YF vaccine virus. In summary, we have developed a robust method for the genetic monitoring of YF vaccines, which has been successfully applied in Bio-Manguinhos since 2009 and could also be used by other manufacturers for YF17D-based vaccines. There were no genetic variation in the Brazilian tested lots, highlighting the safety, production consistency and, more importantly, the genetic stability of Bio-Manguinhos' YF vaccine in the last 3 decades. PMID- 30009852 TI - Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP. AB - Although PTHrP is implicated in several cancers, its role in chemoresistance is not fully elucidated. We found that in CRC cells, PTHrP exerts proliferative and protective effects and induces cell migration. The aim of this work was to further study the effects of PTHrP in CRC cells. Herein we evidenced, for the first time, that PTHrP induces resistance to CPT-11 in Caco-2 and HCT116 cells; although both cell lines responded to the drug through different molecular mechanisms, the chemoresistance by PTHrP in these models is mediated through ERK, which in turn is activated by PCK, Src and Akt. Moreover, continue administration of PTHrP in nude mice xenografts increased the protein levels of this MAPK and of other markers related to tumorigenic events. The understanding of the molecular mechanisms leading to ERK 1/2 activation and the study of ERK targets may facilitate the development of new therapeutic strategies for CRC treatment. PMID- 30009853 TI - Interferon-gamma release assay for tuberculosis screening of solid-organ transplant recipients is cost-effective. AB - OBJECTIVES: Tuberculosis (TB) is a serious infectious disease with high mortality for solid-organ transplantation. Preventive therapy of latent tuberculosis infection (LTBI) has been considered to reduce TB risk and improve outcomes of transplantation. The aim of this study was to evaluate the cost-effectiveness of the interferon-gamma release assays (IGRAs); QuantiFERON(r)-TB Gold in-Tube (QFT) and T-SPOT(r).TB (TSPOT)), for kidney, liver and lung transplant recipients in low TB incidence countries. METHODS: Decision trees and Markov models were developed for four strategies; QFT, TSPOT, the tuberculin skin test (TST) and no screening. Targeted populations were hypothetical cohorts of kidney, liver and lung transplant recipients aged 40 years using a societal perspective on a lifetime horizon. Per-person costs, effectiveness and incremental cost effectiveness ratios were calculated and compared. RESULTS: QFT was the most cost effective (Kidney; US$ 5679, 3.026 QALYs, Liver; US$ 5914, 2.365 QALYs, Lung; US$ 6092, 3.761 QALYs). No screening was the least effective. Cost-effectiveness was not sensitive to BCG vaccination rate, and the costs of screening tests and treatment. CONCLUSIONS: TB screening using IGRA with individualized TB risk assessment and follow-up monitoring of drug toxicity during LTBI treatment is recommended for solid organ transplantation, on the basis of the benefits and cost-effectiveness. PMID- 30009854 TI - Double micro-guide-wire technique to facilitate microcatheter navigation through tortuous intracranial vasculature. AB - We report a case in which navigation of the micro catheter (Headway 027) with the conventional single microwire technique became impossible because of the difficult intracranial vascular anatomy. In order to achieve access, we used two Terumo 012 inches micro guide-wires with a 45 degrees angle inside a single micro catheter. The manoeuver was easy and can be reproduced in specific and challenging cases. PMID- 30009855 TI - B lymphocytes: Crucial contributors to brain development and neurological diseases. AB - The immune system is a major contributor to brain homeostasis and pathogenesis of neurological diseases. However, the role of B lymphocytes (cells) in the brain is poorly understood. In this review, we describe the functions of the different subtypes of B cells in brain development and neurological diseases. B cells are classified into several subtypes according their function and gene expression. B 1a cells, which participate in innate immunity by producing natural antibodies, are abundant in the developing brain, and mediate oligodendrocyte development. In conditions such as autoimmune encephalomyelitis, spinal cord injury, and stroke, B-2 cells exacerbate the pathology by producing pathogenic autoantibodies. On the other hand, regulatory B cells suppress inflammation by secreting interleukin-10 and play beneficial roles in pathological conditions. Here, we summarize the distribution and function of B cells during brain development and neurological diseases. PMID- 30009856 TI - 2'-hydroxycinnamaldehyde inhibits cancer cell proliferation and tumor growth by targeting the pyruvate kinase M2. AB - It is reported that 2'-hydroxycinnamaldehyde (HCA), isolated from cinnamon, has anti-tumor effects through the modulation of multi-target molecules. In this study, we identified pyruvate kinase M2 (PKM2) as a direct target of HCA by use of biochemical methods including affinity chromatography, drug affinity responsive target stability, and cellular thermal shift assay. PKM2 is up regulated in multiple cancer types and is considered as a potential target for cancer therapy. HCA binds directly to PKM2 and selectively decreases the phosphorylation of PKM2 at Tyr105, indicating a potential anti-proliferative effect on prostate cancer cells. As a PKM2 activator, HCA increases pyruvate kinase activity by promoting the tetrameric state of PKM2. However, HCA suppresses protein kinase activity of PKM2 by decreasing the phosphorylation at Tyr105. Moreover, this leads to a decrease of PKM2-mediated STAT3 phosphorylation at Tyr705 and a down-regulation of target genes, including MEK5 and cyclin D1. Furthermore, HCA suppresses tumor growth and the release of tumor extracellular vesicles in vivo by inhibiting the phosphorylation of PKM2. Collectively, our results suggest that HCA may be a potential anticancer agent targeting PKM2 in cancer progression. PMID- 30009858 TI - Associations between blood lead, olfaction and fine-motor skills in elderly men: Results from the Heinz Nixdorf Recall Study. AB - Lead (Pb) is a recognized neurotoxin. Pb2+ can interfere with divalent metal transporters and ion channels and may thus affect other brain metals and cation signaling in neurons. Thereby, cognitive and sensory functions can be impaired. Whereas cognitive effects are well described less is known about olfaction and motor functions in the general population at currently lower exposure levels. The objective of this study was to evaluate the influence of Pb in blood (PbB) on odor identification and fine motor skills within the framework of the Heinz Nixdorf Recall Study (HNRS), a prospective cohort study among an elderly German population. Data on odor identification assessed with Sniffin' sticks and fine motor test results were collected during the second follow-up of HNRS (2011-2014) in 1188 elderly men aged 55 to 86 years. PbB was determined in 1140 blood samples archived at baseline (2000-2003) and in 796 samples from the second follow-up. The association between PbB and impaired odor identification (normosmia as reference) was estimated with proportional odds ratios (PORs) with 95% confidence intervals (CI). The odds ratios (OR) of substantially impaired dexterity (tapping hits <10th percentile, errors in aiming, line tracing, or steadiness>90th percentile) were estimated with mixed logistic regression models for test results with both hands, where PbB was adjusted for covariates. PbB at baseline (median 32.9 MUg/L; 2.27% >=90 MUg/L) was higher than at follow-up (25.9 MUg/L; 0.84% >=90 MUg/L). The individual concentrations were correlated (Spearman rs 0.59, 95% CI 0.54 - 0.63). PORs of an impaired odor identification in men with baseline PbB >=90 MUg/L were 1.96 (95% CI 0.94-4.11) and 1.57 (95% CI 0.47-5.19) with follow up PbB. Fine-motor tests were not affected by elevated PbB with the exception of tapping in men with follow-up PbB >=50 MUg/L (OR 2.14, 95% CI 1.09-4.23). Increasing age had strong effects on all outcomes. Low education was associated with impaired odor identification, tapping, and aiming. Also, alcohol consumption and current smoking affected the test results, particularly steadiness. In this community-based cohort of elderly men, we could confirm indication of an influence of elevated PbB on odor identification. Small numbers of men with elevated PbB due to an on-going trend of decreasing PbB in the general population, strong covariates and multiple comparisons hamper the evaluation of adversity of these effects of PbB on olfaction and dexterity. PMID- 30009857 TI - Antibacterial effects and cytotoxicity of an adhesive containing low concentration of silver nanoparticles. AB - OBJECTIVES: To evaluate the antibacterial effects, cytotoxicity and microtensile bond strength of an adhesive containing low concentrations of silver nanoparticles (NAg). METHODS: Various concentrations of NAg (50, 100, 150, 200 and 250 ppm) were incorporated into the primer of the Scotchbond Multi-Purpose adhesive system (SBMP). Antibacterial activity was examined using a broth microdilution assay to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), agar diffusion assay and the MTT assay was used to examine the biofilm metabolic activity (S. mutans). The Microtensile Bond Test (MUTBS) was performed after 24 h, followed by 6-months storage in distilled water. Cytotoxicity was assessed with an MTT reduction assay in human dental pulp stem cells viability after exposure to Nag-conditioned culture media during 0, 24, 48, and 72 h. The results were statistically analyzed (alpha <= 0.05). RESULTS: MIC was found between NAg 25 and 50 ppm MBC was determined at 50 ppm of NAg. Bacterial activity inhibition was higher than control in all NAg groups compared to control in agar diffusion assay. Biofilm inhibition was statistically higher in 250 ppm NAg than control. All NAg groups and SBMP presented similar cytotoxicity in each period. Adhesives with NAg 200 and 250 ppm and SBMP (control) presented the highest MUTBS values, similar to that of SBMP control, in both instances (24 h and 6 months) (p > 0.05). CONCLUSIONS: The commercial primer containing NAg 250 ppm showed both antibacterial effect and reliable bond strength with no cytotoxicity increase. The addition of NAg to primers seems promising for the improvement of conventional dental adhesives efficacy. CLINICAL SIGNIFICANCE: The addition of low concentrations of NAg (250 ppm) to primers were effective to improve antibacterial effect preserving the bond strength and the biocompatibility of the commercial product. NAg/primer association could protect the tooth-adhesive interface increasing dental restoration longevity. PMID- 30009860 TI - 27-hydroxycholesterol decreases cell proliferation in colon cancer cell lines. AB - Colorectal cancer (CRC) is the third most diagnosed cancer in the western world, affecting 1 out of approximately 22 people in their lifetime. Several epidemiological studies suggest a positive association between high plasma cholesterol levels and colorectal cancer. However, the molecular mechanisms by which cholesterol may alter the risk of colorectal cancer (CRC) are ill-defined as the cholesterol lowering drugs statins do not appear to decrease a patient's risk of developing colorectal cancer. Cholesterol is metabolized to active derivatives including cholesterol oxidization products (COP), known as oxysterols, which have been shown to alter cellular proliferation. These metabolites and not cholesterol per se, may therefore affect the risk of developing colorectal cancer. The cholesterol metabolite or the oxysterol 27 hydroxycholesterol (27-OHC) is the most abundant oxysterol in the plasma and has been shown to be involved in the pathogenesis of several cancers including breast and prostate cancer. However, the role of 27-OHC in colorectal cancer has not been investigated. We treated Caco2 and SW620, two well characterized colon cancer cells with low, physiological and high concentrations of 27-OHC, and found that 27-OHC reduces cellular proliferation in these cells. We also found that the effects of 27-OHC on cell proliferation are not due to cellular cytotoxicity or apoptotic cellular death. Additionally, 27-OHC-induced reduction in cell proliferation is independent of actions on its target nuclear receptors, liver-X receptors (LXR) and estrogen receptors (ER) activation. Instead, our study demonstrates that 27-OHC significantly decreases AKT activation, a major protein kinase involved in the pathogenesis of cancer as it regulates cell cycle progression, protein synthesis, and cellular survival. Our data shows that treatment with 27-OHC substantially decreases the activation of AKT by reducing levels of its active form, p-AKT, in Caco2 cells but not SW620 cells. All together, our results show for the first time that the cholesterol metabolite 27 OHC reduces cell proliferation in colorectal cancer cells. PMID- 30009859 TI - Caloric restriction can affect one-carbon metabolism during pregnancy in the rat: A transgenerational model. AB - One-carbon metabolism is critical to pregnancy outcomes, because it determines the availability of nutrients involved in cell divisions and DNA methylation. The aim of this study was to analyze how 50% prenatal calorie restriction affected one-carbon metabolism in pregnant Wistar rats of the F0 to F2 generations. Mean choline (p < 0.001), betaine (p < 0.001), and S-adenosylmethionine (SAM) (p < 0.05) concentrations were respectively about 40%, 45%, and 20% lower in the F0_R (R - restricted diet) than in the F0_C (C - control diet). Homocysteine, S adenosylhomocysteine (SAH), and trimethylamine oxide concentrations were unaffected. In the F1_R, the SAM-to-SAH ratio was 25% higher (p < 0.05) than in the F1_C. No differences between the C and R groups were observed in the F2 generation. The SAM concentrations in the F1_R were higher than in the F0_R and the F2_R (p < 0.01). The relative transcript levels of Mat1a, Bhmt, Cbs, Pemt, and Mthfr were only slightly affected by the diet, with changes of less than a factor of 2.0. Cbs activity in the F2_R was significantly higher than in the F2_C (p < 0.001). Food deprivation may affect one-carbon metabolism in pregnant rats, but it does not stimulate persistent metabolic changes that can be observed during the pregnancy of their progeny of the F1 or F2 generations. PMID- 30009861 TI - Differential regulation of ion channels function by proteolysis. AB - Ion channels are pore-forming protein complexes in membranes that play essential roles in a diverse array of biological activities. Ion channel activity is strictly regulated at multiple levels and by numerous cellular events to selectively activate downstream effectors involved in specific biological activities. For example, ions, binding proteins, nucleotides, phosphorylation, the redox state, channel subunit composition have all been shown to regulate channel activity and subsequently allow channels to participate in distinct cellular events. While these forms of modulation are well documented and have been extensively reviewed, in this article, we will first review and summarize channel proteolysis as a novel and quite widespread mechanism for altering channel activity. We will then highlight the recent findings demonstrating that proteolysis profoundly alters Inositol 1,4,5 trisphosphate receptor activity, and then discuss its potential functional ramifications in various developmental and pathological conditions. PMID- 30009862 TI - Effects of dietary alpha-linolenic acid-enriched diacylglycerol oil on embryo/fetal development in rats. AB - Recent studies suggest that diets supplemented with alpha-linolenic acid (ALA) enriched diacylglycerol (DAG) oil provide potential health benefits in preventing or managing obesity. However, available safety information about reproductive and developmental toxicities of ALA-DAG oil is limited. This study was conducted to clarify the effect, if any, of ALA-DAG oil on embryo-fetal development, following maternal exposure during the critical period of major organogenesis. ALA-DAG oil was administered via gavage to pre-mated female Sprague Dawley rats from gestation day 6 through 19, at dose levels of 0, 1.25, 2.5, and 5.0 mL/kg/day (equivalent to 0, 1149, 2325, and 4715 mg/kg/day, respectively), with total volume adjusted to 5 mL/kg/day with rapeseed oil. All females survived to the scheduled necropsy. There were no treatment-related changes in clinical or internal findings, maternal body weights, feed consumption, intrauterine growth, survival, and number of implantations. No ALA-DAG oil-related fetal malformations or developmental variations were noted. A maternal maximum tolerated dose for ALA DAG oil could not be achieved in this study. Based on these results, a dose level of 5.0 mL/kg (4715 mg/kg/day), the highest dose tested, was considered as the no observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity. PMID- 30009863 TI - Applying a weight of evidence approach to the evaluation of developmental toxicity of biopharmaceuticals. AB - Toxicity studies in pregnant animals are not always necessary for assessing the human risk of developmental toxicity of biopharmaceuticals. The growing experience and information on target biology and molecule-specific pharmacokinetics present a powerful approach to accurately anticipate effects of target engagement by biopharmaceuticals using a weight of evidence approach. The weight of evidence assessment should include all available data including target biology, pharmacokinetics, class effects, genetically modified animals, human mutations, and a thorough literature review. When assimilated, this weight of evidence evaluation may be sufficient to inform risk for specific clinical indications and patient populations. While under current guidance this approach is only applicable for drugs and biologics for oncology, the authors would like to suggest that this approach may also be appropriate for other disease indications. When there is an unacceptable level of uncertainty and a toxicity study in pregnant animals could impact human risk assessment, then such studies should be considered. Determination of appropriate nonclinical species for developmental toxicity studies to inform human risk should consider species specific limitations, reproductive physiology, and pharmacology of the biopharmaceutical. This paper will provide considerations and examples of the weight of evidence approach to evaluating the human risk of developmental toxicity of biopharmaceuticals. PMID- 30009864 TI - Second primary melanomas: Increased risk and decreased time to presentation in patients exposed to tanning beds. AB - BACKGROUND: Melanoma incidence has increased; the primary modifiable risk factor is ultraviolet radiation (UVR) from the sun or artificial UVR (arUVR) from tanning beds. OBJECTIVE: To determine whether patients who developed melanoma after arUVR exposure from tanning beds have unique characteristics. METHODS: A retrospective study of 434 melanoma patients was performed. Patients who consented at the initial appointment completed a questionnaire regarding phenotypic traits, medical history, and UVR exposure. RESULTS: Compared with patients aged >=40 years, younger patients, especially women, had greater lifetime exposure to arUVR. At any age, patients with multiple primary melanomas had a higher probability of exposure to arUVR. For all patients with additional primary melanomas, those exposed to arUVR acquired their second primary melanoma significantly earlier; 67% of patients exposed to arUVR through tanning beds had their second primary diagnosed at the time of or within 1 year of their original diagnosis compared with 28% of nontanners (P = .011). Median time to diagnosis of second primary melanoma in patients exposed to arUVR versus those not exposed was 225 days versus 3.5 years, respectively (P = .027). LIMITATIONS: The study was conducted in 1 geographic area with a relatively small sample size. CONCLUSION: Our findings provide evidence for heightened surveillance in melanoma patients exposed to arUVR. PMID- 30009865 TI - Sun protection behaviour after diagnosis of high-risk primary melanoma and risk of a subsequent primary. AB - BACKGROUND: Melanoma survivors are at high risk of further primary melanomas. OBJECTIVE: To assess sun behaviour after melanoma diagnosis and in relation to further primary melanomas. METHODS: We applied repeated measures latent class analysis to reported primary prevention behaviour at time of diagnosis and six monthly for two years post-diagnosis in patients with clinical stage IB-II melanoma. Correlates of behaviour trajectories and risk of subsequent primaries were determined using multivariable logistic and Cox-regression analyses, respectively. RESULTS: Among 448 male and 341 female patients, sunscreen use fell into three trajectories: 'stable, never-use' (26% males; 12% females); 'stable, sometimes-use' (35% males; 29% females); 'increased to often-use' (39% males; 59% females). Most reduced their weekend sun exposure but in 82% of males and 69% of females it remained raised. Males, smokers, the less-educated, those who tanned or those not self-checking their skin, were more likely to have trajectories of inadequate protection. Patients with melanoma history pre-study doubled their risk of another primary melanoma in the next 2 years if sunscreen use in that time was inadequate (HR 2.45, 95% CI 1.00-6.06). LIMITATIONS: Patient-reported data susceptible to recall bias. CONCLUSION: Our results may assist clinicians to identify patients not using adequate sun protection and provide information for patient counselling. PMID- 30009866 TI - Analysis of awareness and knowledge about Mycobacterium chimaera invasive infections among doctors and medical students. PMID- 30009867 TI - Mycobacterium chimaera-contaminated heater-cooler devices: the inner surface as the missing link? PMID- 30009868 TI - Successful termination of sustained transmission of resident MRSA following extensive NICU refurbishment: an intervention study. AB - BACKGROUND: Neonatal sepsis is a leading cause of morbidity and mortality in neonatal units worldwide. Meticillin-resistant Staphylococcus aureus (MRSA) has become a leading causative pathogen. Many neonatal units experience endemic colonization and infection of their infants, which is often very challenging to successfully eradicate. AIM: To assess the impact of neonatal unit refurbishment and redesign on endemic MRSA colonization and infection. METHODS: A retrospective review was carried out over an eight-year period in a 14-cot, level 2-3 neonatal unit in University Hospital Galway, a large university teaching hospital in the West of Ireland. Surveillance, colonization, and infection data for a four-year period pre and four-year period post neonatal unit refurbishment are described. Clinical and microbiological data were collected on all MRSA-colonized and infected infants between 2008 and 2015. Molecular typing data are available for MRSA isolates. An interrupted time-series design was used, with unit refurbishment as the intervention. FINDINGS: Our neonatal unit had a pattern of sustained transmission of endemic resident MRSA strains which we could not eradicate despite repeated standard infection control interventions. Complete unit refurbishment led to successful termination of sustained transmission of these strains. Colonization decreased and no infants were actively infected post refurbishment of the unit. CONCLUSION: We report successful termination of sustained transmission of endemic strains of MRSA from our neonatal unit following complete unit redesign and refurbishment. PMID- 30009869 TI - Faecal microbiota transplantation with frozen capsules for relapsing Clostridium difficile infections: the first experience from 15 consecutive patients in France. PMID- 30009870 TI - Exploring the relationship between fairness and 'brain types' in children with high-functioning autism spectrum disorder. AB - BACKGROUND: Existing research typically focuses on only one domain of cognition with regard to fairness-theory of mind or executive function. However, children with High-functioning autism spectrum disorder (HF-ASD) are cognitively impaired in both domains. Moreover, little is known about fairness characteristics in children with HF-ASD in relation to both domains of cognition. METHODS: Thirty children with HF-ASD as well as 39 children with typical development (TD) were evaluated in this study. We investigated the development of children's fairness characteristics as a responder in a mini ultimatum game (UG). The different 'brain types,' i.e., with or without HF-ASD, were evaluated using the Empathy Questionnaire-Systemizing Questionnaire (E/SC-Q). Furthermore, we explored the relationship between fairness and brain types using Pearson correlation analyses. RESULTS: Children in the HF-ASD group were more likely to accept unfair offers than were children in the TD group (chi2 = 17.513, p = .025). In the HF-ASD group, the acceptance rate of unfair offers was correlated with the discrepancy score (r = 0.363, p = .048), while there were no significant correlations in the TD group. In HF-ASD group, compared with Type S, acceptance rate of unfair offer was significant higher in Extreme Type S 'brain type' (F = 28.584, p < .001). While dividing TD participants by 'brain type', there was no significant difference in acceptance rate of unfair offer among five difference 'brain types' (F = 1.131, p = .358). Stepwise regression revealed that Extreme Type S positively predicted acceptance of unfair offers (F [1, 68] = 8.695, p < .001). DISCUSSION: Our findings show that children with HF-ASD were more likely to accept an unfair offer; in particular, the more unbalanced the development of empathy and systemizing was, the more significant the unfairness preference observed. Extreme Type S positively predicted the acceptance of unfair offers by children with HF-ASD. REGISTRATION OF CLINICAL TRIALS: World Health Organization class I registered international clinical trial platform, ChiCTR-ROC-17012877. PMID- 30009871 TI - Multidimensional imaging techniques for prediction of treatment response in major depressive disorder. AB - A large number of studies have attempted to use neuroimaging tools to aid in treatment prediction models for major depressive disorder (MDD). Most such studies have reported on only one dimension of function and prediction at a time. In this study, we used three different tasks across domains of function (emotion processing, reward anticipation, and cognitive control, plus resting state connectivity completed prior to start of medication to predict treatment response in 13-36 adults with MDD. For each experiment, adults with MDD were prescribed only label duloxetine (all experiments), whereas another subset were prescribed escitalopram. We used a KeyNet (both Task derived masks and Key intrinsic Network derived masks) approach to targeting brain systems in a specific match to tasks. The most robust predictors were (Dichter et al., 2010) positive response to anger and (Gong et al., 2011) negative response to fear within relevant anger and fear TaskNets and Salience and Emotion KeyNet (Langenecker et al., 2018) cognitive control (correct rejections) within Inhibition TaskNet (negative) and Cognitive Control KeyNet (positive). Resting state analyses were most robust for Cognitive control Network (positive) and Salience and Emotion Network (negative). Results differed by whether an -fwhm or -acf (more conservative) adjustment for multiple comparisons was used. Together, these results implicate the importance of future studies with larger sample sizes, multidimensional predictive models, and the importance of using empirically derived masks for search areas. PMID- 30009872 TI - The sinister face of heme oxygenase-1 in brain aging and disease. AB - Under stressful conditions, cellular heme catabolism to carbon monoxide, iron and biliverdin is mediated by the 32 kDa enzyme, heme oxygenase-1 (HO-1). A wide range of pro-oxidant and inflammatory stimuli act on diverse consensus sequences within the Hmox1 promoter to rapidly induce the gene. There is ample evidence attesting to the beneficial effects of HO-1 upregulation in brain. By converting pro-oxidant heme to the antioxidants, biliverdin and bilirubin, HO-1/biliverdin reductase may help restore a more favorable tissue redox microenvironment. Contrariwise, in some cell types and under certain circumstances, heme-derived carbon monoxide and iron may amplify intracellular oxidative stress and exacerbate the disease process. This inimical side of neural HO-1 has often been ignored in biomedical literature promulgating interventions aimed at boosting central HO-1 expression for the management of diverse CNS conditions and is the focus of the current review. A comprehensive model of astroglial stress is presented wherein sustained Hmox1 induction promotes oxidative mitochondrial membrane damage, iron sequestration and mitophagy (macroautophagy). The HO-1 mediated gliopathy renders nearby neuronal constituents vulnerable to oxidative injury and recapitulates 'core' neuropathological features of many aging-related neurodegenerative and some neurodevelopmental brain disorders. A balanced literature should acknowledge that, in a host of chronic human CNS afflictions, the glial HO-1 response may serve as a robust transducer of noxious stimuli, an important driver of relevant neuropathology and a potentially disease-modifying therapeutic target. PMID- 30009873 TI - A general framework dedicated to computational morphogenesis Part II - Knowledge representation and architecture. AB - In our previous paper we introduced morphogenesis and post-embryonic life as arising from cells interacting via coupled chemical, electrical and mechanical processes occurring across multiple organization levels. We reviewed these processes from the perspectives of developmental biology and how they relate to physics-based constitutive equations that are well suited to model intercellular interactions' fields. In this paper we will describe a knowledge representation and architectural design strategy that can organize and encode the biochemical, biological and biophysical data necessary to represent and model the highly specialized and diversified cells that constitute living tissues. Since there are about 200 different types of cells in mammalian tissues, a huge amount of molecular, cellular and tissue data must be accounted for. This data cannot be incorporated in an ad hoc manner but, on the contrary, must be organized according to some sound principles. We give an overview of these principles and describe how they can be incorporated as proper features of a Knowledge Base System (KBS) dedicated to computational morphogenesis (CM). PMID- 30009874 TI - Assessing visual modulation along the human subcortical auditory pathway. AB - Experience of the world is inherently multisensory. It has been suggested that audiovisual modulation occurs as early as subcortical auditory stages. However, this was based on the frequency-following response, a measure recently found to be significantly generated from cortical sources. It therefore remains unclear whether subcortical auditory processing can indeed be modulated by visual information. We aimed to trace visual modulation along the auditory pathway by comparing auditory brainstem response (ABR) and middle-latency response (MLR) between unimodal auditory and multimodal audiovisual conditions. EEG activity was recorded while participants attended auditory clicks and visual flashes, either synchronous or asynchronous. No differences between auditory and audiovisual responses were observed at ABR or MLR levels. It suggested that ascending auditory processing does not seem to be modulated by visual cues at subcortical levels, at least for rudimentary stimuli. Multimodal modulation in the auditory brainstem observed in previous studies might therefore originate from cortical sources and top-down processes. More studies are needed to further disentangle subcortical and cortical influences on audiovisual modulation along the auditory pathway. PMID- 30009875 TI - Neural substrates of emotional interference: A quantitative EEG study. AB - Emotional stimuli are known to capture attention and disrupt the executive functioning. However, the dynamic interplay of neural substrates of emotion and executive attentional network is widely unexplored. The present study attempts to elucidate the areas implicated during emotional interference condition. Fifteen right handed individuals [24.64 +/- 2.63 years] performed two emotional interference tasks - Face Word Interference and Word Face Interference. Single trial EEG was recorded during baseline (eyes open) and during the tasks. The activity of the cortical sources was compared between the tasks and baseline for 66 gyri using sLORETA software. Eighteen gyri in Face Word Interference and fifty four gyri in Word Face Interference have shown significantly decreased activity [p < 0.05/66] with respect to baseline respectively. Interestingly, in both the interference tasks, there was disengagement of fronto-parietal attentional networks (implicating the probable ability of emotional stimuli to disrupt cognition) and the areas associated with default mode network. Further, during baseline there was significant activity in premotor cortical areas, which may be due to active inhibition of motor movements associated with response. PMID- 30009876 TI - Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14. AB - BACKGROUND: In humans, bitterness perception is mediated by ~25 bitter taste receptors present in the oral cavity. Among these receptors three, TAS2R10, TAS2R14 and TAS2R46, exhibit extraordinary wide agonist profiles and hence contribute disproportionally high to the perception of bitterness. Perhaps the most broadly tuned receptor is the TAS2R14, which may represent, because of its prominent expression in extraoral tissues, a receptor of particular importance for the physiological actions of bitter compounds beyond taste. METHODS: To investigate how the architecture and composition of the TAS2R14 binding pocket enables specific interactions with a complex array of chemically diverse bitter agonists, we carried out homology modeling and ligand docking experiments, subjected the receptor to point-mutagenesis of binding site residues and performed functional calcium mobilization assays. RESULTS: In total, 40 point mutated receptor constructs were generated to investigate the contribution of 19 positions presumably located in the receptor's binding pocket to activation by 7 different TAS2R14 agonists. All investigated positions exhibited moderate to pronounced agonist selectivity. CONCLUSIONS: Since numerous modifications of the TAS2R14 binding pocket resulted in improved responses to individual agonists, we conclude that this bitter taste receptor might represent a suitable template for the engineering of the agonist profile of a chemoreceptive receptor. GENERAL SIGNIFICANCE: The detailed structure-function analysis of the highly promiscuous and widely expressed TAS2R14 suggests that this receptor must be considered as potentially frequent target for known and novel drugs including undesired off effects. PMID- 30009877 TI - Reconstituting the formation of hierarchically porous silica patterns using diatom biomolecules. AB - The genetically-controlled formation of complex-shaped inorganic materials by living organisms is an intriguing phenomenon. It illustrates our incomplete understanding of biological morphogenesis and demonstrates the feasibility of ecologically benign routes for materials technology. Amorphous SiO2 (silica) is taxonomically the most widespread biomineral, with diatoms, a large group of single-celled microalgae, being the most prolific producers. Silica is the main component of diatom cell walls, which exhibit species-specific patterns of pores that are hierarchically arranged and endow the material with advantageous properties. Despite recent advances in characterizing diatom biomolecules involved in biosilica morphogenesis, the mechanism of this process has remained controversial. Here we describe the in vitro synthesis of diatom-like, porous silica patterns using organic components that were isolated from biosilica of the diatom Cyclotella cryptica. The synthesis relies on the synergism of soluble biomolecules (long-chain polyamines and proteins) with an insoluble nanopatterned organic matrix. Biochemical dissection of the process revealed that the long chain polyamines rather than the proteins are essential for efficient in vitro synthesis of the hierarchically porous silica patterns. Our results support the organic matrix hypothesis for morphogenesis of diatom biosilica and introduce organic matrices from diatoms as a new tool for the synthesis of meso- to microporous inorganic materials. PMID- 30009878 TI - Unnecessary food allergy testing by primary care providers: Ethical implications for the specialist. PMID- 30009879 TI - Resolution of eosinophilia and elevated immunoglobulin E with ibrutinib for chronic lymphocytic leukemia. PMID- 30009880 TI - Does moisturizing the skin equate with barrier repair therapy? PMID- 30009881 TI - Fisetin impedes developmental methylmercury neurotoxicity via downregulating apoptotic signalling pathway and upregulating Rho GTPase signalling pathway in hippocampus of F1 generation rats. AB - Methyl mercury is a teratogenic and neurodevelopmental toxicant in the environment. MeHg affects several biological pathways critical for brain development. The present study validated the effect of Fisetin on developmental MeHg exposure induced alterations in mitochondrial apoptotic pathway and Rho GTPase mRNA expressions in hippocampus of F1 generation rats. Pregnant Wistar rats were grouped as Group I : administered with vehicle control, Group II: MeHg (1.5 mg/kg b.w), Group III: MeHg + Fisetin (10 mg/kg b.w), Group IV: MeHg + Fisetin (30 mg/kg b.w), Group V: MeHg + Fisetin (50 mg/kg b.w), Group VI: MeHg + Fisetin (70 mg/kg b.w), Group VII: Fisetin (30 mg/kg b.w) alone. Fisetin reduced mercury accumulation in offspring brain. In hippocampus, Fisetin preserved mitochondrial total thiol status, glutathione antioxidant system, mitochondrial metabolic integrity and respiratory chain activity. Fisetin ameliorated apoptotic signals by preventing Cytochrome c release, down regulating ERK 1/2 and Caspase 3 gene expression. Fisetin also upregulated mRNA expressions of RhoA/Rac1/Cdc42 in hippocampus. Predominant effect of Fisetin was to reduce mercury accumulation in offspring brain there by diminishing the toxic effect of MeHg. Hence we showed that, gestational intake of Fisetin (30 mg/kg b.w.) impedes developmental MeHg neurotoxicity by regulating mitochondrial apoptotic and Rho GTPase signalling molecules and by reducing the mercury accumulation in hippocampus of F1 generation rats. PMID- 30009882 TI - Disappearance of cerebrovascular laminin immunoreactivity as related to the maturation of astroglia in rat brain. AB - The present paper provides novel findings on the temporo-spatial correlation of perivascular laminin immunoreactivity with the early postnatal astrocyte development. The cerebrovascular laminin immunoreactivity gradually disappears during development. The fusion of the glial and vascular basal laminae during development makes the laminin epitopes inaccessible for antibody molecules (Krum et al., 1991, Exp Neurol 111:151). The fusion is supposed to correlate with the maturation of the glio-vascular connections. Glial development was followed by immunostaining for GFAP (glial fibrillary acidic protein), S100 protein, glutamine synthetase as glial markers and for nestin to visualize the immature glial structures. Our investigation focused on the period from postnatal day (P)2 to P16, on the dorso-parietal pallium. In the wall of the telencephalon the laminin immunoreactivity disappeared between P5 and P10; in subcortical structures it persisted to P12 or even to P16. Its disappearance overlapped the period when GFAP-immunopositive astrocytes were taking the place of radial glia. Despite the parallel time courses, however, the spatial patterns of the two processes were just the opposite: disappearance of the laminin immunoreactivity progressed from the middle zone whereas the appearance of GFAP from the pial surface and the corpus callosum. Rather, the regression of the vascular laminin immunoreactivity followed the progression of the immunoreactivities of glutamine synthetase and S100 protein. Therefore, the regression really correlates with a 'maturation' of astrocytes which, however, affects other astrocyte functions rather than cytoskeleton. PMID- 30009883 TI - Stem cell-based Lung-on-Chips: The best of both worlds? AB - Pathologies of the respiratory system such as lung infections, chronic inflammatory lung diseases, and lung cancer are among the leading causes of morbidity and mortality, killing one in six people worldwide. Development of more effective treatments is hindered by the lack of preclinical models of the human lung that can capture the disease complexity, highly heterogeneous disease phenotypes, and pharmacokinetics and pharmacodynamics observed in patients. The merger of two novel technologies, Organs-on-Chips and human stem cell engineering, has the potential to deliver such urgently needed models. Organs-on Chips, which are microengineered bioinspired tissue systems, recapitulate the mechanochemical environment and physiological functions of human organs while concurrent advances in generating and differentiating human stem cells promise a renewable supply of patient-specific cells for personalized and precision medicine. Here, we discuss the challenges of modeling human lung pathophysiology in vitro, evaluate past and current models including Organs-on-Chips, review the current status of lung tissue modeling using human pluripotent stem cells, explore in depth how stem-cell based Lung-on-Chips may advance disease modeling and drug testing, and summarize practical consideration for the design of Lung-on Chips for academic and industry applications. PMID- 30009884 TI - Top-down fabrication of shape-controlled, monodisperse nanoparticles for biomedical applications. AB - Nanoparticles for biomedical applications are generally formed by bottom-up approaches such as self-assembly, emulsification and precipitation. But these methods usually have critical limitations in fabrication of nanoparticles with controllable morphologies and monodispersed size. Compared with bottom-up methods, top-down nanofabrication techniques offer advantages of high fidelity and high controllability. This review focuses on top-down nanofabrication techniques for engineering particles along with their biomedical applications. We present several commonly used top-down nanofabrication techniques that have the potential to fabricate nanoparticles, including photolithography, interference lithography, electron beam lithography, mold-based lithography (nanoimprint lithography and soft lithography), nanostencil lithography, and nanosphere lithography. Varieties of current and emerging applications are also covered: (i) targeting, (ii) drug and gene delivery, (iii) imaging, and (iv) therapy. Finally, a future perspective of the nanoparticles fabricated by the top-down techniques in biomedicine is also addressed. PMID- 30009885 TI - Battle of GLP-1 delivery technologies. AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action. PMID- 30009888 TI - Metabolomic analysis of cholestatic liver damage in mice. AB - Cholestasis is characterized by the obstruction of bile duct, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The complicated etiology and injury mechanism greatly limits the development of new drugs for its treatment. To better understand the mechanism of cholestatic liver damage, ultra performance liquid chromatography-linked electrospray ionization quadrupole time of-flight mass spectrometry (UPLC-ESI-QTOFMS) and multivariate data analysis were used to determine the metabolic changes in three recognized mouse cholestasis models. The cholestatic liver damage was generated by alphanaphthyl isothiocyanate (ANIT), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and lithocholic acid (LCA). The results indicated that the levels of bile acids were commonly increased in plasma of three mouse cholestasis models, while arginine was decreased. The level of plasma glutathione was decreased in ANIT- and LCA induced intrahepatic PBC and PSC, respectively. But, the liver glutathione was decreased in DDC induced extrahepatic PSC. The level of plasma phospholipids was elevated in ANIT and DDC models, whereas that was depleted in LCA model. And protoporphyrin IX was significantly increased in the liver of DDC model. These metabolomics data could potentially distinguish the metabolic differences of three types of cholestasis, contributing to the understanding of the potential mechanism of cholestatic liver damage. PMID- 30009889 TI - The role of nuclear factor erythroid 2-related factor 2 in hepatoprotective activity of natural products: A review. AB - Internal metabolism and environmental toxicant exposure can be caused to generate reactive oxygen species in human organelles which lead to oxidative stress. The nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper (bZip) transcription factor, controls the expression of antioxidant response element (ARE)-dependent genes to regulate cellular resistance to oxidants. Nrf2 is an essential factor for hepatoprotection against drugs and xenobiotics. The key role of Nrf2 in hepatoprotection has been highlighted since Nrf2 knockout mice showed high sensitivity to xenobiotic-induced hepatotoxicity. Some natural products including polyphenols, terpenoids and alkaloids can induce Nrf2 expression as a key protein in the antioxidant defense system of hepatocytes. This review outlines natural product activators of Nrf2 that protect the liver from toxicity induced by xenobiotics. PMID- 30009890 TI - Enterococcus spp. in Ragusano PDO and Pecorino Siciliano cheese types: A snapshot of their antibiotic resistance distribution. AB - In the present study, 110 enterococci were isolated from two Sicilian cheese types, Ragusano PDO and Pecorino Siciliano. Isolates, firstly identified by MALDI TOF/MS and a multiplex PCR assay, were tested for susceptibility to the most relevant clinical antibiotics. Clonal relationships among isolates were evaluated by pulsed-field-gel electrophoresis (PFGE) analysis and the presence of vanA and vanB genes, in vancomycin resistant enterococci (VRE), was investigated. Overall, E. faecalis, E. durans (35% for each species) and E. faecium (28%) were the major identified species. Different occurrence between cheese types was revealed. Most isolates from Ragusano PDO cheese were identified as E. durans (46%) and/or E. faecalis (43%), while E. faecium (605) was mainly detected in Pecorino Siciliano cheese. High incidence of resistance (97% of total strains) was detected for rifampicin, erythromycin and ampicillin. Moreover, 83 isolates (75%) exhibited multidrug-resistant phenotypes and the one VRE (vanB) isolate was identified as E. durans. PFGE analysis clustered isolates into 22 genotypes and the presence of the same PFGE types, for both E. durans and E. faecalis, in the two cheese types, suggest the link between enterococci and geographical area of production. Results of present study raise concerns about possible role of dairy enterococci as reservoirs of antibiotic resistance. PMID- 30009887 TI - A review on core-shell structured unimolecular nanoparticles for biomedical applications. AB - Polymeric unimolecular nanoparticles (NPs) exhibiting a core-shell structure and formed by a single multi-arm molecule containing only covalent bonds have attracted increasing attention for numerous biomedical applications. This unique single-molecular architecture provides the unimolecular NP with superior stability both in vitro and in vivo, a high drug loading capacity, as well as versatile surface chemistry, thereby making it a desirable nanoplatform for therapeutic and diagnostic applications. In this review, we surveyed the architecture of various types of polymeric unimolecular NPs, including water dispersible unimolecular micelles and water-soluble unimolecular NPs used for the delivery of hydrophobic and hydrophilic agents, respectively, as well as their diverse biomedical applications. Future opportunities and challenges of unimolecular NPs were also briefly discussed. PMID- 30009891 TI - Convection enhanced delivery of liposome encapsulated doxorubicin for brain tumour therapy. AB - Convection enhanced delivery is promising to overcome the blood brain barrier. However, the treatment is less efficient in clinic due to the rapid elimination of small molecular drugs in brain tumours. In this study, numerical simulation is applied to investigate the convection enhanced delivery of liposome encapsulated doxorubicin under various conditions, based on a 3-D brain tumour model that is reconstructed from magnetic resonance images. Treatment efficacy is evaluated in terms of the tumour volume where the free doxorubicin concentration is above LD90. Simulation results denote that intracerebral infusion is effective in increasing the interstitial fluid velocity and inhibiting the fluid leakage from blood around the infusion site. Comparisons with direct doxorubicin infusion demonstrate the advantages of liposomes in enhancing the doxorubicin accumulation and penetration in the brain tumour. Delivery outcomes are determined by both the intratumoural environment and properties of therapeutic agents. The treatment efficacy can be improved by either increasing the liposome solution concentration and infusion rate, administrating liposomes in the tumour with normalised microvasculature density, or using liposomes with low vascular permeability. The delivery is less sensitive to liposome diffusivity in the examined range (E-11~E 7 cm2/s) as convective transport is dominative in determining the liposome migration. Drug release rate is able to be optimised by keeping a trade-off between enhancing the drug penetration and providing sufficient free doxorubicin for effective cell killing. Results from this study can be used to improve the regimen of CED treatments. PMID- 30009886 TI - Tumor targeting via EPR: Strategies to enhance patient responses. AB - The tumor accumulation of nanomedicines relies on the enhanced permeability and retention (EPR) effect. In the last 5-10 years, it has been increasingly recognized that there is a large inter- and intra-individual heterogeneity in EPR mediated tumor targeting, explaining the heterogeneous outcomes of clinical trials in which nanomedicine formulations have been evaluated. To address this heterogeneity, as in other areas of oncology drug development, we have to move away from a one-size-fits-all tumor targeting approach, towards methods that can be employed to individualize and improve nanomedicine treatments. To this end, efforts have to be invested in better understanding the nature, the complexity and the heterogeneity of the EPR effect, and in establishing systems and strategies to enhance, combine, bypass and image EPR-based tumor targeting. In the present manuscript, we summarize key studies in which these strategies are explored, and we discuss how these approaches can be employed to enhance patient responses. PMID- 30009892 TI - Targeting sialic acid residues on lung cancer cells by inhalable boronic acid decorated albumin nanocomposites for combined chemo/herbal therapy. AB - Etoposide (ETP), as a potential treatment for lung cancer, has limited application due to its poor solubility, and systemic side effects. In the current study, we propose inhalable boronate-targeted HSA nanocomposites for combined delivery of ETP and the herbal drug, berberine (BER) for localized therapy of lung cancer. First, ETP was pre-formulated as phospholipid complex (EPC) to enhance drug solubility and facilitate its encapsulation within the hydrophilic albumin nanoparticles (NPs). Second, EPC and BER were then co-loaded with high efficiency into HSA NPs as a synergistic therapy for lung cancer. The NPs displayed suitable size around 200 nm and sequential drug release pattern. Moreover, conjugation of aminophenylboronic acid (APBA) to HSA NPs resulted in enhanced cytotoxicity and internalization into A549 lung cancer cells, compared to non-targeted NPs or free drugs via binding to sialic acid residues over expressed by cancer cells. Using mannitol as a spray-drying carrier, the developed inhalable nanocomposites demonstrated deep pulmonary deposition, confirmed by small MMAD (2.112 MUm) and high FPF (77.86%). In vivo investigations in lung cancer animal models revealed the superior anti-tumor efficacy of the inhalable nanocomposites. Overall, the inhalable APBA-HSA nanocomposites offered an alternative strategy for systemic delivery of ETP and BER in lung cancer therapy. PMID- 30009894 TI - Non-viral ocular gene therapy, pEYS606, for the treatment of non-infectious uveitis: Preclinical evaluation of the medicinal product. AB - Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secreted therapeutic proteins into the eye, non-viral gene therapy using plasmid electrotransfer in the ciliary muscle has been proposed. In this paper, we report the development steps of pEYS606, a clinical-grade plasmid DNA, devoid of antiobiotic selection gene, encoding a fusion protein consisting of the extracellular domain of the soluble p55 TNF-alpha receptor linked to the human IgG1 Fc domain (hTNFR-Is/hIgG1 or Protein 6), with high affinity for human TNF-alpha, for non-viral gene transfer into the ocular ciliary muscle. Electrotransfer of pEYS606 in the ciliary muscle significantly reduced ocular inflammation in two well-established rat models of uveitis, the endotoxin-induced uveitis (EIU) and the experimental autoimmune uveitis (EAU). In addition, in EAU, a significant protection of photoreceptors was demonstrated after pEYS606 treatment. The improved pharmacokinetic profile of intraocularly-secreted protein as compared to direct intravitreous injection of recombinant protein allowed to demonstrate Protein 6 efficacy at very low concentrations. Based on these results, a phase I/II clinical trial is conducted [ClinicalTrials.gov Identifier: NCT03308045]. PMID- 30009893 TI - Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain. AB - Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier (BBB) and minimizing systemic exposure. It also uses FUS-induced microbubble cavitation to enhance transport of intranasally (IN) administered agents to the FUS-targeted brain location. Previous studies have provided proof-of-concept data showing the feasibility of FUSIN to deliver dextran and the brain-derived neurotrophic factor to the caudate putamen of mouse brains. The objective of this study was to evaluate the biodistribution of IN administered gold nanoclusters (AuNCs) and assess the feasibility and short-term safety of FUSIN for the delivery of AuNCs to the brainstem. Three experiments were performed. First, the whole-body biodistribution of IN administered 64Cu-alloyed AuNCs (64Cu-AuNCs) was assessed using in vivo positron emission tomography/computed tomography (PET/CT) and verified with ex vivo gamma counting. Control mice were intravenously (IV) injected with the 64Cu-AuNCs. Second, 64Cu-AuNCs and Texas red-labeled AuNCs (TR AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. 64Cu AuNCs or TR-AuNCs were administered to mice through the nasal route, followed by FUS sonication at the brainstem in the presence of systemically injected microbubbles. The spatial distribution of 64Cu-AuNCs and TR-AuNCs were examined by autoradiography and fluorescence microscopy of ex vivo brain slices, respectively. Third, histological analysis was performed to evaluate any potential histological damage to the nose and brain after FUSIN treatment. The experimental results revealed that IN administration induced significantly lower 64Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of 64Cu-AuNCs and TR AuNCs at the FUS-targeted brain region compared with IN delivery alone. No histological-level tissue damage was detected in the nose, trigeminal nerve, and brain. These results suggest that FUSIN is a promising technique for noninvasive, spatially targeted, and safe delivery of nanoparticles to the brain with minimal systemic exposure. PMID- 30009895 TI - Carboxymethyl chitosan as an antifungal agent on gauze. AB - Chitosan is a biopolymer that has antifungal activity against C. albicans. Chemical modification of chitosan can provide it with new functional properties for a wide range of biological and biomedical applications. Carboxymethyl chitosan is a derivative of chitosan obtained by etherification of alkaline chitosan with monochloroacetic acid. Carboxymethyl chitosan has a higher solubility than chitosan; therefore it is more readily applicable for use in various fields. Chitosan also has antifungal activity against C. albicans. This study evaluated carboxymethyl chitosan as a gauze-coating material to be used for its antifungal properties. This study also optimized the coating process. Gauze was coated with carboxymethyl chitosan then characterized by Fourier Transform Infra-Red Spectrophotometer (FTIR), X-ray diffraction and scanning electron microscopy (SEM). The antifungal activities of gauze-coated samples were then tested by the diffusion method. The results show that the optimum conditions for the process of coating gauze with carboxymethyl chitosan are dipping ten times at a concentration of 1% for 50 s. Antifungal activities of carboxymethyl chitosan coated gauze as measured by the diameter of the growth inhibition area are 0.30 cm higher than chitosan-coated gauze, which has a growth-inhibition diameter of 0.12 cm. PMID- 30009896 TI - Microwave-assisted synthesis of Pd3Ag nanocomposite via nature polysaccharide applied to glucose detection. AB - In this work, a green strategy is performed to fabricate Pd3Ag nanoparticles (NPs) using plant-extracted polysaccharide (Lilium brownie polysaccharide, LBP). As-obtained Pd3Ag nanocomposite (Pd3Ag-LBP/C) is surveyed including transmission election microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and powder X ray diffraction (XRD). The result of glucose detection application shows that the Pd3Ag-LBP/C glassy carbon electrode (GCE) exhibits good stability and sensitivity. It can completely cover the normal blood glucose concentration (3-8 mM) with high sensitivity of 77.20 MUA mM-1 cm-2. This work undoubtedly has positive effects on green synthesis development. It not only proves the practicability of building nanomaterials by polysaccharide, but also offers an environmentally friendly way for fabricating other nanomaterials. PMID- 30009897 TI - Effects of allantoin and dimethyl sulfoxide on the thermal aggregation of lysozyme. AB - Allantoin is used to suppress protein aggregation without decreasing the melting temperature. However, the solubility of allantoin in water or buffer solutions is too low (approximately 30 mM at ambient temperature) to be used as a protein aggregation suppressor in various situations. Here we show that a high concentration solution of allantoin in neat dimethyl sulfoxide (DMSO) is useful as a stock solution for the additive that controls protein aggregation. The allantoin concentration from 10 to 100 mM in 10% (v/v) DMSO significantly suppressed the thermal aggregation of hen egg white lysozyme as a model protein, with increasing allantoin concentration. The residual activity of lysozyme in 10% DMSO and 100 mM allantoin after heating at 90 degrees C for 10 min was increased >3-fold compared to that without allantoin. Thus, it was concluded that allantoin in DMSO is an effective stock solution for practical application in enhancing the recovery of enzymatic activity and suppressing the formation of small aggregate of protein. PMID- 30009898 TI - Purification and characterization of two isoforms of exoinulinase from Penicillium oxalicum BGPUP-4 for the preparation of high fructose syrup from inulin. AB - Two exoinulinases, Exo-I and Exo-II from the culture broth of Penicillium oxalicum BGPUP-4 was purified using three-step purification method i.e., isopropanol precipitation, Q-Sepharose and Sephadex G-100 column chromatography. The molecular weight of Exo-I and Exo-II was determined to be 64.85 kDa and 32.54 kDa, respectively using MALDI-TOF. Exo-I and Exo-II showed high specificity for inulin and their respective Vmax/Km ratio was 3.74 and 7.20. Besides, both the inulinases also displayed specificity for lactose, sucrose and raffinose. Exo-I and Exo-II were stable at a pH range of 4.0-8.0 with pH optima 5.0. Optimal temperature for both the inulinases was 55 degrees C, and both the isoforms retained approximately 50% of their activity up to 70 degrees C. Ag+, Hg2+, Ba2+, Cu2+ and Ca2+ ions shown stimulatory effect on inulinases activity, while Fe2+, Mn2+, Co2+and EDTA completely inhibited enzyme activity. Purified enzyme was successfully used for the preparation of high fructose syrup from inulin. PMID- 30009899 TI - Facile immobilization of Pseudomonas fluorescens lipase on polyaniline nanofibers (PANFs-PFL): A route to develop robust nanobiocatalyst. AB - Herein, we demonstrate the immobilization of Pseudomonas fluorescens lipase (PFL) on polyaniline nanofibers (PANFs) via physical adsorption. Polyaniline nanofibers (PANFs) were synthesized by the oxidative polymerization of aniline. The developed robust nanobiocatalyst (PANFs-PFL) exhibited eight times higher activity than free PFL. In addition, immobilization of lipase on PANFs imparted operational stability of the nanobioconjugate. The various reaction parameters for immobilization (viz. reaction time, pH, stirring rate and enzyme-support ratio) were optimized using statistical design in terms of lipase activity and loading. Furthermore, facile separation, enhanced reusability (upto 6 cycles) and thermostability (upto 75 degrees C) were additional advantages of the nanobioconjugate. The catalytic prowess of nanobioconjugate was examined in the kinetic resolution of (RS)-N-(4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide and (RS)-1-(1-naphthyl) ethanol in comparison to free PFL. PANFs-PFL demonstrated 49.9% and 48.1% conversion for (RS)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide and (RS)-1-(1-naphthyl) ethanol, respectively which signified its importance as a nanobiocatalyst. PMID- 30009900 TI - Preferential recognition of advanced glycation end products by serum antibodies and low-grade systemic inflammation in diabetes mellitus and its complications. AB - BACKGROUND: Advanced glycation end products (AGEs) have shown to possess antigenicity. This study analyzes the detrimental effect of non-enzymatic glycation on human serum albumin (HSA) leading to the production of antibodies. METHODS: HSA (20 MUM) incubated with d-glucose formed AGEs confirmed by scanning electron microscopy (SEM). DNA-damage was assessed with comet assay. Antibodies against in-vitro formed AGEs was evaluated in the sera of diabetic patients by enzyme-linked immunosorbent assay. Molecular docking was performed to demonstrate affinity of native and glycated-HSA with IgG. Low-grade systemic inflammation was quantified with IL-4, IL-6, TNF-alpha and NF-kbeta in serum and mRNA expression. RESULTS: Scanning Electron Microscopy showed the formation of aggregates in glycated-HSA. Comet assay showed DNA damage T2DM with CKD. Serum auto-antibodies in diabetes patients with chronic kidney disease (CKD) showed appreciably high recognition with glycated-HSA compared to native HSA. Molecular docking showed less affinity of glycated-HSA with IgG. Serum IL-4, IL-6, and TNF-alpha were found significantly higher in T2DM with CKD compared to T2DM and healthy ones. mRNA expression of IL-4, IL-6 and NF-kbeta are also found significantly higher in T2DM with CKD. CONCLUSION: The non-enzymatic glycation-induced damage to the HSA generate neo-epitopes that possess immunogenic response and low-grade systemic inflammation. PMID- 30009901 TI - Antithrombotic potential of esculin 7, 3', 4', 5', 6'-O-pentasulfate (EPS) for its role in thrombus reduction using rat thrombosis model. AB - Currently available anticoagulants for prevention and treatment of thrombosis have several limitations, thus, small organic scaffolds that can dissolve clots in vivo in a dose dependent manner with lesser side effects are highly desirable. Here we report the synthesis of esculin pentasulfate (EPS) and assessment of its in vitro, in vivo and ex vivo anticoagulant and antithrombotic potential. Assessment of in vitro clotting times showed prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) in the presence of EPS. EPS also showed remarkable reduction in thrombus formation when administered in occlusion induced thrombotic rats at a low dose (2.5 mg/kg). Further, assessment of clot rate with plasma isolated from EPS treated rats confirmed its anticoagulation potential. EPS at varying concentrations showed no significant cytotoxic effect on HEK293 cell line. Further, molecular docking analysis of EPS with known anticoagulant proteins [(antithrombin (ATIII) and heparin cofactor II (HCF II)] that require heparin revealed good binding affinity (-7.9 kcal/mol) with ATIII but not with HCF II. ATIII when incubated with EPS showed increased fluorescence intensity, with no change in secondary structure. Overall, our results clearly show the in vivo modulation of thrombus formation using a modified natural scaffold EPS. PMID- 30009902 TI - Preparation of graphene oxide/chitosan/ferrite nanocomposite for Chromium(VI) removal from aqueous solution. AB - A magnetically modified graphene oxide/chitosan/ferrite (GCF) nanocomposite material was synthesized and exploited for removal of Chromium(VI) from aqueous solution. The GCF nanocomposite material was characterized by powder-X-ray diffraction (powder-XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope- energy dispersive X-ray (SEM-EDX) analysis, transmission electron microscopy (TEM) thermogravimetric analysis (TGA), UV-vis diffusive reflectance spectra and Brunauer-Emmett-Teller (BET) analysis. The effect of pH, adsorbent dose, contact time and initial Cr(VI) metal ion concentration were studied in batch process. The GCF nanocomposite material showed an adsorption capacity of 270.27 mg g-1 for Cr(VI) at pH 2.0. The adsorption mechanism of GCF adsorbent material was well described by Langmuir isotherm and pseudo second order kinetic model, with a high regression coefficient (<0.99). The results have shown that GCF nanocomposite material can be used as a suitable adsorbent for removal of Cr(VI) from wastewater. PMID- 30009903 TI - Removal of hazardous pollutants using bifunctional hydrogel obtained from modified starch by grafting copolymerization. AB - The removal of industrial pollutants from wastewater is important to protect human health and the environment. For this reason, bifunctional hydrogel was synthesized by radiation-induced grafting copolymerization of 2-acrylamido-2 methylpropane-1-sulphonic acid (AMPS) and dimethylaminoethyl methacrylate (DMAEMA) onto starch and subsequent chemical modification of the prepared hydrogel by benzyl chloride. The physical and chemical properties of the hydrogel AMPS co DMAEMA modified with ion-exchange groups were investigated by FT-IR, DSC and SEM techniques. The modified copolymers were examined for the removal of basic dyes, cobalt ions, and phosphate anions from aqueous solution. The maximum adsorption capacities of dye, cobalt and phosphate ions were 600 mg/g, 350 mg/g, and 650 mg/g, respectively at the optimum conditions. The adsorption of dye, Co2+ ions, and phosphate anions onto the hydrogel obeyed both Langmuir and Freundlich models. The adsorption kinetics of dye was found to follow closely the pseudo first-order kinetic model rather than the pseudo-second-order kinetic model. The kinetic study of Co2+ ions adsorption indicates that it obeys pseudo-second-order kinetic model rather than pseudo-first order one. PMID- 30009904 TI - Hypolipidaemic and anti-lipidperoxidant activities of Ganoderma lucidum polysaccharide. AB - Ganoderma lucidum polysaccharide (GLP) was prepared by hot water extraction and partly characterised by high-performance gel filtration chromatography and its monosaccharide composition. Male Sprague-Dawley rats were randomly divided into four groups: one group received a high-fat diet (control group) and the three other groups received a high-fat diet containing 100, 300 and 500 mg/kg of GLP. GLP administration reduced the body weight gain, food efficiency ratio, levels of plasma triacylglycerol (TG), plasma total cholesterol (TC) and low-density lipoprotein cholesterol and liver weight, TC and TG levels and malondialdehyde values, improved the levels of faecal fat, cholesterol and plasma high-density lipoprotein cholesterol and enhanced the activities of serum superoxide dismutase and glutathione peroxidase in rats compared with the control group. The appropriate dose of GLP was 300 mg/kg. Results indicate that GLP exhibits hypolipidaemic and lipid antioxidant activities and may be used as a drug for hyperlipidaemia treatment. PMID- 30009905 TI - Biocompatible starch-halloysite hybrid: An efficient support for immobilizing Pd species and developing a heterogeneous catalyst for ligand and copper free coupling reactions. AB - Combining the exceptional features of halloysite and starch, a unique hybrid was synthesized based on conjugation of amine-functionalized starch with Cl halloysite nanoclay followed by coordination of Pd (II) acetate. The resultant hybrid catalyst, Pd@Hal-SA, was used as a heterogeneous catalyst for promoting copper and ligand-free coupling reactions under mild reaction condition. The catalyst exhibited high catalytic activity and recyclability (up to 10 reaction runs) with slight loss of the catalytic activity that stemmed from slight Pd leaching. The comparison of the catalytic activity of Pd-Hal, Pd-SA and Pd@Hal-SA confirmed the superior performance of the latter, indicating the contribution of two components, SA and Hal to the catalysis. Moreover, the catalytic activity of Pd@Hal-SA was higher than that of Pd@Hal + SA, implying that the use of hybrid system was more efficient that use of individual components in a separated form, due to the synergism between SA and Hal. PMID- 30009906 TI - Biflavones from Ginkgo biloba as novel pancreatic lipase inhibitors: Inhibition potentials and mechanism. AB - Reduction of lipid absorption has been recognized as an attractive approach for the discovery of new drugs to treat obesity and overweight. The leave extract of Ginkgo biloba has been widely used for the treatment of metabolic diseases (such as hyperlipidemia) in both eastern and western countries, but the bioactive compounds in Ginkgo biloba and the underlying mechanism have not been fully characterized. This study aimed to investigate the inhibition potentials and mechanism of major biflavones from G. biloba on pancreatic lipase (PL), a key target regulating lipid absorption. The results clearly demonstrated that all tested biflavones in G. biloba including isoginkgetin, bilobetin, ginkgetin and sciadopitysin, displayed strong to moderate inhibitory effects on PL with the IC50 values ranging from 2.90 MUM to 12.78 MUM. Further investigations on both inhibition kinetic analyses and docking simulations demonstrated that isoginkgetin, bilobetin and ginkgetin were potent PL inhibitors (Ki < 2.5 MUM), which could create strong interactions with the catalytic triad of PL via hydrogen bonding. These findings provided a new powerful evidence for explaining the hypolipidemic effects of G. biloba, while these newly identified PL inhibitors from G. biloba could serve as lead compounds for the development of biflavonoid-type PL inhibitors. PMID- 30009907 TI - Alcohol-soluble polysaccharide from Astragalus membranaceus: Preparation, characteristics and antitumor activity. AB - The alcohol-soluble polysaccharide (ASP) was extracted from Astragalus membranaceus, and their preliminary structural characteristics and in vivo antitumor activity were investigated in this study. The contents of total sugar, protein and uronic acid in ASP was 92.04%, 0.51% and 1.42%, respectively. FTIR and IC results indicated that ASP (about 2.1 * 103 Da) was a neutral polysaccharide composed of arabinose, galactose, glucose and mannose (molar ratio: 1.00:0.98:3.01:1.52) with pyranose ring and alpha-type glycosidic linkages. Besides, ASP could significantly inhibit the growth of H22 heptoma cells in vivo via improving the levels of serum cytokines (TNF-alpha, IL-2 and IFN-gamma) and activities of immune cells (macrophages, lymphocytes and NK cells), thereby inducing tumor cell apoptosis and attenuating their accessional damages. These results suggested that ASP may serve as a novel potential antitumor agent in the future. PMID- 30009908 TI - Effect of temperature and shear on the microstructure of a microbial polysaccharide secreted by Sphingomonas species in aqueous solution. AB - Diutan gum is a biological polymer produced by Sphingomonas sp. In aqueous solution it shows gel-like structure under quiescent conditions. However, the flow-induced evolution of its viscoelastic properties and its microstructure are not known. In this work, the viscoelastic moduli were obtained under a flow field, applied in parallel, as a function of the temperature for 0.5 wt% diutan gum aqueous solutions. As both stress and temperature increase a decrease in the viscoelastic properties occurred, due to the fact that the molecular interactions decreased. Nevertheless, at stresses within the zero-shear viscosity region of the flow curves, no changes were observed. In addition, high stress values dampened the effect of the temperature. The results obtained are very interesting from an industrial application perspective. PMID- 30009909 TI - Synthesis and characterization of Sb2S3-CeO2/chitosan-starch as a heterojunction catalyst for photo-degradation of toxic herbicide compound: Optical, photo reusable, antibacterial and antifungal performances. AB - Heterostructured Sb2S3-CeO2 composites and Sb2S3-CeO2 on chitosan-starch nanocomposites have been provided with chemical manner. The characterization was performed by various instruments such as, scanning electron microscopy, Brunauer Emmett-Teller surface area measurements, X-ray diffraction analysis, energy dispersive X-ray spectrometer and UV-Vis absorption spectroscopy. The mean crystallite sizes of CeO2, Sb2S3-CeO2 and Sb2S3-CeO2/chitosan-starch are 25.12, 51.11 and 64.12 nm, respectively. The energy band gaps of CeO2, Sb2S3-CeO2 and Sb2S3-CeO2/chitosan-starch are appraised to be 3.01, 2.41, and 2.23 eV, respectively. Photocatalytic properties of the as-prepared products for degradation of Paraquat as a toxic organic compound are investigated under UV light irradiation at room temperature. The Sb2S3-CeO2 and Sb2S3-CeO2/chitosan starch exhibited high photocatalytic performance. Moreover, the possible mechanism of photocatalytic degradation for Paraquat was proposed. The photocatalyst as hydroxide form existing in the product provides more OH during the degradation process, as well as influences the band gap of the product due to present the electron-hole pairs. The optimum effects such as time and pH were obtained 7 and 30 min for photo-degradation process. The antibacterial and fungicidal property of Sb2S3-CeO2/chitosan-starch nanocomposites was investigated and demonstrates good efficiency in antimicrobial efficiency compared to CeO2, and Sb2S3-CeO2. PMID- 30009910 TI - Evaluation of different saccharides and chitin as eco-friendly additive to improve the magnetic cross-linked enzyme aggregates (CLEAs) activities. AB - The cross-linked enzyme aggregates (CLEAs) involves formation of a number of covalent bonds between enzyme and the matrix using glutaraldehyde. In general, amino groups of lysine, sulfhydryl groups of cysteine, phenolic OH groups of tyrosine, or imidazol group of histidine are used for enzyme binding under mild conditions. The main advantage of this method is its simplicity, economic advantages in the industrial bio catalysis. The Fe3O4 magnetic nanoparticles were synthesized by coprecipitating Fe2+and Fe3+in alkaline solution. Tannic acid was used to functionalize the Fe3O4 magnetic nanoparticles. After functionalization process, tannic acid magnetic cross-linked enzyme aggregates of enzyme (TA-MNPs CLEAs) were prepared by cross-linking of enzyme aggregates with different saccharides as additive. The present result reported high stability, simplicity, low cost and recyclability of a saccharide-TA-MNPs-CLEAs-enzyme make it efficient as a highly active biocatalyst in biotechnological applications. The obtained results suggest that disaccharides (maltose, sucrose and lactose) and polysaccharide such as starch are eco-friendly additives to TA-MNPs-lipase and TA MNPs-CLEAs-peroxidase and can become a powerful biocatalyst in industry applications. PMID- 30009911 TI - Influence of carrageenan molecular structures on electromechanical behaviours of poly(3-hexylthiophene)/carrageenan conductive hydrogels. AB - The kappa, iota, and lambda carrageenans were fabricated by solution casting as soft and electrically responsive actuators. The poly(3-hexylthiophene) (P3HT) was added as a dispersed phase to improve the electrical and electromechanical properties of the pristine carrageenan hydrogels. The electromechanical properties of the carrageenan hydrogels were investigated under the effects of electric field strength, carrageenan type namely kappa, iota, and lambda, operating temperature, and P3HT concentration. The electromechanical responses of the pristine carrageenans increased with increasing sulfated groups present; the lambda-carragenan hydrogel provided the highest storage modulus sensitivity of 4.0 under applied electric field strength of 800 V/mm. With increasing temperature, the double-helical structure of the kappa-carrageenan hydrogel changed into a random coil leading to the increase in the storage modulus response. On the other hand, the P3HT/kappa-carrageenan hydrogel blend at 0.10%v/v P3HT provided the high storage modulus sensitivity of 2.20 at the electric field strength of 800 V/mm. The higher dielectrophoretic forces were due to the additional P3HT electronic polarization, but lower deflections relative to those of the pristine kappa-carrageenan hydrogel. Both kappa- and lambda carrageenans with the double helical structures are shown here as possible candidates to be fabricated as electroactive hydrogels for actuator or biomedical applications. PMID- 30009912 TI - CuNPs-magadiite/chitosan nanocomposite beads as advanced antibacterial agent: Synthetic path and characterization. AB - In this work, an inorganic-organic nanocomposite was prepared by combining copper exchanged-magadiite (Cu-magadiite) with chitosan. The synthesis was carried out by direct dispersion of the Cu-magadiite in the chitosan matrix. The mixture obtained is shaped into beads with an average diameter of about 1-1.2 mm. These beads were then contacted with a solution of NaBH4 in order to reduce loaded copper ions into copper nanoparticles species. The resulting nanocomposite (Cu NPs-magadiite/chitosan) was characterized by XRD, FTIR, SEM, TG, UV-visible DR and EDX analysis. The results show that the magadiite was completely exfoliated confirming the formation of the organic-inorganic composite. Indeed, the encapsulation of magadiite was confirmed by the SEM images, which is presented as micron free aggregates included in the cavities of a continuous polysaccharide matrix. Otherwise, they confirm also the formation of CuNPs which are probably immobilized inside the magadiite-chitosan solid matrix. The antibacterial activity against E. coli and S. aureus was highlighted by the disc inhibition method and the minimum inhibitory concentration (MIC) was determined. The CuNPs magadiite/chitosan nanocomposite showed a very efficient bactericidal effect against both pathogen bacteria. Additionally, the MIC values obtained for nanocomposite are of 0.25 MUg/L against S. aureus and of 0.50 MUg/L against E. coli. PMID- 30009913 TI - Interaction of silica nanoparticles with tau proteins and PC12 cells: Colloidal stability, thermodynamic, docking, and cellular studies. AB - Study on the side effects of the nanoparticles (NPs) can provide useful information regarding their biological and medical applications. Herein, the colloidal stability of the silicon dioxide NPs (SiO2 NPs) in the absence and presence of tau was investigated by TEM and DLS techniques. Afterwards, the thermodynamic parameters of interaction between SiO2 NPs and tau were determined by fluorescence spectroscopy and docking studies. Finally, the cytotoxic effects of SiO2 NPs on the viability of PC12 cells were investigated by MTT, AO/EB staining and flow cytometry assays. TEM, DLS, and zeta potential investigations revealed that tau can reduce the colloidal stability of SiO2 NPs. Fluorescence spectroscopy study indicated that SiO2 NPs bound to the tau with high affinity through hydrogen bonds and van der Waals interactions. Docking study also determined that Ser, Thr and Tyr residues provide a polar microenvironment for SiO2 NPs/tau interaction. Cellular studies demonstrated that SiO2 NPs can induce cell mortality through both apoptosis and necrosis mechanisms. Therefore, it may be concluded that the biological systems such as nervous system proteins can affect the colloidal stability of NPs and vice versa NPs in the biological systems can bind to proteins and cell membranes non-specifically and may induce toxicity. PMID- 30009914 TI - Isolation and characterization of cellulose nanocrystals from pueraria root residue. AB - Cellulose nanocrystals (CNCs) were successfully fabricated from waste pueraria root residue after starch extraction via the phosphoric acid hydrolysis method by a series of chemical treatment processes including ultrasonic washing, pectin elimination, bleaching, alkali boiling, and phosphoric acid hydrolysis. The high aspect ratio of CNCs with a crystallinity index of 60 +/- 4.10% was observed by X ray diffraction (XRD) and transmission electronic microscopy (TEM). The TEM results showed that CNCs were rod-like particles with 100-330 nm in length and 2 to 6 nm in width. The average aspect ratio of the CNCs was 40 +/- 10. The XRD results also indicated that the crystalline structure of CNC was cellulose I, compared to that of MCC with the crystallinity index declining from 60 +/- 4.10% to 48 +/- 0.37%. The FTIR spectra showed the resulting samples were the cellulose species. Interestingly, stable colloidal suspensions were determined by the zeta potential measurement. The thermal properties of CNCs were investigated by thermogravimetric analysis, revealing that CNCs exhibited lower thermal stability compared to those of MCC and the raw pueraria root residue. This study provides a cost effective method and mild process conditions for preparing CNCs from waste pueraria root residue. PMID- 30009915 TI - Mechanical and barrier properties of corn distarch phosphate-zein bilayer films by thermocompression. AB - Corn distarch phosphate-zein bilayer films (C-Z) fabricated from corn distarch phosphate-based films (C) laminated on zein-based films (Z) by thermocompression. The strong interaction between starch and zein molecules was formed by hydrogen bonding, which resulted in good thermal stability of bilayer films. Moreover, bilayer films exhibited better mechanical properties and ductility than monolayer Z films, and concomitantly enhanced the moisture barrier and oxygen barrier for monolayer C films. The tensile strength (TS) and elongation at break (EAB) of the C-Z bilayer films (the ratio C:Z was 6:4) increased by 74.04% and 348.13% over the Z films, respectively. Compared with C films, the water vapor permeability (WVP) and oxygen permeability (OP) of the C-Z bilayer films (the ratio C:Z was 6: 4) decreased by 31.53 and 24.26%, respectively. PMID- 30009916 TI - Single nucleotide polymorphisms in cytokine/chemokine genes are associated with severe infection, ulcer grade and amputation in diabetic foot ulcer. AB - Compared to other complications the genetics of diabetic foot ulcer is poorly studied. The Interleukin (IL)-6 (-174G > C/rs1800795), Tumor Necrosis Factor (TNF)-alpha (-308G > A/rs1800629) and (-238G > A/rs361525) and Stromal cell Derived Factor (SDF)-1 (+801G > A/rs1801157) are well characterized single nucleotide polymorphisms (SNPs) which were previously shown to be associated with Diabetic Foot Ulcer (DFU). In the present study, we looked at the association of these SNPs with foot microbial infection, Wagner's ulcer grade and treatment procedure, along with serum levels of these cytokines (intermediate phenotype) and other serum biomarkers (adiponectin, leptin, CRP and HOMA-IR) in subjects with DFU. Subjects with DFU (n = 270) were genotyped by PCR-RFLP and the serum levels of IL-6, TNF-alpha and SDF-1 were determined by ELISA. Microbial infections were determined by standard microbiological methods. Ulcer grade and treatment procedures were recorded. IL-6 (-174G > C), TNF-alpha (-308G > A) and SDF-1 (+801G > A) SNPs were associated with severe microbial infections. TNF alpha (-308G > A) and (-238G > A) SNPs were associated with severe ulcer grades. SDF-1 (+801G > A) SNP was associated with major amputation even after adjusting for confounding variables. Identification of these SNPs in DFU subjects would help in identifying high risk individuals who need better treatment care. PMID- 30009917 TI - Characterization and evaluation of smart releasing polysaccharide from yellow poinciana seed of Jharkhand. AB - Polysaccharides with unique functional and drug release characteristics have received more and more attention in the field of drug delivery systems. In this study, characterization of polysaccharide (PPSP) from yellow poinciana seeds and its utility as pharmaceutical excipient was investigated. The molecular weight of isolated PPSP was found to be 1.33 * 102 kDa. The high swelling and water binding capacity, low moisture content and fat-binding capacity of isolated polysaccharide explore to use as an excipient for drug delivery. The micromeritic properties revealed its flow and compressibility properties rendering its use in tablet manufacturing. Zeta potential measurements revealed PPSP as non-ionic polysaccharide. TGA data reveals a thermally stable polysaccharide and SEM confirms the fibrous network-like structure. The monosaccharide analysis confirmed the presence of galactose (49.94%), glucose (22.69%), mannose (15.99%), rhamnose (2.36%), arabinose (5.74%) and fucose (3.30%). The XRD pattern and viscosity measurements confirm the semi-crystalline nature and shear thinning behavior of polysaccharide respectively. The drug release profile indicates that the polysaccharide can be used as a potential agent for the design of smart pH sensitive drug delivery systems. PMID- 30009918 TI - Biophysical and functional perturbation analyses at cancer-associated P187 and K240 sites of the multifunctional NADP(H):quinone oxidoreductase 1. AB - Once whole-genome sequencing has reached the clinical practice, a main challenge ahead is the high-throughput and accurate prediction of the pathogenicity of genetic variants. However, current prediction tools do not consider explicitly a well-known property of disease-causing mutations: their ability to affect multiple functional sites distant in the protein structure. Here we carried out an extensive biophysical characterization of fourteen mutant variants at two cancer-associated sites of the enzyme NQO1, a paradigm of multi-functional protein. We showed that the magnitude of destabilizing effects, their molecular origins (structural vs. dynamic) and their efficient propagation through the protein structure gradually led to functional perturbations at different sites. Modulation of these structural perturbations also led to switches between molecular phenotypes. Our work supports that experimental and computational perturbation analyses would improve our understanding of the molecular basis of many loss-of-function genetic diseases as well as our ability to accurately predict the pathogenicity of genetic variants in a high-throughput fashion. PMID- 30009919 TI - Injectable and self-crosslinkable hydrogels based on collagen type II and activated chondroitin sulfate for cell delivery. AB - Injectable hydrogels are attractive and alternative scaffolds for cell delivery because they could form in situ, simulate natural tissue and fill any shape of defect. This study aimed at fabricating injectable, self-crosslinkable and biomimetic hydrogels based on collagen type II (Col II) and activated chondroitin sulfate (CS-sNHS) under physiological conditions without the addition of any catalysts or crosslinking agents. The inner morphology of hydrogels was detected by scanning electron microscopy, and it showed that fibrous structure formed in the hydrogels. The gelation time, water absorption capacity and the mechanical property of hydrogels were closely related to the weight ratio of Col II and CS sNHS in hydrogels. Chondrocytes were encapsulated into these hydrogels, and the effect of hydrogels on survival, proliferation, morphology of cells and remolding of extracellular matrix was investigated. The results demonstrated that chondrocytes survived well and showed round or oval morphology in these hydrogels, in addition, the matrix in hydrogels had been remolded and the collagen fibers displayed periodic alternation of light and shade. These results implied that the injectable and self-crosslinkable hydrogels were alternative carriers for chondrocyte delivery. PMID- 30009920 TI - Transcriptomic analysis of differentially expressed genes and related pathways in Harmonia axyridis after sulfoxaflor exposure. AB - Harmonia axyridis (Pallas) is a major biological control agent that is indirectly threatened by sulfoxaflor insecticide applications targeting pests in agro ecosystems. However, the genome-wide response of H. axyridis to sulfoxaflor remains largely unknown. Here, we used high-throughput RNA-seq technology to characterize the variation in the transcriptomic profile of second-instar H. axyridis larvae after exposure to sulfoxaflor. Two libraries were generated, with 50,702,976 and 47,005,096 clean reads for the sulfoxaflor treatment and control, respectively; these were grouped into 112,497 transcripts and 52,229 unigenes, of which 33,820 and 25,175 unigenes were respectively matched to proteins in the NCBI (Nr) and Swiss-Prot databases. From these unigenes, 794 significant differentially expressed genes (DEGs) consisting of 446 up- and 348 down regulated genes, namely P450s, GSTs, USTs, ESTs, and others, were identified between the sulfoxaflor-treated and control groups. Furthermore, these DEGs were involved in several KEGG pathways including drug metabolism and metabolism of xenobiotic pathways. For transcriptome validation, 10 specifically expressed genes were selected and verified by quantitative real-time PCR analysis. Together, these results demonstrated that sulfoxaflor induces notable variation in the transcriptome profile and pathways of H. axyridis, which establishes a basis for further molecular investigations. PMID- 30009921 TI - Aging modulates microglia phenotypes in neuroinflammation of MPTP-PD mice. AB - As the crucial etiological factor, aging-related microglia activation promotes the development of Parkinson's disease (PD). However, the molecular and functional changes of aged-microglia and their contribution to neurodegeneration in PD are only partially understood, which was investigated in our study. Female C57BL/6 mice were randomly divided into four groups, included young-control group, young-MPTP group, aged-control group and aged-MPTP group. Pole test and adhesive removal test were firstly performed. ELISA assay was used to detect the content of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF alpha) in brain tissue. Then we tested the expression of tyrosine hydroxylase (TH), p-nuclear transcription factor (NF-kappaB), toll-like receptor2 (TLR2), arginase-1 (arg-1), inducible nitric oxide synthase (iNOS) by western blot and immunofluorescence analysis. Our results showed that aging promoted M1 microglia activation and inhibited M2 microglia activation in SN in MPTP-PD model, accompanied by the elevation of proinflammatory cytokine (TNF-alpha and IL 1beta). Consequently, aging significantly aggravated motor dysfunction and dopaminergic neuron loss in SN. Besides, compared with young-MPTP group, the protein expression of TLR2 and p-NF-kappaB-p65 increased obviously in aged-MPTP group. The results revealed that aging aggravated inflammatory response by modulated microglia phenotypes transition in SN in PD, and contributed to further understand the pathogenesis of PD. PMID- 30009922 TI - Robust identification of gene-environment interactions for prognosis using a quantile partial correlation approach. AB - Gene-environment (G-E) interactions have important implications for the etiology and progression of many complex diseases. Compared to continuous markers and categorical disease status, prognosis has been less investigated, with the additional challenges brought by the unique characteristics of survival outcomes. Most of the existing G-E interaction approaches for prognosis data share the limitation that they cannot accommodate long-tailed or contaminated outcomes. In this study, for prognosis data, we develop a robust G-E interaction identification approach using the censored quantile partial correlation (CQPCorr) technique. The proposed approach is built on the quantile regression technique (and hence has a solid statistical basis), uses weights to easily accommodate censoring, and adopts partial correlation to identify important interactions while properly controlling for the main genetic and environmental effects. In simulation, it outperforms multiple competitors with more accurate identification. In the analysis of TCGA data on lung cancer and melanoma, biologically sensible findings different from using the alternatives are made. PMID- 30009923 TI - A genetic association test through combining two independent tests. AB - Gene- and pathway-based variant association tests are important tools in finding genetic variants that are associated with phenotypes of interest. Although some methods have been proposed in the literature, powerful and robust statistical tests are still desirable in this area. In this study, we propose a statistical test based on decomposing the genotype data into orthogonal parts from which powerful and robust independent p-value combination approaches can be utilized. Through a comprehensive simulation study, we compare the proposed test with some existing popular ones. Our simulation results show that the new test has great performance in terms of controlling type I error rate and statistical power. Real data applications are also conducted to illustrate the performance and usefulness of the proposed test. PMID- 30009924 TI - Conduit Route Selection for Total Cavopulmonary Connection in Patients with Apicocaval Juxtaposition. AB - Apicocaval juxtaposition (ACJ) may complicate the selection of conduit route in patients with single ventricles when total cavopulmonary connection (TCPC) is performed. We reviewed our experience of pathway selection and evaluated the clinical results. Of 128 patients who underwent TCPC at our hospital between January 2009 and April 2016, 31 with ACJ were included in this study. In 24 patients, the conduit was placed between the inferior vena cava (IVC) and the ipsilateral pulmonary artery. To avoid compression of the conduit and pulmonary veins in 5 patients, the conduit was placed between the IVC and the contralateral pulmonary artery. In 2 patients, the tube graft was anastomosed with the IVC orifice within the atrium, then guided through the atrial free wall and anastomosed with the contralateral pulmonary artery outside the heart (intra/extracardiac Fontan). Patient demographics were compared with those of patients without ACJ. The mean age and body weight at surgery were 58.5 +/- 32.4 months and 16.2 +/- 6.0 kg, respectively. The mean postoperative pulmonary artery pressure was 15 +/- 3 mm Hg. The postoperative data did not differ significantly from that of patients without ACJ who underwent extracardiac TCPC. One patient died of overwhelming infection. The mean follow-up was 17.5 +/- 15.4 months (range, 1-65 months). There were no conduit-related early or late complications. TCPC in patients with ACJ can be performed with excellent early and midterm results. The route between the IVC and the ipsilateral pulmonary artery is our preference. PMID- 30009925 TI - Electrocardiographic and echocardiographic changes during therapeutic hypothermia in encephalopathic infants with long-term adverse outcome. AB - AIM: To assess the electrocardiography and echocardiography changes during therapeutic hypothermia and rewarming period in encephalopathic infants with long term adverse neurological outcome. METHODS: Prospective multicentre longitudinal study. We included 64 consecutive infants with moderate or severe hypoxic ischaemic encephalopathy undergoing therapeutic hypothermia who had 18-24 month outcome data. We analysed electrocardiography and heart rate changes before, during and after therapeutic hypothermia. Superior vena cava flow, left ventricular cardiac output and stroke volume were studied using echocardiography during and immediately after therapeutic hypothermia. An abnormal outcome was defined as death or moderate/severe disability at 18-24 months. RESULTS: Neonates with higher superior vena cava flow pre-rewarming had significantly higher odds of documented long-term adverse outcome when compared to newborns with good outcome (OR 1.57; 95%CI, 1.1-1.78; p = 0.01 after adjustment). QTc and RR intervals were significantly longer at 12, 24, 36 and 48 h in infants with good outcome compared with those with adverse outcome (p < 0.001). During therapeutic hypothermia, infants with poor outcome had a higher heart rate at 12, 24, 36, 48, 60 h after birth compared with those with good outcome (p < 0.001). From 36 h on, heart rate gradually increased and RR and QTc intervals progressively shortened with values back to normal after rewarming. CONCLUSIONS: Infants with hypoxic ischaemic encephalopathy who have adverse neurological outcome show a preferential cerebral blood flow redistribution during therapeutic hypothermia. Infants with poor outcome have higher heart rate and shorter RR and QTc intervals during therapeutic hypothermia. PMID- 30009926 TI - Video performance-debriefings and ventilation-refreshers improve quality of neonatal resuscitation. AB - AIM: Providers caring for newly born infants require skills and knowledge to initiate prompt and effective positive pressure ventilation (PPV) if the newborn does not breathe spontaneously after birth. We hypothesized implementation of high frequency/short duration deliberate practice training and post event video based debriefings would improve process of care and decreases time to effective spontaneous respiration. METHODS: Pre- and post-interventional quality study performed at two Norwegian university hospitals. All newborns receiving PPV were prospectively video-recorded, and initial performance data guided the development of educational interventions. A priori primary outcome was changed from process of care using the Neonatal Resuscitation Performance Evaluation (NRPE) score to time to effective spontaneous respiration as the NRPE score could only be obtained from one site due to lack of staff resources. RESULTS: Over 12 months, 297 PPV-Refreshers and 52 performance debriefings were completed with 227 unique providers attending a PPV-Refresher and 93 unique providers completed a debriefing. We compared 102 PPV-events pre- to 160 PPV-events post-bundle implementation. The time to effective spontaneous respiration decreased from median (95% confidence interval) 196 (140-237) to 144 (120-163) s, p = 0.010. The NRPE-score increased significantly from median 77% (75-81) pre- to 89% (86-92) post-implementation, p < 0.001. There were no significant differences in time to heart rate >100 beats/min or number of newborns transferred to intensive care. CONCLUSION: High frequency/short duration deliberate practice PPV psychomotor training combined with performance-focused team debriefings using video recordings of actual resuscitations may improve time to effective spontaneous breathing and adherence to guidelines during real neonatal resuscitations. PMID- 30009927 TI - Characterisation of rainbow trout peripheral blood leucocytes prepared by hypotonic lysis of erythrocytes, and analysis of their phagocytic activity, proliferation and response to PAMPs and proinflammatory cytokines. AB - Rapid and high quality preparation of peripheral blood leucocytes (PBL) is important in fish immunology research and in particular for fish vaccine development, where multiple immune parameters can be monitored on the same fish over time. Fish PBL are currently prepared by density separation using Percoll or Hispaque-1.077, which is time consuming, costly and prone to erythrocyte contamination. We present here a modified PBL preparation method that includes a 20 s hypotonic lysis of erythrocytes and a subsequent separation of PBL from cell debris by a cell strainer. This method is simple, rapid and cost effective. The PBL obtained are similar in cellular composition to those prepared by density separation but have less erythrocyte contamination as demonstrated by FACS analysis and the expression of cell marker genes. Marker gene analysis also suggested that PBL prepared by hypotonic lysis are superior to those obtained by the gradient method in that some high-density cells (certain B cell types and neutrophils) might be lost using the latter. The PBL prepared in this way can proliferate in response to the T cell mitogen PHA, and both lymphoid and myeloid cells can phagocytose fluorescent beads and bacteria, with the latter enhanced by treatment with pro-inflammatory cytokines (IL-1beta and IL-6). Furthermore, the PBL can respond to stimulation with PAMPs (LPS, poly I:C) and cytokines (IL-1beta and IFNgamma) in terms of upregulation of proinflammatory cytokine gene expression. Such data demonstrate the utility of this approach (hypotonic lysis of erythrocytes) for PBL isolation and will enable more studies of their role in disease protection in future immunological and vaccine development research in fish. PMID- 30009928 TI - An ML protein from the silkworm Bombyx mori may function as a key accessory protein for lipopolysaccharide signaling. AB - Lipopolysaccharide (LPS) is a common component of the outermost cell wall in Gram negative bacteria. In mammals, LPS serves as an endotoxin that can be recognized by a receptor complex of TLR4 (Toll-like receptor 4) and MD-2 (myeloid differentiation-2) and subsequently induce a strong immune response to signal the release of tumor necrosis factor (TNF). In Drosophila melanogaster, no receptors for LPS have been identified, and LPS cannot activate immune responses. Here, we report a protein, BmEsr16, which contains an ML (MD-2-related lipid-recognition) domain, may function as an LPS receptor in the silkworm Bombyx mori. We showed that antibacterial activity in the hemolymph of B. mori larvae was induced by Escherichia coli, peptidoglycan (PGN) and LPS and that the expression of antimicrobial peptide genes was also induced by LPS. Furthermore, both the expression of BmEsr16 mRNA in the fat body and the expression of BmEsr16 protein in the hemolymph were induced by LPS. Recombinant BmEsr16 bound to LPS and lipid A, as well as to PGN, lipoteichoic acid, but not to laminarin or mannan. More importantly, LPS-induced immune responses in the hemolymph of B. mori larvae were blocked when the endogenous BmEsr16 protein was neutralized by polyclonal antibody specific to BmEsr16. Our results suggest that BmEsr16 may function as a key accessory protein for LPS signaling in B. mori. PMID- 30009929 TI - TRAF3 enhances STING-mediated antiviral signaling during the innate immune activation of black carp. AB - Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a main regulator of antiviral and anti-inflammatory pathways in mammals, which is considered to induce type I interferon (IFN) activation and negatively regulate the activation of the canonical and non-canonical NF-kappaB pathways. To elucidate its function in teleost fish, TRAF3 homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized in this study. The open reading frame (ORF) of black carp TRAF3 (bcTRAF3) consists of 1722 nucleotides and bcTRAF3 contains 574 amino acids. bcTRAF3 protein migrated around 65 KDa in immunoblot analysis of both EPC and HEK293T cells. bcTRAF3 was identified as a cytosolic protein and suggested to form aggregates or be associated with vesicles scattering in the cytoplasm. It was interesting that both NF-kappaB and IFN transcription was activated by bcTRAF3 in reporter assay. When co-expressed with black carp STING (bcSTING), bcTRAF3 was redistributed in the cytoplasm and its subcellular location overlapped with that of bcSTING no matter what the cells was infected with GCRV or not, which suggested the association between these two molecules. bcSTING mediated IFN production was up-regulated by bcTRAF3 in a dose dependent manner in reporter assay. Accordingly, EPC cells transfected with both bcSTING and bcTRAF3 showed enhanced antiviral activity comparing EPC cells expressing bcSTING alone. Taken together, the data generated in this paper supported the conclusion that bcTRAF3 was recruited into host innate immune activation and positively regulated bcSTING-mediated antiviral signaling. PMID- 30009930 TI - Maternal discouragement and child intake of a palatable dessert: A multilevel sequential analysis. AB - BACKGROUND: Family mealtimes are often marked by parent-child conflict, which may arise when children's eating behaviors do not match parental expectations. Little is known about how children respond to parents' comments to discourage eating. OBJECTIVE: The objective of this study was to examine the likelihood of a child taking a bite following a maternal statement to discourage child intake. METHODS: 50 mother-child dyads (mean child age 71.8 months) participated in a laboratory eating task with cupcakes. Video recordings were reliably coded for maternal statements to discourage child intake (varying by domains of affective valence and directness) and child bites. Multilevel sequential analysis was performed to determine differences in pairs' antecedent statement to discourage child intake and a child's discouraged bite. RESULTS: Children were significantly more likely to be non-compliant by taking a bite following negative (vs. positive), indirect (vs. direct) and negative direct (vs. positive direct) statements to discourage child intake (that is, a "discouraged bite"). There were no differences in children taking discouraged bites following a negative indirect vs. positive indirect statement to discourage child intake. CONCLUSIONS: Children may be more apt to comply with their mother's mealtime commands if they are delivered with a direct approach and a positive affective valence. Future work should examine the longitudinal effects of using positive direct mealtime commands on children's food intake, weight gain and emotional health. PMID- 30009931 TI - Development and initial validation evidence for a mindful eating questionnaire for children. AB - Mindful eating interventions have become a focus among health professionals, which warrants a need for a psychometrically solid assessment tool. The current study outlines the development and initial validation of the Mindful Eating Questionnaire (MEQ) adapted for Children (MEQ-C). Participants included 262 third through fifth grade students (53% female, 57% white, non-Hispanic) who participated in a mindful eating intervention Foodie U. Data was also collected from 140 parents. Exploratory factor analysis delineated two factors (Awareness and Mindless Eating). Test-retest analysis with a subsample (n = 93) indicated moderate correlations for both factors. The two subscales have good construct validity and can be utilized in an exploratory sense for mindful eating interventions among children. Specifically, the eight-item mindless eating subscale has good internal consistency reliability and can independently be used as a questionnaire to assess overall mindless eating practices among children. Further research is needed to explore and better understand domains of mindful eating among children besides awareness. PMID- 30009932 TI - Emotional overeating is common and negatively associated with alcohol use in normal-weight female university students. AB - INTRODUCTION: Eating in response to specific emotional cues was hitherto investigated in relation to weight gain, eating disorders, and psychiatric and addictive disorders. Given the difficulties in treating established obesity, preventive interventions towards normal-weight subjects could be more appropriate and cost effective. In order to design such interventions, it is important to characterize emotional overeating in normal-weight subjects, especially young women. METHODS: Female university students aged 18-24 years with healthy Body Mass Index (comprised between 18.5 and 24.9) were asked to complete questionnaires while attending a medical consultation. Emotional Eating frequency in the last 28 days was assessed together with data on habitual physical activity, drinking patterns, substance abuse, suspected eating disorders and cognitive/behavioural components of eating. Sociodemographic data and tobacco use were also collected. RESULTS: Half of participants reported intermittent Emotional Overeating in the last 28 days, mostly during one to five days in the last 28 days, in response to Anxiety (51.3%), Loneliness (45.1%), Sadness (44.8%), and Happiness (43.6%), and to a lesser extent in response to Tiredness (27.4%) and Anger (14.6%). In multivariate analysis, Distress-Induced Overeating (DIO) correlated positively with inability to resist emotional cues, disordered eating symptoms, and loss of control over food intake. It correlated negatively with moderate and excessive drinking. CONCLUSION: A large proportion of normal weight female students used intermittent overeating episodes as a time-limited response to emotional states, especially anxiety. DIO was negatively correlated with alcohol use, which suggests two distinct and somewhat exclusive ways of coping with negative emotions. It was higher in the minority of students with disordered eating symptoms and loss of control over food intake, highlighting the need for a systematic screening in all female students entering college. PMID- 30009934 TI - Type 2 diabetes and influence of diabetes-specific distress on depression. AB - AIMS: Common psycho-social emotional reactions of patients with diabetes may be termed as diabetes-specific distress which is conceptually distinctive from depression. In patients with type 2 diabetes, different screening methods for depression may get influenced by simultaneous presence of diabetes distress. This study was planned to assess magnitude and relationship of depression and diabetes specific distress in patients with type 2 diabetes. METHODS: Two hundred and fifty (250) adult patients with type 2 diabetes (T2DM) were assessed for depression based on Beck Depression Inventory (BDI) and Diagnostic and Statistical Manual, Fourth edition (DSM IV) criteria. Diabetes specific distress was assessed as per Diabetes Distress Scale (DDS) score. RESULTS: Among study population of 250 adult T2DM patients, based on BDI score, 97 (38.8%) patients were found to suffer from depression and based on DSM IV criteria, prevalence of depression was 29.2%. A total of 62 (24.8%) patients were found to suffer from diabetes specific distress based on DDS score. Patients with severe diabetes specific distress had associated matching of symptoms with mild depression based on BDI score which was also statistically significant (p < 0.0001). However, these same individuals were non-depressed as per DSM-IV criteria. CONCLUSION: Recognizing depression with self-administered questionnaires may be influenced by concomitant presence of symptoms due to diabetes specific distress. Therefore, proper diagnosis of depression may be established by structured clinical interview and psycho-social management of type 2 diabetes should possibly include both assessment of depression and diabetes specific distress. PMID- 30009933 TI - Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder. AB - A variety of human and animal studies support the hypothesis that serotonin (5 hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5 HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, and review evidence implicating perinatal disruptions in 5-HT signaling in the pathophysiology of autism spectrum disorder. We discuss the importance, and relative dearth, of studies that explore the possible correlation to autism in the interactions between important intrinsic and extrinsic factors that may disrupt 5-HT homeostasis during development. In particular, we focus on exposure to 5-HT transport altering mechanisms such as selective serotonin reuptake inhibitors or genetic polymorphisms in primary or auxiliary transporters of 5-HT, and how they relate to neurological stores of serotonin and its precursors. A deeper understanding of the many mechanisms by which 5-HT signaling can be disrupted, alone and in concert, may contribute to an improved understanding of the etiologies and heterogeneous nature of this disorder. We postulate that extreme bidirectional perturbations of these factors during development likely compound or synergize to facilitate enduring neurochemical changes resulting in insufficient or excessive 5-HT signaling, that could underlie the persistent behavioral characteristics of autism spectrum disorder. PMID- 30009935 TI - Efficacy of low-level light therapy for treatment of diabetic foot ulcer: A systematic review and meta-analysis of randomized controlled trials. AB - AIMS: The goal of this systematic review and meta-analysis based on seven Randomized control trials (RCTs) is to examine whether Low-level light therapy (LLLT) is effective at healing diabetic foot ulcer (DFU) and to provide evidence based recommendations and clinical guidelines for the future clinical treatment of DFUs. METHODS: Medline, Embase, Scopus, Cochrane Library, and Web of Science databases were searched for studies published up to June 30, 2017, without language or data restrictions. RCTs that investigated the use of LLLT for DFU treatment were included. Standard methods of meta-analysis were performed to evaluate outcomes of LLLT on the healing of DFU. RESULTS: Seven RCTs involving 194 participants were eligible for this systematic review and meta-analysis. The results of meta-analysis showed that LLLT has emerged as a potential noninvasive treatment for DFUs, as LLLT was found to effectively reduce the ulcer area [weighted mean difference (WMD) 34.18, 95% confidence intervals (CI) 19.38-48.99, P < 0.00001], improve the complete healing rate [odds ratio (OR) 6.72, 95% CI 1.99-22.64, P = 0.002]. Qualitative analysis of the included RCTs found that LLLT also played a role in the treatment of DFUs through promoting rapid granulation formation and shortening ulcer closure time, as well as alleviating foot ulcer pain. None of the treatment-related adverse event was reported. CONCLUSIONS: LLLT was recognized as a potential method in the comprehensive treatment of DFUs. Further well designed and high-quality studies are required to confirm the role of LLLT in the management of DFUs. PMID- 30009936 TI - Increased mortality among patients with diabetes following first-ever transfemoral amputation. AB - AIMS: Transfemoral amputation (TFA) is associated with a high postoperative mortality though it is unclear whether diabetes is associated with an increased mortality or not. The aim was to examine mortality at 1 week and 1 year after first-ever TFA with special reference to diabetes. METHODS: We included 162 first ever TFAs from 1996 to 2012. Mortality data were collected with the use of the Swedish personal identification number. RESULTS: The median age was 85 years. Diabetes mellitus were present in 19% (n = 30) of the patients and 67% (n = 109) had cardiovascular disease. Mortality was significantly higher for patients with diabetes compared to patients without diabetes at 1 week (30% vs. 8%, p = 0.001) and at 1 year (80% vs. 57%, p = 0.02). This difference was significant in multivariable analysis. CONCLUSIONS: We conclude that postoperative mortality was high. The high mortality rate emphasizes the need for early and adequate evaluation of every patients overall condition and whether amputation is beneficial or not. Although further studies are needed to analyze the specific causes of early death in amputees and we suggest close monitoring of blood-sugar in patients with diabetes and early treatment of infections and cardiac events in all patients. PMID- 30009937 TI - Persistence of newer anti-obesity medications in a real-world setting. AB - AIMS: Evaluate real-world data on persistence with anti-obesity medications (AOMs) and explore associated patient factors. METHODS: Truven Health MarketScan(r) data were analyzed to evaluate utilization of AOMs approved for long-term use between 4/2015 and 3/2016. Kaplan-Meier survival analyses were used to evaluate treatment persistence. A multivariate analysis was performed to identify associations between persistence and relevant factors. RESULTS: In total, 26,522 adult patients were identified as newly prescribed naltrexone/bupropion (44.0%, mean age 47.1, 80.5% female), lorcaserin (24.8%, 48.5, 79.3%), phentermine/topiramate extended release (15.8%, 46.7, 82.2%) or liraglutide 3.0 mg (15.4%, 46.9, 72.4%). At 6 months, 41.8% of patients were still on liraglutide 3.0 mg, compared to 15.9% lorcaserin (p < 0.001), 18.1% naltrexone/bupropion (p < 0.001), and 27.3% phentermine/topiramate (p < 0.001). After adjusting for baseline factors, patients on liraglutide 3.0 mg had significantly lower risk of discontinuation compared to those on lorcaserin (HR = 0.46, p < 0.0001), naltrexone/bupropion (HR = 0.48, p < 0.0001), and phentermine/topiramate (HR = 0.64, p < 0.0001) over the course of follow-up (mean follow-up duration, 342-427 days). Older age, male gender, having hyperlipidemia, and no prior phentermine use were associated with higher persistence. Over 95% of study patients had commercial insurance. CONCLUSIONS: In a real-world setting, patients on liraglutide 3.0 mg had the highest persistence rate of the four AOMs studied. PMID- 30009938 TI - First stratified diabetes prevalence data for Republic of Macedonia derived from the National eHealth System. AB - AIMS: To find diabetes prevalence of diagnosed cases, stratified by gender, age, and urban/rural municipalities in the Republic of Macedonia, based on data derived from the National eHealth System. METHODS: The National eHealth System was searched for all patients with ICD-10 diagnoses E10-E14 in their electronic healthcare records. Data records from the National eHealth System contained patient's gender, date of birth, place of living, and ICD-10 code. RESULTS: Total number of diagnosed diabetes cases was 84,568: 36,119 males (42.7%) and 48,449 females (57.3%). Diabetes prevalence of diagnosed cases in population 20-79 years was 5.0% (n = 78,233; N = 1,562,203), prevalence was higher in females than in males (4.6% vs 3.4%); in rural than in urban municipalities (5.6% vs 3.6%), and was highest in the age group 60-79 years (14.6%). CONCLUSION: These were the first findings on diabetes prevalence of diagnosed cases in the Republic of Macedonia derived from the National eHealth System, stratified by age, gender, and urban/rural municipalities. These data could enable more precise estimations of the total diabetes prevalence in the country, including both diagnosed and undiagnosed cases, and further analysis of the risk factors leading to higher diabetes prevalence in females and rural municipalities in the Republic of Macedonia. PMID- 30009940 TI - Application of competing risks analysis improved prognostic assessment of patients with decompensated chronic heart failure and reduced left ventricular ejection fraction. AB - OBJECTIVE: The Kaplan-Meier method may overestimate absolute mortality risk (AMR) in the presence of competing risks. Urgent heart transplantation (UHT) and ventricular assist device implantation (VADi) are important competing events in heart failure. We sought to quantify the extent of bias of the Kaplan-Meier method in estimating AMR in the presence of competing events and to analyze the effect of covariates on the hazard for death and competing events in the clinical model of decompensated chronic heart failure with reduced ejection fraction (DCHFrEF). STUDY DESIGN AND SETTING: We studied 683 patients. We used the cumulative incidence function (CIF) to estimate the AMR at 1 year. CIF estimate was compared with the Kaplan-Meier estimate. The Fine-Gray subdistribution hazard analysis was used to assess the effect of covariates on the hazard for death and UHT/VADi. RESULTS: The Kaplan-Meier estimate of the AMR was 0.272, whereas the CIF estimate was 0.246. The difference was more pronounced in the patient subgroup with advanced DCHF (0.424 vs. 0.338). The Fine-Gray subdistribution hazard analysis revealed that established risk markers have qualitatively different effects on the incidence of death or UHT/VADi. CONCLUSION: Competing risks analysis allows more accurately estimating AMR and better understanding the association between covariates and major outcomes in DCHFrEF. PMID- 30009939 TI - Lower alpha fetoprotein and higher risk of hepatocellular carcinoma, study from the type 2 diabetes mellitus patients. AB - AIMS: To explore the association of type 2 diabetes mellitus (T2DM) with hepatocellular carcinoma (HCC) and alpha fetoprotein (AFP). METHODS: 750 patients with T2DM (T2DM group), 800 healthy people (control group) and 501 patients newly diagnosed with HCC were recruited from 2010 to 2016. The HCC patients were further divided into a HCC with T2DM (HCC+DM) group and a HCC without diabetes mellitus (HCC+NDM) group. RESULTS: The T2DM group had a 12.61% lower geometric mean AFP level than the healthy control group (2.08 vs. 2.38 MUg/L, P < 0.001). Of 501 HCC patients, 230 (45.91%) had T2DM. When compared to the HCC+NDM group, the HCC+DM group had a higher negative rate of AFP (55.22% vs. 37.26%, P < 0.001), worse liver function (P = 0.011) and a 64.87% lower geometric mean AFP level (25.71 vs. 73.18 MUg/L, P < 0.001). T2DM was significantly associated with the risk of high-grade (grade 3 and 4) HCC (OR = 2.02, 95% CI 1.18-3.44, P = 0.010). CONCLUSIONS: T2DM was associated with lower AFP level, worse liver function and higher risk of high-grade HCC. We speculated that low AFP levels in diabetics might delay and interfere with HCC diagnosis, leading to higher degree of malignant HCC. PMID- 30009941 TI - Using a single noninferiority margin or preserved fraction for an entire pharmacological class was found to be inappropriate. AB - OBJECTIVE: To assess the impact on noninferiority decisions when using a single margin or single preserved fraction (PF) for all noninferiority trials within a pharmacological class. STUDY DESIGN AND SETTING: A search in PubMed, EMBASE, and CENTRAL resulted in seven active-controlled statin trials (nine noninferiority comparisons) for treating hyperlipidemia. The impact of using a single margin was assessed by calculating whether this margin corresponds to different PFs among comparator statins which will demonstrate that the threshold of demonstrating noninferiority (in terms of the PF) varies among comparator statins. The use of a single PF was assessed by reanalyzing noninferiority in the included trials with new margins (based on the single PF) for each comparator statin. RESULTS: The use of a single margin resulted in PFs that range between 81% and 89% for the different comparators (i.e., different thresholds). The use of a single PF resulted in four of nine (44%) different noninferiority conclusions compared with the original analyses. CONCLUSION: The threshold of demonstrating noninferiority with a single margin or single PF of the effect per pharmacological class may not be consistent with using a margin/PF for each comparator separately and may impact the conclusions of noninferiority. PMID- 30009942 TI - The development of an ICF-based questionnaire for patients with chronic conditions in primary care. AB - OBJECTIVES: We developed a self-reported questionnaire for patients in primary care with chronic conditions aged 50 years or older. The questionnaire supports a more person-centered approach by adopting a biopsychosocial focus on functional status instead of a focus on disease. STUDY DESIGN AND SETTING: Based on the International Classification of Functioning, Disability and Health (ICF), an ICF Primary Care set for patients with chronic conditions was constructed in three phases. In the first phase, we identified relevant ICF categories for the ICF Primary Care set by using existing ICF sets for chronic health conditions. The ICF Primary Care set was completed by a multidisciplinary expert panel and consisted of 52 ICF categories covering ICF's body functions, activities, participation, environmental factors, and personal factors. In the last phase, we constructed a draft version of the questionnaire by converting the ICF categories from the ICF Primary Care set into questions and corresponding scales. To improve the draft version of the questionnaire, we conducted cognitive interviews with patients with chronic conditions in an iterative process, focusing on the problems patients experienced in answering the items of the questionnaire. Interview analysis was used for assessing the content and construct validity of the questionnaire. RESULTS: Thirty cognitive interviews with patients were conducted in five different interview rounds. In these interviews, we identified 124 problems in the responding process of answering the questionnaire, mostly concerning difficulties with the comprehension of the constructs of the questions. The number of problems reduced from an average of 11 problems per interview in the first round to an average of two problems in the last round. CONCLUSION: Conclusion: The final version of the questionnaire demonstrated high content and construct validity (i.e., patients are well capable of describing their functional status in terms of ICF) and is applicable in primary care in the Netherlands. PMID- 30009943 TI - Production of (S)-1,2-propanediol from l-rhamnose using the moderately thermophilic Clostridium strain AK1. AB - Clostridium strain AK1 was investigated for its capacity of producing 1,2 propanediol from l-rhamnose but not l-fucose. The maximum yields of 1,2 propanediol from rhamnose was 0.81 mol 1,2-PD/mol l-rhamnose. The influence of different initial substrate concentrations as well as the effect of temperature and pH on 1,2-PD production was investigated. PMID- 30009944 TI - Correlation between restriction endonuclease analysis and PCR ribotyping for the identification of Clostridioides (Clostridium) difficile clinical strains. AB - Restriction endonuclease analysis (REA) and PCR ribotyping are two typing systems that have been frequently utilized for molecular epidemiologic characterization of Clostridioides (Clostridium) difficile. To correlate typing data obtained from each method, we performed both REA and PCR ribotyping on a large and diverse set of historical and contemporary C. difficile infection clinical isolates. Eighty isolates were selected from each reference laboratory in the United States (Microbiology Reference Laboratory, Hines VA Medical Center) and United Kingdom (Clostridium difficile Network for England and Northern Ireland laboratory, University of Leeds). The 160 isolates were assigned to 82 unique ribotypes and 51 unique REA groups (116 unique REA types). In general, concordance between typing methods was good. Dendrogram analysis of PCR ribotype band patterns demonstrated close genetic relationships among strain types with discordant REA and ribotype assignments. While REA typing was more discriminatory, several REA types in this study were further discriminated by PCR ribotyping, indicating that discriminatory value of these typing methods may be strain dependent. These data will assist with molecular epidemiologic surveillance of strains identified by these two commonly used C. difficile typing systems. PMID- 30009945 TI - Cancer invasion into musculature: Mechanics, molecules and implications. AB - Tumor invasion along structural interphases of surrounding tumor-free tissue represents a key process during tumor progression. Much attention has been devoted to mechanisms of tumor cell migration within extracellular matrix (ECM) rich connective tissue, however a comprehensive understanding of tumor invasion into tissue of higher structural complexity, such as muscle tissue, is lacking. Muscle invasion in cancer patients is often associated with destructive growth and worsened prognosis. Here, we review biochemical, geometrical and mechanical cues of smooth and skeletal muscle tissues and their relevance for guided invasion of cancer cells. As integrating concept, muscle-organizing ECM-rich surfaces of the epi-, peri- and endomysium provide cleft-like confined spaces along interfaces between dynamic muscle cells, which provide molecular and physical cues that guide migrating cancer cells, forming a possible contribution to cancer progression. PMID- 30009946 TI - Unraveling the 3D genome of human malaria parasites. AB - The chromosomes within the eukaryotic cell nucleus are highly dynamic and adopt complex hierarchical structures. Understanding how this three-dimensional (3D) nuclear architectureaffects gene regulation, cell cycle progression and disease pathogenesis are important biological questions in development and disease. Recently, many genome-wide technologies including chromosome conformation capture (3C) and 3C-based methodologies (4C, 5C, and Hi-C) have been developed to investigate 3D chromatin structure. In this review, we introduce 3D genome methodologies, with a focus on their application for understanding the nuclear architecture of the human malaria parasite, Plasmodium falciparum. An increasing amount of evidence now suggests that gene regulation in the parasite is largely regulated by epigenetic mechanisms and nuclear reorganization. Here, we explore the 3D genome architecture of P. falciparum, including local and global chromatin structure. In addition, molecular components important for maintaining 3D chromatin organization including architectural proteins and long non-coding RNAs are discussed. Collectively, these studies contribute to our understanding of how the plasticity of 3D genome architecture regulates gene expression and cell cycle progression in this deadly parasite. PMID- 30009947 TI - Increased choriocapillaris vessel density in amblyopic children: a case-control study. AB - PURPOSE: To investigate the choriocapillaris in children with amblyopia, using optical coherence tomography angiography (OCT-A). METHODS: Patients with amblyopia and age-matched controls were prospectively imaged using OCT-A. On OCT A, the choriocapillaris measures 30 MUm starting 31 MUm posterior to the retinal pigment epithelium. The section of choriocapillaris under superficial retinal vessels was excluded from analysis to avoid shadowing or projection artifacts. The main outcome measure was choriocapillaris vessel density. Secondary outcome measures were foveal macular thickness and parafoveal macular thickness. RESULTS: A total of 20 eyes of 16 patients with amblyopia and 25 eyes of 25 controls were included. Mean age of amblyopic subjects was 7.6 +/- 3.6 years; of controls, 9.3 +/- 2.2 years (P = 0.10). Mean refractive error of subjects was 4.3 +/- 6.2 D; of controls, 0.0 +/- 1.6 D (P = 0.004). Mean choriocapillaris vessel density was 74.8 +/- 5.8 in the amblyopic group and 71.1 +/- 3.6 in the control group, which was significant even after adjusting for age and refractive error (P = 0.012). There was no difference between groups in foveal macular thickness or parafoveal macular thickness; however, outer parafoveal macular thickness (the inner boundary of the inner nuclear layer to the retinal pigment epithelium outer boundary) was significantly greater in amblyopic eyes than in control eyes, even after adjusting for age and refractive error (203 +/- 11 MUm and 189 +/- 12 MUm, resp. [P = 0.014]). CONCLUSIONS: In our study cohort, amblyopic eyes were found to have increased choriocapillaris vessel density as well as a greater outer parafoveal macular thickness, which may be due to alterations in outer retinal maturation. PMID- 30009948 TI - Strabismus in retinoblastoma survivors with long-term follow-up. AB - PURPOSE: To report the long-term strabismus rate in salvaged retinoblastoma (Rb) patients and investigate possible risk factors leading to strabismus. METHODS: The medical records of patients with Rb presenting at a single institution over a 9-year period were reviewed retrospectively with regard to ocular alignment outcomes after long-term follow-up. RESULTS: A total of 64 eyes of 42 patients (22 bilateral cases [52%]) were included, presenting with International Intraocular Retinoblastoma Classification (IIRC) in the worse eye as follows: group A (n = 1), B (n = 16), C (n = 12), D (n = 11), no Rb (n = 2). Fifteen patients (36%) were initially referred because of family history of Rb. Mean age at presentation was 8.2 months (range, 0.3-58.3 months). Overall treatments included intravenous chemotherapy (62 eyes), intraophthalmic artery chemotherapy (10 eyes), brachytherapy (11 eyes), transpupillary thermotherapy (22 eyes), cryotherapy (47 eyes), and external beam radiotherapy (4 eyes). At final follow up (mean, 93.7 months), 69% of patients had strabismus, with exotropia being the most common type (n = 18), followed by esotropia (n = 8), and alternate exotropia/esotropia (n = 3). On univariate analysis, the worse eye group IIRC and cTNMH, sporadic cases, strabismus, and foveal tumor at presentation were found to be significantly associated with strabismus at final follow-up (P <= 0.043). On multivariate analysis, only foveal involvement was found to be significant (P < 0.001). CONCLUSIONS: Strabismus, exotropia in particular, is a common adverse sequela following successful conservative treatment for Rb, with 69% of the present cohort having some type of deviation after long-term follow-up, for which foveal tumor at presentation was found to be a significant risk factor. PMID- 30009949 TI - Porphyrins and related macrocycles: Combining photosensitization with radio- or optical-imaging for next generation theranostic agents. AB - This review summarises recent research into combining the photosensitizing properties of porphyrins with imaging techniques such as PET and NIR fluorescence for so called "theranostic" applications, which combine biomedical imaging and therapeutic potential into a single administered substance. The photophysical mechanisms of both the therapeutic and diagnostic properties of porphyrins are discussed, as well as key characteristics that are required in order to deliver the most effective treatment. PMID- 30009950 TI - The promiscuous estrogen receptor: Evolution of physiological estrogens and response to phytochemicals and endocrine disruptors. AB - Many actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor-alpha (ERalpha) and ERbeta. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), Delta5 androstenediol, 5alpha-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Delta5-androstenediol, 5alpha-androstanediol, and 27 hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and Delta5 androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen. In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain. Some of these ER actions in non-reproductive tissues appeared early in vertebrate evolution, long before the emergence of mammals. PMID- 30009951 TI - SIRT2 plays a novel role on progesterone, estradiol and testosterone synthesis via PPARs/LXRalpha pathways in bovine ovarian granular cells. AB - SIRT2 has been shown to possess NAD+-dependent deacetylase and desuccinylase enzymatic activities, it also regulates metabolism homeostasis in mammals. Previous data has suggested that resveratrol, a potential activator of Sirtuins, played a stimulation role in steroidogenesis. Unfortunately, to date, the physiological roles of SIRT2 in ovarian granular cells (GCs) are largely unknown. Here, we studied the function and molecular mechanisms of SIRT2 on steroid hormone synthesis in GCs from Qinchuan cattle. Immunohistochemistry and western blotting showed that SIRT2 was expressed not only in GCs and cumulus cells, but also in oocytes and theca cells. We found that the secretion of progesterone was induced, whereas that of estrogen and testosterone secretion was suppressed by treatment with the SIRT2 inhibitor (Thiomyristoyl or SirReal2) or siRNA. Additionally, the PPARs/LXRalpha signaling pathways were suppressed by SIRT2 siRNA or inhibitors. The mRNA expression of CYP17, aromatase and StAR was suppressed, but the abundance of CYP11A1 mRNA was induced by SIRT2 inhibition. Furthermore, the PPARalpha agonist or PPARgamma antagonist could mimic the effects of SIRT2 inhibition on hormones levels and gene expression associated with steroid hormone biosynthesis. In turn, those effects were abolished by the LXRalpha agonist (LXR-623). Together, these data support the hypothesis that SIRT2 regulates steroid hormone synthesis via the PPARs/LXRalpha pathways in GCs. PMID- 30009952 TI - Changes in testicular morphology and oxidative stress biomarkers in 60-day-old Sprague Dawley rats following exposure to continuous 900-MHz electromagnetic field for 1 h a day throughout adolescence. AB - The purpose of this study was to investigate the 60-day-old male rat testis following exposure to continuous 900-megahertz (MHz) electromagnetic field (EMF) throughout the adolescent period using histopathological and biochemical analysis methods. Twenty-four Sprague Dawley rats aged 21 days were randomly and equally (n = 8) divided into three groups. No procedure was performed on the control group rats. The sham group rats were held in an EMF-cage without exposure to EMF. The EMF group rats were exposed to continuous 900-MHz EMF for 1 h each day inside the EMF-cage during adolescence. On postnatal day 60 the testes were extracted and divided into right and left halves. The right half was used for histopathological evaluation and the left half for biochemical analyses. Our results show that changes may occur in morphology and oxidative stress biomarkers in the rat testis following exposure to continuous 900-MHz EMF throughout the adolescent period. PMID- 30009953 TI - Alterations in the memory of rat offspring exposed to low levels of fluoride during gestation and lactation: Involvement of the alpha7 nicotinic receptor and oxidative stress. AB - Daily exposure to fluoride (F) depends mainly on the intake of this element with drinking water. When administered during gestation and lactation, F has been associated with cognitive deficits in the offspring. However, the mechanisms underlying the neurotoxicity of F remain obscure. In the current study, we investigated the effects of oral exposure to low levels of F during the gestational and lactation periods, on the memory of adult female rat offspring. We also considered a possible underlying neurotoxic mechanism. Our results showed that this exposure reduced step-down latency in the inhibitory avoidance task, and decreased both mRNA expression of the alpha7 nicotinic receptor (nAChR) and catalase activity in hippocampus. Our data indicates that low F concentrations administrated during gestation and lactation decrease the memory of 90-day-old female offspring. This suggests that the mechanism might be connected with an alpha7 nAChR deficit in the hippocampus, induced by oxidative stress. PMID- 30009954 TI - Rosmarinic acid compromises human sperm functions by an intracellular Ca2+ concentration-related mechanism. AB - Rosmarinic acid (RA), a natural phenolic ester, is cytoprotective for male reproduction in animal models. The present study investigated the in vitro actions of RA on human sperm functions. Human sperm were exposed to 1, 10, 100, and 1000 MUM RA in vitro and sperm functions were examined. The results showed that although RA did not affect human sperm viability, RA at 10-1000 MUM dose dependently reduced sperm motility, penetration ability, capacitation, and spontaneous acrosome reaction. In addition, the intracellular Ca2+ concentration ([Ca2+]i), which serve as a key regulator of sperm function, was decreased by RA (10-1000 MUM) in a dose-dependent manner. Furthermore, the current of the sperm specific potassium channel, KSPER, which is predominant for Ca2+ influx in sperm, was dose-dependently inhibited by 10-1000 MUM RA. Therefore, we conclude that in vitro exposure to RA can compromise human sperm functions by decreasing sperm [Ca2+]i through the suppression of KSPER current. PMID- 30009955 TI - How soon will digital endpoints become a cornerstone for future drug development? AB - Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems. PMID- 30009956 TI - Prevalence and molecular subtyping of Blastocystis from dairy cattle in Kanagawa, Japan. AB - Blastocystis is an intestinal protist, commonly found in the human population and in a wide range of animals globally. Currently, isolates from mammalian and avian hosts are classified into 17 subtypes (STs) based on phylogeny of the small subunit rRNA gene (SSU rDNA), of which ten (ST1-9, 12) are reported in humans. ST10 is a major ST reported from livestock cattle. However, other STs including ST1, 3, 4, 5, and 6, which have the potential to be transmitted to humans, are also reported from cattle in several countries. Although a survey has been conducted previously in western Japan for livestock cattle, there is no information available regarding other parts of Japan. Therefore, this study surveyed the prevalence of Blastocystis and its STs in cattle from Kanagawa prefecture, eastern Japan. Fecal specimens, collected from 133 dairy cattle on four different farms, were subjected to a short-term xenic in vitro culture and Blastocystis were identified by microscopic examination. Seventy-two cattle were positive for Blastocystis (54.1%). Direct sequences for the partial SSU rDNA were obtained for 45 samples. Based on nucleotide sequence homology search and phylogenetic analysis, 44 isolates were identified as ST14 and one as ST10. Our study confirms the presence of these STs in dairy cattle in Japan for the first time. The STs identified here, ST10 and ST14, support previous findings that Bovidae may be the natural host for both STs. PMID- 30009957 TI - Heterologous expression of the human polybromo-1 protein in the methylotrophic yeast Pichia pastoris. AB - The human polybromo-1 protein (BAF180) is a known driver mutation in clear cell renal cell carcinoma, where it is mutated in approximately 40% of cases. BAF180 is the chromatin-targeting subunit of the PBAF complex. BAF180 has six bromodomains, two BAH domains, and one HMG box. Bromodomains are known to recognize acetylated-lysines on histones and play a role in nucleosome recognition. BAH domains are required for ubiquitination of PCNA, a key regulator of DNA damage. The putative HMG box, if functional, may be involved in DNA binding. While the binding specificities of individual bromodomains have been studied by our lab and others, the results have failed to reach a consensus. The acetyl-histone binding features of the full-length protein is unknown and is the motivation for this work. The hypothetical HMG and BAH domains have not been studied and the actual function of these regions is currently unknown. Thus, the precise interactions of this large and complex protein are not well-studied. Advances in understanding this large protein have been hindered by the inability to express and purify recombinant full-length BAF180 protein. Currently, only phenomenological studies using BAF180 expressed in mammalian cells have been conducted. Here, we report the successful expression, purification of full-length biologically active BAF180 protein using the GAP promoter in the heterologous host Pichia pastoris. The ability to express full-length and mutated BAF180 will allow for biophysical binding studies. Knowledge of the binding interactions is critical for us to understand the role of BAF180 in cancer development and its progression. PMID- 30009958 TI - Time spent with residual viraemia after virological suppression below 50 HIV-RNA copies/mL according to type of first-line antiretroviral regimen. AB - PURPOSE: To investigate if the regimen used when starting antiretroviral therapy (ART) affects the time spent with residual viraemia (RV) after achieving <50 HIV RNA copies/mL. METHODS: Retrospective cohort study on patients infected with human immunodeficiency virus (HIV), followed prospectively, who started ART with a boosted protease inhibitor (PI/r)-, a non-nucleoside reverse transcriptase inhibitor (NNRTI)- or an integrase inhibitor (InSTI)-based triple regimen, or a regimen with more than three drugs. RV was defined as any detectable polymerase chain reaction (PCR) signal <50 HIV-RNA copies/mL, as assessed by kinetic PCR or Abbott real-time PCR. The percentage of time spent with RV (%RV) was calculated as the cumulative follow-up time spent with RV on the observed follow-up, and was estimated using a generalized linear model. RESULTS: Seven hundred and seventy one patients (33%, 32%, 30% and 5% receiving PI/r-, NNRTI-, InSTI-based triple regimens, or a regimen with more than three drugs, respectively) were included in the analysis. After a median of 2.16 (interquartile range 1.27-3.16) years of follow-up, adjusted means of %RV were 37.9% [95% confidence interval (CI) 30.3 45.4%], 23.9% (95% CI 16-31.8%), 25.3% (95% CI 17.8-32.7%) and 45.5% (95% CI 34.6 56.4%) in the PI/r, NNRTI, InSTI and more than three drugs groups, respectively; %RV was significantly higher in patients who started ART with a regimen with more than three drugs (P=0.030), and was significantly lower in patients who started ART with an NNRTI-based regimen (P<0.0001) or an InSTI-based regimen (P=0.030) than in those who started ART with a PI/r-based regimen. %RV was independently associated with pre-ART HIV-RNA (P<0.0001), time to HIV-RNA <50 copies/mL (P<0.0001), NRTI backbone (P=0.037) and baseline HIV-RNA (P<0.0001). CONCLUSION: First-line regimens based on PIs/r or on more than three drugs are associated with a greater percentage of time spent with RV after achieving virological suppression. PMID- 30009959 TI - Co-occurrence of mcr-3 and blaNDM-5 genes in multidrug-resistant Klebsiella pneumoniae ST709 from a commercial chicken farm in China. PMID- 30009961 TI - Influence of posture on relationships between pelvic parameters and lumbar lordosis: Comparison of the standing, seated, and supine positions. A preliminary study. AB - BACKGROUND: Pelvic incidence (PI) is an anatomical parameter that is considered invariable in a given individual. Although changes in posture influence the mobile lumbar spine, lumbar lordosis (LL) and the pelvis are typically evaluated only in the standing position. Thus, whether other positions commonly used during daily activities influence the relationship between LL and PI is unknown. The objective of this study was to determine whether LL and sacral slope (SS) correlated with PI, using two standardised positions, seated and supine, different from the standing position that is generally used. HYPOTHESIS: We are supposing that lumbar lordosis and sacral sloop are correlated to pelvic incidence whatever the posture. The goal of this study was to confirm or deny this hypothesis, using two standardize positions (sitting and lying) different that the usual standing position. LL and SS correlate with PI in the standing, seated, and supine positions. METHOD: Lumbar and pelvic parameters were measured on radiographs obtained in the standing, seated, and supine positions in 15 asymptomatic adult volunteers younger than 50years of age. Mean values with their standard deviations were computed and compared across the three positions using ANOVA. Spearman's test was applied to assess correlations. RESULTS: PI had the same value in all three positions. The L1-S1 LL angle was 54.8+/-9.8 degrees in the standing position, 15.9+/-14.6 degrees in the seated position, and 50.2+/ 9.6 degrees in the supine position. Pelvic tilt (PT) in the same three positions was 12.1+/-6.3 degrees , 37.7+/-10.4 degrees , and 9.5+/-5.1 degrees , respectively; and SS was 37.1+/-6.3 degrees , 11.3+/-10.8 degrees , and 41+/-7.2 degrees , respectively. Correlations were strongest in the supine position between PI and LL (r=0.72), LL and SS (r=0.9), and PI and SS (r=0.84). CONCLUSION: Whereas PI remains unchanged in a given individual, lumbar lordosis and sacral orientation show significant changes across positions used in daily life, with the greatest changes seen in the seated position. During spinal fusion surgery, adjusting LL based on IP is crucial even in patients who have limited physical activity. LEVEL OF EVIDENCE: IV. PMID- 30009960 TI - A catenin-dependent balance between N-cadherin and E-cadherin controls neuroectodermal cell fate choices. AB - Characterizing endogenous protein expression, interaction and function, this study identifies in vivo interactions and competitive balance between N-cadherin and E-cadherin in developing avian (Gallus gallus) neural and neural crest cells. Numerous cadherin proteins, including neural cadherin (Ncad) and epithelial cadherin (Ecad), are expressed in the developing neural plate as well as in neural crest cells as they delaminate from the newly closed neural tube. To clarify independent or coordinate function during development, we examined their expression in the cranial region. The results revealed surprising overlap and distinct localization of Ecad and Ncad in the neural tube. Using a proximity ligation assay and co-immunoprecipitation, we found that Ncad and Ecad formed heterotypic complexes in the developing neural tube, and that modulation of Ncad levels led to reciprocal gain or reduction of Ecad protein, which then alters ectodermal cell fate. Here, we demonstrate that the balance of Ecad and Ncad is dependent upon the availability of beta-catenin proteins, and that alteration of either classical cadherin modifies the proportions of the neural crest and neuroectodermal cells that are specified. PMID- 30009962 TI - Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers. AB - Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN. PMID- 30009963 TI - Vimentin as antigenic target in autoimmunity: A comprehensive review. AB - Vimentin is a protein of intermediate filament family, which is expressed in all mesenchymal cells. Vimentin plays a key role in the physiology of the cell, cellular interactions and the functioning of the immune system. Post translationally modified and native forms of vimentin are involved in the pathogenesis of inflammation and many autoimmune diseases: rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, antiphospholipid syndrome, Crohn's disease, ankylosing spondyloarthritis and idiopathic pulmonary fibrosis. Modifications of the protein lead to the formation of antigenic epitopes and, as a result, to the synthesis of antibodies. Citrullinated, carbamylated and acetylated forms of vimentin participate in the pathogenesis of RA, and antibodies against them serve as diagnostic and prognostic markers of the disease. Epitopes of native vimentin are antigenic in the group of HLA-DRB1*0301 positive patients with sarcoidosis. In addition, vimentin takes part in pathogenesis of tubulointerstitial inflammation and glomerulonephritis in lupus. In antiphospholipid syndrome interactions of vimentin and cardiolipin on the surface of apoptotic cells lead to the formation of an immunogenic complex. Antibodies against vimentin/cardiolipin complex are involved in the mechanism of thrombogenesis and serve to identify patients seronegative for antibodies to cardiolipin and beta2glycoprotein-I with the clinical features. Post translationally modified form of the protein is citrullinated and MMP-degraded vimentin, which was found in serum of patients with Crohn's disease and ankylosing spondyloarthritis. PMID- 30009964 TI - Psychometric Properties of the Needs Assessment Tool-Progressive Disease Cancer in U.K. Primary Care. AB - BACKGROUND: The assessment of patients' needs for care is a critical step in achieving patient-centered cancer care. Tools can be used to assess needs and inform care planning. The Needs Assessment Tool:Progressive Disease-Cancer (NAT:PD-C) is an Australian oncology clinic tool for assessment by clinicians of patients' and carers' palliative care needs. This has not been validated in the U.K. primary care setting. AIM: The aim of this study was to test the psychometric properties and acceptability of a U.K. primary care adapted NAT:PD C. DESIGN: Reliability: NAT:PD-C-guided video-recorded consultations were viewed, rated, and rerated by clinicians. Weighted Fleiss' kappa and prevalence- and bias adjusted kappa statistics were used. Construct: During a consultation, general medical practitioners (GPs) used NAT:PD-C, patient measures (Edmonton Symptom Assessment Scale; Research Utilisation Group Activities of Daily Living; Palliative care Outcome Score; Australian Karnofsky Performance Scale), and carer measures (Carer Strain Index; Carer Support Needs Assessment Tool). Kendall's Tau b was used. SETTING/PARTICIPANTS: GPs, nurses, patients, and carers were recruited from primary care practices. RESULTS: Reliability: All patients' well being items and four of five items in the carer/family ability to care section showed adequate interrater reliability. There was moderate test-retest reliability for five of six in the patients' well-being section and five of five in the carer/family ability to care section. Construct: There was at least fair agreement for five of six of patients' well-being items; high for daily living (Kendall's Tau-b = 0.57, P < 0.001). The NAT:PD-C has adequate carer construct validity (five of eight) with strong agreement for two of eight patients. Over three-quarters of GPs considered the NAT:PD-C to have high acceptability. CONCLUSION: The NAT PD-C is reliable, valid, and acceptable in the UK primary care setting. Effectiveness in reducing patient and carer unmet needs and issues regarding implementation are yet to be evaluated. PMID- 30009965 TI - Drugs Used for Euthanasia: A Repeated Population-Based Mortality Follow-Back Study in Flanders, Belgium, 1998-2013. AB - CONTEXT: According to guideline recommendations, barbiturates and neuromuscular relaxants are the recommended drugs for euthanasia. OBJECTIVES: To describe changes over time in drugs used to perform euthanasia and differences in case characteristics according to the drugs used. METHODS: Repeated population-based mortality follow-back study among physicians attending a large representative sample of deaths in 1998, 2007, and 2013 in Flanders, Belgium. RESULTS: In 1998, we identified 25 euthanasia cases (1.2% of all deaths), 142 cases in 2007 (2.0% of all deaths), and 349 cases in 2013 (4.6% of all deaths). Use of recommended drugs to perform euthanasia increased from 11.9% of euthanasia cases in 1998 to 55.3% in 2007 and 66.8% in 2013 (P < 0.001). In 2013, cases with recommended drugs compared with nonrecommended drugs more often involved requests expressed both orally and in writing (86.8%/14.1%; P < 0.001), consultation with colleague physicians (93.8%/69.1%; P < 0.001), and administration in the presence of another physician (98.3%/54.3%; P < 0.001), and were more often self-labeled by physicians as euthanasia (95.5%/0.9%; P < 0.001) and reported to the euthanasia review committee (92.3%/3.8%; P < 0.001). Between 2007 and 2013, physicians consistently labeled cases in which nonrecommended drugs were used as palliative sedation (72.8%/78.4%; P = 0.791) or alleviation of pain and symptoms (13.2%/15.0%; P > 0.999). CONCLUSION: Physicians in Flanders are increasingly using the recommended drugs for euthanasia. This suggests that guidelines and training regarding the conduct and pharmacological aspects of euthanasia may have had important effects on the practice of euthanasia. However, the declining but persisting use of nonrecommended drugs requires further attention. PMID- 30009966 TI - Grieving to Grieve. PMID- 30009967 TI - Validation of Two Pain Assessment Tools Using a Standardized Nociceptive Stimulation in Critically Ill Adults. AB - CONTEXT: The Behavioral Pain Scale (BPS) or the Critical-Care Pain Observation Tool (CPOT) are recommended in practice guidelines for pain assessment in critically ill adults unable to self-report. However, their use in another language requires cultural adaptation and validation testing. OBJECTIVES: Cross cultural adaptation of the CPOT and BPS English versions into Brazilian Portuguese, and their validation by comparing behavioral scores during rest, standardized nociceptive stimulation by pressure algometry (SNSPA), and turning were completed. In addition, we explored clinical variables that could predict the CPOT and BPS scores. METHODS: A prospective cohort study was conducted with 168 medical-surgical critically ill adults unable to self-report in the intensive care unit. Two nurses were trained to use the CPOT and BPS Brazilian Portuguese versions at the following assessments: 1) baseline at rest, 2) after SNSPA with a pressure of 14 kgf/cm2, 3) during turning, and 4) 15 minutes after turning. RESULTS: Inter-rater reliability of nurses' CPOT and BPS scores was supported by high weighted kappa >0.7. Discriminative validation was supported with higher CPOT and BPS scores during SNSPA or turning in comparison to baseline (P < 0.001). The Glasgow Coma Scale score was the only variable that predicted CPOT and BPS scores with explained variance of 44.5% and 55.2%, respectively. CONCLUSION: The use of the Brazilian CPOT and BPS versions showed good reliability and validity in critically ill adults unable to self-report. A standardized procedure, the SNSPA, was used for the first time in the validation process of these tools and helped us improve the validation process. PMID- 30009968 TI - Fan Therapy Is Effective in Relieving Dyspnea in Patients With Terminally Ill Cancer: A Parallel-Arm, Randomized Controlled Trial. AB - CONTEXT: Dyspnea is a common distressing symptom among patients with advanced cancer. OBJECTIVE: The objective of this study was to determine the effect of fan therapy on dyspnea in patients with terminally ill cancer. METHODS: This parallel arm, randomized controlled trial included 40 patients with advanced cancer from a palliative care unit at the National Cancer Center Hospital in Japan. All patients experienced dyspnea at rest with a score of at least three points on a subjective 0- to 10-point Numerical Rating Scale (NRS), showed peripheral oxygen saturation levels of >=90%, had an Eastern Cooperative Oncology Group grade of 3 or 4, and were aged 20 years or more. In one group, a fan was directed to blow air on the patient's face for five minutes. This group was compared to a control group wherein air was blown to the patient's legs. Patients were randomly assigned to each group. The main outcome measure was the difference in dyspnea NRS scores between fan-to-face and fan-to-legs groups. RESULTS: No significant differences were seen in baseline dyspnea NRS between groups (mean score, 5.3 vs. 5.1, P = 0.665). Mean dyspnea changed by -1.35 points (95% CI, -1.86 to -0.84) in patients assigned to receive fan-to-face and by -0.1 points (-0.53 to 0.33) in patients assigned to receive fan-to-legs (P < 0.001). The proportion of patients with a one-point reduction in dyspnea NRS was significantly higher in the fan-to face arm than in the fan-to-legs arm (80% [n = 16] vs. 25% [n = 5], P = 0.001). CONCLUSION: Fan-to-face is effective in alleviating dyspnea in patients with terminally ill cancer. PMID- 30009969 TI - Phytochemical analysis and antimicrobial activity of some medicinal plants against selected pathogenic microorganisms. AB - The aim of the present study is to investigate the antimicrobial potency of leaves from various extracts of Capparis zeylanica, Streblus asper and Tribulus terrestris were evaluated. In addition, this is the first report on MIC, MBC/MFC antimicrobial activities of above mentioned plants and also identify the phytochemical, functional groups by GC-MS and FT-IR respectively. Soxhlet extraction method was used for preparation of different extracts viz., aqueous, petroleum ether, ethyl acetate and methanol. The extracts were examined against Staphylococcus epidermidis, Enterococcus faecallis, Salmonella paratyphi, Shigella dysenteriae, Candida albicans and Mycobacterium tuberculosis by agar well diffusion method, and Minimum Inhibitory Concentratioon (MIC), Minimum Bactericidal/Fungicidal Concentration (MBC/MFC) values were determined through micro dilution method. Phytochemical analysis of compounds was carried out by GC MS analysis and functional groups were identified by FT-IR. Based on the outcome of our results, Ethyl acetate extract Showed significant antimicrobial activity against the tested pathogens especially, for C. albicans (40 mm) followed by ethyl acetate of S. asper against S. paratyphi (38 mm). While, the least inhibition was observed with aqueous extract of T. terrestris against S. paratyphi (10 mm). The MIC ranged from 3.21 mg/ml to 50 mg/ml and MBC/MFC 6.25 mg/ml to 50 mg/ml was recorded. Ethyl acetate extracts of almost all samples showed better activity than other extracts in inhibition growth of pathogens. Phytochemical analysis exhibited the presence of Steroids, tannins and cardiac glycosides were found only in ethyl acetate extract of C. zeylanica. Functional group of leaf extract was confirmed by FT-IR spectrum and GC-MS analysis of the ethyl acetate extract revealed the presence of 20 compounds. The results revealed that ethyl acetate extract of C. zeylanica leaves has potential activity than the other extracts as well as standard drugs (Gentamycin and Ketocozole). Hence, this plant may be recommended for further studies in isolation of active compounds and related pharmacological activities. PMID- 30009970 TI - Bio-inspired nanomaterials in agriculture and food: Current status, foreseen applications and challenges. AB - Nanotechnology is a potential area that revolutionizes almost every sector of life and is predicted to become a major economic force in the near future. Recently, nanomaterials have received great attention for their properties at nanoscale regime and their applications in many areas primarily, agriculture and food sectors. The Nanomaterials are dispersed or solid particles, with a size range of 1-100 nm. In recent times, there has been an increased research work in this area to synthesize nanomaterials using various approaches. The use of natural biomolecules using 'green' approach play key role in the synthesis of nanomaterials having different shapes and sizes. Further this 'green synthesis' approach not only minimize the cost but also limit the need of hazardous chemicals and stimulates synthesis of greener, safe and environmentally friendly nanoparticles. The present review focus on studies based on the biosynthesis of nanoparticles using biomolecules such as plants, bacteria, fungi, etc. The text summarizes the recent work done globally by renowned researchers in area of biosynthesis of nanomaterials. It also discusses the potential applications of biologically mediated nanomaterials in the areas of agriculture and food and a critical evaluation of challenges within this field. PMID- 30009971 TI - Isoalantolactone protects LPS-induced acute lung injury through Nrf2 activation. AB - Isoalantolactone (ISO), a sesquiterpene lactone isolated from Inula helenium, is known to have anti-inflammatory activity. Here, using a mouse model of acute lung injury, we investigated the effects of ISO on lung inflammation in vivo. ISO (2.5, 5, 10 mg/kg) was administered 1 h before LPS treatment. Histopathological changes suggested that ISO attenuated the injury of lung tissues induced by LPS. ISO also inhibited LPS-induced MPO activity, MDA content, lung W/D ratio, and the production of inflammatory cytokines TNF-alpha and IL-1beta. LPS decreased the activities of the antioxidant enzymes SOD, GPX, and CAT and the decreases were inhibited by ISO. Further studies were performed to detect the Nrf2 and NF-kappaB signaling pathway. The results showed that ISO significantly suppressed LPS induced NF-kappaB activation, as well as PI3K and AKT phosphorylation. Additionally, the expression of Nrf2 and HO-1 were dose-dependently up-regulated by the treatment of ISO. Taken together, the results indicate the protective action of ISO against LPS-induced ALI were through activation of the Nrf2 signaling pathway. PMID- 30009972 TI - First report of the distribution of Locus of Adhesion and Autoaggregation (LAA) pathogenicity island in LEE-negative Shiga toxin-producing Escherichia coli isolates from Argentina. AB - Shiga toxin-producing Escherichia coli (STEC) are important foodborne pathogens that can cause severe disease. The ability to adhere to epithelial cells is an important virulence trait and pathogenicity islands (PAIs) play an important role. Recently, researchers identified a member of the Heat-resistant agglutinin family and characterized this antigen named Hemagglutinin from Shiga toxin producing E. coli (Hes). More importantly, they showed that hes and other genes such as iha, pagC and agn43 were integrated in each of the four modules present in the new PAI named Locus of Adhesion and Autoaggregation (LAA) whose presence is associated with severe disease linked to with LEE-negatives STEC. The distribution of LAA among STEC strains isolates from different origins between 2000 and 2015 from cattle, the farm environment, and food and harboring diverse virulence was investigated. The STEC strains were characterized by PCR to detect three modules of LAA and agn43 (as marker of module IV), and phylogenetic groups were determined. LAA was found in 46% of LEE-negative STEC corresponding to serogroups O91, O174, O113, O171, O178, O130 and others. The presence of this PAI is associated with strains harboring stx2 (56%) and belonging to phylogroup B1 (91%). LAA is a novel pathogenicity island associated with strains isolated from Hemolytic Uremic Syndrome cases. Therefore, the results of this study contribute to a better understanding regarding the pathogenicity of this emergent subset of STEC strains harboring LAA as a predictor of virulence of LEE-negative STEC strains. PMID- 30009973 TI - The TRPM2 channel nexus from oxidative damage to Alzheimer's pathologies: An emerging novel intervention target for age-related dementia. AB - Alzheimer's disease (AD), an age-related neurodegenerative condition, is the most common cause of dementia among the elder people, but currently there is no treatment. A number of putative pathogenic events, particularly amyloid beta peptide (Abeta) accumulation, are believed to be early triggers that initiate AD. However, thus far targeting Abeta generation/aggregation as the mainstay strategy of drug development has not led to effective AD-modifying therapeutics. Oxidative damage is a conspicuous feature of AD, but this remains poorly defined phenomenon and mechanistically ill understood. The TRPM2 channel has emerged as a potentially ubiquitous molecular mechanism mediating oxidative damage and thus plays a vital role in the pathogenesis and progression of diverse neurodegenerative diseases. This article will review the emerging evidence from recent studies and propose a novel 'hypothesis' that multiple TRPM2-mediated cellular and molecular mechanisms cascade Abeta and/or oxidative damage to AD pathologies. The 'hypothesis' based on these new findings discusses the prospect of considering the TRPM2 channel as a novel therapeutic target for intervening AD and age-related dementia. PMID- 30009974 TI - Radial subluxation in relation to hand strength and radiographic severity in trapeziometacarpal osteoarthritis. AB - OBJECTIVE: Greater joint laxity and radial subluxation of the thumb metacarpal base have been shown to be risk factors for the development of trapeziometacarpal osteoarthritis in an asymptomatic and radiographically normal joint. Despite this, it is unknown whether joint laxity changes with disease progression from mild to severe osteoarthritis. This study aimed to investigate the relationship between joint laxity and osteoarthritis severity, using the trapeziometacarpal subluxation ratio as an indicator of joint laxity. METHOD: Baseline data were used from the first 100 participants included in the COMBO (Efficacy of combined conservative therapies on clinical outcomes in base of thumb OA) trial. All participants had bilateral posteroanterior (PA) and Eaton stress view hand radiographs, as well as grip and tip-pinch strength measurements. The PA view was used to assess Kellgren-Lawrence and Eaton grades, and the Eaton stress view was used to assess the trapeziometacarpal joint subluxation ratios. Generalised estimating equations were utilized to account for the fact that hand data are paired, and within-person measurements are therefore not independent. RESULTS: Lower radial subluxation ratios were associated with higher Kellgren-Lawrence grades (B-coefficient -0.302; p-value 0.027), and lower grip strength scores (B coefficient 2.06; p-value 0.006). CONCLUSIONS: Radial subluxation ratios decreased with increasing disease severity, contrary to the progression from a normal joint to one with mild osteoarthritis, wherein higher joint laxity is a risk factor for disease. This may be explained by the mechanical stabilization provided by osteophytes and capsular changes in worsening osteoarthritis, as has been shown to be the case in the knee. TRIAL REGISTRATION NUMBER: ACTRN 12616000353493. LEVEL OF EVIDENCE: III. PMID- 30009975 TI - Deciphering biochemical basis of Qingkailing injection-induced anaphylaxis in a rat model by time-dependent metabolomic profiling based on metabolite polarity oriented analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Qingkailing injection (QKLI) is prepared from eight traditional Chinese medicinal materials or their extracts, which is widely used in clinical practice to treat the upper respiratory inflammation, pneumonia, high fever and viral encephalitis, nonetheless, suffering from serious anaphylaxis. AIM OF STUDY: This study aims to develop an integrative metabolomics approach for deciphering the biochemical basis of QKLI induced anaphylaxis (QKLI IA). MATERIALS AND METHODS: The accuracy of animal modeling, the coverage of detected metabolites and the timeliness of pathological reaction are three key factors for revealing the biochemical basis of disease with untargeted metabolomics. In this study, firstly, the allergic rats (responders) were first screened by passive cutaneous anaphylaxis experiment and then were utilized for modeling. To cover a wider range of metabolites, a large-scale untargeted metabolomics based on metabolites polarity-oriented analysis was performed using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, to evaluate the timeliness of QKLI-IA, a time-dependent metabolomic profiling including the early, mid and late anaphylaxis stages of QKLI-IA, was performed. RESULTS: Corresponding to early, mid and late anaphylaxis stages of QKLI-IA, 14, 9 and 4 potential biomarkers were identified, respectively. Metabolism pathway analysis revealed that QKLI-IA resulted in dynamic changes in serum amino acid, fatty acid, glycerolipid, and phospholipid metabolisms. Twenty-four metabolites were found with identical fluctuating trends across the three stages of QKLI-IA. The results indicate that the pathogenesis of QKLI-IA is closely related to arachidonic acid metabolism. CONCLUSION: This research provides a methodology reference for revealing the biochemical basis of disease using metabolomic profiling and offers a new insight to understand the pathogenesis of QKLI-IA. PMID- 30009976 TI - Wound healing and anti-inflammatory activities induced by a Plantago australis hydroethanolic extract standardized in verbascoside. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Plantago australis is a popular plant found to be widely spread in Latin America. In folk medicine, the seeds and leaves are used mainly for anti-inflammatory, wound healing, among others. The verbascoside, a phenolic glycoside, is an active chemical component described in this species of plant, which has antioxidant, anti-inflammatory and healing effects. PURPOSE: The aim of the present study was to evaluate whether P. australis hydroethanolic extract (PAHE) standardized in verbascoside could promote wound healing associated with anti-inflammatory action within both in vitro and in vivo models. METHODS: For the wound healing activity, we used a Scratch Test, an assay capable of evaluating the migratory ability of keratinocyte cells (HaCat) in vitro and thereby confirming the activity in rats. For the anti-inflammatory activity, the inflammation was induced with LPS in microglial murine cells (N9). Inflammatory mediators (IL-6, IL-10, IL-12p70, INFgamma, MCP-1 and TNFalpha) were measured and the activity of superoxide dismutase (SOD), catalase (CAT), and mitochondrial membrane potential were evaluated. In addition, using paw edema induced by carrageenan in rats, the anti-inflammatory activity in vivo was analyzed. RESULTS: The PAHE and verbascoside, induced a significant increase in migration of keratinocytes, at all concentrations tested when compared to the negative control. The wound healing activity in vivo showed that the PAHE accelerated the process. The treatments with PAHE and verbascoside induce increases in the antioxidants enzymes, suggesting a possible activation of these enzymes. However, this did not result in an increase in the expression of inflammatory mediators in microglial cells. In LPS activated cells the verbascoside displayed a significant reduction of TNFalpha, IL-6, IL-12p70, MCP-1 and INFgamma, while the PAHE only displayed statistically significant reduction in TNFalpha. Interestingly, both the compounds could reduce the oxidative parameters in N9 cells activated by LPS. Additionally, pretreatment with PAHE inhibited the paw edema in rats. CONCLUSION: The results suggest that PAHE has wound healing activity, improving cells migration and, as well as was able to reverse the oxidation effect in LPS activated N9 cells. The wound-healing and anti-inflammatory activities of PAHE were confirmed in vivo. In addition, the presence of verbascoside can be related to PAHE effects, since this compound was capable of increase keratinocytes migration and inhibiting inflammation mediators. PMID- 30009977 TI - Mechanisms underlying vasorelaxation induced in the porcine coronary arteries by Thymus linearis, Benth. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Thymus linearis, Benth indigenous to Pakistan has been traditionally used for the treatment of various diseases including hypertension. AIM OF THE STUDY: Present study aims to investigate vasorelaxant effect of Thymus linearis and its underlying vasorelaxation mechanisms in porcine coronary artery rings. MATERIALS AND METHODS: Aqueous-methanolic extract of aerial parts of Thymus linearis was prepared by maceration process and then bio guided fractionation was carried out using different solvents. The effects of extract and subsequent fractions were assessed on coronary artery rings with intact and denuded endothelium. The mechanisms of vasorelaxant effect were investigated using different pharmacological tools. The in-vitro inhibitory effects of the test fractions were also assessed on purified phophodiestrases using radioenzymatic assay. Phytochemical studies were carried out using GCMS. RESULTS: The aqueous-methanolic extract elicited similar relaxations in coronary artery rings with and without endothelium in dose dependent fashion and removal of endothelium did not alter this response. Further, n-butanolic fraction of Thymus liniaris (TLB) was found to be the most potent among other derived fractions. TLB did not alter the relaxation produced by endothelium dependent vasodilators in rings with intact endothelium. However, TLB significantly potentiated the relaxation elicited by cyclic AMP and cyclic GMP elevating drugs but not those to soluble guanylyl cyclase activators (YC-1 and BAY 41-2272) and K+ channel openers (levcromakalim and 1-EBIO). Pretreatment with TLB inhibited in a concentration-dependent manner contractions to KCl, CaCl2 and U46619 in coronary artery rings without endothelium. Further, TLB was found to non selectively inhibit the PDE activity in concentration manner. CONCLUSION: n Butanolic fraction of Thymus linearis possesses endothelium independent vasorelaxant effects in coronary artery by direct acting on the smooth muscles. These effects involve the elevation of the cyclic AMP and cyclic GMP possibly through the inhibition of various PDEs. GCMS analysis revel presence of thymole and carvacrol as major constituents. Furthermore, these investigations also support the folklore use of Thymus linearis in hypertension. PMID- 30009978 TI - Effects of Dangguisusan, a prescription of Korean medicine on controlled cortical impact-induced traumatic brain injury mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dangguisusan (DGSS) is a widely used prescription for the treatment of traumatic injury in Korean medicine. AIM OF THE STUDY: To demonstrate the effects of DGSS on a mouse model of traumatic brain injury (TBI) for providing scientific evidence in clinical use. MATERIALS AND METHODS: TBI was induced in a mouse model using the controlled cortical impact method. Water extract of DGSS (50, 150, and 450 mg/kg) was administered twice a day for 8 d. Histological analyses were performed 8 d after TBI. Moreover, beam-walking, grip strength, and novel object recognition (NOR) tests were conducted to evaluate the effects on motor function, muscle strength, and cognitive memory function, respectively. RESULT: DGSS inhibited body weight loss, hippocampal damage, and neuronal loss in the thalamic region. Furthermore, it reduced transverse time and foot faults in the beam-walking test at 3 d and increased the muscle strength in the grip-strength test at 3 and 8 d. It also improved the recognition index (%) in the NOR test. However, DGSS did not show protective effects against total damage. CONCLUSIONS: DGSS might improve sensory-motor and cognitive functions after TBI with partial protective effects against brain damage. The present findings provide a scientific basis for the clinical use of DGSS in TBI. PMID- 30009979 TI - Neuroprotective effect of Asparagus racemosus root extract via the enhancement of brain-derived neurotrophic factor and estrogen receptor in ovariectomized rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Asparagus racemosus (AR) is well known as an Ayurvedic rasayana which used traditionally by Ayurvedic practitioners for nervous disorders and prevent aging. In our previous study it was found that ethanol AR root extract can improve learning and memory impairment, induced by an ovariectomy, but the extract's mechanisms as a neuroprotective property are still unknown. AIM OF THE STUDY: This study aimed to examine the effects and mechanisms of ethanol AR root extract on the alteration of brain-derived neurotrophic factor (BDNF) and estrogen receptor (ER) subtypes in ovariectomized (OVX) rats. MATERIALS AND METHODS: Adult female Wistar rats were divided into five groups, 4 groups underwent ovariectomy, and one group was designed to be the sham control group. Two groups were gavaged with propylene glycol for sham, and a second group similarly prepared for OVX. Two further groups of OVX rats were gavaged once daily, one group with 100 mg/kg b.w. of ethanol AR root extract and the second group with 1000 mg/kg b.w. of ethanol AR root extract. The fifth group was gavaged once daily with 0.1 mg/kg b.w. of 17alpha-ethynylestradiol (EE). BDNF, ERalpha and ERbeta expression were evaluated by western blot analysis. RESULTS: The western blot analysis revealed that the OVX rats showed a significant decrease in BDNF and a down-regulation of ERalpha and ERbeta in the frontal cortex and hippocampus. It was also demonstrated that EE and AR root extract increased BDNF, ERalpha and ERbeta in the frontal cortex and hippocampus of ovariectomized rats. CONCLUSIONS: Based on these results, the enhancement of BDNF and ERs up-regulation may be involved in the neuroprotective effects of ethanol AR root extract in ovariectomized rat. PMID- 30009980 TI - Reduced-Intensity Conditioning and Dual T Lymphocyte Suppression with Antithymocyte Globulin and Post-Transplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Haploidentical Hematopoietic Stem Cell Transplants for Hematological Malignancies. AB - Haploidentical hematopoietic stem cell transplantation (haploHSCT) with conditioning regimens using post-transplant cyclophosphamide (PTCy) for peripheral blood stem cell (PBSC) grafts is limited by comparably higher rates of acute and chronic graft-versus-host disease (GVHD). Antithymocyte globulin (ATG) may mitigate this risk. We evaluated haploHSCT after reduced-intensity conditioning (RIC) with ATG, PTCy, and cyclosporine to prevent rejection and GVHD. Fifty adults underwent haploHSCT from August 2016 to February 2018. RIC included fludarabine (30 mg/m2/day on days -5 to -2), busulfan (3.2 mg/m2/day on days -3 and -2), and total body irradiation (200 cGy) on day -1. Unmanipulated PBSCs were infused on day 0. GVHD prophylaxis included ATG (4.5 mg/kg over days 3 to -1), PTCy (50 mg/kg/day on days +3 and +4), and cyclosporine from day +5. Median age was 56 years (range, 22 to 70 years); 25 (73.5%) patients were in first complete remission (CR1), 5 (14.7%) were in second complete remission (CR2), and 8 (23.5%) had active disease. Median time to neutrophil engraftment was 16 days (range, 8 to 43 days). At day +100, the cumulative incidence of acute GVHD of any grade, and grades III to IV was 38.3% and 5.2%, respectively. Mild chronic GVHD was seen in 15.5%. Cytomegalovirus (CMV) reactivation occurred in 37 (74%) cases and CMV disease occurred in 4 (11.5%) cases. Epstein-Barr virus (EBV) reactivation occurred in 21 (61.8%) patients. The incidence of histologically confirmed post-transplantation lymphoproliferative disorder (PTLD) was 5.8%. Four patients received rituximab. There were no CMV, EBV, or PTLD-related deaths. Six month and 1-year overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were 73.9%, 10.2%, and 19.4%, respectively, and 48.1%, 16% and 38.2%, respectively. Infection was the most common cause of death (18%). Unmanipulated haploidentical PBSC transplantation following RIC with ATG, PTCy, and cyclosporine as a GVHD prevention strategy results in low rates of acute and chronic GVHD. PMID- 30009981 TI - Reduced Relapse Incidence with FLAMSA-RIC Compared with Busulfan/Fludarabine for Acute Myelogenous Leukemia Patients in First or Second Complete Remission: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. AB - Busulfan/fludarabine (BuFlu) is a widely used conditioning regimen for patients with myeloid malignancies. The sequential FLAMSA (fludarabine + Ara-C + amsacrine chemotherapy) protocol followed by either cyclophosphamide and total body irradiation (FLAMSA-TBI) or cyclophosphamide and busulfan (FLAMSA-Bu) has shown remarkable activity in high-risk acute myelogenous leukemia (AML) patients. Here we compare the outcomes of AML patients transplanted in first complete remission (CR1) or second complete remission (CR2) after conditioning with BuFlu or FLAMSA. Eligible patients had their first allogeneic stem cell transplantation for AML in CR1 or CR2 between January 2005 and June 2016. Donors were matched related or unrelated with up to 1 mismatch. Conditioning consisted of either BuFlu or FLAMSA. Propensity score matching was applied and comparisons were performed using weighted Cox regression. BuFlu conditioning was used in 1197 patients, whereas FLAMSA-TBI and FLAMSA-Bu were used in 258 and 141 patients, respectively. Median follow-up of survivors was 24.72 months. In univariate analysis, relapse incidence (RI) was 30.3%, 21.9%, and 23.1% in the BuFlu, FLAMSA-TBI, and FLAMSA Bu groups, respectively (P < .01), and nonrelapse mortality at 2 years was 16.1%, 16.4%, and 26.7%, respectively (P < .01). Leukemia-free survival (LFS) at 2 years was 53.6%, 61.6%, and 50.1%, respectively (P = .03). Weighted Cox regression revealed that FLAMSA-TBI compared with BuFlu was associated with lower RI (hazard ratio [HR], .64; 95% confidence interval [CI], .42 to .98; P = .04) and a trend for better LFS (HR, .72; 95% CI, .49 to 1.06; P = .09). These results suggest that compared with BuFlu, conditioning with FLAMSA-TBI leads to reduced RI at 2 years in AML patients transplanted in CR1 or CR2. PMID- 30009982 TI - Initial High Viral Load Is Associated with Prolonged Shedding of Human Rhinovirus in Allogeneic Hematopoietic Cell Transplant Recipients. AB - Recent data suggest human rhinovirus (HRV) is associated with lower respiratory tract infection and mortality in hematopoietic cell transplant (HCT) recipients. Examining risk factors for prolonged viral shedding may provide critical insight for the development of novel therapeutics and help inform infection prevention practices. Our objective was to identify risk factors for prolonged shedding of HRV post-HCT. We prospectively collected weekly nasal samples from allogeneic HCT recipients from day 0 to day 100 post-transplant, and performed real-time reverse transcriptase PCR (December 2005 to February 2010). Subjects with symptomatic HRV infection and a negative test within 2 weeks of the last positive were included. Duration of shedding was defined as time between the first positive and first negative samples. Cycle threshold (Ct) values were used as a proxy for viral load. HRV species were identified by sequencing the 5' noncoding region. Logistic regression analyses were performed to evaluate factors associated with prolonged shedding (>=21 days). We identified 38 HCT recipients with HRV infection fulfilling study criteria (32 adults, 6 children). Median duration of shedding was 9.5 days (range, 2 to 89 days); 18 patients had prolonged shedding. Among 26 samples sequenced, 69% were species A, and species B and C accounted for 15% each; the median shedding duration of HRV did not differ among species (P = .17). Bivariable logistic regression analyses suggest that initial high viral load (low Ct value) is associated with prolonged shedding. HCT recipients with initial high viral loads are at risk for prolonged HRV viral shedding. PMID- 30009984 TI - Polysorbate 20 non-ionic surfactant enhances retinal gene delivery efficiency of cationic niosomes after intravitreal and subretinal administration. AB - The success of non-viral vectors based on cationic niosomes for retinal gene delivery applications depends on the ability to achieve persistent and high levels of transgene expression, ideally from a single administration. In this work, we studied the effect of the non-ionic surfactant component of niosomes in their transfection efficiency in rat retina. For that purpose, three niosome formulations that only differed in the non-ionic tensioactives were elaborated. Niosomes contained: cationic lipid 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), helper lipid squalene and polysorbate 20, polysorbate 80 or polysorbate 85. Niosomes and corresponding nioplexes were fully characterized in terms of size, polydispersity index, zeta potential, morphology and ability to protect and release DNA. In vitro experiments were carried out to evaluate transfection efficiency, cell viability and intracellular trafficking pathways of the formulations. Nioplexes based on polysorbate 20 niosomes were the most efficient transfecting retinal cells in vitro. Moreover, subretinal and intravitreal administration of those nioplexes in vivo showed also high levels of transgene expression in rat retinas. Our results demonstrate that the incorporation of polysorbate 20 in cationic niosomes enhances retinal gene delivery. Thus, this formulation emerges as a potential non-viral candidate to efficiently transfer specific therapeutic genes into the eye for biomedical purposes. PMID- 30009983 TI - Microfluidic-assisted nanoprecipitation of (PEGylated) poly (d,l-lactic acid-co caprolactone): Effect of macromolecular and microfluidic parameters on particle size and paclitaxel encapsulation. AB - In this work we evaluate the effect of polymer composition and architecture of (PEGylated) polyesters on particle size and paclitaxel (PTX) loading for particles manufactured via microfluidic-assisted, continuous-flow nanoprecipitation using two microfluidic chips with different geometries and mixing principles. We have prepared poly (d,l-lactic acid-co-caprolactone) (PLCL) from ring-opening polymerization (ROP) of LA and CL mixtures and different (macro) initiators (namely, 1-dodecanol, a MeO-PEG-OH, and a 4-armed star PEG OH), rendering polyesters that vary in monomer composition (i.e. LA/CL ratios) and architecture (i.e. linear vs 4-armed star). Continuous-flow nanoprecipitation was assayed using two microfluidic chips: a cross-flow chip with a X-shaped mixing junction (2D laminar flow focusing) and a micromixer featuring a Y-shaped mixing junction and a split and recombine path (2D laminar flow focusing convinced with stream lamination for faster mixing). Nanoparticle formulations were produced with Z-average sizes in the range of 30-160 nm, although size selectivity could be seen for different polymer/chip combinations; for instance, smaller particles were obtained with Y-shaped micromixer (30-120 nm), specially for the PEGylated polyesters (30-50 nm), whereas the cross-flow chip systematically produced larger particles (80-160 nm). Loading of the anti-cancer drug paclitaxel (PTX) was also heavily influenced not only by the nature of the polyester, but also by the geometry of the microfluidic chip; higher drug loadings were obtained with the cross-flow reactor and the star block copolymers. Finally, decreasing the LA/CL ratio generally had a positive effect on drug loading. PMID- 30009985 TI - Novel salts of dipicolinic acid as viscosity modifiers for high concentration antibody solutions. AB - Concentrated monoclonal antibody (mAb) solutions can lead to high viscosity as a result of protein-protein interactions and pose challenges for manufacture. Dipicolinic acid (DPA, pyridine-2,6-dicarboxylic acid) is a potential excipient for reduction of protein solution viscosity and here we describe new DPA salts with improved aqueous solubility. Crystallinity and solubility screens identified ethanolamine and diethanolamine as two promising counterions which generated crystalline, high melting point, anhydrous salt forms of DPA at 2:1 M stoichiometry. These salts significantly reduced the solution viscosity of five mAbs, equal to or better than that for the addition of arginine hydrochloride at equivalent osmolality. The presence of the DPA salts in solution did not significantly perturb the melting point of the mAbs, as determined by calorimetry, indicating an absence of any destabilization of protein conformation. Addition of the DPA salts to the mAb solutions stored at 5 degrees C over 6 months did not cause additional loss of the monomer fraction, though evidence of increased aggregation and fragmentation for three of the five mAbs was observed during 40 degrees C (accelerated and stressed) storage. Overall, this study demonstrates that ethanolamine-DPA and diethanolamine-DPA can serve as two novel excipients for viscosity reduction and could be considered by formulation scientists when developing highly concentrated mAb formulations. PMID- 30009986 TI - Proteogenomic analysis of Mycobacterium tuberculosis Beijing B0/W148 cluster strains. AB - : Nowadays proteomics is one of the major instruments for editing and correcting annotation of genomic information. The correct genome annotation is necessary for omics studies of clinically relevant pathogens like Mycobacterium tuberculosis as well as for the progress in drug design and in silico biology. Here, we focused on the proteogenomic analysis of W-148 strain belonging to the Beijing B0/W148 cluster. This cluster, also known as a "successful" clone possesses unique pathogenic properties and has a unique genome organization. Taking into account high similarity of cluster strains at the genomic level we analyzed MS/MS dataset obtained for 63 clinical isolates of Beijing B0/W148. Based on H37Rv and W-148 annotations we identified 2546 proteins representing more than 60% of total proteome. A set of peptides (n = 404) specific for W-148 was found when compared with H37Rv. Start sites for 32 genes were corrected based on the combination of LC-MS/MS proteomic data with genomic six-frame translation. Additionally, we have shown the presence of peptides related to 10 genes earlier known as "pseudogenes". SIGNIFICANCE: Mycobacterium tuberculosis is one of the most dangerous pathogens. Phylogenetically, it may be divided into major lineages and among them, lineage 2 (predominantly Beijing genotype) one of the most successful lineages with an increasing prevalence in the global population. At the same time, strains of the Beijing B0/W148 cluster, a "successful" clone of Mycobacterium tuberculosis possess even more interesting features. Only one complete genome of this cluster, W-148, present in the NCBI database (CP012090.1) and it demonstrates a number of significant differences from the well-known reference genome H37Rv. For the W-148 strain many genes are annotated as "pseudo" and no attempts were made to correct this. Thereby, in this study, we have conducted a proteomic analysis of the cluster strains and corrected current genome annotation. We hope that the data obtained will help to increase the quality of identifications in proteomic and transcriptomic analysis of M. tuberculosis Beijing B0/W148 cluster strain in subsequent studies. PMID- 30009989 TI - Sensitization to amoxicillin/clavulanic acid may underlie severe rashes in children treated for infectious mononucleosis. PMID- 30009987 TI - Developmental expression of the zebrafish Arf-like small GTPase paralogs arl13a and arl13b. AB - Members of the Arf-like (Arl) family of small GTP-binding proteins regulate a number of cellular functions and play important roles in cilia structure and signaling. The small GTPase Arl13a is a close paralog to Arl13b, a small GTPase required for normal cilia formation that causes Joubert Syndrome when mutated. As mutation of arl13b causes a slow retinal degeneration in zebrafish (Song et al., 2016), we hypothesized that expression of arl13a may provide functional redundancy. We determined the expression domains of arl13a and arl13b during zebrafish development and examined subcellular localization by expression of fluorescence fusion proteins. Both genes are widely expressed during early cell division and gastrulation and Arl13a and Arl13b both localize to microtubules in ciliated and dividing cells of the early zebrafish embryo. Between 2 and 5 days post fertilization (dpf), arl13b is expressed in neural tissues while expression of arl13a is downregulated by 2 dpf and restricted to craniofacial structures. These results indicate that arl13a and arl13b have evolved different roles and that arl13a does not function in the zebrafish retina. PMID- 30009988 TI - Provocation Tests in Nonimmediate Hypersensitivity Reactions to beta-Lactam Antibiotics in Children: Are Extended Challenges Needed? AB - BACKGROUND: beta-Lactam antibiotics are the most common trigger of reactions in children with most of them being nonimmediate (85.5%), but proven allergy after the allergological workup is between 7% and 10%. There is no agreement on how to perform the provocation tests in these types of hypersensitivity reactions. OBJECTIVE: To determine whether or not repeated doses of the beta-lactams are required to reproduce a nonimmediate reaction in children. METHODS: This is a retrospective observational study. We included children under 14 years who were referred for a nonimmediate reaction to beta-lactams. All patients underwent a 1 day hospital provocation and were kept under observation at home during the following days for at least the time elapsed between the first dose and the symptoms of the index reaction. If no reaction was triggered, the patient resumed the provocation at home with 2 daily therapeutic doses for an equal of interval time. RESULTS: Ninety-seven patients were included in the study. A positive reaction was recorded in 14 of them (14.4%). The short hospital provocation triggered 3 immediate reactions and 8 delayed reactions. The home rechallenge developed 1 immediate reaction and 2 delayed reactions. CONCLUSIONS: Nonimmediate reactions to beta-lactams in children may be triggered with a 1-day provocation test. We suggest to perform a 1-day provocation test followed by an observational period of at least the time interval of the index reaction. If this challenge is negative, an extended home provocation could subsequently be carried out. PMID- 30009990 TI - Classification of ADHD with bi-objective optimization. AB - Attention Deficit Hyperactive Disorder (ADHD) is one of the most common diseases in school aged children. In this paper, we consider using fMRI data with classification techniques to aid the diagnosis of ADHD and propose a bi-objective ADHD classification scheme based on L1-norm support vector machine (SVM). In our classification model, two objectives, namely, the margin of separation and the empirical error are considered at the same time. Then the normal boundary intersection (NBI) method of Das and Dennis is used to solve the bi-objective optimization problem. A representative nondominated set which reflects the entire trade-off information between the two objectives is obtained. Each representative nondominated point in the set corresponds to an efficient classifier. Finally a decision maker can choose a final efficient classifier from the set according to the performance of each classifier. Our scheme avoids the trial and error process for regularization hyper-parameter selection. Experimental results show that our bi-objective optimization classification scheme for ADHD diagnosis performs considerably better than some traditional classification methods. PMID- 30009991 TI - A scalable method for supporting multiple patient cohort discovery projects using i2b2. AB - Although i2b2, a popular platform for patient cohort discovery using electronic health record (EHR) data, can support multiple projects specific to individual disease areas or research interests, the standard approach for doing so duplicates data across projects, requiring additional disk space and processing time, which limits scalability. To address this deficiency, we developed a novel approach that stored data in a single i2b2 fact table and used structured query language (SQL) views to access data for specific projects. Compared to the standard approach, the view-based approach reduced required disk space by 59% and extract-transfer-load (ETL) time by 46%, without substantially impacting query performance. The view-based approach has enabled scalability of multiple i2b2 projects and generalized to another data model at our institution. Other institutions may benefit from this approach, code of which is available on GitHub (https://github.com/wcmc-research-informatics/super-i2b2). PMID- 30009992 TI - Author's Reply. PMID- 30009993 TI - The role of the hypothalamus in modulation of respiration. AB - The hypothalamus is a higher center of the autonomic nervous system and maintains essential body homeostasis including respiration. The paraventricular nucleus, perifornical area, dorsomedial hypothalamus, and lateral and posterior hypothalamus are the primary nuclei of the hypothalamus critically involved in respiratory control. These hypothalamic nuclei are interconnected with respiratory nuclei located in the midbrain, pons, medulla and spinal cord. We provide an extensive review of the role of the above hypothalamic nuclei in the maintenance of basal ventilation, and modulation of respiration in hypoxic and hypercapnic conditions, during dynamic exercise, in awake and sleep states, and under stress. Dysfunction of the hypothalamus causes abnormal breathing and hypoventilation. However, the cellular and molecular mechanisms how the hypothalamus integrates and modulates autonomic and respiratory functions remain to be elucidated. PMID- 30009994 TI - Seasonal variation in travel health information seeking. PMID- 30009995 TI - More fish-happier mom, smarter child? PMID- 30009996 TI - Probiotics for the treatment of depressive symptoms: An anti-inflammatory mechanism? AB - During the past decade, there has been renewed interest in the relationship between brain-based disorders, the gut microbiota, and the possible beneficial effects of probiotics. Emerging evidence suggests that modifying the composition of the gut microbiota via probiotic supplementation may be a viable adjuvant treatment option for individuals with major depressive disorder (MDD). Convergent evidence indicates that persistent low-grade inflammatory activation is associated with the diagnosis of MDD as well as the severity of depressive symptoms and probability of treatment response. The objectives of this review are to (1) evaluate the evidence supporting an anti-inflammatory effect of probiotics and (2) describe immune system modulation as a potential mechanism for the therapeutic effects of probiotics in populations with MDD. A narrative review of studies investigating the effects of probiotics on systemic inflammation was conducted. Studies were identified using PubMed/Medline, Google Scholar, and clinicaltrials.gov (from inception to November 2017) using the following search terms (and/or variants): probiotic, inflammation, gut microbiota, and depression. The available evidence suggests that probiotics should be considered a promising adjuvant treatment to reduce the inflammatory activation commonly found in MDD. Several controversial points remain to be addressed including the role of leaky gut, the role of stress exposure, and the role of blood-brain-barrier permeability. Taken together, the results of this review suggest that probiotics may be a potentially beneficial, but insufficiently studied, antidepressant treatment intervention. PMID- 30009997 TI - Can neuroimmune mechanisms explain the link between ultraviolet light (UV) exposure and addictive behavior? AB - High ultraviolet (UV) light exposure on the skin acts as a reinforcing stimulus, increasing sun-seeking behavior and even addiction-like sun seeking behavior. However, the physiological mechanisms that underlie this process remain to be defined. Here, we propose a novel hypothesis that neuroimmune signaling, arising from inflammatory responses in UV-damaged skin cells, causes potentiated signaling within the cortico-mesolimbic pathway, leading to increased sun-seeking behaviors. This hypothesized UV-induced, skin-to-brain signaling depends upon cell stress signals, termed alarmins, reaching the circulation, thereby triggering the activation of innate immune receptors, such as toll-like receptors (TLRs). This innate immune response is hypothesized to occur both peripherally and centrally, with the downstream signaling from TLR activation affecting both the endogenous opioid system and the mesolimbic dopamine pathway. As both neurotransmitter systems play a key role in the development of addiction behaviors through their actions at key brain regions, such as the nucleus accumbens (NAc), we hypothesize a novel connection between UV-induced inflammation and the activation of pathways that contribute to the development of addiction. This paper is a review of the existing literature to examine the evidence which suggests that chronic sun tanning resembles a behavioral addiction and proposes a novel pathway by which persistent sun-seeking behavior could affect brain neurochemistry in a manner similar to that of repeated drug use. PMID- 30009998 TI - Acylated ghrelin suppresses the cytokine response to lipopolysaccharide and does so independently of the hypothalamic-pituitary-adrenal axis. AB - Ghrelin, one of the major metabolic hormones involved in controlling energy balance, has recently been shown to have other properties including regulating the hypothalamic-pituitary-adrenal (HPA) axis response to psychological stress and being a potent anti-inflammatory agent. Ghrelin's HPA axis and anti inflammatory actions have previously been identified as principally due to the acylated form (AG). However, our recent work has also suggested a role for des acylated ghrelin (DAG) in these functions. Here we hypothesized ghrelin's anti inflammatory activity is mediated by the HPA axis and this effect is differentially executed by AG and DAG. We gave adult male Wistar rats a concomitant injection of AG or DAG and lipopolysaccharide (LPS) and measured their effects on circulating cytokines, stress hormones and neuronal activation of the paraventricular nucleus of the hypothalamus (PVN). AG, but not DAG significantly suppressed the pro- and anti-inflammatory cytokine response induced by LPS in vivo. DAG also had no effects on any components of the HPA axis. AG, despite stimulating neuronal activation in the PVN in vivo and stimulating ACTH release from the pituitary in vitro, did not affect the HPA axis response to LPS. These findings suggest AG's anti-inflammatory effects are independent of its actions on the HPA axis and have implications for the potential use of this peptide for treatment of inflammatory conditions without compromising HPA axis activity. PMID- 30010000 TI - Nano-topography: Quicksand for cell cycle progression? AB - The 3-D spatial and mechanical features of nano-topography can create alternative environments, which influence cellular response. In this paper, murine fibroblast cells were grown on surfaces characterized by protruding nanotubes. Cells cultured on such nano-structured surface exhibit stronger cellular adhesion compared to control groups, but despite the fact that stronger adhesion is generally believed to promote cell cycle progression, the time cells spend in G1 phase is doubled. This apparent contradiction is solved by confocal microscopy analysis, which shows that the nano-topography inhibits actin stress fiber formation. In turn, this impairs RhoA activation, which is required to suppress the inhibition of cell cycle progression imposed by p21/p27. This finding suggests that the generation of stress fibers, required to impose the homeostatic intracellular tension, rather than cell adhesion/spreading is the limiting factor for cell cycle progression. Indeed, nano-topography could represent a unique tool to inhibit proliferation in adherent well-spread cells. PMID- 30010001 TI - D159 and S167 are protective residues in the prion protein from dog and horse, two prion-resistant animals. AB - Prion diseases are fatal neurodegenerative diseases caused by misfolding of the prion protein (PrP). These conditions affect humans and animals, including endemic forms in sheep and deer. Bovine, rodents, and many zoo mammals also developed prion diseases during the "mad-cow" epidemic in the 1980's. Interestingly, rabbits, horses, and dogs show unusual resistance to prion diseases, suggesting that specific sequence changes in the corresponding endogenous PrP prevents the accumulation of pathogenic conformations. In vitro misfolding assays and structural studies have identified S174, S167, and D159 as the key residues mediating the stability of rabbit, horse, and dog PrP, respectively. Here, we expressed the WT forms of rabbit, horse, and dog PrP in transgenic Drosophila and found that none of them is toxic. Replacing these key residues with the corresponding amino acids in hamster PrP showed that mutant horse (S167D) and dog (D159N) PrP are highly toxic, whereas mutant rabbit (S174 N) PrP is not. These results confirm the impact of S167 and D159 in local and long-range structural features in the globular domain of PrP that increase its stability, while suggesting the role of additional residues in the stability of rabbit PrP. Identifying these protective amino acids and the structural features that stabilize PrP can contribute to advance the field towards the development of therapies that halt or reverse the devastating effects of prion diseases. PMID- 30010003 TI - Astrocyte-derived Jagged-1 mitigates deleterious Notch signaling in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset devastating degenerative disease mainly affecting motor neurons. Motor neuron degeneration is accompanied and aggravated by oligodendroglial pathology and the presence of reactive astrocytes and microglia. We studied the role of the Notch signaling pathway in ALS, as it is implicated in several processes that may contribute to this disease, including axonal retraction, microgliosis, astrocytosis, oligodendrocyte precursor cell proliferation and differentiation, and cell death. We observed abnormal activation of the Notch signaling pathway in the spinal cord of SOD1G93A mice, a well-established model for ALS, as well as in the spinal cord of patients with sporadic ALS (sALS). This increased activation was particularly evident in reactive GFAP-positive astrocytes. In addition, one of the main Notch ligands, Jagged-1, was ectopically expressed in reactive astrocytes in spinal cord from ALS mice and patients, but absent in resting astrocytes. Astrocyte-specific inactivation of Jagged-1 in presymptomatic SOD1G93A mice further exacerbated the activation of the Notch signaling pathway and aggravated the course of the disease in these animals without affecting disease onset. These data suggest that aberrant Notch signaling activation contributes to the pathogenesis of ALS, both in sALS patients and SOD1G93A mice, and that it is mitigated in part by the upregulation of astrocytic Jagged-1. PMID- 30010002 TI - Activation of cyclin D1 affects mitochondrial mass following traumatic brain injury. AB - Cell cycle activation has been associated with varying types of neurological disorders including brain injury. Cyclin D1 is a critical modulator of cell cycle activation and upregulation of Cyclin D1 in neurons contributes to the pathology associated with traumatic brain injury (TBI). Mitochondrial mass is a critical factor to maintain the mitochondrial function, and it can be regulated by different signaling cascades and transcription factors including NRF1. However, the underlying mechanism of how TBI leads to impairment of mitochondrial mass following TBI remains obscure. Our results indicate that augmentation of CyclinD1 attenuates mitochondrial mass formation following TBI. To elucidate the molecular mechanism, we found that Cyclin D1 interacts with a transcription factor NRF1 in the nucleus and prevents NRF1's interaction with p300 in the pericontusional cortex following TBI. As a result, the acetylation level of NRF1 was decreased, and its transcriptional activity was attenuated. This event leads to a loss of mitochondrial mass in the pericontusional cortex following TBI. Intranasal delivery of Cyclin D1 RNAi immediately after TBI rescues transcriptional activation of NRF1 and recovers mitochondrial mass after TBI. PMID- 30010004 TI - Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. AB - BACKGROUND: Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment. METHODS: Hypertensive male rats (n = 13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n = 5). RESULTS: Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic resonance imaging to assess structural brain damage, we found compromised gray (dorsolateral cortex: p = .018) and white matter (corpus callosum: p = .016; external capsule: p = .049) structural integrity, reduced cerebral blood flow (dorsolateral cortex: p = .005; hippocampus: p < .001; corpus callosum: p = .001; external capsule: p < .001) and a significant drop in cortical oxygen levels (p < .05). Consistently, we found reduced oxygen carrying neuronal neuroglobin (p = .008), suggestive of chronic cerebral hypoperfusion in high salt-fed rats. We also observed a corresponding increase in free radicals (NADPH oxidase: p = .013), p-Tau (pThr231) in dorsolateral cortex (p = .011) and hippocampus (p = .003), active interleukin 1beta (p < .001) and neurodegeneration (dorsolateral cortex: p = .043, hippocampus: p = .044). Human patients with subcortical ischemic vascular disease, a type of vascular dementia (n = 38; mean age = 68; male/female ratio = 23/15) showed reduced hippocampal volumes and cortical shrinking (p < .05) consistent with the neuronal cell death observed in our hypertensive rat model as compared to healthy controls (n = 47; mean age = 63; male/female ratio = 18/29). CONCLUSIONS: Our data support an association between hypertension-induced vascular dysfunction and the sporadic occurrence of phosphorylated tau and cell death in the rat model, correlating with patient brain atrophy, which is relevant to vascular disease. PMID- 30009999 TI - Stress and aging act through common mechanisms to elicit neuroinflammatory priming. AB - Over the course of an animal's lifespan, there is a protracted breakdown in basic homeostatic functions. Stressors (both psychological and physiological) can accelerate this process and compromise multiple homeostatic mechanisms. For example, both stress and aging can modulate neuroinflammatory function and cause a primed phenotype resulting in a heightened neuroinflammatory profile upon immune activation. Microglia, the brain's resident myeloid cell, produce "silent" immune machinery in response to stress and aging that does not cause immediate immune activation; rather, these changes prime the cell for a subsequent immune insult. Primed microglia exhibit a hyperinflammatory response upon immune activation that can exacerbate pathology. In this review, we will explore parallels between stress- and aging-induced neuroinflammatory priming. First, we will provide a background on the basic principles of neuroimmunology. Next, we will discuss evidence that neuroinflammatory responses become primed in the context of both stress and aging. We will also describe cell-specific contributions to neuroinflammatory priming with a focus on microglia. Finally, common mechanisms underlying priming in the context of stress and aging will be discussed: these mechanisms include glucocorticoid signaling; accumulation of danger signals; dis-inhibition of microglia; and breakdown of circadian rhythms. Overall, there are multifarious parallels between stress- and aging-elicited neuroinflammatory priming, suggesting that stress may promote a form of premature aging. Further unravelling mechanisms underlying priming could lead to improved treatments for buffering against stress- and aging-elicited behavioral pathologies. PMID- 30010005 TI - Placebo hampers ability to self-regulate brain activity: A double-blind sham controlled neurofeedback study. AB - It is still poorly understood how unspecific effects peripheral to the supposed action mechanism of neurofeedback (NF) influence the ability to self-regulate one's own brain signals. Recently, skeptical researchers have even attributed the lion's part of therapeutic outcomes of NF to placebo and other psychosocial factors. Here, we investigated whether and by which mechanisms unspecific factors influence neural self-regulation during NF. To manipulate the impact of unspecific influences on NF performance, we used a sham transcranial direct current stimulation (tDCS) as active placebo intervention suggesting positive effects on NF performance. Our results show that the expectation of receiving brain stimulation, which should boost neural self-regulation, interferes with the ability to self-regulate the sensorimotor rhythm in the EEG. Hence, these results provide evidence that placebo reduces NF performance, and thereby challenge current theories on unspecific effects related to NF. PMID- 30010006 TI - Nonlinear effective connectivity measure based on adaptive Neuro Fuzzy Inference System and Granger Causality. AB - Exploring brain networks is an essential step towards understanding functional organization of the brain, which needs characterization of linear and nonlinear connections based on measurements like EEG or MEG. Conventional measures of connectivity are mostly linear and bivariate. This paper proposes an effective connectivity measure called Adaptive Neuro-Fuzzy Inference System Granger Causality (ANFISGC). The proposed measure is based on the symplectic geometry embedding dimension, Adaptive Neuro-Fuzzy Inference System (ANFIS) predictor, and Granger Causality (GC). It is a powerful predictor that detects both linear and nonlinear causal information flow. It is not bivariate and thus can distinguish between direct and indirect connections. The performance of the proposed method is evaluated and compared with those of the Linear Granger Causality (LGC), Kernel Granger Causality (KGC), combination of Pairwise Granger Causality and Conditional Granger Causality (PwGC + CGC), Transfer Entropy (TE), and Phase Transfer Entropy (PTE) methods using simulated and experimental MEG data. Simulation results show that ANFISGC outperforms the other methods in detecting both linear and nonlinear connections and, by increasing the coupling strength between nodes, the value of ANFISGC increases. In the analysis of the time series of the brain sources of epilepsy patients obtained from the MEG inverse problem, the regions found by ANFISGC were more similar to the clinical findings than those found by the other methods. PMID- 30010007 TI - Neuro-cognitive mechanisms of global Gestalt perception in visual quantification. AB - Recent neuroimaging studies identified posterior regions in the temporal and parietal lobes as neuro-functional correlates of subitizing and global Gestalt perception. Beyond notable overlap on a neuronal level both mechanisms are remarkably similar on a behavioral level representing both a specific form of visual top-down processing where single elements are integrated into a superordinate entity. In the present study, we investigated whether subitizing draws on principles of global Gestalt perception enabling rapid top-down processes of visual quantification. We designed two functional neuroimaging experiments: a task identifying voxels responding to global Gestalt stimuli in posterior temporo-parietal brain regions and a visual quantification task on dot patterns with magnitudes within and outside the subitizing range. We hypothesized that voxels activated in global Gestalt perception should respond stronger to dot patterns within than those outside the subitizing range. The results confirmed this prediction for left-hemispheric posterior temporo-parietal brain areas. Additionally, we trained a classifier with response patterns from global Gestalt perception to predict neural responses of visual quantification. With this approach we were able to classify from TPJ Gestalt ROIs of both hemispheres whether a trial requiring subitizing was processed. The present study demonstrates that mechanisms of subitizing seem to build on processes of high level visual perception. PMID- 30010009 TI - Neurobiology, not artifacts: Challenges and guidelines for imaging the high risk infant. AB - The search for the brain-basis of atypical development in human infants is challenging because the process of imaging and the generation of the MR signal itself relies on assumptions that reflect biophysical properties of the brain tissue. These assumptions are not inviolate, have been questioned by recent empirical evidence from high risk infant-sibling studies, and to date remain largely underexamined at the between-group level. In particular, I consider recent work showing that infants at High vs. Low familial risk (HR vs. LR, respectively) for developing Autism Spectrum Disorders (ASD) have atypical patterns of head movements during an MR scan that are functionally important-they are linked to future learning trajectories in toddlerhood. Addressing head movement issues in neuroimaging analyses in infant research as well as understanding the causes of these movements from a developmental perspective requires acknowledging the complexity of this endeavor. For example, head movement signatures in infants can interact with experimental task conditions (such as listening to language compared to sleeping), autism risk, and age. How can new knowledge about newborns' individual, subject-specific behavioral differences which may impact MR signal acquisition and statistical inference ignite critical thinking for the field of infant brain imaging across the spectrum of typical and atypical development? Early behavioral differences between HR and LR infant cohorts that are often examples of "artifactual" confounds in MR work provide insight into nascent neurobiological differences, including biophysical tissue properties and hemodynamic response variability, in these and related populations at risk for atypical development. Are these neurobiological drivers of atypical development? This work identifies important knowledge gaps and suggests guidelines at the leading edge of baby imaging science to transform our understanding of atypical brain development in humans. The precise study of the neurobiological underpinnings of atypical development in humans calls for approaches including quantitative MRI (qMRI) pulse sequences, multi-modal imaging (including DTI, MRS, as well as MEG), and infant-specific HRF shapes when modeling BOLD signal. PMID- 30010008 TI - On the importance of precise electrode placement for targeted transcranial electric stimulation. AB - Transcranial electric stimulation (TES) is an increasingly popular method for non invasive modulation of brain activity and a potential treatment for neuropsychiatric disorders. However, there are concerns about the reliability of its application because of variability in TES-induced intracranial electric fields across individuals. While realistic computational models offer can help to alleviate these concerns, their direct empirical validation is sparse, and their practical implications are not always clear. In this study, we combine direct intracranial measurements of electric fields generated by TES in surgical epilepsy patients with computational modeling. First, we directly validate the computational models and identify key parameters needed for accurate model predictions. Second, we derive practical guidelines for a reliable application of TES in terms of the precision of electrode placement needed to achieve a desired electric field distribution. Based on our results, we recommend electrode placement accuracy to be < 1 cm for a reliable application of TES across sessions. PMID- 30010010 TI - Improving PET/MR brain quantitation with template-enhanced ZTE. AB - PURPOSE: The impact of MR-based attenuation correction on PET quantitation accuracy is an ongoing cause of concern for advanced brain research with PET/MR. The purpose of this study was to evaluate a new, template-enhanced zero-echo-time attenuation correction method for PET/MR scanners. METHODS: 30 subjects underwent a clinically-indicated 18F-FDG-PET/CT, followed by PET/MR on a GE SIGNA PET/MR. For each patient, a 42-s zero echo time (ZTE) sequence was used to generate two attenuation maps: one with the standard ZTE segmentation-based method; and another with a modification of the method, wherein pre-registered anatomical templates and CT data were used to enhance the segmentation. CT data, was used as gold standard. Reconstructed PET images were qualified visually and quantified in 68 volumes-of-interest using a standardized brain atlas. RESULTS: Attenuation maps were successfully generated in all cases, without manual intervention or parameter tuning. One patient was excluded from the quantitative analysis due to the presence of multiple brain metastases. The PET bias with template-enhanced ZTE attenuation correction was measured to be -0.9% +/- 0.9%, compared with -1.4% +/- 1.1% with regular ZTE attenuation correction. In terms of absolute bias, the new method yielded 1.1% +/- 0.7%, compared with 1.6% +/- 0.9% with regular ZTE. Statistically significant bias reduction was obtained in the frontal region (from -2.0% to -1.0%), temporal (from -1.2% to -0.2%), parietal (from -1.9% to -1.1%), occipital (from -2.0% to -1.1%) and insula (from -1.4% to -1.1%). CONCLUSION: These results indicate that the co-registration of pre-recorded anatomical templates to ZTE data is feasible in clinical practice and can be effectively used to improve the performance of segmentation-based attenuation correction. PMID- 30010011 TI - Selectivity of phospholipid hydrolysis by phospholipase A2 enzymes in activated cells leading to polyunsaturated fatty acid mobilization. AB - Phospholipase A2s are enzymes that hydrolyze the fatty acid at the sn-2 position of the glycerol backbone of membrane glycerophospholipids. Given the asymmetric distribution of fatty acids within phospholipids, where saturated fatty acids tend to be present at the sn-1 position, and polyunsaturated fatty acids such as those of the omega-3 and omega-6 series overwhelmingly localize in the sn-2 position, the phospholipase A2 reaction is of utmost importance as a regulatory checkpoint for the mobilization of these fatty acids and the subsequent synthesis of proinflammatory omega-6-derived eicosanoids on one hand, and omega-3-derived specialized pro-resolving mediators on the other. The great variety of phospholipase A2s, their differential substrate selectivity under a variety of pathophysiological conditions, as well as the different compartmentalization of each enzyme and accessibility to substrate, render this class of enzymes also key to membrane phospholipid remodeling reactions, and the generation of specific lipid mediators not related with canonical metabolites of omega-6 or omega-3 fatty acids. This review highlights novel findings regarding the selective hydrolysis of phospholipids by phospholipase A2s and the influence this may have on the ability of these enzymes to generate distinct lipid mediators with essential functions in biological processes. This brings a new understanding of the cellular roles of these enzymes depending upon activation conditions. PMID- 30010012 TI - DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling. AB - Acute lung injury (ALI) is a common complication of sepsis that often leads to fatal lung disease without effective therapies. It is known that bone marrow derived macrophages are important in resolving the inflammation and maintaining tissue homeostasis. Here, we hypothesize that treatment in combination of DNA methyl transferase inhibitor (DNMTi) 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) mitigates the inflammation induced pyroptosis and apoptosis during endotoxemia induced ALI. To test this hypothesis, the mice challenged with a sublethal dose of LPS followed by one-hour post-treatment with a single dose of Aza and TSA intraperitoneally showed a substantial attenuation of apoptosis and inflammation. Importantly, we observed significant changes in the mitochondrial membrane structure, and lower levels of DNA fragmentation, reduced expression of apoptotic and pyroptotic genes both transcriptionally and translationally in LPS induced BMDMs treated by a combination of Aza and TSA than in LPS-induced BMDMs treated with either drug alone. The protection was mediated by an inhibition of JNK-ERK and STAT3-JMJD3 activated pathways. Thus, targeting these important signaling pathways with the combination of Aza and TSA would be a good treatment modality for ALI. PMID- 30010013 TI - Roles of microRNA in prostate cancer cell metabolism. AB - MicroRNAs are non-coding RNA which functions as regulators of genes expression. MicroRNAs have shown their biological functions in cell proliferation, cell cycle, cell metabolism, apoptosis, invasion and metastasis. Cancer cells have the ability to grow in the absence of growth factors by increased metabolic activity. MicroRNAs regulate cell metabolic processes by targeting the key enzymes or transporters and change the metabolic activities by interfering with oncogenes/tumor suppressors, hypoxia, signalling pathways and cell adhesion. This review mainly explains the roles of microRNAs in prostate cancer cell metabolism, such as glucose uptake, glycolysis and lactate secretion, lipid metabolism and interaction with signalling pathways. The relation of microRNAs with hypoxia and cell adhesion in cell metabolism is also highlighted. Therefore, miRNAs help in regulating the metabolism of survived tumor cells, understanding such miRNA mediated interaction could lead to new avenues in therapeutic application to treat PCa. PMID- 30010014 TI - Functional domains of Litopenaeus vannamei transglutaminase and their involvement in immunoregulation in shrimp. AB - Shrimps, which mainly rely on their innate immune system to response to infectious pathogens, have clottable proteins as an important component of this system. While transglutaminases (TGase) are found in Litopenaeus vannamei and constitute part of the coagulation system, the specific immune-related roles played by its functional domains in the immunoregulation of shrimp has not been well understood. In the present study, we report that the Ig-like domain of L. vannamei transglutaminase (TGase-C) is the main immune-related domain among the three functional domains, as it had higher bacterial agglutinative activity against Vibrio parahaemolyticus and Streptococcus iniae. Using Co immunoprecipitation and LC-MS/MS analysis, TGase-C was shown to interact with 474 proteins, of which 52 proteins were annotated to L. vannamei. More than half of the L. vannamei annotated proteins have immune-related functions, including apoptosis. Further analysis using pull-down assay revealed that TGase-C interacted with CAP-3 (a homologue of caspase 3). In addition, siRNA-mediated knockdown of LvTGase significantly (p < 0.01) increased the expression level of LvCAP-3 coupled with a significant (p < 0.01) increase in caspase 3/7 activity, suggesting that probably LvTGase participates in shrimp immune response by modulating the activity of LvCAP-3. These findings thus suggest the Ig-like functional domain of L. vannamei's transglutaminase is the domain that is involved in immunoregulation in shrimp. PMID- 30010015 TI - Effects of dietary 1,8-cineole supplementation on physiological, immunological and antioxidant responses to crowding stress in rainbow trout (Oncorhynchus mykiss). AB - The aim of the present study was to investigate beneficial effects of dietary 1,8 cineole (cineole) supplementation on physiological, immunological and antioxidant responses of rainbow trout (Oncorhynchus mykiss) to crowding stress. The fish were fed for 50 days with diets containing 0 (control), 0.05, 0.1, 0.25, 0.5 and 1% cineole prior to exposure to a 14-day crowding stress. Serum stress markers (cortisol, glucose, lactate, T4 and T3), antioxidant responses [catalase (CAT) and superoxide dismutase (SOD) activities and total antioxidant capacity (TAC) and malondyaldehyde (MDA) levels] and immune responses [lysozyme and alternative complement (ACH50) activity, and total immunoglobulin (Ig) levels], and blood leukocyte (WBC) and differential counts were measured before and after crowding stress. Results showed that 1% cineole was capable to reduce the basal and stress induced cortisol elevation and increase the serum T3 levels after stress. Increase in dietary cineole levels significantly decreased serum cortisol, glucose and lactate levels. Increase in dietary cineole levels significantly increased serum CAT, SOD, lysozyme and ACH50 activities, and TAC and eosinophil levels, and decreased MDA and monocyte levels. After the stress, there was no significant difference in the control group CAT and SOD activities compared to the basal values; however, CAT activities decreased and SOD activities increased in the cineole-treated groups compared to the basal values. Nevertheless, the control group had significantly lower CAT and SOD activities compared to the fish treated with 0.1-1% cineole. Cineole significantly increased blood WBC and serum lysozyme, ACH50 and total Ig. Moreover, cineole administration significantly mitigated the stress-induced decrease in total Ig levels as well as increase in leukocyte count. The cineole-treated fish had higher survival and growth performance compared to the control group. Although all levels of cineole (0.05 1%) showed beneficial effects on different tested factors, 0.5 and 1% levels had beneficial effects on most of the tested factors; thus, are recommended for dietary inclusion to suppress adverse effects of stress in trout. PMID- 30010016 TI - Optimisation of electroporation and lipofection protocols to derive the black tiger shrimp cell line (Penaeus monodon). AB - To achieve in creating permanent shrimp cell lines, cellular arrest of primary cells in the culture is needed to be firstly solved. Considering the insertion of some markers affecting cellular proliferation into primary haemocytes in order to produce the black tiger shrimp cell line and the very low percent of transduced cells previously reported in penaeid shrimps, these paved us the way to set up suitable gene delivery protocols to increase percent of transduced cells in the shrimp as our primary aim. In this study, electroporation and lipofection were used to transfer construct plasmids (pLL3.7 plasmids containing CMV promoters and pGL-IE1-126(A)-EGFP plasmids carrying WSSV IE1 promoters) into primary haemocytes. As it was difficult to distinguish between cells expressing EGFP signal and auto-fluorescence of many dead cells occurred by electroporation during the first 72 h of experiment; so, only lipofection was managed to deliver plasmids into primary cells. Surprisingly, numbers of suspected proliferative cells were derived after electroporation with no insertion of immortalising markers. These cells survived in vitro for up to 45 days with high rate of cell viability, but the number of viable cells decreased throughout the experiment. In addition, these cells expressed genes and proteins closely related to hyaline cells determined using RT-PCR and western blot. For the lipofection experiment, no green fluorescence signal was detected in any primary cell introduced with these plasmids, suggesting that plasmids were not successfully inserted into cells. Also, a number of primary haemocytes had the apoptotic cell death characteristic within 5 days after lipofection. These possibly result from using inappropriate lipofection protocol and chemical substances. In summary, finding out suitable protocols to elevate the percent of transduced cells is still necessary. Additionally, continuous shrimp cell lines would be possibly established by transforming suspected proliferative cells derived from electroporation in this study. PMID- 30010017 TI - Differential lncRNA expression profiles reveal the potential roles of lncRNAs in antiviral immune response of Crassostrea gigas. AB - Long noncoding RNAs (lncRNAs) may play widespread roles in various biological processes. However, systematic profiles of lncRNAs in the biological responses of Pacific Oyster (Crassostrea gigas) to pathogen infection have not yet been demonstrated. Here, we have conducted an exhaustive comparative transcriptome analysis using a bioinformatics approach to exam the functions of lncRNAs response to Ostreid herpesvirus 1MUVar (OsHV-1MUVar) challenge. In total, 101 differentially expressed lncRNAs (DE-lncRNA) during OsHV-1MUVar infections were identified. Compared with differentially expressed mRNAs (DE-mRNA), DE-lncRNAs are shorter in terms of overall length but longer in terms of exon length. These lncRNAs shared similar characteristics with previously reported invertebrate lncRNAs, such as relatively low GC content, low exon number and low sequence conservation, but low expression level were not observed. 20 DE-lncRNAs are typically co-expressed with their neighboring genes annotated as GO terms (GO: 0044237), indicating that these lncRNAs are involved in binding and cellular process functions in cis mode. The weighted gene co-expression network (WGCNA) analysis resulted in 15 modules. The highlighted blue module was specifically demonstrated a co-expression relationship between 14 DE-lncRNAs and 17 immune related DE-mRNAs (IR-DE-mRNA). Three hub lncRNAs within this module were co expressed with one hub IR-DE-mRNA involved in fibrinogen-related protein. It was speculated that lncRNAs is extensively involved in oyster antiviral innate immune system. The present study will facilitate subsequently experimental studies to unravel the function of lncRNAs in marine invertebrate response to pathogen infection. PMID- 30010018 TI - Hemolymph transcriptome analysis of Chinese mitten crab (Eriocheir sinensis) with intact, left cheliped autotomy and bilateral eyestalk ablation. AB - In the pond culture of Eriocheir sinensis, high limb-autotomy seriously affects the quality and culture's economic efficiency. Based on our previous studies, limb autotomy can induce the changes of hematological immune response in E. sinensis hemolymph. Eyestalk ablation can accelerate the regeneration of limbs after autotomy. To detect the important functional genes related to the hematological molecular immunity of E. sinensis, we compared and analyzed the hemolymph transcriptome data of the intact crab, left cheliped autotomized crabs and bilateral eyestalk ablation crabs with high-throughput sequencing techniques. The results showed that the three groups obtained 62 172 414, 68 143 682, and 67 811 618 clean reads, respectively. A total of 9567 differentially expressed genes were obtained by multiple comparison of the three groups' libraries. Gene ontology (GO) functional classification analysis shows that the differential genes belong to 42 categories of biological process, cellular components and molecular function. The differentially expressed genes in the three libraries were enriched to 344 specific KEGG metabolic pathways by KEGG enrichment analysis, such as the up-regulated gene (dual oxidase (Duox), tyrosine 3 monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAQ)) in MAPK signaling pathway, the up-regulated gene (aldehyde dehydrogenase 1 (ALDH 1)) and down-regulated gene (UDP-glucuronosyltransferase 2 (UGT 2)) in metabolism of the xenobiotics by cytochrome P450 pathway, the down-regulated gene (actin gene (AG), heat shock protein 90 (HSP 90)) in fluid shear stress and atherosclerosis pathway. To verify the expression levels of DEGs identified by RNA-Seq, the above six hematological immune-related genes were selected for qRT-PCR validation, the qRT-PCR results were consistent with the DEGs results. Our research obtained abundant E. sinensis hemolymph transcriptome information by RNA-Seq, which provides multi-level information for the cloning of novel genes and the study of hemolymph molecular immunology mechanisms of E. sinensis. PMID- 30010019 TI - Molecular cloning and functional characterisation of NLRX1 in grass carp (Ctenopharyngodon idella). AB - The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. In the present study, the NLR family gene NLRX1 from grass carp (Ctenopharyngodon idella) was cloned and characterised. NLRX1 was widely expressed in all tissues examined, albeit at varying levels. After exposure to the grass carp reovirus (GCRV), NLRX1 mRNA expression levels were altered in immune organs, and dramatically altered in liver. Subcellular localisation indicated that NLRX1 protein co-localised with the mitochondria in the transfected cells. Additionally, the bimolecular fluorescence complementation (BiFC) system was introduced to detect the interaction between tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) and NLRX1. Moreover, deficient of NLRX1 in CIK cells with small interference RNA (siRNA) promoted polyinosinic:polycytidylic acid (poly (I:C)) induced IFN-related genes production, including IRF3, IRF7, and IFN-I, which reveals that NLRX1 is a negative regulator of IFN. Taken together, our results demonstrate that NLRX1 gene plays an important role in innate immune regulation and provide new insights into understanding the functional characteristics of the NLRX1 in teleosts. PMID- 30010020 TI - Molecular identification and functional characterization of IRAK-3 from a teleost fish, the orange-spotted grouper (Epinephelus coioides). AB - Interleukin-1 receptor-associated kinase-3 (IRAK-3) is a unique IRAK family member, which negatively regulates the TLR-mediated immune response in mammals. However, the function of IRAK-3 remains to be elucidated in fish. In the present study, an IRAK-3 cDNA sequence (EcIRAK-3) with an ORF of 1776 bp encoding 591 amino acids was identified in the orange-spotted grouper (Epinephelus coioides). Sequence analysis indicated that EcIRAK-3 shared the conserved structure characteristics and functional sites of vertebrate IRAK-3, and has a high sequence identity and phylogenetic relationship with that of other fish species. The genomic EcIRAK-3 ORF contained 13 exons and 12 introns, which was similar to that of most other fish species. In healthy grouper, EcIRAK-3 was ubiquitously expressed in seven tested tissues with the highest expression in the gills. Following Cryptocaryon irritans infection, the EcIRAK-3 transcript was up regulated in the gills during the course of the experiment, but down-regulated in the spleen at an earlier point in time. EcIRAK-3 was localized in both the cytoplasm and nucleus in a condensed form, and its cellular distribution was affected by the death domain and ProST domain. In addition, EcIRAK-3 significantly increased MyD88-mediated NF-kappaB activity, and its function was ProST domain and kinase domain dependent. Taken together, the results obtained here have contributed to the understanding of the function of IRAK-3 in fish. PMID- 30010021 TI - Meta-analysis of antiviral protection of white spot syndrome virus vaccine to the shrimp. AB - Currently, white spot syndrome virus (WSSV) is one of the most serious pathogens that impacts shrimp farming around the world. A WSSV vaccine provides a significant protective benefit to the host shrimp. Although various types of vaccines against WSSV have emerged, the immune effects among them were not compared, and it remains unclear which type of vaccine has the strongest protective effect. Meanwhile, due to the lack of effective routes of administration and immunization programs, WSSV vaccines have been greatly limited in the actual shrimp farming. To answer these questions, this study conducted a comprehensive meta-analysis over dozens of studies and compared all types WSSV vaccines, which include sub-unit protein vaccines, whole virus inactivated vaccines, DNA vaccines and RNA-based vaccines. The results showed that the RNA based vaccine had the highest protection rate over the other three types of vaccines. Among the various sub-unit protein vaccines, VP26 vaccine had the best protective effects than other sub-unit protein vaccines. Moreover, this study demonstrated that vaccines expressed in eukaryotic hosts had higher protection rates than that of prokaryotic systems. Among the three immunization modes (oral administration, immersion and injection) used in monovalent protein vaccines, oral administration had the highest protection rate. In natural conditions, shrimp are mostly infected by the virus orally. These results provide a guide for exploration of a novel WSSV vaccine and help facilitate the application of WSSV vaccines in shrimp farming. PMID- 30010022 TI - Adaptive optics ophthalmoscopy: Application to age-related macular degeneration and vascular diseases. AB - Adaptive optics (AO)-enhanced en face retinal imaging, termed here AO ophthalmoscopy (AOO) has reached a level of robustness which fuels its increasing use in research and clinical centers. Here we will review the contribution of clinical AOO to the understanding and monitoring of 1) age-related macular degeneration and 2) vascular diseases. The main contributions of AOO to the phenotyping of AMD are a better identification of drusen, a better delineation of the limits of atrophy, and the identification of novel features such as punctate hyperreflectivity and mobile melanin-containing clumps. Characterization of progression of atrophy is facilitated by time-lapse imaging. In vessels, AOO enables the observation and measurement of parietal structures and the observation of microscopic pathological features such as small hemorrhages and inflammatory cell accumulations. PMID- 30010024 TI - A Footprint of Plant Desiccation Tolerance. Does It Exist? PMID- 30010025 TI - Genome Editing and Double-Fluorescence Proteins Enable Robust Maternal Haploid Induction and Identification in Maize. PMID- 30010026 TI - Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderly Patients Hospitalized for Heart Failure. AB - BACKGROUND: The impact of frailty on long-term prognosis in patients with heart failure (HF) remains unclear, and there is no simple and objective assessment for it. This study was performed to examine the association between frailty score and clinical outcome in elderly patients hospitalized for HF. METHODS AND RESULTS: A retrospective cohort study was performed with 603 elderly patients with HF (mean age 75 +/- 6 years, 378 [62.7%] men). Frailty was measured by a composite of 4 markers combined into a frailty score (possible range 0-12): gait speed, handgrip strength, serum albumin, and activities of daily living status. The patient population was divided into 2 groups with frailty score <5 (non-frail) or >=5 (frail). The end point was all-cause mortality. Over a mean follow-up period of 1.7 +/- 0.5 years, 89 patients died. After adjustment for several preexisting factors associated with prognosis, the frailty score (hazard ratio [HR] 1.11; P = .014) and frailty (HR 1.75; P = .036) were independently associated with all cause mortality. The inclusion of frailty score significantly increased both continuous net reclassification improvement (0.341; P = .002) and integrated discrimination improvement (0.016; P = .039) for all-cause mortality. CONCLUSIONS: A simple and objective frailty score was associated with health outcome in elderly patients hospitalized for HF. PMID- 30010023 TI - Manganese toxicity is targeting an early step in the dopamine signal transduction pathway that controls lateral cilia activity in the bivalve mollusc Crassostrea virginica. AB - Manganese is a neurotoxin causing manganism, a Parkinson-like clinical disorder. Manganese has been shown to interfere with dopaminergic neurotransmission, but the neurotoxic mechanism involved is not fully resolved. In the bivalve mollusc Crassostrea virginica also known as the eastern oyster, beating rates of lateral cilia of the gill are controlled by dopaminergic-serotonergic innervation originating from their cerebral and visceral ganglia. Terminal release of dopamine activates D2-like receptors on these gill cells inhibiting adenylyl cyclase and slowing cilia beating rates. In C. virginica, manganese treatment disrupts this dopaminergic innervation of the gill, preventing the normal cilio inhibitory response of lateral cells to dopamine. In this study an adenylyl cyclase activator (forskolin) and two different inhibitors (MDL-12,330A and SQ 22,536) were used to determine if manganese had any effects on the adenylyl cyclase step of the dopamine D2 receptor signal transduction pathway. The results showed that neither the adenylyl cyclase activator nor the inhibitors were affected by manganese in the control of lateral ciliary activity. This suggests that in C. virginica the mechanism of manganese toxicity on the dopaminergic control of lateral ciliary activity is targeting an early step in the D2R signal transduction pathway, which may involve interference with D2 receptor activation or alternatively some other downstream signaling activity that does not affect adenylyl cyclase. PMID- 30010027 TI - Effects of the HEART Camp Trial on Adherence to Exercise in Patients With Heart Failure. AB - BACKGROUND: Few exercise training studies in patients with heart failure (HF) report adherence to guideline-recommended 150 minutes of moderate-intensity exercise per week, and no studies have focused on a primary outcome of adherence. METHODS AND RESULTS: This randomized controlled trial evaluated the effect of a multicomponent intervention, Heart Failure Exercise and Resistance Training (HEART) Camp, on adherence to exercise (after 6, 12, and 18 months) compared with an enhanced usual care (EUC) group. Patients (n = 204) were 55.4% male, overall average age was 60.4 years, and 47.5% were nonwhite. The HEART Camp group had significantly greater adherence at 12 (42%) and 18 (35%) months compared with the EUC group (28% and 19%, respectively). No significant difference (P > .05) was found at 6 months. The treatment effect did not differ based on patient's age, race, gender, marital status, type of HF (preserved or reduced ejection fraction) or New York Heart Association functional class. Left ventricular ejection fraction (LVEF) significantly moderated the treatment effect, with greater adherence at higher LVEF. CONCLUSIONS: The multicomponent HEART Camp intervention showed efficacy with significant effects at 12 months and 18 months. Adherence levels remained modest, indicating a need for additional research to address methods and strategies to promote adherence to exercise in patients with HF. PMID- 30010028 TI - Myocardial Contraction Fraction by M-Mode Echocardiography Is Superior to Ejection Fraction in Predicting Mortality in Transthyretin Amyloidosis. AB - BACKGROUND: Transthyretin amyloidosis (ATTR) is often associated with cardiac involvement manifesting as conduction disease as well as restrictive cardiomyopathy causing heart failure and death. Myocardial contraction fraction (MCF), the ratio of left ventricular stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that is superior to ejection fraction (EF) in predicting mortality in patients with primary amyloid light chain cardiac amyloidosis. We hypothesized that MCF would be an independent predictor of survival in TTR-CA. METHODS AND RESULTS: MCF was derived from 2 dimensional echocardiography-guided M-mode data for 530 subjects in the Transthyretin Amyloidosis Outcomes Survey (THAOS) database: age 61 +/- 16years, 74% male, 158 wild-type (ATTRwt) and 372 mutant (ATTRm), follow-up 1.5 +/- 1.7years. Using multivariate Cox proportional hazard regression models, MCF <25% was highly associated with survival (hazard ratio [HR] 8.5, 95% confidence interval [CI] 4.8-14.9,-P < .0001), which was stronger than the association of EF dichotomized at 50% (HR 2.8, 95% CI 1.8-4.4; P < .0001). MCF <25% remained significantly predictive of survival in a multivariate model that included systolic blood pressure, estimated glomerular filtration rate <65 mL.min-1.m-2, New York Heart Association (NYHA) functional class, and health status based on the EuroQol-5D-3L questionnaire (area under the receiver operating characteristic curve [AUC] = 0.83, 95% CI 0.78-0.89). CONCLUSIONS: MCF was superior to EF in predicting mortality in patients with ATTR. A predictive model combining MCF with systolic blood pressure, renal function, NYHA functional class, and health status was strongly associated with survival in patients with ATTR. CLINICALTRIALS. GOV IDENTIFIER: NCT00628745. PMID- 30010029 TI - miR-145-loaded micelleplexes as a novel therapeutic strategy to inhibit proliferation and migration of osteosarcoma cells. AB - Osteosarcoma (OS), the main primary malignancy of bone, is the second leading cause of cancer in children and young adults. Despite the advances in modern treatments, the 5-year survival rate is retained in 60-70%, since the conventional treatment options available are associated with relapse, chemoresistance, and development of metastases, which frequently lead to patients death. In this regard, there is an increasing need to search and develop novel and alternative therapeutic approaches. Concerning this, gene therapy appears as an innovative and promising treatment option. This therapeutic option aims to deliver genetic material, through nanosystems, to repress or replace the expression of mutated genes involved in important regulatory pathways. To attain this goal, gene therapy is decidedly dependent on the efficiency of utilized vectors, constituting such a very important parameter to take in consideration. In this work, the main goal was centered on the development and full characterization of an efficient micellar nanosystem, based on the chemical conjugation between the amphiphilic copolymer Pluronic(r) L64 and the cationic polymer polyethyleneimine (PEI), to deliver the therapeutic miRNA-145 into OS cells leading to inhibition of cell proliferation and migration, and ultimately inducing cell death, crafting a novel anticancer therapeutic approach to OS. PMID- 30010030 TI - Antiproliferative and antimetastatic properties of 3-benzyloxy-16 hydroxymethylene-estradiol analogs against breast cancer cell lines. AB - Despite emerging new therapeutic opportunities, cancer is still a major health problem and a leading cause of death worldwide. Breast tumors are the most frequently diagnosed female malignancies, and the triple-negative subtype is associated with poorer prognosis and lower survival rates than other breast cancer types. The aims of the present study were to determine the anticancer potency of a set of C-3 and C-16 modified estradiol-derivatives against a panel of breast cancer cell lines, and to characterize the mechanism of action of two selected compounds (1 and 5) against the MDA-MB-231 triple-negative breast cancer cell line. Growth-inhibitory properties were investigated by an MTT-assay. Cell cycle analysis by flow cytometry has revealed G1 phase accumulation and indicated the proapoptotic effect of 1 and 5 through the elevation of the apoptotic subG1 phase on MDA-MB-231 cells after 24 h treatment. The antimetastatic activities of these compounds were examined by wound healing and Boyden chamber assays, and both compounds were shown to significantly inhibit the migration and invasion of MDA-MB-231 cells at sub-antiproliferative concentrations. Gelatin zymography assay has indicated that matrix metalloproteinase-2 and -9 are not involved in the antimetastatic action of the molecules. Western blot analysis was performed with 24 h incubation to examine the possible changes in the level of focal adhesion kinase (FAK), and both compounds were found to inhibit the phosphorylation of FAK in a concentration-dependent manner in MDA-MB-231 cells. The results of this study demonstrate that C-3 and C-16 modified estradiol derivatives are potent antiproliferative and antimetastatic compounds against a triple-negative breast cancer cell line with a mechanism of action involving the inhibition of FAK, a novel anticancer therapeutic target. Therefore, these findings can be utilized in the development of promising anticancer agents with steroid skeleton. PMID- 30010031 TI - Study on the dissolution improvement of albendazole using reconstitutable dry nanosuspension formulation. AB - The aim of the study was to improve the solubility and dissolution rate of the poorly water soluble drug albendazole via surfactant assisted media milling process. Preparation of a nanosuspension and then post-processing with a solidification technique applied to improve the applicability of nanosuspension in a solid dosage forms carrier. The dry nanosuspension was obtained using microcrystalline cellulose as solid carrier after tray drying at 40 degrees C. Both reconstitution from the solid carrier and dissolution profile studies were investigated in biorelevant Artificial Rumen Fluid (ARF) at pH = 6.50 and dissolution media at pH = 1.20 and pH = 6.80. Reconstitution studies have demonstrated that the mean hydrodynamic diameter values of albendazole crystals released from the dry suspension were nanosized (intensity weighted hydrodynamic diameter values: 200.40 +/- 2.318 nm in ARF at pH = 6.50, 197.17 +/- 0.208 nm in dissolution medium at pH = 6.80). Thermodynamic solubility studies have indicated a 2.98 times increase in water solubility (144.41 +/- 0.09 MUg/ml milled, 48.38 +/- 0.01 MUg/ml unmilled, 8.21 +/- 0.02 MUg/ml albendazole powder) in ARF at pH = 6.50, and 2.33 times in dissolution medium at pH = 6.8: (146.27 +/- 0.28 MUg/ml milled, 62.71 +/- 0.04 MUg/ml unmilled, 9.00 +/- 0.01 MUg/ml albendazole powder), and 13.65% increase at pH = 1.20 (1728.31 +/- 3.31 MUg/ml milled, 1559.41 +/- 0.40 MUg/ml unmilled, 1520.70 +/- 1.39 MUg/ml albendazole powder), dissolution rates have also increased. Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM) imaging investigations detected no albendazole nanocrystals on the surface of the carrier, which demonstrated the incorporation of albendazole into the microcrystalline cellulose solid carrier structure. PMID- 30010032 TI - Interaction between 3,4-dichlorophenyl-propenoyl-sec.-butylamine (3,4-DCPB), an antiepileptic drug, and cytochrome P450 in rat liver microsomes and recombinant human enzymes in vitro. AB - The compound 3,4-dichlorophenyl-propenoyl-sec.-butylamine (3,4-DCPB) is an antiepileptic drug. The purpose of the present research was to identify cytochrome P450 (CYP450) responsible for the metabolism of 3,4-DCPB and evaluate the effects of 3,4-DCPB on the activities of CYP450 enzymes. 3,4-DCPB was incubated with rat liver microsomes (RLMs) plus six CYP450 enzyme-specific inhibitors, or six recombinant human CYP450 enzymes (rhCYP450s). The concentrations of 3,4-DCPB and six CYP450 enzyme-activities probe drugs were detected by high-performance liquid chromatographic (HPLC). The results showed that the prototype of 3,4-DCPB was metabolized by multiple CYP450 enzymes into three metabolites, and the predominant isoforms were CYP2D6 (metabolite M1), CYP1A2 (M2), CYP2C19 and CYP3A4 (M3), respectively., in the presence of beta NADPH (1 mM) in RLMs or rhCYP450s. Compared with the control (PB-), phenobarbital pre-treatment (PB+) significantly enhanced levels (all of p < 0.01) of hydroxylmethytobutamide (CYP2C9), 4-hydroxy-mephenytoin (CYP2C19), acetaminophen (CYP1A2), 6-hydroxychlorzoxazone (CYP2E1) and oxidized nifedipine (CYP3A4), respectively, in spite of dextrophan (CYP2D6) was not markedly enhanced in RLMs. Conversely, the inhibitory ratios of 3,4-DCPB (16 MUg/mL, 59 MUM) on the activities of CYP2C9, CYP2C19, CYP1A2 and CYP2D6 were 97.6%, 59.0%, 53.5% and 36.5%, respectively. However, CYP2E1 (both of PB- and PB+) and CYP3A4 (PB+) were not inhibited by 3,4-DCPB in RLMs. In conclusion, the present study showed that 3,4-DCPB was metabolized by multiple CYP450 enzymes. 3,4-DCPB inhibited the activities of CYP2C9, CYP2C19, CYP1A2 and CYP2D6, rather than that CYP2E1 and CYP3A4 enzymes, suggesting that the different effects of 3,4-DCPB on the CYP450 enzymes might influence metabolic drug-drug interaction in antiepileptics therapy. PMID- 30010033 TI - DNMT1 controls LncRNA H19/ERK signal pathway in hepatic stellate cell activation and fibrosis. AB - Hepatic stellate cells (HSCs) activation is considered as a pivotal event in liver fibrosis. In HSCs activation and fibrosis, epigenetic events are important. Although HSCs activation alters DNA methylation, it is unknown, whether it also affects other epigenetic processes, including LncRNA and its recognition. The aim of this study was to identify the mechanism of DNA methyltransferase 1 (DNMT1) expression and its role in regulating LncRNA H19 during HSCs activation and fibrosis. Expression of DNMT1 and LncRNA H19 were determined in activated HSCs and CCl4-induced rat liver fibrosis tissue. The relationship between the LncRNA H19 and DNMT1 expression was examined in vitro. LncRNA H19 expression was reduced in activated HSCs and rat liver fibrosis tissue, whereas DNMT1 expression and methylation of the LncRNA H19 promoter were increased. Treatment of HSCs of DNMT1 siRNA blocked cell proliferation. Knockdown of DNMT1 elevated H19 expression in activated HSCs, and over-expression of DNMT1 inhibited H19 expression in activated HSCs. Moreover, we investigated the effect of H19 on ERK signal pathway. Treatment HSCs with H19-siRNA increased the expression of p-ERK1/2 in HSCs. Treatment with 5'-aza-2'-deoxycytidine in activated HSCs model reduced fibrosis gene and DNMT1 expression, enhanced H19 expression, and attenuated HSCs activation. These data connect HSCs activation with a DNMT1-LncRNA H19 epigenetic pathway that is important for liver fibrosis. PMID- 30010034 TI - Transplacental transfer and metabolism of diuron in human placenta. AB - Diuron is a broad-spectrum phenylurea derived herbicide which is commonly used across the globe. Diuron is toxic to the reproductive system of animals and carcinogenic to rat urothelium, and recently found to be genotoxic in human cells. In in vivo, it is metabolized predominately into 3-(3,4-dichlorophenyl)-1 methyl urea (DCPMU) in humans and 3-(3, 4-dichlorophenyl)urea (DCPU) in animals. Information on diuron toxicokinetics and related toxicity in human placenta is absent. We have investigated the toxicokinetics of diuron in ex vivo human placental perfusion and in in vitro human placental microsomes and human trophoblastic cancer cells (BeWo). Diuron crossed human placenta readily in placental perfusion. Furthermore, diuron was metabolized into DCPMU in perfused placenta and in in vitro incubations using microsomes from placentas of smokers. In incubations with placental microsomes from non-smokers, and in BeWo cells, metabolism to DCPMU was detected but only with the highest used diuron concentration (100 MUM). Diuron metabolism was inhibited upon addition of alpha naphthoflavone, a CYP1A1 inhibitor, underscoring the role of CYP1A1 in the metabolism. In conclusion, it is evident that diuron crosses human placenta and diuron can be metabolized in the placenta to a toxic metabolite via CYP1A1. This implicates in vivo fetal exposure to diuron if pregnant women are exposed to diuron, which may result in fetotoxicity. PMID- 30010035 TI - A Systems Biology Approach for Studying Heterotopic Ossification: Proteomic Analysis of Clinical Serum and Tissue Samples. AB - Heterotopic ossification (HO) refers to the abnormal formation of bone in soft tissue. Although some of the underlying processes of HO have been described, there are currently no clinical tests using validated biomarkers for predicting HO formation. As such, the diagnosis is made radiographically after HO has formed. To identify potential and novel biomarkers for HO, we used isobaric tags for relative and absolute quantitation (iTRAQ) and high-throughput antibody arrays to produce a semi-quantitative proteomics survey of serum and tissue from subjects with (HO+) and without (HO-) heterotopic ossification. The resulting data were then analyzed using a systems biology approach. We found that serum samples from subjects experiencing traumatic injuries with resulting HO have a different proteomic expression profile compared to those from the matched controls. Subsequent quantitative ELISA identified five blood serum proteins that were differentially regulated between the HO+ and HO- groups. Compared to HO- samples, the amount of insulin-like growth factor I (IGF1) was up-regulated in HO+ samples, whereas a lower amount of osteopontin (OPN), myeloperoxidase (MPO), runt-related transcription factor 2 (RUNX2), and growth differentiation factor 2 or bone morphogenetic protein 9 (BMP-9) was found in HO+ samples (Welch two sample t-test; P < 0.05). These proteins, in combination with potential serum biomarkers previously reported, are key candidates for a serum diagnostic panel that may enable early detection of HO prior to radiographic and clinical manifestations. PMID- 30010037 TI - Hypermethylated LATS2 gene with decreased expression in female breast cancer: A case control study from North India. AB - BACKGROUND: LATS2, a presumed tumor suppressor gene located on chromosome 13q11 12 is involved in cell growth related activity like regulation of cell cycle at G1/S. The reduced expression of LATS2 has been reported in many tumors; including tumors of Breast, which is to the best of our knowledge has not been studied in north Indian female breast cancer population. OBJECTIVE: Here, we looked upon the expression pattern and methylation status of the LATS2 gene in north Indian female breast cancer cases to further strengthen its role as a tumor suppressor gene and more importantly as a cancer biomarker. METHODS: mRNA expression level was determined by real time PCR in 140 Breast cancer patients, Protein expression was studied by Immunohistochemistry and Promoter methylation was studied by Methylation specific PCR. All findings were correlated with clinicopathological features. RESULTS: LATS2 mRNA expression was remarkably downregulated in 67.85% (95/140) cases. The expression of Large Associated Tumor Suppressor 2 at protein level was also absent in 67.85% (95/140) cases. The absence of LATS2 protein strongly correlated with promoter hypermethylation where 91 out of a total of 107 hyper methylated cases showed absence of protein (91/107, 85%). The absence of LATS2 protein was strongly significant with HER2 neu status (0.01), TNM staging (0.009) and Molecular subtype (0.024). CONCLUSION: The decreased expression in breast cancer seems to be associated with hypermethylation of LATS2 promoter regions. Further LATS2 as a tumor suppressor can be recognized as a promising Biomarker in Breast cancer pathogenesis. Though, further studies, targeting larger sets of breast cancer population are required to establish LATS2 as a promising biomarker. PMID- 30010036 TI - 5-Hydroxymethylome in Circulating Cell-free DNA as A Potential Biomarker for Non small-cell Lung Cancer. AB - Non-small-cell lung cancer (NSCLC), the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminating tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identified six potential biomarkers from 66 patients and 67 healthy controls (mean decrease accuracy >3.2, P < 3.68E-19) using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient's cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC. PMID- 30010038 TI - Horizontal transfer of exosomal CXCR4 promotes murine hepatocarcinoma cell migration, invasion and lymphangiogenesis. AB - Exosomes have been demonstrated as an important factor to influence cancer invasion and metastasis. Previous studies have shown that CXC chemokine recepter 4 (CXCR4) and stromal cell-derived factor-1alpha (SDF-1alpha) mediates matrix metalloproteinases (MMPs) secretions to facilitate lymph node metastasis of hepatocarcinoma cells. In this study, we demonstrated that exosomes containing elevated CXCR4 from high lymph node metastatic mouse hepatocarcinoma Hca-F cells were able to promote the migration and invasion of a paired syngeneic Hca-P cells that have low metastatic potential. Such impact on enhanced migratory and invasive capacities of Hca-P cells was triggered by the internalization of exosomes isolated from Hca-F cells. This was possibly due to the horizontal transferring of CXCR4 via exosomes. The lymphatic endothelial cells (LECs) increased the migration and invasion of Hca-F cells probably by expressing SDF 1alpha which bound with CXCR4 in the Hca-F cells and subsequently enhanced the secretions of MMP-9, MMP-2 and vascular endothelial growth factor C (VEGF-C). Exosomal CXCR4 from Hca-F cells promoted LECs proliferative rate and lymphatic tube formation ability. Our findings suggest that horizontal transfer of exosomal CXCR4 can promote murine hepatocarcinoma cell migration, invasion and lymphangiogenesis, and exosomal CXCR4 might be a novel therapeutic target against tumor lymphatic metastasis. PMID- 30010039 TI - Use of modified U1 small nuclear RNA for rescue from exon 7 skipping caused by 5' splice site mutation of human cathepsin A gene. AB - Cathepsin A (CTSA) is a multifunctional lysosomal enzyme, and its hereditary defect causes an autosomal recessive disorder called galactosialidosis. In a certain number of galactosialidosis patients, a base substitution from adenine to guanine is observed at the +3 position of the 7th intron (IVS7 +3a>g) of the CTSA gene. With this mutation, a splicing error occurs; and consequently mRNA lacking the 7th exon is produced. This skipping of exon 7 causes a frame shift of the transcripts, resulting in a non-functional CTSA protein and hence galactosialidosis. This mutation seems to make the interaction between the 5' splice site of intron 7 of pre-mRNA and U1 small nuclear RNA (U1 snRNA) much weaker. In the present study, to produce properly spliced mRNA from the CTSA gene harboring this IVS7 +3a>g mutation, we examined the possible usefulness of modified U1 snRNA that could interact with the mutated 5'-splice site. Toward this goal, we first prepared a model system using a mutant CTSA mini gene plasmid for delivery into HeLa cells. Then, we examined the effectiveness of modified U1 snRNA on the formation of properly spliced mRNA from this mutant CTSA mini gene. As a result, we succeeded in obtaining improved formation of properly spliced CTSA mRNA. Our results suggest the usefulness of modified U1 snRNA for rescue from exon 7 skipping caused by the IVS7 +3a>g mutation of the CTSA gene. PMID- 30010040 TI - Transcriptome analyses reveal genes of alternative splicing associated with muscle development in chickens. AB - Alternative splicing (AS) of pre-mRNA is a central mode of genetic regulation in higher eukaryotes. High-throughput experimental verification of alternative splice forms, functional characterization, and regulation of alternative splicing are key directions for research. However, little information is available on the transcriptome-wide changes during different ages in different chicken breeds. In this study, the sequencing reads of chicken muscle tissues collected from White feather broiler (day 42) and Luning Chicken (day 70, 120, 150) were mapped to the chicken genome. Results showed that a total of 16,958 genes were annotated, with 2230 differentially expressed genes (DEGs) when comparing White feather broiler and Luning Chicken, and an average of 700 DEGs when comparing different ages in Luning Chicken. Functional classification by Gene Ontology (GO) and pathways analysis for selecting the genes showed most DEGs were related to muscle development and immune response. Of the 16,958 genes, a total of 6249 genes (36.85%) underwent AS events, and over 40% were specifically expressed in each library. Additionally, 6 DEGs (SRPK3, ENSGALG00000022884, CCL4, GATM, SESN1, PTTG1IP) involved in muscle development and immunity response were found to be alternatively spliced among all the four muscle tissues. In conclusion, we present a complete dataset involving the spatial and temporal transcriptome of chicken muscle tissue using RNA -seq. These data will facilitate the understanding of the effects of breed and age on the development of muscle and uncover that AS events of candidate genes may have important functional roles in regulation of muscle development in chicken. PMID- 30010041 TI - Dynamic expression of vasotocin and isotocin receptor genes in the marbled eel (Anguilla marmorata) following osmotic challenges. AB - To examine the physiological roles of arginine vasotocin receptor (AVTR) and isotocin receptor (ITR) in osmoregulation of a euryhaline teleost, the marbled eel (Anguilla marmorata), three different genes coding for AVTRV1a2, AVTRV2 and ITR were cloned by screening an A. marmorata cDNA library. These receptors were expressed differentially and ubiquitously in the eight tissues we examined. The changes in mRNA expression levels of AVTRV1a2, AVTRV2, and ITR were assessed in a time-course study following salinity transfer from fresh water (FW, 00/00) to fresh water (FW, 00/00), brackish water (BW, 100/00) or saline water (SW, 250/00). When eels were transferred to BW, mRNA levels underwent an adaptive period, from 0 to 24 h, and a chronic regulatory period, starting at 24 h after transfer. In the adaptive period, the relative mRNA expression of AVTRV1a2, AVTRV2, and ITR increased in BW. But after this adaptive period, the mRNA levels of the three genes were significantly decreased compared to FW (control group, 0 h). The mRNA expression levels of AVTRV1a2, AVTRV2 and ITR were low in SW. The protein level of AVTRV1a2, a key protein in the brain, was also investigated and found to be consistent with mRNA results. Our results indicated that the nonapeptide receptor system may play a role in the acute stress response induced by hyper-osmotic challenge in marbled eels. PMID- 30010042 TI - Evaluation of serum SLCO1B1 levels and genetic variants of SLCO1B1 rs4149056 and rs2306283 in patients with early and exudative age-related macular degeneration. AB - PURPOSE: To determine SLCO1B1 rs4149056 and rs2306283 gene polymorphisms and SLCO1B1 serum levels in patients with early and exudative age-related macular degeneration. MATERIALS AND METHODS: The study enrolled 206 patients with exudative AMD, 253 patients with early AMD and 301 control subjects. DNA was extracted from peripheral venous blood leukocytes using commercial kits. Genotyping of SLCO1B1 rs4149056 and rs2306283 was carried out using a real-time polymerase chain reaction (RT-PCR) method. Serum SLCO1B1 levels were measured using SLCO1B1 ELISA kit. RESULTS: We found statistically significant differences in genotype (T/T, T/C and C/C) distribution of SLCO1B1 rs4149056 variant between the patients with exudative AMD and control group (52.4%, 47.6% and 0% vs. 64.8%, 31.6% and 13.7%, respectively, p < 0.001). Univariate binary logistic regression analysis showed that age was a risk factor for exudative AMD development. Also, T/C variant was associated with 1.9-fold increased Odds ratio of exudative AMD development under a codominant model (OR = 1.863; 95% CI: 1.290;2.689; p < 0.001). The results remained of the same statistical significance after multivariate analysis. On the other hand, C allele was associated with 1.6-fold increased odds ratio of exudative AMD development (OR = 1.563; 95% CI: 1.035;2.359; p = 0.034) only after adjustment for age. No significant associations were found in analysis of genotypes and alleles at rs2306283. Serum SLCO1B1 concentration was significantly higher in early AMD patients than in healthy controls (median, IQR: 2.92 ng/ml, 5.01 ng/ml versus 1.26 ng/ml, 2.63 ng/ml, respectively, p = 0.025), as well as in exudative AMD patients than in controls (median, IQR: 2.72 ng/ml, 5.71 ng/ml versus 1.26 ng/ml, 2.63 ng/ml, respectively, p = 0.002). Furthermore, subjects with rs4149056 T/C genotype had higher SLCO1B1 serum levels than those with T/T genotype (median, IQR: 3.73 ng/ml, 3.14 ng/ml versus 1.23 ng/ml, 1.47 ng/ml, respectively, p = 0.037). CONCLUSION: Our study determined that SLCO1B1 (c.521 T > C) rs4149056 T/C genotype and C allele may be associated with exudative age-related macular degeneration, as well as with elevated serum SLCO1B1 levels. Also, higher serum SLCO1B1 levels were found to be associated with early and exudative age-related macular degeneration. PMID- 30010043 TI - CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non-Small Cell Lung Cancer. AB - INTRODUCTION: Lung cancer is the leading cause of cancer-related deaths worldwide. ALK receptor tyrosine kinase gene (ALK) rearrangement has been identified in 3% to 5% of patients with NSCLC. The most common ALK rearrangement is echinoderm microtubule associated protein like 4 (EML4)-ALK, with several variants that can be targeted by the tyrosine kinase inhibitor crizotinib. METHODS: In this study using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel cut-like homeobox 1 gene (CUX1)-ALK fusion gene in a patient with lung adenocarcinoma. The exact CUX1-ALK fusion transcript was determined by RNA sequencing and confirmed by reverse-transcriptase polymerase chain reaction. The oncogenic ability of CUX1-ALK fusion gene was further validated in cells of the line 293T for the activation of anaplastic lymphoma kinase (ALK) self phosphorylation and downstream signaling pathways. RESULTS: After detection of the CUX1-ALK fusion gene, RNA sequencing analysis of formalin-fixed paraffin embedded sections from the primary tumor specimen was applied to reveal a 97 nucleotide fragment from CUX1 intron 8 inserted before the nucleotide 53 position in ALK exon 20. Expression of the cut-like homeobox 1-ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including the mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription, and phosphoinositide 3-kinase/AKT signaling pathways, which could all be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib, with a progression-free survival of 20 months. CONCLUSIONS: This study provides the novel finding of a CUX1-ALK fusion gene from a patient with NSCLC that could provide personalized treatment solutions for the maximum benefit to patients with NSCLC. PMID- 30010044 TI - Robotic-assisted pedicle screw placement fails to reduce overall postoperative complications in fusion surgery. AB - BACKGROUND CONTEXT: Surgeons have increasingly adopted robotic-assisted lumbar spinal fusion due to indications that robotic-assisted surgery can reduce pedicle screw misplacement. However, the impact of robotic-assisted spinal fusion on patient outcomes is less clear. PURPOSE: This study aimed to compare rates of perioperative complications between robotic-assisted and conventional lumbar spinal fusion. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: A total of 520 patients undergoing lumbar fusion were analyzed. The average ages of patients in the robotic-assisted versus conventional groups were 60.33 and 60.31, respectively (p=.987). Patients with a diagnosis of fracture, traumatic spinal cord injury, spina bifida, neoplasia, or infection were excluded. OUTCOME MEASURES: This study compared the rates perioperative major and minor complications for elective lumbar fusion between each cohort. METHODS: This study screened hospital discharges in the United States from 2010 to 2014 using the National Inpatient Sample and the Nationwide Inpatient Sample (NIS). The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes were used to identify 209,073 patients who underwent conventional lumbar fusion (ICD 81.04-8) and 279 patients who underwent robotic assisted lumbar fusion (ICD 81.04-8 and ICD 17.41, 17.49). Major and minor complications were identified using ICD-9-CM diagnosis codes. The robotic assisted and conventional fusion groups were statistically matched on age, year, sex, indication, race, hospital type, and comorbidities. Univariate and multivariate logistic regression were used to compare risks of major and minor complications. RESULTS: We matched 257 (92.11%) robotic-assisted patients with an equal number of patients undergoing conventional lumbar fusion. Minor complications occurred in 16.73% of cases in the conventional group and 31.91% of cases in the robotic-assisted group (p<.001). Major complications occurred in 6.61% of the conventional cases compared to 8.17% of robotic-assisted cases (p=.533). For robotic-assisted fusion, multivariate analysis revealed that there was no difference in the likelihood of major complications (OR=0.834, 95% CI=0.214-3.251) or minor complications (OR = 1.450, 95% CI=0.653-3.220). CONCLUSIONS: In a statistically matched cohort, patients who underwent robotic assisted lumbar fusion had similar rates of major and minor complications compared to patients who underwent conventional lumbar fusion. PMID- 30010045 TI - Alterations in 90-day morbidity, mortality, and readmission rates following spine surgery in Medicare Accountable Care Organizations (2009-2014). AB - BACKGROUND CONTEXT: The impact of Accountable Care Organizations (ACOs) on healthcare quality and outcomes, including morbidity, mortality, and readmissions, has not been substantially investigated, especially following spine surgery. PURPOSE: To evaluate the impact of ACO formation on postoperative outcomes in the 90-day period following spine surgery. STUDY DESIGN: Retrospective review of national Medicare claims data (2009-2014). PATIENT SAMPLE: Patients who underwent one of four lumbar spine surgical procedures in an ACO or non-ACO. OUTCOME MEASURES: The development of in-hospital mortality, complications or hospital readmission within 90 days of the surgical procedure. METHODS: The primary outcome measures included postsurgical complications and readmissions at 90 days following surgery. In-hospital mortality and 30-day outcomes were considered secondarily. The primary predictor variable consisted of ACO enrollment designation. Multivariable logistic regression analysis was utilized to adjust for confounders and determine the independent effect of ACO enrollment on postsurgical outcomes. The multivariable model included a propensity score adjustment that accounted for factors associated with the preferential enrollment of patients in ACOs, namely, sociodemographic characteristics, medical co-morbidities, hospital teaching status, bed size, and location. RESULTS: In all, there were 344,813 patients identified for inclusion in this analysis with 97% (n = 332,890) treated in non-ACOs and 3% (n = 11,923) in an ACO. Although modest changes were apparent across both ACOs and non-ACOs over the time-period studied, improvements were slightly more dramatic in non ACOs leading to statistically significant differences in both 90-day complications and readmissions. Specifically, in the period 2012-2014, ACOs demonstrated an 18% increase in the odds of 90-day complications and a 14% elevation in the odds of 90-day readmissions when compared to non-ACOs. There was no difference in hospital mortality between ACOs and non-ACOs. CONCLUSIONS: Our study of Medicare data from 2009 to 2014 failed to demonstrate superior reductions in postoperative morbidity, mortality, and readmissions for beneficiaries treated in ACOs as compared to non-ACOs. These results indicate that meaningful changes in postoperative outcomes should not be anticipated based on organizational participation in ACOs at present. PMID- 30010046 TI - Minimum clinically important difference of the health-related quality of life scales in adult spinal deformity calculated by latent class analysis: is it appropriate to use the same values for surgical and nonsurgical patients? AB - BACKGROUND CONTEXT: Health-related quality of life (HRQOL) parameters have been shown to be reliable and valid in patients with adult spinal deformity (ASD). Minimum clinically important difference (MCID) has become increasingly important to clinicians in evaluating patients with a threshold of improvement that is clinically relevant. PURPOSE: To calculate MCID and minimum detectable change (MDC) values of total scores of the Core Outcome Measures Index (COMI), Oswestry Disability Index (ODI), Physical Component Summary (PCS), Mental Component Summary (MCS) of the Short Form 36 (SF-36), and Scoliosis Research Society 22R (SRS-22R) in surgically and nonsurgically treated ASD patients who have completed an anchor question at pretreatment and 1-year follow-up. STUDY DESIGN/SETTING: Prospective cohort. PATIENT SAMPLE: Surgical and nonsurgical patients from a multicenter ASD database. OUTCOME MEASURES: Self-reported HRQOL measures (COMI, ODI, SF-36, SRS-22R, and anchor question). METHODS: A total of 185 surgical and 86 nonsurgical patients from a multicenter ASD database who completed pretreatment and 1-year follow-up HRQOL scales and the anchor question at the first year follow-up were included. The anchor question was used to determine MCID for each HRQOL measure. MCIDs were calculated by an anchor-based method using latent class analysis (LCA) and MDCs by a distribution-based method. RESULTS: All differences between means of baseline and first year postoperative total score measures for all scales demonstrated statistically significant improvements in the overall population as well as the surgically treated patients but not in the nonsurgical group. The calculated MDC and MCID values of HRQOL parameters in the entire study population were 1.34 and 2.62 for COMI, 10.65 and 14.31 for ODI, 6.09 and 7.33 for SF-36 PCS, 6.14 and 4.37 for SF-36 MCS, and 0.42 and 0.71 for SRS-22R. The calculated MCID values for surgical and non-surgical treatment groups were 2.76 versus 1.20 for COMI, 14.96 versus 2.45 for ODI, 7.83 versus 2.15 for SF-36 PCS, 5.14 versus 2.03 for SF-36 MCS, and 0.94 versus 0.11 for SRS-22R; the MDC values for surgical and nonsurgical treatment groups were 1.22 versus 1.51 for COMI, 10.27 versus 9.45 for ODI, 5.16 versus 6.77 for SF-36 PCS, 6.05 versus 5.67 for SF-36 MCS, and 0.38 versus 0.43 for SRS-22R. CONCLUSIONS: This study has demonstrated that MCID calculations for the HRQOL scales in ASD using LCA yield values comparable to other studies that had used different methodologies. The most important finding was the significantly different MCIDs for COMI, ODI, SF-36 PCS and SRS-22 in the surgically and nonsurgically treated cohorts. This finding suggests that a universal MCID value, inherent to a specific HRQOL for an entire cohort of ASD may not exist. Use of different MCIDs for surgical and nonsurgical patients may be warranted. PMID- 30010047 TI - Cystathionine beta synthase-hydrogen sulfide system in paraventricular nucleus reduced high fatty diet induced obesity and insulin resistance by brain-adipose axis. AB - Hydrogen sulfide (H2S) is an essential neuromodulator, generates by cystathionine beta synthase (CBS) or 3-mecaptopyruvate sulfurtransferase (3MST) in the brain. H2S can mediate paraventricular nucleus (PVN) neuron activity, and regulate neuroendocrine hormones secretion. On the other hand, CBS deficiency caused metabolic disorder and body weight reduction. However, whether CBS/H2S of PVN regulates neuroendocrine hormones to mediate energy metabolism is unknown. Here, we first identified the CBS co-localization with thyrotropin-releasing hormone (TRH) and corticotropin releasing hormone (CRH) positive neurons. In HFD induced obese rats, CBS protein of hypothalamus decreased. By contrast, overexpression CBS in PVN via lentivirus, lowered food uptake, body weight and fat mass, and reduced blood glucose, lipid disorders and insulin resistance. Intriguingly, CBS overexpression increased the pre-TRH expression, slightly elevated plasma thyroxine and thyrotropin level, but decreased the plasma ACTH and corticosterone level. Then, we found that mTOR activation contributed to pre-TRH up-regulation by CBS/H2S system. In db/db obese mice, hypothalamus CBS/H2S system also down regulated association with reduction pre-TRH expression; in contrast, CBS overexpression in PVN slightly elevated plasma leptin. Next, leptin stimulated FOXO3a nuclear translocation, increased FOXO3a binding activity to two binding sites of CBS promoter, and then enhanced CBS protein expression. In conclusion, leptin activates neuron CBS-H2S system by FOXO3a, regulates neuroendocrine hormones to modulate the energy homeostasis, thus highlights a new brain-adipose feedback axis in energy metabolism. PMID- 30010048 TI - Myosin phosphatase accelerates cutaneous wound healing by regulating migration and differentiation of epidermal keratinocytes via Akt signaling pathway in human and murine skin. AB - Wound healing is a complex sequence of cellular and molecular processes such as inflammation, cell migration, proliferation and differentiation. ROCK is a widely investigated Ser/Thr kinase with important roles in rearranging the actomyosin cytoskeleton. ROCK inhibitors have already been approved to improve corneal endothelial wound healing. The purpose of this study was to investigate the functions of myosin phosphatase (MP or PPP1CB), a type-1 phospho-Ser/Thr-specific protein phosphatase (PP1), one of the counter enzymes of ROCK, in skin homeostasis and wound healing. To confirm our hypotheses, we applied tautomycin (TM), a selective PP1 inhibitor, on murine skin that caused the arrest of wound closure. TM suppressed scratch closure of HaCaT human keratinocytes without having influence on the survival of the cells. Silencing of, the regulatory subunit of MP (MYPT1 or PPP1R12A), had a negative impact on the migration of keratinocytes and it influenced the cell-cell adhesion properties by decreasing the impedance of HaCaT cells. We assume that MP differentially activates migration and differentiation of keratinocytes and plays a key role in the downregulation of transglutaminase-1 in lower layers of skin where no differentiation is required. MAPK Proteome Profiler analysis on human ex vivo biopsies with MYPT1-silencing indicated that MP contributes to the mediation of wound healing by regulating the Akt signaling pathway. Our findings suggest that MP plays a role in the maintenance of normal homeostasis of skin and the process of wound healing. PMID- 30010049 TI - Frequency and Characteristics of Recommendations from Interdisciplinary Outpatient Cancer Rehabilitation Monthly Team Meetings. AB - BACKGROUND: Ambulatory cancer rehabilitation programs vary widely in the types of services offered, and there is a lack of consistency with respect to the coordination of rehabilitation with oncologic treatment plans. There are no guidelines for outpatient interdisciplinary rehabilitation team meetings, and the types and characteristics of recommendations that a physiatrist can provide during these meetings have not been reported. OBJECTIVE: To identify the frequency and characteristics of different types of recommendations that were derived through monthly interdisciplinary outpatient rehabilitation team meetings involving physiatrists, physical therapists, and occupational therapists. DESIGN: Case series-descriptive study. SETTING: Quaternary cancer center. PARTICIPANTS: Outpatient rehabilitation cancer patients discussed during consecutive monthly team meetings. MAIN OUTCOME MEASURE(S): Frequency and characteristics of recommendations. RESULTS: Over a 7-month period, there were 57 potential patients to be discussed, and 42 patients were discussed. Among the 42 patients, 30 received recommendations, which yields 71% of patients receiving at least 1 recommendation. Some patients required repeated discussions in different months; thus, a total of 71 discussions occurred and resulted in 51 recommendations. Out of the 71 discussions, 41 (58%) discussions resulted in recommendations such as coordination of care in 19 (37%) cases, physiatry clinic follow-up in 9 cases (18%), oncology clinic follow-up in 7 cases (14%), and orders for referrals to other health professionals were placed in 5 cases (10%). Thirty discussions (42%) did not result in any recommendations, with the most common reason being stable or having improved functional status. CONCLUSIONS: In contrast to acute inpatient rehabilitation interdisciplinary weekly team meetings required by Centers for Medicare and Medicaid Services, there are no guidelines for outpatient interdisciplinary rehabilitation team meetings. Thus, the types and characteristics of recommendations that a physiatrist can provide during these meetings have not been previously reported. Regularly scheduled outpatient interdisciplinary cancer rehabilitation team meetings increase communication among rehabilitation specialists to identify outpatients experiencing barriers to therapy progress, provide recommendations to address those barriers, and reassess rehabilitation goals previously established. LEVEL OF EVIDENCE: IV. PMID- 30010050 TI - Bone Marrow-Derived and Adipose-Derived Mesenchymal Stem Cell Therapy in Primary Knee Osteoarthritis: A Narrative Review. AB - Regenerative medicine in the context of musculoskeletal injury is a broad term that offers potential therapeutic solutions to restore or repair damaged tissue. The current focus in recent literature and clinical practice has been on cell based therapy. In particular, much attention has been centered on autologous bone marrow concentrate (BMAC) and adipose-derived (AD) mesenchymal stem cells (MSCs) for cartilage and tendon disorders. This article provides an overview of MSC derived therapy and offers a comprehensive review of adipose- and bone marrow derived MSC therapy in primary knee osteoarthritis OA. LEVEL OF EVIDENCE: To be determined. PMID- 30010051 TI - Proximal Iliotibial Band Syndrome in a Runner: A Case Report. AB - Overuse injuries of the hip are frequent among runners and often present a diagnostic dilemma requiring imaging modalities beyond radiographs, delayed diagnosis, and prolonged time away from sport and activity. We report a case of a 38-year-old female recreational runner with progressive lateral hip pain and magnetic resonance imaging findings of edema along the gluteal aponeurotic fascia and origin of the tensor fascia lata muscle consistent with the diagnosis of enthesopathy of the proximal iliotibial band. PMID- 30010052 TI - Interdisciplinary Pain Management Improves Pain and Function in Pediatric Patients with Chronic Pain Associated with Joint Hypermobility Syndrome. AB - BACKGROUND: The relation between chronic musculoskeletal pain and joint hypermobility in a small percentage of the pediatric population is well described. However, literature discussing the treatment of chronic pain associated with joint hypermobility in pediatrics is limited. The present study examines the impact of interdisciplinary treatment on chronic pain in pediatrics with joint hypermobility syndrome. OBJECTIVE: To determine if pediatric patients with chronic pain related to joint hypermobility can be effectively treated with an intensive, interdisciplinary pain management program, as measured by changes in pain, psychosocial and physical functioning, as well as parental coping. DESIGN: Retrospective cohort study. SETTING: Urban academic tertiary intensive outpatient interdisciplinary pain management clinic. PARTICIPANTS: The study involved 30 patients who met the criteria for a diagnosis of joint hypermobility and chronic pain and completed an interdisciplinary pain management program. INTERVENTION: All patients were treated in an intensive pediatric interdisciplinary pain management program for a duration of 6 to 8 weeks. The program provided physical therapy, occupational therapy, psychological counseling, and weekly pediatric rehabilitation medicine follow-up. MAIN OUTCOME MEASURES: Outcome measures included numeric rating scale pain scores, the Bath Adolescent Pain Questionnaire, and the Bath Adolescent Pain-Parent Impact Questionnaire. Changes from pre- to post-treatment were analyzed using paired samples t tests. RESULTS: Patients endorsed pre- to post-treatment improvements in pain, depression, general anxiety, pain-related anxiety, social functioning, and physical functioning (P < .05). The patients' parents showed significant improvements in depression, anxiety, catastrophic thinking, self-blame and helplessness, leisure functioning, and parental behavior (P < .05). CONCLUSION: The present findings suggest that an intensive interdisciplinary rehabilitation pain management program yields short-term improvements in pain, emotional and physical function, and daily activity in a pediatric population diagnosed with joint hypermobility. Parents also experienced benefits from the program. A larger prospective study with longer-term follow-up is needed. LEVEL OF EVIDENCE: Level III. PMID- 30010053 TI - A homozygous CEP57 c.915_925dupCAATGTTCAGC mutation in a patient with mosaic variegated aneuploidy syndrome with rhizomelic shortening in the upper and lower limbs and a narrow thorax. AB - Mosaic variegated aneuploidy syndrome (MVA) is a rare autosomal recessive disorder characterized by random chromosome gains and losses. Mutations in BUB1B and CEP57 genes have been involved in MVA. Here we report on a male child with MVA due to c.915_925dupCAATGTTCAGC mutation in the CEP57 gene. Our patient was homozygous for this mutation and he is the first case with rhizomelic shortening of both the upper and lower limbs and mild respiratory insufficiency due to a narrow thorax. It is also the second MVA Mexican family reported with this mutation that lives in the northwestern region of Mexico, suggesting a "local founding effect". Additional cases are needed to better understand the MVA genotype-phenotype relationship. PMID- 30010054 TI - Differing pattern of influenza vaccination uptake in nurses between clinical and long term care facilities setting, 2014-2018. AB - OBJECTIVES: We aimed to compare the influenza vaccination pattern between clinical and long term care facility (LTCF) nurses. METHODS: Between 2014 and 2018 an annual online survey was administered to nurses after onset of the winter influenza season in Hong Kong. Factors associated with vaccination were examined separately for clinical and LTCF nurses in univariate analyses and multilevel logistic regression analyses. RESULTS: Of 4675 responses collected in the 5-year period, 18% came from nurses of LTCF. The overall vaccination rate before the respective influenza season was 32% (34% in 2013/14 to 36% in 2017/18) for LTCF nurses and 38% (32% to 45%) for clinical nurses. Past vaccination history and absence of side effects were generally associated with vaccination uptake. Male gender, student nurses and infrequent patient contacts were significantly associated with vaccination in clinical but not LTCF nurses. A higher proportion of LTCF nurses were not vaccinated because it was not a work requirement. CONCLUSIONS: Vaccination coverage among nurses in Hong Kong was persistently below 50% in the last 5 years. In LTCF, strategies for making vaccines easily accessible to nurses should be developed, while nurses with frequent patient contacts should be prioritized for scaling up vaccination. PMID- 30010055 TI - Transvenous lead extraction during uninterrupted warfarin therapy: Feasibility and outcomes. AB - BACKGROUND: Uninterrupted anticoagulation is important for patients at high risk for thromboembolism. Bridging with heparin/enoxaparin increases the risk of hematoma and infection. There are no published data on the feasibility of transvenous lead extraction (TLE) during uninterrupted anticoagulation. OBJECTIVE: The purpose of this study was to examine the feasibility and safety of TLE during uninterrupted warfarin therapy with therapeutic international normalized ratio (INR). METHODS: We performed a retrospective study of patients undergoing TLE while receiving uninterrupted warfarin therapy with INR >=2.0 at a high-volume center. RESULTS: Between March 2011 and December 2016, 1212 patients underwent TLE. Of these patients, 62 underwent TLE during uninterrupted warfarin therapy with therapeutic INR (mean 2.5 +/- 0.5; range 2.0-4.5). The cohort was 85% male, mean age 65 years, CHA2DS2-VASc score 3.4 +/- 1.6, and left ventricular ejection fraction 41% +/- 16%. A total of 114 of 116 leads were completely removed. These include 45 (38.4%) defibrillator leads of average age 7.8 +/- 3.7 years, 65 (55.6%) pace-sense leads of average age 10.5 +/- 6.6 years, and 6 (5.2%) coronary sinus lead of average age 5.5 +/- 3.4 years. There was a 98.4% procedural and clinical success rate. Two patients had procedure-related complications: 1 small pericardial effusion that resolved spontaneously, and 1 femoral vein tear due to extraction of a large mass of a disrupted implantable cardioverter-defibrillator lead requiring vascular repair. CONCLUSION: TLE during uninterrupted warfarin therapy with therapeutic INR may be considered in patients at high risk for thromboembolism if performed by experienced operators at high volume centers. PMID- 30010056 TI - What is the real recurrence rate after cryoballoon-based pulmonary vein isolation? Lessons from rhythm follow-up based on implanted cardiac devices with continuous atrial monitoring. AB - BACKGROUND: Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging clinical results for the treatment of paroxysmal atrial fibrillation (AF) and persistent AF. However, rhythm follow-up after PVI is mainly based on Holter electrocardiography of limited duration. OBJECTIVE: The purpose of this study was to assess the real AF burden following CB2-based PVI in patients with implanted cardiac devices. METHODS: A total of 670 consecutive patients underwent CB2-based PVI at 3 electrophysiology centers. In 66 patients (9.9%), an implantable cardiac device with continuous monitor function was independently implanted before the procedure (device group). This patient cohort was compared to propensity score-matched patients without cardiac devices (n = 66; control group). RESULTS: A total of 254 of 258 PVs (98.4%0 in the device group were successfully isolated using only CB2. Postprocedural device interrogation found no device or lead malfunction related to the procedure. Periprocedural complications were registered in 7 of 66 patients (11%) in the device group and in 6 of 66 patients (9%) in the control group (P = .770). Phrenic nerve palsy occurred in 6 of 66 patients (9%) in the device group) and in 2 of 66 patients (3%) in the control group) (P = .274). Clinical success in terms of freedom from AF recurrence after a 1-year follow-up period was 63.8% (95% confidence interval 53-77) in the device group and 77.3% (95% confidence interval 68-88) in the control group (P = .038). In the device group, AF/AT burden decreased from 41.8% +/- 35.0% before the procedure to 10.2% +/- 22.4% after 1 year (P <.0001). CONCLUSION: CB2-PVI seems safe and feasible in patients with an implanted cardiac device. A significantly higher AF/AT burden was seen in patients with an implanted cardiac device compared to a control group. PMID- 30010058 TI - Artificial Protein Scaffold System (AProSS): An efficient method to optimize exogenous metabolic pathways in Saccharomyces cerevisiae. AB - Scaffold proteins influence cellular signaling by orchestrating multiple enzymes, receptors or ion channels, and could be tailored to enhance the efficiency of biochemical reactions by positioning related enzymes physically together. However, the number of applicable domains remains small, and the construction of scaffold proteins with optimal domain ratio could be tedious and time-consuming. In this study, we outlined a modular design to quickly assemble scaffold proteins using protein interaction domains, which have been constructed into a standardized vector. We generated multiple protein interaction domains and ligands for making artificial scaffold proteins. At the same time, we developed a robust Golden-Gate-based molecular toolkit for the construction of artificial scaffold proteins, allowing a variance of domain types, number, and positions. The synthesized domain-ligand interaction was verified by yeast two-hybrid and split-GFP assays. Using synthetic scaffolds, we demonstrated an increase in the yield of two target products by 29% and 63% respectively. Moreover, we demonstrated that the synthetic scaffold could be applied to rewire the metabolic flux. Our system could be a useful tool for metabolic engineering and beyond. PMID- 30010057 TI - Supraventricular tachycardias, conduction disease, and cardiomyopathy in 3 families with the same rare variant in TNNI3K (p.Glu768Lys). AB - BACKGROUND: Rare genetic variants in TNNI3K encoding troponin-I interacting kinase have been linked to a distinct syndrome consisting primarily of supraventricular tachycardias and variably expressed conduction disturbance and dilated cardiomyopathy in 2 families. OBJECTIVE: The purpose of this study was to identify new genetic variants associated with inherited supraventricular tachycardias, cardiac conduction disease, and cardiomyopathy. METHODS: We conducted next generation sequencing in 3 independent multigenerational families with atrial/junctional tachycardia with or without conduction disturbance, dilated cardiomyopathy, and sudden death. We also assessed the effect of identified variant on protein autophosphorylation. RESULTS: In this study, we uncovered the same ultra-rare genetic variant in TNNI3K (c.2302G>A, p.Glu768Lys), which co-segregated with disease features in all affected individuals (n = 23) from all 3 families. TNNI3K harboring the TNNI3K-p.Glu768Lys variant displayed enhanced kinase activity, in line with expectations from previous mouse studies that demonstrated increased conduction indices and procardiomyopathic effects with increased levels of Tnni3k. CONCLUSION: This study corroborates further the causal link between rare genetic variation in TNNI3K and this distinct complex phenotype, and points to enhanced kinase activity of TNNI3K as the underlying pathobiological mechanism. PMID- 30010059 TI - Tracing the emerging genotypes of human respiratory syncytial virus in Beijing by evolution analysis of the attachment glycoprotein (G) gene. AB - BACKGROUND: Emerging human respiratory syncytial virus (HRSV) genotypes, such as ON1 and BA9, are becoming the dominant genotypes prevailing worldwide. Objective To trace the emerging HRSV genotypes in Beijing. METHODS: HRSV-positive specimens as determined by direct immunofluorescence, collected from children diagnosed with bronchiolitis from July 2006 to June 2016, were typed by real-time PCR, then genotyped by phylogenetic analyses of the full attachment glycoprotein (G) gene. A Bayesian skyline plot was constructed to analyze the population dynamics for identified HRSV strains, and selective pressure was analyzed. RESULTS: The previous dominant HRSV A genotype, NA1, was replaced by ON1 in 2014. BA9 was the dominant HRSV B genotype for the duration of the study. The time to the most recent common ancestor (tMRCA) for HRSV A is since the 1943-1944 season; for the genotypes NA1 and ON1, since the 1999-2000 season and 2010-2011 season, respectively. The tMRCA for HRSV B is since the 1956-1957 season; for the genotypes BA and BA9, from the 1998-1999 season and 2005-2006 season, respectively. The mean evolutionary rate of HRSV A (3.65 * 10-3) was faster than those of HRSV B (3.11 * 10-3), and the genotypes NA1 (2.01 * 10-3) and ON1 (1.66 * 10-3). The estimated effective population size (EPS) infected by HRSV A changed significantly from 2012 to 2013, which is consistent with the detection of ON1. Most positive selection sites were concentrated in the second highly variable region (HVR2) of the G gene. CONCLUSIONS: Over the 10-year period from 2006 to 2016, the dominant genotypes in Beijing were NA1, ON1, and BA9. The HRSV strains in Beijing may have their own unique phylogenetic characteristics. PMID- 30010060 TI - Interleukin-4 and STAT6 promoter polymorphisms but not interleukin-10 or 13 are essential for schistosomiasis and associated disease burden among Nigerian children. AB - Schistosomiasis is endemic in many parts of rural Africa, with previous reports showing interleukin-13 polymorphisms as drivers of infectivity and disease severity in West Africa while IL-13/IL-4 polymorphisms contributes to patterns of reinfection in East Africa. We have shown that there is a genetic delineation in susceptibility to and severity of infectious diseases in Africa, in addition to sub-continental differences in disease pattern. Therefore, which immunoregulatory biomarkers are essential in driving S. haematobium infection or regulate disease burden among Nigerian school children? One hundred and thirty one age and sex matched schistosome-infected children and 275 uninfected controls, of same ethnicity, recruited from southwestern Nigeria, were screened for variability of cytokine genes, IL-10 (rs1800872), IL-13 (rs7719175), IL-4 (rs2243250) and STAT6 (rs3024974), utilizing a polymerase chain reaction-restriction fragment length polymorphism assay. We found no difference in genotypic or allelic frequencies of IL-10 and IL-13 promoter polymorphisms alone or in association with disease. Contrariwise, we report significant differences in the frequencies of IL-4 and STAT6 variants between groups. For IL-4, the rs2243250 T/T variant was significantly different for genotypes (71.6% versus 51.2%; p < .0004) and alleles (82.6% versus 71.1%; p < .001) between disease and control groups respectively. For STAT6 (rs3024974), the frequencies of genotypes C/C and C/T are 75.4% and 24.6%, both showing an association with disease; none of the infected subjects had the T/T variant. Despite minor differences in disease covariates, we found no association between IL-4 and STAT6 variants with age, gender or anemia. However, mean egg count (indicative of disease burden), was regulated based on IL-4 variants, with highest burden in infected subjects with rs2243250 T/T variant (mean egg count: 207.5 eggs/10 ml of urine) versus rs2243250 C/T heterozygotes (mean egg count: 84.3 eggs/10 ml of urine) versus rs2243250 C/C (mean egg count: 127.9 eggs/10 ml of urine). Comparing rs2243250 C/T versus rs2243250 T/T (p < .008) or rs2243250 C/C + C/T versus rs2243250 T/T (p < .016) reveals an association with disease burden. We conclude that the IL-4 promoter gene is a susceptibility factor for schistosomiasis, and essential to regulate disease burden, with worse disease among carriers of the rs2243250 T/T variant. The absence of the STAT6, rs3024974T/T variant among infected subjects reveal the necessity of the STAT6 promoter gene in driving susceptibility to schistosomiasis in Nigeria. PMID- 30010061 TI - Prospective, comparative clinical study between high-dose colistin monotherapy and colistin-meropenem combination therapy for treatment of hospital-acquired pneumonia and ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae. AB - OBJECTIVES: In clinical practice, colistin is used as combination therapy to improve its antibacterial activity, despite the consequent increase in toxicity. This prospective, comparative study evaluated the effectiveness and adverse effects of using colistin alone at a loading dose of 9 million international units (MIU) followed by 3 MIU every 8h (q8h) versus colistin+meropenem 1g q8h in treating multidrug-resistant (MDR) Klebsiella pneumoniae-induced hospital acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). The primary outcome measure was in-hospital mortality. The secondary measure was the occurrence of colistin toxicity. METHODS: A total of 60 patients were divided into two groups (30 patients each); the first group received intravenous colistin at a mean daily dose of 8.304 MIU and the second group received colistin 8.58 MIU combined with meropenem (mean daily dose of 2.88g for 15 days). RESULTS: The colistin-meropenem combination group showed a significant decrease in mortality versus colistin alone [16.7% (5/30) vs. 43.3% (13/30); P=0.047]. The improved clinical response mediated by combination therapy was not associated with any significant nephrotoxicity, hepatotoxicity or neurotoxicity. Moreover, the 42 surviving patients showed normal procalcitonin values associated with a decrease in SOFA score, whilst 12 of them showed significantly elevated C-reactive protein (CRP) (P=0.0002). CONCLUSIONS: This study revealed the superiority of colistin meropenem combination therapy over colistin monotherapy in the treatment of MDR K. pneumoniae-induced HAP or VAP and highlights the advantage of procalcitonin over CRP as a marker for eradication of sepsis and suspension of therapy. PMID- 30010062 TI - Modern Management of Meningiomas Compressing the Optic Nerve: A Systematic Review. AB - OBJECTIVE: Meningiomas that compress the optic nerve (ON) can lead to different visual outcomes depending on the segment of ON affected (intraorbital, canalicular, and intracranial). In this study, we performed a comprehensive comparison of the management options (surgery, radiation, or observation alone) for meningiomas compressing the ON, categorized by location and relation to the ON. METHODS: MEDLINE, EMBASE, Web of Science, and the Cochrane Database of Systematic reviews databases were searched according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data were extracted from the articles regarding anatomic location, initial visual impairment, surgical procedure, visual outcome, morbidity and mortality, gross total removal, and requirement for postoperative radiotherapy. RESULTS: Of the 47 articles eligible for full-text reading, 9 surgical studies met our inclusion criteria. Data from 317 patient cases were extracted. In patients in whom the intracranial segment of the ON was impaired in isolation, 49% experienced visual improvement after surgery. When the meningioma affected the canalicular segment or intraorbital segment, visual improvement after surgery was 31% and 11%, respectively. Of patients who underwent surgery for the intraorbital segment of the ON, 56% experienced a decline in visual outcome. CONCLUSIONS: When a neurosurgeon deals with a meningioma compressing the ON, opening the optic canal is suggested if invasion is suspected on the preoperative imaging. Extra caution should be used when operating on meningiomas with ON sheath adhesion, given the higher evidence of postoperative visual worsening. PMID- 30010063 TI - Glioblastoma Multiforme in a Patient with Celiac Disease: Management of Seizures After Gross Total Tumor Resection. AB - BACKGROUND: A 55-year-old woman with a history of celiac disease presented with focal seizures and a mass lesion located at the left frontal lobe. Management of seizures in these patients is challenging. CASE DESCRIPTION: The patient underwent a navigation-assisted tumor resection. A week later, she returned to her regular diet, but 12 days after surgery she started the same pattern seizures. CONCLUSION: A patient suffering from glioblastoma multiforme who presents with seizures and has a history of celiac disease must be treated more aggressively than usual, with dual or triple anticonvulsant scheme therapy, and provided a strict gluten-free diet after tumor resection. PMID- 30010064 TI - Role of Apolipoprotein E Genotypes in Aneurysmal Subarachnoid Hemorrhage: Susceptibility, Complications, and Prognosis. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease. Emerging evidence has indicated that the apolipoprotein E (ApoE) genotype might be associated with the risk of aSAH as well as complications and outcomes after aSAH, although the results remain controversial. METHODS: We searched published literature on PubMed, Embase, China National Knowledge Infrastructure, and Wanfang database to identify studies involving the ApoE genotype and aSAH. A meta analysis was performed to summarize the relationship between ApoE genotype and aSAH, including susceptibility, complications, and prognosis. RESULTS: Eighteen studies were considered eligible for inclusion. Generally, epsilon4 carriers had increased risk of aSAH (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.01 1.49). White patients with the epsilon2/epsilon2 genotype had a greater risk of aSAH (OR 3.38, 95% CI 1.13-10.11). The patients with aSAH carrying the epsilon4 allele had an increased risk of poor outcome (OR 2.21, 95% CI 1.21-4.05) compared with non-epsilon4 carriers, especially in Asian patients (OR 4.99, 95% CI 1.73 14.40). ApoE epsilon4 carriers have increased risk of delayed ischemic neurologic deficit compared with non-epsilon4 carriers in the overall population. No significant difference was detected regarding the effect of certain ApoE genotypes on aSAH admission severity, rebleeding, or cerebral vasospasm after aSAH. CONCLUSIONS: We found that the ApoE genotype was significantly associated with aSAH risk, whereas its effect on certain ethnic populations differs. Patient carrying the epsilon4 allele might have a worse outcome, whereas current evidence was insufficient to prove the association between ApoE genotypes and post-SAH complications. PMID- 30010065 TI - Hemodynamics in Ruptured Intracranial Aneurysms with Known Rupture Points. AB - BACKGROUND: Hemodynamics plays an important role in aneurysm rupture. Microsurgical clipping provides the best chance to confirm the rupture point. The aim of this study was to explore the associations between the rupture point and hemodynamics. METHODS: Computational fluid dynamic simulations were performed on 16 intracranial aneurysms. The rupture point was detected at the time of clipping by 3 independent neurosurgeons. Hemodynamic parameters, including wall shear stress (WSS) and oscillatory shear index (OSI), were calculated at the rupture point and the whole aneurysm sac. Intra-aneurysmal flow patterns and flow impingement were also studied. RESULTS: The time-averaged WSS was 3.4855 +/- 3.8881 Pa at the aneurysm sac, which was significantly larger than that at the rupture point (1.5403 +/- 2.3688 Pa, P = 0.002). The OSI at the rupture point (0.0354 +/- 0.0459) was larger than at the sac (0.0220 +/- 0.0232) without difference. Thirteen aneurysms (81.3%) showed a complex flow pattern in the aneurysm sac; however, more than two thirds of the cases (68.7%) did not show a flow impact at the rupture point. Of these cases with daughter blebs, the rupture points were confirmed at the blebs in 6 cases. Two cases did not show association between blebs and rupture point. CONCLUSIONS: The hemodynamic characteristics at the rupture point were different from the aneurysm sac, and the WSS was significantly lower at the rupture point. Further study on the rupture risk assessment is still needed with more data and detailed information. PMID- 30010066 TI - Emergency Superficial Temporal Artery-Superior Cerebellar Artery Bypass for the Refractory Vertebrobasilar Insufficiency with Partial Mastoidectomy. AB - BACKGROUND: Although it is well-known that vertebrobasilar insufficiency (VBI) because of atherothrombosis with bilateral vertebral artery (VA) occlusion is resistant to medical treatment from the acute to subacute stages, the most appropriate treatment for progressive infarction at these stages remains unclear. Here, we described a patient with VBI who underwent emergency superficial temporal artery-superior cerebellar artery (STA-SCA) bypass under partial mastoidectomy after confirming mismatch between diffusion-weighted imaging (DWI) findings and clinical symptoms. The patient showed a good outcome with this approach. To our knowledge, our surgical strategy has not been previously reported. CASE DESCRIPTION: The patient was a 71-year-old woman with progressive infarction because of atherothrombosis with bilateral VA occlusions resistant to maximum medical treatment. Emergency STA-SCA bypass under partial mastoidectomy was performed after confirming DWI findings and symptom mismatch. A good outcome was archived, and no additional cerebral infarctions were noted. CONCLUSIONS: Emergency bypass should be considered as a treatment option for VBI that is resistant to maximal medical treatment after confirming DWI findings and symptom mismatch. Our approach involving partial mastoidectomy provides a wide and shallow operative field for STA-SCA bypass, which allows accurate bypass with good outcomes. PMID- 30010067 TI - Quantitative Anatomic Analysis of the Transcallosal-Transchoroidal Approach and the Transcallosal-Subchoroidal Approach to the Floor of the Third Ventricle: An Anatomic Study. AB - OBJECTIVE: To compare transcallosal-transchoroidal and transcallosal-subchoroidal approaches to the ipsilateral and contralateral edges of the floor of the third ventricle using quantitative analyses. METHODS: Five formalin-fixed cadaveric human heads (10 sides) were examined under the operating microscope. Quantitative measurements (area of surgical freedom and angle of attack) were obtained using 3 T magnetic resonance imaging and a StealthStation image guidance system. The limits of the surgical approaches were shown by touching a probe to 6 designated points on the floor of the third ventricle. RESULTS: The transchoroidal approach provided greater surgical freedom than the subchoroidal approach to access ipsilateral and contralateral middle landmarks at the edges of the floor of the third ventricle in both longitudinal and horizontal planes (P <= 0.03). No significant difference between the 2 approaches was found in accessing the anterior and posterior landmarks of the third ventricle in each plane. The surgical freedom to the contralateral anterior, middle, and posterior landmarks was greater than to the ipsilateral landmarks in both the transchoroidal and subchoroidal approaches. CONCLUSIONS: The transcallosal-transchoroidal approach, compared with the transcallosal-subchoroidal approach, may provide better exposure and require less retraction for removal of ipsilateral or contralateral lesions located in the midbrain or hypothalamus and situated near the floor of the third ventricle. The contralateral transcallosal approach with either the transchoroidal or subchoroidal approach may provide good surgical freedom for removal of lesions located near the floor of the third ventricle, such as lesions in the midbrain. PMID- 30010068 TI - Predictors of Nonneurologic Complications and Increased Length of Stay After Cervical Spine Osteotomy. AB - BACKGROUND: Although previous studies have used National Surgical Quality Improvement Program (NSQIP) data to study complications of thoracolumbar spinal deformity surgery, investigation of cervical spine deformity surgery has been limited. We performed a retrospective analysis of the NSQIP database to identify predictors of complications after cervical spine osteotomy. METHODS: Patients undergoing cervical spine osteotomy were identified in the NSQIP dataset using Current Procedural Terminology codes from years 2007-2016. For each patient, patient and case clinical characteristics, length of stay (LOS), and diagnosis of a nonneurologic complication (including reoperation and readmission) were abstracted. Patient and case clinical predictors of any of the reported complications and increased LOS were identified in multivariate logistic and Poisson regression analyses, respectively. RESULTS: There were 950 patients identified with mean age 56.1 +/- 12.4 years and mean body mass index 29.9 +/- 6.8. Mean LOS was 3.5 +/- 4.9 days. Overall medical complication rate was 15.8%. The most common complications were transfusion (78; 8.2%), readmission (45; 4.7%), reoperation (32; 3.4%), and reintubation (28; 3.0%). Risk factors for any complication included increased age (P = 0.0467), American Society of Anesthesiologists classification III (P = 0.0023) and IV (P = 0.0013), and increased operative duration (P < 0.0001). Risk factors for increased LOS were decreased functional status (P = 0.0037), disseminated cancer (P = 0.0061), American Society of Anesthesiologists classification III and IV (P < 0.0001), increased operative duration (P < 0.0001), and orthopaedic surgeon (vs. neurosurgeon) (P = 0.0156). CONCLUSIONS: This study is the largest to date of patients undergoing cervical osteotomy and provides useful clinical data for patient selection and counseling and 30-day reoperation and readmission rates. PMID- 30010069 TI - Denosumab Treatment for a Residual Giant Cell Tumor of the Clivus: A Case Report and Review of the Literature. AB - BACKGROUND: Giant cell tumors (GCTs) are a locally aggressive primary bone neoplasm of osteoclast-like cells. These lesions largely occur in the epiphyses of long bones, but there have been rare reports of occurrence in the pelvis, spine, or skull. Of those located in the skull, involvement of the clivus has been rarely reported. CASE DESCRIPTION: We present a case of an 18-year-old woman presenting with a third nerve palsy, found to have a lytic lesion of the upper clivus that was primarily treated with endoscopic endonasal resection. Her third nerve palsy resolved postoperatively, and subsequent histopathologic analysis revealed a GCT. Six-month postoperative magnetic resonance imaging (MRI) revealed progression of residual disease for which she was treated with adjuvant denosumab. This treatment resulted in a significant decrease in the tumor size. She subsequently underwent proton beam radiation. At 1-year postsurgery, the patient's MRI remained stable after completing denosumab and proton therapy. She was neurologically intact and had no issues from her treatment. CONCLUSIONS: Denosumab has demonstrated anti-GCT efficacy. In combination with proton therapy, it has the potential to spare a young, vulnerable population from adverse long term effects of traditional adjuvant radiation therapy. To our knowledge, this is the first report of the use of denosumab in the treatment of GCT of the clivus in the United States. PMID- 30010070 TI - Presurgical Thalamus and Brainstem Shifts Predict Distal Motor Function Recovery After Anatomic Hemispherectomy. AB - BACKGROUND: Anatomic hemispherectomy is an effective surgical treatment for patients with hemispherical intractable epilepsy. Different degrees of brain shifting have been observed, but whether these shifts can predict motor function recovery is unknown. The aim of this study was to analyze the correlation between brain shift ratios of different brain areas and motor function before and after surgery. METHODS: Medical records and magnetic resonance imaging of 23 patients who underwent anatomic hemispherectomy from 2006 to 2013 at a single center were retrospectively reviewed. Proximal and distal muscle strengths of both arms and legs were measured before and after surgery to determine motor function outcomes. Brain shift ratios of frontal lobe, temporal lobe, parieto-occipital lobe, thalamus, brainstem, and cerebellum were measured before and after surgery to test which shifts could effectively predict motor function outcomes. RESULTS: Fifteen patients (65.2%) showed different degrees of presurgical brain shifting. Brain shift ratios of all measured brain areas were generally increased after anatomic hemispherectomy. After surgery, 13 patients (56.5%) exhibited improved proximal muscle strength, whereas 10 (43.5%) in distal. Significant correlations were found only between muscle strength improvements of distal arms or legs and presurgical brain shift ratios of thalamus or brainstem (all P < 0.05). Distal muscle strength improvements also correlated with age at seizure onset. CONCLUSIONS: Patients with hemispherical intractable epilepsy with larger presurgical shifts of thalamus and brainstem exhibited improved muscle strength, especially in distal muscles, after anatomic hemispherectomy. This result was more likely in patients who were older at the time of seizure onset. These presurgical shifts of thalamus and brainstem may be used for predicting motor function recovery after hemispherectomy for a subset of patients, which is beneficial for surgical planning. PMID- 30010071 TI - Flexible Neuroendoscopic Diagnosis and Management of Ventricular Tumors: A Retrospective Cohort Study. AB - BACKGROUND: Ventricular tumors (VTs) represent approximately 10% of intracranial lesions and are associated with hydrocephalus in 73.9%-100% of patients. We present our experience using flexible neuroendoscopy as a diagnostic and hydrocephalus-related treatment strategy for paraventricular and intraventricular tumors. METHODS: This retrospective cohort included 27 pediatric and 21 adult patients with paraventricular or intraventricular tumors treated with flexible neuroendoscopy. Terminally ill patients and patients with incomplete data were excluded. RESULTS: Male and female patients comprised 52% and 48% of the population, respectively. Mean patient age was 20.45 years (+/-18.65 SD). The most common tumor location was the thalamic and pineal region. Conclusive pathologic diagnosis was obtained in 40 patients (83.3%); the most common type of tumor was astrocytoma. Hydrocephalus was present in 38 (79.1%) patients, who were treated successfully with endoscopic procedures. There were no major complications. CONCLUSIONS: Flexible neuroendoscopy is a strategic tool for diagnosis of VTs, especially in patients with associated hydrocephalus and VTs unreachable by other means. Flexible neuroendoscopy has a high rate of definitive diagnosis with low associated complications. More studies evaluating the long term efficacy of flexible neuroendoscopy for hydrocephalus associated with VTs are needed. PMID- 30010072 TI - Intracranial Meningioma Surgery: Value-Based Care Determinants in New York State, 1995-2015. AB - OBJECTIVE: Intracranial meningiomas are the most commonly diagnosed brain tumor in the United States. With increasing incidence, efficient allocation of limited health care resources is a critical component of emerging value-based models of care. The purpose of this study was to evaluate the effect of patient and hospital variables on metrics of value-based care. METHODS: The Statewide Planning and Research Cooperative System database was queried for records of patients undergoing intracranial meningioma surgery in New York State from 1995 to 2015. Multivariate logistic regression was used to investigate the effect of hospital volume and patient demographics on 30-day readmissions, 30-day mortality, prolonged length of stay (pLOS), and excess hospital charges. RESULTS: Among the 14,239 patients included, 10,252 (72%) cases were performed at high volume centers (HVC) (>75th percentile). HVC were associated with lower rates of readmissions, mortality, and pLOS, but higher hospital charges. In the multivariate analysis, HVC had reduced odds of pLOS (odds ratio, 0.56; P < 0.0001) and 30-day mortality (odds ratio, 0.39; P < 0.0001). Patient variables associated with adverse outcomes in the multivariate model included advanced age, male gender, higher Charlson Comorbidity Index, lower socioeconomic status (low income, Medicaid, and Medicare insurance), black race, and Hispanic ethnicity. These populations were more likely to undergo treatment at lower-volume centers. CONCLUSIONS: This statewide population analysis of readmissions, mortality, length of stay, and hospital charges after intracranial meningioma surgery identified patient predictors of adverse outcomes. These determinants may be used by hospitals to develop improved systems of care in at-risk populations. PMID- 30010073 TI - Feasibility and Midterm Outcomes of Endovascular Coil Embolization of an Unruptured Middle Cerebral Artery Aneurysm with an Incorporated Branch. AB - BACKGROUND: Endovascular coiling has emerged as an option for the management of unruptured intracranial aneurysms, which was traditionally treated via surgical clipping. Unlike aneurysms elsewhere, aneurysms of the middle cerebral artery (MCA) have several features that are favorable for surgery. However, endovascular treatment can be difficult for MCA aneurysms, especially if they have incorporated branches. We report the results of coil embolization of incorporated MCA aneurysms. METHODS: From 2012 to 2017, 129 unruptured aneurysms including 10 incorporated MCA aneurysms were treated. The mean neck, height, and width of the aneurysms were 3.74 +/- 1.07, 4.26 +/- 1.06, and 3.97 +/- 1.03, respectively. The mean aspect ratio, neck/sac width, and sac width/neck were 1.19 +/- 0.37, 1.09 +/ 0.21, and 0.95 +/- 0.18, respectively. RESULTS: Nine cases of incorporated MCA aneurysms were treated using the double microcatheter technique, whereas the triple microcatheter technique was used in 1 case. There were no procedure related complications. Postcoiling angiograms showed that 4 aneurysms achieved complete occlusion (40%), 5 had a remnant neck (50%), and 1 had a remnant sac (10%). During the follow-up period, (26.0 +/- 4.5 months; range, 3-49 months), there were no incidents of recurrence and bleeding. One patient experienced a small cerebral infarction 1 month after the procedure, but it did not lead to any permanent neurologic deficits. CONCLUSIONS: Branch-incorporated MCA aneurysms can be treated with coil embolization, with few procedural complications and midterm durability with appropriate techniques and devices. PMID- 30010074 TI - Giant Craniospinal Intramedullary Neurenteric Cyst in Infant-Case Report and Review of Literature. AB - BACKGROUND: Neurenteric cysts are rare congenital lesions derived from an anomalous connection between the primitive ectoderm and endoderm. CASE DESCRIPTION: A 2-month-old infant presented with an insidious onset of upper limb weakness. Magnetic resonance imaging of the spine revealed a contrast-enhancing solid mass located anterior to the spinal cord at the level of the cervicothoracic junction, which was isointense on T1-weighted images and hyperintense on T2-weighted images. The lesion was associated with marked spinal cord compression and also with a giant intramedullary cyst that extended proximally into the cranium. Spinal dysraphism was noted. The patient underwent cervicothoracic laminotomy, drainage of the cyst contents, and a complete excision of the solid component. Neurologic function recovery was observed postoperatively. CONCLUSIONS: We report and discuss the clinical presentation, pathogenesis, and neuroradiologic findings in an infantile case of a giant craniospinal intramedullary neurenteric cyst. Early recognition is beneficial because of its benign nature and good clinical outcome following total surgical resection. PMID- 30010075 TI - The Top 50 Most-Cited Articles on Thoracolumbar Fractures. AB - OBJECTIVE: To identify the top 50 most-cited articles in the literature focusing on thoracolumbar spine fractures. METHODS: Using the ISI Web of Science version 5.11 database and the search phrase "thoracolumbar fracture," we queried for the 50 most-cited articles on thoracolumbar fractures. The study was performed in September 2017. We searched for articles published between 1900 and 2017. Articles were sorted and ranked based on the total number of citations. We evaluated the following information pertaining to each article: first author, year of publication, journal, and title. RESULTS: A total of 2718 studies matched our search criteria, of which the top 50 most-cited ranged between 267 and 81 citations. Twelve articles were cited more than 200 times. The article by McLain et al. was the most-cited article, with 267 citations, followed by Vaccaro et al. with 237 and Mumford et al. with 236. The majority of the studies originated from the United States (n = 26) and were published in the 1990s. Spine was the most frequent destination journal (n = 26), followed by the Journal of Bone and Joint Surgery (n = 7). Most of the articles focused on the clinical management of thoracolumbar fracture (82%). Vaccaro and McAfee were the most cited first authors, with 3 articles each. CONCLUSIONS: Thoracolumbar fractures are the most common injuries of the spine, and the incidence is increasing globally. To understand current treatment guidelines and how treatment of these fractures has evolved, it is important to know the most-cited articles pertaining to these fractures. PMID- 30010076 TI - Anatomic Variations of the Lateral Femoral Cutaneous Nerve: Remnants of Atypical Nerve Growth Pathways Revisited by Intraneural Fascicular Dissection and a Proposed Classification. AB - OBJECTIVE: To trace anatomic variations of the lateral femoral cutaneous nerve (LFCN) in its intrapelvic course. METHODS: Forty cadavers (80 sides) fixed in 10% formalin solution were dissected. The following parameters were recorded: LFCN diameter and variations in its origin and number. The dissection comprised exposure and excision of the lumbar plexus, together with the roots of LFCN, followed by retrograde intraneural fascicular dissection using microsurgical instruments. RESULTS: Several types of LFCN origin from the lumbar plexus were observed. Typically, the LFCN appears as a single trunk arising from dorsal divisions of the ventral rami of the lumbar plexus. The most prevalent origin of the nerve was from the L2 and L3 roots (47 cases; 58.75%). The LFCN took an origin from the L1-L2 level in 12 cases (15%) and from the L2 nerve in 9 cases (11.25%). The main observed variations were the presence of the accessory LFCN (2 cases; 2.5%) and branching of the LFCN from the femoral nerve (6 cases; 7.5%). Communications between the LFCN and the femoral or genitofemoral nerves also were observed occasionally. An atypical course of the LFCN with respect to the anterior psoas was observed in our material in 3 of the 80 sides (3.75% of the examined LFCN specimens). CONCLUSIONS: Considerable variability in the origin and the course of the LFCN was observed, which should be taken into account during clinical assessment of nerve lesions and during surgery via transpsoas approaches to the lumbar spine. PMID- 30010077 TI - Brainstem Congestion Due to Dural Arteriovenous Fistula at the Craniocervical Junction: Case Report and Review of the Literature. AB - BACKGROUND: Dural arteriovenous fistulas (DAVFs) at the craniocervical junction are rare. Clinical manifestations range from acute or chronic myelopathy to subarachnoid hemorrhage to brainstem dysfunction. We encountered 4 cases of DAVFs at the craniocervical junction with progressive brainstem dysfunction and investigated the typical magnetic resonance imaging (MRI) features using T2 weighting imaging, susceptibility-weighted imaging, diffusion-weighted imaging, and contrast-enhanced imaging. Literature review revealed 10 case reports of DAVFs at the craniocervical junction manifesting with brainstem dysfunction. CASE DESCRIPTION: Four patients presented with DAVFs at the craniocervical junction with progressive brainstem dysfunction. Two patients underwent midline suboccipital craniotomy and C1 laminectomy, and 1 patient underwent transarterial endovascular embolization with Onyx 18 under general anesthesia. All neurologic deficits gradually improved after the operation. In the fourth case, the patient received conservative treatment and did not undergo any surgical procedure. MRI showed high signal intensity on T2-weighted imaging, magnetic resonance angiography, and magnetic resonance venography. Abnormal dilated vessels and flow void signs around the lesions were detected on susceptibility-weighted imaging and contrast-enhanced images. Two cases revealed no abnormalities and had improved neurological deficits than those showed on diffusion-weighted imaging. CONCLUSIONS: Susceptibility-weighted imaging, diffusion-weighted imaging, or contrast-enhanced scanning should be used during MRI examination of patients with progressive brainstem dysfunction to differentiate DAVFs at the craniocervical junction from other diseases, such as glioma or infection. Prompt diagnosis using MRI is of great significance in producing good functional outcomes of the patients. PMID- 30010078 TI - Endoscopic Endonasal Surgery for Removal of Pituitary Adenomas: A Surgical Case Series of Treatment Results Using Different 2- and 3-Dimensional Visualization Systems. AB - BACKGROUND: Endoscopic endonasal transsphenoidal surgery (EETS) is a common treatment for patients with pituitary adenomas (PAs). A disadvantage of endoscopic surgery has been the lack of stereoscopic vision and depth perception. Recent developments offer high-definition 3-dimensional (3D-HD) visualization with a higher resolution and better image quality compared with 3D standard endoscopy (3D-SD). In this study, we compared treatment results of surgically treated patients with PAs using 3 different visualization systems: 2-dimensional (2D)-HD, 3D-SD, and 3D-HD. METHODS: Data from patients with primary PAs that were surgically treated between December 2008 and December 2017 were analyzed. Preoperative and postoperative tumor size and location, perioperative complications, and ophthalmologic, endocrine, and clinical outcomes were compared. RESULTS: A total of 170 patients underwent endoscopic resection of a primary PA (54 patients with 2D-HD, 75 with 3D-SD, and 41 with 3D-HD). Preoperatively, no statistical differences were found for tumor size, extension, and endocrine and ophthalmologic status. Tumor resection was not statistically different among the 3 groups. Complete resection was performed in 33 patients (80%) in the 3D-HD group, 54 patients (72%) in the 3D-SD group, and 39 patients (72%) in the 2D-HD group. The number of complications was not different across the groups (P = 0.436). Ophthalmologic outcomes did not differ based on EETS technique. The rate of new pituitary insufficiency was slightly lower in the 3D HD group compared with 2D-HD and 3D-SD groups (4.8%, 16.6%, and 12%, respectively; P = 0.290). CONCLUSIONS: Although the resection rate was higher in the 3D-HD group, and subjective advantages of the 3D-HD endoscopes were noted, there were no significant differences in terms of gross total resection or new hormonal deficits among the 3 groups. PMID- 30010079 TI - High maternal osteocalcin levels during pregnancy is associated with low birth weight infants: A nested case-control study in China. AB - BACKGROUND: Low birth weight infants (LBW) are at risk of chronic diseases in later life due to the disorder of energy metabolism during pregnancy. Osteocalcin (OC) has been identified as a hormone that regulate energy metabolism. However, few studies have researched on the associations between maternal serum OC levels and low birth weight infants. OBJECTIONS: To examine the associations between maternal serum OC concentrations and LBW. METHODS: This was a nested case-control study involving a total of 230 pregnant women delivering LBW and 382 control pregnant women (matched for infant gender, gestational age at blood draw, region of Maternity and Child Healthcare Hospital and maternal age in 1: (1-2) ratio). One serum sample was collected from each pregnant woman at 5-35 weeks' gestation. Pregnant women were divided into 3 groups (1st, 2nd and 3rd trimester group). There were 60 and 142 and 28 pregnant women delivering LBW in the first, second and third trimester, respectively. Similarly, there were 101 and 233 and 48 controls in the first, second and third trimester, respectively. Maternal serum OC and 25(OH)D concentrations were categorized into low and high levels, the low level used as reference in analyses. Binary logistic regression model was used to compute odd radio (ORs) for LBW according to levels of maternal serum OC and 25(OH)D. RESULTS: Compared with the subjects in low level in first trimester, LBW was two times as likely to occur among pregnancy women with high serum OC concentrations (OR = 2.04, 95%CI:1.05-3.96). After adjusted for confounding factors, a significant positive relationship still existed (adjusted ORs = 2.29, 95%CI: 1.11-4.72). In second trimester, women in high level of serum OC had nearly 1.6 times the risk of delivering LBW infants as those in the low level (OR = 1.55, 95%CI: 1.01-2.37). After adjusted for confounding factors, the ORs increased (ORs = 1.59, 95%CI:1.03-2.45). No significant associations were found between maternal serum OC levels and LBW in third trimester. In addition, there were no associations between maternal 25(OH)D concentrations and LBW during pregnancy. CONCLUSION: High maternal serum OC levels in the first or the second trimester during pregnancy may be associated with the risk of LBW. PMID- 30010080 TI - Identification of TGFbeta-related genes regulated in murine osteoarthritis and chondrocyte hypertrophy by comparison of multiple microarray datasets. AB - OBJECTIVE: Osteoarthritis (OA) is a joint disease characterized by progressive degeneration of articular cartilage. Some features of OA, including chondrocyte hypertrophy and focal calcification of articular cartilage, resemble the endochondral ossification processes. Alterations in transforming growth factor beta (TGFbeta) signaling have been associated with OA as well as with chondrocyte hypertrophy. Our aim was to identify novel candidate genes implicated in chondrocyte hypertrophy during OA pathogenesis by determining which TGFbeta related genes are regulated during murine OA and endochondral ossification. METHODS: A list of 580 TGFbeta-related genes, including TGFbeta signaling pathway components and TGFbeta-target genes, was generated. Regulation of these TGFbeta related genes was assessed in a microarray of murine OA cartilage: 1, 2 and 6 weeks after destabilization of the medial meniscus (DMM). Subsequently, genes regulated in the DMM model were studied in two independent murine microarray datasets on endochondral ossification: the growth plate and transient embryonic cartilage (joint development). RESULTS: A total of 106 TGFbeta-related genes were differentially expressed in articular cartilage of DMM-operated mice compared to sham-control. From these genes, 43 were similarly regulated during chondrocyte hypertrophy in the growth plate or embryonic joint development. Among these 43 genes, 18 genes have already been associated with OA. The remaining 25 genes were considered as novel candidate genes involved in OA pathogenesis and endochondral ossification. In supplementary data of published human OA microarrays we found indications that 15 of the 25 novel genes are indeed regulated in articular cartilage of human OA patients. CONCLUSION: By focusing on TGFbeta-related genes during OA and chondrocyte hypertrophy in mice, we identified 18 known and 25 new candidate genes potentially implicated in phenotypical changes in chondrocytes leading to OA. We propose that 15 of these candidates warrant further investigation as therapeutic target for OA as they are also regulated in articular cartilage of OA patients. PMID- 30010081 TI - Pulsed electromagnetic fields modulate bone metabolism via RANKL/OPG and Wnt/beta catenin pathways in women with postmenopausal osteoporosis: A pilot study. AB - Pulsed electromagnetic fields (PEMFs) have been proven to enhance in vitro and in vivo osteogenesis with unknown mechanism. Aim of our study was to explore whether RANKL/OPG and Wnt/beta-Catenin pathways could be involved in bone response to PEMFs in a setting of postmenopausal osteoporotic women. Forty-three women (mean age 62.8 +/- 4.5 yr.) were randomized into two groups. The PEMFs group received PEMFs treatment (50 min treatment session/day, 6 treatment sessions/week, for a total of 25 times), by wearing a specific gilet applied to the trunk and connected to the electromagnetic device (Biosalus, by HSD Srl, Serravalle RSM), while women assigned to control group received sham PEMFs with the same device. BSAP as bone formation and CTX as bone resorption markers, RANKL, OPG, beta Catenin, DKK-1 and sclerostin were obtained at baseline, after 30 and 60 days. In PEMFs group, BSAP levels significantly increased after 30 and 60 days while CTX concentrations decreased at day 60. RANKL levels significantly decreased after 60 days. OPG was not significantly changed, but the RANKL/OPG ratio significantly decreased at day 30. DKK-1 levels decreased, while beta-catenin concentrations increased after 30 and 60 days (P < 0.05). No significant changes of calcium, phosphorus, creatinine and sclerostin were detected. In the PEMFs group, at day 30, Deltasclerostin was associated with DeltaRANKL/OPG ratio (r = -0.5, P = 0.03) and DeltaDKK-1 was associated with Deltabeta-Catenin (r = -0.47, P = 0.02). In women with postmenopausal osteoporosis, our data provide evidence of a PEMFs modulation of RANKL/OPG and Wnt/beta-Catenin signaling pathways able to explain the metabolic effects of PEMFs on bone. PMID- 30010082 TI - Impact of aging on bone, marrow and their interactions. AB - Hematopoiesis in land dwelling vertebrates and marine mammals occurs within the bone marrow, continually providing mature progeny over the course of an organism's lifetime. This conserved dependency highlights the critical relationship between these two organs, yet the skeletal and hematopoietic systems are often thought of as separate. In fact, data are beginning to show that skeletal disease pathogenesis influences hematopoiesis and viceversa, offering novel opportunities to approach disease affecting bone and blood. With a growing global population of aged individuals, interest has focused on cell autonomous changes in hematopoietic and skeletal systems that result in dysfunction. The purpose of this review is to summarize the literature on aging effects in both fields, and provide critical examples of organ cross-talk in the aging process. PMID- 30010083 TI - A two phase regulation of bone regeneration: IL-17F mediates osteoblastogenesis via C/EBP-beta in vitro. AB - T lymphocytes and pro-inflammatory cytokines, specifically interleukin-17F (IL 17F) have been identified as important regulators in bone regeneration during fracture repair. To better understand the molecular mechanisms of IL-17F-mediated osteoblastogenesis, a mouse pre-osteoblast cell line (MC3T3-E1) was utilized to characterize the intracellular signal transduction of IL-17F. Comparisons to the established canonical Wnt signaling pathway were made using Wnt3a ligand. Our results demonstrated greater bone marker gene expression in IL-17F-treated cells, compared to cells treated with Wnt3a. Western blot analysis confirmed degradation of beta-catenin and up-regulation of two key proteins in osteoblast differentiation, Runx2 and C/EBP-beta, in response to IL-17F treatment. RNA silencing of IL-17F receptors, IL-17Ra and IL-17Rc via siRNA transfection resulted in decreased expression of Act2, Runx2, and C/EBP-beta, demonstrating the direct ligand-receptor interaction between IL-17F and IL-17Ra/c as an activator of osteoblastogenesis. Our findings suggest that IL-17F promotes osteoblast differentiation independent of the canonical Wnt pathway and beta catenin signaling, presenting new insights on modulating the adaptive immune response in the inflammatory phase, temporally distinct from the reparative and remodeling phases of fracture healing. PMID- 30010084 TI - Dietary sugar intake does not pose any risk of bone loss and non-traumatic fracture and is associated with a decrease in all-cause mortality among Chinese elderly: Finding from an 11-year longitudinal study of Mr. and Ms. OS Hong Kong. AB - BACKGROUND: The association of dietary sugar intake and skeletal health remains uncertain in the elderly. We aimed to investigate the association of sugar intake with the bone health and mortality of Chinese elderly. METHODS: An analysis was conducted through an 11-year longitudinal study (Mr. and Ms. OS Hong Kong). Four thousand Chinese elderly aged 65 and older were recruited from the local community between 2001 and 2003. Sugar intake was assessed at baseline by a validated 329-item Food Frequency Questionnaire and a local sugar database. The bone mineral density (BMD) was examined at baseline and the fourth year follow-up by a dual-energy X-ray absorptiometry. Data on the incidence of non-traumatic fractures (total, hip and osteoporotic sites) and all-cause mortality were collected. The multivariable logistic and Cox regression models were used to test the associations of sugar intake with bone health and all-cause mortality. RESULTS: No significant association was observed between sugar intakes and BMD changes in the fourth year's follow-up. During a total 34,483 person years' follow-up, we documented 433 non-traumatic fractures and 769 deaths. Although lack of significant association with the incidence of non-traumatic fractures, high added sugar intakes were significantly associated with a low risk of all cause mortality among the elderly with a hazard ratio of 0.750 (95% CI: 0.590 0.954, P for trend = 0.007) in the highest quintile compared with that in the lowest quintile. CONCLUSION: The amount of sugar consumed by the Chinese elderly did not pose any risk of bone loss and fracture. Moreover, high sugar intake of the elderly was associated with a low rate of all-cause mortality. PMID- 30010085 TI - Randomized trial of a patient-centered decision aid for promoting informed decisions about lung cancer screening: Implementation of a PCORI study protocol and lessons learned. AB - PURPOSE: We describe the methods, stakeholder engagement, and lessons learned from a study comparing a video decision aid to standard educational materials on lung cancer screening decisions. METHODS: The study followed rigorous methodology standards from the Patient-Centered Outcomes Research Institute. The importance of patient-centeredness and patient/stakeholder engagement are reflected across the study's conceptualization, execution, interpretation, and dissemination efforts. Advisory groups of current and former smokers, quitline service providers, clinicians, and patient advocates were formed for the project. The study used both retrospective and prospective recruitment strategies. Randomization of patients occurred within state-based quitlines, with aggressive tracking of participants. We collected data at baseline and 1-week, 3-month and 6 months after receiving the intervention. The patient-centered outcomes included whether patients' receiving the decision aid a) felt better prepared to make a decision, b) felt more informed about the screening decision, c) had more clarity on their values regarding the benefits and harms of lung cancer screening, and d) were more knowledgeable about lung cancer screening than patients receiving the standard education materials. Exploratory outcomes included making an appointment with a health care provider to discuss screening, scheduling and completing lung cancer screening. RESULTS: We have enrolled and randomized 516 quitline patients and learned many lessons about executing the trial based on significant patient and stakeholder engagement. CONCLUSIONS: Conducting patient-centered outcomes research requires new ways of thinking and continuously checking-in with patients/stakeholders. The engagement of quitline service providers and patient advisors has been key to successful recruitment and dissemination planning. PCORI CER-1306-03385 ClinicalTrials.gov NCT ID: NCT02286713. PMID- 30010087 TI - Plasmonic color filters fabricated via oxide-based nanotransfer printing. AB - Plasmonic filters have recently become a topic of significant interest because they are suitable for a wide range of applications. However, effective fabrication of plasmonic filters remains a challenge. In this paper, we demonstrate a simple method for fabricating plasmonic color filters based on nanotransfer printing (nTP) , using SiO2 as a hard mask for Al etching. nTP was performed on a 100 nm Al layer deposited on a glass wafer substrate with a 10 nm Al layer and a 20 nm SiO2 layer with a nanohole pattern. The 10 nm Al layer and 20 nm SiO2 layers were previously transferred from a polymer stamp prepared to create patterns of subwavelength-sized holes. The plasmonic filters were ultimately fabricated using the SiO2 layer as a hard mask to selectively etch the Al layer. The optical properties of the fabricated plasmonic filters were evaluated using experimental and simulation tools. In addition, we analyzed the results of nTP on the Al and SiO2 films by varying the temperature, pressure, and SiO2-film thickness. We believe that this technique is a promising method for fabricating nanostructures and for widening the scope of practical application of plasmonics because of its high efficiency and cost-effectiveness. PMID- 30010088 TI - Ensembling convolutional and long short-term memory networks for electrocardiogram arrhythmia detection. AB - OBJECTIVE: Atrial fibrillation is a common type of heart rhythm abnormality caused by a problem with the heart's electrical system. Early detection of this disease has important implications for stroke prevention and management. Our objective is to construct an intelligent tool that assists cardiologists in identifying automatically cardiac arrhythmias and noise in electrocardiogram (ECG) recordings. APPROACH: Our base deep classifier combined a convolutional neural network (CNNs) and a sequence of long short-term memory units, with pooling, dropout and normalization techniques to improve their accuracy. The network predicted a classification at every 18th input sample and the final prediction was selected for classification. Ten standalone models that used our base classifier architecture were first cross-validated separately on 90% of the PhysioNet/CinC Challenge 2017 dataset and then tested on 10%. An ensemble classifier selected the label of the best average probability from the ten sub models to improve prediction quality. MAIN RESULTS: Our original result submitted to the challenge gave a mean F1-measure of 80%. The new proposed method improved the test score to 82%, which was tied for the third-highest score in the follow up phase of the challenge. SIGNIFICANCE: Without employing a time-consuming feature engineering step, the ensemble classifier trained with this architecture provided a robust solution to the problem of detecting cardiac arrhythmia from noisy ECG signals. In addition, interpretation of the classifier by inspection of its network parameters and predictions revealed what aspects of the ECG signal the classifier considered most discriminating. PMID- 30010086 TI - Nicotine replacement therapy sampling via primary care: Methods from a pragmatic cluster randomized clinical trial. AB - BACKGROUND: Primary care is the most important point of healthcare contact for smokers. Brief physician advice to quit, based on the 5As/AAR model, offers some efficacy but is inconsistently administered and has limited population impact. Nicotine replacement therapy (NRT) sampling, defined as provision of a brief NRT starter kit, when added to the 5As/AAR, is well-suited to primary care because it is simple, brief, and can be provided to all smokers. This article describes the design and methods of an ongoing comparative effectiveness trial testing standard care vs. standard care + NRT sampling within primary care. METHODS: Smokers were recruited directly from primary care practices between July 2014 and December 2017 within an established network of South Carolina clinics. Interventions were delivered randomly by clinic personnel, and phone-based follow-ups were centrally coordinated by research staff to track outcomes through six months post intervention. Primary study aims are to examine the impact of NRT sampling on smoking, inclusive of cessation, quit attempts, and uptake of evidence-based treatment. RESULTS: Twenty-two clinics were recruited. Across clinics, patient census ranged from 985 to 10,957 and number of providers ranged from 1 to 63. Average patient age across clinics was 52.9 years and smoking prevalence across ranged from 10.6% to 28.5%. CONCLUSION: Improving the effectiveness and reach of brief interventions within primary care could have a considerable impact on population quit rates. We consider the advantages and disadvantages of key methodological decisions relevant to the design of future primary care-based cessation trials. PMID- 30010089 TI - Characterization of the coordination of agonist and antagonist muscles among stroke patients, healthy late middle-aged and young controls using a myoelectric controlled interface. AB - OBJECTIVE: The coordination of agonist and antagonist muscles around a single joint plays an important role in daily activities. The aim of this study was to apply a myoelectric-controlled interface (MCI) with different dimensions to investigate stroke- and aging-induced deteriorations in the coordination of agonist and antagonist muscles. APPROACH: Eight stroke patients (affected sides), ten healthy late middle-aged controls and eighteen healthy young controls were enrolled to perform tracking tasks during voluntary isometric elbow flexion and extension by modulating their biceps and triceps activities with 1D or 2D MCI. The root mean square error (RMSE) between actual and target agonist activations, normalized agonist and antagonist activations, and co-contraction index (CI) and normalized elbow torque were used to quantify the movement performance. MAIN RESULTS: During elbow extension, significant increases in RMSE were identified in stroke patients with increasing MCI dimensionality, whereas significant decreases in normalized agonist and antagonist activations and normalized elbow torque were observed in all three groups. In addition, significant decreases in CI were observed in both control groups (P < 0.05). During elbow flexion and extension, RMSE increased in the following order: young controls < late middle-aged controls < stroke patients. By contrast, CI was significantly higher in stroke patients and late middle-aged controls than in young controls, possibly due to stroke- and aging-induced loss of skill in modulating the coordination of agonist and antagonist muscles when meeting the demands of a changing environment. SIGNIFICANCE: This study suggests that 2D MCI might be applied as a rehabilitation tool to achieve fine control of abnormal muscle coordination. PMID- 30010090 TI - Corrigendum: Generation and stability of dynamical skyrmions and droplet solitons (2018 Nanotechnology 29 325302). PMID- 30010091 TI - Atomic layer deposition for spacer defined double patterning of sub-10 nm titanium dioxide features. AB - The next generation of hard disk drive technology for data storage densities beyond 5 Tb/in2 will require single-bit patterning of features with sub-10 nm dimensions by nanoimprint lithography. To address this challenge master templates are fabricated using pattern multiplication with atomic layer deposition (ALD). Sub-10 nm lithography requires a solid understanding of materials and their interactions. In this work we study two important oxide materials, silicon dioxide and titanium dioxide, as the pattern spacer and look at their interactions with carbon, chromium and silicon dioxide. We found that thermal titanium dioxide ALD allows for the conformal deposition of a spacer layer without damaging the carbon mandrel and eliminates the surface modification due to the reactivity of the metal-organic precursor. Finally, using self-assembled block copolymer lithography and thermal titanium dioxide spacer fabrication, we demonstrate pattern doubling with 7.5 nm half-pitch spacer features. PMID- 30010092 TI - In vivo stability evaluation of Mg substituted low crystallinity beta-tricalcium phosphate granules fabricated through dissolution-precipitation reaction for bone regeneration. AB - Although beta-tricalcium phosphate (beta-TCP) is widely used in clinical applications as a bone substitute owing to its positive tissue response and its ability to be replaced by new bone through a bone-remodeling process, it has the limitation of rapid resorption in vivo, which might become a reason for tissue atrophy and high crystallinity, which decrease biocompatibility. A reduction in the crystallinity might increase the biocompatibility of the bone substitute. To overcome the drawbacks of beta-TCP, decrease in crystallinity and solubility, both are required. Therefore, in this study, the feasibility of fabricating Mg substituted low crystalline beta-TCP (Mg-LC-beta-TCP) granules formed in aqueous solution was evaluated in vivo focusing long-term adsorption and bone formation in bone defects formed in the rabbit femur using sintered beta-TCP granules as a control. With Mg-LC-beta-TCP, the resorption of the substitute was suppressed, and no tissue atrophy was observed even at 24 weeks post-implantation, whereas a few granules with surrounding tissue atrophy were observed at 12 weeks post implantation. Tartrate-resistant acid phosphatase-staining indicated that the density of osteoclasts type cells with Mg-LC-beta-TCP was significantly lower than that with beta-TCP, and also the numbers of osteoblasts type cells with Mg LC-beta-TCP were significantly higher than that with beta-TCP. It is suggested that Mg substitution to form low crystallinity beta-TCP is a valuable way to overcome the limitations of beta-TCP as a bone substitute. PMID- 30010093 TI - Composition and strain relaxation of In x Ga1-x N graded core-shell nanorods. AB - Two In x Ga1-x N nanorod samples with graded In compositions of x = 0.5-0 (Ga rich) and x = 0.5-1 (In-rich) grown by molecular beam epitaxy were studied using transmission electron microscopy. The nanorods had a wurtzite crystal structure with growth along [Formula: see text] and core-shell structures with an In-rich core and Ga-rich shell. Energy-dispersive x-ray analysis confirmed grading over the entire compositional range and showed that the axial growth rate was primarily determined by the In flux, and the radial growth rate by the Ga flux. There was no evidence of misfit dislocations due to grading, but the strain due to the lattice mismatch between the In-rich core and Ga-rich shell was relaxed by edge dislocations at the core-shell interface with Burgers vectors [Formula: see text] and [Formula: see text]. PMID- 30010094 TI - HD-sEMG-based research on activation heterogeneity of skeletal muscles and the joint force estimation during elbow flexion. AB - OBJECTIVE: To investigate the activation heterogeneity of skeletal muscles and realize the joint force estimation during the elbow flexion task. APPROACH: When an isometric elbow flexion task was performed, high-density surface electromyography (HD-sEMG) signals from a [Formula: see text] grid covering the front and inside of the upper arm and the generated joint force were recorded synchronously. HD-sEMG signals were preprocessed and then decomposed into source signals corresponding to biceps brachhi (BB) and brachialis (BR) and their contribution vectors using a fast, independent component analysis (FastICA) algorithm. The activation heterogeneity of BB and BR was investigated from the activation level and activation region, initially. Then, the contribution combinations of two sources were classified into several major clusters using the K-means clustering method. Afterwards, input signals for force estimation were extracted from the major clusters corresponding to different combinations, and the polynomial fitting technique was adopted as the force estimation model. Finally, the force estimation results were obtained and the analysis around the force estimation performance using different input signals was conducted. MAIN RESULTS: Ten subjects were recruited in this research. The experimental results demonstrated that it is feasible to analyze the activation heterogeneity of muscles from the activation level and activation region, and to select the appropriate region of the HD-sEMG grid for high performance force estimation. For the isometric elbow flexion task, joint force estimation accuracy could be improved when the input signal was extracted from the specific area where the contribution difference of BB and BR to the HD-sEMG signals were relatively small. SIGNIFICANCE: The proposed framework provided a novel way to explore the relationship between muscle activation and the generating joint force, and could be extended to multiple noteworthy research fields such as myoelectric prostheses, sports biomechanics, and muscle disease diagnosis. PMID- 30010095 TI - Depletion-model-based numerical simulation of the kinetics of red blood cell aggregation under sinusoidal pulsatile flow. AB - BACKGROUND: Previous numerical modeling studies on red blood cell (RBC) aggregation have elucidated the inverse relationship between shear rate and RBC aggregation under steady flow. However, information on the cyclic variation in RBC aggregation under pulsatile flow remains lacking. OBJECTIVE: RBC aggregation was simulated to investigate the complex interrelationships among the parameters of RBC motion under pulsatile flow. METHODS: A two-dimensional particle model was used to simulate RBC motion driven by hydrodynamic, aggregation, and elastic forces in a sinusoidal pulsatile flow field. The kinetics of RBCs motion was simulated on the basis of the depletion model. RESULTS: The simulation results corresponded with previously obtained experimental results for the formation and destruction of RBC aggregates with a parabolic radial distribution during a pulsatile cycle. In addition, the results demonstrated that the cyclic variation in the mean aggregate size of RBCs increased as velocity amplitude increased from 1 cm/s to 3 cm/s under a mean steady flow of 2 cm/s, as mean steady flow velocity decreased from 6 cm/s to 2 cm/s under a velocity amplitude of 1.5 cm/s, and as stroke rate decreased from 180 beats per minute (bpm) to 60 bpm. CONCLUSIONS: The present simulation results verified previous experimental results and improved the current understanding of the complex spatiotemporal changes experienced by RBC aggregates during a sinusoidal pulsatile cycle. PMID- 30010096 TI - Biomechanical properties of veins cultured in vitro under elevated internal pressure. AB - BACKGROUND: The venous response to elevated blood pressure (BP) is of major importance because it is closely related to the etiology of venous diseases and the competency of vein grafts. In vitro culture experiments may provide useful information on the function of vein grafts because it is easier to separate mechanical and hemodynamic effects from other systemic influences compared to in vivo experiments. OBJECTIVE: To study the effects of BP elevation on wall dimensions and mechanical properties of in vitro cultured veins. METHODS: Rabbit femoral veins were cultured in vitro under internal pressures of 1 to 50 mmHg for 1 week, and their wall dimensions, biomechanical properties, and histology were determined. RESULTS: No significant differences were observed in internal vein diameter and wall thickness among vessels cultured at 10-50 mmHg compared to non cultured control vessels. For an internal pressure of 10 mmHg applied to vessels during culture (equivalent to in vivo working BP), wall circumferential stress was maintained within control levels. There were no significant effects of pressure on basal tone and contractility of vascular smooth muscle and vascular compliance. CONCLUSIONS: The in vitro results were essentially similar to those obtained from previous in vivo animal experiments, indicating that in vitro tissue culture techniques are applicable to studies of venous remodeling. PMID- 30010097 TI - Knee musculoskeletal impairments and associated pain factors among rice farmers. AB - BACKGROUND: Rice farming is done using manual methods and involves strenuous labour, which can lead to musculoskeletal disorders. OBJECTIVE: To identify the factors associated with knee musculoskeletal impairments and related pain among rice farmers complaining of knee pain. METHODS: The study employed a community based, cross-sectional design. Full-time rice farmers (n= 201) were surveyed. A questionnaire was used to record demographics and details of farm work; followed by a physical examination of knee structures impairments. RESULTS: The prevalence of knee impairment was highest among farmers with joint dysfunction (79.6%), followed by those with dysfunctional hamstring muscles (52.74%), quadriceps muscles (44.28%), neural tissue (38.81%), and ligaments (1.99%). It was lowest among farmers with meniscus dysfunction (1.49%). Stooping with twisting was strongly associated with knee joint and quadricep muscle impairment. Stooping with twisting and carrying loads were associated with hamstring muscle impairment. Stooping while twisting and being overweight was associated with neural tissue impairment. Being overweight was significantly associated with ligament impairment. There were no factors significantly associated with meniscus dysfunction. CONCLUSIONS: Knee musculoskeletal impairments is common among Thai rice farmers. Joint dysfunction was common. The factors associated with knee musculoskeletal impairments included being overweight, stooping while twisting and carrying heavy weight. PMID- 30010098 TI - Wearing high-heeled shoes increases the foot arch angle inducing measurable changes in the musculoskeletal system. AB - BACKGROUND AND OBJECTIVE: The study determined the effects of females wearing high-heeled shoes on the lower extremity musculoskeletal system and somatometry. METHODS: The study was carried out with 136 females between 18 and 45 years old. The first group consisted of 66 females wearing 5 cm or higher high-heeled shoes, at least 5 hours a day, three days a week, and at least one year. The second group consisted of 70 females wearing shoes with heel height less than 5 cm for at least one year. RESULTS: Differences in length parameters may result from the narrow and pointed toe of the high-heeled shoe. These shoes distribute the pressure on the caput ossis metatarsi I and compress the foot in this area. Differences in anthropometric measurements show that females wearing high-heeled shoes have more slender and aesthetic foot structure. CONCLUSION: These findings show that regular wearing of high-heeled shoes causes changes via the increased foot arch structure. These alterations result from regional, racial, gender, heel height, shoe type (shape), and shoe habits. PMID- 30010099 TI - Strategy on navigating obstacle in patients with lumbar spinal stenosis: Relationship among trunk and pelvic movement, swing toe clearance, and muscle coordination of the stance limb. AB - BACKGROUND AND OBJECTIVE: Lumbar spinal stenosis (LSS) is a common spinal disorder that causes patients to assume a forward-trunk posture. Spinal alignment affects gait, muscle activity, and trunk-pelvis-limb coordination because the lumbar spine and muscles interact to allow load transfer between the lower back and pelvis during sagittal trunk movement. Therefore, we investigated the relationships among trunk and pelvic movement, swing toe clearance, and muscle coordination (isolated contraction ratios) of the stance limb during obstacle crossing by patients with LSS. METHODS: Ten patients with LSS and ten control subjects were enrolled. All navigated an obstacle during walking. Kinematic data from the trunk and lower extremities were monitored using a three-dimensional motion analysis system. In addition, we measured the isolated contraction ratios of the gluteus medius (GMed) and vastus lateralis (VL) using surface electromyography. RESULTS: The normalized lead limb distance was significantly lower in the LSS group than in controls. The spine flexion angle when the swinging limb toe was above the obstacle was higher, but the pelvic anterior tilting angle was lower, in the LSS group. LSS patients also had a significantly lower isolated contraction ratio of the GMed in the trailing stance limb but a significantly higher VL. CONCLUSIONS: Patients with LSS adapted a poor posture and their thoracic and spinal regions were hyperflexed with restricted pelvic obliquity. This created an inefficient gait, a shorter leading limb step, and less stable muscle coordination in the stance limb. Our findings may help healthcare professionals manage patients with LSS. PMID- 30010100 TI - The relation between abdominal muscle asymmetry and trunk postural stability: An ultrasound imaging study. AB - BACKGROUND: The core stability theory has emphasized symmetric co-contraction of both anterolateral abdominal muscles (AAM), but there is a lack of research on whether the symmetric co-contraction of AAM is related to the postural stability of the trunk. OBJECTIVE: This study aimed to investigate the correlation between the symmetric co-contraction of bilateral AAM and trunk angular displacement during sudden trunk perturbation. METHODS: Eighteen subjects were asked to maintain half-seated posture against backward trunk perturbation. Muscle thicknesses of external oblique (EO), internal oblique (IO), and transversus abdominis (TrA) were measured using ultrasound imaging. 3D motion analysis system was utilized to calculate the amount of trunk angular displacement during perturbation. RESULTS: There were significant differences of side-to-side muscle thickness in TrA (P= 0.02) and EO (P= 0.02), but the difference disappeared during sudden external loading. No significant correlation was identified between the asymmetry of abdominal muscle thickness and the amount of trunk angular displacement. CONCLUSIONS: These findings indicate that the side-to-side asymmetry of AAM measured in a static position is rarely related to the core stability because the asymmetry can disappear during trunk stabilization. PMID- 30010101 TI - Evaluation of neural therapy effect in patients with piriformis syndrome. AB - BACKGROUND: The aim of this study was to explore the effect of neural therapy on pain and functionality in patients with low back pain due to piriformis syndrome. It also aimed to find out any possible links between the clinical changes and demographic features. METHOD: One hundred and two patients were randomly divided into two groups (neural therapy and control). All patients were given stretching exercises for the piriformis muscle. The patients in the neural therapy group additionally received 6 sessions of neural therapy. The visual analog scale (VAS) and Oswestry Disability Index (ODI) were noted before and after the treatment in both groups. RESULTS: The VAS and ODI improved in both groups. However, improvement of the VAS and ODI scores were more obvious in the neural therapy group. The changes of VAS and ODI values did not show any correlations with the demographic features. CONCLUSION: After the neural therapy, the patients with low back pain due to piriformis syndrome may have improvement in both pain and functioning. PMID- 30010102 TI - Electromyographic analysis of selected shoulder muscles during rehabilitation exercises. AB - BACKGROUND: Overhead work-activities and repetitive use of arm in occupational tasks are known risk factors to cause shoulder injury that often develops to functional disability. Rehabilitation exercises (REs) are capable of slowing this development. OBJECTIVE: The main objective of the present work is to experiment with common REs and to identify those which produce significant integrated electromyography (iEMG) activation of selected shoulder muscles namely, posterior deltoid, infraspinatus, teres minor, upper trapezius, middle trapezius and lower trapezius. METHODS: Ten healthy male occupational workers, exposed to the risk of shoulder injury, performed six REs while iEMG activities of concerning muscles are recorded using Biopac MP 150 system. REs are cross-examined statistically to select those which yield higher iEMG activations. RESULTS: Results indicate that upper trapezius presents the highest iEMG activity in exercise 6 (standing ER at 90? abduction and 90? elbow flexion). Middle trapezius and lower trapezius show highest activation in exercise 1 (prone horizontal abduction at 90? with full external rotation with thumb right up). Also, posterior deltoid, infraspinatus, and teres minor have the highest iEMG activity in this exercise. CONCLUSIONS: Results provide basic information to select appropriate rehabilitation programs for occupational workers exposed to the risk of shoulder injury. PMID- 30010103 TI - Musculoskeletal problems and attitudes towards footwear among university students. AB - BACKGROUND AND OBJECTIVE: Footwear preferences and habits may be related to musculoskeletal system problems. This study was designed to determine the relationship between the selection of footwear, musculoskeletal problems and the affecting factors among university students from that different division. METHODS: Four hundred and sixty-six university students in the divisions of Physiotherapy Rehabilitation, Nursing and Business Administration participated in this study. The data was collected using a questionnaire developed by the researchers and the Extended Nordic Musculoskeletal Questionnaire. RESULTS: Of the participants, 68.5% preferred to wear sports shoes; 24.0% of the participants had foot pain. Comfort, robustness and quality come to the fore in the behavioural patterns of young and healthy individuals regarding footwear. Those who experienced foot and lower back pain considered such parameters as quality, fitness for foot health, flexibility and lightness in footwear. CONCLUSIONS: While patterns such as foot health, flexibility and lightness are reflected in the footwear preferences of those who have lower back pain, those who have pain or problems in their feet take into consideration the quality, lightness, fitness to foot health. The relationship determined in the present study shows that those who experience pain are more selective in their footwear preferences. PMID- 30010104 TI - The effect of therapeutic abdominal drawing-in maneuver using ultrasonography on lateral abdominal muscle thickness and balance. AB - BACKGROUND: Lateral abdominal muscles control the lumbar region and this manages the stability of the trunk through co-contraction. Abdominal drawing-in maneuver (ADIM) is the basis method for spine stabilization to restore proper neuromuscular control. OBJECTIVE: To investigate the effect of therapeutic abdominal drawing-in maneuver on abdominal muscle thickness and balance. METHODS: Twenty healthy adults were divided into 2 groups. The experimental group performed a bridging exercise with ADIM whereas the control group performed a bridging exercise without ADIM. The exercise was conducted 3 times a week for 4 weeks. Ultrasonography was used to measure the thickness of abdominal muscles. Balance ability was evaluated using Tetrax device. The Wilcoxon signed ranks test for comparison of pre and post values and Mann Whitney U test for comparison between groups were used. RESULTS: After 4 weeks, there was a significant difference in the thickness of TrA between groups (p< 0.05) whereas no significant difference in IO and EO (p> 0.05). In stability values, the experimental group showed significant changes in stability indexes of standing with eyes open (NO) and standing on the pillow with eyes closed (PC) after the exercise period and there was a significant difference in NO between two groups. CONCLUSIONS: Performing the bridging exercise with abdominal drawing-in maneuver is a more effective way to strengthen the abdominal muscles and stabilize the body than bridging exercise only. PMID- 30010105 TI - Effects of various treatment approaches for treatment efficacy for late stage breast cancer and expression level of TIMP-1 and MMP-9. AB - Breast cancer is one common female specific malignant tumor and has gradually increased incidence. Matrix metalloproteinase-9 (MMMP-9) and its inhibitor TIMP-1 participate in tumor invasion and metastasis. This study analyzed the effect of various treatment approaches on TIMP-1 and MMP-9 levels in terminal stage breast cancer. Post-op breast cancer patients including chemo-radio therapy group, radio chemo therapy group and simultaneously chemo- and radio-therapy group were compared for efficacy, along with assays for TIMP-1 and MMP-9 levels for analyzing their correlation with clinical-pathological features of breast cancer. Chemo + radio-therapy group had lower focal recurrence and distal metastasis than the other two groups, plus higher 5-year survival rates (p<0.05). After treatment, all patients showed lower serum MMP-9 level, activity and higher TIMP 1 levels than those before treatment (p< 0.05). Concurrent radio + chemo-therapy group showed lower serum MMP-9 level, activity and higher TIMP-1 levels (p< 0.05 compared to the other two groups). Serum MMP-9 and TIMP-1 levels after treatment are correlated with patient age, pathological grade, tumor size and lymph node metastasis (p< 0.05). Simultaneous chemo- and radio-therapy on breast cancer patients after surgery could reduce focal recurrent rate or distal metastasis rate, thus improving 5-year survival rate. MMP-9 and TIMP-1 levels are correlated with age, pathological grade, tumor size and lymph node metastasis of breast cancer patients. PMID- 30010106 TI - Annexin A5 overexpression might suppress proliferation and metastasis of human uterine cervical carcinoma cells. AB - BACKGROUND: Annexin A5 (ANXA5) is a kind of Ca2+-dependent phospholipid binding protein which is involved in cell membrane dynamics and organization. Recent data showed that ANXA5 might involve in tumorigenesis. OBJECTIVE: To explore what role ANXA5 play in human uterine cervical carcinoma. MATERIALS AND METHODS: In this study, a recombined ANXA5 plasmid was constructed and uterine cervical carcinoma cell lines HeLa and SiHa were transfected with it. After ANXA5 overexpression was determined by Western Blot, cell proliferation test was detected by MTT assay and colony formation assay respectively. FACS assay and Hochest33258 staining methods were employed to detect cell apoptosis. To further investigate whether ANXA5 influence cell migration and invasion, wound healing assay and transwell assay were applied. At the same time, the relative mechanism was investigated. RESULTS: When ANXA5 expression increased, cell proliferation was inhibited by regulating the expression of bcl-2 and bax while cell metastasis was suppressed by regulating E-cadherin and MMP-9 expression. CONCLUSION: ANXA5 overexpression in the uterine cervical carcinoma might play important roles in cell proliferation and metastasis of uterine cervical cancer cells and act as an anti-cancer gene in uterine cervical cancer. PMID- 30010107 TI - Correlations of MRI manifestations with survivin gene expression in primary hepatic carcinoma. AB - OBJECTIVE: To investigate the correlations of magnetic resonance imaging (MRI) manifestations with survivin gene expression in primary hepatocellular carcinoma (HCC). METHODS: A total of 84 HCC patients receiving partial hepatectomy in the Surgery Department and Oncology Department in our hospital from April 2011 to May 2014 were recruited. At 1 week before operation, MRI was used to examine the imaging features of liver, a certain size of area was defined and the signal value of each sequence was recorded. HCC and para-carcinoma tissues were collected after operation, and the expression levels of survivin were detected via immunohistochemistry (IHC). All patients were followed up for 30 months after operation, and the Kaplan-Meier survival curve was drawn. The correlations of survivin expression with MRI features and signal parameters of each sequence were analyzed. RESULTS: There was no expression of survivin in normal liver tissues. In HCC and para-carcinoma tissues, the nuclei of positive cells showed brown yellow. The positive expression rate of survivin in HCC tissues was 76.19% (64/84), which was significantly higher than that in para-carcinoma tissues (20.81%, 20/84) (p< 0.05). The overall survival (OS) of patients with high expression of survivin was 12.5 months, which was significantly shorter than that of patients with low expression of survivin (17.6 months) (p< 0.05). Results of chi-square test showed that the survivin level had no correlations with the MRI scan shape and edge in the tumor area (p> 0.05), but it was significantly correlated with tumor diameter, MRI enhancement features and lymphatic metastasis (p< 0.05). Pearson correlation analyses revealed that the survivin IHC score was not correlated with in-phase T1-weighted gradient-recalled echo (GRE), hepatic arterial-phase T1-weighted GRE, portal venous-phase T1-weighted GRE and equilibrium-phase T1-weighted GRE signals (p> 0.05). Besides, the survivin IHC score was negatively correlated with opposed-phase T1-weighted GRE (r=-0.46, p= 0.038), but positively correlated with T2-weighted fast spin echo signal (r= 0.49, p= 0.025). CONCLUSION: Survivin is significantly up-regulated in HCC tissues and associated with tumor growth and lymph node metastasis. Clinical detection of survivin level combined with MRI examination might be beneficial for clinical diagnosis and treatment of HCC. PMID- 30010108 TI - Correlations of TNM staging and lymph node metastasis of gastric cancer with MRI features and VEGF expression. AB - OBJECTIVE: To investigate the correlations of expression of vascular endothelial growth factor (VEGF) in gastric cancer tissues of patients and magnetic resonance imaging (MRI) features with clinical tumor-node-metastasis (TNM) staging and lymph node metastasis, and to analyze the diagnostic value of MRI features for preoperative TNM staging and lymph node metastasis of patients with gastric cancer, and the roles of VEGF in tumor development and metastasis. METHODS: A total of 120 gastric cancer patients treated in our hospital from May 2015 to July 2017 were selected as objects of study. The VEGF protein expressions in gastric cancer tissues of patients with different TNM staging and lymph node metastasis degrees were detected using immunohistochemical method, and the correlations of VEGF protein expression with TNM staging and lymph node metastasis were analyzed. Before operation, MRI was used to predict TNM staging and lymph node metastasis of all patients, and prediction results were compared with postoperative pathological diagnosis results. At the same time, the differences in lymph node apparent diffusion coefficient (ADC), long diameter and short diameter, relative ADC of primary lesion (rADCp) and relative ADC of muscle (rADCm) were compared and analyzed between lymph node metastasis group and non lymph node metastasis group. RESULTS: The VEGF expression in patients with stage N3 gastric cancer was about 7 times that in patients with stage-N0 gastric cancer, and it was increased with the increased degree of lymph node metastasis (p< 0.01). The VEGF expression in patients with distant metastasis of tumor cells was significantly higher than that in patients without distant metastasis (p< 0.01). The expression of VEGF in stage-T4 gastric cancer was about 10 times that in stage-Tis cancer, and the larger the infiltration depth of tumor cells was, the higher the expression level of VEGF would be (p< 0.01). The VEGF expression in gastric cancer tissues was positively correlated with the infiltration depth, lymph node metastasis and distant metastasis of tumor cells. Moreover, the prediction results of MRI for TNM staging and lymph node metastasis before operation were compared with postoperative pathological results, and it was found that there was better consistency (Kappa = 0.739). ADC, rADCp and rADCm in gastric cancer patients without lymph node metastasis were significantly higher than those in patients with lymph node metastasis, but the short diameter and long diameter were obviously shorter than those in patients with lymph node metastasis, and the differences were statistically significant (p< 0.05). CONCLUSION: The VEGF protein expression in gastric cancer tissues is positively correlated with TNM staging and lymph node metastasis in patients. The preoperative prediction results of MRI are well consistent with postoperative pathological results, and MRI features are correlated with lymph node metastasis in patients, which has an important guiding significance for the diagnosis and treatment of gastric cancer. PMID- 30010109 TI - Targeting signal-transducer-and-activator-of-transcription 3 sensitizes human cutaneous melanoma cells to BRAF inhibitor. AB - Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. To define molecular mechanisms of vemurafenib resistance, we generated A375-R, WM35 R cell lines resistant to vemurafenib and show that the phosphorylated (p)-STAT3 was upregulated in these cells in vitro and in vivo. In particular, activation of the Signal-transducer-and-activator-of-transcription 3 (STAT3) pathway was associated with vemurafenib resistance. Inhibition of this pathway with STAT3 specific siRNA (shRNA) sensitized A375-R, WM35-R cells to vemurafenib and induced apoptosis in vitro and in vivo. Moreover, targeting STAT3 induced expression of miR-579-3p and elicited resistance to vemurafenib. However, targeting microRNA (miR)-579-3p with anti-miR-579-3p reversed the resistance to vemurafenib. Together, these results indicated that STAT3-mediated downexpression of miR-579 3p caused resistance to vemurafenib. Our findings suggest novel approaches to overcome resistance to vemurafenib by combining vemurafenib with STAT3 sliencing or miR-579-3p overexpression. PMID- 30010110 TI - Integrin alpha6 as an invasiveness marker for hepatitis B viral X-driven hepatocellular carcinoma. AB - BACKGROUND: Hepatitis B virus (HBV) accounts for more than 60% of hepatocellular carcinoma (HCC) cases. However, there is limited information about the features of HBV-driven HCC that differentiate it from other types of HCC. OBJECTIVE: The aim of this study is to find a gene specific to HBV-driven HCC and understand its role during tumorigenesis. METHODS: The differences in gene expression patterns were analyzed among patients with hepatitis virus-unrelated liver cirrhosis, and hepatitis C virus- and HBV-driven HCC. Genes expressed only in HBV patients were compared to genes of transgenic mice expressing hepatitis B viral X gene. RESULTS: Integrin alpha6 was commonly overexpressed in both HBV-driven HCC patients and transgenic mice expressing viral X. This gene's activation induced overexpression of integrin alpha6, as well as formation of integrins alpha6beta1 and alpha6beta4, without changing the expression of non-integrin laminin receptors. Suppression of integrin alpha6 caused significant inhibition of tumor migration in vitro. CONCLUSIONS: This study found a significant association between HBV and integrin alpha6, which may be responsible for early migration and invasion of HCC. Thus, integrin alpha6 is a predictive marker for tumor recurrence and invasiveness of HBV-driven HCC. PMID- 30010112 TI - The differential enhancement pattern of contrast enhanced ultrasound and magnetic resonance imaging characteristics in hepatic angiomyolipoma: 7 cases report. AB - OBJECTIVE: To compare the enhancement pattern of hepatic angiomyolipoma (HAML) on contrast enhanced ultrasound (CEUS) and magnetic resonance (MR). METHODS: The data of seven patients (females; age 28-52 years; mean, 42 years) with histologically proven HAMLs were retrospectively reviewed. All patients underwent CEUS and MR examination. The images were analyzed by two experienced doctors who blinded to the clinical and pathological information of cases. RESULTS: The mean diameter of the nodule was 5.7 cm (range: 3.2-10 cm). Histopathologic results revealed 4 nodules to be myomatous type and 3 nodules to be mixed type. All nodules showed hyperenhanced during arterial phase on both CEUS and MRI. During portal and delayed phase, washout was more showed on MRI (5/7, 71.4% ) than on CEUS (2/7, 28.6% ). CONCLUSIONS: There is discrepancy of enhancement pattern between CEUS and MRI. The quick wash-in and sustained hyperenhancement on CEUS may be helpful for the diagnosis of HAML. PMID- 30010111 TI - Long non-coding RNA TP73-AS1 sponges miR-194 to promote colorectal cancer cell proliferation, migration and invasion via up-regulating TGFalpha. AB - OBJECTIVE: Colorectal cancer (CRC) is the 3rd most common cancer worldwide. Recently, long non-coding RNAs (lncRNAs) were found to be critical modulators in the CRC progression. The aim of this study is to investigate the potential roles of lncRNA P73 antisense RNA 1T (TP73-AS1) in CRC development and progression. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to determine relevant gene expression levels; western blot was performed to determine protein expression levels; CCK-8, colony formation, wound healing and Transwell invasion assays were used to determined CRC cell proliferation, migration and invasion; in vivo tumor growth was assessed in xenograft mice model. RESULTS: TP73-AS1 was up regulated in both CRC tissues and CRC cell lines. Overexpression of TP73-AS1 was associated with metastasis and advanced clinical stages in CRC patients. Overexpression of TP73-AS1 promoted CRC cell growth, proliferation, migration and invasion in vitro; and knockdown of TP73-AS1 significantly inhibited CRC cell growth, proliferation, migration and invasion in vitro as well as tumor growth in vivo. Bioinformatics analysis and luciferase reporter assay indicated that TP73 AS1 could bind directly with miR-194, and TP73-AS1 negatively regulated the expression of miR-194 in CRC cells. Further study indicated that miR-194 negatively regulated the downstream target of transforming growth factor alpha (TGFalpha) via targeting its 3' untranslated region, and TP73-AS1 positively regulated the expression of TGFalpha in CRC cells. Moreover, overexpression of miR-194 suppressed CRC cell proliferation and invasion, and attenuated the effects of TP73-AS1 overexpression on CRC cell proliferation and invasion. Silence of TGFalpha inhibited CRC cell proliferation and invasion, and also reversed the effects of TP73-AS1 overexpression on CRC cell proliferation and invasion. CONCLUSIONS: this study demonstrated that TP73-AS1 regulated CRC progression by acting as a competitive endogenous RNA to sponge miR-194 to modulate the expression of TGFalpha. PMID- 30010113 TI - Effects of two selected SSRIs on hemorheological parameters in rats. AB - BACKGROUND: Selective Serotonin Reuptake Inhibitors (SSRIs), antidepressants commonly used in cardiovascular diseases (CVDs), inhibit the re-uptake of serotonin not only into neurons but also into platelets. Hence they increase the level of serotonin in plasma. OBJECTIVE: This study was aimed to clarify the effects of two selected SSRIs on plasma serotonin level, hemorheological parameters (hematocrit, erythrocyte deformability, erythrocyte aggregation and plasma viscosity) and selected oxidative stress markers (MDA, GSH, GSSG levels in plasma and erythrocytes). METHODS: Two different SSRIs (Fluvoxamine and Sertraline) were administered to male Sprague-Dawley rats in acute (5 days) or chronic fashion (21 days) at 20 mg/kg/day dose. RESULTS: Aggregation amplitude (AMP) decreased significantly in the chronic sertraline and acute fluvoxamine groups; aggregation half time (t1/2) decreased significantly in the chronic fluvoxamine group. Biochemical parameters indicating oxidative stress significantly increased in the chronic sertraline group. CONCLUSIONS: Since SSRI's are commonly used in patients with CVDs, complementary studies are needed to assess the impact of such changes in hemorheological parameters on the risk for CVD, and to reveal the effects of other SSRIs on hemorheological parameters. PMID- 30010115 TI - The predictive value of a modified Carpentier classification in patients with coincidental mitral regurgitation undergoing TAVI for severe aortic valve stenosis1. AB - INTRODUCTION: Concomitant mitral-regurgitation (MR) is frequently observed in patients undergoing trans-catheter aortic valve implantation (TAVI). The predictive value of MR etiology remains to be elucidated. METHODS: 600 patients with coincidental MR (>=moderate) undergoing TAVI were categorized according to a modified Carpentier classification [Groups: no/mild MR, n = 477; left atrial (LA) functional MR, n = 18; MR due to left ventricular dilatation, n = 29; degenerative MR, n = 50; MR with restricted leaflet motion n = 26]. MR improvement and patient outcome was compared among the groups in a retrospective analysis. RESULTS: MR regression was most pronounced in patients with restricted leaflet motion after 6 months, although a significant improvement was observed in all subgroups. MR relief was predominantly observed within the first 30 days after TAVI. Only patients with restricted leaflet motion experienced further improvement thereafter.In the entire cohort a total of 15 strokes (2.5%) during the first 30 days after TAVI were observed, with the highest incidence in the LA functional cohort (3 events, 17%; p = 0.008). In multivariate analysis, organic etiology was associated with an increased 1-year mortality.In conclusion, despite significant MR regression in all MR groups, some individuals may require additional mitralvalve repair after TAVI. According to our data the timing of these procedures should be based on the underlying MR etiology. The Carpentier classification in patients with coincidental MR undergoing TAVI for severe AS may also have prognostic implications as we found an increased incidence of strokes in our LA functional cohort and a worse mortality rates in organic MR. PMID- 30010116 TI - Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. AB - Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Delta-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Delta-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Delta-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus 2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy. PMID- 30010114 TI - Perfusion maintains functional potential in denervated mimic muscles in early persistent facial paralysis which requires early microsurgical treatment - the histoanatomic basis of the extratemporal facial nerve trunk assessing axonal load in the context of possible nerve transfers1. AB - BACKGROUND AND OBJECTIVES: Early persistent facial paralysis is characterized by intact muscles of facial expression through maintained perfusion but lacking nerve supply. In facial reanimation procedures aiming at restoration of facial tone and dynamics, neurotization through a donor nerve is performed. Critical for reanimating target muscles is axonal capacity of both donor and recipient nerves. In cases of complete paralysis, the proximal stump of the extratemporal facial nerve trunk may be selected as a recipient site for coaptation. To further clarify the histological basis of this facial reanimation procedure we conducted a human cadaver study examining macro and micro anatomical features of the facial nerve trunk including its axonal capacity in human cadavers. Axonal loads, morphology and morbidity of different donor nerves are discussed reviewing literature in context of nerve transfers. METHODS: From 6/2015 to 9/2016 in a group of 53 fresh frozen cadavers a total of 106 facial halves were dissected. Biopsies of the extratemporal facial nerve trunk (FN) were obtained at 1 cm distal to the stylomastoid foramen. After histological processing and digitalization of 99 specimens available, 97 were selected eligible for fascicle counts and 87 fulfilled quality criteria for a semi-automated computer-based axon quantification software using ImageJ/Fiji. RESULTS: An average of 3.82 fascicles (range, 1 to 9) were noted (n = 97). 6684+/-1884 axons (range, 2655- 12457) were counted for the entire group (n = 87). Right facial halves showed 6364+/-1904 axons (n = 43). Left facial halves demonstrated 6996+/-1833 axons (n = 44) with no significant difference (p = 0.73). Female cadavers featured 6247+/-2230 (n = 22), male showed 6769+/-1809 axons (n = 40). No statistical difference was seen between genders (p = 0.59). A comparison with different studies in literature is made. The nerve diameter in 82 of our specimens could be measured at 1933+/-424 MUm (range, 975 to 3012). CONCLUSIONS: No donor nerve has been described to match axonal load or fascicle number of the extratemporal facial nerve main trunk. However, the masseteric nerve may be coapted for neurotization of facial muscles with a low complication rate and good clinical outcomes. Nerve transfer is indicated from 6 months after onset of facial paralysis if no recovery of facial nerve function is seen. PMID- 30010117 TI - ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-beta Peptide Efflux in an in vitro Model of the Blood-Brain Barrier. AB - The role of ABCA7 in brain homeostasis and Alzheimer's disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell (r) inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro, these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Abeta peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage, Lrp1, Abcb1, Abcc1, and Abcg2. Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein's involvement in cholesterol metabolism and amyloid clearance at the BBB. PMID- 30010118 TI - Prevalence and Determinants of Agonistic Autoantibodies Against alpha1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population Based DelpHi-Study. AB - BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against alpha1-adrenergic receptors (alpha1-AR-agAAB) and agABB directed against beta2-adrenergic receptors (beta2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing alpha1-AR-agAAB and n = 21 (22%) beta2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have alpha1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between alpha1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB. PMID- 30010119 TI - 18F-FDG PET for Prediction of Conversion to Alzheimer's Disease Dementia in People with Mild Cognitive Impairment: An Updated Systematic Review of Test Accuracy. AB - BACKGROUND: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment (MCI). OBJECTIVES: To update the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease (AD) dementia at follow-up. METHODS: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies. RESULTS: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56-100%, specificity 24-100%). The most consistently high sensitivity and specificity values (approximately >=80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies. CONCLUSION: Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (>=5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18F-FDG PET in people with MCI is needed. PMID- 30010120 TI - Dual-Task Gait and Alzheimer's Disease Genetic Risk in Cognitively Normal Adults: A Pilot Study. AB - BACKGROUND: Dual-task paradigms, in which an individual performs tasks separately and then concurrently, often demonstrate that people with neurodegenerative disorders experience more dual-task interference, defined as worse performance in the dual-task condition compared to the single-task condition. OBJECTIVE: To examine how gait-cognition dual-task performance differs between cognitively normal older adults with and without an APOE E4 allele. METHODS: Twenty-nine individuals ages 60 to 72 with normal cognition completed a dual-task protocol in which walking and cognitive tasks (executive function, memory) were performed separately and concurrently. Fourteen participants carried APOE E4 alleles (E3/E4 or E2/E4); fifteen had APOE genotypes (E2/E2, E2/E3, or E3/E3) associated with lower risk of Alzheimer's disease (AD). RESULTS: The two risk groups did not differ by age, sex, race, education, or gait or cognitive measures under single task conditions. Compared to low risk participants, APOE E4 carriers tended to exhibit greater dual-task interference. Both the memory and executive function tasks resulted in dual-task interference on gait, but effect sizes for a group difference were larger when the cognitive task was executive function. In the dual-task protocol that combined walking and the executive function task, effect sizes for group difference in gait interference were larger (0.62- 0.70) than for cognitive interference (0.45- 0.47). DISCUSSION: Dual-task paradigms may reveal subtle changes in brain function in asymptomatic individuals at heightened risk of AD. PMID- 30010121 TI - Ceramide Accumulation Is Associated with Declining Verbal Memory in Coronary Artery Disease Patients: An Observational Study. AB - BACKGROUND: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression. OBJECTIVE: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD. METHODS: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test 2nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND). RESULTS: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = - 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 (b[SE] = - 1.11['], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline. CONCLUSION: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity. PMID- 30010123 TI - Unusual Clinical Presentations Challenging the Early Clinical Diagnosis of Creutzfeldt-Jakob Disease. AB - The introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials. PMID- 30010125 TI - Amyloid-beta25-35 Upregulates Endogenous Neuroprotectant Neuroglobin via NFkappaB Activation in vitro. AB - Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer's disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Abeta25-35, the neurotoxic fragment of Abeta1 - 40 and Abeta1 - 42, but was not further increased by a higher dose of Abeta25-35. Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor kappaB (NFkappaB), kappaB2 and kappaB3 sites located in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Abeta25-35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Abeta25-35 induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Abeta25-35, which is responsible for protecting against Abeta25-35-mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD. PMID- 30010124 TI - Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer's Disease. AB - In the following brief report, we examined gender differences in incidence rates of any dementia, Alzheimer's disease (AD) alone, and non-Alzheimer's dementia alone in 16,926 women and men in the Swedish Twin Registry aged 65+. Dementia diagnoses were based on clinical workup and national health registry linkage. Incidence rates of any dementia and AD were greater in women than men, with any dementia rates diverging after age 85 and AD rates diverging around 80. This pattern is consistent with women's survival to older ages compared to men. These findings are similar to incidence rates reported in other Swedish samples. PMID- 30010122 TI - Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort. AB - BACKGROUND: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease causing mutations. OBJECTIVE: We aimed to identify whether NPS could be driven by distinct structural correlates. METHODS: One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS. RESULTS: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe. CONCLUSION: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders. PMID- 30010126 TI - TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia. AB - BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43. PMID- 30010127 TI - Cognitive Function in Individuals with Normal Weight Obesity: Results from the Third National Health and Nutrition Examination Survey (NHANES III). AB - BACKGROUND/OBJECTIVE: Normal weight obesity (NWO) is associated with increased risk of metabolic syndrome, cardiovascular- and all-cause mortality. However, no data have been reported on the relationship between adiposity and cognitive performance in NWO. We therefore studied the association between cognitive function and body fat percentage (BF%) in NWO, using a representative sample of the United States population. METHODS: A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. Cognitive function was measured by three validated cognitive tests: simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT). The association between BF% and cognitive performance was evaluated in 2,039 adults aged 20-59 years and with a body mass index ranging from 18.5 to 24.9 kg/m2. Linear regression modeling was used to adjust for potential confounders. RESULTS: Increased BF% was significantly associated with poorer performance on SDLT in the entire study sample (coefficient [95% CI]: 0.15 [0.01, 0.29]) and with poorer performance on SDST in the age group 20-29 years (coefficient [95% CI]: 0.30 [0.10, 0.49]). Increased BF% did not significantly predict poorer performance on SRTT. CONCLUSION: Higher BF% is significantly associated with poorer cognitive function in a nationally representative sample of US adults with NWO. The identification of possible complications associated with increased adipose tissue underlines the need to measure body fat content in NWO individuals, whose metabolic and cognitive dysfunction could go undetected for years due to their young age and normal body weight. PMID- 30010128 TI - Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA related inflammation (CAA-ri). OBJECTIVE: To compare hemorrhagic and diffusion weighted imaging (DWI) MRI features in CAA and CAA-ri. METHODS: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben positron emission tomography (FBB-PET) were also analyzed. RESULTS: In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Abeta42 levels in CAA ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). CONCLUSION: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Abeta42 levels, and more severe amyloid load on FBB-PET. PMID- 30010129 TI - The GWAS Risk Genes for Depression May Be Actively Involved in Alzheimer's Disease. AB - Depression is one of the most frequent psychiatric symptoms observed in people during the development of Alzheimer's disease (AD). We hypothesized that genetic factors conferring risk of depression might affect AD development. In this study, we screened 31 genes, which were located in 19 risk loci for major depressive disorder (MDD) identified by two recent large genome-wide association studies (GWAS), in AD patients at the genomic and transcriptomic levels. Association analysis of common variants was performed by using summary statistics of the International Genomics of Alzheimer's Project (IGAP), and association analysis of rare variants was conducted by sequencing the entire coding region of the 31 MDD risk genes in 107 Han Chinese patients with early-onset and/or familial AD. We also quantified the mRNA expression alterations of these MDD risk genes in brain tissues of AD patients and AD mouse models, followed by protein-protein interaction network prediction to show their potential effects in AD pathways. We found that common and rare variants of L3MBTL2 were significantly associated with AD. mRNA expression levels of 18 MDD risk genes, in particular SORCS3 and OAT, were differentially expressed in AD brain tissues. 13 MDD risk genes were predicted to physically interact with core AD genes. The involvement of HACE1, NEGR1, and SLC6A15 in AD was supported by convergent lines of evidence. Taken together, our results showed that MDD risk genes might play an active role in AD pathology and supported the notion that depression might be the "common cold" of psychiatry. PMID- 30010130 TI - The Impact of a Shared Decision-Making Training Program on Dementia Care Planning in Long-Term Care. AB - BACKGROUND: Shared decision-making (SDM) can be a way for staff to adopt international recommendations advocating the involvement of nursing home residents and their family members in care planning and the development of personalized care plans. OBJECTIVE: The main aim was to analyze the effects of training nursing home staff in the implementation of SDM on agreement of residents' 'life-and-care plans' with the recommendations (primary outcome) and on family caregivers' quality of life and sense of competence, and staff's job satisfaction (secondary outcomes). METHODS: In the intervention condition, staff attended a training program on the use of SDM with residents and family caregivers in the care planning process. In the control condition, care planning as usual took place. For the primary outcome, in-depth qualitative and quantitative analyses of the care plans were performed. Multivariate Permutation Tests were applied to assess the impact on secondary outcomes. RESULTS: Forty nine residents and family caregivers and 34 professionals were involved. Overall, many of the care plans developed during the intervention showed a high level of agreement with the care planning recommendations. Both Italian and Dutch care plans showed improvement in the number of clear problem statements (p < 0.001). In Italy, significant improvements (p < 0.05) were also found regarding specific care objectives, documentation of objectives met, and of residents and families' involvement. No impact was found on secondary outcomes. CONCLUSION: The involvement of residents and family caregivers in care planning contributed to an improvement of the residents' care plans, but it did not have an effect on family caregivers and staff outcomes. PMID- 30010131 TI - Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation. AB - BACKGROUND: Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia. OBJECTIVE: To determine whether a TMS multi paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI). METHODS: A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed. RESULTS: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%. CONCLUSIONS: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis. PMID- 30010132 TI - MRI-Based Screening of Preclinical Alzheimer's Disease for Prevention Clinical Trials. AB - The identification of healthy individuals harboring amyloid pathology represents one important challenge for secondary prevention clinical trials in Alzheimer's disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60% of unnecessary CSF/PET tests and to reduce 47% of the cost of recruitment. This recruitment strategy capitalizes on available MR scans to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for preclinical AD screening. This protocol could foster the development of secondary prevention strategies for AD. PMID- 30010133 TI - Assessing the Limitations and Biases in the Current Understanding of Chronic Traumatic Encephalopathy. AB - Chronic traumatic encephalopathy (CTE) is considered to be a progressive neurodegenerative disease caused by mild traumatic brain injury (mTBI). Recently there has been a significant amount of media attention surrounding the commonness of CTE in professional athletes, particularly American football, based on several postmortem case series. However, despite the persuasive claims made by the media about CTE, research on the disease and the effects of mTBI in general remain in its infancy. Commonly cited case series studying CTE are limited by methodological biases, pathological inconsistencies, insufficient clinical data, and a reliance on inherently biased postmortem data. These case series do not allow for the collection of any epidemiological data and are not representative of the general population. The exaggerated assumptions and assertions taken from these studies run the risk of creating a self-fulfilling prophecy for individuals who believe they are at risk and have the potential to negatively influence sports-related policymaking. This review outlines the status and limitations of recent CTE case series and calls for future prospective, longitudinal studies to further characterize the pathological and clinical hallmarks of CTE. PMID- 30010135 TI - TREM1 mRNA Expression in Leukocytes and Cognitive Function in Japanese Patients with Alzheimer's Disease. AB - BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer's disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown. OBJECTIVE: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients. METHODS: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter. RESULTS: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Asberg Depression Rating Scale (p = 0.047, r = - 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001). CONCLUSION: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis. PMID- 30010134 TI - Distinct Cognitive and Brain Morphological Features in Healthy Subjects Unaware of Informant-Reported Cognitive Decline. AB - BACKGROUND: Subtle cognitive decline preceding cognitive impairment can be self perceived, referred to as subjective cognitive decline (SCD), or go unrecognized. OBJECTIVE: To study the clinical, cognitive, and structural neuroimaging characteristics of psychometrically normal subjects without self-awareness of cognitive decline (unaware decliners, UD) and to compare them with SCD participants and controls. METHODS: 2,640 participants from the ALFA cohort, 1,899 controls, 173 UD (decline reported by the informant only), and 568 SCD underwent clinical and cognitive explorations. A subset of 530 underwent structural MRI (379 Controls; 43 UD; 108 SCD). Linear models adjusting for confounders (age, sex, education, and mood state) were used to assess group differences on cognition and voxel-wise grey matter (GM) volumes. RESULTS: 6.6% were UD while 21.5% SCD. No differences in anxiety and depression were observed between controls and UD, while SCD did (p < 0.01). UD showed lower performance in the Memory Binding Test free recall (p < 0.005) than controls, but no differences compared to SCD. Right medial frontal and insular increments of GM volumes were observed in UD with respect to controls. Informant report of decline in UD and SCD was associated with lower left hippocampal GM volume but related to memory performance only in UD (rho = 0.46, p = 0.002). CONCLUSIONS: UD had worse memory performance than controls which correlated with hippocampal GM volume and presented brain volume increments in self-appraisal areas (medial frontal and insula). Individuals unaware of cognitive decline may represent a distinct group at risk for cognitive impairment and support the usefulness of informant-reported cognitive decline. PMID- 30010136 TI - Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons. AB - Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-beta (Abeta) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Abeta and p-Tau are two major pathogenic molecules with tau acting downstream to Abeta to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3beta. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes. PMID- 30010137 TI - Cognitive Training Improves Ratio Processing and Decision Making in Patients with Mild Cognitive Impairment. AB - BACKGROUND: Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers. OBJECTIVE: To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk. METHODS: In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week. RESULTS: The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type. CONCLUSION: Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models. PMID- 30010138 TI - Speech emotion recognition based on brain and mind emotional learning model. AB - Speech emotion recognition is a challenging obstacle to enabling communication between humans and machines. The present study introduces a new model of speech emotion recognition based on the relationship between the human brain and mind. According to this relationship, the proposed model consists of two parts: the brain short term memory (BSTM) and mind long term memory (MLTM). The input of the BSTM is emotional speech signals. Then, this part gives one copy of information to the MLTM. The reason is that the brain needs to save information as knowledge in a bigger and safer place similar to the human mind. The proposed model not only provides a computational model of speech emotion recognition based on the relationship between the BSTM and MLTM, but also illustrates a new relationship between brain and mind. The proposed model has been compared with different models of recognition. As the aim is to prove the efficiency of the suggested model, the effect of noise with different noise rates on the input signals has been analyzed in the experiment part. Experimental results show that the proposed algorithm has a powerful capability to identify and explore human emotion even in the noisy environment. PMID- 30010139 TI - Possible prophylactic anti-excitotoxic and anti-oxidant effects of virgin coconut oil on aluminium chloride-induced Alzheimer's in rat models. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects an estimated 5.4 million people worldwide. However, there remains no curative treatment for the condition. Abeta and hyperphosphorylated tau accumulation are the main hallmarks of the disease; they interfere with glutamate uptake and mediate glutamate excitotoxicity, oxidative stress, inflammation and neurodegeneration. As virgin coconut oil (VCO) is well-known as an antioxidant and anti-inflammatory natural compound, the purpose of the present study was to assess the possible prophylactic effect of VCO on aluminium chloride (AlCl3)- induced AD in rat. Alzheimer was induced by intraperitoneal injections of aluminium chloride (AlCl3) for 45 days (40 ml/kg per day), and our results showed that oral administration of VCO (5 ml per day for 30 days) prior to the administration of AlCl3 significantly reduced the glutamate level in both the hippocampus and prefrontal cortex compared to an VCO non-administrated AD group. Moreover, VCO significantly increased the glutathione (GSH) level in both the hippocampus and cortex and significantly decreased the malondialdehyde (MDA) level in only the cortex of the AlCl3-induced AD rat model compared to an AlCl3 induced AD rat model with no VCO. Our findings therefore show that VCO preserved the ultrastructural morphology of the hippocampus and cortex of the AlCl3-induced AD rat model, potentially providing protection against the neurodegeneration in AD of both cortical and hippocampal neurons. In conclusion, VCO has a potential prophylactic effect for memory enhancement, anti-excitotoxicity and antioxidants in AD model. AD is the leading cause of dementia worldwide, and it has no particular effective cure. The AD incidence rate increases with age and causes neurodegeneration and memory impairment. As virgin coconut oil (VCO) is well known as an antioxidant and anti-inflammatory natural compound, this study focused on investigating the possible prophylactic effect of VCO on AD. PMID- 30010140 TI - Bioinformatic analysis for the identification of key candidate genes and pathways in the substantia nigra in Parkinson's disease. AB - Parkinson's disease is one of the most common diseases in the elderly population, and the substantia nigra is generally involved in the disease process; however, the signaling pathways and related genes underlying Parkinson's disease remain unclear. This study integrated three cohorts of profile datasets to elucidate the potential key candidate genes and pathways in Parkinson's disease. The expression profiles of GSE8397, GSE20186 and GSE49036 were included 55 available substantia nigra tissue samples from individuals diagnosed with Parkinson's disease and 33 substantia nigra tissue samples from healthy controls. These samples were integrated and thoroughly analyzed. Differentially expressed genes (DEGs) were sorted, and candidate genes and pathway enrichments were analyzed. A DEG associated protein-protein interaction network analysis was performed. 27 shared downregulated DEGs were identified from the three GSE datasets. The DEGs were clustered based on function and signaling pathway with significant enrichment analysis. 52 edges were identified from the DEG protein-protein interaction network complex, which included dopamine metabolism, nerve conduction, reduced neuronal toxicity and proliferation pathways. Using integrated bioinformatic analysis, we identified candidate genes and pathways in Parkinson's disease that could improve our understanding of underlying molecular events, which could be potential therapeutic targets for Parkinson's disease. PMID- 30010141 TI - Prenatal, Neonatal, and Early Childhood Features in Congenital Myotonic Dystrophy. AB - BACKGROUND: Congenital myotonic dystrophy (CDM) is the neonatal onset and most severe presentation of Myotonic Dystrophy type 1. Since it first description, perinatal complications have been detailed including prolonged hospital stay, respiratory and feeding therapy during the neonatal period, although long-term complications are less documented. OBJECTIVE: Present a prospective cohort of CDM and compare it to the literature of other CDM case series, to adequately describe and contrast the prenatal, neonatal and infancy features of CDM. METHODS: A 5 year cohort of CDM eligible cases was conducted via the Canadian Pediatric Surveillance Program. 38 patients met the inclusion criteria. Comparison to other CDM case series published in the literature between 1992 and 2016 about perinatal and infancy morbidity. RESULT: From a total of 118 cases, the most frequent features were Polyhydramnios (58%), feeding therapy (77%), intubation and ventilation (58%); neonatal death was reported in 16% of the cases; the most frequent long-term morbidity were respiratory tract infections. CONCLUSIONS: We performed a detailed description of the main perinatal features of CDM and precise documentation of the mortality and morbidity during the first five years of life. This is an essential step in the knowledge of the natural history of CDM. PMID- 30010143 TI - Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise. AB - BACKGROUND: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown preclinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of mineralocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters. OBJECTIVE: We aimed to test whether therapeutic effects of mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors are detectable using three different reported methods of exacerbating the mdx phenotype. METHODS: We tested treatment with lisinopril and the mineralocorticoid receptor antagonist spironolactone in: 10 week-old exercised, 1 year-old sedentary, and 5 month-old isoproterenol treated mdx mice and performed comprehensive functional and histological measurements. RESULTS: None of the protocols to exacerbate mdx phenotypes resulted in dramatically enhanced pathology and no significant benefit was observed with treatment. CONCLUSIONS: Since endogenous mineralocorticoid aldosterone production from immune cells in dystrophic muscle may explain antagonist efficacy, it is likely that these drugs work optimally during the narrow window of peak inflammation in mdx mice. Exercised and aged mdx mice do not display prolific damage and inflammation, likely explaining the absence of continued efficacy of these drugs. Since inflammation is more prevalent in DMD patients, the therapeutic window for mineralocorticoid receptor antagonists in patients may be longer. PMID- 30010144 TI - Evolvability and Neurodegenerative Disease: Antagonistic Pleiotropy Phenomena Derived from Amyloid Aggregates. AB - At present, the precise physiological role of neurodegenerative disease-related amyloidogenic proteins (APs), including alpha-synuclein in Parkinson's disease and beta-amyloid in Alzheimer's disease, remains unclear. Because of similar adaptability of both human brain neurons and yeast cells to diverse environmental stressors, we previously proposed that the concept of evolvability in yeast prion could also be applied to APs in human brain. However, the mechanistic relevance of evolvability to neurodegenerative disorders is elusive. Therefore, our objective is to discuss our hypothesis that evolvability and neurodegenerative disease may represent a form of antagonistic pleiotropy derived from the aggregates of APs. Importantly, such a perspective may provide an outlook of the entire course of sporadic neurodegenerative diseases. PMID- 30010145 TI - Recruitment and Retention in Clinical Trials of Deep Brain Stimulation in Early Stage Parkinson's Disease: Past Experiences and Future Considerations. AB - BACKGROUND: Clinical trials are often hindered by inadequate patient recruitment. Overly optimistic investigator predictions of participation can lead to unmet recruitment goals and costly trial extensions. A patient-focused approach estimating recruitment in clinical trials may provide higher accuracy. OBJECTIVE: To assess the feasibility of recruitment in a future deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) multicenter trial by understanding motivations and concerns to participation of past and potential future DBS in early-stage PD clinical trial subjects. METHODS: To identify motivating factors and barriers influencing trial participation, an end-of-trial survey was administered to subjects enrolled in a DBS in early-stage PD pilot trial with subjects randomized to receive DBS plus optimal drug therapy (DBS+ODT) or ODT alone (NCT#00282152, IDE#G050016). Pilot trial survey results were analyzed in conjunction with results of a previously-reported survey querying PD patients about potential participation in a trial for DBS in early-stage PD with similar inclusion/exclusion criteria. RESULTS: Pilot trial subjects reported high levels of satisfaction with their participation in the study. Similar motivations and barriers to participation were expressed in comparable proportions by subjects who successfully completed the pilot trial and patients with early-stage PD considering enrollment in a comparable DBS study. CONCLUSIONS: The FDA has approved a prospective, randomized, double-blind, phase III, multicenter, pivotal clinical trial evaluating DBS in early-stage PD (IDE#G050016). These results suggest that the successful recruitment and retention of early-stage PD subjects, as observed in the pilot trial, is attainable in a future pivotal trial. PMID- 30010142 TI - New Pathways and Therapeutic Targets in Autoimmune Myasthenia Gravis. AB - Acquired Myasthenia Gravis (MG) is a neuromuscular disease caused by autoantibodies against components of the neuromuscular junction. It is a prototype organ-specific autoimmune disease with well-defined antigenic targets mainly the nicotinic acetylcholine receptor (AChR). Patients suffer from fluctuating, fatigable muscle weakness that worsens with activity and improves with rest.Various therapeutic strategies have been used over the years to alleviate MG symptoms. These strategies aim at improving the transmission of the nerve impulse to muscle or at lowering the immune system with steroids or immunosuppressant drugs. Nevertheless, MG remains a chronic disease and symptoms tend to persist in many patients, some being or becoming refractory over time. In this review, based on recent experimental data on MG or based on results from clinical trials for other autoimmune diseases, we explore new potential therapeutic approaches for MG patients, going from non-specific approaches with the use of stem cells with their anti-inflammatory and immunosuppressive properties to targeted therapies using monoclonal antibodies specific for cell surface antigens or circulating molecules. PMID- 30010146 TI - Hematochezia and thrombocytopenia in a 3-day-old infant: Congenital adenoviral infection. AB - Neonatal adenovirus infection is infrequent, but in most cases the outcome of the infection is fatal. In this case report we describe the hospital course of a 3 day old newborn patient presenting with bloody stools and thrombocytopenia that remained clinically stable and had a benign course following Adenovirus 40/41 infection detected in stool. Neonatal adenovirus infection should be considered in the differential diagnosis of neonatal sepsis and pneumonia but also in patients that present with hematochezia, thrombocytopenia and/or other less specific signs and symptoms of viral illness. PMID- 30010147 TI - Tube dependency as a result of prematurity. AB - BACKGROUND: Enteral nutrition support (ENS) is a standard of care in all NICUs. As a result of long-term ENS, tube dependency can develop. Tube dependency is an inability to make the transition from tube to oral feeds despite the absence of medical reasons for ENS and might lead to symptoms like oral aversion and food refusal. This study aims to evaluate the prevalence of prematurity in a large cohort of tube dependent children. METHODS: Prospectively collected data on tube dependent children who participated in a program based on the "Graz Model of tube weaning" from January 2009 to December 2015 was analysed quantitatively. RESULTS: The study cohort consisted of 711 tube dependent children. Using ICD-10 classification, 378 children (53.2%) were born prematurely, with 103 extremely preterm infants (EPI; including children <29 weeks of gestational age and 275 preterm infants (PI; between 29 and 36+6 weeks of gestational age). More than half (55.4%) of all included patients were female, 51.8% were tube fed via a percutaneous endoscopic gastrostomy (PEG-) tube, 45.8% had a nasogastric (NG-) tube and 2.4% were tube fed via Jejunal (J-) tube. 66% of all EPI and 63.3% of all PI were tube fed since birth. 83.5% of all EPI had no additional diagnoses beyond their extreme prematurity. No differences in tube weaning outcomes between preterm and full term infants were shown. CONCLUSION: Prematurity, especially extreme prematurity, is associated with an increased risk for development of tube dependency. Preventive measures for this specific group of children should be considered. PMID- 30010148 TI - Does virtual reality training using the Xbox Kinect have a positive effect on physical functioning in children with spastic cerebral palsy? A case series. AB - PURPOSE: The present study investigated the effects of virtual reality (VR) training using the Xbox Kinect on motor function, balance, gait, and functional mobility in children with cerebral palsy (CP). METHOD: This was a case series. Four children with spastic diplegic cerebral palsy were provided VR training using the Xbox Kinect for 12 sessions (three sessions per week for 4 weeks). At baseline and follow-up, physical function was measured using the following: Selective Motor Control (SMC) for motor function, Pediatric Balance Scale (PBS) for balance, Timed Up and Go (TUG) test and Functional Mobility Scale (FMS) for functional mobility, and 6-meter walk test (6WT) for gait. RESULTS: As compared with the baseline scores, SMC, PBS, TUG, FMS, and 6MWT scores after training showed improvements. In participant 1, PBS and TUG scores improved after VR training. In participant 2, SMC (left ankle dorsiflexor, left knee extensor), PBS, TUG, and FMS scores improved after training. In participant 3, SMC (left hip flexor), TUG, FMS, and 6MWT scores improved after training. In participant 4, SMC (right ankle dorsiflexor), PBS, TUG, FMS, and 6MWT scores improved after training. CONCLUSION: The results show that VR training using the Xbox Kinect may improve physical functioning in children with spastic diplegic cerebral palsy. However, its utility in the rehabilitation of children with CP requires further investigation. PMID- 30010149 TI - A Global Family Quality of Life Scale: Preliminary psychometric evidence. AB - PURPOSE: Psychometric data are reported for a new Global Family Quality of Life Scale (G-FQOLS) (3-items) evaluating family members, parents and adolescent/young adults (AYA). METHODS: Families (N= 209) were interviewed in a study addressing secondary conditions and adaptation in families of AYA with and without spina bifida (SB). Principal component factor analysis with Varimax rotation, Cronbach alpha, and Intraclass correlation (ICC) for parent-AYA agreement of FQOL assessment were conducted. RESULTS: A single factor with an eigenvalue greater than 1 was identified. Factor loadings were 0.79-0.94. Internal reliabilities were strong (alpha= 0.86-0.90). ICC coefficients between parent and AYA ratings were 0.38-0.48. CONCLUSION: This study provides preliminary support for the G FQOLS. This global appraisal of Family Quality of Life (FQOL) reflects a participant's personal weighting of domains important to him/her. PMID- 30010150 TI - Healthcare professionals' perspective on the delivery of care to children with Acquired Brain Injury (ABI) and communication with their parents. AB - PURPOSE: The purpose of this study was to understand healthcare providers' perspective and responsivity to families' needs in rehabilitative care delivery for children with Acquired Brain Injury (ABI). METHODS: Three focus group sessions were conducted to explore and understand multidisciplinary healthcare professionals' (Hcps) perspectives about the care they deliver to parents of children with ABI. Convenience sampling was used to recruit healthcare providers (total sample size = 15) from a large rehabiliation centre of an urban setting in western Canada. Data was collected through semi-structured interviews and analysed thematically. RESULTS: Findings from this study revealed Hcps' perspectives on their day-to-day delivery of care and furthered our understanding of their challenges. It also increased our awareness about the rewards that Hcp gain as a result of their work. Five main themes emerged: (1) Getting back to normal; (2) Hsps' roles and perception; (3) Challenges in practices; (4) Practice rewards; (5) a focus on solutions/ideas for better healthcare delivery. CONCLUSION: Hcps' perspectives on their day-to-day delivery of care to families who have a child with ABI enhance our knowledge about the existing challenges and complexities. Findings from this study have significant implication for rehabilitation services in making rehabilitation goals more achievable for families of children with ABI. PMID- 30010151 TI - Reliability, construct validity and usability of the Eating and Drinking Ability Classification System (EDACS) among Dutch children with Cerebral Palsy. AB - PURPOSE: To assess the interrater reliability, construct validity and usability of the Eating and Drinking Ability Classification System (EDACS) among Dutch children with Cerebral Palsy (CP) when used by speech and language therapists (SLTs) familiar and unfamiliar with the child's eating and drinking performance and parents. METHODS: Translation was undertaken using the method of Eremenco. Agreement between SLTs and parents when using EDACS was determined by intraclass correlation coefficient (ICC) and linear weighted Kappa (kappaW). Associations with other functional classification systems including the Dysphagia Management Staging Scale (DMSS) were investigated to determine construct validity by Kendall's tau-b. RESULTS: Thirty-one SLTs classified 149 children (67 girls; mean 10 y, SD 4 y, range 3-21 y) with EDACS. Pairs of SLTs showed good agreement ([ICC] = 0.84; 95% confidence interval [CI] 0.79-0.88; [kappaW] = 0.71). Eighty one parents showed good agreement with SLTs (n= 31) as well (ICC = 0.80; 95% CI 0.71-0.87; kappaW= 0.61). There was a significant and strong positive correlation of EDACS with DMSS (Kendall's tau-b 0.81) supporting its construct validity. Usability of EDACS was generally good. CONCLUSION: The Dutch version of EDACS is reliable and valid, and can be used easily by (familiar and unfamiliar) SLTs and parents of children with CP. Parents and professionals showed a high level of consistency when classifying eating and drinking abilities. EDACS enables uniform and efficient communication about safety and efficiency of functional eating and drinking ability in clinical and research contexts. PMID- 30010152 TI - A systematic review on quantifiable physical risk factors for non-specific adolescent low back pain. AB - PURPOSE: The aim of this systematic review was to analyze the results of studies on quantifiable physical risk factors (beyond questionnaires) for adolescent low back pain (LBP). METHODS: A systematic search was conducted in Medline (OvidSP), Premedline (PubMed), EMBASE, Cochrane, CINAHL, PEDro and PsycINFO. Cross sectional, prospective and retrospective English language studies on LBP in adolescents aged 10 to 18 years were included. RESULTS: Twenty-two mostly cross sectional studies were included. Trunk muscle endurance in particular seemed to be associated with adolescent LBP, while a possible association of trunk muscle strength and spinal flexibility was less clear. CONCLUSION: There is a need for prospective studies on quantifiable physical risk factors for adolescent LBP. Such studies should focus on back and abdominal muscle endurance, possibly in combination with sagittal spinal mobility, sagittal postural alignment and neurodynamics as possible modifiable risk factors for LBP. PMID- 30010154 TI - From the Editor. PMID- 30010155 TI - Adipose-derived stem cell conditioned medium impacts asymptomatic peripheral neuromuscular denervation in the mutant superoxide dismutase (G93A) transgenic mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is devastating, leading to paralysis and death. Disease onset begins pre-symptomatically through spinal motor neuron (MN) axon die-back from musculature at ~47 days of age in the mutant superoxide dismutase 1 (mSOD1G93A) transgenic ALS mouse model. This period may be optimal to assess potential therapies. We previously demonstrated that post symptomatic adipose-derived stem cell conditioned medium (ASC-CM) treatment is neuroprotective in mSOD1G93A mice. We hypothesized that early disease onset treatment could ameliorate neuromuscular junction (NMJ) disruption. OBJECTIVE: To determine whether pre-symptom administration of ASC-CM prevents early NMJ disconnection. METHODS: We confirmed the NMJ denervation time course in mSOD1G93A mice using co-labeling of neurofilament and post-synaptic acetylcholine receptors (AchR) by alpha-bungarotoxin. We determined whether ASC-CM ameliorates early NMJ loss in mSOD1G93A mice by systemically administering 200MUl ASC-CM or vehicle medium daily from post-natal days 35 to 47 and quantifying intact NMJs through co labeling of neurofilament and synaptophysin with alpha-bungarotoxin in gastrocnemius muscle. RESULTS: Intact NMJs were significantly decreased in 47 day old mSOD1G93A mice (p < 0.05), and daily systemic ASC-CM prevented disease induced NMJ denervation compared to vehicle treated mice (p < 0.05). CONCLUSIONS: Our results lay the foundation for testing the long-term neurological benefits of systemic ASC-CM therapy in the mSOD1G93A mouse model of ALS. PMID- 30010156 TI - Curcumin alleviates lipopolysaccharide-induced neuroinflammation in fetal mouse brain. AB - BACKGROUND/OBJECTIVE: Curcumin exerts multiple functions including antioxidant and anti-inflammation, and has been shown protective potential on neurological disorders. Maternal or intrauterine infection/inflammation is one of the major factors underlying perinatal brain damage. This study aimed to determine whether maternal administration of curcumin has attenuation on neuroinflammation in fetal brain caused by lipopolysaccharide (LPS) administration. METHODS: LPS was used to establish mouse fetal brain injury model, and we investigated the effects of curcumin (40 mg/kg) on the fetal mouse brain by evaluating the morphological change of the neuronal cells and the expression of different pro-inflammatory cytokines and chemokines at protein and mRNA levels in the fetal brains, the maternal serum and amniotic fluid. RESULTS: Our results demonstrated that maternal administration of curcumin has attenuation on neuroinflammation in the fetal brain induced by LPS. Pretreatment of curcumin in the LPS-induced mice effectively reestablished the neuronal cell morphology, attenuated the expression of soluble intercellular adhesion molecule-1, sE-Selectin, macrophage chemoattractant protein-1 and cytokine-induced neutrophil chemoattractant-1 in the maternal serum, decreased the expression of cyclooxygenase-2, interleukin-1 beta and chemokine (C-C motif) ligand 2 in the brain, and suppressed interleukin 6 (IL-6) mRNA transcription in the amniotic fluid. In addition, curcumin suppressed the LPS-induced microglia activation. CONCLUSIONS: Our study in animal models indicates that maternal administration of curcumin alleviates neuroinflammation in the fetal brain caused by LPS. Long-term consumption of curcumin might improve the neurological outcomes of premature neonates delivered from dams suffering from infection/ inflammation. PMID- 30010157 TI - Effect of pre-surgery assessments on the prognosis of patients received extracranial-intracranial bypass surgery. AB - BACKGROUND: Extracranial-intracranial (EC-IC) bypass surgery has been used to improve the conditions of cerebral ischemia symptoms for selected patients resulting from diverse complications such as stroke and atherosclerotic disease. However, several clinical trials showed EC-IC bypass surgery failed to prevent recurrent ischemic stroke in certain patients. OBJECTIVE: Our clinical trial aimed to investigate whether there is a correlation between pre-surgery assessments and prognosis of patients received EC-IC bypass operation. METHODS: We divided all patients into 4 groups according to their compensatory stages of cerebral ischemia. The values of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and oxygen extraction fraction (OEF) were obtained by computed tomography perfusion (CTP), single photon emission computed tomography (SPECT), and positron emission tomography (PET) at different time points before and after EC-IC bypass surgery. We assessed the correlations between the compensatory stage with modified Rankin scale (mRS) scores, survival rates, stroke and TIA incidences over the 12 months after surgery. RESULTS: Patients with normal CBF, normal or increased CBV, and normal OEF tended to have a better prognosis after the EI-CI bypass operation than patients with abnormal CBF, CBV and OEF. However, patients with abnormal CBF and CBV, and increased OEF showed elevated mRS, less survival rates, and higher stroke and TIA incidences over the 12 months after surgery, compared to the groups with normal CBF, CBV and OEF. CONCLUSIONS: Our results suggest that a defined compensatory stage of cerebral ischemia might be useful for the prognosis of patients receiving EI-CI bypass surgery. PMID- 30010159 TI - Retraction: New insights into virulence mechanisms of rice pathogen Acidovorax avenae subsp. avenae strain RS-1 following exposure to beta-lactam antibiotics. AB - This corrects the article DOI: 10.1038/srep22241. PMID- 30010158 TI - High Expression of Ubiquitin-Specific Protease 8 (USP8) Is Associated with Poor Prognosis in Patients with Cervical Squamous Cell Carcinoma. AB - BACKGROUND Cervical cancer is one of the most common female malignancies in the world. The ubiquitin-specific protease 8 (USP8) functions by removing ubiquitin from protein substrates, and its potential role in cancer development was recently uncovered in lung cancer. The aim of this study was to investigate the expression and function of USP8 in cervical squamous cell carcinoma (CSCC). MATERIAL AND METHODS Immunohistochemical staining and quantitative PCR were performed to explore the expression of USP8 in both CSCC tissues and adjacent normal cervical tissues. Univariate and multivariate analyses were conducted to evaluate the clinical significance of USP8 in CSCC. Proliferation, migration, and invasion abilities of 2 CSCC cell lines were assessed after overexpression or silencing USP8, respectively. RESULTS Both the RNA and protein levels of USP8 were upregulated in CSCC tissues compared to normal cervical tissues. High expression of USP8 was correlated with advanced tumor stage and high recurrence risk. Moreover, USP8 was identified as a novel independent prognostic factor for CSCC patients. Cellular studies showed that USP8 can enhance the proliferation, migration, and invasion abilities of CSCC cells, thereby promoting tumor progression. CONCLUSIONS High expression of USP8 is frequent in CSCC tissues, which promotes tumor proliferation and invasion, and is correlated with a poor overall survival. Targeting USP8 may be a novel direction for drug development for CSCC therapy. PMID- 30010160 TI - Silicosis in Switzerland. AB - OBJECTIVES: The correlation between quartz dust concentrations in the Swiss enterprises and the incidence of silicosis and other related diseases acknowledged as occupational diseases (OD) was investigated. MATERIAL AND METHODS: Quartz dust concentrations were obtained from Suva's databases of occupational health surveillance measurements between 2005 and 2014. Information on quartz dust-related diseases was from medical dossiers of workers with OD acknowledged by Suva between 2005 and 2014. RESULTS: The median quartz dust concentration of the 2579 measurements between 2005 and 2014 was 0.09 mg/m3 (alveolar fraction). Out of all measurements, 28% were above the Swiss occupational exposure limit (OEL) of 0.15 mg/m3 (alveolar fraction). One hundred eighty-one individuals suffered from acknowledged quartz dust-related disease (179 silicosis and 2 chronic obstructive pulmonary disease (COPD)). Additionally, 8 out of these workers were diagnosed with lung cancer and 55 with COPD of a non-specified cause. Out of all workers, 46% were exposed to silica dust for the first time before 1975 when the current Swiss OEL was introduced. Out of the foreign workers, 63% began to work abroad, during which they could have at least partly acquired their silicosis. Out of all workers, 75% were ever-smokers. CONCLUSIONS: The incidence of silicosis decreased drastically from approximately 300 cases/year in the 1970s to fewer than 20 cases/year 20 years ago. Several findings of this study that could help to interpret the ongoing occurrence of the disease include excessive exposure in or outside of Switzerland in former or current times, vulnerability to the development of silicosis due to cigarette smoke, or poor compliance with wearing breathing masks. Int J Occup Med Environ Health 2018;31(5):659-676. PMID- 30010161 TI - [Biological agents intentionally used in Poland based on data from the National Register Of Biological Agents]. AB - BACKGROUND: Paper presents the intentional use of biological agents for industrial, diagnostic and research purposes in enterprises in Poland. MATERIAL AND METHODS: The source of data is the National Register of Biological (in Polish KRCB) - the type of the database that gathers data about the intentional use of biological agents at work in Poland. The analysis includes tabular summaries of the data as of December 2017. RESULTS: Notifications were sent by 598 enterprises for: diagnostic - 67.5%, research - 25% and industrial purposes - 75%. Those mostly were hospital diagnostic laboratories - 36%, entities other than hospitals - 32% and higher education and research units - 13%. In total, 4477 workers (91.3% women, 8.7% men) were exposed to biological agents. Agents from 2nd and 3rd group of risk were used in 581 and 106 enterprises, respectively. Escherichia coli bacteria was most frequently used (with the exception of non-pathogenic strains) in 504 enterprises (3529 exposed workers), Staphylococcus aureus - 495 enterprises (3464 workers) and Pseudomonas aeruginosa - 459 enterprises (3157 workers). In 58 enterprises, biological agents recognized by the International Agency for Research on Cancer as carcinogenic were used (viruses: hepatitis B virus (HBV) - 10 enterprises and 257 workers, hepatitis C virus (HCV) - 10 enterprises and 232 workers, Epstein-Barr virus (EBV) - 9 enterprises and 227 workers, human immunodeficiency virus type 1 (HIV-1) - 8 enterprises and 186 workers, human papilloma virus (HPV) - 3 enterprises and 94 workers, human herpes virus type 8 (HHV-8) - 3 enterprises and 22 workers, human T-lymphotropic virus type 1 (HTLV-1) - 1 enterprise and 17 workers; parasites: Schistosoma haematobium - 2 enterprises and 4 workers, Clonorchis viverrini - 1 enterprises and 2 workers, Clonorchis sinensis - 1 enterprises and 2 workers; bacteria: Helicobacter pylori 10 enterprises and 137 workers). CONCLUSIONS: The network organization, legal base and central nature cause that the KRCB is a unique database that allows for diagnosis of the situation and tracking of dynamics in the context of occupational exposure to biological agents used intentionally in enterprises in Poland. Med Pr 2018;69(4):413-424. PMID- 30010162 TI - [The usefulness of bronchial challenge tests in the diagnosis of occupational asthma]. AB - Bronchial hyperresponsiveness (BHR) is the individual ability to respond with bronchoconstriction to a variety of specific and nonspecific stimuli which do not cause these symptoms among healthy subjects. Bronchial hyperresponsiveness is one of the hallmark features of asthma. The degree of bronchial hyperresponsiveness is variable among individuals with asthma and may correlate to its severity (the more severe asthma the higher bronchial hyperreactivity). Bronchial hyperresponsiveness is evaluated by performing bronchial provocation test (BPT). Provocation tests are classified - according to their mechanisms - into direct and indirect tests. Direct challenge tests are highly sensitive and they are used primarily to rule out asthma. In contrast, provocation tests with indirect stimuli are less sensitive but more specific to the direct tests; they are used generally to confirm the diagnosis of asthma and they allow for more accurate conclusions about inflammatory lesions in the case of a patient. Bronchial provocation tests play a significant role in occupational medicine. They are particularly relevant to be performed prior to employment, during periodic examinations, and to diagnose and monitor both occupational asthma and work related asthma. This article presents selected bronchial provocation tests and their usefulness in the diagnosis of occupational asthma. Med Pr 2018;69(4):457 471. PMID- 30010163 TI - A smart photosensitizer based on a red emitting solution processable porous polymer: generation of reactive oxygen species. AB - A novel approach for the fabrication of a solution processable conjugated porous organic polymer (CzBDP) involving a flexible core composed of carbazole and boron dipyrromethene was developed. The red emitting soluble polymer was found to be an excellent probe for the generation of both singlet oxygen and superoxide anion radicals under visible light irradiation. PMID- 30010164 TI - Multiplex imaging of live breast cancer tumour models through tissue using handheld surface enhanced spatially offset resonance Raman spectroscopy (SESORRS). AB - Through utilizing the depth penetration capabilities of SESORS, multiplexed imaging and classification of three singleplex nanotags and a triplex of nanotags within breast cancer tumour models is reported for the first time through depths of 10 mm using a handheld SORS instrument. PMID- 30010165 TI - High affinity single-chain variable fragments are specific and versatile targeting motifs for extracellular vesicles. AB - Exosomes are extracellular vesicles that mediate cell-to-cell communication by transferring biological cargo, such as DNA, RNA and proteins. Through genetic engineering of exosome-producing cells or manipulation of purified exosomes, it is possible to load exosomes with therapeutic molecules and target them to specific cells via the display of targeting moieties on their surface. This provides an opportunity to exploit a naturally-occurring biological process for therapeutic purposes. In this study, we explored the potential of single chain variable fragments (scFv) as targeting domains to achieve delivery of exosomes to cells expressing a cognate antigen. We generated exosomes targeting the Her2 receptor and, by varying the affinity of the scFvs and the Her2 expression level on recipient cells, we determined that both a high-affinity anti-Her2-scFv (KD<= 1 nM) and cells expressing a high level (>=106 copies per cell) of Her2 were optimally required to enable selective uptake. We also demonstrate that targeting exosomes to cells via a specific cell surface receptor can alter their intracellular trafficking route, providing opportunities to influence the efficiency of delivery and fate of intracellular cargo. These experiments provide solid data to support the wider application of exosomes displaying antibody fragments as vehicles for the targeted delivery of therapeutic molecules. PMID- 30010167 TI - A distance-based paper sensor for the determination of chloride ions using silver nanoparticles. AB - We report for the first time the development of a distance-based paper sensor for a simple, inexpensive, instrument-free, and portable determination of chloride ions. Our analysis reaction is based on the oxidative etching of silver nanoparticles (AgNPs) to form AgCl in the presence of Cl- and H2O2. H2O2 reacts with AgNPs in the channel of the paper device and Cl- in the sample forming a white precipitate (AgCl) where the white color band length is proportional to the Cl- concentration. Quantification of Cl- is achieved by measuring the length of the white color band using a ruler printed on the side of the channel. Under optimal conditions, the distance-based paper sensor was characterized by a working range of 25-1000 mg L-1 (R2 = 0.9954) and the naked eye detection limit (LOD) was 2 mg L-1 (0.08 MUg). Our sensor was found to be reproducible with a relative standard deviation of less than 4.51% (n = 10). The levels of Cl- in real water samples measured using our proposed device were within the error of the values measured using traditional tests but without the need for any external instrumentation. Therefore, our proposed method presents acceptable accuracy, precision, and high selectivity for point of need monitoring of Cl- in real water samples. PMID- 30010166 TI - Pinpointing the active species of the Cu(DAT) catalyzed oxygen reduction reaction. AB - Dinuclear CuII complexes bearing two 3,5-diamino-1,2,4-triazole (DAT) ligands have gained considerable attention as a potential model system for laccase due to their low overpotential for the oxygen reduction reaction (ORR). In this study, the active species for the ORR was investigated. The water soluble dinuclear copper complex (Cu(DAT)) was obtained by mixing a 1 : 1 ratio of Cu(OTf)2 and DAT in water. The electron paramagnetic resonance (EPR) spectrum of Cu(DAT) showed a broad axial signal with a g factor of 2.16 as well as a low intensity Ms = +/-2 absorption characteristic of the Cu2(MU-DAT)2 moiety. Monitoring the typical 380 nm peak with UV-Vis spectroscopy revealed that the Cu2(MU-DAT)2 core is extremely sensitive to changes in pH, copper to ligand ratios and the presence of anions. Electrochemical quartz crystal microbalance experiments displayed a large decrease in frequency below 0.5 V versus the reversible hydrogen electrode (RHE) in a Cu(DAT) solution implying the formation of deposition. Rotating ring disk electrode experiments showed that this deposition is an active ORR catalyst which reduces O2 all the way to water at pH 5. The activity increased significantly in the course of time. X-ray photoelectron spectroscopy was utilized to analyze the composition of the deposition. Significant shifts in the Cu 2p3/2 and N 1s spectra were observed with respect to Cu(DAT). After ORR catalysis at pH 5, mostly CuI and/or Cu0 species are present and the deposition corresponds to previously reported electrodepositions of copper. This leads us to conclude that the active species is of a heterogeneous nature and lacks any structural similarity with laccase. PMID- 30010168 TI - Capillary microfluidics in microchannels: from microfluidic networks to capillaric circuits. AB - Microfluidics offer economy of reagents, rapid liquid delivery, and potential for automation of many reactions, but often require peripheral equipment for flow control. Capillary microfluidics can deliver liquids in a pre-programmed manner without peripheral equipment by exploiting surface tension effects encoded by the geometry and surface chemistry of a microchannel. Here, we review the history and progress of microchannel-based capillary microfluidics spanning over three decades. To both reflect recent experimental and conceptual progress, and distinguish from paper-based capillary microfluidics, we adopt the more recent terminology of capillaric circuits (CCs). We identify three distinct waves of development driven by microfabrication technologies starting with early implementations in industry using machining and lamination, followed by development in the context of micro total analysis systems (MUTAS) and lab-on-a chip devices using cleanroom microfabrication, and finally a third wave that arose with advances in rapid prototyping technologies. We discuss the basic physical laws governing capillary flow, deconstruct CCs into basic circuit elements including capillary pumps, stop valves, trigger valves, retention valves, and so on, and describe their operating principle and limitations. We discuss applications of CCs starting with the most common usage in automating liquid delivery steps for immunoassays, and highlight emerging applications such as DNA analysis. Finally, we highlight recent developments in rapid prototyping of CCs and the benefits offered including speed, low cost, and greater degrees of freedom in CC design. The combination of better analytical models and lower entry barriers (thanks to advances in rapid manufacturing) make CCs both a fertile research area and an increasingly capable technology for user-friendly and high performance laboratory and diagnostic tests. PMID- 30010169 TI - Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 mitigate alcoholic steatosis in mice by inhibiting LPS-mediated NF-kappaB activation through restoration of the disturbed gut microbiota. AB - Long-term exposure to ethanol simultaneously causes gastrointestinal inflammation, liver injury, and steatosis. In the present study, we investigated the effects of Bifidobacterium longum LC67, Lactobacillus plantarum LC27, and their mixture (LM) against ethanol-induced steatosis in mice. Exposure to ethanol caused liver damage: it increased ALT, AST, TG, TC, and lipopolysaccharide levels in the blood and induced NF-kappaB activation in the liver. Oral administration of LC27, LC67, or LM in mice reduced ethanol-induced ALT, AST, TG, and TC levels in the blood and liver. These also suppressed ethanol-induced NF-kappaB activation and alpha-smooth muscle actin expression in the liver and increased ethanol-suppressed AMPK activation. Treatment with LC27, LC67, or LM increased ethanol-suppressed alcohol dehydrogenase and acetaldehyde dehydrogenase activities in the liver, as well as tight junction protein expression in the liver and colon. Moreover, treatment with LC27, LC67, or LM restored the ethanol disturbed gut microbiota composition, such as the increased population of Proteobacteria, and inhibited fecal and blood lipopolysaccharide levels. These inhibited NF-kappaB activation and increased tight junction protein expression in ethanol- or lipopolysaccharide-stimulated Caco-2 cells. These findings suggest that LC27, LC67, and LM can alleviate alcoholic steatosis by inhibiting LPS mediated NF-kappaB activation through restoration of the disturbed gut microbiota. PMID- 30010170 TI - Magnetic anisotropy and relaxation behavior of six-coordinate tris(pivalato) Co(ii) and -Ni(ii) complexes. AB - Experimental and theoretical studies of magnetic anisotropy and relaxation behavior of six-coordinate tris(pivalato)-Co(ii) and -Ni(ii) complexes (NBu4)[M(piv)3] (piv = pivalate, M = Co, 1; M = Ni, 2), with a coordination configuration at the intermediate between an octahedron and a trigonal prism, are reported. Direct current magnetic data and high-frequency and -field EPR spectra (HFEPR) of 1 have been modeled by a general Hamiltonian considering the first order orbital angular momentum, while the spin Hamiltonian was used to interpret the data of 2. Both 1 and 2 show easy-axis magnetic anisotropies, which are further supported by ab initio calculations. Alternating current (ac) magnetic susceptibilities reveal slow magnetic relaxation at an applied dc field of 0.1 T in 1, which is characteristic of a field-induced single-ion magnet (SIM), but 2 does not exhibit single-ion magnetic properties at 1.8 K. Detailed analyses of relaxation times show a dominant contribution of a Raman process for spin relaxation in 1. PMID- 30010171 TI - Electrochemical calcium extraction from 1D-Ca3Co2O6. AB - The electrochemical oxidation of a transition metal oxide through calcium extraction is achieved for the first time. The 1D framework of Ca3Co2O6 is maintained upon oxidation and the new phase formed exhibits a modulated structure. The process occurs at high potential and is partially reversible, which opens prospects for a calcium battery proof-of-concept. PMID- 30010172 TI - The chemical fingerprint of hair melanosomes by infrared nano-spectroscopy. AB - In situ characterization of the chemical and structural properties of black and white sheep hair was performed with a spatial resolution of 25 nm using infrared nano-spectroscopy. Comparing data sets from two types of hair allowed us to isolate the keratin FTIR fingerprint and so mark off chemical properties of the hair's melanosomes. From a polarization sensitive analysis of the nano-FTIR spectra, we showed that keratin intermediate filaments (IFs) present anisotropic molecular ordering. In stark contrast with white hair which does not contain melanosomes, in black hair, we spatially resolved single melanosomes and achieved unprecedented assignment of the vibrational modes of pheomelanin and eumelanin. The in situ experiment presented here avoids harsh chemical extractive methods used in previous studies. Our findings offer a basis for a better understanding of the keratin chemical and structural packing in different hair phenotypes as well as the involvement of melanosomes in hair color and biological functionality. PMID- 30010173 TI - Construction of supramolecular hydrogels using photo-generated nitric oxide radicals. AB - Photo-generated nitric oxide radicals (NO) derived from sodium nitroprusside dihydrate (SNP) are employed for the construction of supramolecular hydrogels based on an amino acid derivative precursor, N-fluorenylmethyloxycarbonyl tyrosine phosphate (FYP), which through dephosphorylation produces the gelator, N fluorenylmethyloxycarbonyl tyrosine (FY). Self-assembly of the amphiphilic gelator yields high-aspect ratio nanofilaments that entangle to form self supporting, viscoelastic hydrogels. The presence of photolyzed SNP yields periodically twisted nanofilaments with opposite chirality to filaments formed through conventional hydrogelation routes. PMID- 30010174 TI - Expression of gamma-tubulin in non-small cell lung cancer and effect on patient survival. AB - INTRODUCTION: It has been reported that overexpression and altered compartmentalization of gamma-tubulin may contribute to tumorigenesis and tumor aggressiveness in a variety of human malignancies. We have shown that gamma tubulin expression and cellular distribution pattern is also altered in non-small cell lung cancer (NSCLC) (Histol Histopathol. 2012; 27: 1183-1194). In the present study we examined the relationship between gamma-tubulin expression and patient overall survival (OS). MATERIAL AND METHODS: Immunohistochemistry was performed, with well-characterized anti-gamma-tubulin antibodies, on 109 formalin fixed, paraffin-embedded NSCLC specimens (p-TNM stage I-III). gamma-Tubulin labeling indexes (LIs) were determined, and the association of gamma-tubulin expression with clinicopathological parameters was evaluated. To analyze OS rates according to gamma-tubulin LIs, patients were categorized into three groups: those with low (0-30%), intermediate (31-69%) or high (70-100%) gamma-tubulin LI. Association of clinicopathological parameters and gamma-tubulin with survival were examined using univariate and multivariate Cox regression analysis. RESULTS: No statistically significant association was seen between gamma-tubulin overexpression and histological type, tumor differentiation, p-TNM stage and adenocarcinoma subtyping. Longer survival was observed in the high gamma-tubulin LI group of patients with p-TNM stages II+III when compared to intermediate or low gamma-tubulin LI groups, but the difference was not statistically significant (p=0.066). On the other hand, when combined low and intermediate gamma-tubulin LI groups (p-TNM stages II+III) where compared to high gamma-tubulin LI group, statistically significant longer survival was observed in high gamma-tubulin group (p=0.021). CONCLUSION: Our findings suggest that level of gamma-tubulin expression may have an impact on patient survival at more advanced NSCLC stages. PMID- 30010175 TI - RE: The Evaluation of the Result of Warm Normal Saline Irrigation in Ureteral Endoscopic Surgeries: A Randomized Clinical Trial. PMID- 30010176 TI - Evaluation of the health behaviors of women in multiple pregnancies - a preliminary study. AB - OBJECTIVES: The aim of the paper was to assess which health behavior indicators were characteristic for women with a multiple pregnancy. MATERIAL AND METHOD: The study involved 35 women in multiple pregnancies. The inclusion criteria were: the completion of the 22nd week of pregnancy (22 Hbd, i.e., 22 weeks and 1/7) and the consent of the women to participate in the study. We used an original questionnaire devised by us specifically for our study, as well as a standardized research tool, Juczynski's Health Behavior Inventory questionnaire, for the assessment of the pregnant women's health behaviors. RESULTS: The overall rate of health behaviors was high and was on average 93.9 +/- 10.8 points (7 sten scores). Indicators of the health behaviors of women in multiple pregnancies were high across all categories. However, the highest rate was observed in preventive behaviors. CONCLUSIONS: The overall rate of health behaviors of women with a multiple pregnancy and all the individual behavior category indicators were high. However, the highest rate was for preventive behaviors. The indicator values of the health behaviors of the pregnant women in the study were not dependent on the variables adopted in this paper. PMID- 30010177 TI - Changes in the IGF-1 and TNF-alpha synthesis pathways before and after three month reduction diet with low glicemic index in women with PCOS. AB - OBJECTIVES: An increase in IGF-I and TNF-alpha may be a cardioprotective effect. To examine the relationships between IGF-I and TNF-alpha and test the anthropometric and biochemical parameters before and after a low-glycemic index reduction diet using a correlation matrix. MATERIAL AND METHODS: Twenty-two women diagnosed with PCOS according to Rotterdam's criteria were eligible for this study, which analysed the results before and after a three months dietary intervention. Body composition measurements were determined by bioimpedance and performed twice, along with the labelling of lipid, carbohydrate and hormonal profiles. IGF-I and TNF-alpha were also determined in the serum. RESULTS: Before dietary intervention, a significant correlation was observed. A correlation was also noted between the increase in TNF-alpha and DHEA-SO4, FSH, glucose level and total cholesterol. The increase in IGF-I was not related to anth-ropometric measurements: however, its concentration was observed to be related to the level of SHBG and HDL. After dietary intervention, the correlation between TNF-alpha and muscle mass percentage was confirmed, as was the correlation between WHR and fasting blood glucose levels. A significant negative correlation was observed between extracellular water, provided in litres, and SHBG level. CONCLUSIONS: One important role of IGF-I in PCOS pathogenesis is the stimulation of increased synthesis of SHBG and HDL. The increased level of IGF-I after the reduction diet had a cardioprotective effect. TNF-alpha inhibits FSH synthesis, preventing the growth of numerous follicles. Its synthesis is also related to DHEA-SO4. After three-month reduction diet does not significantly reduce TNF-alpha. PMID- 30010178 TI - The assessment of GWAS - identified polymorphisms associated with infertility risk in Polish women with endometriosis. AB - OBJECTIVES: Genome-wide association studies in patients with endometriosis revealed ten significant single nucleo-tide polymorphisms (SNPs) in the Caucasian population, which include rs12700667 near NFE2L3, rs12037376 in WNT4, rs7521902 near WNT4, rs13394619 in GREB1, rs10859871 near VEZT, rs1537377 near CDKN2B-AS1, rs4141819 near ETAA1, rs7739264 near ID4, rs1519761 near RND3 and rs6542095 near IL1A. MATERIAL AND METHODS: We replicated ten polymorphisms among infertile women with endometriosis (n = 315) and healthy fertile women (n = 406) in the Polish Caucasian population. Genotyping was conducted either by high-resolution melting curve analysis or by a pre-designed TaqMan probe. RESULTS: For all infertile women with endometriosis, the p values of the Cochran-Armitage trend test for the rs12700667 SNP was ptrend = 0.038 and the odds ratio (OR) for the risk allele frequency (RAF) of rs12700667 was 1.304 (95% CI = 1.009-1.685; p = 0.042). In patients with endometriosis with severity stages III/IV, ptrend for rs12700667 SNP was 0.036 and OR for the RAF was 1.394 (95% CI = 1.010-1.923; p = 0.043). In infertile women with endometriosis with severity stages III/IV for rs4141819 SNP, we observed ptrend = 0.026 and for RAF the OR = 1.350 (95% CI = 1.032-1.766; p = 0.029). CONCLUSIONS: Our results demonstrate association of RAF of rs12700667 and rs4141819 SNPs with infertility in Polish women with advanced endometriosis. PMID- 30010179 TI - Role of lymphadenectomy in disease-free and overall survival on low risk endometrium cancer patients. AB - OBJECTIVES: Evaluation of the effect of lymphadenectomy in disease-free and overall survival on the low risk corpus cancer. MATERIAL AND METHODS: Between 1994 and 2012, a total of 257 patients with endometrioid type, grade 1 or 2, myometrial invasion < 1/2, no intraoperative evidence of macroscopic extrauterine spread was treated surgically. Pelvic lymphadenec-tomy was performed in 184 cases, and not performed in 73 cases. RESULTS: There was no difference between two groups about tumor sizes. Also lymphovascular space invasion and histo-logic grade of two groups were similar. Omission of LA did not worsen DFS and OS in early stage low risk corpus cancer. CONCLUSIONS: Patients who have low risk corpus cancer, can be treated optimally with hysterectomy only. PMID- 30010180 TI - Assessment of nasal and oral flow of amniotic fluid in 46 non-anomalous fetuses with sonographic and echocardiographic examination. AB - OBJECTIVES: The aim of the paper was to assess nasal and oral amniotic fluid flows, with the use of color ultrasound and spectral Doppler, in normal fetuses. MATERIAL AND METHODS: Forty-six fetuses of singleton gestations were studied prospectively. Spectrum imaging and maximal nasal fluid flow velocities were described. Episodes of regurgitation (external flow from the mouth), swallowing (internal flow at the level of oropharynx and then entrance to the esophagus) were evaluated in two groups: Fetuses < 27 weeks of gestation and 27 weeks of gestation and older. Statistical analysis was done using Fischer exact test and t test at p = 0.05. RESULTS: Twenty-one fetuses were < 27 weeks of gestational age and presented mean maximal both inspiratory and expiratory nasal fluid flow velocities significantly lower than twenty-five fetuses who were >= 27 weeks of gestational age (p = 0.035 and p = 0.031 respectively, t-test). Episodes of regurgitation were observed more frequently in group of "younger" fetuses (p = 0.006, Fischer exact test). There was no statistically significant relationship between irregular nasal flow spectrum by color Doppler and gestational age group (p = 0.264, Fischer exact test). CONCLUSIONS: Episodes of regurgitation occurred in normal fetuses < 27th week of gestation. Fast amniotic nasal fluid flows without episodes of regurgitation were observed more frequently in fetuses >= 27 weeks and it could be interpreted as an additional sonographic feature of prenatal maturation. PMID- 30010181 TI - Rapid cervical phIGFBP-1 test in asymptomatic twin pregnancies is inefficient in predicting preterm delivery prior to 34 gestational weeks. AB - OBJECTIVES: To assess the effectiveness of a rapid second trimester test for cervical phIGFBP-1 in the prediction of sponta-neous preterm delivery prior to 34 weeks in asymptomatic twin pregnancies. MATERIAL AND METHODS: A prospective observational study conducted on 232 twin pregnancies tested for phIGFBP-1 at 20 24 weeks of gestation. 151 patients assessed as asymptomatic, with cervical length > 25 mm at 20-24 weeks were analysed. The primary outcome was the delivery < 34 weeks of gestation. RESULTS: The spontaneous preterm delivery before completing 34 weeks occurred in 23 patients (15.2%), including 9 in dichorionic and 14 in monochorionic pregnancies. The sensitivity of phIGFBP-1 test was 0.39 and specificity 0.63 in predicting delivery before 34 gestational weeks. phIGFBP 1 had a low positive predictive value of 0.16 and high negative predictive value (0.85). Both positive and negative predictive values of delivery < 34 weeks were close to 1. CONCLUSIONS: A test for phIGFBP1 presence is not an effective additional tool for predicting preterm delivery before 34 weeks in twin gestation. PMID- 30010182 TI - Next generation sequencing as a new detection strategy for maternal cell contamination in clinical prenatal samples. AB - OBJECTIVES: The maternal cell contamination in chorionic villus or amniotic fluid presents a serious preanalytical risk for prenatal misdiagnosis. The following study presents and validates a novel process for identifying MCC by detecting short tandem repeat markers on Ion Proton system. Initially, MCC testing was performed during the detection of chromosomal abnormalities so as to improve the detection efficiency and accuracy of this method. MATERIAL AND METHODS: More than 70 STR loci were selected to establish the detection progress. Capillary electrophoresis was used to compare the next generation sequencing detection results, as well as to identify the optimal STR on Ion Proton system. Evaluation criteria for maternal cell contamination were set, and the automated data analysis was performed. The detection sensitivity was validated via 4 groups with mixed samples and different proportions. RESULTS: Consequently, twenty-three clinical samples were tested to evaluate the detection accuracy. In addition, 14 reli-able STR loci, which were stably detected in more than 25 samples, were found. The detection sensitivity in maternal cell contamination was no less than 20%, while its accuracy reached 100% in clinical samples. CONCLUSIONS: Finally, we established and validated a novel detection procedure for maternal cell contamination in clinical prenatal samples using next generation sequencing. This procedure allowed us to simultaneously perform prenatal test-ing and MCC testing. Unlike the traditional capillary electrophoresis, this method is rapid, highly sensitive, and suitable for wide range of clinical applications. PMID- 30010183 TI - How to identify pregnant women at risk of pre-eclampsia? - a review of the current literature. AB - Pre-eclampsia remains a major cause of poor perinatal outcome worldwide. As administering acetylsalicylic acid in a high risk population reduces the risk of PE, it is essential to identify women at risk of PE. Several algorithms for PE risk assessment have been developed. They include maternal factors combined with uterine artery pulsatility index, mean arterial pressure, serum pregnancy associated plasma protein-A, placental growth factor, and serum soluble fms-like tyrosine kinase-1. Beside PE prophylaxis with acetylsalicylic acid, a proper management of women considered at a high risk of PE is essential. The sFlt-1:PlGF ratio between 20 and 34 + 6 weeks may be used to predict a short-term absence of PE or to predict the risk of PE diagnosis within 4 weeks and a significant shortening of the duration of pregnancy associated with it. The sFlt-1:PlGF ratio may be helpful in deciding about hospitalization or choosing the optimal time for corticosteroid administration in women at risk of PE. It may also help to reduce overall healthcare costs. PMID- 30010184 TI - The course and delivery of a pregnancy in a patient with autoimmune hepatitis complicated by cirrhosis of the liver. PMID- 30010185 TI - Standards of Polish Society of Gynecologists and Obstetricians in management of women with diabetes. PMID- 30010186 TI - Inherited THPO mutation, with morphology resembling chronic myeloid leukaemia. PMID- 30010188 TI - Fatigue biases the decoy effect in males but not females. AB - Individuals often need to make critical decisions even when they are in a fatigued state. Mental fatigue may lead to increased susceptibility to distraction and poor information processing but it is unclear exactly how fatigue shapes individuals' decision-making. We studied how mental fatigue influences sensitivity to contextual information, indexed as decoy bias. Mental fatigue was induced using a multi-source interference task, and decoy bias was assessed using a gambling task, in 124 young adults. Results showed that mental fatigue increased decoy bias through enhanced perceptual salience of contextual cues, but only in males. The findings provide insight into a gender-specific relationship between fatigue and poor judgments. This study extends the current literature on links between fatigue and poor decision-making by documenting a possible mechanism of the association. The results may have practical implications for designing optimal working hours and safeguarding people from suboptimal decisions. PMID- 30010187 TI - Ruxolitinib in elderly patients with myelofibrosis: impact of age and genotype. A multicentre study on 291 elderly patients. AB - Ruxolitinib is a JAK1/2 inhibitor that may control myelofibrosis (MF)-related splenomegaly and symptoms and can be prescribed regardless of age. While aging is known to correlate with worse prognosis, no specific analysis is available to confirm that ruxolitinib is suitable for use in older populations. A clinical database was created in 23 European Haematology Centres and retrospective data on 291 MF patients treated with ruxolitinib when aged >=65 years were analysed in order to assess the impact of age and molecular genotype on responses, toxicities and survival. Additional mutations were evaluated by a next generation sequencing (NGS) approach in 69 patients with available peripheral blood samples at the start of ruxolitinib treatment. Compared to older (age 65-74 years) patients, elderly (>=75 years) showed comparable responses to ruxolitinib, but higher rates of drug-induced anaemia and thrombocytopenia and worse survival. Nonetheless, the ruxolitinib discontinuation rate was comparable in the two age groups. Number and types of molecular abnormalities were comparable across age groups. However, the presence of high molecular risk (HMR) mutations significantly affected survival, counterbalancing the effect of aging. Indeed, elderly patients with <2 HMR mutated genes had a comparable survival to older patients with >=2 HMR mutations. Given that responses were not influenced by age, older age per se should not be a limitation for ruxolitinib administration. NGS analysis of HMR mutations also confirmed a strong predictive value in elderly patients. PMID- 30010189 TI - Reduced regulatory T cells (Treg) in bone marrow preferentially associate with the expansion of cytotoxic T lymphocytes in low risk MDS patients. PMID- 30010190 TI - Recognition of all basic emotions varies in accuracy and reaction time: A new verbal method of measurement. AB - To study different aspects of facial emotion recognition, valid methods are needed. The more widespread methods have some limitations. We propose a more ecological method that consists of presenting dynamic faces and measuring verbal reaction times. We presented 120 video clips depicting a gradual change from a neutral expression to a basic emotion (anger, disgust, fear, happiness, sadness and surprise), and recorded hit rates and reaction times of verbal labelling of emotions. Our results showed that verbal responses to six basic emotions differed in hit rates and reaction times: happiness > surprise > disgust > anger > sadness > fear (this means these emotional responses were more accurate and faster). Generally, our data are in accordance with previous findings, but our differentiation of responses is better than the data from previous experiments on six basic emotions. PMID- 30010191 TI - In the eyes of the beholder: Parental and professional value mismatch in child risk and protection in two communities in Israel. AB - This paper aims to identify several of the mismatches at play when social workers encounter families belonging to diverse groups and assess risk, well-being and protection for children. Two minority groups in Israel were studied: the Ultra Orthodox Jewish community and Jewish immigrants from Ethiopia. A context-informed approach was adopted to explore the subjective perceptions and constructions of "risk," "well-being," and "protection" among parents of the two communities (N = 60) and the social workers who work with them (N = 50). The social workers included some who belong to the minority groups they serve and others who are from the majority group. The analysis of the interviews yielded two main themes: (a) an understanding of the discrepancies in parents' and professionals' perceptions and constructions of "risk" and "protection" for children as the product of differences in the values, norms and contexts of these two groups; and (b) the implications of these discrepancies for the relationship between professionals/social service agencies and parents who are potential service users. Our findings call upon professionals to re-visit "universals" in the "risk" discourse while taking into account the realms of culture, ethnicity, religiosity, spirituality and community life when assessing risk and treating children and families of minority communities. PMID- 30010192 TI - A causal model for the quality of nursing care in Thailand. AB - BACKGROUND: A growing global nursing shortage has affected the quality of care (QOC) provision. AIM: To test the structure-process-outcome model for quality of nursing care in regional medical centres in Thailand. METHODS: A cross-sectional study with multi-stage, proportional stratified random sampling. The sample comprised 136 units, 916 nurses and 943 patients from nine regional medical centres. Data were collected from six instruments in February-June 2016 and analysed with structural equation modelling. RESULTS: The modified model fitted the empirical data. The nurse practice environment (NPE) had a negative direct effect on pressure ulcer prevalence and a positive direct effect on patient satisfaction, perceived QOC and interpersonal processes of care (IPC). Increasing the patient-to-nurse ratio had a positive direct effect on catheter-associated urinary tract infections and pressure ulcer prevalence and had negative direct effects on patient satisfaction and perceived QOC. Skill mix had negative direct effects on the two former conditions but had a positive direct effect on patient satisfaction. The patient-to-nurse ratio and skill mix also had indirect effect on four outcomes via NPE. LIMITATIONS: The generalizability of findings may be limited to settings similar to this study. CONCLUSION: We empirically demonstrated that NPE, patient-to-nurse- ratio and skill mix had direct effects on unfinished nursing care and four outcomes. Also, the IPC had significant influence on patient satisfaction. IMPLICATIONS FOR NURSING AND HEALTH POLICY: The findings add to increasing international evidence that favourable nurse working conditions, low nurse-to-patient ratio and richer skill mix result in positive patient outcomes. Health systems can foster nurses to perform high quality care by improving work conditions, and providing sufficient nurses and resources. PMID- 30010193 TI - Lions and leopards coexist without spatial, temporal or demographic effects of interspecific competition. AB - Although interspecific competition plays a principal role in shaping species behaviour and demography, little is known about the population-level outcomes of competition between large carnivores, and the mechanisms that facilitate coexistence. We conducted a multilandscape analysis of two widely distributed, threatened large carnivore competitors to offer insight into coexistence strategies and assist with species-level conservation. We evaluated how interference competition affects occupancy, temporal activity and population density of a dominant competitor, the lion (Panthera leo), and its subordinate competitor, the leopard (Panthera pardus). We collected camera-trap data over 3 years in 10 study sites covering 5,070 km2 . We used multispecies occupancy modelling to assess spatial responses in varying environmental and prey conditions and competitor presence, and examined temporal overlap and the relationship between lion and leopard densities across sites and years. Results showed that both lion and leopard occupancy was independent of-rather than conditional on-their competitor's presence across all environmental covariates. Marginal occupancy probability for leopard was higher in areas with more bushy, "hideable" habitat, human (tourist) activity and topographic ruggedness, whereas lion occupancy decreased with increasing hideable habitat and increased with higher abundance of very large prey. Temporal overlap was high between carnivores, and there was no detectable relationship between species densities. Lions pose a threat to the survival of individual leopards, but they exerted no tractable influence on leopard spatial or temporal dynamics. Furthermore, lions did not appear to suppress leopard populations, suggesting that intraguild competitors can coexist in the same areas without population decline. Aligned conservation strategies that promote functioning ecosystems, rather than target individual species, are therefore advised to achieve cost- and space-effective conservation. PMID- 30010194 TI - Social support for elderly people over 65 years in Spain. AB - AIMS: To determine what social support is available in Spain to people over 65 who also dedicate hours of their time to the care of others who are older. BACKGROUND: Demographic and social changes are leading to growth of the population. The social support available to older people in the final stage of life affects their health. METHODS: A cross-sectional study was conducted involving the records of older, non-institutionalized individuals residing in Spain, obtained from the European Health Survey of 2014. The method of collecting information used in the European Survey was personal interviews assisted by a computer. RESULTS: The records of 6520 older people were studied; 40.1% of the participants studied had expressed the possibility of having three to five people available in case of a serious problem, and 83.6% reported that the rest of the people around them were very interested in what happens to them. With respect to care, only 7% of the older people studied mentioned performing care tasks. CONCLUSIONS: Social support is beneficial to older people, regardless of whether they perform care tasks, because it acts as a protective factor against problems such as loneliness, stress and depression. The profile of a primary caregiver in this age range is a married, middle-class woman with primary schooling who is caring for a first-degree relative. IMPLICATIONS FOR NURSING AND HEALTH POLICY: These data suggest that it is necessary for nurses to know about the needs of older people to implement societal measures of health promotion, prevention and education that favour social cohort. In addition, health policymakers should establish programmes that improve the social support of non-institutionalized older people. PMID- 30010195 TI - The effects of breathing at a frequency of 0.1 Hz on affective state, the cardiovascular system, and adequacy of ventilation. AB - The present study aimed to investigate changes induced by breathing at 0.1 Hz in affective state, cardiovascular activity, and adequacy of ventilation as well as the relation between changes in peripheral physiological processes and alteration of affect. Eighty-three participants were randomly assigned to one of three groups: Two groups doing paced breathing at 0.1 Hz, one with and the other without a cover story hiding the goal of the experiment, and, as a control, paced breathing at 0.28 Hz. We measured the effects of breathing at 0.1 Hz on affective state (unpleasant and pleasant arousals), respiratory sinus arrhythmia (RSA), sympathetic control of the heart (preejection period, PEP), and adequacy of ventilation as measured by partial pressure of end-tidal CO2 (PetCO2 ). The use of a cover story did not influence the effects of paced breathing on the study outcomes. In the 0.1 Hz groups, unpleasant arousal decreased only among men. Changes in RSA were not related to changes in affect. Respiratory frequency did not influence PEP. However, changes in PEP were inversely related to changes in pleasant arousal. PetCO2 decreased in all conditions, and a larger drop in PetCO2 predicted a greater decrease in unpleasant arousal. The results obtained corroborate previous findings showing that slow paced breathing may lead to moderate hyperventilation among untrained participants and suggest that hyperventilation during breathing at 0.1 Hz is not deep enough to produce an increase in affective arousal. PMID- 30010196 TI - The impact of exercise and nutrition on the regulation of skeletal muscle mass. AB - The maintenance of skeletal muscle mass and strength throughout life is a key determinant of human health and well-being. There is a gradual loss of both skeletal muscle mass and strength with ageing (a process termed sarcopenia) that increases the risk of functional dependence, morbidity and mortality. Understanding the factors that regulate the size of human muscle mass, particularly during the later years of life, has therefore become an area of intense scientific inquiry. The amount of muscle mass is determined by coordinated changes in muscle protein synthesis (MPS) and muscle protein breakdown (MPB). In this review, we assess both classical and contemporary work that has examined how resistance exercise and nutrition impact on MPS and MPB. Special consideration is given to the role of different sources of dietary protein (food vs. supplements) and non-protein nutrients such as omega-3 fatty acids in regulating MPS. We also critically evaluate recent studies that have employed novel 'omic' technologies such as dynamic protein profiling to probe for changes in rates of MPS and MPB at the individual protein level following exercise. Finally, we provide suggestions for future research that we hope will yield important information for the development of exercise and nutritional strategies to counteract muscle loss in a variety of clinical settings. PMID- 30010197 TI - Alpha-band functional connectivity during cued versus implicit modality-specific anticipatory attention: EEG-source coherence analysis. AB - The anticipation of future events based on a background experience is one of the main components of any goal-directed behavior. Anticipatory attention can be either voluntary (explicit) or involuntary (implicit). We presumed that these two types of anticipatory attention differed in terms of cortical functional organization. We examined this assumption with an experimental model consisting of three experimental sessions (cued attention, implicit learning, and baseline) that were equal in terms of stimuli, motor responses, and cognitive task. Participants were asked to discriminate the temporal order of stimuli within a pair presented in either the visual or auditory sensory modality. Prestimulus functional connectivity was assessed via alpha-band coherence computed in the source space for preselected regions of interests. Functional links between the cortices of the frontoparietal control system increased during the cued attention condition and did not increase during the implicit anticipation condition. The buildup of implicit anticipation was accompanied by the strengthening of functional links between the intraparietal, ventral premotor, and presupplementary motor areas. It was discovered that both cued and implicit types of anticipation were underlain by functional modality-specific cortical links. PMID- 30010198 TI - Effects of menstrual cycle phase on electrocortical response to reward and depressive symptoms in women. AB - The menstrual cycle impacts mood and neural response to reward-phenomena that may be related to natural fluctuations in ovarian hormones. Using a within-subject design, the present study examined ovarian hormones (i.e., estradiol and progesterone) and ERPs in response to feedback indicating gains and losses in both the follicular and luteal phases of the menstrual cycle. We examined whether hormone levels and variation in neural response to reward and loss across menstrual cycle phases were associated with depressive symptoms. Participants high in depressive symptoms showed a reduced reward positivity (RewP) to monetary gains during the luteal phase of the menstrual cycle as compared to the follicular phase, while those low in depressive symptoms showed no change in the RewP to monetary gains between phases. Thus, increased fluctuation in the neural response to gains (but not losses) across menstrual cycle phases was associated with greater depression symptoms. Overall, findings indicate that hormonal fluctuations associated with the menstrual cycle may relate to depressive symptoms by altering reward sensitivity. Furthermore, fluctuation in the neural response to rewards over the menstrual cycle may play an important role in the expression of depressive symptoms. PMID- 30010199 TI - Disentangling the drivers of invasion spread in a vector-borne tree disease. AB - Pine wilt disease (PWD) invaded southern Japan in the early 1900s and has gradually expanded its range to northern Honshu (Japanese mainland). The disease is caused by a pathogenic North American nematode, which is transmitted by native pine sawyer beetles. Recently, the disease has invaded other portions of East Asia and Europe where extensive mortality of host pines is anticipated to resemble historical patterns seen in Japan. There is a critical need to identify the main drivers of PWD invasion spread so as to predict the future spread and evaluate containment strategies in newly invaded world regions. But the coupling of pathogen and vector population dynamics introduces considerable complexity that is important for understanding this and other plant disease invasions. In this study, we analysed historical (1980-2011) records of PWD infection and vector abundance, which were spatially extensive but recorded at coarse categorical levels (none, low and high) across 403 municipalities in northern Honshu. We employed a multistate occupancy model that accounted both for demographic stochasticity and observation errors in categorical data. Analysis revealed that sparse sawyer populations had lower probabilities of transition to high abundance than did more abundant populations even when regional abundance stayed the same, suggesting the existence of positive density dependence, that is an Allee effect, in sawyer dynamics. Climatic conditions (average accumulated degree days) substantially limited invasion spread in northern regions, but this climatic influence on sawyer dynamics was generally weaker than the Allee effect. Our results suggest that tactics (eg sanitation logging of infected pines) which strengthen Allee effects in sawyer dynamics may be effective strategies for slowing the spread of PWD. PMID- 30010200 TI - Data-adaptive additive modeling. AB - In this paper, we consider fitting a flexible and interpretable additive regression model in a data-rich setting. We wish to avoid pre-specifying the functional form of the conditional association between each covariate and the response, while still retaining interpretability of the fitted functions. A number of recent proposals in the literature for nonparametric additive modeling are data adaptive, in the sense that they can adjust the level of flexibility in the functional fits to the data at hand. For instance, the sparse additive model makes it possible to adaptively determine which features should be included in the fitted model, the sparse partially linear additive model allows each feature in the fitted model to take either a linear or a nonlinear functional form, and the recent fused lasso additive model and additive trend filtering proposals allow the knots in each nonlinear function fit to be selected from the data. In this paper, we combine the strengths of each of these recent proposals into a single proposal that uses the data to determine which features to include in the model, whether to model each feature linearly or nonlinearly, and what form to use for the nonlinear functions. We establish connections between our approach and recent proposals from the literature, and we demonstrate its strengths in a simulation study. PMID- 30010201 TI - An automated independent workflow for the analysis of massively parallel sequence data from forensic SNP assays. AB - Illumina and Thermo Fisher Scientific have developed assays that permit the sequencing of forensically relevant single nucleotide polymorphisms (SNPs), along with software to determine the associated genotypes. Currently there is no method to either independently confirm the genotypes determined using the manufacturer's software, or to compare genotypes and quality metrics among samples processed using both platforms. This paper outlines an automated workflow developed in CLC Genomics Workbench that permits accurate, fast and independent analysis of SNP sequence data from either platform. To facilitate the straightforward comparison of genotypes generated from both the manufacturer's software and the independent CLC analysis, a Python script was written. Data for a total of 323 forensically relevant ancestry, identity and phenotypic SNPs can be analyzed, and the resulting genotypes, coverage, quality flags and major allele frequencies are easily compared across samples and platforms. PMID- 30010202 TI - Light-induced self-thermophoresis of Janus spheroidal nanoparticles. AB - A theoretical framework is provided for determining the self-thermophoretic velocity of a light irradiated spheroidal Janus nanoparticle consisting of symmetric dielectric and perfectly conducting semi-spheroids. The analysis is based on solving the linearized Joule heating problem due to uniform laser irradiance and on explicitly determining the temperature fields inside and outside the particle. We employ the thermoelectric (Peltier- Seebeck) methodology to find the surface self - induced temperature gradient and the related slip velocity which determines the autonomous phoretic (self - propulsion) mobility of the Janus particle. Simplified explicit expressions for the self - thermophoretic velocities of spheroidal (prolate and oblate) Janus particles in terms of their aspect ratios are found and few practical limiting cases (i.e., sphere, disk and needle) are also discussed. PMID- 30010203 TI - Contactless conductivity detection for analytical techniques: Developments from 2016 to 2018. AB - The publications concerning capacitively coupled contactless conductivity detection for the 2-year period from mid-2016 to mid-2018 are covered in this update to the earlier reviews of the series. Relatively few reports on fundamental investigations or new designs have appeared in the literature in this time interval, but the development of new applications with the detection method has continued strongly. Most often, contactless conductivity measurements have been employed for the detection of inorganic or small organic ions in conventional capillary electrophoresis, less often in microchip electrophoresis. A number of other uses, such as detection in chromatography or the gauging of bubbles in streams have also been reported. PMID- 30010204 TI - Cutaneous lymphomatoid granulomatosis with long-term absence of lung involvement. PMID- 30010205 TI - Comparison of two correlated ROC surfaces at a given pair of true classification rates. AB - The receiver operating characteristic (ROC) curve is typically employed when one wants to evaluate the discriminatory capability of a continuous or ordinal biomarker in the case where two groups are to be distinguished, commonly the "healthy" and the "diseased." There are cases for which the disease status has three categories. Such cases employ the ROC surface, which is a natural generalization of the ROC curve for three classes. In this paper, we explore new methodologies for comparing two continuous biomarkers that refer to a trichotomous disease status, when both markers are applied to the same patients. Comparisons based on the volume under the surface have been proposed before, but that measure is often not clinically relevant. Here, we focus on comparing two correlated ROC surfaces at given pairs of true classification rates, which are more relevant to patients and physicians. We propose delta-based parametric techniques, power transformations to normality, and bootstrap-based smooth nonparametric techniques to investigate the performance of an appropriate test. We evaluate our approaches through an extensive simulation study and apply them to a real dataset from prostate cancer screening. PMID- 30010206 TI - Negative-pressure closure was superior to tie-over technique for stabilization of split-thickness skin graft in large or muscle-exposing defects: A retrospective study. AB - Skin grafts are frequently used for the reconstruction of skin defects, and optimal stabilization of the graft is essential for successful reconstruction. Although the tie-over technique has been widely used as a standard method in Japan, we sometimes encounter cases with significant graft loss due to suboptimal stabilization of the graft. Reported risk factors for increased graft loss include the following: defects of a large size, with muscle exposure, and located in the trunk and extremities. Recent studies have demonstrated the usefulness of negative-pressure closure (NPC) for the stabilization of skin grafts due to the uniform pressure it provides across the graft. Therefore, since March 2017, we have used NPC for skin graft stabilization in patients with defects in the trunk and extremities of more than 10 cm in size or with muscle exposure. We carried out a retrospective comparative study of the outcome of the conventional tie-over technique versus NPC. Mann-Whitney U-test revealed that NPC showed significantly higher graft survival rate than tie-over method (P = 0.0012). In addition, NPC showed a tendency toward shorter operative times (from skin graft harvest to the completion of the graft stabilization) than the tie-over method (P = 0.0931). These results suggest that NPC may be superior to the tie-over method for stabilization of skin grafts especially in large or muscle-exposing defects in the trunk or extremities. PMID- 30010207 TI - A Bayesian analysis of small n sequential multiple assignment randomized trials (snSMARTs). AB - Designing clinical trials to study treatments for rare diseases is challenging because of the limited number of available patients. A suggested design is known as the small n sequential multiple assignment randomized trial (snSMART), in which patients are first randomized to one of multiple treatments (stage 1). Patients who respond to their initial treatment continue the same treatment for another stage, while those who fail to respond are rerandomized to one of the remaining treatments (stage 2). The data from both stages are used to compare the efficacy between treatments. Analysis approaches for snSMARTs are limited, and we propose a Bayesian approach that allows for borrowing of information across both stages. Through simulation, we compare the bias, root-mean-square error, width, and coverage rate of 95% confidence/credible interval of estimators from of our approach to estimators produced from (i) standard approaches that only use the data from stage 1, and (ii) a log-Poisson model using data from both stages whose parameters are estimated via generalized estimating equations. We demonstrate the root-mean-square error and width of 95% confidence/credible intervals of our estimators are smaller than the other approaches in realistic settings, so that the collection and use of stage 2 data in snSMARTs provide improved inference for treatments of rare diseases. PMID- 30010208 TI - Phylogeography and population genomics of a lotic water beetle across a complex tropical landscape. AB - The habitat template concept applied to a freshwater system indicates that lotic species, or those which occupy permanent habitats along stream courses, are less dispersive than lentic species, or those that occur in more ephemeral aquatic habitats. Thus, populations of lotic species will be more structured than those of lentic species. Stream courses include both flowing water and small, stagnant microhabitats that can provide refuge when streams are low. Many species occur in these microhabitats but remain poorly studied. Here, we present population genetic data for one such species, the tropical diving beetle Exocelina manokwariensis (Dytiscidae), sampled from six localities along a ~300 km transect across the Birds Head Peninsula of New Guinea. Molecular data from both mitochondrial (CO1 sequences) and nuclear (ddRAD loci) regions document fine scale population structure across populations that are ~45 km apart. Our results are concordant with previous phylogenetic and macroecological studies that applied the habitat template concept to aquatic systems. This study also illustrates that these diverse but mostly overlooked microhabitats are promising study systems in freshwater ecology and evolutionary biology. With the advent of next-generation sequencing, fine-scale population genomic studies are feasible for small nonmodel organisms to help illuminate the effect of habitat stability on species' natural history, population structure and geographic distribution. PMID- 30010209 TI - Pyoderma gangrenosum reproduced by an electric current flow. PMID- 30010210 TI - Improvement in abnormal coronary arteries estimated by coronary computed tomography angiography after secukinumab treatment in a Japanese psoriatic patient. PMID- 30010211 TI - Effect of Notch1 gene on remyelination in multiple sclerosis in mouse models of acute demyelination. AB - This study aims to explore the effects of Notch1 gene on remyelination in multiple sclerosis (MS). A mouse model of acute demyelination was successfully established and the model mice were grouped as cuprizone (CPZ) group, CPZ + small interfering RNA (siRNA)-Notch1 (siNotch1) group, and CPZ + siRNA negative control (NC) group. Meanwhile, another 3 groups (control, control + siNotch1, and control + siRNA NC) were established in normal mice. The changes of weight and maintenance time in rotating drum of mice were observed. Western blot analysis for the protein expressions related to Notch signaling pathway and oligodendrocyte (OL) differentiation in the corpus callosum of the mice. After model establishment, the weight of CPZ-induced demyelinated mice was decreased. During the repair period, the balance ability and movement of the mice was recovered, especially for those injected with siNotch1 plasmid. After model establishment, the number of myelinated axons was decreased. In comparison with the CPZ and CPZ siRNA NC groups, the CPZ + siNotch1 group had a decrease in the number of premature OLs, but increase in mature OLs, and a decrease in oligodendrocyte precursor cells and astrocytes. The expressions of proteins related to Notch signaling pathway, such as HES, Jagged-1 were decreased in the CPZ + siNotch1 group in contrast to the CPZ and CPZ + siRNA groups, but the OL related transcription factor Sox10 was increased in the CPZ + siNotch1 group than in the CPZ + siRNA NC and CPZ groups, and Id2 was decreased. Our study provided evidence that the inhibition of Notch1 gene could accelerate remyelination in MS. PMID- 30010212 TI - Regional variation in drivers of connectivity for two frog species (Rana pretiosa and R. luteiventris) from the U.S. Pacific Northwest. AB - Comparative landscape genetics has uncovered high levels of variability in which landscape factors affect connectivity among species and regions. However, the relative importance of species traits versus environmental variation for predicting landscape patterns of connectivity is unresolved. We provide evidence from a landscape genetics study of two sister taxa of frogs, the Oregon spotted frog (Rana pretiosa) and the Columbia spotted frog (Rana luteiventris) in Oregon and Idaho, USA. Rana pretiosa is relatively more dependent on moisture for dispersal than R. luteiventris, so if species traits influence connectivity, we predicted that connectivity among R. pretiosa populations would be more positively associated with moisture than R. luteiventris. However, if environmental differences are important drivers of gene flow, we predicted that connectivity would be more positively related to moisture in arid regions. We tested these predictions using eight microsatellite loci and gravity models in two R. pretiosa regions and four R. luteiventris regions (n = 1,168 frogs). In R. pretiosa, but not R. luteiventris, connectivity was positively related to mean annual precipitation, supporting our first prediction. In contrast, connectivity was not more positively related to moisture in more arid regions. Various temperature metrics were important predictors for both species and in all regions, but the directionality of their effects varied. Therefore, the pattern of variation in drivers of connectivity was consistent with predictions based on species traits rather than on environmental variation. PMID- 30010213 TI - Identifying genomic hotspots of differentiation and candidate genes involved in the adaptive divergence of pea aphid host races. AB - Identifying the genomic bases of adaptation to novel environments is a long-term objective in evolutionary biology. Because genetic differentiation is expected to increase between locally adapted populations at the genes targeted by selection, scanning the genome for elevated levels of differentiation is a first step towards deciphering the genomic architecture underlying adaptive divergence. The pea aphid Acyrthosiphon pisum is a model of choice to address this question, as it forms a large complex of plant-specialized races and cryptic species, resulting from recent adaptive radiation. Here, we characterized genomewide polymorphisms in three pea aphid races specialized on alfalfa, clover and pea crops, respectively, which we sequenced in pools (poolseq). Using a model-based approach that explicitly accounts for selection, we identified 392 genomic hotspots of differentiation spanning 47.3 Mb and 2,484 genes (respectively, 9.12% of the genome size and 8.10% of its genes). Most of these highly differentiated regions were located on the autosomes, and overall differentiation was weaker on the X chromosome. Within these hotspots, high levels of absolute divergence between races suggest that these regions experienced less gene flow than the rest of the genome, most likely by contributing to reproductive isolation. Moreover, population-specific analyses showed evidence of selection in every host race, depending on the hotspot considered. These hotspots were significantly enriched for candidate gene categories that control host-plant selection and use. These genes encode 48 salivary proteins, 14 gustatory receptors, 10 odorant receptors, five P450 cytochromes and one chemosensory protein, which represent promising candidates for the genetic basis of host-plant specialization and ecological isolation in the pea aphid complex. Altogether, our findings open new research directions towards functional studies, for validating the role of these genes on adaptive phenotypes. PMID- 30010215 TI - Long noncoding RNA LINC00961 inhibits cell proliferation and induces cell apoptosis in human non-small cell lung cancer. AB - Long noncoding RNAs (LncRNAs) have been identified in multiple human cancer types, including lung cancer. An increasing number of studies have indicated that lncRNAs can function as important gene regulators. However, the biological mechanism of LINC00961 in lung cancerremains poorly understood. In our current study, we recognized lncRNA LINC00961, and we observed that it was significantly reduced in human non-small cell lung cancer (NSCLC) tissues. LINC00961 was elevated by infecting LV-LINC00961, while decreased by LV-shLINC00961 in H226 and A549 cells. Furthermore, it was shown that LINC00961 overexpression greatly inhibited lung cancer cell proliferation, whereas downregulated LINC00961 induced cell proliferation. In addition, further experiments showed that restoration of LINC00961 could dramatically increase apoptotic ratios of NSCLC H226 and A549 cells, and knockdown of LINC00961 exhibited an opposite effect. Moreover, Western blot analysis showed that upregulation of LINC00961 repressed proliferating cell nuclear antigen expression and increased Bax expression, indicating that it acts as an important pro-apoptosis gene. Conversely, inhibition of LINC00961 induced proliferating cell nuclear antigen expression and restrained Bax protein levels. Taking these together, LINC00961 might play a tumor suppressive role in NSCLC progression, and it could serve as a novel prognostic biomarker in NSCLC diagnosis and treatment. PMID- 30010214 TI - Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo. AB - Nuclear factor of activated T cells (NFAT) c2 is important for the immune response and it compensates for NFATc1 for its effects on osteoclastogenesis, but its role in this process is not established. To study the function of NFATc2 in the skeleton, Nfatc2loxP/loxP mice, where the Nfact2 exon 2 is flanked by loxP sequences, were created and mated with mice expressing the Cre recombinase under the control of the Lyz2 promoter. Bone marrow-derived macrophage (BMM) from Lyz2Cre/WT ;Nfatc2Delta/Delta mice cultured in the presence of macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand exhibited a decrease in the number and size of osteoclasts and a smaller sealing zone when compared to BMMs from Nfatc2loxP/loxP littermate controls. Bone resorption was decreased in osteoclasts from Lyz2Cre/WT ;Nfatc2Delta/Delta mice. This demonstrates that NFATc2 is necessary for optimal osteoclast maturation and function in vitro. Male and female Lyz2Cre/WT ;Nfatc2Delta/Delta mice did not exhibit an obvious skeletal phenotype by microcomputed tomography (MUCT) at either 1 or 4 months of age when compared to Nfatc2loxP/loxP sex-matched littermates. Bone histomorphometry confirmed the MUCT results, and conditional 4 month-old Lyz2Cre/WT ;Nfatc2Delta/Delta mice did not exhibit changes in parameters of bone histomorphometry. In conclusion, NFATc2 is necessary for optimal osteoclastogenesis in vitro, but its downregulation in the myeloid lineage has no consequences in skeletal remodeling in vivo. PMID- 30010216 TI - Wnt11 promotes BMP9-induced osteogenic differentiation through BMPs/Smads and p38 MAPK in mesenchymal stem cells. AB - Bone morphogenetic protein 9 (BMP9), as one of the most potent osteogenic factors, is a promising cytokine for bone tissue engineering. Wnt11 can regulate the development of the skeletal system and is related to high bone mass syndrome. However, the effect of Wnt11 on BMP9-induced osteogenic differentiation remains unknown. In this study, we investigated the relationship between Wnt11- and BMP9 induced osteogenic differentiation in mesenchymal stem cells (MSCs). We recapitulated the osteogenic potential of BMP9 in C3H10T1/2 cells. The messenger RNA expression of Wnt11 is detectable in the available progenitor cells, and BMP9 can obviously increase the protein level of Wnt11 in these cells. Exogenous Wnt11 potentiates the effect of BMP9 on increasing alkaline phosphatase (ALP) activities, the expression of osteopontin (OPN), and Runt-related transcription factor 2 (Runx2), so does matrix mineralization in C3H10T1/2 cells. Although Wnt11 cannot increase the BMP9-induced ectopic bone formation, it can increase the bone density induced by BMP9 apparently. Wnt11 increases the level of p Smad1/5/8, as well as p-p38. Meanwhile, Wnt11 promotes the effect of BMP9 on increasing the levels of p-Smad1/5/8 and p-p38. Inhibition of p38 decreases the BMP9-induced ALP activities, the expression of OPN, and the mineralization in C3H10T1/2 cells. However, all of these effects of the p38 inhibitor on BMP9 induced osteogenic markers can be almost reversed by the overexpression of Wnt11. Our findings suggested that Wnt11 can enhance the osteogenic potential of BMP9 in MSCs, and this effect may be partly mediated through enhancing BMPs/Smads and the p38 MAPK signal, which was induced by BMP9. PMID- 30010217 TI - The Impact of Delivery in a Rural County on a Cohort of Women Living with HIV Infection and Their Infants. AB - PURPOSE: We sought to determine if infants born in rural counties had an increased risk of contracting HIV. METHODS: Data were obtained from the South Carolina Department of Health and Environmental Control for all women living with HIV delivering from 2004 to 2014. In this retrospective cohort study, maternal and neonatal outcomes from urban and rural counties were compared. Binomial statistical analyses were conducted using Wilcoxon Rank Sum Tests, chi2 or Fisher's exact tests. Logistic regression analyses were performed to evaluate factors associated with perinatal HIV infection. FINDINGS: Six hundred and sixty six women living with HIV had 868 pregnancies and delivered 885 infants; 17% (148) were born in rural counties. Eleven infants (1.2%) were diagnosed with perinatal HIV infection. The proportion of women taking antenatal antiretroviral therapy (ART) was similar between rural and urban counties (84% vs 87%; P = .3), but women in urban counties were more likely to have an HIV RNA viral load <40 copies/mL before delivery (32% vs 42%; P = .05). Factors associated with perinatal HIV infection were intra- and postpartum maternal HIV diagnosis (aOR 61.4 [95% CI: 6.7-562.5]; P < .001), parenteral drug use (aOR 7.5 [1.6-34.7]; P = .01), and preterm birth (<37 weeks gestation) (aOR 4.6 [1.2-17.8]; P = .3). CONCLUSIONS: Delivery in a rural county was not associated with an increased risk of perinatal HIV transmission. Women delivering in rural counties taking ART were less likely to have HIV viral suppression, which is a risk factor for perinatal HIV infection. PMID- 30010218 TI - Synthetic small RNAs: Current status, challenges, and opportunities. AB - Small regulatory RNAs act at the levels of transcription, posttranscription, and translation, with numerous roles that include binding to protein targets, protein modification, binding to messenger RNA targets, and regulation of gene expression. We discuss the development of a number of riboregulators and riboswitches, highlighting their use in metabolic engineering and genetic control. Riboregulators and riboswitches are self-assembled RNA molecules that can dynamically change their conformation, acting as regulatory switches that affect biological changes. They have currently been designed, characterized, and implemented in a wide range of organisms and cell types, including bacteria, yeast, and mammalian cells. We have identified and examined the recent advances in RNA synthetic biology, underlining the potential future development of their use and capabilities, noting how these can be ultimately expanded and improved into novel biotechnological, biomedical, and industrial applications. PMID- 30010219 TI - Disruption of SOX6 gene using CRISPR/Cas9 technology for gamma-globin reactivation: An approach towards gene therapy of beta-thalassemia. AB - Elevation of Hemoglobin F ameliorates symptoms of beta-thalassemia, a common autosomal recessive disorder. The transcription factor SOX6 plays a key role in the gamma to beta-globin gene switching. In the current investigation, a mutation was induced using the CRISPR/Cas9 technology in the binding domain region of SOX6 to reactivate gamma-globin expression. Three CRISPR/Cas9 cassettes were provided, whose single-guide RNAs targeted different regions in the SOX6 gene-binding domain. After transfection of K562 cells with CRISPR a, b and c, and subsequent erythroid differentiation, the indel percentage of the cells was about 30%, 25%, and 24%, respectively. Relative quantification showed that the gamma-globin mRNA level increased to 1.3-, 2.1-, and 1.1-fold in the cells treated with CRISPR/Cas9 a, b, and c, respectively, compared with untreated cells. Our results show that mutation induction in the binding site of the SOX6 gene leads to gamma-globin reactivation. These findings support the idea that CRISPR interrupts the SOX6 binding site, and, as a result, SOX6 is incapable of binding the gamma-globin promoter. In conclusion, SOX6 disruption could be considered as a therapeutic approach for beta-thalassemia treatment. CRISPR/Cas9 was selected for this purpose as it is the most rapidly evolving technology. PMID- 30010220 TI - Species- and C-terminal linker-dependent variations in the dynamic behavior of FtsZ on membranes in vitro. AB - Bacterial cell division requires the assembly of FtsZ protofilaments into a dynamic structure called the 'Z-ring'. The Z-ring recruits the division machinery and directs local cell wall remodeling for constriction. The organization and dynamics of protofilaments within the Z-ring coordinate local cell wall synthesis during cell constriction, but their regulation is largely unknown. The disordered C-terminal linker (CTL) region of Caulobacter crescentus FtsZ (CcFtsZ) regulates polymer structure and turnover in solution in vitro, and regulates Z-ring structure and activity of cell wall enzymes in vivo. To investigate the contributions of the CTL to the polymerization properties of FtsZ on its physiological platform, the cell membrane, we reconstituted CcFtsZ polymerization on supported lipid bilayers (SLB) and visualized polymer dynamics and structure using total internal reflection fluorescence microscopy. Unlike Escherichia coli FtsZ protofilaments that organized into large, bundled patterns, CcFtsZ protofilaments assembled into small, dynamic clusters on SLBs. Moreover, CcFtsZ lacking its CTL formed large networks of straight filament bundles that underwent slower turnover than the dynamic clusters of wildtype FtsZ. Our in vitro characterization provides novel insights into species- and CTL-dependent differences between FtsZ assembly properties that are relevant to Z-ring assembly and function on membranes in vivo. PMID- 30010221 TI - Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/beta-catenin pathway in pancreatic cancer cells. AB - The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/beta-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy. PMID- 30010222 TI - New insights into the efficacy of SR-16234, a selective estrogen receptor modulator, on the growth of murine endometriosis-like lesions. AB - PROBLEM: To evaluate the effects of SR-16234 (SR), a selective estrogen receptor modulator (SERM), on murine endometriosis-like lesions. METHOD OF STUDY: BALB/c mice (n = 53) were used to establish the murine endometriosis model. Ovariectomized, estradiol replaced, 6-week-old murine endometriosis model were injected with lipopolysaccharide (LPS) with or without SR (1 mg/kg/d) or vehicle, over a period of 4 weeks. Upon treatment completion, the endometriosis-like lesions that developed in the abdominal cavity of mice were counted, measured, and collected. Gene expression of inflammatory cytokines and estrogen receptor (ER) in the lesions was assessed by real-time RT-PCR. Immunohistochemical analysis was used to evaluate the effect of SR on cell proliferation, angiogenic activity, inflammation, and NF-kappaB phosphorylation. RESULTS: Treatment with SR significantly reduced the total number and size of lesions per mouse without inducing endometrial growth. In addition, SR downregulated LPS-enhanced Vegf, Il 6, Ptgs-2, and Ccl-2 and ER mRNA expression in endometriosis-like lesions. Immunohistochemical analysis demonstrated a decrease in percentage of positive cells of Ki67, and intensity and rate of positive cells of ERalpha, CD3, F4/80, PECAM by SR treatment. SR also decreased the expression of NF-kappaB p65 and phospho-NF-kappaB p65. CONCLUSION: SR has a regressive effect on the development of murine endometriosis-like lesions. PMID- 30010223 TI - In Reply. PMID- 30010224 TI - Aqueous Synthesis of Ultrathin Platinum/Non-Noble Metal Alloy Nanowires for Enhanced Hydrogen Evolution Activity. AB - Although aqueous synthesis of nanocrystals is advantageous in terms of the cost, convenience, environmental friendliness, and surface cleanness of the product, nanocrystals of Pt and non-noble metal alloys are difficult to obtain with controlled morphology and composition from this synthesis owing to a huge gap between the reduction potentials of respective metal salts. This huge gap could now be remedied by introducing a sulfite into the aqueous synthesis, which is believed to resemble an electroless plating mechanism, giving rise to a colloid of Pt-M (M=Ni, Co, Fe) alloy nanowires with an ultrasmall thickness (ca. 2.6 nm) in a high yield. The sulfite also leads to the formation of surface M-S bonds and thus atomic-level Pt/M-S(OH) interfaces for greatly boosted hydrogen evolution kinetics under alkaline conditions. An activity of 75.3 mA cm-2 has been achieved with 3 MUg of Pt in 1 m KOH at an overpotential of 70 mV, which is superior to previously reported catalysts. PMID- 30010225 TI - Evolutionary dynamics of quantitative variation in an adaptive trait at the regional scale: The case of zinc hyperaccumulation in Arabidopsis halleri. AB - Metal hyperaccumulation in plants is an ecological trait whose biological significance remains debated, in particular because the selective pressures that govern its evolutionary dynamics are complex. One of the possible causes of quantitative variation in hyperaccumulation may be local adaptation to metalliferous soils. Here, we explored the population genetic structure of Arabidopsis halleri at fourteen metalliferous and nonmetalliferous sampling sites in southern Poland. The results were integrated with a quantitative assessment of variation in zinc hyperaccumulation to trace local adaptation. We identified a clear hierarchical structure with two distinct genetic groups at the upper level of clustering. Interestingly, these groups corresponded to different geographic subregions, rather than to ecological types (i.e., metallicolous vs. nonmetallicolous). Also, approximate Bayesian computation analyses suggested that the current distribution of A. halleri in southern Poland could be relictual as a result of habitat fragmentation caused by climatic shifts during the Holocene, rather than due to recent colonization of industrially polluted sites. In addition, we find evidence that some nonmetallicolous lowland populations may have actually derived from metallicolous populations. Meanwhile, the distribution of quantitative variation in zinc hyperaccumulation did separate metallicolous and nonmetallicolous accessions, indicating more recent adaptive evolution and diversifying selection between metalliferous and nonmetalliferous habitats. This suggests that zinc hyperaccumulation evolves both ways-towards higher levels at nonmetalliferous sites and lower levels at metalliferous sites. Our results open a new perspective on possible evolutionary relationships between A. halleri edaphic types that may inspire future genetic studies of quantitative variation in metal hyperaccumulation. PMID- 30010226 TI - Ecology can inform genetics: Disassortative mating contributes to MHC polymorphism in Leach's storm-petrels (Oceanodroma leucorhoa). AB - Studies of MHC-based mate choice in wild populations often test hypotheses on species exhibiting female choice and male-male competition, which reflects the general prevalence of females as the choosy sex in natural systems. Here, we examined mutual mate-choice patterns in a small burrow-nesting seabird, the Leach's storm-petrel (Oceanodroma leucorhoa), using the major histocompatibility complex (MHC). The life history and ecology of this species are extreme: both partners work together to fledge a single chick during the breeding season, a task that requires regularly travelling hundreds of kilometres to and from foraging grounds over a 6- to 8-week provisioning period. Using a 5-year data set unprecedented for this species (n = 1078 adults and 925 chicks), we found a positive relationship between variation in the likelihood of female reproductive success and heterozygosity at Ocle-DAB2, a MHC class IIB locus. Contrary to previous reports rejecting disassortative mating as a mechanism for maintaining genetic polymorphism in this species, here we show that males make significant disassortative mate-choice decisions. Variability in female reproductive success suggests that the most common homozygous females (Ocle-DAB2*01/Ocle-DAB2*01) may be physiologically disadvantaged and, therefore, less preferred as lifelong partners for choosy males. The results from this study support the role of mate choice in maintaining high levels of MHC variability in a wild seabird species and highlight the need to incorporate a broader ecological framework and sufficient sample sizes into studies of MHC-based mating patterns in wild populations in general. PMID- 30010227 TI - Evaluation of glucocorticoid compared with immunoglobulin therapy of severe immune thrombocytopenia during pregnancy: Response rate and complication. AB - PROBLEM: Evaluate the response rate of glucocorticoid (GC) and/or immunoglobulin (IVIg) therapy in severe thrombocytopenia of immune thrombocytopenia (ITP) pregnant patients and the influence on maternal and neonatal outcomes. METHOD OF STUDY: This is a prospective observational cohort study. Pregnant ITP patients with platelet count less than 30 * 109 /L and their newborn infants participated in this research. Over a 3-year period, 87 patients were allocated to 4 groups: group 1 (n = 18) were treated by oral prednisone, group 2 (n = 20) with IVIg, group 3 (n = 22) with prednisone/methlyprednisone plus IVIg, and group 4 were non treatment controls (n = 27). Diagnosis and therapy were based on guideline from the 2011 American Society of Hematology criteria, and the initial dose of prednisone was 1 mg/kg day. Their newborns were followed up to 1 year old. RESULTS: The response rate among patients who ever received prednisone therapy was 35.5% (11/31) overall, while the IVIg response rate was 55.9% (19/34). The incidence of pregnancy induced hypertension in GC therapy group was significantly higher than controls (22.2% and 13.6% vs 0%). There was no significant difference in neonatal outcomes in treatment groups in comparison with controls. The rate of Neonatal follow-up within 1 year old was 63%, and there is no evidence indicated intrauterine GC exposure influence the growth and development. CONCLUSION: GC therapy of 1 mg/kg for ITP patients during pregnancy is less efficiency than non pregnant population and increases the incidence of hypertensive disorders. The use of lower starting doses of prednisone may be suggested for use in pregnancy. PMID- 30010228 TI - Interplay Between Sensation Seeking and Parental Rules in the Emergence of Heavy Episodic Drinking. AB - This study examined the parallel mediational processes between sensation seeking and parental rules on alcohol, in the emergence of heavy episodic drinking (HED) in adolescents. Data were drawn from a U.K. clustered randomized control trial (control arm only, N ~ 6,300, Mage at baseline = 12.5). Using parallel process latent growth curve analysis, stricter parental rules at baseline were found to be associated with greater declines in sensation seeking over time and a lower risk of HED at follow-up (+33 months). Higher initial levels of sensation seeking predicted a faster relaxation of parental rules and a greater risk of HED. By maintaining strict rules about alcohol, parents may promote a positive reduction in sensation seeking and a lower risk of HED. PMID- 30010229 TI - The Frequency of Substantial Salvageable Penumbra in Thrombectomy-ineligible Patients with Acute Stroke. AB - BACKGROUND AND PURPOSE: Endovascular therapy (ET) has become the standard of care for selected patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, many LVO or medium vessel occlusion (MVO) patients are ineligible for ET, including some who harbor salvageable tissues. To develop complementary therapies for these patients, it is important to delineate their prevalence, clinical features, and outcomes. METHODS: In a prospectively maintained database, we reviewed consecutive AIS patients between December 2015 and September 2016. Based on the first multimodal computed tomography or magnetic resonance imaging, patients were categorized as having substantial penumbra if perfusion lesion volume (Tmax >6 seconds) exceeded ischemic core volume (relative cerebral blood flow <30% on CT perfusion or apparent diffusion coefficient <620 on diffusion weighted image) by >=20%. RESULTS: Among 174 consecutive AIS patients presenting within 24 hours of last known well time, 29 (17%) had LVO or MVO and substantial penumbra, but were deemed ET ineligible. Among these patients, mean age was 81 (+/-13), 45% were female, and median National Institute of Health Stroke Scale score was 11 (interquartile range [IQR]: 5-19). The most common reasons for not pursuing ET were: distal occlusion (28%), mild neurologic deficit (16%), and temporally advanced core injury (16%). Ischemic core volume was 20 mL (+/-31), penumbral volume was 54 mL (+/-63), and mismatch ratio median was 5.6 (IQR: 2-infinite). Severe disability or death at discharge (modified Rankin scale: 4-6) occurred in 72% of the patients. CONCLUSION: Even in the modern stent retriever era, 1 in 6 AIS patients presents with substantial penumbra judged not appropriate for ET. This population may benefit from the development of alternative therapies, including collateral enhancement, neuroprotection, and thrombectomy devices deployable in distal arteries. PMID- 30010230 TI - Reliability of HEARTSMAP as a Tool for Evaluating Psychosocial Assessment Documentation Practices in Emergency Departments: A Methodologic Issue. PMID- 30010231 TI - A Silver Nanocluster Containing Interstitial Sulfur and Unprecedented Chemical Bonds. AB - The emergence of thiolated metal nanoclusters provides opportunities to identify significant and unprecedented phenomena because they are at quantum sizes and can be characterized with X-ray crystallography. Recently silver nanoclusters have received extensive interest owing to their merits, such as low-cost and rich properties. Herein, a thiolated silver nanocluster [Ag46 S7 (SPhMe2 )24 ]NO3 (Ag46 for short) with a face-centered cubic (fcc) structure was successfully synthesized and structurally resolved by X-ray analysis. Most importantly, interstitial sulfur was found in the lattice void of Ag46 without lattice distortion or expansion, indicating that the classic theory of interstitial metal solid solutions might be not applicable at quantum size. Furthermore, unprecedented chemical bonds and unique structural features (such as asymmetrically coordinated MU4 -S) were found in Ag46 and might be related to the interstitial sulfur, which is supported by natural population analyses. PMID- 30010232 TI - D-dimer in Adolescent Pulmonary Embolism. AB - BACKGROUND: D-dimer is used to aid in diagnosing adult pulmonary embolism (PE). D dimer has not been validated in adolescents. Clinicians must balance the risk of overtesting with that of a missed PE. D-dimer may be useful in this context. This study evaluates D-dimer in PE-positive and PE-negative adolescents. METHODS: PE positive patients < 22 years were diagnosed with PE by computed tomography (CT) or high-probability ventilation/perfusion, seen at emergency departments (EDs)/hospitals within a 16-hospital system across two states, January 1998 through December 2016. Of the 189 PE-positive patients, 88 (46.5%) had a D-dimer and were matched 1:1 by age, sex, and race to patients suspected of PE but confirmed negative by CT angiogram. RESULTS: Ages of PE-positive patients ranged from 13 to 21 years, 64 (73%) were female, and 52 (60%) were Caucasian. Mean D dimer was significantly higher (3,256 ng/mL, 95% confidence interval [CI] = 2,505 4,006 ng/mL) in PE-positive versus PE-negative patients (1,244 ng/mL, 95% CI = 493-1,995 ng/mL; p < 0.001). Mean D-dimer was higher in patients with massive or submassive PE (8,742 ng/mL, 95% CI = 5,994-11,491 ng/mL), followed by PE in central (4,795 ng/mL [95% CI = 3,465-6,125 ng/mL), lobar (3,758 ng/mL [95% CI = 1,841-5,676), and distal (2,327 ng/mL [95% CI = 1,273-3,381 ng/mL]) arteries. When comparing thresholds of positive D-dimer (>=500, >=750, and >=1,000 ng/mL), D-dimer had sensitivities of 90, 82, and 67% and specificities of 16, 53, and 67%, respectively. Negative predictive values were 61, 75, and 71% while positive likelihood ratios were 1.1, 1.8, and 2.2, respectively. CONCLUSIONS: This study represents the largest available cohort of adolescent patients examining the diagnostic value of D-dimer for PE. Our results indicate that depending on the threshold selected, D-dimer can be a sensitive test for PE in adolescents and that discriminative value is higher for a cutoff of 750 ng/mL than that for 500 ng/mL. Prospective studies investigating the diagnostic value of D-dimer and a clinical decision rule for PE in pediatrics are needed. PMID- 30010233 TI - Blueprints for the rational design of therapeutic mutacin 1140 variants. AB - Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Saturation mutagenesis was employed to substitute every amino acid of a lantibiotic called mutacin 1140 (MU1140), creating an unbiased expression library of 418 variants that was used to study the permissiveness to mutagenesis and the "drugability" of several compounds. Contrasting previous reports, the results from this study supported that not all residues involved in lanthionine bridge formation were critical for maintaining optimal activity. While substitutions in lanthionine bridges in Ring A, C, and D invariably lead to inactive variants, permissive substitutions in Abu8 and Ala11 (Ring B) were observed, albeit infrequently. Further, the data generated suggested that the unsaturated bond from Dha5 (Ser5) may not be critically involved in Lipid-II binding but still important for conferring optimal activity. This study identified additional permissive mutations of Ser5, including Ser5His, Ser5Met, Ser5Gln, and Ser5Leu. In contrast, no permissive substitutions were identified for Dhb14, which suggested that this residue may be critical for optimal activity. Novel blueprints are proposed for directing further development of MU1140 variants and other lantibiotics, which may enable the rational design, development, manufacture, and formulation of an entirely new class of anti infectives. PMID- 30010234 TI - The "concept-reality mismatch" in the globalization era as a psychosocial stressor contributing to the occurrence of mental disorders. AB - AIMS: The "concept-reality mismatch" in the globalization era is a novel conceptualization of psychosocial stress due to difficulties in experiencing five of the most important positive emotions for psychological well-being. These emotions are love, trust, faith, pleasure and self-esteem. METHODS: a narrative overview of the literature using the terms "positive emotions," "positive psychology," "globalization" and "self-discrepancy" has been done. Selected articles are those considered to support the basic ideas mentioned in this hypothesis. RESULTS: Differences in how adolescents and young adults experience positive emotions in real life in relation to their conceptual background exist. Authentic love described in books and movies might become perceived as more difficult to find. Trust, in the era of long distance relationships, is being built based on different criteria than those adolescents and young adults are taught to apply. Faith is challenged by the facility of accessing scientific data and by the lack of parental positive influence towards religiosity. Pleasure is being claimed as a right to cope with stress even artificially. Self-esteem is becoming more and more restricted to wealth, beauty and fame as promoted by modern communication technologies. CONCLUSIONS: The "concept-reality mismatch" may be considered as an essential and preventable psychosocial stressor contributing to the development of mental and substance use disorders in the modern world. Studies evaluating this hypothesis and elaborating on its management strategies are needed in the near future. PMID- 30010235 TI - Pressure-Induced Emission Enhancement, Band-Gap Narrowing, and Metallization of Halide Perovskite Cs3 Bi2 I9. AB - Low-toxicity, air-stable bismuth-based perovskite materials are attractive substitutes for lead halide perovskites in photovoltaic and optoelectronic devices. The structural, optical, and electrical property changes of zero dimensional perovskite Cs3 Bi2 I9 resulting from lattice compression is presented. An emission enhancement under mild pressure is attributed to the increase in exciton binding energy. Unprecedented band gap narrowing originated from Bi-I bond contraction, and the decrease in bridging Bi-I-Bi angle enhances metal halide orbital overlap, thereby breaking through the Shockley-Queisser limit under relatively low pressure. Pressure-induced structural evolutions correlate well with changes in optical properties, and the changes are reversible upon decompression. Considerable resistance reduction implies a semiconductor-to conductor transition at ca. 28 GPa, and the final confirmed metallic character by electrical experiments indicates a wholly new electronic property. PMID- 30010236 TI - OneTwoTree: An online tool for phylogeny reconstruction. AB - Phylogeny reconstruction is a key instrument in numerous biological analyses, ranging from evolutionary and ecology research, to conservation and systems biology. The increasing accumulation of genomic data makes it possible to reconstruct phylogenies with both high accuracy and at increasingly finer resolution. Yet, taking advantage of the enormous amount of sequence data available requires the use of computational tools for efficient data retrieval and processing, or else the process could quickly become an error-prone endeavour. Here, we present OneTwoTree (http://onetwotree.tau.ac.il/), a Web based tool for tree reconstruction based on the supermatrix paradigm. Given a list of taxa names of interest as the sole input requirement, OneTwoTree retrieves all available sequence data from NCBI GenBank, clusters these into orthology groups, identifies the most informative set of markers, searches for an appropriate outgroup, and assembles a partitioned sequence matrix that is then used for the final phylogeny reconstruction step. OneTwoTree further allows users to control various steps of the process, such as the merging of sequences from similar clusters, or phylogeny reconstruction based on markers from a specific genome type. By comparing the performance of OneTwoTree to a manually reconstructed phylogeny of the Antirrhineae tribe, we show that the use of OneTwoTree resulted in substantially higher data coverage in terms of both taxon sampling and the number of informative markers assembled. OneTwoTree provides a flexible online tool for species-tree reconstruction, aimed to assist researchers ranging in their level of prior expertise in the task of phylogeny reconstruction. PMID- 30010237 TI - Low-Coordinate Barium Boryloxides: Synthesis and Dehydrocoupling Catalysis for the Production of Borasiloxanes. AB - The first soluble barium boryloxides [Ba]- OB{CH(SiMe3 )2 } are presented. These mono- or dinuclear complexes feature low coordination numbers, as low as two for [Ba(OB{CH(SiMe3 )2 }2 )2 ], which is further stabilized by intra- and intermolecular Ba???H3 C agostic interactions. Barium boryloxides and the parent [Ba{N(SiMe3 )2 }2 ?(thf)2 ] catalyze the dehydrocoupling of borinic acids with hydrosilanes, providing borasiloxanes under mild conditions. PMID- 30010238 TI - Miniaturized capillary ion chromatograph with UV light-emitting diode based indirect absorbance detection for anion analysis in potable and environmental waters. AB - A miniaturized, flexible, and low-cost capillary ion chromatography system has been developed for anion analysis in water. The ion chromatography has an open platform, modular design, and allows for ease of modification. The assembled platform weighs ca. 0.6 kg and is 25 * 25 cm in size. Isocratic separation of common anions (F- , Cl- , NO2- , Br- , and NO3- ) could be achieved in under 15 min using sodium benzoate eluent at a flow rate of 3 MUL/min, a packed capillary column (0.150 * 150 mm) containing Waters IC-Pak 10 MUm anion exchange resin, and light-emitting diode based indirect UV detection. Several low UV light-emitting diodes were assessed in terms of sensitivity, including a new 235 nm light emitting diode, however, the highest sensitivity was demonstrated using a 255 nm light-emitting diode. Linear calibration ranges applicable to typical natural water analysis were obtained. For retention time and peak area repeatability, relative standard deviation values ranged from 0.60-0.95 and 1.95-3.53%, respectively. Several water samples were analysed and accuracy (recovery) was demonstrated through analysis of a prepared mixed anion standard. Relative errors of -0.36, -1.25, -0.80, and -0.76% were obtained for fluoride, chloride, nitrite, and nitrate, respectively. PMID- 30010239 TI - People who experience seclusion in adult mental health inpatient services: An examination of health of the nation outcome scales scores. AB - The Health of the Nation Outcomes Scales (HoNOS) provides an overview of a person's behaviour, impairment, clinical symptoms, and social functioning. This study investigated the profile of people who had been secluded in New Zealand's adult mental health inpatient services using 12 individual HoNOS ratings. Routinely collected clinical data were extracted from the Programme for the Integration of Mental Health Data (PRIMHD). This is the national data set for mental health and addiction services. A logistic regression model was fitted to the data which adjusted for age, sex, ethnicity, bed nights, compulsory treatment, and district health board. After adjustment, three HoNOS items significantly predicted the risk of seclusion: overactive, aggressive, disruptive, or agitated behaviour (adjusted OR = 4.82, 95% CI [3.88, 5.97], P < 0.001); problem drinking or drug-taking (adjusted OR = 1.51, 95% CI [1.25, 1.82], P < 0.001); and problems with hallucinations and delusions (adjusted OR = 1.33, 95% CI [1.09, 1.63], P = 0.006). In addition, two HoNOS items were protective for seclusion: nonaccidental self-injury (adjusted OR = 0.65, 95% CI [0.51, 0.83], P < 0.001) and depressed mood (adjusted OR = 0.58, 95% CI [0.47, 0.72], P < 0.001). Thus, responding effectively to agitation and/or aggression, substance use, and psychosis plays an important role in reducing the use of seclusion. Mental health nurses and other workers can reduce seclusion through early assessment, effective communication, de-escalation techniques, reduction tools, trauma-informed care, and consulting with consumers and whanau. PMID- 30010240 TI - Glioblastoma, 47XXY/45,X mosaicism, and hyperpigmented skin lesions. PMID- 30010241 TI - Platelet inhibitory effects of the Phase 3 anticancer and normal tissue cytoprotective agent, RRx-001. AB - The platelet inhibitory effects of the Phase 3 anticancer agent and nitric oxide (NO) donor, RRx-001, (1-bromoacetyl-3,3-dinitroazetidine) were examined ex vivo and compared with the diazeniumdiolate NO donor, diethylenetriamine NONOate (DETA NONOate), which spontaneously releases nitric oxide in aqueous solution. In the absence of red blood cells and in a dose-dependent manner, DETA-NONOate strongly inhibited platelet aggregation induced by several stimuli (ADP, epinephrine and collagen) whereas RRx-001 only slightly inhibited platelet aggregation under the same conditions in a dose-dependent manner; these antiaggregant effects were blocked when both DETA-NONOate and RRx-001 were co-incubated with carboxy-PTIO (CPTIO 0.01-100 micromol), a widely accepted NO scavenger. However, in the presence of red blood cells from healthy human donors, RRx-001, which binds covalently to haemoglobin (Hb) and catalyses the production of NO from endogenous nitrite, more strongly inhibited the aggregation of platelets than DETA-NONOate in a dose-dependent manner likely because haemoglobin avidly scavenges nitric oxide and reduces its half-life; the RRx-001-mediated platelet inhibitory effect was increased in the presence of nitrite. The results of this study suggest that RRx-001-bound Hb (within RBCs) plays an important role in the bioconversion of NO2- to NO. , which makes RRx-001 a more physiologically relevant inhibitor of platelet aggregation than other nitric oxide donors, whose effects are attenuated in the presence of red blood cells. Therefore, RRx-001-mediated platelet inhibition is a potentially useful therapeutic property, especially in hypercoagulable cancer patients that are at an increased risk of thrombotic complications. PMID- 30010242 TI - Salmonella exploits host Rho GTPase signalling pathways through the phosphatase activity of SopB. AB - Salmonella uses Type 3 secretion systems (T3SSs) to deliver virulence factors, called effectors, into host cells during infection. The T3SS effectors promote invasion into host cells and the generation of a replicative niche. SopB is a T3SS effector that plays an important role in Salmonella pathogenesis through its lipid phosphatase activity. Here, we show that SopB mediates the recruitment of Rho GTPases (RhoB, RhoD, RhoH, and RhoJ) to bacterial invasion sites. RhoJ contributes to Salmonella invasion, and RhoB and RhoH play an important role in Akt activation. R-Ras1 also contributes to SopB-dependent Akt activation by promoting the localised production of PI(3,4)P2 /PI(3,4,5)P3 . Our studies reveal new signalling factors involved in SopB-dependent Salmonella infection. PMID- 30010243 TI - Chromatographic characterization of amphiphilic di- and tri-block copolymers of poly(ethylene oxide) and poly(epsilon-caprolactone). AB - Amphiphilic di- and tri-block copolymers based on poly(ethylene oxide) as a hydrophilic segment and poly(epsilon-caprolactone) as a hydrophobic part are synthesized by the ring-opening polymerization of epsilon-caprolactone while using poly(ethylene glycol)s and methoxy poly(ethylene glycol)s of varying molar masses as macro-initiators. The synthesized block copolymers are characterized with respect to their total relative molar mass and its distribution by size exclusion chromatography. Liquid chromatography at critical conditions of both blocks is established for the analysis of individual block lengths and tracking presence of unwanted homopolymers of both types in the block copolymer samples. New critical conditions of polycaprolactone on reversed phase column are reported using organic mobile phase. The established critical conditions of polycaprolactone extended the applicable molar mass range significantly compared to already reported critical conditions of polycaprolactone in aqueous mobile phase. Block copolymers are also analyzed at critical conditions of poly(ethylene glycol). Complete analysis of the di- and tri-block copolymers at corresponding critical conditions provided a fair estimate of molar mass of non-critical block besides information regarding presence of homopolymers of both types in the samples. PMID- 30010245 TI - Crystal structure of Arabidopsis thaliana RabA1a. AB - RabGTPase is a member of the Ras superfamily of small GTPases, which share a GTP binding pocket containing highly conserved motifs that promote GTP hydrolysis. In Arabidopsis, the RabA group, which corresponds to the Rab11 group in animals, functions in the recycling of endosomes that control docking and fusion during vesicle transport. However, their molecular mechanisms remain unknown. In this study, we determined the crystal structures of the GDP-bound inactive form and both GppNHp- and GTP-bound active forms of RabA1a, at resolutions of 2.8, 2.6, and 2.6 A, respectively. A bound sulfate ion in the active site of the GDP-bound structure stabilized Switch II by bridging the interaction between a magnesium ion and Arg74. Comparisons of the two states of RabA1a with Rab11 proteins revealed clear differences in the Switch I and II loops. These results suggested that conformational change of the Switch regions of RabA1a, derived by GTP or GDP binding, could maintain subcellular membrane traffic through the specific interaction of effector molecules. PMID- 30010244 TI - Dual effects of baicalin on osteoclast differentiation and bone resorption. AB - Osteoclasts (OC) are critical cells responsible for many bone diseases such as osteoporosis. It is of great interest to identify agents that can regulate the activity of OC to treat osteolytic bone diseases. In this study, we found that baicalin exerted a two-way regulatory effect on OC in a concentration-dependent manner in vitro and in vivo. In detail, baicalin at a low concentration (below 1 MUmol/L) enhanced OC differentiation and bone resorption, but baicalin at a high concentration (above 2 MUmol/L) exhibited inhibitory effects on OC. We demonstrated that baicalin at low concentrations enhanced the mitogen-activated protein kinase (MAPK) (ERK) signalling pathway and activated c-Fos and NFATc1 expression, and thus enhanced gene expression, OC differentiation and bone resorption. However, baicalin at higher levels not only suppressed ERK phosphorylation and c-fos and NFATc1 expression, but also altered the expression of apoptosis-related proteins, and therefore inhibiting OC function. This dual effect was further verified in an LPS-induced mouse calvarial osteolysis model, evidenced by enhanced osteolysis at a lower concentration but reduced bone loss at a higher concentration. Overall, our findings indicate that baicalin exerts dose-dependent effects on OC formation and function. Therefore, caution should be applied when using baicalin to treating OC-related bone diseases. PMID- 30010246 TI - A new genetic tool to improve immune-compromised mouse models: Derivation and CRISPR/Cas9-mediated targeting of NRG embryonic stem cell lines. AB - Development of human hematopoietic stem cells and differentiation of embryonic stem (ES) cells/induced pluripotent stem (iPS) cells to hematopoietic stem cells are poorly understood. NOD (Non-obese diabetic)-derived mouse strains, such as NSG (NOD-Scid-il2Rg) or NRG (NOD-Rag1-il2Rg), are the best available models for studying the function of fetal and adult human hematopoietic cells as well as ES/iPS cell-derived hematopoietic stem cells. Unfortunately, engraftment of human hematopoietic stem cells is very variable in these models. Introduction of additional permissive mutations into these complex genetic backgrounds of the NRG/NSG mice by natural breeding is a very demanding task in terms of time and resources. Specifically, since the genetic elements defining the NSG/NRG phenotypes have not yet been fully characterized, intense backcrossing is required to ensure transmission of the full phenotype. Here we describe the derivation of embryonic stem cell (ESC) lines from NRG pre-implantation embryos generated by in vitro fertilization followed by the CRISPR/CAS9 targeting of the Gata-2 locus. After injection into morula stage embryos, cells from three tested lines gave rise to chimeric adult mice showing high contribution of the ESCs (70% 100%), assessed by coat color. Moreover, these lines have been successfully targeted using Cas9/CRISPR technology, and the mutant cells have been shown to remain germ line competent. Therefore, these new NRG ESC lines combined with genome editing nucleases bring a powerful genetic tool that facilitates the generation of new NOD-based mouse models with the aim to improve the existing xenograft models. PMID- 30010247 TI - Magnetic chitosan functionalized with beta-cyclodextrin as ultrasound-assisted extraction adsorbents for the removal of methyl orange in wastewater coupled with high-performance liquid chromatography. AB - Three types of choline chloride based deep eutectic solvents were prepared and used to modify magnetic chitosan. The adsorption capacity of the three deep eutectic-solvent-modified magnetic chitosan/carboxymethyl-beta-cyclodextrin for removing methyl orange from wastewater was examined. The different deep eutectic solvents were used to strengthen the adsorption capacity of magnetic chitosan. Deep-eutectic-solvent-modified magnetic chitosan/carboxymethyl-beta-cyclodextrin materials were characterized by Fourier transform infrared spectroscopy and Brunauer-Emmett-Teller surface area measurements. Among the three deep eutectic solvents, choline chloride/glycerol (1:2) modified magnetic chitosan/carboxymethyl-beta-cyclodextrin showed the highest adsorption capacity to methyl orange. Therefore, choline chloride/glycerol (1:3, 1:4, 1:5, 1:6) deep eutectic solvents were prepared for the assay, and choline chloride/glycerol modified magnetic chitosan/carboxymethyl-beta-cyclodextrin prepared with choline chloride/glycerol (1:3) (volume: 40 MUg, contact time: 30 min, and pH: 6) had the best adsorption capacity over the concentration range of 10-200 MUg/mL. PMID- 30010248 TI - Design and Synthesis of DNA-Interactive beta-Carboline-Oxindole Hybrids as Cytotoxic and Apoptosis-Inducing Agents. AB - A new series of (E)-3-[(1-aryl-9H-pyrido[3,4-b]indol-3-yl)methylene]indolin-2-one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT-15, HCT-116, A549, NCI-H460, and MCF-7, including HFL. Among the tested compounds, (E)-1 benzyl-5-bromo-3-{[1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3 yl]methylene}indolin-2-one (10 s) showed potent cytotoxicity against HCT-15 cancer cells with an IC50 value of 1.43+/-0.26 MUm and a GI50 value of 0.89+/ 0.06 MUm. Notably, induction of apoptosis by 10 s on the HCT-15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V-FITC/PI, DCFDA, and JC-1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT-15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT-15 cancer cells led to decreased expression of anti-apoptotic Bcl-2 and increased protein expression of both pro-apoptotic Bax and caspase-3, -8, and -9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT-15 cancer cells by 10 s in a dose-dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular-docking studies showed that compound 10 s has typical intercalation with DNA. PMID- 30010249 TI - Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway. AB - Tumour growth depends on a continual supply of the nutrients and oxygen, which are offered by tumour angiogenesis. Our previous study showed that dipalmitoylphosphatidic acid (DPPA), a bioactive phospholipid, inhibits the growth of triple-negative breast cancer cells. However, its direct effect on angiogenesis remains unknown. Our work showed that DPPA significantly suppressed vascular growth in the chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. Meanwhile, tumour angiogenesis and tumour growth were inhibited by DPPA in the tumour tissues of an experimental breast cancer model, a subcutaneous xenograft mouse model and a genetically engineered spontaneous breast cancer mouse model (MMTV-PyMT). Furthermore, DPPA directly inhibited the proliferation, migration and tube formation of vascular endothelial cells. The anti-angiogenic effect of DPPA was regulated by the inhibition of Cut-like homeobox1 (CUX1), which transcriptionally inhibited fibroblast growth factor 1 (FGF1), leading to the downregulation of hepatocyte growth factor (HGF). This work first demonstrates that DPPA directly inhibits angiogenesis in cancer development. Our previous work along with this study suggest that DPPA functions as an anti-tumour therapeutic drug that inhibits angiogenesis. PMID- 30010250 TI - Bimetallic NiMoN Nanowires with a Preferential Reactive Facet: An Ultraefficient Bifunctional Electrocatalyst for Overall Water Splitting. AB - Faceted nanomaterials with highly reactive exposed facets have been the target of intense researches owing to their significantly enhanced catalytic performance. NiMoN nanowires with the (100) facet preferentially exposed were prepared by an in situ N/O exchange and the morphology tuned by using a rationally designed NiMoO4 precursor. The facet-tuned NiMoN nanowires exhibited excellent electrocatalytic activity for the hydrogen evolution reaction (HER) under both alkaline and acidic conditions that was comparable to that of noble metal platinum. DFT calculations further revealed that the catalytic activity of NiMoN nanowires towards HER on the (100) reactive facet is significantly greater than that on the (001) or (101) facets, owing to the low adsorption free energy of H* (DeltaGH* ) on the (100) facet. The NiMoN nanowires also demonstrated outstanding activity towards the alkaline oxygen evolution reaction and an excellent durable activity for overall water splitting, with a cell potential as low as 1.498 V at 20 mA cm-2 . This work provides insights into improving electrocatalytic activity and developing advanced non-noble metal bifunctional electrocatalysts. PMID- 30010251 TI - Clinical characteristics of self-reported nocturia in patients with interstitial cystitis, and effects of bladder hydrodistention (with fulguration of Hunner lesions) on nocturia. AB - OBJECTIVE: The aim of this study was to investigate the clinical characteristics of nocturia in patients with interstitial cystitis (IC), and the effects of bladder hydrodistention (with fulguration of Hunner lesions) on nocturia. METHODS: The records of 81 patients who were diagnosed with IC were reviewed. Clinical characteristics were evaluated using the Interstitial Cystitis Symptom Index (ICSI), a visual analogue scale (VAS), and bladder diary data. Differences in characteristics between Hunner- and non-Hunner-type IC were compared. Correlations between nocturia and other clinical variables were assessed. Stepwise multiple regression analysis was performed to identify factors associated with nocturia. Further, changes in nocturia before and after hydrodistention (with fulguration of Hunner lesions) were analyzed. RESULTS: The mean (+/- SD) age of patients was 62.2 +/- 15.3 years. Significant differences in nocturia were observed between Hunner- and non-Hunner-type IC. Nocturia was positively correlated with age, urgency score (ICSI and VAS), mean number of urgency episodes per 24 hours and the nocturnal polyuria (NP) index, and negatively correlated with average voided volume. Age, NP index, average voided volume, and the presence of Hunner lesions were independent factors associated with nocturia. Bladder hydrodistention significantly decreased nocturia in non Hunner type IC without NP. In addition, regardless of the presence or absence of NP, bladder hydrodistention with fulguration of Hunner lesions significantly decreased nocturia in Hunner-type IC. CONCLUSIONS: The severity of nocturia is associated with age, NP, average voided volume, and the presence of Hunner lesions in IC patients. Bladder hydrodistention (with fulguration of Hunner lesions) has the potential to decrease nocturia. PMID- 30010252 TI - Value of computed tomography in calculating prostate volume when transrectal ultrasonography is not applicable. AB - OBJECTIVE: The aim of this study was to evaluate the value of computed tomography (CT) in determining total prostate volume (TPV), as an alternative to transrectal ultrasonography (TRUS) when TRUS is not available. METHODS: The patient cohort included patients who underwent both CT and TRUS within a 3-month interval from January 2012 to December 2013 at a single institution. In all, 67 non-contrast and 217 contrast-enhanced CT images were reviewed twice by 3 independent observers 2 months after the initial evaluation. Prostate length and width were measured on axial images and height was measured on sagittal images. To compare differences between CT and TRUS in TPV estimation, the CT/TRUS ratio of TPV was calculated and a Bland-Altman plot was constructed. Inter- and intraobserver variabilities and the effect of contrast enhancement were also evaluated statistically. RESULTS: The mean (+/- SD) age of patients was 64.5 +/-10.8 years and the mean time interval between CT and TRUS was 16.3 +/- 22.6 days. The mean TRUS-measured TPV was 44.7 +/- 24.9 mL and the mean CT/TRUS TPV ratio was 0.80 +/ 0.20, indicating that TPV estimated by CT is 20% lower than that determined by TRUS, regardless of contrast enhancement (P > .05). The mean difference in TPV between TRUS and CT was 11.3 +/- 14.3 mL, with differences of 1.7, 9.9, and 32.9 mL for prostate volumes of <=30, >30-60, and >60 mL, respectively. Interobserver variability was excellent (r > 0.9), whereas intraobserver variability was very good (r > 0.7). CONCLUSION: CT is a reliable method for prostate volume measurement and is well correlated with TRUS. Although CT estimates of TPV are 20% lower than those obtained using TRUS, CT can be used as an alternative to TRUS when TRUS is not available. PMID- 30010253 TI - Layered Boron-Nitrogen-Carbon-Oxygen Materials with Tunable Composition as Lithium-Ion Battery Anodes. AB - The insertion of heteroatoms with different electronegativity into carbon materials can tune their chemical, electronic, and optical properties. However, in traditional solid-state synthesis, it is challenging to control the reactivity of monomers, and therefore, the amount and position of heteroatoms in the final materials. Herein, a simple, scalable, and general molten-state route to synthesize boron-nitrogen-carbon-oxygen (BNCO) materials with tunable boron nitrogen-carbon composition, as well as electronic and optical properties, is reported. The new synthetic approach consists of polycyclic aromatic hydrocarbons (PAHs) and ammonia-borane as reactants that form a clear liquid-state stage spanning a wide temperature range, before the solid-state reaction. The molten state stage enhances the control over the synthetic intermediates and final materials, owing to improved monomer miscibility and reactivity. The BNCO composition and optical properties are tuned by the PAH selection and final reaction temperature. The advantages of this method are demonstrated herein through the tunable optical properties, excellent stability to oxidization, facile deposition on substrates, and good activity as an anode material in lithium-ion batteries. PMID- 30010254 TI - Lower urinary tract symptoms in patients with prostate cancer under and after intensity-modulated radiation therapy. AB - OBJECTIVE: The aim of the present study was to collect data on the characteristics, degree, and natural course of urinary complications, as well as self-care for such complications, in patients during and after prostate intensity modulated radiation therapy (IMRT). METHODS: Quality of life data were collected retrospectively for all eligible patients who underwent IMRT. In all eligible patients, urinary symptoms were evaluated using questionnaires and face-to-face interview. Participants were asked to respond to a self-administered questionnaire concerning the core lower urinary tract symptom score during the course of IMRT and up to 12 months after the completion of IMRT. RESULTS: In all, 29 eligible patients were included in the study. The frequency of urinary symptoms increased over of the course of IMRT, decreased at >=3 months after completion of IMRT, and disappeared 6 months after IMRT. Responses to the questionnaire revealed a variety of approaches to self-care and adaptations by patients to manage urinary symptoms. CONCLUSIONS: During and after IMRT for localized prostate cancer, patients often developed more frequent urination and urgency than at the start of IMRT, and recovered 3-6 months after the completion of IMRT. Based on the present study, clinicians and nurses could help convey this information to patients and thus offer better support. PMID- 30010255 TI - The increased expression of Piezo1 and Piezo2 ion channels in human and mouse bladder carcinoma. AB - BACKGROUND: Piezo1/2, a mechanically activated ion channel, is believed to play an important role in bladder carcinogenesis process. Piezo1/2 expression has not been previously reported in urinary bladder carcinoma, and little is known about its significance in bladder carcinogenesis. OBJECTIVES: In our study, we aimed to evaluate the Piezo1 and Piezo2 expression as developmental in mouse bladder tissue and bladder cancer tissue of mice and humans. MATERIAL AND METHODS: The detection of developmental expression was performed on P0-P90 days in bladder tissue of Balb/c strain mice. Mice were divided into bladder cancer (n = 40) and control groups (n = 10). Bladder cancer in mice was created by using N-butyl-N-(4 hydroxybutyl)nitrosamine (BBN). In the study, 60 human subjects were included, whose normal tissues were used as controls. After the histopathological evaluation, the expression of Piezo1/2 genes was examined by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry in tumor and normal tissues. RESULTS: In developmental period of the mice, Piezo1 expression increased on days 21 and 90, whereas Piezo2 expression increased on day 7 and decreased on day 90 in mouse bladder tissues. There was a significant increase in the expression of Piezo1/2 in both cancer groups compared to the control group. Piezo1 expression was significantly increased at tumor size, stage and grade. Piezo2 expression was upregulated in high grade tumors in human subjects. CONCLUSIONS: The developmental changes of Piezo expression on specific days demonstrate the role of these channels in bladder cancer development. The dysfunction of Piezo1/2 expression may contribute to the carcinogenesis of bladder cancer by causing proliferative changes and angiogenesis. The expression of Piezo1/2 can provide new prognostic information for disease progression. PMID- 30010256 TI - An initial evaluation of cytotoxicity, genotoxicity and antibacterial effectiveness of a disinfection liquid containing silver nanoparticles alone and combined with a glass-ionomer cement and dentin bonding systems. AB - BACKGROUND: Bacterial reinfection of dental cavities remains an unsolved clinical problem. The search for methods enabling the limitation of the bacterial factor has become the fundamental goal of the dental materials research. Silver nanoparticles (AgNPs) are used as disinfection agents. An incomplete polymerization of the polymer resins combined with AgNPs, along with the increase of the release of the unbound monomers, have been found. OBJECTIVES: The aim of this study was to evaluate the vitality of the human dental pulp stem cells (DPSCs) in response to a disinfection agent containing silver and gold nanoparticles (NPs), different bonding systems, glass-ionomer cement (GIC), and their combinations with the disinfection agent. Also, the influence of these materials both on the secretory function of DPSCs and on their antibacterial properties were established. MATERIAL AND METHODS: Cytotoxicity (MTT assay) and genotoxicity (enzyme-linked immunosorbent assay - ELISA) assays were used in the study. Antibacterial features were assessed by the optical density (OD) measurement of the bacteria (Streptococcus mutans, Streptococcus salivarius and Lactobacillus acidophilus) kept in the dental materials. RESULTS: The disinfection liquid proved to be biocompatible. However, it relevantly interfered with the total-etch bonding system in terms of vitality, which may have serious clinical implications. Its combination with the self-etching system was biocompatible, yet it impaired the antibacterial action of the system. An enhancement of antibacterial action of GIC with AgNPs was found. CONCLUSIONS: The disinfection liquid and GIC were biocompatible toward the DPSCs in terms of cytotoxicity and genotoxicity. Simultaneous usage of AgNPs with other dental materials did not affect the biocompatibility of the used materials. The disinfection liquid and GIC acted as antibacterial agents against all studied bacteria species. Used together with GIC and the total-etch bonding system, the disinfection liquid seemed to be efficient toward bacteria, yet it relevantly impaired the antibacterial action of self-etching systems. PMID- 30010257 TI - Surgery:The way of the future. AB - The devastation wrought by bacterial infection in the preantibiotic era is perhaps best exemplified by the First World War. Bacterial infection in soldiers was high because of soil-contaminated shrapnel and shells. As a result, many soldiers lost life and limb. If antibiotics had been available, many may have lived. The pioneering work of Sir Alexander Fleming on the battlefields led to his discovery of penicillin which revolutionised the treatment of bacterial infections and supports so much of modern medicine. PMID- 30010258 TI - Registrar perceptions on general surgical training in South Africa: A report by the South African Society of Surgeons in Training (SASSiT). AB - BACKGROUND: Surgical training varies significantly amongst universities within the same country. This trend is reflected in South Africa and provides an opportunity for innovation to improve the quality of general surgical training. OBJECTIVE: To assess the perceptions of South African general surgery registrars regarding surgical training. METHOD: A prospective descriptive study was performed by means of a confidential questionnaire distributed to general surgical registrars at all eight training centers in South Africa. Participants were asked to give comments regarding adequacy of formal academic teaching, level of supervision during surgical procedures, exposure to and training in minimally invasive surgery (MIS), and preparation for examinations. Descriptive statistics were generated with Microsoft Excel. Ethics clearance was obtained from the University of the Witwatersrand Human Research Ethics Committee. RESULTS: Of 200 questionnaires distributed 105 (52.5%) were returned. 44% (105/241) of all registrars from six training institutions participated. 89.5% (94/105) of respondents reported that they attended less than six hours of formal academic teaching per week and 71.4% (75/105) indicated that their institution offered less than six hours of formal academic teaching per week. 76.2% (80/105) of respondents regarded lack of protected academic time as the greatest obstacle to their surgical training and 95.2% (99/105) reported that clinical responsibilities prevented them from attending formal academic teaching regularly. Overall, only 31.4% (33/105), 41.9% (44/105) and 37.1% (39/105) were satisfied with the amount of formal academic teaching, level of supervision during theatre procedures and exposure to minimally invasive surgery respectively. Lack of resources and lack of appropriate skills were identified as a hindrance to MIS training by 47.6% (50/105) and 28.6% (30/105) of respondents respectively. CONCLUSION: Surgical registrars are dissatisfied with the amount of formal academic teaching and protected academic time, level of supervision in theatre and their exposure to MIS. These challenges compromise trainees' ability to practice independently after qualification. Numerous interventions are necessary and possible to address these challenges. PMID- 30010259 TI - Surgical resources in South Africa: an analysis of the inequalities between the public and private sector. AB - BACKGROUND: The full extent of the global burden of surgical disease is largely unknown, however, the scope of the problem is thought to be large. Despite the substantial burden of surgical disease, surgical services are inaccessible to many of those who need them most. There are disparities between public and private sectors in South Africa, which compound inequitable access to surgical care. This study forms part of a series analysing surgical resources in South Africa. METHOD: This study involved a descriptive analysis of surgical resources and included the total number of hospitals, of hospital beds, the number of surgical beds, the number of general surgeons (specialist and non-specialist), and the number of functional operating theatres in South Africa. A comparison was performed between the public and private sectors. Hospitals were contacted during the period from 1 October 2014 until 31 December 2014. RESULTS: Surgical resources were concentrated in metropolitan areas of urban provinces. There were striking differences between the public and private sectors, where private resources were comparable to those available in high income countries (HICs). CONCLUSION: Improving access to surgical services in lower middle income countries (LMICs) requires addressing gaps between the public and private sector regarding infrastructure, personnel, as well as equipment. These data identified disparities between geographic regions which may be contributing to ongoing inequity in South Africa, and by doing so allows for evidence-based planning towards improving surgical infrastructure and workforce. PMID- 30010260 TI - The effect of pregnancy and delivery on anal function in black Africans and Indians. AB - BACKGROUND: Occult anal sphincter disruption, following childbirth may contribute to the development of anal incontinence (AI). The type and mechanism of injury may differ between first and subsequent deliveries. OBJECTIVES: To describe the effect of pregnancy and delivery on the endosonographic morphology of the anal sphincter and on anal sphincter pressures, and to highlight any differences in these between nulliparous and multiparous Black African and Indian women. METHOD: One hundred Black African and Indian women delivering at two hospitals in the Pietermaritzburg area underwent anal endosonography and manometry in the third trimester of pregnancy and 24 hours post-delivery. Those with occult injury were followed up at 6 weeks and six months. Participants were asked about bowel symptoms at each visit. Ante-natal and intra-partum obstetric data was also recorded. RESULTS: The majority were Black African (82%), and 76% were multiparous. Symptoms of urgency increased from 9% antenatally to 14.6% post delivery, decreasing to 8.3% at six months. Symptoms of AI increased from 10% antenatally to 12.5% post-delivery, falling to 3.1% at six months. Internal sphincter defects were more common among primiparous and multiparous women delivering vaginally. There was a significant drop in functional anal length post delivery, irrespective of the mode of delivery. Anal pressures also fell post delivery and at six weeks post-partum. However, by six months there appeared to be a return to pregnancy values. CONCLUSION: Occult anal sphincter injuries and reduced anal pressures occur after delivery, in the absence of clinically detected anal sphincter trauma, irrespective of the mode of delivery. PMID- 30010262 TI - An evaluation of mini-laparotomy cholecystectomy in the laparoscopic era: a rural experience. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard for the management of symptomatic cholelithiasis and complications of gallstone disease. Mini laparotomy cholecystectomy (MOC) may be a more appropriate option in the resource constrained rural setting due to its widespread applicability and comparable outcome with LC. The study aimed to provide an epidemiological analysis of gallstone disease in the rural population and to evaluate the outcome of MOC in a rural hospital. METHOD: A retrospective chart analysis of 248 patients undergoing cholecystectomy in a rural regional referral hospital in KwaZulu-Natal from January 2009 to December 2013 was undertaken. RESULTS: Of the 248 patients, the majority were females (n = 211, [85%]). The most frequent indications for cholecystectomy included: biliary colic (n = 115, [46.3%]); acute cholecystitis (n = 80, [32.3%]); gallstone pancreatitis (n = 27, [10.8%]). Forty cases (16.1%) were converted to open cholecystectomy (OC). The median operative time was 40 minutes (range18-57). Twenty-three morbidities (9.3%) occurred including: bile leaks (n = 6, [2.4%]); bleeding from drain site (n = 1, [0.4%]), incisional hernia (n = 8 [3.2%]) and wound sepsis (n = 8 [3.2%]). The median length of hospital stay in patients who underwent MOC was 48 hours (range: 24-72 hours) and the median time to return to work was 10 days (range: 4-14 days). There was one mortality in the entire cohort. CONCLUSION: MOC is a safe and feasible operation for symptomatic cholelithiasis when cholecystectomy is indicated. The low operative morbidity and mortality in the context of a high risk patient profile and complicated gallstone disease makes this procedure an alternative to LC where LC is inaccessible. PMID- 30010261 TI - Sonar guided focused parathyroidectomy under cervical block. AB - BACKGROUND: Presentation of hyperparathyroidism varies and is highly non specific. The automated calcium analyzer has made the diagnosis easy. Similarly, the advent of Sestamibi scan has paved the way to minimally invasive parathyroidectomy indicated for parathyroid adenoma. There is no uniformity in the extent of minimally invasive parathyroidectomy that is done through limited incision under radio or sonar guidance and endoscopically. In this study, we are presenting the focused parathyroidectomy performed under sonar guidance and superficial cervical block (SCB). The prerequisite is concordant preoperative Sestamibi and ultrasound imaging. METHOD: A two-year review of parathyroidectomies performed between January 2013 and December 2014. OBJECTIVE: To reflect on the result of sonar-guided focused parathyroidectomy under SCB. RESULTS: There was good correlation between the pre-operative imaging, the intra operative findings and the postoperative histology result of the 15 cases analysed. CONCLUSION: The focused parathyroidectomy under SCB yielded a good result with concordant preoperative Sestamibi and ultrasound findings. PMID- 30010263 TI - Resection of biliary mucinous cystic neoplasms of the liver: a prospective cohort series of 13 consecutive patients. AB - BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are uncommon neoplastic septated intrahepatic cysts which are often incorrectly diagnosed and have the potential for malignant transformation. OBJECTIVE: To assess the outcome of surgical resection of BMCNs. METHOD: A prospective liver surgery database was used to identify patients who underwent surgery at Groote Schuur Hospital Complex for BMCN from 1999 to 2015. Demographic variables including age and gender were documented as well as detailed preoperative imaging, location and size, operative treatment, extent of resection, histology, postoperative complications and outcome. RESULTS: Thirteen female patients (median age 45 years) had surgery. Eleven were diagnosed by imaging for symptoms. Two were jaundiced. One cyst was found during an elective cholecystectomy. Five cysts were located centrally in the liver. Before referral three cysts were treated with percutaneous drainage and two were treated with operative deroofing. Six patients had anatomical liver resections and seven patients had non anatomical liver resections of which two needed ablation of residual cyst wall. One patient needed a biliary-enteric reconstruction to treat a fistula. Median operative time was 183 minutes (range: 130-375). No invasive carcinoma was found. There was no operative mortality. One surgical site infection and one intra-abdominal collection were treated. Two patients developed recurrent BMCN after 24 months. CONCLUSION: BMCNs should be considered in middle aged women who have well encapsulated multilocular liver cysts. Treatment of large central BMCNs adjacent to vascular and biliary structures may require technically complex liver resections and are best managed in a specialised hepato-pancreatico-biliary unit. PMID- 30010264 TI - Suture material use and procurement: an audit of a public hospital surgical system in Gauteng, South Africa. AB - BACKGROUND: Surgical systems are integral to successful, safe and cost effective clinical practice and must balance surgical demands on consumable items and their costs. Suture material is a key consumable resource, and was evaluated in an audit of consumable use and cost as well as the procurement systems within the South African Gauteng public health care sector. AIMS: To determine suture use and cost in the four commonest general surgical procedures - abdominal wall closure, mastectomy, appendicectomy and inguinal hernia repair - in three academic Gauteng hospitals. Performance and availability were evaluated as a secondary aim in suture material use. METHOD: A prospective observational study. Suture use was documented by the surgeon at the time of the procedure and qualitative investigation at relevant hospital departments determined suture material procurement and expenditure. RESULTS: The surgeons in three facilities documented consistent material type and average number of units used; however, in some cases there was a lack of availability of appropriate material and breakage of generic material intraoperatively. There is no consistent and consolidated electronic record-keeping of suture stock and cost in all three hospitals, therefore cost of suture material used was not obtainable. CONCLUSION: Clinical deficiencies in availability and quality of material may have adverse implications for patient health, healthcare costs and budgets through procedure related complications and should be investigated. There is a lack of communication between the financial management, procurement officers, hospital and theatre stores and theatre staff. It is suggested that clinical protocols and system-based strategies be put in place to manage surgical consumables. PMID- 30010265 TI - Association between crural vessel patency and successful transmetatarsal amputation: a single centre experience. AB - BACKGROUND: Transmetatarsal amputation (TMA) has a reputation for failure, centred around wound breakdown. No study has looked at the direct association between the patency of individual crural arteries and the healing of TMA. TMA relies on a posterior skin flap which derives its blood supply from the posterior tibial (PT) artery. We investigated the association between PT patency and achievement of successful TMA. METHODS: A retrospective review of all patients undergoing TMA for complications of peripheral arterial occlusive disease in a regional vascular tertiary referral centre over a 9 year period (2006-2015). TMA was considered successful by the absence of a higher-level amputation. Follow-up was for a minimum of 12 months. RESULTS: 24 patients (21 male; mean age 64 years) were studied. TMA was successful in 16 (67%). On statistical analysis, successful TMA was not significantly associated with vessel patency in either superficial femoral artery (SFA), or any single or combination of named crural artery. CONCLUSION: TMA healing can be achieved in the absence of a patent posterior tibial artery. We support the role of TMA in selected patients, given its benefits compared to transtibial amputation. PMID- 30010266 TI - Open versus laparoscopic appendicectomy in acute appendicitis: results of a district general hospital. AB - BACKGROUND: Despite multiple studies comparing the two methods, the real advantages of laparoscopic appendicectomy (LA) compared to open appendicectomy (OA) are still unclear. Purpose of the current study was to compare the results between the two techniques in a district general hospital. METHODS: The electronic records of all patients who underwent OA or LA in a one year period were reviewed retrospectively. The comparative data points assessed included age, gender, overall complications, length of stay and Clavien-Dindo Classification of Surgical Complications, including the rates of the main types of complications. RESULTS: 300 patients were included in the study. 166 patients underwent OA and 134 patients LA. Postoperative complications were documented in 26 patients (8.7%). LA was employed predominantly in female patients (p = 0.004) and in older patients (p = 0.0015) and was associated with significantly more negative appendicectomies than OA (p = 0.002). No statistically significant difference was noted with regards to the length of hospital stay (p = 0.577), overall postoperative morbidity (p = 0.543) and grading of complications (p = 0.460). Finally, following comparison of the incidence of specific types of complications, only wound infections were significantly different, in favour of LA. CONCLUSION: LA is safe and effective, however, besides the lower incidence of wound sepsis, demonstrates no clear advantage over OA. The selection between OA and LA should thus be tailored to the clinical scenario and the surgeon's preference. PMID- 30010267 TI - Investigating racial differences in clinical and pathological features of prostate cancer in South African men. AB - BACKGROUND: Men with West African ancestry living in Europe and North America are at higher risk of being diagnosed with prostate cancer, are diagnosed at a younger age, and have more severe disease characteristics. Published reports present a conflicting picture of the disease in sub-Saharan Africa. We aimed to study the clinical and pathological features of men undergoing prostate biopsy from different racial backgrounds in South Africa in an attempt to characterise the disease locally. Our hypothesis was that black African men presenting to our service had more severe disease characteristics than other patients. METHODS: All patients who underwent a prostate biopsy at Groote Schuur Hospital, Cape Town from July 2008 to July 2014 were studied. For each patient, data were collected on age, self-assigned race, presenting symptoms, prostate-specific antigen (PSA) level, prostate volume, and histological diagnosis. RESULTS: A total of 1016 patients were studied. 162 (15.9%) were black and 854 (84.1%) were coloured (mixed ancestry), white, or Asian. Black patients were compared as a group to the coloured, white and Asian patients. The black patients in the series had higher PSA values (mean 167.8 vs 47.7, median 16.4 vs 10.9, p < 0.001), were more likely to be diagnosed with cancer (57.4% vs 44.5%, p = 0.003), were more likely to present with locally advanced cancer (T3/4 16.1% vs 8.9%, p = 0.028), and were more likely to have high grade disease (Gleason >= 8 45.2% vs 30.5%, p = 0.011). There was no difference in age, presenting symptoms, or prostate volume. CONCLUSION: The black men diagnosed with prostate cancer at Groote Schuur Hospital had significantly worse clinical and pathological characteristics than the non-black men. Interpreting these differences as representative of a more common or aggressive disease among black men is not possible due to study limitations. PMID- 30010268 TI - Process improvements raise SPD standards and quality. PMID- 30010269 TI - Serious fun: Using humor to engage OR staff. PMID- 30010270 TI - Wearable technology brings both benefits and risks to the OR. PMID- 30010271 TI - Secure apps loop in families during surgery. PMID- 30010272 TI - OR competency programs boost staff loyalty and productivity. PMID- 30010273 TI - Fatal attacks at ASCs spur stronger safety measures. PMID- 30010274 TI - A new type of ATP-sensitive potassium channelopathy : Cantu syndrome. AB - Multiple mutations in Kir6.x and SURx genes have implicated ATP-sensitive potassium (KATP) channels and, as a result, have led to diverse diseases, ranging from diabetes and hyperinsulinism to cardiac arrhythmias and cardiovascular disease. These diseases are referred to as KATP channelopathies. Recently, Cantu syndrome (CS), which was found to be caused by mutations in the ABCC9 or KCNJ8 gene, was newly added to the list of KATP channelopathies. CS is a rare multi organ disease characterized by congenital hypertrichosis, characteristic face, persistent ductus arteriosus, cardiomegaly, intrauterine overgrowth, and skeletal abnormalities. Congenital hypertrichosis and coarse face have been confirmed in all CS patients. On the other hand, cardiovascular and skeletal abnormalities vary widely in severity, even in some familial cases and in isolated cases sharing the same mutation. Information about genotype-phenotype correlations in CS are described here. PMID- 30010275 TI - Short-term efficacy and safety of rufinamide for Lennox-Gastaut syndrome. AB - Objective: We examined the short-term efficacy and safety of rufinamide (RFN) in patients with Lennox-Gastaut syndrome (LGS). Methods: We performed a retrospective review of clinical records of patients with LGS who started RFN treatment between July 2013 and June 2014 at the Hokkaido Medical Center for Child Health and Rehabilitation and Midorigaoka Ryo-iku-en. Efficacy and safety were evaluated when the patients had completed three months of treatment. Patients were classified into four categories according to percent seizure reduction : remission (seizure-free), response (seizure reduction>=50%), no change (seizure reduction<50% or increase) and aggravation (seizure increase>=50%). Responder rate (RR) was the percentage of patients with>=50% decrease in seizure frequency. Results: Thirteen LGS patients (8 males, 5 females) were studied. The efficacy for tonic seizures (13 patients) was remission 1 patient, response 3 patients, no change 8 patients and aggravation 1 patient, with RR of 30.8%. Two patients discontinued LGS due to seizure aggravation. Four patients experienced transient remission. For generalized tonic clonic seizures (2 patients), 1 patient achieved remission and 1 patient showed no change. Two patients of atonic seizures showed no change. Of 2 patients of atypical absence, 1 patient showed response and 1 patient no change. Eight patients had adverse effects such as somnolence (6 patients), sleep disturbance (1 patient), and appetite loss (4 patients) including weight loss in 2 patients. There were no severe adverse effects and no discontinuation due to adverse effects. Conclusions: Short-term effectiveness for tonic seizures was observed when patients with LGS were treated with RFN, with transient remission in some patients. We consider that RFN is worth trying in patients with LGS due to its efficacy for tonic seizures and absence of severe adverse effects. PMID- 30010276 TI - Measuring body composition by bioelectrical impedance analysis for nutritional management in children with respirator-dependent severe motor and intellectual disabilities due to hypoxia. AB - Objective: Nutritional management in children with medically dependent severe motor and intellectual disabilities (SMID) is difficult. SMID children with respirator support sometimes showed obesity in spite of proper nutrition. The optimal energy intake in these children remains unclear. The objective of this study is to determine the features of body composition and the optimal calorie intake in children with respirator-dependent SMID due to severe hypoxia. Methods: The study was a retrospective chart review of five children with respirator dependent SMID due to severe hypoxia. They were treated between 2012 and 2015 at the National Center for Child Health and Development in Tokyo, Japan. Their ages ranged from one to nine years. All patients were clinically stable under continuous mechanical ventilation. Body composition including body fat percentage (%Fat), muscle mass (MM) and fat-free mass (FFM) were measured by a multi frequency bioelectrical impedance analysis (BIA) (InBody S20(r)). When necessary, adjustments for calorie intake were made. Results: %FAT was high (range, 40 to 70%) and MM was low, indicating that all children were under excessive nutrition. A markedly decrease in FFM was also observed. After the adjustment, daily calorie intake was maintained at 210 to 350 kcal/day. Daily calorie intake per FFM ranged from 25 to 42 kcal/kg/day. Conclusions: The children's body composition revealed that FFM was decreased. As FFM is a major influencing factor for basal metabolic rate, FFM-based calorie adjustment is useful to determine the optimal calorie intake in children with respirator-dependent SMID due to severe hypoxia. Nutritional assessment using BIA is recommended in such children. PMID- 30010277 TI - Case study of a spinal muscular atrophy type 1 patient retaining one allele of the SMN1 gene. PMID- 30010278 TI - Combinatory use of central venous catheter and ethanol lock for a patient with X linked lissencephaly with ambiguous genitalia (XLAG) syndrome. AB - X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome is a disorder associated with severe intellectual disability and intractable epilepsy. Intractable diarrhea is also observed frequently. At present, pathogenic background of diarrhea is not revealed and the essential treatment has not yet established. We encountered a patient with XLAG, who showed intractable diarrhea. Lactose removed hypoallergenic milk and somatostatin analogs were ineffective. For enteral nutrition was impossible, a tunneled central venous catheters was inserted to obtain a sustained parenteral nutrition management. However, catheter related bloodstream infections were repeated in a short period of time. Thus, we introduced ethanol lock therapy for infectious disease prevention purposes. As a result, we succeeded continuous treatments with preserving the catheter. PMID- 30010280 TI - [In Process]. PMID- 30010279 TI - [A Clinical Study on 64 Cases of Laryngeal Granuloma]. AB - Vocal process granulomas are mainly associated with vocal abuse, gastroesophageal reflux disease (GERD), orendotracheal intubation. In the present study, we evaluate the prognostic factors and the usefulness of a grading systemin 64 patients with vocal process granulomas. We classified the granuloma which limited the vocal process of the arytenoidcartilage as grade I, and which originated from the vocal process but extended beyond the vocal process of thearytenoid cartilage as grade II, according to the grading system proposed by Wang CP, et al. First, we treated this diseasewith conservative treatments including a proton pump inhibitor, steroid inhalation, or voice therapy. Surgical treatmentwas reserved for failures of conservative treatments or when the diagnosis was in doubt. The overall post-surgicalrecurrence rate was 65.7%, and it was significantly higher in male than female patients, and in younger than olderpatients. The overall remission rate was 79.7%. A multivariate analysis revealed that Grade II was a significantly poorprognostic factor and the patients with BMI >=23 or Age <60 had a tendency to have a poor remission rate. The gradingsystem is useful for anticipating the prognosis in cases of vocal process granuloma. PMID- 30010282 TI - [In Process]. PMID- 30010281 TI - A female patient with a hot spot mutation of PRRT2 gene suffering from several types of epileptic seizures in infancy. AB - Benign familial infantile epilepsy (BFIE) is characterized by non-febrile focal seizures, which sometimes evolve to secondarily generalized seizures and are usually resolved in the second year. Proline-rich transmembrane protein 2 (PRRT2) is confirmed as the major cause of BFIE, familial paroxysmal kinesigeneic dystonia (PKD) and infantile convulsions and choreoathetosis (ICCA) syndrome. We examined a female patient with a hot spot mutation of PRRT2 gene. She had recurrent tonic seizures when she was three months old. The seizures were controlled by several kinds of anticonvulsants. Then, she had several times of focal seizures daily at nine months old. However, the seizures were stopped by small amounts of carbamazepine. Later, when she was two years old, she experienced frequent motor seizures characterized by truncal flexion and swaying the body with partially disturbed consciousness. Her father also had the same PRRT2 gene mutation and non-febrile seizures in infancy. The patient had mild to moderate mental retardation, whereas her father was mentally normal. Therefore, the patient revealed a quiet different phenotype from that of her father as a carrier of the same PRRT2 gene mutation. We speculate that the PRRT2 mutation had caused the BFIE-like seizures both in the patient and her father, whereas other unknown genetic factors specific for the patient might be associated with the atypical seizures observed only in her. PMID- 30010283 TI - [In Process]. PMID- 30010284 TI - [In Process]. PMID- 30010285 TI - The developmental characteristics of locomotion and sleep in cyclic vomiting syndrome and the effects of drug therapy. AB - Objective: To evaluate the characteristics of patients with cyclic vomiting syndrome (CVS) and the efficacy of prophylaxis therapy. Methods: We defined the patients as "CV (+) " if they had multiple neuromuscular diseases and as "CV (-) " if they did not. We compared the two groups according to their background and the type of medications and their effects. We also evaluated their locomotion and sleep pattern. Results: There was no significant difference between CV (+) and CV (-) with regard to the association with migraine. Pharmacotherapy with cyproheptadine and valproate had high success rate for both CV (-) and CV (+). The rate of delayed locomotion development and atonia during non-REM sleep was high in both CV (+) and CV (-). Conclusions: We postulate that the association of serotonergic neurons is one of the important factors in both CV (+) and CV (-). PMID- 30010286 TI - Study of death with the severely disabled. AB - Objective: The characteristics of death in patients with severe mental and physical disabilities include, a short period from the onset of symptoms to death and sudden death in the young. However in recent years, it has not been rare for such patients to live to more than 50 years old. We examined the survival rate and current state of death within 24 hours among this patient population at our center. Methods: We identified 314 deaths from April 1 in 1969 to March 31 in 2013 and a total of 388 survivors during this date range. Based on confirmation, cases of death occurring within 24 hours from onset were extracted. The probability of survival was estimated and graphed using the Kaplan-Meier method, and factors influencing the characteristics of death within 24 hours and/or the survival rate were investigated using medical records after 1995. Results: The median age at survival was 56 years. The need for gastrostomy feeding was associated with a 2.4 times higher mortality rate than oral feeding. The survival estimate at 60 years for the cases of gastrostomy feeding was 34%, and the survival estimate at 70 years for the cases involving severe motor impairment was 34%. The age distribution showed no significant differences between the two groups, i. e.; cases of death within 24 hours and others. In the cases of death within 24 hours, the patients were tracheotomized and/or not followed with a monitor, which suggests that death may occur in all cases, irrespective of the patient's condition. Conclusions: This study showed that patients with severe motor impairment may survive beyond 70 years of age. Death within 24 hours is not associated with a specific mortality age and can occur in any patient regardless of the severity of their condition, accounting for a relatively high proportion of causes of death, even now. PMID- 30010287 TI - [A Case Treated with Selective Embolization for Hemorrhage during Tonsillectomy]. AB - Though tonsillectomy is one of the most common surgical procedures in otorhinolaryngology generally for benigndiseases and mainly for young people, uncontrollable perioperative bleeding associated with tonsillectomy is a rare butpotentially life-threatening event. We report herein on a case of a 19-year old female with uncontrollable hemorrhageduring a tonsillectomy, which was controlled through selective embolization. To the best of our knowledge, this is thefirst report on endovascular treatment in the management of tonsillectomy associated intraoperative uncontrollablehemorrhage rather than postoperative bleeding. Selective embolization for perioperative bleeding during a tonsillectomyis considered as an efficient and important therapeutic option in the definitive treatment of this life-threatening occurrence.We also reviewed patients who underwent tonsillectomy in our hospital in the past five years. The ratio of postoperativehemorrhage was 11.8%. All patients with post-tonsillectomy hemorrhage were classified as grade 1 bleeding(spontaneous cessation). PMID- 30010288 TI - [A Case of Absolute Ethanol Sclerotherapy and an Adhesion Maneuverfor Refractory Epistaxis Associated with Osler's Disease]. AB - Case Report : We report herein on the case of a 75 years old woman with refractory epistaxis associated with Osler'sdisease. Anemia and recurrent epistaxis occurred 10 years previously, and anemia was treated by a physician near thepatient's home. Because she had gradually become unable to control her epistaxis, she visited our hospital. We diagnosedOsler's disease based on her family history, past history, and dilatory changes in the peripheral and nasal mucosavessels. A skin graft failed and ultrasonic coagulation was not so effective. The refractory epistaxis was due to a connectedarteriovenous fistula of the right upper nasal valve. Following ethanol injection sclerotherapy and an adhesionmaneuver, the epistaxis was well controlled. PMID- 30010289 TI - Efficacy of vigabatrin therapy for tuberous sclerosis with infantile spasms. AB - Objective: To evaluate the effects and tolerability of vigabatrin (VGB) in children with tuberous sclerosis (TS) with infantile spasms or tonic seizures. Methods: We examined the impact of VGB on a series of 17 children with TS visiting Tohoku University Hospital in Japan during April 2010 and May 2015. To minimize potential adverse effects, VGB was given to the patients for limited 6 months with titration from 30 mg/kg/day as an initial dose. Results: Main seizure types were classified into spasms (n=10) or tonic seizures (n=7). Seizure reduction was positively associated with seizure type of infantile spasms, lower maximum dosage, younger age on VGB administration, and earlier VGB treatment after the diagnosis. Seizure type of infantile spasm was an independent favorable predictor and also associated with long-term seizure reduction. Major adverse events included psychiatric symptoms (n=7) and electroretinogram (ERG) abnormalities (n=2). All symptoms were recovered by reducing the dosage of VGB. Conclusion: VGB is effective and well tolerated as first-line treatment for TS children with infantile spasms. Our "low dosage and limited period" protocol is efficient for improving seizure control as well as minimizing the potential risks of VGB. PMID- 30010290 TI - [Pharyngoesophageal Reconstruction Using a Laryngotracheal Flap Following Resection for Hypopharyngeal Cancer]. AB - We used hemilaryngotracheal tissue without tumor involvement as a laryngotracheal flap (LTF) for immediate repairof a pharyngoesophageal defect following resection for hypopharyngeal cancer.Five cases of lateralized advanced hypopharyngeal cancer were treated in our department. The median age was 82years, ranging from 64 to 90 years. Four tumors were T3 stage, and the other was T2.A pharyngocutaneous fistula developed in one patient. The postoperative swallowing function was satisfactory, butone patient developed difficulty in eating a normal diet, because of pharyngoesophageal stenosis at 7 months afterchemoradiotherapy. During the follow-up period, there was no locoregional recurrence. One patient had lung metastasis,and died of the disease. One patient died of another cause. Three patients are alive without evidence of the disease.Reconstruction of the hypopharynx with an LTF is a minimally invasive method compared with the radial forearmfree flap and free jejunal flap. For selected cases of advanced hypopharyngeal cancer, this method would be one of thechoices to reconstruct the pharyngoesophageal defect. PMID- 30010291 TI - Effects and limits of acute noninvasive positive pressure ventilation in children with severe motor and intellectual disabilities with pneumonia/bronchitis. AB - Objective: We have frequently applied noninvasive positive pressure ventilation (NPPV) to treat acute respiratory failure in children with severe motor and intellectual disabilities. We investigated the features and causes of conditions requiring endotracheal intubation. We aimed to determine whether phlegm expulsion using appropriate breathing physiotherapy with NPPV could avoid the need for endotracheal intubation in such patients. Methods: Between December 2010 and November 2012, 21 children with 51 episodes of acute respiratory failure were placed on NPPV at our hospital. We investigated the ratio, background, and causes of conditions requiring endotracheal intubation. Results: Pneumonia and bronchitis caused 30 and 21 episodes of respiratory failure, respectively. Respiratory infection required endotracheal intubation in 8 of 30 episodes of pneumonia, and in none of the 21 episodes of bronchitis. Respiratory infections were caused by upper airway obstruction with large amounts of secretion (n=4), lower airway obstruction due to atelectasis (n=3) and a combination of both (n=1). The frequency of breathing physiotherapy was significantly higher for all patients who required assistance with active phlegm expulsion than in those who did not (p=0.006). More patients on endotracheal intubation also required phlegm aspiration compared with other patients (p=0.019). Conclusion: We applied NPPV to acute respiratory failure in children with severe motor and intellectual disabilities. This allowed 84% of them to avoid endotracheal intubation. Acute respiratory failure did not improve in any patient who required endotracheal intubation, but we also used NPPV with breathing physiotherapy and postural drainage. Assistance with phlegm expulsion is hampered in children with severe motor and intellectual disabilities due to conditions such as thoracic deformations, joint contracture and glossoptosis. We consider that assistance with phlegm expulsion using appropriate breathing physiotherapy with NPPV is very important for such patients. PMID- 30010292 TI - The clinical features of patients suffering from psychogenic non-epileptic seizures with or without epileptic seizures. AB - Objective: We investigated the clinical characteristics of pediatric psychogenic non-epileptic seizures (PNES). Methods: We studied 15 children and adolescents with PNES, who were divided into 3 groups : 1) a group with epilepsy (7 patients), 2) a group without epilepsy and mental retardation (MR) (7 patients), and 3) a group with MR (1 patient), according to the guideline for the diagnosis and treatment of PNES established by the Japan Epilepsy Society. Results: Remission of epilepsy and PNES was achieved in only 2 patients in the group with epilepsy. In the group without epilepsy and MR, antiepileptic drugs (AEDs) could be discontinued entirely in all the patients, however, the treatment for PNES could be completed in only one patient. Treatment of epilepsy and PNES could be completed in the one patient with MR. Conclusions: It is important for pediatric neurologists to explain the good news to the parents of children in the group without epilepsy or MR, that the patient does not have epilepsy and does not require treatment with AEDs. For the group with MR, understanding should be encouraged about the development of the child. Because treatment is difficult in the group with epilepsy and PNES, cooperation among the pediatric neurologists, pediatric psychiatrists and clinical psychologists is more important. PMID- 30010294 TI - [In Process]. PMID- 30010293 TI - A patient with Joubert syndrome who developed sleep-related breathing disorder at 15 years of age. AB - Joubert syndrome is characterized by neonatal breathing disorders that are thought to improve with age, but recent findings indicate that sleep-related breathing disorders can occur even after infancy. A 15-year-old boy who had a breathing disorder during the neonatal period developed mental retardation and hypotonia. He was diagnosed with Joubert syndrome based on the clinical course and molar tooth sign on brain MRI at 9 years of age. Daytime sleepiness developed at 15 years of age. An interview and the results of sleep questionnaires (Epworth sleepiness scale, Pediatric sleep questionnaire and Pittsburgh sleep quality index), indicated that the patient had daytime sleepiness and a sleep-related breathing disorder. Overnight polysomnography showed central apnea with an apnea hypopnea index of 16, indicating that the patient had central sleep apnea syndrome. After nighttime oxygen therapy at home for one month, the sleep questionnaires showed improved daytime sleepiness and the sleep-related breathing disorder. The improvement persisted for over 12 months thereafter. Sleep-related breathing disorders could be indicated by non-specific complaints such as daytime sleepiness and lead to appropriate therapies. Such disorders should be considered as a complication of Joubert syndrome even after infancy. PMID- 30010295 TI - [In Process]. PMID- 30010296 TI - Ulcers on the epiglottis caused by a nasogastric tube in three adults with severe motor and intellectual disabilities. AB - Nasogastric tube feeding is a common method of parenteral nutrition. We observed ulcers on the epiglottis caused by a nasogastric tube in three adults with severe motor and intellectual disabilities (SMID) during examination with a laryngeal fiberscope while swallowing. These ulcers were healed by changing the method of inserting the nasogastric tube. The patients were three men aged 25, 39, and 55 years. The muscle tone of the whole body was increased in all of the patients. Two patients had severe scoliosis, and the other patient had lordosis in the thoracic vertebrae and had received laryngo-tracheal diversion. All of the patients received intermittent or continuous respiratory care. The pharynx of the patients with severe scoliosis became thinner and the feeding tubes ran obliquely. The feeding tube in the patient who received laryngo-tracheal diversion entered the cut and closed trachea through the glottis. Ulcers were observed on the laryngeal side of the epiglottis in all of the patients. The ulcers were healed by preventing feeding tubes from running obliquely or by using the naso-gastric tube made of different materials in the patients with severe scoliosis. In the patient who received laryngo-tracheal diversion, we succeeded in avoiding the glottis by keeping his face forward while inserting the feeding tube. Then feeding tubes were changed with guidewires, and the ulcers were healed. When using nasogastric tube feeding for persons with SMID with a large increase in muscle tone and/or with severe scoliosis, adopting a method of inserting feeding tubes that avoids damaging the epiglottis with a laryngeal fiberscope is required. PMID- 30010297 TI - [In Process]. PMID- 30010298 TI - [In Process]. PMID- 30010299 TI - Tuberous sclerosis with infantile spasm and subependymal giant cell astrocytoma. AB - Tuberous sclerosis complex (TSC) is a genetic disease affecting many organ systems and showing different symptoms in each age group. We encountered a TSC patient with intractable epilepsy who had brain tumors suspected to be subependymal giant cell astrocytoma (SEGA). We used adrenocorticotropic hormone and ordinal antiepileptic drugs at first, but they showed limited effectiveness. After we tried several treatments for epilepsy, we started to use everolimus to prevent tumor growth. As a result, the development of the tumor stopped and the epileptic attack improved simultaneously. The frequency and duration of each epileptic spasm and seizure became milder, and the electroencephalogram findings also improved. The mental development had regressed when the epilepsy started, but it started to progress again after the epileptic attack disappeared. Everolimus may be used for treatment of intractable epilepsy with TSC in patients with a growing SEGA. PMID- 30010300 TI - [Eight Cases of Small Cell Neuroendocrine Carcinoma of the Head and Neck]. AB - Small cell neuroendocrine carcinoma of the head and neck is a rarely occurring poorly differentiated and high-grademalignant neoplasm characterized by highly active proliferation of neuroendocrine tumor cells. There are no establishedtherapies for this disease. To clarify the clinical course and develop effective treatment(s) for the carcinoma, wereviewed the data of 8 patients of small cell neuroendocrine carcinoma of the head and neck treated by us between 2006and 2014 at the Department of Otolaryngology, Gifu University School of Medicine and our affiliated hospitals.The patients consisted of 3 men and 5 women, ranging in age from 38 to 84 years old (mean : 60.9 years). Thetumor arose from the nasal cavity or the paranasal sinuses in 3 cases, from the parotid grand in 2 cases, from the oropharynxin 2 cases, and from the hypopharynx in 1 case. The tumor that arose from the hypopharynx was a combinedsmall-cell carcinoma with squamous cell carcinomas, and the one that arose from the oropharynx had already metastasizedto the brain.Most of the patients were treated by chemotherapy and radiotherapy based on the treatment employed for small cellcarcinoma of the lung. Only the patient in whom the tumor arose from a paranasal sinus was treated by surgery despitethe definitive diagnosis of small cell carcinoma.We selected CPT 11 and a platinum agent for 4 patients, and VP-16 and a platinum agent for 3 patients as the first-line chemotherapy. Although two patients showed carcinoma free survival, one died of recurrence of the regional lymphnode metastases and five died of distant metastases despite the absence of locoregional recurrence. The 5-year survivalrate was a dismal 25%, suggesting that we need to establish effective treatment(s) for the control of distant metastases incases of the small cell neuroendocrine carcinoma of the head and neck. PMID- 30010301 TI - Molecular therapies for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder, which is characterized by progressive muscle wasting, ultimately resulting in the death of patients in their twenties or thirties. In DMD the dystrophin gene is mutated, which results in a deficiency of the muscle dystrophin. Although expression of dystrophin is a fundamental treatment for DMD, no effective treatment for DMD is available until now. Promising molecular therapies which are mutation-specific have been developed. Antisense oligonucleotide-mediated exon skipping that convert out-of-frame mRNA into in-frame mRNA, thereby enabling semifunctional dystrophin production, is recognized as the most promising treatment for DMD. We demonstrated that the intravenous administration of the antisense oligonucleotide against the splicing enhancer sequence induced exon skipping and produced the dystrophin protein in DMD case for the first time. After extensive studies, antisense oligonucleotides comprising different monomers have undergone clinical trials and provided favorable results, enabling improvements in ambulation of DMD patients Induction of the read-through of nonsense mutations is expected to produce dystrophin in DMD patients with nonsense mutations. The clinical effectiveness of gentamicxin and PTC124 has been reported. We have demonstrated the effectiveness of arbekacin-mediated read through in vitro. We have already begun an investigator initiated clinical trial of nonsense mutation read-through therapy using arbekacin. Some of these drug candidates are planned to undergo submission for approval to regulatory agencies in the US and EU. We hope that these molecular therapies will contribute towards DMD treatment. PMID- 30010302 TI - We have we learned from T4? PMID- 30010303 TI - [Tonsillectomy in Cases with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome]. AB - The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatorydisease, characterized, as its name suggests, by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.This syndrome is the most common cause of recurrent fever in children, however the rate of recognition of this syndromeis still low. Tonsillectomy has been suggested as an effective treatment, even though the precise, pathophysiologyunderlying this syndrome remains unknown. In this study, we investigated the outcomes in patients who underwent tonsillectomy.In particular, we examined the surgical outcomes and clinical features of the patients who underwent tonsillectomy.A total of 19 patients with PFAPA syndrome underwent tonsillectomy at our hospital from July 2013 to May2016. Before the surgery, while all the patients had received medications, none showed complete resolution of the syndromes.However, of the 19 patients, 15 showed complete resolution of the syndrome immediately after the surgery.Four patients had fever even after the surgery. Three patients showed partial remission, with the frequency and durationof the episodes decreasing after the surgery. However, in one patient, the fever persisted as before the surgery. Therewere no significant differences in the clinical characteristics, such as the age at onset, fever episodes, associated symptoms,or age at surgery among the three groups. However, we observed a trend towards a higher frequency of a familyhistory in patients with persistent symptoms after surgery. Tonsillectomy was highly effective against PFAPA syndrome,however, some patients failed to respond to the procedure. Therefore, it is important to carefully evaluate the risks andbenefits in each case. The indications for tonsillectomy have not yet been clearly established. It is essential to continuefurther investigations to establish effective therapeutic strategies for this syndrome. PMID- 30010304 TI - Challenging perceptions: medical cannabis. PMID- 30010305 TI - Alteration of cytokines in serum and cerebrospinal fluid before and after high dose immunoglobulin therapy in patients with West syndrome. AB - Objective: To elucidate the pathophysiology of West syndrome and mechanism of immunoglobulin therapy for this syndrome, we investigated serum and cerebrospinal fluid (CSF) cytokine levels before and after high-dose intravenous immunoglobulin (IVIG) therapy in patients with West syndrome. Methods: We measured serum and CSF cytokine levels of 11 patients with West syndrome who was referred to Saitama Children's Medical Center from April 2010 to May 2014. All patients received IVIG, ranging from 200 to 500 mg/kg/day for 3 consecutive days (initial IVIG treatment), before adrenocorticotrophic hormone therapy. When spasms disappeared within 2 weeks after initial IVIG treatment, maintenance IVIG treatment was commenced. We measured cytokines level in patients before and after initial IVIG treatment. We compared the levels of cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, Interferon gamma, Granulocyte macrophage colony stimulating factor, IL-18, Tumor necrosis factor-alpha?TNF-alpha?) in serum and CSF, and between the seizure-free group and seizure-persisting group. Seizure free was defined as remission of spasms within 2 weeks after initial IVIG treatment and no relapse for at least 1 week after remission. Results: After IVIG therapy, 5 of 11 patients were in the seizure-free group (4 males, 1 cryptogenic) while 6 were in the seizure-persisting group (2 males, 1 cryptogenic). Levels of IL-1beta, IL-10, IL-18, and TNF-alpha in serum were significantly higher than those in CSF before initiation of IVIG. Before IVIG treatment, the level of IL-8 in CSF was significantly higher than that in serum, while the serum IL-18 level in the seizure-free group was significantly lower than that in the seizure-persisting group. Alterations of serum IL-18 level and CSF IL-8 level were different between the seizure-free and seizure-persisting groups. Conclusions: Serum IL-18 and CSF IL-8 may be important factors for elucidating the pathophysiology of West syndrome and mechanism of IVIG therapy. PMID- 30010306 TI - [A Case Report of Acute Angioedema that Showed Dramatic Response to Administration of a C1-inactivator]. AB - Angioedema is characterized by rapid and severe swelling of the subcutaneous and submucosal tissues. Angioedemainvolving the upper airway can lead to life threatening airway obstruction, and needs prompt diagnosis and treatment.Herein, we report a case of acute angioedema which was suspected as having been caused by estrogen imbalance. A 32-year-old woman who was taking a fertility drug for infertility treatment, presented with sudden swelling of the face andneck region and breathing difficulty. Her symptoms continued to progress despite antibiotic and corticosteroidadministration. We suspected hereditary angioedema (HAE), and administered a C1-inactivator, which led to immediateand dramatic resolution of the symptoms. Since the C4 and C1-inhibitor levels were normal, the possibility of HAE typeIII was considered. However, another possibility was that her complicated hormonal condition, including oral intake of afertility drug, menstruation, and mental stress may have led to estrogen imbalance causing angioedema. Currently, avariety of hormone therapies is widely used ; therefore, caution is needed against the development of estrogen-dependentangioedema. PMID- 30010307 TI - Experience with levetiracetam to epilepsy cases in neurodevelopmental disorders. AB - Objective: As a treatment for cases of developmental disorder accompanied with epilepsy, the author examined the efficacy and tolerability of combined administration of levetiracetam (LEV) on the cases. Methods: There were 21 participants (male-to-female-ratio was 16 to 5, 6 in their 10s, 7 in their 20s, 7 in their 30s and 1 in their 40s) to whom LEV was prescribed from October 2011 to December 2014. The effect was classified as loss of seizure, effective (more than 75% reduction in the number of seizures, more than 50% reduction in the number of seizures), unchanged (no change), and aggravation (increase in the number of seizures). Results: The study included 19 autistic spectrum disorder (ASD) cases (13 with profound intellectual disability, 5 with severe intellectual disability, and 1 with high functioning autism), 1 borderline intelligence case, and 1 attention deficit/hyper activity disorder (AD/HD) case. By classification of epilepsy seizure, there were 15 symptomatic localization-related epilepsy cases and 6 generalized epilepsy cases. The initial dose of LEV was an average of 488.1 mg/day, and the maintenance dose was an average of 1,714.2 mg/day. The average duration of administration was 2 years and 3 months. In terms of the response rate, there were 11 cases of loss of seizure (52.4%), 4 cases of more than 75% reduction in the number of seizures, (19.0%), and 3 cases of more than 50% reduction in the number of seizures (14.3%). The overall response rate was 85.7% (18 cases). 14.3% was unchanged (3 cases). No aggravation case was observed. There was only one case of dizziness in the initial period, but all cases continued taking LEV. The kinds of anticonvulsant agent could be adjusted from 2.5 at the beginning of LEV administration to 1.5. Emotional stability was also observed. Some cases could stop taking tranquilizers. Conclusions: LEV showed high response rate and tolerability on the cases of ASD and other developmental disorder accompanied with epilepsy. Administration of this drug led to reduction in the number of concomitant medications, which indicates the possibility that LEV may contribute to enhancing compliance. PMID- 30010309 TI - [A Case of Idiopathic Bridging Vocal Fold Adhesion that was Treated by Ambulatory Surgery under Local Anesthesia]. AB - Patients with vocal fold adhesions usually undergo surgery under general anesthesia, because of the possibility ofpostoperative adhesions according to the severity and cause. However, it has been reported that patients with minorbridging adhesion can be treated by only discission without any postoperative adhesion. Herein, we report the case of apatient with idiopathic bridging vocal fold adhesions who was treated by ambulatory surgery at the ENT clinic andshowed a benign course. A male former professional singer who was in his 70s presented with a history of cough followed by the developmentof bridging central vocal fold adhesion. On the 10th day after the initial visit, we performed discission of the adhesionunder local anesthesia using a surgical knife for the vocal fold. Although a delicate surgical technique is desirable for phonosurgery, we were able to perform surgery under local anesthesia in this case, because the adhesion was minor. We consider that endoscopic laryngeal surgery under localanesthesia is useful for the treatment of patients with bridging adhesions. PMID- 30010310 TI - Mechanistic Understanding of Improved Performance of Graphene Cathode Inverted Organic Light-Emitting Diodes by Photoemission and Impedance Spectroscopy. AB - Modification of multilayer graphene films was investigated for a cathode of organic light-emitting diodes (OLEDs). By doping the graphene/electron transport layer (ETL) interface with Li, the driving voltage of the OLED was reduced dramatically from 24.5 to 3.2 V at a luminance of 1000 cd/m2. The external quantum efficiency was also enhanced from 3.4 to 12.9%. Surface analyses showed that the Li doping significantly lowers the lowest unoccupied molecular orbital level of the ETL, thereby reducing the electron injection barrier and facilitating electron injection from the cathode. Impedance spectroscopy analyses performed on electron-only devices (EODs) revealed the existence of distributed trap states with a well-defined activation energy, which is successfully described by the Havriliak-Negami capacitance functions and the temperature independent frequency dispersion parameters. In particular, the graphene EOD showed a unique high-frequency feature as compared to the indium tin oxide one, which could be explained by an additional parallel capacitance element. PMID- 30010311 TI - Highly Dispersive MoP Nanoparticles Anchored on Reduced Graphene Oxide Nanosheets for an Efficient Hydrogen Evolution Reaction Electrocatalyst. AB - Electrochemical water-splitting with non-noble metal catalysts provides an eco friendly strategy for renewable production of hydrogen. In this study, the MoP@C@reduced graphene oxide (rGO) composite was prepared via mild reactions through a chemical bath and postannealing process. With the assistance of citric acid, the MoP@C@rGO composite containing ultrafine MoP nanoparticles with a size of 3 nm anchored on two-dimensional C/rGO nanosheets has been obtained. The chelation effect with citric acid and the merits of rGO not only lead to affordable active sites but also improved the electrical conductivity and stability at the same time. Serving as the hydrogen evolution reaction (HER) electrocatalyst, the MoP@C@rGO composite presents a small overpotential of 168.9 mV at 10 mA cm-2. It has superior durability when compared to samples of pure MoP, MoP@C, and MoP@rGO. The relative high activity and stable performance as well as the simple preparation process make the MoP@C@rGO composite a promising HER electrocatalyst. PMID- 30010312 TI - Bioinspired Further Enhanced Dry Adhesive by the Combined Effect of the Microstructure and Surface Free-Energy Increase. AB - Silicone elastomers are known for having low surface free energies generally leading to poor adhesive performances. This surface characteristic can be enhanced by plasma treatments. The microstructured silicone elastomer surfaces can demonstrate superior adhesive performance that is more than 10 times higher in terms of pull-off forces, compared to their unstructured counterpart. Here, we have demonstrated that the combination of these two methods further enhances adhesive performance, especially when the surfaces are biomimetic micro/nanopatterned with, e.g., beetle-inspired mushroom-shaped adhesive microstructure (MSAMS). The plasma treatment time and pressure parameters were varied for the unstructured and MSAMS poly(vinylsiloxane) surfaces to find optimum parameters for maximum adhesion performance. Air plasma treatment induced average adhesive enhancement forces up to 30% on the unstructured surface, but the MSAMS surface demonstrated an enhancement of adhesive forces up to 91% higher than that of an untreated, microstructured control, despite the plasma-treated surface area of the structured surface being only 50% of that of the unstructured surface. High-speed video-recordings of individual microstructures in contact with a glass surface shows that the origin of the adhesion enhancement is due to the special detachment mechanism of individual microstructures that allows sustaining a wider contact area at detachment. We believe that this integration of the plasma treatment with MSAMS suggests a versatile way of functionalization that can further advance the adhesive ability of low-surface-energy polymer surfaces. PMID- 30010313 TI - The Palladium-Catalyzed Ullmann Cross-Coupling Reaction: A Modern Variant on a Time-Honored Process. AB - Cross-coupling reactions, especially those that are catalyzed by palladium, have revolutionized the way in which carbon-carbon bonds can be formed. The most commonly deployed variants of such processes are the Suzuki-Miyaura, Mizoroki Heck, Stille, and Negishi cross-coupling reactions, and these normally involve the linking of an organohalide or pseudohalide (such as a triflate or nonaflate) with an organo-metallic or -metalloid such as an organo-boron, -magnesium, -tin, or -zinc species. Since the latter type of coupling partner is often prepared from the corresponding halide, methods that allow for the direct cross-coupling of two distinct halogen-containing compounds would provide valuable and more atom economical capacities for the formation of carbon-carbon bonds. While the venerable Ullmann reaction can in principle achieve this, it has a number of drawbacks, the most significant of which is that homocoupling of the reaction partners is a competitive, if not the dominant, process. Furthermore, such reactions normally occur only under forcing conditions (viz., often at temperatures in excess of 250 degrees C). As such, the Ullmann reaction has seen only limited application in this regard, especially as a mid- to late-stage feature of complex natural product synthesis. This Account details the development of the palladium-catalyzed Ullmann cross-coupling reaction as a useful method for the assembly of a range of heterocyclic systems relevant to medicinal and/or natural products chemistry. These couplings normally proceed under relatively mild conditions (<100 degrees C) over short periods of time and, usually, to the exclusion of (unwanted) homocoupling events. The keys to success are the appropriate choice of coupling partners, the form of the copper metal employed, and the choice of reaction solvent. At the present time, the cross-coupling partners capable of engaging in the title reaction are confined to halogenated and otherwise electron-deficient arenes and, as complementary reactants, alpha- or beta-halogenated, alpha,beta-unsaturated aldehydes, ketones, esters, lactones, lactams, and cycloimides. Nitro-substituted (and halogenated) arenes, in particular, serve as effective participants in these reactions, and the products of their coupling with the above-mentioned carbonyl-containing systems can be manipulated in a number of different ways. Depending on the positional relationship between the nitro and carbonyl groups in the cross coupling product, the reduction of the former group, which can be achieved under a range of different conditions, provides, through intramolecular nucleophilic addition reactions, including Schiff base condensations, access to a diverse range of heterocyclic systems. These include indoles, quinolines, quinolones, isoquinolines, carbazoles, and carbolines. Tandem variants of such cyclization processes, in which Raney cobalt is used as a catalyst for the chemoselective reduction (by dihydrogen) of nitro and nitrile groups (but not olefins), allow for the assembly of a range of structurally challenging natural products, including marinoquinoline A, (+/-)-1-acetylaspidoalbidine, and (+/-)-gilbertine. PMID- 30010314 TI - Sulfonato-beta-Cyclodextrin Mediated Supramolecular Nanoparticle for Controlled Release of Berberine. AB - A kind of supramolecular assemblies was constructed from two water-soluble and biocompatible saccharides, sulfonato-beta-cyclodextrin (SCD) and chitosan, and characterized by dynamic light scattering (DLS), UV-vis, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The results showed that such nanoparticles presented good stability and controlled loading/release property, which enabled them as good drug carrier for berberine chloride (BE), a representative drug from traditional Chinese herbs. That is, the nanoparticles can load BE with high stability in a low-pH environment like that of the stomach but released BE when moved to a high-pH environment like that of the intestine. PMID- 30010315 TI - Label-Free Simultaneous Analysis of Fe(III) and Ascorbic Acid Using Fluorescence Switching of Ultrathin Graphitic Carbon Nitride Nanosheets. AB - A simple chemical oxidation and ultrasound exfoliation method has been developed to synthesize the two-dimensional and ultrathin-layer materials-graphitic carbon nitride nanosheets (g-C3N4 NNs). The prepared ultrathin g-C3N4 NNs display strong fluorescence and stability, including good photostability and excellent antisalt ability. Herein, a new "on-off-on" fluorescent switching sensor is designed. The iron ion (Fe3+) has an ultrasensitive response to quench the fluorescence of g C3N4 NNs based on the synergistic effect between inner filter effect and photoinduced electron transfer. The linear limit for Fe3+ was from 0.05 to 30 MUmol L-1 with a detection limit of 0.018 MUmol L-1. Meanwhile, the fluorescence of g-C3N4 NNs can recover through the redox reaction between Fe3+ and ascorbic acid (AA). In addition, the linear range for AA was from 0.2 to 112.5 MUmol L-1 with a 0.086 MUmol L-1 detection limit. The proposed method exhibited rapid response, excellent selectivity, wide detection range, and low detection limit for simultaneous analysis of Fe3+ and AA, and it was applied for the determination of Fe3+ and AA in water sample and human serum with satisfactory results. PMID- 30010316 TI - One-Pot Two-Step Metabolic Labeling of Teichoic Acids and Direct Labeling of Peptidoglycan Reveals Tight Coordination of Both Polymers Inserted into Pneumococcus Cell Wall. AB - A method for labeling teichoic acids in the human pathogen Streptococcus pneumoniae has been developed using a one-pot two-step metabolic labeling approach. The essential nutriment choline modified with an azido-group was incorporated and exposed at the cell surface more rapidly than it reacted with the strain promoted azide alkyne cycloaddition (SPAAC) partner also present in the medium. Once at the cell surface on teichoic acids, coupling of the azido group could then occur within 5 min by the bio-orthogonal click reaction with a DIBO-linked fluorophore. This fast and easy method allowed pulse-chase experiments and was combined with another fluorescent labeling approach to compare the insertion of teichoic acids with peptidoglycan synthesis with unprecedented temporal resolution. It has revealed that teichoic acid and peptidoglycan processes are largely concomitant, but teichoic acid insertion persists later at the division site. PMID- 30010317 TI - Keratin-Templated Synthesis of Metallic Oxide Nanoparticles as MRI Contrast Agents and Drug Carriers. AB - Keratin is a family of cysteine-rich structural fibrous proteins abundantly present in skin and skin appendages. Inspired by the template synthesis strategy, in this work, keratin was utilized for the first time as a platform template to synthesize metallic oxide nanoparticles, such as MnO2 (MnNPs@Keratin) and Gd2O3 (GdNPs@Keratin), in a simple and environment-benign fashion. These nanoparticles possess good colloid stability and biocompatibility, high T1 relaxivity ( r1 value = 6.8 mM-1s-1 for MnNPs@Keratin and 7.8 mM-1s-1 for GdNPs@Keratin), and superior in vivo magnetic resonance imaging performance of tumor. Moreover, these keratin-templated nanoparticles have great potential as drug carriers with the capacity of redox-responsive drug release due to the existence of disulfide cross linking in keratin coating. These results suggest that keratin can be a promising platform template for the development of metal-based nanoparticles for cancer diagnosis and therapy. PMID- 30010318 TI - Analogues of Arylamide Phenylpiperazine Ligands To Investigate the Factors Influencing D3 Dopamine Receptor Bitropic Binding and Receptor Subtype Selectivity. AB - We have previously reported on the ability of arylamide phenylpiperazines to bind selectively to the D3 versus the D2 dopamine receptor subtype. For these studies, we used LS-3-134 as the prototypic arylamide phenylpiperazine ligand because it binds with high affinity at D3 dopamine receptor (0.17 nM) and exhibits >150-fold D3 vs D2 receptor binding selectivity. Our goal was to investigate how the composition and size of the nonaromatic ring structure at the piperazine position of substituted phenylpiperazine analogues might influence binding affinity at the human D2 and D3 dopamine receptors. Two factors were identified as being important for determining the binding affinity of bitropic arylamide phenylpiperazines at the dopamine D3 receptor subtype. One factor was the strength of the salt bridge between the highly conserved residue Asp3.32 with the protonated nitrogen of the nonaromatic ring at the piperazine position. The second factor was the configuration of the unbound ligand in an aqueous solution. These two factors were found to be related to the logarithm of the affinities using a simple correlation model, which could be useful when designing high affinity subtype selective bitropic ligands. While this model is based upon the interaction of arylamide phenylpiperazines with the D2 and D3 D2-like dopamine receptor subtypes, it provides insights into the complexity of the factors that define a bitropic mode of the binding at GPCRs. PMID- 30010319 TI - Design and Integration of Flexible Sensor Matrix for in Situ Monitoring of Polymer Composites. AB - Sensory polymer composites are highly desirable for applications such as in situ and real-time production processes and structural health monitoring, and for technologies that include human-machine interfaces for the next generation of Internet of Things. However, the development of these materials is still in its infancy: these materials have been reported, but the large-scale fabrication of polymer composites with versatile and customizable sensing capabilities has yet to be demonstrated. Here, we report on a scalable fabrication strategy that enables such materials by designing and integrating PCB technology-inspired large area flexible sensor matrices into polymer composites. The integrated sensor matrices successfully monitored in situ the production processes and structural health of an industrial polymer composite: from the application of vacuum, resin flow and polymerization, production defects, and temperature distribution. Our results demonstrate that the proposed strategy is a simple and effective solution as a distributed monitoring platform for polymer composites and shows the potential toward next generation of sensory polymer composites. PMID- 30010320 TI - Biochemical and Structural Analysis of FomD That Catalyzes the Hydrolysis of Cytidylyl ( S)-2-Hydroxypropylphosphonate in Fosfomycin Biosynthesis. AB - In fosfomycin biosynthesis, the hydrolysis of cytidylyl ( S)-2 hydroxypropylphosphonate [( S)-HPP-CMP] to afford ( S)-HPP is the only uncharacterized step. Because FomD is an uncharacterized protein with a DUF402 domain that is encoded in the fosfomycin biosynthetic gene cluster, FomD was hypothesized to be responsible for this reaction. In this study, FomD was found to hydrolyze ( S)-HPP-CMP to give ( S)-HPP and CMP efficiently in the presence of Mn2+ or Co2+. FomD also hydrolyzed cytidylyl 2-hydroxyethylphosphonate (HEP-CMP), which is a biosynthetic intermediate before C-methylation. The kcat/ KM value of FomD with ( S)-HPP-CMP was 10-fold greater than that with HEP-CMP, suggesting that FomD hydrolyzes ( S)-HPP-CMP rather than HEP-CMP in bacteria. The crystal structure of FomD showed that this protein adopts a barrel-like fold, which consists of a large twisted antiparallel beta-sheet. This is a key structural feature of the DUF402 domain-containing proteins. Two metal cations are located between the FomD barrel and the two alpha-helices at the C-terminus and serve to presumably activate the phosphonate group of substrates for hydrolysis. Docking simulations with ( S)-HPP-CMP suggested that the methyl group at the C2 position of the HPP moiety is recognized by a hydrophobic interaction with Trp68. Further mutational analysis suggested that a conserved Tyr107 among the DUF402 domain family of proteins activates a water molecule to promote nucleophilic attack on the phosphorus atom of the phosphonate moiety. These findings provide mechanistic insights into the FomD reaction and lead to a complete understanding of the fosfomycin biosynthetic pathway in Streptomyces. PMID- 30010321 TI - Supramolecular Assemblies on Surfaces: Nanopatterning, Functionality, and Reactivity. AB - Understanding how molecules interact to form large-scale hierarchical structures on surfaces holds promise for building designer nanoscale constructs with defined chemical and physical properties. Here, we describe early advances in this field and highlight upcoming opportunities and challenges. Both direct intermolecular interactions and those that are mediated by coordinated metal centers or substrates are discussed. These interactions can be additive, but they can also interfere with each other, leading to new assemblies in which electrical potentials vary at distances much larger than those of typical chemical interactions. Earlier spectroscopic and surface measurements have provided partial information on such interfacial effects. In the interim, scanning probe microscopies have assumed defining roles in the field of molecular organization on surfaces, delivering deeper understanding of interactions, structures, and local potentials. Self-assembly is a key strategy to form extended structures on surfaces, advancing nanolithography into the chemical dimension and providing simultaneous control at multiple scales. In parallel, the emergence of graphene and the resulting impetus to explore 2D materials have broadened the field, as surface-confined reactions of molecular building blocks provide access to such materials as 2D polymers and graphene nanoribbons. In this Review, we describe recent advances and point out promising directions that will lead to even greater and more robust capabilities to exploit designer surfaces. PMID- 30010322 TI - Small Meets Smaller: Effects of Nanomaterials on Microbial Biology, Pathology, and Ecology. AB - As functionalities and levels of complexity in nanomaterials have increased, unprecedented control over microbes has been enabled, as well. In addition to being pathogens and relevant to the human microbiome, microbes are key players for sustainable biotechnology. To overcome current constraints, mechanistic understanding of nanomaterials' physicochemical characteristics and parameters at the nano-bio interface affecting nanomaterial-microbe crosstalk is required. In this Perspective, we describe key nanomaterial parameters and biological outputs that enable controllable microbe-nanomaterial interactions while minimizing design complexity. We discuss the role of biomolecule coronas, including the problem of nanoantibiotic resistance, and speculate on the effects of nanomaterial-microbe complex formation on the outcomes and fates of microbial pathogens. We close by summarizing our current knowledge and noting areas that require further exploration to overcome current limitations for next-generation practical applications of nanotechnology in medicine and agriculture. PMID- 30010323 TI - Methanococcus maripaludis Employs Three Functional Heterodisulfide Reductase Complexes for Flavin-Based Electron Bifurcation Using Hydrogen and Formate. AB - Hydrogenotrophic methanogens oxidize molecular hydrogen to reduce carbon dioxide to methane. In methanogens without cytochromes, the initial endergonic reduction of CO2 to formylmethanofuran with H2-derived electrons is coupled to the exergonic reduction of a heterodisulfide of coenzymes B and M by flavin-based electron bifurcation (FBEB). In Methanococcus maripaludis, FBEB is performed by a heterodisulfide reductase (Hdr) enzyme complex that involves hydrogenase (Vhu), although formate dehydrogenase (Fdh) has been proposed as an alternative to Vhu. We have identified and purified three Hdr complexes of M. maripaludis, where homodimeric Hdr complexes containing (Vhu)2 or (Fdh)2 were found, in addition to a heterocomplex that contains both Vhu and Fdh. Formate was found in in vitro assays using the purified Hdr complex to act directly as the electron donor for FBEB via the associated Fdh. Furthermore, while ferredoxin was slowly reduced to 30% [-360 mV vs the standard hydrogen electrode (SHE)] by H2 and formate (0.8 atm and 30 mM, according to thermodynamics), the addition of CoB-S-S-CoM as the high potential electron acceptor ( E degrees ' = -140 mV vs SHE; to induce FBEB) resulted in the rapid and more complete reduction of Fd to 94% (-455 mV vs SHE). PMID- 30010324 TI - Crystal Chemistry of Vanadium-Bearing Ellestadite Waste Forms. AB - Vanadate ellestadites Ca10(SiO4) x(VO4)6-2 x(SO4) xCl2, serving as prototype crystalline matrices for the fixation of pentavalent toxic metals (V, Cr, As), were synthesized and characterized by powder X-ray and neutron diffraction (PXRD and PND), electron probe microanalysis (EPMA), Fourier transform infrared spectroscopy (FTIR), and solid-state nuclear magnetic resonance (SS-NMR). The ellestadites 0.19 < x < 3 adopt the P63/ m structure, while the vanadate endmember Ca10(VO4)6Cl2 is triclinic with space group P1. A miscibility gap exists for 0.77 < x < 2.44. The deficiency of Cl in the structure leads to short range disorder in the tunnel. Toxicity characteristic leaching testing (TCLP) showed the incorporation of vanadium increases ellestadite solubility, and defined a waste loading limit that should not exceed 25 atom % V to ensure small release levels. PMID- 30010325 TI - Correction to "New Class of Anion-Accelerated Amino-Cope Rearrangements as Gateway to Diverse Chiral Structures". PMID- 30010326 TI - Improving Data Reporting in Ecotoxicological Studies. PMID- 30010327 TI - Investigating the Luminescence Behaviors and Temperature Sensing Properties of Rare-Earth-Doped Ba2In2O5 Phosphors. AB - We present a strategy for selecting an optimal material in a particular temperature range by investigating the relationship between the absolute sensitivity ( Sa) and energy gap (Delta E), as well as the relationship between Sa and temperature on the basis of Yb3+/Ln3+ (Ln = Er3+, Ho3+)-codoped Ba2In2O5 phosphors. Through an investigation of optical performance, the phosphors exhibit near-infrared (NIR) downshifting and visible upconversion (UC) emissions under 980 nm excitation. The NIR spectral range from 700 to 1800 nm is referred to as the "biological window". The NIR emission peaks of Er3+ and Ho3+ are located at 1550 nm of the third biological window and 1192 nm of the second biological window, respectively. The temperature sensing behaviors based on the UC luminescence in Yb3+/Ln3+-codoped Ba2In2O5 phosphors are recorded by the fluorescence intensity ratio (FIR) technique in the temperature range from 303 to 573 K. The Ba2In2O5:Er3+/Yb3+ sample is usable at temperatures above 350 K, and the Ho3+/Yb3+-codoped Ba2In2O5 phosphor is suitable at temperatures below 350 K in our experimental region. The above results show that the Ba2In2O5:Ln3+/Yb3+ phosphors could be promising candidates for optical temperature sensors and applications in the biological imaging field. PMID- 30010328 TI - Influence of Radicals on Magnetization Relaxation Dynamics of Pseudo-Octahedral Lanthanide Iminopyridyl Complexes. AB - Controlling quantum tunneling of magnetization (QTM) is a persistent challenge in lanthanide-based single-molecule magnets. As the exchange interaction is one of the key factors in controlling the QTM, we targeted lanthanide complexes with an increased number of radicals around the lanthanide ion. On the basis of our targeted approach, a family of pseudo-octahedral lanthanide/transition-metal complexes were isolated with the general molecular formula of [M(L*-)3] (M = Gd (1), Dy (2), Er (3), Y (4)) using the redox-active iminopyridyl (L*-) ligand exclusively, which possess the highest ratio of radicals to lanthanide reported for discrete metal complexes. Direct current magnetic susceptibility studies suggest that dominant antiferromagnetic interactions exist between the radical and lanthanide ions in all of the complexes, which is strongly corroborated by magnetic data fitting using a Heisenberg-Dirac-Van Vleck (HDVV) Hamiltonian (-2 J Hamiltonian). A good agreement between the fit and the experimental magnetic data obtained using g = 2, Jrad-rad = -111.9 cm-1 for 4 and g = 1.99, Jrad-rad = 111.9 cm-1, JGd-rad = -1.85 cm-1 for 1. Complex 2 shows frequency-dependent slow magnetization relaxation dynamics in the absence of an external magnetic field, while 3 shows field-induced frequency-dependent chiM'' signals. An ideal octahedral geometry around the lanthanide ion is predicted to be unsuitable for the design of a single-molecule magnet (SMM); nevertheless, complex 2 exhibits slow relaxation of magnetization with a record high anisotropy barrier for a six coordinate Dy(III) complex. A rationale for this unusual behavior is detailed and reveals the strength of the synthetic methodology developed. PMID- 30010329 TI - Metal-Substrate Cooperation Mechanism for Dehydrogenative Amidation Catalyzed by a PNN-Ru Catalyst. AB - The pyridine-based PNN ruthenium pincer complex (PNN)Ru(CO)(H) can catalyze the well-known dehydrogenative amidation reaction, but the mechanism is not fully understood. In this work, we find there exists an alternative metal-substrate cooperation mechanism in this reaction system, which is more favorable than the aromatization-dearomatization mechanism. The possible reaction of the excess base t-BuO- with catalyst species (PNN)Ru(CO)(H) is studied, indicating t-BuO- is able to facilitate the ligand substitution and enhance catalytic activities. With the bifunctional Ru-N moiety, the imine-substituted species (PN)(imine)Ru(CO)(H) 5 could serve as an alternative catalytic species and efficiently facilitate some elementary steps such as the hydrogen transfer, hydrogen elimination, and C-N coupling. Meanwhile, the C-N coupling step proceeds via the split of aldehydic C H bond across the Ru(II)-imine bond, which results in an amide bond directly. The hemiaminal is uninvolved in the C-N coupling process. Finally, the formation of linear peptides and cyclic dipeptides are unveiled by the newly proposed mechanism. The metal-substrate cooperation could widely exist in transition metal catalyst systems with a large influence on the reaction activity. PMID- 30010330 TI - Bioaccumulation and Biotransformation of Triclosan and Galaxolide in the Freshwater Oligochaete Limnodrilus hoffmeisteri in a Water/Sediment Microcosm. AB - Personal care products are widely used in our daily life in considerable quantities and discharged via the down-the-drain route to aquatic environments, resulting in potential risks to aquatic organisms. We investigated bioaccumulation and biotransformation of two widely used personal care products, triclosan (TCS) and galaxolide (HHCB) spiked to sediment, in the oligochaete worm Limnodrilus hoffmeisteri in water/sediment microcosms. After 7 days of sediment exposure to 3.1 MUg of TCS or HHCB/g of dry weight sediment, the accumulation of TCS and HHCB in L. hoffmeisteri reached equilibrium, at which point the biota sediment accumulation factors (BSAFs) were 2.07 and 2.50 for TCS and HHCB, respectively. The presence of L. hoffmeisteri significantly accelerated the dissipation of the levels of TCS and HHCB in the microcosms, with approximately 9.03 and 2.90% of TCS and HHCB, respectively, eliminated from the water/sediment systems after exposure for 14 days in the presence of worms. Two biotransformation products, methyl triclosan and triclosan O-sulfate, were identified for TCS in worm tissue, whereas only methyl triclosan was identified in the sediment. Unlike TCS, no evidence of biotransformation products was found for HHCB in either worm tissue or sediment. These experiments demonstrate that L. hoffmeisteri biotransformed TCS through methylation and sulfation, whereas HHCB biotransformation was undetectable. PMID- 30010331 TI - Intergrowth between the Oxynitride Perovskite SrTaO2N and the Ruddlesden-Popper Phase Sr2TaO3N. AB - Strontium tantalum oxynitrides were prepared within the nominal composition range of 1.0 <= x <= 2.0, where x = Sr/Ta atomic ratio. A gradual structural transition was observed between the perovskite SrTaO2N and the Ruddlesden-Popper phase Sr2TaO3N with increasing SrO content. X-ray diffraction analyses showed that a single-phase perovskite was obtained up to x = 1.1, after which Sr2TaO3N gradually appeared at x >= 1.25. High-resolution scanning transmission electron microscopy observations identified the gradual intergrowth of a Ruddlesden-Popper Sr2TaO3N type planar structure interwoven with the perovskite crystal lattice upon increasing x. The crystal lattice at x = 1.4 was highly defective and consisted primarily of perovskite intergrown with a large amount of the Ruddlesden-Popper phase structure. This Ruddlesden-Popper phase layer intergrowth is a characteristic of an oxynitride perovskite rather than the Ruddlesden-Popper defects previously reported in oxide perovskites. Partial substitution of Ta with Sr was also evident in this perovskite lattice. Just below x = 2, a perovskite type structure was intergrown as defects in the Ruddlesden-Popper Sr2TaO3N. Characterization of Sr2TaO3N in ambient air was challenging due to its moisture sensitivity. Thermal analysis demonstrated that this material was relatively stable up to approximately 1400 degrees C in comparison with SrTaO2N perovskite, especially under nitrogen. Sr2TaO3N could keep its structure in a sealed tube, and some amount of SrCO3 was observed in XRD after 10 days of exposure to 75% relative humidity under prior ambient conditions. A compact of this material had a relative density of 96% after sintering at 1400 degrees C under 0.2 MPa of nitrogen, even though a drastic loss of nitrogen was previously reported for a SrTaO2N perovskite under these same conditions. Postammonolysis of the Sr2TaO3N ceramics was not required prior to studying its dielectric behavior. This is in contrast to the SrTaO2N perovskite, which requires postammonolysis to recover its stoichiometric composition and electrical insulating properties. PMID- 30010332 TI - Synthesis, Crystal Structure, and Optical Gap of Two-Dimensional Halide Solid Solutions CsPb2(Cl1- xBr x)5. AB - Exploring new perovskite-related solid-state materials and the investigating composition-dependent structural and physical properties are highly important for advanced functional material development. Herein, we present the successful hydrothermal synthesis of tetragonal CsPb2Cl5 and the anion-exchange phase formation of CsPb2(Cl1- xBr x)5 ( x = 0-1) solid solutions. The CsPb2(Cl1- xBr x)5 crystal structures, which crystallize in the tetragonal system, space group I4/ mcm, with parameters similar to those of CsPb2Cl5, have been determined by Rietveld analysis. The optical band gap was obtained by UV-vis spectroscopy, and the band structure was further calculated by the full-potential method within the generalized gradient approximation. It was revealed that the band gap in CsPb2(Cl1- xBr x)5 solid solutions can be tuned over the range of 4.5-3.8 eV by anion substitution. PMID- 30010333 TI - Characterization of the Chemical Space of Known and Readily Obtainable Natural Products. AB - Natural products remain one of the most productive sources of chemical inspiration for the development of new drugs. The structures of more than 250 000 natural products are available from public databases. At least 10% of these compounds are readily obtainable for experimental testing from commercial vendors and public research institutions. While the physicochemical properties of known natural products have been thoroughly studied and compared to those of drugs and other types of small molecules, the information available on the content, coverage, and relevance of individual virtual and physical natural product libraries is clearly limited. The aim of this study was the development of a detailed understanding of the coverage of chemical space by known and readily obtainable natural products and by individual natural product databases. For this purpose, we compiled comprehensive data sets of known and readily obtainable natural products from 18 virtual databases (including the Dictionary of Natural Products), nine physical libraries, and the Protein Data Bank (PDB). We also developed and employed an algorithm ("SugarBuster") for the removal of sugars and sugar-like moieties, which are generally not in the focus of interest for drug discovery, from natural products. In addition, we devised a rule-based approach for the automated classification of natural products into natural product classes (alkaloids, steroids, flavonoids, etc.). Among the most important results of this study is the finding that the readily obtainable natural products are highly diverse and populate regions of chemical space that are of high relevance to drug discovery. In some cases, substantial differences in the coverage of natural product classes and chemical space by the individual databases are observed. More than 2000 natural products are identified for which at least one X-ray crystal structure of the compound in complex with a biomacromolecule is available from the PDB. PMID- 30010334 TI - Two-Step Synthesis of VO2 (M) with Tuned Crystallinity. AB - Highly crystallized monoclinic vanadium dioxide, VO2 (M), is successfully synthesized by a two-step thermal treatment: thermolysis of vanadyl ethylene glycolate (VEG) and postannealing of the poorly crystallized VO2 powder. In the first thermolysis step, the decomposition of VEG at 300 degrees C is investigated by X-ray diffraction and scanning electron microscopy (SEM). A poorly crystallized VO2 powder is obtained at a strict time of 3 min, and it is found that the residual carbon content in the powder played a critical role in the post crystallization of VO2 (M). After postannealing at 500 and 700 degrees C in an oxygen-free atmosphere, VO2 particles of various morphologies, of which the crystallite size increases with increasing temperature, are observed by SEM and transmission electron microscopy. The weight percent of crystalline VO2, calculated using the Fullprof program, increases from 44% to 79% and 100% after postannealing. The improved crystallinity leads to an improvement in metal insulator transition behaviors demonstrated by sharper and more intense differential scanning calorimetry peaks. Moreover, V2O3 and V2O5 with novel and particular microstructures are also successfully prepared with a similar two-step method using postannealing treatment under reductive or oxidizing atmospheres, respectively. PMID- 30010335 TI - Machine Learning Directed Search for Ultraincompressible, Superhard Materials. AB - In the pursuit of materials with exceptional mechanical properties, a machine learning model is developed to direct the synthetic efforts toward compounds with high hardness by predicting the elastic moduli as a proxy. This approach screens 118 287 compounds compiled in crystal structure databases for the materials with the highest bulk and shear moduli determined by support vector machine regression. Following these models, a ternary rhenium tungsten carbide and a quaternary molybdenum tungsten borocarbide are selected and synthesized at ambient pressure. High-pressure diamond anvil cell measurements corroborate the machine-learning prediction of the bulk modulus with less than 10% error, as well as confirm the ultraincompressible nature of both compounds. Subsequent Vickers microhardness measurements reveal that each compound also has an extremely high hardness exceeding the superhard threshold of 40 GPa at low loads (0.49 N). These results show the effectiveness of materials development through state-of-the-art machine-learning techniques by identifying functional inorganic materials. PMID- 30010336 TI - How Does a Heme Carbene Differ from Diatomic Ligated (NO, CO, and CN-) Analogues in the Axial Bond? AB - Compared to well studied diatomic ligands (NO, CN-, CO), the axial bonds of carbene hemes is much less known although its significance in biological chemistry. The unusually large quadrupole splitting (Delta EQ = +2.2 mm.s-1) and asymmetric parameter (eta = 0.9) of the five-coordinate heme carbene [Fe(TTP)(CCl2)], which is the largest among all known low spin ferrohemes, has driven investigations by means of Mossbauer effect Nuclear Resonance Vibrational Spectroscopy (NRVS). Three distinct measurements on one single crystal (two in plane and one out-of-plane) have demonstrated comprehensive vibrational structures including stretch (429) and bending modes (472 cm-1) of the axial Fe CCl2, and revealed iron vibrational anisotropy in three orthogonal directions for the first time. Frontier orbital analysis especially comparisons with diatomic analogues (NO, CN-, CO) suggest that CCl2, similar to NO, has led to strong but anisotropic pi bonding in a ligand-based "4C"-coordinate which induced the vibrational anisotropies and very large Mossbauer parameters. This is contrasted to CN- and CO complexes which possess a porphyrin-based "4N"-coordinate electronic and vibrational structures due to inherent on-axis linear ligation. PMID- 30010337 TI - Development and Validation of Molecular Overlays Derived from Three-Dimensional Hydrophobic Similarity with PharmScreen. AB - Molecular alignment is a standard procedure for three-dimensional (3D) similarity measurements and pharmacophore elucidation. This process is influenced by several factors, such as the physicochemical descriptors utilized to account for the molecular determinants of biological activity and the reference templates. Relying on the hypothesis that the maximal achievable binding affinity for a drug like molecule is largely due to desolvation, we explore a novel strategy for 3D molecular overlays that exploits the partitioning of molecular hydrophobicity into atomic contributions in conjunction with information about the distribution of hydrogen-bond (HB) donor/acceptor groups. A brief description of the method, as implemented in the software package PharmScreen, including the derivation of the fractional hydrophobic contributions within the quantum mechanical version of the Miertus-Scrocco-Tomasi (MST) continuum model, and the procedure utilized for the optimal superposition between molecules, is presented. The computational procedure is calibrated by using a data set of 402 molecules pertaining to 14 distinct targets taken from the literature and validated against the AstraZeneca test, which comprises 121 experimentally derived sets of molecular overlays. The results point out the suitability of the MST-based hydrophobic parameters for generating molecular overlays, as correct predictions were obtained for 94%, 79%, and 54% of the molecules classified into easy, moderate, and hard sets, respectively. Moreover, the results point out that this accuracy is attained at a much lower degree of identity between the templates used by hydrophobic/HB fields and electrostatic/steric ones. These findings support the usefulness of the hydrophobic/HB descriptors to generate complementary overlays that may be valuable to rationalize structure-activity relationships and for virtual screening campaigns. PMID- 30010338 TI - Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor gamma (RORgamma or RORc) Inhibitors: Hits and Misses. AB - The nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORgamma or RORc) is a key transcription factor for the production of pro inflammatory cytokines implicated in the pathogenesis of autoimmune diseases. Recently, small molecule inhibitors of RORc drew the enormous attention of the research community worldwide as a possible therapy for autoimmune diseases, mediated by the IL-17 cytokine. With the clinical proof-of-concept inferred from a small molecule inhibitor VTP-43742 for psoriasis and recent inflow of several RORc inhibitors into the clinic for therapeutic interventions in autoimmune diseases, this field continues to evolve. This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases. PMID- 30010340 TI - Diastereoselective alpha-Sulfenylation of N- tert-Butanesulfinyl Imidates. AB - A diastereoselective alpha-sulfenylation of chiral alpha-aryl/alkyl N- tert butanesulfinyl imidates has been developed. Suitable sulfur electrophiles can be used as sulfenylating reagents to intercept aza-enolates generated from imidate deprotonation, giving alpha-thiofunctionalized imidates in good yields with high diastereocontrol. This protocol for C-S bond formation can efficiently synthesize enantioenriched 1,2-sulfanyl amine derivatives such as sulconazole. PMID- 30010339 TI - Valuable Compound Extraction, Anaerobic Digestion, and Composting: A Leading Biorefinery Approach for Agricultural Wastes. AB - In a society where the environmental conscience is gaining attention, it is necessary to evaluate the potential valorization options for agricultural biomass to create a change in the perception of the waste agricultural biomass from waste to resource. In that sense, the biorefinery approach has been proposed as the roadway to increase profit of the agricultural sector and, at the same time, ensure environmental sustainability. The biorefinery approach integrates biomass conversion processes to produce fuels, power, and chemicals from biomass. The present review is focused on the extraction of value-added compounds, anaerobic digestion, and composting of agricultural waste as the biorefinery approach. This biorefinery approach is, nevertheless, seen as a less innovative configuration compared to other biorefinery configurations, such as bioethanol production or white biotechnology. However, any of these processes has been widely proposed as a single operation unit for agricultural waste valorization, and a thoughtful review on possible single or joint application has not been available in the literature up to now. The aim is to review the previous and current literature about the potential valorization of agricultural waste biomass, focusing on valuable compound extraction, anaerobic digestion, and composting of agricultural waste, whether they are not, partially, or fully integrated. PMID- 30010341 TI - Kleinhospitine E and Cycloartane Triterpenoids from Kleinhovia hospita. AB - A novel cycloartane triterpenoid alkaloid, kleinhospitine E (1), six new cycloartane triterpenoids (2-7), three known cycloartane triterpenoids (8-10), and taraxerone (11) were isolated from a methanol extract of Kleinhovia hospita. Their structures were elucidated by 1D- and 2D-NMR spectroscopy as well as HRMS analysis. The absolute configurations of all isolated compounds were determined from their ECD spectra by comparison with theoretical values. Kleinhospitine E (1) is the first cycloartane alkaloid possessing an unusual gamma-lactam with an oxopropylidene side chain. Compounds 2, 3, and 6 were assigned as cycloartane triterpenoids with a 9alpha,10alpha-cyclopropyl ring, which is found rarely among naturally occurring compounds, while 4 and 5 were established as isomers of compound 3 containing a 21,23-diacetal side chain. Biological evaluation revealed that compounds 4 and 9 exhibited more potent antiproliferative activities against a multidrug-resistant tumor cell line compared with its parent chemosensitive cell line. Furthermore, compound 6 exhibited submicromolar anti-HIV activity. PMID- 30010342 TI - Contact Line Pinning Is Not Required for Nanobubble Stability on Copolymer Brushes. AB - Whereas nanobubble stability on solid surfaces is thought to be based on local surface structure, in this work, we show that nanobubble stability on polymer brushes does not appear to require contact-line pinning. Glass surfaces were functionalized with copolymer brushes containing mixtures of hydrophobic and hydrophilic segments, exhibiting water contact angles ranging from 10 to 75 degrees . On unmodified glass, dissolution and redeposition of nanobubbles resulted in reformation in mostly the same locations, consistent with the contact line pinning hypothesis. However, on polymer brushes, the nucleation sites were random, and nanobubbles formed in new locations upon redeposition. Moreover, the presence of stable nanobubbles was correlated with global surface wettability, as opposed to local structure, when the surface exceeded a critical water contact angle of 50 or 60 degrees for polymers containing carboxyl or sulfobetaine groups, respectively, as hydrophilic side chains. The critical contact angles were insensitive to the identity of the hydrophobic segments. PMID- 30010343 TI - Existence of Two Fluorescence Bands in all- trans-Polyenes with Six and Seven Double Bonds. AB - From the analysis of UV/vis absorption, emission, and excitation of emission spectra of all- trans-alpha,omega-tetra- tert-butylpolyenes with six and seven double-bonds (3,14-di( tert-butyl)-2,2,15,15-tetramethyl-3,5,7,9,11,13 hexadecahexaene (ttbP6), and 3,16-di( tert-butyl)-2,2,17,17-tetramethyl 3,5,7,9,11,13,15-octadecaheptaene (ttbP7)) it is concluded that these hydrocarbons do not exhibit dual S1/S2 fluorescence, as could be inferred from the work of Christensen et al. [ J. Phys. Chem. A 2008 , 112 , 12629 - 12636 ]. The spectral data for ttbP6 and ttbP7 display a unique fluorescence from their S1 states. PMID- 30010344 TI - Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity. AB - Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC50 0.16-0.82 MUM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells. PMID- 30010345 TI - Temperature Resistant Binary SLES/Nonionic Surfactant Mixtures at the Air/Water Interface. AB - Surface compositions of adsorbed monolayers at the air/water interface, formed from binary surfactant mixtures in equilibrium, have been studied using neutron reflectivity at three discrete temperatures: 10, 25, and 40 degrees C. The binary compositions studied are sodium lauryl dodecyl ether sulfate (SLES EO3)/C12E n, where n = 6 and 8, at a fixed concentration of 2 mM with and without the addition of 0.1 M NaCl. Without NaCl, the nonionic surfactant dominates at the interface and nonideal mixing behavior is observed. This is modeled using the pseudophase approximation with a quadratic expansion of the free energy of mixing. The addition of 0.1 M NaCl screens the charge interaction between the surfactants and drives the surface composition of each system closer to that of the bulk composition. However, model fits to both the micelles and surface layers suggest that nonideal mixing is still taking place, although it is difficult to establish the extent of nonideality due to the limited data quality. The effect of temperature changes on the surface adsorption and composition of the surfactant mixtures is minimal and within error, with and without NaCl, but the critical micelle concentrations are significantly affected. This indicates the dominant influence of steric hindrances and surfactant charge interactions in determining interfacial behavior for these surfactants, relative to the temperature changes. The study also highlights the delicate effect of a relatively small change in the number of EO groups on mixing behavior. PMID- 30010347 TI - Cultural and community resources protect Latino migrant day laborers from discrimination-related distress. AB - OBJECTIVES: The purpose of this study is to test the relationship between discrimination and psychological distress in Latino migrant day laborers (LMDLs), including potential protective factors: access to cultural resources (e.g., festivals, people from one's country of origin), including community services perceived to be culturally competent, and contact with family in country of origin (e.g., phone/text, visits). Findings expand our understanding of discrimination-related psychological distress, in a particularly stigmatized population of Latinos, and how cultural and community resources may help mitigate discrimination-related distress. METHODS: We conducted a cross-sectional survey of 344 LMDLs in the San Francisco Bay Area from February to July 2014. Participants were 46.5% Mexican and 50.7% Central American, 91.9% undocumented, and 40.5 years of age on average (SD = 10.8). Mediation and moderation analyses tested whether protective factors would mitigate discrimination-related distress. RESULTS: Discrimination was related to depression, anxiety, and desesperacion, the latter a popular Latino idiom of psychological distress, and this relationship was mediated by access to cultural resources and use of culturally competent community services. CONCLUSIONS: Culturally competent community services, including cultural resources from country of origin, may help mitigate discrimination-related distress in LMDLs. However, such interventions are likely to have diminishing returns unless the structural vulnerability of LMDLs is addressed (e.g., expanding work authorization, sanctuary city ordinances). Implications for future research include developing multilevel measures of LMDL discrimination that include structural factors perceived as discriminatory (i.e., antiloitering city ordinances, immigration control). (PsycINFO Database Record PMID- 30010346 TI - Formation of Well-Defined Vesicles by Styrene Addition to a Nonionic Surfactant and Their Polymerization Leading to Viscous Hybrid Systems. AB - Self-assembled structures in aqueous solutions can be fixed by polymerization after adding hydrophobic monomers and can thereby be used as templates which allow to substantially alter the properties of these systems. In this work, we started from a self-assembled micellar system consisting of the nonionic surfactants tetradecyldimethylamine oxid and Pluronic L35 to which styrene was added as a polymerizable monomer. Interestingly, it was observed that styrene induces a transition from micelles to well-defined vesicles in a similar manner as a typical cosurfactant. The structural transition of the aggregates upon styrene addition as well as the structures formed after initiating a polymerization reaction were investigated by means of turbidity, dynamic and static light scattering, small-angle neutron scattering, and rheology measurements. Especially the scattering results confirmed the interesting effect of styrene on the mesoscopic structure and showed a structural evolution from rod like micelles for low styrene concentrations to vesicles at intermediate styrene amounts, and then finally the formation of microemulsion droplets for high styrene content. Their polymerization of the vesicles again leads to a shape change to wormlike, polymerized aggregates, whose presence then results in rather viscous systems. In contrast, the microemulsions with higher styrene content then are templated and retain their size after polymerization, thereby leading to nanolattices. PMID- 30010348 TI - Forward-facing predators attract attention in humans (Homo sapiens). AB - Even prey that successfully evade attack incur costs when responding to predators. These nonlethal costs can impact their reproductive success and survival. One strategy that prey can use to minimize these costs is to adjust their antipredator behavior based on the perceived level of risk. We tested whether humans adopt this strategy by presenting participants with photographic arrays of predators (lions) that varied in their level of risk. While their eye movements were recorded, the participants searched for a forward-facing predator (signifying potential predator interest; high-risk target) among an array of inattentive predators that were facing away (low-risk distractors) or searched for a predator that was facing away from them among an array of forward-facing predators. As a control, participants also searched through similar arrays that displayed a potential prey species (impalas) rather than predators. Participants detected forward-facing predators more quickly than predators facing away from them. Unexpectedly, they were also quicker at detecting forward-facing prey versus prey facing away from them, but slower to detect these forward-facing prey compared with forward-facing predators. They were slower to detect predators and prey facing away from them because they spent more time looking at the forward facing distractors and looked at more of those distractors. The results indicate that human attention is drawn toward dangerous predators with forward-facing orientations, and this could allow humans to quickly assess predator intentions. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30010349 TI - Development of self-esteem from age 4 to 94 years: A meta-analysis of longitudinal studies. AB - To investigate the normative trajectory of self-esteem across the life span, this meta-analysis synthesizes the available longitudinal data on mean-level change in self-esteem. The analyses were based on 331 independent samples, including data from 164,868 participants. As effect size measure, we used the standardized mean change d per year. The mean age associated with the effect sizes ranged from 4 to 94 years. Results showed that average levels of self-esteem increased from age 4 to 11 years (cumulative d = 0.34; cumulative ds are relative to age 4), remained stable from age 11 to 15, increased strongly until age 30 (cumulative d = 1.05), continued to increase until age 60 (cumulative d = 1.30), peaked at age 60 and remained constant until age 70, declined slightly until age 90 (cumulative d = 1.15), and declined more strongly until age 94 (cumulative d = 0.76). Moderator analyses were conducted for the full set of samples and for the subset of samples between ages 10 to 20 years. Although the measure of self-esteem accounted for differences in effect sizes, the moderator analyses suggested that the pattern of mean-level change held across gender, country, ethnicity, sample type, and birth cohort. The meta-analytic findings clarify previously unresolved issues about the nature and magnitude of self-esteem change in specific developmental periods (i.e., childhood, adolescence, and old age) and draw a much more precise picture of the life span trajectory of self-esteem. (PsycINFO Database Record PMID- 30010351 TI - Oregon recreational marijuana legalization: Changes in undergraduates' marijuana use rates from 2008 to 2016. AB - There have been few studies of marijuana use before and after recreational marijuana legalization (RML) in affected states. We tested whether marijuana use rates increased more among college students in Oregon than in non-RML states following Oregon RML in July 2015. Repeated cross-sectional National College Health Assessment-II surveys were completed by random samples of students within participating colleges from 2008 to 2016. Data were from 4-year institutions that participated both before and after Oregon RML. Undergraduates (ages 18-26 years) from 2 institutions in Oregon (n = 7,412) and 123 institutions (n = 274,340) in non-RML U.S. states self-reported use of marijuana, tobacco, alcohol, and other drugs in the past 30 days. Mixed-effects regressions accounted for clustering of participants within institutions and controlled for individual-, context-, and institution-level factors as well as secular changes in substance use rates from 2008 to 2016. Following RML, Oregon students (compared to non-RML-state students) showed relative increases in rates of marijuana use (odds ratio [OR] = 1.29, 95% confidence interval [CI: 1.13, 1.48], p = .0002, and decreases in tobacco use rates (OR = .71, 95% CI [.60, .85], p < .0001). Changes in marijuana use after RML did not differ significantly for participants under and over age 21 years. Some study limitations would be addressed with higher survey response rates, inclusion of other Oregon institutions, and controls for marijuana and other substance policies. Still, findings are consistent with an effect of RML on rates of marijuana use among young adult college students, which may have important public health implications. (PsycINFO Database Record PMID- 30010352 TI - Contemporary applications of moderation analysis in counseling psychology. AB - Moderation analyses represent a statistical technique that can be particularly useful for counseling psychology researchers. This technique allows researchers to assess whether a given relationship depends on a third, moderating variable. The present article provides a brief overview of moderation, followed by 3 broad areas relevant for research: designing a study, analyzing the data, and interpreting results. Particular focus is applied to the topic of latent variable moderation, including an applied example with real data. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30010350 TI - The effect of laboratory manipulations of negative affect on alcohol craving and use: A meta-analysis. AB - Scientific and lay theories propose that negative affect plays a causal role in problematic alcohol use. Despite this common belief, supporting experimental evidence has been mixed. Thus, the goals of this study were to (a) meta analytically quantify the degree to which experimentally manipulated negative affect influenced alcohol use and craving in the laboratory, (b) examine whether the size of this effect depended on key manipulation characteristics (i.e., self relevance of the stressor, timing of the end of the stressor, and strength of negative affect induction) or sample characteristics (i.e., substance use history). Across 41 studies (N = 2,403), we found small-to-medium effects for more use (dav = .31, 95% confidence interval; CI [.11, .50]) and craving (dav = .39, 95% CI [.04, .74]) following a negative affect manipulation than a control manipulation. We also found a significant increase in craving from pre- to postaffect induction (dav = .36, 95% CI [.14, .58]). This suggests the mixed results from the prior literature were likely because of statistically underpowered studies. The moderator hypotheses received weak support, with few significant results in the predicted direction. Our meta-analysis provides clarity about a previously inconclusive set of results and highlights the need for more ecologically valid manipulations of affect in future work. (PsycINFO Database Record PMID- 30010354 TI - Infants' evaluation of prosocial and antisocial agents: A meta-analysis. AB - Over the past decade, numerous studies have reported that infants prefer prosocial agents (those who provide help, comfort, or fairness in distributive actions) to antisocial agents (those who harm others or distribute goods unfairly). We meta-analyzed the results of published and unpublished studies on infants aged 4-32 months and estimated that approximately two infants out of three, when given a choice between a prosocial and an antisocial agent, choose the former. This preference was not significantly affected by age or other factors, such as the type of dependent variable (selective reaching or helping) or the modality of stimulus presentation (cartoons or real events). Effect size was affected by the type of familiarization events: giving/taking actions increased its magnitude compared with helping/hindering actions. There was evidence of a publication bias, suggesting that the effect size in published studies is likely to be inflated. Also, the distribution of children who chose the prosocial agent in experiments with N = 16 suggested a file-drawer problem. (PsycINFO Database Record PMID- 30010355 TI - Text message exchanges between older adults with serious mental illness and older certified peer specialists in a smartphone-supported self-management intervention. AB - OBJECTIVE: To identify the strategies peer specialists use to provide illness self-management support for older adults with serious mental illness (SMI) through text messaging. METHOD: Transcripts of text message exchanges between 8 older adult participants with SMI who completed the PeerTECH intervention and 3 older adult certified peer specialists who delivered the 12-week program were analyzed. Text message analyses explored themes relevant to peer support and health behavior change. Quantitative data comprised frequency of text messages by either the peer or consumer. RESULTS: Consumers (N = 8) had a mean age of 68.8 years (SD = 4.9) and were mainly women (88%), White (100%), and married (75%). Certified peer specialists (N = 3) were all 55 or older; 100% were female, 66% identified as White, and 33% identified as African American. Overall, peers sent 215 text messages whereas consumers sent 141 text messages. In the peer specialist-consumer text message exchanges, we identified 4 themes on different aspects of illness self-management, including health behavior change, self management therapeutic techniques, engagement in health technology, and peer support. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This exploratory qualitative study offers preliminary support that peers are able to use text messages to support the delivery of a peer-delivered home-based medical and psychiatric self management intervention. Certified peer specialists can potentially provide a range of illness self-management support to older adults with SMI via text messaging. These findings will inform the development of standardized peer text messaging services to augment evidence-based illness self-management interventions for older adults with SMI. (PsycINFO Database Record PMID- 30010356 TI - Understanding the lived experience of cognitive remediation in schizophrenia: A qualitative comparison with an active control. AB - OBJECTIVE: Cognitive remediation (CR) is a promising method of improving cognitive functioning in people with schizophrenia. Nevertheless, the lived experience of participation, and whether this differs from computer game (CG) playing control conditions, remains poorly understood. This study aimed to qualitatively compare the experience of participating in these 2 interventions. METHOD: Forty-two outpatients with schizophrenia or schizoaffective disorder completed a qualitative survey with 7 open-ended questions after completing 10 weeks of CR (n = 22) or CG (n = 20). An iterative and inductive thematic analysis was used to identify and tally reoccurring codes and facilitate their organization into overarching themes. RESULTS: Four high-order themes summarized the data: (a) Perceived benefits; (b) Experience of group; (c) Operation of group; and (d) Suggestions for improvement. Participation was described as enjoyable with similar levels of social and intrinsic benefits reported by study completers in both CR and CG groups. CR completers were more likely to report improvements in memory and everyday functioning as well as greater opportunities to acquire new cognitive skills and experience personal and cognitive challenge. CR completers also described the pursuit of shared goals with other peers. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: CR and CG share qualitative benefits in schizophrenia. CR may, however, offer a supportive environment where participants can encounter and surmount personal challenges, learn new abilities that may be functionally relevant and experience team-based success. These benefits may be unique to CR and contribute to increases in self-efficacy, which could bridge the gap between capacity and real world functioning in schizophrenia. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30010357 TI - Comorbid language and behavior problems: Development, frameworks, and intervention. AB - Children and youth rely on language skills to navigate environments, many of which are multifaceted and complex. In a society in which successful interactions involve language and prosocial behavior, children who struggle with language or classroom behavior are predisposed to failure. The present perspectives article (a) summarizes the comorbidity of and relations between language skills and behavior problems, (b) provides examples of recent descriptive and experimental studies on these relations, (c) overviews current theoretical frameworks for situating empirical research in this area, and (d) recommends directions for future research. (PsycINFO Database Record PMID- 30010353 TI - Meditation smartphone application effects on prehypertensive adults' blood pressure: Dose-response feasibility trial. AB - OBJECTIVE: Essential hypertension (EH) is the most common chronic disease in the United States and a major cause of morbidity and mortality. Lifestyle interventions (e.g., diet, exercise, stress management) to reduce blood pressure (BP) are often complex with varying effectiveness. Breathing awareness meditation (BAM) is a stress management strategy with encouraging effects on BP, though widespread dissemination is hampered by the lack of an easy-to-use methodology to train and monitor BAM practices. A smartphone application (Tension Tamer [TT]) that implements BAM and tracks adherence has shown promise in addressing these gaps. This 6-month dose-response feasibility trial evaluated effects of the app on BP to further optimize BAM user guidelines. METHODS: Sixty-four adults with prehypertension were randomized to complete TT-guided BAM sessions for 5-, 10-, or 15-min intervals twice daily over 6 months. Continuous heart rate readings derived from the phone's video camera via reflective photoplethysmography were used as feedback and as an index of time-stamped adherence. Outcomes (resting BP, HR) were collected at baseline, 1-, 3-, and 6-months. RESULTS: Mixed modeling results showed a significant time effect for systolic BP (SBP) with a dose response effect at Months 3 and 6. Adherence declined over time and was lowest in the 15-min dose condition, though SBP reductions were maintained. Generally, adherence was negatively associated with dose as the study progressed. CONCLUSIONS: Smartphone-implemented BAM appears to reduce SBP and can be a low cost method to reach large populations. (PsycINFO Database Record PMID- 30010358 TI - Literature reading modulates pronoun resolution in counterfactual world: Evidence from event-related potentials. AB - Counterfactuals are contrary-to-fact statements that are widely used in daily life to convey thoughts about what might have been. Different from fact-based processing, successful counterfactual comprehension requires readers to keep in mind both suppositional information and presupposed fact. Using event-related potentials, the present study investigates how the process of establishing a coreferential relation (i.e., pronoun resolution) is influenced by counterfactual context, and whether it will be modulated by individual difference in literature reading. We compared the P600 (a positive-going deflection, which often reaches its peak around 600 milliseconds after presentation of the stimulus) effects elicited by gender-mismatched pronouns in three conditionals (causal vs. hypothetical vs. counterfactual) between two groups (literature exposure high- vs. low-level group). Results show that for low-level group, incongruent pronouns elicited robust P600 effects across all three conditionals, while for high-level group, the P600 effects were pronounced only in causal and hypothetical conditionals, but not in counterfactual conditionals. These findings suggest (a) different from causal and hypothetical conditionals, the dual meaning and pragmatic implications of counterfactuals may prompt people to go beyond here and now to elaborate their mental models and entertain alternative interpretations, and (b) substantial literature exposure would further enhance pragmatic inference of counterfactual context, leading high-level readers more inclined to elaborate discourse with possible alternative inferences, while leaving low-level readers habitually resort to more straightforward coreferential interpretation. (PsycINFO Database Record PMID- 30010359 TI - Statistics learned are statistics forgotten: Children's retention and retrieval of cross-situational word learning. AB - Children are able to resolve the referential ambiguity of learning new words by tracking co-occurrence probabilities across moments in time, a behavior termed cross-situational word learning (CSWL). Although we know that children can use co occurrence data to map words to objects, the literature has a striking limitation: research has focused on encoding of language and, consequently, children's CSWL has only been assessed at an immediate test. The current research addressed this gap in the literature by examining whether children can retain and retrieve learned words after a retention interval, and whether children's age and individual cognitive abilities contribute to their CSWL performance. The results revealed that children were able to retain and retrieve co-occurrence statistics, but only reliably so at the end of early childhood. Moreover, children's visual recognition memory abilities and the timing of learning events were the two key factors that contributed to children's performance. These findings have implications for theories and computational models of CSWL, and suggest that more research is needed to understand the processes that support CSWL after encoding. (PsycINFO Database Record PMID- 30010360 TI - The compatibility of clinical child mental health treatment and evidence-based treatment protocols. AB - Few children with mental health problems receive evidence-based psychotherapy, partly because of unsuccessful dissemination of evidence-based treatments (EBTs). Previous research suggests that the length and structure of EBT protocols for anxiety disorders may impede their adoption in community practice. To examine the potential discrepancy between EBT protocols and clinical practice across disorders, we examined patient diagnoses and average length of treatment for childhood psychiatric disorders in a regional medical center where child and adolescent patients from the community have access to mental health care. The findings suggest that although a large portion of youth seeking mental health care presented with symptoms consistent with those addressed by common evidence based psychotherapy protocols, less than half of these patients ever met with a therapist and less than 10% of those attended a sufficient number of sessions to complete a full treatment protocol. These results underscore the need to develop brief and flexible EBT protocols, such as modular treatments, that introduce essential elements early in the course of treatment. (PsycINFO Database Record PMID- 30010361 TI - Housing trajectories of teen mothers and their families over 28 years. AB - Housing has received little attention in the research on teen mothers. A qualitative longitudinal study presented a unique opportunity to examine how teen mothers house their families over time. The study began in 1988 and has followed teen mothers and family members for 7 waves over 28 years. The 7th wave began in 2016. The specific aims of this substudy were to describe the housing trajectories of teen mothers over 28 years and to explore how their housing trajectories were shaped by family resources, housing programs, and discrimination. Data from 9 families were analyzed using interpretive phenomenology. Housing instability was pervasive for Black mothers who were disadvantaged as children. Their stories included many moves, doubling up, sending children to live with others, depression, unreliable partners, and racism. Housing instability was a source of toxic stress, interrupted personal and family goals, undermined family routines, and reflected a legacy of discriminatory housing policies. In contrast, White advantaged mothers were stably housed as children and adults, which reflected longstanding family resources, stable marriages, husbands' steady employment, and tax deductions for homeownership. These stark differences in housing trajectories reflect and reproduce multigenerational social and health inequities. (PsycINFO Database Record PMID- 30010362 TI - Correlates of depression in caregivers of Ultra-Orthodox frail older adults. AB - Depression is the most frequent negative health outcome among informal caregivers. The aims of the current study were (a) to assess the level of depression, (b) to explore associations among care recipients' characteristics, caregivers' characteristics, situational factors, and depression among Ultra Orthodox Jewish (UOJ) caregivers. A total of 112 (44 men and 68 women) UOJ primary caregivers of frail older adults were interviewed face-to-face in their homes, using valid and reliable measures. Participants reported a notable depressive symptomatology. Three variables emerged as significant predictors of caregiver depression: higher external control (chance), being a spouse, and lower levels of social support. External locus of control, being a spouse, and social support were found to be highly important factors for explaining depression among UOJ caregivers. Resources should be allocated to target spousal caregivers with lower levels of social support and a greater sense of external locus of control in order to alleviate their depressive symptomatology. (PsycINFO Database Record PMID- 30010363 TI - Problem solving skills and deficits among homeless veterans with serious mental illness. AB - Few interventions train homeless consumers in housing-related independent living skills. To inform the development of such interventions for the Department of Veterans Affairs' Supported Housing consumers with serious mental illness, we examined these consumers' problem-solving skills and deficits. We performed semistructured interviews and cognitive tests with 20 consumers who retained housing for >=1 year ("stayers") and 20 consumers who lost housing in <1 year ("exiters"). Salient types of problems were identified in the qualitative data; we categorized problem-solving approaches by complexity level and identified differences in problem-solving complexity by consumers' housing outcomes. Instrumental (e.g., money management), interpersonal, and health-related problems were prominent in consumers' narratives. Cognition was poor among stayers and exiters. Problem-solving approaches were highly relevant to day-to-day functioning in supported housing. There was a trend toward greater problem solving complexity in stayers versus exiters. These data explore potential challenges faced in supported housing and help inform the development of a Veterans Affairs-based housing-focused skills training intervention. (PsycINFO Database Record PMID- 30010364 TI - Therapeutic alliance, cultural competence and minority status in premature termination of psychotherapy. AB - Premature termination is a pervasive barrier to effective implementation of outpatient psychotherapy that frequently results in poorer outcomes for clients as well as poor resource allocation for clients, therapists, and society. Despite its high prevalence and cost, premature termination remains poorly understood, especially from the clients' perspective. The current study addressed some gaps in the literature using a national online survey design that permitted investigation of a broad range of potential predictors of premature termination. Participants were 278 respondents from Amazon.com's Mechanical Turk who completed an online survey about their treatment history, their most recent outpatient therapy experience and therapist, termination status, reasons for terminating prematurely (if applicable), treatment satisfaction, and demographics. Results indicated that being a woman, identifying as a sexual minority, and having a therapist low in perceived multicultural competence were associated with increased risk of premature termination. However, the best predictors of premature termination were a weak therapeutic alliance and symptoms of depression. These results support previous research that shows both client and therapist variables contribute to premature termination. Potential interventions that can be implemented by providers or agencies to reduce premature termination are discussed, along with limitations of the study and recommendations for future research. (PsycINFO Database Record PMID- 30010365 TI - Psychosis in public mental health: Provider perspectives on clinical relationships and barriers to the improvement of services. AB - Whereas a growing literature has sought to understand challenges involved in the dissemination and implementation of specific evidence-based practices (EBP), few studies have centered on the perspectives of front-line community providers regarding best practices, clinical ideals and barriers to quality improvement for clients with psychosis. The goal of this project was to lay a foundation for future work aimed at improving the overall quality and impact of the multifaceted services typically provided to adults with psychosis served by the public mental health system. The findings reported here draw on a series of in-depth interviews and focus groups with 34 clinicians based at multiple inner-city community mental health sites. The project was participatory and service user co-led. Analyses focus on participant's perspectives concerning optimal services for clients with psychosis and perceived barriers to improving services. Providers strongly underscored the centrality of relationship quality versus mastery of specialized techniques and of deeper experiential engagement with the subjective meaning of the experience of psychosis. Asked about barriers to quality improvement, they described both macrolevel social forces, including chronic underfunding and overreliance on manualized approaches to distress, as well as cross-cutting clinical challenges not typically captured in the literature on more specific, targeted interventions. Our discussion focuses on the implications of these findings with respect to research and quality improvement and concludes with a call to increase investment and attention to the perspectives of front-line providers and the issue of workforce and organizational capacity vis-a-vis psychosis. (PsycINFO Database Record PMID- 30010366 TI - Frontoparietal processing of stress-relevant information differs in individuals with a negative cognitive style. AB - Prior research indicates that cognitive vulnerabilities can render individuals more susceptible to psychopathology in the wake of stressful events. However, little work has directly targeted the neural mechanisms involved. In this study, we examined functional magnetic resonance imaging (fMRI) activity as a function of negative cognitive style, a well-studied cognitive vulnerability for depression. We adapted a robust paradigm in which undergraduate students completed fMRI testing after a known ecologically valid stressor (a midterm exam). Negative cognitive style correlated with brain activity in response to both negative and exam-related information in dorsolateral prefrontal cortex and/or angular gyrus, both regions involved in abstract, self-referential thought. There were commonalities and differences in patterns of activity, suggesting that these individuals may process domain-general and domain-specific negative information in different ways but drawing upon a common frontoparietal network. This study, thus, identifies a potential brain network associated with negative cognitive style, and enhances our understanding of neural mechanisms of cognitive vulnerability to psychopathology. (PsycINFO Database Record PMID- 30010367 TI - Narcissist or narcissistic? Evaluation of the latent structure of narcissistic personality disorder. AB - We investigated the latent structure of narcissistic personality disorder by comparing dimensional, hybrid, and categorical latent variable models, using confirmatory factor analysis (CFA), nonparametric and semiparametric factor analysis, and latent class analysis, respectively. We first explored these models in a clinical sample and then preregistered replication analyses in 4 additional data sets (with national, undergraduate, community, and mixed community/clinical samples) to test whether the best-fitting model would generalize across different data sets with different sample compositions. A 1-factor CFA outperformed categorical models in fit and reliability, suggesting the criteria do not serve to distinguish a narcissist class or subtypes; rather, a narcissistic dimension underlies the narcissistic personality disorder construct. The CFA also outperformed hybrid models, indicating that people fall within the same continuous distribution, rather than composing homogenous groups of relative severity (nonparametric factor analysis) or pulling apart into mixtures of discrete distributions (semiparametric factor analysis) along that spectrum. (PsycINFO Database Record PMID- 30010368 TI - The bias toward intentionality in schizophrenia: Automaticity, context, and relationships to symptoms and functioning. AB - Previous research on attributions in schizophrenia has focused on whether individuals make hostile, intentional attributions for ambiguous negative events. It is unclear, however, whether individuals with schizophrenia differ from controls in their general judgments of intentionality judgments in nonconflict and emotionally neutral situations. Research in social psychology suggests that nonclinical individuals present with an automatic bias to see intentionality and that this bias is regulated by the operation of controlled processes. The present study examined whether this general intentionality bias distinguishes individuals with schizophrenia (n = 213) from nonpatient controls (n = 151). Indeed, individuals with schizophrenia were more likely to attribute intentional motives to others' actions relative to controls. This intentionality bias was related to hostility, role functioning, and independent living skills. These findings may provide one domain to examine in future approaches to social cognition in schizophrenia. (PsycINFO Database Record PMID- 30010370 TI - Rapid timing of musical aesthetic judgments. AB - In recent years, psychological models of perception have undergone reevaluation due to a broadening of focus toward understanding not only how observers perceive stimuli but also how they subjectively evaluate stimuli. Here, we investigated the time course of such aesthetic evaluations using a gating paradigm. In a series of experiments, participants heard excerpts of classical, jazz, and electronica music. Excerpts were of different durations (250 ms, 500 ms, 750 ms, 1,000 ms, 2,000 ms, 10,000 ms) or note values (eighth note, quarter note, half note, dotted-half note, whole note, and entire 10,000 ms excerpt). After each excerpt, participants rated how much they liked the excerpt on a 9-point Likert scale. In Experiment 1, listeners made accurate aesthetic judgments within 750 ms for classical and jazz pieces, while electronic pieces were judged within 500 ms. When translated into note values (Experiment 2), electronica and jazz clips were judged more quickly than classical. In Experiment 3, we manipulated the familiarity of the musical excerpts. Unfamiliar clips were judged more quickly (500 ms) than familiar clips (750 ms), but there was overall higher accuracy for familiar pieces. Finally, we investigated listeners' aesthetic judgments continuously over the time course of more naturalistic (60 s) excerpts: Within 3 s, listeners' judgments differed between most- and least-liked pieces. We suggest that such rapid aesthetic judgments represent initial gut-level decisions that are made quickly, but that even these initial judgments are influenced by characteristics such as genre and familiarity. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30010369 TI - Testing formal predictions of neuroscientific theories of ADHD with a cognitive model-based approach. AB - Neuroscientific theories of attention-deficit/hyperactivity disorder (ADHD) alternately posit that cognitive aberrations in the disorder are due to acute attentional lapses, slowed neural processing, or reduced signal-to-noise ratios. However, they make similar predictions about behavioral summary statistics (response times [RTs] and accuracy), hindering the field's ability to produce strong and specific tests of these theories. The current study uses the linear ballistic accumulator (LBA; Brown & Heathcote, 2008), a mathematical model of choice RT tasks, to distinguish between competing theory predictions. Children with ADHD (n = 80) and age-matched controls (n = 32) completed a numerosity discrimination paradigm at 2 levels of difficulty, and RT data were fit to the LBA model to test theoretical predictions. Individuals with ADHD displayed slowed processing of evidence for correct responses (signal) relative to their peers but comparable processing of evidence for error responses (noise) and between-trial variability in processing (performance lapses). The findings are inconsistent with accounts that posit an increased incidence of attentional lapses in the disorder and provide partial support for those that posit slowed neural processing and lower signal-to-noise ratios. Results also highlight the utility of well-developed cognitive models for distinguishing between the predictions of etiological theories of psychopathology. (PsycINFO Database Record PMID- 30010371 TI - Children use polysemy to structure new word meanings. AB - It is well-known that children rapidly learn words, following a range of heuristics. What is less well appreciated is that-because most words are polysemous and have multiple meanings (e.g., "glass" can label a material and drinking vessel)-children will often be learning a new meaning for a known word, rather than an entirely new word. Across 4 experiments we show that children flexibly adapt a well-known heuristic-the shape bias-when learning polysemous words. Consistent with previous studies, we find that children and adults preferentially extend a new object label to other objects of the same shape. But we also find that when a new word for an object ("a gup") has previously been used to label the material composing that object ("some gup"), children and adults override the shape bias, and are more likely to extend the object label by material (Experiments 1 and 3). Further, we find that, just as an older meaning of a polysemous word constrains interpretations of a new word meaning, encountering a new word meaning leads learners to update their interpretations of an older meaning (Experiment 2). Finally, we find that these effects only arise when learners can perceive that a word's meanings are related, not when they are arbitrarily paired (Experiment 4). Together, these findings show that children can exploit cues from polysemy to infer how new word meanings should be extended, suggesting that polysemy may facilitate word learning and invite children to construe categories in new ways. (PsycINFO Database Record PMID- 30010372 TI - Teleface: Serial reproduction of faces reveals a whiteward bias in race memory. AB - How is race encoded into memory when viewing faces? Here we demonstrate a novel systematic bias in which our memories of faces converge on certain prioritized regions in our underlying "face space," as they relate to perceived race. This convergence was made especially salient using a new visual variant of the method of serial reproduction: "TeleFace." A single face was briefly presented, with its race selected from a smooth continuum between White and Black (matched for mean luminance). The observer then reproduced that face, using a slider to morph a test face along this continuum. Their response was then used as the face initially presented to the next observer, and so on down the line in each reproduction chain. White observers' chains consistently and steadily converged onto faces significantly Whiter than they had initially encountered-Whiter than both the original face in the chain and the continuum's midpoint-regardless of where chains began. Indeed, even chains beginning near the Black end of the continuum inevitably ended up well into White space. Very different patterns resulted when the same method was applied to other arbitrary face stimuli. These results highlight a systematic bias in memory for race in White observers, perhaps contributing to the more general notion in social cognition research of a 'White default.' (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30010373 TI - Investigating masked priming along the "vision-for-perception" and "vision-for action" dimensions of unconscious processing. AB - The study of nonconscious priming is rooted in a long research tradition in experimental psychology and plays an important role for a range of topics, including visual recognition, emotion, decision making, and memory. Prime stimuli can be transiently suppressed from awareness by using a variety of psychophysical paradigms. The aim is to understand which stimulus features can be processed nonconsciously and influence behavior toward subsequently presented probe stimuli. Here, we tested the notion that continuous flash suppression (CFS), a relatively new method of interocular suppression, selectively disrupts stimulus identification mediated by the ventral "vision-for-perception" pathway, while preserving action-relevant stimulus features processed by the dorsal "vision-for action" pathway. Given the far-reaching implications of this notion for the influential two visual systems hypothesis, and visual cognition in general, we investigated its empirical basis in a series of seven masked priming experiments using CFS. We did not find evidence for nonconscious priming of object categorization by action-relevant features. Based on these results, we recommend skepticism about the notion that the processing of action-relevant features under CFS is selectively preserved in the "vision-for-action" pathway. Second, we conclude that CFS experiments are less informative than approaches using visible stimuli, when the aim is to gather data in relation to the two visual systems hypothesis. Third, we propose that future nonconscious priming studies should carefully consider the position of suppression paradigms within a functional hierarchy of unconscious processing, thus constraining hypothesis generation to effects that are plausible given the employed methodology. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30010374 TI - All tears are crocodile tears: Impaired perception of emotion authenticity in psychopathic traits. AB - In everyday life, other peoples' distress is sometimes genuine (e.g., real sadness) and sometimes pretended (e.g., feigned sadness aimed at manipulating others). Here, we present the first study of how psychopathic traits affect responses to genuine versus posed distress. Using facial expression stimuli and testing individual differences across the general population (N = 140), we focus on the affective features of psychopathy (e.g., callousness, poor empathy, shallow affect). Results show that although individuals low on affective psychopathy report greater arousal and intent to help toward faces displaying genuine relative to posed distress, these differences weakened or disappeared with higher levels of affective psychopathy. Strikingly, a key theoretical prediction-that arousal should mediate the association between affective psychopathy and intent to help-was supported only for genuine distress and not for posed distress. A further novel finding was of reduced ability to discriminate the authenticity of distress expressions with higher affective psychopathy, which, in addition to and independently of arousal, also mediated the association between affective psychopathy and reduced prosociality. All effects were specific to distress emotions (did not extend to happiness, anger, or disgust), and to affective psychopathy (did not extend to Factor 2 psychopathy, disinhibition, or boldness). Overall, our findings are highly consistent with Blair's theorizing that atypical processing of distress emotions plays a key etiological role in the affective aspects of psychopathy. We go beyond these ideas to add novel evidence that unwillingness to help others is also associated with a failure to fully appreciate the authenticity of their distress. (PsycINFO Database Record PMID- 30010375 TI - Illuminating ipsative change in personality disorder and normal personality: A multimethod examination from a prospective longitudinal perspective. AB - Research suggests that both personality disorder (PD) and normal personality change as systems of variables (e.g., the general factor of PD), rather than as individual variables (e.g., neuroticism). Consequently, understanding PD and normal personality as multidimensional systems may yield additional insights over traditional single-variable approaches. Normal personality change has been attributed to increase across adaptive traits (i.e., the maturity principle), suggesting that shifts in the overall magnitude of construct expression plays a role in systemic change. We examined the extent to which total ipsative, system level change was accounted for by shifts in the overall level of constructs (i.e., severity/maturity) as well as shifts in the configuration of PD and normal personality (i.e., style) across self-report and structured interview. Results demonstrated that overall change in PD and normal personality measured via self report reflected both stylistic and severity change, whereas structured interview of PD primarily reflected shifts in profile severity. (PsycINFO Database Record PMID- 30010376 TI - Attentional biases and trauma status: Do psychotic-like experiences matter? AB - OBJECTIVE: In a large undergraduate sample, we explored whether attentional biases were similar between individuals reporting positive psychotic-like experiences (PLEs) with a history of traumatic life events (TLEs) compared with individuals with a TLE history alone. METHOD: Participants completed the Emotional Stroop Task, and self-report questionnaires of TLEs and PLEs. RESULTS: Although reaction time (RT) to physical, sexual, emotional, and overall trauma words was associated with TLEs, only RT to physical abuse and overall trauma words remained significantly associated with TLE status after controlling for age, race, and neutral word RT. Contrary to our hypotheses, PLEs were not associated with RT to TLE words and there were no significant interactions between TLE history and PLEs on RT to TLE-salient stimuli. CONCLUSION: Findings suggest that psychosis risk alone does not appear to exacerbate attentional biases and that TLE history may exert similar influence on attention regardless of psychosis risk. In conclusion, phenotypes associated with TLEs may be similar in populations potentially at risk for psychosis. (PsycINFO Database Record PMID- 30010377 TI - The Disorganized Response Scale: Construct validity of a potential self-report measure of disorganized attachment. AB - OBJECTIVE: Based on the paucity of self-report measures of disorganized attachment (DA), we developed and tested a scale examining adults' self-reported disorganized verbalizations, cognitions, and behaviors when discussing their childhoods. METHOD: The Disorganized Response Scale (DRS) was created and administered to 640 university students, and its associations with variables known to covary with DA, such as childhood maltreatment, insecure attachment, and psychological symptoms, were examined. RESULTS: Factor analysis of DRS items revealed a single 15-item dimension that reflected participants' self-reported disorganized responses when discussing their childhoods. Structural equation modeling indicated a good fit to a model in which fearful caretaking and childhood abuse and neglect were associated with the DRS. In turn, the DRS, along with anxious and avoidant attachment, was independently related to symptoms and partially mediated the relationship between child maltreatment and symptomatology. Hierarchical multiple regression indicated that the DRS accounted for significant additional variance in posttraumatic stress, externalization, somatization, and, especially, dissociation, even after demographics and both anxious and avoidant attachment were taken into account. CONCLUSIONS: Analyses support the construct validity of the DRS as a measure of disorganized attachment related responses in adults. Further research is indicated to replicate these findings and to evaluate their convergence with interview measures of DA. (PsycINFO Database Record PMID- 30010378 TI - Women's self-perceptions in the aftermath of trauma: The role of trauma centrality and trauma-type. AB - OBJECTIVE: Traumatic events tend to play a major role in the way we perceive ourselves. Whereas the links between posttraumatic stress disorder (PTSD) and self-perceptions are well examined, less is known regarding other factors that may be involved in the erosion of self-perceptions. We sought to examine the contribution of trauma-centrality and trauma-type to the erosion of self perceptions following trauma. Our hypotheses were (a) trauma-centrality is significantly related to impairments in self-perceptions, (b) sexual assault (SA) is related to greater erosion in self-perceptions compared with motor vehicle accident (MVA) and to unexpected death (bereavement), and (c) the effects of trauma-centrality and trauma-type on self-perceptions remain significant when statistically controlling for levels of PTSD symptoms. METHOD: Adult American women (N = 108: SA = 48, MVA = 38, bereavement = 22) were recruited via online labor market and completed self-report measures of trauma history, PTSD symptoms, trauma-centrality, and several aspects of self-perceptions. RESULTS: PTSD symptoms, trauma-centrality, and trauma-type were each found to contribute to the prediction of certain aspects of self-perceptions. Specifically, trauma centrality was related to negative posttraumatic cognitions above and beyond the effects of PTSD symptoms. In addition, SA was related to greater impairments in global and domain-specific self-perceptions compared with MVA and bereavement. CONCLUSION: Our findings highlight the roles of trauma-centrality and trauma-type in the erosion of self-perceptions following trauma. Our data emphasize the importance of considering the multiple factors influencing self-perceptions and of adopting a multifaceted conceptualization of the self in trauma-related research and clinical practice. (PsycINFO Database Record PMID- 30010379 TI - Differential relationships of guilt and shame on posttraumatic stress disorder among veterans. AB - OBJECTIVE: Despite important conceptual differences between shame and guilt, literature distinguishing these emotions in relation to posttrauma functioning for veterans has been largely theoretical. This is the first study to concurrently examine trauma-related guilt and internalized shame in relation to PTSD severity as the dependent variable. Our primary aim was to examine guilt and shame on PTSD symptom severity within the same model. A secondary aim was to evaluate whether trauma-related guilt can occur independent of shame. METHOD: Participants were 144 veterans seeking PTSD treatment. Regression analysis was used for our primary aim. Chi-square was used for our secondary aim to examine the percentage of participants categorized one standard deviation above (high) and below (low) the mean for shame and guilt. RESULTS: Entered together, internalized shame (beta = .44, p < .001) and guilt-related distress (beta = .32, p < .001) were related to PTSD severity. Guilt cognitions and global guilt were unrelated to PTSD. Analyses showed significant differences in participants categorized as low/high shame and low/high global guilt (chi2 = 14.22, p < .001), guilt-related distress (chi2 = 15.09, p < .001), and guilt cognitions (chi2 = 13.16, p < .001). Across guilt subscales, "shame-free" trauma-related guilt did not exist (0%). Conclusions Internalized shame and guilt distress were both related to PTSD severity; however, shame added variance not already accounted for by guilt. Tangney, Stuewig, and Mashek (2007) stipulate that guilt becomes maladaptive when fused with shame; however, our results indicate trauma-related guilt is possibly always fused with shame. (PsycINFO Database Record PMID- 30010380 TI - Acts of omission, altered worldviews, and psychological problems among military veterans. AB - OBJECTIVE: The present study explored acts of omission (i.e., inactions) among military service members. We also investigated whether the meanings and interpretations that service members assign to their actions and inactions, particularly alterations to their conceptualization of themselves, others, and the world (i.e., altered worldviews) would be associated with psychological problems (specifically, depression, suicidality, posttraumatic stress disorder [PTSD], and alcohol use). METHOD: A sample of 50 Iraq/Afghanistan military veterans (8% female) completed questionnaires measuring their (in)actions and the meanings and interpretations attached to those (in)actions. They also completed questionnaires measuring PTSD, depression, suicidality, alcohol use, and combat/postcombat experience. RESULTS: Higher levels of acts of omission were associated with higher levels of altered worldviews and psychological problems. Altered worldviews were strongly associated with PTSD, depression, and suicidality, even after taking into account age, gender, combat/postcombat experiences, and guilt/shame. CONCLUSION: Altered worldviews and acts of omission were strongly associated with psychological problems. (PsycINFO Database Record PMID- 30010381 TI - PTSD and relationship satisfaction in female survivors of sexual assault. AB - OBJECTIVE: Intimate relationships are critical to posttrauma functioning and recovery. The vast majority of research focusing on PTSD and relationship functioning has focused exclusively on male combat veterans, from whom female sexual assault survivors may differ in critical ways. This study investigates the strength of the association between PTSD symptoms and relationship satisfaction, as well as the role of three interpersonal processes (sexuality, communication, and hostility) in female sexual assault survivors. METHOD: Data was collected from female survivors of sexual assault in romantic relationships via online survey. RESULTS: PTSD symptom severity and relationship satisfaction were not significantly correlated. The direct effect of PTSD symptom severity on relationship satisfaction was positive, whereas indirect effects through negative communication, positive communication, and sexual satisfaction were all significantly negative, as expected. Finally, the correlation of PTSD symptom severity with relationship satisfaction differed depending on whether or not participants were in treatment. Results suggest that for those not in treatment, greater PTSD symptoms are associated with poorer relationship satisfaction. CONCLUSIONS: Preliminary evidence suggests that communication and sexual satisfaction may be particularly salient issues for sexual assault survivors' posttrauma psychopathological and relationship functioning, but participation in treatment may be associated with reduced impact of PTSD symptoms on interpersonal functioning. (PsycINFO Database Record PMID- 30010382 TI - Factors associated with antisocial behavior in patients with developmental disorder. AB - Objective: This study investigated the factors associated with antisocial behavior (AB) in children with developmental disorder and effective treatments. Methods: Participants were 110 schoolchildren with developmental disorder and with or without accompanying AB who visited our hospital between October 2009 and October 2012. Among the children with AB, those who exhibited one or more symptoms of conduct disorder (CD) were assigned to the CD subgroup. We examined the background characteristics, past history, type of antisocial behavior, and symptom improvement after treatment in the children with AB and compared the relevant factors with children with developmental disorder without AB. Results: Of the 110 participants, 72 (65.5%) did not exhibit AB and 38 (34.5%) did, 7 (5.5%) of whom fulfilled the criteria for CD. Compared to the children without AB, the children with AB showed a significantly higher occurrence of attention deficit/hyperactivity disorder (AD/HD), maltreatment, institutionalization due to maltreatment, parental mental/psychological problems, and family instability. After medical treatment combined with social-skills training and parental education, 22 of the 38 children with AB showed improved behavior. In the CD subgroup, 4 children were diagnosed with AD/HD and 3 with pervasive developmental disorder, and none of the 7 improved with treatment. Conclusion: AB was associated with AD/HD, maltreatment, institutionalization, parental mental/psychological problems, and family instability. The most effective therapy was parental education. Children with AB need early intervention given that those who already exhibited symptoms of CD showed little improvement with treatment. PMID- 30010383 TI - Implications of Tides for Life on Exoplanets. AB - As evident from the nearby examples of Proxima Centauri and TRAPPIST-1, Earth sized planets in the habitable zone of low-mass stars are common. Here, we focus on such planetary systems and argue that their (oceanic) tides could be more prominent due to stronger tidal forces. We identify the conditions under which tides may exert a significant positive influence on biotic processes including abiogenesis, biological rhythms, nutrient upwelling, and stimulating photosynthesis. We conclude our analysis with the identification of large-scale algal blooms as potential temporal biosignatures in reflectance light curves that can arise indirectly as a consequence of strong tidal forces. Key Words: Tidal effects-Abiogenesis-Biological clocks-Planetary habitability-Temporal biosignatures. Astrobiology 18, 967-982. PMID- 30010384 TI - A Clinical Comparison of Linear- and Surface Area-Based Methods of Measuring Glenoid Bone Loss. AB - BACKGROUND: The purpose of this study was to determine whether linear-based measurement significantly overestimates glenoid bone loss in comparison with surface area-based measurement in patients with recurrent anterior shoulder instability and glenoid bone loss. HYPOTHESIS: Linear-based measurement will significantly overestimate glenoid bone loss in comparison with surface area based measurement in patients with anterior shoulder instability and glenoid bone loss. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Thirty patients with anterior shoulder instability underwent preoperative bilateral shoulder computed tomography (CT) scans. Three-dimensional CT (3D-CT) reconstruction with humeral head subtraction was performed to obtain an en face view of the 3D-CT glenoid. Glenoid bone loss was measured with the surface area and linear methods of measurement. Statistical analysis was performed with a paired 2-tailed t test. RESULTS: Twenty-eight patients (5 female and 23 male; mean age, 25.1 years; age range, 15-58 years) were included in the study; 17 patients underwent a glenoid augmentation procedure, and 11 underwent arthroscopic Bankart repair. The mean percentage glenoid bone loss calculated with the surface area and linear methods was 12.8% +/- 8.0% and 17.5% +/- 9.7% ( P < .0001), respectively. For the 17 patients who underwent glenoid augmentation, mean percentage bone loss with the surface area and linear methods was 16.6% +/- 7.9% and 23.0% +/- 8.0% ( P < .0001), respectively. CONCLUSION: Linear measurement of glenoid bone loss significantly overestimates bone loss compared with surface area measurement in patients with anterior glenoid bony defects. These results indicate that these different methods cannot be used interchangeably and cannot be used with the same critical thresholds for glenoid bone loss. PMID- 30010385 TI - The Bioavailability of Various Oral Forms of Folate Supplementation in Healthy Populations and Animal Models: A Systematic Review. AB - BACKGROUND AND AIMS: Folate is an essential nutrient required for many different functions in the body. It is particularly important for DNA synthesis, immune functions, and during pregnancy. Folate supplements are commonly prescribed by health professionals for a number of different conditions, however, the absorption of the different derivatives remains unclear. The aim of this review was to assess the bioavailability of various forms of folate supplements in healthy populations and animal models. METHODS: A systematic literature review was conducted of original research, which assessed the bioavailability of different oral forms of folate in healthy adults or animal models. The following databases were searched: PubMed (U.S. National Library of Medicine), ProQuest Medical Collection (ProQuest) and ScienceDirect (Elsevier) up to March 30, 2017. The inclusion criteria consisted of both animal and human research, no disease state or condition, and assessed levels after an intervention of a folate derivative. RESULTS: A total of 23 studies out of 5226 met the full inclusion criteria. Of these, 4 were animal studies and 19 were human studies. There was variation in supplement forms used with the most commonly tested being folic acid followed by 5-methylenetetrahydrofolate (5-MTHF). Dosages ranged from 25 MUg up to 200 mg. Only three studies found a statistically significant difference in folate bioavailability when evaluating different supplement forms. These studies found 5-MTHF to be more effective at increasing folate levels in participants. CONCLUSIONS: This review has found a number of methodological limitations and conflicting results. Only three out of the 23 studies assessed found a statistically significant difference between different supplemental forms of folate. Quality absorption studies assessing the bioavailability of oral folate supplements are crucial if clinicians are to make effective evidence-based recommendations. More research is required for greater clarification regarding the bioavailability of these supplements. PMID- 30010386 TI - Evaluation of a Novel Parent-Rated Scale for Selective Mutism. AB - Assessment of selective mutism (SM) is hampered by the lack of diagnostic measures. The Frankfurt Scale of Selective Mutism was developed for kindergarteners, schoolchildren, and adolescents, including the diagnostic scale (DS) and the severity scale (SS). The objective of this study was to evaluate this novel, parent-rated questionnaire among individuals aged 3 to 18 years ( n = 334) with SM, social phobia, internalizing disorders, and a control group. Item analysis resulted in high item-total correlations, and internal consistency in both scales was excellent with Cronbach's alpha = .90-.98. Exploratory factor analysis of the SS consistently yielded a one-factor solution. Mean sum scores of the DS differed significantly between the diagnostic groups, and the receiver operating characteristic analysis resulted in optimal cutoffs for distinguishing SM from all other groups with the area under the curves of 0.94-1.00. The SS sum scores correlated significantly with SM's clinician-rated symptom severity. PMID- 30010387 TI - A New Approach to Measuring the Temperature of Fluids Reaching 300 C and 2 mol/kg NaCl Based on the Raman Shift of Water. AB - The OH stretching band of water is very sensitive to temperature and salinity for the existence of hydrogen bonds between H2O molecules. In this study, the OH stretching band was deconvoluted into two Gaussian peaks, with peak 1 at approximately 3450 cm-1 and peak 2 at approximately 3200 cm-1. The positions of peaks 1 and 2 both shifted to higher wavenumbers with increasing temperature from 50 C to 300 C. The effects of salinity in the range of 0-2 mol/kg NaCl on the OH stretching band were also studied. Linearity for the relationship between Raman shift of peak 1 and temperature increased as the salt concentration increased from 0 to 2 mol/kg, while peak 2 displayed an opposing trend. Two temperature calibration models were developed based on the temperature-dependent changes in the Raman frequency shifts of peaks 1 and 2 (precision of 0.9 C and 1.0 C, respectively). The calibration models for temperature were successfully applied to determining the temperatures of deep-sea hydrothermal fluids in the Okinawa Trough hydrothermal field. The degree of mixing of hydrothermal fluids and ambient seawater during in situ Raman measurements was estimated by the difference in temperatures determined through these calibration models and those measured through thermocouple sensors. PMID- 30010389 TI - Comments on the June 7, 2018, NASA News Release and Papers. PMID- 30010388 TI - Delayed Rehabilitation After Lateral Meniscal Allograft Transplantation Can Reduce Graft Extrusion Compared With Standard Rehabilitation. AB - BACKGROUND: Meniscal extrusion prevention would be important for restoring normal knee kinematics, even though the effect of graft extrusion after meniscal allograft transplantation (MAT) has not been clearly identified. HYPOTHESIS: When compared with standard rehabilitation protocols, delayed rehabilitation after lateral MAT could reduce graft extrusion. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 53 patients who underwent lateral MAT with the keyhole technique from June 2011 to March 2015 were included. Graft extrusion and lateral compartment articular cartilage loss on magnetic resonance imaging, joint space width (JSW) on weightbearing radiographs, and clinical outcomes (including subjective scores and functional tests) of 25 patients who underwent standard rehabilitation (group S) after lateral MAT were compared with those of 28 patients who underwent delayed rehabilitation (group D), which included immobilization during the first 3 weeks and use of unloading braces for 9 weeks. RESULTS: Mean +/- SD follow-up times for groups S and D were 25.7 +/- 6.4 and 24.5 +/- 7.1 months, respectively. Although the postoperative clinical outcomes did not differ between the groups, graft extrusion (3.2 +/- 1.5 mm vs 1.8 +/- 1.6 mm) and relative percentage of extrusion (32.2% +/- 14.6% vs 17.3% +/- 16.6%) were greater in group S than in group D ( P < .001 for both). The percentage of patients with graft extrusion (>=3 mm) was 52% in group S and 21.4% in group D. JSWs on Rosenberg view decreased by 0.1 mm in group S but increased by 0.3 mm in group D ( P = .035). Kellgren-Lawrence grade and modified Outerbridge grade progressed by 44% and 44% among patients in group S and by 17.9% and 21.4% among patients in group D, respectively. There were significant correlations between the coronal graft extrusion and postoperative JSWs on full extension (-0.452) and Rosenberg (-0.410) views, Kellgren-Lawrence grade (0.727), and modified Outerbridge grade (0.732) on magnetic resonance imaging ( P < .001 for all). CONCLUSION: Compared with standard rehabilitation, delayed rehabilitation showed less coronal graft extrusion and joint space narrowing on weightbearing and reduced the progression of arthrosis, although the rehabilitation protocols showed no differences in clinical outcomes. PMID- 30010390 TI - Anti-proliferative, pro-apoptotic and anti-oxidative activity of Lactobacillus and Bifidobacterium strains: A review of mechanisms and therapeutic perspectives. AB - Lactobacillus and Bifidobacterium strains, their isolated constituents and substances that they secrete exert various anti-cancer actions, resulting from their anti-proliferative, pro-apoptotic and anti-oxidant properties. They can express and secrete anti-oxidant enzymes, bind reactive oxygen species, release small molecular weight anti-oxidants and chelate transition metals, preventing detrimental actions of many carcinogens. Lactobacillus and Bifidobacterium can interact with proteins regulating the cell cycle inhibiting proliferation of cancer cells, which often are intrinsically resistant to apoptosis. Lactobacilli and bifidobacteria can break this resistance through activation of pro-caspases and downregulation of the anti-apoptotic Bcl-2 and upregulation of pro-apoptotic Bax proteins. Anti-cancer effects of these bacteria can be also associated with their multi-pathways action in the microbiota. However, exact mechanism of their anti-cancer action is poorly known and needs further studies, which are justified by the important role of these bacteria in cancer biology as well as their potential preventive and therapeutic use. PMID- 30010391 TI - Asymptomatic carriage of antibiotic-resistant Gram-positive cocci among different background populations in East Timor, Southeast Asia. AB - Dissemination of pathogenic multiresistant bacteria is of public health concern. Reliable data can be difficult to obtain, especially in developing countries. This work aimed to characterize the skin and oropharyngeal microbiota, as well as their antimicrobial resistance profiles, of East-Timor populations to identify potentially pathogenic Gram-positive cocci. In order to assess the prevalence of pathogenic bacteria in East-Timor, the oropharyngeal and skin microbiota of 74 individuals was characterized. Gram-positive cocci were evaluated and their antimicrobial resistance profiles were determined. A total of 228 oropharyngeal and 278 skin samples were obtained. The population consisted of 36.5% of asymptomatic carriers of Gram-positive cocci. Kocuria rosea (n = 7, 19.4%), Staphylococcus spp. (n = 6, 16.7%), and Micrococcus luteus (n = 6, 16.7%) were isolated, among others. Antimicrobial resistance levels ranged between 0% and 36.1%, and a multiresistance profile was observed in one third of the isolates. Gram-positive cocci colonization was associated with age group. Prevalence of multiresistant isolates was higher in males who were sampled at the refugee camp. Results show that the prevalence of antimicrobial resistance on East Timor may be underestimated. This study represents the first step toward the full characterization of potential pathogenic Gram-positive cocci present in the populations from East Timor. PMID- 30010392 TI - Comparison of polymerase chain reaction-restriction enzyme analysis method and DNA sequence analysis results in the identification of non-tuberculous mycobacteria. AB - The typing of non-tuberculous mycobacteria (NTM) is important from a clinical and epidemiological perspective. The polymerase chain reaction-restriction enzyme analysis (PRA) method and DNA sequence analysis method were utilized to target a gene region that codes the 65-kDa heat-shock protein for typing 150 suspected NTM samples isolated from the respiratory tract. Mycobacterium abscessus, Mycobacterium xenopi, Mycobacterium fortuitum, and Mycobacterium peregrinum were most frequently found by both methods. Six isolates that could not be defined by the PRA method were defined as Nocardia cyriacigeorgica, Nocardia abscessus, and Mycobacterium intracellulare by DNA sequence analysis. Discordance between the results of the two methods was observed for only one isolate. The isolate that was defined as Mycobacterium gordonae type 6 by the PRA method was defined as Mycobacterium senegalense by sequence analysis. The PRA method is simple and gives rapid results. Compared with DNA sequence analysis, it gives consistent and reliable results up to a ratio of 90%. DNA sequence analysis is the gold standard method in which all strains can be defined. However, given our laboratory conditions, its disadvantage is that it takes longer to reach a diagnosis than through the PRA method. PMID- 30010393 TI - Characterization of macrolide-resistant non-invasive pneumococci in the pre vaccine era in Serbia. AB - Numerous reports have confirmed that increased macrolide use in the treatment of respiratory tract infection has contributed to the emergence of antibiotic resistance worldwide. Studies have also shown that pneumococcal vaccine can reduce pneumococcal resistance. The aim of this study was to determine the prevalence of co-resistance to penicillin and other antibiotics in macrolide resistant (MR) non-invasive pneumococcal isolates and to evaluate serotype distribution in resistant strains in the pre-vaccine era in Serbia. About 80% of MR isolates expressed the MLS phenotype with very high resistance to both erythromycin and clindamycin. A total of 132 (84.1%) MR isolates were multiresistant, i.e., they were resistant to erythromycin, penicillin, tetracycline, and trimethoprim-sulfamethoxazole. Among 157 MR pneumococci, 11 different serotypes were found. Four serotypes, 19F, 14, 6B, and 23F, accounted for 77.7% of all MR pneumococcal isolates. Among isolates with the cMLS phenotype, serotypes 19F and 14 were predominant, whereas serotype 6A was the most common among those with the M phenotype, followed by 14. In conclusion, co resistance to macrolides and penicillin in our non-invasive pneumococcal isolates is high. The majority of tested strains (~80%) belonged to the four serotypes (19F, 14, 6B, and 23F) that are included in all conjugate vaccine formulations. PMID- 30010394 TI - DNA microarray technology and bioinformatic web services. AB - The pan-genomic microarray technique is used for environmental and/or clinical studies. Although microarray is an accurate and sharp diagnostic tool, the expertized bioinformaticians were able to minimize the outcome biases and maximize the flexibility and accuracy of the technique. The knowledge of bioinformatics plays a key role in association with probe designing and the utilization of correct probe sets and platforms. This technique is divided into two parts as dry lab (in silico studies) and wet lab (in vitro studies). Each part covers the other and are known as complementary divisions. In the case of microarray probe designing, a wide range of software, tools, and databases are necessary. Obviously, the application of right databases, software, and tools decreases the probable biases in the outcomes. Due to the importance of suitable probe designing, this article has focused its look onto a variety of online/offline databases, software, and tools. PMID- 30010395 TI - A computational framework to simulate the endolymph flow due to vestibular rehabilitation maneuvers assessed from accelerometer data. AB - Vertiginous symptoms are one of the most common symptoms in the world, therefore investing in new ways and therapies to avoid the sense of insecurity during the vertigo episodes is of great interest. The classical maneuvers used during vestibular rehabilitation consist in moving the head in specific ways, but it is not fully understood why those steps solve the problem. To better understand this mechanism, a three-dimensional computational model of the semicircular ducts of the inner ear was built using the finite element method, with the simulation of the fluid flow being obtained using particle methods. To simulate the exact movements performed during rehabilitation, data from an accelerometer were used as input for the boundary conditions in the model. It is shown that the developed model responds to the input data as expected, and the results successfully show the fluid flow of the endolymph behaving coherently as a function of accelerometer data. Numerical results at specific time steps are compared with the corresponding head movement, and both particle velocity and position follow the pattern that would be expected, confirming that the model is working as expected. The vestibular model built is an important starting point to simulate the classical maneuvers of the vestibular rehabilitation allowing to understand what happens in the endolymph during the rehabilitation process, which ultimately may be used to improve the maneuvers and the quality of life of patients suffering from vertigo. PMID- 30010396 TI - Septic Arthritis After Anterior Cruciate Ligament Reconstruction: How Important Is Graft Salvage? AB - BACKGROUND: Septic arthritis (SA) of the knee after anterior cruciate ligament reconstruction (ACLR) is a rare but potentially devastating condition. In certain cases, graft removal becomes necessary. PURPOSE: To evaluate clinical, subjective, and radiologic outcomes of patients with SA after ACLR and assess whether graft retention has superior clinical results as compared with graft removal. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All patients who were at least 12 months out from arthroscopic treatment of SA after isolated ACLR at our institution were eligible for inclusion. Patients were categorized into 2 groups: group 1, patients with initial graft retention; group 2, patients with initial graft removal. Group 2 was subdivided into 2 groups: group 2a, patients with graft reimplantation; group 2b, patients without graft reimplantation. Objective and subjective assessments were obtained at follow-up, including the International Knee Documentation Committee (IKDC) knee examination form, KT-1000 arthrometer measurements, WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score, Lysholm score, and IKDC subjective evaluation. Radiologic assessment was performed with pre- and postoperative magnetic resonance imaging. RESULTS: Of the 41 patients included, 33 (81%) were available for follow-up at a mean +/- SD 54.7 +/- 24.4 months at an age of 28.4 +/- 9.3 years. When compared with patients from group 2 (n = 12), patients from group 1 (n = 21) obtained significantly better results on the objective IKDC score (normal or nearly normal: group 1, 66.6%; group 2, 36.4%; P = .047) and KT 1000 measurements (group 1, 1.3 +/- 1.0 mm; group 2, 2.9 +/- 1.5 mm; P = .005). Group 1 also scored better than group 2 on the Lysholm ( P = .007), IKDC subjective ( P = .011), and WOMAC ( P = .069) measures. Between groups 2a (n = 4) and 2b (n = 8), no significant differences in outcomes could be detected ( P values, .307-.705), although patients with anterior cruciate ligament graft reimplantation showed a clear tendency toward better results in objective and not subjective parameters. Magnetic resonance imaging evaluation showed higher rates of cartilage damage and meniscal tears among patients with graft resection versus graft retention. CONCLUSION: Patients with graft retention showed superior postoperative results when compared with patients who underwent initial graft resection, although subanalysis showed comparable outcomes between graft retention and reimplantation. Thus, while graft-retaining protocols should have the highest priority in the treatment of SA after ACLR, graft reimplantation should be performed in cases where graft resection becomes necessary, to avoid future cartilage and meniscal lesions. Finally, further studies with larger numbers of patients are needed to gain a better understanding of the outcomes of patients with SA after ACLR. PMID- 30010397 TI - Survival of Tomato Outbreak Associated Salmonella Serotypes in Soil and Water and the Role of Biofilms in Abiotic Surface Attachment. AB - Salmonella serotypes linked to tomato-associated outbreaks were evaluated for survival in soil and water over a 40-day period. Salmonella enterica serotypes Anatum, Baildon, Braenderup, Montevideo, Newport, and Javiana were inoculated separately into sterile soil and water, followed by plating onto TSAYE and XLT4 at 10-day intervals. Biofilm production by Salmonella serotypes was measured on both quartz particles (soil surrogate) and glass coverslips, and was evaluated using a crystal violet dye assay. Salmonella populations in soil and water over 40 days indicated no significant differences between Salmonella serotypes tested (p > 0.05). Over a 40-day period, there was a 1.84 +/- 0.22 log CFU/g and 1.56 +/ 0.54 CFU/mL decrease in populations of Salmonella in soil and water, respectively. Enumeration indicated that Salmonella population fluctuated in water but decreased linearly in soil. All serotypes tested produced the "red dry and rough" morphotype on Congo Red agar. Biofilm produced by all the Salmonella serotypes tested was significantly different on quartz particles than on glass coverslips (p < 0.0001), indicating that material and surface characteristics could affect biofilm development. The ability of Salmonella serotypes to persist in soil or water and attach to abiotic surfaces through biofilm formation affirms that contact surfaces, soil, water, and sediment should be considered as possible sources of cross-contamination in the farm environment. PMID- 30010398 TI - Application of Fourier Transform Infrared Spectroscopy for the Quality and Safety Analysis of Fats and Oils: A Review. AB - Fats and oils are essential food components. Their quality and safety pose major concerns for consumers and food producers because of factors such as oxidation and rancidity, excessive levels of trans fatty acid (TFA), and widespread adulteration. Thus, a rapid and easy-to-use technique must be exploited for quality parameter evaluation and monitoring to ensure the edibility, safety, and quality of fats and oils. In the last decades, Fourier transform infrared (FTIR) spectroscopy has shown great potential in analyzing fats and oils given its speed and simplicity. FTIR-based analytical techniques for common intrinsic quality parameters, including peroxide value, free fatty acid, moisture, TFA, iodine value, as well as oxidation stability, adulteration, and classification of various fats and oils, are summarized in this review. The advantages and disadvantages of selected infrared spectral accessories and sample preparation and spectral processing methods are highlighted. The prospects and reformative aspects for future application of the FTIR technique in the field of fats and oils are also discussed. This review may serve as a basis for applying FTIR not only in future research but also in the fat and oil industries. PMID- 30010399 TI - Preliminary evaluation of plasticizer and BPA in Tunisian cosmetics and investigation of hazards on human skin cells. AB - In this study, 18 plasticizer (phthalates, adipates, sebacates, and others) and BPA residues in some cosmetic samples collected from Tunisian market are evaluated by micro-matrix solid-phase dispersion combined with GC-MS. In parallel, the impact of these molecules and the cosmetics in the human epithelial cell lines is investigated. The cytotoxic activity of cosmetic extracts is evaluated in vitro against B16 and Hep-2 human skin cell lines using the 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay. This study shows that the tested cosmetic products could constitute a hazard to the consumer health and wellness and that strict safety analysis on cosmetic products needs to be carried out before they are marketed. PMID- 30010400 TI - Computational biomechanical analysis of postoperative inferior tibiofibular syndesmosis: a modified modeling method. AB - To analyze the biomechanical effect of syndesmotic screw through three and four cortices, a total of 12 finite element models simulating healthy ankles, tibiofibular syndesmosis injured ankles, and post-operative ankles by screw fixations through three or four cortices were built. A set of biomechanical data were obtained to find that screw fixation methods for inferior tibiofibular syndesmosis can help recover most of the biomechanical relations of the ankle especially the tricortical fixation, while the screw of quadricortical fixation bear more stress than the tricortical fixation. The modeling method for finite element models was also modified for saving more time and realizing personalized modeling for clinical application. PMID- 30010401 TI - DRESS Following FIRES: A Clinical Conundrum. PMID- 30010402 TI - hsa_circ_0000177-miR-638-FZD7-Wnt Signaling Cascade Contributes to the Malignant Behaviors in Glioma. AB - As a new member of the noncoding RNA family, circular RNAs (circRNAs) have been demonstrated as critical regulators in various physiological and pathological processes, such as tumorigenesis. However, the role of circRNAs has not been well understood until now. In our study, we found that circRNA hsa_circ_0000177 was upregulated in glioma tissues and cell lines. Also, hsa_circ_0000177 overexpression was associated with poor prognosis in glioma patients. Through functional experiments, we found that hsa_circ_0000177 knockdown dramatically inhibited glioma cell proliferation and invasion in vitro. Consistently, hsa_circ_0000177 knockdown significantly repressed glioma growth in vivo. In terms of mechanism, we used bioinformatics analysis and identified hsa_circ_0000177 as a miR-638 sponge. We showed that miR-638 inhibition could restore the proliferation and invasion of glioma cells transfected with hsa_circ_0000177 small interfering RNA. Furthermore, we demonstrated that frizzled class receptor 7 (FZD7) was targeted by miR-638 and upregulated by hsa_circ_0000177. Through upregulating FZD7 expression, hsa_circ_0000177 activated Wnt signaling and facilitated glioma growth. Taken together, our study revealed a novel signaling pathway involved in glioma progression. PMID- 30010403 TI - Optimal pressure comfort design for pilot helmets. AB - With the development of high-performance fighters, the function of pilot helmets is also constantly upgrading, and helmet-mounted display (HMD) has become a future development trend. To solve the inter-restriction between the eye position control and the pressure comfort under high overloads of pilot helmets, this paper optimizes the helmet design by building a head-helmet finite element model: (1) Under a 10 G overload, the deformation of helmet soft liner should not exceed 2 mm; and (2) The combination of liner materials used in various areas should satisfy the requirements of most comfortable head pressure distribution (Pfront: Ptop: Pside: Pback = 2:2:1:3). The study on 46 different combinations of materials finds that the helmet can meet both the eye position maintenance requirement under overloads and the requirement of comfortable pressure distribution when linear elastic materials with Young's modulus of 1000 pa, 55000 pa and 65000 pa are used for the side, top and front parts of the head, and nonlinear elastic hyperfoam material with two-fold stress variation is used for the head back area. PMID- 30010405 TI - Cytotoxic lanostane triterpenoids from the stems of Schisandra glaucescens. AB - Phytochemical investigation on the stems of Schisandra glaucescens resulted into the isolation of three new lanostane triterpenoids, 12-hydroxyschiglausin B (1), 12-hydroxykadsuphilactone B (2), and 20R-hydroxyschinalactone C (3). Structural elucidation of all the compounds was accomplished by spectral methods. The isolated compounds were tested in vitro for cytotoxic activities. As a result, triterpenoids 1 and 2 showed cytotoxic activities for all six tested tumor cell lines with IC50 values less than 15 MUM. PMID- 30010404 TI - Evaluation of N-Succinimidyl S-Acetylthioacetate Ligand for Radiolabeling of Humanized Antibodies with 188Rhenium. AB - Radioimmunotherapy offers an effective way to direct ionizing radiation to cancer cells through attachment of radionuclides to antibodies while limiting negative effects of off-target irradiation. This, however, requires effective facile methods for attachment of therapeutic radionuclides onto antibodies. Herein, the authors report their efforts in evaluating N-succinimidyl S-acetylthioacetate (SATA), a commercially available reagent, for use as a bifunctional chelating agent (BCA) to attach 188Rhenium (188Re) onto h8C3, a humanized IgG antibody that can effectively target extracellular melanin present in malignant melanoma. Micro single photon emission computer tomography/computer tomography was used to determine an effective timeline for antibody uptake in B16-F10 tumor bearing C57BL6 mice guiding the selection of 188Re with its 16.9 h physical half-life. Radio instant thin layer chromatography coupled with radio high-performance liquid chromatography was used to assess radioisotope incorporation, as well as stability during the labeling process for SATA conjugated h8C3. It was determined that despite the relatively mild conditions used, incorporation of the SATA conjugate resulted in antibody instability during labeling requiring a different BCA to facilitate rhenium incorporation onto the antibodies. PMID- 30010406 TI - Thinking more broadly about policy responses to problematic video game use: A response to Kiraly et al. (2018). AB - Kiraly et al. (2018) did an excellent job of reviewing policies that are undertaken to prevent and respond to problematic video game use. I argue that there has been a failure of imagination when considering public policy - generally, we only think of governmental or legislative policies. This paper identifies several other ways we could consider public policy, providing examples of some that have already been enacted and suggesting others that could be, all without governmental intervention. These types of policies may not only be more practical, but also be more effective. PMID- 30010407 TI - The imperative of integrating empirical and theoretical considerations when developing policy responses to Internet-gaming disorder. AB - This commentary proposes an integrative approach of theoretical and empirical considerations when developing policy responses to Internet-gaming disorder and when evaluating their efficacy. It complements the overview by Kiraly et al. (2018) about preventive and treatment programs by referring to a lack of inclusion of internal factors, such as individual aspects and cognitions, and missing empirical evidence. This commentary claims the integration of current research addressing individual predisposing and maintaining factors in order to evaluate existing programs and to enhance the exchange between actors including policy. This integrative approach has the potential to develop successful preventive strategies, which could be implemented realistically and socially responsible. PMID- 30010408 TI - Addressing problematic video game use: A multimethod, dual-context perspective on leisure-time use. AB - A more integrative approach to the prevention of problematic gaming behavior is recommended in Kiraly et al.'s review. We discuss the Dutch policy responses to problematic gaming behavior and suggest two alternatives to the dominant survey research approach to achieve this. Employing time-use/diary studies allows us to map out the full scope of leisure-time use and employing log-data analysis improves our understanding of gamer behavior within the virtual context. All of these approaches would benefit from accounting for the diversity of within virtual context behavior. The approach is summarized as a multimethod, dual context approach to understanding leisure-time behavior. PMID- 30010409 TI - Attention-deficit hyperactivity disorder and addictions (substance and behavioral): Prevalence and characteristics in a multicenter study in France. AB - AIM: The aim of this study is to determine the possible links between attention deficit hyperactivity disorder (ADHD) and the presence of concomitant addictions with or without substance use in a French student population. MEASURES: A battery of questionnaire measuring socioeconomic characteristics, university curriculum, ADHD (Wender Utah Rating Scale and Adult ADHD Self-Report Scale), substance consumptions (alcohol, tobacco, and cannabis), and behavioral addictions [(eating disorders (SCOFF)], Internet addiction (Internet Addiction Test), food addiction (Yale Food Addiction Scale), compulsive buying (Echeburua's), and problem gambling (The Canadian Problem Gambling Index)] and measures of physical activity (Godin's Leisure Time Exercise Questionnaire) was filled up by university students in Rouen and Nanterre in France. RESULTS: A total of 1,517 students were included (472 from Paris Nanterre and 1,042 from Rouen). The mean age was 20.6 years (SD = 3.6) and the sex ratio male to female was 0.46. The prevalence of ADHD among the students (current ADHD with a history of ADHD in childhood) was 5.6%. A quarter (25.7%) of students had already repeated their university curriculum, compared to 42.2% among the students with ADHD. Students with possible ADHD had repeated classes more often and believed to have a lower academic level than the students without ADHD. Significant differences were found as students with ADHD were less likely to succeed in their studies (repeated classes more often) than non-ADHD students, and considered their academic level to be lower. They also had significantly higher scores on substance (alcohol, cannabis, and tobacco) as well as behavioral addictions (gambling, compulsive buying disorder, eating disorders, and Internet addiction). CONCLUSION: It seems essential to determine students' problems and propose interventions adapted to students' needs, in order to reduce the negative impact on their future academic and global successes. PMID- 30010411 TI - Prevalence of Internet addiction disorder in Chinese university students: A comprehensive meta-analysis of observational studies. AB - BACKGROUND AND AIMS: Internet addiction disorder (IAD) is common in university students. A number of studies have examined the prevalence of IAD in Chinese university students, but the results have been inconsistent. This is a meta analysis of the prevalence of IAD and its associated factors in Chinese university students. METHODS: Both English (PubMed, PsycINFO, and Embase) and Chinese (Wan Fang Database and Chinese National Knowledge Infrastructure) databases were systematically and independently searched from their inception until January 16, 2017. RESULTS: Altogether 70 studies covering 122,454 university students were included in the meta-analysis. Using the random-effects model, the pooled overall prevalence of IAD was 11.3% (95% CI: 10.1%-12.5%). When using the 8-item Young Diagnostic Questionnaire, the 10-item modified Young Diagnostic Questionnaire, the 20-item Internet Addiction Test, and the 26-item Chen Internet Addiction Scale, the pooled prevalence of IAD was 8.4% (95% CI: 6.7%-10.4%), 9.3% (95% CI: 7.6%-11.4%), 11.2% (95% CI: 8.8%-14.3%), and 14.0% (95% CI: 10.6%-18.4%), respectively. Subgroup analyses revealed that the pooled prevalence of IAD was significantly associated with the measurement instrument (Q = 9.41, p = .024). Male gender, higher grade, and urban abode were also significantly associated with IAD. The prevalence of IAD was also higher in eastern and central of China than in its northern and western regions (10.7% vs. 8.1%, Q = 4.90, p = .027). CONCLUSIONS: IAD is common among Chinese university students. Appropriate strategies for the prevention and treatment of IAD in this population need greater attention. PMID- 30010412 TI - Cortisol and behavioral reaction of low and high sensation seekers differ in responding to a sport-specific stressor. AB - BACKGROUND/OBJECTIVES: Sensation seeking is closely related to practicing high risk sports. This domain offers individuals an opportunity to achieve an increased level of arousal. Moreover, stress reactivity implies interindividual differences in the capacity to respond to a stressor. The purpose of this study was to examine whether high sensation seekers (HSS) compared to low sensation seekers (LSS) experience lower levels of stress on a physiological and psychological basis. Stress was induced in a sport-specific experimental paradigm with a climbing task through a jump into the rope. METHODS: Two extreme groups (n = 28 male athletes) were examined in a mixed-factorial design (between: HSS vs. LSS; within: repeated measurements of several variables related to stress reactivity - cortisol, heart rate, anxiety). RESULTS: In response to the stressor HSS compared to LSS released a significantly lower amount of cortisol and needed less time for the climbing task. Heart rate and anxiety were not significant. CONCLUSIONS: Individuals seem to react physiologically differently to a sport specific stressor, depending on their level of sensation seeking. HSS seem to be less strained, and seem to perform better. These findings might be relevant not only for the evaluation of (sport-) psychological interventions but also for other contexts (e.g., special forces). PMID- 30010410 TI - Including gaming disorder in the ICD-11: The need to do so from a clinical and public health perspective. AB - The proposed introduction of gaming disorder (GD) in the 11th revision of the International Classification of Diseases (ICD-11) developed by the World Health Organization (WHO) has led to a lively debate over the past year. Besides the broad support for the decision in the academic press, a recent publication by van Rooij et al. (2018) repeated the criticism raised against the inclusion of GD in ICD-11 by Aarseth et al. (2017). We argue that this group of researchers fails to recognize the clinical and public health considerations, which support the WHO perspective. It is important to recognize a range of biases that may influence this debate; in particular, the gaming industry may wish to diminish its responsibility by claiming that GD is not a public health problem, a position which maybe supported by arguments from scholars based in media psychology, computer games research, communication science, and related disciplines. However, just as with any other disease or disorder in the ICD-11, the decision whether or not to include GD is based on clinical evidence and public health needs. Therefore, we reiterate our conclusion that including GD reflects the essence of the ICD and will facilitate treatment and prevention for those who need it. PMID- 30010413 TI - Women's role in male circumcision promotion in Rakai, Uganda. AB - Medical male circumcision (MMC) has expanded in sub-Saharan Africa, yet uptake remains sub-optimal. We sought to understand women's perceptions of and influence on MMC in Rakai, Uganda. We conducted in-depth interviews with 27 women in fishing and trading communities, including women married to circumcised and uncircumcised men, single women, and sex workers. Data analysis followed a team based framework approach. All female participants preferred circumcised men because of perceived reduced HIV and sexually transmitted infection (STI) risk, improved penile hygiene, and increased sexual pleasure. Perceived negative aspects included abstinence during wound healing, potentially increased male sexual risk behaviors, fear of being blamed for HIV acquisition, and economic insecurity due to time off work. Participants felt women could persuade their partners to be circumcised, accompany them to the clinic, refuse sex with uncircumcised men, and participate in community MMC activities. Findings support women's important role in MMC acceptance. PMID- 30010414 TI - Colonization of Pigs Experimentally Infected with a Monophasic Variant of Salmonella Typhimurium. AB - The monophasic variant of Salmonella Typhimurium is highly prevalent in human and in pork. However, little is known about colonization dynamics and serology in pigs. We orally inoculated 24 seven-week-old piglets with 109 CFU/pig of a porcine strain of monophasic Salmonella Typhimurium in an experimental trial. Three groups of eight piglets were orally inoculated and monitored for 21, 49, or 84 days post-inoculation until necropsied. From 3 days post-inoculation to necropsy, individual feces were sampled twice weekly and blood once weekly. At necropsy, the tonsils, mesenteric lymph nodes, and the contents of the duodenum, jejunum, ileum, and cecum were collected from each pig. We determined the number of CFU/g in all the samples and measured also Salmonella antibodies in OD% in all blood samples. At different times during the trial, we tested by MLVA (Multilocus Variable Number Tandem Repeat Analysis) the genomic stability of the strain after passing through the intestinal tract. Salmonella was continuously excreted by pigs, ranging from 1.4 to 5.8 log10 CFU/g. At necropsy, Salmonella was present in all samples, but the tonsils were particularly infected. Salmonella antibodies were detected in five pigs 7 days post-inoculation. At 49 days post-inoculation, all the pigs were seropositive. We observed new MLVA types for 3.3% of the isolates tested over the trial. Our study allowed us to show the serovar's ability to persist in pigs after infection up to 84 days post-inoculation. We demonstrated that Salmonella seroconversion appeared earlier than in naturally infected pigs and that the strain's genome can evolve after passing through the digestive tract of pigs. PMID- 30010416 TI - Transcriptome analysis of three cultivars of Poria cocos reveals genes related to the biosynthesis of polysaccharides. AB - Poria cocos (P. cocos) polysaccharides (PCPs) are used to improve immunity and possess antitumor activities. We compared three cultivars of P. cocos (5.78, XJ 28 and JHYH) PCP contents. Then we determined that malZ, galA, SORD, gnl and bglX are key enzymes within the PCP biosynthetic pathway by using HiSeq2500 transcriptome and qRT-PCR validation. Our results provide more detailed information about the PCP biosynthesis pathway at the molecular level in P. cocos and establish the functions for the molecular breeding to produce polysaccharides in general for therapeutic use in Chinese medicinal plants. PMID- 30010415 TI - FEBio finite element models of the human lumbar spine. AB - Finite element analysis has proven to be a viable method for assessing many structure-function relationships in the human lumbar spine. Several validated models of the spine have been published, but they typically rely on commercial packages and are difficult to share between labs. The goal of this study is to present the development of the first open-access models of the human lumbar spine in FEBio. This modeling framework currently targets three deficient areas in the field of lumbar spine modeling: 1) open-access models, 2) accessibility for multiple meshing schemes, and 3) options to include advanced hyperelastic and biphasic constitutive models. PMID- 30010417 TI - A novel computational method to determine subject-specific bite force and occlusal loading during mastication. AB - The evaluation of three-dimensional occlusal loading during biting and chewing may assist in development of new dental materials, in designing effective and long-lasting restorations such as crowns and bridges, and for evaluating functional performance of prosthodontic components such as dental and/or maxillofacial implants. At present, little is known about the dynamic force and pressure distributions at the occlusal surface during mastication, as these quantities cannot be measured directly. The aim of this study was to evaluate subject-specific occlusal loading forces during mastication using accurate jaw motion measurements. Motion data was obtained from experiments in which an individual performed maximal effort dynamic chewing cycles on a rubber sample with known mechanical properties. A finite element model simulation of one recorded chewing cycle was then performed to evaluate the deformation of the rubber. This was achieved by imposing the measured jaw motions on a three dimensional geometric surface model of the subject's dental impressions. Based on the rubber's deformation and its material behaviour, the simulation was used to compute the resulting stresses within the rubber as well as the contact pressures and forces on the occlusal surfaces. An advantage of this novel modelling approach is that dynamic occlusal pressure maps and biting forces may be predicted with high accuracy and resolution at each time step throughout the chewing cycle. Depending on the motion capture technique and the speed of simulation, the methodology may be automated in such a way that it can be performed chair-side. The present study demonstrates a novel modelling methodology for evaluating dynamic occlusal loading during biting or chewing. PMID- 30010418 TI - Effect of Liposome Treatment on Hemorheology and Metabolic Profile of Human Red Blood Cells During Hypothermic Storage. AB - BACKGROUND: Ex vivo cold storage of red blood cells (RBCs) for transfusion has long been associated with hypothermic storage lesions. It has been proposed that liposomes can be used to mitigate hemorheological elements of RBC membrane storage lesions. This study aimed to determine the appropriate liposome treatment time and assess the effects of liposome treatment on RBC's hemorheological and metabolic profiles. MATERIALS AND METHODS: Unilamellar liposomes were synthesized to contain a bilayer of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC):cholesterol (7:3 mol%). Packed human RBCs (n = 4) were divided into untreated control (HEPES-NaCl solution) and liposome-treated samples (2 mM DOPC liposomes) and treated at days 2, 21, and 42 of hypothermic storage. RBC quality assessment included percent hemolysis, deformability, aggregation, hematological indices, microvesiculation, supernatant potassium, adenosine triphosphate (ATP), and 2,3-diphosphoglycerate (2,3-DPG). RESULTS: Among the parameters affected by liposome treatment time were deformability, aggregation amplitude (Amp), mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and microparticle mean fluorescence intensity. After 6 weeks of storage, aggregation index (AI) and Amp were significantly increased in liposome-treated RBCs (AI: 45.38 +/- 1.92% vs. 41.54 +/- 4.10%, p = 0.020; Amp: 16.38 +/- 2.17 arbitrary units [au] vs. 12.22 +/- 3.29 au, p = 0.019). Despite comparable hemolysis levels at 3 and 6 weeks, DOPC-treated RBCs showed significantly increased potassium levels for the same time points (3 weeks: 31.2 +/- 2.7 mmol/L vs. 30.8 +/- 2.7 mmol/L, p = 0.007; 6 weeks: 45.0 +/- 3.0 mmol/L vs. 43.8 +/- 3.4 mmol/L, p = 0.013). ATP and 2,3-DPG levels were comparable throughout storage. CONCLUSIONS: Liposome treatment seemed to be more beneficial when performed at the beginning of storage up to day 21. DOPC liposome treatment resulted in an improvement in human RBC hemorheology upon storage, with no significant impact on metabolic profile. PMID- 30010419 TI - How many nerve fibres can be separated as donor from an integral nerve trunk when reconstructing a peripheral nerve trauma with amplification method by artificial biochitin conduit? AB - Using portion of a nearby nerve trunk to reconstruct a severe nerve lesion by artificial biodegradable chitin conduit is the core practicable method based on peripheral nerve amplification regeneration. However, the quantitative influences on skeletal muscle function corresponding to the injury of the donated nerve fibres were not previously reported. Here, we aimed to explore the compensative capacity in tibialis anterior muscles of rats with the models of acute tibialis anterior nerve branch injuries. The tibialis anterior branch of deep peroneal nerve was transected in various levels each time. Both the decreased treads of maximal compound muscle action potential (CMAP) amplitude and complete tetanic tension of the tibialis anterior muscle in rats were similar with the increasing numbers of damaged nerve fibres, which showed two S-shaped curves. When the nerve injury level was less than approximately 10%, the skeletal muscle function remained normal through complete compensation of motor endplates. As the injury degree went from 10% to 85%, the muscle function was partially impaired due to the broken compensation of motor endplates. When the nerve injury level was over approximately 85%, the skeletal muscle function was totally lost. It suggests that within a certain level of nerve injury, the skeletal muscle function maintained basically unchanged via complete compensation of motor endplates. Such nerve fibres may be used as donor nerve to repair peripheral nerve injury. PMID- 30010420 TI - Computational modeling and analysis of thoracolumbar spine fractures in frontal crash reconstruction. AB - OBJECTIVE: This study aimed to reconstruct 11 motor vehicle crashes (6 with thoracolumbar fractures and 5 without thoracolumbar fractures) and analyze the fracture mechanism, fracture predictors, and associated parameters affecting thoracolumbar spine response. METHODS: Eleven frontal crashes were reconstructed with a finite element simplified vehicle model (SVM). The SVM was tuned to each case vehicle and the Total HUman Model for Safety (THUMS) Ver. 4.01 was scaled and positioned in a baseline configuration to mimic the documented precrash driver posture. The event data recorder crash pulse was applied as a boundary condition. For the 6 thoracolumbar fracture cases, 120 simulations to quantify uncertainty and response variation were performed using a Latin hypercube design of experiments (DOE) to vary seat track position, seatback angle, steering column angle, steering column position, and D-ring height. Vertebral loads and bending moments were analyzed, and lumbar spine indices (unadjusted and age-adjusted) were developed to quantify the combined loading effect. Maximum principal strain and stress data were collected in the vertebral cortical and trabecular bone. DOE data were fit to regression models to examine occupant positioning and thoracolumbar response correlations. RESULTS: Of the 11 cases, both the vertebral compression force and bending moment progressively increased from superior to inferior vertebrae. Two thoracic spine fracture cases had higher average compression force and bending moment across all thoracic vertebral levels, compared to 9 cases without thoracic spine fractures (force: 1,200.6 vs. 640.8 N; moment: 13.7 vs. 9.2 Nm). Though there was no apparent difference in bending moment at the L1-L2 vertebrae, lumbar fracture cases exhibited higher vertebral bending moments in L3-L4 (fracture/nonfracture: 45.7 vs. 33.8 Nm). The unadjusted lumbar spine index correctly predicted thoracolumbar fracture occurrence for 9 of the 11 cases (sensitivity = 1.0; specificity = 0.6). The age-adjusted lumbar spine index correctly predicted thoracolumbar fracture occurrence for 10 of the 11 cases (sensitivity = 1.0; specificity = 0.8). The age-adjusted principal stress in the trabecular bone was an excellent indicator of fracture occurrence (sensitivity = 1.0; specificity = 1.0). A rearward seat track position and reclined seatback increased the thoracic spine bending moment by 111-329%. A more reclined seatback increased the lumbar force and bending moment by 16-165% and 67 172%, respectively. CONCLUSIONS: This study provided a computational framework for assessing thoracolumbar fractures and also quantified the effect of precrash driver posture on thoracolumbar response. Results aid in the evaluation of motor vehicle crash-induced vertebral fractures and the understanding of factors contributing to fracture risk. PMID- 30010421 TI - Effects of Washington State's alcohol ignition interlock laws on DUI recidivism: An update. AB - OBJECTIVE: The objective of this study was to examine the effects of changes to Washington State's alcohol ignition interlock laws: moving issuance of interlock orders from the courts to the driver licensing department (July 2003); extending the interlock order requirement to all persons convicted of driving under the influence (DUI; June 2004); allowing an interlock in lieu of an administrative driver's license suspension (January 2009); and requiring proof of interlock installation to reinstate the driver's license (January 2011). METHOD: Trends in conviction types, interlock installation rates, and 2-year cumulative recidivism rates were examined for first-time and repeat offenders with convictions stemming from DUI arrests during 1999-2012. Autoregressive integrated moving average (ARIMA) models examined the association between law changes and installation rates, law changes and recidivism rates, and installation rates and recidivism rates. RESULTS: During the study period, there was a large increase in the proportion of first-time DUI arrests reduced to alcohol-related negligent/reckless driving convictions, offenses not requiring interlock orders. The interlock installation rate increased substantially and the recidivism rate declined substantially among both first and repeat offenders. Based on the ARIMA models for first offenders, the 2004 and 2009 law changes were associated with increased interlock installation rates and lower recidivism rates. For first offenders arrested during the last quarter of 2012, the model estimates a 26% reduction in the recidivism rate (from an expected 7.7% without the 4 laws to 5.6%). A 1 percentage point increase in the interlock installation rate was associated with a 0.06 percentage point decline in the recidivism rate among first offenders. If the association carried forward and if the installation rate had been 100% rather than 38% in the last quarter of 2012, the 2-year recidivism rate would have been reduced from 5.6 to 2%. Among repeat offenders, the 2003 and 2009 law changes were associated with increased interlock installation rates, and the 2009 law change was associated with a nonsignificant decline in recidivism. CONCLUSIONS: In Washington, rates of interlock installations increased as interlock laws were strengthened, and the increase was associated with reductions in recidivism among first DUI offenders. Washington's experience suggests that states can reduce DUI recidivism by requiring interlock orders for all offenders, allowing offenders to install interlocks in lieu of an administrative driver's license suspension, and closing statutory loopholes that allow plea reductions to convictions without interlock orders. PMID- 30010422 TI - The Stony Brook Health Enhancement Program: The development of an active control condition for mind-body interventions. AB - This article describes the development of a manualized, eight-session multiple health behavior change program which addresses sleep, exercise, nutrition, substance use, and working with one's healthcare team. Our goal was to design a structured, evidence-based program that could be facilitated by a single health professional and could act as an active, credible control for mind-body intervention studies. Psychoeducational content was adapted from the latest government and peer-reviewed guidelines. Preliminary work suggests the program is acceptable and feasible for use in patients of varying ages with heterogeneous mental and physical health problems. It is adaptable for both face-to-face and online delivery. PMID- 30010423 TI - Erickson solution-focused coaching for weight management in obese patients with obstructive sleep apnoea: ECOHEALTH pilot study. AB - Coaching as a lifestyle modification approach to weight management is insufficiently explored in obstructive sleep apnoea. We investigated anthropometry and body composition after 20 weeks of Erickson coaching in 26 obstructive sleep apnoea patients (19 males; 47.6 +/- 2.4 years). Body weight, neck circumference, waist-to-hip ratio and %body fat significantly decreased after 20 weeks. The mean weight loss was 5.2 per cent +/- 1.0 per cent; 20 (77%) participants achieved target reduction of >3 per cent. Coaching session attendance ( p = 0.006) and reaching personal goal related to physical performance ( p = 0.044) were independently associated with weight loss (multiple regression model R2 = 0.608, p < 0.001). Erickson solution-focused coaching supports adherence to healthy lifestyle and weight reduction in obstructive sleep apnoea. PMID- 30010424 TI - The prevalence and correlates of texting while driving among a population-based sample of Ontario students. AB - OBJECTIVE: Texting while driving (TWD) has a deleterious impact on driving performance and may pose a significant challenge to traffic safety. This challenge may be particularly relevant for young and inexperienced drivers. This study examined the prevalence and risk factors of writing text messages or emails while driving during the past 12 months. METHOD: This study analyzed a subpopulation of 1,133 licensed students 16 years of age or older from the 2013 Ontario Student Drug Use Survey (OSDUHS), a population-based survey of students in Ontario, Canada. RESULTS: Our results indicate that 36% of licensed drivers reported writing a text message while driving during the past 12 months; of those who did, 56% reported doing so 4 or more times. Graduated licensing was the strongest factor predicting TWD. Compared to students with the more restrictive G1 license, students with a G2 or full license were 9.4 times more likely to report TWD after controlling for the effect of all other factors. Older students, white students, and students attending school in urban centers were more likely to report TWD, and the amount of time spent on social media sites, being a passenger with a driver using substances, and past-year collisions were also significantly associated with TWD. Gender differences and participation in driver education training were not associated with TWD. CONCLUSIONS: This research demonstrates that TWD is an extremely common behavior among licensed student drivers in Ontario, particularly among those who have passed the first stage of graduated licensing. TWD is associated with other risky driving behaviors and outcomes, and the findings from this study underscore the need to better understand the harms associated with this behavior. PMID- 30010425 TI - Morphology and histology of silent and symptom-causing atherosclerotic carotid plaques - Rationale and design of the Helsinki Carotid Endarterectomy Study 2 (the HeCES2). AB - INTRODUCTION: Every fifth ischemic stroke is caused by thromboembolism originating from an atherosclerotic carotid artery plaque. While prevention is the most cost-effective stroke therapy, antiplatelet and cholesterol-lowering drugs have a ceiling effect in their efficacy. Therefore, discovery of novel pathophysiologic targets are needed to improve the primary and secondary prevention of stroke. This article provides a detailed study design and protocol of HeCES2, an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis. MATERIALS AND METHODS: Recruitment and carotid endarterectomies of the study patients with carotid atherosclerosis were performed from October 2012 to September 2015. After brain and carotid artery imaging, endarterectomised carotid plaques (CPs) and blood samples were collected from 500 patients for detailed biochemical and molecular analyses. Findings to date: We developed a morphological grading for macroscopic characteristics within CPs. The dominant macroscopic CP characteristics were: smoothness 62%, ulceration 61%, intraplaque hemorrhage 60%, atheromatous gruel 59%, luminal coral-type calcification 34%, abundant (44%) and moderate (39%) intramural calcification, and symptom-causing "hot spot" area 53%. Future plans: By combining clinically oriented and basic biomedical research, this large-scale study attempts to untangle the pathophysiological perplexities of human carotid atherosclerosis. Key Messages This article is a rationale and design of the HeCES2 study that is an observational prospective cohort study with the objective to investigate the pathophysiology of carotid atherosclerosis. The HeCES2 study strives to develop diagnostic algorithms including radiologic imaging to identify carotid atherosclerosis patients who warrant surgical treatment. In addition, the study aims at finding out new tools for clinical risk stratification as well as novel molecular targets for drug development. PMID- 30010426 TI - Physical activity and all-cause mortality in Korean older adults. AB - BACKGROUND: The association between physical activity (PA) and all-cause mortality may be modulated by potential confounders. AIM: To investigate the association between weekly PA and all-cause mortality in a population-based prospective study. SUBJECTS AND METHODS: The study sample included Korean older adults aged 60 years and older who participated in baseline assessments (n = 15 416) in 2008 and completed follow-up visits in 2011 (n = 14,976). Primary outcome was 3-year all-cause mortality. RESULTS: Compared with sufficiently active individuals (with Hazard Ratio (HR) = 1), completely inactive and insufficiently active individuals had a significantly higher risk of all-cause mortality (HR = 2.086, 95% CI = 1.639-2.655, p < 0.00 and HR = 1.644, 95% CI = 1.013-2.668, p = 0.044, respectively), even after adjustments for age and sex, health-related behaviour factors (i.e. smoking, alcohol intake and nutritional risk), cognitive impairment and components of frailty phenotype (i.e. involuntary weight loss, exhaustion and slowness). In addition, the inverse association between PA and all cause mortality is differently modulated by potential confounders, including age, sex, smoking, depressive symptoms, cognitive impairment and involuntary weight loss. CONCLUSION: PA was inversely and independently associated with all-cause mortality in Korean older adults. PMID- 30010427 TI - Relationship between intelligence quotient (IQ) and cerebral metabolic rate of oxygen in patients with neurobehavioural disability after traumatic brain injury. AB - OBJECTIVE: Cerebral metabolism may play a significant role in neurobehavioural disability following traumatic brain injury (TBI). In this study, we examined the relationship between intelligence quotient (IQ) and the cerebral metabolic rate of oxygen (CMRO2) in the lateral prefrontal cortex, which was measured by 15O labelled gas positron emission tomography (PET), in patients with TBI. MATERIALS AND METHODS: The subjects were 12 patients (eight males and four females) who suffered from neurobehavioural disability following TBI. Their mean age was 33.3 years. The cause of injury was traffic accidents in all patients and the mean period after injury was 44.8 months. These patients underwent 15O-labelled gas PET and tests using either the Wechsler Adult Intelligence Scale-Revised (WAIS-R) or the Wechsler Intelligence Scale for Children-Revised (WISC-R). Pearson's correlation between CMRO2 and total IQ (TIQ) was calculated. RESULTS: A statistically significant correlation was observed between TIQ and CMRO2 in the right Brodmann areas (BAs) 44 and 45. The lower the WAIS score, the higher the CMRO2 in both areas. CONCLUSION: Neurological function negatively correlated with the metabolism of oxygen. It was possible that changes in brain networks increased the neuronal activity in the undamaged areas and that the increased activity compensated for the function decline. PMID- 30010428 TI - Biology of Cancer; From Cellular Cancerogenesis to Supracellular Evolution of Malignant Phenotype. AB - Until now cancerogenesis has been studied in close relation with the corresponding malignant phenotype. Such unified approach defines cancer as uncontrolled cellular multiplication, associating invasion and metastasis. Contrary to the classical approach, this paper presents cancerous disease from two distinct perspectives: cancerogenesis as the cause (investigated especially to cellular or molecular level), and malignant phenotype as the resulting effect (with supracellular evolution). It is advanced the perspective that exacerbated cell division in cancer would be actually a very responsive event to supracellular signals, which are received from extracellular matrix and supracellular programs of the body. PMID- 30010429 TI - The Use of E-Learning in Medical Education for Mountain Rescuers Concerning Hypothermia. AB - : Podsiadlo, Pawel, Sylweriusz Kosinski, Tomasz Darocha, Kinga Salapa, Tomasz Sanak, and Hermann Brugger. The use of e-learning in medical education for mountain rescuers concerning hypothermia. High Alt Med Biol 19:272-277, 2018. OBJECTIVE: Victims of mountain accidents are often exposed to wet and cold environments which may increase the risk of hypothermia. Mountain rescuers should be able to recognize and manage hypothermia. We aimed to assess relevant knowledge in professional and volunteer mountain rescuers, as well as to evaluate the efficacy of an e-learning platform for continuing medical education. METHODS: An e-learning platform was developed to provide access to updated information about hypothermia. Volunteer and professional mountain rescuers participated in an e-learning course. Pretest, post-test, and specific lesson test scores were compared. After 1 year, a follow-up course was performed. RESULTS: In total, 187 rescuers, comprising 136 (72.7%) volunteers and 51 (27.3%) professionals, were enrolled. Ahead of the course, no difference in knowledge was found between professionals and volunteers. After the course, one's knowledge of hypothermia increased significantly (p < 0.001). The scores achieved in the field management of hypothermia were better among professional rescuers than among volunteer rescuers (p = 0.003), whereas in post-traumatic hypothermia half of the results were insufficient in both groups. Moreover, 57 rescuers repeated the course after 12 months. While professionals partially retained the achieved level of knowledge, the volunteers had dropped back to their initial level. CONCLUSIONS: The e-learning course increased the knowledge of hypothermia among mountain rescuers. The poor retention after 1 year indicates that the interval between lectures should be reduced. An e-learning platform is an effective tool for the medical education of mountain rescuers. PMID- 30010430 TI - "Taking responsibility for my health": Health system barriers and women's attitudes toward cervical cancer screening in Romania and Bulgaria. AB - The study used mixed-methods to illustrate the complexity of the interplay between the contexts in Bulgaria and Romania and women's attitudes and behaviors related to screening. A secondary analysis of quantitative data from Romanian (n = 1053) and Bulgarian (n = 1099) women and qualitative interviews ( n = 30 Romanian, n = 35 Bulgarian) was performed. Low rates of screening attendance were found in both countries. Regression analysis illustrates that attitudes and social norms significantly predicted intentions and screening behavior in both countries. Thematic analysis revealed that systemic barriers and cultural meanings were relevant to women's decisions to attend screening or avoid contact with the health-care system. PMID- 30010431 TI - The effect of time on cognitive impairments after non-traumatic subarachnoid haemorrhage and after traumatic brain injury. AB - OBJECTIVES: To compare the effect of time on cognitive impairments after Subarachnoid Haemorrhage and Traumatic Brain Injury and explore associations with baseline variables and global function. METHODS: Patients with a Glasgow Coma Scale score of 3-13, were assessed at 3, 6 and 12 months post injury by use of BNIS for cognitive impairment, RLAS-R to categorise cognitive and behavioural function, Barthel Index to assess performance of daily living, HADS to screen for depression and anxiety, and EuroQoL-5D, LiSat-11 and Glasgow Outcome Scale Extended to assess global function. RESULTS: BNIS T-scores did not differ significantly between groups and the proportion of patients with cognitive impairments was not significantly different at any time point. Cognition improved significantly between all time points in both groups except from 6 to 12 months after TBI. Generalised estimating equation showed non-significant signs of slower recovery of BNIS T-scores over time after SAH. Acute GCS scores were associated with BNIS T-scores after TBI but not after SAH. At 12 months, similar proportions of patients with SAH and TBI had good outcome. CONCLUSIONS: Cognitive improvements after SAH and TBI exhibit similarities and correlate with global function. GCS scores are associated with outcome after TBI but not after SAH. PMID- 30010432 TI - Validation of a proteomic biomarker panel to diagnose minor-stroke and transient ischaemic attack: phase 2 of SpecTRA, a large scale translational study. AB - OBJECTIVE: To validate our previously developed 16 plasma-protein biomarker panel to differentiate between transient ischaemic attack (TIA) and non-cerebrovascular emergency department (ED) patients. METHOD: Two consecutive cohorts of ED patients prospectively enrolled at two urban medical centers into the second phase of SpecTRA study (training, cohort 2A, n = 575; test, cohort 2B, n = 528). Plasma samples were analyzed using liquid chromatography/multiple reaction monitoring-mass spectrometry. Logistic regression models which fit cohort 2A were validated on cohort 2B. RESULTS: Three of the panel proteins failed quality control and were removed from the panel. During validation, panel models did not outperform a simple motor/speech (M/S) deficit variable. Post-hoc analyses suggested the measured behaviour of L-selectin and coagulation factor V contributed to poor model performance. Removal of these proteins increased the external performance of a model containing the panel and the M/S variable. CONCLUSIONS: Univariate analyses suggest insulin-like growth factor-binding protein 3 and serum paraoxonase/lactonase 3 are reliable and reproducible biomarkers for TIA status. Logistic regression models indicated L-selectin, apolipoprotein B-100, coagulation factor IX, and thrombospondin-1 to be significant multivariate predictors of TIA. We discuss multivariate feature subset analyses as an exploratory technique to better understand a panel's full predictive potential. PMID- 30010433 TI - Pulsatile flow through a constricted tube: effect of stenosis morphology on hemodynamic parameters. AB - In this paper, we investigate pulsatile flow through a constricted tube with the aim of assessing the effect of stenosis morphology on hemodynamic parameters. The fluid-solid interaction of pulsatile flow through a compliant tube with elastic walls was simulated using an arbitrary Lagrangian-Eulerian (ALE) finite-element method. We consider blood flow through various mild stenoses of 25.8% severity in diameter with trapezoidal and bell-like morphologies at a fixed Womersley number of 7.75. The results show that the distribution of the time-averaged wall shear stress (TAWSS), which is the main factor affecting the hemodynamic parameters, strongly depends on the axial stretch of the stenosis; elongation of the stenotic region increases by 41.1% the maximum TAWSS for stenoses of trapezoidal morphology whereas the maximum TAWSS decreases by 14.8% for the corresponding stenoses of bell-like morphology. The present findings indicate that risk factors due to atherosclerosis may vary in a complicated manner as an atheromatous plaque gradually builds up and morphs with time. PMID- 30010434 TI - Recurrence prediction using microRNA expression in hormone receptor positive breast cancer during tamoxifen treatment. AB - PURPOSE: To identify miRNAs associated with distant recurrence during tamoxifen treatment and build a recurrence prediction model. MATERIALS AND METHODS: We measured the expression of five miRNAs (miR-134, miR-125b-5P, miRNA-30a, miR-10a 5p and miR-222). A total of 176 tumour tissues from 176 patients who had hormone receptor positive breast cancer with tamoxifen treatment were used to measure miRNA expression using quantitative real-time PCR (qRT-PCR). RESULTS: The five miRNAs were all up-regulated in distant recurrence cases within 5 years after surgery and during tamoxifen treatment. Kaplan-Meier survival analyses based on expression cut-offs determined by receiver characteristics curves (ROC) showed that high expression of miR-134, miR-125b-5P, miRNA-30a, miR-10a-5p and miR-222 were significantly (log-rank p-value =0.006, p-value <0.0001, p-value <0.0001, p value <0.0001 and p-value <0.0001, respectively) associated with short relapse free time. Our results were used to build a combined 3 miRNAs expression model. It could be used to categorize high-risk subset of patients with short relapse free survival (AUC =0.891, p-value <0.0001). CONCLUSIONS: Distant recurrence during tamoxifen treatment of hormone positive breast cancer might be affected by tamoxifen resistance related miRNAs. Such distant recurrence can be predicted using miRNA measurement. PMID- 30010435 TI - Chronic effects of neurotrauma consortium: a combined comparative analysis of six studiesIntroduction to Special edition of Brain Injury. PMID- 30010436 TI - Responsive polymer conjugates for drug delivery applications: recent advances in bioconjugation methodologies. AB - Protein-polymer conjugates have achieved tremendous attention in the last few years, since their importance in diverse fields including drug delivery, biotechnology and nanotechnology. Over the past few years, numerous chemical strategies have been developed to conjugate different synthetic polymers onto proteins and great progress has been made. Currently, there are a handful of therapeutic polymer conjugates that have been approved by the FDA, while many hundreds of products are under extensive clinical trials and preclinical development phases. In this way, the development of novel techniques for conjugation, especially living radical polymerisation (LRP) has greatly enhanced the potential to broaden the scope of therapeutic conjugates. As a consequence, versatile techniques have developed, such as the 'grafting from' approach, which allows modifications of biomacromolecules at the atomic level, and subsequently preparing well-defined stimuli-responsive conjugates. These strategies present a unique perspective for therapy expansion of a new generation of 'smart' products with proprieties that can be finely controlled and tuned rather than just enhanced. This article highlights recent advances in the synthesis and application of protein-polymer conjugates by controlled radical polymerisation techniques, with special emphasis on stimuli-responsive conjugates on new applications in biomedical and pharmaceutical areas. PMID- 30010437 TI - Insights into the intestinal bacterial metabolism of flavonoids and the bioactivities of their microbe-derived ring cleavage metabolites. AB - Flavonoids are a group of phytochemicals widely distributed in plants, fruits, and vegetables that possess numerous bioactivities. After oral administration, flavonoids can be metabolized by the intestinal bacteria into a wide range of low molecular-weight phenolic acids. In this review, the intestinal bacterial metabolic pathways of different flavonoids (flavones, isoflavones, flavonols, flavanones, and chalcones) and the bioactivities of their microbe-derived ring cleavage metabolites are summarized. Flavonoids undergo different intestinal bacterial metabolic reactions, depending on the characteristics of their structure. Free hydroxyl groups, especially 5 and 4' free hydroxyl groups play significant roles in fission metabolism. Microbe-derived ring cleavage metabolites such as 3,4-dihydroxyphenylacetic acid (3,4-DHPAA) and 3,4 dihydroxytoluene (3,4-DHT) possess various bioactivities including antioxidant, anti-inflammatory, antidiabetic, neuroprotective, and anti-colon cancer effects. Also, the intestinal bacteria associated with the bacterial metabolism of flavonoids are covered in this review. PMID- 30010438 TI - The role of "Integrated Pulmonary Index" monitoring during morphine-based intravenous patient-controlled analgesia administration following supratentorial craniotomies: a prospective, randomized, double-blind controlled study. AB - OBJECTIVE: Morphine is commonly used in post-operative analgesia, but opioid related respiratory depression causes a general reluctance for its use. The "Integrated Pulmonary Index" is a tool calculated from non-invasively obtained respiratory and hemodynamic parameters. The aim of this prospective, randomized, double blind, and placebo-controlled study is to determine a more safe and effective dose for morphine in patient-controlled analgesia following supratentorial craniotomy using the "Integrated Pulmonary Index". METHODS: This study included 60 patients (ASA I, II, and III). All patients used iv PCA for 24 h following supratentorial craniotomy. The PCA was set to administer a bolus dose of 1 mg morphine in Group 1 and 0.5 mg morphine in Group 2. The PCA contained placebo in Group 3 and patients received dexketoprofen 50 mg iv after awakening, repeated every 8 h. The IPI and NRS scores, total morphine consumption, and morphine related side-effects were recorded at 10 min, 1, 2, 6, 12, and 24 h post operatively. The lowest IPI score, count of apnea, and desaturation events were recorded during the study period. RESULTS: The IPI scores were similar among the groups. Although a statistically significant difference was not observed among the groups the lowest IPI scores were observed in Group 1; apnea and desaturation counts were also higher in Group 1. Statistically significant differences were not observed among the groups in terms of pain scores, but were lower in Groups 1 and 2 compared to Group 3. CONCLUSION: Patient controlled analgesia with 0.5 mg morphine may be safe and effective for pain management following supratentorial craniotomies. Integrated pulmonary index can be used for detecting opioid-induced respiratory depression. Clinical Trials registration number: NCT02929147. PMID- 30010439 TI - Everyday life in older men living alone - a complex view needing a biopsychosocial perspective. AB - PURPOSE: To explore how older men living alone, describe their everyday activities and their abilities as well as how they could be helped in everyday life. MATERIALS AND METHODS: Qualitative semi-structured interviews were analysed with inductive content analysis. Eight men aged 65+ years were included. They were all living alone, albeit with home help services. They were able to walk and had sufficient cognitive ability. RESULTS: The analysis resulted in one theme "A driving force of managing activities and overcome hindering factors requires a broad spectrum of prerequisites for participating in everyday life" with the following four categories: Importance of everyday activities; individual prerequisites enabling everyday activities; body and mind inhibit, and react to the decreased, abilities; and importance of the environment. CONCLUSIONS: The results generate a complex view of older men's everyday life. It is important for older men's independence that health care and rehabilitation staff adopt a comprehensive view and work from a biopsychosocial (BPS) perspective. Implications for rehabilitation To be an older man living alone might mean a decreased health and good health is a strong predictor for increased abilities in everyday activities. The living situation of older men living alone is not well studied and needs to be explored to a greater extend, especially from their own perspective. An interaction of biological, psychological, and social factors was expressed as important for older men's everyday life, in accordance with the biopsychosocial (BPS) model. The expressed importance of participation as well as performing both physical and social activities reflects the need of individualised goals in rehabilitation according to the behavioural medicine approach. It is of outmost importance that health care and rehabilitation staff in contact with this group has a comprehensive view and works from a biopsychosocial (BPS) perspective, for maintenance of the older men's independence in everyday life. PMID- 30010441 TI - The benefits of practical clinical trials over traditional randomized clinical trials for opioid management. PMID- 30010440 TI - Preferred posture in lying and its association with scoliosis and windswept hips in adults with cerebral palsy. AB - OBJECTIVE: The aim of this study was to clarify the association of scoliosis and windswept hips with immobility, lying position, and time in lying, in adults with cerebral palsy (CP). METHODS: This cross-sectional study included 830 adults (469 males and 361 females) with a diagnosis of CP, 16-73 years, and classified at levels I-V according to the Gross Motor Function Classification System (GMFCS). Subjects' Gross motor function classification system level, presence and severity of scoliosis, hip and knee joint range of movement, lying position, postural ability in lying, and time in lying were used to identify connections between them. RESULTS: Adults who are immobile in the lying position have higher odds of both scoliosis and windswept hips. Spending more than 8 h daily in the same lying position, increased the odds of having scoliosis, while lying solely in a supine position, resulted in higher odds of windswept hips. CONCLUSIONS: The "preferred" habitual posture frequently observed in immobile adults with CP, leads to established distortion of their body shape. The results indicate the need for early introduction of appropriate posture control, in immobile individuals with CP, from a young age. Implications for rehabilitation The preferred posture, observed in immobile adults with cerebral palsy, leads to a distortion of their body shape. One in four adults with cerebral palsy use only one position when in bed. The results indicate the need for early introduction of appropriate posture control in individuals unable to change position. PMID- 30010442 TI - Point-cloud registration using adaptive radial basis functions. AB - Non-rigid registration is a common part of bioengineering model-generation workflows. Compared to common mesh-based methods, radial basis functions can provide more flexible deformation fields due to their meshless nature. We introduce an implementation of RBF non-rigid registration with iterative knot placement to adaptively reduce registration error. The implementation is validated on surface meshes of the femur, hemi-pelvis, mandible, and lumbar spine. Mean registration surface errors ranged from 0.37 to 0.99 mm, Hausdorff distance from 1.84 to 2.47 mm, and DICE coefficients from 0.97 to 0.99. The implementation is available for use in the free and open-source GIAS2 library. PMID- 30010443 TI - Establishing dimensionality of sexual behaviours in patients with regional brain dysfunction. AB - OBJECTIVE: To develop a validated, caregiver-based measurement scale to assess sexual changes across several domains in a sample of 86 patients with penetrating traumatic brain injury (TBI) and 65 patients with neurodegeneration due to frontotemporal dementia and corticobasal syndrome. METHODS: A new measure, the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), was constructed. Dimensionality, monotonicity, item discrimination power, and scalability were evaluated using nonparametric Mokken item response theory (IRT) methodology. RESULTS: Three primary domains were established. The domains presented with sufficient reliability (rho .70 to .80), while meeting the Mokken IRT criteria of medium scalability. The domains were labeled 'Prosocial sexual behaviour' (H = .42), 'Sexual interest' (H = .50), and 'Inappropriate sexual behaviour' (H = .41). A fourth dimension emerged, 'Detachment' (H = .47), but with very few items. CONCLUSIONS: Construct validity was established for groups of items pertaining to three unique aspects of sexuality. These findings support further use of the SNIQ in assessing and researching sexual behaviours in patients with dementia and brain injury. PMID- 30010444 TI - Advances in microwave-assisted synthesis and the impact of novel drug discovery. AB - INTRODUCTION: Microwave (MW)-assisted synthesis of biologically active compounds has received a lot of attention in the last decades due to the advantages that such a technique offers compared to traditional heating procedures. Areas covered: The authors provide a focused review on the recent applications of this technique for drug design purposes. MW syntheses have been used for designing libraries of compounds, in combinatorial and multicomponent approaches, for lead optimization, as well as for forcing reactions which do not occur or occur in low yields using traditional methods. Expert opinion: This technique offers significant advantages over the traditional heating due to the fact that the reaction time is shortened, the possibility to have concurrent side reactions is decreased and the use of smaller amounts of polluting solvents is also reduced. However, no significant technical advances have been reported for MW-assisted devices in the last years, with the important novelty being only in the type of reactions/compounds that have been investigated and synthesized using the MW heating approach. PMID- 30010445 TI - The efficacy of inhaled antibiotics in non-cystic fibrosis bronchiectasis. AB - INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) is considered a chronic heterogenic pulmonary disease, characterized by the permanent and abnormal enlargement and thickening of bronchial walls, impaired mucociliary clearance, and suppuration. Inhaled antibiotics have been used for a long time in patients with cystic fibrosis but are seldom used in those with NCFB and few randomized clinical trials are available in this population. Areas covered: This review summarizes current clinical evidence of efficacy, adverse events, and future directions of inhaled antibiotics in NCFB. Expert commentary: Inhaled antibiotics are theoretically a promising therapeutic option for patients with NCFB, owing to the achieved high pulmonary concentrations and the irrelevant systemic adverse effects. In the era of multidrug resistance, we call for comprehensive clinical trials in this field to corroborate the merits of inhaled antibiotics in NCFB patients. PMID- 30010447 TI - Precision dosing in clinical medicine: present and future. PMID- 30010446 TI - Quantitation of intracellular triphosphate metabolites of antiretroviral agents in peripheral blood mononuclear cells (PBMCs) and corresponding cell count determinations: review of current methods and challenges. AB - INTRODUCTION: Peripheral blood mononuclear cells (PBMCs) are a critical component of the immune system and the target cells for human immunodeficiency virus, type 1 (HIV-1) infection. Nucleoside/nucleotide analogs for the treatment of HIV infection are prodrugs that require cellular activation to triphosphate (TP) metabolites for antiviral activity. A reliable method of PBMC isolation and subsequent cell counting, as well as an accurate bioanalytical determination of the TPs in PBMCs are important for understanding the intracellular pharmacokinetic (PK) of the TPs and its correlation with plasma PK, the drug effect, and dose determination. Areas covered: The authors review the challenges and solutions in PBMC sample collection, sample processing, cell lysis, cell counting methods, analyte extraction, and liquid chromatography/tandem mass spectrometry (LC-MS/MS) quantitative analysis of the nucleoside reverse transcriptase inhibitor-triphosphate (NRTI-TP) metabolites, and analogs. Expert opinion: Analyzing large numbers of clinical PBMC samples for determination of NRTI-TPs and analogs in PBMCs requires not only a validated LC-MS/MS bioanalytical method but also reliable methods for PBMC isolation, counting, cell lysis, and analyte recovery, and an approach for assessing analyte stability. Furthermore, a simple, consistent, and validated cell counting method often involves DNA quantitation of the PBMCs samples collected from clinical studies. PMID- 30010448 TI - Important but far away: adolescents' beliefs, awareness and experiences of fertility and preconception health. AB - OBJECTIVES: The aim was to explore adolescents' beliefs and awareness regarding fertility and preconception health, as well as their views and experiences of information about fertility and preconception health directed at their age group. METHODS: We performed seven semi-structured focus group interviews among upper secondary school students (n = 47) aged 16-18 years in two Swedish counties. Data were analysed by qualitative content analysis. RESULTS: One theme ('important but far away') and five categories ('starting a family far down on the list'; 'high awareness but patchy knowledge of fertility and preconception health'; 'gender roles influence beliefs about fertility and preconception health'; 'wish to preserve fertility and preconception health in order to keep the door to procreation open'; 'no panacea - early and continuous education about fertility and preconception health') emerged from the interviews. Participants recognised the importance of preconception health and were highly aware of the overall importance of a healthy lifestyle. Their knowledge, however, was patchy and they had difficulties relating to fertility and preconception health on a personal and behavioural level. Participants wanted more information but had heterogeneous beliefs about when, where and how this information should be given. CONCLUSION: The adolescents wanted information on fertility and preconception health to be delivered repeatedly as well as through different sources. PMID- 30010449 TI - Endoscopic predictive factors associated with local recurrence after gastric endoscopic submucosal dissection. AB - OBJECTIVE: Endoscopic submucosal dissection (ESD) has been accepted as the treatment of choice for gastric epithelial neoplasia. Endoscopic characteristics of the primary lesion and post-ESD scars may be informative to predict the possibility of local recurrence. METHODS: Between November 2008 and July 2015, a retrospective study was conducted in a single-tertiary referral hospital. Consecutive patients who underwent ESD for early gastric cancer (EGC) or high grade dysplasia were analyzed to evaluate the incidence of local recurrence and associated endoscopic characteristics. RESULTS: A total of 639 lesions were analyzed. The rates of en-bloc and complete resection were 98.1% and 95.5%, respectively. A total of 15 local recurrent lesions were found (2.3%). The endoscopic findings of primary lesions associated with local recurrence were a lesion size >=20 mm (odds ratio, OR, 4.408; 95% confidence interval, CI, 1.369 14.186, p = .013) and incomplete endoscopic resection (OR 17.059, 95% CI 4.887 59.551, p < .001). During follow-up endoscopic examinations, atypical scar findings (non-flat morphology, erythematous color change and uneven surface pattern) were significant endoscopic findings to predict local recurrence. Local recurrence was absent for ESD scars with even-flat morphology without erythema. CONCLUSION: Lesions with larger size (>= 20 mm) and incompletely resected lesions had higher risk of local recurrence. Endoscopic forceps biopsy is unnecessary for even-flat ESD scar without erythematous changes. PMID- 30010450 TI - The risk of developing a mismatch repair deficient colorectal cancer after undergoing cholecystectomy. AB - OBJECTIVES: Mismatch repair deficient (dMMR) colorectal cancer (CRC) is caused by inactivation of the MMR DNA repair system, most commonly via epigenetic inactivation of the MLH1 gene, and these tumors occur most frequently in the right colon. The objective was to determine whether cholecystectomy (CCY) increases the risk of a dMMR CRC by comparing CCY incidence in patients with dMMR CRC and proficient MMR (pMMR) CRC to unaffected controls. MATERIALS AND METHODS: All patients diagnosed with CRC in Iceland from 2000 to 2009 (n = 1171) were included. They had previously been screened for dMMR by immunohistochemistry (n = 129 were dMMR). Unaffected age- and sex-matched controls (n = 17,460) were obtained from large Icelandic cohort studies. Subjects were cross-referenced with all pathology databases in Iceland to establish who had undergone CCY. Odds ratios were calculated using unconditional logistic regression. RESULTS: Eighteen (13.7%) dMMR CRC cases and 90 (8.7%) pMMR CRC cases had undergone CCY compared to 1532 (8.8%) controls. CCY-related odds ratios (OR) were 1.06 (95% CI 0.90-1.26, p = .577) for all CRC, 1.16 (95% CI 0.66-2.05 p = .602) for dMMR CRCand 1.04 (95% CI 0.83-1.29, p = .744) for pMMR CRC. Furthermore, OR for dMMR CRC was 0.51 (95% CI 0.16-1.67, p = .266), 2.04 (95% CI 0.92-4.50, p = .080) and 1.08 (95% CI 0.40 2.89, p = .875) <10 years, 10-20 years and >20 years after a CCY, respectively. CONCLUSIONS: There was no evidence of increased risk of developing dMMR CRC after CCY although a borderline significantly increased 2-fold risk was observed 10-20 years after CCY. Larger studies are warranted to examine this further. PMID- 30010451 TI - The prognosis of infants with neonatal respiratory inhibition syndrome. AB - OBJECTIVE: The goal of this study was to investigate the prognosis of infants with neonatal respiratory inhibition syndrome (NRIS). METHODS: Infants with a gestational age of at least 36 weeks and a birth weight of at least 2000 g who were born at Nara Prefecture General Medical Center, in Nara, Japan, between March 2013 and June 2016 were screened for NRIS using our established method. NRIS was defined as severe hypoxemia caused by respiratory inhibition immediately after crying (RIAC) or gastroesophageal reflux (RIGER) or as a respiratory pause during feeding (feeding hypoxemia), accompanied clinically by central cyanosis and a decrease in SpO2 to less than 70%. All infants were monitored using pulse oximetry immediately after birth. Diagnosis of RIAC, feeding hypoxemia, and RIGER are based on observation by both parents and medical staff as well as on on screen computer analysis using specific software. All infants were examined at a one-month check-up. Parents of the infants who experienced one or more episodes of NRIS accompanied by a decrease in SpO2 to less than 70% for more than approximately 60 s received a questionnaire by mail about their child's development. We conducted a logistic regression analysis with developmental problems as the dependent variable. RESULTS: NRIS was observed in 362 (28.5%) infants; 216 (17.0%) infants showed RIAC, 254 (20.0%) infants showed feeding hypoxemia, and 54 (4.2%) infants showed RIGER. Although all infants were monitored in the maternity ward nursery, 184 (85.2%) infants with RIAC and 111 (43.7%) infants with feeding hypoxemia were overlooked. All infants with NRIS were found to have successfully recovered at one month after birth. Sixty-two cases were examined in the follow-up study by the mailed questionnaire. The median age of the subjects at time of study was 22 months. Fourteen cases (22.6%) exhibited developmental problems including delayed speech development, stereotyped interests and behaviors, sensory disturbance, hyperactivity, delayed motor development, and short stature. Developmental problems tended to relate to shorter gestational age (odds ratio, 0.622; p = .068; 95% CI, 0.373-1.036), smaller birth weight (odds ratio, 0.998; p = .069; 95% CI, 0.997-1.000), and maximum duration of SpO2 to less than 70% by RIAC (odds ratio, 1.009; p = .086; 95% CI, 0.999-1.020). All cases had experienced severe hypoxemia accompanied by a decrease in SpO2 to less than 60%. Seven cases had experienced prolonged hypoxemia accompanied by a decrease in SpO2 to less than 70% for at least 2 min. Among the subjects, 19 infants were examined closely, and their natural course of NRIS was observed in the neonatal intensive care unit. No cases demonstrated abnormal findings with blood examinations, chest-abdominal X-ray, echocardiogram, laryngoendoscopy, hearing loss screening, or mass screening. Only one case had a small intracranial hemorrhage as evidenced in a magnetic resonance imaging of the head. CONCLUSIONS: The infants with severe NRIS tended to have developmental problems. Spreading knowledge about NRIS worldwide is thought to be very important. PMID- 30010452 TI - Medical cannabis legalization and state-level prevalence of serious mental illness in the National Survey on Drug Use and Health (NSDUH) 2008-2015. AB - Although research has established a link between cannabis legalization and use, and cannabis use and mental health, the relationship between medical cannabis legalization and mental health remains uncharacterized. This analysis investigated the relationship between state medical cannabis laws (restrictive, i.e. covering a narrow set of medical conditions; or liberal, i.e. covering a broad range of medical conditions), whether the law permits patients to petition their physician to approve medical cannabis use for specific medical conditions, and state prevalence of serious mental illness (SMI) in the National Survey of Drug Use and Health 2008-2015. In a covariate-adjusted meta-regression, liberal laws were significantly associated with higher prevalence of SMI (Coeff = 0.003, SE = 0.001, p < .001). Restrictive laws (Coeff = 0.001, SE = 0.001, p = .285) and the ability to petition physician approval (Coeff = -0.001, SE = 0.001, p = .140) were non-significant. When added to the model, state past-year cannabis use was significantly associated with higher prevalence of SMI (Coeff = 0.037, SE = 0.015, p = .018), liberal laws remained significant (Coeff = 0.002, SE = 0.001, p = .015), and restrictive laws (Coeff = -0.0001, SE = 0.001, p = .945) and the ability to petition a physician (Coeff = 0.001, SE = 0.001, p = .290) remained non-significant. Medical cannabis laws are likely related to state mental health, and a higher prevalence of cannabis use partially explains this relationship. PMID- 30010453 TI - Assessing the pattern of recurrence in Danish stage I lung cancer patients in relation to the follow-up program: are we failing to identify patients with cerebral recurrence? AB - BACKGROUND: There is paucity of evidence regarding the optimal follow-up (FU) regimen for lung cancer. Consequently, FU is organized differently across countries. The Danish FU regimen has short FU intervals with a computed tomography (CT) scan of the chest and upper abdomen every three months in the early phase (first 2 years), then every six months in the late phase of FU (3rd, 5th year). Characterizing recurrences missed by the FU program in terms of site, tumor histology, department, and phase of FU, could improve the FU program. MATERIAL AND METHOD: A case-control study of curatively treated stage I lung cancer patients who attended the Danish FU-program and had recurrence identified through the follow-up program (controls, FU group) or outside FU program (cases, symptomatic group). RESULTS: Of 233 included patients with recurrence, the FU group constituted 85% (n = 197). Among the 15% (n = 36) in the symptomatic group, 53% had involvement of the central nervous system compared with 3% in the FU group. The unadjusted odds ratio (OR) for having an isolated brain recurrence (IBR) in the symptomatic group was 52.3 (95%CI: 15.1-181.4) as compared with the FU group. The OR for having a symptomatic recurrence in the early phase of FU was 2.5 (95%CI: 0.7-8.7) compared with the late phase. CONCLUSIONS: The FU program did not identify the majority of patients with IBR. Including cerebral imaging in the FU program may result in an earlier detection of brain metastases. These matters should be studied in a prospective setting. PMID- 30010454 TI - Belief in medication and adherence to antiepileptic drugs in people with epilepsy: a cross-sectional study from rural India. AB - AIM OF THE STUDY: This study was aimed to assess belief in medication and non adherence to antiepileptic drugs (AEDs) in people with epilepsy (PWE) from rural India. And furthermore to study the demographic and seizure attributes influencing the adherence. MATERIALS AND METHODS: Present cross-sectional study included 230 adult PWE. Adherence level was assessed by using validated Morisky Green test and patient's beliefs towards usage of AEDs by utilizing Beliefs about Medicine Questionnaire (BMQ). RESULTS: On the Morisky-Green scale, 57% patients were reported non-adherent to treatment: 49.6% had moderate and 7.4% had low adherence levels. Non-adherence was considerably associated with lower socioeconomical status (p<.001), severity of seizures (p<.001), and duration of epilepsy (p<.041). The connection between seizures recurrence and non-adherence was measurably noteworthy (p<.001). Non-adherent patients had more concern about the potential adverse effects of AEDs (p<.0013). CONCLUSIONS: Beliefs about medicines are a contributing factor to adherence towards AEDs and more concern was common among non-adherent patients. The reinforcement of epilepsy services in rural and underserved areas can be done by providing a regular, uninterrupted, and free supply of AEDs on monthly basis in the government hospitals. There is a need for awareness and educational programs by healthcare professionals at different levels, to support and encourage positive beliefs, and discourage myths against AEDs in order to increase patient's adherence. PMID- 30010455 TI - Ferulic acid protects against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells via the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway. AB - PURPOSE: Intestinal epithelial barrier dysfunction is crucial in the pathogenesis of intestinal and systemic diseases. Ferulic acid (FA) possesses promising antioxidant activities. In a previous study, we demonstrated potentially protective effects of FA against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells. However, the underlying mechanisms are unclear. The present study aimed to elucidate whether FA protects IEC-6 cells from heat stress-induced intestinal epithelial barrier dysfunction via antioxidative mechanisms. MATERIALS AND METHODS: IEC-6 cells were pretreated with FA prior to hyperthermia exposure at 42 degrees C for 6 h, and the levels of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), nitrogen oxide (NO), and superoxide dismutase (SOD) activity were analyzed. The intestinal epithelial barrier function was determined by transepithelial electrical resistance (TER) values and 4-kDa fluorescein isothiocyanate-dextran (FD4) flux in IEC-6 cell monolayers. Expression of related proteins was detected by Western blotting. RESULTS: FA suppressed heat stress-induced intestinal oxidative stress damage by reducing ROS, MDA and NO production, while enhancing SOD activity. Furthermore, FA treatment strengthened intestinal barrier function via increasing the phosphorylation levels of Akt, nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expression, which was reversed by zinc protoporphyrin (an HO-1 inhibitor). Additionally, LY294002, a specific PI3K/Akt inhibitor, significantly suppressed FA-induced Nrf2 nuclear translocation and HO 1 protein expression and inhibited FA-induced occludin and ZO-1 protein expression. CONCLUSIONS: FA protected against heat stress-induced intestinal epithelial barrier dysfunction via activating the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in IEC-6 cells. PMID- 30010456 TI - Platelet aggregation in healthy women during normal pregnancy - a longitudinal study. AB - Increased platelet activation is involved in obstetric complications such as preeclampsia and intrauterine growth retardation. It is of interest to study platelet aggregation during pregnancy, since increased aggregation theoretically could be a mechanism associated with placenta-mediated complications, which possibly could be prevented by drugs inhibiting platelet aggregation. There are, however, few robust studies describing platelet aggregation during normal pregnancy. The present longitudinal study was performed in order to study platelet aggregation during normal pregnancy resulting in a healthy child, during the puerperium and in nonpregnant, fertile women. Healthy, nonsmoking, pregnant women (n = 104), aged under 39 years and with BMI < 35, were followed during pregnancy and postpartum. Twenty-seven nonpregnant, non-puerperal, fertile women were studied for comparison. Platelet aggregation was determined with multiple electrode impedance aggregometry and analyzed at inclusion, 4 times during pregnancy and after at least 3 months postpartum. Platelet aggregation postpartum was compared with gestational weeks 8-15 and 37-40, respectively, and with nonpregnant, fertile women. Hemoglobin, leucocyte count, platelet count, prothrombin time, and activated partial thromboplastin time were determined at inclusion in order to verify normal hemostasis. Activation of platelets by arachidonic acid, adenosine diphosphate (ADP), and thrombin receptor activating peptide (trap-6) resulted in less aggregation during pregnancy, compared with postpartum (p < 0.03-< 0.001). Platelet aggregation following activation by collagen was unchanged. A minor increase in aggregation as pregnancy continued was found related to ADP (p < 0.021). Positive correlations were found between platelet counts and platelet aggregation. Postpartum platelet aggregation after activation with arachidonic acid, collagen, and trap-6 was lower than in the non puerperal fertile state. Other hemostatic analyses were normal. In conclusion, there is a minor decrease in platelet aggregation after activation with arachidonic acid, trap-6, and ADP, measured with multiple electrode impedance aggregometry during normal pregnancy resulting in healthy babies, compared with the postpartum period. The small changes in platelet aggregation may be a consequence of a minor decrease in platelet count and probably lack clinical significance under normal conditions. Interindividual variations at certain time points are substantial, which limits the usefulness of the multiple electrode impedance aggregometry for determining minor changes in platelet function. PMID- 30010457 TI - Spontaneous recovery of fear differs among early - late adolescent and adult male mice. AB - Adolescence is a vulnerable period for developing anxiety-related mental disorders such as post-traumatic stress disorder (PTSD), which requires a long term course of therapy when a traumatic event has been experienced during childhood. However, the biological mechanism underlying these age-dependent characteristics remains unclear. In the present study, we used early adolescent, late adolescent and adult (4-, 8-, and 15-week old) male mice to examine age differences in fear memory, fear extinction, and spontaneous recovery of fear. We also measured the activation of extracellular signal-regulated kinase (ERK) 2 in the dorsal hippocampus (dHip) and the basolateral amygdala (BLA) following a spontaneous recovery test. Our major findings were as follows: (1) early adolescent and adult mice did not recover the fear response; only late adolescent mice recovered the fear response. (2) The ERK2 in the dHip was more activated after the spontaneous recovery test in late adolescent mice than in adult mice, and the ERK2 in the BLA was more activated after the spontaneous recovery test in adult mice than in late adolescent mice. These results suggest that there exists a unique period in which spontaneous recovery occurs and that these late adolescent behavioral signatures may be related to alteration in the ERK2 phosphorylation in the dHip and BLA. PMID- 30010458 TI - Colon targeted curcumin microspheres laden with ascorbic acid for bioavailability enhancement. AB - An objective of the present study was to prepare colon-specific microspheres of curcumin (CUR) containing ascorbic acid (AA) for improved oral bioavailability. 32 factorial design was used to optimise chitosan microspheres (CSMS) containing CUR and AA. Subsequently, optimised CSMS were coated with Eudragit S-100, for delivery to colon. In vitro drug release, in vivo pharmacokinetics, and organ distribution studies were performed in Albino Wistar rats. Stabilisation of CUR in alkaline pH was successfully guarded by AA to the extent 98.5-100%. Results revealed complete amorphisation/molecular dispersion of CUR. Bioavailability enhancement of CUR and 90% of MS in colon at the end of 8 h in animals, deciphered successful design of colon-specific CUR MS. It can be concluded that AA in MS shielded the degradation of CUR. The developed double coat MS could be considered as a promising colon-targeted system for CUR aiming bioavailability enhancements. PMID- 30010459 TI - Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type-2 inflammation: a patent evaluation (WO2017/058370). AB - INTRODUCTION: Activity modulators of carbonic anhydrases hold great potential for several therapeutic applications against ophthalmologic and neurological disease, cancer, and infectious diseases. The involvement of carbonic anhydrase in the regulation of mast cell response opens new ways for the treatment of mastocytosis, allergic inflammation, and parasite infection. Areas covered: The application claims the use of carbonic anhydrase activity modulators (inhibitors or activators) for treating allergic disease, bacterial infection, fungal infection, viral infection, mastocytosis, or mast cell-mediated inflammation. Expert opinion: Although there is a lack of essential biological data, this patent proposes a new type of applications for carbonic anhydrase inhibitors and deserves further studies. This may lead to new advances in the field of carbonic anhydrase with potential therapeutic implications in the management of type-2 inflammation. PMID- 30010461 TI - Clinical Profile of HLA B-27-Associated Uveitis Patients in a Tertiary Care Eye Hospital in Eastern India. AB - PURPOSE: To analyse clinical profile of the patients with HLA B 27- associated uveitis in a tertiary care eye hospital in Eastern India Method: Retrospective analysis of 61 eyes of 43 patients with HLA B27- associated uveitis between 2015 and 2016. RESULT: We observed a male predominance (67%), and more unilateral involvement (58%) in our patients. The mean age of presentation was 44.7 +/-11.7 years. Significant vitritis and macular edema were noted in 14 and 7 eyes respectively. In addition to topical therapy, oral steroid was required in 49% patients and 58% patients were treated with methotrexate. Five patients (12%) required biologicals. There was improvement in BCVA at final follow-up (p<0.001). CONCLUSION: Compared to the existing literature, the current study observed relatively high age of presentation and frequent posterior segment involvement with less systemic association. PMID- 30010460 TI - A membrane fusion protein, Ykt6, regulates epithelial cell migration via microRNA mediated suppression of Junctional Adhesion Molecule A. AB - Vesicle trafficking regulates epithelial cell migration by remodeling matrix adhesions and delivering signaling molecules to the migrating leading edge. Membrane fusion, which is driven by soluble N-ethylmaleimide-sensitive factor associated receptor (SNARE) proteins, is an essential step of vesicle trafficking. Mammalian SNAREs represent a large group of proteins, but few have been implicated in the regulation of cell migration. Ykt6 is a unique SNARE existing in equilibrium between active membrane-bound and inactive cytoplasmic pools, and mediating vesicle trafficking between different intracellular compartments. The biological functions of this protein remain poorly understood. In the present study, we found that Ykt6 acts as a negative regulator of migration and invasion of human prostate epithelial cells. Furthermore, Ykt6 regulates the integrity of epithelial adherens and tight junctions. The observed anti-migratory activity of Ykt6 is mediated by a unique mechanism involving the expressional upregulation of microRNA 145, which selectively decreases the cellular level of Junctional Adhesion Molecule (JAM) A. This decreased JAM-A expression limits the activity of Rap1 and Rac1 small GTPases, thereby attenuating cell spreading and motility. The described novel functions of Ykt6 could be essential for the regulation of epithelial barriers, epithelial repair, and metastatic dissemination of cancer cells. PMID- 30010462 TI - An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. AB - INTRODUCTION: P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are highly expressed in the placenta and fetus throughout gestation and can modulate exposure and toxicity of drugs and xenobiotics to the vulnerable fetus during the sensitive times of growth and development. We aim to provide an update on current knowledge on placental and fetal expressions of the two transporters in different species, and to provide insight on interpreting transporter expression and fetal exposure relative to the concept of fraction of drug transported. Areas covered: Comprehensive literature review through PubMed (primarily from July 2010 to February 2018) on P-gp and BCRP expression and function in the placenta and fetus of primarily human, mouse, rat, and guinea pig. Expert opinion: While there are many commonalities in the expression and function of P-gp and BCRP in the placenta and fetal tissues across species, there are distinct differences in expression levels and temporal changes. Further studies are needed to quantify protein abundance of these transporters and functionally assess their activities at various gestational stages. Combining the knowledge of interspecies differences and the concept of fraction of drug transported, we may better predict the magnitude of impact these transporters have on fetal drug exposure. PMID- 30010463 TI - The transcription-independent mitochondrial cell death pathway is defective in non-transformed cells containing the Pro47Ser variant of p53. AB - Approximately half of all human cancers contain mutations in the TP53 tumor suppressor. In addition to mutations, there are single nucleotide polymorphisms (SNPs) in TP53 that can dampen p53 function, and can increase cancer risk and decrease the efficacy of cancer therapy. Approximately 6% of Africans and 1% of African-Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser, or S47). The S47 variant is associated with increased breast cancer risk in pre-menopausal African Americans, and in a mouse model for the S47 variant, mice are predisposed to spontaneous cancers. We recently showed that the S47 variant is impaired for p53-mediated apoptosis in response to radiation and some genotoxic agents, particularly cisplatin. Here we identify the mechanism for impaired apoptosis of S47 in response to cisplatin. We show that following cisplatin treatment, the S47 variant shows normal stabilization and serine 15 phosphorylation, but reduced ability to bind to the peptidyl prolyl isomerase PIN1, which controls the mitochondrial localization of p53. This is accompanied by impaired mitochondrial localization of S47, along with decreased induction of cleaved caspase-3. Interestingly, we show that this defect occurs only for cisplatin and not for camptothecin. These findings show that normal tissues may respond differently to genotoxic stress depending upon this TP53 genotype. These data suggest that toxicity to cisplatin may be decreased in S47 individuals, and that this compound may be a superior treatment option for these individuals. PMID- 30010464 TI - Period from Loss of the Ability to Access Toilets Independently to Death in End Stage Cancer Patients. AB - BACKGROUND: Toileting independence is considered to be important factors for achieving a "good death" for terminally ill patients. AIM: To clarify the period from loss of the ability to access toilets independently to death in end-stage cancer patients. DESIGN: Observational study. SETTING/PARTICIPANTS: The medical records of all end-stage cancer patients who had died while using home care services provided by Medical Corporation Kagayaki General Home Care Clinic between September 2011 and August 2017, were retrospectively reviewed. RESULTS: A total of 220 patients were included. The median time from total dependence in toileting to death was 6.0 (95% confidence interval: 5.0-7.0) days. When the duration was 7 days or shorter and 21 days or shorter, the cumulative death rate was 55.9% and 86.4% respectively. CONCLUSION: A large percentage of terminally ill cancer patients maintained the ability to access toilets independently until very close to the end of their lives, so the duration of total assistance needed was shorter. These findings may be useful to make a care plan to support achieving "good death" for patients. PMID- 30010465 TI - Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo. AB - VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells. PMID- 30010467 TI - Information and communication technology use in daily life among young adults with mild-to-moderate intellectual disability. AB - BACKGROUND: Information and communication technology (ICT) increases participation in life activities, and young adults are frequent users. Young adults with intellectual disability (ID) do not use ICT as much as their peers, and little is known about how ICT is used by young adults with ID. This study describes the use of ICT from the perspective of young adults with mild to moderate ID in a municipal social care context. METHOD: Semi-structured interviews were used to collect information from 11 young adults with mild-to moderate ID living in residential care and analysed using a content analysis. RESULTS: ICT was used for family relationships, daily support, interactions based on interests and amusement, and as support for offline activities. Family members were important providers of support for ICT use. CONCLUSION: Young adults with mild-to-moderate ID use ICT in their daily life. The social care context needs to be further investigated due to its influence on the young adults' access to ICT and need of support. PMID- 30010466 TI - Place of Care Trajectories in the Last Two Weeks of Life: A Population-Based Cohort Study of Ontario Decedents. AB - BACKGROUND/OBJECTIVES: Place of death is a commonly reported indicator of palliative care quality, but does not provide details of service utilization near end of life. This study aims to explore place of care trajectories in the last two weeks of life in a general population and by disease cohorts. DESIGN/SETTING: A retrospective population-based cohort study using linked administrative-health data to examine Ontario decedents between April 1, 2010 and December 31, 2012. MEASUREMENTS: Place of care trajectories in the last two weeks of life. RESULTS: We identified 235,159 decedents. Of which, 215,533 represented the major cohorts of our analysis-cancer (32%), frailty (29%), and organ failure (31%). Sixty-one percent of all decedents died in hospital-based settings. Place of care utilization trends show us a marked increase in use of palliative-acute hospital care (13%-26%) and acute hospital care (12%-25%) and a small decrease in community care use (15%-12%) in the last two weeks of life. Those with cancer were the largest users of palliative-acute hospital care, while those with organ failure were the largest users of acute-hospital care. CONCLUSIONS: Place of care trajectories show a marked rise in care in hospital-based settings from 29% to 61% in the last two weeks of life. Nearly half of all hospital deaths had palliative care as the main service provided. Place of care trajectories differ greatly by disease cohort. Exploring place of care trajectories in the last two weeks of life can illuminate end-of-life utilization patterns not evident when reporting solely place of death. PMID- 30010469 TI - A decline in cognitive function should lead to a change in disease-modifying therapy - No. PMID- 30010468 TI - The lncRNA RHPN1-AS1 downregulation promotes gefitinib resistance by targeting miR-299-3p/TNFSF12 pathway in NSCLC. AB - Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has exhibited notable clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of gefitinib resistance. The present study aimed to investigate the effects of the long non-coding RNA, RHPN1-AS1 on gefitinib resistance in NSCLC and explore the underlying mechanisms. In this study, RHPN1-AS1 was observed to be downregulated in gefitinib resistant patients and NSCLC cell lines. Besides, decreased expression of RHPN1-AS1 was found to be associated with poor prognosis of NSCLC patients. RHPN1-AS1 knockdown conferred gefitinib resistance to gefitinib sensitive NSCLC cells, whereas the overexpression of RHPN1-AS1 sensitized gefitinib resistant NSCLC cells to gefitinib treatment. Mechanistically, RHPN1-AS1 was found to positively regulate the expression of TNFSF12 by directly interacting with miR-299-3p. Collectively, RHPN1-AS1 modulates gefitinib resistance through miR-299-3p/TNFSF12 pathway in NSCLC. Our findings indicate that RHPN1-AS1 may serve as not only a prognostic biomarker for gefitinib resistance but also as a promising therapeutic biomarker and target for the treatment of NSCLC patients. PMID- 30010470 TI - Does the Hazard of Chlamydia Increase with the Number of Gonorrhea Diagnoses? A Large Population-Based Study Among U.S. Army Women. AB - BACKGROUND: In the U.S. military, chlamydia and gonorrhea are common sexually transmitted infections, especially among female service members. The aim of this study was to determine whether the number of gonorrhea diagnoses sustained an increased hazard of chlamydia among military women. METHODS: This population based study involved an analysis of all female gonorrhea cases in the U.S. Army reported in the Defense Medical Surveillance System between 2006 and 2012. The effect of the number of gonorrhea diagnoses on the hazard of chlamydia was analyzed using the Prentice-Williams-Peterson gap-time model. RESULTS: Among 3,618 women with gonorrhea diagnosis, 702 (19.4%) had a subsequent chlamydia diagnosis yielding a rate of 6.06 (95% CI = 5.63-6.53) cases per 100 person years. Compared to women with one gonorrhea diagnosis, the hazard ratio of chlamydia for women with two gonorrhea diagnoses was 5.09 (95% CI = 4.42-5.86) and for women with three gonorrhea diagnoses was 6.53 (95% CI = 3.93-10.83). The median time to chlamydia diagnosis decreased from 2.39 to 0.67 years for women with two to three gonorrhea diagnoses. CONCLUSIONS: The hazard of chlamydia increased significantly with the number of gonorrhea diagnoses and the median time to chlamydia diagnosis decreased with an increasing number of gonorrhea diagnoses among U.S. Army women. PMID- 30010472 TI - Sex Differences in Cardiac Troponin Testing in Patients Presenting to the Emergency Department with Chest Pain. AB - BACKGROUND: Elevated cardiac troponin (cTn), with signs/symptoms of ischemia, is a key element in a diagnosis of myocardial infarction (MI). Underdiagnosis of MI in women has been attributed to atypical symptoms, inconsistent ECG findings, and less diagnostic testing. We sought to determine if there are sex differences in cTn testing following presentation to the emergency department (ED) with a chief complaint of ischemic chest pain (CP) and if presentation affects diagnostic assessment. METHODS: All adults presenting to six hospital EDs in the Vancouver, Canada with a chief complaint of ischemic CP from 2009 to 2013 were included. The highest cTn level within 24 hours of ED presentation was used. CP was classified into cardiac- or respiratory dominant based on standard Canadian Emergency Department Triage and Acuity Scale coding. Chi-square testing was used to test for sex differences in CP categories and cTn testing within 24 hours. Logistic regression models were used to examine the association between sex, cTn testing, and CP categories. RESULTS: Of 27,063 patients with ischemic CP, cardiac presentation was more common in men than women, irrespective of age. Among cardiac CP, 24.7% of men were <50 years compared to 18.2% of women; however, more women (19.9%) than men (11.6%) were >80 years. Overall, women were 1.8% less likely to have cTn testing; in patients <50 years, testing was markedly lower in women compared to men [odds ratio, OR (95% confidence intervals, CI) 0.78 (0.70 0.87)]. The odds of cardiac catheterization within 90 days of ED presentation were lower in women [OR, (95% CI) 0.52 (0.44-0.63)]. Even with cardiac CP, 17.7% of women versus 32.7% of men had cardiac catheterization. CONCLUSIONS: In men and women presenting to the ED with ischemic CP, cTn testing overall is similar except among young women under 50 years old, where it is markedly lower. Women undergo less cardiac catheterization, irrespective of CP type. PMID- 30010471 TI - Oxidative stress and NF-kappaB signaling are involved in LPS induced pulmonary dysplasia in chick embryos. AB - Inflammation or dysbacteriosis-derived lipopolysaccharides (LPS) adversely influence the embryonic development of respiratory system. However, the precise pathological mechanisms still remain to be elucidated. In this study, we demonstrated that LPS exposure caused lung maldevelopment in chick embryos, including higher embryo mortality, increased thickness of alveolar gas exchange zone, and accumulation of PAS+ immature pulmonary cells, accompanied with reduced expression of alveolar epithelial cell markers and lamellar body count. Upon LPS exposure, pulmonary cell proliferation was significantly altered and cell apoptosis was inhibited as well, indicating a delayed progress of pulmonary development. LPS treatment also resulted in reduced CAV-1 expression and up regulation of Collagen I, suggesting increased lung fibrosis, which was verified by Masson staining. Moreover, LPS induced enhanced Nrf2 expression in E18 lungs, and the increased reactive oxygen species (ROS) production was confirmed in MLE 12 cells in vitro. Antioxidant vitamin C restored the LPS induced down-regulation of ABCA3, SP-C and GATA-6 in MLE-12 cells. Furthermore, LPS induced activation of NF-kappaB signaling in MLE-12 cells, and the LPS-induced decrease in SP-C expression was partially abrogated by blocking NF-kappaB signaling with Bay-11 7082. Bay-11-7082 also inhibited LPS-induced increases of ROS and Nrf2 expression. Taken together, we have demonstrated that oxidative stress and NF kappaB signaling are involved in LPS induced disruption of pulmonary cell development in chick embryos. PMID- 30010474 TI - Epidemiology of Obesity and Associated Comorbidities. AB - Obesity currently affects 78.6 million people (33%) in the United States and is expected to increase to over 50% of the population by 2030. This epidemic is fueled by the growing rate of obesity in adolescents. The new science of obesity indicates that there is a tipping point at which genetic resetting occurs and it is reached when adipose tissue dysfunction occurs. It is becoming clear that obesity is less an ongoing personal choice than a fact of biology. With this review, we aim to describe the epidemiology of obesity and the associated comorbidities. PMID- 30010473 TI - Diabetes decreases patency of tunneled catheters in hemodialysis patients after first effective thrombolysis with urokinase. AB - INTRODUCTION: Fibrinolysis is one of the methods extending the use of vascular access in patients with tunneled venous catheters thrombosis. The aim of this study was to assess one-year maintenance of tunneled catheters patency after first effective thrombolysis with urokinase and identify its predictors. METHODS: Retrospective analysis included 85 patients (age 69 +/- 13 years) with permanent venous catheter thrombosis treated with urokinase at one center in the period 2010-2016. Urokinase was used (depending on weight) at a dose of 10,000 or 20,000 IU in an 8 h infusion to each catheter line. Assessment of one-year efficacy of fibrinolysis included the time between fibrinolysis and following thrombosis of the same catheter in patients that have previously obtained at least partial blood flow. The analysis included medication, comorbidities, catheter patency time and INR value during first thrombosis episode. RESULTS: There were 62.4% patients with type-2 diabetes and 11.8% with neoplasm. The thrombolysis procedure was effective in 73 patients (85.9%). An analysis of the one-year efficacy of thrombolysis procedure included 73 patients. Among them, 23 experienced next episode of catheter-related thrombosis within a year postprocedure. Diabetes increased the risk for recurrent thrombosis [HR =3.19 (1.09-9.41); p = .03]. CONCLUSIONS: Patients with diabetes are at higher risk of recurrent catheter related thrombosis and therefore may require more aggressive anticoagulation therapy for its prevention. PMID- 30010475 TI - Laparoscopic Roux-en-Y Gastric Bypass: Surgical Technique and Tips for Success. AB - Obesity is a worldwide increasing concern, and its prevalence has risen rapidly over the past several decades. Since nonsurgical treatment for weight loss in morbidly obese patients has poor long-term outcomes, bariatric surgery has gained acceptance and popularity in the last years. The laparoscopic Roux-en-Y gastric bypass has proved to be safe and effective, with successful long-term outcomes in morbidly obese patients. Key elements for the success of the operation are careful patient selection, a comprehensive preoperative evaluation, and a properly executed operation that respects the key technical elements. PMID- 30010476 TI - A decline in cognitive function should lead to a change in disease-modifying therapy - Yes. PMID- 30010477 TI - Correction to: Crowe et al., Innovations actively shaping speech-language pathology evidence-based practice. PMID- 30010478 TI - Music in the diagnosis, treatment and prognosis of people with prolonged disorders of consciousness. AB - Using music with people with prolonged disorders of consciousness (PDOC) has progressed considerably in recent years. Using both imaging and behavioural measures has revealed music's potential for enhancing arousal and awareness, boosting cognition and improving behavioural outcomes when compared to non-music conditions. Furthermore, music may have prognostic potential with this population. Explanations for these effects draw on music's potential to simultaneously excite the networks implicated in internal self-referential awareness and external awareness. A music-based protocol and measure for PDOC has been standardised that demonstrates particular sensitivity to assessment of auditory responsiveness, an important factor with a population where visual impairment is prevalent. Such measures can now contribute to interdisciplinary assessment of awareness in people with PDOC. Reviewing the latest research on this topic, priorities for research are identified. These include examining music's potential for prognosis of recovery, as well as its influence on the rate of emergence from PDOC, particularly its capacity to elicit heightened responsiveness across sensory domains when compared to non-music interventions. Research comparing the efficacy of live versus recorded music will help to inform evidence-based protocols. Lastly, its potential as a modality for assessment and treatment with paediatric PDOC populations should also be explored. PMID- 30010479 TI - Chromoendoscopy Plus Mucosal Resection Versus Conventional Electrocoagulation for Intestinal Polyps in Children: Two Case Series. AB - BACKGROUND: Conventional high-frequency electrocoagulation (HFEC) of intestinal polyps may be difficult in children and endoscopic mucosal resection (EMR) could be a less invasive option. Chromoendoscopy improves tissue localization during endoscopy, but its exact influence on the outcomes of children with intestinal lesions is still unknown. AIMS: To analyze a series of children treated with EMR or HFEC and assess the value of chromoendoscopy. METHODS: This was a retrospective analysis of two case series of patients treated at the Gastroenterology Department of the Guiyang Children's Hospital between February 2014 and November 2016. The children underwent EMR (n = 34) or conventional HFEC (n = 120). Demographic, clinical, and perioperative data were analyzed. RESULTS: The polyps were larger in the HFEC group [median, 3.9 (0.1-27.0) versus 1.3 (0.03 64.0) mm, P = .03]. There was a higher frequency of multiple polyps in the EMR group (50.0% versus 15.1%, P < .001). Operation time and intraoperative bleeding were similar between the two groups (both P > .05). Hospital stay was longer with EMR than with HFEC [median, 5 (3-12) versus 4 (2-14) days, P = .02]. There was no intestinal perforation in either group. Postoperative bleeding amount was similar in both groups (P = .73). In the EMR group, 19 patients were operated using chromoendoscopy, whereas only 2 patients in the HFEC group were operated. CONCLUSION: EMR could be appropriate for the treatment of intestinal polyps in children. PMID- 30010480 TI - Trends in Alcohol-Related Disparities Between Heterosexual and Sexual Minority Youth from 2007 to 2015: Findings from the Youth Risk Behavior Survey. AB - PURPOSE: The purpose of this study was to assess trends in alcohol-related disparities between heterosexual and sexual minority adolescents in the United States from 2007 to 2015. METHODS: Data were pooled from the 2007, 2009, 2011, 2013, and 2015 Youth Risk Behavior Surveys (N = 207,367) to estimate trends, disparities, and changes in disparities of four alcohol-related behaviors (i.e., lifetime alcohol use, early onset use (<13 years of age), past 30-day use, and past 30-day heavy episodic drinking [HED]) among heterosexual youth and three subgroups of sexual minority youth (SMY) (i.e., gay/lesbian, bisexual, and unsure). Models were sex stratified and adjusted for age, race/ethnicity, and state of data collection. RESULTS: The prevalence of all alcohol-related behaviors declined from 2007 to 2015 for heterosexual youth, but not as consistently for SMY. Disparities in alcohol-related behaviors between heterosexual youth and SMY largely remained stable or widened from 2007 to 2015. Disparities in lifetime alcohol use and past 30-day use were larger between heterosexual boys and gay boys in 2015 relative to 2007. Disparities in early onset use and past 30-day HED were also larger between heterosexual girls and lesbian girls in 2015 relative to 2007. The disparity in past 30-day use between heterosexual girls and bisexual girls was smaller in 2015 compared with 2007. CONCLUSIONS: Despite overall declines in adolescent alcohol use, alcohol-related disparities between heterosexual youth and SMY persist and, for some SMY, they have widened. PMID- 30010482 TI - A decline in cognitive function should lead to a change in disease-modifying therapy - Commentary. PMID- 30010481 TI - Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial. AB - This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan(r)), or European Union-sourced RTX (EU-RTX; MabThera(r)) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-last), AUC from time zero to infinity (AUC0-infinity), and maximum concentration (Cmax) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80-125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was -2.13 (0.175) for CT-P10 and -2.09 (0.176) for RTX. The 95% CI (-0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (-0.04) was entirely within the efficacy equivalence margin of +/-0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24. PMID- 30010483 TI - Balance control is impaired in adults with sickle cell anaemia. AB - BACKGROUND: Musculoskeletal involvement and cerebrovascular disease are common in sickle cell anaemia (SCA). These changes are potentially important factors that modify the control of balance in this population. OBJECTIVE: To assess balance control in adults with SCA and investigate the associations among balance, posture and muscle function. METHODS: Twenty neurologically intact (i.e. without previous episodes of overt stroke or transient ischaemic attack) adults with SCA and 18 controls were evaluated. All participants underwent static balance measurement through stabilometry, postural evaluation through photogrammetry and assessment of muscle function through handgrip and respiratory muscle strength. RESULTS: Compared to the controls, the adults with SCA exhibited greater displacement of the centre of mass, particularly in the mediolateral direction. Moreover, the adults with SCA exhibited greater postural deviations for the following variables: angles of the right and left hip, horizontal asymmetry of the scapula in relation to T3, angles of the right and left leg-heel and horizontal alignment of the pelvis. Handgrip strength, respiratory muscle strength and haemoglobin (Hb) levels were significantly correlated with postural balance measurements. Significant correlations between balance and posture were only observed between the variables of balance and the postural parameters that involved the angulations calculated from the vertical alignment of the pelvis, hip and ankle. CONCLUSIONS: Neurologically intact adults with SCA exhibit damage in static balance, particularly in the mediolateral direction. These patients present postural deviations due to changes in the hip and ankle joints. In addition, balance control is related to posture, Hb level and muscle function. PMID- 30010484 TI - Social information processing skills link executive functions to aggression in adolescents with mild to borderline intellectual disability. AB - Executive Functions (EFs) have been associated with aggression in children and adolescents. EFs as higher-order cognitive abilities are assumed to affect cognitive functions such as Social Information Processing (SIP). We explored SIP skills as a mediating mechanism linking EFs to aggression in adolescents with mild to borderline intellectual disability (MBID with IQ from 50-84), a high risk group for aggressive behaviors and EF impairments. A total of 153 adolescents (Mage = 15.24, SD = 1.35; 54% male) with MBID participated. Focused attention, behavioral inhibition, and working memory were tested with multiple neurocognitive tasks to define latent EF constructs. Participants responded to a video-based SIP task. A latent construct for aggression was defined by caretaker, teacher, and adolescent self-reports of aggression (Child Behavior Check List, Teacher Report Form, and Youth Self Report). Structural equation modeling was performed to test mediation. Results were consistent with mediation of the relation between focused attention and aggression by SIP, namely via hostile interpretations and self-efficacy for aggression. Behavioral inhibition was linked to aggression, but this relation was not mediated by SIP. The relation between working memory and aggression was mediated by SIP, namely via hostile interpretations, aggressive response generation and via self-efficacy for aggressive responses. Bearing the cross-sectional design in mind, support was found for SIP skills as a mechanism linking EFs, in particular focused attention and working memory, to aggression, providing a viable explanation for the high vulnerability of adolescents with MBID for aggression. PMID- 30010485 TI - Intra-abdominal abscess due to fish bone perforation of small bowel. PMID- 30010486 TI - What do hospitalists experience as barriers and helpful factors for having ACP conversations? A systematic qualitative evidence synthesis. AB - BACKGROUND: Hospitalists seem to struggle with advance care planning implementation. One strategy to help them is to understand which barriers and helpful factors they may encounter. AIMS: This review aims to give an overview on what hospitalists experience as barriers and helpful factors for having advance care planning conversations. METHOD: A systematic synthesis of the qualitative literature was conducted. DATA SOURCES: A bibliographic search of English peer reviewed publications in PubMed, Embase, CINAHL, Central, PsycINFO, and Web of Science was undertaken. RESULTS: Hospitalists report lacking communication skills which lead to difficulties with exploring values and wishes of patients, dealing with emotions of patients and families and approaching the conversation about letting a patient die. Other barriers are related to different interpretations of the concept advance care planning, cultural factors, like being lost in translation, and medicolegal factors, like fearing prosecution. Furthermore, hospitalists report that decision-making is often based on irrational convictions, and it is highly personal. Physician and patient characteristics, like moral convictions, experience, and personality play a role in the decision making process. Hospitalists report that experience and learning from more experienced colleagues is helpful. Furthermore, efficient multidisciplinary co operation is helping. CONCLUSION: This systematic review shows that barriers are often related to communication issues and the convictions of the involved hospitalist. However, they seem to be preventable by creating a culture where experienced professionals can be consulted, where convictions can be questioned, and where co-operation within and between organizations is encouraged. This knowledge can serve as a basis for implementation. PMID- 30010487 TI - Bacillus subtilis highly efficient protein expression systems that are chromosomally integrated and controllable by glucose and rhamnose. AB - To achieve rhamnose-inducible efficient protein expression in Bacillus subtilis, we assembled the strong promoters of B. subtilis cdd and ylbP genes and the regulatory region (PrhaEW) of B. subtilis rhaEWRBMA operon, whose transcription is induced by rhamnose and repressed by glucose, to produce various hybrid constructs. These constructs were evaluated using B. subtilis strains carrying a fusion of each construct to the gene encoding a mutated green fluorescent protein in the chromosome. When these strains were cultivated in the presence of glucose or rhamnose, the strain carrying a fusion of a partial PrhaEW region, lacking the intrinsic Shine-Dalgarno (SD) sequence, and the ylbP SD sequence most strictly controlled the promoter activity depending on sugar species. Moreover, the strain carrying a fusion of the cdd core promoter and the ylbP SD sequence showed the highest promoter activity when it was cultivated in the presence of glucose until the late stationary phase. Abbreviations: RNAP: RNA polymerase; cre: catabolite responsive element; SD: Shine-Dalgarno; PAGE: polyacrylamide gel electrophoresis; GFP: green fluorescent protein; OD600: optical density at 600 nm; LB: Luria Bertani; a.u.: arbitrary unit; SDS: sodium dodecyl sulfate. PMID- 30010488 TI - Surgical site infection after primary total knee arthroplasty is associated with a longer duration of surgery. AB - PURPOSE: Surgical site infection (SSI) is a serious complication following total knee arthroplasty (TKA) leading to considerable morbidity. The incidence is reported to be up to 2%. Risk factors continue to be an area of intense debate. Our study aims to report the incidence of SSI and identify possible risk factors in our patients undergoing TKA. METHODS: Prospectively collected data for 905 patients who underwent elective unilateral TKA by a single surgeon from February 2004 to July 2014 were reviewed. Patient demographics and relevant co-morbidities such as diabetes and heart disease were analysed. The presence of superficial wound infections and/or prosthetic joint infections was included. RESULTS: The overall infection rate was 1.10% (10 of 905 patients). Six patients (0.66%) were diagnosed with superficial infections and four with PJI (0.44%). The mean operative duration for TKA with SSI was significantly longer at 90.5 +/- 28.2 min, compared to 72.2 +/- 20.3 min in TKA without SSI ( p = 0.03). All superficial infections occurred within the first month post-surgery and were self limiting with oral antibiotics. The four patients with PJI required repeated procedures following TKA, including debridement, implant removal and/or revision arthroplasty. None of the 10 patients had a history of diabetes. There were no significant differences in demographics and co-morbidities between those who developed infection after TKA and those who did not. CONCLUSION: An overwhelming majority had good outcomes with only four deep infections resulting in revision surgery. We report that the risk of infection in TKA was significantly associated with a longer operative duration. PMID- 30010489 TI - Bilateral open pneumothorax resulting in a sucking chest wound. PMID- 30010490 TI - Reexamining the Link Between Economic Downturns and Racial Antipathy: Evidence That Prejudice Against Blacks Rises During Recessions. AB - Scholars have long argued that economic downturns intensify racial discord. However, empirical support for this relationship has been mixed, with most recent studies finding no evidence that downturns provoke greater racial animosity. Yet most past research has focused on hate crimes, a particularly violent and relatively infrequent manifestation of racial antipathy. In this article, we reexamine the relationship between economic downturns and racial acrimony using more subtle indicators of racial animosity. We found that during economic downturns, Whites felt less warmly about Blacks (Studies 1 and 2), held more negative explicit and implicit attitudes about Blacks, were more likely to condone the use of stereotypes, and were more willing to regard inequality between groups as natural and acceptable (Study 2). Moreover, during downturns, Black musicians (Study 3) and Black politicians (Study 4) were less likely to secure a musical hit or win a congressional election. PMID- 30010491 TI - Oxidative stress, antioxidant capacity, biomolecule damage, and inflammation symptoms of sickle cell disease in children. AB - BACKGROUND: The phenotypic expression of sickle cell disease (SCD) is a complex pathophysiologic condition. However, sickle erythrocytes might be the cause for multiple sources of pro-oxidant processes with consequent linked to chronic and systemic oxidative stress. Herein, we explored the SCD phenomena could be the result in formation of oxidative stress as well as inflammation in children. MATERIAL AND METHODS: Blood samples of 147 SCD subjects were evaluated. A control group was formed of 156 individuals without SCD. Different oxidative stress markers and inflammatory mediators were measured by using various biochemical techniques. Plasma samples were collected from blood for the measurement of antioxidants and reactive oxygen species (ROS). RESULTS: The levels of plasma hydroxyl radical (HO*), and nitric oxide (NO) production were higher in SCD children in compared to control groups. The plasma antioxidants capacities such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx) and protein thiol levels were significantly reduced in SCD children. The plasma lipid peroxidation, protein carbonylation, DNA damage markers were significantly altered in different age groups of SCD children. Further, our results showed that SCD children have chronic inflammatory disease due to persistent alteration of haemoglobin content, reticulocyte, total bilirubin, platelet, creatinine, leukocytes, and altered expression of inflammatory mediators in compared to control groups. CONCLUSION: SCD children have high oxidative stress, and conversely, decreased antioxidant activity. Decrease in antioxidant activity might explained the reduction in lipid peroxidation, protein carbonylation and increased inflammation, which in turn intensify the symptoms of SCD in children. PMID- 30010492 TI - Confidence intervals for proportion ratios of stratified correlated bilateral data. AB - In stratified bilateral studies, responses from two paired body parts are correlated. Confidence intervals (CIs), which reveal various features of the data, should take the correlations into account. In this article, five CI methods (sample-size weighted naive Maximum likelihood estimation (MLE)-based Wald-type CI, complete MLE-based Wald-type CI, profile likelihood CI, MLE-based score CI and pooled MLE-based Wald-type CI) are derived for proportion ratios under the assumption of equal correlation coefficient within each stratum. Monte Carlo simulation shows that the complete MLE-based Wald-type CI approach generally produces the shortest mean interval width and satisfactory empirical coverage probability with close form solution; while the profile likelihood CI and the MLE based score CI provide preferred ratio of non coverage probability and are more symmetric. Two real examples are used to demonstrate the performance of the proposed methods. PMID- 30010493 TI - In Defense of the Commons: Young Children Negatively Evaluate and Sanction Free Riders. AB - Human flourishing depends on individuals paying costs to contribute to the common good, but such arrangements are vulnerable to free riding, in which individuals benefit from others' contributions without paying costs themselves. Systems of tracking and sanctioning free riders can stabilize cooperation, but the origin of such tendencies is not well understood. Here, we provide evidence that children as young as 4 years old negatively evaluate and sanction free riders. Across six studies, we showed that these tendencies are robust, large in magnitude, tuned to intentional rather than unintentional noncontribution, and generally consistent across third- and first-party cases. Further, these effects cannot be accounted for by factors that frequently co-occur with free riding, such as nonconforming behaviors or the costs that free riding imposes on the group. Our findings demonstrate that from early in life, children both hold and enforce a normative expectation that individuals are intrinsically obligated to contribute to the common good. PMID- 30010494 TI - Effects of activity intensity, time, and intermittent doffing on daily limb fluid volume change in people with transtibial amputation. AB - BACKGROUND: The volume of a prosthesis user's residual limb changes during the day and may affect the fit of the prosthesis. These changes must be managed by the user to prevent discomfort, skin breakdown, and falls. OBJECTIVES: The objectives were to test how activity, time of day, and intermittent doffing affected residual limb fluid volume in people with transtibial amputation. STUDY DESIGN: Standardized, repeated measure (A-B-A) out-of-laboratory protocol. METHODS: Participants with transtibial amputation completed three 6-h test sessions. Two sessions served as controls (A protocol) during which participants left their prosthesis donned, and one session was an intervention (B protocol) where participants doffed their prosthesis twice for 20 min during the 6 h of testing. Within-socket fluid volume was measured using a custom portable bioimpedance analysis system. RESULTS: A total of 13 participants completed the study. The rate of limb fluid volume loss was higher early in the session compared with late in the session. Participants experienced less fluid volume loss during high activity than low activity. Socket users with pin suspension experienced less posterior fluid volume loss when they intermittently doffed their prosthesis. Intermittent doffing did not benefit limb fluid volume of mechanical vacuum and suction suspension users. CONCLUSION: High activity may reduce fluid volume loss compared with low activity. Intermittent doffing may provide volume accommodation for transtibial prosthesis users with pin suspension. Clinical relevance Prosthetists should query their patients about the intensity of activity they conduct when advising them on limb volume management. Patients using sockets with pin suspension may be able to offset limb fluid volume loss by periodically doffing the prosthesis. PMID- 30010495 TI - Eye Tracking as a Debriefing Tool in Upset Prevention and Recovery Training (UPRT) for General Aviation Pilots. AB - Upset Prevention and Recovery Training (UPRT) is intended to improve the ability of pilots to recognize and avoid situations that can lead to airplane upsets and to improve their ability to recover control of an airplane that has exceeded the normal flight envelope. To this end, a set of different training contents - from theoretical knowledge of aerodynamics and human factors to practice-based flight training - is necessary. In order to support the debriefing with an objective feedback, and because visual scanning is a core competence, two studies on subjective evaluation of aviation pilots - one conducted in a flight simulator and the other one in-flight - focused on the practical application of eye tracking as a debriefing tool in UPRT. From a practitioner's perspective, eye tracking appeared to be a useful method in terms of visualising instrument scanning techniques, supporting the instructor with objective debriefing material and fostering self-awareness in human processes. The discussion recommends adjusted UPRT instructor training and further improvements to eye tracking hardware and software. PMID- 30010496 TI - Biodegradation of pharmaceuticals and personal care products in the sequential combination of activated sludge treatment and soil aquifer treatment. AB - Soil aquifer treatment (SAT), applied after activated sludge treatment (AST), has been widely used for wastewater reclamation. AST and SAT show potential for removing micropollutants, including pharmaceuticals and personal care products (PPCPs). However, the role of sequential combination of AST and SAT on the biodegradation of PPCPs was not clear in previous studies. In this study, the removal characteristics of PPCPs in AST and SAT were evaluated to assess the legitimacy of sequential combination of AST and SAT. SAT showed effective removals of antibiotics (> 80%), including fluoroquinolones and macrolides by sorption, but poor removals of amide pharmaceuticals (i.e. carbamazepine and crotamiton) were observed in both AST and SAT. Additionally, biodegradation contributed to the effective removal of carboxylic PPCPs (i.e. ketoprofen and gemfibrozil) in both ASTs and SAT, but effective biodegradation of halogenated acid and polycyclic aromatic compounds (i.e. clofibric acid and naproxen) was observed only in SAT (82.1% and 81.8%, respectively). Furthermore, the microbial substrate metabolic patterns showed that amino acids, amines, and polymers were biodegradable in SAT, which was fit for the biodegradation characteristics of PPCPs in SAT. For microbial communities, Proteobacteria were dominant in AST and SAT, but Acidobacteria and Actinobacteria were more abundant in SAT than AST, which could contribute to the effective removals of halogenated acid in SAT. Considering PPCP biodegradation and substrate metabolism, SAT displays a wider range on the biodegradation than AST. Therefore, we conclude that these two processes can complement each other when used for controlling PPCPs. PMID- 30010497 TI - Carbonaceous decomposition of a recalcitrant effluent treated by the photo-Fenton process: a kinetic approach. AB - Natural effluents with marked variation in their chemical composition over decomposition time in the matrix from which they are generated have a complex composition and are not totally known in most cases. Landfill leachate can be considered an effluent with complex composition, requiring imminent and more comprehensive studies on organic load degradation. Such complexity of numerous organic compounds (most of them recalcitrant humic and fulvic substances) demands a large number of kinetic equations to satisfactorily describe the temporal evolution of such conversion. Thereby, this work aims to study a kinetic approach grounded on previously consolidated chemical reactions of radical generation through the photo-Fenton mechanism. A molar balance was developed for each species in a batch photo-Fenton process and the resulting ordinary differential equations were numerically solved in MATLABTM. The kinetic model satisfactorily described an organic load conversion of the effluent under the various experimental conditions studied herein. Experimental trends could be represented by a free-radical mechanism and a degradation rate equation of first order for organic carbon, hydroxyl radical and H+. The model fittings revealed a hydroxyl radical/organic carbon stoichiometric ratio of 2:1. The kinetic study has confirmed the importance of pH levels for the reaction medium, and indicated that degradation rate depends on the medium organic composition, which provided an exponential function of conversion for the degradation rate coefficient. The model simulations corroborated the positive effect of sunlight on the radical generation through [Formula: see text] decomposition reaction with a rate coefficient in the range 4 * 10-3-2 * 10-1 s-1. PMID- 30010498 TI - Evaluating inter-aural hearing preservation in bilateral paediatric cochlear implantation. AB - OBJECTIVE: To examine inter-aural hearing preservation results in children undergoing simultaneous bilateral cochlear implantation (CI). METHODS: Retrospective case review in tertiary referral centre. All children undergoing simultaneous bilateral CI between January 2013 and June 2014 (18 months). Patients eligible for inclusion in the study had pre-operative hearing thresholds of <90 dB at 250 Hz and >=100 dB at 500 Hz. Patients with anatomical cochlear anomalies or missing data were excluded. Seven patients were included, 1 male, 6 female, mean age of 12 years 11 months at the time of surgery. All patients had simultaneous bilateral cochlear implant surgery, using the same implant and technique. All patients had pre- and post-operative unaided pure tone audiometry. Inter-aural hearing preservation results were compared in each patient. RESULTS: The achieved hearing preservation for 14 ears was complete in 5, partial in 7, and minimal in 2. Measurable hearing preservation was achieved in 86% overall. Inter-aural analysis revealed that only 2 (subjects 1 and 4) of the 7 patients had preservation results within the same preservation group (complete/partial/minimal). The mean inter-aural preservation difference was 30.7% with a range from 12.4% to 65.2%. CONCLUSIONS: Several factors and techniques have already been identified in the wider literature to explain differences in hearing preservation results in CI. However, despite controlling for known factors, we demonstrate variable inter-aural results. This suggests that there may be more factors beyond the surgeon's control influencing our ability to provide consistent results. PMID- 30010499 TI - Individual user involvement at Healthy Life Centres: a qualitative study exploring the perspective of health professionals. AB - : The aim of this study was to explore how professionals experience user involvement at an individual level and how they describe involving users at Healthy Life Centres. Four focus group interviews were conducted with a total of 23 professionals. Data were analysed using systematic text condensation. Four themes were identified: (1) Involving users through motivational interviewing; (2) Building a good and trustful relation; (3) Assessing and adjusting to the user's needs and life situation; and(4) Strengthening the user's ownership and participation in the lifestyle change process. Motivational interviewing was described by the professionals as a way to induce and ensure user involvement. However, seeing motivational interviewing and user involvement as the same concept might reduce user involvement from being a goal in itself and evolve into a means of achieving lifestyle changes. The professionals might be facing opposing discourses in their practice and a dilemma of promoting autonomy and involvement and at the same time promoting change in a predefined direction. Greater emphasis should thus be put on systematic reflection among professionals about what user involvement implies in the local Healthy Life Centre context and in each user's situation. ABBREVIATIONS: HLC: Healthy Life Centre; MI: Motivational Interviewing; NCD: Non-communicable diseases; STC: Systematic Text Condensation. SDT: Self-determination theory. PMID- 30010500 TI - A new lumbar fixation device alternative to pedicle-based stabilization for lumbar spine: In vitro cadaver investigation. AB - CONTEXT: To evaluate the stability provided by a new bilateral fixation technique using an in vitro investigation for posterior lumbar segmental instrumentation. DESIGN: Experimental cadaver study. In this study, we propose an alternative technique for a posterior lumbar fixation technique called "inferior-oblique transdiscal fixation" (IOTF). SETTING: Study performed at Engineering Center for Orthopedic Research Exellence (ECORE) in Toledo University-Ohio. PARTICIPANTS: Six human lumbar cadaveric specimen used in this study. INTERVENTIONS: In this study, we propose an alternative technique for a posterior lumbar fixation technique called "inferior-oblique transdiscal fixation" (IOTF). As a novel contribution to the classical technique, the entry point of the screw is the supero-lateral point of the intersecting line drawn between the corpus and the pedicle of the upper vertebra. This approach enables the fixation of two adjacent vertebrae using a single screw on each side without utilizing connecting rods. OUTCOME MEASURES: Flexion (Flex), extension (Ext), right and left lateral bending (LB & RB), and right and left axial rotation (LR & RR), and the position data were captured at each load step using the Optotrak motion measurement system and compared for IOTF and posterior transpedicular stabilization. RESULTS: The Posterior stabilization system (PSS) and IOTF significantly reduced the ROM of L4 L5 segment compared to intact segment's ROM. During axial rotation (AR) IOTF fused index segment more than PSS. Besides this, addition of transforaminal lumbar interbody fusion (TLIF) cage improved the stabilization of IOTF system during flexion, extension and lateral bending. Whereas, PSS yielded better fusion results during extension compared to IOTF with and without interbody fusion cages. CONCLUSIONS: We hypothesized that the new posterior bilateral system would significantly decrease motion compared to the intact spine. This cadaver study showed that the proposed new posterior fusion technique IOTF fused the index segment in a similar fashion to the classical pedicle screw fusion technique. PMID- 30010501 TI - Influence of human-machine interactions and task demand on automation selection and use. AB - A seminal work by Sheridan and Verplank depicted 10 levels of automation, ranging from no automation to an automation that acts completely autonomously without human support. These levels of automation were later complemented with a four stage model of human information processing. Next, human-machine cooperation centred models and associated cooperation modes were introduced. The objective of the experiment was to test which human-machine theorie describe automation use better. The participants were asked to choose repeatedly between four automation types (i.e. no automation, warning, co-action, function delegation) to complete three multi-attribute task battery tasks. The results showed that the participants favour the selection of automation types offering the best human machine interactions quality rather that the most effective automation type. Contrary to human-machine cooperation models, technology centred models could not predict accurately automation selection. The most advanced automation was not the most selected. Practitioner Summary: The experiment dealt with how people select different automation types to complete the multi-attribute task battery that emulates recreational aircraft pilot tasks. Automation performance was not the main criteria that explain automation use, as people tend to select an automation type based on the quality of the human-machine cooperation. PMID- 30010503 TI - [Congress Dates]. PMID- 30010502 TI - Contributions of a regional approach to document hematologic disease in Mexico: a 10-year experience in an open population. AB - OBJECTIVES: To demonstrate the importance of regional efforts to register features and report frequency of hematology diseases in the context of incomplete national registries. METHODS: Frequencies and salient characteristics of hematologic diseases in Northeast Mexico were documented in a reference center at a tertiary care university hospital during the decade 2005-2015. Disease categories were grouped by age, sex and diagnosis. Age group distribution followed WHO guidelines in years as children (0-17), adults (18-64) and elders (+65). RESULTS: 2406 patients were included: 1239 (51.5%) were females and 1167 (48.5%) males; F:M ratio was 1.06:1; median age was 35 years (0-95). The frequency by age group included adults, 1370 cases (56.9%), children, 695 cases (28.9%), and elderly, 341 (14.2%). Most frequent diagnoses were acute lymphoblastic leukemia (ALL) 18.2% (n = 438), anemia 15.9% (n = 383), non Hodgkin's lymphoma (NHL) 15.7% (n = 378), immune thrombocytopenic purpura (ITP) 9.8% (n = 235) and Hodgkin's lymphoma (HL) 6.5% (n = 156). Median age for the whole cohort was 35 years; for children, was 6 years, for adults 40 and for the elderly 73. Results for ALL, anemia and ITP were comparable to high-income countries; NHL, HL and chronic myeloid leukemia presented a decade earlier. DISCUSSION: Complete, opportune reliable information on the number of cases, age and sex distribution with the potential to influence strategies for timely diagnosis and treatment options for important hematologic diseases can be accrued by regional centers. CONCLUSION: Information on hematology diseases derived of regional registries in low-middle income countries is a reasonable alternative to complement and update national registries. PMID- 30010505 TI - [Contents]. PMID- 30010504 TI - [Authors]. PMID- 30010506 TI - Elucidation of 2, 4-Dichlorophenol degradation by Bacillus licheniformis strain SL10. AB - 2,4-Dichlorophenol (2,4-DCP) is a priority pollutant according to US Environmental Protection Agency. Its use in various chemical industries and its presence in the effluent necessitate effective removal studies. The present study focuses on degradation of 2,4-DCP by phenol adapted bacteria Bacillus licheniformis strain SL10 (MTCC 25059) at a relatively faster rate. The organism exhibited tolerance to 150 ppm of 2,4-DCP and showed a linear relationship between the growth and substrate concentration (umax 0.022/h) and the inhibitory concentration was 55.74 mg/L. The degradation efficiency of the organism was 74% under optimum conditions but increased to 97% when the growth medium containing nil sodium chloride. The degradation of 2,4-DCP was effected by the action of extracellular cocktail enzyme containing Catechol 2, 3 dioxygenase (C23DO), phenol hydroxylase and Catechol, 1,2 dioxygenase (C12DO). In vitro enzymatic degradation studies exhibit 98% degradation of 50 ppm of 2,4-DCP within 2 h. Analyses of degradation products infer that the chosen organism followed a meta cleavage pathway while degrading 2,4-DCP. In conclusion, the bacteria Bacillus licheniformis strain SL10 finds potential application in the remediation of 2,4 DCP. PMID- 30010507 TI - The enhanced effect of oxalic acid on the electroreduction of Cr(VI) via formation of intermediate Cr(VI)-oxalate complex. AB - In this study, the enhanced effect of oxalic acid (Ox) on Cr(VI) electroreduction was evaluated. It was found that for Cr(VI)-contaminated solution ([Cr(VI)]0 = 1.0 mM, pH = 3.0), addition of 5.0 mM Ox can significantly increase Cr(VI) reduction from 0.36 to 1.0 mM within 90 min electrolysis reaction, accompanying with the increase of current efficiency from 19% to 53%. Increasing initial Ox concentration (0-10 mM) and electric current (10-40 mA) facilitated Cr(VI) reduction, whereas it was inhibited with decreasing solution pH value (2.0-3.5) and elevating Cr(VI) concentration (0.1-2.0 mM), respectively. Results show that reactive electron was the primary reductant for the heterogeneous reduction of Cr(VI) on the cathode. In addition, Ox can also serve as an electron donor for the homogeneous reduction of Cr(VI). During this process, the formation of Cr(VI) oxalate complex is indispensable for the enhanced Cr(VI) reduction. The coordination of Ox with Cr(VI) did not only make the structure of Cr(VI) more distorted but also improved the reactivity of Cr(VI) in Cr(VI)-oxalate complex toward reduction reaction. In general, this study provides an energy-efficient and environmentally benign strategy for the treatment of Ox and Cr(VI) co contaminated wastewater. PMID- 30010508 TI - Modeling methane oxidation in landfill cover soils as indicator of functional stability with respect to gas management. AB - A performance-based method for evaluating methane (CH4) oxidation as the best available control technology (BACT) for passive management of landfill gas (LFG) was applied at a municipal solid waste (MSW) landfill in central Washington, USA, to predict when conditions for functional stability with respect to LFG management would be expected. The permitted final cover design at the subject landfill is an all-soil evapotranspirative (ET) cover system. Using a model, a correlation between CH4 loading flux and oxidation was developed for the specific ET cover design. Under Washington's regulations, a MSW landfill is functionally stable when it does not present a threat to human health or the environment (HHE) at the relevant point of exposure (POE), which was conservatively established as the cover surface. Approaches for modeling LFG migration and CH4 oxidation are discussed, along with comparisons between CH4 oxidation and biodegradation of non CH4 organic compounds (NMOCs). The modeled oxidation capacity of the ET cover design is 15 g/m2/day under average climatic conditions at the site, with 100% oxidation expected on an annual average basis for fluxes up to 8 g/m2/day. This translates to a sitewide CH4 generation rate of about 260 m3/hr, which represents the functional stability target for allowing transition to cover oxidation as the BACT (subject to completion of a confirmation monitoring program). It is recognized that less than 100% oxidation might occur periodically if climate and/or cover conditions do not precisely match the model, but that residual emissions during such events would be de minimis in comparison with published limit values. Accordingly, it is also noted that nonzero net emissions may not represent a threat to HHE at a POE (i.e., a target flux between 8 and 15 g/m2/day might be appropriate for functional stability) depending on the site reuse plan and distance to potential receptors. Implications: This study provides a scientifically defensible method for estimating when methane oxidation in landfill cover soils may represent the best available control technology for residual landfill gas (LFG) emissions. This should help operators and regulators agree on the process of safely eliminating active LFG controls in favor of passive control measures once LFG generation exhibits asymptotic trend behavior below the oxidation capacity of the soil. It also helps illustrate the potential benefits of evolving landfill designs to include all-soil vegetated evapotranspirative (ET) covers that meet sustainability objectives as well as regulatory performance objectives for infiltration control. PMID- 30010509 TI - Determining optimal poststroke exercise: Study protocol for a randomized controlled trial investigating therapeutic intensity and dose on functional recovery during stroke inpatient rehabilitation. AB - Rationale A top priority in stroke rehabilitation research is determining the appropriate exercise dose to optimize recovery. Although more intensive rehabilitation very early after stroke may be deleterious to recovery, inpatient rehabilitation, occurring after acute care, may be a more appropriate setting to assess therapeutic dose on neurological recovery. Hypothesis Individuals receiving higher intensity and dose exercise programs will yield greater improvements in walking ability over usual inpatient physical therapy care. Methods and design Seventy-five individuals across seven inpatient rehabilitation sites in Canada will be randomized into one of three treatment programs, each 5 days/week, for four weeks and monitored for exertion (heart rate) and repetitions (step count). Study outcomes The primary outcome measure is the 6 min walk and secondary outcomes include functional independence, cognitive, and quality-of life measures. Outcome data will be assessed at four time points. Summary This trial will contribute to our knowledge of the therapeutic intensity and dose necessary to maximize functional recovery at a very important stage of rehabilitation and neural recovery poststroke. PMID- 30010510 TI - An innovative approach to identifying learning needs for intrinsic CanMEDS roles in continuing professional development. AB - CONTEXT: The CanMEDS framework promotes the development of competencies required to be an effective physician. However, it is still not well understood how to apply such frameworks to CPD contexts, particularly with respect to intrinsic competencies. OBJECTIVE: This study explores whether physician narratives around challenging cases would provide information regarding learning needs that could help guide the development of CPD activities for intrinsic CanMEDS competencies. METHODS: We surveyed medical and surgical specialists from Southern Ontario using an online survey. To assess perceived needs, participants were asked, 'Describe three CPD topic you would like to learn about in the next 12 months'. To identify learning needs that may have arisen from problems encountered in practice, participants were asked, 'Describe three challenging situations encountered in the past 12 months.' Responses to the two open-ended questions were analyzed using thematic content analysis. RESULTS: Responses were received from 411 physicians, resulting in 226 intrinsic CanMEDS codes for perceived learning needs and 210 intrinsic codes for challenges encountered in practices. Discrepancies in the frequency of intrinsic roles were observed between the two questions. Specifically, Leader (28%), Scholar (43%), and Professional (16%) roles were frequently described perceived learning needs, as opposed to challenges in practice (Leader: 3%; Scholar: 2%; and Professional: 8%. Conversely, Communicator 39%, Health Advocate 39%, and to a lesser extent Collaborator 11%) roles were frequently described in narratives surrounding challenges in practice, but appeared in <10% of descriptions of perceived learning needs (Communicator: 4%; Health Advocate 6%; Collaborator: 3%). CONCLUSION: The present study provides insight into potential learning needs associated with intrinsic CanMEDS competencies. Discrepancies in the frequency of intrinsic CanMEDS roles coded for perceived learning needs and challenges encountered in practice may provide insight into the selection and design of CPD activities. PMID- 30010511 TI - Management and outcome of colorectal cancer during pregnancy: report of 41 cases. AB - BACKGROUND: Colorectal cancer in pregnancy is rare, with an incidence of 0.8 per 100,000 pregnancies. Advanced disease (stage III or IV) is diagnosed more frequently in pregnant patients. We aimed to review all cases of colorectal cancer in pregnancy from the International Network on Cancer, Infertility and Pregnancy database in order to learn more about this rare disease and improve its management. METHODS: Data on the demographic features, symptoms, histopathology, diagnostic and therapeutic interventions and outcomes (obstetric, neonatal and maternal) were analysed. RESULTS: Twenty-seven colon and 14 rectal cancer cases were identified. Advanced disease was present in 30 patients (73.2%). During pregnancy, 21 patients (51.2%) received surgery and 12 patients (29.3%) received chemotherapy. Thirty-three patients (80.5%) delivered live babies: 21 by caesarean section and 12 vaginally. Prematurity rate was high (78.8%). Eight babies were small for gestational age (27.6%). Three patients (10.7%) developed recurrence of disease. Overall 2-year survival was 64.4%. CONCLUSION: Despite a more frequent presentation with advanced disease, colorectal cancer has a similar prognosis in pregnancy when compared with the general population. Diagnostic interventions and treatment should not be delayed due to the pregnancy but a balance between maternal and foetal wellbeing must always be kept in mind. PMID- 30010512 TI - The prognostic significance of tall cells in papillary thyroid carcinoma: A case control study. AB - The subtype of the papillary thyroid carcinoma tall-cell variant has a worse prognosis than does the conventional papillary type (papillary thyroid carcinoma). The new World Health Organization 2017 classification defines a tall cell variant as a tumour consisting of over 30% of cells that are two or three times as tall as they are wide. However, thresholds have differed. Our aim was to study how tall cells affect the prognosis of papillary thyroid carcinoma patients and to determine, for such cells, a cut-off percentage. Our cohort included 65 papillary thyroid carcinoma patients who underwent surgery at Helsinki University Hospital between 1973 and 1996: originally, 36 otherwise-matched patient pairs, eventually comprising 34 patients with an adverse outcome plus 31 who had recovered. All samples were digitally scanned and scored by two investigators based on tall cell composition. The cohort was analysed with four tall cell thresholds: 10%, 30%, 50% and 70% with a median follow-up of 22 years. In survival analysis, only the 70% threshold showed a correlation with reduced overall survival, disease-specific survival and relapse-free survival. A correlation also emerged with death from papillary thyroid carcinoma. In multivariate analysis, a 70% cut-off and age at diagnosis significantly affected DSS. Increasing tall cell score correlated with increasing age and extrathyroidal extensions. A tall cell composition of 10%, 30% or 50% showed no correlation with adverse outcome and suggests that the choice of pathologists reporting tall-cell variant should be a 70% threshold. PMID- 30010513 TI - Zinc Depletion Increases Readmission in Older Patients: An Example of Interactions Between Nutrition and Disease. AB - BACKGROUND: ill health may lead to poor nutrition and poor nutrition to ill health, so identifying priorities for management still remains a challenge. The aim of this report is to present data on the impact of plasma zinc (Zn) depletion on important health outcomes after adjusting for other poor prognostic indicators in hospitalised patients. METHODS: Hospitalised acutely ill older patients who were part of a large randomised controlled trial had their nutritional status assessed using anthropometric, hematological and biochemical data. Plasma Zn concentrations were measured at baseline, 6 weeks and at 6 months using inductively- coupled plasma spectroscopy method. Other clinical outcome measures of health were also measured. RESULTS: A total of 345 patients assessed at baseline, 133 at 6 weeks and 163 at 6 months. At baseline 254 (74%) patients had a plasma Zn concentration below 10.71 MUmol/L indicating biochemical depletion. The figures at 6 weeks and 6 months were 86 (65%) and 114 (70%) patients respectively. After adjusting for age, co-morbidity, nutritional status and tissue inflammation measured using CRP, only muscle mass and serum albumin showed significant and independent effects on plasma Zn concentrations. The risk of non elective readmission in the 6-months follow up period was significantly lower in patients with normal Zn concentrations compared with those diagnosed with Zn depletion (adjusted hazard ratio 0.62 (95% CI: 0.38 to 0.99), p = 0.047. CONCLUSIONS: Zn depletion is common and associated with increased risk of readmission in acutely-ill older patients, however, the influence of underlying comorbidity on these results can not excluded. PMID- 30010514 TI - Effect of Vitamin E Supplementation on Plasma and Urine Levels of Isoprostane F2alpha in Randomized Controlled Clinical Trials: A Systematic Review and Meta Analysis. AB - Vitamin E can reduce the level of lipid peroxidation and the related markers such as urine and plasma levels of isoprostanes. However, effects of vitamin E supplementation on plasma and urine level of isoprostane F2alpha as markers of lipid peroxidation were conflicting in various clinical trials. The current meta analysis was carried out to determine the effects of vitamin E supplementation on plasma and urine levels of isoprostanes F2alpha in randomized clinical trials. A systematic search of RCTs was carried out in PubMed, Scopus, Science Direct and Cochrane Library databases. OF 889 relevantly founded articles, only four articles with five arms met the criteria for meta-analysis of plasma level of isoprostanes F2alpha. For the urine level of isoprostane F2alpha, three studies with 14 arms were included in the meta-analysis. After pooled analyzing, a significant reduction of 6.98 ng / l was seen in plasma level of isoprostane F2alpha in vitamin E receiving group (95% CI = -11.2, -2.76; P < 0.001) while no significant heterogeneity was seen between the studies included in this meta analysis (P = 0.81 and I2 = 0.0%). However, the pooled effect of vitamin E supplementation on urine level of isoprostane F2alpha was not statistically significant (-11.31 pg / mg creatinine (95% CI = -26.4, 3.78; P = 0.88). Results of this meta-analysis have shown that vitamin E supplementation can only reduce plasma level of isoprostane F2alpha and has no significant effect on reducing urine level of this biomarker. PMID- 30010515 TI - A Systematic Review on the Role of Natural Products in Modulating the Pathways in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder to date, with no cure or preventive therapy. Histopathological hallmarks of AD include deposition of beta-amyloid plaques and formation of neurofibrillary tangles in brain. Despite extensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look for alternative therapies and new drugs. Use of natural products in medicine has gained popularity in recent years and several natural compounds with neuroprotective effects have been studied in detail. Some of them target the disease pathways and improve cognition by directly affecting amyloidogenesis, programmed cell death and increase neuronal cell survival. Currently, phytochemicals like polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received a special attention from the scientific community against the pathological processes in conditions like cancer, cardiovascular diseases and neurodegenerative diseases. Many efforts have been made to unravel the molecular mechanisms and the specific interactions of phytochemicals, which targets disease pathways in the AD. Further studies on these natural products and their mechanism of action, target specific effect in disease pathology parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine in treatment of AD. This review presents detailed information on natural products like polyphenols, alkaloids and terpenes with their potential effects in Alzheimer's disease. PMID- 30010516 TI - Emerging Relationships Between Vitamin D Status, Physical Activity Habits, and Immune Indices in College-Aged Females. AB - It has been determined that individuals who are regularly physically active have more favorable inflammatory profiles; less is known about how vitamin D levels can impact inflammation. This study explored the relationship between inflammatory indices in physically active (PA) and not physically active (NPA) individuals with 25-hydroxyvitamin D (25OHD) concentrations either above or below optimal concentrations. All female subjects (n = 63, age 19 - 35 years) were evaluated for body composition, maximal aerobic capacity (VO2peak), and anaerobic power (Wingate). Blood samples were analyzed for 25OHD and C-reactive protein (CRP), stimulated with lipopolysaccharide (LPS) and assessed for interleukin-6 (IL-6) production, and used for flow cytometric analysis. PA (n = 30) had higher 25OHD levels (45.2 +/- 2.7 vs. 17.05 +/- 1.4 ng / mL; p = 0.015), higher VO2peak (p < 0.0001), lower body weight (p = 0.039) and lower estimated percent body fat (p = 0.011) compared to NPA (n = 33). PA also had lower LPS-stimulated IL-6 production compared to NPA (p = 0.0163), although there were no differences between resting CRP concentrations. NPA with optimal 25OHD had fewer total monocytes, CD14+CD16-cells, CD14+CD16+ cells, and decreased TLR4 expression on CD14+CD16+ cells compared to NPA with suboptimal 25OHD (< 32 ng / mL). In summary, regular physical activity was associated with higher serum 25OHD, healthier measures of body composition, and reduced stimulated IL-6 production. However, optimal vitamin D status was not associated with anti-inflammatory benefits beyond those which are provided by regular physical activity. PMID- 30010517 TI - A study on near zero liquid discharge approach for the treatment of reverse osmosis membrane concentrate by electrodialysis. AB - A lab-scale electrodialysis (ED) which consisted of 11 pieces of cation-exchange membranes and 10 pieces of anion-exchange membranes was used to treat concentrated brine of Reverse osmosis (RO) membrane. The effect of operating parameters such as applied voltage, flowrate, and operating mode was investigated to measure the performance of a lab-scale ED. Three different voltages (5, 10, and 15 V) and flowrates (20, 30, and 40 L/h) were applied in order to optimize the operating conditions of the ED system. The maximum TDS removal efficiencies were 85%, 97%, and 98% for 5, 10, and 15 V, respectively. It was concluded that the desalination efficiencies were almost the same at flowrates values of 20, 30 and 40 L/h. The TDS concentration of the treated brine in the concentrate compartment rises to the highest value of 25,400 mg/L with desalination rate of 92.5% after five cycle operation. Moreover, the desalinated brine can be used as fresh water. PMID- 30010518 TI - CT HEAD? Reviewing the newest validation of the Ottawa Subarachnoid Hemorrhage Rule. PMID- 30010519 TI - The role of propofol on mouse oocyte meiotic maturation and early embryo development. AB - SummaryPropofol is a intravenous anaesthetic most commonly used in ultrasound oocyte retrieval. We studied if the use of propofol had an effect on mouse oocyte maturation, pregnancy, childbirth and progeny and investigated the correlation between propofol side effects and reproductive performance in mice. There was no statistical difference in mating, pregnancy, childbirth, litter size, the number of stillbirths and survival between each group (P>0.05). Propofol also had no effect on polar body extrusion in oocyte maturation as well as on pronucleus formation and, subsequently, early embryo development (P>0.05). An increased concentration of propofol had no effect on this result, although propofol at more than 0.01 mg/ml reduced polar body extrusion. Different concentrations of propofol had no effect on oocyte culture in vitro, pronucleus formation and early embryo development. PMID- 30010520 TI - Herbage intake and growth of rabbits under different pasture type, herbage allowance and quality conditions in organic production. AB - A lack of knowledge about rabbit herbage intake during grazing limits the development of organic rabbit production. This study describes rabbit herbage intake under a wide range of grazing conditions and characterises the factors that decrease rabbit herbage intake and daily weight gain. It was conducted with growing rabbits reared in moving cages with 0.4 m2 of grazing area per rabbit. Rabbits grazed on pastures dominated by legumes (LEG) or grass and forbs (GRF) and received 60 g/day per rabbit of a complete pelleted feed. Three trials were performed in winter, summer and spring. Mean herbage allowance was 27% higher in LEG (62.3 g dry matter (DM)/kg metabolic weight (MW), equal to kg0.75) than in GRF (49.2 g DM/kg MW). Herbage intake varied greatly (36.3+/-18.0 g DM/kg MW) among trials and was higher in LEG than in GRF (39.5v.34.1 g DM/kg MW). For both pasture types, herbage intake was logarithmically related to herbage allowance and plateaued around 75 g DM/kg MW. Crude protein and digestible energy (DE) intake differed by pasture type and season. Mean CP intake was 40% higher in LEG (15.0 g/kg MW) than in GRF (10.7 g/kg MW). In summer, mean DE intake was 27% higher in LEG than in GRF but no significant differences in DE intake were found between LEG and GRF in winter and spring. Maximum DE intake plateaued near 1000 kJ/kg MW. Daily weight gain was always higher for rabbits grazing LEG (mean=22.6 g) than GRF (mean=16.0 g). Weight gain was significantly related to CP intake, whereas DE intake had no significant effect. Meeting the objective of mean daily weight gain of 20 g requires herbage intake of 32 and 50 g DM/kg MW in LEG and GRF, respectively. Therefore, according to the herbage use efficiency observed in our experiments, herbage allowance must reach 42 and 78 g DM/kg MW in LEG and GRF, respectively. When herbage allowance is lower, rabbits cannot meet the CP intake (13 g/kg MW) required for this weight gain objective. PMID- 30010521 TI - Finding the humanity: Learning to listen in emergency medicine. PMID- 30010522 TI - Kushneria phyllosphaerae sp. nov. and Kushneria endophytica sp. nov., plant growth promoting endophytes isolated from the halophyte plant Arthrocnemum macrostachyum. AB - Two endophytic bacteria (EAod3T and EAod7T) were isolated from the aerial part of plants of Arthrocnemum macrostachyum growing in the Odiel marshes (Huelva, Spain). Phylogenetic analysis based on 16S rRNA gene sequences indicated their affiliation to the genus Kushneria. 16S rRNA gene sequences of strains EAod3T and EAod7T showed the highest similarity to Kushneria marisflavi DSM 15357T (99.0 and 97.6 %, respectively). Digital DNA-DNA hybridization studies between the draft genomes of strain EAod3T and K. marisflavi DSM 15357T corresponded to 28.5 % confirming the novel lineage of strain EAod3T in the genus Kushneria. Cells of both strains were Gram-staining-negative, aerobic and motile rods able to grow at 4-37 degrees C, at pH 5.0-8.0 and tolerate 0.5-25 % NaCl (w/v). They presented ubiquinone Q9 and C16 : 0, C16 : 1omega7c/C16 : 1omega6c and C18 : 1omega7c as the major fatty acids. The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Based on the phenotypic and phylogenetic results, strains EAod3T (=CECT 9073T=LMG 29856T) and EAod7T (=CECT 9075T=LMG 29858T) are proposed as new representatives of the genus Kushneria, and the proposed names are Kushneria phyllosphaerae sp. nov. and Kushneria endophytica sp. nov., respectively. The whole genome sequence of strain EAod3T has a total length of 3.8 Mbp and a G+C content of 59.3 mol%. PMID- 30010523 TI - Euzebya rosea sp. nov., a rare actinobacterium isolated from the East China Sea and analysis of two genome sequences in the genus Euzebya. AB - Rare Actinobacteria, known as non-Streptomyces, hold great potential to produce new bioactive compounds for drug development. A strain designated DSW09T, which belongs those rare Actinobacteria, was isolated from surface seawater of the East China Sea. The cells were aerobic, Gram-positive, non-motile, non-spore-forming and rod-shaped (0.4 um wide and 1.5-4.0 um long). The closest relative was Euzebya tangerina F10T (96.46 % of 16S rRNA gene similarity). Cell growth occurred at 15-45 degrees C (optimum, 25-30 degrees C), at pH 6.0-9.0 (pH 6.0 7.0) and at NaCl concentrations of 0.5-5.0 % (w/v; 1.0-4.0 %). The major cellular fatty acids were summed feature 3 (comprising C16 : 1omega7c and/or C15 : 0iso 2OH), C17 : 1omega8c and C16 : 0. The predominant polar lipid was diphosphatidylglycerol. The predominant menaquinone was MK-9(H4). The cell-wall peptidoglycan was A1 gamma-type, containing meso-DPA. The major cell-wall sugars were rhamnose and ribose. The genome size was 5 509 297 bp with a 71.29 mol% G+C content for strain DSW09T, while 4 781 440 bp with a 68.87 mol% G+C content for E. tangerina F10T. The average nucleotide identity and digital DNA-DNA hybridization values between strain DSW09T and E. tangerina F10T were 73.44 % and 16.43 %, respectively. Based on phylogenetic, phenotypic, chemotaxonomic evidence and genomic analyses, strain DSW09T is a novel species of genus Euzebya, for which the name Euzebya rosea sp. nov. is proposed. The type strain is DSW09T (=DMS 104446T=MCCC 1K03290T). PMID- 30010524 TI - Frankia irregularis sp. nov., an actinobacterium unable to nodulate its original host, Casuarina equisetifolia, but effectively nodulates members of the actinorhizal Rhamnales. AB - A red pigmented actinobacterium designated G2T, forming extremely branched vegetative hyphae, vesicles and mutilocular sporangia, was isolated from Casuarina equisetifolia nodules. The strain failed to nodulate its original host plant but effectively nodulated members of actinorhizal Rhamnales. The taxonomic position of G2T was determined using a polyphasic approach. The peptidoglycan of the strain contained meso-diaminopimelic acid as diagnostic diamino acid, galactose, glucose, mannose, rhamnose, ribose and xylose. The polar lipid pattern consisted of phosphatidylinositol (PI), diphosphatidylglycerol (DPG), glycophospholipids (GPL1-2), phosphatidylglycerol (PG), aminophospholipid (APL) and unknown lipids (L). The predominant menaquinones were MK-9 (H4) and MK-9 (H6) while the major fatty acids were iso-C16 : 0, C17 : 1omega8c and C15 : 0. The size of the genome of G2T was 9.5 Mb and digital DNA G+C content was 70.9 %. The 16S rRNA gene showed 97.4-99.5 % sequence identity with the type strains of species of the genus Frankia. Digital DNA -DNA hybridisation (dDDH) values between G2T and its nearest phylogenetic neighbours Frankia elaeagniand Frankia discariaewere below the threshold of 70 %. On the basis of these results, strain G2T (=DSM 45899T=CECT 9038T) is proposed to represent the type strain of a novel species Frankia irregularis sp. nov. PMID- 30010525 TI - Lactobacillus terrae sp. nov., a novel species isolated from soil samples in the Republic of Korea. AB - A novel strain, designated NIBRBAC000499792T, was isolated from a soil sample collected at Jukgye, Dongnam, Cheonan, Republic of Korea. Cells were Gram positive, non-motile, non-spore-forming, rod-shaped, oxidase-negative and catalase-negative. Colonies grown on de Man, Rogosa and Sharpe agar were white, circular, raised and entire. Analysis of the 16S rRNA gene sequence analysis revealed that strain NIBRBAC000499792T belongs to the genus Lactobacillus (family Lactobacillaceae) and is most closely related to Lactobacillus nodensis DSM 19682T (96.1 % similarity) and Lactobacillus tucceti KCTC 21005T (96.7 %). The results of DNA-DNA hybridization experiments demonstrated that strain NIBRBAC000499792T represents a novel species. Major fatty acids are C18 : 1omega9c, C16 : 0 and unidentified 18.846 and/or C19 : 1omega6c and/or C19 : 0cyclo. The predominant respiratory quinones are menaquinone-8 and menaquinone-9. The major polar lipids are phosphatidylglycerol and diphosphatidylglycerol. The minor polar lipids are one unidentified aminophospholipid, one unidentified phospholipid, and four unidentified lipids. Next-generation sequencing analysis of strain NIBRBAC000499792T indicated that the total genome size was 1 548 794 bp with a G+C content of 33.1 mol%, 1586 coding sequences, 50 tRNAs and nine rRNAs. The most closely related genomes belonged to Lactobacillus species. Most metabolic pathways were related to carbon metabolism and carbon fixation. Based on this polyphasic analysis, strain NIBRBAC000499792T represents a novel species of the genus Lactobacillus, for which the name Lactobacillus terrae sp. nov. is proposed, with the type strain NIBRBAC000499792T (=KCTC 21093T=JCM 32269T). PMID- 30010526 TI - Mangrovicella endophytica gen. nov., sp. nov., a new member of the family Aurantimonadaceae isolated from Aegiceras corniculatum. AB - A Gram-negative, aerobic, motile and short-rod-shaped bacterium, designated strain 5T4P-12-1T, was isolated from a piece of surface-sterilized bark of Aegiceras corniculatum collected from Cotai Ecological Zones in Macao, China and tested by a polyphasic approach to clarify its taxonomic position. Strain 5T4P-12 1T grew optimally with 0-1 % (w/v) NaCl at 30 degrees C and at pH 7.0-8.0. The 16S rRNA gene sequence of strain 5T4P-12-1T had the highest similarity (96.7 %) to Aureimonas altamirensis DSM 21988T. Phylogenic analysis based on 16S rRNA gene sequences and coding sequences of 98 protein clusters showed that the strain represented a novel genus of the family Aurantimonadaceae. The predominant quinone system of strain 5T4P-12-1T was ubiquinone 10. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylmethylethanolamine, an unidentified aminophospholipid, three unidentified aminolipids, three unidentified phospholipids and three unidentified lipids. The major fatty acids (>10 % of total fatty acids) were C18 : 1omega7c (55.4 %) and C18 : 1 2-OH (15.6 %). The DNA G+C content of strain 5T4P-12-1T was 66.5 mol%. Based on the phylogenic, phenotypic and chemotaxonomic features, strain 5T4P-12-1T is considered to represent a novel species of a new genus in the family Aurantimonadaceae, for which the name Mangrovicella endophytica gen. nov., sp. nov. is proposed. The type strain is 5T4P-12-1T (=KCTC 62053T=CGMCC 1.16279 T). PMID- 30010527 TI - Winogradskyella tangerina sp. nov., a member of the Flavobacteriaceae isolated from coastal sediment. AB - A Gram-stain-negative, rod-shaped bacterium (designated strain M1309T), with slow gliding motility, was isolated from marine sediment obtained off the coast of Weihai, PR China. The growth of M1309T was observed at 16-42 degrees C (optimum, 37 degrees C) and pH 6.5-8.0 (optimum, 7.0-7.5) in the presence of 2.0-6.0 % (w/v) NaCl (optimum, 2.0-3.0 %). Phylogenetic analyses based on the 16S rRNA gene sequence revealed that the strain represented a member of the genus Winogradskyella. M1309T exhibited the highest 16S rRNA gene sequence similarity, of 95.5 %, to Winogradskyella poriferorum JCM 12885T. Chemotaxonomic analysis revealed that the sole respiratory quinone was menaquinone 6 (MK-6) and the major fatty acids included iso-C15 : 0, iso-C15 : 1G and iso-C17 : 0 3-OH. The major polar lipids included phosphatidylethanolamine, two aminolipids, and three unidentified lipids. The DNA G+C content of the strain was 36.1 mol%. On the basis of phenotypic distinctiveness and phylogenetic divergence, strain M1309T is considered to represent a novel species of the genus Winogradskyella, for which the name Winogradskyella tangerina sp. nov. is proposed. The type strain is M1309T (=KCTC 52896T=MCCC 1K03310T). PMID- 30010528 TI - Sphingomonas aeria sp. nov., isolated from air. AB - A Gram-negative, aerobic, non-spore-forming, non-motile, yellow-pigmented and rod shaped bacterial strain, designated B093034T, was isolated from air at the foot of Xiangshan mountain, located in Beijing, China. Cells of strain B093034T were oxidase-negative and catalase-positive. Growth was observed at 4-41 degrees C, at pH 4.5-10.0 and at 0-7 % (w/v) NaCl. The isolate contained Q-10 as the predominant isoprenoid quinone, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C16 : 0 and C14 : 02-OH as the major fatty acids, sym-homospermidine as the major polyamine, and sphingoglycolipid, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, diphosphatidylglycerol, aminolipid, two unidentified phospholipids and three unidentified polar lipids as the polar lipids. The DNA G+C content was 67.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain B093034T grouped with members of the genus Sphingomonas and was closely related to Sphingomonas sanguinis IFO 13937T (96.49 % similarity), Sphingomonas pseudosanguinis G1-2T (96.37 %), Sphingomonas ginsenosidimutansGsoil 1429T (95.99 %) and Sphingomonas endophytica YIM 65583T (95.78 %). On the basis of the polyphasic evidence presented here, strain B093034T represents a novel species of the genus Sphingomonas, for which the name Sphingomonasaeria sp. nov. is proposed. The type strain is B093034T (=CFCC 13949T=LMG 30133T). PMID- 30010529 TI - Sphaerisporangium rhizosphaerae sp. nov., an actinomycete isolated from the rhizosphere soil of a rubber tree (Hevea brasiliensis Muell. Arg). AB - A novel actinomycete, designated strain NEAU-mq3T, was isolated from the rhizosphere soil of a rubber tree (Hevea brasiliensis Muell. Arg) collected from Xianglu Mountain in Heilongjiang Province, north-east China, and characterized by using a polyphasic approach. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the organism should be assigned to the genus Sphaerisporangium and that it forms a monophyletic clade with its closest relatives 'Sphaerisporangium dianthi' NEAU-CY18T (99.2 % 16S rRNA gene sequence similarity) and Sphaerisporangium cinnabarinum JCM 3291T (98.8 %). Morphological and chemotaxonomic properties of strain NEAU-mq3T were also consistent with the description of the genus Sphaerisporangium. The whole-cell sugars were madurose, mannose, ribose and glucose. The menaquinones were MK-9(H2), MK-9(H4), MK-9(H0) and MK-9(H6). The diagnostic diamino acid of the peptidoglycan was meso diaminopimelic acid. The phospholipid profile consisted of diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol mannoside, an unidentified polar lipid and an unidentified phospholipid. The major fatty acids were identified as iso-C16 : 0, 10-methyl C17 : 0, C16 : 1omega7c and C17 : 1omega7c. DNA-DNA hybridization experiments and phenotypic tests were carried out between strain NEAU-mq3T and its most closely related strains, which further clarified their relatedness and demonstrated that NEAU-mq3T could be distinguished from these strains. Therefore, it is concluded that strain NEAU-mq3T represents a novel species of the genus Sphaerisporangium, for which the name Sphaerisporangium rhizosphaerae sp. nov. is proposed. The type strain is NEAU-mq3T (=CGMCC 4.7429T=JCM 32389T). PMID- 30010530 TI - Rats! Hantavirus: A Case Report of a Suspected Case in Eastern Tennessee. AB - INTRODUCTION: Hantavirus is an RNA virus that is transmitted to humans by inhalation of aerosolized excrement from infected rodents. This case report demonstrates the value of taking a thorough social history and highlights the challenges associated with early diagnosis of this viral infection. CASE PRESENTATION: We highlight a case of suspected hantavirus infection with subtle gastrointestinal and pulmonary symptoms that challenged the initial diagnosis. DISCUSSION: Efforts are needed to improve clinical recognition and rapid detection of hantavirus infections, to reduce associated mortality. In a patient presenting with gastrointestinal prodromal symptoms followed by cardiopulmonary findings, physicians should pay special attention to that patient's living conditions and maintain a high index of suspicion for hantavirus infection. Early diagnosis is critical to prevent rapid deterioration to hantavirus pulmonary syndrome in some patients. PMID- 30010531 TI - Implementing a Protocol to Optimize Detection of Chromosome Abnormalities in Cases of Miscarriage or Stillbirth at a Midwestern Teaching Hospital. AB - CONTEXT: Results from chromosome testing after spontaneous abortion (SAB) or intrauterine fetal demise (IUFD) are useful in patient counseling; however, results can be inconclusive when cell cultures for chromosomes are unable to grow from products of conception. Chromosomal microarray analysis (CMA) can analyze DNA from nonviable fetal tissue. OBJECTIVE: To examine whether establishing a genetic testing protocol for karyotype and CMA on SAB and IUFD tissues increases diagnostic yield. DESIGN: A retrospective chart review was conducted in cases of SAB or IUFD when karyotyping and/or CMA was requested, comparing two periods: Preprotocol and postprotocol implementation. MAIN OUTCOME MEASURES: Diagnostic yield was compared by using the number of determinate test results in the preprotocol and postprotocol study periods. A case was considered to have indeterminate results when the final genetic test results reported no fetal tissue or no cell culture growth. RESULTS: A total of 55 preprotocol and 52 postprotocol patients were analyzed. Diagnostic yield increased from 72.7% to 94.2% after implementation of the genetic testing protocol (p = 0.0004). Indeterminate results occurred more frequently before compared with after implementation of the protocol. CONCLUSION: A protocol of reflexing to CMA or proceeding directly with CMA gives a higher diagnostic yield in the genetic evaluation of SAB or IUFD. Institutions should consider implementing a genetic testing protocol to improve diagnostic yield. Our study results emphasize the importance of proceeding directly to microarray analysis and give support for current clinical recommendations for genetic testing after fetal demise. PMID- 30010534 TI - Continuity of Care in Residency Teaching Practices: Lessons from "Bright Spots". AB - Continuity of care is a challenge in primary care residency teaching clinics. Resident physicians have competing inpatient and outpatient responsibilities and often spend only 1 to 2 half-days per week in the clinic. Their clinic schedules are often pieced together after the needs of inpatient and specialty rotations are met. Similarly, faculty clinicians often balance limited clinic time with teaching, research, or administrative responsibilities. Seeking approaches to improve continuity of care, we visited 23 internal medicine, family medicine, and pediatric residency clinics across the US. This article highlights strategies to optimize continuity of care pioneered by 3 "bright spot" residency teaching clinics with high-continuity performance. The strategies include adopting a strong continuity culture and patient scheduling algorithms that prioritize continuity, appointing a team continuity anchor, and/or reorganizing resident and faculty schedules to maximize continuity. We hope that these perspectives can assist residency teaching practices to improve continuity of care for their patients. PMID- 30010532 TI - Marijuana's Influence on Pain Scores, Initial Weight Loss, and Other Bariatric Surgical Outcomes. AB - INTRODUCTION: Pain management can be challenging following bariatric surgery, and patients with obesity tend to increase opioid use after undergoing surgery. This report quantifies marijuana (MJ) use and its relationship to pain and other surgery-related outcomes in a population from a state that has legalized MJ. METHODS: Data were collected for consecutive patients undergoing weight reduction surgeries between May 1, 2014 and July 31, 2015. Demographics, preoperative comorbidities, medications, and perioperative opioid use were analyzed. The primary outcome evaluated was inpatient opioid pain medication use quantified using natural log morphine equivalents. Secondary outcomes included percentage of total body weight loss after three months, postoperative complications, and changes in medical comorbidities. RESULTS: A total of 434 patients, among whom 36 (8.3%) reported MJ use, comprised the study population. Perioperative opioid requirements were significantly higher in the MJ-user group (natural log morphine equivalents of 3.92 vs 3.52, p = 0.0015) despite lower subjective pain scores (3.70 vs 4.24, p = 0.07). MJ use did not affect percentage of 90-day total body weight loss, development of postoperative complications, or improvement in medical comorbidities. CONCLUSION: Perioperative opioid use was significantly higher in the MJ-user group despite lower subjective pain scores. The difference in opioid requirements suggests an interaction between MJ use and opioid tolerance or pain threshold. The percentage of total body weight loss, improvement in medical comorbidity, and incidence of postoperative complications at 90-day follow-up were not affected by MJ use in this cohort analysis. PMID- 30010535 TI - Palliative Surgery for Metastatic Fungating Phyllodes Tumors: A Series of Two Cases. AB - INTRODUCTION: Local treatment of metastatic cystosarcoma phyllodes is classically viewed with skepticism because it does not provide survival benefit. When these advanced tumors ulcerate, they reduce quality of life dramatically because of associated pain, infection, malodor, massive discharge, and bleeding. CASE PRESENTATIONS: Two patients with metastatic cystosarcoma phyllodes presented to our hospital with recurrent disease featuring foul-smelling, ulcerated chest wall masses that caused physical pain and social exclusion. The first patient underwent radical chest wall resection with pedicled lattisimus dorsi flap reconstruction. The second patient underwent wide local excision with split thickness skin grafting. There was significant improvement in the quality of life for these patients after the operations. DISCUSSION: Though both patients finally succumbed to progressive metastatic disease, palliative resection allowed them to have good social and family support to the end. Palliative surgery plays an important role in alleviating suffering of patients with metastatic fungating cystosarcoma phyllodes and has the potential to improve their quality of life significantly. PMID- 30010536 TI - Understanding Waste in Health Care: Perceptions of Frontline Physicians Regarding Time Use and Appropriateness of Care They and Others Provide. AB - BACKGROUND: Approximately 30% of total US health care spending is thought to be "wasted" on activities like unnecessary and inefficiently delivered services. OBJECTIVES: To assess the perceptions of clinic-based physicians regarding their use of time and appropriateness of care provided. DESIGN: Cross-sectional online survey of all Southern California Permanente Medical Group partner and associate physicians (N = 1034) who were primarily providing clinic-based care in 1 of 4 geographically and operationally distinct Kaiser Permanente Southern California Medical Centers. MAIN OUTCOME MEASURES: The proportion of time spent on direct patient care tasks perceived to require the respondent's clinical/specialty training as a physician or another physician who has similar years of clinical training (vs physicians with fewer years of clinical training, nonphysicians, or automated or computerized systems), and the proportion of care provided by the respondent and by other physicians with whom they are familiar that is perceived to be appropriate (vs equivocal or inappropriate). RESULTS: More than 61% of respondents indicated that 15% of their time spent on direct patient care could be shifted to nonphysicians, and between 10% and 16% of care provided was equivocal or inappropriate. DISCUSSION: The low proportion of care perceived as equivocal or inappropriate indicates there is little room for reducing such care or that physicians have difficulty assessing care appropriateness. The latter suggests that attempts to reduce or to eliminate inappropriate care may be unsuccessful until physician beliefs, knowledge, or behaviors are better understood and addressed. CONCLUSION: On the basis of these findings, it is apparent that within at least one health care system, the opportunity to increase value through task shifting and avoiding inappropriate care is more narrow than commonly perceived on a national level. PMID- 30010537 TI - Balloons of Hope. AB - A neurology fellow describes an emotionally draining workday beginning with a long commute delayed by a scene of accidental death. During patient rounds, the day continued with misery as this physician watched and declared brain death in two patients. Opioids took away the life of a young, loving father from his growing family. Opioids robbed an unborn child from seeing her mother. Opioids made this physician feel helpless and caused him to think, Why is this happening? How to stop it? And when does it end? This narrative essay illustrates, with words and art, the need to stamp out the opioid epidemic. PMID- 30010538 TI - An Observational Study of Cardiovascular Risks Associated with Rheumatoid Arthritis Therapies: A Comparison of Two Analytical Approaches. AB - BACKGROUND AND OBJECTIVES: Comparative safety studies typically use hierarchical treatment categories that lump monotherapy and combination therapy. The consequence of this approach on study results is not clear. For example, studies of tumor necrosis factor inhibitors usually lump users regardless of whether they are using the drug alone or in combination with other agents. This study explored the importance of lumping vs splitting users of monotherapy and combination therapy. We also explored whether the timing of disenrollment from Health Plan membership was informative as an outcome variable when interpreting unmeasured, time-varying confounding. METHODS: This observational cohort study included Kaiser Permanente Northern California 2003 to 2013 members with rheumatoid arthritis who started methotrexate. The study end point was a major cardiovascular event. In Cox proportional hazards analysis, we compared treatment classifications using five lumped categories with treatment classification using nine split categories. We also studied disenrollment as an outcome. RESULTS: Among 5885 patients, 238 experienced serious cardiovascular events during an average follow-up of 4.25 years. Analysis of drug treatments using 5 lumped categories was difficult to interpret because treatment effects and drug users were mixed. In contrast, analysis of 9 drug categories that split monotherapies from combination therapy was easier to interpret, although confidence intervals were wider. Analysis of drug treatment in relation to disenrollment provided useful information with which to assess study validity, although the power of the analysis was limited. CONCLUSION: In comparative safety studies, we recommend greater transparency in classifying treatment and evaluating disenrollment. PMID- 30010539 TI - Synergy between the small intrinsically disordered protein Hsp12 and trehalose sustain viability after severe desiccation. AB - Anhydrobiotes are rare microbes, plants and animals that tolerate severe water loss. Understanding the molecular basis for their desiccation tolerance may provide novel insights into stress biology and critical tools for engineering drought-tolerant crops. Using the anhydrobiote, budding yeast, we show that trehalose and Hsp12, a small intrinsically disordered protein (sIDP) of the hydrophilin family, synergize to mitigate completely the inviability caused by the lethal stresses of desiccation. We show that these two molecules help to stabilize the activity and prevent aggregation of model proteins both in vivo and in vitro. We also identify a novel in vitro role for Hsp12 as a membrane remodeler, a protective feature not shared by another yeast hydrophilin, suggesting that sIDPs have distinct biological functions. PMID- 30010542 TI - Calcium and zinc tune autoinflammatory Toll-like receptor 4 signaling by S100A12. PMID- 30010543 TI - Models for nociception stimulation and memory effects in awake and aware healthy individuals. AB - OBJECTIVE: This paper introduces a primer in the healthcare practice, namely a mathematical model and methodology for detecting and analysing nociceptor stimulation followed by related tissue memory effects. METHODS: Non-invasive nociceptor stimulus protocol and prototype device for measuring bioimpedance is provided. Various time instants, sensor location and stimulus train have been analysed. RESULTS: The method and model indicate that nociceptor stimulation perceived as pain in awake healthy volunteers is non-invasively detected. The existence of a memory effect is proven from data. Sensor location had minimal effect on detection level, while day-to-day variability was observed without being significant. CONCLUSION: Following this experimental study, the model enables a comprehensive management of chronic pain patients, and possibly other analgesia, or pain related regulatory loops. SIGNIFICANCE: A device and methodology for non-invasive for detecting nociception stimulation have been developed. The proposed method and models have been validated on healthy volunteers. PMID- 30010540 TI - Hypoxia-inducible factor cell non-autonomously regulates C. elegans stress responses and behavior via a nuclear receptor. AB - The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, the C. elegans gene cyp-36A1, is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior. cyp-36A1 encodes a cytochrome P450 enzyme that we show controls expression of more than a third of HIF-induced genes. CYP-36A1 acts cell non autonomously by regulating the activity of the nuclear hormone receptor NHR-46, suggesting that CYP-36A1 functions as a biosynthetic enzyme for a hormone ligand of this receptor. We propose that regulation of HIF effectors through activation of cytochrome P450 enzyme/nuclear receptor signaling pathways could similarly occur in humans. PMID- 30010541 TI - Membrane insertion of alpha-xenorhabdolysin in near-atomic detail. AB - alpha-Xenorhabdolysins (Xax) are alpha-pore-forming toxins (alpha-PFT) that form 1-1.3 MDa large pore complexes to perforate the host cell membrane. PFTs are used by a variety of bacterial pathogens to attack host cells. Due to the lack of structural information, the molecular mechanism of action of Xax toxins is poorly understood. Here, we report the cryo-EM structure of the XaxAB pore complex from Xenorhabdus nematophila and the crystal structures of the soluble monomers of XaxA and XaxB. The structures reveal that XaxA and XaxB are built similarly and appear as heterodimers in the 12-15 subunits containing pore, classifying XaxAB as bi-component alpha-PFT. Major conformational changes in XaxB, including the swinging out of an amphipathic helix are responsible for membrane insertion. XaxA acts as an activator and stabilizer for XaxB that forms the actual transmembrane pore. Based on our results, we propose a novel structural model for the mechanism of Xax intoxication. PMID- 30010544 TI - Monitoring the Relative Blood Pressure Using a Hydraulic Bed Sensor System. AB - We propose a non-wearable hydraulic bed sensor system that is placed underneath the mattress to estimate the relative systolic blood pressure of a subject, which only differs from the actual blood pressure by a scaling and an offset factor. Two types of features are proposed to obtain the relative blood pressure, one based on the strength and the other on the morphology of the bed sensor BCG pulses. The relative blood pressure is related to the actual by a scale and an offset factor that can be obtained through calibration. The proposed system is able to extract the relative blood pressure more accurately with a less sophisticated sensor system compared to those from the literature. We tested the system using a dataset collected from 48 subjects right after active exercises. Comparison with the ground truth obtained from the blood pressure cuff validates the promising performance of the proposed system, where the mean correlation between the estimate and the ground truth is near 90% for the strength feature and 83% for the morphology feature. PMID- 30010545 TI - Improving Accuracy of Non-invasive Hemoglobin Monitors: A Functional Regression Model for Streaming SpHb Data. AB - OBJECTIVE: The propose of this article is to develop a method for improving the accuracy of SpHb monitors, which are non-invasive hemoglobin monitoring tools, leading to better critical care protocols in trauma care. METHODS: The proposed method is based on fitting smooth spline functions to SpHb measurements collected over a time window and then using a functional regression model to predict the true HgB value for the end of the time window. RESULTS: The accuracy of the proposed method is compared to traditional methods. The mean absolute error between the raw SpHb measurements and the gold standard hemoglobin measurements was 1.26 g/Dl. The proposed method reduced the mean absolute error to 1.08 g/Dl. CONCLUSION: Fitting a smooth function to SpHb measurements improves the accuracy of Hgb predictions. SIGNIFICANCE: Accurate prediction of current and future HgB levels can lead to sophisticated decision models that determine the optimal timing and amount of blood product transfusions. PMID- 30010546 TI - Computer-Vision Techniques for Water-Fat Separation in Ultra-High Field MRI Local Specific Absorption Rate Estimation. AB - OBJECTIVE: The purpose is to prove that computer-vision techniques allow synthesizing water-fat separation maps for local specific absorption rate (SAR) estimation, when patient-specific water-fat images are not available. METHODS: We obtained ground truth head models by using patient-specific water-fat images. We obtained two different label-fusion water-fat models generating a water-fat multi atlas and applying the STAPLE and local-MAP-STAPLE label-fusion methods. We also obtained patch-based water-fat models applying a local group-wise weighted combination of the multi-atlas. Electromagnetic (EM) simulations were performed and B1+ magnitude and 10g averaged SAR maps were generated. RESULTS: We found local approaches provide a high DICE overlap (72.6+/-10.2% fat and 91.6+/-1.5% water in local-MAP-STAPLE, and 68.8+/-8.2% fat and 91.1+/-1.0% water in patch based), low Hausdorff distances (18.6+/-7.7mm fat and 7.4+/-11.2mm water in local MAP-STAPLE, and 16.4+/-8.5mm fat and 7.2+/-11.8mm water in patch-based) and a low error in volume estimation (15.6+/-34.4% fat and 5.6+/-4.1% water in the local MAP-STAPLE, and 14.0+/-17.7% fat and 4.7+/-2.8% water in patch-based). The positions of the peak 10g-averaged local SAR hotspots were the same for every model. CONCLUSION: We have created patient-specific head models using three different computer-vision based water-fat separation approaches and compared the predictions of B1+ field and SAR distributions generated by simulating these models. Our results prove that a computer-vision approach can be used for patient specific water-fat separation, and utilized for local SAR estimation in high field MRI. SIGNIFICANCE: Computer-vision approaches can be used for patient specific water-fat separation and for patient specific local SAR estimation, when water-fat images of the patient are not available. PMID- 30010547 TI - Ionic direct current modulation for combined inhibition/excitation of the vestibular system. AB - OBJECTIVE: Prosthetic electrical stimulation delivered to the vestibular nerve could provide therapy for people suffering from bilateral vestibular dysfunction (BVD). Common encoding methods use pulse-frequency modulation (PFM) to stimulate the semicircular canals of the vestibular system. We previously showed that delivery of ionic direct current (iDC) can also modulate the vestibular system. In this study we compare the dynamic range of head velocity encoding from iDC modulation to that of PFM controls. METHODS: Gentamicin-treated wild-type chinchillas were implanted with microcatheter tubes that delivered ionic current to the left ear vestibular canals and stimulated with steps of anodic/cathodic iDC or PFM. Evoked vestibulo-ocular reflex (VOR) eye velocity was used to compare PFM and iDC vestibular modulation. RESULTS: Cathodic iDC steps effectively elicited eye rotations consistent with an increased firing rate of the implanted semicircular canal afferents. Anodic iDC current steps elicited eye rotations in the opposite direction that, when paired with an adapted cathodic offset, increased the dynamic range of eye rotation velocities in comparison to PFM controls. CONCLUSION: Our results suggest that iDC modulation can effectively modulate the vestibular system across a functional range of rotation vectors and velocities, with a potential benefit over a PFM stimulation paradigm. SIGNIFICANCE: In conjunction with a safe DC delivery system, iDC modulation could potentially increase the range of simulated head rotation velocities available to neuroelectric vestibular prostheses. PMID- 30010548 TI - StackGAN++: Realistic Image Synthesis with Stacked Generative Adversarial Networks. AB - Although Generative Adversarial Networks (GANs) have shown remarkable success in various tasks, they still face challenges in generating high quality images. In this paper, we propose Stacked Generative Adversarial Networks (StackGANs) aimed at generating high-resolution photo-realistic images. First, we propose a two stage generative adversarial network architecture, StackGAN-v1, for text-to-image synthesis. The Stage-I GAN sketches the primitive shape and colors of a scene based on a given text description, yielding low-resolution images. The Stage-II GAN takes Stage-I results and the text description as inputs, and generates high resolution images with photo-realistic details. Second, an advanced multi-stage generative adversarial network architecture, StackGAN-v2, is proposed for both conditional and unconditional generative tasks. Our StackGAN-v2 consists of multiple generators and multiple discriminators arranged in a tree-like structure; images at multiple scales corresponding to the same scene are generated from different branches of the tree. StackGAN-v2 shows more stable training behavior than StackGAN-v1 by jointly approximating multiple distributions. Extensive experiments demonstrate that the proposed stacked generative adversarial networks significantly outperform other state-of-the-art methods in generating photo-realistic images. PMID- 30010549 TI - Generalized mean apparent propagator (GMAP) MRI to measure and image advective and dispersive flows in medicine and biology. AB - Water transport in biological systems spans different regimes with distinct physical behaviors: diffusion, advection, and dispersion. Identifying these regimes is of paramount importance in many in vivo applications, among them, measuring microcirculation of blood in capillary networks and cerebrospinal fluid (CSF) transport in the glymphatic system. Diffusion magnetic resonance imaging (dMRI) can be used to encode water displacements, and a Fourier transform of the acquired signal furnishes a displacement probability density function, known as the propagator. This transformation normally requires the use of a fast Fourier transform (FFT), which presents major feasibility challenges when scanning in vivo, mainly because of dense signal sampling, resulting in long acquisition times. A second approach to reconstruct the propagator is by using analytical representation of the signal, overcoming many of the FFT's limitations. In all analytical implementations of dMRI to date, the translational motion of water has been assumed to be exclusively diffusive, which is the case only in the absence of flow. However, retaining the phase information from the diffusion signal provides the ability to measure both mean coherent velocity and random diffusion from a single experiment. We implement and extend an analytical framework, mean apparent propagator (MAP), which can account for non-zero flow conditions. We call this method generalized MAP, or GMAP. We describe a numerical optimization scheme and implement it on data from an MRI flow phantom constructed from a pack of 10 MUm beads. The advantages of GMAP over the FFT-based method in the context of sampling density and low-flow detection were demonstrated, and analytically derived propagator moments were shown to agree with theoretical values even after data subsampling. GMAP would enables the detection of microflow in vivo that could help elucidate many important biological processes. PMID- 30010550 TI - Towards Intra-operative Prostate Photoacoustic Imaging: Configuration Evaluation and Implementation Using the da Vinci Research Kit. AB - We compare different possible scanning geometries for prostate photoacoustic tomography (PAT) while considering a realistic reconstruction scenario in which the limited-view of the prostate and the directivity effect of the transducer are taken into account. Simulations and experiments confirm that an intra-operative configuration in which the photoacoustic signal is received by a pick-up transducer from the anterior surface of the prostate provides the best approach. We propose a PAT acquisition system that includes a da Vinci system controlled by the da Vinci Research Kit, an illumination laser and an ultrasound machine with parallel data acquisition. The robot maneuvers the pick-up transducer to form a cylindrical detection surface around the prostate. The robot is programmed to acquire trajectories in which the transducer face is parallel to and oriented towards a rotational tomography axis while the laser is fired and PAT data is collected at regular intervals. We present our initial images acquired with this novel system. PMID- 30010551 TI - PAT - Probabilistic Axon Tracking for Densely Labeled Neurons in Large 3D Micrographs. AB - A major goal of contemporary neuroscience research is to map the structural connectivity of mammalian brain using microscopy imaging data. In this context, the reconstruction of densely labeled axons from two-photon microscopy images is a challenging and important task. The visually overlapping, crossing, and often strongly distorted images of the axons allow many ambiguous interpretations to be made. We address the problem of tracking axons in densely labeled samples of neurons in large image datasets acquired from marmoset brains. Our highresolution images were acquired using two-photon microscopy and they provided whole brain coverage, occupying terabytes of memory. Both the image distortions and the large dataset size frequently make it impractical to apply present-day neuron tracing algorithms to such data due to the optimization of such algorithms to the precise tracing of either single or sparse sets of neurons. Thus, new tracking techniques are needed. We propose a probabilistic axon tracking algorithm (PAT). PAT tackles the tracking of axons in two steps: locally (L-PAT) and globally (G-PAT). L-PAT is a probabilistic tracking algorithm that can tackle distorted, cluttered images of densely labeled axons. LPAT divides a large micrograph into smaller image stacks. It then processes each image stack independently before mapping the axons in each image to a sparse model of axon trajectories. GPAT merges the sparse L PAT models into a single global model of axon trajectories by minimizing a global objective function using a probabilistic optimization method.We demonstrate the superior performance of PAT over standard approaches on synthetic data. Furthermore, we successfully apply PAT to densely labeled axons in large images acquired from marmoset brains. PMID- 30010552 TI - Live Tracking and Dense Reconstruction for Hand-held Monocular Endoscopy. AB - Contemporary endoscopic Simultaneous Localization And Mapping (SLAM) methods accurately compute endoscope poses, however, they only provide a sparse 3D reconstruction that poorly describes the surgical scene. We propose a novel dense SLAM method whose qualities are: 1) Monocular, requiring only RGB images of a hand-held monocular endoscope. 2) Fast, providing endoscope positional tracking and 3D scene reconstruction, running in parallel threads. 3) Dense, yielding an accurate dense reconstruction. 4) Robust, to the severe illumination changes, poor texture and small deformations that are typical in endoscopy. 5) Self contained, without needing any fiducials nor external tracking devices, therefore it can be smoothly integrated into the surgical workflow. It works as follows. Firstly, accurate cluster frame poses are estimated using the sparse SLAM feature matches. The system segments clusters of video frames according to a parallax criteria. Next, dense matches between cluster frames are computed in parallel by a variational approach that combines Zero Mean Normalized Cross Correlation (ZNCC) and a gradient Huber norm regularizer. This combination copes with challenging lighting and textures at an affordable time budget on a modern GPU. It can outperform pure stereo reconstructions because the frames cluster can provide larger parallax from the endoscope's motion. We provide an extensive experimental validation on real sequences of the porcine abdominal cavity, both in-vivo and exvivo. We also show a qualitative evaluation on human liver. Additionally, we show a comparison with other dense SLAM methods showing the performance gain in terms of accuracy, density and computation time. PMID- 30010553 TI - Magnetoencephalography with optically pumped 4He magnetometers at ambient temperature. AB - In this paper, we present the first proof of concept confirming the possibility to record magnetoencephalographic (MEG) signals with Optically Pumped Magnetometers (OPMs) based on the parametric resonance of 4He atoms. The main advantage of this kind of OPM is the possibility to provide a tri-axis vector measurement of the magnetic field at room-temperature (the 4He vapor is neither cooled nor heated). The sensor achieves a sensitivity of 210 fT/?Hz in the bandwidth [2 Hz - 300 Hz]. MEG simulation studies with a brain phantom were cross validated with real MEG measurements on a healthy subject. For both studies, MEG signal was recorded consecutively with OPMs and Superconducting Quantum Interference Devices (SQUIDs) used as reference sensors. For healthy subject MEG recordings, three MEG proofs of concept were carried out: auditory and visual evoked fields (AEF, VEF), and spontaneous activity. M100 peaks have been detected on evoked responses recorded by both OPMs and SQUIDs with no significant difference in latency. Concerning spontaneous activity, an attenuation of the signal power between 8-12 Hz (alpha band) related to eyes opening has been observed with OPM similarly to SQUID. All these results confirm that the room temperature vector 4He OPMs can record MEG signals and provide reliable information on brain activity. PMID- 30010554 TI - Can atlas-based auto-segmentation ever be perfect? Insights from Extreme Value Theory. AB - Atlas-based segmentation is used in radiotherapy planning to accelerate the delineation of organs at risk (OARs). Atlas selection has been proposed to improve the performance of segmentation, assuming that the more similar the atlas is to the patient the better the result. It follows that the larger the database of atlases from which to select, the better the results should be. This work seeks to estimate a clinically achievable expected performance under this assumption. Assuming a perfect atlas selection, Extreme Value Theory has been applied to estimate accuracy of single-atlas and multi-atlas segmentation given a large database of atlases. For this purpose, clinical contours of most common OARs on CT of the head and neck (N=316) and thoracic (N=280) cases were used. This study found that while for most organs "perfect" segmentation cannot be reasonably expected, auto-contouring performance of a level corresponding to clinical quality could be consistently expected given a database of 5000 atlases under the assumption of perfect atlas selection. PMID- 30010555 TI - Design and Implementation of a Transmit/Receive Ultrasound Phased Array for Brain Applications. AB - Focused ultrasound phased array systems have attracted increased attention for brain therapy applications. However, such systems currently lack a direct and real-time method to intraoperatively monitor ultrasound pressure distribution for securing treatment. This study proposes a dual-mode ultrasound phased array system design to support transmit/receive operations for concurrent ultrasound exposure and backscattered focal beam reconstruction through a spherically focused ultrasound array. A 256-channel ultrasound transmission system was used to transmit focused ultrasonic energy (full 256 channels), with an extended implementation of multiple-channel receiving function (up to 64 channels) using the same 256-channel ultrasound array. A coherent backscatter-received beam formation algorithm was implemented to map the point spread function (PSF) and focal beam distribution under a free-field/transcranial environment setup, with the backscattering generated from a strong scatterer (a point reflector or a microbubble-perfused tube) or a weakly scattered tissue-mimicking graphite phantom. Our results showed that PSF and focal beam can be successfully reconstructed and visualized in free-field conditions and can also be transcranially reconstructed following skull-induced aberration correction. In vivo experiments were conducted to demonstrate its capability to preoperatively and semiquantitatively map a focal beam to guide blood-brain barrier opening. The proposed system may have potential for real-time guidance of ultrasound brain intervention, and may facilitate the design of a dual-mode ultrasound phased array for brain therapeutic applications. PMID- 30010556 TI - Lag-One Coherence as a Metric for Ultrasonic Image Quality. AB - Reliable assessment of image quality is an important but challenging task in complex imaging environments such as those encountered in vivo. To address this challenge, we propose a novel imaging metric, known as the lag-one coherence (LOC), which leverages the spatial coherence between nearest-neighbor array elements to provide a local measure of thermal and acoustic noise. In this paper, we derive the theory that relates LOC and the conventional image quality metrics of contrast and contrast-to-noise ratio (CNR) to channel noise. Simulation and phantom studies are performed to validate this theory and compare the variability of LOC to that of conventional metrics. We further evaluate the performance of LOC using matched measurements of contrast, CNR, and temporal correlation from in vivo liver images formed with varying mechanical index (MI) to assess the feasibility of adaptive acoustic output selection using LOC feedback. Simulation and phantom results reveal a lower variability in LOC relative to contrast and CNR over a wide range of clinically relevant noise levels. This improved stability is supported by in vivo measurements of LOC which show an increased monotonicity with changes in MI compared to matched measurements of contrast and CNR (88.6% and 85.7% of acquisitions, respectively). The sensitivity of LOC to stationary acoustic noise is evidenced by positive correlations between LOC and contrast ( ) and LOC and CNR ( ) at high acoustic output levels in the absence of thermal noise. Results indicate that LOC provides repeatable characterization of patient-specific trends in image quality, demonstrating feasibility in the selection of acoustic output using LOC and its application for in vivo image quality assessment. PMID- 30010557 TI - Directivity and Frequency-Dependent Effective Sensitive Element Size of Needle Hydrophones: Predictions From Four Theoretical Forms Compared With Measurements. AB - Directivity is a hydrophone specification that describes response as a function of angle of incidence. The goal of this study was to compare, in the context of needle hydrophones, the commonly used rigid baffle model for hydrophone directivity to three alternative models: soft baffle, unbaffled (UB), and rigid piston (RP). Directivity measurements were performed at 1, 2, 3, 4, 6, 8, and 10 MHz from +/-7 degrees in two orthogonal planes for two ceramic and two polymer needle hydrophones with nominal geometrical sensitive element diameters of 200, 400, 600, and 1000 . Effective hydrophone sensitive element radius was estimated by least-squares fitting the four models to directivity measurement data using the sensitive element radius (a) as an adjustable parameter. For > 4 (where and = wavelength), the RP model outperformed the other three models. For , the average error in estimated sensitive element radius was 7% [95% confidence interval (CI): 3%-12%] for the RP model while the lowest average error by the other three models was 46% (95% CI: 38%-54%) for the UB model. PMID- 30010558 TI - Quantitative Assessment of the Effect of the Out-of-Plane Movement of the Homogenous Ellipsoidal Model of the Left Ventricle on the Deformation Measures Estimated Using 2-D Speckle Tracking-An In-Silico Study. AB - Effect of the out-of-plane (OOP) movement amplitude on estimates of global displacements (radial, circumferential) and strains (radial , circumferential ) was studied in an ellipsoidal model of the left ventricle using finite-element modeling (FEM), synthetic ultrasonic data, and short-axis view. This effect was assessed using median of the absolute relative error (RE) of the global parameters. FEM provided node displacements for synthetic ultrasonic data and reference data generation. Displacements were estimated using block-matching (BM) and B-spline (BS) methods. FEM-derived data analysis, free from errors resulting from speckle tracking, indicated that the tissue motion introduced REs of global strain estimates below 4.5%. The effect of the OOP motion amplitude on strain estimates was strain specific and depended on the displacement estimation method. In the case of , the increase of the OOP amplitude resulted in quasi-linear increase of the RE from approximately 10% to 15%. The modulus of the end-systolic (ES) errors of the estimates almost linearly increased with increasing OOP amplitude approximately from 10% to 16%. REs of the estimate were close to 80% and 40%, respectively, in the case of the BM and BS methods, and increased with increasing OOP amplitude. The modulus of the ES errors of the estimates in the case of the BS method was about -40% and showed low sensitivity to the OOP amplitude; in the BM case, these errors varied approximately from -70% to -58% for OOP amplitude from 0 to 15 mm. PMID- 30010559 TI - Fourier-Domain Beamforming and Structure-Based Reconstruction for Plane-Wave Imaging. AB - Ultrafast imaging based on coherent plane-wave compounding is one of the most important recent developments in medical ultrasound. It significantly improves the image quality and allows for much faster image acquisition. This technique, however, requires large computational load motivating methods for sampling and processing rate reduction. In this work, we extend the recently proposed frequency-domain beamforming (FDBF) framework to plane-wave imaging. Beamforming in frequency yields the same image quality while using fewer samples. It achieves at least fourfold sampling and processing rate reduction by avoiding oversampling required by standard processing. To further reduce the rate, we exploit the structure of the beamformed signal and use compressed sensing methods to recover the beamformed signal from its partial frequency data obtained at a sub-Nyquist rate. Our approach obtains tenfold rate reduction compared with standard time domain processing. We verify performance in terms of spatial resolution and contrast based on the scans of a tissue mimicking the phantom obtained by a commercial Aixplorer system. In addition, in vivo carotid and thyroid scans processed using standard beamforming and FDBF are presented for qualitative evaluation and visual comparison. Finally, we demonstrate the use of FDBF for shear-wave elastography by generating velocity maps from the beamformed data processed at sub-Nyquist rates. PMID- 30010560 TI - Multi-Oriented and Multi-Lingual Scene Text Detection with Direct Regression. AB - Multi-oriented and multi-lingual scene text detection plays an important role in computer vision area and is challenging due to the wide variety of text and background. In this paper, firstly we point out the two key tasks when extending CNN based object detection frameworks to scene text detection. The first task is to localize the text region by a down-sampled segmentation based module, and the second task is to regress the boundaries of text region determined by the first task. Secondly, we propose a scene text detection framework based on fully convolutional network (FCN) with a bi-task prediction module in which one is pixel-wise classification between text and non-text, and the other is pixel-wise regression to determine the vertex coordinates of quadrilateral text boundaries. Post-processing for word-level detection is based on Non-Maximum Suppression (NMS), and for line-level detection we design a heuristic line segments grouping method to localize long text lines. We evaluated the proposed framework on various benchmarks including multi-oriented and multi-lingual scene text datasets, and achieved state-of-the-art performance on most of them. We also provide abundant ablation experiments to analyze several key factors in building high performance CNN based scene text detection systems. PMID- 30010561 TI - Quality-of-Experience for Adaptive Streaming Videos: An Expectation Confirmation Theory Motivated Approach. AB - The dynamic adaptive streaming over HTTP (DASH) provides an inter-operable solution to overcome volatile network conditions, but how the human visual quality-ofexperience (QoE) changes with time-varying video quality is not well understood. Here, we build a large-scale video database of time-varying quality and design a series of subjective experiments to investigate how humans respond to compression level, spatial and temporal resolution adaptations. Our path analytic results show that quality adaptations influence the QoE by modifying the perceived quality of subsequent video segments. Specifically, the quality deviation introduced by quality adaptations is asymmetric with respect to the adaptation direction, which is further influenced by other factors such as compression level and content. Furthermore, we propose an objective QoE model by integrating the empirical findings from our subjective experiments and the expectation confirmation theory (ECT). Experimental results show that the proposed ECT-QoE model is in close agreement with subjective opinions and significantly outperforms existing QoE models. The video database together with the code are available online at https://ece.uwaterloo.ca/~zduanmu/tip2018ectqoe/. PMID- 30010562 TI - Attentive Linear Transformation for Image Captioning. AB - We propose a novel attention framework called attentive linear transformation (ALT). Instead of learning the spatial or channel-wise attention in existing models, ALT learns to attend to the high-dimensional transformation matrix from the image feature space to the context vector space. Thus ALT can learn various relevant feature abstractions, including spatial attention, channel-wise attention and visual dependence. Besides, we propose a soft threshold regression to predict the attention probabilities for local regions. Soft threshold regression preserves more useful visual information than popular softmax regression. Extensive experiments on the MS COCO and the Flickr30k datasets demonstrate the superiority of our model compared with other state-of-the-art methods. PMID- 30010563 TI - Hyperspectral Image Super-Resolution with a Mosaic RGB Image. AB - Recently, many hyperspectral (HS) image superresolution methods that merge a low spatial resolution HS image and a high spatial resolution three-channel RGB image have been proposed in spectral imaging. A largely ignored fact is that most existing commercial RGB cameras capture high resolution images by a single CCD/CMOS sensor equipped with a color filter array (CFA). In this paper, we account for the common imaging mechanism of commercial RGB cameras, and propose to use a mosaic RGB image for HS image super-resolution, which prevents demosaicing error and thus its propagation into the HS image super-resolution results. We design a proper nonlocal low-rank regularization to exploit the intrinsic properties - rich self-repeating patterns and high correlation across spectra - within HS images of natural scenes, and formulate the HS image super resolution task into a variational optimization problem, which can be efficiently solved via the alternating direction method of multipliers (ADMM). The effectiveness of the proposed method has been evaluated on two benchmark datasets, demonstrating that the proposed method can provide substantial improvement over the current state-of-the-art HS image superresolution methods without considering the mosaicing effect. Finally, we show that our method can also perform well in the real capture system. PMID- 30010564 TI - Weighted Large Margin Nearest Center Distance-Based Human Depth Recovery With Limited Bandwidth Consumption. AB - This paper proposes a weighted large margin nearest center (WLMNC) distance-based human depth recovery method for tele-immersive video interaction systems with limited bandwidth consumption. In the remote stage, the proposed method highly compresses the depth data of the remote human into skeletal block structures by learning the WLMNC distance, which is equivalent to downsampling the human depth map at $64{?times}$ the sampling rate. In the local stage, the method first recovers a rough human depth map based on a WLMNC distance augmented clustering approach and then obtains a fine depth map based on a rough depth-guided autoregressive model to preserve the depth discontinuities and suppress texture copy artifacts. The proposed WLMNC distance is learned by the large margin clustering problem with a weighted hinge loss to balance the clustering accuracy and depth recovery accuracy and is verified to be able to preserve depth discontinuities between skeletal block structures with occlusion. A theoretical analysis is conducted to verify the effectiveness of using the weighted hinge loss. Furthermore, a novel data set containing various types of human postures with self-occlusion is built to benchmark the human depth recovery methods. The quantitative comparison with the state-of-the-art depth recovery methods on the introduced benchmark data set demonstrates the effectiveness of the proposed method for human depth recovery with such a high upsampling rate. PMID- 30010565 TI - More is Better: Precise and Detailed Image Captioning Using Online Positive Recall and Missing Concepts Mining. AB - Recently, a great progress in automatic image captioning has been achieved by using semantic concepts detected from the image. However, we argue that existing concepts-to-caption framework, in which the concept detector is trained using the image-caption pairs to minimize the vocabulary discrepancy, suffers from the deficiency of insufficient concepts. The reasons are two-fold: 1) the extreme imbalance between the number of occurrence positive and negative samples of the concept and 2) the incomplete labeling in training captions caused by the biased annotation and usage of synonyms. In this paper, we propose a method, termed online positive recall and missing concepts mining, to overcome those problems. Our method adaptively re-weights the loss of different samples according to their predictions for online positive recall and uses a two-stage optimization strategy for missing concepts mining. In this way, more semantic concepts can be detected and a high accuracy will be expected. On the caption generation stage, we explore an element-wise selection process to automatically choose the most suitable concepts at each time step. Thus, our method can generate more precise and detailed caption to describe the image. We conduct extensive experiments on the MSCOCO image captioning data set and the MSCOCO online test server, which shows that our method achieves superior image captioning performance compared with other competitive methods. PMID- 30010566 TI - Self-Similarity Constrained Sparse Representation for Hyperspectral Image Super Resolution. AB - Fusing a low-resolution hyperspectral image with the corresponding high resolution multispectral image to obtain a high-resolution hyperspectral image is an important technique for capturing comprehensive scene information in both spatial and spectral domains. Existing approaches adopt sparsity promoting strategy, and encode the spectral information of each pixel independently, which results in noisy sparse representation. We propose a novel hyperspectral image super-resolution method via a self-similarity constrained sparse representation. We explore the similar patch structures across the whole image and the pixels with close appearance in local regions to create globalstructure groups and local spectral super-pixels. By forcing the similarity of the sparse representations for pixels belonging to the same group and super-pixel, we alleviate the effect of the outliers in the learned sparse coding. Experiment results on benchmark datasets validate that the proposed method outperforms the stateof- the-art methods in both quantitative metrics and visual effect. PMID- 30010567 TI - Low Rank Matrix Recovery via Robust Outlier Estimation. AB - In practice, high-dimensional data are typically sampled from low-dimensional subspaces, but with intrusion of outliers and/or noises. Recovering the underlying structure and the pollution from the observations is of utmost importance to understanding the data. Besides properly modeling the subspace structure, how to handle the pollution is a core question regarding the recovery quality, the main origins of which include small dense noises and gross sparse outliers. Compared with the small noises, the outliers more likely ruin the recovery, as their arbitrary magnitudes can dominate the fidelity, and thus lead to misleading/erroneous results. Concerning the above, this paper concentrates on robust outlier estimate for low rank matrix recovery, termed as ROUTE. The principle is to classify each entry as an outlier or an inlier (with confidence). We formulate the outlier screening and the recovery into a unified framework. To seek the optimal solution to the problem, we first introduce a block coordinate descent based optimizer (ROUTE-BCD), then customize an alternating direction method of multipliers based one (ROUTE-ADMM). Through analyzing theoretical properties and practical behaviors, ROUTE-ADMM shows its superiority over ROUTE BCD in terms of computational complexity, initialization insensitivity and recovery accuracy. Extensive experiments on both synthetic and real data are conducted to show the efficacy of our strategy and reveal its significant improvement over other state-of-the-art alternatives. Our code is publicly available at https://sites.google.com/view/xjguo/route. PMID- 30010568 TI - Video Captioning by Adversarial LSTM. AB - In this paper, we propose a novel approach to video captioning based on adversarial learning and Long-Short Term Memory (LSTM). With this solution concept we aim at compensating for the deficiencies of LSTM-based video captioning methods that generally show potential to effectively handle temporal nature of video data when generating captions, but that also typically suffer from exponential error accumulation. Specifically, we adopt a standard Generative Adversarial Network (GAN) architecture, characterized by an interplay of two competing processes: a "generator", which generates textual sentences given the visual content of a video, and a "discriminator" which controls the accuracy of the generated sentences. The discriminator acts as an "adversary" towards the generator and with its controlling mechanism helps the generator to become more accurate. For the generator module, we take an existing video captioning concept using LSTM network. For the discriminator, we propose a novel realization specifically tuned for the video captioning problem and taking both the sentences and video features as input. This leads to our proposed LSTM-GAN system architecture, for which we show experimentally to significantly outperform the existing methods on standard public datasets. PMID- 30010569 TI - Color Contrast-Preserving Decolorization. AB - Decolorization is to convert a color image into a gray scale image while preserve image features like salient structure and chrominance contrast. The sign of the color contrast is crucial for the decolorization algorithm and is usually determined in existing works by giving a strict defined color order or twomode weak order. In this paper, a fast computation on color order is achieved via a simple global mapping which is introduced in a linear parametric model using an extended structure transfer filter. The values of the parameters are obtained via an elegant approximation method. A local decolorization algorithm is finally designed on basis of the global linear mapping so that both color and spatial information are preserved robustly and accurately. Experimental results show that the proposed decolorization algorithms obtain a good performance among existing quality metrics for the decolorization. In addition, the proposed global decolorization algorithm is friendly to mobile devices with limited computational resource. PMID- 30010570 TI - Low-Rank Sparse Preserving Projections for Dimensionality Reduction. AB - Learning an efficient projection to map high-dimensional data into a lower dimensional space is a rather challenging task in the community of pattern recognition and computer vision. Manifold learning is widely applied because it can disclose the intrinsic geometric structure of data. However, it only concerns the geometric structure and may lose its effectiveness in case of corrupted data. To address this challenge, we propose a novel dimensionality reduction method by combining the manifold learning and low-rank sparse representation, termed low rank sparse preserving projections (LSPP), which can simultaneously preserve the intrinsic geometric structure and learn a robust representation to reduce the negative effects of corruptions. Therefore, LSPP is advantageous to extract robust features. Because the formulated LSPP problem has no closed-form solution, we use the linearized alternating direction method with adaptive penalty and eigen-decomposition to obtain the optimal projection. The convergence of LSPP is proven, and we also analyze its complexity. To validate the effectiveness and robustness of LSPP in feature extraction and dimensionality reduction, we make a critical comparison between LSPP and a series of related dimensionality reduction methods. The experimental results demonstrate the effectiveness of LSPP. PMID- 30010571 TI - Hadamard Coding for Supervised Discrete Hashing. AB - In this paper, we propose a learning-based supervised discrete hashing method. Binary hashing is widely used for large-scale image retrieval as well as video and document searches because the compact binary code representation is essential for data storage and reasonable for query searches using bit-operations. The recently proposed supervised discrete hashing (SDH) method efficiently solves mixed-integer programming problems by alternating optimization and the discrete cyclic coordinate descent (DCC) method. Based on some preliminary experiments, we show that the SDH method can be simplified without performance degradation. We analyze the simplified model and provide a mathematically exact solution thereof; we reveal that the exact binary code is provided by a "Hadamard matrix." Therefore, we named our method Hadamard codedsupervised discrete hashing (HC SDH). In contrast to SDH, our model does not require an alternating optimization algorithm and does not depend on initial values. HC-SDH is also easier to implement than iterative quantization (ITQ). Experimental results involving a large-scale database show that Hadamard coding outperforms conventional SDH in terms of precision, recall, and computational time. On the large datasets SUN-397 and ImageNet, HC-SDH provides a superior mean average of precision (mAP) and top accuracy compared to the conventional SDH methods with the same code length and FastHash. The training time of HC-SDH is 170 times faster than conventional SDH and the testing time including the encoding time is seven times faster than FastHash which encodes using a binary-tree. PMID- 30010572 TI - Structurally Incoherent Low-Rank Nonnegative Matrix Factorization for Image Classification. AB - As a popular dimensionality reduction method, nonnegative matrix factorization (NMF) has been widely used in image classification. However, the NMF does not consider discriminant information from the data themselves. In addition, most NMF based methods use the Euclidean distance as a metric, which is sensitive to noise or outliers in data. To solve these problems, in this paper, we introduce structural incoherence and low-rank to NMF and propose a novel nonnegative factorization method, called structurally incoherent low-rank NMF (SILR-NMF), in which we jointly consider structural incoherence and low-rank properties of data for image classification. For the corrupted data, we use the norm as a constraint to ensure the noise is sparse. SILR-NMF learns a clean data matrix from the noisy data by low-rank learning. As a result, the SILR-NMF can capture the global structure information of the data, which is more robust than local information to noise. By introducing the structural incoherence of the learned clean data, SILR NMF ensures the clean data points from different classes are as independent as possible. To verify the performance of the proposed method, extensive experiments are conducted on six image databases. The experimental results demonstrate that our proposed method has substantial gain over existing NMF approaches. PMID- 30010573 TI - Information Fusion for Human Action Recognition via Biset/Multiset Globality Locality Preserving Canonical Correlation Analysis. AB - In this paper, we study the problem of human action recognition, in which each action is captured by multiple sensors and represented by multisets. We propose two novel information fusion techniques for fusing the information from multisets. The first technique is biset globality locality preserving canonical correlation analysis (BGLPCCA), which aims to learn the common feature subspace between two sets. The second technique is multiset globality locality preserving canonical correlation analysis (MGLPCCA), which aims to deal with three or more sets. The proposed BGLPCCA and MGLPCCA are able to learn a low-dimensional common subspace that preserves the local and global structures of data samples. Moreover, two novel descriptors are presented for both depth and skeleton. We then propose a new human action recognition framework employing the proposed BGLPCCA or MGLPCCA to learn the shared subspace from multiple sets of features including skeleton, depth, and optical flow. Extensive experiments on five publicly available datasets (MSR Action3D, UTD multimodal human action dataset, multimodal action database, Kinect activity recognition dataset, and SBU Kinect interaction dataset) demonstrate the effectiveness of the proposed framework. PMID- 30010574 TI - Exemplar-aided Salient Object Detection via Joint Latent Space Embedding. AB - Traditional unsupervised salient object detection methods majorly rely on pre defined assumptions about saliency. However, these assumptions may not be sufficient for handling test images of varied content and context. Meanwhile, supervised models learn saliency knowledge from thousands of annotated images, which are usually expensive to obtain. In this paper, we propose an exemplar aided salient object detection method, which can complement heuristic saliency assumptions by leveraging only a few exemplar images. This is a challenging task since the appearances between the query images and the exemplars can be quite different. We handle it by learning the matching relationship of the intra-class instances in a latent embedding space in an online fashion. Given a test image and an annotated reference image (retrieved from several exemplar images), our method transfers the foreground and background information of the reference image to the test image via a joint latent embedding of image superpixels. Extensive experiments show that our method can easily improve the performance of existing unsupervised methods even when a very small reference image dataset (e.g. one image) is used. In addition, our method is able to attain competitive performance against fully supervised methods. PMID- 30010575 TI - Recognition From Web Data: A Progressive Filtering Approach. AB - Leveraging the abundant number of web data is a promising strategy in addressing the problem of data lacking when training convolutional neural networks (CNNs). However, the web images often contain incorrect tags, which may compromise the learned CNN model. To address this problem, this paper focuses on image classification and proposes to iterate between filtering out noisy web labels and fine-tuning the CNN model using the crawled web images. Overall, the proposed method benefits from the growing modeling capability of the learned model to correct labels for web images and learning from such new data to produce a more effective model. Our contribution is two-fold. First, we propose an iterative method that progressively improves the discriminative ability of CNNs and the accuracy of web image selection. This method is beneficial toward selecting high quality web training images and expanding the training set as the model gets ameliorated. Second, since web images are usually complex and may not be accurately described by a single tag, we propose to assign a web image multiple labels to reduce the impact of hard label assignment. This labeling strategy mines more training samples to improve the CNN model. In the experiments, we crawl 0.5 million web images covering all categories of four public image classification data sets. Compared with the baseline which has no web images for training, we show that the proposed method brings notable improvement. We also report the competitive recognition accuracy compared with the state of the art. PMID- 30010576 TI - Quality Robust Mixtures of Deep Neural Networks. AB - We study deep neural networks for classification of images with quality distortions. Deep network performance on poor quality images can be greatly improved if the network is fine-tuned with distorted data. However, it is difficult for a single fine-tuned network to perform well across multiple distortion types. We propose a mixture of experts based ensemble method, MixQualNet, that is robust to multiple different types of distortions. The "experts" in our model are trained on a particular type of distortion. The output of the model is a weighted sum of the expert models, where the weights are determined by a separate gating network. The gating network is trained to predict weights for a particular distortion type and level. During testing, the network is blind to the distortion level and type, yet can still assign appropriate weights to the expert models. In order to reduce the computational complexity, we introduce weight sharing into the MixQualNet. We utilize the TreeNet weight sharing architecture as well as introduce the Inverted TreeNet architecture. While both weight sharing architectures reduce memory requirements, our proposed Inverted TreeNet also achieves improved accuracy. PMID- 30010577 TI - Image Stacks as Parametric Surfaces: Application to Image Registration. AB - We introduce a framework in which a stack of images is considered to be a 2-D parametric surface embedded in a higher dimensional space. This is a simple yet powerful idea, known in the literature but not exploited to its fullest. We discuss the properties of image stacks as parametric surfaces, apply this framework to image registration by presenting the image stack surface relative area (ISSRA) registration measure. We show the power of ISSRA as an effective objective function for image registration. Essentially, it shows good performance across a variety of different categories of registration problems: pairwise, groupwise, affine, and non-rigid. Mutual information (MI)-a classical and effective approach for registration-is widely considered to be a good choice for multimodal and pairwise registration while being difficult to extend to the groupwise setting. We discuss the deficiency of MI in the groupwise case from a theoretical point of view, present its connection to ISSRA in the pairwise case, and then show the ready extensibility of ISSRA to the groupwise setting. Experiments and comparisons are performed on different categories of image registration to showcase ISSRA's wide range of applicability to registration problems in practice. PMID- 30010578 TI - Spontaneous Expression Recognition using Universal Attribute Model. AB - Spontaneous expression recognition refers to recognizing non-posed human expressions. In literature, most of the existing approaches for expression recognition mainly rely on manual annotations by experts, which is both time consuming and difficult to obtain. Hence, we propose an unsupervised framework for spontaneous expression recognition that preserves discriminative information for the videos of each expression without using annotations. Initially, a large Gaussian mixture model called universal attribute model (UAM) is trained to learn the attributes of various expressions implicitly. Attributes are the movements of various facial muscles that are combined to form a particular facial expression. Then a concatenated mean vector called the super expression-vector (SEV) is formed by using a maximum a posteriori adaptation of the UAM means for each expression clip. This SEV contains attributes from all the expressions resulting in a high dimensional representation. To retain only the attributes of that particular expression clip, the SEV is decomposed using factor analysis to produce a low-dimensional expression-vector. This procedure does not require any class labels and produces expression-vectors that are distinct for each expression irrespective of high inter-actor variability present in spontaneous expressions. On spontaneous expression datasets like BP4D and AFEW, we demonstrate that expression-vector achieves better performance than state-of-the art techniques. Further, we also show that UAM trained on a constrained dataset can be effectively used to recognize expressions in unconstrained expression videos. PMID- 30010579 TI - Mathematical Modeling of EEG Signals-Based Brain-Control Behavior. AB - Brain-control behaviors (BCBs) are behaviors of humans that communicate with external devices by means of the human brain rather than peripheral nerves or muscles. In this paper, to understand and simulate such behaviors, we propose a mathematical model by combining a queuing network-based encoding model with a brain-computer interface model. Experimental results under the static tests show the effectiveness of the proposed model in simulating real BCBs. Furthermore, we verify the effectiveness and applicability of the proposed model through the dynamic experimental tests in a simulated vehicle. This paper not only promotes the understanding and prediction of BCBs, but also provides some insights into assistive technology on brain-controlled systems and extends the scope of research on human behavior modeling. PMID- 30010580 TI - Evaluation of Myoelectric Control Learning Using Multi-Session Game-Based Training. AB - While training is critical for ensuring initial success as well as continued adoption of a myoelectric powered prosthesis, relatively little is known about the amount of training that is necessary. In previous studies, participants have completed only a small number of sessions, leaving doubt about whether the findings necessarily generalize to a longer-term clinical training program. Furthermore, a heavy emphasis has been placed on a functional prosthesis use when assessing the effectiveness of myoelectric training. Although well-motivated, this all-inclusive approach may obscure more subtle improvements made in underlying muscle control that could lead to tangible benefits. In this paper, a deeper exploration of the effects of myoelectric training was performed by following the progress of 30 participants as they completed a series of ten 30 min training sessions over multiple days. The progress was assessed using a newly developed set of metrics that was specifically designed to quantify the aspects of muscle control that are foundational to the strong myoelectric prosthesis use. It was determined that, while myoelectric training can lead to improvements in muscle control, these improvements may take longer than previously considered, even occurring after improvements in the training game itself. These results suggest the need to reconsider how and when transfer from training activities is assessed. PMID- 30010581 TI - Stimuli and Feature Extraction Algorithms for Brain-Computer Interfaces: A Systematic Comparison. AB - A brain-computer interface (BCI) is a system that allows communication between the central nervous system and an external device. The BCIs developed by various research groups differ in their main features and the comparison across studies is therefore challenging. Here, in the same group of 19 healthy participants, we investigate three different tasks (SSVEP, P300, and hybrid) that allowed four choices to the user without previous neurofeedback training. We used the same 64 channel EEG equipment to acquire data, while participants performed each of the tasks. We systematically compared the participants' offline performance on the following parameters: 1) accuracy; 2) BCI Utility (in bits/min); and 3) inefficiency/illiteracy. In addition, we evaluated the accuracy as a function of the number of electrodes. In this paper, the SSVEP task outperformed the other tasks in bit rate, reaching an average and maximum BCI Utility of 63.4 and 91.3 bits/min, respectively. All participants achieved an accuracy level above70% on both SSVEP and P300 tasks. Furthermore, the average accuracy of all tasks was highest if a reduced subset with 4-12 electrodes was used. These results are relevant for the development of online BCIs intended for the real-life applications. PMID- 30010582 TI - Analyses of EEG Oscillatory Activities during Slow and Fast Repetitive Movements using Holo-Hilbert Spectral Analysis. AB - Neural oscillatory activities existing in multiple fre-quency bands usually represent different levels of neurophysiolog-ical meanings, from micro-scale to macro-scale organizations. In this study, we adopted Holo-Hilbert spectral analysis (HHSA) to study the amplitude-modulated (AM) and frequency-modulated (FM) components in sensorimotor Mu rhythm, induced by slow- and fast-rate repetitive movements. The HHSA-based approach is a two-layer empirical mode decomposition (EMD) architecture, which firstly decomposes the EEG signal into a series of frequency-modulated intrinsic mode functions (IMF) and then decomposes each frequency-modulated IMF into a set of amplitude-modulated IMFs. With the HHSA, the FM and AM components were incor-porated with their instantaneous power to achieve full-informa-tional spectral analysis. We observed that the instantaneous power induced by slow-rate movements was significantly higher than that induced by fast-rate movements (p < 0.01, Wilcoxon signed rank test). The alpha-band AM frequencies induced by slow-rate movements were higher than those induced by fast-rate move-ments, while no statistical difference was found in beta-band AM frequencies. In addition, to study the functional coupling between the primary sensorimotor area and other brain regions, spectral coherence was applied and statistical difference was found in frontal area in slow-rate versus fast-rate movements. The discrep-ancy between slow- and fast-rate movements might be owing to the change of motor functional modes from default mode network (DMN) to automatic timing with the increase of movement rates. The use of HHSA for oscillatory activity analysis can be an effi-cient tool to provide informative interaction among different fre-quency bands. PMID- 30010583 TI - Different Anti-Vaping Campaigns Attracting the Same Opponent Community. AB - E-cigarettes (vape) are now the most commonly used tobacco product among youth in the United States. Ads are claiming e-cigarettes help smokers quit, but most of them contain nicotine, which can cause addiction and harm the developing adolescent brain. Therefore, national, state, and local health organizations have proposed anti-vaping campaigns to warn the potential risks of e-cigarettes. However, there is some evidence that these products may reduce harm for adult users who reduce or quit combustible cigarette smoking, and with little evidence that e-cigarettes cause long-term harm, pro-vaping advocates have used this equivocal evidence base to oppose the anti-vaping media campaign messaging, generating a very high volume of oppositional messages on social media. Thus, when we analyze the feedback of anti-vaping campaigns, it is crucial to partition the audience into different clusters according to their attitudes and affiliations. Motivated by this, in this paper, we propose the "community detection on anti-vaping campaign audience" problem and design the "community detection based on social, repost and content relation, (Sorento)" algorithm to solve it. Sorento computes users' intimacy scores based on their social connections, repost relations, and content similarities. The community detection results achieved by Sorento demonstrate that though anti-vaping campaigns are proposed in different areas at different times, their opponent messages are mainly posted by the same community of pro-vapors. PMID- 30010584 TI - MedCo: Enabling Secure and Privacy-Preserving Exploration of Distributed Clinical and Genomic Data. AB - The increasing number of health-data breaches is creating a complicated environment for medical-data sharing and, consequently, for medical progress. Therefore, the development of new solutions that can reassure clinical sites by enabling privacy-preserving sharing of sensitive medical data in compliance with stringent regulations (e.g., HIPAA, GDPR) is now more urgent than ever. In this work, we introduce MedCo, the first operational system that enables a group of clinical sites to federate and collectively protect their data in order to share them with external investigators without worrying about security and privacy concerns. MedCo uses (a) collective homomorphic encryption to provide trust decentralization and end-to-end confidentiality protection, and (b) obfuscation techniques to achieve formal notions of privacy, such as differential privacy. A critical feature of MedCo is that it is fully integrated within the i2b2 (Informatics for Integrating Biology and the Bedside) framework, currently used in more than 300 hospitals worldwide. Therefore, it is easily adoptable by clinical sites. We demonstrate MedCo's practicality by testing it on data from The Cancer Genome Atlas in a simulated network of three institutions. Its performance is comparable to the ones of SHRINE (networked i2b2), which, in contrast, does not provide any data protection guarantee. PMID- 30010585 TI - Correction to "Compact Nonlinear Model of an Implantable Electrode Array for Spinal Cord Stimulation". PMID- 30010586 TI - A Nanowatt Real-Time Cardiac Autonomic Neuropathy Detector. AB - This paper presents an electrocardiogram (ECG) processor on chip for full ECG feature extraction and cardiac autonomic neuropathy (CAN) classification. Full ECG extraction is performed using absolute value curve length transform (A-CLT) for $?text{QRS}_{?text{peak}}$ detection and using low-pass differentiation for other ECG features such as $?text{QRS}_{?text{on}}$, $?text{QRS}_{?text{off}}$, Pwave, and Twave. The proposed QRS detector attained a sensitivity of 99.37% and predictivity of 99.38%. The extracted $?text{QRS}_{?text{peak}}$ to $?text{QRS}_{?text{peak}}$ intervals (RR intervals) along with QT intervals enable CAN severity detection, which is a cardiac arrhythmia usually seen in diabetic patients leading to increased risk of sudden cardiac death. This paper presents the first hardware real-time implementation of CAN severity detector that is based on RR variability and QT variability analysis. RR variability metrics are based on mean RR interval and root mean square of standard differences of the RR intervals. The proposed architecture was implemented in 65 nm technology and consumed 75 nW only at 0.6 V, when operating at 250 Hz. Ultralow power dissipation of the system enables it to be integrated into wearable healthcare devices. PMID- 30010587 TI - Hodgkin-Huxley Neuron and FPAA Dynamics. AB - We present the experimental silicon results on the dynamics of a Hodgkin-Huxley neuron implemented on a reconfigurable platform. The circuit has been inspired by the similarity between biology and silicon, by modeling ion channels and their time constants. Another significant motivation behind this paper is to make the system available to circuit designers as well as users in the neuroscience community. The open-source tool infrastructure and a remote system ease the accessibility of our system to a number of users. We demonstrate the reproducibility of the results by replicating the dynamics across different boards along with responses from different inputs and with different parameters. The reconfigurability enables one to make use of a single primary design to obtain a variety of results. The measurements are taken from the system compiled on a field programmable analog array fabricated on a 350-nm process. PMID- 30010588 TI - Adapting ISFETs for Epigenetics: An Overview. AB - This paper gives an overview of how CMOS design methods can be applied to ion sensitive field effect transistor (ISFETs) for pH-based DNA methylation and miRNA detection. Design specifications are fundamentally defined by the choice of analysis. As such, the focus for DNA methylation was on developing front-end analogue circuits to carry out Methylation-specific PCR (MSP) for Point-of-Care applications, and sequencing for detailed analysis. The use of MSP prompted the design of an ISFET weak inversion current mirror topology for differential sensing and reduction of drift and temperature sensitivities. The primary limitation in ion-semiconductor sequencing is base calling of repeated nucleotides known as homopolymers. Implementation of a switched current integrator can potentially increase both accuracy and window for detection, within the frequency region of DNA reactions. For quantifying miRNAs, digital back-end processing circuits were considered toward a fully portable platform that can carry out real-time monitoring of DNA amplification reactions. Two systems to evaluate threshold cycles were developed, based on the Derivative method and a new proposed 3-point exponential evaluation aim to reduce detection time simultaneously. Both implementations were tested with datasets from fluorescent qPCR reactions, as well as pH-LAMP experiments that have been optimized for on-chip amplifications. All designs were fabricated in unmodified CMOS with performance assessed based on functionality as well as pH-resolution required in practice. PMID- 30010589 TI - A Low-Cost, Standalone, and Multi-Tasking Watch for Personalized Environmental Monitoring. AB - A novel hardware approach with four physical layers and several integrated and add-on sensors for a comprehensive physical and chemical environmental parameter (toxic gases, sound level, air pressure, humidity, temperature, and motion tracking) monitoring is introduced in this paper. To provide flexibility, the system is modular and each sensor functions independently. The whole solution is small, compact, light, and wrist worn. It is working in low power consumption mode and operates for several hours. The device has two layers to implement the sensors and one layer for a warning system driver to enable the vibrating motor and beeper in emergency status. The forth layer is the hardware flex interface that is connected to the display and sound module and provides the possibility of the hardware extension for further development. The gas sensor node includes the sensor attached to the driver (located at the top) and is replaceable with other target gas sensors from the same family. The warning system is located at the bottom of the proposed device. The sampled data from the sensors are monitored in real time via the display and are sent to an Android smartphone for permanent storage via Bluetooth Low Energy(BLE) 4.1. Consequently, these data will be directed to a cloud for further medical analyses. Power consumption, results, device efficiency, and packet protocol justification are evaluated in this paper. PMID- 30010590 TI - Superresolution Line Scan Image Sensor for Multimodal Microscopy. AB - A low-cost contact scanning microscope is presented which performs optical imaging of millimeter-scale samples with multiple sensory modalities at a spatial resolution better than the pixel size in both x and y dimensions. The 7.5 mm 3.2 mm 0.35 m CMOS image sensor is comprised of 214 scanning lines of 256 pixels, each line horizontally shifted by 300 nm with respect to the adjacent lines. When scanning in the y dimension, this results in a staircase-like staggered-pixels organization with an effective spatial resolution in the x dimension of less than the pixel size, with a theoretical limit of 300 nm, subject to the light diffraction limit and to photodiode size-dependent spatial aliasing. The height of the resulting pixel "staircases" is capped at 2.5 mm by wrapping the 215th row back to the first row, yielding an approximately 2 mm 2.5 mm instantaneous scanning window size. The spatial resolution in the y dimension is set by the sample scanning rate and the frame rate, subject to the same limitations. Integration of multiple scanning lines naturally lends itself to the inclusion of multiple sensory modalities, with five modalities included as an example: High resolution (up to 300 nm), fluorescence-sensitive, and triple-orientation light polarization-sensitive pixels. The resulting modified scanning pattern is digitized by on-chip column-parallel 2nd order Delta-Sigma ADCs with ENOB of 9.1 and is reconstructed into a full-resolution image in software. Experimental measurements, where contact-scanning is emulated by the sample image moving on an LCD monitor and projected through a lens, support the validity of the presented concept. PMID- 30010591 TI - Analysis and Simulation of Capacitor-Less ReRAM-Based Stochastic Neurons for the in-Memory Spiking Neural Network. AB - The stochastic neuron is a key for event-based probabilistic neural networks. We propose a stochastic neuron using a metal-oxide resistive random-access memory (ReRAM). The ReRAM's conducting filament with built-in stochasticity is used to mimic the neuron's membrane capacitor, which temporally integrates input spikes. A capacitor-less neuron circuit is designed, laid out, and simulated. The output spiking train of the neuron obeys the Poisson distribution. Using the 65-nm CMOS technology node, the area of the neuron is , which is one ninth the size of a 1 pF capacitor. The average power consumption of the neuron is 1.289 W. We introduce the neural array-A modified one-transistor-one-ReRAM (1T1R) crossbar that integrates the ReRAM neurons with ReRAM synapses to form a compact and energy efficient in-memory spiking neural network. A spiking deep belief network (DBN) with a noisy rectified linear unit (NReLU) is trained and mapped to the spiking DBN using the proposed ReRAM neurons. Simulation results show that the ReRAM neuron-based DBN is able to recognize the handwritten digits with 94.7% accuracy and is robust against the ReRAM process variation effect. PMID- 30010592 TI - CMOS Luminescence Imager With Ambient Light Compensation and Lifetime to Frequency Conversion. AB - This paper presents a novel CMOS image sensor for luminescence imaging with direct lifetime-dependent digital pulse frequency modulated output. Recently reported parasitic insensitive multicycle charge modulation scheme is applied to accumulate photon-generated charges in discrete programmable time windows over multiple exposures. An autoreset pulse serving as the digital output is generated by comparing the multicycle charge integrated output with a reference threshold. The detected luminescence's lifetime is extracted by monitoring the frequency in this digital pulse. To compensate for the background photocurrent generated by ambient light and built-in offset, a charge pump based calibration circuitry is also proposed. Driven by a 10-KHz clock signal with 20-MUs pulse width as the integration time window, the proposed circuitry can achieve responsivity and resolution at 575 nm wavelength. It has lifetime resolution of 8 ns. The proposed sensor chip was applied for lifetime measurement of a Ru(dpp)3(PF6)2 fluorescent sample whose lifetime was estimated to be 4.2 MUs. A two-dimensional luminescence intensity and lifetime images of a single white LED have also been obtained to further validate its functionality. PMID- 30010593 TI - Implantable Wireless Intracranial Pressure Monitoring Based on Air Pressure Sensing. AB - A wireless intracranial pressure (ICP) monitoring system based on the air pressure sensing is proposed in this work. The proposed system is composed of an implantable ICP sensing device and a portable wireless data recorder. The ICP sensing device consists of an air pressure sensor, an ultra-thin air pouch for pressure sensing, and a low-power dedicated system-on-a-chip (SoC) for the data acquisition control and wireless transmission. The SoC consists of a power management unit, a wake-up controller, the sensor interface, a wireless transmitter, and the workflow control logic. The SoC is fabricated in 0.18 MUm CMOS technology with a die area of 3.04 mm * 2 mm. Experimental results show that the prototype implantable ICP device has achieved a resolution of 0.2 mmHg and a battery lifetime of 1 week with a 3 V 50 mAh battery. The ICP device has been tested in the liquid environment. The nonlinearity error is less than +/-0.4 mmHg for the full measurement range of -20 to +150 mmHg. Compared to the other implantable wireless ICP solutions in the literature, the proposed system alleviates the biocompatibility issue and increases the measurement accuracy. PMID- 30010594 TI - Blood Cholesterol Monitoring With Smartphone as Miniaturized Electrochemical Analyzer for Cardiovascular Disease Prevention. AB - Currently, cardiovascular diseases become one of the major threat to human's life. The early prevention of cardiovascular diseases plays a critical role in the healthcare engineering. Point of care monitoring the blood lipid level is capable of making the positive contribution to the prevention of cardiovascular disease. Ubiquitous smartphones paved the way as the flexible and widespread platform for the interaction of various health information. In this manuscript, we report the world's first medical smartphone as an electrochemical analyzer for blood lipid monitoring. Integrating an electrochemical analyzer into a smartphone allows us to measure the current generated by the enzymatic reaction with the total cholesterol test strip. The disposable test strip is used to convert the biochemical signal to electrical signal through the electrochemical reaction. The proposed medical smartphone can provide accurate evaluation of patient's blood lipid level as compared to the clinical biochemical analyzer. The proposed medical smartphone system is a promising platform as a point-of-care device for blood total cholesterol (TC) monitoring, which can be applied for long-term prevention of cardiovascular disease due to its portability, reliability, lower cost, convenience, and internet-based medical data interaction. PMID- 30010595 TI - Heterogeneous Integration of CMOS Sensors and Fluidic Networks Using Wafer-Level Molding. AB - Direct sensing in liquids using CMOS-integrated optical and electrical sensors is attractive for lab-on-chip applications, where close physical proximity between sample and sensor can obviate optical lenses, enhance electrical sensitivity, and decrease noise due to parasitics. However, controlled delivery of fluid samples to the chip surface presents an ongoing challenge for lab-on-CMOS development, where traditional wire-bond packaging prevents integration of planar microfluidics. In this paper, we present a method for scalable heterogeneous integration of microfluidic channels and silicon-integrated circuit substrates using a commercial fan-out wafer-level packaging approach. The planar surface supports multiple approaches for fluidic integration; we present both a stacked laser-cut fluidic assembly and the fabrication of monolithic SU-8 microchannels over the IC surface. As a proof-of-principle, both electrical and fluidic routing are provided to a custom 0.18-m CMOS optical sensor IC, and optical transmission and fluorescence measurement experiments are demonstrated. PMID- 30010596 TI - Practical Inductive Link Design for Biomedical Wireless Power Transfer: A Tutorial. AB - Wireless power transfer systems, particularly those based on inductive coupling, provide an increasingly attractive method to safely deliver power to biomedical implants. Although there exists a large body of literature describing the design of inductive links, it generally focuses on single aspects of the design process. There is a variety of approaches, some analytic, some numerical, each with benefits and drawbacks. As a result, undertaking a link design can be a difficult task, particularly for a newcomer to the subject. This tutorial paper reviews and collects the methods and equations that are required to design an inductive link for biomedical wireless power transfer, with a focus on practicality. It introduces and explains the published methods and principles relevant to all aspects of inductive link design, such that no specific prior knowledge of inductive link design is required. These methods are also combined into a software package (the Coupled Coil Configurator), to further simplify the design process. This software is demonstrated with a design example, to serve as a practical illustration. PMID- 30010597 TI - Parallel Distribution of an Inner Hair Cell and Auditory Nerve Model for Real Time Application. AB - This paper summarizes recent efforts in implementing a model of the ear's inner hair cell and auditory nerve on a neuromorphic hardware platform, the SpiNNaker machine. This exploits the massive parallelism of the target architecture to obtain real-time modeling of a biologically realistic number of human auditory nerve fibres. We show how this model can be integrated with additional modules that simulate previous stages of the early auditory pathway running on the same hardware architecture, thus producing a full-scale spiking auditory nerve output from a single sound stimulus. The results of the SpiNNaker implementation are shown to be comparable with a MATLAB version of the same model algorithms, while removing the inherent performance limitations associated with an increase in auditory model scale that are seen in the conventional computer simulations. Finally, we outline the potential for using this system as part of a full-scale, real-time digital model of the complete human auditory pathway on the SpiNNaker platform. PMID- 30010598 TI - Real-Time Event-Driven Classification Technique for Early Detection and Prevention of Myocardial Infarction on Wearable Systems. AB - A considerable portion of government health-care spending is allocated to the continuous monitoring of patients suffering from cardiovascular diseases, particularly myocardial infarction (MI). Wearable devices present a cost effective means of monitoring patients' vital signs in ambulatory settings. A major challenge is to design such ultra-low energy devices for long-term patient monitoring. In this paper, we present a real-time event-driven classification technique based on the random forest classification scheme, which uses a confidence-related decision-making process. The main goal of this technique is to maintain a high classification accuracy while reducing the complexity of the classification algorithm. We validate our approach on a well-established and complete MI database (Physiobank, PTB Diagnostic ECG database). Our experimental evaluation demonstrates that our real-time classification scheme outperforms the existing approaches in terms of energy consumption and battery lifetime by a factor of 2.60, with no classification quality loss. PMID- 30010599 TI - A 12.8 k Current-Mode Velocity-Saturation ISFET Array for On-Chip Real-Time DNA Detection. AB - This paper presents a large-scale CMOS chemical-sensing array operating in current mode for real-time ion imaging and detection of DNA amplification. We show that the current-mode operation of ion-sensitive field-effect transistors in velocity saturation devices can be exploited to achieve an almost perfect linearity in their input-output characteristics (pH-current), which are aligned with the continuous scaling trend of transistors in CMOS. The array is implemented in a 0.35-m process and includes 12.8 k sensors configured in a 2T per pixel topology. We characterize the array by taking into account nonideal effects observed with floating gate devices, such as increased pixel mismatch due to trapped charge and attenuation of the input signal due to the passivation capacitance, and show that the selected biasing regime allows for a sufficiently large linear range that ensures a linear pH to current despite the increased mismatch. The proposed system achieves a sensitivity of 1.03 A/pH with a pH resolution of 0.101 pH and is suitable for the real-time detection of the NDM carbapenemase gene in E. Coli using a loop-mediated isothermal amplification. PMID- 30010600 TI - A High-Resolution Opto-Electrophysiology System With a Miniature Integrated Headstage. AB - This work presents a fully integrated neural interface system in a small form factor (1.9 g), consisting of a MULED silicon optoelectrode (12 MULEDs and 32 recording sites in a 4-shank configuration), an Intan 32-channel recording chip, and a custom optical stimulation chip for controlling 12 MULEDs. High-resolution optical stimulation with approximately 68.5 nW radiant flux resolution is achieved by a custom LED driver ASIC, which enables individual control of up to 48 channels with a current precision of 1 MUA, a maximum current of 1.024 mA, and an update rate of >10 kHz. Recording is performed by an off-the-shelf 32-channel digitizing front-end ASIC from Intan. Two compact custom interface printed circuit boards were designed to link the headstage with a PC. The prototype system demonstrates precise current generation, sufficient optical radiant flux generation , and fast turn-on of MULEDs . Single animal in vivo experiments validated the headstage's capability to precisely modulate single neuronal activity and independently modulate activities of separate neuronal populations near neighboring optoelectrode shanks. PMID- 30010602 TI - Automated Layer Segmentation of Retinal Optical Coherence Tomography Images Using a Deep Feature Enhanced Structured Random Forests Classifier. AB - Optical coherence tomography (OCT) is a high-resolution and non-invasive imaging modality that has become one of the most prevalent techniques for ophthalmic diagnosis. Retinal layer segmentation is very crucial for doctors to diagnose and study retinal diseases. However, manual segmentation is often a time-consuming and subjective process. In this work, we propose a new method for automatically segmenting retinal OCT images, which integrates deep features and hand-designed features to train a structured random forests classifier. The deep convolutional features are learned from deep residual network. With the trained classifier, we can get the contour probability graph of each layer, finally the shortest path is employed to achieve the final layer segmentation. The experimental results show that our method achieves good results with the mean layer contour error of 1.215 pixels whereas that of the state-of-the-art was 1.464 pixels, and achieve a F1 score of 0.885 which is also better than 0.863 that is obtained by the state-of the-art method. PMID- 30010601 TI - Multiclass Nonnegative Matrix Factorization for Comprehensive Feature Pattern Discovery. AB - In this big data era, interpretable machine learning models are strongly demanded for the comprehensive analytics of large-scale multiclass data. Characterizing all features from such data is a key but challenging step to understand the complexity. However, existing feature selection methods do not meet this need. In this paper, to address this problem, we propose a Bayesian multiclass nonnegative matrix factorization (MC-NMF) model with structured sparsity that is able to discover ubiquitous and class-specific features. Variational update rules were derived for efficient decomposition. In order to relieve the need of model selection and stably describe feature patterns, we further propose MC-NMF with stability selection, an ensemble method that collectively detects feature patterns from many runs of MC-NMF using different hyperparameter values and training subsets. We assessed our models on both simulated count data and multitumor ribonucleic acid-seq data. The experiments revealed that our models were able to recover predefined feature patterns from the simulated data and identify biologically meaningful patterns from the pan-cancer data. PMID- 30010603 TI - Drug repositioning for schizophrenia and depression/anxiety disorders: A machine learning approach leveraging expression data. AB - Development of new medications is a lengthy and costly process, and drug repositioning might help to shorten the development cycle. We present a machine learning (ML) workflow to drug discovery or repositioning by predicting indication for a particular disease based on drug expression profiles, with a focus on applications in psychiatry. Drugs that are not originally indicated for the disease but with high predicted probabilities serve as candidates for repurposing. This approach is widely applicable to any chemicals or drugs with expression profiles measured, even if drug targets are unknown. It is also highly flexible as virtually any supervised learning algorithms can be used. We employed the ML approach to identify repositioning opportunities for schizophrenia as well as depression and anxiety disorders. We applied various state-of-the-art ML approaches, including deep neural networks (DNN), support vector machines (SVM), elastic net regression, random forest and gradient boosted trees. The predictive performance of the five approaches in cross-validation did not differ substantially, with SVM slightly outperforming the others. However, other methods also reveal literature-supported repositioning candidates of different mechanisms of actions. As a further validation, we showed that the repositioning hits are enriched for psychiatric medications considered in clinical trials. We also examined the correlation between predicted probabilities of treatment potential and the number of related research articles, and found significant correlations for all methods, especially DNN. Finally, we propose that ML may provide a new avenue to exploring drug mechanisms via examining the variable importance of gene features. PMID- 30010604 TI - Finite-Time Decentralized Control of IT2 T-S Fuzzy Interconnected Systems With Discontinuous Interconnections. AB - This paper investigates the finite-time decentralized control problem for interconnected systems with discontinuous interconnections. By using the interval type-2 Takagi-Sugeno (IT2 T-S) fuzzy model, a unified IT2 T-S fuzzy interconnected system is provided, in which the global system is described as a fuzzy blending of local subsystems under IF-THEN rules. In addition, based on the differential inclusion theory, the solutions of such discontinuous system are defined in the sense of Filippov. In order to stabilize the considered system in finite time, several decentralized discontinuous state feedback controllers are proposed. Furthermore, by the finite-time stabilization theory and generalized Lyapunov functional method, decentralized control is carried out and several sufficient criteria are derived to ensure the finite-time stabilization of the concerned system. Correspondingly, the settling times for stabilization are given. Finally, the proposed methodology is illustrated by an example. PMID- 30010605 TI - Robust Consensus Nonlinear Information Filter for Distributed Sensor Networks With Measurement Outliers. AB - The traditional consensus-based filters are widely used in distributed sensor networks. However, they suffer from divergence when outliers occur. This paper proposes a robust consensus nonlinear information filter for distributed state estimation with measurement outliers. Unlike the Gaussian assumption in traditional consensus filers, the measurement of each sensor node is modeled here as a multivariate Student-t process with unknown parameters of the sufficient statistic. The variational Bayesian method is employed to jointly estimate the state and the parameters. As the state and parameters are coupled, the updated equation can be solved by fixed point iteration. The centralized outliers robust information filter is first derived for multiple sensors. It is then extended to a distributed version to fuse information from multiple interconnected local estimators. The integral of the consensus-based nonlinear filter is approximated by Gaussian approximation under the framework of the information filter. The consensuses are based on both likelihoods and prior probability distributions. The consensus and convergence of the proposed method are also analyzed. Simulation results show that the proposed approach is effective in dealing with outliers. PMID- 30010606 TI - Zero-Shot Learning via Latent Space Encoding. AB - Zero-shot learning (ZSL) is typically achieved by resorting to a class semantic embedding space to transfer the knowledge from the seen classes to unseen ones. Capturing the common semantic characteristics between the visual modality and the class semantic modality (e.g., attributes or word vector) is a key to the success of ZSL. In this paper, we propose a novel encoder-decoder approach, namely latent space encoding (LSE), to connect the semantic relations of different modalities. Instead of requiring a projection function to transfer information across different modalities like most previous work, LSE performs the interactions of different modalities via a feature aware latent space, which is learned in an implicit way. Specifically, different modalities are modeled separately but optimized jointly. For each modality, an encoder-decoder framework is performed to learn a feature aware latent space via jointly maximizing the recoverability of the original space from the latent space and the predictability of the latent space from the original space. To relate different modalities together, their features referring to the same concept are enforced to share the same latent codings. In this way, the common semantic characteristics of different modalities are generalized with the latent representations. Another property of the proposed approach is that it is easily extended to more modalities. Extensive experimental results on four benchmark datasets [animal with attribute, Caltech UCSD birds, aPY, and ImageNet] clearly demonstrate the superiority of the proposed approach on several ZSL tasks, including traditional ZSL, generalized ZSL, and zero-shot retrieval. PMID- 30010607 TI - Finite-Time Consensus of Opinion Dynamics and Its Applications to Distributed Optimization Over Digraph. AB - In this paper, some efficient criteria for finite-time consensus of a class of nonsmooth opinion dynamics over a digraph are established. The lower and upper bounds on the finite settling time are obtained based respectively on the maximal and minimal cut capacity of the digraph. By using tools of the nonsmooth theory and algebraic graph theory, the Caratheodory and Filippov solutions of nonsmooth opinion dynamics are analyzed and compared in detail. In the sense of Filippov solutions, the dynamic consensus is demonstrated without a leader and the finite time bipartite consensus is also investigated in a signed digraph correspondingly. To achieve a predetermined consensus, a leader agent is introduced to the considered agent networks. As an application, the nonsmooth compartmental dynamics in the presence of a leader is embedded in the proposed continuous-time protocol to solve the distributed optimization problems over an unbalanced digraph. The convergence to the optimal solution by using the proposed distributed algorithm is guaranteed with appropriately selected parameters. To verify the effectiveness of the proposed protocols, three numerical examples are performed. PMID- 30010608 TI - Fast Learning With Polynomial Kernels. AB - This paper proposes a new learning system of low computational cost, called fast polynomial kernel learning (FPL), based on regularized least squares with polynomial kernel and subsampling. The almost optimal learning rate as well as the feasibility verifications including the subsampling mechanism and solvability of FPL are provided in the framework of learning theory. Our theoretical assertions are verified by numerous toy simulations and real data applications. The studies in this paper show that FPL can reduce the computational burden of kernel methods without sacrificing its generalization ability very much. PMID- 30010609 TI - Joint Pricing and Decision-Making for Heterogeneous User Demand in Cognitive Radio Networks. AB - The cognitive radio technique allows secondary users (SUs) to share the spectrum with primary users (PUs) in an exclusive or opportunistic manner. This paper studies spectrum pricing conducted by spectrum owners, that is, primary operators (POs), and SU decision-making strategies for three kinds of duopoly markets. The single-band exclusive use market considers two POs with each providing a single band dedicated to SUs. A pre-emptive resume priority (PRP) M/M/1 queueing model is presented, based on which SUs decide to join which PO and which queue. We prove the existence of a unique Wardrop equilibrium for the decision-making process, and a unique Nash equilibrium for the proposed parallel pricing strategy. In a single-band mixed use market, the competition of two POs is represented by a Stackelberg game. We formulate the spectrum sharing among PU and SUs with a 3-level PRP M/M/1 queueing structure, and derive the close form expressions of SUs' queueing delay. In a multiband exclusive use market, where POs have to determine how many bands they will rent as well as the admission price, we define the problem as a mixed integer linear programming problem and propose a global particle swarm optimization algorithm to find the global optimum. Finally, we study a generalized scenario with multiple POs and multiple priority queues. PMID- 30010610 TI - Optimizing HIV Interventions for Multiplex Social Networks via Partition-Based Random Search. AB - There are multiple modes for human immunodeficiency virus (HIV) transmissions, each of which is usually associated with a certain key population (e.g., needle sharing among people who inject drugs). Recent field studies revealed the merging trend of multiple key populations, making HIV intervention difficult because of the existence of multiple transmission modes in such complex multiplex social networks. In this paper, we aim to address this challenge by developing a multiplex social network framework to capture the multimode transmission across two key populations. Based on the multiplex social network framework, we propose a new random search method, named partition-based random search with network and memory prioritization (PRS-NMP), to identify the optimal subset of high-value individuals in the social network for interventions. Numerical experiments demonstrated that the proposed PRS-NMP-based interventions could effectively reduce the scale of HIV transmissions. The performance of PRS-NMP-based interventions is consistently better than the benchmark nested partitions method and network-based metrics. PMID- 30010611 TI - Prediction of chemotherapy response in ovarian cancer patients using a new clustered quantitative image marker. AB - This study aimed to investigate the feasibility of integrating image features computed from both spatial and frequency domain to better describe the tumor heterogeneity for precise prediction of tumor response to postsurgical chemotherapy in patients with advanced-stage ovarian cancer. A computer-aided scheme was applied to first compute 133 features from five categories namely, shape and density, fast Fourier transform, discrete cosine transform (DCT), wavelet, and gray level difference method. An optimal feature cluster was then determined by the scheme using the particle swarm optimization algorithm aiming to achieve an enhanced discrimination power that was unattainable with the single features. The scheme was tested using a balanced dataset (responders and non responders defined using 6 month PFS) retrospectively collected from 120 ovarian cancer patients. By evaluating the performance of the individual features among the five categories, the DCT features achieved the highest predicting accuracy than the features in other groups. By comparison, a quantitative image marker generated from the optimal feature cluster yielded the area under ROC curve (AUC) of 0.86, while the top performing single feature only had an AUC of 0.74. Furthermore, it was observed that the features computed from the frequency domain were as important as those computed from the spatial domain. In conclusion, this study demonstrates the potential of our proposed new quantitative image marker fused with the features computed from both spatial and frequency domain for a reliable prediction of tumor response to postsurgical chemotherapy. PMID- 30010612 TI - Single crystal growth and anisotropic physical properties of Sm4Co3Ga16. AB - We have synthesized high quality single crystals of Sm4Co3Ga16 with gallium flux and investigated its physical properties with electrical resistivity, magnetization and specific-heat measurements. Antiferromagnetic transition below 6.7 K has been detected. No superconducting transitions have been dectected down to 0.5 K from our single crystals. Based on our experimental result, Sm3+ state in Sm4Co3Ga16 is likely well localized, in which stable magnetic moment in its doubly degenerated ground state contributes to the magnetic order with little interference of Kondo type of interaction. PMID- 30010613 TI - Validating a Monte Carlo approach to absolute dose quality assurance for proton pencil beam scanning. AB - For radiotherapy, it is crucial to guarantee that the delivered dose matches the planned dose. Therefore, patient specific quality assurance (QA) of absolute dose distributions is necessary. Here, we investigate the potential of replacing patient specific QA for pencil beam scanned proton therapy with Monte Carlo simulations. First, the set-up of the automated Monte Carlo model is presented with an emphasis on the absolute dose validation. Second, the absolute dose results obtained from the Monte Carlo simulation for a comprehensive set of patient fields are compared to patient specific QA measurements. Absolute doses measured with the Farmer chamber are shown to be 1.4% higher than the doses measured with the Semiflex chamber. For single energy layers, Monte Carlo simulated doses are 2.1% +/- 0.4% lower than the ones measured with the ionization chamber and 1.1% +/- 1.0% lower than measurements compared to patient field verification measurements. After rescaling to account for this 1.1% discrepancy, 98 fields (94.2%) agree within 2% to measurements, the maximum difference being 2.3%. In conclusion, an automated, easy-to-use Monte Carlo calculation system has been set up. This system reproduced patient specific QA results over a wide range of cases, showing that the time consuming measurements could be reduced or even replaced using Monte Carlo simulations without jeopardizing treatment quality. PMID- 30010614 TI - Metal-organic framework derived cobalt phosphosulfide with ultrahigh microwave absorption properties. AB - Nanostructure composites of ferromagnetic materials embedded in nanoporous carbon (NC) derived from metal-organic frameworks (MOFs) have attracted enormous attention due to their potential application in many fields, such as microwave absorption, energy storage, and conversion. The rational design of nanocomposites holds a determinant factor for overcoming the challenges involving the microwave absorption performance. Herein, CoS2/NC, CoP/NC, and CoS2-xPx/NC with a rhombic dodecahedral structure have been successfully fabricated by using the template cobalt-based MOFs (ZIF-67). A morphology analysis indicates that ferromagnetic nanoparticles are embedded in NC matrix. It is obvious that the rhombic dodecahedron can be maintained after the phosphorization and sulfurization of Co/NC derived from the thermal decomposition of ZIF-67. The microwave absorption performance can obviously be improved by the phosphorization and sulfurization of Co/NC. CoS2-xPx/NC exhibits an excellent microwave absorption property and the minimum reflection loss (RL) of CoS2-xPx/NC can reach -68 dB at 14.6 GHz with a thickness of 1.5 mm. An RL value less than -10 dB can be achieved in the microwave frequency range of 12.7-17.3 GHz (4.6 GHz) with a thickness of 1.5 mm for CoS2-xPx/NC. This article offers a novel way to fabricate cobalt-based materials/carbon composites for an excellent microwave absorber. PMID- 30010615 TI - Topologically protected edge transport of sound in coupled cavities of a modified honeycomb lattice. AB - In this work, we investigate comprehensively the unidirectional transport of sound in coupled cavities of a modified honeycomb lattice. The results clearly show that a pair of topological states carrying opposite pseudospins can be constructed at the edge of truncated lattices of non-trivial band gaps, which is different from previous schemes where topological states with opposite pseudospins were constructed at the interface of modified honeycomb lattices of trivial and non-trivial band gaps. Our work paves the way to exploring unidirectional edge transport of sound with topological protection in closed systems that are beneficial in large-scale device integration and low-loss operation. PMID- 30010616 TI - Large-scale Au nanoparticle cluster arrays with tunable particle numbers evolved from colloidal lithography. AB - The assembly of metal nanoparticles (NPs) can regulate their plasmon resonance properties to pursue the best properties for applications. However, the controllable assembly of large-scale metal NP cluster arrays remains a significant challenge. This paper presents a novel strategy to prepare large scale Au NP cluster arrays based on colloidal lithography and template-guided self-assembly technique. The NPs arrays are fabricated by introducing Au NPs onto the quaternized poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) brush templates via electrostatic interaction. The number of Au NPs in cluster can be arbitrarily tuned by changing the surface area of the polymer templates created by colloidal lithography, which resulted in tunable plasmonic properties. The prepared Au NP cluster arrays were used for surface enhanced Raman scattering (SERS) and the SERS properties of the Au NP cluster arrays were studied. PMID- 30010617 TI - A biomimicking design for mechanical knee joints. AB - In this paper we present a new bioinspired bicondylar knee joint that requires a smaller actuator size when compared to a constant moment arm joint. Unlike existing prosthetic joints, the proposed mechanism replicates the elastic, rolling and sliding elements of the human knee. As a result, the moment arm that the actuators can impart on the joint changes as function of the angle, producing the equivalent of a variable transmission. By employing a similar moment arm angle profile as the human knee the peak actuator force for stair ascent can be reduced by 12% compared to a constant moment arm joint addressing critical impediments in weight and power for robotics limbs. Additionally, the knee employs mechanical 'ligaments' containing stretch sensors to replicate the neurosensory and compliant elements of the joint. We demonstrate experimentally how the ligament stretch can be used to estimate joint angle, therefore overcoming the difficulty of sensing position in a bicondylar joint. PMID- 30010618 TI - Antibiotic therapy-induced collateral damage: IgA takes center stage in pulmonary host defense. AB - The use of broad-spectrum antibiotics in empirical antimicrobial therapy is a lifesaving strategy for patients in intensive care. At the same time, antibiotics dramatically increase the risk for nosocomial infections, such as hospital acquired pneumonia caused by Pseudomonas aeruginosa, and other antibiotic resistant bacteria. In this issue of the JCI, Robak and colleagues identified a mechanism by which depletion of resident gut and lung microbiota by antibiotic treatment results in secondary IgA deficiency and impaired anti-P. aeruginosa host defense. Impaired defenses could be improved by substitution of polyclonal IgA via the intranasal route in a mouse model of pneumonia. Importantly, antibiotic treatment caused lung IgA deficiency that involved reduced TLR dependent production of a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) in intensive care unit patients. These patients might therefore benefit from future strategies to increase pulmonary IgA levels. PMID- 30010619 TI - GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. AB - The mechanisms of pain induction by inflammation have been extensively studied. However, the mechanisms of pain resolution are not fully understood. Here, we report that GPR37, expressed by macrophages (MPhis) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa2+) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa2+ increases in peritoneal MPhis. Activation of GPR37 by NPD1 and TX14 triggers MPhi phagocytosis of zymosan particles via calcium signaling. Hind paw injection of pH sensitive zymosan particles not only induces inflammatory pain and infiltration of neutrophils and MPhis, but also causes GPR37 upregulation in MPhis, phagocytosis of zymosan particles and neutrophils by MPhis in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in MPhi phagocytic activity and delayed resolution of inflammatory pain. Gpr37 deficient MPhis also show dysregulations of proinflammatory and antiinflammatory cytokines. MPhi depletion delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient MPhis promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating MPhi phagocytosis and inflammatory pain resolution. PMID- 30010621 TI - Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias? AB - Brown et al. report that two weeks of exogenous leptin administration to leptin naive individuals with lipodystrophy resulted in increased energy expenditure and lipolysis, decreased ectopic liver fat, improved hepatic and peripheral insulin sensitivity, and attenuated dyslipidemia. Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity. This asymmetry in responses to leptin initiation and cessation is consistent with the other aspects of leptin biology that are dependent on the metabolic context in which this adipocyte-derived hormone functions. PMID- 30010620 TI - Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. AB - Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy. PMID- 30010622 TI - Reinforcing our pipeline: trainee-driven approaches to improving physician scientist training. PMID- 30010624 TI - A tribute to Donald W. Seldin. PMID- 30010623 TI - P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. AB - Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL 17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy. PMID- 30010627 TI - Balancing dual demands on the physician-scientist workforce. PMID- 30010625 TI - The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. AB - Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA. PMID- 30010626 TI - Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2. AB - The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25 dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1-/- mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing. PMID- 30010628 TI - Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37. AB - Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein-coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain. PMID- 30010629 TI - Ranolazine Induced Delirium as a Rare Side Effect. PMID- 30010630 TI - Hemophagocytic Lymphohistiocytosis: Potentially Underdiagnosed in Intensive Care Units. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis in adults (aHLH) is a rare life threatening hyperinflammatory syndrome caused by excessive activation of macrophages and CD8+ T-cells. Due to the clinical overlap with severe sepsis, aHLH often remains undiagnosed resulting in poor outcome. Here, we present a retrospective study of incidence, clinical findings, and the outcome of aHLH in intensive care units (ICUs). METHODS: This retrospective analysis was performed at the university hospital Charite - Universitatsmedizin Berlin. We gathered data from 556 out of 46,532 patients admitted to our anesthesiological ICUs between 2006 and 2013, who had at least one plasma ferritin measurement during ICU treatment, and were at least 18 years old. Of these, 244 patients with ferritin at least 500 MUg/L and available datasets of at least 4 HLH-2004 criteria were included. HLH-2004 diagnostic criteria and the recently published HScore were used. An aHLH expert team retrospectively reviewed the potential aHLH cases. RESULTS: Seventy-one of the included 244 patients died; 9 out of the 244 patients were retrospectively classified as aHLH of whom 4 patients had died (44.4%). Two of the 9 aHLH patients had been correctly diagnosed and had received specific aHLH treatment. Thus, 7 out of 9 patients (77.8%) remained undetected. ICU patients with at least 1 captured ferritin value and hyperferritinemia showed an aHLH rate of 3.7%, which rises up to 5.6% when only deceased patients are considered. Mortality in this selected cohort is 44.4%. CONCLUSIONS: Overall, 7 out of 9 patients (77.8%) suffering from aHLH remained undiagnosed. Awareness of this life-threatening syndrome, especially in ICUs, should be raised. The inclusion of ferritin into the admission lab panel for ICU is warranted.Clinical trial registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016. As this is a retrospective study, trial registration was after final data collection date. PMID- 30010631 TI - Co-Chaperone-Mediated Suppression of LPS-Induced Cardiac Toxicity Through NFkappaB Signaling. AB - Co-chaperone cytoplasmic constitutive active/androstane receptor retention protein (CCRP), a member of heat shock protein (HSP) 40, was first characterized to retain a nuclear-destined protein in the cytoplasm. Here we have used CCRP KO mice and demonstrated that CCRP suppresses lipopolysaccharide (LPS)-induced cardiac toxicity in mice. LPS treatment decreased heart rates in CCRP KO mice, but not in wild-type (WT) mice. In addition, LPS-treated KO mice showed reduced fraction shortening, an indicator of ventricular contractile function, to a greater degree than WT mice did. Rat cardiomyocyte-derived H9c2 cells, in which CCRP is not expressed, were used to examine a cell signal through which CCRP suppressed LPS-induced cardiac toxicity. Overexpression of CCRP prevented p65, a nuclear factor kappaB (NFkappaB) subunit, from accumulating in the nucleus after LPS treatment. As observed with H9c2 cells, nuclear accumulation of p65 was found to be higher in the hearts of KO mice than WT mice after LPS treatment. Furthermore, induction of TNFalpha by LPS was markedly suppressed by CCRP in H9c2 cells as well as in LPS-treated mouse serum. In supporting the notion that CCRP repressed the LPS-induced NFkappaB signaling, pretreatment with pyrrolidinedithiocarbamate, an NFkappaB signaling inhibitor, or anti-TNF-alpha antibody before LPS treatment restored heart rates decreased in KO mice after LPS treatment in a dose-dependent manner. Our present study characterized a novel physiological role of CCRP in protecting cardiac functions through the inhibition of NFkappaB signaling. PMID- 30010633 TI - Optogenetics Identification of a Neuronal Type with a Glass Optrode in Awake Mice. AB - It is a major concern in neuroscience how different types of neurons work in neural circuits. Recent advances in optogenetics have enabled the identification of the neuronal type in in vivo electrophysiological experiments in broad brain regions. In optogenetics experiments, it is critical to deliver the light to the recording site. However, it is often hard to deliver the stimulation light to the deep brain regions from the brain's surface. Especially, it is difficult for the stimulation light to reach the deep brain regions when the optical transparency of the brain surface is low, as is often the case with recordings from awake animals. Here, we describe a method to record spike responses to the light from an awake mouse using a custom-made glass optrode. In this method, the light is delivered through the recording glass electrode so that it is possible to reliably stimulate the recorded neuron with light in the deep brain regions. This custom-made optrode system consists of accessible and inexpensive materials and is easy to assemble. PMID- 30010632 TI - Optogenetic Entrainment of Hippocampal Theta Oscillations in Behaving Mice. AB - Extensive data on relationships of neural network oscillations to behavior and organization of neuronal discharge across brain regions call for new tools to selectively manipulate brain rhythms. Here we describe an approach combining projection-specific optogenetics with extracellular electrophysiology for high fidelity control of hippocampal theta oscillations (5-10 Hz) in behaving mice. The specificity of the optogenetic entrainment is achieved by targeting channelrhodopsin-2 (ChR2) to the GABAergic population of medial septal cells, crucially involved in the generation of hippocampal theta oscillations, and a local synchronized activation of a subset of inhibitory septal afferents in the hippocampus. The efficacy of the optogenetic rhythm control is verified by a simultaneous monitoring of the local field potential (LFP) across lamina of the CA1 area and/or of neuronal discharge. Using this readily implementable preparation we show efficacy of various optogenetic stimulation protocols for induction of theta oscillations and for the manipulation of their frequency and regularity. Finally, a combination of the theta rhythm control with projection specific inhibition addresses the readout of particular aspects of the hippocampal synchronization by efferent regions. PMID- 30010634 TI - Assessment of Kidney Function in Mouse Models of Glomerular Disease. AB - The use of murine models to mimic human kidney disease is becoming increasingly common. Our research is focused on the assessment of glomerular function in diabetic nephropathy and podocyte-specific VEGF-A knock-out mice; therefore, this protocol describes the full kidney work-up used in our lab to assess these mouse models of glomerular disease, enabling a vast amount of information regarding kidney and glomerular function to be obtained from a single mouse. In comparison to alternative methods presented in the literature to assess glomerular function, the use of the method outlined in this paper enables the glomerular phenotype to be fully evaluated from multiple aspects. By using this method, the researcher can determine the kidney phenotype of the model and assess the mechanism as to why the phenotype develops. This vital information on the mechanism of disease is required when examining potential therapeutic avenues in these models. The methods allow for detailed functional assessment of the glomerular filtration barrier through measurement of the urinary albumin creatinine ratio and individual glomerular water permeability, as well as both structural and ultra structural examination using the Periodic Acid Schiff stain and electron microscopy. Furthermore, analysis of the genes dysregulated at the mRNA and protein level enables mechanistic analysis of glomerular function. This protocol outlines the generic but adaptable methods that can be applied to all mouse models of glomerular disease. PMID- 30010636 TI - Informatic Analysis of Sequence Data from Batch Yeast 2-Hybrid Screens. AB - We have adapted the yeast 2-hybrid assay to simultaneously uncover dozens of transient and static protein interactions within a single screen utilizing high throughput short-read DNA sequencing. The resulting sequence datasets can not only track what genes in a population that are enriched during selection for positive yeast 2-hybrid interactions, but also give detailed information about the relevant subdomains of proteins sufficient for interaction. Here, we describe a full suite of stand-alone software programs that allow non-experts to perform all the bioinformatics and statistical steps to process and analyze DNA sequence fastq files from a batch yeast 2-hybrid assay. The processing steps covered by these software include: 1) mapping and counting sequence reads corresponding to each candidate protein encoded within a yeast 2-hybrid prey library; 2) a statistical analysis program that evaluates the enrichment profiles; and 3) tools to examine the translational frame and position within the coding region of each enriched plasmid that encodes the interacting proteins of interest. PMID- 30010635 TI - A Small Animal Model of Ex Vivo Normothermic Liver Perfusion. AB - There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, normothermic ex vivo liver perfusion (NEVLP) has been introduced as a method to evaluate and modify organ function. NEVLP has many advantages in comparison to hypothermic and subnormothermic perfusion including reduced preservation injury, restoration of normal organ function under physiologic conditions, assessment of organ performance, and as a platform for organ repair, remodeling, and modification. Both murine and porcine NEVLP models have been described. We demonstrate a rat model of NEVLP and use this model to show one of its important applications - the use of a therapeutic molecule added to liver perfusate. Catalase is an endogenous reactive oxygen species (ROS) scavenger and has been demonstrated to decrease ischemia-reperfusion in the eye, brain, and lung. Pegylation has been shown to target catalase to the endothelium. Here, we added pegylated-catalase (PEG-CAT) to the base perfusate and demonstrated its ability to mitigate liver preservation injury. An advantage of our rodent NEVLP model is that it is inexpensive in comparison to larger animal models. A limitation of this study is that it does not currently include post-perfusion liver transplantation. Therefore, prediction of the function of the organ post transplantation cannot be made with certainty. However, the rat liver transplant model is well established and certainly could be used in conjunction with this model. In conclusion, we have demonstrated an inexpensive, simple, easily replicable NEVLP model using rats. Applications of this model can include testing novel perfusates and perfusate additives, testing software designed for organ evaluation, and experiments designed to repair organs. PMID- 30010637 TI - Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions. AB - The three-dimensional organization of the genome is linked to its function. For example, regulatory elements such as transcriptional enhancers control the spatio temporal expression of their target genes through physical contact, often bridging considerable (in some cases hundreds of kilobases) genomic distances and bypassing nearby genes. The human genome harbors an estimated one million enhancers, the vast majority of which have unknown gene targets. Assigning distal regulatory regions to their target genes is thus crucial to understand gene expression control. We developed Promoter Capture Hi-C (PCHi-C) to enable the genome-wide detection of distal promoter-interacting regions (PIRs), for all promoters in a single experiment. In PCHi-C, highly complex Hi-C libraries are specifically enriched for promoter sequences through in-solution hybrid selection with thousands of biotinylated RNA baits complementary to the ends of all promoter-containing restriction fragments. The aim is to then pull-down promoter sequences and their frequent interaction partners such as enhancers and other potential regulatory elements. After high-throughput paired-end sequencing, a statistical test is applied to each promoter-ligated restriction fragment to identify significant PIRs at the restriction fragment level. We have used PCHi-C to generate an atlas of long-range promoter interactions in dozens of human and mouse cell types. These promoter interactome maps have contributed to a greater understanding of mammalian gene expression control by assigning putative regulatory regions to their target genes and revealing preferential spatial promoter-promoter interaction networks. This information also has high relevance to understanding human genetic disease and the identification of potential disease genes, by linking non-coding disease-associated sequence variants in or near control sequences to their target genes. PMID- 30010638 TI - Tracing Gene Expression Through Detection of beta-galactosidase Activity in Whole Mouse Embryos. AB - The Escherichia coli LacZ gene, encoding beta-galactosidase, is largely used as a reporter for gene expression and as a tracer in cell lineage studies. The classical histochemical reaction is based on the hydrolysis of the substrate X gal in combination with ferric and ferrous ions, which produces an insoluble blue precipitate that is easy to visualize. Therefore, beta-galactosidase activity serves as a marker for the expression pattern of the gene of interest as the development proceeds. Here we describe the standard protocol for the detection of beta-galactosidase activity in early whole mouse embryos and the subsequent method for paraffin sectioning and counterstaining. Additionally, a procedure for clarifying whole embryos is provided to better visualize X-gal staining in deeper regions of the embryo. Consistent results are obtained by performing this procedure, although optimization of reaction conditions is needed to minimize background activity. Limitations in the assay should be also considered, particularly regarding the size of the embryo in whole mount staining. Our protocol provides a sensitive and a reliable method for beta-galactosidase detection during the mouse development that can be further applied to the cryostat sections as well as whole organs. Thus, the dynamic gene expression patterns throughout development can be easily analyzed by using this protocol in whole embryos, but also detailed expression at the cellular level can be assessed after paraffin sectioning. PMID- 30010639 TI - Specific and Accurate Detection of the Citrus Greening Pathogen Candidatus liberibacter spp. Using Conventional PCR on Citrus Leaf Tissue Samples. AB - Citrus greening, also known as huanglongbing, is a destructive citrus disease ravaging citrus farms globally. This disease causes asymmetrical yellow leaf mottling, vein yellowing, defoliation, root decay, and ultimately, the death of the citrus plant. When infected, the citrus plants have stunted growth and produce flowers out of season. These flowers rarely yield fruit, and those that do yield small, bitter, irregularly shaped citrus fruit that are not desirable. This disease is spread by the Asian citrus psyllid, Diaphorina citri, and by the grafting of infected citrus tissue. The pathogen has a long and variable incubation period within the citrus plant-sometimes years, before symptoms appear. Attempts to culture this pathogen in vitro have been unsuccessful, possibly due to the low and uneven concentration of the pathogen within infected citrus tissue, or because it is difficult to replicate the environmental conditions conducive to growth of the pathogen. It is very difficult to identify the disease before it has spread, due to its long incubation period and researchers' inability to culture the pathogen. As a result, the disease only becomes apparent after suddenly destroying a citrus farmer's entire yield. Presented here is a method for the accurate and specific detection of the citrus greening pathogen, Candidatus liberibacter spp. using a genomic DNA extraction kit and PCR. This method is simple, efficient, cost effective, and adaptable for quantitative analysis. This method can be adapted for use on any citrus tissue; however, it is potentially limited by the amount of pathogen present in the tissue. Nevertheless, this method will allow citrus farmers to identify infected citrus plants earlier, and curb the spread of this destructive disease before it can further spread. PMID- 30010640 TI - Implantation of Electrospun Vascular Grafts with Optimized Structure in a Rat Model. AB - Here, we present a protocol to fabricate macroporous PCL vascular graft and describe an evaluation protocol by using a rat model of abdominal aorta replacement. The electrospun vascular grafts often possess relatively small pores, which limit cell infiltration into the grafts and hinder the regeneration and remodeling of the neo-arteries. In this study, PCL vascular grafts with thicker fibers (5 - 6 um) and larger pores (~30 um) were fabricated by using a modified processing technique. The long-term performance of the graft was evaluated by implantation in a rat abdominal aorta model. Ultrasound analysis showed that the grafts remained patent without aneurysm or stenosis occurring even after 12 months of implantation. Macroporous structure improved the cell ingrowth and thus promoted tissue regenerated at 3 months. More importantly, there was no sign of adverse remodeling, such as calcification within the graft wall after 12 months. Therefore, electrospun PCL vascular grafts with modified macroporous processing hold potential to be an artery substitute for long-term implantation. PMID- 30010641 TI - Single-cell Analysis of Immunophenotype and Cytokine Production in Peripheral Whole Blood via Mass Cytometry. AB - Cytokines play a pivotal role in the pathogenesis of autoimmune diseases. Hence, the measurement of cytokine levels has been the focus of multiple studies in an attempt to understand the precise mechanisms that lead to the breakdown of self tolerance and subsequent autoimmunity. Approaches thus far have been based on the study of one specific aspect of the immune system (a single or few cell types or cytokines), and do not offer a global assessment of complex autoimmune disease. While patient sera-based studies have afforded important insights into autoimmunity, they do not provide the specific cellular source of the dysregulated cytokines detected. A comprehensive single-cell approach to evaluate cytokine production in multiple immune cell subsets, within the context of "intrinsic" patient-specific plasma circulating factors, is described here. This approach enables monitoring of the patient-specific immune phenotype (surface markers) and function (cytokines), either in its native "intrinsic pathogenic" disease state, or in the presence of therapeutic agents (in vivo or ex vivo). PMID- 30010642 TI - Multi-color Localization Microscopy of Single Membrane Proteins in Organelles of Live Mammalian Cells. AB - Knowledge about the localization of proteins in cellular subcompartments is crucial to understand their specific function. Here, we present a super resolution technique that allows for the determination of the microcompartments that are accessible for proteins by generating localization and tracking maps of these proteins. Moreover, by multi-color localization microscopy, the localization and tracking profiles of proteins in different subcompartments are obtained simultaneously. The technique is specific for live cells and is based on the repetitive imaging of single mobile membrane proteins. Proteins of interest are genetically fused with specific, so-called self-labeling tags. These tags are enzymes that react with a substrate in a covalent manner. Conjugated to these substrates are fluorescent dyes. Reaction of the enzyme-tagged proteins with the fluorescence labeled substrates results in labeled proteins. Here, Tetramethylrhodamine (TMR) and Silicon Rhodamine (SiR) are used as fluorescent dyes attached to the substrates of the enzymes. By using substrate concentrations in the pM to nM range, sub-stoichiometric labeling is achieved that results in distinct signals. These signals are localized with ~15-27 nm precision. The technique allows for multi-color imaging of single molecules, whereby the number of colors is limited by the available membrane-permeable dyes and the repertoire of self-labeling enzymes. We show the feasibility of the technique by determining the localization of the quality control enzyme (Pten)-induced kinase 1 (PINK1) in different mitochondrial compartments during its processing in relation to other membrane proteins. The test for true physical interactions between differently labeled single proteins by single molecule FRET or co-tracking is restricted, though, because the low labeling degrees decrease the probability for having two adjacent proteins labeled at the same time. While the technique is strong for imaging proteins in membrane compartments, in most cases it is not appropriate to determine the localization of highly mobile soluble proteins. PMID- 30010643 TI - Spectral Reflectometric Microscopy on Myelinated Axons In Situ. AB - In a mammalian nervous system, myelin provides an electrical insulation by enwrapping the axon fibers in a multilayered spiral. Inspired by its highly organized subcellular architecture, we recently developed a new imaging modality, named spectral reflectometry (SpeRe), which enables unprecedented label-free nanoscale imaging of the live myelinated axons in situ. The underlying principle is to obtain nanostructural information by analyzing the reflectance spectrum of the multilayered subcellular structure. In this article, we describe a detailed step-by-step protocol for performing a basic SpeRe imaging of the nervous tissues using a commercial confocal microscopic system, equipped with a white-light laser and a tunable filter. We cover the procedures of sample preparation, acquisition of spectral data, and image processing for obtaining nanostructural information. PMID- 30010644 TI - Bioprintable Alginate/Gelatin Hydrogel 3D In Vitro Model Systems Induce Cell Spheroid Formation. AB - The cellular, biochemical, and biophysical heterogeneity of the native tumor microenvironment is not recapitulated by growing immortalized cancer cell lines using conventional two-dimensional (2D) cell culture. These challenges can be overcome by using bioprinting techniques to build heterogeneous three-dimensional (3D) tumor models whereby different types of cells are embedded. Alginate and gelatin are two of the most common biomaterials employed in bioprinting due to their biocompatibility, biomimicry, and mechanical properties. By combining the two polymers, we achieved a bioprintable composite hydrogel with similarities to the microscopic architecture of a native tumor stroma. We studied the printability of the composite hydrogel via rheology and obtained the optimal printing window. Breast cancer cells and fibroblasts were embedded in the hydrogels and printed to form a 3D model mimicking the in vivo microenvironment. The bioprinted heterogeneous model achieves a high viability for long-term cell culture (> 30 days) and promotes the self-assembly of breast cancer cells into multicellular tumor spheroids (MCTS). We observed the migration and interaction of the cancer-associated fibroblast cells (CAFs) with the MCTS in this model. By using bioprinted cell culture platforms as co-culture systems, it offers a unique tool to study the dependence of tumorigenesis on the stroma composition. This technique features a high-throughput, low cost, and high reproducibility, and it can also provide an alternative model to conventional cell monolayer cultures and animal tumor models to study cancer biology. PMID- 30010645 TI - Testing Animal Anxiety in Rats: Effects of Open Arm Ledges and Closed Arm Wall Transparency in Elevated Plus Maze Test. AB - The elevated plus maze test is a behavioral test for assessing animal anxiety in rodents. Although this test is widely applied in the field of behavioral science, conflicting outcomes are often provided from different laboratories. To identify reasons for the different outcomes, we previously focused on arm features, which differ between laboratories, most notably the presence/absence of ledges at the sides of open arms and the transparency/opaqueness of closed arm walls. In a previous report, we used a custom designed container to compare rat behavior on different combinations of open and closed arm designs under otherwise identical experimental conditions, and showed that differences in arm features interfere with experimental outcomes. In brief, open arm ledges significantly increased anxiety-like behavior in rats, while transparent arms may also have decreased this behavior. Furthermore, we verified a higher detection sensitivity of the effect of an anxiolytic drug in a combination of no-ledged open arm + opaque walled closed arm compared with a combination of ledged open arm + transparent walled closed arm. In this report, we introduce our protocol for the elevated plus maze test, together with discussion of the key results from the previous report and our experimental experience. We believe this report will provide useful information for researchers who have employed or who plan to use the elevated plus maze in their studies. PMID- 30010646 TI - Concurrent EEG and Functional MRI Recording and Integration Analysis for Dynamic Cortical Activity Imaging. AB - Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are two of the fundamental noninvasive methods for identifying brain activity. Multimodal methods have sought to combine the high temporal resolution of EEG with the spatial precision of fMRI, but the complexity of this approach is currently in need of improvement. The protocol presented here describes the recently developed spatiotemporal fMRI-constrained EEG source imaging method, which seeks to rectify source biases and improve EEG-fMRI source localization through the dynamic recruitment of fMRI sub-regions. The process begins with the collection of multimodal data from concurrent EEG and fMRI scans, the generation of 3D cortical models, and independent EEG and fMRI processing. The processed fMRI activation maps are then split into multiple priors, according to their location and surrounding area. These are taken as priors in a two-level hierarchical Bayesian algorithm for EEG source localization. For each window of interest (defined by the operator), specific segments of the fMRI activation map will be identified as active to optimize a parameter known as model evidence. These will be used as soft constraints on the identified cortical activity, increasing the specificity of the multimodal imaging method by reducing cross talk and avoiding erroneous activity in other conditionally active fMRI regions. The method generates cortical maps of activity and time-courses, which may be taken as final results, or used as a basis for further analyses (analyses of correlation, causation, etc.) While the method is somewhat limited by its modalities (it will not find EEG-invisible sources), it is broadly compatible with most major processing software, and is suitable for most neuroimaging studies. PMID- 30010647 TI - Treating Low Back Pain in Failed Back Surgery Patients with Multicolumn-lead Spinal Cord Stimulation. AB - Failed back surgery syndrome (FBSS) refers to persistent, chronic pain following spinal surgery. Spinal cord stimulation with dorsal epidural leads can be used to treat back and leg pain in FBSS patients. This paper presents a detailed protocol for using spinal cord stimulation with surgical leads in FBSS patients. In our department, with the patient under general anesthesia, we place the lead in the epidural space by means of a small laminectomy at the 10th thoracic level. Placement of the lead is followed by a 1 month trial period with an externalized lead. If pain relief is greater than 50% at the end of this 1 month stimulation trial (required by Belgian reimbursement criteria), an internal pulse generator is then placed under the skin and connected to the lead in a second surgical procedure. We have demonstrated that using this technique in rigorously selected FBSS patients can significantly improve back pain, leg pain, patient activity, and quality of life for a sustained period of time. PMID- 30010649 TI - Preparation of Aligned Steel Fiber Reinforced Cementitious Composite and Its Flexural Behavior. AB - The aim of this work is to present an approach, inspired by the way in which a compass needle maintains a consistent orientation under the action of the Earth's magnetic field, for manufacturing a cementitious composite reinforced with aligned steel fibers. Aligned steel fiber reinforced cementitious composites (ASFRC) were prepared by applying a uniform electromagnetic field to fresh mortar containing short steel fibers, whereby the short steel fibers were driven to rotate in alignment with the magnetic field. The degree of alignment of steel fibers in hardened ASFRC was assessed both by counting steel fibers in fractured cross-sections and by X-ray computed tomography analysis. The results from the two methods show that the steel fibers in ASFRC were highly aligned while the steel fibers in non-magnetically treated composites were randomly distributed. The aligned steel fibers had a much higher reinforcing efficiency, and the composites, therefore, exhibited significantly enhanced flexural strength and toughness. The ASFRC is thus superior to SFRC in that it can withstand greater tensile stress and more effectively resist cracking. PMID- 30010648 TI - Pre-Conditioning the Airways of Mice with Bleomycin Increases the Efficiency of Orthotopic Lung Cancer Cell Engraftment. AB - Lung cancer is a deadly treatment refractory disease that is biologically heterogeneous. To understand and effectively treat the full clinical spectrum of thoracic malignancies, additional animal models that can recapitulate diverse human lung cancer subtypes and stages are needed. Allograft or xenograft models are versatile and enable the quantification of tumorigenic capacity in vivo, using malignant cells of either murine or human origin. However, previously described methods of lung cancer cell engraftment have been performed in non physiological sites, such as the flank of mice, due to the inefficiency of orthotopic transplantation of cells into the lungs. In this study, we describe a method to enhance orthotopic lung cancer cell engraftment by pre-conditioning the airways of mice with the fibrosis inducing agent bleomycin. As a proof-of-concept experiment, we applied this approach to engraft tumor cells of the lung adenocarcinoma subtype, obtained from either mouse or human sources, into various strains of mice. We demonstrate that injuring the airways with bleomycin prior to tumor cell injection increases the engraftment of tumor cells from 0-17% to 71 100%. Significantly, this method enhanced lung tumor incidence and subsequent outgrowth using different models and mouse strains. In addition, engrafted lung cancer cells disseminate from the lungs into relevant distant organs. Thus, we provide a protocol that can be used to establish and maintain new orthotopic models of lung cancer with limiting amounts of cells or biospecimen and to quantitatively assess the tumorigenic capacity of lung cancer cells in physiologically relevant settings. PMID- 30010650 TI - Murine Oropharyngeal Aspiration Model of Ventilator-associated and Hospital acquired Bacterial Pneumonia. AB - Murine infection models are critical for understanding disease pathogenesis and testing the efficacy of novel therapeutics designed to combat causative pathogens. Infectious pneumonia is among the most common infections presented by patients in the clinic and thus warrants an appropriate in vivo model. Typical pneumonia models use intranasal inoculation, which deposits excessive organisms outside the lung, causing off-target complications and symptoms, such as sinusitis, gastritis, enteritis, physical trauma, or microparticle misting to mimic aerosol spread more typical of viral, tuberculous, or fungal pneumonia. These models do not accurately reflect the pathogenesis of typical community- or healthcare-acquired bacterial pneumonia. In contrast, this murine model of oropharyngeal aspiration pneumonia mimics the droplet route in healthcare acquired pneumonia. Inoculating 50 uL of the bacteria suspension into the oropharynx of anesthetized mice causes reflexive aspiration, which results in pneumonia. With this model, one can examine the pathogenesis of pneumonia-causing pathogens and new treatments to combat these diseases. PMID- 30010651 TI - The Replica Set Method: A High-throughput Approach to Quantitatively Measure Caenorhabditis elegans Lifespan. AB - The Replica Set method is an approach to quantitatively measure lifespan or survival of Caenorhabditis elegans nematodes in a high-throughput manner, thus allowing a single investigator to screen more treatments or conditions over the same amount of time without loss of data quality. The method requires common equipment found in most laboratories working with C. elegans and is thus simple to adopt. The approach centers on assaying independent samples of a population at each observation point, rather than a single sample over time as with traditional longitudinal methods. Scoring entails adding liquid to the wells of a multi-well plate, which stimulates C. elegans to move and facilitates quantifying changes in healthspan. Other major benefits of the Replica Set method include reduced exposure of agar surfaces to airborne contaminants (e.g. mold or fungus), minimal handling of animals, and robustness to sporadic mis-scoring (such as calling an animal as dead when it is still alive). To appropriately analyze and visualize the data from a Replica Set style experiment, a custom software tool was also developed. Current capabilities of the software include plotting of survival curves for both Replica Set and traditional (Kaplan-Meier) experiments, as well as statistical analysis for Replica Set. The protocols provided here describe the traditional experimental approach and the Replica Set method, as well as an overview of the corresponding data analysis. PMID- 30010652 TI - Pancreatic Islet Embedding for Paraffin Sections. AB - Experiments using isolated pancreatic islets are important for diabetes research, but islets are expensive and of limited abundance. Islets contain a mixed cell population in a structured architecture that impacts function, and human islets are widely variable in cell type composition. Current frequently used methods to study cultured islets include molecular studies performed on whole islets, lumping disparate islet cell types together, or microscopy or molecular studies on dispersed islet cells, disrupting islet architecture. For in vivo islet studies, paraffin-embedded pancreas sectioning is a powerful technique to assess cell-specific outcomes in the native pancreatic environment. Studying post culture islets by paraffin sectioning would offer several advantages: detection of multiple outcomes on the same islets (potentially even the exact-same islets, using serial sections), cell-type-specific measurements, and maintaining native islet cell-cell and cell-substratum interactions both during experimental exposure and for analysis. However, existing techniques for embedding isolated islets post-culture are inefficient, time consuming, prone to loss of material, and generally produce sections with inadequate islet numbers to be useful for quantifying outcomes. Clinical pathology laboratory cell block preparation facilities are inaccessible and impractical for basic research laboratories. We have developed an improved, simplified bench-top method that generates sections with robust yield and distribution of islets. Fixed islets are resuspended in warm histological agarose gel and pipetted into a flat disc on a standard glass slide, such that the islets are distributed in a plane. After standard dehydration and embedding, multiple (10+) 4 - 5 um sections can be cut from the same islet block. Using this method, histological and immunofluorescent analyses can be performed on mouse, rat, and human islets. This is an effective, inexpensive, time-saving approach to assess cell-type-specific, intact architecture outcomes from cultured islets. PMID- 30010653 TI - A Rapid Image-based Bacterial Virulence Assay Using Amoeba. AB - Traditional bacterial virulence assays involve prolonged exposure of bacteria over the course of several hours to host cells. During this time, bacteria can undergo changes in the physiology due to the exposure to host growth environment and the presence of the host cells. We developed an assay to rapidly measure the virulence state of bacteria that minimize the extent to which bacteria grow in the presence of host cells. Bacteria and amoebae are mixed together and immobilized on a single imaging plane using an agar pad. The procedure uses single-cell fluorescence imaging with calcein-acetoxymethyl ester (calcein-AM) as an indicator of host cell health. The fluorescence of host cells is analyzed after 1 h of exposure of host cells to bacteria using epifluorescence microscopy. Image analysis software is used to compute a host killing index. This method has been used to measure virulence within planktonic and surface-attached Pseudomonas aeruginosa sub-populations during the initial stage of biofilm formation and may be adapted to other bacteria and other stages of biofilm growth. This protocol provides a rapid and robust method of measuring virulence and avoids many of the complexities associated with the growth and maintenance of mammalian cell lines. Virulence phenotypes measured here using amoebae have also been validated using mouse macrophages. In particular, this assay was used to establish that surface attachment upregulates virulence in P. aeruginosa. PMID- 30010654 TI - High-throughput DNA Extraction and Genotyping of 3dpf Zebrafish Larvae by Fin Clipping. AB - Zebrafish (Danio rerio) possess orthologues for 84% of the genes known to be associated with human diseases. In addition, these animals have a short generation time, are easy to handle, display a high reproductive rate, low cost, and are easily amenable to genetic manipulations by microinjection of DNA in embryos. Recent advances in gene editing tools are enabling precise introduction of mutations and transgenes in zebrafish. Disease modeling in zebrafish often leads to larval phenotypes and early death which can be challenging to interpret if genotypes are unknown. This early identification of genotypes is also needed in experiments requiring sample pooling, such as in gene expression or mass spectrometry studies. However, extensive genotypic screening is limited by traditional methods, which in most labs are performed only on adult zebrafish or in postmortem larvae. We addressed this problem by adapting a method for the isolation of PCR-ready genomic DNA from live zebrafish larvae that can be achieved as early as 72 h post-fertilization (hpf). This time and cost-effective technique, improved from a previously published genotyping protocol, allows the identification of genotypes from microscopic fin biopsies. The fins quickly regenerate as the larvae develop. Researchers are then able to select and raise the desired genotypes to adulthood by utilizing this high-throughput PCR-based genotyping procedure. PMID- 30010655 TI - Intracranial Subarachnoidal Route of Infection for Investigating Roles of Streptococcus suis Biofilms in Meningitis in a Mouse Infection Model. AB - Streptococcus suis is not only a major bacterial pathogen of pigs worldwide but also an emerging zoonotic agent. In humans and pigs, meningitis is a major manifestation of S. suis infections. A suitable infection model is an essential tool to understand the mechanisms of diseases caused by pathogens. Several routes of infection in mice have been developed to study the pathogenesis of S. suis infection. However, the intraperitoneal, intranasal, and intravenous routes of infection are not suitable for studying the roles of S. suis surface components in meningitis directly in the brain, such as the extracellular matrix from biofilms. Although intracisternal inoculation has been used for S. suis infection, the precise injection site has not been described. Here, the intracranial subarachnoidal route of infection was described in a mouse model to investigate the roles of biofilms in S. suis meningitis. S. suis planktonic cells or biofilm state cells were directly injected into the subarachnoid space of mice through the injection site located 3.5 mm rostral from the bregma. Histopathological analysis and increased mRNA expression of TLR2 and cytokines of the brain tissue from mice injected with biofilm state cells clearly indicated that S. suis biofilm plays definitive roles in S. suis meningitis. This route of infection has obvious advantages over other routes of infection, allowing the study of the host-bacterium interaction. Furthermore, it permits the effect of bacterial components on host immune responses directly in the brain to be assessed, and mimics bacterial entrance into the central nervous system. This route of infection can be extended for investigating the mechanisms of meningitis caused by other bacteria. In addition, it can also be used to test the efficacy of drugs against bacterial meningitis. PMID- 30010656 TI - Methods for Image-based Surveys of Benthic Macroinvertebrates and Their Habitat Exemplified by the Drop Camera Survey for the Atlantic Sea Scallop. AB - Underwater imaging has long been used in the field of marine ecology but decreasing costs of high-resolution cameras and data storage have made the approach more practical than in the past. Image-based surveys allow for initial samples to be revisited and are non-invasive compared to traditional survey methods that typically involve nets or dredges. Protocols for image-based surveys can vary greatly but should be driven by target species behavior and survey objectives. To demonstrate this, we describe our most recent methods for an Atlantic sea scallop (Placopecten magellanicus) drop camera survey to provide a procedural example and representative results. The procedure is divided into three critical steps that include survey design, data collection, and data products. The influence of scallop behavior and the survey goal of providing an independent assessment of the U.S. sea scallop resource on the survey procedure are then discussed in the context of generalizing the method. Overall, the broad applicability and flexibility of the University of Massachusetts Dartmouth School for Marine Science and Technology (SMAST) drop camera survey demonstrates the method could be generalized and applied to a variety of sessile invertebrates or habitat focused research. PMID- 30010657 TI - Plant-Microbe Interaction: Transcriptional Response of Bacillus Mycoides to Potato Root Exudates. AB - Beneficial plant-associated bacteria play an important role in promoting growth and preventing disease in plants. The application of plant growth-promoting rhizobacteria (PGPR) as biofertilizers or biocontrol agents has become an effective alternative to the use of conventional fertilizers and can increase crop productivity at low cost. Plant-microbe interactions depend upon host plant secreted signals and a reaction hereon by their associated bacteria. However, the molecular mechanisms of how beneficial bacteria respond to their associated plant derived signals are not fully understood. Assessing the transcriptomic response of bacteria to root exudates is a powerful approach to determine the bacterial gene expression and regulation under rhizospheric conditions. Such knowledge is necessary to understand the underlying mechanisms involved in plant-microbe interactions. This paper describes a detailed protocol to study the transcriptomic response of B. mycoides EC18, a strain isolated from the potato endosphere, to potato root exudates. With the help of recent high-throughput sequencing technology, this protocol can be performed in several weeks and produce massive datasets. First, we collect the root exudates under sterile conditions, after which they are added to B. mycoides cultures. The RNA from these cultures is isolated using a phenol/chloroform method combined with a commercial kit and subjected to quality control by an automated electrophoresis instrument. After sequencing, data analysis is performed with the web-based T-REx pipeline and a group of differentially expressed genes is identified. This method is a useful tool to facilitate new discoveries on the bacterial genes involved in plant-microbe interactions. PMID- 30010658 TI - In Situ Measurement and Correlation of Cell Density and Light Emission of Bioluminescent Bacteria. AB - There is a considerable number of bacterial species capable of emitting light. All of them share the same gene cluster, namely the lux operon. Despite this similarity, these bacteria show extreme variations in characteristics like growth behavior, intensity of light emission or regulation of bioluminescence. The method presented here is a newly developed assay that combines recording of cell growth and bioluminescent light emission intensity over time utilizing a plate reader. The resulting growth and light emission characteristics can be linked to important features of the respective bacterial strain, such as quorum sensing regulation. The cultivation of a range of bioluminescent bacteria requires a specific medium (e.g., artificial sea water medium) and defined temperatures. The easy to handle, non-bioluminescent standard-research bacterium Escherichia coli (E. coli), on the other hand, can be cultivated inexpensively in high quantities in laboratory scale. Exploiting E. coli by introducing a plasmid containing the whole lux operon can simplify experimental conditions and additionally opens up many possibilities for future applications. The expression of all lux genes utilizing an E. coli expression strain was achieved by construction of an expression plasmid via Gibson cloning and insertion of four fragments containing seven lux genes and three rib genes of the lux-rib operon into a pET28a vector. E. coli based lux gene expression can be induced and controlled via Isopropyl beta-D-thiogalactopyranosid (IPTG) addition resulting in bioluminescent E. coli cells. The advantages of this system are to avoid quorum sensing regulation restrictions and complex medium compositions along with non-standard growth conditions, such as defined temperatures. This system enables analysis of lux genes and their interplay, by the exclusion of the respective gene from the lux operon, or even addition of novel genes, exchanging the luxAB genes from one bacterial strain by another, or analyzing protein complexes, such as luxCDE. PMID- 30010659 TI - Real-time Pressure-volume Analysis of Acute Myocardial Infarction in Mice. AB - Acute myocardial infarction can lead to acute heart failure and cardiogenic shock. The evaluation of hemodynamics is critical for the evaluation of any potential therapeutic approach directed against acute left ventricular (LV) dysfunction. Current imaging modalities (e.g., echocardiography and magnetic resonance imaging) have several limitations since data on LV pressure cannot directly be measured. LV catheterization in mice undergoing coronary artery occlusion could serve as a novel method for a real-time evaluation of LV function. At the beginning of the procedure, mice were anesthetized followed by endotracheal intubation. For LV catheterization, the right carotid artery was exposed via middle-neck incision. The catheter was introduced and placed into the LV cavity. Left thoracotomy was conducted and the left main coronary artery (LCA) was ligated. To induce reperfusion, the suture was released after 45 min. Pressure-volume data was recorded at all times. Ligation of the LCA caused a decrease in LV systolic function as evidenced by a 30% reduction in stroke volume, LV ejection fraction (EF), and cardiac output. Maximum dP/dt as a parameter for LV contractility was also significantly reduced and diastolic function was severely impaired (minimum dP/dt -40%). Reperfusion over a period of 20 min did not lead to a complete recovery of LV function. Real-time pressure volume analysis served as a valid procedure for monitoring cardiac function during acute myocardial infarction in mice. Maintaining stable anesthesia and a standardized surgical approach was crucial to ensure valid results. As the early phase of acute myocardial infarction is critical for morbidity and mortality, the delineated method could be beneficial for preclinical evaluation of new strategies for cardioprotection. PMID- 30010660 TI - Fabrication of Gradient Nanopattern by Thermal Nanoimprinting Technique and Screening of the Response of Human Endothelial Colony-forming Cells. AB - Nanotopography can be found in various extracellular matrices (ECMs) around the body and is known to have important regulatory actions upon cellular reactions. However, it is difficult to determine the relation between the size of a nanostructure and the responses of cells owing to the lack of proper screening tools. Here, we show the development of reproducible and cost-effective gradient nanopattern plates for the manipulation of cellular responses. Using anodic aluminum oxide (AAO) as a master mold, gradient nanopattern plates with nanopillars of increasing diameter ranges [120-200 nm (GP 120/200), 200-280 nm (GP 200/280), and 280-360 nm (GP 280/360)] were fabricated by a thermal imprinting technique. These gradient nanopattern plates were designed to mimic the various sizes of nanotopography in the ECM and were used to screen the responses of human endothelial colony-forming cells (hECFCs). In this protocol, we describe the step-by-step procedure of fabricating gradient nanopattern plates for cell engineering, techniques of cultivating hECFCs from human peripheral blood, and culturing hECFCs on nanopattern plates. PMID- 30010661 TI - An Optical Assay for Synaptic Vesicle Recycling in Cultured Neurons Overexpressing Presynaptic Proteins. AB - At active presynaptic nerve terminals, synaptic vesicles undergo cycles of exo- and endocytosis. During recycling, the luminal domains of SV transmembrane proteins become exposed at the cell surface. One of these proteins is Synaptotagmin-1 (Syt1). An antibody directed against the luminal domain of Syt1, once added to the culture medium, is taken up during the exo-endocytotic cycle. This uptake is proportional to the amount of SV recycling and can be quantified through immunofluorescence. Here, we combine Syt1 antibody uptake with double transfection of cultured hippocampal neurons. This allows us to (1) localize presynaptic sites based on expression of recombinant presynaptic marker Synaptophysin, (2) determine their functionality using Syt1 uptake, and (3) characterize the targeting and effects of a protein of interest, GFP-Rogdi. PMID- 30010662 TI - Recording Spatially Restricted Oscillations in the Hippocampus of Behaving Mice. AB - The local field potential (LFP) emerges from ion movements across neural membranes. Since the voltage recorded by LFP electrodes reflects the summed electrical field of a large volume of brain tissue, extracting information about local activity is challenging. Studying neuronal microcircuits, however, requires a reliable distinction between truly local events and volume-conducted signals originating in distant brain areas. Current source density (CSD) analysis offers a solution for this problem by providing information about current sinks and sources in the vicinity of the electrodes. In brain areas with laminar cytoarchitecture such as the hippocampus, one-dimensional CSD can be obtained by estimating the second spatial derivative of the LFP. Here, we describe a method to record multilaminar LFPs using linear silicon probes implanted into the dorsal hippocampus. CSD traces are computed along individual shanks of the probe. This protocol thus describes a procedure to resolve spatially restricted neuronal network oscillations in the hippocampus of freely moving mice. PMID- 30010663 TI - Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation. AB - For years, the inability of replicating formation of insoluble alpha-synuclein (alphaS) inclusions in cell cultures has been a great limitation in the study of alphaS aggregation in Parkinson's Disease (PD). Recently, the development of new animal models through the exogenous inoculation of brain extracts from diseased alphaS transgenic mice or PD patients has given new hopes to the possibility of creating more adequate cell models of alphaS aggregation. Unfortunately, when it comes to cells in cultures, administration of raw brain extracts has not proven as successful as in mice and the source of choice of exogenous aggregates is still in vitro preformed alphaS fibrils. We have developed a method to induce the formation of intracellular alphaS inclusions in primary neurons through the exogenous administration of native microsomes-associated alphaS aggregates, a highly toxic alphaS species isolated from diseased areas of transgenic mice. This fraction of alphaS aggregates that is associated with the microsomes vesicles, is efficiently internalized and induces the formation of intracellular inclusions positive for aggregated and phosphorylated alphaS. Compared to in vitro-preformed fibrils which are made from recombinant alphaS, our method is faster and guarantees that the pathogenic seeding is made with authentic alphaS aggregates extracted from diseased animal models of PD, mimicking more closely the type of inclusions obtained in vivo. As a result, availability of tissues rich in alphaS inclusions is mandatory. We believe that this method will provide a versatile cell-based model to study the microscopic aspects of alphaS aggregation and the related cellular pathophysiology in vivo and will be a starting point for the creation of more accurate and sophisticated cell paradigm of PD. PMID- 30010664 TI - Construction and Operation of a Light-driven Gold Nanorod Rotary Motor System. AB - The possibility to generate and measure rotation and torque at the nanoscale is of fundamental interest to the study and application of biological and artificial nanomotors and may provide new routes towards single cell analysis, studies of non-equilibrium thermodynamics, and mechanical actuation of nanoscale systems. A facile way to drive rotation is to use focused circularly polarized laser light in optical tweezers. Using this approach, metallic nanoparticles can be operated as highly efficient scattering-driven rotary motors spinning at unprecedented rotation frequencies in water. In this protocol, we outline the construction and operation of circularly-polarized optical tweezers for nanoparticle rotation and describe the instrumentation needed for recording the Brownian dynamics and Rayleigh scattering of the trapped particle. The rotational motion and the scattering spectra provides independent information on the properties of the nanoparticle and its immediate environment. The experimental platform has proven useful as a nanoscopic gauge of viscosity and local temperature, for tracking morphological changes of nanorods and molecular coatings, and as a transducer and probe of photothermal and thermodynamic processes. PMID- 30010665 TI - A High-throughput, High-content, Liquid-based C. elegans Pathosystem. AB - The number of new drugs identified by traditional, in vitro screens has waned, reducing the success of this approach in the search for new weapons to combat multiple drug resistance. This has led to the conclusion that researchers do not only need to find new drugs, but also need to develop new ways of finding them. Amongst the most promising candidate methods are whole-organism, in vivo assays that use high-throughput, phenotypic readouts and hosts that range from Caenorhabditis elegans to Danio rerio. These hosts have several powerful advantages, including dramatic reductions in false positive hits, as compounds that are toxic to the host and/or biounavailable are typically dropped in the initial screen, prior to costly follow up. Here we show how our assay has been used to interrogate host variation in the well-documented C. elegans-Pseudomonas aeruginosa liquid killing pathosystem. We also demonstrate several extensions of this well-worked out technique. For example, we are able to carry out high throughput genetic screens using RNAi in 24- or 96-well plate formats to query host factors in this host-pathogen interaction. Using this assay, whole genome screens can be completed in only a few months, which can dramatically simplify the task of identifying drug targets, potentially without the need for laborious biochemical purification approaches. We also report here a variation of our method that substitutes the gram-positive bacterium Enterococcus faecalis for the gram-negative pathogen P. aeruginosa. Much as is the case for P. aeruginosa, killing by E. faecalis is time-dependent. Unlike previous C. elegans-E. faecalis assays, our assay for E. faecalis does not require preinfection, improving its safety profile and reducing the chances of contaminating liquid-handling equipment. The assay is highly robust, showing ~95% death rates 96 h post infection. PMID- 30010666 TI - Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy. AB - Huntington's Disease (HD) is an inherited fatal neurodegenerative disease caused by a CAG expansion (>=36) in the first exon of the HD gene, resulting in the expression of the Huntingtin protein (Htt) or N-terminal fragments thereof with an expanded polyglutamine (polyQ) stretch. The exon1 of the Huntingtin protein (Httex1) is the smallest Htt fragment that recapitulates many of the features of HD in cellular and animal models and is one of the most widely studied fragments of Htt. The small size of Httex1 makes it experimentally more amenable to biophysical characterization using standard and high-resolution techniques in comparison to longer fragments or full-length Htt. However, the high aggregation propensity of mutant Httex1 (mHttex1) with increased polyQ content (>=42) has made it difficult to develop efficient expression and purification systems to produce these proteins in sufficient quantities and make them accessible to scientists from different disciplines without the use of fusion proteins or other strategies that alter the native sequence of the protein. We present here a robust and optimized method for the production of milligram quantities of native, tag-free Httex1 based on the transient fusion of small ubiquitin related modifier (SUMO). The simplicity and efficiency of the strategy will eliminate the need to use non-native sequences of Httex1, thus making this protein more accessible to researchers and improving the reproducibility of experiments across different laboratories. We believe that these advances will also facilitate future studies aimed at elucidating the structure-function relationship of Htt as well as developing novel diagnostic tools and therapies to treat or slow the progression of HD. PMID- 30010667 TI - Fabricating Reactive Surfaces with Brush-like and Crosslinked Films of Azlactone Functionalized Block Co-Polymers. AB - In this paper, fabrication methods that generate novel surfaces using the azlactone-based block co-polymer, poly (glycidyl methacrylate)-block-poly (vinyl dimethyl azlactone) (PGMA-b-PVDMA), are presented. Due to the high reactivity of azlactone groups towards amine, thiol, and hydroxyl groups, PGMA-b-PVDMA surfaces can be modified with secondary molecules to create chemically or biologically functionalized interfaces for a variety of applications. Previous reports of patterned PGMA-b-PVDMA interfaces have used traditional top-down patterning techniques that generate non-uniform films and poorly controlled background chemistries. Here, we describe customized patterning techniques that enable precise deposition of highly uniform PGMA-b-PVDMA films in backgrounds that are chemically inert or that have biomolecule-repellent properties. Importantly, these methods are designed to deposit PGMA-b-PVDMA films in a manner that completely preserves azlactone functionality through each processing step. Patterned films show well-controlled thicknesses that correspond to polymer brushes (~90 nm) or to highly crosslinked structures (~1-10 MUm). Brush patterns are generated using either the parylene lift-off or interface directed assembly methods described and are useful for precise modulation of overall chemical surface reactivity by adjusting either the PGMA-b-PVDMA pattern density or the length of the VDMA block. In contrast, the thick, crosslinked PGMA-b-PVDMA patterns are obtained using a customized micro-contact printing technique and offer the benefit of higher loading or capture of secondary material due to higher surface area to volume ratios. Detailed experimental steps, critical film characterizations, and trouble-shooting guides for each fabrication method are discussed. PMID- 30010668 TI - Rapid, Safe, and Simple Manual Bedside Nucleic Acid Extraction for the Detection of Virus in Whole Blood Samples. AB - The rapid diagnosis of an infection is essential for the outbreak management, risk containment, and patient care. We have previously shown a method for the rapid bedside inactivation of the Ebola virus during blood sampling for safe nucleic acid (NA) tests by adding a commercial lysis/binding buffer directly into the vacuum blood collection tubes. Using this bedside inactivation approach, we have developed a safe, rapid, and simplified bedside NA extraction method for the subsequent detection of a virus in lysis/binding buffer-inactivated whole blood. The NA extraction is directly performed in the blood collection tubes and requires no equipment or electricity. After the blood is collected into the lysis/binding buffer, the contents are mixed by flipping the tube by hand, and the mixture is incubated for 20 min at room temperature. Magnetic glass particles (MGPs) are added to the tube, and the contents are mixed by flipping the collection tube by hand. The MGPs are then collected on the side of the blood collection tube using a magnetic holder or a magnet and a rubber band. The MGPs are washed three times, and after the addition of elution buffer directly into the collection tube, the NAs are ready for NA tests, such as qPCR or isothermal loop amplification (LAMP), without the removal of the MGPs from the reaction. The NA extraction method is not dependent on any laboratory facilities and can easily be used anywhere (e.g., in field hospitals and hospital isolation wards). When this NA extraction method is combined with LAMP and a portable instrument, a diagnosis can be obtained within 40 min of the blood collection. PMID- 30010669 TI - Experimental Methods for Spin- and Angle-Resolved Photoemission Spectroscopy Combined with Polarization-Variable Laser. AB - The goal of this protocol is to present how to perform spin- and angle-resolved photoemission spectroscopy combined with polarization-variable 7-eV laser (laser SARPES), and demonstrate a power of this technique for studying solid state physics. Laser-SARPES achieves two great capabilities. Firstly, by examining orbital selection rule of linearly polarized lasers, orbital selective excitation can be carried out in SAPRES experiment. Secondly, the technique can show full information of a variation of the spin quantum axis as a function of the light polarization. To demonstrate the power of the collaboration of these capabilities in laser-SARPES, we apply this technique for the investigations of spin-orbit coupled surface states of Bi2Se3. This technique affords to decompose spin and orbital components from the spin-orbit coupled wavefunctions. Moreover, as a representative advantage of using the direct spin detection collaborated with the polarization-variable laser, the technique unambiguously visualizes the light polarization dependence of the spin quantum axis in three-dimension. Laser-SARPES dramatically increases a capability of photoemission technique. PMID- 30010670 TI - Co-expression of Multiple Chimeric Fluorescent Fusion Proteins in an Efficient Way in Plants. AB - Information about the spatiotemporal subcellular localization(s) of a protein is critical to understand its physiological functions in cells. Fluorescent proteins and generation of fluorescent fusion proteins have been wildly used as an effective tool to directly visualize the protein localization and dynamics in cells. It is especially useful to compare them with well-known organelle markers after co-expression with the protein of interest. Nevertheless, classical approaches for protein co-expression in plants usually involve multiple independent expression plasmids, and therefore have drawbacks that include low co expression efficiency, expression-level variation, and high time expenditure in genetic crossing and screening. In this study, we describe a robust and novel method for co-expression of multiple chimeric fluorescent proteins in plants. It overcomes the limitations of the conventional methods by using a single expression vector that is composed of multiple semi-independent expressing cassettes. Each protein expression cassette contains its own functional protein expression elements, and therefore it can be flexibly adjusted to meet diverse expression demand. Also, it is easy and convenient to perform the assembly and manipulation of DNA fragments in the expression plasmid by using an optimized one step reaction without additional digestion and ligation steps. Furthermore, it is fully compatible with current fluorescent protein derived bio-imaging technologies and applications, such as FRET and BiFC. As a validation of the method, we employed this new system to co-express fluorescently fused vacuolar sorting receptor and secretory carrier membrane proteins. The results show that their perspective subcellular localizations are the same as in previous studies by both transient expression and genetic transformation in plants. PMID- 30010671 TI - Fabrication of Magnetic Nanostructures on Silicon Nitride Membranes for Magnetic Vortex Studies Using Transmission Microscopy Techniques. AB - Electron and x-ray magnetic microscopies allow for high-resolution magnetic imaging down to tens of nanometers. However, the samples need to be prepared on transparent membranes which are very fragile and difficult to manipulate. We present processes for the fabrication of samples with magnetic micro- and nanostructures with spin configurations forming magnetic vortices suitable for Lorentz transmission electron microscopy and magnetic transmission x-ray microscopy studies. The samples are prepared on silicon nitride membranes and the fabrication consists of a spin coating, UV and electron-beam lithography, the chemical development of the resist, and the evaporation of the magnetic material followed by a lift-off process forming the final magnetic structures. The samples for the Lorentz transmission electron microscopy consist of magnetic nanodiscs prepared in a single lithography step. The samples for the magnetic x-ray transmission microscopy are used for time-resolved magnetization dynamic experiments, and magnetic nanodiscs are placed on a waveguide which is used for the generation of repeatable magnetic field pulses by passing an electric current through the waveguide. The waveguide is created in an extra lithography step. PMID- 30010672 TI - Preclinical Assessment of the Bioactivity of the Anticancer Coumarin OT48 by Spheroids, Colony Formation Assays, and Zebrafish Xenografts. AB - In vitro and in vivo pre-clinical screening of novel therapeutic agents are an essential tool in cancer drug discovery. Although human cancer cell lines respond to therapeutic compounds in 2D (dimensional) monolayer cell cultures, 3D culture systems were developed to understand the efficacy of drugs in more physiologically relevant models. In recent years, a paradigm shift was observed in pre-clinical research to validate the potency of new molecules in 3D culture systems, more precisely mimicking the tumor microenvironment. These systems characterize the disease state in a more physiologically relevant manner and help to gain better mechanistic insight and understanding of the pharmacological potency of a given molecule. Moreover, with the current trend in improving in vivo cancer models, zebrafish has emerged as an important vertebrate model to assess in vivo tumor formation and study the effect of therapeutic agents. Here, we investigated the therapeutic efficacy of hydroxycoumarin OT48 alone or in combination with BH3 mimetics in lung cancer cell line A549 by using three different 3D culture systems including colony formation assays (CFA), spheroid formation assay (SFA) and in vivo zebrafish xenografts. PMID- 30010673 TI - Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. AB - CRISPR-Cas9 is poised to become the gene editing tool of choice in clinical contexts. Thus far, exploration of Cas9-induced genetic alterations has been limited to the immediate vicinity of the target site and distal off-target sequences, leading to the conclusion that CRISPR-Cas9 was reasonably specific. Here we report significant on-target mutagenesis, such as large deletions and more complex genomic rearrangements at the targeted sites in mouse embryonic stem cells, mouse hematopoietic progenitors and a human differentiated cell line. Using long-read sequencing and long-range PCR genotyping, we show that DNA breaks introduced by single-guide RNA/Cas9 frequently resolved into deletions extending over many kilobases. Furthermore, lesions distal to the cut site and crossover events were identified. The observed genomic damage in mitotically active cells caused by CRISPR-Cas9 editing may have pathogenic consequences. PMID- 30010674 TI - Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. AB - Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-gamma-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8+ lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME. PMID- 30010677 TI - Mechanistic insights into the iridium catalysed hydrogenation of ethyl acetate to ethanol: a DFT study. AB - Density functional theory study of the hydrogenation of ethyl acetate catalysed by iridium complexes [Cp*Ir(bpy)OH2]2+ reveals a direct C-O bond cleavage mechanism with two cascade catalytic cycles for the hydrogenation of ethyl acetate to aldehyde and the hydrogenation of aldehyde to ethanol. Calculation results indicate that the rate-determining state in the whole catalytic reaction is the direct C-O bond cleavage for the formation of aldehyde and ethanol with a total free energy barrier of 25.5 kcal mol-1, which is 0.6 kcal mol-1 more favorable than the mechanism proposed by Goldberg and co-workers in their experimental study. PMID- 30010675 TI - Comprehensive multi-center assessment of small RNA-seq methods for quantitative miRNA profiling. AB - RNA-seq is increasingly used for quantitative profiling of small RNAs (for example, microRNAs, piRNAs and snoRNAs) in diverse sample types, including isolated cells, tissues and cell-free biofluids. The accuracy and reproducibility of the currently used small RNA-seq library preparation methods have not been systematically tested. Here we report results obtained by a consortium of nine labs that independently sequenced reference, 'ground truth' samples of synthetic small RNAs and human plasma-derived RNA. We assessed three commercially available library preparation methods that use adapters of defined sequence and six methods using adapters with degenerate bases. Both protocol- and sequence-specific biases were identified, including biases that reduced the ability of small RNA-seq to accurately measure adenosine-to-inosine editing in microRNAs. We found that these biases were mitigated by library preparation methods that incorporate adapters with degenerate bases. MicroRNA relative quantification between samples using small RNA-seq was accurate and reproducible across laboratories and methods. PMID- 30010676 TI - Multiplexed identification, quantification and genotyping of infectious agents using a semiconductor biochip. AB - The emergence of pathogens resistant to existing antimicrobial drugs is a growing worldwide health crisis that threatens a return to the pre-antibiotic era. To decrease the overuse of antibiotics, molecular diagnostics systems are needed that can rapidly identify pathogens in a clinical sample and determine the presence of mutations that confer drug resistance at the point of care. We developed a fully integrated, miniaturized semiconductor biochip and closed-tube detection chemistry that performs multiplex nucleic acid amplification and sequence analysis. The approach had a high dynamic range of quantification of microbial load and was able to perform comprehensive mutation analysis on up to 1,000 sequences or strands simultaneously in <2 h. We detected and quantified multiple DNA and RNA respiratory viruses in clinical samples with complete concordance to a commercially available test. We also identified 54 drug resistance-associated mutations that were present in six genes of Mycobacterium tuberculosis, all of which were confirmed by next-generation sequencing. PMID- 30010678 TI - ALKBH5-induced demethylation of mono- and dimethylated adenosine. AB - RNA contains methylated A-base derivatives. A methylation to m6A and then demethylation regulate homeostasis in mRNA. It is assumed that m6A is mainly demethylated by the alpha-ketoglutarate dependent oxidase ALKBH5. Here we show that ALKBH5 also demethylates the dimethylated adenosine m62A, which is a non canonical base present in ribosomal RNA. PMID- 30010679 TI - PtPt interaction triggered tuning of circularly polarized luminescence activity in chiral dinuclear platinum(ii) complexes. AB - Circularly polarized luminescence (CPL) activity switched by PtPt interaction is disclosed in two couples of dinuclear Pt(ii) complex enantiomers. Upon varying the length of the bridging ligand, intramolecular metal-metal interaction manipulation is achieved as evidenced from crystal structures. Complex (-)-1 exhibiting strong PtPt interaction displays red phosphorescence with a maximum peak at 638 nm, while complex (-)-2 exhibiting weak PtPt interaction displays green phosphorescence with a maximum peak at 530 nm. The observed CPL was opposite in sign for the two complexes. TD-DFT simulations further confirmed the influence of the PtPt distance on the difference in the electronic optical activities. PMID- 30010680 TI - Study of light-induced formation of photodimers in the i-motif nucleic acid structure by rapid-scan FTIR difference spectroscopy and hybrid hard- and soft modelling. AB - The i-motif is a DNA structure formed by cytosine-rich sequences, very relevant from a biochemical point of view and potentially useful in nanotechnology as pH sensitive nanodevices or nanomotors. To provide a different view on the structural changes and dynamics of direct excitation processes involving i-motif structures, the use of rapid-scan FTIR spectroscopy is proposed. Hybrid hard- and soft-modelling based on the Multivariate Curve Resolution by Alternating Least Squares (MCR-ALS) algorithm has been used for the resolution of rapid-scan FTIR spectra and the interpretation of the photochemically induced time-dependent conformational changes of i-motif structures. The hybrid hard- and soft-modelling version of MCR-ALS (HS-MCR), which allows the introduction of kinetic models to describe process behavior, provides also rate constants associated with the transitions modeled. The results show that UV irradiation does not produce degradation of the studied sequences but induces the formation of photodimers. The presence of these affect much more the stability of i-motif structures formed by short sequences than that of those formed by longer sequences containing additional structural stabilizing elements, such as hairpins. PMID- 30010683 TI - Spontaneous directional transportations of water droplets on surfaces driven by gradient structures. AB - Spontaneous directional transportation of droplets on solid surfaces driven by structure gradients has attracted much attention due to its large-scale applications, such as heat transfer, microfluidic devices, water collection, and separation. It also provides new insight for theoretical research into the interactions between droplets and solid surfaces. This review article summarizes recent progress in the spontaneous directional transportation of droplets on surfaces with structure gradients. Currently, surfaces with structure gradients can be divided into three types: wedge corners with a gradient opening angle, wedge-shaped surfaces, and conical substrates. This review focuses on their basic theory, detailed transport processes, fabrication methods, influence factors and application development. Finally, a perspective of this mode of transportation for future development is proposed. PMID- 30010684 TI - Well-dispersed ultrasmall VC nanoparticles embedded in N-doped carbon nanotubes as highly efficient electrocatalysts for hydrogen evolution reaction. AB - The rational design and synthesis of ultrasmall metal-based electrocatalysts using earth-abundant elements for the hydrogen evolution reaction (HER) have been widely considered as a promising route for achieving improved catalytic properties. Herein, a metal-triggered confinement strategy to prepare well dispersed ultrasmall VC nanoparticles (~3 nm) embedded within N-doped carbon nanotubes (VC@NCNT) by using Co metal as the crystallization promoter is reported. When used as a HER electrocatalyst for water splitting, the resultant VC@NCNT catalyst exhibits low overpotentials (acid medium: 161 mV; alkaline medium: 159 mV; neutral medium: 266 mV) for driving a current density of 10 mA cm 2, remarkable durability at least for 100 h, and ~100% faradaic yield in both acid and alkaline media. Such excellent electrocatalytic HER performance is ascribed to the synergistic contribution of high pyridinic N-doping, outstanding conductivity of carbon nanotubes, and exposed abundant catalytic active sites of ultrasmall VC nanoparticles. PMID- 30010686 TI - Development of a thermosensitive protein conjugated nanogel for enhanced radio chemotherapy of cancer. AB - Although chemo-radiotherapy has been widely applied in clinics for cancer treatment, current strategies still face many challenges including serious side effects and drug resistance. Herein, we develop a chemically cross-linked poly N,N'-dimethyl aminoethyl methacrylate (PDMAEMA) smart nanogel as an excellent thermosensitive nanocarrier to load both an anticancer drug, doxorubicin (DOX) and a radioisotope, 131I-labeled albumin, for enhanced chemo-radioisotope therapy. Such a PDMAEMA nanogel in the solution form at room temperature can be easily injected into a tumor, in which it would be transformed into a gel at body temperature. Sustained drug release occurs in the tumor owing to the pH sensitive switching activity of the nanogel. In addition, the in situ thermogelling behavior of PDMAEMA leads to the long-term retention of 131I-labeled albumin within the tumor. In vivo chemo-radiotherapy is then conducted, achieving excellent therapeutic efficacy due to the sustained drug release and 131I retention for a long time in the cancer lesions. Our newly developed strategy of using a thermosensitive polymer for enhancing chemo-radiotherapy may be considered as a promising platform for combined cancer therapy without inducing obvious side-effects compared to the traditional chemo or radiotherapy. PMID- 30010687 TI - Facile fabrication of porous ZnS nanostructures with a controlled amount of S vacancies for enhanced photocatalytic performances. AB - ZnS nanostructures of barbell-shaped porous and hollow nanoplates with a controlled amount of S vacancies have been facilely fabricated via the hydrothermal treatment of ZnS(en)0.5 (en = ethylenediamine) nanoplates. The amount of S vacancies as well as the morphologies of ZnS nanostructures have been controlled by adjusting the hydrolysis time; the layered structure of ZnS(en)0.5 nanoplates decomposes to yield discrete ZnS nanoparticles at two end facets of template nanoplates, producing barbell-shaped porous and hollow ZnS nanoplates with abundant S vacancies finally. The photocatalytic activity of ZnS nanostructures prepared via hydrolysis for 4 h is 8.2 times higher than that of commercial ZnS. The photocatalytic activity of ZnS nanostructures increases with the increase of emission at 390 nm arising from sulfur vacancies, suggesting that the high photocatalytic efficiency of ZnS nanostructures results mainly from the high amount of sulfur vacancies. Surface defects such as sulfur vacancies can trap photogenerated electrons to block the recombination of charges, enhancing the photocatalytic efficiency of the as-prepared ZnS nanostructures. It has also been found that both OH and O2- act as the major reactive species in the photocatalytic decomposition of rhodamine B via our prepared ZnS nanostructures. Barbell-shaped porous and hollow ZnS nanoplates are suggested to have great applicability to photocatalysts in waste-water treatment. PMID- 30010688 TI - Fluorescence assay for alkaline phosphatase based on ATP hydrolysis-triggered dissociation of cerium coordination polymer nanoparticles. AB - Alkaline phosphatase (ALP) is a significant biomarker for diagnostics. Simple, selective and sensitive detection of ALP activity is thus of critical importance. In this study, an artful fluorescence assay for ALP is proposed based on adenosine triphosphate (ATP) hydrolysis-triggered disassociation and fluorescence quenching of cerium coordination polymer nanoparticles (CPNs). ATP, a recognized natural substrate of phosphatase, can serve as a superb "antenna" to sensitize the luminescence of Ce3+ with the aid of tris(hydroxymethyl) aminomethane (Tris), forming Ce3+-ATP-Tris CPNs. In the presence of ALP, ATP will be catalytically converted into adenosine and inorganic orthophosphate, however neither of them can sensitize Ce3+ in alkaline media. As a result, the obtained CPNs are disassociated, inducing the quenching of the fluorescence. On this basis, a straightforward fluorescence assay for ALP activity is rationally developed. The fluorescence quenching efficiency shows a linear relationship for ALP within the activity range from 0.1 to 10 mU mL-1 with a detection limit of 0.09 mU mL-1 under the optimal experimental conditions. Moreover, this facile yet effective fluorescence method featured simplicity, cost-effectiveness, high sensitivity and high selectivity and can be successfully utilized for the quantitative detection of ALP in human serum samples. PMID- 30010689 TI - A graphene-based fluorescent nanoprobe for simultaneous monitoring of miRNA and mRNA in living cells. AB - Since microRNA-21 (miR-21) and protein programmed cell death 4 (PDCD4) are implicated in tumor progression, simultaneous monitoring of the dynamic variation of miR-21 and PDCD4 mRNA in living cells is of great interest for understanding their relationship in the pathology of the disease. Herein, a versatile nanoprobe based on graphene oxide (GO) and DNA was prepared which can simultaneously monitor and visualize miR-21 and PDCD4 mRNA in living cells. In vitro experiments demonstrate that the nanoprobe exhibits outstanding selectivity and high sensitivity towards miR-21 and PDCD4 mRNA. Moreover, by exploiting the DNA/GO sensing platform, simultaneous imaging of miR-21 and PDCD4 mRNA in MCF-7 human breast cancer cells has been realized. More significantly, an inverse correlation between miR-21 and PDCD4 mRNA was verified by fluorescence confocal imaging and RT-PCR results, indicating the distinguishing ability of the nanoprobe at various expression levels of RNAs. The current strategy provides a promising tool to implement the detection of miR-21 and PDCD4 mRNA in cancer cells and can be expected to be applied for other biomolecular sensing. PMID- 30010690 TI - UGT73F17, a new glycosyltransferase from Glycyrrhiza uralensis, catalyzes the regiospecific glycosylation of pentacyclic triterpenoids. AB - The regiospecific glycosylation of pentacyclic triterpenoids by UGT73F17, a new glycosyltransferase from Glycyrrhiza uralensis, is highlighted. UGT73F17 exhibited strict substrate specificity toward the carboxyl group at C-30/C-29 of pentacyclic triterpenoids, and showed high promiscuity to sugar donors. UGT73F17 represents the first identified triterpenoid 30/29-O-glycosyltransferase, and could be used as an effective biocatalyst to synthesize glycosyl ester saponins. PMID- 30010691 TI - Furosemide-induced pseudoporphyria in a patient with chronic kidney disease: case report. AB - INTRODUCTION: Pseudoporphyria is a rare photodermatosis with characteristics similar to those of porphyria cutanea tarda, without, however, presenting abnormalities in porphyrin metabolism. Its etiology is related to chronic kidney disease, ultraviolet radiation and certain medications. The aim of the present study is to describe a case of furosemide-related pseudoporphyria in a patient with chronic kidney disease. CASE DESCRIPTION: A 76-year-old male patient with stage 4 chronic kidney disease and in continuous use of furosemide presented ulcerated lesions with peripheral erythema and central hematic crust in the legs. On a skin infection suspicion, treatment with quinolone and neomycin sulfate was initiated, without improvement. A biopsy of the lesion was performed, with histopathological examination demonstrating findings compatible with porphyria, although the patient did not present high porphyrin levels. The diagnosis of furosemide-induced pseudoporphyria was then established, with medication suspension, and there was a significant improvement of the lesions. DISCUSSION: There are few cases of pseudoporphyria described, but it is believed that this condition is underdiagnosed, especially in patients with chronic kidney disease. Both clinical and histopathological findings closely resemble porphyria, differentiating it from normal levels of porphyrin in plasma, urine, or feces. CONCLUSIONS: Although the lesions are mostly benign, they may increase the morbidity and mortality of these patients, so a proper diagnosis and early treatment are extremely important. PMID- 30010692 TI - The relationship between proton pump inhibitors and renal disease. AB - Proton pump inhibitors (PPIs) bind to enzyme H+/K+-ATPase and inhibit its activity in the stomach, thus decreasing the secretion of gastric acid. PPIs may trigger acute interstitial nephritis, a potentially severe adverse event commonly associated with acute kidney injury. Studies have found that prolonged use of PPIs may increase the risk of chronic kidney disease (CKD). The increase in prescription and inadequate use of this class of medication calls for studies on the effects of prolonged PPI therapy on renal function. Therefore, this review aimed to analyze recent studies on the matter and discuss the possible consequences of the long-term use of PPIs on renal function. PMID- 30010693 TI - Epidemiological, clinical, and laboratory factors associated with chronic kidney disease in Mexican HIV-infected patients. AB - AIM: To determine the prevalence of chronic kidney disease (CKD) and the epidemiological, clinical, and laboratory factors associated with CKD in Mexican HIV-infected patients. METHODS: Cross-sectional study. We included 274 patients with HIV/AIDS. CKD was defined by the estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2 assessed by CKD-EPI) and albuminuria criteria from KDIGO guidelines. Clinical, epidemiological, and laboratory characteristics were compared between patients with and without CKD. The factors associated with CKD were assessed by logistic regression analysis. RESULTS: The mean age was 41+/-11 years, and 72.3% of the patients were men. The global prevalence of CKD was 11.7% (n = 32); 7.2% (n = 20) were defined by eGFR criterion; 7.6% (n = 21), by the albuminuria criterion; and 3.2% (n = 9), by both CKD criteria. The most frequently observed stages of CKD were KDIGO G3A1 stage with 4.7% (n = 13), KDIGO G1A2 stage with 3.6% (n = 10) and KDIGO G3A2 stage with 1.7% (n = 5). The factors associated with CKD were use of abacavir/lamivudine (OR 3.2; 95% CI 1.1-8.9; p = 0.03), a CD4 lymphocyte count < 400 cells/uL (OR 2.6; 95% 1.03-6.4, p = 0.04), age (OR 1.1; 95% CI 1.04-1.2, p = 0.001) and albuminuria (OR 19.98; 95% CI: 5.5 72.2; p < 0.001). CONCLUSIONS: CKD was a frequent complication in HIV-infected patients. These findings confirm the importance of screening and the early detection of CKD, as well as the importance of identifying and treating traditional and non-traditional risk factors associated with CKD. PMID- 30010694 TI - Cost-Effectiveness of Renal Denervation Therapy for Treatment-Resistant Hypertension: A Best Case Scenario. AB - BACKGROUND: Renal denervation (RDN) is effective at reducing blood pressure (BP) among patients with treatment-resistant hypertension (TRH). However, recent findings regarding the effectiveness of RDN for BP reduction compared with standard treatment of care (SoC) has initiated a rigorous debate about its role in TRH management. In this study, we sought to determine the thresholds for cardiovascular risk and costs of RDN which would make RDN cost-effective. METHODS: A Markov model was constructed to simulate cardiovascular events over a lifetime among TRH subjects aged 60 years at baseline, and without prior cardiovascular disease. The effect on lowering BP was based on results observed in clinical trials of RDN undertaken to date, and the expected subsequent change to cardiovascular risk was drawn from a published meta-regression. Cost and utility data were drawn from published sources. Incremental cost-effectiveness ratios (ICER) in terms of Australian dollars (AUD) per life year and per quality adjusted life year (QALY) gained were estimated to assess RDN cost-effectiveness relative to SoC from the Australian health care perspective, assuming a willingness-to-pay threshold of AUD 50,000. RESULTS: Over a lifetime horizon, the model predicted that at the current estimated costs of RDN (AUD 9531/?6573, 1? = 1.45 AUD), it would be cost-effective only if it was targeted to patients whose 10-year predicted cardiovascular risk was at least 13.2% initially. The ICERs (discounted) were AUD 49,519 per life year gained and AUD 47,130 per QALY gained. CONCLUSIONS: At current costs and based on currently observed effects on BP reduction, RDN would be cost-effective among patients with TRH. PMID- 30010695 TI - Response to "Yogurt Intake and Risk of Cardiovascular Disease Among Hypertensive Individuals: Is It Time for a Clinical Trial?" PMID- 30010696 TI - Tools for testing decision-making capacity in dementia. AB - Background: dementia is a common cause of altered decision-making capacity. Determining whether an individual has the ability to make a specific decision can be very challenging for both clinicians and researchers. The UK legislation requires that we both promote residual capacity where possible, and protect vulnerable adults who cannot make independent decisions. We evaluated published instruments designed to aid in the assessment of capacity, focussing on those meeting the UK legal requirements. We also consider further disease and culture specific factors which may influence decision making. Methods: a search of electronic databases was made for articles published between 2000 and 2017 detailing structured tools for the assessment of mental capacity. These were evaluated against the UK legal requirements. Results: nine tools were identified which fulfilled the UK legal requirements. Their design and structure varied, as did the level of reliability and validity data available. Some instruments can be tailored for a specific decisional scenario, whilst others are designed for use by particular patient groups. Discussion: a wide range of mental capacity assessment instruments is available, but not all fulfil the UK legal requirements. Healthcare professionals and researchers should be mindful of personal, cultural and disease-specific factors when assessing capacity. No gold standard for capacity assessment exists, which hampers the evaluation of different approaches. A combination of the opinion of a healthcare professional or researcher trained in capacity evaluation, plus the use of a structured assessment tool is the most robust approach. PMID- 30010697 TI - Do portable nursing stations within bays of hospital wards reduce the rate of inpatient falls? An interrupted time-series analysis. AB - Background: falls can negatively affect patients, resulting in loss of independence and functional decline and have substantial healthcare costs. Hospitals are a high-risk falls environment and regularly introduce, but seldom evaluate, policies to reduce inpatient falls. This study evaluated whether introducing portable nursing stations in ward bays to maximise nurse-patient contact time reduced inpatient falls. Methods: inpatient falls data from local hospital incident reporting software (Datix) were collected monthly (April 2014 December 2017) from 17 wards in Stoke Mandeville and Wycombe General Hospitals, the UK. Portable nursing stations were introduced in bays on these wards from April 2016. We used a natural experimental study design and interrupted time series analysis to evaluate changes in fall rates, measured by the monthly rate of falls per 1000 occupied bed days (OBDs). Results: the wards reported 2875 falls (April 2014-December 2017). The fallers' mean age was 78 (SD = 13) and 58% (1624/2817) were men. Most falls, 99.41% (2858/2875), resulted in none, low or moderate harm, 0.45% (13/2875) in severe harm and 0.14% (4/2875) in death. The monthly falls rate increased by 0.119 per 1000 OBDs (95% CI: 0.045, 0.194; P = 0.002) before April 2016, then decreased by 0.222 per 1000 OBDs (95% CI: -0.350, 0.093; P = 0.001) until December 2017. At 12 months post-intervention, the absolute difference between the estimated post-intervention trend and pre intervention projected estimate was 2.84 falls per 1000 OBDs, a relative reduction of 26.71%. Conclusion: portable nursing stations were associated with lower monthly falls rates and could reduce inpatient falls across the NHS. PMID- 30010699 TI - Delirium screening in older patients. PMID- 30010698 TI - Effect of 12 wk of resistant starch supplementation on cardiometabolic risk factors in adults with prediabetes: a randomized controlled trial. AB - Background: Type 2 resistant starch (RS2) has been shown to improve glycemic control and some cardiovascular endpoints in rodent and human studies. Objective: The aim of this study was to perform one of the first randomized clinical trials in adults with prediabetes and one of the longest trials to test whether RS2 can improve cardiometabolic health. Design: 68 overweight [body mass index (BMI) >=27 kg/m2] adults aged 35-75 y with prediabetes were randomized to consume 45 g/d of high-amylose maize (RS2) or an isocaloric amount of the rapidly digestible starch amylopectin (control) for 12 wk. At baseline and postintervention, ectopic fat depots (visceral adipose tissue, intrahepatic lipids, and intramyocellular lipids) were measured by magnetic resonance imaging/spectroscopy, energy metabolism by respiratory chamber, and carbohydrate metabolism by glycated hemoglobin (HbA1c), an intravenous glucose tolerance test, and a meal tolerance test. Cardiovascular risk factors-serum lipids, blood pressure, heart rate, and inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], interleukin 6, and tumor necrosis factor [TNF]-alpha)-were also measured. The primary endpoints were insulin sensitivity, insulin secretion, ectopic fat, and markers of inflammation. Data were primarily analyzed as treatment effects via a linear mixed model both with and without the addition of covariates. Results: Relative to the control group, RS2 lowered HbA1c by a clinically insignificant 0.1 +/- 0.2% (Delta = -1 +/- 2 mmol/mol; P = 0.05) but did not affect insulin secretion, insulin sensitivity, the disposition index, or glucose or insulin areas under the curve relative to baseline (P >= 0.23). RS2 decreased heart rate by 5 +/- 9 beats/min (P = 0.02) and TNF-alpha concentrations by 2.1 +/- 2.7 pg/mL (P = 0.004), relative to the control group. Ectopic fat, energy expenditure, substrate oxidation, and all other cardiovascular risk factors were unaffected (P >= 0.06). Conclusions: 12 wk of supplementation with resistant starch reduced the inflammatory marker TNF-alpha and heart rate, but it did not significantly improve glycemic control and other cardiovascular disease risk factors, in adults with prediabetes. This trial was registered at clinicaltrials.gov as NCT01708694. PMID- 30010701 TI - Corrigendum. PMID- 30010700 TI - Prevalence of Self-Reported Hypertension in Deaf Adults Who Use American Sign Language. AB - BACKGROUND: In the United States, roughly one-third of adults have hypertension; another third have prehypertension. The prevalence of hypertension in deaf American Sign Language (ASL) users is unknown. We address this gap through a descriptive study for the prevalence of hypertension in the American Deaf community and discuss future directions to address this issue. METHODS: Self reported data for 1,388 ASL using deaf adults were compared with a secondary data of 2,830 English-speaking hearing adults. Frequency and percentages were used to describe the prevalence of hypertension in the deaf community. Age-weighted analysis was used to compare unmodifiable risk factors and hypertension rate between deaf and hearing adults. RESULTS: Deaf and hearing samples' hypertension rates for gender and age were similar. Significant group differences between deaf and hearing samples emerged across race. Compared with the hearing controls, our deaf sample demonstrated a significantly decreased risk for hypertension with a prevalence of 37% (compared with 45% in the hearing sample). CONCLUSIONS: Although the hypertension rate for gender and age was similar across deaf and hearing samples, between-group disparities exist for race. The lower rate of hypertension in our deaf sample is likely a consequence of underdiagnoses due to lower health literacy and poor patient-physician communication. Furthermore, deaf black Americans' lower rates compared with hearing black Americans may be due to poor patient-physician communication, not having regular providers or social stressors. It is recommended that modifiable risk factors and social determinants be investigated to determine their effect on hypertension within the deaf community. PMID- 30010702 TI - No Evidence of "healthy neuroticism" in the Hawaii Personality and Health Cohort. AB - Background: Heterogeneity in the effects of trait neuroticism on mortality has inspired recent theories of "healthy neuroticism," or the possibility that neuroticism can lead people down either healthy or unhealthy behavioral pathways. The logical extension of this theory is that some construct-perhaps another trait, financial resource, or health-relevant situation-changes the relationship between neuroticism and health. The other possibility is that different components of neuroticism lead to different health behaviors and therefore different outcomes. Purpose: The current study systematically examines the relationship between child and adult neuroticism and various health indicators including perceptions of health, behaviors, health outcomes, and biomarkers of health. Finally, we examine both potential moderators of the associations with neuroticism and examine its facet structure. Methods: The current study utilizes data from the Hawaii Longitudinal Study of Personality and Health, which includes both adult (IPIP-NEO) and childhood (teacher-reported) measures of personality and socioeconomic status, as well as a variety of health outcomes, from self reported health and health behavior to biological markers, such as cholesterol and blood glucose levels. Sample sizes range from 299 to 518. Results: The relationship between neuroticism and health was not consistently moderated by any other variable, nor were facets of neuroticism differentially related to health. Conclusions: Despite a systematic investigation of the potential "paths" which may differentiate the relationship of neuroticism to health, no evidence of healthy neuroticism was found. PMID- 30010703 TI - Childhood Psychological Distress and Healthy Cardiovascular Lifestyle 17-35 Years Later: The Potential Role of Mental Health in Primordial Prevention. AB - Background: Maintaining a healthy lifestyle in adulthood has been shown to significantly reduce cardiovascular disease risk. Increasing evidence suggests that behavioral risk factors for cardiovascular disease are established in childhood; however, limited research has evaluated whether childhood psychological factors play a role. Purpose: To evaluate the association between childhood psychological distress and young to mid adulthood healthy lifestyle. Methods: Using prospective data from the 1958 British Birth Cohort, we assessed whether psychological distress in childhood (captured by internalizing and externalizing symptoms at ages 7, 11, and 16 years) predicted healthy lifestyle at ages 33 (N = 10,748) and 42 (N = 9,581) years. Healthy lifestyle was measured using an index previously demonstrated to predict cardiovascular disease, consisting of five components: absence of smoking, moderate alcohol consumption, regular physical activity, healthy diet, and ideal body weight. Results: Few participants (3.8% at age 33 years and 2.8% at age 42 years) endorsed all five healthy lifestyle components. Linear regression models, adjusting for potential child- and family-level confounders, revealed that higher distress levels in childhood were negatively associated with healthy lifestyle at age 33 years (beta = -0.11, SE = 0.01, p < .001) and 42 years (beta = -0.13, SE = 0.01, p < .001). Higher distress was also associated with significantly lower odds of endorsing each lifestyle component, except physical activity, at both ages. Additional analyses indicated that childhood distress levels were highest among those whose lifestyle scores were low at age 33 and further declined between ages 33 and 42. Conclusions: Psychological distress in childhood may indicate children at risk of less healthy lifestyle practices later in life. Although our findings are preliminary, psychological distress may also provide an important target for public health interventions aimed at preventing cardiovascular disease. PMID- 30010704 TI - The Effects of Exercise on Physical and Psychological Outcomes in Cancer Caregivers: Results From the RECHARGE Randomized Controlled Trial. AB - Background: Family caregivers to cancer patients are at risk for physical and psychological morbidity as a direct result of being in the caregiver role. Exercise as an intervention to support caregiver health and well-being has been tested in other caregiver populations; however, no randomized controlled trials testing the effects of an aerobic and resistance training program have been conducted where cancer caregivers only have participated. Purpose: To examine the effects of a 12-week exercise program on quality of life (Short Form 36 v2), psychological outcomes, physical activity levels, and physical fitness in caregivers to cancer patients. Methods: Seventy-seven caregivers were randomized to either an exercise intervention or wait-list control. Two participants in the exercise arm dropped out immediately after their baseline assessment. Outcome data for n = 77 participants were analyzed using intention-to-treat analysis with linear mixed models. Results: Significant group by time interaction effects were detected for exercise on the mental health component score of quality of life, self-reported weekly exercise levels, and the six-minute walk test. Small to medium effect sizes were detected on several outcomes including physical health component of quality of life (d = 0.36), mental health component of quality of life (d = 0.74), depression (d = 0.41), anxiety (d = 0.35), physical activity levels (d = 0.80), and the six-minute walk test (d = 0.21). Conclusions: The findings suggest that exercise may improve health and well-being and could be considered as an additional type of support offered to cancer caregivers. Clinical trial registration no: NCT02580461. PMID- 30010705 TI - To Know Another's Pain: A Meta-analysis of Caregivers' and Healthcare Providers' Pain Assessment Accuracy. AB - Background: Acute and chronic pain affects millions of adults yet it is often inadequately assessed and treated. Purpose: The purpose of the present meta analysis was to examine the overall level of pain assessment accuracy among caregivers and providers and identify patient, observer, and assessment level factors that moderate pain assessment accuracy. Methods: A systematic literature search was conducted in PubMed and PsycINFO to identify studies addressing providers' pain assessment accuracy, or studies that compared patients' self report of pain with observers' (healthcare providers, caregivers, and strangers) assessment of pain. We present two separate meta-analyses examining the overall effect of under-/overestimation of pain and correlational pain assessment accuracy. Results: Seventy-six articles meeting inclusion criteria yielded 94 independent effect sizes for the correlational accuracy meta-analysis. Ninety articles yielded 103 independent effect sizes for the paired comparison meta analysis. The correlational pain assessment meta-analysis showed that in general, observers were significantly better than chance when assessing pain; however, the paired comparison meta-analysis showed that observers significantly underestimated patients' pain. Patient's age and gender, pain type, and provider type moderated these effects. Conclusions: Results suggest that certain healthcare providers and caregivers need training to more accurately assess patient pain and that there are particular groups of patients who may be at a greater risk for having their pain inaccurately assessed. PMID- 30010706 TI - Integrating Self-Affirmation and Implementation Intentions: Effects on College Student Drinking. AB - Background: High levels of alcohol consumption are an enduring health risk among college students. Integrating multiple, complementary behavior change theories may offer a promising approach to promote reductions in alcohol consumption. Purpose: The current study tested if integrating self-affirmation and implementation intentions would be more effective than a self-affirmation only, implementation intentions only, or control condition at reducing alcohol consumption in college students over a 2-week period. Method: Two hundred and ninety-three college students who reported drinking in the past month were randomly assigned to a condition in a 2 (self-affirmation: values vs. control writing task) * 2 (implementation intentions: formed vs. not formed) between subjects factorial design. Participants first completed a self-affirmation or control writing task, then read an article describing the risks of drinking. Next, all participants reported their common drinking behaviors and contexts, and then selected two harm-reduction strategies forming (or not forming) implementation intentions to use the strategies. Alcohol consumption was measured 1 and 2 weeks after the experiment. Results: Participants in the integrated self affirmation and implementation intention condition were most likely to abstain from drinking 1 week later. Affirmed participants continued to be more likely to abstain from drinking 2 weeks later. Conclusions: The findings support the efficacy of integrating self-affirmation and implementation intentions to reduce college student drinking (ClinicalTrials.gov number NCT02926794). PMID- 30010707 TI - Maladaptive Personality Traits and 10-Year Course of Psychiatric and Medical Symptoms and Functional Impairment Following Trauma. AB - Background: Personality is a major predictor of many mental and physical disorders, but its contributions to illness course are understudied. Purpose: The current study aimed to explore whether personality is associated with a course of psychiatric and medical illness over 10 years following trauma. Methods: World Trade Center (WTC) responders (N = 532) completed the personality inventory for DSM-5, which measures both broad domains and narrow facets. Responders' mental and physical health was assessed in the decade following the WTC disaster during annual monitoring visits at a WTC Health Program clinic. Multilevel modeling was used in an exploratory manner to chart the course of health and functioning, and examine associations of maladaptive personality domains and facets with intercepts (initial illness) and slopes (course) of illness trajectories. Results: Three maladaptive personality domains-negative affectivity, detachment and psychoticism-were uniquely associated with initial posttraumatic stress disorder (PTSD); detachment and psychoticism were also associated with initial functional impairment. Five facets-emotional lability, anhedonia, callousness, distractibility and perceptual dysregulation-were uniquely associated with initial mental and physical health and functional impairment. Anxiousness and depressivity facets were associated with worse initial levels of psychiatric outcomes only. With regard to illness trajectory, callousness and perceptual dysregulation were associated with the increase in PTSD symptoms. Anxiousness was associated with greater persistence of respiratory symptoms. Conclusions: Several personality domains and facets were associated with initial levels and long-term course of illness and functional impairment in a traumatized population. Results inform the role of maladaptive personality in the development and maintenance of chronic mental-physical comorbidity. Personality might constitute a transdiagnostic prognostic and treatment target. PMID- 30010708 TI - Global Versus Momentary Osteoarthritis Pain and Emotional Distress: Emotional Intelligence as Moderator. AB - Background: Pain and emotional well-being are complexly associated both globally and in the moment. Emotional regulation strategies may contribute to that complexity by shaping the pain-well-being association. Purpose: Using emotional intelligence (EI) as an integrative conceptual framework, this study probed the role of emotional regulation in the associations of osteoarthritis pain with emotional well-being in varying time frames. Perceived attention to, clarity, and regulation of emotions were examined as predictors of well-being, and as moderators of the well-being-pain association, at global and momentary (within day) levels. Methods: In a microlongitudinal study, 218 older adults with physician-diagnosed knee osteoarthritis self-reported global pain, depressive symptoms, and EI (mood attention, clarity, and repair). Momentary pain and positive and negative affect were then assessed four times daily for 7 days. EI subscales were examined as moderators of the pain-well-being association at global and momentary levels, controlling demographics and general health. Results: Global and momentary pain were positively associated with mood clarity and negatively with attention, but not with repair. Clarity and repair negatively predicted depression, and buffered effects of pain on depression. Momentary negative affect was negatively predicted by mood clarity and repair; again, clarity and mood repair buffered effects of momentary pain on negative affect. Only mood repair predicted positive affect, with no interactions emerging. Conclusions: Attention to mood states exacerbates the experience of pain in both short and long terms. In contrast, both mood clarity and ability to repair moods appear important to both momentary and longer-term emotional well-being. PMID- 30010710 TI - Corrigendum to: How trees allocate carbon for optimal growth: insight from a game theoretic model. PMID- 30010709 TI - Sense of Purpose Moderates the Associations Between Daily Stressors and Daily Well-being. AB - Background: Having a sense of purpose in life has been consistently demonstrated as a predictor of positive health outcomes, including less perceived stress, yet, little is known about the role of sense of purpose on stressful days. Purpose: The current study investigated the sense of purpose as a moderator of stressor related changes in daily physical symptoms, positive affect, and negative affect. Methods: A subset of the Midlife in the United States study (n = 1949, mage: 56.4 years) reported their sense of purpose, along with up to eight daily assessments of stressors, affect, and physical symptoms. Multilevel models evaluated whether sense of purpose was associated with deviations in affect or physical symptom reporting on days when participants reported a stressor versus days when stressors did not occur. Results: Sense of purpose was associated with higher daily positive affect, lower daily negative affect, and fewer daily physical symptoms. Compared with individuals who reported lower levels of purpose, those reporting higher levels encountered the same number of daily stressors, yet showed less of an increase in negative affect and physical symptoms on stressor days than on stressor-free days. Purpose did not predict changes in positive affect in response to daily stressors. Conclusions: Findings provide evidence that a purposeful life may be characterized by lower negative affect and physical symptom reporting on stressful days. PMID- 30010711 TI - RNA/DNA structures recognized by RNase H2. AB - Ribonuclease H (RNase H) [EC 3.1.26.4] is an enzyme that specifically degrades RNA from RNA/DNA hybrids. Since its discovery in 1969, the enzyme has been extensively studied for its catalytic mechanism and physiological role. RNase H has been classified into two major families, Type 1 and Type 2. Type 1 enzymes are designated RNase HI in prokaryotes and RNase H1 in eukaryotes, while Type 2 enzymes are designated RNase HII in prokaryotes and RNase H2 in eukaryotes. Type 2 enzymes are able to cleave the 5'-phosphodiester bond of one ribonucleotide embedded in a DNA double strand. Recent studies have shown that RNase H2 is involved in excision of a single ribonucleotide embedded in genomic DNA and removal of an R-loop formed in cells. It is also involved in double-strand break of DNA and its repair. In this review, we aim to outline the structures recognized by RNase H2. PMID- 30010712 TI - Uncertainty quantification, propagation and characterization by Bayesian analysis combined with global sensitivity analysis applied to dynamical intracellular pathway models. AB - Motivation: Dynamical models describing intracellular phenomena are increasing in size and complexity as more information is obtained from experiments. These models are often over-parameterized with respect to the quantitative data used for parameter estimation, resulting in uncertainty in the individual parameter estimates as well as in the predictions made from the model. Here we combine Bayesian analysis with global sensitivity analysis in order to give better informed predictions; to point out weaker parts of the model that are important targets for further experiments, as well as to give guidance on parameters that are essential in distinguishing different qualitative output behaviours. Results: We used approximate Bayesian computation (ABC) to estimate the model parameters from experimental data, as well as to quantify the uncertainty in this estimation (inverse uncertainty quantification), resulting in a posterior distribution for the parameters. This parameter uncertainty was next propagated to a corresponding uncertainty in the predictions (forward uncertainty propagation), and a global sensitivity analysis was performed on the prediction using the posterior distribution as the possible values for the parameters. This methodology was applied on a relatively large model relevant for synaptic plasticity, using experimental data from several sources. We could hereby point out those parameters that by themselves have the largest contribution to the uncertainty of the prediction as well as identify parameters important to separate between qualitatively different predictions.This approach is useful both for experimental design as well as model building. Availability: Source code is freely available at https://github.com/alexjau/uqsa. PMID- 30010713 TI - A practical guide for DNase-seq data analysis: from data management to common applications. AB - Deoxyribonuclease I (DNase I)-hypersensitive site sequencing (DNase-seq) has been widely used to determine chromatin accessibility and its underlying regulatory lexicon. However, exploring DNase-seq data requires sophisticated downstream bioinformatics analyses. In this study, we first review computational methods for all of the major steps in DNase-seq data analysis, including experimental design, quality control, read alignment, peak calling, annotation of cis-regulatory elements, genomic footprinting and visualization. The challenges associated with each step are highlighted. Next, we provide a practical guideline and a computational pipeline for DNase-seq data analysis by integrating some of these tools. We also discuss the competing techniques and the potential applications of this pipeline for the analysis of analogous experimental data. Finally, we discuss the integration of DNase-seq with other functional genomics techniques. PMID- 30010714 TI - Physiological RNA dynamics in RNA-Seq analysis. AB - Physiological RNA dynamics cause problems in transcriptome analysis. Physiological RNA accumulation affects the analysis of RNA quantification, and physiological RNA degradation affects the analysis of the RNA sequence length, feature site and quantification. In the present article, we review the effects of physiological degradation and accumulation of RNA on analysing RNA sequencing data. Physiological RNA accumulation and degradation probably led to such phenomena as incorrect estimations of transcription quantification, differential expressions, co-expressions, RNA decay rates, alternative splicing, boundaries of transcription, novel genes, new single-nucleotide polymorphisms, small RNAs and gene fusion. Thus, the transcriptomic data obtained up to date warrant further scrutiny. New and improved techniques and bioinformatics software are needed to produce accurate data in transcriptome research. PMID- 30010715 TI - A comprehensive survey of models for dissecting local ancestry deconvolution in human genome. AB - Over the past decade, studies of admixed populations have increasingly gained interest in both medical and population genetics. These studies have so far shed light on the patterns of genetic variation throughout modern human evolution and have improved our understanding of the demographics and adaptive processes of human populations. To date, there exist about 20 methods or tools to deconvolve local ancestry. These methods have merits and drawbacks in estimating local ancestry in multiway admixed populations. In this article, we survey existing ancestry deconvolution methods, with special emphasis on multiway admixture, and compare these methods based on simulation results reported by different studies, computational approaches used, including mathematical and statistical models, and biological challenges related to each method. This should orient users on the choice of an appropriate method or tool for given population admixture characteristics and update researchers on current advances, challenges and opportunities behind existing ancestry deconvolution methods. PMID- 30010716 TI - Hierarchical optimization for the efficient parametrization of ODE models. AB - Motivation: Mathematical models are nowadays important tools for analyzing dynamics of cellular processes. The unknown model parameters are usually estimated from experimental data. These data often only provide information about the relative changes between conditions, hence, the observables contain scaling parameters. The unknown scaling parameters and corresponding noise parameters have to be inferred along with the dynamic parameters. The nuisance parameters often increase the dimensionality of the estimation problem substantially and cause convergence problems. Results: In this manuscript, we propose a hierarchical optimization approach for estimating the parameters for ordinary differential equation (ODE) models from relative data. Our approach restructures the optimization problem into an inner and outer subproblem. These subproblems possess lower dimensions than the original optimization problem, and the inner problem can be solved analytically. We evaluated accuracy, robustness, and computational efficiency of the hierarchical approach by studying three signaling pathways. The proposed approach achieved better convergence than the standard approach and required a lower computation time. As the hierarchical optimization approach is widely applicable, it provides a powerful alternative to established approaches. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010717 TI - The small peptide world in long noncoding RNAs. AB - Long noncoding RNAs (lncRNAs) are a group of transcripts that are longer than 200 nucleotides (nt) without coding potential. Over the past decade, tens of thousands of novel lncRNAs have been annotated in animal and plant genomes because of advanced high-throughput RNA sequencing technologies and with the aid of coding transcript classifiers. Further, a considerable number of reports have revealed the existence of stable, functional small peptides (also known as micropeptides), translated from lncRNAs. In this review, we discuss the methods of lncRNA classification, the investigations regarding their coding potential and the functional significance of the peptides they encode. PMID- 30010718 TI - A parallel computational framework for ultra-large-scale sequence clustering analysis. AB - Motivation: The rapid development of sequencing technology has led to an explosive accumulation of genomic data. Clustering is often the first step to be performed in sequence analysis. However, existing methods scale poorly with respect to the unprecedented growth of input data size. As high-performance computing systems are becoming widely accessible, it is highly desired that a clustering method can easily scale to handle large-scale sequence datasets by leveraging the power of parallel computing. Results: In this paper, we introduce SLAD (Separation via Landmark-based Active Divisive clustering), a generic computational framework that can be used to parallelize various de novo operational taxonomic unit (OTU) picking methods and comes with theoretical guarantees on both accuracy and efficiency. The proposed framework was implemented on Apache Spark, which allows for easy and efficient utilization of parallel computing resources. Experiments performed on various datasets demonstrated that SLAD can significantly speed up a number of popular de novo OTU picking methods and meanwhile maintains the same level of accuracy. In particular, the experiment on the Earth Microbiome Project dataset (~2.2B reads, 437GB) demonstrated the excellent scalability of the proposed method. Availability and implementation: Open-source software for the proposed method is freely available at https://www.acsu.buffalo.edu/~yijunsun/lab/SLAD.html. Supplementary information: Supplementary data is available at Bioinformatics online. PMID- 30010719 TI - BrainImageR: Spatiotemporal gene set analysis referencing the human brain. AB - Motivation: Neuronal analyses such as transcriptomics, epigenetics, and genome wide association studies must be assessed in the context of the human brain to generate biologically meaningful inferences. It is often difficult to access primary human brain tissue; therefore, approximations are made using alternative sources such as peripheral tissues or in vitro-derived neurons. Gene sets from these studies are then assessed for their association with the post-mortem human brain. However, most analyses of post-mortem datasets are achieved by building new computational tools each time in-house, which can cause discrepancies from study to study. The field is in need of a user-friendly tool to examine spatiotemporal expression with respect to the postmortem brain. Such a tool will be of use in the molecular interrogation of neurological and psychiatric disorders, with direct advantages for the disease-modeling and human genetics communities. Results: We have developed brainImageR, an R package that calculates both the spatial and temporal association of a dataset with post-mortem human brain. BrainImageR identifies anatomical regions enriched for candidate gene set expression. It further predicts the developmental time point of the sample, a task that has become increasingly important in the field of in vitro neuronal modeling. These functionalities of brainImageR enable a quick and efficient characterization of a given dataset across normal human brain development. Availability and Implementation: BrainImageR is released under the Creative Commons CC BY-SA 4.0 license and can be accessed directly at brainimager.salk.edu or the R code can be downloaded through github at https://github.com/saralinker/brainImageR. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010720 TI - Distinct inflammatory profile in preeclampsia and postpartum preeclampsia reveal unique mechanisms. AB - Preeclampsia (PE) is a poorly understood pregnancy complication. It has been suggested that changes in the maternal immune system may contribute to PE, but evidence of this remains scarce. Whilst PE is commonly experienced pre-partum, it can also occur in the postpartum period (postpartum PE-PPPE), and the mechanisms involved are unknown. Our goal was to determine whether changes occur in the maternal immune system and placenta in pregnancies complicated with PE and PPPE, compared to normal term pregnancies.We prospectively recruited women and collected blood samples to determine the circulating immune profile, by flow cytometry, and assess the circulating levels of inflammatory mediators and angiogenic factors. Placentas were collected for histological analysis.Levels of alarmins in the maternal circulation showed increased uric acid in PE and elevated high-mobility group box 1 (HMGB1) in PPPE. Analysis of maternal immune cells revealed distinct profiles in PE vs PPPE. PE had increased percentage of lymphocytes and monocytes whilst PPPE had elevated NK and NK-T cells as well. Elevated numbers of immune cells (CD45 + ) were detected in placentas from women that developed PPPE, and those were macrophages (CD163 + ).This works reveal changes within the maternal immune system in both PE and PPPE, and indicates a striking contrast in how this occurs. Importantly, elevated immune cells in the placenta of women with PPPE strongly suggest a prenatal initiation of the pathology. A better understanding of these changes will be beneficial to identify women at high risk of PPPE and to develop novel therapeutic targets. PMID- 30010721 TI - Reduction of Kiss1 expression in the anteroventral perivascular nucleus is associated with atrazine-induced attenuation of the luteinizing hormone surge in female rats. AB - Atrazine, a commonly used herbicide, suppresses the luteinizing hormone (LH) surge in female rats, although the underlying mechanism remains unclear. Kisspeptin, encoded by the Kiss1 gene, is a hypothalamic peptide that controls gonadotropin-releasing hormone (GnRH) release from the GnRH neurons. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) are involved in regulating pre-ovulatory GnRH and LH surge. To clarify the effect of atrazine on the LH surge in female rats, we investigated its effects on hypothalamic GnRH and kisspeptin. Ovariectomized female rats in a high-dose estradiol supplementation model were orally administered vehicle or 100 mg/kg of atrazine once daily for 5 days. This attenuated the LH surge but did not affect baseline LH levels, with no difference in hypothalamic GnRH levels between the vehicle-treated and atrazine treated animals. After the fifth treatment, subcutaneous administration of kisspeptin (at 0, 0.1, 1, and 10 nmol/kg) induced a dose-dependent LH release almost equivalent in the vehicle- and atrazine-treated animals, suggesting that GnRH neurons maintain normal responsiveness to kisspeptin. However, Kiss1 mRNA expression levels in the AVPV were significantly reduced in the atrazine-treated animals. Given the normal response of GnRH neurons to exogenously administered kisspeptin, the suppressive effect of atrazine may be explained by suppression of Kiss1 expression in the AVPV leading to the attenuation of kisspeptin release from kisspeptin neurons in the AVPV. Further studies are warranted to elucidate more precisely the mechanism of atrazine's involvement in the suppression of Kiss1 mRNA expression in the AVPV. PMID- 30010722 TI - Dynamic chromatin accessibility unveils a regulatory landscape in early embryogenesis in human. PMID- 30010723 TI - PGE2 increases inflammatory damage in Escherichia coli-infected bovine endometrial tissue in vitro via the EP4-PKA signaling pathway. AB - Endometritis is the most common bovine uterine disease following parturition. The role of prostaglandin E2 (PGE2) in the regulation of endometrial inflammation and repair is well understood. Excess PGE2 is also generated in multiple inflammatory diseases, including endometritis. However, it remains unclear whether PGE2 is associated with pathogen-induced inflammatory damage to the endometrium. To clarify the role of PGE2 in pathogen-induced inflammatory damage, this study evaluated the production of PGE2, inflammatory factors, and damage-associated molecular patterns (DAMPs) in cultured Escherichia coli-infected bovine endometrial tissue. PGE2 production was significantly higher in E. coli-infected tissue, and in E. coli-infected tissue treated with 15-prostaglandin dehydrogenase (15-PGDH) inhibitors, as compared to uninfected tissue. Phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1) were also upregulated in E. coli-infected tissue, while concentrations of arachidonic acid (AA), leukotrienes, DAMPs, and other pro inflammatory factors increased. The accumulation of PGE2 clearly damaged the cultured tissue. Treatment with the COX-2, mPGES-1, EP4, and protein kinase A (PKA) inhibitors decreased the production of PGE2, inflammatory factors, and DAMPs, simultaneously alleviating the E. coli-induced endometrial tissue damage. Therefore, the PGE2 that was generated by COX-2 and mPGES-1 accumulated, and this pathogenic PGE2 increased inflammatory damage by upregulating inflammatory factors and DAMPs in E. coli-infected bovine endometrial tissue. This upregulation of inflammatory factors and DAMPs might be regulated by the EP4-PKA signaling pathway. PMID- 30010724 TI - Female-to-male sex reversal in orange-spotted grouper (Epinephelus coioides) caused by over-expressing of Amh in vivo. AB - A variety of mechanisms are involved in sex determination in vertebrates. The orange-spotted grouper (Epinephelus coioides), a teleost fish, functions first as females and later as a male and is an ideal model to investigate the regulation of sexual fate. Here, we report female-to-male sex reversal in juvenile orange spotted groupers caused by over-expressing anti-Mullerian hormone (Amh). Tissue distribution analyses showed that amh and amhrII primarily expressed in the gonad, and expression level in the testis was much higher than that in the ovary. In gonads, the expression of amh was located in the Sertoli cells around spermatogonia of the testis and in the zona pellucida of the mature ovary, the expression of amhrII was located in the Sertoli cells of the testis and in the oocytes of the ovary. Decrease in female-related genes and serum 17beta-estradiol level, increase in male-related genes and serum 11-ketotestosterone, ovarian regression, and spermatogonia proliferation were observed during plasmid feeding experiment. These results illustrate that amh over-expression plasmid feeding can induce a female-to-male transition in grouper. PMID- 30010725 TI - WBP2 shares a common location in mouse spermatozoa with WBP2NL/PAWP and like its descendent is a candidate mouse oocyte activating factor. AB - The sperm-borne oocyte-activating factor (SOAF) resides in the sperm perinuclear theca (PT). A consensus has been reached that SOAF most likely resides in the post-acrosomal sheath (PAS), which is the first region of the PT to solubilize upon sperm-oocyte fusion. There are two SOAF candidates under consideration: PLCZ1 and WBP2NL. A mouse gene germline ablation of the latter showed that mice remain fertile with no observable phenotype despite the fact that a competitive inhibitor of WBP2NL, derived from its PPXY motif, blocks oocyte activation when co-injected with WBP2NL or spermatozoa. This suggested that the ortholog of WBP2NL, WBP2, containing the same domain and motifs associated with WBP2NL function, might compensate for its deficiency in oocyte activation. Our objectives were to examine whether WBP2 meets the developmental criteria established for SOAF and whether it has oocyte activating potential. Immunoblotting detected WBP2 in mice testis and sperm and immunofluorescence localized WBP2 to the PAS and perforatorium of the PT. Immunohistochemistry of the testes revealed that WBP2 reactivity was highest in round spermatids and immunofluorescence detected WBP2 in the cytoplasmic lobe of elongating spermatids and co-localized it with the microtubular manchette during PT assembly. Microinjection of the recombinant forms of WBP2 and WBP2NL into metaphase II mouse oocytes resulted in comparable rates of oocyte activation. This study shows that WBP2 shares a similar testicular developmental pattern and location with WBP2NL and a shared ability to activate the oocyte, supporting its consideration as a mouse SOAF component that can compensate for a WBP2NL. PMID- 30010726 TI - Actin cytoskeleton dynamics in mammalian oocyte meiosis. AB - During mitosis, cells undergo symmetrical cell division, while oocyte meiotic maturation undergoes two consecutive, asymmetric divisions that generate a totipotent haploid oocyte and two small polar bodies not involved in DNA replication. This specialized division allows most maternal components be maintained in the oocytes for early embryo development. Nuclear positioning, germinal vesicle breakdown, spindle migration, spindle rotation, chromosome segregation, and polar body extrusion are the most critical cellular processes during oocyte meiosis I and II, and a growing number of studies primarily using the mouse oocyte model revealed that actin filaments were critical for these processes, especially for spindle migration. Several important molecules have been reported to be involved in these processes. One family of molecules are the small GTPases, such as Rho GTPases, Ran GTPases, and Rab GTPases and another are the actin nucleators, such as the formin family and the Arp2/3 complex. The present review summarizes recent progress made regarding the roles of actin filaments in the asymmetric oocyte division. PMID- 30010727 TI - Targeted ablation of Wnt4 and Wnt5a in Mullerian duct mesenchyme impedes endometrial gland development and causes partial Mullerian agenesis. AB - Both Wnt4 and Wnt5a have well-established roles in the embryonic development of the female reproductive tract, as well as in implantation, decidualization and ovarian function in adult mice. Although these roles appear to overlap, whether Wnt5a and Wnt4 are functionally redundant in these tissues has not been determined. Here, we addressed this by concomitantly inactivating Wnt4 and Wnt5a in the Mullerian mesenchyme and in ovarian granulosa cells by crossing mice bearing floxed alleles to the Amhr2cre strain. Whereas fertility was reduced by ~50% in Wnt4flox/flox; Amhr2cre/+ and Wnt5aflox/flox; Amhr2cre/+ females, Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ mice were either nearly or completely sterile. Loss of fertility was not due to an ovarian defect, as serum ovarian hormone levels, follicle counts and ovulation rates were comparable to controls. Conversely, the uterus was abnormal in Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ mice, with thin myometrial and stromal layers, frequent fibrosis and a >90% reduction in numbers of uterine glands, suggesting redundant or additive roles of Wnt4 and Wnt5a in uterine adenogenesis. Loss of fertility in Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ mice was attributed to defects in decidualization, implantation and placental development, the severity of which were proportional to the extent of gland loss. Furthermore, a third of Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ females had a partial agenesis of Mullerian duct derived structures (anterior vagina and cervix, or a partial or complete uterine horn), but with normal oviducts and ovaries. Together, our results suggest that Wnt4 and Wnt5a play redundant roles in the development of the female reproductive tract, and may provide insight into the etiology of certain cases of Mullerian agenesis in women. PMID- 30010728 TI - Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization. AB - Epidemiological studies have revealed that offspring conceived by in vitro fertilization (IVF) have an elevated risk of cardiovascular malformations at birth, and are more predisposed to cardiovascular diseases in late childhood. Unfortunately, the underlying mechanisms influencing compromised cardiovascular function in IVF-conceived children remain unclear. Moreover, the continuing implications for the cardiovascular health of these children as they move into adulthood and old age, have yet to be determined. The renin-angiotensin system (RAS) plays an essential role in both the pathogenesis of congenital heart disease in fetuses and cardiovascular dysfunction in adults. This study aimed to assess the relative expression levels of genes in the RAS pathway in mice conceived using IVF, compared to natural mating with superovulation. In addition, the relative expression of candidate genes expressed in the myocardial tissue of newborn, adult and old mice was determined between the IVF and naturally mated populations. Results demonstrated that expression of the angiotensin II receptor type 1 (AGTR1), connective tissue growth factor (CTGF), and collagen 3 (COL3), in the myocardial tissue of IVF-conceived mice, was elevated at 3 weeks, 10 weeks, and 1.5 years of age, when compared to their non-IVF counterparts. These data were supported by microRNA microarray analysis of the myocardial tissue of aged IVF-conceived mice, where miR-100, miR-297, and miR-758, which interact with COL3, AGTR1 and COL1 respectively, were upregulated when compared to naturally mated mice of the same age. Interestingly, bisulfite sequencing data indicated that IVF-conceived mice exhibited decreased methylation of CpG sites in Col1. In support of our in vivo investigations, miR-297 overexpression was shown to upregulate AGTR1 and CTGF, and increased cell proliferation in cultured H9c2 cardiomyocytes. These findings indicate that the altered expression of RAS in myocardial tissue might contribute to cardiovascular malformation and/or dysfunction in IVF-conceived offspring. Furthermore, these cardiovascular abnormalities might be the result of altered DNA methylation and abnormal regulation of microRNAs. PMID- 30010729 TI - On the Meaning(s) of Perceived Complexity in the Chemical Senses. AB - Complexity is a term that is often invoked by those writing appreciatively about the taste, aroma/bouquet, and/or flavor of food and drink. Typically, the term is used as though everyone knows what is being talked about. Rarely is any explanation given, and the discussion soon moves on to other topics. However, oftentimes it is not at all clear what, exactly, is being referred to. A number of possibilities are outlined here, including physical complexity at the level of individual molecules, at the level of combinations of molecules giving rise to a specific flavor profile (e.g., as in a glass of quality wine or a cup of specialty coffee), at the level of combinations of distinct ingredients/elements (e.g., as when composing a particularly intricate dish in a high-end restaurant, say, or when pairing food with wine), and/or the number of stimuli/steps involved in the process of creation. Of course, people might also be referring to some aspect of their perceptual experience, and one of the intriguing questions in this space concerns the nature of the relationship(s) between these different ways of conceptualizing complexity in the chemical senses. However, given that physical/chemical and perceived complexity so often diverge, we argue that it is the latter notion, or rather inferred complexity, that is the most relevant when it comes to the chemical senses. Finally, we look at the role of expertise and review the evidence suggesting that inferred complexity can emerge either from a unitary taste experience that is judged to be complex, or from a tasting experience having multiple individuable elements. PMID- 30010730 TI - RabGTD: a comprehensive database of rabbit genome and transcriptome. AB - The rabbit is a very important species for both biomedical research and agriculture animal breeding. They are not only the most-used experimental animals for the production of antibodies, but also widely used for studying a variety of human diseases. Here we developed RabGTD, the first comprehensive rabbit database containing both genome and transcriptome data generated by next-generation sequencing. Genomic variations coming from 79 samples were identified and annotated, including 33 samples of wild rabbits and 46 samples of domestic rabbits with diverse populations. Gene expression profiles of 86 tissue samples were complied, including those from the most commonly used models for hyperlipidemia and atherosclerosis. RabGTD is a web-based and open-access resource, which also provides convenient functions and friendly interfaces of searching, browsing and downloading for users to explore the big data.Database URL: http://www.picb.ac.cn/RabGTD/. PMID- 30010732 TI - Effect of Color and Contrast of Highbush Blueberries to Host-Finding Behavior by Drosophila suzukii (Diptera: Drosophilidae). AB - Drosophila suzukii Matsumara (Diptera: Drosophilidae) has become a serious pest in soft-skin fruits and berries, infesting both ripe and ripening fruits. Crop damage in highbush blueberry has been particularly severe. During blueberry fruit development, fruits of various degrees of ripeness are present simultaneously. In addition, foliage color changes as the season progresses. We investigated the influence of blueberry fruit and leaf color on host-finding behavior in D. suzukii. Opposing shifts between reflectance spectra of ripening fruits and senescing leaves increased contrast between ripe fruit and senesced foliage. Developmental changes in contrast between fruit color and leaf color may act as a visual contextual cue in finding suitable host fruits. Opposing shifts in reflectance spectra of ripening fruits and senescing leaves increased the contrast between ripe fruit and senesced foliage. These opposing changes in color may contribute to the attractiveness of blueberry fruit as a late season host for D. suzukii. PMID- 30010731 TI - Leveraging prior knowledge for protein-protein interaction extraction with memory network. AB - Automatically extracting protein-protein interactions (PPIs) from biomedical literature provides additional support for precision medicine efforts. This paper proposes a novel memory network-based model (MNM) for PPI extraction, which leverages prior knowledge about protein-protein pairs with memory networks. The proposed MNM captures important context clues related to knowledge representations learned from knowledge bases. Both entity embeddings and relation embeddings of prior knowledge are effective in improving the PPI extraction model, leading to a new state-of-the-art performance on the BioCreative VI PPI dataset. The paper also shows that multiple computational layers over an external memory are superior to long short-term memory networks with the local memories.Database URL: http://www.biocreative.org/tasks/biocreative-vi/track-4/. PMID- 30010733 TI - Predictive value of diffusion-weighted MR imaging in early response to chemoradiotherapy of esophageal cancer: a meta-analysis. AB - The results of diffusion-weighted MR imaging (DW-MRI) in predicting early response to chemoradiotherapy in patients with esophageal cancer varied in different studies. We performed this meta-analysis to evaluate the predictive values of DW-MRI and compare the diagnostic efficacy of different apparent diffusion coefficients (ADCs). A comprehensive literature search was performed to identify relevant articles published before November 2017. The quality of study was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under receiver operating characteristic curve of ADC values were calculated to determine the diagnostic performance. Seven studies with a total of 236 patients were included. The pooled sensitivity, specificity, DOR, and area under curve were 93% (95% CI 77%-98%), 85% (95% CI 72%-93%), 78 (95% CI 15-401), and 0.91 (95% CI 0.89-0.94), respectively, for the ?ADC; and 75% (95% CI 62%-84%), 90% (95% CI 67%-97%), 26 (95% CI 6-110), and 0.85 (95% CI 0.82-0.88), respectively, for the post-ADC. For pre-ADC, meta-analysis was not performed because of conflicting results. In conclusions, our results demonstrate that DW-MRI has good performance for evaluating the response to chemoradiation therapy in patients with esophageal cancer. ?ADC and post-ADC are promising reliable and valuable predictors. PMID- 30010734 TI - Faecal Microbiota Transplantation Reduces Susceptibility to Epithelial Injury and Modulates Tryptophan Metabolism of the Microbial Community in a Piglet Model. AB - Background and Aims: Faecal microbiota transplantation [FMT] has shown promise as a treatment for inflammatory bowel disease [IBD]. Using a piglet model, our previous study indicated that exogenous faecal microbiota can increase the expressions of tight junction proteins, mucin and antimicrobial peptide in the intestinal mucosa, suggesting a beneficial effect of FMT on gut barrier and gastrointestinal health. However, specific connections between FMT-induced microbial changes and modulation of the intestinal barrier remain to be fully illustrated. Here, we aimed to determine the potential role of metabolic function of gut microbiota in the beneficial effects of FMT. Methods: The influence of FMT on the maintenance of intestinal homeostasis was assessed by early-life gut microbiota intervention on newborn piglets and subsequent lipopolysaccharide [LPS] challenge. Analysis of the gut microbiome and metabolome was carried out by 16S rRNA gene sequencing and multiple mass spectrometry platforms. Results: FMT modulated the diversity and composition of colonic microbiota and reduced the susceptibility to LPS-induced destruction of epithelial integrity and severe inflammatory response. Metabolomic analysis revealed functional changes of the gut metabolome along with a significant increase of the typical microbiota derived tryptophan catabolite indole-3-acetic acid in the colonic lumen. In concordance with the metabolome data, metagenomics prediction analysis based on 16S rRNA gene sequencing also demonstrated that FMT modulated the metabolic functions of gut microbiota associated with indole alkaloid biosynthesis, cytochrome P450 and intestinal homeostasis, which coincided with up-regulation of cytokine interleukin-22 and enhanced activation of aryl hydrocarbon receptor in the recipient colon. Conclusions: Our data reveal a regulatory effect of FMT on tryptophan metabolism of gut microbiota in the recipient colon, which may play a potential role in maintenance of the intestinal barrier. PMID- 30010735 TI - Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance. AB - Elite athletic competitions have separate male and female events due to men's physical advantages in strength, speed, and endurance so that a protected female category with objective entry criteria is required. Prior to puberty, there is no sex difference in circulating testosterone concentrations or athletic performance, but from puberty onward a clear sex difference in athletic performance emerges as circulating testosterone concentrations rise in men because testes produce 30 times more testosterone than before puberty with circulating testosterone exceeding 15-fold that of women at any age. There is a wide sex difference in circulating testosterone concentrations and a reproducible dose-response relationship between circulating testosterone and muscle mass and strength as well as circulating hemoglobin in both men and women. These dichotomies largely account for the sex differences in muscle mass and strength and circulating hemoglobin levels that result in at least an 8% to 12% ergogenic advantage in men. Suppression of elevated circulating testosterone of hyperandrogenic athletes results in negative effects on performance, which are reversed when suppression ceases. Based on the nonoverlapping, bimodal distribution of circulating testosterone concentration (measured by liquid chromatography-mass spectrometry)-and making an allowance for women with mild hyperandrogenism, notably women with polycystic ovary syndrome (who are overrepresented in elite athletics)-the appropriate eligibility criterion for female athletic events should be a circulating testosterone of <5.0 nmol/L. This would include all women other than those with untreated hyperandrogenic disorders of sexual development and noncompliant male-to-female transgender as well as testosterone-treated female-to-male transgender or androgen dopers. PMID- 30010736 TI - Placebo Effect on the Health-related Quality of Life of Inflammatory Bowel Disease Patients: A Systematic Review With Meta-analysis. AB - Background and Aims: Placebo effect in health-related quality of life [HRQoL] of inflammatory bowel disease [IBD] patients has been poorly characterised. This systematic review and meta-analysis aimed to assess: i] mean improvements in IBDQ [Inflammatory Bowel Disease Questionnaire] and SF-36 [36-Item Short Form Health Survey] scores among placebo-treated IBD patients; and ii] the proportion of placebo-treated patients achieving IBDQ-defined response and remission and correspondent odds ratios [OR]. Methods: Literature search was performed using four databases. Mean differences and ORs were computed using the random-effects model. Univariate and multivariate regressions were performed to evaluate the weight of different factors on the placebo effect. Results: From the 328 identified records 26 were included in the study, comprising 2842 placebo-treated IBD patients. Pooled mean differences on IBDQ following placebo administration were above the clinically meaningful improvement [>=16 points] in ulcerative colitis [UC] patients during the induction regimen (17.67; 95% confidence interval [CI]: 12.90, 22.44) and during maintenance in both Crohn's disease [CD] [27.60; 95% CI: 14.29, 40.91] and UC patients [27.50; 95% CI: 18.73, 36.27]. The treatment regimen was the only significant variable in multivariate analysis, with lower placebo-related IBDQ improvements during induction. Maintenance trials' inclusion criteria were also relevant. The proportions of placebo-treated patients achieving IBDQ-defined response and remission were 0.42 [95% CI: 0.49, 0.56] and 0.31 [95% CI: 0.28, 0.34], respectively, with 0.49 and 0.40 the ORs for response and remission. Significant improvements were also observed on SF-36 score. Conclusions: Herein we prove that placebo effect on HRQoL is meaningful, providing insights about implications for clinical trials' design and interpretation and for IBD management. PMID- 30010737 TI - A set of domain rules and a deep network for protein coreference resolution. AB - Current research of bio-text mining mainly focuses on event extractions. Biological networks present much richer and meaningful information to biologists than events. Bio-entity coreference resolution (CR) is a very important method to complete a bio-event's attributes and interconnect events into bio-networks. Though general CR methods have been studies for a long time, they could not produce a practically useful result when applied to a special domain. Therefore, bio-entity CR needs attention to better assist biological network extraction. In this article, we present two methods for bio-entity CR. The first is a rule-based method, which creates a set of syntactic rules or semantic constraints for CR. It obtains a state-of-the-art performance (an F1-score of 62.0%) on the community supported dataset. We also present a machine learning-based method, which takes use of a recurrent neural network model, a long-short term memory network. It automatically learns global discriminative representations of all kinds of coreferences without hand-crafted features. The model outperforms the previously best machine leaning-based method. PMID- 30010739 TI - Failure of MMP-9 antagonists in IBD: demonstrating the importance of molecular biology and well-controlled preclinical studies. PMID- 30010740 TI - The electrocardiogram and the phenotypic expression of hypertrophic cardiomyopathy. PMID- 30010738 TI - HRPDviewer: human ribosome profiling data viewer. AB - Translational regulation plays an important role in protein synthesis. Dysregulation of translation causes abnormal cell physiology and leads to diseases such as inflammatory disorders and cancers. An emerging technique, called ribosome profiling (ribo-seq), was developed to capture a snapshot of translation. It is based on deep sequencing of ribosome-protected mRNA fragments. A lot of ribo-seq data have been generated in various studies, so databases are needed for depositing and visualizing the published ribo-seq data. Nowadays, GWIPS-viz, RPFdb and TranslatomeDB are the three largest databases developed for this purpose. However, two challenges remain to be addressed. First, GWIPS-viz and RPFdb databases align the published ribo-seq data to the genome. Since ribo seq data aim to reveal the actively translated mRNA transcripts, there are advantages of aligning ribo-req data to the transcriptome over the genome. Second, TranslatomeDB does not provide any visualization and the other two databases only provide visualization of the ribo-seq data around a specific genomic location, while simultaneous visualization of the ribo-seq data on multiple mRNA transcripts produced from the same gene or different genes is desired. To address these two challenges, we developed the Human Ribosome Profiling Data viewer (HRPDviewer). HRPDviewer (i) contains 610 published human ribo-seq datasets from Gene Expression Omnibus, (ii) aligns the ribo-seq data to the transcriptome and (iii) provides visualization of the ribo-seq data on the selected mRNA transcripts. Using HRPDviewer, researchers can compare the ribosome binding patterns of multiple mRNA transcripts from the same gene or different genes to gain an accurate understanding of protein synthesis in human cells. We believe that HRPDviewer is a useful resource for researchers to study translational regulation in human.Database URL: http://cosbi4.ee.ncku.edu.tw/HRPDviewer/ or http://cosbi5.ee.ncku.edu.tw/HRPDviewer/. PMID- 30010741 TI - Microbial Communities in the Rhizosphere and the Root of Lettuce as Affected by Salmonella-Contaminated Irrigation Water. AB - Reclaimed wastewater is increasingly used as a source of irrigation water in croplands. The enteric pathogens in reclaimed wastewater may accumulate in soil and plants and cause food safety concerns. The objective of this study was to determine the effects of irrigation water containing Salmonella on the microbial communities in the rhizosphere and in the root of lettuce. The effects were also examined with three variables (soil texture, lettuce cultivar, and harvest time) in a factorial design. Analyses on the 16S rRNA gene sequences show that the microbial communities in the root were significantly different from those in the rhizosphere, although ~80% of the microbes in the root originated from the rhizosphere. Salmonella in irrigation water significantly altered the structure of the microbial community in the rhizosphere, but not in the root. Salmonella internalized in lettuce root was observed when contaminated water was used for irrigation. Compared to lettuce cultivar and harvest time, soil texture played a more significant role in shaping the bacterial communities in rhizosphere and root. Results from the study could advance the understanding about the long-term impacts of reclaimed wastewater as a source of irrigation water on the microbiota associated with leafy green vegetables. PMID- 30010742 TI - A long way to go: 20-year trends from multiple surveillance systems show a still huge use of tobacco in minors in Italy. AB - Background: Main aim was to describe youth smoking prevalence in Italy over the last two decades, and to provide recent trends in knowledge, attitudes towards smoking, awareness of anti-tobacco mass media campaigns, second-hand smoke (SHS) exposure and access to cigarettes. Methods: Figures from three surveillance systems, with 12 representative cross-sectional surveys (about 43 000 participants): European School Survey Project on Alcohol and Other Drugs, 15-16 year-old students, 1995-2015; Health Behaviour in School-aged Children, 11-, 13-, 15-year-old students, 2002-14 and Global Youth Tobacco Survey, 13-15-year-old students, 2010, 2014. Results: Among 11- and 13-year-old students, daily and non daily smokers decreased by 30-50% from 2002 to 2014. Among 15-16-year-old adolescents, ever smokers significantly decreased by 10% in the period 1995-2015, whereas current and daily smokers have been stalling or even increased. Appeal of smoking increased in 2014 compared to 2010, perception of SHS as harmful, and awareness of recent anti-tobacco mass media campaigns decreased. Moreover, a significant 30% reduction in reporting retailers did not refuse to sell cigarettes to adolescents and a decrease in reporting to buy cigarettes were reported. Conclusions: Policies enforced in Italy over the last 20 years slightly reduced ever smokers, but did not decrease current and daily smokers in 15-16 year-old adolescents, and determined an impact among younger adolescents. Stricter rules on youth tobacco access reduced ease of access to cigarettes, but did not affect adolescents' tobacco use. Stronger tobacco control measures are urgently needed in order to determine a steeper decline in smoking prevalence in adolescents. PMID- 30010743 TI - Active bacterioplankton community response to dissolved 'free' deoxyribonucleic acid (dDNA) in surface coastal marine waters. AB - Seawater contains dissolved 'free' DNA (dDNA) that is part of a larger <0.2 um pool of DNA (D-DNA) including viruses and uncharacterised bound DNA. Previous studies have shown that bacterioplankton readily degrade dDNA, and culture-based approaches have identified several potential dDNA-utilising taxa. This study characterised the seasonal variation in D-DNA concentrations at Station L4, a coastal marine observatory in the Western English Channel, and linked changes in concentration to cognate physicochemical and biological factors. The impact of dDNA addition on active bacterioplankton communities at Station L4 was then determined using 16S rRNA high-throughput sequencing and RNA Stable Isotope Probing (RNA SIP) with 13C-labelled diatom-derived dDNA. Compared to other major bacterioplankton orders, the Rhodobacterales actively responded to dDNA additions in amended microcosms and RNA SIP identified two Rhodobacterales populations most closely associated with the genera Halocynthiibacter and Sulfitobacter that assimilated the 13C-labelled dDNA. Here we demonstrate that dDNA is a source of dissolved organic carbon for some members of the major bacterioplankton group the Marine Roseobacter Clade. This study enhances our understanding of roles of specific bacterioplankton taxa in dissolved organic matter cycling in coastal waters with potential implications for nitrogen and phosphorus regeneration processes. PMID- 30010744 TI - Infectious and dermatological diseases among arriving migrants on the Italian coasts. AB - Background: Since 2008 Italy has been the destination of the 'central Mediterranean route', used by migrants to reach Europe. The aim of this study is to describe demographic characteristics and health problems of migrants at the time of arrival on the Italian coasts, focussing on dermatological and infectious diseases. Methods: Cross-sectional study of data routinely collected (n = 6, 188) by the National Institute for Health Migration and Poverty (INMP) in the centres for migrants of Lampedusa and Trapani-Milo (2015-16). Logistic models were performed to identify factors associated with scabies, varicella and the occurrence of two or more not related diagnosis. Results: The average age was 21.6 years; 83.5% of the patients were males. The most frequent countries of origin were Eritrea, Nigeria, and Somalia. The most frequent diagnosis was scabies (58% of patients), skin infections, pediculosis and dermatitis; respiratory infections and varicella were the most represented infectious diseases. The diagnosis of scabies was more probable among Somalis (OR: 11.60) and Eritreans (OR: 10.05); the diagnosis of varicella was more probable among Ghanaians (OR: 13.58) and Nigerians (OR: 9.79). Somalis (OR: 4.10) and Eritreans (OR: 3.32) were the patients more likely to receive two or more diagnosis. Conclusions: The majority of the diseases affecting migrants is in most cases, related to the migration experience and is likely not to represent a major threat for public health. Up-to-date information regarding the burden of diseases is needed in order to identify the health needs of incoming migrants and to arrange the appropriate response in terms of health services provision. PMID- 30010745 TI - Adolescents consulting general practitioners for psychological problems-a nationwide, register-based study in Norway. AB - Background: Psychological problems are increasing among adolescents, but little is known about the role of GPs in this area. Objectives: This study aims to investigate the frequency of GP consultations with a psychological diagnosis in adolescence and predictors for such help seeking. Methods: Nationwide longitudinal register-based study investigating GP consultations among adolescents aged 13-17 years (N = 123 516) in Norway. First, all GP consultations within the study population were identified from the national GP claims register for 2006-11. Second, adolescents with a first-time consultation with a psychological diagnosis at age 15-16 years were identified, and prior GP consultations, prior somatic diagnoses, parental education and GP and GP-practice characteristics were assessed as possible predictors for seeking help. Results: From age 13 to 17 years, 15.3% of girls and 13.0% of boys had >=1 GP consultation with a psychological diagnosis. In total, 6.8% of girls and 4.8% of boys consulted a GP for the first time with a psychological problem at age 15-16 years. For both sexes, number of prior GP consultations and a prior diagnosis of headache and abdominal pain predicted consulting with an internalizing problem (depression, anxiety and stress). A prior headache diagnosis predicted consulting for behavioural problems. Psychological diagnoses were more often found among adolescents with lower parental education. There were only minor associations with GP characteristics. Conclusions: Norwegian adolescents often consult a GP and one in seven had a GP-diagnosed psychological problem at age 13-17. Policies to improve mental health care for adolescents should include strengthening of GP services. PMID- 30010746 TI - Patients on levothyroxine replacement in the community: association between hypothyroidism symptoms, co-morbidities and their quality of life. AB - Introduction: Patients may be symptomatic, resulting in lower quality of life (QOL), despite L-thyroxine (LT4) therapy for hypothyroidism or having normal thyroid function. We hypothesized that their clinical symptoms of hypothyroidism and co-morbidities were associated with QOL. Objective: The study aimed to determine the association between the hypothyroid-related symptoms of Asian patients on LT4 treatment, their co-morbidities and their QOL. Method: A questionnaire survey was conducted from November 2015 to July 2016 on consecutive multi-ethnic Asian patients on LT4 treatment for their hypothyroidism in a public primary care clinic in Singapore. Data on their demography, clinical symptoms, morbidity status, QOL scores based on the EQ5D instrument and thyroid function tests were computed and analysed, including logistic regression analysis to identify factors associated with lower QOL. Results: Complete data of 226 Asian patients (79.0% women; 74.2% Chinese, 10.0% Malay, 13.1% Indian and 2.6% other minority groups; median age 57 years; 27.5% had previous thyroid surgery) were analysed. Their QOL was not associated with their socio-demographic profiles, clinical parameters and latest thyroid-stimulating hormone and free thyroxine levels. Patients reporting weight gain, dry or coarse skin, leg swelling, feeling weak and carpal tunnel syndrome had significantly lower QOL; 53.6% of them with any single symptom had lower QOL. More patients had lower QOL if they had two or more symptoms and multiple medical conditions. Conclusion: In Asian patients with hypothyroidism, weight gain, feeling tired, feeling weak, having dry or coarse skin, leg swelling and increased number of co-morbidities and symptoms were significantly associated with poorer QOL. PMID- 30010747 TI - Gut microbial and metabolomic profiles after fecal microbiota transplantation in pediatric ulcerative colitis patients. AB - Ulcerative colitis is a chronic inflammatory disease of the colon that carries a significant disease burden in children. Therefore, new therapeutic approaches are being explored to help children living with this disease. Fecal microbiota transplantation (FMT) has been successful in some children with ulcerative colitis. However, the mechanism of its therapeutic effect in this patient population is not well understood. To characterize changes in gut microbial and metabolomic profiles after FMT, we performed 16S rRNA gene sequencing, shotgun metagenomic sequencing, virome analysis and untargeted metabolomics by gas chromatography-time of flight-mass spectrometry on stool samples collected before and after FMT from four children with ulcerative colitis who responded to this treatment. Alpha diversity of the gut microbiota increased after intervention, with species richness rising from 251 (S.D. 125) to 358 (S.D. 27). In responders, the mean relative abundance of bacteria in the class Clostridia shifted toward donor levels, increasing from 33% (S.D. 11%) to 54% (S.D. 16%). Patient metabolomic and viromic profiles exhibited a similar but less pronounced shift toward donor profiles after FMT. The fecal concentrations of several metabolites were altered after FMT, correlating with clinical improvement. Larger studies using a similar multi-omics approach may suggest novel strategies for the treatment of pediatric ulcerative colitis. PMID- 30010748 TI - Transfemoral vascular access in electrophysiology: should we exclusively rely on ultrasound guidance? PMID- 30010749 TI - Improving the learning of chemical-protein interactions from literature using transfer learning and specialized word embeddings. AB - In this paper, we explore the application of artificial neural network ('deep learning') methods to the problem of detecting chemical-protein interactions in PubMed abstracts. We present here a system using multiple Long Short Term Memory layers to analyse candidate interactions, to determine whether there is a relation and which type. A particular feature of our system is the use of unlabelled data, both to pre-train word embeddings and also pre-train LSTM layers in the neural network. On the BioCreative VI CHEMPROT test corpus, our system achieves an F score of 61.51% (56.10% precision, 67.84% recall). PMID- 30010750 TI - A Field Sensor: computing the composition and intent of PubMed queries. AB - PubMed(r) is a search engine providing access to a collection of over 27 million biomedical bibliographic records as of 2017. PubMed processes millions of queries a day, and understanding these queries is one of the main building blocks for successful information retrieval. In this work, we present Field Sensor, a domain specific tool for understanding the composition and predicting the user intent of PubMed queries. Given a query, the Field Sensor infers a field for each token or sequence of tokens in a query in multi-step process that includes syntactic chunking, rule-based tagging and probabilistic field prediction. In this work, the fields of interest are those associated with (meta-)data elements of each PubMed record such as article title, abstract, author name(s), journal title, volume, issue, page and date. We evaluate the accuracy of our algorithm on a human-annotated corpus of 10 000 PubMed queries, as well as a new machine annotated set of 103 000 PubMed queries. The Field Sensor achieves an accuracy of 93 and 91% on the two corresponding corpora and finds that nearly half of all searches are navigational (e.g. author searches, article title searches etc.) and half are informational (e.g. topical searches). The Field Sensor has been integrated into PubMed since June 2017 to detect informational queries for which results sorted by relevance can be suggested as an alternative to those sorted by the default date sort. In addition, the composition of PubMed queries as computed by the Field Sensor proves to be essential for understanding how users query PubMed. PMID- 30010751 TI - Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study. AB - Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies. Patients and methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review. Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade >=3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%). Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated. ClinicalTrials.gov number: NCT02149108 (LUME-Colon 1). PMID- 30010753 TI - Uncontrolled Hypertension Is Common in Glaucoma Clinics. AB - BACKGROUND: To determine the magnitude of uncontrolled hypertension and smoking among patients visiting an eye clinic, and ascertain if referral to care providers is effective. METHODS: Information on smoking status and blood pressure (BP) was collected among patients >=18 years visiting an eye clinic. Those with high BP (systolic: >=140 mm Hg and/or diastolic: >=90 mm Hg) received a pamphlet on harms of hypertension on vision and were referred to a primary care physician. Smokers received a pamphlet on negative effects of smoking on vision and were offered referral to a tobacco quitline. Patients were followed up for referral outcome within 10 weeks from screening. RESULTS: Screening: A total of participants screened included 140 (29.5%) with high BP and 31 (6.6%) current smokers. In the high BP group, 92 (66%) subjects were previously diagnosed with hypertension. Follow-up: Of the 140 participants with elevated BP, 84 (60%) responded to follow-up. Among these 84 participants, 57 (67.9%) had consulted primary care, of whom 5 (8.8%) reported being newly diagnosed with hypertension, and 11 (19.3%) reported a change in their antihypertensive prescription. Among the 31 smokers, 24 (77.4%) were willing for quitline referral. Sixteen (66.7%) of these patients responded to follow-up, 8 (50%) of whom reported participation in a smoking-cessation program with 1 patient (6.3%) successfully quitting smoking. CONCLUSIONS: Nearly one-third of patients attending an eye clinic had elevated BP, and a smaller, but substantial, number of patients were current smokers. Eye clinics may serve as point for identification and referral of these patients with unmet needs. PMID- 30010752 TI - Inter and Intraspecific Genomic Divergence in Drosophila montana Shows Evidence for Cold Adaptation. AB - The genomes of species that are ecological specialists will likely contain signatures of genomic adaptation to their niche. However, distinguishing genes related to ecological specialism from other sources of selection and more random changes is a challenge. Here, we describe the genome of Drosophila montana, which is the most extremely cold-adapted Drosophila species known. We use branch tests to identify genes showing accelerated divergence in contrasts between cold- and warm-adapted species and identify about 250 genes that show differences, possibly driven by a lower synonymous substitution rate in cold-adapted species. We also look for evidence of accelerated divergence between D. montana and D. virilis, a previously sequenced relative, but do not find strong evidence for divergent selection on coding sequence variation. Divergent genes are involved in a variety of functions, including cuticular and olfactory processes. Finally, we also resequenced three populations of D. montana from across its ecological and geographic range. Outlier loci were more likely to be found on the X chromosome and there was a greater than expected overlap between population outliers and those genes implicated in cold adaptation between Drosophila species, implying some continuity of selective process at these different evolutionary scales. PMID- 30010755 TI - Evaluation of Antibiotic-Impregnated Mesh in Preventing the Recurrence of Capsular Contracture. AB - Background: Capsular contracture (CC) is the most frequently reported complication following breast augmentation. A growing body of evidence implicates subclinical (biofilm) infection around breast implants as an important cause of CC, however effective prophylactic and treatment modalities remain controversial. Objectives: This article aims to review a single surgeon's experience using an antibiotic-impregnated mesh as a prophylactic measure against biofilm formation and recurrent CC. Methods: This study retrospectively reviewed 5 consecutive patients presenting with CC (Baker grades III and IV) who were managed by capsulectomy with implant replacement and simultaneous insertion of an antibiotic impregnated mesh. Patient demographics and major complications were recorded, including capsular contracture recurrence, reoperation, and infection. Results: Complete correction of the contracture with no recurrence was achieved in all patients at a median follow up of 25 months. Conclusions: This study demonstrates a novel technique using an antibiotic mesh to reduce bacterial access to breast implants at the time of insertion. Further investigation is warranted with more clinical cases in order to recommend this technique for the management of subclinical infection and CC. PMID- 30010754 TI - Chromosome-level reference genome of the Siamese fighting fish Betta splendens, a model species for the study of aggression. AB - Background: Siamese fighting fish Betta splendens are notorious for their aggressiveness and accordingly have been widely used to study aggression. However, the lack of a reference genome has, to date, limited the understanding of the genetic basis of aggression in this species. Here, we present the first reference genome assembly of the Siamese fighting fish. Findings: Frist, we sequenced and de novo assembled a 465.24-Mb genome for the B. splendens variety Giant, with a weighted average (N50) scaffold size of 949.03 Kb and an N50 contig size of 19.01 Kb, covering 99.93% of the estimated genome size. To obtain a chromosome-level genome assembly, we constructed one Hi-C library and sequenced 75.24 Gb reads using the BGISEQ-500 platform. We anchored approximately 93% of the scaffold sequences into 21 chromosomes and evaluated the quality of our assembly using the high-contact frequency heat map and Benchmarking Universal Single-Copy Orthologs. We also performed comparative chromosome analyses between Oryzias latipes and B. splendens, revealing a chromosome conservation evolution in B. splendens. We predicted 23,981 genes assisted by RNA-sequencing data generated from brain, liver, muscle, and heart tissues of Giant and annotated 15% repetitive sequences in the genome. Additionally, we resequenced five other B. splendens varieties and detected ~3.4 M single-nucleotide variations and 27,305 insertions and deletions. Conclusions: We provide the first chromosome-level genome for the Siamese fighting fish. The genome will lay a valuable foundation for future research on aggression in B. splendens. PMID- 30010757 TI - "Me Too" Isn't Just About Somebody Else. PMID- 30010759 TI - The legacy of Thomas Tursz: building a leading comprehensive cancer center in Europe. PMID- 30010756 TI - Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial. AB - Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64. PMID- 30010758 TI - Whole genome and transcriptome maps of the entirely black native Korean chicken breed Yeonsan Ogye. AB - Background: Yeonsan Ogye (YO), an indigenous Korean chicken breed (Gallus gallus domesticus), has entirely black external features and internal organs. In this study, the draft genome of YO was assembled using a hybrid de novo assembly method that takes advantage of high-depth Illumina short reads (376.6X) and low depth Pacific Biosciences (PacBio) long reads (9.7X). Findings: The contig and scaffold NG50s of the hybrid de novo assembly were 362.3 Kbp and 16.8 Mbp, respectively. The completeness (97.6%) of the draft genome (Ogye_1.1) was evaluated with single-copy orthologous genes using Benchmarking Universal Single Copy Orthologs and found to be comparable to the current chicken reference genome (galGal5; 97.4%; contigs were assembled with high-depth PacBio long reads (50X) and scaffolded with short reads) and superior to other avian genomes (92%-93%; assembled with short read-only or hybrid methods). Compared to galGal4 and galGal5, the draft genome included 551 structural variations including the fibromelanosis (FM) locus duplication, related to hyperpigmentation. To comprehensively reconstruct transcriptome maps, RNA sequencing and reduced representation bisulfite sequencing data were analyzed from 20 tissues, including 4 black tissues (skin, shank, comb, and fascia). The maps included 15,766 protein coding and 6,900 long noncoding RNA genes, many of which were tissue-specifically expressed and displayed tissue-specific DNA methylation patterns in the promoter regions. Conclusions: We expect that the resulting genome sequence and transcriptome maps will be valuable resources for studying domestic chicken breeds, including black-skinned chickens, as well as for understanding genomic differences between breeds and the evolution of hyperpigmented chickens and functional elements related to hyperpigmentation. PMID- 30010760 TI - Training and validation of a novel 4-miRNA ratio model (MiCaP) for prediction of postoperative outcome in prostate cancer patients. AB - Background: New molecular biomarkers for prostate cancer (PC) prognosis are urgently needed. Ratio-based models are attractive, as they require no additional normalization. Here, we train and independently validate a novel 4-miRNA prognostic ratio model for PC. Patients and methods: By genome-wide miRNA expression profiling of PC tissue samples from 123 men who underwent radical prostatectomy (RP) (PCA123, training cohort), we identified six top candidate prognostic miRNAs and systematically tested their ability to predict postoperative biochemical recurrence (BCR). The best miRNA-based prognostic ratio model (MiCaP) was validated in two independent cohorts (PCA352 and PCA476) including >800 RP patients in total. Clinical end points were BCR and prostate cancer-specific survival (CSS). The prognostic potential of MiCaP was assessed by univariate and multivariate Cox-regression analyses and Kaplan-Meier analyses. Results: We identified a 4-miRNA ratio model, MiCaP (miR-23a-3p*miR-10b-5p)/(miR 133a*miR-374b-5p), that predicted time to BCR independently of routine clinicopathologic variables in the training cohort (PCA123) and was successfully validated in two independent RP cohorts. In addition, MiCaP was a significant predictor of CSS in univariate analysis [HR 3.35 (95% CI 1.34 - 8.35), P = 0.0096] and in multivariate analysis [HR 2.43 (95% CI 1.45-4.07), P = 0.0210]. As proof-of-principle, we also analyzed MiCaP in plasma samples from 111 RP patients. A high MiCaP score in plasma was significantly associated with BCR (P = 0.0036, Kaplan-Meier analysis). Limitations include low mortality rates (CSS: 5.4%). Conclusions: We identified a novel 4-miRNA ratio model (MiCaP) with significant independent prognostic value in three RP cohorts, indicating promising potential to improve PC risk stratification. PMID- 30010761 TI - Biomonitoring of Benzene and Effect of Wearing Respirators during an Oil Spill Field Trial at Sea. AB - Objectives: The main aim of this study was to assess the biological uptake of benzene and polycyclic aromatic hydrocarbons (PAHs) for subjects exposed to fresh crude oil released at sea. Methods: The study included 22 subjects participating in an 'oil-on-water' field trial in the North Sea. Over 2 consecutive days, there were six releases with two different types of fresh crude oils. Exposed subjects (n = 17) were either located in small, open-air boats downwind and close to the released oil (<50 m) or on the main deck of two large vessels further from the released oil (100-200 m). Subjects assumed to be unexposed (n = 5) were located indoors on the command bridge of either vessel. Full-shift personal benzene exposure was monitored with passive thermal desorption tubes (ATD-tubes) packed with Tenax TA and subsequent gas chromatographic analysis. Urine samples were collected before and after work-shift on both days and analyzed for urinary markers of benzene [(S-phenylmercapturic acid (SPMA)] and PAHs [1-hydroxypyrene (1-OH)]. Information about the use of personal protective equipment, smoking habits, location, work tasks, and length of work-shift were recorded by a questionnaire. Results: Subjects located in the small boats downwind and close to the released oil were exposed to relatively high concentrations of benzene (arithmetic mean = 0.2 ppm, range 0.002-1.5 ppm) compared to the occupational exposure limits (OELs) for 8 h (1 ppm) and 12 h (0.6 ppm). Although respirators were available to all exposed subjects, SPMA was detected in post-shift urine (0.5-3.3 umol mol-1) of five exposed subjects reporting not wearing respirators, all located in the small boats downwind and close to the released oil. For exposed subjects wearing respirators (n = 12), the post-shift urinary SPMA was below the detection limit (0.8 umol mol-1) even when the benzene exposure exceeded the OELs. Urinary levels of PAH were within the reference range of what is considered as background levels (<0.4 umol mol-1). Conclusions: During the initial stages of a bulk oil spill at sea, when the evaporation of benzene is at its highest, it is important to use appropriate respirators to prevent biological uptake of benzene. PMID- 30010764 TI - Racial Residential Segregation and Hypertensive Disorder of Pregnancy Among Women in Chicago: Analysis of Electronic Health Record Data. AB - BACKGROUND: Racial residential segregation is associated with higher rates of chronic hypertension, as well as greater risk of preterm birth and low birthweight. However, few studies have examined associations between segregation and hypertensive disorder of pregnancy (HDP). METHODS: Electronic health records from 4,748 singleton births among non-Hispanic black women at Prentice Women's Hospital in Chicago, IL (2009-2013) were geocoded to the census tract level. Residential segregation was measured using the Gi* statistic, a z-score measuring the extent to which each individual's neighborhood composition deviates from the composition of the larger surrounding area. Segregation was categorized as low (z < 0), medium (z = 0-1.96) or high (z > 1.96). We estimated cross-sectional associations of segregation with HDP using multilevel logistic regression models with census tract random intercepts. Models adjusted for neighborhood poverty and maternal characteristics. We also examined effect modification by neighborhood poverty. RESULTS: Overall, 27.2% of women lived in high segregation, high-poverty neighborhoods. Racial residential segregation was not associated as a main effect with HDP in models adjusting for neighborhood poverty and maternal characteristics. However, at higher levels of neighborhood poverty (>20%), women living in high- and medium-segregated neighborhoods had greater odds of HDP relative to those in low-segregation neighborhoods (P interaction: 0.002). CONCLUSIONS: In this sample of non-Hispanic black women in Chicago, racial residential segregation was associated with greater prevalence of HDP among those living in higher poverty neighborhoods. Understanding sources of heterogeneity in the relationship between segregation and health will help refine targeted intervention efforts to reduce disparities. PMID- 30010765 TI - Combining plasma-based biosources to predict treatment response in NSCLC patients. PMID- 30010763 TI - Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer. AB - Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes. Patients and methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of >=15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with >=20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with >=15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons. PMID- 30010762 TI - A similarity-based approach to leverage multi-cohort medical data on the diagnosis and prognosis of Alzheimer's disease. AB - Motivation: Heterogeneous diseases such as Alzheimer's disease (AD) manifest a variety of phenotypes among populations. Early diagnosis and effective treatment offer cost benefits. Many studies on biochemical and imaging markers have shown potential promise in improving diagnosis, yet establishing quantitative diagnostic criteria for ancillary tests remains challenging. Results: We have developed a similarity-based approach that matches individuals to subjects with similar conditions. We modeled the disease with a Gaussian process, and tested the method in the Alzheimer's Disease Big Data DREAM Challenge. Ranked the highest among submitted methods, our diagnostic model predicted cognitive impairment scores in an independent dataset test with a correlation score of 0.573. It differentiated AD patients from control subjects with an area under the receiver operating curve of 0.920. Without knowing longitudinal information about subjects, the model predicted patients who are vulnerable to conversion from mild cognitive impairment to AD through the similarity network. This diagnostic framework can be applied to other diseases with clinical heterogeneity, such as Parkinson's disease. PMID- 30010766 TI - Clustering trees: a visualization for evaluating clusterings at multiple resolutions. AB - Clustering techniques are widely used in the analysis of large datasets to group together samples with similar properties. For example, clustering is often used in the field of single-cell RNA-sequencing in order to identify different cell types present in a tissue sample. There are many algorithms for performing clustering, and the results can vary substantially. In particular, the number of groups present in a dataset is often unknown, and the number of clusters identified by an algorithm can change based on the parameters used. To explore and examine the impact of varying clustering resolution, we present clustering trees. This visualization shows the relationships between clusters at multiple resolutions, allowing researchers to see how samples move as the number of clusters increases. In addition, meta-information can be overlaid on the tree to inform the choice of resolution and guide in identification of clusters. We illustrate the features of clustering trees using a series of simulations as well as two real examples, the classical iris dataset and a complex single-cell RNA sequencing dataset. Clustering trees can be produced using the clustree R package, available from CRAN and developed on GitHub. PMID- 30010767 TI - Gummy Smile Treatment: Proposal for a Novel Corrective Technique and a Review of the Literature. AB - Background: A perfect smile is dictated by the balance among 3 parameters: the white (teeth), the pink (gum), and the lips: excessive gingival display while smiling has been a cause of esthetic embarrassment for many patients, thus affecting their psychosocial behavior. With respect to different etiologies, treatment of gummy smile must be properly planned: treatment options include facial surgery, oral surgery, or laser. Objectives: Given the growing demand for less invasive techniques and observed complications secondary to botulinum toxin injection, we present a novel treatment option aimed at correcting gummy smile using hyaluronic acid injection and review the published techniques and the anatomy of the involved facial muscles. Methods: The treatment was performed by infiltration in the paranasal area, in the location of the most cranial portion of the nasojugal fold, about 3 mm lateral to the alar cartilage wing, according to a vector perpendicular to the cutaneous plane, to gently compress the lateral fibers of the levator labii superioris alaeque nasi without invading it. A Vycross(r) technology filler was used for all the treatments. Results: All patients had an immediate improvement, with a maximum duration ranging from 186 to 240 days (mean, 213 days), according to parameters of the Global Aesthetic Improvement Scale (GAIS 4.06). Conclusions: This new, less invasive and safer technique to correct dynamic excessive gingival display was shown to be feasible and safe with a long-lasting result. This treatment could be a novel effective option for experienced injectors to treat aesthetic facial flaws. Level of Evidence 4: PMID- 30010769 TI - Calcium signalling regulates the functions of the bZIP protein VIP1 in touch responses in Arabidopsis thaliana. AB - Background and Aims: VIP1 is a bZIP transcription factor in Arabidopsis thaliana. VIP1 and its close homologues transiently accumulate in the nucleus when cells are exposed to hypo-osmotic and/or mechanical stress. Touch-induced root bending is enhanced in transgenic plants overexpressing a repression domain-fused form of VIP1 (VIP1-SRDXox), suggesting that VIP1, possibly with its close homologues, suppresses touch-induced root bending. The aim of this study was to identify regulators of these functions of VIP1 in mechanical stress responses. Methods: Co immunoprecipitation analysis using VIP1-GFP fusion protein expressed in Arabidopsis plants identified calmodulins as VIP1-GFP interactors. In vitro crosslink analysis was performed using a hexahistidine-tagged calmodulin and glutathione S-transferase-fused forms of VIP1 and its close homologues. Plants expressing GFP-fused forms of VIP1 and its close homologues (bZIP59 and bZIP29) were submerged in hypotonic solutions containing divalent cation chelators, EDTA and EGTA, and a potential calmodulin inhibitor, chlorpromazine, to examine their effects on the nuclear-cytoplasmic shuttling of those proteins. VIP1-SRDXox plants were grown on medium containing 40 mm CaCl2, 40 mm MgCl2 or 80 mm NaCl. MCA1 and MCA2 are mechanosensitive calcium channels, and the hypo-osmotic stress dependent nuclear-cytoplasmic shuttling of VIP1-GFP in the mca1 mca2 double knockout mutant background was examined. Key Results: In vitro crosslink products were detected in the presence of CaCl2, but not in its absence. EDTA, EGTA and chlorpromazine all inhibited both the nuclear import and the nuclear export of VIP1-GFP, bZIP59-GFP and bZIP29-GFP. Either 40 mm CaCl2or 80 mm NaCl enhanced the VIP-SRDX-dependent root bending. The nuclear-cytoplasmic shuttling of VIP1 was observed even in the mca1 mca2 mutant. Conclusions: VIP1 and its close homologues can interact with calmodulins. Their nuclear-cytoplasmic shuttling requires neither MCA1 nor MCA2, but does require calcium signalling. Salt stress affects the VIP1-dependent regulation of root bending. PMID- 30010770 TI - Commentary on: Physical Properties of Silicone Gel Breast Implants. PMID- 30010771 TI - The Impact on Mortality and Societal Costs From Smoking Cessation in Aesthetic Plastic Surgery in the United States. AB - Background: It is common practice to require patients to stop smoking prior to elective plastic surgery procedures. Scarce research exists describing the impact on mortality and associated societal cost savings with regards to smoking cessation in aesthetic surgery. Objective: Our objective is to demonstrate that smoking cessation in anticipation for aesthetic surgery significantly reduces mortality reduction and societal cost savings. Methods: We performed a systematic literature review of five common aesthetic procedures (reduction mammaplasty, breast augmentation, facelift, rhinoplasty, and abdominoplasty) to determine patient smoking rates and subsequent recidivism. Sensitivity analyses estimated life years saved using ranges of recidivism from our literature review and assessed total lifetime savings, including direct and productivity costs, while adjusting for inflation (3%) and interest (5%). One life saved was equated to 45 life years saved. Results: Between May 2008 to May 2013, 7,867 patients stopped smoking prior to undergoing aesthetic plastic surgery procedures. Assuming a reported recidivism rate of 68%, smoking cessation prior to aesthetic plastic surgery is associated with 429 lives saved and a total lifetime savings of $524.4 million over the five-year period. Total lives saved ranged from 214 (84% recidivism) to 885 (34% recidivism), and total lifetime cost savings ranged from $262.2 million (84% recidivism) to $1.08 billion (34% recidivism). Conclusions: Presently, smoking cessation before aesthetic surgery significantly saves patient lives with yearly $104.9 million of societal cost savings in the United States. Future reductions in the presently high recidivism rate would lead to additional lives saved and reduced societal costs. PMID- 30010768 TI - SL-quant: a fast and flexible pipeline to quantify spliced leader trans-splicing events from RNA-seq data. AB - Background: The spliceosomal transfer of a short spliced leader (SL) RNA to an independent pre-mRNA molecule is called SL trans-splicing and is widespread in the nematode Caenorhabditis elegans. While RNA-sequencing (RNA-seq) data contain information on such events, properly documented methods to extract them are lacking. Findings: To address this, we developed SL-quant, a fast and flexible pipeline that adapts to paired-end and single-end RNA-seq data and accurately quantifies SL trans-splicing events. It is designed to work downstream of read mapping and uses the reads left unmapped as primary input. Briefly, the SL sequences are identified with high specificity and are trimmed from the input reads, which are then remapped on the reference genome and quantified at the nucleotide position level (SL trans-splice sites) or at the gene level. Conclusions: SL-quant completes within 10 minutes on a basic desktop computer for typical C. elegans RNA-seq datasets and can be applied to other species as well. Validating the method, the SL trans-splice sites identified display the expected consensus sequence, and the results of the gene-level quantification are predictive of the gene position within operons. We also compared SL-quant to a recently published SL-containing read identification strategy that was found to be more sensitive but less specific than SL-quant. Both methods are implemented as a bash script available under the MIT license [1]. Full instructions for its installation, usage, and adaptation to other organisms are provided. PMID- 30010772 TI - Addressing the quality of life needs of older patients with cancer: a SIOG consensus paper and practical guide. AB - Around 60% of people living with cancer are aged 65 years or older. Older cancer patients face a unique set of age-associated changes, comorbidities and circumstances that impact on their quality of life (QoL) in ways that are different from those affecting younger patients. A Task Force of the International Society of Geriatric Oncology recommends and encourages all healthcare professionals involved in cancer care to place greater focus on the QoL of older people living with cancer. This paper summarizes current thinking on the key issues of importance to addressing QoL needs of older cancer patients and makes a series of recommendations, together with practical guidance. PMID- 30010774 TI - Exploring the sound-modulated delay in tomato ripening through expression analysis of coding and non-coding RNAs. AB - Background and Aims: Sound is omnipresent in nature. Recent evidence supports the notion that naturally occurring and artificially generated sound waves induce inter- and intracellular changes in plants. These changes, in turn, lead to diverse physiological changes, such as enhanced biotic and abiotic stress responses, in both crops and model plants. Methods: We previously observed delayed ripening in tomato fruits exposed to 1 kHz sound vibrations for 6 h. Here, we evaluated the molecular mechanism underlying this delaying fruit ripening by performing RNA-sequencing analysis of tomato fruits at 6 h, 2 d, 5 d and 7 d after 1 kHz sound vibration treatment. Key Results : Bioinformatic analysis of differentially expressed genes and non-coding small RNAs revealed that some of these genes are involved in plant hormone and cell wall modification processes. Ethylene and cytokinin biosynthesis and signalling-related genes were downregulated by sound vibration treatment, whereas genes involved in flavonoid, phenylpropanoid and glucan biosynthesis were upregulated. Furthermore, we identified two sound-specific microRNAs and validated the expression of the pre microRNAs and the mRNAs of their target genes. Conclusions: Our results indicate that sound vibration helps to delay fruit ripening through the sophisticated regulation of coding and non-coding RNAs and transcription factor genes. PMID- 30010773 TI - A Randomized Controlled Trial of the Safety and Immunogenicity of Tetanus, Diphtheria, and Acellular Pertussis Vaccine Immunization During Pregnancy and Subsequent Infant Immune Response. AB - Background: Immunization of pregnant women with tetanus-diphtheria-acellular pertussis vaccine (Tdap) provides protection against pertussis to the newborn infant. Methods: In a randomized, controlled, observer-blind, multicenter clinical trial, we measured the safety and immunogenicity of Tdap during pregnancy and the effect on the infant's immune response to primary vaccination at 2, 4, and 6 months and booster vaccination at 12 months of age. A total of 273 women received either Tdap or tetanus-diphtheria (Td) vaccine in the third trimester and provided information for the safety analysis and samples for the immunogenicity analyses; 261 infants provided serum for the immunogenicity analyses. Results: Rates of adverse events were similar in both groups. Infants of Tdap recipients had cord blood levels that were 21% higher than maternal levels for pertussis toxoid (PT), 13% higher for filamentous hemagglutinin (FHA), 4% higher for pertactin (PRN), and 7% higher for fimbriae (FIM). These infants had significantly higher PT antibody levels at birth and at 2 months and significantly higher FHA, PRN, and FIM antibodies at birth and 2 and 4 months, but significantly lower PT and FHA antibody levels at 6 and 7 months and significantly lower PRN and FIM antibody levels at 7 months than infants whose mothers received Td. Differences persisted prebooster at 12 months for all antigens and postbooster 1 month later for PT, FHA, and FIM. Conclusions: This study demonstrated that Tdap during pregnancy results in higher levels of antibodies early in infancy but lower levels after the primary vaccine series. Clinical Trials Registration: NCT00553228. PMID- 30010775 TI - Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18. AB - Background: Bone marrow (BM) involvement defines advanced-stage Hodgkin lymphoma and thus has impact on the assignment to treatment. Our aim was to evaluate whether the established BM biopsy may be omitted in patients if 18F fluorodeoxyglucose positron emission tomography (PET) scanning is carried out during staging. Patients and methods: Our analysis set consisted of 832 Hodgkin lymphoma patients from the German Hodgkin Study Group trials HD16, HD17, and HD18 who underwent both PET scanning and BM biopsy before treatment. All PET studies were centrally reviewed and BM was categorized as showing focal involvement or not. Results: Taking BM biopsy as reference standard, baseline PET showed a negative predictive value of 99.9% [95% confidence interval (CI) 99.2% to 100%] with true-negative results in 702 of 703 cases. The sensitivity of PET for detecting BM involvement was 95.0% (95% CI 75.1% to 99.9%) as it could identify 19 out of 20 patients with positive BM biopsy. Moreover, PET found 110 additional subjects with focal BM lesions who would have been considered negative by biopsy. Conclusions: When compared with BM biopsy, PET was able to detect focal BM lesions in a large number of additional patients. This indicates that conventional BM biopsy may substantially underestimate the actual incidence of BM involvement. Given the high negative predictive value, baseline PET scanning can safely be used to exclude BM involvement in Hodgkin lymphoma. BM biopsy should be considered only in such patients in whom PET-detected lesions lead to a change of treatment protocol. Registered trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD16-NCT00736320, HD17-NCT01356680, and HD18 NCT00515554. PMID- 30010776 TI - Value of ultrasound for access guidance and detection of subclinical vascular complications in the setting of atrial fibrillation cryoballoon ablation. AB - Aims: Vascular complications are the most common complications of atrial fibrillation (AF) ablation. Cryoballoon (CB) ablation for AF needs the insertion of a large 15 Fr sheath in the femoral vein. Our aim was to investigate the impact of vascular ultrasound (US) in guiding access and evaluating post procedural subclinical complications in a large, multi-centre patient cohort that underwent CB ablation. Methods and results: A total cohort of 1435 consecutive patients were subdivided in 870 US -/-, 265 US -/+, and 300 US +/+ patients depending on US performance for: venipuncture guidance/post-procedural evaluation. Major clinical complications (requiring intervention and/or prolonged stay) were assessed. Irrespective of the clinical status, major US events were systematically determined in the subgroups with US evaluation 1 day post procedure, if evidence of inadvertent artery puncture/cannulation (communication between artery and collection or artery-vein, regardless of the thrombosis state). Major clinical events were encountered in 1.7% (15/870), 1.1% (3/265), and 0% of patients in US -/-, US -/+, and US +/+ group, respectively (P = 0.02 between US -/- and US +/+ group). In the US -/- group, 5/10 (50%) of pseudo aneurysms were diagnosed during readmission after a mean of 24 +/- 11 days post procedure. No delayed presentation was seen in the US -/+ group. Major US events during the US protocol post-procedure were seen in 3.8% (10/265) vs. 0.3% (1/300) of patients in US -/+ vs. US +/+ group, respectively, P = 0.004. Conclusion: US guided venipuncture was associated with a near-to-zero risk of vascular complications in our patients undergoing CB ablation. PMID- 30010777 TI - CoMSA: Compression of protein multiple sequence alignment files. AB - Motivation: Bioinformatics databases grow rapidly and achieve values hardly to imagine a decade ago. Among numerous bioinformatics processes generating hundreds of GB ismultiple sequence alignments of protein families. Its largest database, i.e., Pfam, consumes 40-230GB, depending of the variant. Storage and transfer of such massive data has become a challenge. Results: We propose a novel compression algorithm, CoMSA, designed especially for aligned data. It is based on a generalisation of the positional Burrows-Wheeler transform for non-binary alphabets. CoMSA handles FASTA, as well as Stockholm files. It offers up to six times better compression ratio than other commonly used compressors, i.e., gzip. Performed experiments resulted in an analysis of the influence of a protein family size on the compression ratio. Availability: CoMSA is available for free at https://github.com/refresh-bio/comsa and http://sun.aei.polsl.pl/REFRESH/comsa. Supplementary information: Supplementary data are available at the publisher Web site. PMID- 30010778 TI - Matt: Unix tools for alternative splicing analysis. AB - Summary: Tracking thousands of alternative splicing (AS) events genome-wide makes their downstream analysis computationally challenging and laborious. Here, we present Matt, the first UNIX command-line toolkit with focus on high-level AS analyses. With 50 commands it facilitates computational AS analyses by i) expediting repetitive data-preparation tasks, ii) offering routine high-level analyses, including the extraction of exon/intron features, discriminative feature detection, motif enrichment analysis, and the generation of motif RNA maps, iii) improving reproducibility by documenting all analysis steps, and iv) accelerating the implementation of own analysis pipelines by offering users to exploit its modular functionality. Availability and Implementation: matt.crg.eu under GNU LGPLv3, together with comprehensive documentation, and application examples. Matt is implemented in Perl and R, invokes pdfLATEX, and depends only on Perl Core modules/the R Base package simplifying its installation. PMID- 30010779 TI - Plasma HPV cell-free DNA monitoring in advanced HPV-associated oropharyngeal cancer. AB - Background: Measuring cell-free (cf)DNA in blood and tissues holds significant potential as a minimally invasive method for disease monitoring in cancer. Cancers arising in the oropharynx and causally linked to human papillomavirus (HPV) represent an ideal model in which to interrogate these methods. Patients and methods: We designed an ultrasensitive and quantitative droplet digital (dd)PCR assay to detect the five dominant high-risk HPV subtypes linked to oropharyngeal cancer (OPC). We enrolled a pilot observational cohort of 22 patients with advanced HPV+ OPC to evaluate the clinical utility of our assay and explore its predictive and prognostic potential. Results: Total tumor burden (TTB) strongly correlated with HPV cfDNA levels (R = 0.91, P = 2.3*10-6) at this cohort size, and in most cases more distant anatomic disease locations predicted increasing HPV cfDNA levels. All participants demonstrated a corresponding change in their HPV cfDNA levels at a median of 16 days (range 12-38) before restaging scans confirming treatment response or progression. Patients with locoregional disease in the head and neck or pulmonary-only metastases had worse outcomes (P = 0.01). Both TTB and median plasma HPV cfDNA levels negatively correlated with survival (R=-0.65, P = 0.01; R=-0.48, P = 0.05, respectively). Conclusion(s): Plasma HPV cfDNA monitoring recapitulates fluctuations in disease status. While blood-based HPV DNA monitoring does not currently have a role in managing HPV+ OPC, these data speak to their broad clinical potential in an era of precision medicine. PMID- 30010780 TI - SPUTNIK: an R package for filtering of spatially related peaks in mass spectrometry imaging data. AB - Summary: SPUTNIK is an R package consisting of a series of tools to filter mass spectrometry imaging peaks characterized by a noisy or unlikely spatial distribution. SPUTNIK can produce mass spectrometry imaging datasets characterized by a smaller but more informative set of peaks, reduce the complexity of subsequent multi-variate analysis and increase the interpretability of the statistical results. Availability: SPUTNIK is freely available online from CRAN repository and at https://github.com/paoloinglese/SPUTNIK. The package is distributed under the GNU General Public License version 3 and is accompanied by example files and data. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010781 TI - Development and validation of alternative cardiovascular risk prediction equations for population health planning: a routine health data linkage study of 1.7 million New Zealanders. AB - Background: Cardiovascular disease (CVD) risk prediction equations are primarily used in clinical settings to inform individual risk management decisions. We sought to develop and validate alternative equations derived solely from linked routinely collected national health data that could be applied countrywide to inform population health planning. Methods: Individual-level linkage of eight administrative health datasets identified all New Zealand residents aged 30-74 years in contact with publicly funded health services during 2006 with no previous hospitalizations for CVD or heart failure, and with complete data on eight pre-specified predictors. The linked health datasets encompassed demographic characteristics, hospitalizations, outpatient visits, primary care enrolment, primary care reimbursement, community laboratory requests, community pharmaceutical dispensing and mortality. Sex-specific Cox models were developed to estimate the risk of CVD death or hospitalization within 5 years and included sex, age, ethnicity, level of deprivation, diabetes, previous hospitalization for atrial fibrillation and baseline preventive pharmacotherapy (blood-pressure lowering, lipid-lowering and antiplatelet/anticoagulant medications) as predictors. Calibration and discrimination were assessed in the whole cohort, in 15-year age bands, in different ethnic groups, in quintiles of deprivation, according to baseline dispensing of pharmacotherapy, and in regional sub populations. Results: First CVD events occurred in 62 031 of the 1 746 695 people during 8 526 024 person-years of follow-up (mean = 4.8 years). Median 5-year CVD risk was 1.1% in women and 2.6% in men. In both sexes, the risk equations were well calibrated throughout the risk range and had good risk discrimination in the national, regional and ethnic populations, within 15-year age bands, in deprivation quintiles and according to baseline medication dispensing. Conclusions: Robust policy-focused CVD risk equations can be developed solely from administrative health data to inform population health planning, and will complement CVD primary prevention at the individual level using clinical risk tools. Similar policy-focused equations could be replicated in countries and regions with linked administrative health datasets. PMID- 30010782 TI - Comparing Electron Leak in Vertebrate Muscle Mitochondria. AB - Mitochondrial electron transfer for oxidative ATP regeneration is linked to reactive oxygen species (ROS) production in aerobic eukaryotic cells. Because they can contribute to signaling as well as oxidative damage in cells, these ROS have profound impact for the physiology and survival of the organism. Although mitochondria have been recognized as a potential source for ROS for about 50 years, the mechanistic understanding on molecular sites and processes has advanced recently. Most experimental approaches neglect thermal variability among species although temperature impacts mitochondrial processes significantly. Here we delineate the importance of temperature by comparing muscle mitochondrial ROS formation across species. Measuring the thermal sensitivity of respiration, electron leak rate (ROS formation), and the antioxidant capacity (measured as H2O2 consumption) in intact mitochondria of representative ectothermic and endothermic vertebrate species, our results suggest that using a common assay temperature is inappropriate for comparisons of organisms with differing body temperatures. Moreover, we propose that measuring electron leak relative to the mitochondrial antioxidant capacity (the oxidant ratio) may be superior to normalizing relative to respiration rates or mitochondrial protein for comparisons of mitochondrial metabolism of ROS across species of varying mitochondrial respiratory capacities. PMID- 30010783 TI - Commentary: The pros of plurality for tuberculosis burden estimates. PMID- 30010784 TI - DMCM: A Data-adaptive Mutation Clustering Method to Identify Cancer-related Mutation Clusters. AB - Motivation: Functional somatic mutations within coding amino acid sequences confer growth advantage in pathogenic process. Most existing methods for identifying cancer-related mutations focus on the single amino acid or the entire gene level. However, gain-of-function mutations often cluster in specific protein regions instead of existing independently in the amino acid sequences. Some approaches for identifying mutation clusters with mutation density on amino acid chain have been proposed recently. But their performance in identification of mutation clusters remains to be improved. Results: Here we present an Data adaptive Mutation Clustering Method (DMCM), in which kernel density estimate (KDE) with a data-adaptive bandwidth is applied to estimate the mutation density, to find variable clusters with different lengths on amino acid sequences.We apply this approach in themutation data of 571 genes in over twenty cancer types from The Cancer Genome Atlas (TCGA). We compare the DMCM with M2C, OncodriveCLUST and Pfam Domain and find that DMCM tends to identify more significant clusters. The cross-validation analysis shows DMCM is robust and cluster cancer type enrichment analysis shows that specific cancer types are enriched for specific mutation clusters. Availability: DMCM is written in Python and analysis methods of DMCM are written in R. They are all released online, available through https://github.com/XinguoLu/DMCM. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010785 TI - What is the true tuberculosis mortality burden? Differences in estimates by the World Health Organization and the Global Burden of Disease study. AB - Background: The World Health Organization (WHO) and the Global Burden of Disease (GBD) study at the Institute for Health Metrics and Evaluation (IHME) periodically provide global estimates of tuberculosis (TB) mortality. We compared the 2015 WHO and GBD TB mortality estimates and explored which factors might drive the differences. Methods: We extracted the number of estimated TB attributable deaths, disaggregated by age, HIV status, sex and country from publicly available WHO and GBD datasets for the year 2015. We 'standardized' differences between sources by adjusting each country's difference in absolute number of deaths by the average number of deaths estimated by both sources. Results: For 195 countries with estimates from both institutions, WHO estimated 1 768 482 deaths attributable to TB, whereas GBD estimated 1 322 916 deaths, a difference of 445 566 deaths or 29% of the average of the two estimates. The countries with the largest absolute differences in deaths were Nigeria (216 621), Bangladesh (49 863) and Tanzania (38 272). The standardized difference was not associated with HIV prevalence, prevalence of multidrug resistance or global region, but did show correlation with the case detection rate as estimated by WHO [r = -0.37, 95% confidence interval (CI): -049; -0.24] or, inversely, with case detection rate based on GBD data (r = 0.44, 95% CI: 0.31; 0.54). Countries with a recent national prevalence survey had higher standardized differences (higher estimates by WHO) than those without (P = 0.006). After exclusion of countries with recent prevalence surveys, the overall correlation between both estimates was r = 0.991. Conclusions: A few countries account for the large global discrepancy in TB mortality estimates. The differences are due to the methodological approaches used by WHO and GBD. The use and interpretation of prevalence survey data and case detection rates seem to play a role in the observed differences. PMID- 30010786 TI - Broom: Application for non-redundant storage of High Throughput Sequencing data. AB - Motivation: The data generation capabilities of High Throughput Sequencing (HTS) instruments have exponentially increased over the last few years, while the cost of sequencing has dramatically decreased allowing this technology to become widely used in biomedical studies. For small labs and individual researchers, however, storage and transfer of large amounts of HTS data present a significant challenge. The recent trends in increased sequencing quality and genome coverage can be used to reconsider HTS data storage strategies. Results: We present Broom, a stand-alone application designed to select and store only high-quality sequencing reads at extremely high compression rates. Written in C ++, the application accepts single and paired-end reads in FASTQ and FASTA formats and decompresses data in FASTA format. Availability: C ++ code available at https://scsb.utmb.edu/labgroups/fofanov/broom.asp. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010787 TI - Comparative assessment of different familial aggregation methods in the context of large and unstructured pedigrees. AB - Motivation: Familial aggregation analysis is an important early step for characterizing the genetic determinants of phenotypes in epidemiological studies. To facilitate this analysis, a collection of methods to detect familial aggregation in large pedigrees has been made available recently. However, efficacy of these methods in real world scenarios remains largely unknown. Here, we assess the performance of five aggregation methods to identify individuals or groups of related individuals affected by a Mendelian trait within a large set of decoys. We investigate method performance under a representative set of combinations of causal variant penetrance, trait prevalence, and number of affected generations in the pedigree. These methods are then applied to assess familial aggregation of familial hypercholesterolemia and stroke, in the context of the Cooperative Health Research in South Tyrol (CHRIS) study. Results: We find that in some situations statistical hypothesis testing with a binomial null distribution achieves performance similar to methods that are based on kinship information, while kinship based methods perform better when information is available on fewer generations. Potential case families from the CHRIS study are reported and the results are discussed taking into account insights from the performance assessment. Availability and implementation: The familial aggregation analysis package is freely available at the Bioconductor repository, http://www.bioconductor.org/packages/FamAgg. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010788 TI -

Determination of Sets of Covariating Gene Expression Using Graph Analysis On Pairwise Expression Ratios. AB - Motivation: RNA quantification experiments result in compositional data, however usual methods for compositional data analysis (additive log ratio [alr], centered log ratio [clr], isometric log ratio [ilr]) do not apply easily and give results difficult to interpret.To handle this,a method based on disjoint subgraphs in a graph whose nodes are the quantified RNAs is proposed. Edges in the graph are defined by lack of change in ratios of the corresponding RNAs between conditions. Results: The methodsis suitedforqRT-PCRandRNA-Seqdata analyses,and leadsto easy to-interpret, graphical results and the identification of set of genes that share a similar behavior when the studied condition changes.ForqRT-PCR data,ithas better statistical properties thanthe common DeltaDeltaCq method. Availability: AnR package,SARP.compo,isavailable on CRAN. Supplementary information: Example scripts are available at Bioinformatics online as supplementary data. PMID- 30010789 TI - pLoc_bal-mAnimal: predict subcellular localization of animal proteins by balancing training dataset and PseAAC. AB - Motivation: A cell contains numerous protein molecules. One of the fundamental goals in cell biology is to determine their subcellular locations, which can provide useful clues about their functions. Knowledge of protein subcellular localization is also indispensable for prioritizing and selecting the right targets for drug development. With the avalanche of protein sequences emerging in the post-genomic age, it is highly desired to develop computational tools for timely and effectively identifying their subcellular localization based on the sequence information alone. Recently, a predictor called "pLoc-mAnimal" was developed for identifying the subcellular localization of animal proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with the multi-label systems in which some proteins, called "multiplex proteins", may simultaneously occur in two or more subcellular locations. Although it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mAnimal was trained by an extremely skewed dataset in which some subset (subcellular location) was about 128 times the size of the other subsets. Accordingly, such an uneven training dataset will inevitably cause a biased consequence. Results: To alleviate such biased consequence, we have developed a new and bias-reducing predictor called pLoc_bal-mAnimal by quasi-balancing the training dataset. Cross validation tests on exactly the same experiment-confirmed dataset have indicated that the proposed new predictor is remarkably superior to pLoc-mAnimal, the existing state-of-the-art predictor, in identifying the subcellular localization of animal proteins. Availability: To maximize the convenience for the vast majority of experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mAnimal/, by which users can easily get their desired results without the need to go through the complicated mathematics. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010790 TI - Metagenomic binning through low-density hashing. AB - Motivation: Vastly greater quantities of microbial genome data are being generated where environmental samples mix together the DNA from many different species. Here, we present Opal for metagenomic binning, the task of identifying the origin species of DNA sequencing reads. We introduce 'low-density' locality sensitive hashing to bioinformatics, with the addition of Gallager codes for even coverage, enabling quick and accurate metagenomic binning. Results: On public benchmarks, Opal halves the error on precision/recall (F1-score) as compared to both alignment-based and alignment-free methods for species classification. We demonstrate even more marked improvement at higher taxonomic levels, allowing for the discovery of novel lineages. Furthermore, the innovation of low-density, even coverage hashing should itself prove an essential methodological advance as it enables the application of machine learning to other bioinformatic challenges. Availability: Full source code and data sets are available at http://opal.csail.mit.edu and https://github.com/yunwilliamyu/opal. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30010791 TI - SMSSVD - SubMatrix Selection Singular Value Decomposition. AB - Motivation: High throughput biomedical measurements normally capture multiple overlaid biologically relevant signals and often also signals representing different types of technical artefacts like e.g. batch effects. Signal identification and decomposition are accordingly main objectives in statistical biomedical modeling and data analysis. Existing methods, aimed at signal reconstruction and deconvolution, in general, are either supervised, contain parameters that need to be estimated or present other types of ad hoc features. We here introduce SubMatrix Selection Singular Value Decomposition (SMSSVD), a parameter-free unsupervised signal decomposition and dimension reduction method, designed to reduce noise, adaptively for each low-rank-signal in a given data matrix, and represent the signals in the data in a way that enable unbiased exploratory analysis and reconstruction of multiple overlaid signals, including identifying groups of variables that drive different signals. Results: The SMSSVD method produces a denoised signal decomposition from a given data matrix. It also guarantees orthogonality between signal components in a straightforward manner and it is designed to make automation possible. We illustrate SMSSVD by applying it to several real and synthetic datasets and compare its performance to golden standard methods like PCA (Principal Component Analysis) and SPC (Sparse Principal Components, using Lasso constraints). The SMSSVD is computationally efficient and despite being a parameter-free method, in general, outperforms existing statistical learning methods. Availability and Implementation: A Julia implementation of SMSSVD is openly available on GitHub (https://github.com/rasmushenningsson/SubMatrixSelectionSVD.jl). Supplementary information: Supplementary Materials are available at Bioinformatics online. PMID- 30010792 TI - AuTom-dualx: a toolkit for fully automatic fiducial marker-based alignment of dual-axis tilt series with simultaneous reconstruction. AB - Motivation: Dual-axis electron tomography is an important 3D macro-molecular structure reconstruction technology, which can reduce artifacts and suppress the effect of missing wedge. However, the fully automatic data process for dual-axis electron tomography still remains a challenge due to three difficulties: (i) how to track the mass of fiducial markers automatically; (ii) how to integrate the information from the two different tilt series; and (iii) how to cope with the inconsistency between the two different tilt series. Results: Here we develop a toolkit for fully automatic alignment of dual-axis electron tomography, with a simultaneous reconstruction procedure. The proposed toolkit and its workflow carries out the following solutions: (i) fully automatic detection and tracking of fiducial markers under large-field datasets; (ii) automatic combination of two different tilt series and global calibration of projection parameters; and (iii) inconsistency correction based on distortion correction parameters and the consequently simultaneous reconstruction. With all of these features, the presented toolkit can achieve accurate alignment and reconstruction simultaneously and conveniently under a single global coordinate system. Availability: The toolkit AuTom-dualx (alignment module dualxmauto and reconstruction module volrec mltm) are accessible for general application at http://ear.ict.ac.cn, and the key source code is freely available under request. PMID- 30010793 TI - Does selective survival before study enrolment attenuate estimated effects of education on rate of cognitive decline in older adults? A simulation approach for quantifying survival bias in life course epidemiology. AB - Background: The relationship between education and late-life cognitive decline is controversial. Selective survival between early life, when education is typically completed, and late life, when cognitive ageing studies take place, could attenuate effect estimates. Methods: We quantified potential survival bias (collider-stratification bias) in estimation of the effect of education on late life cognitive decline by simulating hypothetical cohorts of 20-year-olds and applying cumulative mortality from US life tables. For each of four causal scenarios (2000 replications each), we compared the estimated versus causal effect of education on cognitive decline over 9 years, starting at age 60, 75 or 90 in random samples of n = 2000 people who survived to each age. Results: Effects of education on cognitive decline were underestimated when both education and U, another determinant of cognitive decline, influenced mortality (collider stratification bias). The magnitude of bias was sensitive to the magnitude of the effect of U on cognitive decline and whether there was a multiplicative interaction between education and U on mortality. For example, when there was a multiplicative interaction between education and U on mortality, 95% confidence interval coverage of the causal effect ranged from 83.4% to 50.4% at age 60 and 25.8% to 0.2% at age 90. Conclusions: Selective survival could lead to underestimation of effects of education on late-life cognitive decline. Our simulations map survival bias to testable assumptions about underlying causal structures. PMID- 30010794 TI - The effect of cumulative soil-transmitted helminth infections over time on child development: a 4-year longitudinal cohort study in preschool children using Bayesian methods to adjust for exposure misclassification. AB - Background: Limited research has documented an association between soil transmitted helminth (STH) infections and child development. This has recently been identified as an important knowledge gap. Methods: A longitudinal cohort study was conducted in Iquitos, Peru, between September 2011 and July 2016. A cohort of 880 children, recruited at 1 year of age, was followed up to 5 years. STH infection was measured annually and child development was measured with the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) at 5 years. Linear-regression models were used to investigate the effect of the number of detected STH infections between 1 and 5 years of age on WPPSI-III scores at 5 years of age. Bayesian latent class analysis was used to adjust for exposure misclassification. Results: A total of 781 (88.8%) children were included in the analysis. In multivariable analysis, adjusted for STH misclassification, increasing numbers of Ascaris, Trichuris, hookworm and any STH infections were associated with lower WPPSI-III scores. Among the largest observed effects were those for the effect of Ascaris infection on verbal IQ scores [difference in IQ (95% CrI) for two, three, and four or five detected infections compared with zero or one infection: -8.27 (-13.85, -3.10), -6.69 (-12.05, -2.05) and -5.06 (-10.75, 0.05), respectively]. Misclassification of STH infection generally led to a bias towards the null. Conclusions: These results document an association between STH infection and child development. The results highlight the importance of adjusting for STH misclassification; however, future research is needed to accurately determine the sensitivity of STH diagnostic techniques. STH control in preschool children may contribute to lowering the disease burden associated with poor child development. PMID- 30010795 TI - ProteomeVis: a web app for exploration of protein properties from structure to sequence evolution across organisms' proteomes. PMID- 30010797 TI - GECO: gene expression correlation analysis after genetic algorithm-driven deconvolution. AB - Motivation: Large-scale gene expression analysis is a valuable asset for data driven hypothesis generation. However, the convoluted nature of large expression datasets often hinders extraction of meaningful biological information. Results: To this end, we developed GECO, a gene expression correlation analysis software that uses a genetic algorithm-driven approach to deconvolute complex expression datasets into two subpopulations that display positive and negative correlations between a pair of queried genes. GECO's mutational enrichment and pairwise drug sensitivity analyses functions that follow the deconvolution step may help to identify the mutational factors that drive the gene expression correlation in the generated subpopulations and their differential drug vulnerabilities. Finally, GECO's drug sensitivity screen function can be used to identify drugs that differentially affect the subpopulations. Availability and Implementation: http://www.proteinguru.com/geco/ and http://www.proteinguru.com/geco/codes/. Supplementary information: Supplementary Data are available at Bioinformatics online. PMID- 30010798 TI - Erratum to: "Is the Red Wolf a Listable Unit Under the US Endangered Species Act?" PMID- 30010796 TI - A novel complex neurological phenotype due to a homozygous mutation in FDX2. AB - Defects in iron-sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis. PMID- 30010799 TI - Embryonic estrogen exposure recapitulates persistent ovarian transcriptional programs in a model of environmental endocrine disruption. AB - Estrogens regulate key aspects of sexual determination and differentiation, and exposure to exogenous estrogens can alter ovarian development. Alligators inhabiting Lake Apopka, FL are historically exposed to estrogenic endocrine disrupting contaminants and are characterized by a suite of reproductive abnormalities, including altered ovarian gene expression and abated transcriptional responses to follicle stimulating hormone. Here, we test the hypothesis that disrupting estrogen signaling during gonadal differentiation results in persistent alterations to ovarian gene expression that mirror alterations observed in alligators from Lake Apopka. Alligator embryos collected from a reference site lacking environmental contamination were exposed to estradiol-17 beta or a non-aromatizable androgen in ovo and raised to the juvenile stage. Changes in basal and gonadotropin-challenged ovarian gene expression were then compared to Apopka juveniles raised under identical conditions. Assessing basal transcription in untreated reference and Apopka animals revealed a consistent pattern of differential expression of key ovarian genes. For each gene where basal expression differed across sites, in ovo estradiol treatment in reference individuals recapitulated patterns observed in Apopka alligators. Among those genes affected by site and estradiol treatment were three aryl hydrocarbon receptor (AHR) isoforms, suggesting that developmental estrogen signaling might program sensitivity to AHR ligands later in life. Treatment with gonadotropins stimulated strong ovarian transcriptional responses, however, the magnitude of responses was not strongly affected by steroid hormone treatment. Collectively, these findings demonstrate that precocious estrogen signaling in the developing ovary likely underlies altered transcriptional profiles observed in a natural population exposed to endocrine disrupting contaminants. PMID- 30010801 TI - Managed and Wild Bee Flower Visitors and Their Potential Contribution to Pollination Services of Low-Chill Highbush Blueberry (Vaccinium corymbosum L.; Ericales: Ericaceae). AB - Highbush blueberry (Vaccinium corymbosum L.; Ericales: Ericaceae) is an important crop grown throughout the eastern United States and Canada. Cross-pollination by insects greatly enhances pollination and fruit set in highbush blueberry. In Florida, low-chill cultivars that flower during the winter when most bees are dormant are used, thus, making it difficult to utilize and depend on unmanaged bees. We investigated flower visitation rates by managed and wild bees and the subsequent berry formation, berry weight, and number of seeds/berry in highbush blueberry fields in north-central Florida. Additionally, we tested three pollinator treatments: 1) pollinator-excluded flowers, 2) open-pollinated treatments that were available to managed and wild bees, and 3) flowers that were hand pollinated. Overall, we found seven native bee species that contribute to highbush blueberry pollination in Florida, but managed honey bees and bumble bees were the main flower visitors. Additionally, 14.5 times more blueberries formed in the open treatments than in the pollinator exclusion treatments, thus illustrating the economic impact bees have on blueberry pollination. Most of the wild bees observed visiting blueberry flowers were ground-nesting species that need uncultivated areas for nesting sites. Therefore, leaving field edges uncultivated and some undisturbed habitat may increase native bee numbers within blueberry farms over time. PMID- 30010802 TI - Whole Blood Gene Expression Associated with Clinical Biological Age. AB - Background: Biologic age may better reflect an individual's rate of aging than chronologic age. Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at one second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (?age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array. Results: Our discovery sample included 2163 participants from the Framingham Offspring cohort (mean age 67+/-9 years, 55% women). A total of 481 genes were significantly associated with ?age (P<2.8x10-6). Among them, 415 genes were validated (P<0.05/481=1.0x10-4) in 2946 participants from the Framingham Third Generation cohort (mean age 46+/- 9 years, 53% women). Many of significant genes were involved in the ubiquitin mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59+/-8, 52% women) found 104 of 415 validated genes reached nominal significance (P <0.05). Conclusion: We identified and validated 415 genes associated with ?age in a community-based cohort. Future functional characterization of the biologic age related gene network may identify targets to test for interventions to delay aging in older adults. PMID- 30010803 TI - Selective killing of human breast cancer cells by the styryl lactone (R) goniothalamin is mediated by glutathione conjugation, induction of oxidative stress and marked reactivation of the R175H mutant p53 protein. AB - The molecular basis of anticancer and apoptotic effects of R-goniothalamin (GON), a plant secondary metabolite was studied. We show that induction of oxidative stress and reactivation of mutant p53 underlie the strong cytotoxic effects of GON against the breast cancer cells. While GON was not toxic to the MCF10a breast epithelial cells, the SKBR3 breast cancer cells harboring an R175H mutant p53 were highly sensitive (IC50 = 7.3 uM). Flow cytometry and other pertinent assays showed that GON induced abundant reactive oxygen species (ROS), glutathione depletion, protein glutathionylation and activation of apoptotic markers. GON was found to conjugate with glutathione both in vitro and in cells and the product was characterized by mass spectrometry. We hypothesized that the redox imbalance induced by GON may affect the structure of the R175H mutant p53 protein, and account for greater cytotoxicity. Using the SKBR3 breast cancer and p53-null H1299 lung cancer cells stably expressing the R175H p53 mutant protein, we demonstrated that GON triggers the appearance of a wild-type-like p53 protein by using conformation-specific antibodies, immunoprecipitation, DNA-binding assays and target gene expression. p53-restoration was associated with a G2/M arrest, senescence, reduced cell migration, invasion and increased cell death. GON elicited a highly synergistic cytotoxicity with cisplatin in SKBR3 cells. In SKBR3 xenografts developed in nude mice, there was a marked tumor growth delay by GON alone and GON + cisplatin combination. Our studies highlight the impact of tumor redox-stress generated by GON in activating the mutant p53 protein for greater antitumor efficacy. PMID- 30010800 TI - Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition. AB - Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies. PMID- 30010804 TI - Molecular Genetics Unveiled Unknown Family Relationships and Hybrids in an Ex Situ Colony of African Penguins (Spheniscus demersus). AB - Genealogical relationships among colony members, inbreeding status, and presence of hybrids are crucial data that can assist zoo curators in captive colony management and decision-making on relocation for reproduction. This study employed molecular markers to study a large colony (n = 56) of African Penguin hosted in an Italian biopark. A panel of 15 STRs (single tandem repeats) was selected, and genotype data were analyzed using COLONY software to determine parentage relationships and compare the existing studbook information to a pedigree built from genetic analyses. The existence of extra-pair mating and the presence of hybrids were investigated: discrepancies in kinship relationships emerged following molecular parentage analysis and 10 unknown genetic relationships were revealed. Infidelity of one member of the pair was observed in 6 cases and extra-pair copulation was assessed by genetic analysis in 2 episodes. One member of the colony was found to be a hybrid (S. demersus * S. humboldti); his progeny, derived by extra-pair copulation, was traced. Three other hidden hybrids were discovered and assessed using the identified candidate private alleles. Overall, our results demonstrate that molecular methods to confirm parentage and analyze relatedness among colony members are a valuable tool to complement studbook-based genetic management of African penguin captive populations. Because a variety of behavioral dynamics (e.g., extra-pair mating) can make observations ineffective in some species and because molecular markers outperform studbook in identifying the presence of hybrids, reliance on studbook information alone is not recommended. PMID- 30010805 TI - Bone and soft tissue turnover in relation to all-cause mortality in postmenopausal women. AB - Background: The relationship between levels of extracellular matrix (ECM) turnover and mortality is currently unknown. The study aimed to determine if levels of ECM turnover are predictors of all-cause mortality in a large cohort of post-menopausal women. Methods: 5,855 postmenopausal Danish women enrolled in the Prospective Epidemiologic Risk Factor (PERF) study. Baseline demographics and serum were collected at registration. Dates of death were obtained from the Danish Death Registry. ECM turnover was evaluated by serological biomarkers measuring bone (telopeptide of type I collagen (CTX-1) and osteocalcin) and soft tissue (formation of type VI collagen (PRO-C6), MMP-degraded type IV collagen (C4M), formation of type III collagen (PRO-C3) and MMP-degraded type I collagen (C1M)) turnover. Multivariate Cox analyses were performed with 3, 5 and 15 years of follow-up. Results: The association of bone turnover (CTX-1 and osteocalcin) with all-cause mortality was U-shaped for all time periods. After adjustment for possible confounders, the lowest quintile of bone formation and degradation remained significant for all time periods. We observed J-shaped association between all-cause mortality and PRO-C6, C4M and PRO-C3, and there was a linear association between C1M and all-cause mortality. After adjustment for possible confounders, the highest quintile of the soft tissue turnover biomarkers (PRO-C6, C4M, PRO-C3 and C1M) remained significantly associated with all-cause mortality for all time periods. Conclusion: Both low and high levels of tissue turnover were associated with increased risk of all-cause mortality in postmenopausal women. Overall, these results highlight the importance of bone and soft tissue homeostasis. PMID- 30010806 TI - The impact of aging, calorie restriction and dietary fat on mitochondrial ultrastructure, dynamics and autophagy markers in mouse skeletal muscle. AB - Loss of skeletal muscle mass and function is a hallmark of aging. This phenomenon has been related to a dysregulation of mitochondrial function and proteostasis. Calorie restriction (CR) has been demonstrated to delay aging and preserve function until late in life, particularly in muscle. Recently, we reported the type of dietary fat plays an important role in determining lifespan extension with 40% CR in male mice. In these conditions, lard fed mice showed an increased longevity compared to mice fed soybean or fish oils. In this paper, we analyze the effect of 40% CR on muscle mitochondrial mass, autophagy and mitochondrial dynamics markers in mice fed these diets. In CR fed animals, lard preserved muscle fibers structure, mitochondrial ultrastructure and fission/fusion dynamics and autophagy, not only compared to control animals, but also compared with CR mice fed soybean and fish oils as dietary fat. We focus our discussion on dietary fatty acid saturation degree as an essential predictor of lifespan extension in CR mice. PMID- 30010807 TI - Cardiac resynchronization is pro-arrhythmic in the absence of reverse ventricular remodelling: a systematic review and meta-analysis. AB - Aims: Cardiac resynchronization therapy (CRT) has been shown to reduce mortality and heart failure (HF) hospitalization but its effects on the rate of ventricular arrhythmias (VAs) appears to be neutral. We hypothesize that CRT with LV epicardial stimulation is inherently pro-arrhythmic and increases VA rates in the absence of reverse ventricular remodelling while conferring an anti-arrhythmic effect in mechanical responders. Methods and results: In this systematic review and meta-analysis, we considered retrospective cohort, prospective cohort, and randomized controlled trials comparing VA rates between cardiac resynchronization therapy-defibrillator (CRT-D) non-responders, CRT-D responders and those with implantable cardioverter-defibrillator (ICD) only. Studies were eligible if they defined CRT-D responders using a discrete left ventricular volumetric value as assessed by any imaging modality. Studies were identified through searching electronic databases from their inception to July 2017. We identified 2579 citations, of which 23 full-text articles were eligible for final analysis. Our results demonstrated that CRT-D responders were less likely to experience VA than CRT-D non-responders, relative risk (RR) 0.49 [95% confidence interval (CI) 0.41 0.58, P < 0.01] and also less than patients with ICD only: RR 0.59 (95% CI 0.50 0.69, P < 0.01). However, CRT-D mechanical non-responders had a greater likelihood of VA compared with ICD only, RR 0.76 (95% CI 0.63-0.92, P = 0.004). Conclusion: CRT-D non-responders experienced more VA than CRT-D responders and also more than those with ICD only, suggesting that CRT with LV epicardial stimulation may be inherently pro-arrhythmic in the absence of reverse remodelling. PMID- 30010808 TI - Translating the Lifestyle Interventions and Independence for Elders Clinical Trial to Older Adults in a Real-World Community-Based Setting. AB - Background: The Lifestyle Interventions and Independence for Elders (LIFE) clinical trial demonstrated that a structured program of physical activity (PA) reduced mobility-disability in older adults by up to 28%. It remains unknown whether the benefits of LIFE PA can be translated to older adults at risk for mobility-disability in real-world community-based settings. To address this knowledge gap, we conducted the ENGAGE pilot study and examined the safety, feasibility and preliminary effectiveness of translating LIFE PA to a community based senior center. Methods: Forty older adults with severe lower extremity functional limitations (age: 76.9 +/- 7.3yrs; BMI: 32.7 +/- 8 kg/m2; 85% female; short physical performance battery (SPPB) score: 6.3 +/- 2.2) were randomized to 24 weeks of PA or a health education (HE) control intervention. Results: Community-based PA was safe (serious adverse events: PA: 0 vs. HE: 2; non-serious adverse events: PA: 3 vs. HE: 1) and participants successfully adhered to the PA intervention (65.2%). Compared to HE, PA participants who attended >= 25% of scheduled visits had meaningful and sustained SPPB improvements at follow-up (between group SPPB score differences: ~ 0.7 units). Conclusions: ENGAGE has demonstrated the preliminary safety, feasibility and effectiveness of LIFE PA in a real-world community-based setting. Larger scale translational studies are needed to further disseminate the benefits of LIFE PA to vulnerable older adults in a variety of community-based settings. PMID- 30010809 TI - Population Genetics and Speciation of Yellow-Bellied, Red-Naped, and Red-Breasted Sapsuckers (Sphyrapicus varius, S. nuchalis, and S. ruber). AB - The root of understanding speciation lies in determining the forces which drive it. In many closely-related species, including Sphyrapicus varius, S. nuchalis, and S. ruber, it is assumed that speciation occurred due to isolation in multiple Pleistocene refugia. We used genetic data from 457 samples at the control region (CR), cytochrome oxidase I (COI), and chromo-helicase DNA binding protein (CHD1Z) to examine range-wide population genetic structure and differentiation amongst these 3 species across each species' breeding range. In addition, we modeled these species' ecological niches for the Holocene (~6000 years ago), Last Glacial Maximum (~22000 years ago), and Last Interglacial (~120000-140000 years ago) to determine if Pleistocene glaciations could have contributed to allopatric distributions, therefore allowing these groups to differentiate. Population genetic data show a potential Pleistocene refugium in Haida Gwaii, an east-west split among S. varius, and low genetic differentiation within each species. Our CR data show some polyphyly, while COI and CHD1Z data show differentiation among species using composite genotypes. Ecological Niche Modeling shows a large amount of niche overlap at each time period suggesting that S. varius, S. nuchalis, and S. ruber may not have been completely allopatric, and these species likely had repeated intermittent contact. Our data support the growing body of research that suggests differentiation despite gene flow. PMID- 30010811 TI - Vaccine Generation of Protective Ebola Antibodies and Identification of Conserved B-Cell Signatures. AB - We recently identified a single potently neutralizing monoclonal antibody (mAb), mAb114, isolated from a human survivor of natural Zaire ebolavirus (EBOV) infection, which fully protects nonhuman primates (NHPs) against lethal EBOV challenge. To evaluate the ability of vaccination to generate mAbs such as mAb114, we cloned antibodies from NHPs vaccinated with vectors encoding the EBOV glycoprotein (GP). We identified 14 unique mAbs with potent binding to GP, 4 of which were neutralized and had the functional characteristics of mAb114. These vaccine-induced macaque mAbs share many sequence similarities with mAb114 and use the same mAb114 VH gene (ie, IGHV3-13) when classified using the macaque IMGT database. The antigen-specific VH-gene repertoire present after each immunization indicated that IGHV3-13 mAbs populate an EBOV-specific B-cell repertoire that appears to become more prominent with subsequent boosting. These findings will support structure-based vaccine design aimed at enhanced induction of antibodies such as mAb114. PMID- 30010812 TI - Synaptic Innervation of the GnRH Neuron Distal Dendron in Female Mice. AB - GnRH neuron cell bodies are scattered throughout the basal forebrain but funnel their projections to the median eminence to release GnRH into the pituitary portal system to control fertility. Prior studies have shown that GnRH neurons located in the anterior hypothalamus send projections to the median eminence that have characteristics of both dendrites and axons. These unusual structures have been termed "dendrons." To address whether the dendron is unique to anterior hypothalamic GnRH neurons or is also a characteristic of more rostral GnRH neurons, we used viral vector-mediated GnRH neuron-specific tract-tracing coupled with CLARITY optical clearing. Individual rostral preoptic area GnRH neurons in female mice were identified to elaborate processes up to 4 mm in length that exhibited spines and projected all the way to the median eminence before branching into multiple short axons. The synaptic innervation patterns of distal GnRH neuron dendrons and their short axons in the vicinity of the median eminence were examined using electron microscopy. This revealed the presence of a high density of synaptic inputs to distal dendrons at the border of the median eminence. In contrast, no synapses were detected on any GnRH neuron axons. These studies demonstrate that GnRH neurons in the rostral preoptic area project dendrons to the edge of the median eminence, whereupon they branch into multiple short axons responsible for GnRH secretion. The dense synaptic innervation of these distal dendrons likely represents an efficient mechanism for controlling GnRH secretion required for fertility. PMID- 30010810 TI - Genome-Wide Sequence Analysis of Kaposi Sarcoma-Associated Herpesvirus Shows Diversification Driven by Recombination. AB - Background: Kaposi sarcoma-associated herpesvirus (KSHV) establishes lifelong infection in the human host and has been associated with a variety of malignancies. KSHV displays striking geographic variation in prevalence, which is highest in sub-Saharan Africa. The current KSHV genome sequences available are all tumor cell line-derived or primary tumor-associated viruses, which have provided valuable insights into KSHV genetic diversity. Methods: Here, we sequenced 45 KSHV genomes from a Ugandan population cohort in which KSHV is endemic; these are the only genome sequences obtained from nondiseased individuals and of KSHV DNA isolated from saliva. Results: Population structure analysis, along with the 25 published genome sequences from other parts of the world, showed whole-genome variation, separating sequences and variation within the central genome contributing to clustering of genomes by geography. We reveal new evidence for the presence of intragenic recombination and multiple recombination events contributing to the divergence of genomes into at least 5 distinct types. Discussion: This study shows that large-scale genome-wide sequencing from clinical and epidemiological samples is necessary to capture the full extent of genetic diversity of KSHV, including recombination, and provides evidence to suggest a revision of KSHV genotype nomenclature. PMID- 30010813 TI - Heritability of Regional Brain Volumes in Large-Scale Neuroimaging and Genetic Studies. AB - Brain genetics is an active research area. The degree to which genetic variants impact variations in brain structure and function remains largely unknown. We examined the heritability of regional brain volumes (P ~ 100) captured by single nucleotide polymorphisms (SNPs) in UK Biobank (n ~ 9000). We found that regional brain volumes are highly heritable in this study population and common genetic variants can explain up to 80% of their variabilities (median heritability 34.8%). We observed omnigenic impact across the genome and examined the enrichment of SNPs in active chromatin regions. Principal components derived from regional volume data are also highly heritable, but the amount of variance in brain volume explained by the component did not seem to be related to its heritability. Heritability estimates vary substantially across large-scale functional networks, exhibit a symmetric pattern across left and right hemispheres, and are consistent in females and males (correlation = 0.638). We repeated the main analysis in Alzheimer's Disease Neuroimaging Initiative (n ~ 1100), Philadelphia Neurodevelopmental Cohort (n ~ 600), and Pediatric Imaging, Neurocognition, and Genetics (n ~ 500) datasets, which demonstrated that more stable estimates can be obtained from the UK Biobank. PMID- 30010815 TI - Red Flour Beetle (Coleoptera: Tenebrionidae) Response to Volatile Cues Varies With Strain and Behavioral Assay. AB - The red flour beetle, Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae), is a major pest of facilities where grain is processed because of its ability to find and colonize food resource patches. Traps baited with pheromone and kairomone lures are commonly used to monitor for the presence of insects in warehouses or flour mills, for example. However, two nonmutually exclusive components, environment and genetics, could influence insect responsiveness to volatiles, impacting the efficacy of monitoring. Intraspecific variation in attraction behavior to food and mates is largely unexplored in stored-product insects, but tapping into natural genetic variation could provide a baseline for identifying genetic mechanisms associated with finding resources. Here, we assess eight strains of T. castaneum for variation in response to kairomone- and pheromone-based lures using three behavioral assays: paired choice with no forced air flow, upwind attraction with forced air flow, and movement pattern in an arena with a single odor source. We find strain-specific responses to kairomones and pheromones and evidence for heritability in behavioral responses. However, environmental coefficients for behavioral responses to both lures are high, suggesting that environment, and its potential interaction with genotype, strongly influences behavioral outcomes in these assays. Furthermore, despite the different environmental conditions among the different behavioral assays, we find a correlation for volatile preference among the assays. Our results provide a baseline assessment of natural variation for preference to kairomone and pheromone lures and suggest that careful consideration of behavioral assay is key to understanding the mechanisms of attraction in these stored-product pests. PMID- 30010814 TI - Trop-2 plasticity is controlled by epithelial-to-mesenchymal transition. AB - The cell surface glycoprotein Trop-2 is commonly overexpressed in carcinomas and represents an exceptional antigen for targeted therapy. Here, we provide evidence that surface Trop-2 expression is functionally connected with an epithelial phenotype in breast and prostate cell lines and in patient tumor samples. We further show that Trop-2 expression is suppressed epigenetically or through the action of epithelial-to-mesenchymal transition transcription factors and that deregulation of Trop-2 expression is linked with cancer progression and poor patient prognosis. Moreover, our data suggest that the cancer plasticity-driven intratumoral heterogeneity in Trop-2 expression may significantly contribute to response and resistance to therapies targeting Trop-2-expressing cells. PMID- 30010816 TI - Comparison of passive and scanning irradiation methods for carbon-ion radiotherapy for breast cancer. AB - The dose distribution of passive and scanning irradiation for carbon-ion radiotherapy for breast cancer was compared in order to determine the preferred treatment method. Eleven Japanese patients who received carbon-ion radiotherapy for breast cancer were retrospectively analyzed. The original clinical plans were used for the passive irradiation method, while the plans for the scanning irradiation method were more recently made. Statistical analysis suggested that there was no significant difference in superiority in terms of dose distribution between the passive and scanning irradiation methods. The present study found that the scanning irradiation method was not always superior to the passive method, despite a previous study having reported the superiority of scanning irradiation. The present result is considered to arise from characteristics of breast cancer treatment, such as the simplicity of the organ at risk and the shallow depth point of the target from the skin. It is noteworthy that the present study suggests that the passive irradiation method can provide better dose distribution, depending on the case. PMID- 30010817 TI - A thioredoxin-mimetic peptide exerts potent anti-inflammatory, anti-oxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat diet. AB - Aims: Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. Here we analyzed whether the thioredoxin-mimetic peptide (TxMP), CB3 might exert anti-oxidative, anti-inflammatory and atheroprotective effects in ApoE2.Ki mice. Methods and Results: We synthesized a small TxMP, Ac-Cys-Pro-Cys-amide, CB3 and characterized its antioxidant and anti inflammatory effects on cultured peritoneal murine macrophages. CB3 significantly and dose-dependently reduced the level of reactive oxygen species in LPS activated macrophages. In addition, it efficiently lowered LPS-induced inflammatory process through NF-kappaB inhibition, as evidenced by the reduced secretion of MCP-1, IL-1beta, IL-6 and TNF-alpha by macrophages. Nevertheless, CB3 did not affect cholesterol accumulation in macrophages. A daily-administered dose of 10 MUg/g body weight CB3 to ApoE2.Ki mice on high fat diet did not affect plasma of total cholesterol and triglycerides levels but significantly reduced the plasma levels of pro-inflammatory cytokines (IL-33 and TNF-alpha) and oxidative markers. In contrast, it significantly induced the plasma levels of anti-inflammatory proteins (adiponectin, IL-10). In addition, CB3 reduced the number of pro-inflammatory M1 macrophages in spleen and decreased the ratio of M1/M2 macrophages in atherosclerotic lesion areas. Finally, CB3 significantly reduced the surface area of aortic lesions. Conclusions: Our results clearly showed that similar to the full length Trx-1, CB3 exerts protective effects, by reducing inflammation and oxidative stress in macrophages and in ApoE2.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis. PMID- 30010818 TI - "How Old Do You Feel?" The Difficulties and Ethics of Operationalizing Subjective Age. AB - This article provides an integrative presentation regarding ageism within the professional culture of gerontological research by examining the operationalization of subjective age, a construct most commonly assessed by asking an individual to report how "old" they feel. According to the life span perspective [Baltes, P. B. (1987). Theoretical propositions of lifespan developmental psychology: On the dynamics between growth and decline. Developmental Psychology, 23, 611-626] and the life course perspective [Elder Jr, G. H. (1975). Age differentiation and the life course. Annual Review of Sociology, 1(1), 165-190.], growing older represents a complex, multidirectional process that encompasses maintenance, growth and decline as well as cultural factors that influence development. Viewing the construct of subjective age from these perspectives casts doubt on the validity of its operationalization. This article argues that operationalizing subjective age in this manner contributes to the dominant societal view of aging as decline by perpetuating the use of the term "old" as an undesirable state. As well, we purport that as gerontological researchers and scholars our professional code of ethics requires us to examine the unintentional communication and perpetuation of ageism by focusing attention on our own use of language. PMID- 30010819 TI - Identity, Semiotics, and Use of Symbols in Adult Day Services. AB - Purpose: This article explores experiences of older adults attending an Adult Day Service (ADS) center. We focus on semiotics, which is ADS clients' use of symbols to communicate with others and to assert their personal and social identities. We refer to the ADS as a semiosphere-a term that refers to the dense, symbolically mediated interactions among this community. Methods: Ethnographers observed and interviewed clients, family, and staff members at the religiously affiliated ADS. They focused on the daily life worlds of those who attended and worked there. Results: We identified three elements through which clients expressed and communicated in semiotic ways, aspects of their identity: (a) music and dance, (b) individual use of a symbol-a doll and, (c) symbolic organization of space through seating patterns at activity tables. Elements were created and shared communally. Discussion: The ADS, as a cultural entity, is itself an illustration of symbolic complexity. Ideologies about aging, dementia, identity, and the ADS' role in improving elders' cognition and health are structured into the setting, forming a semiosphere. Our study revealed that elders, with staff members' help, created a cultural world at the ADS. PMID- 30010820 TI - Aging in Brazil. AB - The population in Brazil is aging at a fast pace and in a context of historical socioeconomic and regional disparities. In the last decades, the country has developed important policies and legal mechanisms to guarantee older adults' right to age well and with dignity. The implementation of these policies and laws, however, has been slow and hampered by lack of coordination and resources. With an estimate of 64 million seniors living in the country by 2050, Brazil has important public policy issues to address, such as the poor implementation of the National Policy of the Elderly, the urgency of Social Security Reform, and the need for a comprehensive long-term care policy for older adults. PMID- 30010821 TI - Age and Sex Are Critical Factors in Ischemic Stroke Pathology. AB - Ischemic stroke is a devastating brain injury resulting in high mortality and substantial loss of function. Understanding the pathophysiology of ischemic stroke risk, mortality, and functional loss is critical to the development of new therapies. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest nonmodifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality and morbidity and poorer functional recovery than their young counterparts. Importantly, patient age modifies the influence of patient sex in ischemic stroke. Early in life, the burden of ischemic stroke is higher in men, but stroke becomes more common and debilitating for women in elderly populations. The profound effects of sex and age on clinical ischemic stroke are mirrored in the results of experimental in vivo and in vitro studies. Here, we review current knowledge on the influence of age and sex in the incidence, mortality, and functional outcome of ischemic stroke in clinical populations. We also discuss the experimental evidence for sex and age differences in stroke pathophysiology and how a better understanding of these biological variables can improve clinical care and enhance development of novel therapies. PMID- 30010822 TI - Selected Phytoestrogens Distinguish Roles of ERalpha Transactivation and Ligand Binding for Anti-Inflammatory Activity. AB - Estrogen receptor alpha (ERalpha) is a ligand-activated transcriptional activator that is also involved vascular inflammation and atherosclerosis. Whether different ligands may affect this activity has not been explored. We screened a panel of phytoestrogens for their role in ERalpha binding and transcriptional transcription, and correlated the findings to anti-inflammatory activities in vascular endothelial cells stably expressing either a wild-type or mutant form of ERalpha deficient in its membrane association. Taxifolin and silymarin were "high binders" for ERalpha ligand binding; quercetin and curcumin were "high activators" for ERalpha transactivation. Using these phytoestrogens as functional probes, we found, in endothelial cells expressing wild-type ERalpha, the ERalpha high activator, but not the ERalpha high binder, promoted ERalpha nuclear translocation, estrogen response element (ERE) reporter activity, and the downstream gene expression. In endothelial cells expressing membrane association deficient mutant ERalpha, the ERalpha nuclear translocation was significantly enhanced by taxifolin and silymarin, which still failed to activate ERalpha. Inflammation response was examined using the systemic or vascular inflammation inducers lipopolysaccharide or oxidized low-density lipoprotein. In both cases, only the ERalpha high activator inhibited nuclear translocation of nuclear factor kappaB, JNK, and p38, and the production of inflammatory cytokines IL-1beta and TNFalpha. We confirm a threshold nuclear accumulation of ERalpha is necessary for its transactivation. The anti-inflammatory activity of phytoestrogens is highly dependent on ERalpha transactivation, less so on the ligand binding, and independent of its membrane association. A pre-examination of phytoestrogens for their mode of ERalpha interaction could facilitate their development as better targeted receptor modifiers. PMID- 30010823 TI - Lipoprotein(a): the perpetual supporting actor. PMID- 30010824 TI - CIT 2018: A New Era, New Journey: Report from the China Interventional Therapeutics (CIT) 2018, the largest interventional cardiology scientific congress in the Asia-Pacific region. PMID- 30010825 TI - Hands-on training in acute cardiac care: Report from the first-ever Acute Cardiovascular Care School in Madrid, Spain, November 2017. PMID- 30010826 TI - Hugo A. Katus MD PhD FESC: After discovering troponin as a biomarker Katus reached out to genome research, improving healthcare in hospitals, and actively teaching, to fill a 13-hour workday schedule. PMID- 30010828 TI - Russian National Congress of Cardiology 2018. PMID- 30010827 TI - The ESC Publications Ethics Committee: Report from the first 5 years' experience of the European Society of Cardiology (ESC) journals family ethics committee. PMID- 30010829 TI - Multiple deprivation and other risk factors for maternal obesity in Portsmouth, UK. AB - Background: Maternal obesity is known to be associated with a range of adverse outcomes, both for the mothers and their children. It may be more prevalent in areas with higher deprivation as measured by the Index of Multiple Deprivation (IMD), but this has not been demonstrated consistently. This study focused primarily on the relationship between maternal obesity and deprivation in a setting where areas of significant deprivation are surrounded by the overall affluent South East England. Methods: The study used the records of 3830 women who delivered under the care of a Portsmouth hospital from 1 April 2013 to 31 March 2014. Logistic regression was used to analyse the association between national IMD quintiles and maternal obesity, accounting for the potential confounders of age, ethnic origin, smoking status and parity. Results: Following adjustment, women in the most deprived IMD quintile were 1.60 (95% CI: 1.13, 2.26) times more likely to be obese compared to those in the least deprived quintile. Maternal obesity was also found to be associated with ethnicity and parity, but not with age or smoking status. Conclusions: Maternal obesity increased with increasing deprivation. IMD may be a useful group-level indicator when planning interventions aimed at tackling maternal obesity. PMID- 30010830 TI - Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance. AB - The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they modulate dopamine or local LHA orexin neurons implicated in energy balance, they may have important, unappreciated roles for coordinating behaviors necessary for proper body weight. In this study, we genetically ablated or chemogenetically inhibited LHA Nts neurons in adult mice to determine their necessity for control of motivated behaviors and body weight. Genetic ablation of LHA Nts neurons resulted in profoundly increased adiposity compared with mice with intact LHA Nts neurons, as well as diminished locomotor activity, energy expenditure, and water intake. Complete loss of LHA Nts neurons also led to downregulation of orexin, revealing important cross-talk between the LHA Nts and orexin populations in maintenance of behavior and body weight. In contrast, chemogenetic inhibition of intact LHA Nts neurons did not disrupt orexin expression, but it suppressed locomotor activity and the adaptive response to leptin. Taken together, these data reveal the necessity of LHA Nts neurons and their activation for controlling energy balance, and that LHA Nts neurons influence behavior and body weight via orexin-dependent and orexin-independent mechanisms. PMID- 30010832 TI - Coordination of Ovulation and Oocyte Maturation: A Good Egg at the Right Time. AB - Ovulation is the appropriately timed release of a mature, developmentally competent oocyte from the ovary into the oviduct, where fertilization occurs. Importantly, ovulation is tightly linked with oocyte maturation, demonstrating the interdependency of these two parallel processes, both essential for female fertility. Initiated by pituitary gonadotropins, the ovulatory process is mediated by intrafollicular paracrine factors from the theca, mural, and cumulus granulosa cells, as well as the oocyte itself. The result is the induction of cumulus expansion, proteolysis, angiogenesis, inflammation, and smooth muscle contraction, which are each required for follicular rupture. These complex intercellular communication networks and the essential ovulatory genes have been well defined in mouse models and are highly conserved in primates, including humans. Importantly, recent discoveries in regulation of ovulation highlight new areas of investigation. PMID- 30010831 TI - Energy shifts induce membrane sequestration of DraG in Rhodospirillum rubrum independent of the ammonium transporters and diazotrophic conditions. AB - Metabolic regulation of Rhodospirillum rubrum nitrogenase is mediated at the post translational level by the enzymes DraT and DraG when subjected to changes in nitrogen or energy status. DraT is activated during switch-off whileDraG is inactivated by reversible membrane association. We confirm here that the ammonium transporter, AmtB1, rather than its paralog AmtB2, is required for ammonium induced switch off. Amongst several substitutions at the N100 position in DraG, only N100K, failed to locate to the membrane following ammonium shock, suggesting loss of interaction through charge repulsion. When switch off was induced by lowering energy levels, either by darkness during photosynthetic growth or oxygen depletion under respiratory conditions, reversible membrane sequestration of DraG was independent of AmtB proteins and occurred even under non-diazotrophic conditions. We propose that under these conditions, changes in redox status or possibly membrane potential induce interactions between DraG and another membrane protein in response to the energy status. PMID- 30010833 TI - Animal Models for Preclinical Development of Allogeneic Hematopoietic Cell Transplantation. AB - Since its inception in the 1950s, hematopoietic cell transplantation (HCT) has become a highly effective clinical treatment for malignant and nonmalignant hematological disorders. This milestone in cancer therapy was only possible through decades of intensive research using murine and canine animal models that overcame what appeared in the early days to be insurmountable obstacles. Conditioning protocols for tumor ablation and immunosuppression of the recipient using irradiation and chemotherapeutic drugs were developed in mouse and dog models as well as postgrafting immunosuppression methods essential for dependable donor cell engraftment. The random-bred canine was particularly important in defining the role of histocompatibility barriers and the development of the nonmyeloablative transplantation procedure, making HCT available to elderly patients with comorbidities. Two complications limit the success of HCT: disease relapse and graft versus host disease. Studies in both mice and dogs have made significant progress toward reducing and to some degree eliminating patient morbidity and mortality associated with both disease relapse and graft versus host disease. However, more investigation is needed to make HCT more effective, safer, and available as a treatment modality for other non-life-threatening diseases such as autoimmune disorders. Here, we focus our review on the contributions made by both the murine and canine models for the successful past and future development of HCT. PMID- 30010834 TI - Hoarseness after radical surgery with systematic lymph node dissection for primary lung cancer. AB - OBJECTIVES: Radical surgery with systematic upper mediastinal node dissection for primary lung cancer can cause recurrent laryngeal nerve (RLN) paralysis, but this is poorly reported. METHODS: We retrospectively reviewed the clinical data for consecutive patients who underwent radical surgery for primary lung cancer with an observation period of at least 12 months. During follow-up, hoarseness and vocal fold movement were assessed clinically and laryngoscopically, respectively. RESULTS: Of the 365 patients included in this study, 22 (6.0%) experienced hoarseness as a complication. All 22 patients who experienced hoarseness had undergone upper mediastinal node dissection. Although 1 of the 22 patients refused to undergo laryngoscopy, we assessed the vocal fold movement in the remaining patients (95.5%). Among these, 5 patients (23.8%) had right RLN paralysis, and 15 (71.4%) had left RLN paralysis and showed no sign of RLN paralysis. Over 1-24 months, vocal cord movement improved in 61.1% (11/18); and over 1-28 months, hoarseness improved in 72.7% (16/22). All patients with right RLN paralysis improved without further treatment. CONCLUSIONS: We conclude that extensive follow-up is necessary to discern whether hoarseness is a temporary or permanent complication of radical surgery in patients with primary lung cancer who have undergone systematic lymph node dissection. PMID- 30010835 TI - A web-based dietary intervention in early pregnancy and neonatal outcomes: a randomized controlled trial. AB - Background: Maternal nutrition is a determinant of pregnancy outcomes. Few studies have evaluated the potential of online nutrition resources to modify behaviour. This randomized controlled trial aimed to determine whether access to a customized evidence-based nutrition website in pregnancy improved neonatal outcomes. Methods: Women <18 weeks gestation were recruited at their convenience. The control group received standard care. In addition to standard care, the intervention group received access to an evidence-based nutrition website, customized to the preferences of pregnant women. Results: Of the 250 women, there were no differences in characteristics between the two groups. Of the women, 91.0% reported they make a conscious effort currently to eat a healthy diet. However, only 19.6% met dietary requirements for calcium, 13.2% for iron, 2.7% for folate and 2.3% for iodine. The most popular website section was pregnancy nutrition advice but engagement was not sustained. Access to the website was not associated with any improvement in clinical outcomes (P > 0.05). Conclusions: We found that provision of a customized website providing nutrition information, did not improve neonatal outcomes. Future studies should explore whether redesign with website interactivity or embedding information on popular digital platforms sustains women's engagement and modifies dietary behaviour. PMID- 30010836 TI - Validation of a rapid and simple high-performance liquid chromatography electrospray ionization-mass spectrometry method for simultaneous analysis of 15 key chemicals in slimming foods and herbal products. AB - A rapid and simple high-performance liquid chromatography/electrospray ionization tandem mass spectrometry method was developed for simultaneous analysis of 15 key chemicals in slimming foods and herbal products. These chemicals were strictly restricted adulterants (phenolphthalein, sibutramine, fenfluramine, clopamide, ephedrine, norpseudoephedrine, caffeine and phenformin) and physiologically relevant active components (l-carnitine, nuciferine, aloe-emodin, rhein, emodin, chrysophanol and physcion). In multi-day validations, intra- (n = 5) and inter day precision (n = 3), limits of detection and limits of quantification for all analytes were 0.60-7.22%, 0.75-9.45%, 0.09-10 MUg/L and 0.30-33.3 MUg/L, respectively. Mean recovery ranged from 71.4% to 116% for all analytes in three representative samples. The method was validated on 17 samples including 12 kinds of slimming foods and five kinds of herbal products, and was shown to be ideal for routine quantification of 15 key chemicals in slimming foods and herbal products, providing an efficient strategy for quality control and food safety evaluation of weight reducing supplements. PMID- 30010837 TI - The conditioned medium of human mesenchymal stromal cells reduces irradiation induced damage in cardiac fibroblast cells. AB - Recently, multipotent mesenchymal stromal cell (MSC) treatment has attracted special attention as a new alternative strategy for stimulating regeneration. Irradiation myocardial fibrosis (IMF) is a major complication associated with total body irradiation for hematopoietic stem cell transplantation, nuclear accidents, and thoracic radiotherapy for lung cancer, esophageal cancer, proximal gastric cancer, breast cancer, thymoma, and lymphoma. The aim of the present study was to assess the therapeutic paracrine effects of human umbilical cord derived mesenchymal stromal cells (UC-MSCs) in the cell model of IMF. For this purpose, primary human cardiac fibroblasts (HCF) cells were irradiated and cultured with the conditioned medium of UC-MSCs (MSCCM). MSCCM promoted cell viability, reduced collagen deposition as measured by Sircol assay and qPCR (Col1A1 and Col1A2), prevented oxidative stress and increased antioxidant status (as measured by malondialdehyde content and the activities and mRNA levels of antioxidant enzymes), and reduced pro-fibrotic TGF-beta1, IL-6 and IL-8 levels (as examined by ELISA kit and qPCR). Pretreatment with inhibitor of NF-kappaB led to a decrease in the levels of TGF-beta1 in cell lysate of HCF cells by ELISA kit. Furthermore, we also found that MSCCM prevented NF-kappaB signaling pathway activation for its proinflammatory actions induced by irradiation. Taken together, our data suggest that MSCCM could reduce irradiation-induced TGF-beta1 production through inhibition of the NF-kappaB signaling pathway. These data provide new insights into the functional actions of MSCCM on irradiation myocardial fibrosis. PMID- 30010839 TI - Association of the rs495392 Klotho polymorphism with atheromatosis progression in patients with chronic kidney disease. AB - Background: Prevalence of atherosclerotic cardiovascular disease and its rate of progression are higher in patients with chronic kidney disease (CKD) compared with the general population. Mineral metabolism parameters have been shown to be involved in the increased velocity of atheromatosis progression. The aim of this study is to determine the role of 11 single-nucleotide polymorphisms (SNPs) of the Klotho gene on the rate of atherosclerosis progression in CKD. Methods: This was a multicentre, prospective, observational study of 1439 CKD patients from the NEFRONA cohort. Carotid and femoral ultrasounds were performed at baseline and after 24 months in 10 arterial territories. Progression of atheromatosis was defined as an increase in the number of territories with plaque. Genotyping of 11 SNPs of the Klotho gene was performed and its association with atheromatosis progression was determined by multivariate logistic regression. Results: Bivariate analysis showed that none of the 11 SNPs was associated with atheroma plaque prevalence, but 3 of them (rs495392, rs562020 and rs567170) showed association with atheromatosis progression. The multivariate analysis revealed that only rs495392 showed a statistically significant association with atheromatosis progression, after adjustment for several parameters known to affect it in CKD patients. Thus, the presence of one allele T was associated with a reduction of 30% of the odds of progression, whereas the presence of the two T alleles was associated with a decrease close to 50%. Conclusions: The presence of the allele T of the SNP rs495392 of the Klotho gene is associated with a decrease in the odds of progression of atheromatosis in CKD patients. PMID- 30010840 TI - The importance of mass diameter in decision-making for preoperative coronary angiography in myxoma patients. AB - OBJECTIVES: Although coronary angiography (CAG) is generally performed to rule out coexisting coronary artery disease in patients with cardiac myxoma, its necessity to evaluate vascular supply of the myxoma is debatable. The aim of this article is to evaluate clinical experience and CAG findings in our patient group. METHODS: This retrospective analysis was performed in 46 patients (17 men, mean age 57.7 +/- 8.6 years), who underwent surgery with an indication for cardiac myxoma between 2004 and 2016 with a CAG performed preoperatively. All CAGs were evaluated in a blinded manner by a cardiac surgeon and a cardiologist separately. Correlations between the presence and pattern of feeding vessels, presence of an arteriocavity fistula (ACF), coronary arterial dominance, size of mass and clinical presentations were analysed. RESULTS: Coronary artery disease defined as >50% obstructive lesions was detected in 10 patients (21.7%). The tumour diameter was found to be significantly higher in patients who had an ACF and a dual feeding artery (P = 0.049 and P = 0.0001, respectively). Additionally, there was a significant relationship between the presence of dual-feeding vessels and ACF (P = 0.014). ROC analysis revealed a cut-off point of 27 mm in diameter based on the presence of an ACF and a dual-feeding artery. In cases with a diameter of 27 mm or above, the risk of existence of an ACF was 4.68-fold greater, with a confidence interval of 95%, and a dual-feeding pattern was seen in all of them. CONCLUSIONS: This study suggests that preoperative CAG can be considered to detect feeding vessels that may lead to a steal phenomenon, which may alter the management in patients with myxoma greater than 27 mm in diameter. PMID- 30010838 TI - Hybrid positron emission tomography-magnetic resonance of the heart: current state of the art and future applications. AB - Hybrid positron emission tomography-magnetic resonance (PET-MR) imaging is a novel imaging modality with emerging applications for cardiovascular disease. PET MR aims to combine the high-spatial resolution morphological and functional assessment afforded by magnetic resonance imaging (MRI) with the ability of positron emission tomography (PET) for quantification of metabolism, perfusion, and inflammation. The fusion of these two modalities into a single imaging platform not only represents an opportunity to acquire complementary information from a single scan, but also allows motion correction for PET with reduction in ionising radiation. This article presents a brief overview of PET-MR technology followed by a review of the published literature on the clinical cardio-vascular applications of PET and MRI performed separately and with hybrid PET-MR. PMID- 30010841 TI - Agricultural contamination impacts antibiotic resistance gene abundances in river bed sediment temporally. AB - Kewaunee County, Wisconsin is an agricultural area dominated by concentrated animal feeding operations and manure fertilized cropland. The objective of this study was to characterize chemical and antibiotic resistance gene (ARG) profiles of 20 surface water locations in Kewaunee County to better understand relationships between agricultural contamination and ARG abundance over one year. Surface water (n = 101) and bed sediment (n = 93) were collected from 20 sites during five timepoints between July 2016 and May 2017. Samples were analyzed for six genes (erm(B), tet(W), sul1, qnrA, intI1 and 16S rRNA) and water chemistry and pollution indicators. qnrA, intI1 and sul1 genes in surface water were significantly higher than erm(B) and tet(W); however, no difference was present in sediment samples. Redundancy analysis identified positive correlations of nitrate, Escherichia coli, and coliforms with tet(W) and intI1 genes in sediment and intI1, sul1 and tet(W) genes in water. Temporal patterns of ARG abundance were identified with significantly higher gene abundances found in sediment during Kewaunee County's manure fertilization period; however, surface water patterns were not distinct. Together, these results suggest Kewaunee County sediments serve as a site of accumulation for non-point source agricultural pollution and ARGs on a temporal scale associated with manure fertilization. PMID- 30010842 TI - Fluorescence spectroscopic detection and measurement of single telomere molecules. AB - Telomeres are the end-caps of chromosomes that serve to protect the integrity of the genome. Below certain critical lengths, the telomeres can no longer fulfill their protective function, and chromosomal instability ensues. Telomeres shorten during normal cell division due to the end replication problem and are implicated in the development of various aging-associated diseases, including cancer. Telomere length has the potential to serve as a useful biomarker in the field of aging and cancer. However, existing methods of telomere measurement are either too laborious, unable to provide absolute measurement of individual telomere lengths, or limited to certain chromosomes or cell types. Here, we describe an easy single-molecule, fluorescence spectroscopic method for measuring the length of telomeres that permits the profiling of absolute telomere lengths in any DNA sample. We have demonstrated the accurate detection of telomeres as short as 100 bp using cloned telomere standards, and have profiled telomere lengths in human cancer cell lines and primary cells. Since this method allows direct comparison between samples, it could greatly improve the clinical utility of telomere biomarkers. PMID- 30010845 TI - Gene Signature of Proliferating Human Pancreatic alpha Cells. AB - Pancreatic alpha cells proliferate at a low rate, and little is known about the control of this process. Here we report the characterization of human alpha cells by large-scale, single-cell RNA sequencing coupled with pseudotime ordering. We identified two large subpopulations and a smaller cluster of proliferating alpha cells with increased expression of genes involved in cell-cycle regulation. The proliferating alpha cells were differentiated, had normal levels of GCG expression, and showed no signs of cellular stress. Proliferating alpha cells were detected in both the G1S and G2M phases of the cell cycle. Human alpha cells proliferate at a fivefold higher rate than human beta cells and express lower levels of the cell-cycle inhibitors CDKN1A and CDKN1C. Collectively, this study provides the gene signatures of human alpha cells and the genes involved in their cell division. The lower expression of two cell-cycle inhibitors in human alpha cells could account for their higher rate of proliferation compared with their insulin-producing counterparts. PMID- 30010846 TI - Who needs editors? The epidemiology of publications in the IJE. PMID- 30010843 TI - Audio-Tactile and Peripersonal Space Processing Around the Trunk in Human Parietal and Temporal Cortex: An Intracranial EEG Study. AB - Interactions with the environment happen within one's peripersonal space (PPS) the space surrounding the body. Studies in monkeys and humans have highlighted a multisensory distributed cortical network representing the PPS. However, knowledge about the temporal dynamics of PPS processing around the trunk is lacking. Here, we recorded intracranial electroencephalography (iEEG) in humans while administering tactile stimulation (T), approaching auditory stimuli (A), and the 2 combined (AT). To map PPS, tactile stimulation was delivered when the sound was far, intermediate, or close to the body. The 19% of the electrodes showed AT multisensory integration. Among those, 30% showed a PPS effect, a modulation of the response as a function of the distance between the sound and body. AT multisensory integration and PPS effects had similar spatiotemporal characteristics, with an early response (~50 ms) in the insular cortex, and later responses (~200 ms) in precentral and postcentral gyri. Superior temporal cortex showed a different response pattern with AT multisensory integration at ~100 ms without a PPS effect. These results, represent the first iEEG delineation of PPS processing in humans and show that PPS and multisensory integration happen at similar neural sites and time periods, suggesting that PPS representation is based on a spatial modulation of multisensory integration. PMID- 30010847 TI - Aquaporin 11 rs2276415 variant and progression of chronic kidney disease. AB - Background: The Aquaporin 11 (AQP11) rs2276415 variant has been implicated in kidney disease in Type 2 diabetes. Association of the AQP11 variant with chronic kidney disease (CKD) beyond diabetic nephropathy is unknown, with no studies reported in the Chinese population. We explored the risk of CKD progression associated with the AQP11 rs2276415 variant in a population-based study in China. Methods: We conducted a prospective cohort study of 620 participants with CKD (Stages 2-5 and who were not receiving dialysis) at the Nephrology Center of First Affiliated Hospital of Jiaxing University between July 2011 and December 2014 and followed up for 3 years. Incident CKD progression, defined as an increase in creatinine levels of at least 0.4 mg/dL (35 umol/L) above baseline or maintenance dialysis initiation or transplantation, was examined by AQP11 genotypes. Results: During the follow-up period, CKD progression developed in 170 individuals. Cumulative events-free survival was significantly dependent on AQP11 genotypes with an apparent gene-dose effect (log-rank P < 0.001). Adjusting for sex, age and major CKD risk factors, the A allele of AQP11 gene (GA + AA) increased the risk of CKD progression by 1.92 (95% confidence interval 1.31- 2.84). Conclusions: The AQP11 rs2276415 variant predicts CKD progression in the Chinese population, independent of traditional risk factors. Exploring the pathways mediating the association may shed light on novel therapeutic targets in the pathophysiology of CKD. PMID- 30010848 TI - Development of significant tricuspid regurgitation over time and prognostic implications: new insights into natural history. AB - Aims: To evaluate the risk factors influencing the development of significant (moderate and severe) tricuspid regurgitation (TR), and its impact on all-cause mortality in large registry of referral centre. Methods and results: In 1000 patients (mean age 68 +/- 13 years; 50.9% male) with documented significant TR, clinical, and echocardiographic data were retrospectively analysed when the echocardiogram showed none/mild TR. Patients with congenital heart disease were excluded. The study population was divided into quartiles according to the time interval between the two echocardiograms: Group 1: <=1.2 years, n = 251; Group 2: 1.3-4.7 years, n = 248, Group 3: 4.8-8.9 years, n = 251; Group 4: >=9.0 years, n = 250. Baseline age [odds ratio (OR) 1.02], presence of pacemaker and defibrillator lead (OR 1.59), presence of mild (vs. none) TR (OR 8.96), reduced tricuspid annulus plane systolic excursion (OR 0.86), and tricuspid annulus dilation (OR 1.06) were independently associated with development of significant TR in a short period of time. Any valvular surgery (without concomitant tricuspid surgery) occurring between both echocardiograms was also associated with a higher risk of fast development of significant TR (OR 1.58). During a median follow-up of 2.9 years after the second echocardiogram (with significant TR), 42.1% patients died. Patients with fast development of significant TR showed worse survival than patients with slower significant TR development (log rank P = 0.001). Fast development of significant TR was independently associated with all cause mortality (hazard ratio per preceding year of development: 0.92, confidence interval 0.90-0.94; P < 0.001). Conclusion: By identifying patients at increased risk of developing significant TR, close echocardiographic surveillance can be indicated permitting effective therapy at an earlier stage to improve survival. PMID- 30010844 TI - KNDy Cells Revisited. AB - In the past decade since kisspeptin/neurokinin B/dynorphin (KNDy) cells were first identified in the mammalian hypothalamus, a plethora of new research has emerged adding insights into the role of this neuronal population in reproductive neuroendocrine function, including the basis for GnRH pulse generation and the mechanisms underlying the steroid feedback control of GnRH secretion. In this mini-review, we provide an update of evidence regarding the roles of KNDy peptides and their postsynaptic receptors in producing episodic GnRH release and assess the relative contribution of KNDy neurons to the "GnRH pulse generator." In addition, we examine recent work investigating the role of KNDy neurons as mediators of steroid hormone negative feedback and review evidence for their involvement in the preovulatory GnRH/LH surge, taking into account species differences that exist among rodents, ruminants, and primates. Finally, we summarize emerging roles of KNDy neurons in other aspects of reproductive function and in nonreproductive functions and discuss critical unresolved questions in our understanding of KNDy neurobiology. PMID- 30010849 TI - Mycobacterium tuberculosis H37Rv expresses differential proteome during intracellular survival within alveolar epithelial cells compared with macrophages. AB - Mycobacterium tuberculosis survives within the infected host cells by escaping phagolysosomal fusion and adaptation to hosts' intracellular milieu. Recently, the role of alveolar epithelial cells (AECs) in the survival of intracellular M. tuberculosis has gained importance. It has been reported that M. tuberculosis causes cytotoxicity in AECs, a phenotype attributed to M. tuberculosis virulence that could be due to the differential gene/protein expression of bacilli in these cells. Thus, the present study focused on comparative proteomic analysis of intracellular mycobacteria within macrophages and epithelial cells. Intracellular mycobacteria from infected alveolar epithelial (A549) and macrophage (THP-1) cell lines were harvested, and two-dimensional polyacrylamide gel electrophoresis of mycobacterial proteins was performed. The protein spots of interest were picked and MALDI-TOF/MS was performed to identify proteins. Differential expression of 11 mycobacterial proteins was found in infected AECs, out of which six proteins were confirmed by MS/MS analysis. The identified proteins mainly belonged to functional categories of virulence, detoxification and adaptation, and are known to take part in metabolism and respiration, maintenance of virulence and survival during stress. These proteins were predicted to contain peptide motifs possessing cell-penetration ability. Expression of such proteins by intracellular mycobacteria could be essential for survival and persistence in AECs in its virulent state, thus contributing to disease pathogenesis. PMID- 30010850 TI - Growth of HIV-1 Molecular Transmission Clusters in New York City. AB - Background: HIV-1 genetic sequences can be used to infer viral transmission history and dynamics. Throughout the United States, HIV-1 sequences from drug resistance testing are reported to local public health departments. Methods: We investigated whether inferred HIV transmission network dynamics can identify individuals and clusters of individuals most likely to give rise to future HIV cases in a surveillance setting. We used HIV-TRACE, a genetic distance-based clustering tool, to infer molecular transmission clusters from HIV-1 pro/RT sequences from 65736 people in the New York City surveillance registry. Logistic and LASSO regression analyses were used to identify correlates of clustering and cluster growth, respectively. We performed retrospective transmission network analyses to evaluate individual- and cluster-level prioritization schemes for identifying parts of the network most likely to give rise to new cases in the subsequent year. Results: Individual-level prioritization schemes predicted network growth better than random targeting. Across the 3600 inferred molecular transmission clusters, previous growth dynamics were superior predictors of future transmission cluster growth compared to individual-level prediction schemes. Cluster-level prioritization schemes considering previous cluster growth relative to cluster size further improved network growth predictions. Conclusions: Prevention efforts based on HIV molecular epidemiology may improve public health outcomes in a US surveillance setting. PMID- 30010851 TI - Magnetic resonance imaging surrogates of molecular subgroups in atypical teratoid/rhabdoid tumor. AB - Background: Recently, 3 molecular subgroups of atypical teratoid/rhabdoid tumor (ATRT) were identified, but little is known of their clinical and magnetic resonance imaging (MRI) characteristics. Methods: A total of 43 patients with known molecular subgroup status (ATRT-sonic hedgehog [SHH], n = 17; ATRT-tyrosine [TYR], n = 16; ATRT-myelocytomatosis oncogene [MYC], n = 10) were retrieved from the EU-RHAB Registry and analyzed for clinical and MRI features. Results: On MRI review, differences in preferential tumor location were confirmed, with ATRT-TYR being predominantly located infratentorially (P < 0.05). Peritumoral edema was more pronounced in ATRT-MYC compared with ATRT-SHH (P < 0.05) and ATRT-TYR (P < 0.05). Conversely, peripheral tumor cysts were found more frequently in ATRT-SHH (71%) and ATRT-TYR (94%) compared with ATRT-MYC (40%, P < 0.05). Contrast enhancement was absent in 29% of ATRT-SHH (0% of ATRT-TYR; 10% of ATRT-MYC; P < 0.05), and there was a trend toward strong contrast enhancement in ATRT-TYR and ATRT-MYC. We found the characteristic (bandlike) enhancement in 28% of ATRT as well as restricted diffusion in the majority of tumors. A midline/off-midline location in the posterior fossa was also not subgroup specific. Visible meningeal spread (M2) at diagnosis was rare throughout all subgroups. Conclusion: These exploratory findings suggest that MRI features vary across the 3 molecular subgroups of ATRT. Within future prospective trials, MRI may aid diagnosis and treatment stratification. PMID- 30010852 TI - Can economic incentives increase the use of home dialysis? AB - There are advantages to home dialysis for patients, and kidney care programs, but use remains low in most countries. Health-care policy-makers have many levers to increase use of home dialysis, one of them being economic incentives. These include how health-care funding is provided to kidney care programs and dialysis facilities; how physicians are remunerated for care of home dialysis patients; and financial incentives-or removal of disincentives-for home dialysis patients. This report is based on a comprehensive literature review summarizing the impact of economic incentives for home dialysis and a workshop that brought together an international group of policy-makers, health economists and home dialysis experts to discuss how economic incentives (or removal of economic disincentives) might be used to increase the use of home dialysis. The results of the literature review and the consensus of workshop participants were that financial incentives to dialysis facilities for home dialysis (for instance, through activity-based funding), particularly in for-profit systems, could lead to a small increase in use of home dialysis. The evidence was less clear on the impact of economic incentives for nephrologists, and participants felt this was less important than a nephrologist workforce in support of home dialysis. Workshop participants felt that patient-borne costs experienced by home dialysis patients were unjust and inequitable, though participants noted that there was no evidence that decreasing patient-borne costs would increase use of home dialysis, even among low-income patients. The use of financial incentives for home dialysis-whether directed at dialysis facilities, nephrologists or patients-is only one part of a high performing system that seeks to increase use of home dialysis. PMID- 30010854 TI - Relationship of diversity and the secondary structure in 16S-23S rDNA internal transcribed spacer: a case in Vibrio parahaemolyticus. AB - The 16S-23S rDNA internal transcribed spacer (ITS) sequence, located in the rrn operon, has been analyzed and evaluated for use in phylogenetic analysis and the detection target of bacteria. The ITS region displays a high level of diversity, being present in multiple copies and displaying variability in both length and sequence, and it carries more phylogenetic information than 16S rDNA. However, appropriately identifying ITS regions to use in analyses is challenging. To solve this problem, we analyzed the ITS regions in Vibrio parahaemolyticus and predicted the secondary structure of each analogous rrn transcript. The genomic DNA of V. parahaemolyticus contains approximately 8-14 rrns, making it more complex than the sequences of most other bacterial species. We analyzed 216 ITSs, of which 206 ITSs come from 18 complete genomes, and 10 ITSs were identified in the present study. The subunits of each ITS were distinguished by their predicted secondary structures. We propose a refined backbone model of the V. parahaemolyticus ITS that can be applied to the sequences of other bacteria. The backbone includes C, V, tDNA and linker blocks. These blocks, which may represent true functional units, may be used as potential targets for phylogenetic analysis or molecular detection. PMID- 30010853 TI - TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma. AB - Background: Meningiomas are mostly benign tumors tending to progress to higher grade lesions. Mutations in the telomerase reverse transcriptase (TERT) gene promoter are comparably rare in meningioma, but were recently suggested to predict risk of recurrence and progression. Here we have analyzed a cohort of World Health Organization grades I-III meningiomas regarding the impact of TERT promoter mutations on patient prognosis and in vitro cell propagation feasibility. Methods: From 110 meningioma patients, 128 tissue samples were analyzed for the TERT promoter mutations C228T and C250T by direct sequencing. Of the 128 samples, 121 were tested for cell propagation in vitro. Telomerase activity, TERT mRNA expression, and telomere lengths were investigated by telomeric repeat amplification protocol assay, reverse transcription PCR, and quantitative PCR, respectively. Impact of the E-twenty-six (ETS) transcription factor inhibitor YK-4-279 on cell viability and TERT promoter activity was analyzed. Results: TERT promoter mutations were found in 5.5% of all samples analyzed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (P < 0.0001 both). Regarding telomere lengths, no significant difference between the TERT promoter wild-type and mutated subgroups was detected. Patients with TERT promoter mutated tumors exhibited significantly shorter overall survival (P = 0.0006; 53.8 vs 115.6 mo). The presence of TERT promoter mutations but not telomerase activity or TERT mRNA expression predicted indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4-279, inducing a distinct downregulation of TERT promoter activity. Conclusion: TERT promoter mutations drive meningioma aggressiveness, resulting in reduced patient survival, but might also open novel therapeutic options for progressive disease. PMID- 30010857 TI - Synaptic Mechanisms for Bandwidth Tuning in Awake Mouse Primary Auditory Cortex. AB - Spatial size tuning in the visual cortex has been considered as an important neuronal functional property for sensory perception. However, an analogous mechanism in the auditory system has remained controversial. In the present study, cell-attached recordings in the primary auditory cortex (A1) of awake mice revealed that excitatory neurons can be categorized into three types according to their bandwidth tuning profiles in response to band-passed noise (BPN) stimuli: nonmonotonic (NM), flat, and monotonic, with the latter two considered as non tuned for bandwidth. The prevalence of bandwidth-tuned (i.e., NM) neurons increases significantly from layer 4 to layer 2/3. With sequential cell-attached and whole-cell voltage-clamp recordings from the same neurons, we found that the bandwidth preference of excitatory neurons is largely determined by the excitatory synaptic input they receive, and that the bandwidth selectivity is further enhanced by flatly tuned inhibition observed in all cells. The latter can be attributed at least partially to the flat tuning of parvalbumin inhibitory neurons. The tuning of auditory cortical neurons for bandwidth of BPN may contribute to the processing of complex sounds. PMID- 30010856 TI - Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease. AB - Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx j) mouse model of WD corrected higher thioredoxin 1 (TNX1) transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of TXN1 and peroxiredoxin 1 (Prdx1) were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A WGBS comparison of human WD liver and tx-j mouse liver demonstrated a significant overlap of differentially methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin (TXN) pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on TXN system related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD. PMID- 30010859 TI - Trichoderma atroviride promotes tomato development and alters the root exudation of carbohydrates, which stimulates fungal growth and the biocontrol of the phytopathogen Phytophthora cinnamomi in a tripartite interaction system. AB - Several species of Trichoderma promote plant growth and help in defense against root pathogens. The role of root-exuded carbohydrates as chemo-attractive stimuli for Trichoderma colonization is attracting considerable interest. In this project, we studied the interaction between Trichoderma atroviride and tomato (Lycopersicon esculentum L. cv. Rio Grande) plants in two different stages, before and during root colonization. In addition, the biocontrol capacity of T. atroviride against the phytopathogen Phytophthora cinnamomi in a tripartite interaction system was examined. We found that the beneficial effects of T. atroviride on plant growth were fine-tuned depending on the progress of interaction. Interestingly, the composition of the carbohydrate exudate from plants interacting with T. atroviride was different from that produced by other treatments and probably provided a nutritional source for the fungus. Particularly, sucrose was found only during root colonization by the fungus. Our data show that root-derived sugars enabled a higher Trichoderma growth rate, and that, in the tripartite interaction system with P. cinnamomi, the fungus competes for space and available soil nutrients more efficiently than P. cinnamomi, thereby antagonizing the growth of the phytopathogen. PMID- 30010861 TI - Response of the European Ladybird Adalia bipunctata and the Invasive Harmonia axyridis to a Neonicotinoid and a Reduced-Risk Insecticide. AB - The spread of the multicolored Asian lady beetle Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae) in Europe coincided with the decline of the native Adalia bipunctata (L.) (Coleoptera: Coccinellidae). Both species are predators of aphids in orchards, and differential susceptibility to insecticides used to control fruit pests may contribute to explain the competitive advantage of the invasive over the native species. In this study, the insecticidal activity of imidacloprid and spinetoram was tested on third instars and adults of both ladybird species under laboratory conditions. Insects were exposed to insecticide residues on potted peach plants that were sprayed with the maximum recommended field doses (100 mg/liter for imidacloprid and 66.67 mg/liter for spinetoram). Mortality was scored after short (2 d for both stages) and long (7 and 10 d for adults and larvae, respectively) exposure periods. The susceptibility to the insecticides was very similar for H. axyridis and A. bipunctata. Imidacloprid caused a significant increase in the mortality of both stages of the two species for every exposure period. On the other hand, when exposed to spinetoram residues, larvae and adults of both ladybirds did not show higher mortality than controls after short and long exposure periods. The pest suppression provided by ladybirds, which could be severely hampered by the applications of nonselective pesticides, might be enhanced by the adoption of reduced-risk insecticides, selective for these beneficial insects. PMID- 30010860 TI - Measuring family planning quality and its link with contraceptive use in public facilities in Burkina Faso, Ethiopia, Kenya and Uganda. AB - The individual impacts of several components of family planning service quality on contraceptive use have been studied, but the influence of a composite measure synthesizing these components has not been often investigated. We (1) develop a composite score for family planning service quality based on health facility data from Burkina Faso, Ethiopia, Kenya and Uganda and (2) examine the influence of structural quality on contraceptive practice in these four countries. We used nationally representative cross-sectional survey data of health facilities and women of reproductive age. First, we constructed quality scores for facilities using principal component analysis to integrate 18 variables. Second, we linked women to their closest facility using geo-coordinates. Third, we estimated multivariable logistic regression models to calculate women's odds ratios for modern contraceptive use adjusting for facilities' quality and other factors. In Burkina Faso, Ethiopia and Uganda, the odds of using a modern method of contraception was greater if the nearest facility provided high- or medium quality services compared with low quality in the univariable model. After controlling for possible confounders, the adjusted odds ratios were significant for high quality (aOR: 3.12, P value: 0.005) and medium quality (aOR: 2.57, P value: 0.009) in Ethiopia and in the hypothesized direction but not statistically significant in Uganda or Burkina Faso, and in the opposite direction in Kenya. A process quality measure-having been visited by a community health worker-was statistically significantly associated with modern contraceptive use in three of the four countries (Burkina Faso aOR: 2.18, P value: 0.000; Ethiopia aOR: 1.78, P value: 0.000; Uganda aOR: 1.96, P value: 0.012). These results suggest that service quality in public facilities may be less relevant to contraceptive use in environments where the universe and reach of providers changes actively. Programs promoting contraception therefore need to consider quality within facility types and their service environments. PMID- 30010862 TI - Novel sequencing technologies to support industrial biotechnology. AB - Industrial biotechnology develops and applies microorganisms for the production of bioproducts and enzymes with applications ranging from food and feed ingredients and processing to bio-based chemicals, biofuels and pharmaceutical products. Next generation DNA sequencing technologies play an increasingly important role in improving and accelerating microbial strain development for existing and novel bio-products via screening, gene and pathway discovery, metabolic engineering and additional optimization and understanding of large scale manufacturing. In this mini-review, we describe novel DNA sequencing and analysis technologies with a focus on applications to industrial strain development, enzyme discovery and microbial community analysis. PMID- 30010863 TI - Halyomorpha halys (Hemiptera: Pentatomidae) Responses to Traps Baited With Pheromones in Peach and Apple Orchards. AB - Monitoring insect populations is a fundamental component of integrated pest management programs. In many cropping systems, monitoring is accomplished through captures in baited traps. The aggregation pheromone and pheromone synergist for the invasive Halyomorpha halys (Hemiptera: Pentatomidae) are known. We compared the response of H. halys to commercial lures in peach and apple orchards. Two commercial pheromone formulations, PHEROCON Trece BMSB ('Trece') and AgBio Inc. Stink Bug Xtra Combo ('Xtra Combo'), were compared with unbaited traps in peach orchards in 2015 and 2016 and in an apple orchard in 2016. In both crops and years, more H. halys responded to the Trece lure, and fruit from trees near baited traps had correspondingly higher injury. In both years, peach fruit near Trece baited traps had significantly higher feeding injury (52.2 +/- 5.0%) than fruit near Xtra Combo baited and unbaited traps (35.2 +/- 4.5% and 22.2 +/- 3.4%, respectively). Injury to apple fruit near baited traps in 2016 was significantly different from fruit near unbaited traps (Trece: 93.0 +/- 3.8%, Xtra Combo: 74.1 +/- 5.1%, and unbaited: 19.0 +/- 2.7%). A field response index, which quantifies attraction of H. halys to each lure, demonstrated an equal response to both lures in 2015 peach and a higher response to Trece lure in 2016 in both crops, which suggests the lure is pulling bugs from a larger area. We conclude that formulation differences, population pressure, and host plant species influence H. halys populations' response and resulting injury, and should be considered for trap-based decision management. PMID- 30010858 TI - A historical review of blastocyst implantation research. AB - Research development on blastocyst implantation was reviewed in three sections: primate implantation, ungulate farm animal implantation, and the general process of blastocyst implantation in small rodents. Future research directions of this area are suggested. PMID- 30010864 TI - Metabotropic glutamate type 5 receptor requires contactin-associated protein 1 to control memory formation. AB - The hippocampus is a key brain region for memory formation. Metabotropic glutamate type 5 receptors (mGlu5R) are strongly expressed in CA1 pyramidal neurons and fine-tune synaptic plasticity. Accordingly, mGlu5R pharmacological manipulation may represent an attractive therapeutic strategy to manage hippocampal-related neurological disorders. Here, by means of a membrane yeast two-hybrid screening, we identified contactin-associated protein 1 (Caspr1), a type I transmembrane protein member of the neurexin family, as a new mGlu5R partner. We report that mGlu5R and Caspr1 co-distribute and co-assemble both in heterologous expression systems and in rat brain. Furthermore, downregulation of Caspr1 in rat hippocampal primary cultures decreased mGlu5R-mediated signaling. Finally, silencing Caspr1 expression in the hippocampus impaired the impact of mGlu5R on spatial memory. Our results indicate that Caspr1 plays a pivotal role controlling mGlu5R function in hippocampus-dependent memory formation. Hence, this new protein-protein interaction may represent novel target for neurological disorders affecting hippocampal glutamatergic neurotransmission. PMID- 30010865 TI - Implications of phytate in plant-based foods for iron and zinc bioavailability, setting dietary requirements, and formulating programs and policies. AB - Plant-based diets in low-income countries (LICs) have a high content of phytic acid (myo-inositol hexaphosphate [InsP6]) and associated magnesium, potassium, and calcium salts. Together, InsP6 acid and its salts are termed "phytate" and are potent inhibitors of iron and zinc absorption. Traditional food processing can reduce the InsP6 content through loss of water-soluble phytate or through phytase hydrolysis to lower myo-inositol phosphate forms that no longer inhibit iron and zinc absorption. Hence, some processing practices can reduce the need for high-dose iron fortificants in plant-based diets and alleviate safety concerns. Dietary phytate-to-iron and phytate-to-zinc molar ratios are used to estimate iron and zinc bioavailability and to identify dietary iron and zinc requirements according to diet type. The European Food Safety Authority has set adult dietary zinc requirements for 4 levels of phytate intake, highlighting the urgent need for phytate food composition data. Such data will improve the ability to estimate the prevalence of inadequate zinc intakes in vulnerable groups in LICs, which will facilitate implementation of targeted policies to alleviate zinc deficiency. PMID- 30010867 TI - Reply: Is the association of replete status in vitamin D with better results in IVF demonstrated? PMID- 30010866 TI - Recombination Signal in Mycobacterium tuberculosis Stems from Reference-guided Assemblies and Alignment Artefacts. AB - DNA acquisition via genetic recombination is considered advantageous as it has the potential to bring together beneficial mutations that emerge independently within a population. Furthermore, recombination is considered to contribute to the maintenance of genome stability by purging slightly deleterious mutations. The prevalence of recombination differs among prokaryotic species and depends on the accessibility of DNA transfer mechanisms. An exceptional example is the human pathogen Mycobacterium tuberculosis (MTB) where no clear transfer mechanisms have been so far characterized and the presence of recombination is questioned. Here, we analyze completely assembled MTB genomes in search for evidence of recombination. We find that putative recombination events are enriched in strains reconstructed by reference-guided assembly and in regions with unreliable alignments. In addition, assembly and alignment artefacts introduce phylogenetic signals that are conflicting the established MTB phylogeny. Our results reveal that the so far reported recombination events in MTB are likely to stem from methodological artefacts. We conclude that no reliable signal of recombination is observed in the currently available MTB genomes. Moreover, our study demonstrates the limitations of reference-guided genome assembly for phylogenetic reconstructions. Rigorously de novo assembled genomes of high quality are mandatory in order to distinguish true evolutionary signal from noise, in particular for low diversity species such as MTB. PMID- 30010868 TI - Right Retrosigmoid Approach for In Situ Occlusion of Brainstem Arteriovenous Malformation Surrounding the Trigeminal Nerve: 3-Dimensional Operative Video. AB - Arteriovenous malformations (AVMs) of the trigeminal root entry zone are rare and can be associated with neurovascular compression syndromes as well as intracranial hemorrhage.1 They generally have a small nidus located on and around the pial surface of the brainstem; thus, they are feasible for surgery. Nevertheless, they represent a challenge given the vicinity and involvement of cranial nerves and brainstem perforators.2-4This video demonstrates the case of a 57-yr-old man with new onset of a severe headache without neurological deficit associated with MRI evidence of a vascular malformation around the cisternal right trigeminal nerve. The nerve showed an altered signal on the MRI. Angiography revealed a Spetzler-Martin grade II AVM with a 16-mm nidus supplied by basilar artery perforators, right anterior inferior cerebellar artery, and the superior cerebellar artery (SCA), with drainage into the superior petrosal vein and sigmoid sinus. After an unsuccessful attempted embolization, the patient was referred for and elected microsurgical treatment. With the patient in a lateral position, a right retrosigmoid approach was performed. After cisternal dissection and identification of the nidus, the feeders were occluded by alternating cauterization and clipping to avoid damage to the critical surrounding structures. The AVM in-situ occlusion was carried on without resection, given the involvement of the trigeminal nerve. The intraoperative indocyanine green angiography allowed recognition of the venous drainage and helped to localize and differentiate the feeders from normal perforators. In the immediate postoperative course, the patient suffered from mild numbness with a V2-V3 distribution that progressively improved. Angiography showed no residual AVM. PMID- 30010869 TI - Fully Endoscopic Supracerebellar Infratentorial Approach for Resection of Third Ventricle Germ Cell Tumor: 2-Dimensional Operative Video. AB - Pineal tumor that extends into the posterior portion of the third ventricle is extremely deep-seated and surgically challenging. Various microscopic approaches have been introduced to acquire access to the posterior third ventricle, but still the exposure and visualization are relatively unfavorable. However, recently the application of high-definition endoscope gave neurosurgeons a much more magnified and clearer view of anatomy around the pineal region and third ventricle. The widely used supracerebellar infratentorial approach has been proven to offer a sufficient surgical corridor for fully endoscopic surgery for pineal tumor.We presented a case of a 13-yr-old male child with a posterior third ventricle tumor, which was surgically resected fully with the endoscope. An informed consent has been obtained from the patient and his guardians. In order to gain enough auto-retraction by gravity, diminish the pitfalls of the semisitting position, and enhance the surgeon's ergonomics, the patient was positioned with a modified "head-up" park bench position (the upper body was elevated and the head was slightly extended instead of anteflexion). The tumor was approached through suboccipital midline supracerebellar infratentorial trajectory. The superficial and deep drainage veins above the vermis were sacrificed and the quadrigeminal cistern was entered to expose the tumor. The first and the most important step of the operation was to de-vascularize the tumor bilaterally, then the tumor could be debulked and circumferentially resected. The gross total resection was achieved.Fully endoscopic supracerebellar infratentorial approach is feasible and efficient when addressing lesions located at the posterior portion of the third ventricle. PMID- 30010870 TI - Is the association of replete status in vitamin D with better results in IVF demonstrated? PMID- 30010872 TI - Letter: Comparison of different vitamin E forms is confounded by heterogeneity in vitamin E effects. PMID- 30010871 TI - Commentary: Surgical Outcomes Following Repeat Transsphenoidal Surgery for Nonfunctional Pituitary Adenomas: A Retrospective Comparative Study. PMID- 30010874 TI - Semantic Congruence Alters Functional Connectivity during Olfactory-Visual Perception. AB - Previous research has shown that humans struggle to interpret multiple perceptual signals when the information provided by these signals is incongruent. In the context of olfactory-visual integration, behavioral and neuronal differences in response to congruent and incongruent stimulus pairs have been established. Here, we explored functional connectivity of the human brain with regard to the perception of congruent and incongruent food stimuli. Participants were simultaneously presented olfactory and visual stimuli of 4 different food objects, 2 healthy and 2 unhealthy objects. Stimulus pairs were grouped into "congruent" (olfactory and visual presentation of the same object), "semi congruent" (stimuli of similar "healthiness"), and "incongruent" (healthy unhealthy stimulus combination). Using functional magnetic resonance imaging and psychophysiological interaction (PPI) analyses, we revealed part of a neural network, the nodes of which show differential connectivity depending on the level of congruency of the presented stimulus combinations. This network relies strongly on, mostly left, inferior frontal gyrus. The analysis of such network transcends standard subtractive designs and indicates the need for more detailed formulations of neuronal models and increased specificity in functional imaging. PMID- 30010873 TI - Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis. AB - Axon degeneration occurs in all neurodegenerative diseases, but the molecular pathways regulating axon destruction during neurodegeneration are poorly understood. Sterile Alpha and TIR Motif Containing 1 (Sarm1) is an essential component of the prodegenerative pathway driving axon degeneration after axotomy and represents an appealing target for therapeutic intervention in neurological conditions involving axon loss. Amyotrophic lateral sclerosis (ALS) is characterized by rapid, progressive motor neuron degeneration and muscle atrophy, causing paralysis and death. Patient tissue and animal models of ALS show destruction of upper and lower motor neuron cell bodies and loss of their associated axons. Here, we investigate whether loss of Sarm1 can mitigate motor neuron degeneration in the SOD1G93A mouse model of ALS. We found no change in survival, behavioral, electrophysiogical or histopathological outcomes in SOD1G93A mice null for Sarm1. Blocking Sarm1-mediated axon destruction alone is therefore not sufficient to suppress SOD1G93A-induced neurodegeneration. Our data suggest the molecular pathways driving axon loss in ALS may be Sarm1-independent or involve genetic pathways that act in a redundant fashion with Sarm1. PMID- 30010875 TI - Statistical primer: checking model assumptions with regression diagnostics. AB - Regression modelling is an important statistical tool frequently utilized by cardiothoracic surgeons. However, these models-including linear, logistic and Cox proportional hazards regression-rely on certain assumptions. If these assumptions are violated, then a very cautious interpretation of the fitted model should be taken. Here, we discuss several assumptions and report diagnostics that can be used to detect departures from these assumptions. Most of the diagnostics discussed are based on residuals: a measure of the difference between the observed and model fitted values. Reliable and generalizable results depend on correctly developed statistical models, and proper diagnostics should play an integral part in the model development. PMID- 30010876 TI - Anidulafungin increases the antibacterial activity of tigecycline in polymicrobial Candida albicans/Staphylococcus aureus biofilms on intraperitoneally implanted foreign bodies. AB - Objectives: We aimed to establish a novel murine intra-abdominal foreign body infection model to study the activity of anidulafungin and tigecycline against dual species Candida albicans/Staphylococcus aureus biofilms. Methods: In vitro and in vivo single and dual species biofilms were developed inside serum-coated triple-lumen catheters placed in 24-well plates or implanted intraperitoneally in BALB/c mice. The effect of tigecycline and anidulafungin alone and in combination was tested using clinically relevant concentrations. Scanning electron microscopy was used to visualize the mature biofilm structure developed intraperitoneally. Flow cytometry was used to determine the immunological response upon infection. Immunoblot analysis allowed us to determine the effect of anidulafungin on poly beta-(1,6)-N-acetylglucosamine in in vitro-grown S. aureus biofilms. Results: We determined the MIC, MBC and in vitro susceptibility profile for anidulafungin and tigecycline against C. albicans and S. aureus in mixed and single species biofilms. We demonstrated that anidulafungin acts synergistically when combined with tigecycline against in vivo intra-abdominal biofilms. Moreover, we reveal that anidulafungin reduces the abundance of S. aureus poly-beta-(1,6)-N acetylglucosamine. The influx of neutrophils is much increased when infected with mixed biofilms compared with single species biofilms. Conclusions: Currently, treatment of intra-abdominal infections, in particular polymicrobial catheter associated peritonitis, is ineffective. To the best of our knowledge, this is the first study that provides insight into new possible options for treatment of C. albicans/S. aureus biofilms present in the abdominal cavity. PMID- 30010877 TI - An ominous swan in the heart. PMID- 30010878 TI - Type A aortic dissection with pulmonary hypertension caused by pulmonary artery compression and acute mitral regurgitation. PMID- 30010879 TI - Corrigendum to 'Randomized trial of the Carpentier-Edwards supra-annular prosthesis versus the Medtronic Mosaic aortic prosthesis: 10-year results' [Eur J Cardiothorac Surg 2018;54:281--7]. PMID- 30010880 TI - Long-term disease control in granulomatosis with polyangiitis: is low-dose rituximab the cure? PMID- 30010881 TI - Prediction of meat quality traits in Nelore cattle by near-infrared reflectance spectroscopy. AB - The main definition for meat quality should include factors that affect consumer appreciation of the product. Physical laboratory analyses are necessary to identify factors that affect meat quality and specific equipment is used for this purpose, which is expensive and destructive, and the analyses are usually time consuming. An alternative method to performing several beef analyses is near infrared reflectance spectroscopy (NIRS), which permits to reduce costs and to obtain faster, simpler, and nondestructive measurements. The objective of this study was to evaluate the feasibility of NIRS to predict shear force [Warner Bratzler shear force (WBSF)], marbling, and color (*a = redness; b* = yellowness; and L* = lightness) in meat samples of uncastrated male Nelore cattle, that were approximately 2-yr-old. Samples of longissimus thoracis (n = 644) were collected and spectra were obtained prior to meat quality analysis. Multivariate calibration was performed by partial least squares regression. Several preprocessing techniques were evaluated alone and in combination: raw data, reduction of spectral range, multiplicative scatter correction, and 1st derivative. Accuracies of the calibration models were evaluated using the root mean square error of calibration (RMSEC), root mean square error of prediction (RMSEP), coefficient of determination in the calibration (R2C), and prediction (R2P) groups. Among the different preprocessing techniques, the reduction of spectral range provided the best prediction accuracy for all traits. The NIRS showed a better performance to predict WBSF (RMSEP = 1.42 kg, R2P = 0.40) and b* color (RMSEP = 1.21, R2P = 0.44), while its ability to accurately predict L* (RMSEP = 1.98, R2P = 0.16) and a* (RMSEP = 1.42, R2P = 0.17) was limited. NIRS was unsuitable to predict subjective meat quality traits such as marbling in Nelore cattle. PMID- 30010882 TI - Diminished ovarian reserve and poor response to stimulation in patients <38 years old: a quantitative but not qualitative reduction in performance. AB - STUDY QUESTION: Do infertile women aged <38 years with quantitative evidence of diminished ovarian reserve and/or poor response to stimulation also exhibit poor oocyte quality as measured by blastulation rates, aneuploidy rates, and live birth rates? SUMMARY ANSWER: Young women with evidence of accelerated follicular depletion, either by precycle ovarian reserve testing or postcycle evidence of low oocyte yield, exhibit equivalent blastulation rates, aneuploidy rates and live birth rates per euploid embryo transfer as age-matched controls with normal precycle and postcycle parameters. WHAT IS KNOWN ALREADY: Previous studies are conflicted as to whether women with evidence of diminished ovarian reserve and/or poor ovarian response are also at increased risk of exhibiting evidence of poor oocyte quality. Most prior studies have failed to adequately control for the confounding effect of female age on typical markers of oocyte quality in poor responders. The rate of follicular depletion occurs at around 38 years on average; thus, evidence of quantitative depletion before this would indicate a premature diminution of ovarian reserve and allow evaluation of whether markers of oocyte quality are tied to quantitative markers. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study at a single center between 2012 and 2016. This time frame was specifically chosen as all embryos were cultured to the blastocyst stage at this center during the study period (no cleavage stage transfers were performed). Two comparisons were made: precycle assessment of ovarian reserve (based on anti-mullerian hormone (AMH) level) and postcycle oocyte yield results. For each comparison, patients in <10th percentile were compared to patients in the interquartile range (IQR) with respect to blastulation rate, aneuploidy rate and live birth rate. A mixed effects model was created to control for female age (in the <38 year old range) and correlation among oocytes from a given cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: For the precycle blastulation analysis, only patients with AMH data available were included (345 patients with AMH in the <10th percentile versus 1758 patients with AMH in the 25th to 75th percentile (IQR)). To compare aneuploidy rates, the subset of these patients who pursued preimplantation genetic testing for aneuploidy (PGT-A) was then analyzed (124 patients in the <10th percentile versus 782 patients in the IQR). For the postcycle blastulation analysis, all patients who proceeded to retrieval (whether or not they also had AMH data available) were included (535 patients with oocyte yield in the <10th percentile versus 2675 patients in the IQR). To compare aneuploidy rates, the subset of these patients who pursued PGT-A was then analyzed (156 patients in the <10th percentile versus 1100 patients in the IQR). MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted odds of a given fertilized oocyte developing to a blastocyst, being aneuploid or leading to a live birth after euploid transfer were no different if the oocyte was retrieved from a cycle with ovarian reserve parameters or oocyte yield in the <10th percentile compared to an oocyte retrieved in a cycle with those parameters in the 25-75th percentile. An AMH level in the <10th percentile did more commonly result in cycle cancellation prior to retrieval and after retrieval prior to transfer due to global arrest of embryos. LIMITATIONS, REASONS FOR CAUTION: The timing of retrieval in patients with fewer oocytes may be more optimal given the greater ability to discern the overall maturity of the cohort, thus enhancing performance per retrieved oocyte. Analyses included only first cycles. Subsequent adjustment of protocol due to prior performance may mean that some patients in the <10th percentile for oocyte yield are actually better prognosis patients than their first cycle indicates. Data on whether or not patients were on oral contraceptives at time that AMH level drawn was not available. Other unknown biases are also likely to be present given retrospective nature of the study. WIDER IMPLICATIONS OF THE FINDINGS: While young women with evidence of quantitative depletion of ovarian reserve have lower live birth rates per stimulation cycle, this not attributable to poor oocyte quality because the blastulation rate per fertilized oocyte and live birth rate per embryo transfer are equivalent to that in women with normal quantitative markers of ovarian reserve. Thus, the pathophysiology mediating a premature quantitative decline in ovarian reserve appears different than that which mediates markers of oocyte quality, such as aneuploidy. Young poor responders may use this information to help guide embryo accumulation strategies when considering their family building plans. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A. PMID- 30010884 TI - Corrigendum. PMID- 30010883 TI - Completeness of reporting in Indian qualitative public health research: a systematic review of 20 years of literature. AB - Background: This study reviewed the completeness of reporting in Indian qualitative public health research (QPHR) studies using the 'Consolidated Criteria for Reporting Qualitative Research' (COREQ) checklist. Methods: Search results from five electronic databases were screened by two independent reviewers. We included English-language, primary QPHR studies from India, which were assessed for their compliance with the COREQ checklist. Each COREQ item was noted as either reported or unreported. Descriptive statistics for the number of COREQ items reported by each study, and the number of studies that reported each COREQ item were reported, as were the items reported in each year, and in pre- and post-COREQ time periods. Results: Of 537 citations, 246 articles were included. Trends demonstrated an increasing number of Indian QPHR studies being published annually, and an overall increase in reporting completeness since 1997. Only two COREQ items were reported in all studies. 52.4% of articles reported between 16 and 21 items, corresponding to 43-57% of items being reported. Six items were reported in fewer than 10% of studies. COREQ domain 1 was least frequently reported. Conclusions: Despite improving trends, the reporting of QPHR in India is incomplete. Authors and journals should ensure adherence to reporting guidelines. PMID- 30010885 TI - A New Automated Method for the Analysis of Aromatic Amines in Human Urine by GC MS/MS. AB - Cigarette smoking significantly increases the risk of cancer and cardiovascular diseases as well as premature death. Aromatic amines (AAs) such as o-toluidine, 2 aminonaphthalene and 4-aminobiphenyl are found in cigarette smoke and are well established human bladder carcinogens presumably acting via the formation of DNA adducts. These amines may be metabolized in the liver to acetylated or glucuronidated forms or oxidized to a hydroxylamine which may react with protein and DNA to form adducts. Free, acetylated and glucuronidated AAs are excreted in urine and can be measured as exposure biomarkers. Using isotope dilution GC MS/MS, our laboratory quantifies six urinary AAs that are known or suspected carcinogens-o-toluidine, 2,6-dimethylaniline, o-anisidine, 1-aminonaphthalene, 2 aminonaphthalene and 4-aminobiphenyl-for large population studies such as the National Health and Nutrition Examination Survey (NHANES). We also monitor two additional corresponding structural isomers-2-aminobiphenyl and 3-aminobiphenyl to verify isomer separation. A new and improved automated sample preparation method was developed to quantify these AAs, in which, sample cleanup was done via Supported Liquid Extraction (SLE+ ISOLUTE(r)) on a Hamilton STARTM workstation. This automated method increased sample throughput by reducing sample cleanup time from 8 to 4 h while maintaining precision (intra and inter-run coefficient of variation <7%) and accuracy (+/-17%). Recent improvements in our GC/MS method have enhanced our assay sensitivity and specificity, resulting in longer analytical column life and maintaining or reducing the limit of detection for all six analytes. Indigo ASCENTTM software (3.7.1, Indigo BioAutomation, Inc.) is used for peak integration, calibration and quantification. A streamlined sample data flow was created in parallel with the automated method, in which samples can be tracked from receiving to final laboratory information management system output with minimal human intervention, minimizing potential human error. This newly validated, automated method and sample data flow are currently applied in biomonitoring of AAs in the US noninstitutionalized population NHANES 2013-2014 cycle. PMID- 30010886 TI - Neonatal Bacteremia and Cutaneous Lesions Caused by Photorhabdus luminescens: A Rare Gram-Negative Bioluminescent Bacterium. AB - Photorhabdus luminescens is a rare bacterium that causes human disease. In this report, we describe the case of a neonate with Photorhabdus luminescens bacteremia, including clinical presentation and treatment; we also report a literature review of rare human diseases. PMID- 30010887 TI - Gaps in health information exchange between hospitals that treat many shared patients. AB - Objective: Hospitals that routinely share patients are those that most critically need to engage in electronic health information exchange (HIE) with each other to ensure clinical information is available to inform treatment decisions. We surveyed pairs of hospitals in a nationwide sample to describe whether and how hospitals within each hospital referral region (HRR) that have the highest shared patient (HSP) volume engaged in HIE with each other. Methods: We used Medicare's Physician Shared Patient Patterns data to identify hospital pairs with the highest shared patient volume in each hospital referral region. We surveyed a purposeful sample of pairs and then calculated descriptive statistics to compare: (1) HIE with the HSP hospital vs HIE with other hospitals, and (2) HIE with the HSP hospital versus federal measures of HIE engagement that are not partner specific. Results: We received responses from 25.5% of contacted hospitals and 33.5% of contacted pairs, allowing us to examine information sharing among 68 hospitals in 63 pairs. 23% of respondents reported worse information sharing with their HSP hospital than with other hospitals while 17% indicated better sharing with their HSP hospital and 48% indicated no difference. Our HSP-specific measures of HIE differed from federal measures of HIE engagement: while 97% of respondents are classified as routinely sending information electronically in federal measures, in our data only 63% did so with their HSP hospital. Conclusions: Despite increased HIE engagement, our descriptive results indicate that HIE is not developing in a way that facilitates information exchange where it might benefit the most patients. New policy efforts, particularly those emerging from the 21st Century Cures Act, need to explicitly pursue strategies that ensure that HSP providers engage in exchange with each other. PMID- 30010889 TI - Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene. AB - Mutations, mostly in the region of the COL10A1 gene encoding the C-terminal non collagenous domain, cause the dwarfism metaphyseal chondrodysplasia type Schmid (MCDS). In most cases, the disease mechanism involves the misfolding of the mutant protein causing increased endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). However, in an iliac crest biopsy, the COL10A1 p.Y632X mutation was found to produce instability of the mutant mRNA such that little mutant protein may be produced. To investigate the disease mechanism further, a gene-targeted mouse model of the Col10a1 p.Y632X mutation was generated. In this model, the mutant mRNA showed no instability, and in mice heterozygous for the mutation, mutant and wild-type mRNAs were present at equal concentrations. The protein was translated from the mutant allele and retained within the cell, triggering increased ER stress and a UPR. The mutation produced a relatively severe form of MCDS. Nevertheless, treatment of the mice with carbamazepine (CBZ), a drug which stimulates intracellular proteolysis and alleviates ER stress, effectively reduced the disease severity in this model of MCDS caused by a premature stop codon in the Col10a1 gene. Specifically, the drug reduced ER stress in the growth plate, restored growth plate architecture toward the wild-type state, significantly increased bone growth and within 2 weeks of treatment corrected the MCDS-induced hip distortion. These results indicate that CBZ is likely to be effective in ongoing clinical trials against all forms of MCDS whether caused by premature stop codons or substitutions. PMID- 30010888 TI - Goblet cell-produced retinoic acid suppresses CD86 expression and IL-12 production in bone marrow-derived cells. AB - Conjunctival goblet cell loss in ocular surface diseases is accompanied by increased number of interleukin-12 (IL-12)-producing antigen-presenting cells (APCs) and increased interferon-gamma (IFN-gamma) expression. This study tested the hypothesis that mouse conjunctival goblet cells produce biologically active retinoic acid (RA) that suppresses CD86 expression and IL-12 production by myeloid cells. We found that conditioned media from cultured conjunctival goblet cells (CjCM) suppressed stimulated CD86 expression, NF-kappaB p65 activation and IL-12 and IFN-gamma production in unstimulated and lipopolysaccharide-stimulated cultured bone marrow-derived cells (BMDCs) containing a mixed population of APCs. Goblet cell-conditioned, ovalbumin-loaded APCs suppressed IFN-gamma production and increased IL-13 production in co-cultured OTII cells. The goblet cell suppressive activity is due in part to their ability to synthesize RA from retinol. Conjunctival goblet cells had greater expression of aldehyde dehydrogenases Aldh1a1 and a3 and ALDEFLUOR activity than cornea epithelium lacking goblet cells. The conditioning activity was lost in goblet cells treated with an ALDH inhibitor, and a retinoid receptor alpha antagonist blocked the suppressive effects of CjCM on IL-12 production. Similar to RA, CjCM increased expression of suppressor of cytokine signaling 3 (SOCS3) in BMDCs. SOCS3 silencing reversed the IL-12-suppressive effects of CjCM. Our findings indicate that conjunctival goblet cells are capable of synthesizing RA from retinol secreted by the lacrimal gland into tears that can condition APCs. Evidence suggests goblet cell RA may function in maintaining conjunctival immune tolerance and loss of conjunctival goblet cells may contribute to increased Th1 priming in dry eye. PMID- 30010890 TI - Supra-annular versus intra-annular prostheses in aortic valve replacement: impact on haemodynamics and clinical outcomes. AB - OBJECTIVES: The superiority of supra-annular aortic prostheses over intra-annular equivalents in long-term haemodynamics and clinical outcomes remains controversial. This study compared outcomes among patients receiving supra annular or intra-annular prostheses during aortic valve replacement. METHODS: We enrolled 587 consecutive patients (mean age 55.1 +/- 11.3 years; 188 women) undergoing aortic valve replacement with either supra-annular (n = 316) or intra annular (n = 271) mechanical prostheses between 2000 and 2016 in our institute. Clinical outcomes and haemodynamic profiles in the 2 groups were compared after propensity score adjustment. RESULTS: Early death (1.1% vs 0.6%; P = 0.863) was equivalent for both groups. Patients receiving supra-annular prostheses showed a lower rate of patient-prosthesis mismatch (1.2% vs 25.8%; P < 0.001). During a median follow-up of 65 months (quartile 1-3, 30-108 months), overall deaths occurred in 84 (14.3%) patients. The latest echocardiographic assessment in the 136 propensity score-matched pairs demonstrated superior haemodynamics with implantation of supra-annular prostheses: peak velocity (2.7 +/- 0.6 vs 2.3 +/- 0.5 m/s; P < 0.001), mean pressure gradient (16.5 +/- 9.0 vs 12.0 +/- 6.2 mmHg; P < 0.001) and left ventricular mass index (113.6 +/- 30.3 vs 105.3 +/- 26.3 g/m2; P = 0.016). After adjusting with inverse-probability-of-treatment weighting, however, the choice of supra-annular over intra-annular prosthesis did not significantly affect the risk of overall mortality (P = 0.693) or major adverse events: stroke (P = 0.944), infective endocarditis (P = 0.958) and reoperation (P = 0.944). CONCLUSIONS: The implantation of supra-annular prostheses resulted in superior haemodynamics and left ventricular mass regression, while conferring no apparent clinical benefits. Follow-up studies are required to further evaluate the impact of superior haemodynamics associated with supra-annular prostheses on long-term clinical outcomes. PMID- 30010891 TI - Minimal disease activity is a stable measure of therapeutic response in psoriatic arthritis patients receiving treatment with adalimumab. AB - Objective: The aim of this study was to evaluate minimal disease activity (MDA) assessments in patients with PsA during routine clinical care. Methods: We used data from a multicentre observational study of patients with active PsA who initiated treatment with adalimumab during routine clinical practice and continued treatment for at least 6 months to evaluate achievement of MDA, individual MDA criteria (modified to conform to study assessments) and ACR responses during 24 months of therapy. Pearson correlation coefficients were used to evaluate the association between MDA and individual criteria at month 6; regression models were used to determine the influence of baseline MDA criteria on achievement of MDA at month 6. Results: A total of 1684 patients were included in these analyses; most had long-standing disease. MDA was achieved by 597 patients (35.5%) at month 6. This proportion increased to 45.5% at month 24 in patients remaining on therapy. MDA status was stable over time; >75% of patients with MDA at month 6 recorded MDA at subsequent visits. Pain was the most difficult individual criterion to achieve, and enthesitis was the least difficult. Higher functional status and fewer tender joints at baseline predicted achievement of MDA at month 6. About half of patients (51.5%) with an ACR20 response at month 6 achieved MDA. Conclusion: In this observational cohort of patients with long-standing disease, MDA provided a stable and valid assessment of clinical status over 24 months. Trial registration: Clinicaltrials.gov, https://clinicaltrials.gov, NCT01111240. PMID- 30010892 TI - Deletion of DNA ligase IV homolog confers higher gene targeting efficiency on homologous recombination in Komagataella phaffii. AB - The non-conventional yeast Komagataella phaffii, formerly Pichia pastoris, is a popular host for recombinant protein production. The relatively lower gene targeting efficiency observed in this species occurs due to high levels of non homologous recombination activity. In the current study, we explored the function of the K. phaffii homolog of DNA ligase IV (Dnl4p) by creating a DNL4-disrupted strain. To assess the roles of non-homologous end joining (NHEJ)-related proteins in this species, strains deleted for either or both genes encoding Dnl4p or the telomeric Ku complex subunit (Ku70p) were generated. These deletions were constructed by either of two distinct marker-recycling methods (yielding either a seamless gene deletion or a Cre-loxP-mediated gene deletion). The resulting dnl4- and/or ku70-deleted K. phaffii strains were used to evaluate gene targeting efficiency in gene knock-out and gene knock-in experiments. The Dnl4p-defective strain showed improved gene targeting efficiency for homologous recombination compared to the wild-type and Ku70p-deffective strains. The dnl4 ku70 double knock-out strain exhibited a further improvement in gene targeting efficiency. Thus, the K. phaffii dnl4 and dnl4 ku70 deletion strains are expected to serve as useful platforms for functional analysis and strain development in this species. PMID- 30010893 TI - Editorial: Polar and Alpine Microbiology. PMID- 30010894 TI - In vitro activity of ceftazidime/avibactam against isolates of Enterobacteriaceae collected in European countries: INFORM global surveillance 2012-15. AB - Objectives: The activity of ceftazidime/avibactam was assessed against 24 750 isolates of Enterobacteriaceae collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistant phenotypes and beta-lactamase content. Methods: Antimicrobial susceptibility testing was performed using broth microdilution and the presence of beta-lactamase genes in isolates of interest was determined using PCR and sequencing. Results: Ceftazidime/avibactam was the most active agent, compared with all other tested comparator agents, against the overall collection of Enterobacteriaceae isolates (99.4% susceptible) and against subsets of ceftazidime-non-susceptible (97.7% susceptible), colistin-resistant (98.2% susceptible), MDR (96.7% susceptible) and meropenem-non-susceptible, MBL negative (98.5% susceptible) isolates. At the country level, susceptibility to ceftazidime/avibactam ranged from 96.3% to 100% among Enterobacteriaceae isolates, with decreased susceptibilities only observed in countries where MBLs were more frequently encountered (e.g. Greece and Romania). Ceftazidime/avibactam was active against 99.7% of Enterobacteriaceae isolates that carried serine beta lactamases, including ESBLs, AmpC cephalosporinases and carbapenemases (KPC, GES and OXA-48-like) in all combinations. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs. Conclusions: The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of Enterobacteriaceae collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes. PMID- 30010895 TI - DEVELOPMENT OF RADIATION DOSE CALCULATION SOFTWARE USING THE SIZE-SPECIFIC DOSE ESTIMATE. AB - We aimed to develop a software for facilitating absorbed dose per pixel (pixel dose) calculation using a size-specific dose estimate (SSDE). We calculated the pixel dose at nine equal points inserted into the radiophotoluminescence glass dosimeter (RPLD) and compared the pixel dose with the measured doses using RPLD. With this method, the relative errors of average pixel dose was -0.1% for adults and 2.86, 3.36 and 1.17% for those aged 10, 5 and 1 years without tube current modulation, respectively. In contrast, the relative error of SSDE was 17.37% for adults and 20.38, 20.73 and 19.20% for those aged 10, 5 and 1 years, respectively. In other words, the pixel dose was almost equal to the measured doses. Therefore, our software can be useful for determining arbitrary point. PMID- 30010896 TI - Economic Injury Levels and Economic Thresholds for Tibraca limbativentris (Hemiptera: Pentatomidae) on Paddy Rice Based on Insect-Days. AB - The rice stalk stink bug Tibraca limbativentris Stal, 1860 (Hemiptera: Pentatomidae) is an important pest of paddy rice (Oryza sativa L.) in South America. Current records of economic injury levels (EILs) and economic thresholds (ETs) for this insect are scarce. In this study, we determined EILs and ETs through cumulative insect-days of T. limbativentris adults in two phenological stages of paddy rice. Five field trials were established for the 2015/16 and 2016/17 crop season. To evaluate the relationship between insect-day and yield, rice plants were infested at V4 and R2 with adult male-female pairs of T. limbativentris. Mixed linear models were fitted utilizing the year and block as random factors to estimate the damage to plant, irrespective of the interference of environmental factors. The yield loss per insect-day was then used to calculate EILs using current market values and control costs. Rice grain yields were reduced by 5.91 kg/ha for each insect-day/m2 when infested during V4 stage, with EILs ranging from 3.88 to 11.61 insect-days/m2, while infestation during R2 stage resulted in a yield reduction of 3.16 kg/ha, with EILs ranging from 8.05 to 21.72 insect-days/m2. The results indicate that yield losses of paddy rice due to T. limbativentris infestation vary according to plant phenological stages and management should consider control cost and market value of rice. These EILs and ETs based on insect-days may be an efficient strategy for decision-making in the management of T. limbativentris on paddy rice. PMID- 30010897 TI - Understanding Causal Pathways in Cryptococcal Meningitis Immune Reconstitution Inflammatory Syndrome. PMID- 30010898 TI - Characterization of two glycosyl hydrolases, putative prophage endolysins, that target Clostridium perfringens. AB - Clostridium perfringens, a spore-forming anaerobic bacterium, causes food poisoning and gas gangrene in humans, and is an agent of necrotizing enteritis in poultry, swine and cattle. Endolysins are peptidoglycan hydrolases from bacteriophage that degrade the bacterial host cell wall causing lysis and thus harbor antimicrobial therapy potential. The genes for the PlyCP10 and PlyCP41 endolysins were found in prophage regions of the genomes from Clostridium perfringens strains Cp10 and Cp41, respectively. The gene for PlyCP10 encodes a protein of 351 amino acids, while the gene for PlyCP41 encodes a protein of 335 amino acids. Both proteins harbor predicted glycosyl hydrolase domains. Recombinant PlyCP10 and PlyCP41 were expressed in E. coli with C-terminal His tags, purified by nickel chromatography, and characterized in vitro. PlyCP10 activity was greatest at pH 6.0, and between 50-100 mM NaCl. PlyCP41 activity was greatest between pH 6.5 and 7.0, and at 50 mM NaCl, with retention of activity as high as 600 mM NaCl. PlyCP10 lost most of its activity above 42 degrees C, whereas PlyCP41 survived at 50 degrees C for 30 minutes and still retained > 60% activity. Both enzymes had lytic activity against 75 C. perfringens strains (isolates from poultry, swine and cattle) suggesting therapeutic potential. PMID- 30010899 TI - The patient perspective on biologic DMARD dose reduction in rheumatoid arthritis: a mixed methods study. AB - Objectives: The aim of this study was to identify the factors that play a role for patients with RA when considering dose reduction (i.e. gradual tapering until discontinuation) of biological DMARDs (bDMARDs), and to determine their relative importance. Methods: A mixed methods design was used in which we identified influencing factors by performing semi-structured interviews and ranked these factors using a Maximum Difference Scaling questionnaire. Also, we looked at the influence of several patient characteristics on this ranking. Results: For sub study 1 and 2, 22 and 192 patients with RA were included, respectively, in the analyses. Thirty factors were identified from the interviews-characterized into nine themes-and appraised in the questionnaire. Most respondents had a positive attitude towards bDMARD dose reduction. The study showed that patients are concerned that dose reduction will lead to a disease flare that affects their daily life (pain, function). It is important for them to know that it is possible to increase the dose if (further) reduction fails and that the bDMARD will be effective again. Patients value the opinion of their rheumatologist, and being involved in the decision to start tapering is highly ranked as well. The most important factors were consistent between different groups of patients. Conclusion: The results from this study facilitate implementation of bDMARD dose reduction; they inform care providers on what is important for patients and provide a basis for shared decision making. PMID- 30010901 TI - Effect of Steam Treatment on Feeding, Mating, and Fecundity of the Common Bed Bug (Hemiptera: Cimicidae). AB - Steam application is an effective and environmentally friendly method for controlling bed bugs, Cimex lectularius L. (Hemiptera: Cimicidae). While a few studies documented the bed bug control efficacy of steam treatment, the sublethal effect of steam treatment on bed bug behavior and female fecundity is unknown. In this study, we evaluated the effect of steam treatment on the movement, feeding, mating behavior, and fecundity of female bed bugs in the laboratory. Bed bug adults received a calibrated steam treatment that caused approximately 28% mortality. The surviving bed bugs were observed for their feeding and mating behavior at 1 d posttreatment, female fecundity during a 7-d observation period, and offspring hatching. Steam-treated bed bugs were less active based on the percentage of bed bugs with movement, moving distance during a 10-min observation period, and feeding rate. However, steam treatment had no significant effect on blood intake (amount of blood taken per meal) among the fed bed bugs. After blood feeding, the steam-treated bed bugs had similar mating events and egg production as the control bed bugs. Furthermore, parental steam exposure had no significant effect on the offspring hatching. In conclusion, steam treatment could temporarily decrease bed bug activity levels and feeding rate, but had no significant impact on bed bug mating behavior and female fecundity. PMID- 30010902 TI - Learning predictive models of drug side-effect relationships from distributed representations of literature-derived semantic predications. AB - Objective: The aim of this work is to leverage relational information extracted from biomedical literature using a novel synthesis of unsupervised pretraining, representational composition, and supervised machine learning for drug safety monitoring. Methods: Using ~80 million concept-relationship-concept triples extracted from the literature using the SemRep Natural Language Processing system, distributed vector representations (embeddings) were generated for concepts as functions of their relationships utilizing two unsupervised representational approaches. Embeddings for drugs and side effects of interest from two widely used reference standards were then composed to generate embeddings of drug/side-effect pairs, which were used as input for supervised machine learning. This methodology was developed and evaluated using cross validation strategies and compared to contemporary approaches. To qualitatively assess generalization, models trained on the Observational Medical Outcomes Partnership (OMOP) drug/side-effect reference set were evaluated against a list of ~1100 drugs from an online database. Results: The employed method improved performance over previous approaches. Cross-validation results advance the state of the art (AUC 0.96; F1 0.90 and AUC 0.95; F1 0.84 across the two sets), outperforming methods utilizing literature and/or spontaneous reporting system data. Examination of predictions for unseen drug/side-effect pairs indicates the ability of these methods to generalize, with over tenfold label support enrichment in the top 100 predictions versus the bottom 100 predictions. Discussion and Conclusion: Our methods can assist the pharmacovigilance process using information from the biomedical literature. Unsupervised pretraining generates a rich relationship-based representational foundation for machine learning techniques to classify drugs in the context of a putative side effect, given known examples. PMID- 30010900 TI - Prospective cohort study of C-reactive protein as a predictor of clinical events in adults with congenital heart disease: results of the Boston adult congenital heart disease biobank. AB - Aims: Despite the well-defined association of high-sensitivity hsCRP with cardiovascular outcomes in apparently healthy adults and those with acquired heart disease, the relevance of this inflammatory marker in adults with congenital heart disease (ACHD) remains unclear. We aimed to examine the clinical correlates and prognostic value of high-sensitivity C-reactive protein levels in ACHD. Methods and results: We conducted a prospective cohort study of (n = 707) outpatient ACHD (age 39 +/- 14 years, 49% women), enrolled mainly at a referral centre, who had serum hsCRP measured in conjunction with a clinical assessment between 2012 and 2016. We analysed clinical correlates of hsCRP and its association with adverse events including the primary combined outcome of all cause mortality or non-elective cardiovascular hospitalization. Higher hsCRP was strongly associated with measures of functional status including New York Heart Association class and peak VO2, and with comorbidities such as atrial arrhythmia. During average follow-up of 815 +/- 536 days, 114 patients (16%) experienced the primary outcome, including 29 deaths. Having elevated hsCRP, in the highest (>=2.98 mg/L) compared with the lower three quartiles, conferred increased risk for the primary outcome [30.5% vs. 11.3%, adjusted hazard ratio (HR) = 2.00, 95% confidence interval (CI) 1.35-2.97; P = 0.0006] and all-cause mortality (11.9% vs. 1.5%, adjusted HR = 4.23, 95% CI 1.87-9.59; P = 0.0006). Elevated hsCRP was associated with adverse outcomes across ACHD subgroups and other patient characteristics. Conclusion: Adults with congenital heart disease with elevated hsCRP have not only worse functional status and exercise capacity, but also greater risk for death or non-elective cardiovascular hospitalization. Further study is warranted to characterize the role of inflammation in the pathophysiology of ACHD. PMID- 30010903 TI - Plasma fractalkine levels are associated with renal inflammation and outcomes in immunoglobulin A nephropathy. AB - Background: A recognized noninvasive biomarker to improve risk stratification of immunoglobulin A nephropathy (IgAN) patients is scarce. Fractalkine has been shown to play a key role in glomerular disease as chemoattractant, adhesion and even fibrosis factor. The current study assessed the possibility of plasma fractalkine as a novel biomarker in IgAN patients. Methods: Plasma fractalkine was measured in 229 patients with renal biopsy consistent IgAN from 2012 to 2014, and clinical, pathological and prognostic relationships were analyzed. Results: The plasma fractalkine levels in IgAN patients were significantly correlated with the creatinine level and 24-h urine protein by both univariate and multivariate analysis. Mesangial hypercellularity was still significantly correlated with the plasma fractalkine levels even after adjustment for other potential predictor variables by multivariate analysis. In addition, the counts of CD20+ B cells or CD68+ macrophage in renal biopsies of IgAN patients were significantly correlated with the plasma fractalkine levels, but not CD4+ and CD8+ T cells. Finally, we concluded that patients with higher plasma fractalkine levels had higher risk of poor renal outcome compared with those with lower plasma fractalkine levels. No association was observed between the CX3CR1 polymorphisms and clinical parameters including plasma fractalkine levels and prognosis. Recombinant fractalkine induced mesangial cells extracellular matrix synthesis and promoted the migration of microphage cells RAW264.7. Conclusions: Plasma fractalkine levels were associated with creatinine level, 24-h urine protein, mesangial hypercellularity pathological damage, the CD68+ macrophage and CD20+ B cell infiltration in renal tissue and renal outcome in IgAN patients. Plasma fractalkine might be a potential prognosis novel predictor in Chinese patients with IgAN. PMID- 30010904 TI - Relationship of coronary artery calcification with renal function decline and mortality in predialysis chronic kidney disease patients. AB - Background: Patients with chronic kidney disease (CKD) have higher levels of coronary artery calcification (CAC) compared with the general population. The role of CAC in renal function decline is not well understood. Methods: In this prospective cohort study of Stages 3-5 CKD patients with CAC scores kidney function decline, development of end-stage kidney disease (ESKD) and all-cause mortality were determined at 5 and 10 years. Baseline variables included markers of CKD and chronic kidney disease mineral and bone disorder (CKD-MBD), demographics and comorbidities. Multivariable analyses identified predictors of outcomes, and survival curves demonstrated the association of CAC score with ESKD and mortality. Results: One hundred and seventy-eight patients were enrolled between 2005 and 2007. Independent predictors of ESKD at 5 years were estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR); at 10 years, eGFR was no longer a predictor, but CAC was now significant. Those who developed ESKD at the fastest rate either had the highest CAC score (>=400 AU) or were youngest and had the lowest calcidiol, and highest serum phosphate, UACR and percentage change in CAC per year. Predictors of eGFR decline over 5 years were UACR, parathyroid hormone and CAC score. Predictors of mortality at 5 years were age, diabetes and eGFR and at 10 years also included CAC score. Conclusions: In Stages 3-5 CKD patients, CAC is an independent predictor of both ESKD and mortality at 10 years. Those who developed ESKD at the fastest rate either had the highest CAC score or the worst CKD-MBD derangements. PMID- 30010905 TI - Association between plasma antibody responses and risk for Cryptococcus associated immune reconstitution inflammatory syndrome. AB - Background: Initiation of antiretroviral therapy (ART) in HIV-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated. Methods: We compared plasma levels of immunoglobulins, Cryptococcus neoformans (CN) glucuronoxylomannan (GXM) capsule-specific and (Lam)inarin-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV infected patients with CM who developed C-IRIS and 63 who did not and evaluated associations of these parameters with risk of C-IRIS. Results: Prior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P=0.0003), Lam-IgM (P=0.0005), Lam-IgG (P=0.002), and GXM-IgM (P=0.002) independent of age, sex, HIV viral load, CD4+ T cell count and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells. Discussion: Antibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM, may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk. PMID- 30010907 TI - Demography and Mass Rearing of the Medicinal Blister Beetle Epicauta impressicornis (Pic) (Coleoptera: Meloidae) at Different Temperatures. AB - The population dynamics of the blister beetle, Epicauta impressicornis (Pic) (Coleoptera: Meloidae) had been investigated from 2014 to 2016 in field. The results showed that E. impressicornis is univoltine and overwintered in the fifth instar in the Luodian area of Guizhou, China. The biological and ecological characteristic of the beetle were analyzed at six temperatures (i.e., 21, 24, 27, 30, 33, and 36 degrees C) in the laboratory using the age-stage, two-sex life table. The developmental duration, longevity, and total preoviposition period were significantly shortened with increases in temperatures. The adult preoviposition periods at 24, 27, and 30 degrees C were significantly longer than at other temperatures, while the fecundities at 27 and 30 degrees C were significantly higher than at other temperatures. Life expectancy (exj) decreased with age and the reproductive value (vxj) increased with age. The intrinsic rate of increase (r = 0.0921 d-1) and finite rate (lambda = 1.0965 d-1) were the highest at 33 degrees C, followed by 30 degrees C (r = 0.0758 d-1, lambda = 1.0788 d-1). Although the net reproductive rate (R0 = 17.63 offspring) was the lowest at 36 degrees C, the values of r (0.0724 d-1) and lambda (1.0751 d-1) were higher at 36 degrees C than those at 21, 24, and 27 degrees C. Our analysis for a mass-rearing system showed the most efficient and economical strategy would be to rear E. impressicornis at 30-33 degrees C. PMID- 30010906 TI - Early Transcriptional Responses After Dengue Vaccination Mirror the Response to Natural Infection and Predict Neutralizing Antibody Titers. AB - Background: Several promising live attenuated dengue vaccines are in development, but information about innate immune responses and early correlates of protection is lacking. Methods: We characterized human genome-wide transcripts in whole blood from 10 volunteers at 11 time points after immunization with the dengue virus type 3 (DENV-3) component of the National Institutes of Health dengue vaccine candidate TV003 and from 30 hospitalized children with acute primary DENV 3 infection. We compared day-specific gene expression patterns with subsequent neutralizing antibody (NAb) titers. Results: The transcriptional response to vaccination was largely confined to days 5-20 and was dominated by an interferon associated signature and a cell cycle signature that peaked on days 8 and 14, respectively. Changes in transcript abundance were much greater in magnitude and scope in symptomatic natural infection than following vaccination (maximum fold change >200 vs 21 postvaccination; 3210 vs 286 transcripts with significant fold change), but shared gene modules were induced in the same sequence. The abundances of 131 transcripts on days 8 and 9 postvaccination were strongly correlated with NAb titers measured 6 weeks postvaccination. Conclusions: Live attenuated dengue vaccination elicits early transcriptional responses that mirror those found in symptomatic natural infection and provide candidate early markers of protection against DENV infection. Clinical Trials Registration: NCT00831012. PMID- 30010908 TI - Novel Imaging Approaches in Inflammatory Bowel Diseases. AB - Inflammatory bowel diseases are chronic autoimmune conditions of the gastrointestinal tract, mainly grouped into ulcerative colitis or Crohn's disease. Traditionally, symptoms have been used to guide IBD management, but this approach is fatally flawed, as symptoms don't correlate with disease activity and often fail to predict disease complications, especially with Crohn's disease. Hence, there is increasing recognition of the need for treatment algorithms based on objective measures of bowel inflammation. In this review, we will focus on advancements in the endoscopic and radiological imaging armamentarium that allow detailed assessments from intestinal mucosa to mesentery. PMID- 30010909 TI - Basonuclin 1 deficiency is a cause of primary ovarian insufficiency. AB - Primary ovarian insufficiency (POI) leads to infertility and premature menopause in young women. The genetic etiology of this disorder remains unknown in most patients. Using whole exome sequencing of a large Chinese POI pedigree, we identified a heterozygous 5 bp deletion inducing a frameshift in BNC1, which is predicted to result in a non-sense-mediated decay or a truncated BNC1 protein. Sanger sequencing identified another BNC1 missense mutation in 4 of 82 idiopathic patients with POI, and the mutation was absent in 332 healthy controls. Transfection of recombinant plasmids with the frameshift mutant and separately with the missense mutant in HEK293T cells led to abnormal nuclear localization. Knockdown of BNC1 was found to reduce BMP15 and p-AKT levels and to inhibit meiosis in oocytes. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility, significantly increased serum follicle-stimulating hormone, decreased ovary size and reduced follicle numbers, consistent with POI. We report haploinsufficiency of BNC1 as an etiology of human autosomal dominant POI. PMID- 30010910 TI - Identification of a novel, methylation-dependent, RUNX2 regulatory region associated with osteoarthritis risk. AB - Osteoarthritis (OA) is a common, multifactorial and polygenic skeletal disease that, in its severest form, requires joint replacement surgery to restore mobility and to relieve chronic pain. Using tissues from the articulating joints of 260 patients with OA and a range of in vitro experiments, including CRISPR Cas9, we have characterized an intergenic regulatory element. Here, genotype at an OA risk locus correlates with differential DNA methylation, with altered gene expression of both a transcriptional regulator (RUNX2), and a chromatin remodelling protein (SUPT3H). RUNX2 is a strong candidate for OA susceptibility, with its encoded protein being essential for skeletogenesis and healthy joint function. The OA risk locus includes single nucleotide polymorphisms (SNPs) located within and flanking the differentially methylated region (DMR). The OA association SNP, rs10948172, demonstrates particularly strong correlation with methylation, and two intergenic SNPs falling within the DMR (rs62435998 and rs62435999) demonstrate genetic and epigenetic effects on the regulatory activity of this region. We therefore posit that the OA signal mediates its effect by modulating the methylation of the regulatory element, which then impacts on gene expression, with RUNX2 being the principal target. Our study highlights the interplay between DNA methylation, OA genetic risk and the downstream regulation of genes critical to normal joint function. PMID- 30010911 TI - Co-harboring of cephalosporin (bla)/colistin (mcr) resistance genes among Enterobacteriaceae from flies in Thailand. AB - The spreading of antimicrobial-resistant Enterobacteriaceae, especially those co harboring plasmid-mediated cephalosporin (bla) and colistin (mcr) resistance genes, is becoming increasingly problematic. As a vector, flies carry antimicrobial-resistant bacteria (ARB) into human and livestock habitats. To investigate ARB in flies, we collected 235 flies from 27 sites (18 urban areas, five pig farms, and four chicken farms) in Thailand during 2013-2015. Cefotaxime resistant Enterobacteriaceae (CtxRE) and bla-positive CtxRE were isolated from 70 (29.8%) and 48 (20.4%) flies, respectively. In 93 bla-positive CtxRE isolates that included Escherichia coli, Enterobacter spp., and Klebsiella pneumoniae from 48 flies, the most frequent bla gene was TEM (n = 62), followed by CTX-M-55 (n = 31), CTX-M-14 (n = 26), CMY-2 (n = 24), and SHV (n = 10), and 58 isolates harbored multiple types of these genes. In addition, we detected the mcr-1 (n = 1) and mcr-3 (n = 19) genes in bla-positive CtxRE isolates from 16 flies. In conjugation experiments, 10 mcr-3- and bla-positive isolates exhibited co transfer of mcr-3 and blaTEM-1 genes. These results suggest that a relatively high proportion of flies in Thailand carries cephalosporin-resistant Enterobacteriaceae harboring co-transmissible cephalosporin and colistin resistance genes. PMID- 30010912 TI - Genotoxicity of flubendazole and its metabolites in vitro and the impact of a new formulation on in vivo aneugenicity. PMID- 30010914 TI - Continuous Monitoring and Feedback Optimizes Blood Volume Inoculated Into Culture Bottles in the Pediatric Intensive Care Unit. AB - In this quasi-experimental study that included 3489 blood culture bottles, interventions that included the distribution of simple weight-stratified guidelines for recommended blood volume and monthly feedback to physicians were effective in optimizing blood volume for culture in a pediatric intensive care unit. PMID- 30010913 TI - Substantial Decline in Prevalence of Vaccine-Type and Nonvaccine-Type Human Papillomavirus (HPV) in Vaccinated and Unvaccinated Girls 5 Years After Implementing HPV Vaccine in Norway. AB - Background: In 2009, quadrivalent human papillomavirus (HPV) vaccine was introduced in a school-based single-cohort program targeting 12-year-old girls in Norway. We estimated the impact of the Norwegian HPV immunization program. Methods: Three birth cohorts of 17-year-old girls, 2 nonvaccine-eligible cohorts (born 1994 or 1996) and 1 vaccine-eligible cohort (born 1997) were invited to deliver urine samples. The samples were analyzed for 37 HPV genotypes. HPV prevalence was compared between birth cohorts and between vaccinated and unvaccinated girls within and across birth cohorts after linkage to the Norwegian Immunisation Registry. Results: In total, 17749 urine samples were analyzed. A 42% (95% confidence interval [CI], 37%-47%) reduction in any HPV type and 81% (95% CI, 76%-85%) reduction in vaccine types (HPV-6/11/16/18) were observed in the vaccine-eligible cohort compared to the 1994 cohort. Vaccine types were reduced by 54% (95% CI, 39%-66%) and 90% (95% CI, 86%-92%) in unvaccinated and vaccinated girls, respectively, from the 1997 cohort, compared with unvaccinated girls born in 1994. A significant reduction was also observed for several nonvaccine types. Vaccine-type prevalence was reduced by 77% (95% CI, 65%-85%) in vaccinated compared with unvaccinated girls from the 1997 cohort. Conclusions: In this largely HPV-naive population, we observed a substantial reduction in vaccine and nonvaccine types in vaccinated and unvaccinated girls following introduction of HPV vaccination. PMID- 30010916 TI - Fermentation of glucose-xylose-arabinose mixtures by a synthetic consortium of single-sugar-fermenting Saccharomyces cerevisiae strains. AB - d-Glucose, d-xylose and l-arabinose are major sugars in lignocellulosic hydrolysates. This study explores fermentation of glucose-xylose-arabinose mixtures by a consortium of three 'specialist' Saccharomyces cerevisiae strains. A d-glucose- and l-arabinose-tolerant xylose specialist was constructed by eliminating hexose phosphorylation in an engineered xylose-fermenting strain and subsequent laboratory evolution. A resulting strain anaerobically grew and fermented d-xylose in the presence of 20 g L-1 of d-glucose and l-arabinose. A synthetic consortium that additionally comprised a similarly obtained arabinose specialist and a pentose non-fermenting laboratory strain, rapidly and simultaneously converted d-glucose and l-arabinose in anaerobic batch cultures on three-sugar mixtures. However, performance of the xylose specialist was strongly impaired in these mixed cultures. After prolonged cultivation of the consortium on three-sugar mixtures, the time required for complete sugar conversion approached that of a previously constructed and evolved 'generalist' strain. In contrast to the generalist strain, whose fermentation kinetics deteriorated during prolonged repeated-batch cultivation on a mixture of 20 g L-1d-glucose, 10 g L-1d-xylose and 5 g L-1l-arabinose, the evolved consortium showed stable fermentation kinetics. Understanding the interactions between specialist strains is a key challenge in further exploring the applicability of this synthetic consortium approach for industrial fermentation of lignocellulosic hydrolysates. PMID- 30010917 TI - Subtelomeric methylation distinguishes between subtypes of Immunodeficiency, Centromeric instability and Facial anomalies syndrome. AB - Human telomeres and adjacent subtelomeres are packaged as heterochromatin. Subtelomeric DNA undergoes methylation during development by DNA methyltransferase 3B (DNMT3B), including the CpG-rich promoters of the long non coding RNA (TERRA) embedded in these regions. The factors that direct DNMT3B methylation to human subtelomeres and maintain this methylation throughout lifetime are yet unknown. The importance of subtelomeric methylation is manifested through the abnormal telomeric phenotype in Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome type 1 patients carrying mutations in DNMT3B. Patient cells demonstrate subtelomeric hypomethylation, accompanied by elevated TERRA transcription, accelerated telomere shortening and premature senescence of fibroblasts. ICF syndrome can arise due to mutations in at least three additional genes, ZBTB24 (ICF2), CDCA7 (ICF3) and HELLS (ICF4). While pericentromeric repeat hypomethylation is evident in all ICF syndrome subtypes, the status of subtelomeric DNA methylation had not been described for patients of subtypes 2-4. Here we explored the telomeric phenotype in cells derived from ICF2-4 patients with the aim to determine whether ZBTB24, CDCA7 and HELLS also play a role in establishing and/or maintaining human subtelomeric methylation. We found normal subtelomeric methylation in ICF2-4 and accordingly low TERRA levels and unperturbed telomere length. Moreover, depleting the ICF2-4-related proteins in normal fibroblasts did not influence subtelomeric methylation. Thus, these gene products are not involved in establishing or maintaining subtelomeric methylation. Our findings indicate that human subtelomeric heterochromatin has specialized methylation regulation and highlight the telomeric phenotype as a characteristic that distinguishes ICF1 from ICF2-4. PMID- 30010915 TI - Impacts of Recurrent Hitchhiking on Divergence and Demographic Inference in Drosophila. AB - In species with large population sizes such as Drosophila, natural selection may have substantial effects on genetic diversity and divergence. However, the implications of this widespread nonneutrality for standard population genetic assumptions and practices remain poorly resolved. Here, we assess the consequences of recurrent hitchhiking (RHH), in which selective sweeps occur at a given rate randomly across the genome. We use forward simulations to examine two published RHH models for D. melanogaster, reflecting relatively common/weak and rare/strong selection. We find that unlike the rare/strong RHH model, the common/weak model entails a slight degree of Hill-Robertson interference in high recombination regions. We also find that the common/weak RHH model is more consistent with our genome-wide estimate of the proportion of substitutions fixed by natural selection between D. melanogaster and D. simulans (19%). Finally, we examine how these models of RHH might bias demographic inference. We find that these RHH scenarios can bias demographic parameter estimation, but such biases are weaker for parameters relating recently diverged populations, and for the common/weak RHH model in general. Thus, even for species with important genome wide impacts of selective sweeps, neutralist demographic inference can have some utility in understanding the histories of recently diverged populations. PMID- 30010918 TI - Epigenetic regulation of intragenic transposable elements: a two-edged sword. AB - Genomes of animals and plants contain a large number of transposable elements (TEs). TEs often transpose into genic regions, affecting expression of surrounding genes. Intragenic TEs mostly reside in introns, and in much the same way as intergenic TEs, they are targeted by repressive epigenetic marks for transcriptional silencing. Silenced intragenic TEs generally co-repress expression of associated genes, while in some cases they significantly enhance splicing and transcript elongation. Genomes have evolved molecular mechanisms that allow the presence of silenced TEs within transcriptionally permissive chromatin environments. Epigenetic modulation of intragenic TEs often contributes to gene regulation, phenotypic expression, and genome evolution. PMID- 30010919 TI - Terminology of Pelvic Floor Muscle Function in Women With and Without Urinary Incontinence: A Systematic Review. AB - Background: Pelvic floor muscle function (PFMF) is a target of the physical therapist intervention for women with urinary incontinence (UI). However, possible variations in PFMF terminology might hamper communication among researchers and health care professionals in Women's Health. Objective: The objective of this study was to investigate the terminology of PFMF regarding clear terms, conceptual definitions, and operational definitions. Data Sources: Data sources include PUBMED, CINAHL, LILACS, and SCIELO. Study Selection: Observational studies investigating any PFMF in women with or without UI, published in English, Spanish, or Portuguese from 2005 through 2017, were considered. Data Extraction: The risk of bias was assessed by a questionnaire on the quality of observational studies. Data on terminology were extracted as terms, conceptual definitions, and operational definitions of PFMF and were synthesized according to key words, key ideas, and key operationalization, respectively. Consistencies and variations were identified for the most frequently investigated PFMF. Data Synthesis: Sixty-four studies were included, and a low risk of bias was identified. All studies presented terms and operational definitions of PFMF, but only 29.7% presented conceptual definitions of those terms. One hundred ninety-six different terms referred to PFMF. According to similarities in terminology, 161 PFMF terms could be grouped under 26 terms; the other 35 were left ungrouped. Therefore, a total of 61 different PFMF terms were identified in the literature. Limitations: A limitation in the study was that only observational studies were included. Conclusions: A large variation in PFMF terminology was identified, precluding data gathering and meta analysis. The lack of use of standardized terminology delays the progress of scientific knowledge and evidence-based practice dissemination. Efforts toward creating a collaborative, consensual terminology based on a sound framework are necessary. PMID- 30010920 TI - Authors' Reply: Comparison of different vitamin E forms is confounded by heterogeneity in vitamin E effects. PMID- 30010921 TI - Reproduction after the loss of a child: a population-based matched cohort study. AB - STUDY QUESTION: Is the death of a child associated with higher subsequent fertility? SUMMARY ANSWER: Women who had lost a child had higher fertility both shortly after the loss and throughout the entire follow-up, independent of the child's age at the time of death. WHAT IS KNOWN ALREADY: Women who lose a child in the perinatal period often have another child shortly after. However, to our knowledge no previous study has investigated if the death of an older child affects reproductive behavior. STUDY DESIGN, SIZE, DURATION: The source population for this matched cohort study consisted of all women who gave birth in Denmark from 1978 to 2004 and in Sweden from 1973 to 2002 (N = 1 979 958). Women were followed through to the end of 2008 in Denmark and the end of 2006 in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had lost a child before the age of 45 years during the study period (exposed group; n = 36 511) were matched with up to five women who were from the same country and of similar age and family characteristics and had not lost a child at the time of matching (unexposed group; n = 182 522). MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 74% of exposed and 46% of unexposed women had another birth (live- or stillbirth) after a gestation of 28 weeks or more. Compared with unexposed women, exposed women had a shorter interpregnancy interval and, consequently, a higher rate of conception leading to a birth (HR = 5.5 [95% CI: 5.4-5.6]). Rates for exposed women were higher from the first month following the child's death, but the largest difference was between 2 and 3 months after the event. This pattern was independent of the age of the deceased child. Exposed women had more subsequent children than unexposed, leading to a comparable number of living children at the end of follow-up. LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of virtually all eligible women and nearly complete follow-up; the potential for selection bias is thus negligible. However, only pregnancies that led to a live birth or a stillbirth could be identified, thus fetal losses occurring before week 28 of gestation were missing. WIDER IMPLICATIONS OF THE FINDINGS: Our findings corroborate the previous evidence suggesting that women try to conceive again shortly after a perinatal death, and many succeed. In addition, this is the first study to investigate the reproductive trajectory after losing an older child. The current study indicates that most women who lose a child between the ages of 6 months and 5 years conceive shortly after the loss, and they have a comparable number of living children at the end of the follow-up compared to those who do not lose a child. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant ERC 2010-StG-260242 from the European Research Council, 176673 and 186200 from the Nordic Cancer Union, DFF-6110-00019 from the Danish Council for Independent Research, 904414 and 15199 from TrygFonden, Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors do not declare any conflicts of interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 30010923 TI - Incorporating Appetite Awareness Training Within Family-Based Behavioral Treatment of Pediatric Obesity: A Randomized Controlled Pilot Study. AB - Objective: To assess additive effects of incorporating appetite awareness training (AAT), a strategy to encourage eating in response to hunger and satiety cues, within a family-based behavioral treatment (FBT) for childhood obesity. Methods: Total 84 families with a child with obesity in the age range of 8-12 years, Body Mass Index Standard Deviation Score (BMI-SDS) >= 2, and a participating parent were randomly allocated to two conditions; standard FBT was compared with FBT incorporating AAT strategies (FBT-AAT). Treatment consisted of group therapy sessions (held separately for children and parents) as well as single-family (parent-child dyad) sessions (24 sessions total) delivered over 18 weeks at a tertiary care outpatient clinic. One booster session was provided 1 year posttreatment and a final follow-up assessment was conducted at 2 years. The primary outcome was change in child standardized body mass index (BMI-SDS). Results: The two conditions did not differ significantly at posttest, but the FBT AAT group was at a significantly lower weight compared with FBT at both the first year, F(1, 82) = 4.150, p<.05, and the second-year follow-ups, F(1, 82) = 14.912, p <.001. It was notable that over the second-year of follow-up, the FBT-AAT group continued to show improvement, whereas the FBT group did not. Conclusions: Incorporating specific self-regulatory training in attending to hunger and fullness signals during a standardized family-based treatment may have enhanced the long-term maintenance of treatment effects. Findings are promising and warrant further study. PMID- 30010924 TI - Disease modelling and drug discovery for hypertrophic cardiomyopathy using pluripotent stem cells: how far have we come? PMID- 30010925 TI - Re-broken and remended male heart. PMID- 30010922 TI - Evolutionary insights into Trm112-methyltransferase holoenzymes involved in translation between archaea and eukaryotes. AB - Protein synthesis is a complex and highly coordinated process requiring many different protein factors as well as various types of nucleic acids. All translation machinery components require multiple maturation events to be functional. These include post-transcriptional and post-translational modification steps and methylations are the most frequent among these events. In eukaryotes, Trm112, a small protein (COG2835) conserved in all three domains of life, interacts and activates four methyltransferases (Bud23, Trm9, Trm11 and Mtq2) that target different components of the translation machinery (rRNA, tRNAs, release factors). To clarify the function of Trm112 in archaea, we have characterized functionally and structurally its interaction network using Haloferax volcanii as model system. This led us to unravel that methyltransferases are also privileged Trm112 partners in archaea and that this Trm112 network is much more complex than anticipated from eukaryotic studies. Interestingly, among the identified enzymes, some are functionally orthologous to eukaryotic Trm112 partners, emphasizing again the similarity between eukaryotic and archaeal translation machineries. Other partners display some similarities with bacterial methyltransferases, suggesting that Trm112 is a general partner for methyltransferases in all living organisms. PMID- 30010926 TI - Thermal Physiology and Developmental Plasticity of Pigmentation in the Harlequin Bug (Hemiptera: Pentatomidae). AB - Traits that promote the maintenance of body temperatures within an optimal range provide advantages to ectothermic species. Pigmentation plasticity is found in many insects and enhances thermoregulatory potential as increased melanization can result in greater heat retention. The thermal melanism hypothesis predicts that species with developmental plasticity will have darker pigmentation in colder environments, which can be an important adaptation for temperate species experiencing seasonal variation in climate. The harlequin bug (Murgantia histrionica, Hemiptera: Pentatomidae, Hahn 1834) is a widespread invasive crop pest with variable patterning where developmental plasticity in melanization could affect performance. To investigate the impact of temperature and photoperiod on melanization and size, nymphs were reared under two temperatures and two photoperiods simulating summer and fall seasons. The size and degree of melanization of adults were quantified using digital imagery. To assess the effect of coloration on the amount of heat absorption, we monitored the temperature of adults in a heating experiment. Overall, our results supported the thermal melanism hypothesis and temperature had a comparatively larger effect on coloration and size than photoperiod. When heated, the body temperature of individuals with darker pigmentation increased more relative to the ambient air temperature than individuals with lighter pigmentation. These results suggest that colder temperatures experienced late in the season can induce developmental plasticity for a phenotype that improves thermoregulation in this species. Our work highlights environmental signals and consequences for individual performance due to thermal melanism in a common invasive species, where capacity to respond to changing environments is likely contributing to its spread. PMID- 30010927 TI - Geographic Variation in Larval Metabolic Rate Between Northern and Southern Populations of the Invasive Gypsy Moth. AB - Thermal regimes can diverge considerably across the geographic range of a species, and accordingly, populations can vary in their response to changing environmental conditions. Both local adaptation and acclimatization are important mechanisms for ectotherms to maintain homeostasis as environments become thermally stressful, which organisms often experience at their geographic range limits. The spatial spread of the gypsy moth (Lymantria dispar L.) (Lepidoptera: Erebidae) after introduction to North America provides an exemplary system for studying population variation in physiological traits given the gradient of climates encompassed by its current invasive range. This study quantifies differences in resting metabolic rate (RMR) across temperature for four populations of gypsy moth, two from the northern and two from southern regions of their introduced range in North America. Gypsy moth larvae were reared at high and low thermal regimes, and then metabolic activity was monitored at four temperatures using stop-flow respirometry to test for an acclimation response. For all populations, there was a significant increase in RMR as respirometry test temperature increased. Contrary to our expectations, we did not find evidence for metabolic adaptation to colder environments based on our comparisons between northern and southern populations. We also found no evidence for an acclimation response of RMR to rearing temperature for three of the four pairwise comparisons examined. Understanding the thermal sensitivity of metabolic rate in gypsy moth, and understanding the potential for changes in physiology at range extremes, is critical for estimating continued spatial spread of this invasive species both under current and potential future climatic constraints. PMID- 30010929 TI - Maternal oversupplementation with folic acid and its impact on neurodevelopment of offspring. AB - Folic acid, a B vitamin, is vital for early neurodevelopment and is well known for its protective effect against neural tube defects. Various national health agencies worldwide recommend that women of childbearing age take approximately 0.4 to 1 mg of supplemental folic acid daily to reduce the risk of neural tube defects in offspring. Several countries have tried to promote folic acid intake through mandatory fortification programs to reduce neural tube defects. Supplementation combined with mandatory fortification of foods has led to high levels of folic acid and related metabolites in women of childbearing age. Recent studies have reported that oversupplementation, defined as exceeding either the recommended dietary allowance or the upper limit of the daily reference intake of folic acid, may have negative effects on human health. This review examines whether maternal oversupplementation with folic acid affects the neurodevelopment of offspring. Data from animal studies suggest there are behavioral, morphological, and molecular changes in the brain of offspring. Additional studies are required to determine both the dosage of folic acid and the timing of folic acid intake needed for optimal neurodevelopment in humans. PMID- 30010930 TI - Transition from a traditional to a comprehensive quality assurance system in Slovenian family medicine practices. AB - In Slovenia, quality of care at the primary healthcare level is formally a priority, but the legislation to ensure quality in this area is proceeding very slowly. The first steps towards a systematic quality control system in Slovenian family medicine were implemented with the initiation of an ongoing project of renewed family medicine practices in 2011 and the introduction of quality indicators. In 2017, an initiative by the Ministry of Health and the Department of Family Medicine at the Faculty of Medicine, the University of Ljubljana, aimed to develop a new approach to quality assurance and an improvement. It comprises four main parts: the family medicine practice team, a quality control group, a quality control office and the Ministry of Health. In this plan, quality is controlled and improved at the micro, mezzo and macro levels.The described system for quality assurance and improvement is still waiting to be implemented in practice, as there is a lack of human and financial resources. PMID- 30010928 TI - Effects of Field-Realistic Concentrations of Carbendazim on Survival and Physiology in Forager Honey Bees (Hymenoptera: Apidae). AB - Carbendazim is nowadays widely used to control fungus in various nectariferous crops. Little is known about how honey bees, Apis mellifera L. (Hymenoptera: Apidae), respond to carbendazim exposure. In this study, the effects of field realistic concentrations of carbendazim (4.516, 0.4516, and 0.04516 ppm) on the survival, biomarker enzyme activity (AChE, GST, CarE, and P450), and four antimicrobial peptide gene expression (hymenoptaecin, defensin, apidaecin, and abaecin) in forager honey bees were evaluated. The forager bees were fed with the pesticides for 10 d. The results showed that the field-realistic concentrations of carbendazim did not affect survival; activities of AChE, GST, and CarE; and expression levels of defensin and abaecin in forager bees. However, 4.516, 0.4516, and 0.04516 ppm of carbendazim all significantly inhibited the expression of hymenoptaecin and apidaecin (P < 0.01), while P450 (7-ethoxycoumarin-O deethylase) activity was downregulated by 4.516 ppm of carbendazim (P < 0.05). Our results indicate that the field-realistic concentrations of carbendazim may alter the immune response and P450-mediated detoxification of honey bees. Thus, carbendazim should be discreetly used on nectariferous crops during florescence. PMID- 30010931 TI - Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk febrile neutropenia: a randomized clinical trial. AB - Objectives: To compare the efficacy of pre-emptive versus empirical antifungal therapy in children with cancer, fever and neutropenia. Methods: This was a prospective, multicentre, randomized clinical trial. Children presenting with persistent high-risk febrile neutropenia at five hospitals in Santiago, Chile, were randomized to empirical or pre-emptive antifungal therapy. The pre-emptive group received antifungal therapy only if the persistent high-risk febrile neutropenia was accompanied by clinical, laboratory, imaging or microbiological pre-defined criteria. The primary endpoint was overall mortality at day 30 of follow-up. Secondary endpoints included invasive fungal disease (IFD)-related mortality, number of days of fever, days of hospitalization and use of antifungal drugs, percentage of children developing IFD, requiring modification of initial treatment strategy and need for ICU. The trial was registered with Registro Brasileiro de Ensaios Clinicos (ReBEC) under trial number RBR-3m9d74. Results: A total of 149 children were randomized, 73 to empirical therapy and 76 to pre emptive therapy. Thirty-two out of 76 (42%) children in the pre-emptive group received antifungal therapy. The median duration of antifungal therapy was 11 days in the empirical arm and 6 days in the pre-emptive arm (P < 0.001), with similar overall mortality (8% in the empirical arm and 5% in the pre-emptive arm, P = 0.47). IFD-related mortality was the same in both groups (3%, P = 0.97), as were the percentage of children with IFD (12%, P = 0.92) and the number of days of fever (9, P = 0.76). The number of days of hospitalization was 19 in the empirical arm and 17 in the pre-emptive arm (P = 0.15) and the need for ICU was 25% in the empirical arm and 20% in the pre-emptive arm (P = 0.47). Conclusions: Pre-emptive antifungal therapy was as effective as empirical antifungal therapy in children with cancer, fever and neutropenia, significantly reducing the use of antifungal drugs. PMID- 30010932 TI - Genome wide analyses uncover allele-specific RNA editing in human and mouse. AB - RNA editing is one of the most common RNA level modifications that potentially generate amino acid changes similar to those resulting from genomic nonsynonymous mutations. However, unlike DNA level allele-specific modifications such as DNA methylation, it is currently unknown whether RNA editing displays allele specificity across tissues and species. Here, we analyzed allele-specific RNA editing in human tissues and from brain tissues of heterozygous mice generated by crosses between divergent mouse strains and found a high proportion of overlap of allele-specific RNA editing sites between different samples. We identified three allele-specific RNA editing sites cause amino acid changes in coding regions of human and mouse genes, whereas their associated SNPs yielded synonymous differences. In vitro cellular experiments confirmed that sequences differing at a synonymous SNP can have differences in a linked allele-specific RNA editing site with nonsynonymous implications. Further, we demonstrate that allele specific RNA editing is influenced by differences in local RNA secondary structure generated by SNPs. Our study provides new insights towards a better comprehension of the molecular mechanism that link SNPs with human diseases and traits. PMID- 30010934 TI - Vigabatrin administration for infants and young children with intractable generalized epilepsy. AB - Objective: This study aimed to investigate the effectiveness of vigabatrin (VGB) for intractable generalized epilepsy in infants and young children. Methods: We retrospectively examined the data of 12 patients who received VGB at our department. There were eight patients with West syndrome, two with early infantile epileptic encephalopathy, one with symptomatic generalized epilepsy, and one with early myoclonic encephalopathy. Results: All patients had drug resistant epilepsy and received at least three antiepileptic drugs (range, 3-10 ; median, 5) before receiving VGB. These drugs included valproate (11 patients), nitrazepam (six patients), adrenocorticotropic hormone (ACTH ; five patients), clonazepam (four patients), and zonisamide (four patients). VGB was effective in only one case of symptomatic West syndrome associated with tuberous sclerosis. In two cases of cryptogenic West syndrome, VGB showed transient effects. Conclusions: VGB showed poor effectiveness for intractable generalized epilepsy in infancy and early childhood, except for West syndrome associated with tuberous sclerosis. Therefore, it is important to carefully select the cases for VGB administration. PMID- 30010935 TI - Intratumoral Rathke's Cleft Cyst Remnants Within Craniopharyngioma, Pituitary Adenoma, Suprasellar Dermoid, and Epidermoid Cysts: A Ubiquitous Signature of Ectodermal Lineage or a Transitional Entity? AB - BACKGROUND: The authors present cystic epithelial masses in the suprasellar region which on histopathology revealed 4 mixed tumors having simple cuboidal epithelium of Rathke's Cleft Cyst (RCC) elements trapped within pituitary adenoma, epidermoid cyst, dermoid cyst, and papillary craniopharyngioma respectively. OBJECTIVE: To highlight the developmental theory of ectodermal continuum in the realm of suprasellar epithelial cystic lesions and examines the cardinal aspects that distinguish RCC from its confounder, ciliary craniopharyngioma. METHODS: The authors performed a medical chart review on 4 patients who had coexisting RCC with craniopharyngioma, pituitary adenoma, suprasellar dermoid, and epidermoid cysts. RESULTS: This series of unique suprasellar lesions elucidate the spectrum of cases from Rathke's cyst to other suprasellar epithelial cysts including a recently identified clinical entity called ciliary craniopharyngioma, which authors feel is a misnomer. The authors also report the first case of ruptured dermoid cyst admixed with elements of Rathke's cyst elements and xanthogranuloma in neurosurgical literature. CONCLUSION: We propose that the new entity of ciliary craniopharyngioma could be just another variant of RCC elements nested within a typical papillary or adamantinomatous lesion. Further study is warranted to understand the implications of natural history with tumors containing RCC elements. PMID- 30010933 TI - MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin deficient mdx mice. AB - Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, leads to severe muscle wasting and eventual death of the afflicted individuals, primarily due to respiratory failure. Deficit in myofiber regeneration, potentially due to an exhaustion of satellite cells, is one of the major pathological features of DMD. Myeloid differentiation primary response 88 (MyD88) is an adaptor protein that mediates activation of various inflammatory pathways in response to signaling from Toll-like receptors and interleukin-1 receptor. MyD88 also regulates cellular survival, proliferation and differentiation in a cell-autonomous manner. However, the role of MyD88 in satellite stem cell homeostasis and function in dystrophic muscle remains unknown. In this study, we demonstrate that tamoxifen-inducible deletion of MyD88 in satellite cells causes loss of skeletal muscle mass and strength in the mdx mouse model of DMD. Satellite cell-specific deletion of MyD88 inhibits myofiber regeneration and stimulates fibrogenesis in dystrophic muscle of mdx mice. Deletion of MyD88 also reduces the number of satellite cells and inhibits their fusion with injured myofibers in dystrophic muscle of mdx mice. Ablation of MyD88 in satellite cells increases the markers of M2 macrophages without having any significant effect on M1 macrophages and expression of inflammatory cytokines. Finally, we found that satellite cell-specific deletion of MyD88 leads to aberrant activation of Notch and Wnt signaling in skeletal muscle of mdx mice. Collectively, our results demonstrate that MyD88-mediated signaling in satellite cells is essential for the regeneration of injured myofibers in dystrophic muscle of mdx mice. PMID- 30010937 TI - The Impact of Different Postgraduate Year Training in Neurosurgery Residency on 30-Day Postoperative Outcomes. AB - BACKGROUND: Previous studies have failed to demonstrate statistically significant differences in postsurgical outcomes between operative cases featuring resident participation compared to attending only; however, the effects of level of postgraduate year (PGY) training have not been explored. OBJECTIVE: To correlate different PGYs in neurosurgery with 30-d postoperative outcomes. METHODS: Using National Surgical Quality Improvement Program 2005-2014, adult neurosurgical cases were divided into subspecialties: spine, open-vascular, cranial, and functional in teaching institutions. Comparison groups: cases involving junior residents (PGY 1-PGY 3), mid-level residents (PGY 4 + PGY 5), and senior residents (PGY 6 + PGY 7). Primary outcome measures included any wound disruption (surgical site infections and/or wound dehiscence), Clavien-Dindo grade IV (life threatening) complications, and death. RESULTS: Compared to junior residents (n = 3729) and mid-level residents (n = 2779), senior residents (n = 3692) operated on patients with a greater comorbidity burden, as reflected by higher American Society of Anesthesiology classifications and decreased level of functional status. Cases with senior resident participation experienced the highest percentages of postoperative wound complications (P = .005), Clavien-Dindo grade IV complications (P = .001), and death (P = .035). However, following multivariable regression, level of residency training in neurosurgery did not predict any of the 3 primary outcome measures. Compared to spinal cases, cranial cases predicted a higher incidence of life-threatening complications (odds ratio 1.84, P < .001). CONCLUSION: Cases in the senior resident cohort were more technically challenging and exhibited a higher comorbidity burden preoperatively; however, level of neurosurgical training did not predict any wound disruption, life-threatening complications, or death. Residents still provide safe and effective assistance to attending neurosurgeons. PMID- 30010938 TI - Malassezia ecology, pathophysiology, and treatment. PMID- 30010939 TI - What is a Weapon? AB - Animals utilise an incredible array of traits for offence and defence during conflict. These traits range from exaggerated morphological structures such as the antlers of stags and the horns of beetles, to an arsenal of noxious chemicals emitted, secreted and injected. However, the breadth of these traits appears to be underappreciated in our current thinking about aggression in animals. Use of the term 'weapon' in the current literature is largely restricted to studies of conspicuous morphological structures used by males during contests over access to females, and as a result, our understanding of other types of weapons is limited. In this paper, I explore the diversity of traits utilised by animals to manipulate and control the behaviour of other individuals in a number of agonistic contexts, with the aim to encourage a reappraisal of the way in which behavioural and evolutionary biologists view animal weapons. I discuss the advantages of including this broader range of traits in studies of animal weaponry and explore the unifying features that distinguish animal weapons from other traits. PMID- 30010936 TI - ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells. AB - The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair by controlling the abundance of the HR machinery. Notably, ATR controls the abundance of HR factors largely via CHK1-dependent transcription, and can also promote stabilization of specific HR proteins. Cancer cells exhibit a strong dependency on ATR signaling for maintaining elevated levels of HR factors, and we propose that increased constitutive ATR signaling caused by augmented replication stress in cancer cells drives the enhanced HR capacity observed in certain tumor types. Overall, these findings define a major pro-HR function for ATR and have important implications for therapy by providing rationale for sensitizing HR-proficient cancer cells to PARP inhibitors. PMID- 30010940 TI - Association between serum ferritin and mortality: findings from the USA, Japan and European Dialysis Outcomes and Practice Patterns Study. AB - Background: The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin-mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ. Methods: Data from 18 261 patients in Phases 4 and 5 (2009-15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders. Results: Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region. Conclusion: The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed. PMID- 30010941 TI - Conversational agents in healthcare: a systematic review. AB - Objective: Our objective was to review the characteristics, current applications, and evaluation measures of conversational agents with unconstrained natural language input capabilities used for health-related purposes. Methods: We searched PubMed, Embase, CINAHL, PsycInfo, and ACM Digital using a predefined search strategy. Studies were included if they focused on consumers or healthcare professionals; involved a conversational agent using any unconstrained natural language input; and reported evaluation measures resulting from user interaction with the system. Studies were screened by independent reviewers and Cohen's kappa measured inter-coder agreement. Results: The database search retrieved 1513 citations; 17 articles (14 different conversational agents) met the inclusion criteria. Dialogue management strategies were mostly finite-state and frame-based (6 and 7 conversational agents, respectively); agent-based strategies were present in one type of system. Two studies were randomized controlled trials (RCTs), 1 was cross-sectional, and the remaining were quasi-experimental. Half of the conversational agents supported consumers with health tasks such as self care. The only RCT evaluating the efficacy of a conversational agent found a significant effect in reducing depression symptoms (effect size d = 0.44, p = .04). Patient safety was rarely evaluated in the included studies. Conclusions: The use of conversational agents with unconstrained natural language input capabilities for health-related purposes is an emerging field of research, where the few published studies were mainly quasi-experimental, and rarely evaluated efficacy or safety. Future studies would benefit from more robust experimental designs and standardized reporting. Protocol Registration: The protocol for this systematic review is registered at PROSPERO with the number CRD42017065917. PMID- 30010943 TI - Rejoinder to "Ethical issues in the use of SMS messaging in HIV care and treatment in low-and-middle-income countries". PMID- 30010944 TI - United States Medical Licensing Exam Step I Score as a Predictor of Neurosurgical Career Beyond Residency. AB - BACKGROUND: United States Medical Licensing Exam (USMLE) Step I score is cited as one of the most important factors when for applying to neurosurgery residencies. No studies have documented a correlation between USMLE Step I score and metrics of neurosurgical career trajectory beyond residency. OBJECTIVE: To determine whether USMLE Step I exam scores are predictive of neurosurgical career beyond residency, as defined by American Board of Neurological Surgery (ABNS) certification status, practice type, academic rank, and research productivity. METHODS: A database of neurosurgery residency applicants who matched into neurosurgery from 1997 to 2007 was utilized that included USMLE Step I score. Online databases were used to determine h-index, National Institutes of Health (NIH) grant funding, academic rank, practice type, and ABNS certification status of each applicant. Linear regression and nonparametric testing determined associations between USMLE Step I scores and these variables. RESULTS: USMLE Step I scores were higher for neurosurgeons in academic positions (237) when compared to community practice (234) and non-neurosurgeons (233, P < .01). USMLE Step I score was not different between neurosurgeons of different academic rank (P = .21) or ABNS certification status (P = .78). USMLE Step I score was not correlated with h-index for academic neurosurgeons (R2 = 0.002, P = .36). CONCLUSION: USMLE Step I score has little utility in predicting the future careers of neurosurgery resident applicants. A career in academic neurosurgery is associated with a slightly higher USMLE Step I score. However, USMLE Step I score does not predict academic rank or productivity (h-index or NIH funding) nor does USMLE Step I score predict ABNS certification status. PMID- 30010942 TI - Combined deficiency of Senataxin and DNA-PKcs causes DNA damage accumulation and neurodegeneration in spinal muscular atrophy. AB - Chronic low levels of survival motor neuron (SMN) protein cause spinal muscular atrophy (SMA). SMN is ubiquitously expressed, but the mechanisms underlying predominant neuron degeneration in SMA are poorly understood. We report that chronic low levels of SMN cause Senataxin (SETX)-deficiency, which results in increased RNA-DNA hybrids (R-loops) and DNA double-strand breaks (DSBs), and deficiency of DNA-activated protein kinase-catalytic subunit (DNA-PKcs), which impairs DSB repair. Consequently, DNA damage accumulates in patient cells, SMA mice neurons and patient spinal cord tissues. In dividing cells, DSBs are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) pathways, but neurons predominantly use NHEJ, which relies on DNA-PKcs activity. In SMA dividing cells, HR repairs DSBs and supports cellular proliferation. In SMA neurons, DNA-PKcs-deficiency causes defects in NHEJ-mediated repair leading to DNA damage accumulation and neurodegeneration. Restoration of SMN levels rescues SETX and DNA-PKcs deficiencies and DSB accumulation in SMA neurons and patient cells. Moreover, SETX overexpression in SMA neurons reduces R-loops and DNA damage, and rescues neurodegeneration. Our findings identify combined deficiency of SETX and DNA-PKcs stemming downstream of SMN as an underlying cause of DSBs accumulation, genomic instability and neurodegeneration in SMA and suggest SETX as a potential therapeutic target for SMA. PMID- 30010945 TI - Certolizumab pegol in the treatment of Takayasu arteritis. AB - Objectives: Certolizumab pegol (CZP) is a PEGylated antigen-binding fragment fragment of a humanized mAb neutralizing TNF. It lacks Fc-fragment and has a very low potential to cross the placenta. We aimed to report the efficacy and safety of CZP in a case series of patients with refractory Takayasu arteritis (TA). Methods: Ten females of reproductive age (18-35 years) with TA were treated with CZP (at a dose of 400 mg at weeks 0, 2 and 4 and at 200 mg every 2 weeks thereafter) for a median of 10 months (range 3-28). Prior to CZP administration all patients received glucocorticoids and +/- MTX, CYC, AZA, HCQ, LEF or MMF. Six patients were previously treated with other biological anti-cytokine drugs. The National Institutes of Health criteria and the Indian Takayasu Clinical Activity Score 2010 were used to define disease activity. Results: All patients rapidly responded to treatment with CZP and were able to taper prednisone and MTX doses. Treatment with CZP resulted in a significant decrease in median serum CRP levels and normalization of Indian Takayasu Clinical Activity Score 2010 score in 9 of 10 patients. Remission of systemic vasculitis was achieved in all patients. Seven patients maintained remission for at least 4 months, while one patient developed relapse after 2 years of CZP treatment. Side effects included mild infections (n = 5). Conclusion: Our case series suggests that CZP may be an effective and steroid-sparing treatment option in patients with active TA even if they did not previously respond to other TNF inhibitors or tocilizumab. PMID- 30010946 TI - Silencing of Four Genes Involved in Chromatin Remodeling by RNA Interference Adversely Affects Fecundity of Bed Bugs (Hemiptera: Cimicidae). AB - DNA, the blue print of life, is densely wrapped around histone proteins to form chromatin. Chromatin remodeling ATPases unwind histone-DNA interactions to facilitate DNA transcription, modification, and repair. Four genes involved in chromatin remodeling, namely, imitation SWI (iswi), chromodomain-helicase-DNA binding protein 1 (chd-1), DNA helicase INO80 (ino80) and mi-2 were silenced through the injection of dsRNA, and phenotypes were assessed in bed bugs. Bed bugs were injected with 0.2 ug dsRNA per insect between the last thoracic segment and first abdominal segment using a fine capillary tube fitted to a nanoinjector. We observed a significant reduction in reproductive potential with all the genes tested, suggesting the essential function of chromatin remodeling ATPases in many cellular processes including egg-laying and egg-hatching. Knockdown of mi-2 and iswi completely inhibited oviposition over time. Real-time quantitative polymerase chain reaction confirmed significant knockdown of targeted mRNAs for at least 30 d, which supports persistence of RNAi in bed bugs. In addition, we observed a significant depletion of targeted transcripts in eggs laid by bed bugs injected with dsRNAs specific to chromatin remodeling ATPases. This study demonstrates the importance of chromatin remodeling ATPase in bed bug reproduction. PMID- 30010948 TI - The ribosomal stalk protein is crucial for the action of the conserved ATPase ABCE1. AB - The ATP-binding cassette (ABC) protein ABCE1 is an essential factor in ribosome recycling during translation. However, the detailed mechanochemistry of its recruitment to the ribosome, ATPase activation and subunit dissociation remain to be elucidated. Here, we show that the ribosomal stalk protein, which is known to participate in the actions of translational GTPase factors, plays an important role in these events. Biochemical and crystal structural data indicate that the conserved hydrophobic amino acid residues at the C-terminus of the archaeal stalk protein aP1 binds to the nucleotide-binding domain 1 (NBD1) of aABCE1, and that this binding is crucial for ATPase activation of aABCE1 on the ribosome. The functional role of the stalk*ABCE1 interaction in ATPase activation and the subunit dissociation is also investigated using mutagenesis in a yeast system. The data demonstrate that the ribosomal stalk protein likely participates in efficient actions of both archaeal and eukaryotic ABCE1 in ribosome recycling. The results also show that the stalk protein has a role in the function of ATPase as well as GTPase factors in translation. PMID- 30010949 TI - Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells. AB - Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)-mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses. PMID- 30010947 TI - Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity. AB - Mycobacterium africanum consists of Lineages L5 and L6 of the Mycobacterium tuberculosis complex (MTBC) and causes human tuberculosis in specific regions of Western Africa, but is generally not transmitted in other parts of the world. Since M. africanum is evolutionarily closely placed between the globally dispersed Mycobacterium tuberculosis and animal-adapted MTBC-members, these lineages provide valuable insight into M. tuberculosis evolution. Here, we have collected 15 M. africanum L5 strains isolated in France over 4 decades. Illumina sequencing and phylogenomic analysis revealed a previously underappreciated diversity within L5, which consists of distinct sublineages. L5 strains caused relatively high levels of extrapulmonary tuberculosis and included multi- and extensively drug-resistant isolates, especially in the newly defined sublineage L5.2. The specific L5 sublineages also exhibit distinct phenotypic characteristics related to in vitro growth, protein secretion and in vivo immunogenicity. In particular, we identified a PE_PGRS and PPE-MPTR secretion defect specific for sublineage L5.2, which was independent of PPE38. Furthermore, L5 isolates were able to efficiently secrete and induce immune responses against ESX-1 substrates contrary to previous predictions. These phenotypes of Type VII protein secretion and immunogenicity provide valuable information to better link genome sequences to phenotypic traits and thereby understand the evolution of the MTBC. PMID- 30010951 TI - In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012-15. AB - Objectives: The activity of ceftazidime/avibactam was assessed against 5716 Pseudomonas aeruginosa isolates collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistance phenotypes and beta-lactamase content. Methods: Antimicrobial susceptibility testing was performed by broth microdilution and beta-lactamase genes were detected by PCR screening and sequencing. Results: Ceftazidime/avibactam was highly active in vitro against the overall collection of P. aeruginosa isolates and colistin-resistant isolates (92.4% and 92.9% susceptible, respectively). Although activity was slightly reduced against MBL-negative subsets of ceftazidime-non-susceptible (79.6% susceptible), meropenem-non-susceptible (85.1% susceptible) and MDR (81.6% susceptible) P. aeruginosa, ceftazidime/avibactam remained the second most active entity, after colistin, compared with all other comparator agents tested. At the country level, susceptibility to ceftazidime/avibactam ranged from 74.6% to 99.6%, with decreased susceptibilities only observed in countries where MBLs are more frequently encountered, such as the Czech Republic, Greece, Romania and Russia. Ceftazidime/avibactam was also active in vitro against 87.6% of meropenem non-susceptible isolates in which no acquired beta-lactamases were detected by molecular methods; these isolates were assumed to hyperproduce the chromosomally encoded AmpC in combination with alterations in OprD or drug efflux. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs. Conclusions: The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of P. aeruginosa collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes. PMID- 30010952 TI - Commentary: Posterior Reversible Encephalopathy Syndrome as a Complication of Induced Hypertension in Subarachnoid Hemorrhage: A Case-Control Study. PMID- 30010950 TI - Fully Human Immunoglobulin G From Transchromosomic Bovines Treats Nonhuman Primates Infected With Ebola Virus Makona Isolate. AB - Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-alpha-1,3-galactose carbohydrates compared with human derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic. PMID- 30010954 TI - Commentary: Mean 6-Year Follow-up of Magnetically Controlled Growing Rod Patients With Early Onset Scoliosis: A Glimpse of What Happens to Graduates. PMID- 30010955 TI - Commentary: Does Stereotactic Radiosurgery Have a Role in the Management of Patients Presenting With 4 or More Brain Metastases? PMID- 30010953 TI - Black-White Difference in the Impact of Long-Term Blood Pressure From Childhood on Adult Renal Function: The Bogalusa Heart Study. AB - BACKGROUND: To examine racial difference in the impact of long-term burden of blood pressure (BP) from childhood on adult renal function between middle-aged blacks and whites. METHODS: The study cohort consisted of 1,646 whites and 866 blacks aged 20-51 years at follow-up who had BP measured at least 4 times since childhood, with a mean follow-up period of 25.3 years. The area under the curve (AUC) was calculated as a measure of long-term burden of BP from childhood to adulthood. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine to assess renal function in adulthood. RESULTS: Black vs. white adults had significantly higher values of eGFR and long-term burden of systolic BP for both males and females. In multivariable linear regression analyses, adjusting for sex, adult age, body mass index, smoking, and alcohol use, adult eGFR was significantly and negatively associated with adult systolic BP (standardized regression coefficient [beta] = -0.10, P = 0.005) and diastolic BP (beta = -0.11, P = 0.003) in blacks, but not in whites. The total BP AUC values were also significantly and negatively associated with adult eGFR (beta = -0.10, P = 0.005 for systolic BP and beta = -0.09, P = 0.013 for diastolic BP) in blacks only. Childhood BP was not significantly associated with adult eGFR in blacks and whites. CONCLUSIONS: These findings suggest that black-white disparities in the influence of elevated BP on the development of renal dysfunction occur in middle adulthood, which underscores the importance of BP control in the black population. PMID- 30010956 TI - Resection of a Thoracic Hemangioblastoma in a Patient With Von Hippel-Lindau: 3 Dimensional Operative Video. AB - This 3-dimensional operative video illustrates resection of a thoracic hemangioblastoma in a 30-year-old female with a history of Von Hippel-Lindau disease. The patient presented with right lower extremity numbness and flank pain. Magnetic resonance imaging (MRI) demonstrated an enhancing intradural intramedullary lesion at T 7 consistent with a hemangioblastoma. The patient underwent a thoracic laminectomy with a midline dural opening for tumor resection. This case demonstrates the principles of intradural intramedullary spinal cord tumor resection. In this particular case, internal debulking was untenable owing to the vascular nature of hemangioblastomas. The operative video demonstrates en bloc tumor removal. Postoperative MRI demonstrated gross total resection. The postoperative course was uneventful. The natural history of this disease, treatment options, and potential complications are discussed. PMID- 30010957 TI - Effects of cotreatment with omega-3 polyunsaturated fatty acids and anticancer agents on oxidative stress parameters: a systematic review of in vitro, animal, and human studies. AB - Context: Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid and eicosapentaenoic acid, demonstrate possible beneficial effects as adjuvants in cancer treatment. One mechanism seems to be related to alterations in the redox status of cancer cells. Such alterations are thought to act in synergy with conventional anticancer agents. Objective: This review examines published data on the effects of cotreatment with anticancer agents and n-3 PUFAS on oxidative stress parameters to determine whether any patterns of oxidative stress alterations can be identified. Data Sources: A systematic search of MEDLINE (via PubMed) was conducted to identify articles published in English, Spanish, or Portuguese until November 2017. Study Selection: The following inclusion criteria were applied: (1) individuals or animals with cancer or malignant cell lines supplemented with some source of n-3 PUFAs; (2) concomitant use of anticancer treatment; and (3) evaluation of oxidative stress-related variables. Data Extraction: A standardized outline was used to extract the following data: study type, supplement used, type of cells, tumor or patient characteristics, study design, anticancer treatment used, and oxidative stress related outcomes. Results: After the literature search and screening of 1563 citations, 28 studies were included for data extraction and evaluation: 16 in vitro studies (2 of which also used in vivo studies), 8 animal studies, and 4 human studies (3 clinical trials and 1 case series). In most in vitro and animal studies, intervention groups receiving cotreatment with n-3 PUFAs showed enhanced lipid peroxidation and cytotoxicity compared with groups receiving anticancer treatment alone. Eleven of the 12 studies that investigated the effect of vitamin E on the sensitivity of cancer cells to the oxidative stress caused by n-3 PUFAs showed that vitamin E abolished the positive effects of cotreatment. Conclusions: Alterations in oxidative stress caused by cotreatment with anticancer agents and n-3 PUFAs can exert positive effects on the efficacy of conventional treatment. This seems to occur in most cells and tumors tested thus far, but not all. Identifying tumors that are sensitive to these oxidative effects may provide support for the rational use of n-3 PUFAs as an adjuvant treatment in specific types of cancer. PMID- 30010958 TI - Host Plant-Mediated Interactions Between 'Candidatus Liberibacter asiaticus' and Its Vector Diaphorina citri Kuwayama (Hemiptera: Liviidae). AB - The Diaphorina citri Kuwayama (Hemiptera: Liviidae) also known as Asian citrus psyllid transmits 'Candidatus Liberibacter asiaticus' (CLas) associated with the citrus Huanglongbing (HLB). Minimizing Asian citrus psyllid populations is one of the most important methods for HLB control. The development and survival of Asian citrus psyllid were evaluated on CLas+ and CLas- plants of Citrus reticulata Blanco. cv. Mashuiju (Sapindales: Rutaceae) or Citrus sunki Hort. ex Tanaka (Sapindales: Rutaceae) to assess the effects of CLas infection on vector populations. The development times were unaffected between CLas+ and CLas- plants for eggs and first to third instar nymphs but decreased for fourth instars, fifth instars, and total nymphal life on CLas+ plants. The survival rates of eggs and first and second instar nymphs were significantly lower, while those of third to fifth instar nymphs were significantly higher on CLas+ plants. However, overall nymphal survival did not differ between CLas+ and CLas- plants. The pre oviposition period of Asian citrus psyllid on CLas+ plants decreased, while oviposition period increased, resulting in significantly higher fecundity and population trend index compared with those on CLas- plants, illustrating an overall fitness benefit of CLas infection to Asian citrus psyllid. On the other hand, the longevity and resistance to starvation and lower temperatures of adults from CLas+ plants were significantly lower than those from CLas- plants suggesting that there may be a fitness cost for Asian citrus psyllid on CLas+ plants. The development time of eggs and nymphs and adult longevity were always shorter on C. reticulata regardless of infection status. This knowledge of host plant, pathogen, and vector interactions is useful for developing Asian citrus psyllid-HLB management programs. PMID- 30010959 TI - Low Temperature-Enhanced Flavonol Synthesis Requires Light-Associated Regulatory Components in Arabidopsis thaliana. AB - Plants are continuously exposed to a myriad of stresses, which lead to the formation of secondary metabolites including flavonoids. Studies suggest that low temperature exposure leads to enhanced flavonoid accumulation in Arabidopsis thaliana. In addition, flavonoid biosynthesis is regulated by light through various regulatory factors. Therefore, plants may possess the capability to integrate light and low temperature signals for survival under freezing conditions. However, the detailed molecular mechanism and the regulatory factors associated with light- and low temperature- responsive flavonoid biosynthesis remain largely unknown. Here, we report a strict requirement for light for the low temperature-enhanced flavonol biosynthesis. Low temperature-induced expression of biosynthetic genes as well as flavonol accumulation was hampered in ELONGATED HYPOCOTYL (hy5) and myb11myb111myb12 triple mutants as compared with the wild type in Arabidopsis. Overexpression of AtHY5 in the hy5 mutant restored induction of gene expression and flavonol accumulation in response to low temperature in light. Metabolite and gene expression analysis also suggests a negative role for CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) in accumulation of flavonols in response to low temperature. Overexpression of AtMYB12 enhanced accumulation of flavonols under low temperature in a light-dependent manner. Together, our analysis suggests the requirement for HY5 and flavonol-specific MYB regulatory factors for low temperature-induced flavonol synthesis. PMID- 30010960 TI - Comparative Safety and Efficacy of Modified TICI 2b and TICI 3 Reperfusion in Acute Ischemic Strokes Treated With Mechanical Thrombectomy. PMID- 30010962 TI - Comparison of Tobacco and Electronic Cigarette Reward Value Measured During a Cue Reactivity Task: An Extension of the Choice-Behavior-Under-Cued-Conditions (CBUCC) Procedure. AB - Introduction: Up to 24% of electronic cigarette (e-cigarette) users are concurrent users of both tobacco and e-cigarettes (dual users). Dual users provide an opportunity to assess key motivational processes supporting e cigarette use, such as the reward value of e-cigarettes. This study used the Choice-Behavior-Under-Cued-Conditions (CBUCC) procedure to examine cue-specific reactions to tobacco and e-cigarettes with a primary focus on evaluating the relative reward value of both forms of cigarettes. Methods: Fifty-four dual users were exposed to a lit tobacco cigarette, their own e-cigarette, or a cup of water across multiple trials. On each trial, participants rated their craving for both tobacco and e-cigarettes and indicated the amount of money they would spend to access the cue. Key measures included craving, amount of money spent to access the cue, latency to access the cue, spending choice time, and consumption. Results: Participants reported significantly higher craving and spent significantly more money on tobacco and e-cigarette trials than on water trials. The magnitude of cue-specific craving was comparable across tobacco and e cigarettes, but participants spent significantly more to access tobacco cigarettes than e-cigarettes. Conclusions: This is the first study to demonstrate cue-specific reactivity to e-cigarettes utilizing a neutral comparison condition and to examine the reward value of e-cigarettes relative to tobacco cigarettes. Overall, the data suggest that e-cigarette puffs are less valued and generate less craving than tobacco cigarette puffs for dual users. The data provide clear support for the utility of CBUCC for examining a range of motivational processes supporting e-cigarette use. IMPLICATIONS: The test procedure used in this research generates multiple indices of nicotine and tobacco motivation and allows for an explicit comparison of those variables in people who use both e-cigarettes and tobacco cigarettes. PMID- 30010961 TI - H3K4me2 and WDR5 enriched chromatin interacting long non-coding RNAs maintain transcriptionally competent chromatin at divergent transcriptional units. AB - Recently lncRNAs have been implicated in the sub-compartmentalization of eukaryotic genome via genomic targeting of chromatin remodelers. To explore the function of lncRNAs in the maintenance of active chromatin, we characterized lncRNAs from the chromatin enriched with H3K4me2 and WDR5 using chromatin RNA immunoprecipitation (ChRIP). Significant portion of these enriched lncRNAs were arranged in antisense orientation with respect to their protein coding partners. Among these, 209 lncRNAs, commonly enriched in H3K4me2 and WDR5 chromatin fractions, were named as active chromatin associated lncRNAs (active lncCARs). Interestingly, 43% of these active lncCARs map to divergent transcription units. Divergent transcription (XH) units were overrepresented in the active lncCARs as compared to the inactive lncCARs. ChIP-seq analysis revealed that active XH transcription units are enriched with H3K4me2, H3K4me3 and WDR5. WDR5 depletion resulted in the loss of H3K4me3 but not H3K4me2 at the XH promoters. Active XH CARs interact with and recruit WDR5 to XH promoters, and their depletion leads to decrease in the expression of the corresponding protein coding genes and loss of H3K4me2, H3K4me3 and WDR5 at the active XH promoters. This study unravels a new facet of chromatin-based regulation at the divergent XH transcription units by this newly identified class of H3K4me2/WDR5 chromatin enriched lncRNAs. PMID- 30010963 TI - Nickel Exposure Has Complex Transgenerational Effects in a Butterfly. AB - Heavy metal pollution is a major problem in urban and industrial environments, and has a myriad of negative effects on animals. Quantifying the amount of population-level variation that exists for heavy metal tolerance and how plastic responses to heavy metals play out across generations are essential for understanding how animals respond to pollution. As an initial step toward studying transgenerational effects and population-level variation in concert, we brought cabbage white butterflies (Pieris rapae) from two populations-collected from St. Paul, MN, and Davis, CA-into common conditions and fed them a diet dosed with nickel. To measure transgenerational effects, we reared a second generation in a fully factorial design, within each population, to achieve all combinations of parent and offspring exposure to nickel or control diets. Across both generations, we quantified survival and other fitness-related traits, including development time, body size, and egg size and number. We found both population differences and complex transgenerational effects, including a positive effect of nickel on survival and development time in one of the populations. Overall, nickel exposure was stressful in one population, mainly after two generations of exposure, and had neutral or slightly positive effects on the other. We found no evidence for costs of mismatch between parental and offspring environments. While the reasons for the differences observed between the two populations are unclear, the variation in nickel tolerance observed in this species suggests that some organisms may be less affected by low levels of heavy metal pollution in urban and industrial areas than expected. PMID- 30010964 TI - Functional Shifts in Bat Dim-Light Visual Pigment Are Associated with Differing Echolocation Abilities and Reveal Molecular Adaptation to Photic-Limited Environments. AB - Bats are excellent models for studying the molecular basis of sensory adaptation. In Chiroptera, a sensory trade-off has been proposed between the visual and auditory systems, though the extent of this association has yet to be fully examined. To investigate whether variation in visual performance is associated with echolocation, we experimentally assayed the dim-light visual pigment rhodopsin from bat species with differing echolocation abilities. While spectral tuning properties were similar among bats, we found that the rate of decay of their light-activated state was significantly slower in a nonecholocating bat relative to species that use distinct echolocation strategies, consistent with a sensory trade-off hypothesis. We also found that these rates of decay were remarkably slower compared with those of other mammals, likely indicating an adaptation to dim light. To examine whether functional changes in rhodopsin are associated with shifts in selection intensity upon bat Rh1 sequences, we implemented selection analyses using codon-based likelihood clade models. While no shifts in selection were identified in response to diverse echolocation abilities of bats, we detected a significant increase in the intensity of evolutionary constraint accompanying the diversification of Chiroptera. Taken together, this suggests that substitutions that modulate the stability of the light-activated rhodopsin state were likely maintained through intensified constraint after bats diversified, being finely tuned in response to novel sensory specializations. Our study demonstrates the power of combining experimental and computational approaches for investigating functional mechanisms underlying the evolution of complex sensory adaptations. PMID- 30010965 TI - Using Primer-ID Deep Sequencing to Detect Recent Human Immunodeficiency Virus Type 1 Infection. AB - Intrahost viral sequence diversity can be evaluated over multiple genomic regions using next-generation sequencing (NGS) and scaled to population-level diversity to identify recent human immunodeficiency virus type 1 infection. Using Primer-ID NGS, we sequenced the reverse transcriptase (RT) and env V1-V3 regions from persons with known infection dates, and assessed the mean (pi) and first quintile of pairwise diversity distributions over time. The receiver operating characteristic area under the curve (AUC) of RT and V1-V3 combined showed excellent discrimination of recent infection <9 months: using pi (only single transmitted variants: AUC, 0.98; threshold <1.03%; sensitivity, 97%; specificity, 89%) and the first quintile (including all variants: AUC, 0.90; threshold <0.60%; sensitivity, 91%; specificity, 92%). PMID- 30010966 TI - The Impact of Anxiety and Depression on the Outcomes of Chronic Low Back Pain Multidisciplinary Pain Management-A Multicenter Prospective Cohort Study in Pain Clinics with One-Year Follow-up. AB - Objective: The psychological health of patients with chronic low back pain (CLBP) influences their response to a number of conservative and invasive pain treatments. However, evidence is still scarce regarding the impact of anxiety and depression in the clinical outcomes of multidisciplinary pain management over time. This study, based on longitudinal data from a clinical practice setting, aimed to assess the effectiveness of the usual multidisciplinary approach provided to CLBP patients and to explore the impact of anxiety and depression symptoms and their interaction on clinical outcomes. Methods: In this study, participants included were adult patients in their first consultation in a multidisciplinary chronic pain clinic. Anxiety and depression symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS). The Brief Pain Inventory (BPI) and the Shortened Treatment Outcomes in Pain Survey (S-TOPS) were used to assess outcomes. Linear mixed effects models were used to assess the impact of anxiety, depression, and their interaction on treatment outcomes. Results: A total of 284 patients (age 60.4 +/- 13.7 years, 74.6% female) with CLBP were included at baseline. The majority of patients had both anxiety and depression and experienced higher pain severity (P < 0.001) and higher pain related disability (P < 0.001). Anxiety and depression mainly predicted changes in pain interference over time. Their interaction significantly predicted changes in pain interference. Conclusions: Anxiety, depression, and their interaction are associated with changes in pain disability at one-year follow-up. These findings encourage the pretreatment screening of anxiety and depression as independent symptoms in patients with CLBP in order to design more tailored and effective multidisciplinary treatments. PMID- 30010967 TI - Supracerebellar Infratentorial and Occipital Transtentorial Approaches to the Pulvinar: Ipsilateral Versus Contralateral Corridors. AB - BACKGROUND: Due to the critical neurovascular structures that surround the pulvinar, deciding the best surgical approach can be challenging, with multiple options available. OBJECTIVE: To analyze and compare the ipsilateral vs the contralateral version of the 2 main approaches to the cisternal pulvinar surface: paramedian supracerebellar infratentorial (PSCI) and interhemispheric occipital transtentorial (IOT). METHODS: The PSCI and IOT approaches were performed on 7 formalin-fixed adult cadaveric heads to evaluate qualitatively and quantitatively the microsurgical exposure of relevant anatomic structures. We quantitatively measured the corridor distance to our target with each approach. RESULTS: The ipsilateral PSCI approach provided an easier access and a better exposure of the anteromedial portion of the cisternal pulvinar surface. The contralateral approach provided a wider and more accessible exposure of the posterolateral portion of the cisternal pulvinar surface. When protrusion of the posterior parahippocampal gyrus above the free edge of the tentorium was present, the contralateral PSCI approach provided an unobstructed view to both areas. The IOT approach provided a better view of the anteromedial portion of the cisternal pulvinar surface, especially with a contralateral approach. CONCLUSION: Multiple approaches to the pulvinar have been described, modified, and improved. Based on this anatomic study we believe that although the corridor distance with a contralateral approach is longer, the surgical view and access can be better. We recommend the use of a PSCI contralateral approach especially when a significant protrusion of the posterior parahippocampal gyrus is present. PMID- 30010968 TI - GIGSEA: Genotype Imputed Gene Set Enrichment Analysis using GWAS Summary Level Data. AB - Availability: GIGSEA is implemented in R, and freely available at www.github.com/zhushijia/GIGSEA. PMID- 30010969 TI - Impact of shift work schedules on actigraphy-based measures of sleep in Hispanic workers: results from the Hispanic Community Health Study/Study of Latinos ancillary Sueno study. AB - Study Objectives: To describe sleep characteristics of shift workers compared with day workers from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sueno ancillary study and test the hypothesis that shift work is associated with shorter sleep duration, worse sleep quality, greater sleep variability, and other sleep/health-related factors. Methods: Employed adults (N = 1253, mean age 46.3 years, 36.3% male) from the Sueno study were included. Measures of sleep duration, timing, regularity, and continuity were calculated from 7 days of wrist-activity monitoring. Participants provided information on demographics, employment, work schedule (day, afternoon, night, split, irregular, and rotating), sleepiness, depressive symptoms, medications, caffeine, and alcohol use. Survey linear regression adjusting for age, sex, background, site, number of jobs, and work hours was used. Results: In age and sex-adjusted models, all shift work schedules were associated with delayed sleep timing. Night and irregular schedules were associated with shorter sleep duration, greater napping, and greater variability of sleep. Afternoon and rotating shifts were associated with lower sleep regularity. In fully adjusted models, night and irregular schedules remained associated with shorter sleep duration, later sleep midpoint, and greater variability in sleep measures compared with day schedules. Split schedules were associated with, less time in bed, less sleep fragmentation, and less wake during the sleep period than day schedules. Conclusions: Work schedule significantly affects sleep-wake with substantial differences between day work and other types of schedule. Detailed assessment of work schedule type not just night shift should be considered as an important covariate when examining the association between sleep and health outcomes. PMID- 30010970 TI - RIPPS: A Plant Phenotyping System for Quantitative Evaluation of Growth Under Controlled Environmental Stress Conditions. AB - High-throughput and accurate measurements of plant traits facilitate identification of gene function. Along with recent advances in quantitative genomics, there is a growing need for precise quantification of multiple traits in plants. However, it is difficult continuously to quantify plant adaptive responses to environmental stress responses such as drought because multiple environmental factors are intricately involved in the phenotype. To solve this problem, we developed an automatic phenotyping system for evaluating the growth responses of individual Arabidopsis plants to a wide range of environmental conditions. The RIKEN Integrated Plant Phenotyping System (RIPPS) controls soil moisture for single plants by automatically weighing and watering 120 continuously rotating pots under controlled light, humidity and temperature growth conditions. RIPPS also records individual rosette size and expansion rate by photographing plants every 2 h. We used RIPPS to establish phenotype evaluation methods for Arabidopsis growth response and water use efficiency under various water conditions, and analyzed the involvement of ABA metabolism in determining water use efficiency. We also used RIPPS to analyze salinity tolerance in Arabidopsis plants. PMID- 30010971 TI - Treatment-based Classification System for Patients With Low Back Pain: The Movement Control Approach. AB - We present the movement control approach as part of the treatment-based classification system. This approach proposes a movement control schema that clarifies that movement control is a product of the interplay among multiple biopsychosocial components. The schema illustrates that for movement to occur in a dynamically controlled fashion, the lumbar spine requires both local mobility and global stability. Local mobility means that the lumbar spine and its adjacent regions possess adequate nerve and joint(s) mobility and soft tissue compliance (ie, the malleability of tissue to undergo elastic deformation). Global stability means that the muscles of the lumbar spine and its adjacent regions can generate activation that is coordinated with various joint movements and incorporated into activities of daily living. Local mobility and global stability are housed within the bio-behavioral and socio-occupational factors that should be addressed during movement rehabilitation. This schema is converted into a practical physical examination to help the rehabilitation provider to construct a clinical rationale as to why the movement impairment(s) exist. The examination findings are used to guide treatment. We suggest a treatment prioritization that aims to consecutively address neural sensitivity, joint(s) and soft tissue mobility, motor control, and endurance. This prioritization enables rehabilitation providers to better plan the intervention according to each patient's needs. We emphasize that treatment for patients with low back pain is not a static process. Rather, the treatment is a fluid process that changes as the clinical status of the patient changes. This movement control approach is based on clinical experience and indirect evidence; further research is needed to support its clinical utility. PMID- 30010972 TI - Endoplasmic Reticulum (ER) Membrane Proteins (LUNAPARKs) are Required for Proper Configuration of the Cortical ER Network in Plant Cells. AB - The endoplasmic reticulum (ER) is a large network made of membranous cisternae and tubules, which accounts for a large proportion of the total lipid bilayer endomembrane of the cell. In mammals and yeast, LUNAPARK proteins are preferentially localized at the three-way junctions of the ER network, stabilizing the junctions and establishing the ER architecture. We identified two Arabidopsis homologs and designated them LNPA and LNPB. Subcellular localization analysis with a non-dimerizable type of green fluorescent protein (GFP) revealed that both LNPA and LNPB are predominantly distributed throughout the ER, but not preferentially localized at the three-way junctions. Quantitative analysis of the network in the double mutant lnpa lnpb revealed that deficiency of LNPA and LNPB caused the cortical ER to develop poor ER cisternae and a less dense tubular network. These phenotypes are opposite to those of LNP-deficient mutants of yeast and mammals. Despite the importance of cysteine residues in the zinc finger motif of the yeast LNP homolog (Lnp1p), the corresponding cysteine residues of LNPA were not necessary for the stabilization of ER morphology because replacing the four cysteine residues in the zinc finger motif of the LNPA protein with alanine residues did not affect its function. A significant phenotype of lnpa lnpb is generation of large spherical structures from the ER. Formation of the structures might reduce the amounts of the ER membrane to be used for generating the network, resulting in poor development of the ER network. Taken together, our results suggest that plant LNPs function differently from those in yeast and mammals: they function to distribute ER membranes appropriately throughout the cells. PMID- 30010973 TI - Optimizing Outcome Prediction Scores in Patients Undergoing Endovascular Thrombectomy for Large Vessel Occlusions Using Collateral Grade on Computed Tomography Angiography. AB - BACKGROUND: Although several outcome prediction scores incorporated with pretreatment variables have been developed for acute ischemic stroke (AIS) patients, there is not currently a prediction score that includes pretreatment imaging that can show salvageable brain tissue. OBJECTIVE: To evaluate whether addition of the collateral grade on computed tomography angiography to previously published prediction scores could increase accuracy of clinical outcome prediction in endovascular thrombectomy (EVT) for AIS. METHODS: This study used a retrospective multicenter registry for patients undergoing EVT for anterior circulation large vessel occlusion. Three previously published outcome prediction scores (Houston intra-arterial therapy 2, HIAT2; totaled health risks in vascular events, THRIVE; and Pittsburgh response to endovascular therapy, PRE scores) were tested in this study. Using 482 deprivation cohorts, areas under the receiver operating characteristic curves (AUC-ROCs) were compared between prediction scores with/without collateral grades in predicting the poor outcomes (modified Rankin Scale 4-6 at 3-mo follow-up) after EVT. We developed modified prediction scores by adding the collateral grade, and their advancement of outcome prediction was validated using 208 independent validation cohorts. RESULTS: AUC ROCs of HIAT2, THRIVE, and PRE scores that incorporated with collateral grade were superior in predicting poor outcomes when compared to that of the unmodified scores (P < 0.001). In modified prediction models, 3, 3, and 10 points were added for poor collateral grade to HIAT2, THRIVE, and PRE score. Modified models outperformed unmodified models in testing of the validation cohorts (P < 0.001). CONCLUSION: The addition of the collateral grade to outcome prediction scores resulted in better prediction of poor outcome after EVT for AIS compared to the prediction scores alone. PMID- 30010974 TI - Physical Therapy Services for People With Intellectual and Developmental Disabilities: The Role of Medicaid Home- and Community-Based Service Waivers. AB - Background: Care and support for people with intellectual and developmental disabilities (IDD) in natural community contexts are increasing. Many people with IDD use physical therapy services to support their community participation. Medicaid Home- and Community-Based Services (HCBS) 1915(c) waivers are the largest providers of long-term services and supports for people with IDD. However, little is known about physical therapy provision under this program. Objective: The aim of this study was to compare the operational definitions of physical therapy service under the HCBS 1915(c) waiver system and to describe projected physical therapy service utilization, spending, and reimbursement for people with IDD across states. Design: This was a cross-sectional, descriptive study. Methods: This study analyzed fiscal year 2015 HCBS IDD waivers from across the nation (N = 111), focusing on physical therapy utilization (total projected spending, total participants, reimbursement rates, and average annual service provision per participant). Service definitions were also analyzed to determine trends across waivers. Results: Fifty-one waivers (45.9%) provided 61 different types of physical therapy services in fiscal year 2015. States utilized waivers to provide long-term remedial care rather than the acute short-term physical therapy. HCBS waiver physical therapy services were often provided in participants' homes and communities to expand physical therapy access and secure the benefits of providing physical therapy services in natural environments. Although most states have adopted similar definitions of physical therapy service, procedures and services vary. Limitations: Medicaid HCBS waivers are state projections made to the federal government rather than actual utilization data. Conclusions: Physical therapy service definitions, projected service utilization, spending, and reimbursement for people with IDD who use Medicaid HCBS waivers vary greatly between states. Physical therapy may be utilized less than expected given the reported benefits for people with IDD. PMID- 30010975 TI - Quality of Life Improvement Following Deep Brain Parkinson's Disease: Development of a Prognostic Model. AB - BACKGROUND: There is a growing attention to determine the factors that predict quality of life (QoL) improvement after deep brain stimulation (DBS) for Parkinson's disease. Prior literature has largely focused on examining predictors one at a time, sometimes controlling for covariates. OBJECTIVE: To develop a model that could be used as a nomogram to predict improvement in QoL following DBS surgery in patients with Parkinson's disease. METHODS: All patients with complete pre- and postoperative movement disorder and neuropsychological testing who underwent DBS at a single institution between 2007-2012 were analyzed. The Parkinson's Disease Questionnaire-39 (PDQ-39) was used to measure QoL. Potential predictive factors, including patient demographics, clinical presentation characteristics, radiographic imaging, and motor and psychological testing were analyzed for impact on QoL. RESULTS: Sixty-seven patients were identified, 36 (53.73%) of whom had meaningfully improved QoL following surgery. Five baseline variables showed significant relationships with the outcome: years since symptom onset, percent change in on/off motor evaluation, levodopa equivalent daily dose, bilateral vs unilateral DBS implantation, and PDQ-39 score. The final model includes PDQ-39, percent change in UPRS-III, and years since symptom onset and is able to predict improvement in QoL with 81% accuracy. CONCLUSION: Our model accurately predicted whether QoL would improve in patients undergoing subthalamic nucleus DBS 81% of the time. Our data may serve as the foundation to further refine a clinically relevant prognostic tool that would assist the decision making process for clinicians and DBS multidisciplinary teams assessing patient candidacy for surgery. PMID- 30010976 TI - Sero-prevalence of leptospirosis and differentiation in blood parameters between positive and negative cases in dogs of Kathmandu Valley. AB - Background: Leptospirosis is a zoonotic disease with worldwide distribution. It affects both humans and animals. Dogs may serve as a sentinel as well as a potential carrier for Leptospira infection in human. This study was conducted with the aim of investigating the sero-prevalence of leptospirosis, and differentiation in blood parameters in positive and negative cases of dogs. Methods: A cross-sectional study was carried out from August 2016 to December 2016 in Kathmandu valley. A total of 70 blood samples were collected from street dogs and tested against Leptospira infection using Immunocomb Canine Leptospira Antibody Test Kit. Results: Out of 70 blood samples tested, eight samples (11.4%) were positive. The average mean and SD of total leucocyte count of positive and negative cases were 79 750+/-12 090/mm3 and 11 026.98+/-4316.742/mm3, respectively. Levels of blood parameters (total leukocyte count (TLC), blood glucose, serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), and calcium and phosphorus) were found to be increased, and significant between positive and negative cases p<0.05, where blood urea and protein remained constant and non-significant. Conclusion: Detection of Leptospira antibody in non-vaccinated dogs indicates a significant threat to human population and demand unique strategic action plan for the control and prevention of disease. PMID- 30010977 TI - Clinimetric Properties and Minimal Clinically Important Differences for a Battery of Gait, Balance, and Cognitive Examinations for the Tap Test in Idiopathic Normal Pressure Hydrocephalus. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is treated by insertion of a ventricular peritoneal (VP) shunt. To help identify who would benefit from a VP shunt, patients undergo a tap test (TT). Several measures can identify change from a TT, but the magnitude of change and the combination of measures that indicate the improvement from a TT is unclear. OBJECTIVE: To develop minimal clinically important differences (MCIDs) for a battery of gait, balance, and cognitive measures in relation to improvement from the TT, and to identify which combination of measures best identifies when improvement has occurred. METHODS: Observational study of iNPH patients undergoing a TT for consideration of a VP shunt. Patients completed the: The Timed Up and Go (TUG), Timed Up and Go cognition (TUG-C), Performance Oriented Mobility Assessment (Tinetti), and Berg Balance Scale (BBS) pre- and post-TT. A Global Rating of Change scale assessed patients' perceived improvements in gait and balance post TT. RESULTS: MCIDs for the TT were (calculated as percentage changes): TUG: 13%, TUG-C: 11% Tinetti: 36%, and BBS: 20%. A combination of the TUG-C and Tinetti resulted in sensitivity of 90.28% to identify improvement, while the Tinetti and BBS resulted in specificity of 98.58% to exclude improvement from a TT. CONCLUSION: These MCIDs provide the first evidence to quantify the significance of post-TT symptom changes and provides objective data to guide recommendations for clinical management. Utilizing a combination of measures, and these MCIDs as cut off values, results in high sensitivity and specificity for identifying improvement from a TT. PMID- 30010978 TI - Role of the fungus-specific flavin carrier Flc1 in antifungal resistance in the fungal pathogen Cryptococcus neoformans. AB - FLC family, a conserved fungus-specific family of integral membrane proteins, has been demonstrated to play important roles in flavin transport, growth, and virulence in several fungi but not yet in Cryptococcus neoformans. In this study, we have identified the single homologue of flavin adenine dinucleotide transporter in the opportunistic pathogen C. neoformans. The computational and phylogenetic analysis confirmed the fungal specificity of cryptococcal Flc1 protein, thus providing a promising drug target for clinical treatment of cryptococcosis. Disruption of FLC1 conferred sensitivity to 1% Congo red and 0.02% SDS, as well as leading to impaired chitin distribution in cell wall as observed with Calcofluor White staining, which collectively indicated the roles of FLC1 in maintenance of cell wall integrity. Further investigations revealed the defects of flc1Delta mutant in resistance to poor nutrition and elevated temperatures, and the ability to undergo invasive growth under nutrient-depleted conditions was reduced as well in flc1Delta mutant, suggesting the roles of Flc1 in response to environmental stresses. More importantly, our results showed that flc1Delta mutant exhibited severe susceptibility to antifungal aminoglycosides (hygromycin B and geneticin) and amphotericin B, but developed multidrug resistance to flucytosine and rapamycin, which provided great hints for therapeutic failure of cryptococcosis in clinic with the standard combination therapy. Finally, typical virulence factors including melanin biosynthesis and capsule formation in flc1Delta mutant were reduced as well, indicating the possible involvement of Flc1 in virulence. PMID- 30010979 TI - Preparation and characterization of manganese, cobalt and zinc DNA nanoflowers with tuneable morphology, DNA content and size. AB - Recently reported DNA nanoflowers are an interesting class of organic-inorganic hybrid materials which are prepared using DNA polymerases. DNA nanoflowers combine the high surface area and scaffolding of inorganic Mg2P2O7 nanocrystals with the targeting properties of DNA, whilst adding enzymatic stability and enhanced cellular uptake. We have investigated conditions for chemically modifying the inorganic core of these nanoflowers through substitution of Mg2+ with Mn2+, Co2+ or Zn2+ and have characterized the resulting particles. These have a range of novel nanoarchitectures, retain the enzymatic stability of their magnesium counterparts and the Co2+ and Mn2+ DNA nanoflowers have added magnetic properties. We investigate conditions to control different morphologies, DNA content, hybridization properties, and size. Additionally, we show that DNA nanoflower production is not limited to F29 DNA polymerase and that the choice of polymerase can influence the DNA length within the constructs. We anticipate that the added control of structure, size and chemistry will enhance future applications. PMID- 30010980 TI - Increasing acceptability and uptake of voluntary male medical circumcision in Zambia: implementing and disseminating an evidence-based intervention. AB - Voluntary medical male circumcision (VMMC) uptake in Africa could prevent 3.4 million HIV infections across a 10 year span. In Zambia, however, ~80 per cent of uncircumcised men report no interest in undergoing VMMC. The Spear & Shield (S&S) intervention has been shown to be more effective than control or observation of only conditions at increasing the number of VMMCs. This study identified predictors of S&S implementation success or failure to create an "early warning" system to enable remedial action during implementation. Participants were n = 48 staff members from 12 community health facilities conducting the S&S program in Lusaka Province, Zambia. Quantitative assessments included demographics, provider attitudes, barriers to research uptake, staff burnout, and organizational readiness. Qualitative interviews were also conducted and quantified for analysis using the Consolidated Framework for Implementation Research (CFIR). Two-thirds (66%) of staff were women with a mean age of 37.67 years (SD = 7.51). Quantitatively, staff performance (p = .033) and decreased levels of staff burnout (p = .025) were associated with S&S implementation success. Qualitatively, constructs such as improved planning, executing, and self reflection and evaluation were associated with S&S implementation success (p = .005). Identifying these factors facilitated remedial action across health facilities. This study illustrates the utility of the CFIR to guide program decision making in VMMC implementation in the Zambian context. Early identification of challenges to implementation may enable remedial action to enhance the likelihood of program sustainability. Effective monitoring strategies for HIV prevention interventions may thus enhance dissemination, implementation, and sustainability goals to bridge research and practice. PMID- 30010982 TI - Seasonal Migration Pattern of Nilaparvata lugens (Hemiptera: Delphacidae) Over the Bohai Sea in Northern China. AB - The brown planthopper Nilaparvata lugens (Stal) (Hemiptera: Delphacidae) is a major, regionally migratory pest of rice crops in Asia. Despite intensive studies, the seasonal pattern of migration in this species remains largely unknown, especially in northern China. Analysis of monitoring data of light trapping at Beihuang island in northern China showed that brown planthopper migrants could be found at the island in any month from July to October. However, the daily number of brown planthopper migrants varied considerably from day to day, month to month, and year to year. Most of migrants were caught from July to September, with fewer in October. Simulation of backward trajectories showed that there was temporal variation in the source areas of brown planthopper migrants trapped at Beihuang. A majority of migrants trapped at Beihuang in July came from south of Beihuang. In contrast, migrants caught in August and September could be from any direction around the island. Results suggested that the brown planthopper migrants likely traveled northward in July, and Multidirectionally in August and September in northern China. Some of brown planthopper in northeastern China could escape the 'Pied Piper effect' and migrate southward in September. PMID- 30010981 TI - Screening Method for Identifying Toxicants Capable of Inducing Astrocyte Senescence. AB - Cellular senescence is a tumor-suppressive mechanism which leads to near irreversible proliferative arrest. However, senescent cells can cause tissue dysfunction, in large part because they express a senescence-associated secretory phenotype (SASP) involving secretion of, amongst other factors, proinflammatory cytokines known to compromise neuronal health. Therefore, established neurotoxicants may cause neurotoxicity in vivo, in part by triggering mitotic cells in the brain to undergo senescence and adopt an inflammatory SASP which in turn could cause deleterious effects to surrounding neurons. To begin to address this hypothesis, we examined whether we could screen known neurotoxicants for their ability to cause astrocytes (a mitotic cell type especially important for maintaining neuronal health) to undergo senescence. For this purpose, we utilized inducible pluripotent stem cell-derived human astrocytes and screened an 80 compound neurotoxicant library provided by the Biomolecular Screening Branch of the NIEHS National Toxicology Program. Here we present a screening method based on induction of the senescent marker, senescent-associated beta-galactosidase (SA beta-gal). We describe in detail an automated method for the unbiased quantitation of percentage of SA-beta-gal + astrocytes. Although our results suggest that conducting an SA-beta-gal senescence screen using human inducible pluripotent stem cell-derived astrocytes may be feasible, they also highlight challenges that likely preclude its adaptation to high-throughput. We also explore the possibility of using primary mouse astrocytes for this purpose and explain why this platform is problematic and very unlikely to yield meaningful results, even in small screens with compound replicates. PMID- 30010983 TI - Sleep restriction during peripuberty unbalances sexual hormones and testicular cytokines in rats. AB - Spermatogenesis and steroidogenesis are not fully established during puberty. Children and adolescents may be chronically sleep deprived due to early school hours and constant exposure to artificial light and interactive activities. We have previously shown that sleep restriction during peripuberty impairs sperm motility and has consequences on epididymal development. This study aimed to evaluate the effect of sleep restriction (SR) during peripuberty on sexual hormones and its impact on testicular tissue. Rats were subjected to 18 hours of SR per day for 21 days or were maintained as controls (C) in the same room. The circulating luteinizing hormone (LH) levels were decreased in SR rats without changes in the follicle stimulating hormone (FSH) levels. The testosterone and corticosterone levels in the SR group were increased in relation to the C group. These alterations impair testicular tissue, with decreased IL-1beta, IL-6, and TNFalpha levels in the testis and diminished seminiferous epithelium height and Sertoli cell number. SR also increased testicular lipid peroxidation with no alteration in antioxidant profiles. There were no significant changes in sperm parameters, seminiferous tubule diameter, histopathology, spermatogenesis kinetics, neutrophil and macrophage recruitment, and IL-10 concentration. Our results show that SR unbalances sexual hormones and testicular cytokines at a critical period of sexual maturation. These changes lead to lipid peroxidation in the testes and negatively influence the testicular tissue, as evidenced by diminished seminiferous epithelium height and Sertoli cell number. PMID- 30010985 TI - Accumulation of Multiple Mutations In Vivo Confers Cross-Resistance to New and Existing Integrase Inhibitors. AB - Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions. The accumulation of multiple integrase substitutions confers high-level resistance to all 5 integrase inhibitors. There is extensive cross-resistance between DTG, BIC, and CAB (r = 0.96-0.97). PMID- 30010984 TI - Early mannitol-triggered changes in the Arabidopsis leaf (phospho)proteome reveal growth regulators. AB - Leaf growth is a complex, quantitative trait, controlled by a plethora of regulatory mechanisms. Diverse environmental stimuli inhibit leaf growth to cope with the perceived stress. In plant research, mannitol is often used to impose osmotic stress and study the underlying growth-repressing mechanisms. In growing leaf tissue of plants briefly exposed to mannitol-induced stress, a highly interconnected gene regulatory network is induced. However, early signalling and associated protein phosphorylation events that probably precede part of these transcriptional changes and that potentially act at the onset of mannitol-induced leaf size reduction are largely unknown. Here, we performed a proteome and phosphoproteome analysis on growing leaf tissue of Arabidopsis thaliana plants exposed to mild mannitol-induced stress and captured the fast (within the first half hour) events associated with this stress. Based on this in-depth data analysis, 167 and 172 differentially regulated proteins and phosphorylated sites were found. We provide these data sets as a community resource and we flag differentially phosphorylated proteins with described growth-regulatory functions, but we also illustrate potential novel regulators of shoot growth. PMID- 30010987 TI - In vitro head-to-head comparison of anticoagulation properties of two heparin brands in a human blood miniature mock loop. AB - OBJECTIVES: The first aim was the development of a human blood miniature mock loop system consisting of 2 identical extracorporeal circuits, which enable systematic head-to-head comparisons of test substances. In a second step, we evaluated the suitability of the mock-loop system, by comparing 2 different brands of heparin (ROTEXMEDICA vs B.BRAUN), which have showed different anticoagulation capacities in the clinic. METHODS: For 1 experiment (18 in total), blood of the same healthy human donor was divided into 2 portions (2 * 50 ml), heparinized with 37.5 IU?ml-1 of the competing test substances and diluted to a haematocrit value of 20-25%. Each mock loop was filled with 70 ml, and in vivo heparin degradation was simulated in 3 different groups by protamine application, representing 0%, 50% and 100% heparin antagonization. At baseline, 5, 60, 120, 240 and 360 min, blood samples were taken to perform thromboelastometry, flow cytometry, haemolysis and general haemostasis analysis. RESULTS: Blood pressure, blood flow and blood temperature within the loops remained stable for 6 h in all groups. After 6 h, in the 100% antagonized ROTEXMEDICA heparin group, significantly increased haemolysis (148.7 +/- 80 mg?dl 1 vs 57.5 +/- 15.8 mg?dl-1), activated platelets (8 +/- 3.8% vs 3.3 +/- 0.7%), D dimers (7376 +/- 7144 ng ml-1 vs 576.2 +/- 190 ng ml-1) and fulminant blood clots were detected. CONCLUSIONS: Our in vitro system is suitable for the detection of reduced anticoagulation capacity of a test drug, which was reported in vivo previously. PMID- 30010988 TI - Working Channel Endoscopic Interlaminar Microdiscectomy: 2-Dimensional Operative Video. AB - This video demonstrates a working channel interlaminar microdiscectomy performed in a patient with significant back and leg pain due to a persistent disc herniation. We describe this technique in detail, describing the endoscopic anatomy and illustrating key steps to safely perform this operation. Due to the limited soft tissue destruction required to access the disc space with this approach, the patient was able to leave the hospital on the day of surgery, and required no pain medication by short-term follow-up a few weeks postoperatively.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The patient gave direct consent for the use of the endoscopic footage and associated information from this surgery for the making of this video. PMID- 30010986 TI - In Vitro Transformation of Human Bronchial Epithelial Cells by Diesel Exhaust Particles: Gene Expression Profiling and Early Toxic Responses. AB - Occupational exposure to diesel exhaust may cause lung cancer in humans. Mechanisms include DNA-damage and inflammatory responses. Here, the potential of NIST SRM2975 diesel exhaust particles (DEP) to transform human bronchial epithelial cells (HBEC3) in vitro was investigated. Long-term exposure of HBEC3 to DEP led to increased colony growth in soft agar. Several DEP-transformed cell lines were established and based on the expression of epithelial-to-mesenchymal transition (EMT) marker genes, one of them (T2-HBEC3) was further characterized. T2-HBEC3 showed a mesenchymal/fibroblast-like morphology, reduced expression of CDH1, and induction of CDH2 and VIM. T2-HBEC3 had reduced migration potential compared with HBEC3 and little invasion capacity. Gene expression profiling showed baseline differences between HBEC3 and T2-HBEC3 linked to lung carcinogenesis. Next, to assess differences in sensitivity to DEP between parental HBEC3 and T2-HBEC3, gene expression profiling was carried out after DEP short-term exposure. Results revealed changes in genes involved in metabolism of xenobiotics and lipids, as well as inflammation. HBEC3 displayed a higher steady state of IL1B gene expression and release of IL-1beta compared with T2-HBEC3. HBEC3 and T2-HBEC3 showed similar susceptibility towards DEP-induced genotoxic effects. Liquid-chromatography-tandem-mass-spectrometry was used to measure secretion of eicosanoids. Generally, major prostaglandin species were released in higher concentrations from T2-HBEC3 than from HBEC3 and several analytes were altered after DEP-exposure. In conclusion, long-term exposure to DEP-transformed human bronchial epithelial cells in vitro. Differences between HBEC3 and T2-HBEC3 regarding baseline levels and DEP-induced changes of particularly CYP1A1, IL 1beta, PGE2, and PGF2alpha may have implications for acute inflammation and carcinogenesis. PMID- 30010989 TI - Letter: Nerve Surgeons' Assessment of the Role of Eduard Pernkopf's Atlas of Topographic and Applied Human Anatomy in Surgical Practice. PMID- 30010990 TI - Chimney technique for coronary obstruction after aortic valve in valve: pros and cons. PMID- 30010991 TI - Letter: Commentary: Utilization of Quantitative Susceptibility Mapping for Direct Targeting of the Subthalamic Nucleus During Deep Brain Stimulation Surgery. PMID- 30010992 TI - Overcoming Challenges of Cranial Nerve Tractography: A Targeted Review. AB - BACKGROUND: Diffusion imaging tractography caught the attention of the scientific community by describing the white matter architecture in vivo and noninvasively, but its application to small structures such as cranial nerves remains difficult. The few attempts to track cranial nerves presented highly variable acquisition and tracking settings. OBJECTIVE: To conduct and present a targeted review collecting all technical details and pointing out challenges and solutions in cranial nerve tractography. METHODS: A "targeted" review of the scientific literature was carried out using the MEDLINE database. We selected studies that reported how to perform the tractography of cranial nerves, and extracted the following: clinical context; imaging acquisition settings; tractography parameters; regions of interest (ROIs) design; and filtering methods. RESULTS: Twenty-one published articles were included. These studied the optic nerves in suprasellar tumors, the trigeminal nerve in neurovascular conflicts, the facial nerve position around vestibular schwannomas, or all cranial nerves. Over time, the number of MRI diffusion gradient directions increased from 6 to 101. Nine tracking software packages were used which offered various types of tridimensional display. Tracking parameters were disparately detailed except for fractional anisotropy, which ranged from 0.06 to 0.5, and curvature angle, which was set between 20 degrees and 90 degrees . ROI design has evolved towards a multi-ROI strategy. Furthermore, new algorithms are being developed to avoid spurious tracts and improve angular resolution. CONCLUSION: This review highlights the variability in the settings used for cranial nerve tractography. It points out challenges that originate both from cranial nerve anatomy and the tractography technology, and allows a better understanding of cranial nerve tractography. PMID- 30010993 TI - Differentially Expressed MicroRNAs Link Cellular Physiology to Phenotypic Changes in Rice Under Stress Conditions. AB - Plant microRNAs (miRNAs) and their target genes have important functional roles in nutrition deficiency and stress response. However, the underlying mechanisms relating relative expression of miRNAs and target mRNAs to morphological adjustments are not well defined. By combining miRNA expression profiles, corresponding target genes and transcription factors that bind to computationally identified over-represented cis-regulatory elements (CREs) common in miRNAs and target gene promoters, we implement a strategy that identifies a set of differentially expressed regulatory interactions which, in turn, relate underlying cellular mechanisms to some of the phenotypic changes observed. Integration of experimentally reported individual interactions with identified regulatory interactions explains how (i) during mineral deficiency osa-miR167 inhibits shoot growth but activates adventitious root growth by influencing free auxin content; (ii) during sulfur deficiency osa-miR394 is involved in adventitious root growth inhibition, sulfur and iron homeostasis, and auxin mediated regulation of sulfur homeostasis; (iii) osa-miR399 contributes to cross talk between cytokinin and phosphorus deficiency signaling; and (iv) a feed forward loop involving the osa-miR166, trihelix and HD-ZIP III transcription factors may regulate leaf senescence during drought. This strategy not only identifies various regulatory interactions connecting phenotypic changes with cellular or molecular events triggered by stress, but also provides a framework to deepen our understanding of stress cellular physiology. PMID- 30010994 TI - Admission and mortality at the main neonatal intensive care unit in Guinea Bissau. AB - Background: The authors assessed the risk of admission and mortality at the main neonatal intensive care unit (NICU) at the National Hospital Simao Mendes (NHSM) in Guinea-Bissau. Methods: The Bandim Health Project (BHP) maintains a health and demographic surveillance system (HDSS) in the capital Bissau, including at the NHSM. Data from January 2008 to August 2013 was used to assess NICU incubator admissions and mortality. Results: The overall NICU admission rate was 4.8% (1575/33,005); the lowest rate in 2012 (4.0% (214/5293)) and the highest rate in 2009 (6.0% (369/6134)). The overall mortality among admitted children was 19.6% (289/1476), declining from 26.7% (68/255) in 2008 to 13.0% (16/123) in 2013. Birth weight <1500 g (OR=353, (95% CI: 244-510) compared with normal birth weight 2500 g-4000 g), Apgar score<=3 (OR=13.2 (9.72-18.0) compared with Apgar score 7 10) and single motherhood (OR=1.44 (1.20-1.74)) were associated with NICU admission. Low Apgar score was a risk factor for NICU mortality (OR=6.21 (2.05 18.81)) and females (OR=0.55 (0.38-0.79) had a lower mortality than males. Conclusion: Approximately 5% of the hospital-born children were admitted to an incubator and among those almost 20% died, although mortality did decline. Male sex, very low birth weight and low Apgar score were strongly associated with NICU admissions and mortality. PMID- 30010995 TI - Molecular Study of Long-Term Survivors of Glioblastoma by Gene-Targeted Next Generation Sequencing. AB - Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS >=36 months) and 45 non-LTS. Using next generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients. PMID- 30010996 TI - Iterative Surgical Resections of Diffuse Glioma With Awake Mapping: How to Deal With Cortical Plasticity and Connectomal Constraints? AB - BACKGROUND: In diffuse glioma, a multistage approach with iterative tailored surgical resections can be considered. OBJECTIVE: To compare results of iterative intrasurgical brain mappings to investigate the potential and limitation of neuroplasticity at the individual stage, and to highlight to what extent it can influence the therapeutic strategy. METHODS: Glioma patients who underwent 2 consecutive awake surgeries with cortical and subcortical stimulation were classified into group 1 (n = 23) if cortical mappings exhibited high level of plasticity (displacement of >=2 sites) or into group 2 (n = 19) with low level of plasticity. RESULTS: Clinical characteristics did not differ significantly between both groups. The borders of the tumors were mostly sharp in group 1 (82.6%) and rather indistinct in group 2 (84.2%), (P = .00001). Tumor remnants were more often cortical (+/- subcortical) in group 1 (39.1%) and more often purely subcortical in group 2 (68.4%; P = .009). In group 1, the time needed to recover independence was significantly shorter at reoperation (37.6 h vs 78.3 h after the first surgery, P = .00003) while this difference was not significant in group 2. The iterative extents of resection (EOR) remain comparable in group 1 (94% vs 92%, P = .40) but were significantly smaller in group 2 at reoperation (94% vs 88%, P = .05). CONCLUSION: More efficient plasticity mechanisms are facilitated by cortical tumors with sharp borders, are associated with an increase of EOR at reoperation and with earlier functional recovery. Tumoral invasion of the white matter tracts represents the main limitation of neuroplasticity: this connectomal constraint limits EOR during second surgery. PMID- 30010997 TI - The Eyes Do not Lie: A Case of Bilateral Subconjunctival Hemorrhages and Orbital Hematoma Postpartum. AB - Subconjunctival hemorrhages are common in trauma and with increased intra abdominal pressure. Despite the sustained pressure endured while pushing, they are rarely observed postpartum and can be an indicator of underlying ophthalmic disease. We present a case of a postpartum patient who developed bilateral subconjunctival hemorrhages with a retro-orbital hematoma. The patient is a 29 year-old gravida-1-para-0 at 41 weeks gestation who underwent an uncomplicated induction and delivery. She developed diplopia and orbital pain postpartum. Imaging revealed an orbital hematoma with an ophthalmologic workup revealing suspected glaucoma. She was followed outpatient with symptomatic treatment and had resolution of symptoms after 4 weeks. This case demonstrates a rare postpartum scenario and the subsequent workup. Subconjunctival hemorrhages are rare in the postpartum period despite prolonged pushing efforts. Incorporating a multidisciplinary approach for diagnosis of a pregnant patient with ophthalmologic disease is required to optimize management in the antepartum, intrapartum, and postpartum periods. PMID- 30010998 TI - Comparative Impact of Chitin Synthesis Inhibitor Baits and Non-repellent Liquid Termiticides on Subterranean Termite Colonies Over Foraging Distances: Colony Elimination Versus Localized Termite Exclusion. AB - This study evaluated the impact of a non-repellent liquid termiticide (fipronil) and a chitin synthesis inhibitor (CSI) termite bait (noviflumuron) on whole colonies of Coptotermes gestroi (Wasmann) (Blattodea: Isoptera: Rhinotermitidae) in laboratory conditions, over a 12-m foraging distance. The protocol simulated the implementation of remedial treatment of an infested structure, where the colony has multiple access routes, and where only a portion of the population was directly exposed to the treatment. Within 2 wk after the implementation of fipronil, all termites within 1.5 m away from the treatment died. The accumulation of cadavers near the treated area resulted in secondary repellency and the colonies avoided the treated area for the remaining 10 wk of the experiment, using alternative foraging galleries. At the end of the 12 wk, colonies exposed to fipronil did not have any difference in population size compared with control colonies. Comparatively, colonies exposed to noviflumuron had no change in foraging activity for the first ~40 d, but then termites progressively ceased their activity throughout their foraging territory. By 12 wk, noviflumuron-exposed colonies were near-elimination, with only a few workers, soldiers remaining, and all colonies were eliminated by 95 d. This study shows that subterranean termite colonies with access to CSI baits are inevitably eliminated, regardless of the position of the bait, while colonies exposed to fipronil are only locally excluded from the area near the treatment, but may maintain their foraging activity in untreated areas, and retain their potential risk for structural damage in the long term. PMID- 30011000 TI - Endovascular Treatment of Ethmoidal Dural Arteriovenous Fistulas Neuroendovascular Surgical Video Demonstration of 2 Cases: 2-Dimensional Operative Video. PMID- 30011001 TI - The NADPH-Dependent Thioredoxin Reductase C-2-Cys Peroxiredoxin Redox System Modulates the Activity of Thioredoxin x in Arabidopsis Chloroplasts. AB - The chloroplast redox network is composed of a complex set of thioredoxins (Trxs), reduced by ferredoxin (Fdx) via a Fdx-dependent Trx reductase (FTR), and an NADPH-dependent Trx reductase with a joint Trx domain, NTRC, which efficiently reduces 2-Cys peroxiredoxins (2-Cys Prxs). Recently, it was proposed that the redox balance of 2-Cys Prxs maintains the redox state of f-type Trxs, thus allowing the proper redox regulation of Calvin-Benson cycle enzymes such as fructose 1,6-bisphosphatase (FBPase). Here, we have addressed whether the action of 2-Cys Prxs is also exerted on Trx x. To that end, an Arabidopsis thaliana quadruple mutant, ntrc-trxx-Delta2cp, which is knocked out for NTRC and Trx x, and contains severely decreased levels of 2-Cys Prxs, was generated. In contrast to ntrc-trxx, which showed a severe growth inhibition phenotype and poor photosynthetic performance, the ntrc-trxx-Delta2cp mutant showed a significant recovery of growth rate and photosynthetic efficiency, indicating that the content of 2-Cys Prxs is critical for the performance of plants lacking both NTRC and Trx x. Light-dependent reduction of FBPase was severely impaired in mutant plants lacking NTRC or NTRC plus Trx x, despite the fact that neither NTRC nor Trx x is an effective reductant of this enzyme. However, FBPase reduction was recovered in the ntrc-trxx-Delta2cp mutant. Our results show that the redox balance of 2-Cys Prxs, which is mostly dependent on NTRC, modulates the activity of Trx x in a similar way as f-type Trxs, thus suggesting that the activity of these Trxs is highly interconnected. PMID- 30010999 TI - The Long-Term Impact of Severe Burn Trauma on Musculoskeletal Health. AB - Severe burn injury causes a profound stress response that leads to muscle and bone cachexia. Evidence suggests that these deficits persist for several months or even years after injury and are associated with growth delay, increased incidence of fractures, and increased hospital admissions for musculoskeletal disorders. Thus, there is an overwhelming need to determine the optimal acute and rehabilitative strategies to mitigate these deficits and improve quality of life for burn survivors. To date, there is limited research on the long-term impact of cachexia on functional performance and overall health, as well as on the lasting impact of pharmacological, nutritional, and exercise interventions. The aim of this review is to emphasize the long-term consequences of musculoskeletal cachexia and determine the best evidence-based strategies to attenuate it. We also underline important knowledge gaps that need to be addressed in order to improve care of burn survivors. PMID- 30011003 TI - Commentary: Iterative Surgical Resections of Diffuse Glioma with Awake Mapping: How to Deal with Cortical Plasticity and Connectomal Constraints? PMID- 30011002 TI - Daily variation in the prokaryotic community during a spring bloom in shelf waters of the East China Sea. AB - To understand prokaryotic responses during a spring bloom in offshore shelf waters, prokaryotic parameters were measured daily at a station located in the middle of the East China Sea over a six-week period from March 25 to May 19. The site experienced a phytoplankton bloom in late April, triggering changes in prokaryotic abundance and production after a lag of approximately one week. Before the bloom, changes in prokaryotic composition were small. Both during the bloom and in the post-bloom period, successive changes among bacterial groups were apparent. A SAR11 group became more dominant during the bloom period, and diverse groups belonging to the Flavobacteriia occurred dominantly during both the bloom and post-bloom periods. However, bacterial community changes at the species level during the bloom and post-bloom periods occurred rapidly in a time scale of a few days. Especially, NS5, NS4 and Formosa bacteria belonging to Flavobacteriia and bacteria belonging to Halieaceae and Arenicellaceae families of Gammaproteobacteria showed a successive pattern with large short-term variation during the period. The changes in prokaryotic composition were found to be related to phytoplankton biomass and composition, as well as seawater temperature and variations in nutrients. PMID- 30011004 TI - Toxoplasma gondii infection and pre-eclampsia among Sudanese women. AB - Background: Pre-eclampsia is the main cause of maternal and perinatal adverse effects. Although the exact mechanism and pathophysiology of pre-eclampsia are not yet fully understood, there are recent studies on the association between various infections and pre-eclampsia. This study investigated the association between maternal Toxoplasma gondii infection and pre-eclampsia. Methods: A case control study was conducted at Saad Abualila Hospital, Khartoum, Sudan. The cases were pregnant women with pre-eclampsia and the controls were healthy pregnant women. Their obstetrics history was collected using a questionnaire. T. gondii antibodies (immunoglobulin G [IgG] and IgM) were analysed in the maternal serum of both the cases and the controls using enzyme-linked immunosorbent assay. Results: Maternal age and parity were not different between the cases and controls (90 women in each arm). There was a significant difference in the maternal anti-T. gondii IgG seropositivity, which was higher in the cases (pre eclampsia) compared with the controls (32.3% vs 4.4%; p<0.001). There was no significant difference in the IgM seropositivity for T. gondii between the cases and controls (3.3% vs 1.1%; p=0.621). Binary logistic regression showed that women with toxoplasma IgG seropositivity were at higher risk for pre-eclampsia (odds ratio 9.40 [95% confidence interval 3.01 to 29.32]; p<0.001). Conclusions: In the current study, T. gondii infection seems to be associated with pre eclampsia. Further research is needed. PMID- 30011006 TI - Species-Specific Means and Within-Species Variance in Glucocorticoid Hormones and Speciation Rates in Birds. AB - At macroevolutionary scales, stress physiology may have consequences for species diversification and subspecies richness. Populations that exploit new resources or undergo range expansion should cope with new environmental challenges, which could favor higher mean stress responses. Within-species variation in the stress response may also play a role in mediating the speciation process: in species with broad variation, there will always be some individuals that can tolerate an unpredictable environment, whereas in species with narrow variation there will be fewer individuals that are able to thrive in a new ecological niche. We tested for the evolutionary relationship between stress response, speciation rate, and subspecies richness in birds by relying on the HormoneBase repository, from which we calculated within- and among-species variation in baseline (BL) and stress induced (SI) corticosterone levels. To estimate speciation rates, we applied Bayesian analysis of macroevolutionary mixtures that can account for variation in diversification rate among clades and through time. Contrary to our predictions, lineages with higher diversification rates were not characterized by higher BL or SI levels of corticosterone either at the tips or at the deeper nodes of the phylogeny. We also found no association between mean hormone levels and subspecies richness. Within-species variance in corticosterone levels showed close to zero repeatability, thus it is highly unlikely that this is a species specific trait that influences diversification rates. These results imply that stress physiology may play a minor, if any, role in determining speciation rates in birds. PMID- 30011005 TI - Translocation kinetics and structural dynamics of ribosomes are modulated by the conformational plasticity of downstream pseudoknots. AB - Downstream stable mRNA secondary structures can stall elongating ribosomes by impeding the concerted movements of tRNAs and mRNA on the ribosome during translocation. The addition of a downstream mRNA structure, such as a stem-loop or a pseudoknot, is essential to induce -1 programmed ribosomal frameshifting (-1 PRF). Interestingly, previous studies revealed that -1 PRF efficiencies correlate with conformational plasticity of pseudoknots, defined as their propensity to form incompletely folded structures, rather than with the mechanical properties of pseudoknots. To elucidate the detailed molecular mechanisms of translocation and -1 PRF, we applied several smFRET assays to systematically examine how translocation rates and conformational dynamics of ribosomes were affected by different pseudoknots. Our results show that initial pseudoknot-unwinding significantly inhibits late-stage translocation and modulates conformational dynamics of ribosomal post-translocation complexes. The effects of pseudoknots on the structural dynamics of ribosomes strongly correlate with their abilities to induce -1 PRF. Our results lead us to propose a kinetic scheme for translocation which includes an initial power-stroke step and a following thermal-ratcheting step. This scheme provides mechanistic insights on how selective modulation of late-stage translocation by pseudoknots affects -1 PRF. Overall our findings advance current understanding of translocation and ribosome-induced mRNA structure unwinding. PMID- 30011007 TI - Comparative analysis of zebrafish and planarian model systems for developmental neurotoxicity screens using an 87-compound library. AB - There is a clear need to establish and validate new methodologies to more quickly and efficiently screen chemicals for potential toxic effects, particularly on development. The emergence of alternative animal systems for rapid toxicology screens presents valuable opportunities to evaluate how systems complement each other. In this article, we compare a chemical library of 87-compounds in two such systems, developing zebrafish and freshwater planarians, by screening for developmental neurotoxic effects. We show that the systems' toxicological profiles are complementary to each other, with zebrafish yielding more detailed morphological endpoints and planarians more behavioral endpoints. Overall, zebrafish was more sensitive to this chemical library, yielding 86/87 hits, compared to 50/87 hits in planarians. The difference in sensitivity could not be attributed to molecular weight, Log Kow or the bioconcentration factor. Of the 87 chemicals, 28 had previously been evaluated in mammalian developmental neuro- (DNT), neuro- or developmental toxicity studies. Of the 28, 20 were hits in the planarian, and 27 were hits in zebrafish. Eighteen of the 28 had previously been identified as DNT hits in mammals and were highly associated with activity in zebrafish and planarian behavioral assays in this study. Only 1 chemical (out of 28) was a false negative in both zebrafish and planarian systems. Differences in endpoint coverage and system sensitivity illustrate the value of a dual systems approach to rapidly query a large chemical-bioactivity space and provide weight of-evidence for prioritization of chemicals for further testing. PMID- 30011008 TI - Comparative Models of Biological and Social Pathways to Predict Child Growth through Age 2 Years from Birth Cohorts in Brazil, India, the Philippines, and South Africa. AB - Background: Early growth faltering accounts for one-third of child deaths, and adversely impacts the health and human capital of surviving children. Social as well as biological factors contribute to growth faltering, but their relative strength and interrelations in different contexts have not been fully described. Objective: The aim of this study was to use structural equation modelling to explore social and biological multidetermination of child height at age 2 y in longitudinal data from 4 birth cohort studies in low- and middle-income countries. Methods: We analyzed data from 13,824 participants in birth cohort studies in Brazil, India, the Philippines, and South Africa. We used exploratory structural equation models, with height-for-age at 24 mo as the outcome to derive factors, and path analysis to estimate relations among a wide set of social and biological variables common to the 4 sites. Results: The prevalence of stunting at 24 mo ranged from 14.0% in Brazil to 67.7% in the Philippines. Maternal height and birthweight were strongly predictive of height-for-age at 24 mo in all 4 sites (all P values <0.001). Three social-environmental factors, which we characterized as "child circumstances," "family socioeconomic status," and "community facilities," were identified in all sites. Each social-environmental factor was also strongly predictive of height-for-age at 24 mo (all P values <0.001), with some relations partly mediated through birthweight. The biological pathways accounted for 59% of the total explained variance and the social environmental pathways accounted for 41%. The resulting path coefficients were broadly similar across the 4 sites. Conclusions: Early child growth faltering is determined by both biological and social factors. Maternal height, itself a marker of intergenerational deprivation, strongly influences child height at 2 y, including indirect effects through birthweight and social factors. However, concurrent social factors, many of which are modifiable, directly and indirectly contribute to child growth. This study highlights opportunities for interventions that address both biological and social determinants over the long and short term. PMID- 30011009 TI - Increasing Clindamycin and Trimethoprim-Sulfamethoxazole Resistance in Pediatric Staphylococcus aureus Infections. AB - The epidemiology of Staphylococcus aureus infection in children is dynamic. We conducted a retrospective observational study on pediatric clinical cultures, performed between 2005 and 2017, that grew S aureus to determine temporal trends in antibiotic resistance. Although methicillin resistance declined, clindamycin and trimethoprim-sulfamethoxazole resistance increased significantly, especially among community-onset isolates. PMID- 30011010 TI - Operative Management of Idiopathic Spinal Cord Herniation: Case Series and Novel Technique for Repair of Recurrent Herniation. AB - BACKGROUND: Idiopathic spinal cord herniation (ISCH) is a rare pathology of the spine defined by herniation of the spinal cord through a dural defect. OBJECTIVE: To highlight the operative management of ISCH and the surgical nuances of ISCH repairs conducted at our institution. METHODS: This retrospective review examines consecutive patients with ISCH who were treated surgically between January 1, 2010, and July 31, 2017, at Barrow Neurological Institute, Phoenix, Arizona. RESULTS: Four patients with ISCH presented with thoracic myelopathy and lower extremity weakness during the study period. Treatment consisted of reduction of the herniated spinal cord and filling of the dural defect with a collagen-based dural regeneration matrix. In 3 patients the dural edges were covered with a collagen-matrix intradural sling, and in 1 patient they were repaired primarily with interrupted sutures. Three of the 4 patients experienced improvement in myelopathic symptoms; the fourth patient suffered neurological decline in the immediate postoperative period. CONCLUSION: ISCH is a complex pathological condition likely to result in progressive myelopathy. Surgery offers patients the possibility of stabilizing the progression of the spinal cord dysfunction and perhaps restoring neurological function. However, extreme care must be taken during surgery to minimize manipulation of the fragile herniated cord. PMID- 30011012 TI - Microsurgical Treatment of Recurrent Conus Medullaris Arteriovenous Malformation: 2-Dimensional Operative Video. AB - Arteriovenous malformations (AVMs) involving the conus medullaris have a unique angioarchitecture due to their involvement of the arterial basket of the conus medullaris, which represents an arterial anastomotic network between the anterior spinal artery (ASA) and posterior spinal arteries (PSAs) at the level of the conus medullaris.1 These lesions consist of a combination of a true AVM nidus, which is usually extramedullary, and direct shunts between the ASA, PSAs, and the venous system. Patients may present with radiculopathy, myelopathy, or subarachnoid hemorrhage.2A 40-yr-old woman status post T11-L1 laminoplasty for resection of a ruptured conus AVM 6 yr prior presented with routine follow-up angiography suggestive of an arteriovenous fistula. She was counseled regarding treatment options including endovascular embolization and microsurgical ligation or resection, and she elected to proceed with surgical treatment. At the time of surgery, a recurrent AVM was noted. A 2-dimensional intraoperative video illustrates the microsurgical treatment of her recurrent conus AVM. The patient recovered well postoperatively. Spinal angiography demonstrated complete obliteration of the lesion. The patient experienced transient urinary retention that was self-limited but otherwise was without any new neurological deficit. Due to the retrospective nature of this report, informed consent was not required.Video used with permission from Barrow Neurological Institute, all rights reserved. PMID- 30011011 TI - Water Contaminants Associated With Unconventional Oil and Gas Extraction Cause Immunotoxicity to Amphibian Tadpoles. AB - Chemicals associated with unconventional oil and gas (UOG) operations have been shown to contaminate surface and ground water with a variety of endocrine disrupting compounds (EDCs) inducing multiple developmental alteration in mice. However, little is known about the impacts of UOG-associated contaminants on amphibian health and resistance to an emerging ranavirus infectious disease caused by viruses in the genus Ranavirus, especially at the vulnerable tadpole stage. Here we used tadpoles of the amphibian Xenopus laevis and the ranavirus Frog virus 3 (FV3) as a model relevant to aquatic environment conservation research for investigating the immunotoxic effects of exposure to a mixture of 23 UOG-associated chemicals with EDC activity. Xenopus tadpoles were exposed to an equimass mixture of 23 UOG-associated chemicals (range from 0.1 to 10 ug/l) for 3 weeks prior to infection with FV3. Our data show that exposure to the UOG chemical mixture is toxic for tadpoles at ecological doses of 5 to 10 ug/l. Lower doses significantly altered homeostatic expression of myeloid lineage genes and compromised tadpole responses to FV3 through expression of TNF-alpha, IL-1beta, and Type I IFN genes, correlating with an increase in viral load. Exposure to a subset of 6 UOG chemicals was still sufficient to perturb the antiviral gene expression response. These findings suggest that UOG-associated water pollutants at low but environmentally relevant doses have the potential to induce acute alterations of immune function and antiviral immunity. PMID- 30011014 TI - Underlying Diseases and Causative Microorganisms of Recurrent Pneumonia in Children: A 13-Year Study in a University Hospital. AB - Pneumonia is a significant cause of death for children, particularly those in developing countries. The records of children who were hospitalized because of pneumonia between January 2003 and December 2015 were retrospectively reviewed, and patients who met the recurrent pneumonia criteria were included in this study. During this 13-year period, 1395 patients were hospitalized with pneumonia; of these, 129 (9.2%) met the criteria for recurrent pneumonia. Underlying diseases were detected in 95 (73.6%) patients, with aspiration syndrome (21.7%) being the most common. Rhinovirus (30.5%), adenovirus (17.2%) and respiratory syncytial virus (13.9%) were the most frequent infectious agents. These results demonstrate that underlying diseases can cause recurrent pneumonia in children. Viruses are also commonly seen in recurrent pneumonia. Appropriate treatments should be chosen based on an analysis of the underlying disease, the patient's clinical condition and the laboratory and radiological data. PMID- 30011015 TI - Educator perspectives on factors influencing children's school-based physical activity. AB - Formative research is an important first step in the design and development of children's school-based physical activity (PA) interventions. Exploration of educator [headteacher and physical education (PE)-co-ordinator] perceptions toward the promotion of school-based PA, including PE delivery has however been limited. This study took a socio-ecological approach to explore the barriers and facilitators of children's school-based PA from the perspective of school educators. Interviews were conducted with headteachers (n = 4), PE-co-ordinators (n = 4) and a deputy headteacher (n = 1) and data thematically analysed using Nvivo software (version 10). Findings suggested that, at an organizational level headteachers were the predominant driving force in the promotion of PA opportunities, yet institutional barriers including low priority for PA and PE were perceived to negate delivery. At an interpersonal level, strategies to increase the delivery of school-based PA were developed, however poor teacher coach relationships and significant others reduced PA promotion opportunities. Child PA was further negated through intrapersonal factors, including lack of PE specific teacher training and varying teacher interest in PA and sport. To increase primary school children's school-based PA, barriers and facilitators at the organizational, interpersonal and intrapersonal level must be considered and targeted and researchers and schools should work in partnership to develop future interventions. PMID- 30011013 TI - Life History Trade-offs within the Context of Mitochondrial Hormesis. AB - Evolutionary biologists have been interested in the negative interactions among life history traits for nearly a century, but the mechanisms that would create this negative interaction remain poorly understood. One variable that has emerged as a likely link between reproductive effort and longevity is oxidative stress. Specifically, it has been proposed that reproduction generates free radicals that cause oxidative stress and, in turn, oxidative stress damages cellular components and accelerates senescence. We propose that there is limited support for the hypothesis because reactive oxygen species (ROS), the free radicals implicated in oxidative damage, are not consistently harmful. With this review, we define the hormetic response of mitochondria to ROS, termed mitochondrial hormesis, and describe how to test for a mitohormetic response. We interpret existing data using our model and propose that experimental manipulations will further improve our knowledge of this response. Finally, we postulate how the mitohormetic response curve applies to variation in animal performance and longevity. PMID- 30011016 TI - Fluoroscopic-Guided Paramedian Approach for Lumbar Catheter Placement in Cerebrospinal Fluid Shunting: Assessment of Safety and Accuracy. AB - BACKGROUND: Spinal catheter insertion in lumboperitoneal (LP) shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with technical difficulties especially in patients with obesity and elderly patients with vertebral deformities. OBJECTIVE: To elucidate the accuracy and safety of image-guided spinal catheter placement using a paramedian approach (PMA). METHODS: We retrospectively analyzed 39 consecutive iNPH patients treated by LP shunting with spinal catheter insertion via the PMA. The success rate of catheter placement and the number of changes in puncture location were evaluated. Accuracy of catheter insertion was assessed by measuring both vertical and horizontal deviations in the point of catheter dural penetration from the center of the interlaminar space. RESULTS: The success rate of catheter placement was 100% (39/39). The difficulty rate for catheter insertion, measured by the number of changes in puncture location, was 2.6% (1/39). No bloody punctures or surgical infections were observed. Accuracy of catheter insertion, measured as the degree of deviation, was 0.5 +/- 1.9 mm horizontally and 0.0 +/- 2.4 mm vertically. The rates of minor complications, including caudal catheter insertion, transient low pressure headache, and root pain, were 5.1% (2/39), 10.4% (4/39), and 0% (0/43), respectively. Subdural hematoma requiring surgical intervention occurred in 1 case (2.6%). During the mean follow-up period of 36 mo, spinal catheter rupture at the level of the spinous processes was not observed. CONCLUSION: Fluoroscopic guided spinal catheter placement via the PMA was safe, accurate, and reliable, even for use in geriatric and obese patients. PMID- 30011017 TI - Parentally inherited long non-coding RNA Cyrano is involved in zebrafish neurodevelopment. AB - Transfer of genetic material from parents to progeny via fusion of gametes is a way to ensure flow of information from one generation to the next. Apart from the genetic material, gametes provide a rich source of other factors such as RNA and proteins which can control traits of the embryo. Non-coding RNAs are not only carriers of regulatory information but can also encode memory of events of parental life. Here, we explore the possibility of parental inheritance of non coding RNAs, especially long non-coding RNAs. Meta-analysis of RNA-seq data revealed several non-coding RNAs present in zebrafish oocyte, sperm and 2cell stage. The embryo is transcriptionally silent at this stage, we rationalize that all the RNAs detectable at 2cell-stage are deposited either by sperm or oocyte or both and thus inherited. In the inherited pool, we noticed a conserved lncRNA, Cyrano previously known for zebrafish brain development. Knockdown of inherited Cyrano by miR-7 without changing zygotic Cyrano altered brain morphology at 24 hpf and 48 hpf. This defect could be partially rescued by injecting full length Cyrano lncRNA or a mutant resilient to knock-down by miR-7. In future, there is ample scope to check the possibility of inherited lncRNAs as carriers of memory of parental life events and building blocks that set up an initial platform for development. PMID- 30011018 TI - Venous Thromboembolism in Patients With Spontaneous Intracerebral Hemorrhage: A Multicenter Study. AB - BACKGROUND: Patients with spontaneous intracerebral hemorrhage (ICH) are predisposed to venous thromboembolic (VTE) complications, such as deep vein thrombosis and pulmonary embolism. OBJECTIVE: To evaluate, in a multicenter, retrospective cohort study, the rate of VTE complications in ICH patients during acute hospitalization, identify potential risk factors, and assess their association with functional outcome. METHODS: We retrospectively analyzed prospectively collected data from 19 centers and 41 sites that participated in the Ethnic/Racial Variations of Intracerebral Hemorrhage study, from August 2010 to February 2016. We compared ICH patients with VTE complications to those without VTE complications. Statistical analyses were performed to determine predictors of VTE complications and poor outcome (modified Rankin Scale >= 4) at discharge and 3-mo follow-up. RESULTS: Of the 2902 ICH patients who were eligible for analysis, 87 (3.0%) had VTE complications: 57 (2.0%) had only deep vein thrombosis, 19 (0.7%) had only pulmonary embolism, and 11 (0.4%) had both. In the multivariable logistic regression analysis, a prior history of VTE (odds ratio [OR] = 6.8; P < .0001), intubation (OR = 4.0; P < .0001), and presence of IVH (OR = 1.8; P = .0157) were independent predictors of VTE complications. After controlling for ICH volume and location, IVH, age, and presenting Glasgow Coma Scale, the occurrence of VTE complications was an independent predictor of poor outcome at discharge (OR = 2.9; P = .002) and 3-mo follow-up (OR = 2.1; P = .02). CONCLUSION: Although VTE complications are uncommon after ICH, they are associated with significantly worse outcomes. Further studies will be needed to determine the optimal treatment regimen for the prevention and treatment of VTE complications in ICH patients. PMID- 30011019 TI - Nitrogen Fertilization Increases the Nutritional Quality of Aphis gossypii (Hemiptera: Aphididae) as Prey for Hippodamia variegata (Coleoptera: Coccinellidae) and Alters Predator Foraging Behavior. AB - Nitrogen (N) fertilization is a common agricultural practice, which, by increasing the quality of plants, also enhances their nutritional suitability for insect herbivores, creating the possibility of a cascade of N across trophic levels, from plant to herbivore to predator. We manipulated the quality of cucumber plants by fertilizing them with three different N rates (110, 160, and 210 ppm), which represented low, medium, and high N levels, respectively. Colonies of Aphis gossypii Glover (Hemiptera: Aphididae) were then reared on these plants and used as prey for adult Hippodamia variegata (Goeze) (Coleoptera: Coccinellidae) in experiments that characterized the predator's foraging behavior and functional response to different aphid densities. The nutritional content of plants and aphids was also measured. As N fertilization increased, so did the nutrient content (total energy) of aphids and this resulted in declining rates of aphid consumption by beetles at higher aphid densities. Females in the 110 N treatment, and males in all treatments, responded to aphids with a type II functional response (decelerating consumption at higher densities), but females in the 160 and 210 ppm N treatments exhibited a type III response (consuming a declining proportion of available aphids at high densities). Beetles fed aphids from the 110 N treatment consumed more prey in both assays than did those fed aphids from the 210 N treatment. Beetle searching time, handling time, and duration of digestive pauses all increased at high levels of N fertilization, especially for females. The results indicate that heavy N fertilization can increase prey nutritional quality to the point where it alters predator foraging and feeding behavior, resulting in slower rates of prey consumption and longer prey handling times. PMID- 30011020 TI - Randomized factorial experiment of components of the SmokeFree Baby smartphone application to aid smoking cessation in pregnancy. AB - Smartphone applications (apps) might be able to reach pregnant smokers who do not engage with face-to-face support. However, we do not know how far pregnant smokers will engage with smoking cessation apps or what components are likely to be effective. This study aimed to assess pregnant smokers' engagement with the SmokeFree Baby app (v1) and to assess the short-term efficacy of selected components ("modules") for smoking abstinence. Positive outcomes would provide a basis for further development and evaluation. SmokeFree Baby was developed drawing on behavior change theories and relevant evidence. Pregnant smokers (18+) who were interested in quitting and set a quit date were recruited. Following multiphase optimization development principles, participants (N = 565) were randomly allocated to one of 32 (2 * 2 * 2 * 2 * 2) experimental groups in a full factorial design to evaluate five modules (each in minimal and full version: identity, health information, stress management, face-to-face support, and behavioral substitution). Measures of engagement included duration and frequency of engagement with the app. Smoking abstinence was measured by self-reported number of smoke-free days up to 4 weeks from the quit date. Participants engaged with the app for a mean of 4.5 days (SD = 8.5) and logged in a mean of 2.9 times (SD = 3.1). Main effects of the modules on the number of smoke-free days were not statistically significant (identity: p = .782, health information: p = .905, stress management: p = .103, face-to-face support: p = .397, behavioral substitution: p = .945). Despite systematic development and usability testing, engagement with SmokeFree Baby (v1) was low and the app did not appear to increase smoking abstinence during pregnancy. PMID- 30011021 TI - Inter- and Intrasexual Interactions in Anoplophora glabripennis (Coleoptera: Cerambycidae) and the Impact of Different Sex Ratios. AB - The behaviors of Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambycidae) during inter- and intrasexual interactions between both solitary and paired individuals at different sex ratios were observed on Acer platanoides L. (Sapindales: Sapindaceae) branches in the laboratory. Intrasexual contact was generally ignored by females, but between males resulted in battles from which one male ultimately retreated. When male size differed, larger males won battles, whereas equally sized males split the wins and battled longer. When males initiated intersexual contact, they quickly found and mounted the female. The female apparently determined if and how long the male could copulate with her by controlling access to her genital opening and males would eventually dismount if the female remained unreceptive. After successful copulation, males ignored female intruders and fought off male challengers, generally without dismounting. Some males dismounted females without attempting to copulate. Individual age and size were not predictive of either female or male choice in a mate. Mating duration was affected by both female receptivity and sex ratios present. Male interruptions of the pair shortened time in copula. Male-skewed sex ratios (1F:2M) significantly shortened the time a male would stay with an unreceptive female. Female-skewed sex ratios (2F:1M) did not impact mating duration. Probability of dispersal both from and within the branch was greater for smaller individuals of both sexes and for males when sex ratios were male-skewed. This information demonstrates how reproductive activity might be impacted as population densities decline during efforts at eradication of this species in North America. PMID- 30011023 TI - Comparison of computerized methods for rapid eye movement sleep without atonia detection. AB - Rapid eye movement (REM) sleep without atonia detection is a prerequisite for diagnosis of REM sleep behavior disorder (RBD). As the visual gold standard method is time-consuming and subjective, several automated methods have been proposed. This study aims to compare their performances: The REM atonia index (RAI), the supra-threshold-REM-activity metric, the Frandsen index, the short/long muscle activity indices, and the Kempfner index algorithms were applied to 27 healthy control participants (C), 25 patients with Parkinson's disease (PD) without RBD (PD-RBD), 29 patients with PD and RBD (PD + RBD), 29 idiopathic patients with RBD, and 36 patients with periodic limb movement disorder (PLMD). The indices were calculated in various configurations: (1) considering all muscle activities; (2) excluding the ones related to arousals; (3) excluding the ones during apnea events; (4) excluding the ones before and after apnea events; (5) combining configurations 2 and 3; and (6) combining configurations 2 and 4. For each of these configurations, the discrimination capability of the indices was tested for the following comparisons: (1) (C, PD RBD, PLMD) vs (PD + RBD, RBD); (2) C vs RBD; (3) PLMD vs RBD; (4) C vs PD-RBD; (5) C vs PLMD; (6) PD-RBD vs PD + RBD; and (7) C vs PLMD vs RBD. Results showed varying methods' performances across the different configurations and comparisons, making it impossible to identify the optimal method and suggesting the need of further improvements. Nevertheless, RAI seems the most sensible one for RBD detection. Moreover, apnea and arousal-related movements seem not to influence the algorithms' performances in patients' classification. PMID- 30011024 TI - Childhood obesity prevention: priority areas for future research and barriers and facilitators to knowledge translation, coproduced using the nominal group technique. AB - Childhood obesity is a significant public health challenge, yet research priorities for childhood obesity prevention are not established. Coproduction of priorities leads to research which may be more translatable to the domains of policy and practice. The aim of the present study was to identify knowledge gaps and research priorities in addition to facilitators and barriers to knowledge translation in childhood obesity prevention. The nominal group technique involving consensus building with researchers, policymakers, and practitioners was employed during workshops at a national obesity conference held over 2 days in May 2017. Seventy-seven people participated in the first round of research prioritization on Day 1, while 14 stakeholders participated on Day 2. The top five research priorities identified were as follows: (i) Evaluate (including economic evaluation) current programs to inform practice and policy; (ii) How to change culture toward addressing the determinants of health; (iii) Implementation science: process; (iv) How to integrate obesity prevention into existing service structures; (v) How to enhance opportunities for habitual physical activity, including free play and active travel. Key themes emerging from this research prioritization exercise were the importance of funding and resources, coproduction of research, and a focus on both implementation research and social determinants within the field of childhood obesity prevention. The coproduced research priorities may help to shape the research agendas of funders and researchers, and aid in the conduct of policy-relevant research and the translation of research into practice in childhood obesity prevention. PMID- 30011022 TI - MouR controls the expression of the Listeria monocytogenes Agr system and mediates virulence. AB - The foodborne pathogen Listeria monocytogenes (Lm) causes invasive infection in susceptible animals and humans. To survive and proliferate within hosts, this facultative intracellular pathogen tightly coordinates the expression of a complex regulatory network that controls the expression of virulence factors. Here, we identified and characterized MouR, a novel virulence regulator of Lm. Through RNA-seq transcriptomic analysis, we determined the MouR regulon and demonstrated how MouR positively controls the expression of the Agr quorum sensing system (agrBDCA) of Lm. The MouR three-dimensional structure revealed a dimeric DNA-binding transcription factor belonging to the VanR class of the GntR superfamily of regulatory proteins. We also showed that by directly binding to the agr promoter region, MouR ultimately modulates chitinase activity and biofilm formation. Importantly, we demonstrated by in vitro cell invasion assays and in vivo mice infections the role of MouR in Lm virulence. PMID- 30011026 TI - Relationship Between Aneurysm Wall Enhancement in Vessel Wall Magnetic Resonance Imaging and Rupture Risk of Unruptured Intracranial Aneurysms. AB - BACKGROUND: The rupture risk assessment of unruptured intracranial aneurysms (IAs) is still challenging. Aneurysm wall enhancement (AWE) on vessel wall magnetic resonance imaging (VW-MRI) is suggested as a potential marker for wall inflammation, but its relationship with rupture risk of unruptured IAs has not been well described. OBJECTIVE: To investigate the correlation between AWE and conventional rupture risk factor of unruptured IAs. METHODS: Clinical data and VW MRI images were retrospectively reviewed in patients with unruptured IAs from January 2015 to December 2016 in our center. One hundred ten patients harboring 140 unruptured IAs were included. The presence of AWE was determined by comparing the postcontrast VW-MRI images with the precontrast ones. The rupture risk based on the PHASES score was calculated for each case. Univariate and multivariate analysis were performed to investigate the association of AWE with rupture risk and other conventional risk factors. RESULTS: AWE was present in 82 (58.6%) lesions. Unruptured IAs with AWE had significantly larger size (P < .001), more irregular shape (P = .003), and different distribution of locations (P = .023) comparing with aneurysms without AWE. The rupture risk score of AWE group was significantly higher than non-AWE group (P < .001). Aneurysm size (odds ratio = 1.536; 95% confidential interval 1.312-1.798; P < .001) and location (odds ratio = 1.592; 95% confidential interval 1.237-2.049; P < .001) were independently related with AWE in multivariate analysis. CONCLUSION: The presence of AWE on VW MRI was highly associated with conventional rupture-related characteristics, including aneurysmal size and location, and was detected more frequently in unruptured IAs with high rupture risk based on the PHASES score. PMID- 30011025 TI - Immunological association of inducible bronchus-associated lymphoid tissue organogenesis in Ag85B-rHPIV2 vaccine-induced anti-tuberculosis mucosal immune responses in mice. AB - We previously reported that Ag85B-expressing human parainfluenza type 2 virus (Ag85B-rHPIV2) was effective as a nasal vaccine against tuberculosis in mice; however, the mechanism by which it induces an immune response remains to be investigated. In the present study, we found that organogenesis of inducible bronchus-associated lymphoid tissue (iBALT) played a role in the induction of antigen-specific T cells and IgA antibody responses in the lung of mice intra nasally administered Ag85B-rHPIV2. We found that expression of Ag85B was dispensable for the development of iBALT, suggesting that HPIV2 acted as an iBALT inducing vector. When iBALT organogenesis was disrupted in Ag85B-rHPIV2-immunized mice, either by neutralization of the lymphotoxin pathway or depletion of CD11b+ cells, Ag85B-specific immune responses (i.e. IFN gamma-producing T cells and IgA antibody) were diminished in the lung. Furthermore, we found that immunization with Ag85B-rHPIV2 induced neutrophil and eosinophil infiltration temporally after the immunization in the lung. Thus, our results show that iBALT organogenesis contributes to the induction of antigen-specific immune responses by Ag85B-rHPIV2 and that Ag85B-rHPIV2 provokes its immune responses without inducing long-lasting inflammation. PMID- 30011029 TI - Corrigendum to "Lipid profile and quality indices of ostrich meat and giblets". PMID- 30011031 TI - In Reply: Nerve Surgeons' Assessment of the Role of Eduard Pernkopf's Atlas of Topographic and Applied Human Anatomy in Surgical Practice. PMID- 30011032 TI - Competing Risks in Older Patients With Cancer: A Systematic Review of Geriatric Oncology Trials. AB - Background: It is increasingly recognized that older adults with cancer represent a diverse cohort of patients and that other comorbidities may have an equal impact on survival and quality of life as any diagnosis of malignancy. Competing risk has consequently emerged as an important concept in the design and reporting of geriatric oncology trials. Methods: We performed a systematic review of phase II and III oncology trials for systemic therapy in older patients with solid organ malignancy from the year 2000 until April 30, 2017. Forty-one trials including 7864 patients were identified for evaluation. Results: Only 15 trials (36.6%) employed disease-related end points to account for death from other causes, and only one study used statistical analysis that addressed competing risk. Seventeen studies (41.5%) of trials included some assessment of comorbidity or frailty. Twenty-one trials (51.2%) included any assessment of quality of life. Conclusions: This review demonstrates clear areas for improvement for future studies and highlights the need for careful consideration of trial design, data collection, and appropriate statistical methodology for reporting of competing risks in geriatric oncology trials. PMID- 30011033 TI - Pathology of Nerve Biopsy and Diagnostic Yield of PCR-Based Clonality Testing in Neurolymphomatosis. AB - Infiltration of the peripheral nervous system (PNS) by lymphoma, called neurolymphomatosis, is a rare condition among the spectrum of lymphoma-associated neuropathies; its diagnosis is challenging. Cerebrospinal fluid (CSF) analysis is of great value, but nerve biopsy (NB) may be necessary to prove invasion by malignant cells. Clonality polymerase chain reaction (PCR)-based analysis is a validated method in the diagnosis of hematological malignancies, but there are very little data on its diagnostic yield on NB samples. We explored the contribution of NB with clonality analysis to the diagnosis of neurolymphomatosis in 15 patients with negative CSF analysis. Moreover, we assessed the performance of clonality testing in a case-control manner, using patients with inflammatory infiltrates on NB as controls. Neurolymphomatosis was the first manifestation of lymphoma in 60% and could be diagnosed on routine histology alone in 40%. Clonality testing showed monoclonal rearrangement in 86.7% and was unsuccessful in 8.1%. Performance of clonality testing was as follows: 92.9% positive predictive value, 90% negative predictive value, 86.7% sensitivity, 94.7% specificity. This study confirms the diagnostic challenge of neurolymphomatosis, the usefulness of NB in patients with negative CSF analysis, and highlights the high yield of PCR-based clonality testing to assess the malignant nature of PNS lymphoid infiltrates. PMID- 30011035 TI - The value of neuraminidase inhibition antibody titers in influenza seroepidemiology. PMID- 30011034 TI - Omeprazole Enhances Mechanical Stress-Induced Root Growth Reduction in Arabidopsis thaliana. AB - Mechanical sensing is one of the most fundamental processes for sessile plants to survive and grow. The response is known to involve calcium elevation in the cell. Arabidopsis seedlings grown horizontally on agar plates covered with a dialysis membrane show a 2-fold reduction in root growth compared with those grown vertically, a response to mechanical stress generated due to gravitropism of the root. To understand the molecular mechanism of how plant roots sense and respond to mechanical stimuli, we screened chemical libraries for compounds that affect the horizontal root growth in this experimental system and found that, while having no effect on root gravitropism, omeprazole known as a proton pump inhibitor significantly enhanced the mechanical stress-induced root growth reduction especially in lower pH media. In contrast, omeprazole reversed neither the alleviation of the mechanical stress-induced growth reduction caused by calcium depletion nor the insensitivity to the mechanical stress in the ethylene signaling mutant ein2. Together with the finding that omeprazole increased expression of touch-induced genes and ETHYLENE RESPONSE FACTOR1, our results suggest that the target of omeprazole mediates ethylene signaling in the root growth response to mechanical stress. PMID- 30011036 TI - Impact of smoking cessation on periodontitis: A systematic review and meta analysis of prospective longitudinal observational and interventional studies. AB - Aims: This systematic review aimed to estimate the effect of tobacco smoking cessation on the risk for periodontitis compared to the risk among never-smokers and to evaluate the effect of tobacco smoking cessation on the clinical outcomes of non-surgical periodontal treatment. Methods: Electronic searches were performed in PubMed, Scopus and Embase. Search strategy included MeSH and free terms: periodontitis, periodontal diseases, smoking, tobacco use, tobacco, tobacco products, cigarette, pipe and cigar. Only original prospective longitudinal observational and interventional studies that investigated the association between smoking and periodontitis onset or progression were included. Meta-analyses were conducted to summarize the evidence. Results: 2,743 articles were identified in electronic searches; out of which only six were included in the meta-analysis. Pooled estimates showed that the risk of periodontitis incidence or progression among those who quitted smoking was not significantly different from the risk for never-smokers (RR 0.97; 95% CI 0.87-1.08). Smokers had approximately 80% higher risk of periodontitis than quitters (RR 1.79; 95%CI 1.36-2.35) and never-smokers (RR 1.82; 95%CI 1.43-2.31). Periodontal therapy resulted in up to 0.2 mm (95%CI -0.32;-0.08) higher gain in attachment level and extra 0.32 mm (95%CI 0.07;0.52) reduction in pocket depth among quitters over non quitters after short follow-up (12-24 months). Conclusions: Few studies on the topic were identified. Smoking cessation reduced the risk for periodontitis onset and progression, and improved the outcomes of nonsurgical periodontal therapy. Implications: This review provides the first quantitative evidence of the impact of smoking cessation on the risk for periodontitis onset and progression. The findings have demonstrated that the risk for periodontitis becomes comparable to that of never-smokers and that nonsurgical periodontal treatment outcomes improve after smoking cessation. Dental professionals ought to consider smoking cessation interventions as a relevant component of the periodontal therapy. PMID- 30011030 TI - Integrating Rio1 activities discloses its nutrient-activated network in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae kinase/adenosine triphosphatase Rio1 regulates rDNA transcription and segregation, pre-rRNA processing and small ribosomal subunit maturation. Other roles are unknown. When overexpressed, human ortholog RIOK1 drives tumor growth and metastasis. Likewise, RIOK1 promotes 40S ribosomal subunit biogenesis and has not been characterized globally. We show that Rio1 manages directly and via a series of regulators, an essential signaling network at the protein, chromatin and RNA levels. Rio1 orchestrates growth and division depending on resource availability, in parallel to the nutrient-activated Tor1 kinase. To define the Rio1 network, we identified its physical interactors, profiled its target genes/transcripts, mapped its chromatin-binding sites and integrated our data with yeast's protein-protein and protein-DNA interaction catalogs using network computation. We experimentally confirmed network components and localized Rio1 also to mitochondria and vacuoles. Via its network, Rio1 commands protein synthesis (ribosomal gene expression, assembly and activity) and turnover (26S proteasome expression), and impinges on metabolic, energy-production and cell-cycle programs. We find that Rio1 activity is conserved to humans and propose that pathological RIOK1 may fuel promiscuous transcription, ribosome production, chromosomal instability, unrestrained metabolism and proliferation; established contributors to cancer. Our study will advance the understanding of numerous processes, here revealed to depend on Rio1 activity. PMID- 30011037 TI - Cumulative Childhood Adversity as a Risk Factor for Common Chronic Pain Conditions in Young Adults. AB - Objective: Multiple and specific types of childhood adverse events are risk factors for chronic pain conditions. Although both can covary, no study has evaluated one aspect while controlling for the other. Therefore, the current study examined whether more adverse events would be a risk factor for common chronic pain conditions and pain medication use in young adults after controlling for different adversity types such as physical, emotional, and sexual traumatic events or vice versa. Methods: This cross-sectional study recruited 3,073 undergraduates (72% female, mean age = 18.8 years, SD = 1.4 years) who completed the survey for current health status and early life traumatic events. Results: More adverse events were associated with a 1.2-1.3-fold increase in the odds of any chronic pain, chronic back pain, headache, and dysmenorrhea with adjusting for adversity types, but they were not associated with the risk of comorbid pain conditions and use of pain medications. In contrast, specific adversity types were unrelated to chronic pain conditions when controlling for the number of adverse events. Conclusions: Cumulative childhood adverse events may be a more relevant risk factor for chronic pain conditions than the experience of a specific type of adverse event. Clinicians and researchers need to evaluate cumulative childhood adversity when assessing its link to chronic pain. PMID- 30011038 TI - Systematic exploration of cell morphological phenotypes associated with a transcriptomic query. AB - Cell morphological phenotypes, including shape, size, intensity, and texture of cellular compartments have been shown to change in response to perturbation with small molecule compounds. Image-based cell profiling or cell morphological profiling has been used to associate changes of cell morphological features with alterations in cellular function and to infer molecular mechanisms of action. Recently, the Library of Integrated Network-based Cellular Signatures (LINCS) Project has measured gene expression and performed image-based cell profiling on cell lines treated with 9515 unique compounds. These data provide an opportunity to study the interdependence between transcription and cell morphology. Previous methods to investigate cell phenotypes have focused on targeting candidate genes as components of known pathways, RNAi morphological profiling, and cataloging morphological defects; however, these methods do not provide an explicit model to link transcriptomic changes with corresponding alterations in morphology. To address this, we propose a cell morphology enrichment analysis to assess the association between transcriptomic alterations and changes in cell morphology. Additionally, for a new transcriptomic query, our approach can be used to predict associated changes in cellular morphology. We demonstrate the utility of our method by applying it to cell morphological changes in a human bone osteosarcoma cell line. PMID- 30011041 TI - Comparison of Trunk Muscle Function Between Women With and Without Diastasis Recti Abdominis at 1 Year Postpartum. AB - Background: A separation of the abdominal muscles at the linea alba, known as diastasis recti abdominis (DRA), can occur after childbirth. However, the impact of DRA on abdominal muscle function is not clear. Objective: The objective was to determine if differences exist in trunk muscle function and self-reported pain and low back dysfunction between women with and without DRA at 12 to 14 months postpartum and if differences that emerge from the data are associated with the magnitude of the interrectus distance (IRD). Design: This study was a prospective, observational, case-control study. Methods: Women with (IRD >= 2.2 cm; n = 18) and without DRA (IRD < 2.2 cm; n = 22) participated. Maximal trunk flexion, extension, and rotation torque-generating capacity (Newton-meters), the Sit-Up test (0 to 3 points), and the Sitting-Rising Test (0 to 10 points), and trunk flexion, extension, and lateral flexion endurance (seconds) were measured. Pain and disability were assessed using numerical pain rating scales (0 to 100) and the Roland Morris Low Back Pain Questionnaire (0 to 24 points). Women were compared using independent t tests and Mann-Whitney U Tests. Pearson product moment and Spearman rank correlation coefficients were used to determine associations; a = .05 was used for all tests. Results: Women with DRA demonstrated significantly lower trunk muscle rotation torque and scored lower on the sit-up test than those without DRA. IRD was negatively correlated with both trunk rotation torque (rho = -0.367) and sit-up test score (rho = -0.514). Limitations: The results of this study should not be generalized to women who present with moderate-to-severe IRDs or to multiparous women. Conclusion: The presence of DRA in primiparous women at 1 year postpartum is associated with trunk rotation strength and ability to perform a sit-up. PMID- 30011040 TI - Corrigendum: WSL5, a pentatricopeptide repeat protein, is essential for chloroplast biogenesis in rice under cold stress. PMID- 30011039 TI - Incorporating uracil and 5-halouracils into short peptide nucleic acids for enhanced recognition of A-U pairs in dsRNAs. AB - Double-stranded RNA (dsRNA) structures form triplexes and RNA-protein complexes through binding to single-stranded RNA (ssRNA) regions and proteins, respectively, for diverse biological functions. Hence, targeting dsRNAs through major-groove triplex formation is a promising strategy for the development of chemical probes and potential therapeutics. Short (e.g., 6-10 mer) chemically modified Peptide Nucleic Acids (PNAs) have been developed that bind to dsRNAs sequence specifically at physiological conditions. For example, a PNA incorporating a modified base thio-pseudoisocytosine (L) has an enhanced recognition of a G-C pair in an RNA duplex through major-groove L.G-C base triple formation at physiological pH, with reduced pH dependence as observed for C+.G-C base triple formation. Currently, an unmodified T base is often incorporated into PNAs to recognize a Watson-Crick A-U pair through major-groove T.A-U base triple formation. A substitution of the 5-methyl group in T by hydrogen and halogen atoms (F, Cl, Br, and I) causes a decrease of the pKa of N3 nitrogen atom, which may result in improved hydrogen bonding in addition to enhanced base stacking interactions. Here, we synthesized a series of PNAs incorporating uracil and halouracils, followed by binding studies by non-denaturing polyacrylamide gel electrophoresis, circular dichroism, and thermal melting. Our results suggest that replacing T with uracil and halouracils may enhance the recognition of an A U pair by PNA.RNA2 triplex formation in a sequence-dependent manner, underscoring the importance of local stacking interactions. Incorporating bromouracils and chlorouracils into a PNA results in a significantly reduced pH dependence of triplex formation even for PNAs containing C bases, likely due to an upshift of the apparent pKa of N3 atoms of C bases. Thus, halogenation and other chemical modifications may be utilized to enhance hydrogen bonding of the adjacent base triples and thus triplex formation. Furthermore, our experimental and computational modelling data suggest that PNA.RNA2 triplexes may be stabilized by incorporating a BrUL step but not an LBrU step, in dsRNA-binding PNAs. PMID- 30011042 TI - Benzo[a]Pyrene-7, 8-Diol-9, 10-Epoxide Suppresses the Migration and Invasion of Human Extravillous Trophoblast Swan 71 Cells Due to the Inhibited Filopodia Formation and Down-Regulated PI3K/AKT/CDC42/PAK1 Pathway Mediated by the Increased miR-194-3p. AB - Proper migration and invasion of trophoblast cells into endometrium is vital for successful embryo implantation during early pregnancy. Benzo[a]pyrene-7, 8-diol 9, 10-epoxide (BPDE) is an ultimate carcinogenic product of benzo[a]pyrene (BaP), which causes multiple trophoblast-related diseases. However, the mechanism of BPDE-inhibited migration/invasion of trophoblast cells is still unclear. In this work, we found that BPDE significantly inhibited the filopodia formation and migration/invasion of human trophoblast Swan 71 cells. BPDE up-regulated the level of miR-194-3p, which further inhibited the phosphoinositide 3-kinase (PI3K)/AKT/ cell division cycle 42/ p21 (RAC1) activated kinase 1 signaling pathway and depressed the filophdia formation of Swan71 cells. Addition of 740 Y P, the activator of phosphoinositide 3-kinase, could stimulate cell migration/invasion, confirming the involvement of this pathway. Knock-down of miR 194-3p up-regulated this pathway and promoted filopodia formation and migration/invasion. Conversely, overexpression of miR-194-3p down-regulated this pathway and inhibited cell migration/invasion. Therefore, miR-194-3p takes important roles in the BPDE-inhibited filopodia formation and cell migration/invasion, providing valuable information in the BPDE-induced dysfunctions of human extravillous trophoblast cells. PMID- 30011043 TI - Commentary: Prescription Drug Monitoring Programs and the Neurosurgeon: Impact on Workflow and Overall Perceptions. PMID- 30011044 TI - Somatotopy and Organization of Spinothalamic Tracts in the Human Cervical Spinal Cord. AB - BACKGROUND: Understanding spinothalamic tract anatomy may improve lesioning and outcomes in patients undergoing percutaneous cordotomy. OBJECTIVE: To investigate somatotopy and anatomical organization of spinothalamic tracts in the human cervical spinal cord. METHODS: Patients with intractable cancer pain undergoing cordotomy underwent preoperative and postoperative quantitative sensory testing for sharp pain and heat pain on day 1 and 7 after cordotomy. Intraoperative sensory stimulation was performed with computed tomography (CT) imaging to confirm the location of the radiofrequency electrode during cordotomy. Postoperative magnetic resonance (MR) imaging was performed to define the location of the lesion. RESULTS: Twelve patients were studied, and intraoperative sensory stimulation combined with CT imaging revealed a somatotopy where fibers from the legs were posterolateral to fibers from the hand. Sharpness detection thresholds were significantly elevated in the area of maximum pain on postoperative day 1 (P = .01). Heat pain thresholds for all areas were not elevated significantly on postoperative day 1, or postoperative day 7. MR imaging confirmed that the cordotomy lesion was in the anterolateral quadrant, and in this location the lesion had a sustained effect on sharp pain but a transient impact on heat pain. CONCLUSION: In the high cervical spinal cord, spinothalamic fibers mediating sharp pain for the arms are located ventromedial to fibers for the legs, and these fibers are spatially distinct from fibers that mediate heat pain. PMID- 30011045 TI - Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma. AB - BACKGROUND: Checkpoint inhibition has demonstrated clinical efficacy in a variety of solid tumors. Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results. OBJECTIVE: To validate the prevalence and prognostic role of PD-L1 expression in a large cohort of diffuse gliomas according to the 2016 revised WHO classification. METHODS: Using tissue microarrays, we compared 5 PD-L1 monoclonal antibodies (n = 56) and validated expression (n = 183) using quantitative immunohistochemistry (IHC) and RNA in situ hybridization (RISH). Expression data from The Cancer Genome Atlas (TCGA) and published studies were compared with clinical outcome. Multiplexed immunophenotyping was used to identify PD-L1+ cell populations in post-treatment glioblastoma. RESULTS: Using a 5% cut-off, PD-L1 expression was significantly associated with a poor prognosis in both histologically defined (n = 125, log rank P < .001) and recurrent isocitrate dehydrogenase (IDH)-wildtype glioblastoma (n = 60, log-rank P = .015). PD-L1 remained a significant negative prognosticator in Cox regression analysis (hazard ratio: 1.96, P = .021). Analysis of TCGA data confirmed decreased overall survival in recurrent non-glioma CpG island methylator phenotype (G-CIMP) glioblastoma (n = 12, log-rank P = .023), but not in glioblastoma as a group (n = 444, log-rank P = .135). PD-L1 RISH showed a significant correlation with IHC (P < .0001). PD-L1 was observed in the proliferating perivascular stem cell and immune niche of post-treatment glioblastoma. CONCLUSION: A 5% PD-L1 expression cut-off identified a subset of glioblastoma that is associated with a worse clinical outcome. This association remained significant within the newly defined IDH-wildtype classification. These findings could have implications for patient stratification in future clinical trials of PD-1/PD-L1 blockade. PMID- 30011046 TI - Pathological and molecular findings of avian reoviruses from clinical cases of tenosynovitis in poultry flocks from Brazil. AB - Avian reoviruses (ARVs) can infect a variety of species worldwide. Birds can present stunting syndrome, respiratory and/or enteric diseases, immunosuppression, malabsorption, viral arthritis/tenosynovitis, and even secondary infections by other microorganisms. Flaws in conventional vaccines and the increase in the diagnostic rate of disease in the last 5 yr suggest the emergence of pathogenic ARVs in the poultry flocks worldwide. This study aimed to characterize birds lesions and to detect/genotype ARVs from a severe outbreak of tenosynovitis in broiler poultry flocks from Brazil. Tissue samples of lesions on pelvic limbs of broiler chicken were collected in poultry flocks with a high condemnation rate of carcasses due to lesions and submitted to histological and molecular analysis. Major gross pathological lesions included marked swelling, edema, and hemorrhages. Serous exudate was present between the tendons and hock joint. Histological examination demonstrated necrosis and inflammation of muscle fibers, mixed inflammatory infiltrate was observed in subcutaneous tissue and tendon sheaths. ARVs RNA was detected in 5 samples tested by polymerase chain reaction. These samples were also genotyped and demonstrated the occurrence of strains of the ARVs lineages II and V in the flocks. These results suggest that theses field ARVs, genetically distant from previously characterized strains, are associated to tenosynovitis and present in commercial Brazilian poultry flocks. PMID- 30011048 TI - In Reply: Commentary: Utilization of Quantitative Susceptibility Mapping for Direct Targeting of the Subthalamic Nucleus During Deep Brain Stimulation Surgery. PMID- 30011047 TI - Choosing sample sizes for various blood parameters of broiler chickens with normal and non-normal observations. AB - Experimental power is a measure of the ability of an experiment to detect differences between treatment means. Researchers design experiments and then calculate the probability that differences are simply due to chance, the null hypothesis. The objective of the analyses reported here was to determine the appropriate number of samples to demonstrate significant differences of various magnitudes from broiler chicken blood constituents. Over 800 samples were taken for a study of the effects of sample storage time, serum vs. plasma, light intensity, and fed vs. fasted birds on blood cholesterol, triglycerides, uric acid, glucose, total protein (TP), albumin, globulin, alanine aminotransferase (ALT), aspartate aminotransferase, gammaGT, creatinine, alkaline phosphatase, Ca and P. Various transformations increased the QQ plot R2 values from 0.000 to 0.149 or 0.00 to 17.62%. Most of the QQ plot R2 values were at or above 0.90. The 1/x2 transformation of blood P data showed the biggest increase in QQ plot R2 (0.846 to 0.995). The different standard deviations and coefficients of variation (CVs) found for each variable resulted in widely different numbers of replicates needed to detect differences in 2 treatment means. The extremes were glucose with a CV of 6.9% and ALT with a CV of 39.7%. For glucose, 15 replicates are needed to find a 10% difference in 97% of experiments; for ALT, 15 replicates would detect a 50% difference 91% of the time. The use of parameters such as cholesterol, glucose, TP, albumin, and globulin showed low CVs, indicating they may be considered as stable parameters. The lower CVs make it possible to find differences with a smaller number of replicates used in studies. As reported, the phosphorus values did not have a normal distribution of the data, so a transformation of these data could be an alternative to better discuss the results found. PMID- 30011049 TI - Lifetime coffee consumption, pineal gland volume, and sleep quality in late life. AB - Study Objectives: Previous studies have shown that coffee consumption may suppress the production of melatonin in pinealocytes through competitive inhibition of adenosine A2 receptors by caffeine. We investigated the impact of lifetime coffee consumption on pineal gland volume and the resulting effects on sleep quality. Methods: We enrolled 162 cognitively normal elderly individuals among the participants in the Korean Longitudinal Study on Cognitive Aging and Dementia. We evaluated the patterns and amounts of coffee consumption using a study-specific standardized interview and assessed sleep quality using the Pittsburgh Sleep Quality Index. We measured the volume of pineal parenchyma (VPP) by manually segmenting the pineal gland on high-resolution three-dimensional T1 weighted magnetic resonance images. We examined the impact of lifetime coffee consumption on the VPP and the resulting effects on sleep quality using analysis of covariance, multiple linear regression, and mediation analyses. Results: We found that smaller VPP was associated with higher cumulative lifetime coffee consumption. Participants who consumed more than 60 cup-years of coffee had VPPs that were smaller by about 20% than individuals who consumed less than 60 cup years of coffee. The VPP mediated the association between lifetime coffee consumption and sleep efficiency and quality. Conclusions: Our findings suggest that high lifetime coffee consumption may reduce VPP, and that this reduction in VPP may impair the quality of sleep in late life. PMID- 30011050 TI - Short-term Medical Complications Following Short Versus Long Cephalomedullary Nails. AB - The purpose of this retrospective cohort study was to evaluate whether there is an increased rate of short-term medical complications following short vs long cephalomedullary nails for the treatment of intertrochanteric hip fractures. A total of 899 patients treated surgically with cephalomedullary nails from January 1, 2005, to September 1, 2014, were included. Patients who received short nails (n=334) were older and had a higher incidence of coronary artery disease and diabetes mellitus compared with patients who received long nails (n=565). The incidences of 30-day medical complications, including myocardial infarction, stroke, deep venous thrombosis, pulmonary embolism, blood transfusion, non surgical site infection, surgical site infection, and mortality, were recorded. The orthopedic complications of periprosthetic fracture of the ipsilateral hip and implant failure through the latest outpatient follow-up were recorded. No significant difference was found between nails for any studied medical complication (63.5% short vs 66.0% long, P=.4393) or mortality (6.9% short vs 5.3% long, P=.3322). There was also no significant difference in the incidence of orthopedic complications (P=.70). Longer operating room time was associated with superficial surgical site infection. [Orthopedics. 2018; 41(5):e636-e642.]. PMID- 30011051 TI - Stand-alone Anterior Lumbar Interbody, Transforaminal Lumbar Interbody, and Anterior/Posterior Fusion: Analysis of Fusion Outcomes and Costs. AB - Fusion outcomes and costs of stand-alone anterior lumbar interbody fusion (ALIF), transforaminal lumbar interbody fusion (TLIF) in association with posterior fusion, and anterior/posterior (A/P) fusion were compared using clinical, radiographic, and billing data. Adult patients with symptomatic 1- or 2-level degenerative disk disease in isolation or in association with a grade 1 or 2 degenerative or lytic spondylolisthesis and canal and/or foraminal stenosis who underwent elective stand-alone ALIF, TLIF, or A/P fusion were compared. The analysis focused primarily on fusion rates and costs and secondarily on radiographic and clinical parameters. One hundred six patients at least 2 years beyond surgery (ALIF, 53; TLIF, 17; A/P fusion, 36) were reviewed. Demographics were similar except for age, with the ALIF group being younger (mean, 37.8 years) than the other groups (TLIF, 53.1 years; A/P fusion, 48.2 years). There were no differences between the groups in fusion rates or outcomes as assessed by the Numeric Rating Scale. Compared with the other 2 groups, the ALIF group had a significantly shorter operative time, less blood loss, and a shorter stay (P<.0001). Evaluation of radiographic parameters revealed significant differences regarding disk angle (P<.001), disk height (P<.0001), and pelvic tilt (P=.001) favoring ALIF and A/P fusion over TLIF. Stand-alone ALIF should be considered in the management of patients with 1- or 2-level lumbar degenerative disk disease for which the pathology can be addressed adequately via this approach. [Orthopedics. 2018; 41(5):e655-e662.]. PMID- 30011052 TI - Reliability of and Correlation Between Measurements of Acetabular Morphology. AB - The authors sought to determine the intra- and interrater reliability of contemporary measures of acetabular morphology among a group of hip surgeons and to determine the correlations between measures of acetabular morphology. On 2 separate occasions, 3 hip surgeons independently performed blinded evaluations of anteroposterior pelvic radiographs of 40 patients. The lateral center-edge angle, medial center-edge angle, acetabular arc, extrusion index, acetabular index, Sharp's angle, posterior wall sign, crossover sign, femoro-epiphyseal acetabular roof index, acetabular wall indexes, and delta angle were assessed. A linear mixed model was used for variance estimation, and kappa and intra-class correlation coefficients were assessed for reliability. Pearson correlation coefficients were calculated for all possible pairs of radiographic measures. The acetabular index had the greatest interrater agreement (0.90; 95% confidence interval [CI], 0.84-0.93), whereas the lateral center-edge angle had the higher intrarater agreement (0.96; 95% CI, 0.92-0.98). The acetabular arc angle had the lowest interrater agreement (0.44; 95% CI, 0.29-0.57), and the Sharp's angle had the lowest intrarater agreement (0.66; 95% CI, 0.41-0.84). The posterior wall sign had an interrater agreement of 0.35 (95% CI, 0.11-0.54) and an intrarater agreement of 0.68 (95% CI, 0.49-0.86). The crossover sign had an interrater agreement of 0.66 (95% CI, 0.43-0.84) and an intrarater agreement of 0.85 (95% CI, 0.52-0.89). The acetabular index, lateral center-edge angle, and extrusion index presented with high coefficients of correlation. In addition, acetabular anteversion correlated with severity of dysplasia. Commonly used parameters such as the acetabular index, lateral center-edge angle, and extrusion index are reliable radiographic parameters to assess acetabular morphology. However, correlation between measures suggests that they may be redundant in quantifying acetabular morphology. [Orthopedics. 2018; 41(5):e629-e635.]. PMID- 30011053 TI - A Comparison of Clinical and Radiological Outcomes of Minimally Invasive and Conventional Plate Osteosynthesis for Midshaft Clavicle Fractures. AB - Thirty patients with displaced midshaft clavicle fractures were prospectively enrolled in this study. Fifteen were randomly assigned to the minimally invasive plate osteosynthesis group and 15 to the conventional plate osteosynthesis group. Constant score, visual analog scale satisfaction score, operative time, scar length, and complications, including hypoesthesia, were evaluated at least 1 year postoperatively to determine functional outcomes and time to bone union as a radiological outcome. Factors related to bone union, including the gap interval between fracture fragments and the number of fracture fragments, were also evaluated. The Constant score and the visual analog scale satisfaction score were higher in the minimally invasive plate osteosynthesis group than in the conventional plate osteosynthesis group; however, there was no significant difference between the groups in these scores or in the time to bone union (all P>.05). Hypoesthesia was the only complication, and its incidence was not different between the groups (P=.249). However, operative time (52.33+/-13.87 vs 110.33+/-25.39 minutes, P<.001) and scar length (64.95+/-3.19 vs 99.39+/-15.98 mm, P<.001) were significantly shorter in the minimally invasive plate osteosynthesis group than in the conventional plate osteosynthesis group, respectively. In the minimally invasive plate osteosynthesis group, time to bone union was significantly correlated with the gap interval (P=.004) and the number of fracture fragments (P=.002). Minimally invasive plate osteosynthesis showed some superiority over conventional plate fixation for midshaft clavicle fractures, having a shorter operative time and scar length. The time to bone union was influenced by the reduction status and the number of fracture fragments in the minimally invasive plate osteosynthesis group. [Orthopedics. 2018; 41(5):e649-e654.]. PMID- 30011054 TI - Normative Functional Outcomes as a New Outcome Assessment Tool Following Hip Procedures. AB - Patient-reported outcome measures play an important role in evaluating the functional outcome of surgical and nonsurgical treatments of the hip joint. One thousand healthy volunteers completed the modified Harris hip score, the University of California, Los Angeles score, the Hip Osteoarthritis Outcome Score, and the Western Ontario and McMaster Universities Osteoarthritis Index score. Between September 2010 and December 2015, a total of 127 periacetabular osteotomies were performed in 111 patients with symptomatic developmental dysplasia of the hip. Forty-two of these patients (10 male and 32 female) met inclusion criteria. Mean follow-up was 32 months (range, 13-59 months). Pre- and postoperative radiographic analysis of the lateral center-edge angle and the acetabular index was conducted in all cases with a proper pelvic anteroposterior radiograph. The patients completed the modified Harris hip score, the University of California, Los Angeles score, the Hip Osteoarthritis Outcome Score, and the Western Ontario and McMaster Universities Osteoarthritis Index score. The authors investigated the influence of various confounding variables to (1) obtain recommendations when outcome scores are being compared between 2 cohorts and (2) define a normative reference level of "hip-healthy" functionality. This normative level of functionality was used as a target level of functionality following a hip procedure such as periacetabular osteotomy. All functional outcome scores had significantly improved 1 year after periacetabular osteotomy; thus, patients were much better than preoperatively. However, only 55% achieved the 95% functionality of the normative population based on modified Harris hip score and University of California, Los Angeles score. The results were worse for the Hip Osteoarthritis Outcome Score subscales. This approach places the results of surgical procedures in a different but potentially more realistic perspective in terms of expectations and goals. [Orthopedics. 2018; 41(5):e663-e670.]. PMID- 30011055 TI - A Biomechanical Study of an Alternative Internal Fixation Method for Transverse Patella Fractures. AB - Pain and reoperation after fixation using tension band wiring and K-wires is not uncommon. A novel hook plate was designed to improve the treatment of patella fractures. The aim of this study was to compare the stability of the hook plate with that of tension band wiring and K-wires in a simulated patellar transverse fracture model (AO/OTA classification 34-C1.1). The authors tested 16 embalmed cadaver knee joints fixed with the hook plate and tension band wiring and K-wires under cyclic loading. Specimens underwent 100 cycles extending the knee joint from 90 degrees of flexion to full extension at a velocity of 50 mm/min. The fracture gap was measured after the initial and last cycles. Data were assessed statistically using the t test, with significance set as P<.05. The fatigue test showed that the fracture gap after 100 cycles was 2.97+/-1.39 mm using tension band wiring and K-wires and 1.53+/-0.93 mm for the hook plate (P=.029). Six of 8 specimens in the tension band wiring and K-wires group met the failure criterion of fracture gap greater than 2 mm vs 1 in the hook plate group (P=.041). From a biomechanical point of view, the hook plate is a valid alternative to tension band wiring and K-wires for fixing patella transverse fractures. Compared with tension band wiring and K-wires, the hook plate may have superior ability in sustaining a reduced transverse patella fracture. [Orthopedics. 2018; 41(5):e643 e648.]. PMID- 30011056 TI - Comparison of Coronal Prosthetic Alignment After Total Knee Arthroplasty Using 3 Computer-Assisted Navigation Systems. AB - Recent advances in surgical tools such as navigation systems have contributed to accurate implantation in total knee arthroplasty. Although several navigation systems have been developed, reports regarding which navigation system has better accuracy are few. Therefore, this study aimed to compare the accuracy of postoperative coronal alignment among 3 navigation systems. A total of 90 knee prostheses were implanted for 90 patients with osteoarthritis. Thirty patients were enrolled in each of the following 3 navigation groups: Stryker Navigation System II (computed tomography-free navigation; Stryker, Mahwah, New Jersey); OrthoPilot version 4.2 navigation system (computed tomography-free navigation; B. Braun Aesculap, Tuttlingen, Germany); and VectorVision navigation system (computed tomography-based navigation system; BrainLAB, Munich, Germany). Thirty consecutive total knee arthroplasties performed via the conventional method without navigation were selected as a control group for comparison with the navigation groups. Postoperative coronal mechanical axis and femoral and tibial coronal component angles were compared among the groups using long-leg standing radiographs for the rate of outliers beyond 3 degrees . No differences were observed in the mean femoral and tibial component angles among the navigation and conventional groups. However, the proportion of outliers beyond 3 degrees was higher in the conventional group than in the 3 navigation groups. No significant differences in the outlying values were found among the 3 navigation groups. These 3 navigation systems achieved equally accurate coronal mechanical alignment with fewer outliers. The navigation systems exhibited more precise implantation than the conventional method. [Orthopedics. 2018; 41(5):e621-e628.]. PMID- 30011057 TI - The assessment of platelet function using multiple electrode aggregometry in practical procedures in anaesthesia. AB - BACKGROUND: Platelets are responsible for primary haemostasis. Patients with suspected platelet dysfunction require prompt clinical assessment when qualifying for emergency surgical procedures. The purpose of this article is to present our experience in platelet function assessment using whole-blood multiple electrode aggregometry (MEA) in various clinical conditions. CASE REPORTS: Retrospective analysis of three patients with thrombocytopathy associated with normal platelet counts was performed using standard laboratory tests complemented by MEA. In two cases, platelet dysfunction was due to antiplatelet drugs, while in one other case it was caused by chronic kidney disease. CONCLUSIONS: Anaesthesiologists strive to make the perioperative period as safe as possible. Platelet function assessment should be considered in every patient in whom haemostatic disturbances are suspected. MEA provides support for clinical decision-making, especially in patients who undergo haemodialysis or require antiplatelet therapy, and are in need of emergency surgery. PMID- 30011058 TI - Reasons for Manuscript Rejection After Peer Review From the Journal Headache. AB - OBJECTIVE: To identify and characterize the reasons manuscripts are rejected after peer review from the journal Headache. BACKGROUND: Numerous editorials, reviews, and research manuscripts have been published on the topic of manuscript rejection. However, few of these papers evaluate the reasons for rejection after peer review systematically. None are specific to the field of neurology or headache medicine. METHODS: A retrospective analysis of all submissions to Headache from January 1, 2014 through December 31, 2016 was performed. Peer reviewer and editor comments for each manuscript were reviewed, and unlimited reasons for rejection were coded for each manuscript. Detailed reasons for rejection were then grouped into 9 broader categories. RESULTS: A total of 784 submissions were received from January 1, 2014 through December 31, 2016. Of those, 336 were immediately rejected and 434 went on to peer review. During this period, the overall rejection rate was 62.6% and the rejection rate after peer review was 35.7%. The 6 most common reasons for rejection after peer review were: flaws in methodology and study design, poor reporting of methodology, poor statistical analysis, overstatement of conclusions, problems with covariates or outcomes, and problems with the control or case group. CONCLUSION: Flaws in methodology and study design were the most common reasons for rejection after peer review from Headache between 2014-2016. PMID- 30011059 TI - Aspirin in primary prevention for patients with diabetes: Still a matter of debate. AB - BACKGROUND: Patients with diabetes are at high cardiovascular (CV) risk due to an exaggerated platelet activation and aggregation. In the first 2000s low-dose aspirin was first recommended for primary prevention, but then re-discussed. METHODS: This short narrative review, based on the material searched for and obtained via PubMed up to February 2018, aims at clarifying this controversial topic. RESULTS: The JPAD2 study has been designed to evaluate the occurrence of any CV event in a cohort of patients with diabetes and concluded that low-dose aspirin did not influence the risk for CV events while increasing the risk for gastrointestinal (GI) bleeding. Reasons for this result can be found in the role of diabetic platelets, which are known to be hyperreactive, thus producing intensified adhesion, activation, and aggregation. In this setting, other associated metabolic conditions can concur to enhance platelet adhesion and activation. Aspirin resistance has been often considered a guilty actor, although many mechanisms have been mistaken for true aspirin resistance, such as patient poor compliance, inadequate dosing, drug interactions, and high-platelet turnover. However, the mere presence of diabetes is not likely to give a net benefit for CV protection with respect to GI bleeding. CONCLUSION: It appears advisable to follow current guidelines addressing first of all classical risk factors and evaluate aspirin therapy in primary prevention only for patients with type 1 or 2 diabetes at increased CV risk and no risk for GI bleeding. Anyway, additional clinical trials are needed to address the current topic. PMID- 30011061 TI - Linking Cigarette Smoking/Tobacco Exposure and Cluster Headache: A Pathogenesis Theory. AB - INTRODUCTION: To propose a hypothesis theory to establish a linkage between cigarette smoking and cluster headache pathogenesis. BACKGROUND: Cluster headache is a primary headache syndrome grouped under the trigeminal autonomic cephalalgias. What distinguishes cluster headache from all other primary headache conditions is its inherent connection to cigarette smoking. It is undeniable that tobacco exposure is in some manner related to cluster headache. The connection to tobacco exposure for cluster headache is so strong that even if an individual sufferer never smoked, then that individual typically had significant secondary smoke exposure as a child from parental smoking behavior and in many instances both scenarios exist. The manner by which cigarette smoking is connected to cluster headache pathogenesis is unknown at present. If this could be determined this may contribute to advancing our understanding of cluster headache pathophysiology. METHODS/RESULTS: Hypothesis statement. CONCLUSION: The hypothesis theory will include several principles: (1) the need of double lifetime tobacco exposure, (2) that cadmium is possibly the primary agent in cigarette smoke that leads to hypothalamic-pituitary-gonadal axis toxicity promoting cluster headache, (3) that the estrogenization of the brain and its specific sexually dimorphic nuclei is necessary to develop cluster headache with tobacco exposure, and (4) that the chronic effects of smoking and its toxic metabolites including cadmium and nicotine on the cortex are contributing to the morphometric and orexin alterations that have been previously attributed to the primary headache disorder itself. PMID- 30011060 TI - Natural T-cell ligands that are created by genetic variants can be transferred between cells by extracellular vesicles. AB - CD4 T cells play a central role as helper cells in adaptive immunity. Presentation of exogenous antigens in MHC class II by professional antigen presenting cells is a crucial step in induction of specific CD4 T cells in adaptive immune responses. For efficient induction of immunity against intracellular threats such as viruses or malignant transformations, antigens from HLA class II-negative infected or transformed cells need to be transferred to surrounding antigen-presenting cells to allow efficient priming of naive CD4 T cells. Here we show indirect antigen presentation for a subset of natural HLA class II ligands that are created by genetic variants and demonstrated that (neo)antigens can be transferred between cells by extracellular vesicles. Intercellular transfer by extracellular vesicles was not dependent on the T-cell epitope, but rather on characteristics of the full-length protein. This mechanism of (neo)antigen transfer from HLA class II-negative cells to surrounding antigen presenting cells may play a crucial role in induction of anti-tumor immunity. PMID- 30011062 TI - Reduction in TIMP-2 serum levels predicts remission of inflammatory bowel diseases. AB - BACKGROUND: Growing evidence indicates tissue inhibitors of matrix metalloproteinases (TIMPs) as potential players in inflammatory bowel disease (IBD), but, no prospective data are available in IBD remission/relapse. MATERIAL & METHODS: In this prospective pilot study, a cohort of IBD patients (n = 32) was enrolled and treated with monoclonal anti-TNF-alpha antibodies. Patients were clinically followed up for a median period of 54 weeks. Serum circulating levels of C-reactive protein (CRP), TIMP-1 and -2, matrix metalloproteinase (MMP)-9 and 8, myeloperoxidase (MPO) and neutrophil elastase (NE) were assessed by ELISA at enrolment and at the end of the treatment. RESULTS: The percentage (%) TIMP-2 reduction from baseline to end of treatment was independently associated with IBD remission at the end of treatment and follow-up as well. ROC curve analysis further confirmed the good prognostic accuracy of % TIMP-2 reduction over the treatment period. Conversely, no other change in inflammatory molecule concentrations was able to predict short- or long-term IBD remission. CONCLUSIONS: This study indicates TIMP-2 reduction during IBD treatment with monoclonal anti-TNF-alpha antibodies as a potential prognostic parameter of short and long term remission. To understand if TIMP-2 is an innocent biomarker or an active pathophysiological factor in IBD remains to be clarified. PMID- 30011063 TI - Circular permutation of a bacterial tyrosinase enables efficient polyphenol specific oxidation and quantitative preparation of orobol. AB - Tyrosinase is a type 3 copper oxygenase that catalyzes a phenol moiety into ortho diphenol, and subsequently to ortho-quinone. Diverse tyrosinases have been observed across the kingdom including Animalia, Bacteria, Plantae, and Fungi. Among the tyrosinases, bacterial, and mushroom tyrosinases have been extensively exploited to prepare melanin, ortho-hydroxy-polyphenols, or novel plant secondary metabolites during the past decade. And their use as a biocatalyst to prepare various functional biocompounds have drawn great attention worldwide. Herein, we tailored a bacterial tyrosinase from Bacillus megaterium (BmTy) using circular permutation (CP) engineering technique which is a novel enzyme engineering technique to covalently link original N and C termini and create new termini on the middle of its polypeptide. To construct a smart rationally-designed CP library, we introduced 18 new termini at the edge of each nine loops that link alpha-helical secondary structure in BmTy. Among the small library, seven functional CP variants were successfully identified and they represented dramatic change in their enzyme characteristics including kinetic properties and substrate specificity. Especially, cp48, 102, and 245 showed dramatically decreased tyrosine hydroxylase activity, behaving like a catechol oxidase. Exploiting the dramatic increased polyphenol oxidation activity of cp48, orobol (3'-hydroxy genistein) was quantitatively synthesized with 1.48 g/L, which was a 6-fold higher yield of truncated wild-type. We examined their kinetic characters through structural speculation, and suggest a strategy to solubilize the insoluble artificial variants effectively. PMID- 30011064 TI - The hunt for the earliest cases of AIDS-related Kaposi sarcoma: a retrospective outbreak investigation. PMID- 30011065 TI - Pemphigus herpetiformis in South Tunisia: a clinical expression of pemphigus foliaceus? AB - BACKGROUND: Pemphigus herpetiformis (PH) is a rare subtype of pemphigus combining clinical features of dermatitis herpetiformis and the immunopathologic characteristics of pemphigus. We aimed to analyze the epidemiological, clinical, and immunological presentation and management of the disease in a cohort of south Tunisian patients with a long-term follow-up. METHODS: We included all patients with confirmed PH followed from January 1987 to December 2015 in the dermatology department. RESULTS: We included 24 south Tunisian female patients with a mean age of 36 years (20-63), mainly from rural origin (84%). All patients had exclusive skin lesions. Clinical features combined erythematous, vesicular, or bullous lesions, with circinate borders mainly on the trunk and limbs associated with severe pruritus (91%). Peripheral hypereosinophilia was noted in 31% of cases. Histological examination demonstrated no intraepithelial (50%), suprabasal (35%), or subcorneal cleavage (15%). Eosinophilic spongiosis was seen in 42% of cases. On direct immunofluorescence, there was an intercellular staining in 96% of cases composed mainly of IgG and C3 (79%). Indirect immunofluorescence was positive in 71% of cases. Reactivity was mainly directed against Dsg1. Dapsone alone was inefficient. All patients received systemic corticosteroids. Most patients (64%) relapsed. Iatrogenic complications and cutaneous infections were noted in 40% and 16% of cases, respectively. CONCLUSION: PH is characterized by the occurrence of exclusive skin lesions in young women with a good response to corticosteroids but not to Dapsone. Reactivity mainly against Dsg1 suggests that PH in south Tunisia is a particular variant of nonendemic pemphigus foliaceus. PMID- 30011066 TI - Validity and reliability of the Danish version of the Ice Expressive Family Functioning and Ice Family Perceived Support questionnaires. AB - AIM: International research has only rarely examined the functioning of families experiencing chronic illness and the perception of nurses towards involving families in patient care. This has also been the case in Denmark. To undertake this kind of research, carefully translated questionnaires are needed. The purpose of this study was therefore to translate the Ice Expressive Family Functioning (ICE-EFFQ) and the Ice Family Perceived Support (ICE-FPSQ) into Danish, and to test the validity and reliability of the Danish versions. METHODS: The study had a cross-sectional design. The questionnaires were translated into Danish using forward-backward translation. Then, they were tested empirically among adult patients with chronic diseases and their family members in three different settings. A total of 81 patients were included in the testing of ICE EFFQ and 70 patients were included in the testing of ICE-FPSQ. Internal consistency reliability was assessed followed by confirmatory factor analysis. RESULTS: Both questionnaires showed acceptable construct validity, reliability (Cronbach's alpha 0.93 and 0.94), internal consistency were confirmed, and there was good reproducibility (Cronbach's alpha 0.76 and 0.77). Furthermore, confirmatory factor analysis showed acceptable to good fit for both questionnaires. CONCLUSIONS: The ICE-EFFQ and the ICE-FPSQ were both found to be valid and reliable instruments to measure family functioning and perceived support among families experiencing chronic illness in a Danish context. PMID- 30011067 TI - Improving the production of recombinant human bone morphogenetic protein-4 in Chinese hamster ovary cell cultures by inhibition of undesirable endocytosis. AB - Endocytic regulation serves a critical role in modulating the extracellular level of signaling molecules, such as bone morphogenetic proteins (BMPs). Unfortunately, endocytosis may result in poor yields of recombinant human BMP-4 (rhBMP-4) from Chinese hamster ovary (CHO) cell cultures. When rhBMP-4 was incubated with CHO cells, rhBMP-4 was actively internalized into cells. Cell surface bound heparan sulfate proteoglycans (HSPGs) served as the major receptors for rhBMP-4 internalization. Removal of cell surface heparan sulfate (HS) by heparinases or reduction of HSPG synthesis by knockdown of xylosyltransferase2 (xylt2) in CHO cells decreased internalization of rhBMP-4. In addition, treatment with endocytosis inhibitors (chlorpromazine, genistein, and dynasore) identified a clathrin- and dynamin-dependent endocytic pathway as the major route for rhBMP 4 internalization. To enhance product yield by minimizing rhBMP-4 internalization in recombinant CHO (rCHO) cell cultures, we have tested various strategies to reduce HSPG synthesis (knockdown of xylt2 and sodium chlorate treatment) or inhibit the binding of rhBMP-4 to cell-surface-bound HSPGs (supplementation with heparin or dextran sulfate [DS]). Among these approaches, DS, which is a linear anionic sulfated polysaccharide with similarity to HS chains, was the most effective in enhancing rhBMP-4 production in rCHO cell cultures. Compared with the control cultures, DS addition to the culture medium (1.0 g/L) resulted in 1.4 fold and 2.3-fold increases in maximum rhBMP-4 concentration in batch and fed batch cultures, respectively. Taken together, the addition of DS, an effective competitor of HSPGs, improved rhBMP-4 production in rCHO cell cultures through blockage of rhBMP-4 internalization. PMID- 30011068 TI - Investigation of the utility of lymph node fine-needle aspiration cytology for the staging of malignant solid tumors in dogs. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) of lymph nodes (LNs) is routinely used for staging canine malignant solid tumors, but studies evaluating its efficacy are limited. OBJECTIVES: The primary objectives of this study were to evaluate the sensitivity/specificity of FNAC and the significance of nondiagnostic FNAC when staging canine malignant tumors. A secondary objective was to determine the prevalence of multiple nodal metastases. METHODS: Lymph nodes draining malignant solid tumors assessed with FNAC and histopathology were included. The sensitivity/specificity of FNAC was determined for LNs with diagnostic FNAC, using histopathology as the gold standard. The proportion of nondiagnostic FNAC and associated histopathologic prevalence of metastasis were determined. Among the tumors with multiple LNs assessed, the prevalence of multiple nodal metastases was determined. RESULTS: The sensitivity of FNAC (194 LNs) was 67% for sarcomas, 100% for carcinomas, 63% for melanomas, 75% for mast cell tumors, and 100% for other round cell tumors. The specificity varied between 83% and 96%. Nondiagnostic FNAC was reported in 25% of LNs sampled (65/259), most of which were nonenlarged and/or difficult to access, and 20% of which were metastatic on histopathology. When several LNs were assessed (88/189 tumors), the prevalence of multiple nodal metastases was 24%. CONCLUSIONS: Histopathologic LN evaluation cannot be robustly substituted with FNAC when staging selected canine solid tumors. When a diagnostic FNAC is elusive, the histopathologic assessment remains ideal. Finally, staging should not always be limited to the assessment of a single LN. PMID- 30011069 TI - The effects of iatrogenic blood contamination on total nucleated cell counts and protein concentrations in canine cerebrospinal fluid. AB - BACKGROUND: Cerebrospinal fluid (CSF) might be altered by iatrogenic blood contamination, precluding accurate diagnostic interpretation. OBJECTIVES: Available formulas to correct for iatrogenic blood contamination are likely unreliable. Study objectives were to determine the effects of blood contamination on total nucleated cell counts (NCCs) and protein concentrations in canine CSF. METHODS: Two methods were followed to evaluate the effect of blood contamination on total NCC and protein concentrations in CSF. First, records from the Colorado State University Veterinary Teaching Hospital were retrospectively searched for dogs where CSF analysis was performed. Total NCCs, RBC counts, protein concentrations, and cytologic interpretations were recorded. Second, CSF from 4 canine patients and 3 research hounds was prospectively analyzed before and after known dilutions of whole blood were added. RESULTS: Of the 787 clinical samples analyzed, 108 samples had a cytologic diagnosis of blood contamination. RBC counts for all clinical samples ranged from 0 to 210,000 cells/MUL. No correlation between total NCCs or protein concentrations with RBC counts were found when all samples were evaluated. Total NCCs and RBCs were weakly correlated in samples with a cytologic diagnosis of blood contamination and when >=500 RBC/MUL was present. When serial dilutions of whole blood were added to normal CSF, no significant changes were observed in the total NCCs of uncontaminated aliquots and contaminated aliquots containing up to 8480 RBC/MUL. CONCLUSIONS: Erythrocyte counts in blood-contaminated canine CSF poorly correlate with total NCCs and protein concentrations. Using formulas to correct total NCCs and protein concentrations for the number of RBCs in CSF is inappropriate. PMID- 30011070 TI - Discovering the ethos of serving in nursing leadership from the first half of the 20th century in three Nordic countries - an idea-historical research approach. AB - The history of ideas may contribute to an awareness and an opening up of deep seated currents of thought that have shaped the inner core of the caring culture and an ethical value base - the ethos of serving in nursing leadership. This article studies how serving as an ethos is represented, which becomes visible and evident in Sophie Mannerheim's, Bertha Wellin's and Bergljot Larsson's nursing leadership. This article also seeks to describe the main features of the idea historical research approach the way in which it is represented within the caring science-tradition. An idea-historical methodological approach informed by Gadamer's philosophy was used for the hermeneutical interpretation within a caring science perspective. Primary and secondary historical sources were explored in the light of nursing praxis and serving. Three general idea patterns were discovered: the innermost room of the heart as the idea of serving, the action of the hand as acts of love and a cultivation of the head towards nursing leadership. These ideas open for a new vision that can bring out new patterns for action in the present and in the nursing leadership of the future. PMID- 30011071 TI - Clinical subtypes and molecular basis of epidermolysis bullosa in Kuwait. AB - BACKGROUND: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous blistering skin disease, but in countries such as Kuwait, there are very limited data on the clinical and molecular pathology of EB. To improve understanding of EB in Kuwait, we report the experience of a local tertiary referral center over a 17.5 year period (January 2000-June 2017) in establishing clinical and molecular diagnoses. METHODS: Review of hospital records and diagnostic reports. Individual cases were diagnosed by combinations of clinical assessment, skin biopsy (immunohistochemistry and transmission electron microscopy), Sanger sequencing of EB genes, and whole exome sequencing. RESULTS: Fifty-four families with EB were registered with the clinic over this period, 41 of whom (84 patients) participated in diagnostic studies. Thirty-seven of these 41 families had consanguineous marriages; 34 had recessive forms of EB, while only seven had dominant subtypes. Recurrent mutations were observed in epidermal dystonin, transglutaminase 5, and type VII collagen. CONCLUSIONS: The prevalence of EB in Kuwait is approximately three times that of internationally cited rates with an over-representation of autosomal recessive variants. Establishing the molecular basis of EB in Kuwait with accurate diagnostic subtyping provides a basis for determining healthcare requirements and improving patient management of EB. PMID- 30011072 TI - Epiregulin promotes the migration and chemotaxis ability of adipose-derived mesenchymal stem cells via mitogen-activated protein kinase signaling pathways. AB - To investigate the function of epiregulin (EREG) in the migration and chemotaxis ability of mesenchymal stem cells. Adipose-derived stem cells (ADSCs) were used in this investigation. Lentiviral EREG short hairpin RNA was applied to silence EREG expression in ADSCs. Human recombinant EREG protein (rhEREG) was used to perform a gain-of-function study. Scratch-simulated wound migration and transwell chemotaxis assays were used to examine the migration and chemotaxis capacity of ADSCs in vitro. Using a Western blot assay, the expressions of p38 mitogen activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), and protein kinase B were detected. Depletion of EREG caused by specific short hairpin RNA restrained the migration and chemotaxis ability of ADSCs and inhibited the expressions of phosphorylated p38 MAPK, JNK, and Erk1/2. rhEREG improved ADSCs migration and chemotaxis capacity, which was repressed by knockdown of EREG and rescued the expressions of phosphorylated p38 MAPK, JNK, and Erk1/2 impaired by silencing EREG. Furthermore, rhEREG-improved migration and chemotaxis ability in EREG depleted-ADSCs was restricted by a specific inhibitor, SB203580, for blocking p38 MAPK signaling, PD98059 for blocking Erk1/2 signaling, or SP600125 for blocking JNK signaling in ADSCs separately. EREG promotes migration and chemotaxis ability of ADSCs through MAPK signaling pathways. PMID- 30011073 TI - Identification of potential pathogenic viruses in patients with acute myocarditis using next-generation sequencing. AB - Myocarditis is an inflammatory disease of the myocardium and leads to cardiac dysfunction and heart failure. Although viral infections are considered to be the most common etiology of myocarditis, the identification of the causative virus is still challenging. Recently, next-generation sequencing (NGS) has been applied in the diagnosis of infectious diseases. The aim of the current study was to comprehensively analyze potential pathogenic microorganisms using NGS in the sera of patients with myocarditis. Twelve pediatric and five adult patients hospitalized for acute myocarditis were included. Serum samples in the acute phase were obtained and analyzed using NGS to detect pathogen-derived DNA and RNA. Viral sequence reads were detected in 7 (41%) of the 17 myocarditis patients by NGS. Among these patients, detection of Epstein-Barr virus, human parvovirus B19, torque teno virus, and respiratory syncytial virus reads by NGS was consistent with polymerase chain reaction or antigen test results in one patient each. A large number of human pegivirus reads were detected from one patient by RNA sequencing; however, its pathogenicity to human is unknown. Conversely, the number of detected virus-derived reads was small in most cases, and the pathophysiological role of these viruses remains to be clarified. No significant bacterial or fungal reads other than normal bacterial flora was detected. These data indicate that comprehensive detection of virus-derived DNA and RNA using NGS can be useful for the identification of potential pathogenic viruses in myocarditis. PMID- 30011074 TI - Feasibility and acceptability of an early home visit intervention aimed at supporting a positive mother-infant relationship for mothers at risk of postpartum depression. AB - AIMS: Perinatal depression is associated with difficulties in the early mother child interaction and negative child outcome. The aim of this study was to assess the feasibility and acceptability of the Newborn Behavioral Observation (NBO) System included in a home visiting programme at well-baby clinics in Norway and to examine compliance with the study protocol for a future clinical trial. The target group was pregnant women at risk for postpartum depression and their partners. METHOD: An open-label study was conducted. A total of 15 pregnant women and 10 partners were recruited during 24-28 weeks of gestation. The NBO was conducted in three home visits during the first four weeks after birth. Data were collected from surveys responded to by parents and healthcare workers at six time points and from video recordings of mother-infant interaction by the Emotional Availability (EA) Scale. The parents' experience of the intervention and data collection was investigated by qualitative analyses of five interviews. The NBO is an individualised, relationship-based method aimed to strengthen the emotional bond between the parents and their infants and enhance the parents' alliance with the healthcare worker. RESULTS: Intervention completion was 97%. Data collection completion was 100% at baseline and the second time-point and dropped to 50% for the mothers and 40% for the fathers at the sixth time-point. However, 79% (11 of 14) of the mothers and infants took part in video recordings for the EA coding at 4 months postpartum (sixth time-point). The usefulness questionnaires showed high acceptability among both parents and healthcare workers. CONCLUSION: This study showed that the NBO conducted in home visits is a feasible and acceptable intervention for both parents and healthcare workers within the well-baby clinic services. A future clinical trial protocol needs adjustments related to data collection. PMID- 30011076 TI - Rapid alignment of functional trait variation with locality across the invaded range of Sahara mustard (Brassica tournefortii). AB - PREMISE OF STUDY: Mechanisms by which invasive species succeed across multiple novel environmental contexts are poorly understood. Functional traits show promise for identifying such mechanisms, yet we lack knowledge of which functional traits are critical for success and how they vary across invaded ranges and with environmental features. We evaluated the widespread recent invasion of Sahara mustard (Brassica tournefortii) in the southwestern United States to understand the extent of functional trait variation across the invaded range and how such variation is related to spatial and climatic gradients. METHODS: We used a common garden approach, growing two generations of plants in controlled conditions sourced from 10 locations across the invaded range. We measured variation within and among populations in phenological, morphological, and physiological traits, as well as performance. KEY RESULTS: We found nine key traits that varied among populations. These traits were related to phenology and early growth strategies, such as the timing of germination and flowering, as well as relative allocation of biomass to reproduction and individual seed mass. Trait variation was related most strongly to variation in winter precipitation patterns across localities, though variations in temperature and latitude also had significant contributions. CONCLUSIONS: Our results identify key functional traits of this invasive species that showed significant variation among introduced populations across a broad geographic and climatic range. Further, trait variation among populations was strongly related to key climatic variables, which suggests that population divergence in these traits may explain the successful colonization of Sahara mustard across its invaded US range. PMID- 30011077 TI - Hierarchically aligned fibrous hydrogel films through microfluidic self-assembly of graphene and polysaccharides. AB - Despite significant interest in developing extracellular matrix (ECM)-inspired biomaterials to recreate native cell-instructive microenvironments, the major challenge in the biomaterial field is to recapitulate the complex structural and biophysical features of native ECM. These biophysical features include multiscale hierarchy, electrical conductivity, optimum wettability, and mechanical properties. These features are critical to the design of cell-instructive biomaterials for bioengineering applications such as skeletal muscle tissue engineering. In this study, we used a custom-designed film fabrication assembly, which consists of a microfluidic chamber to allow electrostatic charge-based self assembly of oppositely charged polymer solutions forming a hydrogel fiber and eventually, a nanocomposite fibrous hydrogel film. The film recapitulates unidirectional hierarchical fibrous structure along with the conductive properties to guide initial alignment and myotube formation from cultured myoblasts. We combined high conductivity, and charge carrier mobility of graphene with biocompatibility of polysaccharides to develop graphene-polysaccharide nanocomposite fibrous hydrogel films. The incorporation of graphene in fibrous hydrogel films enhanced their wettability, electrical conductivity, tensile strength, and toughness without significantly altering their elastic properties (Young's modulus). In a proof-of-concept study, the mouse myoblast cells (C2C12) seeded on these nanocomposite fibrous hydrogel films showed improved spreading and enhanced myogenesis as evident by the formation of multinucleated myotubes, an early indicator of myogenesis. Overall, graphene-polysaccharide nanocomposite fibrous hydrogel films provide a potential biomaterial to promote skeletal muscle tissue regeneration. PMID- 30011078 TI - What is your diagnosis? Bladder mass in a mare. PMID- 30011079 TI - Effect of 5-fluorouracil on excision repair cross-complementing 1 expression and consequent cytotoxicity regulation in human gastric cancer cells. AB - Gastric cancer is the third leading cause of cancer mortality all over the world. The combination therapy of surgery with chemotherapy, that is, 5-fluorouracil (5 FU) and platinum-containing anticancer drugs, is becoming a current clinical strategy for patients with gastric cancer because of the lower curative rate and higher cancer recurrence rate of patients treated with only surgery. However, the development of drug resistance in cancer cells is still the most challenge in clinical chemotherapy. Excision repair cross-complementing 1 (ERCC1), an essential member of nucleotide excision repair system, recently has been suggested to be a predictive biomarker of treatment evaluation and might affect the outcomes of chemotherapy. Thus, this study was aimed to investigate whether ERCC1 expression could be regulated, and its role in gastric cancer cells treated with 5-FU and the underlying mechanism. Human AGS gastric cancer cells were used in this study. It was shown that ERCC1 expression could be upregulated in AGS cells treated with 5-FU and this upregulation could subsequently attenuate the cytotoxicity of 5-FU in AGS cells. Moreover, 5-FU-upregulated ERCC1 expression was regulated by extracellular signal-regulated kinase (ERK) 1/2 and p38 signaling through activating the transcription factor c-jun/activator protein (AP)-1. These results indicated the role of ERCC1 in the development of drug resistance to 5-FU in AGS cells. The mechanism elucidation concerning the ERK1/2 and p38 kinases and transcription factor c-jun/AP-1 might contribute another idea to the development of chemotherapy strategy for the gastric cancers in the future. PMID- 30011080 TI - Biocrusts benefit from plant removal. AB - PREMISE OF THE STUDY: Productivity in drylands may depend on the sensitivity of interactions between plants and biocrusts. Given future climate variability, it is essential to understand how interactions may be context-dependent with precipitation regime. Furthermore, little is known about the additional interactions of these producers with the belowground biota (e.g., roots, fungi, microarthropods). We evaluated the effect of removal (such as could occur following disturbance) and net interaction of plants and biocrusts and additionally manipulated the abiotic and biotic context. METHODS: We established field mesocosms containing grass (Bouteloua gracilis) and surrounding biocrusts, then clipped the plant or heat-sterilized the biocrust to simulate the loss of dryland producers. To test for context-dependency on the precipitation pattern, we imposed a large, infrequent or small, frequent precipitation regime. A mesh barrier was used to impede belowground connections that may couple the dynamics of producers. Productivity was assessed by plant biomass and biocrust chlorophyll content. KEY RESULTS: Biocrusts increased chlorophyll content more when plants were removed than when they were present in the first year, but only in the small, frequent precipitation regime. In contrast, plant growth slightly declined with biocrust removal. Plant biomass and biocrust chlorophyll content were negatively correlated in the second year, suggesting net competition. Belowground connectivity weakly promoted overall biocrust relative productivity, but was generally weakly detrimental to plant relative productivity. CONCLUSIONS: Altered precipitation patterns can amplify positive effects of plant removal on biocrust producers. Furthermore, we discovered that belowground networks contributed to dryland productivity by promoting biocrust performance. PMID- 30011075 TI - Early life adversity and health-risk behaviors: proposed psychological and neural mechanisms. AB - Early life adversity (ELA) is associated with poorer health in adulthood, an association explained, at least in part, by increased engagement in health-risk behaviors (HRBs). In this review, we make the case that ELA influences brain development in ways that increase the likelihood of engaging in HRBs. We argue that ELA alters neural circuitry underpinning cognitive control as well as emotional processing, including networks involved in processing threat and reward. These neural changes are associated psychologically and behaviorally with heightened emotional reactivity, blunted reward responsivity, poorer emotion regulation, and greater delay discounting. We then demonstrate that these adaptations to ELA are associated with an increased risk of smoking cigarettes, drinking alcohol, and eating high-fat, high-sugar foods. Furthermore, we explore how HRBs affect the brain in ways that reinforce addiction and further explain clustering of HRBs. PMID- 30011081 TI - ST2 regulates bone loss in a site-dependent and estrogen-dependent manner. AB - Interleukin-33 (IL-33) and its receptor, ST2, are implicated in bone remodeling. The lack of estrogen after menopause results in an accelerated bone loss. Here we investigated the role of ST2 in the bone loss induced by estrogen deficiency. ST2 deficient mice (ST2-/- ) and their littermates (wildtype [WT]) were ovariectomized (OVX), while ovary-intact mice were used as controls. Bone sites were analyzed by microcomputed tomography, histomorphometry, and quantitative real-time polymerase chain reaction (qPCR). Deletion of IL-33 or ST2 resulted in a similar bone loss in the femur and maxilla. Ovariectomy in WT mice caused bone loss in the same areas. The lack of ST2 in OVX mice did not alter bone remodeling in the femur but prevented bone loss in the maxilla. Consistently, ovariectomy increased the IL-33 messenger RNA (mRNA) levels in the maxilla but not in the femur. Under mechanical stimulation, ovariectomy and ST2 deletion independently increased bone remodeling induced by orthodontic tooth movement, which was also associated with a greater number of osteoclasts and a reduced number of osteoblasts in the maxillary bone. ST2-/- OVX mice, however, displayed twice as many osteoblasts as that of WT OVX mice. Ovariectomy and ST2 deletion differently altered the cytokine mRNA levels in the maxilla. Remarkably, interleukin-10 expression was decreased in both WT OVX and ST2-/- mice, and this reduction was completely restored in ST2-/- OVX mice. The results demonstrate that estrogen and IL33/ST2 independently protect against bone loss. However, the ovariectomy induced bone loss is IL-33/ST2-dependent in the maxilla but not in the femur, indicating a bimodal and site-specific role of ST2 in bone remodeling. PMID- 30011082 TI - Binding of p67phox to Nox2 is stabilized by disulfide bonds between cysteines in the 369 Cys-Gly-Cys371 triad in Nox2 and in p67phox. AB - A central event in the activation of the phagocyte NADPH oxidase involves binding of p67phox to the dehydrogenase region of Nox2. The identity of the binding site in Nox2 is unknown. By measuring binding of p67phox to synthetic Nox2 peptides, we previously identified a sequence corresponding to Nox2 residues 357-383, as a potential binding site. A key role was attributed to a 369 Cys-Gly-Cys371 triad, shared by peptides 357-371 (peptide 24) and 369-383 (peptide 28). In this study, we show that (1) oxidation of cysteines in peptides 24 and 28 by a variety of oxidants markedly enhances the binding of p67phox ; (2) replacing cysteines by arginine abolishes the response to oxidants and the enhanced binding of p67phox ; (3) oxidants act by generating an intramolecular disulfide bond linking cysteines 369 and 371, generating such bond during peptide synthesis reproduces the effect of oxidants; (4) for the disulfide bond to lead to enhanced binding, cysteines must be separated by an intervening residue; bonds joining adjacent cysteines, or cysteines located on two peptides, do not enhance binding; (5) dissociating disulfide bonds by reducing agents abolishes enhanced binding; (6) treating p67phox with the alkylating agent N-ethylmaleimide suppresses binding; and (7) mutating all nine cysteines in p67phox to serines abolishes binding and diminishes the ability of p67phox to support NADPH oxidase activation in vitro. Results show that the primary interaction of p67phox with Nox2 is followed by a stabilizing step, based on the establishment of disulfide bonds between cysteine(s) in the 369 Cys-Gly-Cys371 triad and cysteine(s) in p67phox . PMID- 30011083 TI - Cost-effectiveness of a tailored Helicobacter pylori eradication strategy based on the presence of a 23S ribosomal RNA point mutation that causes clarithromycin resistance in Korean patients. AB - BACKGROUND AND AIM: The Helicobacter pylori eradication rate using conventional triple therapy has decreased due to clarithromycin (CAM) resistance in H. pylori. Recently, dual priming oligonucleotide (DPO)-based multiplex polymerase chain reaction (PCR) can be used to detect H. pylori and point mutations in the 23S ribosomal RNA gene causing CAM resistance. This study aimed to evaluate the success rate and cost-effectiveness of tailored H. pylori eradication using DPO PCR. METHODS: The H. pylori-positive patients diagnosed by a rapid urease test or DPO-PCR were enrolled from a single academic hospital. The patients with positive rapid urease test results received a CAM-based triple regimen. In the tailored therapy group that underwent DPO-PCR testing, patients with A2142G and/or A2143G point mutations were treated with a bismuth-containing quadruple regimen. The cost-effectiveness of H. pylori eradication success was evaluated according to the average cost per patient and the incremental cost-effectiveness ratio. RESULTS: A total of 243 patients were allocated to the triple therapy group and 124 patients to the tailored therapy group. The first-line eradication rate of H. pylori was significantly higher in the tailored therapy group than in the conventional triple therapy group (92.7% vs 76.5%, P < 0.001). The average costs per patient for tailored therapy were $307.37 and $299.59 for first-line and second-line treatments, respectively. Compared with triple therapy, the incremental cost-effectiveness ratios of tailored therapy were $3.96 and -$3.81 per patient for first-line and second-line treatments, respectively. CONCLUSION: In Korea, tailored H. pylori eradication using DPO-PCR may be more cost-effective than conventional triple therapy. PMID- 30011084 TI - The proto-oncogene function of Mdm2 in bone. AB - Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2Tg ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2TgOb ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals. PMID- 30011085 TI - Economic evaluation of sexed semen use in Iranian dairy farms according to field data. AB - In this study, at first, the reproductive consequences of sexed semen use were quantified and then the cost-benefit of sexed semen use on Iranian commercial dairy farms was evaluated. Retrospective data collected during 2006 to 2013 from four large dairy farms in the Isfahan province of Iran were used for this study. These data included of 13,003 heifers records, from which 11.2% used sexed semen from 33 different bulls. All data were analysed using a multivariable logistical regression model, GENMOD procedure from SAS software. The analyses included economic values (EVs) when sexed semen was used in 1, 2 and 3 consecutive services compared with conventional semen use for all insemination. Results showed that rates of female born from sexed semen (86.3%) were 1.8 times higher than those from conventional semen (48.5%). Conception rates were 43.8% for sexed and 59.2% for conventional semen (p < 0.0001). Abortion (4.4% vs. 5.4%) and stillbirth (8.4% vs. 7.2%) rates were not significantly different between sexed and conventional semen (p = 0.09). Dystocia rates were 15.5% for sexed and 19.6% for conventional semen (p = 0.002). Sexed semen use showed negative EVs through all investigated scenarios. The EVs from the implementation of 1, 2 and 3 sexed semen breedings were estimated to be $-6.69, $-14.01 and $-19.08, respectively. Total insemination cost and increased cost of age at first calving were the most important components associated with negative EV for sexed semen. Sensitivity analysis showed that proportion of conception rates of sexed semen to conventional semen and female calf value were the most important biological and economic factors influencing on the EV of sexed semen, respectively. Breakeven would be obtained with 77.4%-79.3% conception rates or female calf value of $719.5-$754.7 through investigated breeding scenarios when all other factors remained the same. PMID- 30011087 TI - The protease inhibitor antipain has a beneficial synergistic effect with trehalose for ram semen cryopreservation. AB - The objective of this study was to examine the different concentrations of antipain and trehalose combination on post-thawed quality of ram semen cryopreserved in tris extender. Ejaculates were collected from four rams using the artificial vagina, pooled at 37 degrees C and diluted with (A0 Tre0 : antipain 0 MUM and trehalose 0 mM (Control); A10 Tre0 ; A50 Tre0 ; A0 Tre30 ; A0 Tre60 ; A10 Tre60 ; A10 Tre30 ; A50 Tre30 and A50 Tre60 ). Diluted semen samples were gradually cooled down from 37 to 5 degrees C in a cold cabinet; then, they were loaded into 0.25 ml straws, frozen and stored in liquid nitrogen. Sperm motility (CASA), viability, membrane functionality and abnormality were evaluated after thawing process. Progressive motility in extender supplemented with A10 Tre0 , A0 Tre30 and A10 Tre60 significantly (p < 0.05) higher as compared to the control (A10 Tre0 ). A10 Tre60 (47.50 +/- 0.73) provided the best maintenance of progressive motility in comparison with the control (40.50 +/ 0.73). No significant differences were observed between all treated groups in terms of total motility, VAP, VSL, VCL, ALH, BCF, STR and LIN. The percentages of sperm with viable were significantly higher in extenders supplemented with A10 Tre0 , A50 Tre0 , A0 Tre30 and A10 Tre60 , compared to control. Addition of A10 Tre0 , A50 Tre0 and A10 Tre60 to extenders improved the percentages of sperm abnormality, compared to the controls. A10 Tre60 (67.84 +/- 1.51) treatment provided the best maintenance of normal morphology compared to the other treatments. The supplementation with A10 Tre0 , A0 Tre60 and A10 Tre60 improved the percentage of sperm membrane functionality when compared to the control (p < 0.05). Comparing these results with those of control diluents, the effects of supplementation were better except for A50 Tre60 group. In conclusion, when combination of antipain (10 MUM) and trehalose (30 and 60 mM) was added, they conferred a great cryosurvival capacity with their synergic effects during freeze-thawing process. PMID- 30011088 TI - TRIM22 regulates macrophage autophagy and enhances Mycobacterium tuberculosis clearance by targeting the nuclear factor-multiplicity kappaB/beclin 1 pathway. AB - Autophagy is a crucial host-defense mechanism against Mycobacterium tuberculosis (Mtb) infection by spanning innate and adaptive immune functions. TRIM22 is a member of tripartite motif family protein which involved in innate immunity and autophagy process. However, its role in the modulation of bacterial infection has not been investigated. Here, we demonstrated that TRIM22 is upregulated in a dose dependent and time-dependent manner during Mtb infection of THP-1 cells. Downregulation of TRIM22 significantly decreased light chain 3 (LC3)-II protein level and the formation of LC3 puncta, while it markedly increased SQSTM1, a marker of autophagic degradation, in Mtb-infected THP-1 cells. What is more, enhanced bacterial survival was observed in TRIM22 knockdown THP-1 cells, while rapamycin abrogated this effect. In the presence of vector containing TRIM22 in THP-1 cells prior to infection, the survival of Mtb was decreased, while BafA restored this effect. Further study demonstrated that TRIM22 expression was regulated by MicroRNA-20b, and that TRIM22 regulates Mtb-infected THP-1 autophagy via the nuclear factor-kappaB/beclin 1 pathway. Using a nuclear factor-kappaB inhibitor BAY 11-7082, we found that TRIM22-induced high expression of LC3-II and the formation of LC3 was substantially attenuated, while the TRIM22-induced low expression of SQSTM1 was markedly increased in BAY 11-7082-treatment cells. In addition, the bacterial survival reduced by TRIM22 was significantly reversed by BAY 11-7082. Overall, these results suggest that TRIM22-augmented autophagy prevents intracellular Mtb to evade autophagic clearance, thereby inhibiting the persistence of Mtb infections. PMID- 30011086 TI - Measures of Physical Performance and Muscle Strength as Predictors of Fracture Risk Independent of FRAX, Falls, and aBMD: A Meta-Analysis of the Osteoporotic Fractures in Men (MrOS) Study. AB - Measures of muscle mass, strength, and function predict risk of incident fractures, but it is not known whether this risk information is additive to that from FRAX (fracture risk assessment tool) probability. In the Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, Hong Kong, United States), we investigated whether measures of physical performance/appendicular lean mass (ALM) by DXA predicted incident fractures in older men, independently of FRAX probability. Baseline information included falls history, clinical risk factors for falls and fractures, femoral neck aBMD, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the relationship between time for five chair stands, walking speed over a 6 m distance, grip strength, ALM adjusted for body size (ALM/height2 ), FRAX probability (major osteoporotic fracture [MOF]) with or without femoral neck aBMD, available in a subset of n = 7531), and incident MOF (hip, clinical vertebral, wrist, or proximal humerus). Associations were adjusted for age and time since baseline, and are reported as hazard ratios (HRs) for first incident fracture per SD increment in predictor using meta-analysis. 5660 men in the United States (mean age 73.5 years), 2764 men in Sweden (75.4 years), and 1987 men in Hong Kong (72.4 years) were studied. Mean follow-up time was 8.7 to 10.9 years. Greater time for five chair stands was associated with greater risk of MOF (HR 1.26; 95% CI, 1.19 to 1.34), whereas greater walking speed (HR 0.85; 95% CI, 0.79 to 0.90), grip strength (HR 0.77; 95% CI, 0.72 to 0.82), and ALM/height2 (HR 0.85; 95% CI, 0.80 to 0.90) were associated with lower risk of incident MOF. Associations remained largely similar after adjustment for FRAX, but associations between ALM/height2 and MOF were weakened (HR 0.92; 95% CI, 0.85 to 0.99). Inclusion of femoral neck aBMD markedly attenuated the association between ALM/height2 and MOF (HR 1.02; 95% CI, 0.96 to 1.10). Measures of physical performance predicted incident fractures independently of FRAX probability. Whilst the predictive value of ALM/height2 was substantially reduced by inclusion of aBMD requires further study, these findings support the consideration of physical performance in fracture risk assessment. (c) 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. PMID- 30011089 TI - Late-onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2-related diseases. AB - Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot-Marie-Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53-year-old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2-related diseases. Sequencing of MFN2 should be considered in all patients presenting with late-onset HSAN. PMID- 30011090 TI - Tissue expression and variation analysis of three bovine adipokine genes revealed their effect on growth traits in native Chinese cattle. AB - Adipokines play a crucial role in the regulation of energy homeostasis; however, little is known about genetic alterations in this family that may contribute to economic traits in cattle. Therefore, this study conducts transcript profiles, variations and association studies of three major adipokines, leptin (LEP), tumour necrosis factor (TNF) and angiopoietin-like protein 8 (ANGPTL8), to evaluate their effects on native Chinese cattle. Using quantitative real-time PCR, the study revealed that the bovine LEP was expressed primarily in the back and visceral fat, while TNF was predominantly expressed in spleen and ANGPTL8 was mainly expressed in back fat and liver. Five single nucleotide polymorphisms (SNPs) including two missense SNPs (SNP1: g.12254T>C and SNP2: g.14177C>T) in LEP, a synonymous SNP (SNP3: g.2130A>G) in TNF and two SNPs (SNP4: g.629G>A and SNP5: g.884T>C) in the 5'UTR of ANGPTL8 were identified and genotyped in 537 individuals from six Chinese cattle breeds. Bioinformatics analysis revealed that SNP1 might disrupt the efficient binding of LEP to its receptor, SNP3 might affect translation efficiency of TNF, and SNP4 and SNP5 were likely to affect stability, splicing and nuclear export of ANGPTL8 mRNA. Consistently, association studies indicated that three SNPs (SNP1, SNP3 and SNP5) were significantly associated with body weight, heart girth, average daily gain, hip width and body length in 100 Nanyang cattle (p < 0.05). Overall, our results support the view that LEP, TNF and ANGPTL8 could be used as biomarkers to improve the growth performance in Chinese cattle selection programmes. PMID- 30011092 TI - Transition to Safer Enteral Connectors Must Happen Now. PMID- 30011091 TI - Fracture Risk After Gastric Bypass Surgery: A Retrospective Cohort Study. AB - Gastric bypass surgery constitutes the most common and effective bariatric surgery to treat obesity. Gastric bypass leads to bone loss, but fracture risk following surgery has been insufficiently studied. Furthermore, the association between gastric bypass and fracture risk has not been studied in patients with diabetes, which is a risk factor for fracture and affected by surgery. In this retrospective cohort study using Swedish national databases, 38,971 obese patients undergoing gastric bypass were identified, 7758 with diabetes and 31,213 without. An equal amount of well-balanced controls were identified through multivariable 1:1 propensity score matching. The risk of fracture and fall injury was investigated using Cox proportional hazards and flexible parameter models. Fracture risk according to weight loss and degree of calcium and vitamin D supplementation 1-year postsurgery was investigated. During a median follow-up time of 3.1 (interquartile range [IQR], 1.7 to 4.6) years, gastric bypass was associated with increased risk of any fracture, in patients with and without diabetes using a multivariable Cox model (hazard ratio [HR] 1.26; 95% CI, 1.05 to 1.53; and HR 1.32; 95% CI, 1.18 to 1.47; respectively). Using flexible parameter models, the fracture risk appeared to increase with time. The risk of fall injury without fracture was also increased after gastric bypass. Larger weight loss or poor calcium and vitamin D supplementation after surgery were not associated with increased fracture risk. In conclusion, gastric bypass surgery is associated with an increased fracture risk, which appears to be increasing with time and not associated with degree of weight loss or calcium and vitamin D supplementation following surgery. An increased risk of fall injury was seen after surgery, which could contribute to the increased fracture risk. (c) 2018 American Society for Bone and Mineral Research. PMID- 30011094 TI - Michael Kleerekoper (August 18, 1944 to May 10, 2018): In Relentless Pursuit of a Better Way. PMID- 30011093 TI - Role of adenosine signaling in the pathogenesis of head and neck cancer. AB - The concentrations of adenosine may increase under ischemic conditions in the tumor microenvironment, and then it enters the systemic circulation. Adenosine controls cancer progression and responses to therapy by regulating angiogenesis, cell survival, apoptosis, cell proliferation, and metastases in tumors. Hence, adenosine metabolism, adenosine-generating enzymes, and adenosine signaling are potentially novel therapeutic targets in a wide range of pathological conditions, including cerebral and cardiac ischemic diseases, inflammatory disorders, immunomodulatory disorders, and, of special interest in this review, cancer. This review summarizes the role of adenosine in the pathogenesis of head and neck cancer for a better understanding of how this may be applied to treating this type of cancer. PMID- 30011095 TI - IL-1beta induces increased tight junction permeability in bovine mammary epithelial cells via the IL-1beta-ERK1/2-MLCK axis upon blood-milk barrier damage. AB - Bovine mastitis occurs frequently in dairy cows and is often caused by various aetiological organisms, for example, Escherichia coli. Lipopolysaccharide (LPS) is a key virulence factor of E. coli. In this study, we stimulated bovine mammary epithelial cells (BMECs) with LPS to investigate the global transcriptional response and identify specific proinflammatory factors that play important roles in blood-milk barrier damage during mastitis caused by E. coli. By performing RNA seq, we identified a large number of significantly differentially expressed genes (DEGs) between the LPS-treated BMECs and the control cells. Among the DEGs, interleukin-1beta (IL-1beta) was selected because its messenger RNA expression was induced by LPS and its enrichment is involved in multiple inflammatory signal pathways, and its roles in blood-milk barrier damage during the process of mastitis were investigated. Exogenous IL-1beta treatment damaged the integrity of the blood-milk barrier, as indicated by the increased BMEC tight junction (TJ) permeability and confirmed by in vitro and in vivo experiments. Furthermore, the IL-1beta-induced increase in the BMEC TJ permeability was mediated by the IL 1beta-ERK1/2-MLCK axis pathway. Our data provide insights into the functions of IL-1beta in blood-milk barrier damage caused by mastitis in dairy cows. PMID- 30011096 TI - Fluoropolymers: The Right Material for the Right Applications. AB - An overview on the synthesis, properties, and applications of fluoropolymers (PFs) is presented. First, a non-exhaustive summary on the homopolymers from conventional radical polymerization of fluoromonomers is proposed. FPs are interesting materials thanks to their outstanding properties such as thermal, oxidative and chemical resistances, low dissipation factor, refractive index, permittivity, and water absorptivity, as well as excellent durability and weatherability. Various strategies of synthesis are proposed, especially on recent studies on radical (co)polymerization of fluoroalkenes, just like their properties and applications ranging from coatings and energy-related materials (e.g. fuel cell membranes, components for lithium ion batteries, electroactive devices, and photovoltaics) to original fluorinated elastomers, surfactants, thermoplastic elastomers, thermostables, and optical devices. PMID- 30011097 TI - Morphological evaluation of Prochilodus lineatus embryos after vitrification thawing in high-osmolarity cryoprotectant solution. AB - We aimed to vitrify embryos of Prochilodus lineatus in a high-osmolarity cryoprotectant solution, evaluating, after the vitrification-thawing process, their morphological changes. Thus, 240 embryos in the 20-somite phase (20S) were exposed for 20 min to one main internal cryoprotectant solution (1,2-propanediol PROP), divided into four immersion sequence steps of five minutes each. The first three steps were performed in solutions containing only a main internal cryoprotectant (PROP-2, 3 and 4 M), and the fourth step in a high-osmolarity solution combining internal (PROP + dimethyl sulphoxide-Me2 SO) and external cryoprotectants (sucrose-SUC). The final concentration of vitrification was PROP 5 M + Me2 SO 5 M + SUC 0.2 M. During vitrification, the straws exhibited a translucent solid appearance; however, during thawing, their structure became totally opaque and white. After thawing, the embryos suffered an increase in volume and presented morphological changes including protrusions on the surface of the yolk sac, yolk sac rupture, and optical vesicle degradation. On the inside, we observed intercellular spaces and a yolk syncytial layer (YSL) with altered chromatin. Yet, structures such as somites, neural tube, endoderm and epidermis presented cells with a nucleus and integral mitochondria. We conclude that the use of the tested cryoprotectant solution permits the formation of a vitreous solid and preserves part of the cells of the blastoderm. Yet, the heating protocol does not control recrystallization, resulting in the formation of serious morphological anomalies that prevent the preservation of the embryonic unit. PMID- 30011098 TI - Increasing methamphetamine doses inhibit glycogen synthase kinase 3beta activity by stimulating the insulin signaling pathway in substantia nigra. AB - Methamphetamine (MA), a highly abused psychostimulant, exerts neurotoxic effects on the dopaminergic system via several neurotoxicity mechanisms in the long-term administration. Since the effect of MA on the signaling insulin pathway is less studied, the current study was designed to evaluate the effect of escalating an MA regimen on different insulin signaling elements in substantia nigra (SN) and striatum of a rat. Increasing MA doses (1-14 mg/kg) were administrated intraperitoneally twice a day for 14 days in rats. In the control group, normal saline was injected in the same volume. On days 1, 14, 28, and 60 after MA discontinuation, molecular assessments were performed. Insulin receptor (IR) and insulin receptor substrate (IRS) 1 and 2 gene expression were evaluated using real-time polymerase chain reaction, and protein levels of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phospho-PI3K, Akt, phospho-Akt, glycogen synthase kinase 3beta (GSK3beta), and phospho-GSK3beta were measured by the Western blot analysis in SN and striatum. Messenger RNA levels of IR and insulin receptor substrate 2 were increased in SN, 1 day after the last injection. Although no changes were observed in PI3K, phospho-PI3K, Akt, phospho-Akt, and GSK3beta levels, increase in the level of inactive form of GSK3beta (phosphorylated on serine 9) was indicated in SN on day 28. In striatum, decreases in IR and phospho-Akt were demonstrated, without any change in other elements. Repeated escalating regimen of MA activated the insulin signaling pathway and inhibited GSK3beta activity in SN. This response, which did not occur in striatum, may act as an adaptive mechanism to prevent MA-induced neurotoxicity in dopaminergic cell bodies. PMID- 30011099 TI - Production Options for Psilocybin: Making of the Magic. AB - The fungal genus Psilocybe and other genera comprise numerous mushroom species that biosynthesize psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine). It represents the prodrug to its dephosphorylated psychotropic analogue, psilocin. The colloquial term "magic mushrooms" for these fungi alludes to their hallucinogenic effects and to their use as recreational drugs. However, clinical trials have recognized psilocybin as a valuable candidate to be developed into a medication against depression and anxiety. We here highlight its recently elucidated biosynthesis, the concurrently developed concept of enzymatic in vitro and heterologous in vivo production, along with previous synthetic routes. The prospect of psilocybin as a promising therapeutic may entail an increased demand, which can be met by biotechnological production. Therefore, we also briefly touch on psilocybin's therapeutic relevance and pharmacology. PMID- 30011100 TI - Response to Osteoporotic Vertebral Fracture Prevalence Varies Widely. PMID- 30011101 TI - Understanding the profile of Personal Alert Victoria clients who fall. AB - Personal response systems are used to support frail, older people, and people with disabilities to live independently in their own homes. This paper describes the patterns, characteristics, and outcomes of Personal Alert Victoria (PAV) clients who experience a fall. It also examines the current falls prevention referral practices of assessors who determine whether an older person would benefit from a personal response system. Deidentified data on clients from the PAV service provider from 2012 to 2014 were linked to routine data maintained by the Department of Health and Human Services in Victoria. Falls prevention referral practices of assessors were examined using an online survey. Personal response systems were most frequently activated because of a fall in this group of older people (n = 16,822; 44%). No demographic or clinical factors differentiated PAV clients who activated the system because of a fall compared to those who did not, despite a significant increase in the rate of falls-related system activations (p = 0.001) and hospitalisation (p < 0.001) between 2012 and 2014. Assessors believed that PAV clients were at increased risk of falls and frequently recommended falls prevention interventions such as strength and balance interventions (n = 112; 93%) in order to address this risk. This study has provided an insight into the issue of falls among PAV clients, which can help guide the tailoring of falls prevention interventions that can be integrated within existing service models. PMID- 30011102 TI - Health supports needed for homeless persons transitioning from hospitals. AB - Being homeless has a negative effect on health and the health needs of individuals experiencing homelessness are complex and challenging to address. As a result of limited access to and use of primary healthcare, the main point of entry into the healthcare system for individuals experiencing homelessness is often hospitals and emergency departments. Persons experiencing homelessness are commonly discharged from hospital settings to locations that do not support recovery or access to follow-up care (e.g. shelters or the street). This can be costly to both the healthcare system and to individuals' health and quality of life. We conducted a scoping review of the literature published between 2007 and 2017 to identify the types of health supports needed for persons experiencing homelessness who are discharged from the hospital. Thirteen literature sources met inclusion criteria and thematic data analyses by two researchers resulted in the identification of six themes related to the types of health supports needed for persons experiencing homelessness who are transitioning (i.e. being discharged) from the hospital. Using a community consultation approach, the scoping review themes were validated with 23 health and shelter service providers and included in our integrated findings. Themes included: (a) a respectful and understanding approach to care, (b) housing assessments, (c) communication/coordination/navigation, (d) supports for after-care, (e) complex medical care and medication management, and (f) basic needs and transportation. These themes were found to resonate with participants of the community consultation workshop. Recommendations for trauma-informed care and patient- or client-centred care approaches are discussed. PMID- 30011103 TI - Feasibility of quantitative ultrashort echo time (UTE)-based methods for MRI of peripheral nerve. AB - Peripheral nerves are a composite tissue consisting of neurovascular elements packaged within a well-organized extracellular matrix. Their composition, size, and anatomy render nerves a challenging medical imaging target. In contrast to morphological MRI, which represents the predominant approach to nerve imaging, quantitative MRI sequences can provide information regarding tissue composition. Here, we applied standard clinical Carr-Purcell-Meiboom-Gill (CPMG) and experimental three-dimensional (3D) ultrashort echo time (UTE) Cones sequences for quantitative nerve imaging including T2 measurement with single-component analysis, T2 * measurement with single-component and bi-component analyses, and magnetization transfer ratio (MTR) analysis. We demonstrated the feasibility and the high quality of single-component T2 *, bi-component T2 *, and MTR approaches to analyze nerves imaged with clinically deployed 3D UTE Cones pulse sequences. For 24 single fascicles from eight nerves, we measured a mean single-component T2 * of 22.6 +/-8.9 ms, and a short T2 * component (STC) with a mean T2 * of 1.7 +/ 1.0 ms and a mean fraction of (6.74 +/-4.31)% in bi-component analysis. For eight whole nerves, we measured a mean single-component T2 * of 16.7 +/-2.2 ms, and an STC with a mean T2 * of 3.0 +/-1.0 ms and a mean fraction of (15.56 +/-7.07)% in bi-component analysis. For nine fascicles from three healthy nerves, we measured a mean MTR of (25.2 +/-1.9)% for single fascicles and a mean MTR of (23.6 +/ 0.9)% for whole nerves. No statistically significant correlation was observed between any MRI parameter and routine histological outcomes, perhaps due to the small sample size and lack of apparent sample pathology. Overall, we have successfully demonstrated the feasibility of measuring quantitative MR outcomes ex vivo, which might reflect features of nerve structure and macromolecular content. These methods should be validated comprehensively on a larger and more diverse set of nerve samples, towards the interpretation of in vivo outcomes. These approaches have new and broad implications for the management of nerve disease, injury, and repair. PMID- 30011105 TI - Capacity building and social marketing promotes healthy lifestyle behaviour in an Australian Aboriginal community. AB - OBJECTIVE: We explored the effectiveness of a project targeting an Australian Aboriginal community. DESIGN: A collaborative approach included stakeholder interviews, an intercept survey, observations and Facebook insights. SETTING: Gippsland encompasses 41 557 km2 of Victoria and has an Aboriginal population of around 4000. PARTICIPANTS: Five stakeholders from local Aboriginal health/sports organisations were interviewed at 6 and 18 months. A total of 49 Aboriginal persons aged 16 years or more, who lived in Gippsland, were surveyed at a community event. Facebook engagement involved 933 people over a 4-week period. MAIN OUTCOME MEASURES: Reach was assessed at 6 and 18 months using Facebook likes and video views. Survey measures addressed campaign awareness, recall and attitudinal and behavioural change. RESULTS: The project provides organisations with skills development, social media production and online resources promoting sports and community events. Stakeholders and survey respondents valued local content, positive stories and awareness-raising elements. Two campaigns developed by state and regional organisations were adapted using locally developed social media with campaign messages. After 18 months, there were 2592 video views and 1738 likes. Forty-seven (69%) of the eligible attendees at the community event completed the survey. Thirty-three (70%) had seen the campaign; 20 (61%) subsequently thought about changing their behaviour and 13 (39%) changed their behaviour. CONCLUSION: The model was mutually beneficial. Partner organisations enabled project access to local events and project staff supported organisational development and event promotion. Social marketing engaged the community and prompted positive behaviour change. Formative work that is undertaken centrally might be useful for organisations to adapt for local campaigns. PMID- 30011104 TI - Wireless amplified NMR detector for improved visibility of image contrast in heterogeneous lesions. AB - To demonstrate the capability of a wireless amplified NMR detector (WAND) to improve the visibility of lesion heterogeneity without the use of exogenous contrast agents, a cylindrically symmetric WAND was constructed to sensitively detect and simultaneously amplify MR signals emitted from adjacent tissues. Based on a two-leg high-pass birdcage coil design, this WAND could be activated by a pumping field aligned along the main field (B0 ), without perturbing MR signal reception. Compared with an equivalent pair of external detectors, the WAND could achieve more than 10-fold gain for immediately adjacent regions. Even for regions with 3.4 radius distance separation from the detector's cylindrical center, the WAND was at least 1.4 times more sensitive than an equivalent pair of surface arrays or at least twice as sensitive as a single-sided external surface detector. When the WAND was inserted into a rat's rectum to observe adjacent tumors implanted beneath the mucosa, it could enhance the detection sensitivity of lesion regions, and thus enlarge the observable signal difference between heterogeneous tissues and clearly identify lesion boundaries as continuous lines in the intensity gradient profile. Hyperintense regions observable by the WAND existed due to higher levels of blood supply, which was indicated by a similar pattern of signal enhancement after contrast agent administration. By better observing the endogenous signal contrast, the endoluminal WAND could characterize lesions without the use of exogenous contrast agents, and thus reduce contrast induced toxicity. PMID- 30011106 TI - Direct Cross-Coupling of Allylic C(sp3 )-H Bonds with Aryl- and Vinylbromides by Combined Nickel and Visible-Light Catalysis. AB - An efficient protocol for the direct allylic C(sp3 )-H bond activation of unactivated tri- and tetrasubstituted alkenes and their functionalization with aryl- and vinylbromides by nickel and visible-light photocatalysis has been developed. The method allows C(sp2 )-C(sp3 ) formation under mild reaction conditions with good functional-group tolerance and excellent regioselectivity. PMID- 30011107 TI - Fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with solid organ transplants: an institutional experience and review of the literature. AB - Clostridium difficile, an anaerobic gram-positive, spore-forming bacillus, has become the most common cause of nosocomial infectious diarrhea, and is associated with increased mortality in all populations. Patients who have received solid organ transplants (SOT) are at increased risk of Clostridium difficile infection (CDI) and CDI recurrence (rCDI). This may be related to chronic immunosuppression, frequent antibiotic exposure, and increased or prolonged hospitalizations. Increased morbidity and mortality from CDI is well-described in SOT patients. Conventional treatments for index and recurrent CDI include vancomycin and fidaxomicin. Fecal microbiota transplantation has emerged as an effective and safe alternative for treating rCDI in the general population. Reports of its safety in certain immunocompromised populations, such as those with inflammatory bowel disease, appear reassuring, but outcomes among SOT patients are less well known. Here, we summarize the experiences published to date on the treatment of rCDI with FMT in SOT patient, and also describe our detailed FMT protocol and experience in treating a series of SOT patients with rCDI. In addition to reporting the safety and efficacy of our FMT experience, we also discuss the diagnostic challenges and considerations in this population of solid organ transplant recipients. PMID- 30011108 TI - Health and functional status, health events, use of healthcare services and costs associated with overactive bladder among the medically complex vulnerable elderly in the US. AB - AIMS: To assess the prevalence of overactive bladder (OAB) among medically complex vulnerable elderly (MCVE) patients in the United States and to compare health status measures, functional status, healthcare events, use of healthcare services and costs between MCVE patients with and without OAB. METHODS: Using the 2001-2010 Medicare Current Beneficiary Surveys, we defined the MCVE as those respondents who were >=65 years old with scores >=3 on the Vulnerable Elders Survey-13. OAB diagnosis codes or self-reported use of antimuscarinic medications were used to identify MCVE individuals with OAB. Multiple regression analyses were used to estimate the adjusted relationship between OAB and the outcome measures. RESULTS: The annual prevalence of OAB among the MCVE increased from 9.6% in 2001 to 13.5% in 2010. MCVE individuals with OAB were more likely to have experienced falls or fractures (odds ratio [OR] = 1.6; 95% confidence interval [CI]: 1.3-2.0), urinary tract infections (OR = 4.3; 95% CI: 3.5-5.4), institutionalization (OR = 1.9; 95% CI: 1.4-2.5), limitations in activity of daily living (ADL) (OR = 1.4; 95% CI: 1.1-1.7) and instrumental ADL (OR = 1.5; 95% CI: 1.2-2.0), hospital admission (OR = 1.6; 95% CI: 1.3-2.0) and emergency department admissions (OR = 1.6; 95% CI: 1.3-2.0) than those without OAB. MCVE individuals with OAB incurred, on average, $7188 (2013 dollars) more in healthcare costs than those without OAB. DISCUSSION/CONCLUSIONS: The prevalence of OAB in the MCVE population increased over time. OAB is associated with substantial clinical and economic burden. Further research is warranted to understand whether better management of the MCVE population with OAB may reduce healthcare resource use. PMID- 30011109 TI - Multi-parametric T2 * magnetic resonance fingerprinting using variable echo times. AB - The use of quantitative imaging biomarkers in the imaging of various disease states, including cancer and neurodegenerative disease, has increased in recent years. T1 , T2 , and T2 * relaxation time constants have been shown to be affected by tissue structure or contrast infusion. Acquiring these biomarkers simultaneously in a multi-parametric acquisition could provide more robust detection of tissue changes in various disease states including neurodegeneration and cancer. Traditional magnetic resonance fingerprinting (MRF) has been shown to provide quick, quantitative mapping of T1 and T2 relaxation time constants. In this study, T2 * relaxation is added to the MRF framework using variable echo times (TE). To demonstrate the feasibility of the method and compare incremental and golden angle spiral rotations, simulated phantom data was fit using the proposed method. Additionally, T1 /T2 /T2 */deltaf MRF as well as conventional T1 , T2 , and T2 * acquisitions were acquired in agar phantoms and the brains of three healthy volunteers. Golden angle spiral rotation was found to reduce inaccuracy resulting from off resonance effects. Strong correlations were found between conventional and MRF values in the T1 , T2 , and T2 * relaxation time constants of the agar phantoms and healthy volunteers. In this study, T2 * relaxation has been incorporated into the MRF framework by using variable echo times, while still fitting for T1 and T2 relaxation time constants. In addition to fitting these relaxation time constants, a novel method for fitting and correcting off resonance effects has been developed. PMID- 30011110 TI - Intragastric balloon therapy leads to normalization of brain magnetic resonance spectroscopic markers of diabetes in morbidly obese patients. AB - Elevated brain myo-inositol (m-Ins) concentration (a putative marker of neuroinflammation) has been reported in patients suffering from type 2 diabetes mellitus (T2DM). Obesity alone and T2DM have been found to be associated with a lower concentration of N-acetyloaspartate and N-acetylaspartylglutamate (tNAA, a marker of neuronal integrity, reflecting neuronal loss or metabolic derangement). It is not clear if these changes reverse with weight loss. The intra-gastric balloon (IGB) is an endoscopic bariatric therapy that leads to massive weight loss and improvement of glycemic control. In this study we evaluated if tNAA/tCr and m-Ins/tCr metabolite ratios are affected by weight loss, where tCr is the signal of creatine containing compounds. Twenty-three morbidly obese patients, 12 of them with T2DM (OD) and 11 without T2DM (OB), as well as 11 healthy controls of normal weight (CON), underwent single voxel spectroscopy at 3 T. Spectra were obtained within a region in the left parietal white matter one month before IGB insertion, three months after IGB insertion, and one month after IGB removal. Before IGB insertion, m-Ins/tCr was 15% higher in OD than in OB (p = 0.005) and 12% higher in OD than in CON (p = 0.03). m-Ins/tCr decreased significantly by 8% over the first three months after IGB insertion (p = 0.01) and remained normal after IGB removal. tNAA/tCr was normal in all groups throughout the study, pointing to normal brain metabolism. Normalization of m-Ins/tCr is consistent with remission of neuroinflammation in patients with T2DM. An evaluation of long term effects of IGB treatment is necessary. PMID- 30011111 TI - Truth disclosure on prognosis: Is it ethical not to communicate personalised risk of death? AB - Predicting risk of death based on personalised and objective clinical indicators is an improvement over intuition and clinical judgement. Risk assessment can benefit clinicians by improving prognostic certainty, and truth disclosure helps patients and families by preventing futile management. Some argue that consent should be obtained before a patient is given an estimate of their prognosis as disclosure of bad news can overburden patients. In this article, we argue that it is unethical not to use existing person-specific information to guide diagnosis and shared decision making on management in partnership with well-informed patients. Disclosure of a poor prognosis should be normalised in personalised medicine, performed incrementally and with sensitivity so that it is acceptable to patients, and only occur if patients want to know it. However, a requirement of consent for truth disclosure should not be mandatory. Despite some level of imprecision, personalised risk estimations can be used to tailor management to the patient's informed wishes and ensure that healthcare providers and families are acting ethically in the patient's best interest. PMID- 30011112 TI - Second cancers in Hodgkin's lymphoma long-term survivals: A 60-year single institutional experience with real-life cohort of 871 patients. AB - BACKGROUND AND PURPOSE: Appropriate surveillance guidelines for patients after successful treatment of Hodgkin's lymphoma (HL) are needed to reduce mortality of iatrogenic secondary cancers (SC). This large single institutional retrospective study analyses the risk of SC in HL patients treated outside of clinical trials over past decades. MATERIAL AND METHODS: Consecutive series of HL patients were analysed with median follow-up 12 years. Standardised incidence ratio (SIR) and absolute excess risk (AER) were calculated for site-specific risk of SC. RESULTS: In total of 871 patients (491 men; median age 34 years), chemotherapy alone, radiotherapy alone, and combined treatment underwent 36%, 40%, and 24% patients. 154 SC were found with significantly increased SIR = 2.9 and AER = 80.8 for all cancers except of nonmelanoma-skin cancer. SC-related death occurred in 71 patients (15% of those who died, 8% of whole cohort). The most common SC were lung (17.5% of all malignancies, SIR = 3.2), breast carcinoma (15.6%, SIR = 4.4), and haematological malignancy (non-Hodgkin's lymphoma SIR = 13.1; leukaemia SIR = 5.8). For SC within radiation field, the highest AER was in breast (AER = 46.9), colorectal (AER = 22.8), and lung cancer (AER = 17). CONCLUSIONS: Patients with HL are generally at great risk of developing SC, which is significantly increased especially by the use of radiotherapy. We suggested special follow-up schema for patients after initial HL treatment suitable for daily real-world clinical practice. The system depends on gender, form of HL treatment and especially the form of radiation therapy in terms of location of radiation fields. PMID- 30011113 TI - Novel non-invasive biomarkers diagnostic of acute rejection in renal transplant recipients: A systematic review. AB - BACKGROUND AND OBJECTIVES: Acute rejection is a significant complication detrimental to kidney transplant function. Current accepted means of diagnosis is percutaneous renal biopsy, a costly and invasive procedure. There is an urgent need to detect and validate non-invasive biomarkers capable of replacing the biopsy. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Comprehensive literature searches of Medline, EMBASE and Cochrane Central Register of Controlled Trials databases were performed. Eligible studies were included as per inclusion criteria and assessed for quality using the GRADE quality of evidence tool. Outcomes evaluated included biomarker diagnostic performance, number of patients/samples, mean age and gender ratio, immunosuppression regime, in addition to clinical applications of the biomarker(s) tested. PRISMA guidelines were followed. Where possible, statistical analysis of comparative performance data was performed. RESULTS: 23 studies were included in this review, including 19 adult, 3 paediatric and 1 mixed studies. A total of 2858 participants and 50 candidate non-invasive tests were identified. Sensitivity, specificity and area under the curve performance values ranged 36%-100%, 30%-100% and 0.55-0.98, respectively. CONCLUSIONS: Although larger, more robust multi-centre validation studies are needed before non-invasive biomarkers can replace the biopsy, numerous candidate tests have demonstrated significant promise for various facets of postoperative management. Suggested uses include: ruling out patients with a low risk of acute rejection to avoid the need for biopsy, non-invasive testing where the biopsy is contraindicated and a prompt diagnosis is needed, and integration into a serial blood monitoring protocol in conjunction with serum creatinine. PMID- 30011114 TI - Missense mutations have unexpected consequences: The McArdle disease paradigm. AB - McArdle disease is a disorder of muscle glycogen metabolism caused by mutations in the PYGM gene, encoding for the muscle-specific isoform of glycogen phosphorylase (M-GP). The activity of this enzyme is completely lost in patients' muscle biopsies, when measured with a standard biochemical test which, does not allow to determine M-GP protein levels. We aimed to determine M-GP protein levels in the muscle of McArdle patients, by studying biopsies of 40 patients harboring a broad spectrum of PYGM mutations and 22 controls. Lack of M-GP protein was found in muscle in the vast majority (95%) of patients, irrespective of the PYGM genotype, including those carrying missense mutations, with few exceptions. M-GP protein biosynthesis is not being produced by PYGM mutations inducing premature termination codons (PTC), neither by most PYGM missense mutations. These findings explain the lack of PYGM genotype-phenotype correlation and have important implications for the design of molecular-based therapeutic approaches. PMID- 30011116 TI - Case law update. PMID- 30011115 TI - Synthesis of Structurally Diverse N-Substituted Quaternary-Carbon-Containing Small Molecules from alpha,alpha-Disubstituted Propargyl Amino Esters. AB - N-containing quaternary stereocenters represent important motifs in medicinal chemistry. However, due to their inherently sterically hindered nature, they remain underrepresented in small molecule screening collections. As such, the development of synthetic routes to generate small molecules that incorporate this particular feature are highly desirable. Herein, we describe the diversity oriented synthesis (DOS) of a diverse collection of structurally distinct small molecules featuring this three-dimensional (3D) motif. The subsequent derivatisation and the stereoselective synthesis exemplified the versatility of this strategy for drug discovery and library enrichment. Chemoinformatic analysis revealed the enhanced sp3 character of the target library and demonstrated that it represents an attractive collection of biologically diverse small molecules with high scaffold diversity. PMID- 30011117 TI - Ensemble versus Local Restructuring of Core-shell Nickel-Cobalt Nanoparticles upon Oxidation and Reduction Cycles. AB - Bimetallic nanoparticles are widely studied, for example in catalysis. However, possible restructuring in the environment of use, such as segregation or alloying, may occur. Taken individually, state-of-the-art analytical tools fail to give an overall picture of these transformations. This study combines an ensemble analysis (near-ambient-pressure X-ray photoelectron spectroscopy) with a local analysis (environmental transmission electron microscopy) to provide an in situ description of the restructuring of core-shell nickel-cobalt nanoparticles exposed to cycles of reduction and oxidation. It reveals a partial surface alloying accompanied by fragmentation of the shell into smaller clusters, which is not reversible. Beyond this case study, the methodology proposed here should be applicable in a broad range of studies dealing with the reactivity of mono- or bi-metallic metal nanoparticles. PMID- 30011118 TI - Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis. AB - Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing. PMID- 30011119 TI - Silenced retrotransposons are major rasiRNAs targets in Arabidopsis galls induced by Meloidogyne javanica. AB - Root-knot nematodes (RKNs, Meloidogyne spp.) are sedentary biotrophic pathogens that establish within the vascular cylinder of plant roots, forming a gall and inducing several feeding cells, giant cells (GCs), essential for completion of their life cycle. GCs suffer gene expression changes, repeated mitosis and endoreduplication events. Transcriptomics has revealed that an extensive down regulation of transcripts, a molecular signature of early-developing galls and GCs that is conserved in tomato and Arabidopsis, may be achieved through small RNA (sRNA) gene silencing pathways. The role of some microRNAs (miRNAs) in plant RKN interactions has recently been addressed, but little is known about the regulatory roles of other sRNA types. Here, we perform a differential accumulation analysis to show which repeat-associated small interfering RNAs (rasiRNAs) are distinctive or enriched in early Arabidopsis galls vs. uninfected roots. Those distinctive from galls are preferentially located in pericentromeric regions with predominant sizes of 24 and 22 nucleotides. Gall-distinctive rasiRNAs target primarily GYPSY and COPIA retrotransposons, which show a marked repression in galls vs. uninfected roots. Infection tests and phenotypic studies of galls from Meloidogyne javanica in Arabidopsis mutants impaired in post transcriptional gene silencing and/or canonical RNA-directed DNA methylation (RdDM) pathways, as well as quantitative polymerase chain reaction analysis, suggest the implication of canonical and non-canonical RdDM pathways during gall formation, possibly through the regulation of retrotransposons. This process may be crucial for the maintenance of genome integrity during the reprogramming process of galls/GCs from their vascular precursor cells, and/or to ensure a faithful DNA replication during the repeated mitosis/endoreduplication that concurs with feeding site formation. PMID- 30011121 TI - Magnetic solid-phase extraction of pyrethroid pesticides in environmental water samples with CoFe2 O4 -embedded porous graphitic carbon nanocomposites. AB - Magnetic CoFe2 O4 -embedded porous graphitic carbon nanocomposites were prepared through a facile solid-phase thermal reaction with NaCl as a template. The material was applied in the magnetic solid-phase extraction process coupled with high performance liquid chromatography with a diode array detector to detect the trace fenpropathrin, cyhalothrin, S-fenvalerate, and bifenthrin in different water samples. The synthesis conditions of nanomaterial including glucose concentration and calcination time on extraction performance for pyrethroid pesticides have been investigated. Different magnetic solid-phase extraction parameters have been studied, such as the nanomaterial amount, solution pH, eluent types, adsorption time, and the reusability. Under the optimum conditions, good recoveries (80.2-110.9%) were achieved with relative standard deviations of 0.2-5.8%. There are probably hydrophobic interactions and dipole-dipole attractions between nanocomposites and the analytes. PMID- 30011120 TI - Molecular mechanisms that limit the costs of NLR-mediated resistance in plants. AB - Crop diseases cause significant yield losses, and the use of resistant cultivars can effectively mitigate these losses and control many plant diseases. Most plant resistance (R) genes encode immune receptors composed of nucleotide-binding and leucine-rich repeat (NLR) domains. These proteins mediate the specific recognition of pathogen avirulence effectors to induce defence responses. However, NLR-triggered immunity can be associated with a reduction in growth and yield, so-called 'fitness costs'. Recent data have shown that plants use an elaborate interplay of different mechanisms to control NLR gene transcript levels, as well as NLR protein abundance and activity, to avoid the associated cost of resistance in the absence of a pathogen. In this review, we discuss the different levels of NLR regulation (transcriptional, post-transcriptional and at the protein level). We address the apparent need for plants to maintain diverse modes of regulation. A recent model suggesting an equilibrium 'ON/OFF state' of NLR proteins, in the absence of a pathogen, provides the context for our discussion. PMID- 30011122 TI - The Meloidogyne graminicola effector Mg16820 is secreted in the apoplast and cytoplasm to suppress plant host defense responses. AB - On invasion of roots, plant-parasitic nematodes secrete effectors to manipulate the cellular regulation of the host to promote parasitism. The root-knot nematode Meloidogyne graminicola is one of the most damaging nematodes of rice. Here, we identified a novel effector of this nematode, named Mg16820, expressed in the nematode subventral glands. We localized the Mg16820 effector in the apoplast during the migration phase of the second-stage juvenile in rice roots. In addition, during early development of the feeding site, Mg16820 was localized in giant cells, where it accumulated in the cytoplasm and the nucleus. Using transient expression in Nicotiana benthamiana leaves, we demonstrated that Mg16820 directed to the apoplast was able to suppress flg22-induced reactive oxygen species production. In addition, expression of Mg16820 in the cytoplasm resulted in the suppression of the R2/Avr2- and Mi-1.2-induced hypersensitive response. A potential target protein of Mg16820 identified with the yeast two hybrid system was the dehydration stress-inducible protein 1 (DIP1). Bimolecular fluorescence complementation resulted in a strong signal in the nucleus. DIP1 has been described as an abscisic acid (ABA)-responsive gene and ABA is involved in the biotic and abiotic stress response. Our results demonstrate that Mg16820 is able to act in two cellular compartments as an immune suppressor and targets a protein involved in the stress response, therefore indicating an important role for this effector in parasitism. PMID- 30011123 TI - Massive up-regulation of LBD transcription factors and EXPANSINs highlights the regulatory programs of rhizomania disease. AB - Rhizomania of sugar beet, caused by Beet necrotic yellow vein virus (BNYVV), is characterized by excessive lateral root (LR) formation leading to dramatic reduction of taproot weight and massive yield losses. LR formation represents a developmental process tightly controlled by auxin signaling through AUX/IAA-ARF responsive module and LATERAL ORGAN BOUNDARIES DOMAIN (LBD) transcriptional network. Several LBD transcription factors play central roles in auxin-regulated LR development and act upstream of EXPANSINS (EXPs), cell wall (CW)-loosening proteins involved in plant development via disruption of the extracellular matrix for CW relaxation and expansion. Here, we present evidence that BNYVV hijacks these auxin-regulated pathways resulting in formation LR and root hairs (RH). We identified an AUX/IAA protein (BvAUX28) as interacting with P25, a viral virulence factor. Mutational analysis indicated that P25 interacts with domains I and II of BvAUX28. Subcellular localization of co-expressed P25 and BvAUX28 showed that P25 inhibits BvAUX28 nuclear localization. Moreover, root-specific LBDs and EXPs were greatly upregulated during rhizomania development. Based on these data, we present a model in which BNYVV P25 protein mimics action of auxin by removing BvAUX28 transcriptional repressor, leading to activation of LBDs and EXPs. Thus, the evidence highlights two pathways operating in parallel and leading to uncontrolled formation of LRs and RHs, the main manifestation of the rhizomania syndrome. PMID- 30011124 TI - Antimony-Functionalized Phosphine-Based Photopolymer Networks. AB - The synthesis of phosphane-ene photopolymer networks, where the networks are composed of crosslinked tertiary alkyl phosphines are reported. Taking advantage of the rich coordination chemistry of alkyl phosphines, stibino-phosphonium and stibino-bis(phosphonium) functionalized polymer networks could be generated. Small-molecule stibino-phosphonium and stibino-bis(phosphonium) compounds have been well characterized previously and were used as models for spectroscopic comparison to the macromolecular analogues by NMR and XANES spectroscopy. This work reveals that the physical and electronic properties of the materials can be tuned depending on the type of coordination environment. These materials can be used as ceramic precursors, where the Sb-functionalized polymers influence the composition of the resulting ceramic. PMID- 30011125 TI - Xanthomonas oryzae pv. oryzae chemotaxis components and chemoreceptor Mcp2 are involved in the sensing of constituents of xylem sap and contribute to the regulation of virulence-associated functions and entry into rice. AB - The Xanthomonas group of phytopathogens causes several economically important diseases in crops. In the bacterial pathogen of rice, Xanthomonas oryzae pv. oryzae (Xoo), it has been proposed that chemotaxis may play a role in the entry and colonization of the pathogen inside the host. However, components of the chemotaxis system, including the chemoreceptors involved, and their role in entry and virulence, are not well defined. In this study, we show that Xoo displays a positive chemotaxis response to components of rice xylem sap-glutamine, xylose and methionine. In order to understand the role of chemotaxis components involved in the promotion of chemotaxis, entry and virulence, we performed detailed deletion mutant analysis. Analysis of mutants defective in chemotaxis components, flagellar biogenesis, expression analysis and assays of virulence-associated functions indicated that chemotaxis-mediated signalling in Xoo is involved in the regulation of several virulence-associated functions, such as motility, attachment and iron homeostasis. The ?cheY1 mutant of Xoo exhibited a reduced expression of genes involved in motility, adhesins, and iron uptake and metabolism. We show that the expression of Xoo chemotaxis and motility components is induced under in planta conditions and is required for entry, colonization and virulence. Furthermore, deletion analysis of a putative chemoreceptor mcp2 gene revealed that chemoreceptor Mcp2 is involved in the sensing of xylem sap and constituents of xylem exudate, including methionine, serine and histidine, and plays an important role in epiphytic entry and virulence. This is the first report of the role of chemotaxis in the virulence of this important group of phytopathogens. PMID- 30011126 TI - Viroid-derived small RNA induces early flowering in tomato plants by RNA silencing. AB - Viroid infection often leads to early flowering in the host plant. This report describes the targeting of the FRIGIDA-like protein 3 (FRL3) mRNA in tomato plants by a small RNA derived from the conserved left terminal region of the potato spindle tuber viroid (PSTVd). This targeting leads to the silencing of the FRL3 mRNA. Viroid infection assays using a severe variant of PSTVd induced early flowering in tomato plants by the down-regulation of greater amounts of the target than did a mild PSTVd variant. The targeting of the FRL3 mRNA by RNA silencing was validated by both an artificial microRNA experiment transiently expressing viroid-derived small RNAs in tomato plants, and by 5' RNA ligase mediated rapid amplification of cDNA ends (RACE). These data unambiguously demonstrated the role of small RNAs in the early flowering seen in viroid infected plants. PMID- 30011127 TI - Using Fluorescence Anisotropy for Ligand Binding Kinetics of Membrane Proteins. AB - Determining ligand binding kinetics provides an indirect route to probe the functional capabilities of the binding pocket of a membrane protein receptor. Presented in this unit are four ligand-binding protocols that provide data useful for characterizing membrane proteins, including equilibrium binding, thermostability, competitive ligand binding, and kinetic ligand binding. These techniques use fluorescence anisotropy, which is safer, less costly, and simpler to execute than radioactive ligand binding. Each protocol may be used on its own or in combination with others to quantify a number of ligand binding constants. (c) 2018 by John Wiley & Sons, Inc. PMID- 30011129 TI - RaxM regulates the AvrXa21 (RaxX)-mediated immune response. AB - Xanthomonas oryzae pv. oryzae (Xoo) is the causal agent of rice bacterial blight disease, which causes a reduction in rice production. The interaction between Xoo and rice is a model for the study of the gene-for-gene hypothesis, in which a resistance (R) gene encoding a product interacts with an effector molecule encoded by a corresponding bacterial avirulence (avr) gene. Rice XA21 functions as a plant innate immune receptor (R protein) and recognizes the avirulence protein (RaxX) of Xoo to induce the immune response and cope with pathogen attack. The sulphuration of RaxX by the tyrosine sulphotransferase RaxST is essential to its activity. The expression of raxST is regulated by the RaxH/RaxR and phoP/phoQ two-component systems. However, the regulation of raxX expression remains unclear. Here, we showed that a gene (raxM) encodes a small protein, which functions as a regulator of raxX expression. raxX and raxM are located upstream of raxST. Transcriptional analysis indicates that raxX and raxM are separately transcribed and the promoter of raxX is located at the raxM coding region. The RaxM protein regulates its own and raxX expression, and is required for the XA21-mediated immunity response. Therefore, we identified a regulator of raxX expression and of the Xoo-rice interaction. Our findings suggest that RaxX is not only regulated at the post-translational level, but also at the transcriptional level. PMID- 30011128 TI - Human Urine-Derived Stem Cell Differentiation to Endothelial Cells with Barrier Function and Nitric Oxide Production. AB - Endothelial cells (ECs) play a key role in revascularization within regenerating tissue. Stem cells are often used as an alternative cell source when ECs are not available. Several cell types have been used to give rise to ECs, such as umbilical cord vessels, or differentiated from somatic stem cells, embryonic, or induced pluripotent stem cells. However, the latter carry the potential risk of chronic immune rejection and oncogenesis. Autologous endothelial precursors are an ideal resource, but currently require an invasive procedure to obtain them from the patient's own blood vessels or bone marrow. Thus, the goal of this study was to determine whether urine-derived stem cells (USCs) could differentiate into functional ECs in vitro. Urine-derived cells were then differentiated into cells of the endothelial lineage using endothelial differentiation medium for 14 days. Changes in morphology and ultrastructure, and functional endothelial marker expression were assessed in the induced USCs in vitro. Grafts of the differentiated USCs were then subcutaneously injected into nude mice. Induced USCs expressed significantly higher levels of specific markers of ECs (CD31, vWF, eNOS) in vitro and in vivo, compared to nondifferentiated USCs. In addition, the differentiated USC formed intricate tubular networks and presented similar tight junctions, and migration and invasion ability, as well as ability to produce nitric oxide (NO) compared to controls. Using USCs as autologous EC sources for vessel, tissue engineering strategies can yield a sufficient number of cells via a noninvasive, simple, and low-cost method suitable for rapid clinical translation. Stem Cells Translational Medicine 2018 Stem Cells Translational Medicine 2018;7:686-698. PMID- 30011130 TI - Suppression of nbe-miR166h-p5 attenuates leaf yellowing symptoms of potato virus X on Nicotiana benthamiana and reduces virus accumulation. AB - MicroRNAs (miRNAs) play essential roles in plant development. There is increasing evidence that changed expression of miRNAs in virus-infected plants contributes to the development of viral symptoms. Here, we analysed the altered expression of miRNAs of Nicotiana benthamiana in response to Potato virus X (PVX) by Illumina Solexa sequencing. One of the 21 miRNAs significantly affected, nbe-miR166h-p5, was closely associated with viral symptoms. Using the Tobacco rattle virus-based miRNA suppression (VbMS) system, we found that the suppression of nbe-miR166h-p5 in plants caused leaves to turn dark green with increased chlorophyll. When PVX was inoculated on nbe-miR166h-p5-suppressed plants, the leaf yellowing symptom of PVX was largely attenuated with less reduction in chlorophyll content, and the accumulation of PVX was decreased. nbe-miR166h-p5 was also up-regulated in plants infected by Turnip mosaic virus (TuMV), and its suppression attenuated the leaf yellowing symptom of TuMV and decreased viral accumulation. Three potential targets of nbe-miR166h-p5 were identified. The results indicate the association of nbe-miR166h-p5 with symptoms of PVX and also with those of TuMV, providing useful information on the relationship between miRNA and viral infection. PMID- 30011131 TI - Production of Human beta-Actin Using a Bacterial Expression System with a Cold Shock Vector. AB - Actin is one of the most abundant proteins in the cytoplasm of eukaryotic cells and plays important roles in a variety of cellular functions. However, it has been difficult to produce actin in substantial amounts using bacterial expression systems. In this article, a new method is described for the production of recombinant actin in bacterial cells. Human beta-actin (His-tagged) can be expressed using a cold shock vector, pCold, in a bacterial expression system and then separated with a Ni-chelating resin, followed by a polymerization/depolymerization cycle or column chromatography with the Ni chelating resin. The purified recombinant beta-actin shows normal polymerization ability compared with commercially available beta-actin purified from human platelets. This article also describes the preparation of mutant actin(G168R). This purified mutant exhibits impaired polymerization ability. The system and procedures described here will provide a useful method for the production of actin isoforms and their mutants. (c) 2018 by John Wiley & Sons, Inc. PMID- 30011132 TI - 1,8-Naphthalimide-Substituted BODIPY Dyads: Synthesis, Structure, Properties, and Live-Cell Imaging. AB - A set of 1,8-naphthalimide (NPI)-substituted 4,4-difluoroboradiaza-s-indacene (BODIPY) dyads 1 a-1 c were designed and synthesized by the Pd-catalyzed Sonogashira cross-coupling reaction of ethynyl substituted NPI 1 with the meso-, beta-, and alpha-halogenated BODIPYs a, b, and c, respectively. The BODIPY 1 c exhibits redshifted absorption, which suggests better electronic communication with substitution at the alpha-position of BODIPY compared with at the meso and beta positions, which was further supported by time-dependent DFT calculations. The optical band gap follows the order 1 a>1 b>1 c. The single-crystal X-ray structures of dyads 1 a-1 c are reported, which reflect planar orientations of the BODIPY units with respect to the NPIs. The DFT-optimized structures show good correlation with the experimental data obtained from the single-crystal X-ray structures. The packing diagram of 1 a shows a sheet-like arrangement, 1 b forms a ladder-like structural motif, and 1 c forms a complex 3D structural arrangement. The dyads 1 a-1 c show low cytotoxicity (IC50 >100 MUm). The confocal microscopy studies with HeLa and A375 cells (when treated with dyads 1 a 1 c) show that all the dyads easily enter the cell membrane and show significant multicolor intracellular fluorescence covering the entire visible range with clear emissions in blue, green, and red channels. PMID- 30011133 TI - Development of an analytical strategy to identify and classify the global chemical constituents of Ziziphi Spinosae Semen by using UHPLC with quadrupole time-of-flight mass spectrometry combined with multiple data-processing approaches. AB - According to traditional Chinese medical theory, Ziziphi Spinosae Semen needs to be stir-fried before clinical application for its sedative-hypnotic effect enhancement. A rapid and comprehensive analysis strategy of ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and multiple data analysis platforms was developed for the efficient and sensitive identification of components in crude and parched Ziziphi Spinosae Semen to explore the composition changes that happen during the stir-frying process. Both positive and negative ion modes were applied for mass spectrometry detection, and 40 components were identified from crude and parched Ziziphi Spinosae Semen, respectively. Principal component analysis and t-test were applied to find differences between crude and parched Ziziphi Spinosae Semen. As a result, Ziziphi Spinosae Semen samples could be clearly divided into two groups according to their processing methods, and 19 key markers that contributed to the classification significantly (P < 0.05) were found. This kind of change in contents of components might be responsible for the recommended clinical application of parched Ziziphi Spinosae Semen. PMID- 30011134 TI - Blood plasma level determination using an automated LC-MSn screening system and electronically stored calibrations exemplified for 22 drugs and two active metabolites often requested in emergency toxicology. AB - Fast and comprehensive qualitative and quantitative methods preferably by gas chromatography-mass spectrometry (GC-MS) and/or liquid chromatography-mass spectrometry (LC-MS) are needed to support the (differential) diagnosis of acute poisonings in emergency toxicology. One option is a commercially available qualitative screening solution based on LC-MSn (Bruker Daltonik ToxtyperTM, TT). Identified and toxicologically relevant compounds should be quantified to assess severity of poisonings. The aim of the present study was to test the TT system for quantification simultaneous with the screening process in blood plasma exemplified for 22 relevant drugs and two active metabolites. A standard liquid liquid extraction was used for sample work-up followed by 1:5 dilution of the final extracts. They were analyzed using the TT system consisting of a Bruker amaZon speed ion trap and a Thermo Fisher Dionex Ultimate 3000 LC system. Plasma levels were assessed using full-scan data and an electronically stored five-point calibration. The calibration model was linear for the studied ranges and could be used for at least two months. The method was validated according to international guidelines. The acceptance criteria recommended for emergency toxicology for accuracy and precision were fulfilled for all tested compounds, but bromazepam, lorazepam, oxycodone, and prothipendyl could reliably be determined only above the therapeutic range. In conclusion, the presented procedure allowed the combination of a comprehensive LC-MSn screening with fast automated assessment of plasma levels for emergency toxicology of tested compounds. PMID- 30011136 TI - Prize Winners at the 7th EuCheMS Chemistry Congress European Chemistry Gold Medal: B. L. Feringa / European Sustainable Chemistry Award: P. J. Dyson / August Wilhelm von Hofmann Memorial Medal: M. Graetzel. PMID- 30011135 TI - Knockdown of a mucin-like gene in Meloidogyne incognita (Nematoda) decreases attachment of endospores of Pasteuria penetrans to the infective juveniles and reduces nematode fecundity. AB - Mucins are highly glycosylated polypeptides involved in many host-parasite interactions, but their function in plant-parasitic nematodes is still unknown. In this study, a mucin-like gene was cloned from Meloidogyne incognita (Mi-muc-1, 1125 bp) and characterized. The protein was found to be rich in serine and threonine with numerous O-glycosylation sites in the sequence. Quantitative real time polymerase chain reaction (qRT-PCR) showed the highest expression in the adult female and in situ hybridization revealed the localization of Mi-muc-1 mRNA expression in the tail area in the region of the phasmid. Knockdown of Mi-muc-1 revealed a dual role: (1) immunologically, there was a significant decrease in attachment of Pasteuria penetrans endospores and a reduction in binding assays with human red blood cells (RBCs), suggesting that Mi-MUC-1 is a glycoprotein present on the surface coat of infective second-stage juveniles (J2s) and is involved in cellular adhesion to the cuticle of infective J2s; pretreatment of J2s with different carbohydrates indicated that the RBCs bind to J2 cuticle receptors different from those involved in the interaction of Pasteuria endospores with Mi-MUC-1; (2) the long-term effect of RNA interference (RNAi) mediated knockdown of Mi-muc-1 led to a significant reduction in nematode fecundity, suggesting a possible function for this mucin as a mediator in the interaction between the nematode and the host plant. PMID- 30011137 TI - The diagnostic and prognostic value of copeptin in cardiovascular disease, current status, and prospective. AB - Copeptin is a glycosylated peptide derived from the cleavage of the precursor of arginine-vasopressin. In contrast to arginine-vasopressin, copeptin is a stable molecule and can easily be measured using a simple rapid assay. The serum concentration of copeptin is increased in several clinical conditions, including hypertension, chronic kidney disease, and, of special interest in this review, in cardiovascular diseases. The diagnostic and prognostic value of copeptin in different cardiovascular diseases (acute coronary syndrome, stable coronary artery disease, congestive heart failure, and acute ischemic stroke) has been reviewed in this article, to provide an understanding of how its measurement may be applied to improve the management of these conditions. PMID- 30011138 TI - Multimodal integration of diffusion MRI for better characterization of tissue biology. AB - The contrast in diffusion-weighted MR images is due to variations of diffusion properties within the examined specimen. Certain microstructural information on the underlying tissues can be inferred through quantitative analyses of the diffusion-sensitized MR signals. In the first part of the paper, we review two types of approach for characterizing diffusion MRI signals: Bloch's equations with diffusion terms, and statistical descriptions. Specifically, we discuss expansions in terms of cumulants and orthogonal basis functions, the confinement tensor formalism and tensor distribution models. Further insights into the tissue properties may be obtained by integrating diffusion MRI with other techniques, which is the subject of the second part of the paper. We review examples involving magnetic susceptibility, structural tensors, internal field gradients, transverse relaxation and functional MRI. Integrating information provided by other imaging modalities (MR based or otherwise) could be a key to improve our understanding of how diffusion MRI relates to physiology and biology. PMID- 30011140 TI - [In Process]. PMID- 30011141 TI - Parents'opinions of the changes in their children's epilepsy treatment during the transition from childhood to adulthood. AB - Objective: Patients with childhood-onset epilepsy often need continued epilepsy treatment into adulthood. We investigated parents' opinions of the changes in their children's epilepsy treatment during the transition from childhood to adulthood using questionnaires and formulated agendas to build the appropriate medical treatment system for epilepsy. Methods: We distributed questionnaires to parents of patients with epilepsy who were 12 to 18 years old. Results: We distributed 176 questionnaires, and analyzed 79 (45%) questionnaires. Most parents (59%) wanted their child to continue treatment for epilepsy in the pediatrics department because of confidence in the current treatment environment. Most parents (73%) were anxious about their child not being treated in the pediatrics department during future epilepsy medical treatments because of concerns about whether a proper handover from the pediatrics department to other departments is possible. No parent was recommended the departmental transition by the primary pediatrician to other courses for future epilepsy treatment, while 19% of par-ents had a sense of incongruity regarding epilepsy treatment at the current pediatrics department. Parents who were anxious about future epilepsy treatments had significantly fewer general-school students than parents without anxiety. In addition, their children had more seizures than children of parents who were not anxious. Furthermore, they wanted their child to continue treatment for epilepsy in the pediatrics department more than the parents without anxiety. Conclusions: Approximately 70% of the parents were anxious about obtaining future epilepsy treatment in clinical departments other than the pediatrics department. To build a satisfactory medical treatment system for patients with epilepsy having different backgrounds and requiring continued treatment in adulthood, it is important to create a cooperating network consisting of pediatricians, neurologists, neurosurgeons, psychiatrists, and epileptologists. PMID- 30011142 TI - Successful immunoglobulin treatment in a case of epileptic encephalopathy. AB - A 6-year-old boy with normal development experienced tonic-clonic seizures and myoclonus. His electroencephalogram showed epileptic discharge and he was administered antiepileptic drugs ; however, they were ineffective. Antiepileptic drugs were discontinued temporarily because of no ictal recordings. He could not walk unaided and his speech reduced gradually. He was admitted to our hospital at the age of seven years and eight months. He experienced daily tonic-clonic seizures and myoclonus. Epileptic encephalopathy related to autoimmunity was suspected as he had psychomotor regression and his cerebrospinal and serum anti glutamate receptor antibody (anti-GluR) levels were elevated. After being administered immunoglobulins, his motor and cognitive functions improved and his seizures almost stopped. After one year, he could walk unaided and speak fluently. We strongly suspect an autoimmune reaction to be the pathological cause because of the effectiveness of immunoglobulin treatment. Immunoglobulin interventions should be considered in patients with unknown-cause, sub-acute onset, and destructively progressive epileptic encephalopathy. PMID- 30011143 TI - A case of acute encephalopathy presenting with transient functional disability in various new tasks and hypoperfusion of the right frontal and temporal lobes on SPECT. AB - We report the case of a 5-year-old boy with acute encephalopathy presenting with transient executive dysfunction such as functional disability in various new tasks and hypoperfusion of the right frontal and temporal lobes on single photon emission tomography (SPECT). He presented with a 2-day history of disturbed consciousness, and electroencephalography in an awaked state showed diffuse high voltage slow waves. Although MRI did not show any abnormality 3 days after initial onset of illness, SPECT showed hypoperfusion of the right frontal and temporal lobes at the same time. At 20 days after onset, the Kaufman assessment battery for children (K-ABC) test showed that sequential processing scale scores were significantly lower than simultaneous processing scale and achievement scale scores. He showed transient executive dysfunction such as functional disability in various new tasks at the same time. Abnormal brain perfusion on SPECT was improved at 8 months after onset and the sequential processing scale of K-ABC was likewise improved at 12 months after onset. These findings suggest that SPECT is helpful for diagnosing pathophysiological mechanisms with acute encephalopathy, and the combination of neuropsychological examination and SPECT study is useful for evaluating higher brain dysfunctions such as executive dysfunction. PMID- 30011145 TI - Neuroradiologists and magnetic resonance imaging. PMID- 30011144 TI - "New continuous tracheal suction technique" used for patients with severe physical and mental disabilities or intractable neurological disease. PMID- 30011146 TI - Importance of the multisystem follow-up in patients with tuberous sclerosis complex. AB - Objective: Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by the formation of hamartoma in multiple organ systems of the body. However, without a well-established cooperative system involving related departments, some organ lesions might be overlooked until symptoms appear or even until the disorder progresses. Therefore, the purpose of this study is to investigate the current status of follow-ups in the TSC patients in the Department of Child Neurology at Okayama University Medical Hospital. Methods: We performed a retrospective chart review of 38 patients with TSC who visited our hospital at least twice between January 2005 and December 2014. Patients were between 3 years and 48 years of age at their latest visit. We divided the patients into a child group and an adult group, and investigated the patients' follow-up data while focusing on the various multiorgan systems. Results: The follow-ups were well conducted in the child group in terms of every organ. In the adult group, neuroimaging tests were unsatisfactorily performed. The kidney has not been examined in seven patients more than five years even though these patients all had kidney lesions. The lung was not been examined in 7 out of 14 female patients over 18 years of age who are most at risk for lymphangioleiomyomatosis (LAM). In 12 out of 18 child patients, echocardiograms were performed every few years, while electrocardiograms to assess underlying conduction defects were rarely performed in either age group. Conclusions: In Europe, guidelines for the management of TSC have been well established. However, in our hospital, the multiorgan system follow-up is not satisfactorily performed especially in adult patients. We decided the establishment of a TSC board in our hospital for the management of this multiorgan disorder. PMID- 30011147 TI - Trends in the prevalence and characteristics of unilateral spastic cerebral palsy in patients born between 1988 and 2007 in Okinawa, Japan. AB - Objective: The objective of this study was to investigate the trends in the prevalence and characteristics of unilateral spastic cerebral palsy among children born between 1988 and 2007 in Okinawa, Japan. Method: We conducted a surveillance of children with cerebral palsy using the local cerebral palsy registration system. For analysis purposes, the study was divided into two periods: periodI (from 1988 to 1997) and periodII (from 1998 to 2007). We performed a chi-squared test and Poisson regression analysis. Result: We observed a significant trend for an increased prevalence of unilateral spastic cerebral palsy in periodII (p<0.01). The number of children with unilateral spastic cerebral palsy who were born with birth weights of 1500 g or more and/or a gestational age of 32 weeks or more was increased in periodII. In addition, brain magnetic resonance imaging and computed tomography scans showed that porencephaly and periventricular white matter damage were common findings in preterm children of gestational age less than 31 weeks in period II. The most frequently observed neuroimaging feature in children with a gestational age of over 32 weeks was brain infarction. Conclusion: We found a trend for an increased prevalence of unilateral spastic cerebral palsy in periodII. However, the cause of this increase is as yet unknown. PMID- 30011148 TI - Angular acceleration and angular jerk of elbow extension-flexion movement as parameters for discriminating a sequential transform of spontaneous movements in early infants. AB - Objective: We assessed the root mean square (RMS) of angular acceleration and the RMS of an angular jerk as expressions of the transformation of spontaneous movements in early infancy. Methods: During 36-56 weeks post-menstrual age (PMA), 15 premature infants (6 male, 9 female; 36 weeks PMA>) were measured every 4 weeks. A three-dimensional motion analyzer (Fastrak system; Polhemus Inc.) was used to measure spontaneous movements of the upper right limb in the supine infants. Upper limb position data were used to calculate the RMS of angular acceleration and the RMS of angular jerk at the elbow. The calculated data were classified into three terms: 36th and 40th week PMA (termI), the 44th and 48th week PMA (termII), and the 52nd and 56th week PMA (termIII). The typical value was the mean value for each term. Results: The RMS of angular acceleration in termII was significantly less than that of termI (p<0.05). The RMS values of angular jerk in termII and termIII were significantly less than that of termI (p<0.05). Conclusion: The RMS of angular acceleration and the RMS of the angular jerk are useful for expressing changes in the strength of spontaneous movements of elbow extension-flexion movements. PMID- 30011149 TI - Anti-epileptics alter hypothyroidism of patients with severe motor and intellectual disabilities. AB - Objective: Anti-epileptic drugs, such as carbamazepine (CBZ) or phenytoin, may induce hypothyroidism in epilepsy patients. We assessed thyroid function of chronic patients with severe motor and intellectual disabilities (SMID) in our hospital. Methods: We examined thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free thyronine (fT3) in 73 patients with SMID (47 men and 26 women, average age 48.4 years, range 30-68 years) without thyroid hormone supplement therapy. We determined the relationship between the thyroid function of patients taking the anti-epileptic drugs CBZ, valproate (VPA), and phenobarbital, other medications including anti-psychotic drugs, and treatments without anti-epileptic or anti-psychotic drugs. Results: TSH levels were not significantly different between the groups taking CBZ (CBZ+med), other anti-epileptic drugs or anti psychotic drugs (CBZ-med), and only medications without anti-epileptic or anti psychotic drugs (Non-med). The CBZ+med group had significantly lower fT4 levels than the CBZ-med or Non-med groups. There was a negative correlation between thyroid function level and the phenobarbital groups. TSH levels of the VPA+med group were significantly higher than VPA-med and Non-med group; fT3 and fT4 levels were not significantly different. Conclusions: Our results indicate that hypothyroidism may be present in patients with SMID taking anti-epileptic drugs. This suggests it is important to regularly measure thyroid function in patients with SMID taking anti-epileptic drugs, especially CBZ. PMID- 30011150 TI - Treatment of self-injurious behaviors in Lesch-Nyhan syndrome with S adenosylmethionine. AB - An 11-year-old boy with Lesch-Nyhan syndrome (LNS) had persistently injured himself by biting his lips and buccal mucosa since infancy. Risperidone was only partially effective in suppressing this behavior. Oral administration of S adenosylmethionine (SAMe), involving increasing the dose from 400 mg to 1 g, resulted in the amelioration of self-injurious behavior and anxiety as well as marked improvement in his self-esteem, performance at school, and friendships. No adverse effects were noted. SAMe may have a favorable effect on symptoms of LNS by activating monoaminergic pathways and/or increasing the adenosine pool in the salvage pathway of guanosine monophosphate synthesis. Defects in these pathways have been essentially implicated in the neurological pathophysiology of LNS. PMID- 30011151 TI - A case of CDKL5 disorder: improved ADL by simple treatment strategy for intractable epileptic seizures. AB - CDKL5 gene mutations are the cause of symptomatic infantile epilepsy in some patients. Such patients present with partial seizures and characteristic hand movements that are often observed in patients with Rett syndrome. This clinical entity has recently been recognized as CDKL5 disorder. In a girl with CDKL5 disorder, who had been treated with combinatory therapy using many anti-epileptic drugs, we were able to control the seizures with valproate monotherapy. As a result of the monotherapy, the patient's seizures ameliorated temporarily and her quality of life improved. Some patients show improvement in seizures during the natural course of CDKL5 disorder. Therefore, there is a possibility that this was also the case in our patient. However, the patient and her family were satisfied with the improvement in quality of life after the withdrawal of the multi-drug combinatory therapy. Thus, it is important to select the best therapy for patients with intractable epilepsy through long term follow-up. PMID- 30011152 TI - A case of Dravet syndrome complicated by human herpesvirus-6 infection-associated acute encephalopathy and choreoathetosis. AB - We report the case of a 14-month-old girl with Dravet syndrome carrying a splice site mutation of c. 1170+1G>A on neuronal sodium channel alpha 1 subunit (SCN1A). She had a history of recurrent febrile or afebrile seizures since 4 months of age and developed acute encephalopathy due to infection with human herpesvirus-6, which presented with high grade fever, severe consciousness disturbances, and prolonged and clustered seizures. Electroencephalography showed a generalized slow activity. Intensive treatments, including mechanical ventilation, continuous thiopental infusion, and high-dose steroid therapy were initiated, and she gradually recovered. During the recovery phase, choreoathetosis-like involuntary movements appeared on the face and limbs, which were treated successfully with haloperidol. MRI findings during the acute phase were normal; however, diffuse cerebral atrophy became evident during the recovery phase. Single photon emission computed tomography (SPECT) of the brain revealed decreased cerebral perfusion over bilateral frontal and temporal lobes; however, perfusion of the occipital lobes, basal ganglia, and cerebellum remained normal. The patient showed serious developmental regression at discharge, with the loss of head control and meaningful words. Patient's clinical course and the findings of SPECT resembled those of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), with the exception of lack of reduced diffusion of the subcortical white matter on the acute phase MRI and the prolonged and severe clinical symptoms. It has been reported that patients with Dravet syndrome are prone to complications, including various types of acute encephalopathies. Therefore, clinicians should carefully manage prolonged febrile seizures in patients with Dravet syndrome. PMID- 30011153 TI - A case report of mitochondrial respiratory chain disorder in the neonatal period for which home mechanical ventilation was introduced. AB - We report the case of a patient born with extreme muscle hypotonia, respiratory failure, and slightly elevated serum levels of lactic acid. Histochemical examination and mitochondrial respiratory chain enzyme activities of a muscle biopsy specimen revealed reduced activities of complexes I, III, and IV, diagnostic of mitochondrial respiratory chain disorder. Hypertrophic cardiomyopathy developed as a complication and additional therapy was administered at 3 months after birth. He was able to be discharged to home on applied home mechanical ventilation with tracheotomy at 1 year old. The patient survived until 4 years and 10 months of age, upon which he died of bronchitis. Early-onset mitochondrial respiratory chain disorder shows very poor prognosis and long-term survival has not been reported. Prompt assessment of mitochondrial respiratory chain enzyme activities is necessary for the diagnosis of congenital nonspecific multiple-organ failure, and early intervention may achieve better prognosis for mitochondrial respiratory chain disorder. PMID- 30011154 TI - An infant in whom contrast-enhanced fluid attenuated inversion recovery (FLAIR) MRI was useful for the diagnosis of meningitis and devising a treatment strategy. AB - A 3-month-old male was brought to our hospital due to fever, poor sucking, and a bulging anterior fontanel. His general condition was poor. Analysis of the cerebrospinal fluid (CSF) showed increases in the cell count (8/MUl) and the polymorphonuclear leukocyte count (2/MUl) but normal sugar (66 mg/dl) and protein (28 mg/dl) levels. A CSF smear showed no bacterial cells. The administration of antibacterial drugs was initiated, and head MRI was performed on the next day. Plain images revealed no abnormalities. However, contrast-enhanced fluid attenuated inversion recovery (FLAIR) MRI showed clear contrast enhancement along the brain surface in the meninges of the left and right frontal and left parietal lobes and fluid retention accompanied by contrast enhancement in a part of the adjacent subdural space. These findings could be confirmed only by contrast enhanced FLAIR MRI. A diagnosis of bacterial meningitis with an unknown cause was made, and the administration of 2 antibacterial drugs was continued. MRI on day 8 of the illness showed the disappearance of contrast enhancement, and plain FLAIR also facilitated a diagnosis of a subdural hygroma. The treatment was effective. At present, the patient is 1 year and 6 months old without sequelae. The diagnosis of bacterial meningitis in infants is difficult based on only symptoms. In its early stage with few abnormal findings in the CSF, diagnosis is sometimes difficult. Antibacterial drug administration should be immediately initiated. However, definite findings are necessary for the continuation of large amounts of antibacterial drugs. Contrast-enhanced FLAIR allows the sensitive visualization of meningeal inflammation and is useful as a complementary diagnostic method for meningitis. In addition, this technique can reveal marked inflammatory lesions such as a subdural hygroma in the early stage, providing information useful for making a diagnosis of bacterial meningitis. PMID- 30011155 TI - Diagnostic value of single photon emission computed tomography (SPECT) for patients with non-herpetic acute limbic encephalitis. AB - To evaluate the diagnostic value of SPECT (single photon emission computed tomography) brain blood flow imaging for patients with non-herpetic acute limbic encephalitis (NHALE). A retrospective review of three patients who had clinical symptoms compatible to NHALE and were positive for anti-N-methyl-d-aspartate-type glutamate receptor (GluRepsilon2) antibody. The patients consisted of a 6-year old female, a 10-year-old female and a 13-year-old male, all of whom had limbic symptoms and were anti-GluRepsilon2 antibody-positive. In all cases, brain MRI failed to detect any abnormality, but SPECT brain blood flow imaging was able to detect blood flow changes. All three cases showed some abnormality in their brain waves, and one of them also developed epilepsy. SPECT brain blood flow imaging may therefore be helpful for diagnosing NHALE which can lead to the development of either epilepsy or cognitive impairment. PMID- 30011156 TI - A clinical course of patient with Aicardi-Goutieres syndrome due to SAMHD1 gene abnormality. PMID- 30011157 TI - Neonatal herpes simplex encephalitis with bilateral temporal mega cystic lesion. PMID- 30011161 TI - Three children with Lennox-Gastaut syndrome presenting long-term good seizure outcome under rufinamide treatment. PMID- 30011162 TI - Bilateral submandibular gland excision for treatment of drooling in a child with mitochondrial encephalomyopathy. PMID- 30011163 TI - Orofacial Cancer, An Emerging Menace with a Changing Trend. PMID- 30011164 TI - Evaluation of histologically confirmed carcinoma of the cervix in Nnewi Nigeria: A five year review. AB - Background: Cervical cancer is the commonest gynaecological cancer in developing countries. It is a major cause of cancer related deaths among women in our subregion. Objective: To determine the incidence, mode of presentation, associated risk factors and management of histologically confirmed carcinoma of the cervix at the Nnamdi Azikiwe University Teaching Hospital, Nnewi. Method: This was a retrospective study of all the cases of histologically confirmed carcinoma of the cervix at the Nnamdi Azikwe University Teaching Hospital, Nnewi, between first of August 2009 and 31st July 2014. Data collected was analysed with SPSS version 20.0 software and presented in tables and charts. Results: Sixty two patients with histological confirmation of cervical cancer were managed in the hospital over a five year period. Forty five of these patients with adequate information in their folders constitute the study group. There was an incidence of 9.2% of all gynaecological admissions. The highest incidence(31.2%) was found in age group 50-59 years. Conclusion: The incidence of cervical cancer is very high in our environment. Majority of the presentations were at the advanced stage of the disease. PMID- 30011165 TI - Palliative care in patients who receive whole brain radiotherapy for brain metastases in Ahmadu Bello University Teaching Hospital, Zaria. AB - Background: Brain Metastases is a devastating complication of Cancer affecting 10 50% of patients with systemic disease. It by far outnumbers primary Brain tumor in a 10:1 ratio. Aims and Objective: To determine the age distribution, gender distribution, tumor of origin, commonest radiotherapy regimen and median survival of patients who received Whole Brain Radiotherapy for Brain Metastases. Materials and Methods: Between May 2006-May 2015 patients who received Whole Brain Radiotherapy for Brain Metastases for confirmed Brain Metastases were studied in a Retrospective study and evaluated with respect to age, gender, tumor of origin and radiotherapy regimen. Patients Case files and treatment files were reviewed and results were analyzed using SPSS version 20th Edition. Results: A total of 30 cases were reviewed. The age range of patients was between 16-70 years with a mean age of 43.5 years. Median age of 41.5 years. 83.4% of patients were female with remaining 16.7% males. The commonest tumor of origin was Breast Cancer (76.7%) followed by Lymphoma (6.7%),Lung (3.3%), Colon(3.3%), Endometrium(3.3%), Pancrease (3.3%), Paranasal Sinus (3.3%). Majority of patients 73.3% received 30Gy in 10# over 2 weeks. Median Survival is 3 months. The most common clinical presentation is Headache (46.6%). Conclusion: Most Patients presented at advanced stages of their diseases. The mean age of patients that received Whole Brain Radiotherapy were in the fifth decade of life. More Females than Males received Whole Brain Radiotherapy. PMID- 30011166 TI - Choice of antihypertensive medications among physicians and its impact on blood pressure control among Nigerians living with hypertension. AB - Background: Hypertension, if untreated or uncontrolled, leads to damage of vital organs such as the brain, heart and the kidneys among others. These complications have been shown to be severer in black Africans. Benefit of treatment has been repeatedly demonstrated by many studies. Therefore, many guidelines have been produced by relevant bodies in different countries in order to assist physicians in making the right choices for blood pressure (BP) control. Most of these bodies produce the guidelines based on the peculiarities of hypertension in their respective population. Several reports have shown how different hypertension is, in black Africans, still there is no published unified guideline for its treatment in this population. Methods: This was a survey of known hypertensives who were on follow up visit. Their prescriptions were assessed for drug name, class and number. Their blood pressures at that visit were also recorded. Prevalence of single therapy and combination therapy were determined. Compliance with the AHA recommended 2 - drug combination was determined. The percentage of BP control as well as the prescribed drugs in each group were also obtained. Results: Those on single agents were 13% out of which 52% were controlled. 87% were on various combination of 2 or more drugs of whom 41.9% of those on 2 drugs and 21.1% of those on more than 2 drugs had controlled BP. BP control in those on 2 drugs was better than in those with > 2 drugs, (p=0.0027). ACEI were the commonest used drug either as single agent (55.9%) or as 2 - drug combination as seen in 54.8% of the subjects on 2 - drug combination. 13 different 2 - drug combinations were identified with the best control in ARB + Diuretic, ACEI + Diuretic and CCB + Diuretic. The least control was observed in the ACEI + CCB group. Compliance with AHA recommendation was good but still 7.7% were under unacceptable group while another 7.7% were unclassified. Conclusion: ACE-Is are becoming the drugs of choice both as monotherapy and as combination therapy. Despite good compliance to AHA recommendation on drug combination, overall control is still a problem which calls for a revisit of these recommendations in Africans. PMID- 30011167 TI - Feasibility and cost analysis of programmatic implementation of Microscopic Observation Drug Susceptibility (MODS) assay in Nigeria. AB - Objectives: Detection of Multi-drug resistant tuberculosis in Nigeria still remains a challenge. We evaluated the feasibility of programmatic implementation of the Microscopic-Observation Drug Susceptibility (MODS) assay, a rapid culture and drug susceptibility testing technique for drug susceptibility testing in a low resource setting. Method: In a novel laboratory setting in Nigeria, we obtained data from the market on the cost of materials necessary for MODS assay. Three routinely collected sputum specimens from 160 tuberculosis suspects were evaluated by smear microscopy while only the early morning specimen was used for MODS culture. Results: MODS assay detected M. tuberculosis in 97.7% (42/43) of smear positive and 6.0% (7/117) of smear negative TB suspects. There was a statistically significant advantage of a single MODS culture over 3 smear microscopies (P=0.019). The modal time from culture of specimen to detection of M. tuberculosis and availability of drug susceptibility result for MODS was 7days with a mean of 8.4 days (Range= 5-13 days). Culture and susceptibility result was available in 18.4% (9/49) of patients within 5days of culture. Turnaround time for smear microscopy in the centers was 3 days. Cost of processing one specimen by MODS assay in the study was USD2.65. Multi-Drug resistant tuberculosis (MDR TB) was detected in 4.1% (2/49) while Isoniazid mono-resistance was detected in 2.0% (1/49) of the culture positive cases. All the drug resistant isolates were from re-treatment cases with a statistically significant association (P=0.005). Conclusion: The MODS technique is simple, and its implementation in this novel setting was feasible. MODS can be scaled up to meet the demand for MDR-TB confirmation in XpertMTB/Rif deployed sites in Nigeria. PMID- 30011168 TI - Pattern of accidents in building construction sites in Obio Akpor Local Government Area of Rivers State, Nigeria. AB - Background: Building construction workers are engaged in a dangerous job, exposing them to an array of hazards. Construction accidents cause deaths, injuries and economic loss each year. The leading cause building site accidents include falls from unsafe working conditions and scaffolding. This study was to determine the pattern of hazards / accidents in building construction sites in Obio Akpor Local Government Area of Rivers State Nigeria. Method: This descriptive cross-sectional study recruited 400 consenting respondents (366 males and 34 females) using a multistage sampling system. They responded to closed ended, structured interviewer/self administered questionnaires which probed socio demographics, occupational history, knowledge and behavior towards workplace hazards. There was also a walk-through survey of sampled work sites. Data collected in Excel spread sheet were analyzed and presented in descriptive and analytical statistics.. Results: This showed 278 (69.50%) of the workers agreed to being exposed to hazards at the work place. The hazards in order of prevalence include noise (31.46%), falling off from the ladder or height (29.25%), slips, trips and low falls (29.04%), dust (24.39%), heat (25.51%), flame/fire (24.94%), puncture wound (22.54%), struck by falling objects (19.18%), gases or vapors (17.27%), fumes (16.16%), cold (18.08). Injuries sustained in this study include musculoskeletal (46.85%), Puncture wounds (32.87%), Electrocutions (8.39%). Conclusion: Hazards abound in building construction sites and efforts at prevention and control are at best poor and ineffective. There is need for institution of safety standards with training of workers on hazards they are likely to confront as they ply their trade. PMID- 30011169 TI - How ophthalmologists and ophthalmologists-in-training in Nigeria use the social media. AB - Background: The social media has revolutionized the practice of medicine in the area of communication and information dissemination. Materials and Methods: This was cross-sectional study of eighty-seven (87) consenting ophthalmologists and ophthalmology residents at the 40th Annual Scientific and General Meeting of the Ophthalmological Society of Nigeria held from 24th to 28th August, 2015 in Jos, Nigeria. Self-administered questionnaires and data obtained were recorded in the data sheets and analysed using the SPSS version 20 (2014). Simple statistics and comparisons of associated variables were made using Chi-square. Results: Of the 87 respondents, 82 (94.2%) used the social media while only 5 (5.8%) were not on any social media platform. WhatsApp was the preferred social media platform with 50 (50.5%) of the respondents using it, followed by Facebook (38; 38.4%), LinkedIn (8;8.1%), Instagram (2;2.0%) and Twitter (1; 1.0%). Majority of the respondents (66; 46.5%) used the social media for social interaction; 43 (30.3%) of them used them to interact and collaborate with colleagues; 21 (14.8%) utilized them for patients' education. Only 6 (4.2%) of the respondents used the social media for marketing of their practice.Fifty-two (59.9%) of the respondents believed that the use of social media had enhanced their practice. Conclusions: The study has shown that majority of the ophthalmologists and residents interviewed were on the social media platform. However, social interaction with friends was the major reason they use the social media. PMID- 30011170 TI - Bacterial contamination in a special care baby unit of a tertiary hospital in Jos, Nigeria. AB - Background: Nosocomial infections pose a great challenge on healthcare systems. Although surfaces in neonatal wards, umbilical stump wounds and catheter are responsible for a high number of nosocomial infections due to bacteria. The aim of this study was to determine the bacterial profile of air and surface contamination in the special care baby unit of a tertiary hospital in Jos, Nigeria. Methods: Surface and air samples were cultured and antibiotic susceptibility of isolated bacteria were determined. Results: The bacterial profile of air and surface samples showed that Klebsiella was the most common bacteria followed by Staphyllococcus; while the least was Escherichia. Most of the bacteria were isolated from the out-born term area of the special care baby unit. All the bacteria isolated were susceptible to ceftriaxone and meropenem. Conclusion: This study showed that all areas of the special care baby unit of the hospital have bacterial, indicating that these are a potential source of cross infection from healthcare workers to the neonatal patients. PMID- 30011171 TI - Pattern of haematologic abnormalities in incident dialysis patients and the effect of using locally derived haematologic reference ranges. AB - Background: The aim of the study was to compare the prevalence of haematologic abnormalities seen in incident haemodialysis patients using standard laboratory reference ranges with reference ranges derived locally. Study Design and Method: This was a retrospective study of 97 patients with renal failure who received haemodialysis at a single dialysis unit in Lagos, Nigeria. All patients were 18 years of age or older, had renal failure requiring dialysis, and had not previously dialyzed. Patients with a history of haemoglobinoapthy or other red cell disorders, recent history of overt blood loss or blood transfusion and pregnancy were excluded. Results: Fifty six (57.7%) of the patients were males; and 55 (56.7%) had chronic kidney disease. There were no significant differences in baseline characteristics between males and females, however, patients with CKD had significantly higher mean systolic and diastolic blood pressures, mean serum creatinines and lower mean haemoglobin concentrations.Overall, anaemia was the most common haematologic abnormality (97.9%), followed by leukocytosis (34.0%). Leukopenia, thrombocytosis and thrombocytopenia were less common (3.1%, 7.2% and 10.3% respectively). The use of locally derived reference ranges was associated with significantly higher frequencies of occurrence of majority of the haematologic abnormalities studied. Conclusion: Haematological abnormalities occurred frequently in the study population. Use locally derived haematologic reference ranges was associated with significant differences in the frequency and pattern of some of the haematologic abnormalities. Further studies are needed to determine the clinical implications of these findings. PMID- 30011172 TI - Epidemiology of skin diseases in University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu State. AB - Background: Several studies have been carried out to determine the patterns of skin diseases across Nigeria and results have shown changing patterns with the trend reflecting a higher tendency for allergic dermatoses in a majority of these studies. This study was carried out to evaluate the current clinical picture of patients presenting to our clinic. Materials and Methods: A prospective study of new patients seen in the skin clinic of University of Nigeria Teaching Hospital (UNTH), Ituku- Ozalla, between November 2013 and August 2014 was carried out. A total of 387 patients' data was analysed. Data collected on patients' sociodemographic status and diagnosis were entered into SPSS Version 17 and analyzed. Diagnosis was based on clinical findings, laboratory diagnosis including biopsy and histopathology were requested when necessary to make a diagnosis. Results: There were more females 245 (63%) than males 142 (37%). Most of the patients (81.9%) were aged above 16years and the commonest skin disease was infections (29.5%) followed by allergic skin diseases (13.6%). There was a significant difference in levels of income of study participants across gender and females who were engaged in unskilled labour were more likely to earn lower than males. Conclusion: Comparing the study findings with an earlier one from the same center, there is a change in pattern with infections being the most common skin disease. These are largely preventable; public enlightenment campaigns and policies to discourage over the counter purchase of prescription strength corticosteroid creams are highly desirable. PMID- 30011173 TI - Assessment of the knowledge, attitude and practice of voluntary non-remunerated blood donation among residents of Ekpoma, a peri-urban community in Edo State. AB - Background: The importance of use of blood and blood products in medical practice cannot be over emphasized. Voluntary non remunerated blood donation forms the basis for ensuring regular availability of safe blood during blood donation and transfusion. However, volunteer blood donors account for less than one-half of blood supply in developing countries. Methodology: To assess the knowledge, attitude and practice of voluntary blood donation by residents of a peri-urban community. A descriptive cross sectional study was carried out using a pre-tested semi-structured self-administered questionnaire among 422 respondents using the multistage sampling technique. The target population were residents of Ekpoma comprising the general public - workers, students of senior secondary schools and tertiary institutions. Variables were entered and analyzed using SPSS software package. The association between participants level of education and other socio demographic factors was tested using chi square were appropriate. Results: The study involved 422 participants, majority of which were males (58.1%). A large proportion of them were between ages 16 and 26. The overall knowledge on blood donation was good, attitude towards voluntary donation was fair conversely practice was poor as 91.5% of respondents had never donated blood. A significant association was observed between sex and blood donation as only 2% of females have been donors. The commonest reason for not donating blood was fear to damage of health as reported in 40.7% of the participants. Conclusion: This study elicits the importance of adopting effective measures in our communities to motivate voluntary blood donation as majority of the participant express willingness in donating blood in the future. Health awareness campaign and motivational programmes should be organized regularly to arouse the interest of the general public in voluntary blood donation exercises. PMID- 30011175 TI - Flame-Spheroidized Phosphate-Based Glass Particles with Improved Characteristics for Applications in Mesenchymal Stem Cell Culture Therapy and Tissue Engineering. AB - The chemical formulation of phosphate-based glasses (PBGs) can be tailored to fit particular end applications such as bone tissue engineering. While most reports to date have evaluated the effect of PBG chemical formulation on bone cells, this study specifically explored the manufacturing process, the changes in physical and chemical properties of PBG particles after flame spheroidization, and subsequent effects on human mesenchymal stem cells (hMSCs), a prime cell type for regenerative medicine applications. Flame spheroidization involves feeding irregular PBG particles (microparticles, MP) into a hot flame, causing them to melt and mold into solid spherical PBG particles (microspheres, MS). The laser diffraction analysis showed an increase in the volume-weighted mean diameter of particles from 48 to 139 MUm after spheroidization and also revealed changes in the chemical composition of smaller MS (< 45 MUm in size), whereas MS in other size ranges did not show significantly different chemical composition compared to MP. Additionally, some air bubbles were entrapped inside particles during spheroidization, causing a 2% drop in relative density of MS. However, the packing density of MS was 30% higher than that of MP. Culture of hMSCs on the particles showed significant improvement in cell spreading on MS compared to that on MP and nearly 2 times higher cell metabolic activity after 7 days of culture, suggesting that MS provided a more favorable support and geometry for hMSC attachment and growth for tissue engineering. PMID- 30011174 TI - Pregnancy outcome in unbooked mothers at a tertiary health institution, South South, Nigeria. AB - Background: Maternal complications and poor perinatal outcome are highly associated with non-utilisation of antenatal and delivery care services. The study aimed at determining the socio-demographical characteristics and feto maternal outcome in unbooked mothers who delivered at a tertiary referral hospital. Materials and Methods: A retrospective study of all unbooked patients managed at the Obstetric unit of the University of Port Harcourt Teaching Hospital (UPTH), Nigeria from January 1, 2009 to December 31, 2013. Data obtained from the theatre records, delivery registers and case notes were analysed using the statistical package SPSS 20. Results: Unbooked mothers constituted 15.8% (2,490) of the deliveries. Majority (81.7%) of the women were aged 20-34 years with a mean age of 30.8 +/- 4.5 years. More than half of the women were Para 1-4 (61.3%). Emergency caesarean section was the mode of delivery in 58.7% of the women. The commonest indication for caesarean section was cephalopelvic disproportion (40%) followed by Obstructed labour (26%). There were 149 maternal deaths, giving maternal mortality ratio of 4654.8/100,000. The perinatal mortality rate was 331.7/1000 births. Conclusion: The study showed a positive correlation between lack of proper antenatal care and adverse pregnancy outcome in unbooked patients. Improvement in the socioeconomic conditions of the populace especially women and the removal of fee for service in maternal care services will help to improve the availability and accessibility of good quality antenatal care. PMID- 30011176 TI - Electric-Field-Induced Excimer Formation at the Interface of Deep-Blue Emission Poly(9,9-dioctyl-2,7-fluorene) with Polyelectrolyte or Its Precursor as Electron Injection Layer in Polymer Light-Emitting Diode and Its Prevention for Stable Emission and Higher Performance. AB - Conjugated polyelectrolytes and their precursors as electron-injection layer (EIL) in polymer light-emitting diode have attracted extensive attention because they allow the use of environmentally stable high work function metals as cathode with efficient electron injection. Here, for the first time, we find that an undesirable green emission component (470-650 nm) in the electroluminescence spectra is observed during continuous operation of deep-blue emission beta-phase poly(9,9-dioctyl-2,7-fluorene) (beta-PFO) device upon introducing polyelectrolyte poly[9,9-bis(6'-(18-crown-6)methoxy)hexyl fluorene] chelating to potassium ion (PFCn6:K+) as EIL. This phenomenon also happens to nonchelating PFCn6, poly[(9,9 bis(3'-( N, N-dimethylamino)propyl)-2,7-fluorene)- alt-2,7-(9,9 dioctylfluorene)], or even nonemissive poly[4-((18-crown-6)methoxy)methyl styrene] chelating to K+ (PSCn6:K+). It can be ascribed to electric-field induction accompanied by thermal motion of a highly polar side chain in the polyelectrolyte leading to local segmental alignment of PFO main chains at the emitting layer (EML)/EIL interface and thus formation of green emission excimer, which is supported by the following observations: appearance of green emission component using nonemissive PSCn6:K+ as EIL, absence of green emission component as the device is operated at low-temperature (78 K) at which molecular thermal motion are frozen, and absence of green emission upon introducing 2,2',2"-(1,3,5 phenylbenzenetriyl)tris[1-phenyl-1 H-benzimidazole] as buffer layer in between EML and EIL for the prevention of direct contact of EML with polyelectrolyte or its precursor EIL. PMID- 30011177 TI - Random Multiple Scattering Enhanced Photoacoustic Gas Spectroscopy with Disordered Porous Ceramics. AB - Light-gas interaction can be enhanced by using disordered porous materials because multiple random scattering increases light intensity near the surface of the material. Here we report signal enhancement of photoacoustic gas spectroscopy with disordered porous ceramics. The amplitude and frequency characteristics of photoacoustic signal due to gas absorption in disordered materials are modeled theoretically. Experiment with a porous Al2O3 sample demonstrates photoacoustic signal enhancement of ~4 times at 5 kHz. PMID- 30011178 TI - Flexible Neuromorphic Architectures Based on Self-Supported Multiterminal Organic Transistors. AB - Because of the fast expansion of artificial intelligence, development and applications of neuromorphic systems attract extensive interest. In this paper, a highly interconnected neuromorphic architecture (HINA) based on flexible self supported multiterminal organic transistors is proposed. Au electrodes, poly(3 hexylthiophene) active channels, and ion-conducting membranes were combined to fabricate organic neuromorphic devices. Especially, freestanding ion-conducting membranes were used as gate dielectrics as well as support substrates. Basic neuromorphic behavior and four forms of spike-timing-dependent plasticity were emulated. The fabricated neuromorphic device showed excellent electrical stability and mechanical flexibility after 1000 bends. Most importantly, the device structure is interconnected in a way similar to the neural architecture of the human brain and realizes not only the structure of the multigate but also characteristics of the global gate. Dynamic processes of memorizing and forgetting were incorporated into the global gate matrix simulation. Pavlov's learning rule was also simulated by taking advantage of the multigate array. Realization of HINAs would open a new path for flexible and sophisticated neural networks. PMID- 30011179 TI - Real-Time Multimodal Bioimaging of Cancer Cells and Exosomes through Biosynthesized Iridium and Iron Nanoclusters. AB - Multimodal bioimaging is a powerful tool for visualizing the abnormal state at the target site of the related disease. In this study, we used multimodal imaging techniques such as computed tomography, fluorescence, and magnetic resonance imaging to improve early and precise diagnosis of tumor. Herein, we reported the facile in situ biosynthesis of iridium and iron oxide nanoclusters (NCs) in cancer cells or tumor tissue. These NCs are used as a multimodal bioimaging probe to improve the image sensitivity and specificity toward the tumor. These NCs are applied for the in vivo multimodal imaging in the form of an imaging probe capable of enhancing the sensitivity of the image and specificity toward the tumor tissue. Our observation demonstrates that highly luminescent and magnetic NCs are not only biocompatible but also tumor-targeted because NC formation does not take place in normal cells and tissues. In addition, we isolated exosomes and the biosynthesized NCs internalized within exosomes, and these exosomes can be used as cancer biomarkers. PMID- 30011180 TI - Chemical Probe To Monitor the Parkinsonism-Associated Protein DJ-1 in Live Cells. AB - Reactive oxygen species (ROS) play an important role in the onset of Parkinson's disease (PD), and deciphering protective mechanisms is a major goal for therapeutic development. Here, DJ-1 (PARK7) gained major attention when a conserved cysteine residue with a putative role in oxidative stress sensing/protection was linked to PD. Inspired by previous studies with a bacterial homologue of DJ-1, several amino-epoxycylcohexenones were screened for enzyme inhibition, and a chemical probe with specificity for the human ortholog was selected for cellular studies. The probe selectively labeled the cysteine oxidation sensor and whole proteome analysis in HeLa, A549, and SHSY5Y cell lines confirmed strong enrichment of reduced DJ-1 as the most prominent target. Increasing levels of oxidative stress diminished this signal demonstrating the utility of our tool compound for selective in situ monitoring of this important biomarker in its reduced state. PMID- 30011181 TI - Nonporous Adaptive Crystals of Pillararenes. AB - Porous materials with high surface areas have drawn more and more attention in recent years because of their wide applications in physical adsorption and energy efficient adsorptive separation processes. Most of the reported porous materials are macromolecular porous materials, such as zeolites, metal-organic frameworks (MOFs), or porous coordination polymers (PCPs), and porous organic polymers (POPs) or covalent organic frameworks (COFs), in which the building blocks are linked together by covalent or coordinative bonds. These materials are barely soluble and thus are not solution-processable. Furthermore, the relatively low chemical, moisture, and thermal stability of most MOFs and COFs cannot be neglected. On the other hand, molecular porous materials such as porous organic cages (POCs), which have been developed very recently, also show promising applications in adsorption and separation processes. They can be soluble in organic solvents, making them solution-processable materials. However, they are usually sensitive to acid/base and humid environments since most of them are based on dynamic covalent bonding. These macromolecular and molecular porous materials usually have two similar features: high Brunauer-Emmett-Teller (BET) surface areas and rigid pore structures, which are stable during adsorption and separation processes. In this Account, we describe a novel class of solid materials for adsorption and separation, nonporous adaptive crystals (NACs), which function at the supramolecular level. They are nonporous in the initial crystalline state, but the intrinsic or extrinsic porosity of the crystals along with a crystal structure transformation is induced by preferable guest molecules. Unlike solvent-induced crystal polymorphism phenomena of common organic crystals that occur at the solid-liquid phase, NACs capture vaporized guests at the solid gas phase. Upon removal of guest molecules, the crystal structure transforms back to the original nonporous structure. Here we focus on the discussion of pillararene-based NACs for adsorption and separation and the crystal structure transformations from the initial nonporous crystalline state to new guest-loaded structures during the adsorption and separation processes. Single-crystal X-ray diffraction, powder X-ray diffraction, gas chromatography, and solution NMR spectroscopy are the main techniques to verify the adsorption and separation processes and the structural transformations. Compared with traditional porous materials, NACs of pillararenes have several advantages. First, their preparation is simple and cheap, and they can be synthesized on a large scale to meet practical demands. Second, pillararenes have better chemical, moisture, and thermal stability than crystalline MOFs, COFs, and POCs, which are usually constructed on the basis of reversible chemical bonds. Third, pillararenes are soluble in many common organic solvents, which means that they can be easily processed in solution. Fourth, their regeneration is simple and they can be reused many times with no decrease in performance. It is expected that this class of materials will not only exert a significant influence on scientific research but also show practical applications in chemical industry. PMID- 30011182 TI - DNA Origami and G-Quadruplex Hybrid Complexes Induce Size Control of Single Walled Carbon Nanotubes via Biological Activation. AB - DNA self-assembly has enabled the programmable fabrication of nanoarchitectures, and these nanoarchitectures combined with nanomaterials have provided several applications. Here, we develop an approach for cutting single-walled carbon nanotubes (SWNTs) of predetermined lengths, using DNA origami and G-quadruplex hybrid complexes. This approach is based on features of DNA: (1) wrapping SWNTs with DNA to improve the dispersibility of SWNTs in water; (2) using G-quadruplex DNA to confine hemin in close proximity to SWNTs and enhance the biological activation of hydrogen peroxide by hemin; and (3) forming DNA origami platforms to allow for the precise placement of G-quadruplexes, enabling size control. These integrated features of DNA allow for temporally efficient cutting of SWNTs into desired lengths, thus expanding the availability of SWNTs for applications in the fields of nanoelectronics, nanomedicine, nanomaterials, and quantum physics, as well as in fundamental studies. PMID- 30011183 TI - Poly-adenine-Coupled LAMP Barcoding to Detect Apple Scar Skin Viroid. AB - Apple Scar Skin Viroid (ASSVd), a nonprotein coding, circular RNA pathogen is relatively difficult to detect by immunoassay. We report here a one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay to improve selectivity for diagnostic use in detecting ASSVd in plants. ASSVd RT-LAMP was accelerated using loop primers and was found to be highly sensitive with a detection limit of 104 copies of cDNA-ASSVd within 30 min. Real-time LAMP and melting curve analysis could differentiate between the true-positive LAMP amplicons and false-positive nonspecific primer amplification products. The optimized RT-LAMP was then followed by the addition of nonthiolated AuNP:poly adenine (A10)-ASSVd LAMP barcodes, showing a high authentication capacity with colorimetric changes. This type of barcoding assay is a potential alternative for rapid and multiple viroid diagnosis, providing for visible sensing in the field that can be applied to viroid-free planting. PMID- 30011184 TI - Design and Investigation of Core/Shell GQDs/hMSN Nanoparticles as an Enhanced Drug Delivery Platform in Triple-Negative Breast Cancer. AB - Due to the excellent photoluminescent properties and singlet oxygen (1O2) generating efficiency, graphene quantum dots (GQDs) with maximal emission in near infrared region (NIR) exhibited great potential in cancer imaging and therapy. However, GQDs can be cleared quickly via the renal system in vivo because of their ultrasmall size, which leads to the compromised cancer cell killing efficacy. Here, we report a hybrid nanoplatform, where GQDs were incorporated into the cavity of hollow mesoporous silica nanoparticles (hMSN) to form GQDs@hMSN-PEG nanoparticles (NPs). Optical characterization indicated that GQDs@hMSN-PEG NPs still maintained good absorption and emission properties from GQDs, and the composite NPs still possessed similar 1O2 generating efficiency. GQDs@hMSN-PEG NPs exhibited good biocompatibility in vitro and in vivo. High cargo-loading efficiency was achieved for doxorubicin (DOX), and the formed GQDs@hMSN(DOX)-PEG NPs showed the feasibility of tumor-oriented drug delivery. The extended retention time in tumor and good drug loading efficacy confirmed that GQDs@hMSN-PEG could serve as one promising candidate for combinational cancer treatment where photodynamic therapy and chemotherapy modules can be integrated into one system. PMID- 30011185 TI - Stability and Mobility of Magnetic Nanoparticles in Biological Environments Determined from Dynamic Magnetic Susceptibility Measurements. AB - Low tumor accumulation following systemic delivery remains a key challenge for advancing many cancer nanomedicines. One obstacle in engineering nanoparticles for high tumor accumulation is a lack of techniques to monitor their stability and mobility in situ. One way to monitor the stability and mobility of magnetic nanoparticles biological fluids in situ is through dynamic magnetic susceptibility measurements (DMS), which under certain conditions provide a measure of the particle's rotational diffusivity. For magnetic nanoparticles modified to have commonly used biomedical surface coatings, we describe a systematic comparison of DMS measurements in whole blood and tumor tissue explants. DMS measurements clearly demonstrated that stability and mobility changed over time and from one medium to another for each different coating. It was found that nanoparticles coated with covalently grafted, dense layers of PEG were the only ones to show good stability and mobility in all settings tested. These studies illustrate the utility of DMS measurements to estimate the stability and mobility of nanoparticles in situ, and which can provide insights that lead to engineering better nanoparticles for in vivo use. PMID- 30011186 TI - Mass Spectrometry-Based Chemical and Enzymatic Methods for Global Analysis of Protein Glycosylation. AB - Glycosylation is one of the most common protein modifications, and it is essential for mammalian cell survival. It often determines protein folding and trafficking, and regulates nearly every extracellular activity, including cell cell communication and cell-matrix interactions. Aberrant protein glycosylation events are hallmarks of human diseases such as cancer and infectious diseases. Therefore, glycoproteins can serve as effective biomarkers for disease detection and targets for drug and vaccine development. Despite the importance of glycoproteins, global analysis of protein glycosylation (either glycoproteins or glycans) in complex biological samples has been a daunting task, and here we mainly focus on glycoprotein analysis using mass spectrometry (MS)-based bottom up proteomics. Although the emergence of MS-based proteomics has provided a great opportunity to analyze glycoproteins globally, the low abundance of many glycoproteins and the heterogeneity of glycans dramatically increase the technical difficulties. In order to overcome these obstacles, considerable progress has been made in recent years, which has contributed to comprehensive analysis of glycoproteins. In our lab, we developed effective MS-based chemical and enzymatic methods to (1) globally analyze glycoproteins in complex biological samples, (2) target glycoproteins specifically on the surface of human cells, (3) systematically quantify glycoprotein and surface glycoprotein dynamics (the abundance changes of glycoproteins as a function of time), and (4) selectively characterize glycoproteins with a particular and important glycan. In this Account, we first briefly describe the glycopeptide/protein enrichment methods in the literature and then discuss the developments of boronic acid-based methods to enrich glycopeptides for large-scale analysis of protein glycosylation. Boronic acids can form reversible covalent interactions with sugars, but the low binding affinity of normal boronic acid-based methods prevents us from capturing glycoproteins with low abundance, which often contain more valuable information. We enhanced the boronic acid-glycan interactions by using a boronic acid derivative (benzoboroxole) and conjugating it onto a dendrimer to allow synergistic interactions between the boronic acid derivative and sugars. The new method is capable of globally analyzing protein glycosylation with site and glycan structure information, especially for those with low abundance. In the next part, we discuss the combination of metabolic labeling, click chemistry and enzymatic reactions, and MS-based proteomics as a very powerful approach for surface glycoproteome analysis in human cells. The methods enable us to specifically identify surface glycoproteins and to quantify their abundance changes and dynamics together with quantitative proteomics. The last section of this Account focuses on chemical and enzymatic methods to study glycoproteins containing a particular and important glycan (the Tn antigen, i.e., O-GalNAc). Although not comprehensive, this Account provides an overview of chemical and enzymatic methods to characterize protein glycosylation in combination with MS based proteomics. These methods will have extensive applications in the fields of biology and biomedicine, which will lead to a better understanding of glycoprotein functions and the molecular mechanisms of diseases. Eventually, glycoproteins will be identified as effective biomarkers for disease detection and drug targets for disease treatment. PMID- 30011187 TI - Solution-Based, Template-Assisted Realization of Large-Scale Graphitic ZnO. AB - With a honeycomb single-atomic-layer structure similar to those of graphene and hexagonal boron nitride (hBN), the graphitic phase of ZnO (gZnO) have been predicted to offer many advantages for engineering, including high-temperature stability in ambient conditions and great potential in heterostructure applications. However, there is little experimental data about this hexagonal phase due to the difficulty of synthesizing large-area gZnO for characterization and applications. In this work, we demonstrate a solution-based approach to realize gZnO nanoflakes with thicknesses down to a monolayer and sizes up to 20 MUm. X-ray photoelectron spectroscopy, X-ray absorption near-edge spectroscopy, photoluminescence, atomic force microscopy, and electron microscopy characterizations are conducted on synthesized gZnO samples. Measurements show significant changes to the electronic band structure compared to its bulk phase, including an increase of the band gap to 4.8 eV. The gZnO nanosheets also exhibit excellent stability at temperatures as high as 800 degrees C in ambient environment. This wide band gap layered material provides us with a platform for harsh environment electronic devices, deep ultraviolet optical applications, and a practical alternative for hBN. Our synthesis method may also be applied to achieve other types of 2D oxides. PMID- 30011188 TI - Aggregation State of Metal-Based Nanomaterials at the Pulmonary Surfactant Film Determines Biophysical Inhibition. AB - Metal-based nanomaterials (MNMs) represent a large category of the engineered nanomaterials, and have been extensively used to enhance the electrical, optical, and magnetic properties of nanoenabled consumer products. Inhaled MNMs can penetrate deeply into the peripheral lung at which they first interact with the pulmonary surfactant (PS) lining of alveoli. Here we studied the biophysical inhibitory potential of representative MNMs on a modified natural PS, Infasurf, using a novel in vitro experimental methodology called the constrained drop surfactometry (CDS). It was found that the biophysical inhibitory potential of six MNMs on Infasurf ranks in the order CeO2 > ZnO > TiO2 > Ag > Fe3O4 > ZrO2 CeO2. This rank of in vitro biophysical inhibition is in general agreement with the in vitro and in vivo toxicity of these MNMs. Directly imaging the lateral structure and molecular conformation of the PS film using atomic force microscopy revealed that there exists a correlation between biophysical inhibition of the PS film by the MNMs and their aggregation state at the PS film. Taken together, our study suggests that the nano-bio interactions at the PS film are determined by multiple physicochemical properties of the MNMs, including not only well-studied properties such as their chemical composition and particle size, but also properties such as hydrophobicity, dissolution rate, and aggregation state at the PS film found here. Our study provides novel insight into the understanding of nanotoxicology and metallomics of MNMs. PMID- 30011189 TI - High-Oxidation-State 3d Metal (Ti-Cu) Complexes with N-Heterocyclic Carbene Ligation. AB - High-oxidation-state 3d metal species have found a wide range of applications in modern synthetic chemistry and materials science. They are also implicated as key reactive species in biological reactions. These applications have thus prompted explorations of their formation, structure, and properties. While the traditional wisdom regarding these species was gained mainly from complexes supported by nitrogen- and oxygen-donor ligands, recent studies with N-heterocyclic carbenes (NHCs), which are widely used for the preparation of low-oxidation-state transition metal complexes in organometallic chemistry, have led to the preparation of a large variety of isolable high-oxidation-state 3d metal complexes with NHC ligation. Since the first report in this area in the 1990s, isolable complexes of this type have been reported for titanium(IV), vanadium(IV,V), chromium(IV,V), manganese(IV,V), iron(III,IV,V), cobalt(III,IV,V), nickel(IV), and copper(II). With the aim of providing an overview of this intriguing field, this Review summarizes our current understanding of the synthetic methods, structure and spectroscopic features, reactivity, and catalytic applications of high-oxidation-state 3d metal NHC complexes of titanium to copper. In addition to this progress, factors affecting the stability and reactivity of high-oxidation-state 3d metal NHC species are also presented, as well as perspectives on future efforts. PMID- 30011190 TI - Understanding the Species Selectivity of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors. AB - To test for on target toxicity of a new chemical entity, it is important to have comparable binding affinities of the compound in the target proteins from humans and the test species. To evaluate our myeloid cell leukemia-1 (Mcl-1) inhibitors, we tested them against rodent Mcl-1 and found a significant loss of binding affinity when compared to that seen with human Mcl-1. To understand the affinity loss, we used sequence alignments and structures of human Mcl-1/inhibitor complexes to identify the important differences in the amino acid sequences. One difference is human L246 (F226 in rat, F227 in mouse) in the ligand binding pocket. Mutating rat F226 to a Leu restores affinity, but the mouse F227L mutant still has a ligand affinity that is lower than that of human Mcl-1. Another mutation of mouse F267, located ~12 A from the ligand pocket, to the human/rat cysteine, F267C, improved the affinity and combined with F227L resulted in a mutant mouse protein with a binding affinity similar to that of human Mcl-1. To help understand the structural components of the affinity loss, we obtained an X ray structure of a mouse Mcl-1/inhibitor complex and identified how the residue changes reduced compound complementarity. Finally, we tested Mcl-1 of other preclinical animal models (canine, monkey, rabbit, and ferret) that are identical to humans in terms of these two residues and found that their Mcl-1 bound our compounds with affinities comparable to that of human Mcl-1. These results have implications for understanding ligand selectivity for similar proteins and for the interpretation of preclinical toxicology studies with Mcl-1 inhibitors. PMID- 30011191 TI - Reliable, Resilient and Sustainable Urban Drainage Systems: An Analysis of Robustness under Deep Uncertainty. AB - Reliability, resilience and sustainability are key goals of any urban drainage system. However, only a few studies have recently focused on measuring, operationalizing and comparing such concepts in a world of deep uncertainty. In this study, these key concepts are defined and quantified for a number of gray, green and hybrid strategies, aimed at improving the capacity issues of an existing integrated urban wastewater system. These interventions are investigated by means of a regret-based approach, which evaluates the robustness (that is the ability to perform well under deep uncertainty conditions) of each strategy in terms of the three qualities through integration of multiple objectives (i.e., sewer flooding, river water quality, combined sewer overflows, river flooding, greenhouse gas emissions, cost and acceptability) across four different future scenarios. The results indicate that strategies found to be robust in terms of sustainability were typically also robust for resilience and reliability across future scenarios. However, strategies found to be robust in terms of their resilience and, in particular, for reliability did not guarantee robustness for sustainability. Conventional gray infrastructure strategies were found to lack robustness in terms of sustainability due to their unbalanced economic, environmental and social performance. Such limitations were overcome, however, by implementing hybrid solutions that combine green retrofits and gray rehabilitation solutions. PMID- 30011192 TI - Enzymatic Synthesis of Nucleobase-Modified Single-Stranded DNA Offers Tunable Resistance to Nuclease Degradation. AB - We synthesized long, nucleobase-modified, single-stranded DNA (ssDNA) using terminal deoxynucleotidyl transferase (TdT) enzymatic polymerization. Specifically, we investigated the effect of unnatural nucleobase size and incorporation density on ssDNA resistance to exo- and endonuclease degradation. We discovered that increasing the size and density of unnatural nucleobases enhances ssDNA resistance to degradation in the presence of exonuclease I, DNase I, and human serum. We also studied the mechanism of this resistance enhancement using molecular dynamics simulations. Our results show that the presence of unnatural nucleobases in ssDNA decreases local chain flexibility and hampers nuclease access to the ssDNA backbone, which hinders nuclease binding to ssDNA and slows its degradation. Our discoveries suggest that incorporating nucleobase modified nucleotides into ssDNA, using enzymatic polymerization, is an easy and efficient strategy to prolong and tune the half-life of DNA-based materials in nucleases-containing environments. PMID- 30011193 TI - Comparison of Two Phosphinidenes Binding to Silicon(IV)dichloride as well as to Silylene. AB - The cyclic alkyl(amino) carbene (cAAC) anchored silylene with two phosphinidenes was isolated as (cAAC)Si{P(cAAC)}2 (3) at room temperature, which was synthesized from the reduction of (Cl2)Si{P(cAAC)}2 (2) using 2 equiv of KC8. Compound 2 resulted from the reaction of 2 equiv of (cAAC)PK (1) with 1 equiv of SiCl4. Compounds 2 and 3 are the first examples where two terminal phosphinidenes are binding each to a silicon center characterized by single crystal X-ray structural analysis. Furthermore, the structure and bonding of compounds 2 and 3 have been investigated by theoretical methods for comparison. PMID- 30011194 TI - Photoredox Catalysis for Building C-C Bonds from C(sp2)-H Bonds. AB - Transition metal-catalyzed C-H bond functionalizations have been the focus of intensive research over the last decades for the formation of C-C bonds from unfunctionalized arenes, heteroarenes, alkenes. These direct transformations provide new approaches in synthesis with high atom- and step-economy compared to the traditional catalytic cross-coupling reactions. However, such methods still suffer from several limitations including functional group tolerance and the lack of regioselectivity. In addition, they often require harsh reaction conditions and some of them need the use of strong oxidant, in a stoichiometric amount, avoiding these processes to be truly eco-friendly. The use of photoredox catalysis has contributed to a significant expansion of the scope of C(sp2)-H bond functionalizations which include the direct arylations, (perfluoro)alkylations, acylations, and even cyanations. Most of these transformations involve the photochemical induced generation of a radical followed by its regioselective addition to arenes, heteroarenes, or alkenes, leading to the building of a new C(sp2)-C bond. The use of photoredox catalysis plays crucial roles in these reactions promoting electron transfer, enabling the generation of radical species and single electron either oxidation or reduction. Such reactions operating at room temperature allow the building of C-C bonds with high chemo-, regio-, or stereoselectivity. This review surveys the formation of C(sp2)-C bonds initiated by photoredox catalysis which involves a C(sp2)-H bond functionalization step, describes the advantages compared to traditional C(sp2)-H bond functionalizations, and presents mechanistic insights into the role played by the photoredox catalysts. PMID- 30011195 TI - Toward Automated Enzymatic Synthesis of Oligosaccharides. AB - Oligosaccharides together with oligonucleotides and oligopeptides comprise the three major classes of natural biopolymers. Automated systems for oligonucleotide and oligopeptide synthesis have significantly advanced developments in biological science by allowing nonspecialists to rapidly and easily access these biopolymers. Researchers have endeavored for decades to develop a comparable general automated system to synthesize oligosaccharides. Such a system would have a revolutionary impact on the understanding of the roles of glycans in biological systems. The main challenge to achieving automated synthesis is the lack of general synthetic methods for routine synthesis of glycans. Currently, the two main methods to access homogeneous glycans and glycoconjugates are chemical synthesis and enzymatic synthesis. Enzymatic glycosylation can proceed stereo- and regiospecifically without protecting group manipulations. Moreover, the reaction conditions of enzyme-catalyzed glycosylations are extremely mild when compared to chemical glycosylations. Over the past few years methodology toward the automated chemical synthesis of oligosaccharides has been developed. Conversely, while automated enzymatic synthesis is conceptually possible, it is not as well developed. The goal of this survey is to provide a foundation on which continued technological advancements can be made to promote the automated enzymatic synthesis of oligosaccharides. PMID- 30011196 TI - Perturbation of Developmental Regulatory Gene Expression by a G-Quadruplex DNA Inducer in the Sea Urchin Embryo. AB - The G-quadruplex (G4) is a four-stranded DNA structure identified in vivo in guanine-rich regions located in the promoter of a number of genes. Intriguing evidence suggested that small molecules acting as G4-targeting ligands could potentially regulate multiple cellular processes via either stabilizing or disruptive effects on G4 motifs. Research in this field aims to prove the direct role of G4 ligands and/or structures on a specific biological process in a complex living organism. In this study, we evaluate in vivo the effects of a nickel(II)-salnaphen-like complex, named Nisaln, a potent G4 binder and stabilizer, during embryogenesis of the sea urchin embryo. We describe developmental defects inflicted by Nisaln and correlate them with variation in the expression of several regulatory genes. It is worth mentioning that we show that Nisaln binds a G4 structure in the promoter of hbox12-a, a gene lying at the top of the developmental regulatory hierarchy, inducing overexpression of this gene. PMID- 30011197 TI - Synthesis and Unprecedented Complexation Properties of beta-Cyclodextrin-Based Ligand for Lanthanide Ions. AB - Here, we report the synthesis and detailed studies on the coordination chemistry of a novel chemically modified polyaminocarboxylate (5) based on beta cyclodextrin (CD) scaffold for lanthanides. The target ligand is prepared in a highly efficient manner (seven total steps) from beta-CD using the readily available iminodiacetic acid as a starting material. A propargyl group is attached to the iminodiacetate via N-alkylation, and the obtained derivative is efficiently conjugated to the beta-CD scaffold via the copper(I)-mediated 1,3 dipolar cycloaddition. The generated 1,2,3-triazolmethyl residues advantageously provide a competent chelating group while displacing the metal coordination center away from the primary rim of beta-CD, to afford the required conformational flexibility. The functional groups from each of the two adjacent glucopyranosyl units of beta-CD complete a uniquely created octavalent coordination sphere for lanthanides while still sparing one site for dynamic water coordination. To help study the coordination chemistry of CD ligand 5, we also design a relevant maltoside ligand 6, which faithfully represents one submetal-binding section of ligand 5. Thanks to HRMS and NMR studies, we successfully elucidate the coordination chemistries of synthesized ligands. The octavalent coordination sphere of ligand 5 shows strong binding affinity to lanthanides. By potentiometric titration experiments, ligand 5 is found to bind gadolinium(III), forming 1:1, 1:2, and 1:3 multinuclear complexes with lanthanides, thus possessing great capacity for catalyzing the dynamic water exchange. Further NMR studies also reveal that the formed ligand 5/Gd(III) complexes show significantly better abilities to alter T1 relaxivities of coordinated water than DOTA-Gd(III) and also some of the synthetic CD probes reported in the literature. PMID- 30011198 TI - Theoretical Modeling of Electronic Excitations of Gas-Phase and Solvated TiO2 Nanoclusters and Nanoparticles of Interest in Photocatalysis. AB - The optical absorption spectra of (TiO2) n, nanoclusters ( n = 1-20) and nanoparticles ( n = 35, 84) have been calculated from the frequency-dependent dielectric function in the independent particle approximation under the framework of density functional theory. The PBE generalized gradient approach based functional, the so-called PBE+ U method and the PBE0 and PBEx hybrid functionals containing 25% and 12.5% of nonlocal Fock exchange, respectively-have been used. The simulated spectra have been obtained in the gas phase and in water on previously PBE0 optimized atomic structures. The effect of the solvent has been accounted for by using an implicit water solvation model. For the smallest nanoclusters, the spectra show discrete peaks, whereas for the largest nanoclusters and for the nanoparticles they resemble a continuum absorption band. In the gas phase and for a given density functional, the onset of the absorption (optical gap, Ogap) remains relatively constant for all nanoparticle sizes although it increases with the percentage of nonlocal Fock exchange, as expected. For all tested functionals, the tendency of Ogap in water is very similar to that observed in the gas phase with an almost constant upshift. For comparison, the optical gap has also been calculated at the TD-DFT level with the PBEx functional in the gas phase and in water. Both approaches agree reasonably well although the TD-DFT gap values are lower than those derived from the dielectric-function. Overall, the position of the spectral maxima and the width of the spectra are relatively constant and independent of particle size which may have implications in the understanding of photocatalysis by TiO2. PMID- 30011199 TI - Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake. AB - The orphan G-protein-coupled receptor GPR88 is highly expressed in the striatum. Studies using GPR88 knockout mice have suggested that the receptor is implicated in alcohol seeking and drinking behaviors. To date, the biological effects of GPR88 activation are still unknown due to the lack of a potent and selective agonist appropriate for in vivo investigation. In this study, we report the discovery of the first potent, selective, and brain-penetrant GPR88 agonist RTI 13951-33 (6). RTI-13951-33 exhibited an EC50 of 25 nM in an in vitro cAMP functional assay and had no significant off-target activity at 38 GPCRs, ion channels, and neurotransmitter transporters that were tested. RTI-13951-33 displayed enhanced aqueous solubility compared to (1 R,2 R)-2-PCCA (2) and had favorable pharmacokinetic properties for behavioral assessment. Finally, RTI 13951-33 significantly reduced alcohol self-administration and alcohol intake in a dose-dependent manner without effects on locomotion and sucrose self administration in rats when administered intraperitoneally. PMID- 30011200 TI - No Structure-Switching Required: A Generalizable Exonuclease-Mediated Aptamer Based Assay for Small-Molecule Detection. AB - The binding of small molecules to double-stranded DNA can modulate its susceptibility to digestion by exonucleases. Here, we show that the digestion of aptamers by exonuclease III can likewise be inhibited upon binding of small molecule targets and exploit this finding for the first time to achieve sensitive, label-free small-molecule detection. This approach does not require any sequence engineering and employs prefolded aptamers which have higher target binding affinities than structure-switching aptamers widely used in current small molecule detecting assays. We first use a dehydroisoandrosterone-3-sulfate binding aptamer to show that target binding halts exonuclease III digestion four bases prior to the binding site. This leaves behind a double-stranded product that retains strong target affinity, whereas digestion of nontarget-bound aptamer produces a single-stranded product incapable of target binding. Exonuclease I efficiently eliminates these single-stranded products but is unable to digest the target-bound double-stranded product. The remaining products can be fluorescently quantified with SYBR Gold to determine target concentrations. We demonstrate that this dual-exonuclease-mediated approach can be broadly applied to other aptamers with differing secondary structures to achieve sensitive detection of various targets, even in biological matrices. Importantly, each aptamer digestion product has a unique sequence, enabling the creation of multiplex assays, and we successfully demonstrate simultaneous detection of cocaine and ATP in a single microliter volume sample in 25 min via sequence-specific molecular beacons. Due to the generality and simplicity of this assay, we believe that different DNA signal-reporting or amplification strategies can be adopted into our assay for target detection in diverse analytical contexts. PMID- 30011201 TI - Probing the OH Oxidation of Pinonic Acid at the Air-Water Interface Using Field Induced Droplet Ionization Mass Spectrometry (FIDI-MS). AB - Gas and aqueous phases are essential media for atmospheric chemistry and aerosol formation. Numerous studies have focused on aqueous-phase reactions as well as coupled gas/aqueous-phase mass transport and reaction. Few studies have directly addressed processes occurring at the air-water interface, especially involving surface-active compounds. We report here the application of field-induced droplet ionization mass spectrometry (FIDI-MS) to chemical reactions occurring at the atmospheric air-water interface. We determine the air-water interfacial OH radical reaction rate constants for sodium dodecyl sulfate (SDS), a common surfactant, and pinonic acid (PA), a surface-active species and proxy for biogenic atmospheric oxidation products, as 2.87 * 10-8 and 9.38 * 10-8 cm2 molec 1 s-1, respectively. In support of the experimental data, a comprehensive gas surface-aqueous multiphase transport and reaction model of general applicability to atmospheric interfacial processes is developed. Through application of the model, PA is shown to be oxidized exclusively at the air-water interface of droplets with a diameter of 5 MUm under typical ambient OH levels. In the absence of interfacial reaction, aqueous- rather than gas-phase oxidation is the major PA sink. We demonstrate the critical importance of air-water interfacial chemistry in determining the fate of surface-active species. PMID- 30011202 TI - De Novo Molecular Design of a Novel Octapeptide That Inhibits In Vivo Melanogenesis and Has Great Transdermal Ability. AB - Cutaneous hyperpigmentation from excess melanogenesis causes serious pigmentary disorders and even melasma. Short peptides (SPs) are garnering attention lately owing to their therapeutic potential in dermatological diseases and low systemic side effects. Here, we show an octapeptide, ansin2, designed de novo from antioxidant SPs we previously reported, significantly inhibiting melanogenesis in B16 cells by decreasing tyrosinase production via regulating the MITF pathway. Ansin2 could also inhibit tyrosinase function by covering its catalytic pocket, which was simulated in docking and LIGPLOT studies. Topical application of ansin2 exhibited evident protection in UVB-induced pigmentation in guinea pig models both in terms of prophylaxis and treatment. Interestingly, unlike other hydrophilic and peptidic drugs that need delivery systems, ansin2 can be efficiently delivered topically to the epidermis and dermis per se without an affiliated moiety. Given that ansin2 lacks unwanted toxicities and immunogenicity, it holds great potential in treating hyperpigmentation in the cosmetics and pharmaceutical industries. PMID- 30011203 TI - Binding of l-Argininamide to a DNA Aptamer: A Volumetric Study. AB - We use a combination of volumetric and spectroscopic techniques to characterize the binding of l-argininamide to its aptamer, the 24-base DNA hairpin 5' d(GATCGAAACGTAGCGCCTTCGATC)-3'. The binding causes increases in volume, Delta V, and adiabatic compressibility, Delta KS, of 12 +/- 7 cm3 mol-1 bar and (73 +/- 8) * 10-4 cm3 mol-1 bar-1, respectively. These volumetric results combined with structural data reveal that the binding is accompanied by release of 73 +/- 27 waters from the hydration shells of the interacting molecules to the bulk. We use the estimated change in hydration to estimate the hydration, Delta Shyd, and configurational, Delta Sconf, contributions to the binding entropy. The large and unfavorable change in configurational entropy, Delta Sconf, is nearly compensated by a favorable change in the hydration contribution, Delta Shyd. PMID- 30011204 TI - Tremorgenic Indole Diterpenes from Ipomoea asarifolia and Ipomoea muelleri and the Identification of 6,7-Dehydro-11-hydroxy-12,13-epoxyterpendole A. AB - Indole diterpene alkaloids have been isolated from Ipomoea asarifolia and I. muelleri and are associated with a tremorgenic syndrome in livestock. To better characterize the tremorgenic activity of the major indole diterpene alkaloids in these two plants, terpendole K (1), 6,7-dehydroterpendole A (2), 11-hydroxy-12,13 epoxyterpendole K (3), terpendole C (5), paxilline (6), and a new compound, 6,7 dehydro-11-hydroxy-12,13-epoxyterpendole A (4), were isolated and evaluated for tremorgenic activity in a mouse model. Compounds 1, 2, 5, and 6 all showed similar and significant signs of tremorgenic activity. In contrast, the 11 hydroxy-12,13-epoxy compounds, 3 and 4, showed no significant tremorgenic activity. PMID- 30011205 TI - TfOH- and HBF4-Mediated Formal Cycloisomerizations and [4+3] Cycloadditions of Allene-alkynylbenzenes. AB - A metal-free, TfOH (1.1 equiv)-mediated formal cycloisomerization of easily prepared allene-alkynylbenzenes to give pyrrolidines and cyclopentanes derivatives was developed. This reaction is initiated by the generation of allylic cation from allene, followed by alkyne's reaction with the allylic cation, to give a vinyl cation, which is finally intercepted by the triflate (TfO) anion. This cycloisomerization can be further tuned to become an acid mediated intramolecular formal [4+3] cycloaddition by using 10 equiv of TfOH (The excess acid was used to promote the Friedel-Crafts reaction of the acid-mediated cycloisomerization products). The present system can also be applied to synthesized F-incorporated products by using HBF4 or Me3OBF4 as the fluoro source. PMID- 30011206 TI - Unraveling the Microscopic Origin of Triplet Lasing from Organic Solids. AB - We present a heuristic mechanism for the origin of the unusual triplet lasing from (E)-3-(((4-nitrophenyl)imino)methyl)-2H-thiochroman-4-olate.BF2.We demonstrate that whereas the moderate lifetime (1.03 MUs) of the first triplet state (T1) prohibits triplet-triplet annihilation, the relatively faster S1 -> T1 intersystem crossing and the 104 times smaller reverse intersystem crossing effectively help achieve population inversion in the T1 state. Furthermore, the triplet lasing wavelength (675 nm) for the tetramer does not overlap with the triplet-triplet absorptions wavelength, indicating that the spin-forbidden emission cross section is very large. Additionally, the almost complete absence of a vibrational progression in the vibronic phosphorescence spectrum of the monomer plays an important role in ensuring efficient triplet-state lasing from this organic material. Our results show that controlling the triplet-state lifetimes combined with lowering of the triplet-triplet absorption in the emission region and small vibronic coupling will be the key steps when designing novel organic triplet-lasing materials. PMID- 30011207 TI - Crossing Classified and Corrected Fewest Switches Surface Hopping. AB - In the traditional fewest switches surface hopping (FSSH), trivial crossings between uncoupled or weakly coupled states have highly peaked nonadiabatic couplings and thus are difficult to deal with in the preferred, adiabatic representation. Here, we classify surface crossings into four general types and propose a parameter-free crossing corrected FSSH (CC-FSSH) algorithm, which could treat multiple trivial crossings within a time interval. As examples, Holstein Hamiltonians with different parameters are adopted to mimic electron dynamics in tens to hundreds of molecules, which suffer from severe trivial crossing problems. Using existed surface hopping approaches as references, we show that CC FSSH exhibits significantly fast time interval convergence and weak system size dependence. In all cases, a reliable description is achieved with a large time interval of 1 fs. With a simple formalism and the ability to describe complex surface crossings, CC-FSSH could potentially simulate general nonadiabatic dynamics in nanoscale materials with a high efficiency. PMID- 30011208 TI - Auger Heating and Thermal Dissipation in Zero-Dimensional CdSe Nanocrystals Examined Using Femtosecond Stimulated Raman Spectroscopy. AB - We report femtosecond stimulated Raman spectroscopy (FSRS) measurements on dispersions of CdSe semiconductor nanocrystals (NCs) as a function of particle size and pump fluence. Upon photoexcitation, we observe depletion of stimulated Raman gain corresponding to generation of longitudinal optical (LO) phonons followed by recovery on picosecond timescales. At higher fluences, production of multiple excitons slows recovery of FSRS signals, which we attribute to sustained increases of LO phonon populations due to multiexcitonic Auger heating. Owing to the discretized electronic structure of these NCs, such heating cannot be readily monitored via electronic spectroscopic analysis of high-energy band tails as has been performed for higher-dimensional materials. Notably, recovery timescales exceed those of the biexcitonic Auger recombination process and as such reveal overall thermalization timescales likely owing to an acoustic phonon thermalization bottleneck that dictates the cooling timescale. PMID- 30011209 TI - In Vitro Osteogenic Differentiation and Antibacterial Potentials of Chalcone Derivatives. AB - Chalcone derivatives have been investigated as therapeutic agents for the anticancer, antioxidant, and anti-inflammatory fields. In this study, we have synthesized four different types of chalcone derivatives and demonstrated in vitro bioactivities. We divided these derivatives into two groups of chalcones on the basis of similar substituents on the aromatic rings, and we tested cell viability and proliferation potentials, which indicated that the methoxy substituent on the A ring could enhance cytotoxicity and antiproliferation potential depending on the chalcone concentration. We also investigated osteogenic differentiation of C2C12 cells by ALP staining, the early marker for osteogenesis, which demonstrated that the chalcones could not only induce activity of BMP-2 but also inhibit the activity of noggin, a BMP antagonist. In addition, chalcone bearing hydroxyl groups at the 2-, 4-, and 6-position on the A ring inhibited treptococcus mutans growth, a major causative agent of dental caries. Therefore, we concluded that the chalcone derivatives synthesized in this research can be good candidates for therapeutic agents promoting bone differentiation, with an expectation of inhibiting S. mutans, in dentistry. PMID- 30011210 TI - Stable, Ultralow Threshold Amplified Spontaneous Emission from CsPbBr3 Nanoparticles Exhibiting Trion Gain. AB - Wet-chemically synthesized cesium lead halide nanoparticles have many attractive properties that make them promising as optical gain media, but generally suffer from poor stability under ambient conditions and an optical gain threshold that is widely believed to be dictated by the need for biexcitons. These conditions make it impractical for such particles to be utilized as gain media given the need to undergo repeated stimulated emission processes at above-threshold pump intensities over long periods of time. We demonstrate that the surface treatment of CsPbBr3 nanoparticles with a mixture of PbBr2, oleic acid, and oleylamine not only raises their fluorescence quantum yield to nearly unity and prolongs their stability in air from days to months, but it also dramatically increases their trion photoluminescence lifetime from ~0.9 to ~1.6 ns. Via a combination of time resolved photoluminescence and transient absorption spectroscopy, we provide evidence for trion gain at sufficiently low pump intensities in which the likelihood of predominantly biexciton-based gain is small. We then show that, in line with theoretical prediction, the amplified spontaneous emission (ASE) threshold of a thin film of surface-treated CsPbBr3 nanoparticles reduces to a record low of ~1.2 MUJ/cm2 with a corresponding average exciton occupancy per nanoparticle of 0.62. The ultralow pump threshold and increased stability allow for stable ASE over millions of laser shots, paving the way for the deployment of these nanoparticles as viable solution-processed optical gain media. PMID- 30011211 TI - Synthesis of Silver Nanowires with Reduced Diameters Using Benzoin-Derived Radicals to Make Transparent Conductors with High Transparency and Low Haze. AB - Reducing the diameter of silver nanowires has been proven to be an effective way to improve their optoelectronic performance by lessening light attenuation. The state-of-the-art silver nanowires are typically around 20 nm in diameter. Herein we report a modified polyol synthesis of silver nanowires with average diameters as thin as 13 nm and aspect ratios up to 3000. The success of this synthesis is based on the employment of benzoin-derived radicals in the polyol approach and does not require high-pressure conditions. The strong reducing power of radicals allows the reduction of silver precursors to occur at relatively low temperatures, wherein the lateral growth of silver nanowires is restrained because of efficient surface passivation. The optoelectronic performance of as prepared 13 nm silver nanowires presents a sheet resistance of 28 Omega sq-1 at a transmittance of 95% with a haze factor of ~1.2%, comparable to that of commercial indium tin oxide (ITO). PMID- 30011212 TI - Copper-Mediated Aminoazidation, Aminohalogenation, and Aminothiocyanation of beta,gamma-Unsaturated Hydrazones: Synthesis of Versatile Functionalized Pyrazolines. AB - A versatile method for the rapid synthesis of diverse functionalized pyrazolines has been developed based on copper-mediated aminofunctionalization of beta,gamma unsaturated hydrazones. The scope of this strategy encompasses a range of difunctionalization reactions: aminoazidation, aminohalogenation, and aminothiocyanation. These reactions provide straightforward access to a series of useful pyrazoline building blocks containing various functional groups that are hard to access traditionally. PMID- 30011213 TI - Promoting Immune Efficacy of the Oral Helicobacter pylori Vaccine by HP55/PBCA Nanoparticles against the Gastrointestinal Environment. AB - The immunogenicity of oral subunit vaccines is poor partly as a result of the harsh milieu of the gastrointestinal (GI) tract. For some pathogens that restrictedly inhabit the GI tract, a vaccine that works in situ may provide more potent protection than vaccines that operate parenterally. Yet, no appropriate delivery system is available for oral subunit vaccines. In this study, we designed HP55/poly( n-butylcyanoacrylate) (PBCA) nanoparticles (NPs) to carry Helicobacter pylori ( H. pylori) subunit vaccine CCF for oral administration in a prophylactic mice model. These NPs, which are synthesized using an interfacial polymerization method, protected the CCF antigen not only from the acidic pH in simulated gastric fluid (SGF, pH 1.2) but also from the proteolysis in simulated intestinal fluid (SIF, pH 7.4). Oral vaccination of mice with HP55/PBCA-CCF NPs promoted the production of serum antigen-specific antibodies, mucosal secretory IgA, and proinflammatory cytokines. Moreover, a Th1/Th17 response and augmented lymphocytes were found in the gastric tissue of HP55/PBCA-CCF NP-immunized mice, which might eventually limit H. pylori colonization. Collectively, these results indicate that HP55/PBCA NPs are promising carriers against the severe situation of the GI tract and thereby may be further utilized for other orally administrated vaccines or drugs. PMID- 30011214 TI - Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-inflammatory Properties and Temperature-Dependent Binding and Release Profile. AB - COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4 carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1beta in LPS-treated THP-1 cells, which was not present in the control with free indomethacin. PMID- 30011215 TI - Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2. AB - Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition. Hepatotoxicity was significantly higher in female rats than that in male rats, as evidenced by histopathological and biochemical tests. Similarly, the toxicokinetic profiles of emodin have time and gender differences, which could cause time and gender differences in hepatotoxicity. The metabolic and transcriptomics data of 55 human liver and 36 human kidney samples demonstrated that UDP-glucuronosyltransferase 2B7 (UGT2B7) was the predominant enzyme for emodin glucuronidation. A genome-wide association study (GWAS) identified that rs11726899 located within ~50 kb of the transcript of UGT2B could significantly affect emodin metabolism. Knockdown of UGT2B7 in HepG2 cells significantly decreased emodin glucuronidation and increased cytotoxicity of emodin. The gene expression and protein levels of UGT2B7 were decreased, but those of the multidrug-resistant-protein 2 (MRP2) were increased in HepG2 cells after being treated with 50 MUM emodin for 48 h. Long-term use of emodin could decrease the intrinsic clearance (CLint, decreased by 18.5%-35.4%) values of zidovidue (UGT2B7 substrate) glucuronide in both male and female liver microsomes from rats administrated with emodin for 28 days, thus causing the accumulation of emodin. However, higher self-induced MRP2 expression and lower hepatotoxicity were observed in emodin-treated male rats compared to that in female rats. Therefore, gender differences in the hepatotoxicity and toxicokinetics of emodin are potentially mediated by the coupling of UGT2B7 and MRP2 in vivo. PMID- 30011216 TI - Cobalt-Catalyzed Acceptorless Dehydrogenative Coupling of Primary Alcohols to Esters. AB - A novel catalytic system with a tripodal cobalt complex is developed for efficiently converting primary alcohols to esters. KO tBu is found essential to the transformation. A preliminary mechanistic study suggests a plausible reaction route that involves an initial Co-catalyzed dehydrogenation of alcohol to aldehyde, followed by a Tishchenko-type pathway to ester mediated by KO tBu. PMID- 30011217 TI - Stereospecific Ring Opening and Cycloisomerization of Aziridines with Propargylamines: Synthesis of Functionalized Piperazines and Tetrahydropyrazines. AB - Stereospecific Cu-catalyzed nucleophilic ring opening of N-sulfonylaziridines with propargylamines and subsequent hydroamination afford piperazines, which leads to double-bond isomerization to furnish tetrahydropyrazines. Optically active aziridines can be cross-coupled with high enantiomeric purities (>98% ee). PMID- 30011218 TI - Total Synthesis of Proteasome Inhibitor (-)-Omuralide through Asymmetric Ketene [2 + 2]-Cycloaddition. AB - The total synthesis of (-)-omuralide, a potent specific proteasome inhibitor, has been achieved through an unprecedented route. The C3 and C4 chiral centers of the natural product have been selectively installed by an asymmetric [2 + 2] cycloaddition between an unusual oxadisilinane ketene and a chiral enol ether, while the gamma-lactam core was prepared by a single-pot two-step Beckmann transposition. The C5 quaternary center was eventually defined by an original selective oxidative desymmetrization of a spiro cyclic oxadisilinane thanks to the anchimeric assistance of a proximal hydroxyl group. PMID- 30011219 TI - Variecolortins A-C, Three Pairs of Spirocyclic Diketopiperazine Enantiomers from the Marine-Derived Fungus Eurotium sp. SCSIO F452. AB - Three pairs of spirocyclic diketopiperazine enantiomers, variecolortins A-C (1 3), were isolated from marine-derived fungus Eurotium sp. SCSIO F452. Compound 1 possesses an unprecedented highly functionalized seco-anthronopyranoid carbon skeleton featuring a 2-oxa-7-azabicyclo[3.2.1]octane core. Compounds 2 and 3 represent rare examples of a 6/6/6/6 tetracyclic cyclohexene-anthrone carbon scaffold. Their structures were determined by spectroscopic analyses, X-ray diffraction, and ECD calculations. Their enantiomers exhibited different antioxidative and cytotoxic activities, and their modes of action were investigated. PMID- 30011220 TI - Formal Insertion of Imines (or Nitrogen Heteroarenes) and Arynes into the C-Cl Bond of Carbon Tetrachloride. AB - The formal insertion of double and triple bonds into the C-Cl bond of carbon tetrachloride has enabled the full utilization of carbon tetrachloride in chemical synthesis. A range of unactivated imines and electron-deficient nitrogen heteroarenes served as effective sources of C=N bonds to react with arynes and carbon tetrachloride to afford functionalized anilines whose core structures are present in some valuable arthropodicides. Control experiments and DFT calculations suggest the involvement of a trichloromethyl anion intermediate. PMID- 30011221 TI - Chronic Obstructive Pulmonary Disease: Back to the Basics. PMID- 30011222 TI - Nasal Positive Airway Pressure and Sleep Apnea. Reflections on an Experimental Method That Became a Therapy. PMID- 30011223 TI - NOVEL BALL HEAD SCREW AND SCREWDRIVER DESIGN FOR IMPLANT-SUPPORTED PROSTHESES WITH ANGLED CHANNELS. A FINITE ELEMENT ANALYSIS. AB - The primary objective of this study was to design the optimal geometry of a novel screwdriver; create the grooves on a ball head screw; and demonstrate its resistance to a torque of up to 40 Ncm at an angulation of 0, 15 and 30 degrees by using nonlinear finite element analysis. A secondary objective was to create a fool-proof and easily recognizable system. The grooved ball head screw and geometry of the screwdriver, functioning from an angulation of 0 degrees to 30 degrees , was generated using Pro-ENGINEER Wildfire 5.0 software. Static structural analyses between bodies in contact were performed at different angles of 0 degrees , 15 degrees and 30 degrees at a torque of 20 Ncm and 40 Ncm, using nonlinear finite element simulation by means of ANSYS 12.0. The maximum stress supported by the ball head screw and screwdriver was similar at 20 Ncm and 40 Ncm. Although greater deformations were found at 40 Ncm, these were small and might not affect the performance of the system. Besides, the rupture torque value for the M2 connection was 55 Ncm for 0 degrees and 30 degrees , and 47.5 Ncm for 15 degrees . Numerical simulation showed that the ball head system design can achieve the mechanical strength requirements expected for screws used in implant supported restorations at an angulation of up to 30 degrees . Finite element analysis showed this novel ball head screw and screwdriver system to be a good solution for angled screw channels in implant-supported prostheses. PMID- 30011224 TI - Health Policy Was Bustin' Out All Over. AB - The Trump administration refused to defend important provisions of the ACA in court and pursued rules that could open the door to less-regulated insurance options. PMID- 30011225 TI - Preservation of Lung Function in Cystic Fibrosis: Are Macrolides the Answer? PMID- 30011226 TI - Numerical model proposed for a temporomandibular joint prosthesis based on the recovery of the healthy movement. AB - The temporomandibular joint (TMJ) is an anatomical set of the buco-maxillary system that allows the movement of the mandible in most varied ways. Several factors can influence the malfunctioning of the joint and lead to the use of a total prosthesis. However, current prostheses do not supply the maximum amplitude of movement during protrusion and opening, due to mainly the anatomical differences between patients. For this reason, this article aims to study the patient's kinematic characteristics for a better comprehension of the problem and, consequently, to develop a numerical model for TMJ prostheses able to recover the healthy movement. The numerical model is based on the development of a mechanical joint whose profile is able to reproduce the movement of the health system. The results obtained through the developed model showed a good agreement with the experimental results, representing, therefore, a promising alternative to approach the problems related to TMJ. PMID- 30011227 TI - Introduction of Pieter T. J. Johnson, recipient of the Henry Baldwin Ward Medal for 2018. AB - Not applicable. PMID- 30011228 TI - Ataluren, a New Therapeutic for Alpha-1 Antitrypsin-Deficient Individuals with Nonsense Mutations. PMID- 30011229 TI - Influence of transmucosal height on loss of prosthetic abutment torque after mechanical cycling. AB - The aim of this study was to measure and record the universal transmucosal abutment height, and evaluate whether it influenced loosening of the abutment screw, by analyzing the torque and detorque values after mechanical cycling. Thirty-six (36) implants, model CM Unitite (SIN), with internal conical connections (3.5 x 10mm) and respective universal prosthetic abutments (n=36, 3.25 x 6mm), were divided into three groups (n=12 each) with respective transmucosal heights of 0.8, 3.5 and 5.5mm. Insertion torque of 20Ncm was used in accordance with the manufacturer's specifications. Afterwards, the samples were submitted to fatigue tests consisting of 500,000 cycles at a frequency of 2Hz, a dynamic compressive load of 120N, and an angle of 30o. The detorque values were measured with a digital torque meter and tabulated to perform statistical analyses; a level of significance of 5% was adopted. The mean detorque values (SD) obtained were 22.83 (6.30), 22.5 (5.45) and 19.41 (4.69) Ncm for transmucosal abutments with heights of 0.8, 3.5 and 5.5mm, respectively, and showed no statistically significant difference (p=0.262). The authors of this study concluded that the transmucosal height of prosthetic abutments submitted to mechanical fatigue did not influence the detorque values. PMID- 30011230 TI - Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells. AB - Dopamine (DA) is a key regulator of circuits controlling movement and motivation. A subset of midbrain DA neurons has been shown to express the vesicular glutamate transporter (VGLUT)2, underlying their capacity for glutamate release. Glutamate release is found mainly by DA neurons of the ventral tegmental area (VTA) and can be detected at terminals contacting ventral, but not dorsal, striatal neurons, suggesting the possibility that target-derived signals regulate the neurotransmitter phenotype of DA neurons. Whether glutamate can be released from the same terminals that release DA or from a special subset of axon terminals is unclear. Here, we provide in vitro and in vivo data supporting the hypothesis that DA and glutamate-releasing terminals in mice are mostly segregated and that striatal neurons regulate the cophenotype of midbrain DA neurons and the segregation of release sites. Our work unveils a fundamental feature of dual neurotransmission and plasticity of the DA system.-Fortin, G. M., Ducrot, C., Giguere, N., Kouwenhoven, W. M., Bourque, M.-J., Pacelli, C., Varaschin, R. K., Brill, M., Singh, S., Wiseman, P. W., Trudeau, L.-E. Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells. PMID- 30011231 TI - Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics. AB - Many medications including antibiotics taste bitter. The potency of these antibiotics on the 25 bitter taste receptors (T2Rs) in humans remains poorly understood. Here we characterize by sensory and structure-function analyses how antibiotics frequently used to treat airway infections in cystic fibrosis activate multiple human T2Rs. The potency of the broad-spectrum antibiotics, tobramycin, levofloxacin, and azithromycin on the highly expressed T2Rs in airways, T2R4, T2R14, and T2R20 was pursued. The amino acids and structural features of T2R4, T2R14, and T2R20 important for antibiotic binding were characterized by mutational analysis in heterologous cell-based assays. Strikingly, extracellular loop 2 in T2Rs performs a key function in binding to antibiotics with contribution from residues in transmembrane helices. Our results suggest that different antibiotics activate multiple T2Rs with different potencies. An understanding of the nonantibiotic and physiologic effects mediated through T2Rs on the host cells is much needed.-Jaggupilli, A., Singh, N., De Jesus, V. C., Gounni, M. S., Dhanaraj, P., Chelikani, P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics. PMID- 30011232 TI - Buried bumper syndrome: do we have enough evidence? AB - Buried Bumper Syndrome (BBS) is a rare complication of percutaneous endoscopic gastrostomy (PEG) tubes. Advice in prevention guidelines differ, but locally agreed protocols can be agreed using the existing evidence. Consideration needs to be given as to how tightly a PEG is clipped after insertion to prevent gastric leakage, and how long after the procedure should it be loosened to prevent BBS. The distance a PEG tube is advanced and whether it should be rotated is also important in order to prevent BBS. The locally developed protocols need to include clear instructions for staff and patients and a supportive education programme, alongside clear record keeping. PMID- 30011233 TI - Interview with Sue Green. PMID- 30011234 TI - Delivering a home enteral feeding service to the residents of Trafford. AB - The number of patients receiving Home Enteral Tube Feeding (HETF) has increased over a number of years. Some patients may have a short term nasogastric/nasojejunal tube placed to help them achieve their nutritional requirements in the short term. Other patients may need to be fed via a gastrostomy tube, either fully or in combination with oral diet long-term. It is important that all patients on HETF receive regular and continuous support. In light of this, Trafford NHS Trust has established a multi-professional nutrition support clinic. PMID- 30011235 TI - Coping with difficult conversations as a nurse and how can services be improved? PMID- 30011236 TI - Nutritional care in Chronic Obstructive Pulmonary Disease. AB - The aim of this article is to provide an overview of the importance of good nutritional care in chronic obstructive pulmonary disease (COPD). It will highlight the importance of nutritional screening and discuss the Managing Malnutrition Pathway in COPD published by BAPEN in 2016. The remainder of the article will provide guidance on what nutritional advice should be provided to COPD patients while undertaking pulmonary rehabilitation. PMID- 30011237 TI - Challenging the status quo and shaping the future. PMID- 30011238 TI - Nasojejunal tube feeding in children: knowledge and practice. AB - Nasojejunal tubes (NJ) are used in small numbers of children outside of neonatal and paediatric intensive care units. There is limited evidence on which to base practice aside from insertion techniques. Ongoing care and management is largely based on historical practice and extrapolation from nasogastric tube practice. This paper presents the historical caseload data for 36 babies and children over a five year period. The children ranged from 0 to 13 years of age, and 95% were less than 2 years old. They had a median of 4 tubes each (range 1 - 46). The paper presents data from two surveys of health professionals that demonstrate a lack of consistency in practice. There are concerns about ongoing position checks and about the radiation burden in these children. Local practice is described that aims to reduce dependence on x-ray procedures and to stimulate debate. Finally, an argument is made for a better evidence base for future practice. PMID- 30011239 TI - How to select the appropriate "neoadjuvant therapy" for hepatocellular carcinoma. PMID- 30011240 TI - ASSOCIATION OF SMOKING HABITS AND HEIGHT OF RESIDUAL BONE ON IMPLANT SURVIVAL RATE IN LATERAL SINUS LIFT: A RETROSPECTIVE STUDY. AB - The primary aim was to evaluate the association of patient related factors, biomaterials and implant characteristics on complications' rate of sinus graft surgery and on implant survival rate in grafted sinus. Secondary aims were to measure bone remodelling around implants and the patients' satisfaction. A retrospective cohort study was designed. Patients who had computer tomography before sinus surgery (T0), orthopantomography after implant surgery (T1) and at follow-up (T2), were included. Specific forms were used to collect clinical data. Radiographic measures were: height of residual bone before sinus surgery measured on computer tomography (T0) and apical and marginal bone levels around implants measured on orthopantomography at T1 and T2. Forty-three lateral sinus lifts were performed. Three grafts failed before implant insertion. Out of 83 implants inserted in 29 patients, a total of 19 failed. Mean follow-up (T2) was 6+/-1,8 years [4;11.2 years]. The multilevel models analysis showed no association between complications' rate and patient related factors, biomaterials and implant characteristics. Smoking (OR of 8.3 - 95%CI 1.46; 48.05, P = 0.0173) and height of residual bone (OR of 0.32 for each mm - 95%CI 0.15; 0.68, P = 0.0034) were associated with implant failure Bone remodelling between T1 and T2 was -0.8+/-0.2 mm for apical bone and -0.6+/-0.3mm for marginal bone. General therapy satisfaction measured in a visual analogue scale was 8.4 +/-1.4. In conclusion lower height of residual bone before sinus surgery and smoking habits had a negative prognostic effect on survival rate of dental implants placed in grafted sinuses. PMID- 30011242 TI - First Report of Gastrointestinal Parasites from Ansell's Mole-Rat ( Fukomys anselli) in Zambia. AB - The endoparasite fauna of Ansell's mole-rat, Fukomys anselli (Burda, Zima, Scharff, Macholan and Kawalika) (Rodentia, Bathyergidae), was studied for the first time near Lusaka, Zambia. We recovered 7 endoparasite taxa including 5 nematodes ( Hexametra sp.; Protospirura numidica Seurat, 1914; Protospirura muricola Gedoelst, 1916; Protospirura sp.; and Mammalakis zambiensis Junker, Lutermann and Mutafchiev, 2017 ); and 2 cestodes ( Inermicapsifer sp. and Rodentolepis cf. microstoma Dujardin, 1845) from 272 individuals sampled between February 2009 and February 2010. Species richness (0-2), prevalence (14.7%), and abundance (0.44 +/- 0.10) were low, probably as a result of the subterranean lifestyle of the study species. Although effect of host sex on helminth burden was largely absent, helminth burden varied with season and breeding status of the host. This may be a result of seasonal variation in burrow size in response to rainfall, but also the division of labor present in the study species. PMID- 30011241 TI - Homogeneous BTK Occupancy Assay for Pharmacodynamic Assessment of Tirabrutinib (GS-4059/ONO-4059) Target Engagement. AB - Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation. We developed a novel duplex homogeneous BTK occupancy assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to measure free and total BTK levels in a multiplexed format. The dual-wavelength emission property of terbium-conjugated anti-BTK antibody served as the energy donor for two fluorescent energy acceptors with distinct excitation and emission spectra. The assay was characterized and qualified using full-length purified recombinant human BTK protein and peripheral blood mononuclear cells derived from healthy volunteers and patients with CLL. We demonstrated assay utility using cells derived from lymph node and bone marrow samples from patients with CLL and DLBCL. Our TR-FRET-based BTK occupancy assay provides accurate, quantitative assessment of BTK occupancy in the clinical trial program for tirabrutinib and is in use in ongoing clinical studies. PMID- 30011243 TI - Presentation of the 2018 ASP Distinguished Service Award to Dennis J. Minchella. PMID- 30011244 TI - Real vs. virtual position of single implants installed in pre-maxilla via guided surgery: A proof of concept analyzing positional deviations. AB - The aim of this research letter was to report the results of a pilot study designed to compare the real and virtual position of implants placed using computer-guided flapless implant surgery for single restorations in the pre maxilla. A total of 8 patients (2 men and 6 women) with a mean age of 40 years (32-73 years) had a total of 11 implants inserted using a tooth-supported stereolithographic guide. After implant placement, the positions (coronal, central, and apical) and angulation of the implants installed in relation to those planned were determined via the superposition of pre- and postoperative 3D models using Dental Slice software (Bioparts, Brasilia, Brazil). The mean angular deviation was 2.54 +/- 0.71 degrees . The deviations found for the coronal, central, and apical positions were 1.3 +/- 0.77 mm, 1.49 +/- 0.58 mm, and 2.13 +/ 1.32 mm, respectively. PMID- 30011245 TI - Time-Interval Emphasis in an Aeronautical Dual-Task Context: A Countermeasure to Task Absorption. AB - OBJECTIVE: We tested a training method intended to prevent unsafe aeronautical behavior (i.e., too much time spent gazing inside the cockpit) induced by the modern cockpit, by teaching individuals to perform a task complementing the see and-avoid mandatory safety task within a limited time interval. BACKGROUND: Aeronautical activities led crews to perform several tasks simultaneously in an ergonomic environment under constant change. See and avoid remains one of the main safety tasks during visual flight. However, modern cockpits induce absorption and impair performance of this safety task. Many laboratory studies showed the relevance of training methods for managing dual-task situations and estimating time intervals. METHOD: A specific virtual environment was developed to expose participants to a dual-task situation in which time-interval emphasis was provided in real time. Two types of emphasis training were tested: a permissive one that allowed participants to pursue the inside-cockpit task beyond the time limit and a nonpermissive one that did not. RESULTS: The best time interval acquisition, with retention up to 24 hr later, was observed in the nonpermissive condition, but task performances immediately after the training sessions were equivalent across conditions. CONCLUSION: Time-emphasis training appears to be an efficient means of promoting absorption resistance while preserving task performance. Transferability of time-interval estimation skills has yet to be tested. APPLICATION: Most areas of application for absorption resistance (aviation, shipping, rail, road, etc.) could benefit from this type of training to manage multitask situations. PMID- 30011246 TI - Helminth Infracommunities of the Montezuma's Frog Lithobates montezumae (Anura: Ranidae) in the Nearctic-Neotropical Transition Zone of Mexico. AB - Thirty specimens of the Montezuma's frog Lithobates montezumae were collected in San Pedro Tlaltizapan, in the Nearctic-Neotropical transition zone of Mexico, in April 2013, in order to establish the helminth infracommunity structure harbored by this amphibian host. A total of 5,493 individual helminths were obtained, representing 6 species (3 trematodes and 3 nematodes). The depauperate structure of the helminth infracommunities established for the studied frogs herein (richness = 2.4; mean abundance = 183.1; Brillouin's diversity = 0.42) fits with those described for the 6 Ranidae species studied in the Nearctic. Three of the 6 species of helminths recovered are generalists, 2 of them with the highest values for prevalence ( Falcaustra mexicana) and mean abundance ( Renifer sp.). The parasite recruitment process (ingestion) determining mean richness in the helminth infracommunities studied here (ingestion) is shared with those reported for the 9 Mexican frog species for which helminthological records exist; however, in this case, mean abundance was determined by directly penetrating species. The use of aquatic habits by this anuran species likely explains why the composition of their helminth infracommunities was mainly constituted of helminths acquired in this environment (5 of 6 species). Finally, the heterogeneity of their taxonomic composition and abundance of helminth species indicate the unpredictable nature of these host-parasite associations. PMID- 30011247 TI - Dynamic Alignment-Free and Reference-Free Read Compression. AB - The advent of high throughput sequencing (HTS) technologies raises a major concern about storage and transmission of data produced by these technologies. In particular, large-scale sequencing projects generate an unprecedented volume of genomic sequences ranging from tens to several thousands of genomes per species. These collections contain highly similar and redundant sequences, also known as pangenomes. The ideal way to represent and transfer pangenomes is through compression. A number of HTS-specific compression tools have been developed to reduce the storage and communication costs of HTS data, yet none of them is designed to process a pangenome. In this article, we present dynamic alignment free and reference-free read compression (DARRC), a new alignment-free and reference-free compression method. It addresses the problem of pangenome compression by encoding the sequences of a pangenome as a guided de Bruijn graph. The novelty of this method is its ability to incrementally update DARRC archives with new genome sequences without full decompression of the archive. DARRC can compress both single-end and paired-end read sequences of any length using all symbols of the IUPAC nucleotide code. On a large Pseudomonas aeruginosa data set, our method outperforms all other tested tools. It provides a 30% compression ratio improvement in single-end mode compared with the best performing state-of the-art HTS-specific compression method in our experiments. PMID- 30011248 TI - Preface: Selected Articles from RECOMB 2017. PMID- 30011249 TI - Longitudinal Genotype-Phenotype Association Study through Temporal Structure Auto Learning Predictive Model. AB - With the rapid development of high-throughput genotyping and neuroimaging techniques, imaging genetics has drawn significant attention in the study of complex brain diseases such as Alzheimer's disease (AD). Research on the associations between genotype and phenotype improves the understanding of the genetic basis and biological mechanisms of brain structure and function. AD is a progressive neurodegenerative disease; therefore, the study on the relationship between single nucleotide polymorphism (SNP) and longitudinal variations of neuroimaging phenotype is crucial. Although some machine learning models have recently been proposed to capture longitudinal patterns in genotype-phenotype association studies, most machine-learning models base the learning on fixed structure among longitudinal prediction tasks rather than automatically learning the interrelationships. In response to this challenge, we propose a new automated time structure learning model to automatically reveal the longitudinal genotype phenotype interactions and exploits such learned structure to enhance the phenotypic predictions. We proposed an efficient optimization algorithm for our model and provided rigorous theoretical convergence proof. We performed experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort for longitudinal phenotype prediction, including 3123 SNPs and 2 biomarkers (Voxel Based Morphometry and FreeSurfer). The empirical results validate that our proposed model is superior to the counterparts. In addition, the best SNPs identified by our model have been replicated in the literature, which justifies our prediction. PMID- 30011250 TI - Effect of soybean oil availabilities on rumen biohydrogenation and duodenal flow of fatty acids in beef cattle fed a diet with crude glycerine. AB - Soybean oil with different ruminal availability (whole soybeans (WS), soybean oil (SO) and calcium salts (CS)) was used to evaluate the fatty acid (FA) intake, rumen biohydrogenation (BH) and duodenal flow of FA in Nellore steers fed diets with crude glycerine (CG). Eight castrated Nellore steers were fitted with a ruminal and duodenal silicone cannula, and distributed in a double, simultaneous, Latin square 4 * 4 design with four diets and four experimental periods. Concentrates contained ground maize, urea, mineral salts, CG (100 g/kg DM) and soybean products with different availability of soybean oil: (1) no additional fat (CO), (2) WS, (3) SO or (4) CS. Fat supplementation was fixed to obtain 50 g ether extract/kg DM. Experimental treatments had no effect on DM intake, DM duodenal flow or ruminal turnover rate of C:16 FA. However, fat addition increased C:18 and turnover rates of total FA rumen (p < 0.05). CS resulted in lower C:18 turnover rates and lower ruminal BH of monounsaturated and unsaturated FA (UFA) than WS (p < 0.05). SO resulted in a greater duodenal flow of C18:0 (stearic acid), C18:1t-11 (vaccenic acid) and saturated FA than the WS and CS diets (p < 0.05). CS resulted in a higher duodenal flow of C18:3n-3 (linolenic acid) than WS (p < 0.05). The association of CG and calcium salts in Nellore steers was the best nutritional strategy to increase duodenal flow of healthier UFA, which may increase the deposition of these FA in meat. However, SO associated with CG association increased the duodenal flow of vaccenic acid, which is main precursor of endogenous synthesis of conjugated linoleic acids in tissues. PMID- 30011251 TI - Teaching Kitchen Collaborative Research Day February 7, 2018. PMID- 30011252 TI - Lateral Epicondylitis "Placebo" Surgery Was Actually a Lateral Denervation Procedure: Letter to the Editor. PMID- 30011253 TI - Should Surgical Repair Be Recommended Over Nonoperative Management for Medial Meniscus Root Tears? Response. PMID- 30011254 TI - Should Surgical Repair Be Recommended Over Nonoperative Management for Medial Meniscus Root Tears? Letter to the Editor. PMID- 30011255 TI - Lateral Epicondylitis "Placebo" Surgery Was Actually a Lateral Denervation Procedure: Response. PMID- 30011256 TI - Use of the False-Profile Radiographic View to Measure Pelvic Incidence. AB - BACKGROUND: Pelvic incidence (PI) is an important variable in assessing spinopelvic balance that is associated with hip pathology. A lateral radiograph of the pelvis can be used to measure PI, but this view is not routinely performed in the clinical setting during evaluation of hip pain. The false-profile (FP) radiographic view of the hip is commonly obtained to measure acetabular coverage. PURPOSE: To evaluate the tolerance of PI measurements to pelvic rotation and assess the feasibility of using an FP radiograph to obtain an accurate measurement of PI. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A mathematical model was developed to predict the change in PI with rotation. Fluoroscopic images were obtained of 6 reconstructed cadaveric adult pelvis and femur specimens at varying degrees of rotation, including a perfect lateral and FP image. PI was measured with the midpoint between the centers of the femoral heads as a reference point. The findings were confirmed clinically by retrospectively reviewing FP radiographs and computed tomography (CT) scans of 40 clinical patients. PI was measured on FP radiographs and CT scans by 2 independent reviewers. RESULTS: With dry cadaveric pelvis specimens, the discrepancy in PI measured between fluoroscopic FP and lateral views was 1.6 degrees (95% CI, 0.7 degrees -2.4 degrees ). There was excellent agreement between CT and FP radiographs with regard to measurement of PI (intraclass correlation coefficient = 0.92; 95% CI, 0.78-0.98). Mean discrepancy in PI measured between the 40 clinical FP radiographs and CT scans was 2.8 degrees (range, 0.1 degrees -9.1 degrees ). CONCLUSION: Increased rotation from a lateral view results in greater error in measuring PI, although relatively nominally with a 2.8 degrees error with the 25 degrees of rotation in clinical true FP views. These data demonstrate that FP radiographs can be used to measure PI with reasonable accuracy. PMID- 30011257 TI - Therapeutic Efficacy of Spherical Aggregated Human Bone Marrow-Derived Mesenchymal Stem Cells Cultured for Osteochondral Defects of Rabbit Knee Joints. AB - BACKGROUND: Engraftment and longevity of transplanted cells are crucial for stem cell-based cartilage treatment. PURPOSE: To determine whether cultured spherical cell masses of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) could improve engraftment at defect sites and to examine their corresponding effects on osteochondral regeneration. STUDY DESIGN: Controlled laboratory study. METHODS: A cylindrical osteochondral defect (5 mm wide * 5 mm deep) was created in trochlear grooves of rabbit knees. The single-cell type of hBM-MSCs with fibrin glue, the spherical type of hBM-MSCs with fibrin glue, and cell-free fibrin glue (control) were each implanted into osteochondral defect sites. A total of 18 rabbit knees were randomly assigned to 1 of the 3 groups (3 rabbits per group). Animals were sacrificed at 6 and 12 weeks after transplantation. Repaired tissues were evaluated via gross examination, histologic examination, and immunofluorescence analysis. RESULTS: Transplantation with spherical hBM-MSCs exhibited superior overall osteochondral restoration when compared with the single-type group, as evidenced by well-ordered mature collagen fibrils produced during subchondral bone formation in the zonation phenomenon. Immunofluorescence analysis of osteochondral defect areas with human-specific antigen revealed a larger number of mesenchymal stem cells in the spherical-type group than the single cell-type group. CONCLUSION: Transplantation of spherical hBM-MSCs was better than single cells from monolayer culture in improving osteochondral regeneration. CLINICAL RELEVANCE: The findings demonstrate a simple strategy for enhancing the potency of stem cells required for restoration of osteochondral defects. Furthermore, this strategy may be implemented with other types of stem/progenitor cell-based therapies. PMID- 30011258 TI - The PDR-type ABC transporters AtrA and AtrG are involved in azole drug resistance in Aspergillus oryzae. AB - For strain improvement of Aspergillus oryzae, development of the transformation system is essential, wherein dominant selectable markers, including drug resistant genes, are available. However, A. oryzae generally has a relatively high resistance to many antifungal drugs effective against yeasts and other filamentous fungi. In the course of the study, while investigating azole drug resistance in A. oryzae, we isolated a spontaneous mutant that exhibited high resistance to azole fungicides and found that pleiotropic drug resistance (PDR) type ATP-binding cassette (ABC) transporter genes were upregulated in the mutant; their overexpression in the wild-type strain increased azole drug resistance. While deletion of the gene designated atrG resulted in increased azole susceptibility, double deletion of atrG and another gene (atrA) resulted in further azole hypersensitivity. Overall, these results indicate that the ABC transporters AtrA and AtrG are involved in azole drug resistance in A. oryzae. PMID- 30011259 TI - Purchasing Over The Counter (OTC) Medicinal Products Containing Codeine - Easy Access, Advertising, Misuse and Perceptions of Medicinal Risk. AB - PURPOSE: Codeine containing medicines can carry a number of health risks associated with the increase in reported misuse and dependence, however they are still readily available over the counter (OTC) in many countries. The aim of this novel study was to report on the results of a survey of customers purchasing OTC codeine containing medicinal products at pharmacies in Ireland, South Africa and England; exploring use, sources of knowledge and perception of risks. METHODS: The study design was an exploratory cross sectional survey. It involved a customer self-administered questionnaire at the point of purchase (n=1230). Relationships between categorical variables were analysed using Pearson chi square for bivariate analysis. Continuous scale variables were analysed using one way analysis of variance. RESULTS: In Ireland 6% stated they purchased codeine containing products weekly, in South Africa 13% and in England 16%. In Ireland and England women are more likely to view codeine containing products as harmful. In England older adults are more likely to perceive codeine containing products as harmful. A higher proportion of customers in South Africa opposed restricting codeine containing products to prescription only when compared with people in Ireland and England. CONCLUSIONS: Codeine containing products are widely purchased and used in all three jurisdictions. Whilst the majority of customers appear to have some awareness and knowledge of risks, it does not materially impact on their purchasing behaviour with a substantial minority purchasing/using such products on a weekly basis. This regularity of purchase whilst indicative of the popularity of such products, may also be a potential indicator of misuse. Future research is needed in relation to cultural and gendered differences and targeted information giving and harm reduction initiatives for safe usage of these medicinal products. PMID- 30011260 TI - A Combined Computer-Aided Approach to Drive the Identification of Potential Epitopes in Protein Therapeutics. AB - BACKGROUND: The identification of fragment sequences, or motifs, within a therapeutic protein that may elicit an immune response when processed by T-cells can be provided by computer-aided approaches. Immunogenicity is a significant problem associated with protein therapeutics and should be investigated in the early stage of protein-based drug development to avoid treatment resistance and potentially life-threatening immune responses. PURPOSE: To provide a combined computer-aided protocol for investigating the immunogenic profile of a recombinant Kunitz-type inhibitor, which has been reported as promising antitumor agent by our research group. METHODS: The combination of databases searching (IEDB and SYFPEITHI) and molecular docking simulations was exploited, herein. This combined protocol has allowed the identification of potential epitopes before in vitro/in vivo evaluation. Predictors of human proteasome cleavage transport and major histocompatibility complex (MHC) binding were considered as overall score assigning the corresponding intrinsic potential of being a T cell epitope to each fragment sequence. The peptides or motifs better classified in the two databases were docked into the three-dimensional (3D) structure of MHC (class I and II) complex to verify the calculated binding affinity. The binding interactions regarding the molecular recognition process by T-cells were also exploited through the MHC:ligand:T-cell complexes. RESULTS: Regarding the Kunitz type sequence, four motifs were identified as potentially epitopes for MHC-I and three motifs were found for MHC-II. But, those motifs were classified as moderately immunogenic. Final remarks: The combined computer-aided protocol has significantly reduced the number of potential epitopes to be considered for further analysis and could be useful to identify immunogenic fragments (high, moderate and low) in protein pharmaceutics before in vitro/in vivo experimentation. PMID- 30011261 TI - Factors Affecting Opioid Treatment in Cancer Patients. AB - PURPOSE: Pain is prevalent in cancer patients, appearing to be moderate to severe in more than one third of them. Despite the fact that fentanyl is widely used with effective analgesic results, some patients do not correspond to treatment, resulting in opioid change. METHODS: This is a cohort study, performed in Greek patients with cancer. Its scope was to identify potential reasons responsible for opioid change, due to transdermal-fentanyl intolerance, resulting from inadequate analgesia (pain relief<33% in 1week) and/or unacceptable adverse-events (grade>=3 at Common Terminology Criteria-v4.0). The final sample included 289 participants. To investigate responsible reasons for transdermal-fentanyl intolerance we studied its relation with patients' history, haematology, biochemistry, body-mass index, demographic and disease related characteristics. The Eastern Cooperative Oncology Group performance status scale, the Mini Mental State Examination questionnaire, the M.D.Anderson Symptom Inventory and the Greek Brief Pain Inventory were also used to measure performance status and quality-of-life for the same reason. RESULTS: Almost one third of the patients had to change to an alternative opioid oral-morphine in order to achieve adequate analgesia or/and avoid adverse-events. The most common adverse-events observed were nausea/vomiting and sleepiness. Statistical analysis demonstrated that younger age (OR=0.976) and obesity (OR=0.29 against underweight, OR=0.39 against normal, OR=0.48 against pre-obese) had a higher possibility to contribute to modification of the analgesic treatment. Furthermore, a higher impact of symptoms in patient's life (OR=1.184) and chemotherapy (OR=2.109) could also contribute to the need of change of the opioid analgesic medication. CONCLUSION: This study found significant variables for transdermal-fentanyl intolerance. This knowledge may help person-center care in moderate to severe cancer pain. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 30011262 TI - Mechanisms Behind Blood Flow Restricted Training and its Effect Towards Muscle Growth. AB - It is widely established throughout the literature that skeletal muscle can induce hypertrophic adaptations following progressive overload of moderate to high-intensity resistance training. However, there has recently been a growing body of research that shows that the combination of blood flow restriction (BFR) with low intensity resistance exercise can induce similar gains in muscular strength and hypertrophic adaptations. The implementation of external pressure cuffs over the most proximal position of the limb extremities with the occlusion of venous outflow of blood distal to the occlusion site defines the BFR methodological protocol. There are various mechanisms through which BFR training may cause the stimulations for skeletal muscle hypertrophy and increases in strength. These may include increases in hormonal concentrations, increases within the components of the intracellular signaling pathways for muscle protein synthesis such as the mTOR pathway, increases within biomarkers denoting satellite cell activity as well as apparent patterns in fiber type recruitment. There have also been scientific findings demonstrating hypertrophic effects within both blood-flow restricted limbs and non-blood flow-restricted muscles during BFR training programs. The purpose behind this critical review will be to provide a comprehensive discussion on relevant literature that can help elucidate the potential underlying mechanisms leading to hypertrophic adaptations following BFR training programs. This review will also explicate the various findings within the literature that focalizes on both blood flow-restricted limb and non blood flow-restricted muscle hypertrophy following bouts of BFR training. Furthermore, this critical review will also address the various needs for future research in the many components underlying the novel modality of BFR training. PMID- 30011264 TI - Sometimes you're the scooper, and sometimes you get scooped: How to turn both into something good. AB - Fast-moving, competitive fields often inadvertently duplicate research. In a research environment that values being first over being robust, this results in one manuscript "scooping" ongoing research from other groups. Opportunities to demonstrate the solidity of a result through coincidental reproduction are thus lost. Here, two group leaders, one the scooper and one the scoopee, discuss their experiences under PLOS Biology's new "complementary research" policy. In this case, submission of the second article followed publication of the first by mere days. Scooper and scoopee discuss how complementary research is good for everyone by expanding the scientific reach of studies that are overlapping but not identical, demonstrating the robustness of related results, increasing readership for both authors, and making "replication" studies cost effective by creatively using resources that have already been spent. PMID- 30011263 TI - miR-106a Reduces 5-Fluorouracil (5-FU) Sensitivity of Colorectal Cancer by Targeting Dual-Specificity Phosphatases 2 (DUSP2). AB - BACKGROUND 5-Fluorouracil (5-FU)-based chemotherapy is a conventional therapeutic approach for the treatment of patients with colorectal cancer (CRC). However, development of 5-FU resistance frequently occurs. We explored a potential method for regulating the sensitivity to 5-FU-based chemotherapy in CRC patients. MATERIAL AND METHODS Cell viability was determined by 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Gene expression levels were detected by real-time quantitative polymerase chain reaction (RT qPCR). Protein expression levels were evaluated by Western blot. TargetScan was used for the prediction of binding sites for miRNA in mRNAs. The interaction between mRNA 3'UTR and miRNA was verified by dual luciferase reporter assay. Tissue samples were obtained from 33 CRC patients who received surgery at Xingtai People's Hospital. RESULTS miR-106a level was associated with 5-FU sensitivity in CRC cells. Overexpression of miR-106a reduced 5-FU sensitivity of HCT116 and SW620 cells, and antagonist of miR-106a sensitized HCT116 and SW620 towards 5-FU. miR-106a overexpression decreased dual-specificity phosphatases 2 (DUSP2) expression at mRNA and protein levels in HCT116 and SW620 cells. Through downregulation of DUSP2, miR-106a elevation increased COX-2 expression and stemness-maintenance genes (SOX2 and OCT4). Furthermore, we predicted that miR 106a directly binds to 3'UTR of DUSP2 mRNA, which was confirmed by dual luciferase assay. Silencing of DUSP2 reversed elevated 5-FU sensitivity induced by miR-106a antagonist in HCT116 cells. A negative correlation was discovered between miR-106a and DUSP2 in tumor samples of CRC patients. CONCLUSIONS miR-106a plays an important role in mediating response to 5-FU-based chemotherapy in CRC and could serve as a potential target for CRC patients. PMID- 30011265 TI - The lncRNA male-specific abdominal plays a critical role in Drosophila accessory gland development and male fertility. AB - Although thousands of long non-coding RNAs (lncRNA) have been identified in the genomes of higher eukaryotes, the precise function of most of them is still unclear. Here, we show that a >65 kb, male-specific, lncRNA, called male-specific abdominal (msa) is required for the development of the secondary cells of the Drosophila male accessory gland (AG). msa is transcribed from within the Drosophila bithorax complex and shares much of its sequence with another lncRNA, the iab-8 lncRNA, which is involved in the development of the central nervous system (CNS). Both lncRNAs perform much of their functions via a shared miRNA embedded within their sequences. Loss of msa, or of the miRNA it contains, causes defects in secondary cell morphology and reduces male fertility. Although both lncRNAs express the same miRNA, the phenotype in the secondary cells and the CNS seem to reflect misregulation of different targets in the two tissues. PMID- 30011266 TI - Cancerin: A computational pipeline to infer cancer-associated ceRNA interaction networks. AB - MicroRNAs (miRNAs) inhibit expression of target genes by binding to their RNA transcripts. It has been recently shown that RNA transcripts targeted by the same miRNA could "compete" for the miRNA molecules and thereby indirectly regulate each other. Experimental evidence has suggested that the aberration of such miRNA mediated interaction between RNAs-called competing endogenous RNA (ceRNA) interaction-can play important roles in tumorigenesis. Given the difficulty of deciphering context-specific miRNA binding, and the existence of various gene regulatory factors such as DNA methylation and copy number alteration, inferring context-specific ceRNA interactions accurately is a computationally challenging task. Here we propose a computational method called Cancerin to identify cancer associated ceRNA interactions. Cancerin incorporates DNA methylation, copy number alteration, gene and miRNA expression datasets to construct cancer-specific ceRNA networks. We applied Cancerin to three cancer datasets from the Cancer Genome Atlas (TCGA) project. Our results indicated that ceRNAs were enriched with cancer related genes, and ceRNA modules in the inferred ceRNA networks were involved in cancer-associated biological processes. Using LINCS-L1000 shRNA-mediated gene knockdown experiment in breast cancer cell line to assess accuracy, Cancerin was able to predict expression outcome of ceRNA genes with high accuracy. PMID- 30011267 TI - Heterogeneity of Orientia tsutsugamushi genotypes in field-collected trombiculid mites from wild-caught small mammals in Thailand. AB - Trombiculid mites are the vectors of scrub typhus, with infected larval mites (chiggers) transmitting the causative agent, Orientia tsutsugamushi, during feeding. Co-existence of multiple O. tsutsugamushi strains within infected mites has previously been reported in naturally infected, laboratory-reared mite lines using molecular methods to characterize the 56-kDa type-specific antigen (TSA) gene. In the current study, more advanced next-generation sequencing technology was used to reveal the heterogeneity of O. tsutsugamushi genotypes in field collected trombiculid mites from rodents and small mammals in scrub typhus endemic areas of Thailand. Twenty-eight trombiculid mites collected from 10 small mammals were positive for O. tsutsugamushi, corresponding to a prevalence rate of 0.7% within the mite population. Twenty-four of the infected mites were Leptotrombidium spp., indicating that this genus is the main vector for O. tsutsugamushi transmission in Thailand. In addition, O. tsutsugamushi was detected in the mite genera Ascoschoengastia, Blankaartia, Gahrliepia, and Lorillatum. Of the 10 infested small animal hosts, six had 2-10 infected mites feeding at the time of collection. Deep sequencing was used to characterize mixed infections (two to three O. tsutsugamushi genotypes within an individual mite), and 5 of the 28 infected mites (17.9%) contained mixed infections. Additionally, 56-kDa TSA gene sequence analysis revealed identical bacterial genotypes among co feeding mites with single or mixed infections. These results suggest that co feeding transmission may occur during the feeding process, and could explain the occurrence of mixed infections in individual mites, as well as the recovery of multiple infected mites from the same host. This study also revealed highly diverse within-host O. tsutsugamushi genotypes. The occurrence of multiple O. tsutsugamushi genotypes within individual mites has important implications, and could provide a mechanism for pathogen evolution/diversification in the mite vector. PMID- 30011268 TI - In vitro-transcribed guide RNAs trigger an innate immune response via the RIG-I pathway. AB - Clustered, regularly interspaced, short palindromic repeat (CRISPR)-CRISPR associated 9 (Cas9) genome editing is revolutionizing fundamental research and has great potential for the treatment of many diseases. While editing of immortalized cell lines has become relatively easy, editing of therapeutically relevant primary cells and tissues can remain challenging. One recent advancement is the delivery of a Cas9 protein and an in vitro-transcribed (IVT) guide RNA (gRNA) as a precomplexed ribonucleoprotein (RNP). This approach allows editing of primary cells such as T cells and hematopoietic stem cells, but the consequences beyond genome editing of introducing foreign Cas9 RNPs into mammalian cells are not fully understood. Here, we show that the IVT gRNAs commonly used by many laboratories for RNP editing trigger a potent innate immune response that is similar to canonical immune-stimulating ligands. IVT gRNAs are recognized in the cytosol through the retinoic acid-inducible gene I (RIG-I) pathway but not the melanoma differentiation-associated gene 5 (MDA5) pathway, thereby triggering a type I interferon response. Removal of the 5'-triphosphate from gRNAs ameliorates inflammatory signaling and prevents the loss of viability associated with genome editing in hematopoietic stem cells. The potential for Cas9 RNP editing to induce a potent antiviral response indicates that care must be taken when designing therapeutic strategies to edit primary cells. PMID- 30011269 TI - Modulation of miR-210 alters phasing of circadian locomotor activity and impairs projections of PDF clock neurons in Drosophila melanogaster. AB - Single microRNAs are usually associated with hundreds of putative target genes that can influence multiple phenotypic traits in Drosophila, ranging from development to behaviour. We investigated the function of Drosophila miR-210 in circadian behaviour by misexpressing it within circadian clock cells. Manipulation of miR-210 expression levels in the PDF (pigment dispersing factor) positive neurons affected the phase of locomotor activity, under both light-dark conditions and constant darkness. PER cyclical expression was not affected in clock neurons, however, when miR-210 was up-regulated, a dramatic alteration in the morphology of PDF ventral lateral neuron (LNv) arborisations was observed. The effect of miR-210 in shaping neuronal projections was confirmed in vitro, using a Drosophila neuronal cell line. A transcriptomic analysis revealed that miR-210 overexpression affects the expression of several genes belonging to pathways related to circadian processes, neuronal development, GTPases signal transduction and photoreception. Collectively, these data reveal the role of miR 210 in modulating circadian outputs in flies and guiding/remodelling PDF positive LNv arborisations and indicate that miR-210 may have pleiotropic effects on the clock, light perception and neuronal development. PMID- 30011270 TI - Inter-subunit interactions drive divergent dynamics in mammalian and Plasmodium actin filaments. AB - Cell motility is essential for protozoan and metazoan organisms and typically relies on the dynamic turnover of actin filaments. In metazoans, monomeric actin polymerises into usually long and stable filaments, while some protozoans form only short and highly dynamic actin filaments. These different dynamics are partly due to the different sets of actin regulatory proteins and partly due to the sequence of actin itself. Here we probe the interactions of actin subunits within divergent actin filaments using a comparative dynamic molecular model and explore their functions using Plasmodium, the protozoan causing malaria, and mouse melanoma derived B16-F1 cells as model systems. Parasite actin tagged to a fluorescent protein (FP) did not incorporate into mammalian actin filaments, and rabbit actin-FP did not incorporate into parasite actin filaments. However, exchanging the most divergent region of actin subdomain 3 allowed such reciprocal incorporation. The exchange of a single amino acid residue in subdomain 2 (N41H) of Plasmodium actin markedly improved incorporation into mammalian filaments. In the parasite, modification of most subunit-subunit interaction sites was lethal, whereas changes in actin subdomains 1 and 4 reduced efficient parasite motility and hence mosquito organ penetration. The strong penetration defects could be rescued by overexpression of the actin filament regulator coronin. Through these comparative approaches we identified an essential and common contributor, subdomain 3, which drives the differential dynamic behaviour of two highly divergent eukaryotic actins in motile cells. PMID- 30011273 TI - The next generation of natural history collections. AB - The last 50 years have witnessed rapid changes in the ways that natural history specimens are collected, preserved, analyzed, and documented. Those changes have produced unprecedented access to specimens, images, and data as well as impressive research results in organismal biology. The stage is now set for a new generation of collecting, preserving, analyzing, and integrating biological samples-a generation devoted to interdisciplinary research into complex biological interactions and processes. Next-generation collections may be essential for breakthrough research on the spread of infectious diseases, feeding Earth's growing population, adapting to climate change, and other grand research challenges. A decade-long investment in research collection infrastructure will be needed. PMID- 30011272 TI - Interaction of the human erythrocyte Band 3 anion exchanger 1 (AE1, SLC4A1) with lipids and glycophorin A: Molecular organization of the Wright (Wr) blood group antigen. AB - The Band 3 (AE1, SLC4A1) membrane protein is found in red blood cells and in kidney where it functions as an electro-neutral chloride/bicarbonate exchanger. In this study, we have used molecular dynamics simulations to provide the first realistic model of the dimeric membrane domain of human Band 3 in an asymmetric lipid bilayer containing a full complement of phospholipids, including phosphatidylinositol 4,5-bisphosphate (PIP2) and cholesterol, and its partner membrane protein Glycophorin A (GPA). The simulations show that the annular layer in the inner leaflet surrounding Band 3 was enriched in phosphatidylserine and PIP2 molecules. Cholesterol was also enriched around Band 3 but also at the dimer interface. The interaction of these lipids with specific sites on Band 3 may play a role in the folding and function of this anion transport membrane protein. GPA associates with Band 3 to form the Wright (Wr) blood group antigen, an interaction that involves an ionic bond between Glu658 in Band 3 and Arg61 in GPA. We were able to recreate this complex by performing simulations to allow the dimeric transmembrane portion of GPA to interact with Band 3 in a model membrane. Large-scale simulations showed that the GPA dimer can bridge Band 3 dimers resulting in the dynamic formation of long strands of alternating Band 3 and GPA dimers. PMID- 30011271 TI - Current challenges and implications for dengue, chikungunya and Zika seroprevalence studies worldwide: A scoping review. AB - BACKGROUND: Arboviral infections are a public health concern and an escalating problem worldwide. Estimating the burden of these diseases represents a major challenge that is complicated by the large number of unapparent infections, especially those of dengue fever. Serological surveys are thus required to identify the distribution of these diseases and measure their impact. Therefore, we undertook a scoping review of the literature to describe and summarize epidemiological practices, findings and insights related to seroprevalence studies of dengue, chikungunya and Zika virus, which have rapidly expanded across the globe in recent years. METHODOLOGY/PRINCIPAL FINDINGS: Relevant studies were retrieved through a literature search of MEDLINE, WHOLIS, Lilacs, SciELO and Scopus (2000 to 2018). In total, 1389 publications were identified. Studies addressing the seroprevalence of dengue, chikungunya and/or Zika written in English or French and meeting the inclusion and exclusion criteria were included. In total, 147 studies were included, from which 185 data points were retrieved, as some studies used several different samples. Most of the studies were exclusively conducted on dengue (66.5%), but 16% were exclusively conducted on chikungunya, and 7 were exclusively conducted on Zika; the remainder were conducted on multiple arboviruses. A wide range of designs were applied, but most studies were conducted in the general population (39%) and in households (41%). Although several assays were used, enzyme-linked immunosorbent assays (ELISAs) were the predominant test used (77%). The temporal distribution of chikungunya studies followed the virus during its rapid expansion since 2004. The results revealed heterogeneity of arboviruses seroprevalence between continents and within a given country for dengue, chikungunya and Zika viruses, ranging from 0 to 100%, 76% and 73% respectively. CONCLUSIONS/SIGNIFICANCE: Serological surveys provide the most direct measurement for defining the immunity landscape for infectious diseases, but the methodology remains difficult to implement. Overall, dengue, chikungunya and Zika serosurveys followed the expansion of these arboviruses, but there remain gaps in their geographic distribution. This review addresses the challenges for researchers regarding study design biases. Moreover, the development of reliable, rapid and affordable diagnosis tools represents a significant issue concerning the ability of seroprevalence surveys to differentiate infections when multiple viruses co-circulate. PMID- 30011274 TI - Study on causes of fever in primary healthcare center uncovers pathogens of public health concern in Madagascar. AB - BACKGROUND: The increasing use of malaria diagnostic tests reveals a growing proportion of patients with fever but no malaria. Clinicians and health care workers in low-income countries have few tests to diagnose causes of fever other than malaria although several diseases share common symptoms. We propose here to assess etiologies of fever in Madagascar to ultimately improve management of febrile cases. METHODOLOGY: Consenting febrile outpatients aged 6 months and older were recruited in 21 selected sentinel sites throughout Madagascar from April 2014 to September 2015. Standard clinical examinations were performed, and blood and upper respiratory specimens were taken for rapid diagnostic tests and molecular assays for 36 pathogens of interest for Madagascar in terms of public health, regardless of clinical status. PRINCIPAL FINDINGS: A total of 682 febrile patients were enrolled. We detected at least one pathogen in 40.5% (276/682) of patients and 6.2% (42/682) with co-infections. Among all tested patients, 26.5% (181/682) had at least one viral infection, 17.0% (116/682) had malaria and 1.0% (7/682) presented a bacterial or a mycobacterial infection. None or very few of the highly prevalent infectious agents in Eastern Africa and Asia were detected in this study, such as zoonotic bacteria or arboviral infections. CONCLUSIONS: These results raise questions about etiologies of fever in Malagasy communities. Nevertheless, we noted that viral infections and malaria still represent a significant proportion of causes of febrile illnesses. Interestingly our study allowed the detection of pathogens of public health interest such as Rift Valley Fever Virus but also the first case of laboratory-confirmed leptospirosis infection in Madagascar. PMID- 30011276 TI - Identifying residual transmission of lymphatic filariasis after mass drug administration: Comparing school-based versus community-based surveillance - American Samoa, 2016. AB - INTRODUCTION: Under the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted seven rounds of mass drug administration (MDA) from 2000 2006. The World Health Organization recommends systematic post-MDA surveillance using Transmission Assessment Surveys (TAS) for epidemiological assessment of recent LF transmission. We compared the effectiveness of two survey designs for post-MDA surveillance: a school-based survey of children aged 6-7 years, and a community-based survey targeting people aged >=8 years. METHODS: In 2016, we conducted a systematic school-based TAS in all elementary schools (N = 29) and a cluster survey in 28 villages on the two main islands of American Samoa. We collected information on demographics and risk factors for infection using electronic questionnaires, and recorded geo-locations of schools and households. Blood samples were collected to test for circulating filarial antigen (CFA) using the Alere Filariasis Test Strip. For those who tested positive, we prepared slides for microscopic examination of microfilaria and provided treatment. Descriptive statistics were performed for questionnaire variables. Data were weighted and adjusted to account for sampling design and sex for both surveys, and for age in the community survey. RESULTS: The school-based TAS (n = 1143) identified nine antigen-positive children and found an overall adjusted CFA prevalence of 0.7% (95% CI: 0.3-1.8). Of the nine positive children, we identified one microfilariaemic 7-year-old child. The community-based survey (n = 2507, 711 households) identified 102 antigen-positive people, and estimated an overall adjusted CFA prevalence of 6.2% (95% CI: 4.5-8.6). Adjusted village-level prevalence ranged from 0-47.1%. CFA prevalence increased with age and was higher in males. Of 86 antigen-positive community members from whom slides were prepared, 22 (25.6%) were microfilaraemic. School-based TAS had limited sensitivity (range 0-23.8%) and negative predictive value (range 25-83.3%) but had high specificity (range 83.3-100%) and positive predictive value (range 0 100%) for identifying villages with ongoing transmission. CONCLUSIONS: American Samoa failed the school-based TAS in 2016, and the community-based survey identified higher than expected numbers of antigen-positive people. School-based TAS was logistically simpler and enabled sampling of a larger proportion of the target population, but the results did not provide a good indication of the overall CFA prevalence in older age groups and was not sensitive at identifying foci of ongoing transmission. The community-based survey, although operationally more challenging, identified antigen-positive individuals of all ages, and foci of high antigen prevalence. Both surveys confirmed recrudescence of LF transmission. PMID- 30011277 TI - Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge. AB - Crimean-Congo hemorrhagic fever (CCHF) is an acute, often fatal viral disease characterized by rapid onset of febrile symptoms followed by hemorrhagic manifestations. The etiologic agent, CCHF orthonairovirus (CCHFV), can infect several mammals in nature but only seems to cause clinical disease in humans. Over the past two decades there has been an increase in total number of CCHF case reports, including imported CCHF patients, and an expansion of CCHF endemic areas. Despite its increased public health burden there are currently no licensed vaccines or treatments to prevent CCHF. We here report the development and assessment of the protective efficacy of an adenovirus (Ad)-based vaccine expressing the nucleocapsid protein (N) of CCHFV (Ad-N) in a lethal immunocompromised mouse model of CCHF. The results show that Ad-N can protect mice from CCHF mortality and that this platform should be considered for future CCHFV vaccine strategies. PMID- 30011275 TI - Dengue infection in India: A systematic review and meta-analysis. AB - INTRODUCTION: Dengue is the most extensively spread mosquito-borne disease; endemic in more than 100 countries. Information about dengue disease burden, its prevalence, incidence and geographic distribution is critical in planning appropriate control measures against dengue fever. We conducted a systematic review and meta-analysis of dengue fever in India. METHODS: We searched for studies published until 2017 reporting the incidence, the prevalence or case fatality of dengue in India. Our primary outcomes were (a) prevalence of laboratory confirmed dengue infection among clinically suspected patients, (b) seroprevalence in the general population and (c) case fatality ratio among laboratory confirmed dengue patients. We used binomial-normal mixed effects regression model to estimate the pooled proportion of dengue infections. Forest plots were used to display pooled estimates. The metafor package of R software was used to conduct meta-analysis. RESULTS: Of the 2285 identified articles on dengue, we included 233 in the analysis wherein 180 reported prevalence of laboratory confirmed dengue infection, seven reported seroprevalence as evidenced by IgG or neutralizing antibodies against dengue and 77 reported case fatality. The overall estimate of the prevalence of laboratory confirmed dengue infection among clinically suspected patients was 38.3% (95% CI: 34.8%-41.8%). The pooled estimate of dengue seroprevalence in the general population and CFR among laboratory confirmed patients was 56.9% (95% CI: 37.5-74.4) and 2.6% (95% CI: 2 3.4) respectively. There was significant heterogeneity in reported outcomes (p values<0.001). CONCLUSIONS: Identified gaps in the understanding of dengue epidemiology in India emphasize the need to initiate community-based cohort studies representing different geographic regions to generate reliable estimates of age-specific incidence of dengue and studies to generate dengue seroprevalence data in the country. PMID- 30011278 TI - Evidence of vertical transmission of Zika virus in field-collected eggs of Aedes aegypti in the Brazilian Amazon. AB - BACKGROUND: Arboviruses are viruses transmitted to humans and other animals by the bite of hematophagous arthropods. Infections caused by chikungunya virus (CHIKV), dengue virus (DENV), Zika virus (ZIKV), and the deadlier yellow fever virus (YFV) are current public health problems in several countries, mainly those located in tropical and subtropical regions. One of the main prevention strategies continues to be vector control, with the elimination of breeding sites and surveillance of infested areas. The use of ovitraps for Aedes mosquitos monitoring has already demonstrated promising results, and maybe be also useful for arboviral surveillance. METHODS: This work aimed to detect natural vertical transmission of arboviruses in Aedes aegypti and Aedes albopictus. Mosquito egg collection was carried out using ovitraps in Itacoatiara, a mid-size city in Amazonas state, Brazil. Collected eggs were allowed to hatch and larvae were tested for CHIKV, DENV, and ZIKV RNA by RT-qPCR. RESULTS: A total of 2,057 specimens (1,793 Ae. aegypti and 264 Ae. albopictus), in 154 larvae pools were processed. Results showed one positive pool for CHIKV and one positive pool for ZIKV. The active ZIKV infection was further confirmed by the detection of the negative-strand viral RNA and nucleotide sequencing which confirmed the Asian genotype. The Infection Rate per 1,000 mosquitoes tested was assessed by Maximum Likelihood Estimation (MLE) with 0.45 and 0.44 for CHIKV and ZIKV, respectively, and by Minimum Infection Rate (MIR) with 0.45 for both viruses. CONCLUSION: To our knowledge, this is the first detection of ZIKV in natural vertical transmission in the Ae. aegypti, a fact that may contribute to ZIKV maintenance in nature during epidemics periods. Furthermore, our results highlight that the use of ovitraps and the molecular detection of arbovirus may contribute to health surveillance, directing the efforts to more efficient transmission blockade. PMID- 30011279 TI - Microheterogeneity-induced conduction slowing and wavefront collisions govern macroscopic conduction behavior: A computational and experimental study. AB - The incidence of cardiac arrhythmias is known to be associated with tissue heterogeneities including fibrosis. However, the impact of microscopic structural heterogeneities on conduction in excitable tissues remains poorly understood. In this study, we investigated how acellular microheterogeneities affect macroscopic conduction under conditions of normal and reduced excitability by utilizing a novel platform of paired in vitro and in silico studies to examine the mechanisms of conduction. Regular patterns of nonconductive micro-obstacles were created in confluent monolayers of the previously described engineered-excitable Ex293 cell line. Increasing the relative ratio of obstacle size to intra-obstacle strand width resulted in significant conduction slowing up to 23.6% and a significant increase in wavefront curvature anisotropy, a measure of spatial variation in wavefront shape. Changes in bulk electrical conductivity and in path tortuosity were insufficient to explain these observed macroscopic changes. Rather, microscale behaviors including local conduction slowing due to microscale branching, and conduction acceleration due to wavefront merging were shown to contribute to macroscopic phenomena. Conditions of reduced excitability led to further conduction slowing and a reversal of wavefront curvature anisotropy due to spatially non-uniform effects on microscopic slowing and acceleration. This unique experimental and computation platform provided critical mechanistic insights in the impact of microscopic heterogeneities on macroscopic conduction, pertinent to settings of fibrotic heart disease. PMID- 30011280 TI - Arab female and male perceptions of factors facilitating and inhibiting their physical activity: Findings from a qualitative study in the Middle East. AB - OBJECTIVES: Physical inactivity is a leading global risk to health by contributing to obesity and other chronic diseases. Many chronic non-communicable diseases, such as cancer, diabetes, and cardiovascular diseases (CVDs), can be prevented and controlled by modifying lifestyle behaviors such as physical activity [PA]. However, prevalence of insufficient physical activity and obesity is high in the Middle East Region. In Qatar, the incidence rates of CVDs, diabetes, colon, and breast cancer have been rising rapidly. The purpose of this study was to explore facilitators and barriers influencing PA of adult Arab men and women living in Qatar and to understand what they think would be helpful to increase PA. The goal of the research is to identify culturally appropriate and effective interventions that improve the health of Arab population. DESIGN: Using the socioecological model as the theoretical framework, we conducted an exploratory qualitative study with 128 Arab adult men and women living in Qatar. We utilized focus group interviews to collect the data and performed thematic analysis to generate themes. RESULTS: At the individual level, perceived benefits of PA, presence of diseases, person's will, motivation and goals, and time to exercise influenced the individual's PA. At the sociocultural level, religious teachings of Islam, cultural, attitude, beliefs, and practices, and informal support influenced the participants' PA. At the organizational and political level, physical environment to exercise, accessibility of facilities, organizational support, and health information about PA influenced their PA. CONCLUSION: Arab men and women are aware of the importance and benefits of PA. They have the motivation to be physically active, but in the absence of supportive environment, their knowledge might not translate into action. Creating supportive environments at multiple levels that are conducive to PA is warranted. PMID- 30011281 TI - Bioaccumulation of methylmercury within the marine food web of the outer Bay of Fundy, Gulf of Maine. AB - Mercury and methylmercury were measured in seawater and biota collected from the outer Bay of Fundy to better document mercury bioaccumulation in a temperate marine food web. The size of an organism, together with delta13 C and delta15 N isotopes, were measured to interpret mercury levels in biota ranging in size from microplankton (25MUm) to swordfish, dolphins and whales. Levels of mercury in seawater were no different with depth and not elevated relative to upstream sources. The delta13 C values of primary producers were found to be inadequate to specify the original energy source of various faunas, however, there was no reason to separate the food web into benthic, demersal and pelagic food chains because phytoplankton has been documented to almost exclusively fuel the ecosystem. The apparent abrupt increase in mercury content from "seawater" to phytoplankton, on a wet weight basis, can be explained from an environmental volume basis by the exponential increase in surface area of smaller particles included in "seawater" determinations. This physical sorption process may be important up to the macroplankton size category dominated by copepods according to the calculated biomagnification factors (BMF). The rapid increase in methylmercury concentration, relative to the total mercury, between the predominantly phytoplankton (<125MUm) and the zooplankton categories is likely augmented by gut microbe methylation. Further up the food chain, trophic transfer of methylmercury dominates resulting in biomagnification factors greater than 10 in swordfish, Atlantic bluefin tuna, harbour porpoise, Atlantic white-sided dolphin and common thresher shark. The biomagnification power of the northern Gulf of Maine ecosystem is remarkably similar to that measured in tropical, subtropical, other temperate and arctic oceanic ecozones. PMID- 30011282 TI - Seroprevalence and risk factors of hepatitis B and C virus infections in female workers of Lao garment factories. AB - The prevalence of hepatitis B and C virus infections may be higher in vulnerable populations or in individuals likely to be exposed through risk behaviors such as female garment factory workers in Lao People's Democratic Republic. A cross sectional study was performed on 400 female garment workers in Vientiane Capital. Women were tested for hepatitis B virus surface antigen and antibodies against hepatitis B core, surface antigen and hepatitis C virus using commercial Enzyme linked immuno-absorbent assays. Participants completed a standardized questionnaire about potential risk factors for both infections. Sixteen women (4+/-1.9%) were HBsAg carriers, 187 (47%) had anti-HBc, 116 (29%) anti-HBs and 7 (1.8+/-1.3%) anti-HCV antibodies. Three factors were significantly associated with the presence of anti-HBc (indicating previous exposure to HBV): (i) residence in dormitories, (ii) more than one sexual partner, (iii) history of abortion. Despite a high risk of exposure, the prevalence of anti HBV and anti HCV infection markers in this sample of female workers was not higher than in the Lao general population. Our data suggest that exposure to HBV happens later during life and was significantly associated with sexual risk behavior. Thus, this study highlights the vulnerability of these women who were mostly young, uneducated, unvaccinated, of rural origin and were not aware of the risk of infections. An occupational health program targeting the female factory workers should be implemented in Lao PDR. PMID- 30011283 TI - Measles virus genotype D4 strains with non-standard length M-F non-coding region circulated during the major outbreaks of 2011-2012 in Spain. AB - In recent decades, vaccination has substantially reduced the number of measles cases to levels close to the elimination stage. However, major measles outbreaks occurred in Europe during 2010-2012, after the introduction of the D4-Enfield lineage. We have performed a molecular characterization of 75 measles virus genotype D4 strains from patients infected in Spain between 2004 and 2012 by sequencing the N-450 region and the M-F non-coding region (M-F NCR) in order to identify genetic features of these viruses. The analysis of the N-450 region confirmed that all samples obtained since 2008 belonged to variants or sets of identical sequences of the D4-Enfield lineage, including a new one named MVs/Madrid.ESP/46.10/. Analysis of the M-F NCR showed insertions and deletions associated with previously described, uncommon non-standard genome length measles viruses. This genetic feature was identified in the D4-Enfield lineage viruses, but not in the other D4 viruses that were circulating in Spain before 2008, suggesting that these non-standard length M-F NCR sequences are characteristic of the D4-Enfield lineage. The results of the phylogenetic analysis of Spanish M-F NCRs suggest higher resolution in discriminating strains than did the N-450 analysis. In addition, the results of the analysis of the M-F NCR on the MVs/Madrid.ESP/46.10/ sub-lineage seem to support the potential utility of this region as a tool for epidemiological surveillance complementary to the N-450 region, as previously suggested. Further investigation on this question, as well as the surveillance of new potentially emerging strains with non-standard length M-F NCR are strongly recommended as part of future strategies for measles elimination. PMID- 30011284 TI - Illict drug use and academia in North Kosovo: Prevalence, patterns, predictors and health-related quality of life. AB - PURPOSE: The purpose of this study were to estimate the prevalence and patterns of illicit drug use in a sample of University students from North Kosovo, to assess factors associated with illicit drug use and to assess health-related quality of life (HRQoL) among students according to illicit drug use. METHODS: A cross-sectional study was conducted at the Student Public Health Center, where 514 University students were enrolled from April to June 2015 in North Kosovo. Participants completed the general socio-demographic and behavioral questionnaire, Beck Depression Inventory (BDI) and the SF-36 questionnaire for HRQoL assessment. Data on lifetime illicit drug use were self-reported. RESULTS: As much as 16.0% of students reported ever illicit drug use. The most frequently used drugs were marijuana (9.3%) and bromazepam (7.6%). Factors associated with ever illicit drug use were: being smoker and alcohol user, having chronic diseases and having higher depressive symptoms score. Ever illicit drug users reported all domains of HRQoL as worse. CONCLUSION: These results could serve as a tool for implementation of preventive strategies and University policies to promote healthy lifestyles and behaviors. Measurement of HRQoL could also be used as indicator of the effect of interventions designed to reduce and/or prevent illicit drug use at institutions of higher education. PMID- 30011285 TI - The "rapid atrial swirl sign" for assessing central venous catheters: Performance by medical residents after limited training. AB - RATIONALE: Central venous catheter (CVC) placement is a standard procedure in critical care. Ultrasound guidance during placement is recommended by current guidelines, but there is no consensus on the best method for evaluating the correct CVC tip position. Recently, the "rapid atrial swirl sign" (RASS) has been investigated in a limited number of studies. OBJECTIVES: We performed a prospective diagnostic accuracy study of focused echocardiography for the evaluation of CVC tip position in our medical ICU and IMC units. METHODS: We performed a prospective diagnostic accuracy study in 100 patients admitted to the Intensive Care Unit and Intermediate Care Unit at our center. The first 10 subjects were assessed by one staff physician investigator (reference cohort), the remaining 90 patients by different residents (test cohort). All patients received a post-procedural chest radiograph (CXR) as gold standard. CVC placement was assessed with focused echocardiography performed by residents after a short training session. A rapid opacification of the right atrium (RASS) after injection of 10 mL of normal saline was regarded as "positive", flush after more than two seconds was defined as "delayed", no flush was a "negative" test result. MEASUREMENTS AND MAIN RESULTS: Overall sensitivity of the RASS was 100% (95% CI 73.54-100%), specificity was 94.32% (CI 87.24-98.13%). Positive and negative predictive values were 70.59% (CI 44.04-89.09%) and 100% (CI 95.65-100%), respectively. Median time for echocardiographic testing was 5 minutes (1-28) in the whole cohort, CXRs were available after 49.5 minutes (13-254). Interrater agreement of the RASS was 0.77 (Cohen's kappa), Measurement of CVC tip position was not different between two observers. Test characteristics were similar among differently experienced residents. CONCLUSIONS: Presence of the RASS by focused echocardiography showed excellent sensitivity and specificity and was equally performed by residents after minimal training. In patients with a positive RASS, routine CXR can be safely omitted, reducing time, costs and radiation exposure. A negative RASS should lead to a search for misplaced catheters. CLINICAL TRIAL REGISTRATION: The study was registered with www.clinicaltrials.gov (NCT02661607). PMID- 30011286 TI - Vaccine uptake and immune responses to HBV infection amongst vaccinated and non vaccinated healthcare workers, household and sexual contacts to chronically infected HBV individuals in the South West Region of Cameroon. AB - BACKGROUND: HBV infection affects about 257 million people globally and Sub Saharan Africa has the highest burden. The disease still constitutes a major public health problem despite the advent of preventive measures like the HBV vaccine. This study was aimed at identifying factors that influence vaccine uptake and the efficacy of administered vaccines among people at high risk of HBV infection. METHODS: This was a cross-sectional study conducted between January 2016 and December 2017. A pretested semi-structured questionnaire was used to capture information on sociodemographic and vaccination status from healthcare workers, household and sexual contacts to HBV infected people. HBV serological panel as well as quantitative anti-HBs ELISA test was done for all participants. Additional information was obtained from the institutions that administered the vaccines. RESULTS: A total of 265 participants with a mean age of 32.1+/-8.7 were enrolled. Eighty (30.2%) of them had received at least 1 dose of the HBV vaccine while 185 (69.8%) were unvaccinated. Healthcare workers were the most vaccinated (37%). Ignorance, negligence, fear of injection and the cost of the vaccine all contributed to poor vaccine uptake in the study population. Natural immunity was seen in 9 (3.4%) of the participants. Only 64.9% of the vaccinated participants attained the desirable level of anti-HBs (>=10mIU/ml) 1-2 months after >= 3 doses of the vaccine. Age, gender, obesity, alcohol and smoking were not significantly associated with poor immune responses. No standardized protocol was followed by the institutions administering the vaccine. CONCLUSION: This study revealed very poor vaccine uptake and poor immune responses to the HBV vaccine in the study population and this should urge the health sector in Cameroon to intensify their sensitization on HBV vaccine, standardize the protocol for storing and administering the vaccine, subsidize the cost of the vaccine especially amongst healthcare workers and encourage anti-HBs post vaccination testing. PMID- 30011287 TI - Species-specific variations in reproductive traits of three yellow catfish species (Pelteobagrus spp.) in relation to habitats in the Three Gorges Reservoir, China. AB - The reproductive biology of three yellow catfish congeners was studied in the Three Gorges Reservoir of the Yangtze River, China. We compared reproductive traits among the lentic, transitional, and lotic zones. A total of 4502 individuals of the three species was collected, and the sex ratio, size at 50% maturity, spawning season, fecundity, and egg size were determined. Results showed that populations inhabiting the lotic zone spawned earlier than those inhabiting the lentic zone. For the three species, fecundities were significantly higher for populations in the lotic zone than for those in the lentic and transitional zones (P < 0.05). Pelteobagrus vachelli (Richardson) and P. fulvidraco (Richardson) displayed an obvious trade-off between egg size and fecundity, whereas P. nitidus (Sauvage et Dabry) produced the largest eggs in the lotic zone. Sex ratios were significantly different among zones (P < 0.05, for each species), but the bias patterns were different. Sizes at 50% maturity of female P. nitidus and P. vachelli were the largest in the lotic zone and the smallest in the transitional zone, but was similar among zones for P. fulvidraco. Overall results suggest that the three yellow catfish species developed different reproductive traits among the three habitats in the TGR, whereas the variations reflected further interspecific differences. Our study indicates the importance of riverine habitats for the conservation of species of fish, even for species such as these eurytopic catfish inhabiting the upper reach of the Yangtze River. This study further suggests that species-specific responses should be considered when evaluating the influences of new hydropower projects, even for such closely related species of fish. PMID- 30011288 TI - Grade 2 disabilities in leprosy patients from Brazil: Need for follow-up after completion of multidrug therapy. AB - BACKGROUND: Leprosy continues to be a public health problem in many countries. Difficulties faced by health services include late diagnosis, under-reporting of new cases, adequate monitoring of disabilities and treatment. Furthermore, systematic follow-up after completion of treatment is important, when new disabilities may occur, or existing disabilities may get worse. The objective of the present study was to determine the prevalence of leprosy-associated grade 2 disabilities (G2D) after completion of multidrug therapy (MDT) and to identify factors associated with G2D. METHODS: We performed a cross-sectional study of 222 leprosy cases registered in Vitoria da Conquista, Bahia state, Brazil from 2001 2014. We performed a clinical examination of the study participants and collected socio-economic and clinical information by interview. We identified factors associated with grade 2 disability (G2D) using logis tic regression. RESULTS: In total, 38 (17.1%) participants were diagnosed with G2D, and 106 (47.7%) with grade 1 disabilities (G1D). The following independent factors were significantly associated with G2D: occurrence of leprosy reaction (adjusted OR = 2.5; 95%CI = 1.09-5.77), thickening and/or tenderness of one or more nerve trunks (adjusted OR = 3.0; CI = 1.13-8.01) and unemployment (adjusted OR = 7.17; CI = 2.44-21.07). CONCLUSIONS: This study shows that physical disabilities remain after completion of MDT and frequently occur in an endemic area in Brazil. Finding new ways to reduce the burden of disability are urgently needed, and may include systematic follow-up of patients after treatment completion combined with evidence-based preventative measures. PMID- 30011289 TI - Questionable research practices in ecology and evolution. AB - We surveyed 807 researchers (494 ecologists and 313 evolutionary biologists) about their use of Questionable Research Practices (QRPs), including cherry picking statistically significant results, p hacking, and hypothesising after the results are known (HARKing). We also asked them to estimate the proportion of their colleagues that use each of these QRPs. Several of the QRPs were prevalent within the ecology and evolution research community. Across the two groups, we found 64% of surveyed researchers reported they had at least once failed to report results because they were not statistically significant (cherry picking); 42% had collected more data after inspecting whether results were statistically significant (a form of p hacking) and 51% had reported an unexpected finding as though it had been hypothesised from the start (HARKing). Such practices have been directly implicated in the low rates of reproducible results uncovered by recent large scale replication studies in psychology and other disciplines. The rates of QRPs found in this study are comparable with the rates seen in psychology, indicating that the reproducibility problems discovered in psychology are also likely to be present in ecology and evolution. PMID- 30011290 TI - Identification of influencers through the wisdom of crowds. AB - Identifying individuals who are influential in diffusing information, ideas or products in a population remains a challenging problem. Most extant work can be abstracted by a process in which researchers first decide which features describe an influencer and then identify them as the individuals with the highest values of these features. This makes the identification dependent on the relevance of the selected features and it still remains uncertain if triggering the identified influencers leads to a behavioral change in others. Furthermore, most work was developed for cross-sectional or time-aggregated datasets, where the time evolution of influence processes cannot be observed. We show that mapping the influencer identification to a wisdom of crowds problem overcomes these limitations. We present a framework in which the individuals in a social group repeatedly evaluate the contribution of other members according to what they perceive as valuable and not according to predefined features. We propose a method to aggregate the behavioral reactions of the members of the social group into a collective judgment that considers the temporal variation of influence processes. Using data from three large news providers, we show that the members of the group surprisingly agree on who are the influential individuals. The aggregation method addresses different sources of heterogeneity encountered in social systems and leads to results that are easily interpretable and comparable within and across systems. The approach we propose is computationally scalable and can be applied to any social systems where behavioral reactions are observable. PMID- 30011291 TI - Relationships among patient characteristics, irradiation treatment planning parameters, and treatment toxicity of acute radiation dermatitis after breast hybrid intensity modulation radiation therapy. AB - To evaluate the relationships among patient characteristics, irradiation treatment planning parameters, and treatment toxicity of acute radiation dermatitis (RD) after breast hybrid intensity modulation radiation therapy (IMRT). The study cohort consisted of 95 breast cancer patients treated with hybrid IMRT. RD grade >=2 (2+) toxicity was defined as clinically significant. Patient characteristics and the irradiation treatment planning parameters were used as the initial candidate factors. Prognostic factors were identified using the least absolute shrinkage and selection operator (LASSO)-based normal tissue complication probability (NTCP) model. A univariate cut-off dose NTCP model was developed to find the dose-volume limitation. Fifty-two (54.7%) of ninety-five patients experienced acute RD grade 2+ toxicity. The volume of skin receiving a dose >35 Gy (V35) was the most significant dosimetric predictor associated with RD grade 2+ toxicity. The NTCP model parameters for V35Gy were TV50 = 85.7 mL and gamma50 = 0.77, where TV50 was defined as the volume corresponding to a 50% incidence of complications, and gamma50 was the normalized slope of the volume response curve. Additional potential predictive patient characteristics were energy and surgery, but the results were not statistically significant. To ensure a better quality of life and compliance for breast hybrid IMRT patients, the skin volume receiving a dose >35 Gy should be limited to <85.7 mL to keep the incidence of RD grade 2+ toxicities below 50%. To avoid RD toxicity, the volume of skin receiving a dose >35 Gy should follow sparing tolerance and the inherent patient characteristics should be considered. PMID- 30011292 TI - Enhancing glucose flux into sweat by increasing paracellular permeability of the sweat gland. AB - Non-invasive wearable biosensors provide real-time, continuous, and actionable health information. However, difficulties detecting diluted biomarkers in excreted biofluids limit practical applications. Most biomarkers of interest are transported paracellularly into excreted biofluids from biomarker-rich blood and interstitial fluid during normal modulation of cellular tight junctions. Calcium chelators are reversible tight junction modulators that have been shown to increase absorption across the intestinal epithelium. However, calcium chelators have not yet been shown to improve the extraction of biomarkers. Here we show that for glucose, a paracellularly transported biomarker, the flux into sweat can be increased by >10x using citrate, a calcium chelator, in combination with electroosmosis. Our results demonstrate a method of increasing glucose flux through the sweat gland epithelium, thereby increasing the concentration in sweat. Future work should examine if this method enhances flux for other paracellularly transported biomarkers to make it possible to detect more biomarkers with currently available biosensors. PMID- 30011293 TI - Preemptively and non-preemptively transplanted patients show a comparable hypercoagulable state prior to kidney transplantation compared to living kidney donors. AB - To prevent renal graft thrombosis in kidney transplantation, centres use different perioperative anticoagulant strategies, based on various risk factors. In our centre, patients transplanted preemptively are considered at increased risk of renal graft thrombosis compared to patients who are dialysis-dependent at time of transplantation. Therefore these patients are given a single dose of 5000 IU unfractionated heparin intraoperatively before clamping of the vessels. We questioned whether there is a difference in haemostatic state between preemptively and non-preemptively transplanted patients and whether the distinction in intraoperative heparin administration used in our center is justified. For this analysis, citrate samples of patients participating in the VAPOR-1 trial were used and several haemostatic and fibrinolytic parameters were measured in 29 preemptively and 28 non-preemptively transplanted patients and compared to 37 living kidney donors. Sample points were: induction anaesthesia (T1), 5 minutes after reperfusion (T2) and 2 hours postoperative (T3). At T1, recipient groups showed comparable elevated levels of platelet factor 4 (PF4, indicating platelet activation), prothrombin fragment F1+2 and D-dimer (indicating coagulation activation) and Von Willebrand Factor (indicating endothelial activation) compared to the donors. The Clot Lysis Time (CLT, a measure of fibrinolytic potential) was prolonged in both recipient groups compared to the donors. At T3, F1+2, PF4 and CLT were higher in non-preemptively transplanted recipients compared to preemptively transplanted recipients. Compared to donors, non-preemptive recipients showed a prolonged CLT, but comparable levels of PF4 and D-dimer. In conclusion pre-transplantation, preemptively and non-preemptively transplanted patients show a comparable enhanced haemostatic state. A distinction in intraoperative heparin administration between preemptive and non-preemptive transplantation does not seem justified. PMID- 30011294 TI - Using social media to quantify spatial and temporal dynamics of nature-based recreational activities. AB - Big data offer a great opportunity for nature-based recreation (NbR) mapping and evaluation. However, it is important to determine when and how it is appropriate to use this resource. We used Scotland as a case study to validate the use of data from Flickr as an indicator of NbR on a national scale and at several regional spatial and temporal resolutions. We compared Flickr photographs to visitor statistics in the Cairngorms National Park (CNP) and determined whether temporal variability in photo counts could be explained by known annual estimates of CNP visitor numbers. We then used a unique recent national survey of nature recreation in Scotland to determine whether the spatial distribution of Flickr photos could be explained by known spatial variability in nature use. Following this validation work, we used Flickr data to identify hotspots of wildlife watching in Scotland and investigated how they changed between 2005 and 2015. We found that spatial and temporal patterns in Flickr count are explained by measures of visitation obtained through surveys and that this relationship is reliable down to a 10 Km scale resolution. Our findings have implications for planning and management of NbR as they suggest that photographs uploaded on Flickr reflect patterns of NbR at spatial and temporal scales that are relevant for ecosystem management. PMID- 30011295 TI - Arecoline inhibits the growth of 3T3-L1 preadipocytes via AMP-activated protein kinase and reactive oxygen species pathways. AB - The present study was designed to investigate the pathways involved in the effect of betel nut arecoline on cell viability in 3T3-L1 preadipocytes. Arecoline, but not arecaidine or guvacine, inhibited preadipocyte viability in a concentration- and time-dependent manner. Arecoline arrested preadipocyte growth in the G2/M phase of the cell cycle; decreased the total levels of cyclin-dependent kinase 1 (CDK1), p21, and p27 proteins; increased p53 and cyclin B1 protein levels; and had no effect on CDK2 protein levels. These results suggested that arecoline selectively affected a particular CDK subfamily. Arecoline inhibited AMP activated protein kinase (AMPK) activity; conversely, the AMPK activator, AICAR, blocked the arecoline-induced inhibition of cell viability. Pre-treatment with the antioxidant, N-acetylcysteine, prevented the actions of arecoline on cell viability, G2/M growth arrest, reactive oxygen species (ROS) production, and the levels of CDK1, p21, p27, p53, cyclin B1, and phospho-AMPK proteins. These AMPK- and ROS-dependent effects of arecoline on preadipocyte growth may be related to the mechanism underlying the modulatory effect of arecoline on body weight. PMID- 30011296 TI - Visual attention in 5-year-olds from three different cultures. AB - Cognitive processes differ markedly between children from different cultures, with best evidence for attention to visual scenes and the activities of others. Children from urban Western cultures tend to focus on focal objects, whereas children from urban East-Asian cultures rather attend to contextual elements of a visual scene. Regarding the attention to others' activities, children from subsistence-based farming communities often observe several activities simultaneously, while children from urban Western contexts focus on activities sequentially. Here we assessed 144 5-year-old children from three prototypical cultural contexts (urban Germany, rural Cameroon, urban Japan) to investigate variations in attention across a variety of tasks. Attention to the elements of a visual scene was assessed in an optical illusion task, in picture descriptions and an eye-tracking paradigm. Attention to and learning from others' activities was assessed in a parallel action task and a rule-based game. Some tasks indicated higher context-sensitive attention in urban Japan, while other findings indicated higher context-sensitive attention in urban Germany. Levels of parallel attention and learning from others' activities were lower in rural Cameroonian children compared to the urban samples. Across tasks, the visual attention measures were unrelated. These findings substantiate that culture has a profound influence on early cognitive development, already in the preschool years. Furthermore, they raise critical questions about the early origins of cultural specificities in attention and the generalizability of attention phenomena beyond specific tasks and populations. PMID- 30011297 TI - Targeted metabolomic approach in men with carotid plaque. AB - BACKGROUND: The aim of the study was to analyse the presence of several metabolites related to atherosclerosis in the plasma of patients with unstable carotid plaque and in the plasma of healthy subjects. MATERIALS AND METHODS: We included 20 patients who had undergone carotid endarterectomy and 20 healthy subjects as a control group. All the subjects recruited were male. We used a metabolomic approach with liquid chromatography coupled to mass spectrometry to evaluate plasma metabolite levels in the metabolic pathway involved in the progression of atherosclerotic plaque. RESULTS: We observed that circulating levels of 20-HETE were significantly higher in patients with atheroma plaque than in healthy subjects (p = 0.018). No differences were found with regard to the other metabolites analysed. We also conducted a random forest analysis and found that 20-HETE was the main differentiator in the list of selected metabolites. In addition, plasma levels of 20-HETE correlated positively with body mass index (r = 0.427, p = 0.007) and diastolic blood pressure (r = 0.365, p = 0.028). CONCLUSION: This study confirms that of all the molecules studied only 20-HETE is related to carotid plaque. Further studies are needed to compare patients with stable carotid plaque vs. patients with unstable carotid plaque in order to confirm that 20-HETE could be a potential factor related to carotid plaque. PMID- 30011298 TI - Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing. AB - There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, mice were treated twice daily with a 2% topical mupirocin ointment for 7 days. For sepsis experiments, mice were treated intraperitoneally with 6 mg/kg daptomycin 2 h and 6 h post-infection and time to moribund monitored for 72 h. Consistent bacterial burden data were obtained from individual mice by regular photon intensity quantification on a Xenogen IVIS Lumina XRMS Series III biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological examination of wounds and bacterial counts in blood correlated closely with disease severity and total flux obtained from Xen29. The bioluminescent murine models provide a refinement to existing techniques of multiple bacterial enumeration during disease pathogenesis and promote animal usage reduction. The models also provide an efficient and information-rich platform for preclinical efficacy evaluation of new drug classes for treating acute and chronic human and animal bacterial infections. PMID- 30011299 TI - Cognitive ability, education and socioeconomic status in childhood and risk of post-stroke depression in later life: A systematic review and meta-analysis. AB - BACKGROUND: Depression after stroke is common and is associated with poorer recovery. Risk factors such as gender, age and stroke severity are established, but it is unclear whether factors from earlier in life might also contribute. METHODS: We searched MEDLINE, PsycINFO, EMBASE and meta-analysed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education and stroke in adulthood. We included all studies reporting data on >50 patients, calculating overall odds ratios (OR), mean difference, correlation, 95% confidence intervals (CI) and 95% predictive intervals (PI) using random effects methods. We quality assessed all studies, performed sensitivity analyses, assessed heterogeneity and publication bias. RESULTS: We identified 33 studies including 2,664 participants with post-stroke depression and 5,460 without (314 participants not classified). Low education (< = 8 years) was associated with post-stroke depression in studies which defined depression as score of mild and above on a depression rating scale (OR 1.47 95% CI 1.10-1.97, p<0.01) but not in studies where depression was defined as severe depressive symptoms or a clinical diagnosis of major depression (OR 1.04 95% CI 0.90-1.31, p = 0.60). Low education was not associated with an increased risk for post-stroke depression in studies that adjusted for age and sex (OR 0.86 95% CI 0.50-1.48 p = 0.58). Those with post-stroke depression had fewer years of education than those without post stroke depression (MD 0.68 95% CI 0.05-1.31 p = 0.04). Few studies adjusted for vascular risk factors or stroke severity. Heterogeneity between studies was moderate and was partly explained by severity of depression. In the one study identified premorbid IQ did not differ between those with post-stroke depression (mean IQ 10.1.8 SD 9.8) vs those without (mean IQ 104 SD 10.1). There were no studies that examined childhood socioeconomic status and risk of post-stroke depression. CONCLUSIONS: Having less education is associated with an increased risk of post-stroke depressive symptoms but with large confidence intervals and heterogeneity. Future studies should explore the relationship between early and late life risk factors to improve risk identification and to target prevention and treatment strategies. PMID- 30011300 TI - Image-guided chemistry altering biology: An in vivo study of thermoembolization. AB - RATIONALE: Advances in image-guided drug delivery for liver cancer have shown a significant survival benefit. However, incomplete treatment is common and residual disease is often found in explanted liver specimens. In addition, the need to treat a malignancy from multiple mechanisms at the same time for optimal outcomes is becoming more widely appreciated. To address this, we hypothesized that an exothermic chemical reaction could be performed in situ. Such a strategy could in principle combine several angles of attack, including ischemia, hyperthermia, acidic protein denaturation, and metabolic modulation of the local environment. METHODS: The University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee approved this study. Outbred swine (25-35 kg, 5 control and 5 experimental) were treated under general anesthesia. Embolization was performed with coaxial microcatheter technique in a segmental hepatic arterial branch using either ethiodized oil as control or with thermoembolic solutionBlood samples were obtained before, immediately after, and the day following the procedure just before CT scans and euthanasia. Livers were explanted and samples were obtained for histologic analysis. RESULTS: All animals survived the procedure and laboratory values of the control and experimental groups remained within normal limits. The control group had a diffuse or cloudy pattern of attenuation on follow-up CT scan the day after, consistent with gradual antegrade sinusoidal transit of the embolic material. The experimental group had clearly defined vascular casts with some degree of peripheral involvement. At histology, the control group samples had the appearance of normal liver, whereas the experimental group had coagulative necrosis in small pale, punctate areas extending several hundred microns away from the treated vessels and a brisk inflammatory response just outside the margins. CONCLUSION: In situ chemistry via thermoembolization shows early promise as a fundamentally new tactic for image-guided therapy of solid tumors. PMID- 30011301 TI - Multiparametric magnetic resonance imaging of experimental chronic kidney disease: A quantitative correlation study with histology. AB - OBJECTIVES: In human chronic kidney disease (CKD) the extent of renal tubulointerstitial fibrosis correlates with progressive loss of renal function. However, fibrosis can so far only be assessed by histology of kidney biopsies. Magnetic resonance imaging (MRI) can provide information about tissue architecture, but its potential to assess fibrosis and inflammation in diseased kidneys remains poorly defined. MATERIALS AND METHODS: We evaluated excised kidneys in a murine adenine-induced nephropathy model for CKD by MRI and correlated quantitative MRI parameters (T1, T2, and T2* relaxation times, apparent diffusion coefficient and fractional anisotropy) with histological hallmarks of progressive CKD, including renal fibrosis, inflammation, and microvascular rarefaction. Furthermore, we analyzed the effects of paraformaldehyde fixation on MRI parameters by comparing kidney samples before and after fixation with paraformaldehyde. RESULTS: In diseased kidneys T2 and T2* relaxation times, apparent diffusion coefficient and fractional anisotropy in the renal cortex and/or outer medulla were significantly different from those in control kidneys. In particular, T2 relaxation time was the best parameter to distinguish control and CKD groups and correlated very well with the extent of fibrosis, inflammatory infiltrates, tubular dilation, crystal deposition, and loss of peritubular capillaries and normal tubules in the renal cortex and outer medulla. Fixation with paraformaldehyde had no impact on T2 relaxation time and fractional anisotropy, whereas T1 times significantly decreased and T2* times and apparent diffusion coefficients increased in fixed kidney tissue. CONCLUSIONS: MRI parameters provide a promising approach to quantitatively assess renal fibrosis and inflammation in CKD. Especially T2 relaxation time correlates well with histological features of CKD and is not influenced by paraformaldehyde fixation of kidney samples. Thus, T2 relaxation time might be a candidate parameter for non-invasive assessment of renal fibrosis in human patients. PMID- 30011302 TI - Data management and sharing in neuroimaging: Practices and perceptions of MRI researchers. AB - Neuroimaging methods such as magnetic resonance imaging (MRI) involve complex data collection and analysis protocols, which necessitate the establishment of good research data management (RDM). Despite efforts within the field to address issues related to rigor and reproducibility, information about the RDM-related practices and perceptions of neuroimaging researchers remains largely anecdotal. To inform such efforts, we conducted an online survey of active MRI researchers that covered a range of RDM-related topics. Survey questions addressed the type(s) of data collected, tools used for data storage, organization, and analysis, and the degree to which practices are defined and standardized within a research group. Our results demonstrate that neuroimaging data is acquired in multifarious forms, transformed and analyzed using a wide variety of software tools, and that RDM practices and perceptions vary considerably both within and between research groups, with trainees reporting less consistency than faculty. Ratings of the maturity of RDM practices from ad-hoc to refined were relatively high during the data collection and analysis phases of a project and significantly lower during the data sharing phase. Perceptions of emerging practices including open access publishing and preregistration were largely positive, but demonstrated little adoption into current practice. PMID- 30011303 TI - Social determinants affecting the use of complementary and alternative medicine in Japan: An analysis using the conceptual framework of social determinants of health. AB - This study aims to use the conceptual framework of social determinants of health (SDH) to elucidate the social determinants that affect the use of complementary and alternative medicine (CAM) from the perspectives of both intermediary and structural determinants. Data were derived from a survey mailed to 1,500 randomly selected residents (20-69 years old; May-July 2009) of Sendai city in Japan. A generalized linear model was used in the analysis, with CAM use over the past one month as the dependent variable, SDH structural and intermediary determinants as independent variables, and demographic characteristics, indicators of health status, and the evaluation of health or healthcare systems as control variables. The prevalence of CAM usage was 62.1%. The generalized linear model showed that middle subjective social status (OR = 1.47; 95% CI: 1.04-2.07) as structural determinants was significantly associated with CAM usage. Adding the intermediary determinants, the same effect was observed. When demographic characteristics, indicators of health status, and the evaluation of health or healthcare systems were introduced as control variables, the associations of the structural determinants disappeared, revealing that hope (OR = 1.25; 95%CI: 1.04-1.50) as intermediary determinants was associated with the use of CAM. Female sex (OR = 1.47; 95% CI: 1.02-2.12) and health anxiety (OR = 1.68; 95% CI: 1.20-2.34) were associated with CAM usage. We found that intermediary rather than structural determinants were associated with CAM usage. Hope as an intermediary determinant was particularly associated with CAM usage. PMID- 30011305 TI - Predictive framework for codend size selection of brown shrimp (Crangon crangon) in the North Sea beam-trawl fishery. AB - The brown shrimp (Crangon crangon) fishery is of great socio-economic importance to coastal communities on the North Sea. The fishery is exploited by beam trawlers often using codends with very small mesh sizes, leading to concerns about catch rates of undersized shrimp. However, little information is available on codend size selection, making it difficult to provide scientifically based advice on alternative codend designs. Therefore, this study establishes a predictive framework for codend size selection of brown shrimp, based on a large selectivity dataset from 33 different codend designs tested during four experimental fishing cruises, during which more than 350,000 brown shrimp were length measured. Predictions by the framework confirm concerns about the exploitation pattern in the fishery, because the retention probability of undersized shrimp reaches 95% with the currently applied designs. The framework predictions allow the exploration of obtainable exploitation patterns depending on codend design. For example, increasing codend mesh size to 25-29 mm would reduce the retention rate of undersized shrimp to a maximum of 50%, depending on codend mesh type. PMID- 30011304 TI - Evaluation of the bag-mediated filtration system as a novel tool for poliovirus environmental surveillance: Results from a comparative field study in Pakistan. AB - Poliovirus (PV) environmental surveillance (ES) plays an important role in the global eradication program and is crucial for monitoring silent PV circulation especially as clinical cases decrease. This study compared ES results using the novel bag-mediated filtration system (BMFS) with the current two-phase separation method. From February to November 2016, BMFS and two-phase samples were collected concurrently from twelve sites in Pakistan (n = 117). Detection was higher in BMFS than two-phase samples for each Sabin-like (SL) PV serotype (p<0.001) and wild PV type 1 (WPV1) (p = 0.065). Seventeen sampling events were positive for WPV1, with eight discordant in favor of BMFS and two in favor of two-phase. A vaccine-derived PV type 2 was detected in one BMFS sample but not the matched two phase. After the removal of SL PV type 2 (SL2) from the oral polio vaccine in April 2016, BMFS samples detected SL2 more frequently than two-phase (p = 0.016), with the last detection by either method occurring June 12, 2016. More frequent PV detection in BMFS compared to two-phase samples is likely due to the greater effective volume assayed (1620 mL vs. 150 mL). This study demonstrated that the BMFS achieves enhanced ES for all PV serotypes in an endemic country. PMID- 30011306 TI - Time course of traumatic neuroma development. AB - This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA. PMID- 30011307 TI - Soil organic matter and CO2 fluxes in small tropical watersheds under forest and cacao agroforestry. AB - Annual estimates of CO2 and dissolved carbon concentrations in the soil profile provide valuable insight into the dynamics of organic matter in soil and the effect of changes to vegetation cover. The aim of this study was to observe the spatial influence of litter decomposition in the first few centimeters of the soil for CO2 fluxes and to describe the processing of soil organic matter throughout the soil profile by comparing three small tropical watersheds. Data were collected biweekly for six months, from December 2015 to May 2016. CO2 was measured using an infrared gas analyzer in fixed chambers and the dissolved carbon of soil solution was analyzed in a TOC analyzer. No differences were found in the total soil CO2 fluxes (control flux treatments) between the three study areas. In both cacao agroforestry systems (managed and unmanaged), total CO2 fluxes were influenced by the decomposition of litter. CO2 emissions in the soil profile of the cacao agroforestry systems were highly variable, compared to the preserved forest, and highly dependent on the soil characteristics attributed to the type of vegetation cover. Although a definite pattern between the temperature and soil moisture was not identified, these parameters showed a strong relationship in controlling the release of CO2 between treatments. The organic and inorganic dissolved carbon patterns in the soil solution of the three areas revealed different responses of soil organic matter processing related to soil characteristics and vegetation. The results confirm the hypothesis that the top of soils (total CO2 fluxes) of both cacao agroforestry systems (managed and unmanaged) emits fluxes of CO2, which do not differ statistically from the preserved forest. However, depending on the soil characteristics, the cacao agroforestry system can result in an accumulation of CO2 and dissolved inorganic carbon in the soil profile that is prone to being transported by hydrological routes to groundwater and stream water. PMID- 30011308 TI - Persistent expression of Cotesia plutellae bracovirus genes in parasitized host, Plutella xylostella. AB - Cotesia plutellae (= vestalis) bracovirus (CpBV) is symbiotic to an endoparasitoid wasp, C. plutellae, and plays crucial roles in parasitism against the diamondback moth, Plutella xylostella. CpBV virion genome consists of 35 circular DNAs encoding 157 putative open reading frames (ORFs). This study re annotated 157 ORFs with update genome database and analyzed their gene expressions at early and late parasitic stages. Re-annotation has established 15 different viral gene families, to which 83 ORFs are assigned with remaining 74 hypothetical genes. Among 157 ORFs, 147 genes were expressed at early or late parasitic stages, among which 141 genes were expressed in both parasitic stages, indicating persistent nature of gene expression. Relative frequencies of different viral circles present in the ovarian lumen did not explain the expression variation of the viral ORFs. Furthermore, expression level of each viral gene was varied during parasitism along with host development. Highly up regulated CpBV genes at early parasitic stage included BEN (BANP, E5R and NAC1), ELP (EP1-like protein), IkB (inhibitor kB), P494 (protein 494 kDa) family genes, while those at late stage were mostly hypothetical genes. Along with the viral gene expression, 362 host genes exhibited more than two fold changes in expression levels at early parasitic stage compared to nonparasitized host. At late stage, more number (1,858) of host genes was regulated. These results suggest that persistent expression of most CpBV genes may be necessary to regulate host physiological processes during C. plutellae parasitism. PMID- 30011309 TI - The impact of self-esteem on the preferential processing of self-related information: Electrophysiological correlates of explicit self vs. other evaluation. AB - Preferential processing of self-related information is a well-documented phenomenon on both the behavioral and neural levels. However, the impact of self esteem on this self-preference has not been studied in a systematic way. Here, the electrophysiological correlates of explicit self-reflection were investigated in individuals with low (LSE) and high self-esteem (HSE). Participants evaluated trait adjectives in reference to the self or to an "other" person (close-other, famous) while EEG was recorded. The analysis of event-related potentials focused on the late positive component (LPC), which exhibits a fronto-central distribution and latency over 500 ms. In both LSE and HSE groups, the amplitudes of LPC were enhanced in the self condition when compared to control conditions (both close-other and famous). Crucially, LPC amplitudes in the HSE group were significantly higher than in the LSE group. Moreover, the self-preference effect, defined as the difference between amplitudes of LPC associated with the evaluation of words in relation to oneself vs. other people, was significantly higher in the HSE group than in the LSE group. Overall, our findings indicate that people with high self-esteem tend to engage in self-referential processing to a higher extent. PMID- 30011310 TI - Distinct expression of the neurotoxic microRNA family let-7 in the cerebrospinal fluid of patients with Alzheimer's disease. AB - MicroRNAs (miRNAs) are non-coding RNAs originally involved in RNA silencing and post-transcriptional regulation of gene expression. We have shown in previous work that the miRNA let-7b can act as a signalling molecule for Toll-like receptor 7, thereby initiating innate immune pathways and apoptosis in the central nervous system. Here, we investigated whether different members of the miRNA family let-7, abundantly expressed in the brain, are released into the human cerebrospinal fluid (CSF) and whether quantitative differences in let-7 copies exist in neurodegenerative diseases. RNA isolated from CSF of patients with Alzheimer's disease (AD) and from control patients with frontotemporal lobe dementia (FTLD), major depressive episode (MDE) without clinical or neurobiological signs of AD, and healthy individuals, was reverse transcribed with primers against nine let-7 family members, and miRNAs were quantified and analyzed comparatively by quantitative PCR. let-7 miRNAs were present in CSF from patients with AD, FTLD, MDE, and healthy controls. However, the amount of individual let-7 miRNAs in the CSF varied substantially. CSF from AD patients contained higher amounts of let-7b and let-7e compared to healthy controls, while no differences were observed regarding the other let-7 miRNAs. No increase in let 7b and let-7e was detected in CSF from FTLD patients, while in CSF from MDE patients, let-7b and let-7e copy levels were elevated. In CSF from AD patients, let-7b and let-7e were associated with extracellular vesicles. let-7 family members present in the CSF mediated neurotoxicity in vitro, albeit to a variable extent. Taken together, neurotoxic let-7 miRNAs are differentially and specifically released in AD, but also in MDE patients. Thus, these miRNAs may mirror common neuropathological paths and by this serve to unscramble mechanisms of different neurodegenerative diseases. PMID- 30011311 TI - Effect of innovation capacity, production capacity and vertical specialization on innovation performance in China's electronic manufacturing: Analysis from the supply and demand sides. AB - Manufacturing in China has developed rapidly with the widening and deepening of globalization, but only innovation can industry keep upgrading and enhancing its international competitiveness. This paper combines Global Value Chains (GVCs) and National Value Chains (NVCs) in a unified theory framework, uses Structural Decomposition Analysis (SDA) to explore how innovation capacity, production capacity, and vertical specialization affect innovation performance from the supply and demand sides by examining the case of Electronic Manufacturing of China. We observe that innovation inputs and outputs present strong regional heterogeneity between coastal and inland regions. Although most regions continue to engage in processing trade or assembly manufacturing in GVCs, NVCs are gradually established and led by coastal regions. The results indicate a good chance for cultivating innovation capacity in coastal regions. After assessing the influence of determinants on innovation performance, we observe that from supply-side, innovation capacity has a positive effect on innovation performance, production capacity in coastal regions is improving, and domestic demand for domestic products is increasingly important. From the demand side, innovation capacity continues to have a positive effect on innovation performance, production capacity improves rapidly, and imported intermediate inputs enhance innovation performance more effectively than domestic intermediate inputs. PMID- 30011313 TI - Webcrawling and machine learning as a new approach for the spatial distribution of atmospheric emissions. AB - In this study we apply two methods for data collection that are relatively new in the field of atmospheric science. The two developed methods are designed to collect essential geo-localized information to be used as input data for a high resolution emission inventory for residential wood combustion (RWC). The first method is a webcrawler that extracts openly online available real estate data in a systematic way, and thereafter structures them for analysis. The webcrawler reads online Norwegian real estate advertisements and it collects the geo position of the dwellings. Dwellings are classified according to the type (e.g., apartment, detached house) they belong to and the heating systems they are equipped with. The second method is a model trained for image recognition and classification based on machine learning techniques. The images from the real estate advertisements are collected and processed to identify wood burning installations, which are automatically classified according to the three classes used in official statistics, i.e., open fireplaces, stoves produced before 1998 and stoves produced after 1998. The model recognizes and classifies the wood appliances with a precision of 81%, 85% and 91% for open fireplaces, old stoves and new stoves, respectively. Emission factors are heavily dependent on technology and this information is therefore essential for determining accurate emissions. The collected data are compared with existing information from the statistical register at county and national level in Norway. The comparison shows good agreement for the proportion of residential heating systems between the webcrawled data and the official statistics. The high resolution and level of detail of the extracted data show the value of open data to improve emission inventories. With the increased amount and availability of data, the techniques presented here add significant value to emission accuracy and potential applications should also be considered across all emission sectors. PMID- 30011312 TI - Clinical significance of CD161+CD4+ T cells in the development of chronic antibody-mediated rejection in kidney transplant recipients. AB - In this study, we investigated whether CD161+CD4+ T cells can reflect the Th17 pathway in kidney transplant recipients (KTRs) and investigated the clinical significance of this cell type in chronic antibody-mediated rejection (cAMR) in KT. First, we investigated the relationship between CD161+CD4+ T and Th17 cells by flow cytometry and microarray analysis in an in vitro study. Second, we compared the proportion of T cell subsets including CD161+CD4+ T cells in cAMR (n = 18), long-term graft survival (LTGS) (n = 46), and interstitial fibrosis/tubular atrophy (IF/TA) (n = 22). We compared CD161+ cell infiltration between cAMR and IF/TA and also examined the effect of CD161+ T cells on human renal proximal tubular epithelial cells (HRPTEpiC). In flow cytometry, the proportion of CD161+CD4+ T cells showed a significant correlation with the proportion of Th17 cells. In microarray analysis, transcripts associated with the Th17 pathway such as IL18RAP, IL-18R1, IL23R, IL12RB2, RORC, TBX21, and EOMES were upregulated in CD161+ cells compared with CD161- cells. In an ex vivo study, only CD161+CD4+ T cells showed a significant increase in the cAMR group compared with IF/TA and LTGS groups. In allograft tissue, CD161+ cells showed a higher level of infiltration in the cAMR group than the IF/TA group. Lastly, CD161+ T cells increased the production of inflammatory cytokines from HRPTEpiC in a dose dependent manner. This study suggests that monitoring of CD161+ T cells can be useful to detect the progression of cAMR. PMID- 30011314 TI - Dietary and physical activity recommendations to prevent type 2 diabetes in South Asian adults: A systematic review. AB - Intervention trials and guidelines for the prevention of type 2 diabetes (T2D) in populations of South Asian origin often include strategies to improve diet and physical activity that are based on those developed for other populations. These may be suboptimal for the South Asian target populations. We aimed to provide an overview of included recommended dietary and physical activity components, and to identify whether these were supported by evidence of their effectiveness. Databases were searched until September 2017 for intervention studies and guidelines with an adult South Asian population without T2D. The protocol was registered in PROSPERO, registration number: CRD42015207067. The quality of included studies and guidelines was assessed. Dietary and physical activity components, and effects on T2D incidence, glycemic status and adiposity measures, were summarized in tabular format and evaluated narratively. Eighteen intervention studies and four guidelines were identified. Dietary and physical activity components were similar to recommendations for the general population. Intervention studies and guidelines did not reference evidence to support the effectiveness of components included in the intervention for South Asian populations in particular. Moreover, we were unable to assess patterns of components to determine the effects of specific components. Evaluation of current and emerging components among South Asian populations and subgroups seems necessary to formulate more specific recommendations in future intervention studies and guidelines. PMID- 30011315 TI - Quintuple labeling in the electron microscope with genetically encoded enhanced horseradish peroxidase. AB - Genetic encoded multilabeling is essential for modern cell biology. In fluorescence microscopy this need has been satisfied by the development of numerous color-variants of the green fluorescent protein. In electron microscopy, however, true genetic encoded multilabeling is currently not possible. Here, we introduce combinatorial cell organelle type-specific labeling as a strategy for multilabeling. First, we created a reliable and high sensitive label by evolving the catalytic activity of horseradish peroxidase (HRP). We then built fusion proteins that targeted our new enhanced HRP (eHRP) to three cell organelles whose labeling pattern did not overlap with each other. The labeling of the endoplasmic reticulum, synaptic vesicles and the plasma membrane consequently allowed for triple labeling in the EM. The combinatorial expression of the three organelle specific constructs increased the number of clearly distinguishable labels to seven. This strategy of multilabeling for EM closes a significant gap in our tool set and has a broad application range in cell biology. PMID- 30011316 TI - Is the golden ratio a universal constant for self-replication? AB - The golden ratio, phi = 1.61803..., has often been found in connection with biological phenomena, ranging from spirals in sunflowers to gene frequency. One example where the golden ratio often arises is in self-replication, having its mathematical origins in Fibonacci's sequence for "rabbit reproduction". Recently, it has been claimed that phi determines the ratio between the number of different nucleobases in human genome. Such empirical examples continue to give credence to the idea that the golden ratio is a universal constant, not only in mathematics but also for biology. In this paper, we employ a general framework for chemically realistic self-replicating reaction systems and investigate whether the ratio of chemical species population follows "universal constants". We find that many self replicating systems can be characterised by an algebraic number, which, in some cases, is the golden ratio. However, many other algebraic numbers arise from these systems, and some of them-such as [Formula: see text] and 1.22074... which is also known as the 3rd lower golden ratio-arise more frequently in self replicating systems than the golden ratio. The "universal constants" in these systems arise as roots of a limited number of distinct characteristic equations. In addition, these "universal constants" are transient behaviours of self replicating systems, corresponding to the scenario that the resource inside the system is infinite, which is not always the case in practice. Therefore, we argue that the golden ratio should not be considered as a special universal constant in self-replicating systems, and that the ratios between different chemical species only go to certain numbers under some idealised scenarios. PMID- 30011317 TI - Assessing sustainability in North America's ecosystems using criticality and information theory. AB - Sustainability is a key concept in economic and policy debates. Nevertheless, it is usually treated only in a qualitative way and has eluded quantitative analysis. Here, we propose a sustainability index based on the premise that sustainable systems do not lose or gain Fisher Information over time. We test this approach using time series data from the AmeriFlux network that measures ecosystem respiration, water and energy fluxes in order to elucidate two key sustainability features: ecosystem health and stability. A novel definition of ecosystem health is developed based on the concept of criticality, which implies that if a system's fluctuations are scale invariant then the system is in a balance between robustness and adaptability. We define ecosystem stability by taking an information theory approach that measures its entropy and Fisher information. Analysis of the Ameriflux consortium big data set of ecosystem respiration time series is contrasted with land condition data. In general we find a good agreement between the sustainability index and land condition data. However, we acknowledge that the results are a preliminary test of the approach and further verification will require a multi-signal analysis. For example, high values of the sustainability index for some croplands are counter-intuitive and we interpret these results as ecosystems maintained in artificial health due to continuous human-induced inflows of matter and energy in the form of soil nutrients and control of competition, pests and disease. PMID- 30011318 TI - Impact of maternal nutritional supplementation in conjunction with a breastfeeding support program during the last trimester to 12 weeks postpartum on breastfeeding practices and child development at 30 months old. AB - BACKGROUND: Maternal nutrition during pregnancy and breastfeeding is important for the healthy growth and development of the fetus and infant. PURPOSE: This study aimed to evaluate the long-term effects of a maternal milk supplementation (MMS) in conjunction with a breastfeeding support program on breastfeeding practices including duration of any breastfeeding and exclusive breastfeeding and child neurodevelopment outcomes at 30 months old. METHODS: We followed up the offspring of 204 Vietnamese women who completed a randomized controlled trial where the intervention group received MMS with a breastfeeding support program from the last trimester to 12 weeks postpartum while the control group received standard care. At 30 months postpartum, information on child feeding practices was collected and child neurodevelopment was assessed by the Bayley Scales of Infant and Toddler Development (Bayley-III). RESULTS: There was no significant difference in the duration of any breastfeeding (ABF) from birth between the groups. However, the intervention group had longer exclusive breastfeeding (EBF) duration (p = 0.0172), higher EBF rate at 6 months (p = 0.0093) and lower risk of discontinuing EBF (p = 0.0071) than the control. Children in the intervention group had significantly higher Bayley-III composite scores in the domains of cognitive (p = 0.0498) and motor (p = 0.0422) functions, as well as a tendency toward better social-emotional behavior (p = 0.0513) than children in the control group. The association between maternal intervention and child development was attenuated after further adjustment for birth weight but not EBF duration, suggesting that improvements in child development may be partially attributed to the benefits of prenatal nutrition supplementation on birth outcomes. CONCLUSIONS: MMS with breastfeeding support during late pregnancy and early postpartum significantly improved EBF practices. The intervention was also associated with improvements in neurodevelopment in children at 30 months old. PMID- 30011319 TI - Performance of an Xpert-based diagnostic algorithm for the rapid detection of drug-resistant tuberculosis among high-risk populations in a low-incidence setting. AB - Timely diagnosis of drug-resistant tuberculosis (DR-TB) is beneficial for case treatment and management. We implemented an algorithm to improve molecular diagnostic utilization to intensify DR-TB case findings. The GeneXpert MTB/RIF (Xpert) test was used for initial diagnosis. Samples with Mycobacterium tuberculosis complex (MTBC)-positive and rifampicin resistance (RR) results were subsequently and simultaneously tested using the GenoType MTBDRplus (DRplus) and MTBDRsl (DRsl) tests. This prospective cohort study enrolled 2957 high-risk DR-TB cases. We tested sputum specimens using conventional mycobacteriological and molecular tests. Gene sequencing was performed to resolve discordant results. According to the Xpert test, 33.6% of specimens were MTBC-positive and 5.1% were RR. RR specimens were further analyzed in the DRplus and DRsl tests. We identified 1 extensively drug-resistant (XDR), 8 pre-XDR, 18 simple multidrug resistant (MDR), 22 mono-RR, and 2 RR cases with concurrent second-line injection DR-TB. Of these, 25 (49%) were relapses, 13 (25.5%) were treatment failures, 10 (19.6%) were from MDR-TB high-incidence areas/countries, 1 was from MDR-TB contact and 2 were unknown. Among culture-positive TB cases, the sensitivities, specificities, and positive predictive values (PPVs) of the Xpert test and RR cases were 73.6% and 100.0%, 85.7% and 98.6%, and 73.5% and 80.0%, respectively. Gene sequencing of discordant results revealed 7 disputed rpoB mutations and 2 silent mutations for RIF, 1 ahpC mutation for isoniazid and 1 gyrA mutation for fluoroquinolone. The algorithm effectively identified approximately 23% of annual MDR-/XDR-TB and 37.5% of RR-TB cases that were enrolled in our DR-TB treatment and management program within 3 days. PMID- 30011320 TI - Effects of work-interval duration and sport specificity on blood lactate concentration, heart rate and perceptual responses during high intensity interval training. AB - The aim of this study was to examine the impacts on blood lactate concentration, measured heart rate and assessment of perceived exertion during split sessions of equal relative load, as also their relationship to the specific sport practised. Nineteen regional-level athletes (nine middle and long-distance runners (cyclic group) and ten field-sport team players (acyclic group)) performed four high intensity interval training (HIIT) sessions with work-interval durations of 10 s, 50 s, 90 s and 130 s. The sessions were carried out at their usual training sites with a separation of at least 48 hours. Blood lactate concentration was measured at rest and 3 min after the completion of each protocol. Heart rate was measured continuously during all sessions with a sampling rate of 1 s, and rating of perceived exertion (RPE) was requested at the end of the trial. The results showed an increase in blood lactate concentration, peak heart rate and rating of perceived exertion during long protocols as compared with short ones. No differences were observed in dependent variables between cyclic and acyclic groups. Significant but moderate correlations were observed between post-exercise blood lactate concentration, peak heart rate and RPE. PMID- 30011321 TI - A 60 Hz uniform electromagnetic field promotes human cell proliferation by decreasing intracellular reactive oxygen species levels. AB - Previously, we showed that exposure of human normal and cancer cells to a 6 mT, 60 Hz gradient electromagnetic field (EMF) induced genotoxicity. Here, we investigated the cellular effects of a uniform EMF. Single or repetitive exposure to a 6 mT, 60 Hz uniform EMF neither induced DNA damage nor affected cell viability in HeLa and primary IMR-90 fibroblasts. However, continuous exposure of these cells to an EMF promoted cell proliferation. Cell viability increased 24.4% for HeLa and 15.2% for IMR-90 cells after a total 168 h exposure by subculture. This increase in cell proliferation was directly correlated with EMF strength and exposure time. When further incubated without EMF, cell proliferation slowed down to that of unexposed cells, suggesting that the proliferative effect is reversible. The expression of cell cycle markers increased in cells continuously exposed to an EMF as expected, but the distribution of cells in each stage of the cell cycle did not change. Notably, intracellular reactive oxygen species levels decreased and phosphorylation of Akt and Erk1/2 increased in cells exposed to an EMF, suggesting that reduced levels of intracellular reactive oxygen species play a role in increased proliferation. These results demonstrate that EMF uniformity at an extremely low frequency (ELF) is an important factor in the cellular effects of ELF-EMF. PMID- 30011322 TI - A standardized protocol for quantification of saccadic eye movements: DEMoNS. AB - OBJECTIVE: Quantitative saccadic testing is a non-invasive method of evaluating the neural networks involved in the control of eye movements. The aim of this study is to provide a standardized and reproducible protocol for infrared oculography measurements of eye movements and analysis, which can be applied for various diseases in a multicenter setting. METHODS: Development of a protocol to Demonstrate Eye Movement Networks with Saccades (DEMoNS) using infrared oculography. Automated analysis methods were used to calculate parameters describing the characteristics of the saccadic eye movements. The two measurements of the subjects were compared with descriptive and reproducibility statistics. RESULTS: Infrared oculography measurements of all subjects were performed using the DEMoNS protocol and various saccadic parameters were calculated automatically from 28 subjects. Saccadic parameters such as: peak velocity, latency and saccade pair ratios showed excellent reproducibility (intra class correlation coefficients > 0.9). Parameters describing performance of more complex tasks showed moderate to good reproducibility (intra-class correlation coefficients 0.63-0.78). CONCLUSIONS: This study provides a standardized and transparent protocol for measuring and analyzing saccadic eye movements in a multicenter setting. The DEMoNS protocol details outcome measures for treatment trial which are of excellent reproducibility. The DEMoNS protocol can be applied to the study of saccadic eye movements in various neurodegenerative and motor diseases. PMID- 30011323 TI - Absence of RstA results in delayed initiation of DNA replication in Escherichia coli. AB - RstB/RstA is an uncharacterized Escherichia coli two-component system, the regulatory effects of which on the E. coli cell cycle remain unclear. We found that the doubling time and average number of replication origins per cell in an DeltarstB mutant were the same as the wild-type, and the average number of replication origins in an DeltarstA mutant was 18.2% lower than in wild-type cells. The doubling times were 34 min, 35 min, and 40 min for the wild-type, DeltarstB, and DeltarstA strains, respectively. Ectopic expression of RstA from plasmid pACYC-rstA partly reversed the DeltarstA mutant phenotypes. The amount of initiator protein DnaA per cell was reduced by 40% in the DeltarstA mutant compared with the wild-type, but the concentration of DnaA did not change as the total amount of cellular protein was also reduced in these cells. Deletion or overproduction of RstA does not change the temperature sensitivity of dnaA46, dnaB252 and dnaC2. The expression of hupA was decreased by 0.53-fold in DeltarstA. RstA interacted with Topoisomerase I weakly in vivo and increased its activity of relaxing the negative supercoiled plasmid. Our data suggest that deletion of RstA leads to delayed initiation of DNA replication, and RstA may affect initiation of replication by controlling expression of dnaA or hupA. Furthermore, the delayed initiation may by caused by the decreased activity of topoisomerase I in RstA mutant. PMID- 30011324 TI - Correction: Identification, Characterization, and Diel Pattern of Expression of Canonical Clock Genes in Nephrops norvegicus (Crustacea: Decapoda) Eyestalk. AB - [This corrects the article DOI: 10.1371/journal.pone.0141893.]. PMID- 30011325 TI - Correction: High mortality of blue, humpback and fin whales from modeling of vessel collisions on the U.S. West Coast suggests population impacts and insufficient protection. AB - [This corrects the article DOI: 10.1371/journal.pone.0183052.]. PMID- 30011326 TI - Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis. AB - BACKGROUND AND AIMS: Expression of carbonic anhydrase IX (CA9), an enzyme expressed in response to hypoxia, acidosis and oncogenic alterations, is reported to be a prognostic factor in HCC patients. Here we evaluated serum CA9 levels in HCC and cirrhosis patients. METHODS: HCC and cirrhosis patients were prospectively recruited and CA9 levels were determined. CA9 levels were compared to stages of cirrhosis and HCC stages. The association of the CA9 levels and overall survival (OS) was assessed. Furthermore, immunohistochemical CA9 expression in HCC and cirrhosis was evaluated. RESULTS: 215 patients with HCC were included. The median serum CA9 concentration in patients with HCC was 370 pg/ml and significantly higher than in a healthy cohort. Patients with advanced cancer stages (BCLC and ALBI score) had hid significant higher levels of CA9 in the serum. HCC patients with high serum CA9 concentrations (>400 pg/ml) had an increased mortality risk (hazard ratio (HR) 1.690, 95% confidence interval (CI) 1.017-2.809, P = 0.043). Serum CA9 concentration in cirrhotic patients did not differ significantly from HCC patients. Higher CA9 levels in cirrhotic patients correlated with portal hypertension and esophageal varices. Patients with ethanol induced cirrhosis had the highest CA9 levels in both cohorts. Levels of CA9 did not correlate with immunohistochemical expression. CONCLUSIONS: We conclude that a high CA9 level is a possible prognostic indicator for a poor outcome in HCC patients. The high CA9 levels are probably mainly associated with portal hypertension. Ductular reactions might be a possible source of serum CA9. PMID- 30011327 TI - The murine female intestinal microbiota does not shift throughout the estrous cycle. AB - : Pregnancy is accompanied by maternal physiological adaptations including metabolic, endocrine, immune, cardiovascular, skeletomuscular and neurological modifications that facilitate fetal and placental growth and development. Emerging evidence suggests that the maternal intestinal microbiota is modified over the course of healthy pregnancy. We have recently identified a maternal intestinal microbial shift within hours of conception; a shift that continued with advancing gestation. It is possible that maternal gut bacterial profiles might be associated with the known endocrine changes that accompany the female reproductive (estrous) cycle. METHODS: To determine whether the estrous cycle influenced the shifts in the maternal intestinal microbiota, time-matched fecal pellets were collected daily for 3 consecutive estrous cycles from individually housed, non-pregnant female C57BL/6J mice (n = 10) fed a control diet. Estrous stage was identified by cell type predominance in vaginal cytological samples. The corresponding fecal pellets for each estrous stage were processed for bacterial 16S rRNA sequencing of the variable 3 (V3) region. RESULTS: Estrous cycle stage accounted for a very small and not statistically significant proportion of the variation in the fecal microbiota according to PERMANOVA testing performed on Bray-Curtis dissimilarity scores. These values displayed no significant clustering of fecal microbial communities by estrous stage. CONCLUSION: The estrous cycle does not result in any significant shift in the intestinal microbial community in the reproductively mature, regularly cycling female mouse. PMID- 30011328 TI - FDG PET/CT for prognostic stratification of patients with metastatic breast cancer treated with first line systemic therapy: Comparison of EORTC criteria and PERCIST. AB - AIM: Evaluate response and predict prognosis of patients with newly diagnosed metastatic breast cancer treated with first line systemic therapy using European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in solid Tumours (PERCIST). METHODS: From December 2006 to August 2013, 57 women with newly diagnosed metastatic breast cancer were retrospectively evaluated. FDG-PET/CT was performed within one month before treatment and repeated after at least 3 cycles of treatment. Metabolic response evaluation was evaluated by two readers according to both EORTC criteria and PERCIST, classifying the patients into 4 response groups: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). RESULTS: With EORTC criteria, 22 patients had CMR, 17 PMR, 6 SMD and 12 PMD. With PERCIST, 20 patients had CMR, 15 PMR, 10 SMD and 12 PMD. There was agreement between EORTC and PERCIST in 84% of the patients. By log-rank analysis, metabolic response evaluated with both EORTC criteria and PERCIST was able to predict overall survival (p = 0.028 and 0.002 respectively). CMR patient group had longer median OS than patients in the combined PMR+SMD+PMD group (60 vs 26 months both with EORTC and PERCIST; p = 0.009 and 0.006 respectively). By multivariate analysis, CMR either with EORTC or PERCIST remained an independent predictor of survival. CONCLUSION: Metabolic response evaluation with EORTC criteria and PERCIST gave similar prognostic stratification for metastatic breast cancer treated with a first line of systemic therapy. PMID- 30011329 TI - Correction: Nonsteroidal anti-inflammatory drug choice and adverse outcomes in clopidogrel users: A retrospective cohort study. AB - [This corrects the article DOI: 10.1371/journal.pone.0193800.]. PMID- 30011330 TI - A plant diterpene counteracts juvenile hormone-mediated gene regulation during Drosophila melanogaster larval development. AB - Many plant species possess compounds with juvenile hormone disruptor (JHD) activity. In some plant species, such activity has been attributed to diterpene secondary metabolites. Plant JHD diterpenes disrupt insect development by interfering with the juvenile hormone (JH)-mediated formation of JH receptor complexes. Here, we demonstrate that a plant extract and a diterpene from Lindera erythrocarpa (methyl lucidone) interfere with the formation of both methoprene tolerant (Met)/Taiman and Germ cell-expressed (GCE)/Taiman heterodimer complexes in yeast two-hybrid assays in vitro. In addition to the in vitro JHD activity, the diterpene and the plant extract from L. erythrocarpa also disrupt the development of larvae and pupae in Drosophila melanogaster. Comparing the transcriptomes of juvenile hormone analog (JHA, methoprene)- and JHD (methyl lucidone)-fed wandering third-instar larvae revealed a large number of genes that were coregulated by JHA and JHD. Moreover, most (83%) of the genes that were repressed by methyl lucidone were significantly activated by methoprene, indicating that JHDs and JHAs have opposing effects on the transcriptional regulation of many JH-dependent genes. Gene ontology analysis also suggested that some of the genes activated-by-JHA/repressed-by-JHD play roles in spermatogenesis. Affymetrix microarray-based analysis indicated that the expression of genes activated-by-JHA/repressed-by-JHD was testis-specific. Together, these results suggest that JH is involved in testis-specific gene expression and that plant JHD diterpenes function as JH antagonists in such JHA mediated gene regulation. PMID- 30011331 TI - Correction: The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes. AB - [This corrects the article DOI: 10.1371/journal.pone.0192770.]. PMID- 30011332 TI - Small-angle X-ray scattering study of the kinetics of light-dark transition in a LOV protein. AB - Light, oxygen, voltage (LOV) photoreceptors consist of conserved photo-responsive domains in bacteria, archaea, plants and fungi, and detect blue-light via a flavin cofactor. We investigated the blue-light induced conformational transition of the dimeric photoreceptor PpSB1-LOV-R66I from Pseudomonas putida in solution by using small-angle X-ray scattering (SAXS). SAXS experiments of the fully populated light- and dark-states under steady-state conditions revealed significant structural differences between the two states that are in agreement with the known structures determined by crystallography. We followed the transition from the light- to the dark-state by using SAXS measurements in real time. A two-state model based on the light- and dark-state conformations could describe the measured time-course SAXS data with a relaxation time tauREC of ~ 34 to 35 min being larger than the recovery time found with UV/vis spectroscopy. Unlike the flavin chromophore-based UV/vis method that is sensitive to the local chromophore environment in flavoproteins, SAXS-based assay depends on protein conformational changes and provides with an alternative to measure the recovery kinetics. PMID- 30011334 TI - Correction: Premature aortic smooth muscle cell differentiation contributes to matrix dysregulation in Marfan Syndrome. AB - [This corrects the article DOI: 10.1371/journal.pone.0186603.]. PMID- 30011333 TI - Identification and characterization of the bZIP transcription factor family and its expression in response to abiotic stresses in sesame. AB - Basic leucine zipper (bZIP) gene family is one of the largest transcription factor families in plants, and members of this family play important roles in multiple biological processes such as light signaling, seed maturation, flower development as well as abiotic and biotic stress responses. Nonetheless, genome wide comprehensive analysis of the bZIP family is lacking in the important oil crop sesame. In the present study, 63 bZIP genes distributed on 14 linkage groups were identified in sesame, and denominated as SibZIP01-SibZIP63. Besides, all members of SibZIP family were divided into nine groups based on the phylogenetic relationship of Arabidopsis bZIPs, which was further supported by the analysis of their conserved motifs and gene structures. Promoter analysis showed that all SibZIP genes harbor cis-elements related to stress responsiveness in their promoter regions. Expression analyses of SibZIP genes based on transcriptome data showed that these genes have different expression patterns in different tissues. Additionally, we showed that a majority of SibZIPs (85.71%) exhibited significant transcriptional changes in responses to abiotic stresses, including drought, waterlogging, osmotic, salt, and cold, suggesting that SibZIPs may play a cardinal role in the regulation of stress responses in sesame. Together, these results provide new insights into stress-responsive SibZIP genes and pave the way for future studies of SibZIPs-mediated abiotic stress response in sesame. PMID- 30011335 TI - Correction: Serum 25-Hydroxyvitamin D Concentrations >=40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0152441.]. PMID- 30011336 TI - Heterogeneity in pneumolysin expression governs the fate of Streptococcus pneumoniae during blood-brain barrier trafficking. AB - Outcome of host-pathogen encounter is determined by the complex interplay between protective bacterial and host defense strategies. This complexity further amplifies with the existence of cell-to-cell phenotypic heterogeneity in pathogens which remains largely unexplored. In this study, we illustrated that heterogeneous expression of pneumolysin (Ply), a pore-forming toxin of the meningeal pathogen, S. pneumoniae (SPN) gives rise to stochastically different bacterial subpopulations with variable fate during passage across blood-brain barrier (BBB). We demonstrate that Ply mediated damage to pneumococcus containing vacuolar (PCV) membrane leads to recruitment of cytosolic "eat-me" signals, galectin-8 and ubiquitin, targeting SPN for autophagic clearance. However, a majority of high Ply producing subset extensively damages autophagosomes leading to pneumococcal escape into cytosol and efficient clearance by host ubiquitination machinery. Interestingly, a low Ply producing subset halts autophagosomal maturation and evades all intracellular defense mechanisms, promoting its prolonged survival and successful transcytosis across BBB, both in vitro and in vivo. Ply therefore acts as both, sword and shield implying that its smart regulation ensures optimal disease manifestation. Our elucidation of heterogeneity in Ply expression leading to disparate infection outcomes attempts to resolve the dubious role of Ply in pneumococcal pathogenesis. PMID- 30011338 TI - Correction: Estuarine crocodiles in a tropical coastal floodplain obtain nutrition from terrestrial prey. AB - [This corrects the article DOI: 10.1371/journal.pone.0197159.]. PMID- 30011337 TI - A unique increase in prefrontal gray matter volume in hoarding disorder compared to obsessive-compulsive disorder. AB - BACKGROUND: Hoarding disorder (HD) is a disease concept newly presented in DSM-5. As far as we know, no studies have examined the structural changes relevant to hoarding by applying the diagnostic criteria of HD in DSM-5. In the present study, we aimed to find abnormalities in gray matter (GM) structures of patients with HD. METHODS: Seventeen patients who met the DSM-5 criteria for HD, 17 obsessive-compulsive disorder (OCD) patients, and 17 healthy controls (HCs) participated in this study. All participants underwent MRI scanning of the brain by a 3.0-Tesla MRI scanner. In a voxel-based morphometric procedure, preprocessed GM structural images were used to compare the three groups. Thereafter we investigated the correlation between the clinical data (age of onset, symptomatic severity) and GM volume. RESULTS: The HD group showed a significantly increased GM volume compared to the OCD and healthy control groups (p<0.05) in both Brodmann area (BA)10 and BA11. There was no significant difference between OCD and healthy control groups. No significant correlation between the clinical data including age of onset, symptom severity score, and GM volume was observed in HD and OCD groups. CONCLUSIONS: The results might help to explain the inconsistency of previous studies. As with OCD, HD is considered to have cognitive dysfunction as its basis. This result is convincing after considering the clinical features of HD and suggested that structural abnormalities in the prefrontal regions might relate to the pathophysiology of HD. PMID- 30011339 TI - Correction: Surveying the spatial distribution of feral sorghum (Sorghum bicolor L.) and its sympatry with johnsongrass (S. halepense) in South Texas. AB - [This corrects the article DOI: 10.1371/journal.pone.0195511.]. PMID- 30011340 TI - Symbolic estrangement or symbolic integration of numerals with quantities: Methodological pitfalls and a possible solution. AB - Previous studies, which examined whether symbolic and non-symbolic quantity representations are processed by two independent systems or by one common system, reached contradicting findings, possibly due to methodological differences. Indeed, some researchers advocate the two systems approach, based on the presence of notation-specific switch cost in conditions where adults have to compare pairs of symbolic and non-symbolic quantities, in combination with the absence of such a cost in conditions containing quantities of the same notation. However, other researchers used matching instructions, and reported a facilitation in the mixed notation conditions, suggesting that the two systems are automatically integrated. In the current study, we conducted three experiments, in which we examined the existence of two separate quantity systems, but we used various experimental manipulations (e.g., task instructions, presentation order) to unravel the previous inconsistent findings. In Experiment 1, we investigated the role of task instructions by presenting participants with pure and mixed notation trials with both comparison and matching tasks. In Experiment 2, we tested the role of blocked and randomized presentation order for the pure and mixed trials. Our data showed that cost for switching between the symbolic and non-symbolic quantities is present, but is prone to a certain methodological drawback: when the differences between the processing times for two sequentially presented stimuli of different notations are not taken into account, this masks the cost for switching between the two systems. To overcome this problem, in Experiment 3 we used an audio-visual paradigm. Overall, our results provide further evidence for the existence of distinct quantity representations, independently of task instructions or presentation order. Additionally, considering this methodological pitfall we argue that the audio-visual paradigm is better suited when investigating the integration between symbolic and non- symbolic quantities. PMID- 30011342 TI - Correction: Routine Outcome Monitoring and Clinical Decision-Making in Forensic Psychiatry Based on the Instrument for Forensic Treatment Evaluation. AB - [This corrects the article DOI: 10.1371/journal.pone.0160787.]. PMID- 30011341 TI - Reasons for dropout from cardiac rehabilitation programs in women: A qualitative study. AB - BACKGROUND: Empirical evidence has shown that cardiac rehabilitation programs are effective in reducing morbidity and mortality, improving quality of life in patients with cardiovascular disease. Despite the benefits, women have a high cardiac rehabilitation dropout rate. Our aim was to explore women's perceptions about the reasons they faced for dropout from these programs. METHODS: Semi structured interviews were conducted with women (n = 10) after dropping out from three different cardiac rehabilitation centers in Spain. In addition, a focus group and a semi-structured interview with cardiovascular professionals were conducted. From a grounded theory perspective, thematic analysis was used to derive themes from interview transcripts. RESULTS: The women were between 41 and 70 years. We identified five general themes that illustrated reasons for cardiac rehabilitation dropout: intrapersonal reasons (self-reported health, self reported mental health, health beliefs); interpersonal reasons (family caregiver role, work conflicts); logistical reasons (transport, distance); cardiac rehabilitation program characteristics (perception of the objective of cardiac rehabilitation, exercise component, inconvenient timing, cardiac rehabilitation equipment); and health system reasons (financial assistance for transport, long waiting list). The cardiovascular professionals found barriers to cardiac rehabilitation completion similar to those found by the women. CONCLUSIONS: In order to prevent cardiac rehabilitation dropout in women, modular and flexible programs are needed. In addition, the inclusion of primary care centers or community resources could improve cardiac rehabilitation completion in women. Psychological assessment and counseling during cardiac rehabilitation should be included as an essential part of the programs and recommended for those women with depressive symptoms. Finally, improved financial assistance for transport from the health system is essential. PMID- 30011343 TI - In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma. AB - While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in three canine HSA cell lines (DEN-, CIN-, and SB-HSA). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, and vascular endothelial growth factor production in HSA cells, while promoting tumor cell apoptosis. VDC 597 demonstrated additive antiproliferative effects when combined with doxorubicin. These results suggest that inhibitors of the PI3K/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, migration, and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and potentially human, HSA. PMID- 30011344 TI - Stereoselective synthesis of 2,6-trans-4-oxopiperidines using an acid-mediated 6 endo-trig cyclisation. AB - An acid-mediated 6-endo-trig cyclisation of amine-substituted enones has been developed for the stereoselective synthesis of trans-6-alkyl-2-methyl-4 oxopiperidines. Performed under conditions that prevent removal of the Boc protecting group or acetal formation, the key cyclisation was found to generate cleanly the 4-oxopiperidine products in high overall yields from a wide range of alkyl substituted enones. The synthetic utility of the trans-6-alkyl-2-methyl-4 oxopiperidines formed from this process was demonstrated with the total synthesis of the quinolizidine alkaloid, (+)-myrtine and the piperidine alkaloid, (-) solenopsin A. PMID- 30011345 TI - Deconstructing the physical processes of digestion: reductionist approaches may provide greater understanding. AB - I provide a broad overview of the physical factors that govern intestinal digestion i.e. the admixture of food particles in digesta with secreted enzymes and the subsequent mass transfer of liberated nutrients from the surfaces of particles to the gut wall, with a view to outlining the quantitative work that is required to determine the relative importance of these factors in the digestion of particular foods. I first discuss what is known of the mechanical forces generated by contraction of the walls of the various segments of the gut and the level of diffusive, and advective mixing that it generates within the lumen. I then discuss the particular physical effects that may limit the digestion of solid, physically and/or chemically homogenous and heterogeneous food particles, notably capillarity, porosity, poro-elastic flow and compaction and their likely effects on diffusive and convective mass transfer at particulate surfaces. Similarly, I discuss mucins and morphology on mass transfer of nutrients to the gut wall i.e. the mucosa. PMID- 30011346 TI - High spontaneous clearance of symptomatic iatrogenic acute hepatitis C genotype 4 infection. AB - Acute hepatitis C (AHC) infection resolves spontaneously in 15% to 40% of patients. Factors favoring spontaneous viral clearance remain undefined. In this study, predictors of spontaneous viral clearance in patients with symptomatic AHC were investigated. Epidemiological, clinical, and virologic parameters were also examined. Patients with symptomatic AHC were enrolled and followed up prospectively. The patients were followed up every 2 weeks in the first month and then monthly for the following 5 months, with a follow-up visit 6 months after the last hepatitis C virus (HCV)-RNA negative sample for those who had cleared the virus. Interleukin (IL)-28B.rs12979860 single-nucleotide polymorphism and HCV genotype were tested at baseline. HCV-RNA was tested during each visit. Patients who remained RNA-positive at 24 weeks were treated with pegylated interferon plus ribavirin for 24 weeks. A total of 30 patients, mostly with iatrogenically acquired AHC genotype 4 infections completed 6-months' follow-up, to either spontaneous clearance or start of treatment. The mean age of the patients was 37 +/- 13 years. In total, 67% of patients were females, and the mean incubation period was 7.6 +/- 3.5 weeks. Viral clearance occurred spontaneously in 19 (63.3%) patients. The average time to clearance was 24.3 +/- 9.6 weeks. A total of 11 patients received therapy, and 8 (72.7%) cleared the virus and had a sustained virologic response to the treatment 24 weeks after the therapy. A total of three patients were treatment nonresponders. IL28B.rs12979860 CC genotype, female gender, and viremia level were not associated with self-limiting AHC in this cohort. In conclusion, patients with symptomatic AHC genotype 4 infection caused by an iatrogenic exposure had higher rates of spontaneous resolution than previously reported. Predicting spontaneous viral clearance after iatrogenic AHC exposure was not possible in this population. PMID- 30011347 TI - Nurses as substitutes for doctors in primary care. AB - BACKGROUND: Current and expected problems such as ageing, increased prevalence of chronic conditions and multi-morbidity, increased emphasis on healthy lifestyle and prevention, and substitution for care from hospitals by care provided in the community encourage countries worldwide to develop new models of primary care delivery. Owing to the fact that many tasks do not necessarily require the knowledge and skills of a doctor, interest in using nurses to expand the capacity of the primary care workforce is increasing. Substitution of nurses for doctors is one strategy used to improve access, efficiency, and quality of care. This is the first update of the Cochrane review published in 2005. OBJECTIVES: Our aim was to investigate the impact of nurses working as substitutes for primary care doctors on:* patient outcomes;* processes of care; and* utilisation, including volume and cost. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), part of the Cochrane Library (www.cochranelibrary.com), as well as MEDLINE, Ovid, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and EbscoHost (searched 20.01.2015). We searched for grey literature in the Grey Literature Report and OpenGrey (21.02.2017), and we searched the International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov trial registries (21.02.2017). We did a cited reference search for relevant studies (searched 27.01 2015) and checked reference lists of all included studies. We reran slightly revised strategies, limited to publication years between 2015 and 2017, for CENTRAL, MEDLINE, and CINAHL, in March 2017, and we have added one trial to 'Studies awaiting classification'. SELECTION CRITERIA: Randomised trials evaluating the outcomes of nurses working as substitutes for doctors. The review is limited to primary healthcare services that provide first contact and ongoing care for patients with all types of health problems, excluding mental health problems. Studies which evaluated nurses supplementing the work of primary care doctors were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently carried out data extraction and assessment of risk of bias of included studies. When feasible, we combined study results and determined an overall estimate of the effect. We evaluated other outcomes by completing a structured synthesis. MAIN RESULTS: For this review, we identified 18 randomised trials evaluating the impact of nurses working as substitutes for doctors. One study was conducted in a middle-income country, and all other studies in high-income countries. The nursing level was often unclear or varied between and even within studies. The studies looked at nurses involved in first contact care (including urgent care), ongoing care for physical complaints, and follow-up of patients with a particular chronic conditions such as diabetes. In many of the studies, nurses could get additional support or advice from a doctor. Nurse-doctor substitution for preventive services and health education in primary care has been less well studied.Study findings suggest that care delivered by nurses, compared to care delivered by doctors, probably generates similar or better health outcomes for a broad range of patient conditions (low- or moderate-certainty evidence):* Nurse-led primary care may lead to slightly fewer deaths among certain groups of patients, compared to doctor-led care. However, the results vary and it is possible that nurse-led primary care makes little or no difference to the number of deaths (low-certainty evidence).* Blood pressure outcomes are probably slightly improved in nurse-led primary care. Other clinical or health status outcomes are probably similar (moderate-certainty evidence).* Patient satisfaction is probably slightly higher in nurse-led primary care (moderate-certainty evidence). Quality of life may be slightly higher (low-certainty evidence).We are uncertain of the effects of nurse led care on process of care because the certainty of this evidence was assessed as very low.The effect of nurse-led care on utilisation of care is mixed and depends on the type of outcome. Consultations are probably longer in nurse-led primary care (moderate-certainty evidence), and numbers of attended return visits are slightly higher for nurses than for doctors (high-certainty evidence). We found little or no difference between nurses and doctors in the number of prescriptions and attendance at accident and emergency units (high-certainty evidence). There may be little or no difference in the number of tests and investigations, hospital referrals and hospital admissions between nurses and doctors (low-certainty evidence).We are uncertain of the effects of nurse-led care on the costs of care because the certainty of this evidence was assessed as very low. AUTHORS' CONCLUSIONS: This review shows that for some ongoing and urgent physical complaints and for chronic conditions, trained nurses, such as nurse practitioners, practice nurses, and registered nurses, probably provide equal or possibly even better quality of care compared to primary care doctors, and probably achieve equal or better health outcomes for patients. Nurses probably achieve higher levels of patient satisfaction, compared to primary care doctors. Furthermore, consultation length is probably longer when nurses deliver care and the frequency of attended return visits is probably slightly higher for nurses, compared to doctors. Other utilisation outcomes are probably the same. The effects of nurse-led care on process of care and the costs of care are uncertain, and we also cannot ascertain what level of nursing education leads to the best outcomes when nurses are substituted for doctors. PMID- 30011348 TI - Children infected by human herpesvirus 6B with febrile seizures are more likely to develop febrile status epilepticus: A case-control study in a referral hospital in Zambia. AB - BACKGROUND: Human herpesvirus 6B (HHV-6B) is the causative agent of Roseola infantum, and has also been suggested to play a role in the pathogenesis of febrile seizures in young children, a percentage of whom go on to develop febrile status epilepticus (FSE), but the existing data is conflicting and inconclusive. HHV-6A is a distinct species, rarely detected in most parts of the world, but prior studies suggest a higher prevalence in febrile African children. We describe a case-control study comparing the frequency of HHV-6A and/or HHV-6B infections in children with febrile seizures (including FSE) and a control group of febrile children without seizures. METHODS: We recruited children aged 6 to 60 months admitted with a febrile illness with (cases) or without (controls) seizures presenting within 48 hours of commencement of fever. Three milliliters of whole blood was centrifuged and plasma stored at -80 degrees C for pooled screening for HHV-6B and HHV-6A by Taqman real-time polymerase chain reaction. RESULTS: 102 cases and 95 controls were recruited. The prevalence of HHV-6B DNA detection did not differ significantly between cases (5.8% (6/102)) and controls (10.5% (10/95)) but HHV-6B infection was associated with FSE (OR, 15; 95% CI, [1.99-120]; P= 0.009). HHV-6A was not detected. CONCLUSION: Prevalence of HHV-6B was similar among cases and controls. Within the FS group, HHV-6B infection was associated with FSE, suggesting HHV-6B infections could play a role in the pathogenesis of FSE. PMID- 30011349 TI - A rare echocardiographic image of aortic prosthetic valve endocarditis complicated with paravalvular abscess, pseudoaneurysm and aorto-right atrial fistula. AB - Early infectious endocarditis (IE) occurs in 3% of prosthesis in the first 12 months. Early IE is more aggressive than late prosthetic valve endocarditis. Mortality remains high, despite combined medical and surgical treatment. We present a case of early IE in aortic prosthetic valve complicated with paravalvular abscess, pseudoaneurysm and aorto- right atrial fistula. PMID- 30011350 TI - Application strategies of serum HBV DNA detection in HBV infection patients: A retrospective study of 5611 specimens. AB - The detection of hepatitis B virus (HBV) DNA plays a critical role in determining the level of viral replication in HBV-infected patients. However, how to select appropriate HBV DNA detection method, low-sensitivity (ls) and hypersensitivity (hs) remains unclear. In this study, hepatitis B surface antigen (HBsAg), hepatitis B e-antigen (HBeAg), alanine transaminase (ALT), aspartate transaminase (AST), and hs HBV DNA titers in serum of 5611 cases with suspected HBV infection were reviewed. Besides, the dynamic changes of HBV DNA and HBsAg in 85 chronic hepatitis B (CHB) patients receiving peginterferon alpha (PegIFNalpha) or entecavir (ETV) were observed. The results showed the positive rate of HBV DNA was 32.8%, of which low viral load (20 to 500 IU/mL) accounted for 51.8%. In the 5611 cases, when the HBsAg was less than 1000 IU/mL, the proportion of low viral load was 76.3%. Moreover, in patients receiving antiviral treatment, when HBsAg was less than 2000 IU/mL (PegIFNalpha) or HBsAg was less than 3500 IU/mL (ETV), the proportion of patients with low viral load was 79.5% or 78.0%, respectively. We developed a strategy of serum HBV DNA detection in HBV-infected patients. When HBsAg was negative, HBV DNA detection should be unnecessary. When HBsAg was 0.05 to 1000 IU/mL, hs HBV DNA should be detected in patients with abnormal level of ALT, AST, or HBeAg. While HBsAg was greater than or equal to 1000 IU/mL, ls HBV DNA was recommended. Moreover, the cutoff value of HBsAg increased during antiviral therapy of CHB patients. In conclusion, hs HBV DNA is of great value in HBV-infected patients with low viral load. HBV DNA detection methods should be selected reasonably according to the levels of HBsAg, HBeAg, ALT, and AST. PMID- 30011351 TI - Coronary risk assessment using traditional risk factors with computed tomography coronary artery calcium scoring: Illustrative cases. AB - A patient's coronary artery calcium score (CACS) is a strong independent predictor of cardiovascular risk. Used in conjunction with traditional measures of risk, the CACS helps the clinician discuss cardiovascular (CV) risk and recommend therapies with the patient. We present several cases in which measurement of the CACS and traditional risk factors were used to help guide the clinician-patient conversation and guide therapies. PMID- 30011352 TI - Immediate impact of percutaneous transvenous mitral commisurotomy on right ventricle longitudinal strain in patients of mitral stenosis. AB - BACKGROUND: Right ventricular (RV) function has prognostic value in terms of survival and symptoms in patients with mitral stenosis (MS). The aim of the study was to assess RV function by strain analysis in the patients of mitral stenosis and the effect of percutaneous transvenous mitral commisurotomy (PTMC) on it. METHODS: Eighty patients of severe mitral stenosis without overt right heart failure and normal sinus rhythm undergoing PTMC were included. Conventional echocardiography and RV function by TDI-derived longitudinal strain and strain rate were assessed prior and 24 hours post PTMC and compared with 40 healthy age matched controls. RESULTS: Eighty subjects (mean age 31 + 10 years, 70% females) were included. Patients with MS had significantly lower RV strain of basal and mid-free wall, tricuspid annular plane systolic excursion (TAPSE), and RV fractional area change (FAC) as compared to controls. There was a significant increase in pre- and post-PTMC in TAPSE (19.5 +/- 2.7 mm vs 21.4 +/- 3.3 mm; P < 0.001), RV basal free wall longitudinal strain (-24.4 + 6.1% vs -27.7 + 5.8%; P < 0.001), and right ventricle mid-free wall longitudinal strain (-25.6 + 5.5% vs 28.6 + 5.1%; P < 0.001), respectively. There was no significant change in RV Tei index (0.43 + 0.06 vs 0.41 + 0.03; P = 0.06). There was a significant negative correlation between RV longitudinal strain and right ventricle systolic pressure, left atrium diameter, RV Tei index, and pulmonary capillary wedge pressure, and positive correlation between RV FAC and RV TAPSE. CONCLUSION: Patients with severe MS with normal RV systolic function had decreased RV strain, which was significantly increased after a successful PTMC with reduction in afterload. PMID- 30011353 TI - Enantioselective alpha-Benzylation of Acyclic Esters Using pi-Extended Electrophiles. AB - The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1-ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX 9065a. PMID- 30011354 TI - Life-course neighbourhood opportunity and racial-ethnic disparities in risk of preterm birth. AB - BACKGROUND: Neighbourhood opportunity, measured by poverty, income and deprivation, has been associated with preterm birth, however little is known about the contribution of early-life and life-course neighbourhood opportunity to preterm birth risk and racial-ethnic disparities. We examined maternal early-life and adult neighbourhood opportunity in relation to risk of preterm birth and racial-ethnic disparities in a population-based cohort of women under age 30. METHODS: We linked census tract poverty data to 2 generations of California births from 1982-2011 for 403 315 white, black, or Latina mothers-infant pairs. We estimated the risk of preterm birth, and risk difference (RD) comparing low opportunity (>=20% poverty) in early life or adulthood to high opportunity using targeted maximum likelihood estimation. RESULTS: At each time point, low opportunity was related to increased preterm birth risk compared to higher opportunity neighbourhoods for white, black and Latina mothers (RDs 0.3-0.7%). Compared to high opportunity at both time points, risk differences were generally highest for sustained low opportunity (RD 1.5, 1.3, and 0.7% for white, black and Latina mothers, respectively); risk was elevated with downward mobility (RD 0.7, 1.3, and 0.4% for white, black and Latina mothers, respectively), and with upward mobility only among black mothers (RD 1.2%). The black-white preterm birth disparity was reduced by 22% under high life-course opportunity. CONCLUSIONS: Early-life and sustained exposure to residential poverty is related to increased PTB risk, particularly among black women, and may partially explain persistent black-white disparities. PMID- 30011355 TI - Metallapentalenofuran: Shifting Metallafuran Rings Promoted by Substituent Effects. AB - Bulky substituents play important roles in controlling the reaction pathways or producing selected products. This work reports that the shift of metallafuran rings in a metallapentalenofuran complex can be promoted by the substituent effect via a reversible C-H bond reductive elimination and oxidative addition. The starting osmapentalyne, a so-called 7-carbon carbolong complex, was produced by the oxidation of a metallapentalenofuran with FeCl3 . It was then allowed to react with nucleophiles, followed by a C-H activation, to give the aforementioned metallapentalenofuran complex. This work enriches the family of carbolong complexes and reveals a new strategy to promote, but not prevent reactions by the bulky substituents. PMID- 30011356 TI - Alkali-Oxygen Batteries Based on Reversible Superoxide Chemistry. AB - Rechargeable superoxide (O2 - ) batteries have the potential to surpass current lithium-ion technology due to their high theoretical energy densities. The use of superoxides as an energy storage material is highly advantageous when compared to their close relatives, peroxides. This is due to enhanced reversibility of the 1 electron redox process. To efficiently stabilize superoxides, larger metal cations are required such as sodium and potassium. Therefore, the two most studied systems are sodium and potassium-oxygen batteries. Both batteries present unique advantages and challenges. In this minireview, we summarize the current research for each superoxide-based battery and offer perspective for further research. PMID- 30011357 TI - Enantioselective alpha-Allylation of Acyclic Esters Using B(pin)-Substituted Electrophiles: Independent Regulation of Stereocontrol Elements through Cooperative Pd/Lewis Base Catalysis. AB - Cooperation between a Lewis base and Pd catalyst enables the direct enantioselective alpha-functionalization of aryl and vinyl acetic acid esters using a bifunctional B(pin)-substituted electrophile. Critical to the success of this method was the recognition that both catalysts could control the necessary stereochemical aspects; the Lewis base catalyst controls the enantioselectivity of the reaction, whereas the Pd catalyst regulates alkenyl-B(pin) configuration. This is the first example of using cooperative catalysis to control both stereochemical features during Pd-catalyzed allylic alkylation. PMID- 30011358 TI - Precessional Motion in Crystalline Solid Solutions of Ionic Rotors. AB - The order-disorder phase transition associated with the uprise of reorientational motion in (DABCOH2)2+ , in the supramolecular salts of general formula [1?(DABCOH2 )]X2 (where 1=12-crown-4, DABCO=1,4-diazabicyclo[2.2.2]octane, and X=Cl- or Br- ), has been investigated by variable temperature X-ray diffraction on single crystals and powder samples, as well as by DSC and solid-state NMR spectroscopy (SSNMR). The two compounds undergo a reversible phase change at 292 and 290 K, respectively. The two crystalline materials form solid solutions [1?(DABCOH2 )]Cl2x Br2(1-x) in the whole composition range (0 < x<1), with a decrease in the temperature of transition to a minimum of ca 280 K, corresponding to x=0.5. Activation energy values for the dynamic processes, evaluated by variable-temperature 13 C magic-angle spinning (MAS) SSNMR and line-shape analysis are ca. 50 kJ mol-1 in all cases. Combined diffraction and spectroscopic evidence has allowed the detection of a novel dynamic process for the (DABCOH2 )2+ dications, based on a room temperature precessional motion that is frozen out below the disorder-order transition; to the best of the authors' knowledge this phenomenon has never been observed before. PMID- 30011359 TI - Deltahedral Organo-Zintl Superhalogens. AB - Zintl ions constitute a special type of naked anionic clusters, mainly consisting of Group 13, 14, and 15 elements of the Periodic Table. Due to the presence of multiple negative ions, the chemistry of Zintl ions is unique. They not only form Zintl phases with alkali and alkaline-earth metal cations, but also form organo Zintl clusters with distinct properties. By first-principles calculations based on density functional theory, we have designed a new deltahedral organo-Zintl cluster with Ge94- as the core and aromatic heterocyclic compounds as ligands. Calculations on such complexes show that they form a special class of system known as a superhalogen (SH), with a high vertical detachment energy of 4.9 eV. The density of states (DOS), partial DOS, and different molecular orbitals give additional information about the bonding features of the complexes. PMID- 30011360 TI - Iterative Assembly of Macrocyclic Lactones using Successive Ring Expansion Reactions. AB - Macrocyclic lactones can be prepared from lactams and hydroxyacid derivatives via an efficient 3- or 4-atom iterative ring expansion protocol. The products can also be expanded using amino acid-based linear fragments, meaning that macrocycles with precise sequences of hydroxy- and amino acids can be assembled in high yields by "growing" them from smaller rings, using a simple procedure in which high dilution is not required. The method should significantly expedite the practical synthesis of diverse nitrogen containing macrolide frameworks. PMID- 30011361 TI - Direct conversion of cellulose into ethanol and ethyl-beta-d-glucoside via engineered Saccharomyces cerevisiae. AB - Simultaneous saccharification and fermentation (SSF) of cellulose via engineered Saccharomyces cerevisiae is a sustainable solution to valorize cellulose into fuels and chemicals. In this study, we demonstrate the feasibility of direct conversion of cellulose into ethanol and a biodegradable surfactant, ethyl-beta-d glucoside, via an engineered yeast strain (i.e., strain EJ2) expressing heterologous cellodextrin transporter (CDT-1) and intracellular beta-glucosidase (GH1-1) originating from Neurospora crassa. We identified the formation of ethyl beta-d-glucoside in SSF of cellulose by the EJ2 strain owing to transglycosylation activity of GH1-1. The EJ2 strain coproduced 0.34 +/- 0.03 g ethanol/g cellulose and 0.06 +/- 0.00 g ethyl-beta-d-glucoside/g cellulose at a rate of 0.30 +/- 0.02 g.L-1 .h-1 and 0.09 +/- 01 g.L-1 .h-1 , respectively, during the SSF of Avicel PH-101 cellulose, supplemented only with Celluclast 1.5 L. Herein, we report a possible coproduction of a value-added chemical (alkyl glucosides) during SSF of cellulose exploiting the transglycosylation activity of GH1-1 in engineered S. cerevisiae. This coproduction could have a substantial effect on the overall technoeconomic feasibility of theSSF of cellulose. PMID- 30011362 TI - Electrochemical and Theoretical Investigations of the Oxidatively Induced Reactivity of the Complex [Fe2 (CO)4 (kappa2 -dmpe)(MU-adtBn )] Related to the Active Site of [FeFe] Hydrogenases. AB - Electrochemical oxidation of the complex [Fe2 (CO)4 (kappa2 -dmpe)(MU-adtBn )] (adtBn =(SCH2 )2 NCH2 C6 H5 , dmpe=Me2 PCH2 CH2 PMe2 ) (1) has been studied by cyclic voltammetry (CV) in acetonitrile and in dichloromethane in the presence of various substrates L (L=MeCN, trimethylphosphite, isocyanide). The oxidized species, [1-MeCN](PF6 )2 , [1-(P(OMe)3 )2 ](PF6 )2 and [1-(RNC)4 ](PF6 )2 (R=tert butyl, xylyl), have been prepared and characterized by IR and NMR spectroscopies and, except [1-MeCN](PF6 )2 , by X-ray diffraction analysis. The crystallographic structures of the new FeII FeII complexes reveal that the association of one additional ligand (P(OMe)3 or RNC) occurs and, according to the nature of the substrates, further substitutions of one or three carbonyl groups, by P(OMe)3 or RNC, respectively, arise. Density functional theory (DFT) calculations have been performed to elucidate and discriminate, in each case, the mechanisms leading to the corresponding oxidized species. Moreover, the different degree of ligand substitution in the diiron core has been theoretically rationalized. PMID- 30011363 TI - Torsional Potentials of Glyoxal, Oxalyl Halides, and Their Thiocarbonyl Derivatives: Challenges for Popular Density Functional Approximations. AB - The reliability of popular density functionals was studied for the description of torsional profiles of 36 molecules: glyoxal, oxalyl halides, and their thiocarbonyl derivatives. HF and 18 functionals of varying complexity, from local density to range-separated hybrid approximations and double-hybrid, have been considered and benchmarked against CCSD(T)-level rotational profiles. For molecules containing heavy halogens, most functionals fail to reproduce barrier heights accurately and a number of functionals introduce spurious minima. Dispersion corrections show no improvement. Calibrated torsion-corrected atom centered potentials rectify the shortcomings of PBE and also improve on sigma hole based intermolecular binding in dimers and crystals. PMID- 30011364 TI - Atomic Force Microscopy Imaging Study of Aligning DNA by Dumbbell-like Au-Fe3O4 Magnetic Nanoparticles. AB - Studies on nucleic acid structure and interactions between nucleic acid and its binding molecules are of great importance for understanding and controlling many important biological processes. Atomic force microscopy (AFM) imaging is one of the most efficient methods to disclose the DNA structure and binding modes between DNA and DNA-binding molecules. Long-chain DNA tends to form a random coiled structure, which prevents direct AFM imaging observation of the subtle structure formed by DNA itself or protein binding. Aligning DNA from the random coiled state into the extended state is not only important for applications in DNA nanotechnology but also for elucidating the interaction mechanism between DNA and other molecules. Here, we developed an efficient method based on the magnetic field to align long-chain DNA on a silicon surface. We used AFM imaging to study the alignment of DNA at the single-molecule level, showing that DNA can be stretched and highly aligned by the manipulation of magnetic nanoparticles tethered to one end of DNA and that the aligned DNA can be imaged clearly by AFM. In the absence of the magnetic field, the aligned DNA can relax back to a random coiled state upon rinsing. Such alignment and relaxation can be repeated many times, which provides an efficient method for the manipulation of individual DNA molecules and the investigation of DNA and DNA-binding molecule interactions. PMID- 30011365 TI - Synthesis and Properties of the Self-Assembly of Gold-Copper Nanoparticles into Nanoribbons. AB - We report the efficient wet-chemical production of self-assembled gold-copper bimetallic nanoparticles (diameter of ~2 nm) into two-dimensional flexible ribbonlike nanostructures. The direct observation of a layered arrangement of particles into nanoribbons was provided through high-resolution transmission electron microscopy and electron tomography. These nanoribbons showed photoluminesce and efficient photocatalytic activity for the conversion of 4 nitrophenol. The thermal stability of the nanoribbons was also measured by in situ heat treatment in the electron microscope, confirming that the self assembled gold-copper nanoribbons efficiently supported up to 350 degrees C. The final morphology of the nanoparticles and their ability to self-assemble into flexible nanoribbons were dependent on concentration and the ratio of precursors. Therefore, these experimental factors were discussed. Remarkably, the presence of copper was found to be critical to triggering the self-assembly of nanoparticles into ordered layered structures. These results for the synthesis and stability of self-assemblies of metallic nanoparticles present a potential extension of the method to producing materials with catalytic applications. PMID- 30011366 TI - Laser-Induced CO2 Generation from Gold Nanorod-Containing Poly(propylene carbonate)-Based Block Polymer Micelles for Ultrasound Contrast Enhancement. AB - Poly(propylene carbonate) (PPC) decomposes at high temperature to release CO2. This CO2-generation temperature of PPC can be reduced down to less than 80 degrees C with the aid of a photoacid generator (PAG). In the present work, we demonstrate that using an additional helper component, surface plasmonic gold nanorods (GNRs), the PPC degradation reaction can also be initiated by infrared (IR) irradiation. For this purpose, a PPC-containing nanoparticle formulation was developed in which PPC-based amphiphilic block copolymers (BCPs), poly(poly(ethylene glycol) methacrylate- b-propylene carbonate- b-poly(ethylene glycol) methacrylate) (PPEGMA-PPC-PPEGMA), were self-assembled with GNRs and PAG molecules via solvent exchange. Under IR irradiation, GNRs produce heat that can cause PPC to decompose into CO2, and PAG (after UV pretreatment) catalyzes this PPC degradation process. Two PPEGMA-PPC-PPEGMA materials were used for this study: PPEGMA7.3K-PPC5.6K-PPEGMA7.3K ("G7C6G7") and PPEGMA2.1K-PPC5.6K-PPEGMA2.1K ("G2C6G2"). Addition of CTAB-coated GNRs dispersed in water to a G2C6G2 solution in DMF produced individually G2C6G2-encapsulated GNRs, whereas the same solvent exchange procedure resulted in the formation of polymer-coated GNR clusters when G7C6G7 was used as the encapsulating material. GNR/G2C6G2 NPs exhibited a surface plasmon resonance peak at 697 nm. The clustered morphology of G7C6G7-encapsulated GNRs caused a blue shift of the absorbance maximum to 511 nm. As a consequence, GNR/G2C6G2 NPs showed a greater absorbance/heat generation rate under IR irradiation than did GNR/G7C6G7 NPs. The IR-induced CO2 generation rate was about 4.2 times higher with the GNR/G2C6G2+PAG sample than that with the GNR/G7C6G7+PAG sample. Both GNR/G7C6G7+PAG and GNR/G2C6G2+PAG systems produced ultrasound contrast enhancement effects under continuous exposure to IR light for >20 min; contrast enhancement was more spatially uniform for the GNR/G2C6G2+PAG sample. These results support the potential utility of PPC as a CO2-generating contrast agent in ultrasound imaging applications. PMID- 30011367 TI - Self-Assembled Thermoresponsive Polymeric Nanogels for 19F MR Imaging. AB - Magnetic resonance imaging using fluorinated contrast agents (19F MRI) enables to achive highcontrast in images due to the negligible fluorine background in living tissues. In this pilot study, we developed new biocompatible, temperature responsive, and easily synthesized polymeric nanogels containing a sufficient concentration of magnetically equivalent fluorine atoms for 19F MRI purposes. The structure of the nanogels is based on amphiphilic copolymers containing two blocks, a hydrophilic poly[ N-(2-hydroxypropyl)methacrylamide] (PHPMA) or poly(2 methyl-2-oxazoline) (PMeOx) block, and a thermoresponsive poly[ N(2,2difluoroethyl)acrylamide] (PDFEA) block. The thermoresponsive properties of the PDFEA block allow us to control the process of nanogel self-assembly upon its heating in an aqueous solution. Particle size depends on the copolymer composition, and the most promising copolymers with longer thermoresponsive blocks form nanogels of suitable size for angiogenesis imaging or the labeling of cells (approximately 120 nm). The in vitro 19F MRI experiments reveal good sensitivity of the copolymer contrast agents, while the nanogels were proven to be noncytotoxic for several cell lines. PMID- 30011368 TI - Chemoenzymatic Synthesis and Pharmacological Characterization of Functionalized Aspartate Analogues As Novel Excitatory Amino Acid Transporter Inhibitors. AB - Aspartate (Asp) derivatives are privileged compounds for investigating the roles governed by excitatory amino acid transporters (EAATs) in glutamatergic neurotransmission. Here, we report the synthesis of various Asp derivatives with (cyclo)alkyloxy and (hetero)aryloxy substituents at C-3. Their pharmacological properties were characterized at the EAAT1-4 subtypes. The l- threo-3-substituted Asp derivatives 13a-e and 13g-k were nonsubstrate inhibitors, exhibiting pan activity at EAAT1-4 with IC50 values ranging from 0.49 to 15 MUM. Comparisons between (dl- threo)-19a-c and (dl- erythro)-19a-c Asp analogues confirmed that the threo configuration is crucial for the EAAT1-4 inhibitory activities. Analogues (3b-e) of l-TFB-TBOA (3a) were shown to be potent EAAT1-4 inhibitors, with IC50 values ranging from 5 to 530 nM. Hybridization of the nonselective EAAT inhibitor l-TBOA with EAAT2-selective inhibitor WAY-213613 or EAAT3-preferring inhibitor NBI-59159 yielded compounds 8 and 9, respectively, which were nonselective EAAT inhibitors displaying considerably lower IC50 values at EAAT1-4 (11-140 nM) than those displayed by the respective parent molecules. PMID- 30011369 TI - Co-delivery of Doxorubicin and Interferon-gamma by Thermosensitive Nanoparticles for Cancer Immunochemotherapy. AB - A dual-sensitive nanoparticle delivery system was constructed by incorporating an acid sensitive hydrazone linker into thermosensitive nanoparticles (TSNs) for co encapsulating doxorubicin (DOX) and interferon gamma (IFNgamma) and to realize the co-delivery of chemotherapy and immunotherapy agents against melanoma. DOX, a chemotherapeutic drug, was conjugated to TSNs by a pH-sensitive chemical bond, and IFNgamma, a potent immune-modulator, was absorbed into TSNs through the thermosensitivity and electrostatics of nanoparticles. Consequently, the dual sensitive drug-loaded TSN delivery systems were successfully built and showed an obvious core-shell structure, good encapsulation efficiency of drugs, sustained and sensitive drug release, prolonged circulation time, as well as excellent synergistic antitumor efficiency against B16F10 tumor bearing mice. Moreover, the combinational antitumor immune responses of hydrazone bearing DOX/IFNgamma-TSN (hyd) were strengthened by activating Th1-type CD4+ T cells, cytotoxic T lymphocytes, and natural killer cells, downregulating the expression levels of immunosuppressive cytokines, such as IL10 and TGFbeta, and upregulating the secretion of IL2 and TNFalpha. Taken together, the multifunctional TSNs system provides a promising strategy for multiple drugs co-delivery with distinct properties. PMID- 30011370 TI - In Situ Observation of Atomic Redistribution in Alloying Gold-Silver Nanorods. AB - The catalytic performance and optical properties of bimetallic nanoparticles critically depend on the atomic distribution of the two metals in the nanoparticles. However, at elevated temperatures, during light-induced heating, or during catalysis, atomic redistribution can occur. Measuring such metal redistribution in situ is challenging, and a single experimental technique does not suffice. Furthermore, the availability of a well-defined nanoparticle system has been an obstacle for a systematic investigation of the key factors governing the atomic redistribution. In this study, we follow metal redistribution in precisely tunable, single-crystalline Au-core, Ag-shell nanorods in situ, both at a single particle and an ensemble-averaged level, by combining in situ transmission electron spectroscopy with in situ extended X-ray absorption fine structure validated by ex situ measurements. We show that the kinetics of atomic redistribution in Au-Ag nanoparticles depend on the metal composition and particle volume, such that a higher Ag content or a larger particle size led to significantly slower metal redistribution. We developed a simple theoretical model based on Fick's first law that can correctly predict the composition- and size-dependent alloying behavior in Au-Ag nanoparticles, as observed experimentally. PMID- 30011371 TI - Molecular Engineering toward Coexistence of Dielectric and Optical Switch Behavior in Hybrid Perovskite Phase Transition Material. AB - Organic-inorganic hybrid perovskites with considerable dielectric differences near the phase transition are potential candidates as phase transition materials (PTMs). However, compared with traditional PTMs, which require multiple switchable channels, the hybrid perovskites so far show only switching behavior in dielectric constants. We herein report a new crystal design strategy and successful synthesis of a two-dimensional perovskite (C6H5C2H4NH3)2MnCl4. In this hybrid perovskite, the manganese chloride octahedron is a crystal field sensitive luminescent molecular system. The distortion level of MnCl64- also depends on temperature during the order-disorder phase transition. Hence, such a manganese octahedron-based perovskite can exhibit switching behaviors in both dielectric and optical properties. We observe a 14% decrease in optical absorption and 1.6 times increase in dielectric constant during the phase transition at 365 K. In addition, the characteristic photoluminescence decreases by 17% in intensity. Such a molecule-based crystal design paves a new way to explore multifunctional PTMs based on organic-inorganic perovskites. PMID- 30011372 TI - Molar Activity of Ga-68 Labeled PSMA Inhibitor Conjugates Determines PET Imaging Results. AB - Radiopharmaceuticals targeting the enzyme prostate-specific membrane antigen (PSMA; synonyms: glutamate carboxypeptidase II, NAALADase; EC 3.4.17.21) have recently emerged as powerful agents for diagnosis and therapy (theranostics) of prostate carcinoma (PCa). The radiation doses for therapeutic application of such compounds are limited by substantial uptakes in kidneys and salivary glands, with excess doses reportedly leading to radiotoxicity-related adverse effects, such as kidney insufficiency or xenostomia. On the basis of the triazacyclononane triphosphinate (TRAP) chelator, monomeric to trimeric conjugates of the PSMA inhibitor motif lysine-urea-glutamic acid (KuE) were synthesized by means of Cu(I)-mediated (CuAAC) or 5-aza-dibenzocyclooctyne (DBCO)-driven, strain-promoted click chemistry (SPAAC), which were labeled with gallium-68 for application in positron emission tomography (PET), and characterized in terms of PSMA affinity (determined in cellular displacement assays against I-125-BA) and lipophilicity (expressed as log D). Using subcutaneous murine LNCaP (PSMA-positive human prostate carcinoma) xenografts, the influence of ligand multiplicity, affinity, polarity, and molar activity (i.e., mass dose) on the uptakes in tumor, kidney, salivary, and background (muscle) was analyzed by means of region-of-interest (ROI) based quantification of small-animal PET imaging data. As expected, trimerization of the KuE motif resulted in high PSMA affinities (IC50 ranging from 6.0-1.5 nM). Of all parameters, molar activity/cold mass had the most pronounced influence on PET uptakes. Because accumulation in nontumor tissues was effected to a larger extent than tumor uptakes, lower molar activities resulted in substantially better tumor-to-organ ratios. For example, for one trimer, 68Ga AhxKuE3 (IC50 = 1.5 +/- 0.3 nM, log D = -3.8 +/- 0.1), a higher overall amount of active compound (12 pmol vs 2 nmol, equivalent to molar activities of 1200 and 8 MBq/nmol) resulted in a remarkable reduction of the kidney-to-tumor ratio from 11.4 to 1.4, respectively, at 60 min p.i. Our study suggests that, for PSMA targeting radiopharmaceuticals, molar activity has a more pronounced influence on small-animal PET imaging results than structural or in vitro parameters. PMID- 30011373 TI - Ager-CreERT2: A New Genetic Tool for Studying Lung Alveolar Development, Homeostasis, and Repair. AB - The alveolar region of the lung is composed of two major epithelial cell types: cuboidal alveolar type 2 cells (AT2 cells), which produce surfactant proteins, and large, thin, alveolar type 1 cells (AT1 cells), specialized for efficient gas exchange. AT1 cells cover more than 95% of the alveolar surface and constitute a major barrier to the entry of pathogenic agents. Relatively few genetic tools are available for studying the development of AT1 cells, the function of genes expressed in them, and the effect of specifically killing them in vivo in the adult lung. One distinguishing feature of AT1 cells is the high level of expression of the gene Ager, encoding the advanced glycation endproduct-specific receptor, a member of the immunoglobulin superfamily of cell surface receptors. In this paper, we report the generation of a novel Ager-CreERT2 allele in which Cre recombinase is inserted into the first coding exon of the endogenous gene. After treatment with tamoxifen the allele enables Ager+ progenitor cells to be efficiently lineage labeled during late embryonic development and AT1 cells to be killed in the adult lung using a Rosa26-diphtheria toxin A allele. Significantly, adult mice in which approximately 50% of the AT1 cells are killed survive the loss; repair is associated with increased proliferation of SFTPC+ (surfactant protein C-positive) AT2 cells and the upregulation of Ager expression. The Ager CreERT2 allele thus expands the repertoire of genetic tools for studying AT1 turnover, physiology, and repair. PMID- 30011374 TI - Restrictive Spirometry Pattern, Cardiac Structure and Function, and Incident Heart Failure in African Americans. The Jackson Heart Study. AB - RATIONALE: Although chronic obstructive pulmonary disease has been related to heart failure, the relationship between the restrictive spirometry pattern (forced vital capacity [FVC] < 80% predicted with preserved forced expiratory volume in 1 second [FEV1]/FVC ratio) and heart failure is poorly understood. OBJECTIVES: To determine whether having a restrictive spirometry pattern is associated with incident heart failure hospitalization. METHODS: Community dwelling African Americans from the Jackson Heart Study (total n = 5,306; analyzed n = 4,210 with spirometry and heart failure outcome data) were grouped by restrictive spirometry (FEV1/FVC >= 0.70, FVC < 80%; n = 840), airflow obstruction (FEV1/FVC < 0.70; n = 341), and normal spirometry (FEV1/FVC >= 0.70, FVC >= 80%; n = 3,029) at the time of baseline examination in 2000-2004. We assessed relationships of echocardiographic parameters and biomarkers with spirometry patterns using regression models. Incident heart failure was defined as an adjudicated hospitalization for heart failure after January 1, 2005 in subjects with no self-reported heart failure history. We used multivariable adjusted Poisson regression models and Cox proportional hazards models, with death treated as a competing risk in the Cox models, to test associations between spirometry patterns and incident heart failure. We also modeled the association of FVC% predicted with heart failure hospitalization risk using a restricted cubic spline after excluding subjects with airflow obstruction. RESULTS: At the time of baseline spirometry, participants with restrictive spirometry had a median age of 57.2 years (interquartile range, 47.8-64.1); 38.1% were male. Compared with normal spirometry, restrictive spirometry was associated with a higher transmitral early (E) wave velocity to atrial (A) wave velocity ratio, higher pulmonary artery systolic pressure, and higher endothelin levels. After a median follow-up time of 8.0 years, 8.0% of subjects with restrictive spirometry (n = 67) had developed incident heart failure, compared with 3.8% of those with normal spirometry (n = 115) and 10.6% of those with airflow obstruction (n = 36). After risk adjustment, both a restrictive pattern (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.0) and airflow obstruction (HR, 1.7; 95% CI, 1.1 2.5) were associated with increased rates of incident heart failure hospitalization compared with normal spirometry. Using flexible modeling, the lowest hazards of heart failure hospitalization were observed around FVC 90-100%, with lower FVC% values associated with an increased incidence of heart failure. CONCLUSIONS: Both a restrictive pattern on spirometry and airflow obstruction identify African Americans with impaired lung health at risk for heart failure. PMID- 30011375 TI - Long-term atorvastatin treatment decreases heart maximal oxygen consumption and its vulnerability to in vitro oxidative stress in Watanabe heritable hyperlipidemic rabbit. AB - Statins are currently used in prevention of cardiovascular diseases in high-risk populations, and could be considered in primary prevention. However, few studies are available on the long-term effects of low doses of statins, especially on mitochondrial function and reactive oxygen species (ROS) metabolism at cardiac level. This study aimed to determine potential effects of a long-term atorvastatin treatment, at low-dose concentration, on the myocardium mitochondrial respiration. Thirty-four Watanabe rabbits were treated or not with atorvastatin (2.5 mg.kg-1.day-1) from the age of 3 to 12 months. Every 3 months, proton leak, basal (V0), and maximal (Vmax) mitochondrial respiration on cardiac permeabilized fibers were measured. Additionally, the vulnerability to ROS, cardiac enzymatic antioxidant defenses, and oxidative damage (lipoperoxidation) were analyzed. Proton leak increased over the duration of the experiment (up to 60% from Vmax at 12 months). Moreover, the statin treatment induced a decrease of Vmax and a decrease of ROS susceptibility of cardiac mitochondria. However, the lipoperoxidation and the antioxidant defenses were not dependent on the presence of statin treatment, or on its duration. This is the first study showing a protective effect of long-term statins treatment against the ROS susceptibility in the cardiac muscle. PMID- 30011377 TI - Erratum. PMID- 30011376 TI - Intramuscular fiber conduction velocity and muscle fascicle length in human vastus lateralis. AB - Muscle fascicle length and muscle fibre conduction velocity are thought to be important parameters for power performance. It might be expected that faster muscle fibre conduction velocities would compensate for longer fascicle lengths to increase the speed of action potential propagation along the elongated fibres. However, the relationship between muscle fascicle length and muscle fibre conduction velocity (MFCV) remains unknown. The aim of the present study was to explore the relationship between average vastus lateralis MFCV and average fascicle length. In seventeen moderately-trained healthy male physical education students (age 23.4 +/- 3.1 years, body height 178 +/- 5.5 cm, body mass 82.7 +/- 6.9 kg, BMI 24.6 +/- 1.5 kg?m-2) resting MFCV was measured with intramuscular microelectrodes while muscle architecture was evaluated with ultrasonography. Fascicle length was highly correlated with total MFCV (r: 0.923, p = 0.000), maximum MFCV (r: 0.949, p = 0.000), and MFCV of the fastest (r: 0.709, p = 0.001), but not of the slowest fibres (r: 0.131, p = 0.616). No significant correlations were also found between vastus lateralis thickness or fascicle angle with any of MFCV parameters (r: 0.145 - 0.430; R2 < 0.130; p > 0.05). These data indicate that average MFCV is associated with average fascicle length in vastus lateralis muscle in different individuals. It seems that participants with longer fascicle lengths have also higher muscle fibre conduction velocities. PMID- 30011378 TI - The gastroprotective effect of N-acetylcysteine and genistein in indomethacin induced gastric injury in rats. AB - The protective effect of N-acetylcysteine (NAC) and genistein (GEN) on an experimental model of indomethacin (IND)-induced gastric injury was investigated. A total of 50 male rats were divided into 5 groups: (1) control, (2) IND, (3) NAC pretreated, (4) GEN pretreated, and (5) NAC+GEN pretreated. Rats in groups 3-5 were orally administered NAC (500 mg/kg), GEN (10 mg/kg), or both, respectively, once daily for 7 days before the induction of gastric injury by IND (50 mg/kg). The stomach was removed for biochemical analysis and histopathological examination. Pretreatment with NAC, GEN, or both significantly improved ulcer indices and increased nitric oxide level and superoxide dismutase activity. They also significantly decreased malondialdehyde, tumour necrosis factor alpha levels, and myeloperoxidase activity, and downregulated matrix metalloproteinase 9 (MMP-9) gene expression compared to the IND group. NAC alone ameliorated IND induced apoptosis, whereas GEN only significantly increased prostaglandin E2 level. Further, coadministration of both resulted in a significantly better gastroprotective effect versus solo administration. Coadministration of NAC and GEN has an additive gastroprotective effect in IND-induced gastric injury, which may be through interaction of their potential cytoprotective, antioxidant, anti inflammatory, and antiapoptotic mechanisms together with regulation of MMP-9 expression. PMID- 30011380 TI - Comparison of Lateralizing Calcaneal Osteotomies for Varus Hindfoot Correction. AB - BACKGROUND: There is limited consensus on the optimal operative technique for correcting heel varus in patients with Charcot-Marie-Tooth (CMT) disease. This comparative study evaluated the ability of 4 lateralizing calcaneal osteotomies, with and without Dwyer wedge resection and coronal rotation of the posterior tuberosity, to correct severe heel varus. METHODS: The computed tomography (CT) scan of a teenage CMT patient with severe hindfoot varus was used to create 3 dimensional (3D)-printed models of the talus, calcaneus, and cuboid. A custom jig facilitated precise replication of the osteotomy cuts. Four different configurations were created: oblique osteotomy with lateralization, oblique osteotomy with lateralization and internal rotation of the posterior tuberosity, Dwyer wedge resection with lateralization, and Dwyer wedge resection with lateralization and internal rotation. CT scans were performed on each model before and after osteotomy. Statistical analysis was used to evaluate differences in several predefined radiographic parameters. RESULTS: The sequential transformations generated increasing lateral translation of the weight-bearing calcaneus. Dwyer wedge osteotomy significantly improved lateralization (effect = 8.0 mm), valgus hindfoot angle (effect = 6.1 degrees), and coronal calcaneal tilt (effect = -17.6 degrees) compared with the oblique osteotomy. Internal rotation of the posterior tuberosity further improved lateralization (effect = 3.3 mm), valgus hindfoot angle (effect = 2.5 degrees), and coronal calcaneal tilt (effect = -11.7 degrees). Dwyer osteotomy models had on average 5-mm shorter posterior tuberosity lengths than the oblique osteotomies. The addition of rotation did not significantly affect length. CONCLUSIONS: Significant lateralization of the posterior tuberosity was achieved in all transformations. The Dwyer wedge osteotomy improved hindfoot valgus angle, coronal calcaneal tilt, and lateralization of the weight-bearing surface compared with oblique osteotomy. Posterior tuberosity internal rotation further lateralized the plantar surface and normalized weight bearing. Lateralization, combined with Dwyer osteotomy and coronal plane internal rotation, achieved the greatest correction of varus heel. CLINICAL RELEVANCE: This study compares multiple lateralizing calcaneal osteotomies and proposes a combined technique of lateralization, Dwyer wedge resection, and coronal plane rotation to address advanced cavovarus hindfoot deformities. PMID- 30011379 TI - Comparison of extraction methods for the characterization of extracellular polymeric substances from aggregates of three biofilm-forming phototrophic microorganisms. AB - This paper aims to define a robust procedure to extract extracellular polymeric substances (EPS) from aggregates of three benthic phototrophic microorganisms: the cyanobacterium Phormidium autumnale, the diatom Nitzschia palea, and the green alga Uronema confervicolum. This study focuses on the extraction efficiency of polysaccharide and protein EPS by using two physical methods (sonication, cation exchange resin) and three chemical methods (formamide, EDTA, Tween 20) with minimum cell lysis. Cell lysis was evaluated by monitoring chlorophyll a release. The results indicated that sonication or incubation of the algae aggregates with 0.25% Tween 20 induced a high level of cell lysis. A combined extraction approach, with an initial dispersing pretreatment (Ultra-Turrax, 13 500 r.min-1, 1 min), followed by formamide addition (0.22%) and then incubation with Dowex cation exchange resin (50 g per g of dry biomass), provided the highest amount of extracted EPS (mostly proteins), with low cell lysis. Furthermore, extracted EPS were characterized by size exclusion chromatography, and the obtained fingerprints revealed similar profiles for the three benthic microorganisms with a majority of low molecular weight polymers (400 to 11 300 Da). However, additional EPS of high (>600 000 Da) and intermediate (20 000 to 80 000 Da) molecular sizes were specifically detected in the diatom extracts. PMID- 30011381 TI - Chronic Cigarette Smoke Exposure Subdues PP2A Activity by Enhancing Expression of the Oncogene CIP2A. AB - Phosphatase activity of the major serine threonine phosphatase, protein phosphatase 2A (PP2A), is blunted in the airways of individuals with chronic obstructive pulmonary disease (COPD), which results in heightened inflammation and proteolytic responses. The objective of this study was to investigate how PP2A activity is modulated in COPD airways. PP2A activity and endogenous inhibitors of PP2A were investigated in animal and cell models of COPD. In primary human bronchial epithelial (HBE) cells isolated from smokers and donors with COPD, we observed enhanced expression of cancerous inhibitor of PP2A (CIP2A), an oncoprotein encoded by the KIAA1524 gene, compared with cells from nonsmokers. CIP2A expression was induced by chronic cigarette smoke exposure in mice that coincided with a reduction in PP2A activity, airspace enlargements, and loss of lung function, as determined by PP2A phosphatase activity, mean linear intercept analysis, and forced expiratory volume in 0.05 second/forced vital capacity. Modulating CIP2A expression in HBE cells by silencing RNA or chemically with erlotinib enhanced PP2A activity, reduced extracellular-signal-regulated kinase phosphorylation, and reduced the responses of matrix metalloproteinases 1 and 9 in HBE cells isolated from subjects with COPD. Enhanced epithelial growth factor receptor responses in cells from subjects with COPD were observed to modulate CIP2A expression levels. Our study indicates that chronic cigarette smoke induction of epithelial growth factor receptor signaling and CIP2A expression can impair PP2A responses that are associated with loss of lung function and enhancement of proteolytic responses. Augmenting PP2A activity by manipulating CIP2A expression may represent a feasible therapeutic approach to counter smoke-induced lung disease. PMID- 30011382 TI - Writing for Public Health: Strategies for Teaching Writing in a School or Program of Public Health. PMID- 30011383 TI - Female rats are more susceptible to metabolic effects of dehydroepiandrosterone treatment. AB - Dehydroepiandrosterone (DHEA) is a steroid hormone that presents several effects on metabolism; however, most of the studies have been performed on male animals, while few authors have investigated possible sex differences regarding the metabolic effects of DHEA. Therefore, the aim of this study was to evaluate the effect of different doses of DHEA on metabolic parameters of male and ovariectomized female Wistar rats. Sex differences were found in the metabolism of distinct substrates and in relation to the effect of DHEA. In respect to the glucose metabolism in the liver, the conversion of glucose to CO2 and the synthesis of lipids from glucose were 53% and 33% higher, respectively, in males. Also, DHEA decreased hepatic lipogenesis only in females. Regarding the hepatic glycogen synthesis pathway, females presented 73% higher synthesis than males, and the effect of DHEA was observed only in females, where it decreased this parameter. In the adipose tissue, glucose uptake was 208% higher in females and DHEA decreased this parameter. In the muscle, glucose uptake was 168% higher in females and no DHEA effect was observed. In summary, males and females present a different metabolic profile, with females being more susceptible to the metabolic effects of DHEA. PMID- 30011384 TI - Raising the Stakes: Assessing Competency with Simulation in Pulmonary and Critical Care Medicine. PMID- 30011385 TI - Event simulation and external validation applied in published health economic models for obesity: a systematic review. AB - INTRODUCTION: This study aims to determine methodological variations in the event simulation approaches of published health economic decision models, in the field of obesity, and to investigate whether their predictiveness and validity were investigated via external event validation techniques, which investigate how well the model reproduces reality. Areas covered: A systematic review identified a total of 87 relevant papers, of which 72 that simulated obesity-associated events were included. Most frequently simulated events were coronary heart disease (~ 83%), type 2 diabetes (~ 74%), and stroke (~ 66%). Only for ten published model based health economic assessments in obesity an external event validation was performed (14%; 10 of 72), and only for one the predictiveness and validity of the event simulation was investigated in a cohort of obese subjects. Expert commentary: We identified a wide range of obesity related event simulation approaches. Published obesity models lack information on the predictive quality and validity of the applied event simulation approaches. Further work on comparing and validating these event simulation approaches is required to investigate their predictiveness and validity, which will offer guidance future modelling in the field of obesity. PMID- 30011386 TI - A pathway leading to a cation-binding pocket determines the selectivity of the NhaP2 antiporter in Vibrio cholerae. AB - The Vc-NhaP2 antiporter from Vibrio cholerae exchanges H+ for K+ or Na+ but not for the smaller Li+. The molecular basis of this unusual selectivity remains unknown. Phyre2 and Rosetta software were used to generate a structural model of the Vc-NhaP2. The obtained model suggested that a cluster of residues from different transmembrane segments (TMSs) forms a putative cation-binding pocket in the middle of the membrane: D133 and T132 from TMS V together with D162 and E157 of TMS VI. The model also suggested that L257, G258, and N259 from TMS IX together with T276, D273, Q280, and Y251 from TMS X as well as L289 and L342 from TMS XII form a transmembrane pathway for translocated ions with a built-in filter determining cation selectivity. Alanine-scanning mutagenesis of the identified residues verified the model by showing that structural modifications of the pathway resulted in altered cation selectivity and transport activity. In particular, L257A, G258A, Q280A, and Y251A variants gained Li+/H+ antiport capacity that was absent in the nonmutated antiporter. T276A, D273A, and L289A variants exclusively exchanged K+ for H+, while a L342A variant mediated Na+/H+ exchange only, thus maintaining strict alkali cation selectivity. PMID- 30011387 TI - DEEP Study: Indirect and Out-of-pocket Costs of Persistent Orofacial Pain. AB - Persistent orofacial pain (POFP) is common and caused by a group of conditions affecting the face, head, or mouth. Recent research highlighted a problematic care pathway with high costs to the health care provider, but the financial impact on patients and employers is not understood. This study aimed to describe patient (out-of-pocket) and employer (indirect) costs of POFP and to identify whether the dichotomized Graded Chronic Pain Scale (GCPS) was predictive of costs. A cohort of 198 patients was recruited from primary and secondary care settings in North East England and followed over a 24-mo period. Patients completed the GCPS and Use of Services and Productivity Questionnaire every 6 mo and a Time and Travel Questionnaire at 14 mo. Questionnaires examined the implications of health care utilization on patients' everyday lives and personal finances. Time and travel costs were calculated and applied to use-of-services data to estimate out-of-pocket costs, while the human capital method and QQ method (quantity and quality of work completed) were used to estimate absenteeism and presenteeism costs, respectively. Per person per 6-mo period (in 2017 pounds sterling), mean out-of-pocket costs were L333 (95% CI, L289 to L377), and indirect costs were L1,242 (95% CI, L1,014 to L1,470). Regression analyses indicated that over 6 mo, the GCPS was predictive of the following: out-of-pocket costs-a difference of L311 between low and high GCPS per person per 6-mo period (95% CI, L280 to L342; P < 0.01, n = 705 observations over 24 mo); indirect costs a difference of L2,312 between low and high GCPS per person per 6-mo period (95% CI, L1,886 to L2,737; P < 0.01; n = 352 observations over 24 mo). This analysis highlights "hidden" costs of POFP and supports the use of the dichotomized GCPS to identify patients at risk of higher impact and associated costs and thereby stratify care pathways and occupational health support appropriately. PMID- 30011388 TI - Adequacy of Samples Obtained by Endobronchial Ultrasound with Transbronchial Needle Aspiration for Molecular Analysis in Patients with Non-Small Cell Lung Cancer. Systematic Review and Meta-Analysis. AB - RATIONALE: Endobronchial ultrasound and transbronchial needle aspiration (EBUS TBNA) are commonly used for the diagnosis and mediastinal staging of lung cancer. Molecular markers are becoming increasingly important in patients with lung cancer to define targetable mutations suitable for personalized therapy, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), reactive oxygen species proto-oncogene (ROS1), and programmed death-ligand 1 (PD L1). OBJECTIVES: To evaluate the adequacy of EBUS-TBNA-derived tissue for molecular analysis. METHODS: We searched the MEDLINE, LILACS, www.clinicaltrials.gov , and Epistemonikos databases through January 2018. DATA EXTRACTION: Two independent reviewers performed the data search, quality assessment, and data extraction. We included both prospective and retrospective studies; risk of bias was evaluated using the ROBINS-I tool. The primary outcome was the proportion of adequate samples obtained by EBUS-TBNA for molecular analysis. Data were pooled by using a binary random effects model. Finally, evidence was rated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. RESULTS: A total of 33 studies including 2,698 participants were analyzed. In 28 studies that evaluated EBUS-TBNA for the identification of EGFR mutations, the pooled probability of obtaining a sufficient sample was 94.5% (95% confidence interval CI], 93.2-96.4%). For identification of ALK mutations, the pooled probability was 94.9% (95% CI, 89.4 98.8%). Finally, the prevalence of EGFR mutation was 15.8% (95% CI, 12.1-19.4%), and the prevalence of ALK mutation was 2.77% (95% CI, 1.0-4.8%). Data for ROS1 and PD-L1 mutations were not suitable for meta-analysis. CONCLUSIONS: EBUS-TBNA has a high yield for molecular analysis of both EGFR and ALK mutations. However, the suitability of TBNA samples for next-generation sequencing is uncertain and should be explored in further studies. Clinical trial registered with PROSPERO (CRD42017080008). PMID- 30011389 TI - Disparities in access to health care in Australia for people with mental health conditions. AB - Objective One aim of Australia's Equally Well National Consensus Statement is to improve monitoring of the physical health of people with mental health conditions, which includes measures of accessibility and people's experiences of physical health care services. The present analysis contributes to this aim by using population survey data to evaluate whether, and in what domains, Australians with a mental health condition experience barriers in accessing care when compared with Australians without a mental health condition.Methods The 2016 Commonwealth Fund International Health Policy Survey includes a sample of 5248 Australian adults. Access to care was measured using 39 survey questions from before to after reaching services. Multivariable logistic regression models were used to identify disparities in barriers to access, comparing experiences of people with and without a self-reported mental health condition, adjusting for age, sex, immigrant status, income and self-rated health.Results Australians with mental health conditions were more likely to experience barriers for 29 of 39 access measures (odds ratio (OR) >1.55; P<0.05). On average, the prevalence of barriers was 10 percentage points higher for those with a condition. When measured as ratios, the largest barriers for people with mental health conditions were for affordability. When measured as percentage point differences, the largest disparities were observed for experiences of not being treated with respect in hospital. Disparities remained after adjusting for income, rurality, education, immigrant status and self-rated health for 25 of 39 measures.Conclusion Compared with the rest of the community, Australians with mental health conditions have additional challenges negotiating the health system, and are more likely to experience barriers to access to care across a wide range of measures. Understanding the extent to which people with mental health conditions experience barriers throughout the pathway to accessing care is crucial to inform care planning and delivery for this vulnerable group. Results may inform improvements in regular performance monitoring of disparities in access for people with mental health conditions.What is known about this topic? A stated national aim of the Equally Well National Consensus Statement is to improve monitoring of the physical health and well-being of people with mental health conditions through measures of service accessibility and people's experiences of physical healthcare services.What does this paper add? This paper highlights areas in which health services are not providing equal access to overall care for people with mental health conditions. The analysis offers quantitative evidence of 'red flag areas' where people with mental health conditions are significantly more likely to experience barriers to access to care.What are the implications for practitioners? Systematic attention across the health system to making care more approachable and accessible for people with mental health conditions is needed. Practitioners may be engaged to discuss possible interventions to improve access disparities for people with mental health conditions. PMID- 30011390 TI - Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model. AB - PURPOSE: Monoclonal antibodies (mAbs) are commonly administered by subcutaneous (SC) route. However, bioavailability is often reduced after SC administration. In addition, the sequential transfer of mAbs through the SC tissue and lymphatic system is not completely understood. Therefore, major objectives of this study were a) To understand absorption of mAbs via the lymphatic system after SC administration using physiologically based pharmacokinetic (PBPK) modeling, and b) to demonstrate application of the model for prediction of SC pharmacokinetics (PK) of mAbs. METHODS: A minimal PBPK model was constructed using various physiological parameters related to the SC injection site and lymphatic system. The remainder of the body organs were represented using a 2-compartment model (central and peripheral compartments), with parameters derived from available intravenous (IV) PK data. The IV and SC clinical PK data of a total of 10 mAbs were obtained from literature. The SC PK data were used to estimate the lymphatic trunk-lymph node (LN) clearance. RESULTS: The mean estimated lymphatic trunk-LN clearance obtained from 37 SC PK profiles of mAbs was 0.00213 L/h (0.001332 to 0.002928, 95% confidence intervals). The estimated lymphatic trunk-LN clearance was greater for the mAbs with higher isoelectric point (pI). In addition, the estimated clearance increased with decrease in the bioavailability. CONCLUSION: The minimal PBPK model identified SC injection site lymph flow, afferent and efferent lymph flows, and volumes associated with the SC injection site, lymphatic capillaries and lymphatic trunk-LN as important physiological parameters governing the absorption of mAbs after SC administration. The model may be used to predict PK of mAbs using the relationship of lymphatic trunk-LN clearance and the pI. In addition, the model can be used as a bottom platform to incorporate SC and lymphatic in vitro clearance data for mAb PK prediction in the future. PMID- 30011391 TI - Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats. AB - PURPUSE: Bacterial co-infections and low grade endotoxemia are common in HIV patients. Inflammation due to endotoxin or HIV may influence the expression and activity of transporters. Kidney transporters influence renal drug clearances including many antiretroviral agents. Our objective was to study the effect of endotoxin and HIV on the renal expression of drug transporters in an HIV transgenic (HIV-Tg) rat model. These rats develop immune dysfunction and AIDS associated conditions like humans. METHODS: Endotoxin or saline was administered intraperitoneally to HIV-Tg or wild type (WT) littermates and kidneys were collected 18 hours later. Expression of transporters and cytokines were measured by qRT-PCR and Western blots. Serum cytokine levels were measured by ELISA. RESULTS: Endotoxin induced serum levels of IL-6, TNF-alpha and IFN-gamma in both HIV-Tg and WT animals. The basal mRNA expression of Oct2, Oct3, Octn1, Mate1, Urat1 and Ent1was significantly lower (33-60%) and the expression of Ent2 and Pept2 was significantly higher (33-45%) in HIV-Tg as compared to WT. While endotoxin significantly downregulated the mRNA expression of Mdra1 and Pept2 in both HIV and WT groups (69-78%), it imposed a significant reduction on the mRNA expression of Oct2, Oct3, Octn1, Mate1, Oat2, urat1, and Ent1 (54-83%) only in the WT group. Endotoxin significantly increased the mRNA expression of Pept1 (140%) in both WT and HIV groups. CONCLUSIONS: HIV and endotoxin each imposed alterations in the expression of many clinically important renal drug transporters although co-infection did not augment this effect. Viral and/or bacterial infections may impact the renal clearance of drug substrates in patients and could potentially be a source of drug-disease interactions. PMID- 30011392 TI - Assessing the Physicochemical Stability of a Compounded Neonatal Trace Element Solution. AB - PURPOSE: Alberta Health Services (AHS) recommends the adoption of a new neonatal multi-trace element formulation containing zinc sulfate, copper sulfate, selenious acid and sodium iodide to be compounded internally in appropriate AHS pharmacies. The objective of this study was to assess the physicochemical stability of this formulation under commonly used storage conditions. METHOD: Three batches of trace element solution were compounded by University of Alberta Hospital pharmacy staff using sterile compounding procedures. Appropriate amount of zinc sulfate (500 mg/mL), copper sulfate (40 mg/mL), selenious acid (4 mg/mL), sodium iodide (2 mg/mL) and sterile water for injection were mixed. Samples from each batch were divided in individual vials and syringes for each time point and kept protected from light either at room temperature (15-30 degrees C) or fridge (2-8 degrees C). Vial samples were also kept at room temperature for 12 h and then transferred to fridge. Vial samples were analyzed at time 0, 12 h, and 1, 3, 7, 9, 30, 60, 90 days for their physical appearance and pH, then centrifuged and assessed for the soluble zinc (atomic absorption), copper (atomic absorption), selenium (ICP-MS) and iodine (HPLC and ICP-MS) concentrations. Syringe samples were tested at time 0 and 12 h for element concentrations. RESULTS: Under all storage conditions, when stored in vials, samples' appearance, pH and soluble zinc, copper and selenium concentrations stayed within the USP acceptable limits up to 90 days. Iodine concentration was within the permitted limits only up to 7 days. The USP recommended HPLC method of iodine analysis seemed inadequate for this preparation and needed modifications, through frequent washing of the column with KI (2 %) solution. Samples kept in syringes at room temperature, showed lower than permitted concentration of Zn at 12h in this study. CONCLUSION: The AHS neonatal multi-trace element formulation seem to be physio-chemically stable up to 7 days in all three storage conditions when kept in vials. A decline in iodine concentration is seen after 7 days irrespective of storage conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 30011393 TI - Effect of a Low-Dose/High-Frequency Training on Real-Life Neonatal Resuscitation in a Low-Resource Setting. AB - BACKGROUND: As intrapartum-related events represent a quarter of all neonatal deaths, education on neonatal resuscitation is a critical priority. OBJECTIVE: To assess the impact of a low-dose/high-frequency neonatal resuscitation training on clinical practice of midwives in a low-resource setting. METHODS: Eight months after a modified Neonatal Resuscitation Program (NRP) course, we implemented a low-dose/high-frequency training for midwives at Beira Central Hospital, Mozambique. The training lasted 6 months and included weekly practice sessions. Fifty consecutive resuscitations after the low-dose/high-frequency training were compared with those registered before (n = 50) and after (n = 50) participation in the adapted NRP course using video recording. RESULTS: All 150 neonates received the initial steps; 103 required bag-mask ventilation and 41 required chest compressions. The scores for initial steps, bag-mask ventilation and chest compressions improved after the course (p < 0.0001, p = 0.005 and p = 0.03) and did not change after the low-dose/high-frequency training (p = 0.34, p = 0.99 and p = 0.30). The low-dose/high-frequency training decreased the total time of the procedure (p < 0.0001) and anticipated start time of airway suctioning and tactile stimulation (p = 0.003 and p < 0.0001), but had no effect on the time of initiation of bag-mask ventilation (p = 0.30). CONCLUSIONS: In a low- income setting, a low-dose/high-frequency training after participation in an adapted NRP course contributed to improving the initiation and times of some procedures. However, many aspects of neonatal resuscitation remained poor. Low-dose/high frequency training should focus on improving the prevention of thermal loss, face mask ventilation and heart rate assessment. PMID- 30011394 TI - Molecular Characterization of a New G (VP7) Genotype in Group B Porcine Rotavirus. AB - Rotaviruses (RVs), a common cause of viral gastroenteritis in humans and animals, are classified into 9 established groups/species (RVA-RVI). Although RVB has been found in several countries, genetic variation among RVB field strains remains poorly characterized. RVB strains can be classified into G genotypes based on a nucleotide (nt) homology that exceeds a cutoff value of 80% for the gene that encodes the structural protein VP7. In this study, we determined the VP7 nt and deduced amino acid sequences of one RVB strain (RB62) identified in a diarrheic fecal sample obtained from a piglet in Brazil in 2012. Comparative analysis of this strain and the strains of the other 21 previously identified VP7 ge-notypes showed that the highest nt identity (71.2%) was found with the porcine PB-70-H5 strain within the G4 genotype. However, when compared with the nonclassified Vietnamese RVB G genotype 14177_18 strain, the nt sequence identity was of 82.9%. These results led us to conclude that the Brazilian strain BR62 and the Vietnamese strain 14177_18 belong to a novel G genotype (G22). PMID- 30011395 TI - Catch-Up Growth, Rapid Weight Growth, and Continuous Growth from Birth to 6 Years of Age in Very-Preterm-Born Children. AB - BACKGROUND: Breastfeeding promotes healthy growth in very-preterm-born infants (VPI), but extra nutritional supply is needed to ensure catch-up growth and brain development. OBJECTIVES: To investigate how different types of post-discharge nutrition affect growth until 6 years of age in children born VPI. METHODS: This was a 6-year follow-up study of 281 VPI. Median gestational age (GA) was 30 + 0 weeks (range 24-32 weeks). When breastfed at discharge, they were randomized to unfortified human milk (UHM) or fortified human milk (FHM). If not breastfed at discharge, they received a preterm formula (PF). The intervention lasted until 4 months of corrected age (CA). At 6 years CA, their height and weight were measured. RESULTS: A total of 239 children participated in the follow-up. UHM feeding compared to both PF- and FHM-feeding resulted in a slower but continuous catch-up growth until 6 years of age. Participants born small-for-GA compared to appropriate-for-GA more often demonstrated continuous catch-up growth until 6 years of age (p = 0.018). Rapid weight growth (a change in z score > 1 SD during a short time period) was found to be most pronounced from 34 weeks post-menstrual age to 2 months CA, and especially among those fed PF (p = 0.002 vs. UHM, p = 0.07 vs. FHM). CONCLUSIONS: Catch-up growth occurred mainly before discharge, regardless of the feeding group. UHM-fed infants demonstrated catch-up growth that was slower, but extended until 6 years of age. Rapid weight growth was most pronounced shortly after discharge and especially if PF-fed. PMID- 30011396 TI - Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs. AB - MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8+ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8+ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8+ T cells. We specifically discuss the effect of miRNAs on key transcription factors, immune checkpoints and signal pathways, which contribute to the differentiation of effector and memory T cell subsets. Ultimately, miRNAs may be easily integrated into existing T cell receptor (TCR) and chimeric antigen receptor (CAR) platforms to promote adoptive T cell therapy with multiple advantages. Thus, combining T cell-based therapy with miRNAs could be considered a promising and robust strategy for cancer treatment. PMID- 30011397 TI - Prognostic Value of Circulating Lipoprotein in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma. AB - BACKGROUND/AIMS: Lipoproteins have been reported to be associated with prognosis in various cancers; however, the prognostic value of lipoproteins in patients with nasopharyngeal carcinoma (NPC) remains largely unknown. We aim to asses the role of circulating lipoproteins in locoregionally advanced NPC patients. METHODS: Between October 2009 and August 2012, a total of 1,081 patients with stage III-IVB NPC were included in the analysis. Circulating high-density lipoprotein (HDL) and low-density lipoprotein (LDL) are the two key lipoproteins, which were measured at baseline. Receiver operating characteristic (ROC) curve analysis was used to evaluate different cut-off points for lipoproteins. Actuarial rates were performed using Kaplan-Meier methods and the log-rank test. RESULTS: The cutoff points of HDL, LDL, and LDL/HDL ratio were 1.17 mmol/L, 3.75 mmol/L, and 2.73, respectively. At 5 years, high HDL (> 1.17 mmol/L) was significantly associated with better overall survival (OS, 86.6% vs. 78.9%; P=0.004), distant metastasis-free survival (DMFS, 86.9% vs. 80.8%; P=0.004), locoregional relapse-free survival (LRFS, 90.8% vs. 85.4%; P=0.010), and progression-free survival (PFS, 79.1% vs. 70.2%; P= 0.001) than low HDL (<=1.17 mmol/L). In contrast, high LDL (> 3.75 mmol/L) tend to be inferior OS (79.1% vs. 84.9%; P= 0.016) in compassion with low LDL (<=3.75 mmol/L). Likewise, patients with high LDL/HDL ratio (> 2.73) tend to be inferior OS (79.3% vs. 86.9%; P=0.001), DMFS (81.9% vs. 86.5%; P=0.030), and PFS (72.6% vs. 77.8%; P= 0.034) than those of low LDL/HDL ratio (<=2.73). In multivariate analysis, baseline HDL was found to be a significant prognostic factor for LRFS (HR= 0.65; 95% CI, 0.45 0.93; P= 0.019) and PFS (HR=0.75; 95% CI, 0.58-0.98; P= 0.034). CONCLUSIONS: Circulating HDL is significantly associated with treatment outcomes in patients with locoregionally advanced NPC. We suggest that HDL measurements will be of great clinical significance in the management of NPC. PMID- 30011398 TI - Elimination of ABO Blood Group Incompatible Fetal Red Blood Cells in the Maternal Circulation: Relevance to the Diagnosis of Fetal-Maternal Hemorrhage. AB - BACKGROUND: Fetal-maternal hemorrhage (FMH) occurs when fetal red blood cells (RBC) pass into the maternal circulation as a result of obstetric- or trauma related complications to pregnancy. Their detection in the maternal blood is commonly used as a diagnostic test. There is, however, a serious and general limitation to this test that is sometimes ignored. Fetal RBC carrying the father's antigens (most crucially, the ABO blood antigens) may be incompatible with the mother's plasma. They are expected to be eliminated by the maternal natural antibodies, thus, negative results may be false. OBJECTIVES: By simulating fetal-maternal ABO incompatibility, we studied the fate of fetal RBC in vitro. METHODS: Adult blood samples (n = 6) of O-blood group (type) were mixed with 1-5% cord blood or neonatal blood of A- or O-type, representing incompatible and compatible fetal RBC, respectively. The survival of fetal RBC was quantified after an overnight incubation. The supernatant was assayed for fetal hemoglobin (HbF) using the spectrophotometric alkaline-resistance benzidine assay, while the pellet was assayed for HbF/carbonic anhydrase (CA) expression in RBC by flow cytometry. The HbFhigh/CAlow phenotype characterizes fetal RBC. RESULTS: Both assays demonstrated disappearance of the fetal RBC due to lysis upon incubation in incompatible blood. CONCLUSIONS: A similar situation may also occur in vivo. Thus, under these conditions, negative results in the FMH test may be false, and lead to misdiagnosis. PMID- 30011399 TI - A Novel Hypothesis on Excessive Activation of Residual B Lymphocytes in Common Variable Immunodeficiency Concurrent with Aseptic, Erosive Polyarthritis. AB - The aim of this study was to report aseptic, erosive polyarthritis in a patient with common variable immunodeficiency (CVID), which is quite different from the vastly more common nonerosive form. Peripheral blood mononuclear cells of the patient were isolated. Flow cytometry was used to analyze the proportion and function of lymphocytes. A Parker-Pearson needle biopsy was performed on the right knee. Four of her unaffected family members were enrolled as controls. A 21 year-old woman was admitted for recurrent polyarthritis of 3-year duration. The right knee, hip, wrist, proximal interphalangeal joints, and left elbow were involved, with progressive joint destruction. She was diagnosed as having CVID based on her recurrent infections, poor response to vaccines, and marked hypogammaglobulinemia. No bacterium or mycobacterium was detected in synovium or synovial fluid. The synovium was infiltrated by lymphocytes rather than neutrophils. Polyarthritis did not resolve by adequate intravenous immunoglobulin substitution and empirical antibiotic treatment, but resolved gradually after treatment with methylprednisolone and tacrolimus, supporting the diagnosis of aseptic polyarthritis. Further analyses showed that although only 0.5% of residual B lymphocytes were existent in peripheral blood of the patient, expressions of activation marker CD69 and production of IL-1beta, IL-6, and TNF alpha were high. Marked infiltration with CD19+B lymphocytes (as well as CD4+ or CD8+ T lymphocytes) was detected in the synovium. The proportion of IL21+CD4+Th cells from peripheral blood of the patient was high. CD4+ Th cells from the patient secreted nearly 3 times more IL-21 than the same cell type analyzed from unaffected family members, perhaps due to excessive compensation to assist the function of residual B lymphocytes. A novel hypothesis in CVID concurrent with aseptic, erosive polyarthritis is that excessive activation of residual B lymphocytes infiltrate into the synovium of the involved joints and lead to polyarthritis and joint destruction. PMID- 30011403 TI - Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review. AB - ATP1A3 mutations have now been recognized in infants, children, and adults presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and most recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand. In this case study, we report on early life epilepsy with episodic apnea potentially secondary to ATP1A3 mutation in a Tunisian child. PMID- 30011404 TI - First-trimester Combined Screening Test for Aneuploidies in Brazilian Unselected Pregnancies: Diagnostic Performance of Fetal Medicine Foundation Algorithm. AB - OBJECTIVE: The main objective of this study was to examine the diagnostic performance of the first-trimester combined test for aneuploidies in unselected pregnancies from Rio de Janeiro and compare it with the examples available in the literature. METHODS: We investigated 3,639 patients submitted to aneuploidy screening from February 2009 to September 2015. The examination is composed of the Fetal Medicine Foundation risk evaluation based on nuchal translucency evaluation, mother's age, presence of risk factors, presence of the nasal bone and Doppler of the ductus venous in addition to biochemical analysis of pregnancy associated plasma protein A (PAPP-A) and beta-human chorionic gonadotropin (beta hCG) markers. The cut-off point for high risk for aneuploidies was defined as greater than 1:100, with intermediate risk defined between 1:100 and 1:1,000, and low risk defined as less than 1:1,000. The variable aneuploidy was considered as a result not only of trisomy of chromosome 21 but also trisomy of chromosomes 13 and 18. RESULTS: Excluding the losses, the results of 2,748 patients were analyzed. The first-trimester combined test achieved 71.4% sensitivity with a 7.4% false-positive (FP) rate, specificity of 92.6%, positive predictive value (PPV) of 6.91% and negative predictive value (NPV) of 99.76%, when the cut-off point considered was greater than 1:1,000. Through a receiving operating characteristics (ROC) curve, the cut-off point that maximized the sensitivity and specificity for the diagnosis of aneuploidies was defined as 1:1,860. When we adjusted the false-positive (FP) rate to 5%, the detection rate for this analysis is 72.7%, with a cut-off point of 1:610. CONCLUSION: The combined test of aneuploidy screening showed a detection rate inferior to those described in the literature for a higher FP rate. PMID- 30011405 TI - Metabolic Alterations in Patients with Pheochromocytoma. AB - Metabolic alterations in patients with hormonally active pheochromocytoma/paraganglioma (PPGL) have been described early on in the literature. The initial findings were related to disturbed glucose homeostasis and lipolysis activation, as well as elevated metabolic rates in affected patients. Similarly, from early autopsy reports, the presence of brown adipose tissue had been noted in PPGL patients. In more recent years, changes in body weight, fat mass and distribution have been analyzed in more detail in addition to activity of brown adipose tissue based on functional imaging techniques. Over the last decades, several larger case series and cohort studies have contributed towards the elucidation of possible mechanism contributing to these clinical observations. Herein, we summarize the clinical and experimental data regarding metabolic alterations and related clinical manifestations in PPGL patients. PMID- 30011406 TI - Stacey L. Clardy, MD, PhD. PMID- 30011407 TI - Autoimmune Neurology. PMID- 30011408 TI - Antibodies in Autoimmune Human Neurological Disease: Pathogenesis and Immunopathology. AB - Immune-mediated processes represent a rapidly expanding categorical etiology for neurological disease manifestations spanning all subspecialties of neurology. Neural autoantibodies can be grossly divided into two main groups based on localization of the antigen: intracellular and cell membrane/synaptic antibodies. Antibodies reactive with neuronal membrane antigens have been identified in serum and cerebrospinal fluid of patients developing neurological disease either independent of or associated with cancer comorbidity, whereas antibodies directed against intracellular targets have a much higher rate of associated malignancy. Antibodies to neuronal membrane proteins such as the N-methyl-D-aspartate (NMDA) receptor are considered directly pathogenic based on disease models. Similar evidence exists for far fewer autoantibodies directed against intracellular targets. Attempts to produce an antibody-mediated animal model of human paraneoplastic disease have been unsuccessful to date. In this article, we review antineural antibodies and their clinical associations, briefly discuss recently characterized entities, and present proposed mechanisms of antibody pathogenicity. PMID- 30011409 TI - Autoimmune and Paraneoplastic Myelopathies. AB - Prompt recognition of an inflammatory myelopathy is critical, as a specific diagnosis and management plan allows for optimal patient outcomes. Many treatment options are now available for autoimmune and paraneoplastic myelopathies, but specific management strategies and expected prognosis vary widely depending on the underlying etiology. An understanding of the relevant clinical details, imaging findings, and other diagnostic information that can help achieve a specific myelopathy diagnosis and treatment plan is essential for all neurologists, given the variety of contexts in which myelopathies are encountered. We provide an outline of the diagnostic evaluation and treatment of various inflammatory myelopathies seen in autoimmune and paraneoplastic diseases, including multiple sclerosis, aquaporin-4 immunoglobulin G (IgG) seropositive neuromyelitis optica spectrum disorder, sarcoidosis, myelin oligodendrocyte glycoprotein IgG associated disease, and other rare inflammatory myelopathies; we also highlight common mimickers of inflammatory myelopathies. PMID- 30011410 TI - Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management. AB - Autoimmune epilepsy is increasingly recognized as a distinct clinical entity, driven in large part by the recent discovery of neural autoantibodies in patients with isolated or predominant epilepsy presentations. Detection of neural autoantibodies in high-risk epilepsy patients supports an immune-mediated cause of seizures and, if applicable, directs the search for an underlying cancer when the paraneoplastic association of the associated antibody is compelling. Early diagnosis of autoimmune epilepsy is crucial, as prompt initiation of immunosuppressive treatment increases the likelihood of achieving either seizure freedom or a substantial reduction in seizure frequency. A practical clinical approach that incorporates risk scores to guide patient selection on the basis of clinical features, neural autoantibodies, and a treatment trial of immunotherapy is suggested. Elucidating an immunological basis of epilepsy provides neurologists with wider treatment options (incorporating immune-suppressive treatment), in addition to standard antiepileptic drugs, which often improves patient outcomes. PMID- 30011411 TI - Autoimmune Dementia. AB - Dementia refers to an acquired syndrome of intraindividual cognitive decline that ultimately interferes with an individual's ability to manage their usual duties at work or home. As experience with the diagnosis and management of patients with autoimmune and paraneoplastic encephalitis (AE) has expanded, it has become increasingly apparent that dementia may arise as a subacute or chronic complication of immune-mediated injury to the central nervous system. Progressive memory and thinking problems may represent the first (or only) sign of an underlying autoimmune or paraneoplastic disease. Accordingly, there is a need to routinely consider the diagnosis of AE in patients with dementia, and to evaluate patients recovering from AE for clinically meaningful cognitive impairment. We review and summarize the available evidence concerning the diagnosis and care of AE patients with associated cognitive impairment, herein referred to as autoimmune dementia (AiD). Relevant information is used to propose a novel diagnostic framework that may be applied to improve recognition, and facilitate the expedited evaluation and treatment of patients with AiD. PMID- 30011412 TI - Autoimmune Movement Disorders. AB - Autoimmune movement disorders are rare but potentially treatable entities. They can present with an excess or paucity of movement and may have other associated neurological symptoms. These disorders were originally recognized by their classic clinical presentations and the cancers associated with them. Recent emphasis has been targeted on associated, and sometimes causative, antibodies. Although some disorders have stereotypical presentations, the spectrum of abnormalities reported in association with antibodies is widening. Determining whether antibodies are incidental or pathogenic and, hence, foregoing or commencing immunotherapy treatment can be challenging for practicing neurologists. Physicians often have to make the decision to empirically treat patients while awaiting test results. Due to the lack of randomized controlled trials, the ideal immunotherapy treatments and regimens are unknown. Patients with intracellularly targeted antibodies tend to fare less well, while those with extracellularly targeted antibody disorders often respond to treatments reducing antibody production. This review aims to summarize reported adult-onset autoimmune movement disorders to date, and to provide a template for the workup and treatment of suspected disorders. Rarer antibodies that are not yet fully characterized, or reported in a few cases only, will not be covered in detail as these are not likely to be readily commercially available. Childhood disorders will be only be mentioned briefly in the discussion, as there is a separate article in this issue on autoimmune neurologic diseases in children. PMID- 30011413 TI - An Overview of Autoimmune and Paraneoplastic Encephalitides. AB - The understanding of the manifestations, mechanisms, and management of autoimmune encephalitis has expanded dramatically in recent decades. Immune-mediated encephalitides are comparable in incidence and prevalence to infectious etiologies, and are associated with significant morbidity, especially when there is a delay in recognition and treatment. As such, clinicians from many specialties must develop a functional understanding of these disorders. Herein we provide an overview of the autoimmune and paraneoplastic encephalitides, including those associated with either intracellular or cell surface/synaptic neuronal autoantibodies. After briefly reviewing the current understanding of the pathobiology of autoimmune encephalitis, we combine a neuroanatomical approach with specific antibody syndromes to provide the reader with a clinically relevant review of these disorders. The clinical manifestations, diagnosis, and management of autoimmune encephalitis are reviewed, with an emphasis on clinical relevance. We also introduce updates in the field, including autoimmune encephalitis associated with novel cancer immunotherapies, infectious triggers of autoimmune encephalitis, and autoimmune encephalitis with demyelinating overlap syndromes. PMID- 30011414 TI - Pathogenic Mechanisms and Clinical Correlations in Autoimmune Myasthenic Syndromes. AB - Autoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein-protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes. PMID- 30011415 TI - Autoimmune Neurologic Diseases in Children. AB - Autoimmune diseases of the nervous system in children are composed of a heterogeneous group of rare disorders that can affect the central or peripheral nervous system at any level. Presentations may occur in children of any age and are typically acute or subacute in onset. Consideration of an autoimmune process as the etiology of neurologic diseases in children is important, as it may lead to early initiation of immunotherapy and an improvement in long-term neurologic outcomes. The developing nervous and immune systems in children create unique challenges in diagnosis and treatment of these rare diseases. In this review, autoimmune diseases affecting the brain, spinal cord, nerve roots, peripheral nerves, neuromuscular junction, and muscle in children are described. PMID- 30011416 TI - Imaging in Autoimmune Neurology. AB - Autoimmune disorders are becoming increasingly recognized within the broader field of neurology. The discovery of multiple, novel, neutrally targeted autoantibodies over the past decade and their translation into commercially available testing, in particular, has aided in the more rapid diagnosis of these disorders. When considering imaging in autoimmune neurologic disorders, it is important, when possible, to visualize the autoimmune process itself, as well as to make sure that the patient does not have an associated malignancy driving the overall process. Positron emission tomographic scans can aid in the detection of small tumors with limited spread, as well as in the visualization of autoimmune processes affecting the brain and/or spinal cord. In autoimmune disorders of the central nervous system, imaging abnormalities can appear within the limbic system, extralimbic areas, and spinal cord. Such imaging abnormalities can serve as objective markers to follow over time to assess patients' responses to treatment. It is important to recognize that overlapping syndromes (for instance, both demyelinating and autoimmune or both infectious and autoimmune) exist and that inflammatory disorders can leave behind sequelae that can be recognized on subsequent imaging. Work is currently underway to develop more specific imaging techniques for autoimmune neurologic disorders. PMID- 30011417 TI - Infection, Immunodeficiency, and Inflammatory Diseases in Autoimmune Neurology. AB - When patients present with neurological syndromes, such as encephalopathy/encephalitis, meningitis, and/or myelopathy/myelitis, the differential diagnosis is often broad, including infectious, inflammatory, autoimmune, vascular, and neoplastic etiologies. Just with inflammatory and autoimmune etiologies alone, there are numerous causative diseases. A comprehensive history and physical examination investigating for extraneurologic manifestations of immune-mediated disease is often necessary. Moreover, evaluating for an underlying infection and/or immunodeficiency becomes a critical aspect to the workup. This article will focus on the association of viral infections and dysregulation of the immune system as triggers of autoimmunity, in addition to various systemic inflammatory diseases that can cause neurological disease either with or without an established rheumatological disorder. PMID- 30011418 TI - Diagnostic and Therapeutic Approach to Autoimmune Neurologic Disorders. AB - The field of autoimmune neurology is evolving rapidly. The discovery of autoantibodies that target neural antigens has expanded swiftly in the last decade. Recognition of the clinical syndromes associated with autoimmune neurologic disorders, and our understanding of the pathophysiology, has progressed significantly. Radiographic, electrophysiological, and laboratory testing (particularly neural autoantibody testing) are fundamental in the diagnosis of autoimmune neurological disorders and in the exclusion of mimics. Furthermore, investigations may serve as a baseline from which objective assessment of improvement or detection of relapse can be made. These disorders can be associated with underlying neoplasms, and screening for malignancy is an essential component of the investigations. Early diagnosis and prompt initiation of immunotherapy can improve neurologic function. The use of immunotherapy, however, can be associated with diverse side effects, and careful monitoring is crucial to prevent complications. Herein the authors address the diagnostic and treatment approach of autoimmune neurologic disorders, with particular focus on antibody-mediated neurologic autoimmunity. PMID- 30011419 TI - Change of Ascending Reticular Activating System Following Shunt Operation for Hydrocephalus in a Subarachnoid Hemorrhage Patient. AB - OBJECTIVE: To demonstrate the change of the ascending reticular activating system (ARAS) concurrent with the recovery of impaired consciousness following a shunt operation in a stroke patient. METHODS: A 65-year-old female patient underwent coiling of a ruptured right posterior communicating artery and, subsequently, underwent right external ventricular drain (EVD) placement, left EVD placement, and lumbar drain placement for management of intraventricular hemorrhage. After 6 months from onset, she began rehabilitation, and brain magnetic resonance imaging showed dilatation of the ventricular system. The patient exhibited impaired alertness, with a Glasgow Coma Scale (GCS) score of 7. At ~ 20 days after starting rehabilitation, the patient underwent a ventriculoperitoneal shunt operation for hydrocephalus. At 10 days postsurgery, her GCS improved to 15. RESULTS: Regarding the change of neural connectivity of the thalamic intralaminar nuclei, compared with preoperative diffusion tensor tractography (DTT), postoperative DTT showed that neural connectivity to the prefrontal cortex was increased in both hemispheres. In terms of configuration of DTT, the lower portion of the ARAS between the reticular formation and the intralaminar thalamic nuclei did not show a significant change. CONCLUSIONS: A patient with subarachnoid and intraventricular hemorrhage showed recovery of an injured ARAS and consciousness after a shunt operation for hydrocephalus. PMID- 30011420 TI - Transfacet Screw Fixation for the Treatment of Lumbar Spinal Stenosis with Mild Instability: A Preliminary Study. AB - BACKGROUND: Lumbar spinal stenosis (LSS) and low-grade degenerative spondylolisthesis are frequently associated with facet joint degeneration, considered the main cause of low back pain. Surgery is the treatment of choice in patients affected by LSS unresponsive to conservative treatment. The aim of this study was to evaluate the clinical and radiologic outcome of patients treated with posterior decompression and transfacet fixation for single-level LSS and facet joint degeneration. METHODS: A total of 25 patients between May 2015 and June 2016 affected by radiologically demonstrated one-level LSS with facet joint degeneration and grade I spondylolisthesis were included in this prospective study. All the patients underwent laminectomy, foraminotomy, and one-level facet fixation (Facet-Link, Inc., Rockaway, New Jersey, United States). Pre- and postoperative clinical (Oswestry Disability Index [ODI], Short Form-36 [SF-36]) and radiologic (radiographs, magnetic resonance imaging, computed tomography) data were collected and analyzed. RESULTS: Mean follow-up was 12 months. The L4 L5 level was involved in 18 patients (72%) and L5-S1 in 7 patients (28%); the average operative time was 80 minutes (range: 65-148 minutes), and the mean blood loss was 160 mL (range: 90-200 mL). ODI and SF-36 showed a statistically significant (p < 0.05) improvement at last follow-up. CONCLUSIONS: Transfacet fixation is a safe and effective treatment option in patients with single-level LSS, facet joint degeneration, and mild instability. PMID- 30011421 TI - Multidimensional improvement in connective tissue disease-associated interstitial lung disease: Two courses of pulse dose methylprednisolone followed by low-dose prednisone and tacrolimus. AB - BACKGROUND AND OBJECTIVE: Corticosteroids and immunosuppressive agents are considered mainstays of therapy for connective tissue disease-related interstitial lung disease (CTD-ILD); however, tacrolimus with corticosteroid therapy has not been fully investigated. Our objectives were to examine the multidimensional therapeutic benefit and tolerability of the combined therapy for the initial treatment of patients with CTD-ILD. METHODS: In this retrospective case series, we identified consecutive CTD-ILD patients treated with tacrolimus plus intravenous (i.v.) methylprednisolone (1000 mg i.v. 3 days a week for 2 weeks) followed by low-dose prednisolone (10 mg/day). We assessed the multidimensional therapeutic benefit and tolerability including lung physiology, exercise capacity, exercise oxygen desaturation, modified Medical Research Council (MMRC) and St George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 26 ILD patients with the underlying CTD diagnoses included 11 with rheumatoid arthritis, 9 with dermatomyositis, 4 with Sjogren's syndrome and 2 others. From baseline to 12 months, the combined therapy significantly improved forced vital capacity (FVC; 77.8% to 94.6%, P < 0.001), diffusing capacity of the lung for carbon monoxide (DLCO ; 66.1% to 75.1%, P < 0.001), 6-min walk distance (6MWD; 530 to 568 m, P = 0.02), lowest oxygen saturation on pulse oximetry (SpO2 ; 85% to 89%, P = 0.01), MMRC (1.3 to 0.8, P = 0.01) and SGRQ (38 to 21, P < 0.001). During the study period, only one patient's therapy was discontinued due to an adverse event and none had a life-threatening adverse event attributed to the combined therapy. CONCLUSION: In our cohort of CTD-ILD, two courses of pulse dose methylprednisolone therapy followed by prednisone and oral tacrolimus appeared to be well tolerated, and to have multidimensional efficacy. PMID- 30011422 TI - Modelling Alzheimer's disease: Insights from in vivo to in vitro three dimensional culture platforms. AB - Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss, impairment of other cognitive functions, and inability to perform activities of daily life. The key to understanding AD aetiology lies in the development of effective disease models, which should ideally recapitulate all aspects pertaining to the disease. A plethora of techniques including in vivo, in vitro, and in silico platforms have been utilized in developing disease models of AD over the years. Each of these approaches has revealed certain essential characteristics of AD; however, none have managed to fully mimic the pathological hallmarks observed in the AD human brain. In this review, we will provide details into the genesis, evolution, and significance of the principal methods currently employed in modelling AD, the advantages and limitations faced in their application, including the headways made by each approach. This review will focus primarily on two-dimensional and three-dimensional in vitro modelling of AD, which during the last few years has made significant breakthroughs in the areas of AD pathology and therapeutic screening. In addition, a glimpse into state-of-the-art neural tissue engineering techniques incorporating biomaterials and microfluidics technologies is provided, which could pave the way for the development of more accurate and comprehensive AD models in the future. PMID- 30011423 TI - Pulmonary infarction: A disease of the (mostly) young. PMID- 30011424 TI - New insight into functional limb regeneration: A to Z approaches. AB - Limb/digit amputation is a common event in humans caused by trauma, medical illness, or surgery. Although the loss of a digit is not lethal, it affects quality of life and imposes high costs on amputees. In recent years, the increasing interest in limb regeneration has led to enhanced scientific knowledge. However, the limited ability to develop functional limb regeneration in the clinical setting suggests that a challenging issue remains in limb regeneration. Recently, the emergence of regenerative engineering is a promising field to address this challenge and close the gap between science and clinical applications. Cell signalling and molecular mechanisms involved in the limb regeneration process have been extensively studied; however, there is still insufficient data on cell therapy and tissue engineering for limb regeneration. In this review, we intend to focus on therapeutic approaches for limb regeneration that are closely related to gene, immune, and stem cell therapies, as well as tissue engineering approaches that take into consideration the peculiar developmental properties of the limbs. In addition, we attempt to identify the challenges of these strategies for limb regeneration studies in terms of clinical settings and as a road map to accomplish the goal of functional human limb regeneration. PMID- 30011425 TI - Influence of Preparation and Exposure Periods of Eluates from Ocular Prosthesis Acrylic Resin in Human Conjunctival Cell Line AB - Background: This study was undertaken to analyze if different preparation and exposure periods of eluates from ocular prosthesis acrylic resin influence the cytotoxicity for conjunctival cells. Methods: Twenty-four acrylic resin specimens were divided, according to the period of eluate exposure to Chang conjunctival cells (24 and 72 hours). Eluates were prepared in four different ways: 24, 48, and 72 hours of resin specimen immersion in medium and 24 hours of immersion in water, followed by 24 hours of immersion in medium. MTT assay was used to evaluate the cytotoxic effect. The production of IL-1beta, IL-6, TNF-alpha, and chemokine macrophage inflammatory protein 1alpha was evaluated by ELISA, while the mRNA expression of type IV collagen (COL IV), transforming growth factor beta (TGF-beta), and matrix metalloproteinase 9 (MMP9) were evaluated by real-time RT PCR technique. The statistical analysis was carried out using ANOVA with Bonferroni post-hoc test and the student's t-test (p < 0.05). Results: Significant quantities of IL-6 (4.594 pg/mL) and mRNA expression of COL IV (1.58) were verified at 72 hours of eluate exposure to cells, as compared to 24 hours. After the 72-hour exposure of eluates to cells, lower cell proliferation (88.4%) and higher IL-6 quantities (12.374 pg/mL), as well as mRNA expression of COL IV (2.21), TGF-beta (2.02), and MMP9 (5.75) were observed, which corresponded to 72 hours of a specimen immersed in medium. Conclusion: Longer periods of eluate preparation and exposure from the acrylic resin to cells are related to higher production of proinflammatory cytokines and extracellular matrix proteins. PMID- 30011426 TI - Direct S-matrix calculation for diffractive structures and metasurfaces. AB - The paper presents a derivation of analytical components of S matrices for arbitrary planar diffractive structures and metasurfaces in the Fourier domain. The attained general formulas for S-matrix components can be applied within both formulations in the Cartesian and curvilinear metric. A numerical method based on these results can benefit from all previous improvements of the Fourier domain methods. In addition, we provide expressions for S-matrix calculation in the case of periodically corrugated layers of two-dimensional materials, which are valid for arbitrary corrugation depth-to-period ratios. As an example, the derived equations are used to simulate resonant grating excitation of graphene plasmons and the impact of a silica interlayer on corresponding reflection curves. PMID- 30011427 TI - Flexoelectro-optic effect and two-beam energy exchange in a hybrid photorefractive cholesteric cell with a short-pitch horizontal helix. AB - We develop a theoretical model to describe two-beam energy exchange in a hybrid photorefractive cholesteric cell with a short-pitch helix oriented parallel to the cell substrates (so-called uniformly lying helix configuration). Weak and strong light beams incident on the hybrid cell interfere and induce a periodic space-charge field in the photorefractive substrate of the cell, which penetrates into the cholesteric liquid crystal (LC). Due to the flexoelectro-optic effect an interaction of the photorefractive field with the LC flexopolarization causes the spatially periodic modulation of the helix axis in the plane parallel to the cell substrates. Coupling of a weak signal beam with a strong pump beam at the LC permittivity grating, induced by the periodically tilted helix axis, leads to the energy gain of the weak signal beam. Dependence of the signal beam gain coefficient on the parameters of the short-pitch cholesteric LC is studied. PMID- 30011428 TI - Comment on "Route from discreteness to the continuum for the Tsallis q-entropy". AB - Several years ago, it had been discussed that nonlogarithmic entropies, such as the Tsallis q-entropy cannot be applied to systems with continuous variables. Now, in their recent paper [Phys. Rev. E 97, 012104 (2018)10.1103/PhysRevE.97.012104], Oikonomou and Bagci have modified the form of the q-entropy for discrete variables in such a way that its continuum limit exists. Here, it is shown that this modification violates the expandability property of entropy, and their work is actually supporting evidence for the absence of the q-entropy for systems with continuous variables. PMID- 30011429 TI - Topology-dependent density optima for efficient simultaneous network exploration. AB - A random search process in a networked environment is governed by the time it takes to visit every node, termed the cover time. Often, a networked process does not proceed in isolation but competes with many instances of itself within the same environment. A key unanswered question is how to optimize this process: How many concurrent searchers can a topology support before the benefits of parallelism are outweighed by competition for space? Here, we introduce the searcher-averaged parallel cover time (APCT) to quantify these economies of scale. We show that the APCT of the networked symmetric exclusion process is optimized at a searcher density that is well predicted by the spectral gap. Furthermore, we find that nonequilibrium processes, realized through the addition of bias, can support significantly increased density optima. Our results suggest alternative hybrid strategies of serial and parallel search for efficient information gathering in social interaction and biological transport networks. PMID- 30011430 TI - Three-stage stochastic pump: Another type of Onsager-Casimir symmetry and results far from equilibrium. AB - The stochastic thermodynamic analysis of a time-periodic single particle pump sequentially exposed to three thermochemical reservoirs is presented. The analysis provides explicit results for flux, thermodynamic force, entropy production, work, and heat. These results apply near equilibrium as well as far from equilibrium. In the linear response regime, a different type of Onsager Casimir symmetry is uncovered. The Onsager matrix becomes symmetric in the limit of zero dissipation. PMID- 30011431 TI - Linking microscopic and macroscopic response in disordered solids. AB - The modulus of a rigid network of harmonic springs depends on the sum of the energies in each of the bonds due to an applied distortion such as compression in the case of the bulk modulus or shear in the case of the shear modulus. However, the distortion need not be global. Here we introduce a local modulus, L_{i}, associated with changing the equilibrium length of a single bond, i, in the network. We show that L_{i} is useful for understanding many aspects of the mechanical response of the entire system. It allows an efficient computation of how the removal of any bond changes the global properties such as the bulk and shear moduli. Furthermore, it allows a prediction of the distribution of these changes and clarifies why the changes of these two moduli due to removal of a bond are uncorrelated; these are the essential ingredients necessary for the efficient manipulation of network properties by bond removal. PMID- 30011432 TI - Explosive death of conjugate coupled Van der Pol oscillators on networks. AB - Explosive death phenomenon has been gradually gaining attention of researchers due to the research boom of explosive synchronization, and it has been observed recently for the identical or nonidentical coupled systems in all-to-all network. In this work, we investigate the emergence of explosive death in networked Van der Pol (VdP) oscillators with conjugate variables coupling. It is demonstrated that the network structures play a crucial role in identifying the types of explosive death behaviors. We also observe that the damping coefficient of the VdP system not only can determine whether the explosive death state is generated but also can adjust the forward transition point. We further show that the backward transition point is independent of the network topologies and the damping coefficient, which is well confirmed by theoretical analysis. Our results reveal the generality of explosive death phenomenon in different network topologies and are propitious to promote a better comprehension for the oscillation quenching behaviors. PMID- 30011433 TI - Approximation to a Fokker-Planck equation for the Brownian motor. AB - An approximate method is proposed and numerically confirmed for a time-dependent Fokker-Planck equation (FPE) modeling the Brownian motor. The situation addressed in this paper is that the potential is spatially asymmetric and multiplicatively modulated. The approximate solution is composed of Sturm-Liouville eigenfunctions. While some time-independent partial differential equations and those perturbed around them have been known to be reduced to ordinary differential equations with a few degrees of freedom, the time-dependent FPE dealt with in this paper is also found to be reduced to an ordinary differential equation. PMID- 30011434 TI - Entropy analysis of frequency and shape change in horseshoe bat biosonar. AB - Echolocating bats use ultrasonic pulses to collect information about their environments. Some of this information is encoded at the baffle structures noseleaves (emission) and pinnae (reception)-that act as interfaces between the bats' biosonar systems and the external world. The baffle beam patterns encode the direction-dependent sensory information as a function of frequency and hence represent a view of the environment. To generate diverse views of the environment, the bats can vary beam patterns by changes to (1) the wavelengths of the pulses or (2) the baffle geometries. Here we compare the variability in sensory information encoded by just the use of frequency or baffle shape dynamics in horseshoe bats. For this, we use digital and physical prototypes of both noseleaf and pinnae. The beam patterns for all prototypes were either measured or numerically predicted. Entropy was used as a measure to compare variability as a measure of sensory information encoding capacity. It was found that new information was acquired as a result of shape dynamics. Furthermore, the overall variability available for information encoding was similar in the case of frequency or shape dynamics. Thus, shape dynamics allows the horseshoe bats to generate diverse views of the environment in the absence of broadband biosonar signals. PMID- 30011436 TI - Hysteresis, neural avalanches, and critical behavior near a first-order transition of a spiking neural network. AB - Many experimental results, both in vivo and in vitro, support the idea that the brain cortex operates near a critical point and at the same time works as a reservoir of precise spatiotemporal patterns. However, the mechanism at the basis of these observations is still not clear. In this paper we introduce a model which combines both these features, showing that scale-free avalanches are the signature of a system posed near the spinodal line of a first-order transition, with many spatiotemporal patterns stored as dynamical metastable attractors. Specifically, we studied a network of leaky integrate-and-fire neurons whose connections are the result of the learning of multiple spatiotemporal dynamical patterns, each with a randomly chosen ordering of the neurons. We found that the network shows a first-order transition between a low-spiking-rate disordered state (down), and a high-rate state characterized by the emergence of collective activity and the replay of one of the stored patterns (up). The transition is characterized by hysteresis, or alternation of up and down states, depending on the lifetime of the metastable states. In both cases, critical features and neural avalanches are observed. Notably, critical phenomena occur at the edge of a discontinuous phase transition, as recently observed in a network of glow lamps. PMID- 30011435 TI - Factors influencing message dissemination through social media. AB - Online social networks strongly impact our daily lives. An internet user (a "Netizen") wants messages to be efficiently disseminated. The susceptible infected-recovered (SIR) dissemination model is the traditional tool for exploring the spreading mechanism of information diffusion. We here test our SIR based dissemination model on open and real-world data collected from Twitter. We locate and identify phase transitions in the message dissemination process. We find that message content is a stronger factor than the popularity of the sender. We also find that the probability that a message will be forwarded has a threshold that affects its ability to spread, and when the probability is above the threshold the message quickly achieves mass dissemination. PMID- 30011437 TI - Multiscale solutions of radiative heat transfer by the discrete unified gas kinetic scheme. AB - The radiative transfer equation (RTE) has two asymptotic regimes characterized by the optical thickness, namely, optically thin and optically thick regimes. In the optically thin regime, a ballistic or kinetic transport is dominant. In the optically thick regime, energy transport is totally dominated by multiple collisions between photons; that is, the photons propagate by means of diffusion. To obtain convergent solutions to the RTE, conventional numerical schemes have a strong dependence on the number of spatial grids, which leads to a serious computational inefficiency in the regime where the diffusion is predominant. In this work, a discrete unified gas kinetic scheme (DUGKS) is developed to predict radiative heat transfer in participating media. Numerical performances of the DUGKS are compared in detail with conventional methods through three cases including one-dimensional transient radiative heat transfer, two-dimensional steady radiative heat transfer, and three-dimensional multiscale radiative heat transfer. Due to the asymptotic preserving property, the present method with relatively coarse grids gives accurate and reliable numerical solutions for large, small, and in-between values of optical thickness, and, especially in the optically thick regime, the DUGKS demonstrates a pronounced computational efficiency advantage over the conventional numerical models. In addition, the DUGKS has a promising potential in the study of multiscale radiative heat transfer inside the participating medium with a transition from optically thin to optically thick regimes. PMID- 30011438 TI - Rheological transition in simple shear of moderately dense assemblies of dry cohesive granules. AB - The rheology of homogeneous cohesive granular assemblies under shear at moderate volume fractions is investigated using the discrete element method for both frictionless and frictional granules. A transition in rheology from inertial to quasistatic scaling is observed at volume fractions below the jamming point of noncohesive systems, which is a function of the granular temperature, energy dissipation, and cohesive potential. The transition is found to be the result of growing clusters, which eventually percolate the domain, and change the mode of momentum transport in the system. Differences in the behavior of the shear stress normalized by the pressure are observed when frictionless and frictional cases are compared. These differences are explained through contact anisotropy after percolation occurs. Both frictionless and frictional systems are found to be vulnerable to instabilities after full system percolation has occurred, where the former becomes thermodynamically unstable and the latter may form shear bands. Finally, implications for constitutive modeling are discussed. PMID- 30011439 TI - N-tag probability law of the symmetric exclusion process. AB - The symmetric exclusion process (SEP), in which particles hop symmetrically on a discrete line with hard-core constraints, is a paradigmatic model of subdiffusion in confined systems. This anomalous behavior is a direct consequence of strong spatial correlations induced by the requirement that the particles cannot overtake each other. Even if this fact has been recognized qualitatively for a long time, up to now there has been no full quantitative determination of these correlations. Here we study the joint probability distribution of an arbitrary number of tagged particles in the SEP. We determine analytically its large-time limit for an arbitrary density of particles, and its full dynamics in the high density limit. In this limit, we obtain the time-dependent large deviation function of the problem and unveil a universal scaling form shared by the cumulants. PMID- 30011440 TI - Manipulation of viscous fingering in a radially tapered cell geometry. AB - When a more mobile fluid displaces another immiscible one in a porous medium, viscous fingering propagates with a partial sweep, which hinders oil recovery and soil remedy. We experimentally investigate the feasibility of tuning such fingering propagation in a nonuniform narrow passage with a radial injection, which is widely used in various applications. We show that a radially converging cell can suppress the common viscous fingering observed in a uniform passage, and a full sweep of the displaced fluid is then achieved. The injection flow rate Q can be further exploited to manipulate the viscous fingering instability. For a fixed gap gradient alpha, our experimental results show a full sweep at a small Q but partial displacement with fingering at a sufficient Q. Finally, by varying alpha, we identify and characterize the variation of the critical threshold between stable and unstable displacements. Our experimental results reveal good agreement with theoretical predictions by a linear stability analysis. PMID- 30011441 TI - Characterization of random features of chaotic eigenfunctions in unperturbed basis. AB - In this paper we study random features manifested in components of energy eigenfunctions of quantum chaotic systems, given in the basis of unperturbed, integrable systems. Based on semiclassical analysis, particularly on Berry's conjecture, it is shown that the components in classically allowed regions can be regarded as Gaussian random numbers in a certain sense, when appropriately rescaled with respect to the average shape of the eigenfunctions. This suggests that when a perturbed system changes from integrable to chaotic, deviation of the distribution of rescaled components in classically allowed regions from the Gaussian distribution may be employed as a measure for the "distance" to quantum chaos. Numerical simulations performed in the Lipkin-Meshkov-Glick model and the Dicke model show that this deviation coincides with the deviation of the nearest level-spacing distribution from the prediction of random-matrix theory. Similar numerical results are also obtained in two models without classical counterpart. PMID- 30011442 TI - Multicritical behavior of the ferromagnetic Blume-Emery-Griffiths model with repulsive biquadratic couplings. AB - The ferromagnetic (J>0) version of the Blume-Emery-Griffiths model in the region of repulsive biquadratic couplings (K<0) is considered on a Cayley tree of coordination z, reducing the statistical problem to the analysis of a two dimensional nonlinear discrete map. In order to investigate the effect of the coordination z on the system multicritical behavior, we study the particular case K/J=-3.5 with the inclusion of crystal fields (D?0), but vanishing external magnetic fields (H=0), for two distinct lattice coordinations (z=4 and z=6). The thermodynamic solutions on the Bethe lattice (the central region of a large Cayley tree) are associated with the attractors of the two-dimensional map. The phase diagrams display several thermodynamic phases (paramagnetic, ferromagnetic, ferrimagnetic, and staggered quadrupolar). In some cases, there are regions of numerical costability of two different attractors of the map, associated with discontinuous phase transitions between the corresponding phases. To verify the thermodynamic stability of the phases and to locate the first-order boundaries, the analytical expression of the Gibbs free energy was obtained by the method proposed by Gujrati [Phys. Rev. Lett. 74, 809 (1995)PRLTAO0031 900710.1103/PhysRevLett.74.809]. For lower coordinations (z=4) the transition between the ferrimagnetic and the staggered quadrupolar phases is always continuous, while the transition between the ferromagnetic and the ferrimagnetic phases is discontinuous at low temperatures, turning into continuous for temperatures above a tricritical point. On the other hand, for higher coordinations (z=6), the transition between the ferromagnetic and the ferrimagnetic phases is always continuous. However, the transition between the ferrimagnetic and the staggered quadrupolar phases is continuous for higher temperatures and discontinuous for temperatures below a tricritical point, in agreement with previous results obtained in the mean-field approximation (infinity-coordination limit). In both cases, the occurrence and the thermodynamic stability of the ferrimagnetic phase is confirmed. PMID- 30011443 TI - Phase transition, scaling of moments, and order-parameter distributions in Brownian particles and branching processes with finite-size effects. AB - We revisit the problem of Brownian diffusion with drift in order to study finite size effects in the geometric Galton-Watson branching process. This is possible because of an exact mapping between one-dimensional random walks and geometric branching processes, known as the Harris walk. In this way, first-passage times of Brownian particles are equivalent to sizes of trees in the branching process (up to a factor of proportionality). Brownian particles that reach a distant reflecting boundary correspond to percolating trees, and those that do not correspond to nonpercolating trees. In fact, both systems display a second-order phase transition between "conducting" and "insulating" phases, controlled by the drift velocity in the Brownian system. In the limit of large system size, we obtain exact expressions for the Laplace transforms of the probability distributions and their first and second moments. These quantities are also shown to obey finite-size scaling laws. PMID- 30011444 TI - Column and film lifetimes in bubble-induced two-liquid flow. AB - We investigated the transient behavior of immiscible two-liquid interfaces initiated by a single rising gas bubble and characterized by liquid "column" and "film" morphologies. To analyze the effect of the buoyancy force, viscosity, and interfacial tension on these morphologies, the single-solution density was controlled continuously by association with the rising velocity of the bubble. It was observed that the extension of the liquid column further into the upper liquid phase owing to the wake flow under the bubble is driven by the buoyancy force, with the velocity decreasing gradually with the distance between the bubble and the liquid-liquid interface. Based on this mechanism, we determined that a strong dimensionless correlation exists between the lifetime of the column and the physical properties of the two liquid phases. On the other hand, gravitational drainage does not affect the film lifetime. However, marginal pinching is dominant, probably owing to the existence of a surface tension gradient between the film and the meniscus. PMID- 30011445 TI - Social influence with recurrent mobility and multiple options. AB - In this paper, we discuss the possible generalizations of the social influence with recurrent mobility (SIRM) model [Phys. Rev. Lett. 112, 158701 (2014)PRLTAO0031-900710.1103/PhysRevLett.112.158701]. Although the SIRM model worked approximately satisfying when U.S. election was modeled, it has its limits: it has been developed only for two-party systems and can lead to unphysical behavior when one of the parties has extreme vote share close to 0 or 1. We propose here generalizations to the SIRM model by its extension for multiparty systems that are mathematically well-posed in case of extreme vote shares, too, by handling the noise term in a different way. In addition, we show that our method opens alternative applications for the study of elections by using an alternative calibration procedure and makes it possible to analyze the influence of the "free will" (creating a new party) and other local effects for different commuting network topologies. PMID- 30011447 TI - Dynamical typicality of isolated many-body quantum systems. AB - Dynamical typicality refers to the property that two pure states, which initially exhibit (almost) the same expectation value for some given observable A, are very likely to exhibit also very similar expectation values when evolving in time according to the pertinent Schrodinger equation. We unify and generalize a variety of previous findings of this type for sufficiently high-dimensional quantum mechanical model systems. Particular emphasis is put on the necessary and sufficient conditions, which the initial expectation value and the spectrum of A have to fulfill. PMID- 30011448 TI - Magnetic energy transient growth in the subcritical Kazantsev model. AB - We study average magnetic field growth in a mirror-symmetrical Kazantsev turbulent flow near the dissipative scales. Our main attention is directed to a subcritical regime, when an exponential decrease of magnetic energy is usually expected. We show that instead of damping, transient energy growth can be obtained, for example, in stochastic processes supported by the large-scale magnetic fields. We calculate the longitudinal correlation functions and demonstrate that they can tend to nonzero stationary solutions, whose localization width is inversely proportional to the square of the magnetic Reynolds numbers and with amplitude depending on the closeness of these numbers to the critical value. We present the local generation effect without any external support, predicted by Zeldovich in 1956. Numerically solving the initial boundary Kazantsev problem on the nonuniform grids, we simulate this process by implicit schemes and discuss the possible consequences of subcritical growth for dynamo theory. PMID- 30011446 TI - Flow of anisometric particles in a quasi-two-dimensional hopper. AB - The stationary flow field in a quasi-two-dimensional hopper is investigated experimentally. The behavior of materials consisting of beads and elongated particles with different aspect ratio is compared. We show, that while the vertical velocity in the flowing region can be fitted with a Gaussian function for beads, in the case of elongated grains the flowing channel is narrower and is bordered with sharper velocity gradient. For this case, we quantify deviations from the Gaussian velocity profile. Relative velocity fluctuations are considerably larger and slower for elongated grains. PMID- 30011449 TI - Continuum rich-get-richer processes: Mean field analysis with an application to firm size. AB - Classical rich-get-richer models have found much success in being able to broadly reproduce the statistics and dynamics of diverse real complex systems. These rich get-richer models are based on classical urn models and unfold step by step in discrete time. Here, we consider a natural variation acting on a temporal continuum in the form of a partial differential equation (PDE). We first show that the continuum version of Simon's canonical preferential attachment model exhibits an identical size distribution. In relaxing Simon's assumption of a linear growth mechanism, we consider the case of an arbitrary growth kernel and find the general solution to the resultant PDE. We then extend the PDE to multiple spatial dimensions, again determining the general solution. We then relax the zero-diffusion assumption and find an envelope of solutions to the general model in the presence of small fluctuations. Finally, we apply the model to size and wealth distributions of firms. We obtain power-law scaling for both to be concordant with simulations as well as observational data, providing a parsimonious theoretical explanation for these phenomena. PMID- 30011450 TI - Hydrodynamics, density fluctuations, and universality in conserved stochastic sandpiles. AB - We study conserved stochastic sandpiles (CSSs), which exhibit an active-absorbing phase transition upon tuning density rho. We demonstrate that a broad class of CSSs possesses a remarkable hydrodynamic structure: There is an Einstein relation sigma^{2}(rho)=chi(rho)/D(rho), which connects bulk-diffusion coefficient D(rho), conductivity chi(rho), and mass fluctuation, or scaled variance of subsystem mass, sigma^{2}(rho). Consequently, density large-deviations are governed by an equilibrium-like chemical potential MU(rho)~lna(rho), where a(rho) is the activity in the system. By using the above hydrodynamics, we derive two scaling relations: As Delta=(rho-rho_{c})->0^{+}, rho_{c} being the critical density, (i) the mass fluctuation sigma^{2}(rho)~Delta^{1-delta} with delta=0 and (ii) the dynamical exponent z=2+(beta-1)/nu_{?}, expressed in terms of two static exponents beta and nu_{?} for activity a(rho)~Delta^{beta} and correlation length xi~Delta^{-nu_{?}}, respectively. Our results imply that conserved Manna sandpile, a well studied variant of the CSS, belongs to a distinct universality not that of directed percolation (DP), which, without any conservation law as such, does not obey scaling relation (ii). PMID- 30011451 TI - Diffusion crossing over a barrier in a random rough metastable potential. AB - We carry out a detailed study of escape dynamics of a particle driven by a white noise over a metastable potential corrugated by spatial disorder in the form of zero-mean random correlated potential. The approach of double-averaging over test particles and statistic ensemble is proposed to calculate the escape rate in a finite-size random rough metastable potential, moreover, the interference mechanism of test particles multi-passing over the saddle point is considered. Through analyzing the dependence of the steady escape rate on various modelled potentials and parameters, we demonstrate that the obstruction induced by roughness leads to a decrease in the steady escape rate with the increase of rough intensity. We also add the random correlated potential into the vicinity of the saddle-point of metastable potentials of three kinds and show an enhancement phenomenon of escape rate similar to the previous study of a surmounting fluctuating sharp barrier. PMID- 30011452 TI - Fluctuations of conformational mobility of macromolecules around the glass transition. AB - The heterogeneity of local dynamics in disordered systems is behind some key features of glass transition. In order to improve our understanding of the molecular dynamics in disordered systems in the vicinity of the glass transition, different parameters have been proposed to quantitatively describe dynamical heterogeneity. In the case of polymers, free volume models relate the macromolecular mobility to the free or accessible volume. The relationship between dynamic heterogeneity and fluctuations of accessible volume seems straightforward. In the present work, the heterogeneity of local dynamics in polymeric systems is analyzed by computer simulation with the bond fluctuation model. The value of the accessible volume around each polymer chain is evaluated from a snapshot or static structure at each system state, resulting in a distribution of accessible volume that reflects system heterogeneity. The relationship between the average value and the standard deviation of free volume distributions at different temperatures fits a master curve for different systems, regardless of the specific inter- and intramolecular interaction potentials that define each material. The dynamic slowdown around the glass transition is accompanied by a clear evolution of the mean value and shape of the accessible free volume distribution. The relative fluctuation of the dynamically accessible volume has been used as a parameter to quantitatively describe heterogeneity. The fluctuation varies with temperature with remarkable differences between the liquid and glassy states of the systems studied, presenting a peak at the glass transition temperature, which can be interpreted as a reflection of the distribution of local glass transition temperatures. PMID- 30011453 TI - Path integral Monte Carlo simulations of warm dense aluminum. AB - We perform first-principles path integral Monte Carlo (PIMC) and density functional theory molecular dynamics (DFT-MD) calculations to explore warm dense matter states of aluminum. Our equation of state (EOS) simulations cover a wide density-temperature range of 0.1-32.4gcm^{-3} and 10^{4}-10^{8} K. Since PIMC and DFT-MD accurately treat effects of the atomic shell structure, we find two compression maxima along the principal Hugoniot curve attributed to K-shell and L shell ionization. The results provide a benchmark for widely used EOS tables, such as SESAME, QEOS, and models based on Thomas-Fermi and average-atom techniques. A subsequent multishock analysis provides a quantitative assessment for how much heating occurs relative to an isentrope in multishock experiments. Finally, we compute heat capacity, pair-correlation functions, the electronic density of states, and to reveal the evolution of the plasma structure and ionization behavior. PMID- 30011454 TI - Spatiotemporal intermittency and localized dynamic fluctuations upon approaching the glass transition. AB - We introduce a robust approach for characterizing spatially and temporally heterogeneous behavior within a system based on the evolution of dynamic fluctuations averaged over different space lengths and timescales. We apply it to investigate the dynamics in two canonical systems as the glass transition is approached: simulated Lennard-Jones liquids and experimental dense colloidal suspensions. In both cases the onset of glassiness is marked by spatially localized dynamic fluctuations originating in regions of correlated mobile particles. By removing the trivial system size dependence we show that the spatial heterogeneity of the dynamics extends to large length scales containing tens to hundreds of particles, corresponding to the timescale of maximally non Gaussian dynamics. PMID- 30011455 TI - Cascade model of wave turbulence. AB - We propose a cascade model of wave turbulence designed to simplify the study of this phenomenon in the way that shell models simplify the study of Navier-Stokes turbulence. The model consists of resonant quartets, in which some modes are driven and damped and others are shared by pairs of quartets and transferring energy between them, mimicking the natural energy transfer mechanism in weakly turbulent waves. A set of detailed-balance conditions singles out the case of the cascade model in equilibrium, for which we can explicitly derive a Gaussian equilibrium measure and a maximum-entropy principle using a Kolmogorov forward equation. Away from equilibrium, we can approximate the second-moment dynamics of the mode amplitudes using kinetic equations. In a nonequilibrium steady state, we can also approximate the higher moments of the driven-damped mode amplitudes and characterize the distribution of the shared-mode amplitudes as Gaussian. For this latter distribution, we find an information-theoretic argument, akin to entropy maximization, which lets us conclude that arbitrary initial shared-mode amplitude distributions approach Gaussian form in forward time. The cascade model may provide insight into mechanisms governing weakly turbulent wave systems and perhaps afford computational savings as compared to direct numerical simulations of the corresponding wavelike equations. PMID- 30011456 TI - Aftershocks in slowly compressed bulk metallic glasses: Experiments and theory. AB - We observe two distinct interevent time patterns in the slip avalanches of compressed bulk metallic glasses (BMGs). Small slip avalanches cluster together in time, but large slip avalanches recur roughly periodically. We compare the timing patterns of BMG slip avalanches with timing patterns of earthquakes and with the predictions of a mean-field model. The time clustering of small avalanches is similar to the known time clustering of earthquake foreshocks and aftershocks. PMID- 30011457 TI - Unified decomposition method to study Rayleigh-Taylor instability in liquids and solids. AB - In the previous studies of Rayleigh-Taylor instability, different methods were used to consider the effects of elasticity, viscosity, and magnetic fields. In this paper, a unified method, which was first used for fluids, is validated for different physical models, where the unstable mode is decomposed into an irrotational part and a rotational part, and the latter one includes the effects of nonconservative forces and constitutive relations. Previous results of solid and liquid with or without the effects of magnetic fields and finite thickness can be easily recovered after applying the corresponding interface boundary conditions. In addition, new approximate but analytical solutions of the growth rates for a semi-infinite solid-solid interface and solid-fluid interface are obtained with substantially improved accuracy in comparison with the previous ones. PMID- 30011458 TI - Comment on "Nonequilibrium thermodynamics with binary quantum correlations". AB - The article [Phys. Rev. E 96, 032106 (2017)10.1103/PhysRevE.96.032106] recovers conservation laws and derives the H-theorem for the kinetic equation with gradient corrections. Here we show that this approach is not valid, leading to missing terms in the balance of energy and momentum and to disagreement with correlation entropy known from the Enskog equation. PMID- 30011459 TI - Dynamics of driven translocation of semiflexible polymers. AB - We study translocation of semiflexible polymers driven by force f_{d} inside a nanometer-scale pore using our three-dimensional Langevin dynamics model. We show that the translocation time tau increases with increasing bending rigidity kappa. Similarly, the exponent beta for the scaling of tau with polymer length N,tau~N^{beta}, increases with increasing kappa as well as with increasing f_{d}. By comparing waiting times between semiflexible and fully flexible polymers we show that for realistic f_{d} translocation dynamics is to a large extent, but not completely, determined by the polymer's elastic length measured in number of Kuhn segments N_{Kuhn}. Unlike in driven translocation of flexible polymers, friction related to the polymer segment on the trans side has a considerable effect on the resulting dynamics. This friction is intermittently reduced by buckling of the polymer segment in the vicinity of the pore opening on the trans side. We show that in the experimentally relevant regime where viscosity is higher than in computer simulation models, the probability for this buckling increases with increasing f_{d}, giving rise to a larger contribution to the trans side friction at small f_{d}. Similarly to flexible polymers, we find significant center-of-mass diffusion of the cis side polymer segment which speeds up translocation. This effect is larger for smaller f_{d}. However, this speedup is smaller than the slowing down due to the trans side friction. At large enough N_{Kuhn}, the roles can be seen to be reversed, and the dynamics of flexible polymers can be reached. However, for example, polymers used in translocation experiments of DNA are elastically so short that the finite-length dynamics outlined here applies. PMID- 30011460 TI - Effect of pressure on segregation in granular shear flows. AB - The effect of confining pressure (overburden) on segregation of granular material is studied in discrete element method (DEM) simulations of horizontal planar shear flow. To mitigate changes to the shear rate due to the changing overburden, a linear with depth variation in the streamwise velocity component is imposed using a simple feedback scheme. Under these conditions, both the rate of segregation and the ultimate degree of segregation in size bidisperse and density bidisperse granular flows decrease with increasing overburden pressure and scale with the overburden pressure normalized by the lithostatic pressure of the particle bed. At overburdens greater than approximately 20 times the lithostatic pressure at the bottom of the bed, the density segregation rate is zero while the size segregation rate is small but nonzero, suggesting that different physical mechanisms drive the two types of segregation. The segregation rate scales close to linearly with the inertial number for both size bidisperse and density bidisperse mixtures under various flow conditions, leading to a proposed pressure dependence term for existing segregation velocity correlations. Surprisingly, particle stiffness has only a minor effect on segregation, although it significantly affects the packing density. PMID- 30011461 TI - Quantum molecular dynamics study on the proton exchange, ionic structures, and transport properties of warm dense hydrogen-deuterium mixtures. AB - Comprehensive knowledge of physical properties such as equation of state (EOS), proton exchange, dynamic structures, diffusion coefficients, and viscosities of hydrogen-deuterium mixtures with densities from 0.1 to 5 g/cm^{3} and temperatures from 1 to 50 kK has been presented via quantum molecular dynamics (QMD) simulations. The existing multi-shock experimental EOS provides an important benchmark to evaluate exchange-correlation functionals. The comparison of simulations with experiments indicates that a nonlocal van der Waals density functional (vdW-DF1) produces excellent results. Fraction analysis of molecules using a weighted integral over pair distribution functions was performed. A dissociation diagram together with a boundary where the proton exchange (H_{2}+D_{2}?2HD) occurs was generated, which shows evidence that the HD molecules form as the H_{2} and D_{2} molecules are almost 50% dissociated. The mechanism of proton exchange can be interpreted as a process of dissociation followed by recombination. The ionic structures at extreme conditions were analyzed by the effective coordination number model. High-order cluster, circle, and chain structures can be founded in the strongly coupled warm dense regime. The present QMD diffusion coefficient and viscosity can be used to benchmark two analytical one-component plasma (OCP) models: the Coulomb and Yukawa OCP models. PMID- 30011462 TI - Oscillatory pulse-front waves in a reaction-diffusion system with cross diffusion. AB - We explore traveling waves with oscillatory tails in a bistable piecewise linear reaction-diffusion system of the FitzHugh-Nagumo type with linear cross diffusion. These waves differ fundamentally from the standard simple fronts of the kink type. In contrast to kinks, the waves studied here have a complex shape profile with a front-back-front (a pulse-front) pattern. The characteristic feature of such pulse-front waves is a hybrid type of the speed diagram, which on the one hand reflects the typical dynamical behavior of the fronts in the FitzHugh-Nagumo model, related to the nonequilibrium Ising-Bloch bifurcation, and on the other hand exhibits also the solitary pulse scenario where several waves appear simultaneously with different speeds of propagation. We describe analytically the wave profiles and heteroclinic trajectories in the phase plane and discuss their morphology and transformation. The phenomena of wave formation and propagation are also studied by numerical simulations of the model partial differential equations. These simulations support the view that the pulse-front waves are constructed of fronts and pulses. PMID- 30011463 TI - Resonant x-ray scattering observation of transitional subphases during the electric-field-induced phase transition in a mixture of Se-containing chiral smectic liquid crystals. AB - Using resonant x-ray scattering techniques, transitional subphases during the electric-field-induced phase transition of a mixture of Se-containing chiral liquid crystals, 80% AS657 and 20% AS620, in a planar-aligned cell geometry were investigated, where the prototypical phase sequence SmC_{A}^{*}-SmC_{gamma}^{*} AF-SmC^{*} was observed; the transitional subphases were formed during the transition from the three-layer periodicity phase to the ferroelectric phase. In the lower-temperature range where the three-layer SmCgamma^{*} phase appeared under the low electric field, nine- and six-layer subphases and a "streak" pattern appeared in sequence after the transition from the SmCgamma^{*} phase with increasing applied electric field; the ferroelectric phase was realized. In the higher-temperature range where the four-layer AF phase appeared under a low electric field, the AF phase changed to a three-layer phase at the medium electric field. The twelve-, nine-, and six-layer subphases subsequently appeared in sequence, and finally the ferroelectric phase was generated with increasing electric field. The molecular arrangements of the field-induced subphases, especially the newly found nine-layer periodicity phase, was analyzed. The successive field-induced phase transition of the present results was compared with that of our previous results for pure Se-containing and Br-containing liquid crystals, and the relation to the three-layer ferrielectric phase was discussed. PMID- 30011464 TI - Topological bounds of bending energy for lipid vesicles. AB - The Helfrich bending energy plays an important role in providing a mechanism for the conformation of a lipid vesicle in theoretical biophysics, which is governed by the principle of energy minimization over configurations of appropriate topological characteristics. We will show that the presence of a quantity called the spontaneous curvature obstructs the existence of a minimizer of the Helfrich energy over the set of embedded ring tori. In addition, despite the well-realized knowledge that lipid vesicles may present themselves in a variety of shapes of complicated topology, there is a lack of topological bounds for the Helfrich energy. To overcome these difficulties, we consider a general scale-invariant anisotropic curvature energy that extends the Canham elastic bending energy developed in modeling a biconcave-shaped red blood cell. We will show that, up to a rescaling of the generating radii, there is a unique minimizer of the energy over the set of embedded ring tori, in the entire parameter regime, which recovers the Willmore minimizer in its Canham isotropic limit. We also show how elevated anisotropy favors energetically a clear transition from spherical-, to ellipsoidal-, and then to biconcave-shaped surfaces, for a lipid vesicle. We then establish some genus-dependent topological lower and upper bounds for the anisotropic energy. Finally, we derive the shape equation of the generalized bending energy, which extends the well-known Helfrich shape equation. PMID- 30011465 TI - Microtubule seams are not mechanically weak defects. AB - Microtubule rigidity is important for many cellular functions to support extended structures and rearrange materials within the cell. The arrangement of the tubulin dimers within the microtubule can be altered to affect the protofilament number and the lattice type. Prior electron microscopy measurements have shown that when polymerized in the presence of a high concentration of NaCl, microtubules were more likely to be ten protofilaments with altered intertubulin lattice types. Specifically, such high-salt microtubules have a higher percentage of seam defects. Such seams have long been speculated to be a mechanically weak location in the microtubule lattice, yet no experimental evidence supported this claim. We directly measured the persistence length of freely fluctuating filaments made either with high salt or without. We found that the microtubules made with high salt were more flexible, by a factor of 2, compared to those polymerized the same way without salt present. The reduced persistence length of the high-salt microtubules can be accounted for entirely by a smaller cross sectional radius of these microtubules, implying that the mixed lattice interactions have little effect on the bending rigidity. Our results suggest that the microtubule seam is not weaker than the typical lattice structure as previously speculated from structural studies. PMID- 30011466 TI - Self-propelled motion switching in nematic liquid crystal droplets in aqueous surfactant solutions. AB - The self-propelled motions of micron-sized nematic liquid crystal droplets in an aqueous surfactant solution have been studied by tracking individual droplets over long time periods. Switching between self-propelled modes is observed as the droplet size decreases at a nearly constant dissolution rate: from random to helical and then straight motion. The velocity of the droplet decreases with its size for straight and helical motions but is independent of size for random motion. The switching between helical and straight motions is found to be governed by the self-propelled velocity, and is confirmed by experiments at various surfactant concentrations. The helical motion appears along with a shifting of a point defect from the self-propelled direction of the droplet. The critical velocity for this shift of the defect position is found to be related with the Ericksen number, which is defined by the ratio of the viscous and elastic stresses. In a thin cell whose thickness is smaller than that of the initial droplet size, the droplets show more complex trajectories, including "figure-8s" and zigzags. The appearance of those characteristic motions is attributed to autochemotaxis of the droplet. PMID- 30011467 TI - High-frequency forced oscillations in neuronlike elements. AB - We analyzed a generic relaxation oscillator under moderately strong forcing at a frequency much greater that the natural intrinsic frequency of the oscillator. Additionally, the forcing is of the same sign and, thus, has a nonzero average, matching neuroscience applications. We found that, first, the transition to high frequency synchronous oscillations occurs mostly through periodic solutions with virtually no chaotic regimes present. Second, the amplitude of the high-frequency oscillations is large, suggesting an important role for these oscillations in applications. Third, the 1:1 synchronized solution may lose stability, and, contrary to other cases, this occurs at smaller, but not at higher frequency differences between intrinsic and forcing oscillations. We analytically built a map that gives an explanation of these properties. Thus, we found a way to substantially "overclock" the oscillator with only a moderately strong external force. Interestingly, in application to neuroscience, both excitatory and inhibitory inputs can force the high-frequency oscillations. PMID- 30011469 TI - Reshaping of a Janus ring. AB - We consider the reshaping of closed Janus filaments acquiring intrinsic curvature upon actuation of a driven component-a nematic elastomer elongating upon phase transition. Linear stability analysis establishes instability thresholds of circles with no imposed twist, dependent on the ratio q of the intrinsic curvature to the inverse radius of the original circle. Twisted circles are proven to be absolutely unstable but the linear analysis well predicts the dependence of the looping number of the emerging configurations on the imposed twist. Modeling stable configurations by relaxing numerically the overall elastic energy detects multiple stable and metastable states with different looping numbers. The bifurcation of untwisted circles turns out to be subcritical, so that nonplanar shapes with a lower energy exist at q below the critical value. The looping number of stable shapes generally increases with q. PMID- 30011468 TI - Robustness of mean field theory for hard sphere models. AB - In very recent work the mean field theory of the jamming transition in infinite dimensional hard sphere models was presented. Surprisingly, this theory predicts quantitatively the numerically determined characteristics of jamming in two and three dimensions. This is a rare and unusual finding. Here we argue that this agreement is nongeneric: only for hard sphere models does it happen that sufficiently close to the jamming density (at any temperature) the effective interactions are binary, in agreement with mean field theory, justifying the truncation of many-body interactions (which is the exact protocol in infinite dimensions). Any softening of the bare hard sphere interactions results in many body effective interactions that are not mean field at any density, making the d=infinity results not applicable. PMID- 30011470 TI - Mode-III interfacial crack propagation in heterogeneous media. AB - We monitor optically the propagation of a slow interfacial mode III crack along a heterogeneous weak interface and compare it to mode I loading. Pinning and depinning of the front on local toughness asperities within the process zone are the main mechanisms for fracture roughening. Geometrical properties of the fracture fronts are derived in the framework of self-affine scale invariance and Family-Vicsek scaling. We characterize the small and large scale roughness exponents zeta_{-}=0.6 and zeta_{+}=0.35, the growth exponent at large scale beta_{+}=0.58, and the power-law exponent of the local velocity distribution of the fracture fronts, eta=2.55. All these analyzed properties are similar to those previously observed for mode I interfacial fractures. We also observe a common power-law decay of the probability distribution function of avalanche area. We finally observe that amplitude of front fluctuations, local rupture velocity correlation in time, and larger size of events highlight more dynamically unstable behavior of mode III crack ruptures. PMID- 30011471 TI - Spreading of a granular droplet under horizontal vibrations. AB - By means of three-dimensional discrete element simulations, we study the spreading of a granular droplet on a horizontally vibrated plate. Apart from a short transient with a parabolic shape, the droplet adopts a triangular profile during the spreading. The dynamics of the spreading is governed by two distinct regimes: a superdiffusive regime in the early stages driven by surface flow followed by a second one which is subdiffusive and governed by bulk flow. The plate bumpiness is found to alter only the spreading rate but plays a minor role on the shape of the granular droplet and on the scaling laws of the spreading. Importantly, we show that in the subdiffusive regime, the effective friction between the plate and the granular droplet can be interpreted in the framework of the MU(I)-rheology. PMID- 30011472 TI - Finite-bath corrections to the second law of thermodynamics. AB - The second law of thermodynamics states that a system in contact with a heat bath can undergo a transformation if and only if its free energy decreases. However, the "if" part of this statement is only true when the effective heat bath is infinite. In this article we remove this idealization and derive corrections to the second law in the case where the bath has a finite size, or equivalently finite heat capacity. This can also be translated to processes lasting a finite time, and we show that thermodynamical reversibility is lost in this regime. We do so in full generality, without assuming any particular model for the bath; the only parameters defining the bath are its temperature and heat capacity. We find connections with second order Shannon information theory, in particular, in the case of Landauer erasure. We also consider the case of nonfluctuating work and derive finite-bath corrections to the min and max free energies employed in single-shot thermodynamics. PMID- 30011473 TI - Exact distribution of spacing ratios for random and localized states in quantum chaotic systems. AB - Typical eigenstates of quantum systems, whose classical limit is chaotic, are well approximated as random states. Corresponding eigenvalue spectra are modeled through an appropriate ensemble described by random matrix theory. However, a small subset of states violates this principle and displays eigenstate localization, a counterintuitive feature known to arise due to purely quantum or semiclassical effects. In the spectrum of chaotic systems, the localized and random states interact with one another and modify the spectral statistics. In this work, a 3*3 random matrix model is used to obtain exact results for the ratio of spacing between a generic and localized state. We consider time-reversal invariant as well as noninvariant scenarios. These results agree with the spectra computed from realistic physical systems that display localized eigenmodes. PMID- 30011474 TI - Two distinct excitable responses for a laser with a saturable absorber. AB - Excitable lasers with saturable absorbers are currently investigated as potential candidates for low level spike processing tasks in integrated optical platforms. Following a small perturbation of a stable equilibrium, a single and intense laser pulse can be generated before returning to rest. Motivated by recent experiments [Selmi et al., Phys. Rev. E 94, 042219 (2016)10.1103/PhysRevE.94.042219], we consider the rate equations for a laser containing a saturable absorber (LSA) and analyze the effects of different initial perturbations. With its three steady states and following Hodgkin classification, the LSA is a Type I excitable system. By contrast to perturbations on the intensity leading to the same intensity pulse, perturbations on the gain generate pulses of different amplitudes. We explain these distinct behaviors by analyzing the slow-fast dynamics of the laser in each case. We first consider a two-variable LSA model for which the conditions of excitability can be explored in the phase plane in a transparent manner. We then concentrate on the full three variable LSA equations and analyze its solutions near a degenerate steady bifurcation point. This analysis generalizes previous results [Dubbeldam et al., Phys. Rev. E 60, 6580 (1999)1063-651X10.1103/PhysRevE.60.6580] for unequal carrier density rates. Last, we discuss a fundamental difference between neuron and laser models. PMID- 30011475 TI - Theory of combustion in disordered media. AB - The conventional theory of combustion describes systems where all of the parameters are spatially homogeneous. On the other hand, combustion in disordered explosives has long been known to occur after local regions of the material, called hot spots, are ignited. In this article we show that a system of randomly distributed hot spots exhibits a dynamic phase transition, which, depending on parameters of the system, can be either first or second order. These two regimes are separated by a tricritical point. We also show that on the qualitative level the phase diagram of the system is universal. It is valid in two and three dimensions, in the cases when the hot spots interact either by heat or sound waves, and in a broad range of microscopic disorder models. PMID- 30011476 TI - Delamination of a thin sheet from a soft adhesive Winkler substrate. AB - A uniaxially compressed thin elastic sheet that is resting on a soft adhesive substrate can form a blister, which is a small delaminated region, if the adhesion energy is sufficiently weak. To analyze the equilibrium behavior of this system, we model the substrate as a Winkler or fluid foundation. We develop a complete set of equations for the profile of the sheet at different applied pressures. We show that at the edge of delamination, the height of the sheet is equal to sqrt[2]l_{c}, where l_{c} is the capillary length. We then derive an approximate solution to these equations and utilize them for two applications. First, we determine the phase diagram of the system by analyzing possible transitions from the flat and wrinkled to delaminated states of the sheet. Second, we show that our solution for a blister on a soft foundation converges to the known solution for a blister on a rigid substrate that assumed a discontinuous bending moment at the blister edges. This continuous convergence into a discontinuous state marks the formation of a boundary layer around the point of delamination. The width of this layer relative to the extent length of the blister, l, scales as w/l~(l_{c}/l_{ec})^{1/2}, where l_{ec} is the elastocapillary length scale. Notably, our findings can provide guidelines for utilizing compression to remove thin biofilms from surfaces and thereby prevent the fouling of the system. PMID- 30011477 TI - Crossover from low-temperature to high-temperature fluctuations: Universal and nonuniversal Casimir forces of isotropic and anisotropic systems. AB - We study the crossover from low-temperature to high-temperature fluctuations including Goldstone-dominated and critical fluctuations in confined isotropic and weakly anisotropic O(n)-symmetric systems on the basis of a finite-size renormalization-group approach at fixed dimension d introduced previously [V. Dohm, Phys. Rev. Lett. 110, 107207 (2013)PRLTAO0031 900710.1103/PhysRevLett.110.107207]. Our theory is formulated within the phi^{4} lattice model in a d-dimensional block geometry with periodic boundary conditions. We calculate the finite-size scaling functions F^{ex} and X of the excess free-energy density and the thermodynamic Casimir force, respectively, for 1<=n<=infinity, 2infinity. Applications are given for L_{?}^{d-1}*L slab geometry with an aspect ratio rho=L/L_{?}>0 and for film geometry (rho=0). Good overall agreement is found with Monte Carlo (MC) data for isotropic spin models with n=1,2,3. For rho=0, the low-temperature limits of F^{ex} and X vanish for n=1, whereas they are finite for n>=2. For rho>0 and n=1, we find a finite low-temperature limit of F^{ex}, which deviates from that of the Ising model. We attribute this deviation to the nonuniversal difference between the phi^{4} model with continuous variables and the Ising model with discrete variables. For n>=2 and rho>0, a logarithmic divergence of F^{ex} in the low-temperature limit is predicted, in excellent agreement with MC data. For 2<=n<=infinity and rhorho_{0}. For anisotropic systems a unified hypothesis of multiparameter universality is introduced for both bulk and confined systems. The dependence of their scaling functions on d(d+1)/2-1 microscopic anisotropy parameters implies a substantial reduction of the predictive power of the theory for anisotropic systems as compared to isotropic systems. An exact representation is derived for the nonuniversal large-distance behavior of the bulk correlation function of anisotropic systems and quantitative predictions are made. The validity of multiparameter universality is proven analytically for the d=2,n=1 universality class. A nonuniversal anisotropy-dependent minimum of the Casimir force scaling function X is found. Both the sign and magnitude of X and the shift of the film critical temperature are affected by the lattice anisotropy. PMID- 30011478 TI - Multipartite entanglement, quantum coherence, and quantum criticality in triangular and Sierpinski fractal lattices. AB - We investigate the quantum phase transitions of the transverse-field quantum Ising model on the triangular lattice and Sierpinski fractal lattices by employing the multipartite entanglement and quantum coherence along with the quantum renormalization group method. It is shown that the quantum criticalities of these high-dimensional models closely relate to the behaviors of the multipartite entanglement and quantum coherence. As the thermodynamic limit is approached, the first derivatives of the multipartite entanglement and quantum coherence exhibit singular behaviors, and the consistent finite-size scaling behaviors for each lattice are also obtained from the first derivatives. The multipartite entanglement and quantum coherence are demonstrated to be good indicators for detecting the quantum phase transitions in the triangular lattice and Sierpinski fractal lattices. Furthermore, the dimensions determine the relations between the critical exponents and the correlation length exponents for these lattices. PMID- 30011479 TI - Magnetic domain wall creep and depinning: A scalar field model approach. AB - Magnetic domain wall motion is at the heart of new magnetoelectronic technologies and hence the need for a deeper understanding of domain wall dynamics in magnetic systems. In this context, numerical simulations using simple models can capture the main ingredients responsible for the complex observed domain wall behavior. We present a scalar field model for the magnetization dynamics of quasi-two dimensional systems with a perpendicular easy axis of magnetization which allows a direct comparison with typical experimental protocols, used in polar magneto optical Kerr effect microscopy experiments. We show that the thermally activated creep and depinning regimes of domain wall motion can be reached and the effect of different quenched disorder implementations can be assessed with the model. In particular, we show that the depinning field increases with the mean grain size of a Voronoi tessellation model for the disorder. PMID- 30011481 TI - Levy walks with variable waiting time: A ballistic case. AB - The Levy walk process for a lower interval of an excursion times distribution (alpha<1) is discussed. The particle rests between the jumps, and the waiting time is position-dependent. Two cases are considered: a rising and diminishing waiting time rate nu(x), which require different approximations of the master equation. The process comprises two phases of the motion: particles at rest and in flight. The density distributions for them are derived, as a solution of corresponding fractional equations. For strongly falling nu(x), the resting particles density assumes the alpha-stable form (truncated at fronts), and the process resolves itself to the Levy flights. The diffusion is enhanced for this case but no longer ballistic, in contrast to the case for the rising nu(x). The analytical results are compared with Monte Carlo trajectory simulations. The results qualitatively agree with observed properties of human and animal movements. PMID- 30011480 TI - Inference of epistatic effects in a key mitochondrial protein. AB - We use Potts model inference to predict pair epistatic effects in a key mitochondrial protein-cytochrome c oxidase subunit 2-for ray-finned fishes. We examine the effect of phylogenetic correlations on our predictions using a simple exact fitness model, and we find that, although epistatic effects are underpredicted, they maintain a roughly linear relationship to their true (model) values. After accounting for this correction, epistatic effects in the protein are still relatively weak, leading to fitness valleys of depth 2Ns?-5 in compensatory double mutants. Interestingly, positive epistasis is more pronounced than negative epistasis, and the strongest positive effects capture nearly all sites subject to positive selection in fishes, similar to virus proteins evolving under selection pressure in the context of drug therapy. PMID- 30011482 TI - Effective interaction between nanoparticles mediated by a symmetric polymer blend. AB - We analytically study the polymer-mediated (PM) interactions between spherical particles immersed in a symmetric polymer blend. By making use of standard methods of the liquid state theory we have found out a nonconventional mechanism of the PM interactions caused by nonuniformities in the local composition of the polymer blend induced by the particles. The relative significance of the contributions to the PM interaction potential due to the finite compressibility of the polymer blend and its compositional nonuniformity is found to drastically depend on the polymer-to-particle size ratio. In the protein limit of relatively small particles, the mechanism due to the compositional nonuniformity, specific to polymer blends, is shown to play a dominant role in the PM interactions. PMID- 30011483 TI - Envelope and phase distribution of a resonance transmission through a complex environment. AB - A transmission amplitude is considered for quantum or wave transport mediated by a single resonance coupled to the background of many chaotic states. Such a model provides a useful approach to quantify fluctuations in an established signal induced by a complex environment. Applying random matrix theory to the problem, we derive an exact result for the joint distribution of the transmission intensity (envelope) and the transmission phase at arbitrary coupling to the background with finite absorption. The intensity and phase are distributed within a certain region, revealing essential correlations even at strong absorption. In the latter limit, we obtain a simple asymptotic expression that provides a uniformly good approximation of the exact distribution within its whole support, thus going beyond the Rician distribution often used for such purposes. Exact results are also derived for the marginal distribution of the phase, including its limiting forms at weak and strong absorption. PMID- 30011484 TI - Plasma-based polarizer and waveplate at large laser intensity. AB - A plasma photonic crystal consists of a plasma density grating which is created in underdense plasma by counterpropagating laser beams. When a high-power laser pulse impinges the crystal, it might be reflected or transmitted. So far only one type of pulse polarization, namely the so-called s wave (or TE mode) was investigated (when the electric field vector is perpendicular to the plane of incidence). Here, when investigating also so-called p waves (or TM modes, where the magnetic field vector is perpendicular to the plane of incidence), it is detected that the transmission and reflection properties of the plasma photonic crystal depend on polarization. A simple analytic model of the crystal allows one to make precise predictions. The first conclusion is that in some operational regime the crystal can act as a plasma polarizer for high-intensity laser pulses. Also, differences in phase velocities for grazing incidence between s and p polarization are found. Thus, secondly, the crystal can be utilized as a waveplate, e.g., transforming linearly polarized laser light into circular polarization. All these processes extend to laser intensities beyond the damage intensities of so far used solid state devices. PMID- 30011485 TI - Synchronization invariance under network structural transformations. AB - Synchronization processes are ubiquitous despite the many connectivity patterns that complex systems can show. Usually, the emergence of synchrony is a macroscopic observable; however, the microscopic details of the system, as, e.g., the underlying network of interactions, is many times partially or totally unknown. We already know that different interaction structures can give rise to a common functionality, understood as a common macroscopic observable. Building upon this fact, here we propose network transformations that keep the collective behavior of a large system of Kuramoto oscillators invariant. We derive a method based on information theory principles, that allows us to adjust the weights of the structural interactions to map random homogeneous in-degree networks into random heterogeneous networks and vice versa, keeping synchronization values invariant. The results of the proposed transformations reveal an interesting principle; heterogeneous networks can be mapped to homogeneous ones with local information, but the reverse process needs to exploit higher-order information. The formalism provides analytical insight to tackle real complex scenarios when dealing with uncertainty in the measurements of the underlying connectivity structure. PMID- 30011486 TI - Contact line friction of electrowetting actuated viscous droplets. AB - We examine the contact line friction coefficient of viscous droplets spreading and retracting on solid surfaces immersed in ambient oil. By using the electrowetting effect, we generate a surface tension imbalance to drive the spreading and the retracting motion of the three-phase contact line (TCL). We show that neither the driving force intensity nor TCL direction significantly influences the friction coefficient. Instead, the friction coefficient depends equivalently on the viscosity of liquid droplets and the surrounding oil. We derive and experimentally verify a transient timescale that can be used to characterize both the spreading and retracting dynamics. PMID- 30011487 TI - Thermodynamics of non-Markovian reservoirs and heat engines. AB - We show that non-Markovian effects of the reservoirs can be used as a resource to extract work from an Otto cycle. The state transformation under non-Markovian dynamics is achieved via a two-step process, namely an isothermal process using a Markovian reservoir followed by an adiabatic process. From second law of thermodynamics, we show that the maximum amount of extractable work from the state prepared under the non-Markovian dynamics quantifies a lower bound of non Markovianity. We illustrate our ideas with an explicit example of non-Markovian evolution. PMID- 30011488 TI - Dependence of extreme events on spatial location. AB - To model the dependence of extreme events on locations, we consider extreme events of Brownian particles in a potential. We find that barring the exception of very large potentials and/or very small regions, in general, the probability of extreme events increases with the potential. Our approach is general and can be useful for studying several complex systems. PMID- 30011489 TI - Pulse wave velocity as a diagnostic index: The effect of wall thickness. AB - Vascular compliance is a major determinant of wave propagation within the vascular system, and hence the measurement of pulse wave velocity (PWV) is commonly used clinically as a method of detecting vascular stiffening. The accuracy of that assessment is important because vascular stiffening is a major risk factor for hypertension. PWV is usually measured by timing a pressure wave as it travels from the carotid artery to the femoral or radial artery and estimating the distance that it traveled in each case to obtain the required velocity. A major assumption on which this technique is based is that the vessel wall thickness h is negligibly small compared with the vessel radius a. The extent to which this assumption is satisfied in the cardiovascular system is not known because the ratio h/a varies widely across different regions of the vascular tree and under different pathological conditions. Using the PWV as a diagnostic test without knowing the effect of wall thickness on the measurement could lead to error when interpreting the PWV value as an index of vessel wall compliance. The aim of the present study was to extend the validity of the current practice of assessing wall stiffness by developing a method of analysis that goes beyond the assumption of a thin wall. We analyzed PWVs calculated with different wall models, depending on the ratio of wall thickness to vessel radius and the results showed that PWV is not reliable when it is estimated with the classic thin wall theory if the vessel wall is not around 25% of vessel radius. If the arterial wall is thicker than 25% of vessel radius, then the wave velocity calculated with the thin wall theory could be overestimated and in the clinical setting, this could lead to a false positive. For thicker walls, a thick wall model presented here should be considered to account for the stresses within the wall thickness that become dominant compared with the wall inertia. PMID- 30011490 TI - Wetting dynamics in two-liquid systems: Effect of the surrounding phase viscosity. AB - This paper reports the experimental results of a water droplet spreading on a glass substrate submerged in an oil phase. The radius of the wetted area grows exponentially over time forming two distinct regimes. The early time dynamics of wetting is characterized with the time exponent of 1, referred to as the viscous regime, which is ultimately transitioned to the Tanner's regime with the time exponent of 0.1. It is revealed that an increase in the ambient phase viscosity over three decades considerably slows down the rate of three-phase contact line movement. A scaling law is developed where the three-phase contact line velocity is a function of both spreading radius and mean viscosity, close to the geometric mean of the droplet and ambient fluids' viscosities. Using the proposed scaling and mean viscosity, all plots of spreading radius for different viscosity ratios collapse to a master curve. Furthermore, several cases with multiple rupture and spreading points, i.e., wetting in a nonideal system, are considered. The growth of an equivalent wetting radius in a multiple point spreading system is predicted by the developed scaling law. PMID- 30011491 TI - Diffusion-dominated mixing in moderate convergence implosions. AB - High-Z material mixed into the fuel degrades inertial fusion implosions and can prevent ignition. Mix is often assumed to be dominated by hydrodynamic instabilities, but we report Omega data, using shells with ~150nm deuterated layers to gain unprecedented resolution, which give strong evidence that the dominant mix mechanism is diffusion for these moderate temperature (?6 keV) and convergence (~12) implosions. Small-scale instability-driven or turbulent mix is negligible. PMID- 30011492 TI - Sinc noise for the Kardar-Parisi-Zhang equation. AB - In this paper we study the one-dimensional Kardar-Parisi-Zhang (KPZ) equation with correlated noise by field-theoretic dynamic renormalization-group techniques. We focus on spatially correlated noise where the correlations are characterized by a sinc profile in Fourier space with a certain correlation length xi. The influence of this correlation length on the dynamics of the KPZ equation is analyzed. It is found that its large-scale behavior is controlled by the standard KPZ fixed point, i.e., in this limit the KPZ system forced by sinc noise with arbitrarily large but finite correlation length xi behaves as if it were excited by pure white noise. A similar result has been found by Mathey et al. [S. Mathey et al., Phys. Rev. E 95, 032117 (2017)2470 004510.1103/PhysRevE.95.032117] for a spatial noise correlation of Gaussian type (~e^{-x^{2}/2xi^{2}}), using a different method. These two findings together suggest that the KPZ dynamics is universal with respect to the exact noise structure, provided the noise correlation length xi is finite. PMID- 30011493 TI - Renyi alpha entropies of quantum states in closed form: Gaussian states and a class of non-Gaussian states. AB - In this work, we study the Renyi alpha entropies S_{alpha}(rho[over ])=(1 alpha)^{-1}ln{Tr(rho[over ]^{alpha})} of quantum states for N bosons in the phase space representation. With the help of the Bopp rule, we derive the entropies of Gaussian states in closed form for positive integers alpha=2,3,4,? and then, with the help of the analytic continuation, acquire the closed form also for real values of alpha>0. The quantity S_{2}(rho[over ]), primarily studied in the literature, will then be a special case of our finding. Subsequently we acquire the Renyi alpha entropies, with positive integers alpha, in closed form also for a specific class of the non-Gaussian states (mixed states) for N bosons, which may be regarded as a generalization of the eigenstates |n> (pure states) of a single harmonic oscillator with n>=1, in which the Wigner functions have negative values indeed. Due to the fact that the dynamics of a system consisting of N oscillators is Gaussian, our result will contribute to a systematic study of the Renyi alpha entropy dynamics when the current form of a non-Gaussian state is initially prepared. PMID- 30011494 TI - Nested polyhedra model of isotropic magnetohydrodynamic turbulence. AB - A nested polyhedra model has been developed for magnetohydrodynamic turbulence. Driving only the velocity field at large scales with random, divergence-free forcing results in a clear, stationary k^{-5/3} spectrum for both kinetic and magnetic energies. Since the model naturally effaces disparate scale interactions, does not have a guide field, and avoids injecting any sign of helicity by random forcing, the resulting three-dimensional k spectrum is statistically isotropic. The strengths and weaknesses of the model are demonstrated by considering large or small magnetic Prandtl numbers. It was also observed that the timescale for the equipartition offset with those of the smallest scales shows a k^{-1/2} scaling. PMID- 30011495 TI - Tight-binding derivation of a discrete-continuous description of mechanochemical coupling in a molecular motor. AB - We present a tight-binding derivation of a discrete-continuous description of mechanochemical coupling in a molecular motor. Our derivation is based on the continuous diffusion equation for overdamped Brownian motion on a time independent tilted periodic potential in two dimensions. The free-energy potential is nonseparable to allow coupling between the chemical and mechanical degrees of freedom. We formally discretize the chemical coordinate by expanding in Wannier states that are localized along the chemical coordinate and parametrized along the mechanical coordinate. A discrete-continuous equation is derived that is valid for anisotropic systems with weak mechanochemical coupling and deep potential wells along the chemical coordinate. The discrete-continuous description is consistent with established theoretical models of molecular motors with discrete chemical states but is constrained by the underlying continuous two dimensional potential. In particular, we derive analytic expressions for the effective potential along the mechanical coordinate and for the rate of thermal hopping between chemical states. We determine the thermodynamic efficiency of energy conversion and find that, for a molecular motor with one chemical state per cycle, the derived discrete-continuous equation can accurately describe mechanochemical coupling but cannot describe energy conversion. PMID- 30011496 TI - Tristability between stripes, up-hexagons, and down-hexagons and snaking bifurcation branches of spatial connections between up- and down-hexagons. AB - Third-order amplitude equations on hexagonal lattices can be used for predicting the existence and stability of stripes, up-hexagons, and down-hexagons in pattern forming systems. These amplitude equations predict the nonexistence of bistable ranges between up- and down-hexagons and tristable ranges between stripes, up-, and down-hexagons. In the present work we use fifth-order amplitude equations for finding such bistable and tristable ranges for a generalized Swift-Hohenberg equation and discuss stationary front connections between up- and down-hexagons. PMID- 30011497 TI - Effect of interactions between multiple interfaces on the rheological characteristics of double emulsions. AB - In this study, we analyzed the rheological characteristics of double emulsions by using a three-dimensional lattice Boltzmann model. Numerical simulations indicate that interactions between multiple interfaces play a vital role in determining the shear stress on interfaces and affect deformations, which influence the relative viscosity of double emulsions. The large shear stress induced by droplets in contact increases the relative viscosity for high volume fractions. The double emulsions also show shear-thinning behavior, which corresponds with the Carreau model. The interfacial interference between the core and the deforming shell cause the relative viscosity to increase with increasing core droplet radius. Finally, we investigated the dependence of the double-emulsion viscosity on the core-droplet viscosity. At high shear rates, the relative viscosity increases with increasing core-droplet viscosity. However, the trend is opposite at low shear rates, which results from the high inward flow (Marangoni flow) at low core-droplet viscosity. PMID- 30011498 TI - Slow spin dynamics and self-sustained clusters in sparsely connected systems. AB - To identify emerging microscopic structures in low-temperature spin glasses, we study self-sustained clusters (SSC) in spin models defined on sparse random graphs. A message-passing algorithm is developed to determine the probability of individual spins to belong to SSC. We then compare the predicted SSC associations with the dynamical properties of spins obtained from numerical simulations and show that SSC association identifies individual slow-evolving spins. Studies of Erdos-Renyi (ER) and random regular (RR) graphs show that spins belonging to SSC are more stable with respect to spin-flip fluctuations, as suggested by the analysis of fully connected models. Further analyses show that SSC association outperforms local fields in predicting the spin dynamics, specifically the group of slow- and fast-evolving spins in RR graphs, for a wide temperature range close to the spin-glass transition. This insight gives rise to a powerful approach for predicting individual spin dynamics from a single snapshot of an equilibrium spin configuration, namely from limited static information. It also implies that single-sample SSC association carries more information than local fields in describing the state of individual spins, when little information can be extracted from the system's topology. PMID- 30011499 TI - Linear stability analysis of thermoviscous instability in immiscible displacement. AB - We study the thermoviscous fingering instability problem that develops when an injected fluid is displacing a fluid with different temperature and viscosity in a Hele-Shaw cell or porous medium. Using linear stability theory, we show how the thermal front caused by the different temperature of the injected fluid impacts the growth rate of instabilities on an immiscible radial displacement front. The immiscible front is stabilized by interfacial tension when the front radius is small but becomes unstable as the front radius grows larger. When the thermal front is unstable, it destabilizes the immiscible fluid front and makes instability possible at smaller front radii. When the thermal front is stable, it stabilizes the fluid front and delays the growth of instabilities. However, the thermal front has only a small impact on the maximum obtainable perturbation growth rates when the front radius is large. In porous medium flow we observe that a thermal front that lags further behind the fluid front is more effective at stabilizing the fluid front. PMID- 30011500 TI - Inverse finite-size scaling for high-dimensional significance analysis. AB - We propose an efficient procedure for significance determination in high dimensional dependence learning based on surrogate data testing, termed inverse finite-size scaling (IFSS). The IFSS method is based on our discovery of a universal scaling property of random matrices which enables inference about signal behavior from much smaller scale surrogate data than the dimensionality of the original data. As a motivating example, we demonstrate the procedure for ultra-high-dimensional Potts models with order of 10^{10} parameters. IFSS reduces the computational effort of the data-testing procedure by several orders of magnitude, making it very efficient for practical purposes. This approach thus holds considerable potential for generalization to other types of complex models. PMID- 30011502 TI - Pair correlation functions for identifying spatial correlation in discrete domains. AB - Identifying and quantifying spatial correlation are important aspects of studying the collective behavior of multiagent systems. Pair correlation functions (PCFs) are powerful statistical tools that can provide qualitative and quantitative information about correlation between pairs of agents. Despite the numerous PCFs defined for off-lattice domains, only a few recent studies have considered a PCF for discrete domains. Our work extends the study of spatial correlation in discrete domains by defining a new set of PCFs using two natural and intuitive definitions of distance for a square lattice: the taxicab and uniform metric. We show how these PCFs improve upon previous attempts and compare between the quantitative data acquired. We also extend our definitions of the PCF to other types of regular tessellation that have not been studied before, including hexagonal, triangular, and cuboidal. Finally, we provide a comprehensive PCF for any tessellation and metric, allowing investigation of spatial correlation in irregular lattices for which recognizing correlation is less intuitive. PMID- 30011501 TI - Entropic bounds on currents in Langevin systems. AB - We derive a bound on generalized currents for Langevin systems in terms of the total entropy production in the system and its environment. For overdamped dynamics, any generalized current is bounded by the total rate of entropy production. We show that this entropic bound on the magnitude of generalized currents imposes power-efficiency tradeoff relations for ratchets in contact with a heat bath: Maximum efficiency-Carnot efficiency for a Smoluchowski-Feynman ratchet and unity for a flashing or rocking ratchet-can only be reached at vanishing power output. For underdamped dynamics, while there may be reversible currents that are not bounded by the entropy production rate, we show that the output power and heat absorption rate are irreversible currents and thus obey the same bound. As a consequence, a power-efficiency tradeoff relation holds not only for underdamped ratchets but also for periodically driven heat engines. For weak driving, the bound results in additional constraints on the Onsager matrix beyond those imposed by the second law. Finally, we discuss the connection between heat and entropy in a nonthermal situation where the friction and noise intensity are state dependent. PMID- 30011503 TI - Role of quantum coherence in the thermodynamics of energy transfer. AB - Recent research on the thermodynamic arrow of time, at the microscopic scale, has questioned the universality of its direction. Theoretical studies showed that quantum correlations can be used to revert the natural heat flow (from the hot body to the cold one), posing an apparent challenge to the second law of thermodynamics. Such an "anomalous" heat current was observed in a recent experiment (K. Micadei et al., arXiv:1711.03323), by employing two spin systems initially quantum correlated. Nevertheless, the precise relationship between this intriguing phenomenon and the initial conditions that allow it is not fully evident. Here, we address energy transfer in a wider perspective, identifying a nonclassical contribution that applies to the reversion of the heat flow as well as to more general forms of energy exchange. We derive three theorems that describe the energy transfer between two microscopic systems, for arbitrary initial bipartite states. Using these theorems, we obtain an analytical bound showing that certain type of quantum coherence can optimize such a process, outperforming incoherent states. This genuine quantum advantage is corroborated through a characterization of the energy transfer between two qubits. For this system, it is shown that a large enough amount of coherence is necessary and sufficient to revert the thermodynamic arrow of time. As a second crucial consequence of the presented theorems, we introduce a class of nonequilibrium states that only allow unidirectional energy flow. In this way, we broaden the set where the standard Clausius statement of the second law applies. PMID- 30011504 TI - Intermittency between avalanche regimes on grain piles. AB - We experimentally investigate discrete avalanches of grains, driven by a low inflow rate, on an erodible pile in a channel. We observe intermittency between one regime, in which avalanches are quasiperiodic and system spanning, and another, in which they pass at irregular intervals and have a power-law size distribution. Observations are robust to changes of inflow rate and grain type and require no tuning of external parameters. We demonstrate that the state of the pile's surface determines whether avalanche fronts propagate to the end of the channel or stop partway down, and we introduce a toy model for the latter case that reproduces the observed power-law size distribution. We suggest direct applications to avalanches of pharmaceutical and geophysical grains, and the possibility of reconciling the "self-organized criticality" predicted by several authors with the hysteretic behavior described by others. PMID- 30011505 TI - Beating effects of vector solitons in Bose-Einstein condensates. AB - We study the beating effects of solitons in multicomponent coupled Bose-Einstein condensate systems. Our analysis indicates that the period of beating behavior is determined by the energy eigenvalue difference in the effective quantum well induced by solitons, and the beating pattern is determined by the eigenstates of a quantum well, which are involved in the beating behavior. We show that the beating solitons correspond to linear superpositions of eigenstates in some quantum wells, and the correspondence relations are identical for solitons in both an attractive interaction and a repulsive interaction condensate. This provides a possible way to understand the beating effects of solitons for attractive and repulsive interaction cases in a unified way, based on the knowledge of quantum eigenstates. Moreover, our results demonstrate many different beating patterns for solitons in multicomponent coupled condensates, in sharp contrast to the beating dark soliton reported before. The beating behavior can be used to test the eigenvalue differences in certain quantum wells, and more abundant beating patterns are expected to exist in more component-coupled systems. PMID- 30011506 TI - Energy conservation and H theorem for the Enskog-Vlasov equation. AB - The Enskog-Vlasov (EV) equation is a widely used semiphenomenological model of gas-liquid phase transitions. We show that it does not generally conserve energy, although there exists a restriction on its coefficients for which it does. Furthermore, if an energy-preserving version of the EV equation satisfies an H theorem as well, it can be used to rigorously derive the so-called Maxwell construction which determines the parameters of liquid-vapor equilibria. Finally, we show that the EV model provides an accurate description of the thermodynamics of noble fluids, and there exists a version simple enough for use in applications. PMID- 30011507 TI - Stokes-Einstein relation of the liquid metal rubidium and its relationship to changes in the microscopic dynamics with increasing temperature. AB - For liquid rubidium the Stokes-Einstein (SE) relation is well fulfilled near the melting point with an effective hydrodynamic diameter, which agrees well with a value from structural investigations. A wealth of thermodynamic and microscopic data exists for a wide range of temperatures for liquid rubidium and hence it represents a good test bed to challenge the SE relation with rising temperature from an experimental point of view. We performed classical molecular dynamics simulations to complement the existing experimental data using a pseudopotential, which describes perfectly the structure and dynamics of liquid rubidium. The derived SE relation from combining experimental shear viscosity data with simulated diffusion coefficients reveals a weak violation at about 1.3T_{melting}~400 K. The microscopic relaxation dynamics on nearest neighbor distances from neutron spectroscopy demonstrate distinct changes in the amplitude with rising temperature. The derived average relaxation time for density fluctuations on this length scale shows a non-Arrhenius behavior, with a slope change around 1.5T_{melting}~450 K. Combining the simulated macroscopic self diffusion coefficient with that microscopic average relaxation time, a distinct violation of the SE relation in the same temperature range can be demonstrated. One can conclude that the changes in the collective dynamics, a mirror of the correlated movements of the particles, are at the origin for the violation of the SE relation. The changes in the dynamics can be understood as a transition from a more viscous liquid metal to a more fluid-like liquid above the crossover temperature range of 1.3-1.5 T_{melting}. The decay of the amplitude of density fluctuations in liquid aluminium, lead, and rubidium demonstrates a remarkable agreement and points to a universal thermal crossover in the dynamics of liquid metals. PMID- 30011508 TI - Production of photoionized plasmas in the laboratory with x-ray line radiation. AB - In this paper we report the experimental implementation of a theoretically proposed technique for creating a photoionized plasma in the laboratory using x ray line radiation. Using a Sn laser plasma to irradiate an Ar gas target, the photoionization parameter, xi=4piF/N_{e}, reached values of order 50ergcms^{-1}, where F is the radiation flux in ergcm^{-2}s^{-1}. The significance of this is that this technique allows us to mimic effective spectral radiation temperatures in excess of 1 keV. We show that our plasma starts to be collisionally dominated before the peak of the x-ray drive. However, the technique is extendable to higher-energy laser systems to create plasmas with parameters relevant to benchmarking codes used to model astrophysical objects. PMID- 30011509 TI - Internal waves in sheared flows: Lower bound of the vorticity growth and propagation discontinuities in the parameter space. AB - This study provides sufficient conditions for the temporal monotonic decay of enstrophy for two-dimensional perturbations traveling in the incompressible, viscous, plane Poiseuille, and Couette flows. Extension of Synge's procedure [J. L. Synge, Proc. Fifth Int. Congress Appl. Mech. 2, 326 (1938); Semicentenn. Publ. Am. Math. Soc. 2, 227 (1938)] to the initial-value problem allow us to find the region of the wave-number-Reynolds-number map where the enstrophy of any initial disturbance cannot grow. This region is wider than that of the kinetic energy. We also show that the parameter space is split into two regions with clearly distinct propagation and dispersion properties. PMID- 30011510 TI - Anomalous bulk behavior in the free parafermion Z(N) spin chain. AB - We demonstrate using direct numerical diagonalization and extrapolation methods that boundary conditions have a profound effect on the bulk properties of a simple Z(N) model for N>=3 for which the model Hamiltonian is non-Hermitian. For N=2 the model reduces to the well-known quantum Ising model in a transverse field. For open boundary conditions, the Z(N) model is known to be solved exactly in terms of free parafermions. Once the ends of the open chain are connected by considering the model on a ring, the bulk properties, including the ground-state energy per site, are seen to differ dramatically with increasing N. Other properties, such as the leading finite-size corrections to the ground-state energy, the mass gap exponent, and the specific-heat exponent, are also seen to be dependent on the boundary conditions. We speculate that this anomalous bulk behavior is a topological effect. PMID- 30011511 TI - Enhanced polymer capture speed and extended translocation time in pressure solvation traps. AB - The efficiency of nanopore-based biosequencing techniques requires fast anionic polymer capture by like-charged pores followed by a prolonged translocation process. We show that this condition can be achieved by setting a pressure solvation trap. Polyvalent cation addition to the KCl solution triggers the like charge polymer-pore attraction. The attraction speeds-up the pressure-driven polymer capture but also traps the molecule at the pore exit, reducing the polymer capture time and extending the polymer escape time by several orders of magnitude. By direct comparison with translocation experiments [D. P. Hoogerheide et al., ACS Nano 8, 7384 (2014)1936-085110.1021/nn5025829], we characterize as well the electrohydrodynamics of polymers transport in pressure-voltage traps. We derive scaling laws that can accurately reproduce the pressure dependence of the experimentally measured polymer translocation velocity and time. We also find that during polymer capture, the electrostatic barrier on the translocating molecule slows down the liquid flow. This prediction identifies the streaming current measurement as a potential way to probe electrostatic polymer-pore interactions. PMID- 30011512 TI - Snakes and ghosts in a parity-time-symmetric chain of dimers. AB - We consider linearly coupled discrete nonlinear Schrodinger equations with gain and loss terms and with a cubic-quintic nonlinearity. The system models a parity time (PT)-symmetric coupler composed by a chain of dimers. We study uniform states and site-centered and bond-centered spatially localized solutions and present that each solution has a symmetric and antisymmetric configuration between the arms. The symmetric solutions can become unstable due to bifurcations of asymmetric ones, that are called ghost states, because they exist only when an otherwise real propagation constant is taken to be complex valued. When a parameter is varied, the resulting bifurcation diagrams for the existence of standing localized solutions have a snaking behavior. The critical gain and loss coefficient above which the PT symmetry is broken corresponds to the condition when bifurcation diagrams of symmetric and antisymmetric states merge. Past the symmetry breaking, the system no longer has time-independent states. Nevertheless, equilibrium solutions can be analytically continued by defining a dual equation that leads to ghost states associated with growth or decay, that are also identified and examined here. We show that ghost localized states also exhibit snaking bifurcation diagrams. We analyze the width of the snaking region and provide asymptotic approximations in the limit of strong and weak coupling where good agreement is obtained. PMID- 30011514 TI - Autocorrelation of the susceptible-infected-susceptible process on networks. AB - In this paper, we focus on the autocorrelation of the susceptible-infected susceptible (SIS) process on networks. The N-intertwined mean-field approximation (NIMFA) is applied to calculate the autocorrelation properties of the exact SIS process. We derive the autocorrelation of the infection state of each node and the fraction of infected nodes both in the steady and transient states as functions of the infection probabilities of nodes. Moreover, we show that the autocorrelation can be used to estimate the infection and curing rates of the SIS process. The theoretical results are compared with the simulation of the exact SIS process. Our work fully utilizes the potential of the mean-field method and shows that NIMFA can indeed capture the autocorrelation properties of the exact SIS process. PMID- 30011513 TI - Motile bacteria in a critical fluid mixture. AB - We studied the swimming of Escherichia coli bacteria in the vicinity of the critical point in a solution of the nonionic surfactant C_{12}E_{5} in buffer solution. In phase-contrast microscopy, each swimming cell produces a transient trail behind itself lasting several seconds. Comparing quantitative image analysis with simulations show that these trails are due to local phase reorganization triggered by differential adsorption. This contrasts with similar trails seen in bacteria swimming in liquid crystals, which are due to shear effects. We show how our trails are controlled, and use them to probe the structure and dynamics of critical fluctuations in the fluid medium. PMID- 30011515 TI - Hierarchical block model for earthquakes. AB - The presented model for earthquakes is based on two fundamental principles: the hierarchical structure of seismic areas and the concept of self-organized criticality. The model reproduces the basic empirical properties of seismic processes: the frequency-energy scaling relation (the Gutenberg-Richter law), the generalized Omori law for temporal decay of aftershocks, the aftershock productivity law, the fractal distributions of hypocenters (epicenters) with power-law dependencies of the number of events on distances between hypocenters (epicenters), and, finally, the gamma distribution for waiting times. In the model, the threshold energies depend on the block sizes and are distributed according to the Gauss law. After strong earthquakes they are redistributed at the decreasing average values. The change of threshold energies leads to the triggering of aftershock series. PMID- 30011516 TI - Nonequilibrium limit-cycle oscillators: Fluctuations in hair bundle dynamics. AB - We develop a framework for the general interpretation of the stochastic dynamical system near a limit cycle. Such quasiperiodic dynamics are commonly found in a variety of nonequilibrium systems, including the spontaneous oscillations of hair cells of the inner ear. We demonstrate quite generally that in the presence of noise, the phase of the limit cycle oscillator will diffuse, while deviations in the directions locally orthogonal to that limit cycle will display the Lorentzian power spectrum of a damped oscillator. We identify two mechanisms by which these stochastic dynamics can acquire a complex frequency dependence and discuss the deformation of the mean limit cycle as a function of temperature. The theoretical ideas are applied to data obtained from spontaneously oscillating hair cells of the amphibian sacculus. PMID- 30011517 TI - Strong disorder leads to scale invariance in complex biological systems. AB - Despite the innate complexity of the cell, emergent scale-invariant behavior is observed in many biological systems. We investigate one example of this phenomenon: the dynamics of large complexes in the bacterial cytoplasm. The observed dynamics of these complexes is scale invariant in three measures of dynamics: mean-squared displacement (MSD), velocity autocorrelation function, and the step-size distribution. To investigate the physical mechanism for this emergent scale invariance, we explore minimal models in which mobility is modeled as diffusion on a rough free-energy landscape in one dimension. We discover that all three scale-invariant characteristics emerge generically in the strong disorder limit. (Strong disorder is defined by the divergence of the ensemble averaged hop time between lattice sites.) In particular, we demonstrate how the scale invariance of the relative step-size distribution can be understood from the perspective of extreme-value theory in statistics (EVT). We show that the Gumbel scale parameter is simply related to the MSD scaling parameter. The EVT mechanism of scale invariance is expected to be generic to strongly disordered systems and therefore a powerful tool for the analysis of other systems in biology and beyond. PMID- 30011518 TI - Cross-stream migration of drops suspended in Poiseuille flow in the presence of an electric field. AB - The present study focuses on the cross-stream migration of a neutrally buoyant two-dimensional drop in a Poiseuille flow in a channel under the influence of an electric field. In the absence of an electric field, the important nondimensional parameters describing this problem are the viscosity ratio (lambda) between the drop fluid and the surrounding medium, the ratio of drop diameter to channel height (a^{*}), and the capillary number (Ca). The influence of all these parameters on drop migration is investigated. It is observed that a large drop moves slowly as compared to a smaller drop, but attains a steady shape at the center line of the channel. The increase in value of the capillary number enhances the cross-stream migration rate, while the increase in viscosity ratio reduces the tendency of the drops to move towards the channel center line. The presence of an electric field introduces additional interfacial stresses at the drop interface, which in turn alters the dynamics observed in the absence of an electric field. Extensive computations are carried out to analyze the combined effect of the electric field and the shear flow on the cross-stream migration of the drop. The computational results for a perfect dielectric indicate that the droplet migration enhances in the presence of an electric field. The permittivity ratio (S) and the electric field strength (E) play major roles in drop migration and deformation. Computations using the leaky dielectric model also show that for certain combinations of electrical properties the drop undergoes immense elongation along the direction of the electric field. The conductivity ratio (R) is again a vital parameter in such a system of fluids. It is further observed that for certain conditions the leaky dielectric drops exhibit rotation together with translation. PMID- 30011519 TI - Dragon-king-like extreme events in coupled bursting neurons. AB - We present evidence of extreme events in two Hindmarsh-Rose (HR) bursting neurons mutually interacting via two different coupling configurations: chemical synaptic and gap junctional-type diffusive coupling. A dragon-king-like probability distribution of the extreme events is seen for combinations of synaptic coupling where small- to medium-size events obey a power law and the larger events that cross an extreme limit are outliers. The extreme events originate due to instability in antiphase synchronization of the coupled systems via two different routes, intermittency and quasiperiodicity routes to complex dynamics for purely excitatory and inhibitory chemical synaptic coupling, respectively. For a mixed type of inhibitory and excitatory chemical synaptic interactions, the intermittency route to extreme events is only seen. Extreme events with our suggested distribution is also seen for gap junctional-type diffusive, but repulsive, coupling where the intermittency route to complexity is found. A simple electronic experiment using two diffusively coupled analog circuits of the HR neuron model, but interacting in a repulsive way, confirms occurrence of the dragon-king-like extreme events. PMID- 30011520 TI - Quantum correlations for a simple kicked system with mixed phase space. AB - We investigate both the classical and quantum dynamics for a simple kicked system (the standard map) that classically has mixed phase space. For initial conditions in a portion of the chaotic region that is close enough to the regular region, the phenomenon of sticking leads to a power-law decay with time of the classical correlation function of a simple observable. Quantum mechanically, we find the same behavior, but with a smaller exponent. We consider various possible explanations of this phenomenon, and settle on a modification of the Meiss-Ott Markov tree model that takes into account quantum limitations on the flux through a turnstile between regions corresponding to states on the tree. Further work is needed to better understand the quantum behavior. PMID- 30011521 TI - Low-frequency discrete breathers in long-range systems without on-site potential. AB - A mechanism of long-range couplings is proposed to realize low-frequency discrete breathers without on-site potentials. The realization of such discrete breathers requires a gap below the band of linear eigenfrequencies. Under the periodic boundary condition of a one-dimensional lattice and the limit of large population, we show theoretically that the long-range couplings universally open the gap below the band irrespective of the coupling functions, while the short range couplings cannot. The existence of the low-frequency discrete breathers, spatial localization, and stability are numerically analyzed from long range to short range. PMID- 30011522 TI - Entrainment of a cellular circadian oscillator by light in the presence of molecular noise. AB - In this paper, we consider a stochastic molecular circadian oscillator described by a sequence of biological reactions and its deterministic kinetics governed by a system of ordinary differential equations in the limit of large numbers of molecules. The oscillations in the model are generated by negative feedback regulation of a gene. The focus of this paper is the entrainment of the oscillator by a periodic light signal that affects the maximal transcription rate of the gene. We introduce two scalings of the model parameters that provide independent control over the natural frequency of the oscillator and the relative noise level. We study entrainment in two ways: by visualizing the stochastic limit cycle in various projections of the discrete phase space of the system and by evaluating the maximum of the normalized cross correlation of the light signal with the number of protein molecules in the cell. The visualization method ignores the phase of the oscillator, and we find in this way that entrainment has a subtle organizing effect on the limit cycle as a whole. The cross correlation results reveal an interval of natural frequencies of the oscillator surrounding the frequency of the light signal within which maximal entrainment occurs with rather sharp drops in entrainment at the edges of this interval. The width of the interval of maximal entrainment increases with the amplitude of the light signal. These statements are applicable both to the stochastic oscillator and to its deterministic limit, but the results are most clear-cut in the deterministic case and degrade from there as the relative noise level increases. PMID- 30011523 TI - Dynamic topologies of activity-driven temporal networks with memory. AB - We propose dynamic scaling in temporal networks with heterogeneous activities and memory and provide a comprehensive picture for the dynamic topologies of such networks, in terms of the modified activity-driven network model [H. Kim et al., Eur. Phys. J. B 88, 315 (2015)EPJBFY1434-602810.1140/epjb/e2015-60662-7]. Particularly, we focus on the interplay of the time resolution and memory in dynamic topologies. Through the random-walk (RW) process, we investigate diffusion properties and topological changes as the time resolution increases. Our results with memory are compared to those of the memoryless case. Based on the temporal percolation concept, we derive scaling exponents in the dynamics of the largest cluster and the coverage of the RW process in time-varying networks. We find that the time resolution in the time-accumulated network determines the effective size of the network, while memory affects relevant scaling properties at the crossover from the dynamic regime to the static one. The origin of memory dependent scaling behaviors is the dynamics of the largest cluster, which depends on temporal degree distributions. Finally, we conjecture of the extended finite size scaling ansatz for dynamic topologies and the fundamental property of temporal networks, which are numerically confirmed. PMID- 30011524 TI - Generalized Langevin equation and fluctuation-dissipation theorem for particle bath systems in external oscillating fields. AB - The generalized Langevin equation (GLE) can be derived from a particle-bath Hamiltonian, in both classical and quantum dynamics, and provides a route to the (both Markovian and non-Markovian) fluctuation-dissipation theorem (FDT). All previous studies have focused either on particle-bath systems with time independent external forces only, or on the simplified case where only the tagged particle is subject to the external time-dependent oscillatory field. Here we extend the GLE and the corresponding FDT for the more general case where both the tagged particle and the bath oscillators respond to an external oscillatory field. This is the example of a charged or polarizable particle immersed in a bath of other particles that are also charged or polarizable, under an external ac electric field. For this Hamiltonian, we find that the ensemble average of the stochastic force is not zero, but proportional to the ac field. The associated FDT reads as =mk_{B}Tnu(t-t^{'})+(gammae)^{2}E(t)E(t^{'}), where F_{p} is the random force, nu(t-t^{'}) is the friction memory function, and gamma is a numerical prefactor. PMID- 30011525 TI - Large deviations of convex hulls of self-avoiding random walks. AB - A global picture of a random particle movement is given by the convex hull of the visited points. We obtained numerically the probability distributions of the volume and surface of the convex hulls of a selection of three types of self avoiding random walks, namely, the classical self-avoiding walk, the smart kinetic self-avoiding walk, and the loop-erased random walk. To obtain a comprehensive description of the measured random quantities, we applied sophisticated large-deviation techniques, which allowed us to obtain the distributions over a large range of support down to probabilities far smaller than P=10^{-100}. We give an approximate closed form of the so-called large deviation rate function Phi which generalizes above the upper critical dimension to the previously studied case of the standard random walk. Further, we show correlations between the two observables also in the limits of atypical large or small values. PMID- 30011526 TI - Topological changes of wave functions associated with Hamiltonian monodromy. AB - Almost everything that happens in classical mechanics also shows up in quantum mechanics when we know where to look for it. A phenomenon in classical mechanics involves topological changes in action-angle loops as a result of passage around a "monodromy circuit." This phenomenon is known by the short name "Hamiltonian monodromy" (or, more ponderously, "nontrivial monodromy of action and angle variables in integrable Hamiltonian systems"). In this paper, we show a corresponding change in quantum wave functions: These wave functions change their topological structure in the same way that the corresponding classical action angle loops change. PMID- 30011527 TI - Asymmetry in indegree and outdegree distributions of gene regulatory networks arising from dynamical robustness. AB - Although outdegree distributions of gene regulatory networks have scale-free characteristics similar to other biological networks, indegree distributions have single-scale characteristics with significantly lower variance than that of outdegree distributions. In this study, we mathematically explain that such asymmetric characteristics arise from dynamical robustness, which is the property of maintaining an equilibrium state of gene expressions against inevitable perturbations to the networks, such as gene dysfunction and mutation of promoters. We reveal that the expression of a single gene is robust to a perturbation for a large number of inputs and a small number of outputs. Applying these results to the networks, we also show that an equilibrium state of the networks is robust if the variance of the indegree distribution is low (i.e., single-scale characteristics) and that of the outdegree distribution is high (i.e., scale-free characteristics). These asymmetric characteristics are conserved across a wide range of species, from bacteria to humans. PMID- 30011528 TI - Correlations between synapses in pairs of neurons slow down dynamics in randomly connected neural networks. AB - Networks of randomly connected neurons are among the most popular models in theoretical neuroscience. The connectivity between neurons in the cortex is however not fully random, the simplest and most prominent deviation from randomness found in experimental data being the overrepresentation of bidirectional connections among pyramidal cells. Using numerical and analytical methods, we investigate the effects of partially symmetric connectivity on the dynamics in networks of rate units. We consider the two dynamical regimes exhibited by random neural networks: the weak-coupling regime, where the firing activity decays to a single fixed point unless the network is stimulated, and the strong-coupling or chaotic regime, characterized by internally generated fluctuating firing rates. In the weak-coupling regime, we compute analytically, for an arbitrary degree of symmetry, the autocorrelation of network activity in the presence of external noise. In the chaotic regime, we perform simulations to determine the timescale of the intrinsic fluctuations. In both cases, symmetry increases the characteristic asymptotic decay time of the autocorrelation function and therefore slows down the dynamics in the network. PMID- 30011529 TI - Analytic model of thermalization: Quantum emulation of classical cellular automata. AB - We introduce a method of quantum emulation of a classical reversible cellular automaton. By applying this method to a chaotic cellular automaton, the obtained quantum many-body system thermalizes while all the energy eigenstates and eigenvalues are solvable. These explicit solutions allow us to verify the validity of some scenarios of thermalization to this system. We find that two leading scenarios, the eigenstate thermalization hypothesis scenario and the large effective dimension scenario, do not explain thermalization in this model. PMID- 30011530 TI - Accuracy optimization of combined multiparameter measuring systems with application to polarized light microscopy. AB - We study the accuracy of combined multiparameter measuring systems (CMPMSs) that determine several unknown quantities from measurements of a single variable at different preprogrammed conditions determined by control parameters. To reduce inaccuracies of determined quantities, we propose a mathematical method for selection of control parameters that are optimal for all possible values of determined quantities. Using the submultiplicativity of the spectral and Frobenius matrix norms, we construct the upper bound of the error function and determine the set of control parameters by minimizing this bound. To demonstrate the capability of our method for CMPMSs, we apply it to the polarized light microscopy technique called LC-PolScope, which is used for determining inhomogeneous two-dimensional fields of optical retardation and orientation of the slow optic axis in thin organic and inorganic samples. We compare the computed set of control parameters with other sets, including the one used in the PolScope, and demonstrate that our choice of control parameters works very well even though it does not take into account any specific features of the PolScope. We expect that our method will be successful in various CMPMSs, as it is applicable to any error distribution of the control parameters and measured values. PMID- 30011531 TI - Creeplike behavior in athermal threshold dynamics: Effects of disorder and stress. AB - We study the dynamical aspects of a statistical-mechanical model for fracture of heterogeneous media: the fiber bundle model with various interaction ranges. Although the model does not include any nontrivial elementary processes such as nonlinear rheology or stochasticity, the system exhibits creeplike behaviors under a constant load being slightly above the critical value. These creeplike behaviors comprise three stages: primary, secondary, and tertiary. In the primary and tertiary stages, the strain rate exhibits power-law behaviors with time, which are well described by the Omori-Utsu and the inverse Omori laws, respectively, although the exponents are larger than those typically observed in experiments. A characteristic time that defines the onset of power-law behavior in the Omori-Utsu law is found to decrease with the strength of disorder in the system. The analytical solution, which agrees with the above numerical results, is obtained for the mean-field limit. Beyond the mean-field limit, the exponent for the Omori-Utsu law tends to be even larger but decreases with the disorder in the system. Increasing the spatial range of interactions, this exponent is found to be independent of disorder and to converge to the mean-field value. In contrast, the inverse Omori law remains independent of the spatial range of interaction and the disorder strength. PMID- 30011532 TI - Nonequilibrium phase transitions of sheared colloidal microphases: Results from dynamical density functional theory. AB - By means of classical density functional theory and its dynamical extension, we consider a colloidal fluid with spherically symmetric competing interactions, which are well known to exhibit a rich bulk phase behavior. This includes complex three-dimensional periodically ordered cluster phases such as lamellae, two dimensional hexagonally packed cylinders, gyroid structures, or spherical micelles. While the bulk phase behavior has been studied extensively in earlier work, in this paper we focus on such structures confined between planar repulsive walls under shear flow. For sufficiently high shear rates, we observe that microphase separation can become fully suppressed. For lower shear rates, however, we find that, e.g., the gyroid structure undergoes a kinetic phase transition to a hexagonally packed cylindrical phase, which is found experimentally and theoretically in amphiphilic block copolymer systems. As such, besides the known similarities between the latter and colloidal systems regarding the equilibrium phase behavior, our work reveals further intriguing nonequilibrium relations between copolymer melts and colloidal fluids with competing interactions. PMID- 30011533 TI - Glassy dynamics in disordered oscillator chains. AB - The escape of energy injected into one site in a disordered chain of nonlinear oscillators is examined numerically. When the disorder has a "fractal" pattern, the decay of the residual energy at the injection site can be fit to a stretched exponential with an exponent that varies continuously with the control parameter. At low temperature, we see evidence that energy can be trapped for an infinite time at the original site, i.e., classical many body localization. PMID- 30011535 TI - Direct test of the Gaussian auxiliary field ansatz in nonconserved order parameter phase ordering dynamics. AB - The assumption that the local order parameter is related to an underlying spatially smooth auxiliary field, u(r[over ?],t), is a common feature in theoretical approaches to non-conserved order parameter phase separation dynamics. In particular, the ansatz that u(r[over ?],t) is a Gaussian random field leads to predictions for the decay of the autocorrelation function which are consistent with observations, but distinct from predictions using alternative theoretical approaches. In this paper, the auxiliary field is obtained directly from simulations of the time-dependent Ginzburg-Landau equation in two and three dimensions. The results show that u(r[over ?],t) is equivalent to the distance to the nearest interface. In two dimensions, the probability distribution, P(u), is well approximated as Gaussian except for small values of u/L(t), where L(t) is the characteristic length-scale of the patterns. The behavior of P(u) in three dimensions is more complicated; the non-Gaussian region for small u/L(t) is much larger than that in two dimensions but the tails of P(u) begin to approach a Gaussian form at intermediate times. However, at later times, the tails of the probability distribution appear to decay faster than a Gaussian distribution. PMID- 30011534 TI - Isochoric structural recovery in molecular glasses and its analog in colloidal glasses. AB - Concentrated colloidal dispersions have been regarded as models for molecular glasses. One of the many ways to compare the behavior in these two different systems is by comparing the structural recovery or the physical aging behavior. However, recent investigations from our group to examine structural recovery in thermosensitive colloidal dispersions have shown contrasting results between the colloidal and the molecular glasses. The differences in the behaviors of the two systems have led us to pose this question: Is structural recovery behavior in colloidal glasses truly distinct from that of molecular glasses or is the conventional experimental condition (isobaric temperature-jumps) in determining the structural recovery in molecular glasses different from the experimental condition in the colloidal experiments (concentration- or volume fraction-jumps); i.e., are colloidal glasses inherently different from molecular glasses or not? To address the question, we resort to model calculations of structural recovery in a molecular glass under constant volume (isochoric) conditions following temperature only- and simultaneous volume- and temperature-jumps, which are closer to the volume fraction-jump conditions used in the thermosensitive colloidal experiments. The current model predictions are then compared with the signatures of structural recovery under the conventional isobaric state in a molecular glass and with structural recovery behavior in colloidal glasses following volume fraction-jumps. We show that the results obtained from the experiments conducted by our group were contrasting to classical molecular glass behavior because the basis of our comparisons were incorrect (the histories were not analogous). The present calculations (with analogous histories) are qualitatively closer to the colloidal behavior. The signatures of "intrinsic isotherms" and "asymmetry of approach" in the current isochoric model predictions are quite different from those in the classical isobaric conditions while the "memory" signatures remain essentially the same. While there are qualitative similarities between the current isochoric model predictions and results from colloidal glasses, it appears from the calculations that the origins of these are different. The isochoric histories in the molecular glasses have compensating effects of pressure and departure from equilibrium which determines the structure dependence on mobility of the molecules. On the other hand, in the colloids it simply appears that the volume fraction-jump conditions simply do not exhibit such structure mobility dependence. The determining interplay of thermodynamic phase variables in colloidal and molecular systems might be very different or at least their correlations are yet to be ascertained. This topic requires further investigation to bring the similarities and differences between molecular and colloidal glass formers into fuller clarity. PMID- 30011536 TI - Anesthesia modifies subthreshold critical slowing down in a stochastic Hodgkin Huxley-like model with inhibitory synaptic input. AB - The dynamics of a stochastic type-I Hodgkin-Huxley-like point neuron model exposed to inhibitory synaptic noise are investigated as a function of distance from spiking threshold and the inhibitory influence of the general anesthetic agent propofol. The model is biologically motivated and includes the effects of intrinsic ion-channel noise via a stochastic differential equation description as well as inhibitory synaptic noise modeled as multiple Poisson-distributed impulse trains with saturating response functions. The effect of propofol on these synapses is incorporated through this drug's principal influence on fast inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA) type-A receptors via reduction of the synaptic response decay rate. As the neuron model approaches spiking threshold from below, we track membrane voltage fluctuation statistics of numerically simulated stochastic trajectories. We find that for a given distance from spiking threshold, increasing the magnitude of anesthetic induced inhibition is associated with augmented signatures of critical slowing: fluctuation amplitudes and correlation times grow as spectral power is increasingly focused at 0 Hz. Furthermore, as a function of distance from threshold, anesthesia significantly modifies the power-law exponents for variance and correlation time divergences observable in stochastic trajectories. Compared to the inverse square root power-law scaling of these quantities anticipated for the saddle-node bifurcation of type-I neurons in the absence of anesthesia, increasing anesthetic-induced inhibition results in an observable exponent <-0.5 for variance and >-0.5 for correlation time divergences. However, these behaviors eventually break down as distance from threshold goes to zero with both the variance and correlation time converging to common values independent of anesthesia. Compared to the case of no synaptic input, linearization of an approximating multivariate Ornstein-Uhlenbeck model reveals these effects to be the consequence of an additional slow eigenvalue associated with synaptic activity that competes with those of the underlying point neuron in a manner that depends on distance from spiking threshold. PMID- 30011537 TI - Revealing in-block nestedness: Detection and benchmarking. AB - As new instances of nested organization-beyond ecological networks-are discovered, scholars are debating the coexistence of two apparently incompatible macroscale architectures: nestedness and modularity. The discussion is far from being solved, mainly for two reasons. First, nestedness and modularity appear to emerge from two contradictory dynamics, cooperation and competition. Second, existing methods to assess the presence of nestedness and modularity are flawed when it comes to the evaluation of concurrently nested and modular structures. In this work, we tackle the latter problem, presenting the concept of in-block nestedness, a structural property determining to what extent a network is composed of blocks whose internal connectivity exhibits nestedness. We then put forward a set of optimization methods that allow us to identify such organization successfully, in synthetic and in a large number of real networks. These findings challenge our understanding of the topology of ecological and social systems, calling for new models to explain how such patterns emerge. PMID- 30011538 TI - Characteristic functions of quantum heat with baths at different temperatures. AB - This paper is about quantum heat defined as the change in energy of a bath during a process. The presentation takes into account recent developments in classical strong-coupling thermodynamics and addresses a version of quantum heat that satisfies quantum-classical correspondence. The characteristic function and the full counting statistics of quantum heat are shown to be formally similar. The paper further shows that the method can be extended to more than one bath, e.g., two baths at different temperatures, which opens up the prospect of studying correlations and heat flow. The paper extends earlier results on the expected quantum heat in the setting of one bath [E. Aurell and R. Eichhorn, New J. Phys. 17, 065007 (2015)NJOPFM1367-263010.1088/1367-2630/17/6/065007; E. Aurell, Entropy 19, 595 (2017)ENTRFG1099-430010.3390/e19110595]. PMID- 30011539 TI - Phase transitions in a multistate majority-vote model on complex networks. AB - We generalize the original majority-vote (MV) model from two states to arbitrary p states and study the order-disorder phase transitions in such a p-state MV model on complex networks. By extensive Monte Carlo simulations and a mean-field theory, we show that for p>=3 the order of phase transition is essentially different from a continuous second-order phase transition in the original two state MV model. Instead, for p>=3 the model displays a discontinuous first-order phase transition, which is manifested by the appearance of the hysteresis phenomenon near the phase transition. Within the hysteresis loop, the ordered phase and disordered phase are coexisting, and rare flips between the two phases can be observed due to the finite-size fluctuation. Moreover, we investigate the type of phase transition under a slightly modified dynamics [Melo et al., J. Stat. Mech. (2010) P110321742-546810.1088/1742-5468/2010/11/P11032]. We find that the order of phase transition in the three-state MV model depends on the degree heterogeneity of networks. For p>=4, both dynamics produce the first-order phase transitions. PMID- 30011540 TI - Common inputs in subthreshold membrane potential: The role of quiescent states in neuronal activity. AB - Experiments in certain regions of the cerebral cortex suggest that the spiking activity of neuronal populations is regulated by common non-Gaussian inputs across neurons. We model these deviations from random-walk processes with q Gaussian distributions into simple threshold neurons, and investigate the scaling properties in large neural populations. We show that deviations from the Gaussian statistics provide a natural framework to regulate population statistics such as sparsity, entropy, and specific heat. This type of description allows us to provide an adequate strategy to explain the information encoding in the case of low neuronal activity and its possible implications on information transmission. PMID- 30011541 TI - Stabilizing effect of volatility in financial markets. AB - In financial markets, greater volatility is usually considered to be synonymous with greater risk and instability. However, large market downturns and upturns are often preceded by long periods where price returns exhibit only small fluctuations. To investigate this surprising feature, here we propose using the mean first hitting time, i.e., the average time a stock return takes to undergo for the first time a large negative (crashes) or positive variation (rallies), as an indicator of price stability, and relate this to a standard measure of volatility. In an empirical analysis of daily returns for 1071 stocks traded in the New York Stock Exchange, we find that this measure of stability displays nonmonotonic behavior, with a maximum, as a function of volatility. Also, we show that the statistical properties of the empirical data can be reproduced by a nonlinear Heston model. This analysis implies that, contrary to conventional wisdom, not only high, but also low volatility values can be associated with higher instability in financial markets. This proposed measure of stability can be extremely useful in risk control. PMID- 30011542 TI - Network community-based model reduction for vortical flows. AB - A network community-based reduced-order model is developed to capture key interactions among coherent structures in high-dimensional unsteady vortical flows. The present approach is data-inspired and founded on network-theoretic techniques to identify important vortical communities that are comprised of vortical elements that share similar dynamical behavior. The overall interaction based physics of the high-dimensional flow field is distilled into the vortical community centroids, considerably reducing the system dimension. Taking advantage of these vortical interactions, the proposed methodology is applied to formulate reduced-order models for the inter-community dynamics of vortical flows, and predict lift and drag forces on bodies in wake flows. We demonstrate the capabilities of these models by accurately capturing the macroscopic dynamics of a collection of discrete point vortices, and the complex unsteady aerodynamic forces on a circular cylinder and an airfoil with a Gurney flap. The present formulation is found to be robust against simulated experimental noise and turbulence due to its integrating nature of the system reduction. PMID- 30011543 TI - Stability estimation of autoregulated genes under Michaelis-Menten-type kinetics. AB - Feedback loops are typical motifs appearing in gene regulatory networks. In some well-studied model organisms, including Escherichia coli, autoregulated genes, i.e., genes that activate or repress themselves through their protein products, are the only feedback interactions. For these types of interactions, the Michaelis-Menten (MM) formulation is a suitable and widely used approach, which always leads to stable steady-state solutions representative of homeostatic regulation. However, in many other biological phenomena, such as cell differentiation, cancer progression, and catastrophes in ecosystems, one might expect to observe bistable switchlike dynamics in the case of strong positive autoregulation. To capture this complex behavior we use the generalized family of MM kinetic models. We give a full analysis regarding the stability of autoregulated genes. We show that the autoregulation mechanism has the capability to exhibit diverse cellular dynamics including hysteresis, a typical characteristic of bistable systems, as well as irreversible transitions between bistable states. We also introduce a statistical framework to estimate the kinetics parameters and probability of different stability regimes given observational data. Empirical data for the autoregulated gene SCO3217 in the SOS system in Streptomyces coelicolor are analyzed. The coupling of a statistical framework and the mathematical model can give further insight into understanding the evolutionary mechanisms toward different cell fates in various systems. PMID- 30011544 TI - Statistical analysis of particle trajectories in living cells. AB - Recent advances in molecular biology and fluorescence microscopy imaging have made possible the inference of the dynamics of molecules in living cells. Such inference allows us to understand and determine the organization and function of the cell. The trajectories of particles (e.g., biomolecules) in living cells, computed with the help of object tracking methods, can be modeled with diffusion processes. Three types of diffusion are considered: (i) free diffusion, (ii) subdiffusion, and (iii) superdiffusion. The mean-square displacement (MSD) is generally used to discriminate the three types of particle dynamics. We propose here a nonparametric three-decision test as an alternative to the MSD method. The rejection of the null hypothesis, i.e., free diffusion, is accompanied by claims of the direction of the alternative (subdiffusion or superdiffusion). We study the asymptotic behavior of the test statistic under the null hypothesis and under parametric alternatives which are currently considered in the biophysics literature. In addition, we adapt the multiple-testing procedure of Benjamini and Hochberg to fit with the three-decision-test setting, in order to apply the test procedure to a collection of independent trajectories. The performance of our procedure is much better than the MSD method as confirmed by Monte Carlo experiments. The method is demonstrated on real data sets corresponding to protein dynamics observed in fluorescence microscopy. PMID- 30011545 TI - Effect of evaporation on step bunching induced by impurities. AB - In this paper, we study the effect of the evaporation of adatoms and impurities on the step bunching induced by impurity. Keeping the ratio of the impingement rate of impurities F_{imp} to that of atoms F constant, we carry out Monte Carlo simulation. In the system with the evaporation of impurities, the growth rate of vicinal face R is proportional to F. This relation is the same as that without the evaporation of impurities. When F is small, the vicinal face is unstable. Compared with the system without the evaporation of impurities, the effect of impurities is weakened. In our simulation, step pairing occurs but large bunches are not formed. When we take account of the evaporation of both impurities and adatoms, the vicinal face grows when F is larger than the equilibrium value F_{eq}. R is not proportional to (F-F_{eq}) and large bunches are formed when F is small. In this paper, we also show how the impurity density on surface sigma_{imp} and that incorporated in solid rho_{imp} are related to the formation of step bunches. PMID- 30011547 TI - Variational encoding of complex dynamics. AB - Often the analysis of time-dependent chemical and biophysical systems produces high-dimensional time-series data for which it can be difficult to interpret which individual features are most salient. While recent work from our group and others has demonstrated the utility of time-lagged covariate models to study such systems, linearity assumptions can limit the compression of inherently nonlinear dynamics into just a few characteristic components. Recent work in the field of deep learning has led to the development of the variational autoencoder (VAE), which is able to compress complex datasets into simpler manifolds. We present the use of a time-lagged VAE, or variational dynamics encoder (VDE), to reduce complex, nonlinear processes to a single embedding with high fidelity to the underlying dynamics. We demonstrate how the VDE is able to capture nontrivial dynamics in a variety of examples, including Brownian dynamics and atomistic protein folding. Additionally, we demonstrate a method for analyzing the VDE model, inspired by saliency mapping, to determine what features are selected by the VDE model to describe dynamics. The VDE presents an important step in applying techniques from deep learning to more accurately model and interpret complex biophysics. PMID- 30011546 TI - Nuclear excitation by electron capture in optical-laser-generated plasmas. AB - The process of nuclear excitation by electron capture in plasma environments generated by the interaction of ultrastrong optical lasers with solid-state samples is investigated theoretically. With the help of a plasma model, we perform a comprehensive study of the optimal parameters for the most efficient nuclear excitation and determine the corresponding laser setup requirements. We discern between the low-density plasma regime, modeled by scaling laws, and the high-density regime, for which we perform particle-in-cell calculations. As a nuclear transition case study we consider the 4.85-keV nuclear excitation starting from the long-lived ^{93m}Mo isomer. Our results show that the optimal plasma and laser parameters are sensitive to the chosen observable and that measurable rates of nuclear excitation and isomer depletion of ^{93m}Mo should be already achievable at laser facilities existing today. PMID- 30011548 TI - Finding the Hannay angle in dissipative oscillatory systems via conservative perturbation theory. AB - Usage of a Hamiltonian perturbation theory for a nonconservative system is counterintuitive and, in general, a technical impossibility by definition. However, the time-independent dual Hamiltonian formalism for the nonconservative systems has opened the door for using various conservative perturbation theories for investigating the dynamics of such systems. Here we demonstrate that the Lie transform Hamiltonian perturbation theory can be adapted to find the perturbative solutions and the frequency corrections for the dissipative oscillatory systems. As a further application, we use the perturbation theory to analytically calculate the Hannay angle for the van der Pol oscillator's limit cycle trajectory when its parameters-the strength of the nonlinearity and the frequency of the linear part-evolve cyclically and adiabatically. For this van der Pol oscillator, we also numerically calculate the corresponding geometric phase and establish its equivalence with the Hannay angle. PMID- 30011549 TI - Free-energy model for nanoparticle self-assembly by liquid crystal sorting. AB - We modeled the experimentally observed self-assembly of nanoparticles (NPs) into shells with diameters up to 10 MUm, via segregation from growing nematic domains. Using field-based Monte Carlo simulations, we found the equilibrium configurations of the system by minimizing a free-energy functional that includes effects of excluded-volume interactions among NPs, orientational elasticity, and the isotropic-nematic phase-transition energy. We developed a Gaussian-profile approximation for the liquid crystal (LC) order-parameter field that provides accurate analytical values for the free energy of LC droplets and the associated microshells. This analytical model reveals a first-order transition between equilibrium states with and without microshells, governed mainly by the competition of excluded-volume and phase-transition energies. By contrast, the LC elasticity effects are much smaller and mostly confined to setting the size of the activation barrier for the transition. In conclusion, field-based thermodynamic methods provide a theoretical framework for the self-assembly of NP shells in liquid crystal hosts and suggest that field-based kinetic methods could be useful to simulate and model the time evolution of NP self-assembly coupled to phase separation. PMID- 30011550 TI - Asymptotic theory of quasiperiodically driven quantum systems. AB - The theoretical treatment of quasiperiodically driven quantum systems is complicated by the inapplicability of the Floquet theorem, which requires strict periodicity. In this work we consider a quantum system driven by a biharmonic driving and examine its asymptotic long-time limit, the limit in which features distinguishing systems with periodic and quasiperiodic driving occur. Also, in the classical case this limit is known to exhibit universal scaling, independent of the system details, with the system's reponse under quasiperiodic driving being described in terms of nearby periodically driven system results. We introduce a theoretical framework appropriate for the treatment of the quasiperiodically driven quantum system in the long-time limit and derive an expression, based on Floquet states for a periodically driven system approximating the different steps of the time evolution, for the asymptotic scaling of relevant quantities for the system at hand. These expressions are tested numerically, finding excellent agreement for the finite-time average velocity in a prototypical quantum ratchet consisting of a space-symmetric potential and a time-asymmetric oscillating force. PMID- 30011551 TI - Dependence of the entrainment on the ratio of amplitudes between two subgroups in the suprachiasmatic nucleus. AB - Organisms can be synchronized not only to the natural 24-h light-dark cycle but also to artificial non-24-h cycles. Interestingly, when the period of the cycle is far from 24 h, organisms may show complicated behavioral patterns. For example, exposed to a 22-h light-dark cycle, in behavioral activity of rats, a phenomenon called "dissociation" emerges, i.e., one periodic component shows a 22 h period and the other shows a period close to the endogenous period of the animal (around 24 h). It has been found that these two components are regulated by two subgroups of the suprachiasmatic nucleus (SCN), respectively, with the ventrolateral part regulating the 22-h component and the dorsomedial part regulating the other component. In the present study, based on a mathematical model, we will examine how the ratio of amplitudes between these two subgroups affects the entrainment of the SCN to the external 22-h light-dark cycle. Our results show that the dissociation happens when the ratio is smaller than 1 and the maximal entrainment (synchronization) ability of the SCN to the external cycle is obtained when the ratio is larger than 1. Our finding sheds light on the dissociation between the subgroups and suggests that the heterogeneity in the amplitudes alter the entrainment ability of the SCN. PMID- 30011552 TI - Additivity of multiple heat reservoirs in the Langevin equation. AB - The Langevin equation greatly simplifies the mathematical expression of the effects of thermal noise by using only two terms, a dissipation term, and a random-noise term. The Langevin description was originally applied to a system in contact with a single heat reservoir; however, many recent studies have also adopted a Langevin description for systems connected to multiple heat reservoirs. This is accomplished through the introduction of a simple summation for the dissipation and random-noise terms associated with each reservoir. However, the validity of this simple addition has been the focus of only limited discussion and has raised several criticisms. Moreover, this additive description has never been either experimentally or numerically verified, rendering its validity is still an open question. Here we perform molecular dynamics simulations for a Brownian system in simultaneous contact with multiple heat reservoirs to check the validity of this additive approach. Our simulation results confirm that the effect of multiple heat reservoirs is additive in general. A very small deviation in the total amount of dissipation and associated noise is found but seems not significant within statistical errors. We find that the steady-state properties satisfy the additivity perfectly and are not affected by this deviation. PMID- 30011553 TI - Quantum heat engines: Limit cycles and exceptional points. AB - We show that the inability of a quantum Otto cycle to reach a limit cycle is connected with the propagator of the cycle being noncompact. For a working fluid consisting of quantum harmonic oscillators, the transition point in parameter space where this instability occurs is associated with a non-Hermitian degeneracy (exceptional point) of the eigenvalues of the propagator. In particular, a third order exceptional point is observed at the transition from the region where the eigenvalues are complex numbers to the region where all the eigenvalues are real. Within this region we find another exceptional point, this time of second order, at which the trajectory becomes divergent. The onset of the divergent behavior corresponds to the modulus of one of the eigenvalues becoming larger than one. The physical origin of this phenomenon is that the hot and cold heat baths are unable to dissipate the frictional internal heat generated in the adiabatic strokes of the cycle. This behavior is contrasted with that of quantum spins as working fluid which have a compact Hamiltonian and thus no exceptional points. All arguments are rigorously proved in terms of the systems' associated Lie algebras. PMID- 30011554 TI - Effects of axial boundary conductivity on a free Stewartson-Shercliff layer. AB - The effects of axial boundary conductivity on the formation and stability of a magnetized free Stewartson-Shercliff layer (SSL) in a short Taylor-Couette device are reported. As the axial field increases with insulating endcaps, hydrodynamic Kelvin-Helmholtz-type instabilities set in at the SSLs of the conducting fluid, resulting in a much reduced flow shear. With conducting endcaps, SSLs respond to an axial field weaker by the square root of the conductivity ratio of endcaps to fluid. Flow shear continuously builds up as the axial field increases despite the local violation of the Rayleigh criterion, leading to a large number of hydrodynamically unstable modes. Numerical simulations of both the mean flow and the instabilities are in agreement with the experimental results. PMID- 30011555 TI - Correlation spreading and properties of the quantum state in quench dynamics. AB - The light cone spreading of correlations following a quantum quench is obtained from first principles. Fully taking into account quantum and interaction effects, the derivation shows how light cone dynamics does not require peculiar properties of the postquench state. PMID- 30011556 TI - Translational mobilities of proteins in nanochannels: A coarse-grained molecular dynamics study. AB - We investigated the translation of a protein through model nanopores using coarse grained (CG) nonequilibrium molecular dynamics (NEMD) simulations and compared the mobilities with those obtained from previous coarse-grained equilibrium molecular dynamics model. We considered the effects of nanopore confinement and external force on the translation of streptavidin through nanopores of dimensions representative of experiments. As the nanopore radius approaches the protein hydrodynamic radius, r_{h}/r_{p}->1 (where r_{h} is the hydrodynamic radius of protein and r_{p} is the pore radius), the translation times are observed to increase by two orders of magnitude. The translation times are found to be in good agreement with the one-dimensional biased diffusion model. The results presented in this paper provide useful insights on nanopore designs intended to control the motion of biomolecules. PMID- 30011557 TI - Constrained information flows in temporal networks reveal intermittent communities. AB - Many real-world networks represent dynamic systems with interactions that change over time, often in uncoordinated ways and at irregular intervals. For example, university students connect in intermittent groups that repeatedly form and dissolve based on multiple factors, including their lectures, interests, and friends. Such dynamic systems can be represented as multilayer networks where each layer represents a snapshot of the temporal network. In this representation, it is crucial that the links between layers accurately capture real dependencies between those layers. Often, however, these dependencies are unknown. Therefore, current methods connect layers based on simplistic assumptions that do not capture node-level layer dependencies. For example, connecting every node to itself in other layers with the same weight can wipe out dependencies between intermittent groups, making it difficult or even impossible to identify them. In this paper, we present a principled approach to estimating node-level layer dependencies based on the network structure within each layer. We implement our node-level coupling method in the community detection framework Infomap and demonstrate its performance compared to current methods on synthetic and real temporal networks. We show that our approach more effectively constrains information inside multilayer communities so that Infomap can better recover planted groups in multilayer benchmark networks that represent multiple modes with different groups and better identify intermittent communities in real temporal contact networks. These results suggest that node-level layer coupling can improve the modeling of information spreading in temporal networks and better capture intermittent community structure. PMID- 30011558 TI - Improved multipoint statistics method for reconstructing three-dimensional porous media from a two-dimensional image via porosity matching. AB - Reconstructing a three-dimensional (3D) structure from a single two-dimensional training image (TI) is a challenging issue. Multiple-point statistics (MPS) is an effective method to solve this problem. However, in the traditional MPS method, errors occur while statistical features of reconstruction, such as porosity, connectivity, and structural properties, deviate from those of TI. Due to the MPS reconstruction mechanism that the voxel being reconstructed is dependent on the reconstructed voxel, it may cause error accumulation during simulations, which can easily lead to a significant difference between the real 3D structure and the reconstructed result. To reduce error accumulation and improve morphological similarity, an improved MPS method based on porosity matching is proposed. In the reconstruction, we search the matching pattern in the TI directly. Meanwhile, a multigrid approach is also applied to capture the large-scale structures of the TI. To demonstrate its superiority over the traditional MPS method, our method is tested on different sandstone samples from many aspects, including accuracy, stability, generalization, and flow characteristics. Experimental results show that the reconstruction results by the improved MPS method effectively match the CT sandstone samples in correlation functions, local porosity distribution, morphological parameters, and permeability. PMID- 30011559 TI - Limits on inferring the past. AB - Here we define and study the properties of retrodictive inference. We derive equations relating retrodiction entropy and thermodynamic entropy, and as a special case, show that under equilibrium conditions, the two are identical. We demonstrate relations involving the Kullback-Leibler divergence and retrodiction probability, and bound the time rate of change of retrodiction entropy. As a specific case, we invert various Langevin processes, inferring the initial condition of N particles given their final positions at some later time. We evaluate the retrodiction entropy for Langevin dynamics exactly for special cases, and find that one's ability to infer the initial state of a system can exhibit two possible qualitative behaviors depending on the potential energy landscape, either decreasing indefinitely, or asymptotically approaching a fixed value. We also study how well we can retrodict points that evolve based on the logistic map. We find singular changes in the retrodictivity near bifurcations. Counterintuitively, the transition to chaos is accompanied by maximal retrodictability. PMID- 30011560 TI - Revealing underlying universal wave fluctuations in a scaled ray-chaotic cavity with remote injection. AB - The Random Coupling Model (RCM) predicts the statistical properties of waves inside a ray-chaotic enclosure in the semiclassical regime by using Random Matrix Theory, combined with system-specific information. Experiments on single cavities are in general agreement with the predictions of the RCM. It is now desired to test the RCM on more complex structures, such as a cascade or network of coupled cavities, that represent realistic situations but that are difficult to test due to the large size of the structures of interest. This paper presents an experimental setup that replaces a cubic-meter-scale microwave cavity with a miniaturized cavity, scaled down by a factor of 20 in each dimension, operated at a frequency scaled up by a factor of 20 and having wall conductivity appropriately scaled up by a factor of 20. We demonstrate experimentally that the miniaturized cavity maintains the statistical wave properties of the larger cavity. This scaled setup opens the opportunity to study wave properties in large structures such as the floor of an office building, a ship, or an aircraft, in a controlled laboratory setting. PMID- 30011561 TI - Progressive quenching: Globally coupled model. AB - We study the processes in which fluctuating elements of a system are progressively fixed (quenched) while keeping the interaction with the remaining unfixed elements. If the interaction is global among Ising spin elements and if the unfixed part is reequilibrated each time after fixing an element, the evolution of a large system is martingale about the equilibrium spin value of the unfixed spins. Due to this property the system starting from the critical point yields the final magnetization, whose distribution shows non-Gaussian and slow transient behavior with the system size. PMID- 30011562 TI - Collective dielectric processes at the transition temperature of the Sm-C^{*} and Sm-A^{*} phase in a ferroelectric liquid crystal. AB - An anomalous dielectric relaxation process, called the partially unwound helical mode (p-UHM), is a collective dielectric process apart from the well known Goldstone and soft mode process; it is studied in the smectic C^{*} (Sm-C^{*}) phase and at the transition temperature of the Sm-C^{*}-Sm-A^{*} phase in the ferroelectric liquid crystal (FLC) material. To avoid the surface effect, a thick cell of 40 MUm thickness was prepared with highly rubbed surfaces of the ITO substrates. It has been observed that the dielectric properties in Sm-C^{*} and at the T_{c} temperature are dominated by the p-UHM process which is dependent on an applied oscillating field in the Sm-C^{*} phase. The probing ac and dc bias field dependences of all these collective dielectric processes have been reported in the Sm-C^{*} and Sm-A^{*} phases of FLC materials. PMID- 30011563 TI - Transport and diffusion of paramagnetic ellipsoidal particles in a rotating magnetic field. AB - Transport and diffusion of paramagnetic ellipsoidal particles under the action of a rotating magnetic field are numerically investigated in a two-dimensional channel. It is found that paramagnetic ellipsoidal particles in a rotating magnetic field can be rectified in the upper-lower asymmetric channel. The transport and the effective diffusion coefficient are much more different and complicated for active particles, while they have similar behaviors and change a little when applying rotating magnetic fields of different frequencies for passive particles. For active particles, the back-and-forth rotational motion facilitates the effective diffusion coefficient and reduces the rectification, whereas the rotational motion synchronous with the magnetic field suppresses the effective diffusion coefficient and enhances the rectification. There exist optimized values of the parameters (the anisotropic degree, the amplitude and frequency of magnetic field, the self-propelled velocity, and the rotational diffusion rate) at which the average velocity and diffusion take their maximal values. Particles with different shapes, self-propelled speeds, or rotational diffusion rates will move to the opposite directions and can be separated by applying rotating magnetic fields of suitable strength and frequency. Our results can be used to separate particles, orient the particles along any direction at will during motion, and control the particle diffusion. PMID- 30011564 TI - Publisher's Note: Empirical analysis of the lane formation process in bidirectional pedestrian flow [Phys. Rev. E 94, 032304 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.94.032304. PMID- 30011565 TI - Large deviations in the presence of cooperativity and slow dynamics. AB - We study simple models of intermittency, involving switching between two states, within the dynamical large-deviation formalism. Singularities appear in the formalism when switching is cooperative or when its basic time scale diverges. In the first case the unbiased trajectory distribution undergoes a symmetry breaking, leading to a change in shape of the large-deviation rate function for a particular dynamical observable. In the second case the symmetry of the unbiased trajectory distribution remains unbroken. Comparison of these models suggests that singularities of the dynamical large-deviation formalism can signal the dynamical equivalent of an equilibrium phase transition but do not necessarily do so. PMID- 30011566 TI - Population extinction under bursty reproduction in a time-modulated environment. AB - In recent years nondemographic variability has been shown to greatly affect dynamics of stochastic populations. For example, nondemographic noise in the form of a bursty reproduction process with an a priori unknown burst size, or environmental variability in the form of time-varying reaction rates, have been separately found to dramatically impact the extinction risk of isolated populations. In this work we investigate the extinction risk of an isolated population under the combined influence of these two types of nondemographic variation. Using the so-called momentum-space Wentzel-Kramers-Brillouin (WKB) approach and accounting for the explicit time dependence in the reaction rates, we arrive at a set of time-dependent Hamilton equations. To this end, we evaluate the population's extinction risk by finding the instanton of the time-perturbed Hamiltonian numerically, whereas analytical expressions are presented in particular limits using various perturbation techniques. We focus on two classes of time-varying environments: periodically varying rates corresponding to seasonal effects and a sudden decrease in the birth rate corresponding to a catastrophe. All our theoretical results are tested against numerical Monte Carlo simulations with time-dependent rates and also against a numerical solution of the corresponding time-dependent Hamilton equations. PMID- 30011567 TI - Hierarchical lattice models of hydrogen-bond networks in water. AB - We develop a graph-based model of the hydrogen-bond network in water, with a view toward quantitatively modeling the molecular-level correlational structure of the network. The networks formed are studied by the constructing the model on two infinite-dimensional lattices. Our models are built bottom up, based on microscopic information coming from atomistic simulations, and we show that the predictions of the model are consistent with known results from ab initio simulations of liquid water. We show that simple entropic models can predict the correlations and clustering of local-coordination defects around tetrahedral waters observed in the atomistic simulations. We also find that orientational correlations between bonds are longer ranged than density correlations, determine the directional correlations within closed loops, and show that the patterns of water wires within these structures are also consistent with previous atomistic simulations. Our models show the existence of density and compressibility anomalies, as seen in the real liquid, and the phase diagram of these models is consistent with the singularity-free scenario previously proposed by Sastry and coworkers [Phys. Rev. E 53, 6144 (1996)1063-651X10.1103/PhysRevE.53.6144]. PMID- 30011568 TI - Spiral waves in driven strongly coupled Yukawa systems. AB - Spiral wave formations are ubiquitous in nature. In the present paper, the excitation of spiral waves in the context of driven two-dimensional dusty plasma (Yukawa system) has been demonstrated at particle level using molecular-dynamics simulations. The interaction amidst dust particles is modeled by the Yukawa potential to take account of the shielding of dust charges by the lighter electron and ion species. The spatiotemporal evolution of these spiral waves has been characterized as a function of the frequency and amplitude of the driving force and dust neutral collisions. The effect of strong coupling has been studied, which shows that the excited spiral wave structures get clearer as the medium gets more strongly coupled. The radial propagation speed of the spiral wave is observed to remain unaltered with the coupling parameter. However, it is found to depend on the screening parameter of the dust medium and decreases when it is increased. In the crystalline phase (with screening parameter kappa>0.58), the spiral wavefronts are shown to be hexagonal in shape. This shows that the radial propagation speed depends on the interparticle spacing. PMID- 30011569 TI - Quantum speed limit constraints on a nanoscale autonomous refrigerator. AB - Quantum speed limit, furnishing a lower bound on the required time for the evolution of a quantum system through the state space, imposes an ultimate natural limitation to the dynamics of physical devices. Quantum absorption refrigerators, however, have attracted a great deal of attention in the past few years. In this paper, we discuss the effects of quantum speed limit on the performance of a quantum absorption refrigerator. In particular, we show that there exists a tradeoff relation between the steady cooling rate of the refrigerator and the minimum time taken to reach the steady state. Based on this, we define a figure of merit called "bounding second order cooling rate" and show that this scales linearly with the unitary interaction strength among the constituent qubits. We also study the increase of bounding second-order cooling rate with the thermalization strength. We subsequently demonstrate that coherence in the initial three qubit system can significantly increase the bounding second order cooling rate. We study the efficiency of the refrigerator at maximum bounding second-order cooling rate and, in a limiting case, we show that the efficiency at maximum bounding second-order cooling rate is given by a simple formula resembling the Curzon-Ahlborn relation. PMID- 30011570 TI - Finite-size scaling for discontinuous nonequilibrium phase transitions. AB - A finite-size scaling theory, originally developed only for transitions to absorbing states [Phys. Rev. E 92, 062126 (2015)PLEEE81539 375510.1103/PhysRevE.92.062126], is extended to distinct sorts of discontinuous nonequilibrium phase transitions. Expressions for quantities such as response functions, reduced cumulants, and equal area probability distributions are derived from phenomenological arguments. Irrespective of system details, all these quantities scale with the volume, establishing the dependence on size. The approach generality is illustrated through the analysis of different models. The present results are a relevant step in trying to unify the scaling behavior description of nonequilibrium transition processes. PMID- 30011571 TI - Shearlet-based measures of entropy and complexity for two-dimensional patterns. AB - New spatial entropy and complexity measures for two-dimensional patterns are proposed. The approach is based on the notion of disequilibrium and is built on statistics of directional multiscale coefficients of the fast finite shearlet transform. Shannon entropy and Jensen-Shannon divergence measures are employed. Both local and global spatial complexity and entropy estimates can be obtained, thus allowing for spatial mapping of complexity in inhomogeneous patterns. The algorithm is validated in numerical experiments with a gradually decaying periodic pattern and Ising surfaces near critical state. It is concluded that the proposed algorithm can be instrumental in describing a wide range of two dimensional imaging data, textures, or surfaces, where an understanding of the level of order or randomness is desired. PMID- 30011572 TI - Comparing skyrmions and merons in chiral liquid crystals and magnets. AB - When chiral liquid crystals or magnets are subjected to applied fields or other anisotropic environments, the competition between favored twist and anisotropy leads to the formation of complex defect structures. In some cases, the defects are skyrmions, which have 180^{?} double twist going outward from the center, and hence can pack together without singularities in the orientational order. In other cases, the defects are merons, which have 90^{?} double twist going outward from the center; packing such merons requires singularities in the orientational order. In the liquid crystal context, a lattice of merons is equivalent to a blue phase. Here we perform theoretical and computational studies of skyrmions and merons in chiral liquid crystals and magnets. Through these studies, we calculate the phase diagrams for liquid crystals and magnets in terms of dimensionless ratios of energetic parameters. We also predict the range of metastability for liquid crystal skyrmions and show that these skyrmions can move and interact as effective particles. The results show how the properties of skyrmions and merons depend on the vector or tensor nature of the order parameter. PMID- 30011573 TI - Thermodynamics of evolutionary games. AB - How cooperation can evolve between players is an unsolved problem of biology. Here we use Hamiltonian dynamics of models of the Ising type to describe populations of cooperating and defecting players to show that the equilibrium fraction of cooperators is given by the expectation value of a thermal observable akin to a magnetization. We apply the formalism to the public goods game with three players and show that a phase transition between cooperation and defection occurs that is equivalent to a transition in one-dimensional Ising crystals with long-range interactions. We then investigate the effect of punishment on cooperation and find that punishment plays the role of a magnetic field that leads to an "alignment" between players, thus encouraging cooperation. We suggest that a thermal Hamiltonian picture of the evolution of cooperation can generate other insights about the dynamics of evolving groups by mining the rich literature of critical dynamics in low-dimensional spin systems. PMID- 30011574 TI - Mechanisms of complex network growth: Synthesis of the preferential attachment and fitness models. AB - We analyze growth mechanisms of complex networks and focus on their validation by measurements. To this end we consider the equation DeltaK=A(t)(K+K_{0})Deltat, where K is the node's degree, DeltaK is its increment, A(t) is the aging constant, and K_{0} is the initial attractivity. This equation has been commonly used to validate the preferential attachment mechanism. We show that this equation is undiscriminating and holds for the fitness model [Caldarelli et al., Phys. Rev. Lett. 89, 258702 (2002)PRLTAO0031-900710.1103/PhysRevLett.89.258702] as well. In other words, accepted method of the validation of the microscopic mechanism of network growth does not discriminate between "rich-gets-richer" and "good-gets-richer" scenarios. This means that the growth mechanism of many natural complex networks can be based on the fitness model rather than on the preferential attachment, as it was believed so far. The fitness model yields the long-sought explanation for the initial attractivity K_{0}, an elusive parameter which was left unexplained within the framework of the preferential attachment model. We show that the initial attractivity is determined by the width of the fitness distribution. We also present the network growth model based on recursive search with memory and show that this model contains both the preferential attachment and the fitness models as extreme cases. PMID- 30011575 TI - Shannon entropy and avoided crossings in closed and open quantum billiards. AB - The relation between Shannon entropy and avoided crossings is investigated in dielectric microcavities. The Shannon entropy of the probability density for eigenfunctions in an open elliptic billiard as well as a closed quadrupole billiard increases as the center of the avoided crossing is approached. These results are opposite to those of atomic physics for electrons. It is found that the collective Lamb shift of the open quantum system and the symmetry breaking in the closed chaotic quantum system have equivalent effects on the Shannon entropy. PMID- 30011576 TI - Networked-oscillator-based modeling and control of unsteady wake flows. AB - A networked-oscillator-based analysis is performed to examine and control the transfer of kinetic energy for periodic bluff body flows. The dynamics of energy fluctuations in the flow field are described by a set of oscillators defined by conjugate pairs of spatial proper orthogonal decomposition (POD) modes. To extract the network of interactions among oscillators, impulse responses of the oscillators to amplitude and phase perturbations are tracked. Tracking small energy inputs and using linear regression, a networked-oscillator model is constructed that reveals energy exchange among the modes. The model captures the nonlinear interactions among the modal oscillators through a linear approximation. A large collection of system responses is aggregated to capture the general network structure of oscillator interactions. The present networked oscillator model describes the modal perturbation dynamics more accurately than the empirical Galerkin reduced-order model. The linear network model for nonlinear dynamics is subsequently utilized to design a model-based feedback controller. The controller suppresses the modal amplitudes that result in wake unsteadiness leading to drag reduction. The strength of the proposed approach is demonstrated for a canonical example of two-dimensional unsteady flow over a circular cylinder. The present formulation enables the characterization of modal interactions to control fundamental energy transfers in unsteady bluff body flows. PMID- 30011577 TI - Hydrodynamics of granular particles on a line. AB - We investigate a lattice model representing a granular gas in a thin channel. We deduce the hydrodynamic description for the model from the microscopic dynamics in the large-system limit, including the lowest finite-size corrections. The main prediction from hydrodynamics, when finite-size corrections are neglected, is the existence of a steady "uniform longitudinal flow" (ULF), with the granular temperature and the velocity gradient both uniform and directly related. Extensive numerical simulations of the system show that such a state can be observed in the bulk of a finite-size system by attaching two thermostats with the same temperature at its boundaries. The relation between the ULF state and the shocks appearing in the late stage of a cooling gas of inelastic hard rods is discussed. PMID- 30011578 TI - Influence of spatial delay on the modulational instability in a composite system with a controllable nonlinearity. AB - A theoretical investigation of the modulational instability (MI) in a composite system with a nonlocal response function is presented. A composite system of silver nanoparticles in acetone is chosen, whose nonlinearity can be delicately varied by controlling the volume fraction of the constituents, thus enabling the possibility of nonlinearity management. A pump-probe counterpropagation configuration has been assumed, and the interplay between the competing nonlinearities and the nonlocalities in the MI dynamics is systematically explored. A different class of nonlocalities have been considered, and the study reveals that the nonlocality critically depends on the kind of nonlocal function. However, the general behavior is that the strength of nonlocality suppresses the MI gain, while for a rectangular function it assists the emergence of new spectral windows. We also show that the cross coupling effects are significant in enhancing MI, especially in the defocusing nonlinearity. We also emphasize the impact of the relative strength of the nonlinearities in the MI dynamics at different settings of competing nonlinearities. Thus, we emphasize the importance of the different class of nonlocal response in the MI dynamics and explore the interplay between the higher order nonlinear effects and nonlocalities in the counterpropagating configurations. PMID- 30011579 TI - Nonlinearity-induced localization in a periodically driven semidiscrete system. AB - We demonstrate that nonlinearity plays a constructive role in supporting the robustness of dynamical localization in a system which is discrete in one dimension and continuous in the orthogonal one. In the linear regime, time periodic modulation of the gradient strength along the discrete axis leads to the usual rapid spread of an initially confined wave packet. Addition of the cubic nonlinearity makes the dynamics drastically different, inducing robust localization of moving wave packets. Similar nonlinearity-induced effects are also produced in the presence of a combination of static and oscillating linear potentials. The predicted dynamical localization in the nonlinear medium can be realized in photonic lattices and Bose-Einstein condensates. PMID- 30011580 TI - Reactions, diffusion, and volume exclusion in a conserved system of interacting particles. AB - Complex biological and physical transport processes are often described through systems of interacting particles. The effect of excluded volume on these transport processes has been well studied; however, the interplay between volume exclusion and reactions between heterogenous particles is less well studied. In this paper we develop a framework for modeling reaction-diffusion processes which directly incorporates volume exclusion. We consider simple reactions (unimolecular and bimolecular) that conserve the total number of particles. From an off-lattice microscopic individual-based model we use the Fokker-Planck equation and the method of matched asymptotic expansions to derive a low dimensional macroscopic system of nonlinear partial differential equations describing the evolution of the particles. A biologically motivated, hybrid model of chemotaxis with volume exclusion is explored, where reactions occur at rates dependent upon the chemotactic environment. Further, we show that for reactions that require particle contact the appropriate reaction term in the macroscopic model is of lower order in the asymptotic expansion than the nonlinear diffusion term. However, we find that the next reaction term in the expansion is needed to ensure good agreement with simulations of the microscopic model. Our macroscopic model allows for more direct parametrization to experimental data than existing models. PMID- 30011581 TI - Diffusion with resetting inside a circle. AB - We study the Brownian motion of a particle in a bounded circular two-dimensional domain in search for a stationary target on the boundary of the domain. The process switches between two modes: one where it performs a two-dimensional diffusion inside the circle and one where it diffuses along the one-dimensional boundary. During the process, the Brownian particle resets to its initial position with a constant rate r. The Fokker-Planck formalism allows us to calculate the mean time to absorption (MTA) as well as the optimal resetting rate for which the MTA is minimized. From the derived analytical results the parameter regions where resetting reduces the search time can be specified. We also provide a numerical method for the verification of our results. PMID- 30011582 TI - Evacuation simulation with consideration of obstacle removal and using game theory. AB - In this paper, we integrate a cellular automaton model with game theory to simulate crowd evacuation from a room with consideration of obstacle removal. The room has one or more exits, one of which is blocked by obstacles. The obstacles at the exit can be removed by volunteers. We investigate the cooperative and defective behaviors of pedestrians during evacuation. The yielder game and volunteer's dilemma game are employed to resolve interpedestrian conflict. An anticipation floor field is proposed to guide the pedestrians to avoid obstacles that are being removed. We conducted experiments to determine how a variety of conditions affect overall crowd evacuation and volunteer evacuation times. The conditions were the start time of obstacle removal, number of obstacles, placement of obstacles, time spent in obstacle removal, strength of the anticipation floor field, and obstacle visibility distance. We demonstrate how reciprocity can be achieved among pedestrians and increases the efficiency of the entire evacuation process. PMID- 30011583 TI - Reply to "Comment on 'Route from discreteness to the continuum for the Tsallis q entropy' ". AB - It has been known for some time that the usual q-entropy S_{q}^{(n)} cannot be shown to converge to the continuous case. In Phys. Rev. E 97, 012104 (2018)PREHBM2470-004510.1103/PhysRevE.97.012104, we have shown that the discrete q-entropy S[over ]_{q}^{(n)} converges to the continuous case when the total number of states are properly taken into account in terms of a convergence factor. Ou and Abe [previous Comment, Phys. Rev. E 97, 066101 (2018)10.1103/PhysRevE.97.066101] noted that this form of the discrete q-entropy does not conform to the Shannon-Khinchin expandability axiom. As a reply, we note that the fulfillment or not of the expandability property by the discrete q entropy strongly depends on the origin of the convergence factor, presenting an example in which S[over ]_{q}^{(n)} is expandable. PMID- 30011584 TI - Critical scaling near the yielding transition in granular media. AB - We show that the yielding transition in granular media displays second-order critical-point scaling behavior. We carry out discrete element simulations in the low-inertial-number limit for frictionless, purely repulsive spherical grains undergoing simple shear at fixed nondimensional shear stress Sigma in two and three spatial dimensions. To find a mechanically stable (MS) packing that can support the applied Sigma, isotropically prepared states with size L must undergo a total strain gamma_{ms}(Sigma,L). The number density of MS packings (?gamma_{ms}^{-1}) vanishes for Sigma>Sigma_{c}~0.11 according to a critical scaling form with a length scale xi?|Sigma-Sigma_{c}|^{-nu}, where nu~1.7-1.8. Above the yield stress (Sigma>Sigma_{c}), no MS packings that can support Sigma exist in the large-system limit L/xi?1. MS packings generated via shear possess anisotropic force and contact networks, suggesting that Sigma_{c} is associated with an upper limit in the degree to which these networks can be deformed away from those for isotropic packings. PMID- 30011585 TI - Universal relations of local order parameters for partially synchronized oscillators. AB - Interactions among discrete oscillatory units (e.g., cells) can result in partially synchronized states when some of the units exhibit phase locking and others phase slipping. Such states are typically characterized by a global order parameter that expresses the extent of synchrony in the system. Here we show that such states carry data-rich information of the system behavior, and a local order parameter analysis reveals universal relations through a semicircle representation. The universal relations are derived from thermodynamic limit analysis of a globally coupled Kuramoto-type phase oscillator model. The relations are confirmed with the partially synchronized states in numerical simulations with a model of circadian cells and in laboratory experiments with chemical oscillators. The application of the theory allows direct approximation of coupling strength, the natural frequency of oscillations, and the phase lag parameter without extensive nonlinear fits as well as a self-consistency check for presence of network interactions and higher harmonic components in the phase model. PMID- 30011586 TI - Mitigation of cross-beam energy transfer in inertial-confinement-fusion plasmas with enhanced laser bandwidth. AB - Cross-beam energy transfer (CBET) is a significant energy-loss mechanism in directly driven inertial-confinement-fusion (ICF) targets. One strategy for mitigating CBET is to increase the bandwidth of the laser light, thereby disrupting the resonant three-wave interactions that underlie this nonlinear scattering process. Here, we report on numerical simulations performed with the wave-based code lpse that show a significant reduction in CBET for bandwidths of 2-5 THz (corresponding to a normalized bandwidth of 0.2%-0.6% at a laser wavelength of 351nm) under realistic plasma conditions. Such bandwidths are beyond those available with current high-energy lasers used for ICF, but could be achieved using stimulated rotation Raman scattering in diatomic gases like nitrogen. PMID- 30011587 TI - Directional change of tracer trajectories in rotating Rayleigh-Benard convection. AB - The angle of directional change of tracer trajectories in rotating Rayleigh Benard convection is studied as a function of the time increment tau between two instants of time along the trajectories, both experimentally and with direct numerical simulations. Our aim is to explore the geometrical characterization of flow structures in turbulent convection in a wide range of timescales and how it is affected by background rotation. We find that probability density functions (PDFs) of the angle of directional change theta(t,tau) show similar behavior as found in homogeneous isotropic turbulence, up to the timescale of the large-scale coherent flow structures. The scaling of the averaged (over particles and time) angle of directional change Theta(tau)=<|theta(t,tau)|> with tau shows a transition from the ballistic regime [Theta(tau)~tau^{c} with c=1] for tau?tau_{eta}, with tau_{eta} the Kolmogorov timescale, to a scaling with smaller exponent c for tau_{eta}?tau?T_{L}, with T_{L} the Lagrangian integral timescale. This scaling exponent is approximately constant in the weakly rotating regime (Rossby number Ro?2.5) and is decreasing for increasing rotation rates when Ro?2.5. We show that this trend in the scaling exponent is related with the large scale coherent structures in the flow; the large-scale circulation for Ro?2.5 and vertically aligned vortices emerging from the boundary layers (BLs) near the top and bottom plates and penetrating into the bulk for Ro?2.5. In the viscous BLs, the PDFs of theta(t,tau) and scaling properties of Theta(tau) are in general different from those measured in the bulk and depend on the type of boundary layer, in particular whether the BL is of Prandtl-Blasius type (Ro?2.5) or of Ekman type (Ro?2.5). When it is of Ekman type, a stronger dynamic coupling exists between the BL and the bulk of the flow, resulting in similar scaling exponents in BL and bulk. PMID- 30011588 TI - Models for randomly distributed nanoscopic domains on spherical vesicles. AB - The existence of lipid domains in the plasma membrane of biological systems has proven controversial, primarily due to their nanoscopic size-a length scale difficult to interrogate with most commonly used experimental techniques. Scattering techniques have recently proven capable of studying nanoscopic lipid domains populating spherical vesicles. However, the development of analytical methods able of predicting and analyzing domain pair correlations from such experiments has not kept pace. Here, we developed models for the random distribution of monodisperse, circular nanoscopic domains averaged on the surface of a spherical vesicle. Specifically, the models take into account (i) intradomain correlations corresponding to form factors and interdomain correlations corresponding to pair distribution functions, and (ii) the analytical computation of interdomain correlations for cases of two and three domains on a spherical vesicle. In the case of more than three domains, these correlations are treated either by Monte Carlo simulations or by spherical analogs of the Ornstein-Zernike and Percus-Yevick (PY) equations. Importantly, the spherical analog of the PY equation works best in the case of nanoscopic size domains, a length scale that is mostly inaccessible by experimental approaches such as, for example, fluorescent techniques and optical microscopies. The analytical form factors and structure factors of nanoscopic domains populating a spherical vesicle provide a new and important framework for the quantitative analysis of experimental data from commonly studied phase-separated vesicles used in a wide range of biophysical studies. PMID- 30011589 TI - Generalized Onsager's reciprocal relations for the master and Fokker-Planck equations. AB - The Onsager's reciprocal relation plays a fundamental role in the nonequilibrium thermodynamics. However, unfortunately, its classical version is valid only within a narrow region near equilibrium due to the linear regression hypothesis, which largely restricts its usage. In this paper, based on the conservation dissipation formalism, a generalized version of Onsager's relations for the master equations and Fokker-Planck equations was derived. Nonlinear constitutive relations with nonsymmetric and positively stable operators, which become symmetric under the detailed balance condition, constitute key features of this new generalization. Similar conclusions also hold for many other classical models in physics and chemistry, which in turn make the current study as a benchmark for the application of generalized Onsager's relations in nonequilibrium thermodynamics. PMID- 30011590 TI - General formulation of long-range degree correlations in complex networks. AB - We provide a general framework for analyzing degree correlations between nodes separated by more than one step (i.e., beyond nearest neighbors) in complex networks. One joint and four conditional probability distributions are introduced to fully describe long-range degree correlations with respect to degrees k and k^{'} of two nodes and shortest path length l between them. We present general relations among these probability distributions and clarify the relevance to nearest-neighbor degree correlations. Unlike nearest-neighbor correlations, some of these probability distributions are meaningful only in finite-size networks. Furthermore, as a baseline to determine the existence of intrinsic long-range degree correlations in a network other than inevitable correlations caused by the finite-size effect, the functional forms of these probability distributions for random networks are analytically evaluated within a mean-field approximation. The utility of our argument is demonstrated by applying it to real-world networks. PMID- 30011591 TI - Orientation of plastic rearrangements in two-dimensional model glasses under shear. AB - The plastic deformation of amorphous solids is mediated by localized shear transformations involving small groups of particles rearranging irreversibly in an elastic background. We introduce and compare three different computational methods to extract the size and orientation of these shear transformations in simulations of a two-dimensional athermal model glass under simple shear. We find that the shear angles are broadly distributed around the macroscopic shear direction, with a more or less Gaussian distribution with a standard deviation of around 20^{?}. The distributions of sizes and orientations of shear transformations display no substantial sensitivity to the shear rate. These results can notably be used to refine the description of rearrangements in elastoplastic models. PMID- 30011592 TI - Harnessing energy-sharing collisions of Manakov solitons to implement universal NOR and OR logic gates. AB - The energy-sharing collision of bright optical solitons in the Manakov system, governing pulse propagation in high birefringent fiber, is employed theoretically to realize optical logic gates. In particular, we successfully construct (theoretically) the universal NOR gate and the OR gate from the energy-sharing collisions of just four bright solitons which can be well described by the exact bright four-soliton solution of the Manakov system. This construction procedure has important merits such as realizing the two input gates with a minimal number of soliton collisions and possibilities of multistate logic. The recent experiments on Manakov solitons suggest the possibility of implementation of this theoretical construction of such gates and ultimately an all-optical computer. PMID- 30011593 TI - Driven Widom-Rowlinson lattice gas. AB - In the Widom-Rowlinson lattice gas, two particle species (A, B) diffuse freely via particle-hole exchange, subject to both on-site exclusion and prohibition of A-B nearest-neighbor pairs. As an athermal system, the overall densities are the only control parameters. As the densities increase, an entropically driven phase transition occurs, leading to ordered states with A- and B-rich domains separated by hole-rich interfaces. Using Monte Carlo simulations, we analyze the effect of imposing a drive on this system, biasing particle moves along one direction. Our study parallels that for a driven Ising lattice gas, the Katz-Lebowitz-Spohn (KLS) model, which displays atypical collective behavior, e.g., structure factors with discontinuity singularities and ordered states with domains only parallel to the drive. Here, other interesting features emerge, including structure factors with kink singularities (best fitted to |q|), maxima at nonvanishing wave-vector values, oscillating correlation functions, and ordering into multiple striped domains perpendicular to the drive, with a preferred wavelength depending on density and drive intensity. Moreover, the (hole-rich) interfaces between the domains are statistically rough (whether driven or not), in sharp contrast with those in the KLS model, in which the drive suppresses interfacial roughness. Defining an order parameter that accounts for the emergence of multistripe states, we map out the phase diagram in the density-drive plane and present preliminary evidence for a critical phase in this driven lattice gas. PMID- 30011594 TI - Symmetrized operator split schemes for force and source modeling in cascaded lattice Boltzmann methods for flow and scalar transport. AB - Operator split forcing schemes exploiting a symmetrization principle, i.e., Strang splitting, for cascaded lattice Boltzmann (LB) methods in two- and three dimensions for fluid flows with impressed local forces are presented. Analogous scheme for the passive scalar transport represented by a convection-diffusion equation with a source term in a novel cascaded LB formulation is also derived. They are based on symmetric applications of the split solutions of the changes on the scalar field or fluid momentum due to the sources or forces over half time steps before and after the collision step. The latter step is effectively represented in terms of the post-collision change of moments at zeroth and first orders, respectively, to represent the effect of the sources on the scalar transport and forces on the fluid flow. Such symmetrized operator split cascaded LB schemes are consistent with the second-order Strang splitting and naturally avoid any discrete effects due to forces or sources by appropriately projecting their effects for higher-order moments. All the force or source implementation steps are performed only in the moment space and they do not require formulations as extra terms and their additional transformations to the velocity space. These result in particularly simpler and efficient schemes to incorporate forces or sources in the cascaded LB methods unlike those considered previously. Numerical study for various benchmark problems in 2D and 3D for fluid flow problems with body forces and scalar transport with sources demonstrate the validity and accuracy, as well as the second-order convergence rate of the symmetrized operator split forcing or source schemes for the cascaded LB methods. PMID- 30011595 TI - Lieb-Robinson bound at finite temperatures. AB - The Lieb-Robinson bound shows that the speed of propagating information in a nonrelativistic quantum lattice system is bounded by a finite velocity, which entails the clustering of correlations. In this paper, we extend the Lieb Robinson bound to quantum systems at finite temperature by calculating the dynamical correlation function at nonzero temperature for systems whose interactions are, respectively, short range, exponentially decaying, and long range. We introduce a simple way of counting the clusters in a cluster expansion by using the combinatoric generating functions of graphs. Limitations and possible applications of the obtained bound are also discussed. PMID- 30011596 TI - Hysteresis in the Ising model with Glauber dynamics. AB - We use Glauber dynamics to study time and temperature dependence of hysteresis in the pure (without quenched disorder) Ising model on cubic, square, honeycomb lattices as well as random graphs. Results are discussed in the context of more extensive studies of hysteresis in the random field Ising model. PMID- 30011597 TI - Comment on "Spectral analysis of deformed random networks". AB - We comment on the findings presented in [Phys. Rev. E 80, 046101 (2009)10.1103/PhysRevE.80.046101] concerning the spacing distribution of the spectrum of sparsely connected random networks. We point out that for clustered networks without any connection among them the spacing distribution is not described by Poisson but rather by a superposition of multiple Gaussian orthogonal ensemble (GOE) statistics. Therefore, the spacing distribution for a network having two dense subnetworks with few connections between the two subnetworks follows a transition from two-GOE to a GOE statistics and not as the article suggests a transition from Poisson statistics to the GOE. PMID- 30011598 TI - Synchronization and entrainment of metapopulations: A trade-off among time induced heterogeneity, dispersal, and seasonal force. AB - Demographic and environmental heterogeneities are prevalent across many natural systems. Earlier studies on metapopulation models have mostly considered heterogeneities either in the demographic parameters or in the interaction strength and topology between the spatially separated patches. In contrast, here we study the dynamics of a metapopulation model where each of the uncoupled patches has different periods of oscillations (period mismatch). We show different synchronization dynamics governed by both period mismatch and dispersal in neighboring patches. Indeed, we find both appearance and disappearance of phase synchronization, quasiperiodic oscillations, and period doubling of limit cycle. We also quantify the effect of seasonal variation (entrainment) and dispersal on species synchrony using phase-response curve and a synchrony measure, which thereof identify the influence of stochasticity on species persistence through trade-off mechanisms. Our results show that trade-offs among period mismatch, dispersal, and external force can drive entrained oscillations as well as asynchronous population dynamics that structure ecological communities. PMID- 30011599 TI - Unified biophysical mechanism for cell-shape oscillations and cell ingression. AB - We describe a mechanochemical and percolation cascade that augments myosin's regulatory network to tune cytoskeletal forces. Actomyosin forces collectively generate cytoskeletal forces during cell oscillations and ingression, which we quantify by elastic percolation of the internally driven, cross-linked actin network. Contractile units can produce relatively large, oscillatory forces that disrupt crosslinks to reduce cytoskeletal forces. A (reverse) Hopf bifurcation switches contractile units to produce smaller, steady forces that enhance crosslinking and consequently boost cytoskeletal forces to promote ingression. We describe cell-shape changes and cell ingression in terms of intercellular force imbalances along common cell junctions. PMID- 30011600 TI - Curvature corrections to the nonlocal interfacial model for short-ranged forces. AB - In this paper we revisit the derivation of a nonlocal interfacial Hamiltonian model for systems with short-ranged intermolecular forces. Starting from a microscopic Landau-Ginzburg-Wilson Hamiltonian with a double-parabola potential, we reformulate the derivation of the interfacial model using a rigorous boundary integral approach. This is done for three scenarios: a single fluid phase in contact with a nonplanar substrate (i.e., wall); a free interface separating coexisting fluid phases (say, liquid and gas); and finally a liquid-gas interface in contact with a nonplanar confining wall, as is applicable to wetting phenomena. For the first two cases our approaches identifies the correct form of the curvature corrections to the free energy and, for the case of a free interface, it allows us to recast these as an interfacial self-interaction as conjectured previously in the literature. When the interface is in contact with a substrate our approach similarly identifies curvature corrections to the nonlocal binding potential, describing the interaction of the interface and wall, for which we propose a generalized and improved diagrammatic formulation. PMID- 30011601 TI - Marginal process framework: A model reduction tool for Markov jump processes. AB - Markov jump process models have many applications across science. Often these models are defined on a state space of product form and only one of the components of the process is of direct interest. In this paper we extend the marginal process framework, which provides a marginal description of the component of interest, to the case of fully coupled processes. We use entropic matching to obtain a finite-dimensional approximation of the filtering equation, which governs the transition rates of the marginal process. The resulting equations can be seen as a combination of two projection operations applied to the full master equation so that we obtain a principled model reduction framework. We demonstrate the resulting reduced description on the totally asymmetric exclusion process. An important class of Markov jump processes are stochastic reaction networks, which have applications in chemical and biomolecular kinetics, ecological models, and models of social networks. We obtain a particularly simple instantiation of the marginal process framework for mass-action systems by using product Poisson distributions for the approximate solution of the filtering equation. We investigate the resulting approximate marginal process analytically and numerically. PMID- 30011602 TI - Magnetosonic waves in a quantum plasma with arbitrary electron degeneracy. AB - Using a two-species quantum hydrodynamic model, we derive the quantum counterpart of magnetosonic waves, in a plasma with arbitrary degree of degeneracy and taking into account quantum diffraction effects due to the matter-wave character of the charge carriers. The weakly nonlinear aspects of the associated quantum magnetosonic wave are accessed by means of perturbation theory, with the derivation of a nonlinear evolution equation admitting solitons, namely, the Korteweg-de Vries equation. The degeneracy and quantum diffraction effects on soliton propagation are determined. A qualitative change on weakly nonlinear magnetosonic waves appears when quantum diffraction matches certain conditions, producing shock solutions instead of solitons, within the approximation level. We also include explicit numeric estimates and a discussion on the coupling (nonideality) parameter for quantum plasmas with intermediate degeneracy degree. PMID- 30011603 TI - Dynamic phase transitions in the presence of quenched randomness. AB - We present an extensive study of the effects of quenched disorder on the dynamic phase transitions of kinetic spin models in two dimensions. We undertake a numerical experiment performing Monte Carlo simulations of the square-lattice random-bond Ising and Blume-Capel models under a periodically oscillating magnetic field. For the case of the Blume-Capel model we analyze the universality principles of the dynamic disordered-induced continuous transition at the low temperature regime of the phase diagram. A detailed finite-size scaling analysis indicates that both nonequilibrium phase transitions belong to the universality class of the corresponding equilibrium random Ising model. PMID- 30011604 TI - Energy transfer dynamics in strongly inhomogeneous hot-dense-matter systems. AB - Direct measurements of energy transfer across steep density and temperature gradients in a hot-dense-matter system are presented. Hot-dense-plasma conditions were generated by high-intensity laser irradiation of a thin-foil target containing a buried metal layer. Energy transfer to the layer was measured using picosecond time-resolved x-ray emission spectroscopy. The data show two x-ray flashes in time. Fully explicit, coupled particle-in-cell and collisional radiative atomic kinetics model predictions reproduce these observations, connecting the two x-ray flashes with staged radial energy transfer within the target. PMID- 30011605 TI - Fluid mixtures in nanotubes. AB - The aim of the paper is the study of fluid mixtures in nanotubes by the methods of continuum mechanics. The model starts from a statistical distribution in mean field molecular theory and uses a density expansion of Taylor series. We get a continuous expression of the volume free energy with density's spatial derivatives limited at the second order. The nanotubes can be filled with liquid or vapor according to the chemical characteristics of the walls and of liquid or vapor mixture bulks. An example of a two-fluid mixture constituted of water and ethanol inside carbon nanotubes at 20^{?}C is considered. When diameters are small enough, nanotubes are filled with a liquid mixture whatever are the liquid or vapor mixture bulks. The carbon wall influences the ratio of the fluid components in favor of ethanol. The fluid mixture flows across nanotubes can be much more important than classical ones and if the external bulk is vapor, then the flow can be several hundred thousand times larger than Poiseuille flow. PMID- 30011606 TI - Consistencies and inconsistencies between model selection and link prediction in networks. AB - A principled approach to understand network structures is to formulate generative models. Given a collection of models, however, an outstanding key task is to determine which one provides a more accurate description of the network at hand, discounting statistical fluctuations. This problem can be approached using two principled criteria that at first may seem equivalent: selecting the most plausible model in terms of its posterior probability; or selecting the model with the highest predictive performance in terms of identifying missing links. Here we show that while these two approaches yield consistent results in most cases, there are also notable instances where they do not, that is, where the most plausible model is not the most predictive. We show that in the latter case the improvement of predictive performance can in fact lead to overfitting both in artificial and empirical settings. Furthermore, we show that, in general, the predictive performance is higher when we average over collections of models that are individually less plausible than when we consider only the single most plausible model. PMID- 30011607 TI - Long-time anomalous swimmer diffusion in smectic liquid crystals. AB - The dynamics of self-locomotion of active particles in aligned or liquid crystalline fluids strongly deviates from that in simple isotropic media. We explore the long-time dynamics of a swimmer moving in a three-dimensional smectic liquid crystal and find that the mean-square displacement transverse to the director exhibits a distinct logarithmic tail at long times. The scaling is distinctly different from that in an isotropic or nematic fluid and hints at the subtle but important role of the director fluctuation spectrum in governing the long-time motility of active particles. Our findings are based on a generic hydrodynamic theory and Brownian dynamics computer simulation of a three dimensional soft mesogen model. PMID- 30011608 TI - Equilibrium and dynamics of strained islands. AB - We focus in this work on the effect of the surface energy anisotropy on an elastically strained semiconductor film and in particular on its role on the coarsening dynamics of elastically strained islands. To study the dynamics of a strained film, we establish a one-dimensional nonlinear and nonlocal partial differential equation which takes into account the elastic, capillary, wetting, and anisotropic effects. We first construct an approximate stationary solution of our model using a variational method and an appropriate ansatz. This stationary solution is used to compute the chemical potential dependence on the island height. In particular, we find that the surface energy anisotropy increases the convexity of the chemical potential and this is shown to have an effect on the driving force for the coarsening. Second, we study the coarsening dynamics of an islands pair by means of numerical simulations. We find that the presence of the surface energy anisotropy may increase or decrease the coarsening time of the system. We show that this phenomenon depends on the initial heights of island pairs. We thus highlight that the driving force for the coarsening is due to the variation of the chemical potential with respect to the islands height and that two different regimes are possible. PMID- 30011610 TI - Correction. PMID- 30011609 TI - Mean-field model for the density of states of jammed soft spheres. AB - We propose a class of mean-field models for the isostatic transition of systems of soft spheres, in which the contact network is modeled as a random graph and each contact is associated to d degrees of freedom. We study such models in the hypostatic, isostatic, and hyperstatic regimes. The density of states is evaluated by both the cavity method and exact diagonalization of the dynamical matrix. We show that the model correctly reproduces the main features of the density of states of real packings and, moreover, it predicts the presence of localized modes near the lower band edge. Finally, the behavior of the density of states D(omega)~omega^{alpha} for omega->0 in the hyperstatic regime is studied. We find that the model predicts a nontrivial dependence of alpha on the details of the coordination distribution. PMID- 30011611 TI - Corrigendum. PMID- 30011612 TI - Impaired bacterial attachment to light activated Ni-Ti alloy. AB - Ni-Ti alloy due to its unique mechanical properties, is used for many types of implants. Failure of these implants can be attributed to many different factors; however infections are a common problem. In this paper, the attachment of the bacteria, Staphylococcus aureus, to the Ni-Ti surface modified by a range of processes with and without of light activation (used to elicit antimicrobial properties of materials) was assessed and related to different surface characteristics. Before the light activation the number of bacterial colony forming units was the greatest for the samples thermally oxidised at 600 degrees C. This sample and the spark oxidised samples showed the highest photocatalytic activity but only the thermally oxidised samples at 600 degrees C showed a significant drop of S. aureus attachment. The findings in this study indicate that light activation and treating samples at 600 degrees C is a promising method for Ni-Ti implant applications with inherent antimicrobial properties. Light activation was shown to be an effective way to trigger photocatalytic reactions on samples covered with relatively thick titanium dioxide via accumulation of photons in the surface and a possible increase in defects which may result in free oxygen. Moreover, light activation caused an increase in the total surface energy. PMID- 30011613 TI - Multiscale mechanical and structural characterizations of Palmetto wood for bio inspired hierarchically structured polymer composites. AB - There has been a great deal of effort focused on engineering polymer composites with hierarchical microstructures consisting of one or more ingredients that can be organized differently across multiple length scales. However, there are hierarchical microstructures that have evolved over eons in biological materials. These unique structure-property relationships may serve as templates for engineering hierarchically structured polymer composites with tailored properties. One such biological material is the Palmetto wood of South Carolina, which was successfully used as a protective structure during the Revolutionary and Civil Wars to absorb cannon shot. Through an assembly of microfibers into macrofibers embedded in a cellulose matrix, the Palmetto wood has optimized its ability to resist failure when subjected to extreme dynamic loading events, such as hurricanes. Understanding of the dynamic and static structure-property relationship in Palmetto wood can facilitate the development of new hierarchically structured polymer composites with increased resistance to failure. Therefore, the structure-property relationship in Palmetto wood has been studied using novel multiscale microstructural and mechanical characterization techniques. Models have been developed that indicate that the hierarchical structure of Palmetto wood obeys the linear Rule-of-Mixtures across multiple length scales. This understanding has led to the development of new polymer composite structures that exhibit properties similar to Palmetto wood using conventional laminated carbon fiber-epoxy composites and new polymer nanocomposites consisting of carbon nanofibers. The use of the nanofibers appears to enhance the interaction between the composite components in a manner similar to the interaction between fibers in the Palmetto wood that enables the laminated composite to behave more like the individual layers by resisting the tendency to delaminate and increasing the Weibull statistical parameters closer to those observed in Palmetto wood. PMID- 30011614 TI - Brushite (CaHPO4.2H2O) to octacalcium phosphate (Ca8(HPO4)2(PO4)4.5H2O) transformation in DMEM solutions at 36.5 degrees C. AB - The purpose of this study was to investigate the transformation of brushite (dicalcium phosphate dihydrate, DCPD, CaHPO4.2H2O) powders at 36.5 degrees C in DMEM (Dulbecco's Modified Eagle Medium) solutions. Two sets of brushite powders with different particle shapes were synthesized to use in the above DMEM study. The first of these brushite powders was prepared by using a method which consisted of stirring calcite (CaCO3) powders in a solution of ammonium dihydrogen phosphate (NH4H2PO4) from 6 to 60min at room temperature. These powders were found to consist of dumbbells of water lily-shaped crystals. The second one of the brushite powders had the common flat-plate morphology. Both powders were separately tested in DMEM-immersion experiments. Monetite (DCPA, CaHPO4) powders were synthesized with a unique water lily morphology by heating the water lily-shaped brushite crystals at 200 degrees C for 2h. Brushite powders were found to transform into octacalcium phosphate (OCP, Ca8(HPO4)2(PO4)4.5H2O) upon soaking in DMEM (Dulbecco's Modified Eagle Medium) solutions at 36.5 degrees C over a period of 24h to 1week. Brushite powders were known to transform into apatite when immersed in synthetic (simulated) body fluid (SBF) solutions. This study found that DMEM solutions are able to convert brushite into OCP, instead of apatite. PMID- 30011615 TI - Microcellular extrusion foaming of poly(lactide)/poly(butylene adipate-co terephthalate) blends. AB - Foamed poly(lactide) (PLA)/poly(butylene adipate-co-terephthalate) (PBAT) blends were processed via the microcellular extrusion process using CO2 as a blowing agent. Talc has been added to promote heterogeneous nucleation. Two types of PLA/PBAT blend systems were investigated: Ecovio, which is a commercially available compatibilized PLA/PBAT blend; and a non-compatibilized PLA/PBAT blend at the same PLA/PBAT ratio (i.e., 45:55 by weight percent). Six different formulations were investigated: pure PLA, PLA-talc, Ecovio, Ecovio-talc, non compatibilized PLA/PBAT blend, and non-compatibilized PLA/PBAT-talc. The effects of various processing parameters such as die temperature, talc and compatibilization on various foaming properties such as cell morphology, volume expansion ratio (VER), open cell content (OCC) and crystallinity were investigated. As per the DSC thermograms, it was observed that compatibilization has merged the two distinctive melting peaks of PLA and PBAT into a single peak while lowering the peak temperature. In general, the addition of talc has decreased the average cell size and VER and increased the cell density and crystallinity; however, it has varying effects on the open cell content. Compatibilization has reduced the average cell size and volume expansion but increased the cell density and had varying and no effects on the OCC and crystallinity, respectively. Similar to compatibilization, the die temperature was found to have varying and no effects on the OCC and crystallinity, respectively. Except for PLA and non-compatibilized PLA/PBAT blend, the cell size and VER of all other formulations did not vary much throughout the entire temperature range (130-150 degrees C). The cell density was found to be insensitive to die temperatures except for Ecovio and Ecovio-talc. PMID- 30011616 TI - Bioactivity and mineralization of hydroxyapatite with bioglass as sintering aid and bioceramics with Na3Ca6(PO4)5 and Ca5(PO4)2SiO4 in a silicate matrix. AB - Hydroxyapatite and Bioglass(r)-45S5 were sintered together creating new ceramic compositions that yielded increased apatite deposition and osteoblast differentiation and proliferation in vitro compared to hydroxyapatite. The sintered products characterized by X-ray diffraction, revealed hydroxyapatite as the main phase when small quantities (1, 2.5 and 5wt.%) of bioglass was added. Bioglass behaved as a sintering aid with beta-TCP (Ca3(PO4)2) being the minor phase. The amount of beta-TCP increased with the amount of bioglass added. In compositions with larger additions of bioglass (10 and 25wt.%), new phases with compositions of calcium phosphate silicate (Ca5(PO4)2SiO4) and sodium calcium phosphate (Na3Ca6(PO4)5) were formed respectively within amorphous silicate matrices. In vitro cell culture studies of the ceramic compositions were examined using bone marrow stromal cell (BMSC). Cell proliferation and differentiation of bone marrow stromal cells into osteoblasts were determined by Pico Green DNA assays and alkaline phosphatase (ALP) activity, respectively. All hydroxyapatite bioglass co-sintered ceramics exhibited larger cell proliferation compared to pure hydroxyapatite samples. After 6days in cell culture, the ceramic with Ca5(PO4)3SiO4 in a silicate matrix formed by reacting hydroxyapatite with 10wt.% bioglass exhibited the maximum proliferation of the BMSC's. The ALP activity was found to be largest in the ceramic with Na3Ca6(PO4)5 embedded in a silicate matrix synthesized by reacting hydroxyapatite with 25wt.% bioglass. PMID- 30011617 TI - The development and characterization of a novel chitosan/carbonised yucca (Yucca flaccida) bio-composite. AB - The aim of the study was to fabricate a biodegradable bio-composite using only natural biological precursors for both composite components, i.e., for a support and for a filler. Bio-composites of biomorphous structure were prepared using monolithic blocks of yucca (Yucca flaccida) carbonised at 550 degrees C as a stiff porous skeleton, and chitosan as a filler that coated the internal surface of the skeleton by a thin film. Highly porous supports and the resultant biomorphous composites were characterized by means of TGA, SEM, low-temperature physical adsorption of nitrogen, as well as electric and ultrasonic measurements. The resultant bio-composites were found to be very light materials with density of about 0.13g/cm3 and very porous (over 90%). They were found to be hierarchically ordered anisotropic structures with a stiff skeleton of dynamic elastic moduli up to 0.8GPa. The specific surface area was found to be 72m2/g giving a surface area of chitosan film equal to about 12m2 for a block sample of a volume of 2cm3. Covering porous support by thin film of chitosan resulted in the increase of electrical conductivity of the resultant composite. PMID- 30011618 TI - Effect of polyvinyl alcohol additive on the pore structure and morphology of the freeze-cast hydroxyapatite ceramics. AB - Porous hydroxyapatite (HAP) ceramics with different morphologies were fabricated by the freeze casting method. The morphologies of HAP ceramics were modified by adjusting the concentration of polyvinyl alcohol (PVA) additive in the HAP slurries. HAP ceramics without PVA additive were composed of non-interconnected macroscopic lamellar pores and porous ceramic walls. With PVA additive, the HAP ceramics were made up of small lamellar pores or three-dimensional reticulate pores and porous ceramic walls. PVA additive had no effect on the phase composition of HAP ceramics. The open porosity and pore connectivity were improved because of the addition of PVA. PMID- 30011619 TI - Preparation, characterization and cytocompatibility of bioactive coatings on porous calcium-silicate-hydrate scaffolds. AB - The major goal of this research was to investigate and characterize the deposition of a biomimetic apatite-like coating onto the surface of 3D porous calcium-silicate-hydrate scaffolds with suitable bioactivity for potential application in bone tissue engineering. Basically, Portland cement, water, sand and lime were mixed for preparing the slurry which was poured into molds, and fine aluminum powder was added as foaming agent resulting on the formation of porous 3D structures. After aging for 28days, these porous inorganic scaffolds were immersed in calcium chloride supersaturated solution in PBS for 7days at 37 degrees C for the biomimetic layer deposition. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier Transformed Infrared Spectroscopy (FTIR) techniques were used in order to characterize the porous scaffolds and the apatite-like biomimetic coating. The results have showed that 3D constructs were successfully produced with interconnected porosity, compressive strength and cytocompatibility appropriate for potential use as an alternative in trabecular bone repair. PMID- 30011620 TI - Nanocrystalline hydroxyapatite bioceramic using microwave radiation: Synthesis and characterization. AB - In this work, we synthesized bioactive hydroxyapatite (Ca10(PO4)6(OH)2, HAp) ceramic powder in the lower-end of nano-regime using microwave radiation, which offers several advantages. The powder was synthesized using calcium nitrate tetrahydrate and sodium phosphate dibasic anhydrous as the starting materials. EDTA served as the complex reagent. The pH of the final suspension was adjusted to 9 by adding ammonium hydroxide. Applied microwave power of 600W, pH of the suspension, mole ratio of Ca/P in the staring chemicals, and the chelating effect of EDTA served as the factors in the synthesis of nanocrystalline HAp powder. The synthesized powder was studied using various characterizing techniques viz., XRD, SEM, HR-TEM, EDS, TG/DTA and FT-IR to determine powder morphology, particle-size, crystallinity, phases, elemental composition and thermal behavior. Results confirmed highly crystalline nano-powder (5-30nm) with elemental composition of Ca and P in HAp phase and possessed mixed (elliptical and rod-shape) morphology. Using the Scherrer formula, the average crystallite size was found to be 12nm. The FT-IR confirmed that the powder is of typical apatite structure. Thermal analysis showed a remarkably lower initial dehydroxylation temperature, compared to micron sized HAp, as reported in literature. PMID- 30011621 TI - Preparation of chitosan/magnetite composite beads and their application for removal of Pb(II) and Ni(II) from aqueous solution. AB - A simple and effective process has been proposed to prepare chitosan/magnetite nanocomposite beads with saturation magnetization value as high as uncoated Fe3O4 nanoparticles (ca. 54emu/g). The reason was that the coating chitosan layer was so thin that it did not affect magnetic properties of these composite beads. Especially, chitosan on the surface of the magnetic Fe3O4 nanoparticles is available for coordinating with heavy metal ions, making those ions removed with the assistance of external magnets. Maximum adsorption capacities for Pb(II) and Ni(II), occurred at pH 6 and under room temperature were as high as 63.33 and 52.55mg/g respectively, according to Langmuir isotherm model. These results permitted to conclude that chitosan/magnetite nanocomposite beads could serve as a promising adsorbent not only for Pb(II) and Ni(II) (pH=4-6) but also for other heavy metal ions in wastewater treatment technology. PMID- 30011622 TI - Capture and release of genomic DNA by PEI modified Fe3O4/Au nanoparticles. AB - Polyethylenimine (PEI) modified Fe3O4/Au nanoparticles were synthesized in aqueous solution and characterized by photo correlation spectroscopy (PCS) and vibrating sample magnetometer (VSM). The so-obtained Fe3O4/Au-PEI nanoparticles were capable of efficient electrostatic capture of DNA. The maximum amount of genomic DNA captured on 1.0mg Fe3O4/Au-PEI nanoparticles was 90MUg. The DNA release behavior was studied and the DNA recovery from Fe3O4/Au-PEI nanoparticles approached 100% under optimal conditions. DNA extraction from mammalian cells using Fe3O4/Au-PEI nanoparticles was successfully performed. Up to approximately 43.1MUg of high-purity (OD260/OD280 ratio=1.81) genomic DNA was extracted from 10mg of liver tissue. The results indicated that the prepared Fe3O4/Au-PEI nanoparticles could be successfully used for DNA capture and release. PMID- 30011623 TI - A photoimmobilizable sulfobetaine-based polymer for a nonbiofouling surface. AB - A novel photoreactive polymer containing sulfobetaine polar groups was prepared by copolymerization of two kinds of methacrylic acids with sulfobetaine and azidoaniline. The polymer was photoimmobilized on polyester and polystyrene surfaces. Its effects on surface modification were investigated from its interactions with water, proteins and cells. Polymer immobilization altered both of the plain surfaces to becoming hydrophilic in a similar range of static contact angles (12.5+/-1.6 degrees on polyester and 14.7+/-2.2 degrees on polystyrene). This suggests that the surfaces were covered with sulfobetaine polar groups. Micropattern immobilization was carried out on both polymers using a photomask. The formed pattern was identical to the photomask, showing that the polymer was formed in response to ultraviolet irradiation. Measurements using atomic force microscopy showed that the polymer was formed at a thickness of 550nm, demonstrating that the polymer was cross-linked with itself and with the substrate molecules. Measurements using time-of-flight secondary ion mass spectrometry detected an abundance of sulfur-containing ions in the patterned polymer, confirming that sulfobetaine had been immobilized. Protein adsorption and mammalian cell adhesiveness were reduced markedly on the immobilized regions. The reduction of cell adhesiveness was concentration-dependent for the immobilized polymer on polyester surfaces. In conclusion, a novel sulfobetaine containing polymer was immobilized photoreactively on conventional polymer surfaces and significantly reduced interactions with proteins and mammalian cells. PMID- 30011624 TI - Poly(glycidyl methacrylate) beads embedded cryogels for pseudo-specific affinity depletion of albumin and immunoglobulin G. AB - Depletion of high abundant proteins like albumin and immunoglobulin G (IgG) can be beneficial in the analysis of serum proteins. For this purpose, Cibacron Blue F3GA and iminodiacetic acid (IDA)-Cu2+ containing poly(glycidyl methacrylate) (PGMA) beads (1.6um in diameter) were embedded into the poly(hydroxyethyl methacrylate) (PHEMA) cryogel. The PGMA beads were prepared by dispersion polymerization. The PGMA beads were modified with Cibacron Blue F3GA and iminodiacetic acid (IDA)-Cu2+ for simultaneous albumin and IgG depletion, respectively. The PHEMA cryogel was synthesized by free radical polymerization in the presence of the modified PGMA beads. The PHEMA and PHEMA/PGMA composite cryogels were characterized by swelling measurements and scanning electron microscopy (SEM). Protein depletion studies were carried out in a continuous experimental set-up in a stacked column. Albumin adsorption capacity of the PGMA Cibacron Blue F3GA beads embedded PHEMA cryogel (PHEMA/PGMA-Cibacron Blue F3GA) was 342mg/g and IgG adsorption capacity of the PGMA-IDA-Cu2+ beads embedded PHEMA cryogel (PHEMA/PGMA-IDA-Cu2+) was 257mg/g. The composite cryogels depleted albumin and IgG from human serum with 89.4% and 93.6% efficiency, respectively. High desorption values (over 90% for both modified cryogels) were achieved with 0.05M phosphate buffer containing1.0M NaCl. PMID- 30011625 TI - Erratum to "A Review of Clinical Tests and Signs for the Assessment of Ulnar Neuropathy" [J Hand Ther 2009;22(3):209-220]. PMID- 30011626 TI - Corrigendum. PMID- 30011627 TI - Correction. PMID- 30011628 TI - Frozen pulp extracts of camu-camu (Myrciaria dubia McVaugh) attenuate the hyperlipidemia and lipid peroxidation of Type 1 diabetic rats. AB - Several epidemiological and experimental studies demonstrate that modulation of inflammatory response and oxidative stress by natural phytochemicals is a promising strategy to prevent and treat many chronic inflammatory diseases. Camu camu is an Amazonian fruit with a high content of antioxidants, especially phenolic compounds and vitamin C. In the present study we evaluated the in vivo effects of chronic ingestion of raw extracts derived from camu-camu (Myrciaria dubia McVaugh) frozen pulp on plasma lipid profile and oxidative stress in streptozotocin-induced diabetic rats. Oral administration of camu-camu raw extracts significantly increased plasma antioxidant activity, reduced triacylglycerol and total cholesterol and lipid peroxidation in the plasma of streptozotocin-induced diabetic rats. However, no effect was observed on glucose metabolism of diabetic rats, probably due to the severity of this model. PMID- 30011629 TI - Antioxidant balance after long-term consumption of standard diets including bread crust glycated compounds by adult rats. AB - The objective of the present study was to evaluate the in vivo uptake of antioxidant capacity (AC) in rats fed on diets containing commonly consumed MRPs obtained from bread crust (BC) at long-term. Additionally we focused on understanding the effects of those compounds on the oxidative status of these animals. The global antioxidant response of the diets was measured. During 88 days, rats were fed control diet or diets containing BC or its soluble high molecular weight, soluble low molecular weight or insoluble fractions (BC, HMW, LMW and insoluble diets, respectively). In the final week, faeces from different dietary treatments were collected to determine the AC still retained in it and then calculate the uptake efficiency of AC. Animals were sacrificed and the liver and biceps brachii muscle were removed to investigate catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels. The addition of BC or its derivatives in the diet led to a significantly higher AC excreted with the faeces and to a lower uptake rate (around 90% in these groups vs. 98% in the control group). The muscle and liver showed different oxidative status after consumption of experimental diets. The muscle evidenced certain oxidative damage due to the BC consumption, more pronounced when the isolated fractions were ingested. However, the BC diet, but not the rest, induced a positive effect on the antioxidant defence in the liver, the key organ for xenobiotic metabolism, with increases in the CAT and GPx activities as well as the GSH stock (56, 20 and 14% with respect to the control group, respectively). The discordance found between the antioxidant status of muscle and antioxidant status of liver highlights the importance of considering several tissues to establish the effect of glycated compounds on the redox balance in an organism. PMID- 30011630 TI - Chromium in soil and tea (Camellia sinensis L.) infusion: Does soil amendment with municipal solid waste compost make sense? AB - In this study, two clones (TV1 and TV23) of tea (Camellia sinensis L.) plants were allowed to grow in earthen pots in a greenhouse, treated with municipal solid waste compost (MSWC) to study the effect of MSWC to the fractionation of chromium (Cr) ion, plant biomass production, plant uptake of Cr, fate of Cr in soils through risk assessment code (RAC) and Cr in tea infusion. Increasing rate of MSWC applications increased both total Cr and DTPA-extractable Cr in soil. Fractionation studies have revealed that Cr in soils was mainly associated with the organic and Fe-Mn oxide and the contribution of residual fractions is nearly 87.7-96.1%. The biomass yields of the tea plants were increased with the increase in MSWC, indicating that nutrient uptake of the plants from MSWC was dependent on the root-MSWC interface. High accumulation of Cr in the root of tea plants and its subsequent lower movement towards aerial parts corroborated the hypothesis that the root of the tea plants acts as a buffer. In this experiment the transfer factor was <1, indicating that the tea plants did not have a significant phytoextraction potential. In the application of 10tha-1 MSWC, Cr was found to be in medium risk for both clones whereas the application of 8tha-1 MSWC showed medium risk with respect to the Cr for TV23 clone applying RAC. Therefore, MSWC amendment rate above 8tha-1 increased the total biomass of the tea plants but posed a threat on environmental prospect with respect to Cr. It was also found that only 2.5MUgL-1 to 4.8MUgL-1 Cr was present in tea infusion when infusion was prepared from tea leaves receiving different doses of MSWC. Furthermore, stepwise regression technique was applied to choose the most significant regression variables to express the variability in leaves, stem, main root and feeder root biomass. The one-way analysis of variance along with the Dunnett's multiple comparison method was used to determine the significant differences between the means of different treatments. On the application of hierarchical cluster analysis, treatments were grouped in two distinct homogeneous groups. PMID- 30011631 TI - Pharmacokinetics of caffeine and its metabolites in plasma and urine after consuming a soluble green/roasted coffee blend by healthy subjects. AB - Coffee is widely consumed worldwide; therefore, the methylxanthines contained in coffee, mainly caffeine (CF), are among the most abundant bioactive compounds in our diet. In the present work, the bioavailability and metabolism of methylxanthines in a commercial soluble green/roasted coffee blend was studied. After a 3-day restriction of methylxanthine-containing foods, fasting healthy subjects (12 men and women) consumed the coffee product containing 70.69mg CF and 0.119mg theobromine (TB). Plasma samples were taken before (t=0h) and after coffee consumption at different time points (0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 9, 10 and 12h). Urine was collected at baseline (-2-0h) and at different intervals (0 2, 2-5, 5-8, 8-12 and 12-24h). Samples were analyzed by HPLC-DAD and LC-MS-QToF, and pharmacokinetic parameters were calculated. CF was the main methylxanthine found in plasma (Cmax=10.50MUM, Tmax=1.2h). In addition, seven methylxanthines and methyluric acids were detected between 0.5 and 12h after coffee intake, paraxanthine (PX) being the major metabolite (Cmax=3.36MUM), followed by 1 methyluric acid (1-MU; Cmax=1.44MUM) and 1-methylxanthine (1-MX; Cmax=1.27MUM), identified in plasma samples for the first time. In 24h urine, eleven methylxanthines and methyluric acids were detected, 1-MU being the major metabolite (Cmax=150.52MUM, Tmax=12h) amounting to 67.7% of the total urinary metabolites. In conclusion, a rapid absorption, metabolization and excretion of caffeine and its derived methylxanthines and methyluric acids have been observed after consumption of a green/roasted coffee product. PMID- 30011632 TI - Microencapsulation of beta-galactosidase with different biopolymers by a spray drying process. AB - The aim of this work was to investigate the possibility of producing microparticles containing beta-galactosidase, using different biopolymers (arabic gum, chitosan, modified chitosan, calcium alginate and sodium alginate) as encapsulating agents by a spray-drying process. This study focused on the enzyme beta-galactosidase, due to its importance in health and in food processing. Encapsulation of beta-galactosidase can increase the applicability of this enzyme in different processes and applications. A series of beta-galactosidase microparticles were prepared, and their physicochemical structures were analyzed by laser granulometry analysis, zeta potential analysis, and by scanning electron microscopy (SEM). Microparticles with a mean diameter around 3MUm have been observed, for all the biopolymers tested. The microparticles formed with chitosan or arabic gum presented a very rough surface; on the other hand, the particles formed with calcium or sodium alginate or modified chitosan presented a very smooth surface. The activity of the enzyme was studied by spectrophotometric methods using the substrate ONPG (O-nitrophenyl-beta,d-galactopyranoside). The microencapsulated beta-galactosidase activity decreases with all the biopolymers. The relative enzyme activity is 37, 20, 20 and 13%, for arabic gum, modified chitosan, calcium alginate and sodium alginate, respectively, when compared with the free enzyme activity. The enzyme microparticles formed with arabic gum shows the smallest decrease of Vmax, followed by the calcium alginate, sodium alginate, and modified chitosan. PMID- 30011633 TI - Molecular interaction between (-)-epigallocatechin-3-gallate and bovine lactoferrin using multi-spectroscopic method and isothermal titration calorimetry. AB - The molecular interaction between bovine lactoferrin (LF) and (-) epigallocatechin-3-gallate (EGCG) was investigated in an aqueous solution at pH6.0. The presence of EGCG did not change the size and turbidity of LF-EGCG complex in an aqueous solution until the LF/EGCG molar ratio was over a critical value of 1:25. The fluorescence spectra revealed that both tryptophanyl and tyrosyl groups of LF were associated with the interaction with EGCG. The infrared spectra of freeze-dried LF-EGCG complexes showed that they were different from those of LF and EGCG alone, FTIR and far-UV CD results indicated that EGCG induced a progressive increase in the proportion of alpha-helix structure at the cost of beta-sheet structure of LF. The near-UV CD data testified that LF tertiary conformation was altered in the presence of EGCG. Isothermal titration calorimetry (ITC) analysis implied that EGCG was spontaneously bound to LF by a two-stage mechanism, about 31 EGCG molecules were integrated with 1 molecule LF and hydrogen bonds were always involved in the assembly process. PMID- 30011634 TI - Infusion, decoction and hydroalcoholic extracts of leaves from artichoke (Cynara cardunculus L. subsp. cardunculus) are effective scavengers of physiologically relevant ROS and RNS. AB - The globe artichoke (Cynara cardunculus L. subsp. cardunculus) is a perennial plant cultivated in the Mediterranean region and Americas for its edible young flower heads and as an interesting source of bioactive compounds. The present study was undertaken to evaluate scavenging capacity against the most physiologically relevant reactive oxygen species (ROS) and reactive nitrogen species (RNS) of three different extracts from artichoke leaves (infusion, decoction and hydroalcoholic) using different solvents, commonly accepted for human consumption (water and a mixture of ethanol/water). Additionally, the phenolic compounds in each extract were identified and quantified by high performance liquid chromatography coupled to diode array and mass spectrometer detectors (HPLC-DAD-MS/MS). Chlorogenic acid was the major phenolic compound identified in all extracts, followed by 1,3-dicaffeoylquinic acid (cynarin), luteolin-7-rutinoside and the infusion extract presented the highest phenolic content (108mg/g extract, dry basis). In general, the extracts of artichoke leaves presented a remarkable capacity to scavenge ROS and RNS with IC50 values in a low MUg/mL range (3.4-43MUg/mL). These findings suggest that artichoke could be a potential source of natural antioxidants and has an undeniable nutraceutical value. PMID- 30011635 TI - Production, characterization and foamability of alpha lactalbumin/glycomacropeptide supramolecular structures. AB - The study of protein interactions has generated great interest in the food industry. Therefore, research on new supramolecular structures shows promise. Supramolecular structures of the whey proteins alpha-lactalbumin and glycomacropeptide were produced under varying heat treatments (25 to 75 degrees C) and acidic conditions (pH3.5 to 6.5). Isothermal titration calorimetry experiments showed protein interactions and demonstrated that this is an enthalpically driven process. Supramolecular protein structures in aqueous solutions were characterized by circular dichroism and intrinsic fluorescence spectroscopy. Additional photon correlation spectroscopy experiments showed that the size distribution of the structures ranged from 4 to 3545nm among the different conditions. At higher temperatures, lower pH increased particle size. The foamability of the supramolecular protein structures was evaluated. Analysis of variance and analysis of regression for foaming properties indicated that the two-factor interactions between pH and temperature exhibited a significant effect on the volume and stability of the foam. PMID- 30011636 TI - Potential of volatile compounds produced by fungi to influence sensory quality of coffee beverage. AB - Fungi are known producers of a large number of volatile compounds (VCs). Several VCs such as 2,4,6 trichloroanisole (TCA), geosmin and terpenes have been found in coffee beverages, and these compounds can be responsible for off-flavor development. However, few studies have related the fungal contamination of coffee with the sensory characteristics of the beverage. The aim of this research was to investigate the production of VCs by fungi isolated from coffee and their potential as modifiers of the sensory coffee beverage quality. Three species were isolated from coffee from the southwest of Sao Paulo state and selected for the study: Penicillium brevicompactum, Aspergillus luchuensis (belonging to section Nigri) and Penicillium sp. nov. (related to Penicillium crustosum). VCs produced by the fungal inoculated in raw coffee beans were extracted and tentatively identified by SPME-GC-MS. Different VCs that may interfere in the coffee beverage quality were detected in the raw coffee beans inoculated with these fungal species (mainly A. luchuensis). Oct-1-en-3-ol was detected in the raw coffee inoculated with A. luchuensis. This compound, which is characterized by earthy and moldy/mushroom aroma, can be related to negative characteristics of coffee beverage in sensory analysis. On the other hand, the presence of some fungal species in the coffee, even at a high percentage of infection, did not necessarily result in loss of the sensorial quality of the beverage, since the samples with a high infection of P. brevicompactum showed positive sensory evaluation. PMID- 30011637 TI - Natural antioxidants against lipid-protein oxidative deterioration in meat and meat products: A review. AB - Oxidation is a well-known non-microbial cause of quality loss in meat. Oxidative stress occurs due to uneven generation of free radicals reactive oxygen species (ROS) and reactive nitrogen species (RNS) which triggers oxidative and/or nitrosative stress and damage of macromolecules including the lipid and protein fractions. Failure of synthetic antioxidants to combat multiple health risks associated with this stress and maintenance of functional integrity of oxidised meat hitherto remains a challenge to the meat industry. A search for a viable alternative amidst the unexploited novel sources of natural antioxidants stands as a sustainable option for preserving the meat quality. In this paper, the potential use of bioactive compounds in medicinal plants is reviewed as phytoremedy against lipid-protein oxidation. Synergistic antimicrobial potentials of these natural antioxidants are also revealed against oxidative deterioration in meat and meat products and, for enhancing their functional properties. PMID- 30011638 TI - Observations on the water distribution and extractable sugar content in carrot slices after pulsed electric field treatment. AB - The impact of pulsed electric field (PEF) processing conditions on the distribution of water in carrot tissue and extractability of soluble sugars from carrot slices was studied. Time domain NMR relaxometry was used to investigate the water proton mobility in PEF-treated carrot samples. Three distinct transverse relaxation peaks were observed in untreated carrots. After PEF treatment only two slightly-overlapping peaks were found; these were attributed to water present in the cytoplasm and vacuole of carrot xylem and phloem tissues. This post-treatment observation indicated an increase in water permeability of tissues and/or a loss of integrity in the tonoplast. In general, the stronger the electric field applied, the lower the area representing transverse relaxation (T2) values irrespective of treatment duration. Moreover an increase in sucrose, beta- and alpha-glucose and fructose concentrations of carrot slice extracts after PEF treatment suggested increases in both cell wall and vacuole permeability as a result of exposure to pulsed electric fields. PMID- 30011639 TI - Depuration kinetics of murine norovirus in shellfish. AB - This study evaluates and compares the uptake rates and depuration kinetics of murine norovirus (MNV-1), as a human norovirus surrogate, in Manila clams (Venerupis philippinarum) and Mediterranean mussels (Mytilus galloprovincialis). Ten trials of 70kg/trial (five with each mollusk) were performed. Mollusks were subjected to a controlled bioaccumulation step of 24h with 102pfu MNV-1/mL seawater. Then, mollusks were relocated in an experimental depuration system for 7days. Viral contamination was quantified after bioaccumulation and then daily during depuration by reverse transcription-real time PCR (RT-qPCR) with TaqMan probes. Infectivity assays were conducted to test the presence of infectious viral particles at the end of the depuration period. Results showed significant differences in the uptake and removal viral rates between molluscan species. The average viral uptake for clams and mussels were 5.4*106 and 4.0*105RNA copies/g digestive tissue respectively, representing an uptake rate >90% higher in clams. The average reductions with regard to the initial levels were 60.5% for clams and 91.6% for mussels. On the other hand, a similar logarithmic trend line in MNV-1 depuration kinetics was observed in both bivalves, with two differentiated phases: an initial rapid reduction of viruses during the first 24-72h of depuration, and a subsequent stabilization with a slower depuration rate. All trials with clams and mussels showed significant viral reductions but remaining virus were still infectious at the end of the process. PMID- 30011640 TI - Chemical composition, nutritional value and antioxidant properties of autochthonous Prunus avium cultivars from Campania Region. AB - During a screening program aimed at the evaluation of antioxidative and antiproliferative properties, as well as nutritional properties of local edible plants, two endemic sweet cherry cultivars ('Del Monte' and 'Della Recca') were of interest. Macronutrient components (proteins, carbohydrates and lipids) of both the cherry cultivars were determined as well as free and total amino acids. Pomological traits were defined. HPLC-ESI/MSn analysis, carried out on phenolic extracts properly prepared by extractive techniques from freeze dried fruits of both the cherry cultivars, showed that investigated cultivars differed in their colorless phenolic composition. Hydroxycinnamoyl quinic acid derivatives were present in both the cherry cultivars. 'Della Recca' cv. was particularly rich in 4-O-coumaroyl quinic and 5-O-caffeoylquinic acid, whereas quercetin-3-O rutinoside was the main phenol compound of 'Del Monte' cultivar. The antiradical properties of the extracts were investigated by DPPH and ABTS methods. 'Della Recca' cv. cherries exhibited a pronounced antiradical activity: at 62.5MUg/mL dose level ABTS radical cation was converted in its reduced form by 88.7% and DPPH radical was reduced by 75.3%. The antiproliferative efficacy of 'Della Recca' and 'Del Monte' extracts were evaluated towards five cancer cell lines (HepG2, A549, HeLa, SK-B-NE(2)-C, and SH-SY5Y) through MTT assay. 'Della Recca' phenol extract showed a dose-dependent inhibiting activity towards cervical cancer HeLa cell line. PMID- 30011641 TI - Structure, physicochemical properties, and uses of millet starch. AB - There has been increased interest in millet utilization due to the various "rediscovered" health benefits and also critical role in food security in semiarid areas of Africa and Asia. The major component of millets is starch, which may amount up to 70% of the seed and determines the quality of millet products. This review summarizes the current knowledge of the isolation, chemical composition, structure, physicochemical properties, enzyme susceptibility, modifications, and uses of millet starch. Lack of systematic knowledge of millet starch seriously hinders further development of millets as sustainable crops. Needed research to diversify the variations in the quality and to improve the utilization of this starch is suggested. PMID- 30011642 TI - Inactivation of Lactobacillus plantarum WCFS1 during spray drying and storage assessed with complementary viability determination methods. AB - Survival of Lactobacillus plantarum WCFS1 spray-dried and stored under different conditions was investigated using complementary methods. One method involved a cell membrane integrity viability-based determination, the other assessed cell growth behavior in a liquid medium by means of detection time or by conventional plating. Survival decreased below 95% when spray drying was carried out at higher outlet spray drying temperatures (Tout>70 degrees C). However, the membrane integrity method provided higher residual viability values compared to the detection time and conventional plating. This suggests that loss of viability may be due to a combination of damage to intracellular components and cell membrane. Also during storage viability based on growth behavior declined faster and was more temperature dependent compared to the viability as determined by the membrane integrity method. Also here additional damage to intracellular components is expected responsible to loss of viability. Major conclusion is that one should not only rely on a cell-membrane integrity based method to assess survival during spray drying and storage of bacteria. Previous studies that did so most probably underestimated viability as critical damage to intracellular components was not assessed. PMID- 30011644 TI - Instrumental evaluation and influence of gender and/or age among consumers on textural preference of deep-fried peanuts. AB - The present study was conducted to evaluate instrumental properties, to perform micro-structural analysis, and to research textural preference among Japanese general consumers (n=330) using raw and deep-fried peanuts with varying frying periods (2, 4, 6, 9, 12, and 15min) at 150 degrees C. The relationship between consumer preference and the influence of gender and/or age among consumers regarding textural preference were evaluated. With increased frying time, the force at failure (FF) decreased from 26N to 18N, and the distance at failure (DF) decreased from 2.4mm to 1.0mm indicating increasing brittleness. A cross sectional micro-structural image indicated increasing heterogeneity during frying. The mean preference score for 4min-, 6min-, 9min-, 12min-, and 15min fried peanuts (3.0 to 3.4) exceeded that for 2min-fried peanuts (2.5 to 2.6), indicating that consumers liked easily broken peanuts. The tendency was more remarkable for middle-aged and elderly subjects (30years old and older) than for young subjects (15 to 29years old). Thus, textural perception may play a more important role in textural preference for older individuals than for young individuals. The Mann-Whitney's U test indicated no difference in textural preference between genders. PMID- 30011643 TI - Metabolomic fingerprints of 21 date palm fruit varieties from Egypt using UPLC/PDA/ESI-qTOF-MS and GC-MS analyzed by chemometrics. AB - Date palm fruits of the species Phoenix dactylifera exhibit a great diversity in sensory attributes including skin color, smell and taste. This study attempts to elucidate the primary and secondary metabolite profiles of 21 date varieties from Egypt. A major difficulty is sugar rich matrix and skin-fibers embedding the secondary metabolites. A total of 49 metabolites extracted from the fruit skin were evaluated in a UPLC/PDA/ESI-qTOF-MS based metabolomics study. The total phenolic contents of the varieties varied from 233 to 1897mg/100g (2.3-19g/kg) dry weight. The predominant flavones were glycosides of luteolin and apigenin, quercetin conjugates were the principal flavonols, whereas caffeoyl shikimic acid was the main hydroxycinnamic acid conjugate. Aside from these major phenolic classes, a group of sphingolipids, fatty and other organic acids was also identified. The total non-fatty organic acid content correlates with reported shelf lives. GC-MS was further utilized to localize primary metabolites in fruits (i.e. sugars and organic acids) with glucose and fructose accounting for up to 95% of TIC among most varieties. Principal component and clustering analyses reveal that flavonols and sugars, both contribute the most to variety classification. This study provides the most complete map for polyphenol & sugar distribution in Egyptian date fruit varieties. By describing the metabolite profiles in a diverse dataset of P. dactylifera, this study provides the basis for future investigations of date fruit nutritional value beyond providing energy and its potential for nutraceutical enhancement or storability. PMID- 30011645 TI - Decontamination efficacy of neutral electrolyzed water to eliminate indigenous flora on a large-scale of cabbage and carrot both in the laboratory and on a real processing line. AB - The decontamination efficacy of neutral electrolyzed water (NEW) was evaluated using shredded cabbages and carrots in both a scalable laboratory system (experiment I) and an actual processing line in a plant (experiment II). In experiment I, the antimicrobial effect of highly concentrated NEW (up to the maximum regulated level: 200ppm) was tested to determine the appropriate conditions for use in an actual plant test: (1) hypochlorous acid (HClO) concentration (100, 150, and 200ppm), (2) ratio of sample weight to NEW volume (1:5, 1:10, and 1:20), and (3) treatment time (5, 10, 20, and 30min), using 2kg of shredded cabbages and carrots. In experiment II, the feasibility of the NEW treatment was validated on an actual processing line (treatment unit: 20kg), including cutting, three washing steps (two air bubble washes for 5min each and 150ppm NEW for 5min at ratio of 1:10), rinsing (5min), and dehydration (5min). Overall, the microbial reductions tended to increase as the HClO concentration, ratio of sample to NEW, and treatment time increased. The results obtained from experiment I indicated that the maximum conditions (NEW 200ppm, 1:20, 30min) achieved 3.3-3.5 log CFU/g reductions in the coliform counts. After treatment with 200ppm NEW for >10min, however, there were noticeable color changes (color differences, DE>5.0) in both the shredded cabbages and carrots. In the experiment II, the microbial populations were not affected by cutting and two air bubble treatments, whereas washing with NEW greatly reduced both the aerobic plate counts (1.93-2.17 log CFU/g) and coliform counts (0.97-1.51 log CFU/g). More than 2 log CFU/g of indigenous flora were reduced from raw materials to final products with both shredded cabbages (2.05-2.48 log CFU/g) and carrots (2.34-2.76 log CFU/g). These results may provide useful recommendations for the practical application of highly concentrated NEW in the fresh-cut produce industry to improve the microbiological safety without quality deterioration. PMID- 30011646 TI - Addition of probiotic bacteria in a semi-hard goat cheese (coalho): Survival to simulated gastrointestinal conditions and inhibitory effect against pathogenic bacteria. AB - In this study, the survival of the probiotics Lactobacillus acidophilus (LA-5), Lactobacillus casei subsp. paracasei (L. casei 01) and Bifidobacterium lactis (BB12) incorporated in a Brazilian semi-hard goat cheese (coalho) when exposed to in vitro simulated conditions of digestion was assessed. The inhibitory effects of these probiotic bacteria were also evaluated against Listeria monocytogenes and Staphylococcus aureus in the goat coalho cheese during refrigerated storage. At the end of the in vitro digestion, all of the probiotic tested strains presented decreased (p<0.05) viable cell counts (5.5-6.0logcfu/g) with respect to those determined before exposure to the mouth conditions (7-8logcfu/g). L. casei subsp. paracasei presented inhibition rate of 7.87% and 23.63% against S. aureus on the 14th and 21st day of storage at 10 degrees C, respectively; against L. monocytogenes these values were 12.96 and 32.99%. Positive inhibition rates of B. lactis toward S. aureus were found on the 1st, 14th and 21st days of storage (16.32%, 10.12% and 3.67%, respectively); and against L. monocytogenes only on the 1st day of storage (3.28%). From these results, goat coalho cheese could be an interesting carrier of probiotic strains of L. acidophilus, L. casei subsp. paracasei and B. lactis. Moreover, L. casei subsp. paracasei, could be used as protective culture for delaying the growth of S. aureus and L. monocytogenes in goat coalho cheese. PMID- 30011647 TI - In vitro antioxidant and anti-inflammation properties of lactic acid bacteria isolated from fish intestines and fermented fish from the Sanriku Satoumi region in Japan. AB - The Ministry of the Environment, Government of Japan, defines a Satoumi as a coastal area where biological productivity and biodiversity has increased through human interaction. As a way to identify new starters and probiotics, we isolated and screened lactic acid bacteria (LAB) with acid, bile, and salt resistance from the intestines of 23 fish and 11 fermented fish samples obtained from the northeastern (Sanriku) Satoumi region of Japan. Of the 301 isolates, 75 strains were selected as LAB, 6 of which clearly showed increased antioxidant activities (DPPH and O2- radical scavenging and Fe-reducing power) in their cultured broth. Four isolates (S-SU1, 3-5) were identified as Lactobacillus plantarum. The two other strains (S-SU2, 6) identified were Lactococcus lactis and Pediococcus pentosaceus. In these in vitro assays, Lc. lactis S-SU2, isolated from sea pineapple kimchi showed the highest radical scavenging capacity. Moreover, the protective effect of heat-killed cells against the toxicity of 3mM H2O2 on Saccharomyces cerevisiae was the highest for Lb. plantarum S-SU1 isolated from a salted squid product, followed by P. pentosaceus S-SU6 isolated from the intestines of blue mackerel. Furthermore, Lb. plantarum S-SU5 showed inhibitory effect against the toxicity of 3mM H2O2 in human enterocyte-like HT-29-luc cells and on nitrite (NO) production in mouse RAW264.7 macrophage cells, which was induced by Escherichia coli O111 lipopolysaccharide (LPS). These results suggest that the selected LAB strains are potential starters and/or functional components with antioxidant and anti-inflammatory properties. PMID- 30011648 TI - Sensory profiling of Egyptian goose (Alopochen aegyptiacus) meat. AB - No sensory profile information is available for Egyptian goose (Alopochen aegyptiacus) meat. The aim of this study was to conduct descriptive analysis in order to establish the sensory attributes of the breast portion of this species. Meat from guineafowl, Pekin duck, ostrich and broiler chicken were used as reference species. Egyptian goose meat had a very intense game aroma, game flavour and metallic aftertaste, mainly attributable to the muscle's high percentage of polyunsaturated fatty acids and Fe. Egyptian goose meat was also low in tenderness and high residue; this may be due to the high level of physical exercise endured by the breast muscle. Egyptian goose meat proved to be similar to ostrich meat regarding appearance (dark, red colour) and low tenderness, but differed from guineafowl and broiler chicken, the latter two meat types illustrated a higher degree of juiciness and tenderness. These results of Egyptian goose meat can now be used for further sensory studies as it is important to also establish the influence of extrinsic factors such as season and gender on the meat quality of this waterfowl species. PMID- 30011649 TI - Dietary fatty acid determines the intestinal absorption of lutein in lutein deficient mice. AB - The present investigation was undertaken to study the influence of dietary lipids [olive (OO), coconut (CNO), groundnut (GNO), soybean (SBO), sunflower (SFO), rice bran (RBO), corn (CO), palm (PO), fish (FO) oils] on the bioavailability and antioxidant property of lutein in lutein deficient (LD) mice. Lutein (200MUM) was dispersed in dietary lipids and administered to LD mice for a period of 15days. The plasma lutein levels were found to be highest in OO (82%) and CNO (68%), when compared to the control (mixed micelle) group. Further, positive correlation was found between intestinal triacylglycerol lipase and plasma lutein levels, confirming the crucial role of intestinal lipase on lutein micellarization and its intestinal uptake. Results revealed an affirmative correlation between triglycerides, low density lipoproteins and high density lipoprotein levels with plasma and tissue lutein levels, signifying their role in the transportation of newly absorbed lutein to target tissues. Furthermore, lutein accumulation in the liver and the eye was highest in the OO (120% and 117%) and CNO (105% and 109%) fed groups, compared to control. Lutein deficiency resulted in elevated (p<0.05) levels of lipid peroxides, superoxide dismutase, and catalase in plasma and liver microsomes, which have been decreased significantly on feeding lutein. These results may be due to the influence of oleic (dominant in OO) and lauric (dominant in CNO) acids on the activity of intestinal lipase, portal absorption, triglycerides, lipoprotein or cholesterol flux between liver and peripheral tissues, which may modulate the uptake and transport of lutein. PMID- 30011650 TI - Regional characteristics of anthocyanin and flavonol compounds from grapes of four Vitis vinifera varieties in five wine regions of China. AB - Anthocyanins and flavonols are important flavonoid metabolites in grapes, making a dominant contribution to the color, the mouth feel and even the flavor of grapes and wines. The accumulation of these flavonoids in grapes is greatly influenced by a many, diverse but interacting factors, of which variety and climate are among the most important ones. In the present study, the anthocyanin and flavonol profiles of four grape varieties (Vitis vinifera L.), Cabernet Sauvignon, Carmenere, Syrah and Merlot, from five major wine regions in China were examined for two consecutive years (2006 and 2007). The results showed that the total anthocyanin content of the berry skins in these cultivars tended to increase from east to west in China, yet the proportion of the acylated anthocyanins displayed the opposite trend. It seemed possible that the western grape regions, with their high altitude and low annual rainfall, had an advantage in producing high level of anthocyanins. In addition, a high proportion of trihydroxylated flavonols were always found in the western region grapes, whereas dihydroxylated flavonols were more prominent in the lower altitude eastern regions. This suggested that the relative amounts of these flavonoid compounds may depend on their corresponding cultivar characteristics, while the amounts are more affected by the environmental factors where they were growing. PMID- 30011651 TI - Modulation of nutritional and antioxidant potential of seeds and pericarp of pea pods treated with microbial consortium. AB - Microbial populations have diverse roles within rhizosphere where interactions among distinct microorganisms along with the host may lead to mutualistic associations. The present study aimed to investigate the nutritional and antioxidant qualities of seeds and pericarp of pea raised from seeds treated with beneficial microbes namely Bacillus subtilis BHHU100, Trichoderma harzianum TNHU27 and Pseudomonas aeruginosa PJHU15 either singly and/or in consortia. A significant increase in total phenolic, flavonoid, ascorbic acid and protein contents, free radical scavenging activity, hydroxyl radical scavenging activity, iron chelation and reducing power were observed in the seeds and pericarp of pods treated with a consortium of microbes in comparison to control pods. Also, the differential accumulation of phenolic compounds, namely, shikimic acid, gallic acid, tannic acid, syringic acid, p-coumaric acid, quercetin and kaempferol, was observed from the HPLC chromatogram of the seed extracts of different treatments. We especially emphasized on dietary importance of the pod pericarp, other than seeds, along with their modulation by microbial consortium. The study also highlights the role of beneficial microbes in improving nutritional value by providing protection against oxidative stress. PMID- 30011652 TI - Fermented or unfermented milk using Bifidobacterium animalis subsp. lactis HN019: Technological approach determines the probiotic modulation of mucosal cellular immunity. AB - Functional foods are important sources of probiotic delivery, mainly by fermented milk products. The physiological benefits attributed to bifido bacteria are their abilities to interfere with the adhesion of pathogenic species to surfaces of intestinal cells, and to enhance the host's immune function through their metabolic activities. However, the effects of a technological approach - fermentation or addition of probiotic in milk, and its efficacy in health are rarely taken into consideration. Hence, fermented or unfermented milk using Bifidobacterium animalis subsp. lactis HN019 were administered to BALB/c mice for 14days. After that, the architecture of the gut was histologically investigated, and the related immune cells were examined by flow cytometry and immunofluorescence. Increase in mucus and cellularity production, changes in immune pattern and preservation of mucosal epithelia in health BALB/c mice were observed only in the fermented milk group. This suggested that changes in functionality of bifidobacteria and/or the metabolites produced by the fermentation process are the keys to improving beneficial effects in the host of the gut mucosa. PMID- 30011653 TI - Balanced incomplete block design: an alternative for data collection in the optimized descriptive profile. AB - The optimized descriptive profile (ODP) is a new descriptive methodology which proposes an optimized sample evaluation by no trained assessors. To permit that assessors with a low degree of training quantitatively evaluate samples consistently, this method proposes the presentation of reference materials ("weak" and "strong") together with all set of samples at the time of evaluation. The attribute-by-attribute protocol is recommended on the ODP technique to allow for comparison among the samples and avoid fatigue, since only one attribute is evaluated at a time. Simultaneous presentation of the samples, together with the reference materials, is the "key point" of the ODP, and therefore the number of samples may be a limiting factor in this technique. The purpose of the present study is to determine if the balanced incomplete block design (BIBD), used in descriptive techniques traditionally, may be an alternative for data collection on this specific methodology, the optimized descriptive profile (ODP). The BIB design does not allow for comparison among all samples together, but only among a fraction of them. Therefore an assessment of the data quality obtained through this design is necessary to increase the applicability of the ODP. In this experiment a specific set of grape juice formulations was used, which presented variations in pulp and sugar contents. Sensory evaluation was conducted with two independent panels, where each panel evaluated the samples using the ODP protocol in a specific design. Thus, one panel evaluated the samples using the balanced complete blocks design (BCBD) and the other panel the balanced incomplete blocks design (BIBD). The data obtained by the two designs were compared in relation to analysis of variation, F-test power and regression models. Data obtained by the ODP conducted in the BIBD was very similar to that of the ODP in the BCBD. In the ANOVA, the formulations differed (p<0.05) in relation to all attributes, showing a test power (1 - beta) greater than 0.95. The regression models obtained in the different designs indicated overlapping of the confidence intervals (CI 95%). Therefore, the BIBD presents itself as an alternative for data collection in the ODP without loss in quality of the results. PMID- 30011654 TI - Cherry tomato supplementation increases the area of the intestinal mucosa and the number of muscle layers in rats. AB - Tomatoes act as prebiotics in the gut. The effects of cherry tomatoes on gastrointestinal health have not yet been studied. Four cherry tomato supplementation diets (CTSDs) were prepared from the juice and cake of fresh and processed (heat-treated) cherry tomatoes. The contents of the gut and histological changes in the cecum and intestine were analyzed at 4weeks in rats fed CTSDs. The lactic acid bacteria level in fecal contents of rats fed CTSDs increased compared with the control. The gut length was longer in rats fed CTSDs than that in control animals. In addition, the cecal propionate level significantly increased (p<0.05), and acetate and butyrate levels decreased compared with control animals, however, regardless of the type of CTSD, the total concentration of short chain fatty acids (SCFAs) in all rats fed different CTSDs was similar with the control. The thicknesses of the mucosa and muscle of the cecum and colon increased in rats fed CTSDs compared with the control. CTSDs increased the area of the mucosa and the number of muscle layers in the intestine and cecum of rats, which strengthened the barrier function and promoted gastrointestinal health. PMID- 30011655 TI - An investigation into the nature of wheat flour dough adhesive behaviour. AB - Wheat flour dough adhesiveness was measured using a probe test developed previously. Six probes made of the following materials were used in adherence measurements: PMMA (polymethylmethacrylate), SS (stainless steel), PE (polyethylene), PVC (polyvinylchloride), PTFE (polytetrafluoroethylene) and PP (polypropylene). The specific energy of separation (omega, J/m2) was seen to vary with dough water content and probe material. The greatest omega was obtained with the PMMA probe, whereas the lowest one was obtained with the SS, PTFE and PP probes. This result was in accordance with the probe surface tension measurements. The amount of water was seen to have a stronger effect on adhesiveness than probe surface tension due to changes in dough rheology. Adherence measurements conducted with different probe materials and withdrawal rates showed that omega could be factorised into two terms, a constant value tentatively related to the thermodynamic work of adhesion, W0, and a viscoelastic function of rate of separation describing the energy dissipation in dough during debonding. A general model developed for pressure-sensitive adhesives (PSAs) was shown applicable to wheat flour dough adhesiveness. It was also demonstrated that the appropriate measure of dough adhesiveness was not the maximum tensile force, but the energy of separation per unit area of interface, as stated before for PSAs. PMID- 30011656 TI - Extraction and characterization of pectic polysaccharides from easy- and hard-to cook common beans (Phaseolus vulgaris). AB - The occurrence of the hard-to-cook (HTC) defect in legumes is characterized by the inability of cotyledons to soften during the cooking process. This phenomenon may be influenced by pectin properties. The objective of this study was to characterize the pectic polysaccharides comprised in the alcohol insoluble residue (AIR) extracted from easy-to-cook (Rose coco) and hard-to-cook (Pinto) common beans. This would provide an insight in the relationship between the pectin properties and HTC defect. The AIR was extracted from raw, half-cooked hard, half-cooked soft and fully-cooked bean samples. Subsequently, it was fractionated into water-, chelator- and Na2CO3-soluble pectin fractions and a hemicellulose fraction. For the AIR and the pectin fractions, determination of the galacturonic acid content, neutral sugars, degree of methylesterfication (DM), degree of acetylation (DAc) and molar mass (MM) distribution was performed. Results on the pectin fractions, MM distribution and pectin content profile, revealed that Rose coco pectin generally showed higher pectin solubility than Pinto. Neutral sugar profiles indicated that Pinto contained higher amounts of branched pectin (i.e. arabinans) than Rose coco. There was no difference between the DM of Pinto and Rose coco, however, the DAc was higher in Rose coco. In conclusion, the differences in pectin structure and solubility properties between easy- and hard-to-cook common beans might contribute to the differences in their cooking behavior. PMID- 30011657 TI - The aggregation of soy protein isolate on the surface of Bifidobacterium. AB - In this study the interaction between soy protein isolate (SPI) and Bifidobacterium was investigated to reveal the protecting mechanism of SPI on Bifidobacterium. The results indicated that the average particle size of the aggregate of SPI and Bifidobacterium longum (B. longum, the better surface hydrophobicity of four Bifidobacterium) exhibited more considerable expansion than SPI alone, from 295.9nm to 404.8nm (the aggregate). It was confirmed that B. longum was localized in the microparticle core, while SPI acted as a wall-coating material, as determined by zeta potential and laser scanning confocal microscopy (LSCM). Surface hydrophobicity, which was described by fluorescence intensity, of the aggregate of SPI and B. longum was decreased to 72% of SPI. The main binding force of the interaction between SPI and B. longum originated from a hydrophobic interaction was verified by isothermal titration calorimetry (ITC). The enthalpy (DeltaH) was determined by ITC to be -3.24kJmol-1 for the adsorption of SPI on B. longum at 25 degrees C and pH7.0. Furthermore, the aggregation was testified to be an endothermic process, and the process was spontaneous and irreversible. The hydrophobic forces between SPI and Bifidobacterium interpreted that SPI has the potential to be a useful food ingredient in protecting probiotics. PMID- 30011658 TI - Fabrication of surfactant-stabilized zein nanoparticles: A pH modulated antisolvent precipitation method. AB - Zein nanoparticles were fabricated by a pH-modulated antisolvent precipitation method using a food-grade non-ionic surfactant (Tween 80) as a stabilizer. The nanoparticles formed had a core-shell structure consisting of a zein core with a diameter around 78nm and a surfactant shell with a thickness around 4nm. The electrical charge on the nanoparticles was mainly determined by zein, going from positive at low pH to negative at high pH with a point of zero charge near pH5. The nanoparticles were stable to aggregation from pH2 to 4.5 (high positive charge) and from pH6.5 to 8 (high negative charge), but they aggregated from pH5 to 6.5 due to weak electrostatic repulsion. The nanoparticles were susceptible to aggregation at high ionic strengths (>=50mM NaCl) at both pH4 and 7. They also exhibited some aggregation upon heating (90 degrees C for 120min) at pH4, but were relatively stable at pH7. The core-shell nanoparticles formed in this study have potential as food-grade delivery systems for encapsulating, protecting, and releasing bioactive molecules in food and pharmaceutical formulations. PMID- 30011659 TI - Determination, analysis and prediction of the volumetric behavior of milk at high pressure. AB - High pressure preservation technologies are consolidating in the food industry as an interesting alternative to traditional thermal processes. Process modeling contributes to its progress and requires the input of food properties like density for calculations. The dependency on pressure of these properties is indispensable but it is rarely available in the literature. The sector of dairy products is an important target for the development of novel foods by high pressure treatments (both high hydrostatic pressure processing and ultra-high pressure homogenization). Thus, the main objective of this research was to characterize the volumetric properties of raw whole milk and skim milk. A variable-volume piezometer with a solid-piston volumeter was employed for this purpose. Density, specific volume, isothermal compressibility and thermal expansion coefficient were determined between 0 and 60 degrees C under pressures up to 350MPa; at atmospheric pressure, measurements cover temperatures up to 90 degrees C. Results show that milk solutes and fats, although present in low quantities in milk compared to water, have an influence which is worthy of consideration on milk volumetric properties. Irregularities appear from 200MPa in the dependencies on temperature of the studied milk properties. From a composition-based model, it is highlighted that milk solutes' specific volume behavior is inverted around 55 degrees C and that milk fats' compressibility goes through a maximum around 30 degrees C. The composition-based model is further developped for the calculation of milk properties as a function of pressure at different temperatures; prediction errors are below 2%. Useful data and equations for high pressure processing simulation are provided together with an original view on the combined effects of pressure and temperature on milk solutes and fats. PMID- 30011660 TI - Comparative evaluation of CO2 drying as an alternative drying technique of basil (Ocimum basilicum L.) - The effect on bioactive and sensory properties. AB - In this study the potential of employing CO2 drying as an alternative to conventional drying techniques of basil was evaluated, with the aim of preservation of native bioactive and sensory properties of basil. For that purpose, optimal CO2 processing conditions were established and compared to air dried and freeze dried basil samples. The contents of bioactive compounds (polyphenols, chlorophylls, ascorbic acid) and antioxidant capacity were determined spectrophotometrically and using high performance liquid chromatography (HPLC-PDA) analysis. Color analysis and essential oil content were also determined, while consumer evaluation of sensory properties was conducted using hedonic scale preference analysis. According to the obtained results, freeze drying was recognized as the most suitable technique for preservation of color, essential oil content, bioactive compounds and antioxidant capacity of basil. The essential oil content of basil ranged from 0.21 to 0.96%, and decreased upon prolongation of CO2 drying time. Among 4 identified phenolic acids (rosmarinic, chicoric, caftaric and caffeic), rosmarinic acid was the most abundant in all samples. Longer CO2 drying duration (4h) also exhibited the most detrimental effect on the polyphenolic compound content and antioxidant capacity of basil. The taste and appearance of CO2 dried basil were scored higher in comparison to air-dried basil, but further optimization of CO2 drying is needed to improve its aroma properties. Based on the obtained results, employing shorter CO2 drying time (2, 3h) and pressures of 80-100bar at 40 degrees C might be a good alternative to freeze drying of basil. PMID- 30011661 TI - Evolution of the Anisakis risk management in the European and Italian context. AB - Due to the social and legislative implications, the presence of Anisakis spp. larvae in fishery products has become a concern for both the consumers and the official Control Authorities. The issuance of a large number of provisions, aimed at better managing fish products intended to be consumed raw or almost raw and the associated risks, resulted in a very complicate legal framework. In this work, we analyzed the evolution of the normative through an overview on the local and international legislations, focusing on issues that are of practical interest for Food Business Operators (FBOs) in the fishery chain. In addition, we performed a survey across the Department of Prevention of the Italian Local Health Authorities (LHA) and the main fish markets in Italy to collect the operating procedures and the monitoring plans. Overall, we found many differences, due to the absence of a national reference standard for the management of the Anisakis risk. From this examination, it turns clear that only a participation of all the involved institutions, a strategy of synergistic interventions, as well as a correct training of FBOs, can result in an effective risk management and a proper risk communication, which should overcome states of confusion and unnecessary negative impacts on the economy. PMID- 30011662 TI - Wheat flour granulometry determines colour perception. AB - Einkorn, durum wheat and Kamut(r) are rich of carotenoids, antioxidants with beneficial effects on human health. In the present study the effect of flour granule size on carotenoid content and colour was assessed; furthermore, the suitability of two colorimeters (Minolta Chroma meter CR-210 and Minolta Chroma meter II Reflectance), a spectrophotometer (Jasco V-650 with integrating sphere) and image analysis to define colour and determine carotenoid concentration in wheat flours of different granulometry was tested. Carotenoid content did not vary across flours of diverse size, except in the finest einkorn fraction (<80MUm), which had lower concentration. For all instruments colour coordinate L* decreased and b* increased with flour size growth, while a* varied with the different devices. A Principal Components Analysis (PCA), performed considering carotenoid content and all colorimetric indices, distinguished einkorn from durum and Kamut(r), and divided samples of different granulometry; a similar result was achieved by a PCA performed on the absorbance spectra from the integrating sphere. The PCA on image texture data classified the samples following flour size. In conclusion, flour colour is determined not only by carotenoid content but also by flour particle size: therefore, direct colour measurement seems not suitable to predict flour carotenoid content. PMID- 30011663 TI - Expanded Fermi Solution to estimate health risks or benefits from interacting factors. AB - Food related health risk/benefit factors might be additive or multiplicative, but some can be interrelated in ways that are neither or both. Since there is always inherent uncertainty concerning the magnitude of risk/benefit factors their contribution is better represented by a probable range than a single numerical value. With the Expanded Fermi Solution method, random values of the factors are generated within their respective ranges and used to calculate the combined risk or benefit based on the chosen mathematical model. In the case of additive or multiplicative independent factors, the combined risks/benefits so calculated have approximately normal or lognormal distribution, respectively, as anticipated from the Central Limit Theorem. The distribution's mode, i.e., the most frequent value, is considered the risk's best estimate. In interactive factors, the emergence of a specific parametric distribution is not guaranteed, but the histogram of the randomly generated combined risks or benefits can be used to identify the best estimate. This is demonstrated with three abstract interactive risk/benefit models of increasing number of parameters and complexity, whose calculation has been automated and posted on the Internet as freely downloadable interactive Wolfram Demonstration. Also given is a hypothetical but realistic example of dose-response based microbial risk assessment where uncertain bacterial growth parameters are involved, which can be implemented with a new Wolfram Demonstration. The methodology and software allow rapid examination of numerous combinations of interactive factors and evaluation of their potential effect on a food's or supplement's risk or benefit. PMID- 30011664 TI - Discrimination of Brazilian artisanal and inspected pork sausages: Application of unsupervised, linear and non-linear supervised chemometric methods. AB - The performance of different chemometric approaches to discriminate artisanal and industrial pork sausages using traditional physicochemical parameters was investigated. A total of 90 samples of sausages marketed in various supermarkets and open-markets in Rio de Janeiro, Brazil were analyzed for their content of moisture, protein, fat, nitrite, sodium and calcium. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used as exploratory methods, while linear and non-linear classification methods, such as k-nearest neighbors (k-NN), soft independent modeling of class analogy (SIMCA), partial least square discriminant analysis (PLSDA) and artificial neural networks (ANN) were used for assessing the data. Different behaviors for all parameters were analyzed between the classes. Principal component analysis and hierarchical cluster analysis did not show a complete discrimination of the samples. KNN and ANN results showed excellent performance for both categories with 100% correct prediction while SIMCA and PLSDA presented performance of 100% and 85.7% for inspected and artisanal sausages, respectively. According to the SIMCA, PLSDA and ANN, the contents of moisture and fat showed the highest discriminative power. Overall, the findings emphasize the use of multivariate techniques to evaluate the quality of processed foods, as pork sausages. PMID- 30011665 TI - Chemopreventive effects of standardized papaya leaf fraction on oxidatively stressed human liver cells. AB - Extract from papaya leaves, a waste material from fruit farms in Malaysia was previously reported to possess remarkable antioxidative activities. In this study, papaya leaf extract was separated into fractions of different polarities [petroleum ether (PE), ethyl acetate (EA), n-butanol (NB) and water (W) fractions]. The aim of this research was to determine the most active fraction in terms of its chemopreventive effects towards oxidative stress and the chemical constituents involved. The cytoprotective nature of the papaya fractions was observed against t-BOOH-induced oxidative stress on HepG2 liver cell line. ROS assay indicated that only PE and EA effectively reduced the increment of radical due to the pro-oxidant, t-BOOH. Nevertheless, PE was a stronger ROS scavenger by demonstrating ROS reducing activity in a dose-dependent manner to the basal level. This fraction was also found to inhibit cell death caused by t-BOOH toxicity, attenuating lactate dehydrogenase enzyme leakage by more than 90% (p<0.05). In addition, gene expression of phase II antioxidant enzymes (hmox-1 and nqo-1) and their transcription factor (nrf-2) were shown to be upregulated upon PE treatment during a time-course study. A GC-MS fingerprint of the active fraction was subsequently obtained with standardization using the marker compound; alpha-tocopherol, a well known antioxidant. However, this pure compound was not as effective as its corresponding PE concentrations in ROS reduction. Hence, PE of papaya leaf extract was a strong antioxidant and cytoprotectant with tremendous potential to be harnessed into the next therapeutic remedy against oxidative stress of the liver. PMID- 30011666 TI - Interaction of cationic antimicrobial (E-polylysine) with food-grade biopolymers: Dextran, chitosan, carrageenan, alginate, and pectin. AB - The cationic biopolymer epsilon-polylysine (epsilon-PL) is a food-grade antimicrobial that is highly effective against food pathogens and spoilage organisms. In compositionally complex environments, the antimicrobial activity of cationic epsilon-PL is likely to be impacted by its interactions with other charged species. The purpose of this study was to characterize the interactions of cationic epsilon-PL with various food grade biopolymers with different charge characteristics: anionic (carrageenan, alginate, pectin), neutral (dextran), and cationic (chitosan). Isothermal titration calorimetry (ITC), micro electrophoresis (ME) and turbidity measurements were used to characterize the interactions and the nature of any aggregates formed. Our measurements suggested that there was little interaction or complex formation between cationic epsilon PL and cationic or neutral biopolymers, but that strong electrostatic interactions and complex formation occurred between cationic epsilon-PL and anionic biopolymers. The solubility of the aggregates formed depended on biopolymer type and the mass ratio of biopolymers to epsilon-PL. The results of this study have important implications for the application of epsilon-PL in compositionally complex systems. PMID- 30011667 TI - Role of growth morphology in the formulation of NaCl-based selective media for injury detection of Escherichia coli, Salmonella Typhimurium and Listeria innocua. AB - Sublethal injury (SI) poses major public health concerns since injured cells are responsible for serious limitations in food diagnostics and are susceptible to recovery, often developing adaptive stress responses. Detection of SI is based on the difference in plate counts between non-selective media, which represent the total cell population, and selective media, to which injured cells become sensitive. Selective media for detection of sublethal membrane damage are often based on NaCl supplement, although there is a lack of consensus in the literature about appropriate levels. Planktonic cells are generally used to investigate SI mechanisms, although they often exhibit different stress tolerance than cell colonies in/on solid food (model) systems. In this work, the effect of growth morphology, colony size and concentration of the gelling agent in the growth media, on the maximum non-inhibitory NaCl concentration in the plating medium was assessed for Escherichia coli, Salmonella Typhimurium and Listeria innocua. Stationary phase cultures of planktonic cells and large and small colonies grown in either 1.5% (w/v) xanthan gum-based system or 2.5% (w/v) xanthan gum-based system exhibited significantly different viable counts and osmotolerance. The effect of cell arrangement and xanthan gum percentage in the growth media depended on the microorganism under investigation. Additionally, differences in the maximum non-inhibitory concentration were evident, with 5.0% (w/v) NaCl for the Gram-negative bacteria and 6.5% (w/v), for L. innocua. Different extent of colony shrinkage and morphological damage was observed as NaCl concentration in the plating medium increased. This information will contribute to define NaCl based selective media for accurate SI detection under realistic scenarios. PMID- 30011668 TI - Effect of konjac glucomannan addition on aroma release in gels containing potato starch. AB - The present study aimed to measure the retention of aroma compounds (ethyl acetate, ethyl hexanoate and carvacrol) in dispersions based on konjac glucomannan and/or potato starch, and to highlight the influence of konjac glucomannan on the mechanisms involved in aroma retention. Publications on the effect of konjac glucomannan on aroma release are scarce. Konjac glucomannan is a polysaccharide used as a food additive for its viscous and emulsifying properties. Retention of aroma compounds in dispersions was calculated from partition coefficients which were measured using the phase ratio variation method. This method, consisting of analyses of the headspace at equilibrium, enables the determination of the partition coefficient of volatile compounds in a gas/liquid system without external or internal calibration. The three aroma compounds chosen for this study behave differently toward amylose. Prior to the release study, the complexing behavior of carvacrol with starch, hitherto unknown, was investigated by X-ray diffraction: V6III amylose complexes were formed with carvacrol. Our results showed no specific interaction between ethyl hexanoate and potato starch or konjac glucomannan. Ethyl acetate retention seemed to be due to trapping in the complex network of polysaccharides and to the density of this network. Retention of carvacrol was influenced by the nature of polysaccharides present in the dispersion, and was mainly governed by specific interaction with starch. Additionally, the addition of konjac glucomannan to potato starch dispersions decreased the retention of volatile compounds complexing starch, but had little effect on the retention of the other aroma compounds. PMID- 30011669 TI - Quality and safety of frying oils used in restaurants. AB - Fresh, in-use and discarded frying oils were collected from randomly selected restaurants in downtown Toronto, Canada, in order to assess the oxidative and hydrolytic state of oil used in commercial practice and consumed regularly by the local population. All in-use and discarded samples showed extremely high levels of oxidation products based on the p-anisidine value (p-AV) (7.610meq/kg) and free fatty acid (FFA) levels (FFA>1%) suggested that 30-35% of in-use frying oils and 45-55% of discarded oils were not acceptable. However, total polar compounds (TPCs), the most widely used measure of frying oil quality in Europe, suggested that the oils were of acceptable quality (15.5>TPC). The TPC test was found to greatly underestimate oil degradation. We recommend that National Public Health authorities include frying oil inspections in their monitoring programs. PMID- 30011670 TI - Retention effect of human saliva on aroma release and respective contribution of salivary mucin and alpha-amylase. AB - As great differences were observed in the amount of alpha-amylase in human saliva, there is a need to better understand the effect of this protein alone or in mixture with mucin on aroma compound partitioning. We report the respective role of mucin and alpha-amylase on the air/liquid partition coefficients of two series of 5 methyl-ketones and 5 ethyl-esters. We confirm that mucin affects the release of aroma compounds and, for the first time, we demonstrate the ability of alpha-amylase to decrease the release of aroma compounds. For both proteins, we report the involvement of hydrophobic effects. Interestingly, no cumulative effect was observed when both proteins were mixed together in solution. We hypothesize that protein-protein interactions occur between the two proteins and decrease the total number of available binding sites for aroma compounds. The effect of human saliva is also investigated and compared to that of artificial salivas. In the presence of human saliva the release of ketones is lower than in water and slightly higher than in the presence of artificial saliva composed of alpha-amylase and/or mucin. Esters are more affected by the presence of human saliva than ketones. This observation is due to the presence of an esterase activity in saliva, which activity increases with the hydrophobicity of esters. The difference observed in aroma release between artificial and human salivas could be explained by the presence of other salivary proteins in human saliva. PMID- 30011671 TI - Beneficial effects of fermented vegetal beverages on human gastrointestinal microbial ecosystem in a simulator. AB - The aim of this study was to evaluate the effects of four beverage formulations (prebiotic - fructooligosaccharide, probiotic - Lactobacillus casei Lc-01, synbiotic - fructooligosaccharide and L. casei Lc-01 and placebo) based on aqueous extracts of soy and quinoa, towards the human intestinal microbiota using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME(r)), a dynamic model of the human gut. To monitor the effects on microbial community composition, plate counts on specific growth media and a PCR-DGGE analysis were performed on samples from all colon compartments - ascending, transverse and descending. To verify the effects on microbial metabolism, we analyzed the ammonium and short chain fatty acids (SCFAs) concentrations. The synbiotic beverage showed the best microbiological results in the ascending colon compartment, stimulating the growth of Lactobacillus spp. and Bifidobacterium spp., and reducing Clostridium spp., Bacteroides spp., enterobacteria and Enterococcus spp. populations in this compartment. A larger reduction (p<0.05) of ammonia ions in the ascending colon was observed during the synbiotic beverage treatment. No statistical difference was observed in SCFA production among the treatments and the basal period. Plate count and DGGE analysis showed the survival of L. casei Lc-01 in the colon. DGGE analysis also showed higher richness and diversity of the Lactobacillus spp. community during the treatment with synbiotic beverage, with higher accentuation in the ascending colon. PMID- 30011672 TI - The influence of ripeness grade on the composition of musts and wines from Vitis vinifera cv. Tempranillo grown in a warm climate. AB - Fruit ripeness has an influence on the phenolic and aromatic composition of grapes and musts and, therefore, on the sensorial characteristics of the resulting wine. The aim of the work described here was to assess the influence of the harvest date on the analytical composition of the musts and wines from the Vitis vinifera cv. Tempranillo grape grown in a warm climate. A hydroalcoholic medium was employed to extract the musts and simulate a traditional maceration process. Phenolic compounds were analysed by colorimetric methods and aroma compounds by gas chromatography/mass-spectrometry. Furthermore, the wines were tested by a sensory panel. A good correlation was obtained between the parameters measured in the must and in the corresponding wine, as well as in the scores recorded in the sensory analysis. In summary, grape ripening was found to have a marked influence on the wine composition and it was possible to establish the key parameters that need to be measured in the must during ripening to identify the optimal harvest date to obtain the best quality wine. PMID- 30011673 TI - Effect of warming on protein, glycogen and fatty acid content of native and invasive clams. AB - Human bivalve consumption in Europe has steadily increased in the last years, particularly during summer months when seawater temperature increases. Since ocean warming is among the current global environmental threats affecting aquatic organisms, it is of paramount importance to investigate its effect on the nutritional quality of seafood products. In this context, the aim of this study was to investigate differences in the nutritional quality (in terms of protein, glycogen and fatty acid, FA, content) and condition of a native (grooved carpet shell, Ruditapes decussatus) and an invasive (Japanese carpet shell, Ruditapes philippinarum) clam species, subjected to warming. Our results clearly reveal that temperature significantly affected the nutritional quality of both clam species, particularly the FA composition. Both clam species responded similarly to warming, by significantly decreasing the content of some fatty acids, but not protein and glycogen levels. A predominance of polyunsaturated FA (PUFA) over saturated FA (SFA) and monounsaturated FA (MUFA) was observed throughout the experiment, as well as high n-3/n-6 and PUFA/SFA ratios. The native clam always revealed higher values of these fatty acids, indicating that this species has a better nutritional quality in comparison to the invasive one. Nonetheless, the loss of n-3 PUFA (in native species), eicosapentaenoic (EPA; in both species) and docosahexaenoic (DHA; in invasive species) acids was considered as the major negative outcome derived from warming, since it contributes to the loss of prime quality fatty acids for human health. However, atherogenic, thrombogenic and hypocholesterolemic/hypercholesterolemic indices (AI, TI and h/H, respectively) remained low in both species, even in warming conditions, suggesting that these food items can be used in a cardio-protective and hypocholesterolemic diet. This study provides new insights to understand and foretell the effects of climate change on nutritional quality of marine organisms. PMID- 30011674 TI - Comparison of rapid sensory characterization methodologies for the development of functional yogurts. AB - Functional food development is a long, complex, expensive and risky process. Methodologies that provide reliable information about the sensory characteristics of the developed products in short time frames can speed up the product development process and contribute to the success of the developed products in the marketplace. In this context, the aim of the present work was to compare three rapid methodologies for sensory characterization with descriptive analysis during the development of low-fat functional yogurts, enriched with probiotics and prebiotics. Eight low-fat probiotic yogurts enriched with a prebiotic ingredient were formulated following a 23 full factorial design with the following factors: sugar concentration, prebiotic ingredient and stabilizer concentration. A panel of 9 trained assessors evaluated samples using descriptive analysis. Besides, the yogurts were evaluated by 3 groups of 81 consumers using three rapid methodologies: check-all-that-apply (CATA) questions, projective mapping and polarized sensory positioning. The three rapid methodologies provided similar information on the main differences among samples. However, several differences can be highlighted. Sample configurations from CATA questions were the most similar to those provided by descriptive analysis, whereas projective mapping provided the least similar configurations. The three methodologies also differed in their ability to detect differences among samples due to formulation variables and the stability of sample configurations. PMID- 30011675 TI - Consumer perceptions of satiating and meal replacement bars, built up from cues in packaging information, health claims and nutritional claims. AB - Previous research has shown that consumers' sensory and hedonic perceptions could be greatly influenced by the messages highlighted on the front of the packaging, particularly nutrition and health claims for reduced-calorie or functional foods. In food products designed for hunger control, mentioning satiating effects or meal replacement could potentially influence the expected satiety or other perceptions, including those associated with a filling effect. This study investigated the effect of packaging information on consumer perceptions of eleven commercial chocolate-flavoured satiating and meal replacement bars. Projective mapping (Napping(r)) with a descriptive step was used to profile the expectations elicited by the eleven bars, based on their extrinsic characteristics (without tasting them), with two different groups of consumers in two different scenarios: mapping the samples' packaging and mapping cards with an identical design showing the most important information displayed on the packaging (product name, nutrition information panel and nutrition and health messages or claims). The terms and comments obtained in the two scenarios were analysed and perceptual spaces were generated from the sample location and attributes obtained in the Napping(r) exercises, using multi factor analysis (MFA). The results showed that when evaluating the real packaging, the consumers mainly focused on the meal replacement- or satiation-related messages and on the images to build up their perception, attaching less or no importance to the nutritional information that was also displayed on the box. When examining the packaging, sensory expectations - which probably emerged from the images of the bars - were also a very important factor in placing the samples in the perceptual space. When looking only at the cards, the consumers' grouping and attribute generation focused in great detail on the nutritional information. The calorie content also became a much more important factor in their perceptions of the bars. Interestingly for the product category analysed, messages about "satiating" and "meal replacement" effects were clearly distinct and negatively correlated in the consumers' minds. PMID- 30011676 TI - Potential use of new Colombian sources of betalains. Color stability of ulluco (Ullucus tuberosus) extracts under different pH and thermal conditions. AB - The potential use of ulluco (Ullucus tuberosus) extracts to be added as natural colorant to other products has been studied. The stability of ulluco extracts at different pHs and temperatures over time has been thoroughly conducted. Our attention was focused on the tristimulus colorimetry, differential colorimetry and betalains related to color. On the basis of the results, although ulluco extract adjusted to pH4 showed a significantly lower color intensity (C*ab~40), the stability of red hue (hab) over time was higher. Betalain content showed the same trend, and lower values in highly-acidic extracts have been reported. It could be also affirmed that visually appreciable color changes (DeltaE*ab>2) were induced when pH changed and different temperatures were applied. Despite of the vivid red color of the initial extracts, ulluco extracts added to low-acidic foodstuffs showed a tendency towards yellowish tonalities (values of hab from 45 degrees to 80 degrees ), mitigated by using refrigeration storage conditions (hab values from 45 degrees to 55 degrees ). PMID- 30011677 TI - Comprehensive characterization of lipids from Amazonian vegetable oils by mass spectrometry techniques. AB - An integrative approach in mass spectrometry (MS) comprising gas chromatography coupled to MS (GC-MS), ultra-efficiency liquid chromatography coupled to MS (UPLC MS) and easy ambient sonic-spray ionization MS (EASI-MS) is proposed for the comprehensive characterization of Amazonian oils. Coconut, andiroba and castor seed oils, which are vastly sold in markets of the Amazonian region of Brazil, were selected as a representative test set. These oils were found to contain several lipids such as triacylglycerides (TAGs), fatty acids (FAs), phytosterols and limonoids. In the analyzed samples 30 different TAGs, 11 FAs, 6 phytosterols and 7 limonoids were identified. The antioxidant capacity (AOC) of the oils, as measured by their oxygen radical absorbance capacity (ORAC), was also used to evaluate their potential biological properties as well as their possible consumption as food. Edible virgin coconut oil was the most active (0.720+/-0.001 Trolox eq./mmol), whereas considerable lower activity was observed for andiroba and castor seed oils. The antimicrobial activities of the oils were also recorded against a panel of pathogenic bacteria and fungi in which andiroba oil was the only one that was active, solely against Enterococcus aeruginosa. PMID- 30011678 TI - The ability to store energy in pea protein gels is set by network dimensions smaller than 50nm. AB - The objective of this study was to identify which length scales set the ability to elastically store energy in pea protein network structures. Various network structures were obtained from pea proteins by varying the pH and salt conditions during gel formation. The coarseness of the network structure was visualized by the use of confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) and ranked from least coarse to most coarse networks. Least coarse networks were formed at a pH away from the isoelectric point (IEP) of pea proteins, and at a low ionic strength, whereas more coarse networks were formed at pH values close to the IEP and at a high ionic strength during gel formation. Mechanical deformation properties of the gels such as elastically stored (recoverable) energy, Young's moduli (stiffness of gels), fracture stress (gel strength), and fracture strain (brittleness of the gels) were measured by the use of a texture analyzer and correlated to the coarseness of the networks structure. The influence of coarseness on the ability of the networks to elastically store energy was observed for length scales below 50nm. The findings show that elastically stored energy of pea protein gels can be modulated via the creation of different network structures below 50nm length scales. The results from this study contribute to a better understanding of the dimensions that set the ability to elastically storage in pea protein gels. If the ability of pea proteins to store energy can be understood, products can be better tailored for consumers. PMID- 30011679 TI - Improved in vitro digestion stability of (-)-epigallocatechin gallate through nanoliposome encapsulation. AB - (-)-Epigallocatechin gallate (EGCG) is unstable and degraded in near-neutral or alkaline fluids. To overcome its limitation, EGCG nanoliposome (EN) was prepared by an ethanol injection method combined with dynamic high-pressure microfluidization. EN possessed good physicochemical characterizations (high entrapment efficiency=92.1%, small average particle size=71.7nm, low polydispersity index=0.286 and zeta potential=-10.81mv). EN exhibited a relative good sustained release property. Stability of EGCG in simulated intestinal fluid (SIF) was significantly improved by nanoliposome encapsulation. After 1.5h incubating in SIF without or with pancreatin, the residual EGCG of EN was 31.2% and 47.7% respectively, but the residual EGCG in EGCG solution was only 3.4% and 3.5% respectively. The degenerations of in vitro antioxidant activities of EGCG were effectively slowed by nanoliposome encapsulation. This study expects to provide theories and practice guides for further applications of EN. PMID- 30011680 TI - A dose-response study of the bioavailability of grape seed proanthocyanidin in rat and lipid-lowering effects of generated metabolites in HepG2 cells. AB - Hyperlipidemia is one of the principal causes of cardiovascular disease and proanthocyanidins (PAs) regulate lipid homeostasis. This study aims to evaluate the concentration of PAs in rat serum after the administration of different doses of PAs and to determine the capacity of these metabolites to reduce de novolipid synthesis in HepG2 cells. Two hours after oral administration of different doses of a grape seed proanthocyanidin extract (GSPE) (1000, 375, 250 and 125mg/kg), serum was semi-purified and characterised by HPLC-ESI-MS/MS before analysing the synthesis and secretion of lipids in HepG2 cells. Results showed a dose-dependent appearance of metabolised PAs in serum at doses up to 375mg/kg and saturation at 1000mg/kg of GSPE. A reduction in cholesterol esters (CE), free cholesterol (FC) and triglycerides (TG) synthesis was observed without dose-dependence when the cells were treated with PAs metabolites. Moreover, a low dose of metabolites (125mg/kg) was sufficient to reduce FC and TG synthesis. In conclusion, the study demonstrated that PAs metabolise in a dose-dependent manner up to 370mg/kg but not dose-dependent effect was shown in reducing the de novosynthesis of lipids. PMID- 30011681 TI - Human saliva protein profile: Influence of food ingestion. AB - Saliva is a mixture composed by the secretions of the major and minor salivary glands, together with the crevicular fluid, bacteria and cellular debris. Due to saliva being a complex and dynamic fluid, the protein profile may qualitatively vary under different conditions. So, in this work, the saliva protein composition on different days, throughout the day and in fasting and fed states was evaluated by high-performance liquid chromatography (HPLC) analysis. The results show that the saliva protein amount has the maximum peak at 2p.m. and at this hour no differences on saliva protein composition were observed on different days. Nevertheless, gPRPs and aPRPs vary significantly throughout the day and after food ingestion in the early afternoon. However, feeding effect seems to be more pronounced in the morning after a fasting period. This fact suggests that besides the influence of food ingestion, saliva protein composition is also influenced by circadian rhythms. This work allows one to comprehend how the different families of salivary proteins (SP) may vary throughout the day and with the influence of food ingestion, which could be a helpful tool in several studies, such as, astringency perception and biological studies. PMID- 30011682 TI - Determination of amorphous/rubbery states in freeze-dried prebiotic sugars using a combined approach of near-infrared spectroscopy and multivariate analysis. AB - Galacto-oligosaccharides (GOS) and lactulose are well-recognized prebiotics widely used in functional food and pharmaceutical products, but there is still a lack of knowledge regarding their physical-chemical properties. In this study, a physical-chemical approach on two GOS of different composition (GOS Cup Oligo H 70(r) and GOS Biotempo) and lactulose was assessed. Mid infrared and Raman spectra of the freeze-dried sugars allowed their structural characterization in the amorphous state, lactulose, showing the main spectral differences. Freeze dried sugars were then equilibrated at 4 degrees C at relative humidity (RH) ranging from 11% to 80%. Near-infrared reflectance spectra were registered in each condition in the 900- to 1700-nm region. A principal component analysis (PCA) was performed on the three sugars equilibrated at different RH. In all the three sugars, the groups observed explained more than 95% of the variance and were related with the RH of the samples. According to the loading plots of PC1, the main differences related with RH were observed in the 1380- to 1500-nm region. As the amorphous states are very sensitive to changes in temperature and moisture content, and the moisture content is related with the parameter T-Tg (T: storage temperature; Tg: vitreous transition temperature), an effort was made to determine this parameter directly from the NIR spectra. To this aim, a partial least square model (PLS) was defined. Tg values obtained by differential scanning calorimetry (DSC) were used to calculate the T-Tg values of reference. The model was validated with an independent set of data. The mean of predicted values fitted nicely T-Tg obtained from DSC (correlation=0.966; R2=0.934), thus supporting the use of the PLS model to investigate unknown samples. The stability of amorphous sugars in foods and pharmaceuticals is of practical and economical importance because it affects different quality attributes of foods, including texture, aroma retention and shelf life. Therefore, predicting T-Tg, a parameter that is independent on the sugar investigated, directly from their NIR spectra is of utmost importance to determine the shelf life of food and food-related products and up to our knowledge has never been determined hereto. PMID- 30011683 TI - Encapsulation, protection, and release of polyunsaturated lipids using biopolymer based hydrogel particles. AB - Delivery systems are needed to encapsulate polyunsaturated lipids, protect them within food products, and ensure their bioavailability within the gastrointestinal tract. Hydrogel particles assembled from food-grade biopolymers are particularly suitable for this purpose. In this study, hydrogel microspheres were fabricated by electrostatic complexation of low methoxy pectin and caseinate by decreasing the solution pH from 7 to 4.5. After hydrogel particle formation, the caseinate was enzymatically cross-linked using transglutaminase to improve the stability of the biopolymer matrix. The effect of hydrogel particle encapsulation on the physical location, chemical stability, and lipase digestibility of emulsified polyunsaturated lipids (fish oil) was investigated. The cross-linked hydrogel particles formed using this process were relatively small (D43=4.6MUm), negatively charged (zeta=-37mV), and evenly distributed within the system. Confocal microscopy confirmed that the fish oil droplets were trapped within casein-rich hydrogel microspheres. Encapsulation of the fish oil droplets improved their stability to lipid oxidation compared to conventional emulsions, which was attributed to a high local concentration of antioxidant protein around the emulsified lipids. The rate and extent of digestion of the encapsulated lipid droplets within a simulated small intestine were similar to those of non-encapsulated ones. These results suggest that casein-rich hydrogel microspheres may protect polyunsaturated lipids in foods and beverages, but release them after ingestion. PMID- 30011684 TI - Overview of Lactobacillus plantarum as a promising bacteriocin producer among lactic acid bacteria. AB - Chemical preservatives have been traditionally used during the manufacturing of processed products. However, the continuous growing interest of consumers for fresh and natural products makes it necessary to search for alternative compounds. In this context, food industries have been widely using lactic acid bacteria (LAB) as natural preservatives, due to their ability to produce antibacterial compounds such as bacteriocins. Similarly, pharmaceutical industries have improved the use of these bacterial peptides, with antibacterial activity, trying to reduce the indiscriminate use of antibiotics in food products for human and animal consumption. Among LAB, Lactobacillus plantarum can be adapted to various niches thanks to its ability to ferment a wide range of carbohydrates. Additionally, it can be used as starter culture in food fermentations and as an ingredient for probiotic foods, contributing to the organoleptic characteristics of foods at the same time prolonging the shelf-life and safety of these products. The amount of valuable substances obtained from L. plantarum species isolated from different ecological niches is also worth noting, thus proving it to be one of the most important and versatile species among LAB. PMID- 30011685 TI - Dietary polysaccharide extracts of Agaricus brasiliensis fruiting bodies: chemical characterization and bioactivities at different levels of purification. AB - Polysaccharides of the European strain of A. brasiliensis were obtained by hot water extraction and ethanol precipitation (HWPE I) of fruiting bodies, and further purified by dialysis (HWPE II) and pronase incubation (PPE). These polysaccharides consisted mainly of (1->6)-beta-d-glucans. PPE was free of proteins and polyphenols as demonstrated by quantitative assays and NMR profiling. They showed a clear IFN-gamma inducing activity in human PBMCs, which suggests these polysaccharides to have proinflammatory effects. Treatment by beta glucosidase caused the polysaccharides to be degraded into smaller fragments and at the same time increased their IFN-gamma inducing activity in PBMCs fourfold. In vitro, PPE showed a dose-dependent inhibition of the proliferation of the human leukemia Jurkat cell. At 100MUg/mL the cells' viability was decreased by appr. 51% compared to the control. EPR spin trapping demonstrated a high antioxidative activity against *OH and *O2- radicals of HWPE I and PPE. Further, the results of the antioxidant assays indicated that antioxidant activity against *OH radicals in the Fenton system was achieved through scavenging or through chelating iron mechanisms. The good immunomodulating and antioxidative properties of A. brasiliensis polysaccharide extract obtained by hot water extraction and ethanol precipitation make it suitable for everyday use as an inexpensive dietary supplement. PMID- 30011686 TI - Diversity and probiotic potentials of lactic acid bacteria isolated from gilaburu, a traditional Turkish fermented European cranberrybush (Viburnum opulus L.) fruit drink. AB - The aim of the present study was to characterize lactic acid bacteria (LAB) strains isolated from traditional fermented gilaburu fruit juice and their probiotic potential. The LAB counts of the fermented gilaburu fruit juice were in the range of 3.92-8.30logcfu/g. Total of 332 isolates belonging to Lactobacillus and Leuconostoc species were characterized from traditional fermented gilaburu juice by genotypic methods. It was also determined that the major LAB strains belong to Lactobacillus plantarum (173 isolates), Lactobacillus casei (52 isolates) and Lactobacillus brevis (24 isolates), while Lactobacillus buchneri, Lactobacillus parabuchneri, Lactobacillus pantheris, Leuconostoc pseudomesenteroides and Lactobacillus harbinensis were the least in isolated LAB strains. In terms of the probiotic potentials, Lb. plantarum strains were able to grow at pH2.5, but 3 of Lb. casei strains, one of each Lb. brevis and Lb. buchneri strains could not grow at the same pH. All selected LAB stains were resistant to bile salt at <=0.3% concentration. While all the LAB species grew at 15 degrees C, two Lactobacillus hordei strains could also grow at 45 degrees C. The highest cell hydrophobicity degrees were for Lb. casei (G20a) and Lb. plantarum (G19e) as 87.5 and 86.0%, respectively. Listeria monocytogenes and Bacillus cereus were the most sensitive bacteria against the selected LAB strains, while Escherichia coli and Staphylococcus aureus were the most resistant. Again all the isolated LAB species were resistant to three antibiotics; kanamycin, streptomycin and vancomycin. Characterization and probiotic potentials of the LAB isolated from fermented gilaburu (Viburnum opulus) juice were studied first time, and further research needs to be done on their behaviors in similar food formulations as a probiotic. PMID- 30011687 TI - Effects of hypercholesterolemic diet enriched with onion as functional ingredient on fatty acid metabolism in Wistar rats. AB - The complex biochemical composition of onions has been studied as a source of biological components with health-related properties. The evolution of hypercholesterolemia is associated with a large range of alterations considered as strong risk factors for many cardiovascular events. The objective of this study was to investigate the effects of onion as functional ingredient on plasma, erythrocyte, liver and adipose tissue fatty acid composition in hypercholesterolemic male Wistar rats. Rats (n=24) were randomly divided into three groups: control (C), high-cholesterol (HC), and high-cholesterol enriched with onion (HCO) groups. At the end of 7weeks, animals were anesthetized and euthanized by extracting blood by cardiac puncture. Plasma, erythrocytes, liver and adipose tissue were collected and immediately stored at -80 degrees C. Fatty acid methyl esters were identified and quantified by GC/MS. Total fatty acid concentration decreased in liver and adipose tissue both in HC and HCO groups. SFA content was significantly higher in plasma, erythrocytes and liver in the C group compared to HC and HCO groups. In contrast, SFAs increased in adipose tissue both in HC and HCO groups compared to the C group. A significant increase in MUFA content in plasma was found in HC and HCO groups compared to the C group; in erythrocytes and liver the increase was lower. In plasma, PUFA content was significantly lower in HC and HCO groups compared to the C group. Interestingly, in liver and adipose tissue, PUFAs increased in HC and HCO groups compared to the C group. Results showed noticeable effects on individual fatty acid composition when assaying high-cholesterol diets in rats, in some cases enhanced by onion enrichment. Further research is needed to deeper understand the involved mechanisms and pathways. PMID- 30011688 TI - Effect of virgin and refined olive oil consumption on gut microbiota. Comparison to butter. AB - There is increasing evidence of the health benefits of olive oil consumption in the diet. Some authors have studied the effect of high fat/high calorie diets and have detected changes on the microbiota. However, these studies are mainly based on saturated fats. Here we present a study on the specific effect on gut bacterial populations of extra virgin olive oil, rich in monounsaturated fatty acids and phenolic compounds, in comparison to refined olive oil, rich in monounsaturated fatty acids but low in phenolic compounds, and to butter, rich in saturated fatty acids and cholesterol. Four groups of animals were studied: one group of mice received a standard chow diet, and the other received three high fat diets, rich in extra virgin olive oil, refined olive oil or butter. Evolution of symbiont population in feces was studied using culture-dependent and culture independent methods. In the latter, the V3 region of 16S rDNA was amplified and separated by denaturing gradient gel electrophoresis; followed by sequencing of the most representative bands. Culture-dependent studies and comparison of the different DGGE profiles throughout the experiment demonstrated that different dietary fats had different effects on gut microbial composition. Butter-induced changes in the microbial counts resembled those previously described in obese individuals. Interestingly, a different behavior between extra virgin and refined olive oil was also observed, extra virgin olive oil being most different from butter. To our knowledge, no studies have analyzed gut microbiota depending on diets with different fatty acid saturations including different types of olive oil. This may offer new data supporting the benefits for health of extra virgin olive oil, so important in the Mediterranean diet. PMID- 30011689 TI - Edible methylcellulose-based films containing fructo-oligosaccharides as vehicles for lactic acid bacteria. AB - The goal of this work was to investigate the physicochemical properties of methylcellulose (MC) based films as stabilizers of two strains of lactobacilli: Lactobacillus delbrueckii subsp. bulgaricus CIDCA 333 and Lactobacillus plantarum CIDCA 83114. The incorporation of 3% w/v fructo-oligosaccharides (FOS) into the MC film formulation improved the viability of L. delbrueckii subsp. bulgaricus CIDCA 333 after film preparation. L. plantarum CIDCA 83114 was intrinsically more resistant as no viability loss was observed upon preparation of the films in the absence of FOS. Scanning electronic microscopy images also showed a good incorporation of microorganisms without affecting the homogeneity of the films. FTIR spectroscopy provided structural information about the bacteria-loaded films. Water sorption isotherms showed an impervious behavior at low aw but on exceeding 0.7 of aw the film started to dissolve and form syrup, causing a drastic drop of bacterial viability (log N/N0<=-5). Dynamic mechanical analysis (DMA) demonstrated that the incorporation of microorganisms into the MC films had no effect on vitreous transition temperatures. FOS incorporated into the MC films had a plasticizing effect. Microorganism-loaded films were stored at relative humidities (RH) ranging from 11 to 75%. Both strains could be stored at 11% RH for 90days. At 33 and 44% RH L. delbrueckii subsp. bulgaricus CIDCA 333 could be stored up to 15days and L. plantarum CIDCA 83114 up to 45days. At 75% RH only L. plantarum CIDCA 83114 could be equilibrated (log N/N0: -2.05+/-0.25), but CFU/g films were undetectable after 15days of storage. The results obtained in this work support the use of MC films containing FOS as a good strategy to immobilize lactic acid bacteria, with potential applications in the development of functional foods. PMID- 30011690 TI - Probiotic bacteria in infant formula and follow-up formula: Microencapsulation using milk and pea proteins to improve microbiological quality. AB - The perceived health benefit of probiotics has led to a rapid expansion of their use in various health-based products. The beneficial effect of these probiotic cells is largely dependent on their ability to reach their appropriate site of action, usually the distal gut, in a viable condition and in sufficient numbers. In an attempt to establish a microbiota in formula-fed infants resembling that of breast-fed ones, infant formula manufacturers are increasingly incorporating probiotics into their products. The administration of probiotic cells via oral administration is associated with a large decrease in the number of viable cells due to the high acid and bile salt concentrations present in the stomach. Powdered infant formulae are also expected to have long term stability particularly in comparison to products normally associated with probiotics, which can adversely affect the viability of probiotic cells. Finally, the processing techniques used to generate infant formula can cause a dramatic loss in the number of viable cells present in the product by the time it is consumed. Microencapsulation technology is emerging as an effective way to protect cells during food processing and also allows targeted delivery of the cells to appropriate sites in the gastro-intestinal tract improving the efficacy of the final product and lowering the economic cost incurred by producers due to logistic and stability issues. In this review, the current situation of probiotics in infant formula, and the encapsulation techniques being developed using milk and pea proteins as encapsulating materials to improve their viability are discussed. PMID- 30011691 TI - Gastroprotective bio-guiding fractionation of hydro-alcoholic extracts from green and black-teas (Camellia sinensis). AB - Hydro-alcoholic extracts from leaves of Camellia sinensis (green- and black-tea leaves) were submitted to a fractionation, promoting the compound separation according to their polarity, and analyzed by ultra-high performance liquid chromatography-mass spectrometry. A wide range of compounds could be identified, such as catechins and their gallate (esters) or oxidation derivatives (theaflavins), glycosylated flavonoids and other phenolics, as well as lipids, saponins and alkaloids. Also have been developed, via bio-guided examination, the gastroprotective property of the compounds identified. The samples were assayed using the model of acute gastric lesions induced in rats by ethanol. Hydro alcoholic extracts of green-tea and black-tea protected the gastric mucosa with ED50=3.6 and 10.2mg/kg, respectively, with participation of gastric mucus and reduced glutathione (GSH). The ethyl acetate fraction from green-tea and aqueous fraction from black-tea were, respectively, 6 and 10 times more effectiveness than the initial extracts. Moreover, the epigallocatechin gallate (EGCG, 0.204mg/kg), a main component of ethyl acetate fraction from green tea, reduced the gastric lesion by 56% and restored the mucus levels, however the rutin (0.0133mg/kg), a flavonoid found in the most active fraction of black-tea, was less significant at the natural concentrations. These results have confirmed that the different compounds present in green- and black-tea hydro-alcoholic extracts and partitioned fractions produce relevant gastroprotection mainly via maintenance of the protective factors, mucus and GSH. PMID- 30011692 TI - Flour quality and disproportionation of bubbles in bread doughs. AB - The bread making process transforms wheat flour doughs into highly porous breads. Bread has been shown (Wang, Austin and Bell, 2011) to be a single, open cell that is massively interconnected giving it a maze-like structure that encompasses the entire volume. The solid strands are also porous and contain closed cells. How the bubbles in dough mix partition into these open and closed cells in bread is not known. This study was undertaken to track changes in bubbles in doughs using 3-D X-ray microtomography techniques as doughs proofed and were baked. The mechanical properties of doughs were measured to establish how dough rheology impacted bubble growth. The doughs were made with 'medium strong' Canadian flour (CWRS) and 'weak' Australian flours (Wylk). Both doughs had similar protein amounts and strain-hardening characteristics; however the CWRS dough was more elastic. The scans identified formation of clusters of partially-coalesced bubbles from which one cluster grew to form a massively interconnected, single, closed cell in doughs as doughs proofed. Microscopy studies confirmed that the open cell in breads was made of partially-coalesced bubbles. Compared to the dough made with the Australian flours, the dough made from Canadian flour had a thicker dough layer separating bubbles, smaller size bubbles and a slower rate of formation of the continuous structure. This study highlights the critical role of dough elasticity and the disproportionation phenomena of bubble growth in controlling the quality of cell structures in dough and baked products. PMID- 30011693 TI - Functional properties and Angiotensin-I converting enzyme inhibitory activity of soy-whey proteins and fractions. AB - Soy proteins when prepared to high purity can confer good functional properties and the whey by-product is a potential source for bioactivity. In this study, we determined the protein, moisture, fiber, solubility, foaming, emulsion properties, as well as Angiotensin-I converting enzyme (ACE-I) inhibitory activity of prepared soy-whey proteins and its fractions. The soy-whey proteins were fractionated into <5, >5, >10, and >50kDa using ultrafiltration. The expanded AACC methods were used to determine protein, moisture, and fiber analyses of the whey and its fractions. Solubility method was conducted to determine the protein solubility profile of the soy-whey and its fractions at varying pHs. Turbidimetric method was used to evaluate emulsifying activity (EA) and emulsion stability (ES). There were significant differences observed in moisture, protein and salt contents between unfractionated, >50kDa and smaller sized fractions. No significant differences were observed with phytic acid and total dietary fiber contents among all samples. The unfractionated whey protein and >50kDa fraction showed better solubility than other fractions. Unfractionated whey protein had the highest foam capacity (42.7mL) while the fraction >5kDa showed the greatest foaming stability (46min). The highest emulsion activity (0.33+/-0.1) and stability (825.1+/-45.1) was obtained with the >50kDa fraction while the unfractionated whey protein had the highest ACE-I inhibition activity. The findings indicate that soy-whey protein fraction (>50kDa) had good solubility, emulsion activity and stability, while the unfractionated whey protein exhibited the strongest ACE-I inhibition percentage (19%). PMID- 30011694 TI - Comparative in vitro intestinal digestion of 1,3-diglyceride and 1-monoglyceride rich oils and their mixtures. AB - Intestinal in vitro digestion of 1,3-diolein (DO), 1-monoolein (MO), DO:MO (1:1) rich oils, and triolein (TO), was performed to study the rate and extent of hydrolysis as well as their bioaccessibility in detail, with special emphasis on 1,3-DO and 1-MO forms, as potential bioactive lipids with additional technological functions such as self-emulsifying lipids. The importance of in vitro conditions on non-desirable acylmigration was also shown. The rate of in vitro intestinal lipolysis was in increasing order TO95%) of DO, MO and DO:MO were found within the micellar phase fraction during digestion, suggesting a high bioaccessibility. A positive correlation between the degree of lipolysis and the number of mixed micelles formed at the end of digestion was found. As summary, the obtained results would enhance the selection of glycerides to formulate ingredients with different purposes. Thus, in case a final high level of 1-MO would be desired to take advantage of the bioactivity of 1-MO, oils under the form of DO or DO:MO might be superior to MO. In case a high 1-MO level together with a low 2-MO level would be desired at the same time, mixtures of DO:MO or MO would be preferred. In case a higher self-emulsifying ability would be desired, the preferred forms would be MO and DO:MO. Finally, in case all the potential functionalities would be desired at the same time, namely the highest bioactivity, together with a high self-emulsifying ability, the mixture DO:MO might be suggested as an interesting product, with the additional economical advantage. PMID- 30011695 TI - Determination of volatile thiols in roasted coffee by derivatization and liquid chromatography-high resolution mass spectrometric analysis. AB - A fast derivatization/extraction method followed by LC-ESI-HRMS was optimized for the determination of volatile thiols in roasted coffee powder, using ebselen as the derivatization agent. The analytical conditions were optimized on real coffee matrix, which was spiked with representative volatile thiols. The method sensitivity, precision, accuracy and selectivity were evaluated by using representative standard thiols. Estimated LOQs were between 0.02 and 14.8ng/kg for the thiols evaluated. Recoveries and intra-day and inter-day RSD values obtained in coffee matrix were in general around 40% and between 11 and 30%, respectively. The optimized and validated method was applied to real coffee samples. According to the established identification criteria, target thiols were identified and quantified in coffee powder samples. Among them, 4-mercapto-1 butanol and 2-methyl-3-tetrahydrofuranthiol were identified and quantified for the first time in roasted coffee. Moreover, an approach based on the formation of a diagnostic product ion was applied to detect non-target thiols, allowing the detection of nineteen thiol derivatives, fourteen of them were tentatively identified on the basis of their molecular formula. Some of them, such as methanethiol and 3-mercapto-3-methylbutyl acetate were known to be present in coffee volatile fraction, while the rest were not previously described in this product. PMID- 30011696 TI - The Amazonian fruit Byrsonima crassifolia effectively scavenges reactive oxygen and nitrogen species and protects human erythrocytes against oxidative damage. AB - A hydrophilic extract of murici (Byrsonima crassifolia), a fruit native to the North and Northeast regions of Brazil, was evaluated in relation to its phenolic composition and in vitro antioxidant potential against some physiologically relevant reactive oxygen and nitrogen species. Additionally, the protective effect of murici extract against peroxyl radical (ROO)-induced toxicity to human erythrocytes was also determined. The major phenolic compound, determined by HPLC DAD-MSn, was quercetin (2.72+/-0.35MUg/mL). The extract was able to scavenge ROO (0.30+/-0.04MUmoltroloxequivalent/mg), hypochlorous acid (IC50=10.0+/-0.1MUg/mL), hydroxyl radical (IC50=7+/-1MUg/mL) and peroxynitrite anion (IC50=21.0+/ 0.6MUg/mL and 17.0+/-1.6MUg/mL, respectively, in absence and presence of NaHCO3). Human erythrocytes were subjected to oxidative damage, but murici extract was not able to inhibit hemolysis, even at the highest tested concentration. On the other hand, the extract inhibited hemoglobin oxidation (IC50=271+/-44MUg/mL), lipid peroxidation (1000MUg/mL) by 48+/-5%, depletion of glutathione (100MUg/mL) by 49+/-2% and formation of its oxidized form (100MUg/mL) by 96+/-4%. PMID- 30011697 TI - Development of interspecific competition models for the growth of Listeria monocytogenes and Lactobacillus on vacuum-packaged chilled pork by quantitative real-time PCR. AB - The competitive growth of Listeria monocytogenes and Lactobacillus on vacuum packaged chilled pork (VPCP) was studied by the use of Real-time PCR assay and selective culture counting method, where the Jameson-effect model and modified Lotka-Volterra model were chosen for the fitting of growth data. Real-time PCR assay was successfully applied to model the growth of the L.monocytogenes and Lactobacillus respectively on VPCP. The Jameson effect was occurred between L.monocytogenes and Lactobacillus when they co-existed in the same culture, and Lactobacillus clearly induced an early stationary phase of L. monocytogenes. The Jameson-effect model could be used to fit the growth curves of L. monocytogenes and Lactobacillus on VPCP. Thus the modified Lotka-Volterra competition model could be used to evaluate the interaction of two bacterial populations during the growth process, and found that the influence from Lactobacillus on L. monocytogenes was much higher than L. monocytogenes on Lactobacillus through the interaction coefficients. In conclusion, bacterial interactions need to be considered in microbial predictive models, which will provide a more practical assessment in predictive microbiology, and the model for the prediction based on the Real-time PCR assay can be used in future studies, especially for research of interaction models. PMID- 30011698 TI - Steady, dynamic and creep rheological analysis as a novel approach to detect honey adulteration by fructose and saccharose syrups: Correlations with HPLC-RID results. AB - In this study, natural honey was adulterated with the addition of adulterants, namely saccharose and fructose syrups at a ratio of 0%, 10%, 20%, 30%, 40% and 50% by weight. Steady, dynamic and creep tests were conducted, revealing that the changes in the flow, viscoelastic and creep behavior of natural honey were clear and remarkable. Syrup addition decreased viscosity (eta), storage (G') and loss modulus (G") values of the control honey samples. Deformation represented by the compliance (J(t)) values was more prominent in the adulterated honey samples. In addition, HPLC-RID analysis was conducted to determine major sugar composition of the adulterated samples. Pearson's correlation test indicated that there were significant (P<0.05; 0.01) correlations between sugar composition and rheology parameters, eta (viscosity), K", K* (intercepts for G" and complex modulus (G*), respectively) and eta0 (viscosity of Maxwell dashpot), suggesting that K', K", K* and eta0 could be prominent indicators for presence of saccharose or fructose syrups added in natural honey within the studied concentration levels. These results suggested that use of steady, dynamic and creep analysis would be a novel and potential approach to detect honey adulteration by fructose and saccharose syrups. PMID- 30011699 TI - Non-destructive evaluation of quality and ammonia content in whole and fresh-cut lettuce by computer vision system. AB - The paper describes the developed hardware and software components of a computer vision system that extracts colour parameters from calibrated colour images and identifies non-destructively the different quality levels exhibited by lettuce (either whole or fresh-cut) during storage. Several colour parameters extracted by computer vision system have been evaluated to characterize the product quality levels. Among these, brown on total and brown on white proved to achieve a good identification of the different quality levels on whole and fresh-cut lettuce (P value<0.0001). In particular, these two parameters were able to discriminate three levels: very good or good products (quality levels from 5 to 4), samples at the limit of marketability (quality level of 3) and waste items (quality levels from 2 to 1). Quality levels were also chemically and physically characterized. Among the parameters analysed, ammonia content proved to discriminate the marketable samples from the waste in both product's typologies (either fresh-cut or whole); even the two classes of waste were well discriminated by ammonia content (P-value<0.0001). A function that infers quality levels from the extracted colour parameters has been identified using a multi-regression model (R2=0.77). Multi-regression also identified a function that predicts the level of ammonia (an indicator of senescence) in the iceberg lettuce from a colour parameter provided by the computer vision system (R2=0.73), allowing a non destructive evaluation of a chemical parameter that is particularly useful for the objective assessment of lettuce quality. The developed computer vision system offers flexible and simple non-destructive tool that can be employed in the food processing industry to monitor the quality and shelf life of whole and fresh-cut lettuce in a reliable, objective and quantitative way. PMID- 30011700 TI - Sensory expectations and perceptions of Austrian and Thai consumers: A case study with six colored Thai desserts. AB - This work studied evaluations by Austrian and Thai consumers of their sensory expectations and perceptions of six Thai desserts, each made in three different colors (green, pink, yellow). The color variants differed only in color but not in their ingredients or taste. Expectation tests were performed by showing pictures of the desserts on a monitor and asking them to evaluate their expected overall liking and expected intensities of sweetness, bitterness, sourness and hardness. Results showed that colors of the products were important in predicting expected liking and taste intensity. For the perceived liking test, the samples were served so they could be tasted, and the perceived liking was scored on a visual analog scale. Austrians expressed a strong preference for yellow products whereas Thais preferred green and pink products. Findings of this study can be used as a model for adapting colors of products for new markets and consumer demand. PMID- 30011701 TI - The sub-species characterization and antimicrobial resistance of Listeria monocytogenes isolated from domestic and imported food products from 2004 to 2011. AB - Thirty-five Listeria monocytogenes strains isolated from domestic and imported food products including seafood, vegetables, and dairy foods were characterized by serotyping, molecular sub-typing, and antimicrobial susceptibility. L. monocytogenes serovars 1/2a and 1/2b strains were dominant as compared to other two serovars 4b and 1/2c strains. The dendrogram of AscI or ApaI-digested PFGE profiles of L. monocytogenes strains was classified into 23 (with 8 groups) or 3 (with 2 groups) different PFGE types, respectively. The AscI-digested groups consisted of the same serovar or food-source. Antimicrobials such as ampicillin, gentamicin, and trimethoprim-sulfamethoxazole are widely used in the treatment of listeriosis. Of the isolates used in this study, NCTR_LM14 and NCTR_LM57 were resistant to several classes of antimicrobials including aminoglycosides, penicillin, tetracycline, glycopeptide and fluoroquinolones. The multi antimicrobial resistant isolates also showed higher efflux pump activity as compared to the antimicrobial sensitive strains NCTR_LM06 and L. monocytogenes EGD-e. This study demonstrates that L. monocytogenes isolates from various food products are genetically diverse with some isolates being resistant to more than 3 different antibiotic classes. This study also indicates that the efflux pump activity of the antibiotic resistant strains was higher than antimicrobial susceptible strains. Therefore, we propose that the antibiotic resistance observed in these strains may be conferred by the results of a highly active efflux pump system. PMID- 30011702 TI - Reduced calorie emulsion-based foods: Protein microparticles and dietary fiber as fat replacers. AB - The potential of using microparticulated whey protein (MWP) in combination with either modified starch or locust bean gum (LBG) as fat mimetics to fabricate reduced calorie emulsion-based sauces and dressings was studied. The influence of food matrix composition (protein, polysaccharide, and fat content), ionic strength, and pH on the properties of thermally processed model emulsions (90 degrees C/10min) was investigated. Increasing protein concentration (2.5-7.5%) increased the mean (d3,2) particle diameter due to the formation of large protein aggregates. All MWP-containing systems had a creamy white appearance with high lightness (L*>75). Addition of fat droplets (5%) further increased their lightness (L*>90) due to enhanced light scattering. Addition of starch, LBG, or MWP increased emulsion viscosity due to the increased effective volume fraction of the dispersed phase. Addition of calcium chloride (10mM) and pH adjustment (2 8) caused little change in the physicochemical properties of the mixed systems. Overall, the appearance and rheological properties of the mixed systems were similar to commercial sauces and dressings. This study demonstrates that reduced calorie food emulsions with appearance and consistency similar to those of full fat versions can be formulated using protein microparticles and polysaccharides. PMID- 30011703 TI - Effects of malting on molecular weight distribution and content of water extractable beta-glucans in barley. AB - In the beer industry beta-glucans are extensively studied non-starch polysaccharides due to their ability to increase the viscosity of solutions and to form gels. The current study was designed to determine the total and water soluble beta-glucan contents of barley during malting. Total and water-soluble beta-glucans were analyzed from two different malts that originated from the same barley but varied in germination time from 36h (malt A) to 72h (malt B). Water soluble beta-glucans were also characterized using high-performance size exclusion chromatography with triple-detector analysis (HPSEC-TDA) to evaluate the variation in molecular weight distributions, intrinsic viscosity, radius of gyration, Mark-Houwink parameters and polydispersity and thus the overall structural changes during malting. Total beta-glucan content decreased from barley to malt due to the action of beta-glucanase and was greatest in malt B (where 92% of beta-glucans were degraded) which highlights the influence of germination time. beta-Glucan solubility increased during malting, again particularly in malt B, where most of beta-glucans became soluble. The beta glucanase activity also affected the molecular weight of the polymers which ranged from 298.103g/mol in barley to 293.103 and 218.103g/mol in malts A and B respectively. The molar mass of the most abundant fraction decreased from barley (256.103g/mol) to malt A (112.103g/mol) and malt B (89.103g/mol), again highlighting the effect of the longer germination time. Proceeding from barley to malt, the cumulative molar mass distribution function confirmed that the weight fraction of polymers below 200.103g/mol increased, while the high molecular weight fraction (between 200.103g/mol and 400.103g/mol) decreased. Moreover, the presence of a higher molecular weight fraction (14-16%) beyond 400.103g/mol which does not change during malting was observed. The Mark-Houwink constants alpha and log k confirmed the random coil conformation of soluble beta-glucans and showed an increase in the compactness of the macromolecules from barley to malts. PMID- 30011704 TI - Effect of the substrate's microstructure on the growth of Listeria monocytogenes. AB - The effect of the microstructure of the medium on the growth of the food-borne pathogen Listeria monocytogenes was studied. The pathogen's growth kinetics was evaluated using liquid substrates and gels formed from different concentrations of sodium alginate (3.0% w/w) and gelatin (0-30.0% w/w). These results were further verified using a model dairy product with solid concentrations varying from 10.0 to 40.0% w/w. The pathogen's growth was faster in the liquid media than in the gels regardless of the gelling agent employed. The substrate's microstructure, apart from altering the growth pattern from planktonic to colonial, resulted in microbial growth suppression; however, each system affected the microorganism's growth in a different way. The suppressing effect of the substrate's microstructure on microbial growth was also dependent on temperature, while the presence of glucose in the solid medium accelerated microbial growth, thus reducing substantially the difference in growth kinetics between the gels and the liquid media. Any increase in the hydrocolloid concentration, which was also reflected in the rheological properties of the structured samples, resulted in a reduction of growth rate and in an increase of the lag phase of the pathogen. Overall, the gelation of the medium was found to exert a stress on the microorganism since the sol-gel transition, when the pathogen was already at the exponential growth phase, resulted in an additional lag phase or a decrease in the growth rate. The relationship between maximum specific growth rate and loss tangent of the gels (tandelta=G"/G') was explored, pointing to the possible use of a single structural parameter to describe food matrix effects on microbial growth kinetics. PMID- 30011705 TI - Inter-individual retronasal aroma release variability during cheese consumption: Role of food oral processing. AB - The aim of our study was to explain inter-individual differences on in vivo aroma release during cheese consumption by oral physiological parameters. To reach this objective, 34 subjects were recruited. Their salivary flow, oral volume and velum opening were determined. Six cheddar-based melted cheeses with different fat levels and firmness were flavoured with nonan-2-one (NO) and ethyl propanoate (EP). During their consumption (free protocol), in vivo retro nasal aroma release was followed by Atmospheric Pressure Chemical Ionisation-Mass Spectrometry (APCI MS). Chewing activity was evaluated by electromyography recordings. Bolus saliva content, mouth-coating, and bolus rheology were also determined. Based on the quantity of aroma released before and after swallowing, subjects can be clustered into three groups: the first one (HRG) is characterized by a large quantity of aroma release whatever the aroma compound; the second one (MRG) showed a large release for EP and a lower one for NO; the third group (LRG) was characterized by a low quantity of aroma release whatever the compound. Whatever the group of subjects, fat and firmness effects differed according to the aroma compound. EP release increased with firmness and fat content, whereas NO release was not affected by firmness and decreased when fat content increased. Physiological parameters which better differentiated the three groups of subjects according to their release behaviour were chewing activity, mouth coating and frequency of velum opening. Subjects from HRG were differentiated from LRG subjects by a higher chewing activity, and more frequent velum opening. Subjects from MRG presented a lower mouth coating explaining their lower release of NO, the more hydrophobic compound. This study shows that the total amount of aroma released in the nasal cavity during food consumption depends not only on the characteristics of the product but also on the oral physiology of the subjects and on their food oral processing. PMID- 30011706 TI - Attentional capture and importance of package attributes for consumers' perceived similarities and differences among products: A case study with breakfast cereal packages. AB - The present work studied attentional capture and importance of package attributes for consumers' perception of similarities and differences among products through a combination of eye-tracking and projective mapping. As a case study, fifty consumers performed a projective mapping task with ten breakfast cereal packages while wearing a mobile eye-tracker. The combination of mobile eye-tracking and projective mapping enabled a more comprehensive analysis of the importance of package attributes for consumer perception. Eye tracking allowed the identification of the most relevant package features for perceived similarity and differences among products and spotted attributes that were attended to but were not relevant, as well as package features that were relevant for categorization but were not largely attended to. Results suggest that studying attentional capture could contribute to better understanding attribute importance for consumer perception. Irrespectively of the saliency, most consumers looked at the same key information, mainly located on the front-of-pack. Few consumers read the nutritional label and ingredient list (a much lower proportion than in previous static eye tracker studies). Results suggested that mobile eye-tracking has a great potential for assessing consumers' evaluation of packages in ecological settings. However, several disadvantages and limitations of the technique should be taken into account. PMID- 30011707 TI - High shear mixer granulation using food grade binders with different thickening power. AB - Mixer agglomeration, in particular high shear wet granulation, is a unit operation typically used in the pharmaceutical industry to improve the flowability, the compressibility, the dosing accuracy during tableting or the content uniformity of a blend. Thanks to its advantages (production of spherical and dense granules, reduction of production time), this technique can be potentially successful also in the food industry as for example in the production of dietary supplements. In this work four thickening agents (povidone, maltodextrin, k-carrageenan and xanthan gum) have been tested to study their effects on the granule growth behavior and on some technologically relevant granule properties (size, shape, strength and flowability). Experiments highlighted the full feasibility of the process and the possibility of using these agents to get products with satisfactory technological properties. The dependence of product properties on the formulation variables (water and binder amount) has been analyzed according to a multivariate approach and a robust predictive tool for the granule size has been developed. Furthermore it was observed that a reduced amount of binding liquid (water) can be used in the presence of strongly thickening binders with a reduction up to 25%. This would decrease drying time and energy requirement and be beneficial especially in the food and food supply industry where products have generally lower added value than in the pharmaceutical one and reducing production costs is critical. PMID- 30011708 TI - Fast method for capsaicinoids analysis from Capsicum chinense fruits. AB - Chili peppers are widely utilized in the world as savory food additives due the pungency induced by the capsaicinoids. Also, these compounds have functional properties as antimutagenic, antitumoral, antioxidant and analgesic. These characteristics increase the interest in this compound class, hence the capsaicinoid analysis must be reproducible and accurate. This study aimed to develop and validate a fast, efficient and reproducible method to analyze capsaicinoids in Brazilian Capsicum chinense fruits. The extracts were obtained after an optimization step that indicated the condition 100% of methanol and 10min on ultrasound assisted extraction. The analyses were carried out in an ultra high performance liquid chromatographic system with detection by a photo diode array and mass spectrometer. The analytical method developed permits the separation of 8 capsaicinoids in 4min of time analysis expending only 2mL of solvent as mobile phase. The validation parameters evaluated for the method show the effectiveness and satisfactory performance to answer the analytical needs of this research area, presenting low values to relative standard deviation in repeatability and reproducibility and recoveries ranged from 88 to 112% for capsaicin and 89 to 109% for dihydrocapsaicin. In the extracts from different accessions of C. chinense fruits analyzed, the contents of capsaicin and dihydrocapsaicin were in the range of 156-1442MUgg-1 and 26-478MUgg-1 of fresh fruit, respectively, showing the large application of this method for quantification of the two major capsaicinoids in fast routine analysis and may be used to determine the concentrations of other minor capsaicinoids once appropriate standards are available. PMID- 30011709 TI - Influence of lactic acid and acetic acid on Salmonella spp. growth and expression of acid tolerance-related genes. AB - Salmonella spp. is an important foodborne pathogen, often associated with meat products. This pathogen presents a complex tolerance mechanism in the presence of organic acids, which is regulated by a diversity of genes, including rpoS, nlpD and clpP. The present study aimed to measure the expression of such genes by Salmonella strains subjected to acid stress conditions, and associate these data with microbial growth. A culture collection composed of 79 strains of Salmonella spp. obtained from bovine and swine production chains was subjected to PFGE using XbaI, and 3 strains (serovars Derby, Typhimurium and Meleagridis) were selected for acid tolerance trials. The selected strains were inoculated in meat extract broth (MEB) added to lactic or acetic acids at a final pH of 4.0, 5.0 or 6.0, and incubated at 37 degrees C for 6, 12, 24 and 48h. As controls, Salmonella strains were inoculated in MEB at pH7.0, and incubated in the same conditions. Bacterial populations were monitored by direct plating and gene expression using qPCR. Salmonella presented similar populations to controls and evident expression of rpoS at pH5.0 and 6.0. However, Salmonella populations were not detectable after 6h at pH4.0. The adaptability of Salmonella to pH5.0 and 6.0 emphasizes the importance of adequate monitoring of pH reduction during cleaning procedures in food industries, such as organic acid spraying in bovine carcasses. The data obtained demonstrated the relevance of rpoS in the acid tolerance mechanism of Salmonella strains, prompting further studies to investigate its expression in meat systems. PMID- 30011710 TI - Proteomic insight into the effect of ethanol on citrinin biosynthesis pathway in Monascus purpureus NTU 568. AB - Monascus species produce several potent bioactive metabolites through polyketide secondary metabolic pathways; however, little is known of the regulation of metabolic processes in this organism. Therefore, we investigated the effect of extreme growth conditions on the production of secondary metabolites by Monascus purpureus strain NTU 568 and identified pathways that plausibly regulate the polyketide pathways by using proteomic analysis. Citrinin, a type of antibiotic, is synthesized through the polyketide pathway in M. purpureus NTU 568. We hypothesized that production of citrinin might be inhibited by ethanol. When M. purpureus NTU 568 was cultured in the medium containing 4% ethanol, the secretion of secondary metabolites was inhibited, but the dry cell weight was increased. We also found that branched chain amino acid degradation and the expression level of aldehyde dehydrogenase (ALDH) were downregulated, but proteins related to the heat shock response were induced. Furthermore, polyketide synthesis-related proteins, fatty acid synthase, epoxide hydrolase, and proteins involved in the shikimate secondary metabolic pathway were inhibited by ethanol treatment. These results suggested that reduced production of polyketide metabolites resulted not only from the expression levels of proteins in the polyketide synthesis pathway but also from reduction in the concentration of primary metabolism-generated molecules (e.g., acetyl-CoA, fatty acids) that are used as substrates for polyketide syntheses. This study provides insights into the polyketide secondary metabolism of Monascus as well as into improvement of the production of bioactive secondary metabolites in Monascus species. PMID- 30011711 TI - Increased loading of vitamin D2 in reassembled casein micelles with temperature modulated high pressure treatment. AB - Native casein micelles were treated (incubated) with vitamin D2 at different hydrostatical pressures (0.1, 200, 400, and 600MPa) and temperatures (10-50 degrees C) in order to load the vitamin. Pressure induced the release of alphas-, beta- and kappa-casein and calcium from the micelle into the soluble phase. During the pressure stable reassembled micelles were created due to a structural rearrangement of hydrophobic interactions between the hydrophobic domains of the caseins and vitamin D2. Treatment at 600MPa and 50 degrees C increased the loading of vitamin D2 per casein from 2.2+/-0.2MUg/mg (native sample) to 10.4+/ 0.2MUg/mg. The reassembled micelles presented an average hydrodynamic diameter of 272+/-10nm and contained 8.1, 10.3 and 0.8mg of alpha-, beta- and kappa-casein, respectively, per 100mg casein. PMID- 30011712 TI - Shear structuring as a new method to make anisotropic structures from soy-gluten blends. AB - The concept of shear-induced structuring was applied to concentrated blends of soy protein isolate (SPI) and wheat gluten (WG) to create novel semi-solid food textures. Concurrent simple shear deformation and heating (95 degrees C) of the protein blends generated original structures consisting of fibers or layers. The ratio of SPI to vital WG and the final concentration determined the morphology of the structure. It is hypothesized that the spatial distribution of the SPI-rich phase and the WG-rich phase in a blend was altered by the shear flow. When both phases became aligned horizontally in the shear cell, a fibrous structure was formed; when they became aligned vertically in the shear cell, a layered structure was formed. The structures obtained were analyzed visually and using texture analysis and scanning electron microscopy. PMID- 30011713 TI - The effects of strawberry, black currant, and chokeberry extracts in a grain dietary fiber matrix on intestinal fermentation in rats. AB - The objective of this work was to study the composition, hydration properties and oil holding capacity, antioxidant properties and the physiological effects on the digestive system of dietary preparations containing wheat or oat fiber enriched with polyphenol extracts from strawberry, chokeberry, and black currant pomace. By the addition of black currant, strawberry and chokeberry polyphenol extracts to grain fibers preparations with corresponding polyphenol content of 0.7%-0.8%, 1.1%-1.2%, and 2.5%-2.9% were obtained. The preparations were used as part (8%) of a modified AIN-93 diet given to growing Wistar rats (8 animals per group) over a period of 4weeks. The highest antioxidant potential had grain-chokeberry preparations with the greatest polyphenol content, while grain-black currant preparations exhibited the lowest antioxidant potential with the smallest polyphenol content. The addition of strawberry and chokeberry extracts caused a decrease in the activity of bacterial beta-glucosidase and alpha-galactosidase, while black currant extract led to increased activity of beta-galactosidase and beta-glucuronidase. The production of short chain fatty acids (SCFAs) in the caecum of rats fed the grain-strawberry preparation, rich in ellagitannins, was considerably higher than the grain-black currant preparation, rich in proanthocyanidins and anthocyans, or the grain-chokeberry preparation with the highest polyphenol content (78.3 vs. 64.7 vs. 56.3MUmol/100g body weight, p=0.012). In comparison to preparations without polyphenols only chokeberry extract significantly decreased SCFA concentration. The grain-strawberry preparations were characterized by a higher antioxidant potential per unit of polyphenol content and exhibited a more beneficial influence on the fermentation processes in the caecum of rats than the grain-black currant and grain-chokeberry preparations. PMID- 30011714 TI - Polyphenolic compounds and anthocyanin content of Prosopis nigra and Prosopis alba pods flour and their antioxidant and anti-inflammatory capacities. AB - The aim of this study was to determine the content of total free and bound phenolics, free and bound flavonoids, anthocyanins, and alkaloids and the profile of polyphenols of edible ripe pods of Prosopis alba and Prosopis nigra. P. alba flour showed significantly higher total (sum of Free- and Bound) phenolic content and total flavonoid compounds than P. nigra (p<0.05) while P. nigra had higher concentrations of anthocyanins than P. alba (p<0.05). The P. nigra flour shows a pattern characterized by the occurrence of anthocyanins as well as 14 flavonoid glycosides, with higher chemical diversity than P. alba, which shows 8 flavonoid glycosides as relevant constituents. The main compounds were quercetin O glycosides and apigenin-based C-glycosides. The phenolic composition of two South American algarrobo pod flour is presented for the first time. P. nigra pods having higher content of anthocyanins are darker (purple) than those of P. alba (light brown). Furthermore, the sugar-free polyphenolic extracts of P. nigra and P. alba as well as anthocyanins enriched extracts from P. nigra showed antioxidant activity. P. nigra and P. alba polyphenolic extracts showed activity against a pro-inflammatory enzyme. In conclusion, algarrobo pods meal contained biologically active polyphenols, with a positive impact on human health. PMID- 30011715 TI - Predicting the quality of wheat flour dough at mixing using an expert system. AB - Modelling the links between the mixing process conditions of wheat flour dough and the properties of the dough is a challenge. This paper presents a systematic modelling approach based on qualitative algebra to represent human expertise in this domain. Qualitative models of wheat dough mixing have been implemented as an expert system, called Ascopain. The relations between the process conditions - flour specifications and kneading conditions - and the dough sensory properties, have been formalised by means of qualitative functions. An extensive evaluation of Ascopain is provided by comparing the simulation results, first to experts' predictions, and second, to experimental results of sensory evaluation of mixed dough properties. The good matching level proves the accuracy and the robustness of the expert-system and, overall, its ability to implement a reasoning on the influences of process conditions to predict actual dough properties, starting from ingredient characteristics. PMID- 30011716 TI - HPLC-MSn identification and quantification of phenolic compounds in hazelnut kernels, oil and bagasse pellets. AB - The paper reports the phenolic content of kernels, bagasse pellets (residue of oil pressing) and oils from five different cultivars and a mix of cultivars. Phenolic compounds were identified by high-performance liquid chromatography coupled with mass spectrometry. Two compounds, glansreginin A and glansreginin B, were detected for the first time in hazelnuts. The main polyphenolic subclass comprised of mono- and oligomeric flavan 3-ols, which accounted between 34.2 and 58.3% in hazelnut kernels and between 36.7 and 48.6% in pellets of the total phenolics detected. In hazelnut oils four compounds have been detected, their content levels ranged from 0.97 to 0.01MUgg-1. Total phenolic content ranged from 491.2 to 1700.4mgGAEkg-1 in kernels, from 848.4 to 1148.5mgGAEkg-1 in pellets and only from 0.14 to 0.25mgGAEg-1 in oils. The percentage of radical scavenging activity ranged from 60.0 to 96.4% for kernels, 63.0 to 73.2% for pellets and from 17.7 to 29.9% for oil. The study provides clear evidence on high phenolic contents and similarly high antioxidant potential of hazelnut kernels and bagasse pellets. The latter could be used as ingredients in cooking and baking or even for production of plant-based pharmaceuticals. PMID- 30011717 TI - Improving the application of SSR polymorphism analysis coupled with Lab-on-a chip(r) capillary electrophoresis to assess food authenticity: Italian pigmented rice as case study. AB - Genetic distances evaluated via SSR-based profiling can be usefully assessed by using capillary electrophoresis. In order to set up a method to distinguish pure Italian rice varieties from imported Asian blends, seven Italian rice genotypes and seven uncharacterized rice samples coming from outside Italy were studied using a classical SSR polymorphism analysis coupled with Lab-on-a-chip(r) microcapillary electrophoresis. A special algorithm for the elaboration of the raw outputs provided by the software was generated, thus overcoming the problems connected to the instrument intrinsic limits of resolution. The results showed that even considering just the smallest verifiable genetic distance between the employed samples, locally cultivated Italian rice varieties clustered separately from other foreign cultivars. Moreover, it was possible to clearly identify an artificial blend formed by Venere rice mixed with a black variety from Thailand, thus confirming the usefulness of this new post-analysis approach. PMID- 30011718 TI - Impact of germination and enzymatic hydrolysis of cowpea bean (Vigna unguiculata) on the generation of peptides capable of inhibiting dipeptidyl peptidase IV. AB - The objective of this work was to determine the impact of germination of cowpea (Vigna unguiculata), combined with enzymatic hydrolysis on the generation of bioactive peptides with dipeptidyl peptidase IV (DPP-IV) inhibition activity and antioxidant capacity. Germination (25 degrees C, up to 48h) and alcalase hydrolysis (up to 4h) significantly increased antioxidant capacity of cowpea proteins from 293.4 to 993.7MUmol TE/g soluble protein (SP). The non-germinated and 1h alcalase hydrolysates showed the highest DPP-IV inhibition (IC50=0.58mgSP/mL), after in vitro simulated gastrointestinal digestion. Selected peptides in the hydrolysates were analyzed by computational modeling. The TTAGLLE peptide interacted with S2 (GLU205, GLU206) and S3 (SER209, ARG358, PHE357) pockets of DPP-IV, and it is expected to inhibit DPP-IV by blocking its active site. Cowpea short time germination (24h) and alcalase protein hydrolysis (1h) can be used to produce ingredients with high antioxidant capacity and DPP-IV inhibition. PMID- 30011719 TI - Facial expressions and autonomous nervous system responses elicited by tasting different juices. AB - The aim of this study was to get a better understanding of reactions elicited by the taste of foods using the example of different juices. The reactions investigated were the rating behavior of self-reported spontaneous liking, various autonomous nervous system (ANS) responses and implicit as well as explicit facial expressions. Therefore, the following four hypotheses were tested: 1) Different sensory stimuli of juices elicit different ANS responses. 2) Differences in facial expressions elicited by sensory stimuli of juices used in an implicit and explicit measurement approach can be detected by using FaceReader 5. 3) Self-reported liking is correlated with the measured ANS parameters and the elicited facial expressions. 4) The measured ANS parameters, facial expressions and self-reported liking allow identical differentiations between samples. Skin conductance level (SCL), skin temperature (ST), heart rate (HR), pulse volume amplitude (PVA) and the facial expressions of 81 participants were analyzed during and shortly after tasting juice samples (implicit measurement approach). Additionally, participants were asked to show how much they liked the tasted sample with an intentional facial expression (explicit measurement approach). Banana, grapefruit, mixed vegetable, orange and sauerkraut juices were used as sensory stimuli. The juices elicited significant differences in SCL and PVA responses and intensities of several facial expressions. For these parameters a moderate correlation with self-reported liking was found, allowing a differentiation between liked, disliked and neutral rated samples. The results show that self-reported liking cannot simply be explained by the measured ANS and implicit facial expression parameters, instead providing different information. Significant differences in facial expressions between the implicit and explicit approach were observed. In the implicit approach participants showed hardly any positive emotions when tasting samples they liked, whereas in the explicit approach they displayed a high degree of positive emotions. In both cases negative emotions were shown more intensely for disliked samples. PMID- 30011720 TI - Elucidation of immediate type I reactions in native and GM mustard (Brassica spp.). AB - Mustard, a widely consumed spice can provoke allergic manifestations in mustard sensitive individuals. The aim of this study is to explore the allergenicity potential of GM mustard varieties (GM-V2 and GM-V4) having increased carotenoid content and compare it with the native (Varuna) and commercially available variety (Urvashi). Mustard protein sensitized (GM and non-GM) BALB/c mice sera were used to identify the allergenic proteins by IgE immunoblotting. Immunoglobulin levels, mouse mast cell protease-1, monocyte chemotactic protein and histamine were measured in serum. The levels of Th1/Th2 transcription factors GATA-3, T-bet, SOCS3, STAT 6 and c-maf in intestinal proteins of all groups were detected by immunoblotting and PCR. Major IgE-binding proteins of 21, 29 and 33kDa were found in all mustard varieties. The enhanced levels of Th2 cytokines IL-4, IL-5 and IL-13 and transcription factors GATA-3 and SOCS-3 were observed. The increased levels of MCP-1, MCPT-1 and histamine were also evident in commercial, native, GM-V2 and GM-V4 varieties of mustard treated groups. Conclusively, all these finding indicate that introduction of GM mustard varieties with increased carotenoid content did not cause any increase in allergenicity as compared to its native counterpart and therefore can be safe from allergenicity point of view. PMID- 30011721 TI - Lactobacillus casei immobilized onto montmorillonite: Survivability in simulated gastrointestinal conditions, refrigeration and yogurt. AB - This study evaluated the survival of Lactobacillus casei when immobilized onto montmorillonite (MMT) and sodium exchanged montmorillonite (Na-MMT) under stress conditions. The results showed that adsorption of L. casei onto MMT and Na-MMT surface reached equilibrium after 1.5h. The percentages of L. casei adsorbed onto the surfaces of MMT and Na-MMT at equilibrium were 55.3% and 83.7%, respectively. L. casei-mineral complexes were characterized by X-ray diffraction, Fourier transformed infrared and thermogravimetric analysis, indicating that L. casei cells were successfully immobilized onto MMT and Na-MMT. Characterization with scanning electron microscope showed that cells attached well to the surface of clay minerals and numerous L. casei cells were observed to form aggregates with clay mineral particles. Immobilization on MMT and Na-MMT protected L. casei from simulated gastrointestinal conditions. Immobilization preserved the counts of L. casei higher than 107CFUmL-1 throughout the storage at refrigerated conditions. Yogurts prepared with L. casei-mineral complex presented lower values for post acidification and higher stability compared to the product prepared with the addition of L. casei in free status. The results of this study suggested the efficiency of immobilization by adsorption onto clay minerals to increase the survival of L. casei in simulated gastrointestinal conditions, refrigerated storage and yogurt. PMID- 30011722 TI - Lycopene and beta-carotene transfer to oil and micellar phases during in vitro digestion of tomato and red carrot based-fractions. AB - The natural structural barriers (i.e. chromoplast substructure and cell wall) in conjunction with the carotenoid hydrophobicity were investigated as factors that may play a role governing the carotenoid transfer efficiency from the tomato and red carrot matrices into the oil and micellar phases during digestion. In addition, the effect of thermal processing on the carotenoid transfer during digestion was studied. While the carotenoid transfer efficiency from the matrix into the oil phase was found to be highly determined by the level of bio encapsulation, the carotenoid hydrophobicity, being lower for lycopene than for beta-carotene, was the main factor influencing the transfer from the oil into the micelles. Overall, the incorporation into the micellar fraction represents the critical step for carotenoid bioaccessibility. Moreover, the effect of thermal treatments on these systems depended on carotenoid species, being negative for lycopene and positive for beta-carotene. PMID- 30011723 TI - Reversion to a control balanced diet is able to restore body weight and to recover altered metabolic parameters in adult rats long-term fed on a cafeteria diet. AB - The increased intake of fat-rich foods is one of the causes of the increasing incidence of obesity. However, there are controversial data on the reversibility of diet-induced obesity and its metabolic complications when adopting a control energy-balanced diet. Our aim was to evaluate the ability to reset not only body weight but also metabolic disorders caused by a highly palatable high fat diet, cafeteria diet, administered to adult rats, when replaced by a control diet (post cafeteria model). Four-months of cafeteria diet-feeding produced important metabolic alterations in comparison to a commercial purified high fat diet: a rapid, drastic increase in body weight, adiposity and related complications such as insulin resistance, decreased glucose tolerance and development of hepatic steatosis. At gene level, decreased lipogenic and increased lipolytic gene expression in key energy homeostatic tissues as a physiological adaptation to increased fat intake was observed. In addition, fasting response of serum parameters and of key genes in lipid metabolism was impaired in cafeteria-fed animals. Contrary to what we have previously described if cafeteria diet is administered early in life, when administered to adult animals, its replacement with a balanced diet is able to restore body weight. Cafeteria diet withdrawal also allows recovery from metabolic damage, gene expression regulation and fasting response, the degree of which is dependent on the time of exposure to the cafeteria diet. In conclusion, adherence to an ad libitum intake of a balanced standard diet can enable the recovery of healthy status in animals which were previously exposed to an unhealthy cafeteria diet in adult age. PMID- 30011724 TI - Survival of hepatitis A virus on various food-contact surfaces during 28days of storage at room temperature. AB - Hepatitis A virus (HAV) infections constitute one of the leading causes of food borne disease outbreaks. HAV spreads readily from one infected person to another through contaminated water or food, via the fecal-oral route. The prevention of HAV infection is therefore important in the preparation of food. The objective of this study was to investigate the survival of HAV on six different food-contact surfaces: ceramic, wood, rubber, glass, stainless steel and plastic. The survival of HAV was measured during storage at room temperature for 28days. On the food contact surfaces, the greatest reduction in HAV was 2.3log10plaque-forming units (PFU)/coupon, observed on stainless steel, while the lowest HAV reduction was 1.4log10PFU/coupon, observed on wood. The values of dR (time required to reduce the virus by 99%) on survival plots of HAV determined by a modified Weibull model were 1396.9h (R2=0.97) on ceramic, 1676.4h (R2=0.98) on wood, 852.7h on rubber (R2=0.95), 1386.4h (R2=0.97) on glass, 428.6h (R2=0.96) on stainless steel and 833.0h (R2=0.97) on plastic. The infectivity of the virus on all six food-contact surfaces was maintained after 28days. Studies show that HAV from food preparation or processing will survive persistently on cookware. This study provides information useful for the control of HAV on different food-contact surfaces and the prevention of food-borne disease. PMID- 30011725 TI - Improvement of antioxidant activity of egg white protein by phosphorylation and conjugation of epigallocatechin gallate. AB - Egg white protein (EWP) was phosphorylated by dry heating in the presence of pyrophosphate. The antioxidant activity of phosphorylated EWP (PP-EWP) was then investigated before and after conjugation of epigallocatechin gallate (EGCG). The binding interaction between EWPs and EGCG was investigated by UV and FTIR, which indicated that more EGCG bound to PP-EWP than to native EWP and dry-heated EWP. The antioxidant activities including ABTS+ free-radical scavenging capacity, oxygen radical antioxidant capacity, reducing power, chelating capacity, and superoxide anion scavenging activity of EWP were remarkably improved by phosphorylation before and after conjugation of EGCG. The improved antioxidant property of PP-EWP can be attributed to the introduced phosphate group, more exposed hydrophobic group, increased surface thiol group of protein, and more EGCG bound to EWP. The secondary structure of PP-EWP decreased with more bound EGCG. This study is the first to describe an improvement in the antioxidant property of EWP by phosphorylation and conjugation of EGCG, thereby providing insight into the design of food protein antioxidant. PMID- 30011726 TI - Influence of cultivar and origin on the flavonol profile of fruits and cladodes from cactus Opuntia ficus-indica. AB - Flavonols are hypothesized to be the most important polyphenolic antioxidants. This present study aimed at investigating flavonols in cactus Opuntia ficus indica fruits from two Egyptian cultivars in comparison to three common Sicilian cultivars, and two further cultivars from South Africa. Besides, cactus O. ficus indica cladodes from Egyptian cultivars have been investigated as well. HPLC-DAD analyses showed that cactus O. ficus-indica fruits and cladodes are mainly characterized by isorhamnetin glycosides. These flavonols were found only in the fruit's peel and the cladodes, but not in the pulp. However, all analyzed cultivars exhibited the same flavonol profile which might therefore serve as a chemical fingerprint with regard to genuineness of cactus O. ficus-indica fruits and cladodes or even food products containing whole cactus fruits as ingredients. The findings obtained have been confirmed both by enzymatic hydrolysis of flavonol glycosides following analysis of the aglycons and by HPLC-ESI-MSn. The concentration of total flavonols ranged from 2.2 to 4.1 and 6.3 to 7.6mg/g (dw) in the fruit peels and the cladodes, respectively. Further, fruit peels and cladodes exhibited high total phenolic contents and antioxidant activities compared to those of the fruit pulps. These investigations valorize cactus fruit's peel and cladode in comparison to fruit's pulp, and may further provide additional data for using flavonols in chemotaxonomic studies of cactus Opuntia spp. and authenticity of cactus O. ficus-indica products. PMID- 30011727 TI - Identification of phenolic compounds by HPLC-ESI-MS/MS and antioxidant activity from Chilean propolis. AB - Propolis is a complex hive product produced by honey bees, Apis mellifera. Its composition and biological activities depend on the vegetation where hives are placed. Propolis is often used as a food supplement. The aim of this research is to determine the antioxidant properties in vitro and the phenolic composition of six propolis collected from the region of Santiago of Chile. We obtained the ethanolic extracts dry and wax free (EEPs) and studied their antioxidant properties by FRAP, ORAC-FL, ORAC-PGR and DPPH radical methods. The total phenols were quantified by a spectrophotometric method and 30 phenolic compounds were identified by HPLC-ESI-MS/MS analysis. Curacavi EEP has the highest relative abundance of caffeic acid phenylethyl ester (CAPE) while Buin EEP has the highest relative abundance of caffeic acid benzyl ester and quercetin. Both have the highest antioxidant activity in vitro in all methods used. Our research shows, for the first time, a comparative analysis of the antioxidant activity and phenolic composition of six Chilean propolis. Pinobanksin is the only phenol present in the six samples of propolis so it may be a good candidate for the standardization of propolis ethanolic extracts in the region of Santiago. PMID- 30011728 TI - Effects of hemicellulose-derived saccharides on behavior of Lactobacilli under simulated gastrointestinal conditions. AB - Four types of purified xylooligosaccharides (XOS) from several lignocellulosic materials, showing different structural features (including chain length, branching, and linkage types), obtained from different feedstocks (Eucalyptus globulus wood, rice husks, wheat bran or barley wastes), were assessed (using fructooligosaccharides as reference substrate) for their effects on the growth of six different probiotic Lactobacillus strains in basal MRS media and survival in different simulated gastrointestinal tract (GIT) conditions. The hydrophobicity of bacterial cells, which measures their potential for epithelial adhesion, was also evaluated. Improved growth of Lactobacillus strains was observed for media containing XOS as the single source of carbohydrate, confirming their role as prebiotics. These oligosaccharides also led to improvement in the resistance of the target Lactobacillus to the simulated GIT environment. The enhancement of the survival rates depended on the type of oligosaccharide. This is the first comparative study of the effects in lactobacilli involving four types of XOS obtained from different lignocellulosic materials. The obtained results show that these oligosaccharides manufactured from alternative sources could be interesting prebiotic substrates with different structures in comparison with the available commercially and with interesting potential towards the development of synbiotic products. PMID- 30011729 TI - Rheological behaviour of selected commercially available baby formulas in simulated human digestive system. AB - A variety of formulas are available in the global market for infants (<12months old) who do not have access to mother's milk. The rheological properties of four different commercially available infant formulas - newborn, anti-reflux, soy and lactose free - in an in vitro digestive system were investigated. The enzymatic saliva when mixed with the formulas did not influence their viscosity in the mouth possibly due to the short residence time. Systematic measurement (every 15min) of viscosity during gastrointestinal digestion process revealed a decrease in viscosity as time progressed. The most interesting observation was that the viscosity of the anti-reflux formula was relatively higher compared to the other formulas throughout the simulated gastrointestinal digestion process. The results suggest that viscosity of the infant formula in the stomach may have a role to play in preventing gastroesophageal reflux. PMID- 30011730 TI - Acquired acid adaptation of Listeria monocytogenes during its planktonic growth enhances subsequent survival of its sessile population to disinfection with natural organic compounds. AB - The abilities of Listeria monocytogenes to adapt to stress and also to attach to surfaces are believed to contribute to its persistence in food processing environments. In this study, the possible influence of acid adaptation of L. monocytogenes cells during their planktonic growth on their subsequent resistance against 3 different natural disinfection treatments (0.05% lactic acid, 1% essential oil or 100% hydrosol of S. thymbra) upon their attachment to stainless steel (SS) was evaluated by simultaneously using the bead vortexing technique and a conductance method. Prior to disinfection, both nonadapted and acid-adapted stationary phase bacteria were left to attach to SS coupons statically incubated for 10days into Brain Heart Infusion (BHI) broth under 3 different temperatures (5, 16 or 30 degrees C). Results revealed that both essential oil and hydrosol presented sufficient bactericidal activity against all formed sessile populations, always resulting in counts following disinfection below the plate counting detection limit. However, the conductance method, able to detect metabolically active sessile bacteria unable to be recovered by the bead vortexing, revealed the positive influence of previously acquired acid adaptation on disinfection resistance of attached cells against these plant extracts. A similar effect of acid adaptation was also evident for lactic acid disinfection. PMID- 30011731 TI - In situ synchrotron radiation X-ray scattering study on the effect of a stearic sucrose ester on polymorphic behavior of a new sunflower oil variety. AB - The effect of the stearic sucrose ester (SE) S-170 on crystallization behavior and polymorphism of two stearins obtained from a new variety of high stearic high oleic sunflower oil was studied by pulsed nuclear magnetic resonance (p-NMR), small (SAXS) and wide (WAXS) angle X-ray scattering using synchrotron light and differential scanning calorimetry (DSC). p-NMR studies showed that there is always a crystallization temperature below which SE S-170 accelerated crystallization and above which SE S-170 delayed nucleation and growth. The effect of SE S-170 strongly depended on supercooling. It was efficient as a seed for high supercooling (low crystallization temperatures) but this efficiency diminished at low supercooling (temperatures close to the melting point) when few crystals were formed. SAXS and WAXS results demonstrated that depending on crystallization temperature SE S-170 promoted crystallization of alpha and beta forms with more polymorphic similarity and inhibited occurrence of beta' forms especially the beta'2 polymorph. However, in some conditions SE S-170 favored crystallization of beta'1 polymorph. DSC experiments showed that SE S-170 significantly diminished total melting enthalpies when the effect was a delay in crystallization. For other conditions no significant differences were found in melting temperatures or total melting enthalpies. When stearins were stored at 25 degrees C, crystallization in the beta2 form was promoted. Depending on crystallization temperature, polymorphic forms beta'1 and beta2 may be obtained as the main polymorphic forms. This is very relevant from the technological point of view. Depending on the application, SE S-170 may help obtain the required polymorphic form: beta'1 form for spreads and beta2 polymorph for chocolate production. PMID- 30011732 TI - Analysis of nonpolar lipophilic aldehydes/ketones in oxidized edible oils using HPLC-QqQ-MS for the evaluation of their parent fatty acids. AB - Six edible oils with different fatty acid compositions were used to explore nonpolar lipophilic aldehydes/ketones produced by possible parent fatty acids after accelerated oxidation. Simultaneous determination of 20 aldehydes and five ketones within the C2-C10 range was carried out using HPLC-QqQ-MS technique. Close relationships among the amounts of aldehyde carbonyls and the initial contents of oleic, linoleic and alpha-linolenic acids were revealed by principal component analysis. Pentanal, hexanal, hexanone, heptanal, 2-propenal, 2 heptenal, 2-octenal, 2-nonenal and 2,4-decadienal were the key carbonyls in close association with the initial content of linoleic acid. Ethanal, acetone, propanal, butanal, 2-pentenal, 2-hexenal, 2,4-heptadienal and 2,4-nonadienal were the key markers closely related with the initial content of alpha-linolenic acid. Furthermore, octanal, octanone, nonanal, nonanone, decanal, decanone and 2 decenal were the oxidation indexes linked to the initial content of oleic acid. The results provide a complete picture of secondary oxidation products in edible oils and possible source of parent fatty acids. PMID- 30011733 TI - Impact of different cocoa hybrids (Theobroma cacao L.) and S. cerevisiae UFLA CA11 inoculation on microbial communities and volatile compounds of cocoa fermentation. AB - The aim of this work was to study the microbial communities and volatile compounds profile of different fermentations: using four different cocoa hybrids and adding Saccharomyces cerevisiae UFLA CA11 as starter culture. Each hybrid showed particular characteristics: size, peel, seed and pulp. The temperature of the cocoa mass increased during fermentations (24 degrees C to 47 degrees C). The hybrid FA13 inoculated with S. cerevisiae showed the lowest temperatures (26 to 37 degrees C). The pulp's compositions were different between the hybrids, mainly regarding citric acid (0.5 to 3.2g/kg). The carbohydrates were more rapidly (60h) metabolized in inoculated fermentations than in spontaneous fermentations (84h). Thirty-nine volatile compounds were identified by GC-FID for all fermentation processes. Esters (14 compounds) and alcohols (12) were the most important groups. Yeast communities were similar among the different processes while bacterial communities were dependent on the hybrid and process. The inoculation accelerated the fermentation and the hybrid characteristics influenced on the fermentation requiring particular management. PMID- 30011734 TI - Preparation and identification of peptides and their zinc complexes with antimicrobial activities from silver carp (Hypophthalmichthys molitrix) protein hydrolysates. AB - The antibacterial activities of peptide-zinc complexes (PZCs) prepared from silver carp (Hypophthalmichthys molitrix) protein hydrolysates treated by four enzymes were evaluated. PZCs prepared from flavourzyme hydrolysates exhibited the highest antibacterial activities. The peptides that were able to produce PZCs with high antibacterial activity were isolated from flavourzyme hydrolysates using chromatographic procedures. Eleven peptides were identified through nano liquid chromatography-electrospray ionization mass spectrometry. Five of these identified peptides were synthesized. The PZCs obtained were characterized and tested for antimicrobial activities. Results suggested that all five PZCs present strong antibacterial activities but no antifungal activities. Peptides with more acidic amino acid residues in their sequences could bind more zinc ions than peptides with fewer acidic amino acid residues. Zinc complexes of acidic amino acid-richer peptides showed stronger antibacterial activities. Results confirmed the antibacterial activities of PZCs from silver carp hydrolysates, and suggested the feasibility of PZCs as a provider of natural zinc ligands for antibacterial agents in the food and feed industries. PMID- 30011735 TI - Stability of a concentrated oil-in-water emulsion model prepared using palm olein based diacylglycerol/virgin coconut oil blends: Effects of the rheological properties, droplet size distribution and microstructure. AB - The rheological properties, microstructure, textural properties, colour and droplet size distribution of mayonnaise-like emulsion models prepared using 10 30wt.% of palm olein-based diacylglycerol (POL-DAG) oil were compared with those of the control (100wt.% VCO) model. There were significant (P<0.05) differences in the particle size distribution of the oil droplets, the textural properties, and the rheological properties of the various emulsion models. The rheological analysis included the determination of the flow curves, yield stress, thixotropy, apparent viscosity, and viscoelastic parameters. The concentrated oil-in-water (O/W) emulsion with 30wt.% POL-DAG substitution exhibited high thixotropy. The POL-DAG content had a substantial effect on the rheological properties of yield stress, storage modulus (G') and loss modulus (G"). The pseudoplastic behaviour of the emulsions was demonstrated. The size of the particles in the 30% POL-DAG substituted emulsion was dramatically increased after one day and 30days of storage. All of the emulsion samples with POL-DAG substituted for VCO showed a relatively non-uniform bimodal droplet size distribution after one day of storage. In general, substitution of 10-20wt.% POL-DAG oil is appropriate for preparing O/W emulsions that had flow curves and textural properties similar to those of the control sample. PMID- 30011736 TI - Isolation and identification of a novel anticoagulant peptide from enzymatic hydrolysates of scorpion (Buthus martensii Karsch) protein. AB - An enzymatic hydrolysis approach was proposed for the preparation of bioactive hydrolysate of scorpion Buthus martensii Karsch (BmK) protein. Results showed that the anticoagulant activity of the hydrolysates of BmK protein was closely related to both the enzyme type and the degree of hydrolysis. Alcalase AF showed to be the best enzymes for the hydrolysis. And the hydrolysis degree (DH) was closely related with the anticoagulant activity of the hydrolyzate. At a DH value of 18% with Alcalase AF, the hydrolyzate exhibited the highest activity. The hydrolysate was then separated and purified by consecutive chromatographic procedures, giving a novel anticoagulant peptide consisting of ten amino acids (MW: 1119.8Da) with its sequence of Val-Glu-Pro-Val-Thr-Val-Asn-Pro- His-Glu identified by MALDI-TOF/TOF MS. The negatively charged amino acids and hydrophobic amino acids may contribute to the anticoagulant activity of the prepared peptides. And the Val residue in N-terminal was also critical for the anticoagulant activity of the BmK peptide. Furthermore, the anticoagulant activity kept stable after in vitro digestive simulation. This research provided a promising bioprocessing route for production of anticoagulant peptides using BmK protein as a potentially valuable bioresource. PMID- 30011737 TI - Bioavailability of cranberry bean hydroalcoholic extract and its inhibitory effect against starch hydrolysis following in vitro gastrointestinal digestion. AB - This study used a simulated in vitro gastrointestinal digestion procedure to assess the bioavailability of a freeze-dried cranberry bean hydroalcoholic extract (polyphenol content of 28.73mgg-1). The amount of polyphenols in 200mg of cranberry bean extract increased from 5.73 (non-digested original) to 11.39mg following gastric digestion, but decreased to 6.05mg during intestinal digestion. When cranberry bean extract was accompanied with starch for the digestion tests, the added cranberry bean extract exhibited a potent inhibitory effect against glucose release during simulated intestinal digestion, with IC50 values of 472mg cranberry bean extract or 13mg polyphenols. A significant decrease in polyphenols was observed for the sample collected from dialysis phase, with only 11% of non digested original polyphenols permeating through the dialysis membrane (0.63mg) and preserving an inhibitory effect against alpha-glucosidase to some extent. Therefore, polyphenol-rich cranberry bean extract may be used to manage postprandial hyperglycemia. PMID- 30011738 TI - Comparing the crystallization and rheological behavior of organogels developed by pure and commercial monoglycerides in vegetable oil. AB - We investigated the crystallization and rheological behavior of organogels developed with commercial (MSGC) and pure (MSGP) monoglycerides in safflower oil solutions (0.5% to 8% wt/wt). The MSGC was composed of 1-mono-stearoyl-glycerol (1-MSG, 37.7%) and 1-mono-palmitoyl-glycerol (1-MPG, 54.0%), and the MSGP essentially by 1-MSG (93.51%). The elastic (G') and loss (G") moduli of the MSGC and MSGP-oil solutions were measured from 80 degrees C until achieving 5 degrees C, and then during isothermal conditions. The d(G')/d(time) rheograms, where d(G')/d(time) is the difference in G' between subsequent time-temperature conditions during cooling, followed closely the phase transition observed by the monoglycerides (MG). The d(G')/d(time) profile showed that the formation of the inverse lamellar alpha mesophase provided a limited structure to the vegetable oil. In contrast, the crystallization of the sub-alpha phase in the MSGC-oil system, and of the sub-alpha1 and sub-alpha2 phases in the MSGP-oil system structured the vegetable oil through the uptake and retention of oil within their microstructure. Additionally, smaller crystals formed the three-dimensional crystal structure in the MSGC organogels. This is in comparison with the larger crystal size observed in MSGP organogels. Nevertheless, for a similar MG concentration the MSGC organogels showed higher G' and solid fat content (SFC) than the MSGP organogels, and the differences were greater as the MG concentration increased. We consider that the mixed sub-alpha structure developed by 1-MSG and 1-MPG in the MSGC-oil systems favored the incorporation and retention of higher amounts of oil, in comparison with the sub-alpha1 and sub alpha2 structures developed just by 1-MSG in the MSGP-oil systems. PMID- 30011739 TI - Fourier transform ion cyclotron resonance mass spectrometrical analysis of raw fermented cocoa beans of Cameroon and Ivory Coast origin. AB - Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) is an ultra-high resolution mass spectrometry technique used mainly in analysis of unresolved complex mixtures comprising tens of thousands of analytes. For the first time, it was used to analyze samples of raw fermented cocoa beans originating from Cameroon and Ivory Coast. The direct infusion mass spectra of the raw fermented cocoa bean extracts showed 10091 and 10911 peaks, resp., rating cocoa among the most complex organic mixtures ever analyzed. Automated molecular formula calculations could assign 2995 and 2968 of the peaks, resp. to formulae containing only C, H, O, N<=3 and S<=1 atoms. The formulae were separated into four groups depending on their heteroatom content and the intensities of the groups were compared in class plots, showing the highest population in the CHON species, but the highest abundance in the CHO species. Elemental ratios obtained from the molecular formulae were plotted in an intensity coded three-dimensional modification of the van Krevelen diagram. For the CHO species, the van Krevelen diagram showed that most of the intensity belongs to the lipid, polyphenol and carbohydrate regions of the plot. The biggest difference was observed in the CHON group, assigned as peptide degradation products, where the Ivorian beans showed greater variety and molecular diversity and higher total intensity of the nitrogen containing compounds, in accordance with the fact that the Ivorian beans show generally higher nitrogen content than the Cameroon beans. FTICR-MS proves capable not only for high-throughput comparison of major classes of metabolites from cocoa samples from different origins, but also can give insight into the different molecular formulae comprising these compound classes. PMID- 30011740 TI - Mathematical modeling of area under the curve assessment criteria to quantify the antioxidant and pro-oxidant capacity: Coffee extracts as a case study. AB - The development of a convenient mathematical application for testing the antioxidant and pro-oxidant capacity is essential in order to investigate potential sources of new agents and processes. In this regard, authors use the standardized values of the area under the curve of a kinetic profile of a dose response agent, as a way to bypass the complex process of analyzing the kinetic variations of agents. In general, linear approaches are used, but such patterns frequently lead to unreliable results and misinterpretations, making it extremely difficult to compare the results from different assays. In this work, we have demonstrated the non-linearity of the dose-response area under the curve assessment criteria by means of simulations. A simple non-linear dose-response model was developed to describe the accurate response. As a case study, experimental data of extracts of unroasted coffee beans from five different country-climate locations for the two most common coffee varieties (Robusta and Arabica) were obtained using the beta-carotene and crocin bleaching in vitro assays. Their antioxidant capacity was analyzed in detail and compared with commercial standards. The results show that the antioxidant capacity was greater than some of the commercial standards in terms of its maximum capacity, while when the analyses are based on rate parameters, the coffee extracts show between 6 and 40 times lower values than the standard antioxidants. In addition, to illustrate the advantages of using the standardized area units and the mathematical model developed, other more complex scenarios were recreated. We believe that the model application developed provides a simple alternative to summarize meaningful parameters that characterize the response, facilitates rigorous comparisons among the effects of different compounds and experimental approaches and helps to comprehend multi-variable scenarios. PMID- 30011741 TI - State of the art on the initiatives and activities relevant to risk assessment and risk management of nanotechnologies in the food and agriculture sectors. AB - The Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) conducted an international expert meeting on the potential food safety implications of the application of nanotechnologies in the food and agriculture sectors in June 2009. The present report reviews national, regional and international activities on the risk assessment and risk management of nanomaterials in the food and agriculture sectors that have been carried out between 2009 and 2012. The full report of the work is presented in a FAO/WHO paper available at http://www.fao.org/food/food-safety-quality/a-z-index/nano. Information and data have been collected on national and international approaches that identify and implement strategies to address potential hazards associated with the use of nanotechnology-related products or techniques. Selected activities by international governmental and nongovernmental organizations were reviewed and the significant achievements are noted. Meta-analysis of scientific reviews addressing risk assessment of nanotechnologies in the food and agriculture sectors was conducted and key principles for the safety assessment of nanomaterials were identified. It was concluded that although the concepts of potential use of nanomaterials in food and the implied benefits for stakeholders including consumers have not changed significantly since 2009, there are new products being developed and claimed to enter the market and national and international interests in considering the needs for applying regulations on engineered nanomaterials are increasing. The number of published risk assessment of products used in foods that are nanomaterials or contain particles that fall within applicable definitions is growing slowly. Several data gaps with respect to interaction between nanomaterials and food matrices, behaviours of nanomaterials in the human body, methods to determine such interactions and behaviours, and the relevance of such data for risk assessment continue to exist. The international collaboration in the area of nanomaterials and nanotechnology in food and agriculture must be strengthened. International efforts on risk assessment and risk communication may benefit from the experience gained at the national and regional levels. Should a sufficient number of case studies of risk assessment of commercial products become available with time, a review of approaches applied and results obtained could support the development of risk assessment procedures acceptable at the international level. PMID- 30011742 TI - Release kinetics of flavonoids in methyl linoleate from microparticles designed with inulin and channelizing agent. AB - Quercetin (Q), naringenin (N) and epicatechin (E) were encapsulated with inulin (In) as encapsulating agent and Capsul (C) as channelizing agent by spray drying and applying a Box-Behnken design. Q-In, N-In, E-In, Q-In-C, N-In-C and E-In-C were characterised by encapsulating efficiency (EE) and their release profile in methyl linoleate (ML). The flavonoid EE was significant higher (p<0.05) for Q and E (over 60%) than for N (~40%) in microparticles either without or with channelizing agent. An increase of the number of flavonoid hydroxyl groups enhanced EE, showing the influence of the flavonoid structural features. The release profile was fitted to Peppas and Higuchi mathematical models. The highest and lowest flavonoid release rate constants were found for N and E, respectively, for microparticles both with and without channelizing agent. The EE as indicator of flavonoid-inulin interaction was inversely related with the release rate constant in ML. Flavonoid release rate constant was significantly higher for microparticles with channelizing agent than for those without it, suggesting that Capsul induces the formation of channels inside the microparticles thus favoring the diffusion of flavonoids to ML. The mechanism of flavonoid release was only determined by channelizing agents, independently of the flavonoid nature, that is, Fickian and non-Fickian diffusion mechanisms in microparticles with and without Capsul, respectively. PMID- 30011743 TI - Erratum. PMID- 30011744 TI - Erratum to "Laparoscopic adjustable gastric banding in adolescents: short-term result". PMID- 30011745 TI - Erratum to "Redo pull-through for obstructive symptoms due to residual aganglionosis and transition zone bowel in Hirschsprung's disease". PMID- 30011746 TI - Serum and tissue transforming growth factor beta1 in children with biliary atresia. PMID- 30011747 TI - Erratum. PMID- 30011748 TI - Corrigendum to "Cystatin C for early detection of renal impairment in diabetes" [Clin. Biochem. 42 (2009) 108-110]. PMID- 30011749 TI - ABCA1 and placental cholesterol efflux: A reply. PMID- 30011750 TI - Erratum. PMID- 30011751 TI - Reply. PMID- 30011752 TI - Giant tumor of the posterior thigh. PMID- 30011753 TI - A young boy with bullae. PMID- 30011754 TI - Correction. PMID- 30011755 TI - RETRACTED: In osteoclasts, dynamic microtubules and their associated protein EB1 control podosomes and bone resorption through cortactin. AB - This abstract has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This abstract has been retracted at the request of Drs. S Stephens, FPL Lai, M Oelkers, K Rottner, W Horne and R Baron. As a result of a PI-initiated inquiry within Harvard, the U.S. Office of Research Integrity (ORI) has determined that Dr Biosse-Duplan falsified histomorphometric and microCT results. PMID- 30011757 TI - Providing high-value care at the right price. PMID- 30011756 TI - The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve-related aortopathy: Executive summary. AB - Bicuspid aortic valve disease is a common congenital cardiac disorder, being present in 1% to 2% of the general population. Associated aortopathy is a common finding in patients with bicuspid aortic valve disease, with thoracic aortic dilation noted in approximately 40% of patients in referral centers. Several previous consensus statements and guidelines have addressed the management of bicuspid aortic valve-associated aortopathy, but none focused entirely on this disease process. The current document is an executive summary of "The American Association for Thoracic Surgery Guidelines on Bicuspid Aortic Valve-Related Aortopathy." All major aspects of bicuspid aortic valve aortopathy, including natural history, phenotypic expression, histology and molecular pathomechanisms, imaging, indications for surgery, surveillance, and follow-up, and recommendations for future research are contained within these guidelines. The current executive summary serves as a condensed version of the guidelines to provide clinicians with a current and comprehensive review of bicuspid aortic valve aortopathy and to guide the daily management of these complex patients. PMID- 30011758 TI - The best treatments for aortic stenosis at the highest patient value-cost, contribution margin, and readmission. PMID- 30011759 TI - Benchmark reoperative mitral surgery: There is room for improvement. PMID- 30011760 TI - Electrical storms in patients with hypertrophic cardiomyopathy: Do we have a solution? PMID- 30011761 TI - A dedicated heart team is needed to maximize the treatment of patients with hypertrophic cardiomyopathy. PMID- 30011762 TI - Straight deep hypothermic circulatory arrest: Cling to old fashion or not? PMID- 30011763 TI - Everything old is new again. PMID- 30011764 TI - More than one way to wire a chest. PMID- 30011765 TI - More wires, more time. PMID- 30011766 TI - Are plasma proteins key players in the pathogenesis of infective endocarditis? PMID- 30011767 TI - Elucidating the mechanisms of infective endocarditis in bovine jugular vein conduits: Are we any closer? PMID- 30011768 TI - Valve-sparing repair during repair of tetralogy of Fallot: Surgical controversies. PMID- 30011769 TI - Intraoperative balloon dilation in tetralogy of Fallot: Is there a "secret sauce"? PMID- 30011770 TI - Valve-sparing repair in tetralogy of Fallot: Does valve biology determine long term outcome? PMID- 30011771 TI - All evidence points to the need for collaborative care. PMID- 30011772 TI - Survival prediction tools for esophageal and gastroesophageal junction cancer: A systematic review. AB - BACKGROUND: Clinical, pathological, and molecular information combined with cancer stage in prognostication algorithms can offer more personalized estimates of survival, which might guide treatment choices. Our aim was to evaluate the quality of prognostication tools in esophageal cancer. METHODS: We systematically searched MedLine and Embase from 2005 to 2017 for studies reporting development or validation of models predicting long-term survival in esophageal cancer. We evaluated tools using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies guidelines and the American Joint Committee on Cancer acceptance criteria for risk models. RESULTS: We identified 16 prognostication tools for patients treated with curative intent and 1 for patients with metastatic disease. These tools frequently excluded adenocarcinoma, contained outdated data, and were developed with a limited sample size. Nine tools were developed in China for squamous cell cancer, and 11 used data on patients diagnosed before 2010. Most tools excluded key prognostic factors such as age and sex. Tumor stage and grade were the most commonly, but not universally, included factors. Twelve tools were designed to predict overall survival; 5 predicted cancer-specific survival. Bootstrap internal validation was performed for most tools; c-statistics ranged from 0.63 to 0.77 and graphically evaluated calibration was "good." Five tools were externally validated; c statistics ranged from 0.70 to 0.77. CONCLUSIONS: Existing tools cannot be confidently used for esophageal cancer prognostication in current clinical practice. Better-quality tools might help to more individually and accurately estimate disease course, select further treatments, and risk-stratify for future clinical trials. PMID- 30011773 TI - Supercharged through a tunnel, is it an action movie? No, it's a novel esophageal reconstruction! PMID- 30011774 TI - Experience from an American Association for Thoracic Surgery Foundation for Thoracic Surgery Training Fellowship: Lung transplantation in Toronto General Hospital. PMID- 30011775 TI - The 3-dimensional cardiac hype cycle. PMID- 30011776 TI - The blue-red divide: What approach? PMID- 30011777 TI - The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve-related aortopathy: Full online-only version. AB - Bicuspid aortic valve disease is the most common congenital cardiac disorder, being present in 1% to 2% of the general population. Associated aortopathy is a common finding in patients with bicuspid aortic valve disease, with thoracic aortic dilation noted in approximately 40% of patients in referral centers. Several previous consensus statements and guidelines have addressed the management of bicuspid aortic valve-associated aortopathy, but none focused entirely on this disease process. The current guidelines cover all major aspects of bicuspid aortic valve aortopathy, including natural history, phenotypic expression, histology and molecular pathomechanisms, imaging, indications for surgery, surveillance, and follow-up, and recommendations for future research. It is intended to provide clinicians with a current and comprehensive review of bicuspid aortic valve aortopathy and to guide the daily management of these complex patients. PMID- 30011778 TI - Wegener granulomatosis of the heart. PMID- 30011779 TI - Correction. PMID- 30011780 TI - A Multilevel Analysis of Perceived Noise Pollution, Geographic Contexts and Mental Health in Beijing. AB - With rapid urbanization and increase in car ownership, ambient noise pollution resulting from diversified sources (e.g., road traffic, railway, commercial services) has become a severe environmental problem in the populated areas in China. However, research on the spatial variation of noise pollution and its potential effects on urban residents' mental health has to date been quite scarce in developing countries like China. Using a health survey conducted in Beijing in 2017, we for the first time investigated the spatial distributions of multiple noise pollution perceived by residents in Beijing, including road traffic noise, railway (or subway) noise, commercial noise, and housing renovation (or construction) noise. Our results indicate that there is geographic variability in noise pollution at the neighborhood scale, and road traffic and housing renovation/construction are the principal sources of noise pollution in Beijing. We then employed Bayesian multilevel logistic models to examine the associations between diversified noise pollution and urban residents' mental health symptoms, including anxiety, stress, fatigue, headache, and sleep disturbance, while controlling for a wide range of confounding factors such as socio-demographics, objective built environment characteristics, social environment and geographic context. The results show that perceived higher noise-pollution exposure is significantly associated with worse mental health, while physical environment variables seem to contribute little to variations in self-reported mental disorders, except for proximity to the main road. Social factors or socio demographic attributes, such as age and income, are significant covariates of urban residents' mental health, while the social environment (i.e., community attachment) and housing satisfaction are significantly correlated with anxiety and stress. This study provides empirical evidence on the noise-health relationships in the Chinese context and sheds light on the policy implications for environmental pollution mitigation and healthy city development in China. PMID- 30011781 TI - Ultrasound-Assisted Extraction of Polysaccharides from Volvariella volvacea: Process Optimization and Structural Characterization. AB - The aims of the present study were to optimize the operational parameters to maximize the yield of ultrasound-assisted polysaccharide extraction from Volvariella volvacea (straw mushroom) fruiting bodies by using for the first time one-factor-at-a-time and three-level Box-Behnken factorial designs. A maximum polysaccharide yield of 8.28 +/- 0.23% was obtained under the optimized conditions of ultrasound power of 175 W, extraction temperature of 57 degrees C, extraction time of 33 min, and the ratio of liquid to raw material of 25:1, respectively. Compared to the hot-water extraction, the ultrasound-assistance favored the extraction of polysaccharides from V. volvacea for its higher polysaccharide yield and efficiency. Further preliminary polysaccharide structural characterization indicated that ultrasound treatment affected the monosaccharide compositions and ratios, and molecular weight range of polysaccharides extracted from V. volvacea. PMID- 30011782 TI - Biodegradable and Toughened Composite of Poly(Propylene Carbonate)/Thermoplastic Polyurethane (PPC/TPU): Effect of Hydrogen Bonding. AB - The blends of Poly(propylene carbonate) (PPC) and polyester-based thermoplastic polyurethane (TPU) were melt compounded in an internal mixer. The compatibility, thermal behaviors, mechanical properties and toughening mechanism of the blends were investigated using Fourier transform infrared spectra (FTIR), tensile tests, impact tests, differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic mechanical analysis technologies. FTIR and SEM examination reveal strong interfacial adhesion between PPC matrix and suspended TPU particles. Dynamic mechanical analyzer (DMA) characterize the glass transition temperature, secondary motion and low temperature properties. By the incorporation of TPU, the thermal stabilities are greatly enhanced and the mechanical properties are obviously improved for the PPC/TPU blends. Moreover, PPC/TPU blends exhibit a brittle-ductile transition with the addition of 20 wt % TPU. It is considered that the enhanced toughness results in the shear yielding occurred in both PPC matrix and TPU particles of the blends. PMID- 30011783 TI - In Silico SAR Studies of HIV-1 Inhibitors. AB - Quantitative Structure Activity Relationships (QSAR or SAR) have helped scientists to establish mathematical relationships between molecular structures and their biological activities. In the present article, SAR studies have been carried out on 89 tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine (TIBO) derivatives using different classifiers, such as support vector machines, artificial neural networks, random forests, and decision trees. The goal is to propose classification models that will be able to classify TIBO compounds into two groups: high and low inhibitors of HIV-1 reverse transcriptase. Each molecular structure was encoded by 10 descriptors. To check the validity of the established models, all of them were subjected to various validation tests: internal validation, Y-randomization, and external validation. The established classification models have been successful. The correct classification rates reached 100% and 90% in the learning and test sets, respectively. Finally, molecular docking analysis was carried out to understand the interactions between reverse transcriptase enzyme and the TIBO compounds studied. Hydrophobic and hydrogen bond interactions led to the identification of active binding sites. The established models could help scientists to predict the inhibition activity of untested compounds or of novel molecules prior to their synthesis. Therefore, they could reduce the trial and error process in the design of human immunodeficiency virus (HIV) inhibitors. PMID- 30011785 TI - Neck Circumference Positively Relates to Cardiovascular Risk Factors in College Students. AB - The objective of this study was to determine the relationship between neck circumference (NC) and other anthropometric measures and examine cut-off points for males and females according to existing waist circumference cut-off levels in this age group. Across 8 universities, 1562 students underwent a physical assessment. Spearman rho correlations (rho) were calculated to determine associations between NC and other continuous variables of health. Receiving operating characteristic curves were constructed to assess the optimal cut-off levels of NC of males and females with central obesity. Participants were predominantly Caucasian (67%), female (70%), and outside of Appalachia (82%). Forty-one percent of males and 34% of females had a BMI >= 25 kg/m2. In both sexes, significant positive correlations were seen between NC and body weight, BMI, waist circumference, hip circumference, and systolic blood pressure (all p values < 0.0001). NC >= 38 cm for males and >=33.5 cm for females were the optimal cut-off values to determine subjects with central obesity. NC has been identified to closely correlate with other anthropometric measurements related to disease and could be used as a convenient, low-cost, and noninvasive measurement in large-scale studies. PMID- 30011786 TI - A Novel Carrier Loop Algorithm Based on Maximum Likelihood Estimation (MLE) and Kalman Filter (KF) for Weak TC-OFDM Signals. AB - Digital broadcasting signals represent a promising positioning signal for indoors applications. A novel positioning technology named Time & Code Division Orthogonal Frequency Division Multiplexing (TC-OFDM) is mainly discussed in this paper, which is based on China mobile multimedia broadcasting (CMMB). Signal strength is an important factor that affects the carrier loop performance of the TC-OFDM receiver. In the case of weak TC-OFDM signals, the current carrier loop algorithm has large residual carrier errors, which limit the tracking sensitivity of the existing carrier loop in complex indoor environments. This paper proposes a novel carrier loop algorithm based on Maximum Likelihood Estimation (MLE) and Kalman Filter (KF) to solve the above problem. The discriminator of the current carrier loop is replaced by the MLE discriminator function in the proposed algorithm. The Levenberg-Marquardt (LM) algorithm is utilized to obtain the MLE cost function consisting of signal amplitude, residual carrier frequency and carrier phase, and the MLE discriminator function is derived from the corresponding MLE cost function. The KF is used to smooth the MLE discriminator function results, which takes the carrier phase estimation, the angular frequency estimation and the angular frequency rate as the state vector. Theoretical analysis and simulation results show that the proposed algorithm can improve the tracking sensitivity of the TC-OFDM receiver by taking full advantage of the characteristics of the carrier loop parameters. Compared with the current carrier loop algorithms, the tracking sensitivity is effectively improved by 2-4 dB, and the better performance of the proposed algorithm is verified in the real environment. PMID- 30011784 TI - Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett's Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives. AB - Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed. PMID- 30011787 TI - Therapeutic Agents with AHR Inhibiting and NRF2 Activating Activity for Managing Chloracne. AB - Chloracne is the major skin symptom caused by dioxin intoxication. Dioxin activates the aryl hydrocarbon receptor (AHR)-cytochrome p450 1A1 (CYP1A1) system, generates oxidative stress, and induces hyperkeratinization of keratinocytes and sebocytes leading to chloracne. Nuclear factor-erythroid 2 related factor-2 (NRF2) is a master switch that induces the expression of various antioxidative enzymes, such as heme oxygenase-1. Cinnamaldehyde is an antioxidant phytochemical that inhibits AHR-CYP1A1 signaling and activates the NRF2 antioxidative axis. The cinnamaldehyde-containing Kampo herbal medicine Keishibukuryogan is capable of improving chloracne in Yusho patients who are highly contaminated with dioxin. Agents with dual functions in promoting AHR CYP1A1 inhibition and NRF2 activation may be useful for managing dioxin-related health hazards. PMID- 30011788 TI - Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. AB - The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, thus preventing translation. Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. This review aims to present and discuss the current clinical and scientific evidence pertaining to inclisiran, which is a new promising agent in the management of hypercholesterolemia. PMID- 30011789 TI - Single Gas Permeance Performance of High Silica SSZ-13 Zeolite Membranes. AB - Continuous and high silica SSZ-13 zeolite membranes were prepared on porous mullite supports from high SiO2/Al2O3 ratio or aluminum-free precursor synthesis gel. Single gas permeance (CO2 and CH4) of the high silica SSZ-13 zeolite membrane was decreased with the SiO2/Al2O3 ratio in the precursor synthesis gel, while the ideal CO2/CH4 selectivity of the membrane was gradually increased. Moreover, effects of synthesis conditions (such as H2O/SiO2 and RNOH/SiO2 ratios of precursor synthesis gel, crystallization time) on the single gas permeance performance of high silica SSZ-13 zeolite membranes were studied in detail. Medium H2O/SiO2 and RNOH/SiO2 ratios in the initial synthesis gel were crucial to prepare the good CO2 perm-selective SSZ-13 zeolite membrane. When the molar composition of precursor synthesis gel, crystallization temperature and time were 1.0 SiO2: 0.1 Na2O: 0.1 TMAdaOH: 80 H2O, 160 degrees C and 48 h, CO2 permeance and ideal CO2/CH4 selectivity of the SSZ-13 zeolite membrane were 0.98 * 10-7 mol/(m2.s.Pa) and 47 at 25 degrees C and 0.4 MPa. In addition, the SiO2/Al2O3 ratio of the corresponding SSZ-13 zeolite was 410 by X-ray fluorescence spectroscopy. PMID- 30011791 TI - Proton-Enhanced Dielectric Properties of Polyoxometalates in Water under Radio Frequency Electromagnetic Waves. AB - Electromagnetic waves, such as microwaves, have been used to enhance various chemical reactions over polyoxometalates. The dielectric properties of catalysts are among the relevant parameters facilitating catalytic reactions under electromagnetic radiation. This study describes the dielectric properties of polyoxometalate catalysts in aqueous and organic solutions to understand the mechanism of interactions between polyoxometalates and electromagnetic waves. Specific loss factors of polyoxometalates were observed at lower frequencies (<1 GHz) by the ionic conduction of the polyoxometalate solution. The evolution of ionic conduction depended strongly on cations rather than anions. Proton-type polyoxometalates exhibited significantly higher loss factors than other cations did. The activation energy for ionic conduction in protonated silicotungstic acid (H4SiW12O40) was significantly low in water (7.6-14.1 kJ/mol); therefore, the high loss factor of protonated polyoxometalates in water was attributed to the proton relay mechanism (i.e., Grotthuss mechanism). The results suggested that the proton relay mechanism at the radio-frequency band is critical for generating selective interactions of polyoxometalates with applied electromagnetic fields. PMID- 30011790 TI - New Aspects of Lipotoxicity in Nonalcoholic Steatohepatitis. AB - NASH is becoming increasingly common worldwide because of the growing global prevalence of obesity and consequently NAFLD. Unfortunately, the mechanism of progression of NAFLD to NASH and then cirrhosis is not completely understood. Several factors, including insulin resistance, inflammation, oxidative stress, lipotoxicity, and bile acid (BA) toxicity, have been reported to be associated with NASH progression. The release of fatty acids from dysfunctional and insulin resistant adipocytes results in lipotoxicity, which is caused by the ectopic accumulation of triglyceride-derived toxic metabolites and the subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. Adipose tissue (AT), especially visceral AT, comprises multiple cell populations that produce adipokines and insulin-like growth factor, plus macrophages and other immune cells that stimulate the development of lipotoxic liver disease. These biomolecules have been recently linked with many digestive diseases and gastrointestinal malignancies such as hepatocellular carcinoma. This made us question what role lipotoxicity has in the natural history of liver fibrosis. Therefore, this review focuses on the close relationship between AT and NASH. A good comprehension of the pathways that are related to dysregulated AT, metabolic dysfunction, and hepatic lipotoxicity will result in the development of prevention strategies and promising therapeutics for patients with NASH. PMID- 30011794 TI - Dual THz Wave and X-ray Generation from a Water Film under Femtosecond Laser Excitation. AB - Simultaneous emission of the THz wave and hard X-ray from thin water free-flow was induced by the irradiation of tightly-focused femtosecond laser pulses (35 fs, 800 nm, 500 Hz) in air. Intensity measurements of the THz wave and X-ray were carried out at the same time with time-domain spectroscopy (TDS) based on electro optic sampling with a ZnTe(110) crystal and a Geiger counter, respectively. Intensity profiles of the THz wave and X-ray emission as a function of the solution flow position along the incident laser axis at the laser focus show that the profile width of the THz wave is broader than that of the X-ray. Furthermore, the profiles of the THz wave measured in reflection and transmission directions show different features and indicate that THz wave emission is, under single pulse excitation, induced mainly in laser-induced plasma on the water flow surface. Under double-pulse excitation with a time separation of 4.6 ns, 5-10 times enhancements of THz wave emission were observed. Such dual light sources can be used to characterise materials, as well as to reveal the sequence of material modifications under intense laser pulses. PMID- 30011793 TI - Managing Aged Animals in Zoos to Promote Positive Welfare: A Review and Future Directions. AB - Improvements in veterinary care, nutrition, and husbandry of animals living in zoos have led to an increase in the longevity of these animals over the past 30 years. In this same time period, the focus of animal welfare science has shifted from concerns over mitigating negative welfare impacts to promoting positive welfare experiences for animals. For instance, providing opportunities for animals to exert agency, solve problems, or acquire rewards are all associated with positive welfare outcomes. Many common age-related changes result in limitations to opportunities for positive welfare experiences, either due to pain or other physical, cognitive, or behavioral limitations. This review aggregates information regarding common age-related physical and behavioral changes across species, discusses how age-related changes may limit positive welfare opportunities of aged animals in human care, and suggests potential management methods to help promote positive welfare for animals at all life stages in zoos and aquariums. PMID- 30011795 TI - Geographical Clustering and Environmental Determinants of Schistosomiasis from 2007 to 2012 in Jianghan Plain, China. AB - This study compared changes in the spatial clustering of schistosomiasis in Jianghan Plain, China by applying Kulldorff's spatial scan statistic. The Geodetector software was employed to detect the environmental determinants of schistosomiasis annually from 2007 to 2012. The most likely spatial cluster in 2007 covered the north-central part of Jianghan Plain, whereas those observed from 2008 to 2012 were toward the south, with extended coverage in generally the same areas across various periods, and some variation nevertheless in precise locations. Furthermore, the 2007 period was more likely to be clustered than any other period. We found that temperature, land use, and soil type were the most critical factors associated with infection rates in humans. In addition, land use and soil type had the greatest impact on the prevalence of schistosomiasis in 2009, whereas this effect was minimal in 2007. The effect of temperature on schistosomiasis prevalence reached its maximum in 2010, whereas in 2008, this effect was minimal. Differences observed in the effects of those two factors on the spatial distribution of human schistosomiasis were inconsistent, showing statistical significance in some years and a lack thereof in others. Moreover, when two factors operated simultaneously, a trend of enhanced interaction was consistently observed. High-risk areas with strong interactions of affected factors should be targeted for disease control interventions. PMID- 30011792 TI - Role of Damage Associated Molecular Pattern Molecules (DAMPs) in Aneurysmal Subarachnoid Hemorrhage (aSAH). AB - Aneurysmal subarachnoid hemorrhage (aSAH) represents only a small portion of all strokes, but accounts for almost half of the deaths caused by stroke worldwide. Neurosurgical clipping and endovascular coiling can successfully obliterate the bleeding aneurysms, but ensuing complications such as cerebral vasospasm, acute and chronic hydrocephalus, seizures, cortical spreading depression, delayed ischemic neurological deficits, and delayed cerebral ischemia lead to poor clinical outcomes. The mechanisms leading to these complications are complex and poorly understood. Early brain injury resulting from transient global ischemia can release molecules that may be critical to initiate and sustain inflammatory response. Hence, the events during early brain injury can influence the occurrence of delayed brain injury. Since the damage associated molecular pattern molecules (DAMPs) might be the initiators of inflammation in the pathophysiology of aSAH, so the aim of this review is to highlight their role in the context of aSAH from diagnostic, prognostic, therapeutic, and drug therapy monitoring perspectives. DAMPs represent a diverse and a heterogenous group of molecules derived from different compartments of cells upon injury. Here, we have reviewed the most important DAMPs molecules including high mobility group box-1 (HMGB1), S100B, hemoglobin and its derivatives, extracellular matrix components, IL 1alpha, IL-33, and mitochondrial DNA in the context of aSAH and their role in post-aSAH complications and clinical outcome after aSAH. PMID- 30011796 TI - CO Preferential Photo-Oxidation in Excess of Hydrogen in Dark and Simulated Solar Light Irradiation over AuCu-Based Catalysts on SBA-15 Mesoporous Silica-Titania. AB - In this work, SBA-15 silica and silica-titania have been used as supports for photocatalysts based on AuCu alloy (Au:Cu = 1) to be used in the preferential oxidation of CO (CO-PROX) in excess of hydrogen at room temperature and atmospheric pressure both in the dark and under simulated solar light irradiation. To study their textural, structural, chemical and optical properties, the samples were characterized by X-ray diffraction (XRD), high resolution transmission electron microscopy (HR-TEM), adsorption-desorption of N2 at -196 degrees C, 13C and 29Si solid state nuclear magnetic resonance (NMR), X ray photoelectron spectroscopy (XPS) and diffuse reflectance ultraviolet-visible (DRUV-vis) spectroscopy. Titanium was present mainly in the form of titania aggregates, but also as small particles interacting with the SBA support. In both catalysts, the metal alloy nanoparticles displayed an average size of 4 nm as demonstrated by TEM measurements. AuCu/Ti-SBA turned out to be photoactive and selective in the photo-CO-PROX reaction showing the highest activity, with conversion and selectivity towards CO2 of 80%, due both to the presence of titania incorporated in SBA-15 and to the synergistic effect of Cu when alloyed with Au. PMID- 30011797 TI - FOXP3 Activates SUMO-Conjugating UBC9 Gene in MCF7 Breast Cancer Cells. AB - Forkhead Box Protein P3 (FOXP3), a transcription factor of the FOX protein family, is essentially involved in the development of regulatory T (Treg) cells, and functions as a tumor suppressor. Although FOXP3 has been widely studied in immune system and cancer development, its function in the regulation of the UBC9 gene (for the sole E2 enzyme of SUMOylation) is unknown. Herein, we find that the overexpression of FOXP3 in human MCF7 breast cancer cells increases the level of UBC9 mRNA. Moreover, the level of UBC9 protein dose-dependently increases in the FOXP3-Tet-off MCF7 cells. Notably, the promoter activity of the UBC9 is activated by FOXP3 in a dose-dependent manner in both the MCF7 and HEK293 cells. Next, by mapping the UBC9 promoter as well as the site-directed mutagenesis and ChIP analysis, we show that the FOXP3 response element at the -310 bp region, but not the -2182 bp region, is mainly required for UBC9 activation by FOXP3. Finally, we demonstrate that the removal of phosphorylation (S418A and Y342F) and the removal of acetylation/ubiquitination (K263R and K263RK268R) of the FOXP3 result in attenuated transcriptional activity of UBC9. Taken together, FOXP3 acts as a novel transcriptional activator of the human UBC9 gene, suggesting that FOXP3 may have physiological functions as a novel player in global SUMOylation, as well as other post-translational modification systems. PMID- 30011799 TI - Anion Doping of Ferromagnetic Thin Films of La0.74Sr0.26MnO3-delta via Topochemical Fluorination. AB - Chemical doping via insertion of ions into the lattice of a host material is a key strategy to flexibly manipulate functionalities of materials. In this work, we present a novel case study on the topotactic insertion of fluoride ions into oxygen-deficient ferromagnetic thin films of La0.74Sr0.26MnO3-delta (LSMO) epitaxially grown onto single-crystal SrTiO3 (STO) substrates. The effect of fluorination on the film structure, composition, and magnetic properties is compared with the case of oxygen-deficient and fully-oxidized LSMO films. Although incorporation of F- anions does not significantly alter the volume of the LSMO unit cell, a strong impact on the magnetic characteristics, including a remarkable suppression of Curie temperature and saturation magnetization accompanied by an increase in magnetic coercivity, was found. The change in magnetic properties can be ascribed to the disruption of the ferromagnetic exchange interactions along Mn-anion-Mn chains driven by F- doping into the LSMO lattice. Our results indicate that F- doping is a powerful means to effectively modify the magnetic functional properties of perovskite manganites. PMID- 30011798 TI - Predictors of Participant Attendance Patterns in a Family-Based Intervention for Overweight and Obese Hispanic Adolescents. AB - This study examined participant attendance patterns and individual (e.g., income), family dynamics (e.g., communication), and cultural (i.e., Americanism, Hispanicism) predictors of these patterns among Hispanic families enrolled in a 12-week family-based intervention, Familias Unidas for Health and Wellness. Hispanic adolescents (n = 140, 49% female, 13.04 +/- 0.87 years old, 36% overweight, 64% obese, 39% immigrants) and their parents (87% female, 42.09 +/- 6.30 years old, BMI 30.99 +/- 6.14 kg/m2, 90% immigrants) were randomized to the intervention condition. A repeated measures latent class analysis that included 12 binary variables (yes/no) of attendance identified three subgroups of attendance patterns: consistently high, moderate and decreasing, and consistently low. An ANOVA was then conducted to examine whether the identified attendance patterns differed by individual, family dynamics, and cultural characteristics at baseline. Parents in the consistently high attendance group had lower Americanism than those in either of the other attendance groups. Adolescents in the consistently high attendance group had lower Hispanicism than those in either of the other attendance groups. No other variables significantly discriminated between attendance groups. Sustained attendance in the Familias Unidas for Health and Wellness intervention may be driven by Hispanic parents' desire to better understand their host culture, connect with other culturally similar parents, and reconnect adolescents with their heritage culture. PMID- 30011800 TI - Orientation of Laurdan in Phospholipid Bilayers Influences Its Fluorescence: Quantum Mechanics and Classical Molecular Dynamics Study. AB - Fluidity of lipid membranes is known to play an important role in the functioning of living organisms. The fluorescent probe Laurdan embedded in a lipid membrane is typically used to assess the fluidity state of lipid bilayers by utilizing the sensitivity of Laurdan emission to the properties of its lipid environment. In particular, Laurdan fluorescence is sensitive to gel vs liquid-crystalline phases of lipids, which is demonstrated in different emission of the dye in these two phases. Still, the exact mechanism of the environment effects on Laurdan emission is not understood. Herein, we utilize dipalmitoylphosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC) lipid bilayers, which at room temperature represent gel and liquid-crystalline phases, respectively. We simulate absorption and emission spectra of Laurdan in both DOPC and DPPC bilayers with quantum chemical and classical molecular dynamics methods. We demonstrate that Laurdan is incorporated in heterogeneous fashion in both DOPC and DPPC bilayers, and that its fluorescence depends on the details of this embedding. PMID- 30011801 TI - Biochar Remediation Improves the Leaf Mineral Composition of Telfairia occidentalis Grown on Gas Flared Soil. AB - This study evaluates the effects of remediation of gas flared soil by biochar on the nutritional composition of cultivated Telfairia occidentalis leaves, relative to non-gas flared soil. Gas flared soils are degraded due to the presence of heavy metals, noxious gases, carbon soot and acidic rain. Biochar produced from oil palm fibre was applied at five different amounts: 0 t ha-1, 7.1 t ha-1, 13.9 t ha-1, 20.9 t ha-1 and 28.0 t ha-1 to containerized soils (both gas flared and control soil), inside a greenhouse, which were allowed to mineralize for two weeks. Two viable seeds of T. occidentalis per replicate were sown. After eight weeks of growth, leaves were harvested, dried and chemically analyzed. Application of biochar significantly increased leaf ash and crude fibre content of Telfairia occidentalis. Plants from soil treated with 13.9 t ha-1 of biochar had the highest concentrations of vitamins A, B1, B2, B6, C and E irrespective of soil type. Maximum increase in leaf vitamin and mineral content was obtained from leaves cultivated on gas flared soil treated with 13.9 t ha-1 and 7.1 t ha-1 of biochar respectively. The results show that biochar treatment can increase leaf mineral concentrations and that this effect is dependent on the amount of biochar application. PMID- 30011802 TI - Impact of Nano-Crystalline Diamond Enhanced Hydrophilicity on Cell Proliferation on Machined and SLA Titanium Surfaces: An In-Vivo Study in Rodents. AB - By coating surfaces with nano-crystalline diamond (NCD) particles, hydrophilicity can be altered via sidechain modifications without affecting surface texture. The present study aimed to assess the impact of NCD hydrophilicity on machined and rough SLA titanium discs on soft tissue integration, using a rodent model simulating submerged healing. Four different titanium discs (machined titanium = M Titanium, NCD-coated hydrophilic machined titanium = M-O-NCD, sand blasted acid etched (SLA Titanium) titanium, and hydrophilic NCD-coated SLA titanium = SLA O NCD) were inserted in subdermal pockets of 12 Wistar rats. After one and four weeks of healing, the animals were sacrificed. Biopsies were embedded in methyl methacrylate (MMA), and processed for histology. The number of cells located within a region of interest (ROI) of 10 um around the discs were counted and compared statistically. Signs of inflammation were evaluated descriptively employing immunohistochemistry. At one week, M-O-NCD coated titanium discs showed significantly higher amounts of cells compared to M Titanium, SLA Titanium, and SLA-O-NCD (p < 0.001). At four weeks, significant higher cell counts were noted at SLA-O-NCD surfaces (p < 0.01). Immunohistochemistry revealed decreased inflammatory responses at hydrophilic surfaces. Within the limits of an animal study, M-O-NCD surfaces seem to stimulate cell proliferation in the initial healing phase, whereas SLA-O-NCD surfaces appeared advantageous afterwards. PMID- 30011803 TI - Analysis of the Characteristics and Sources of Carbonaceous Aerosols in PM2.5 in the Beijing, Tianjin, and Langfang Region, China. AB - PM2.5 samples from Beijing, Tianjin, and Langfang were simultaneously collected from 20 November 2016 to 25 December 2016, and the organic carbon (OC) and elemental carbon (EC) content in the samples were measured and analyzed. The pollution characteristics and sources of OC and EC in atmospheric PM2.5 for three adjacent cities were discussed. The average mass concentrations of OC in PM2.5 in Beijing, Tianjin, and Langfang were 27.93 +/- 23.35 MUg/m3, 25.27 +/- 12.43 MUg/m3, and 52.75 +/- 37.97 MUg/m3, respectively, and the mean mass concentrations of EC were 6.61 +/- 5.13 MUg/m3, 6.14 +/- 2.84 MUg/m3, and 12.06 +/- 6.81 MUg/m3, respectively. The average mass concentration of total carbon (TC) accounted for 30.5%, 24.8%, and 49% of the average mass concentration of PM2.5 in the atmosphere. The total carbonaceous matter (TCA) in Beijing, Tianjin, and Langfang was 51.29, 46.57, and 96.45 MUg/m3, respectively. The TCA was the main component of PM2.5 in the region. The correlation between OC and EC in the three cities showed R2 values of 0.882, 0.633, and 0.784 for Beijing, Tianjin, and Langfang, respectively, indicating that the sources of urban carbonaceous aerosols had good consistency and stability. The OC/EC values of the three sampling points were 4.48 +/- 1.45, 4.42 +/- 1.77, and 4.22 +/- 1.29, respectively, considerably greater than 2, indicating that the main sources of pollution were automobile exhaust, and the combustion of coal and biomass. The OC/EC minimum ratio method was used to estimate the secondary organic carbon (SOC) content in Beijing, Tianjin and Langfang. Their values were 10.73, 10.71, and 19.51, respectively, which accounted for 38%, 42%, and 37% of the average OC concentration in each city, respectively. The analysis of the eight carbon components showed that the main sources of pollutants in Beijing, Tianjin, and Langfang were exhaust emissions from gasoline vehicles, but the combustion of coal and biomass was relatively low. The pollution of road dust was more serious in Tianjin than in Beijing and Langfang. The contribution of biomass burning and coal-burning pollution sources to atmospheric carbon aerosols in Langfang was more prominent than that of Beijing and Tianjin. PMID- 30011804 TI - Test of the Deception Hypothesis in Atlantic Mollies Poecilia mexicana-Does the Audience Copy a Pretended Mate Choice of Others? AB - Animals often use public information for mate-choice decisions by observing conspecifics as they choose their mates and then copying this witnessed decision. When the copier, however, is detected by the choosing individual, the latter often alters its behavior and spends more time with the previously non-preferred mate. This behavioral change is called the audience effect. The deception hypothesis states that the choosing individual changes its behavior to distract the audience from the preferred mate. The deception hypothesis, however, only applies if the audience indeed copies the pretended mate choice of the observed individual. So far, this necessary prerequisite has never been tested. We investigated in Atlantic molly males and females whether, first, focal fish show an audience effect, i.e., alter their mate choices in the presence of an audience fish, and second, whether audience fish copy the mate choice of the focal fish they had just witnessed. We found evidence that male and female Atlantic mollies copy the pretended mate choice of same-sex focal fish. Therefore, a necessary requirement of the deception hypothesis is fulfilled. Our results show that public information use in the context of mate choice can be costly. PMID- 30011805 TI - Tracing Recombinant Bovine Somatotropin Ab(Use) Through Gene Expression in Blood, Hair Follicles, and Milk Somatic Cells: A Matrix Comparison. AB - The use of recombinant bovine somatotropin (rbST) in dairy cattle is forbidden in the European Union. Due to the very low circulating concentration of rbST in treated animals, its direct detection is still a challenge. Therefore, the use of indirect methods to detect the ab(use) of rbST in dairy cattle appears as a good alternative. In the past few years, gene expression demonstrated its utility in screening the use of illicit substances in both humans and animals. In this study, a comparison of three types of matrices (milk somatic cells, blood, and hair follicles) was carried out to evaluate their potential use for routine control of rbST using 15 gene-expression profiles. A total of six rbST-treated cows and three control cows were included in the study. A subcutaneous injection containing 500 mg of rbST was administered to the treated group. Samples of the three matrices were collected before rbST administration, and at three and nine days after treatment. The quality of RNA extracted was higher in the blood and hair-follicle samples than in the milk somatic cells. In the three matrices, there were significant differences in the expression of some genes, with milk somatic cells and blood presenting the the best matrices. On this note, the cyclin D1 (CCND1), interleukin 1 beta (IL-1beta), tumor necrosis factor (TNF), and insulin-like growth factor 1 receptor (IGF-1R) genes showed potential as biomarkers of rbST treatment. Therefore, blood, somatic cells, and follicle hair should be considered as promising sources of RNA, and can be used in gene expression assays to routinely control the illicit use of rbST. PMID- 30011806 TI - Cost-Effective Technologies to Study the Arctic Ocean Environment ?. AB - The Arctic region is known to be severely affected by climate change, with evident alterations in both physical and biological processes. Monitoring the Arctic Ocean ecosystem is key to understanding the impact of natural and human induced change on the environment. Large data sets are required to monitor the Arctic marine ecosystem and validate high-resolution satellite observations (e.g., Sentinel), which are necessary to feed climatic and biogeochemical forecasting models. However, the Global Observing System needs to complete its geographic coverage, particularly for the harsh, extreme environment of the Arctic Region. In this scenario, autonomous systems are proving to be valuable tools for increasing the resolution of existing data. To this end, a low-cost, miniaturized and flexible probe, ArLoC (Arctic Low-Cost probe), was designed, built and installed on an innovative unmanned marine vehicle, the PROTEUS (Portable RObotic TEchnology for Unmanned Surveys), during a preliminary scientific campaign in the Svalbard Archipelago within the UVASS project. This study outlines the instrumentation used and its design features, its preliminary integration on PROTEUS and its test results. PMID- 30011808 TI - Amorphous Nanosuspensions Aggregated from Paclitaxel-Hemoglobulin Complexes with Enhanced Cytotoxicity. AB - Amorphous nanosuspensions (ANSs) enable rapid release and improved delivery of a poorly water-soluble drug; however, their preparation is challenging. Here, using hemoglobin (Hb) as a carrier, ANSs aggregated from paclitaxel (PTX)-Hb complexes were prepared to improve delivery of the hydrophobic anti-cancer agent. An affinity study demonstrated strong interaction between Hb and PTX. Importantly, the complexes could aggregate into <300 nm ANSs with high drug loading, which acidic condition facilitated their formation. Furthermore, the ANSs possessed improved cytotoxicity against cancer cells over the crystalline nanosuspensions. Taken together, ANSs aggregated from PTX-Hb complexes were developed, which could kill cancer cells with high efficiency. PMID- 30011809 TI - Preparation and Characterization of AgNPs In Situ Synthesis on Polyelectrolyte Membrane Coated Sericin/Agar Film for Antimicrobial Applications. AB - Antibacterial materials are of great importance in preventing bacterial adhesion and reproduction in daily life. Silver nanoparticle (AgNP) is a broad-spectrum antibacterial nanomaterial that has attracted significant attentions for its ability to endow natural materials with antibacterial ability. Silk sericin (SS) has a great advantage for biomaterial application, as it is a natural protein with excellent hydrophilicity and biodegradability. In this study, we prepared AgNPs and polyelectrolyte membrane (PEM) modified SS/Agar films through the layer by-layer adsorption technique and ultraviolet-assisted AgNPs synthesis method. The film was well characterized by scanning electron microscopy, energy dispersive spectroscopy, X-ray diffraction, fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy. Other properties such as water contact angle, wettability and tensile strength, the release of silver were also studied. The antimicrobial activity of AgNPs-PEM-SS/Agar film was investigated against Escherichia coli and Staphylococcus aureus as the model microorganisms by the inhibition zone and bacterial growth curve assays. The results suggested that the AgNPs-PEM-SS/Agar film had excellent mechanical performance, high hydrophilicity, prominent water absorption ability, as well as outstanding and durable antibacterial activity. Therefore, the prepared novel AgNPs-PEM-SS/Agar composite film is proposed as a potentially favorable antibacterial biomaterial for biomedical applications. PMID- 30011807 TI - Autoantibodies as Potential Biomarkers in Breast Cancer. AB - Breast cancer is a major cause of mortality in women; however, technologies for early stage screening and diagnosis (e.g., mammography and other imaging technologies) are not optimal for the accurate detection of cancer. This creates demand for a more effective diagnostic means to replace or be complementary to existing technologies for early discovery of breast cancer. Cancer neoantigens could reflect tumorigenesis, but they are hardly detectable at the early stage. Autoantibodies, however, are biologically amplified and hence may be measurable early on, making them promising biomarkers to discriminate breast cancer from healthy tissue accurately. In this review, we summarized the recent findings of breast cancer specific antigens and autoantibodies, which may be useful in early detection, disease stratification, and monitoring of treatment responses of breast cancer. PMID- 30011810 TI - The Association between Epidermal Growth Factor Receptor (EGFR) Gene Polymorphisms and Lung Cancer Risk. AB - Lung cancer is the leading cause of cancer death globally. The epidermal growth factor receptor (EGFR) plays an important role in cell proliferation and signaling. In this study, we examined the association between EGFR gene polymorphisms and lung cancer risk among the Jordanian population. A total of 129 patients with primary lung cancer and 129 matched healthy controls were recruited into this study. EGFR rs712829, rs712830, rs2072454, and rs11543848 single nucleotide polymorphisms (SNPs) were genotyped to test for their association with lung cancer risk. A significant association was observed between the rs712829 SNP and lung cancer risk (p < 0.05) where the GG + GT genotypes were higher in lung cancer patients when compared to controls. In addition, no association was detected between rs712830, rs2072454, and rs11543848 SNPs and lung cancer risk. When patients were stratified according to the lung cancer type, a significant association was detected between both rs712829 and rs2072454 and adenocarcinoma lung cancer (p < 0.05). Haplotype analysis of all four SNPs showed a significant association between the TCCG haplotype and both lung cancer and the adenocarcinoma subtype (p < 0.001). In conclusion, EGFR rs712829, rs2072454 SNPs, and TCCG haplotypes are associated with a risk of lung cancer among Jordanians. Since genetic associations are affected by the genetic background of populations, more studies in other Arab populations are required to confirm the present findings. PMID- 30011812 TI - Engineering Vehicles Detection Based on Modified Faster R-CNN for Power Grid Surveillance. AB - Engineering vehicles intrusion detection is a key problem for the security of power grid operation, which can warn of the regional invasion and prevent external damage from architectural construction. In this paper, we propose an intelligent surveillance method based on the framework of Faster R-CNN for locating and identifying the invading engineering vehicles. In our detection task, the type of the objects is varied and the monitoring scene is large and complex. In order to solve these challenging problems, we modify the network structure of the object detection model by adjusting the position of the ROI pooling layer. The convolutional layer is added to the feature classification part to improve the accuracy of the detection model. We verify that increasing the depth of the feature classification part is effective for detecting engineering vehicles in realistic transmission lines corridors. We also collect plenty of scene images taken from the monitor site and label the objects to create a fine-tuned dataset. We train the modified deep detection model based on the technology of transfer learning and conduct training and test on the newly labeled dataset. Experimental results show that the proposed intelligent surveillance method can detect engineering vehicles with high accuracy and a low false alarm rate, which can be used for the early warning of power grid surveillance. PMID- 30011811 TI - Farrerol Ameliorates TNBS-Induced Colonic Inflammation by Inhibiting ERK1/2, JNK1/2, and NF-kappaB Signaling Pathway. AB - Farrerol, a type of 2, 3-dihydro-flavonoid, is obtained from Rhododendron. Previous studies have shown that Farrerol performs multiple biological activities, such as anti-inflammatory, antibacterial, and antioxidant activity. In this study, we aim to investigate the effect of Farrerol on colonic inflammation and explore its potential mechanisms. We found that the effect of Farrerol was evaluated via the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in mice and found that Farrerol has a protective effect on TNBS induced colitis. Farrerol administration significantly improved the weight change, clinical scores, colon length, and intestinal epithelium barrier damage and markedly decreased the inflammatory cytokines production in TNBS-induced mice. The protective effect of Farrerol was also observed in LPS-induced RAW264.7 cells. We found that Farrerol observably reduced the production of inflammatory mediators including IL-1beta, IL-6, TNF-alpha, COX-2, and iNOS in LPS-induced RAW264.7 cells via suppressing AKT, ERK1/2, JNK1/2, and NF-kappaB p65 phosphorylation. In conclusion, the study found that Farrerol has a beneficial effect on TNBS-induced colitis and might be a natural therapeutic agent for IBD treatment. PMID- 30011813 TI - Microstructure and Mechanical Properties of Si3N4-Fe3Si Composites Prepared by Gas-Pressure Sintering. AB - Si3N4-Fe3Si composites were prepared using Fe-Si3N4 as the source of Fe3Si by gas pressure sintering. By adding different amounts of Fe-Si3N4 into the starting powders, Si3N4-Fe3Si composites with various Fe3Si phase contents were obtained. The microstructure and mechanical properties of the composites were investigated. With the increase of Fe-Si3N4 contents, the content and particle size of Fe3Si both increased. When more than 60 wt. % Fe-Si3N4 were added, the abnormal growth of Fe3Si particles occurred and oversized Fe3Si particles appeared, leading to non-uniform microstructures and worse mechanical properties of the composites. It has been found that Fe3Si particles could toughen the composites through particle pull-out, interface debonding, crack deflection, and particle bridging. Uniform microstructure and improved mechanical properties (flexural strength of 354 MPa and fracture toughness of 8.4 MPa.m1/2) can be achieved for FSN40. PMID- 30011814 TI - Host Protein BAG3 is a Negative Regulator of Lassa VLP Egress. AB - Lassa fever virus (LFV) belongs to the Arenaviridae family and can cause acute hemorrhagic fever in humans. The LFV Z protein plays a central role in virion assembly and egress, such that independent expression of LFV Z leads to the production of virus-like particles (VLPs) that mimic egress of infectious virus. LFV Z contains both PTAP and PPPY L-domain motifs that are known to recruit host proteins that are important for mediating efficient virus egress and spread. The viral PPPY motif is known to interact with specific host WW-domain bearing proteins. Here we identified host WW-domain bearing protein BCL2 Associated Athanogene 3 (BAG3) as a LFV Z PPPY interactor using our proline-rich reading array of WW-domain containing mammalian proteins. BAG3 is a stress-induced molecular co-chaperone that functions to regulate cellular protein homeostasis and cell survival via Chaperone-Assisted Selective Autophagy (CASA). Similar to our previously published findings for the VP40 proteins of Ebola and Marburg viruses, our results using VLP budding assays, BAG3 knockout cells, and confocal microscopy indicate that BAG3 is a WW-domain interactor that negatively regulates egress of LFV Z VLPs, rather than promoting VLP release. Our results suggest that CASA and specifically BAG3 may represent a novel host defense mechanism, whereby BAG3 may dampen egress of several hemorrhagic fever viruses by interacting and interfering with the budding function of viral PPxY-containing matrix proteins. PMID- 30011815 TI - Influence of Food Neophobia Level on Fruit and Vegetable Intake and Its Association with Urban Area of Residence and Physical Activity in a Nationwide Case-Control Study of Polish Adolescents. AB - Among the factors that may influence fruit and vegetable intake, there is a food neophobia level, but the other elements, including physical activity and place of residence, must also be taken into account as interfering ones. The aim of the study was to analyze the association between food neophobia level and the intake of fruits and vegetables in a nationwide case-control study of Polish adolescents (12-13 years), including the influence of gender, the physical activity program participation and the place of residence. The #goathletics Study was conducted among a group of 1014 adolescents, 507 individuals representative for a nationwide physical activity program "Athletics for All" participants (characterized by an active lifestyle) and 507 pair-matched individuals (characterized by sedentary behavior), while 502 were representative for urban and 512 for suburban area. The assessment of food neophobia level was based on the Food Neophobia Scale questionnaire and the assessment of fruit and vegetable intake was based on the validated food frequency questionnaire. It was observed that higher food neophobia level is associated with a lower fruit and vegetable intake, that was stated both for girls and boys, as well as both for individuals characterized by an active lifestyle and those characterized by sedentary behavior, both from urban and suburban area. Food neophobic individuals characterized by an active lifestyle and those from urban areas were characterized by a higher fruit intake than individuals characterized by sedentary behavior and those from suburban areas, from the same food neophobia category. It was found that food neophobia may reduce fruit and vegetable intake, but the physical activity education with peers may reduce the observed influence and should be applied especially in the case of neophobic individuals from suburban areas. PMID- 30011817 TI - Multistep Optimization of beta-Glucosidase Extraction from Germinated Soybeans (Glycine max L. Merril) and Recovery of Isoflavone Aglycones. AB - Epicotyls from germinated soybeans (EGS) have great potential as sources of endogenous beta-glucosidase. Furthermore, this enzyme may improve the conversion of isoflavones into their corresponding aglycones. beta-Glucosidase may also increase the release of aglycones from the cell wall of the plant materials. Therefore, the aim of this work was to optimize both the extraction of beta glucosidase from EGS and to further examine its application in defatted soybean cotyledon to improve the recovery of aglycones, which were evaluated by ultra high performance liquid chromatography (UHPLC). A multistep optimization was carried out and the effects of temperature and pH were investigated by applying a central composite design. The linear effect of pH and the quadratic effect of pH and temperature were significant for the extraction of beta-glucosidase and recovery aglycones, respectively. Optimum extraction of beta-glucosidase from EGS occurred at 30 degrees C and pH 5.0. Furthermore, the maximum recovery of aglycones (98.7%), which occurred at 35 degrees C and pH 7.0-7.6 during 144 h of germination, increased 8.5 times with respect to the lowest concentration. The higher bioaccessibility of aglycones when compared with their conjugated counterparts is well substantiated. Therefore, the data provided in this contribution may be useful for enhancing the benefits of soybean, their products, and/or their processing by-products. PMID- 30011816 TI - Association between Blood 25-Hydroxyvitamin D Levels and Survival in Colorectal Cancer Patients: An Updated Systematic Review and Meta-Analysis. AB - Previous meta-analyses have shown an improved survival with higher blood 25 hydroxyvitamin D (25(OH)D) concentrations in patients with colorectal cancer (CRC). However, a number of much larger studies have been published since then. We provide an updated meta-analysis to synthesize current evidence. PubMed and Web of Science databases were systematically searched for eligible studies. The dose-response relationships and pooled hazard ratios for overall and CRC-specific survival comparing the highest versus the lowest categories of blood 25(OH)D concentrations were assessed. Subgroup analyses based on study geographic location, year of publication, sample size, length of follow-up time and stage were conducted to explore potential sources of heterogeneity. Overall, 11 original studies with a total of 7718 CRC patients were included. The dose response meta-analysis showed an improvement in survival outcomes with increasing blood 25(OH)D concentrations. Pooled hazard ratios (95% confidence intervals) comparing highest versus lowest categories were 0.68 (0.55-0.85) and 0.67 (0.57 0.78) for overall and CRC-specific survival, respectively. Associations were more prominent among studies conducted in Europe, with larger sample sizes, and including stage I-IV patients. This updated meta-analysis reveals robust evidence of an association between higher blood 25(OH)D concentrations and better survival in CRC patients. The potential for enhancing prognosis of CRC patients by vitamin D supplementation should be explored by randomized trials. PMID- 30011819 TI - Modified Porous SiO2-Supported Cu3(BTC)2 Membrane with High Performance of Gas Separation. AB - The structures and applications of metal-organic framework materials (MOFs) have been attracting great interest due to the wide variety of possible applications, for example, chemical sensing, separation, and catalysis. N-[3 (Trimethoxysilyl)propyl]ethylenediamine is grafted on a porous SiO2 disk to obtain a modified porous SiO2 disk. A large-scale, continuous, and compact Cu3(BTC)2 membrane is prepared based on a modified porous SiO2 disk. The chemical structure, surface morphology, thermal stability, mechanical stability, and gas separation performance of the obtained Cu3(BTC)2 membrane is analyzed and characterized by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and a gas separation experiment. The results show that the prepared Cu3(BTC)2 membrane has an intact morphology with its crystal. It is continuous, compact, and intact, and has good thermal stability and mechanical stability. The result of the gas separation experiment shows that the Cu3(BTC)2 membrane has a good selectivity of hydrogen and can be used to recover and purify hydrogen. PMID- 30011820 TI - Shaping Streamflow Using a Real-Time Stormwater Control Network. AB - "Smart" water systems are transforming the field of stormwater management by enabling real-time monitoring and control of previously static infrastructure. While the localized benefits of active control are well-established, the potential for system-scale control of watersheds is poorly understood. This study shows how a real-world smart stormwater system can be leveraged to shape streamflow within an urban watershed. Specifically, we coordinate releases from two internet-controlled stormwater basins to achieve desired control objectives downstream-such as maintaining the flow at a set-point, and generating interleaved waves. In the first part of the study, we describe the construction of the control network using a low-cost, open-source hardware stack and a cloud based controller scheduling application. Next, we characterize the system's control capabilities by determining the travel times, decay times, and magnitudes of various waves released from the upstream retention basins. With this characterization in hand, we use the system to generate two desired responses at a critical downstream junction. First, we generate a set-point hydrograph, in which flow is maintained at an approximately constant rate. Next, we generate a series of overlapping and interleaved waves using timed releases from both retention basins. We discuss how these control strategies can be used to stabilize flows, thereby mitigating streambed erosion and reducing contaminant loads into downstream waterbodies. PMID- 30011818 TI - Epithelial Cell Cycle Behaviour in the Injured Kidney. AB - Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been repeatedly demonstrated that dysregulation of the cell cycle can cause injured kidneys to progress to CKD. More precisely, severe AKI causes PTCs to arrest in the G1/S or G2/M phase of the cell cycle, leading to maladaptive repair and a fibrotic outcome. The mechanisms causing these arrests are far from known. The arrest might, at least partially, be attributed to DNA damage since activation of the DNA-damage response pathway leads to cell cycle arrest. Alternatively, cytokine signalling via nuclear factor kappa beta (NF-kappabeta) and p38-mitogen activated protein kinase (p38-MAPK) pathways, and reactive oxygen species (ROS) can play a role independent of DNA damage. In addition, only a handful of cell cycle regulators (e.g., p53, p21) have been thoroughly studied during renal repair. Still, why and how PTCs decide to arrest their cell cycle and how this arrest can efficiently be overcome remain open and challenging questions. In this review we will discuss the evidence for cell cycle involvement during AKI and development of CKD together with putative therapeutic approaches. PMID- 30011821 TI - Multi-Stakeholder Perspectives of Factors That Influence Contact Centre Call Agents' Workplace Physical Activity and Sedentary Behaviour. AB - Contact centre call agents are highly sedentary at work, which can negatively affect cardio-metabolic health. This qualitative cross-sectional study explored factors influencing call agents' workplace physical activity (PA) and sedentary behaviour (SB), and perspectives on strategies to help agents move more and sit less at work. Semi-structured interviews and focus groups with call agents (n = 20), team leaders (n = 11) and senior staff (n = 12) across four contact centres were guided by the socio-ecological model and analysed thematically. Agents offered insights into the impact of high occupational sitting and low PA on their physical and mental health, and factors influencing their motivation to move more and sit less at work. Team leaders, although pivotal in influencing behaviours, identified their own workload, and agents' requirement to meet targets, as factors influencing their ability to promote agents to move more and sit less at work. Further, senior team leaders offered a broad organisational perspective on influential factors, including business needs and the importance of return on investment from PA and SB interventions. Unique factors, including continuous monitoring of productivity metrics and personal time, a physical connection to their workstation, and low autonomy over their working practices, seemed to limit call agents' opportunity to move more and sit less at work. Proposed strategies included acknowledgement of PA and SB within policy and job roles, height adjustable workstations, education and training sessions and greater interpersonal support. Additionally, measuring the impact of interventions was perceived to be key for developing a business case and enhancing organisational buy-in. Multi-level interventions embedded into current working practices appear important for the multiple stakeholders, while addressing concerns regarding productivity. PMID- 30011823 TI - Development of a User-Adaptable Human Fall Detection Based on Fall Risk Levels Using Depth Sensor. AB - Unintentional falls are a major public health concern for many communities, especially with aging populations. There are various approaches used to classify human activities for fall detection. Related studies have employed wearable, non invasive sensors, video cameras and depth sensor-based approaches to develop such monitoring systems. The proposed approach in this study uses a depth sensor and employs a unique procedure which identifies the fall risk levels to adapt the algorithm for different people with their physical strength to withstand falls. The inclusion of the fall risk level identification, further enhanced and improved the accuracy of the fall detection. The experimental results showed promising performance in adapting the algorithm for people with different fall risk levels for fall detection. PMID- 30011822 TI - Precision Medicine for Alzheimer's Disease Prevention. AB - Precision medicine is an approach to medical treatment and prevention that takes into account individual variability in genes, environment, and lifestyle and allows for personalization that is based on factors that may affect the response to treatment. Several genetic and epigenetic risk factors have been shown to increase susceptibility to late-onset Alzheimer's disease (AD). As such, it may be beneficial to integrate genetic risk factors into the AD prevention approach, which in the past has primarily been focused on universal risk-reduction strategies for the general population rather than individualized interventions in a targeted fashion. This review discusses examples of a "one-size-fits-all" versus clinical precision medicine AD prevention strategy, in which the precision medicine approach considers two genes that can be commercially sequenced for polymorphisms associated with AD, apolipoprotein E (APOE), and methylenetetrahydrofolate reductase (MTHFR). Comparing these two distinct approaches provides support for a clinical precision medicine prevention strategy, which may ultimately lead to more favorable patient outcomes as the interventions are targeted to address individualized risks. PMID- 30011824 TI - Keggin-Type Heteropoly Salts as Bifunctional Catalysts in Aerobic Baeyer-Villiger Oxidation. AB - The cobalt, manganese, and iron salts of tungstophosphoric or molybdophosphoric acid with growing content of metals were applied for the first time as catalysts in the Baeyer-Villiger (BV) oxidation of cyclohexanone to epsilon-caprolactone with molecular oxygen. The catalysts were characterized with Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence (XRF), and ethanol decomposition reaction. Introduction of transition metals into the heteropoly structure increases the activity of resulting heteropoly salts in comparison with parent heteropolyacids. It was shown that the most active catalysts are salts of the heteropoly salts with one metal atom introduced and one proton left (HMPX) type, (where M = Co, Fe, Mn, and X = W, Mo) with the metal to proton ratio equal one. Among all of the studied catalysts, the highest catalytic activity was observed for HCoPW. The effect indicates that both the acidic and redox properties are required to achieve the best performance. The Baeyer-Villiger (BV) oxidation mechanism proposed identifies the participation of heteropoly compounds in three steps of the investigated reaction: oxidation of aldehyde to peracid (redox function), activation of carbonyl group (Lewis acidity), and decomposition of the Criegee adduct to epsilon-caprolactone (Bronsted acidity). PMID- 30011826 TI - Hydrolytic Hydrogen Production on Al-Sn-Zn Alloys Processed by High-Pressure Torsion. AB - Aluminium-tin-based alloys with different compositions were synthesized by a high pressure torsion (HPT) method. The effect of different alloying elements and processing routes on the hydrogen generation performance of the alloys was investigated. The results show that Zn can enhance the hydrogen generation rate and yield by promoting pitting corrosion. The highest reactivity in water was achieved for an Al-30wt %Sn-10wt %Zn alloy. Detailed analysis of the Al-30wt %Sn 10wt %Zn alloy shows that increasing the shear strain and the resultant formation of ultrafine grains and phase mixing enhance the hydrogen generation rate through the effects of both nanogalvanic cells and pitting corrosion. PMID- 30011825 TI - Epidemiological Trends of Antibiotic Resistant Gonorrhoea in the United Kingdom. AB - Gonorrhoea is one of the most common sexually-transmitted bacterial infections, globally and in the United Kingdom. The levels of antibiotic resistance in gonorrhoea reported in recent years represent a critical public health issue. From penicillins to cefixime, the gonococcus has become resistant to all antibiotics that have been previously used against it, in each case only a matter of years after introduction as a first-line therapy. After each instance of resistance emergence, the treatment recommendations have required revision, to the point that only a few antibiotics can reliably be prescribed to treat infected individuals. Most countries, including the UK, now recommend that gonorrhoea be treated with a dual therapy combining ceftriaxone and azithromycin. While this treatment is still currently effective for the vast majority of cases, there are concerning signs that this will not always remain the case, and there is no readily apparent alternative. Here, we review the use of antibiotics and epidemiological trends of antibiotic resistance in gonorrhoea from surveillance data over the past 15 years in the UK and describe how surveillance could be improved. PMID- 30011828 TI - Novel Polyketides Produced by the Endophytic Fungus Aspergillus Fumigatus from Cordyceps Sinensis. AB - Five new polyketides, including two pairs of enantiomers and a racemate, were isolated from the fermentation broth of Aspergillus fumigatus, an endophytic fungus isolated from Cordyceps sinensis. Their structures were identified using one-dimensional (1D) and two-dimensional (2D) NMR experiments, and the absolute configurations of the enantiomers were confirmed using electronic circular dichroism (ECD) calculations. Compounds 1a and 2a exhibited inhibitory activity against the MV4-11 cell line in vitro, with IC50 values of 23.95 uM and 32.70 uM, respectively. PMID- 30011827 TI - Association of Dietary Patterns with Metabolic Syndrome: Results from the Kardiovize Brno 2030 Study. AB - Although metabolic syndrome (MetS) could be handled by lifestyle interventions, its relationship with dietary patterns remains unclear in populations from Central Europe. Using data from the Kardiovize Brno cohort, the present study aims to identify the main dietary patterns and to evaluate their association with MetS risk in a random urban sample from Brno, Czech Republic. In a cross sectional study of 1934 subjects aged 25-65 years (44.3% male), dietary patterns were derived by food frequency questionnaire (FFQ) administration and principal component analysis. Metabolic syndrome was defined according to the International Diabetes Federation statement. Logistic regression models were applied. High adherence to the prudent dietary pattern was associated with lower odds of abdominal obesity, abnormal glucose concentration, and MetS. By contrast, high adherence to the western dietary pattern was associated with higher odds of abnormal glucose, triglycerides and blood pressure levels. Whilst our results confirm the deleterious effect of a western dietary pattern on several metabolic risk factors, they also indicate that the consumption of a diet rich in cereals, fish, fruit and vegetables is associated with a healthier metabolic profile. However, further prospective research is warranted to develop and validate novel potential preventive strategies against MetS and its complications. PMID- 30011830 TI - Synthesis and Characterizations of (CoxMg(2-x))SiO4 Forsterite Ceramic Pigments from Mirror Waste. AB - Ceramic pigments have been widely used in a variety of industries because of their excellent properties, such as high thermal stability, low-cost productions, and simple manufacturing processes. Re-use of mirror waste, which consists of silicon dioxide greater than 70%, is a method that can reduce raw materials cost. In this work, ceramic pigment with forsterite structure, Mg2SiO4, was synthesized via conventional solid state reaction by using mirror waste as a precursor. Solid solutions of Co-doped forsterite pigment, CoxMg(2-x)SiO4 where x = 0.02-1.6, were calcined at 1000 degrees C for 2 h. The calcined powders were characterized by X ray diffraction technique (XRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), UV Vis spectrophotometer, and color measurement (CIEL*a*b*). XRD results confirmed that forsterite phase was found as a main phase in the ceramic powder. However, the forsterite phase decreased with increased concentration of Co to x = 0.8-1.6. This could be because of the solubility limit of Co in solid solution. In addition, the use of mirror waste as a raw material was able to reduce calcination temperature compared to the use of oxide reagents. Color measurements or CIEL*a*b* color space of forsterite pigments were located in red-blue quadrant for Co-doped pigment. PMID- 30011831 TI - Design of Security Paper with Selective Frequency Reflection Characteristics. AB - In this research, a security paper based on frequency selective structure technologies was designed and fabricated using selective wave reflection characteristics to prevent the offline leakage of confidential documents. Document leakage detection systems using security papers detect security papers using transceiving antenna gates. For the application of such systems, the structure must be designed with excellent reflection performance and stability at the angle of incidence. For this purpose, a loop and patch-type frequency selective structure based on a four-legged element structure was designed to have X-band frequency reflection characteristics. This design was based on optimized variables and was realized through the screen printing method using silver ink on A4 paper. It was verified that both the design and simulation results matched well. To verify its actual applicability, a detector module operable at 10 GHz was manufactured to observe both the security paper detection range in relation to distance with a signal strength of -10 dBm and the detection area in relation to the number of times that the security paper had been folded. PMID- 30011829 TI - Molecular Regulation of Nitrate Responses in Plants. AB - Nitrogen is an essential macronutrient that affects plant growth and development. Improving the nitrogen use efficiency of crops is of great importance for the economic and environmental sustainability of agriculture. Nitrate (NO3-) is a major form of nitrogen absorbed by most crops and also serves as a vital signaling molecule. Research has identified key molecular components in nitrate signaling mainly by employing forward and reverse genetics as well as systems biology. In this review, we focus on advances in the characterization of genes involved in primary nitrate responses as well as the long-term effects of nitrate, especially in terms of how nitrate regulates root development. PMID- 30011832 TI - The German Food Bank System and Its Users-A Cross-Sectional Study. AB - Although food banks are a well-known resource for low-income people struggling to meet their food needs, they have rarely been investigated on a large scale. This study aims to contribute to the actual debate about the potential and limitations of food banks to decrease the prevalence of food insecurity by providing a representative picture of the German food bank system and its users. Publicly accessible data were used to map residents, public welfare recipients, and food banks. In addition, a comprehensive survey was distributed to all 934 "Tafel" food banks. The results show that nearly all residents and welfare recipients have access to at least one food bank located in the districts in which they reside. Differences in the density of food banks exist between eastern and western Germany. Food banks provide mainly healthy fresh food, but they heavily rely on food donations from local retailers and on volunteer labor. Although changes in the number of user households by income seem to mirror trends in the number of welfare recipients, food bank users appear to represent only a fraction of the food-insecure population in Germany. Food banks might have the potential to improve users' diet and food security, but they are not able to reach all food insecure residents in Germany. PMID- 30011833 TI - LifeChair: A Conductive Fabric Sensor-Based Smart Cushion for Actively Shaping Sitting Posture. AB - The LifeChair is a smart cushion that provides vibrotactile feedback by actively sensing and classifying sitting postures to encourage upright posture and reduce slouching. The key component of the LifeChair is our novel conductive fabric pressure sensing array. Fabric sensors have been explored in the past, but a full sensing solution for embedded real world use has not been proposed. We have designed our system with commercial use in mind, and as a result, it has a high focus on manufacturability, cost-effectiveness and adaptiveness. We demonstrate the performance of our fabric sensing system by installing it into the LifeChair and comparing its posture detection accuracy with our previous study that implemented a conventional flexible printed PCB-sensing system. In this study, it is shown that the LifeChair can detect all 11 postures across 20 participants with an improved average accuracy of 98.1%, and it demonstrates significantly lower variance when interfacing with different users. We also conduct a performance study with 10 participants to evaluate the effectiveness of the LifeChair device in improving upright posture and reducing slouching. Our performance study demonstrates that the LifeChair is effective in encouraging users to sit upright with an increase of 68.1% in time spent seated upright when vibrotactile feedback is activated. PMID- 30011835 TI - Correlations of Molecular Weights of beta-Glucans from Qingke (Tibetan Hulless Barley) to Their Multiple Bioactivities. AB - beta-glucans have been considered the major bioactive components in Qingke (Tibetan hulless barley). However, the structure-function relationships of beta glucans from Qingke have seldom been investigated. Whether the bioactivities of Qingke beta-glucans are closely correlated to their molecular weights remains unknown. Therefore, in order to explore Qingke beta-glucans as functional/healthy food ingredients for industrial applications, and to better understand their structure-function relationships, correlations of molecular weights of Qingke beta-glucans to their in vitro binding properties, inhibitory activities on digestive enzymes (alpha-amylase and pancreatic lipase), anti-inflammatory activities, and anticancer activities were systematically investigated. Results showed that the in vitro binding properties and the inhibitory activities on alpha-amylase and pancreatic lipase of Qingke beta-glucans were positively correlated to their molecular weights. However, the anti-inflammatory activities of Qingke beta-glucans increased as their molecular weights decreased. Furthermore, Qingke beta-glucans exhibited selectively anti-cancer activities in vitro. Positive and negative correlations of molecular weights to inhibitory effects against A549 cells and MDA-MB-231 cells were observed, respectively. However, the inhibitory effects of Qingke beta-glucans against HCT116 cells were not associated with their molecular weights. Results suggested that the molecular weights of Qingke beta-glucans significantly affected their bioactivities, which was beneficial for a better understanding of their structure-function relationships. Moreover, results showed that Qingke beta-glucans could be further explored as functional/healthy food ingredients for industrial applications due to their multiple health benefits. PMID- 30011837 TI - Percolated Si:SiO2 Nanocomposites: Oven- vs. Millisecond Laser-Induced Crystallization of SiOx Thin Films. AB - Three-dimensional nanocomposite networks consisting of percolated Si nanowires in a SiO2 matrix, Si:SiO2, were studied. The structures were obtained by reactive ion beam sputter deposition of SiOx (x ~ 0.6) thin films at 450 ?C and subsequent crystallization using conventional oven, as well as millisecond line focus laser treatment. Rutherford backscattering spectrometry, Raman spectroscopy, X-ray diffraction, cross-sectional and energy-filtered transmission electron microscopy were applied for sample characterization. While oven treatment resulted in a mean Si wire diameter of 10 nm and a crystallinity of 72% within the Si volume, almost single-domain Si structures of 30 nm in diameter and almost free of amorphous Si were obtained by millisecond laser application. The structural differences are attributed to the different crystallization processes: conventional oven tempering proceeds via solid state and millisecond laser application via liquid phase crystallization of Si. The five orders of magnitude larger diffusion constant in the liquid phase is responsible for the three-times larger Si nanostructure diameter. In conclusion, laser treatment offers not only significantly shorter process times, but moreover, a superior structural order of nano-Si compared to conventional heating. PMID- 30011836 TI - Effect of Supplementation of a Whey Peptide Rich in Tryptophan-Tyrosine-Related Peptides on Cognitive Performance in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Study. AB - : Background: Previous epidemiological and clinical studies have shown that dairy products have beneficial effects on cognitive decline and dementia. Enzymatic digestion of whey protein produces a whey peptide rich in tryptophan-tyrosine related peptides which improve cognitive performance in mice. We evaluated the effects of whey peptides on cognitive functions in healthy adults in a randomized, double-blind, placebo-controlled design. Methods: 101 healthy adults (45 to 64 years), with a self-awareness of cognitive decline received either whey peptide or placebo supplements for 12 weeks. Changes in cognitive function were assessed using neuropsychological tests at 6 and 12 weeks after the start of supplementation. Results: Verbal fluency test (VFT) score changes tended to be higher in the whey peptide group compared with the placebo at 12 weeks. Subgroup analysis classified by the degree of subjective fatigue showed that changes in the VFT as well as the Stroop and subjective memory function tests between baseline and 6 weeks of intervention were significantly better in subjects with high-level fatigue from the whey peptide group as compared to the placebo group. CONCLUSIONS: Intake of whey peptide might improve cognitive function in healthy middle- and older-aged adults with high subjective fatigue levels. Further studies will elucidate the relationship among cognitive improvement, whey peptides, and psychological fatigue. PMID- 30011834 TI - Implications of AMPK in the Formation of Epithelial Tight Junctions. AB - Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of membrane components; and (ii) TJ regulate the selective paracellular permeability. Disruption of TJ is regarded as one of the earliest hallmarks of epithelial injury, leading to the loss of cell polarity and tissue disorganization. Many factors have been identified as modulators of TJ assembly/disassembly. More specifically, in addition to its role as an energy sensor, adenosine monophosphate-activated protein kinase (AMPK) participates in TJ regulation. AMPK is a ubiquitous serine/threonine kinase composed of a catalytic alpha-subunit complexed with regulatory beta-and gamma-subunits. AMPK activation promotes the early stages of epithelial TJ assembly. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the TJ-associated protein zonula occludens (ZO)-1, thereby facilitating ZO-1 distribution to the plasma membrane. In the present review, we detail the signaling pathways up-and down-stream of AMPK activation at the time of Ca2+ induced TJ assembly. PMID- 30011839 TI - A PolSAR Image Segmentation Algorithm Based on Scattering Characteristics and the Revised Wishart Distance. AB - A novel segmentation algorithm for polarimetric synthetic aperture radar (PolSAR) images is proposed in this paper. The method is composed of two essential components: a merging order and a merging predicate. The similarity measured by the complex-kind Hotelling-Lawley trace (HLT) statistic is used to decide the merging order. The merging predicate is determined by the scattering characteristics and the revised Wishart distance between adjacent pixels, which can greatly improve the performance in speckle suppression and detail preservation. A postprocessing step is applied to obtain a satisfactory result after the merging operation. The decomposition and merging processes are iteratively executed until the termination criterion is met. The superiority of the proposed method was verified with experiments on two RADARSAT-2 PolSAR images and a Gaofen-3 PolSAR image, which demonstrated that the proposed method can obtain more accurate segmentation results and shows a better performance in speckle suppression and detail preservation than the other algorithms. PMID- 30011838 TI - Recent Developments in Using Drosophila as a Model for Human Genetic Disease. AB - Many insights into human disease have been built on experimental results in Drosophila, and research in fruit flies is often justified on the basis of its predictive value for questions related to human health. Additionally, there is now a growing recognition of the value of Drosophila for the study of rare human genetic diseases, either as a means of validating the causative nature of a candidate genetic variant found in patients, or as a means of obtaining functional information about a novel disease-linked gene when there is little known about it. For these reasons, funders in the US, Europe, and Canada have launched targeted programs to link human geneticists working on discovering new rare disease loci with researchers who work on the counterpart genes in Drosophila and other model organisms. Several of these initiatives are described here, as are a number of output publications that validate this new approach. PMID- 30011840 TI - Enhanced Visible Light Driven Photocatalytic Behavior of BiFeO3/Reduced Graphene Oxide Composites. AB - BiFeO3/Reduced Graphene Oxide (BFO/RGO) composites have been fabricated by a simple hydrothermal method. The X-ray diffraction (XRD), scanning electron microscopy (SEM), Raman, and X-ray photoelectron spectroscopy (XPS) analysis reveal that graphene oxide was reduced in hydrothermal process and BFO/RGO composites were successfully synthesized. UV-visible absorption and photoluminescence properties show that the introduction of RGO can effectively reduce the recombination of photogenerated electron and hole pairs. Compared to the pristine BFO, the photocatalytic performance of BiFeO3 Graphene Oxide (BGO) composites is enhanced for the degradation of Methylene blue (MB) solution under visible light irradiation, and the result shows that the optimal amount of Graphene Oxide (GO) in the composites is 60 mg (BGO60). The excellent photocatalytic performance is mainly ascribed to improved light absorption, increased reactive sites, and the low recombination rate of electron-hole pairs. This work can provide more insights into designing advanced photocatalysts for wastewater treatment and environmental protection. PMID- 30011841 TI - Psoriasis Severity-A Risk Factor of Insulin Resistance Independent of Metabolic Syndrome. AB - BACKGROUND: It is still debatable whether psoriasis increases cardiovascular risk indirectly since it is associated with metabolic syndrome or is an independent cardiovascular risk factor. The aim of this study was to evaluate psoriasis severity as an independent predictor of insulin resistance (IR) irrespective of the presence of metabolic syndrome (MetS). METHODS: This was a case control study including 128 patients stratified into two groups: patients with psoriasis and metabolic syndrome vs. patients with psoriasis and no metabolic syndrome. MetS was diagnosed according to ATP III criteria with homeostatic model assessment of insulin resistance (HOMA-IR), as well as a homeostatic model assessment of beta cell function (HOMA-beta) were calculated. RESULTS: Compared to subjects without metabolic syndrome, patients with metabolic syndrome had a significantly higher Psoriasis Area Severity Index (PASI) values (p < 0.001). The strongest correlation was established for HOMA-IR and the PASI index (p < 0.001), even after adjustment for body mass index (BMI) in regression analysis model. In patients without MetS and severe forms of disease, the HOMA-IR and HOMA-beta values were significantly higher compared to mild forms of disease (p < 0.001 for all) while in subjects with MetS no difference was established for HOMA-IR or HOMA-beta based on disease severity. CONCLUSIONS: Psoriasis severity is an independent risk factor of HOMA-IR, the strongest association being present in the non-MetS group, who still had preserved beta cell function suggesting direct promotion of atherosclerosis via insulin resistance depending on the disease severity, but irrespective of the presence of metabolic syndrome. PMID- 30011842 TI - Review of Low-Cost Photoacoustic Sensing and Imaging Based on Laser Diode and Light-Emitting Diode. AB - Photoacoustic tomography (PAT), a promising medical imaging method that combines optical and ultrasound techniques, has been developing for decades mostly in preclinical application. A recent trend is to utilize the economical laser source to develop a low-cost sensing and imaging system, which aims at an affordable solution in clinical application. These low-cost laser sources have different modulation modes such as pulsed modulation, continuous modulation and coded modulation to generate different profiles of PA signals in photoacoustic (PA) imaging. In this paper, we review the recent development of the photoacoustic sensing and imaging based on the economical laser sources such as laser diode (LD) and light-emitting diode (LED) in different kinds of modulation types, and discuss several representative methods to improve the performance of such imaging systems based on low-cost laser sources. Finally, some perspectives regarding the future development of portable PAT systems are discussed, followed by the conclusion. PMID- 30011844 TI - Deceptive Jamming Detection for SAR Based on Cross-Track Interferometry. AB - Deceptive jamming against synthetic aperture radar (SAR) can create false targets or deceptive scenes in the image effectively. Based on the difference in interferometric phase between the target and deceptive jamming signals, a novel method for detecting deceptive jamming using cross-track interferometry is proposed, where the echoes with deceptive jamming are received by two SAR antennas simultaneously and the false targets are identified through SAR interferometry. Since the derived false phase is close to a constant in interferogram, it is extracted through phase filtering and frequency detection. Finally, the false targets in the SAR image are obtained according to the detected false part in the interferogram. The effectiveness of the proposed method is validated by simulation results based on the TanDEM-X system. PMID- 30011843 TI - Unbiased Lipidomic Profiling of Triple-Negative Breast Cancer Tissues Reveals the Association of Sphingomyelin Levels with Patient Disease-Free Survival. AB - The reprogramming of lipid metabolism is a hallmark of many cancers that has been shown to promote breast cancer progression. While several lipid signatures associated with breast cancer aggressiveness have been identified, a comprehensive lipidomic analysis specifically targeting the triple-negative subtype of breast cancer (TNBC) may be required to identify novel biomarkers and therapeutic targets for this most aggressive subtype of breast cancer that still lacks effective therapies. In this current study, our global LC-MS-based lipidomics platform was able to measure 684 named lipids across 15 lipid classes in 70 TNBC tumors. Multivariate survival analysis found that higher levels of sphingomyelins were significantly associated with better disease-free survival in TNBC patients. Furthermore, analysis of publicly available gene expression datasets identified that decreased production of ceramides and increased accumulation of sphingoid base intermediates by metabolic enzymes were associated with better survival outcomes in TNBC patients. Our LC-MS lipidomics profiling of TNBC tumors has, for the first time, identified sphingomyelins as a potential prognostic marker and implicated enzymes involved in sphingolipid metabolism as candidate therapeutic targets that warrant further investigation. PMID- 30011846 TI - Modeling and Analysis of a Novel Ultrasensitive Differential Resonant Graphene Micro-Accelerometer with Wide Measurement Range. AB - A novel, ultrahigh-sensitivity wide-range resonant micro-accelerometer using two differential double-clamped monolayer graphene beams is designed and investigated by steady-state simulation via COMSOL Multiphysics software in this paper. Along with stiffness-enhanced optimized folded support beams, two symmetrical 3-GPa prestressed graphene nano-beams serve as resonant sensitive elements with a size of 10 MUm * 1 MUm (length * width) to increase the acceleration sensitivity while extending the measurement range. The simulation results show that the accelerometer with cascade-connected graphene and proof-mass assembly exhibits the ultrahigh sensitivity of 21,224 Hz/g and quality factor of 9773 in the range of 0-1000 g. This is remarkably superior to previously reported studies characterized by attaching proof mass to the graphene components directly. The proposed accelerometer shows great potential as an alternative to quartz and silicon-based resonant sensors in high-impact and highly sensitive inertial measurement applications. PMID- 30011845 TI - A Liquid Chromatography with Tandem Mass Spectrometry-Based Proteomic Analysis of Cells Cultured in DMEM 10% FBS and Chemically Defined Medium Using Human Adipose Derived Mesenchymal Stem Cells. AB - Human adipose-derived mesenchymal stem cells (hADSCs) are representative cell sources for cell therapy. Classically, Dulbecco's Modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) has been used as culture medium for hADSCs. A chemically defined medium (CDM) containing no heterologous animal components has recently been used to produce therapeutic hADSCs. However, how the culture environment using a medium without FBS affects the protein expression of hADSC is unclear. We subjected hADSCs cultured in CDM and DMEM (10% FBS) to a protein expression analysis by tandem mass spectrometry liquid chromatography and noted 98.2% agreement in the proteins expressed by the CDM and DMEM groups. We classified 761 proteins expressed in both groups by their function in a gene ontology analysis. Thirty-one groups of proteins were classified as growth related proteins in the CDM and DMEM groups, 16 were classified as antioxidant activity-related, 147 were classified as immune system process-related, 557 were involved in biological regulation, 493 were classified as metabolic process related, and 407 were classified as related to stimulus responses. These results show that the trend in the expression of major proteins related to the therapeutic effect of hADSCs correlated strongly in both groups. PMID- 30011847 TI - Estimation of Salt Intake Assessed by 24-Hour Urinary Sodium Excretion among Somali Adults in Oslo, Norway. AB - High dietary salt intake is associated with increased blood pressure (BP) and cardiovascular disease (CVD) risk. The migration of Somalis from East Africa to Norway may have altered their dietary habits, making them vulnerable to adverse health outcomes. Since little is known about the lifestyle and health status of this population, the purpose of our study was to estimate salt intake in Somali adults in Oslo, Norway. In this cross-sectional study, we included 161 Somali adults (76 men, 86 women) from the Sagene borough in Oslo, Norway. Sodium and potassium excretion was assessed through the collection of 24-hour urine. Creatinine-based exclusions were made to ensure completeness of urine collections. Sodium excretion corresponding to an estimated dietary salt intake of 8.66 +/- 3.33 g/24 h was found in men and 7.39 +/- 3.64 g/24 h in women (p = 0.013). An estimated 72% of participants consumed >5 g salt/day. The Na:K ratio was 2.5 +/- 1.2 in men and 2.4 +/- 1.1 in women (p = 0.665). In conclusion, estimated salt intake was, while above the WHO recommendation, within the lower range of estimated salt intakes globally and in Western Europe. Further research is required to assess the health benefits of sodium reduction in this Somali immigrant population. PMID- 30011849 TI - Single-Walled Carbon Nanotube (SWCNT) Loaded Porous Reticulated Vitreous Carbon (RVC) Electrodes Used in a Capacitive Deionization (CDI) Cell for Effective Desalination. AB - Acid-functionalized single-walled carbon nanotube (a-SWCNT)-coated reticulated vitreous carbon (RVC) composite electrodes have been prepared and the use of these electrodes in capacitive deionization (CDI) cells for water desalination has been the focus of this study. The performance of these electrodes was tested based on the applied voltage, flow rate, bias potential and a-SWCNT loadings, and then evaluated by electrosorption dynamics. The effect of the feed stream directly through the electrodes, between the electrodes, and the distance between the electrodes in the CDI system on the performance of the electrodes has been investigated. The interaction of ions with the electrodes was tested through Langmuir and Freundlich isotherm models. A new CDI cell was developed, which shows an increase of 23.96% in electrosorption capacity compared to the basic CDI cells. Moreover, a comparison of our results with the published results reveals that RVC/a-SWCNT electrodes produce 16 times more pure water compared to the ones produced using only CNT-based electrodes. Finally, it can be inferred that RVC/a SWCNT composite electrodes in newly-developed CDI cells can be effectively used in desalination technology for water purification. PMID- 30011848 TI - Role of mTOR in Glucose and Lipid Metabolism. AB - The mammalian target of rapamycin, mTOR is the master regulator of a cell's growth and metabolic state in response to nutrients, growth factors and many extracellular cues. Its dysregulation leads to a number of metabolic pathological conditions, including obesity and type 2 diabetes. Here, we review recent findings on the role of mTOR in major metabolic organs, such as adipose tissues, liver, muscle, pancreas and brain. And their potentials as the mTOR related pharmacological targets will be also discussed. PMID- 30011850 TI - Effects of Linalyl Acetate on Thymic Stromal Lymphopoietin Production in Mast Cells. AB - Thymic stromal lymphopoietin (TSLP) is an important factor responsible for the pathogenesis of allergic diseases, such as atopic dermatitis and asthma. Because linalyl acetate (LA) possesses a wide range of pharmacological properties, being antispasmodic, anti-inflammatory, and anti-hyperpigmentation, we hypothesized that LA could inhibit TSLP. Therefore, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, caspase-1 assay, Western blot analysis, fluorescent analyses of the intracellular calcium levels, and the phorbol myristate acetate (PMA)-induced edema model were used to investigate how LA inhibits the production of TSLP in HMC-1 cells. LA reduced the production and mRNA expression of TSLP in HMC-1 cells. LA also inhibited the activation of nuclear factor-kappaB and degradation of IkappaBalpha. PMA plus A23187 stimulation up-regulated caspase-1 activity in HMC-1 cells; however, this up regulated caspase-1 activity was down-regulated by LA. Finally, LA decreased intracellular calcium levels in HMC-1 cells as well as PMA-induced ear swelling responses in mice. Taken together, these results suggest that LA would be beneficial to treatment of atopic and inflammatory diseases by reducing TSLP. PMID- 30011854 TI - Nutrition Transition and Traditional Food Cultural Changes in Sri Lanka during Colonization and Post-Colonization. AB - Sri Lanka was a colony of the Portuguese, Dutch, and British. The simplification of Sri Lankan food culture can be seen most clearly today, including how the diet has been changed in the last 400 years since the colonial occupation began. Therefore, greater efforts must be made to uncover the colonial forces that have undermined food security and health in Sri Lanka. Also traditional eating habits, which are associated with countless health benefits, have been gradually replaced by the globalized food system of multinational corporations and hidden hunger, a system inherent in the emergence of non-communicable diseases, such as cancer, diabetes, cholesterol, and kidney disease epidemics, in Sri Lanka. This article discusses factors that have underpinned the dietary change in Sri Lanka from its early colonization to the post-colonization period. The research followed the integrated concept in ethnological and sociological study approaches. The study examined literature and conducted several interviews with field experts and senior people in marginal areas in Sri Lanka. This study examines the Sri Lankan traditional food system and how it changed after the colonial period, including the main changes and their impact on current micronutrient deficiencies and non communicable diseases. PMID- 30011852 TI - PPARgamma Controls Ectopic Adipogenesis and Cross-Talks with Myogenesis During Skeletal Muscle Regeneration. AB - Skeletal muscle is a regenerative tissue which can repair damaged myofibers through the activation of tissue-resident muscle stem cells (MuSCs). Many muscle diseases with impaired regeneration cause excessive adipose tissue accumulation in muscle, alter the myogenic fate of MuSCs, and deregulate the cross-talk between MuSCs and fibro/adipogenic progenitors (FAPs), a bi-potent cell population which supports myogenesis and controls intra-muscular fibrosis and adipocyte formation. In order to better characterize the interaction between adipogenesis and myogenesis, we studied muscle regeneration and MuSC function in whole body Pparg null mice generated by epiblast-specific Cre/lox deletion (PpargDelta/Delta). We demonstrate that deletion of PPARgamma completely abolishes ectopic muscle adipogenesis during regeneration and impairs MuSC expansion and myogenesis after injury. Ex vivo assays revealed that perturbed myogenesis in PpargDelta/Delta mice does not primarily result from intrinsic defects of MuSCs or from perturbed myogenic support from FAPs. The immune transition from a pro- to anti-inflammatory MuSC niche during regeneration is perturbed in PpargDelta/Delta mice and suggests that PPARgamma signaling in macrophages can interact with ectopic adipogenesis and influence muscle regeneration. Altogether, our study demonstrates that a PPARgamma-dependent adipogenic response regulates muscle fat infiltration during regeneration and that PPARgamma is required for MuSC function and efficient muscle repair. PMID- 30011853 TI - Anti-Osteoporotic Effects of Polysaccharides Isolated from Persimmon Leaves via Osteoclastogenesis Inhibition. AB - Persimmon (Diospyros kaki L.f.) leaves have traditionally been used as a phytomedicine, in health beverages to treat cardiovascular and respiratory disease and to promote maternal health in East Asia. In particular, polysaccharides from persimmon are known to have anti-coagulant, anti-oxidant, and immune-stimulatory activities. However, their beneficial effects against osteoporosis have not been reported. In the present study, we investigated the anti-osteoporotic effects of polysaccharides from persimmon leaves (PLE0) using an in vivo model of ovariectomy (OVX)-induced bone loss and an in vitro system of receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation. In the OVX mouse model, PLE0 remarkably improved OVX-induced trabecular bone loss by suppressing osteoclast activity. In primary bone marrow derived macrophages (BMMs), PLE0 dose-dependently inhibited osteoclast differentiation. In addition, PLE0 down-regulated RANKL-induced activation of mitogen-activated protein kinases (MAPKs) such as p38, ERK, and JNK resulting in suppression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression. Our results indicate that PLE0 has anti-osteoporotic effects in OVX induced bone loss via inhibition of osteoclast differentiation. Taken together, PLE0 from persimmon may prevent postmenopausal bone loss and osteoporotic bone fragility. PMID- 30011855 TI - Evolutionary Divergent Suppressor Mutations in Conformational Diseases. AB - Neutral and adaptive mutations are key players in the evolutionary dynamics of proteins at molecular, cellular and organismal levels. Conversely, largely destabilizing mutations are rarely tolerated by evolution, although their occurrence in diverse human populations has important roles in the pathogenesis of conformational diseases. We have recently proposed that divergence at certain sites from the consensus (amino acid) state during mammalian evolution may have rendered some human proteins more vulnerable towards disease-associated mutations, primarily by decreasing their conformational stability. We herein extend and refine this hypothesis discussing results from phylogenetic and structural analyses, structure-based energy calculations and structure-function studies at molecular and cellular levels. As proof-of-principle, we focus on different mammalian orthologues of the NQO1 (NAD(P)H:quinone oxidoreductase 1) and AGT (alanine:glyoxylate aminotransferase) proteins. We discuss the different loss-of-function pathogenic mechanisms associated with diseases involving the two enzymes, including enzyme inactivation, accelerated degradation, intracellular mistargeting, and aggregation. Last, we take into account the potentially higher robustness of mammalian orthologues containing certain consensus amino acids as suppressors of human disease, and their relation with different intracellular post-translational modifications and protein quality control capacities, to be discussed as sources of phenotypic variability between human and mammalian models of disease and as tools for improving current therapeutic approaches. PMID- 30011851 TI - Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development. AB - During the last decade there has been a growing interest in glycoimmunology, a relatively new research field dealing with the specific interactions of carbohydrates with the immune system. Pathogens' cell surfaces are covered by a thick layer of oligo- and polysaccharides that are crucial virulence factors, as they mediate receptors binding on host cells for initial adhesion and organism invasion. Since in most cases these saccharide structures are uniquely exposed on the pathogen surface, they represent attractive targets for vaccine design. Polysaccharides isolated from cell walls of microorganisms and chemically conjugated to immunogenic proteins have been used as antigens for vaccine development for a range of infectious diseases. However, several challenges are associated with carbohydrate antigens purified from natural sources, such as their difficult characterization and heterogeneous composition. Consequently, glycoconjugates with chemically well-defined structures, that are able to confer highly reproducible biological properties and a better safety profile, are at the forefront of vaccine development. Following on from our previous review on the subject, in the present account we specifically focus on the most recent advances in the synthesis and preliminary immunological evaluation of next generation glycoconjugate vaccines designed to target bacterial and fungal infections that have been reported in the literature since 2011. PMID- 30011857 TI - Variation Trends of Fine Particulate Matter Concentration in Wuhan City from 2013 to 2017. AB - Fine particulate matter (PM2.5) is directly associated with smog and has become the primary factor that threatens air quality in China. In order to investigate the variation patterns of PM2.5 concentrations in various regions of Wuhan city across different time spans, we analyzed continuous monitoring data from six monitoring sites in Wuhan city from 2013 to 2017. The results showed that the PM2.5 concentration from the various monitoring sites in the five-year period showed a decreasing trend. January, October, and December are the three months with relatively high mean monthly PM2.5 concentrations in the year, while June, July, and August are the three months with relatively low mean monthly PM2.5 concentrations in the year. The number of days with a daily mean concentration of 35-75 MUg/m3 was the highest, while the number of days with a daily mean concentration of more than 250 MUg/m3 was the lowest. PM2.5 accounted for a large proportion of the major pollutants and is the main source of air pollution in Wuhan city, with an average proportion of over 46%. PMID- 30011856 TI - Facile Preparation of N-Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities. AB - According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N-Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC50 values of 0.58-0.87 nM against different strains of Plasmodium falciparum (Pf) and selectivity indices (SI) >195, on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC50 0.9-1.1 nM). Notably, the D-glucose, D maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC50 values of 0.78-0.87 uM and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 uM, and a SI of 88 with the same cell lines. Overall, the N glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O-glycosides previously obtained from DHA. PMID- 30011858 TI - Differential Roles of Tumor Necrosis Factor Ligand Superfamily Members as Biomarkers in Pancreatic Cancer. AB - The tumor necrosis factor-related weak inducer of apoptosis (TWEAK) belongs to the tumor necrosis factor ligand superfamily, which was shown to play an important role in inflammatory and malignant gastrointestinal diseases, including colitis or colorectal cancer. However, in contrast to other members of the TNF ligand superfamily, its role as a biomarker in pancreatic cancer is currently unknown. We analyzed serum levels of A proliferation-inducing ligand (APRIL) and TWEAK in 134 patients with pancreatic cancer. Results were compared with 50 healthy controls and correlated with clinical data. Intratumoral expression of APRIL and TWEAK in pancreatic cancer was analysed using the datasets made available by the TCGA-LIHC project. APRIL serum levels were significantly elevated in patients with pancreatic cancer compared to healthy controls, which is in line with previous findings. Notably, the diagnostic accuracy of circulating APRIL levels was similar to CA19-9, an established tumor marker for pancreatic cancer. In contrast, serum concentrations of TWEAK were decreased in pancreatic cancer patients. Interestingly, no differences in TWEAK concentrations became apparent between different clinical subgroups of pancreatic cancer. Moreover, within our cohort of patients, TWEAK levels did not correlate with the patients' prognosis and the diagnostic as well as prognostic potential of TWEAK was lower than CA 19-9, when analyzed in this setting. Finally, using data from the TCGA-LIHC project, we demonstrate that expression levels of TWEAK and APRIL represent prognostic markers for patients' survival according to Kaplan-Meier curve analyses. TWEAK and APRIL serum concentrations are regulated differently in patients with pancreatic cancer, highlighting diverse roles of variant TNF ligands in this type of cancer. PMID- 30011859 TI - A Combined Approach of NMR and Mass Spectrometry Techniques Applied to the alpha Cyclodextrin/Moringin Complex for a Novel Bioactive Formulation ?. AB - Moringin, obtained via enzymatic conversion of the glucosinolate precursor glucomoringin, is an uncommon member of the isothiocyanate class, and has been proven to possess a broad range of biological activities such as antitumor activity, protection against neurodegenerative disorders and bactericidal effects. Since moringin is weakly soluble in water and unstable in aqueous medium, cyclodextrins (CDs) were considered for the development of a new moringin formulation, with a view to improving its solubility and stability in aqueous solution for use as an anti-inflammatory. A combined structural study using proton nuclear magnetic resonance (1H-NMR), diffusion-ordered spectroscopy (DOSY) and ion mobility mass spectrometry (IM-MS) is reported, highlighting the formation of a 1:1 alpha-CD/moringin inclusion complex. The association constant K was determined (1300 M-1 at 300 K). Completion of the structural characterization was performed by T-ROESY and MS/MS experiments, which evidenced the mode of penetration of moringin into alpha-CD. Finally, the "chaperone-like" properties of alpha-CD with respect to the stability of moringin have been highlighted. PMID- 30011860 TI - Potential Impact of COMT-rs4680 G > A Gene Polymorphism in Coronary Artery Disease. AB - Purpose: Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 G > A or Val108 > 158Met or rs4680 G > A influences COMT enzyme activity. The three phenotypes of the COMT enzyme activities include COMT A/A with low enzyme activity, COMT A/G with medium enzyme activity and COMT G/G with high enzyme activity. The Met allele is associated with low enzymatic activity resulting in higher levels of prefrontal dopamine. Conversely, the Val allele is associated with high enzymatic activity and lower levels of prefrontal dopamine. The Met allele has been associated with several psychiatric disorders such as panic disorder. Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and coronary artery diseases risk, but the results are inconclusive. Therefore our study was aimed to explore the association between COMT Val158Met polymorphism and the risk of coronary artery disease in India. Methology: This study was conducted on 100 clinically confirmed cases of coronary artery diseases and 100 healthy controls. COMT Val158Met genotyping was performed by allele-specific polymerase chain reaction (AS-PCR). Results: A significant correlation was observed in the COMT Val158Met genotype distribution between the coronary artery disease cases and healthy controls (p = 0.008). The frequencies of all three genotypes, GG, GA, AA, reported in the CAD patients were 10%, 70%, and 20%, and 30%, 60%, and 10% in the healthy controls respectively. An increased risk of coronary artery disease was observed in the codominant inheritance model for COMT-GA vs. GG genotype with an OR of 3.5, 95% CI (1.58-7.74) p = 0.002) and COMT-AA vs. GG genotype with an OR of 6.0 95% CI (2.11-17.3) p = 0.003). The higher risk of coronary artery disease was observed in the dominant inheritance model for COMT (GA + AA) vs. GG genotype (OR 3.85, 95% CI 1.76-8.4, p < 0.007), whereas a non-significant association was found in recessive model for COMT (GG + GA vs. AA) (OR = 2.01, 95% CI (0.86-4.7) p = 0.72). The results indicated that A allele significantly increased the risk of coronary artery disease compared to the G allele (OR = 1.8, 95% CI (1.20-2.67) p = 0.004). COMT Val158Met polymorphism leads to a 6.0, 3.5 and 1.8-fold increased risk of developing coronary artery disease in the Indian population and providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusions: It is concluded that COMT-AA genotype and A allele are significantly associated with an increased susceptibility to coronary artery disease in Indian population. A larger sample size can be the key to progress in establishing the genetic co-relationship of COMT polymorphism and cardiovascular disease. PMID- 30011862 TI - Effects of Applying Different Resonance Amplitude on the Performance of the Impedance-Based Health Monitoring Technique Subjected to Damage. AB - Smart materials such as piezoelectric transducers can be used for monitoring the health of building structures. In this study, a structural health monitoring technique known as the electromechanical impedance (EMI) method is investigated. Although the EMI method has the advantage of using a single piezoelectric patch that acts both as the actuator and as the sensor, there are still many issues to be addressed. To further understand the problem, the performance of the EMI method on a structure subjected to progressive damage at different resonance frequency ranges and peak amplitudes was investigated using three different statistical metrics: root-mean-square deviation (RMSD), mean absolute percentage deviation (MAPD) and correlation coefficient deviation (CCD). Metal plates were used throughout the study. The results acquired could be used to further understand the damage identification performance of the EMI method. PMID- 30011861 TI - Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women. AB - Vitamin D (VD) deficiency is associated with reproductive failure. However, the relationship between VD and maternal immunity remains unclear. We investigated the clinical efficacy of VD in maternal T-helper (Th) cytokines in 276 infertile women and examined for Th1 and Th2 cells based on the deficient, insufficient, and sufficient serum 25-hydroxyvitamin D3 (25[OH]VD) levels (<12, 12-30, and >30 ng/mL, respectively). Most infertile women had a low-level of VD (87.3%). Immunological tests of pre-/post-VD supplementation were performed in patients who were deficient and insufficient in VD. Of 23 patients, 11 (47.8%) exhibited sufficient VD levels after supplementation. Th1/Th2 cell ratio in patients with insufficient VD was significantly decreased after supplementation (p = 0.004). After supplementation, serum 25(OH)VD levels of the patients: 11 in the sufficient group showed significant decreases in Th1 cell level and Th1/Th2 cell ratio (p = 0.032 and 0.010, respectively), whereas no significant differences in Th1/Th2 cell ratio were recognized in the insufficient group. Furthermore, mid luteal endometrial biopsies (n = 18) were processed for primary cultures and measured interferon [IFN]-gamma and interleukin [IL]-4 in condition media. Decidualizing cultures with 1,25-dihydroxvitamin D3 (1,25[OH]2VD) decreased IFN gamma. Sufficient VD supplementation in women with insufficient VD may optimize maternal T-helper cytokines during pregnancy via rebalancing the Th1/Th2 cell ratio. PMID- 30011863 TI - Model-Based Position and Reflectivity Estimation of Fiber Bragg Grating Sensor Arrays. AB - We propose an efficient model-based signal processing approach for optical fiber sensing with fiber Bragg grating (FBG) arrays. A position estimation based on an estimation of distribution algorithm (EDA) and a reflectivity estimation method using a parametric transfer matrix model (TMM) are outlined in detail. The estimation algorithms are evaluated with Monte Carlo simulations and measurement data from an incoherent optical frequency domain reflectometer (iOFDR). The model based approach outperforms conventional Fourier transform processing, especially near the spatial resolution limit, saving electrical bandwidth and measurement time. The models provide great flexibility and can be easily expanded in complexity to meet different topologies and to include prior knowledge of the sensors. Systematic errors due to crosstalk between gratings caused by multiple reflections and spectral shadowing could be further considered with the TMM to improve the performance of large-scale FBG array sensor systems. PMID- 30011864 TI - Application of Flexible Four-In-One Microsensor to Internal Real-Time Monitoring of Proton Exchange Membrane Fuel Cell. AB - In recent years, the development of green energy sources, such as fuel cell, biomass energy, solar energy, and tidal energy, has become a popular research subject. This study aims at a flexible four-in-one microsensor, which can be embedded in the proton exchange membrane fuel cell (PEMFC) for real-time microscopic diagnosis so as to assist in developing and improving the technology of the fuel cell. Therefore, this study uses micro-electro-mechanical systems (MEMS) technology to integrate a micro humidity sensor, micro pH sensor, micro temperature sensor, and micro voltage sensor into a flexible four-in-one microsensor. This flexible four-in-one microsensor has four functions and is favorably characterized by small size, good acid resistance and temperature resistance, quick response, and real-time measurement. The goal was to be able to put the four-in-one microsensor in any place for measurement without affecting the performance of the fuel cell. PMID- 30011865 TI - Evaluating Geometric Measurement Accuracy Based on 3D Reconstruction of Automated Imagery in a Greenhouse. AB - Geometric dimensions of plants are significant parameters for showing plant dynamic responses to environmental variations. An image-based high-throughput phenotyping platform was developed to automatically measure geometric dimensions of plants in a greenhouse. The goal of this paper was to evaluate the accuracy in geometric measurement using the Structure from Motion (SfM) method from images acquired using the automated image-based platform. Images of nine artificial objects of different shapes were taken under 17 combinations of three different overlaps in x and y directions, respectively, and two different spatial resolutions (SRs) with three replicates. Dimensions in x, y and z of these objects were measured from 3D models reconstructed using the SfM method to evaluate the geometric accuracy. A metric power of unit (POU) was proposed to combine the effects of image overlap and SR. Results showed that measurement error of dimension in z is the least affected by overlap and SR among the three dimensions and measurement error of dimensions in x and y increased following a power function with the decrease of POU (R2 = 0.78 and 0.88 for x and y respectively). POUs from 150 to 300 are a preferred range to obtain reasonable accuracy and efficiency for the developed image-based high-throughput phenotyping system. As a study case, the developed system was used to measure the height of 44 plants using an optimal POU in greenhouse environment. The results showed a good agreement (R2 = 92% and Root Mean Square Error = 9.4 mm) between the manual and automated method. PMID- 30011867 TI - Inversion of Rice Biophysical Parameters Using Simulated Compact Polarimetric SAR C-Band Data. AB - Timely and accurate estimation of rice parameters plays a significant role in rice monitoring and yield forecasting for ensuring food security. Compact polarimetric (CP) synthetic aperture radar (SAR), a good compromise between the dual- and quad-polarized SARs, is an important part of the new generation of Earth observation systems. In this paper, the ability of CP SAR data to retrieve rice biophysical parameters was explored using a modified water cloud model. The results showed that S1 was superior to other CP variables in rice height inversion with a coefficient of determination (R2) of 0.92 and a root-mean-square error (RMSE) of 5.81 cm. RL was the most suitable for inverting the volumetric water content of the rice canopy, with an R2 of 0.95 and a RMSE of 0.31 kg/m3. The m-chi decomposition produced the highest accuracies for the ear biomass: R2 was 0.89 and RMSE was 0.17 kg/m2. The highest accuracy of leaf area index (LAI) retrieval was obtained for RH (right circular transmit and horizontal linear receive) with an R2 of 0.79 and a RMSE of 0.33. This study illustrated the capability of CP SAR data with respect to retrieval of rice biophysical parameters, especially for height, volumetric water content of the rice canopy, and ear biomass, and this mode may offer the best option for rice-monitoring applications because of swath coverage. PMID- 30011866 TI - Printable Nanomaterials for the Fabrication of High-Performance Supercapacitors. AB - In recent years, supercapacitors are attracting great attention as one kind of electrochemical energy storage device, which have a high power density, a high energy density, fast charging and discharging, and a long cycle life. As a solution processing method, printing technology is widely used to fabricate supercapacitors. Printable nanomaterials are critical to the fabrication of high performance supercapacitors by printing technology. In this work, the advantages of printing technology are summarized. Moreover, various nanomaterials used to fabricate supercapacitors by printing technology are presented. Finally, the remaining challenges and broad research as well as application prospects in printing high-performance supercapacitors with nanomaterials are proposed. PMID- 30011868 TI - Design, Development and FE Thermal Analysis of a Radially Grooved Brake Disc Developed through Direct Metal Laser Sintering. AB - The present research work analyzed the effect of design modification with radial grooves on disc brake performance and its thermal behavior by using additive manufacturing based 3D printed material maraging steel. Temperature distribution across the disc surface was estimated with different boundary conditions such as rotor speed, braking pressure, and braking time. Design modification and number of radial grooves were decided based on existing dimensions. Radial grooves were incorporated on disc surface through Direct Metal Laser Sintering (DMLS) process to increase surface area for maximum heat dissipation and reduce the stresses induced during braking process. The radial grooves act as a cooling channels which provides an effective means of cooling the disc surface which is under severe condition of sudden fall and rise of temperatures during running conditions. ANSYS software is used for transient structural and thermal analysis to investigate the variations in temperatures profile across the disc with induced heat flux. FE based thermo-structural analysis was done to determine thermal strains induced in disc due to sudden temperature fluctuations. The maximum temperature and Von Mises stress in disc brake without grooves on disc surface were observed which can severely affect thermal fatigue and rupture brake disc surface. It was been observed by incorporating the radial grooves that the disc brake surface is thermally stable. Experimental results are in good agreement with FE thermal analysis. DMLS provides easy fabrication of disc brake with radial grooves and enhancement of disc brake performance at higher speeds and temperatures. Therefore, DMLS provides an effective means of implementing product development technology. PMID- 30011869 TI - An Occlusion-Robust Feature Selection Framework in Pedestrian Detection ?. AB - Better features have been driving the progress of pedestrian detection over the past years. However, as features become richer and higher dimensional, noise and redundancy in the feature sets become bigger problems. These problems slow down learning and can even reduce the performance of the learned model. Current solutions typically exploit dimension reduction techniques. In this paper, we propose a simple but effective feature selection framework for pedestrian detection. Moreover, we introduce occluded pedestrian samples into the training process and combine it with a new feature selection criterion, which enables improved performances for occlusion handling problems. Experimental results on the Caltech Pedestrian dataset demonstrate the efficiency of our method over the state-of-art methods, especially for the occluded pedestrians. PMID- 30011872 TI - Mouthwitch: A Novel Head Mount Type Hands-Free Input Device that Uses the Movement of the Temple to Control a Camera. AB - We have developed an interface (mouthwitch) for a head-mounted type camera with which pictures can be taken with a head-mounted camera, hands-free, simply by "opening your mouth continuously for approximately one second and then closing it again". This mouthwitch uses a sensor equipped with an LED and photo transistor on the temple to optically measure the changes in the form of the temple that occur when the mouth is opened and closed. Eight test subjects (males and females aged between 21 and 44 years old) performed evaluation tests using this mouthwitch when resting, speaking, chewing, walking, and running. The results showed that all test subjects were able to open and close the mouth, and the measurement results pertaining to the temple shape changes that occurred at this time were highly reproducible. Additionally, the average value for accuracy obtained for the eight test subjects through the verification tests was 100% when resting, chewing, or walking, and 99.8% when speaking or running. Similarly, the average values for precision were 100% for all items, and the average values for recall were 100% when resting or chewing, 98.8% when speaking, 97.5% when walking, and 87.5% when running. PMID- 30011871 TI - Convenient Method of Synthesizing Aryloxyalkyl Esters from Phenolic Esters Using Halogenated Alcohols. AB - A facile one-pot synthetic method of building aryloxyalkyl esters was developed using various types of phenolic esters with halogenated alcohols. The ready availability of both starting materials, coupled with the required simple experimental technique, enables the current synthetic method of producing aryloxyalkyl esters in a fast and efficient way. It is noteworthy that acyl transfer was demonstrated in this reaction. PMID- 30011870 TI - Clinical Assessment of Dental Implant Stability During Follow-Up: What Is Actually Measured, and Perspectives. AB - The optimization of loading protocols following dental implant insertion requires setting up patient-specific protocols, customized according to the actual implant osseointegration, measured through quantitative, objective methods. Various devices for the assessment of implant stability as an indirect measure of implant osseointegration have been developed. They are analyzed here, introducing the respective physical models, outlining major advantages and critical aspects, and reporting their clinical performance. A careful discussion of underlying hypotheses is finally reported, as is a suggestion for further development of instrumentation and signal analysis. PMID- 30011873 TI - Review of Short-Form Questions for the Evaluation of a Diet, Physical Activity, and Sedentary Behaviour Intervention in a Community Program Targeting Vulnerable Australian Children. AB - Childhood obesity is associated with low socioeconomic status in developed countries, and community programs can deliver cost-effective obesity interventions to vulnerable children and adolescents at scale. Evaluating these programs in a low-cost, time-efficient, and culturally appropriate way with valid and reliable measures is essential to determining their effectiveness. We aimed to identify existing valid and reliable short-form instruments (<=50 items for diet, <=15 items for physical activity) suitable for the assessment of change in diet, physical activity, and sedentary behaviour in an Australian obesity intervention program for children and adolescents aged 7-13 years from low socioeconomic groups, with a focus on Aboriginal and Torres Strait Islander children. Relevant electronic databases were searched, with a focus on Australian literature. Validity and/or reliability studies using diet instruments (5), physical activity/sedentary behaviour instruments (12), and diet and physical activity/sedentary behaviour instruments used with Aboriginal and Torres Strait Islander (3) children were identified. Seven questions on diet, one question on physical activity, and no questions on sedentary behaviour were recommended. These questions can be used for evaluation in community-based obesity programs among Australian children and adolescents, including those from low socioeconomic groups and Aboriginal and Torres Strait Islander children. PMID- 30011874 TI - Uncertainty Characterisation of Mobile Robot Localisation Techniques using Optical Surveying Grade Instruments. AB - Recent developments in localisation systems for autonomous robotic technology have been a driving factor in the deployment of robots in a wide variety of environments. Estimating sensor measurement noise is an essential factor when producing uncertainty models for state-of-the-art robotic positioning systems. In this paper, a surveying grade optical instrument in the form of a Trimble S7 Robotic Total Station is utilised to dynamically characterise the error of positioning sensors of a ground based unmanned robot. The error characteristics are used as inputs into the construction of a Localisation Extended Kalman Filter which fuses Pozyx Ultra-wideband range measurements with odometry to obtain an optimal position estimation, all whilst using the path generated from the remote tracking feature of the Robotic Total Station as a ground truth metric. Experiments show that the proposed method yields an improved positional estimation compared to the Pozyx systems' native firmware algorithm as well as producing a smoother trajectory. PMID- 30011876 TI - Wireless Chipless System for Humidity Sensing. AB - This work describes a fully wireless sensory system where a chipless strategy is followed in the sensor part. Alternatively, to characterize only the sensing element, we present the response of the reader antenna when the sensing element is placed in its vicinity: changes in the parameter of interest are seen by the reader through inductive coupling, varying its frequency response. The sensing part consists of a LC circuit manufactured by printing techniques on a flexible substrate, whose electrical permittivity shows dependence with the moisture content. The measurement distance show significant differences in the frequency response: a change of 700 kHz is observed when the measurement is performed directly on the wireless chipless sensor between 20% and 80%RH, while this variation in frequency is reduced more than three times when measuring at the reader antenna with 5 mm distance between elements. Furthermore, we demonstrate the importance of the separation between reader and sensor to get a reliable measuring system. PMID- 30011875 TI - Mucins and Truncated O-Glycans Unveil Phenotypic Discrepancies between Serous Ovarian Cancer Cell Lines and Primary Tumours. AB - Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer. PMID- 30011877 TI - How Does Low Socioeconomic Status Increase Blood Lead Levelsin KoreanChildren? AB - Although studies have shown that a low socioeconomic status (SES) is associated with high blood lead levels (BLLs) in children, the mechanism underlying this observation is not well known. To determine how SES influences BLLs via environmental factors in Korean children, we conducted a population-based cross sectional study of 4744 children aged 5-13 years. Questionnaires on sociodemographic information, environmental factors, and food consumption were administered to the children's parents. BLLs in the study subjects were measured.The complete set of hypothesized associations was assessed using regression analysis and structural equation modeling. SES was associated with high BLLs. The total effects of nutritional factors, lead in the air and total length of nearby roads, and agriculture on BLLs were -0.062 (p < 0.001), 0.068 (p = 0.005), and 0.038 (p = 0.035), respectively. The direct effects of playing outdoors and SES on BLLs were 0.113 (p < 0.001) and -0.111 (p < 0.001), respectively. Although playing outdoors had a greater direct effect on BLLs than did SES, the total effect of SES (standardized beta = -0.132, p < 0.001) was greater than that of other sources owing to indirect effects (beta = -0.020, p = 0.004). A low SES was a major risk factor for elevated BLLs via environmental factors. PMID- 30011878 TI - Harmonizing Outcomes for Genomic Medicine: Comparison of eMERGE Outcomes to ClinGen Outcome/Intervention Pairs. AB - Genomic medicine is moving from research to the clinic. There is a lack of evidence about the impact of genomic medicine interventions on health outcomes. This is due in part to a lack of standardized outcome measures that can be used across different programs to evaluate the impact of interventions targeted to specific genetic conditions. The eMERGE Outcomes working group (OWG) developed measures to collect information on outcomes following the return of genomic results to participants for several genetic disorders. These outcomes were compared to outcome intervention pairs for genetic disorders developed independently by the ClinGen Actionability working group (AWG). In general, there was concordance between the defined outcomes between the two groups. The ClinGen outcomes tended to be from a higher level and the AWG scored outcomes represented a subset of outcomes referenced in the accompanying AWG evidence review. eMERGE OWG outcomes were more detailed and discrete, facilitating a collection of relevant information from the health records. This paper demonstrates that common outcomes for genomic medicine interventions can be identified. Further work is needed to standardize outcomes across genomic medicine implementation projects and to make these publicly available to enhance dissemination and assist in making precision public health a reality. PMID- 30011879 TI - Identification of Long Non-Coding RNAs Related to Skeletal Muscle Development in Two Rabbit Breeds with Different Growth Rate. AB - Skeletal muscle development plays an important role in muscle quality and yield, which decides the economic value of livestock. Long non-coding RNAs (lncRNAs) have been reported to be associated with skeletal muscle development. However, little is revealed about the function of lncRNAs in rabbits' muscle development. LncRNAs and mRNAs in two rabbit breeds (ZIKA rabbits (ZKR) and Qixin rabbits (QXR)) with different growth rates at three developmental stages (0 day, 35 days, and 84 days after birth) were researched by transcriptome sequencing. Differentially expressed lncRNAs and mRNAs were identified for two rabbit breeds at the same stages by DESeq package. Co-expression correlation analysis of differentially expressed lncRNAs and mRNAs were performed to construct lncRNA mRNA pairs. To explore the function of lncRNAs, Gene Ontology (GO) analysis of co expression mRNAs in lncRNA-mRNA pairs were performed. In three comparisons, there were 128, 109, and 115 differentially expressed lncRNAs, respectively. LncRNAs TCONS_00013557 and XR_518424.2 differentially expressed in the two rabbit breeds might play important roles in skeletal muscle development, for their co-expressed mRNAs were significantly enriched in skeletal muscle development related GO terms. This study provides potentially functional lncRNAs in skeletal muscle development of two rabbit breeds and might be beneficial to the production of rabbits. PMID- 30011880 TI - Inhibitory Effect of PgAFP and Protective Cultures on Aspergillus parasiticus Growth and Aflatoxins Production on Dry-Fermented Sausage and Cheese. AB - Aflatoxigenic molds can grow and produce aflatoxins on dry-fermented meat and cheese. The small, basic, cysteine-rich antifungal protein PgAFP displays a time limited inhibitory ability against unwanted molds by increasing reactive oxygen species (ROS), which can lead to increased aflatoxin production. However, calcium abolishes the inhibitory effect of PgAFP on certain Aspergillus spp. To maximize the antifungal effect, this protein may be combined with protective cultures. Yeasts and lactic acid bacteria may counteract the impact of calcium on PgAFP fungal inhibition. The objective of this work was to study the effect of PgAFP and different combined treatments with Debaryomyces hansenii and/or Pediococcus acidilactici against growth of and aflatoxin production by an aflatoxigenic strain of Aspergillus parasiticus in both culture media and dry-fermented foods with low or high calcium levels. Aflatoxins production was increased by PgAFP but dramatically reduced by P. acidilactici in low calcium culture medium, whereas in the Ca-enriched culture medium, all treatments tested led to low aflatoxins levels. To study whether PgAFP and the protective microorganisms interfere with ROS and aflatoxin production, the relative expression of genes foxA, which is involved in peroxisomal beta-oxidation, and aflP, which is required for aflatoxin biosynthesis, were evaluated. The aflatoxin overproduction induced by PgAFP seems not to be linked to peroxisomal beta-oxidation. The combination of PgAFP and D. hansenii provided a successful inhibitory effect on A. parasiticus growth as well as on aflatoxin production on sliced dry-fermented sausage and cheese ripened up to 15 days, whereas P. acidilactici did not further enhance the protective effect of the two former agents. Therefore, the combined treatment of PgAFP and D. hansenii seems to provide a promising protective mean against aflatoxin-producing A. parasiticus on dry-fermented foods. PMID- 30011881 TI - Spontaneous Shape Alteration and Size Separation of Surfactant-Free Silver Particles Synthesized by Laser Ablation in Acetone during Long-Period Storage. AB - The technique of laser ablation in liquids (LAL) has already demonstrated its flexibility and capability for the synthesis of a large variety of surfactant free nanomaterials with a high purity. However, high purity can cause trouble for nanomaterial synthesis, because active high-purity particles can spontaneously grow into different nanocrystals, which makes it difficult to accurately tailor the size and shape of the synthesized nanomaterials. Therefore, a series of questions arise with regards to whether particle growth occurs during colloid storage, how large the particle size increases to, and into which shape the particles evolve. To obtain answers to these questions, here, Ag particles that are synthesized by femtosecond (fs) laser ablation of Ag in acetone are used as precursors to witness the spontaneous growth behavior of the LAL-generated surfactant-free Ag dots (2-10 nm) into different polygonal particles (5-50 nm), and the spontaneous size separation phenomenon by the carbon-encapsulation induced precipitation of large particles, after six months of colloid storage. The colloids obtained by LAL at a higher power (600 mW) possess a greater ability and higher efficiency to yield colloids with sizes of <40 nm than the colloids obtained at lower power (300 mW), because of the generation of a larger amount of carbon 'captors' by the decomposition of acetone and the stronger particle fragmentation. Both the size increase and the shape alteration lead to a redshift of the surface plasmon resonance (SPR) band of the Ag colloid from 404 nm to 414 nm, after storage. The Fourier transform infrared spectroscopy (FTIR) analysis shows that the Ag particles are conjugated with COO- and OH- groups, both of which may lead to the growth of polygonal particles. The CO and CO2 molecules are adsorbed on the particle surfaces to form Ag(CO)x and Ag(CO2)x complexes. Complementary nanosecond LAL experiments confirmed that the particle growth was inherent to LAL in acetone, and independent of pulse duration, although some differences in the final particle sizes were observed. The nanosecond-LAL yields monomodal colloids, whereas the size-separated, initially bimodal colloids from the fs-LAL provide a higher fraction of very small particles that are <5 nm. The spontaneous growth of the LAL-generated metallic particles presented in this work should arouse the special attention of academia, especially regarding the detailed discussion on how long the colloids can be preserved for particle characterization and applications, without causing a mismatch between the colloid properties and their performance. The spontaneous size separation phenomenon may help researchers to realize a more reproducible synthesis for small metallic colloids, without concern for the generation of large particles. PMID- 30011883 TI - Low-Temperature Superplasticity and Deformation Mechanism of Ti-6Al-4V Alloy. AB - The low-temperature superplastic tensile behavior and the deformation mechanisms of Ti-6Al-4V alloy are investigated in this paper. Through the experiments carried out, elongation to failure (delta) is calculated and a set of values are derived that subsequently includes the strain rate sensitivity exponent (m), deformation activation energy (Q) at low-temperature superplastic deformation, and the variation of delta, m and Q at different strain rates and temperatures. Microstructures are observed before and after superplastic deformation. The deformation mechanism maps incorporating the density of dislocations inside grains at temperatures of 973 and 1123 K are drawn respectively. By applying the elevated temperature deformation mechanism maps based on Burgers vector compensated grain size and modulus compensated stress, the dislocation quantities and low-temperature superplastic deformation mechanisms of Ti-6Al-4V alloy at different temperatures within appropriate processing regime are elucidated. PMID- 30011884 TI - Parameter Estimation of Signal-Dependent Random Noise in CMOS/CCD Image Sensor Based on Numerical Characteristic of Mixed Poisson Noise Samples. AB - Parameter estimation of Poisson-Gaussian signal-dependent random noise in the complementary metal-oxide semiconductor/charge-coupled device image sensor is a significant step in eliminating noise. The existing estimation algorithms, which are based on finding homogeneous regions, acquire the pair of the variances of noise and the intensities of every homogeneous region to fit the linear or piecewise linear curve and ascertain the noise parameters accordingly. In contrast to the existing algorithms, in this study, the Poisson noise samples of all homogeneous regions in every block image are pieced together to constitute a larger sample following the mixed Poisson noise distribution; then, the mean and variance of the mixed Poisson noise sample are deduced. Next, the mapping function among the noise parameters to be estimated-variance of Poisson-Gaussian noise and that of Gaussian noise corresponding to the stitched region in every block image-is constructed. Finally, the unbiased estimations of noise parameters are calculated from the mapping functions of all the image blocks. The experimental results confirm that the proposed method can obtain lower mean absolute error values of estimated noise parameters than the conventional ones. PMID- 30011882 TI - Computational Methodologies in the Exploration of Marine Natural Product Leads. AB - Computational methodologies are assisting the exploration of marine natural products (MNPs) to make the discovery of new leads more efficient, to repurpose known MNPs, to target new metabolites on the basis of genome analysis, to reveal mechanisms of action, and to optimize leads. In silico efforts in drug discovery of NPs have mainly focused on two tasks: dereplication and prediction of bioactivities. The exploration of new chemical spaces and the application of predicted spectral data must be included in new approaches to select species, extracts, and growth conditions with maximum probabilities of medicinal chemistry novelty. In this review, the most relevant current computational dereplication methodologies are highlighted. Structure-based (SB) and ligand-based (LB) chemoinformatics approaches have become essential tools for the virtual screening of NPs either in small datasets of isolated compounds or in large-scale databases. The most common LB techniques include Quantitative Structure-Activity Relationships (QSAR), estimation of drug likeness, prediction of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, similarity searching, and pharmacophore identification. Analogously, molecular dynamics, docking and binding cavity analysis have been used in SB approaches. Their significance and achievements are the main focus of this review. PMID- 30011885 TI - Pharmacokinetic Comparisons of Multiple Triterpenic Acids from Jujubae Fructus Extract Following Oral Delivery in Normal and Acute Liver Injury Rats. AB - Jujubae Fructus, the dried fruit of Ziziphus jujuba, has been used as Chinese medicine and food for centuries. Triterpenic acids have been found to be the major bioactive constituents in Jujubae Fructus responsible for their hepatoprotective activity in previous phytochemical and biological studies, while few pharmacokinetic studies have been conducted. To reveal the kinetics of the triterpenic acids under the pathological liver injury state, an established ultra performance liquid chromatography coupled with a mass spectrometry method was applied for the simultaneous quantitation of seven triterpenic acids (ceanothic acid, epiceanothic acid, pomonic acid, alphitolic acid, maslinic acid, betulinic acid, and betulonic acid) in plasma samples of normal and acute liver injury rats induced by CCl4. The results showed that there were significant differences (p < 0.05) in the pharmacokinetic parameters of seven triterpenic acids between model and normal groups. The AUC0-t and AUC0-infinity of epiceanothic acid (5227 +/- 334 MUg⋅h/L vs. 1478 +/- 255 MUg ? h/L and 6127 +/- 423 MUg ? h/L vs. 1482 +/- 255 MUg ? h/L, respectively) and pomonic acid (4654 +/- 349 MUg ? h/L vs. 1834 +/- 225 MUg ? h/L and 4776 +/- 322 MUg ? h/L vs. 1859 +/- 230 MUg ? h/L, respectively) in model rats were significantly higher than those in normal rats, and the CLz/F of them were significantly decreased (0.28 +/- 0.02 L/h/kg vs. 1.36 +/- 0.18 L/h/kg and 19.96 +/- 1.30 L/h/kg vs. 53.15 +/- 5.60 L/h/kg, respectively). In contrast, the above parameters for alphitolic acid, betulinic acid and betulonic acid exhibited the quite different trend. This pharmacokinetic research might provide useful information for the clinical usage of triterpenic acids from Jujubae Fructus. PMID- 30011886 TI - Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability ?. AB - Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL. PMID- 30011889 TI - Molecular and Cellular Mechanisms of Aging and Age-related Disorders. PMID- 30011887 TI - Potential for Mitochondrial DNA Sequencing in the Differential Diagnosis of Gynaecological Malignancies. AB - In the event of multiple synchronous gynecological lesions, a fundamental piece of information to determine patient management, prognosis, and therapeutic regimen choice is whether the simultaneous malignancies arise independently or as a result of metastatic dissemination. An example of synchronous primary tumors of the female genital tract most frequently described are ovarian and endometrial cancers. Surgical findings and histopathological examination aimed at resolving this conundrum may be aided by molecular analyses, although they are too often inconclusive. High mitochondrial DNA (mtDNA) variability and its propensity to accumulate mutations has been proposed by our group as a tool to define clonality. We showed mtDNA sequencing to be informative in synchronous primary ovarian and endometrial cancer, detecting tumor-specific mutations in both lesions, ruling out independence of the two neoplasms, and indicating clonality. Furthermore, we tested this method in another frequent simultaneously detected gynecological lesion type, borderline ovarian cancer and their peritoneal implants, which may be monoclonal extra-ovarian metastases or polyclonal independent masses. The purpose of this review is to provide an update on the potential use of mtDNA sequencing in distinguishing independent and metastatic lesions in gynecological cancers, and to compare the efficiency of molecular analyses currently in use with this novel method. PMID- 30011888 TI - Assessment of the Sensitizing Potential of Proteins in BALB/c Mice: Comparison of Three Protocols of Intraperitoneal Sensitization. AB - Most food allergy cases are associated with a limited group of allergens. This could be attributed to an increased ability of some foods to sensitize and trigger allergic reactions. However, there are no validated animal models to evaluate the sensitizing or allergenic potentials of proteins. Our aim was to evaluate three protocols of adjuvant-free intraperitoneal sensitization that differ in the time points for sample collection (days 14, 28 and 35 from beginning of the sensitization) and also in the number of immunizations (2, 5 and 3, respectively). Ovalbumin (OVA; 0.05 mg), cow milk proteins (CMP; 0.025, 0.05 and 0.25 mg), and potato acid phosphatase (PAP; low allergenic protein; 250.0 mg) were administered intraperitoneally (ip) to BALB/c mice (n = 4-6) and the protein specific IgE and IgG antibody responses were evaluated using ELISA. Additional serum protein-specific IgE antibodies evaluations were carried out after IgG depletion. Anti-OVA IgE antibodies were detected in mice from all three protocols. The responses were higher in the group of mice that underwent the 28 day protocol than in those that underwent the 14- or 35-day protocols (p < 0.01 and p < 0.05, respectively). Anti-CMP IgE antibodies were detected in both the 14 and 28-day protocols, but the response was higher in the group that underwent the 28-day protocol (p < 0.001). The anti-CMP IgE antibody response detection was improved after serum IgG depletion (p < 0.001). Anti-PAP IgE antibodies were not detected. Mice with undetectable serum levels of protein-specific IgE triggered anti-OVA, -CMP, and -PAP IgG responses. An adjuvant-free 28-day protocol with five ip immunizations seems appropriate for evaluation of the inherent sensitizing or allergenic capacity of the studied proteins. Reproducible results were obtained utilizing the BALB/c mouse strain. Inter-laboratory studies including a larger number of proteins should be carried out to validate this model. PMID- 30011890 TI - Effect of Dietary Ginger (Zingiber officinale Roscoe) and Multi-Strain Probiotic on Growth and Carcass Traits, Blood Biochemistry, Immune Responses and Intestinal Microflora in Broiler Chickens. AB - A total of 225 day-old male broiler chicks (Ross-308) were randomly allocated to five treatment groups, with three replicates in a completely randomized design for 42 days. Birds were fed a basal-diet supplemented with: no additive (control diet), multi-strain probiotic (Lactobacillus acidophilus, Lactobacillus casei, Enterococcus faecium and Bifidobacterium thermophilum), or 0.15, 0.20 and 0.25% ginger (Z. officinale) powder, respectively. The results show no significant differences among treatments for growth traits and carcass characteristics, whereas using probiotics and ginger at all levels resulted in a significant decrease of gizzard weight and abdominal fat compared to the control group. Dietary treatments did not affect blood biochemistry and antibody production against sheep red blood cells (SRBC), IgG and IgM; however, antibody titre was higher in birds fed 0.25% ginger than other diets after 7 days post injection. The Lactobacillus counts in ileal content of birds fed 0.20 and 0.25% ginger were higher compared to the other treatments. In conclusion, dietary supplementation with either ginger or probiotics showed a significant influence on birds' immune response, probably because ginger had strong antioxidant activity and the probiotics stimulated the production of natural antibodies. PMID- 30011892 TI - Characterization and Applications of Nanoparticles Modified in-Flight with Silica or Silica-Organic Coatings. AB - Nanoparticles are coated in-flight with a plasma-enhanced chemical vapor deposition (PECVD) process at ambient or elevated temperatures (up to 300 degrees C). Two silicon precursors, tetraethyl orthosilicate (TEOS) and hexamethyldisiloxane (HMDSO), are used to produce inorganic silica or silica organic shells on Pt, Au and TiO2 particles. The morphology of the coated particles is examined with transmission electron microscopy (TEM) and the chemical composition is studied with Fourier-transform infrared spectroscopy (FTIR), Energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS). It is found that both the precursor and certain core materials have an influence on the coating composition, while other parameters, such as the precursor concentration, aerosol residence time and temperature, influence the morphology, but hardly the chemical composition. The coated particles are used to demonstrate simple applications, such as the modification of the surface wettability of powders and the improvement or hampering of the photocatalytic activity of titania particles. PMID- 30011891 TI - Immunomodulatory Protein Hydrolysates and Their Application. AB - Immunomodulatory protein hydrolysate consumption may delay or prevent western immune-related diseases. In order to purposively develop protein hydrolysates with an optimal and reproducible immunomodulatory effect, knowledge is needed on which components in protein hydrolysates are responsible for the immune effects. Important advances have been made on this aspect. Also, knowledge on mechanisms underlying the immune modulating effects is indispensable. In this review, we discuss the most promising application possibilities for immunomodulatory protein hydrolysates. In order to do so, an overview is provided on reported in vivo immune effects of protein hydrolysates in both local intestinal and systemic organs, and the current insights in the underlying mechanisms of these effects. Furthermore, we discuss current knowledge and physicochemical approaches to identify the immune active protein sequence(s). We conclude that multiple hydrolysate compositions show specific immune effects. This knowledge can improve the efficacy of existing hydrolysate-containing products such as sports nutrition, clinical nutrition, and infant formula. We also provide arguments for why immunomodulatory protein hydrolysates could be applied to manage the immune response in the increasing number of individuals with a higher risk of immune dysfunction due to, for example, increasing age or stress. PMID- 30011893 TI - Application of Spray Drying Particle Engineering to a High-Functionality/Low Solubility Milk Thistle Extract: Powders Production and Characterization. AB - Many natural compounds having antioxidant and anti-inflammatory activity are a potential target for new therapies against chronic inflammatory syndromes. The oral administration of functional herbal supplements may become a prevention strategy or therapy adjuvant for susceptible patients. A case study is our milk thistle (Silybum marianum) extract rich in silymarin complex. A water-soluble microencapsulated powder system was developed by a spray drying technique to improve the poor silymarin bioactivity after oral administration. Sodium carboxymethylcellulose (NaCMC) was employed as coating/swelling polymer matrix and sodium lauryl sulfate (SLS) as the surfactant (1:1:0.05 w/w/w). A H2O/EtOH/acetone (50/15/35 v/v/v) solvent system was used as liquid feed. The microsystems were capable of improving the in vitro dissolution and permeation rates, suggesting an enhancement of bioactivity after oral administration. The microsystems protect the antioxidant activity of silymarin after harsh storage conditions period and do not affect the anti-inflammatory properties of the raw extract (efficient already at lower concentrations of 0.312 mg/mL) to reduce dendritic cells (DCs) inflammatory cytokine secretion after lipopolysaccharide administration. This approach allows managing particle size, surface properties and release of bioactive agents improving the bioactivity of a herbal supplement and is also possibly applicable to many other similar natural products. PMID- 30011895 TI - Physico-Mechanical Properties and Microstructure of Polymer Concrete with Recycled Glass Aggregate. AB - The paper presents an analysis of the possibility of using glass waste from worn out lighting materials as an aggregate for a polymer concrete. Glass waste was obtained from the company utilizing glass lighting elements, which was then subjected to crushing. The aggregate obtained was subjected to the tests of basic features, which were compared with aggregates that are traditionally applied to concretes. The next stage of the research program was the production of a polymer concrete that contained glass aggregate. Several types of mixtures were prepared in which glass waste was combined in various proportions with traditional sand gravel aggregate. As a part of the research, the basic physical and mechanical characteristics of polymer concretes were determined. The microstructure of composites was also analyzed using a scanning electron microscope. The results of the research have shown that the aggregate obtained from glass waste can be successfully used for the production of a polymer concrete. The most beneficial physico-mechanical properties were obtained for a composite in which glass waste was used as a 50% substitute for traditional aggregate. PMID- 30011894 TI - Essential Oils as Feed Additives-Future Perspectives. AB - The inconsistency of phytogenic feed additives' (PFA) effects on the livestock industry poses a risk for their use as a replacement for antibiotic growth promoters. The livestock market is being encouraged to use natural growth promotors, but information is limited about the PFA mode of action. The aim of this paper is to present the complexity of compounds present in essential oils (EOs) and factors that influence biological effects of PFA. In this paper, we highlight various controls and optimization parameters that influence the processes for the standardization of these products. The chemical composition of EOs depends on plant genetics, growth conditions, development stage at harvest, and processes of extracting active compounds. Their biological effects are further influenced by the interaction of phytochemicals and their bioavailability in the gastrointestinal tract of animals. PFA effects on animal health and production are also complex due to various EO antibiotic, antioxidant, anti quorum sensing, anti-inflammatory, and digestive fluids stimulating activities. Research must focus on reliable methods to identify and control the quality and effects of EOs. In this study, we focused on available microencapsulation techniques of EOs to increase the bioavailability of active compounds, as well as their application in the animal feed additive industry. PMID- 30011896 TI - Synthetic Cannabinoid use in a Case Series of Patients with Psychosis Presenting to Acute Psychiatric Settings: Clinical Presentation and Management Issues. AB - BACKGROUND: Novel Psychoactive Substances (NPS) are a heterogeneous class of synthetic molecules including synthetic cannabinoid receptor agonists (SCRAs). Psychosis is associated with SCRAs use. There is limited knowledge regarding the structured assessment and psychometric evaluation of clinical presentations, analytical toxicology and clinical management plans of patients presenting with psychosis and SCRAs misuse. METHODS: We gathered information regarding the clinical presentations, toxicology and care plans of patients with psychosis and SCRAs misuse admitted to inpatients services. Clinical presentations were assessed using the PANSS scale. Vital signs data were collected using the National Early Warning Signs tool. Analytic chemistry data were collected using urine drug screening tests for traditional psychoactive substances and NPS. RESULTS: We described the clinical presentation and management plan of four patients with psychosis and misuse of SCRAs. CONCLUSION: The formulation of an informed clinical management plan requires a structured assessment, identification of the index NPS, pharmacological interventions, increases in nursing observations, changes to leave status and monitoring of the vital signs. The objective from using these interventions is to maintain stable physical health whilst rapidly improving the altered mental state. PMID- 30011898 TI - A Sensitive Potentiometric Sensor for Isothermal Amplification-Coupled Detection of Nucleic Acids. AB - A disposable potentiometric sensor was newly developed for the amplification coupled detection of nucleic acids. The hydrogen-ion is generally released during isothermal amplification of nucleic acids. The surface potential on the oxide functionalized electrode of the extended gate was directly measured using full electrical circuits with the commercial metal-oxide semiconductor field-effect transistors (MOSFETs) and ring oscillator components, which resulted in cost effective, portable and scalable real-time nucleic acid analysis. The current starved ring oscillator changes surface potential to its frequency depending on the square of the variation in pH with a high signal-to-noise ratio during isothermal amplification. The device achieves a conversion rate of 20.5 kHz/mV and a detection resolution of 200 uV for the surface potential. It is demonstrated that the sensor successfully monitors in real-time isothermal amplification of the extracted nucleic acids from Salmonella pathogenic bacteria. The in situ variations in the frequency of the pH-sensitive sensor were compared with the results of both a conventional optical device and pH-meter during isothermal amplification. PMID- 30011899 TI - Peanut Consumption in Malawi: An Opportunity for Innovation. AB - Peanuts are a valuable source of nutrients, but peanut consumption patterns, consumption frequencies, and the factors influencing peanut consumption in Malawi are not known. This study surveyed consumers to fill this knowledge gap and to assess Malawian consumers' readiness to try new food products. Out of the 489 respondents surveyed, all but three consumed peanuts (in any form). The majority (70.4%) consumed peanuts at least three times in a week. Chi-square test showed that demographic and socioeconomic variables had significant effects (p < 0.05) on peanut product preferences, the frequency of peanut consumption, and readiness to try new foods. For instance, women mostly preferred peanut flour compared to men, and peanut butter was the most preferred form for younger consumers. Logistic regression analysis showed that consumers with high school education or below were 2.35 times more likely to eat peanuts more often than consumers with post high school education. Among the participants that were ready to try new foods (54%), men and those with post high school education were 1.90 and 2.74 times more likely to try new foods than their respective counterparts. In general, the diversity of peanut products on the Malawian market is limited, and socioeconomic restrictions override consumer preferences. Therefore, future peanut-based food products innovations should explore ways to overcome such restrictions. PMID- 30011897 TI - Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with alpha Lipoic Acid in the Axial Positions. AB - Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1 cyclobutanedicarboxylate) analogue the antioxidant alpha-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis [PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters. PMID- 30011900 TI - Design and Validation of an FPGA-Based Configurable Transcranial Doppler Neurofeedback System for Chronic Pain Patients. AB - Neurofeedback is a self-regulation technique that can be applied to learn to voluntarily control cerebral activity in specific brain regions. In this work, a Transcranial Doppler-based configurable neurofeedback system is proposed and described. The hardware configuration is based on the Red Pitaya board, which gives great flexibility and processing power to the system. The parameter to be trained can be selected between several temporal, spectral, or complexity features from the cerebral blood flow velocity signal in different vessels. As previous studies have found alterations in these parameters in chronic pain patients, the system could be applied to help them to voluntarily control these parameters. Two protocols based on different temporal lengths of the training periods have been proposed and tested with six healthy subjects that were randomly assigned to one of the protocols at the beginning of the procedure. For the purposes of the testing, the trained parameter was the mean cerebral blood flow velocity in the aggregated data from the two anterior cerebral arteries. Results show that, using the proposed neurofeedback system, the two groups of healthy volunteers can learn to self-regulate a parameter from their brain activity in a reduced number of training sessions. PMID- 30011901 TI - Antiradical Activity of Porphyrins with a Diisobornylphenol Fragment at the Macrocycle Periphery. AB - This article focuses on the antiradical activity of a number of 2,6 diisobornylphenol-porphyrin conjugates with various spacers between the porphyrin and phenolic fragments in the model reaction of ethylbenzene oxidation initiated by azoisobutyric acid dinitrile. The study has shown that the electronic effects of the groups directly related to the 2,6-diisobornylphenol fragment exert the predominant influence both on the reactivity of the phenolic hydroxyl group in interaction with free radicals and on the antiradical activity of the molecule as a whole. The antiradical activity of the molecule is generally less affected by the nature of the substituents in the porphyrin macrocycle, mainly due to a change in the stoichiometric inhibition coefficient in the presence of relatively easily oxidizable groups. It was found that the length of the spacer between the porphyrin and phenolic fragments does not affect the antiradical activity of the conjugate. PMID- 30011903 TI - Importance of Welfare and Ethics Competence Regarding Animals Kept for Scientific Purposes to Veterinary Students in Australia and New Zealand. AB - Veterinarians are in a strong position of social influence on animal-related issues. Hence, veterinary schools have an opportunity to raise animal health and welfare standards by improving veterinary students' animal welfare and ethics (AWE) education, including that related to animals used for scientific purposes. A survey of 851 students in the early, mid, and senior stages of their courses at all eight veterinary schools across Australia and New Zealand was undertaken on their first day of practice (or Day One Competences) to explore how veterinary students viewed the importance of their competence in the management of welfare and ethical decision-making relating to animals kept for scientific purposes. From highest to lowest, the rankings they assigned were: Animal Ethics Committee (AEC) Procedures or Requirements; 3Rs (Replacement, Refinement and Reduction); Humane Endpoints; Euthanasia; "What Is a Research Animal?"; and Conscientious Objections. Female students rated Conscientious Objections, Humane Endpoints, and Euthanasia significantly higher than male students did across the three stages of study. The score patterns for these three variates showed a trend for the male students to be more likely to score these topics as extremely important as they advanced through the course, but female students' scores tended to decline slightly or stay relatively stable. No gender differences emerged for the three variates: 3Rs (Replacement, Refinement and Reduction); AEC Procedures or Requirements; and "What Is a Research Animal?". This study demonstrates that understandings of the regulatory and normative frameworks are considered most important in animal welfare and ethics competence in veterinary students. To the authors' knowledge, this is the first study to investigate what importance veterinary students place on their competence regarding animals kept for scientific purposes. PMID- 30011904 TI - Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations. AB - The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addition to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes. PMID- 30011902 TI - Vitamin D and Uterine Fibroids-Review of the Literature and Novel Concepts. AB - This article provides a detailed review of current knowledge on the role of vitamin D and its receptor in the biology and management of uterine fibroids (UFs). Authors present ideas for future steps in this area. A literature search was conducted in PubMed using the following key words: "uterine fibroid" and "vitamin D". The results of the available studies, published in English from January 2002 up to April 2018, have been discussed. Vitamin D is a group of steroid compounds with a powerful impact on many parts of the human body. This vitamin is believed to regulate cell proliferation and differentiation, inhibit angiogenesis, and stimulate apoptosis. Nowadays, hypovitaminosis D is believed to be a major risk factor in the development of UFs. In many studies vitamin D appears to be a powerful factor against UFs, resulting in inhibition of tumor cell division and a significant reduction in its size, however, the exact role of this compound and its receptor in the pathophysiology of UFs is not fully understood. According to available studies, vitamin D and its analogs seem to be promising, effective, and low-cost compounds in the management of UFs and their clinical symptoms, and the anti-tumor activities of vitamin D play an important role in UF biology. The synergy between vitamin D and selected anti-UF drugs is a very interesting issue which requires further research. Further studies about the biological effect of vitamin D on UF biology are essential. Vitamin D preparations (alone or as a co-drugs) could become new tools in the fight with UFs, with the additional beneficial pleiotropic effect. PMID- 30011906 TI - The State of Knowledge about Nutrition Sources of Vitamin D, Its Role in the Human Body, and Necessity of Supplementation among Parents in Central Poland. AB - The percentage of children with vitamin D deficiency in Poland is alarming. The aim of the study was to assess the knowledge about sources of food and the function of vitamin D, as well as the frequency of its supplementation. A survey was conducted among the parents of children from Central Poland attending primary schools, and a questionnaire containing mainly open-ended questions was used to collect the data. Most mothers knew at least one of the functions of vitamin D in the body but had a low level of knowledge about its dietary sources. Only a small group of respondents supplemented themselves and their children with vitamin D. Statistically significant influences on the level of knowledge about the functions and sources of vitamin D were place of residence (i.e., better knowledge in the countryside) and mothers' level of education (i.e., the better educated, the greater knowledge). In the case of monthly income level, such impact was observed only in relation to the knowledge of vitamin D functions. Concerning the frequency of supplementation, only maternal level of education had a statistically significant effect (i.e., the higher the education level, the higher the frequency of supplementation). In addition, mothers who were aware of functions of vitamin D and nutritional sources, significantly more frequently supplemented vitamin D. PMID- 30011905 TI - Effects of a Ruthenium Schiff Base Complex on Glucose Homeostasis in Diet-Induced Pre-Diabetic Rats. AB - Pre-diabetes is a condition that precedes type 2 diabetes mellitus (T2DM) that is characterised by elevated glycated haemoglobin (HbA1c). The management of pre diabetes includes the combination of dietary and pharmacological interventions to increase insulin sensitivity. However, poor patient compliance has been reported with regard to dietary interventions, therefore, new alternative drugs are required that can be effective even without the dietary intervention. In our laboratory, we have synthesised a novel ruthenium complex that has been shown to have elevated biological activity. This study investigated the effects of this complex in both the presence and absence of dietary intervention on glucose handling in a diet-induced pre-diabetes rat model. Pre-diabetic animals were randomly assigned to respective treatment groups. The ruthenium complex was administered to pre-diabetic rats once a day every third day for 12 weeks. The administration of the ruthenium complex resulted in reduced fasting blood glucose, food intake, and body weight gain which was associated with decreased plasma ghrelin, insulin, and HbA1c levels in both the presence and absence of dietary intervention. The administration of the ruthenium complex ameliorated glycaemic control and insulin sensitivity in pre-diabetic rats. The results of this study warrant further investigations as this compound could potentially be able to re-sensitize insulin resistant cells and reduce the incidence of T2DM. PMID- 30011907 TI - Porphyrin-Functionalized Zinc Oxide Nanostructures for Sensor Applications. AB - Hybrid materials made of wide band gap semiconductors and dye molecules are largely studied mainly for photovoltaic applications. However, these materials also show interesting chemical sensitivity. Zinc oxides (ZnO) and porphyrins are good examples of a metal oxide semiconductor and a dye molecule that give rise to a hybrid material with such interesting properties. ZnO has been studied for sensors, optoelectronics, electronic devices, photo-anodes for dye-sensitized solar cells, and for mechanical energy harvesting. Porphyrins, on the other side, can be synthesized in order to mimic their roles in living systems such as oxygen transport and charge transfer for catalytic processes in animals and photosynthesis in plants. This paper provides a review of the chemical sensing properties of porphyrin-capped ZnO nanostructures. The methodologies to functionalize the ZnO surface with porphyrins are illustrated with emphasis on the relationships between the material preparation and its sensing properties. The development of sensors is described through the application of the hybrid materials to different transducers. PMID- 30011908 TI - Isolation and Identification of the Anti-Oxidant Constituents from Loropetalum chinense (R. Brown) Oliv. Based on UHPLC-Q-TOF-MS/MS. AB - The aim of this study was to identify the chemical constituents of Loropetalum chinense (R. Brown) Oliv. (LCO) and determine which of these had antioxidant effects. The chemical composition of a 70% ethanol extract of LCO was analyzed systematically using UHPLC-Q-TOF-MS/MS. The chemical components of the 70% ethanol extract of LCO were then separated and purified using macroporous resin and chromatographic techniques. Antioxidant activity was evaluated using a DPPH assay. In total, 100 compounds were identified tentatively, including 42 gallic acid tannins, 49 flavones, and 9 phenolic compounds. Of these, 7 gallium gallate, 4 flavonoid and 8 quinic acid compounds were separated and purified from the 70% ethanol extract of LCO. The compounds identified for the first time in LCO and in the genus Loropetalum were 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-beta-d glucopyranoside, protocatechuic acid, ethyl gallate, 5-O-caffeoylquinic acid, 3-O caffeoylquinic acid, 3,5-O-diocaffeoylquinic acid, 4,5-O-diocaffeoylquinic acid and 3,4-O-diocaffeoylquinic acid. The 50% inhibitory concentration (IC50) values of compounds 1,2,3,4,6-penta-O-galloyl-beta-d-glucose, gallic acid, protocatechuic acid, and ethyl gallate were 1.88, 1.05, 1.18, and 1.05 MUg/mL, respectively. Compared with the control group (VC) (2.08 MUg/mL), these compounds exhibited stronger anti-oxidation activity. This study offered considerable insight into the chemical composition of LCO, with preliminary identification of the antioxidant ingredients. PMID- 30011909 TI - Conjugation of Nanomaterials and Nematic Liquid Crystals for Futuristic Applications and Biosensors. AB - The established role of nematic liquid crystals (NLCs) in the recent rapid development of displays has motivated researchers to modulate the electro-optical properties of LCs. Furthermore, adding nanomaterials into NLCs has led to enhancements of the properties of NLCs, like reduced threshold of the operating voltage, variation in pretilt angle, reduced switching time, etc. These enhanced properties, due to interfacial dynamics, are enabling wider applications of NLCs and nanomaterials. The recent literature of nanomaterial-doped NLCs is rich with various kinds of nanomaterials in a variety of NLCs. The light has been focused on the most widely used and studied gold nanoparticles in NLCs. The intrinsic inherent property of easy excitation of surface plasmons polaritons (SPP) is the mediating interaction of NLC electric dipoles and the polarization of charges in the GNP surface. The concepts and methods for the application of metal nanomaterials as dopants in NLCs are discussed for future applications, especially biosensors. The biosensing application of NLCs alone has already been proven in the literature. However, it is always desirable to further enhance the detection efficiency and selectivity, which have been achieved by the conjugation of GNPs and nickel nanoparticles with NLCs and their compatibility with biological materials. This aspect of future application of nanoparticles and NLC makes the point more selective to be included in the present manuscript. PMID- 30011910 TI - Testosterone and Cortisol Responses to Five High-Intensity Functional Training Competition Workouts in Recreationally Active Adults. AB - To determine the salivary steroid response to high-intensity functional training (HIFT) competition workouts, saliva samples were collected from ten recreationally trained male and female competitors during a 5-week (WK1-WK5) international competition. Competitors arrived at their local affiliate and provided samples prior to (PRE) their warm-up, immediately (IP), 30-min (30P), and 60-min (60P) post-exercise. Samples were analyzed for concentrations of testosterone (T), cortisol (C), and their ratio (TC). Generalized linear mixed models with repeated measures revealed significant main effects for time (p < 0.001) for T, C, and TC. Compared to PRE-concentrations, elevated (p < 0.05) T was observed at IP on WK2-WK5 (mean difference: 135-511 pg.mL-1), at 30P on WK3 (mean difference: 81.0 +/- 30.1 pg.mL-1) and WK5 (mean difference: 56.6 +/- 22.7 pg.mL-1), and at 60P on WK3 (mean difference: 73.5 +/- 29.7 pg.mL-1) and WK5 (mean difference: 74.3 +/- 28.4 pg.mL-1). Compared to PRE-concentrations, elevated (p < 0.05) C was noted on all weeks at IP (mean difference: 9.3-15.9 ng.mL-1) and 30P (mean difference: 6.0-19.9 ng.mL-1); significant (p < 0.006) elevations were noted at 60P on WK1 (mean difference: 9.1 +/- 3.0 ng.mL-1) and WK5 (mean difference: 12.8 +/- 2.9 ng.mL-1). Additionally, TC was significantly reduced from PRE-values by 61% on WK1 at 60P (p = 0.040) and by 80% on WK5 at 30P (p = 0.023). Differences in T, C, and TC were also observed between weeks at specific time points. Although each workout affected concentrations in T, C, and/or the TC ratio, changes appeared to be modulated by the presence of overload and workout duration. During periods of elevated training or competition, athletes and coaches may consider monitoring these hormones for consistency and as a means of assessing workout difficulty. PMID- 30011911 TI - Overview on the Antihypertensive and Anti-Obesity Effects of Secondary Metabolites from Seaweeds. AB - Hypertension and obesity are two significant factors that contribute to the onset and exacerbation of a cascade of mechanisms including activation of the sympathetic and renin-angiotensin systems, oxidative stress, release of inflammatory mediators, increase of adipogenesis and thus promotion of systemic dysfunction that leads to clinical manifestations of cardiovascular diseases. Seaweeds, in addition to their use as food, are now unanimously acknowledged as an invaluable source of new natural products that may hold noteworthy leads for future drug discovery and development, including in the prevention and/or treatment of the cardiovascular risk factors. Several compounds including peptides, phlorotannins, polysaccharides, carotenoids, and sterols, isolated from brown, red and green macroalgae exhibit significant anti-hypertensive and anti obesity properties. This review will provide a comprehensive overview of the recent advances on bioactive pure compounds isolated from different seaweed sources focusing on their potential use as drugs to treat or prevent hypertension and obesity. On the other hand, although it is obvious that macroalgae represent promising sources of antihypertensive and anti-obesity compounds, it is also clear that further efforts are required to fully understand their cellular mechanisms of action, to establish structure-inhibition relationships and mainly to evaluate them in pre-clinical and clinical trials. PMID- 30011914 TI - Loosening Monitoring of the Threaded Pipe Connection Using Time Reversal Technique and Piezoceramic Transducers. AB - Threaded pipe connections are commonly used in the oil and gas industry in particular to connect casting strings, drill pipe strings, production and transportation risers, and pipelines. As the most critical components in the entire chain, maintaining a sealed and secure connection while being subjected to environmental loads and pollution is very important and necessary to reduce potential leakage risk and guarantee the safety of the entire chain. In this paper, an effective approach using time reversal technique and lead zirconate titanate (PZT) transducer was developed to monitor the looseness of the threaded pipe connection. Two threaded pipeline segments connected with a metal coupling were assembled to simulate the threaded connection in the pipeline system. Two PZT patches were mounted on the surface of one pipeline segment and the pipe coupling, respectively. By loosening the threaded connection with different rotation angles, several looseness scenarios were experimentally investigated. For each looseness condition, the developed time reversal-based approach was performed and the corresponding response signal was acquired and analyzed. The experimental results demonstrate that the peak value of the focused signal detected by the PZT sensor decreases with the increase of the looseness degree. The entire test conducted from tightened connection to loosened connection was repeated eight times to validate the repeatability of the developed method and the consistency of the detection results. In addition, the reliability of the developed method was studied by involving high disturbances when the signal was measured. All the test results show that the developed method has a great potential to be employed in practical applications for monitoring the looseness condition of the threaded pipe connection, especially in an environment with severe noises and disturbances. PMID- 30011915 TI - Lagging-Domain Model for Compensation of Hysteresis of xMR Sensors in Positioning Applications. AB - The hysteresis of magnetoresistive sensors remains a considerable cause of inaccuracy of positioning applications. The phenomena itself has been well studied and described by different physical and phenomenological models. Various biasing techniques have been proposed. However, the increased fabrication and computational price they require is undesirable. In this paper, a computational algorithm for the compensation of hysteresis of linear and rotary encoders is proposed. A lagging-domain model based on play operators is presented for prediction of hysteresis. The outlined procedure for the calibration of parameters allows the use of the algorithm for various types of encoders without knowing their exact material properties. The method was tested on different anisotropic magnetoresistive and tunneling magnetoresistive sensors. Results show that the impact of hysteresis was reduced by up to 90% without a significant increase of computational time or production costs. PMID- 30011913 TI - Genome-Wide Characterization and Expression Analyses of Pleurotus ostreatus MYB Transcription Factors during Developmental Stages and under Heat Stress Based on de novo Sequenced Genome. AB - Pleurotus ostreatus is a commercially grown mushroom species in China. However, studies on the mechanisms of the fruiting body development and stress response of P. ostreatus are still at a primary stage. In this study, we report the entire genome sequence of P. ostreatus CCMSSC03989. Then, we performed comprehensive genome-wide characterization and expression analysis of the MYB transcription factor family during a series of developmental stages and under the condition of heat stress. A 34.76 Mb genome was obtained through next-generation sequencing (NGS) and Bionano optical mapping approaches. The genome has a scaffold N50 of 1.1 Mb and contains 10.11% repeats, and 10,936 gene models were predicted. A total of 20 MYB genes (PoMYB) were identified across the genome, and the full length open reading frames were isolated. The PoMYBs were classified into 1 repeat (1R), 2R, and 3R-MYB groups according to their MYB domain repeat numbers, and 3R-MYBs possessed relatively more introns than 1R and 2R-MYBs. Based on phylogenetic analysis, the PoMYBs were divided into four groups and showed close relationships with the MYB genes of plants and fungi. RNA-sequencing (RNA-Seq) and quantitative PCR (qPCR) analyses revealed that PoMYB expression showed stage specific patterns in reproductive stages and could be induced by heat stress. The P. ostreatus draft genome will promote genome-wide analysis, and our study of PoMYBs will promote further functional analysis of MYB genes in mushrooms. PMID- 30011916 TI - Modification of Polyhedral Oligomeric Silsesquioxanes (POSS) Molecules by Ruthenium Catalyzed Cross Metathesis. AB - The scope of ruthenium (Ru)-catalyzed cross metathesis (CM) of allyl-decorated polyhedral oligomeric silsesquioxanes (POSS) was explored. A variety of different commercial and non-commercial ruthenium complexes were tested to determine that the nitro-activated Ru catalyst is optimal for this transformation. The reported transformation was used to prepare selected hybrid steroid-POSS compounds. PMID- 30011912 TI - Cell Signaling in Neuronal Stem Cells. AB - The defining characteristic of neural stem cells (NSCs) is their ability to multiply through symmetric divisions and proliferation, and differentiation by asymmetric divisions, thus giving rise to different types of cells of the central nervous system (CNS). A strict temporal space control of the NSC differentiation is necessary, because its alterations are associated with neurological dysfunctions and, in some cases, death. This work reviews the current state of the molecular mechanisms that regulate the transcription in NSCs, organized according to whether the origin of the stimulus that triggers the molecular cascade in the CNS is internal (intrinsic factors) or whether it is the result of the microenvironment that surrounds the CNS (extrinsic factors). PMID- 30011917 TI - Thermal and Guest-Assisted Structural Transition in the NH2-MIL-53(Al) Metal Organic Framework: A Molecular Dynamics Simulation Investigation. AB - Reversible structural transition between the Large (LP) and Narrow Pore (NP) forms (breathing phenomena) of the MIL-53(X, X = Al, Cr, Fe, Ga) Metal Organic Framework (MOF) is probably one of the most amazing physical properties of this class of soft-porous materials. Whereas great attention has been paid to the elucidation of the physical mechanism ruling this reversible transition, the effect of the functionalization on the flexibility has been less explored. Among functionalized MIL-53(Al) materials, the case of NH2-MIL-53(Al) is undoubtedly a very intriguing structural transition rarely observed, and the steadier phase corresponds to the narrow pore form. In this work, the flexibility of the NH2-MIL 53(Al) metal organic framework was investigated by means of molecular dynamics simulations. Guest (methanol) and thermal breathing of the NH2-MIL-53(Al) was thus explored. We show that it is possible to trigger a reversible transition between NP and LP forms upon adsorption, and we highlight the existence of stable intermediate forms and a very large pore phase. Furthermore, the NP form is found thermodynamically stable from 240 to 400 K, which is the result of strong intramolecular hydrogen bonds. PMID- 30011918 TI - Angiopoietin-Like 3 (ANGPTL3) and Atherosclerosis: Lipid and Non-Lipid Related Effects. AB - Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies. PMID- 30011919 TI - New Octadecanoid Enantiomers from the Whole Plants of Plantago depressa. AB - In this study, 19 octadecanoid derivatives-four pairs of enantiomers (1-8), two racemic/scalemic mixtures (9-10), and nine biosynthetically related analogues were obtained from the ethanolic extract of a Chinese medicinal plant, Plantago depressa Willd. Their structures were elucidated on the basis of detailed spectroscopic analyses, with the absolute configurations of the new compounds assigned by time-dependent density functional theory (TD-DFT)-based electronic circular dichroism (ECD) calculations. Six of them (1, 3-6, and 9) were reported for the first time, while 2, 7, and 8 have been previously described as derivatives and are currently obtained as natural products. Our bioassays have established that selective compounds show in vitro anti-inflammatory activity by inhibiting lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells. PMID- 30011920 TI - The Proportion of Fermented Milk in Dehydrated Fermented Milk-Parboiled Wheat Composites Significantly Affects Their Composition, Pasting Behaviour, and Flow Properties on Reconstitution. AB - Dairy and cereal are frequently combined to create composite foods with enhanced nutritional benefits. Dehydrated fermented milk-wheat composites (FMWC) were prepared by blending fermented milk (FM) and parboiled wheat (W), incubating at 35 degrees C for 24 h, drying at 46 degrees C for 48 h, and milling to 1 mm. Increasing the weight ratio of FM to W from 1.5 to 4.0 resulted in reductions in total solids (from 96 to 92%) and starch (from 52 to 39%), and increases in protein (15.2-18.9%), fat (3.7-5.9%), lactose (6.4-11.4%), and lactic acid (2.7 4.2%). FMWC need to be reconstituted prior to consumption. The water-holding capacity, pasting viscosity, and setback viscosity of the reconstituted FMWC (16.7% total solids) decreased with the ratio of FM to W. The reconstituted FMWC exhibited pseudoplastic flow behaviour on shearing from 18 to 120 s-1. Increasing the FM:W ratio coincided with a lower yield stress, consistency index, and viscosity at 120 s-1. The results demonstrate the critical impact of the FM:W ratio on the composition, pasting behavior, and consistency of the reconstituted FMWC. The difference in consistency associated with varying the FM:W ratio is likely to impact on satiety and nutrient value of the FMWCs. PMID- 30011923 TI - Interaction of a Preventative Fungicide Treatment and Root Rot Pathogen on Ambrosia Beetle Attacks during a Simulated Flood Event. AB - Flooding can increase tree susceptibility to root rot pathogens as well as attacks by ambrosia beetles attracted to stress-induced ethanol emissions. The objective of this study was to investigate the interaction of a preventative fungicide treatment and root infection with Phytophthora cinnamomi on ambrosia beetle attacks in flood stressed trees. A fungicide (Pageant(r) Intrinsic(r)) was evaluated in two flood trials using Eastern redbud and tulip poplar trees with treatments including the fungicide with or without pathogen or no fungicide with or without pathogen. Fungicide treated trees had fewer ambrosia beetle attacks, particularly in trees without P. cinnamomi co-infection. In a follow-up experiment, ethanol content was evaluated in flooded redbuds to determine if the fungicide treatment reduced stress-induced compounds. All flood stressed trees began producing ethanol within 24 h post flooding, regardless of fungicide treatment or P. cinnamomi infection. We conclude that pre-treatments of a fungicide can provide protection from ambrosia beetle attacks during an extreme flood event, but that protection is reduced if a root rot pathogen is also present. Additionally, rejection of fungicide treated trees was not related to the absence of ethanol, as the fungicide-treated plants released ethanol in quantities similar to non-treated trees. PMID- 30011924 TI - A Practical Approach for High Precision Reconstruction of a Motorcycle Trajectory Using a Low-Cost Multi-Sensor System. AB - Motorcycle drivers are considered among the most vulnerable road users, as attested by the number of crashes increasing every year. The significant part of the fatalities relates to "single vehicle" loss of control in bends. During this investigation, a system based on an instrumented multi-sensor platform and an algorithmic study was developed to accurately reconstruct motorcycle trajectories achieved when negotiating bends. This system is used by the French Gendarmerie in order to objectively evaluate and to examine the way riders take their bends in order to better train riders to adopt a safe trajectory and to improve road safety. Data required for the reconstruction are acquired using a motorcycle that has been fully instrumented (in VIROLO++ Project) with several redundant sensors (reference sensors and low-cost sensors) which measure the rider actions (roll, steering) and the motorcycle behavior (position, velocity, acceleration, odometry, heading, and attitude). The proposed solution allowed the reconstruction of motorcycle trajectories in bends with a high accuracy (equal to that of fixed point positioning). The developed algorithm will be used by the French Gendarmerie in order to objectively evaluate and examine the way riders negotiate bends. It will also be used for initial training and retraining in order to better train riders to learn and estimate a safe trajectory and to increase the safety, efficiency and comfort of motorcycle riders. PMID- 30011922 TI - Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors. AB - Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4a-f, potential Michael acceptors, and their reduced analogues succindiamides 5a-f were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates 2a,b to corresponding acids 3a,b, and a coupling reaction with halogenanilines. 1-[bis(Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 b]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hunig's base. Compounds 4 and 5 were evaluated against a panel of bacteria, several Mycobacterium strains, fungi, a set of viruses, and nine different human tumor cell lines. p-Chlorofumardiamide 4d showed significant activity against Staphylococcus aureus,Streptococcus pneumoniae and Acinetobacter baumannii, but also against Candida albicans (minimum inhibitory concentration (MIC) 6.1-12.5 ug/mL). Together with p-fluoro and p-CF3 fumardiamides 4b,f, compound 4d showed activity against Mycobacterium marinum and 4b,f against M. tuberculosis. In biofilm eradication assay, most of the bacteria, particularly S. aureus, showed susceptibility to fumardiamides. m-CF3 and m-chloroaniline fumardiamides 4e and 4c showed significant antiviral activity against reovirus-1, sindbis virus and Punta Toro virus (EC50 = 3.1-5.5 uM), while 4e was active against coxsackie virus B4 (EC50 = 3.1 uM). m-Fluoro derivative 4a exerted significant cytostatic activity (IC50 = 5.7-31.2 MUM). Acute lymphoblastic leukemia cells were highly susceptible towards m-substituted derivatives 4a,c,e (IC50 = 6.7-8.9 MUM). Biological evaluations revealed that fumardiamides 4 were more active than succindiamides 5 indicating importance of Michael conjugated system. PMID- 30011921 TI - Specification and Patterning of Drosophila Appendages. AB - Appendages are external projections of the body that serve the animal for locomotion, feeding, or environment exploration. The appendages of the fruit fly Drosophilamelanogaster are derived from the imaginal discs, epithelial sac-like structures specified in the embryo that grow and pattern during larva development. In the last decades, genetic and developmental studies in the fruit fly have provided extensive knowledge regarding the mechanisms that direct the formation of the appendages. Importantly, many of the signaling pathways and patterning genes identified and characterized in Drosophila have similar functions during vertebrate appendage development. In this review, we will summarize the genetic and molecular mechanisms that lead to the specification of appendage primordia in the embryo and their posterior patterning during imaginal disc development. The identification of the regulatory logic underlying appendage specification in Drosophila suggests that the evolutionary origin of the insect wing is, in part, related to the development of ventral appendages. PMID- 30011925 TI - Quantitative Microbial Risk Assessment for Workers Exposed to Bioaerosol in Wastewater Treatment Plants Aimed at the Choice and Setup of Safety Measures. AB - Biological risk assessment in occupational settings currently is based on either qualitative or semiquantitative analysis. In this study, a quantitative microbial risk assessment (QMRA) has been applied to estimate the human adenovirus (HAdV) health risk due to bioaerosol exposure in a wastewater treatment plant (WWTP). A stochastic QMRA model was developed considering HAdV as the index pathogen, using its concentrations in different areas and published dose-response relationship for inhalation. A sensitivity analysis was employed to examine the impact of input parameters on health risk. The QMRA estimated a higher average risk in sewage influent and biological oxidation tanks (15.64% and 12.73% for an exposure of 3 min). Sensitivity analysis indicated HAdV concentration as a predominant factor in the estimated risk. QMRA results were used to calculate the exposure limits considering four different risk levels (one illness case per 100, 1.000, 10.000, and 100.000 workers): for 3 min exposures, we obtained 565, 170, 54, and 6 GC/m3 of HAdV. We also calculated the maximum time of exposure for each level for different areas. Our findings can be useful to better define the effectiveness of control measures, which would thus reduce the virus concentration or the exposure time. PMID- 30011927 TI - mPILOT-Magnetic Field Strength Based Pedestrian Indoor Localization. AB - An indoor localization system based on off-the-shelf smartphone sensors is presented which employs the magnetometer to find user location. Further assisted by the accelerometer and gyroscope, the proposed system is able to locate the user without any prior knowledge of user initial position. The system exploits the fingerprint database approach for localization. Traditional fingerprinting technology stores data intensity values in database such as RSSI (Received Signal Strength Indicator) values in the case of WiFi fingerprinting and magnetic flux intensity values in the case of geomagnetic fingerprinting. The down side is the need to update the database periodically and device heterogeneity. We solve this problem by using the fingerprint database of patterns formed by magnetic flux intensity values. The pattern matching approach solves the problem of device heterogeneity and the algorithm's performance with Samsung Galaxy S8 and LG G6 is comparable. A deep learning based artificial neural network is adopted to identify the user state of walking and stationary and its accuracy is 95%. The localization is totally infrastructure independent and does not require any other technology to constraint the search space. The experiments are performed to determine the accuracy in three buildings of Yeungnam University, Republic of Korea with different path lengths and path geometry. The results demonstrate that the error is 2-3 m for 50 percentile with various buildings. Even though many locations in the same building exhibit very similar magnetic attitude, the algorithm achieves an accuracy of 4 m for 75 percentile irrespective of the device used for localization. PMID- 30011928 TI - Investigation of Electrochemical, Optical and Thermal Effects during Flash Sintering of 8YSZ. AB - This paper reports the electrochemical, optical and thermal effects occurring during flash sintering of 8 mol % yttria-stabilized zirconia (8YSZ). In-situ observations of polycrystalline and single crystal specimens revealed electrochemical blackening/darkening during an incubation period prior to flash sintering. The phenomenon is induced by cathodic partial reduction under DC fields. When using a low frequency AC field (0.1-10 Hz) the blackening is reversible, following the imposed polarity switching. Thermal imaging combined with sample colour changes and electrical conductivity mapping give a complete picture of the multi-physical phenomena occurring during each stage of the flash sintering event. The partial reduction at the cathode causes a modification of the electrical properties in the sample and the blackened regions, which are close to the cathode, are more conductive than the remainder of the sample. The asymmetrical nature of the electrochemical reactions follows the field polarity and causes an asymmetry in the temperature between the anode and cathode, with the positive electrode tending to overheat. It is also observed that the phenomena are influenced by the quality of the electrical contacts and by the atmosphere used. PMID- 30011926 TI - Engineering Cell Adhesion and Orientation via Ultrafast Laser Fabricated Microstructured Substrates. AB - Cell responses depend on the stimuli received by the surrounding extracellular environment, which provides the cues required for adhesion, orientation, proliferation, and differentiation at the micro and the nano scales. In this study, discontinuous microcones on silicon (Si) and continuous microgrooves on polyethylene terephthalate (PET) substrates were fabricated via ultrashort pulsed laser irradiation at various fluences, resulting in microstructures with different magnitudes of roughness and varying geometrical characteristics. The topographical models attained were specifically developed to imitate the guidance and alignment of Schwann cells for the oriented axonal regrowth that occurs in nerve regeneration. At the same time, positive replicas of the silicon microstructures were successfully reproduced via soft lithography on the biodegradable polymer poly(lactide-co-glycolide) (PLGA). The anisotropic continuous (PET) and discontinuous (PLGA replicas) microstructured polymeric substrates were assessed in terms of their influence on Schwann cell responses. It is shown that the micropatterned substrates enable control over cellular adhesion, proliferation, and orientation, and are thus useful to engineer cell alignment in vitro. This property is potentially useful in the fields of neural tissue engineering and for dynamic microenvironment systems that simulate in vivo conditions. PMID- 30011929 TI - Construction of Thermo-Responsive Elastin-Like Polypeptides (ELPs)-Aggregation Induced-Emission (AIE) Conjugates for Temperature Sensing. AB - In this work, an aggregation-induced emission (AIE) molecule (tetraphenylethene derivative, TPE-COOH) was conjugated to elastin-like polypeptides (ELPs40) via an amide bond to form ELPs40-TPE. The successful synthesis of ELPs40-TPE was confirmed by Circular Dichroism spectroscopy, gel electrophoresis, UV-vis absorption, and fluorescence emission spectroscopy. ELPs40-TPE possessed both amphiphilicity and the features of an AIE, and the fluorescence intensity was dependent on the local temperature. The Hela cells imaging indicated that ELPs40 TPE has great potential for bio-imaging applications because of its advantages of high fluorescence intensity, good water-solubility, and remarkable biocompatibility. PMID- 30011930 TI - Optimal Camera Pose and Placement Configuration for Maximum Field-of-View Video Stitching. AB - An optimal camera placement problem is investigated. The objective is to maximize the area of the field of view (FoV) of a stitched video obtained by stitching video streams from an array of cameras. The positions and poses of these cameras are restricted to a given set of selections. The camera array is designed to be placed inside the abdomen to support minimally invasive laparoscopic surgery. Hence, a few non-traditional requirements/constraints are imposed: Adjacent views are required to overlap to support image registration for seamless video stitching. The resulting effective FoV should be a contiguous region without any holes and should be a convex polygon. With these requirements, traditional camera placement algorithms cannot be directly applied to solve this problem. In this work, we show the complexity of this problem grows exponentially as a function of the problem size, and then present a greedy polynomial time heuristic solution that approximates well to the globally optimal solution. We present a new approach to directly evaluate the combined coverage area (area of FoV) as the union of a set of quadrilaterals. We also propose a graph-based approach to ensure the stitching requirement (overlap between adjacent views) is satisfied. We present a method to find a convex polygon with maximum area from a given polygon. Several design examples show that the proposed algorithm can achieve larger FoV area while using much less computing time. PMID- 30011931 TI - Effect of Tb-doped Concentration Variation on the Electrical and Dielectric Properties of CaF2 Nanoparticles. AB - Calcium fluoride (CaF2) nanoparticles with various terbium (Tb) doping concentrations were investigated by X-ray diffraction (XRD), transmission electron microscopy (TEM), and alternating current (AC) impedance measurement. The original shape and structure of CaF2 nanoparticles were retained after doping. In all the samples, the dominant charge carriers were electrons, and the F- ion transference number increased with increasing Tb concentration. The defects in the grain region considerably contributed to the electron transportation process. When the Tb concentration was less than 3%, the effect of the ionic radius variation dominated and led to the diffusion of the F- ions and facilitated electron transportation. When the Tb concentration was greater than 3%, the increasing deformation potential scattering dominated, impeding F- ion diffusion and electron transportation. The substitution of Ca2+ by Tb3+ enables the electron and ion hopping in CaF2 nanocrystals, resulting in increased permittivity. PMID- 30011932 TI - Indigenous Australians Perceptions' of Physical Activity: A Qualitative Systematic Review. AB - Given poorer health and higher rates of chronic disease seen in Indigenous populations around the world and the evidence linking exercise with health and wellbeing, recommendations for encouraging and increasing Indigenous people's participation in physical activity are needed. This paper systematically reviews published qualitative research papers exploring issues related to the perspectives of Indigenous Australians around physical activity. Key terms relevant to attitudes, beliefs, and perceptions of Indigenous Australians on physical activity and sport were explored in 11 electronic bibliographic databases including EMBASE, Medline and Web of Science. Of the 783 studies screened, eight qualitative studies met the selection criteria; only one was exclusively undertaken in a rural setting. Four major themes emerged: family and community, culture and environment, sport, and gender differences. Men highlighted sport and going on walkabout as preferred types of physical activity while women preferred family-focused activities and activities and support for women's sport. Several studies found exercise was supported when in the context of family and community but was considered shameful when done only for oneself. Sport was regarded as playing an influential role in bringing communities together. Group, community, or family activities were desired forms of physical activity with the environment they are conducted in of high importance. These findings should inform future research and intervention programs aimed at addressing the physical activity levels of Indigenous Australians and may be relevant to other Indigenous populations. PMID- 30011934 TI - Accounting for Fairness in a Two-Stage Stochastic Programming Model for Kidney Exchange Programs. AB - Kidney exchange programs, which allow a potential living donor whose kidney is incompatible with his or her intended recipient to donate a kidney to another patient in return for a kidney that is compatible for their intended recipient, usually aims to maximize the number of possible kidney exchanges or the total utility of the program. However, the fairness of these exchanges is an issue that has often been ignored. In this paper, as a way to overcome the problems arising in previous studies, we take fairness to be the degree to which individual patient-donor pairs feel satisfied, rather than the extent to which the exchange increases social benefits. A kidney exchange has to occur on the basis of the value of the kidneys themselves because the process is similar to bartering. If the matched kidneys are not of the level expected by the patient-donor pairs involved, the match may break and the kidney exchange transplantation may fail. This study attempts to classify possible scenarios for such failures and incorporate these into a stochastic programming framework. We apply a two-stage stochastic programming method using total utility in the first stage and the sum of the penalties for failure in the second stage when an exceptional event occurs. Computational results are provided to demonstrate the improvement of the proposed model compared to that of previous deterministic models. PMID- 30011933 TI - Mechanisms of Tumor Growth Inhibition by Depletion of gamma Glutamylcyclotransferase (GGCT): A Novel Molecular Target for Anticancer Therapy. AB - gamma-Glutamylcyclotransferase (GGCT), which is one of the major enzymes involved in glutathione metabolism, is upregulated in a wide range of cancers-glioma, breast, lung, esophageal, gastric, colorectal, urinary bladder, prostate, cervical, ovarian cancers and osteosarcoma-and promotes cancer progression; its depletion leads to the suppression of proliferation, invasion, and migration of cancer cells. It has been demonstrated that the suppression or inhibition of GGCT has an antitumor effect in cancer-bearing xenograft mice. Based on these observations, GGCT is now recognized as a promising therapeutic target in various cancers. This review summarizes recent advances on the mechanisms of the antitumor activity of GGCT inhibition. PMID- 30011936 TI - A Non-Destructive System Based on Electrical Tomography and Machine Learning to Analyze the Moisture of Buildings. AB - This article presents the results of research on a new method of spatial analysis of walls and buildings moisture. Due to the fact that destructive methods are not suitable for historical buildings of great architectural significance, a non destructive method based on electrical tomography has been adopted. A hybrid tomograph with special sensors was developed for the measurements. This device enables the acquisition of data, which are then reconstructed by appropriately developed methods enabling spatial analysis of wet buildings. Special electrodes that ensure good contact with the surface of porous building materials such as bricks and cement were introduced. During the research, a group of algorithms enabling supervised machine learning was analyzed. They have been used in the process of converting input electrical values into conductance depicted by the output image pixels. The conductance values of individual pixels of the output vector made it possible to obtain images of the interior of building walls as both flat intersections (2D) and spatial (3D) images. The presented group of algorithms has a high application value. The main advantages of the new methods are: high accuracy of imaging, low costs, high processing speed, ease of application to walls of various thickness and irregular surface. By comparing the results of tomographic reconstructions, the most efficient algorithms were identified. PMID- 30011935 TI - Poly Organotin Acetates against DNA with Possible Implementation on Human Breast Cancer. AB - Two known tin-based polymers of formula {[R3Sn(CH3COO)]n} where R = n-Bu- (1) and R = Ph- (2),were evaluated for their in vitro biological properties. The compounds were characterized via their physical properties and FT-IR, 119Sn Mossbauer, and 1H NMR spectroscopic data. The molecular structures were confirmed by single-crystal X-Ray diffraction crystallography. The geometry around the tin(IV) ion is trigonal bi-pyramidal. Variations in O-Sn-O...Sn' torsion angles lead to zig-zag and helical supramolecular assemblies for 1 and 2, respectively. The in vitro cell viability against human breast adenocarcinoma cancer cell lines: MCF-7 positive to estrogens receptors (ERs) and MDA-MB-231 negative to ERs upon their incubation with 1 and 2 was investigated. Their toxicity has been studied against normal human fetal lung fibroblast cells (MRC-5). Compounds 1 and 2 exhibit 134 and 223-fold respectively stronger antiproliferative activity against MDA-MB-231 than cisplatin. The type of the cell death caused by 1 or 2 was also determined using flow cytometry assay. The binding affinity of 1 and 2 towards the CT-DNA was suspected from the differentiation of the viscosity which occurred in the solution containing increasing amounts of 1 and 2. Changes in fluorescent emission light of Ethidium bromide (EB) in the presence of DNA confirmed the intercalation mode of interactions into DNA of both complexes 1 and 2 which have been ascertained from viscosity measurements. The corresponding apparent binding constants (Kapp) of 1 and 2 towards CT-DNA calculated through fluorescence spectra are 4.9 * 104 (1) and 7.3 * 104 (2) M-1 respectively. Finally, the type of DNA binding interactions with 1 and 2 was confirmed by docking studies. PMID- 30011937 TI - Septic Pulmonary Emboli or Pulmonary Metastasis in a Patient with Diabetes Mellitus? AB - Emphysematous pyelonephritis is a rare but life-threatening infection characterized by an accumulation of gas in the renal parenchyma. A high mortality rate was reported, and timely administration of broad-spectrum antibiotics for enteric gram-negative bacilli, such as Escherichia coli, Enterobacter, and Klebsiella pneumoniae, was recommended for improving the clinical outcome. Computed tomography is a useful tool for identifying gas accumulation within the perirenal space. Abdominal ultrasound and abdominal plain film are alternative options with lower accuracy rates. Here, we present the case of a 49-year-old male patient who presented with acute-onset progressive abdominal cramping pain and dysuria. Diffuse bilateral opacities over the lung field and a heterogeneous mass with air density in the abdomen were found on radiological examination. Multiple septic pulmonary emboli and emphysematous pyelonephritis were diagnosed using computed tomography. After emergency percutaneous nephrostomy and administration of broad-spectrum antibiotics, the patient was discharged in a stable condition and followed up at the outpatient department. This report also describes the clinical and imaging features of emphysematous pyelonephritis and highlights that early diagnosis and timely administration of broad-spectrum antibiotics may help avoid a potentially devastating outcome. PMID- 30011938 TI - Optimization of Scanning and Counting Sensor Layout for Full Route Observability with a Bi-Level Programming Model. AB - Utilizing the data obtained from both scanning and counting sensors is critical for efficiently managing traffic flow on roadways. Past studies mainly focused on the optimal layout of one type of sensor, and how to optimize the arrangement of more than one type of sensor has not been fully researched. This paper develops a methodology that optimizes the deployment of different types of sensors to solve the well-recognized network sensors location problem (NSLP). To answer the questions of how many, where and what types of sensors should be deployed on each particular link of the network, a novel bi-level programming model for full route observability is presented to strategically locate scanning and counting sensors in a network. The methodology works in two steps. First, a mathematical program is formulated to determine the minimum number of scanning sensors. To solve this program, a new 'differentiating matrix' is introduced and the corresponding greedy algorithm of 'differentiating first' is put forward. In the second step, a scanning map and an incidence matrix are incorporated into the program, which extends the theoretical model for multiple sensors' deployment and provides the replacement method to reduce total cost of sensors without loss of observability. The algorithm developed at the second step involved in two coefficient matrixes from scanning map and incidence parameter enumerate all possibilities of replacement schemes so that cost of different combination schemes can be compared. Finally, the proposed approach is demonstrated by comparison of Nguyen Dupuis network and real network, which indicates the proposed method is capable to evaluate the trade-off between cost and all routes observability. PMID- 30011939 TI - A Novel Radiation Method for Preparing MnO2/BC Monolith Hybrids with Outstanding Supercapacitance Performance. AB - A novel facile process for fabrication of amorphous MnO2/bamboo charcoal monolith hybrids (MnO2/BC) for potential supercapacitor applications using gamma irradiation methods is described. The structural, morphological and electrochemical properties of the MnO2/BC hybrids have been investigated using X ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), cyclic voltammetry (CV), galvanostatic charge/discharge (GCD) and electrochemical impedance spectroscopy (EIS) techniques. The combination of BC (electrical double layer charge) and MnO2 (pseudocapacitance) created a complementary effect, which enhanced the specific capacitance and good cyclic stability of the MnO2/BC hybrid electrodes. The MnO2/BC hybrids showed a higher specific capacitance (449 F g-1 at the constant current density of 0.5 A g-1 over the potential range from -0.2 V to 0.8 V), compared with BC (101 F g-1) in 1 M of Na2SO4 aqueous electrolyte. Furthermore, the MnO2/BC hybrid electrodes showed superior cycling stability with 78% capacitance retention, even after 10,000 cycles. The experimental results demonstrated that the high performance of MnO2/BC hybrids could be a potential electrode material for supercapacitors. PMID- 30011941 TI - Novel High-Sensitivity Racetrack Surface Plasmon Resonance Sensor Modified by Graphene. AB - In order to overcome the existing challenges presented by conventional sensors, including their large size, a complicated preparation process, and difficulties filling the sensing media, a novel high-sensitivity plasmonic resonator sensor which is composed of two graphene-modified straight waveguides, two metallic layers, and a racetrack nanodisk resonator is proposed in this study. The transmission characteristics, which were calculated by the finite element theory, were used to further analyze the sensing properties. The results of quantitative analysis show that the proposed plasmonic sensor generates two resonance peaks for the different incident wavelengths, and both resonance peaks can be tuned by temperature. In addition, after optimizing the structural parameters of the resonator, the Q value and the refractive sensitivity reached 21.5 and 1666.67 nmRIU-1, respectively. Compared with other studies, these values translate to a better performance. Furthermore, a temperature sensitivity of 2.33 nm/5 degrees C was achieved, which allows the sensor to be easily applied to practical detection. The results of this study can broaden the useful range for a nanometer scale temperature sensor with ultrafast real-time detection and resistance to electromagnetic interference. PMID- 30011940 TI - Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes. AB - DNA topoisomerase II (TOP2) activity involves a normally transient double-strand break intermediate in which the enzyme is coupled to DNA via a 5'-phosphotyrosyl bond. However, etoposide and other topoisomerase drugs poison the enzyme by stabilising this enzyme-bridged break, resulting in the accumulation of TOP2-DNA covalent complexes with cytotoxic consequences. The phosphotyrosyl diesterase TDP2 appears to be required for efficient repair of this unusual type of DNA damage and can remove 5'-tyrosine adducts from a double-stranded oligonucleotide substrate. Here, we adapt the trapped in agarose DNA immunostaining (TARDIS) assay to investigate the role of TDP2 in the removal of TOP2-DNA complexes in vitro and in cells. We report that TDP2 alone does not remove TOP2-DNA complexes from genomic DNA in vitro and that depletion of TDP2 in cells does not slow the removal of TOP2-DNA complexes. Thus, if TDP2 is involved in repairing TOP2 adducts, there must be one or more prior steps in which the protein-DNA complex is processed before TDP2 removes the remaining 5' tyrosine DNA adducts. While this is partly achieved through the degradation of TOP2 adducts by the proteasome, a proteasome-independent mechanism has also been described involving the SUMOylation of TOP2 by the ZATT E3 SUMO ligase. The TARDIS assay was also adapted to measure the effect of TDP2 knockdown on levels of SUMOylated TOP2-DNA complexes, which together with levels of double strand breaks were unaffected in K562 cells following etoposide exposure and proteasomal inhibition. PMID- 30011942 TI - Short-Term Traffic State Prediction Based on the Spatiotemporal Features of Critical Road Sections. AB - Recently, short-term traffic prediction under conditions with corrupted or missing data has become a popular topic. Since a road section has predictive power regarding the adjacent roads at a specific location, this paper proposes a novel hybrid convolutional long short-term memory neural network model based on critical road sections (CRS-ConvLSTM NN) to predict the traffic evolution of global networks. The critical road sections that have the most powerful impact on the subnetwork are identified by a spatiotemporal correlation algorithm. Subsequently, the traffic speed of the critical road sections is used as the input to the ConvLSTM to predict the future traffic states of the entire network. The experimental results from a Beijing traffic network indicate that the CRS ConvLSTM outperforms prevailing deep learning (DL) approaches for cases that consider critical road sections and the results validate the capability and generalizability of the model when predicting with different numbers of critical road sections. PMID- 30011943 TI - Intracellular Localization of Blattella germanica Densovirus (BgDV1) Capsid Proteins. AB - Densovirus genome replication and capsid assembly take place in the nucleus of the infected cells. However, the mechanisms underlying such processes as the delivery of virus proteins to the nucleus and the export of progeny virus from the nucleus remain elusive. It is evident that nuclear transport signals should be involved in these processes. We performed an in silico search for the putative nuclear localization signal (NLS) and nuclear export signal (NES) motifs in the capsid proteins of the Blattella germanica Densovirus 1 (BgDV1) densovirus. A high probability NLS motif was found in the common C-terminal of capsid proteins together with a NES motif in the unique N-terminal of VP2. We also performed a global search for the nuclear traffic signals in the densoviruses belonging to five Densovirinae genera, which revealed high diversity in the patterns of NLSs and NESs. Using a heterologous system, the HeLa mammalian cell line expressing GFP-fused BgDV1 capsid proteins, we demonstrated that both signals are functionally active. We suggest that the NLS shared by all three BgDV1 capsid proteins drives the trafficking of the newly-synthesized proteins into the nucleus, while the NES may play a role in the export of the newly-assembled BgDV1 particles into the cytoplasm through nuclear pore complexes. PMID- 30011944 TI - Polypyrrole/Agarose Hydrogel-Based Bladder Volume Sensor with a Resistor Ladder Structure. AB - Chronic monitoring of bladder activity and urine volume is essential for patients suffering from urinary dysfunctions. However, due to the anatomy and dynamics of the bladder, chronic and precise monitoring of bladder activity remains a challenge. Here, we propose a new sensing mechanism that measures the bladder volume using a resistive ladder network with contact switches. Instead of measuring the impedance between the electrode continuously, the proposed sensor provides a digitized output ('on' or 'off') when the bladder volume reaches a certain threshold value. We present simple proof-of-concept sensors which compare the discrete-mode operation to the continuous-mode operation. In addition, by using multiple pairs of this contact-mode switch in a resistor ladder structure, we demonstrate monitoring of the bladder volume in four discrete steps using an idealized balloon and an ex vivo pig's bladder. We implemented the resistive ladder network using a conductive polypyrrole/agarose hydrogel composite which exhibits a Young's modulus comparable to that of the bladder wall. Compared to the continuous-mode operation, the proposed sensing mechanism is less susceptible to drift due to material degradation and environmental factors. PMID- 30011945 TI - An Extract Purified from the Mycelium of a Tomato Wilt-Controlling Strain of Fusarium sambucinum Can Protect Wheat against Fusarium and Common Root Rots. AB - An approach to manage seed-transmitted Fusarium crown-foot-root rot (FCR, Fusarium spp.) and common root rot (CRR, Bipolaris sorokiniana) on wheat, avoiding environmental risks of chemicals, is seed treatments with microbial metabolites. F. sambucinum strain FS-94 that induces resistance to tomato wilt was shown by this study to be a source of non-fungitoxic wheat-protecting metabolites, which were contained in a mycelium extract purified by gel chromatography and ultrafiltration. Plant-protecting effect of the purified mycelial extract (PME) was demonstrated in vegetation experiments using a rolled towel assay and by small-plot field trials. To elucidate mechanisms putatively underlying PME protective activity, tests with cultured Triticum aestivum and T. kiharae cells, particularly the extracellular alkalinization assay, as well as gene expression analysis in germinated wheat seeds were used. Pre-inoculation treatments of seeds with PME significantly decreased the incidence (from 30 to 40%) and severity (from 37 to 50%) of root rots on seedlings without any inhibition of the seed germination and potentiation of deoxynivalenol (DON), DON monoacetylated derivatives and zearalenon production in FCR agents. In vegetation experiments, reductions in the DON production were observed with doses of 0.5 and 1 mg/mL of PME. Pre-sowing PME application on seeds of two spring wheat cultivars naturally infected with FCR and CRR provided the mitigation of both diseases under field conditions during four growing seasons (2013-2016). PME-induced ion exchange response in cultured wheat cells, their increased survivability, and up regulated expression of some defensins' genes in PME-exposed seedlings allow the suggestion of the plant-mediated character of disease-controlling effect observed in field. PMID- 30011946 TI - Fabrication and In Vitro Characterization of Bioactive Glass/Nano Hydroxyapatite Reinforced Electrospun Poly(epsilon-Caprolactone) Composite Membranes for Guided Tissue Regeneration. AB - BACKGROUND: Current resorbable and non-resorbable membranes act as a physical barrier to avoid connective and epithelial tissue downgrowth into the defect, favoring the regeneration of periodontal tissues. These conventional membranes possess many structural and bio-functional limitations. We hypothesized that the next-generation of guided tissue regeneration (GTR) membranes for periodontal tissue engineering will be a biologically active, spatially designed nanofibrous biomaterial that closely mimics the native extra-cellular matrix (ECM). METHODS: GTR membranes made of poly(epsilon-Caprolactone) with a molecular weight of 80,000 reinforced with different weight concentrations of nano Hydroxyapatite/Bioactive glass (2%, 5%, 10%, 15%) is fabricated by the method of electrospinning. After fabrication, in vitro properties are evaluated. RESULTS: The electrospun nanofibrous membranes possessed excellent mechanical properties initially and after one month of degradation in phosphate buffer solution (PBS). Moreover, none of the fabricated membranes were found to be cytotoxic at lower concentrations and higher concentrations. Comparing the overall properties, PCL (poly(e-caprolactone)) + BG (Bioactive glass) 2% exhibited superior cell attachment and percentage of viable cells, increased fiber and pore diameter which satisfies the ideal properties needed for GTR membranes. CONCLUSION: Composite nanofibrous membranes prepared by electrospinning are suitable for use as a GTR membrane and are a useful prototype for further development of a final membrane for clinical use. PMID- 30011948 TI - A 35 MHz/105 MHz Dual-Element Focused Transducer for Intravascular Ultrasound Tissue Imaging Using the Third Harmonic. AB - The superharmonic imaging of tissue has the potential for high spatial and contrast resolutions, compared to the fundamental and second harmonic imaging. For this technique, the spectral bandwidth of an ultrasound transducer is divided for transmission of ultrasound and reception of its superharmonics (i.e., higher than the second harmonic). Due to the spectral division for the transmission and reception, transmitted ultrasound energy is not sufficient to induce superharmonics in media without using contrast agents, and it is difficult that a transducer has a -6 dB fractional bandwidth of higher than 100%. For the superharmonic imaging of tissue, thus, multi-frequency array transducers are the best choice if available; transmit and receive elements are separate and have different center frequencies. However, the construction of a multi-frequency transducer for intravascular ultrasound (IVUS) imaging is particularly demanding because of its small size of less than 1 mm. Here, we report a recently developed dual-element focused IVUS transducer for the third harmonic imaging of tissue, which consists of a 35-MHz element for ultrasound transmission and a 105-MHz element for third harmonic reception. For high quality third harmonic imaging, both elements were fabricated to have the same focus at 2.5 mm. The results of tissue mimicking phantom tests demonstrated that the third harmonic images produced by the developed transducer had higher spatial resolution and deeper imaging depth than the fundamental images. PMID- 30011947 TI - SiCILIA-Silicon Carbide Detectors for Intense Luminosity Investigations and Applications. AB - Silicon carbide (SiC) is a compound semiconductor, which is considered as a possible alternative to silicon for particles and photons detection. Its characteristics make it very promising for the next generation of nuclear and particle physics experiments at high beam luminosity. Silicon Carbide detectors for Intense Luminosity Investigations and Applications (SiCILIA) is a project starting as a collaboration between the Italian National Institute of Nuclear Physics (INFN) and IMM-CNR, aiming at the realization of innovative detection systems based on SiC. In this paper, we discuss the main features of silicon carbide as a material and its potential application in the field of particles and photons detectors, the project structure and the strategies used for the prototype realization, and the first results concerning prototype production and their performance. PMID- 30011949 TI - Oral Symptoms and Oral Health-Related Quality of Life in People with Rare Diseases in Germany: A Cross-Sectional Study. AB - Background: The aim of this study was to collect information on oral health related quality of life (OHRQoL) in people with rare diseases. Methods: A questionnaire comprising free text questions and the German version of the standardized Oral Health Impact Profile-14 (OHIP-14) questionnaire on OHRQoL was developed. All participants who indicated oral symptoms in the questionnaire were included in a cluster analysis. Different cluster analyses were performed (Ward's, k-Means) to find symptom profile groups in the data. Results: A total of 484 questionnaires with 96 rare diseases were included in the study. The most reported symptoms were anomalies of the tooth formation, dysgnathia, changes in number of the teeth, and malocclusions. The OHIP mean values of the five resulting symptom clusters ranged from 15.1 to 19.9, which is very high compared to the general population in Germany, which has a mean value of 4.09. Discussion: All investigated symptoms show a negative association with OHRQoL, but the strongest were for symptoms of the oral mucosa and periodontal diseases. All the symptoms described in this cluster analysis can lead to considerably higher mean values of the OHIP total score among people with rare disease and thus to worse OHRQoL than reported in the general population. PMID- 30011950 TI - Roof-Inhabiting Cousins of Rock-Inhabiting Fungi: Novel Melanized Microcolonial Fungal Species from Photocatalytically Reactive Subaerial Surfaces. AB - Subaerial biofilms (SAB) are an important factor in weathering, biofouling, and biodeterioration of bare rocks, building materials, and solar panel surfaces. The realm of SAB is continually widened by modern materials, and the settlers on these exposed solid surfaces always include melanized, stress-tolerant microcolonial ascomycetes. After their first discovery on desert rock surfaces, these melanized chaetothyrialean and dothidealean ascomycetes have been found on Mediterranean monuments after biocidal treatments, Antarctic rocks and solar panels. New man-made modifications of surfaces (e.g., treatment with biocides or photocatalytically active layers) accommodate the exceptional stress-tolerance of microcolonial fungi and thus further select for this well-protected ecological group. Melanized fungal strains were isolated from a microbial community that developed on highly photocatalytic roof tiles after a long-term environmental exposure in a maritime-influenced region in northwestern Germany. Four of the isolated strains are described here as a novel species, Constantinomyces oldenburgensis, based on multilocus ITS, LSU, RPB2 gene phylogeny. Their closest relative is a still-unnamed rock-inhabiting strain TRN431, here described as C. patonensis. Both species cluster in Capnodiales, among typical melanized microcolonial rock fungi from different stress habitats, including Antarctica. These novel strains flourish in hostile conditions of highly oxidizing material surfaces, and shall be used in reference procedures in material testing. PMID- 30011951 TI - Microwave-Assisted Synthesis of Some Potential Bioactive Imidazolium-Based Room Temperature Ionic Liquids. AB - An environmentally-friendly and easy synthesis of a series of novel functionalized imidazolium-based ionic liquids (ILs) is described under both the conventional procedure and microwave irradiation. The structures of newly synthesized room-temperature ionic liquids (RTILs) were established by different spectral analyses. All ILs (1-14) were screened for their in vitro antimicrobial activity against a panel of clinically isolated bacteria. The results of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) showed that some of the tested ILs are very promising anti-bacterial agents especially those containing an alkyl chain with a phenyl group (most notably 1, 2, 12, and 13). PMID- 30011952 TI - Comparative Analysis of Impatiens Leaf Transcriptomes Reveal Candidate Genes for Resistance to Downy Mildew Caused by Plasmopara obducens. AB - Impatiens downy mildew (IDM) is a devastating disease to garden impatiens. A good understanding of IDM resistance in New Guinea impatiens is essential for improving garden impatiens resistance to this disease. The present study was conducted to sequence, assemble, annotate and compare the leaf transcriptomes of two impatiens cultivars differing in resistance to IDM, reveal sequence polymorphisms and identify candidate genes for IDM resistance. RNA-Seq was performed on cultivars Super Elfin(r) XP Pink (SEP) and SunPatiens(r) Compact Royal Magenta (SPR). De novo assembly of obtained sequence reads resulted in 121,497 unigenes with an average length of 1156 nucleotides and N50 length of 1778 nucleotides. Searching the non-redundant protein and non-redundant nucleotide, Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes and Clusters of Orthologous Groups and Gene Ontology databases, resulted in annotation of 57.7% to 73.6% of the unigenes. Fifteen unigenes were highly similar to disease resistance genes and more abundant in the IDM-resistant cultivar than in the susceptible cultivar. A total of 22,484 simple sequence repeats (SSRs) and 245,936 and 120,073 single nucleotide polymorphisms (SNPs) were identified from SPR and SEP respectively. The assembled transcripts and unigenes, identified disease resistance genes and SSRs and SNPs sites will be a valuable resource for improving impatiens and its IDM resistance. PMID- 30011953 TI - Development of Conjugate Addition of Lithium Dialkylcuprates to Thiochromones: Synthesis of 2-Alkylthiochroman-4-ones and Additional Synthetic Applications. AB - Lithium dialkylcuprates undergo conjugate addition to thiochromones to afford 2 alkylthiochroman-4-ones in good yields. This approach provide an efficient and general synthetic approach to privileged sulfur-containing structural motifs and valuable precursors for many pharmaceuticals, starting from common substrates thiochromones. Good yields of 2-alkyl-substituted thiochroman-4-ones are attained with lithium dialkylcuprates, lithium alkylcyanocuprates or substoichiometric amount of copper salts. The use of commercially available inexpensive alkyllithium reagents will expedite the synthesis of a large library of 2-alkyl substituted thiochroman-4-ones for additional synthetic applications. PMID- 30011955 TI - Investigation of the Propagation of Stress Wave in Nickel-Titanium Shape Memory Alloys. AB - Based on irreversible thermodynamic theory, a new constitutive model incorporating two internal variables was proposed to investigate the phase transformation and plasticity behavior in nickel-titanium (NiTi) shape memory alloys (SMAs), by taking into account four deformation stages, namely austenite elastic phase, phase transition, martensitic elastic phase, and plastic phase. The model using the material point method (MPM) was implemented by the FORTRAN code to investigate the stress wave and its propagation in a NiTi rod. The results showed that its wave propagation exhibited martensitic and austenitic elastic wave, phase transition wave, and plastic wave. However, a double-wave structure including the martensitic and austenitic elastic wave and plastic wave occurred when the martensitic elastic wave reached the phase transformation wave. Thus, the reflection wave at a fixed boundary exhibited a different behavior compared with the elastic one, which was attributed to the phase transition during the process of reflection. It was found that the stress increment was proportional to the velocity of phase transition wave after the stress wave reflection. In addition, the influences of loading direction and strain rate on the wave propagation were examined as well. It was found that the phase transition wave velocity increased as the strain rate increased. The elastic wave velocity of martensite under compressive conditions was larger than that under tensile loading. In contrast, the plastic wave velocity under compression was less than that subjected to the tensile load. PMID- 30011954 TI - Prenatal Exposure to Aluminum and Status of Selected Essential Trace Elements in Rural South African Women at Delivery. AB - This study sought to evaluate the in utero exposure to aluminum and status of selected trace elements in South African women at delivery since aluminum is known to be toxic in all developmental stages even at low concentrations. Serum aluminum was negatively correlated with aluminum in urine, both uncorrected and corrected for creatinine, which suggests the retention of aluminum in body stores. Serum copper and zinc levels were found to be high in this study population. Serum copper levels were negatively correlated with aluminum in serum (beta = -0.095; p = 0.05). There was a marginal negative correlation between aluminum levels in serum and manganese levels in whole blood (beta = -0.087; p = 0.08). Copper levels in maternal serum were negatively correlated with birth weight and the length of neonates. There were a number of positive correlations between maternal characteristics and birth outcomes. Mothers who consumed root vegetables frequently appeared to be protected from aluminum retention and increased body burden since their serum aluminum levels were found to be significantly lower. The findings of the current study can be used as a baseline for further research on aluminum exposure and its associated interactions and outcomes in vulnerable populations. PMID- 30011956 TI - Nutritional Interventions as Beneficial Strategies to Delay Cognitive Decline in Healthy Older Individuals. AB - Current demographic trends indicate that the population is aging. The aging process is inevitably connected with cognitive decline, which manifests itself in worsening working memory, processing speed, and attention. Therefore, apart from pharmacological therapies, non-pharmacological approaches which can influence cognitive performance (such as physical activities or healthy diet), are being investigated. The purpose of this study is to explore the types of nutritional interventions and their benefits in the prevention and delay of cognitive delay in healthy older individuals. The methods used in this study include a literature review of the available studies on the research topic found in Web of Science, Scopus, and MEDLINE. The findings show that nutritional intervention has a positive impact on cognitive function in healthy older people. However, it seems that the interactions between more than one nutrient are most effective. The results reveal that specifically the Mediterranean diet appears to be effective in this respect. Moreover, the findings also indicate that multi-domain interventions including diet, exercise, cognitive training, and vascular risk monitoring have a far more significant effect on the enhancement of cognitive functions among healthy older individuals. PMID- 30011958 TI - Strategic Location-Based Random Routing for Source Location Privacy in Wireless Sensor Networks. AB - Wireless sensor networks (WSNs) are deployed in sensitive applications, such as in military and asset monitoring. In these applications, it is important to ensure good source location privacy. This is owing to the open nature of WSNs and the easiness of an adversary to eavesdrop on sensor communication and back trace the location of the source node. This paper proposes a scheme to preserve the source location privacy based on random routing techniques. To achieve high privacy, packets are randomly routed from the source to the sink node through strategically positioned mediate or diversion nodes. The random selection of mediate or diversion nodes is location-based. Depending on the location of the source node, packets are forwarded through different regions of the network. The proposed scheme guarantees that successive packets are routed through very different routing paths and adversaries find it confusing to back trace them to the source node location. Simulation results demonstrate that the proposed scheme effectively confuses the adversary and provides higher source location privacy to outperform other routing-based source location privacy schemes. PMID- 30011959 TI - Lagrange Programming Neural Network for TOA-Based Localization with Clock Asynchronization and Sensor Location Uncertainties. AB - Source localization based on time of arrival (TOA) measurements in the presence of clock asynchronization and sensor position uncertainties is investigated in this paper. Different from the traditional numerical algorithms, a neural circuit named Lagrange programming neural network (LPNN) is employed to tackle the nonlinear and nonconvex constrained optimization problem of source localization. With the augmented term, two types of neural networks are developed from the original maximum likelihood functions based on the general framework provided by LPNN. The convergence and local stability of the proposed neural networks are analyzed in this paper. In addition, the Cramer-Rao lower bound is also derived as a benchmark in the presence of clock asynchronization and sensor position uncertainties. Simulation results verify the superior performance of the proposed LPNN over the traditional numerical algorithms and its robustness to resist the impact of a high level of measurement noise, clock asynchronization, as well as sensor position uncertainties. PMID- 30011957 TI - Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer. AB - Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients' specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC. PMID- 30011960 TI - A Novel Method for Estimating Free Space 3D Point-of-Regard Using Pupillary Reflex and Line-of-Sight Convergence Points. AB - In this paper, a novel 3D gaze estimation method for a wearable gaze tracking device is proposed. This method is based on the pupillary accommodation reflex of human vision. Firstly, a 3D gaze measurement model is built. By uniting the line of-sight convergence point and the size of the pupil, this model can be used to measure the 3D Point-of-Regard in free space. Secondly, a gaze tracking device is described. By using four cameras and semi-transparent mirrors, the gaze tracking device can accurately extract the spatial coordinates of the pupil and eye corner of the human eye from images. Thirdly, a simple calibration process of the measuring system is proposed. This method can be sketched as follows: (1) each eye is imaged by a pair of binocular stereo cameras, and the setting of semi transparent mirrors can support a better field of view; (2) the spatial coordinates of the pupil center and the inner corner of the eye in the images of the stereo cameras are extracted, and the pupil size is calculated with the features of the gaze estimation method; (3) the pupil size and the line-of-sight convergence point when watching the calibration target at different distances are computed, and the parameters of the gaze estimation model are determined. Fourthly, an algorithm for searching the line-of-sight convergence point is proposed, and the 3D Point-of-Regard is estimated by using the obtained line-of sight measurement model. Three groups of experiments were conducted to prove the effectiveness of the proposed method. This approach enables people to obtain the spatial coordinates of the Point-of-Regard in free space, which has great potential in the application of wearable devices. PMID- 30011961 TI - Inheritance and Genetic Mapping of the Reduced Height (Rht18) Gene in Wheat. AB - Short-statured plants revolutionized agriculture during the 1960s due to their ability to resist lodging, increased their response to fertilizers, and improved partitioning of assimilates which led to yield gains. Of more than 21 reduced height (Rht) genes reported in wheat, only three-Rht-B1b, Rht-D1b, and Rht8-were extensively used in wheat breeding programs. The remaining reduced height mutants have not been utilized in breeding programs due to the lack of characterization. In the present study, we determined the inheritance of Rht18 and developed a genetic linkage map of the region containing Rht18. The height distribution of the F2 population was skewed towards the mutant parent, indicating that the dwarf allele (Rht18) is semi-dominant over the tall allele (rht18). Rht18 was mapped on chromosome 6A between markers barc146 and cfd190 with a genetic distance of 26.2 and 17.3 cM, respectively. In addition to plant height, agronomically important traits, like awns and tiller numbers, were also studied in the bi-parental population. Although the average tiller number was very similar in both parents, the F2 population displayed a normal distribution for tiller number with the majority of plants having phenotype similar to the parents. Transgressive segregation was observed for plant height and tiller number in F2 population. This study enabled us to select a semi-dwarf line with superior agronomic characteristics that could be utilized in a breeding program. The identification of SSRs associated with Rht18 may improve breeders' effectiveness in selecting desired semi-dwarf lines for developing new wheat cultivars. PMID- 30011962 TI - Seasonal Growth of Zygophyllum dumosum Boiss.: Summer Dormancy Is Associated with Loss of the Permissive Epigenetic Marker Dimethyl H3K4 and Extensive Reduction in Proteins Involved in Basic Cell Functions. AB - Plants thriving in desert environments are suitable for studying mechanisms for plant survival under extreme seasonal climate variation. We studied epigenetic mechanisms underlying seasonal growth cycles in the desert plant Zygophyllum dumosum Boiss., which was previously shown to be deficient in repressive markers of di-methyl and tri-methyl H3K9 and their association with factors regulating basic cell functions. We showed a contingent association between rainfall and seasonal growth and the epigenetic marker of dimethyl H3K4, which disappears upon entry into the dry season and the acquisition of a dormant state. DNA methylation is not affected by a lack of H3K9 di-methyl and tri-methyl. Changes in methylation can occur between the wet and dry season. Proteome analysis of acid soluble fractions revealed an extensive reduction in ribosomal proteins and in proteins involved in chloroplasts and mitochondrial activities during the dry seasons concomitantly with up-regulation of molecular chaperone HSPs. Our results highlight mechanisms underlying Z. dumosum adaptation to seasonal climate variation. Particularly, summer dormancy is associated with a loss of the permissive epigenetic marker dimethyl H3K4, which might facilitate genome compaction concomitantly with a significant reduction in proteins involved in basic cell functions. HSP chaperones might safeguard the integrity of cell components. PMID- 30011963 TI - Age-Related Changes in MicroRNA in the Rat Pituitary and Potential Role in GH Regulation. AB - The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis has recently been recognized as an important factor related to the longevity of many organisms. MicroRNAs (miRNAs or miRs) could also participate in diverse biological processes. However, the role of miRNAs in the decline of pituitary GH during the growth process remains unclear. To better characterize the effects of miRNAs on the pituitary, we used a miRNA microarray to investigate the miRNA profile in the rat pituitary from postnatal development throughout the growth process. Then, in vitro experiments were conducted to analyze the miRNAs' potential roles related to GH regulation. Taken together, the microarray results indicated that there were 22 miRNAs differentially expressed during pituitary development. The bioinformatics analysis suggested that the most differentially expressed miRNAs may participate in multiple pathways associated with the pituitary function. Furthermore, the in vitro findings demonstrated that miR-141-3p was involved in GH regulation. PMID- 30011964 TI - Tenogenesis of Decellularized Porcine Achilles Tendon Matrix Reseeded with Human Tenocytes in the Nude Mice Xenograft Model. AB - Cultivation of autologous human tenocytes in a cell-free xenogenic extracellular tendon matrix (xECM) could present an approach for tendon reconstruction. The aim of this study was to achieve tendon-like tissue formation by implanting decellularized porcine Achilles tendons recellularized with human hamstring tendon-derived tenocytes into nude mice. The structure of decellularized xECM was histologically monitored before being dynamically reseeded with human tenocytes. After 6-12 weeks in vivo, construct quality was monitored using macroscopical and histological scoring systems, vitality assay and quantitative DNA and glycosaminoglycan (GAG) assays. For comparison to tendon xECM, a synthetic polyglycolic acid (PGA) polymer was implanted in a similar manner. Despite decellularized xECM lost some GAGs and structure, it could be recellularized in vitro with human tenocytes, but the cell distribution remained inhomogeneous, with accumulations at the margins of the constructs. In vivo, the xECM constructs revealed in contrast to the PGA no altered size, no inflammation and encapsulation and a more homogeneous cell distribution. xECM reseeded with tenocytes showed superior histological quality than cell-free implanted constructs and contained surviving human cells. Their DNA content after six and 12 weeks in vivo resembled that of native tendon and xECM recellularized in vitro. Results suggest that reseeded decellularized xECM formed a tendon-like tissue in vivo. PMID- 30011965 TI - Nurses' Attitudes toward, and Needs for Online Learning: Differences between Rural and Urban Hospitals in Shanghai, East China. AB - Health professionals need continuing education to maintain their qualifications and competency. Online learning increases the accessibility and flexibility of continuing education. Assessment of nurses' attitudes toward, and needs for, online learning can provide suggestions regarding learning program design and delivery. This study aimed to evaluate Chinese nurses' attitudes toward, and needs for, online learning, and to explore the differences in attitudes and needs between nurses working in rural and urban hospitals. This work is a secondary analysis of a multicenter cross-sectional study conducted in Shanghai in 2015 (n = 550). Multiple regression techniques were used to determine the factors associated with nurses' attitudes toward, and needs for, online learning. Results showed that nurses in rural hospitals had more positive attitudes toward online learning (102.7 +/- 14.2) than those in urban hospitals (98.3 +/- 12.9) (p < 0.001). For rural hospitals, nurses who could use computers and access the internet in their workplace reported more positive attitudes than those who could not. For urban hospitals, nurse educators showed significantly more positive attitudes than others. Communication skills (86.5%) and patient education (86.3%) were the most commonly-reported learning needs for nurses regardless of their working settings. Chinese nurses were willing to adopt online learning as a continuing education method. Nurses working in rural hospitals displayed more positive attitudes toward, and needs for, online learning than those working in urban hospitals. Nursing educators and managers should develop online learning programs and provide appropriate support to fulfill nurses' learning needs, especially for those working in rural healthcare settings. PMID- 30011967 TI - A Component Decomposition Model for 3D Laser Scanning Pavement Data Based on High Pass Filtering and Sparse Analysis. AB - High-precision 3D laser scanning pavement data contains rich pavement scene information and certain components associations. Moreover, for pavement maintenance and management, there is an urgent need to develop automatic methods that can extract comprehensive information about different pavement indicators simultaneously. By analyzing the frequency and sparse characteristics of pavement distresses and performance indicators-including the cracks, road markings, rutting, potholes, textures-this paper proposes 3D pavement components decomposition model (3D-PCDM) which decomposes the 3D pavement profiles into sparse components x, low-frequency components f, and vibration components t. Designed high-pass filter was first employed to separate f, then, x and t are separated by total variation de-noising which based on sparse characteristics. Decomposed x can be used to characterize the location and depth information of sparse and sparse derived signals such as cracks, road marks, grooves, and potholes in profiles. Decomposed f can be used to determine the slow deformation of pavement. While decomposed t reflects the fluctuation of the pavement material particles. Experiments were conducted using actual pavement 3D data, the decomposed components can obtain by 3D-PCDM. The effectiveness and accuracy of the x are verified by actual cracks and road markings, the accuracy of extracted sparse components is over 92.75%. PMID- 30011968 TI - Joint Full-Duplex/Half-Duplex Transmission-Switching Scheduling and Transmission Energy Allocation in Cognitive Radio Networks with Energy Harvesting. AB - The full-duplex transmission protocol has been widely investigated in the literature in order to improve radio spectrum usage efficiency. Unfortunately, due to the effect of imperfect self-interference suppression, the change in transmission power and path loss of non-line-of-sight fading channels will strongly affect performance of full-duplex transmission mode. This entails that the full-duplex transmission protocol is not always a better selection compared to the traditional half-duplex transmission protocol. Considering solar energy harvesting-powered cognitive radio networks (CRNs), we investigate a joint full duplex/half-duplex transmission switching scheduling and transmission power allocation in which we utilize the advantages of both half-duplex and full-duplex transmission modes for maximizing the long-term throughput of cognitive radio networks. First, we formulate the transmission rate of half-duplex and full duplex links for fading channels between cognitive user and base station in which the channel gain is assumed to follow an exponential distribution. Afterward, by considering the availability probability of the primary channel, the limitation of the energy-harvesting capacity of the cognitive user, and the transmission capacity of half-duplex and full-duplex links, we describe the problem in terms of long-term expected throughput. The problem is then solved by adopting the partially observable Markov decision process framework to find the optimal transmission policy for the transmission pair between cognitive user and base station in order to maximize the long-term expected throughput. The optimal policy consists of either the half-duplex or the full-duplex transmission protocols as well as the corresponding amount of transmission energy in each time slot. In addition, to reduce the complexity in formulation and calculation, we also apply the actor-critic-based learning method to solve the considered problem. Finally, the performance of the proposed scheme was evaluated by comparing it with a conventional scheme in which the context of energy harvesting and long-term throughput is not considered. PMID- 30011970 TI - Multimodal Biometric Recognition Based on Convolutional Neural Network by the Fusion of Finger-Vein and Finger Shape Using Near-Infrared (NIR) Camera Sensor. AB - Finger-vein recognition, which is one of the conventional biometrics, hinders fake attacks, is cheaper, and it features a higher level of user-convenience than other biometrics because it uses miniaturized devices. However, the recognition performance of finger-vein recognition methods may decrease due to a variety of factors, such as image misalignment that is caused by finger position changes during image acquisition or illumination variation caused by non-uniform near infrared (NIR) light. To solve such problems, multimodal biometric systems that are able to simultaneously recognize both finger-veins and fingerprints have been researched. However, because the image-acquisition positions for finger-veins and fingerprints are different, not to mention that finger-vein images must be acquired in NIR light environments and fingerprints in visible light environments, either two sensors must be used, or the size of the image acquisition device must be enlarged. Hence, there are multimodal biometrics based on finger-veins and finger shapes. However, such methods recognize individuals that are based on handcrafted features, which present certain limitations in terms of performance improvement. To solve these problems, finger-vein and finger shape multimodal biometrics using near-infrared (NIR) light camera sensor based on a deep convolutional neural network (CNN) are proposed in this research. Experimental results obtained using two types of open databases, the Shandong University homologous multi-modal traits (SDUMLA-HMT) and the Hong Kong Polytechnic University Finger Image Database (version 1), revealed that the proposed method in the present study features superior performance to the conventional methods. PMID- 30011969 TI - A Non-Enzymatic Method to Obtain a Fat Tissue Derivative Highly Enriched in Adipose Stem Cells (ASCs) from Human Lipoaspirates: Preliminary Results. AB - Adipose tissue possesses phenotypic gene expression characteristics that are similar to human mesenchymal stem cells (hMSCs). Nevertheless, the multilineage potential may be inhibited, and cells may not expand adequately to satisfy the requirements of Good Manufacturing Practice (cGMP). An autologous hMSC-enriched fat product would fulfil the void from a biomedical and clinical perspective. In this study, we suggest a novel mechanism using a closed system without enzymes, additives or other modifications, which will produce non-expanded, accessible material. This decentralized fat product, unlike unprocessed lipoaspirates, adequately encloses the vascular stroma with adipocytes and stromal stalks along with their vascular channels and lumina. This fat product contained hASCs and fewer hematopoietic elements such as lipoaspirates, which were digested enzymatically according to flow cytometric investigations, and molecular analysis also showed significant hASC uniformity within the cells of the stromal vascular tissue. Moreover, the fat product produced a higher quantity of hASCs similar to hMSCs in isolation with the typical characteristics of an osteogenic, chondrogenic and adipogenic lineage. Interestingly, these properties were evident in the non-enzymatic derived adipose tissue, as opposed to hASCs in isolation from the enzymatically digested lipoaspirates, suggesting that the aforementioned procedure may be an adequate alternative to regenerate and engineer tissue for the treatment of various medical conditions and promote efficient patient recovery. PMID- 30011972 TI - The musculature of squid arms and tentacles: Ultrastructural evidence for functional differences. AB - The transverse muscle mass of the arm and the transverse and circular muscle masses of the tentacle of squid (Loligo pealei and Illex illecebrosus) were examined by transmission electron microscopy. Previous work had indicated that although similar in gross arrangement, the transverse muscle mass of the tentacle creates rapid elongation during prey capture while the transverse muscle mass of the arm is involved in creating bending movements. The difference in function between the transverse muscle masses of the arms and tentacles is reflected in differences in ultrastructure. The transverse muscle mass of the arm is made up of regular, obliquely striated muscle fibers 1-6 MUm in diameter. The transverse and associated circular muscle masses of the tentacle are made up of cross striated muscle fibers 1-3 MUm in diameter. The cross-striated muscle fibers have A bands approximately 0.5 MUm (I. illecebrosus) and 0.9 MUm (L. pealei) in length and a resting sarcomere length of 0.9 MUm (I. illecebrosus) and 1.6 MUm (L. pealei), suggesting a relatively high shortening speed for this muscle type. The cross-striated cells are not divided up into myofibrils, and the sarcoplasmic reticulum is located beneath the sarcolemma. Vernier displacements of the sarcomeres were observed. The myofilaments of the obliquely striated muscle fibers of the arm surround a central core containing mitochondria and the cell nucleus. The sarcoplasmic reticulum of the obliquely striated cells is located beneath the sarcolemma, in the plane of the Z elements, and surrounding the mitochondrial core. PMID- 30011973 TI - Tooth replacement and growth in the young green iguana, Iguana iguana. AB - A study using eight rapidly growing young green iguanas (Iguana iguana; initial mean weight 68.0 +/- 3.8 gm) examined the changes in the wave replacement of teeth, the increased size of the teeth, and the posterior migration of tooth positions over a period of 16 weeks. The teeth increase in width as the lizards grow. The tooth positions shifted posteriorly, providing adequate space for the larger replacement teeth. These observations suggest that the wave replacement of teeth allows for growth of the dentition in length and height adequate to maintain tooth size in proportion to the overall size of the individual. PMID- 30011974 TI - The ultrastructure of the cardiac ganglion of the desert scorpion, Paruroctonus mesaensis (Scorpionida: Vaejovidae). AB - Light and electron microscopy of the pacemaker ganglion of the scorpion heart indicate that it is about 15 mm long and 50 MUm in diameter and extends along the dorsal midline of the heart. The largest cell bodies (30-45 MUm in diameter) occur in clusters along the length of the ganglion. The ganglion appears to be innervated with fibers from the subesophageal and first three abdominal ganglia. The cardiac ganglion is surrounded by a neurilemma and a membranous sheath. The latter is apparently derived from connective tissue cells seen outside the ganglion. Nerve fibers other than those in the neuropil areas are usually surrounded by membrane and cytoplasm of glial cells. Often there are several layers of glial membrane, forming a loose myelin. The cardiac nerves to the heart muscle are also surrounded by a neurilemma, and the axons are surrounded by glia. The motor nerves contain lucent vesicles 60-100 nm and opaque granules 120-180 nm in diameter. In the cardiac ganglion, some nerve cell bodies have complex invaginations of glial processes forming a peripheral trophospongium. In the neuropil areas, nerve cell processes are often in close apposition. The septilaminar configuration typical of gap junctions is common, with gap distances of 1-4 nm. In tissues stained with lanthanum phosphate during fixation, we found gaps with unstained connections (1-2 nm diameter) between nerve-nerve and glial nerve cell processes. Annular or double-membrane vesicles in various stages of formation were also seen in some nerve fibers in ganglia stained with lanthanum phosphate. Nerve endings with electron-lucent vesicles 40-60 nm in diameter are abundant in the cardiac ganglion, suggesting that these contain the excitatory transmitter of intrinsic neurons of the ganglion. Less abundant are fibers with membrane-limited opaque granules, circular or oblong in shape and as much as 330 nm in their longest dimension. Also seen were some nerve endings with both vesicles and granules. PMID- 30011975 TI - Ultrastructure of salivary glands of Ornithodoros (Ornithodoros) moubata (Ixodoidea: Argasidae). AB - The paired salivary glands of unfed adult Ornithodoros (Ornithodoros) moubata are composed of type I (agranular) and type II (granular) alveoli. Type I alveoli consis of one large central cell surrounded by peripheral cells having the morphology of fluid-transporting epithelia. Type II alveoli contain granular and agranular cells; the former are comprised of morphologically distinct types of cells (a, b, and c) containing granules of different structures and chemical composition with respect to polysaccharide and protein. The agranular cells are the interstitial and cap cells. Golgi bodies and rough endoplasmic reticulum (RER) are found in all granular cells and apparently are involved in granule formation. No appreciable structural changes were observed in type I alveoli during or after feeding. Type c cell granules are released before granules from types a and b cells and may contain anticoagulant substances that promote the blood flow of the host during the tick feeding. Although the cap cells are not structurally affected by feeding, interstitial cells are developed into transporting epithelia. PMID- 30011966 TI - Targeting Mitochondrial Ion Channels to Fight Cancer. AB - In recent years, several experimental evidences have underlined a new role of ion channels in cancer development and progression. In particular, mitochondrial ion channels are arising as new oncological targets, since it has been proved that most of them show an altered expression during tumor development and the pharmacological targeting of some of them have been demonstrated to be able to modulate cancer growth and progression, both in vitro as well as in vivo in pre clinical mouse models. In this scenario, pharmacology of mitochondrial ion channels would be in the near future a new frontier for the treatment of tumors. In this review, we discuss the new advances in the field, by focusing our attention on the improvements in new drug developments to target mitochondrial ion channels. PMID- 30011971 TI - Conserved Active-Site Residues Associated with OAS Enzyme Activity and Ubiquitin Like Domains Are Not Required for the Antiviral Activity of goOASL Protein against Avian Tembusu Virus. AB - Interferon (IFN)-induced 2'-5'-oligoadenylate synthetase (OAS) proteins exhibit an extensive and efficient antiviral effect against flavivirus infection in mammals and birds. Only the 2'-5'-oligoadenylate synthetase-like (OASL) gene has been identified thus far in birds, except for ostrich, which has both OAS1 and OASL genes. In this study, we first investigated the antiviral activity of goose OASL (goOASL) protein against a duck-origin Tembusu virus (DTMUV) in duck embryo fibroblast cells (DEFs). To investigate the relationship of conserved amino acids that are related to OAS enzyme activity and ubiquitin-like (UBL) domains with the antiviral activity of goOASL, a series of mutant goOASL plasmids was constructed, including goOASL-S64C/D76E/D78E/D144T, goOASL?UBLs and goOASL?UBLs S64C/D76E/D78E/D144T. Interestingly, all these mutant proteins significantly inhibited the replication of DTMUV in DEFs in a dose-dependent manner. Immunofluorescence analysis showed that the goOASL, goOASL-S64C/D76E/D78E/D144T, goOASL?UBLs and goOASL?UBLs-S64C/D76E/D78E/D144T proteins were located not only in the cytoplasm where DTMUV replicates but also in the nucleus of DEFs. However, the goOASL and goOASL mutant proteins were mainly colocalized with DTMUV in the cytoplasm of infected cells. Our data indicated that goOASL could significantly inhibit DTMUV replication in vitro, while the active-site residues S64, D76, D78 and D144, which were associated with OAS enzyme activity, the UBL domains were not required for the antiviral activity of goOASL protein. PMID- 30011976 TI - The occurrence of abnormal sperm in the cauda epididymis of Rhinolophus capensis (Mammalia: Chiroptera). AB - The spermatozoa of Rhinolophus capensis are stored in the cauda epididymidis for about 10 months, 4 months prior to copulation and 6 months after copulation. Electron microscopy has shown the occurrence of sperm defects (mitochondrial proliferation, bending and coiling of the tail, and Dag defect) throughout the period of sperm storage. However, these defects are more common during the postcopulation period, when excess spermatozoa are being removed, suggesting that they may be associated with sperm degradation. PMID- 30011977 TI - The seminal receptacle and sperm storage in Cochlostoma montanum (Issel) (Gastropoda: Prosobranchia). AB - Females of Cochlostoma montanum (Prosobranchia, Cochlostomatidae) have a seminal receptacle which is not a separate diverticulum of the oviduct. The seminal receptacle derives from a differentiated portion of the renal oviduct which has an inner wall composed of only one layer of cells. These cells are of two different types, both actively involved in secretory activity. One type is represented by goblet cells filled with large vesicles containing an electron dense, homogeneous, and partially paracrystalline material. This material is expelled into the lumen through macro-apocrine or holocrine types of secretion. The other type is represented by ciliated cells rich in small vesicles containing granular material. Probably neither kind of secretion has a nutritive function; rather they serve as matrix for spermatozoa that immobilize them and prevent their expulsion from the receptacular portion of the oviduct. Spermatozoa are inserted in invaginations of the apex of both these epithelial cells. The sperm plasma membrane covering the acrosome forms long digitations which expand toward the corresponding invaginations of the receptaculum cells. This type of adhesion is a novelty for Mollusca and resembles that in seminal receptacles of some Annelida. PMID- 30011978 TI - Ultrastructural analysis of spermiogenesis in Admetus pomilio (Arachnida, amblypygi). AB - The mature spermatozoon of Admetus pomilio is a spherical cell containing nucleus and tightly coiled flagellum. In early spermatids the Golgi apparatus forms the acrosomal vesicle and at the opposite side the distal centriole gives rise to the axonemal complex of the sperm tail. As the nucleus elongates, chromatin forms twisted filaments and the spermatid nucleus takes on a helical form. Microtubules are juxtaposed with the nucleus envelope, which is separated from a central chromatin mass by an electron lucid region. A long perforatorium, located on the border of the chromatin mass, runs helically in the nucleus from the centriolar region to subacrosomal space. During tail elongation, the anterior part of the axoneme is surrounded by a long, spiral mitochondrial sheath. In the late spermatid, chromatin filaments appear twisted and become aggregated. The nucleus and flagellum undergo further contortions in which the nucleus coils and the flagellum winds up into the body of the cell and coils in a regular fashion. The mitochondrial sheath surrounds about 2/3 of the 9 + 3 axoneme. These features of spermatid ultrastructure resemble those in the primitive Liphistiomorpha. PMID- 30011979 TI - The unique fibrillar matrix of the marine sponge Stelletta grubii. AB - In this astrophorid sponge, both intercellular fibrils and spongin microfibrils are elaborated with the former forming exceptionally dense arrangements throughout much of the matrix. Fibrils are very dense below the surface where they surround the small silica asters and throughout the cortex in the form of bundles that can form pseudo-plywood arangements. In the endosome, fibril bundles are isolated and fewer in number. The surfaces of the large silica spicules are uniquely encased by intercellular fibrils or compacted intercellular fibrils that form a type of "fibrillar spongin" or spongin microfibrils intermixed with fibrils. Well developed microfibrillar spongin, intermixed with some fibrils, encases larger spicules below the sponge surface within the tissue and extends above the tissue surrounding spicules that emerge from the sponge thus placing this fibrillar matrix in direct contact with the sea water. The results of other studies suggest that the fibrils and microfibrils of this species are collagenous. The elaboration of these special matrices indicates that the differentiation of spongocytes (which secrete microfibrils) is weak and that the activity of lophocytes (which secrete fibril bundles) is highly labile. The variability of the fibrillar arrangements in this species supports the view that astrophorid sponges are possibly important for understanding the phylogeny of the organic skeletal matrix of sponges. PMID- 30011980 TI - The silk and silk production system of the funnel-web mygalomorph spider Euagrus (Araneae, Dipluridae). AB - The silk production systems of several specimens representing at least three species of the mygalomorph genus Euagrus were examined by dissection and by a variety of absorption and fluorescent histochemical techniques. The intrageneric variation is primarily restricted to gland number, with larger numbers of glands in the larger-bodied species. The silk glands are arranged in four groups each serving one of four spinnerets. Spigot morphology is uniform, consisting of a long, slender shaft of slightly variable length emerging from an enlarged sac shaped base. Only one gland type is identified histochemically, although a considerable range in size and shape is observed. Each gland has three secretory zones, a distal one that produces a largely hydrophobic protein core and medial and proximal zones that produce distinct charged protein coatings. Amino acid analysis of the silk indicates a composition very similar to the frame threads and draglines of araneomorph spiders. The high percentage of short side-chain amino acids implies a polymer structure able to support the suspended entrapment web found in Euagrus and its relatives (but which is rare in most other nonaraneomorph families). Dry silk examined under high magnification appears smooth and homogenous. The fact that in the web larger threads appear to fibrillate suggests that Euagrus silk is polyfilamentous. PMID- 30011981 TI - The mechanism of frill erection in the bearded dragon Amphibolurus barbatus with comments on the jacky lizard A. muricatus (Agamidae). AB - Amphibolurus barbatus has a threat display which includes the erection of the gular regions as a frill and may also include wide opening of the mouth to display a yellow mouth lining. Frill erection involves protraction, depression, and lateral expansion of the hyoid apparatus. Electrical stimulation of the hyoid muscles and dissection of the hyoid apparatus were used to examine specializations for producing frill erection. Specializations of the hyoid skeleton include the absence of a ceratobranchial II, presence of a synovial joint between the ceratohyal and body of the hyoid, and combined shortening of the entoglossal process and lengthening of the posterior arches. The only apparent specialization of the hyoid musculature is the anterior displacement of the origin of m. hyomandibularis. All of the hyoid muscles are involved in some way in frill erection and the actions of each muscle is described. The characteristic frill erection in the threat display of Amphibolurus barbatus is possible because of the 1:2 ratio of the anterior and posterior parts of the apparatus and the absence of the ceratobrnchial II. PMID- 30011982 TI - Ovarian Gynandroblastoma with a Juvenile Granulosa Cell Tumor Component in a Postmenopausal Woman: A Case Report and Literature Review. AB - Gynandroblastoma is an extremely rare sex cord-stromal tumor with both female (granulosa cell tumor) and male (Sertoli-Leydig cell tumor) elements. Juvenile granulosa cell tumors are also very rare and are so named because they usually occur in children and adolescents. A 71-year-old woman with right upper quadrant abdominal pain visited our hospital. Pelvic computed tomography showed a large multilocular cystic mass, suspected to be of ovarian origin. We performed a total abdominal hysterectomy (total abdominal hysterectomy was performed) with bilateral salpingooophorectomy. A 13-cm multilocular cystic mass with serous fluid was observed in her right ovary. Upon microscopic examination, the solid component of the mass showed both Sertoli-Leydig cell and juvenile granulosa cell differentiation, which we diagnosed as gynandroblastoma. Gynandroblastoma with a juvenile granulosa cell tumor component is extremely rare and, until now, only six cases have been reported in the English literature. We report the first gynandroblastoma with a juvenile granulosa cell tumor component diagnosed in an elderly patient, along with a literature review. PMID- 30011983 TI - Verification of Low Risk for Perihippocampal Recurrence in Patients with Brain Metastases Who Received Whole-Brain Radiotherapy with Hippocampal Avoidance. AB - Purpose: The purpose of this study was to analyze the patterns of failure and survival outcome in patients with brain metastases who received whole-brain radiotherapy (WBRT) with hippocampal avoidance (HA) using simultaneous integrated boost (SIB) on metastatic brain tumors. Materials and Methods: We retrospectively reviewed 42 patients treated with HA-WBRT for brain metastases. A total of 25 Gy for whole brain and 35-55 Gy for gross tumors were delivered with 10 fractionations. Local tumor and intracranial progression were defined as a recurrence or tumor progression in SIB field and any recurrence or tumor progression within whole brain, respectively. Progression in HA zone was defined as the recurrence within the area expanded 5 mm from HA zone. Results: Median follow-up duration was 10.0 months (range, 4.1 to 56.4 months). Intracranial progression was observed in 13 patients (31.0%) and the median duration from the start of HA-WBRT to progression was 10.6 months (range, 0.9 to 33.0 months). Local tumor progression and new metastasis outside SIB field occurred in 10 patients (23.8%) and nine patients (21.4%), respectively. There was no isolated hippocampal metastasis, except only one patient (2.4%) with multiple metastases inside and outside HA zone simultaneously. Median survival time and intracranial progression-free survival rate at 1-year were 19.4 months (95% confidence interval [CI], 9.6 to 29.2) and 71.5%, respectively, and those for overall survival were 26.5 months (95% CI, 15.4 to 37.5) and 67.9%, respectively. Conclusions: HA-WBRT was associated with low risk of new metastasis in HA region in the patients with brain metastases. These findings would serve as useful guidance on applying HA-WBRT in clinical practice. PMID- 30011984 TI - Health-Related Quality of Life Changes in Prostate Cancer Patients after Radical Prostatectomy: A Longitudinal Cohort Study. AB - Purpose: Health-related quality of life (HRQOL) information related to radical prostatectomy (RP) is valuable for prostate cancer (PC) patients needing to make treatment decisions. We aimed to investigate HRQOL change in PC patients who underwent three types of RP (open, laparoscopic, or robotic) and compared their HRQOL with that of general population. Materials and Methods: Patients were prospectively recruited between October 2014 and December 2015. EORTC QLQ-C30 and PC-specific module (PR25) were administered before surgery (baseline) and at postoperative 3 and 12 months. At each time point, HRQOL was compared, and a difference of 10 out of 0-100 scale was considered clinically significant. Results: Among 258 screened patients, 209 (41 open, 63 laparoscopic, and 105 robotic surgeries) were included. Compared to baseline, physical, emotional, and cognitive functioning improved at 12 months. Role functioning worsened at 3 months, but recovered to baseline at 12 months. Pain, insomnia, diarrhea, and financial difficulties also significantly improved at 12 months. Most PR25 scales excluding bowel symptoms deteriorated at 3 months. Urinary symptoms and incontinence aid recovered at 12 months, whereas sexual activity and sexual function remained poor at 12 months. Clinically meaningful differences in HRQOL were not observed according to RP modalities. Compared to the general population, physical and role functioning were significantly lower at 3 months, but recovered by 12 months. Social functioning did not recover. Conclusion: Most HRQOL domains showed recovery within 12 months after RP, excluding sexual functioning and social functioning. Our findings may guide patients considering surgical treatment for PC. PMID- 30011985 TI - Exploring the Addressability of DNA Decorated Multifunctional Gold Nanoparticles with DNA Origami Template. AB - The hybridization of gold nanoparticles (AuNPs), along with other nanomaterials, has encouraged applications in biomedical imaging, plasmonic enhancement, and catalysts. However, the rational organization of AuNPs in nanotechnology fields remains difficult, which might require multiaddressability of nanoparticles for heterogeneous conjugation. In this work, multifunctional AuNPs were developed by conjugation of two types of DNA strands containing different sequences, which allowed the AuNPs to recognize multiple binding sites. The ratio of different sequences of DNA, and the different lengths of coding DNA oligos on the surface of the AuNPs, had varied influences on the functionality of the multifunctional DNA-AuNPs. This new type of DNA-decorated nanoparticles will enhance the diversity and complexity of nanoparticle-based bottom-up fabrication in materials science and bionanotechnology. PMID- 30011986 TI - Chemical Composition and Emissions Factors for Cookstove Startup (Ignition) Materials. AB - Air pollution from cookstoves creates a substantial human and environmental health burden. A disproportionate fraction of emissions can occur during stove ignition (startup) compared to main cooking, yet startup material emissions are poorly quantified. Laboratory tests were conducted to measure emissions from startups using kerosene, plastic bags, newspaper, fabric, food packaging, rubber tire tubes, kindling, footwear, and wood shims. Measured pollutants included: fine particulate matter mass (PM2.5), PM2.5 elemental and organic carbon, methane, carbon monoxide, carbon dioxide, benzene, and formaldehyde. Results demonstrate substantial variability in the measured emissions across materials on a per-startup basis. For example, kerosene emitted 496 mg PM2.5 and 999 mg CO per startup, whereas plastic bags emitted 2 mg PM2.5 and 30 mg CO. When considering emissions on a per-mass basis, the ordering of materials from highest-to-lowest emissions changes, emphasizing the importance of establishing how much material is needed to start a stove. The proportional contribution of startups to overall emissions varies depending on startup material type, stove type, and cooking event length; however, results demonstrate that startup materials can contribute substantially to a cookstove's emissions. Startup material choice is especially important for cleaner stove-fuel combinations where the marginal benefits of reduced emissions are potentially greater. PMID- 30011987 TI - Responses of Fresh-Cut Strawberries to Ethanol Vapor Pretreatment: Improved Quality Maintenance and Associated Antioxidant Metabolism in Gene Expression and Enzyme Activity Levels. AB - Strawberries were treated with different concentrations of ethanol vapor and then cut into four wedges and stored at 4 degrees C for 1 week. It was found that 4 mL/kg of ethanol was the optimal concentration to reduce the decrease of firmness and weight loss. Total phenolics content, total flavonoid and anthocyanin contents, antioxidant enzyme activities, and gene expression related to the antioxidant were elevated using the ethanol treatment. Ethanol vapor also suppressed microbial growth and promoted free radical (hydroxyl and DPPH) scavenging capacities and four kinds of esters and bioactive components in strawberry wedges. Moreover, ethanol enhanced antioxidant enzyme activities including superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) by activating related gene expression. The results of our research indicate that ethanol vapor has potential application in preserving quality and improving antioxidant capacity of fresh-cut strawberries. PMID- 30011988 TI - Synthesis of 2'-Deoxy-alpha-l-threofuranosyl Nucleoside Triphosphates. AB - alpha-l-Threofuranosyl nucleic acid (TNA) is an artificial genetic polymer in which the natural five-carbon ribose sugar found in RNA has been replaced with an unnatural four-carbon threose sugar. Despite a different sugar-phosphate backbone, TNA is capable of forming stable, antiparallel Watson-Crick duplex structures with itself and with complementary strands of DNA and RNA. This property of intersystem base pairing, coupled with the chemical simplicity of threose relative to ribose, provides support for TNA as a candidate RNA progenitor in the evolution of life. In an effort to evaluate the functional properties of TNA by in vitro evolution, engineered polymerases have been developed that are capable of copying information back and forth between DNA and TNA. However, the current generation of TNA polymerases function with reduced activity relative to their natural counterparts, which limits the evaluation of TNA as a primordial genetic material. Here, we describe the chemical synthesis and polymerase recognition of 2'-deoxy-alpha-l-threofuranosyl nucleoside 3' triphosphates (dtNTPs) as chain-terminating reagents in a polymerase-mediated TNA synthesis reaction. The synthesis of dtNTPs should make it possible to investigate the mechanism of TNA synthesis by X-ray crystallography by trapping the polymerase in the catalytically active conformation. PMID- 30011989 TI - Development of Biphasic Formulations for Use in Electrowetting-Based Liquid Lenses with a High Refractive Index Difference. AB - Commercial electrowetting-based liquid lenses are optical devices containing two immiscible liquids as an optical medium. The first phase is a droplet of a high refractive index oil phase placed in a ring-shaped chassis. The second phase is electrically conductive and has a similar density over a wide temperature range. Droplet curvature and refractive index difference of two liquids determine the optical strength of the lens. Liquid lenses take advantage of the electrowetting effect, which induces a change of the interface's curvature by applying a voltage, thereby providing a variable focal that is useful in autofocus applications. The first generation of lens modules were highly reliable, but the optical strength and application scope was limited by a low refractive index difference between the oil and conductive phase. Described herein is an effort to increase the refractive index difference between both phases, while maintaining other critical application characteristics of the liquids, including a low freezing point, viscosity, phase miscibility, and turbidity after thermal shock. An important challenge was the requirement that both phases have to have matching densities and hence had to be optimized simultaneously. Using high throughput experimentation in conjunction with statistical design of experiments (DOE), we have developed a series of empirical models to predict multiple physicochemical properties of both phases and derived ideal locations within the formulation space. This approach enabled the development of reliable liquid lenses with a previously unavailable refractive index difference of Delta nD of >=0.290, which enabled true optical zooming capability. PMID- 30011991 TI - Synthesis of 1,2-Dihydroquinazolines via Rearrangement of Indazolium Salts. AB - A convenient synthesis of 1,2-dihydroquinazolines via rearrangement of indazolium salts was described. A mechanistic study using isotope labeling experiment revealed that the rearrangement passes through cleavage of N-N bond/ring opening after basic deprotonation of 2-benzyl in indazolium salts to yield intermediate E, which proceeds in an intramolecular N-nucleophilic addition to form the observed product. Computational analyses imply that the pathway of the rearrangement is determined by the energy barriers of the ring-closing process and the stability of the product. PMID- 30011990 TI - Carnitine Precursors and Short-Chain Acylcarnitines in Water Buffalo Milk. AB - Ruminants' milk contains delta-valerobetaine originating from rumen through the transformation of dietary Nepsilon-trimethyllysine. Among ruminant's milk, the occurrence of delta-valerobetaine, along with carnitine precursors and metabolites, has not been investigated in buffalo milk, the second most worldwide consumed milk, well-known for its nutritional value. HPLC-ESI-MS/MS analyses of bulk milk revealed that the Italian Mediterranean buffalo milk contains delta valerobetaine at levels higher than those in bovine milk. Importantly, we detected also gamma-butyrobetaine, the l-carnitine precursor, never described so far in any milk. Of interest, buffalo milk shows higher levels of acetylcarnitine, propionylcarnitine, butyrylcarnitine, isobutyrylcarnitine, and 3 methylbutyrylcarnitine (isovalerylcarnitine) than cow milk. Moreover, buffalo milk shows isobutyrylcarnitine and butyrylcarnitine at a 1-to-1 molar ratio, while in cow's milk this ratio is 5 to 1. Results indicate a peculiar short-chain acylcarnitine profile characterizing buffalo milk, widening the current knowledge about its composition and nutritional value. PMID- 30011992 TI - 2-Acetylthienopyridine Synthesis via Thiolation and Copper-Catalyzed Cyclization of o-Propynol Fluoropyridine Using Xanthate as a Thiol Surrogate. AB - 2-Acylthienopyridines and related heterocycles are readily prepared in moderate to good yields under mild conditions by a nucleophilic thiolation, copper catalyzed cyclization, and an oxidation cascade process using potassium xanthate as the thiol source. Moreover, excellent chemoselectivity, broad substrate scope, and good functional group tolerance are prominent features of this transformation. PMID- 30011993 TI - Cascade Trisulfur Radical Anion (S3*-) Addition/Electron Detosylation Process for the Synthesis of 1,2,3-Thiadiazoles and Isothiazoles. AB - Trisulfur radical anion (S3*-) mediated reactions with in situ formed azoalkenes and alpha,beta-usaturated N-sulfonylimines for the construction of 1,2,3 thiadiazoles and isothiazoles has been developed. S3*- is in situ generated from potassium sulfide in DMF. These two approaches provide a new, safe, and simple way to construct 4-subsituted 1,2,3-thiadiazoles, 5-subsituted 1,2,3 thiadiazoles, and isothiazole in good yields. The reactions include the formation of the new C-S and N-S bonds via S3*- addition and electron detosylation under mild conditions. PMID- 30011994 TI - Sulfide-Derived Copper for Electrochemical Conversion of CO2 to Formic Acid. AB - The electrochemical CO2 reduction reaction (CO2RR) has gained attention recently due to rising concern over atmospheric carbon levels, but catalyst selectivity and efficiency remain a challenge, particularly for products other than CO. Here, we report the selective formation of formate using a sulfide-derived copper (SD Cu) catalyst for CO2RR. On the basis of in situ and postelectrolysis spectroscopy, we propose that this selectivity is due to stronger binding of the CO intermediate originating from remaining subsurface sulfur atoms. PMID- 30011995 TI - Investigating the Many Roles of Internal Water in Cytochrome c Oxidase. AB - Cytochrome c oxidase (C cO) is the terminal enzyme in the respiratory electron transport chain. As part of its catalytic cycle, C cO transfers protons to its Fe Cu binuclear center (BNC) to reduce oxygen, and in addition, it pumps protons across the mitochondrial inner, or bacterial, membrane where it is located. It is believed that this proton transport is facilitated by a network of water chains inside the enzyme. Here we present an analysis of the hydration of C cO, including the BNC region, using a semi-empirical hydration program, Dowser++, recently developed in our group. Using high-resolution X-ray data, we show that Dowser++ predictions match very accurately the water molecules seen in the D- and K-channels of C cO, as well as in the vicinity of its BNC. Moreover, Dowser++ predicts many more internal water molecules than is typically seen in the experiment. However, no significant hydration of the catalytic cavity in C cO described recently in the literature is observed. As Dowser++ itself does not account for structural changes of the protein, this result supports the earlier assessment that the proposed wetting transition in the catalytic cavity can only either be due to structural rearrangements of BNC, possibly induced by the charges during the catalytic cycle, or occur transiently, in concert with the proton transfer. Molecular dynamics simulations were performed to investigate the global dynamic nature of Dowser++ waters in C cO, and the results suggest a consistent explanation as to why some predicted water molecules would be missing in the experimental structures. Furthermore, in light of the significant protein hydration predicted by Dowser++, the dielectric constant of the hydrated cavities in C cO was also investigated using the Frohlich-Kirkwood model; the results indicate that in the cavities where water is packed sufficiently densely the dielectric constant can approach values comparable even to that of bulk water. PMID- 30011996 TI - Hyaluronic Acid-Methotrexate Conjugates Coated Magnetic Polydopamine Nanoparticles for Multimodal Imaging-Guided Multistage Targeted Chemo Photothermal Therapy. AB - Combination cancer therapy with various kinds of therapeutic approaches could improve the effectiveness of treatment while reducing side effects. Herein, we elaborately developed a theranostics nanoplatform based on magnetic polydopamine (MPDA) coated with hyaluronic acid-methotrexate conjugates (MPDA@HA-MTX) for chemo-photothermal treatment (PTT). In this nanoplatform, Fe3O4 served as the core was applied as contrast agent for T2-weighted magnetic resonance imaging (MRI) and early phase magnet targeting. Meanwhile, PDA was used as a versatile shell for effective loading of chemotherapeutic doxorubicin (DOX) to achieve controlled release and PTT simultaneously. Moreover, HA-MTX conjugates could offer later-phase specific cellular dual-targeting ability during the therapy. Both in vitro and in vivo studies demonstrated that DOX-loaded MPDA@HA-MTX (MPDA/DOX@HA-MTX) exhibited the preferential tumor accumulation, enhanced specificity to target tumor cells, pH-/laser-responsive release, and high tumor cell-killing efficiency. By combined chemo-PTT under the guidance of fluorescence/MR imaging, the tumors in mice were completely eliminated after treatment, indicating that MPDA@HA-MTX nanoparticles have great potential as a novel drug-loading platform for imaging-guided multistage targeted chemo photothermal combination therapy. PMID- 30011998 TI - Association Between Preconception Care and Birth Outcomes. AB - PURPOSE: To evaluate the association between preconception care and the risk of adverse birth outcomes. DESIGN: A quasi-experimental study comparing 2 groups: (1) integrated maternal health care (MHC) program (with preconception care) and (2) standard MHC program (without preconception care). SETTING: Maternal health care clinics in Alvand and Qazvin cities in Qazvin Province, Iran. PARTICIPANTS: A total of 152 and 247 Iranian women aged 16 to 35 years were enrolled in the integrated MHC and standard MHC program, respectively. MEASURES: The birth outcomes measured included low birth weight, preterm birth, maternal and neonatal complications, and mode of delivery (normal vaginal delivery and cesarean delivery). ANALYSIS: Multiple logistic regression was performed to determine the impact of preconception care and risk of adverse birth outcomes with adjusted odds ratios (ORs) as effect sizes. RESULTS: One hundred forty-seven women in integrated MHC and 218 women in standard MHC completed this study. Preconception care was associated with reduced risk of preterm birth (OR = 0.298; 95% confidence interval [CI] = 0.120-0.743; P = .009), low birth weight (OR = 0.406; 95% CI = 0.169-0.971; P = .043), maternal complication (OR = 0.399; 95% CI = 0.241-0.663; P < .001), and neonatal complications (OR = 0.460; 95% CI = 0.275 0.771; P = .003). CONCLUSION: The findings of the present study revealed advantages of preconception care with reduced adverse birth outcomes. PMID- 30011997 TI - Health-related quality of life, treatment adherence and psychosocial support in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) share similar quality of life impairment. The aim of the present study was to investigate health-related quality of life (HRQoL) and its relation to the perception of treatment and psychosocial support among PAH and CTEPH patients. All adult PAH or CTEPH patients in the Swedish Pulmonary Arterial Hypertension Register were invited to participate in a national cohort survey. The survey included the EuroQol 5-dimensions (EQ-5D) instrument that measures an individual's HRQoL; the Beliefs about Medicines Questionnaire-Specific Scale that assesses the perception of PAH-specific treatment; the Mastery scale that evaluates the feeling of control and ability to cope with the disease; and the Social Network and Support Scale that maps the social support network. Of the 440 invited patients, 74% responded. Mean age was 66 +/- 14 years, 58% were female and 69% diagnosed with PAH. Patients with PAH were younger, more often female and had a lower EQ-5D index (0.67 +/- 0.29 vs. 0.73 +/- 0.25, p = 0.050) than patients with CTEPH. Patients with a low EQ-5D index had more concerns about treatment ( p = 0.004), lower coping ability ( p < 0.001), less emotional support ( p = 0.003) and less accessible social network ( p = 0.002). In conclusion, patients with an impaired HRQoL also reported negative effects on their social support network, ability to handle stressors and concerns about treatment. PMID- 30011999 TI - An infrequent complication of a not so infrequent disease. Hit by HIT. AB - Heparin-induced thrombocytopenia is not uncommon in cardiac surgery. Thrombosis is the most frequent complication. A 77-year-old man suffered cardiac arrest due to right coronary emboli. Transesophageal echocardiography revealed tissue valve thrombosis. He required support with an extracorporeal membrane oxygenator that also thrombosed. Heparin-induced thrombocytopenia was diagnosed, and anticoagulation was switched to argatroban. Heparin- induced thrombocytopenia normally presents as vascular thrombosis. In this case, the first symptom was tissue valve thrombosis causing an acute coronary syndrome. It is not an uncommon complication and should be considered if unexpected thrombosis and a sudden drop in platelet count develops after heparin exposure. PMID- 30012000 TI - Arch branch endografts for arch aneurysms associated with bovine anomaly. AB - Bovine aortic arch is known to be associated with an increased rate of aortic arch expansion. The most frequently observed human variant of bovine aortic arch is a common origin of the innominate trunk and left common carotid artery. This is a report of two patients who had successful custom-made arch branch endograft treatment for an arch aneurysm associated with bovine arch anomaly. Modular endovascular repair of aortic arch aneurysms using an inner-branched device adds to the armamentarium of treatment options, and is a minimally invasive management modality without the need for sternotomy or intraoperative extracorporeal bypass. PMID- 30012001 TI - Deep Ultraviolet Standoff Photoacoustic Spectroscopy of Trace Explosives. AB - We demonstrate deep ultraviolet (UV) photoacoustic spectroscopy (PAS) of trace explosives using a sensitive microphone at meter standoff distances. We directly detect 10 ug/cm2 of pentaerythritol tetranitrate (PETN), 2,4,6-trinitrotoluene (TNT), and ammonium nitrate (AN) with 1 s accumulations from a 3 m standoff distance. Large PAS signals for standoff detection are achieved by exciting into the absorption bands of the explosives with a 213 nm laser. We also investigate the impact of the deep UV photochemistry of AN on the PAS signal strength and stability. We find that production of gaseous species during photolysis of AN enhances the PAS signal strength. This deep UV photochemistry can, however, limit the PAS signal lifetimes when detecting trace quantities. PMID- 30012002 TI - Attendance in Recreational Groups for Persons With Dementia: The Impact of Stimulus and Environmental Factors. AB - OBJECTIVES: Participation in group activities can benefit persons with dementia, alleviating boredom, improving affect, maintaining function, and decreasing problematic behaviors. METHODS: We describe patterns of attendance of residents with dementia at nursing home activity groups and investigate stimulus and environmental factors that may affect attendance. RESULTS: Residents participated in 60.8% of the activities, with reasons for nonattendance including refusal (9.7%), not being on the unit (7.8%), being asleep (6.8%), and being involved in activities of daily living and other activities (8.3%). On average, 3.5 other residents not recruited for the study chose to participate in each group session. Group attendance was significantly related to group topic. IMPLICATION: The need for activities was evident by the attendance of both invited and other residents. Understanding the factors that affect attendance is the first step toward developing procedures to maximize participation in activities in order to decrease loneliness and boredom in this population. PMID- 30012003 TI - Trends in age- and sex-specific prevalence and incidence of cardiovascular disease in Western Australia. AB - Background Temporal trends in incidence and mortality of cardiovascular disease (CVD) have been well described, with recent data suggesting declining improvements in those aged under 55 years. However, little is known about the combined impact of incidence and mortality trends on disease prevalence, an important indicator of disease burden and cost. We analysed changes in age specific and age-standardised temporal trends in prevalence and incidence of CVD subtypes. Methods Annual prevalence and incidence rates of coronary heart disease, cerebrovascular disease and peripheral arterial disease for the Western Australian population for 1995-2010 were calculated using data from the Western Australian Data Linkage System. Joinpoint regression analyses were used to identify joinpoints in trends in age-specific and age-standardised annual prevalence and incidence rates for each CVD subtype. Results Between 1995 and 2010, age- and sex-specific incidence and prevalence of the CVD subtypes generally decreased among middle-aged and older adults, but were stable or increased among younger adults. In < 55 year olds, increases in incidence tended to occur from 2003, while increases in prevalence were from 2007/2008. Declines in age-standardised incidence were greater than those in crude incidence, with changes in population structure having a greater impact among men than women. Conclusions The majority of CVDs occurs in older adults. Our findings of generally worsening trends in prevalence in younger adults across most CVD subtypes were in contrast to generally declining trends in older age groups. These data highlight the importance of monitoring prevalence and incidence, particularly in younger adults. PMID- 30012004 TI - Huntington's disease: Neuropsychiatric manifestations of Huntington's disease. AB - OBJECTIVES: Huntington's disease (HD) is a profoundly incapacitating, and ultimately fatal, neurodegenerative disease. HD is presently incurable, so the current goal is to allow affected individuals to live as well as possible with the illness, to maximise functional independence and quality of life for the person with HD, their carers and family members. This clinical update review focuses on the common neuropsychiatric manifestations in HD, and outlines and evaluates the various neuropsychiatric facets of HD, including the aetiology, symptoms and diagnosis. CONCLUSIONS: Neuropsychiatric symptoms can precede the classic motor clinical symptoms of HD (prodromal HD) by decades, and cause significant functional impairment. HD provides key insights and understanding into the organic psychiatric disorders, including contemporary clinical insights into the process of neurodegeneration and manifestation of neuropsychiatric symptoms. PMID- 30012005 TI - Incorporating Bereaved Parents as Faculty Facilitators and Educators in Teaching Principles of Palliative and End-of-Life Care. AB - BACKGROUND:: Education and training for interdisciplinary pediatric providers requires training in principles of palliative and end-of-life (EOL) care. The experiences of bereaved parents can inform and enhance palliative care educational curricula in uniquely powerful and valuable ways. The objective of this study is to present an innovative palliative care educational program facilitated by trained bereaved parents who serve as volunteer educators in local and national palliative care educational forums and to describe how incorporation of bereaved parents in these educational forums affects participant comfort with communication and management of children at the EOL. METHODS:: Parent educators underwent both general and session-specific training and participated in debriefings following each session. Survey tools were developed or adapted to determine how bereaved parent educators affected participant experiences in 3 different educational forums. Pre- and postsession surveys with incorporation of retrospective preprogram assessment items to control for response shift were used in the evaluation of institutional seminars on pediatric palliative and EOL care and role-play-based communication training sessions. Results from feedback surveys sent to attendees were used to appraise the participants' experience at the international oncology symposium. RESULTS:: Involvement of trained parent educators across diverse, interdisciplinary educational forums improved attendee comfort in communicating with, and caring for, patients and families with serious illness. Importantly, parent educators also derive benefit from involvement in educational sessions with interdisciplinary clinicians. CONCLUSIONS:: Integration of bereaved parents into palliative and EOL care education is an innovative and effective model that benefits both interdisciplinary clinicians and bereaved parents. PMID- 30012006 TI - Asymmetric Versus Symmetric Filter Wheels and Associated Processing Algorithms: Results from Asynchronous Fluorescence Imaging Photometer Measurements of Phytoplankton. AB - The use of rotating filter wheels is common in photometric applications. Traditional filter wheel designs typically exhibit a number of filter openings spaced evenly about the circumference of the wheel. In this work we examine a number of shortcomings of this traditional filter design in measurements of phytoplankton fluorescence made with our fluorescence imaging photometer (FIP). We present an alternative asymmetric wheel design that offers a number of advantages over the traditional design as well as a new processing algorithm designed to accommodate convolution of signals from adjacent channels inherent in measurements collected with the asymmetric design. This approach eliminates the need for a separate signal to establish timing and wheel position, unambiguously establishes filter order even when the direction of rotation is unknown, allows for better estimates of signal baseline, and is more resilient to effects of vibration and other dynamic processes that could occur on the time scale of wheel rotation. We demonstrate performance improvements for phytoplankton fluorescence measurements associated with the new wheel design and algorithm compared with previously published methods using the FIP. Both the improved image processing algorithm and filter wheel design were found to reduce noise in our measurements significantly. PMID- 30012007 TI - Traditional and augmented reality mirror therapy for patients with chronic phantom limb pain (PACT study): results of a three-group, multicentre single blind randomized controlled trial. AB - OBJECTIVE:: To compare the effects of traditional mirror therapy (MT), a patient centred teletreatment (PACT) and sensomotor exercises without a mirror on phantom limb pain (PLP). DESIGN:: Three-arm multicentre randomized controlled trial. SETTING:: Rehabilitation centres, hospital and private practices. SUBJECTS:: Adult patients with unilateral lower limb amputation and average PLP intensity of at least 3 on the 0-10 Numeric Rating Scale (NRS). INTERVENTIONS:: Subjects randomly received either four weeks of traditional MT followed by a teletreatment using augmented reality MT, traditional MT followed by self-delivered MT or sensomotor exercises of the intact limb without a mirror followed by self delivered exercises. MAIN MEASURES:: Intensity, frequency and duration of PLP and patient-reported outcomes assessing limitations in daily life at baseline, 4 weeks, 10 weeks and 6 months. RESULTS:: In total, 75 patients received traditional MT ( n = 25), teletreatment ( n = 26) or sensomotor exercises ( n = 24). Mean (SD) age was 61.1 (14.2) years and mean (SD) pain intensity was 5.7 (2.1) on the NRS. Effects of MT at four weeks on PLP were not significant. MT significantly reduced the duration of PLP at six months compared to the teletreatment ( P = 0.050) and control group ( P = 0.019). Subgroup analyses suggested significant effects on PLP in women, patients with telescoping and patients with a motor component in PLP. The teletreatment had no additional effects compared to self-delivered MT at 10 weeks and 6 months. CONCLUSION:: Traditional MT over four weeks was not more effective than sensomotor exercises without a mirror in reducing PLP, although significant effects were suggested in some subgroups. PMID- 30012008 TI - What will it really take to end the HIV epidemic? PMID- 30012012 TI - Prolonged Intubation Injuries of the Larynx: Endoscopic Diagnosis, Classification, And Treatment. AB - Laryngeal trauma from prolonged endotracheal intubation occurs in patients of all ages. Most changes are superficial and heal quickly. Injuries that are found consistently during intubation include nonspecific changes, edema, granulation tissue, ulceration, and othermiscellaneous injuries. In thispapersignificant, severe, and lasting trauma of the larynx has been classified on thebasis of theknown factors in pathogenesis, observations made atendoscopy, and photographic documentation. This classification has required introduction of new descriptive terminology: "tongues of granulation tissue," "ulcerated troughs," "healed furrows," and "healed fibrous nodule." During intubation the degree of injury can be precisely assessed under general anesthesia by using telescopes for image magnification, thus assisting adecision whether to continue intubation orperform tracheotomy to minimize long-term morbidity. Changes that are found after extubation result from granulation tissue, ulceration, ora combination of both and have been illustrated on flow charts; a knowledge and understanding of these sequelae allows them to be identified by both indirect and direct laryngoscopy so that treatment can be planned. PMID- 30012013 TI - Few European Adults are Living a Healthy Lifestyle. AB - PURPOSE: This study aimed to measure healthy lifestyle for European adults. DESIGN: Cross-sectional study. SETTINGS: In 20 European countries. PARTICIPANTS: A total of 34 993 (16 749 men, 18 244 women) European adults. MEASURES: Data were from the 2014 European Social Survey (n = 34 993) on 4 modifiable behaviors (physical activity, fruit and vegetable consumption, not drinking alcohol to excess, and not smoking) as well as sleep quality. ANALYSIS: Behaviors were combined and formed a healthy lifestyle measure. Binary logistic regression was done to determine associations of healthy lifestyle and sociodemographic characteristics. RESULTS: Only 5.8% of the adults reported a healthy lifestyle. The prevalence of having a healthy lifestyle varied among European countries. The lowest rates were in Hungary (1.3%) and Czech Republic (1.9%). The highest rates were in United Kingdom (8.6%) and Finland (9.2%). Those who presented a higher likelihood of having a healthy lifestyle were middle age (odds ratio [OR] = 1.20), older people (OR = 1.34), having higher household income (OR = 1.33), being a student (OR = 1.38), and retired (OR = 1.31). Those less likely to have a healthy lifestyle were lived without a partner (OR = 0.82), unemployed (OR = 0.73), and lived in rural areas (OR = 0.86). CONCLUSIONS: Few European adults were practicing 5 healthy behaviors. This should be a message for governments and be considered in the establishment of preventive public policies in the areas of health and health education. PMID- 30012014 TI - Participant Satisfaction and Perceptions About Program Impact in the Medicaid Incentives for Prevention of Chronic Disease Pilot Program. AB - PURPOSE: Evaluate the Centers for Medicare & Medicaid Incentives for Prevention of Chronic Diseases (MIPCD) program in terms of participant satisfaction and self reported program impact. DESIGN: Participant survey (mail/telephone follow-up), English and Spanish (N = 2274). SETTINGS: Ten states in MIPCD program. PARTICIPANTS: Medicaid beneficiaries. INTERVENTION: Incentive-based health promotion programs targeting diabetes prevention and management, smoking cessation, and weight, hypertension, and cholesterol management. MEASURES: Dependent measures are (1) overall program satisfaction and (2) self-reported program impact, operationalized as whether program helped with understanding health issues, learning ways to take care of health, and encouraging healthy lifestyle changes. ANALYSIS: Multilevel multivariable ordinal logistic regression models to identify predictors of overall program satisfaction and program impact. RESULTS: Sixty-seven percent were very satisfied with the program, and 76% strongly agreed the program encouraged healthy lifestyle changes. Age (59+ vs <45 years) and being female predicted overall program satisfaction. Satisfaction with specific aspects of the program including communication with staff, accessibility, and incentives predicted higher overall satisfaction. Age (45-52 vs <45 years) and being black or Hispanic predicted higher program impact. Points redeemable for rewards performed worse than money-valued incentives in terms of encouraging lifestyle changes (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.11-0.82). Participants receiving incentives valued at $25 to <$100 were more likely to report higher agreement that the program helped them learn ways to care for their health (OR, 1.72; 95% CI, 1.21-2.44) and encouraged lifestyle changes (OR, 1.46; 95% CI, 1.02-2.10), compared to participants receiving incentives valued at $0 to <$25. Incentives valued at $100 to <$400 predicted higher agreement that the program helped with understanding of health issues (OR, 1.62; 95% CI, 1.13-2.33), compared to incentives valued at $0 to <$25. CONCLUSION: Effective chronic disease prevention programs are needed for Medicaid populations. Study findings highlight important considerations for incentive based programs. PMID- 30012015 TI - Accurate prediction of human miRNA targets via graph modeling of the miRNA-target duplex. AB - miRNAs are involved in many critical cellular activities through binding to their mRNA targets, e.g. in cell proliferation, differentiation, death, growth control, and developmental timing. Accurate prediction of miRNA targets can assist efficient experimental investigations on the functional roles of miRNAs. Their prediction, however, remains a challengeable task due to the lack of experimental data about the tertiary structure of miRNA-target binding duplexes. In particular, correlations of nucleotides in the binding duplexes may not be limited to the canonical Watson Crick base pairs (BPs) as they have been perceived; methods based on secondary structure prediction (typically minimum free energy (MFE)) have only had mix success. In this work, we characterized miRNA binding duplexes with a graph model to capture the correlations between pairs of nucleotides of an miRNA and its target sequences. We developed machine learning algorithms to train the graph model to predict the target sites of miRNAs. In particular, because imbalance between positive and negative samples can significantly deteriorate the performance of machine learning methods, we designed a novel method to re-sample available dataset to produce more informative data learning process. We evaluated our model and miRNA target prediction method on human miRNAs and target data obtained from mirTarBase, a database of experimentally verified miRNA-target interactions. The performance of our method in target prediction achieved a sensitivity of 86% with a false positive rate below 13%. In comparison with the state-of-the-art methods miRanda and RNAhybrid on the test data, our method outperforms both of them by a significant margin. The source codes, test sets and model files all are available at http://rna-informatics.uga.edu/?f=software&p=GraB-miTarget . PMID- 30012016 TI - What's next for DRACMA? PMID- 30012017 TI - Novel contribution to the simultaneous monitoring of pramipexole dihydrochloride monohydrate and levodopa as co-administered drugs in human plasma utilizing UPLC MS/MS. AB - An efficient, selective, sensitive, and rapid ultra-performance liquid chromatography tandem mass spectrometry method was established and validated for the quantification of pramipexole dihydrochloride monohydrate and levodopa simultaneously in human plasma with the aid of diphenhydramine as an internal standard. A simple protein precipitation technique with HPLC grade acetonitrile was efficiently utilized for the cleanup of plasma. The analysis was performed using a Hypersil gold 50 mm * 2.1 mm (1.9 um) column and a mobile phase of 0.2% formic acid and methanol (90: 10 v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source operated in the positive mode was set up in the selective reaction monitoring mode (SRM) to detect the ion transitions m/z 212.15 ->153.01, m/z 198.10-> 135.16, and m/z 255.75 -> 166.16 for pramipexole dihydrochloride monohydrate, levodopa, and diphenhydramine, respectively. The method was thoroughly validated according to FDA guidelines and proved to be linear, accurate, and precise over the range 100-4000 pg/mL for pramipexole dihydrochloride monohydrate and 60-4000 ng/mL for levodopa. The proposed method was effectively applied for monitoring both drugs in plasma samples of healthy volunteers. PMID- 30012018 TI - Associations Between Hand Hygiene Education and Self-Reported Hand-Washing Behaviors Among Korean Adults During MERS-CoV Outbreak. AB - BACKGROUND: Hand washing is an effective way to prevent transmission of infectious diseases. Education and promotional materials about hand washing may change individuals' awareness toward hand washing. Infectious disease outbreak may also affect individuals' awareness. AIMS: Our study aimed to examine associations between hand-washing education and self-reported hand-washing behaviors among Korean adults during the year of the Middle East respiratory syndrome (MERS) outbreak. METHODS: Data from the 2015 Community Health Survey were used for this study. The total study population comprised 222,599 individuals who were older than 20 years of age. A multiple linear regression model was used to investigate associations between hand hygiene education and self-reported hand-washing behaviors. Subgroup analyses stratified by age, sex, income, and MERS outbreak regions were also performed. RESULTS: Individuals who received hand-washing education or saw promotional materials related to hand washing had significantly higher scores for self-reported use of soap or sanitizer (beta = 0.177, P < .0001) and self-reported frequency of hand washing (beta = 0.481, P < .0001) than those who did not have such experiences. The effect of hand-washing education on self-reported behavior change was greater among older adults, women, and lower income earners. The effect of hand hygiene education on self-reported use of soap or sanitizer was similar regardless of whether the participants lived in MERS regions. CONCLUSION: Our findings emphasize the importance of education or promotions encouraging hand washing, especially for older adults, women, and lower income earners. In addition, MERS outbreak itself affected individuals' awareness of hand-washing behaviors. Well organized campaigns that consider these factors are needed to prevent infectious diseases. PMID- 30012019 TI - Optical Performance of the Cornea One Year Following Keratoconus Treatment with Corneal Collagen Cross-Linking. AB - PURPOSE: The purpose of the study is to assess changes in optical performance of the cornea in patients with keratoconus following treatment with corneal collagen crosslinking (CXL). MATERIALS AND METHODS: One hundred and eleven eyes of 111 consecutive keratoconus patients with 12-month follow-up after CXL were included. The changes in the visual acuity, manifest refractive errors, and corneal topographic parameters were evaluated. Sirius dual-scanning corneal tomography was used to determine the effectiveness of CXL on each patient's total corneal optical quality; preoperative and 12-month postoperative measurements were analyzed over a 4-mm stimulated pupil and were compared with regards to higher order corneal aberrations (total amount of higher order aberrations [HOAs], vertical coma, horizontal coma, vertical trefoil, oblique trefoil, and spherical aberration), vertical and horizontal modulation transfer function (MTF), and Strehl ratio of point spread function (PSF). RESULTS: At 12 months, there was a significant improvement in mean uncorrected visual acuity (UCVA) (P < 0.001), best corrected visual acuity (BCVA) (P < 0.001), spherical equivalent refraction (P = 0.007), and manifest astigmatic refraction (P < 0.001). The corneal topographic measurements revealed a significant decrease in the mean simulated keratometry-1, simulated keratometry -2, and maximum keratometry compared with the baseline measurements (P < 0.001, for all). In addition, there were significant improvements in mean root mean square error values for corneal total HOA (P < 0.001), vertical coma (P < 0.001), and vertical trefoil (P = 0.008) following CXL. Mean MTF and Strehl ratio did not change after CXL (P > 0.05). The improvement in UCVA significantly correlated with the changes in vertical trefoil (r = -0.191, P = 0.044), and the improvement in BCVA and the changes in manifest astigmatic correction were also significantly correlated (r = -0.247, P = 0.009) 12 months after CXL. CONCLUSIONS: CXL treatment for keratoconus led to an improvement in visual, refractive, topographic, and most corneal HOAs outcomes at the 12-month follow-up. However, these improvements were not enough to increase corneal MTF and the Strehl ratio of PSF. PMID- 30012021 TI - Physicochemical characterization of colored soluble protein fractions extracted from Spirulina ( Spirulina platensis). AB - The aim of this study was to evaluate the physicochemical properties of Spirulina colored soluble protein fractions extracted from spray-dried Spirulina powder. Three fractions, including the blue soluble Spirulina protein, the green soluble Spirulina protein, and the total soluble Spirulina protein fractions were obtained. Investigations on their behavior at air/water interface were carried out using dynamic methods of drop volume and bubble pressure surface tension measurements. Evaluation of their monolayer films' mechanical behavior was done via compression isotherms using Langmuir film balance. The protein contents of the fractions were 82.76, 82.29, and 74.53% for the blue, the green, and the total fractions, respectively. Surface tension decay increased with increasing concentration for all the fractions. No significant difference in surface tension decay was observed between the samples at 0.3% (w/w). Surface tension decay was less important at pH 3 for all the fractions. The total fraction and the blue fraction appeared to form more elastic films than the green fraction. The blue soluble fraction also presented the highest collapse pressure and initial expansion area. PMID- 30012020 TI - Anticipatory postural adjustments in the shoulder girdle in the reach movement performed in standing by post-stroke subjects. AB - After a stroke in middle cerebral artery territory, there is a high probability of dysfunction of the ventromedial pathways, mainly related with postural control mechanisms such as the anticipatory postural adjustments (APAs). According to neuroanatomical knowledge, these pathways have a predominant ipsilesional disposition, which justifies a bilateral postural control dysfunction, often neglected in rehabilitation. In order to assess this bilateral postural control dysfunction, electromyography activity was assessed in eight post-stroke and 10 healthy individuals in the anterior deltoids, the superior and lower trapezius, and the latissimus dorsi as they reached for a bottle with both upper limbs separately at a self-selected velocity and fast velocity while standing associated with trunk kinematics analysis. Through this analysis it was possible to compare the timing of APAs in scapular muscles between sides in post-stroke and with healthy individuals, and to verify if there is a relation between the timing and the displacement of the trunk in the temporal window of the APAs. Indeed, post-stroke individuals show a delayed activation of APAs on scapular girdle muscles on both ipsilesional and contralesional sides, which were not reflected in the trunk displacement. PMID- 30012022 TI - Long-term effects of vestibular rehabilitation and head-mounted gaming task procedure in unilateral vestibular hypofunction: a 12-month follow-up of a randomized controlled trial. AB - OBJECTIVE: To investigate the long-term effects of adding virtual reality-based home exercises to vestibular rehabilitation in people with unilateral vestibular hypofunction. DESIGN: Follow-up otoneurological examination in two randomized groups following a previous one-month trial. SETTING: Tertiary rehabilitation center. SUBJECTS: A total of 47 patients with unilateral vestibular hypofunction, one group ( n = 24) undergoing conventional vestibular rehabilitation and the other one ( n = 23) implementing, in addition, head-mounted gaming home exercises, 20 minutes per day for one month. INTERVENTIONS: One year after completing rehabilitation, patients underwent testing with static posturography, video head impulse test, self-report questionnaires, and a performance measure. MAIN MEASURES: Vestibulo-ocular reflex gain, posturographic parameters such as length, surface, and fast Fourier transform power spectra, self-report, and gait performance measure scores. RESULTS: Vestibulo-ocular reflex gain was significantly better with respect to pretreatment in both groups. The mixed method group showed significantly higher gain scores: mean (standard deviation (SD)) at 12 months was 0.71 (0.04), versus 0.64 (0.03) for the vestibular rehabilitation-only group ( P < 0.001). Accordingly, some classical posturography scores such as surface with eyes open and length with eyes closed and low frequency power spectra were significantly different between groups, with the virtual reality group showing improvement ( P < 0.001). Self-report measures were significantly better in both groups compared to pretreatment, with significant improvement in the mixed-method group as compared to conventional rehabilitation alone: Dizziness Handicap Inventory mean total score was 24.34 (2.8) versus 35.73 (5.88) with a P-value <0.001. CONCLUSION: Results suggest that head-mounted gaming home exercises are a viable, effective, additional measure to improve long term vestibular rehabilitation outcomes. PMID- 30012023 TI - Can the inclusion of black soldier fly (Hermetia illucens) in diet affect the flesh quality/nutritional traits of rainbow trout (Oncorhynchus mykiss) after freezing and cooking? AB - Physical and chemical parameters of rainbow trout fillets were tested during 120 days of frozen storage and following cooking. The fillets were obtained from rainbow trout-fed diets where dietary fishmeal was substituted with Hermetia illucens meal at 0, 25 and 50% inclusion levels, corresponding to control (C), Hi25, and Hi50 diets. Variations in quality traits of fillets emerged after 30 days of frozen storage, however they remained almost unchanged for the other 90 days. Increasing levels of H. illucens did not affect pH, shear stress, colour and water holding capacity of fillets. Saturated fatty acids were highly present in Hi50 samples, the polyunsaturated and some monounsaturated ones were higher in C than Hi50, whereas Hi25 always assumed intermediate contents in raw and cooked samples. A medium substitution at the 25% seemed to be the most practical application of insect meal in order to not modify too much the fillets characteristics. PMID- 30012024 TI - Attachment patterns moderate the relation between coping flexibility and illness acceptance among kidney transplant recipients. AB - BACKGROUND AND OBJECTIVES: Post-transplant kidney recipients may experience psychological concerns which have been associated with negative health behaviors. Illness acceptance might have an important role in this process. In line with the Conservation of Resources Theory (COR), the current study aimed to examine the relationship between coping flexibility, attachment patterns and illness acceptance among post-transplant kidney recipients, and to evaluate whether attachment patterns moderate the link between coping flexibility and illness acceptance. DESIGN: The study employed a cross-sectional design. METHODS: Ninety four post-transplant kidney recipients completed questionnaires assessing demographic and medical characteristics, illness acceptance, coping flexibility and attachment patterns. RESULTS: Our results indicated that coping flexibility was positively associated with illness acceptance. Moreover, attachment moderated this link, as high coping flexibility was associated with increased illness acceptance among individuals with low levels of attachment anxiety, a finding which was not significant when high levels of anxiety were reported. CONCLUSIONS: This study highlights the potential importance of building greater flexibility in order to enhance illness acceptance among kidney transplants recipients. Moreover, the role of insecure attachment patterns in health-related outcomes among kidney transplants recipients is emphasized. PMID- 30012026 TI - Factores personales que afectan la calidad de vida de mujeres con cancer de mama del noreste de Mexico: Personal factors that affect quality of life of women with breast cancer from the northeast of Mexico. AB - Introduccion: La terapia sistemica para el cancer de mama afecta la calidad de vida de las mujeres y sus familias. Se analizo la influencia de los factores personales sobre la percepcion de calidad de vida de mujeres en tratamiento para el cancer mamario. Metodos: Participaron noventa y cinco asistentes a la consulta de un hospital publico del noreste de Mexico. Se aplicaron dos Cuestionarios de la Organizacion Europea para la Investigacion y Tratamiento del Cancer (EORTC QLQ C30 y EORTC QLQ-BR23). Resultados: La edad promedio fue de 55 anos ( DE = 9.24). Las participantes destacaron por presentar valores altos para el estado de salud global y niveles bajos en funcionamiento ( rango = 11.71 a 18.42). El insomnio y el impacto economico fueron las areas mas afectadas. Con el incremento de la edad, se observo menor afectacion por sintomas mamarios, funcion y el disfrute sexual ( r = -.273, -.349 y -.304 respectivamente, p < .01). Conclusion: La situacion laboral, estado civil, paridad y lugar de procedencia promovieron afectacion diferencial en algunos sintomas incluyendo la imagen corporal. La aplicacion de estos cuestionarios permitiria la identificacion de necesidades de cuidado fisico u emocional en la practica clinica. PMID- 30012025 TI - Acute renal involvement in organophosphate poisoning: histological and immunochemical investigations. AB - PURPOSE: Today, the long-term effects of partial exposure of cholinesterase on the kidney continue to be a research topic. In this study, we aimed to histopathologically investigate the possible effect of acute toxicity due to fenthion, an organophosphate (OP) compound, on the kidneys. METHODS: In all, 21 rats were randomly divided into three groups. Experimental group was each administered intraperitoneal 0.8 g/kg fenthion within physiologic serum. Sham group was only administered intraperitoneal physiologic serum. The control group continued normal nutrition with no procedure performed. After 24 h, all rats were sacrificed by cervical dislocation. Half of the recipient kidney tissues were examined histopathologically and the other half biochemically. RESULTS: No histopathological findings were found in the control group. Rats in the experimental group were observed to have epithelial cell disorganization in tubules, moderate epithelial cell loss, and degeneration. Again, expansion of tubules, vacuolization of tubular epithelial cells, and tubular structure approaching atrophy were observed, with cells approaching apoptosis and common hemorrhage noted although rats in the sham group were observed to have mild tubular degeneration. CONCLUSIONS: It should not be forgotten that one of the causes of systemic complaints linked to acute toxicity exposed to the OP compound of fenthion may be cellular injury to glomerular and tubular structures in the kidneys. PMID- 30012027 TI - A survey of ambulatory-treated asthma and correlation with weather and air pollution conditions within Taiwan during 2001-2010. AB - OBJECTIVE: This study of asthma was performed to evaluate annual trends in emergency department (ED) for 10 years. Weather and air pollution factors affecting asthma were also studied in order to identify the important factors and alert the public in advance. METHODS: A survey of ambulatory-treated asthma patients was performed and the correlations with weather and air pollution factors examined in a cohort of one million patients in 2010. The fixed-cohort study analyzed trends, medical costs, and annual prevalence grouped by age and gender. RESULTS: The number of asthma patients visiting EDs and non-emergency (non-ED) clinics significantly increased, with average annual percentage changes (AAPCs) of 2.3 and 4.6%, respectively. The average direct medical cost for EDs was increased significantly as compared with that of non-ED visits. Classification of asthma visits by hospital level indicated that local hospitals and others exhibited a significantly increasing trend (AAPC =15.3% [95% CI: 14.3 16.2]). The annual prevalence of asthma in males, females, and children was significantly increased (AAPCs of 1.5, 1.8, and 3.9%, respectively). Asthma patient hospitalizations were significantly correlated with temperature, humidity, and air pollution factors. CONCLUSIONS: The number of non-ED visits due to asthma increased, and the average direct medical cost for ED admissions also increased. Asthma patients tended to visit local hospitals primarily. Asthma visits by children increased, but a decrease was observed in adults. The number of hospitalized asthma patients was negatively correlated with temperature and humidity but positively correlated with the levels of PM2.5, PM10, and NO2. PMID- 30012028 TI - Understanding the Care Needs and Profile of People Living at Home With Moderate to Advanced Stage Parkinson Disease. AB - BACKGROUND: In the United Kingdom, people with Parkinson disease (PD) and atypical parkinsonism will require more support with their care needs as the condition progresses. There are few data on the nature of care input required and the amount of informal and formal care needed by people with PD to enable them to remain within their own home. METHOD: All people with moderate to advanced stage (Hoehn and Yahr III-V) idiopathic PD and atypical parkinsonism under the care of the Northumbria Healthcare NHS Foundation Trust PD service and living in their own home were invited to take part in The Northumbria Care Needs Project, a 10 year prospective longitudinal study. At baseline, data regarding formal (paid) personal and domestic care input and use of respite care, sitting services, and day centers were collected. We also collected data on patient cognitive disability, functional disability, and disease severity and informal carer tasks. RESULTS: Of 162 people with PD included in the study, only 25.2% accessed formal domestic care and the same proportion formal personal care. In contrast, 80.2% identified an informal carer who helped with these tasks. Despite greater level of functional disability in those with an informal carer, levels of formal personal care input were similar to those with and without a formal carer. Levels of formal domestic carer input were higher in those without an informal carer. CONCLUSIONS: Use of formal care services was relatively uncommon in our cohort and much of the burden of caring appears to be being met by informal carers. PMID- 30012029 TI - Assessment of Corneal Endothelium during Continued Organ Culture of Pre-Stripped Human Donor Tissue for DMEK Surgery. AB - PURPOSE: To measure corneal endothelial cell (EC) quality and quantity following Descemet membrane (DM) stripping of human donor corneas and continued storage in organ culture medium containing dextran. METHODS: DM stripping was performed in 30 organ cultured, corneoscleral discs. Corneas were divided into 3 groups of 10 corneas each. Baseline mean EC density (cells/mm2) was 2,372 (SD +/- 259) in group 1, 2,540 (SD +/- 266) in group 2, and 2,665 (SD +/- 263) in group 3. Following subtotal DM stripping, culture was continued at 31 degrees C for 24 hours (group 1), 72 hours (group 2), and 120 hours (group 3), respectively. EC density was measured before stripping and at the end of culture. At the end of culture, corneal EC morphology was graded using a scoring system and EC viability was measured by detection of adenosine triphosphate. RESULTS: At the end of culture, mean EC density was 2,159 (SD +/- 293) in group 1, 1,946 (SD +/- 182) in group 2, and 2,047 (SD +/- 225) in group 3. This constitutes an EC loss of 9,1% (SD +/- 5,3%) in group 1, 23,0 % (SD +/- 6,5%) in group 2, and 22,7% (SD +/- 9,1%) in group 3 (p < 0.001). After completion of follow-up, all groups contained corneas with EC counts < 2,000 cells/mm2. Cell morphology scores did not differ between the three experimental groups. EC viability measurements showed a tendency toward lower readings with extended length of culture. CONCLUSIONS: Corneal EC loss does occur following DM stripping and continued organ culture. EC loss increases with storage past 24 hours, but donor corneas may fall below 2,000 cells/mm2 independently of storage duration. The use of eye bank prepared donor lamellae for Descemet Membrane Endothelial Keratoplasty (DMEK) may increase patient safety by offering standardized quality control before tissue release. PMID- 30012030 TI - Ultrasound-guided transvaginal radiofrequency ablation of uterine fibroids assisted by virtual needle tracking system: a preliminary study. AB - PURPOSE: The purpose of this study was to assess the feasibility and outcome of transvaginal ultrasound (US)-guided radiofrequency ablation of uterine fibroids assisted by a real-time virtual needle tracking (VT) system. METHODS: Between January 2017 and February 2018, 19 patients (age 45 +/- 8 y, range 36-53 y) with 25 symptomatic uterine fibroids underwent transvaginal radiofrequency ablation (RFA) at a single center. Mean number of fibroids for patient was 1.7 (min, max: 1-3). Patients with more than one fibroid were 10 (52.6%). Uterine fibroids (mean volume: 13.6 mL; range: 5.3-41.9 mL) were treated with a dedicated internally cooled 17 G 35 cm RF needle with 1 cm or variable active tip and the moving shot technique. An electromagnetic system was used for showing a virtual needle during the procedure. Contrast-enhanced ultrasound evaluation was performed before and immediately at the end of procedure. Feasibility of the procedure, technical success rate, volume percentage reduction at 1, 3 and 6 months, clinical outcome (QOL score) and complications were analyzed. RESULTS: Procedure was feasible in 19/19 patients (100%). Technical success was achieved in 100% of 25 treated fibroids. Mean fibroids volume decreased from 13.6 ml at baseline to 5.9 ml at 6 month (reduction rate 62.7%, range 48.5-76.9; p < .05). No major immediate or late complications occurred. Minor complications occurred in two patients. QOL score significantly improved from 68 +/- 36 at baseline to 97 +/- 16 at six months follow-up (p < .05). CONCLUSION: Transvaginal US-guided RFA assisted by a real-time VT system is a feasible, safe and effective technique for the treatment of uterine fibroids. PMID- 30012032 TI - Challenges for Migrant and Cross-Border Populations With Diabetes Mellitus at Mae Tao Clinic in the Mae Sot-Myawaddy Border Region of Thailand and Myanmar. AB - The Mae Tao Clinic was established by Dr Cynthia Maung in 1989 in Mae Sot, Thailand, close to the border with Myanmar. The clinic provides primary health care, education, and protection to vulnerable and displaced people living in the Thailand-Myanmar border area. The leading vision of the organization is that all people from Burma (Myanmar) will have access to quality, equitable, and affordable health care, education, and protection in respect of all human rights. On yearly basis, the Mae Tao Clinic consults more than 100 000 outpatients and admits more than 10 000 patients to receive inpatient care. Many of the people served by the clinic cannot access affordable health care elsewhere principally due to lack of legal status, unaffordable costs, and language barriers. PMID- 30012031 TI - Influence of uridine diphosphate-glucuronosyltransferases (1A9) polymorphisms on mycophenolic acid pharmacokinetics in patients with renal transplant. AB - BACKGROUND: There are differences in pharmacokinetic of mycophenolic acid among individuals. The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MPA. The aim of this study was to explain MPA pharmacokinetics in UGT1A9 1399 C > T polymorphisms in Turkish renal transplant patients. PATIENTS AND METHODS: One hundred and twenty-five living-donor transplant recipients and 100 healthy control subjects underwent UGT1A9 1399 C > T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Concentrations of MPA were determined with Cloned Enzyme Donor Immunoassay (CEDIA). Besides that, all the patients were monitored for acute rejection and graft function during the study period. RESULTS: The UGT1A9 1399 C > T CC, CT, and TT genotype frequencies among patients were, respectively, 68.0%, 23.2%, and 8.8%. The CC, CT, and TT genotype frequencies among controls were, respectively, 63.0%, 23.0%, and 14.0%. There was no significant difference between patients and controls (p = .480, p = .999, p = .286, respectively). At first month, respectively, through blood concentrations of MPA were significantly higher in UGT1A9 1399 C > T TT carriers than in CT and CC carriers (p = .046). The doses for these patients were lower at first month (p = .021). Acute rejection episodes were not associated with the CC vs CT or TT genotypes (p = .064). CONCLUSIONS: Our results demonstrated a correlation between the UGT1A9 1399 C > T polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT1A9 polymorphism may help to achieve target of MPA blood concentrations. PMID- 30012033 TI - Effects of upper limb resistance exercise on aerobic capacity, muscle strength, and quality of life in COPD patients: a randomized controlled trial. AB - OBJECTIVE:: To evaluate the effects of upper limb resistance exercise on the functional capacity, muscle function, and quality of life in patients with chronic obstructive pulmonary disease. SETTING:: Clinical School of Physiotherapy in a Public University of Brazil. SUBJECTS:: 58 patients were recruited; of these, 7 were excluded and 51 individuals were enrolled. INTERVENTION:: Control group performed warm-up, aerobic exercise, inspiratory muscle training, and session stretching, followed by massage therapy. The treatment group performed warm-up, aerobic exercise, inspiratory muscle training, three sets of upper limb resistance exercise, and session stretching, followed by massage therapy. Total three sessions per week for eight weeks. PRIMARY OUTCOME MEASURES:: 6-minute walk test, respiratory and peripheral muscle strength, dyspnea, and quality of life. Normality of the data was tested using the Shapiro-Wilk test; paired analysis of variance was used for intergroup analyses. RESULTS:: 51 patients (25 in the control group and 26 in the treatment group); 41% of the subjects were men. Mean forced expiratory volume was 2.6 +/- 0.6 L, and mean body mass index was 27.3 +/- 7.0 kg/m2. The upper limb resistance exercise resulted in significantly greater benefit in terms of exercise capacity (88.5 +/- 81.9 m, P = 0.043), inspiratory muscle strength (22.9 +/- 24.2 cm H2O, P = 0.001), upper limb muscle strength (2.3 +/- 3.1 kg, P = 0.027), and quality of life scores (-15.3 +/- 10.9 points, P = 0.000). CONCLUSION:: Upper limb resistance exercise improved the exercise capacity, respiratory muscle strength, and quality of life. PMID- 30012034 TI - Chronic myeloid leukemia and pregnancy: patient and partner perspectives. PMID- 30012035 TI - Usher Syndrome and Color Vision. AB - PURPOSE: The aim of this study is to report on the results of color vision testing in a European cohort of patients with Usher syndrome (USH). We describe the results in relation to Usher type (USH1 and USH2), age and visual acuity. METHODS AND METHODS: The color vision of 220 genetically confirmed adult USH patients, aged 18-70 years, was analyzed with one of three methods: the Farnsworth D-15 Dichotomous test (D-15) along with the Lanthony desaturated 15 Hue tests (D-15d), the Roth 28-Hue test, or the Ishihara 14-plate test. Visual acuity was measured with either the ETDRS or the SNELLEN charts. The Confusion index, the Selectivity index and the Confusion angle were calculated for the panel tests and used for analysis. The numbers of plates that could not be read were analyzed for the Ishihara test. RESULTS: For the panel tests, the degree of color loss (Confusion index) is similar in both subtypes of USH, but the polarization of error scores (Selectivity index) is significantly lower in USH1 than USH2, showing more diffuse errors than those found in USH2. There is no significant correlation between logMAR visual acuity and the Confusion or the Selectivity indices. Additionally, we find a significant correlation between patient age and the degree and the polarity of the loss only in USH2. There was no difference between USH1 and USH2 in the results of the Ishihara test. CONCLUSIONS: The examination of color vision in patients with USH shows a significant difference in the pattern of color vision loss in USH1 and USH2 patients, but not in the severity of the loss. In USH2, we find a correlation between patient age and the degree and the polarity of the loss. These results may be due to differences in the pathogenesis of retinal dystrophy in USH1 and USH2. PMID- 30012036 TI - Validity of the Actigraph GT3x and influence of the sensor positioning for the assessment of active energy expenditure during four activities of daily living in stroke subjects. AB - OBJECTIVE:: To explore the validity of the Actigraph and the influence of the placement of the sensor when estimating the active energy expenditure in four common daily activities (transfers, manual task, walking in overground and walking up and down stairs) in stroke survivors. DESIGN:: Cross-sectional study. SETTING:: Department of Physical Medicine and Rehabilitation. SUBJECTS:: A total of 46 subjects affected with stroke sequelae were wearing the Actigraph on three different locations-ankle, hip and wrist on the non-affected side-and performed four tasks: transfers, manual task, walking on flat ground and walking up and down stairs. MAIN MEASURES:: The values of active energy expenditure estimated by the Actigraph were compared to those measured by a portable breathing gas exchange analyzer Metamax3B. The accuracy and agreement between Actigraph and Metamax values were analyzed with mean bias, root mean square error, correlation coefficient and Bland-Altman plots for each task and each sensor location. RESULTS:: The mean bias between the Metamax and Actigraph placed on wrist, hip and ankle were, respectively, MD = 1.16 kcal (%MD = 3%), MD =-20.44 kcal (%MD = 58%) and MD = 17.64 kcal (%MD = 50%). The agreement with the Metamax was poor in general regardless of the sensor location and type of task ( r = 0.12-0.58). CONCLUSION:: This study found large differences and a poor agreement between the active energy expenditure as measured by the Actigraph and the Metamax according to the location of the sensor and the type of task performed by the subject. PMID- 30012037 TI - "Leaving the placenta in situ approach" (LISA) in a patient with placenta increta leading to delayed spontaneous delivery of the placenta. AB - AIM: Based on the recent FIGO recommendations, we wish to report on preservation of the uterus in a patient with placenta increta by applying the leaving the placenta in situ approach. METHODS: A 30-year-old gravida 2, Para 1 was referred at 25 + 5 gestational weeks due to a placenta previa bipartita increta diagnosed by transvaginal ultrasound, a history of a cesarean and vaginal bleeding. After informed consent, the parents opted for conservative treatment. The patient was admitted and the options of treatment were communicated within a multidisciplinary team. At 31 + 4 gestational weeks, severe recurrent hemorrhage led to a repeat cesarean. RESULTS: A boy of 1910 g was delivered and the placenta was left in situ. Estimated blood loss was <200 ml. An MRI on day 13 still showed regular placental circulation, but after 4 weeks, perfusion and HCG levels had significantly decreased. The patient was examined every 3 days and readmitted after 6 weeks with a sudden rise of d-dimers. Within 24 hours, the complete placenta was delivered. On postoperative day 54, MRI confirmed uterine involution without a placental tissue. CONCLUSIONS: Delayed placental delivery in patients with abnormal placental invasion is a legitimate option to preserve fertility and possibly to reduce intrapartum hemorrhage. PMID- 30012038 TI - An evaluation of group reminiscence arts sessions for people with dementia living in care homes. AB - Dementia has been identified as one of the major challenges in the 21st Century. The detrimental effects of dementia can jeopardise personhood, thus person centred interventions including reminiscence and arts practice have been recommended as tools to promote social inclusion and improve the quality of life. This study aimed to evaluate the effectiveness of group reminiscence arts sessions for people living with dementia in care homes (residential and nursing homes) using a comparative and time series design to collect data on quality of life. The intervention was conducted in six care homes in London over a period of 24 weeks and compared with six care homes not receiving the intervention (control). Dementia Care Mapping was used as the primary data collection instrument to measure positive behaviours and rate quality of life before, during and after group reminiscence arts sessions. The evaluation team observed the sessions at three-weekly intervals. Statistical modelling found that positive behaviours and quality of life of care home residents participating in group reminiscence arts sessions increased over the 24-week period. Well-being increased sharply during each session and plateaued at 50 minutes with a sustained positive effect after the sessions. On a longer timescale, well-being and quality of life increased slowly and steadily from one session to the next. The findings were statistically significant ( p < 0.001). The study concludes that group reminiscence arts sessions can have a positive and sustained impact on the quality of life of people with dementia. However, the evidence on the sustainability of the effect over time remains unknown. More research is needed to assess in much greater depth the association between quality of life and group reminiscence arts sessions. PMID- 30012040 TI - Predictors of Adverse Outcomes in Free Flap Reconstruction: A Single-Institution Experience. AB - OBJECTIVE: Understanding the independent predictors of poor outcomes in free flap surgery is essential for patient selection. We aim to determine the independent predictors of major complications, flap survival, and extended hospital stays. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: We reviewed medical records from all vascularized tissue transfers in the head and neck between 2007 and 2014 at our institution. We recorded demographics, medical comorbidities, disease characteristics, flap characteristics, and intraoperative events. We defined outcomes as major complications in the 30-day postoperative period, flap death or partial flap survival, and a length of stay >=14 days. We used bivariate and multivariate methods to test for associations. RESULTS: Of 170 free flap operations, 44% had major complications; 11% fully or partially failed; and 27% required an extended hospital stay. Independent predictors of major complications were age >=60 years (odds ratio [OR], 3.7; P = .001), revision surgery (OR, 3.5; P = .004), and a prior neck dissection (OR, 3.5; P = .004). Independent predictors of flap failure were revision surgery (OR, 4.1, P = .01) and the use of a plate (OR, 3.7; P = .03). Revision surgery was independently associated with a longer stay (OR, 3.0; P = .01), and the use of a radial forearm flap was associated with a shorter stay (OR, 0.3, P = .047). CONCLUSION: These results underscore that caution is warranted in revision flap surgery, patients with prior neck operations, and patients aged >=60 years. PMID- 30012039 TI - Variability of Gross Tumor Volume Delineation for Stereotactic Body Radiotherapy of the Lung With Tri-60Co Magnetic Resonance Image-Guided Radiotherapy System (ViewRay): A Comparative Study With Magnetic Resonance- and Computed Tomography Based Target Delineation. AB - INTRODUCTION: To evaluate the intra-/interobserver variability of gross target volumes between delineation based on magnetic resonance imaging and computed tomography in patients simulated for stereotactic body radiotherapy for primary lung cancer and lung metastasis. MATERIALS AND METHODS: Twenty-five patients (27 lesions) who underwent computed tomography and magnetic resonance simulation with the MR-60Co system (ViewRay) were included in the study. Gross target volumes were delineated on the magnetic resonance imaging (GTVMR) and computed tomography (GTVCT) images by 2 radiation oncologists (RO1 and RO2). Volumes of all contours were measured. Levels of intraobserver (GTVMR_RO vs GTVCT_RO) and interobserver (GTVMR_RO1 vs GTVMR_RO2; GTVCT_RO1 vs GTVCT_RO2) agreement were evaluated using the generalized kappa statistics and the paired t test. RESULTS: No significant volumetric difference was observed between all 4 comparisons (GTVMR_RO1 vs GTVCT_RO1, GTVMR_RO2 vs GTVCT_RO2, GTVMR_RO1 vs GTVMR_RO2, and GTVCT_RO1 vs GTVCT_RO2; P > .05), with mean volumes of GTVs ranging 5 to 6 cm3. The levels of agreement between those 4 comparisons were all substantial with mean kappa values of 0.64, 0.66, 0.74, and 0.63, respectively. However, the interobserver agreement level was significantly higher for GTVCT compared to GTVMR ( P <.001). The mean kappa values significantly increased in all 4 comparisons for tumors >5 cm3 compared to tumors <=5 cm3 (all P < .05). CONCLUSION: No significant differences in volumes between magnetic resonance- and computed tomograpghy-based Gross target volumes were found among 2 ROs. Magnetic resonance-based GTV delineation for lung stereotactic body radiotherapy also demonstrated acceptable interobserver agreement. Tumors >5 cm3 show higher intra-/interobserver agreement compared to tumors <5 cm3. More experience should be accumulated to reduce variability in magnetic resonance-based Gross target volumes delineation in lung stereotactic body radiotherapy. PMID- 30012041 TI - Age-Related Differences in Postural and Goal-Directed Movements During Medial Lateral Rhythmic Stepping. AB - Lateral stability and weight transfer are important for successful stepping and are associated with falls in older adults (OAs). This study assessed the influence of step pacing frequency during medial-lateral stepping in place on body center of mass and lower limb movement in young adults, middle-aged adults, and OAs. Medial-lateral center of mass and stepping limb motion and lower limb loading data were collected. Center of mass motion decreased with increasing pacing frequency and increased to a lesser extent with decreasing pacing frequency. Step length was relatively resistant to changes in pacing frequency. OAs exhibited reductions in whole body and stepping motion compared with younger adults. OAs exhibited greater support limb loading. OAs adapt both postural and stepping strategies to successfully step under time-critical conditions. PMID- 30012042 TI - Comparative effectiveness of telemonitoring versus usual care for type 2 diabetes: A systematic review and meta-analysis. AB - Aims This study evaluated clinical effectiveness of telemonitoring on the management of patients with type 2 diabetes. Methods We searched Ovid-Medline, Ovid-EMBASE, and the Cochrane Library to identify randomized controlled trials that compared telemonitoring and usual care in patients with type 2 diabetes. Results Thirty-eight studies (6855 patients) were included. Telemonitoring was associated with a significant decrease in glycated haemoglobin levels compared to usual care (weighted mean difference -0.42%, 95% confidence interval -0.56 to 0.27) but there was evidence of heterogeneity ( I2 = 96.9%). Telemonitoring was associated with a significant glycated haemoglobin reduction when biological data were transmitted through a web-based device weekly, when voice feedback was performed daily or immediately and when patients were provided with counselling. Telemonitoring also reduced glycated haemoglobin level in studies that monitored patients' medication adherence, provided counselling, education and alarm message. The rate of achieving glycated haemoglobin levels of < 7% was 1.8 times higher in the telemonitoring group compared to the usual care group (risk ratio 1.83, 95% confidence interval 1.35 to 2.47, I2 = 0%). There was also significant reduction in systolic blood pressure (weighted mean difference -1.33 mm Hg) and body mass index (weighted mean difference -0.25 kg/m2), but the clinical relevance of these results can be questioned. The data available on patient satisfaction, quality of life, medication adherence, prescription changes, stress and depression were limited. Conclusions Telemonitoring interventions may be a better option than usual care in improving glycated haemoglobin control of patients with type 2 diabetes. Further studies should assess clinical benefit according to specific delivery modes of the intervention and patient-reported outcomes. PMID- 30012043 TI - Comparison of two prevalent individually ventilated caging systems for detection of murine infectious agents via exhaust air particles. AB - We compared the efficacies of two different individually ventilated cage systems (Allentown and Tecniplast) for health monitoring (HM) of murine infectious agents using exhaust air particle (EAP) capture and real-time PCR. After three months of monitoring, both EAP capture media allowed detection of Helicobacter, Pasteurella and Entamoeba. Use of the EAP real-time PCR for HM reduces the number of mice used. PMID- 30012044 TI - Task Difficulty Makes 'No' Response Different From 'Yes' Response in Detection of Fragmented Object Contours. AB - Two-alternative forced choice tasks are often used in object detection, which regards detecting an object as a 'yes' response and detecting no object as a 'no' response. Previous studies have suggested that the processing of yes/no responses arises from identical or similar processing. In this study, we investigated the difference of processing between detecting an object ('yes' response) and not detecting any object ('no' response) by controlling the task difficulty in terms of fragment length and stimulus duration. The results indicated that a 'yes' response depends on accurate and stable decisions through grouping processing, and a 'no' response might involve two distinct processing, including accurate decisions and intuitive decisions. Accurate decisions of 'no' may arise after the rejection of a 'yes' response with grouping processing, which is an accurate but slow response in an easy task. Intuitive decisions of 'no' arise as the result of breaking down the decision process when the received information was insufficient for grouping processing in a difficult task. Therefore, intuitive decisions of 'no' arise quickly but are inaccurate. The different processes associated with yes/no responses were discussed in terms of the hierarchal structure of object recognition, especially with respect to receiving information and grouping. PMID- 30012045 TI - Ibrutinib-related atrial fibrillation: Therapeutic challenges. AB - Ibrutinib is a drug used in several lymphohyperplastic diseases. Its use is associated with an increased risk of atrial fibrillation. New-onset atrial fibrillation in this setting is a true challenge as several antiarrhythmic drugs are not indicated and long-term anticoagulation has several limitations. Herein, we describe our experience in treating a 55-year-old patient receiving ibrutinib who presented with new-onset atrial fibrillation and borderline arterial pressure. Since first-line therapies, electrical cardioversion and ablation, could not be performed, rhythm control with intravenous administration of amiodarone was attempted and led to prompt sinus rhythm restoration. We discuss the therapeutic challenges related to sinus rhythm restoration and anticoagulation in this group of atrial fibrillation patients. PMID- 30012046 TI - Comparing Cold/Liquid Diet vs Regular Diet on Posttonsillectomy Pain and Bleeding. AB - Objective Tonsillectomy is a common operation; however, there are controversial opinions regarding the posttonsillectomy diet. The aim of this study was to compare the effects of cold/liquid diet vs regular diet on posttonsillectomy pain and bleeding. Study Design Prospective randomized controlled trial. Setting Tertiary referral center. Subjects and Methods In total, 194 children who underwent tonsillectomy (with or without adenoidectomy) were randomly allocated into 2 groups. A total of 100 patients were allocated in the cold/liquid diet, and 94 patients were allocated in the regular diet group. Pain score was recorded for the first 7 days, and rate of hemorrhage was recorded for 10 days after surgery. Results The participants' age range was 3 to 17 years. The mean pain score level in the regular diet group after breakfast, lunch, and dinner was not statistically significant in comparison with the cold/liquid diet group. One patient in the regular diet group was admitted to the hospital due to secondary bleeding, but it stopped without any intervention. Conclusion Most otolaryngologists believe in dietary restrictions following tonsillectomy. However, there is much controversy regarding posttonsillectomy dietary advice in the literature. In addition, only a few randomized clinical trials have focused on this subject. We found that there was no difference between regular diet and cold/liquid diet in terms of posttonsillectomy pain and bleeding. Hence, we do not recommend a limited posttonsillectomy diet. PMID- 30012048 TI - Treatment of varicose veins, international consensus on which major complications to discuss with the patient: A Delphi study. AB - Objective To reach consensus on which complications of varicose vein treatments physicians consider major or minor, in order to standardize the informed consent procedure and improve shared decision-making. Methods Using the e-Delphi method, expert physicians from 10 countries were asked to rate complications as "major" or "minor" on a 5-point Likert scale. Reference articles from a Cochrane review on varicose veins were used to compose the list of complications. Results Participating experts reached consensus on 12 major complications: allergic reaction, cellulitis requiring intravenous antibiotics/intensive care, wound infection requiring debridement, hemorrhage requiring blood transfusion/surgical intervention, pulmonary embolism, skin necrosis requiring surgery, arteriovenous fistula requiring repair, deep venous thrombosis, lymphocele, thermal injury, transient ischemic attack/stroke, and permanent discoloration. Conclusion An international consensus was reached about what physicians consider to be major complications of varicose vein treatments. This consensus may assist in standardizing the information physicians discuss with patients prior to varicose vein treatment. PMID- 30012047 TI - A Review on Differences in Effects on Normal and Malignant Cells and Tissues to Electroporation-Based Therapies: A Focus on Calcium Electroporation. AB - Calcium electroporation is a potential novel anticancer treatment, where high concentrations of calcium are introduced into the cell cytosol by electroporation. This is a method where short, high-voltage pulses induce a transient permeabilization of the cell membrane and thereby allow influx and efflux of ions and molecules. Electroporation is used in combination with chemotherapeutic drugs (electrochemotherapy) as a standard treatment for cutaneous metastases, and electroporation using a higher electric field and number of pulses (irreversible electroporation) is increasingly being used as an anticancer treatment. In this review, calcium electroporation is described with emphasis on the investigations of differences in the effect on normal and malignant cells and tissues in vitro and in vivo. Calcium electroporation has been shown to induce cell death in vitro and tumor necrosis in vivo with a difference in sensitivity between different tumor types. Normal cells treated in vitro are significantly less affected than cancer cells, and a similar trend is shown in vivo where muscle and skin tissue surrounding a treated tumor as well as muscle and skin directly treated with calcium electroporation were less affected than tumors. The mechanism behind this difference in sensitivity is not fully understood but might be affected by differences in electric impedance, membrane repair, and expression of plasma membrane calcium ATPases in normal and malignant cells. The research on calcium electroporation shows a potential novel anticancer treatment with significant effect on cancer cells and tissues while normal cells and tissues are clearly less affected. PMID- 30012049 TI - Three-year recurrence of Dupuytren's contracture after needle fasciotomy and collagenase injection: a two-centre randomized controlled trial. AB - : Collagenase injection and needle fasciotomy have similar short-term outcomes in the treatment of Dupuytren's contracture. The purpose of this study was to compare the recurrence rate of these two procedures 3 years after index treatment of primary disease. We enrolled 93 patients (96 rays) from a previous two-centre randomized controlled trial. The rays that had been retreated or showed an increase in the total passive extension deficit of 30 degrees or more compared with 3 months after treatment were regarded as recurrences. Seventeen of 40 needle fasciectomies and 12 of 36 of collagenase injections had recurred. This difference was not statistically significant. We conclude that collagenase injection and needle fasciotomy have similar 3-year recurrence rates in the treatment of Dupuytren's contracture. LEVEL OF EVIDENCE: I. PMID- 30012050 TI - Comparison of Lurasidone Versus Quetiapine for the Treatment of Delirium in Critically Ill Patients. PMID- 30012051 TI - PD-L1 Expression and Tumor-Infiltrating Lymphocytes in High-Risk and Metastatic Cutaneous Squamous Cell Carcinoma. AB - Objective To characterize programmed death-ligand 1 (PD-L1) expression and tumor infiltrating lymphocyte (TIL) positivity for locally aggressive or regionally metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC). Study Design Retrospective chart review, followed by immunohistochemical staining of archived tumor specimens. Setting Tertiary academic medical center. Subjects and Methods After identification of 101 patients treated surgically for locally advanced or regionally metastatic cHNSCC, archived tissue was stained and graded for PD-L1 expression in addition to TIL presence. Cross-tabulation was performed to examine the association between either of these variables and clinicopathologic features and outcomes. Results A total of 101 patients met inclusion criteria, but archived tissue was available only for 83 (31 primaries, 52 metastases). The majority of primary tumors demonstrated grade 1 PD-L1 staining, while grade 2 staining was more likely for metastases. Neither high- nor low-grade PD-L1 expression correlated with any clinicopathologic variable for primary tumors. However, for metastases, high-grade staining was significantly associated with regional recurrence (15 of 19, P = .02). TILs were present for 65% of primary tumors and 90% of regional metastases but did not correlate with any clinicopathologic variables. Conclusion Diffuse expression of PD-L1 in this study highlights the possibility of using immunotherapy in the form of programmed death 1/PD-L1 blockade to improve treatment for this devastating disease. However, further studies are needed to clarify the significance of PD-L1 expression and TIL positivity for locally advanced or regionally metastatic cHNSCC. PMID- 30012052 TI - Brain Activation During Passive and Volitional Pedaling After Stroke. AB - BACKGROUND: Prior work indicates that pedaling-related brain activation is lower in people with stroke than in controls. We asked whether this observation could be explained by between-group differences in volitional motor commands and pedaling performance. METHODS: Individuals with and without stroke performed passive and volitional pedaling while brain activation was recorded with functional magnetic resonance imaging. The passive condition eliminated motor commands to pedal and minimized between-group differences in pedaling performance. Volume, intensity, and laterality of brain activation were compared across conditions and groups. RESULTS: There were no significant effects of condition and no Group * Condition interactions for any measure of brain activation. Only 53% of subjects could minimize muscle activity for passive pedaling. CONCLUSIONS: Altered motor commands and pedaling performance are unlikely to account for reduced pedaling-related brain activation poststroke. Instead, this phenomenon may be due to functional or structural brain changes. Passive pedaling can be difficult to achieve and may require inhibition. PMID- 30012053 TI - The Roles of Declarative Knowledge and Working Memory in Explicit Motor Learning and Practice Among Children With Low Motor Abilities. AB - Effective learning methods are essential for motor skill development and participation in children with low motor abilities. Current learning methods predominantly aim to increase declarative knowledge through explicit instructions that necessitate sufficient working memory capacity. This study investigated the roles of declarative knowledge and working memory capacity in explicit motor learning of children with low motor abilities. We studied both acquisition performance (i.e., performance during practice) and learning (i.e., the improvement in performance from pretest to posttest). After practice with explicit instructions, children with low motor abilities showed significant learning, albeit that improvement was relatively small. However, working memory capacity and declarative knowledge did not predict learning. By contrast, working memory capacity and declarative knowledge did predict performance during practice. These findings suggest that explicit instructions enhance motor performance during practice, but that motor learning per se is largely implicit in children with low motor abilities. PMID- 30012054 TI - Redesigning Transplant Organ Labeling to Prevent Patient Harm and Organ Loss. AB - BACKGROUND: In 2012, the Health Resources and Services Administration and the United Network for Organ Sharing launched the "Electronic Tracking and Transportation" (ETT) project, in response to "labeling and packaging issues" being a frequently reported safety incident. This article describes an improvement project conducted as part of this United Network for Organ Sharing project. METHODS: An interdisciplinary team conducted a Process Failure Modes and Effects Analysis, laboratory simulations of organ labeling during procurement, and a heuristic evaluation of a label software application to inform the design of TransNet, a system that uses barcode technology at the point of organ recovery. A total of 42 clinicians and staff from 10 organ procurement organizations and 2 transplant centers in the United States participated. Processes Addressed: Key features of the redesigned labeling system include independent, double entry of label information into the software application, a machine-readable barcode on each organ's label, and a handheld printer for at "point of use" label printing. OUTCOMES: The new labeling system, TransNet, has become mandatory since June 2017. A survey conducted on early adopters (N = 11), after 1 year of use, indicates the process is safer and more efficient. IMPLICATIONS FOR PRACTICE: The findings from this study suggest that the application of quality planning methods, common in other industries, when redesigning a health-care process, are valuable and revelatory and should be adopted more extensively. Future evaluation of TransNet effectiveness to reduce safety incidents is critical. PMID- 30012055 TI - Working memory in older adults declines with age, but is modulated by sex and education. AB - Working memory (WM), which underlies the temporary storage and manipulation of information, is critical for multiple aspects of cognition and everyday life. Nevertheless, research examining WM specifically in older adults remains limited, despite the global rapid increase in human life expectancy. We examined WM in a large sample ( N = 754) of healthy older adults (aged 58-89) in a non-Western population (Chinese speakers) in Taiwan, on a digit n-back task. We tested not only the influence of age itself and of load (1-back vs. 2-back) but also the effects of both sex and education, which have been shown to modulate WM abilities. Mixed-effects regression revealed that, within older adulthood, age negatively impacted WM abilities (with linear, not nonlinear, effects), as did load (worse performance at 2-back). In contrast, education level was positively associated with WM. Moreover, both age and education interacted with sex. With increasing age, males showed a steeper WM decline than females; with increasing education, females showed greater WM gains than males. Together with other findings, the evidence suggests that age, sex, and education all impact WM in older adults, but interact in particular ways. The results have both basic research and translational implications and are consistent with particular benefits from increased education for women. PMID- 30012056 TI - Voxelwise computed diffusion-weighted imaging for the detection of cytotoxic oedema in brain imaging: a pilot study. AB - Aim To evaluate voxelwise computed diffusion-weighted imaging (vcDWI) for the detection of cytotoxic oedema in brain imaging and to quantify the benefit of lesion contrast in comparison to standard b = 1000 s/mm2 by the example of acute ischaemic stroke. Materials and methods A retrospective evaluation of 66 patients (63 +/- 15.9 years) suspected for acute ischaemic stroke who received diffusion weighted magnetic resonance imaging and fluid-attenuated inversion recovery sequence. A neuroradiologist evaluated all examinations for acute ischaemic stroke based on diffusion-weighted imaging, the apparent diffusion coefficient and fluid-attenuated inversion recovery (reference standard) and 6 weeks later the vcDWI in a randomised manner. Time of analysis was noted. Signal intensities were acquired in lesions, in healthy tissue as well as in the cerebrospinal fluid. Contrast ratios and coefficients of variation were computed. Results A total of 218 lesions was found in 46/66 patients. vcDWI identified all patients and lesions correctly. The median evaluation time was 36 seconds (4-126 s) for the vcDWI and 44 seconds (9-186 s; P < 0.001) for the diffusion-weighted imaging/apparent diffusion coefficient reading. The contrast ratio in vcDWI (mean value 2.57, range 1.73-4.11) was higher than in b = 1000 s/mm2 (2.33, 0.83-3.85, P = 0.03) and the apparent diffusion coefficient map (1.83, 1.00-3.00, P < 0.001), respectively. Coefficients of variation in lesions and tissue did not differ significantly between vcDWI and b = 1000 s/mm2 ( P = 0.81/ P = 0.26). The signal intensity of cerebrospinal fluid was lower in vcDWI than in b = 1000 mm2/s (0.08 and 34.8, P < 0.001). Conclusion It could be shown that vcDWI has the potential to accelerate the detection of diffusion-restricted lesions in neuroimaging by improving the contrast ratios and reducing the T2 shine-through effect in comparison to standard diffusion-weighted imaging in brain imaging. PMID- 30012057 TI - Hospital-Acquired Infections in Critically Ill Patients With Cancer. AB - Hospital-acquired infections are a common and costly problem facing critically ill patients in the intensive care unit (ICU). Critically ill patients with cancer are a particularly vulnerable subpopulation who possesses additional, nonmodifiable risk factors for developing these infections and, in many cases, are at increased risk of death as a result. This review will describe the most common nosocomial infections patients with cancer acquire while in the ICU: ventilator-associated events, central line-associated bloodstream infection, catheter-associated urinary tract infections, and Clostridium difficile infection. PMID- 30012058 TI - Scaling Relationship of In Vivo Muscle Contraction Strength of Rabbits Exposed to High-Frequency Nanosecond Pulse Bursts. AB - We studied the influence of various parameters of high-frequency nanosecond pulse bursts on the strength of rabbit muscle contractions. Ten unipolar high-frequency pulse bursts with various field intensities E (1 kV/cm, 4 kV/cm, and 8 kV/cm), intraburst frequencies f (10 kHz, 100 kHz, and 1 MHz), and intraburst pulse numbers N (1, 10, and 100) were applied using a pair of plate electrodes to the surface skin of the rabbits' biceps femoris, and the acceleration signal of muscle contraction near the electrode was measured using a 3-axis acceleration sensor. A time- and frequency-domain analysis of the acceleration signals showed that the peak value of the signal increases with the increasing strength of the pulse burst and that the frequency spectra of the signals measured under various pulse bursts have characteristic frequencies (at approximately 2 Hz, 32 Hz, 45 Hz, and 55 Hz). Furthermore, we processed the data through multivariate nonlinear regression analysis and variance analysis and determined that the peak value of the signal scales with the logarithm to the base 10 of EN x, where x is a value that scales with the logarithm to the base 10 of intraburst frequency (f). These results indicate that for high-frequency nanosecond pulse treatment of solid tumors in or near muscles, when the field strength is relatively high, the intraburst frequency and the intraburst pulse number require appropriate selection to limit the strength of muscle contraction as much as possible. PMID- 30012059 TI - The relationships between the medical learners' motivations and strategies to learning medicine and learning outcomes. AB - BACKGROUND: One of the strongly theorized areas of research associated with learning outcomes has been the approaches to learning. Few studies have been focused on examining the relationship between the approaches to learning medicine (ALM) and learning outcomes. OBJECTIVES: The objectives were: (1) to conduct psychometric testing of the ALM questionnaire; and (2) to examine the association between medical learners' ALM and learning outcomes. DESIGN: We developed the ALM questionnaire which was a modification of the Revised Learning Process questionnaire. We defined the learning outcome of each house officer as the class rank in his/her graduating class. Exploratory factor analysis was used to examine the factor structure of the ALM questionnaire. We conducted Pearson's and Spearman's Rank correlation coefficients for examining the linear relationships between two continuous variables, and between a continuous variable and a categorical variable, respectively. Stepwise multivariate linear regression analysis with backward elimination was undertaken to examine the correlation between the ALM and the learning outcome. RESULTS: A house officer with deep strategies (relating multiple ideas and truly understanding the course content) or surface motivations (aim for qualification) was more likely to have a better learning outcome as indicated by a better class rank based on his/her academic performance. Furthermore, a house officer with surface learning strategies (minimizing the study scope to merely passing the examination) to learning medicine was more likely to have an unfavorable class rank. CONCLUSIONS: This study represents the first report of the correlation between house officers' ALM and learning outcomes. House officers with deep strategies were more likely to have better learning outcomes. In particular, house officers with a surface motive to learning medicine, i.e., aiming for qualification, were surprisingly correlated with better learning outcomes. PMID- 30012060 TI - Daily dynamic assessment and modelling of intersession processes in ambulatory psychotherapy: A proof of concept study. AB - BACKGROUND: the typical mode of assessment in studies on intersession processes (ISP) in psychotherapy is using cross-sectional or weekly measurements. Daily dynamics of intersession processes have not yet been studied. METHOD: intersession process data from 22 ambulatory psychotherapy cases were collected in a naturalistic study with high temporal resolution, resulting in a total of 1026 daily measurements. Multilevel vector autoregressive (VAR) modelling was applied to discover the temporal course and causal influences among intersession processes. Centrality analysis was applied to discover unique functions of various intersession process variables. RESULTS: a group-level network structure was discovered, offering first insights on the role of different intersession processes during psychotherapy. Centrality analysis revealed unique roles for various aspects of the intersession process. Temporal distance from the last session had only weak influence on the ISP. CONCLUSIONS: using short, daily measures, the unique role of various aspects of the ISP were uncovered. Some aspects of the ISP, like recalling session contents or reflection on future session contents, are facilitators of overall ISP intensity. Other aspects like thoughts on payment or appointments or negative treatment-related emotions are likely to suppress ISP. PMID- 30012062 TI - 2018-2019 Conferences. PMID- 30012061 TI - End-Stage Osteoarthritis of the First Metatarsophalangeal Joint: What Has Changed in Our Practice? PMID- 30012063 TI - Marginal Gains. PMID- 30012065 TI - A Foreign Body Through the Shoe of a Person With Diabetic Peripheral Neuropathy Alters Contralateral Biomechanics: Captured Through Innovative Plantar Pressure Technology. AB - High plantar pressure as a result of diabetic peripheral neuropathy is often reported as a major risk factor for ulceration. However, previous studies are confined to laboratories with equipment limited by cables, reducing the validity of measurements to daily life. The participant concerned in this case report was wearing an innovative plantar pressure feedback system as part of a wider study. The system allows for continuous plantar pressure monitoring and provides feedback throughout all activities of daily living. The participant concerned was a 59-year-old male with type 2 diabetes who presented with severe peripheral neuropathy. In addition, the right ankle had previously undergone fusion. Between monthly study appointments, the participant unknowingly had a screw embedded in his right shoe, while pressure was being recorded. Although no significant differences in pressure were present for the right foot with the embedded screw, the contralateral foot showed significantly higher pressure when the screw was embedded, compared with pre and post time periods. The increase in pressure on the contralateral foot is expected to result from the protrusion of the screw in the right shoe, causing a perturbation to balance and a shift in the center of pressure toward the contralateral side. This compensatory effect is likely to have been magnified by the limited mobility of the fused right ankle. These findings highlight the importance of checking both feet for ulcer risk, in the event of receiving high-pressure feedback. This innovative technology may improve our understanding of diabetic plantar foot ulcer development. PMID- 30012068 TI - Speed Against Fidelity of Communications: A Battle for Editors. PMID- 30012067 TI - Evaluation of Wound Dressing Made From Spider Silk Protein Using in a Rabbit Model. AB - The aim of the present article was to study the healing of wounds using spider silk. Eight New Zealand female rabbits were selected as animal model. First, 3 identical wounds with length of 15 mm and a depth of 4 mm on the back of each rabbit were created. The first group, as standard control, did not receive any special treatment, they were treated only with saline and Vaseline locally. The second group, as positive control, received a thin film of phenytoin 1% ointment locally. The third group, as treated group, received a thin film of spider silk protein. At the end of the study, a biopsy of skin was done. After tissue preparation, all sections were evaluated. Some morphometrical parameters such as counting cells, fibroblasts, blood vessels, determination of the area of the wound closure, necrotic tissue, speed of wound healing, and epidermal thickness were done, and for data statistical analysis, SPSS software and Excel software were used. The results of this study showed that spider silk dressing may benefit as a possible effect of nanoparticles in the test preparation in wound healing. PMID- 30012069 TI - High-Resolution Spectral Analysis Accurately Identifies the Bacterial Signature in Infected Chronic Foot Ulcers in People With Diabetes. AB - Diabetic foot infections are a major cause of hospitalization, and delayed treatment can lead to numerous complications. The aim of this research was to investigate high-resolution spectroscopy of the wound center and periwound area for real-time estimation of multispectral signature of bacteria at the base of diabetic foot ulcers. We investigated the spectrum of the reflected visual light from diabetic foot ulcers and developed a method that identifies the presence of bacteria in the wound infections. We undertook a prospective pilot study on 18 patients with type 1 and type 2 diabetes and chronic diabetic foot ulcers. The spectral coefficients were directly compared with the results from the wound swab. The results of the multispectral analysis demonstrated 100% sensitivity, with 100% negative predictive values of identifying the presence of the bacteria, which was the cause of the infection in the wound. The results of our study suggest that the changes in the multispectral properties of the wound can be used to identify the presence of bacteria in the infected area using a noninvasive device without any contact with the wound. This technique holds great promise for real-time objective evaluation of the wound infection status beyond the standard visual assessment of diabetic foot ulcers. PMID- 30012064 TI - Screening for cognitive deficits with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia scale. AB - OBJECTIVE:: This study aimed to evaluate the validity of the Evaluation of Cognitive Processes involved in Disability in Schizophrenia scale (ECPDS) to discriminate for cognitive impairment in schizophrenia. DESIGN:: This multicentre cross-sectional study used a validation design with receiver operating characteristic (ROC) curve analysis. SETTINGS:: The study was undertaken in a French network of seven outward referral centres. SUBJECTS:: We recruited individuals with clinically stable schizophrenia diagnosed based on the Structured Clinical Interview for assessing Diagnostic and Statistical Manual of Mental Disorders (4th ed., rev.; DSM-IV-R) criteria. MAIN MEASURES:: The index test for cognitive impairment was ECPDS (independent variable), a 13-item scale completed by a relative of the participant. The reference standard was a standardized test battery that evaluated seven cognitive domains. Cognitive impairment was the dependent variable and was defined as an average z-score more than 1 SD below the normative mean in two or more cognitive domains. RESULTS:: Overall, 97 patients were included (67 with schizophrenia, 28 with schizoaffective disorder, and 2 with schizophreniform disorder). The mean age was 30.2 (SD 7.7) years, and there were 75 men (77.3%). There were 59 (60.8%) patients with cognitive impairment on the neuropsychological battery, and the mean ECPDS score was 27.3 (SD 7.3). The ROC curve analysis showed that the optimal ECPDS cut-off was 29.5. The area under the curve was 0.77, with 76.3% specificity and 71.1% sensitivity to discriminate against cognitive impairment. CONCLUSION:: The ECPDS is a valid triage tool for detecting cognitive impairment in schizophrenia, before using an extensive neuropsychological battery, and holds promise for use in everyday clinical practice. PMID- 30012070 TI - Pressure Ulcers: Risk Stratification and Prognostic Factors That Promote Recurrence After Reconstructive Surgery. AB - The aim of this study was to identify overall recurrence rates after reconstructive surgery in patients with pressure ulcers and to identify risk factors that associated with recurrence after reconstructive surgery. This study was done in Faculty of Medicine Chiang Mai University, including recurrence at the same site as well as on new sites, between January 1998 and December 2015. 165 patients with 272 pressure ulcers were retrospectively collected and analyzed. The overall pressure ulcer recurrence rate was 16.54% (45 from 272 ulcers) from an overall patient recurrence of 19.39% (32 from 165 patients). From multivariable analysis, we found 9 prognostic factors that were statistically significant for recurrence after surgery, divided into 2 groups: uncontrollable and controllable factors. Uncontrollable factors consisted of being female (hazard ratio [HR]=1.90;95%CI=1.54-2.34), being older than 45 years (HR=1.67;95%CI=1.40-2.0), and location of pressure ulcers on ischium (HR=1.65; 95% CI=1.51-1.80) and sacrum (HR=1.17;95%CI=1.10-1.23). Controllable factors included spasticity (HR=1.11;95%CI=1.04-1.20), incomplete healing before discharge (HR=5.42;95% CI=3.95-7.44), serum albumin level <=3 g/dL (HR=1.27;95%CI=1.13-1.43), pressure ulcer stage 4 (HR=1.90;95%CI=1.41-2.54), non muscle-based procedure (HR=3.82;95%CI=2.54-5.76), and length of hospitalization >21 days (HR=2.94;95%CI=1.60-5.40). Patients with these factors were strongly advised to address and improve all these factors for decreasing the recurrence rate after reconstructive surgery. PMID- 30012071 TI - Brokering Student Well-Being: Understanding the Work of School Health Administrators. AB - Despite a well-documented need for school health programs (SHPs) among schoolchildren, there is little school health funding in California and limited research on the role of those who manage SHPs. This qualitative study investigated the work of a selected group of school health administrators (SHAs) in California. Study aims were to explore SHA job pathways and responsibilities, the contextual factors influencing their work, and how they get their work done, given limited funding for SHPs. Thirty in-depth, semistructured interviews were conducted with SHAs and their staff, supervisors, and deputy SHAs. The main themes and subthemes are (1) district hierarchies marginalize SHAs and (2) in response to this marginalization, SHAs engage in brokering strategies to get their work done, including (a) raising awareness, (b) cultivating powerful allies, and (c) adjusting to working conditions. Despite structural disempowerment, SHAs have developed strategies to secure political support for SHPs and school nurses. PMID- 30012072 TI - Eradicating hepatitis C: The need for a public health response. AB - Hepatitis C is a global public health issue affecting 150-170 million people worldwide, and over 227,000 Australians with an increasing morbidity resulting from the infection. The Australian Government funded access through the national health scheme to Direct Acting Antiviral (DAA) medication for all people with hepatitis C, regardless of disease staging or mode of transmission to eradicate hepatitis C in Australia. The availability of these drugs not only alters the end result of hepatitis C treatment from that of sustained viral response to cure, but necessitates a refocusing of the public health response to hepatitis C. This project, conducted prior to this funding announcement, interviewed key stakeholders in Australia to investigate the potential impact of DAAs on individuals with hepatitis C and their public health implications. The findings include that while DAAs are revolutionary, there remains essential barriers to their uptake including stigma and discrimination, and a lack of attention to the systematic implementation of the cure. PMID- 30012073 TI - Histopathology of Unilateral Cryptorchidism. AB - Defective mini-puberty inducing insufficient gonadotropin secretion is one of the most common causes of nonobstructive azoospermia in men suffering from congenital isolated unilateral or bilateral cryptorchidism. The aim of our study was to determine the risk for azoospermia by histologic criteria in a cohort of unilateral cryptorchid boys undergoing orchidopexy and bilateral testicular biopsy. We performed a retrospective analysis of data available in the library of the Cryptorchidism Research Institute, Liestal, Switzerland. Complete histological evaluations were available for 319 boys operated on for unilateral cryptorchidism with simultaneous biopsy of the contralateral descended testicle. The median age was 39 (5-192) months and 58 patients were <18 months of age. Forty-eight percent of undescended testis (UDT) and 21% of contralateral testis had no A dark (Ad) spermatogonia. Furthermore, in 11% of boys Ad spermatogonia were lacking in both testes. Positive correlation was found between the spermatogonia/tubule ratio of the UDT and contralateral testis (Spearman rank order correlation is 0.16, P = .003). The extent of alteration in the UDT correlated with the contralateral descended testis, indicating that unilateral cryptorchidism is a bilateral disease. Observed impaired transition from gonocytes into Ad spermatogonia indicates defective mini-puberty, providing one of explanations for azoospermia and infertility development in unilateral cryptorchid men. PMID- 30012074 TI - Associations Between the Features of Gross Placental Morphology and Birthweight. AB - The placenta plays a critical role in regulating fetal growth. Recent studies suggest that there may be sex-specific differences in placental development. The purpose of our study was to evaluate the associations between birthweight and placental morphology in models adjusted for covariates and to assess sex-specific differences in these associations. We analyzed data from the Stillbirth Collaborative Research Network's population-based case-control study conducted between 2006 and 2008, which recruited cases of stillbirth and population-based controls in 5 states. Our analysis was restricted to singleton live births with a placental examination (n = 1229). Characteristics of placental morphology evaluated include thickness, surface area, difference in diameters, shape, and umbilical cord insertion site. We used linear regression to model birthweight as a function of placental morphology and covariates. Surface area had the greatest association with birthweight; a reduction in surface area of 83 cm2, which reflects the interquartile range, is associated with a 260.2-g reduction in birthweight (95% confidence interval, -299.9 to -220.6), after adjustment for other features of placental morphology and covariates. Reduced placental thickness was also associated with lower birthweight. These associations did not differ between males and females. Our results suggest that reduced placental thickness and surface area are independently associated with lower birthweight and that these relationships are not related to sex. PMID- 30012075 TI - Travel History Is Important! A Case of Trypanosoma cruzi Identified by Placental Examination. PMID- 30012076 TI - Regret-Based Decision-Making Style Acts as a Dispositional Factor in Risky Choices. AB - People who anticipate the potential regret of one's decisions are believed to act in a more risk-averse manner and, thus, display fewer risk-taking behaviors across many domains. We conducted two studies to investigate whether individual differences in regret-based decision-making (a) reflect a unitary cognitive-style dimension, (b) are stable over time, and (c) predict later risk-taking behavior. In Study 1, 332 participants completed a regret-based decision-making style scale (RDS) to evaluate its psychometric qualities. In Study 2, participants ( N = 119) were tested on two separate occasions to assess the association between RDS and risk-taking. At Time 1, participants completed the RDS, as well as trait measures of anxiety and depression. One month later, they completed the Balloon Analogue Risk Task (BART) and state mood (Positive/Negative affect) scales. The RDS had a sound unidimensional factorial structure and was stable over time. Further, higher reported RDS scores were significantly associated with less risk-taking on the BART, holding other variables constant. These studies suggest that individual differences in regret-based decision-making may lead to a more cautious approach to real-world risk behaviors. PMID- 30012077 TI - Mixed Reality Technology Launches in Orthopedic Surgery for Comprehensive Preoperative Management of Complicated Cervical Fractures. PMID- 30012078 TI - Bioabsorbable Drug-Eluting Stent Versus Bare Metal Stent in Iliac Artery Evaluated by Optical Coherence Tomography: An In Vivo Study in Porcine. AB - OBJECTIVE: This study aimed to compare, using optical coherence tomography (OCT), the outcomes of bioabsorbable drug-eluting stent with those of bare metal stent (BMS) following implantation in porcine iliac artery. METHODS: After the placement of BMS and bioabsorbable drug-eluting stents, we used OCT and digital subtraction angiography to investigate stent appositions, arterial neointima, evagination, and restenosis at 1 and 3 months. RESULTS: At 1 and 3 months after stent implantation, OCT study was performed to investigate 32 stents and 21 788 struts. Thirty-three malapposed struts were found in the bioabsorbable drug eluting stent groups and 2 were found in BMS groups. The average neointimal thickness, area, and in-stent stenosis were significantly lower in bioabsorbable drug-eluting stents than in BMS, while the frequency of malapposed struts was higher in the bioresorbable drug-eluting stent groups. Average neointimal thickness was lower in bioabsorbable drug-eluting stents than in BMS at 1 (0.19 +/- 0.09 vs 0.67 +/- 0.75 mm; P < .001) and 3 months (0.21 +/- 0.08 vs 1.52 +/- 0.28 mm; P < .001). CONCLUSION: Our study suggested that bioabsorbable drug eluting stent is more effective in decreasing arterial restenosis than BMS in animal models. PMID- 30012079 TI - How healthy are children one year after discharge from nutritional rehabilitation centres? AB - Nutritional rehabilitation centres (NRCs) have been established to ensure the nutritional recovery of severely malnourished children. The long-term nutritional outcomes in children discharged from NRCs have not been described. In this retrospective cohort study, the nutritional status of 514 children was assessed one year after discharge. Household and maternal data, as well as data regarding variables related to the children's stay at the NRC, were collected. A total of 33.4% had moderate malnutrition and 11.7% had severe malnutrition. The mean weight for height Z-score at admission, discharge and one year after discharge were -3.61, -1.90 and -2.34, respectively. Thus, long-term monitoring and follow up of children discharged from NRCs till they achieve normal nutritional status is mandatory. PMID- 30012080 TI - 2,4-D poisoning: a review with illustration of two cases. AB - 2,4-D (2,4-dichlorphenoxyacetic acid) is a chlorphenoxy group pesticide. Its relative safety and broad leaf selectivity makes it a favourite herbicide of many home gardeners and agricultural workers. Severe systemic toxicity requiring hospital admission and intensive care usually occurs following intentional oral ingestion. 2,4-D poisoning is an under-recognised cause of a potentially lethal toxic syndrome, especially in low- and middle-income countries, where such compounds are widely used in farming and readily available in households. It warrants close monitoring and high-quality supportive care along with plasma alkalinisation or extracorporeal removal of the toxin. We present a short review on 2,4-D poisoning and describe two illustrative cases with significant oral ingestion resulted in early and rapidly developing systemic toxicity. Both patients were admitted to the intensive care unit; one patient was managed with alkaline diuresis and other case required three sessions of haemodialysis. PMID- 30012081 TI - Maternal knowledge, attitude and practices during childhood diarrhoea. AB - Diarrhoea and pneumonia account for most deaths in children aged < 5 years. However, most diarrhoeal deaths are preventable with appropriate hygienic measures and timely initiation of rehydration therapy. A cross-sectional study was conducted on 280 mothers with children aged 2-59 months with acute watery diarrhoea at a tertiary hospital. One-fifth of respondents were illiterate and only one-third of mothers pre-treated water to make it drinkable. Mean knowledge scores for hand washing, diarrhoea prevention and complications of diarrhoea were poor, though higher in educated mothers ( P < 0.05). Scores were similar for the first episode or repeat episodes of diarrhoea. Only 50.4% and 55.2% mothers knew the correct method of Oral Rehydration Solution (ORS) preparation and administration, respectively. Lack of adequate maternal knowledge and practices concerning childhood diarrhoea highlights the need for patient counselling and education, especially among the illiterate in India. PMID- 30012082 TI - Time spent being malnourished during the first five years of life! An unseen aspect of child malnutrition. AB - The burden of malnutrition is often estimated in terms of 'prevalence' without considering two important contributing factors: incidence and duration. To illustrate this, we conducted a community-based retrospective cohort study involving 24,278 children enrolled in an integrated child development scheme in India. Anthropometric data of study participants from birth to five years of age were collected from the growth charts maintained by Anganwadi workers. Of all the growth charts reviewed, 1460 (6.0%) children died before their fifth birthday and 4013 (16.5%) were excluded after initial screening because either the growth chart was incomplete (4.8%) or had missing entries (11.7%). Of the remaining 20,265 children included in the study, in the first five years of their life, 35.6% suffered from exclusive moderate malnourishment and 9.4% from severe malnourishment. The most common age groups for the onset of moderate and severe malnutrition were 9-11 months and 12-15 months, respectively. The mode, median and mean duration of time spent by children being severely underweight was 3, 7 and 8.4 months respectively, and being moderately underweight was 8, 11 and 15.1 months, respectively. Thus, a comprehensive strategy for preventing the onset of malnutrition (both moderate and severe) among children is urgently needed. PMID- 30012083 TI - Ultrasonographic assessment of ophthalmic diseases in low-income countries. AB - We undertook a study between December 2016 and February 2017 on 1637 of 2101 patients with clearly documented findings. These underwent ocular B-scan ultrasonography (USG). Their ages were in the range of 10 days to 92 years; among these patients, 921 (56.26%) were male and 224 (13.68%) were children. Among the adults, 669 (40.86%) patients had anterior segment and 636 (38.85%) had posterior segment pathology. In addition, there were 108 (6.59%) with orbital pathology. Our experience is that USG is an effective, quick, low-cost and non-invasive diagnostic tool for the diagnosis of various ocular and orbital conditions in high patient volume centres (including children and adults) especially where resources are limited. PMID- 30012084 TI - The most 5' truncating homozygous mutation of WNT1 in siblings with osteogenesis imperfecta with a variable degree of brain anomalies: a case report. AB - BACKGROUND: WNT1 mutations cause bone fragility as well as brain anomalies. There are some reported cases of WNT1 mutations with normal cognition. Genotype and phenotype correlation of WNT1 mutations has not been established. CASE PRESENTATION: Here we present two female siblings with osteogenesis imperfecta (OI) born to a consanguineous couple. Both sustained severe bone deformities. However, only the younger had severe brain anomalies resulting in an early death from pneumonia, while the older had normal intellectual development. Next generation sequencing showed a homozygous mutation, c.6delG, p.Leu3Serfs*36 in WNT1. To our knowledge, it is the most 5' truncating mutation to date. CONCLUSION: This report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development. PMID- 30012085 TI - Association between nonalcoholic fatty liver disease and subclinical atherosclerosis: a cross-sectional study on population over 40 years old. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) refers to fatty infiltration of liver in the absence of excessive alcohol abuse. However, the problem that whether NAFLD is correlated with subclinical atherosclerosis assessed by carotid intima-media thickness (CIMT) and brachial-ankle pulse wave velocity (ba-PWV) remains a source of controversy. This can be attributed to the differences in diagnosis methods, population ethnicity, sampling size and bias. This study aimed to further investigate the association of NAFLD with subclinical atherosclerosis. METHODS: A cross-sectional study was carried out in the current study on population aged over 40 years derived from Kailuan community-based prospective study among Chinese adults from June 2010 to June 2011. NAFLD was evaluated through ultrasonography and histories of alcohol consumption. Clinical parameters and medical histories of patients were collected in the manner of interview performed by trained investigators using the standardized questionnaires. The biochemical parameters were analyzed at the central laboratory. CIMT and ba-PWV of each patient were measured. Multivariate logistic regression was used to analyze the associations of NAFLD with subclinical atherosclerosis assessed by CIMT or ba-PWV. RESULTS: A total of 4112 participants aged over 40 years were enrolled from Kailuan cohort, including 2229 men and 1883 women. The overall prevalence of NAFLD was 38.2% in the total population. Statistically significant differences were found in CIMT (P < 0.0001) and ba-PWV (P = 0.0007) according to the presence of NAFLD. It is notably that the multivariate logistic regression revealed NAFLD was independently associated with elevated CIMT after adjusting the conventional cardiovascular and metabolic risk factors (OR = 1.663, 95% CI = 1.391-1.989, P < 0.0001). In addition, NAFLD was also found to be positively associated with elevated ba-PWV after adjusting age, gender, BMI, current smoking and regular exercising (OR = 1.319, 95% CI = 1.072-1.624, P = 0.0089). CONCLUSIONS: Our findings suggest that NAFLD is remarkably correlated with subclinical atherosclerosis, which should be strongly advised to engage in the preventive strategies for cardiovascular diseases (CVDs). PMID- 30012087 TI - Discovering themes in biomedical literature using a projection-based algorithm. AB - BACKGROUND: The need to organize any large document collection in a manner that facilitates human comprehension has become crucial with the increasing volume of information available. Two common approaches to provide a broad overview of the information space are document clustering and topic modeling. Clustering aims to group documents or terms into meaningful clusters. Topic modeling, on the other hand, focuses on finding coherent keywords for describing topics appearing in a set of documents. In addition, there have been efforts for clustering documents and finding keywords simultaneously. RESULTS: We present an algorithm to analyze document collections that is based on a notion of a theme, defined as a dual representation based on a set of documents and key terms. In this work, a novel vector space mechanism is proposed for computing themes. Starting with a single document, the theme algorithm treats terms and documents as explicit components, and iteratively uses each representation to refine the other until the theme is detected. The method heavily relies on an optimization routine that we refer to as the projection algorithm which, under specific conditions, is guaranteed to converge to the first singular vector of a data matrix. We apply our algorithm to a collection of about sixty thousand PubMed R documents examining the subject of Single Nucleotide Polymorphism, evaluate the results and show the effectiveness and scalability of the proposed method. CONCLUSIONS: This study presents a contribution on theoretical and algorithmic levels, as well as demonstrates the feasibility of the method for large scale applications. The evaluation of our system on benchmark datasets demonstrates that our method compares favorably with the current state-of-the-art methods in computing clusters of documents with coherent topic terms. PMID- 30012086 TI - Interactive effect of 24-epibrassinolide and silicon alleviates cadmium stress via the modulation of antioxidant defense and glyoxalase systems and macronutrient content in Pisum sativum L. seedlings. AB - BACKGROUND: This study assessed the effects of 24-epibrassinolide (EBL, 10-7M) and silicon (2 mM) on the alleviation of cadmium (Cd, 150 mg L-1) toxicity in Pisum sativum L. seedlings via the modulation of growth, antioxidant defense, glyoxalase system, and nutrient uptake. RESULTS: Shoot and root lengths declined by 46.43% and 52.78%, respectively, following Cd stress. Shoot and root dry weights also declined with Cd toxicity. Biochemical and physiological aspects exhibit significant decline including total chlorophyll (33.09%), carotenoid (51.51%), photosynthetic efficiency (32.60%), photochemical quenching (19.04%), leaf relative water content (40.18%), and gas exchange parameters (80.65%). However, EBL or Si supplementation alone or in combination modulates the previously mentioned parameters. Cadmium stress increased proline and glycine betaine (GB) contents by 4.37 and 2.41-fold, respectively. Exposure of plants to Cd stress increased the accumulation of H2O2, malondialdehyde content, electrolyte leakage, and methylglyoxal, which declined significantly with EBL and Si supplementation, both individually and in combination. Similarly, Cd stress adversely affected enzymatic and non-enzymatic antioxidants, but EBL and/or Si supplementation maintained antioxidant levels. Glyoxalase I (GlyI) accumulated after Cd stress and increased further with the application of EBL and Si. However, GlyII content declined after Cd stress but increased with supplementation of EBL and Si. Cadmium accumulation occurred in the following order: roots > shoots>leaves. Supplementation with EBL and Si, individually and in combination reduced Cd accumulation and enhanced the uptake of macronutrients and micronutrients in shoots and roots, which declined with Cd toxicity. CONCLUSION: The application of 24-EBL and Si, individually and in combination, alleviated the adverse effects of Cd by improving growth, biochemical parameters, nutrient uptake, osmolyte accumulation, and the anti-oxidative defense and glyoxalase systems in Pisum sativum seedlings. PMID- 30012088 TI - Matataki: an ultrafast mRNA quantification method for large-scale reanalysis of RNA-Seq data. AB - BACKGROUND: Data generated by RNA sequencing (RNA-Seq) is now accumulating in vast amounts in public repositories, especially for human and mouse genomes. Reanalyzing these data has emerged as a promising approach to identify gene modules or pathways. Although meta-analyses of gene expression data are frequently performed using microarray data, meta-analyses using RNA-Seq data are still rare. This lag is partly due to the limitations in reanalyzing RNA-Seq data, which requires extensive computational resources. Moreover, it is nearly impossible to calculate the gene expression levels of all samples in a public repository using currently available methods. Here, we propose a novel method, Matataki, for rapidly estimating gene expression levels from RNA-Seq data. RESULTS: The proposed method uses k-mers that are unique to each gene for the mapping of fragments to genes. Since aligning fragments to reference sequences requires high computational costs, our method could reduce the calculation cost by focusing on k-mers that are unique to each gene and by skipping uninformative regions. Indeed, Matataki outperformed conventional methods with regards to speed while demonstrating sufficient accuracy. CONCLUSIONS: The development of Matataki can overcome current limitations in reanalyzing RNA-Seq data toward improving the potential for discovering genes and pathways associated with disease at reduced computational cost. Thus, the main bottleneck of RNA-Seq analyses has shifted to achieving the decompression of sequenced data. The implementation of Matataki is available at https://github.com/informationsea/Matataki . PMID- 30012089 TI - Profiling of testis-specific long noncoding RNAs in mice. AB - BACKGROUND: Spermatogenesis, which is the complex and highly regulated process of producing haploid spermatozoa, involves testis-specific transcripts. Recent studies have discovered that long noncoding RNAs (lncRNAs) are novel regulatory molecules that play important roles in various biological processes. However, there has been no report on the comprehensive identification of testis-specific lncRNAs in mice. RESULTS: We performed microarray analysis of transcripts from mouse brain, heart, kidney, liver and testis. We found that testis harbored the highest proportion of tissue-specific lncRNAs (11%; 1607 of 14,256). Testis also harbored the largest number of tissue-specific mRNAs among the examined tissues, but the proportion was lower than that of lncRNAs (7%; 1090 of 16,587). We categorized the testis-specific lncRNAs and found that a large portion corresponded to long intergenic ncRNAs (lincRNAs). Genomic analysis identified 250 protein-coding genes located near (<= 10 kb) 194 of the loci encoding testis specific lincRNAs. Gene ontology (GO) analysis showed that these protein-coding genes were enriched for transcriptional regulation-related terms. Analysis of male germ cell-related cell lines (F9, GC-1 and GC-2) revealed that some of the testis-specific lncRNAs were expressed in each of these cell lines. Finally, we arbitrarily selected 26 testis-specific lncRNAs and performed in vitro expression analysis. Our results revealed that all of them were expressed exclusively in the testis, and 23 of the 26 showed germ cell-specific expression. CONCLUSION: This study provides a catalog of testis-specific lncRNAs and a basis for future investigation of the lncRNAs involved in spermatogenesis and testicular functions. PMID- 30012090 TI - Self-reported measures in health research for people with intellectual disabilities: an inclusive pilot study on suitability and reliability. AB - BACKGROUND: The lack of suitable and reliable scales to measure self-reported health and health behaviour among people with intellectual disabilities (ID) is an important methodological challenge in health research. This study, which was undertaken together with co-researchers with ID, explores possibilities for self reported health scales by adjusting, testing, and reflecting on three self reported health scales. METHODS: In an inclusive process, the researchers and co researchers with ID adjusted the SBQ (sedentary behaviour), SQUASH (physical activity), and SRH (self-reported health) scales, after which a test-retest study among adults with ID was performed. Test outcomes were analysed on suitability and test-retest reliability, and discussed with the co-researchers with ID to reflect on outcomes and to make further recommendations. RESULTS: Main adjustments made to the scales included: use easy words, short sentences, and easy answer formats. Suitability (N = 40) and test-retest reliability (N = 15) was higher for the adjusted SQUASH (SQUASH-ID), in which less precise time-based judgements are sought, than in the adjusted SBQ (SBQ-ID). Suitability and test retest reliability were fair to moderate for the SRH-ID and CHS-ID. The main outcome from the reflection was the recommendation to use SQUASH-ID answer options, in which less precise time-based judgements were sought, in the SBQ-ID as well. CONCLUSIONS: This study served as a pilot of an inclusive process in which people with ID collaborated in adjusting, testing, and reflecting on self reported health scales. Although the adjusted self-reported measurements may be reliable and suitable to the target group, the adjustments needed may impair measurement precision. This study's results contribute to informed decision making on the adaptation and use of self-reported health scales for people with ID. PMID- 30012091 TI - Cyclic AMP signaling in Dictyostelium promotes the translocation of the copine family of calcium-binding proteins to the plasma membrane. AB - BACKGROUND: Copines are calcium-dependent phospholipid-binding proteins found in many eukaryotic organisms and are thought to be involved in signaling pathways that regulate a wide variety of cellular processes. Copines are characterized by having two C2 domains at the N-terminus accompanied by an A domain at the C terminus. Six copine genes have been identified in the Dictyostelium genome, cpnA - cpnF. RESULTS: Independent cell lines expressing CpnA, CpnB, CpnC, CpnE, or CpnF tagged with green fluorescent protein (GFP) were created as tools to study copine protein membrane-binding and localization. In general, the GFP-tagged copine proteins appeared to localize to the cytoplasm in live cells. GFP-tagged CpnB, CpnC, and CpnF were also found in the nucleus. When cells were fixed or when live cells were treated with calcium ionophore, the GFP-tagged copine proteins were found associated with the plasma membrane and vesicular organelles. When starved Dictyostelium cells were stimulated with cAMP, which causes a transitory increase in calcium concentration, all of the copines translocated to the plasma membrane, but with varying magnitudes and on and off times, suggesting each of the copines has distinct calcium-sensitivities and/or membrane-binding properties. In vitro membrane binding assays showed that all of the GFP-tagged copines pelleted with cellular membranes in the presence of calcium; yet, each copine displayed distinct calcium-independent membrane-binding in the absence of calcium. A lipid overlay assay with purified GFP-tagged copine proteins was used to screen for specific phospholipid-binding targets. Similar to other proteins that contain C2 domains, GFP-tagged copines bound to a variety of acidic phospholipids. CpnA, CpnB, and CpnE bound strongly to PS, PI(4)P, and PI(4,5)P2, while CpnC and CpnF bound strongly to PI(4)P. CONCLUSIONS: Our studies show that the Dictyostelium copines are soluble cytoplasmic and nuclear proteins that have the ability to bind intracellular membranes. Moreover, copines display different membrane-binding properties suggesting they play distinct roles in the cell. The transient translocation of copines to the plasma membrane in response to cAMP suggests copines may play a specific role in chemotaxis signaling. PMID- 30012092 TI - Variability in distribution and use of tuberculosis diagnostic tests in Kenya: a cross-sectional survey. AB - BACKGROUND: Globally, 40% of all tuberculosis (TB) cases, 65% paediatric cases and 75% multi-drug resistant TB (MDR-TB) cases are missed due to underreporting and/or under diagnosis. A recent Kenyan TB prevalence survey found that a significant number of TB cases are being missed here. Understanding spatial distribution and patterns of use of TB diagnostic tests as per the guidelines could potentially help improve TB case detection by identifying diagnostic gaps. METHODS: We used 2015 Kenya National TB programme data to map TB case notification rates (CNR) in different counties, linked with their capacity to perform diagnostic tests (chest x-rays, smear microscopy, Xpert MTB/RIF(r), culture and line probe assay). We then ran hierarchical regression models for adults and children to specifically establish determinants of use of Xpert(r) (as per Kenyan guidelines) with county and facility as random effects. RESULTS: In 2015, 82,313 TB cases were notified and 7.8% were children. The median CNR/100,000 amongst 0-14yr olds was 37.2 (IQR 20.6, 41.0) and 267.4 (IQR 202.6, 338.1) for >=15yr olds respectively. 4.8% of child TB cases and 12.2% of adult TB cases had an Xpert(r) test done, with gaps in guideline adherence. There were 2,072 microscopy sites (mean microscopy density 4.46/100,000); 129 Xpert(r) sites (mean 0.31/100,000); two TB culture laboratories and 304 chest X-ray facilities (mean 0.74/100,000) with variability in spatial distribution across the 47 counties. Retreatment cases (i.e. failures, relapses/recurrences, defaulters) had the highest odds of getting an Xpert(r) test compared to new/transfer-in patients (AOR 7.81, 95% CI 7.33-8.33). Children had reduced odds of getting an Xpert(r) (AOR 0.41, CI 0.36-0.47). HIV-positive individuals had nearly twice the odds of getting an Xpert(r) test (AOR 1.82, CI 1.73-1.92). Private sector and higher level hospitals had a tendency towards lower odds of use of Xpert(r). CONCLUSIONS: We noted under-use and gaps in guideline adherence for Xpert(r) especially in children. The under-use despite considerable investment undermines cost-effectiveness of Xpert(r). Further research is needed to develop strategies enhancing use of diagnostics, including innovations to improve access (e.g. specimen referral) and overcoming local barriers to adoption of guidelines and technologies. PMID- 30012093 TI - GtTR: Bayesian estimation of absolute tandem repeat copy number using sequence capture and high throughput sequencing. AB - BACKGROUND: Tandem repeats comprise significant proportion of the human genome including coding and regulatory regions. They are highly prone to repeat number variation and nucleotide mutation due to their repetitive and unstable nature, making them a major source of genomic variation between individuals. Despite recent advances in high throughput sequencing, analysis of tandem repeats in the context of complex diseases is still hindered by technical limitations. We report a novel targeted sequencing approach, which allows simultaneous analysis of hundreds of repeats. We developed a Bayesian algorithm, namely - GtTR - which combines information from a reference long-read dataset with a short read counting approach to genotype tandem repeats at population scale. PCR sizing analysis was used for validation. RESULTS: We used a PacBio long-read sequenced sample to generate a reference tandem repeat genotype dataset with on average 13% absolute deviation from PCR sizing results. Using this reference dataset GtTR generated estimates of VNTR copy number with accuracy within 95% high posterior density (HPD) intervals of 68 and 83% for capture sequence data and 200X WGS data respectively, improving to 87 and 94% with use of a PCR reference. We show that the genotype resolution increases as a function of depth, such that the median 95% HPD interval lies within 25, 14, 12 and 8% of the its midpoint copy number value for 30X, 200X WGS, 395X and 800X capture sequence data respectively. We validated nine targets by PCR sizing analysis and genotype estimates from sequencing results correlated well with PCR results. CONCLUSIONS: The novel genotyping approach described here presents a new cost-effective method to explore previously unrecognized class of repeat variation in GWAS studies of complex diseases at the population level. Further improvements in accuracy can be obtained by improving accuracy of the reference dataset. PMID- 30012094 TI - Phosphorylation of Arabidopsis SINA2 by CDKG1 affects its ubiquitin ligase activity. AB - BACKGROUND: SEVEN IN ABSENTIA (SINA) is a RING domain-containing ubiquitin ligase involved in Drosophila eye formation. SINA-like proteins in plants are involved in several signaling pathways. Of the 18 SINA-like proteins identified in Arabidopsis, SEVEN IN ABSENTIA 2 (SINA2) lacks a canonical RING domain and is thought to lack ubiquitin ligase activity. RESULTS: Our results show that SINA2 has E3 ligase activity in vitro, raising the possibility that a modified B-box domain may compensate for its lack of a RING domain. SINA2 physically interacts with the nuclear protein CYCLIN-DEPENDENT KINASE G1 (CDKG1), which acts as a positive regulator of plant responses to abiotic stress. CDKG1 is expressed in multiple tissues and its expression increased in response to abscisic acid (ABA) and osmotic stress. Transgenic Arabidopsis plants that ectopically express CDKG1 exhibit increased tolerance to ABA and osmotic stress treatments during seed germination and cotyledon development, while the loss-of-function cdkg1 mutant plants show reduced tolerance to ABA and osmotic stress treatments. Moreover, CDKG1-dependent phosphorylation of SINA2 positively affects its E3 ubiquitin ligase activity. CONCLUSIONS: Based on these results, we propose that CDKG1 modulates SINA2 ubiquitin ligase activity to regulate its effect on plant responses to ABA and osmotic stress. PMID- 30012095 TI - Netpredictor: R and Shiny package to perform drug-target network analysis and prediction of missing links. AB - BACKGROUND: Netpredictor is an R package for prediction of missing links in any given unipartite or bipartite network. The package provides utilities to compute missing links in a bipartite and well as unipartite networks using Random Walk with Restart and Network inference algorithm and a combination of both. The package also allows computation of Bipartite network properties, visualization of communities for two different sets of nodes, and calculation of significant interactions between two sets of nodes using permutation based testing. The application can also be used to search for top-K shortest paths between interactome and use enrichment analysis for disease, pathway and ontology. The R standalone package (including detailed introductory vignettes) and associated R Shiny web application is available under the GPL-2 Open Source license and is freely available to download. RESULTS: We compared different algorithms performance in different small datasets and found random walk supersedes rest of the algorithms. The package is developed to perform network based prediction of unipartite and bipartite networks and use the results to understand the functionality of proteins in an interactome using enrichment analysis. CONCLUSION: The rapid application development envrionment like shiny, helps non programmers to develop fast rich visualization apps and we beleieve it would continue to grow in future with further enhancements. We plan to update our algorithms in the package in near future and help scientist to analyse data in a much streamlined fashion. PMID- 30012096 TI - Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population. AB - BACKGROUND: Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes. RESULTS: We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 * 10- 4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1). CONCLUSIONS: We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis. PMID- 30012097 TI - DNA methylation and genetic degeneration of the Y chromosome in the dioecious plant Silene latifolia. AB - BACKGROUND: S. latifolia is a model organism for the study of sex chromosome evolution in plants. Its sex chromosomes include large regions in which recombination became gradually suppressed. The regions tend to expand over time resulting in the formation of evolutionary strata. Non-recombination and later accumulation of repetitive sequences is a putative cause of the size increase in the Y chromosome. Gene decay and accumulation of repetitive DNA are identified as key evolutionary events. Transposons in the X and Y chromosomes are distributed differently and there is a regulation of transposon insertion by DNA methylation of the target sequences, this points to an important role of DNA methylation during sex chromosome evolution in Silene latifolia. The aim of this study was to elucidate whether the reduced expression of the Y allele in S. latifolia is caused by genetic degeneration or if the cause is methylation triggered by transposons and repetitive sequences. RESULTS: Gene expression analysis in S. latifolia males has shown expression bias in both X and Y alleles. To determine whether these differences are caused by genetic degeneration or methylation spread by transposons and repetitive sequences, we selected several sex-linked genes with varying degrees of degeneration and from different evolutionary strata. Immunoprecipitation of methylated DNA (MeDIP) from promoter, exon and intron regions was used and validated through bisulfite sequencing. We found DNA methylation in males, and only in the promoter of genes of stratum I (older). The Y alleles in genes of stratum I were methylation enriched compared to X alleles. There was also abundant and high percentage methylation in the CHH context in most sequences, indicating de novo methylation through the RdDM pathway. CONCLUSIONS: We speculate that TE accumulation and not gene decay is the cause of DNA methylation in the S. latifolia Y sex chromosome with influence on the process of heterochromatinization. PMID- 30012098 TI - Preliminary results of official influenza and acute respiratory infection surveillance in two towns of Burkina Faso, 2013-2015. AB - BACKGROUND: In 2010, influenza, influenza-like illness (ILI) and acute respiratory infection (ARI) surveillance was established by the government of Burkina Faso. We provide preliminary descriptive results from this surveillance activity. METHODS: The study period was 2013 through 2015. Two primary healthcare facilities in Bobo-Dioulasso district reported ILI in outpatients. Influenza virology, using reverse transcription-polymerase chain reaction (rRT-PCR), was available for a proportion of ILI patients. One hospital, in the capital Ouagadougou, reported ARI in both outpatients and inpatients (hospitalized). Inpatients admitted with ARI were considered severe ARI (SARI). We estimated the proportion of primary care outpatient visits that were ILI, and the proportion of those that were due to influenza, by age. We estimated the proportion of hospital outpatient visits that were ARI and the proportion of those that were SARI, by age. RESULTS: Among combined outpatient visits in the Bobo-Dioulasso facilities, 19.6% were for ILI. One half (49.9%) of outpatient visits in infants and 30.9% in 1-4 year-olds were ILI. Among ILI outpatient visits 14.8% were due to influenza virus and, of these, 58.5% were type A and 41.5% type B. At the Ouagadougou hospital, 6.7% of outpatient visits were ARI, and 22.3% of those were SARI. The highest proportions of ARI were among infants (19.8%) and 1-4 year-olds (16.0%). The proportion of ARI that was SARI was highest among >=15 year-olds (31.5%) followed by 1-4 year-olds (22.4%). Overall, 4.1% of SARI patients died. CONCLUSIONS: These preliminary data indicate the importance of respiratory infections among health care attendances in Burkina Faso, and influenza may be an important contributor to these. PMID- 30012099 TI - Epidemiology of HBoV1 infection and relationship with meteorological conditions in hospitalized pediatric patients with acute respiratory illness: a 7-year study in a subtropical region. AB - BACKGROUND: Human bocavirus 1 (HBoV1) is an important cause of acute respiratory illness (ARI), yet the epidemiology and effect of meteorological conditions on infection is not fully understood. To investigate the distribution of HBoV1 and determine the effect of meteorological conditions, hospitalized pediatric patients were studied in a subtropical region of China. METHODS: Samples from 11,399 hospitalized pediatric patients (<=14 years old), with ARI were tested for HBoV1 and other common respiratory pathogens using real-time PCR, between July 2009 and June 2016. In addition, local meteorological data were collected. RESULTS: Of the 11,399 patients tested, 5606 (49.2%) were positive for at least one respiratory pathogen. Two hundred forty-eight of 11,399 (2.2%) were positive for HBoV1 infection. Co-infection was common in HBoV1-positive patients (45.2%, 112/248). A significant difference in the prevalence of HBoV1 was found in patients in different age groups (p < 0.001), and the peak prevalence was found in patients aged 7-12 months (4.7%, 56/1203). Two HBoV1 prevalence peaks were found in summer (between June and September) and winter (between November and December). The prevalence of HBoV1 was significantly positively correlated with mean temperature and negatively correlated with mean relative humidity, and the mean temperature in the preceding month had better explanatory power than the current monthly temperature. CONCLUSIONS: This study provides a better understanding of the characteristics of HBoV1 infection in children in subtropical regions. Data from this study provide useful information for the future control and prevention of HBoV1 infections. PMID- 30012100 TI - Variables affecting penetrance of gastric and duodenal phenotype in familial adenomatous polyposis patients. AB - BACKGROUND: Patients with familial adenomatous polyposis (FAP) frequently undergo colectomy to reduce the 70 to 90% lifetime risk of colorectal cancer. After risk reducing colectomy, duodenal cancer and complications from duodenal surgeries are the main cause of morbidity. Our objective was to prospectively describe the duodenal and gastric polyp phenotype in a cohort of 150 FAP patients undergoing pre-screening for a chemoprevention trial and analyze variables that may affect recommendations for surveillance. METHODS: Individuals with a diagnosis of FAP underwent prospective esophagogastroduodenoscopy using a uniform system of mapping of size and number of duodenal polyps for a 10 cm segment. Gastric polyps were recorded as the total number. RESULTS: The distribution of the count and sum diameter of duodenal polyps were statistically different in two genotype groups, those with APC mutations associated with classic FAP had a greater count (median 17) and sum diameter of polyps (median 32 mm) than those with APC mutations associated with attenuated FAP (median count 4 and median sum diameter of 7 mm) (p < 0.0001). The number of gastric polyps did not differ based on genotype (p = 0.67) but advancing age correlated with severity of gastric polyposis (p = 0.019). Spigelman (modified) staging of II or greater was found in 88% of classic FAP patients and 48% attenuated FAP patients. Examples of severe and mild upper GI phenotype are observed in patients with identical APC mutations, showing that the APC mutation location is not absolutely predictive of an upper GI phenotype. CONCLUSIONS: Most FAP patients have duodenal and gastric polyps which become more prevalent and advanced with age. Standard upper endoscopic surveillance is recommended based on personal history independent of APC mutation location. TRIAL REGISTRATION: NCT 01187901 registered August 24, 2010, prospective to enrollment. PMID- 30012103 TI - Fatal heart failure caused by severe pulmonary regurgitation, tricuspid regurgitation and late-onset mitral stenosis in an adult patient with Noonan syndrome: a case report. AB - BACKGROUND: In patients with Noonan syndrome (NS), cardiac disorders such as pulmonary valve stenosis (PS) or hypertrophic cardiomyopathy (HCM) are common. While some patients can develop heart failure associated with HCM, the long-term outcome of adult patients with NS is reported to be good. Fatal outcomes of heart failure in patients with NS but without HCM are rare. CASE PRESENTATION: We report a 25-year-old Japanese woman diagnosed with NS in adulthood. She exhibited short stature and minor facial dysmorphism and was diagnosed with PS at 1 year of age. After surgical valvuloplasty for PS at 6 years of age, her general condition became stable without specific medical treatment. She discontinued regular medical follow-up for PS. At 21 years of age, she developed acute decompensated heart failure, which was mainly right-sided heart failure due to severe pulmonary regurgitation (PR) and tricuspid regurgitation (TR). There was no evidence of HCM or PS recurrence. On the basis of the history of PS and characteristic physical features including short stature, webbed neck, and hypertelorism, she was clinically diagnosed with NS. At 25 years of age, she developed heart failure of both sides due to PR, TR and late-onset severe mitral stenosis (MS). The etiology of MS was uncertain. Owing to the patient's condition, surgical options were considered to be extremely high risk. She was treated with optimal medical treatment as well as the occasional abdominal cavity drainage for recurrent ascites; however, she died of decompensated heart failure at 27 years of age. CONCLUSIONS: We describe an adult patient with NS without HCM who died of heart failure caused by severe PR, TR and MS. Clinicians should recognize that ongoing or late-onset cardiac disorders can develop in patients with NS, and lead to fatal heart failure. Optimal medical follow-up to monitor cardiac function and early identification of heart failure are important. PMID- 30012102 TI - A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non demented patients with transient ischemic attack: the PREVENT study. AB - BACKGROUND: Late-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer's vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline. METHODS: A total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer's pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid beta1-42) and by MR measurements of iron accumulation, a marker for Alzheimer's-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer's disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively. DISCUSSION: The PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging. PMID- 30012101 TI - Juvenile stress induces behavioral change and affects perineuronal net formation in juvenile mice. AB - BACKGROUND: Many neuropsychiatric disorders develop in early life. Although the mechanisms involved have not been elucidated, it is possible that functional abnormalities of parvalbumin-positive interneurons (PV neurons) are present. Several previous studies have shown that juvenile stress is implicated in the development of neuropsychiatric disorders. We aimed to clarify the effects of juvenile stress on behavior and on the central nervous system. We investigated behavioral abnormalities of chronically-stressed mice during juvenilehood and the effect of juvenile stress on PV neurons and WFA-positive perineuronal nets (PNNs), which are associated with vulnerability and plasticity in the mouse brain. RESULTS: Due to juvenile stress, mice showed neurodevelopmental disorder like behavior. Juvenile stressed mice did not show depressive-like behaviors, but on the contrary, they showed increased activity and decreased anxiety-like behavior. In the central nervous system of juvenile stressed mice, the fluorescence intensity of WFA-positive PNNs decreased, which may signify increased vulnerability. CONCLUSION: This study suggested that juvenile stressed mice showed behavioral abnormalities, resembling those seen in neuropsychiatric disorders, and increased brain vulnerability. PMID- 30012104 TI - Underreporting of stillbirths in Pakistan: perspectives of the parents, community and healthcare providers. AB - BACKGROUND: Pakistan has the highest rate of stillbirths globally. Not much attention has been given so far to exploring the sociocultural factors hindering the reportage of stillbirths and the causes of death. Therefore, the aim of this study was to assess the perspectives of parents, communities and healthcare providers regarding the sociocultural practices and health system-related factors contributing to stillbirths and their underreporting. METHODS: This study used a qualitative approach including in-depth interviews and 14 focus group discussions to collect data from four districts of Pakistan. We conducted 285 in-depth interviews and 14 focus group discussions with health professionals - mainly active in the areas of maternal and child health - and parents who had experienced stillbirth. Constant comparative method and analytical induction method were performed to analyze the data. RESULTS: The results of this study show that stillbirth is frequently misclassified and, therefore, an underreported phenomenon in Pakistan. It is an outcome of sociocultural practices, such as the social meaning of stillbirth and their understanding about the conflict between cultural and medical anatomy. In addition to grief and psychological distress, it endangers the maternal identity and worth in society in contrast to the mothers of live-born children. CONCLUSION: The misclassification of stillbirth, especially by healthcare providers, is a significant impediment to designing preventive strategies for stillbirth. We recommend that the reporting system for stillbirth should be aligned with the WHO definition of stillbirth to avoid its underreporting. Reporting procedures at a more administrative level need to be made uniform and simplified. PMID- 30012105 TI - Optical coherence tomography patterns and outcomes of contusion maculopathy caused by impact of sporting equipment. AB - BACKGROUND: To describe the patterns and outcomes of contusion maculopathy after ocular contusions resulting from accidental impact with sporting equipment. METHODS: We conducted a retrospective study of interventional case series. PATIENT POPULATION: Twenty-one eyes of 21 patients who sustained blunt ocular trauma while playing a sport. Intervention/Observation Procedure(s): Surgery or observation by optical coherence tomography (OCT). MAIN OUTCOME MEASURE(S): The morphologic changes within the macula in the early stages after injury and changes in visual function in the early and recovery stages after injury. RESULTS: In the early stage, OCT visualized four injury patterns: type Iota, commotio retinae (14.3%, 3 eyes) with increased reflectivity of the ellipsoid zone and retinal pigment epithelium; type II, incomplete macular hole(38.1%, 8 eyes) with three structural changes, i.e., a partial V-shaped macular hole, a jar shaped macular hole with retinal tissue at the bottom, and a connective bridge attached to retinal tissues; type III, full-thickness macular hole (33.3%, 7 eyes); and type IV, foveal hemorrhage (14.3%, 3 eyes). During recovery, OCT images of types Iota and II showed almost normal macular morphology with better visual acuity (mean +/- SD,0.02 +/- 0.1 and 0.14 +/- 0.21logMAR.). In types III and IV, the visual prognosis was poor (0.52 +/- 0.34 and 0.22 +/- 0.16), OCT images showed retinal atrophy at the fovea despite vitrectomy and sulfur hexafluoride (SF6) gas tamponade. CONCLUSION: Early OCT images identified four patterns of contusion maculopathy with different treatment outcomes. In types Iota and II, the visual function and retinal morphology remained intact. With types III and IV, respectively, the treatments of vitrectomy and SF6 gas tamponade for patients were effective. PMID- 30012106 TI - CXCR4 and its ligand CXCL12 display opposite expression profiles in feline mammary metastatic disease, with the exception of HER2-overexpressing tumors. AB - BACKGROUND: The receptor CXCR4 and its ligand CXCL12 play crucial roles in breast cancer. Despite the fact that the spontaneous feline mammary carcinoma (FMC) is considered a suitable model for breast cancer studies, the importance of the CXCR4/CXCL12 axis in FMC is completely unknown. Therefore, this work aims to elucidate the role of CXCR4 and its ligand in the progression of FMC and metastatic disease. METHODS: CXCR4 and CXCL12 expression was analyzed by immunohistochemistry and immunofluorescence on primary tumors (PT), regional and distant metastases of female cats with mammary carcinoma and correlated with serum CXCL12 levels, tumor molecular subtypes and clinicopathological features. RESULTS: CXCR4 was more expressed in PT than in metastases (p = 0.0067), whereas CXCL12 was highly expressed in metastatic lesions located in liver and lung (p < 0.0001), as reported for human breast cancer. Moreover, cats with CXCR4 positive PT exhibited significantly lower serum CXCL12 levels than cats with CXCR4 negative mammary carcinomas (p = 0.0324). At metastatic lesions, HER2 overexpressing tumors presented higher CXCR4 expression than the other molecular tumor subtypes (p = 0.012) and significant differences in overall (p = 0.0147) and disease-free survival (p = 0.0279) curves between the cats with CXCL12 positive and CXCL12 negative tumors were found. Indeed, CXCL12 negative PT were associated with unfavorable prognosis in cats with HER2-overexpressing tumors. CONCLUSIONS: This work exposes part of the complex interaction between CXCR4 and CXCL12 in PT, but also in metastases of a breast cancer model. These findings could uncover novel therapeutic tools to be used in cats and humans. PMID- 30012107 TI - Serum free light chain levels and renal function at diagnosis in patients with multiple myeloma. AB - BACKGROUND: Renal impairment (RI) is common in multiple myeloma (MM) and is associated with poor survival. This study reports the associations between renal function and disease characteristics including serum free light chain (FLC) level at diagnosis in patients with MM. METHODS: Using data from the Medical Research Council Myeloma IX trial, a multicentre, randomized, open-label, phase III and factorial-design trial, we assessed the relationships between renal function, demographic, and disease characteristics, including serum FLC levels, in 1595 newly diagnosed MM patients. Multivariable linear regression was utilised to identify factors that were associated with renal function at diagnosis. A receiver operating characteristic curve (ROC) was used to identify the optimal threshold for serum FLC level at diagnosis to predict severe RI. RESULTS: 52.8% of patients had an estimated glomerular filtration rate (eGFR) >=60 ml/min/1.73 m2 (no RI), 37.3% an eGFR 30-59 ml/min/1.73 m2 (mild to moderate RI), and 9.8% an eGFR < 30 ml/min/1.73 m2 (severe RI). In a multivariable analysis, factors independently and negatively associated with eGFR at diagnosis were: higher serum FLC level, female gender, and older age. Elevated serum FLC level at diagnosis, irrespective of the paraprotein type, was strongly associated with severe RI. Receiver operating characteristic curve analysis showed a serum FLC level of > 800 mg/L as the optimal cut-off associated with severe RI (area under curve 0.86, 95% confidence interval 0.77-0.84). CONCLUSION: There was a strong relationship between higher serum FLC levels at diagnosis and the severity of RI that was irrespective of the paraprotein type. We report an increased risk of severe RI in patients presenting with serum FLC levels above 800 mg/L at diagnosis. PMID- 30012108 TI - CEDAR OnDemand: a browser extension to generate ontology-based scientific metadata. AB - BACKGROUND: Public biomedical data repositories often provide web-based interfaces to collect experimental metadata. However, these interfaces typically reflect the ad hoc metadata specification practices of the associated repositories, leading to a lack of standardization in the collected metadata. This lack of standardization limits the ability of the source datasets to be broadly discovered, reused, and integrated with other datasets. To increase reuse, discoverability, and reproducibility of the described experiments, datasets should be appropriately annotated by using agreed-upon terms, ideally from ontologies or other controlled term sources. RESULTS: This work presents "CEDAR OnDemand", a browser extension powered by the NCBO (National Center for Biomedical Ontology) BioPortal that enables users to seamlessly enter ontology based metadata through existing web forms native to individual repositories. CEDAR OnDemand analyzes the web page contents to identify the text input fields and associate them with relevant ontologies which are recommended automatically based upon input fields' labels (using the NCBO ontology recommender) and a pre defined list of ontologies. These field-specific ontologies are used for controlling metadata entry. CEDAR OnDemand works for any web form designed in the HTML format. We demonstrate how CEDAR OnDemand works through the NCBI (National Center for Biotechnology Information) BioSample web-based metadata entry. CONCLUSION: CEDAR OnDemand helps lower the barrier of incorporating ontologies into standardized metadata entry for public data repositories. CEDAR OnDemand is available freely on the Google Chrome store https://chrome.google.com/webstore/search/CEDAROnDemand. PMID- 30012109 TI - Calcium currents in striatal fast-spiking interneurons: dopaminergic modulation of CaV1 channels. AB - BACKGROUND: Striatal fast-spiking interneurons (FSI) are a subset of GABAergic cells that express calcium-binding protein parvalbumin (PV). They provide feed forward inhibition to striatal projection neurons (SPNs), receive cortical, thalamic and dopaminergic inputs and are coupled together by electrical and chemical synapses, being important components of the striatal circuitry. It is known that dopamine (DA) depolarizes FSI via D1-class DA receptors, but no studies about the ionic mechanism of this action have been reported. Here we ask about the ion channels that are the effectors of DA actions. This work studies their Ca2+ currents. RESULTS: Whole-cell recordings in acutely dissociated and identified FSI from PV-Cre transgenic mice were used to show that FSI express an array of voltage gated Ca2+ channel classes: CaV1, CaV2.1, CaV2.2, CaV2.3 and CaV3. However, CaV1 Ca2+ channel carries most of the whole-cell Ca2+ current in FSI. Activation of D1-like class of DA receptors by the D1-receptor selective agonist SKF-81297 (SKF) enhances whole-cell Ca2+ currents through CaV1 channels modulation. A previous block of CaV1 channels with nicardipine occludes the action of the DA-agonist, suggesting that no other Ca2+ channel is modulated by D1-receptor activation. Bath application of SKF in brain slices increases the firing rate and activity of FSI as measured with both whole-cell and Ca2+ imaging recordings. These actions are reduced by nicardipine. CONCLUSIONS: The present work discloses one final effector of DA modulation in FSI. We conclude that the facilitatory action of DA in FSI is in part due to CaV1 Ca2+ channels positive modulation. PMID- 30012110 TI - Feasibility and acceptability of home-based HIV testing among refugees: a pilot study in Nakivale refugee settlement in southwestern Uganda. AB - BACKGROUND: Refugees in sub-Saharan Africa face both the risk of HIV infection and barriers to HIV testing. We conducted a pilot study to determine the feasibility and acceptability of home-based HIV testing in Nakivale Refugee Settlement in Uganda and to compare home-based and clinic-based testing participants in Nakivale. METHODS: From February-March 2014, we visited homes in 3 villages in Nakivale up to 3 times and offered HIV testing. We enrolled adults who spoke English, Kiswahili, Kinyarwanda, or Runyankore; some were refugees and some Ugandan nationals. We surveyed them about their socio-demographic characteristics. We evaluated the proportion of individuals encountered (feasibility) and assessed participation in HIV testing among those encountered (acceptability). We compared characteristics of home-based and clinic-based testers (from a prior study in Nakivale) using Wilcoxon rank sum and Pearson's chi-square tests. We examined the relationship between a limited number of factors (time of visit, sex, and number of individuals at home) on willingness to test, using logistic regression models with the generalized estimating equations approach to account for clustering. RESULTS: Of 566 adults living in 319 homes, we encountered 507 (feasibility = 90%): 353 (62%) were present at visit one, 127 (22%) additional people at visit two, and 27 (5%) additional people at visit three. Home-based HIV testing participants totaled 378 (acceptability = 75%). Compared to clinic-based testers, home-based testers were older (median age 30 [IQR 24-40] vs 28 [IQR 22-37], p < 0.001), more likely refugee than Ugandan national (93% vs 79%, < 0.001), and more likely to live >=1 h from clinic (74% vs 52%, < 0.001). The HIV prevalence was lower, but not significantly, in home-based compared to clinic-based testing participants (1.9 vs 3.4% respectively, p = 0.27). Testing was not associated with time of visit (p = 0.50) or sex (p = 0.66), but for each additional person at home, the odds of accepting HIV testing increased by over 50% (OR 1.52, 95%CI 1.12-2.06, p = 0.007). CONCLUSIONS: Home based HIV testing in Nakivale Refugee Settlement was feasible, with 90% of eligible individuals encountered within 3 visits, and acceptable with 75% willing to test for HIV, with a yield of nearly 2% individuals tested identified as HIV positive. PMID- 30012111 TI - AKT isoform-specific expression and activation across cancer lineages. AB - BACKGROUND: Aberrant AKT activation is prevalent across human cancer lineages, providing an important therapeutic target. AKT comprises three isoforms that mediate critical non-redundant, even opposing functions in cancer pathophysiology. Therefore, targeting specific AKT isoforms in particular cancers may be more effective than pan-AKT inhibition while avoiding disadvantages of pan AKT inhibition. Currently, AKT isoform-specific expression and activation in cancer are not clearly characterized. METHODS: We systematically characterized AKT isoform-specific expression and activation in 211 cancer cell lines derived from different lineages and genetic backgrounds using a reverse-phase protein array platform. RESULTS: We found that phosphorylation, but not expression, of AKT1 and AKT2 was coordinated in most but not all cells. Different cancer lineages displayed differential AKT1 and AKT2 expression and phosphorylation. A PIK3CA hotspot mutation H1047R but not E545K was associated with selective activation of AKT2 but not AKT1. CONCLUSIONS: Our study identified and validated AKT isoform-specific expression and phosphorylation in certain cell lines and demonstrated that genetic changes can affect AKT isoform-specific activation. These results provide a more precise understanding of AKT isoform-specific signaling and, in addition, facilitate AKT isoform targeting for personalized cancer therapies. PMID- 30012112 TI - Maternal and infant death after probable vertical transmission of chikungunya virus in Brazil - case report. AB - BACKGROUND: Chikungunya virus infection in neonates is relatively rare and can lead to death. CASE PRESENTATION: We report the occurrence of the first death of a mother and child after probable vertical transmission of chikungunya virus in Brazil. A 28-year-old pregnant woman with hypertension presented with symptoms compatible with an arboviral disease at 34 weeks' gestation. She developed preeclampsia with severe respiratory failure which resulted in the emergency cesarean section, and the patient died 12 days after the onset of symptoms. The pre-term newborn weighed 2535 g, with an Apgar score of 4/8. He was referred to the neonatal ICU with neutrophilia and thrombocytopenia, several seizure episodes, and hemorrhagic disorders, which resulted in death. Chikungunya IgM antibody was detected in the cerebrospinal fluid. CONCLUSIONS: We present the first documented maternal and neonatal death in Brazil after probable chikungunya infection during pregnancy. PMID- 30012113 TI - Clinical management of respiratory syndrome in patients hospitalized for suspected Middle East respiratory syndrome coronavirus infection in the Paris area from 2013 to 2016. AB - BACKGROUND: Patients with suspected Middle East respiratory syndrome coronavirus (MERS-CoV) infection should be hospitalized in isolation wards to avoid transmission. This suspicion can also lead to medical confusion and inappropriate management of acute respiratory syndrome due to causes other than MERS-CoV. METHODS: We studied the characteristics and outcome of patients hospitalized for suspected MERS-CoV infection in the isolation wards of two referral infectious disease departments in the Paris area between January 2013 and December 2016. RESULTS: Of 93 adult patients (49 male (52.6%), median age 63.4 years) hospitalized, 82 out of 93 adult patients had returned from Saudi Arabia, and 74 of them were pilgrims (Hajj). Chest X-ray findings were abnormal in 72 (77%) patients. The 93 patients were negative for MERS-CoV RT-PCR, and 70 (75.2%) patients had documented infection, 47 (50.5%) viral, 22 (23.6%) bacterial and one Plasmodium falciparum malaria. Microbiological analysis identified Rhinovirus (27.9%), Influenza virus (26.8%), Legionella pneumophila (7.5%), Streptococcus pneumoniae (7.5%), and non-MERS-coronavirus (6.4%). Antibiotics were initiated in 81 (87%) cases, with two antibiotics in 63 patients (67.7%). The median duration of hospitalization and isolation was 3 days (1-33) and 24 h (8-92), respectively. Time of isolation decreased over time (P < 0.01). Two patients (2%) died. CONCLUSION: The management of patients with possible MERS-CoV infection requires medical facilities with trained personnel, and rapid access to virological results. Empirical treatment with neuraminidase inhibitors and an association of antibiotics effective against S. pneumoniae and L. pneumophila are the cornerstones of the management of patients hospitalized for suspected MERS-CoV infection. PMID- 30012114 TI - Simulation shows undesirable results for competing risks analysis with time dependent covariates for clinical outcomes. AB - BACKGROUND: We evaluate three methods for competing risks analysis with time dependent covariates in comparison with the corresponding methods with time independent covariates. METHODS: We used cause-specific hazard analysis and two summary approaches for in-hospital death: logistic regression and regression of the subdistribution hazard. We analysed real hospital data (n=1864) and considered pneumonia on admission / hospital-acquired pneumonia as time independent / time-dependent covariates for the competing events 'discharge alive' and 'in-hospital death'. Several simulation studies with time-constant hazards were conducted. RESULTS: All approaches capture the effect of time independent covariates, whereas the approaches perform differently with time dependent covariates. The subdistribution approach for time-dependent covariates detected effects in a simulated no-effects setting and provided counter-intuitive effects in other settings. CONCLUSIONS: The extension of the Fine and Gray model to time-dependent covariates is in general not a helpful synthesis of the cause specific hazards. Cause-specific hazard analysis and, for uncensored data, the odds ratio are capable of handling competing risks data with time-dependent covariates but the use of the subdistribution approach should be neglected until the problems can be resolved. For general right-censored data, cause-specific hazard analysis is the method of choice. PMID- 30012115 TI - The detrimental effects of radiotherapy interruption on local control after concurrent chemoradiotherapy for advanced T-stage nasopharyngeal carcinoma: an observational, prospective analysis. AB - BACKGROUND: Previous studies have reported radiotherapy interruption (RTI) is associated with poor local control in two-dimensional radiotherapy (2DRT) era. However, it remains unclear whether RTI still affects local control for advanced T stage (T3-4) in the intensity-modulated radiation therapy (IMRT) era. We aim to evaluate whether RTI affects local control for T3-4 NPC treated with definitive IMRT. METHODS: In this observational prospective study, 447 T3-4 NPC patients treated with IMRT plus concurrent chemotherapy were included. All patients completed the planned radiotherapy course, and RTI was defined as the actual time taken to finish the prescribed course of radiotherapy minus the planned radiotherapy time. Receiver operating characteristic (ROC) curve was used for determined the cutoff point of RTI. The effects of RTI on local control were analyzed in multivariate analysis. RESULTS: At 5 years, the local relapse-free survival (LRFS) and overall survival (OS) rates were 93.7 and 85.7%, respectively. The cutoff RTI for LRFS was 5.5 days by ROC curve. Compared to patients with RTI > 5 days, patients with RTI <= 5 days had a significantly lower rate of LRFS (97% vs. 83%; P < 0.001). In multivariate analysis, RTI was a risk factor independently associated with LRFS (HR = 9.64, 95% CI, 4.10-22.65), but not for OS (HR = 1.09, 95% CI, 0.84-1.64). CONCLUSIONS: The current analysis demonstrates a significant correlation between prolonged RTI and local control in NPC, even when concurrent chemotherapy is used. We consider that attention to RTI seems to be warranted for patients with advanced T-stage NPC in the era of IMRT. PMID- 30012117 TI - Understanding reasons for unmet health care needs in Korea: what are health policy implications? AB - BACKGROUND: To ensure equal access to necessary care regardless of an individual's socioeconomic status, it is crucial to understand the factors that act as barriers. Unmet health care needs can arise for a variety of complex reasons, including personal choice, financial barriers, or lack of services, and each of these reasons requires a different policy approach. Researchers have advocated for a more granular measure of unmet health care need for better policy implication. This study aimed to assess various factors associated with different types of unmet health care needs in Korea. METHODS: The Korean National Health and Nutrition Examination Survey (KNHANES) 2010-2012 was used to analyze responses from 17,610 individuals over age 19. To measure the unmet needs of this population, self-reported experience in the past 1 year was used, and individual's reasons for unmet need were sorted into three distinct categories - availability, acceptability, accessibility. Four different logistic regression models stratified by gender were used to examine the relationship between socioeconomic factors and unmet needs. RESULTS: While income was not a significant factor for men, women with lower incomes showed a higher likelihood of experiencing unmet need. In addition, women with lower incomes showed higher odds of having acceptability-related unmet needs during the past 1 year compared to men. Education and income levels were associated with accessibility-related unmet needs for both women and men. CONCLUSION: As unmet health care needs are considered to be a critical indicator of a country's health care system, it is crucial to identify and eliminate any obstacles that prevent access to health care services. Under the current universal health care system in Korea, women, particularly those of lower income and lower educational levels, have limited access to necessary health care services. A gender-specific health care plan is recommended to reduce the higher rate of unmet needs experienced by this group. To reduce accessibility-related unmet needs, increasing available services for younger age groups, reflecting their needs of health services, needs to be considered. PMID- 30012116 TI - The Smart City Active Mobile Phone Intervention (SCAMPI) study to promote physical activity through active transportation in healthy adults: a study protocol for a randomised controlled trial. AB - BACKGROUND: The global pandemic of physical inactivity represents a considerable public health challenge. Active transportation (i.e., walking or cycling for transport) can contribute to greater total physical activity levels. Mobile phone based programs can promote behaviour change, but no study has evaluated whether such a program can promote active transportation in adults. This study protocol presents the design and methodology of The Smart City Active Mobile Phone Intervention (SCAMPI), a randomised controlled trial to promote active transportation via a smartphone application (app) with the aim to increase physical activity. METHODS/DESIGN: A two-arm parallel randomised controlled trial will be conducted in Stockholm County, Sweden. Two hundred fifty adults aged 20 65 years will be randomised to either monitoring of active transport via the TRavelVU app (control), or to a 3-month evidence-based behaviour change program to promote active transport and monitoring of active travel via the TRavelVU Plus app (intervention). The primary outcome is moderate-to-vigorous intensity physical activity (MVPA in minutes/day) (ActiGraph wGT3x-BT) measured post intervention. Secondary outcomes include: time spent in active transportation measured via the TRavelVU app, perceptions about active transportation (the Transport and Physical Activity Questionnaire (TPAQ)) and health related quality of life (RAND-36). Assessments are conducted at baseline, after the completed intervention (after 3 months) and 6 months post randomisation. DISCUSSION: SCAMPI will determine the effectiveness of a smartphone app to promote active transportation and physical activity in an adult population. If effective, the app has potential to be a low-cost intervention that can be delivered at scale. TRIAL REGISTRATION: ClinicalTrials.gov NCT03086837 ; 22 March, 2017. PMID- 30012118 TI - Re-development of mental health first aid guidelines for supporting Aboriginal and Torres Strait islanders who are experiencing suicidal thoughts and behaviour. AB - BACKGROUND: Suicide is a leading cause of death among Indigenous Australians. Friends, family and frontline workers (for example, teachers, youth workers) are often best positioned to provide initial assistance if someone is suicidal. Culturally appropriate expert consensus guidelines on how to provide mental health first aid to Australian Aboriginal and Torres Strait Islander persons who are experiencing suicidal thoughts or behaviour were developed in 2009. This study describes the re-development of these guidelines to ensure they contain the most current recommended helping actions. METHODS: The Delphi consensus method was used to elicit consensus on potential helping statements to be included in the guidelines. These statements describe helping actions that Indigenous community members and non-Indigenous frontline workers can take, and information they should have, to help someone who is experiencing suicidal thoughts or displaying suicidal behaviour. A panel was formed, comprising 27 Aboriginal and Torres Strait Islander people who have expertise in Indigenous suicide prevention. The panellists were presented with the helping statements via online questionnaires and were encouraged to suggest re-wording of statements and any additional helping statements that were not included in the original questionnaire. Statements were only accepted for inclusion in the guidelines if they were endorsed by >=90% of panellists as essential or important. RESULTS: From a total of 301 statements shown to the expert panel, 172 were endorsed as helping statements to be including in the re-developed guidelines. CONCLUSIONS: Aboriginal and Torres Strait Islander suicide prevention experts were able to reach consensus on appropriate strategies for providing mental health first aid to an Aboriginal or Torres Strait Islander person experiencing suicidal thoughts or behaviour. The re-development of the guidelines has resulted in more comprehensive guidance than the earlier version, for which the panel had rated 166 helping statements and had endorsed 52. These re-developed guidelines can be used to inform Indigenous suicide gatekeeper training courses. PMID- 30012119 TI - Traumatic journeys; understanding the rhetoric of patients' complaints. AB - BACKGROUND: Research on patients' complaints about healthcare has tended to focus on the typology of complaints and complainants to homogenise complaints and better understand safety implications. Nonetheless, complaints speak to a broader spectrum of harm and suffering that go beyond formal adverse events. Complaints about care episodes can take considerable time and effort, generate negative energy and may leave a dogged 'minority' embittered. METHODS: This study provides an overview of the process and rhetoric of how patients formulate written complaints. We collated a data corpus comprising 60 letters of complaints and their responses over a period of one month. This paper focuses on the complaint letters only. National Health Service (NHS) Complaint Department staff in a healthcare area in the United Kingdom (UK) anonymized the letters. We took a broad qualitative approach to analysing the data drawing upon Discourse Analysis focusing on the rhetorical and persuasive strategies employed by the complainants. RESULTS: What patients complained about related to how they complained, with complainants expending considerable effort in persuasive rhetoric that sought to legitimise the complaint drawing upon different sources of epistemic authority. The complainants struggle to be an 'objective' witness as the complaint evolves from an implicit neglect narrative to increasing 'noise' with other features such as Direct Reported Speech used to animate and authenticate the narrative. Many of the complex complaints appeared to evidence some psychological distress. This was associated with the complainants' reports of experiencing cumulative poor health care and their repeated failure to resolve the complaint. The subsequent delicate and potentially stigmatized formal act of complaining was a source of additional distress. CONCLUSIONS: Complaints are involved narratives often predicated on the expectation they will not be given due credence. Health care staff may benefit from understanding how complaints are formulated to be able to more appropriately address the focus and extent of patients' grievances from the outset and therefore, reduce the considerable associated harm. PMID- 30012120 TI - Changing the housing environment to reduce obesity in public housing residents: a cluster randomized trial. AB - BACKGROUND: Public housing residents face significant social, economic, and physical barriers to the practice of health behaviors for prevention of chronic disease. Research shows that public housing residents are more likely to report higher rates of obesity, current smoking, disability, and insufficient physical activity compared to individuals not living in public housing. Because these behaviors and conditions may be shaped by the built and social environments in which they live, we conducted a study to test an environmental level diet and physical activity intervention targeting obesity among urban public housing developments. METHODS: This study was a cluster randomized controlled trial of public housing developments, the unit of analysis and randomization. A total of 10 public housing developments were recruited and subsequently randomized to either receive the intervention package or to serve as comparison sites. The year long intervention included components to change the dietary and physical activity related environments of the developments. Surveys at baseline and one-year follow up provided data on changes in behaviors and weight from participants in both intervention and control developments. RESULTS: Intervention participants significantly changed their eating and activity behaviors and body weight from baseline to one-year follow-up (p's < .05) while comparison participants reported no significant changes in any study variable. CONCLUSIONS: These data provide initial support for the idea that interventions targeting the environment of public housing developments can assist residents to change unhealthy behaviors and can possibly reduce the high levels of chronic disease among public housing residents. PMID- 30012121 TI - Increased interleukin 1alpha and interleukin 1beta expression is involved in the progression of periapical lesions in primary teeth. AB - BACKGROUND: Interleukin 1 (IL-1) is involved in bone resorption. However, the role of IL-1 in periapical lesions characterized by periapical bone destruction in primary teeth has not yet been fully elucidated. This study aimed to detect the distribution and expression of IL-1 in periapical lesions in primary teeth and assess the relationship between the cytokines and the degree of inflammatory cell infiltration. METHODS: A total of 106 chronic periapical lesions in primary teeth were harvested. Haematoxylin and eosin (H&E) staining was used to determine the histological type and the inflammatory cell infiltration grade (mild, moderate, and severe), and immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to detect the distribution and expression of IL-1alpha and IL-1beta. RESULTS: Of the 106 chronic periapical lesion samples, there were 85 cases of periapical granuloma, accounting for 80.19% of the total samples, and 21 cases of radicular cysts, accounting for 19.81%; no cases of abscess were detected. Immunohistochemistry results showed that both IL-1alpha and IL-1beta were expressed in periapical granulomas and cysts. ELISA results showed that IL 1alpha and IL-1beta levels were higher in the periapical granuloma group than in the radicular cyst and normal control groups (P < 0.05). In the periapical granuloma group, IL-1alpha and IL-1beta were detected at higher levels in the severe inflammatory cell infiltration subgroup than in the mild-inflammatory cell infiltration subgroup (P < 0.05), and IL-1beta expression was also higher in the moderate inflammatory cell infiltration subgroup than in the mild inflammatory cell infiltration subgroup (P < 0.01). A significant positive correlation was observed between the protein expression levels of IL-1alpha and IL-1beta and the inflammation grade in periapical granulomas from primary teeth (P < 0.05). CONCLUSION: Expression levels of the cytokines IL-1alpha and IL-1beta in periapical granulomas from primary teeth increased with increasing inflammatory severity and appeared to be a contributing factor to the progression of periapical lesions. PMID- 30012122 TI - Protocol for a phase III pragmatic stepped wedge cluster randomised controlled trial comparing the effectiveness and cost-effectiveness of screening and guidelines with, versus without, implementation strategies for improving pain in adults with cancer attending outpatient oncology and palliative care services: the Stop Cancer PAIN trial. AB - BACKGROUND: Pain is a common and distressing symptom in people with cancer, but is under-recognised and under-treated. Australian guidelines for 'Cancer Pain Management in Adults' are available on the Cancer Council Australia Cancer Guideline Wiki. This study aims to evaluate the effectiveness and cost effectiveness of a suite of guideline implementation strategies for improving pain outcomes in adults with cancer in oncology and palliative care outpatient settings. METHODS: The study will use a stepped-wedge cluster randomised controlled design, with oncology and palliative care outpatient services as the clusters. Patients will be eligible if they are adults with cancer and pain presenting to participating services during the study period. During an initial control arm, services will routinely screen patients for average and worst pain over the past 24 h using a 0-10 numerical rating scale (NRS) and have unfettered access to online guidelines. During the intervention arm, staff at each service will be encouraged to use: 1) a patient education booklet and self-management resource; 2) an online spaced learning cancer pain education module for clinicians from different disciplines; and 3) audit and feedback of service performance on key indices of cancer pain screening, assessment and management. Service-based clinical change champions will lead implementation of these strategies. The trial's primary outcome will be the probability that patients initially screened as having moderate-severe (>=5/10 NRS) worst pain experience a clinically important improvement one week later, defined as >= 30% reduction. Secondary outcomes will include patient empowerment and quality of life, carer experience, and cost-effectiveness. For the main analysis, linear mixed models will be used, accounting for clustering and the longitudinal design. Eighty-two patients per service at six services (N = 492) will provide > 90% power. A qualitative sub-study and analyses of structural and process factors will explore opportunities for further refinement and tailoring of the intervention. DISCUSSION: This pragmatic trial will inform implementation of guidelines across a range of oncology and palliative care outpatient service contexts. If found effective, the implementation strategies will be made freely available on the Wiki alongside the guidelines. TRIAL REGISTRATION: Registered 23/01/2015 on the Australian New Zealand Clinical Trials Registry ( ACTRN12615000064505 ). PMID- 30012123 TI - Financial transfers from adult children and depressive symptoms among mid-aged and elderly residents in China - evidence from the China health and retirement longitudinal study. AB - BACKGROUND: Although the awareness of mental health problems in late life is rising, the association between financial transfers to the older generations from children and mental health at older ages in China has received little attention. This study examines the association between financial transfers from children and depressive symptoms among the mid-aged and elderly residents (from 45 years of age and older) in China. METHODS: We used the data from the China Health and Retirement Longitudinal Study (CHARLS, 2013) (n = 10,935) This included data on financial transfers from all non-co-resident children to their parents, and the individual scores on depressive symptoms as measured by the 10-item Center for Epidemiologic Studies-Depression Scale (CESD-10). A two-level - individual and community levels - mixed linear model was deployed to explore their association. RESULTS: Financial transfers from children to parents was the major component of inter-generational financial transfers in Chinese families. A higher financial support from non-co-resident children was signivicantly and positively related to fewer depressive symptoms (coef. = - 0.195,P-value< 0.001) among both the mid aged and elderly parents. CONCLUSIONS: Financial transfers from non-co-resident children are associated with depressive symptoms among mid-aged and elderly residents in the China situation. Taxation and other policy measures should encourage and facilitate these type of financial transfers and prevent a decrease of support from children to parents. PMID- 30012124 TI - Living with severe perinatal depression: a qualitative study of the experiences of labour migrant and refugee women on the Thai-Myanmar border. AB - BACKGROUND: Perinatal depression is an important contributor to maternal morbidity and mortality worldwide. Migrant women, particularly those resettling within low- and middle-income settings, are at increased risk of perinatal depression due to multiple stressors experienced before, during and after migration. Evidence on migrant perinatal mental health to date has focused largely on women in high-income destination countries, leaving the voices of displaced women in low-income settings unheard. This study addresses the current evidence gap by exploring the experiences of migrant women living on the Thai Myanmar border. METHODS: In-depth interviews were conducted with pregnant and post-partum labour migrant and refugee women on the Thai-Myanmar border who had been diagnosed with severe depression. An interview guide covering women's current and past life experiences, social support and the impact of depression on social and occupational functioning was used as a prompt. Thematic analysis was used to identify themes emerging from women's narratives. RESULTS: Eleven pregnant and post-partum women with severe perinatal depression took part. Participating women provided extensive insight into the many difficult aspects of their lives that they perceived as contributing to their depression status. Predominant themes emerging from women's narratives included difficult relationships with partners, challenging life situations, mechanisms for coping with depression and impressions of mental health care. CONCLUSIONS: Labour migrant and refugee women with severe perinatal depression face a wide range of chronic stressors at the individual, household and community levels that are likely to have both short- and long-term negative effects on their mental well being and day-to-day functioning. Participating women responded positively to the mental health support they received, and findings provide important insights into how services might further support their needs. PMID- 30012125 TI - A gene regulatory network underlying the formation of pre-placodal ectoderm in Xenopus laevis. AB - BACKGROUND: The neural plate border ectoderm gives rise to key developmental structures during embryogenesis, including the neural crest and the preplacodal ectoderm. Many sensory organs and ganglia of vertebrates develop from cranial placodes, which themselves arise from preplacodal ectoderm, defined by expression of transcription factor Six1 and its coactivator Eya1. Here we elucidate the gene regulatory network underlying the specification of the preplacodal ectoderm in Xenopus, and the functional interactions among transcription factors that give rise to this structure. RESULTS: To elucidate the gene regulatory network upstream of preplacodal ectoderm formation, we use gain- and loss-of-function studies to explore the role of early ectodermal transcription factors for establishing the preplacodal ectoderm and adjacent ectodermal territories, and the role of Six1 and Eya1 in feedback regulation of these transcription factors. Our findings suggest that transcription factors with expression restricted to ventral (non-neural) ectoderm (AP2, Msx1, FoxI1, Vent2, Dlx3, GATA2) and those restricted to dorsal (neural) ectoderm (Pax3, Hairy2b, Zic1) are required for specification of both preplacodal ectoderm and neural crest in a context dependent fashion and are cross-regulated by Eya1 and Six1. CONCLUSION: These findings allow us to elucidate a detailed gene regulatory network at the neural plate border upstream of preplacodal ectoderm formation based on functional interactions between ectodermal transcription factors. We propose a new model to explain the formation of immediately juxtaposed preplacodal ectoderm and neural crest territories at the neural plate border, uniting previous models. PMID- 30012126 TI - Mediating role of emotional labor in the association between emotional intelligence and fatigue among Chinese doctors: a cross-sectional study. AB - BACKGROUND: Fatigue is highly prevalent among doctors worldwide. However, no research has been done to examine the associations of emotional intelligence (EI) and emotional labor strategy with fatigue among Chinese doctors. This study aimed to examine whether or not emotional labor strategy mediates the association between EI and fatigue in this occupational group. METHODS: A cross-sectional study was conducted in Shenyang from March to April 2014. A set of self administered questionnaires was distributed to 950 doctors, including Chalder Fatigue Scale (CFS), Wong and Law Emotional Intelligence Scale (WLEIS) and a 14 item emotional labor scale. Complete responses were obtained from 740 (77.9%) participants. Hierarchical linear regression was performed to examine the associations of EI and emotional labor strategies (surface acting, SA; deep acting, DA; natural acting, NA) with fatigue. Asymptotic and resampling strategies were used to examine the mediating roles of emotional labor strategies. RESULTS: The mean score of fatigue was 8.02 (SD = 3.39). After adjusting for age, gender, marital status, job rank, monthly income, weekly working time, shift and department, EI was negatively associated with fatigue (beta = - 0.270, P < 0.001). SA was positively associated with fatigue (beta = 0.168, P < 0.001), whereas NA was negatively associated with fatigue (beta = - 0.105, P = 0.004); however, DA was not significantly associated with fatigue (beta = 0.034, P = 0.381). Thus, SA (a * b = - 0.026, BCa 95% CI: - 0.050, - 0.011) and NA (a * b = - 0.024, BCa 95% CI: - 0.046, - 0.006) significantly mediated the association between EI and fatigue, respectively. CONCLUSIONS: There was a high level of fatigue among Chinese doctors. EI could indirectly reduce fatigue partially through modifying SA and NA strategies, respectively. EI intervention, education and training in emotional labor should be carried out to cope with fatigue. PMID- 30012127 TI - Cultural orientations and information systems success in public and private hostitals: preliminary evidences from Italy. AB - BACKGROUND: The effective adoption and use of digital and computerized systems and records in hospitals are crucial for increasing the overall quality, safety and outcomes of any national health community. Prior research found that hospitals' dominant cultural orientation affects the adoption of new technology. However, the organizational culture of hospitals can greatly vary between public and private hospitals. Thus, the ownership type of the hospital is likely to affect, to some extent, the aforementioned relationship between culture and information system success. The present article focuses in detail on this issue and attempts to answer the following research question: which cultural orientations are promoting information system success in public and private hospitals? METHODS: The authors develop and test two hypotheses about this relationship via two regression approaches (single-level and multi-level). The authors collected data from 172 respondents-clinicians and non-clinicians-working in two (one public and one private) hospitals in Campania, one of the largest regions in Italy. RESULTS: The findings of this study show clear differences between private and public hospitals. First, a dominant cultural orientation that emphasizes flexibility values (clan and adhocracy cultures) positively influences information systems success in terms of individual impact. Second, the influence of a clan orientation on individual impact is stronger in the public hospital. Third, the influence of an adhocracy orientation is stronger in the private hospital. Overall, the type of ownership-either public or private-of these healthcare organizations affects the link between cultural orientations and IS success. CONCLUSION: Managers of private hospitals should offer to their employees the opportunity to adopt and implement new information systems processes driven by openness towards the external environment in order to benchmark and learn from what was done previously in other organizations. Managers of public hospitals should set up human resource management practices, knowledge creation mechanisms, and internal communication capable of generating a friendly learning environment for their employees when adopting new technology. PMID- 30012128 TI - Curriculum and training needs of mid-level health workers in Africa: a situational review from Kenya, Nigeria, South Africa and Uganda. AB - BACKGROUND: Africa's health systems rely on services provided by mid-level health workers (MLWs). Investment in their training is worthwhile since they are more likely to be retained in underserved areas, require shorter training courses and are less dependent on technology and investigations in their clinical practice than physicians. Their training programs and curricula need up-dating to be relevant to their practice and to reflect advances in health professional education. This study was conducted to review the training and curricula of MLWs in Kenya, Nigeria, South Africa and Uganda, to ascertain areas for improvement. METHODS: Key informants from professional associations, regulatory bodies, training institutions, labour organisations and government ministries were interviewed in each country. Policy documents and training curricula were reviewed for relevant content. Feedback was provided through stakeholder and participant meetings and comments recorded. 421 District managers and 975 MLWs from urban and rural government district health facilities completed self administered questionnaires regarding MLW training and performance. RESULTS: Qualitative data indicated commonalities in scope of practice and in training programs across the four countries, with a focus on basic diagnosis and medical treatment. Older programs tended to be more didactic in their training approach and were often lacking in resources. Significant concerns regarding skills gaps and quality of training were raised. Nevertheless, quantitative data showed that most MLWs felt their basic training was adequate for the work they do. MLWs and district managers indicated that training methods needed updating with additional skills offered. MLWs wanted their training to include more problem-solving approaches and practical procedures that could be life-saving. CONCLUSIONS: MLWs are essential frontline workers in health services, not just a stop-gap. In Kenya, Nigeria and Uganda, their important role is appreciated by health service managers. At the same time, significant deficiencies in training program content and educational methodologies exist in these countries, whereas programs in South Africa appear to have benefited from their more recent origin. Improvements to training and curricula, based on international educational developments as well as the local burden of disease, will enable them to function with greater effectiveness and contribute to better quality care and outcomes. PMID- 30012130 TI - Barriers and facilitators for guideline adherence in diagnostic imaging: an explorative study of GPs' and radiologists' perspectives. AB - BACKGROUND: Diagnostic imaging has been a part of medicine for the last century. It has been difficult to implement guidelines in this field, and unwarranted imaging has been a frequent problem. Some work has been done to explain these phenomena separately. Identifying the barriers to and facilitators of guideline use has been one strategy. The aim of this study is to offer a more comprehensive explanation of deviations from the guideline by studying the two phenomena together. METHODS: Eight general practitioners and 10 radiologists from two counties in Norway agreed to semi-structured interviews. Topics covered in the interviews were knowledge of the guideline, barriers to and facilitators of guideline use, implementation of guidelines and factors that influence unwarranted imaging. RESULTS: Several barriers to and facilitators of guideline use were identified. Among these are lack of time, pressure from patients, and guidelines being too long, rigid or unclear. Facilitators of guideline use were easy accessibility and having the guidelines adapted to the target group. Some of the factors that influence unwarranted imaging are lack of time, pressure from patients and availability of imaging services. CONCLUSION: There are similarities between the perceived barriers for guideline adherence and the perceived factors that influence unwarranted imaging. There may be a few reasons that explains the deviation from guidelines, and the amount of unwarranted imaging. PMID- 30012129 TI - Concurrent somatic KRAS mutation and germline 10q22.3-q23.2 deletion in a patient with juvenile myelomonocytic leukemia, developmental delay, and multiple malformations: a case report. AB - BACKGROUND: The proto-oncogene KRAS performs an essential function in normal tissue signaling, and the mutation of KRAS gene is a key step in the development of many cancers. Somatic KRAS mutations are often detected in patients with solid and non-solid tumors, whereas germline KRAS mutations are implicated in patients with the Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome and Costello syndrome. The deletion of chromosome 10q22.3-q23.2 is a rare cytogenetic abnormality, which often leads to distinct facial appearance and delays in speech and global development. CASE PRESENTATION: Herein, we report the case of a 4-year old boy diagnosed with juvenile myelomonocytic leukemia. The boy also had syndromic features, such as speech and motor developmental delay, multiple congenital malformations, including distinct facial features, club feet, and cryptorchidism. Using whole-exome sequencing, we identified a pathogenic mutation in KRAS [c.34G > A, p.Gly12Ser] isolated from peripheral blood DNA. Sanger sequencing confirmed the wild-type sequence in the parents and patient's salivary cell DNA indicating its somatic state. A 7311-kb deletion in 10q22.3-q23.2 was also revealed by chromosomal microarray analysis, which was later proved as a germline de novo variant. CONCLUSION: Juvenile myelomonocytic leukemia in the patient was attributed to a somatic KRAS mutation, whereas the syndromic features of the patient were considered a consequence of germline chromosome 10q22.3-q23.2 deletion. Genetic testing for patients with complicated phenotypes can be valuable in detecting multiple pathogenic variants. PMID- 30012131 TI - Engineering of Escherichia coli for Krebs cycle-dependent production of malic acid. AB - BACKGROUND: Malate is a C4-dicarboxylic acid widely used as an acidulant in the food and beverage industry. Rational engineering has been performed in the past for the development of microbial strains capable of efficient production of this metabolite. However, as malate can be a precursor for specialty chemicals, such as 2,4-dihydroxybutyric acid, that require additional cofactors NADP(H) and ATP, we set out to reengineer Escherichia coli for Krebs cycle-dependent production of malic acid that can satisfy these requirements. RESULTS: We found that significant malate production required at least simultaneous deletion of all malic enzymes and dehydrogenases, and concomitant expression of a malate insensitive PEP carboxylase. Metabolic flux analysis using 13C-labeled glucose indicated that malate-producing strains had a very high flux over the glyoxylate shunt with almost no flux passing through the isocitrate dehydrogenase reaction. The highest malate yield of 0.82 mol/mol was obtained with E. coli Deltamdh Deltamqo DeltamaeAB DeltaiclR DeltaarcA which expressed malate-insensitive PEP carboxylase PpcK620S and NADH-insensitive citrate synthase GltAR164L. We also showed that inactivation of the dicarboxylic acid transporter DcuA strongly reduced malate production arguing for a pivotal role of this permease in malate export. CONCLUSIONS: Since more NAD(P)H and ATP cofactors are generated in the Krebs cycle-dependent malate production when compared to pathways which depend on the function of anaplerotic PEP carboxylase or PEP carboxykinase enzymes, the engineered strain developed in this study can serve as a platform to increase biosynthesis of malate-derived metabolites such as 2,4-dihydroxybutyric acid. PMID- 30012133 TI - Primary caregivers, healthcare workers, teachers and community leaders' perceptions and experiences of their involvement, practice and challenges of disclosure of HIV status to children living with HIV in Malawi: a qualitative study. AB - BACKGROUND: The World Health Organisation has recommended that healthcare workers, teachers and community leaders work with parents to support children living with HIV. The aim of this study was to assess the perceptions and experiences of primary caregivers and other care providers such as healthcare workers, teachers, and community leaders regarding their involvement, practice and challenges of HIV disclosure to children aged between 6 and 12 years living with HIV in Malawi. METHODS: Twelve focus group discussions and 19 one-on-one interviews involving a total of 106 participants were conducted in all three administrative regions of Malawi. The interviews and focus group discussions explored perceptions and experiences regarding involvement, practice and challenges of disclosure of HIV status to children. Data were analysed using thematic analysis. RESULTS: Primary caregivers, healthcare workers, teachers, and community leaders all reported that the disclosure of HIV status to children was not well coordinated because each of the groups of participants was working in isolation instead of working as a team. A "working together" model emerged from the data analysis where participants expressed the need for them to work as a team in order to promote safe and effective HIV status disclosure through talking about HIV, sharing responsibility and open communication. Participants reported that by working together, the team members would ensure that the prevalence of HIV disclosure to young children increases and that there would be a reduction in any negative impact of disclosure. CONCLUSION: Global resources are required to better support children living with HIV and their families. Healthcare workers and teachers would benefit greatly from training in working together with families living with HIV and, specifically, training in the disclosure process. Resources, in the form of books and other educational materials, would help them explain HIV and its effective management to children and families. PMID- 30012132 TI - The impact of demographic changes, exogenous boosting and new vaccination policies on varicella and herpes zoster in Italy: a modelling and cost effectiveness study. AB - BACKGROUND: The present study aims to evaluate the cost-effectiveness of the newly introduced varicella and herpes zoster (HZ) vaccination programmes in Italy. The appropriateness of the introduction of the varicella vaccine is highly debated because of concerns about the consequences on HZ epidemiology and the expected increase in the number of severe cases in case of suboptimal coverage levels. METHODS: We performed a cost-utility analysis based on a stochastic individual-based model that considers realistic demographic processes and two different underlying mechanisms of exogenous boosting (temporary and progressive immunity). Routine varicella vaccination is given with a two-dose schedule (15 months, 5-6 years). The HZ vaccine is offered to the elderly (65 years), either alone or in combination with an initial catch-up campaign (66-75 years). The main outcome measures are averted cases and deaths, costs per quality-adjusted life years gained, incremental cost-effectiveness ratios, and net monetary benefits associated with the different vaccination policies. RESULTS: Demographic processes have contributed to shaping varicella and HZ epidemiology over the years, decreasing varicella circulation and increasing the incidence of HZ. The recent introduction of varicella vaccination in Italy is expected to produce an enduring reduction in varicella incidence and, indirectly, a further increase of HZ incidence in the first decades, followed by a significant reduction in the long term. However, the concurrent introduction of routine HZ vaccination at 65 years of age is expected to mitigate this increase and, in the longer run, to reduce HZ burden to its minimum. From an economic perspective, all the considered policies are cost-effective, with the exception of varicella vaccination alone when considering a time horizon of 50 years. These results are robust to parameter uncertainties, to the two different hypotheses on the mechanism driving exogenous boosting, and to different demographic projection scenarios. CONCLUSIONS: The recent introduction of a combined varicella and HZ vaccination programme in Italy will produce significant reductions in the burden of both diseases and is found to be a cost-effective policy. This programme will counterbalance the increasing trend of zoster incidence purely due to demographic processes. PMID- 30012134 TI - Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-kappaB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT). AB - BACKGROUND: Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2 fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells. METHODS: Interleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-kappaB) and mitogen activated protein kinase (MAPK) pathways. RESULTS: Histamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 +/- 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC50) value of 4.91 +/- 2.50 MUM and median lethal concentration (LC50) value of 28.82 +/- 7.56 MUM. In gene expression level, we found that MS65 inhibits NF-kappaB and MAPK pathways through suppression of IKK/IkappaB/NFkappaB and c-Raf/MEK/ERK inflammatory cascades. CONCLUSION: Taken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases. PMID- 30012135 TI - Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial. AB - BACKGROUND: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. METHODS: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. RESULTS: Not applicable. CONCLUSION: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02967653 . Registered in February 2017. PMID- 30012136 TI - Are standardized caries risk assessment models effective in assessing actual caries status and future caries increment? A systematic review. AB - BACKGROUND: Assessing caries risk is an essential element in the planning of preventive and therapeutic strategies. Different caries risk assessment (CRA) models have been proposed for the identification of individuals running a risk of future caries. This systematic review was designed to evaluate whether standardized caries risk assessment (CRA) models are able to evaluate the risk according to the actual caries status and/or the future caries increment. METHODS: Randomized clinical trials, cross-sectional studies, cohort studies, comparative studies, validation studies and evaluation studies, reporting caries risk assessment using standardized models (Cariogram, CAMBRA, PreViser, NUS-CRA and CAT) in patients of any age related to caries data recorded by DMFT/S or ICDAS indices, were included. PubMed, Scopus and Embase were searched from 2000 to 2016. A search string was developed. All the papers meeting the inclusion criteria were subjected to a quality assessment. RESULTS: One thousand three undred ninety-two papers were identified and 32 were included. In all but one, the Cariogram was used both as sole model or in conjunction with other models. All the papers on children (n = 16) and adults (n = 12) found a statistically significant association between the risk levels and the actual caries status and/or the future caries increment. Nineteen papers, all using the Cariogram except one, were classified as being of good quality. Three of four papers comprising children and adults found a positive association. For seven of the included papers, Cariogram sensibility and specificity were calculated; sensibility ranged from low (41.0) to fairly low (75.0), while specificity was higher, ranging from 65.8 to 88.0. Wide 95% confidence intervals for both parameters were found, indicating that the reliability of the model differed in different caries risk levels. CONCLUSIONS: The scientific evidence relating to standardized CRA models is still limited; even if Cariogram was tested in children and adults in few studies of good quality, no sufficient evidence is available to affirm the method is effective in caries assessment and prediction. New options of diagnosis, prognosis and therapy are now available to dentists but the validity of standardized CRA models still remains limited. PMID- 30012137 TI - Health expenditure, child and maternal mortality nexus: a comparative global analysis. AB - BACKGROUND: This paper provides empirical evidence on how the relationship between health expenditure and health outcomes varies across countries at different income levels. METHOD: Heterogeneity and cross-section dependence were controlled for in the panel data which consist of 161 countries over the period 1995-2014. Infant, under-five and maternal mortality along with life expectancy at birth were selected as health outcome measures. Cross-sectional augmented IPS unit root, panel autoregressive distributed lag, Dumitrescu-Hurlin and Toda Yamamoto approach to Granger causality tests were used to investigate the relationship across four income groups. An impulse response function modelled the impact on health outcomes of negative shocks to health expenditure. RESULTS: The results indicate that the health expenditure and health outcome link is stronger for low-income compared to high-income countries. Moreover, rising health expenditure can reduce child mortality but has an insignificant relationship with maternal mortality at all income levels. Lower-income countries are more at risk of adverse impact on health because of negative shocks to health expenditure. Variations in child mortality are better explained by rising health expenditure than maternal mortality. However, the estimated results showed dissimilarity when different assumptions and methods were used. CONCLUSION: The influence of health expenditure on health outcome varies significantly across different income levels except for maternal health. Policymakers should recognize that increasing spending has a minute potential to improve maternal health. Lastly, the results vary significantly due to income level, choice of assumptions (homogeneity, cross section independence) and estimation techniques used. Therefore, findings of the cross-country panel studies should be interpreted with cautions. PMID- 30012139 TI - Evaluating the implementation related challenges of Shasthyo Suroksha Karmasuchi (health protection scheme) of the government of Bangladesh: a study protocol. AB - BACKGROUND: Rapidly increasing healthcare costs and the growing burden of non communicable diseases have increased the out-of-pocket (OOP) spending (63.3% of total health expenditure) in Bangladesh. This increasing OOP spending for healthcare has catastrophic economic impact on households. To reduce this burden, the Health Economics Unit (HEU) of the Ministry of Health and Family Welfare has developed the Shasthyo Surokhsha Karmasuchi (SSK) health protection scheme for the below-poverty line (BPL) population. The key actors in the scheme are HEU, contracted scheme operator and hospital. Under this scheme, each enrolled household is provided 50,000 BDT (620 USD) coverage per year for healthcare services against a government financed premium of 1000 BDT (12 USD). This initiative faces some challenges e.g., delays in scheme activities, registering the targeted population, low utilization of services, lack of motivation of the providers, and management related difficulties. It is also important to estimate the financial requirement for nationwide scale-up of this project. We aim to identify these implementation-related challenges and provide feedback to the project personnel. METHODS: This is a concurrent process documentation using mixed-method approaches. It will be conducted in the rural Kalihati Upazila where the SSK is being implemented. To validate the BPL population selection process, we will estimate the positive predictive value. A community survey will be conducted to assess the knowledge of the card holders about SSK services. From the SSK information management system, numbers of different services utilized by the card holders will be retrieved. Key-informant interviews with personnel from three key actors will be conducted to understand the barriers in the implementation of the project as per plan and gather their suggestions. To estimate the project costs, all inputs to be used will be identified, quantified and valued. The nationwide scale-up cost of the project will be estimated by applying economic modeling. DISCUSSION: SSK is the first ever government initiated health protection scheme in Bangladesh. The study findings will enable decision makers to gain a better understanding of the key challenges in implementation of such scheme and provide feedback towards the successful implementation of the program. PMID- 30012138 TI - Transposable element insertions shape gene regulation and melanin production in a fungal pathogen of wheat. AB - BACKGROUND: Fungal plant pathogens pose major threats to crop yield and sustainable food production if they are highly adapted to their host and the local environment. Variation in gene expression contributes to phenotypic diversity within fungal species and affects adaptation. However, very few cases of adaptive regulatory changes have been reported in fungi and the underlying mechanisms remain largely unexplored. Fungal pathogen genomes are highly plastic and harbor numerous insertions of transposable elements, which can potentially contribute to gene expression regulation. In this work, we elucidated how transposable elements contribute to variation in melanin accumulation, a quantitative trait in fungi that affects survival under stressful conditions. RESULTS: We demonstrated that differential transcriptional regulation of the gene encoding the transcription factor Zmr1, which controls expression of the genes in the melanin biosynthetic gene cluster, is responsible for variation in melanin accumulation in the fungal plant pathogen Zymoseptoria tritici. We show that differences in melanin levels between two strains of Z. tritici are due to two levels of transcriptional regulation: (1) variation in the promoter sequence of Zmr1 and (2) an insertion of transposable elements upstream of the Zmr1 promoter. Remarkably, independent insertions of transposable elements upstream of Zmr1 occurred in 9% of Z. tritici strains from around the world and negatively regulated Zmr1 expression, contributing to variation in melanin accumulation. CONCLUSIONS: Our studies identified two levels of transcriptional control that regulate the synthesis of melanin. We propose that these regulatory mechanisms evolved to balance the fitness costs associated with melanin production against its positive contribution to survival in stressful environments. PMID- 30012140 TI - Implementation of informatics for integrating biology and the bedside (i2b2) platform as Docker containers. AB - BACKGROUND: Informatics for Integrating Biology and the Bedside (i2b2) is an open source clinical data analytics platform used at over 200 healthcare institutions for querying patient data. The i2b2 platform has several components with numerous dependencies and configuration parameters, which renders the task of installing or upgrading i2b2 a challenging one. Even with the availability of extensive documentation and tutorials, new users often require several weeks to correctly install a functional i2b2 platform. The goal of this work is to simplify the installation and upgrade process for i2b2. Specifically, we have containerized the core components of the platform, and evaluated the containers for ease of installation. RESULTS: We developed three Docker container images: WildFly, database, and web, to encapsulate the three major deployment components of i2b2. These containers isolate the core functionalities of the i2b2 platform, and work in unison to provide its functionalities. Our evaluations indicate that i2b2 containers function successfully on the Linux platform. Our results demonstrate that the containerized components work out-of-the-box, with minimal configuration. CONCLUSIONS: Containerization offers the potential to package the i2b2 platform components into standalone executable packages that are agnostic to the underlying host operating system. By releasing i2b2 as a Docker container, we anticipate that users will be able to create a working i2b2 hive installation without the need to download, compile, and configure individual components that constitute the i2b2 cells, thus making this platform accessible to a greater number of institutions. PMID- 30012141 TI - Increasing influenza and pneumococcal vaccine uptake in the elderly: study protocol for the multi-methods prospective intervention study Vaccination60. AB - BACKGROUND: Influenza and pneumococcal vaccination can prevent disease and potentially life-threatening complications like sepsis. Elderly people have an increased risk of severe disease and therefore constitute a major target group for vaccination. To increase vaccination coverage, targeted interventions are needed that take theory-based specific determinants of vaccination behaviour into account. Moreover, message and campaign design should consider specific age related characteristics (e.g., information processing, media use). The aim of this study is (i) to identify the specific informational and interventional needs of this risk group, (ii) to design and implement a targeted intervention aiming to decrease vaccine hesitancy, increase vaccine uptake and decrease the health and economic burden due to the respective diseases, and (iii) to measure the effect of this evidence-informed intervention on various levels. METHODS: Prospective, multi-methods intervention study targeting individuals aged >=60 years in a model region in Germany (federal state of Thuringia, 500,000 inhabitants >=60 years old). The development of the intervention follows theory based and evidence-informed principles: Data from a cross-sectional representative study provide insights into specific determinants of the target group's vaccination behaviour. Additionally, media use is analysed to identify adequate communication channels for specific subgroups. In pilot studies, the intervention materials are adapted to the specific cognitive requirements of the target group. For development and implementation of the intervention, an interdisciplinary and trans-sectoral approach is used, including psychology, communication science, design, medical science, epidemiology and various public health players. The intervention will be implemented in autumn and winter 2017/18 and 2018/19 and adjusted in between. Evaluation of the intervention includes: awareness, use and recall of intervention materials, effects on changes in determinants of vaccination behaviour, self-reported vaccine uptake, and vaccination coverage in the intervention area (primary outcomes), as well as disease incidences (secondary outcomes) and the economic burden of influenza, pneumonia, invasive pneumococcal disease and sepsis for the healthcare system (tertiary outcomes). DISCUSSION: The data will add to the body of evidence on the effectiveness of evidence-informed vaccination campaign development as well as on the clinical and economic effects of pneumococcal and influenza vaccination. The effect of the intervention will teach valuable lessons about the principles of campaign development and evaluation, and can motivate a subsequent nationwide intervention. TRIAL REGISTRATION: DRKS00012653 . Registered 24.11.2017. Retrospectively registered. PMID- 30012142 TI - Exercise in the treatment of clinical anxiety in general practice - a systematic review and meta-analysis. AB - BACKGROUND: Anxiety disorders are common, yet treatment options in general practice are often limited to medication or CBT. There is a lack of evidence for the effectiveness of exercise in the treatment of anxiety in patients who present to general practice and also about the intensity of exercise required to lead to improvement. The aim of this systematic review was to assess the use of exercise versus waiting list control groups in the treatment of anxiety and also to assess the benefit of high intensity exercise vs low intensity exercise. Long term follow up scores were also analysed. We included patients who met diagnostic criteria for anxiety disorders or had clinically raised anxiety levels on a validated rating scale and performed a subgroup analysis of the outcomes between the two groups. The intervention was any aerobic exercise programme carried out for at least two weeks, or exercise carried out at high intensity for at least two weeks. The comparison groups were either a waiting list control group or low intensity exercise. METHOD: Systematic review of randomised controlled trials. Three databases were searched; CENTRAL, Medline and Embase. Outcome assessment was based on validated anxiety rating scales. The quality of the studies was appraised according to the Cochrane Risk of Bias tool. Effect sizes were calculated using the standardised mean difference. RESULTS: Fifteen studies were identified with a total of 675 patients. Nine trials had participants with diagnosed anxiety disorders and six trials had participants with raised anxiety on a validated rating scale. Aerobic exercise was effective in the treatment of raised anxiety compared to waiting list control groups (effect size - 0.41, 95% CI = - 0.70 to - 0.12). High intensity exercise programmes showed greater effects than low intensity programmes. There was no significant difference in outcomes between groups of patients with diagnosed anxiety disorders and patients who had raised anxiety on a rating scale. Conclusions were limited by the small number of studies and wide variation in the delivery of exercise interventions. CONCLUSION: Exercise programmes are a viable treatment option for the treatment of anxiety. High intensity exercise regimens were found to be more effective than low intensity regimens. The results have implications for the use of exercise schemes in General Practice. PMID- 30012143 TI - Environmental health risks and benefits of the use of mosquito coils as malaria prevention and control strategy. AB - BACKGROUND: Malaria is an infectious disease that causes many deaths in sub Saharan Africa. In resource-poor malaria endemic communities, mosquito coils are commonly applied in households to repel the vector mosquito that transmits malaria parasites. In applying these coils, users have mainly been interested in the environmental health benefits potentially derived from repelling the mosquito, while oblivious of the environmental health risks that may be associated with exposure to emissions from the use of mosquito coil. This study evaluated the effectiveness of the mosquito coil, ascertained and/or estimated the toxic emissions that may emanate from the coil, and determined its overall appropriateness by conducting a risk-benefit analysis of the use of this strategy in malaria prevention at household levels. METHODS: The repellent ability of mosquito coils was tested by conducting a mosquito knockdown/mortality test in experimental chambers synonymous of local room spaces and conditions. The gaseous and particulate emissions from the mosquito coil were also analysed. Additional scenarios were generated with the Monte Carlo technique and a risk-benefit analysis was conducted applying @Risk software. RESULTS: Mosquito mortality arising from the application of various mosquito coils averagely ranged between 24 and 64%, which might not provide adequate repellency effect. Emissions from the mosquito coil were also found to contain CO, VOCs, SO2, NO2, PM2.5 and PM10. The Hazard Index of the respective pollutants characterized over a lifetime exposure scenario was low (< 1 for each pollutant), which suggests that the concentrations of the specific chemicals and particulate matter emitted from the mosquito coil may not constitute adverse environmental health risk. CONCLUSION: Although the risk of morbidity from the use of the mosquito coil was low, the coil yielded limited protection as a mosquito avoidance method. It may, therefore, have a reduced benefit in controlling malaria and should be applied sparingly in a highly regulated manner only when traditionally proven effective vector control strategies are not available or too expensive for resource-poor malaria endemic regions. PMID- 30012144 TI - Comorbidities and COPD severity in a clinic-based cohort. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality around the world. The aim of our study was to determine the association between specific comorbidities and COPD severity. METHODS: Pulmonologists included patients with COPD using a web-site questionnaire. Diagnosis of COPD was made using spirometry post-bronchodilator FEV1/FVC < 70%. The questionnaire included the following domains: demographic criteria, clinical symptoms, functional tests, comorbidities and therapeutic management. COPD severity was classified according to GOLD 2011. First we performed a principal component analysis and a non-hierarchical cluster analysis to describe the cluster of comorbidities. RESULTS: One thousand, five hundred and eighty-four patients were included in the cohort during the first 2 years. The distribution of COPD severity was: 27.4% in group A, 24.7% in group B, 11.2% in group C, and 36.6% in group D. The mean age was 66.5 (sd: 11), with 35% of women. Management of COPD differed according to the comorbidities, with the same level of severity. Only 28.4% of patients had no comorbidities associated with COPD. The proportion of patients with two comorbidities was significantly higher (p < 0.001) in GOLD B (50.4%) and D patients (53.1%) than in GOLD A (35.4%) and GOLD C ones (34.3%). The cluster analysis showed five phenotypes of comorbidities: cluster 1 included cardiac profile; cluster 2 included less comorbidities; cluster 3 included metabolic syndrome, apnea and anxiety-depression; cluster 4 included denutrition and osteoporosis and cluster 5 included bronchiectasis. The clusters were mostly significantly associated with symptomatic patients i.e. GOLD B and GOLD D. CONCLUSIONS: This study in a large real-life cohort shows that multimorbidity is common in patients with COPD. PMID- 30012145 TI - Chloroquine resistance is associated to multi-copy pvcrt-o gene in Plasmodium vivax malaria in the Brazilian Amazon. AB - BACKGROUND: The resistance of Plasmodium vivax to chloroquine has become an obstacle to control strategies based on the use of anti-malarials. The current study investigated the association between P. vivax CQ-resistance in vivo with copy number variation and mutations in the promoter region in pvcrt-o and pvmdr1 genes. METHODS: The study included patients with P. vivax that received supervised treatment with chloroquine and primaquine. Recurrences were actively recorded during this period. RESULTS: Among the 60 patients with P. vivax, 25 were CQ-resistant and 35 CQ-susceptible. A frequency of 7.1% of multi-copy pvcrt o was observed in CQ-susceptible samples and 7.7% in CQ-resistant at D0 (P > 0.05) and 33.3% in CQ-resistant at DR (P < 0.05). For pvmdr1, 10.7% of the CQ susceptible samples presented multiple copies compared to 11.1% in CQ-resistant at D0 and 0.0% in CQ-resistant at DR (P > 0.05). A deletion of 19 bp was found in 11/23 (47.6%) of the patients with CQ-susceptible P. vivax and 3/10 (23.1%) of the samples with in CQRPv at D0. At day DR, 55.5% of the samples with CQRPv had the 19 bp deletion. For the pvmdr-1 gene, was no variation in the analysed gene compared to the P. vivax reference Sal-1. CONCLUSIONS: This was the first study with 42-day clinical follow-up to evaluate the variation of the number of copies and polymorphisms in the promoter region of the pvcrt-o and pvmdr1 genes in relation to treatment outcomes. Significantly higher frequency of multi-copy pvcrt-o was found in CQRPv samples at DR compared to CQ-susceptible, indicating parasite selection of this genotype after CQ treatment and its association with CQ-resistance in vivo. PMID- 30012146 TI - A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron(r) (Peginterferon alfa-2b) and Actimmune(r) (Interferon gamma-1b) for intra peritoneal administration in recurrent ovarian cancer. AB - BACKGROUND: Ovarian cancer has no definitive second line therapeutic options, and largely recurs in the peritoneal cavity. Locoregional immune therapy using both interferons and monocytes can be used as a novel approach. Interferons have both cytostatic and cytotoxic properties, while monocytes stimulated with interferons have potent cytotoxic properties. Due to the highly immune suppressive properties of ovarian cancer, ex vivo stimulation of autologous patient monocytes with interferons and infusion of all three agents intraperitoneally (IP) can provide a strong pro-inflammatory environment at the site of disease to kill malignant cells. METHODS: Patient monocytes are isolated through counterflow elutriation and stimulated ex vivo with interferons and infused IP through a semi-permanent catheter. We have designed a standard 3 + 3 dose escalation study to explore the highest tolerated dose of interferons and monocytes infused IP in patients with chemotherapy resistant ovarian cancer. Secondary outcome measurements of changes in the peripheral blood immune compartment and plasma cytokines will be studied for correlations of response. DISCUSSION: We have developed a novel immunotherapy focused on the innate immune system for the treatment of ovarian cancer. We have combined the use of autologous monocytes and interferons alpha and gamma for local-regional administration directly into the peritoneal cavity. This therapy is highly unique in that it is the first study of its type using only components of the innate immune system for the locoregional delivery consisting of autologous monocytes and dual interferons alpha and gamma. Trial Registration ClinicalTrials.gov Identifier: NCT02948426, registered on October 28, 2016. https://clinicaltrials.gov/ct2/show/NCT02948426. PMID- 30012148 TI - Correction to: Global and local perspectives on tobacco harm reduction: what are the issues and where do we go from here? AB - After publication of the original article [1], the authors noticed an error in the Competing interests section. PMID- 30012147 TI - Community-based malaria control in southern Malawi: a description of experimental interventions of community workshops, house improvement and larval source management. AB - BACKGROUND: Increased engagement of communities has been emphasized in global plans for malaria control and elimination. Three interventions to reinforce and complement national malaria control recommendations were developed and applied within the context of a broad-based development initiative, targeting a rural population surrounding a wildlife reserve. The interventions, which were part of a 2-year research trial, and assigned to the village level, were implemented through trained local volunteers, or 'health animators', who educated the community and facilitated collective action. RESULTS: Community workshops on malaria were designed to increase uptake of national recommendations; a manual was developed, and training of health animators conducted, with educational content and analytical tools for a series of fortnightly community workshops in annual cycles at village level. The roll-back malaria principle of diagnosis, treatment and use of long-lasting insecticidal nets was a central component of the workshops. Structural house improvement to reduce entry of malaria vectors consisted of targeted activities in selected villages to mobilize the community into voluntarily closing the eaves and screening the windows of their houses; the project provided wire mesh for screening. Corrective measures were introduced to respond to field challenges. Committees were established at village level to coordinate the house improvement activities. Larval source management (LSM) in selected villages consisted of two parts: one on removal of standing water bodies by the community at large; and one on larviciding with bacterial insecticide Bacillus thuringiensis israelensis by trained village committees. Community workshops on malaria were implemented as 'core intervention' in all villages. House improvement and LSM were implemented in addition to community workshops on malaria in selected villages. CONCLUSIONS: Three novel interventions for community mobilization on malaria prevention and control were described. The interventions comprised local organizational structure, education and collective action, and incorporated elements of problem identification, planning and evaluation. These methods could be applicable to other countries and settings. PMID- 30012149 TI - A novel ultrasound scanning approach for evaluating femoral cartilage defects of the knee: comparison with routine magnetic resonance imaging. AB - BACKGROUND: This study aimed to assess a novel ultrasound (US) scanning approach in evaluating knee femoral cartilaginous defects, compared with magnetic resonance imaging (MRI, commonly used for knee imaging) and arthroscopy (gold standard). METHODS: Sixty-four consecutive patients (65 knees) were prospectively evaluated between April 2010 and July 2011. RESULTS: The overall sensitivity (62.2 and 69.4%), specificity (92.9 and 90.5%), accuracy (75.4 and 78.5%), and adjusted positive (88.7 and 90.4%) and negative predictive (69.5 and 73.3%) were similar for both radiologists (weighted kappa = 0.76). Furthermore, agreement between grading by US and MRI was substantial (weighted kappa = 0.61). CONCLUSIONS: In conclusion, the novel US scanning approach allows similar diagnostic performance compared to routine MRI for knee cartilage defects. US is more accessible, easier to perform, and less expensive than MRI, with potential advantages of easier initial screening and assessment of cartilage defects. PMID- 30012150 TI - The effect of ambient particle matters on hospital admissions for cardiac arrhythmia: a multi-city case-crossover study in China. AB - BACKGROUND: The relationship between particle matters (PMs) and cardiac arrhythmia has been investigated in numerous studies. However, evidence from developing countries is limited. The aim of this study was to evaluate the association between ambient PMs and hospital admissions for cardiac arrhythmia in China and to examine the potential effect modifiers. METHODS: A time-stratified case-crossover analysis was conducted in 26 large Chinese cities. In total, we identified 175,265 hospital admissions for cardiac arrhythmia between January 2014 and December 2015 from electronic hospitalization summary reports. Conditional logistic regression was performed to estimate the percentage changes in cardiac arrhythmia admissions in relation to interquartile range increases in air pollutants. Age, gender and prespecified comorbid health conditions including hypertension, diabetes, congestive heart failure and hyperlipidemia were stratified to evaluate susceptibility factors. RESULTS: PMs levels were positively associated with the number of hospital admissions for cardiac arrhythmia. Both PM2.5 and PM10 had the strongest impact on lag 2 days. An interquartile range increase in PM2.5 (47.5 MUg/m3) and PM10 (76.9 MUg/m3) concentrations on lag 2 days was associated with increments of 2.09% (95%CI, 1.58 2.60%) and 2.33% (95%CI, 1.68-2.97%) in hospital admission for cardiac arrhythmia, respectively. Evidence of effect modification by age and comorbid diabetes was observed. The elderly (> 65 years) and patients with comorbid diabetes were more likely to be hospitalized for cardiac arrhythmia following exposure to high levels of PMs. CONCLUSIONS: This study found an increased risk of arrhythmia admissions associated with PM2.5 and PM10 levels among 26 Chinese cities. The associations of PMs with arrhythmia admissions were stronger in aged population and people with diabetes. PMID- 30012151 TI - Client satisfaction with family planning services in the area of high unmet need: evidence from Tanzania Service Provision Assessment Survey, 2014-2015. AB - BACKGROUND: Client satisfaction has been found to be an important factor for the uptake and continuation of family planning services. This study aimed to examine the current status of and factors associated with client's satisfaction with family planning services in Tanzania, which has a high unmet need for family planning. METHODS: The study used data from the Tanzania Service Provision Assessment survey of 2014-2015. A facility was classified as having high service readiness for FP if it scored at least 67.7% on a composite score based on three domains (staff training and guidelines, basic diagnostic equipment, and basic medicines), following criteria developed by the World Health Organization. The exit interview questionnaire was used to collect information from women about their level of satisfaction, whether "very satisfied," "more or less satisfied," or not satisfied with the services received. The response was dichotomized into "Yes" if the woman reported being very satisfied with services received otherwise coded as "No". Unadjusted and adjusted logistic regression models were used to assess the association between the client satisfaction and covariate variables; service readiness, facility type, managing authority, location, management meetings, supervision, provider's sex, and working experience, clients' age and education. All analyses were weighted to correct for non-response, disproportionate and complex sampling by using the "SVY" command in Stata 14. RESULTS: Out of the 1188 facilities included in the survey, 427 (35.9%) provided family planning services. A total of 1746 women participated in observations and exit interviews. Few (22%) facilities had a high readiness to provide family planning services. While most facilities had the recommended equipment available, only 42% stocked contraceptives (e.g. oral pills, injectable contraceptives and/or condoms). Further, trained staff and clinical guidelines were present in only 30% of services. Nevertheless, the majority (91%) of clients reported that they were satisfied with services. In the multivariate analysis, a high service readiness score [AOR = 2.5, 95% CI; 1.1-6.0], receiving services from private facilities [AOR = 2.3, 95% CI; 1.1-5.0], and being in the age group 20 to 29 years [AOR = 0.3, 95% CI; 0.1-0.7] were all significantly associated with clients' satisfaction with family planning services. CONCLUSION: There is a high level of client satisfaction with family planning services in Tanzania. Maintaining and exceeding this level will require improvements in the provision of staff training and the availability of contraceptives in existing services. PMID- 30012152 TI - Pharmacokinetics of mefloquine administered with artesunate in patients with uncomplicated falciparum malaria from the Brazilian Amazon basin. AB - BACKGROUND: A fixed-dose combination of mefloquine with artesunate was evaluated in cases of falciparum malaria in the Brazilian Amazon basin with acceptable efficacy, safety and tolerability. However, there are no data on the pharmacokinetics of mefloquine in this coformulation in Brazil, which is valuable to evaluate whether Plasmodium is exposed to an effective concentration of the drug. METHODS: A prospective, single-arm study was conducted in male patients with slide-confirmed infection by Plasmodium falciparum using two tablets of a fixed-dose combination of artesunate (100 mg) and mefloquine base (200 mg) once daily and over 3 consecutive days. Serial blood samples were collected at admission and throughout 672 h post-administration of the drugs. Mefloquine was measured in each blood sample by high-performance liquid chromatography. The pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: A total of 61 patients were enrolled in the study and 450 whole blood samples were collected for mefloquine measurement. The mefloquine half-life was 10.25 days, the maximum concentration (Cmax) was 2.53 ug/ml, the area-under-the curve (AUC0-infinity) was 359 ug/ml h, the observed clearance (Cl/f) was 0.045 l/kg/h and the volume of distribution (V/f) was 14.6 l/kg. Mefloquine concentrations above 0.5 ug/ml were sustained for a mean time of 9.2 days. CONCLUSION: The pharmacokinetic parameters of mefloquine determined in the study suggest an adequate exposure of parasite to mefloquine in the multiple oral dose regimen of the fixed dose combination of mefloquine and artesunate. PMID- 30012154 TI - A cross-sectional analysis of ITN and IRS coverage in Namibia in 2013. AB - BACKGROUND: Achieving vector control targets is a key step towards malaria elimination. Because of variations in reporting of progress towards vector control targets in 2013, the coverage of these vector control interventions in Namibia was assessed. METHODS: Data on 9846 households, representing 41,314 people, collected in the 2013 nationally-representative Namibia Demographic and Health Survey were used to explore the coverage of two vector control methods: indoor residual spraying (IRS) and insecticide-treated nets (ITNs). Regional data on Plasmodium falciparum parasite rate in those aged 2-10 years (PfPR2-10), obtained from the Malaria Atlas Project, were used to provide information on malaria transmission intensity. Poisson regression analyses were carried out exploring the relationship between household interventions and PfPR2-10, with fully adjusted models adjusting for wealth and residence type and accounting for regional and enumeration area clustering. Additionally, the coverage as a function of government intervention zones was explored and models were compared using log-likelihood ratio tests. RESULTS: Intervention coverage was greatest in the highest transmission areas (PfPR2-10 >= 5%), but was still below target levels of 95% coverage in these regions, with 27.6% of households covered by IRS, 32.3% with an ITN and 49.0% with at least one intervention (ITN and/or IRS). In fully adjusted models, PfPR2-10 >= 5% was strongly associated with IRS (RR 14.54; 95% CI 5.56-38.02; p < 0.001), ITN ownership (RR 5.70; 95% CI 2.84-11.45; p < 0.001) and ITN and/or IRS coverage (RR 5.32; 95% CI 3.09-9.16; p < 0.001). CONCLUSIONS: The prevalence of IRS and ITN interventions in 2013 did not reflect the Namibian government intervention targets. As such, there is a need to include quantitative monitoring of such interventions to reliably inform intervention strategies for malaria elimination in Namibia. PMID- 30012155 TI - Actions of primary health care professionals to reduce maternal mortality in the Brazilian Northeast. AB - BACKGROUND: Maternal mortality is a global public health problem. Statistics show that in 2013, 289,000 women died from complications during pregnancy, childbirth or the postpartum period worldwide. Between 2010 and 2015, there were 10,075 maternal deaths in Brazil, 3,522of which occurred in the Northeast region. The aim of this study was to investigate the actions taken by primary health care (PHC) professionals to reduce maternal mortality. METHOD: This was a cross sectional, descriptive field study with a qualitative approach. The sample comprised 81 graduate-level professionals working in PHC in the state of Ceara, Brazil. Data were collected from January to March 2016 using structured interviews, which were digitally audio recorded and transcribed. The results were organized using collective subject discourse and analyzed according with the relevant literature. RESULTS: The PHC professionals took both individual and joint measures to reduce maternal mortality. These activities included home visits, health education, active searches, prenatal care consultations, referrals to specialized care and outreach. The challenges that must be overcome to prevent maternal mortality include poor care and ineffective public policies that are associated with a lack of managerial support. CONCLUSION: Interaction among professionals in the health care network is critical to the development of cross sectoral projects that improve the quality of women's health care. Prenatal care is a key factor in reducing maternal death and enables the identification and classification of the risks to which pregnant women may be exposed and the implementation of early actions that can ensure a safe and uncomplicated delivery. However, all of these actions require effective public policies and managerial support. PMID- 30012153 TI - Myricetin antagonizes semen-derived enhancer of viral infection (SEVI) formation and influences its infection-enhancing activity. AB - BACKGROUND: Semen is a critical vector for human immunodeficiency virus (HIV) sexual transmission and harbors seminal amyloid fibrils that can markedly enhance HIV infection. Semen-derived enhancer of viral infection (SEVI) is one of the best-characterized seminal amyloid fibrils. Due to their highly cationic properties, SEVI fibrils can capture HIV virions, increase viral attachment to target cells, and augment viral fusion. Some studies have reported that myricetin antagonizes amyloid beta-protein (Abeta) formation; myricetin also displays strong anti-HIV activity in vitro. RESULTS: Here, we report that myricetin inhibits the formation of SEVI fibrils by binding to the amyloidogenic region of the SEVI precursor peptide (PAP248-286) and disrupting PAP248-286 oligomerization. In addition, myricetin was found to remodel preformed SEVI fibrils and to influence the activity of SEVI in promoting HIV-1 infection. Moreover, myricetin showed synergistic effects against HIV-1 infection in combination with other antiretroviral drugs in semen. CONCLUSIONS: Incorporation of myricetin into a combination bifunctional microbicide with both anti-SEVI and anti-HIV activities is a highly promising approach to preventing sexual transmission of HIV. PMID- 30012156 TI - Real-time intra-fraction motion management in breast cancer radiotherapy: analysis of 2028 treatment sessions. AB - BACKGROUND: Intra-fraction motion represents a crucial issue in the era of precise radiotherapy in several settings, including breast irradiation. To date, only few data exist on real-time measured intra-fraction motion in breast cancer patients. Continuous surface imaging using visible light offers the capability to monitor patient movements in three-dimensional space without any additional radiation exposure. The aim of the present study was to quantify the uncertainties of possible intra-fractional motion during breast radiotherapy. MATERIAL AND METHODS: One hundred and four consecutive patients that underwent postoperative radiotherapy following breast conserving surgery or mastectomy were prospectively evaluated during 2028 treatment sessions. During each treatment session the patients' motion was continuously measured using the CatalystTM optical surface scanner (C-RAD AB, Sweden) and compared to a reference scan acquired at the beginning of each session. The Catalyst system works through an optical surface imaging with light emitting diode (LED) light and reprojection captured by a charge coupled device (CCD) camera, which provide target position control during treatment delivery with a motion detection accuracy of 0.5 mm. For 3D surface reconstruction, the system uses a non-rigid body algorithm to calculate the distance between the surface and the isocentre and using the principle of optical triangulation. Three-dimensional deviations and relative position differences during the whole treatment fraction were calculated by the system and analyzed statistically. RESULTS: Overall, the maximum magnitude of the deviation vector showed a mean change of 1.93 mm +/- 1.14 mm (standard deviation [SD]) (95%-confidence interval: [0.48-4.65] mm) and a median change of 1.63 mm during dose application (beam-on time only). Along the lateral and longitudinal axis changes were quite similar (0.18 mm +/- 1.06 mm vs. 0.17 mm +/- 1.32 mm), on the vertical axis the mean change was 0.68 mm +/- 1.53 mm. The mean treatment session time was 154 +/- 53 (SD) seconds and the mean beam-on time only was 55 +/ 16 s. According to Friedman's test differences in the distributions of the three possible directions (lateral, longitudinal and vertical) were significant (p < 0.01), in post-hoc analysis there were no similarities between any two of the three directions. CONCLUSION: The optical surface imaging system is an accurate and easy tool for real-time motion management in breast cancer radiotherapy. Intra-fraction motion was reported within five millimeters in all directions. Thus, intra-fraction motion in our series of 2028 treatment sessions seems to be of minor clinical relevance in postoperative radiotherapy of breast cancer. PMID- 30012157 TI - Women's preferences for contraceptive counseling in Mexico: Results from a focus group study. AB - BACKGROUND: Client-centered contraceptive counseling is critical to meeting demand for contraception and protecting human rights. However, despite various efforts to optimize counseling, little is known outside of the United States about what individuals themselves value in counseling. In the present study we investigate women's preferences for contraceptive counseling in Mexico to inform efforts to improve service quality. METHODS: We conducted applied qualitative research, using six focus group discussions with 43 women in two cities in Mexico with distinct sizes and sociocultural contexts (Mexico City and Tepeji del Rio, Hidalgo) to assess contraceptive counseling preferences. We used a framework approach to thematically code and analyze the transcriptions from focus groups. RESULTS: Consistent with quality of care and human rights frameworks for family planning service delivery, participants expressed a desire for privacy, confidentiality, informed choice, and respectful treatment. They expanded on usual concepts of respectful care within family planning to include avoidance of sexual assault or harassment-in line with definitions of respectful care in maternal health. In contrast to counseling approaches with method effectiveness as the organizing principle, participants preferred counseling centered on personalized assessments of needs and preferences. Many, particularly older, less educated women, highly valued hearing provider opinions about what method they should use, based on those personalized assessments. Participants highlighted the necessity of clinical assessments or physical exams to inform provider recommendations for appropriate methods. This desire was largely due to beliefs that more exhaustive medical exams could help prevent negative contraceptive outcomes perceived to be common, in particular expulsion of intra-uterine devices (IUDs), by identifying methods compatible with a woman's body. Trust in provider, built in various ways, was seen as essential to women's contraceptive needs being met. CONCLUSIONS: Findings shed light on under-represented perspectives of clients related to counseling preferences. They highlight specific avenues for service delivery improvement in Mexico to ensure clients experience privacy, confidentiality, informed choice, respectful treatment, and personalized counseling-including around reasons for higher IUD expulsion rates postpartum during contraceptive visits. Findings suggest interventions to improve provider counseling should prioritize a focus on relationship-building to foster trust, and needs assessment skills to facilitate personalization of decision-making support without imposition of a provider's personal opinions. Trust is particularly important to address in family planning given historical abuses against women's autonomy that may still influence perspectives on contraceptive programs. Findings can also be used to improve quantitative client experience measures. PMID- 30012158 TI - An IFNgamma/CXCL2 regulatory pathway determines lesion localization during EAE. AB - BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNgamma receptor (IFNgammaR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNgamma-dependent pathways that regulate their production remain to be elucidated. METHODS: The spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry. RESULTS: CNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNgammaRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNgamma directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNgamma. CONCLUSIONS: We provide evidence for an IFNgamma regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNgamma signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNgamma, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNgamma and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations. PMID- 30012159 TI - Pulsatile flow drivers in brain parenchyma and perivascular spaces: a resistance network model study. AB - BACKGROUND: In animal models, dissolved compounds in the subarachnoid space and parenchyma have been found to preferentially transport through the cortex perivascular spaces (PVS) but the transport phenomena involved are unclear. METHODS: In this study two hydraulic network models were used to predict fluid motion produced by blood vessel pulsations and estimate the contribution made to solute transport in PVS and parenchyma. The effect of varying pulse amplitude and timing, PVS dimensions, and tissue hydraulic conductivity on fluid motion was investigated. RESULTS: Periodic vessel pulses resulted in oscillatory fluid motion in PVS and parenchyma but no net flow over time. For baseline parameters, PVS and parenchyma peak fluid velocity was on the order of 10 MUm/s and 1 nm/s, with corresponding Peclet numbers below 103 and 10-1 respectively. Peak fluid velocity in the PVS and parenchyma tended to increase with increasing pulse amplitude and vessel size, and exhibited asymptotic relationships with hydraulic conductivity. CONCLUSIONS: Solute transport in parenchyma was predicted to be diffusion dominated, with a negligible contribution from convection. In the PVS, dispersion due to oscillating flow likely plays a significant role in PVS rapid transport observed in previous in vivo experiments. This dispersive effect could be more significant than convective solute transport from net flow that may exist in PVS and should be studied further. PMID- 30012160 TI - Childhood hypophosphatasia: to treat or not to treat. AB - BACKGROUND: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from dysfunction of the tissue non-specific alkaline phosphatase enzyme. Its manifestations are extremely variable, ranging from early lethality to disease limited to the dentition. The disease is life-threatening when manifesting within the first six months of life, excepting the extremely rare benign perinatal hypophosphatasia. Childhood hypophosphatasia, defined as onset of symptoms between six months and eighteen years, can manifest as rickets, pain, decreased mobility, deficits of growth, and fractures. Historical treatment has generally involved a combination of dietary and rehabilitative interventions. MAIN DOCUMENT: Asfotase alfa (StrensiqTM), is a first-in-class bone-targeted recombinant tissue nonspecific alkaline phosphatase which has shown significant improvements in morbidity and mortality in patients with perinatal and infantile hypophosphatasia. Subsequent research has also shown improvements in morbidity for patients with childhood hypophosphatasia as measured by improvement in rickets, growth, strength, mobility, and quality of life. This enzyme replacement therapy has generally been well-tolerated, with most adverse reactions being mild to-moderate in nature. The author shares their approach to decisions on commencement of ERT based from experience of managing approximately fifteen patients across the age spectrum. This approach focuses on assessing the severity of five key manifestations of childhood HPP: decreased mobility, pain, rickets, deficits of growth, and fractures. PMID- 30012161 TI - Linkage of national soil quality measurements to primary care medical records in England and Wales: a new resource for investigating environmental impacts on human health. AB - BACKGROUND: Long-term, low-level exposure to toxic elements in soil may be harmful to human health but large longitudinal cohort studies with sufficient follow-up time to study these effects are cost-prohibitive and impractical. Linkage of routinely collected medical outcome data to systematic surveys of soil quality may offer a viable alternative. METHODS: We used the Geochemical Baseline Survey of the Environment (G-BASE), a systematic X-ray fluorescence survey of soil inorganic chemistry throughout England and Wales to obtain estimates of the concentrations of 15 elements in the soil contained within each English and Welsh postcode area. We linked these data to the residential postcodes of individuals enrolled in The Health Improvement Network (THIN), a large database of UK primary care medical records, to provide estimates of exposure. Observed exposure levels among the THIN population were compared with expectations based on UK population estimates to assess representativeness. RESULTS: Three hundred seventy-seven of three hundred ninety-five English and Welsh THIN practices agreed to participate in the linkage, providing complete residential soil metal estimates for 6,243,363 individuals (92% of all current and former patients) with a mean period of prospective computerised medical data collection (follow-up) of 6.75 years. Overall agreement between the THIN population and expectations was excellent; however, the number of participating practices in the Yorkshire & Humber strategic health authority was low, leading to restricted ranges of measurements for some elements relative to the known variations in geochemical concentrations in this area. CONCLUSIONS: The linked database provides unprecedented population size and statistical power to study the effects of elements in soil on human health. With appropriate adjustment, results should be generalizable to and representative of the wider English and Welsh population. PMID- 30012162 TI - Memory and exploratory behavior impairment in ovariectomized Wistar rats. AB - BACKGROUND: Estrogen deficiency is linked to changes in several physiological processes, but the extent to which it associates with cognitive changes in menopause context is controversial. RATIONALE: We evaluated the impact of ovariectomy on memory processes and normal exploratory behavior in Wistar rats. METHODS: Young adult rats (4-6 months) were either ovariectomized (OVX group) (N = 10), sham operated (N = 10), or untouched (naive controls) (N = 8). Afterwards, they were monitored for 12 weeks during which their cognitive functions were evaluated at first week (S1), second (S2), every 3 weeks (S5, S8) and then at week 12 (S12) using: (i) object recognition test to evaluate the short-term and long-term non-spatial memory; (ii) the object placement test to assess the spatial memory; and (iii) normal exploratory behavior components like locomotor and vertical activities in an open field arena. RESULTS: Marked changes in ovariectomized rats were observed in long-term non-spatial memory (~ 40% change vs. naive and sham, P < 0.001) and spatial memory (~ 30% change, P < 0.05) from S2. Instead, from S5 the exploratory behavior was affected, with decreases in line crossing and rearing episode numbers (~ 40% change, P < 0.01), and in the time spent in the center of open field arena (~ 60% change, P < 0.01). CONCLUSIONS: Our findings support the involvement of sex hormones in cognitive functions in female rats and suggest that controversy on the importance of cognitive affections in menopause context may emerge from differences between short-term and long-term memory processes. PMID- 30012163 TI - Widening inequalities in multimorbidity? Time trends among the working population between 2005 and 2015 based on German health insurance data. AB - BACKGROUND: Previous research has produced evidence for social inequalities in multimorbidity, but little is known on how these disparities change over time. Our study investigates the development of social inequalities in multimorbidity among the middle-aged and older working population. Special attention is paid to whether differing time trends between socio-economic status (SES) groups have taken place, increasing or decreasing inequalities in multimorbidity. METHODS: The analyses are based on claims data of a German statutory health insurance company covering an observation period from 2005 to 2015. Multimorbidity prevalence risks are estimated using logistic generalized estimation equations (GEE) models. Predicted probabilities of multimorbidity prevalence are used to assess time trends in absolute social inequalities in terms of educational level, income, and occupational group. RESULTS: The prevalence risks of multimorbidity rose among all SES groups and social gradients persist throughout the observation period, indicating significantly higher multimorbidity prevalence risks for individuals with lower SES. Widening absolute inequalities are found among men in terms of educational level and among women in terms of occupational groups. CONCLUSIONS: The increases in multimorbidity prevalence among the working population are accompanied by widening social inequalities, pointing towards a growing disadvantage for men and women in lower SES groups. The rising burden and the increasing inequalities among the working population stress the importance of multimorbidity as a major public health concern. PMID- 30012164 TI - High dose-rate tandem and ovoid brachytherapy in cervical cancer: dosimetric predictors of adverse events. AB - BACKGROUND: Brachytherapy (BT) is a vital component of the curative treatment of locally advanced cervical cancer. The American Brachytherapy Society has published guidelines for high dose rate (HDR) BT with recommended dose limits. However, recent reports suggest lower doses may be needed to avoid toxicity. The purpose of this study is to investigate incidence and predictive factors influencing gastrointestinal (GI) and genitourinary (GU) toxicity following HDR intracavitary brachytherapy for locally advanced cervical cancer. METHODS: We retrospectively evaluated a cohort of patients with locally advanced cervical cancer who received CT-based HDR BT. Cumulative doses were calculated using the linear-quadratic model. Statistical analyses were used to investigate clinical and dosimetric predictors of GI and GU toxicity following HDR brachytherapy according to CTCAE v4.0 grading criteria. RESULTS: Fifty-six women with FIGO IB1 IVA cervical cancer were included. The overall rate of any GU adverse event (Grade 1+) was 23.3% (n = 13) and severe adverse events (Grade 3+) was 7.1% (n = 4). Of those, the bladder equivalent dose in 2- Gray (Gy) fractions (EQD2) D2cc was >=80 for three of the four patients. The overall rate of any GI adverse event was 26.8% (n = 15) and the rate of severe adverse events was 14.3% (n = 8). Of those, six of the eight patients had a rectal EQD2 D2cc >= 65 Gy and seven patients had a sigmoid D2cc >= 65 Gy. Amongst clinically meaningful factors for development of adverse events (i.e. diabetes, smoking status, ovoid size, and treatment duration), there were no statistically significant prognostic factors identified. CONCLUSIONS: Severe adverse events are observed even with adherence to current ABS guidelines. In the era of recent multi-institutional study results, our data also supports more stringent dosimetric goals. We suggest cumulative D2cc dose limits of: less than 80 Gy for the bladder and less than 65 Gy for the rectum and sigmoid. PMID- 30012165 TI - Preliminary evaluation of the reliability, validity and feasibility of the arm activity measure - Thai version (ArmA-TH) in cerebrovascular patients with upper limb hemiplegia. AB - BACKGROUND: Upper limb hemiplegia following cerebrovascular diseases can result in significant functional limitation. To assess such functional disturbance requires a comprehensive, valid and reliable tool. The Arm Activity Measure (ArmA) is a comprehensive, valid and reliable self-report questionnaire to assess real-life function for upper limb hemiplegia. However, it has never been translated for use in different languages. The purpose of this study is to translate and cross-culturally adapt the Arm Activity Measure (ArmA) questionnaire into a Thai version and to evaluate content validity, internal consistency and feasibility. METHODS: The ArmA was translated and culturally adapted according to published cross-cultural adaptation guidelines resulting in the Thai version of ArmA (ArmA-TH). Forty Thai patients with upper limb hemiplegia resulting from cerebrovascular disorders participated in field-testing of the ArmA-TH. Its feasibility was evaluated. Content validity index for item (I CVI) and score (S-CVI) were examined. Inter-rater reliability was evaluated by Gwet's AC2. Internal consistency was measured using Cronbach's alpha coefficient. RESULTS: Forty patients (29 males, 11 females) with upper limb spasticity due to stroke or TBI were included. The average age of patients was 54.5 years (SD 15.0). Twenty-seven patients (67.5%) completed the questionnaire within 5 min or less, average time taken was 4.45 (1.73) min. For both subscales, patients reported the ArmA-TH to be relevant (85%) and easy to use (67.5%). More than 80% of patients found the passive subscale useful, almost 80% found the active subscale useful. Overall S-CVI was 0.83, S-CVI for passive and active function subscale was 0.79 and 0.86 respectively. The inter-rater reliability coefficients for ArmA-TH was 0.81. Cronbach's alpha was 0.90 for the overall ArmA, 0.89 and 0.88 for the passive and active function subscales. CONCLUSIONS: The ArmA-TH was a feasible self-report questionnaire to assess hemiplegic upper limb function with good content validity, inter-rater reliability and internal consistency. PMID- 30012166 TI - PEGylated self-assembled enzyme-responsive nanoparticles for effective targeted therapy against lung tumors. AB - BACKGROUND: Matrix-metalloproteinases, which are overexpressed in many types of cancer, can be applied to improve the bioavailability of chemotherapeutic drugs and guide therapeutic targeting. Thus, we aimed to develop enzyme-responsive nanoparticles based on a functionalized copolymer (mPEG-Peptide-PCL), which was sensitive to matrix metalloproteinase, as smart drug vesicles for enhanced biological specificity and reduced side effects. RESULTS: The rate of in vitro curcumin (Cur) release from Cur-P-NPs was not markedly accelerated in weakly acidic tumor microenvironment, indicating a stable intracellular concentration and a consistent therapeutic effect. Meanwhile, P-NPs and Cur-P-NPs displayed prominent biocompatibility, biostability, and inhibition efficiency in tumor cells. In addition, Cur-P-NPs showed higher fluorescence intensity than Cur-NPs in tumor cells, implying enhanced cell permeability and targeting ability. Moreover, the internalization and intracellular transport of Cur-P-NPs were mainly via macropinocytosis. Studies of pharmacodynamics and cellular uptake in vitro and biodistribution in vivo demonstrated that Cur-P-NPs had stronger target efficiency and therapeutic effect than Cur-DMSO and Cur-NPs in tumor tissue. CONCLUSION: Results indicate that Cur-P-NPs can be employed for active targeted drug delivery in cancer treatment and other biomedical applications. PMID- 30012167 TI - CNN models discriminating between pulmonary micro-nodules and non-nodules from CT images. AB - BACKGROUND: Early and automatic detection of pulmonary nodules from CT lung screening is the prerequisite for precise management of lung cancer. However, a large number of false positives appear in order to increase the sensitivity, especially for detecting micro-nodules (diameter < 3 mm), which increases the radiologists' workload and causes unnecessary anxiety for the patients. To decrease the false positive rate, we propose to use CNN models to discriminate between pulmonary micro-nodules and non-nodules from CT image patches. METHODS: A total of 13,179 micro-nodules and 21,315 non-nodules marked by radiologists are extracted with three different patch sizes (16 * 16, 32 * 32 and 64 * 64) from LIDC/IDRI database and used in the experiments. Three CNN models with different depths (1, 2 or 4 convolutional layers) are designed; their performances are evaluated by the fivefold cross-validation in term of the accuracy, area under the curve (AUC), F-score and sensitivity. The network parameters are also optimized. RESULTS: It is found that the performance of the CNN models is greatly dependent on the patches size and the number of convolutional layers. The CNN model with two convolutional layers presented the best performance in case of 32 * 32 patches size, achieving an accuracy of 88.28%, an AUC of 0.87, a F-score of 83.45% and a sensitivity of 83.82%. CONCLUSIONS: The CNN models with appropriate depth and size of image patches can effectively discriminate between pulmonary micro-nodules and non-nodules, and reduce the false positives and help manage lung cancer precisely. PMID- 30012168 TI - Feasibility of basic transesophageal echocardiography in hemorrhagic shock: potential applications during resuscitative endovascular balloon occlusion of the aorta (REBOA). AB - BACKGROUND: There are numerous studies in the cardiovascular literature that have employed transesophageal echocardiography (TEE) in swine models, but data regarding the use of basic TEE in swine models is limited. The primary aim of this study is to describe an echocardiographic method that can be used with relative ease to qualitatively assess cardiovascular function in a porcine hemorrhagic shock model using resuscitative endovascular balloon occlusion of the aorta (REBOA). METHODS: Multiplane basic TEE exams were performed in 15 during an experimental hemorrhage model using REBOA. Cardiac anatomical structure and functional measurements were obtained. In a convenience sample (two animals from each group), advanced functional cardiovascular measurements were obtained before and after REBOA inflation for comparison with qualitative assessments. RESULTS: Basic TEE exams were performed in 15 swine. Appropriate REBOA placement was confirmed using TEE in all animals and verified with fluoroscopy. Left ventricular volume was decreased in all animals, and left ventricular systolic function increased following REBOA inflation. Right ventricular systolic function and volume remained normal prior to and after hemorrhage and REBOA use. Mean ejection fraction (EF) decreased from 64% (S.D. 9.6) to 62.1 (S.D. 16.8) after hemorrhage and REBOA inflation (p = 0.76); fractional area of change (FAC) decreased from 49.8 (S.D. 9.0) to 48.5 (S.D. 13.6) after hemorrhage and REBOA inflation (p = 0.82). CONCLUSION: Basic TEE, which requires less training than advanced TEE, may be employed by laboratory investigators and practitioners across a wide spectrum of experimental and clinical settings. PMID- 30012169 TI - Physical frailty characteristics have a differential impact on symptoms as measured by the CAT score: an observational study. AB - BACKGROUND: The physical frailty status affects the health status of patients with chronic obstructive pulmonary disease (COPD). The objective was to determine if the individual physical frailty characteristics have a differential impact on the CAT score. METHODS: This observational study included 137 patients with stable COPD. Physical frailty was measured with unintentional weight loss, low physical activity, exhaustion, slow walking speed and low grip strength and health status assessed with the COPD Assessment test (CAT). The following variables were evaluated as potential determinants of CAT: sex, age, body mass index, smoking, dyspnea, exacerbations, comorbidities, %FEV1, %FVC, anxiety and depression. RESULTS: The prevalence of characteristics for individual frailty was as follows: low grip strength, 60.6%; low physical activity, 27.0%; exhaustion, 19.7%; slow walking speed, 9.5%; and unintentional weight loss, 7.3%. A total of 17.5% of the patients were non-frail, 73.7% were pre-frail and only 8.7% were frail. One of the five frailty characteristics, exhaustion (adjusted beta coefficient 5.12 [standard error = 1.27], p = 0.001) was an independent determinant of CAT score in the final regression model which was adjusted by other independent determinants of CAT (dyspnea, exacerbations and anxiety). CONCLUSIONS: Due to the fact that exhaustion is a frequent and relevant psychological symptom on CAT score of patients with COPD, interventions should reduce that stress. Future research should explore how exhaustion persists or remits over time. PMID- 30012170 TI - Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer. AB - BACKGROUND: The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function. METHODS: We sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples. RESULTS: Our data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival. CONCLUSIONS: MicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression. PMID- 30012171 TI - PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells. AB - BACKGROUND: The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. METHODS: Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with gammaH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of gammaH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. RESULTS: PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clonogenicity, and synergistically induced cell apoptosis and DNA damage, while had no detectable toxicity to normal prostate epithelial cells. Mechanistically, veliparib or SAHA alone reduced BRCA1 or UHRF1 protein levels, co-treatment with veliparib and SAHA synergistically reduced BRCA1 protein levels by targeting the UHRF1/BRCA1 protein complex, the depletion of UHRF1 resulted in the degradation of BRCA1 protein, while the elevation of UHRF1 impaired co treatment-reduced BRCA1 protein levels. Co-administration of both drugs synergistically decreased the growth of xenografts. CONCLUSIONS: Our studies revealed that the synergistic lethality of HDAC and PARP inhibitors resulted from promoting DNA damage and inhibiting HR DNA damage repair pathways, in particular targeting the UHRF1/BRCA1 protein complex. The synergistic lethality of veliparib and SAHA shows great potential for future PCa clinical trials. PMID- 30012172 TI - Genetic polymorphisms in the circumsporozoite protein of Plasmodium malariae show a geographical bias. AB - BACKGROUND: Plasmodium malariae is characterized by its long asymptomatic persistence in the human host. The epidemiology of P. malariae is incompletely understood and is hampered by the limited knowledge of genetic polymorphisms. Previous reports from Africa have shown heterogeneity within the P. malariae circumsporozoite protein (pmcsp) gene. However, comparative studies from Asian countries are lacking. Here, the genetic polymorphisms in pmcsp of Asian isolates have been characterized. METHODS: Blood samples from 89 symptomatic P. malariae infected patients were collected, from Thailand (n = 43), Myanmar (n = 40), Lao PDR (n = 5), and Bangladesh (n = 1). pmcsp was amplified using semi-nested PCR before sequencing. The resulting 89 pmcsp sequences were analysed together with 58 previously published pmcsp sequences representing African countries using BioEdit, MEGA6, and DnaSP. RESULTS: Polymorphisms identified in pmcsp were grouped into 3 populations: Thailand, Myanmar, and Kenya. The nucleotide diversity and the ratio of nonsynonymous to synonymous substitutions (dN/dS) in Thailand and Myanmar were higher compared with that in Kenya. Phylogenetic analysis showed clustering of pmcsp sequences according to the origin of isolates (Asia vs. Africa). High genetic differentiation (Fst = 0.404) was observed between P. malariae isolates from Asian and African countries. Sequence analysis of pmcsp showed the presence of tetrapeptide repeat units of NAAG, NDAG, and NAPG in the central repeat region of the gene. Plasmodium malariae isolates from Asian countries carried fewer copies of NAAG compared with that from African countries. The NAPG repeat was only observed in Asian isolates. Additional analysis of 2 T cell epitopes, Th2R and Th3R, showed limited heterogeneity in P. malariae populations. CONCLUSIONS: This study provides valuable information on the genetic polymorphisms in pmcsp isolates from Asia and advances our understanding of P. malariae population in Asia and Africa. Polymorphisms in the central repeat region of pmcsp showed association with the geographical origin of P. malariae isolates and can be potentially used as a marker for genetic epidemiology of P. malariae population. PMID- 30012174 TI - Correction to: Emerging role of lipid metabolism alterations in Cancer stem cells. AB - In the publication of this article [1], there is an error in the Figure caption of Figs. 2, 3 and 4. This has now been included in this correction. The authors declare that these corrections do not change the results or conclusions of this paper. PMID- 30012173 TI - Phosphonate coating of SiO2 nanoparticles abrogates inflammatory effects and local changes of the lipid composition in the rat lung: a complementary bioimaging study. AB - BACKGROUND: The well-known inflammatory and fibrogenic changes of the lung upon crystalline silica are accompanied by early changes of the phospholipid composition (PLC) as detected in broncho-alveolar lavage fluid (BALF). Amorphous silica nanoparticles (NPs) evoke transient lung inflammation, but their effect on PLC is unknown. Here, we compared effects of unmodified and phosphonated amorphous silica NP and describe, for the first time, local changes of the PLC with innovative bioimaging tools. METHODS: Unmodified (SiO2-n), 3 (trihydroxysilyl) propyl methylphosphonate coated SiO2-n (SiO2-p) as well as a fluorescent surrogate of SiO2-n (SiO2-FITC) nanoparticles were used in this study. In vitro toxicity was tested with NR8383 alveolar macrophages. Rats were intratracheally instilled with SiO2-n, SiO2-p, or SiO2-FITC, and effects on lungs were analyzed after 3 days. BALF from the right lung was analyzed for inflammatory markers. Cryo-sections of the left lung were subjected to fluorescence microscopy and PLC analyses by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MS), Fourier transform infrared microspectroscopy (FT-IR), and tandem mass spectrometry (MS/MS) experiments. RESULTS: Compared to SiO2-p, SiO2-n NPs were more cytotoxic to macrophages in vitro and more inflammatory in the rat lung, as reflected by increased concentration of neutrophils and protein in BALF. Fluorescence microscopy revealed a typical patchy distribution of SiO2-FITC located within the lung parenchyma and alveolar macrophages. Superimposable to this particle distribution, SiO2-FITC elicited local increases of phosphatidylglycerol (PG) and phosphatidylinositol (PI), whereas phoshatidylserine (PS) and signals from triacylgyceride (TAG) were decreased in the same areas. No such changes were found in lungs treated with SiO2-p or particle-free instillation fluid. CONCLUSIONS: Phosphonate coating mitigates effects of silica NP in the lung and abolishes their locally induced changes in PLC pattern. Bioimaging methods based on MALDI-MS may become a useful tool to investigate the mode of action of NPs in tissues. PMID- 30012175 TI - Concurrent exergaming and transcranial direct current stimulation to improve balance in people with Parkinson's disease: study protocol for a randomised controlled trial. AB - BACKGROUND: People with Parkinson's disease (PD) commonly experience postural instability, resulting in poor balance and an increased risk of falls. Exercise based video gaming (exergaming) is a form of physical training that is delivered through virtual reality technology to facilitate motor learning and is efficacious in improving balance in aged populations. In addition, studies have shown that anodal transcranial direct current stimulation (a-tDCS), when applied to the primary motor cortex, can augment motor learning when combined with physical training. However, no studies have investigated the combined effects of exergaming and tDCS on balance in people with PD. METHODS/DESIGN: Twenty-four people with mild to moderate PD (Hoehn and Yahr scale score 2-4) will be randomly allocated to receive one of three interventions: (1) exergaming + a-tDCS, (2) exergaming + sham a-tDCS or (3) usual care. Participants in each exergaming group will perform two training sessions per week for 12 weeks. Each exergaming session will consist of a series of static and dynamic balance exercises using a rehabilitation-specific software programme (Jintronix) and 20 minutes of either sham or real a-tDCS (2 mA) delivered concurrently. Participants allocated to usual care will be asked to maintain their normal daily physical activities. All outcome measures will be assessed at baseline and at 6 weeks (mid-intervention), 12 weeks (post-intervention) and 24 weeks (3-month follow-up) after baseline. The primary outcome measure will be the Limits of Stability Test. Secondary outcomes will include measures of static balance, leg strength, functional capacity, cognitive task-related cortical activation, corticospinal excitability and inhibition, and cognitive inhibition. DISCUSSION: This will be the first trial to target balance in people with PD with combined exergaming and a-tDCS. We hypothesise that improvements in balance, functional and neurophysiological outcome measures, and neurocognitive outcome measures will be greater and longer lasting following concurrent exergaming and a-tDCS than in those receiving sham tDCS or usual care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000594426 ). Registered on 9 May 2016. PMID- 30012176 TI - Inhibin B in healthy and cryptorchid boys. AB - BACKGROUND: Cryptorchidism, the most common male genital abnormality observed in paediatrics, might often be associated with long-term functional consequences and can even reoccur after a successful orchidopexy. Serum markers that identify cryptorchid boys with gonadal dysfunction early should be useful in a decision making process. Inhibin B, produced during all of childhood but altered in cryptorchid subjects, appears strictly related to Sertoli cells, and its levels directly reflect the status of the testis germinative epithelium. Unfortunately, its precise roles in bilateral and unilateral cryptorchidism are still debated and being unravelled. Herein, we report the most current knowledge about inhibin B in both healthy boys and those with cryptorchidism to discuss and clarify its potential clinical applications. DISCUSSION: Inhibin B represents a simple and repeatable serum marker and it seems to well asses the presence and function of the testicular tissue. Testicular tissue in prepubertal age is largely made up of Sertoli cells; inhibin B, coming from working Sertoli cells, allows to indirectly evaluate their function. Besides, inhibin B is produced throughout childhood, even before puberty, in contrast with central hormones, and it is not influenced by androgens during puberty, in contrast with other testicular hormones. Although further studies are needed, low levels of inhibin B have been related with low testicular score and/or with consistent alterations of testicular parameters at histological examination. This means that inhibin B could be an indirect marker of testicular functions that could even replace testicular biopsies, but current data are inconsistent to confirm this potential role of inhibin B in cryptorchidism. CONCLUSION: Inhibin B represents an effective candidate for early identification of testicular dysfunction after orchidopexy for cryptorchidism. Unfortunately, current data cannot exactly clarify the real role of inhibin B as a predictor of future testicular function in cryptorchidism and future long-term follow-up studies, with repeated inhibin B checks both in cryptorchid and in formerly cryptorchid children and adolescents, will permit to assess if previous normal levels of inhibin B would match with future normal pubertal development and fertility potential. PMID- 30012177 TI - Motor neuron and pancreas homeobox 1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2. AB - BACKGROUND: Uncontrolled proliferation is thought to be the most fundamental characteristic of cancer. Detailed knowledge of cancer cell proliferation mechanisms would not only benefit understanding of cancer progression, but may also provide new clues for developing novel therapeutic strategies. METHODS: In vitro function of MNX1 (Motor neuron and pancreas homeobox 1) in bladder cancer cell was evaluated using MTT assay, colony formation assay, and bromodeoxyuridine incorporation assay. Real-time PCR and western blotting were performed to detect MNX1 and CCNE1/2 expressions. In vivo tumor growth was conducted in BALB/c-nu mice. RESULTS: We reported that MNX1 is responsible for sustaining bladder cancer cell proliferation. Abnormal MNX1 upregulation in bladder cancer cell lines and 167 human tissue specimens; high MNX1 expression levels correlated significantly with shorter 5-year overall and relapse-free survival in the bladder cancer patients. Furthermore, MNX1 overexpression accelerated bladder cancer cell proliferation and tumorigenicity both in vitro and in vivo, whereas MNX1 downregulation arrested it. In addition, MNX1 transcriptionally upregulated CCNE1 and CCNE2 by directly bounding to their promoters, which promoted G1-S transition in the bladder cancer cells. CONCLUSION: These findings reveal an oncogenic role and novel regulatory mechanism of MNX1 in bladder cancer progression and suggest that MNX1 is a potential prognostic biomarker and therapeutic target. PMID- 30012178 TI - SEALIVE: the use of technical vessel-sealing devices for recipient hepatectomy in liver transplantation: study protocol for a randomized controlled trial. AB - BACKGROUND: The surgical technique used in liver transplantation has undergone constant evolution in an effort to develop a safe, highly standardized procedure. Despite this, the initial step of recipient hepatectomy has not been the focus of clinical research thus far. Due to advanced coagulopathy in liver transplant recipients, this part of the operation still carries the risk of severe hemorrhage. This trial is designed to compare an electrothermal bipolar vessel sealing device (LigaSureTM) and an ultrasound dissector (HARMONIC ACE(r)+7) with standard surgical techniques during the recipients' hepatectomy in liver transplantation. METHODS/DESIGN: In a single-center, prospective, randomized, controlled, parallel, three-armed, confirmatory, open trial, LigaSureTM and HARMONIC ACE(r)+7 will be compared with standard surgical techniques that use titanium clips and conventional knot-tying ligations during recipient hepatectomy in liver transplantation. Intraoperative total blood loss is the primary endpoint of the trial. Secondary endpoints include blood loss during hepatectomy, the duration of both the hepatectomy and the entire surgical procedure, and blood transfusion requirements of the procedure. To generate reliable data, intraoperative blood loss will be recorded with respect to all rinse fluids during surgery, ascites, and by weighing used swabs. At 80% power and an alpha of 0.025 for both of the experimental groups, 23 subjects will be analyzed per protocol in each study arm in order to detect clinically relevant reduction of intraoperative blood loss. The intention-to-treat analysis will include 69 patients. The follow-up period for each patient will be 90 days for safety reasons, whereas all clinical outcomes will be measured within the first 10 postoperative days. DISCUSSION: To our knowledge, this is the first prospective, randomized trial comparing two innovative technical methods of vessel sealing and dissection with standard techniques for recipient hepatectomy. This will be done to detect relevant reduction of intraoperative blood loss during liver transplant. The results of the trial are expected to improve patient outcome and safety after liver transplant and to increase the general safety of this procedure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT 03323242 . Registered on October 26, 2017. PMID- 30012179 TI - Six-month field efficacy and safety of the combined treatment of dogs with Frontline Tri-Act(r) and NexGard Spectra(r). AB - BACKGROUND: Safety and efficacy of the combined monthly use of spot-on fipronil 6.76% w/v / permethrin 50.48% w/v (Frontline Tri-Act(r)) and chewable tablets of afoxolaner 1.9% w/w / milbemycin oxime 0.4% w/w (NexGard Spectra(r)) in dogs was evaluated in a field study over a period of 6 months. METHODS: Forty-one healthy dogs living in highly endemic area for canine leishmaniosis and other canine vector borne diseases (VBD) were included in the study at the beginning of the Leishmania transmission season. Sixteen dogs were pet dogs living each in a single household; twenty-five dogs were hunting dogs living in three kennels. At inclusion, the dogs were ELISA (rapid test) negative for antibodies to Anaplasma, Borrelia, Ehrlichia, and for antigens of Dirofilaria. The dogs were also negative for blood microfilariae at the Knott's test, and no clinical or haematological abnormalities were observed. Of the included dogs, six hunting, apparently healthy, dogs were ELISA (rapid test) positive to Leishmania, and some were naturally infected by gastrointestinal nematodes (58.5%) and/or infested by fleas (58.5%) and ticks (9.8%). All the included dogs were treated at Days 0, 28, 56, 84, 112 and 140, and followed-up for efficacy until the study end (Day 168). RESULTS: No adverse events related to the two products, nor skin reactions, general signs, or changes in the haematological profile, were observed during the study. At Day 14, anthelminthic efficacy was 100% for Toxocara canis, Toxascaris leonina and Capillaria aerophila, while few hunting dogs were still shedding eggs of Trichuris vulpis (1/25 hunting dog) and Ancylostomatidae (9/25 hunting dogs). All pet dogs were nematode free at the end of the study. Hunting dogs were free of roundworms and whipworms. Twenty-four hours after the first treatment, 95.8% of the ectoparasite infested dogs were free from fleas and ticks. Ectoparasites were significantly controlled during the 6-month study period, with 100% efficacy on both fleas and ticks from Day 56 to Day 168. Blood and serum samples collected on Day 168 were tested for vector-borne pathogens using same methods of the inclusion and no new seroconversions or circulating blood microfilariae were observed. CONCLUSIONS: Concomitant use of Frontline Tri-Act(r) and NexGard Spectra(r) in dogs for six months was well tolerated. The combination was effective in controlling fleas, ticks, gastro-intestinal nematodes, and neither new seroconversion to the tested vector-borne pathogens nor blood microfilariae were detected in treated dogs at the end of the study. PMID- 30012181 TI - Preventing false discovery of heterogeneous treatment effect subgroups in randomized trials. AB - BACKGROUND: Heterogeneous treatment effects (HTEs), or systematic differences in treatment effectiveness among participants with different observable features, may be important when applying trial results to clinical practice. Current methods suffer from a potential for false detection of HTEs due to imbalances in covariates between candidate subgroups. METHODS: We introduce a new method, matching plus classification and regression trees (mCART), that yields balance in covariates in identified HTE subgroups. We compared mCART to a classical method (logistic regression [LR] with backwards covariate selection using the Akaike information criterion ) and two machine-learning approaches increasingly applied to HTE detection (random forest [RF] and gradient RF) in simulations with a binary outcome with known HTE subgroups. We considered an N = 200 phase II oncology trial where there were either no HTEs (1A) or two HTE subgroups (1B) and an N = 6000 phase III cardiovascular disease trial where there were either no HTEs (2A) or four HTE subgroups (2B). Additionally, we considered an N = 6000 phase III cardiovascular disease trial where there was no average treatment effect but there were four HTE subgroups (2C). RESULTS: In simulations 1A and 2A (no HTEs), mCART did not identify any HTE subgroups, whereas LR found 2 and 448, RF 5 and 2, and gradient RF 5 and 24, respectively (all false positives). In simulation 1B, mCART failed to identify the two true HTE subgroups whereas LR found 4, RF 6, and gradient RF 10 (half or more of which were false positives). In simulations 2B and 2C, mCART captured the four true HTE subgroups, whereas the other methods found only false positives. All HTE subgroups identified by mCART had acceptable treated vs. control covariate balance with absolute standardized differences less than 0.2, whereas the absolute standardized differences for the other methods typically exceeded 0.2. The imbalance in covariates in identified subgroups for LR, RF, and gradient RF indicates the false HTE detection may have been due to confounding. CONCLUSIONS: Covariate imbalances may be producing false positives in subgroup analyses. mCART could be a useful tool to help prevent the false discovery of HTE subgroups in secondary analyses of randomized trial data. PMID- 30012180 TI - Effect of transcranial direct current stimulation associated with hypocaloric diet on weight loss and metabolic profile in overweight or obesity: study protocol for a double-blind, randomized controlled clinical trial. AB - BACKGROUND: Dietary interventions have limited success in promoting sustainable weight loss; new treatments allowing better compliance with hypocaloric diets should be developed. The aim of this trial is to describe the effects of a protocol combining repetitive active transcranial direct current stimulation (tDCS) with a hypocaloric diet on weight loss and food consumption in overweight or obese adults. METHODS/DESIGN: Overweight or obese adults between 20 and 50 years of age with stable weight over the last 4 months will be selected for a 4 week randomized clinical trial of fixed-dose tDCS (20 sessions; 5 consecutive weekdays/wk, 2 mA, 20 minutes) over the right dorsolateral prefrontal cortex associated with a weight loss diet. The subjects will be randomly assigned in a 1:1 ratio and stratified by sex to active tDCS + diet or sham tDCS + diet. The study will be conducted at the Endocrine and Metabolism Unit of the Hospital de Clinicas de Porto Alegre, Brazil. The primary outcome is weight loss. Energy and macronutrient consumption, as well as adherence to the diet, will be assessed using 3-day weighed dietary records. Changes in blood glucose and plasma insulin will be assessed, and participants will complete self-report questionnaires to assess changes in mood and food behavior. All analyses will be done on a per protocol and intention-to-treat basis. DISCUSSION: This study explores the potential role of tDCS as an adjunctive treatment with a hypocaloric diet for obesity management. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02683902 . Registered on 11 January 2016. PMID- 30012182 TI - Amino acid permease 3 (aap3) coding sequence as a target for Leishmania identification and diagnosis of leishmaniases using high resolution melting analysis. AB - BACKGROUND: The leishmaniases comprise a spectrum of clinical manifestations caused by different species of Leishmania. Identification of species is important for diagnosis, treatment and follow-up management. However, there is no gold standard for species identification. High resolution melting analysis (HRM) offers a possibility to differentiate Leishmania species without the need for processing of the PCR-product. The amino acid permease 3 (aap3) gene is an exclusive target for trypanosomatids and is conserved among Leishmania spp., thus it can be a valuable target for an HRM assay for diagnosis of the leishmaniases. RESULTS: The HRM dissociation profiles of three amplicons targeting the aap3 coding region allowed the discrimination of L. (Leishmania) donovani, L. (L.) infantum, L. (L.) major, L. (L.) tropica, L. (L.) mexicana, L. (L.) amazonensis, L. (Viannia) braziliensis, L. (V.) guyanensis, L. (V.) lainsoni, L. (V.) naiffi and L. (V.) shawi using DNA from promastigote cultures. The protocol was validated with DNA samples from clinical infection in humans and a cat, naturally infected sand flies, and experimentally infected mice. CONCLUSIONS: HRM analysis using the aap3 coding sequence as target is a relatively cheap, fast and robust strategy to detect and discriminate Leishmania species from all the endemic regions worldwide. The target and method proved to be useful in clinical, field and experimental samples, thus it could be used as a tool in diagnosis as well as ecological and epidemiological studies. PMID- 30012183 TI - Attraction of Rhodnius prolixus males to a synthetic female-pheromone blend. AB - BACKGROUND: The triatomine bug Rhodnius prolixus Stal, 1859 (Heteroptera: Reduviidae) is the primary vector of Chagas disease in Colombia and Venezuela. An important step in controlling Chagas disease is monitoring the growth and spread of bug populations to inform effective management. Such monitoring could be carried out using pheromone traps. To develop effective pheromone traps, it is vital to understand the pheromone chemistry of R. prolixus. Previous studies have found that female R. prolixus metasternal gland secretions induce males to: leave shelters, take off, orientate during walking, aggregate around mating pairs, and mate. This study aims to identify a synthetic blend of female metasternal gland compounds that could be used to attract R. prolixus. RESULTS: We investigated the electrophysiological activity of the ten most abundant compounds in female R. prolixus metasternal glands using single sensillum recordings. In total we obtained 60 recordings from basiconic sensilla in male R. prolixus. In 31 of these recordings, responses to individual compounds were observed. Each of the ten tested compounds elicited neuron responses in a minimum of eight recordings. Having confirmed their electrophysiological activity, we tested these ten compounds by presenting them to male Rhodnius prolixus in a "T" olfactometer. Male bugs showed a significant preference for the blend of metasternal gland compounds compared to the clean air control. CONCLUSIONS: A simple blend of ten compounds found in female R. prolixus metasternal glands is attractive to conspecific males. All compounds in the blend are either commercially available at low cost, or easily synthetically prepared from simple precursors. We hope that this blend will be evaluated as a lure for pheromone traps in field bioassays. PMID- 30012184 TI - NYD-OP7/PLC regulatory signaling pathway regulates deltamethrin resistance in Culex pipiens pallens (Diptera: Culicidae). AB - BACKGROUND: Investigation of insecticide resistance mechanisms is considered a vital first step towards the creation of effective strategies to control resistant mosquitoes and manage mosquito-borne diseases. Our previous study revealed that NYD-OP7 may be associated with deltamethrin resistance in Culex pipiens pallen. However, the precise function of NYD-OP7 in deltamethrin resistance is still unclear. In this study, we investigated the role of NYD-OP7 in the molecular mechanisms underlying pyrethroid resistance. RESULTS: Knockdown of NYD-OP7 not only increased the susceptibility of the mosquitoes to deltamethrin in vivo but also simultaneously repressed both expression and enzyme activity of its downstream effector molecule, phospholipase C (PLC) and expression of several insecticide resistance-related P450 genes. Knockdown of PLC also sensitized the mosquitoes to deltamethrin and reduced the expression of the P450 genes. CONCLUSIONS: Our results revealed that NYD-OP7 and its downstream effector PLC contribute to deltamethrin resistance by regulating the expression of P450s in Cx. pipiens pallens. PMID- 30012185 TI - Use of monomeric and oligomeric flavanols in the dietary management of patients with type 2 diabetes mellitus and microalbuminuria (FLAVA trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2D) are prone to micro- and macro-vascular complications. Monomeric and oligomeric flavanols (MOF) isolated from grape seeds (Vitis vinifera) have been linked to improved endothelial function and vascular health. The aim of this study is to determine the effect of a daily supplementation of 200 mg MOF on renal endothelial function of patients with T2D and microalbuminuria. METHODS/DESIGN: For this double-blind, placebo controlled, randomized, multicenter trial 96 individuals (ages 40-85 years) with T2D and microalbuminuria will be recruited. Participants will be randomly assigned to the intervention group, receiving 200 mg of MOF daily for 3 months, or to the control group, receiving a placebo. The primary endpoint is the evolution over time in albumin excretion rate (AER) until 3 months of intervention as compared with placebo. Secondary endpoints are the evolution over time in established plasma markers of renal endothelial function-asymmetric dimethylarginine (ADMA), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and von Willebrand Factor (vWF)-until 3 months of intervention as compared with placebo. Mixed modeling will be applied for the statistical analysis of the data. DISCUSSION: We hypothesize that T2D patients with microalbuminuria have a medically determined requirement for MOF and that fulfilling this requirement will result in a decrease in AER and related endothelial biomarkers. If confirmed, this may lead to new insights in the dietary management of patients with T2D. TRIAL REGISTRATION: Nederlands Trial Register, NTR4669 , registered on 7 July 2014. PMID- 30012186 TI - Non-specific complaints at emergency department presentation result in unclear diagnoses and lengthened hospitalization: a prospective observational study. AB - BACKGROUND: Up to 20% of patients admitted to an emergency department present with non-specific complaints. Retrospective studies suggest an increased risk of misdiagnosis and hospital admission for these patients, but prospective comparisons of the outcomes of emergency patients with non-specific complaints versus specific complaints are lacking. METHODS: All consecutive patients >=18 years of age admitted to any internal medicine ward at Bern University Hospital via the emergency department from August 15th 2015 to December 7th 2015 were prospectively included and followed up upon. Patients with non-specific complaints were compared against those with specific complaints regarding the quality of their emergency department diagnosis, length of hospital stay and in hospital mortality. RESULTS: Seven hundred and-eleven patients, 165 (23.21%) with non-specific complaints and 546 with specific complaints, were included in this study. No differences between patient groups regarding age, gender or initial severity of the medical problem (deducted from triage category and treatment in a resuscitation bay) were found. Patients with non-specific complaints received more unspecific diagnoses (30.3% vs. 23.1%, p = 0.001, OR = 1.82 [95% CI 1.159 2.899]), were hospitalized significantly longer (Median = 6.51 (IQR = 5.85) vs. 5.22 (5.83) days, p = 0.025, d = 0.2) but did not have a higher mortality than patients with specific complaints (7.3% vs. 3.7%, p = 0.087, OR 1.922 [95% CI 0.909-4.065]). CONCLUSIONS: Non-specific complaints in patients admitted to an emergency department result in low-quality diagnoses and lengthened hospitalization, despite the patients being comparable to patients with specific complaints at admission. PMID- 30012187 TI - Prophylactic intravitreal 5-fluorouracil and heparin to prevent proliferative vitreoretinopathy in high-risk patients with retinal detachment: study protocol for a randomized controlled trial. AB - BACKGROUND: Proliferative vitreoretinopathy (PVR) is the major cause for postoperative failure after vitreo-retinal surgery for primary rhegmatogenous retinal detachment (RRD). Adjunct pharmaceutical therapy was found to be ineffective once PVR is established. Preliminary data suggest that prevention of PVR yields better functional outcome. So far, there is no standard therapy to prevent PVR. METHODS/DESIGN: This is a randomized, double-blind, controlled, multicenter, interventional trial with one interim analysis. High-risk patients for PVR with primary RRD will be allocated equally to the following treatment arms: (a) verum: intraoperative adjuvant application of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV) and (b) placebo: routinely used intraocular infusion with balanced salt solution during routine PPV. PVR risk is assessed by non-invasive aqueous flare measurement by using laser flare photometry. The primary endpoint of the trial is the occurrence of PVR grade CP (C: full-thickness retinal folds or subretinal strands in clock hours; P: located posterior to equator) 1 or higher within 12 weeks after treatment. Secondary endpoints include PVR grade CA (A: located anterior to equator), best corrected visual acuity, number and extent of surgical procedures to achieve retinal re-attachment, and occurrence of drug related adverse events within 12 weeks. It is assumed, on the basis of previously published results, that the incidence of PVR grade CP 1 is 35% in the control group and that a reduction by one third would be clinically relevant. Given the sequential design and adjustment for a dropout rate of 5%, a total sample size of 560 patients (280 per group) was calculated to ensure a power of 80% for the confirmatory analysis. DISCUSSION: The present trial uses intraoperative intravitreal 5-FU and LMWH as a prophylactic therapy in high-risk patients with primary RRD, aiming to reduce the incidence of PVR in the group that receives the trial drug. Using laser flare photometry to identify high-risk patients for PVR, this trial will test the effectiveness of a simple treatment to prevent PVR. TRIAL REGISTRATION: EudraCT no.: 2015-004731-12, registered October 21, 2015; ClinicalTrials.gov Identifier: NCT02834559 , registered July 12, 2016. Protocol version: Version 02. Date: September 18, 2016. PMID- 30012188 TI - Hypertension management for community-dwelling older people with diabetes in Nanchang, China: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Although China has a large number of older people living with diabetes and hypertension, the primary care system is underdeveloped and so management of these conditions in community care settings is suboptimal. Studies have shown that the collaborative care model across care settings that address both pharmacology and nonpharmacology interventions can achieve hypertension control for older people with diabetes. Barriers to implementing and evaluating this model of care are widely recognized in low and middle-income countries including China. This study will therefore test the hypothesis that a hypertension management program built on collaboration between hospitals and community health service centers in China can improve blood pressure control in people aged 60 years and older with diabetes as compared to usual care. METHODS: A cluster randomized controlled trial will randomly allocate 10 wards from four hospitals in Nanchang to either an intervention group (N = 5) or a usual care group (N = 5). At least 27 participants will be recruited from each ward and the estimated sample size will be 135 patients in each group. The intervention includes individualized self-care education prior to discharge and 6-month follow up in community health service centers. Health professionals from both hospitals and community health service centers will be resourced to collaborate on the implementation of the postdischarge interventions that reinforce self-care. The primary outcome is systolic blood pressure at 6-month follow-up adjusted for baseline value. Secondary outcomes are self-care knowledge, treatment adherence, HbA1c and lipid levels, quality of life, the incidence of adverse events and the incidence of unplanned hospital readmission at 6-month follow-up adjusted for baseline value. A multilevel mixed-effect linear regression model will be used to compare the changes in health outcomes between the intervention and usual care groups. DISCUSSION: This study will determine whether collaborative care among health professionals between hospitals and community health service centers will improve hypertension management for older people with diabetes in the study sites. The program, if effective, will have an immediate application to hypertension management in the healthcare system in China. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12617001352392 . Retrospectively registered on 26 September 2017. PMID- 30012189 TI - Pike intestinal reaction to Acanthocephalus lucii (Acanthocephala): immunohistochemical and ultrastructural surveys. AB - BACKGROUND: The Northern pike, Esox lucius, is a large, long-lived, top-predator fish species and occupies a broad range of aquatic environments. This species is on its way to becoming an important model organism and has the potential to contribute new knowledge and a better understanding of ecology and evolutionary biology. Very few studies have been done on the intestinal pathology of pike infected with helminths. The present study details the first Italian record of adult Acanthocephalus lucii reported in the intestine of E. lucius. RESULTS: A total of 22 pike from Lake Piediluco (Central Italy) were examined, of which 16 (72.7%) were infected with A. lucii. The most affected areas of gastrointestinal tract were the medium and distal intestine. The intensity of infection ranged from 1 to 18 parasites per host. Acanthocephalus lucii penetrated mucosal and submucosal layers which had a high number of mast cells (MCs) with an intense degranulation. The cellular elements involved in the immune response within the intestine of pike were assessed by ultrastructural techniques and immunohistochemistry using antibodies against met-enkephalin, immunoglobulin E (IgE)-like receptor (FCepsilonRIgamma), histamine, interleukin-6, interleukin 1beta, substance P, lysozyme, serotonin, inducible-nitric oxide synthase (i-NOS), tumor necrosis factor-alpha (TNF-alpha) and the antimicrobial peptide piscidin 3 (P3). In intestines of the pike, several MCs were immunopositive to 9 out of the 11 aforementioned antibodies and infected fish had a higher number of positive MCs when compared to uninfected fish. CONCLUSIONS: Pike intestinal tissue response to A. lucii was documented. Numerous MCs were seen throughout the mucosa and submucosal layers. In infected and uninfected intestines of pike, MCs were the dominant immune cell type encountered; they are the most common granulocyte type involved in several fish-helminth systems. Immunopositivity of MCs to 9 out of 11 antibodies is of great interest and these cells could play an important key role in the host response to an enteric helminth. This is the first report of A. lucii in an Italian population of E. lucius and the first account on positivity of MCs to piscidin 3 and histamine in a non-perciform fish. PMID- 30012190 TI - Whole brain radiation therapy alone versus radiosurgery for patients with 1-10 brain metastases from small cell lung cancer (ENCEPHALON Trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Conventional whole brain radiotherapy (WBRT) has been established as the treatment standard in patients with cerebral metastases from small-cell lung cancer (SCLC), however, it has only modest efficacy and limited prospective data is available for WBRT as well as local treatments such as stereotactic radiosurgery (SRS). METHODS/DESIGN: The present single-center prospective randomized study, conducted at Heidelberg University Hospital, compares neurocognitive function, as objectively measured by significant deterioration in Hopkins Verbal Learning Test - Revised total recall at 3 months. Fifty-six patients will be randomized to receive either SRS of all brain metastases (up to ten lesions) or WBRT. Secondary endpoints include intracranial progression (local tumor progression and number of new cerebral metastases), extracranial progression, overall survival, death due to brain metastases, local (neurological) progression-free survival, progression-free survival, changes in other cognitive performance measures, quality of life and toxicity. DISCUSSION: Recent evidence suggests that SRS might be a promising treatment option for SCLC patients with brain metastases. The present trial is the first to prospectively investigate the treatment response, toxicity and neurocognition of WBRT and SRS in SCLC patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT03297788 . Registered September 29, 2017. PMID- 30012191 TI - Immunosuppressive property of submandibular lymph nodes in patients with head and neck tumors: differential distribution of regulatory T cells. AB - OBJECTIVE: Different sensitizations and immune responses are thought to be induced in response to antigens at different mucosal sites between the oral floor and nose. The aim of this study was to investigate differences in the distributions of lymphocyte subsets in the submandibular (SM) and upper jugular (UJ) lymph nodes (LNs), which are supposed to be regional LNs of the oral floor and nasal mucosa, respectively. SMLNs and UJLNs were collected from patients with head and neck tumors who underwent surgical resection. The populations of T cells, Natural Killer (NK) cells, Natural Killer T (NKT) cells, regulatory T cells (Tregs) and dendritic cells (DCs) in LNs without metastasis were analyzed by flow cytometry. The high-affinity IgE receptor (FcepsilonRI) expression of LN cells were also evaluated. RESULTS: The proportions of CD4+CD25+Foxp3+ Tregs, CD4+CD45RA-Foxp3high effector Tregs and FcepsilonRIalpha+CD33+CD11c+ DCs were significantly larger in SMLNs compared with UJLNs, while those of CD3+ T cells, CD3-CD56+ NK cells, CD3+Valpha24+Vbeta11+ NKT cells, and CD123+CD303+ DCs did not show any significant differences between SMLNs and UJLNs. The differential distributions of CD4+CD25+Foxp3+ Tregs were observed regardless of tumor region, LN metastasis and clinical staging. These data indicate that SMLNs may have immunosuppressive properties compared with UJLNs. PMID- 30012192 TI - Community-based provision of direct-acting antiviral therapy for hepatitis C: study protocol and challenges of a randomized controlled trial. AB - BACKGROUND: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to treatment. Direct acting antiviral (DAA) treatment can be provided in primary healthcare services (PHCS), improving accessibility, and, potentially, retention in care. Here, we describe our protocol for assessing the effectiveness of providing DAAs in PHCS, and the impact on the HCV care cascade. In addition, we reflect on the challenges of conducting a model of care study during a period of unprecedented change in HCV care and treatment. METHODS: Consenting patients with HCV infection attending 13 PHCS in Australia or New Zealand are randomized to receive DAA treatment at the local tertiary institution (standard care arm), or their PHCS (intervention arm). The primary endpoint is the proportion commenced on DAAs and cured. Treatment providers at the PHCS include: hepatology nurses, primary care practitioners, or, in two sites, a specialist physician. All PHCS offer opioid substitution therapy. DISCUSSION: The Prime Study is the first real-world, randomized, model of care study exploring the impact of community provision of DAA therapy on HCV-treatment uptake and cure. Although the study has faced challenges unique to this period of time characterized by changing treatment and service delivery, the data gained will be of critical importance in shaping health service policy that enables the elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT02555475 . Registered on 15 September 2015. PMID- 30012193 TI - Baduanjin exercise for patients with ischemic heart failure on phase-II cardiac rehabilitation (BEAR trial): study protocol for a prospective randomized controlled trial. AB - BACKGROUND: Preliminary evidence based on clinical observations suggests that meditative exercise may offer potential benefits for patients with chronic heart failure (CHF). Cardiac rehabilitation (CR), as a class-IA indication in clinical practice guidelines, has been established as an effective strategy to improve quality of life and prognosis of CHF patients. Baduanjin exercise is an important component of traditional Chinese Qigong exercises. However, its benefits for CHF have not been rigorously tested. We sought to investigate whether Baduanjin, as an adjunct to standard care, improves cardiopulmonary function, exercise tolerance, and quality of life in patients with CHF caused by coronary artery disease (CAD). METHODS/DESIGN: In this randomized controlled trial, 120 patients will be randomly allocated in a 1:1 ratio to Baduanjin exercise combined with conventional exercise of CR (Baduanjin exercise group) or conventional exercise of CR alone (conventional exercise group). In addition to conventional physical activity, participants in the Baduanjin exercise group will participate in a 45 min Baduanjin exercise training session twice a week, for 12 weeks. The primary outcome is walking distance in the 6-min Walk Test (6MWT), and the secondary outcomes are peak oxygen uptake (VO2 peak), ventilatory anerobic threshold (VAT), The minute ventilation to carbon dioxide production relationship (VE/VCO2 slope), left ventricular end-diastolic volume index (LVEDVi), left ventricular ejection fraction (LVEF), quality of life assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), amino-terminal pro-brain natriuretic peptide (NT proBNP), hs-CRP, heart rate variability (HRV), New York Heart Association (NYHA) classification, and major adverse cardiovascular events. DISCUSSION: This is the first trial to evaluate the effects of a Baduanjin exercise-based CR program on cardiopulmonary function and exercise tolerance in ischemic CHF patients. If successful, it will prove the value of Baduanjin exercise in improving cardiopulmonary function and exercise tolerance in patients with ischemic heart failure on phase-II CR, and may further develop a Chinese Qigong exercise-based CR framework. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03229681 . Registered retrospectively on 23 July 2017. PMID- 30012194 TI - BMP4 promotes hepatocellular carcinoma proliferation by autophagy activation through JNK1-mediated Bcl-2 phosphorylation. AB - BACKGROUND: Autophagy is a conserved catabolic process with complicated roles in tumor development. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor (TGF-beta) family of regulatory proteins, plays a crucial role in human malignancies. However, whether BMP4 contributes to the regulation of autophagy in hepatocellular carcinoma (HCC) progression remains elusive. METHODS: Functional analysis of BMP4 on HCC proliferation and autophagy was performed both in vitro and in vivo in HepG2 and HCCLM3 cells. Autophagic activity was estimated by Western blot for autophagic marker proteins and by transmission electron microscopy (TEM). Transfection of mRFP-GFP-LC3 adenovirus was applied to observe autophagic flux and high content screening was used for quantification. The signaling pathway of BMP4-regulated HCC proliferation and autophagy was investigated by Western blot. RESULTS: BMP4 treatment promoted HCC cells proliferation and induced autophagy. The in vivo xenograft model supported that BMP4 overexpression promoted the growth of HCC cells and autophagy induction while BMP4 knockdown exerted the opposite effect. 3-MA pre-treatment or knockdown of Beclin-1 (BECN1) blocked HCC autophagy by decreasing the expression of LC3-II and subsequently attenuated BMP4-induced autophagy and cells proliferation enhanced by BMP4 in vitro and in vivo. Mechanistic study revealed that the induction of autophagy by BMP4 was mediated through activating the JNK1/Bcl2 pathway. Furthermore, the JNK1 inhibitor and knockdown of JNK1 could attenuate autophagy induced by BMP4 and eliminated BMP4-promoted HCC cells growth. CONCLUSIONS: BMP4 promoted HCC proliferation by autophagy activation through JNK1/Bcl-2 signaling. PMID- 30012195 TI - Discordant anti-mullerian hormone (AMH) and follicle stimulating hormone (FSH) among women undergoing in vitro fertilization (IVF): which one is the better predictor for live birth? AB - BACKGROUND: This study sought to clarify the roles of Anti-mullerian hormone (AMH) and follicle stimulating hormone (FSH) in predicting live birth, especially in patients with discordant AMH and FSH. A large IVF data set provided by eIVF(r), consisting of 13,964 cycles with AMH, FSH, age, BMI, and birth outcomes were evaluated. Patients were categorized into four groups: Good prognosis group (AMH >=1 ng/ml; FSH < 10 mIU/ml), Poor prognosis group (AMH < 1 ng/ml; FSH >=10 mIU/ml), Reassuring AMH group (AMH >=1 ng/ml; FSH >=10 mIU/ml), and Reassuring FSH group (AMH < 1 ng/ml; FSH < 10 mIU/ml). The interaction between AMH, FSH, and their impact on live birth rate among these four groups was evaluated using Generalized Additive Mixed Modeling (GAMM). RESULTS: Analysis revealed a nonlinear relationship of AMH and FSH with live birth rate among all ages. Among the four groups, the good prognosis group had the highest live birth rate while the poor prognosis group had the lowest live birth rate (29.3% vs 13.1%, p < 0.005). In the discordant groups, the live birth rate of the reassuring AMH group was significantly higher than the reassuring FSH group (22.8% vs 15.6%, p < 0.005). CONCLUSIONS: Although both FSH and AMH are widely use to assess the ovarian reserve in women undergoing evaluation for infertility, AMH appears to be superior to FSH among all age groups. This is particularly important for patients with discordant AMH and FSH where reassuring AMH is a better clinical predictor of cycle success. PMID- 30012196 TI - Consistency of Integrated Management of Newborn and Childhood Illness (IMNCI) in Shire Governmental Health Institution in 2017. AB - OBJECTIVE: In an effort to reduce infant mortality and morbidity, the World Health Organization and other technical partners developed the Integrated Management of Newborn and Childhood Illness (IMNCI). This study focuses on assessment of consistency and completeness of integrated management of neonatal and child hood illness in primary health care units. RESULTS: A total of 384 cases were taken from 3562 cases both from young infant registration (under-2 month old) and child registration (2 months-5 year old). Out of 384 cases, 241 (62.8%) cases were correctly classified and 143 (37.2%) were incorrect classifications. Similarly 164 (42.7%) cases were treated correctly where as 220 (57.3%) treated incorrectly. Only 95 (24.7%) cases have given appropriate appointments where as 289 (75.3%) cases were appointed incorrectly. The overall consistency of IMNCI management is poor. Unless continuous follow up of and training was given, children are not treated as expected. More over using electronic method of IMNCI may alleviate the problem. PMID- 30012197 TI - Accumulation of potential driver genes with genomic alterations predicts survival of high-risk neuroblastoma patients. AB - BACKGROUND: Neuroblastoma is the most common pediatric malignancy with heterogeneous clinical behaviors, ranging from spontaneous regression to aggressive progression. Many studies have identified aberrations related to the pathogenesis and prognosis, broadly classifying neuroblastoma patients into high- and low-risk groups, but predicting tumor progression and clinical management of high-risk patients remains a big challenge. RESULTS: We integrate gene-level expression, array-based comparative genomic hybridization and functional gene interaction network of 145 neuroblastoma patients to detect potential driver genes. The drivers are summarized into a driver-gene score (DGscore) for each patient, and we then validate its clinical relevance in terms of association with patient survival. Focusing on a subset of 48 clinically defined high-risk patients, we identify 193 recurrent regions of copy number alterations (CNAs), resulting in 274 altered genes whose copy-number gain or loss have parallel impact on the gene expression. Using a network enrichment analysis, we detect four common driver genes, ERCC6, HECTD2, KIAA1279, EMX2, and 66 patient-specific driver genes. Patients with high DGscore, thus carrying more copy-number-altered genes with correspondingly up- or down-regulated expression and functional implications, have worse survival than those with low DGscore (P = 0.006). Furthermore, Cox proportional-hazards regression analysis shows that, adjusted for age, tumor stage and MYCN amplification, DGscore is the only significant prognostic factor for high-risk neuroblastoma patients (P = 0.008). CONCLUSIONS: Integration of genomic copy number alteration, expression and functional interaction-network data reveals clinically relevant and prognostic putative driver genes in high-risk neuroblastoma patients. The identified putative drivers are potential drug targets for individualized therapy. REVIEWERS: This article was reviewed by Armand Valsesia, Susmita Datta and Aleksandra Gruca. PMID- 30012198 TI - Streptococcus agalactiae prevalence and antimicrobial susceptibility pattern in vaginal and anorectal swabs of pregnant women at a tertiary hospital in Cameroon. AB - OBJECTIVE: Group B Streptococcus (GBS) or Streptococcus agalactiae is part of the normal flora of the gut and genital tract, thus carrier pregnant women can transmit this germ to newborns which could cause early neonatal infection. In Cameroon, few studies have been conducted on GBS, thus this study sought to detect the rectal and vaginal colonization rates and the antibiotic susceptibility profile of the identified strains in pregnant women. We therefore conducted a cross-sectional study over a 6 months period analysing vaginal and anorectal samples obtained from 100 pregnant women. Cultures for the isolation of GBS were carried out according to standard microbiological methods and grouping done using the Pastorex strep Kit. All strains isolated were used for susceptibility test to various antibiotics as recommended by the French microbiology society, using the disk-diffusion method. RESULTS: The detected colonization rate was 14%. No resistance to ampicillin, oxacillin, amoxycillin clavulanate, cefotaxime, pristinamycin, vancomycin and clindamycin was found. Just 12, 94 and 82% of strains showed sensitivity to gentamycin, erythromycin and cefoxitin respectively. This study therefore revealed that at least one out of every ten women is GBS colonized and strains showed uniform sensitivity to beta lactamines. However, decreased sensitivity to erythromycin was detected. PMID- 30012199 TI - Cranial neural tube defect after trimethoprim exposure. AB - OBJECTIVES: The Neural Tube Defects Research Group of University of Malaya was approached to analyze a tablet named TELSE, which may have resulted in a baby born with central nervous system malformation at the University of Malaya Medical Centre. In this animal experimental study, we investigated the content of TELSE and exposure of its contents that resulted in failure of primary neurulation. RESULTS: Liquid Chromatography Tandem Mass spectrophotometry analysis of the TELSE tablet confirmed the presence of trimethoprim as the active compound. The TELSE tablet-treated females produced significant numbers of embryos with exencephaly (n = 8, 36.4%, *P < 0.0001), in all litters. The TELSE tablet-treated females subsequently given folic acid did not result in pregnancies despite there being evidence of possible resorption. Furthermore, after multiple rounds of mating which did not yield viable pregnancies, eventually, 2 embryos with exencephaly were harvested in a litter of 6 at 0.05% w/v pure trimethoprim once. The use of trimethoprim, a folic acid antagonist, peri-conceptionally increased the risk of exencephaly in the mouse. PMID- 30012200 TI - miR-589 promotes gastric cancer aggressiveness by a LIFR-PI3K/AKT-c-Jun regulatory feedback loop. AB - BACKGROUND: As novel biomarkers for various cancers, microRNAs negatively regulate genes expression via promoting mRNA degradation and suppressing mRNA translation. miR-589 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in gastric cancer. Here, we aim to investigate the biological effect of miR-589 on gastric cancer and to reveal the possible mechanism. METHODS: Real-time PCR was performed to evaluate the expression of miR-589 in 34 paired normal and stomach tumor specimens, as well as gastric cell lines. Functional assays, such as wound healing, transwell assays and in vivo assays, were used to detect the biological effect of miR-589 and LIFR. We determined the role of miR-589 in gastric cancer tumorigenesis in vivo using xenograft nude models. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were performed for target evaluation, and the relationships were confirmed by western blot assay. RESULT: MiR-589 expression was significantly higher in tumor tissues and gastric cancer cells than those in matched normal tissues and gastric epithelial cells, respectively. Clinically, overexpression of miR-589 is associated with tumor metastasis, invasion and poor prognosis of GC patients. Gain- and loss-of function experiments showed that miR-589 promoted cell migration, metastasis and invasion in vitro and lung metastasis in vivo. Mechanistically, we found that miR 589 directly targeted LIFR to activate PI3K/AKT/c-Jun signaling. Meanwhile, c-Jun bound to the promoter region of miR-589 and activated its transcription. Thus miR 589 regulated its expression in a feedback loop that promoted cell migration, metastasis and invasion. CONCLUSION: Our study identified miR-589, as an oncogene, markedly induced cell metastasis and invasion via an atypical miR-589 LIFR-PI3K/AKT-c-Jun feedback loop, which suggested miR-589 as a potential biomarker and/or therapeutic target for the gastric cancer management. PMID- 30012201 TI - Fresh versus frozen embryo transfer for full-term singleton birth: a retrospective cohort study. AB - BACKGROUND: Improvements in vitrification and frozen embryo transfer (FET) technologies have rapidly increased, and some evidence suggests that FET may increase pregnancy rates and lead to more favourable perinatal outcomes. However, the outcome of interest should be offspring safety. Therefore, the primary objective of our study was to investigate whether FET was preferable to fresh embryo transfer (ET) in terms of full-term neonatal birthweight and congenital malformations. METHODS: This was a retrospective cohort study of patients with no pregnancy-related complications who underwent first fresh ETs (n = 2059) or FETs (n = 2053), resulting in full-term singletons births. Outcome measures were neonatal birthweight, low birthweight (LBW), small-for-gestational age (SGA), large-for-gestational age (LGA), macrosomia and congenital malformations. Additionally, we used logistic regression to adjust for baseline characteristics (age, BMI, No. of embryos transferred and embryo stage) between the two groups. RESULTS: The mean neonatal birthweight was higher for singletons born after FET than for singletons born after fresh ET (3468.7 +/- 475.3 vs. 3386.7 +/- 448.1; p < 0.001). The frequencies of full-term singleton LBW and SGA after FET were significantly lower than those after fresh ET (1.7% vs. 3.0 and 4.4% vs. 6.7%, respectively), with adjusted rate ratios of 0.59 (95% CI, 0.37 to 0.98; p = 0.026) and 0.73 (95% CI, 0.55 to 0.99; p = 0.041), respectively. FET resulted in higher frequencies of macrosomia and LGA (15.1% vs 10.2 and 22.8% vs. 17.5%, respectively) than fresh ET, with adjusted rate ratios of 1.43 (95% CI, 1.16 to 1.75; p = 0.001) and 1.26 (95% CI, 1.07 to 1.49; p = 0.007), respectively. Furthermore, the incidence of congenital malformations was not different between the two groups (1.2% vs. 0.9%), with a rate ratio of 0.288. CONCLUSIONS: After the cycles with pregnancy-related complications were excluded and after adjustments for baseline characteristics, women undergoing FET were associated with a higher neonatal birthweight than women undergoing fresh ET cycles. Additionally, the FET protocol was associated with lower rates of LBW and SGA and higher rates of macrosomia and LGA than the fresh ET protocol. Meanwhile, no difference in the congenital malformation rate was evident between the two groups. PMID- 30012202 TI - A national survey of Ixodidae ticks on privately owned dogs in Italy. AB - BACKGROUND: The geographical distribution of ticks on companion animals needs to be monitored to develop and plan effective control measures, as suggested by the European Scientific Counsel on Companion Animal Parasites. The aim of this study was to conduct the first Italian national survey of tick distribution on privately owned dogs. METHODS: The study was performed over 20 months (February 2016 - September 2017) and involved 153 veterinary practices in 64 different provinces covering 17/20 (85%) Italian regions. Participating practitioners were asked to examine five different dogs per month at random and complete a questionnaire for each dog. Differences in tick infestation associated with: sex, age and hair length (long and short); the dog's habitat (indoor or outdoor/kennel); and the dog's environment (urban or rural/sylvatic) were evaluated. The attachment site of ticks on the dog was also recorded. Acaricide efficacy was evaluated for the subset of dogs for which complete information on product used, date of sampling and date of last ectoparasiticide treatment was available. RESULTS: Of the 3026 dogs examined, 1383 (45.7%) were carrying at least one tick. Overall, 2439 tick samples were collected and a total of 14 tick species identified. Rhipicephalus sanguineus group were the most predominant ticks (63.6%), followed by Ixodes ricinus (30.6%) and I. hexagonus (5.6%). Twenty four dogs had mixed tick infestations. Long-haired dogs had a higher tick infestation risk as did dogs with outdoor and rural/sylvatic lifestyles. Ticks were located on the head (37.4%), the neck (28.8%), the muzzle (15.5%) and the back (15.3%). A higher prevalence of Rhipicephalus was found in the interdigital spaces (10.8%) compared to Ixodes (0.2%). Finally, ectoparasiticide treatments were found significantly protective against tick infestation, especially orally administered formulations. CONCLUSIONS: Privately owned dogs in Italy have a high prevalence (45.7%) of infestation with ixodid ticks and this risk varies by dog phenotype and lifestyle. PMID- 30012203 TI - A darker chromatic variation of Rhodnius pallescens infected by specific genetic groups of Trypanosoma rangeli and Trypanosoma cruzi from Panama. AB - BACKGROUND: Rhodnius pallescens, the only species of this genus reported in Panama, has a wide geographical distribution and is associated with most cases of Chagas disease and human infections with Trypanosoma rangeli in this country. Thus far, no phenotypic variants of this triatomine have been registered. Similarly, genotyping of the trypanosomes that infect this vector has only been partially evaluated. RESULTS: A total of 347 specimens of R. pallescens were collected in Attalea butyracea palm trees located near a mountainous community of the district of Santa Fe, province of Veraguas. Bugs were slightly longer and had a darker coloration compared to that reported for this species. Infection rates for trypanosomes performed with three PCR analyses showed that 41.3% of the adult triatomines were positive for T. cruzi, 52.4% were positive for T. rangeli and 28.6% had mixed T. cruzi/T. rangeli infections. Based on cox2 analysis, TcI was the single T. cruzi discrete typing unit (DTU) detected, and a genetic variant of KP1(-)/lineage C was the only genetic group found for T. rangeli. CONCLUSIONS: A darker chromatic variation of R. pallescens predominates in a mountainous region of Panama. These triatomines show high trypanosome infection rates, especially with T. rangeli. Regarding T. rangeli genetic diversity, complementary studies using other molecular markers are necessary to better define its phylogenetic position. PMID- 30012204 TI - Knowledge is power: general practitioners prescribing of new oral anticoagulants in Ireland. AB - OBJECTIVE: New oral anticoagulants (NOACs) aim to overcome warfarin's shortcomings, however their pharmacokinetic characteristics make prescribing complex. Thus it is imperative that general practitioners (GPs) are aware of specific treatments so as to maximise their benefits and minimise their pitfalls. This study explores GPs attitudes and experiences with prescribing NOACs in Ireland where, despite clear national prescribing guidelines advocating warfarin as first line therapy, the number of patients being prescribed NOACs for the first time is growing. RESULTS: Using primary data collected from GPs in Ireland the factors influencing the likelihood of a GP initiating a prescription for a NOAC are determined using a probit model. Results indicate 46% of the sample initiated NOAC prescriptions and GP practice size is a significant factor influencing this. Analysis revealed no difference regarding the sources of information considered important amongst GPs when prescribing new drugs. However, there were differences in which factors were considered important when prescribing anticoagulants between initiating and non-initiating NOAC prescribers. The results of this study suggest better utilisation of existing information and education tools for GPs prescribing NOACs and managing NOAC patients is imperative, to ensure the right anticoagulant is prescribed for the right patient at the right time. PMID- 30012206 TI - Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab. AB - BACKGROUND: Treatment of metastatic melanoma patients with immune checkpoint inhibitors is an important standard of care. Side effects are due to immune activation, can affect virtually all organ systems, and are occasionally severe. Although hematologic toxicity has been reported, we present a case of hemophagocytic lymphohistiocytosis (HLH) due to immune checkpoint inhibitor therapy. CASE PRESENTATION: A patient with metastatic melanoma was treated with one course of ipilimumab + nivolumab and presented 3 weeks later with severe anemia and hyperferritinemia. A bone marrow biopsy revealed necrotic tumor cells, infiltrating T cells, and hemophagocytosis. The patient was treated with high dose steroids; 12 months later, the patient remains off all therapy and in complete remission of both HLH and metastatic melanoma. CONCLUSIONS: The hemophagocytic syndromes are attributable to dysregulated immune activation and share pathophysiologic mechanisms with immune activation from checkpoint inhibitors. Increasing use of regimens that include immune checkpoint inhibition require vigilant monitoring for immune-activating side effects as they can occasionally be life threatening, as in this case of HLH. PMID- 30012205 TI - Production of amphiregulin and recovery from influenza is greater in males than females. AB - BACKGROUND: Amphiregulin (AREG) is an epidermal growth factor that is a significant mediator of tissue repair at mucosal sites, including in the lungs during influenza A virus (IAV) infection. Previous research illustrates that males of reproductive ages experience less severe disease and recover faster than females following infection with IAV. METHODS: Whether males and females differentially produce and utilize AREG for pulmonary repair after IAV infection was investigated using murine models on a C57BL/6 background and primary mouse and human epithelial cell culture systems. RESULTS: Following sublethal infection with 2009 H1N1 IAV, adult female mice experienced greater morbidity and pulmonary inflammation during the acute phase of infection as well as worse pulmonary function during the recovery phase of infection than males, despite having similar virus clearance kinetics. As compared with females, AREG expression was greater in the lungs of male mice as well as in primary respiratory epithelial cells derived from mouse and human male donors, in response to H1N1 IAVs. Internalization of the epidermal growth factor receptor (EGFR) was also greater in respiratory epithelial cells derived from male than female mice. IAV infection of Areg knock-out (Areg-/-) mice eliminated sex differences in IAV pathogenesis, with a more significant role for AREG in infection of male compared to female mice. Deletion of Areg had no effect on virus replication kinetics in either sex. Gonadectomy and treatment of either wild-type or Areg-/- males with testosterone improved the outcome of IAV as compared with their placebo-treated conspecifics. CONCLUSIONS: Taken together, these data show that elevated levels of testosterone and AREG, either independently or in combination, improve resilience (i.e., repair and recovery of damaged tissue) and contribute to better influenza outcomes in males compared with females. PMID- 30012207 TI - Determination of the binding affinities of Neisseria meningitidis serogroup W capsule polymerase with two nucleotide sugar substrates. AB - OBJECTIVE: Meningococcal meningitis is a public health burden. Immunization strategies have reduced global incidence of the disease. Glycoconjugate vaccines are the most effective type of vaccine to combat most causes of meningococcal meningitis. These vaccines contain capsular polysaccharide fragments from disease causing serogroups of Neisseria meningitidis that are chemically attached to a carrier protein. The enzymes responsible for capsular polysaccharide synthesis can serve as tools to make these critical vaccine components. One such enzyme is the N. meningitidis serogroup W capsule polymerase. This enzyme is responsible for creating the galactose-sialic acid containing capsular polysaccharide of this serogroup. Our aim in this study was to determine the binding affinities of nucleotide sugar donors CMP-sialic acid and UDP-galactose using a coupled transferase assay to inform future work to modulate polysaccharide synthesis by this enzyme. RESULTS: We determined a Km of 66.8 uM for CMP-sialic acid and a Km for UDP-galactose of 3.9 uM. These values are lower than reported values for other retaining galactosyltransferases and inverting sialyltransferases respectively. There were difficulties obtaining reliable data for galactosyltransferase activity. An alternate strategy is needed to assess kinetic parameters of the separate transferase activities for this enzyme. PMID- 30012208 TI - Protective roles of autophagy in retinal pigment epithelium under high glucose condition via regulating PINK1/Parkin pathway and BNIP3L. AB - BACKGROUND: Our study aimed to investigate the roles of autophagy against high glucose induced response in retinal pigment epithelium (ARPE-19 cells). METHODS: The morphological changes and reactive oxygen species (ROS) generation in ARPE-19 cells under high glucose treatment were respectively detected using the transmission electron microscopy and flow cytometry. The expression levels of Parkin, PINK1, BNIP3L, LC3-I and LC3-II in ARPE-19 cells received high glucose treatment were measured by western blot after pretreatment of carbonyl cyanide m chlorophenylhydrazone (CCCP), 3-methyladenine (3-MA), N-acetyl cysteine (NAC) or cyclosporin A (CsA) followed by high glucose treatment. RESULTS: ARPE-19 cells subjected to high glucose stress showed an obvious reduction in the LC3-I expression and significant increase in the number of autophagosomes, in the intracellular ROS level, and in the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). Pretreatment with CCCP significantly reduced the LC3-I expression and increased the expression levels of Parkin, PINK1, BNIP3L and LC3 II (p < 0.05). ARPE-19 cells pretreated with CsA under high glucose stress showed markedly down-regulated expressions of Parkin, PINK1 and BNIP3L compared with the cells treated with high glucose (p < 0.05). Pretreatment of ARPE-19 cells with NAC or 3-MA under high glucose stress resulted in a marked reduction in the expression levels of PINK1, BNIP3L and LC3-II (p < 0.05). Meanwhile, the expression level of Parkin in the ARPE-19 cells pretreated with NAC under high glucose stress was comparable with that in the control cells. CONCLUSION: Autophagy might have protective roles against high glucose induced injury in ARPE19 cells via regulating PINK1/Parkin pathway and BNIP3L. PMID- 30012209 TI - Sick sinus syndrome associated with anti-programmed cell death-1. AB - BACKGROUND: Use of anti-programmed cell death-1 (anti-PD-1) has been successful in treating many types of cancers. Despite its promising efficacy, immune-related adverse events are still a major concern. Immune-related cardiotoxicity, which is rare but fatal, has recently become a focus of attention. Cardiotoxicities including myocarditis, cardiomyopathy, cardiac fibrosis, heart block and cardiac arrest have been reported. Of these toxicities, myocarditis is often accompanied by dysrhythmia. The presentation of sick sinus syndrome as an immune-related adverse event has not yet been reported. Here, we reported the first case of sick sinus syndrome, a rare toxicity induced by anti-PD-1. CASE PRESENTATION: A 42 year-old male patient who had metastatic hepatocellular carcinoma failed treatment with sorafenib. Pembrolizumab at a fixed dose of 100 mg every three weeks was given. His heart rate gradually slowed down and he presented sick sinus syndrome with a lowest heart rate of 38 bpm after six cycles of pembrolizumab. He denied chest tightness, cold sweating, palpitation and dyspnea. Lab data including cardiac enzyme, electrolytes and thyroid function were all within a normal range. Simultaneously, he complained of fatigue, dizziness and anorexia with hypotension. Lab data revealed low cortisol and ACTH levels. Anti-PD-1 induced adrenal insufficiency was suspected. Low-dose cortisone (12.5 mg) was prescribed, and the patient's symptoms, hypotension and sick sinus syndrome showed rapid improvement. Cortisone was gradually titrated and discontinued three weeks later. His sick sinus syndrome did not relapse and the cortisol and ACTH level returned to normal. CONCLUSIONS: Sick sinus syndrome caused by anti-PD-1 treatment is a rare adverse event. With the development of sick sinus syndrome, myocarditis should be the first differential diagnosis because of its lethality. From this case, we learned that sick sinus syndrome may be a presentation of immune- or adrenal insufficiency-mediated sinus node dysfunction, both could be reversed with a glucocorticoid supplement. PMID- 30012211 TI - Extracorporeal membrane oxygenation support in a newborn with lower urinary tract obstruction and pulmonary hypoplasia: a case report. AB - BACKGROUND: Survival of neonates with intrauterine renal insufficiency and oligo- or anhydramnios correlates with the severity of secondary pulmonary hypoplasia. Early prenatal diagnosis together with repetitive amnioinfusions and modern intensive care treatment have improved the prognosis of these neonates. Extracorporeal membrane oxygenation is an established treatment option, mainly applied to neonates with pulmonary hypoplasia caused by congenital diaphragmatic hernia. However, a few case reports of extracorporeal membrane oxygenation in neonates with lower urinary tract obstruction have been published. CASE PRESENTATION: We describe a case of a Caucasian male infant with prenatally diagnosed lower urinary tract obstruction and secondary pulmonary hypoplasia who was delivered spontaneously at 36 + 2 weeks of gestation. Venovenous extracorporeal membrane oxygenation was initiated on the first day of life for severe respiratory failure and consecutive hypoxemia despite treatment with inhaled nitric oxide and high-frequency oscillation. The patient was supported by extracorporeal membrane oxygenation for 10 days and extubated 6 weeks later. Hemofiltration was required on the second day of life because of renal insufficiency and was later replaced by peritoneal dialysis. The child was discharged after 4 months with nasal high-flow mild oxygen therapy and peritoneal dialysis. CONCLUSION: Neonatal extracorporeal membrane oxygenation support is a possible treatment option for neonates with lower urinary tract obstruction and pulmonary hypoplasia. PMID- 30012210 TI - The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). AB - Lung cancer is the leading cause of cancer-related mortality worldwide, with non small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field. PMID- 30012212 TI - MicroRNA expression profiling of goat peripheral blood mononuclear cells in response to peste des petits ruminants virus infection. AB - Peste des petits ruminants virus (PPRV) belongs to the genus Morbillivirus that causes an acute and highly contagious disease in goats and sheep. Virus infection can trigger the change in the cellular microRNA (miRNA) expression profile, which play important post-transcriptional regulatory roles in gene expression and can greatly influence viral replication and pathogenesis. Here, we employed deep sequencing technology to determine cellular miRNA expression profile in goat peripheral blood mononuclear cells (PBMC) infected with Nigeria 75/1 vaccine virus, a widely used vaccine strain for mass vaccination programs against Peste des petits ruminants. Expression analysis demonstrated that PPRV infection can elicit 316 significantly differentially expressed (DE) miRNA including 103 known and 213 novel miRNA candidates in infected PBMC at 24 hours post-infection (hpi) as compared with a mock control. Target prediction and functional analysis of these DEmiRNA revealed significant enrichment for several signaling pathways including TLR signaling pathways, PI3K-Akt, endocytosis, viral carcinogenesis, and JAK-STAT signaling pathways. This study provides a valuable basis for further investigation of the roles of miRNA in PPRV replication and pathogenesis. PMID- 30012213 TI - A challenging coexistence of central diabetes insipidus and cerebral salt wasting syndrome: a case report. AB - BACKGROUND: Combined central diabetes insipidus and cerebral salt wasting syndrome is a rare clinical finding. However, when this happens, mortality is high due to delayed diagnosis and/or inadequate treatment. CASE PRESENTATION: A 42-year-old white man was referred to neurosurgery due to a non-functional pituitary macroadenoma. He underwent a partial resection of the tumor on July 2, 2015. On the day following surgery he presented polyuria with sodium 149 mEq/L, plasma osmolality 301 mOsm/kg, and urine osmolality 293 mOsm/kg. He started nasal desmopressin 0.05 mg/day with good response. He was already on dexamethasone 4 mg and levothyroxine 75 mcg due to hypopituitarism after surgery. On July 9 he became confused. Cerebral computed tomography was performed with no significant changes. His natremia dropped to 128 mEq/L with development of polyuria despite maintenance of desmopressin dose. His hemoglobin and hematocrit rose from 9.1 g/L to 11.6 g/L and 27.5 to 32.5, respectively. His thyroid function was normal and he was on hydrocortisone 30 mg/day. At 12 p.m. 150 mg/hydrocortisone infusion was initiated, but sodium did not increase. Plasma and urine osmolality were 264 mOsm/kg and 679 mOsm/kg, respectively. At 4 p.m. hydrocortisone was increased and hypertonic saline replacement started. Two hours later he was dehydrated with polyuria and vomiting, and natremia of 124 mEq/L. Hyponatremia was very resistant to treatment despite hypertonic saline replacement, hence desmopressin was suspended. The following day, urine spot analysis showed that natriuresis was 63 mEq/L with serum sodium 132 mEq/L. This was interpreted as a cerebral salt wasting syndrome and control was achieved with aggressive hypertonic saline replacements and fludrocortisone 0.1 mg/three times a day. CONCLUSIONS: We present a rare case of a patient with diabetes insipidus and cerebral salt wasting syndrome, who was successfully treated. Hyponatremia in a patient with diabetes insipidus may erroneously be interpreted as inadequate diabetes insipidus control or as syndrome of inappropriate antidiuretic hormone secretion, leading to therapeutic errors. Thus, all clinical and analytical data should be evaluated together for early and correct diagnosis. PMID- 30012214 TI - Point-of-care umbilical arterial lactate and newborn outcomes in a low resource setting: cohort study. AB - OBJECTIVE: Birth asphyxia contributes substantially to the burden of intrapartum stillbirth and neonatal mortality in resource limited countries. We investigated clinical correlates and neonatal outcomes of lactate analysis of umbilical arterial cord blood in a large referral maternity unit in Malawi using a point-of care test (Lactate Xpress, Nova Biomedical, Runcorn, UK) and examined maternal and neonatal characteristics and outcomes. RESULTS: There were 389 live births and 12 intrapartum stillbirths during the study. The median umbilical arterial lactate concentration was 3.4 mmol/L (interquartile range 2.6-4.9). Umbilical arterial lactate concentrations among the 45 babies admitted for special neonatal care were above 5 mmol/L in 16/45 (36%) of cases, with no fatality below 13 mmol/L. A positive malaria rapid diagnostic test was associated with hyperlactatemia (p < 0.05). In receiver-operator characteristic (ROC) analysis using a lactate cutoff of 5 mmol/L, areas under the curve were 0.72 (95% CI 0.66 0.79) and 0.64 (95% CI 0.58-0.69) for the Apgar score at 1 and 5 min respectively. This approach can identify safely those newborns that are unlikely to require additional monitoring. Scale-up implementation research in low resource country referral units is needed. The influence of malaria on neonatal hyperlactatemia requires further exploration. PMID- 30012215 TI - Imprint cytology: a useful screening test for diagnosis of Helicobacter pylori in resource poor settings. AB - OBJECTIVE: The study aimed to compare the usefulness of two staining methods for imprint cytology for diagnosis of Helicobacter pylori infection. Gastric biopsy specimens (from dyspeptic patients attending routine upper gastrointestinal endoscopy) were placed on glass slides to obtain imprints. The imprints were stained with Toluidine blue and Giemsa stains separately and observed under *400 magnification using a light microscope. Imprinted biopsies were sectioned and stained with H & E stain and Giemsa stain for histological analysis. Diagnosis of H. pylori infection in both imprint and histological sections were confirmed by a consultant pathologist. The sensitivity, specificity, positive predictive value and negative predictive value of each stain were calculated and benchmarked against histological diagnosis. RESULTS: Of the 55 dyspeptic patients enrolled in the study, 5 were positive for H. pylori by Toluidine blue stain and 4 by Giemsa stain. The sensitivity of Toluidine blue stain (57.1%) was higher than Giemsa stain (42.9%) while the specificity of both stains was equal (97.9%). Giemsa stain gave a better discrimination for identification of H. pylori bacteria among the mucosal background. Imprint cytology is a rapid, simple and cost effective diagnosis method that can supplement histological diagnosis. PMID- 30012216 TI - Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. AB - BACKGROUND: Previous studies have suggested that elevated neutrophil-to lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors. METHODS: This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves. RESULTS: In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60-5.08; p < 0.0001) and LDH (HR = 2.51; 95% CI 1.36-4.64; p < 0.0001) maintained a significant association with OS in multivariate analysis. Patients with baseline NLR >=5 had significantly worse OS and PFS than patients with NLR < 5, as did patients with baseline dNLR >=3 versus < 3. Optimal cut-off values were >= 4.7 for NLR and >= 3.8 for dNLR. Using this >=4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR< 3.8 was also associated with better OS and PFS. CONCLUSION: Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma. PMID- 30012217 TI - Norwegian translation, cultural adaption and testing of the Person-centred Practice Inventory - Staff (PCPI-S). AB - BACKGROUND: Person-centred health care has widespread recognition, but there are few instruments aimed at measuring the provision of person-centred practice among health care professionals across a range of settings. The Person-centred Practice Inventory - Staff (PCPI-S) is a new instrument for this purpose, theoretically aligned with McCormack & McCance's person-centred framework, which has been translated and culturally adapted into Norwegian. METHODS: The study used a two stage research design involving: translation and cultural adaption of the PCPI-S from English to Norwegian language (phase 1), and a quantitative cross sectional survey following psychometric evaluation (phase 2). Confirmatory factor analysis was used to examine the theoretical measurement model. RESULTS: The translation and cultural adaption was carried out according to ten recommend steps. Discrepancies were addressed and revised by all translators until consensus was reached on a reconciled version of the translation. A sample of 258 health care staff participated in the survey. The model fit statistics were overall positive; the model requires minor modifications and these are mostly confined to correlated errors. CONCLUSIONS: The translation and cultural adaption process of the PCPI-S from English to Norwegian language was a demanding process in order to retain the conceptual meanings of the original instrument. Overall, the psychometric properties of the tool were acceptable, but testing on a larger sample size is recommended. PMID- 30012218 TI - Medical tourism and national health care systems: an institutionalist research agenda. AB - Although a growing body of literature has emerged to study medical tourism and address the policy challenges it creates for national health care systems, the comparative scholarship on the topic remains too limited in scope. In this article, we draw on the existing literature to discuss a comparative research agenda on medical tourism that stresses the multifaceted relationship between medical tourism and the institutional characteristics of national health care systems. On the one hand, we claim that such characteristics shape the demand for medical tourism in each country. On the other hand, the institutional characteristics of each national health care system can shape the very nature of the impact of medical tourism on that particular country. Using the examples of Canada and the United States, this article formulates a systematic institutionalist research agenda to explore these two related sides of the medical tourism-health care system nexus with a view to informing future policy work in this field. PMID- 30012219 TI - Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy. AB - BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder. PMID- 30012221 TI - ER stress regulates alkaline phosphatase gene expression in vascular smooth muscle cells via an ATF4-dependent mechanism. AB - OBJECTIVE: Vascular calcification is the deposition of hydroxyapatite crystals in the blood vessel wall. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) plays a key role in this process. Increased expression of alkaline phosphatase (ALP) occurs in some in vitro models of VSMC calcification and is thought to be crucial for mineralization, however, little is known about the transcriptional regulation of ALP in VSMCs. Recently, ALP upregulation was shown to coincide with endoplasmic reticulum (ER) stress-mediated vascular calcification, specifically with expression of the transcription factor ATF4. As no direct links between ALP expression and ER stress have previously been demonstrated in VSMCs, the aim of this study was to investigate whether ATF4 interacts directly with the ALP promoter. RESULTS: The present study shows that ALP mRNA and activity were significantly increased by ER stress treatment of human primary VSMCs in vitro and that this was ATF4-dependent. Bioinformatics analysis predicted two ATF4 binding sites in ER-stress responsive regions of the ALP promoter (- 3631 to - 2048 bp from the first intron). However, we found that ATF4 does not bind within this fragment of the ALP promoter region. PMID- 30012222 TI - In-home assessment of either topical fluralaner or topical selamectin for flea control in naturally infested cats in West Central Florida, USA. AB - BACKGROUND: An investigation was conducted in West Central Florida, USA to evaluate the efficacy of either topically applied fluralaner or topically applied selamectin to control flea infestations, minimize dermatologic lesions and reduce pruritus in naturally flea infested cats over a 12-week period. When dogs were present in the households, they were treated with either oral fluralaner (if household cats were treated with topical fluralaner) or oral sarolaner (if household cats were treated with topical selamectin). METHODS: Thirty-one cats in 20 homes were treated once with fluralaner topical solution on day 0 and 18 dogs in these homes were administered a single fluralaner chewable. Twenty-nine cats in 18 homes were treated once monthly with a selamectin topical solution for 3 treatments and 13 dogs in these same homes were treated once monthly for 3 treatments with a sarolaner chewable. Fleas on cats were counted by flea combing, fleas on dogs were estimated using visual area counts and fleas in the indoor premises were assessed using intermittent-light flea traps. Blinded-assessments of feline dermatologic lesions were conducted monthly and pruritus severity was evaluated by pet owners. RESULTS: A single topical application of fluralaner reduced flea populations on cats by 96.6% within 7 days and by 100% at 12 weeks post-treatment. This efficacy was significantly greater than selamectin treatment where single topical application reduced flea populations on cats by 79.4% within 7 days of initial treatment and 3 consecutive monthly treatments reduced flea populations by 91.3% at the end of 12 weeks. At the end of the 12-week study, all fluralaner-treated cats were flea-free and this was significantly greater than the 38.5% of selamectin treated cats that were flea-free. At the end of the study, fleas were completely eradicated (from cats, dogs and homes) in 95.0% of fluralaner treatment group homes, significantly greater than the 31.3% of selamectin/sarolaner treatment group homes with complete flea eradication. Owner reported cat pruritus was reduced similarly in both treatment groups. Significant improvements in dermatologic lesion scores were achieved by day 30 in fluralaner treated cats and by day 60 in selamectin treated cats. CONCLUSIONS: An in-home investigation in subtropical Florida found that 1 application of topical fluralaner eliminated flea infestations on cats and in homes significantly more effectively than 3 consecutive monthly doses of selamectin. PMID- 30012224 TI - Dynamic transmission modelling to address infant pneumococcal conjugate vaccine schedule modifications in the UK. AB - The 13-valent pneumococcal conjugate vaccine (PCV) has been part of routine immunisation in a 2 + 1 schedule (two primary infant doses and one booster during the second year of life) in the UK since 2010. Recently, the UK's Joint Committee on Vaccination and Immunisation recommended changing to a 1 + 1 schedule while conceding that this will increase disease burden; however, uncertainty remains on how much pneumococcal burden - including invasive pneumococcal disease (IPD) and non-invasive disease - will increase. We built a dynamic transmission model to investigate this question. The model predicted that a 1 + 1 schedule would incur 8777-27 807 additional cases of disease and 241-743 more deaths over 5 years. Serotype 19A caused 55-71% of incremental IPD cases. Scenario analyses showed that booster dose adherence, effectiveness against carriage and waning in a 1 + 1 schedule had the most influence on resurgence of disease. Based on the model assumptions, switching to a 1 + 1 schedule will substantially increase disease burden. The results likely are conservative since they are based on relatively low vaccine-type pneumococcal transmission, a paradigm that has been called into question by data demonstrating an increase of IPD due to several vaccine serotypes during the last surveillance year available. PMID- 30012225 TI - The geography of parasite discovery across taxa and over time. AB - We need reliable data on the spatial distribution of parasites in order to achieve an inventory of global parasite biodiversity and establish robust conservation initiatives based on regional disease risk. This requires an integrated and spatially consistent effort toward the discovery of new parasite species. Using a large and representative dataset on the geographical coordinates where 4943 helminth species were first discovered, we first test whether the geographical distribution of parasite species reports is spatially congruent across helminth higher taxa; i.e. whether areas, where many trematodes are found, are also areas where many nematodes or cestodes have been discovered. Second, we test whether the global geographical distribution of new helminth species reports has changed significantly over time, i.e. across the last few decades. After accounting for spatial autocorrelation in the data, we find no strong statistical support for either of the patterns we investigated. Overall, our results indicate that helminth species discoveries are both spatially incongruent among higher taxa of helminths, and inconsistent over time. These findings suggest that the global parasite discovery effort is inefficient, spatially biased and subject to idiosyncrasies. Coordinated biodiscovery programmes, involving research teams with expertise in multiple taxonomic groups, seem the best approach to remedy these issues. PMID- 30012223 TI - Assessment of cross-protection induced by a bluetongue virus (BTV) serotype 8 vaccine towards other BTV serotypes in experimental conditions. AB - Bluetongue disease is caused by bluetongue virus (BTV) and BTV serotype 8 (BTV8) caused great economic damage in Europe during the last decade. From 1998 to 2007, in addition to BTV8, Europe had to face the emergence of BTV1, 2, 4, 9, and 16, spreading in countries where the virus has never been detected before. These unprecedented outbreaks trigger the need to evaluate and compare the clinical, virological and serological features of the European BTV serotypes in the local epidemiological context. In this study groups of calves were infected with one of the following European BTV serotypes, namely BTV1, 2, 4, 9 and 16. For each tested serotype, two groups of three male Holstein calves were used: one group vaccinated against BTV8, the other non-vaccinated. Clinical signs were quantified, viral RNA was detected in blood and organs and serological relationship was assessed. Calves were euthanized 35 days post-infection and necropsied. Most of the infected animals showed mild clinical signs. A partial serological cross reactivity has been reported between BTV8 and BTV4, and between BTV1 and BTV8. BTV2 and BTV4 viral RNA only reached low levels in blood, when compared to other serotypes, whereas in vitro growth assays could not highlight significant differences. Altogether the results of this study support the hypothesis of higher adaptation of some BTV strains to specific hosts, in this case calves. Furthermore, cross-protection resulting from a prior vaccination with BTV8 was highlighted based on cross-neutralization. However, the development of neutralizing antibodies is probably not totally explaining the mild protection induced by the heterologous vaccination. PMID- 30012226 TI - Special Report: WADEM Climate Change Position Statement. AB - The World Association for Disaster and Emergency Medicine (WADEM; Madison, Wisconsin USA) is a multi-disciplinary professional association whose mission is the global improvement of prehospital and emergency health care, public health, and disaster health and preparedness. In April 2017, the biennial general meeting of the World Congress for Disaster and Emergency Medicine (WCDEM) endorsed the WADEM Climate Change Position Statement, which was subsequently published in Prehospital and Disaster Medicine in July 2017. This special report examines literature used and reviews the process of development of this Position Statement as a product of WADEM.Cuthbertson J, Archer F, Robertson A. Special report: WADEM climate change position statement. Prehosp Disaster Med. 2018;33(4):428-431. PMID- 30012228 TI - Evaluation de Marche vers le futur, un programme novateur de prevention des chutes offert par videoconference. AB - ABSTRACTSeveral fall prevention programs have been implemented to reduce falls among seniors. In some rural areas or in French-speaking minority communities, the availability of such programs is limited. The objectives of this paper are to: (a) describe the Fall Prevention Program Marche vers le futur, offered in French, by videoconference; and (b) present the results of the evaluation of the program objectives. Results demonstrate that participants have improved their physical abilities, gained knowledge, adopted new behaviors and lifestyle habits. In short, Marche vers le futur reduces fall risk factors in a manner equal or superior to other programs. Marche vers le futur has made possible the provision of services in French in communities where availability of French-language resources is very limited, therefore fostering equity in access to health services. PMID- 30012227 TI - Depression, violence and cortisol awakening response: a 3-year longitudinal study in adolescents. AB - BACKGROUND: Despite evidence of links between depression and violent outcomes, potential moderators of this association remain unknown. The current study tested whether a biological marker, cortisol, moderated this association in a longitudinal sample of adolescents. METHODS: Participants were 358 Dutch adolescents (205 boys) with a mean age of 15 years at the first measurement. Depressive symptoms, the cortisol awakening response (CAR) and violent outcomes were measured annually across 3 years. The CAR was assessed by two measures: waking cortisol activity (CAR area under the curve ground) and waking cortisol reactivity (CAR area under the curve increase). Within-individual regression models were adopted to test the interaction effects between depressive symptoms and CAR on violent outcomes, which accounted for all time-invariant factors such as genetic factors and early environments. We additionally adjusted for time varying factors including alcohol drinking, substance use and stressful life events. RESULTS: In this community sample, 24% of adolescents perpetrated violent behaviours over 3 years. We found that CAR moderated the effects of depressive symptoms on adolescent violent outcomes (betas ranged from -0.12 to -0.28). In particular, when the CAR was low, depressive symptoms were positively associated with violent outcomes in within-individual models, whereas the associations were reversed when the CAR was high. CONCLUSIONS: Our findings suggest that the CAR should be investigated further as a potential biological marker for violence in adolescents with high levels of depressive symptoms. PMID- 30012229 TI - Carbon Monoxide Poisoning in Miami-Dade County Following Hurricane Irma in 2017. AB - OBJECTIVE: The Florida Department of Health in Miami-Dade County (DOH-Miami-Dade) investigated 106 reported carbon monoxide (CO) exposures over a 9-day timeframe after Hurricane Irma. This report evaluates risk factors for CO poisoning and the importance of heightened surveillance following natural disasters. METHODS: Data on CO poisoning cases from September 9 to 18, 2017 were extracted from Merlin, the Florida Department of Health Surveillance System. Medical records were obtained and follow-up interviews were conducted to collect data on the confirmed CO poisoning cases. Data were analyzed using SAS v9.4. RESULTS: Ninety-one of the 106 people exposed to CO met the case definition for CO poisoning: 64 confirmed, 7 probable, and 20 suspect cases. Eighty-eight percent of the affected individuals were evaluated in emergency departments and 11.7% received hyperbaric oxygen treatment. The most frequently reported symptoms included headache (53.3%), dizziness (50.7%), and nausea (46.7%). Three patients expired due to their exposure to CO. CONCLUSIONS: Post Hurricane Irma, the DOH-Miami-Dade investigated numerous cases for CO exposure. By understanding who is most likely to be impacted by CO and the impact of generators' location on people's health, education efforts can be tailored to the population most at risk and further CO exposures and related mortalities following natural disasters can be reduced. (Disaster Med Public Health Preparedness. 2018;page 1 of 3). PMID- 30012230 TI - Was that my name? Infants' listening in conversational multi-talker backgrounds. AB - This study tested infants' ability to segregate target speech from a background of ecologically valid multi-talker speech at a 10 dB SNR. Using the Headturn Preference Procedure, 72 English-learning 5-, 9-, and 12-month-old monolinguals were tested on their ability to detect and perceive their own name. At all three ages infants were able to detect the presence of the target speech, but only at 9 months did they show sensitivity to the phonetic details that distinguished their own name from other names. These results extend previous findings on infants' speech perception in noise to more naturalistic forms of background speech. PMID- 30012220 TI - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. AB - BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6 associated conduction changes. PMID- 30012231 TI - Diversity of Cryptosporidium in common voles and description of Cryptosporidium alticolis sp. n. and Cryptosporidium microti sp. n. (Apicomplexa: Cryptosporidiidae). AB - Fecal samples from wild-caught common voles (n = 328) from 16 locations in the Czech Republic were screened for Cryptosporidium by microscopy and PCR/sequencing at loci coding small-subunit rRNA, Cryptosporidium oocyst wall protein, actin and 70 kDa heat shock protein. Cryptosporidium infections were detected in 74 voles (22.6%). Rates of infection did not differ between males and females nor between juveniles and adults. Phylogenetic analysis revealed the presence of eight Cryptosporidium species/genotypes including two new species, C. alticolis and C. microti. These species from wild-caught common voles were able to infect common and meadow voles under experimental conditions, with a prepatent period of 3-5 days post-infection (DPI), but they were not infectious for various other rodents or chickens. Meadow voles lost infection earlier than common voles (11-14 vs 13 16 DPI) and had significantly lower infection intensity. Cryptosporidium alticolis infects the anterior small intestine and has larger oocysts (5.4 * 4.9 um), whereas C. microti infects the large intestine and has smaller oocysts (4.3 * 4.1 um). None of the rodents developed clinical signs of infection. Genetic and biological data support the establishment of C. alticolis and C. microti as separate species of the genus Cryptosporidium. PMID- 30012232 TI - Nurse practitioner consultations in primary health care: a case study-based survey of patients' pre-consultation expectations, and post-consultation satisfaction and enablement. AB - BACKGROUND: Research has not yet fully investigated links to consultation duration, patient expectations, satisfaction, and enablement in nurse practitioner consultations. This study was developed to address some of these research gaps in nurse practitioner consultations, particularly with a focus on expectations, satisfaction, and enablement.AimTo explore the influence of pre consultation expectations, and consultation time length durations on patient satisfaction and enablement in nurse practitioner consultations in primary health care. DESIGN: Survey component of a larger convergent parallel mixed methods case study designed to conjointly investigate the communication processes, social interactions, and measured outcomes of nurse practitioner consultations. The survey element of the case study focusses on investigating patients' pre consultation expectations and post-consultation patient satisfaction and enablement. METHODS: A questionnaire measuring pre-consultation expectations, and post-consultation satisfaction and enablement, completed by a convenience sample of 71 adults consulting with nurse practitioners at a general practice clinic. Initial fieldwork took place in September 2011 to November 2012, with subsequent follow-up fieldwork in October 2016. RESULTS: Respondents were highly satisfied with their consultations and expressed significantly higher levels of enablement than have been seen in previous studies of enablement with other types of clinicians (P=0.003). A significant, small to moderate, positive correlation of 0.427 (P=0.005) between general satisfaction and enablement was noted. No significant correlation was seen between consultation time lengths and satisfaction or enablement. CONCLUSION: Higher levels of patient enablement and satisfaction are not necessarily determined by the time lengths of consultations, and how consultations are conducted may be more important than their time lengths for optimising patient satisfaction and enablement. PMID- 30012233 TI - Acceptance and Commitment Therapy for Psychosis and Trauma: Investigating Links between Trauma Severity, Attachment and Outcome. AB - BACKGROUND: Although Acceptance and Commitment Therapy (ACT) may be effective for individuals with psychosis and a history of childhood trauma, little is known about predictors of treatment response among such patients. AIMS: The current study examined: (1) whether severity of trauma predicted treatment response, and (2) profiles of patients with regard to their responses to treatment. METHOD: Fifty participants with psychosis and childhood trauma history were recruited and randomized to take part in either eight sessions of group-based ACT, or to be on a waiting list for the ACT group (i.e. treatment as usual group). The entire sample was used for the first part of the analyses (aim 1), whereas subsequent subsample analyses used only the treatment group (n = 30 for aim 2). RESULTS: It was found that trauma severity did not moderate the effectiveness of ACT on symptom severity, participants' ability to regulate their emotional reactions, or treatment compliance with regard to help-seeking. In addition, among those receiving ACT, the results revealed three distinct and clinically relevant change profiles. Avoidant attachment style and number of sessions attended were predictive of belonging to the different clusters or profiles. Patients in the profile representing the least amount of clinical change attended an average of two sessions less than those in the other change profiles. CONCLUSION: ACT offered in a group format appears to be a promising treatment for those with psychosis and history of trauma regardless of trauma severity. Given the brevity of the intervention, patients should be encouraged to attend each session to obtain maximum benefit. PMID- 30012234 TI - Getting a balance between generalisation and specialisation in mental health services: a defence of general services. AB - Mental health services in the UK National Health Service have evolved to include primary-care generalist, secondary-care generalist and secondary-care specialist services. We argue that there continues to be an important role for the secondary care generalists as they minimise interfaces, can live with diagnostic uncertainty and support continuity of care. The lack of commissioning and clinical boundaries in secondary-care generalist services can undermine their feasibility, leading to difficulties recruiting and retaining staff. There is a risk of a polo-mint service, where the specialist services on the edge are well resourced, but the secondary-care generalist services taking the greatest burden struggle to recruit and retain clinicians. We need to establish equity in resources and expectations between generalist and specialist mental health services.Declaration of interestNone. PMID- 30012235 TI - Utilization of Mobile Integrated Health Providers During a Flood Disaster in South Carolina (USA). AB - As health care systems in the United States have become pressured to provide greater value, they have embraced the adoption of innovative population health solutions. One of these initiatives utilizes prehospital personnel in the community as an extension of the traditional health care system. These programs have been labeled as Community Paramedicine (CP) and Mobile Integrated Health (MIH). While variation exists amongst these programs, generally efforts are targeted at individuals with high rates of health care utilization. By assisting with chronic disease management and addressing the social determinants of health care, these programs have been effective in decreasing Emergency Medical Services (EMS) utilization, emergency department visits, and hospital admissions for enrolled patients.The actual training, roles, and structure of these programs vary according to state oversight and community needs, and while numerous reports describe the novel role these teams play in population health, their utilization during a disaster response has not been previously described. This report describes a major flooding event in October 2015 in Columbia, South Carolina (USA). While typical disaster mitigation and response efforts were employed, it became clear during the response that the MIH providers were well-equipped to assist with unique patient and public health needs. Given their already well established connections with various community health providers and social assistance resources, the MIH team was able to reconnect patients with lost medications and durable medical equipment, connect patients with alternative housing options, and arrange access to outpatient resources for management of chronic illness.Mobile integrated health teams are a potentially effective resource in a disaster response, given their connections with a variety of community resources along with a unique combination of training in both disease management and social determinants of health. As roles for these providers are more clearly defined and training curricula become more developed, there appears to be a unique role for these providers in mitigating morbidity and decreasing costs in the post-disaster response. Training in basic disaster response needs should be incorporated into the curricula and community disaster planning should identify how these providers may be able to benefit their local communities.Gainey CE, Brown HA, Gerard WC. Utilization of mobile integrated health providers during a flood disaster in South Carolina (USA). Prehosp Disaster Med. 2018;33(4):432-435. PMID- 30012236 TI - Genetic parameters of milk fatty acid profile in sheep: comparison between gas chromatographic measurements and Fourier-transform IR spectroscopy predictions. AB - Fatty acid (FA) composition is a key component of sheep milk nutritional quality. However, breeding for FA composition in dairy sheep is hampered by the logistic and phenotyping costs. This study was aimed at estimating genetic parameters for sheep milk FA and to test the feasibility of their routine measurement by using Fourier-transform IR (FTIR) spectroscopy. Milk FA composition of 989 Sarda ewes farmed in 48 flocks was measured by gas chromatography (FAGC). Moreover, FTIR spectrum was collected for each sample, and it was used to predict FA composition (FAFTIR) by partial least squares regression: 700 ewes were used for estimating model parameters, whereas the remaining 289 animals were used to validate the model. One hundred replicates were performed by randomly assigning animals to estimation and validation data set, respectively. Variance components for both measured and predicted traits were estimated with an animal model that included the fixed effects of parity, days in milking interval, lambing month, province, altitude of flock location, the random effects of flock-test-date and animal genetic additive. Genetic correlations among FAGC, and between corresponding FAGC and FAFTIR were estimated by bivariate analysis. Coefficients of determination between FAGC and FAFTIR ranged from moderate (about 0.50 for odd- and branched chain FA) to high (about 0.90 for de novo FA) values. Low-to-moderate heritabilities were observed for individual FA (ranging from 0.01 to 0.47). The largest value was observed for GC measured C16:0. Low-to-moderate heritabilities were estimated for FA groups. In most of cases, heritabilites were slightly larger for FAGC than FAFTIR. Estimates of genetic correlations among FAGC showed a large variability in magnitude and sign. The genetic correlation between FAFTIR and FAGC was higher than 60% for all investigated traits. Results of the present study confirm the existence of genetic variability of the FA composition in sheep and suggest the feasibility of using FAFTIR as proxies for these traits in large scale breeding programs. PMID- 30012237 TI - Social care: an essential aspect of mental health rehabilitation services. AB - This study is aimed at the importance of social care in rehabilitation. A brief overview of the social care theme is used as the methodology. There is a tension in mental health care between biological and psychological treatments that focus on deficits at the individual level (symptoms, disabilities) and social interventions that try to address local inequalities and barriers in order to improve access for service users to ordinary housing, employment and leisure opportunities. The history of mental health care tells us that social care is often underfunded and too easily dismissed as not the business of health care. But too much emphasis on a health model of individual deficits is a slippery slope to institutionalisation by way of therapeutic nihilism. Rehabilitation services follow the biopsychosocial model but with a shift in emphasis, recognising the vital role played by social interventions in improving the functional outcomes that matter to service users including access to housing, occupation, leisure facilities and the support of family and friends. In conclusion, rehabilitation is framed within a model of personal recovery in which the target of intervention is to boost hope and help the individual find a meaning to life, living well regardless of enduring symptoms. PMID- 30012238 TI - Disaster Exercises to Prepare Hospitals for Mass-Casualty Incidents: Does it Contribute to Preparedness or is it Ritualism? AB - : IntroductionThe central question this study sought to answer was whether the team members of Strategic Crisis Teams (SCTs) participating in mass-casualty incident (MCI) exercises in the Netherlands learn from their participation. METHODS: Evaluation reports of exercises that took place at two different times were collected and analyzed against a theoretical model with several dimensions, looking at both the quality of the evaluation methodology (three criteria: objectives described, link between objective and items for improvement, and data collection method) and the learning effect of the exercise (one criterion: the change in number of items for improvement). RESULTS: Of all 32 evaluation reports, 81% described exercise objectives; 30% of the items for improvement in the reports were linked to these objectives, and 22% of the 32 evaluation reports used a structured template to describe the items for improvement. In six evaluation categories, the number of items for improvement increased between the first (T1) and the last (T2) evaluation report submitted by hospitals. The number of items remained equal for two evaluation categories and decreased in six evaluation categories. CONCLUSION: The evaluation reports do not support the ideal-typical disaster exercise process. The authors could not establish that team members participating in MCI exercises in the Netherlands learn from their participation. More time and effort must be spent on the development of a validated evaluation system for these simulations, and more research into the role of the evaluator is needed.Verheul MLMI, Duckers MLA, Visser BB, Beerens RJJ, Bierens JJLM. Disaster exercises to prepare hospitals for mass-casualty incidents: does it contribute to preparedness or is it ritualism? Prehosp Disaster Med. 2018;33(4):387-393. PMID- 30012239 TI - Lung Lobe Torsion in an Adult Male Common Marmoset (Callithrix jacchus). AB - A 6-y-old, intact, pair-housed male common marmoset (Callithrix jacchus) presented with acute onset dyspnea and tachypnea immediately after sedation with alfaxalone; a history of gradual weight loss initiated the examination under sedation. Thoracic radiographs revealed significant right-lung consolidation, with a vesicular gas pattern in the right caudodorsal lung field, pleural effusion, and dorsal displacement of the heart. The marmoset was euthanized due to his unstable condition and poor prognosis. At necropsy, the cranial and middle lobes of the right lung were homogenously dark red-brown, enlarged, edematous, and twisted around the longitudinal axis at the hilus. The left lung lobes were pale pink and slightly edematous. In light of the clinical and gross necropsy findings, acute torsion of the right cranial and middle lung lobes was diagnosed. Predisposing conditions for lung lobe torsion include trauma, neoplasia, pulmonary disease, previous thoracic surgery, and diaphragmatic hernia, but none of these applied to this case. Initial therapy for lung lobe torsion is to stabilize the patient and treat for underlying conditions, with prompt surgical resection as the treatment of choice. To our knowledge, this report is the first description of lung lobe torsion in an experimentally unmanipulated New World NHP. PMID- 30012240 TI - Effects of 3 Rodent Beddings on Biochemical Measures in Rats and Mice. AB - Components of bedding might interact with experimental treatments and affect the outcome of various experiments. Here we studied the biochemical effects of 3 rodent bedding materials that are commonly used in Egypt. Male and female rats and mice were assigned randomly into 4 single-sex and single-species groups (10 animals per group). Three types of bedding-rice straw, wheat straw, and pine wood shavings-were evaluated. After 4 wk, animals were euthanized, and biochemical parameters were measured. In male and female rats given wood shavings, serum ALT activity and malondialdehyde concentration increased whereas catalase activity decreased compared with levels in the wheat straw group. In contrast, ALT activity and malondialdehyde concentrations decreased but CAT activity increased in rats housed on rice straw compared with wheat straw. Serum AST and ALT activities increased in male and female mice exposed to rice straw, whereas the malondialdehyde concentration increased and catalase decreased in the wood shavings group relative to the wheat straw group. In mice exposed to wheat straw, AST and ALT activities and malondialdehyde concentrations decreased and CAT activity increased compared with the other groups. Because our results showed that exposure to wood shavings affects some biochemical parameters of rats and mice, we do not recommend its use as laboratory animal bedding. We consider that, of the materials tested, rice straw bedding is the best bedding material for rats, whereas wheat straw is best for mice. PMID- 30012241 TI - Building oral health capacity in a women's health service. AB - Adult women in Australia are more likely than men to have no teeth, more missing teeth or have a dental hospital admission. Experiences of war, family and domestic violence, mental health or alcohol and other drug use problems may also negatively affect women's oral health. Yet, oral health is often excluded from primary healthcare. Little is known about what helps or inhibits primary healthcare service workers to promote oral health to women in need. Identifying the perceptions and experiences of such workers is a step towards a strategy to develop resources to support them in raising oral health issues with disadvantaged clients. This paper presents findings from a qualitative study conducted at a community-based women's health service, which used focus groups to investigate workers' perceptions of promoting oral health and accessing services for their clients. Findings indicated how structural issues informed oral healthcare, where workers generally did not consider oral health their responsibility, were reluctant to raise the issue with clients and had limited oral health knowledge and resources. To overcome these barriers, workers identified the need for oral health resources and better linkages to the dental system to help support their clients. PMID- 30012242 TI - Mast Cells Stimulated with Peptidoglycan from Staphylococcus aureus Augment the Development of Th1 Cells. AB - BACKGROUND: The skin of patients with atopic dermatitis (AD) is superficially colonized by Staphylococcus aureus. We have previously found that percutaneous permeation of peptidoglycan (PEG) from S. aureus increases the number of mast cells in the dermis, as seen in skin lesions of AD patients. The purpose of the present study was to clarify the influence of PEG on T helper type 1 (Th1)/ T helper type 2 (Th2) cell development mediated by mast cells. METHODS: Mast cells were induced by long-term culture of murine spleen cells in medium supplemented with tumor necrosis factor (TNF)- a. Ovalbumin (OVA) peptide-pulsed mast cells were incubated with naive Th cells in the presence or absence of PEG. Five days later, Th cells in the culture were stimulated with phorbol 12-myristate 13 acetate (PMA) and ionomycin, and Th1/Th2 cytokine production was investigated by enzyme-linked immunosorbent assay. RESULTS: It was confirmed that the mast cells we obtained had surface expression of I-Ad, worked as antigen-presenting cells, and induced Th1 cell and Th2 cell development. The stimulation of mast cells with PEG enhanced the development of Th1 cells but not that of Th2 cells. The increase of Th1 cell development stimulated by PEG was associated with an increase in the expression of Notch ligand Delta 1 in the mast cells. Furthermore, treatment of mast cells with the macrolide antibiotic josamycin suppressed Th1 cell development and this was correlated with a reduction of both Delta 1 expression and interleukin (IL)-12 production in mast cells. CONCLUSIONS: Colonization of S. aureus on the lesioned skin of AD patients contributes to not only an increase in the number of mast cells but also Th1 cell development mediated by mast cells in the dermis and subsequent induction of chronic inflammation, which is characterized by up-regulation of the Th1 cytokine, interferon (IFN)- g. Therefore, application of josamycin to the lesional skin of AD patients may provide relief from chronic inflammation mediated by mast cells. PMID- 30012243 TI - Cryopreservation of Dental Stem Cells. AB - Nowadays, regenerative and reparative medicine has grown in popularity. Dental stem cells are easily accessible source of adult stem cells. They can be harvested by a tooth extraction or spontaneous deciduous tooth exfoliation. They have to be isolated, expanded and stored until time they would be needed for individual stem cell therapy. Cryopreservation is both a short-term and long-term storage of tissues or cells at sub-zero temperatures. There are several methods of cryopreservation requiring different technologies. The objective of this review is to compare them and highlight their advantages and disadvantages. PMID- 30012244 TI - Exhaled Breath Condensate: Pilot Study of the Method and Initial Experience in Healthy Subjects. AB - Analysis of Exhaled breath condensate (EBC) is a re-discovered approach to monitoring the course of the disease and reduce invasive methods of patient investigation. However, the major disadvantage and shortcoming of the EBC is lack of reliable and reproducible standardization of the method. Despite many articles published on EBC, until now there is no clear consensus on whether the analysis of EBC can provide a clue to diagnosis of the diseases. The purpose of this paper is to investigate our own method, to search for possible standardization and to obtain our own initial experience. Thirty healthy volunteers provided the EBC, in which we monitored the density, pH, protein, chloride and urea concentration. Our results show that EBC pH is influenced by smoking, and urea concentrations are affected by the gender of subjects. Age of subjects does not play a role. The smallest coefficient of variation between individual volunteers is for density determination. Current limitations of EBC measurements are the low concentration of many biomarkers. Standardization needs to be specific for each individual biomarker, with focusing on optimal condensate collection. EBC analysis has a potential become diagnostic test, not only for lung diseases. PMID- 30012245 TI - Immunohistochemical Expression of CDC7 in Dentigerous Cyst, Odontogenic Keratocyst and Radicular Cyst. AB - CDC7 is a serine/threonine kinase which has an essential role in initiation of DNA proliferation and S phase. It increases the invasion and proliferation in many pathologic lesions. This study aimed to evaluate the expression of CDC7 in the most common odontogenic cysts. We evaluated 17 dentigerous cysts, 18 odontogenic keratocysts (OKC) and 13 radicular cysts immunohistochemically. The mean expression of CDC7 was analyzed using ANOVA and Post-HOC methods. All specimens revealed CDC7 expression. Higher expression of CDC7 in OKC and radicular cyst was shown in comparison to dentigerous cyst (P < 0.001), while radicular cyst and OKC groups showed no difference in CDC7 expression (P = 0.738). The high expression of CDC7 in OKC suggests that this protein could be related to the higher proliferation rate and invasiveness of OKC. On the other hand, the higher CDC7 expression in radicular cyst may simply be related to inflammation as this cyst is neither aggressive nor invasive. PMID- 30012246 TI - Modulation of Rat Liver Regeneration after Partial Hepatectomy by Dietary Cholesterol. AB - INTRODUCTION: The aim of study was to evaluate impact of long-term dietary cholesterol overload on the cholesterol homeostasis and liver regeneration. MATERIAL AND METHODS: Serum lipid parameters, 14C-cholesterol incorporation, liver DNA synthesis and protein expression was determined in partially hepatectomized (PH) rats fed with a standard (SLD) or hypercholesterolemic (CHOL) diet. RESULTS: 29-day intake of CHOL diet before PH produced increase in serum total cholesterol, LDL lipoprotein, and triglyceride concentration. PH provoked decrease in serum total cholesterol and triglyceride concentration in both groups. PH was associated with increase in serum ALT activity more pronounced in CHOL animals. Hepatic DNA synthesis was increased after PH in both groups, but lower in CHOL. Hypercholesterolemic diet reduced the absorption of radiolabelled cholesterol in intestine and then activity in blood and liver. The 14C cholesterol hepatic activities tend to increase after PH in both groups. CHOL diet produced up-regulation of Acyl-CoA:cholesterol acyltransferase-2 protein expression. PH was associated with increase of LDL receptor and Acyl CoA:cholesterol acyltransferase-2 protein expression in both dietary groups. DISCUSSION: Liver regeneration after PH is negatively influenced by CHOL diet. The increased uptake of cholesterol in the liver after PH associated with up regulation of LDL receptor protein expression suggests preferential use of extrahepatic cholesterol by the liver. PMID- 30012247 TI - Giant Uterine Leiomyoma in a Young Woman as an Incidental Finding After a Car Accident: a Case Report. AB - Leiomyomas are the most common benign tumor of the uterus. Occasionally, they may reach an extreme dimension. The authors present a case of a 44-year old woman, who suffered a car accident as a driver of personal motor vehicle. At the hospital, a huge tumor mass filling the entire abdominopelvic cavity was incidentally detected. The patient admitted a progressive abdominal enlargement for the last 5 years. An urgent laparotomy was performed, during which a giant, well-demarcated tumor arising from the uterine body had been disclosed. It was completely surgically removed and sent for histopathology. Grossly, the tumor measured 30 * 30 * 20 cm in the largest diameters and weighed 8.1 kg. The tissue was markedly edematous with foci of massive hemorrhages and contained confluent pseudocystic formations of various sizes, filled with a fluid and fresh blood. Solid foci of rubber consistency were also visible. Microscopic examination revealed a conventional subserous uterine leiomyoma with marked regressive and degenerative changes. Giant uterine leiomyomas occur extremely rare, but because of the often unexpected finding and atypical presentation, they may represent a great diagnostic challenge for both, pathologists and clinicians. At the biopsy examination, a multiple-section sampling is very important to avoid the possibility of underlying malignancy. PMID- 30012248 TI - A Bilateral, Non-syndromic, Type III Second Branchial Arch Sinus in a Neonate: a Case Report. AB - : The incidence of a second branchial arch sinus accounts for 26-60% of all existing congenital malformations deriving from the branchial apparatus. They are most usually detected between 14 months and 7 years of age, while their incidence during neonatal period and infancy accounts for 0.06% of all cases. The aim of this case study is to emphasize three rare characteristic features: the manifestation during neonatal period, the bilateral localization and the ultrasonographic diagnostic documentation. A 25 days old girl was admitted by her parents due to the presence of mucoid excretion from two small openings found on the neck. These openings were found bilaterally, between the mid and lower third of the anterior border of sternocleidomastoid muscle. Diagnosis was confirmed via ultrasonography. The patient underwent elective surgery during early infancy and both branchial fistulas were excised. Patient's postoperative course was uneventful. IN CONCLUSION: - in cases of a bilateral second branchial arch sinus, the branchio-oto-renal (BOR) or branchio-otic (BO) syndromes must be excluded; - ultrasound scan can be used for the thorough evaluation of the sinus anatomic course and the relationship with the adjacent anatomic structures; - rompt diagnosis and early therapeutic intervention, even during neonatal period, ensures an uneventful post-operation course. PMID- 30012249 TI - Fountain's Sign as a Diagnostic Key in Acute Idiopathic Scrotal Edema: Case Report and Review of the Literature. AB - The acute idiopathic scrotal edema (AISE) is a self-limited disease of unknown etiology, characterized by edema and erythema of the scrotum and the dartos, without expansion to the underlying layers of scrotum's wall or to the endoscrotal structures. Boys younger than 10 years old are usually involved in 60 90% of all cases. Diagnosis is made after exclusion of other causes of acute scrotum. We present a case of a 7-year old boy, who was admitted to the Emergency Department due to development of scrotal edema and erythema over the last 48 hours, which extended to the base of the penis. The patient mentioned that he first noticed the erythema on the anterior surface of the right hemiscrotum, which gradually extended. Physical examination did not reveal presence of pathology involving the endoscrotal structures, indicative of need for urgent surgical intervention. Transillumination was negative for blue dot sign. Ultrasonographic examination of the scrotum documented the homogeneity of the testicular parenchyma, while color Doppler revealed the presence of fountain's sign (equal arterial blood supply to both testicles). Conservative strategy was followed and the patient gradually improved within the next three days. In conclusion, meticulous physical examination along with ultrasonographic examination of the suffering scrotum, especially with the highlighting of fountain's sign with color Doppler, document the diagnosis of AISE. Thus, need for urgent surgical investigation of the suffering scrotum due to diagnostic doubt is limited. PMID- 30012252 TI - Life expectancy and poverty. PMID- 30012251 TI - Vaccination in a "me first" era. PMID- 30012253 TI - Improving tracking of aid for women's, children's, and adolescents' health. PMID- 30012250 TI - Photocatalytic decomposition effect of erbium doped cerium oxide nanostructures driven by visible light irradiation: Investigation of cytotoxicity, antibacterial growth inhibition using catalyst. AB - Cerium (IV) oxide (CeO2) is the most accessible noble rare earth metal oxide for the excitation of the excitons by light-harvesting performance. The present work is focused on Erbium doped ceria nanoparticles that were beneficially obtained by hydrothermal method from cerium nitrate and Erbium nitrate as precursors for decomposition of Rhodamine-B (RhB) dye in the polluted waste water removed from the industries. Dye removal efficiency of the catalyst was found to be nearly ~94%. The structural phases, functional groups and the transitions are identified with the help of various techniques. XRD pattern determines the development of cubic phase with the particle size is 20 nm. Highly crystalline nature of as synthesized nanomaterials with an average diameter of 35 nm was investigated by HRSEM. The crystalline size, shape and textural morphology, of the Erbium doped ceria nanostructures were analysed by HRTEM. Our results suggest, that the concentration of OH- ion determines the lattice constants and oxygen vacancy in the nanostructures which stimulate the probability of photocatalytic decomposition effect of organic pollutants, due to synergistic approach. In this context, both unhydrolyzed things and their swiftly drip from deceased or scratched cells with conceded membranes, even when the cells embrace some are outstanding attention. Although, the loss of viable cells also depends on epithelial cell dynamically conceal of numerous molar matrix. PMID- 30012254 TI - Early life nutritional supplements and later metabolic disease. PMID- 30012255 TI - All simulation models of breast cancer are wrong but some are useful. PMID- 30012256 TI - Use of indications to identify appropriate caesarean section rates. PMID- 30012257 TI - Call to address ethnic inequalities in access to RMNCH services. PMID- 30012258 TI - Sustainable Development Goal 3 is unlikely to be achieved without renewed effort. PMID- 30012259 TI - Strengthening eye health evidence for children in low-income and middle-income countries. PMID- 30012260 TI - Institutional challenges to achieving health equity in Ecuador. PMID- 30012261 TI - Implications of converging conflicts, emergencies, and mass gatherings for global health security. PMID- 30012262 TI - Collaboration for impact in global health. PMID- 30012263 TI - Parasitic and parachute research in global health. PMID- 30012264 TI - Parasitic and parachute research in global health. PMID- 30012265 TI - Parasitic and parachute research in global health. PMID- 30012266 TI - Measuring health and economic wellbeing in the Sustainable Development Goals era: development of a poverty-free life expectancy metric and estimates for 90 countries. AB - BACKGROUND: The Sustainable Development Goals (SDGs), adopted in September, 2015, emphasise the link between health and economic development policies. Despite this link, and the multitude of targets and indicators in the SDGs and other initiatives, few monitoring tools explicitly incorporate measures of both health and economic status. Here we propose poverty-free life expectancy (PFLE) as a new metric that uses widely available data to provide a composite measure of population health and economic wellbeing. METHODS: We developed a population level measure of PFLE and computed this summary measure for 90 countries with available data. Specifically, we used Sullivan's method, as in many health expectancy measures, to incorporate the prevalence of poverty by age and sex from household economic surveys into demographic life tables based on mortality rates from the 2015 Global Burden of Disease Study (GBD). For comparison, we also recalculated all PFLE measures using life tables from WHO and the UN. PFLE estimates for each country, stratified by sex, are the average number of poverty free years a person could expect to live if exposed to current mortality rates and poverty prevalence in that country. FINDINGS: The average PFLE in the 90 countries included in this study was 66.0 years (95% uncertainty interval [UI] 64.5-67.3) for females and 61.6 years (60.1-62.9) for males, whereas life expectancy estimates were 76.3 years (95% UI 74.0-78.2) for females and 71.0 years (68.7-73.0) for males. PFLE varied widely between countries, ranging from 9.9 years (95% UI 9.1-10.5) for both sexes combined in Malawi, to 83.2 years (83.0-83.5) in Iceland, the latter differing only marginally from life expectancy in that country. In 67 of 90 countries, the difference between life expectancy and PFLE was greater for females than for males, indicating that women generally live more years of life in poverty than men do. Results were consistent when using GBD, WHO, or UN life tables. INTERPRETATION: Differences in PFLE between countries are substantially greater than differences in life expectancy. Despite general improvements in survival in most regions of the world in the past decades, the focus in the SDG era on ending poverty brings into sharp relief the importance of ensuring that years of added life are lived with at least a minimum standard of economic wellbeing. Although summary measures of population health provide overall measures of survivorship and functional health, our new measure of PFLE provides complementary information that can inform and benchmark policies seeking to improve both health and economic wellbeing. FUNDING: None. PMID- 30012267 TI - Tracking aid for global health goals: a systematic comparison of four approaches applied to reproductive, maternal, newborn, and child health. AB - BACKGROUND: Four initiatives have estimated the value of aid for reproductive, maternal, newborn, and child health (RMNCH): Countdown to 2015, the Institute for Health Metrics and Evaluation (IHME), the Muskoka Initiative, and the Organisation for Economic Co-operation and Development (OECD) policy marker. We aimed to compare the estimates, trends, and methodologies of these initiatives and make recommendations for future aid tracking. METHODS: We compared estimates of aid for RMNCH from the four initiatives for all years available at the time of our analysis (1990-2016). We used publicly available datasets for IHME and Countdown. We produced estimates for Muskoka and the OECD policy marker using data in the OECD Creditor Reporting System. We sought to explain differences in estimates by critically comparing the methods used by each approach to identify and analyse aid, and quantifying the effects of these choices on estimates. FINDINGS: All four approaches indicated substantial increases over time in global aid for RMNCH, but estimates of aid amounts and year-on-year trends differed substantially, especially for individual donors and recipient countries. Muskoka (US$ 13.0 billion in 2013, constant 2015 US$) and Countdown's RMNCH estimates ($13.1 billion in 2013) tended to be the highest and most similar, although they often indicated different year-on-year trends. IHME produced lower estimates ($10.8 billion in 2013), which often indicated different trends from the other approaches. The OECD policy marker produced by far the lowest estimates ($2.0 billion in 2013) because half of bilateral donors did not report on it consistently and those who did tended to apply it narrowly. Estimates differed across approaches primarily because of differences in methods for distinguishing aid for RMNCH from aid for other purposes; adjustments for inflation, exchange rates, and under-reporting; whether donors were credited for their support to multilateral institutions; and the handling of aid to unspecified recipients. INTERPRETATION: The four approaches are likely to lead to different conclusions about whether individual donors and recipient countries have fulfilled their obligations and commitments and whether aid was sufficient, targeted to countries with greater need, or effective. We recommend that efforts to track aid for the Sustainable Development Goals reflect their multisectoral and interconnected nature and make analytical choices that are appropriate to their objectives, recognising the trade-offs between simplicity, timeliness, precision, accuracy, efficiency, flexibility, replicability, and the incentives that different metrics create for donors. FUNDING: Subgrant OPP1058954 from the US Fund for UNICEF under their Countdown to 2015 for Maternal, Newborn and Child Survival Grant from the Bill & Melinda Gates Foundation. PMID- 30012268 TI - Exposure to improved nutrition from conception to age 2 years and adult cardiometabolic disease risk: a modelling study. AB - BACKGROUND: Low-income and middle-income countries with populations that are chronically undernourished in early life are undergoing a nutrition transition and are experiencing an epidemic of cardiometabolic disease. These dual burdens are thought to be causally related; therefore, the extent to which improvements in early-life nutrition can offset adult-onset disease is important. The aim of this study was to examine whether improvement of protein-energy nutrition from conception to age 2 years can attenuate the risk of cardiometabolic disease. METHODS: We followed up a cohort of 2392 individuals born between Jan 1, 1962, and Feb 28, 1977, in four villages in Guatemala who had participated in a cluster randomised protein-energy nutritional supplementation (Atole) trial. Of 1661 participants available for follow-up from Feb 26, 2015, to April 29, 2017, we studied 684 women and 455 men. We assessed cardiometabolic disease risk at ages 37-54 years using anthropometry, fasting and post-challenge glucose, fasting lipid concentrations, and blood pressure. We used generalised linear and logistic regression modelling to estimate the effect of Atole from conception to age 2 years (the first 1000 days) on cardiometabolic disease risk. FINDINGS: Exposure to Atole from conception to age 2 years was associated with increased fatness (body-mass index [1.29 kg/m2, 95% CI 0.08 to 2.50], body fat [1.73%, 0.20 to 3.26], and obesity [odds ratio 1.94, 1.11 to 3.40]), diastolic blood pressure (1.59 mm Hg, -0.74 to 3.92), and blood lipids (total cholesterol [10.10 mg/dL, 0.80 to 19.40] and non-HDL cholesterol [10.41 mg/dL, 1.51 to 19.31]), reduced post-challenge glucose (-5.84 mg/dL, -12.51 to 0.83), and reduced odds of diabetes (odds ratio 0.46, 0.21 to 0.97). We found stratum heterogeneity by sex in pooled models for non-HDL cholesterol (4.34 mg/dL, 95% CI -6.86 to 15.55 for women vs 19.84 mg/dL, 5.86 to 33.82 for men) and post-challenge glucose (-0.19 mg/dL, -8.63 to 8.24 for women vs -13.10 mg/dL, -23.64 to -2.56 for men). p values for interaction of sex and exposure to Atole from conception to age 2 years were 0.09 and 0.04, respectively. INTERPRETATION: Improved protein-energy nutrition from conception to the 2nd birthday reduced the odds of diabetes at ages 37-54 years; however, this protein-energy supplementation also increased the risk of obesity and several obesity-related conditions. Our findings suggest a mixed ability of protein-energy nutritional supplementation in early life to prevent adult cardiometabolic disease incidence in the context of high childhood stunting and high adult overweight and obesity. FUNDING: National Institutes of Health. PMID- 30012269 TI - Early detection and treatment strategies for breast cancer in low-income and upper middle-income countries: a modelling study. AB - BACKGROUND: Poor breast cancer survival in low-income and middle-income countries (LMICs) can be attributed to advanced-stage presentation and poor access to systemic therapy. We aimed to estimate the outcomes of different early detection strategies in combination with systemic chemotherapy and endocrine therapy in LMICs. METHODS: We adapted a microsimulation model to project outcomes of three early detection strategies alone or in combination with three systemic treatment programmes beyond standard of care (programme A): programme B was endocrine therapy for all oestrogen-receptor (ER)-positive cases; programme C was programme B plus chemotherapy for ER-negative cases; programme D was programme C plus chemotherapy for advanced ER-positive cases. The main outcomes were reductions in breast cancer-related mortality and lives saved per 100 000 women relative to the standard of care for women aged 30-49 years in a low-income setting (East Africa; using incidence data and life tables from Uganda and data on tumour characteristics from various East African countries) and for women aged 50-69 years in a middle-income setting (Colombia). FINDINGS: In the East African setting, relative mortality reductions were 8-41%, corresponding to 23 (95% uncertainty interval -12 to 49) to 114 (80 to 138) lives saved per 100 000 women over 10 years. In Colombia, mortality reductions were 7-25%, corresponding to 32 (-29 to 70) to 105 (61 to 141) lives saved per 100 000 women over 10 years. INTERPRETATION: The best projected outcomes were in settings where access to both early detection and adjuvant therapy is improved. Even in the absence of mammographic screening, improvements in detection can provide substantial benefit in settings where advanced-stage presentation is common. FUNDING: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Cancer Center Support Grant of the US National Institutes of Health. PMID- 30012270 TI - An approach to identify a minimum and rational proportion of caesarean sections in resource-poor settings: a global network study. AB - BACKGROUND: Caesarean section prevalence is increasing in Asia and Latin America while remaining low in most African regions. Caesarean section delivery is effective for saving maternal and infant lives when they are provided for medically-indicated reasons. On the basis of ecological studies, caesarean delivery prevalence between 9% and 19% has been associated with better maternal and perinatal outcomes, such as reduced maternal land fetal mortality. However, the specific prevalence of obstetric and medical complications that require caesarean section have not been established, especially in low-income and middle income countries (LMICs). We sought to provide information to inform the approach to the provision of caesarean section in low-resource settings. METHODS: We did a literature review to establish the prevalence of obstetric and medical conditions for six potentially life-saving indications for which caesarean section could reduce mortality in LMICs. We then analysed a large, prospective population-based dataset from six LMICs (Argentina, Guatemala, Kenya, India, Pakistan, and Zambia) to determine the prevalence of caesarean section by indication for each site. We considered that an acceptable number of events would be between the 25th and 75th percentile of those found in the literature. FINDINGS: Between Jan 1, 2010, and Dec 31, 2013, we enrolled a total of 271 855 deliveries in six LMICs (seven research sites). Caesarean section prevalence ranged from 35% (3467 of 9813 deliveries in Argentina) to 1% (303 of 16 764 deliveries in Zambia). Argentina's and Guatemala's sites all met the minimum 25th percentile for five of six indications, whereas sites in Zambia and Kenya did not reach the minimum prevalence for caesarean section for any of the indications. Across all sites, a minimum overall caesarean section of 9% was needed to meet the prevalence of the six indications in the population studied. INTERPRETATION: In the site with high caesarean section prevalence, more than half of the procedures were not done for life-saving conditions, whereas the sites with low proportions of caesarean section (below 9%) had an insufficient number of caesarean procedures to cover those life-threatening causes. Attempts to establish a minimum caesarean prevalence should go together with focusing on the life-threatening causes for the mother and child. Simple methods should be developed to allow timely detection of life-threatening conditions, to explore actions that can remedy those conditions, and the timely transfer of women with those conditions to health centres that could provide adequate care for those conditions. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. PMID- 30012271 TI - Ethnic group inequalities in coverage with reproductive, maternal and child health interventions: cross-sectional analyses of national surveys in 16 Latin American and Caribbean countries. AB - BACKGROUND: Latin American and Caribbean populations include three main ethnic groups: indigenous people, people of African descent, and people of European descent. We investigated ethnic inequalities among these groups in population coverage with reproductive, maternal, newborn, and child health interventions. METHODS: We analysed 16 standardised, nationally representative surveys carried out from 2004 to 2015 in Latin America and the Caribbean that provided information on ethnicity or a proxy indicator (household language or skin colour) and on coverage of reproductive, maternal, newborn, and child health interventions. We selected four outcomes: coverage with modern contraception, antenatal care coverage (defined as four or more antenatal visits), and skilled attendants at birth for women aged 15-49 years; and coverage with three doses of diphtheria-pertussis-tetanus (DPT3) vaccine among children aged 12-23 months. We classified women and children as indigenous, of African descent, or other ancestry (reference group) on the basis of their self-reported ethnicity or language. Mediating variables included wealth quintiles (based on household asset indices), woman's education, and urban-rural residence. We calculated crude and adjusted coverage ratios using Poisson regression. FINDINGS: Ethnic gaps in coverage varied substantially from country to country. In most countries, coverage with modern contraception (median coverage ratio 0.82, IQR 0.66-0.92), antenatal care (0.86, 0.75-0.94), and skilled birth attendants (0.75, 0.68-0.92) was lower among indigenous women than in the reference group. Only three countries (Nicaragua, Panama, and Paraguay) showed significant gaps in DPT3 coverage between the indigenous and the reference groups. The differences were attenuated but persisted after adjustment for wealth, education, and residence. Women and children of African descent showed similar coverage to the reference group in most countries. INTERPRETATION: The lower coverage levels for indigenous women are pervasive, and cannot be explained solely by differences in wealth, education, or residence. Interventions delivered at community level-such as vaccines-show less inequality than those requiring access to services, such as birth attendance. Regular monitoring of ethnic inequalities is essential to evaluate existing initiatives aimed at the inclusion of minorities and to plan effective multisectoral policies and programmes. FUNDING: The Bill & Melinda Gates Foundation (through the Countdown to 2030 initiative) and the Wellcome Trust. PMID- 30012272 TI - Divergent trends in ischaemic heart disease and stroke mortality in India from 2000 to 2015: a nationally representative mortality study. AB - INTRODUCTION: India accounts for about a fifth of cardiovascular deaths globally, but nationally representative data on mortality trends are not yet available. In this nationwide mortality study, we aimed to assess the trends in ischaemic heart disease and stroke mortality over 15 years using the Million Death Study. METHODS: We determined national and subnational cardiovascular mortality rates and trends by sex and birth cohort using cause of death ascertained by verbal autopsy from 2001 to 2013 among 2.4 million households. We derived mortality rates for ischaemic heart disease and stroke by applying mortality proportions to UN mortality estimates for India and projected the rates from 2000 to 2015. FINDINGS: Cardiovascular disease caused more than 2.1 million deaths in India in 2015 at all ages, or more than a quarter of all deaths. At ages 30-69 years, of 1.3 million cardiovascular deaths, 0.9 million (68.4%) were caused by ischaemic heart disease and 0.4 million (28.0%) by stroke. At these ages, the probability of dying from ischaemic heart disease increased during 2000-15, from 10.4% to 13.1% in men and 4.8% to 6.6% in women. Ischaemic heart disease mortality rates in rural areas increased rapidly and surpassed those in urban areas. By contrast, the probability of dying from stroke decreased from 5.7% to 5.0% in men and 5.0% to 3.9% in women. A third of premature stroke deaths occurred in the northeastern states, inhabited by a sixth of India's population, where rates increased significantly and were three times higher than the national average. The increased mortality rates of ischaemic heart disease nationally and stroke in the northeastern states were higher in the cohorts of adults born in the 1970s onwards, than in earlier decades. A large and growing proportion of the ischaemic heart disease nationally and stroke deaths in high-burden states reported earlier diagnosis of cardiovascular disease, but low medication use. INTERPRETATION: The unexpectedly diverse patterns of cardiovascular mortality require investigation to identify the role of established and new cardiovascular risk factors. Secondary prevention with effective and inexpensive long-term treatment and adult smoking cessation could prevent substantial numbers of premature deaths. Without progress against the control of cardiovascular disease in India, global goals to reduce non-communicable diseases by 2030 will be difficult to achieve. FUNDING: Fogarty International Center of the US National Institutes of Health, Dalla Lana School of Public Health, University of Toronto, Indian Council of Medical Research, and the Disease Control Priorities. PMID- 30012273 TI - Smartphone-based screening for visual impairment in Kenyan school children: a cluster randomised controlled trial. AB - BACKGROUND: Childhood visual impairment is a major public health concern that requires effective screening and early intervention. We investigated the effectiveness of Peek school eye health, a smartphone-based sight test and referral system (comprising Peek Acuity test, sight simulation referral cards, and short message service [SMS] reminders), versus standard care (Snellen's Tumbling-E card and written referral). METHODS: We initially compared the performance of both the Snellen Tumbling-E card and the Peek Acuity test to a standard backlit EDTRS LogMAR visual acuity test chart. We did a cluster randomised controlled trial to compare the Peek school eye health system with standard school screening care, delivered by school teachers. Schools in Trans Nzoia County, Kenya, were eligible if they did not have an active screening programme already in place. Schools were randomly allocated (1:1) to either the Peek school eye health screening and referral programmes (Peek group) or the standard care screening and referral programme (standard group). In both groups, teachers tested vision of children in years 1-8. Pupils with visual impairment (defined as vision less than 6/12 in either eye) were referred to hospital for treatment. Referred children from the standard group received a written hospital referral letter. Participants and their teachers in the Peek group were shown their simulated sight on a smartphone and given a printout of this simulation with the same hospital details as the standard referral letter to present to their parent or guardian. They also received regular SMS reminders to attend the hospital. The primary outcome was the proportion of referred children who reported to hospital within 8 weeks of referral. Primary analysis was by intention to treat, with the intervention effect estimated using odds ratios. This trial is registered with Pan African Clinical Trial Registry, number PACTR201503001049236. FINDINGS: Sensitivity was similar for the Peek test and the standard test (77% [95% CI 64.8-86.5] vs 75% [63.1-85.2]). Specificity was lower for the Peek test than the standard test (91% [95% CI 89.3-92.1] vs 97.4% [96.6 98.1]). Trial recruitment occurred between March 2, 2015, and March 13, 2015. Of the 295 eligible public primary schools in Trans Nzoia County, 50 schools were randomly selected and assigned to either the Peek group (n=25) or the standard group (n=25). 10 579 children were assessed for visual impairment in the Peek group and 10 284 children in the standard group. Visual impairment was identified in 531 (5%) of 10 579 children in the Peek group and 366 (4%) of 10 284 children in the standard care group. The proportion of pupils identified as having visual impairment who attended their hospital referral was significantly higher in the Peek group (285 [54%] of 531) than in the standard group (82 [22%] of 366; odds ratio 7.35 [95% CI 3.49-15.47]; p<0.0001). INTERPRETATION: The Peek school eye health system increased adherence to hospital referral for visual impairment assessment compared with the standard approach among school children. This indicates the potential of this technology package to improve uptake of services and provide real-time visibility of health service delivery to help target resources. FUNDING: Seeing is Believing, Operation Eyesight Universal, Queen Elizabeth Diamond Jubilee Trust, and Wellcome Trust. PMID- 30012274 TI - A Review of Patterns of Multiple Paternity Across Sea Turtle Rookeries. AB - Why females would mate with multiple partners and have multiple fathers for clutches or litters is a long-standing enigma. There is a broad dichotomy in hypotheses ranging from polyandry having benefits to simply being an unavoidable consequence of a high incidence of male-female encounters. If females simply give in to mating when it is too costly to avoid being harassed by males (convenience polyandry), then there should be a higher rate of mating as density increases. However, if females actively seek males because they benefit from multiple mating, then mating frequency, and consequently the incidence of multiple paternity of clutches, should be high throughout. To explore these competing explanations, here we review the incidence of multiple paternity for sea turtles nesting around the World. Across 30 rookeries, including all 7 species of sea turtle, the incidence of multiple paternity was only weakly linked to rookery size (r2=0.14). However, using high resolution at-sea GPS tracking we show that the specifics of movement patterns play a key role in driving packing density and hence the likely rate of male-female encounters. When individuals use the same focal areas, packing density could be 100* greater than when assuming individuals move independently. Once the extent of adult movements in the breeding season was considered so that movements and abundance could be combined to produce a measure of density, then across rookeries we found a very tight relationship (r2=0.96) between packing density and the incidence of multiple paternity. These findings suggest that multiple paternity in sea turtles may have no benefit, but is simply a consequence of the incidence of male-female encounters. PMID- 30012275 TI - The Biology of Seamounts: 25 Years on. AB - Seamounts are one of the major biomes of the global ocean. The last 25 years of research has seen considerable advances in the understanding of these ecosystems. The interactions between seamounts and steady and variable flows have now been characterised providing a better mechanistic understanding of processes influencing biology. Processes leading to upwelling, including Taylor column formation and tidal rectification, have now been defined as well as those leading to draw down of organic matter from the ocean surface to seamount summit and flanks. There is also an improved understanding of the interactions between seamounts, zooplankton and micronekton communities especially with respect to increased predation pressure in the vicinity of seamounts. Evidence has accumulated of the role of seamounts as hot spots for ocean predators including large pelagic fish, sharks, pinnipeds, cetaceans and seabirds. The complexity of benthic communities associated with seamounts is high and drivers of biodiversity are now being resolved. Claims of high endemism resulting from isolation of seamounts as islands of habitat and speciation have not been supported. However, for species characterised by low dispersal capability, such as some groups of benthic sessile or low-mobility invertebrates, low connectivity between seamount populations has been found with evidence of endemism at a local level. Threats to seamounts have increased in the last 25 years and include overfishing, destructive fishing, marine litter, direct and indirect impacts of climate change and potentially marine mining in the near future. Issues around these threats and their management are discussed. PMID- 30012276 TI - Potential Impacts of Offshore Oil and Gas Activities on Deep-Sea Sponges and the Habitats They Form. AB - Sponges form an important component of benthic ecosystems from shallow littoral to hadal depths. In the deep ocean, beyond the continental shelf, sponges can form high-density fields, constituting important habitats supporting rich benthic communities. Yet these habitats remain relatively unexplored. The oil and gas industry has played an important role in advancing our knowledge of deep-sea environments. Since its inception in the 1960s, offshore oil and gas industry has moved into deeper waters. However, the impacts of these activities on deep-sea sponges and other ecosystems are only starting to become the subject of active research. Throughout the development, operation and closure of an oil or gas field many activities take place, ranging from the seismic exploration of subseafloor geological features to the installation of infrastructure at the seabed to the drilling process itself. These routine activities and accidental releases of hydrocarbons during spills can significantly impact the local marine environment. Each phase of a field development or an accidental oil spill will therefore have different impacts on sponges at community, individual and cellular levels. Legacy issues regarding the future decommissioning of infrastructure and the abandonment of wells are also important environmental management considerations. This chapter reviews our understanding of impacts from hydrocarbon exploration and exploitation activities on deep-sea sponges and the habitats they form. These impacts include those (1) at community level, decreasing the diversity and density of benthic communities associated with deep sea sponges owing to physical disturbance of the seabed; (2) at individual level, interrupting filtration owing to exposure to increased sedimentation; and (3) at cellular level, decreasing cellular membrane stability owing to exposure to drill muds. However, many potential effects not yet tested in deep-sea sponges but observed in shallow-water sponges or other model organisms should also be taken into account. Furthermore, to the best of our knowledge, no studies have shown impact of oil or dispersed oil on deep-sea sponges. To highlight these significant knowledge gaps, a summary table of potential and known impacts of hydrocarbon extraction and production activities combined with a simple "traffic light" scheme is also provided. PMID- 30012278 TI - Sensation seeking, binge-type eating disorders, victimization, and PTSD in the National Women's Study. AB - OBJECTIVE: Higher degrees of sensation seeking (SS) are reported in community and clinical samples of individuals with eating disorders with binge-type features (BTEDs), but no reports exist in representative probability samples of adult women. Additionally, SS has been linked to victimization and PTSD, also associated with BTEDs, yet interrelationships between these variables are unexplored. METHODS: A national, probability sample of 3006 adult women (>=18 y/o) completed structured telephone interviews including assessments for victimization, PTSD, bulimia nervosa (BN) and binge eating disorder (BED). The survey included the 6 items of the Disinhibition-Intentions for the Future (DIF) subscale of Zuckerman's Sensation Seeking Scale-VI, which asks how likely participants would be to engage in given activities. Total SS score (TSSS-DIFS) was the sum of the 6 items' scores. Differences among the 3 groups (BN, BED, non BN/BED) were compared using ANOVA covaried by age and post-hoc t-tests. Multiple regression tested the effects of age, number of victimization experiences (NVE), lifetime PTSD, and BTEDs on TSSS-DIFS. RESULTS: There were significant differences in TSSS-DIFS across BTED diagnoses (p <= .001). Participants with BN (p <= .002) and those with BED (p <= .01) had significantly higher scores than those without BTEDs. These findings persisted in both groups after correcting for NVE and lifetime PTSD. TSSS-DIFS was significantly higher in participants with BTED with PTSD versus those without (p <= .025). DISCUSSION: SS traits related to disinhibition occur more commonly in U.S. adult women with BN and BED, even after controlling for NVE and PTSD, which were also associated with higher TSSS-DIFS. PMID- 30012279 TI - Effects of mesoscopic susceptibility and transverse relaxation on diffusion NMR. AB - Measuring molecular diffusion is based on the spatial encoding of spin-carrying molecules using external Larmor frequency gradients. Intrinsic variations of the Larmor frequency and of the local relaxation rate, commonly present in structurally complex samples, interfere with the external gradients, confounding the NMR-measured diffusion propagator. Here we consider, analytically and numerically, the effects of the mesoscopic magnetic structure (local susceptibility and transverse relaxation rate) on the NMR-measured "apparent" diffusion coefficient (ADC). We show that in the fast diffusion regime, when molecules spread past the correlation length of the magnetic structure, the deviation of ADC from the genuine diffusion coefficient increases as a power law of diffusion time. The effect of mesoscopically varying transverse relaxation rate is sequence-independent and always leads to the decrease of ADC with time, whereas the effect sign for the mesoscopic Larmor frequency variations depends on the presence of refocussing pulses in the diffusion sequence. We connect this unexpectedly diverging with time ADC discrepancy to the spatial statistics of the mesocopic magnetic structure. Our results establish a novel kind of NMR contrast tied to the microstructural complexity, and can be applied to discern the mesoscopic effects of hindrances to molecular diffusion, susceptibility variations, and varying local relaxation rate, on the measured diffusion propagator. In particular, we numerically show that the susceptibility effect of a microvascular network is sufficient to explain the observed ADC decrease due to superparamagnetic iron-oxide contrast injection in monkeys. PMID- 30012277 TI - Mediterranean Bioconstructions Along the Italian Coast. AB - Marine bioconstructions are biodiversity-rich, three-dimensional biogenic structures, regulating key ecological functions of benthic ecosystems worldwide. Tropical coral reefs are outstanding for their beauty, diversity and complexity, but analogous types of bioconstructions are also present in temperate seas. The main bioconstructions in the Mediterranean Sea are represented by coralligenous formations, vermetid reefs, deep-sea cold-water corals, Lithophyllum byssoides trottoirs, coral banks formed by the shallow-water corals Cladocora caespitosa or Astroides calycularis, and sabellariid or serpulid worm reefs. Bioconstructions change the morphological and chemicophysical features of primary substrates and create new habitats for a large variety of organisms, playing pivotal roles in ecosystem functioning. In spite of their importance, Mediterranean bioconstructions have not received the same attention that tropical coral reefs have, and the knowledge of their biology, ecology and distribution is still fragmentary. All existing data about the spatial distribution of Italian bioconstructions have been collected, together with information about their growth patterns, dynamics and connectivity. The degradation of these habitats as a consequence of anthropogenic pressures (pollution, organic enrichment, fishery, coastal development, direct physical disturbance), climate change and the spread of invasive species was also investigated. The study of bioconstructions requires a holistic approach leading to a better understanding of their ecology and the application of more insightful management and conservation measures at basin scale, within ecologically coherent units based on connectivity: the cells of ecosystem functioning. PMID- 30012280 TI - SERIAL transmit - parallel receive (STxPRx) MR imaging produces acceptable proton image uniformity without compromising field of view or SAR guidelines for human neuroimaging at 9.4 Tesla. AB - PURPOSE: Non-uniform B1+ excitation and high specific absorption rates (SAR) compromise proton MR imaging of human brain at 9.4 T (400.5 MHz). By combining a transmit/receive surface coil array using serial transmission of individual coils with a total generalized variation reconstruction of images from all coils, acceptable quality human brain imaging is demonstrated. METHODS: B0 is shimmed using sodium MR imaging (105.4 MHz) with a birdcage coil. Proton MR imaging is performed with an excitation/receive array of surface coils. The modified FLASH pulse sequence transmits serially across each coil within the array thereby distributing SAR in time and space. All coils operate in receive mode. Although the excitation profile of each transmit coil is non-uniform, the sensitivity profile estimated from the non-transmit receive coils provides an acceptable sensitivity correction. Signals from all coils are combined in a total generalized variation (TGV) reconstruction to provide a full field of view image at maximum signal to noise (SNR) performance. RESULTS: High-resolution images across the human head are demonstrated with acceptable uniformity and SNR. CONCLUSION: Proton MR imaging of the human brain is possible with acceptable uniformity at low SAR at 9.4 Tesla using this serial excitation and parallel reception strategy with TGV reconstruction. PMID- 30012281 TI - Fat reduction: Pathophysiology and treatment strategies. AB - The advances in understanding the pathophysiology and anatomy of adipose tissue together with the emergence of technological innovations in procedures and devices for fat reduction have led to a dramatic rise in patient demand for this procedure. The objective of this continuing medical education series, which is intended for the novice or experienced dermatologist, is to provide an update of the pathophysiology and anatomic considerations of adipose tissue, and detail the liposuction procedure, from patient selection/management to the latest developments in liposuction devices. Information presented was collected from peer-reviewed literature, the latest guidelines of the American Society of Plastic Surgeons, and the authors' personal clinical experience. The goal of these continuing medical education articles is to assist physicians in providing the best clinical care for their patients who are requesting fat reduction. PMID- 30012282 TI - Fat reduction: Complications and management. AB - Despite the favorable safety profile of liposuction, complications occur that need to be appropriately managed. In the second article in this continuing medical education series, the range of complications that may arise from liposuction are described, and the latest best practices to manage them are discussed. Specific technical strategies to prevent and minimize the risk of complications are also presented. Early recognition, accurate diagnosis, and proper clinical management can ensure an optimal outcome and patient satisfaction in individuals who are investing in fat reduction procedures. PMID- 30012283 TI - Comment on: "When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council". PMID- 30012284 TI - Response to "Comment on: 'When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council'". PMID- 30012285 TI - Bullous pemphigoid and diabetes mellitus: Are we missing the larger picture? PMID- 30012286 TI - Reply to: "Bullous pemphigoid and diabetes mellitus: Are we missing the larger picture?" PMID- 30012287 TI - Re-evaluating pyoderma gangrenosum patients for Behcet disease before initiating any invasive procedures is essential. PMID- 30012288 TI - Reply to: "Re-evaluating pyoderma gangrenosum patients for Behcet disease before initiating any invasive procedures is essential". PMID- 30012289 TI - A dynamic emulator for physically based flow simulators under varying rainfall and parametric conditions. AB - This work presents a method to emulate the flow dynamics of physically based hydrodynamic simulators under variations of time-dependent rainfall and parametric scenarios. Although surrogate modelling is often employed to deal with the computational burden of this type of simulators, common techniques used for model emulation as polynomial expansions or Gaussian processes cannot deal with large parameter space dimensionality. This restricts their applicability to a reduced number of static parameters under a fixed rainfall process. The technique presented combines the use of a modified Unit Hydrograph (UH) scheme and a polynomial chaos expansion (PCE) to emulate flow from physically based hydrodynamic models. The novel element of the proposed methodology is that the emulator compensates for the errors induced by the assumptions of proportionality and superposition of the UH theory when dealing with non-linear model structures, whereas it approximates properly the behaviour of a physically based simulator to new (spatially-uniform) rainfall time-series and parametric scenarios. The computational time is significantly reduced, which makes the practical use of the model feasible (e.g. real time control, flood warning schemes, hydraulic structures design, parametric inference etc.). The applicability of this methodology is demonstrated in three case studies, through the emulation of a simplified non-linear tank-in-series routing structure and of the 2D Shallow Water Equations (2D-SWE) solution (FLOW-R2D) in two computational domains. Results indicate that the proposed emulator can approximate with a high degree of accuracy the behaviour of the original models under a wide range of rainfall inputs and parametric values. PMID- 30012290 TI - The Basic Science of Dupuytren Disease. AB - Dupuytren disease is a fibroproliferative condition affecting the hands of millions of patients worldwide. The hypothesis of pathogenesis involves genetic factors and internal factors. Recent genome-wide association studies have provided much needed evidence for the long-held belief of a strong genetic component to the pathogenesis of Dupuytren disease. Specifically, abnormal activation of the Wnt signaling pathway plays an important role. Regarding internal factors, microvascular angiopathy and ischemia have been shown to lead to activation of transforming growth factor-beta1 and proliferation of myofibroblasts. PMID- 30012291 TI - Risk Factors, Disease Associations, and Dupuytren Diathesis. AB - Dupuytren disease (DD) is a benign, fibroproliferative disease of unknown cause. The disease predominantly affects the palms of the hands, causing permanent digital contracture of affected digits. DD is a late-onset disease and is often progressive, irreversible, and bilateral. The disease has a significant impact on the health care economy. The mainstay of treatment of DD is surgical excision of diseased palmar fascia. There is evidence of genetic susceptibility. This article introduces the epidemiology of DD and examines the Dupuytren diathesis to highlight the importance of identifying clinical severity in relation to patient counseling and recurrence risk following treatment. PMID- 30012292 TI - Normal and Pathologic Anatomy of Dupuytren Disease. AB - Dupuytren disease causes nodules and thickened fascial cords in the hands of affected individuals. In this article, the author explains normal fascial anatomy of the hand and describes how it relates to the pathologic anatomy found in Dupuytren disease. Anatomic findings in diseased cords are described, with particular reference to dangers encountered in treatment of this condition. PMID- 30012293 TI - Needle Aponeurotomy for Dupuytren Disease. AB - Needle aponeurotomy is an effective, minimally invasive treatment for metacarpophalangeal and interphalangeal joint contractures caused by Dupuytren disease. Multiple joints and digits can be safely treated in 1 session. Needle aponeurotomy is more cost-effective and has a significantly lower complication rate compared with open fasciectomy and collagenase injections. Recurrence rates are higher compared with open fasciectomy and collagenase injections. Patient satisfaction rates are high following needle aponeurotomy; the single clinic visit required and the minimal downtime after treatment are advantages unique to this procedure compared with other treatment modalities, including open fasciectomy, dermatofasciectomy, collagenase injections, and lipofilling. PMID- 30012294 TI - Development of Collagenase Treatment for Dupuytren Disease. AB - Proof-of-principle, basic-science studies, using a rat-tail tendon model and surgically removed Dupuytren cords, began collagenase Clostridium histolyticum (CCH) development. Clinical studies in humans were then conducted, where the primary endpoint was reduction in contracture to within 0 degrees to 5 degrees of extension. Phase 2 studies, which confirmed the optimal dose of collagenase as 0.58 mg, showed injectable CCH reduced contractures in MP and PIP joints to within 0 degrees to 5 degrees in many joints and was well tolerated. Clinical results from phase 3 studies confirmed the efficacy and safety of injectable CCH as a viable nonsurgical intervention. PMID- 30012295 TI - Fasciectomy for Dupuytren Contracture. AB - This article discusses limited fasciectomy for Dupuytren contracture, reviews the literature to list common complications, addresses the observations that need to be made after surgery, and systematically reviews the literature for 2 clinical questions: (1) regarding leaving wounds open and (2) the use of postoperative splintage. PMID- 30012296 TI - Alternative and Adjunctive Treatments for Dupuytren Disease. AB - Clinicians struggle with limited efficacy and durability of standard treatments when treating patients with Dupuytren disease diathesis. Alternative treatments such as low-dose radiation therapy in early phase of disease, supplemental pharmacotherapy with anti-inflammatory and/or anti-mitotic drugs, as well as other pharmacologic targets, and more aggressive surgery such as dermofasciectomy all have been reported with variable success or with serious side effects that hamper their standard use. This article gives an overview of the available literature. PMID- 30012297 TI - Comparative Outcomes of Dupuytren Disease Treatment. AB - Despite more than a hundred years of publications on Dupuytren disease, there has been a lack of consensus on definitions and outcomes until recently. Staging and classifications systems have an important historical context; however, more recently, outcomes rely on patient-reported outcomes, angular correction, and definitions of recurrence. This article reviews commonly used assessments, classifications, and staging systems for Dupuytren disease. PMID- 30012298 TI - Complications of Treatment for Dupuytren Disease. AB - Dupuytren contracture is a progressive disease involving collagen within the palmar fascia. When the contracture progresses to meet specific parameters, intervention is considered and includes collagenase injection, percutaneous or open fasciotomy, or palmar fasciectomy. Complications after treatment include contracture recurrence, digital nerve injury or postoperative neurapraxia, flexor tendon injury/rupture, delayed wound healing or skin necrosis, dysvascular digit/arterial injury, hematoma, and infection. Patients with severe or recurrent Dupuytren contracture are more likely to experience complications. Patient education is paramount; one must consider the patient's goals for treatment, functional requirements, time frame for recovery, and tolerance for complications when deciding about treatment. PMID- 30012299 TI - The Role of Hand Therapy in Dupuytren Disease. AB - The role of hand therapy in the treatment of Dupuytren disease varies depending on the patient and the procedure. There is limited evidence for hand therapy as a preventive treatment of Dupuytren disease. Before corrective treatment, the hand therapist can contribute with assessments to promote evaluation of outcome. After corrective treatment, hand therapy is tailored to each patient's needs and consists of orthoses, exercise, edema control, and pain or scar management. Orthoses are usually part of the hand therapy protocol after corrective procedures despite lack of strong supporting evidence and should be provided based on individual patient needs. PMID- 30012300 TI - Treatment of Recurrent Dupuytren Disease. AB - Treatment of recurrent Dupuytren disease is challenging. Multiple options exist, each having relative benefits and weaknesses. Choice for optimal treatment is made on a case-by-case basis, with shared decision making with the patient. Percutaneous and enzymatic techniques are best reserved for patients with well defined recurrent disease and offer the benefit of quicker recovery with minimal or no scarring. Surgical treatments have higher risks of neurovascular injury and scarring, but lower recurrence rates. Staged continuous passive elongation followed by dermofasciectomy may lower neurovascular injury and improve outcomes. Salvage procedures may be necessary in patients with poor tissue beds and neurovascular compromise. PMID- 30012301 TI - Advances in Minimally Invasive Treatment of Dupuytren Disease. AB - A comparison is provided between minimally invasive techniques and limited fasciectomy (LF) in the treatment of Dupuytren disease. A technique called percutaneous needle aponeurotomy and lipofilling is described. In a randomized controlled trial, there is no significant difference between this technique and LF after 1 year in contracture correction and recurrent contractures. At 5 years postoperative, however, there is a significant change in recurrence rates in favor of LF. Patients with moderate diathesis should choose between minimally invasive technique with early recurrence, fast recovery, and few complications versus late recurrence, slower recovery, and more complications, as observed with LF or dermofasciectomy. PMID- 30012302 TI - Bringing It All Together: A Practical Approach to the Treatment of Dupuytren Disease. AB - As minimally invasive options for treatment of Dupuytren contractures become increasingly widespread, it is important that the evidence is carefully evaluated and patients are informed of the risks and benefits of the options available. The authors advocate a shared decision-making process, using evidence-based medicine, to guide patients in their treatment choices. In this article, the authors present their thoughtful approach to selecting the appropriate Dupuytren treatment of patients, along with detailed, practical technical tips to avoid complications during the execution of these interventions; both collagenase injection and limited fasciectomy techniques are described in detail. PMID- 30012303 TI - Dupuytren Disease. PMID- 30012304 TI - Errata. PMID- 30012305 TI - [Modern Immuno-oncology: a new paradigm in Pathology]. PMID- 30012306 TI - [Study of the evolution in the activity of a Department of Pathology from a third level hospital in the last decade (2007-2016)]. AB - OBJECTIVE: To study the evolution of variables of interest in a department of pathology from a third level hospital during the last decade and to evaluate the impact on these of the hospital relocation in 2014. MATERIAL AND METHOD: Retrospective observational study in which the recorded samples (biopsies, cytology specimens, FNA, autopsies, intraoperative) as well as the complementary techniques (IHC, Histochemistry, IF and FISH) and portfolio of services were analyzed during the years 2007-2016 inclusive. For the statistical analysis, the five-year periods 2007-2011 and 2012-2016 were compared. RESULTS: The following variables were statistically significant: cytology (34055.8+/-1994.0 vs 26590.4+/ 2938.3, p=0.002), autopsies (156.2+/-27.3 vs 122.0+/-14.78, p=0.039), immunohistochemistry (17855.4+/-3424.2 vs 28559.2+/-4734.7, p=0.003), histochemistry (11117.8+/-2300.9 vs 6225.0+/-1330.5, p=0.003) and immunofluorescence (610.2+/-185.3 vs. 1205.4+/-154.0, p=0.001). Statistical correlations of interest among variables have been identified. In 2014, it was observed that the variables of greater specific weight (biopsies, cytology, IHQ and histochemistry) in the work load of the Department showed an average decrease of 12.5%. A generalized increase in the panel of available samples has been identified, the largest increase being seen in the number of antibodies (78.7%), histochemistry (38.7%) and FISH (400%). CONCLUSION: Relevant variations in work volume, as well as the service portfolio, have been identified, especially in the techniques aimed at improving diagnostic accuracy (IHQ and FI), and a significant decrease in the number of cytology specimens, autopsies and histochemistry. In the year 2014 a decrease of more than 12% in the main variables of the study was observed. PMID- 30012307 TI - [Early diagnosis of cervix cancer: Correlation between cytology, colposcopy and biopsy]. AB - OBJECTIVE: To determine the concordance between cytology, colposcopy and cervical biopsy in abnormal cytologies. MATERIAL AND METHODS: An observational cross sectional, clinically based, single center study was performed. The selected population consisted of 416 women between the ages of 25 and 65 who had undergone colposcopy for abnormal cytologies at the Reina Sofia Hospital, Cordoba, between August 1st, 2014, and September 30th, 2016. Statistical analysis was performed using the Kappa index for the degree of concordance between cytology, colposcopy and biopsy. RESULTS: There was an insignificant concordance between cytology and colposcopy (k=0.16; 95% CI 0.09-0.22), a moderate concordance between colposcopy and biopsy (k=0.57; 95% CI 0.47-0.68) and an insignificant concordance between cytology and biopsy (k=0.21 (95% CI 0.08-0.34). CONCLUSIONS: Better concordance was found between colposcopy and biopsy than between either cytology and biopsy or cytology and colposcopy. PMID- 30012308 TI - [Proposal of the SEOM, SEAP and SEFH for the creation of a National Strategy for Precision Medicine in Cancer]. AB - Precision medicine is an emerging approach to the prevention and treatment of disease that takes into account variability in genes, environment and lifestyle for each individual. Precision medicine is transforming clinical and biomedical research, as well as health care itself, from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational and knowledge-related challenges. Without a national strategy, precision medicine which eventually will be implemented one way or another- could take place without the appropriate planning to guarantee technical quality and equal access to the best practices for all citizens, thus violating the rights of patients and professionals as well as jeopardizing the solvency of the healthcare system. This paper from the Spanish Societies of Medical Oncology (SEOM), Pathology (SEAP) and Hospital Pharmacy (SEFH), highlights the need to institute a consensual national strategy for the development of precision medicine in our country, reviews the national and international context, comments on the opportunities and challenges for implementing precision medicine and outlines the objectives of a national strategy on precision medicine in cancer. PMID- 30012309 TI - [Histiocytic and dendritic cell neoplasms: Review of the literature]. AB - Histiocytic and dendritic cell neoplasms (HDN) are rare and their biology, prognosis, treatment and terminology are still under discussion. They are composed of macrophage and dendritic-derived cells and show a wide range of clinical, morphological and prognostic features. Clinicopathological correlation and a broad immunohistochemical panel are required to establish a correct diagnosis. After the detection of BRAF mutations in Langerhans cell histiocytosis, the potential role of other molecular alterations is being studied. We have reviewed the literature published in the last 10 years to provide an overview of NHD, with particular emphasis their molecular features. PMID- 30012310 TI - [Thrombotic microangiopathy/haemolytic uraemic syndrome. Histopathology update]. AB - Thrombotic microangiopathy (TMA) encompasses different entities known as haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The histopathological characteristics have remained constant since the initial description and consist in glomerular-type affectation with the presence of double contours, mesangiolysis and microthrombi. It is generally accepted that the vascular damage is related to the prognosis. Ultrastructure, together with conventional histology, shows notable changes in both capillaries and endothelial cells. A comprehensive histopathological study of the renal biopsy, using electronmicroscopy, is useful in the confirmation of a clinical suspicion and demonstrates the pathogenetic mechanisms in the microcirculatory damage. The close resemblance between the ultrastructural appearance and that seen with the light microscope of TMA and transplant glomerulopathy (TG) is precisely what suggests that both entities are subject to the same etiopathogenetic mechanism in which the endothelial cell is targeted. Recent advances in the pathology of atypical HUS, its relation with complement system and the discovery of specific therapeutic targets, has rekindled an interest in the study of TMA and the importance of renal biopsy. PMID- 30012311 TI - [Low-grade fibromyxoid sarcoma, an essential differential diagnosis in myxoid tumors with benign appearance]. AB - Low-grade fibromyxoid sarcoma is a rare neoplasm, primarily affecting young adults. It is a fibroblastic tumor with a deceptively benign appearance, which may produce local recurrences and late distant metastases. We present a case of an 11-year-old girl with a lesion on her thigh that was completely excised. Histopathology revealed a well-delimited neoplasm with myxoid stroma and fusiform cellularity without atypia or mitosis. Immunohistochemical expression of MUC4, together with molecular biology, which detected FUS-CREB3L2 fusion gene expression, confirmed the diagnosis of low-grade fibromyxoid sarcoma. We review the differential diagnosis of soft-tissue myxoid tumors, especially those with a benign appearance, highlighting the importance of immunohistochemical and molecular studies to rule out low-grade fibromyxoid sarcoma. PMID- 30012312 TI - [Intravascular leiomyomatosis with intracardiac extension]. AB - Intravascular leiomyomatosis is a rare condition characterized by histologically benign smooth muscle cell growth within the uterine veins and inferior vena cava and, rarely, into the right chambers of the heart. A 39-year-old female with a history of hysterectomy for uterine leiomyoma was admitted for lower limb oedema and progressive dyspnea of 5 months' duration. Transthoracic echocardiography and contrast-enhanced computed tomography showed a large mass extending through the inferior vena cava into the right chambers of the heart. As there was a suspicion of an intravenous thrombus, the patient underwent surgical resection. The histopathology of the resected mass led to a diagnosis of Intravascular leiomyomatosis with intracardiac extension. PMID- 30012313 TI - Paclitaxel-induced cutaneous change mimicking malignancy in a previous cutaneous eruption. AB - Taxanes are antineoplastic drugs that can cause dermatotoxicity which can mimic an intraepidermal carcinoma. A 65-year-old woman presented with a cutaneous eruption suggestive of a paraneoplastic syndrome. Imaging studies showed multiple peritoneal nodules and associated ascites. A sample taken from the greater omentum revealed an adenocarcinoma. Clinical data and family history pointed to a gynecological origin of the tumor and the patient was treated with carboplatin and paclitaxel. A new cutaneous biopsy showed that the epidermis was acanthotic with atypical keratinocytes, abundant mitoses, and apoptotic figures, arising concerns of malignancy. According to the Plummer and Shea criteria, the lesion was ultimately interpreted as reactive cutaneous hyperplasia and expression of the taxane effect. We report, for the first time, paclitaxel-induced histologic changes on a previous cutaneous eruption. Pathologists should be aware of the profound cytopathic effects of taxane therapy in order to interpret skin biopsies of patients undergoing this treatment. PMID- 30012314 TI - [Inflammatory myofibroblastic tumor of the breast: A rare entity]. AB - Also known as inflammatory pseudotumor, inflammatory myofibroblastic tumor is now considered a true low-grade neoplasm. Although the lung is the most common site, it has been described in many other locations, including the breast; the first report of breast involvement was by Pettinato et al. in 1988. We report the case of a 52-year-old perimenopausal woman presenting with a slow-growing mass in her right breast. Mammography revealed a well demarcated lesion which was hypoechoic on ultrasound. A needle biopsy was performed yielding an initial diagnosis of myofibroma and the mass was resected. Histopathology of the 5-cm tumor revealed a fusocellular proliferation with a striking presence of inflammatory cells, morphologically and immunohistochemically concordant with inflammatory myofibroblastic tumor. The patient underwent further surgery to ensure free margins and after a negative extension study (PET-CT) is receiving no further therapy. To date, she has shown no signs of recurrence 8 months postoperatively. Inflammatory myofibroblastic tumor of the breast is very infrequent, with less than 30 reported cases. Differential diagnosis with both benign and malignant entities is extensive and it may precede or coexist with carcinoma of the adjacent breast. Although it is considered a low-malignant potential lesion, there are well documented cases of recurrence and even metastasis. Surgical resection with wide margins is the primary treatment and no systemic therapy is indicated; however, clinical follow-up is mandatory as there are no well established criteria as yet to predict the biological behavior of this tumor. PMID- 30012315 TI - [Wunderlich syndrome due to a ruptured iliac vein secondary to deep venous thrombosis]. AB - Wunderlich syndrome, or spontaneous retroperitoneal hematoma, secondary to spontaneous rupture of the iliac vein is a rare clinical entity and a medical emergency. Often the aetiology is difficult to identify and different hypotheses have been proposed, such as the presence of hormonal, inflammatory and/or mechanical factors. It may be important to assess the presence of a factor that triggered the deep vein thrombosis and secondary rupture of the iliac vein and retroperitoneal hematoma. We present a case where venous thrombosis could have caused rupture of the iliac vein and we discuss the entity in light of the current literature. PMID- 30012317 TI - Precision Medicine for Prosthetic Valve Deterioration: A Glimpse Into the Future? PMID- 30012316 TI - Hemodynamic Deterioration of Surgically Implanted Bioprosthetic Aortic Valves. AB - BACKGROUND: Dysmetabolic profile has been associated with native aortic valve stenosis. However, there are limited data on the effects of an atherogenic milieu and its potential implications on the structural and hemodynamic deterioration of aortic bioprosthetic valves. OBJECTIVES: This prospective longitudinal study sought to determine the predictors and impact on outcomes of hemodynamic valve deterioration (HVD) of surgically implanted aortic bioprostheses. METHODS: A total of 137 patients with an aortic bioprosthesis implanted for a median time of 6.7 (interquartile range: 5.1 to 9.1) years prospectively underwent a first (baseline) assessment with complete Doppler echocardiography, quantitation of bioprosthesis leaflet calcification by multidetector computed tomography (CT), and a fasting blood sample to assess cardiometabolic risk profile. All patients underwent a second (follow-up) Doppler echocardiography examination at 3 (interquartile range: 2.9 to 3.3) years post-baseline visit. HVD was defined by an annualized change in mean transprosthetic gradient >=3 mm Hg/year and/or worsening or transprosthetic regurgitation by >=1/3 class. The primary endpoint was a nonhierarchical composite of death from any cause or aortic reintervention procedure (redo surgical valve replacement or transcatheter valve-in-valve implantation) for bioprosthesis failure. RESULTS: Thirty-four patients (25.6%) had leaflet calcification on baseline CT, and 18 patients (13.1%) developed an HVD between baseline and follow-up echocardiography. Fifty-two patients (38.0%) met the primary endpoint during subsequent follow-up after the second echocardiographic examination. Leaflet calcification (hazard ratio [HR]: 2.58; 95% confidence interval [CI]: 1.35 to 4.82; p = 0.005) and HVD (HR: 5.12; 95% CI: 2.57 to 9.71; p < 0.001) were independent predictors of the primary endpoint. Leaflet calcification, insulin resistance (homeostatic model assessment index >=2.7), lipoprotein-associated phospholipase A2 activity (Lp-PLA2 per 0.1 nmol/min/ml increase), and high level of proprotein convertase subtilisin/kexin 9 (PCSK9) (>=305 ng/ml) were associated with the development of HVD after adjusting for age, sex, and time interval since aortic valve replacement. CONCLUSIONS: HVD identified by Doppler echocardiography is independently associated with a marked increase in the risk of valve reintervention or mortality in patients with a surgical aortic bioprosthesis. A dysmetabolic profile characterized by elevated plasma Lp-PLA2, PCSK9, and homeostatic model assessment index was associated with increased risk of HVD. The presence of leaflet calcification as detected by CT was a strong predictor of HVD, providing incremental risk-predictive capacity. PMID- 30012318 TI - Concomitant Oral Anticoagulant and Nonsteroidal Anti-Inflammatory Drug Therapy in Patients With Atrial Fibrillation. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications that can potentially increase the risk of bleeding and thrombosis. OBJECTIVES: This study quantified the effect of NSAIDs in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial. METHODS: This was a post hoc analysis of NSAIDs in the RE-LY study, which compared dabigatran etexilate (DE) 150 and 110 mg twice daily (b.i.d.) with warfarin in patients with atrial fibrillation. Treatment-independent, multivariate-adjusted Cox regression analysis assessed clinical outcomes by comparing NSAID use with no NSAID use. Interaction analysis was obtained from treatment-dependent Cox regression modeling. Time-varying covariate analysis for NSAID use was applied to the Cox model. RESULTS: Among 18,113 patients in the RE-LY study, 2,279 patients used NSAIDs at least once during the trial. Major bleeding was significantly elevated with NSAID use (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.40 to 2.02; p < 0.0001). NSAID use did not significantly alter the risk of major bleeding for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.63 and 0.93, respectively). Gastrointestinal major bleeding was significantly elevated with NSAID use (HR: 1.81; 95% CI: 1.35 to 2.43; p < 0.0001). The rate of stroke or systemic embolism (stroke/SE) with NSAID use was significantly elevated (HR: 1.50; 95% CI: 1.12 to 2.01; p = 0.007). The use of NSAIDs did not significantly alter the relative efficacy on stroke/SE for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.59 and 0.54, respectively). Myocardial infarction rates were similar with NSAID use compared with no NSAID use (HR: 1.22; 95% CI: 0.77 to 1.93; p = 0.40). Patients were more frequently hospitalized if they used an NSAID (HR: 1.64; 95% CI: 1.51 to 1.77; p < 0.0001). CONCLUSIONS: The use of NSAIDs was associated with increased risk of major bleeding, stroke/SE, and hospitalization. The safety and efficacy of DE 150 and 110 mg b.i.d. relative to warfarin were not altered. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY]; NCT00262600). PMID- 30012319 TI - Are NSAIDs Double Trouble? PMID- 30012320 TI - Sex-Based Differences in Outcomes of Oral Anticoagulation in Patients With Atrial Fibrillation. AB - BACKGROUND: Women with atrial fibrillation are at a higher risk of stroke, despite treatment with warfarin. It is unclear if women treated with direct oral anticoagulants (DOACs) have better clinical outcomes, especially when considering the quality of anticoagulation control of warfarin. OBJECTIVES: This study compared the effectiveness and safety outcomes of DOACs versus warfarin in men and women with stratifications for anticoagulation control. METHODS: Patients newly diagnosed with atrial fibrillation and prescribed oral anticoagulants during 2010 to 2015 were identified using the Hong Kong clinical database. Propensity score matching was performed in men and women separately. Further analysis was conducted to stratify warfarin users according to their anticoagulation control. Cox regression was used to compare the risk of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), gastrointestinal bleeding, and all-cause mortality in the specific sex. RESULTS: There were 4,972 men and 4,834 women successfully matched in our cohort. Compared with warfarin, DOAC use was associated with a lower risk of ICH (hazard ratio [HR]: 0.16; 95% confidence interval [CI]: 0.06 to 0.40) and all-cause mortality (HR: 0.55; 95% CI: 0.39 to 0.77) in women but not in men. The treatment by sex interaction was significant for ICH only, and a significantly lower risk of ICH remained in the DOAC group when compared with warfarin users with good anticoagulation control (HR: 0.13; 95% CI: 0.02 to 1.00) among women only. The risks of ischemic stroke or systemic embolism and gastrointestinal bleeding with DOACs versus warfarin were comparable in both sexes. CONCLUSIONS: DOACs were associated with a lower risk of ICH and all-cause mortality in women only, where the association of lower ICH risk remained when compared with warfarin users with good anticoagulation control. PMID- 30012321 TI - Sex Implications in the Response to Anticoagulant Therapy in Atrial Fibrillation. PMID- 30012323 TI - Refining Lipoprotein(a) Associated Cardiovascular Risk in Women. PMID- 30012322 TI - Lipoprotein(a) and Cardiovascular Risk Prediction Among Women. AB - BACKGROUND: Although lipoprotein(a) [Lp(a)] is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial. OBJECTIVES: This study examined the association and clinical utility of Lp(a) with incident CVD in women. METHODS: A turbidimetric assay assessed Lp(a) in 3 cohorts of women (the WHS [Women's Health Study] [N = 24,558], a case-cohort sample from the WHI [Women's Health Initiative] Observational Study [n = 1,815 cases, subcohort n = 1,989], and the JUPITER [Justification for Use of Statins in Prevention] trial [n = 2,569]) and in men from JUPITER (n = 5,161). A WHS derivation sample (n = 16,400) determined the form of association with incident CVD. This was tested in WHS validation data (n = 8,158) and the other study samples. Models including traditional CV risk factors but with and without Lp(a) were compared using risk reclassification. RESULTS: In the WHS, there was a curvilinear association, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol (TC) >220 mg/dl. In the WHS test sample, there was a small but significant change in the C-statistic (0.790 to 0.797; p = 0.035) but no improvement in measures of reclassification. This pattern was replicated among women in the WHI and JUPITER trial. In contrast, there was a strong association of Lp(a) with CVD among men with low TC levels in JUPITER. CONCLUSIONS: In 3 cohorts of women, Lp(a) was associated with CVD only among those with high TC, and improvement in prediction was minimal. These data have implications for Lp(a) in clinical practice among women and for trials of Lp(a)-lowering agents. PMID- 30012324 TI - Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease. AB - BACKGROUND: Identification of biomarkers that cause coronary artery disease (CAD) has led to important advances in prevention and treatment. Epidemiological analyses have identified many biomarker-CAD relationships; however, these associations may arise from reverse causation and/or confounding and therefore may not represent true causal associations. Mendelian randomization (MR) analyses overcome these limitations. OBJECTIVES: This study sought to identify causal mediators of CAD through a comprehensive screen of 237 biomarkers using MR. METHODS: MR was performed by identifying genetic determinants of 227 biomarkers in ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial participants (N = 4,147) and combining these with genetic effects on CAD from the CARDIoGRAM consortium (60,801 cases and 123,504 controls). Blood concentrations of novel biomarkers identified by MR were then tested for association with incident major adverse cardiovascular events in ORIGIN. RESULTS: Six biomarkers were found to be causally linked to CAD after adjustment for multiple hypothesis testing. The causal role of 4 of these is well documented, whereas macrophage colony-stimulating factor 1 (CSF1) and stromal cell-derived factor 1 (CXCL12) have not previously been reported, to the best of our knowledge. MR analysis predicted an 18% higher risk of CAD per SD increase in CSF1 (odds ratio: 1.18; 95% confidence interval: 1.08 to 1.30; p = 2.1 * 10-4) and epidemiological analysis identified a 16% higher risk of major adverse cardiovascular events per SD (hazard ratio: 1.16; 95% confidence interval: 1.09 to 1.23; p < 0.001). Elevated CXCL12 levels were also identified as a causal risk factor for CAD with consistent epidemiological results. Furthermore, genetically predicted CSF1 and CXCL12 levels were associated with CAD in the UK Biobank (n = 343,735). CONCLUSIONS: The study identified CSF1 and CXCL12 as causal mediators of CAD in humans. Understanding the mechanism by which these markers mediate CAD will provide novel insights into CAD and could lead to new approaches to prevention. These results support targeting inflammatory processes and macrophages, in particular, to prevent CAD, consistent with the recent CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study). (Outcome Reduction With Initial Glargine Intervention [ORIGIN]; NCT00069784). PMID- 30012325 TI - Making the Most out of Mendel's Laws in Complex Coronary Artery Disease. PMID- 30012326 TI - The Evolving Future of PCSK9 Inhibitors. AB - Variants in proprotein convertase subtilisin/kexin type 9 (PCSK9) provide insights into mechanisms regulating low-density lipoprotein (LDL) levels. Human monoclonal antibodies that target PCSK9 lower LDL cholesterol (LDL-C) levels by 55% to 72% in different high-risk patient groups. Clinical trials with PCSK9 inhibitors have demonstrated reductions in atherosclerotic cardiovascular disease events, particularly in patients with recent acute coronary syndrome, multivessel coronary artery disease, or peripheral arterial disease. Commonly observed profound reductions in LDL-C to levels <25 mg/dl have been accompanied by even lower rates of atherosclerotic cardiovascular disease events, thus supporting the concept that there may be no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been accompanied by a safety profile that has been very favorable. On the basis of clinical trial evidence, LDL lowering with PCSK9 inhibitors is recommended for high-risk patients with LDL C levels >=70 mg/dl on maximally tolerated oral therapies including statins and/or ezetimibe. PMID- 30012327 TI - Meta-Analysis for the Prognosis of On-Pump Versus Off-Pump Coronary Artery Bypass Grafting. PMID- 30012328 TI - Long-Term Survival With On-Pump Coronary Artery Bypass Grafting. PMID- 30012329 TI - Long-Term Outcomes Following Off-Pump Coronary Artery Bypass Grafting: Fixed Effects Versus Random-Effects Models. PMID- 30012330 TI - Reply: On the Use of Odds Ratios Versus Hazard Ratios, Meta-Regression, and Heterogeneity in Meta-Analyses. PMID- 30012331 TI - Elevated Cardiac Troponin T in Skeletal Myopathies: Skeletal TnT Cross-Reactivity and/or Cardiac TnT Expression? PMID- 30012332 TI - Reply: Elevated Cardiac Troponin T in Skeletal Myopathies: Skeletal TnT Cross Reactivity and/or Cardiac TnT Expression? PMID- 30012333 TI - Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. AB - Mitochondria regulate hepatic lipid metabolism and oxidative stress. Ultrastructural mitochondrial lesions, altered mitochondrial dynamics, decreased activity of respiratory chain complexes, and impaired ability to synthesize adenosine triphosphate are observed in liver tissues from patients with alcohol associated and non-associated liver diseases. Increased lipogenesis with decreased fatty acid beta-oxidation leads to the accumulation of triglycerides in hepatocytes, which, combined with increased levels of reactive oxygen species, contributes to insulin resistance in patients with steatohepatitis. Moreover, mitochondrial reactive oxygen species mediate metabolic pathway signaling; alterations in these pathways affect development and progression of chronic liver diseases. Mitochondrial stress and lesions promote cell death, liver fibrogenesis, inflammation, and the innate immune responses to viral infections. We review the involvement of mitochondrial processes in development of chronic liver diseases, such as nonalcoholic fatty, alcohol-associated, and drug associated liver diseases, as well as hepatitis B and C, and discuss how they might be targeted therapeutically. PMID- 30012334 TI - Gastrointestinal and Extra-Intestinal Manifestations of IgG4-Related Disease. AB - IgG4-related disease (IgG4-RD) is a chronic relapsing multi-organ fibro inflammatory syndrome of presumed autoimmune etiology. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4+ cells. Increased titers of autoantibodies against a spectrum of self-antigens and response to steroids have led to its characterization as an autoimmune disease. However, the pathognomonic antigens probably differ among manifestations, and different antigens or autoantibodies produce similar immune reactions in different organs. Little is known about the pathogenic effects, if any, of serum IgG4 or IgG4+ plasma cells in tissues. Despite several animal models of the disease, none truly recapitulates human IgG4-RD. Histologic analyses of tissues from patients with IgG4-RD reveal a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, although these features vary among organs. Typical presentation and imaging findings include mass-forming synchronous or metachronous lesions in almost any organ, but most commonly in the pancreas, bile duct, retroperitoneum, kidneys, lungs, salivary and lacrimal glands, orbit, and lymph nodes. In all organs, inflammation can be reduced by corticosteroids and drugs that deplete B cells, such as rituximab. Patients with IgG4-RD have relapses that respond to primary therapy. Intense fibrosis accompanies the inflammatory response, leading to permanent organ damage and insufficiency. Death from IgG4-RD is rare. IgG4-RD is a multi-organ disease with predominant pancreatico-biliary involvement. Despite its relapsing-remitting course, patients have an excellent prognosis. PMID- 30012336 TI - Editorial Comment. PMID- 30012337 TI - Reply by Authors. PMID- 30012335 TI - Contribution of hypertension to severe maternal morbidity. AB - BACKGROUND: Maternal mortality and severe maternal morbidity are growing public health concerns in the United States. The Centers for Disease Control and Prevention Severe Maternal Morbidity measure provides insight into processes underlying maternal mortality and may highlight modifiable risk factors for adverse maternal health outcomes. OBJECTIVE: The primary objective of this study was to evaluate the association between hypertensive disorders and severe maternal morbidity at a regional perinatal referral center. We hypothesized that women with preeclampsia with severe features would have a higher rate of severe maternal morbidity compared to normotensive women. We also assessed the proportion of severe maternal morbidity diagnoses that were present on admission, in contrast to those arising during the delivery hospitalization. STUDY DESIGN: In this retrospective cross-sectional analysis, we assessed rates of severe maternal morbidity diagnoses (eg, renal insufficiency, shock, and sepsis) and procedures (eg, transfusion and hysterectomy) for all 7025 women who delivered at the University of Washington Medical Center from Oct. 1, 2013, through May 31, 2017. Severe maternal morbidity was determined from prespecified International Classification of Diseases diagnosis and procedure codes; all diagnoses were confirmed by chart review. Present-on-admission rates were calculated for each diagnosis through hospital administrative data provided by the Vizient University Health System Consortium. Maternal demographic and clinical characteristics were compared for women with and without severe maternal morbidity. The chi2 and Fisher exact tests were used to determine statistical significance. Odds ratios and 95% confidence intervals were calculated for the associations between maternal demographic and clinical characteristics and severe maternal morbidity. RESULTS: Of 7025 deliveries, 284 (4%) had severe maternal morbidity; 154 had transfusion only, 27 had other procedures, and 103 women had 149 severe maternal morbidity diagnoses (26 women had multiple diagnoses). Severe preeclampsia occurred in 438 deliveries (6.2%). Notably, hypertension was associated with severe maternal morbidity in a dose-dependent fashion, with the strongest association observed for preeclampsia with severe features (odds ratio, 5.4; 95% confidence interval, 3.9-7.3). Severe maternal morbidity was also significantly associated with preeclampsia without severe features, chronic hypertension, preterm delivery, pregestational diabetes, and multiple gestation. Among women with severe maternal morbidity, over one third of preterm births were associated with maternal hypertension. American Indian/Alaskan Native women had significantly higher severe maternal morbidity rates compared to other racial/ethnic groups (11.7% vs 3.9% for Whites, P < .01). Overall, 39.6% of severe maternal morbidity diagnoses were present on admission. CONCLUSION: Hypertensive disorders in pregnancy are strongly associated with severe maternal morbidity in a dose-dependent relationship, suggesting that strategies to address rising maternal morbidity rates should include early recognition and management of hypertension. Prevention strategies focused on hypertension might also impact medically indicated preterm deliveries. The finding of increased severe maternal morbidity among American Indian/Alaskan Native women, a disadvantaged population in Washington State, underscores the role that socioeconomic factors may play in adverse maternal health outcomes. As 39% of severe maternal morbidity diagnoses were present on admission, this measure should be risk-adjusted if used as a quality metric for comparison between hospitals. PMID- 30012338 TI - Editorial Comment. PMID- 30012340 TI - Reply by Authors. PMID- 30012339 TI - Editorial Comment. PMID- 30012341 TI - Editorial Comment. PMID- 30012342 TI - Reactive oxygen species and NADPH oxidase 4 involvement in osteoarthritis. AB - Osteoarthritis (OA) is a degenerative chronic disease affecting >300,000 million people around the world as of 2016. Symptomatic measures exist, but there are hardly any curative treatments available. Disruption of the cartilage homeostasis in favor of catabolism leads to cartilage destruction. ROS-macromolecular-induced damage is significantly greater in OA cartilage and OA is described as low-grade chronic systemic inflammation. This review aimed to assess the critical role of cartilage ageing and oxidative stress in the OA process, focusing in particular on NADPH oxidase and especially Nox4 involvement. With age, hypertrophic senescent cells with an altered redox cell profile accumulated. Chondrocytes are more sensitive to oxidant-mediators and the serum level of pro-inflammatory mediators increases. Age-related advanced glycation end products impact on extra cellular matrix (ECM) properties leading to the apoptosis of chondrocytes. A focus on NADPH oxidase-mediated-ROS signaling highlighted the very specific Nox4 isoform, which plays a role on the final common pathway targeting chondrocyte cells. IL-1beta-mediated Nox4 stimulation induced an increase in the levels released by the chondrocyte of MMP-1 and MMP-13 proteins, which are involved in ECM degradation. In comparison with the other Nox isoforms, Nox4 remains unusual, since it is constitutively active, does not depend on cytosolic activator proteins and seems to generate H2O2 thanks to the specific conformation of the Nox4 E-loop. Nox4-induced ROS production appears an essential actor in the OA process and it could be relevant to focus on this target in the aim of discovering and developing new therapeutic strategies. PMID- 30012343 TI - Grouper (Epinephelus coioides) antimicrobial peptide epinecidin-1 exhibits antiviral activity against foot-and-mouth disease virus in vitro. AB - Picornavirus is a highly contagious virus that usually infects cloven hoofed animals and causes foot-and-mouth disease. This disease is a major threat to livestock breeding worldwide and may lead to huge economic losses. Because effective vaccines or antiviral drugs remain unavailable, the search for new agents to combat FMDV infections is ongoing. Antimicrobial peptides are known to possess a broad range of biological activities, including antibacterial, antiviral, antitumor and immunomodulatory effects. In this work, we used a cell culture FMDV replication assay to evaluate several antimicrobial peptides for their ability to act as antiviral agents. We found that a synthesized form of the Epinephelus coioides antimicrobial peptide, epinecidin-1 (Epi-1), was effective at combatting FMDV. Epi-1 is known to have broad spectrum antimicrobial activity and low toxicity to normal eukaryotic cells, making it a good candidate for use as a therapeutic agent.The 50% cytotoxic concentration (CC50) for BHK-21 cells was 19.5 MUg/ml for synthesized Epi-1, and the 50% effective concentration (EC50) for viral inhibition was 0.6 MUg/ml. The selectivity index was 31.4, as calculated by the CC50/EC50 ratio. Furthermore, Epi-1 showed virucidal activity against FMDV at high concentrations. Interestingly, our data also showed that FMDV infection was most impaired when Epi-1 was treated at the time of viral adsorption. Taken together, our data show that Epi-1 may be a promising candidate for development as an anti-FMDV agent. PMID- 30012345 TI - Burkholderia cepacia complex infections: More complex than the bacterium name suggest. AB - Burkholderia cepacia complex (Bcc) is an emerging pathogen causes life threatening infections in cystic fibrosis patients. This narrative review aims to highlight an update on the epidemiology, the microbiological diagnostic methods, the antimicrobial resistance mechanisms, and the most current as well the promising therapeutic options for Bcc. Although Bcc plays a role in crop growth due to its fungicidal activity and pesticide metabolizer, it has been frequently implicated in outbreaks in the United States and Worldwide due to contaminated medicines or medical devices. Phenotypic methods of microbial identification often lack sensitivity. Consequently, the diagnosis is mainly based on molecular testing which is critical for species identification. Disc diffusion is a poorly reproducible method for antibiotic susceptibility testing of Bcc when compared to broth microdilution, agar dilution or Etest. Bcc is naturally resistant to many antimicrobialagents including carboxypenicillins, polymyxin, and often, aminoglycosides due to the efflux pump activity. Treatment is often based on antimicrobial susceptibility data. However, trimethoprim-sulfamethoxazole, meropenem, doripenem, doxycycline, minocycline, and ceftazidime have been shown to be among the most active antimicrobial agents to date. Further studies are needed to compare the current antimicrobial agents and to study new inhibitors of the different efflux pumps implicated in the resistance of Bcc to antibiotics. Furthermore, harmonization of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines is highly important to fight against the rapidly emerging resistant bacteria e.g. Bcc. PMID- 30012344 TI - Proapoptic and immunotoxic effects of sulfur-fumigated polysaccharides from Smilax glabra Roxb. in RAW264.7 cells. AB - The herbs with sulfur-fumigation may induce chemical transformation thus causing harmful effects on patients. In the current study, the difference of physicochemical property from sulfur-fumigated Smilax glabra Roxb. polysaccharides (SSGRP) and non-fumigated Smilax glabra Roxb. polysaccharides (NSGRP) were characterized and compared, such as external appearance, dissolvability, extraction yield, glucose content, inorganic elements analysis, UV and IR scanning spectrum. Additionally, the immunotoxicity and mechanisms of SSGRP and NSGRP on immune response of murine abdominal RAW264.7 macrophage cells were evaluated by cell viability, flow cytometry, quantitative real-time PCR and western blotting analyses. The results demonstrated that NSGRP could not affect the proliferation of RAW264.7 cells but SSGRP could effectively inhibit the cells viability by inducing apoptosis. SSGRP could also up-regulated the mRNA expression of apoptosis factors including Bax and caspase-8. Further investigation elucidated that NSGRP exhibited excellent immunomodulatory activity of RAW264.7 cells, however, SSGRP might inhibit the activity through down regulating the tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) mRNA expression as well as blocking the phosphorylation of phosphorylated extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). In conclusion, our study suggested that sulfur-fumigation displayed significant immune toxicity on immune response of murine abdominal RAW264.7 macrophages, and the study provided new insights in controlling the sulfur-fumigation processing and storage method in Chinese herbal medicines. PMID- 30012346 TI - Repair of Hemi-Truncus with "Irreversible" Pulmonary Hypertension. AB - Anomalous origin of the pulmonary artery from the ascending aorta (AOPA) can lead to congestive heart failure in infancy and with advancing age many patients will develop severe pulmonary hypertension. Surgical intervention had high mortality/morbidity risk if this happens. Strategies to manage these patients seem only limited to heart-lung transplantation or lung transplantation. Here, we successfully carried out surgical intervention to in an adult patient who had anomalous origin of the right pulmonary artery from the ascending aorta with high pressures in the ascending aorta and normally originating pulmonary artery. PMID- 30012347 TI - Response to aspirin therapy in patients with myeloproliferative neoplasms depends on the platelet count. AB - Patients with myeloproliferative neoplasms (MPN) are at an increased risk of thrombotic events even during antiplatelet therapy with aspirin. In the current study, we sought to investigate the association of the platelet count with the inhibitory potential of antiplatelet therapy in MPN. We determined arachidonic acid (AA)- and adenosine diphosphate (ADP)-inducible platelet reactivity by multiple electrode aggregometry in 93 patients with essential thrombocythemia, polycythemia vera or primary myelofibrosis. In patients without aspirin therapy (n = 44), the platelet count did not correlate with platelet aggregation. In aspirin-treated patients (n = 49), we observed a moderate correlation of residual AA-inducible platelet aggregation with the platelet count (r = 0.49; P < 0.001). Further, patients with high on-treatment residual platelet reactivity to AA (HRPR AA) had a significantly higher platelet count than patients without HRPR AA (547 * 109/L [340 - 644 * 109/L] vs 358 * 109/L [242 - 501 * 109/L], P = 0.01). Receiver-operating characteristic curve analysis revealed a platelet count of >=317 * 109/L as best threshold to distinguish between patients without and with HRPR AA (area under the curve: 0.73). After adding the direct ADP P2Y12 inhibitor cangrelor to blood samples from all 93 patients in vitro, residual ADP-inducible platelet reactivity correlated weakly with the platelet count (r = 0.26, P = 0.01), but the platelet count did not differ significantly between patients with and without HRPR ADP (396 * 109/L [316 - 644 * 109/L] vs 340 * 109/L [241 - 489 * 109/L]; P = 0.2). In conclusion, our findings suggest that the extent of platelet inhibition by aspirin in patients with MPN at least in part depends on their individual platelet count. PMID- 30012348 TI - Feasibility of left atrial appendage device closure following chronically failed surgical ligation. AB - BACKGROUND: Incomplete surgical left atrial appendage occlusion (S-LAAO) with a narrow neck has been shown to predict an increased rate of embolic stroke. Patients with a previously attempted S-LAAO were systematically excluded from all clinical trials of LAA closure devices. OBJECTIVE: The purpose of this study was to evaluate the feasibility of Watchman LAA device closure for patients referred with chronically incomplete S-LAAO. METHODS: A prospective single-arm feasibility cohort evaluated only subjects undergoing Watchman LAA closure following incomplete S-LAAO. Patients referred and implanted were followed in the Vanderbilt LAA Registry. Preprocedure computed tomographic angiography and transesophageal echocardiography (TEE) were performed to evaluate suitability for closure, with 45-day follow-up TEE postimplant. RESULTS: All attempted LAA closures after incomplete S-LAAO were successful (n = 6). Mean age was 76.3 +/- 7 years. Mean CHADS2Vasc score was 3.8 +/- 0.8, and HAS-BLED score was 3.5 +/- 0.5. At 45-day follow up, all subjects had complete device seal with no thrombus on device and had transitioned to clopidogrel plus aspirin. Three subjects had narrow ostial necks with a maximum diameter <=9 mm. In all cases, the 4.7-mm Watchman access sheath was able to cross the ostial stricture. Mean occluder size implanted was 28 +/- 4 mm. Mean LAA dimension by TEE in the 45 degrees and 135 degrees views for depth was 31 mm and ostial diameter was 11 * 16 mm, below the minimum Watchman indication for use of 17 mm. No major intraoperative complications occurred. CONCLUSION: Watchman LAA closure seems to be feasible in patients with chronically incomplete S-LAAO, including subjects with a narrow neck <9 mm in width. PMID- 30012349 TI - AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders. AB - Aldo-Keto-Reductase 1C3 (type 5 17beta-hydroxysteroid dehydrogenase (HSD)/prostaglandin (PG) F2alpha synthase) is the only 17beta-HSD that is not a short-chain dehydrogenase/reductase. By acting as a 17-ketosteroid reductase, AKR1C3 produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates for aromatase. AKR1C3 is implicated in the production of androgens in castration-resistant prostate cancer (CRPC) and polycystic ovarian syndrome; and is implicated in the production of aromatase substrates in breast cancer. By acting as an 11-ketoprostaglandin reductase, AKR1C3 generates 11beta-PGF2alpha to activate the FP receptor and deprives peroxisome proliferator activator receptorgamma of its putative PGJ2 ligands. These growth stimulatory signals implicate AKR1C3 in non-hormonal dependent malignancies e.g. acute myeloid leukemia (AML). AKR1C3 moonlights by acting as a co-activator of the AR and stabilizes ubiquitin ligases. AKR1C3 inhibitors have been used clinically for CRPC and AML and can be used to probe its pluripotency. PMID- 30012351 TI - Developmental and reproduction toxicity studies of glycolipids from Dacryopinax spathularia. AB - The developmental and reproduction toxicity potential of jelly mushroom glycolipids from Dacryopinax spathularia was studied in Crl:CD (SD) rats by daily oral gavage administration at doses of 150, 500 or 1000 mg/kg/day. Pregnant female rats in the developmental study received the test article from Gestation Days 6-19. F0 and F1 parental animals in the 2-generation reproduction toxicity study were dosed for a minimum of 70 days prior to mating and throughout mating, gestation, and lactation, until the day prior to euthanasia (following weaning of litters on postnatal day 21). The offspring of the F0 and F1 generations were potentially exposed to the test article in utero and via the milk while nursing. In the developmental study, there were no adverse effects on intrauterine growth and survival, or fetal morphology. In the 2-generation reproduction toxicity study, there were no adverse effects on observed parameters including macroscopic or microscopic findings, or organ weights for F0 or F1 animals, no effects on reproductive performance, and no test article-related effects on F1 and F2 postnatal survival, development, or growth. Therefore, the no-observed-adverse effect level (NOAEL) for parental systemic toxicity, parental reproductive toxicity, and developmental/neonatal toxicity, was considered to be 1000 mg/kg/day, the highest dosage tested. PMID- 30012350 TI - RIFM Fragrance ingredient safety assessment, methylheptenol, CAS Registry Number 1335-09-7. PMID- 30012352 TI - Dietary patterns of Australian children at three and five years of age and their changes over time: A latent class and latent transition analysis. AB - Consuming a healthy diet characterised by a variety of nutritious foods is essential for promoting and maintaining health and wellbeing, yet the diets of Australian children continue to fall well short of national healthy eating recommendations. This research endeavours to identify patterns of dietary intake in Australian children at three and five years of age and investigate associations between early childhood dietary patterns and socio-economic and demographic indicators and Body Mass Index (BMI), as well as identify changes in children's dietary patterns over time. Cross-sectional dietary patterns were derived for 1565 and 631 children aged three and five years, respectively using Latent Class Analysis (LCA), with changes over time analysed with Latent Transition Analysis (LTA). Demographic variables of interest included child sex, parental age, family status, and use of childcare services and socio-economic variables included education, income and employment status. Three patterns of dietary intake were identified at three years (Highly Unhealthy, Healthier and Moderately Unhealthy) and two patterns at five years (Unhealthy and Healthier). Children with younger mothers, working mothers, fathers with a higher BMI and living in a two-carer household were more likely to have unhealthy eating patterns at three years, and children with working mothers and living in a two carer household were more likely to have unhealthy patterns of dietary intake at five years. Approximately one eighth of the sample transitioned from the healthier to unhealthy pattern of dietary intake from three to five years. The quality of Australian children's diets appears to be declining through the early childhood years, continuing to highlight the importance of nutrition policies and interventions targeted towards the early years of life. PMID- 30012353 TI - Investigating the perception of face identity in adults on the autism spectrum using behavioural and electrophysiological measures. AB - In the present study, we investigated face processing in individuals with self reported Autism Spectrum Disorder (ASD, n = 16) and typically developing control participants (n = 16) using behavioural and electrophysiological measures. As a measure of their face memory, we administered the Cambridge Face Memory Test to participants in the ASD group. The results showed that the scores of the ASD participants were reliably below the age- and gender-matched norms of neurotypical individuals. To measure brain responses to faces, we used the fast periodic visual stimulation method, presenting photographs of a same-identity face (i.e., base face) at a constant frequency of 6 Hz (F) interleaved with different-identity faces (i.e., the oddball faces) presented at 1.2 Hz. The 6 Hz presentation of the base face and 1.2 Hz presentation of the oddball face elicited periodic brain responses corresponding to face detection and face individuation processes, respectively. Participants viewed four blocks of upright faces and four blocks of inverted faces. The results showed an enhanced EEG response to upright base faces at 6 Hz frequency and its harmonics compared to inverted faces, and the response was most focal over medial occipital channels. An enhanced response was found to upright oddball faces at 1.2 Hz and its harmonics compared to the inverted faces, and the response was centred over occipito-temporal channels in the right hemisphere. Critically, no differences or interactions were found between the ASD and typically developing groups in the responses to either the 6 Hz base faces or the 1.2 oddball faces. These results suggest that in individuals with ASD, the earlier stage of face perception, as measured by the fast periodic visual stimulation paradigm, can be dissociated from the later memory stage of face processing, as assessed by the Cambridge Face Memory Test. PMID- 30012354 TI - Rational design of multimodal therapeutic nanosystems for effective inhibition of tumor growth and metastasis. AB - : Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-kappaB agent, p65-shRNA, for effective treatment of metastatic breast cancer. In our design, we first conjugated DOX via an acid labile linker onto gold nanorods that were pre-modified with the tumor targeting peptide RGD and a positively charged, disulfide cross-linked short polyethylenimines (DSPEI), and then incorporated shRNA through electrostatic complexation with DSPEI. We show that this "all in one" nanotherapeutic system (RDG/shRNA@DOX) can be effectively internalized through RGD-mediated endocytosis, followed by stimuli-responsive intracellular co-release of DOX and shRNA. Our in vitro experiments suggest that this multimodal system can significantly inhibit cell proliferation, angiogenesis, and invasion of metastatic MDA-MB-435 cancer cells. Systemic administration of RDG/shRNA@DOX into a metastatic mouse model led to enhanced tumor accumulation, and, most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides important insight into the rational design of therapeutic systems for the effective treatment of metastatic carcinoma. STATEMENT OF SIGNIFICANCE: The key to successfully treat metastatic cancer is the simultaneous inhibition of both tumor growth and metastasis. This represents a great challenge for the design of drug delivery systems since multimodal therapeutic agents must be rationally combined to overcome the respective biological mechanisms underpinning tumor cell proliferation and invasion. Toward this end, we developed a hybrid nanomedicine platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-kappaB agent, p65-shRNA, for effective treatment of metastatic breast cancer. We showed that this multimodal system (RDG/shRNA@DOX) enhanced tumor accumulation, led to prolonged circulation, and most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides significant insight into the rational design of therapeutic systems for the effective treatment of metastatic cancer. PMID- 30012356 TI - Mining features for biomedical data using clustering tree ensembles. AB - The volume of biomedical data available to the machine learning community grows very rapidly. A rational question is how informative these data really are or how discriminant the features describing the data instances are. Several biomedical datasets suffer from lack of variance in the instance representation, or even worse, contain instances with identical features and different class labels. Indisputably, this directly affects the performance of machine learning algorithms, as well as the ability to interpret their results. In this article, we emphasize on the aforementioned problem and propose a target-informed feature induction method based on tree ensemble learning. The method brings more variance into the data representation, thereby potentially increasing predictive performance of a learner applied to the induced features. The contribution of this article is twofold. Firstly, a problem affecting the quality of biomedical data is highlighted, and secondly, a method to handle that problem is proposed. The efficiency of the presented approach is validated on multi-target prediction tasks. The obtained results indicate that the proposed approach is able to boost the discrimination between the data instances and increase the predictive performance. PMID- 30012357 TI - The Fourth Edition of the Universal Definition of Myocardial Infarction. PMID- 30012355 TI - Rationale and design of a placebo controlled randomized trial to assess short term, high-dose oral cholecalciferol on select laboratory and genomic responses in African Americans with hypovitaminosis D. AB - Cardiovascular Disease (CVD) and related disorders remain a leading cause of health disparities and premature death for African Americans. Hypovitaminosis D is disproportionately prevalent in African Americans and has been linked to CVD and CVD risk factors including hypertension, diabetes and obesity. Thus, hypovitaminosis D may represent a common pathway influencing CV risk factors in a select subgroup of persons. The purpose of this paper is to report the study design of a prospective eight week prospective double-blind randomized, placebo controlled trial (n = 330 allocated 2:1 to intervention vs. control) to assess the effect of placebo vs. high-dose oral cholecalciferol (100,000 IU vitamin D3 at baseline and week 2) on 6-week change of select biologic cardiometabolic risk factors (including parathyroid hormone to assess biologic activity, pro inflammatory/pro-thrombotic/fibrotic markers, insulin sensitivity and vitamin D metabolites) and their relationship to vitamin D administration and modification by vitamin D receptor polymorphisms in overweight, hypertensive African Americans with hypovitaminosis D. Findings from this trial will present insights into potential causal links between vitamin D repletion and mechanistic pathways of CV disease, including established and novel genomic markers. PMID- 30012358 TI - Medical Principles in Obstetrical Consults. PMID- 30012359 TI - Should Patients Infected with Borrelia burgdorferi No Longer Be Referred to as Having Lyme Disease? PMID- 30012360 TI - Implementation of a Multidisciplinary Inpatient Cardiology Service to Improve Heart Failure Outcomes in Guyana. AB - BACKGROUND: Guyana is a small developing country with a high burden of cardiovascular disease and extensive barriers to optimal care delivery. We investigated the effectiveness of a newly established multidisciplinary inpatient cardiology service in this setting. METHODS: We performed an interrupted time series cohort study of heart failure (HF) patients admitted to the Georgetown Public Hospital Corporation from January to December 2015 and July 2016 to December 2017. The primary outcome was discharge on guideline-directed medical therapy (GDMT). Secondary outcomes included length of hospitalization and all cause mortality. RESULTS: We identified 740 patients, 347 (46.9%) of whom were admitted after service implementation. The postimplementation cohort was more likely to be discharged on a beta-blocker (66.6% vs 41.7%; P < .01) and mineralocorticoid receptor antagonist (31.7% vs 15.3%; P = .01). They were also more likely to undergo echocardiography (60.8% vs 40.5%; P < .01) and chest x rays (70.6% vs 46.6%; P < .01). Hospitalization length (10.0 +/- 13.1 vs 9.8 +/- 10.1 days) and readmissions within 90 days (19.0% vs 19.1%) were not significantly different. There were fewer deaths in the postimplementation cohort compared with the preimplementation cohort (12/347 vs 28/393). CONCLUSIONS: Establishment of a multidisciplinary inpatient cardiology service demonstrated increased adherence to GDMT without extending length of hospitalization. PMID- 30012361 TI - Circulating Cardiac Troponin I Levels Measured by a Novel Highly Sensitive Assay in Acute Decompensated Heart Failure: Insights From the ASCEND-HF Trial. AB - BACKGROUND: Circulating cardiac troponin levels (cTn), representative of myocardial injury, are commonly elevated in heart failure (HF) and related to adverse clinical events. However, whether cTn represents a spectrum of risk in HF is unclear. METHODS: Baseline, 48-72-hour, and 30-day plasma cTnI was measured with the use of a new highly sensitive assay in 900 subjects with acute decompensated HF (ADHF) in ASCEND-HF. Multivariable models determined the relationship between cTnI and outcomes. RESULTS: The median (interquartile range) cTnI was 16.4 (9.3-31.6) ng/L at baseline, 14.1 (7.8-29.7) ng/L at 48-72 hours, and 11.6 (6.8-22.5) ng/L at 30 days. After additional adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) to established risk predictors, both baseline (odds ratio [OR] 1.25; P = .03) and 48-72-hour (OR 1.43; P = .001) cTnI were associated with higher risk for death or worsening HF before discharge. However, only cTnI at 30 days was associated with 180-day death (hazard ratio 1.25; P = .007). There were no curvilinear associations between changing cTnI and clinical outcomes. CONCLUSIONS: Circulating cTnI level was associated with clinical outcomes in ADHF, but these observations diminished with additional adjustment for NT-proBNP. Although they likely represent a spectrum of risk in ADHF, these findings question the implications of changing cTnI levels during treatment. PMID- 30012362 TI - The 5-level diagnostic report model as an essential approach for adding value to laboratory testing. AB - BACKGROUND: Clinical laboratory results have limited value unless they are appropriately analyzed and interpreted. Clinicians may neglect key abnormal laboratory findings because they lack time or sufficient information to adequately analyze the volume of test results received. It is important that the clinical significance of test results is analyzed and communicated appropriately in the report. METHODS: To maximize the utility of laboratory testing and ensure optimal patient care, we developed the 5-level clinical laboratory diagnostic report. This report includes a comprehensive analysis of all test results, reported step by step according to clinical disease system. RESULTS: The 5-level model includes description, summary, analysis, and interpretation of test results, all of which help clinicians to develop a thorough, deep, and integrated understanding of the clinical significance of large amounts of complicated and scattered laboratory testing results. CONCLUSIONS: The 5-level report model is an effective and efficient approach to supporting clinical diagnosis and improving the value of clinical laboratory results. PMID- 30012363 TI - Cost-Effectiveness of Urinary Biomarker Panel in Prostate Cancer Risk Assessment. AB - PURPOSE: SelectMDx (MDxHealth(r)) is a panel of urinary biomarkers used in conjunction with traditional risk factors to individualize risk prediction for clinically significant prostate cancer. In this study we sought to characterize the effectiveness of SelectMDx in a population of American men with elevated prostate specific antigen. MATERIALS AND METHODS: We developed a Markov decision analytical model to simulate the chain of events and downstream outcomes associated with ultrasound guided prostate biopsy and a strategy in which the biomarker panel is implemented prior to biopsy. The primary outcome was health outcomes, measured in QALYs (quality-adjusted life years). The secondary outcome was health care costs from the Medicare payer perspective. Multiple 1-way sensitivity analyses were performed to characterize model robustness. RESULTS: The expected mean QALYs per patient under the current standard was 10.796 at a cost of $11,060 during an 18-year horizon. Incorporating the urinary biomarker panel resulted in an expected mean of 10.841 QALYs per patient and a mean cost of $9,366, representing an average of 0.045 QALYs gained at a cost savings of $1,694 per patient. When extrapolating these data to a conservative estimate of 311,879 men per year undergoing biopsy, one would expect that the biomarker panel would result in an incremental 14,035 QALYs gained at a cost savings of $528,323,026 in each yearly cohort. The biomarker panel strategy dominated the current standard across a wide range of sensitivity analyses. CONCLUSIONS: Routine use of the SelectMDx urinary biomarker panel to guide biopsy decision making improved health outcomes and lowered costs in American men at risk for prostate cancer. This strategy may optimize the value of prostate cancer risk assessment in an era of increasing financial accountability. PMID- 30012364 TI - A Critical Analysis of Bulbar Urethroplasty Stricture Recurrence: Characteristics and Management. AB - PURPOSE: We evaluated the management of recurrent bulbar urethral stricture disease after urethroplasty at our institution. MATERIALS AND METHODS: We performed an institution review board approved, retrospective case study of our urethroplasty database to collect stricture related and postoperative information with an emphasis on bulbar urethral stricture disease recurrence after urethroplasty between 1996 and 2012. Repair types included primary anastomotic, augmented anastomotic and onlay repair. Recurrence, which was defined as the need for intervention, was diagnosed with cystoscopy or retrograde urethrogram. RESULTS: We identified 437 men who underwent urethroplasty of bulbar urethral stricture disease as performed by 2 surgeons from January 1996 to December 2012. Of the men 395 had available followup data. Recurrence was identified in 25 men (6.3%), of whom all presented with symptoms, including a weak stream in 23, urinary tract infection in 1 and pyelonephritis in 1. Median time to recurrence was 10 months. Recurrence was initially treated endoscopically in 23 of 25 cases (92%), dilatation in 12 and visual urethrotomy in 11. In 5 patients (22%) further recurrence developed after endoscopic treatment, which was managed by repeat urethroplasty in 2, self-calibration only in 2 and visual urethrotomy with subsequent self-calibration in 1. We identified 2 distinct phenotypes of recurrent stricture, including type A-short focal recurrence, which may be salvaged with an endoscopic procedure, and type B-the long graft length type, which is less likely to be salvaged with endoscopy. CONCLUSIONS: Recurrence after urethroplasty is most likely to develop within the first 12 months. Type A short focal recurrence may be managed by a salvage endoscopic procedure, including dilation or visual urethrotomy. These data on the phenotype of recurrence may be useful for patient treatment. PMID- 30012365 TI - Colpectomy Significantly Reduces the Risk of Urethral Fistula Formation after Urethral Lengthening in Transgender Men Undergoing Genital Gender Affirming Surgery. AB - PURPOSE: We assessed the effect of performing colpectomy before (primary) or after (secondary) gender affirming surgery with single stage urethral lengthening on the incidence of urethral fistula in transgender men. MATERIALS AND METHODS: We retrospectively reviewed the charts of all transgender men who underwent gender affirming surgery with urethral lengthening between January 1989 and November 2016 at VU University Medical Center. Patient demographics, surgical characteristics, fistulas and fistula management, and primary and secondary colpectomy were recorded. Descriptive statistics were calculated and incidence rates were compared. RESULTS: A total of 294 transgender men underwent gender affirming surgery with urethral lengthening. A urethral fistula developed in 111 of the 232 patients (48%) without colpectomy and in 13 of the 62 (21%) who underwent primary colpectomy (p <0.01). Secondary colpectomy resulted in 100% fistula closure when performed in 17 patients with recurrent urethral fistula at the proximal urethral anastomosis and the fixed part of the neourethra. CONCLUSIONS: Primary colpectomy decreases the incidence rate of urethral fistulas. Secondary colpectomy is also an effective treatment of fistulas at the proximal urethral anastomosis and the fixed part of the neourethra. PMID- 30012366 TI - Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma. AB - PURPOSE: We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. MATERIALS AND METHODS: We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. RESULTS: Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. CONCLUSIONS: Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients. PMID- 30012367 TI - Patients with a Prolonged Intensive Care Unit Length of Stay Have Decreased Health-Related Quality of Life After Cardiac Surgery. AB - Cardiac surgery patients with a prolonged ICU length of stay (prICULOS) have lower rates of functional survival following their procedure, however detailed information on their health related quality of life (HRQoL) is lacking. We sought to investigate the potential need for intervention in these high-risk patients through comprehensive HRQoL assessments in the months to year following their surgery. A prospective, observational pilot study was undertaken and cardiac surgery patients with a prICULOS (ICU length of stay of >=5 days) were recruited. A control group was obtained through recruitment of cardiac surgery patients with an ICU length of stay of <5 days. In-person clinical or telephone survey HRQoL assessments were completed at 3-6 months and 1-year time points after their procedure. The standardized mean difference (SMD) was calculated for all study variable comparisons to quantify the standardized effect size observed between non-prICULOS and prICULOS patients. 789 cardiac procedures were performed during the study period and 89 patients experienced a prICULOS (10.7%). Of these 89 patients, 35 prICULOS patients were recruited along with 35 controls. 29 out of 35 prICULOS patients completed the study (83%). At the 3-6 month follow up the prICULOS patients had higher levels of weight loss, fear of falling, and driving deficits. At 1-year, prICULOS patients had persistent difficulties with activities of daily living and required more family and external support. This study demonstrates the need for closer follow up and intervention for cardiac surgery patients with a prICULOS who were found to have poorer mid and long-term HRQoL. PMID- 30012368 TI - Apical Muscular Ventricular Septal Defects: Surgical Strategy Using Three Dimensional Printed Model. AB - To evaluate the utility of a three-dimensional printed model (3D-model) for surgical decision planning in a complex case of multiple ventricular septal defect (VSD) (so-called Swiss-cheese septum). A 3 month-old-girl with diagnosis of multiple apical VSDs in the trabecular septum, perimembranous VSD, and atrial septal defect that resulted in congestive heart failure was referred for surgical intervention. Due to inconclusive understanding of the total number, openings and locations of the apical VSDs, there were concerns regarding the best surgical approach. Using computed tomography images, a 3D-model was fabricated by fused deposition modeling of polyurethane filament. The 3D model helped identifying the total number of VSD, their origins and exits as well as the minimum number of septal bands to resect, the optimal patch size and morphology to completely close all VSDs without reducing significantly the RV cavity. The procedure was successfully replicated in the patient by right atrial approach, resulting in good RV cavity size, function and no residual VSDs evaluated by transesophageal echocardiography. Direct evaluation of the 3D printed replica anatomy and surgical simulation may help optimizing surgical approach, patch size and location and therefore it might reduce complications and residual defects. PMID- 30012369 TI - Clinical Experience of Thoracoscopic Sleeve Lobectomy Using a Novel Needle Holder. AB - Thoracoscopic bronchoplasty requires high technique to control stitching during bronchial reconstruction. Improved quality of suturing instrument may contribute to overcome this difficulty of bronchial anastomosis. Recently, a unique and expected articulated instrument for suturing has been launched on endoscopic surgery. We have successfully performed two cases of thoracoscopic sleeve lobectomy using this instrument. PMID- 30012370 TI - Is It Conceivable to Still Perform the Cut and Sew Cox Maze III Procedure in the Current Era? AB - To determine whether cut and sew Cox maze III procedure is still associated with adequate safety endpoints when performed in conjunction with other open-heart procedures. Between January 2008 and January 2015, 113 consecutive adult patients were submitted to cut and sew Cox maze III procedure in association with other operations for structural heart disease. Mean age was 49 years and 80 (70.8%) were females. Longstanding or persistent atrial fibrillation has occurred in 87.6% and rheumatic heart disease in 80.7%. Valve surgery was performed in 98.2%. The number of associated procedures was correlated with morbidity and hospital mortality. Overall mean cardiopulmonary bypass and aortic cross-clamping times were 129 +/- 26 and 105 +/- 23 minutes, respectively. Hospital mortality was 1.77%, re-exploration for bleeding 0.9%, cerebrovascular accident 1.8%, and acute renal failure requiring hemodialysis 2.6%. The greater number of associated procedures did not correlate with poorer safety outcomes. Permanent pacemaker was required in 18.2% of those with three associated procedures, as opposed to 4% with two procedures and no requirement with one procedure (P = .01). Frequency of sinus rhythm was 88%, 88%, and 85% at 6, 12, and 24 months, respectively. In a contemporary single-center cohort of predominantly rheumatic patients, the surgical treatment of atrial fibrillation associated with structural heart disease by means of cut and sew Cox maze III procedure is safe, with low morbidity and mortality rates. Surgical complexity, defined by number of associated procedures, did not translate into poorer safety endpoints, except for greater need of permanent pacemaker. PMID- 30012371 TI - "Frozen Apex" Repair of a Dilated Cardiomyopathy. AB - We try to make surgical ventricular restoration simpler and more adjustable to safely enhance ventricular function. In eight patients with DiDonato type III dilated cardiomyopathy, we applied a few short-axis purse-string sutures to the endocardial side of the left ventricular apex ("Frozen-Apex" restoration) to make a smaller, cone-shaped apex, based on the concept that the left ventricular apex is important in its existence, but not in its function. The procedure took less than 15 minutes in all the patients. There was no hospital or late death with the follow-up of 549 +/- 389 days. Mid-late postoperatively, New York Heart Association functional class changed from 3.5 +/- 0.8 (preoperative) to 1.6 +/- 0.6 (P = 0.000 vs preoperative), left ventricular diastolic diameter from 64 +/- 16 to 61 +/- 15 mm, systolic diameter from 57 +/- 15 to 50 +/- 17mm (P = 0.070), ejection fraction from 27 +/- 10 to 40 +/- 16% (P = 0.014). Diastolic function as assessed by the ratio of the early to late ventricular filling velocities, the ratio of mitral annular early diastolic velocity to early mitral inflow velocity, and estimated right ventricular pressure remained at the similar level to preoperative one. The new ventricular restoration was associated with better systolic left ventricular function without deteriorating diastolic one. It may improve the outcome of the treatment of selected patients with dilated cardiomyopathy. PMID- 30012372 TI - The Relationship Between General Intelligence and Cortical Structure in Healthy Individuals. AB - Considerable work in recent years has examined the relationship between cortical thickness (CT) and general intelligence (IQ) in healthy individuals. It is not known whether specific IQ variables (i.e., perceptual reasoning [PIQ], verbal comprehension IQ [VIQ], and full-scale IQ [FSIQ]) are associated with multiple cortical measures (i.e., CT, cortical volume (CV), cortical surface area (CSA) and cortical gyrification (CG)) within the same individuals. Here we examined the association between these neuroimaging metrics and IQ in 56 healthy adults. At a cluster-forming threshold (CFT) of p < 0.05, we observed significant positive relationships between CT and all three IQ variables in regions within the posterior frontal and superior parietal lobes. Regions within the temporal and posterior frontal lobes exhibited positive relationships between CV and two IQ variables (PIQ and FSIQ) and regions within the inferior parietal lobe exhibited positive relationships between CV and PIQ. Additionally, CV was positively associated with VIQ in the left insula and with FSIQ within the inferior frontal gyrus. At a more stringent CFT (p < 0.01), the CT-PIQ, CT-VIQ, CT-FSIQ, and CV PIQ relationships remained significant within the posterior frontal lobe, as did the CV-PIQ relationship within the temporal and inferior parietal lobes. We did not observe statistically significant relationships between IQ and either CSA or CG. Our findings suggest that the neural basis of IQ extends beyond previously observed relationships with fronto-parietal regions. We also conclude that CT and CV may be more useful metrics than CSA or CG in the study of intellectual abilities. PMID- 30012373 TI - The Role of Sunscreen in the Prevention of Cutaneous Melanoma and Non-Melanoma Skin Cancer. PMID- 30012374 TI - Short- and long-term gene expression profiles induced by inhaled TiO2 nanostructured aerosol in rat lung. AB - The number of workers potentially exposed to nanoparticles (NPs) during industrial processes is increasing, although the toxicological properties of these compounds still need to be fully characterized. As NPs may be aerosolized during industrial processes, inhalation represents their main route of occupational exposure. Here, the short- and long-term pulmonary toxicological properties of titanium dioxide were studied, using conventional and molecular toxicological approaches. Fischer 344 rats were exposed to 10 mg/m3 of a TiO2 nanostructured aerosol (NSA) by nose-only inhalation for 6 h/day, 5 days/week for 4 weeks. Lung samples were collected up to 180 post-exposure days. Biochemical and cytological analyses of bronchoalveolar lavage (BAL) showed a strong inflammatory response up to 3 post-exposure days, which decreased overtime. In addition, gene expression profiling revealed overexpression of genes involved in inflammation that was maintained 6 months after the end of exposure (long-term response). Genes involved in oxidative stress and vascular changes were also up regulated. Long-term response was characterized by persistent altered expression of a number of genes up to 180 post-exposure days, despite the absence of significant histopathological changes. The physiopathological consequences of these changes are not fully understood, but they should raise concerns about the long-term pulmonary effects of inhaled biopersistent NPs such as TiO2. PMID- 30012375 TI - Impact of hand sanitizer format (gel/foam/liquid) and dose amount on its sensory properties and acceptability for improving hand hygiene compliance. AB - BACKGROUND: Effective alcohol-based hand rubs (ABHRs) and healthcare worker compliance with hand hygiene guidelines are important in the prevention of infection transmission in healthcare settings. Compliance to hand hygiene guidelines is affected by many factors including education, ABHR availability, time pressure, skin health, and user acceptance of the sensory properties of ABHRs during and after application. AIM: To examine the effect of ABHR format (gel/foam/liquid) and dose (0.7 mL, 1.5 mL, 3 mL) on its sensory properties and acceptability, and to consider how this might affect healthcare workers' hand hygiene compliance. METHODS: Sensory descriptive analysis established key sensory differences between ten market-leading ABHRs (three gels, four foams, two liquids, one aerosol foam). Focus groups reinforced these differences. FINDINGS: All formats were less desirable at the highest dose as they were more difficult to handle than the lower doses. Foams and gels became stickier, less clean feeling and slower to dry at higher doses. Liquids gave a cleaner, smoother, more moisturized feel, but the increased difficulty in handling and applying the product negated these benefits. Overall, the gel and foam formats were more desirable than the liquid. The key desirable properties include: fast absorption, soft/moisturized hand feel, not sticky, clean feel, and low smell. CONCLUSION: The 1.5 mL dose yielded the most acceptable properties with no extreme negative consequences. The foam provided the benefits of both the liquid and gel and combined them into a more widely acceptable format that may lead to greater hand hygiene compliance. PMID- 30012376 TI - An outbreak of multidrug-resistant Pseudomonas aeruginosa in a burns service in the North of England: challenges of infection prevention and control in a complex setting. AB - BACKGROUND: Burns patients are at high risk of nosocomial infection, and Pseudomonas aeruginosa is one of the most common causes of wound and systemic infections resulting in significant morbidity and mortality in burns patients. AIM: To describe an outbreak of multidrug-resistant P. aeruginosa (MDR-Pa) at a specialist burns service and highlight the challenges in identifying the reservoir of infection despite extensive epidemiological, microbiological, and environmental investigations. METHODS: Multi-disciplinary outbreak control investigation. FINDINGS: Following an inter-hospital transfer of a burns patient from another country, an admission screen revealed that the patient was colonized with MDR-Pa. Subsequently nine more patients contracted MDR-Pa in the period from November 2015 to September 2017. Given the relatively long gap between confirmation of the index and subsequent cases, it was not possible to identify with certainty the reservoirs and mechanisms of spread of infection, although contamination of the burns service environment and equipment are likely to be contributory factors. CONCLUSION: Preventing infection transmission in specialist burns services is highly challenging, and it may not always be possible to identify and eradicate the reservoirs of infection for P. aeruginosa outbreaks. Our study supports the literature, providing additional evidence that inanimate, common contact surfaces play an important role in nosocomial transmission of P. aeruginosa. These surfaces should either be decontaminated efficiently between patient contacts or be single patient use. Enhanced vigilance is crucial, and, with strict adherence to infection prevention and control procedures, it is possible to reduce the risk of acquisition and spread of infection in patients. PMID- 30012377 TI - First Lebanese Antibiotic Awareness Week campaign: knowledge, attitudes and practices towards antibiotics. AB - Antibiotic resistance (ABR) is a major global health threat that increases the risk of treatment failure and increases medical costs. One of the most common factors contributing to the spread of ABR is self-medication. The public, as well as workers in clinical and veterinary sectors, commit false practices towards appropriate antibiotic use, favouring the spread of resistance. As such, the first Lebanese Antibiotic Awareness Week campaign was initiated with a human centred and interactive approach. The data showed a strikingly low level of antibiotic awareness. Cooperation between relevant stakeholders, policy-makers and health actors is crucial to control and overcome the problem of ABR. PMID- 30012378 TI - Make economics your friend. AB - In this essay I define the discipline of economics and say why it's useful. I review methods for measuring economic outcomes relevant to those working to prevent infections, and review how decision-makers should use the information to help choose the best among competing programmes. I finish by arguing that good economics can improve the amount of health gained from an infection prevention service working under conditions of scarce resources. PMID- 30012379 TI - A pilot study assessing patient-centred care in patients with chronic health conditions attending chiropractic practice. AB - OBJECTIVES: The primary aim of this pilot study was to determine the feasibility of conducting a mixed- methods study assessing the extent patients with chronic health conditions perceive chiropractic care to be patient-centred. DESIGN: A sequential mixed methods feasibility study with a quantitative priority. SETTING: Two private chiropractic clinics in Calgary, Alberta, Canada. MAIN OUTCOME MEASURES: Feasibility outcomes included pilot study participation, consent and completion rates. Demographic and health information and a modified version of the Patient Assessment of Chronic Illness Care (PACIC). RESULTS: Over three weeks, 90 participants were recruited, 86 enrolled, and 78 provided complete data, with only one who commented on the clarity of paperwork. Included participants were on average 47.1 years of age and 60.3% were female. They had an average of 1.8 chronic conditions with 60% having chronic spinal pain. They reported seeing an average of 2.9 other health professionals for their chronic health condition and averaged 12.9 chiropractic visits in the past year. The average overall modified PACIC score was 3.29 on a 5-point scale. Higher scores were seen on the 'patient activation', 'delivery system design/decision support', and 'problem solving/contextual' subscales, with lower scores seen on the 'goal setting/tailoring' and 'follow-up/coordination' subscales. Interview data generally supported those findings. CONCLUSIONS: The pilot study results support the feasibility of the methods for a subsequent large-scale study. These preliminary results suggest that the degree of patient-centredness compares favourably to similar studies in primary medical care. PMID- 30012380 TI - Understanding rationales for acupuncture treated individuals' beliefs in acupuncture effects, to be able to maximize therapeutic results: A qualitative analysis. AB - OBJECTIVE: To investigate how individuals expressed rationales for their beliefs regarding efficacy of acupuncture. METHODS: Qualitative data from participants of two different randomized sham-controlled trials, of relaxing (non-cancer volunteers of the general population) or antiemetic (patients with cancer undergoing radiotherapy) effects of acupuncture was analyzed. Participants (n = 441) received genuine (n = 120 and n = 100) or sham (n = 121 and n = 100) (telescopic blunt sham-needle) relaxing or antiemetic acupuncture. The participants (n = 428; 97% response rate) expressed their belief regarding the efficacy of acupuncture, and n = 264 delivered qualitative rationales for their belief, analyzed using qualitative content analysis. RESULTS: Of the 428 participants, 35 (8%) believed entirely that the acupuncture was effective, 209 (49%) believed much, 136 (32%) believed moderately, 39 (9%) believed a little, and 9 (2%) did not believe that the acupuncture was effective. Five categories and seven subcategories represented the meaning units of the central message of the rationales for the treatment belief. Participants with positive beliefs (believed entirely/much, n = 244) presented rationales related to: "Experienced positive effects", "Knowledge regarding effect-mechanisms of acupuncture", and "General trustworthiness of acupuncture". Participants with more negative beliefs (believed a little or not, n = 48) presented rationales related to: "Lack of feasibility of the acupuncture", "Varying effects", and "The effect is individual, not available for everybody". CONCLUSION: In order to strengthen acupuncture treated patients' beliefs in the efficacy of acupuncture during clinical practice or research, acupuncture therapists may consider emphasizing these aspects in the therapeutic situation. PMID- 30012381 TI - A methimazole resistant patient with Graves' disease (GD): A case report of mid term management with herbal decoctions mainly composed of Anemarrhena Bunge. AB - Graves' disease (GD) is the most common cause of hyperthyroidism. Anti-thyroid drugs, including methimazole, are the most commonly selected treatment option for this condition. But for decades, no additional drug option has been added. Anemarrhena Bunge has been used in many herbal decoctions for patients who had hyperthyroidism-like symptoms, such as sweating, heat intolerance, and anxiety. In this case study, a patient with GD who had once achieved therapeutic goals with methimazole but then re-developed hyperthyroidism was treated with only herbal decoctions, and achieved euthyroidism, normalization of T3, T4 levels for 13 months and maintenance of thyroid stimulating hormone (TSH) levels for 8 months and TSH binding inhibitory immunoglobulins (TBII)-negative status for 13 months (TSH and TBII level before treatment: 0.01 MUIU/mL, 10.94 IU/L; TSH level normalization after 14 months from the initiation of the treatment: 0.75 MUIU/mL, TBII level normalization after 9 months from the initiation of the treatment: 0.8 IU/L). The patient did not report any adverse effects related to this treatment. A herbal decoction with Anemarrhena Bunge might be effective in patients who are resistant to methimazole treatments, a finding which needs further investigation in future. PMID- 30012382 TI - Pilates in noncommunicable diseases: A systematic review of its effects. AB - OBJECTIVES: Chronic cardiovascular diseases, cancer, chronic respiratory diseases and diabetes are the four major groups of non-communicable diseases (NCDs) and the main cause of mortality worldwide. Pilates has been described as an effective intervention to promote healthy behaviors and physical activity in people with chronic diseases. However, the evidence of its effects in NCDs have not been systematized. We investigated the effects of Pilates in the four major groups of NCDs. DESIGN: A systematic review was performed. Searches were conducted on Cochrane Library, EBSCO, PubMed, Science Direct, Scopus and Web of Science databases. Studies were rated with the quality assessment tool for quantitative studies. As a meta-analysis was not possible to conduct, a best-evidence synthesis was used. RESULTS: Twelve studies, mostly of moderate quality, were included with 491 participants (78.6% females; age range 13-70 years old) with breast cancer (n = 3), diabetes (n = 3), chronic stroke (2 years post stroke) (n = 2), chronic obstructive pulmonary disease (n = 1), cystic fibrosis (n = 1), heart failure (n = 1) and arterial hypertension (n = 1). The best-evidence synthesis revealed strong evidence for improving exercise tolerance; moderate evidence for improving symptoms, muscle strength and health-related quality of life and limited or conflicting evidence on vital signs, metabolic parameters, body composition, respiratory function, functional status, balance, flexibility and social support. CONCLUSIONS: Pilates should be considered for patients with NCDs, as it improves exercise tolerance. Future studies with robust methodologies are still needed to clarify its effectiveness on outcomes with moderate, limited or conflicting evidence and to establish the most suitable intervention protocol. PMID- 30012383 TI - Use of melatonin as adjunctive therapy in neonatal sepsis: A systematic review and meta-analysis. AB - BACKGROUND: Sepsis remains one of the major causes of neonatal mortality and morbidity. Increased production of free radicals and pro-inflammatory cytokines, combined with the innately low levels of plasma antioxidants in neonates, have been implicated in the pathogenesis and complications of neonatal sepsis. To date, few clinical trials on the beneficial effects of exogenous melatonin on improvement of clinical outcomes in septic neonates have been conducted. METHODS: The electronic databases including PubMed, Embase, and Cochrane Central Register of Controlled Trials were systematically searched on July 2017 for clinical studies that reported the effects of melatonin as an adjuvant therapy in neonatal sepsis. Serum levels of C-reactive protein (CRP) as biomarker endpoint and recovery of sepsis as clinical endpoint were used to compare treatment responses between groups. The Risk of Bias Assessment tool for Non-Randomized Studies (RoBANS) and the Cochrane Collaboration Risk of Bias tool were used to assess the quality of included studies. RESULTS: Three studies with a total of 120 participants were included in the systematic review and meta-analysis. Pooled analysis revealed statistically significant mean differences in CRP serum levels (mg/L) between groups at 24 h post-adjunctive therapy with melatonin (-1.739 mg/L; 95% CI: -3.205 to -0.273; P = 0.020). Additionally, adjunctive therapy with melatonin significantly improved clinical condition of sepsis in neonates from the intervention group, compared to the control group, within 3 days of therapy (RR: 2.212; 95% CI: 1.452 to 3.371; P < 0.0005). CONCLUSIONS: Findings showed that administration of melatonin as adjunctive therapy significantly reduced an inflammatory biomarker and improved sepsis status in neonate. Larger scale studies with higher validity are needed to demonstrate clear clinical benefits of the therapy. PMID- 30012384 TI - Correlations between brain changes and pain management after cognitive and meditative therapies: A systematic review of neuroimaging studies. AB - BACKGROUND: There are different ways of dealing with pain and cognitive and meditative therapies (CMT) are alternative ways to regulate the emotions associated with pain. Current studies apply neuroimaging techniques trying to elucidate the neural mechanisms of cognitive strategies for pain. This systematic review aimed to summarize the evidence on brain activity changes after CMT, which include cognitive behavioral therapy, mindfulness and/or meditation, for pain management as well as to evaluate clinical pain outcomes. METHODS: Electronic databases - Pubmed, EMBASE, PsycINFO, Science Direct, Scopus - were searched to find randomized controlled trials (RCTs) examining neuroimaging data of CMT for chronic pain patients or healthy individuals with experimental pain. Two reviewers independently selected the relevant trials, rated for quality assessment and extracted all data using a standardized form. Primary outcome was brain activity changes (activation, deactivation or functional connectivity). Secondary outcomes were pain intensity, self-management, pain coping, quality of life, anxiety and depression. RESULTS: Nine RCTs were included involving 280 adults (18-59 years), 139 chronic pain patients vs. 148 healthy subjects. Three main kinds of intervention were identified: cognitive-behavioral therapy (n = 4), mindfulness meditation (n = 4) and transcendental meditation technique (n = 1). Neuroimaging results revealed distinct patterns of activity, but the main findings were related to increased activation of prefrontal cortex (PFC), specially dorsolateral prefrontal cortex (dlPFC) and ventrolateral prefrontal cortex (vlPFC), orbitofrontal cortex (OBF), somatosensory cortices (SSC) and limbic system in chronic pain population; and increased activation of anterior cingulate cortex (ACC), anterior insular cortex (AI) and decreased activation of thalamus in healthy individuals following CMT. CONCLUSION: This result means that regulation of pain by CMT can alter functioning of brain regions in an extensive network including non-nociceptive regions. CMT reduced the affective experience of pain, while reductions of pain intensity ratings were less consistent. Brain changes have been demonstrated as a result of the application of psychological measures and may represent the clinical implications of changes in brain activity or morphology. PMID- 30012385 TI - Association between dietary flavonoids intake and prostate cancer risk: A case control study in Sicily. AB - OBJECTIVES: The aim of this study is to test the association between dietary flavonoids intake and prostate cancer (PCa) in a sample of southern Italian individuals. DESIGN: A population-based case-control study on the association between PCa and dietary factors was conducted from January 2015 to December 2016, in a single institution. SETTING: Patients with elevated PSA (Prostate Specific Antigen) and/or suspicion of PCa underwent transperineal prostate biopsy (>=12 cores). A total of 118 histopathological-verified PCa cases were collected and matched with controls, which were selected from a sample of 2044 individuals randomly recruited among the same reference population. Finally, a total of 222 controls were selected. MAIN OUTCOME MEASURES: Prevalence of PCa. RESULTS: Consumption of certain groups of flavonoids significantly differed between controls and cases, in particular: flavonols (63.36 vs 37.14 mg/d, P < 0.001), flavanols (107.61 vs. 74.24 mg/d, P = .016), flavanones (40.92 vs. 81.32 mg/d, P < 0.001), catechins (63.36 vs. 36.18 mg/d, P = .006). In the multivariate model, flavanols and flavones were associated with reduced risk of PCa, despite not in the highest quartile of intake. Higher flavonol and catechin intake was consistently associated with reduced risk of PCa (Odds Ratio (OR) = 0.19, 95% CI: 0.06-0.56 and OR = 0.12, 95% CI: 0.04-0.36). In contrast, the highest intake of flavanones was positively associated with PCa. CONCLUSION: Flavonols and catechins have proved to be the most promising molecules for a potential protective role against PCa. Nevertheless, further research on flavanones is needed to better establish whether they are associated with PCa. PMID- 30012386 TI - Herbal medicine for hemorrhage-related hydrocephalus: A systematic review of randomised controlled trials. AB - BACKGROUND & OBJECTIVE: Hemorrhage related hydrocephalus is a common complication intraventricular hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage and traumatic brain injury. It increases morbidity and disability. The aim of this review is to assess the efficacy of herbal medicine for hemorrhage related hydrocephalus. METHODS: We searched randomized controlled trials (RCTs) investigating herbal medicine through 13 electronic databases. Extracting and assessing the data were performed independently by two authors. The Cochrane risk of bias tool was used to assess the risk of bias. RESULTS: We identified 15 trials investing 12 different herbal formulas. The methodological quality was generally low. In the 11 RCTs of comparisons with conventional treatment alone, herbal medicine plus conventional treatment showed a significant improvement on ventriculomegaly after treatment. Also, the 12 RCTs showed a significant difference on clinical signs and symptoms between two groups. We pooled the data of five trials compared Zhongfengxingnao liquid and Salviae Miltiorrhizae Radix plus conservative treatment with conservative treatment. There were significant effects on normalizing ventricle volume (Huckman index, RR 2.49; 95% CI 1.24 5.00, n = 80) and improving of Chinese scale of clinical neurologic deficit (MD 8.07; 95% CI -9.40 to -6.75, n = 264). CONCLUSION: Herbal medicine has potential benefits on improving ventriculomegaly and clinical signs and symptoms. However, a relatively small participants number and methodological limitations reduced the strength of the evidence. More rigorous trials are warranted. PMID- 30012387 TI - Horticultural therapy program for middle-aged women's depression, anxiety, and self-identify. AB - OBJECTIVES: The objective of this study was to investigate the effect of a horticultural therapy program on reducing middle-aged women's depression and anxiety and improving their self-identity. DESIGN AND SETTING: Participants were 36 women aged 40-59 years who attended the D Culture Center in Incheon, South Korea (control, n = 18; experimental, n = 18). INTERVENTION: The study was conducted in July-August 2017; the experimental group participated twice/week for 12 sessions. MAIN OUTCOME MEASURES: The Menopause Symptom Index, Self-rating Depression Scale, State-Trait Anxiety Inventory, and Dignan Ego-identity Scale were used pre- and post-test. Independent sample t-tests and matching sample t tests were performed to verify pre-evaluation homogeneity between groups; to determine the changes in depression, anxiety, and ego identity before and after the program; and to compare the efficacy between the groups, respectively. RESULTS: Depression and anxiety scores were significantly lower (p < 0.001) and self-identity was significantly higher (p = 0.003) among the experimental group compared to the control. The control group showed no significant changes in study variables. CONCLUSIONS: The horticultural therapy program was effective at decreasing depression and anxiety and improving self-identity in middle-aged women. PMID- 30012388 TI - Medical Infrared Thermography in back pain osteopathic management. AB - OBJECTIVES: The objective of this study was to provide proof-of-concept for the use of Medical Infrared Thermography to verify both diagnosis and osteopathic management accuracy in back pain. METHODS: A 50-year-old woman with acute back pain syndrome volunteered to participate in this study. RESULTS: Prior the treatment, thermal image reveals that in a sagittal plane, the inflammation extends from vertebra D8 to L3 with a maximum inflammation between vertebrae D10 to L1. Post-treatment, Medical Infrared Thermography only shows a slight inflammation along the lumbar furrow that does not induce pain in the patient. CONCLUSION: Medical Infrared Thermography has made it possible to scientifically support the osteopathic approach to back pain, both in the initial diagnostic phase and in the validation phase of treatment effectivess. PMID- 30012389 TI - Anxiety related to De Qi psychophysical responses as measured by MASS: A sub study embedded in a multisite randomised clinical trial. AB - Acupuncture has been broadly applied in the management of many diseases and conditions; however, its mechanism of action has been partially elucidated. Additionally, assessment of psychophysical responses in the acupuncture therapy is not common regarding anxiety disorder studies. Taken together, the therapeutic effect of acupuncture appears when De Qi psychophysical response is experienced following stimulation of the afferent sensory nerves. The present study investigates the level of anxiety perceived at different occasions in acupuncture and mock laser group. Furthermore, it examines the relationship between perceived De Qi psychophysical response and the level of anxiety experienced during administration of each intervention. The study was embedded in a two-arm parallel design multi-center, randomized clinical trial, the Tennis Elbow Acupuncture International Study-China, Hong Kong, Australia, Italy. Participants' level of anxiety was measured using a validated instrument, the Massachusetts General Hospital Acupuncture Sensation Mood Scale. Ninety-six participants with Lateral Elbow Pain were randomly allocated into two groups; the acupuncture treatment group (n = 47) and the inactive mock laser control group (n = 49). Data were collected immediately following the interventions at the first and the ninth session within the clinical trial. Acupuncture with De Qi did not induce higher level of anxiety compared to prior administration of acupuncture. In fact, participants were more relaxed after receiving acupuncture than those who received mock laser. There was also a weak association between participants' perception of anxiety during acupuncture and the MASS De Qi Index in session nine only (p < 0.01). Further investigation of the result revealed weak positive correlation between anxiety perceived during administration of acupuncture and the following De Qi characteristics; 'soreness' (p < 0.01), 'Deep pressure' (p < 0.05), 'Heaviness' (p < 0.05), and 'Fullness/distension' (p < 0.05). Acupuncture can be regarded as a potential therapy for preoperative anxiety through its possible regulatory function of emotion. While culture may not alter the expectation of the individual regarding anxiety, symptomology associated with anxiety should be understood within the context of the cultural background. PMID- 30012390 TI - A modified 6-form Tai Chi for patients with COPD. AB - BACKGROUND AND OBJECTIVE: 24-form Tai Chi is a traditional exercise popular among old people in China, but it has some complex movements beyond of capabilities of patients with COPD. This study was to modify and simplify 24-form Tai Chi and evaluate effects of the modified Tai Chi on lung function, exercise capacity, dyspnea symptom and health status in patients with COPD. METHODS: A two-step procedure was applied: an initial qualitative research module consisting of focus group discussion, expert consultation and patient interviews was conducted to simplified and modified 24-form Tai Chi for patients with COPD. Then, a randomized controlled trial consisting of 60 patients with II to IV COPD was conducted to evaluate effects of the modified Tai Chi on lung function (FEV1%), exercise capacity (Six minutes walking distance,6MWD), dyspnea symptom (Modified Medical Research Council Scale, mMRC) and health status (COPD Assessment Test, CAT). All measures were obtained at baseline, 3-month follow-up and 9-month follow-up. RESULTS: A new simpler 6-form Tai Chi that combining characteristics of COPD, the experts' wisdom and patients' needs was developed. Patients with COPD can grasp it in about 3 h and participants showed 86.0% adherence to the Tai Chi training and no negative accidents occurred. Generalized estimating equations (GEE) showed that there were significant differences in FEV1%, 6MWD and CAT scores between modified Tai Chi (MTC) group and the control group over time (model group * time interaction chi2 = 13.68, P < 0.001; chi2 = 192.39, P < 0.001;chi2 = 6.05, P = 0.014, respectively), however, no statistical significance in mMRC scores was found between the 2 groups over time (model group * time interaction chi2 = 3.54, P = 0.06). The baseline of FEV1%,6MWD, mMRC scores and CAT scores are significant covariates for lung function, exercise capacity, dyspnea symptom and health status, respectively (chi2 = 149.43, P < 0.001; chi2 = 5.78, P = 0.016; chi2 = 66.71, P < 0.001; chi2 = 81.83, P < 0.001, respectively). CONCLUSIONS: This modified 6-form Tai Chi routine is easy to grasp, easy to adhere to, safe to practice and effective to improve lung function, exercise capacity, health status and to prevent dyspnea symptom from getting worse for patients with COPD and it can be recommended as a suitable exercise therapy for them. PMID- 30012391 TI - Effect of Thai instrumental folk music on blood pressure: A randomized controlled trial in stage-2 hypertensive patients. AB - BACKGROUND: From epidemiologic data, half of hypertensive patients did not achieve the target blood pressure with pharmacotherapy, partly due to poor compliance. Music therapy is an adjunctive therapy which was proved effective for blood pressure reduction. We aimed to investigate the effect of Thai instrumental folk music listening on blood pressure in Thai hypertensive patients. DESIGN, SETTING AND SUBJECTS: A randomized controlled trial, conducted in the stage-2 hypertensive patients at Srinagarind Hospital, Khon Kaen, Thailand. METHODS: One hundred-twenty participants were randomized to music listening group and control group (1:1). The music listening group was assigned to listen to Thai instrumental folk music once a day for one month. OUTCOME MEASURES: The primary and secondary outcome measures were home blood pressure (Day 0th and 30th) and office blood pressure (Day 0th and 120th), respectively. RESULTS: Home systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the music listening group were significantly reduced compared with baseline (-9.5 +/- 7.1 mmHg (95%CI -11.43, -7.64) and -6.1 +/- 5.7 mmHg (95%CI -7.51, -4.53), respectively). Both home SBP and DBP at day 30th of the music listening group were significantly lower than in the control group (-6.0 mmHg (95%CI -8.58, -3.40) and -3.15 mmHg (95%CI -5.20, -1.09), respectively), while the differences of office SBP and DBP between two groups were not significant. CONCLUSION: This study demonstrated that Thai instrumental folk music listening was effective for SBP and DBP reduction in stage-2 HT patients. This therapy can be used as an alternating approach simultaneously with pharmacological treatment. This trial was registered retrospectively after completion to ClinicalTrials.gov registration number: NCT03381820. PMID- 30012392 TI - Efficacy and tolerability of micronized purified flavonoid fractions (MPFF) for haemorrhoids: A systematic review and meta-analysis. AB - OBJECTIVE: To present a systematic review of randomised controlled trials (RCTs) examining the effects of MPFF in the management of haemorrhoid symptoms. METHODS: Electronic databases including CENTRAL, CINAHL, EMBASE, MEDLINE were searched up to April 2018 for relevant RCTs. Journal and conference proceedings were also searched. Two review authors independently selected trials, extracted data, assessed the risks of bias in included trials and graded the quality of evidence. Meta-analyses were conducted for studies presenting similar outcomes. RESULTS: Ten RCTs involving 1164 participants were included. These RCTs varied in terms of patients' grade of haemorrhoids, length of trials, and outcome assessed. Most of the studies did not describe adequately the process of randomisation and allocation concealment. The pooled analysis of data from three studies indicated that there was significant difference between groups for the bleeding outcome, favoring the MPFF group (RR 1.46; 95% CI 1.10-1.93; p = 0.008). Except for bleeding, the current evidence did not show MPFF has significant effects on all the other outcomes examined when compared with placebo. Even then, the quality of evidence for bleeding was judged as low due to the small number and inconsistent results among the included studies. CONCLUSION: This review highlights the need for further rigorous research if MPFF was to be routinely used for the treatment of haemorrhoid symptoms. PMID- 30012393 TI - Prevalence and profile of Australian chiropractors treating athletes or sports people: A cross-sectional study. AB - OBJECTIVES: A range of health-care professionals including chiropractors provide treatment for sports-related health problems. This study reports analyses from the first national workforce survey to determine practitioner and practice related factors associated with the frequent treatment of athletes or sports people by Australian chiropractors. DESIGN AND SETTING: A 21-item questionnaire collecting information pertaining to practitioner and practice-related characteristics was distributed to all Australian registered chiropractors, as part of the Australian Chiropractic Research Network (ACORN) project and attracted a response rate of 43% (n = 2005). Statistical analyses compared the frequency of treating athletes or sports people against a wide range of relevant practitioner and practice characteristics. RESULTS: Of the respondents, 49.5% (n = 936) reported frequently treating athletes or sports people, and these chiropractors were more likely to be male as well as report more patient care hours and patient visits per week than those chiropractors who did not frequently treat athletes or sports people. Chiropractors who frequently treat athletes or sports people were also more likely to perform multi-modal management, have multi disciplinary practitioner relations, use diagnostic equipment and discuss nutrition and medication use as part of their patient care than those chiropractors who did not frequently treat athletes or sports people. CONCLUSIONS: Nearly half of participating Australian chiropractors treat athletes or sports people frequently. The current and potential role of chiropractors in sports medicine appears significant. Further research is needed to examine the role, practices and outcomes of such chiropractic care helping to, provide treatment and policy development in this area of clinical management. PMID- 30012394 TI - Effectiveness of autogenic training on headache: A systematic review. AB - PURPOSE: To investigate the impact of length of autogenic training (AT) use, alone and with the addition of adjunct treatments, on intensity and duration of primary headache in adults age 19 and older. METHODS: We searched articles published in English and Korean from 1926 to 2016. A search of seven domestic and foreign databases was conducted from September 25, 2016 to December 30, 2016 using the search terms "autogenic training," "autogen," "relaxation," and "headache." The search was documented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search yielded a total of 262 papers; a multi-step screening and selection process ultimately yielded six articles of randomized controlled trials (RCTs) for the systematic review. Cochrane's Risk of Bias Tool was used to evaluate the quality of the selected papers. RESULTS: Five of the six studies demonstrated statistically significant reduction in headache by AT-only or biofeedback-assisted AT. The reviewed studies varied in characteristics of subjects, length of autogenic training and practice, use of adjunct therapies, and use of headache measures. CONCLUSIONS: The small number of studies retrieved in this review, with their variations in AT interventions used, in AT training/practice time, and headache measures used, did not facilitate rigorous evaluation of the effectiveness of specific AT approaches nor of the optimum length of AT practice for reduction of headache. More research is needed on the effectiveness of AT-only for headache, the most effective duration of autogenic training and practice, and the type(s) of headache for which it is most effective. PMID- 30012395 TI - Herbopolis - A mobile serious game to educate players on herbal medicines. AB - BACKGROUND: Use of herbal medicines is common. There is a need for education in this area. Mobile games are useful educational tools for motivating learning. A mobile game on herbal medicines can potentially enhance players' herb-related knowledge. Our objective was to develop a mobile game to motivate players to learn more about herbal medicines. METHODS: Game development comprised of storyboarding, user interface design, database development, server development and distribution. A pilot usability study was conducted for the game prototype. Data was gathered through user registration, background data collection and a post-game survey containing a quiz on herbs encountered in the game. Mann-Whitney U test, chi-squared test and Spearman's correlation coefficient were used for data analysis. RESULTS: "Herbopolis" is an in-house developed mobile game of the simulation genre. Players are tasked to manage a city specializing in the production and sale of herbal products. Nineteen out of 24 participants downloaded and played the game, and completed the post-game survey. Heuristic evaluations for usability, playability and educability were generally positive. Strong positive associations were observed between player level (r = 0.810, p < 0.001) and gameplay time (r = 0.757, p < 0.001) with quiz scores. Female players scored higher in the quiz (p = .044), played for more days (p = .010) and attained higher levels (p = .010) than male players. CONCLUSION: Players are motivated to learn about herb-related information through playing "Herbopolis". Our results support its use for improving knowledge on herbal medicines. Future game iterations to improve robustness and performance will likely to improve its reception and effectiveness in learning. PMID- 30012396 TI - Utilization of complementary and integrative health services and opioid therapy by patients receiving Veterans Health Administration pain care. AB - OBJECTIVES: The aims of the current study were to characterize veterans who used a complementary and integrative health (CIH) service in the Veterans Health Administration (VHA) and to assess the extent to which using a CIH-related service was associated with receiving an opioid analgesic prescription following the initiation of specialty pain service, a time at which higher intensity care is needed for patients experiencing greater psychiatric and medical complexity. DESIGN: This study utilized a retrospective cohort design of veterans using specialty pain services. The index visit was defined as the first specialty pain visit in Fiscal Years 2012-2015. Demographics, opioid analgesic prescriptions, psychiatric disorder diagnoses, medical comorbidity, pain severity scores, and pain conditions were extracted from VHA administrative data. SETTING: The cohort was comprised of veterans who had at least one visit with a specialty pain service as identified by a billing code. MAIN OUTCOME MEASURES: The main outcome measures were use of a CIH-related service in the 365 days prior to the index visit and opioid analgesic prescription within 365 days after the index visit. Adjusted logistic regression analyses accounted for key covariate and potential confounding variables. RESULTS: Use of CIH-related services was relatively low across the cohort (1.9%). Veterans who used a CIH-related service in the 365 days prior to the index visit were more likely to be female, be younger, have less medical comorbidity, have less severe pain, and were less likely to have received an opioid prescription in the 365 days prior to the index visit. After accounting for key covariates and potential confounders, veterans who used a CIH-related service were less likely to receive an opioid analgesic prescription in the 365 days following the index visit. CONCLUSION: CIH-related services were not commonly used among Veterans initiating specialty pain services. Engaging in CIH related services prior to specialty pain services is associated with decreased opioid analgesic and non-opioid analgesic prescriptions. PMID- 30012397 TI - Preliminary evidence for feasibility, efficacy, and mechanisms of Alexander technique group classes for chronic neck pain. AB - OBJECTIVES: To determine feasibility and potential of Alexander technique (AT) group classes for chronic neck pain and to assess changes in self-efficacy, posture, and neck muscle activity as potential mechanisms for pain reduction. DESIGN: A single-group, multiple-baseline design, with two pre-tests to control for regression toward the mean, a post-test immediately after the intervention, and another post-test five weeks later to examine retention of benefits. Participants were predominately middle-aged; all had experienced neck pain for at least six months. INTERVENTION: Participants attended ten one-hour group classes in AT, an embodied mindful approach that may reduce habitual overactivation of muscles, including superficial neck muscles, over five weeks. OUTCOME MEASURES: (1) self-reports: Northwick Park Questionnaire (to assess neck pain and associated disability) and Pain Self-Efficacy Questionnaire; (2) superficial neck flexor activation and fatigue (assessed by electromyography and power spectral analysis) during the cranio-cervical flexion test; (3) posture during a video game task. RESULTS: There were no significant changes in outcomes between pre tests. All participants completed the intervention. After the intervention: (1) participants reported significantly reduced neck pain; (2) fatigue of the superficial neck flexors during the cranio-cervical flexion test was substantially lower; (3) posture was marginally more upright, as compared to the second pre-intervention values. Changes in pain, self-efficacy, and neck muscle fatigue were retained at the second post-test and tended to be correlated with one another. CONCLUSIONS: Group AT classes may provide a cost-effective approach to reducing neck pain by teaching participants to decrease excessive habitual muscle contraction during everyday activity. PMID- 30012398 TI - Integrated therapy improve urinary total protein in patients with lupus nephritis: A case report. AB - OBJECTIVES: To report on the potential effectiveness of Chinese herbal medicine (CHM) as part of an integrated treatment for lupus nephritis. CLINICAL FEATURES AND OUTCOME: A 55-year-old female with systemic lupus erythematosus had experienced bilateral lower-limbs edema for half a year. Her urinary total protein (M-TP) was 1367.9 mg/24 h. Lupus nephritis (LN) was suspected by the Division of Rheumatology without a renal biopsy. Oral corticosteroid medication did not improve the edema; therefore, the patient requested CHM for integrated therapy, and was subsequently treated for seven months with a modified CHM prescription mainly composed of Zhi-Bo-Di-Huang-Wan, Gui-Shao-Zhi-Mu-Tang, and Zhu-Ling-Tang. After three days of CHM, her bilateral lower-limbs edema significantly improved, and after 143 days, her M-TP decreased from 1367.9 mg/24 h to 143.6 mg/24 h. CONCLUSIONS: Integrated therapy could significantly improve proteinuria by reducing this LN patients' urinary total protein, which further implies that CHM may have a protective effect against the progression of LN in this patient. PMID- 30012399 TI - An experimental study in distinguishing an authentic herbal substance from sham herbal substances. AB - OBJECTIVES: An unblinded randomised trial can result in biased treatment effect estimates and lead to erroneous conclusions on the efficacy of the therapeutic intervention. Unlike pharmaceutical substances, Chinese herbal medicines have special characteristics including texture, colour, odour and taste as the origin of these constituents are different. In addition, its distinctive odour makes blinding of Chinese herbal medicine RCTs very difficult, as the placebo substance needs to match the special characteristics of the herbal substance being investigated. For these reasons, two studies were undertaken to evaluate whether a participant could distinguish a herbal intervention capsule (Ganopoly combination) when compared to three types of capsules containing culinary materials following a visual, odour and taste evaluation. DESIGN: Study One, was a pilot involving eleven participants (n = 11) while Study Two, involved eighty one participants (n = 81) and was conducted to make improvements on Study One. For both studies, participants were asked to identify which of four capsules were a herbal substance following a visual, smell and taste evaluation. RESULTS: For study One it was found that for both odour (p = .484) and visual appearance (p = .077) the number of participants selecting the herbal substance was not significantly different from what may have been selected by chance. This was not the case for taste where significantly more participants selected capsule B as the herbal substance (p = .004). For Study Two test it was found that all three evaluations for odour, visual appearance and taste significantly more participants selected the herbal substance (p < .0001 in all cases). This indicates that the participant guesses were not evenly distributed across the four choices and suggests a failure to blind. CONCLUSION: The failure to blind participants highlights the difficulties in preparing sham herbal substances that look, smell and taste like the real herbal substance. PMID- 30012401 TI - Integrative medicine is becoming mainstream: Research on multimodal interventions needs to catch up. PMID- 30012400 TI - Garlic clove applied as vaginal suppository - A case report. AB - OBJECTIVE: Besides conventional drugs, various vaginal disorders are often treated with complementary and alternative medicines. Different natural products are often used in treatment of genital infections. The aim is to present a case of treatment of vaginal infection with a garlic clove. METHODS: A detailed interview was conducted with the subject whose condition was described in this case. RESULTS: Young woman was diagnosed with vaginal Ureaplasma sp. infection. After failed local treatment with antibiotics and antifungals, subject obtained advice to treat the disorder with incised clove of garlic. Control examination by her gynecologist confirmed that infection was successfully cured. Subject experienced no adverse effects. CONCLUSIONS: Garlic clove successfully cured vaginal infection presented in this case. However, application to genital organs should be reserved for dosage forms, in order to prevent potential toxicity and to obtain reproducibility of active compounds concentrations. PMID- 30012402 TI - Effects of sequential exposure to water accommodated fraction of crude oil and chlorpyrifos on molecular and biochemical biomarkers in rainbow trout. AB - Fish can be simultaneously or sequentially exposed to various kinds of pollutants, resulting in combined effects. Polycyclic aromatic hydrocarbons induce cytochrome P450 monooxygenase 1A (CYP1A) expression, which catalyzes the conversion of the organophosphorus insecticide chlorpyrifos (CPF) into its most active derivative, CPF-oxon. CPF-oxon inhibits CYP1A and other enzymes, including carboxylesterases (CEs) and acetylcholinesterase (AChE). We studied the effects of an in vivo exposure to crude oil water accommodated fraction (WAF) followed by an ex vivo exposure of liver tissue to CPF on the expression of Cyp1a, AhR and ARNT mRNA, CYP1A protein and on the activity of biomarker enzymes in the rainbow trout (Oncorhynchus mykiss). Juvenile rainbow trout were exposed to WAF (62 MUg L 1 TPH) for 48 h. Then, liver was dissected out, sliced and exposed to 20 MUg L-1 CPF ex vivo for 1 h. Liver tissue was analyzed for mRNA and protein expression and for CEs, AChE, glutathione S-transferase (GST) and CYP1A (EROD) activity. WAF induced Cyp1a mRNA and CYP1A protein expression by 10-fold and 2.5-8.3-fold, respectively, with no effect of CPF. WAF induced AhR expression significantly (4 fold) in control but not in CPF treated liver tissue. ARNT mRNA expression was significantly lowered (5-fold) by WAF. CPF significantly reduced liver EROD activity, independently of WAF pre-treatment. CEs activity was significantly inhibited in an additive manner following in vivo exposure to WAF (42%) and ex vivo exposure to CPF (19%). CPF exposure inhibited AChE activity (37%) and increased GST activity (42%). PMID- 30012403 TI - Molecular-level insight into hot-melt loading and drug release from mesoporous silica carriers. AB - Drug amorphisation by loading to inorganic mesoporous carriers represents an emerging area of improving the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). In this work, for the first time, a molecular-level insight into the process of API loading to mesoporous SiO2 (silica) carriers by the hot-melt impregnation method and its subsequent release during dissolution was obtained using ATR-FTIR spectroscopic imaging. A physical mixture of ibuprofen crystals and mesoporous silica particles was heated and the dynamics of melt loading into the silica pore structure was directly observed in situ by ATR-FTIR spectroscopic imaging. The loss of crystallinity, the redistribution of the API in the silica pore network and the subsequent stabilisation of the amorphous form upon cooling were proven. The API was involved in two different kinds of molecular-level interactions: API dimers in the amorphous bulk, and individual API molecules adsorbed on the silica surface. The melt-loaded silica carriers were comprehensively characterised by DSC, SEM and dissolution tests, which proved dissolution rate enhancement due to amorphisation of the API. Drug release form the hot-melt loaded mesoporous silica carriers was observed in real time and the conditions leading to local re crystallisation of super-saturated solution of the API were identified. PMID- 30012404 TI - Comparison of particle size methodology and assessment of nanoparticle tracking analysis (NTA) as a tool for live monitoring of crystallisation pathways. AB - Sample complexity and polydispersity presents challenges surrounding particle size measurements for nanoparticles (NPs). To ensure the delivery of high quality products to the marketplace it is imperative that this task is performed with the greatest accuracy and certainty. For this reason, particle sizing via more than one technique is critical to the success of the formulation process. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) are techniques that size particles based on their Brownian motion in liquid medium. However, each technique has advantages and disadvantages associated with its application. This study was designed with the intent of comparing these techniques in a critical manner. NPs were formed using three Biopharmaceutics Classification System class II compounds: itraconazole, ketoconazole and posaconazole, using an anti-solvent addition, bottom up method. The impact of polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether with a molecular weight 2000 Da, as stabilizers, was assessed using these two particle sizing techniques. Mie light scattering theory was successfully used to explain the relationship between material composition and particle scattering power. A change in material refractive index, associated with an amorphous to crystalline solid state transformation, was predominantly responsible for the observed change in the light scattering power of posaconazole nano-dispersions. The innovative application of NTA for the live tracking of these physical processes was explored for the first time. This novel finding can serve to deepen our understanding of the dynamic crystallisation pathway undertaken by a nanoparticle. PMID- 30012405 TI - Management of Single Uncomplicated Dental Extractions and Postoperative Bleeding Evaluation in Patients With Factor V Deficiency: A Local Antihemorrhagic Approach. AB - PURPOSE: The aim of the present study was to analyze the management of single dental extractions and postoperative bleeding in patients with a diagnosis of factor V deficiency. A careful evaluation of each case will allow the team to categorize the risk and operate safely, minimizing the incidence of intraoperative and postoperative complications. If necessary, the oral maxillofacial surgeon can choose to do so in collaboration with the hematologist on a case-by-case basis. PATIENTS AND METHODS: The present retrospective study included 5 patients with mild congenital factor V deficiency who had undergone at least 1 dental extraction. Mouth rinse with tranexamic acid, nonresorbable sutures, and gelatin sponge packed in the alveolar socket were used to obtain hemostasis. No systemic therapies, such as fresh frozen plasma, platelet concentrate, or recombinant activated factor VII, were administered. RESULTS: Twenty-five teeth were extracted. The factor V plasma levels ranged from 14.1 to 22.4%. Local antihemorrhagic treatments resulted in good hemostasis. No hemorrhagic complications or intraoperative or postoperative major bleeding was observed. CONCLUSIONS: Dental extractions appear to be safe procedures for patients with mild factor V deficiency when a bleeding risk assessment has been performed in conjunction with a hematologist and an appropriate treatment protocol is followed. Our treatment protocol was found to be effective and well tolerated by all the patients. PMID- 30012407 TI - Depressive and Anxiety Symptoms in Adult Congenital Heart Disease: Prevalence, Health Impact and Treatment. AB - Over 1.4 million adults in the United States are living with congenital heart disease (CHD), which can vary widely in disease burden and risk for future cardiovascular complications. As a result, some CHD survivors may experience greater emotional distress, including symptoms of depression and anxiety. This review summarizes the developing research literature on the prevalence, health impact, as well as screening and treatment of depressive and anxiety symptoms among adult CHD survivors. Additionally, the review will highlight findings from the acquired heart disease literature, a well-studied area that can inform research and clinical care practices for CHD survivors with depressive and/or anxiety symptoms. The review concludes with considerations for depression and anxiety screening in medical settings and identifying referral resources for treatment. PMID- 30012406 TI - A simple supported tubulated bilayer system for evaluating protein-mediated membrane remodeling. AB - Fusion and fission of cellular membranes involve dramatic, protein-mediated changes in membrane curvature. Many of the experimental methods useful for investigating curvature sensing or generation require specialized equipment. We have developed a system based on supported lipid bilayers (SLBs) in which lipid tubules are simple to produce and several types of membrane remodeling events can be readily imaged using widely available instrumentation (e.g., tubule fission and/or membrane budding). Briefly, high ionic strength during lipid bilayer deposition results in incorporation of excess lipids in the SLB. After sequentially washing with water and physiological ionic strength buffer solutions, lipid tubules form spontaneously. We find that tubule formation results from solution-dependent spreading of the SLB; washing from water into physiological ionic strength buffer solution leads to expansion of the bilayer and formation of tubules. Conversely, washing from physiological buffer into water results in contraction of the membrane and loss of tubules. We demonstrate the utility of these supported tubulated bilayers, termed "STuBs," with an investigation of Sar1B, a small Ras family G-protein known to influence membrane curvature. The addition of Sar1B to STuBs results in dramatic changes in tubule topology and eventual tubule fission. Overall, STuBs are a simple experimental system, useful for monitoring protein-mediated effects on membrane topology in real time, under physiologically relevant conditions. PMID- 30012408 TI - Screening for esophageal varices in patients with hepatocellular carcinoma. PMID- 30012409 TI - Importance of timely eradication of Helicobacter pylori to prevent peptic ulcer recurrence and gastric cancer. PMID- 30012410 TI - Antimicrobial decontamination of endoscopes: Are we there yet? PMID- 30012411 TI - Duodenoscope-related and echoendoscope-related infections: Is "never" possible? PMID- 30012412 TI - Monitoring compliance with colorectal cancer screening: Do we have it covered? PMID- 30012413 TI - Mucosal exposure devices for colonoscopy: see the forest for the trees. PMID- 30012414 TI - Aspiring to inspIRE: catheter-directed electrical therapy and biliary metal stent patency. PMID- 30012415 TI - The role of co-axially placed double-pigtail stents within lumen-apposing metal stents in draining pancreatic fluid collections. PMID- 30012416 TI - Response. PMID- 30012417 TI - Depressive- and anxiety-like phenotypes in young adult APPSwe/PS1dE9 transgenic mice with insensitivity to chronic mild stress. AB - Early Alzheimer's disease (AD) and depression share many symptoms, but the underlying mechanisms are not clear. Therefore, characterizing the shared and different biological changes between the two disorders will be helpful in making an early diagnosis and planning treatment. In the present study, 8-week-old APPSwe/PS1dE9 transgenic mice received chronic mild stress (CMS) for 8 weeks followed by a series of behavioral, biochemical and pathological analyses. APPSwe/PS1dE9 mice showed depressive- and anxiety-like behaviors, and reduced sociability, accompanied by high levels of soluble beta-amyloid, glial activation, neuroinflammation and brain derived neurotrophic factor signaling disturbance in the hippocampus. Notably, APPSwe/PS1dE9 mice exposure to CMS partially aggravated anxiety-like states rather than depressive-like responses and sociability deficits, with further elevated hippocampal interleukin-6 and tumor necrosis factor-alpha levels. These results demonstrated that young adult APPSwe/PS1dE9 have depressive- and anxiety-like phenotypes that were resistant to CMS compared to wild-type mice. This finding may help to understand the pathogenic mechanism of psychiatric symptoms associated with early AD. PMID- 30012418 TI - Mass spectrometry and DigiWest technology emphasize protein acetylation profile from Quisinostat-treated HuT78 CTCL cell line. AB - : Histone deacetylases (HDACs) are key enzymes involved in epigenetic modulation and were targeted by HDAC inhibitors (HDACis) for cancer treatment. The action of HDACis is not restricted to histones and also prevents deacetylation of other proteins, supporting their wide biological actions. The HuT78 cell line is recognized as a key tool to support and understand cutaneous T-cell lymphoma (CTCL) biology and was used as a predictive model since HDACi such as Vorinostat and Panobinostat have both demonstrated apoptotic activities in HuT78 cells and in primary blood CTCL cells. In this study, Quisinostat (JNJ-26481585) a novel second-generation HDACi with highest potency for HDAC1, was tested on HuT78 cell line. Quantitative mass spectrometry (MS)-based proteomics after acetylated lysine peptide enrichment and a targeted antibody-based immunoassay (DigiWest) were used as complementary technologies to assess the modifications of the acetylated proteome. As expected, several acetylated lysines of histones were increased by the HDACi. Additional acetylated non-histone proteins were modulated after treatment with Quisinostat including the nucleolin (a major nucleolar protein), the replication protein A 70 kDa DNA-binding subunit, the phosphoglycerate kinase 1, the stress-70 protein, the proto-oncogene Myc and the serine hydroxymethyltransferase. A better knowledge of histone and non-histone acetylated protein profile after Quisinostat treatment can strongly support the understanding of non-clinical and clinical results of this HDACi. These technological tools can also help in designing new HDACis in a pharmaceutical drug discovery program. SIGNIFICANCE: A better knowledge of histone and non histone acetylated protein profile after HDAC inhibitors (HDACis) treatment can strongly support the understanding of non-clinical and clinical investigations in a pharmaceutical drug discovery program. Relative quantification using mass spectrometry -based proteomics after acetylated-lysine peptide enrichment and a targeted antibody-based immunoassay (DigiWest) are proposed as complementary technologies to assess the modifications of the acetylated proteome. Quisinostat (JNJ-26481585) a novel second-generation HDACi with highest potency for HDAC1 was better characterized in vitro in HuT78 cells to support and understand cutaneous T-cell lymphoma (CTCL) therapeutic research program. PMID- 30012419 TI - Quality control of single amino acid variations detected by tandem mass spectrometry. AB - : Study of single amino acid variations (SAVs) of proteins, resulting from single nucleotide polymorphisms, is of great importance for understanding the relationships between genotype and phenotype. In mass spectrometry based shotgun proteomics, identification of peptides with SAVs often suffers from high error rates on the variant sites detected. These site errors are due to multiple reasons and can be confirmed by manual inspection or genomic sequencing. Here, we present a software tool, named SAVControl, for site-level quality control of variant peptide identifications. It mainly includes strict false discovery rate control of variant peptide identifications and variant site verification by unrestrictive mass shift relocalization. SAVControl was validated on three colorectal adenocarcinoma cell line datasets with genomic sequencing evidences and tested on a colorectal cancer dataset from The Cancer Genome Atlas. The results show that SAVControl can effectively remove false detections of SAVs. SIGNIFICANCE: Protein sequence variations caused by single nucleotide polymorphisms (SNPs) are single amino acid variations (SAVs). The investigation of SAVs may provide a chance for understanding the relationships between genotype and phenotype. Mass spectrometry (MS) based proteomics provides a large-scale way to detect SAVs. However, using the current analysis strategy to detect SAVs may lead to high rate of false positives. The SAVControl we present here is a computational workflow and software tool for site-level quality control of SAVs detected by MS. It accesses the confidence of detected variant sites by relocating the mass shift responsible for an SAV to search for alternative interpretations. In addition, it uses a strict false discovery rate control method for variant peptide identifications. The advantages of SAVControl were demonstrated on three colorectal adenocarcinoma cell line datasets and a colorectal cancer dataset. We believe that SAVControl will be a powerful tool for computational proteomics and proteogenomics. PMID- 30012421 TI - Peroxisomes and cancer: The role of a metabolic specialist in a disease of aberrant metabolism. AB - Cancer is irrevocably linked to aberrant metabolic processes. While once considered a vestigial organelle, we now know that peroxisomes play a central role in the metabolism of reactive oxygen species, bile acids, ether phospholipids (e.g. plasmalogens), very-long chain, and branched-chain fatty acids. Immune system evasion is a hallmark of cancer, and peroxisomes have an emerging role in the regulation of cellular immune responses. Investigations of individual peroxisome proteins and metabolites support their pro-tumorigenic functions. However, a significant knowledge gap remains regarding how individual functions of proteins and metabolites of the peroxisome orchestrate its potential role as a pro-tumorigenic organelle. This review highlights new advances in our understanding of biogenesis, enzymatic functions, and autophagic degradation of peroxisomes (pexophagy), and provides evidence linking these activities to tumorigenesis. Finally, we propose avenues that may be exploited to target peroxisome-related processes as a mode of combatting cancer. PMID- 30012422 TI - Production of bioactive hepcidin by recombinant DNA tagging with an elastin-like recombinamer. AB - With the lack of new chemical antibiotics and increasing pathogen resistance to those available, new alternatives are being explored. Antimicrobial peptides (AMPs) with a broad range of effects, including antibacterial, antifungal, and antiviral actions, have emerged as one of the options. They can be produced by recombinant DNA technology, but the chromatographic methods used for peptide purification are expensive and time consuming. Here, we describe the design, production, purification and assessment of the antibacterial activity of the human peptide hepcidin, using an elastin-like recombinamer as fusion partner. The recombinant protein Hep-A200 was produced in Escherichia coli and purified by a non-chromatographic procedure, exploiting the thermal properties of the A200 elastin-like recombinamer. Recombinant Hep-A200 was found to retain antibacterial activity against Gram-positive and Gram-negative species. PMID- 30012420 TI - Embryonic atrazine exposure elicits proteomic, behavioral, and brain abnormalities with developmental time specific gene expression signatures. AB - : Atrazine (ATZ), the second most commonly used herbicide in the United States, is an endocrine disrupting chemical linked to cancer and a common drinking water contaminant. This study further investigates ATZ-related developmental toxicity by testing the following hypotheses in zebrafish: the effects of embryonic ATZ exposure are dependent on timing of exposure; embryonic ATZ exposure alters brain development and function; and embryonic ATZ exposure changes protein abundance in carcinogenesis-related pathways. After exposing embryos to 0, 0.3, 3, or 30 parts per billion (ppb) ATZ, we monitored the expression of cytochrome P450 family 17 subfamily A member 1 (cyp17a1), glyoxalase I (glo1), ring finger protein 14 (rnf14), salt inducible kinase 2 (sik2), tetratricopeptide domain 3 (ttc3), and tumor protein D52 like 1 (tpd52l1) at multiple embryonic time points to determine normal expression and if ATZ exposure altered expression. Only cyp17a1 had normal dynamic expression, but ttc3 and tpd52l1 had ATZ-related expression changes before 72 h. Larvae exposed to 0.3 ppb ATZ had increased brain length, while larvae exposed to 30 ppb ATZ were hypoactive. Proteomic analysis identified altered protein abundance in pathways related to cellular function, neurodevelopment, and genital-tract cancer. The results indicate embryonic ATZ toxicity involves interactions of multiple pathways. SIGNIFICANCE: This is the first report of proteomic alterations following embryonic exposure to atrazine, an environmentally persistent pesticide and common water contaminant. Although the transcriptomic alterations in larval zebrafish with embryonic atrazine exposure have been reported, neither the time at which gene expression changes occur nor the resulting proteomic changes have been investigated. This study seeks to address these knowledge gaps by evaluating atrazine's effect on gene expression through multiple time points during embryogenesis, and correlating changes in gene expression to pathological alterations in brain length and functional changes in behavior. Finally, pathway analysis of the proteomic alterations identifies connections between the molecular changes and functional outcomes associated with embryonic atrazine exposure. PMID- 30012423 TI - The effects of reduced hemodynamic loading on morphogenesis of the mouse embryonic heart. AB - Development of the embryonic heart involves an intricate network of biochemical and genetic cues to ensure its proper growth and morphogenesis. However, studies from avian and teleost models reveal that biomechanical force, namely hemodynamic loading (blood pressure and shear stress), plays a significant role in regulating heart development. To study how hemodynamic loading impacts development of the mammalian embryonic heart, we utilized mouse embryo culture and manipulation techniques and performed optical projection tomography imaging followed by morphometric analysis to determine how reduced-loading affects heart volume, myocardial thickness, trabeculation and looping. Our results reveal that hemodynamic loading can regulate these features at different thresholds. Intermediate levels of hemodynamic loading are sufficient to promote proper myocardial growth and heart size, but insufficient to promote looping and trabeculation. Whereas, low levels of hemodynamic loading fails to promote proper growth of the myocardium and heart size. These results reveal that the regulation of heart development by biomechanical force is conserved across many vertebrate classes, and this study begins to elucidate how these specific forces regulate development of the mammalian heart. PMID- 30012424 TI - First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with an estimated prevalence of 1/500. More than 40 genes have been reported to cause HCM. Among them, CSRP3 is usually included on HCM gene panels used for molecular diagnosis by next-generation sequencing (NGS). To provide new insights into the pathophysiology of hypertrophic cardiomyopathy, a NGS workflow based on a panel of 48 cardiomyopathies-causing genes was analyzed on a cohort of 542 HCM patients. As expected, this molecular approach led to identify most pathogenic or likely pathogenic variants into prevalent HCM-causing genes: MYBPC3 (123/542; 22.7%), MYH7 (48/542; 8.9%), TNNT2 (12/542; 2.2%), and TNNI3 (10/542; 1.8%). Among MYBPC3 variants, 96 led to a premature stop codon (78%). More surprisingly, our molecular study led also to detect, for the first time, homozygous CSRP3 truncating variants in two unrelated HCM probands. Meta-analysis of rare previously reported CSRP3 variants on HCM probands using ACMG guidelines indicate that only one variation (p.Cys58Gly) could be considered as likely pathogen. By combining meta-analysis results and identification of two unrelated HCM patients with homozygous CSRP3 truncating variants, we suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal recessive inheritance rather than with an autosomal dominant transmission as usually reported on HCM (OMIM 612124). PMID- 30012425 TI - Conserved structure and function of chemokine CXCL8 between Chinese tree shrews and humans. AB - Chemokines represent a superfamily of small secretion proteins that functionally mediate immune cell transmigration in normal or inflammatory conditions. Although anatomic and polygenetic evidence suggests that tree shrews are primate-like species, understanding of the structure and function of tree shrew chemokines has only just commenced. In this study, we cloned tree shrew chemokine CXCL8 and its cognate receptors. Predicted three-dimensional (3D) structures showed that binding domains in CXCL8 and CXCR1/2 were highly conserved between tree shrews and humans. We found that the human CXCL8 (hCXCL8) protein induced migration of tree shrew peripheral blood mononuclear cells (PBMCs) expressed by CXCR1/2 (tsCXCR1/2). Blocking interaction between hCXCL8 and tsCXCR1/2 with allosteric antagonists (reparixin and SB265610) significantly decreased tree shrew PBMC transmigration. Over-expressing tree shrew CXCR1 in human HEK 293 T cells further enhanced cellular in vitro transmigration. Similar to primate species, our findings suggest that CXCL8 and CXCR1/2 constitute a structurally- and functionally-conserved chemotaxis responsible for tree shrew immune activities. PMID- 30012426 TI - A Qualitative Study Exploring Contraceptive Practices and Barriers to Long-Acting Reversible Contraceptive Use in a Sample of Adolescents Living in the Southern United States. AB - STUDY OBJECTIVE: To understand contraceptive practices of female adolescents in the Deep South and determine barriers to their use of long-acting reversible contraception (LARC). DESIGN: Semistructured interviews were conducted that addressed current contraceptive choice, factors influencing choice, LARC awareness, concerns, and barriers to using LARC. Interviews were audio recorded, transcribed, and analyzed using qualitative content analysis to identify themes. SETTING: Adolescent medicine clinic in an urban academic medical center in the Deep South region of the United States. PARTICIPANTS: Sexually active girls between the ages of 14 and 21 years who were not currently using LARC. INTERVENTIONS AND MAIN OUTCOME MEASURES: Themes generated during semistructured interviews. RESULTS: Fifteen participants were interviewed with a mean age of 17 years. Fourteen of 15 were African American. Thirteen of 15 were currently using non-LARC methods and 2 of 15 were not using any contraceptive method. Contraceptive choice was driven by perceived ease of use, desire for pregnancy prevention, and seeking relief of menstrual concerns. Thirteen of 15 participants were aware of LARC with 11 of 15 (73%) noting information came from a health care provider. Barriers to current and future LARC use included concerns about side effects, LARC ineffectiveness, device longevity, and LARC invasiveness. Sixty three percent of participants noted that they would not consider using a LARC in the future. CONCLUSION: Increasing use of LARC goes beyond awareness. Concerns about effectiveness, future fertility, duration of devices, and perceived invasiveness represent barriers for adolescents. Further research is needed to determine how to address these barriers because it pertains to counseling of sexually active girls on the use of LARC. PMID- 30012427 TI - A Spontaneous Pregnancy in a Patient with Turner Syndrome with 45,X/47,XXX Mosaicism: A Case Report and Review of the Literature. AB - BACKGROUND: Turner syndrome is a chromosomal abnormality, due to a total or partial loss of 1 of the X chromosomes and is mostly characterized clinically by short stature and primary ovarian insufficiency. Spontaneous pregnancies are rare (5%) and of relatively high risk. This is 1 of few reported cases of spontaneous conception and favorable prognosis in a patient with Turner syndrome and a 45,X/47,XXX karyotype. CASE: A 21-year-old woman with Turner mosaicism (45,X/47,XXX) who had a full-term, uncomplicated pregnancy after spontaneous conception, gave birth to a healthy female (46,XX) infant. SUMMARY AND CONCLUSION: Spontaneous pregnancies in women with Turner syndrome are a rarity. Fertility preservation methods are being discussed. Due to the high reported incidence of neonatal, obstetric, maternal, and especially cardiovascular complications in those pregnancies, close monitoring is essential. PMID- 30012428 TI - Adnexal Torsion in Children and Adolescents: A Retrospective Review of 245 Cases at a Single Institution. AB - STUDY OBJECTIVE: Adnexal torsion (AT) requires urgent surgical intervention to preserve ovarian function. Historically, treatment for AT was oophorectomy because of concerns related to leaving a nonviable ischemic ovary. No published studies support these theoretical concerns and current literature supports conservative management. The aim of this study was to review the institutional outcomes for AT cases, including salvage rates and complications. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This study was approved by the institutional review board at Baylor College of Medicine. A retrospective chart review on cases of AT from 2007 to 2016 at a single Children's hospital was performed on the basis of International Classification of Diseases, 10th revision and Current Procedural Terminology codes. A standardized chart review form was used in data extraction. Statistical analysis was performed using SAS version 9.4 (SAS Institute). RESULTS: Chart review identified 245 torsion cases in 237 patients. The mean age was 12.4 +/- 3.29 years. Of the participants, 230 (94%) underwent minimally invasive laparoscopy with ovarian preservation in 233 (95%) of the cases. There were no complications due to detorsion of the affected adnexa. Intraoperatively, the right adnexa was affected in 134 (55%) cases and a lesion was noted in 193 (79%) cases, most commonly paratubal cysts and mature teratomas. The malignancy rate was low, noted only in 4/245 patients at (1.2%). Pediatric gynecology performed most of the cases (n = 214; 87%). CONCLUSION: The findings of our study continue to support the conservative management of patients with AT. PMID- 30012429 TI - Obesity Is Independently Associated With Higher Annual Burden and Costs of Hospitalization in Patients With Inflammatory Bowel Diseases. AB - BACKGROUND & AIMS: Approximately 15%-40% patients with inflammatory bowel diseases (IBD) are obese. There is an inconsistent association between obesity and IBD phenotype and course. We conducted a nationally representative cohort study to estimate and compare the burden, costs, and causes for hospitalization in obese vs. non-obese patients with IBD. METHODS: Using the Nationwide Readmissions Database 2013, we identified obese (based on administrative claims code) and non-obese patients who had been hospitalized at least once, from January through June 2013, and followed them for re-hospitalization until December 2013. We compared annual burden (total days spent in hospital), costs, causes, and outcomes of hospitalization between obese and non-obese patients after 1:1 propensity score matching. RESULTS: We identified 42,285 patients with IBD, of which 12.4% were obese. After propensity score matching, we included 5128 obese and 5128 non-obese IBD patients in our analysis. Compared to non-obese patients, obese patients spent more days in hospital annually (median, 8 vs 5 days) (P < .01), with higher hospitalization-related costs (median, $17,277 vs $11,847) (P < .01); this pattern persisted in subsets of high-need and high-cost patients. Compared to non-obese patients, obese patients were more likely to be hospitalized with preventable admissions (19% vs 15%) or cardiopulmonary complications (16% vs 12%). CONCLUSIONS: In an analysis of data on patients with IBD from the Nationwide Readmissions Database 2013, we found obesity to be independently associated with higher burden and costs of hospitalizations. Strategies should be considered to target obesity as adjunctive therapy for patients with IBD. PMID- 30012430 TI - Treatments for Crohn's Disease-Associated Bowel Damage: A Systematic Review. AB - BACKGROUND & AIMS: Despite significant advances in the treatment of Crohn's disease (CD), most patients still develop stricturing or penetrating complications that require surgical resections. We performed a systematic review of mechanisms and potential treatments for tissue damage lesions in CD patients. METHODS: We searched the PubMed, MBASE, and Cochrane databases from September 2016 through July 2017 for full-length articles on CD, fibrosis, damage lesions, mesenchymal stem cells, and/or treatment. We also searched published conference abstracts and performed manual searches of all reference lists of relevant articles. RESULTS: Mechanisms of intestinal damage in patients with CD include fibroblast proliferation and migration, activation of stellate cells, recruitment of intestinal or extra-intestinal fibroblast, and cell trans-differentiation. An altered balance of metalloproteinases and tissue inhibitors of metalloproteinases might contribute to fistula formation. Treatment approaches that reduce excessive transforming growth factor beta (TGFB) activation might be effective in treating established intestinal damage. Stem cell therapies have been effective in tissue damage lesions in CD. Particularly, randomized controlled trials have shown local injections of mesenchymal stem cells to heal perianal fistulas. CONCLUSION: In a systematic review of mechanisms and treatments of bowel wall damage in patients with CD, we found a need to test drugs that reduce TGFB and increase healing of transmural damage lesions and to pursue research on local injection of mesenchymal stem cells. PMID- 30012431 TI - Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post-hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2). METHODS: The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti-TNF therapy, baseline corticosteroid use, and baseline serum levels of C-reactive protein. RESULTS: Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: -0.27 vs placebo: -0.11; P < .01), total number of daily bowel movements (-1.06 vs -0.27; P < .0001), and rectal bleeding subscore (-0.30 vs -0.14; P < .01) by day 3. Compared with placebo, more tofacitinib-treated patients had reductions from baseline in stool frequency subscore (by >=1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by >=1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups. CONCLUSIONS: In a post-hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951. PMID- 30012432 TI - Obesity and Weight Gain Are Associated With Progression of Fibrosis in Patients With Non-alcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: The effects of weight change on the progression of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) in the general population are unclear. We evaluated the association of weight change and baseline body mass index (BMI) with fibrosis progression, determined by non invasive measurement of a marker, in young and middle-aged adults with NAFLD. METHODS: We performed a prospective cohort study of 40,700 adults with NAFLD in Korea who received regular health screening examinations and were followed for a median 6.0 years. Weight change was defined as the difference between weights measured at baseline and at a subsequent follow-up visit. The progression from a low to an intermediate or high probability of advanced fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: During 275,451.5 person-years of follow-up, 5454 subjects with a low APRI progressed to an intermediate or high APRI. Multivariable-adjusted hazard ratios for APRI progression, determined by comparing the first and second weight change quintiles (the weight-loss group) and the fourth and fifth quintiles (weight-gain group) with the third quintile (weight-stable group, reference), were 0.68 (95% CI, 0.62-0.74), 0.86 (95% CI, 0.78-0.94), 1.17 (95% CI, 1.07-1.28), and 1.71 (95% CI, 1.58-1.85), respectively. The multivariable-adjusted hazard ratios for APRI progression were determined by comparing subjects with BMIs of 23-24.9, 25-29.9, and >=30 with subjects with BMIs of 18.5-22.9 kg/m2 (reference); these ratios were 1.13 (95% CI, 1.02-1.26), 1.41 (95% CI, 1.28-1.55), and 2.09 (95% CI, 1.86 2.36), respectively. CONCLUSIONS: In a prospective cohort study of 40,700 adults with NAFLD, we found obesity and weight gain to be independently associated with increased risk of fibrosis progression, based on APRI. Maintaining a normal healthy weight and preventing weight gain may help reduce fibrosis progression in individuals with NAFLD. PMID- 30012434 TI - Is Biology or the Endoscopist to Blame for Postcolonoscopy Colorectal Cancer? PMID- 30012433 TI - Lower Annual Rate of Progression of Short-Segment vs Long-Segment Barrett's Esophagus to Esophageal Adenocarcinoma. AB - BACKGROUND & AIMS: European guidelines recommend different surveillance intervals of non-dysplastic Barrett's esophagus (NDBE) based on segment length, as opposed to guidelines in the United States, which do recommend surveillance intervals based on BE length. We studied rates of progression of NDBE to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in patients with short-segment BE using the definition of BE in the latest guidelines (length >=1 cm). METHODS: We collected demographic, clinical, endoscopy, and histopathology data from 1883 patients with endoscopic evidence of NDBE (mean age, 57.3 years; 83.5% male; 88.1% Caucasians) seen at 7 tertiary referral centers. Patients were followed for a median 6.4 years. Cases of dysplasia or EAC detected within 1 year of index endoscopy were considered prevalent and were excluded. Unadjusted rates of progression to HGD or EAC were compared between patients with short (>=1 and <3) and long (>=3) BE lengths using log-rank tests. A subgroup analysis was performed on patients with a documented Prague C&M classification. We used a multivariable proportional hazards model to evaluate the association between BE length and progression. Adjusted hazards ratios were calculated after adjusting for variables associated with progression. RESULTS: We found 822 patients to have a short-segment BE (SSBE) and 1061 to have long segment BE (LSBE). We found patients with SSBE to have a significantly lower annual rate of progression to EAC (0.07%) than of patients with LSBE (0.25%) (P = .001). For the combined endpoint of HGD or EAC, annual progression rates were significantly lower among patients with SSBE (0.29%) compared to compared to LSBE (0.91%) (P < .001). This effect persisted in multivariable analysis (hazard ratio, 0.32; 95% CI, 0.18 0.57; P < .001). CONCLUSION: We analyzed progression of BE (length >=1 cm) to HGD or EAC in a large cohort of patients seen at multiple centers and followed for a median 6.4 years. We found a lower annual rate of progression of SSBE to EAC (0.07%/year) than of LSBE (0.25%/year). We propose lengthening current surveillance intervals for patients with SSBE. PMID- 30012435 TI - Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection. AB - BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents. METHODS: We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid reducing agents. RESULTS: Of the 401 patients (17%) who reported use of acid reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI. CONCLUSIONS: In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION 4), NCT02446717 (MAGELLAN-I). PMID- 30012436 TI - Risk of Bias Analysis of Systematic Reviews of Probiotics for Treatment of Irritable Bowel Syndrome. PMID- 30012437 TI - Erratum to "Selective Changes in Locomotor Activity in Mice Due to Low-intensity Microwaves Amplitude Modulated in the EEG Spectral Domain" [Neuroscience 359 (2017) 40-48]. PMID- 30012438 TI - Characterisation of a class 1 integron associated with the formation of quadruple blaGES-5 cassettes from an IncP-1beta group plasmid in Pseudomonas aeruginosa. AB - Integrons are genetic platforms responsible for the dissemination of antimicrobial resistance genes among Gram-negative bacteria, primarily due to their association with transposable elements and conjugative plasmids. In this study, a cassette array containing four identical blaGES-5 genes embedded in a class 1 integron located on an IncP-1beta group plasmid from a clinical Pseudomonas aeruginosa strain was identified. Comparative genome analysis and conjugation assay showed that the plasmid pICP-4GES lacked the trbN, trbO and trbP genes but was conjugable. Antimicrobial susceptibility testing revealed that compared with single-copy blaGES-5 complementary strains, both the cloned and chromosome-targeted expression of four copies of blaGES-5 increased the minimum inhibitory concentration (MIC) by one to two dilutions for most of the selected antimicrobials. Quantitative real-time reverse transcription PCR (RT-qPCR) showed that the four consecutive cassettes increased blaGES-5 expression by approximately two-fold compared with the single-copy blaGES-5 strain, suggesting that the level of gene expression was not directly proportional to copy number. In addition, the gene cassette capture assay showed that the global blaGES-5 transfer frequency reached 5.38 * 10-4. PMID- 30012439 TI - In vitro activity of tigecycline and comparators (2014-2016) among key WHO 'priority pathogens' and longitudinal assessment (2004-2016) of antimicrobial resistance: a report from the T.E.S.T. study. AB - We report contemporary (2014-2016) Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) global data on activity of tigecycline and comparators against WHO 'priority pathogens', and global trends (2004-2016) in antimicrobial resistance. MICs were determined using CLSI broth microdilution methodology. Antimicrobial resistance was determined using CLSI breakpoints (FDA breakpoints for tigecycline). Data are reported for Africa, Asia, Europe, North America and South America. From 2014-2016, Africa, Asia and South America reported highest resistance rates among Acinetobacter baumannii; North America lowest (all antimicrobials tested). The tigecycline MIC90 against A. baumannii was 2 mg/L in all regions except South America (1 mg/L). Among Enterobacteriaceae, meropenem resistance was low and tigecycline resistance was <=1.3% in all regions (Escherichia coli, 0.0-0.3%; Klebsiella pneumoniae 0.0-1.3%; Enterobacter spp. 0.5-1.1%; Serratia marcescens 0.0-1.3%). Ceftriaxone resistance among E. coli ranged from 14.5% (North America) to 54.7% (Asia), and among K. pneumoniae from 9.1% (North America) to 54.0% (South America). North America reported highest rates of vancomycin-resistant Enterococcus faecium (64.6%); Europe lowest (17.7%). The tigecycline MIC90 against methicillin-resistant Staphylococcus aureus (MRSA) ranged from 0.12 mg/L (Africa and North America) to 0.5 mg/L (Asia). From 2004-2016, carbapenem resistance increased among A. baumannii (all regions), reaching 92.3% in Africa and 85.7% in South America (2016). Rates of ceftriaxone-resistant E. coli increased in all regions except Asia. Ceftriaxone resistance in K. pneumoniae increased in Europe. Rates of vancomycin-resistant E. faecium and MRSA were highest in North America and South America (and Asia for MRSA); lowest in Europe. PMID- 30012440 TI - Evaluation of the efficacy and safety of ceftazidime/avibactam in the treatment of Gram-negative bacterial infections: a systematic review and meta-analysis. AB - Data on the efficacy and safety of ceftazidime/avibactam (CAZ-AVI) are limited. A systematic review and meta-analysis was conducted to clarify the role of CAZ-AVI for patients with serious Gram-negative bacterial infections. The PubMed, EMBASE and Cochrane Library databases were searched for randomised controlled trials (RCTs) and cohort studies involving CAZ-AVI. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Twelve articles (4951 patients) were included, consisting of nine RCTs and three observational studies comparing CAZ-AVI with other regimens, e.g. carbapenems or colistin. CAZ-AVI showed a comparable clinical response (RR = 0.99, 95% CI 0.96-1.02; I2 = 0%) and non-inferior bacterial eradication (RR = 1.04, 95% CI 0.93-1.17; I2 = 79.1%) to carbapenems. No significant difference was detected between groups regarding mortality and adverse events. Moreover, subgroup analyses demonstrated that CAZ-AVI improved the clinical response (RR = 1.61, 95% CI 1.13-2.29) with reduced mortality (RR = 0.29, 95% CI 0.13-0.63) in patients infected by carbapenem-resistant Enterobacteriaceae versus comparators. Likewise, CAZ-AVI improved the clinical cure rate of bloodstream infections (RR = 2.11, 95% CI 1.54-2.88). An improved ability of CAZ-AVI in microbiological eradication was also detected in patients with complicated urinary tract infections (RR = 1.13, 95% CI 1.05-1.21). CAZ-AVI exhibited comparable efficacy and safety with carbapenems. Therefore, this agent might be a potential powerful agent for patients with serious Gram-negative bacterial infections. PMID- 30012441 TI - Comparative efficacy of antibiotics in treating experimental Clostridium septicum infection. AB - Clostridium septicum is a highly pathogenic microbe that causes gas gangrene in humans, and is the principal cause of spontaneous gas gangrene in patients with gastrointestinal maladies, including adenocarcinoma of the colon. Despite modern approaches to manage C. septicum infection, morbidity and mortality remain high (>60%). At present, no objective in-vivo data exist supporting the current antibiotic treatment recommendations for C. septicum infection. Utilizing an established murine model of clostridial myonecrosis, this study investigated the efficacy of standard antibiotics for anaerobic Gram-positive soft tissue infections (penicillin, clindamycin, tetracycline and vancomycin) in treating C. septicum gas gangrene. Following intramuscular challenge with 1 * 106 colony forming units of C. septicum, antibiotics were administered by intraperitoneal injection every 4 h for a total of four doses. At 30 h, all animals in all treatment groups survived the C. septicum challenge, compared with no survivors in the untreated controls (100% mortality by 10 h). However, by 60 h, mice treated with vancomycin exhibited 40% mortality, with no mortality observed in any other antibiotic treatment group. Microbroth dilution minimum inhibitory concentration analyses for three strains of C. septicum also demonstrated high susceptibility to penicillin, clindamycin and tetracycline, but considerably lower susceptibility to vancomycin. This study suggests that penicillin, clindamycin and tetracycline are suitable alternatives for the treatment of C. septicum infection in humans. PMID- 30012442 TI - Emergence of unusual vanA/vanB2 genotype in a highly mutated vanB2-vancomycin resistant hospital-associated E. faecium background in Vietnam. AB - Enterococcus faecium has become a globally disseminated nosocomial pathogen mainly because of acquisition and diffusion of virulence factors and multidrug resistance determinants, including glycopeptides, which are some of the last resort antimicrobials used to treat more serious infections common in high-risk patients. In this study we investigated and characterized hospital-associated (HA) E. faecium isolates collected at Hue Central Hospital, Vietnam. Our results highlighted the spread among hospital wards of a surprisingly heterogeneous multidrug-resistant E. faecium population comprising five different CC17-related sequence types (STs), of which 46% VREf carry the vanB gene. Whole genome sequencing of selected E. faecium isolates showed that VREf from different STs carried the same chromosomal integrated Tn1549-like transposon, with a highly mutated vanB2-operon, showing an increased level of vancomycin resistance (VanB phenotype) and able, in one isolate, to confer resistance to teicoplanin (VanA incongruent phenotype). Two unusual vanA/vanB2-type strains were detected within the vanB2-type ST17 population, harbouring a Tn1546-vanA-like transposon in pJEG40-like plasmids. Wg-SNPs-based analysis showed the genetic relatedness of VSEf/VREf of the same STs and indicated lateral exchange of the Tn1549-like element among isolates followed by clonal expansion. Microevolution among ST17 isolates, including the vanA/vanB2-type strains, and inter-wards VREf transmission, were highlighted. The use of teicoplanin is strongly discouraged in the study hospital because of the spreading of Tn1549-vanB2 associated to teicoplanin resistance. A rational use of glycopeptides and effective surveillance measures are required to reduce nosocomial VSEF/VREf spread and to avoid the rise of unusual and misleading VREf genotypes. PMID- 30012443 TI - Predictive Factors for Abdominal Aortic Aneurysm Shrinkage One Year after Successful Endovascular Aneurysm Repair. AB - BACKGROUND: Often, we experience cases of aneurysm shrinkage and no aneurysm shrinkage after successful endovascular aortic aneurysm repair, without postoperative endoleaks. We studied these cases to ascertain the predictive factors for aneurysm shrinkage. METHODS: From 2007 to 2014, we selected 255 cases that comprised aneurysm shrinkage (>4 mm) and no-shrinkage cases (shrinkage from 0 to 4 mm). Excluding 36 cases of endoleaks, 43 cases without 1-year follow-up computed tomography scan, and 3 cases of aortic dissection, we assessed 93 cases of aneurysm shrinkage (S group) and 80 cases of no aneurysm shrinkage (N group) at 1-year follow-up. RESULTS: No significant differences were found in sex, comorbidities (diabetes mellitus, chronic kidney disease, hemodialysis, and malignancy), and medications (antiplatelet drugs, anticoagulant drugs, steroids, and statins). Advanced age was a strong negative predictive factor for aneurysm shrinkage (N: 75.0 +/- 1.0 vs. S: 72.1 +/- 0.9 years; P = 0.023), and intraoperative endoleaks were more frequent in the N group (N: 31.3 vs. S: 9.7%; P = 0.001). Neck thrombus was more likely in the N group (N: 17.5 vs. S: 7.5%; P = 0.045), but it had a strong correlation with intraoperative endoleaks (P = 0.008). In the multivariate analysis, patient age and intraoperative endoleaks were predictive factors for aneurysm shrinkage. CONCLUSIONS: Advanced age and intraoperative endoleaks were negative predictive factors for aneurysm shrinkage at 1-year follow-up after successful endovascular treatment without postoperative endoleaks. PMID- 30012444 TI - Aggressive Decongestion in Limbs with Lymphedema without Subcutaneous Echo-Free Space. AB - BACKGROUND: To study the impact of aggressive decongestion in limbs with lymphedema without subcutaneous echo-free space (SEFS) in subcutaneous tissue ultrasonography. METHODS: In 13 patients with arm lymphedema (ALE) (13 arms) and 16 patients with leg lymphedema (LLE) (18 legs) without SEFS, an aggressive decongestion was performed as the first phase of complex decongestive therapy. Measurements of circumference and calculation of limb volume were performed before and after the treatment. RESULTS: In ALE, no significant reduction in arm volume (median -63 [range -251 to 176] mL) or edema ratio (-4 [-15 to 12]%) was confirmed. On the other hand, a small but significant reduction in leg volume ( 207 [-834 to 131] mL, P < 0.001) and edema ratio (-4 [-14 to 2]%, P < 0.01) was confirmed in LLE. CONCLUSION: In limbs with lymphedema without SEFS, the impact of aggressive decongestion seemed limited. PMID- 30012445 TI - Significance and Risk Factors for Intraprosthetic Mural Thrombus in Abdominal Aortic Endografts: A Systematic Review and Meta-analysis. AB - BACKGROUND: The detection of intraprosthetic thrombus (IPT) deposits is a common finding during follow-up for endovascular abdominal aneurysm repair (EVAR); however, its clinical significance is still debated. The aim of this study was to determine if IPT represents a risk factor for thromboembolic events (TEs; endograft or limb thrombosis, or distal embolization) after EVAR. METHODS: A systematic review of English literature was undertaken until November 2017. Studies providing 2-group comparison (patients with IPT development on postoperative computed tomography angiography versus patients without IPT) with extractable outcome data (TE related to IPT and/or risk factors for IPT development) were included. Meta-analysis was performed when comparative data were given in 2 or more articles. RESULTS: Five single-center studies (808 patients) were analyzed. IPT detection at any time during follow-up occurred in 20.8% (168/808) of patients. Extractable data for postoperative TE were available in 4 studies (613 patients): on comparative meta-analysis, IPT was not significantly associated with TE occurrence during follow-up (odds ratio 2.25, 95% confidence interval [CI] 0.50-10.1; P = 0.29). IPT is generally detected during the first year after EVAR (maximum reported median: 12 months, range: 1.2 23). Polyester graft material (odds ratio 2.34, 95% CI 1.53-3.58; P < 0.001) and aorto-uni-iliac configuration of the endograft (odds ratio 3.27, 95% CI 1.66 6.44; P = 0.001) were confirmed as risk factors for IPT formation on meta analysis. The literature systematic review suggests that IPT formation may be also associated with long main bodies and large necks. CONCLUSIONS: IPT detection on postoperative computed tomography angiography was not significantly associated with the occurrence of TE over time. The aorto-uni-iliac configuration and the use of polyester fabric for endografts were confirmed as risk factors for IPT development. PMID- 30012446 TI - Current Experience and Midterm Follow-up of Immediate-Access Arteriovenous Grafts. AB - BACKGROUND: No independent reviews, with midterm follow-up, of current experience with immediate-access arteriovenous grafts (IAAVGs) exist. The goal of this project was to assess the real-world performance of 2 different IAAVGs over a 2 year period at a large tertiary referral center. METHODS: Between January 2014 and April 2016, all consecutive patients who underwent placement of Acuseal (Gore) or Flixine (Maquet) IAAVGs were identified for retrospective analysis from the electronic medical record and Vascular Quality Initiative database. Primary, primary-assisted and secondary patency rates, time to first cannulation, time to tunneled catheter removal, and overall survival were recorded. RESULTS: Forty three patients were identified to have undergone placement of IAAVG, 31 Acuseal (72%), and 12 Flixine (28%). Of the Acuseal cohort, 7 were implanted with outflow through a HeRO catheter system (Merit Medical). Mean follow-up time was 8.4 months. Overall survival was 57.4% at 18 months. Overall primary, primary assisted, and secondary patency at 18 months were 33.36%, 34.31%, and 51.03%, respectively. Eighty three percent of grafts were successfully cannulated, and 78% of preexisting catheters were removed. Mean time to successful graft cannulation and catheter removal were 14.85 and 32.26 days, respectively. CONCLUSIONS: Real-world experience with novel arteriovenous access grafts is consistent with results from industry-sponsored studies. Early cannulation of immediate-access grafts can be successfully performed in a wide variety of patients. However, prolonged catheter dwell times persist despite increased rates of successful early-graft cannulation. Further study of methods for promoting catheter removal in this patient population is warranted. PMID- 30012447 TI - Lumbar Artery Injury during Transforaminal Percutaneous Endoscopic Lumbar Discectomy: Successful Treatment by Emergent Transcatheter Arterial Embolization. AB - Injury to the lumbar artery during percutaneous endoscopic lumbar discectomy (PELD) is a very severe complication and only rarely reported. We present a 64 year-old patient with an injury to the right third lumbar artery during PELD which was successfully treated with intraoperative angiography and coil embolization. To our knowledge, this is the first report of the use of intraoperative angiography and coil embolization to treat a lumbar artery that had been lacerated during PELD. PMID- 30012448 TI - Rosai-Dorfman Disease Presenting as Peripheral Vascular Insufficiency. AB - Rosai-Dorfman (-Destombes) disease (RDDD) is a rare idiopathic disorder of histiocyte proliferation, usually involving lymph node stations. The most common clinical finding is a bilateral cervical lymphadenopathy, fever, and weight loss. Arterial or venous structures are notably not involved. We hereby present a case of a 78-year-old Caucasian man, presenting with symptoms of progressive arterial insufficiency and right lower-limb edema, along with a nonpulsatile mass at the middle third of the thigh. Initial diagnostic hypothesis was a superficial femoral artery aneurysm thrombosis with a secondary postcompressive superficial femoral vein thrombosis. Duplex examination showed right superficial femoral arterial and venous thrombosis, along with a hypoechogenic mass causing compression of the neurovascular bundle. Suspecting a connective tissue sarcoma, computed tomography scan was performed after combined en bloc removal of the mass along with femoral artery and vein and prosthetic reconstruction of vascular continuity. Histopathology diagnosis was connective tissue RDDD. The atypical presentation of this rare syndrome induces us to include in differential diagnosis, among other more common forms of external compression of the neurovascular bundles, even rare conditions such as these, which generally only involve lymphatic stations. PMID- 30012449 TI - Laparoscopic Peritoneal Dialysis Surgery is Safe and Effective in Patients with Prior Abdominal Surgery. AB - BACKGROUND: Despite the lower cost, improved early survival, and preservation of the remaining kidney function, peritoneal dialysis is used by only 8.8% of the dialysis population in the USA. Intraabdominal adhesions reported in 70-90% of patients with prior abdominal surgery (PAS) reduce the peritoneal surface area and may increase the intraoperative and postoperative morbidity. The objective of this study is to evaluate the outcomes of laparoscopic peritoneal dialysis (LPD) catheter placement in patients with and without PAS. METHODS: Patients who had LPD catheters placed between January 2014 and August 2016 were retrospectively reviewed. A Kaplan-Meier analysis was performed to assess the revision-free catheter survival (RFCS) and revision-assisted catheter survival (RACS) between the 2 groups. RESULTS: One hundred forty-two patients had had LPD catheter placed during the study time, 82 (58%) with PAS. Lysis of adhesions (LOA) was required in 26 patients (28%) with PAS. Demographics and comorbidities were similar, but more women had PAS (65% vs. 35%, P < 0.001). Seventeen patients (12%) required revision, with no difference between the 2 groups. Both RFCS and RACS were similar in patients without and with PAS (P = 0.38 and 0.98, respectively). RFCS was 73% vs. 64% at 1 year (no PAS versus PAS) and 62% vs. 51% at 2 years, whereas RACS was 84% vs. 77% at 1 year (no PAS versus PAS) and 69% vs. 68% at 2 years. Only 2 intraoperative complications occurred, namely a superficial liver injury and pelvic hematoma. Three complications (0.02%) occurred within 30 days, namely 1 peritonitis and 2 catheter malfunctions. Overall complication rate was 25%, predominantly poor drainage (17% and 22% for PAS and no PAS, respectively), and there were no differences between the subgroups. No deaths occurred within a year of surgery during the study follow-up. CONCLUSIONS: LPD and LOA can be performed safely in patients with multiple PAS. When possible, LPD catheters should be part of the vascular surgery training armamentarium and offered to patients with PAS. PMID- 30012450 TI - Left Atrial Myxoma Presenting as an Embolic Shower: A Case Report and Review of Literature. AB - Myxomas are the most common primary cardiac neoplasms. Multimodality imaging is essential for proper diagnosis and treatment. The cardiovascular manifestations depend on myxomas location and size. Intracardiac obstruction, constitutional symptoms, and infected myxomas have been described. Though uncommon, myxomas should also be included in the diagnosis of peripheral embolization to the extremities or visceral aorta. We hereby present a rare case of left atrial myxoma with multiple systemic emboli and a review of the associated literature. PMID- 30012451 TI - Endovascular Management of Tracheo-Subclavian Fistula. AB - Tracheoarterial fistula is a rare complication of tracheostomy with an incidence of less than 1%. Survival of this disease entity is low, and it likely results from a major open operation in a high-risk surgical group. In our review of the literature, a tracheoinnominate artery fistula is the most commonly reported arterial fistula. However, we present a rare case of tracheo-left subclavian artery fistula. We have identified 1 previous case of tracheo-left subclavian fistula as a source of massive tracheal bleeding. In our case report, we describe the successful management of this disease by endograft placement. Owing to its rarity, there are no guidelines on the management approach to tracheoarterial fistulas, but given the difficulty of controlling this problem via median sternotomy, the placement of a covered stent may be the best therapy. Initially, case reports showed a role for endograft placement as a temporizing measure, but the risk of infection may be sufficiently low to justify this approach as a definitive therapy. Upon a 6-month follow-up, our patient remains without recurrence of bleeding or infection, and computed tomography angiography of the chest with 3D reconstruction has shown patency of the endovascular stent with resolution of the associated pseudoaneurysm. PMID- 30012452 TI - Femoral Bifurcation Endarterectomy with Transection-Eversion of the Superficial Femoral Artery: Technique and Results. AB - BACKGROUND: We evaluated the results of femoral bifurcation endarterectomy using the eversion technique with transection of the superficial femoral artery (femoral bifurcation endarterectomy with eversion [FBEE]). METHODS: We included all patients who underwent a femoral revascularization using the eversion technique, with or without antegrade or retrograde revascularization, from January 2006 to December 2015. Data were retrospectively collected. Primary and primary assisted patency (PAP) of the femoral bifurcation were analyzed. Secondary outcomes were 30-day postoperative complications. RESULTS: A total of 129 patients (143 limbs) underwent consecutive FBEE (86.8% men, with a mean age of 69.7 years). Patients presented with claudication (93, 65%) and critical ischemia (46, 32.2%). Primary patency was 96.3%, 94.6%, and 93% at 1, 2, and 5 years, respectively. PAP was 99% at 3 time points. Reintervention was necessary in 8 patients during follow-up. The 30-day mortality was 0.7% (1 patient), and the access complication rate was 18.8% (n = 27), of which only 2.8% (n = 4) were major complications. CONCLUSIONS: This retrospective study confirmed the efficiency and the reproducibility of this technique for the treatment of femoral bifurcation lesions. This technique allowed treating extensive atherosclerotic lesions of the deep femoral artery and may be associated with antegrade and retrograde revascularizations. PMID- 30012453 TI - Femoral Access for Iliac Branched Endoprosthesis Deployment in Patients with a Prior Bifurcated Aortic Stent Graft. AB - This series describes an innovative technique to deploy iliac branched endoprostheses (IBEs) in patients with preexisting endovascular aneurysm repair (EVAR). It demonstrates an alternative approach that may be preferred when brachial access is anatomically challenging or when access site complications are of concern. We detail a technique that uses transfemoral access to bring IBE device components up and over an infrarenal endograft bifurcation and into proper position. This series suggests that endovascular specialists should consider the advantages and disadvantages of a transfemoral approach when selecting the best method of repairing a patient's iliac artery aneurysm after prior EVAR. PMID- 30012454 TI - Delayed Superficial Femoral Artery Covered Stent Infection: Report of Two Cases and Review of Literature. AB - In recent years, endovascular procedures have become a first-line therapy for peripheral arterial disease. As a result, an increased number of patients received stent grafts to treat their persistent superficial femoral artery (SFA) lesions. Although the risk of stent-graft infection in that location exists, it is exceptionally rare. Successful management of this condition requires removal of the infected stent graft in combination with appropriate antibiotic therapy and debridement of necrotic tissue, as well as revascularization, with avoidance of prosthetic material. We describe 2 cases of infected stent grafts in the SFA that presented late after the original intervention. An 83-year-old man presented 8 years after the original operation, and a 57-year-old woman presented 2 years after the original operation. Both infected stent grafts were excised, and complete destruction of the native arterial wall was evident during exploration. PMID- 30012455 TI - Posttraumatic Reconstruction of External Iliac and Common Femoral Veins Using Femoral Vein Interposition Autograft. AB - Posttraumatic reconstruction of large lower extremity veins is a challenging and rarely performed procedure. We describe a case of an 18-year-old male traffic accident victim presenting with extensive venous injury of the right inguinal region including external iliac vein and common femoral vein requiring immediate ligation. Owing to life-threatening phlegmasia cerulea dolens, venous reconstruction was successfully performed using an femoral vein interposition autograft from the contralateral lower limb. PMID- 30012456 TI - Determining the Diagnostic Value of 18F-Fluorodeoxyglucose Positron Emission/Computed Tomography in Detecting Prosthetic Aortic Graft Infection. AB - BACKGROUND: To determine the diagnostic value of 18F-fluorodeoxyglucose positron emission/computed tomography (FDG PET/CT) in detecting prosthetic aortic graft infection (AGI). METHODS: Twenty-one patients with prosthetic grafts for abdominal aortic aneurysms underwent FDG PET/CT scans for suspected graft infection over a 15-month period. Images were evaluated for tracer pattern and grade of FDG uptake in addition to measuring the maximal standardized uptake value (SUVmax). Two independent nuclear medicine physicians retrospectively evaluated all imaging. The images from a control group of patients with aortic grafts who underwent FDG PET/CT scans for onco-hematological indications were evaluated to establish radiological characteristics of asymptomatic grafts. Secondary parameters that are associated with graft infection such as components of the peripheral blood count were collected. Graft infection status was determined using microbiological outcomes following graft explantation or radiological drainage of perigraft collections and correlated with results of the FDG PET/CT scans to determine infective status. RESULTS: In the control group, the pattern of FDG uptake was homogenous and diffuse. The mean SUVmax was 3.5 (+/ 1.3). Thirteen out of 21 grafts were confirmed as infected. Tracer uptake in infected grafts displayed an intense and focal pattern, with a median grade of uptake of 4 vs. 2 on a validated 4 point grading scale. The area under the receiver operating curve for FDG PET/CT in detecting infection was 0.85 (+/-0.15) P = 0.01. Sensitivity was 92%, specificity 63%, and positive and negative predictive values of 80% and 83%, respectively. The SUVmax was significantly higher in infected than noninfected grafts, (10.3 +/- 4.2 vs. 5.4 +/- 3.4) P = 0.02. According to the receiver operating characteristic analysis, SUVmax greater than 6.3 represented the optimal cutoff between infective and noninfective outcome. Of the secondary parameters collected, grade of uptake and SUVmax were the only significant predictors of infection (odds ratio 2.5, 1.5 respectively) P = 0.05. White cell count, erythrocyte sedimentation rate, and C-reactive protein demonstrated nonsignificant odds ratios of 1.4, 0.9, and 1.0, respectively. CONCLUSIONS: FDG PET/CT is a valuable diagnostic test for identifying AGI. Infected grafts display significantly greater FDG uptake in a distinctive intense focal perigraft pattern and distribution. SUVmax greater than 6.3 is a good cutoff to determine infective status. PMID- 30012457 TI - Mechanisms Underlying Atheroma Induction: The Roles of Mechanotransduction, Vascular Wall Cells, and Blood Cells. AB - BACKGROUND: The objective of this article is to review cellular mechanism of atherosclerosis (AS) development. The pathogenesis of AS comprises a sequence of biological events leading to build up of a dense or loose atheromatous plaque (AP). METHODS: In this review, we tried to attempt to analyze the cellular mechanisms underlying AS development, including the roles of monocytes/macrophages and smooth muscle cells in the formation of stable/unstable APs. RESULTS: As a rule, APs are formed in the regions with irregular blood flow; both mechanical perturbations of the vascular wall and several biological events contribute to plaque formation. Blood lipid/lipoprotein deposition, recruitment of monocytes/macrophages, foam cell formation, migration and proliferation of smooth muscle cells, secretion of extracellular matrix, and formation of the connective tissue in plaques are among the latter events. CONCLUSIONS: The review briefs the contributions of different processes to atheroma formation and describes the molecular mechanisms involved in AS development. AP transcriptome studies will be helpful in the identification of the key genes involved in atheroma transformation and development as well as discovery of the new targets for diagnosis and therapy. PMID- 30012458 TI - Neural correlates underlying spatial and verbal working memory in children with different mathematics achievement levels: An event-related potential study. PMID- 30012459 TI - Efficacy and outcomes of a summer-based pediatric vision screening program. AB - PURPOSE: To investigate the prevalence of decreased visual acuity and uncorrected refractive error in school-aged children participating in summer programs. METHODS: During the summers of 2014-2016, Wills Eye Hospital collaborated with summer programs in Philadelphia to provide vision screenings for underserved children. Parental consent was obtained prior to vision screening. Fail criteria included children in grades K-1 (ages 5-6) with visual acuity worse than 20/40 in either eye, children in grades 2-6 (ages 7-13) with visual acuity worse than 20/30 in either eye, or children with >=2 lines of interocular difference. If decreased visual acuity was correctable to >=20/30 by the onsite optometrist, two pairs of free eyeglasses were provided. Children with other ocular abnormalities were referred to pediatric ophthalmology. RESULTS: Of 1,627 children screened, 360 children (22.1%) did not pass vision screening, and 64 (3.9%) were referred. The prevalence of decreased distance visual was 34.1%. Younger children were more likely to have worse visual acuity than older children (OR = 0.943; P = 0.023; 95% CI, 0.896-0.992). Myopia (73%), astigmatism (56.8%), hyperopia (15.5%), spherical anisometropia (12.5%), and cylindrical anisometropia (11.9%) presented in the 303 children who underwent a manifest refraction. Myopia increased with age (OR = 0.818; P = 0.001; 95% CI, 0.724-0.922), whereas astigmatism decreased (OR = 0.817; P < 0.001; 95% CI, 0.728-0.913) with age. Two pairs of glasses were provided to 301 children. CONCLUSIONS: Partnership with summer programs and other community initiatives to provide vision screenings facilitates access to eye care ultimately aimed at improving social functioning and academic performance. PMID- 30012460 TI - Targeting AgRP neurons to maintain energy balance: Lessons from animal models. AB - The current obesity epidemic is a major worldwide health and economic burden. In the modern environment, an increase in the intake of high-fat and high-sugar foods plays a crucial role in the development of obesity by disrupting the mechanisms governing food intake and energy balance. Food intake and whole-body energy balance are regulated by the central nervous system through a sophisticated neuronal network located mostly in the hypothalamus. In particular, the hypothalamic arcuate nucleus (ARC) is a fundamental center that senses hormonal and nutrient-related signals informing about the energy state of the organism. The ARC contains two small, defined populations of neurons with opposite functions: anorexigenic proopiomelanocortin (POMC)-expressing neurons and orexigenic Agouti-related protein (AgRP)-expressing neurons. AgRP neurons, which also co-produce neuropeptide Y (NPY) and gamma-Aminobutyric acid (GABA), are involved in an increase in hunger and a decrease in energy expenditure. In this review, we summarize the key findings from the most common animal models targeting AgRP neurons and the tools used to discern the role of this specific neuronal population in the control of peripheral metabolism, appetite, feeding related behavior, and other complex behaviors. We also discuss how knowledge gained from these studies has revealed new pathways and key proteins that could be potential therapeutic targets to reduce appetite and food addictions in obesity and other diseases. PMID- 30012461 TI - HCV-induced EGFR-ERK signaling promotes a pro-inflammatory and pro-angiogenic signature contributing to liver cancer pathogenesis. AB - HCV is a major risk factor for hepatocellular carcinoma (HCC). HCC development in chronically infected HCV patients has until now been attributed to persistent inflammation and interference of viral proteins with host cell signaling. Since activation of the epidermal growth factor receptor (EGFR) presents a crucial step in HCV entry, we aimed at investigating whether EGFR signaling may contribute to the pathogenesis of HCV-related HCC. By applying microarray analysis, we generated a gene expression signature for secreted proteins in HCV-infected hepatoma cells. This gene signature was enriched for inflammatory and angiogenic processes; both crucially involved in HCC development. RT-qPCR analysis, conducted on the entire list of upregulated genes, confirmed induction of 11 genes (AREG, IL8, CCL20, CSF1, GDF15, IGFBP1, VNN3, THBS1 and PAI-1) in a virus titer- and replication-dependent manner. EGFR activation in hepatoma cells largely mimicked the gene signature seen in the infectious HCV model. Further, the EGFR-ERK pathway, but not Akt signaling, was responsible for this gene expression profile. Finally, microarray analysis conducted on clinical data from the GEO database, revealed that our validated gene expression profile is significantly represented in livers of patients with HCV-related liver pathogenesis (cirrhosis and HCC) compared to healthy livers. Taken together, our data indicate that persistent activation of EGFR-ERK signaling in chronically infected HCV patients may induce a specific pro-inflammatory and pro-angiogenic signature that presents a new mechanism by which HCV can promote liver cancer pathogenesis. A better understanding of the key factors in HCV-related oncogenesis, may efficiently direct HCC drug development. PMID- 30012462 TI - Ginsenoside Rd ameliorates colitis by inducing p62-driven mitophagy-mediated NLRP3 inflammasome inactivation in mice. AB - Previous studies reported that Ginsenoside Rd (Rd) had anti-inflammatory and anti cancer effects. However, the molecular mechanism underlying the inhibition effect of Rd on colitis in mice hasn't been clarified clearly. Here, in our study, we detected the effects of Rd on dextran sulfate sodium (DSS)-induced murine colitis, and found that oral administration of Rd dose-dependently alleviated DSS induced body weight loss, colon length shortening and colonic pathological damage with lower myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities and higher glutathione level. In addition, the production of pro inflammatory cytokines (IL-1beta, TNF-a and IL-6) in both serum and colonic tissues were significantly down-regulated by Rd administration. The activation of NLRP3 inflammasome was also suppressed in Rd-treated group, resulting in reduced caspase-1 production and IL-1beta secretion. In vitro, Rd remarkably inhibited NLRP3 inflammasome activation which was mostly dependent on the mitochondrial translocation of p62 and mitophagy. Importantly, Rd-driven inhibition of the NLRP3 inflammasome was significantly blocked by various autophagy inhibitors. Furthermore, upregulation of AMPK/ULK1 signaling pathway accounted for Rd-induced autophagy, which was also seen in vivo. In conclusion, our results demonstrated the function of Rd on the inhibition NLRP3 inflammasome and its potential application for the treatment of NLRP3-associated diseases. PMID- 30012463 TI - Differential expression of microRNAs in recombinant Chinese hamster ovary cells treated with sodium butyrate using digital RNA counting. AB - Sodium butyrate (NaBu) is an efficient supplement for increasing recombinant protein production in Chinese hamster ovary (CHO) cell culture. To elucidate the effects of NaBu on miRNA expression profile in recombinant CHO (rCHO) cells, differentially expressed miRNAs in NaBu-treated rCHO cells were assessed by NanoString nCounter analysis. This result showed that eight mature mouse miRNAs (let-7b, let-7d, miR-15b, miR-25, miR-27a, miR-99a, miR-125a-5p, and miR-125b-5p) were differentially expressed. Furthermore, quantitative real-time RT-PCR analysis of eight mature CHO miRNAs, annotated using a miRBase database, confirmed the transcriptomic findings. Among the potential corresponding target mRNAs for the selected mature miRNAs, seven cell growth-related target genes (e2f2, akt2, mtor, bcl-2, bim, p38alpha, and bmf) and five N-glycosylation related target genes (neu1, b4galt3, gale, man1b1 and mgat4a) were selected by considering the effectiveness of NaBu on rCHO cell culture. The altered expression patterns of the 12 target mRNAs were inversely correlated with those of the selected mature miRNAs. Altogether, NanoString nCounter analysis may be useful for identifying differentially expressed miRNAs in rCHO cells. PMID- 30012464 TI - Extraversion and behavioural approach system in stimulus analysis and motor response initiation. AB - In this study, we attempt to validate previous findings on extraversion-related differences in speed of sensorimotor processing and to extend them into Behavioural Approach System (BAS) subtraits within the framework of the revised Reinforcement Sensitivity Theory (rRST) of personality. Here, we assessed psychological traits of extraversion (E), four BAS facets (Goal-Drive Persistence, BAS-GDP; Reward Interest, BAS-RI; Reward Reactivity, BAS-RR; Impulsivity, BAS-I), Behavioural Inhibition System (BIS), and Fight-Flight-Freeze System (FFFS) in 51 volunteers (28 women). Stimulus-locked lateralized readiness potential (S-LRP), response-locked LRP (R-LRP), stimulus-locked and response locked forearm electromyogram (S-EMG and R-EMG), and P3 components of the event related potentials (ERPs), were recorded during the performance of a two-choice Go/NoGo visual letter-digit discrimination task varying in task difficulty. High extraverts, relative to introverts and individuals high relative to low on BAS RI, were more likely to exhibit shorter S-LRP latencies and stimulus- and response-locked EMG latencies. Additionally, high BAS-I had a shorter R-RLP latency than low BAS-I participants for the difficult task. High FFFS levels were associated with longer S-LRP and S-EMG latencies, while high BIS levels had larger response accuracy. Extraverts, relative to introverts, along with those high relative to low on BAS-RR and BAS-I, exhibited smaller P3 amplitudes. The faster cortical premotor initiation, found in individuals high on extraversion, BAS-RI and low on FFFS, may account for their faster peripheral motor response initiation and execution. Smaller P3 amplitudes in extraverts and individuals high on BAS-RR and BAS-I may indicate reduced perceptual processing capacity in these individuals. PMID- 30012466 TI - KRAB-containing zinc finger protein ZNF496 inhibits breast cancer cell proliferation by selectively repressing ERalpha activity. AB - KRAB-containing zinc finger proteins (KZNF) constitute the largest family of transcriptional regulators in humans and play critical roles in normal development and tumorigenesis. However, the function and mechanism of most KZNFs remain unclear. Here, we report that ZNF496, a KZNF family member, interacts with the DNA binding domain (DBD) of estrogen receptor alpha (ERalpha) via its C2H2 domain. This interaction decreases ERalpha binding to chromatin DNA and results in the repression of ERalpha transactivation, the selective suppression of ERalpha target genes, and ultimately in a reduction of ERalpha-positive cell growth in the presence of E2. An analysis of clinical data revealed that the downregulation of ZNF496 expression is observed only in ERalpha-positive and not in ERalpha-negative breast cancer tissues when compared with that in matched adjacent tissues. Lastly, we also observed that the downregulation of ZNF496 is associated with poor recurrence-free survival among patients with breast cancer. Collectively, our findings demonstrate that ZNF496 is a novel ERalpha-binding protein that acts as a target gene-specific ERalpha corepressor and inhibits the growth of ERalpha-positive breast cancer cells. PMID- 30012465 TI - Structure-function comparisons of (p)ppApp vs (p)ppGpp for Escherichia coli RNA polymerase binding sites and for rrnB P1 promoter regulatory responses in vitro. AB - Precise regulation of gene expression is crucial for bacteria to respond to changing environmental conditions. In addition to protein factors affecting RNA polymerase (RNAP) activity, second messengers play an important role in transcription regulation, such as well-known effectors of the stringent response: guanosine 5'triphosphate-3'diphosphate and guanosine 3', 5'-bis(diphosphate) [(p)ppGpp]. Although much is known about importance of the 5' and 3' moieties of (p)ppGpp, the role of the guanine base remains somewhat cryptic. Here, we use (p)ppGpp's adenine analogs [(p)ppApp] to investigate how the nucleobase contributes to determine its binding site and transcriptional regulation. We determined X-ray crystal structure of Escherichia coli RNAP-(p)ppApp complex, which shows the analogs bind near the active site and switch regions of RNAP. We have also explored the regulatory effects of (p)ppApp on transcription initiating from the well-studied E. coli rrnB P1 promoter to assess and compare properties of (p)ppApp with (p)ppGpp. We demonstrate that contrary to (p)ppGpp, (p)ppApp activates transcription at this promoter and DksA hinders this effect. Moreover, pppApp exerts a stronger effect than ppApp. We also show that when ppGpp and pppApp are present together, the outcome depends on which one of them was pre incubated with RNAP first. This behavior suggests a surprising Yin-Yang like reciprocal plasticity of RNAP responses at a single promoter, occasioned simply by pre-exposure to one or the other nucleotide. Our observations underscore the importance of the (p)ppNpp's purine nucleobase for interactions with RNAP, which may lead to a better fundamental understanding of (p)ppGpp regulation of RNAP activity. PMID- 30012467 TI - Real-time observation of nucleoplasmin-mediated DNA decondensation and condensation reveals its specific functions as a chaperone. AB - Fertilization requires decondensation of promatine-condensed sperm chromatin, a dynamic process serving as an attractive system for the study of chromatin reprogramming. Nucleoplasmin is a key factor in regulating nucleosome assembly as a chaperone during fertilization process. However, knowledge on nucleoplasmin in chromatin formation remains elusive. Herein, magnetic tweezers (MT) and a chromatin assembly system were used to study the nucleoplasmin-mediated DNA decondensation/condensation at the single-molecular level in vitro. We found that protamine induces DNA condensation in a stepwise manner. Once DNA was condensed, nucleoplasmin, polyglutamic acid, and RNA could remove protamine from the DNA at different rates. The affinity binding of the different polyanions with protamine suggests chaperone-mediated chromatin decondensation activity occurs through protein-protein interactions. After decondensation, both RNA and polyglutamic acid prevented the transfer of histones onto the naked DNA. In contrast, nucleoplasmin is able to assist the histone transfer process, even though it carries the same negative charge as RNA and polyglutamic acid. These observations imply that the chaperone effects of nucleoplasmin during the decondensation/condensation process may be driven by specific spatial configuration of its acidic pentamer structure, rather than by electrostatic interaction. Our findings offer a novel molecular understanding of nucleoplasmin in sperm chromatin decondensation and subsequent developmental chromatin reprogramming at individual molecular level. PMID- 30012468 TI - Management of Asymptomatic Submucous Myomas in Women of Reproductive Age: A Consensus Statement from the Global Congress on Hysteroscopy Scientific Committee. PMID- 30012469 TI - Novel Neovaginoplasty using Rudimentary Uterine Horn serosa and pelvic peritoneum as a graft in Mullerian Anomalies with Vaginal Agenesis. AB - STUDY OBJECTIVE: To study the outcome of a novel method of laparoscopic neovaginal reconstruction using rudimentary uterine horn serosa and pelvic peritoneum as a graft. DESIGN CLASSIFICATION: Canadian Task Force classification II-1 SETTING: University hospital PATIENTS: Retrospective study of 14 patients from 2000 to 2014 of patients with vaginal agenesis who underwent laparoscopic neovagina reconstruction using rudimentary uterine horn serosa and pelvic peritoneum as a graft. INTERVENTION: Patients with vaginal agenesis associated with Mullerian agenesis who requested surgery. Tertiary referral centre and laparoscopic unit. Creation of neovagina using rudimentary uterine horn serosa and pelvic peritoneum as a graft via a combined laparoscopic and vagina route. MEASUREMENTS AND MAIN RESULTS: Data was collected retrospectively includingpost operative vaginal length and width, complications, stenosis or re-operations, dyspareuniaand sexual satisfaction. There were no major complications from the surgery with no rectal perforation, bladder or ureteric injury. The post operative vaginal length was 5-7cm with a mean of 6cm and a width of 2 fingerbreadths. Operation time ranged from 60-228minutes with a mean duration of 143 minutes. Blood loss ranged from 10mls to 300mls with an average of 100mls. Duration of hospital stay ranged from 5-9 days with a mean of 6.6 days. Follow up period ranged from 3 months to 84 months with an average follow up of 20months. CONCLUSION: Lee's method of neovaginoplasty using rudimentary uterine horn serosa and pelvic peritoneum as a graft is a good method for neovagina creation with minimal morbidity, fast recovery and minimal complications. This method results in good anatomical and functional outcome and can be a method that is widely used. PMID- 30012470 TI - Rickettsia sibirica mongolitimonae human infection: A diagnostic challenge. PMID- 30012471 TI - From Hajj services to Mass Gathering Medicine: Saudi Arabia formalizes a novel discipline. PMID- 30012472 TI - Slovakia reports highest occurrence of alimentary tick-borne encephalitis in Europe: Analysis of tick-borne encephalitis outbreaks in Slovakia during 2007 2016. AB - BACKGROUND: Slovakia is well-known for tick-borne encephalitis alimentary (TBE) outbreaks in Europe for a long time. Since the first known and largest TBE alimentary outbreak in 1951 (at territory of Slovakia) until today, none of the European countries report a comparable number of TBE alimentary outbreaks with probable and laboratory confirmed food transmission factor as Slovakia. METHODS: We analyzed TBE outbreak confirmed cases reported in Slovakia from web-based Epidemiological Information System (EPIS) during the period 2007-2016. RESULTS: During years 2007-2016 we recorded 26 TBE alimentary outbreaks. In most outbreaks (22 out of 26) the probable transmission factor of TBE virus was identified within epidemiological context. In 4 outbreaks the transmission factor was laboratory confirmed. The most common probable and confirmed transmission factor of alimentary TBE outbreaks was milk and milk products of goat origin. CONCLUSION: There should be more effort of laboratory clarification of TBE transmission factor in Slovakia. It is important to be aware of the issue of Slovakia from the point of tourism and prevention, but also due to potential risks of consumption of raw milk and its products that became popular in recent years not only in Slovakia. PMID- 30012473 TI - The Kv1.3 channel-inhibitory toxin BF9 also displays anticoagulant activity via inhibition of factor XIa. AB - The Kv1.3 channel plays potential roles in immune, inflammation and coagulation system. Many studies showed that Kv1.3 channel inhibitors have immunosuppressive and anti-inflammatory activities, but no Kv1.3 channel inhibitors have been found to have anticoagulation activities. Here, based on our previous work about Kv1.3 channel toxin peptide inhibitors, we first attempt to test anticoagulation activities of four known venom-derived Kv1.3 channel inhibitors with different structural folds: BmKTX with CSalpha/beta structural fold, OmTx3 with CSalpha/alpha structural fold, BF9 with Kuntz-type structural fold, and SjAPI-2 with Ascaris-type structural fold. Our results showed that BmKTX and OmTx3 have no activities towards both intrinsic and extrinsic coagulation pathway, SjAPI-2 just has weak activity towards intrinsic coagulation pathway, and BF9 has potent activity towards intrinsic coagulation pathway with no apparent effect on extrinsic coagulation pathway. Enzyme and inhibitor reaction kinetics experiments further showed that BF9 inhibited intrinsic coagulation pathway-associated coagulation factor XIa, but have no apparent effects on common coagulation pathway coagulation factor IIa. Structure-activity relationship showed that Gly14, Asn17, Ala18 and Ile20 of BF9 are main residues involved in the inhibiting effect on factor XIa. To the best of our knowledge, BF9 is the first anticoagulant with Kv1.3 channel inhibitory activity. Together, our present studies found the first dual functional peptides with Kv1.3 channel and coagulation factor XIa inhibitory activities, and provided a new molecular template for the lead drug discovery towards immune and thrombosis-associated human diseases. PMID- 30012474 TI - Nephroprotective effect of saxagliptin against gentamicin-induced nephrotoxicity, emphasis on anti-oxidant, anti-inflammatory and anti-apoptic effects. AB - Nephrotoxicity is a serious adverse effect frequently encountered with aminoglycosides administration. Given the value of aminoglycosides in management of serious infections, nephro-protection is highly recommended. The current study investigated the nephro-protective effect of saxagliptin (SAXA) (12.5 mg/kg, I.P.) against gentamicin (GEN)-induced nephrotoxicity in rats. SAXA administration for 14 days conferred significant nephro-protection against GEN induced nephrotoxicity manifested in decreased kidney/somatic index, enhanced cytoprotection and significant decrease in serum LDH activity together with functional renal improvement; significant increase in creatinine clearance with significant reduction in serum creatinine, BUN, proteinuria and albuminuria. Oxidant/antioxidants hemostasis was significantly improved with SAXA treatment with significant reduction in kidney MDA content and enhancement of GSH concentration and catalase activity. Moreover, kidney content of NO significantly declined with significant decline in kidney tumor necrosis factoralpha (TNFalpha), vascular adhesion molecule-1 (VCAM-1) and caspase-3 content. Ultimately, SAXA administration was associated with significant attenuation of GEN-induced necrotic and inflammatory changes. In conclusion; the modulatory effect of SAXA on inflammatory cytokines, its anti-apoptic properties, ameliorative impact on oxidative load and positive impact on host antioxidant defenses accounts for the observed nephro-protective impact. PMID- 30012475 TI - Regulation of apolipoprotein A-I gene expression by the histamine H1 receptor: Requirement for NF-kappaB. AB - AIMS: Earlier it had been found by us that apolipoprotein A-I (apo A-I) is suppressed by histamine in HepG2 cells. Histamine has been shown to regulate NF kappaB activity, though not in hepatocytes. Therefore we examined the role of the histamine receptors and NF-kappaB in histamine-mediated apo A-I gene expression in HepG2 liver cells. MAIN METHODS: The effect of histamine on histamine H1 receptor expression, and NF-kappaB p65 and p50 subunits was examined by Western blot. Histamine H1 receptor involvement was examined by loss-of-function (via siRNA) and gain-of-function studies overexpressing the histamine H1 receptor. The requirement for the p65 subunit of NF-kappaB for histamines effect was elucidated by loss-of-function studies (siRNA). Finally, the effect of histamine on NF kappaB binding to the apo A-I gene promoter was examined by chromatin immunoprecipitation. KEY FINDINGS: Treatment of HepG2 cells with histamine had no effect on histamine H1 receptor expression. However, treatment with histamine increased NF-kappaB p65 and p50 subunit expression significantly. At low levels, the exogenous histamine H1 receptor plasmid suppressed apo A-I gene promoter activity while addition of higher levels of plasmid DNA actually increased apo A I gene promoter activity. Inhibition of NF-kappaB activity with SN50 prevented histamine from repressing apo A-I promoter activity as did silencing p65 expression via siRNA. Finally, treatment with histamine increased binding of the p65 subunit of NF-kappaB to the apo A-I gene promoter. SIGNIFICANCE: Histamine suppresses apo A-I gene expression in hepatocytes via the histamine H1 receptor by elevating NF-kappaB expression and binding to the apo A-I promoter. PMID- 30012476 TI - Down-regulation of lncRNA MEG3 promotes endothelial differentiation of bone marrow derived mesenchymal stem cells in repairing erectile dysfunction. AB - AIMS: In the treatment of diabetes mellitus associated erectile dysfunction (DMED), the intracavernous and periprostatic implantations of bone marrow derived mesenchymal stem cells (BM-MSCs) represent the new therapeutic approaches with great applied prospect. However, the specific mechanisms of BM-MSCs protecting erectile function remain largely unknown. MATERIALS AND METHODS: The DMED rats were induced and the erectile function was assessed in the models with or without BM-MSCs implantation using intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. The differentiation of BM-MSCs toward endothelial cells (ECs) was induced by exogenous vascular endothelial growth factor (VEGF) in vitro. RNA pull down and RIP assays were performed to explore the interaction between MEG3 and FOXM1 protein. KEY FINDINGS: Intracavernous implantation of BM-MSCs effectively improved the erectile function of DMED rats, which was accompanied by a significant decrease in the expression of MEG3 in the corpus cavernosum tissues. Also, our study revealed that MEG3 expression was significantly down-regulated during the endothelial differentiation of BM-MSCs in vitro. The down-regulation of MEG3 was further confirmed to be conducive to the differentiation of BM-MSCs toward ECs. More importantly, MEG3 promoted the degradation of FOXM1 protein via facilitating FOXM1 ubiquitination, thereby decreasing VEGF expression, which ultimately regulated the endothelial differentiation of BM-MSCs. SIGNIFICANCE: Taken together, our findings presented the vital role of MEG3 in the repairing processes of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSCs-mediated DMED repairing. PMID- 30012477 TI - Greater wax moth Galleria mellonella (Lepidoptera: Pyralidae) as a resistant model host for Nosema pyrausta (Microsporidia: Nosematidae). AB - Galleria mellonella fed 3 million Nosema pyrausta spores per larva showed 0 and 5% infestation rate at 30 degrees C and 24 degrees C, respectively. N. pyrausta virulence did not increase after passage through G. mellonella for three generations. When larvae were pretreated with phenylthiourea, Bacillus thuringiensis or combination of both, infection rates were 11%, 15% and 22%, respectively. Injection of untreated and potassium hydroxide-primed spores resulted in approximately 10% and 50% infection, respectively. G. mellonella is resistant to high dosages of N. pyrausta spores, serving as a prospective model of insect resistance to microsporidia, while host immunosuppression and/or spore activation increases success of the pathogen. PMID- 30012478 TI - Classical test theory and item response theory produced differences on estimation of reliable clinical index in World Health Organization Disability Assessment Schedule 2.0. AB - OBJECTIVE: World Health Organization Disability Assessment Schedule (WHODAS) 2.0 is currently one of the most used instruments in disability assessment. The objective of this study was to analyze the clinically reliable change of WHODAS 2.0 by applying both Classical Test Theory (CTT) and the Item Response Theory (IRT). STUDY DESIGN AND SETTING: The sample consisted of 179 patients with dual pathology. The standard error of measurement (SEM) was estimated using the CTT and the rating testlet model. RESULTS: Reliability estimated by Cronbach's alpha provided acceptable values for all domains. The Rasch analysis revealed an adequate capacity to discriminate between people with high and low disability in terms of total scores but not in terms of domains. The SEM varies according to the baseline scores, failing to detect clinically reliable change in patients with lower scores. Kappa coefficients are low for the most of dimensions (except participation) and adequate for total scores. CONCLUSION: The use of total WHODAS 2.0 scores may be useful from a clinical perspective; however, more evidence is required for domain scores to support its usefulness. The decision to use the CTT or the IRT impacts in terms of calculating clinically reliable change. PMID- 30012479 TI - Cytotoxicity of anticancer candidate salinomycin and identification of its metabolites in rat cell cultures. AB - Salinomycin (SAL) is a polyether antibiotic, which is commonly used as a coccidiostat and has recently shown to exhibit anticancer activity. The toxic action of the drug may be connected with the extent and routes of its biotransformation. The cytotoxic potential of SAL and its combination with tiamulin and prednisolone was investigated using three cell models from rat: primary hepatocytes, hepatoma cells (FaO) and myoblasts (L6). The four biochemical endpoints were assessed: mitochondrial and lysosomal activity, total cell protein content and membrane integrity. The metabolites of SAL in the medium from cell cultures were determined using LC-MS/MS. The cytotoxicity of SAL was time-, concentration- and cells dependent. The most sensitive endpoint was the inhibition of lysosomal activity. Tiamulin increased SAL cytotoxicity, whereas the opposite results were observed for prednisolone. Primary hepatocytes were the most efficient in SAL biotransformation both in terms of its intensity and number of produced metabolites. The range of the cytotoxicity and mode of salinomycin interaction with tiamulin and prednisolone cannot be explained by the biotransformation alone. PMID- 30012480 TI - Apoptotic and antiproliferative effects of Stigmast-5-en-3-ol from Dendronephthya gigantea on human leukemia HL-60 and human breast cancer MCF-7 cells. AB - The genus Dendronephthya encompasses marine soft corals that produce a wide spectrum of biofunctional terpenoids. Anticancer properties of these metabolites are widely exploited as potential chemotherapeutic agents. The present study reports the purification and isolation of a potential antiproliferative constituent, stigmast-5-en-3-ol from the 70% ethanol extract of the soft coral Dendronephthya gigantea. Among several other 3beta-hydroxy-Delta5-steroidal congeners, stigmast-5-en-3-ol indicated prominent antiproliferative effects on HL 60 (leukemia) and MCF-7 (breast cancer) cell lines with IC50 values of 37.82 and 45.17 MUg/ml respectively. Stigmast-5-en-3-ol increased apoptotic body formation, accumulation of sub G1 apoptotic cells, and DNA damage in HL-60 and MCF-7 cells. It increased the expression of Bax, caspases, and PARP cleavage while decreasing Bcl-xL levels in both cancer cell lines indicating that the effects are arbitrated via the mitochondria-mediated apoptotic pathway. Steroidal derivatives were identified by GC MS/MS and the identity of stigmast-5-en-3-ol was confirmed by NMR spectra. The present study suggests that stigmast-5-en-3-ol could be a promising candidate for anticancer drug research. PMID- 30012481 TI - Physicochemical properties and formation mechanism of electrostatic complexes based on epsilon-polylysine and whey protein: Experimental and molecular dynamics simulations study. AB - epsilon-Polylysine (epsilon-PL) is a new natural food-grade antimicrobial that has been widely applied in the food and beverage industry. This study characterized the physicochemical properties of an electrostatic complex of the epsilon-PL and whey protein at different whey protein-to-epsilon-PL mass ratios, pH, and ionic strength by using the turbidity measurements, size and zeta potential measurements. The interaction and formation mechanism of the electrostatic complexes are explored by analysis of the hydrogen bonds and ion pairs, hydrophobic and hydrophilic solvent assessable surface area and secondary structure using molecular dynamics simulations. The experimental results showed that the epsilon-PL bound to the surface of whey protein forming an electrostatic complex which could be either soluble or insoluble depending on the whey protein to-epsilon-PL mass ratios, pH, and ionic strength. The molecular dynamics simulations results showed that conformational rearrangements of alpha lactalbumin and bridging effect of beta-lactoglobulin occurred. The interaction was mostly driven by the hydrogen bonds and ion pairs, which mainly occurred in the hydrophilic part of the whey protein surface. This study provides the theoretical basis that will facilitate more rational application of epsilon-PL in the food matrix. PMID- 30012482 TI - Isolation and chemical characterization of a novel immunostimulating galactofucan from freshwater Azolla filiculoides. AB - Water-soluble polysaccharides were isolated from Azolla filiculoides to determine their chemical and structural characteristics as well as anticancer and immunostimulatory activities. Crude and fractions (F1 and F2) were mainly composed of neutral sugars (70.0-80.1%), proteins (2.1-14.2%) and uronic acids (1.2-10.8%). The polysaccharides were mostly formed of different levels of fucose (23.8-61.2%), galactose (28.5-38.7%), mannose (7.5-16.7%), xylose (13.3-13.6%), glucose (12.7-13.3%), arabinose (5.5-11.6%) and rhamnose (8.0-9.5%) units. The polysaccharide molecules contained one or more sub-fractions with average molecular weight ranging from 992 to 2162 * 103 g/mol. Crude and fractionated polysaccharides induced RAW264.7 macrophages to release pro-inflammatory mediators and cytokines including nitric oxide, IL-1beta, TNF-alpha, IL-6, IL-10 and IL-12 through NF-kappaB and MAPKs signaling pathways as confirmed by the presence of p-NK-kappaB, p-JNK, p-ERK and p-38 proteins in the cell cytoplasm. The most immunostimulating polysaccharide, F2, consisted of alternating ->3)-Fuc (1-> and ->4)-Fuc-(1 -> residues. PMID- 30012483 TI - Preparation and release characteristics of mesalazine loaded calcium pectin silica gel beads based on callus cultures pectins for colon-targeted drug delivery. AB - The aim of this work is to produce calcium pectin-silica gel beads containing mesalazine as a drug model in order to control the drug release in the colon. The mesalazine loaded calcium pectin-silica gel beads were prepared using the ionotropic gelation method. Energy-dispersive X-ray analysis revealed that increasing the Na2SiO3 concentration led to an increase of the silicon content on the surface and in the cross-sections of the beads. The addition of Na2SiO3 to the gel formulations made from the duckweed callus culture pectin led to a decrease in the swelling degree that appeared to be related to the higher gel strength of these beads. The beads made from pectins of campion and duckweed callus cultures with adding of 22.2 mg/ml of Na2SiO3 showed the lowest release of mesalazine in simulated gastric and intestinal fluids. An increase in the reaction time up to 60 min during incubation in the cross-linking solution of CaCl2 led to a slower release of drug from the beads. An elevated release of mesalazine was achieved in the simulated colonic fluid. Prepared calcium pectin silica gel beads containing mesalazine as a drug model can be proposed for controlled drug release in the colon. PMID- 30012484 TI - Preparation of chitosan/poly vinyl alcohol films and their inhibition of biofilm formation against Pseudomonas aeruginosa PAO1. AB - Poly (vinyl alcohol) (PVA) and chitosan (CH)-based blend films were prepared via a simple mixing and casting method. The films were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and ultraviolet-visible spectroscopy (UV-vis). Mechanical properties, thermogravimetric (TG), derivative thermogravimetric (DTG), and the inhibition of biofilm formation against Pseudomonas aeruginosa PAO1 (P. aeruginosa PAO1) of CH/PVA films were investigated. The results indicated that CH and PVA in the blend films interacted by physical crosslinks consisting of intermolecular hydrogen bonds and intermolecular hydrogen bonds with compatibility, and were more thermally-stable than that of PVA. CH addition decreased the tensile strength and the light transmittance. CH60:PVA40 film showed notable activity against adhesion and inhibited biofilm formation of P. aeruginosa PAO1, indicating that CH60:PVA40 film could be applied as an antimicrobial and biofilm inhibiting food packaging material. PMID- 30012485 TI - Structural and functional consequences of EF-hand I recovery in mnemiopsin 2. AB - Mnemiopsin 2 from Mnemiopsis leidyi is a calcium-regulated photoprotein which has luminescence properties in the presence of calcium and coelenterazine. All calcium-regulated photoproteins contain EF-hand loops consisting of 12 individual residues in which the 6th position is occupied by Gly. However, the 6th residue in mneniopsin 2 is Glu rather than Gly. Here, we investigated the structural and functional consequences of substitution of Glu by Gly (E50G variant) using site directed mutagenesis and spectroscopic procedures. It was revealed that the luminescence activity of the variant was about 17 times greater than that of wild type (WT) photoprotein. In comparison with WT protein, our variant showed higher optimum temperature and calcium sensitivity as well as slower rate of luminescence decay. Homology modeling and sequence analysis with other known photoproteins showed that EF-hand I loop can affect the luminescence activity of E50G variant. Structural studies using circular dichroism and fluorescence spectroscopy revealed that mutation leads to the reduction in secondary structural content and local structural alterations. Finally, it can be concluded that the activity of E50G variant increases as a result of more flexibility that brought about by Gly essential for adopting the correct conformation for functional activity. PMID- 30012486 TI - Phosphorylation of phosvitin plays a crucial effects on the protein-induced differentiation and mineralization of osteoblastic MC3T3-E1 cells. AB - This study investigated the effects of phosvitin (PV), one of the major proteins from egg yolk, with different degree of phosphorylation on the physiology of an osteoblast (MC3T3-E1) cell line. The proliferation and differentiation of MC3T3 E1 were analyzed using the CCK-8 and the alkaline phosphatase (ALP) assay, respectively. The effect of PV on the mineralization of MC3T3-E1 was monitored using the Alizarin-red staining. PV at 100 MUg/mL increased the ALP activity by 145% of the control after 7 days of incubation. PV also stimulated the proliferation and differentiation of MC3T3-E1 in a phosphorylation level dependent manner. The RT-PCR reactions indicated that PV stimulated the expression of BMP-2 and OPG mRNA in a phosphorylation-dependent manner, but inhibited RANKL mRNA expression in MC3T3-E1. This result suggested that the phosphate groups in PV not only stimulated the proliferation and differentiation of MC3T3-E1, but also controlled the mineralization by regulating the expression of BMP-2, RANKL and OPG mRNA in the osteoblast cell. PMID- 30012487 TI - Immobilization of Aspergillus ficuum tannase in calcium alginate beads and its application in the treatment of boldo (Peumus boldus) tea. AB - Tannase (tannin acyl hydrolase, E.C. 3.1.1.20) is an enzyme that catalyzes the hydrolysis of ester and depside linkages in hydrolysable tannins such as tannic acid, releasing gallic acid and glucose. It has several commercial applications in food industry, among which are gallic acid production, reduction of tannin content in fruit juices, and preparation of instantaneous tea. In this study we immobilized Aspergillus ficuum tannase in calcium alginate beads and then used it to treat boldo (Peumus boldus) tea. Such a technique allowed entrapping tannase with a 75% efficiency and appreciably increasing its thermal and pH stability compared with the free enzyme. Storage stability and reuse of the immobilized enzyme were very promising, in that about 60% of starting enzyme activity was retained after bead storage for 90 days at 4 degrees C or after six cycles of use. Boldo tea treatment with immobilized tannase for 120 min at 40 degrees C led to 31 and 60% removals of tannins and epigallocatechin gallate, an increase of about two orders of magnitude in gallic acid content, 56 and 109% increases in total flavonoids and epigallocatechin contents, a 42.8% increase in antioxidant activity and significant enhancements of tea color, clarity and pH. PMID- 30012488 TI - Starch films loaded with donut-shaped starch-quercetin microparticles: Characterization and release kinetics. AB - Starch films loaded with donut-shaped starch-quercetin microparticles were prepared from two different botanical origins. The quercetin release kinetics through the films were studied. The donut-shaped starch-quercetin microparticles were prepared by thermal aqueous-alcoholic treatment. The quercetin loading percentage and therefore the antioxidant activity were higher for the microparticles from legume than those of cereal origins. The starch-quercetin microparticles also showed higher thermal stability than the starch granules. The starch films were produced using the solution casting method. The films with more microparticles content showed higher thermal stability. In-vitro release studies of the quercetin through the films were performed in aqueous-ethanolic medium. The quercetin released reached the equilibrium in 1 to 4 days for the films of cereal starch and in more than a week for the films of legume origin. The release data were fitted to Peppas-Sahlin model that suggests the release kinetics were controlled mainly by fickian diffusion. The produced biofilms can be utilized mainly for active food packaging applications. PMID- 30012489 TI - Chitosans as new tools against biofilms formation on the surface of silicone urinary catheters. AB - Urinary catheters contamination by microorganisms is a major cause of hospital acquired infections and represents a limitation for long-term use. In this work, biofilms of Klebsiella pneumoniae and Escherichia coli clinical isolates were developed on urinary catheters for 48 and 72 h in artificial urine medium (AUM) with different molecular weight chitosans (AUM-CS solutions) at pH 5.0. The number of viable bacteria was determined by standard plate count agar while crystal violet (CV) staining was carried out to assess biomass production (optical density at 570 nm) in the mentioned conditions. Re-growth of each strain was also evaluated after 24 h re-incubation of the treated catheters. Significant decreases of log CFU/catheter and biomass production were observed for all the biofilms developed in AUM-CS compared with the controls in AUM. The percentages of biofilm removal were slightly higher for E. coli biofilms (up to 90.4%) than those of K. pneumoniae (89.7%); in most cases, the complete inhibition of bacterial re-growth on treated catheter pieces was observed. Contact time influenced chitosan efficacy rather than its molecular weight or the biofilms age. The results confirmed the potentiality of chitosans as a biomacromolecule tool to contrast biofilm formation and reduce bacterial re-growth on urinary catheters. PMID- 30012490 TI - Chitosan combined with swimming promotes health in rats. AB - PURPOSE: Chitosan is an easily accessible and biocompatible natural molecule which facilitate the immune system. In recent studies, chitosan is being applied to the drug nanosphere to deliver drugs. However, whether chitosan could promote health under exercising condition remains yet to be elucidated. Hence, we designed to investigate the effect of chitosan on swimming rats. METHODS: Sprague Dawley (SD) rats were divided into four groups, exercise with chitosan, exercise with water, sedentary with chitosan, and sedentary with water. After four weeks of exercise and chitosan/water gavage, the blood was collected, and its biochemical index, complete blood count, and related parameters, and cytokines were detected and analyzed. RESULTS: The level of blood urea nitrogen (p = 0.0380), total cholesterol (p = 0.048), and low-density lipoprotein (p = 0.0338) were decreased, while the number of red blood cells (p = 0.001), hematocrit (p = 0.01), and mean corpuscular volume (p = 0.039) were increased in chitosan group. Furthermore, the combination of chitosan and swimming decreased the red blood cells distribution width. CONCLUSIONS: Our study support that chitosan could facilitate the health during exercise. PMID- 30012491 TI - In-situ green myco-synthesis of silver nanoparticles onto cotton fabrics for broad spectrum antimicrobial activity. AB - In the realm of green synthesis of metals nanoparticles for medical textile application, silver nanoparticles (AgNPs) were biosynthesized in situ cotton fabrics for the first time by using fungi for rendering cotton fabrics antimicrobial activity with abroad range towards different pathogenic organisms. Herein, five different isolated fungi from medicinal plants were identified and optimized their growth media prior examined their ability to reduce Ag+ ions to AgNPs in-situ cotton fabrics along with ex-situ method. Synthesis of AgNPs were characterized by making use of instruments e.g. UV-vis spectroscopy, Transmission Electron Microscopy (TEM), Selected Area Electron Diffraction (SAED), Scanning Electron Microscopy (SEM), and Fourier Transform Infrared (FTIR). Whereas antimicrobial activities of the resultant cotton fabrics were investigated against Gram positive (S. aureus ATCC29213), Gram negative (E. coli ATCC 25922), Yeast (C. albicans ATCC10321) and, fungi (A. niger NRC 53). Results revealed the successful biosynthesis of AgNPs using different fungus strains whether in-situ cotton fabrics or ex-situ manner. The size of the resultant AgNPs by ex-situ method were varied (5-20 nm). The antimicrobial activity of the in-situ treated cotton samples exhibited different behaviors towards both pathogenic bacteria and fungi. This manner opens up a new way to discover the ability of nanobiotechnology to provide world with substitutional aids mimic to synthetic materials. PMID- 30012494 TI - Randomized Trial of a Low-Literacy Chronic Pain Self-Management Program: Analysis of Secondary Pain and Psychological Outcome Measures. AB - Based on input of rural, largely Hispanic persons with chronic pain, a low literacy, 6-month self-management program was developed, drawing on elements of existing pain toolkits. In a randomized trial, low-income, primarily Hispanic patients with chronic pain received the program in 6 sessions of 1-on-1 meetings with a trained health educator in clinic or in 8 group lectures by experts in the community. Intention-to-treat analyses in linear mixed-effects models were conducted for 5 secondary outcomes at 6 months, including Brief Pain Inventory pain severity and interference, Patient Health Questionnaire-9, 12-Item Short Form Survey Mental Component Summary, and Tampa Scale for Kinesiophobia-11. A total of 111 participants were randomized (15.9% of 700 initially eligible from 3 clinics), and 67 (60.4%) completed 6-month measures. Among completers, the clinic arm improved on 4 measures and community arm on 3 measures (all P < .05). Effect sizes were small to moderate (.41-.52). In intention-to-treat analyses, both arms improved on 4 of 5 measures (all P <= .001) versus baseline, with clinically significant changes in Brief Pain Inventory pain severity and interference. Improvement in multiple outcomes after this chronic pain self-management program for low-income patients warrants further study. PERSPECTIVE: In an evaluation of a low-literacy, 6-month chronic pain self-management program, similar improvements were observed among primarily Hispanic participants whether the intervention was delivered by a health educator or in groups with lectures from experts. PMID- 30012493 TI - Comparative ploidy response to experimental hydrogen peroxide exposure in Atlantic salmon (Salmo salar). AB - While research into the growth, survival, nutrition and, more recently, disease susceptibility of triploid Atlantic salmon has expanded, there remains an overall lack of studies assessing the response of triploids to chemical treatments. It is essential that the response of triploids to disease treatments be characterised to validate their suitability for commercial production. This study aimed to investigate and compare the stress and immune responses of triploid and diploid Atlantic salmon following an experimental treatment with hydrogen peroxide (H2O2). A dose response test was first undertaken to determine a suitable test dose for both diploid and triploid Atlantic salmon. Following this, diploids and triploids were exposed to H2O2 (1800 ppm) for 20 min, as per commercial practices, after which blood glucose and lactate, and plasma cortisol and lysozyme were measured, along with the expression of oxidative stress and immune related genes. In the first 6 h post-exposure to H2O2, comparable mortalities occurred in both diploid and triploid Atlantic salmon. Cortisol, glucose and lactate were not significantly influenced by ploidy suggesting that, physiologically, triploid Atlantic salmon are able to cope with the stress associated with H2O2 exposure as well as their diploid counterparts. Exposure to H2O2 significantly elevated the expression of cat and sod2 in diploid livers and gr, il1beta and crp/sap1b in diploid gills, while it significantly decreased the expression of saa5 and crp/sap1a in diploid gills. In triploids, the expression levels of cat, hsp70, sod1, saa5, crp/sap1a and crp/sap1b in liver was significantly higher in fish exposed to H2O2 compared to control fish. The expression of gr, sod1 and il1beta in triploid gills was also elevated in response to H2O2 exposure. This study represents the first experimental evidence of the effects of H2O2 exposure on triploid Atlantic salmon and continues to support their application into commercial production. PMID- 30012495 TI - Enhancing effects of myricetin on the osteogenic differentiation of human periodontal ligament stem cells via BMP-2/Smad and ERK/JNK/p38 mitogen-activated protein kinase signaling pathway. AB - Myricetin is a flavonoid that found in berries, onions, and red grapes. It has been reported to have various pharmacological effects such as anti-inflammation, anti-oxidant and anti-cancer activities. However, the underlying mechanisms of myricetin on osteogenic differentiation remain unknown in human periodontal ligament stem cells (hPDLSCs). In this study, we investigated the ability of myricetin to increase osteogenic differentiation and its underlying molecular mechanisms. Myricetin significantly increased cell proliferation, alkaline phosphatase (ALP) activity, and alizarin red-mineralization activity in hPDLSCs in a dose-dependent manner. Furthermore, myricetin dose-dependently increased osteogenic-related mRNA and protein levels. Interestingly, it enhanced osteogenesis by up-regulating bone morphogenetic protein-2 (BMP-2), which induced the expression of BMP receptor type IB, Smad-1/5/9. It also enhanced the phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs) and Smads. We confirmed that the treatment of myricetin increased phosphorylated GSK-3beta and beta-catenin which is related to osteogenesis. In our studies, myricetin induced increment of ALP activity was decreased by ERK (PD98059), JNK (SP600125), p38 (SB203580), and Smad 1/5/9 (LDN193189) inhibitors. ERK and p38 inhibitors showed the greatest inhibition among the four kinds of inhibitors. These results demonstrate that myricetin promoted osteogenic differentiation by the up regulation of ALP activity and expression of osteogenic-related factors through BMP-2/Smad and ERK/JNK/p38 MAPK pathways. PMID- 30012492 TI - Harnessing albumin as a carrier for cancer therapies. AB - Serum albumin, a natural ligand carrier that is highly concentrated and long circulating in the blood, has shown remarkable promise as a carrier for anti cancer agents. Albumin is able to prolong the circulation half-life of otherwise rapidly cleared drugs and, importantly, promote their accumulation within tumors. The applications for using albumin as a cancer drug carrier are broad and include both traditional cancer chemotherapeutics and new classes of biologics. Strategies for leveraging albumin for drug delivery can be classified broadly into exogenous and in situ binding formulations that utilize covalent attachment, non-covalent association, or encapsulation in albumin-based nanoparticles. These methods have shown remarkable preclinical and clinical successes that are examined in this review. PMID- 30012496 TI - Attenuation of oxidative stress and hypertension in an animal model of HELLP syndrome. AB - HELLP (hemolysis elevated liver enzyme low platelet) syndrome is associated with hypertension, inflammation, oxidative stress and endothelial activation. The objective of this study was to determine if oxygen scavenging or endothelin A receptor antagonism improved hypertension and oxidative stress. sFlt-1 and sEndoglin were infused via mini-osmotic pump into normal pregnant rats (NP) on gestational day 12 to create HELLP syndrome. On gestational day 18 arterial catheters were inserted and on gestational day 19 mean arterial pressure was analyzed in rats; serum, urine and tissues were collected for molecular analysis. HELLP rats had significantly increased MAP compared to control normal pregnant rats (P < 0.0005). Endothelin A receptor antagonism via ABT-627 and Tempol, superoxide dismutase mimetic, were administered to a subset of normal pregnant and HELLP rats beginning on gestational day 13 and attenuated mean arterial pressure in HELLP rats (P < 0.05; P < 0.005). There were no statistically significant differences in mean arterial pressure between NP+ETA Receptor or NP+Tempol treated rats and NP rats (P = 0.22). Endothelin A receptor blockade significantly decreased HELLP induced isoprostane excretion (P < 0.0005), placental and hepatic reactive oxygen species (P < 0.05; P < 0.0005) and increased placental total antioxidant capacity (P < 0.005) compared to untreated HELLP rats. Similar results in isoprostane (P < 0.005), hepatic reactive oxygen species (P < 0.05) and placental total antioxidant capacity (P < 0.05) were seen in HELLP rats treated with Tempol or Endothelin A receptor antagonist vs. untreated HELLP rats. These data demonstrated a role for oxidative stress in contributing to the hypertension, placental and liver damage that is seen in HELLP syndrome. PMID- 30012497 TI - The effect of zinc supplementation on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. AB - Previous studies have shown zinc has potential anti-inflammatory and anti oxidative effects. However, findings from clinical trials about the effect of zinc on plasma C-reactive protein (CRP) appeared inconsistent and uncertain. Therefore, the aim of this meta-analysis was to summarize the effect of zinc supplementation on plasma CRP concentrations in adults. The literature search through PubMed, SCOPUS, and Google Scholar were done to find published studies up to October 2017. Random or fixed-effects model depending on the results of heterogeneity tests were used to estimate the pooled effect size. Between-study heterogeneity was assessed using Cochran's Q test and I2 index. Funnel plot and Egger's regression test were used to assess publication bias. Our search found 1505 publications, of which 8 randomized controlled trials (RCTs) were eligible to be included in the analysis. The results of the meta-analysis displayed a significant reduction in circulating CRP levels (WMD: - 1.68 mg/l; 95% CI: - 2.4 to - 0.9, P = <0.001) following zinc supplementation. In the subgroup analysis, supplementation dosage, study quality, study population, and baseline CRP level were the potential sources of heterogeneity. Participants took equal to 50 mg/d zinc (WMD: - 1.97 mg/l; 95% CI: - 2.28 to - 1.67, P = <0.001), low quality studies (WMD: - 2.9 mg/l; 95% CI: - 3.68 to - 2.12, P = <0.001) and those with renal dysfunction (WMD: - 7.43 mg/l; 95% CI: - 12.57 to -2.29, P = 0.005) showed greater improvement in CRP levels. In conclusion, zinc supplementation may have a beneficial effect on the serum CRP, especially at doses equal to 50 mg/d and in renal insufficiency patients compared with healthy subjects. PMID- 30012499 TI - Blockade of JAK2/STAT3 intensifies the anti-tumor activity of arsenic trioxide in acute myeloid leukemia cells: Novel synergistic mechanism via the mediation of reactive oxygen species. AB - Reactive oxygen species (ROS) are essential mediators of crucial cellular processes including apoptosis, proliferation, survival and cell cycle. Their regulatory role in cancer progression has seen in different human malignancies such as acute myeloid leukemia (AML). AML patients suffer from high resistance of the tumors against routine therapeutics including ATO. ATO enhance reactive oxygen species levels and induce apoptosis and suppresses proliferation in AML cells. However, some pathways such as JAK2/STAT3 ease anti-tumor activity of ATO by reducing reactive oxygen species amount and protecting the cell from apoptosis. In the present study, we use ruxolitinib (potent JAK2 inhibitor) to increase the sensitivity of AML cells to ATO treatment. We test, the effect of this combination on metabolic activity, proliferation, colony formation, cell cycle distribution, apoptosis, oxidative stress and DNA damage. Our results showed that combination of ATO with ruxolitinib synergistically reduced metabolic activity, proliferation and survival of AML cell lines. This combination induced G1/S cell cycle arrest because of reactive oxygen species elevation and GSH reduction. Besides, enhancement of reactive oxygen species increased apoptosis rate in combination samples. We uncovered that the synergistic anti-tumor effect of ATO and ruxolitinib in AML cells mediates via reactive oxygen species elevation and DNA damage. Overall, our results show that the combinatorial therapy of AML cells is more effective than solo-targeted therapy. PMID- 30012498 TI - Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression. AB - Opioid-induced respiratory depression (OIRD) involves decreased sensitivity of ventilatory control systems to decreased blood levels of oxygen (hypoxia) and elevated levels of carbon dioxide (hypercapnia). Understanding the sites and mechanisms by which opioids elicit respiratory depression is pivotal for finding novel therapeutics to prevent and/or reverse OIRD. To examine the contribution of carotid body chemoreceptors OIRD, we used whole-body plethysmography to evaluate hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses including changes in frequency of breathing, tidal volume, minute ventilation and inspiratory drive, after intravenous injection of morphine (10 mg/kg) in sham-operated (SHAM) and in bilateral carotid sinus nerve transected (CSNX) Sprague-Dawley rats. In SHAM rats, morphine produced sustained respiratory depression (e.g., decreases in tidal volume, minute ventilation and inspiratory drive) and reduced the HVR and HCVR responses. Unexpectedly, morphine-induced suppression of HVR and HCVR were substantially greater in CSNX rats than in SHAM rats. This suggests that morphine did not compromise the function of the carotid body-chemoafferent complex and indeed, that the carotid body acts to defend against morphine-induced respiratory depression. These data are the first in vivo evidence that carotid body chemoreceptor afferents defend against rather than participate in OIRD in conscious rats. As such, drugs that stimulate ventilation by targeting primary glomus cells and/or chemoafferent terminals in the carotid bodies may help to alleviate OIRD. PMID- 30012500 TI - Persistent therapeutic effect of a novel alpha5-GABAA receptor antagonist in rodent preclinical models of vascular cognitive impairment. AB - This study examined the potential of the selective extra-synaptic alpha5-GABAA receptor inhibitor S44819 (Egis-13529) to improve cognitive performance in preclinical models of vascular cognitive impairment (VCI). Chronic hypoperfusion of the brain in mice was induced by permanent occlusion of the right common carotid artery (rUCO). rUCO induced impairments of cognitive function in the object recognition test (OR) and the rewarded T-maze (RTM). In both tests, a single oral treatment with S44819 (OR - 0.1-3 mg/kg, RTM - 1-3 mg/kg p.o.) significantly reduced the effect of rUCO. Long-term treatment with S44819 (1-10 mg/kg twice daily p.o. for 14 days), that was initiated 24 h after surgery and was followed by a 10- or 13-day wash-out period, fully prevented the decline of cognitive performance of rUCO mice. In rats, occlusion of the middle cerebral artery (MCA) for 30 min caused a significantly diminished performance in the OR. This was prevented by S44819 given p.o. 15 mg/kg twice daily for 8 days, starting 7 days after surgery and tested following a 7-day wash-out period. Taken together, S44819 markedly and stably improved reference and working memory impaired by rUCO in mice. In rats, the compound effectively suppressed the development of cognitive impairment after mild stroke. In conclusion, as longer term administration led to a persistent reversal of the cognitive deficits, it appears that S44819 may have symptomatic, as well as disease-modifying effects in models of VCI. Proof of concept is therefore provided for testing S44819 in the therapy of VCI and post-stroke dementia in humans. PMID- 30012501 TI - T63 inhibits osteoclast differentiation through regulating MAPKs and Akt signaling pathways. AB - Inhibition of excessive osteoclast differentiation and activity is a valid approach for the treatment of osteoporosis. T63 is a small-molecule compound identified from a high throughput screening based on RUNX2 transcriptional activity, and has been reported to stimulate osteoblast formation. However, whether the compound has any effect on osteoclast differentiation remains unknown. Here, we examined the in vitro effect of T63 on osteoclastogenesis. T63 was found to inhibit the number of TRAP-positive cells in an osteoblast osteoclast co-culture system, and inhibited Rankl expression in the preosteoblast MC3T3-E1 cells. The compound also directly suppressed RANKL-induced osteoclast differentiation in both dose- and time-dependent manner, as evidenced by the decrease of TRAP activity, F-actin formation and osteoclastogenesis-related genes expression in RAW264.7 cells. Moreover, pretreatment with T63 markedly decreased the activation of mitogen-activated protein kinases and Akt, both of which are positively involved in the regulation of osteoclastogenesis. Collectively, our findings suggest T63 has a protective effect against bone loss by inhibiting bone resorption. Its regulatory effect on bone metabolism makes the compound a more promising candidate for the potential application in the treatment of osteoporosis. PMID- 30012502 TI - Expression of active matrix metalloproteinase-9 as a likely contributor to the clinical failure of aclerastide in treatment of diabetic foot ulcers. AB - Chronic wounds are a complication of diabetes. Treatment for diabetic foot ulcers is complex with little clinical recourse, resulting in 108,000 lower-limb amputations annually in the United States alone. Matrix metalloproteinases (MMPs) play important roles in the pathology and in the repair of chronic wounds. We previously identified active MMP-8 and MMP-9 in wounds of diabetic mice and determined that MMP-8 accelerates wound repair, while MMP-9 is the culprit for the diabetic wound being refractory to healing. Aclerastide, a peptide analog of angiotensin II, recently failed in phase III clinical trials for treatment of diabetic foot ulcers. We demonstrate herein that treatment of wounds of diabetic mice with aclerastide results in elevated levels of reactive oxygen species and of active MMP-9, which is likely an important contributor to the failure of aclerastide in clinical trials. PMID- 30012503 TI - Plasma citrulline is a sensitive safety biomarker for small intestinal injury in rats. AB - Plasma citrulline is decreased in cases of severe intestinal injury with apparent villus and cellular atrophy. However, the fluctuation of plasma citrulline in slight intestinal injury remains to be investigated. To clarify this, irinotecan at 30 mg/kg or 60 mg/kg was administered intravenously to rats. Irinotecan reduced plasma citrulline concentrations compared to those in the pair-fed control, being concurrent with slight single cell necrosis and mucosal epithelium regeneration in the small intestine without apparent villus and cellular atrophy. Gene expression of enzymes converting glutamine to citrulline was decreased in the small intestine of the injury model. Moreover, citrulline and arginine levels in the ileum were decreased without alterations to glutamine and glutamate levels, indicating that citrulline synthesis from glutamine was impaired. Metabolome analysis revealed that plasma citrulline and arginine levels were decreased, while there were no marked alterations in other amino acids, metabolites of glycolysis, ketone bodies, or fatty acids. These results suggested that a decreased plasma citrulline level was unlikely to result from amino acid catabolism in response to malnutrition. In conclusion, plasma citrulline concentration reflects slight intestinal injury without apparent villus and cellular atrophy, and thus, it would be a sensitive biomarker for the small intestinal injury. PMID- 30012504 TI - Xenoestrogen interference with nongenomic signaling actions of physiological estrogens in endocrine cancer cells. AB - Rapid nongenomic signaling by estrogens (Es), initiated near the cell membrane, provides new explanations for the potent actions of environmental chemicals that imperfectly mimic physiological Es. These pathways can affect tumor growth, stabilization, or shrinkage via a number of signaling streams such as activation/inactivation of mitogen-activated protein kinases and caspases, generation of second messengers, and phospho-triggering of cyclin instability. Though prostate cancers are better known for their responsiveness to androgen deprivation, ~17% of late stage tumors regress in response to high dose natural or pharmaceutical Es; however, the mechanisms at the cellular level are not understood. More accurate recent measurements show that estradiol (E2) levels decline in aging men, leading to the hypothesis that maintaining young male levels of E2 may prevent the growth of prostate cancers. Major contributions to reducing prostate cancer cell numbers included low E2 concentrations producing sustained ERK phospho-activation correlated with generation of reactive oxygen species causing cancer cell death, and phospho-activation of cyclin D1 triggering its rapid degradation by interrupting cell cycle progression. These therapeutic actions were stronger in early stage tumor cells (with higher membrane estrogen receptor levels), and E2 was far more effective compared to diethylstilbestrol (the most frequently prescribed E treatment). Xenoestrogens (XEs) exacerbated the growth of prostate cancer cells, and as we know from previous studies in pituitary cancer cells, can interfere with the nongenomic signaling actions of endogenous Es. Therefore, nongenomic actions of physiological levels of E2 may be important deterrents to the growth of prostate cancers, which could be undermined by the actions of XEs. PMID- 30012505 TI - Retrospective multicenter study by the French Spine Society of surgical treatment for spinal metastasis in France. AB - INTRODUCTION: The occurrence of spinal metastasis is a turning point in the progression of cancer. The optimal management has not been well defined. The aim of this study was to identify the various treatments currently being used in France and to determine the benefits of surgical treatment. MATERIAL AND METHODS: The records of patients treated between 2011 and 2015 at seven spine surgery centers in France were reviewed retrospectively. The pain level (VAS), McAfee scale, walking ability and Frankel Grade were evaluated at inclusion and at 6 months postoperative. The Tomita and Tokuhashi prognostic scores were also determined. RESULTS: The cohort consisted of 319 patients. Preoperatively, 63.5% of patients could walk without assistance and 66% were Frankel Grade E. Twenty percent of patients were bed-ridden according to the Karnofsky Performance Status. According to the Tokuhashi criteria, 44% were predicted to have less than 6 months to live. The Tomita score recommended palliative surgery in 48% of cases. Potentially unstable lesions were present in 67% of patients. The surgical indication was made because of a neurological deficit in 40% of cases, to alleviate pain in 30% of cases, and for an instability in 30% of cases. Spinal cord decompression and posterior fixation were the most common procedures. The overall complication rate was 38.6%. At 6-months postoperative, 24 patients had died of the 245 available for review. Only 13 patients could not walk (5.3%), 69.4% of patients were Frankel Grade E and pain levels were significantly lower that preoperatively (2.4 vs. 4.6, p<0.001). DISCUSSION: This study's findings are evidence of the difficulties encountered when treating spinal metastases. The main prognostic scores do not appear to be valid for these patients. A large number of patients were operated urgently because of a neurological deficit, before the treatment could be discussed in a multidisciplinary team (MDT) meeting. Nevertheless, the surgical treatment of these patients is associated with an acceptable complication rate and clinical improvement. CONCLUSION: Surgical treatment of spinal metastases is not well standardized; thus many different strategies are used. There is evidence that it improves the quality of life in most patients by reducing their pain and allowing them to walk again. However, this treatment must be discussed in the context of an MDT meeting before it is carried out. These patients should be evaluated early on by a spine surgeon to reduce the need for emergency surgery when a neurological deficit appears. PMID- 30012507 TI - Smooth pursuit of amodally completed images. AB - In order to evaluate the effect of the parafoveal area of the retina on smooth pursuit, we compared the horizontal smooth pursuit of visible and amodally completed stimuli in people with central vision loss and controls. In the amodally completed stimuli, a black mask covered the bottom vertex of a moving diamond which is the feature whose movement participants had to track. Both the visible and the amodally completed stimuli moved along regular and irregular sinusoidal motion paths. Our results show that people with central vision loss are able to track a perceptually completed moving stimulus albeit with lower gain, larger tracking errors, and more saccadic eye movements than people with normal vision. Just as the controls, however, people with central vision do better in the no mask condition showing that visual feedback from eccentric vision can improve performance. PMID- 30012506 TI - Anticancer effects of some novel dichloroacetophenones through the inhibition of pyruvate dehydrogenase kinase 1. AB - Targeting pyruvate dehydrogenase kinase 1 (PDK1) has been suggested as a potential anticancer strategy. 2,2-dichloroacetophenone (DAP) is a PDK1 inhibitor exhibiting weak anticancer potency and poor selectivity. The current study describes the characterization of three potent compounds 54, 55 and 64, which tightly bound to PDK1 with Kd values of 1.29, 0.97, and 0.58 MUM, respectively, and activated pyruvate dehydrogenase complex with EC50 values of 0.68, 0.49, and 0.33 MUM, respectively. In contrast with DAP, these analogues were more potent and selective against PDK1, reduced proliferation and survival of NCI-H1975 cells, and suppressed tumor growth in a NCI-H1975 xenograft mouse model. Moreover, compounds 54, 55 and 64 depolarized mitochondrial membrane potential, induced cell apoptosis, decreased extracellular lactate formation, and increased reactive oxygen species production in NCI-H1975 cells. They may serve as potential modulators to regulate mitochondrial function and reprogram metabolism in cancer cells which could represent promising compounds for further development of potent PDK1 inhibitors. PMID- 30012508 TI - Dendrimers: A versatile nanocarrier for drug delivery and targeting. AB - Dendrimers are novel polymeric nanoarchitectures characterized by hyper-branched 3D-structure having multiple functional groups on the surface that increases their functionality and make them versatile and biocompatible. Their unique properties like nanoscale uniform size, high degree of branching, polyvalency, water solubility, available internal cavities and convenient synthesis approaches make them promising agent for biological and drug delivery applications. Dendrimers have received an enormous attention from researchers among various nanomaterials. Dendrimers can be used as a carrier for diverse therapeutic agents. They can be used for reducing drug toxicities and enhancement of their efficacies. The present review provide a comprehensive outline of synthesis of dendrimers, interaction of dendrimer with guest molecules, properties, characterization and their potential applications in pharmaceutical and biomedical field. PMID- 30012509 TI - A rare case of super-refractory epileptic status in pregnant woman: Schizencephaly. AB - Schizencephaly is an anomaly of the subtotal brain development, which occurs as the presence of a cleft lined with grey matter extending from subarachnoid space to the ventricles. It may be manifested by psychomotor retardation, paresis or partial seizures and drug-resistant convulsions. The clinical expression of schizencephaly depends on the bilaterality of the slit, its size and its seat. The diagnostic strategy of schizencephaly in the ante- and postnatal period has been revolutionised by MRI imaging, the only technique able to provide an accurate and complete lesional assessment, particularly in type I. We report the case of a 34-year-old pregnant woman at the 25th weeks of amenorrhea, who presented a super-refractory epileptic-status due to a right schizencephaly. The diagnosis of eclampsia was excluded. This case report is very particular cause of the late appearance of epileptic seizures in this pregnant woman who has never done so. PMID- 30012510 TI - Which indicators used to assess quality performance in Intensive Care Units? A systematic review of medical literature. AB - OBJECTIVE: Collect, through a literature review, the indicators recommended for the measurement of performance in the Intensive Care Unit (ICU) and determine their typology. METHODS: This systematic review was conducted in Medline, using the following search strategy: ("Critical Care"[Mesh] or "Critical Care Nursing"[Mesh] or "Intensive Care Units"[Mesh]) and "Quality Indicators, Health Care"[Mesh] and (hasabstract[text] and "2012/01/01"[PDat]: "2016/12/31"[PDat] AND "humans"[MeSH Terms] and [English(lang) or French(lang)]). RESULTS: Overall, a total of 176 articles were selected for inclusion, of which 140 articles were available. The most frequent journal was: "Critical Care Medicine" (12%). Half of the articles have been published in USA. The analysis of these articles allowed the development of a list of 92 performance indicators in the ICU. The majority of quality indicators were global (63%) and used in a polyvalent ICU (86%). Regarding the domain, the indicators were distributed as follows: 19% "input", 40% "process" and 41% "output". CONCLUSION: This study proposes a set of close to one hundred most-studied ICU performance indicators related essentially to "process". This study is only the first step in a performance improvement quality. The next step will be to use these indicators to develop a performance dashboard of the ICU based on clinical expertise. PMID- 30012511 TI - Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia. AB - INTRODUCTION: Preterm infants are at high risk for white matter injury and subsequent neurodevelopmental impairments. Mesenchymal stem/stromal cells (MSC) have anti-inflammatory/immunomodulatory actions and are of interest for neural repair in adults and newborns. This study examined the neuroprotective effects of allogeneic MSC, derived from preterm umbilical cord blood (UCB), in a preterm sheep model of white matter injury. METHODS: Quad-lineage differentiation, clonogenicity and self-renewal ability of UCB-derived MSC were confirmed. Chronically instrumented fetal sheep (0.7 gestation) received either 25 min hypoxia-ischemia (HI) to induce preterm brain injury, or sham-HI. Ten million MSC, or saline, were administered iv to fetuses at 12 h after HI. Fetal brains were collected 10d after HI for histopathology and immunocytochemistry. RESULTS: HI induced white matter injury, as indicated by a reduction in CNPase-positive myelin fiber density. HI also induced microglial activation (Iba-1) in the periventricular white matter and internal capsule (P < .05 vs control). MSC administration following HI preserved myelination (P < .05), modified microglial activation, and promoted macrophage migration (CD163) and cell proliferation (Ki 67) within cerebral white matter (P < .05). Cerebral CXCL10 concentration was increased following MSC administration (P < .05), which was likely associated with macrophage migration and cell proliferation within the preterm brain. Additionally, MSC administration reduced systemic pro-inflammatory cytokine TNFalpha at 3d post-HI (P < .05). CONCLUSIONS: UCB-derived MSC therapy preserved white matter brain structure following preterm HI, mediated by a suppression of microglial activation, promotion of macrophage migration and acceleration of self repair within the preterm brain. UCB-derived MSC are neuroprotective, acting via peripheral and cerebral anti-inflammatory and immunomodulatory mechanisms. PMID- 30012512 TI - Study on evaluation of toxicology and quality control of Yimusake tablet. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Yimusake tablet (YMSK-T) is a type of Xinjiang Uygur Medicine, which affects curing diseases of impotence and premature ejaculation. It has remarkable pharmacological effects that mainly involve improving the number and shape of smooth muscle cells in the corpus cavernosum and enhancing the relaxation and contraction function of corpus cavernosum smooth muscle. AIM OF THE STUDY: The YMSK-T prescription, which consists of 11 traditional herbs, has significant pharmacological effects, however the evaluation of toxicology and quality control of the preparation has not yet been reported. Therefore, in this study, we evaluated the toxicology and quality control of YMSK-T to ensure its safety and effectiveness in clinical applications. MATERIALS AND METHODS: Male rats were divided into three groups and were given continuous gavage administration of high, medium and low concentrations of YMSK-T. To determine hematopoietic parameters, orbital blood was collected at regular intervals. At termination of the experiment, rats were dissected for histopathological examination. According to the function of the prescription medicinal materials, seven active components were selected for content determination under the same chromatographic condition of using 0.2% aqueous phosphoric acid (solvent A) and acetonitrile (solvent B) with a 40min post time: 0-13min, 20% ->30% B; 13-26min, 30% ->72% B; 26-38min, 72% ->92% B; 38 40min, 92% ->96% B. The column was maintained at 25 degrees C and the total sample injection was 10MUL. RESULTS: Our data showed that using a large dose (400X the dosage used in humans) of YMSK-T resulted in myocardium and liver damage, and eventually death of the rats. At sub-chronic toxicity, no significant differences were observed among indexes about relative organ weight, hematology, serum biochemistry and histopathological examination, and rats behaved normally. Our results also demonstrated that the YMSK-T dosage used was not toxic in the normal range. The linearity of each component was sufficient (correlation coefficients>0.9997). Moreover, the relative standard deviations of precision, repeatability, stability, and recovery were less than 2.0%, which showed that the method for determination of content was stable and reliable. CONCLUSIONS: YMSK-T has been found to be relatively safe in a rat model, and the method of content determination can be used for quality control of YMSK-T. Toxicology and quality control studies indicated that, the drug is safe and effective for clinical application. PMID- 30012513 TI - Artemisia pollen is the main vector for airborne endotoxin. AB - BACKGROUND: Endotoxin (LPS) released from gram-negative bacteria causes strong immunologic and inflammatory effects and, when airborne, can contribute to respiratory conditions, such as allergic asthma. OBJECTIVES: We sought to identify the source of airborne endotoxin and the effect of this endotoxin on allergic sensitization. METHODS: We determined LPS levels in outdoor air on a daily basis for 4 consecutive years in Munich (Germany) and Davos (Switzerland). Air was sampled as particulate matter (PM) greater than 10 MUm (PM > 10) and PM between 2.5 and 10 MUm. LPS levels were determined by using the recombinant Factor C assay. RESULTS: More than 60% of the annual endotoxin exposure was detected in the PM > 10 fraction, showing that bacteria do not aerosolize as independent units or aggregates but adhered to large particles. In Munich 70% of annual exposure was detected between June 12th and August 28th. Multivariate modeling showed that endotoxin levels could be explained by phenological parameters (ie, plant growth). Indeed, days with high airborne endotoxin levels correlated well with the amount of Artemisia pollen in the air. Pollen collected from plants across Europe (100 locations) showed that the highest levels of endotoxin were detected on Artemisia vulgaris (mugwort) pollen, with little on other pollen. Microbiome analysis showed that LPS concentrations on mugwort pollen were related to the presence of Pseudomonas species and Pantoea species communities. In a mouse model of allergic disease, the presence of LPS on mugwort pollen was needed for allergic sensitization. CONCLUSIONS: The majority of airborne endotoxin stems from bacteria dispersed with pollen of only one plant: mugwort. This LPS was essential for inducing inflammation of the lung and allergic sensitization. PMID- 30012514 TI - Human cystatin SN is an endogenous protease inhibitor that prevents allergic rhinitis. AB - BACKGROUND: Protease allergens disrupt epithelial barriers to exert their allergenicity. Cystatin SN (encoded by CST1) is an endogenous cysteine protease inhibitor upregulated in nasal epithelia in patients with allergic rhinitis (AR). OBJECTIVE: We sought to investigate the protective effect of human cystatin SN on AR symptoms using pollen-induced AR mouse models. METHODS: We performed an in vitro protease activity assay to evaluate the effect of recombinant human cystatin SN (rhCystatin SN) on Japanese cedar (JC) or ragweed proteases. A human nasal epithelial cell line, RPMI 2650, was used to examine tight junction (TJ) disruption in vitro. Mice were sensitized and nasally challenged with JC or ragweed pollens with or without rhCystatin SN to examine the effect of rhCystatin SN on AR symptoms and the epithelial barrier in vivo. Because mice lack CST1, we generated transgenic (Tg) mice expressing human CST1 under control of its genomic control region (hCST1-Tg mice) to examine the role of cystatin SN in physiologically expressed conditions. RESULTS: rhCystatin SN inhibited JC but not ragweed protease activities and prevented JC-induced but not ragweed-induced TJ disruption in vitro. Exogenous administration of rhCystatin SN ameliorated JC induced but not ragweed-induced sneezing and nasal TJ disruption in vivo. Furthermore, hCST1-Tg mice showed decreased JC-induced but not ragweed-induced sneezing symptoms and nasal TJ disruption compared with wild-type mice. CONCLUSION: Human cystatin SN suppresses AR symptoms through inhibiting allergen protease activities and protecting the nasal TJ barrier in an allergen-specific manner. We propose that upregulation of nasal endogenous protease inhibitors, including cystatin SN, is a novel therapeutic strategy for protease allergen induced AR. PMID- 30012515 TI - Probing membrane protein ground and conformationally excited states using dipolar and J-coupling mediated MAS solid state NMR experiments. AB - The intrinsic conformational plasticity of membrane proteins directly influences the magnitude of the orientational-dependent NMR interactions such as dipolar couplings (DC) and chemical shift anisotropy (CSA). As a result, the conventional cross-polarization (CP)-based techniques mainly capture the more rigid regions of membrane proteins, while the most dynamic regions are essentially invisible. Nonetheless, dynamic regions can be detected using experiments in which polarization transfer takes place via J-coupling interactions. Here, we review our recent efforts to develop single and dual acquisition pulse sequences with either 1H or 13C detection that utilize both DC and J-coupling mediated transfer to detect both rigid and mobile regions of membrane proteins in native-like lipid environments. We show the application of these new methods for studying the conformational equilibrium of a single-pass membrane protein, phospholamban, which regulates the calcium transport across the sarcoplasmic reticulum (SR) membrane by interacting with the SR Ca2+-ATPase. We anticipate that these methods will be ideal to portray the complex dynamics of membrane proteins in their native environments. PMID- 30012516 TI - An important role of the biarticular hamstrings is to exert internal/external rotation moments on the tibia during vertical jumping. AB - Most research considering biarticular muscle function has tended to focus on the sagittal plane. Instead, the purpose of this study was to evaluate the internal/external rotation moment arms of the biarticular muscles of the knee, and then to explore their function. The FreeBody musculoskeletal model of the lower limb was used to calculate the moment arms and moments that each of the muscles of the knee exerted on the proximal tibia of 12 athletic males during vertical jumping. Biceps femoris and tensor fascia latae were external rotators of the tibia, whereas semimembranosus, semitendinosus, sartorius, gracilis, popliteus and the patellar tendon were internal rotators. The magnitudes of the internal/external rotation and flexion moments exerted on the tibia by the biarticular hamstrings were similar, suggesting that the creation of internal/external rotation is a key aspect of their role. One potential reason is to stabilise the tibia during femoral extension (and it is argued that it may be helpful to characterise the creation of active joint stability as the stabilisation of one segment during the rotation of an adjacent segment). A second explanation may be to mechanically couple hip abduction when the hip is flexed with internal rotation of the tibia. PMID- 30012517 TI - Free-energy minimization in joint agent-environment systems: A niche construction perspective. AB - The free-energy principle is an attempt to explain the structure of the agent and its brain, starting from the fact that an agent exists (Friston and Stephan, 2007; Friston et al., 2010). More specifically, it can be regarded as a systematic attempt to understand the 'fit' between an embodied agent and its niche, where the quantity of free-energy is a measure for the 'misfit' or disattunement (Bruineberg and Rietveld, 2014) between agent and environment. This paper offers a proof-of-principle simulation of niche construction under the free energy principle. Agent-centered treatments have so far failed to address situations where environments change alongside agents, often due to the action of agents themselves. The key point of this paper is that the minimum of free-energy is not at a point in which the agent is maximally adapted to the statistics of a static environment, but can better be conceptualized an attracting manifold within the joint agent-environment state-space as a whole, which the system tends toward through mutual interaction. We will provide a general introduction to active inference and the free-energy principle. Using Markov Decision Processes (MDPs), we then describe a canonical generative model and the ensuing update equations that minimize free-energy. We then apply these equations to simulations of foraging in an environment; in which an agent learns the most efficient path to a pre-specified location. In some of those simulations, unbeknownst to the agent, the 'desire paths' emerge as a function of the activity of the agent (i.e. niche construction occurs). We will show how, depending on the relative inertia of the environment and agent, the joint agent-environment system moves to different attracting sets of jointly minimized free-energy. PMID- 30012519 TI - Red Journal Readers' Top Articles From 2017. PMID- 30012520 TI - The Air Out There: Treatment Planning When Target Volumes Extend Beyond the Skin. PMID- 30012521 TI - Consider Using Virtual Bolus. PMID- 30012518 TI - Perceived discrimination is associated with the inflammatory response to acute laboratory stress in women at risk for cardiovascular disease. AB - Cardiovascular disease (CVD) is the leading cause of death in the United States and exacts a disproportionate toll on minorities. Growing evidence demonstrates that perceived discrimination is a significant contributing factor to psychological distress, chronic low-grade inflammation, and cardiovascular health. However, little is known regarding the extent to which perceived discrimination contributes to the inflammatory response to acute stress. Therefore, the purpose of this study was to examine the influence of perceived discrimination on the inflammatory response to a laboratory acute stress paradigm in women at risk for CVD. A cross-sectional sample of 99 postmenopausal women (50 African American and 49 non-Hispanic White) (mean age 60.2 years) with at least two risk factors for CVD underwent the Trier Social Stress Test (TSST). Subjects completed the Detroit Area Study Discrimination Scale (DAS-DS) Everyday Discrimination subscale and provided blood and saliva samples prior to the TSST and every 15 min up to 90 min post-TSST to measure a pro-inflammatory cytokine, interleukin-6 (IL-6). Perceived discrimination was significantly associated with the salivary IL-6 response to the TSST (b = 0.49, SE = 0.13, p = <0.001) controlling for age, race, marital status, household income, BMI, statin use, childhood maltreatment, depressive symptoms, and subjective social status. Women who reported higher levels of perceived discrimination had higher levels of salivary IL-6 at baseline and following the TSST as compared to women who reported lower levels of perceived discrimination. Results suggest that higher levels of perceived discrimination, regardless of race and socioeconomic status, may heighten levels of inflammation, prior to and following an acute stress exposure. The circulating Il-6 response was associated with BMI only and did not correlate with salivary IL-6. These data suggest that perceived discrimination may contribute to the salivary-IL-6 acute stress response. However, more research is needed to help clarify the complex relationships among stress and salivary proinflammatory cytokines. PMID- 30012522 TI - Employ Piece-wise Optimization. PMID- 30012523 TI - Consider Re-simulation or Evaluate With and Without Density Overrides. PMID- 30012524 TI - Emerging Magnetic Resonance Imaging Technologies for Radiation Therapy Planning and Response Assessment. AB - Functional and molecular MRI techniques are capable of measuring biologic properties of tumor tissue. Knowledge of these biological properties may improve radiation treatment by more accurately identifying tumor volumes, characterizing radioresistant subvolumes of tumor before radiation therapy (RT), and identifying recurrent disease after RT. Intravoxel incoherent motion MRI, blood oxygenation level-dependent MRI, tissue oxygenation level-dependent MRI, hyperpolarized 13C MRI, and chemical exchange saturation transfer MRI are relatively new MRI techniques that have shown promise for contributing to RT planning and response assessment. This review critically evaluates these emerging MR techniques, their potential role in RT planning, utility to date, and challenges to integration into the current clinical workflow. PMID- 30012525 TI - Magnetic Resonance Imaging-Guided Radiation Therapy: A Short Strengths, Weaknesses, Opportunities, and Threats Analysis. PMID- 30012526 TI - Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. AB - PURPOSE: The safety of combined immunotherapy and thoracic radiation therapy (iRT) has been understudied. We evaluated toxicities in patients receiving iRT from 3 single-institutional phase 1/2 trials. METHODS AND MATERIALS: Clinical/treatment characteristics and toxicities (per the Common Toxicity Criteria for Adverse Events, version 4.0) were extracted. For purposes of this analysis, groupings were made into (1) patients receiving immunotherapy plus stereotactic body radiation therapy (50 Gy/4 fractions or 60 Gy/10 fractions), (2) immunotherapy plus 45 Gy/15 fractions, and (3) twice-daily chemoimmunoradiotherapy (45 Gy in twice-daily fractions). RESULTS: None of the 60 patients undergoing immunotherapy plus stereotactic body radiation therapy (50 Gy, n = 49; 60 Gy, n = 11) experienced grade >=4 events. There were 34 instances of any grade 3 event (in 15 total patients), with 9 pulmonary specific grade 3 events (in 4 patients). In the patients receiving 45 Gy/15 fractions (small cell lung cancers, n = 26; non-small cell lung cancers, n = 27), there were 2 grade 4 events (in the same patient), along with 17 grade 3 toxicities experienced by 10 total patients (2 pulmonary specific). Lastly, in the twice-daily cohort (n = 22), there were 5 grade 4 events (3 of which occurred in 1 patient) and 16 grade 3 toxicities occurring in 8 total patients (half of which were hematologic). CONCLUSIONS: Administration of combined iRT is safe in the short term. Toxicities did not appreciably associate with demographics or dosimetry. PMID- 30012527 TI - A Randomized Comparison of Radiation Therapy Techniques in the Management of Node Positive Breast Cancer: Primary Outcomes Analysis. AB - PURPOSE: Although inverse-planned intensity modulated radiotherapy (IMRT) and deep inspiration breath hold (DIBH) may allow for more conformal dose distributions, it is unknown whether using these technologies reduces cardiac or pulmonary toxicity of breast radiotherapy. METHODS AND MATERIALS: A randomized controlled trial compared IMRT-DIBH versus standard, free-breathing, forward planned, three-dimensional conformal radiotherapy in patients with left-sided, node-positive breast cancer in whom the internal mammary nodal region was targeted. Endpoints included dosimetric parameters and changes in pulmonary and cardiac perfusion and function, measured by single photon emission computed tomography (SPECT) scans and pulmonary function testing performed at baseline and 1 year post treatment. RESULTS: Of 62 patients randomized, 54 who completed all follow-up procedures were analyzed. Mean doses to the ipsilateral lung, left ventricle, whole heart, and left anterior descending coronary artery were lower with IMRT-DIBH; the percent of left ventricle receiving >=5 Gy averaged 15.8% with standard radiotherapy and 5.6% with IMRT-DIBH (P < .001). SPECT revealed no differences in perfusion defects in the left anterior descending coronary artery territory, the study's primary endpoint, but did reveal statistically significant differences (P = .02) in left ventricular ejection fraction (LVEF), a secondary endpoint. No differences were found for lung perfusion or function. CONCLUSION: The small but statistically significant benefit in preservation of cardiac LVEF observed here should motivate future studies that include LVEF as a potentially meaningful endpoint. Future studies should disaggregate the impact of IMRT from that of DIBH. Clinical practice should recognize the importance of minimizing cardiac dose, even when already low in comparison to historical levels. PMID- 30012528 TI - Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer. AB - There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose limiting toxicity and will be amended to reduce radiation therapy dose. PMID- 30012529 TI - Development and Preliminary Evaluation of a Murine Model of Chronic Radiation Induced Proctitis. AB - PURPOSE: Radiotherapy (RT) is commonly used to treat most pelvic malignancies. While treatment is often effective, curative radiation doses to the rectum can result in chronic radiation-induced proctitis, which is characterized by diarrhea, tenesmus, and/or rectal bleeding, recently termed pelvic radiation disease. An animal model of chronic radiation-induced proctitis would be useful to test both preventative and therapeutic strategies to limit this morbidity but has been elusive because of the high rodent mortality associated with acute bowel RT injury. The objective of this research was to develop a novel mouse model of chronic radiation-induced proctitis using advanced technology. METHODS AND MATERIALS: Using an X-RAD 225-Cx (Precision X-Ray) small animal irradiator, multiple plan configurations were evaluated for planning treatment volume and organ-at-risk avoidance to deliver a 15 Gy 3D conformal treatment plan. The final plan was verified by high resolution 3D dosimetry (PRESAGE/optical-CT), and delivered using a single arc. Mice were monitored for mortality for 250 days, followed by histopathological correlates including mucicarmine, Masson's trichrome, and fecal pellet length. RESULTS: Six beam arrangements were considered: single and parallel-opposed fields with whole-pelvis coverage, and collimated fields in parallel-opposed, 3-field, 4-field, and arc geometries. A collimated arc plan offered superior planning treatment volume coverage and organ at-risk avoidance compared to whole-pelvis irradiation. Treatment verification with PRESAGE 3D dosimetry (Heuris Inc) showed >99% of voxels passing gamma analysis with 2%/2 mm criteria. Our treatment resulted in no acute mortality and 40% mortality at 250 days. Histopathological analysis showed increased mucous production and fibrosis of the irradiated colon, but no change in fecal pellet length. CONCLUSIONS: Our model was able to target successfully lower colon and rectum with lower mortality than other published models. This permitted measurement of late effects that recapitulate some features of rectal damage in humans. PMID- 30012530 TI - In Reply to Juretic and Suton. PMID- 30012531 TI - In Regard to Yadav et al. PMID- 30012532 TI - In Regard to Ward et al. PMID- 30012533 TI - In Reply to Yildirim and Topkan. PMID- 30012534 TI - The Radiation Safety of 5G Wi-Fi: Reassuring or Russian Roulette? PMID- 30012535 TI - Erratum to: Sarria GJ, Saria GR, Pinillos LV. The Inca Trail to the Present: The Development of Radiation Therapy in Peru. Int J Radiat Oncol Biol Phys 2018;101:244-249. PMID- 30012536 TI - Discovery of immunoglobulin T in Nile tilapia (Oreochromis niloticus): A potential molecular marker to understand mucosal immunity in this species. AB - Immunoglobulin molecules play an important role in the immune defense system in all jawed vertebrates, by protecting the organism from a wide variety of pathogens. Nile tilapia (Oreochromis niloticus) is extensively cultivated worldwide, with a strong established market demand. It constitutes one of the model species for the study of fish immunology and its genome is currently fully sequenced. The presence of the immunoglobulin M gene in this species is well documented, as well as its major role in systemic immunity. To date, the IgT gene from O. niloticus has not been identified and, therefore, no information is available on the role of this immunoglobulin isotype in the immune response in tilapia. In the present work, novel secreted and membrane immunoglobulin T isotypes and a fragment of IgM were isolated from tilapia head kidney lymphocytes. Their transcriptional profiles were analyzed by quantitative PCR in larval development and in different tissues of healthy or lipopolysaccharide/Edwardsiella tarda-challenged tilapia adults. The presence of IgT and IgM were detected in early stages of larval development. Additionally, these genes exhibited differential expression profiles in basal conditions and after E. tarda infection in adult tilapia, in accord with the proposed effector functions of these immunoglobulins in the systemic and mucosal compartments. Our results suggest the potential involvement of this new Ig in mucosal immunity in tilapia. PMID- 30012538 TI - Helicokinin alters ion transport in the secondary cell-containing region of the Malpighian tubule of the larval cabbage looper Trichoplusia ni. AB - Excretion in insects is accomplished by the combined actions of the Malpighian tubules (MTs) and hindgut, which together form the functional kidney. MTs of many insect groups consist of principal cells (PC) and secondary cells (SC). In most insect groups SCs are reported to secrete ions from haemolymph into the tubule lumen. Paradoxically, SCs in the MTs of the lepidopteran cabbage looper T. ni are used to reabsorb Na+ and K+ back into haemolymph. The current study was designed to investigate the effects and mode of action of the lepidopteran kinin, Helicokinin (HK), on ion transport in the SC-containing region of MT of T. ni. We identified a HK receptor (HK-R) homologue in T. ni and detected its expression in the SC-containing region of the MTs. The mRNA abundance of hk-r altered in response to changes in dietary K+ and Na+ content. HK-R immunolocalized to both PCs and SCs. Ramsay assays of preparations of the isolated distal ileac plexus (DIP) indicated that [HK] = 10-8 M: (i) decreased fluid secretion rate in unstimulated and serotonin-stimulated preparations, and (ii) increased [Na+]/[K+] ratio in the secreted fluid. Scanning ion-selective electrode technique measurements revealed that HK reduced: (i) K+ secretion by the PCs, and (ii) Na+ reabsorption by the SCs in intact tubules. In vitro incubation of the DIP with HK resulted in reduced mRNA abundance of hk-r as well as Na+/K+-ATPase subunit alpha (NKAalpha), Na+/K+/Cl- co-transporter (nkcc), Na+/H+ exchangers (nhe) 7 and 8, and aquaporin (aqp) 1. Taken together, results of the current study suggest that HK is capable of altering fluid secretion rate and [Na+]/[K+] ratio of the fluid, and that HK targets both PCs and SCs in the DIP of T. ni. PMID- 30012537 TI - Quantifying the performance of MEG source reconstruction using resting state data. AB - In magnetoencephalography (MEG) research there are a variety of inversion methods to transform sensor data into estimates of brain activity. Each new inversion scheme is generally justified against a specific simulated or task scenario. The choice of this scenario will however have a large impact on how well the scheme performs. We describe a method with minimal selection bias to quantify algorithm performance using human resting state data. These recordings provide a generic, heterogeneous, and plentiful functional substrate against which to test different MEG recording and reconstruction approaches. We used a Hidden Markov model to spatio-temporally partition data into self-similar dynamic states. To test the anatomical precision that could be achieved, we then inverted these data onto libraries of systematically distorted subject-specific cortical meshes and compared the quality of the fit using cross validation and a Free energy metric. This revealed which inversion scheme was able to identify the least distorted (most accurate) anatomical models, and allowed us to quantify an upper bound on the mean anatomical distortion accordingly. We used two resting state datasets, one recorded with head-casts and one without. In the head-cast data, the Empirical Bayesian Beamformer (EBB) algorithm showed the best mean anatomical discrimination (3.7 mm) compared with Minimum Norm/LORETA (6.0 mm) and Multiple Sparse Priors (9.4 mm). This pattern was replicated in the second (conventional dataset) although with a marginally poorer (non-significant) prediction of the missing (cross-validated) data. Our findings suggest that the abundant resting state data now commonly available could be used to refine and validate MEG source reconstruction methods and/or recording paradigms. PMID- 30012539 TI - The role of glucocorticoids in the vertebrate response to weather. AB - Changes in the environment related to inclement weather can threaten survival and reproductive success both through direct adverse exposure and indirectly by decreasing food availability. Glucocorticoids, released during activation of the hypothalamic-pituitary-adrenal axis as part of the stress response, are an important candidate for linking vertebrate coping mechanisms to weather. This review attempts to determine if there is a consensus response of glucocorticoids to exposure to weather-related stimuli, including food availability, precipitation, temperature and barometric pressure. The included studies cover field and laboratory studies for all vertebrate taxa, and are separated into four exposure periods, e.g., hours, days, weeks and months. Each reported result was assigned a score based on the glucocorticoid response, e.g., increased, no change, or decreased. Short-term exposure to weather-related stimuli, of up to 24 h, is generally associated with increased glucocorticoids (79% of studies), suggesting that these stimuli are perceived as stressors by most animals. In contrast, the pattern for exposures longer than 24 h shows more variation, even though a majority of studies still report an increase (64%). Lack of glucocorticoid increases appeared to result from instances where: (1) prolonged exposure was a predictable part of the life history of an animal; (2) environmental context was important for the ultimate effect of a stimulus (e.g., precipitation limited food availability in one environment, but increased food in another); (3) prolonged exposure induced chronic stress; and (4) long-term responses appeared to reflect adaptations to seasonal shifts, instead of to short term weather. However, there is a strong bias towards studies in domesticated laboratory species and wild animals held in captivity, indicating a need for field studies, especially in reptiles and amphibians. In conclusion, the accumulated literature supports the hypothesis that glucocorticoids can serve as the physiological mechanism promoting fitness during inclement weather. PMID- 30012540 TI - Phage display: an important tool in the discovery of peptides with anti-HIV activity. AB - Human immunodeficiency virus (HIV) remains a worldwide health problem despite huge investments and research breakthroughs, and no single drug is effective in killing the virus yet. Among new strategies to control HIV infection, the phage display (PD) technology has become a promising tool in the discovery of peptides that can be used as new drugs, or also as possible vaccine candidates. This review discusses basic aspects of PD and its use to advance two main objectives related to combating HIV-1 infection: the identification of peptides that inhibit virus replication and the identification of peptides that induce the production of neutralizing antibodies. We will cover the different approaches used for mapping and selection of mimotopes, and discuss the promising results of these biologicals as antiviral agents. PMID- 30012541 TI - State of art and limitations in genetic engineering to induce stable chondrogenic phenotype. AB - Current protocols for chondrocyte expansion and chondrogenic differentiation of stem cells fail to reduce phenotypic loss and to mitigate hypertrophic tendency. To this end, cell genetic manipulation is gaining pace as a means of generating cells with stable chondrocyte phenotype. Herein, we provide an overview of candidate genes that either induce cartilage regeneration or inhibit cartilage degeneration. We further discuss in vitro, ex vivo and in vivo viral transduction and non-viral transfection strategies for targeted cells (chondrocytes, mesenchymal stem cells, induced pluripotent stem cells and synovial cells), along with the most representative results obtained in pre-clinical models and in clinical trials. We highlight current challenges and associated risks that slowdown clinical acceptance and commercialisation of gene transfer technologies. PMID- 30012542 TI - Early experience of transcatheter correction of superior sinus venosus atrial septal defect with partial anomalous pulmonary venous drainage. AB - AIMS: Superior sinus venosus atrial septal defect (SVASD) is commonly associated with partial anomalous pulmonary venous drainage (PAPVD). We aimed to describe the first series of percutaneous SVASD and PAPVD correction using a two-step simulation for procedural planning. METHODS AND RESULTS: Patients with SVASD and right PAPVD with a clinical indication for correction were selected. They underwent an ex vivo procedural simulation on a 3D-printed model followed by an in vivo simulation using balloon inflation in the targeted stent landing zone. The percutaneous procedure consisted in deploying a 10-zig custom-made covered stent in the SVC-RA junction. Five patients were referred for preprocedural evaluation and were deemed suitable for percutaneous correction. The procedure was successful in all patients with no residual interatrial shunt and successful redirection of the pulmonary venous drainage to the left atrium. At a median clinical follow-up of 8.1 months (2.6-19.8), no adverse events were noted, and all patients showed clinical improvement. During follow-up, transthoracic echocardiography and multidetector cardiac tomography in four patients or invasive angiography in one patient demonstrated a patent SVC stent, and no residual SVASD and unobstructed PV drainage in all patients. CONCLUSIONS: In selected patients using a two-stage simulation strategy, percutaneous correction of SVASD with PAPVD is feasible and safe, and led to favourable short-term outcomes. PMID- 30012543 TI - Health Information on Firefighter Websites: Structured Analysis. AB - BACKGROUND: Owing to the fact that firefighters have unique health risks, access to firefighter-specific internet-based health information is a potential mechanism for achieving better health and work outcomes. OBJECTIVE: The objective of our study was to identify the amount and nature of health information resources available on Canadian firefighter-specific websites and the extent to which resources are consistent across websites as a surrogate indicator of diffusion of information. METHODS: A search of health resources on firefighter websites (union and employer) for all Canadian provinces, major cities and a subset of smaller cities, and the International Association of Fire Fighters (IAFF) website was conducted on Google (July 2017). Content was identified and classified based on the type of resource, health focus, and location. The quantity and nature of the resources were summarized using descriptive statistics. RESULTS: Among all (N=313) websites reviewed, 41 websites had health information with a cumulative total of 128 resources that addressed firefighter mental (59/128, 46.1%), physical (43/128, 33.6%), and work health (26/128, 20.3%). The highest density of information was found on international and national websites (13 resources per website) and the least on local websites (1 resource per 7 websites). Three provinces (Ontario, Quebec, and British Columbia) hosted 81% (65/80) of the provincial, territorial and local resources. General mental health (20/59, 34%), posttraumatic stress disorder (14/59, 24%), and suicide (14/59, 24%) were the most prevalent topics within the mental health resources, whereas half (21/43, 49%) of all physical health resources were on cancer. No resources from Northern Canada were found. Musculoskeletal health was not mentioned in any of the resources identified. There was minimal cross-linking of resources across sites (only 4 resources were duplicated across sites), and there was no clear indication of how the content was vetted or evaluated for quality. CONCLUSIONS: There was wide variation in the amount and type of information available on different firefighter websites with limited diffusion of information across jurisdictions. Quality evaluation and coordination of resources should be considered to enhance firefighters' access to quality health information to meet their specific needs. Mental health and cancer information aligned with high rates of these health problems in firefighters, whereas the lack of information on musculoskeletal health was discordant with their high rate of work injury claims for these problems. PMID- 30012545 TI - Creating Low-Cost 360-Degree Virtual Reality Videos for Hospitals: A Technical Paper on the Dos and Don'ts. AB - This article will provide a framework for producing immersive 360-degree videos for pediatric and adult patients in hospitals. This information may be useful to hospitals across the globe who may wish to produce similar videos for their patients. Advancements in immersive 360-degree technologies have allowed us to produce our own "virtual experience" where our children can prepare for anesthesia by "experiencing" all the sights and sounds of receiving and recovering from an anesthetic. We have shown that health care professionals, children, and their parents find this form of preparation valid, acceptable and fun. Perhaps more importantly, children and parents have self-reported that undertaking our virtual experience has led to a reduction in their anxiety when they go to the operating room. We provide definitions, and technical aspects to assist other health care professionals in the development of low-cost 360-degree videos. PMID- 30012544 TI - Community Volunteer Support for Families With Young Children: Protocol for the Volunteer Family Connect Randomized Controlled Trial. AB - BACKGROUND: Use of community volunteers to support vulnerable families is a widely employed strategy with a long history. However, there has been minimal formal scientific investigation into the effectiveness of volunteer home visiting programs for families. There is also a need for research examining whether volunteer home visiting leads to improved outcomes for volunteers. OBJECTIVE: The objective of this paper is to describe the research protocol for a pragmatic randomized controlled trial (RCT) of the Volunteer Family Connect intervention, a volunteer home visiting program designed to support families of young children who experience social isolation or a lack of parenting confidence and skills. The project is being conducted in partnership with 3 leading not-for-profit organizations, designed to contribute to the body of evidence that informs decisions about appropriate family support services according to the level of need. It is the first study to examine outcomes for both the families and the volunteers who deliver the service. METHODS: The RCT is being conducted in 7 sites across Australia. We aim to recruit 300 families to the study: 150 control (services as usual) and 150 intervention (services as usual + volunteer home visiting) families. Intervention families will receive the service for 3-12 months according to their needs, and all participants will complete 6 data collection points over 15 months. A minimum of 80 volunteers will also be recruited, along with a matched community comparison group. The volunteers will complete 3 data collection points over 12 months. Primary outcomes include community connectedness and parenting competence. Secondary outcomes include parent physical and mental health; general parent well-being; parent empowerment; the child-parent relationship; sustainability of family routines; child immunization; child nutrition or breastfeeding; number of accidental injury reports; and volunteer health, well-being, and community connectedness. RESULTS: This effectiveness trial was funded in 2016, and we aim to complete data collection by the end of 2018. The first results are expected to be submitted early in 2019. CONCLUSIONS: There is a need to rigorously assess volunteer home visiting and whether it has a unique and important role on the service landscape, complementary to professional services. This research is the first trial of a volunteer home visiting program to be conducted in Australia and one of the largest of its kind worldwide. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12616000396426; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370304 (Archived by WebCite athttp://www.webcitation.org/70q42fU7V). REGISTERED REPORT IDENTIFIER: RR1-10.2196/1000. PMID- 30012546 TI - Software for Administering the National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events: Usability Study. AB - BACKGROUND: The US National Cancer Institute (NCI) developed software to gather symptomatic adverse events directly from patients participating in clinical trials. The software administers surveys to patients using items from the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) through Web-based or automated telephone interfaces and facilitates the management of survey administration and the resultant data by professionals (clinicians and research associates). OBJECTIVE: The purpose of this study was to iteratively evaluate and improve the usability of the PRO-CTCAE software. METHODS: Heuristic evaluation of the software functionality was followed by semiscripted, think-aloud protocols in two consecutive rounds of usability testing among patients with cancer, clinicians, and research associates at 3 cancer centers. We conducted testing with patients both in clinics and at home (remotely) for both Web-based and telephone interfaces. Furthermore, we refined the software between rounds and retested. RESULTS: Heuristic evaluation identified deviations from the best practices across 10 standardized categories, which informed initial software improvement. Subsequently, we conducted user based testing among 169 patients and 47 professionals. Software modifications between rounds addressed identified issues, including difficulty using radio buttons, absence of survey progress indicators, and login problems (for patients) as well as scheduling of patient surveys (for professionals). The initial System Usability Scale (SUS) score for the patient Web-based interface was 86 and 82 (P=.22) before and after modifications, respectively, whereas the task completion score was 4.47, which improved to 4.58 (P=.39) after modifications. Following modifications for professional users, the SUS scores improved from 71 to 75 (P=.47), and the mean task performance improved significantly (4.40 vs 4.02; P=.001). CONCLUSIONS: Software modifications, informed by rigorous assessment, rendered a usable system, which is currently used in multiple NCI-sponsored multicenter cancer clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01031641; https://clinicaltrials.gov/ct2/show/NCT01031641 (Archived by WebCite at http://www.webcitation.org/708hTjlTl). PMID- 30012548 TI - The Development of Complex Digital Health Solutions: Formative Evaluation Combining Different Methodologies. AB - BACKGROUND: The development of digital health solutions for current health care settings requires an understanding of the complexities of the health care system, organizational setting, and stakeholder groups and of the underlying interplay between stakeholders and the technology. The digital health solution was founded on the basis of an information and communication technology platform and point-of care devices enabling home-based monitoring of disease progression and treatment outcome for patients with rheumatoid arthritis (RA). OBJECTIVE: The aim of this paper is to describe and discuss the applicability of an iterative evaluation process in guiding the development of a digital health solution as a technical and organizational entity in three different health care systems. METHODS: The formative evaluation comprised the methodologies of contextual understanding, participatory design, and feasibility studies and included patients, healthcare professionals, and hardware and software developers. In total, the evaluation involved 45 patients and 25 health care professionals at 3 clinical sites in Europe. RESULTS: The formative evaluation served as ongoing and relevant input to the development process of the digital health solution. Through initial field studies key stakeholder groups were identified and knowledge obtained about the different health care systems, the professional competencies involved in routine RA treatment, the clinics' working procedures, and the use of communication technologies. A theory-based stakeholder evaluation achieved a multifaceted picture of the ideas and assumptions held by stakeholder groups at the three clinical sites, which also represented the diversity of three different language zones and cultures. Experiences and suggestions from the patients and health care professionals were sought through participatory design processes and real-life testing and actively used for adjusting the visual, conceptual, and practical design of the solution. The learnings captured through these activities aided in forming the solution and in developing a common understanding of the overall vision and aim of this solution. During this process, the 3 participating sites learned from each other's feed-back with the ensuing multicultural inspiration. Moreover, these efforts also enabled the consortium to identify a 'tipping point' during a pilot study, revealing serious challenges and a need for further development of the solution. We achieved valuable learning during the evaluation activities, and the remaining challenges have been clarified more extensively than a single-site development would have discovered. The further obstacles have been defined as has the need to resolve these before designing and conducting a real-life clinical test to assess the outcome from a digital health solution for RA treatment. CONCLUSIONS: A formative evaluation process with ongoing involvement of stakeholder groups from 3 different cultures and countries have helped to inform and influence the development of a novel digital health solution, and provided constructive input and feedback enabling the consortium to control the development process. PMID- 30012547 TI - Web-Based Intervention Using Behavioral Activation and Physical Activity for Adults With Depression (The eMotion Study): Pilot Randomized Controlled Trial. AB - BACKGROUND: Physical activity is a potentially effective treatment for depression and depressive relapse. However, promoting physical activity in people with depression is challenging. Interventions informed by theory and evidence are therefore needed to support people with depression to become more physically active. eMotion is a Web-based intervention combining behavioral activation and physical activity promotion for people in the community with symptoms of depression. OBJECTIVE: The objectives were to assess the feasibility and acceptability of delivering eMotion to people in the community with symptoms of depression and to explore outcomes. METHODS: Participants with elevated depressive symptoms were recruited from the community through various methods (eg, social media) and randomized to eMotion or a waiting list control group for 8 weeks. eMotion is an administratively supported weekly modular program that helps people use key behavior change techniques (eg, graded tasks, action planning, and self-monitoring) to re-engage in routine, pleasurable, and necessary activities, with a focus on physical activities. Feasibility data were collected that included the following: recruitment and trial retention rates; fidelity of intervention delivery, receipt, and enactment; and acceptability of the intervention and data collection procedures. Data were collected for the primary (depression) and secondary outcomes (eg, anxiety, physical activity, fidelity, and client satisfaction) at baseline and 2 months postrandomization using self-reported Web-based questionnaires and accelerometers. Delivery fidelity (logins, modules accessed, time spent) was tracked using Web usage statistics. Exploratory analyses were conducted on the primary and secondary outcomes. RESULTS: Of the 183 people who contacted the research team, 62 were recruited and randomized. The mean baseline score was 14.6 (SD 3.2) on the 8-item Patient Health Questionnaire depression scale (PHQ-8). Of those randomized, 52 participants provided accelerometer-recorded physical activity data at baseline that showed a median of 35.8 (interquartile range [IQR] 0.0-98.6) minutes of moderate-to-vigorous physical activity (MVPA) recorded in at least 10-minute bouts per week, with only 13% (7/52) people achieving guideline levels (150 minutes of MVPA per week). In total, 81% (50/62) of participants provided follow up data for the primary outcome (PHQ-8), but only 39% (24/62) provided follow-up accelerometer data. Within the intervention group, the median number of logins, modules accessed, and total minutes spent on eMotion was 3 (IQR 2.0-8.0), 3 (IQR 2.0-5.0), and 41.3 (IQR 18.9-90.4), respectively. Acceptability was mixed. Exploratory data analysis showed that PHQ-8 levels were lower for the intervention group than for the control group at 2 months postrandomization (adjusted mean difference -3.6, 95% CI -6.1 to -1.1). CONCLUSIONS: It was feasible to deliver eMotion in UK communities to inactive populations. eMotion has the potential to be effective and is ready for testing in a full-scale trial. Further work is needed to improve engagement with both the intervention and data collection procedures. TRIAL REGISTRATION: ClinicalTrials.gov NCT03084055; https://clinicaltrials.gov/ct2/show/NCT03084055 (Archived by WebCite at http://www.webcitation.org/6zoyM8UXa). PMID- 30012549 TI - Using eHealth to Reach Black and Hispanic Men Who Have Sex With Men Regarding Treatment as Prevention and Preexposure Prophylaxis: Protocol for a Small Randomized Controlled Trial. AB - BACKGROUND: Black and Hispanic men who have sex with men in the United States continue to be disproportionately affected by HIV and AIDS. Uptake of and knowledge about biobehavioral HIV prevention approaches, such as treatment as prevention and preexposure prophylaxis, are especially low in these populations. eHealth campaigns and social media messaging about treatment as prevention and preexposure prophylaxis may help to fill this gap in knowledge and lead to increased uptake of such strategies; however, no evidence exists of the effects of these targeted forms of communication on treatment as prevention and preexposure prophylaxis uptake in these populations. OBJECTIVE: We describe the protocol for a 3-part study aiming to develop and evaluate an eHealth intervention with information about treatment as prevention and preexposure prophylaxis for HIV-positive and HIV-negative black and Hispanic men who have sex with men. METHODS: Phases 1 and 2 will involve focus groups and cognitive interviews with members of the target populations, which we will use to create a culturally tailored, interactive website and applicable social media messaging for these men. Phase 3 will be a small randomized controlled trial of the eHealth intervention, in which participants will receive guided social media messages plus the newly developed website (active arm) or the website alone (control arm), with assessments at baseline and 6 months. RESULTS: Participant recruitment began in August 2017 and will end in August 2020. CONCLUSIONS: Public health interventions are greatly needed to increase knowledge about and uptake of biobehavioral HIV prevention strategies such as treatment as prevention and preexposure prophylaxis among black and Hispanic men who have sex with men. eHealth communication campaigns offer a strategy for engaging these populations in health communication about biobehavioral HIV prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT03404531; https://www.clinicaltrials.gov/ct2/show/NCT03404531 (Archived by WebCite at http://www.webcitation.org/70myofp0R). REGISTERED REPORT IDENTIFIER: RR1 10.2196/11047. PMID- 30012551 TI - GP fails in legal bid to prevent patient seeing GMC report. PMID- 30012550 TI - How do we interpret readmission rates? PMID- 30012552 TI - Prednisolone induces osteoporosis-like phenotypes via focal adhesion signaling pathway in zebrafish larvae. AB - Patients taking glucocorticoid or glucocorticoid-like drugs for an extended period of time may develop osteoporosis, termed glucocorticoid-induced osteoporosis (GIOP). GIOP is the most common form of secondary osteoporosis, but the mechanism underlying its development is unclear. In the present study, we used prednisolone to treat zebrafish larvae to investigate GIOP. Our RNA deep sequencing (RNA-seq) results show that prednisolone affects genes known to act in the extracellular region. Therefore the extracellular region, extracellular matrix, and collagen trimer might be involved in glucocorticoid-induced osteoporosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the focal adhesion signaling pathway is the most enriched signaling pathway in terms of differentially expressed genes (DEGs). In this pathway, integrin subunit alpha 10 (itga10) and integrin subunit beta like 1 (itgbl1), genes encoding two adapter proteins, were down-regulated in the prednisolone treated larvae. Further experiments showed that prednisolone contributes to GIOP by down-regulating itga10 and itgbl1. PMID- 30012554 TI - Exploring young women's perspectives of a targeted support programme for teenage parents. AB - CONTEXT: Teenage parents and their children are at risk of poorer outcomes than older mothers, and their peers. OBJECTIVE: Evaluate participants' experiences of a targeted teenage parent support programme. DESIGN: A qualitative study was conducted to gain feedback from participants of a locally commissioned teenage parent support programme. Four focus groups were held with participants attending the programme in different areas of the county, and analysed using applied thematic analysis. PARTICIPANTS: Teenage mothers aged 16-19 years from vulnerable backgrounds (n=18) attending a teenage parent support programme in County Durham. RESULTS: Two major themes emerged from the analysis focusing on factors influencing enrolment and continued engagement and how the programme leads to personal development for mother and child.The majority of participants felt that the group fostered a supportive environment and led to a reduction in social isolation. The provision of free transport and childcare onsite was seen as a key component of the service without which many would not have been able to attend. DISCUSSION: The programme appeared effective at increasing the emotional and social capabilities of teenage mothers. It had a positive impact on parents' engagement in education and employment, as well as impacting on children's social development. CONCLUSIONS: Targeted support programmes have the ability to increase social and emotional capabilities of teenage mothers and their children. They can increase engagement in education and employment for teenage mothers. The provision of transport and free child care places can enhance engagement in such programmes. PMID- 30012553 TI - PRP-19, a conserved pre-mRNA processing factor and E3 ubiquitin ligase, inhibits the nuclear accumulation of GLP-1/Notch intracellular domain. AB - The Notch signalling pathway is a conserved and widespread signalling paradigm, and its misregulation has been implicated in numerous disorders, including cancer. The output of Notch signalling depends on the nuclear accumulation of the Notch receptor intracellular domain (ICD). Using the Caenorhabditis elegans germline, where GLP-1/Notch-mediated signalling is essential for maintaining stem cells, we monitored GLP-1 in vivo We found that the nuclear enrichment of GLP-1 ICD is dynamic: while the ICD is enriched in germ cell nuclei during larval development, it is depleted from the nuclei in adult germlines. We found that this pattern depends on the ubiquitin proteolytic system and the splicing machinery and, identified the splicing factor PRP-19 as a candidate E3 ubiquitin ligase required for the nuclear depletion of GLP-1 ICD. PMID- 30012556 TI - Strategies to avoid unnecessary emergency admissions. PMID- 30012557 TI - Adults' Perceptions of Nicotine Harm to Children. AB - BACKGROUND: Given the changing landscape of tobacco products in recent years, the array of products through which children could be exposed to nicotine has grown substantially. Thus, it is particularly important to understand adults' perceptions of the harms of nicotine to children and to identify any sociodemographic factors related to inaccurate risk perceptions. METHODS: Data were drawn from 2015 to 2016 US nationally representative surveys (n = 11 959). Using multinomial logistic regression analyses, we examined whether race, sex, education, tobacco product use, and having a minor child in the home are associated with the level of perceived harmfulness of nicotine to children. RESULTS: Although the majority of respondents characterized nicotine as "definitely harmful" to children, there were notable subgroup differences. Compared with women, men had significantly lower odds of characterizing nicotine as "definitely harmful" to children. Tobacco product users had significantly lower odds of endorsing "definitely harmful" or "don't know" than nonusers. African American non-Hispanic individuals, Hispanic individuals, and "other" non Hispanic individuals had significantly lower odds of endorsing "definitely harmful" or "maybe harmful" than white individuals. CONCLUSIONS: Although most adults perceive nicotine exposure as harmful for children, there are important differences based on sex, racial and/or ethnic background, and tobacco use status. The results reveal the need for public health efforts to better understand and target inaccurate risk perceptions among specific subgroups. PMID- 30012555 TI - Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy. AB - Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons-a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)-through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing of Mdm2 and Mdm4, two nonredundant repressors of p53. Decreased inclusion of critical Mdm2 and Mdm4 exons is most prominent in SMA motor neurons and correlates with both snRNP reduction and p53 activation in vivo. Importantly, increased skipping of Mdm2 and Mdm4 exons regulated by SMN is necessary and sufficient to synergistically elicit robust p53 activation in wild type mice. Conversely, restoration of full-length Mdm2 and Mdm4 suppresses p53 induction and motor neuron degeneration in SMA mice. These findings reveal that loss of SMN-dependent regulation of Mdm2 and Mdm4 alternative splicing underlies p53-mediated death of motor neurons in SMA, establishing a causal link between snRNP dysfunction and neurodegeneration. PMID- 30012558 TI - The National Opioid Epidemic and the Risk of Outpatient Opioids in Children. PMID- 30012559 TI - Outpatient Opioid Prescriptions for Children and Opioid-Related Adverse Events. AB - BACKGROUND AND OBJECTIVES: Little is known about opioid prescribing for children without severe conditions. We studied the prevalence of and indications for outpatient opioid prescriptions and the incidence of opioid-related adverse events in this population. METHODS: This retrospective cohort study between 1999 and 2014 included Tennessee Medicaid children and adolescents aged 2 to 17 without major chronic diseases, prolonged hospitalization, institutional residence, or evidence of a substance use disorder. We estimated the annual prevalence of outpatient opioid prescriptions and incidence of opioid-related adverse events, defined as an emergency department visit, hospitalization, or death related to an opioid adverse effect. RESULTS: There were 1 362 503 outpatient opioid prescriptions; the annual mean prevalence of opioid prescriptions was 15.0%. The most common opioid indications were dental procedures (31.1% prescriptions), outpatient procedure and/or surgery (25.1%), trauma (18.1%), and infections (16.5%). There were 437 cases of opioid-related adverse events confirmed by medical record review; 88.6% were related to the child's prescription and 71.2% had no recorded evidence of deviation from the prescribed regimen. The cumulative incidence of opioid-related adverse events was 38.3 of 100 000 prescriptions. Adverse events increased with age (incidence rate ratio = 2.22; 95% confidence interval, 1.67-2.96; 12-17 vs 2-5 years of age) and higher opioid doses (incidence rate ratio = 1.86 [1.45-2.39]; upper versus lower dose tertiles). CONCLUSIONS: Children without severe conditions enrolled in Tennessee Medicaid frequently filled outpatient opioid prescriptions for acute, self-limited conditions. One of every 2611 study opioid prescriptions was followed by an opioid-related adverse event (71.2% of which were related to therapeutic use of the prescribed opioid). PMID- 30012560 TI - A Hippo Pathway-Related GCK Controls Both Sexual and Vegetative Developmental Processes in the Fungus Sordaria macrospora. AB - The supramolecular striatin-interacting phosphatases and kinases (STRIPAK) complex is conserved from yeast to human, and regulates a variety of key biological processes. In animals, this complex consists of the scaffold protein striatin, the protein phosphatase 2A, and kinases, such as germinal center kinase (GCK) III and GCKIV family members, as well as other associated proteins. The STRIPAK complex was identified as a negative regulator of the Hippo pathway, a large eukaryotic signaling network with a core composed of a GCK and a nuclear Dbf2-related kinase. The signaling architecture of the Hippo core resembles the fungal septation initiation network (SIN) that regulates cytokinesis in fission yeast as well as septation in filamentous fungi. In the filamentous model fungus Sordaria macrospora, core components of the STRIPAK complex have been functionally described and the striatin homolog PRO11 has been shown to interact with the GCK SmKIN3. However, the exact role of SmKIN3 in fungal development has not yet been fully elucidated. Here, we provide comprehensive genetic and functional analysis of SmKIN3 from S. macrospora Using deletion mutants and site directed mutagenesis, along with phenotypic and phylogenetic analysis, we provide compelling evidence that SmKIN3 is involved in fruiting body formation, hyphal fusion, and septation. Strains carrying the ATP-binding mutant SmKIN3K39R, as well as a double-deletion strain lacking SmKIN3 and the core STRIPAK subunit PRO11, also revealed severe developmental defects. Collectively, this study suggests that SmKIN3 links both the SIN and STRIPAK complex, thereby regulating multiple key cellular processes. PMID- 30012563 TI - Phase I Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer. AB - Purpose: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20 lyase (lyase) and androgen receptor (AR) inhibitor with antitumor activity in vitro and in vivo This open-label phase I clinical study evaluated the safety, tolerability, pharmacokinetics and activity of once-daily seviteronel in male chemotherapy-naive subjects with castration-resistant prostate cancer (CRPC).Patients and Methods: Seviteronel was administered at 600 mg once daily with dose titration (DT) and in modified 3 + 3 dose escalation once-daily cohorts at 600, 750, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability, and the MTD of seviteronel in chemotherapy-naive subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA), and enzalutamide. Secondary objectives were to assess pharmacokinetics, PSA, tumor response, and endocrine results.Results: Twenty-one subjects were enrolled. No dose-limiting toxicities (DLT) were observed through 750 mg once daily. Most treatment-emergent adverse events (AE) reported at grade 1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), blurred vision (38%), and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption.Conclusions: Once-daily seviteronel was generally well tolerated in this phase I study of men with CRPC, a majority of which had progressed on prior AA or enzalutamide, or both. Of the doses evaluated, 600 mg once daily was chosen as the recommended phase II dose for future studies in subjects with CRPC. Clin Cancer Res; 24(21); 5225-32. (c)2018 AACR. PMID- 30012562 TI - IFNL4-DeltaG Allele Is Associated with an Interferon Signature in Tumors and Survival of African-American Men with Prostate Cancer. AB - Purpose: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American (AA) patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the IFNlambda4 (IFNL4) gene.Experimental Design: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses. We also overexpressed IFNL4 in human prostate cancer cells.Results: We found that a distinct interferon (IFN) signature that is analogous to the previously described "IFN-related DNA damage resistance signature" (IRDS) occurs in prostate tumors. Evaluation of two independent patient cohorts revealed that IRDS is detected about twice as often in prostate tumors of AA than European-American men. Furthermore, analysis in TCGA showed an association of increased IRDS in prostate tumors with decreased disease-free survival. To explain these observations, we assessed whether IRDS is associated with an IFNL4 germline variant (rs368234815 DeltaG) that controls production of IFNlambda4, a type III IFN, and is most common in individuals of African ancestry. We show that the IFNL4 rs368234815 DeltaG allele was significantly associated with IRDS in prostate tumors and overall survival of AA patients. Moreover, IFNL4 overexpression induced IRDS in three human prostate cancer cell lines.Conclusions: Our study links a germline variant that controls production of IFNlambda4 to the occurrence of a clinically relevant IFN signature in prostate tumors that may predominantly affect men of African ancestry. Clin Cancer Res; 24(21); 5471-81. (c)2018 AACR. PMID- 30012561 TI - A Genome-Wide Screen Reveals a Role for the HIR Histone Chaperone Complex in Preventing Mislocalization of Budding Yeast CENP-A. AB - Centromeric localization of the evolutionarily conserved centromere-specific histone H3 variant CENP-A (Cse4 in yeast) is essential for faithful chromosome segregation. Overexpression and mislocalization of CENP-A lead to chromosome segregation defects in yeast, flies, and human cells. Overexpression of CENP-A has been observed in human cancers; however, the molecular mechanisms preventing CENP-A mislocalization are not fully understood. Here, we used a genome-wide synthetic genetic array (SGA) to identify gene deletions that exhibit synthetic dosage lethality (SDL) when Cse4 is overexpressed. Deletion for genes encoding the replication-independent histone chaperone HIR complex (HIR1, HIR2, HIR3, HPC2) and a Cse4-specific E3 ubiquitin ligase, PSH1, showed highest SDL. We defined a role for Hir2 in proteolysis of Cse4 that prevents mislocalization of Cse4 to noncentromeric regions for genome stability. Hir2 interacts with Cse4 in vivo, and hir2? strains exhibit defects in Cse4 proteolysis and stabilization of chromatin-bound Cse4 Mislocalization of Cse4 to noncentromeric regions with a preferential enrichment at promoter regions was observed in hir2? strains. We determined that Hir2 facilitates the interaction of Cse4 with Psh1, and that defects in Psh1-mediated proteolysis contribute to increased Cse4 stability and mislocalization of Cse4 in the hir2? strain. In summary, our genome-wide screen provides insights into pathways that regulate proteolysis of Cse4 and defines a novel role for the HIR complex in preventing mislocalization of Cse4 by facilitating proteolysis of Cse4, thereby promoting genome stability. PMID- 30012565 TI - Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance. AB - Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients.Experimental Design: A total of 115 AGC patients, including 56 of histopathologic HER2+ (hHER2+) subjects who received first-line HER2 targeted therapy plus chemotherapy, and 59 of hHER2- patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy.Results: A fluctuated positive HER2 phenotype on CTCs (cHER2+) was revealed, showing cHER2+ at different time intervals during treatment. Acquisition of the cHER2+ phenotype in 91.0% of hHER2+ and 76.2% hHER2- patients was demonstrated to correlate with development of resistance to trastuzumab targeted therapy for hHER2+ patients and chemotherapy alone for hHER2- patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2+ phenotype, which provides a growth advantage to HER2+ CTCs against therapeutic pressure, leading to the development of therapeutic resistance.Conclusions: Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2+ on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. Clin Cancer Res; 24(21); 5261-71. (c)2018 AACR. PMID- 30012564 TI - Activating Transcription Factor 4 Modulates TGFbeta-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling. AB - Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFbeta1. ATF4 is overexpressed in patients with triple negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFbeta and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature.Experimental Design: Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFbeta and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX).Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD dependent crosstalk between ATF4 and TGFbeta was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFbeta/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer.Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697-709. (c)2018 AACR. PMID- 30012566 TI - The Splicing Factor PTBP1 Promotes Expression of Oncogenic Splice Variants and Predicts Poor Prognosis in Patients with Non-muscle-Invasive Bladder Cancer. AB - Purpose: Non-muscle-invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e., PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in patients with NMIBC.Experimental Design: A cohort of 152 patients presenting with primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by IHC, and the results were correlated with clinical data using Kaplan-Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer-related genes was investigated in cancer cell lines and in patients' specimens.Results: Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in patients with NMIBC. Interestingly, downregulation of PTBP1 in bladder cancer cell lines affected prosurvival features. Accordingly, PTBP1 modulated AS of bladder cancer-related genes in cell lines and patient's specimens.Conclusions: PTBP1 expression correlates with disease progression, poor prognosis, and worse survival in patients with NMIBC. Downregulation of PTBP1 expression affects prosurvival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as an outcome predictor in this disease. Clin Cancer Res; 24(21); 5422-32. (c)2018 AACR. PMID- 30012567 TI - Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration. AB - Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.Results: Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. Clin Cancer Res; 24(22); 5622-34. (c)2018 AACR. PMID- 30012569 TI - DI-tector: defective interfering viral genomes' detector for next-generation sequencing data. AB - Defective interfering (DI) genomes, or defective viral genomes (DVGs), are truncated viral genomes generated during replication of most viruses, including live viral vaccines. Among these, "panhandle" or copy-back (cb) and "hairpin" or snap-back (sb) DI genomes are generated during RNA virus replication. 5' cb/sb DI genomes are highly relevant for viral pathogenesis since they harbor immunostimulatory properties that increase virus recognition by the innate immune system of the host. We have developed DI-tector, a user-friendly and freely available program that identifies and characterizes cb/sb genomes from next generation sequencing (NGS) data. DI-tector confirmed the presence of 5' cb genomes in cells infected with measles virus (MV). DI-tector also identified a novel 5' cb genome, as well as a variety of 3' cb/sb genomes whose existence had not previously been detected by conventional approaches in MV-infected cells. The presence of these novel cb/sb genomes was confirmed by RT-qPCR and RT-PCR, validating the ability of DI-tector to reveal the landscape of DI genome population in infected cell samples. Performance assessment using different experimental and simulated data sets revealed the robust specificity and sensitivity of DI-tector. We propose DI-tector as a universal tool for the unbiased detection of DI viral genomes, including 5' cb/sb DI genomes, in NGS data. PMID- 30012568 TI - Increasing the length of poly-pyrimidine bulges broadens RNA conformational ensembles with minimal impact on stacking energetics. AB - Helical elements separated by bulges frequently undergo transitions between unstacked and coaxially stacked conformations during the folding and function of noncoding RNAs. Here, we examine the dynamic properties of poly-pyrimidine bulges of varying length (n = 1-4, 7) across a range of Mg2+ concentrations using HIV-1 TAR RNA as a model system and solution NMR spectroscopy. In the absence of Mg2+, helices linked by bulges with n >= 3 residues adopt predominantly unstacked conformations (stacked population <15%), whereas one-bulge and two-bulge motifs adopt predominantly stacked conformations (stacked population >74%). In the presence of 3 mM Mg2+, the helices predominantly coaxially stack (stacked population >84%), regardless of bulge length, and the midpoint for the Mg2+ dependent stacking transition is within threefold regardless of bulge length. In the absence of Mg2+, the difference between free energy of interhelical coaxial stacking across the bulge variants is estimated to be ~2.9 kcal/mol, based on an NMR chemical shift mapping with stacking being more energetically disfavored for the longer bulges. This difference decreases to ~0.4 kcal/mol in the presence of Mg2+ NMR RDCs and resonance intensity data show increased dynamics in the stacked state with increasing bulge length in the presence of Mg2+ We propose that Mg2+ helps to neutralize the growing electrostatic repulsion in the stacked state with increasing bulge length thereby increasing the number of coaxial conformations that are sampled. Energetically compensated interhelical stacking dynamics may help to maximize the conformational adaptability of RNA and allow a wide range of conformations to be optimally stabilized by proteins and ligands. PMID- 30012572 TI - Erratum. PMID- 30012570 TI - Nano LC-MS using capillary columns enables accurate quantification of modified ribonucleosides at low femtomol levels. AB - Post-transcriptional chemical modifications of (t)RNA molecules are crucial in fundamental biological processes, such as translation. Despite their biological importance and accumulating evidence linking them to various human diseases, technical challenges have limited their detection and accurate quantification. Here, we present a sensitive capillary nanoflow liquid chromatography mass spectrometry (nLC-MS) pipeline for quantitative high-resolution analysis of ribonucleoside modifications from complex biological samples. We evaluated two porous graphitic carbon (PGC) materials and one end-capped C18 reference material as stationary phases for reversed-phase separation. We found that these matrices have complementing retention and separation characteristics, including the capability to separate structural isomers. PGC and C18 matrices yielded excellent signal-to-noise ratios in nLC-MS while differing in the separation capability and sensitivity for various nucleosides. This emphasizes the need for tailored LC-MS setups for optimally detecting as many nucleoside modifications as possible. Detection ranges spanning up to six orders of magnitude enable the analysis of individual ribonucleosides down to femtomol concentrations. Furthermore, normalizing the obtained signal intensities to a stable isotope labeled spike-in enabled direct comparison of ribonucleoside levels between different samples. In conclusion, capillary columns coupled to nLC-MS constitute a powerful and sensitive tool for quantitative analysis of modified ribonucleosides in complex biological samples. This setup will be invaluable for further unraveling the intriguing and multifaceted biological roles of RNA modifications. PMID- 30012573 TI - Revisiting the therapeutic time window dogma: successful thrombectomy 6 days after stroke onset. AB - Stroke is the leading cause of serious long-term disability in the USA. Recent clinical trials, DAWN and DEFUSE 3, have expanded the endovascular therapeutic time window which has been adopted by the American Heart Association stroke guideline. However, there continues to be a dilemma as to what is the best approach for patients who present beyond the time window set by these trials and the current guideline. The interval from arterial occlusion to completion of brain tissue infarction varies from patient to patient and depends on the actual time and also a physiological clock or a tissue time window. Offering endovascular treatment based solely on a rigid time criterion excludes patients who may have a clinical benefit because of potentially salvageable tissue. We present a case of a patient who underwent successful stroke thrombectomy 6 days after stroke onset. PMID- 30012574 TI - Diagnosis of human bovine tuberculosis aided by PET/CT scanning and EBUS-TBNA. AB - Human bovine tuberculosis is a rare zoonotic infection in developed countries which has been achieved predominantly by effective eradication programmes in cattle. The principal modes of transmission are consumption of unpasteurised dairy products and close contact with infected cattle. The clinical and radiological presentation is indistinguishable from tuberculosis caused by Mycobacterium tuberculosis The diagnosis should be considered in individuals with relevant risk factors who present with intra/extrathoracic pathology. We describe and discuss a case of bovine tuberculosis with a synchronous primary bronchus carcinoma in an immunocompetent individual who presented with a solitary pulmonary nodule and contralateral mediastinal lymphadenopathy on CT imaging. The diagnosis of M. bovis infectionwas aided by 18F-fluorodeoxyglucose positron emission tomography/CT imaging and endobronchial ultrasound-guided mediastinal lymph node sampling. PMID- 30012575 TI - Chirping and asymmetric jamming avoidance responses in the electric fish Distocyclus conirostris. AB - Electrosensory systems of weakly electric fish must accommodate competing demands of sensing the environment (electrolocation) and receiving social information (electrocommunication). The jamming avoidance response (JAR) is a behavioral strategy thought to reduce electrosensory interference from conspecific signals close in frequency. We used playback experiments to characterize electric organ discharge frequency (EODf), chirping behavior and the JAR of Distocyclus conirostris, a gregarious electric fish species. EODs of D. conirostris had low frequencies (~80-200 Hz) that shifted in response to playback stimuli. Fish consistently lowered EODf in response to higher-frequency stimuli but inconsistently raised or lowered EODf in response to lower-frequency stimuli. This led to jamming avoidance or anti-jamming avoidance, respectively. We compare these behaviors with those of closely related electric fish (Eigenmannia and Sternopygus) and suggest that the JAR may have additional social functions and may not solely minimize the deleterious effects of jamming, as its name suggests. PMID- 30012576 TI - Cardiorespiratory interactions in the Pacific spiny dogfish, Squalus suckleyi. AB - Elasmobranchs are a group of cartilaginous fish with no direct sympathetic innervation of the heart or gills. Fast cardiorespiratory regulation is controlled solely by the parasympathetic branch of the autonomic nervous system. Cardiovascular changes associated with ventilation are commonly present in the form of respiratory sinus arrhythmia (RSA) and as cardiorespiratory synchrony (CRS, in which there is a 1:1 beat to breath ratio). The latter has been hypothesized to maximize oxygen uptake, coupling the pulsatile flows of blood and water in the gills. Given this, we hypothesized that CRS should be more prevalent in situations of low oxygen supply and RSA should be abolished by vagotomy. To test this, we investigated the role of the vagus nerve in mediating cardiorespiratory responses to changing environmental oxygen conditions in the elasmobranch Squalus suckleyi Hypoxia and hyperoxia had little effect on heart rate but did alter breathing frequency and amplitude. Atropine yielded an overall tachycardia in all oxygen conditions and abolished all heart rate variability (HRV), suggesting that HRV solely reflects fluctuating vagal tonus on the heart. Regardless of the presence of atropine, hypoxia still induced an increase in ventilation rate and depth. CRS was only found during progressive hyperoxia post atropine, when heart rate was uninhibited and ventilation was slowed owing to the increase in oxygen supply, suggesting that in S. suckleyi, CRS is an epiphenomenon and not actively regulated to maximize gas exchange efficiency. PMID- 30012571 TI - Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population. AB - Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84*10-23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72*10-25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82*10-9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09*10-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01*10-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS. PMID- 30012577 TI - Automated measurement of upper thermal limits in small aquatic animals. AB - We present a method for automating the measurement of upper thermal limits in small aquatic organisms. Upper thermal limits are frequently defined by the cessation of movement at high temperature, with measurement being performed by manual observation. Consequently, estimates of upper thermal limits may be subject to error and bias, both within and among observers. Our method utilises video-based tracking software to record the movement of individuals when exposed to high, lethal temperatures. We develop an algorithm in the R computing language that can objectively identify the loss of locomotory function from tracking data. Using independent experimental data, we validate our approach by demonstrating the expected response in upper thermal limits to acclimation temperature. PMID- 30012578 TI - Research for health in the Americas. PMID- 30012582 TI - Jury awards $4.7bn damages against Johnson & Johnson in talcum cancer case. PMID- 30012579 TI - LETM1 couples mitochondrial DNA metabolism and nutrient preference. AB - The diverse clinical phenotypes of Wolf-Hirschhorn syndrome (WHS) are the result of haploinsufficiency of several genes, one of which, LETM1, encodes a protein of the mitochondrial inner membrane of uncertain function. Here, we show that LETM1 is associated with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates the activity of an ancillary metabolic enzyme, pyruvate dehydrogenase. LETM1 deficiency in WHS alters mitochondrial morphology and DNA organization, as does substituting ketone bodies for glucose in control cells. While this change in nutrient availability leads to the death of fibroblasts with normal amounts of LETM1, WHS-derived fibroblasts survive on ketone bodies, which can be attributed to their reduced dependence on glucose oxidation. Thus, remodeling of mitochondrial nucleoprotein complexes results from the inability of mitochondria to use specific substrates for energy production and is indicative of mitochondrial dysfunction. However, the dysfunction could be mitigated by a modified diet-for WHS, one high in lipids and low in carbohydrates. PMID- 30012581 TI - mitoTev-TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels. AB - Pathogenic mitochondrial DNA (mtDNA) mutations often co-exist with wild-type molecules (mtDNA heteroplasmy). Phenotypes manifest when the percentage of mutant mtDNA is high (70-90%). Previously, our laboratory showed that mitochondria targeted transcription activator-like effector nucleases (mitoTALENs) can eliminate mutant mtDNA from heteroplasmic cells. However, mitoTALENs are dimeric and relatively large, making it difficult to package their coding genes into viral vectors, limiting their clinical application. The smaller monomeric GIY-YIG homing nuclease from T4 phage (I-TevI) provides a potential alternative. We tested whether molecular hybrids (mitoTev-TALEs) could specifically bind and cleave mtDNA of patient-derived cybrids harboring different levels of the m.8344A>G mtDNA point mutation, associated with myoclonic epilepsy with ragged red fibers (MERRF). We tested two mitoTev-TALE designs, one of which robustly shifted the mtDNA ratio toward the wild type. When this mitoTev-TALE was tested in a clone with high levels of the MERRF mutation (91% mutant), the shift in heteroplasmy resulted in an improvement of oxidative phosphorylation function. mitoTev-TALE provides an effective architecture for mtDNA editing that could facilitate therapeutic delivery of mtDNA editing enzymes to affected tissues. PMID- 30012583 TI - The Conorfamide RPRFa Stabilizes the Open Conformation of Acid-Sensing Ion Channel 3 via the Nonproton Ligand-Sensing Domain. AB - Acid-sensing ion channel 3 (ASIC3) is a proton-gated Na+ channel with important roles in pain. ASIC3 quickly desensitizes in less than a second, limiting its capacity to sense sustained acidosis during pain. RFamide neuropeptides are modulators of ASIC3 that slow its desensitization and induce a variable sustained current. The molecular mechanism of slowed desensitization and the RFamide binding site on ASIC3 are unknown. RPRFamide, a RFamide from the venom of a cone snail, has a comparatively high affinity for ASIC3 and strongly slows its desensitization. Here we show that covalent binding of a UV-sensitive RPRFamide variant to ASIC3 prevents desensitization, suggesting that RPRFamide has to unbind from ASIC3 before it can desensitize. Moreover, we show by in silico docking to a homology model of ASIC3 that a cavity in the lower palm domain, which is also known as the nonproton ligand-sensing domain, is a potential binding site of RPRFamide. Finally, using extensive mutagenesis of residues lining the nonproton ligand-sensing domain, we confirm that this domain is essential for RPRFamide modulation of ASIC3. As comparative analysis of ASIC crystal structures in the open and in the desensitized conformation suggests that the lower palm domain contracts during desensitization, our results collectively suggest that RPRFamide, and probably also other RFamide neuropeptides, bind to the nonproton ligand-sensing domain to stabilize the open conformation of ASIC3. PMID- 30012580 TI - A versatile drug delivery system targeting senescent cells. AB - Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal beta-galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galacto-oligosaccharides. We show that gal-encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy-induced senescence, gal-encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib. Moreover, in a model of pulmonary fibrosis in mice, gal-encapsulated cytotoxics target senescent cells, reducing collagen deposition and restoring pulmonary function. Finally, gal-encapsulation reduces the toxic side effects of the cytotoxic drugs. Drug delivery into senescent cells opens new diagnostic and therapeutic applications for senescence-associated disorders. PMID- 30012584 TI - Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy. AB - Metformin, an oral antihyperglycemic, is increasingly being prescribed to pregnant women with gestational diabetes. Metformin is a hydrophilic cation and relies on organic cation transporters to move across cell membranes. We previously demonstrated that human and mouse placentas predominantly express organic cation transporter 3 (OCT3), but the impact of this transporter on maternal and fetal disposition of metformin is unknown. Using immunofluorescence colocalization studies in term human placenta, we showed that OCT3 is localized to the basal (fetal-facing) membrane of syncytiotrophoblast cells with no expression on the apical (maternal-facing) membrane. OCT3 positive staining was also observed in fetal capillaries. To determine the in vivo role of OCT3 in maternal and fetal disposition of metformin, we determined metformin maternal pharmacokinetics and overall fetal exposure in wild-type and Oct3-null pregnant mice. After oral dosing of [14C]metformin at gestational day 19, the systemic drug exposure (AUC0-infinity) in maternal plasma was slightly reduced by ~16% in the Oct3-/- pregnant mice. In contrast, overall fetal AUC0-infinity was reduced by 47% in the Oct3-/- pregnant mice. Consistent with our previous findings in nonpregnant mice, metformin tissue distribution was respectively reduced by 70% and 52% in the salivary glands and heart in Oct3-/- pregnant mice. Our in vivo data in mice clearly demonstrated a significant role of Oct3 in facilitating metformin fetal distribution and exposure during pregnancy. Modulation of placental OCT3 expression or activity by gestational age, genetic polymorphism, or pharmacological inhibitors may alter fetal exposure to metformin or other drugs transported by OCT3. PMID- 30012585 TI - TNP-470 skews DC differentiation to Th1-stimulatory phenotypes and can serve as a novel adjuvant in a cancer vaccine. AB - Fumagillin is an antiangiogenic and antineoplastic fungal natural product, and TNP-470 is one of its most potent analogs. Decades of studies revealed that TNP 470 has potent anticancer activities via destruction of neovasculature. In stark contrast, TNP-470 has been reported to suppress lymphocyte proliferation, thereby limiting its clinical potentials. In an attempt to investigate whether the similar or opposite immunomodulatory effect of TNP-470 could act on myeloid cells, we found that TNP-470 potentiates the immunogenicity of dendritic cells (DCs) toward a phenotype with T helper cell type 1 (Th1)-stimulatory features. Using DC vaccine on a murine melanoma cancer model, the TNP-470-treated DC vaccine could significantly induce tumor-specific immunogenicity and substantially enhance tumor eradication when compared with vehicle-treated DC vaccine in a prophylactic setting. Enhanced tumor-specific immunogenicity and delayed tumor progression were observed in a therapeutic setting upon the TNP-470 treated DC vaccine. Our data showed that TNP-470 potentiates Toll-like receptor signaling, including NF-kappaB activation, in DCs to transcriptionally activate interleukin-12 production, thus inducing a Th1-immune response. Our current study uncovers a novel immune function of TNP-470 in DCs and redefines its role as a novel class of small molecule immune adjuvant in DC-based cancer vaccine given potentiation of DC immunogenicity is a major roadblock in DC vaccine development. Our study not only provides a novel adjuvant for ex vivo-cultured patient specific DC vaccines for cancer treatment but also discovers the distinct immunostimulatory function of TNP-470 in DCs of myeloid lineage that differs from its immunosuppressive function in lymphoid cells. PMID- 30012586 TI - ALK7 expression in prolactinoma is associated with reduced prolactin and increased proliferation. AB - Prolactinoma represents the most frequent hormone-secreting pituitary tumours. These tumours appear in a benign form, but some of them can reach an invasive and aggressive stage through an unknown mechanism. Discovering markers to identify prolactinoma proliferative and invading character is therefore crucial to develop new diagnostic/prognostic strategies. Interestingly, members of the TGFbeta Activin/BMP signalling pathways have emerged as important actors of pituitary development and adult function, but their role in prolactinomas remains to be precisely determined. Here, using a heterotopic allograft model derived from a rat prolactinoma, we report that the Activins orphan type I receptor ALK7 is ectopically expressed in prolactinomas-cells. Through immunohistological approaches, we further confirm that normal prolactin-producing cells lack ALK7 expression. Using a series of human tumour samples, we show that ALK7 expression in prolactinomas cells is evolutionary conserved between rat and human. More interestingly, our results highlight that tumours showing a robust expression of ALK7 present an increased proliferation as address by Ki67 expression and retrospective analysis of clinical data from 38 patients, presenting ALK7 as an appealing marker of prolactinoma aggressiveness. Beside this observation, our work pinpoints that the expression of prolactin is highly heterogeneous in prolactinoma cells. We further confirm the contribution of ALK7 in these observations and the existence of highly immunoreactive prolactin cells lacking ALK7 expression. Taken together, our observations suggest that Activin signalling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas. PMID- 30012587 TI - Penetrance of phaeochromocytoma in RET G533C carriers differs between South America and Europe. PMID- 30012588 TI - Correction for Fregel et al., Ancient genomes from North Africa evidence prehistoric migrations to the Maghreb from both the Levant and Europe. PMID- 30012590 TI - Species diversity concurrently dilutes and amplifies transmission in a zoonotic host-pathogen system through competing mechanisms. AB - In this era of unprecedented biodiversity loss and increased zoonotic disease emergence, it is imperative to understand the effects of biodiversity on zoonotic pathogen dynamics in wildlife. Whether increasing biodiversity should lead to a decrease or increase in infection prevalence, termed the dilution and amplification effects, respectively, has been hotly debated in disease ecology. Sin Nombre hantavirus, which has an ~35% mortality rate when it spills over into humans, occurs at a lower prevalence in the reservoir host, the North American deermouse, in areas with higher small mammal diversity-a dilution effect. However, the mechanism driving this relationship is not understood. Using a mechanistic mathematical model of infection dynamics and a unique long-term, high resolution, multisite dataset, it appears that the observed dilution effect is a result of increasing small-mammal diversity leading to decreased deermouse population density and, subsequently, prevalence (a result of density-dependent transmission). However, once density is taken into account, there is an increase in the transmission rate at sites with higher diversity-a component amplification effect. Therefore, dilution and amplification are occurring at the same time in the same host-pathogen system; there is a component amplification effect (increase in transmission rate), but overall a net dilution because the effect of diversity on reservoir host population density is stronger. These results suggest we should focus on how biodiversity affects individual mechanisms that drive prevalence and their relative strengths if we want to make generalizable predictions across host-pathogen systems. PMID- 30012589 TI - Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure. AB - Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3',5'-monophosphate (cGMP) signaling, underpinned, in part, by up regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1alpha (GC-1alpha-/-) or natriuretic peptide-responsive GC-A (GC-A-/-), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A-/- mice but is absent in animals null for GC-1alpha or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy. PMID- 30012591 TI - Wafer-recyclable, environment-friendly transfer printing for large-scale thin film nanoelectronics. AB - Transfer printing of thin-film nanoelectronics from their fabrication wafer commonly requires chemical etching on the sacrifice of wafer but is also limited by defects with a low yield. Here, we introduce a wafer-recyclable, environment friendly transfer printing process that enables the wafer-scale separation of high-performance thin-film nanoelectronics from their fabrication wafer in a defect-free manner that enables multiple reuses of the wafer. The interfacial delamination is enabled through a controllable cracking phenomenon in a water environment at room temperature. The physically liberated thin-film nanoelectronics can be then pasted onto arbitrary places of interest, thereby endowing the particular surface with desirable add-on electronic features. Systematic experimental, theoretical, and computational studies reveal the underlying mechanics mechanism and guide manufacturability for the transfer printing process in terms of scalability, controllability, and reproducibility. PMID- 30012593 TI - Robert W. Kates (1929-2018): Grappled with problems of the human environment. PMID- 30012592 TI - Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth. AB - The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells. PMID- 30012594 TI - Essential nucleotide- and protein-dependent functions of Actb/beta-actin. AB - The highly similar cytoplasmic beta- and gamma-actins differ by only four functionally similar amino acids, yet previous in vitro and in vivo data suggest that they support unique functions due to striking phenotypic differences between Actb and Actg1 null mouse and cell models. To determine whether the four amino acid variances were responsible for the functional differences between cytoplasmic actins, we gene edited the endogenous mouse Actb locus to translate gamma-actin protein. The resulting mice and primary embryonic fibroblasts completely lacked beta-actin protein, but were viable and did not present with the most overt and severe cell and organismal phenotypes observed with gene knockout. Nonetheless, the edited mice exhibited progressive high-frequency hearing loss and degeneration of actin-based stereocilia as previously reported for hair cell-specific Actb knockout mice. Thus, beta-actin protein is not required for general cellular functions, but is necessary to maintain auditory stereocilia. PMID- 30012595 TI - Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice. AB - Rett syndrome (RTT) is a genetic disorder resulting from a loss-of-function mutation in one copy of the X-linked gene methyl-CpG-binding protein 2 (MECP2). Typical RTT patients are females and, due to random X chromosome inactivation (XCI), ~50% of cells express mutant MECP2 and the other ~50% express wild-type MECP2. Cells expressing mutant MECP2 retain a wild-type copy of MECP2 on the inactive X chromosome (Xi), the reactivation of which represents a potential therapeutic approach for RTT. Previous studies have demonstrated reactivation of Xi-linked MECP2 in cultured cells by biological or pharmacological inhibition of factors that promote XCI (called "XCI factors" or "XCIFs"). Whether XCIF inhibitors in living animals can reactivate Xi-linked MECP2 in cerebral cortical neurons, the cell type most therapeutically relevant to RTT, remains to be determined. Here, we show that pharmacological inhibitors targeting XCIFs in the PI3K/AKT and bone morphogenetic protein signaling pathways reactivate Xi-linked MECP2 in cultured mouse fibroblasts and human induced pluripotent stem cell derived postmitotic RTT neurons. Notably, reactivation of Xi-linked MECP2 corrects characteristic defects of human RTT neurons including reduced soma size and branch points. Most importantly, we show that intracerebroventricular injection of the XCIF inhibitors reactivates Xi-linked Mecp2 in cerebral cortical neurons of adult living mice. In support of these pharmacological results, we also demonstrate genetic reactivation of Xi-linked Mecp2 in cerebral cortical neurons of living mice bearing a homozygous XCIF deletion. Collectively, our results further establish the feasibility of pharmacological reactivation of Xi linked MECP2 as a therapeutic approach for RTT. PMID- 30012596 TI - Molecular switch-like regulation enables global subunit coordination in a viral ring ATPase. AB - Subunits in multimeric ring-shaped motors must coordinate their activities to ensure correct and efficient performance of their mechanical tasks. Here, we study WT and arginine finger mutants of the pentameric bacteriophage phi29 DNA packaging motor. Our results reveal the molecular interactions necessary for the coordination of ADP-ATP exchange and ATP hydrolysis of the motor's biphasic mechanochemical cycle. We show that two distinct regulatory mechanisms determine this coordination. In the first mechanism, the DNA up-regulates a single subunit's catalytic activity, transforming it into a global regulator that initiates the nucleotide exchange phase and the hydrolysis phase. In the second, an arginine finger in each subunit promotes ADP-ATP exchange and ATP hydrolysis of its neighbor. Accordingly, we suggest that the subunits perform the roles described for GDP exchange factors and GTPase-activating proteins observed in small GTPases. We propose that these mechanisms are fundamental to intersubunit coordination and are likely present in other ring ATPases. PMID- 30012597 TI - Schwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUN. AB - Schwann cells (SCs), the glia of the peripheral nervous system, play an essential role in nerve regeneration. Upon nerve injury, SCs are reprogrammed into unique "repair SCs," and these cells remove degenerating axons/myelin debris, promote axonal regrowth, and ultimately remyelinate regenerating axons. The AP-1 transcription factor JUN is promptly induced in SCs upon nerve injury and potently mediates this injury-induced SC plasticity; however, the regulation of these JUN-dependent SC injury responses is unclear. Previously, we produced mice with a SC-specific deletion of O-GlcNAc transferase (OGT). This enzyme catalyzes O-GlcNAcylation, a posttranslational modification that is influenced by the cellular metabolic state. Mice lacking OGT in SCs develop a progressive demyelinating peripheral neuropathy. Here, we investigated the nerve repair process in OGT-SCKO mutant mice and found that the remyelination of regenerating axons is severely impaired. Gene expression profiling of OGT-SCKO SCs revealed that the JUN-dependent SC injury program was elevated in the absence of injury and failed to shut down at the appropriate time after injury. This aberrant JUN activity results in abnormalities in repair SC function and redifferentiation and prevents the timely remyelination. This aberrant nerve injury response is normalized in OGT-SCKO mice with reduced Jun gene dosage in SCs. Mechanistically, OGT O-GlcNAcylates JUN at multiple sites, which then leads to an attenuation of AP-1 transcriptional activity. Together, these results highlight the metabolic oversight of the nerve injury response via the regulation of JUN activity by O GlcNAcylation, a pathway that could be important in the neuropathy associated with diabetes and aging. PMID- 30012598 TI - The impact of environmental change on the use of early pottery by East Asian hunter-gatherers. AB - The invention of pottery was a fundamental technological advancement with far reaching economic and cultural consequences. Pottery containers first emerged in East Asia during the Late Pleistocene in a wide range of environmental settings, but became particularly prominent and much more widely dispersed after climatic warming at the start of the Holocene. Some archaeologists argue that this increasing usage was driven by environmental factors, as warmer climates would have generated a wider range of terrestrial plant and animal resources that required processing in pottery. However, this hypothesis has never been directly tested. Here, in one of the largest studies of its kind, we conducted organic residue analysis of >800 pottery vessels selected from 46 Late Pleistocene and Early Holocene sites located across the Japanese archipelago to identify their contents. Our results demonstrate that pottery had a strong association with the processing of aquatic resources, irrespective of the ecological setting. Contrary to expectations, this association remained stable even after the onset of Holocene warming, including in more southerly areas, where expanding forests provided new opportunities for hunting and gathering. Nevertheless, the results indicate that a broader array of aquatic resources was processed in pottery after the start of the Holocene. We suggest this marks a significant change in the role of pottery of hunter-gatherers, corresponding to an increased volume of production, greater variation in forms and sizes, the rise of intensified fishing, the onset of shellfish exploitation, and reduced residential mobility. PMID- 30012599 TI - Data-driven body-machine interface for the accurate control of drones. AB - The accurate teleoperation of robotic devices requires simple, yet intuitive and reliable control interfaces. However, current human-machine interfaces (HMIs) often fail to fulfill these characteristics, leading to systems requiring an intensive practice to reach a sufficient operation expertise. Here, we present a systematic methodology to identify the spontaneous gesture-based interaction strategies of naive individuals with a distant device, and to exploit this information to develop a data-driven body-machine interface (BoMI) to efficiently control this device. We applied this approach to the specific case of drone steering and derived a simple control method relying on upper-body motion. The identified BoMI allowed participants with no prior experience to rapidly master the control of both simulated and real drones, outperforming joystick users, and comparing with the control ability reached by participants using the bird-like flight simulator Birdly. PMID- 30012600 TI - Amygdala lesions eliminate viewing preferences for faces in rhesus monkeys. AB - In free-viewing experiments, primates orient preferentially toward faces and face like stimuli. To investigate the neural basis of this behavior, we measured the spontaneous viewing preferences of monkeys with selective bilateral amygdala lesions. The results revealed that when faces and nonface objects were presented simultaneously, monkeys with amygdala lesions had no viewing preference for either conspecific faces or illusory facial features in everyday objects. Instead of directing eye movements toward socially relevant features in natural images, we found that, after amygdala loss, monkeys are biased toward features with increased low-level salience. We conclude that the amygdala has a role in our earliest specialized response to faces, a behavior thought to be a precursor for efficient social communication and essential for the development of face selective cortex. PMID- 30012601 TI - New molecular switch architectures. AB - In this paper we elaborate on recently developed molecular switch architectures and how these new systems can help with the realization of new functions and advancement of artificial molecular machines. Progress in chemically and photoinduced switches and motors is summarized and contextualized such that the reader may gain an appreciation for the novel tools that have come about in the past decade. Many of these systems offer distinct advantages over commonly employed switches, including improved fidelity, addressability, and robustness. Thus, this paper serves as a jumping-off point for researchers seeking new switching motifs for specific applications, or ones that address the limitations of presently available systems. PMID- 30012602 TI - Aspirin binds to PPARalpha to stimulate hippocampal plasticity and protect memory. AB - Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide. Here we report that peroxisome proliferator-activated receptor alpha (PPARalpha), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed proteomic analyses including cheminformatics, thermal shift assays, and TR-FRET revealed that aspirin, but not other structural homologs, acts as a PPARalpha ligand through direct binding at the Tyr314 residue of the PPARalpha ligand binding domain. On binding to PPARalpha, aspirin stimulated hippocampal plasticity via transcriptional activation of cAMP response element-binding protein (CREB). Finally, hippocampus-dependent behavioral analyses, calcium influx assays in hippocampal slices and quantification of dendritic spines demonstrated that low-dose aspirin treatment improved hippocampal plasticity and memory in FAD5X mice, but not in FAD5X/Ppara-null mice. These findings highlight a property of aspirin: stimulating hippocampal plasticity via direct interaction with PPARalpha. PMID- 30012603 TI - Insights into bacterial lipoprotein trafficking from a structure of LolA bound to the LolC periplasmic domain. AB - In Gram-negative bacteria, outer-membrane lipoproteins are essential for maintaining cellular integrity, transporting nutrients, establishing infections, and promoting the formation of biofilms. The LolCDE ABC transporter, LolA chaperone, and LolB outer-membrane receptor form an essential system for transporting newly matured lipoproteins from the outer leaflet of the cytoplasmic membrane to the innermost leaflet of the outer membrane. Here, we present a crystal structure of LolA in complex with the periplasmic domain of LolC. The structure reveals how a solvent-exposed beta-hairpin loop (termed the "Hook") and trio of surface residues (the "Pad") of LolC are essential for recruiting LolA from the periplasm and priming it to receive lipoproteins. Experiments with purified LolCDE complex demonstrate that association with LolA is independent of nucleotide binding and hydrolysis, and homology models based on the MacB ABC transporter predict that LolA recruitment takes place at a periplasmic site located at least 50 A from the inner membrane. Implications for the mechanism of lipoprotein extraction and transfer are discussed. The LolA-LolC structure provides atomic details on a key protein interaction within the Lol pathway and constitutes a vital step toward the complete molecular understanding of this important system. PMID- 30012606 TI - Theoretical search for heterogeneously architected 2D structures. AB - Architected 2D structures are of growing interest due to their unique mechanical and physical properties for applications in stretchable electronics, controllable phononic/photonic modulators, and switchable optical/electrical devices; however, the underpinning theory of understanding their elastic properties and enabling principles in search of emerging structures with well-defined arrangements and/or bonding connections of assembled elements has yet to be established. Here, we present two theoretical frameworks in mechanics-strain energy-based theory and displacement continuity-based theory-to predict the elastic properties of 2D structures and demonstrate their application in a search for novel architected 2D structures that are composed of heterogeneously arranged, arbitrarily shaped lattice cell structures with regulatory adjacent bonding connections of cells, referred to as heterogeneously architected 2D structures (HASs). By patterning lattice cell structures and tailoring their connections, the elastic properties of HASs can span a very broad range from nearly zero to beyond those of individual lattice cells by orders of magnitude. Interface indices that represent both the pattern arrangements of basic lattice cells and local bonding disconnections in HASs are also proposed and incorporated to intelligently design HASs with on-demand Young's modulus and geometric features. This study offers a theoretical foundation toward future architected structures by design with unprecedented properties and functions. PMID- 30012604 TI - Astrocytes restore connectivity and synchronization in dysfunctional cerebellar networks. AB - Evidence suggests that astrocytes play key roles in structural and functional organization of neuronal circuits. To understand how astrocytes influence the physiopathology of cerebellar circuits, we cultured cells from cerebella of mice that lack the ATM gene. Mutations in ATM are causative of the human cerebellar degenerative disease ataxia-telangiectasia. Cerebellar cultures grown from Atm-/- mice had disrupted network synchronization, atrophied astrocytic arborizations, reduced autophagy levels, and higher numbers of synapses per neuron than wild type cultures. Chimeric circuitries composed of wild-type astrocytes and Atm-/- neurons were indistinguishable from wild-type cultures. Adult cerebellar characterizations confirmed disrupted astrocyte morphology, increased GABAergic synaptic markers, and reduced autophagy in Atm-/- compared with wild-type mice. These results indicate that astrocytes can impact neuronal circuits at levels ranging from synaptic expression to global dynamics. PMID- 30012605 TI - Delineating the role of cooperativity in the design of potent PROTACs for BTK. AB - Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity. PMID- 30012607 TI - Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors. AB - Trait-like differences in cognitive performance after sleep loss put some individuals more at risk than others, the basis of such disparities remaining largely unknown. Similarly, interindividual differences in impairment in response to alcohol intake have been observed. We tested whether performance impairments due to either acute or chronic sleep loss can be predicted by an individual's vulnerability to acute alcohol intake. Also, we used positron emission tomography (PET) to test whether acute alcohol infusion results in an up-regulation of cerebral A1 adenosine receptors (A1ARs), similar to the changes previously observed following sleep deprivation. Sustained attention in the psychomotor vigilance task (PVT) was tested in 49 healthy volunteers (26 +/- 5 SD years; 15 females) (i) under baseline conditions: (ii) after ethanol intake, and after either (iii) total sleep deprivation (TSD; 35 hours awake; n = 35) or (iv) partial sleep deprivation (PSD; four nights with 5 hours scheduled sleep; n = 14). Ethanol- versus placebo-induced changes in cerebral A1AR availability were measured in 10 healthy male volunteers (31 +/- 9 years) with [18F]8-cyclopentyl-3 (3-fluoropropyl)-1-propylxanthine (CPFPX) PET. Highly significant correlations between the performance impairments induced by ethanol and sleep deprivation were found for various PVT parameters, including mean speed (TSD, r = 0.62; PSD, r = 0.84). A1AR availability increased up to 26% in several brain regions with ethanol infusion. Our studies revealed individual trait characteristics for being either vulnerable or resilient to both alcohol and to sleep deprivation. Both interventions induce gradual increases in cerebral A1AR availability, pointing to a potential common molecular response mechanism. PMID- 30012609 TI - Evaporation-induced foam stabilization in lubricating oils. AB - Foaming in liquids is ubiquitous in nature. Whereas the mechanism of foaming in aqueous systems has been thoroughly studied, nonaqueous systems have not enjoyed the same level of examination. Here we study the mechanism of foaming in a widely used class of nonaqueous liquids: lubricant base oils. Using a newly developed experimental technique, we show that the stability of lubricant foams can be evaluated at the level of single bubbles. The results obtained with this single bubble technique indicate that solutocapillary flows are central to lubricant foam stabilization. These solutocapillary flows are shown to originate from the differential evaporation of multicomponent lubricants-an unexpected result given the low volatility of nonaqueous liquids. Further, we show that mixing of some combinations of different lubricant base oils, a common practice in the industry, exacerbates solutocapillary flows and hence leads to increased foaming. PMID- 30012608 TI - Cholesterol promotes Cytolysin A activity by stabilizing the intermediates during pore formation. AB - Pore-forming toxins (PFTs) form nanoscale pores across target membranes causing cell death. Cytolysin A (ClyA) from Escherichia coli is a prototypical alpha helical toxin that contributes to cytolytic phenotype of several pathogenic strains. It is produced as a monomer and, upon membrane exposure, undergoes conformational changes and finally oligomerizes to form a dodecameric pore, thereby causing ion imbalance and finally cell death. However, our current understanding of this assembly process is limited to studies in detergents, which do not capture the physicochemical properties of biological membranes. Here, using single-molecule imaging and molecular dynamics simulations, we study the ClyA assembly pathway on phospholipid bilayers. We report that cholesterol stimulates pore formation, not by enhancing initial ClyA binding to the membrane but by selectively stabilizing a protomer-like conformation. This was mediated by specific interactions by cholesterol-interacting residues in the N-terminal helix. Additionally, cholesterol stabilized the oligomeric structure using bridging interactions in the protomer-protomer interfaces, thereby resulting in enhanced ClyA oligomerization. This dual stabilization of distinct intermediates by cholesterol suggests a possible molecular mechanism by which ClyA achieves selective membrane rupture of eukaryotic cell membranes. Topological similarity to eukaryotic membrane proteins suggests evolution of a bacterial alpha-toxin to adopt eukaryotic motifs for its activation. Broad mechanistic correspondence between pore-forming toxins hints at a wider prevalence of similar protein membrane insertion mechanisms. PMID- 30012611 TI - US particulate matter air quality improves except in wildfire-prone areas. AB - Using data from rural monitoring sites across the contiguous United States, we evaluated fine particulate matter (PM2.5) trends for 1988-2016. We calculate trends in the policy-relevant 98th quantile of PM2.5 using Quantile Regression. We use Kriging and Gaussian Geostatistical Simulations to interpolate trends between observed data points. Overall, we found positive trends in 98th quantile PM2.5 at sites within the Northwest United States (average 0.21 +/- 0.12 ug.m-3.y 1; +/-95% confidence interval). This was in contrast with sites throughout the rest of country, which showed a negative trend in 98th quantile PM2.5, likely due to reductions in anthropogenic emissions (average -0.66 +/- 0.10 ug.m-3.y-1). The positive trend in 98th quantile PM2.5 is due to wildfire activity and was supported by positive trends in total carbon and no trend in sulfate across the Northwest. We also evaluated daily moderate resolution imaging spectroradiometer (MODIS) aerosol optical depth (AOD) for 2002-2017 throughout the United States to compare with ground-based trends. For both Interagency Monitoring of Protected Visual Environments (IMPROVE) PM2.5 and MODIS AOD datasets, we found positive 98th quantile trends in the Northwest (1.77 +/- 0.68% and 2.12 +/- 0.81% per year, respectively) through 2016. The trend in Northwest AOD is even greater if data for the high-fire year of 2017 are included. These results indicate a decrease in PM2.5 over most of the country but a positive trend in the 98th quantile PM2.5 across the Northwest due to wildfires. PMID- 30012610 TI - Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset. AB - The recruitment and evolutionary optimization of promiscuous enzymes is key to the rapid adaptation of organisms to changing environments. Our understanding of the precise mechanisms underlying enzyme repurposing is, however, limited: What are the active-site features that enable the molecular recognition of multiple substrates with contrasting catalytic requirements? To gain insights into the molecular determinants of adaptation in promiscuous enzymes, we performed the laboratory evolution of an arylsulfatase to improve its initially weak phenylphosphonate hydrolase activity. The evolutionary trajectory led to a 100,000-fold enhancement of phenylphosphonate hydrolysis, while the native sulfate and promiscuous phosphate mono- and diester hydrolyses were only marginally affected (<=50-fold). Structural, kinetic, and in silico characterizations of the evolutionary intermediates revealed that two key mutations, T50A and M72V, locally reshaped the active site, improving access to the catalytic machinery for the phosphonate. Measured transition state (TS) charge changes along the trajectory suggest the creation of a new Michaelis complex (E*S, enzyme-substrate), with enhanced leaving group stabilization in the TS for the promiscuous phosphonate (betaleavinggroup from -1.08 to -0.42). Rather than altering the catalytic machinery, evolutionary repurposing was achieved by fine-tuning the molecular recognition of the phosphonate in the Michaelis complex, and by extension, also in the TS. This molecular scenario constitutes a mechanistic alternative to adaptation solely based on enzyme flexibility and conformational selection. Instead, rapid functional transitions between distinct chemical reactions rely on the high reactivity of permissive active-site architectures that allow multiple substrate binding modes. PMID- 30012614 TI - Archaeobotanical evidence reveals the origins of bread 14,400 years ago in northeastern Jordan. AB - The origins of bread have long been associated with the emergence of agriculture and cereal domestication during the Neolithic in southwest Asia. In this study we analyze a total of 24 charred food remains from Shubayqa 1, a Natufian hunter gatherer site located in northeastern Jordan and dated to 14.6-11.6 ka cal BP. Our finds provide empirical data to demonstrate that the preparation and consumption of bread-like products predated the emergence of agriculture by at least 4,000 years. The interdisciplinary analyses indicate the use of some of the "founder crops" of southwest Asian agriculture (e.g., Triticum boeoticum, wild einkorn) and root foods (e.g., Bolboschoenus glaucus, club-rush tubers) to produce flat bread-like products. The available archaeobotanical evidence for the Natufian period indicates that cereal exploitation was not common during this time, and it is most likely that cereal-based meals like bread become staples only when agriculture was firmly established. PMID- 30012613 TI - Suppression of Staphylococcus aureus virulence by a small-molecule compound. AB - Emerging antibiotic resistance among bacterial pathogens has necessitated the development of alternative approaches to combat drug-resistance-associated infection. The abolition of Staphylococcus aureus virulence by targeting multiple virulence gene products represents a promising strategy for exploration. A multiplex promoter reporter platform using gfp-luxABCDE dual-reporter plasmids with selected promoters from S. aureus-virulence-associated genes was used to identify compounds that modulate the expression of virulence factors. One small molecule compound, M21, was identified from a chemical library to reverse virulent S. aureus into its nonvirulent state. M21 is a noncompetitive inhibitor of ClpP and alters alpha-toxin expression in a ClpP-dependent manner. A mouse model of infection indicated that M21 could attenuate S. aureus virulence. This nonantibiotic compound has been shown to suppress the expression of multiple unrelated virulence factors in S. aureus, suggesting that targeting a master regulator of virulence is an effective way to control virulence. Our results illustrate the power of chemical genetics in the modulation of virulence gene expression in pathogenic bacteria. PMID- 30012612 TI - Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome. AB - Once activated at the surface of cells, G protein-coupled receptors (GPCRs) redistribute to endosomes, where they can continue to signal. Whether GPCRs in endosomes generate signals that contribute to human disease is unknown. We evaluated endosomal signaling of protease-activated receptor-2 (PAR2), which has been proposed to mediate pain in patients with irritable bowel syndrome (IBS). Trypsin, elastase, and cathepsin S, which are activated in the colonic mucosa of patients with IBS and in experimental animals with colitis, caused persistent PAR2-dependent hyperexcitability of nociceptors, sensitization of colonic afferent neurons to mechanical stimuli, and somatic mechanical allodynia. Inhibitors of clathrin- and dynamin-dependent endocytosis and of mitogen activated protein kinase kinase-1 prevented trypsin-induced hyperexcitability, sensitization, and allodynia. However, they did not affect elastase- or cathepsin S-induced hyperexcitability, sensitization, or allodynia. Trypsin stimulated endocytosis of PAR2, which signaled from endosomes to activate extracellular signal-regulated kinase. Elastase and cathepsin S did not stimulate endocytosis of PAR2, which signaled from the plasma membrane to activate adenylyl cyclase. Biopsies of colonic mucosa from IBS patients released proteases that induced persistent PAR2-dependent hyperexcitability of nociceptors, and PAR2 association with beta-arrestins, which mediate endocytosis. Conjugation to cholestanol promoted delivery and retention of antagonists in endosomes containing PAR2 A cholestanol-conjugated PAR2 antagonist prevented persistent trypsin- and IBS protease-induced hyperexcitability of nociceptors. The results reveal that PAR2 signaling from endosomes underlies the persistent hyperexcitability of nociceptors that mediates chronic pain of IBS. Endosomally targeted PAR2 antagonists are potential therapies for IBS pain. GPCRs in endosomes transmit signals that contribute to human diseases. PMID- 30012615 TI - NIH funding longevity by gender. AB - Women have achieved parity with men among biomedical science degree holders but remain underrepresented in academic positions. The National Institutes of Health (NIH)-the world's largest public funder of biomedical research-receives less than one-third of its new grant applications from women. Correspondingly, women compose less than one-third of NIH research grantees, even though they are as successful as men in obtaining first-time grants. Our study examined women's and men's NIH funding trajectories over time (n = 34,770), exploring whether women remain funded at the same rate as men after receiving their first major research grants. A survival analysis demonstrated a slightly lower funding longevity for women. We next examined gender differences in application, review, and funding outcomes. Women individually held fewer grants, submitted fewer applications, and were less successful in renewing grants-factors that could lead to gender differences in funding longevity. Finally, two adjusted survival models that account for initial investigator characteristics or subsequent application behavior showed no gender differences, suggesting that the small observed longevity differences are affected by both sets of factors. Overall, given men's and women's generally comparable funding longevities, the data contradict the common assumption that women experience accelerated attrition compared with men across all career stages. Women's likelihood of sustaining NIH funding may be better than commonly perceived. This suggests a need to explore women's underrepresentation among initial NIH grantees, as well as their lower rates of new and renewal application submissions. PMID- 30012617 TI - Multidecadal, county-level analysis of the effects of land use, Bt cotton, and weather on cotton pests in China. AB - Long-term changes in land use, climate, and agricultural technologies may affect pest severity and management. The influences of these major drivers can only be identified by analyzing long-term data. This study examines panel data on land use, adoption of genetically modified Bacillus thuringiensis (Bt) insect resistant cotton, weather, pest severity, and insecticide use on three major cotton pests for 51 counties in China during 1991-2015. Bt cotton had pervasive effects on the whole pest complex in cotton and its management. Adoption resulted in major reductions in insecticide use for bollworm control. The resulting restoration of aphid biological control decreased aphid severity. However, mirid bugs, which have few effective natural enemies in cotton, increased in severity with warming May and reduced insecticide spraying against bollworm. The effects of landscape on pest severity were pest specific. The severity of cotton aphid and mirid bugs decreased with higher land use diversity, but the severity of highly polyphagous cotton bollworm was unrelated to land use diversity. Shares of forest, water body, and unused land area were negatively associated with the severity of mirid bugs, whereas cotton bollworm responded positively to the shares of water body and unused land area. Farmers sprayed insecticides at mild infestation levels and responded aggressively to severe bollworm outbreaks. Findings support the usefulness of Bt-based plant resistance as a component of integrated pest management (IPM) but highlight the potential for unexpected outcomes resulting from agro-ecosystem feedback loops as well as the importance of climate. PMID- 30012616 TI - Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill. AB - Influenza hemagglutinin (HA) mediates viral entry into host cells through a large scale conformational rearrangement at low pH that leads to fusion of the viral and endosomal membranes. Crystallographic and biochemical data suggest that a loop-to-coiled-coil transition of the B-loop region of HA is important for driving this structural rearrangement. However, the microscopic picture for this proposed "spring-loaded" movement is missing. In this study, we focus on understanding the transition of the B loop and perform a set of all-atom molecular dynamics simulations of the full B-loop trimeric structure with the CHARMM36 force field. The free-energy profile constructed from our simulations describes a B loop that stably folds half of the postfusion coiled coil in tens of microseconds, but the full coiled coil is unfavorable. A buried hydrophilic residue, Thr59, is implicated in destabilizing the coiled coil. Interestingly, this conserved threonine is the only residue in the B loop that strictly differentiates between the group 1 and 2 HA molecules. Microsecond-scale constant temperature simulations revealed that kinetic traps in the structural switch of the B loop can be caused by nonnative, intramonomer, or intermonomer beta-sheets. The addition of the A helix stabilized the postfusion state of the B loop, but introduced the possibility for further beta-sheet structures. Overall, our results do not support a description of the B loop in group 2 HAs as a stiff spring, but, rather, it allows for more structural heterogeneity in the placement of the fusion peptides during the fusion process. PMID- 30012619 TI - Linear response of east Greenland's tidewater glaciers to ocean/atmosphere warming. AB - Predicting the retreat of tidewater outlet glaciers forms a major obstacle to forecasting the rate of mass loss from the Greenland Ice Sheet. This reflects the challenges of modeling the highly dynamic, topographically complex, and data-poor environment of the glacier-fjord systems that link the ice sheet to the ocean. To avoid these difficulties, we investigate the extent to which tidewater glacier retreat can be explained by simple variables: air temperature, meltwater runoff, ocean temperature, and two simple parameterizations of "ocean/atmosphere" forcing based on the combined influence of runoff and ocean temperature. Over a 20-y period at 10 large tidewater outlet glaciers along the east coast of Greenland, we find that ocean/atmosphere forcing can explain up to 76% of the variability in terminus position at individual glaciers and 54% of variation in terminus position across all 10 glaciers. Our findings indicate that (i) the retreat of east Greenland's tidewater glaciers is best explained as a product of both oceanic and atmospheric warming and (ii) despite the complexity of tidewater glacier behavior, over multiyear timescales a significant proportion of terminus position change can be explained as a simple function of this forcing. These findings thus demonstrate that simple parameterizations can play an important role in predicting the response of the ice sheet to future climate warming. PMID- 30012618 TI - MIZ1 regulates ECA1 to generate a slow, long-distance phloem-transmitted Ca2+ signal essential for root water tracking in Arabidopsis. AB - Ever since Darwin postulated that the tip of the root is sensitive to moisture differences and that it "transmits an influence to the upper adjoining part, which bends towards the source of moisture" [Darwin C, Darwin F (1880) The Power of Movement in Plants, pp 572-574], the signal underlying this tropic response has remained elusive. Using the FRET-based Cameleon Ca2+ sensor in planta, we show that a water potential gradient applied across the root tip generates a slow, long-distance asymmetric cytosolic Ca2+ signal in the phloem, which peaks at the elongation zone, where it is dispersed laterally and asymmetrically to peripheral cells, where cell elongation occurs. In addition, the MIZ1 protein, whose biochemical function is unknown but is required for root curvature toward water, is indispensable for generating the slow, long-distance Ca2+ signal. Furthermore, biochemical and genetic manipulations that elevate cytosolic Ca2+ levels, including mutants of the endoplasmic reticulum (ER) Ca2+-ATPase isoform ECA1, enhance root curvature toward water. Finally, coimmunoprecipitation of plant proteins and functional complementation assays in yeast cells revealed that MIZ1 directly binds to ECA1 and inhibits its activity. We suggest that the inhibition of ECA1 by MIZ1 changes the balance between cytosolic Ca2+ influx and efflux and generates the cytosolic Ca2+ signal required for water tracking. PMID- 30012620 TI - Hippocampus-dependent emergence of spatial sequence coding in retrosplenial cortex. AB - Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions. Overall, spatial activity in RSC was experience-dependent, emerging gradually over time, but, as seen in the hippocampus, the spatial code changed dynamically across days. Bilateral but not unilateral hippocampal lesions impeded the development of spatial activity in RSC. Thus, the emergence of spatial activity in RSC, a major recipient of hippocampal information, depends critically on an intact hippocampus; the indirect connections between the dysgranular RSC and the hippocampus further indicate that hippocampus may exert such influences polysynaptically within neocortex. PMID- 30012622 TI - Electrometry by optical charge conversion of deep defects in 4H-SiC. AB - Optically active point defects in various host materials, such as diamond and silicon carbide (SiC), have shown significant promise as local sensors of magnetic fields, electric fields, strain, and temperature. Modern sensing techniques take advantage of the relaxation and coherence times of the spin state within these defects. Here we show that the defect charge state can also be used to sense the environment, in particular high-frequency (megahertz to gigahertz) electric fields, complementing established spin-based techniques. This is enabled by optical charge conversion of the defects between their photoluminescent and dark charge states, with conversion rate dependent on the electric field (energy density). The technique provides an all-optical high-frequency electrometer which is tested in 4H-SiC for both ensembles of divacancies and silicon vacancies, from cryogenic to room temperature, and with a measured sensitivity of [Formula: see text] Finally, due to the piezoelectric character of SiC, we obtain spatial 3D maps of surface acoustic wave modes in a mechanical resonator. PMID- 30012621 TI - Monovalent ions modulate the flux through multiple folding pathways of an RNA pseudoknot. AB - The functions of RNA pseudoknots (PKs), which are minimal tertiary structural motifs and an integral part of several ribozymes and ribonucleoprotein complexes, are determined by their structure, stability, and dynamics. Therefore, it is important to elucidate the general principles governing their thermodynamics/folding mechanisms. Here, we combine laser temperature-jump experiments and coarse-grained simulations to determine the folding/unfolding pathways of VPK, a variant of the mouse mammary tumor virus (MMTV) PK involved in ribosomal frameshifting. Fluorescent nucleotide analogs (2-aminopurine and pyrrolocytidine) placed at different stem/loop positions in the PK serve as local probes allowing us to monitor the order of assembly of VPK that has two constituent hairpins with different intrinsic stabilities. We show that at 50 mM KCl, the dominant folding pathway populates only the more stable hairpin intermediate; as the salt concentration is increased, a parallel folding pathway emerges involving the less stable hairpin as an alternate intermediate. Notably, the flux between the pathways is modulated by the ionic strength. Our findings support the principle that the order of PK structure formation is determined by the relative stabilities of the hairpins, which can be altered by sequence variations or salt concentrations. The experimental results of salt effects on the partitioning between the two folding pathways are in remarkable agreement with simulations that were performed with no adjustable parameters. Our study not only unambiguously demonstrates that VPK folds by parallel pathways but also showcases the power of combining experiments and simulations for a more enriched description of RNA self-assembly. PMID- 30012623 TI - Pupil mimicry promotes trust through the theory-of-mind network. AB - The human eye can provide powerful insights into the emotions and intentions of others; however, how pupillary changes influence observers' behavior remains largely unknown. The present fMRI-pupillometry study revealed that when the pupils of interacting partners synchronously dilate, trust is promoted, which suggests that pupil mimicry affiliates people. Here we provide evidence that pupil mimicry modulates trust decisions through the activation of the theory-of mind network (precuneus, temporo-parietal junction, superior temporal sulcus, and medial prefrontal cortex). This network was recruited during pupil-dilation mimicry compared with interactions without mimicry or compared with pupil constriction mimicry. Furthermore, the level of theory-of-mind engagement was proportional to individual's susceptibility to pupil-dilation mimicry. These data reveal a fundamental mechanism by which an individual's pupils trigger neurophysiological responses within an observer: when interacting partners synchronously dilate their pupils, humans come to feel reflections of the inner states of others, which fosters trust formation. PMID- 30012624 TI - Biogenesis of a 22-nt microRNA in Phaseoleae species by precursor-programmed uridylation. AB - Phased, secondary siRNAs (phasiRNAs) represent a class of small RNAs in plants generated via distinct biogenesis pathways, predominantly dependent on the activity of 22-nt miRNAs. Most 22-nt miRNAs are processed by DCL1 from miRNA precursors containing an asymmetric bulge, yielding a 22/21-nt miRNA/miRNA* duplex. Here we show that miR1510, a soybean miRNA capable of triggering phasiRNA production from numerous nucleotide-binding leucine-rich repeat (NB-LRRs), previously described as 21 nt in its mature form, primarily accumulates as a 22 nt isoform via monouridylation. We demonstrate that, in Arabidopsis, this uridylation is performed by HESO1. Biochemical experiments showed that the 3' terminus of miR1510 is only partially 2'-O-methylated because of the terminal mispairing in the miR1510/miR1510* duplex that inhibits HEN1 activity in soybean. miR1510 emerged in the Phaseoleae ~41-42 million years ago with a conserved precursor structure yielding a 22-nt monouridylated form, yet a variant in mung bean is processed directly in a 22-nt mature form. This analysis of miR1510 yields two observations: (i) plants can utilize postprocessing modification to generate abundant 22-nt miRNA isoforms to more efficiently regulate target mRNA abundances; and (ii) comparative analysis demonstrates an example of selective optimization of precursor processing of a young plant miRNA. PMID- 30012627 TI - Expand the Pool of Living Donors for Kidney Transplantation. PMID- 30012628 TI - Genetic Contribution to Risk for Diabetic Kidney Disease. PMID- 30012625 TI - Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites. AB - Upon activation, the epidermal growth factor receptor (EGFR) phosphorylates tyrosine residues in its cytoplasmic tail, which triggers the binding of Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains and initiates downstream signaling. The sequences flanking the tyrosine residues (referred to as "phosphosites") must be compatible with phosphorylation by the EGFR kinase domain and the recruitment of adapter proteins, while minimizing phosphorylation that would reduce the fidelity of signal transmission. To understand how phosphosite sequences encode these functions within a small set of residues, we carried out high-throughput mutational analysis of three phosphosite sequences in the EGFR tail. We used bacterial surface display of peptides coupled with deep sequencing to monitor phosphorylation efficiency and the binding of the SH2 and PTB domains of the adapter proteins Grb2 and Shc1, respectively. We found that the sequences of phosphosites in the EGFR tail are restricted to a subset of the range of sequences that can be phosphorylated efficiently by EGFR. Although efficient phosphorylation by EGFR can occur with either acidic or large hydrophobic residues at the -1 position with respect to the tyrosine, hydrophobic residues are generally excluded from this position in tail sequences. The mutational data suggest that this restriction results in weaker binding to adapter proteins but also disfavors phosphorylation by the cytoplasmic tyrosine kinases c-Src and c-Abl. Our results show how EGFR-family phosphosites achieve a trade-off between minimizing off-pathway phosphorylation and maintaining the ability to recruit the diverse complement of effectors required for downstream pathway activation. PMID- 30012626 TI - Specific cardiolipin-SecY interactions are required for proton-motive force stimulation of protein secretion. AB - The transport of proteins across or into membranes is a vital biological process, achieved in every cell by the conserved Sec machinery. In bacteria, SecYEG combines with the SecA motor protein for secretion of preproteins across the plasma membrane, powered by ATP hydrolysis and the transmembrane proton-motive force (PMF). The activities of SecYEG and SecA are modulated by membrane lipids, particularly cardiolipin (CL), a specialized phospholipid known to associate with a range of energy-transducing machines. Here, we identify two specific CL binding sites on the Thermotoga maritima SecA-SecYEG complex, through application of coarse-grained molecular dynamics simulations. We validate the computational data and demonstrate the conserved nature of the binding sites using in vitro mutagenesis, native mass spectrometry, biochemical analysis, and fluorescence spectroscopy of Escherichia coli SecYEG. The results show that the two sites account for the preponderance of functional CL binding to SecYEG, and mediate its roles in ATPase and protein transport activity. In addition, we demonstrate an important role for CL in the conferral of PMF stimulation of protein transport. The apparent transient nature of the CL interaction might facilitate proton exchange with the Sec machinery, and thereby stimulate protein transport, by a hitherto unexplored mechanism. This study demonstrates the power of coupling the high predictive ability of coarse-grained simulation with experimental analyses, toward investigation of both the nature and functional implications of protein lipid interactions. PMID- 30012629 TI - COL4A3 Gene Variants and Diabetic Kidney Disease in MODY. AB - BACKGROUND AND OBJECTIVES: Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4alpha3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants. RESULTS: HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4alpha3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. CONCLUSIONS: The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD. PMID- 30012631 TI - Advancing health research through research governance. PMID- 30012630 TI - ABO-Incompatible Kidney Transplant Outcomes: A Meta-Analysis. AB - BACKGROUND AND OBJECTIVES: ABO blood group-incompatible kidney transplantation is considered a safe procedure, with noninferior outcomes in large cohort studies. Its contribution to living kidney transplantation programs is substantial and growing. Outcomes compared with center-matched ABO blood group-compatible control patients have not been ascertained. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Comprehensive searches were conducted in Embase, Medline, Cochrane, Web-of-Science, and Google Scholar. Meta-analyses Of Observational Studies in Epidemiology study guidelines for observational studies and Newcastle Ottawa bias scale were implemented to assess studies. Meta-analysis was performed using Review Manager 5.3. A subgroup analysis on antibody removal technique was performed. RESULTS: After identifying 2728 studies addressing ABO-incompatible kidney transplantation, 26 studies were included, describing 1346 unique patients who were ABO-incompatible and 4943 ABO-compatible controls. Risk of bias was low (all studies >=7 of 9 stars). Baseline patient characteristics revealed no significant differences in immunologic risk parameters. Statistical heterogeneity of studies was low (I2 0% for graft and patient survival). One-year uncensored graft survival of patients who were ABO-incompatible was 96% versus 98% in ABO compatible controls (relative risk, 0.97; 95% confidence interval, 0.96 to 0.98; P<0.001). Forty-nine percent of reported causes of death in patients who were ABO incompatible were of infectious origin, versus only 13% in patients who were ABO compatible (P=0.02). Antibody-mediated rejection (3.86; 95% confidence interval, 2.05 to 7.29; P<0.001), severe nonviral infection (1.44; 95% confidence interval, 1.13 to 1.82; P=0.003), and bleeding (1.92; 95% confidence interval, 1.36 to 2.72; P<0.001) were also more common after ABO-incompatible transplantation. CONCLUSIONS: ABO-incompatible kidney transplant recipients have good outcomes, albeit inferior to center-matched ABO-compatible control patients. PMID- 30012633 TI - Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation. AB - Tumor-associated macrophages (TAMs) express programmed cell death ligand 1 (PD L1) and contribute to the immune-suppressive tumor microenvironment. Although the role of the PD-L1 and PD-1 interaction to regulate T-cell suppression is established, less is known about PD-L1 signaling in macrophages and how these signals may affect the function of TAMs. We used in vitro and in vivo models to investigate PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on TAM responses. Treatment of mouse and human macrophages with PD-L1 antibodies increased spontaneous macrophage proliferation, survival, and activation (costimulatory molecule expression, cytokine production). Similar changes were observed in macrophages incubated with soluble CD80 and soluble PD 1, and in PD-L1-/- macrophages. Macrophage treatment with PD-L1 antibodies upregulated mTOR pathway activity, and RNAseq analysis revealed upregulation of multiple macrophage inflammatory pathways. In vivo, treatment with PD-L1 antibody resulted in increased tumor infiltration with activated macrophages. In tumor bearing RAG-/- mice, upregulated costimulatory molecule expression by TAMs and reduced tumor growth were observed. Combined PD-1/ PD-L1 antibody treatment of animals with established B16 melanomas cured half of the treated mice, whereas treatment with single antibodies had little therapeutic effect. These findings indicate that PD-L1 delivers a constitutive negative signal to macrophages, resulting in an immune-suppressive cell phenotype. Treatment with PD-L1 antibodies reverses this phenotype and triggers macrophage-mediated antitumor activity, suggesting a distinct effect of PD-L1, but not PD-1, antibody treatment. Cancer Immunol Res; 6(10); 1260-73. (c)2018 AACR. PMID- 30012634 TI - Strengthening institutional capacity for equitable health research: lessons from Latin America and the Caribbean. PMID- 30012635 TI - The rise of apoptosis: targeting apoptosis in hematologic malignancies. AB - Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma-extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies. PMID- 30012636 TI - Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications. AB - Monoclonal gammopathy is a common condition, particularly in the elderly. It can indicate symptomatic multiple myeloma or another overt malignant lymphoid disorder requiring immediate chemotherapy. More frequently, it results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic, and requires regular monitoring only, defining a monoclonal gammopathy of unknown significance (MGUS). Sometimes, although quiescent and not requiring any treatment per se, the clone is associated with potentially severe organ damage due to the toxicity of the monoclonal immunoglobulin or to other mechanisms. The latter situation is increasingly observed but still poorly recognized and frequently undertreated, although it often requires rapid specific intervention to preserve involved organ function. To improve early recognition and management of these small B-cell clone-related disorders, we propose to introduce the concept of monoclonal gammopathy of clinical significance (MGCS). This report identifies the spectrum of MGCSs that are classified according to mechanisms of tissue injury. It highlights the diversity of these disorders for which diagnosis and treatment are often challenging in clinical practice and require a multidisciplinary approach. Principles of management, including main diagnostic and therapeutic procedures, are also described. Importantly, efficient control of the underlying B-cell clone usually results in organ improvement. Currently, it relies mainly on chemotherapy and other anti-B-cell/plasma cell agents, which should aim at rapidly producing the best hematological response. PMID- 30012637 TI - Sex Matters: Male Hamsters Are More Susceptible to Lethal Infection with Lower Doses of Pathogenic Leptospira than Female Hamsters. AB - A somewhat contradictory published body of evidence suggests that sex impacts severity outcomes of human leptospirosis. In this study, we used an acute animal model of disease to analyze leptospirosis in male and female hamsters infected side by side with low but increasing doses of Leptospira interrogans serovar Copenhageni. We found that male hamsters were considerably more susceptible to leptospirosis, given that only 6.3% survived infection, whereas 68.7% of the females survived the same infection doses. In contrast to the females, male hamsters had high burdens of L. interrogans in kidney and high histopathological scores after exposure to low infection doses (~103 bacteria). In hamsters infected with higher doses of L. interrogans (~104 bacteria), differences in pathogen burdens as well as cytokine and fibrosis transcript levels in kidney were not distinct between sexes. Our results indicate that male hamsters infected with L. interrogans are more susceptible to severe leptospirosis after exposure to lower infectious doses than females. PMID- 30012639 TI - Promoting high quality research into priority health needs in Latin America and Caribbean. PMID- 30012640 TI - Productivity burden of smoking in Australia: a life table modelling study. AB - OBJECTIVES: This study aimed to examine the impact of smoking on productivity in Australia, in terms of years of life lost, quality-adjusted life years (QALYs) lost and the novel measure of productivity-adjusted life years (PALYs) lost. METHODS: Life table modelling using contemporary Australian data simulated follow up of current smokers aged 20-69 years until age 70 years. Excess mortality, health-related quality of life decrements and relative reduction in productivity attributable to smoking were sourced from published data. The gross domestic product (GDP) per equivalent full-time (EFT) worker in Australia in 2016 was used to estimate the cost of productivity loss attributable to smoking at a population level. RESULTS: At present, approximately 2.5 million Australians (17.4%) aged between 20 and 69 years are smokers. Assuming follow-up of this population until the age of 70 years, more than 3.1 million years of life would be lost to smoking, as well as 6.0 million QALYs and 2.5 million PALYs. This equates to 4.2% of years of life, 9.4% QALYs and 6.0% PALYs lost among Australian working-age smokers. At an individual level, this is equivalent to 1.2 years of life, 2.4 QALYs and 1.0 PALY lost per smoker. Assuming (conservatively) that each PALY in Australia is equivalent to $A157 000 (GDP per EFT worker in 2016), the economic impact of lost productivity would amount to $A388 billion. CONCLUSIONS: This study highlights the potential health and productivity gains that may be achieved from further tobacco control measures in Australia via application of PALYs, which are a novel, and readily estimable, measure of the impact of health and health risk factors on work productivity. PMID- 30012638 TI - Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice. AB - Bordetella pertussis is the primary causative agent of pertussis (whooping cough), which is a respiratory infection that leads to a violent cough and can be fatal in infants. There is a need to develop more effective vaccines because of the resurgence of cases of pertussis in the United States since the switch from the whole-cell pertussis vaccines (wP) to the acellular pertussis vaccines (aP; diphtheria-tetanus-acellular-pertussis vaccine/tetanus-diphtheria-pertussis vaccine). Adenylate cyclase toxin (ACT) is a major virulence factor of B. pertussis that is (i) required for establishment of infection, (ii) an effective immunogen, and (iii) a protective antigen. The C-terminal repeats-in-toxin domain (RTX) of ACT is sufficient to induce production of toxin-neutralizing antibodies. In this study, we characterized the effectiveness of vaccines containing the RTX antigen against experimental murine infection with B. pertussis RTX was not protective as a single-antigen vaccine against B. pertussis challenge, and adding RTX to 1/5 human dose of aP did not enhance protection. Since the doses of aP used in murine studies are not proportionate to mouse/human body masses, we titrated the aP from 1/20 to 1/160 of the human dose. Mice receiving 1/80 human aP dose had bacterial burden comparable to those of naive controls. Adding RTX antigen to the 1/80 aP base resulted in enhanced bacterial clearance. Inclusion of RTX induced production of antibodies recognizing RTX, enhanced production of anti-pertussis toxin, decreased secretion of proinflammatory cytokines, such as interleukin-6, and decreased recruitment of total macrophages in the lung. This study shows that adding RTX antigen to an appropriate dose of aP can enhance protection against B. pertussis challenge in mice. PMID- 30012641 TI - Circulating Proenkephalin, Acute Kidney Injury, and Its Improvement in Patients with Severe Sepsis or Shock. AB - BACKGROUND: Acute kidney injury (AKI) occurs in many critically ill patients and is associated with high mortality. We examined whether proenkephalin could predict incident AKI and its improvement in septic patients. METHODS: Plasma proenkephalin A 119-159 (penKid) was assayed in 956 patients with sepsis or septic shock enrolled in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial to test its association with incident AKI, improvement of renal function, need for renal replacement therapy (RRT), and mortality. RESULTS: Median [Q1-Q3] plasma penKid concentration on day 1 [84 (20-159) pmol/L[ was correlated with serum creatinine concentration (r = 0.74); it was higher in patients with chronic renal failure and rose progressively with the renal Sequential Organ Failure Assessment subscore. It predicted incident AKI within 48 h (adjusted odds ratio, 3.3; 95% CI, 2.1-5.1; P < 0.0001) or 1 week [adjusted hazard ratio, 2.1 (1.7 2.8); P < 0.0001] and future RRT during the intensive care unit stay [odds ratio, 4.0 (3.0-5.4)]. PenKid was also associated with improvements in renal function in patients with baseline serum creatinine >2 mg/dL, both within the next 48 h [adjusted odds ratio, 0.31 (0.18-0.54), P < 0.0001] and 1 week [0.23 (0.12 0.45)]. The time course of penKid concentrations predicted AKI and 90-day mortality. CONCLUSIONS: Early measurement and the trajectory of penKid predict incident AKI, improvement of renal function, and the need for RRT in the acute phase after intensive care unit admission during sepsis or septic shock. PenKid measurement may be a valuable tool to test early therapies aimed at preventing the risk of AKI in sepsis. PMID- 30012642 TI - Does evidence based medicine adversely affect clinical judgment? PMID- 30012643 TI - Increase in circulating cells coexpressing M1 and M2 macrophage surface markers in patients with systemic sclerosis. PMID- 30012644 TI - High-volume general practitioners in Alberta: a descriptive analysis. AB - BACKGROUND: Alberta is considering capping daily fee-for-service physician billings, but little is known about high-volume practice in the province and its impact on patient health outcomes. In this initial study, we conducted a descriptive analysis of general practitioners' patient volumes and billing practices in relation to associated practitioner demographic characteristics. METHODS: We conducted a retrospective descriptive analysis of the associations of practitioner characteristics, including full-time versus non-full-time practice, provider sex, years in practice, geographic location and international medical graduate status, with high-volume (> 50 visits/d) practice using general practice billing data from 2011 to 2016. Use of general practitioner service codes was described and compared by general practitioner volume status, with adjustment for physician demographic characteristics and geographic parameters. RESULTS: We included 3465 general practitioners practising fee-for-service in Alberta between 2011 and 2016, of whom 233 (6.7%) were identified as high-volume providers. Physicians who had been in practice longer (odds ratio [OR] 1.04 per year, 95% confidence interval [CI] 1.02-1.05) and international medical graduates (OR 1.89, 95% CI 1.40-2.54) were more likely to exceed 50 patient visits/day. Female physicians were less likely to exceed 50 patient visits/day (OR 0.14, 95% CI 0.07 0.28). Rural practice location was negatively associated with high-volume practice (OR 0.87, 95% CI 0.79-0.95) when we controlled for zone within the province. Zone 5 (North) was associated with high-volume practice (OR 1.95, 95% CI 1.06-3.58). Less than full-time practice was prevalent (1836 providers [53.0%]). High-volume general practitioners billed fewer service codes requiring longer visits, except for the most highly remunerated code (patients with complex health issues). INTERPRETATION: These results can inform policy-makers when considering payment system changes. Our next step is to examine the association of high-volume practice with outcomes important to patients, such as evidence of treatment failure (emergency department visits and hospital admissions) for conditions sensitive to primary care management. PMID- 30012645 TI - Effect of an innovative community-based care model, the Monarch Centre, on postpartum length of stay: an interrupted time-series study. AB - BACKGROUND: Reduction in postpartum length of stay has been advocated within a context of reducing health care system costs and maintaining quality of care. We assessed trends in postpartum length of stay for vaginal and cesarean deliveries at an academic hospital, The Ottawa Hospital, before and after the implementation in 2014 of a novel community-based postpartum outpatient clinic, the Monarch Centre. METHODS: The Monarch Centre model of postpartum care consists of prebooked appointments at the postpartum clinic, scheduled within 48 hours of hospital discharge. Clients receive maternal assessment including mood screening and care, neonatal care, laboratory testing including infant total serum bilirubin level, and breast-feeding assessment and support. Family physicians, lactation consultants and registered nurses are available for consultation at the appointment, and there is coordination with institutional care, community partners and primary care providers. We used interrupted time-series regression models to assess trends in postpartum length of stay at The Ottawa Hospital between January 2012 and December 2016. RESULTS: There were 16 023 deliveries with 16 515 babies born over the study period. The mean postpartum length of stay was 46 hours (66 h for cesarean deliveries and 37 h for vaginal deliveries). Eighteen months after implementation of the centre, the average length of stay following a cesarean birth had decreased by 20 hours, a relative reduction of 27% (95% confidence interval [CI] 9.5 to 30.4); for vaginal deliveries, length of stay was reduced by 6 hours, a relative reduction of 18% (95% CI 5.2 to 31.1), and by 12 hours among typical cases (relative reduction 28%, 95% CI 19.2 to 36.6). There was a decrease in the proportion of women with a length of stay exceeding 48 hours after centre implementation. An increase in the rate of 30-day readmission from 1.1% to 1.9% was observed among babies. INTERPRETATION: A strong association was found between implementation of a community-based multidisciplinary postpartum clinic and declines in postpartum length of stay. This alternative model of postpartum care is safe, has the potential for reducing provider costs and should be considered for further implementation at provincial and national levels. PMID- 30012646 TI - E-cigarette adverts and children's perceptions of tobacco smoking harms: an experimental study and meta-analysis. AB - OBJECTIVES: Children exposed to electronic cigarette (e-cigarette) adverts may perceive occasional tobacco smoking as less harmful than children not exposed to e-cigarette adverts. Given the potential cross-cueing effects of e-cigarette adverts on tobacco smoking, there is an urgent need to establish whether the effect found in prior research is robust and replicable using a larger sample and a stronger control condition. DESIGN: A between-subjects experiment with one independent factor of two levels corresponding to the advertisements to which participants were exposed: glamorous adverts for e-cigarettes, or adverts for objects unrelated to smoking or vaping. PARTICIPANTS: English school children aged 11-16 (n=1449). OUTCOMES: Perceived harm of occasional smoking of one or two tobacco cigarettes was the primary outcome. Secondary outcomes included: perceived harm of regular tobacco smoking, susceptibility to tobacco smoking and perceived prevalence of tobacco smoking in young people. Perceptions of using e cigarettes were gauged by adapting all the outcome measures used to assess perceptions of tobacco smoking. RESULTS: Tobacco smokers and e-cigarette users were excluded from analyses (final sample n=1057). Children exposed to glamorous e-cigarette adverts perceived the harms of occasional smoking of one or two tobacco cigarettes to be lower than those in the control group (Z=-2.13, p=0.033). An updated meta-analysis comprising three studies with 1935 children confirmed that exposure to different types of e-cigarette adverts (glamorous, healthful, flavoured, non-flavoured) lowers the perceived harm of occasional smoking of one or two tobacco cigarettes (Z=3.21, p=0.001). CONCLUSIONS: This study adds to existing evidence that exposure to e-cigarette adverts reduces children's perceptions of the harm of occasional tobacco smoking. PMID- 30012647 TI - The effect of surgery on fat mass, lipid and glucose metabolism in mild primary hyperparathyroidism. AB - CONTEXT: Mild primary hyperparathyroidism has been associated with increased body fat mass and unfavorable cardiovascular risk factors. OBJECTIVE: To assess the effect of parathyroidectomy on fat mass, glucose and lipid metabolism. Design, Patients, Interventions, Main outcome measures: 119 patients previously randomized to observation (OBS; n=58) or parathyroidectomy (PTX; n=61) within the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, an open randomized multicenter study, were included. Main outcome measures for this study were the differences in fat mass, markers for lipid- and glucose metabolism between OBS and PTX five years after randomization. RESULTS: In the OBS group, total cholesterol (Total-C) decreased from mean 5.9 (+/-1.1) to 5.6 (+/-1.0) mmol/l (P=0.037) and LDL-Cholesterol (LDL-C) decreased from 3.7 (+/-1.0) to 3.3 (+/-0.9) mmol/l (P=0.010). In the PTX group, the Total-C and LDL-C remained unchanged resulting in a significant between group difference over time (P=0.013 and P=0.026, respectively). This difference was driven by patients who started with lipid lowering medication during the study period (OBS: 5; PTX: 1). There was an increase in trunk fat mass in the OBS group, but no between group differences over time. Mean 25(OH) Vitamin D increased in the PTX group (p<0.001), but did not change in the OBS group. No difference in parameters of glucose metabolism was detected. CONCLUSION: In mild PHPT, the measured metabolic and cardiovascular risk factors were not modified by PTX. Observation seems safe and cardiovascular risk reduction should not be regarded as a separate indication for parathyroidectomy based on the results from this study. PMID- 30012648 TI - Post-chemotherapy serum anti-mullerian hormone level predicts ovarian function recovery. AB - In the era of precision medicine, the prediction of ovarian function recovery from chemotherapy-induced amenorrhoea using feasible biological markers may be helpful to optimise the treatment strategy for young patients with hormone receptor-positive breast cancer. The purpose of this study was to investigate the accuracy of post-chemotherapy biological markers for predicting the recovery of ovarian function in breast cancer patients of the ASTRRA trial, with chemotherapy induced amenorrhoea. Using data of 82 participants from a single institution in the ASTRRA trial, the post-chemotherapy serum levels of the anti-mullerian hormone (AMH), estradiol, inhibin B, and other clinical factors associated with chemotherapy-induced amenorrhoea were evaluated. Recovery of ovarian function was defined by the resumption of menstruation manifested by vaginal bleeding. Fifty two patients regained menstruation within 55 months after enrolment. In univariate analysis, <40 years of age (p=0.009), estradiol >=37 pg/mL (p=0.003), or AMH >=800 pg/mL (p=0.026) were associated with recovery of menstruation. On multivariate analysis, estradiol (hazard ratio: 3.171, 95% CI: 1.306-7.699, p=0.011) and AMH (hazard ratio: 2.853, 95% CI: 1.011-8.046, p=0.048) remained as significant independent predictors for resumption of menstruation. The diagnostic accuracy of age, estradiol, and AMH in predicting the resumption of menstruation was 38.3%, 23.3%, and 86.7%, respectively. In conclusion, post-chemotherapy AMH level might be a relatively accurate predictor of the recovery of ovarian function, presented by resumption of menstruation in breast cancer patients with chemotherapy-induced amenorrhoea. PMID- 30012650 TI - What's happening in Neurology(r). PMID- 30012651 TI - What's happening in Neurology(r)Clinical Practice. PMID- 30012649 TI - Sexual steroid hormone receptors profiles in ovarian carcinoma in Mexican women. AB - The significance of the presence of androgen receptor (AR), estrogen receptor alpha (ER), and progesterone receptor (PR) in ovarian cancer patient survival has been a matter of numerous studies. This study was aimed to describe the expression profile of the three sexual steroid receptors in high grade serous, endometrioid, mucinous and low grade serous ovarian carcinoma and its association to the proliferation index in patients with primary ovarian carcinoma diagnosis, before any treatment. Eighty-one samples were obtained from the National Institute of Cancerology in Mexico City and were evaluated for the presence of AR, ER, PR and Ki67 by immunohistochemistry. The four subtypes of ovarian carcinoma displays a specific profile of the eight possible combinations of the steroid receptors with significant differences within the profile and the histological subtypes. High-grade serous carcinoma was characterized by a high frequency of both, triple negative and AR+ ER- PR+ profiles. Endometrioid carcinoma presented a higher frequency of triple positive profile. The presence of only AR+ profile was not observed in the endometrioid tumors. The relationship of the receptor profile with the proliferation index in the tumor epithelium shows that the expression of only ER is associated to a reduced proliferation index in endometrioid carcinoma. Steroid hormone receptor expression and co expression could help characterize ovarian carcinoma. PMID- 30012652 TI - What's happening in Neurology(r)Genetics. PMID- 30012653 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 30012654 TI - Gelastic attack in a child with moyamoya disease. PMID- 30012655 TI - Child Neurology: Siblings with infantile epilepsy and developmental delay: A circuitous path to genomic diagnosis. AB - OBJECTIVE: Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder with a variable phenotype. METHODS: We report 2 full siblings, a brother and sister, with a unique familial 2.4 Mb microdeletion at 14q13.1-14q13.3 by microarray (first identified in the brother, Mayo Clinical Laboratories, 2010). RESULTS: Both children presented with infantile spasms that evolved to intractable epilepsy and profound developmental delay. They share distinctive dysmorphic features: long expressionless facies, full cheeks, flattened midface, full lips, and generalized hypotonia. Only the sister has hemophagocytic lymphohistiocytosis (HLH). Testing in the brother revealed 3 variants of unknown significance (VUS) (Greenwood Genetics, epilepsy/seizure panel, 145 genes, 2015). The sister had normal results with a different gene panel (GeneDx, infantile epilepsy panel, 75 genes, 2016) but it did not include the 3 genes in which VUS were identified in her brother. Whole exome sequencing in the mother, father, and both siblings was negative without VUS (GeneDx, XomeDx, 2016). There were no variants within the deleted interval in the intact allele for both children. Parental fluorescent in situ hybridization studies for 14q13.1-14q13.3, done in 2017, were normal. Haplotype analysis of the intact chromosome 14 in the sister supported paternal origin for the deletion and likely germline mosaicism in the father. Haploinsufficiency of genes in the deleted region has not been associated with an abnormal phenotype. CONCLUSIONS: These children have a specific, recognizable neurodevelopmental phenotype and 14q13 microdeletion. This report highlights the challenges of coordinating and interpreting genetic testing in syndromic epilepsy. PMID- 30012656 TI - Editors' note: Blood pressure from mid- to late life and risk of incident dementia. PMID- 30012657 TI - Reader response: Blood pressure from mid- to late life and risk of incident dementia. PMID- 30012658 TI - Reader response: Blood pressure from mid- to late life and risk of incident dementia. PMID- 30012659 TI - Author response: Blood pressure from mid- to late life and risk of incident dementia. PMID- 30012660 TI - Teaching NeuroImages: Isolated pontine involvement in subacute sclerosing panencephalitis. PMID- 30012661 TI - Teaching NeuroImages: Spinal cord syrinx secondary to a spinal dural arteriovenous fistula. PMID- 30012662 TI - Teaching Video NeuroImages: Propriospinal myoclonus as a sequela of Guillain Barre syndrome. PMID- 30012663 TI - Case of severe acute hepatitis A virus infection in United Nations peacekeepers in South Sudan. AB - Hepatitis A virus (HAV) is a major cause of acute viral hepatitis, which can lead to severe cases and acute liver failure. A 41-year-old Chinese military officer of the United Nations peacekeeping forces in South Sudan manifested fever, jaundice and coagulation dysfunction. The patient initially had a negative anti HAV IgM antibody test result but a positive anti-HAV-IgM antibody test result five days after his alanine aminotransferase (ALT) levels peaked. He was given telemedicine consultation and was transferred to a Chinese military hospital specialising in infectious diseases for treatment of severe acute HAV infection. The peak ALT, aspartate aminotransferase, total bilirubin and international standard ratio were 5410 U/L, 3475 U/L, 225.1 umol/L and 2.12 during hospitalisation, respectively. Military personnel undergoing missions in areas with high prevalence of HAV should be tested for previous HAV infection before departure if they have not been previously vaccinated. If negative results are obtained, they should be vaccinated. Anti-HAV-IgM examination should be repeated after the first negative test result is obtained to eliminate the effects of a window period if a clinical suspicion exists. If a life-threatening case of HAV infection is present, the patient should be transported to a base military hospital specialising in infectious diseases for treatment. PMID- 30012664 TI - Association of betel nut chewing with exercise performance in a military male cohort: the CHIEF study. AB - INTRODUCTION: Betel nut chewing may cause obesity, neurohormonal activation and inflammation, possibly impairing exercise performances. METHODS: We examined the cross-sectional association in 4388 military male adults aged 18-50 years from the cardiorespiratory fitness in armed forces study in Taiwan between 2013 and 2014. The status of betel nut chewing was classified as current and former/never based on each participant's response to a questionnaire. Physical fitness was evaluated by three basic exercise tests including 3000 m running, 2 min sit-ups and 2 min push-ups. Multiple logistic regression for the best 10% and the worst 10% performers in each exercise, and linear regression were used to determine the relationship. RESULTS: There were 564 current chewers and 3824 non-current chewers for the analysis. The linear regression shows that current betel nut chewing was positively correlated with 3000 m running duration (r=0.37, p=0.042) after adjusting for age, service specialty, body mass index, exercise frequency and alcohol intake. In addition, the logistic regression shows that as compared with non-current chewers, current chewers had lower odds of being the top 10% performers in 2 min push-ups and higher odds of being the bottom 10% performers in 2 min sit-ups (ORs and 95% CIs: 0.71 (0.50 to 0.99) and 1.32 (1.00 to 1.75), respectively). However, the associations between betel nut chewing and physical fitness were all insignificant after further adjusting for current smoking. CONCLUSIONS: Our findings suggest that the impairment of physical fitness associated with betel nut chewing of military young men might be mainly mediated or moderated by the coexisted cigarette smoking. PMID- 30012665 TI - Military assistance to the civil authority: medical liaison with the Manchester clinicians after the Arena bombing. AB - UK Defence Medical Services' personnel have experienced an intense exposure to patients injured during war over the last decade and a half. As some bitter lessons of war surgery were relearned and innovative practices introduced, outcomes for patients impr oved consistently as experience accumulated. The repository of many of the enduring lessons learnt at the Role 4 echelon of care remain at the Queen Elizabeth Hospital Birmingham (QEHB), with the National Health Service and Defence Medical Services personnel who treated the returning casualties. On 22 May 2017, a terrorist detonated an improvised explosive device at the Manchester Arena, killing 22 and wounding 159 people. In the aftermath of the event, QEHB was requested to provide support to the Manchester clinicians and teleconferencing and then two clinical visits were arranged. This short report describes the nature of the visits, outlines the principles of Military Aid to the Civil Authority and looks to the future role of the Defence Medical Services in planning and response to UK terrorism events. PMID- 30012666 TI - Responding to the marauding terror attack: the police perspective. AB - UKpolice forces have had to adapt their tactical approach to the emerging terror threat that now faces the UK. This has led to an evolution in the training, education and conduct of authorised firearms officers and an increased capability in the provision of immediate lifesaving care to injured casualties. This article intends to describe the police response to a marauding terror attack and describes the medical capabilities authorised firearms officers possess in order to educate other emergency service responders to such an event. The challenges of training for a major terrorist event and the benefits of collaborative working with other emergency service personnel are discussed. PMID- 30012667 TI - England's childhood obesity action plan II. PMID- 30012670 TI - IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer. AB - Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1beta in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c+ myeloid cells. IL1beta production is triggered by cancer cell membrane-derived TGFbeta. Neutralizing TGFbeta or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2- breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).Significance: IL1beta orchestrates tumor promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. Cancer Res; 78(18); 5243-58. (c)2018 AACRSee related commentary by Dinarello, p. 5200. PMID- 30012669 TI - The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. AB - Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants CYP2C9*2 and CYP2C9*3 encode proteins with reduced enzymatic activity, and individuals carrying these variants metabolize drugs more slowly than individuals with wild-type CYP2C9*1, potentially affecting their response to drugs and altering their risk of disease. Although genetic differences in CYP2C9-dependent oxidation of arachidonic acid (AA) have been reported, the roles of CYP2C9*2 and CYP2C9*3 in EET biosynthesis and their relevance to disease are unknown. Here, we report that CYP2C9*2 and CYP2C9*3 metabolize AA less efficiently than CYP2C9*1 and that they play a role in the progression of non-small cell lung cancer (NSCLC) via impaired EET biosynthesis. When injected into mice, NSCLC cells expressing CYP2C9*2 and CYP2C9*3 produced lower levels of EETs and developed fewer, smaller, and less vascularized tumors than cells expressing CYP2C9*1. Moreover, endothelial cells expressing these two variants proliferated and migrated less than cells expressing CYP2C*1. Purified CYP2C9*2 and CYP2C9*3 exhibited attenuated catalytic efficiency in producing EETs, primarily due to impaired reduction of these two variants by NADPH-P450 reductase. Loss-of-function SNPs within CYP2C9*2 and CYP2C9*3 were associated with improved survival in female cases of NSCLC. Thus, decreased EET biosynthesis represents a novel mechanism whereby CYPC29*2 and CYP2C9*3 exert a direct protective role in NSCLC development.Significance: These findings report single nucleotide polymorphisms in the human CYP2C9 genes, CYP2C9*2 and CYP2C9*3, exert a direct protective role in tumorigenesis by impairing EET biosynthesis. Cancer Res; 78(17); 4865-77. (c)2018 AACR. PMID- 30012671 TI - A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis. AB - Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFkappaB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFkappaB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE2 receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer.Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg Cancer Res; 78(19); 5586-99. (c)2018 AACR. PMID- 30012668 TI - Maternal Proteins That Are Phosphoregulated upon Egg Activation Include Crucial Factors for Oogenesis, Egg Activation and Embryogenesis in Drosophila melanogaster. AB - Egg activation is essential for the successful transition from a mature oocyte to a developmentally competent egg. It consists of a series of events including the resumption and completion of meiosis, initiation of translation of some maternal mRNAs and destruction of others, and changes to the vitelline envelope. This major change of cell state is accompanied by large scale alteration in the oocyte's phosphoproteome. We hypothesize that the cohort of proteins that are subject to phosphoregulation during egg activation are functionally important for processes before, during, or soon after this transition, potentially uniquely or as proteins carrying out essential cellular functions like those they do in other (somatic) cells. In this study, we used germline-specific RNAi to examine the function of 189 maternal proteins that are phosphoregulated during egg activation in Drosophila melanogaster We identified 53 genes whose knockdown reduced or abolished egg production and caused a range of defects in ovarian morphology, as well as 51 genes whose knockdown led to significant impairment or abolishment of the egg hatchability. We observed different stages of developmental arrest in the embryos and various defects in spindle morphology and aberrant centrosome activities in the early arrested embryos. Our results, validated by the detection of multiple genes with previously-documented maternal effect phenotypes among the proteins we tested, revealed 15 genes with newly discovered roles in egg activation and early embryogenesis in Drosophila. Given that protein phosphoregulation is a conserved characteristic of this developmental transition, we suggest that the phosphoregulated proteins may provide a rich pool of candidates for the identification of important players in the egg-to-embryo transition. PMID- 30012672 TI - Activation of NKT Cells in an Anti-PD-1-Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells. AB - PD-1-based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1 resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand alpha galactosylceramide (alphaGC) can enhance the antitumor effect in anti-PD-1 resistant tumors by restoring the effector function of tumor antigen-specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by alphaGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between alphaGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1-resistant cancer.Significance: These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. Cancer Res; 78(18); 5315-26. (c)2018 AACR. PMID- 30012673 TI - BMX-Mediated Regulation of Multiple Tyrosine Kinases Contributes to Castration Resistance in Prostate Cancer. AB - Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate-specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a prostate cancer xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients.Significance: The tyrosine kinase BMX is negatively regulated by androgen and contributes to castration-resistant prostate cancer by enhancing the phosphorylation and activation of multiple receptor tyrosine kinases following ADT. Cancer Res; 78(18); 5203-15. (c)2018 AACR. PMID- 30012674 TI - Incretin-Based Therapies and Diabetic Retinopathy: Real-World Evidence in Older U.S. Adults. AB - OBJECTIVE: Recent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics. RESEARCH DESIGN AND METHODS: We implemented an active comparator, new-user cohort design using a nationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP1RA) versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models. RESULTS: We identified 213,652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79-1.04) by comparing DPP4i to SU (n = 39,292 and 87,073); 0.91 (0.75 1.11), DPP4i to TZD (n = 51,410 and 22,231); 0.50 (0.39-0.65), GLP1RA to LAI (n = 9,561 and 82,849); and 0.75 (0.53-1.06), GLP1RA to TZD (n = 10,355 and 27,345). CONCLUSIONS: Our population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk. PMID- 30012676 TI - Multiple lesions of skull and cervical spine: a rare presentation of unicameral bone cysts. AB - A 55-year-old man with a history of Benign Paroxysmal Positional Vertigo unalleviated by Epley manoeuvre presented to an otolaryngologist for dizziness, right ear fullness and headache. MRI of the brain showed numerous marrow replacing lesions throughout the calvarium, skull base and upper cervical spine which were hypointense on T1-weighted images, hyperintense on T2-weighted images and avidly enhanced following contrast, concerning for a malignant process such as metastatic disease or multiple myeloma (figure 1). Systemic X-ray survey (spine, skull, chest, pelvis, all long bones) and nuclear medicine whole body bone scan were negative except for the lesions seen on MRI. beta-2microglobin, immunoglobin and monoclonal protein electrophoresis were negative for myeloma or immunological process. Given the concern for metastatic disease, biopsy of a skull lesion was recommended. Pathological analysis of a calvarial lesion was consistent with unicameral bone cyst (figure 1). No ongoing therapy was offered; however, brain and spine surveillance imaging will continue. PMID- 30012677 TI - Orbitocerebral mucormycosis and intracranial haemorrhage: a role for caution with steroids in suspected giant cell arteritis. AB - A 75-year-old man with type 2 diabetes mellitus presented with complete loss of vision in his right eye and severe headaches for the past 24 hours. He had been treated for suspected giant cell arteritis (GCA) with high-dose corticosteroids which were being tapered to stop after an inconclusive right temporal artery biopsy and an erythrocyte sedimentation rate (ESR) value of 8. His current acute presentation, however, raised further concern for partially treated GCA and precipitated treatment with pulsed methylprednisolone. The patient, taking metformin, developed diabetic ketoacidosis and was transferred to the intensive care unit where a swollen, painful right eye with chemosis and complete ophthalmoplegia was subsequently revealed to be secondary to cavernous sinus thrombosis. Rhino-orbital skin necrosis with positive samples for the organism Rhizopus on eventual orbital exenteration revealed angioinvasive fungal infection, mucormycosis, to be the cause. We discuss here the lessons learnt, and how best to treat a susceptible cohort within our ageing western population. PMID- 30012678 TI - Emphysematous Osteomyelitis. PMID- 30012679 TI - Case of fatal familial insomnia caused by a d178n mutation with phenotypic similarity to Hashimoto's encephalopathy. AB - Fatal familial insomnia (FFI) is a rare prion disease commonly inherited in an autosomal dominant pattern from a mutation in the PRioN Protein (PRNP) gene. Hashimoto's encephalopathy (HE) is characterised by encephalopathy associated with antithyroid peroxidase (TPO) or antithyroglobulin (Tg) antibodies. These two conditions characteristically have differing clinical presentations with dramatically different clinical course and outcomes. Here, we present a case of FFI mimicking HE. A woman in her 50s presented with worsening confusion, hallucinations, tremor and leg jerks. Several maternal relatives had been diagnosed with FFI, but the patient had had negative genetic testing for PRNP. MRI of brain, cervical and thoracic spine were unremarkable except for evidence of prior cervical transverse myelitis. Cerebrospinal fluid analysis was normal. Anti-TPO and anti-Tg antibodies were elevated. She was started on steroids for possible HE and showed improvement in symptoms. Following discharge, the results of her PRNP gene test returned positive for variant p.Asp178Asn. PMID- 30012680 TI - Campylobacter fetus spondylodiscitis in a patient with HIV infection and restored CD4 count. AB - Campylobacter fetus (C. fetus) is a rare condition and mostly seen in elderly or immunocompromised patients. We present the first case of C. fetus spondylodiscitis in a virologically suppressed HIV seropositive patient with low back pain. MRI was performed and showed spondylodiscitis of the L4-L5 region. Empirical antibiotic therapy with flucloxacillin was started after blood cultures were drawn and an image-guided disc biopsy was performed. Blood cultures remained negative. The anaerobic culture of the puncture biopsy of the disc revealed presence of C. fetus after which the antibiotic treatment was switched to ceftriaxone. Guided by the susceptibility results, the therapy was switched to ciprofloxacin orally for 6 weeks after which the patient made full clinical, biochemical and radiographic recovery. Since no other immune-deficient conditions were noted, it is important to highlight that patients with HIV infection with restored CD4 counts and complete virological suppression can still be susceptible for infections caused by rare pathogens. Low back pain should raise suspicion for these conditions and should be examined properly. PMID- 30012681 TI - Spontaneous migration into the stomach and out of the intestine, as late complication of a gastric band. PMID- 30012682 TI - The treatment of trismus with Ativan: a 3-year-old with difficulty opening her mouth. PMID- 30012683 TI - Rare cause of voiding dysfunction in an adult man: urethral diverticulum compressing the anterior urethra. PMID- 30012685 TI - Temporal Expectation Modulates the Cortical Dynamics of Short-Term Memory. AB - Increased memory load is often signified by enhanced neural oscillatory power in the alpha range (8-13 Hz), which is taken to reflect inhibition of task irrelevant brain regions. The corresponding neural correlates of memory decay, however, are not yet well understood. In the current study, we investigated auditory short-term memory decay in humans using a delayed matching-to-sample task with pure-tone sequences. First, in a behavioral experiment, we modeled memory performance over six different delay-phase durations. Second, in a MEG experiment, we assessed alpha-power modulations over three different delay-phase durations. In both experiments, the temporal expectation for the to-be-remembered sound was manipulated so that it was either temporally expected or not. In both studies, memory performance declined over time, but this decline was weaker when the onset time of the to-be-remembered sound was expected. Similarly, patterns of alpha power in and alpha-tuned connectivity between sensory cortices changed parametrically with delay duration (i.e., decrease in occipitoparietal regions, increase in temporal regions). Temporal expectation not only counteracted alpha power decline in heteromodal brain areas (i.e., supramarginal gyrus), but also had a beneficial effect on memory decay, counteracting memory performance decline. Correspondingly, temporal expectation also boosted alpha connectivity within attention networks known to play an active role during memory maintenance. The present data show how patterns of alpha power orchestrate short-term memory decay and encourage a more nuanced perspective on alpha power across brain space and time beyond its inhibitory role.SIGNIFICANCE STATEMENT Our sensory memories of the physical world fade quickly. We show here that this decay of short-term memory can be counteracted by so-called temporal expectation; that is, knowledge of when to expect a sensory event that an individual must remember. We also show that neural oscillations in the "alpha" (8-13 Hz) range index both the degree of memory decay (for brief sound patterns) and the respective memory benefit from temporal expectation. Spatially distributed cortical patterns of alpha power show opposing effects in auditory versus visual sensory cortices. Moreover, alpha tuned connectivity changes within supramodal attention networks reflect the allocation of neural resources as short-term memory representations fade. PMID- 30012684 TI - Archaeal Unfoldase Counteracts Protein Misfolding Retinopathy in Mice. AB - Deregulation of cellular proteostasis due to the failure of the ubiquitin proteasome system to dispose of misfolded aggregation-prone proteins is a hallmark of various neurodegenerative diseases in humans. Microorganisms have evolved to survive massive protein misfolding and aggregation triggered by heat shock using their protein-unfolding ATPases (unfoldases) from the Hsp100 family. Because the Hsp100 chaperones are absent in homoeothermic mammals, we hypothesized that the vulnerability of mammalian neurons to misfolded proteins could be mitigated by expressing a xenogeneic unfoldase. To test this idea, we expressed proteasome-activating nucleotidase (PAN), a protein-unfolding ATPase from thermophilic Archaea, which is homologous to the 19S eukaryotic proteasome and similar to the Hsp100 family chaperones in rod photoreceptors of mice. We found that PAN had no obvious effect in healthy rods; however, it effectively counteracted protein-misfolding retinopathy in Ggamma1 knock-out mice. We conclude that archaeal PAN can rescue a protein-misfolding neurodegenerative disease, likely by recognizing misfolded mammalian proteins.SIGNIFICANCE STATEMENT This study demonstrates successful therapeutic application of an archaeal molecular chaperone in an animal model of neurodegenerative disease. Introducing the archaeal protein-unfolding ATPase proteasome-activating nucleotidase (PAN) into the retinal photoreceptors of mice protected these neurons from the cytotoxic effect of misfolded proteins. We propose that xenogeneic protein-unfolding chaperones could be equally effective against other types of neurodegenerative diseases of protein-misfolding etiology. PMID- 30012686 TI - Abnormal Low-Frequency Oscillations Reflect Trait-Like Pain Ratings in Chronic Pain Patients Revealed through a Machine Learning Approach. AB - Measures of moment-to-moment fluctuations in brain activity of an individual at rest have been shown to be a sensitive and reliable metric for studying pathological brain mechanisms across various chronic pain patient populations. However, the relationship between pathological brain activity and clinical symptoms are not well defined. Therefore, we used regional BOLD signal variability/amplitude of low-frequency oscillations (LFOs) to identify functional brain abnormalities in the dynamic pain connectome in chronic pain patients that are related to chronic pain characteristics (i.e., pain intensity). Moreover, we examined whether there were sex-specific attributes of these functional brain abnormalities and whether functional brain abnormalities in patients is related to pain intensity characteristics on different time scales. We acquired resting state functional MRI and quantified frequency-specific regional LFOs in chronic pain patients with ankylosing spondylitis. We found that patients exhibit frequency-specific aberrations in LFOs. Specifically, lower-frequency (slow-5) abnormalities were restricted to the ascending pain pathway (thalamus and S1), whereas higher-frequency abnormalities also included the default mode (i.e., posterior cingulate cortex; slow-3, slow-4) and salience (i.e., mid-cingulate cortex) networks (slow-4). Using a machine learning approach, we found that these abnormalities, in particular within higher frequencies (slow-3), can be used to make generalizable inferences about patients' average pain ratings (trait-like pain) but not current (i.e., state-like) pain levels. Furthermore, we identified sex differences in LFOs in patients that were not present in healthy controls. These novel findings reveal mechanistic brain abnormalities underlying the longer lasting symptoms (trait pain intensity) in chronic pain.SIGNIFICANCE STATEMENT Measures of moment-to-moment fluctuations in brain activity of an individual at rest have been shown to be a reliable metric for studying functional brain associated with chronic pain. The current results demonstrate that dysfunction in these intrinsic fluctuations/oscillations in the ascending pain pathway, default mode network, and salience network during resting state display sex differences and can be used to make inferences about trait-like pain intensity ratings in chronic pain patients. These results provide robust and generalizable implications for investigating brain mechanisms associated with longer lasting/trait-like chronic pain symptoms. PMID- 30012687 TI - Binocular neuronal processing of object motion in an arthropod. AB - Animals use binocular information to guide many behaviors. In highly visual arthropods, complex binocular computations involved in processing panoramic optic flow generated during self-motion occur in the optic neuropils. However, the extent to which binocular processing of object motion occurs in these neuropils remains unknown. We investigated this in a crab, where the distance between the eyes and the extensive overlapping of their visual fields advocate for the use of binocular processing. By performing in vivo intracellular recordings from the lobula (third optic neuropil) of male crabs, we assessed responses of object motion sensitive neurons to ipsilateral or contralateral moving objects under binocular and monocular conditions. Most recorded neurons responded to stimuli seen independently with either eye, proving that each lobula receives profuse visual information from both eyes. The contribution of each eye to the binocular response varies among neurons, from those receiving comparable inputs from both eyes to those with mainly ipsilateral or contralateral components, some including contralateral inhibition. Electrophysiological profiles indicated that a similar number of neurons were recorded from their input or their output side. In monocular conditions, the first group showed shorter response delays to ipsilateral than to contralateral stimulation, while the second group showed the opposite. These results fit well with neurons conveying centripetal and centrifugal information from and toward the lobula respectively. Intracellular and massive stainings provided anatomical support for this and for direct connections between the two lobulae, but simultaneous recordings failed to reveal such connections. Simplified model circuits of interocular connections are discussed.SIGNIFICANCE STATEMENTMost active animals became equipped with two eyes, which contributes to functions like depth perception, objects spatial location and motion processing, all used for guiding behaviors. In visually active arthropods, binocular neural processing of the panoramic optic flow generated during self-motion happens already in the optic neuropils. However, whether binocular processing of single object motion occurs in these neuropils remained unknown. We investigated this in a crab, where motion-sensitive neurons from the lobula can be recorded in the intact animal. Here we demonstrate that different classes of neurons from the lobula compute binocular information. Our results provide new insight into where and how the visual information acquired by the two eyes is first combined in the brain of an arthropod. PMID- 30012689 TI - Neural Firing Patterns Are More Schematic and Less Sensitive to Changes in Background Visual Scenes in the Subiculum than in the Hippocampus. AB - Literature suggests that the hippocampus is central to processing visual scenes to remember contextual information, but the roles of its downstream structure, subiculum, remain unknown. Here, single units were recorded simultaneously in the dorsal CA1 and subiculum while male rats made spatial choices using visual scenes as cues in a T-maze. The firing fields of subicular neurons were schematically organized following the task structure, largely divided into pre-choice and post choice epochs, whereas those of CA1 cells were more punctate and bound to specific locations. When the rats were tested with highly familiar scenes, neurons in the CA1 and subiculum were indistinguishable in coding the task related information (e.g., scene, choice) through rate remapping. However, when the familiar scenes were blurred parametrically, the neurons in the CA1 responded sensitively to the novelty in task demand and changed its representations parametrically following the physical changes of the stimuli, whereas these functional characteristics were absent in the subiculum. These results suggest that the unique function of the hippocampus is to acquire contextual representations in association with discrete positions in space, especially when facing new and ambiguous scenes, whereas the subiculum may translate the position bound visual contextual information of the hippocampus into schematic codes once learning is established.SIGNIFICANCE STATEMENT Although the potential functional significance has been recognized for decades for the subiculum, its exact roles in a goal-directed memory task still remain elusive. In the current study, we present experimental evidence that may indicate that the neural population in the subiculum could translate the location-bound spatial representations of the hippocampus into more schematic representations of task demands. Our findings also imply that the visual scene-based codes conveyed by the hippocampus and subiculum may be identical in a well learned task, whereas the hippocampus may be more specialized in representing altered visual scenes than the subiculum. PMID- 30012688 TI - Perinatal exposure to an environmentally relevant mixture of phthalates results in a lower number of neurons and synapses in the medial prefrontal cortex and decreased cognitive flexibility in adult male and female rats. AB - The growth and organization of the developing brain is known to be influenced by hormones, but little is known about whether disruption of hormones affects cortical regions, like the medial prefrontal cortex (mPFC). This region is particularly important given its involvement in executive functions and implication in the pathology of many neuropsychiatric disorders. Here, we examine the long-term effects of perinatal exposure to endocrine-disrupting compounds, the phthalates, on the mPFC and associated behavior. This investigation is pertinent as humans are ubiquitously exposed to phthalates through a variety of consumer products and phthalates can readily cross the placenta and be delivered to offspring via lactation. Pregnant dams orally consumed an environmentally relevant mixture of phthalates at 0, 200, or 1000 MUg/kg/day through pregnancy and for 10 days while lactating. As adults, offspring were tested in an attentional set-shifting task, which assesses cognitive flexibility. Brains were also examined in adulthood for stereological quantification of the number of neurons, glia, and synapses within the mPFC. We found that, independent of sex, perinatal phthalate exposure at either dose resulted in a reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. Interestingly, the number of synapses was correlated with cognitive flexibility, such that rats with fewer synapses were less cognitively flexible than those with more synapses. These results demonstrate that perinatal phthalate exposure can have long-term effects on the cortex and behavior of both male and female rats.SIGNIFICANCE STATEMENTHumans globally are exposed on a daily basis to a variety of phthalates, which are endocrine-disrupting chemicals. The effects of phthalate exposure on the developing brain, especially on cognitively relevant regions like the medial prefrontal cortex (mPFC), is not known. Here, we use a rat model of human prenatal exposure to an environmentally relevant mixture of phthalates and find there is an appreciable reduction in neuron number, synapse number, and size of the mPFC and a deficit in cognitive flexibility. These results may have serious implications for humans given the mPFC is involved in executive functions and is implicated in the pathology of many neuropsychiatric disorders. PMID- 30012675 TI - Low-Dose Anti-Thymocyte Globulin (ATG) Preserves beta-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. AB - OBJECTIVE: A pilot study suggested that combination therapy with low-dose anti thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of beta-cell function in patients with new-onset T1D (duration <100 days). RESEARCH DESIGN AND METHODS: A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided P value < 0.025. RESULTS: The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) (P = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo (P = 0.031). HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, P = 0.002 and 0.011, respectively. CONCLUSIONS: Low-dose ATG slowed decline of C-peptide and reduced HbA1c in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease. PMID- 30012690 TI - Neuronal Correlates of Serial Decision-Making in the Supplementary Eye Field. AB - Human behavior is influenced by serial decision-making: past decisions affect choices that set the context for selecting future options. A primate brain region that may be involved in linking decisions across time is the supplementary eye field (SEF), which, in addition to its well known visual responses and saccade related activity, also signals the rules that govern flexible decisions and the outcomes of those decisions. Our hypotheses were that SEF neurons encode events during serial decision-making and link the sequential decisions with sustained activity. We recorded from neurons in the SEF of two rhesus monkeys (Macaca mulatta, one male, one female) that performed a serial decision-making task. The monkeys used saccades to select a rule that had to be applied later in the same trial to discriminate between visual stimuli. We found, first, that SEF neurons encoded the spatial parameters of saccades during rule selection but not during visual discrimination, suggesting a malleability to their movement-related tuning. Second, SEF activity linked the sequential decisions of rule selection and visual discrimination, but not continuously. Instead, rule-encoding activity appeared in a "just-in-time" manner before the visual discrimination. Third, SEF neurons encoded trial outcomes both prospectively, before decisions within a trial, and retrospectively, across multiple trials. The results thus identify neuronal correlates of rule selection and application in the SEF, including transient signals that link these sequential decisions. Its activity patterns suggest that the SEF participates in serial decision-making in a contextually dependent manner as part of a broader network.SIGNIFICANCE STATEMENT Much research has gone into studying the neurobiological basis of single, isolated decisions. An important next step is to understand how the brain links multiple decisions to generate a coherent stream of thought and behavior. We studied neural activity related to serial decision-making in an area of frontal cortex known as the supplementary eye field (SEF). Neural recordings were conducted in monkeys that performed a serial decision-making task in which they selected and applied rules. We found that SEF neurons convey signals for serial decision making, including transient encoding of one decision at the time it is needed for the next one and longer-term representations of trial outcomes, suggesting that the region plays a role in continuity of cognition and behavior. PMID- 30012691 TI - Cerebellar Processing Common to Delay and Trace Eyelid Conditioning. AB - Results from previous lesion studies have been interpreted as evidence that the cerebellar cortex plays different roles for delay and trace conditioning of eyelid responses. However, the cerebellar cortex is organized by parasagittal stripes of Purkinje cells (PCs) that converge onto common deep nucleus neurons and receive common or related climbing fiber inputs. Based on this organization, we hypothesized that cerebellar tasks involving the same response system, such as delay and trace eyelid conditioning, would engage the same PCs and that the relationships between PC activity and expression of behavioral responses would be similar for both tasks. To test these hypotheses, we used tetrode recordings from eyelid PCs in rabbits during expression of delay- and trace-conditioned eyelid responses. Previous recording studies during delay conditioning described a strong relationship between eyelid PC activity and the kinematics of conditioned eyelid responses. The present results replicate these findings for delay conditioning and show that the same relationship exists during trace eyelid conditioning. During transitions from delay to trace responding, the relationship between eyelid PCs and behavioral responses was relatively stable. We found that an inverse firing rate model tuned to predict PC activity during one training paradigm could then predict equally well the PC activity during the other training paradigm. These results provide strong evidence that cerebellar cortex processing is similar for delay and trace eyelid conditioning and that the parasagittal organization of the cerebellum, not the conditioning paradigm, dictate which neurons are engaged to produce adaptively timed conditioned responses.SIGNIFICANCE STATEMENT A variety of evidence from eyelid conditioning and other cerebellar-dependent behaviors indicates that the cerebellar cortex is necessary for learning and proper timing of cerebellar learned responses. Debates exist about whether trace eyelid conditioning data show that fundamentally different mechanisms operate in the cerebellum during tasks when input from the forebrain is necessary for learning. We show here that learning-related changes in a specific population of Purkinje cells control the timing and amplitude of cerebellar responses the same way regardless of the inputs necessary to learn the task. Our results indicate the parasagittal organization of the cerebellar cortex, not the complexity of inputs to the cerebellum, determines which neurons are engaged in the learning and execution of cerebellar-mediated responses. PMID- 30012693 TI - Persistent Sodium Current Drives Excitability of Immature Renshaw Cells in Early Embryonic Spinal Networks. AB - Spontaneous network activity (SNA) emerges in the spinal cord (SC) before the formation of peripheral sensory inputs and central descending inputs. SNA is characterized by recurrent giant depolarizing potentials (GDPs). Because GDPs in motoneurons (MNs) are mainly evoked by prolonged release of GABA, they likely necessitate sustained firing of interneurons. To address this issue we analyzed, as a model, embryonic Renshaw cell (V1R) activity at the onset of SNA (E12.5) in the embryonic mouse SC (both sexes). V1R are one of the interneurons known to contact MNs, which are generated early in the embryonic SC. Here, we show that V1R already produce GABA in E12.5 embryo, and that V1R make synaptic-like contacts with MNs and have putative extrasynaptic release sites, while paracrine release of GABA occurs at this developmental stage. In addition, we discovered that V1R are spontaneously active during SNA and can already generate several intrinsic activity patterns including repetitive-spiking and sodium-dependent plateau potential that rely on the presence of persistent sodium currents (INap). This is the first demonstration that INap is present in the embryonic SC and that this current can control intrinsic activation properties of newborn interneurons in the SC of mammalian embryos. Finally, we found that 5 MUm riluzole, which is known to block INaP, altered SNA by reducing episode duration and increasing inter-episode interval. Because SNA is essential for neuronal maturation, axon pathfinding, and synaptogenesis, the presence of INaP in embryonic SC neurons may play a role in the early development of mammalian locomotor networks.SIGNIFICANCE STATEMENT The developing spinal cord (SC) exhibits spontaneous network activity (SNA) involved in the building of nascent locomotor circuits in the embryo. Many studies suggest that SNA depends on the rhythmic release of GABA, yet intracellular recordings of GABAergic neurons have never been performed at the onset of SNA in the SC. We first discovered that embryonic Renshaw cells (V1R) are GABAergic at E12.5 and spontaneously active during SNA. We uncover a new role for persistent sodium currents (INaP) in driving plateau potential in V1R and in SNA patterning in the embryonic SC. Our study thus sheds light on a role for INaP in the excitability of V1R and the developing SC. PMID- 30012692 TI - The Transmembrane Domain of Synaptobrevin Influences Neurotransmitter Flux through Synaptic Fusion Pores. AB - The soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins synaptobrevin (Syb), syntaxin, and SNAP-25 function in Ca2+-triggered exocytosis in both endocrine cells and neurons. The transmembrane domains (TMDs) of Syb and syntaxin span the vesicle and plasma membrane, respectively, and influence flux through fusion pores in endocrine cells as well as fusion pores formed during SNARE-mediated fusion of reconstituted membranes. These results support a model for exocytosis in which SNARE TMDs form the initial fusion pore. The present study sought to test this model in synaptic terminals. Patch-clamp recordings of miniature EPSCs (mEPSCs) were used to probe fusion pore properties in cultured hippocampal neurons from mice of both sexes. Mutants harboring tryptophan at four different sites in the Syb TMD reduced the rate-of-rise of mEPSCs. A computer model that simulates glutamate diffusion and receptor activation kinetics could account for this reduction in mEPSC rise rate by slowing the flux of glutamate through synaptic fusion pores. TMD mutations introducing positive charge also reduced the mEPSC rise rate, but negatively charged residues and glycine, which should have done the opposite, had no effect. The sensitivity of mEPSCs to pharmacological blockade of receptor desensitization was enhanced by a mutation that slowed the mEPSC rate-of-rise, suggesting that the mutation prolonged the residence of glutamate in the synaptic cleft. The same four Syb TMD residues found here to influence synaptic release were found previously to influence endocrine release, leading us to propose that a similar TMD-lined fusion pore functions widely in Ca2+-triggered exocytosis in mammalian cells.SIGNIFICANCE STATEMENT SNARE proteins function broadly in biological membrane fusion. Evidence from non-neuronal systems suggests that SNARE proteins initiate fusion by forming a fusion pore lined by transmembrane domains, but this model has not yet been tested in synapses. The present study addressed this question by testing mutations in the synaptic vesicle SNARE synaptobrevin for an influence on the rise rate of miniature synaptic currents. These results indicate that synaptobrevin's transmembrane domain interacts with glutamate as it passes through the fusion pore. The sites in synaptobrevin that influence this flux are identical to those shown previously to influence flux through endocrine fusion pores. Thus, SNARE transmembrane domains may function in the fusion pores of Ca2+ triggered exocytosis of both neurotransmitters and hormones. PMID- 30012694 TI - Emergence of an Adaptive Command for Orienting Behavior in Premotor Brainstem Neurons of Barn Owls. AB - The midbrain map of auditory space commands sound-orienting responses in barn owls. Owls precisely localize sounds in frontal space but underestimate the direction of peripheral sound sources. This bias for central locations was proposed to be adaptive to the decreased reliability in the periphery of sensory cues used for sound localization by the owl. Understanding the neural pathway supporting this biased behavior provides a means to address how adaptive motor commands are implemented by neurons. Here we find that the sensory input for sound direction is weighted by its reliability in premotor neurons of the midbrain tegmentum of owls (male and female), such that the mean population firing rate approximates the head-orienting behavior. We provide evidence that this coding may emerge through convergence of upstream projections from the midbrain map of auditory space. We further show that manipulating the sensory input yields changes predicted by the convergent network in both premotor neural responses and behavior. This work demonstrates how a topographic sensory representation can be linearly read out to adjust behavioral responses by the reliability of the sensory input.SIGNIFICANCE STATEMENT This research shows how statistics of the sensory input can be integrated into a behavioral command by readout of a sensory representation. The firing rate of midbrain premotor neurons receiving sensory information from a topographic representation of auditory space is weighted by the reliability of sensory cues. We show that these premotor responses are consistent with a weighted convergence from the topographic sensory representation. This convergence was also tested behaviorally, where manipulation of stimulus properties led to bidirectional changes in sound localization errors. Thus a topographic representation of auditory space is translated into a premotor command for sound localization that is modulated by sensory reliability. PMID- 30012695 TI - In Spoken Word Recognition, the Future Predicts the Past. AB - Speech is an inherently noisy and ambiguous signal. To fluently derive meaning, a listener must integrate contextual information to guide interpretations of the sensory input. Although many studies have demonstrated the influence of prior context on speech perception, the neural mechanisms supporting the integration of subsequent context remain unknown. Using MEG to record from human auditory cortex, we analyzed responses to spoken words with a varyingly ambiguous onset phoneme, the identity of which is later disambiguated at the lexical uniqueness point. Fifty participants (both male and female) were recruited across two MEG experiments. Our findings suggest that primary auditory cortex is sensitive to phonological ambiguity very early during processing at just 50 ms after onset. Subphonemic detail is preserved in auditory cortex over long timescales and re evoked at subsequent phoneme positions. Commitments to phonological categories occur in parallel, resolving on the shorter timescale of ~450 ms. These findings provide evidence that future input determines the perception of earlier speech sounds by maintaining sensory features until they can be integrated with top-down lexical information.SIGNIFICANCE STATEMENT The perception of a speech sound is determined by its surrounding context in the form of words, sentences, and other speech sounds. Often, such contextual information becomes available later than the sensory input. The present study is the first to unveil how the brain uses this subsequent information to aid speech comprehension. Concretely, we found that the auditory system actively maintains the acoustic signal in auditory cortex while concurrently making guesses about the identity of the words being said. Such a processing strategy allows the content of the message to be accessed quickly while also permitting reanalysis of the acoustic signal to minimize parsing mistakes. PMID- 30012699 TI - Training in Structural Heart Disease: Call to Action. PMID- 30012696 TI - Identification of VAPA and VAPB as Kv2 Channel-Interacting Proteins Defining Endoplasmic Reticulum-Plasma Membrane Junctions in Mammalian Brain Neurons. AB - Membrane contacts between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are ubiquitous in eukaryotic cells and are platforms for lipid and calcium signaling and homeostasis. Recent studies have revealed proteins crucial to the formation and function of ER-PM junctions in non-neuronal cells, but little is known of the ER-PM junctions prominent in aspiny regions of mammalian brain neurons. The Kv2.1 voltage-gated potassium channel is abundantly clustered at ER-PM junctions in brain neurons and is the first PM protein that functions to organize ER-PM junctions. However, the molecular mechanism whereby Kv2.1 localizes to and remodels these junctions is unknown. We used affinity immunopurification and mass spectrometry-based proteomics on brain samples from male and female WT and Kv2.1 KO mice and identified the resident ER vesicle associated membrane protein-associated proteins isoforms A and B (VAPA and VAPB) as prominent Kv2.1-associated proteins. Coexpression with Kv2.1 or its paralog Kv2.2 was sufficient to recruit VAPs to ER-PM junctions. Multiplex immunolabeling revealed colocalization of Kv2.1 and Kv2.2 with endogenous VAPs at ER-PM junctions in brain neurons from male and female mice in situ and in cultured rat hippocampal neurons, and KO of VAPA in mammalian cells reduces Kv2.1 clustering. The association of VAPA with Kv2.1 relies on a "two phenylalanines in an acidic tract" (FFAT) binding domain on VAPA and a noncanonical phosphorylation-dependent FFAT motif comprising the Kv2-specific clustering or PRC motif. These results suggest that Kv2.1 localizes to and organizes neuronal ER-PM junctions through an interaction with VAPs.SIGNIFICANCE STATEMENT Our study identified the endoplasmic reticulum (ER) proteins vesicle-associated membrane protein-associated proteins isoforms A and B (VAPA and VAPB) as proteins copurifying with the plasma membrane (PM) Kv2.1 ion channel. We found that expression of Kv2.1 recruits VAPs to ER-PM junctions, specialized membrane contact sites crucial to distinct aspects of cell function. We found endogenous VAPs at Kv2.1-mediated ER-PM junctions in brain neurons and other mammalian cells and that knocking out VAPA expression disrupts Kv2.1 clustering. We identified domains of VAPs and Kv2.1 necessary and sufficient for their association at ER-PM junctions. Our study suggests that Kv2.1 expression in the PM can affect ER-PM junctions via its phosphorylation dependent association to ER-localized VAPA and VAPB. PMID- 30012700 TI - Hypercoagulable Workup in Thrombotic Cardiovascular Diseases. PMID- 30012697 TI - Differentiation of Human Medial Prefrontal Cortex Activity Underlies Long-Term Resistance to Forgetting in Memory. AB - It is well known that distributing study events over time leads to better memory over long time scales, compared with massing study events together. One explanation for such long-term resistance to forgetting is that distributed study leads to neural differentiation in memory, which supports retrieval of past experiences by disambiguating highly similar memory representations. Neuroanatomical models of episodic memory retrieval propose that the hippocampus and medial prefrontal cortex (MPFC) work together to enable retrieval of behaviorally appropriate memories. However, it is not known how representations in these regions jointly support resistance to forgetting long after initial learning. Using fMRI, we measured differentiation in retrieved memory representations following an extended delay in male and female human participants. After 1 week, word-object associations were better remembered if studied across 2 d (overnight), allowing associations to be learned in distinct temporal contexts, compared with learning within a single day (same day). MPFC retrieval patterns showed differentiation for overnight relative to same day memories, whereas hippocampal patterns reflected associative retrieval success. Overnight memory differentiation in MPFC was higher for associative than item memories and higher than differentiation assessed over a brain-wide set of retrieval-active voxels. The memory-related difference in MPFC pattern differentiation correlated with memory success for overnight learning and with hippocampal-MPFC functional connectivity. These results show that learning information across days leads to differentiated MPFC memory representations, reducing forgetting after 1 week, and suggest this arises from persistent interactions between MPFC and hippocampus.SIGNIFICANCE STATEMENT Neural activity in both the hippocampus and medial prefrontal cortex (MPFC) has been linked to memory-related representations, but prior work has not examined how these representations support episodic memory retrieval over extended time scales that are characteristic of everyday retrieval. We show that differentiation in MPFC activity 1 week after encoding is higher for retrieved information learned across 2 d compared with within a single day. In hippocampus, differentiation was greater for detailed memory retrieval but was not influenced by whether information had been learned over 1 or 2 d. Differentiation in MPFC predicted behavioral robustness to forgetting and was correlated with hippocampal-MPFC connectivity. The results suggest that context-based differentiation supports robust long-term memory via persistent MPFC-hippocampal interactions. PMID- 30012701 TI - Acute Ischemic Stroke Biology Demands Fast Treatment. PMID- 30012698 TI - Three-tiered score for Ki-67 and p16ink4a improves accuracy and reproducibility of grading CIN lesions. AB - AIMS: To investigate the accuracy and reproducibility of a scoring system for cervical intraepithelial neoplasia (CIN1-3) based on immunohistochemical (IHC) biomarkers Ki-67 and p16ink4a. METHODS: 115 cervical tissue specimens were reviewed by three expert gynaecopathologists and graded according to three strategies: (1) CIN grade based on H&E staining only; (2) immunoscore based on the cumulative score of Ki-67 and p16ink4a only (0-6); and (3) CIN grade based on H&E supported by non-objectified IHC 2 weeks after scoring 1 and 2. The majority consensus diagnosis of the CIN grade based on H&E supported by IHC was used as the Reference Standard. The proportion of test positives (accuracy) and the absolute agreements across pathologists (reproducibility) of the three grading strategies within each Reference Standard category were calculated. RESULTS: We found that immunoscoring with positivity definition 6 yielded the highest proportion of test positives for Reference Standard CIN3 (95.5%), in combination with the lowest proportion of test positives in samples with CIN1 (1.8%). The proportion of test positives for CIN3 was significantly lower for sole H&E staining (81.8%) or combined H&E and IHC grading (84.8%) with positivity definition >=CIN3. Immunoscore 6 also yielded high absolute agreements for CIN3 and CIN1, but the absolute agreement was low for CIN2. CONCLUSIONS: The higher accuracy and reproducibility of the immunoscore opens the possibility of a more standardised and reproducible definition of CIN grade than conventional pathology practice, allowing a more accurate comparison of CIN-based management strategies and evaluation of new biomarkers to improve the understanding of progression of precancer from human papillomavirus infection to cancer. PMID- 30012702 TI - Permanently Farnesylated Prelamin A, Progeria, and Atherosclerosis. PMID- 30012704 TI - Designing a Better Mousetrap: Reflections on the November 28, 2017, US Food and Drug Administration Meeting on Next-Generation "High-Sensitivity" Cardiac Troponin Assays to Diagnose Myocardial Infarction. PMID- 30012706 TI - Double-Strand DNA Sensing Aim2 Inflammasome Regulates Atherosclerotic Plaque Vulnerability. PMID- 30012707 TI - Letter by Murakami et al Regarding Article, "Systemic Right Ventricle in Adults with Congenital Heart Disease: Anatomic and Phenotypic Spectrum and Current Approach to Management". PMID- 30012708 TI - Response by Brida et al to Letter Regarding Article, "Systemic Right Ventricle in Adults With Congenital Heart Disease: Anatomic and Phenotypic Spectrum and Current Approach to Management". PMID- 30012709 TI - Letter by Reiffel Regarding Article, "Unique ECG During Sinus Rhythm in a Patient With A Postmyocardial Infarction-Sustained Ventricular Tachycardia". PMID- 30012703 TI - Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. AB - Lipid droplets (LDs) are distinct and dynamic organelles that affect the health of cells and organs. Much progress has been made in understanding how these structures are formed, how they interact with other cellular organelles, how they are used for storage of triacylglycerol in adipose tissue, and how they regulate lipolysis. Our understanding of the biology of LDs in the heart and vascular tissue is relatively primitive in comparison with LDs in adipose tissue and liver. The National Heart, Lung, and Blood Institute convened a working group to discuss how LDs affect cardiovascular diseases. The goal of the working group was to examine the current state of knowledge on the cell biology of LDs, including current methods to study them in cells and organs and reflect on how LDs influence the development and progression of cardiovascular diseases. This review summarizes the working group discussion and recommendations on research areas ripe for future investigation that will likely improve our understanding of atherosclerosis and heart function. PMID- 30012710 TI - Response by Farre and Wellens to Letter Regarding Article, "Unique ECG During Sinus Rhythm in a Patient With a Postmyocardial Infarction-Sustained Ventricular Tachycardia". PMID- 30012711 TI - Letter by Rajtar-Salwa and Dimitrow Regarding Article, "Exercise and Hypertrophic Cardiomyopathy: Time for a Change of Heart". PMID- 30012712 TI - Response by Saberi and Day to Letter Regarding Article, "Exercise and Hypertrophic Cardiomyopathy: Time for a Change of Heart". PMID- 30012713 TI - Letter by Dharmarajan and Dharmarajan Regarding Article, "Asymptomatic ST-Segment Elevation ECG in Patient With Kidney Failure". PMID- 30012714 TI - Response by Sotananusak and Meemook to Letter Regarding Article, "Asymptomatic ST Segment-Elevation ECG in Patient With Kidney Failure". PMID- 30012716 TI - Improving public health and health systems through evidence informed policy in the Americas. PMID- 30012715 TI - Transcriptional activity of oestrogen receptors in the course of embryo development. AB - Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals. PMID- 30012720 TI - I, Sex Robot: the health implications of the sex robot industry. PMID- 30012717 TI - Effect of antiretroviral therapy on allele-associated Lp(a) level in women with HIV in the Women's Interagency HIV Study. AB - We previously demonstrated an association between lipoprotein (a) [Lp(a)] levels and atherosclerosis in human immunodeficiency virus (HIV)-seropositive women. The effects of antiretroviral therapy (ART) on Lp(a) levels in relation to apo(a) size polymorphism remain unclear. ART effects on allele-specific apo(a) level (ASL), an Lp(a) level associated with individual apo(a) alleles within each allele-pair, were determined in 126 HIV-seropositive women. ART effects were tested by a mixed-effects model across pre-ART and post-ART first and third visits. Data from 120 HIV-seronegative women were used. The mean age was 38 years; most were African-American (~70%). Pre-ART ASLs associated with the larger (4.6 mg/dl vs. 8.0 mg/dl, P = 0.024) or smaller (13 mg/dl vs. 19 mg/dl, P = 0.041) apo(a) sizes were lower in the HIV-seropositive versus HIV-seronegative group, as was the prevalence of a high Lp(a) level (P = 0.013). Post-ART ASL and prevalence of high Lp(a) or apo(a) sizes and frequency of small size apo(a) (?22 kringles) did not differ between the two groups. ART increased Lp(a) level (from 18 to 24 mg/dl, P < 0.0001) and both ASLs (P < 0.001). In conclusion, regardless of genetic control, Lp(a) can be modulated by HIV and its treatment. ART initiation abrogates HIV-induced suppression of Lp(a) levels and ASLs, contributing to promote CVD risk in HIV-seropositive individuals. PMID- 30012718 TI - Characterizing meiotic chromosomes' structure and pairing using a designer sequence optimized for Hi-C. AB - In chromosome conformation capture experiments (Hi-C), the accuracy with which contacts are detected varies due to the uneven distribution of restriction sites along genomes. In addition, repeated sequences or homologous regions remain indistinguishable because of the ambiguities they introduce during the alignment of the sequencing reads. We addressed both limitations by designing and engineering 144 kb of a yeast chromosome with regularly spaced restriction sites (Syn-HiC design). In the Syn-HiC region, Hi-C signal-to-noise ratio is enhanced and can be used to measure the shape of an unbiased distribution of contact frequencies, allowing to propose a robust definition of a Hi-C experiment resolution. The redesigned region is also distinguishable from its native homologous counterpart in an otherwise isogenic diploid strain. As a proof of principle, we tracked homologous chromosomes during meiotic prophase in synchronized and pachytene-arrested cells and captured important features of their spatial reorganization, such as chromatin restructuration into arrays of Rec8-delimited loops, centromere declustering, individualization, and pairing. Overall, we illustrate the promises held by redesigning genomic regions to explore complex biological questions. PMID- 30012721 TI - Advance notice of contraceptive availability at surgical abortion: a pilot randomised controlled trial. AB - BACKGROUND: With advance notice about the availability and effectiveness of contraceptive methods, abortion patients have more time and information for decision-making. We assessed the impact of an informational telephone call prior to the surgical abortion visit on patient contraceptive knowledge. METHODS: This was a pilot randomised controlled trial. Prior to their abortion visit, participants were randomised to the intervention message, a standardised notification about the availability, effectiveness and safety of long-acting (LARC) and short-acting reversible contraception (SARC) on the day of the abortion, or to the control message, a reiteration of appointment logistics without information about contraception. At the visit, participants completed a pre-procedure survey to assess contraceptive knowledge and usefulness of the intervention. The primary outcome was knowledge of LARC availability immediately after surgical abortion. A secondary outcome was contraceptive method uptake. RESULTS: We enrolled 234 subjects. The pre-visit telephone notification improved knowledge that LARC is available immediately after surgical abortion (71.3% vs 50.9%, P<0.01). Participants in both study arms found the telephone notifications useful. Post-abortion contraceptive method choice did not differ between study arms. CONCLUSIONS: Advance notice about contraception was acceptable to surgical abortion patients and improved their contraceptive knowledge. TRIAL REGISTRATION NUMBER: NCT02836561. PMID- 30012722 TI - Navigating change. PMID- 30012723 TI - Venus. PMID- 30012725 TI - Occult blood in faeces: a window into health beyond the colorectum? PMID- 30012724 TI - Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality. AB - OBJECTIVE: An association between detectable faecal haemoglobin (f-Hb) and both the risk of death from colorectal cancer (CRC) and all-cause mortality has been reported. We set out to confirm or refute this observation in a UK population and to explore the association between f-Hb, as indicated by a positive guaiac faecal occult blood test (gFOBT) result, and different causes of death. DESIGN: All individuals (134 192) who participated in gFOBT screening in Tayside, Scotland between 29/03/2000 and 29/03/2016 were studied by linking their test result (positive or negative) with mortality data from the National Records of Scotland database and following to 30/03/2016. RESULTS: Those with a positive test result (n=2714) had a higher risk of dying than those with a negative result, from CRC: HR 7.79 (95% CI 6.13 to 9.89), p<0.0001, (adjusted for, gender, age, deprivation quintile and medication that can cause bleeding) and all non-CRC causes: HR 1.58 (95% CI 1.45 to 1.73), p<0.0001.. In addition, f-Hb detectable by gFOBT was significantly associated with increased risk of dying from circulatory disease, respiratory disease, digestive diseases (excluding CRC), neuropsychological disease, blood and endocrine disease and non-CRC. CONCLUSION: The presence of detectable f-Hb is associated with increased risk of death from a wide range of causes. PMID- 30012726 TI - Redirection of metabolism in response to fatty acid kinase in Staphylococcus aureus. AB - Staphylococcus aureus is capable of phosphorylating exogenous fatty acids via the fatty acid kinase FakA for incorporation into the bacterium's membrane. Additionally, FakA plays a significant role in virulence factor regulation and skin infections. We previously showed that a fakA mutant displays altered growth kinetics in vitro, observed during late-exponential phase of growth. Here, we demonstrate that the absence of FakA leads to key metabolic changes. First, the fakA mutant has an altered acetate metabolism with acetate being consumed at an increased rate than the wild-type strain. Moreover, the growth benefit was diminished with inactivation of the acetate-generating enzyme AckA. Using a mass spectrometry-based approach, we identified altered concentrations of TCA cycle intermediates and both intracellular and extracellular amino acids. Together, these data demonstrate a change in carbohydrate carbon utilization and altered amino acid metabolism in the fakA mutant. Energy status analysis revealed the mutant had a similar ADP/ATP ratio, but reduced adenylate energy charge. The inactivation of fakA changed the NAD+/NADH and NADP+/NADPH ratio, indicating a more oxidized cellular environment. Evidence points towards the global metabolic regulatory proteins CcpA and CodY being important contributors for the altered growth in a fakA mutant. Indeed, it was found that directing amino acids from the urea cycle into the TCA cycle via glutamate dehydrogenase was an essential component of S. aureus growth after glucose depletion. Together, this data identifies a previously unidentified role for FakA in the global physiology of S. aureus that links external fatty acid utilization and central metabolism.Importance The fatty acid kinase, FakA, of Staphylococcus aureus plays several important roles in the cell. FakA is important for the activation of the SaeRS two-component system and secreted virulence factors like alpha-hemolysin. However, the contribution of FakA to cellular metabolism has not been explored. Here, we highlight the metabolic consequence of removal of FakA from the cell. The absence of FakA leads to altered acetate metabolism, altered redox balance, as well as a change in intracellular amino acids. Additionally, the use of environmental amino acids sources is affected by FakA. Together, these results demonstrate for the first time that FakA provides a link between the pathways for exogenous fatty acid use, virulence factor regulation, and other metabolic processes. PMID- 30012727 TI - The Chaperone Activities of DsbG and Spy Restore Peptidoglycan Biosynthesis in the elyC Mutant by Preventing Envelope Protein Aggregation. AB - Peptidoglycan (PG) is the main structural component of bacterial envelopes. It protects bacterial cells against variations in osmotic pressure and cell lysis. The newly discovered Escherichia coli factor ElyC has been shown to be important for peptidoglycan biosynthesis at low temperatures. PG production in DeltaelyC mutant cells is totally blocked after a few hours of growth at 21 degrees C, triggering cell lysis. In this study, we took a candidate approach to identify genetic suppressors of the DeltaelyC mutant cell lysis phenotype. We identified the periplasmic proteins DsbG and Spy as multicopy suppressors and showed that their overproduction restores PG biosynthesis in the DeltaelyC mutant. Interestingly, we found that DsbG acts by a novel mechanism, which is independent of its known reductase activity and substrates. DsbG, like Spy, acts as a chaperone to reduce the amounts of protein aggregates in the envelopes of DeltaelyC cells. In fact, we found that the amount of protein aggregates was greater in the DeltaelyC mutant than in the wild type. Taken together, our results show a protein-folding defect in the envelope compartments of DeltaelyC cells that blocks PG production, and they reveal a new physiological activity of DsbG.IMPORTANCE Peptidoglycan biosynthesis is a dynamic and well-controlled pathway. The molecular assembly of PG and the regulatory pathways ensuring its maintenance are still not well understood. Here we studied the newly discovered Escherichia coli factor ElyC, which is important for PG biosynthesis at low temperatures. We revealed an important protein-folding defect in the DeltaelyC mutant and showed that overproduction of the periplasmic chaperone DsbG or Spy was sufficient to correct the protein-folding defect and restore PG biosynthesis. These results show that the PG defect in the absence of ElyC is caused, at least in part, by a protein-folding problem in the cell envelope. Furthermore, we showed, for the first time, that the periplasmic protein DsbG has chaperone activity in vivo. PMID- 30012728 TI - Rickettsia Lipid A Biosynthesis Utilizes the Late Acyltransferase LpxJ for Secondary Fatty Acid Addition. AB - Members of the Rickettsia genus are obligate intracellular, Gram-negative coccobacilli that infect mammalian and arthropod hosts. Several rickettsial species are human pathogens and are transmitted by blood-feeding arthropods. In Gram-negative parasites, the outer membrane (OM) sits at the nexus of the host pathogen interaction and is rich in lipopolysaccharide (LPS). The lipid A component of LPS anchors the molecule to the bacterial surface and is an endotoxic agonist of Toll-like receptor 4 (TLR4). Despite the apparent importance of lipid A in maintaining OM integrity, as well as its inflammatory potential during infection, this molecule is poorly characterized in Rickettsia pathogens. In this work, we have identified and characterized new members of the recently discovered LpxJ family of lipid A acyltransferases in both Rickettsia typhi and Rickettsia rickettsii, the etiological agents of murine typhus and Rocky Mountain spotted fever, respectively. Our results demonstrate that these enzymes catalyze the addition of a secondary acyl chain (C14/C16) to the 3'-linked primary acyl chain of the lipid A moiety in the final steps of the Raetz pathway of lipid A biosynthesis. Since lipid A architecture is fundamental to bacterial OM integrity, we believe that rickettsial LpxJ may be important in maintaining membrane dynamics to facilitate molecular interactions at the host-pathogen interface that are required for adhesion and invasion of mammalian cells. This work contributes to our understanding of rickettsial outer membrane physiology and sets a foundation for further exploration of the envelope and its role in pathogenesis.IMPORTANCE Lipopolysaccharide (LPS) triggers an inflammatory response through the TLR4-MD2 receptor complex and inflammatory caspases, a process mediated by the lipid A moiety of LPS. Species of Rickettsia directly engage both extracellular and intracellular immunosurveillance, yet little is known about rickettsial lipid A. Here, we demonstrate that the alternative lipid A acyltransferase, LpxJ, from Rickettsia typhi and R. rickettsii catalyzes the addition of C16 fatty acid chains into the lipid A 3'-linked primary acyl chain, accounting for major structural differences relative to the highly inflammatory lipid A of Escherichia coli. PMID- 30012729 TI - Fluorescence-based detection of natural transformation in drug resistant Acinetobacter baumannii. AB - Acinetobacter baumannii is a nosocomial agent with a high propensity for developing resistance to antibiotics. This ability relies on horizontal gene transfer mechanisms occurring in the Acinetobacter genus, including natural transformation. To study natural transformation in bacteria, the most prevalent method uses selection for the acquisition of an antibiotic resistance marker in a target chromosomal locus by the recipient cell. Most clinical isolates of A. baumannii are resistant to multiple antibiotics limiting the use of such selection-based method. Here we report the development of a phenotypic and selection-free method based on flow cytometry to detect transformation events in multidrug resistant (MDR) clinical A. baumannii isolates. To this end, we engineered a translational fusion between the abundant and conserved A. baumannii nucleoprotein (HU) and the superfolder green fluorescent protein (sfGFP). The new method was benchmarked against the conventional antibiotic selection-based method. Using this new method, we investigated several parameters affecting transformation efficiencies and identified conditions of transformability one hundred times higher than those previously reported. Using optimized transformation conditions, we probed natural transformation in a set of MDR clinical and non-clinical animal A. baumannii isolates. Regardless of their origin, the majority of the isolates displayed natural transformability, indicative of a conserved trait in the species. Overall, this new method and optimized protocol will greatly facilitate the study of natural transformation in the opportunistic pathogen A. baumanniiIMPORTANCE Antibiotic resistance is a pressing global health concern with the rise of multiple and pan-resistant pathogens. The rapid and unfailing resistance to multiple antibiotics of the nosocomial agent Acinetobacter baumannii, notably to carbapenems, prompt to understand the mechanisms behind acquisition of new antibiotic resistance genes. Natural transformation, one of horizontal gene transfer mechanisms in bacteria, was only recently described in A. baumannii and could explain its ability to acquire resistance genes. We developed a reliable method to probe and study natural transformation mechanism in A. baumannii More broadly, this new method based on flow cytometry will allow experimental detection and quantification of horizontal gene transfer events in multidrug resistant A. baumannii. PMID- 30012731 TI - Genetic, Biochemical, and Molecular Characterization of Methanosarcina barkeri Mutants Lacking Three Distinct Classes of Hydrogenase. AB - The methanogenic archaeon Methanosarcina barkeri encodes three distinct types of hydrogenase, whose functions vary depending on the growth substrate. These include the F420-dependent (Frh), methanophenazine-dependent (Vht), and ferredoxin-dependent (Ech) hydrogenases. To investigate their physiological roles, we characterized a series of mutants lacking each hydrogenase in various combinations. Mutants lacking Frh, Vht, or Ech in any combination failed to grow on H2-CO2, whereas only Vht and Ech were essential for growth on acetate. In contrast, a mutant lacking all three grew on methanol with a final growth yield similar to that of the wild type and produced methane and CO2 in the expected 3:1 ratio but had a ca. 33% lower growth rate. Thus, hydrogenases play a significant, but nonessential, role during growth on this substrate. As previously observed, mutants lacking Ech failed to grow on methanol-H2 unless they were supplemented with biosynthetic precursors. Interestingly, this phenotype was abolished in the Deltaech Deltafrh and Deltaech Deltafrh Deltavht mutants, consistent with the idea that hydrogenases inhibit methanol oxidation in the presence of H2, which prevents production of the reducing equivalents needed for biosynthesis. Quantification of the methane and CO2 produced from methanol by resting cell suspensions of various mutants supported this conclusion. On the basis of the global transcriptional profiles, none of the hydrogenases were upregulated to compensate for the loss of the others. However, the transcript levels of the F420 dehydrogenase operon were significantly higher in all strains lacking frh, suggesting a mechanism to sense the redox state of F420 The roles of the hydrogenases in energy conservation during growth with each methanogenic pathway are discussed.IMPORTANCE Methanogenic archaea are key players in the global carbon cycle due to their ability to facilitate the remineralization of organic substrates in many anaerobic environments. The consequences of biological methanogenesis are far-reaching, with impacts on atmospheric methane and CO2 concentrations, agriculture, energy production, waste treatment, and human health. The data presented here clarify the in vivo function of hydrogenases during methanogenesis, which in turn deepens our understanding of this unique form of metabolism. This knowledge is critical for a variety of important issues ranging from atmospheric composition to human health. PMID- 30012730 TI - More than rotating flagella: LPS as a secondary receptor for flagellotropic phage 7-7-1. AB - Bacteriophage 7-7-1, a member of the Myoviridae family, infects the soil bacterium Agrobacterium sp. H13-3. Infection requires attachment to actively rotating bacterial flagellar filaments, with flagellar number, length, and rotation speed being important determinants for infection efficiency. To identify secondary receptor(s) on the cell surface, we isolated motile, phage-resistant Agrobacterium sp. H13-3 transposon mutants. Transposon insertion sites were pinpointed using arbitrary-primed polymerase chain reaction and bioinformatics analyses. Three genes were recognized, whose corresponding proteins had the following computationally predicted functions: AGROH133_07337, a glycosyl transferase, AGROH133_13050, a UDP-glucose 4-epimerase, and AGROH133_08824, an integral cytoplasmic membrane protein. The first two gene products are part of the lipopolysaccharide (LPS) synthesis pathway, while the latter is predicted to be a relatively small (13.4 kDa) cytosolic membrane protein with up to four transmembrane helices. Phenotypes of transposon mutants were verified by complementation and site-directed mutagenesis. Additional characterization of motile, phage resistant mutants is also described. Given these findings, we propose a model for Agrobacterium sp. H13-3 infection by bacteriophage 7-7-1 where the phage initially attaches to the flagellar filament and is propelled down towards the cell surface by clockwise flagellar rotation. The phage then attaches to and degrades the LPS to reach the outer membrane, and ejects its DNA into the host using its syringe-like contractile tail. We hypothesize that the integral membrane protein plays an important role in events following viral DNA ejection or in LPS processing and/or deployment. The proposed two-step attachment mechanism may be conserved among other flagellotropic phages infecting Gram negative bacteria.IMPORTANCE Flagellotropic bacteriophages belong to tailed phage order Caudovirales, which are the most abundant in the virome. While it is known that these viruses adhere to the bacterial flagellum and use flagellar rotation to reach the cell surface, their infection mechanisms are poorly understood. Characterizing flagellotropic phage-host interactions is crucial to understanding how microbial communities are shaped. Using a transposon mutagenesis approach combined with a screen for motile, phage-resistant mutants, we identified lipopolysaccharides as the secondary cell surface receptor for phage 7-7-1. This is the first cell surface receptor identified for flagellotropic phages. One hypothetical membrane protein was also recognized as essential for infection. These new findings, together with previous results, culminated in an infection model for phage 7-7-1. PMID- 30012733 TI - Children's understanding of death: from biology to religion. AB - Young children construct a biological conception of death, recognizing that death terminates mental and bodily processes. Despite this recognition, many children are receptive to an alternative conception of death, which affirms that the deceased has an afterlife elsewhere. A plausible interpretation of children's receptivity to this alternative conception is that human beings, including young children, are naturally disposed to remember and keep in mind individuals to whom they are attached even when those individuals leave and are absent for extended periods. This disposition is reflected in the pervasive tendency to talk about death as a departure rather than a terminus. It also enables the living to sustain their ties to the dead, even if, in the case of death, the departure is permanent rather than temporary. Linguistic and developmental evidence for these claims is reviewed. Possible biological origins and implications for archaeological research are also discussed.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012732 TI - Coherent Feedforward Regulation of Gene Expression by Caulobacter sigmaT and GsrN during Hyperosmotic Stress. AB - GsrN is a conserved small RNA that is under transcriptional control of the general stress sigma factor, sigmaT, and that functions as a posttranscriptional regulator of Caulobacter crescentus survival under multiple stress conditions. We have defined features of GsrN structure that determine survival under hyperosmotic stress, and we have applied transcriptomic and proteomic methods to identify regulatory targets of GsrN under hyperosmotic conditions. The 5' end of GsrN, which includes a conserved cytosine-rich stem-loop structure, is necessary for cell survival after osmotic upshock. GsrN both activates and represses gene expression in this stress condition. Expression of an uncharacterized open reading frame predicted to encode a glycine zipper protein, osrP, is strongly activated by GsrN. Our data support a model in which GsrN physically interacts with osrP mRNA through its 5' C-rich stem-loop to enhance OsrP protein expression. We conclude that sigT, gsrN, and osrP form a coherent feedforward loop in which sigmaT activates gsrN and osrP transcription during stress and GsrN activates OsrP protein expression at the posttranscriptional level. This study delineates transcriptional and posttranscriptional layers of Caulobacter gene expression control during hyperosmotic stress, uncovers a new regulatory target of GsrN, and defines a coherent feedforward motif in the Caulobacter general stress response (GSR) regulatory network.IMPORTANCE Bacteria inhabit diverse niches and must adapt their physiology to constant environmental fluctuations. A major response to environmental perturbation is to change gene expression. Caulobacter and other alphaproteobacteria initiate a complex gene expression program known as the general stress response (GSR) under conditions including oxidative stress, osmotic stress, and nutrient limitation. The GSR enables cell survival in these environments. Understanding how bacteria survive stress requires that we dissect gene expression responses, such as the GSR, at the molecular level. This study is significant, as it defines transcriptional and posttranscriptional layers of gene expression regulation in response to hyperosmotic stress. We further provide evidence that a coherent feedforward motif influences the system properties of the Caulobacter GSR pathway. PMID- 30012734 TI - Sources of children's knowledge about death and dying. AB - In the last century, decreases in infant and child mortality, urbanization and increases in healthcare efficacy have reduced children's personal exposure to death and dying. So how do children acquire accurate conceptions of death in this context? In this paper, we discuss three sources of children's learning about death and dying, namely, direct experience of death, parental communication about death and portrayals of death in the media and the arts. We conclude with recommendations about how best to teach modern children about this aspect of life.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012736 TI - The lure of death: suicide and human evolution. AB - At some point in evolutionary history, human beings came to understand, as no non human animals do, that death brings to an end a person's bodily and mental presence in the world. A potentially devastating consequence was that individuals, seeking to escape physical or mental pain, might choose to kill themselves.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012737 TI - The moral standing of the dead. AB - In choosing to do certain things, we appear to presuppose that we can act in the interests the dead, and that we have a duty to do so. For example, some of us go to great lengths to carry out their final wishes. Given that the dead no longer exist, however, it seems that nothing can be good or bad for them: they lack prudential interests. In that case, it is hard to see how we could owe them anything. They seem to lack moral standing altogether. In this essay, I will rebut this line of thought. I will claim that in some cases things that happen after people die are indeed good or bad for them. Their interests can still be advanced or hindered, so the dead have moral standing.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012735 TI - The integrated motivational-volitional model of suicidal behaviour. AB - Suicide is a major public health concern accounting for 800 000 deaths globally each year. Although there have been many advances in understanding suicide risk in recent decades, our ability to predict suicide is no better now than it was 50 years ago. There are many potential explanations for this lack of progress, but the absence, until recently, of comprehensive theoretical models that predict the emergence of suicidal ideation distinct from the transition between suicidal ideation and suicide attempts/suicide is key to this lack of progress. The current article presents the integrated motivational-volitional (IMV) model of suicidal behaviour, one such theoretical model. We propose that defeat and entrapment drive the emergence of suicidal ideation and that a group of factors, entitled volitional moderators (VMs), govern the transition from suicidal ideation to suicidal behaviour. According to the IMV model, VMs include access to the means of suicide, exposure to suicidal behaviour, capability for suicide (fearlessness about death and increased physical pain tolerance), planning, impulsivity, mental imagery and past suicidal behaviour. In this article, we describe the theoretical origins of the IMV model, the key premises underpinning the model, empirical tests of the model and future research directions.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012738 TI - Changing relationship between the dead and the living in Japanese prehistory. AB - The aim of this paper is to propose a new insight on the changing burial practice by regarding it as a part of the cognitive system for maintaining complex social relationships. Development of concentrated burials and their transformation in Japanese prehistory are examined to present a specific case of the changing relationship between the dead and the living to highlight the significance of the dead in sociocultural evolution. The essential feature of the burial practices observed at Jomon sites is the centrality of the dead and their continuous presence in the kinship system. The mortuary practices discussed in this paper represent a close relationship between the dead and the living in the non hierarchical complex society, in which the dead were not detached from the society, but kept at its core, as a materialized reference of kin networks.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012740 TI - Social bonds with the dead: how funerals transformed in the twentieth and twenty first centuries. AB - Evolutionary thanatology includes the study of necrophoresis-the removal of dead individuals by the living among social insects. In human societies, 'necrophoresis' is performed via the funeral ceremony. In pre-modern societies, relatives and local community members helped to conduct funerals. In this way, holding a funeral was a form of mutual help, a social exchange of duty and responsibility essential to individuals. These societies developed systems to ensure the survival of humans as social animals based on mutual trust built over long periods of time within the same community. Contemporary societies are undermining these systems. Compared to funerals in pre-modern societies, holding a funeral in a modern society is a complicated process that requires professionals with specialized knowledge and skills. If people feel they can face mortality without support from relatives or the local community, and that they cannot necessarily expect a future return on the effort invested in community based social relationships, they may begin to disengage from such relationships. In the context of modernization, the clearest changes in collective funerary behaviours include decreased funeral attendance and the above-mentioned outsourcing of funerary services. As such, it can be said that bonds with the dead changed completely under modernization, especially in the twentieth and twenty-first centuries. To establish a sociology of death with a clearer focus on how funeral ceremonies have been affected by modernization, there is a need for research concerned with human behavioural changes regarding the treatment of corpses-that is, a 'funeralogy'. Accordingly, this study aimed to investigate how modernization has complexified the handling of deceased bodies as death-related services have become commoditized and outsourced while, at the same time, local communities are becoming disengaged from their traditional roles in funeral ceremonies. To this end, fieldwork was conducted in several countries. Moreover, data from surveys conducted by the Social Well-Being Research Consortium in Asia in five East and Southeast Asian countries were quantitatively analysed. The findings highlight the modernization of funerals with the outsourcing of funeral services from the perspective of socio-economic development.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012739 TI - Complicated grief: recent developments in diagnostic criteria and treatment. AB - Although grief is a natural response to loss among human beings, some people have a severe and prolonged course of grief. In the 1990s, unusual grief persisting with a high level of acute symptoms became known as 'complicated grief (CG)'. Many studies have shown that people who suffer from CG are at risk of long-term mental and physical health impairments and suicidal behaviours; it is considered a pathological state, which requires clinical intervention and treatment. DSM-5 (2013 Diagnostic and statistical manual of mental disorders, 5th edn) proposed 'persistent complex bereavement disorder' as a psychiatric disorder; it is similar to CG in that it is a trauma- and stress-related disorder. In recent years, there has been considerable research on the treatment of CG. Randomized controlled trials have suggested the efficacy of cognitive behavioural therapy including an exposure component that is targeted for CG. However, experts disagree about the terminology and diagnostic criteria for CG. The ICD-11 (International classification of diseases, 11th revision) beta draft proposed prolonged grief disorder as a condition that differs from persistent complex bereavement disorder with respect to terminology and the duration of symptoms. This divergence has arisen from insufficient evidence for a set of core symptoms and the biological basis of CG. Future studies including biological studies are needed to reach consensus about the diagnostic criteria for CG.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012741 TI - Speaking of death. AB - As a human-specific trait, language offers a unique window on human cognition. Grammatical constraints on the ways we speak about events, for instance, have long been thought to reveal the representational formats that our minds impose on the ways that we think about events. In recent research, verbs that name events of death have stood out as key counterexamples to standard theories of the grammatical constraints on possible verbs. The special status of these thanatological verbs raises two important questions: why, given the vast number of verbs in any language, is it that verbs of death hold this special status, and what do they tell us about the restrictions on the representational format for possible verbs? This paper reexamines the evidence coming from verbs of death, confirming that they are counterexamples to standard theories, but that their behaviour suggests a more revealing constraint on our mental representations-that our minds impose strict restrictions on the format of asserted meaning. Thus, the constraints on linguistic representation and the human mind offer a unique perspective on the mental representations of thanatological phenomena.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012742 TI - Hominin evolutionary thanatology from the mortuary to funerary realm: the palaeoanthropological bridge between chemistry and culture. AB - Palaeoanthropology, or more precisely Palaeolithic archaeology, offers the possibility of bridging the gap between mortuary activities that can be observed in the wider animal community and which relate to chemistry and emotion; to the often-elaborate systems of rationalization and symbolic contextualisation that are characteristic of recently observable societies. I draw on ethological studies to provide a core set of mortuary behaviours one might expect hominoids to inherit, and on anthropological observations to explore funerary activity represented in the Middle and Upper Palaeolithic, in order to examine how a distinctly human set of funerary behaviours arose from a more widespread set of mortuary behaviours. I suggest that the most profound innovation of the hominins was the incorporation of places into the commemoration of the dead, and propose a falsifiable mechanism for why this came about; and I suggest that the pattern of the earliest burials fits with modern hunter-gatherer belief systems about death, and how these vary by social complexity. Finally, I propose several research questions pertaining to the social context of funerary practices, suggesting how a hominin evolutionary thanatology may contribute not only to our understanding of human behavioural evolution, but to a wider thanatology of the animal kingdom.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012743 TI - Chimpanzees and death. AB - Information about responses to death in nonhuman primates is important for evolutionary thanatology. This paper reviews the major causes of death in chimpanzees, and how these apes respond to cues related to dying and death. Topics covered include disease, human activities, predation, accidents and intra species aggression and cannibalism. Chimpanzees also kill and sometimes eat other species. It is argued that, given their cognitive abilities, their experiences of death in conspecifics and other species are likely to equip chimpanzees with an understanding of death as cessation of function and irreversible. Whether they might understand that death is inevitable-including their own death, and biological causes of death is also discussed. As well as gathering more fundamental information about responses to dying and death, researchers should pay attention to possible cultural variations in how great apes deal with death.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012745 TI - Occurrence and variability of tactile interactions between wild American crows and dead conspecifics. AB - Observations of some mammals and birds touching their dead provoke questions about the motivation and adaptive value of this potentially risky behaviour. Here, we use controlled experiments to determine if tactile interactions are characteristic of wild American crow responses to dead crows, and what the prevalence and nature of tactile interactions suggests about their motivations. In Experiment 1, we test if food or information acquisition motivates contact by presenting crows with taxidermy-prepared dead crows, and two species crows are known to scavenge: dead pigeons and dead squirrels. In Experiment 2, we test if territoriality motivates tactile interactions by presenting crows with taxidermy crows prepared to look either dead or upright and life-like. In Experiment 1, we find that crows are significantly less likely to make contact but more likely to alarm call and recruit other birds in response to dead crows than to dead pigeons and squirrels. In addition, we find that aggressive and sexual encounters with dead crows are seasonally biased. These findings are inconsistent with feeding or information acquisition-based motivation. In Experiment 2, we find that crows rarely dive-bomb and more often alarm call and recruit other crows to dead than to life-like crows, behaviours inconsistent with responses given to live intruders. Consistent with a danger response hypothesis, our results show that alarm calling and neighbour recruitment occur more frequently in response to dead crows than other stimuli, and that touching dead crows is atypical. Occasional contacts, which take a variety of aggressive and sexual forms, may result from an inability to mediate conflicting stimuli.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012744 TI - Managing the risks and rewards of death in eusocial insects. AB - Eusocial insects frequently face death of colony members as a consequence of living in large groups where the success of the colony is not dependent on the fate of the individual. Whereas death of conspecifics commonly triggers aversion in many group-living species due to risk of pathogens, eusocial insects perform cooperative corpse management. The causes and social context of the death, as well as feeding and nesting ecology of the species, influence the way that corpses are treated. The corpse itself releases cues that dictate the colony's response. As a result, social insects exhibit behavioural responses that promote disease resistance, colony defence and nutrient recycling. Corpse management represents a unique adaption that enhances colony success, and is another factor that has enabled eusocial insects to be so successful. In this review, we summarize the causes of death, the sensory detection of death and corpse management strategies of social insects. In addition, we provide insights into the evolution of behavioural response to the dead and the ecological relevance of corpse management.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012746 TI - Social relationships and death-related behaviour in aquatic mammals: a systematic review. AB - Some aquatic mammals appear to care for their dead, whereas others abandon their live offspring when conditions are unfavourable. This incredible variety in behaviours suggests the importance of comparing and contrasting mechanisms driving death-related behaviours among these species. We reviewed 106 cases of aquatic mammals (81 cetaceans and 25 non-cetaceans) reacting to a death event, and extrapolated 'participant' (age class, sex, relationship and decomposition) and 'social' characteristics (escorting, calf dependence, alloparental care, herding and dispersal patterns) from published and unpublished literature. A multiple correspondence analysis (MCA) was performed to explore the relationships between these characteristics and death-related behaviours, with species clustered based on MCA scores. Results showed that both cetaceans and non cetaceans react to death but in different ways. Non-cetaceans, characterized by a short maternal investment, were observed to protect the dead (defending it from external attacks), while cetaceans spent much longer with their offspring and display carrying (hauling, spinning, mouthing with the carcass and diving with it) and breathing-related (lifting and sinking the carcass) activities with the dead generally in association with other conspecifics. Our work emphasizes the need of increased documentation of death-related cases around the world to improve our understanding of aquatic mammals and their responses to death.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012747 TI - Behaviour of nonhuman primate mothers toward their dead infants: uncovering mechanisms. AB - In comparative thanatology, most reports for nonhuman mammals concern mothers' behavioural responses to their dead offspring: most prominently, dead-infant carrying (sometimes of extended duration); but also inspection, proximity, maternal care such as grooming, protective behaviours and filial cannibalism. Documented across many primate species, these behaviours remain poorly understood in all. The literature is dominated by relatively brief qualitative descriptions of isolated anecdotal cases in apes and monkeys. We argue for quantitative coding in case reports, alongside analyses of longitudinal records of such events to allow objective evaluation of competing theories, and systematic comparisons within and across species and populations. Obtaining necessary datasets depends on raised awareness in researchers of the importance of recording occurrences and knowledge of pertinent data to collect. We review proposed explanatory hypotheses and outline data needed to test each empirically. To determine factors influencing infant-corpse carriage, we suggest analyses of deaths resulting in 'carry' versus 'no carry'. For individual cases, we highlight behavioural variables to code and the need for hormonal samples. We discuss mothers' stress and welfare in relation to infant death, continued transportation and premature removal of the corpse. Elucidating underlying proximate and ultimate causes is important for understanding phylogeny of maternal responses to infant death.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012748 TI - Evolutionary thanatology. AB - Societies, including those of humans, have evolved multiple ways of dealing with death across changing circumstances and pressures. Despite many studies focusing on specialized topics, for example necrophoresis in eusocial insects, mortuary activities in early human societies, or grief and mourning in bereavement, there has been little attempt to consider these disparate research endeavours from a broader evolutionary perspective. Evolutionary thanatology does this by adopting an explicit evolutionary stance for studies of death and dying within the sociological, psychological and biological disciplines. The collection of papers in this themed issue demonstrates the value of this approach by describing what is known about how various nonhuman species detect and respond to death in conspecifics, how problems of disposing of the dead have evolved in human societies across evolutionary time and also within much shorter time frames, how human adults' understanding of death develops, and how it is ultimately reflected in death-related language. The psychological significance and impact of death is clearly seen in some species' grief-like reactions to the loss of attachment figures, and perhaps uniquely in humans, the existence of certain psychological processes that may lead to suicide. Several research questions are proposed as starting points for building a more comprehensive picture of the ontogeny and phylogeny of how organisms deal with death.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012750 TI - The Late Upper Palaeolithic and earliest Mesolithic evidence of burials in Europe. AB - Burials of the Late Palaeolithic (14 000-11 600 cal years before present, henceforth BP) are a rare phenomenon in Europe. Several sites possess burials of single and double individuals. As with the preceding Magdalenian, the burial of more than two individuals in the same grave cutting seems to be unusual, but does occur occasionally. The deposition of isolated and disarticulated human remains with or without cut marks seems additionally to belong to the Magdalenian context. In the final Palaeolithic phase (13 000-11 600 cal years BP) there is evidence for cemetery-like clusters of burials, which contrast to the Magdalenian evidence, instead showing some similarities with the succeeding Mesolithic. The earliest Mesolithic burials 11 600-10 500 cal BP) are a very rare phenomenon, covering a short time span between the beginning of the Preboreal and the beginning of the Boreal phase of the early Holocene. Here the evidence includes single inhumations, cemetery-like structures and a number of isolated human remains. Caves and rock shelters were the most common places for inhumations in both the final Palaeolithic and the early Mesolithic. Although the number of sites with a chronological continuity from the LUP to the Early Mesolithic burial is low, several aspects indicate a general continuity in burial patterns over this period. Apart from this continuity, the Mesolithic burials in general seem to represent a new level of diversity in burial practices.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012749 TI - Comparative thanatology, an integrative approach: exploring sensory/cognitive aspects of death recognition in vertebrates and invertebrates. AB - Evolutionary thanatology benefits from broad taxonomic comparisons of non-human animals' responses to death. Furthermore, exploring the sensory and cognitive bases of these responses promises to allow classification of the underlying mechanisms on a spectrum from phylogenetically ancient to more derived traits. We draw on studies of perception and cognition in invertebrate and vertebrate taxa (with a focus on arthropods, corvids, proboscids, cetaceans and primates) to explore the cues that these animals use to detect life and death in others, and discuss proximate and ultimate drivers behind their capacities to do so. Parallels in thanatological behaviour exhibited by the last four taxa suggest similar sensory-cognitive processing rules for dealing with corpses, the evolution of which may have been driven by complex social environments. Uniting these responses is a phenomenon we term 'animacy detection malfunction', whereupon the corpse, having both animate and inanimate attributes, creates states of fear/curiosity manifested as approach/avoidance behaviours in observers. We suggest that integrating diverse lines of evidence (including the 'uncanny valley' effect originating from the field of robotics) provides a promising way to advance the field, and conclude by proposing avenues for future research.This article is part of the theme issue 'Evolutionary thanatology: impacts of the dead on the living in humans and other animals'. PMID- 30012751 TI - In Vivo Efficacy of Meropenem with a Novel Non-beta-Lactam-beta-Lactamase Inhibitor, Nacubactam, against Gram-Negative Organisms Exhibiting Various Resistance Mechanisms in a Murine Complicated Urinary Tract Infection Model. AB - Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-beta-lactam-beta-lactamase inhibitor with in vitro activity against class A and class C beta-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common beta-lactamases. Here, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem or nacubactam alone against 10 Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM enzyme-producing isolates. Selected isolates had meropenem-nacubactam MICs between 1 and 8 MUg/ml. Meropenem nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving a >=3 log reduction from the 48-h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed antibacterial properties, achieving a >1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam-resistant isolates, meropenem-nacubactam demonstrated increased antibacterial kill upwards of 6 log10 CFU in comparison to the 48-h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in humans against MDR Enterobacteriaceae, although further clinical data supporting meropenem-nacubactam efficacy are needed. PMID- 30012752 TI - Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity. AB - Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at Mycobacterium tuberculosis Ambroxol, a lead compound, emerged from a screen for autophagy-inducing drugs. At clinically relevant doses, ambroxol induced autophagy in vitro and in vivo and promoted mycobacterial killing in macrophages. Ambroxol also potentiated rifampin activity in a murine tuberculosis model. PMID- 30012753 TI - Combination of Tenofovir and Emtricitabine with Efavirenz Does Not Moderate Inhibitory Effect of Efavirenz on Mitochondrial Function and Cholesterol Biosynthesis in Human T Lymphoblastoid Cell Line. AB - Efavirenz (EFV), the most popular nonnucleoside reverse transcriptase inhibitor, has been associated with mitochondrial dysfunction in most in vitro studies. However, in real life the prevalence of EFV-induced mitochondrial toxicity is relatively low. We hypothesized that the agents given in combination with EFV moderate the effect of EFV on mitochondrial function. To test this hypothesis, we cultured a human T lymphoblastoid cell line (CEM cells) with EFV alone and in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) to investigate the effects on mitochondrial respiration and function and cholesterol biosynthesis. There was a statistically significant concentration- and time dependent apoptosis, reduction in mitochondrial membrane potential, and increase in production of reactive oxygen species in cells treated with either EVF alone or in combination with TDF plus FTC. Compared to dimethyl sulfoxide-treated cells, EFV-treated cells had significant reduction in oxygen consumption rate contributed by basal mitochondrial respiration and decreased protein expression of electron transport chain complexes (CI, CII, and CIV). Treatment with EFV resulted in a decrease in mitochondrial DNA content and perturbation of more coding genes (n = 13); among these were 11 genes associated with lipid or cholesterol biosynthesis. Our findings support the growing body of knowledge on the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. Interestingly, combining TDF and FTC with EFV did not alter the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. The gap between the prevalence of EFV-induced mitochondrial toxicity in in vitro and in vivo studies could be due to individual differences in the pharmacokinetics of EFV. PMID- 30012754 TI - Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis. AB - Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2 sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs. PMID- 30012755 TI - Pharmacodynamics of Daptomycin against Enterococcus faecium and Enterococcus faecalis in the Murine Thigh Infection Model. AB - The Clinical and Laboratory Standards Institute (CLSI) daptomycin MIC susceptibility breakpoint for the treatment of enterococcal infections is <=4 MUg/ml. However, patients receiving daptomycin for the treatment of infections caused by enterococci with MICs of <=4 MUg/ml may experience treatment failures. We assessed the pharmacodynamics of daptomycin against enterococci in a neutropenic murine thigh infection model and determined the exposures necessary for bacteriostasis and a 1-log10-CFU reduction of Enterococcus faecalis and Enterococcus faecium We further characterized daptomycin efficacy at clinically achievable exposures. Six E. faecium and 6 E. faecalis isolates (daptomycin MICs, 0.5 to 32 MUg/ml) were studied. Daptomycin was administered at various doses over 24 h to achieve area under the free drug concentration-time curve-to-MIC ratios (fAUC0-24/MIC) ranging from 1 to 148. Daptomycin regimens that simulate mean human exposures following doses of 6, 8, and 10 mg/kg of body weight/day were also studied. Efficacy was assessed by the differences in the number of log10 CFU per thigh at 24 h. The Hill equation was used to estimate the fAUC0-24/MIC required to achieve bacteriostasis and a 1-log10-CFU reduction. For E. faecium, a 1-log10-CFU reduction required an fAUC0-24/MIC of 12.9 (R2 = 0.71). For E. faecalis, a 1-log10-CFU reduction was not achieved, while the fAUC0-24/MIC required for stasis was 7.2 (R2 = 0.8). With a human-simulated regimen of 6 mg/kg/day, a 1-log10-CFU reduction was observed in 3/3 E. faecium isolates with MICs of <4 MUg/ml and 0/3 E. faecium isolates with MICs of >=4 MUg/ml; however, a 1-log10-CFU reduction was not achieved for any of the 6 E. faecalis isolates. These results, alongside clinical data, prompt a reevaluation of the current breakpoint. PMID- 30012756 TI - Pharmacokinetics, Tolerability, and Safety of Murepavadin, a Novel Antipseudomonal Antibiotic, in Subjects with Mild, Moderate, or Severe Renal Function Impairment. AB - This open-label, nonrandomized, single-dose, phase 1 study evaluated the pharmacokinetics and safety of murepavadin, a novel peptide antibiotic for the treatment of serious Pseudomonas aeruginosa infections. The study was conducted in 32 subjects of either sex in 4 groups (up to 8 per group) with mild (group 1), moderate (group 2), and severe (group 3) renal function impairment or with normal renal function (group 4). The degree of renal impairment of the subjects was classified at screening according to the estimated creatinine clearance (CLCr) according to the Cockcroft-Gault equation. All subjects received a single 2.2 mg/kg of body weight intravenous infusion of murepavadin administered over 3 h. Exposure to murepavadin in plasma increased in subjects with renal function impairment, with the area under the plasma concentration-time curve from zero to infinity (AUC0-infinity) increasing about 2.0- to 2.5-fold for subjects with renal function impairment compared to subjects with normal renal function, whereas the increases in maximum observed plasma concentration (Cmax) were about 1.5-fold for subjects with renal function impairment compared to subjects with normal renal function. The total clearance (CL) of murepavadin was lower in all groups of subjects with renal function impairment, with group means ranging from 2.4 liters/h to 3.8 liters/h, compared to 7.0 liters/h in subjects with normal renal function. Accordingly, the terminal elimination half-life (t1/2) prolonged up to 24 h with decreasing renal function compared to 7.7 h in subjects with normal renal function. Murepavadin was well tolerated in all renal function groups. As the elimination of murepavadin is affected by renal function, a dose adjustment is warranted in subjects with impaired renal function. (This paper has been registered at ClinicalTrials.gov under identifier NCT02110459.). PMID- 30012757 TI - Clinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections. AB - Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1 January 2010 and 30 June 2016. We defined probable or proven breakthrough IFIs using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% received the oral suspension and 48% received the tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft-versus-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indications between patients receiving the different formulations. The incidence and incidence rate of probable or proven IFIs were 1.6% and 3.2 per 10,000 posaconazole days, respectively. There was no significant difference in the rate of IFIs between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio = 0.8, 95% confidence interval [CI] = 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured, and the concentrations in 7/8 were above 0.7 MUg/ml. Posaconazole was discontinued early in 15.5% of courses; however, the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference = -0.13 to 0.06). In conclusion, the incidence of breakthrough IFIs was low among patients receiving posaconazole prophylaxis and not significantly different between patients receiving the tablet formulation and those receiving the oral suspension formulation. PMID- 30012758 TI - Effect of the Synthetic Bile Salt Analog CamSA on the Hamster Model of Clostridium difficile Infection. AB - Clostridium difficile infection (CDI) is the leading cause of antibiotic associated diarrhea and has gained worldwide notoriety due to emerging hypervirulent strains and the high incidence of recurrence. We previously reported protection of mice from CDI using the antigerminant bile salt analog CamSA. Here we describe the effects of CamSA in the hamster model of CDI. CamSA treatment of hamsters showed no toxicity and did not affect the richness or diversity of gut microbiota; however, minor changes in community composition were observed. Treatment of C. difficile-challenged hamsters with CamSA doubled the mean time to death, compared to control hamsters. However, CamSA alone was insufficient to prevent CDI in hamsters. CamSA in conjunction with suboptimal concentrations of vancomycin led to complete protection from CDI in 70% of animals. Protected animals remained disease-free at least 30 days postchallenge and showed no signs of colonic tissue damage. In a delayed-treatment model of hamster CDI, CamSA was unable to prevent infection signs and death. These data support a putative model in which CamSA reduces the number of germinating C. difficile spores but does not keep all of the spores from germinating. Vancomycin halts division of any vegetative cells that are able to grow from spores that escape CamSA. PMID- 30012759 TI - In Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung Disease. AB - Although it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide susceptible MAC-LD between January 2008 and December 2013, 274 patients who were treated with a standard regimen for >=12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MICs of antimicrobial agents were determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs of >=8 MUg/ml. Treatment success rate was significantly different between MAC isolates with MICs of >=8 MUg/ml for rifampin and ethambutol and those with MICs of <8 MUg/ml for rifampin and/or ethambutol (64.9% versus 85.3%, P < 0.001). Multivariate analysis showed that an MIC of >=8 MUg/ml for both drugs and initial sputum acid-fast bacillus (AFB) smear positivity were independent risk factors for an unfavorable response (adjusted odds ratio [OR] = 3.154, 95% confidence interval [CI] = 1.641 to 6.063, and P = 0.001 for an MIC of >=8 MUg/ml; adjusted OR = 2.769, 95% CI = 1.420 to 5.399, and P = 0.003 for initial sputum AFB smear positivity). These findings suggest that the in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD. PMID- 30012760 TI - Screening of Preselected Libraries Targeting Mycobacterium abscessus for Drug Discovery. AB - Mycobacterium abscessus is intrinsically resistant to many antimycobacterial antibiotics, which presents serious problems in therapy. Here, we describe the development of a novel phenotype-based microscopic and computerized imaging drug screening approach. A pilot screen of 568 compounds from two libraries identified 17 hits. Eleven of these compounds are described for the first time as active against M. abscessus The impact of growth media on the activity of these compounds was tested, revealing that cation-adjusted Mueller-Hinton broth (MHII) supports better growth of actively replicating M. abscessus and improves the activity of associated compounds. PMID- 30012761 TI - Broad Spectrum and Safety of Oral Treatment with a Promising Nitrosylated Chalcone in Murine Leishmaniasis. AB - The oral efficacy and safety of a leishmanicidal nitrochalcone (CH8) were studied in BALB/c mouse infections with Leishmania amazonensis and Leishmania infantum Although 10-fold-higher doses of CH8 were needed to produce the same antiparasitic effect as that seen with the reference drug miltefosine, the latter was nephrotoxic, whereas CH8 restored disease toxicity markers to normal. This study shows the therapeutic potential of an orally active and hepato /nephroprotective chalcone against cutaneous and visceral leishmaniases. PMID- 30012763 TI - Impact of Antibiotic Treatment on the Burden of Nasal Staphylococcus aureus among Hospitalized Patients. AB - We examined the impact of systemic antibiotics on the burden of nasal Staphylococcus aureus in hospitalized patients. Of 1,482 patients, 237 (16%) had nasal methicillin-susceptible S. aureus (MSSA) and 92 (6%) had nasal methicillin resistant S. aureus (MRSA) on admission. Treatment regimens that included agents with inhibitory activity against MRSA or MSSA significantly reduced the burden of carriage, whereas regimens lacking anti-MRSA activity, including fluoroquinolones, promoted MRSA overgrowth. PMID- 30012762 TI - Characterization of the AmpC beta-Lactamase from Burkholderia multivorans. AB - Burkholderia multivorans is a member of the Burkholderia cepacia complex, a group of >20 related species of nosocomial pathogens that commonly infect individuals suffering from cystic fibrosis. beta-Lactam antibiotics are recommended as therapy for infections due to Bmultivorans, which possesses two beta-lactamase genes, blapenA and blaAmpC PenA is a carbapenemase with a substrate profile similar to that of the Klebsiella pneumoniae carbapenemase (KPC); in addition, expression of PenA is inducible by beta-lactams in Bmultivorans Here, we characterize AmpC from Bmultivorans ATCC 17616. AmpC possesses only 38 to 46% protein identity with non-Burkholderia AmpC proteins (e.g., PDC-1 and CMY-2). Among 49 clinical isolates of Bmultivorans, we identified 27 different AmpC variants. Some variants possessed single amino acid substitutions within critical active-site motifs (Omega loop and R2 loop). Purified AmpC1 demonstrated minimal measurable catalytic activity toward beta-lactams (i.e., nitrocefin and cephalothin). Moreover, avibactam was a poor inhibitor of AmpC1 (Kiapp > 600 MUM), and acyl-enzyme complex formation with AmpC1 was slow, likely due to lack of productive interactions with active-site residues. Interestingly, immunoblotting using a polyclonal anti-AmpC antibody revealed that protein expression of AmpC1 was inducible in Bmultivorans ATCC 17616 after growth in subinhibitory concentrations of imipenem (1 MUg/ml). AmpC is a unique inducible class C cephalosporinase that may play an ancillary role in Bmultivorans compared to PenA, which is the dominant beta-lactamase in Bmultivorans ATCC 17616. PMID- 30012764 TI - Validation of Heel Stick Microsampling To Optimize Micafungin Doses in Neonates and Young Infants. AB - Major gaps exist in our knowledge of antimicrobial pharmacokinetics in critically ill neonates and infants that require validated microsampling and bioanalysis methods to support therapeutic drug monitoring. We compared serially collected intravenous (i.v.) and heel stick capillary (HSC)-sampled plasma concentrations of micafungin (8 mg/kg) in eight infants born preterm with systemic candidiasis. The mean (standard deviation) micafungin area under the plasma concentration-time curve to infinity (AUCinf) was 316 (65.0) h . mg/liter based on HSC concentrations that strongly correlated (R2 = 0.92) with i.v. values to support dose adjustment. PMID- 30012765 TI - Evaluation of Oritavancin Combinations with Rifampin, Gentamicin, or Linezolid against Prosthetic Joint Infection-Associated Methicillin-Resistant Staphylococcus aureus Biofilms by Time-Kill Assays. AB - The antibiofilm activity of oritavancin in combination with rifampin, gentamicin, or linezolid was evaluated against 10 prosthetic joint infection (PJI)-related methicillin-resistant Staphylococcus aureus (MRSA) isolates by time-kill assays. Oritavancin combined with rifampin demonstrated statistically significant bacterial reductions compared with those of either antimicrobial alone for all 10 isolates (P <= 0.001), with synergy being observed for 80% of the isolates. Oritavancin and rifampin combination therapy may be an option for treating MRSA PJI. PMID- 30012766 TI - Significantly Improved Pharmacokinetics Enhances In Vivo Efficacy of APX001 against Echinocandin- and Multidrug-Resistant Candida Isolates in a Mouse Model of Invasive Candidiasis. AB - APX001 is a first-in-class, intravenous and orally available, broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 to 2.75 h in mice versus 2 to 2.5 days in humans), making the exploration of efficacy in mouse models difficult. After pretreatment with 1-aminobenzotriazole (ABT), a nonspecific cytochrome P450 inhibitor, greatly increased plasma APX001A exposure was observed in mice of different strains and of both genders. As a consequence, 26 mg/kg APX001 plus ABT sterilized kidneys in mice infected with Candida albicans, while APX001 alone at the same dose resulted in a modest burden reduction of only 0.2 log10 CFU/g, relative to the vehicle control. In the presence of ABT, 2 days of once-daily dosing with APX001 at 26 mg/kg also demonstrated significant in vivo efficacy in the treatment of Candida glabrata infections in mice. Potent kidney burden reduction was achieved in mice infected with susceptible, echinocandin-resistant, or multidrug-resistant strains. In contrast, the standard of care (micafungin) was ineffective in treating infections caused by the resistant C. glabrata isolates. PMID- 30012767 TI - Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis. AB - Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0 24) were 109.49, 97.86, 145.33, and 207.04 MUg . h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 MUg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.). PMID- 30012768 TI - Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro. AB - The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using Xenopus laevis oocytes and stably transfected HEK-293 cells in vitro The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and the Km values of ethambutol were found to be 526.1 +/- 15.6, 212.0 +/- 20.1, 336.8 +/- 20.1, and 455.0 +/- 28 MUM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, the Km of prothionamide was 805.8 +/- 23.4 MUM for OCT1, while the Km values of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 +/- 14.1 and 161.4 +/- 10.6 MUM, respectively. The estimated in vivo drug-drug interaction indexes from in vitro transporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs. PMID- 30012769 TI - A Prospective Real-World Study of the Impact of an Antifungal Stewardship Program in a Tertiary Respiratory-Medicine Setting. AB - There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to health care systems. An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice-monthly multidisciplinary team meetings, and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team. During the first 18 months of implementation, the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated, followed by asthma and interstitial lung disease. There was a significant sustained reduction in monthly antifungal expenditure (P = 0.005) by L130,000 per month. There was also a significant reduction in antifungal use, measured as the defined daily dose/100 bed days (P = 0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole (P = 0.086) and a significant increase in therapeutic levels of posaconazole (P < 0.0001). This study shows that an effective antifungal stewardship program can significantly reduce expenditure in a specialist respiratory service. PMID- 30012770 TI - Novel Potent Capsid Assembly Modulators Regulate Multiple Steps of the Hepatitis B Virus Life Cycle. AB - The assembly of hepatitis B virus (HBV) core protein (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid assembly modulators (CAMs) induce the formation of empty capsid or aberrant capsid devoid of pregenomic RNA (pgRNA) and finally block relaxed circular DNA neosynthesis and virion progeny. In this study, the novel CAMs JNJ 827 and JNJ-890 were found to be potent inhibitors of HBV replication with respective half-maximal effective concentrations of 4.7 and 66 nM, respectively, in HepG2.117 cells. Antiviral profiling in differentiated HepaRG (dHepaRG) cells and primary human hepatocytes revealed that these compounds efficiently inhibited HBV replication, as well as de novo establishment of covalently closed circular DNA (cccDNA). In addition to these two known effects of CAMs, we observed for the first time that a CAM, here JNJ-827, when added postinfection for a short-term period, significantly reduced hepatitis B e antigen (HBeAg) secretion without affecting the levels of cccDNA amount, transcription, and hepatitis B surface antigen (HBsAg) secretion. This inhibitory activity resulted from a direct effect of JNJ-827 on HBeAg biogenesis. In a long-term treatment condition using persistently infected dHepaRG cells, JNJ-827 and JNJ-890 reduced HBsAg concomitantly with a decrease in viral total RNA and pgRNA levels. Altogether, these data demonstrate that some CAMs could interfere with multiple functions of HBc in the viral life cycle. PMID- 30012771 TI - In Silico Typing and Comparative Genomic Analysis of IncFIIK Plasmids and Insights into the Evolution of Replicons, Plasmid Backbones, and Resistance Determinant Profiles. AB - IncFIIK plasmids are associated with the acquisition and dissemination of multiple-antimicrobial resistance in Klebsiella pneumoniae and often encountered in clinical isolates of this species. Since the phylogeny and evolution of IncFIIK plasmids remain unclear, here we performed large-scale in silico typing and comparative analysis of these plasmids in publicly available bacterial/plasmid genomes. IncFIIK plasmids are prevalent in K. pneumoniae, being found in 69% of sequenced genomes, covering 66% of sequenced STs (sequence types), but sparse in other Enterobacteriaceae IncFIIK replicons have three lineages. One IncFIIK allele could be found in distinct K. pneumoniae STs, highlighting the lateral genetic flow of IncFIIK plasmids. A set of 77 IncFIIK plasmids with full sequences were further analyzed. A pool of 327 antibiotic resistance genes or remnants were annotated in 75.3% of these plasmids. Plasmid genome comparison reiterated that they often contain other replicons belonging to IncFIA, IncFIB, IncFIIYp, IncFIIpCRY, IncR, IncL, and IncN groups and that they share a conserved backbone featuring an F-like conjugation module that has divergent components responsible for regulation and mating pair stabilization. Further epidemiological studies of IncFIIK plasmids are required due to the sample bias of K. pneumoniae genomes in public databases. This study provides insights into the evolution and structures of IncFIIK plasmids. PMID- 30012772 TI - Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention. AB - Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4' ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK 8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK 8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted. PMID- 30012773 TI - Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin. AB - Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted. PMID- 30012775 TI - Validation of a Dried Blood Spot Ceftriaxone Assay in Papua New Guinean Children with Severe Bacterial Infections. AB - Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study, we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children with severe illness from Papua New Guinea (PNG), a setting in which health care resources are limited and anemia is common. Using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5 to 10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models. Ten children were recruited with an admission hematocrit of 0.22 to 0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman's rank correlation coefficient [rs] = 0.94 [95% confidence interval, 0.91 to 0.97], P < 0.0001). A marked systematic hematocrit bias was observed, with lower hematocrits resulting in underestimation of DBS predicted plasma concentration. After adjustment for red cell partitioning and hematocrit bias, a population PK model comparing plasma and DBS-predicted plasma concentrations did not differ in terms of key PK parameters, including clearance, volume of distribution, and residual variability. The performance of the ceftriaxone DBS assay is robust and provides reassurance that this platform can be used as a surrogate for plasma concentrations to provide valid PK and PK/pharmacodynamic studies of severely unwell children hospitalized in a resource limited setting. It highlights the importance of hematocrit bias in validation studies of DBS assays. PMID- 30012774 TI - In Vitro Antiviral Activity of Cabotegravir against HIV-2. AB - We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naive individuals. HIV-2 was sensitive to cabotegravir in single-cycle and spreading-infection assays, with 50% effective concentrations (EC50s) in the low to subnanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for antiretroviral therapy and preexposure prophylaxis in HIV-2-prevalent settings. PMID- 30012776 TI - Microdialysis Study of Aztreonam-Avibactam Distribution in Peritoneal Fluid and Muscle of Rats with or without Experimental Peritonitis. AB - The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular veins, hind leg muscles, and peritoneal cavities of control rats (n = 5) and rats with intra-abdominal sepsis (n = 9) induced by cecal ligation and punctures. ATM and AVI probe recoveries in each medium were determined for both molecules in each rat by retrodialysis by drug. ATM-AVI combination was administered as an intravenous bolus at a dose of 100-25 mg . kg-1 Microdialysis samples were collected over 120 min, and ATM-AVI concentrations were determined by liquid chromatography-tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was conducted and nonparametric tests were used for statistical comparisons between groups (infected versus control) and medium. ATM and AVI distribution in intraperitoneal fluid and muscle was rapid and complete both in control rats and in rats with peritonitis, and the concentration profiles in blood, intraperitoneal fluid, and muscle were virtually superimposed, in control and infected animals, both for ATM and AVI. No statistically significant difference was observed between unbound tissue extracellular fluid and systemic areas under the curve for both molecules in control and infected animals. In the present study, intraperitoneal infection induced by cecal ligation and puncture had no apparent effect on ATM and AVI pharmacokinetics in rats. PMID- 30012777 TI - Nucleus-Encoded Protein BFA1 Promotes Efficient Assembly of the Chloroplast ATP Synthase Coupling Factor 1. AB - F-type ATP synthases produce nearly all of the ATP found in cells. The catalytic module F1 commonly comprises an alpha3beta3 hexamer surrounding a gamma/epsilon stalk. However, it is unclear how these subunits assemble to form a catalytic motor. In this work, we identified and characterized a chloroplast protein that interacts with the CF1beta, gamma, and epsilon subunits of the chloroplast ATP synthase and is required for assembly of its F1 module. We named this protein BIOGENESIS FACTOR REQUIRED FOR ATP SYNTHASE1 (BFA1) and determined its crystal structure at 2.8-A resolution. BFA1 is comprised primarily of two interacting beta-barrels that are oriented nearly perpendicularly to each other. The contact region between BFA1 and the CF1beta and gamma subunits was further mapped by yeast two-hybrid assays. An in silico molecular docking analysis was performed and revealed close fitting contact sites without steric conflicts between BFA1 and CF1beta/gamma. We propose that BFA1 acts mainly as a scaffold protein promoting the association of a CF1alpha/beta heterodimer with CF1gamma. The subsequent assembly of other CF1alpha/beta heterodimers may shift the position of the CF1gamma subunit to complete assembly of the CF1 module. This CF1 assembly process is likely to be valid for other F-type ATP synthases, as their structures are highly conserved. PMID- 30012778 TI - Is lack of social support associated with a delay in seeking medical care? A cross-sectional study of Minnesota and Tennessee residents using data from the Behavioral Risk Factor Surveillance System. AB - OBJECTIVE: Previous studies have demonstrated an association between social support and lower morbidity and mortality. Delay in seeking medical care is associated with poor health outcomes. The relationship between social support and delay in seeking medical care has not been established. We sought to determine whether lack of social support is associated with higher rates of delays in seeking needed medical care. METHODS: This is a cross-sectional observational study using data from the 2013 and 2014 Centers for Disease Control Behavioral Risk Factor Surveillance System. Participants who were asked questions about delays in medical care and social support were included. The primary outcome was a self-reported delay in seeking needed medical care. The primary independent variable of interest was a dichotomised measure of social support. Multivariable logistic regression was performed, adjusting for demographics, socioeconomic status, comorbidities and access to care. RESULTS: Participants without social support were more likely to report delaying needed medical care when compared with participants with social support (38%vs19%, p<0.001). The association between lack of social support and delays in care persisted after adjustment for demographics, socioeconomic status, comorbidities and access to care (OR 1.72; 95% CI 1.45 to 2.06; p<0.001). CONCLUSIONS: Lack of perceived social support is associated with patient-reported delay of needed medical care. This association may contribute to the poor health outcomes experienced by those with a lack of social support. PMID- 30012779 TI - Does glucagon-like peptide-1 (GLP-1) receptor agonist stimulation reduce alcohol intake in patients with alcohol dependence: study protocol of a randomised, double-blinded, placebo-controlled clinical trial. AB - INTRODUCTION: Alcohol dependence is a major public health problem. It is underdiagnosed and undertreated. Even when treated, more than 2/3 of patients in abstinence-oriented treatment will relapse within the first year. Thus, there is an urgent need for efficacious medical treatment of alcohol dependence. Glucagon like peptide-1 (GLP-1) receptor stimulation has proven to reduce alcohol consumption in preclinical experiments. However, the effect of GLP-1 receptor agonists in humans has to our knowledge, not yet been investigated. METHODS AND ANALYSIS: Design, participants and intervention: The effect of the once-weekly GLP-1-receptor-agonist exenatide will be investigated in a double-blinded, placebo-controlled, randomised clinical trial. 114 outpatients will be recruited and randomised to treatment with either placebo or exenatide once weekly for 26 weeks as a supplement to cognitive-behavioural therapy. The primary endpoint is reduction in number of 'heavy drinking days'. The secondary endpoints include changes in total alcohol consumption, days without consumption, changes in brain activity and function, smoking status, cognition, measures of quality of life and changes in phosphatidylethanol as a biomarker of alcohol consumption from baseline to follow-up at week 26. Status: Currently recruiting patients. ETHICS AND DISSEMINATION: Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study results will be disseminated by peer-review publications and conference presentations and has the potential to reveal a completely new medical treatment of alcohol dependence. PMID- 30012780 TI - Using an interactive virtual environment to integrate a digital Action Research Arm Test, motor imagery and action observation to assess and improve upper limb motor function in patients with neuromuscular impairments: a usability and feasibility study protocol. AB - INTRODUCTION: In the recent past, training systems using an interactive virtual environment have been introduced to neurorehabilitation. Such systems can be applied to encourage purposeful limb movements and will increasingly be used at home by the individual patient. Therefore, an integrated valid and reliable assessment tool on the basis of such a system to monitor the recovery process would be an essential asset. OBJECTIVES: The aim of the study is to evaluate usability, feasibility and validity of the digital version of the Action Research Arm Test using the Bi-Manu-Trainer system as a platform. Additionally, the feasibility and usability of the implementation of action observation and motor imagery tasks into the Bi-Manu-Trainer software will be evaluated. PATIENTS AND METHODS: This observational study is planned as a single-arm trial for testing the new assessment and the action observation and motor imagery training module. Therefore, 75 patients with Parkinson's disease, multiple sclerosis, stroke, traumatic brain injury or Guillain-Barre syndrome will be included. 30 out of the 75 patients will additionally take part in a 4-week training on the enhanced Bi Manu-Trainer system. Primary outcomes will be the score on the System Usability Scale and the correlation between the conventional and digital Action Research Arm Test scores. Secondary outcomes will be hand dexterity, upper limb activities of daily living and quality of life. HYPOTHESIS: We hypothesise that the digital Action Research Arm Test assessment is a valid and essential tool and that it is feasible to incorporate action observation and motor imagery into Bi-Manu-Trainer practice. The results are expected to give recommendations for necessary modifications and might also contribute knowledge concerning the application of action observation and motor imagery tasks using a training system such as the Bi Manu-Trainer. TRIAL REGISTRATION NUMBER: NCT03268304; Pre-results. PMID- 30012781 TI - Social network analysis of psychological morbidity in an urban slum of Bangladesh: a cross-sectional study based on a community census. AB - OBJECTIVES: To test whether social ties play any roles in mitigating depression and anxiety, as well as in fostering mental health among young men living in a poor urban community. SETTING: A cohort of all young men living in an urban slum in Dhaka, the capital of Bangladesh. PARTICIPANTS: All men aged 18-29 years (n=824) living in a low-income urban community at the time of the survey. PRIMARY AND SECONDARY OUTCOME MEASURES: Unspecified psychological morbidity measured using the General Health Questionnaire, 12-item (GHQ-12), where lower scores suggest better mental status. RESULTS: The GHQ scores (mean=9.2, SD=4.9) suggest a significant psychological morbidity among the respondents. However, each additional friend is associated with a 0.063 SD lower GHQ score (95% CI -0.106 to -0.021). Between centrality measuring the relative importance of the respondent within his social network is also associated with a 0.103 SD lower GHQ score (95% CI -0.155 to -0.051), as are other measures of social network ties. Among other factors, married respondents and recent migrants also report a better mental health status. CONCLUSIONS: Our results underscore the importance of social connection in providing a buffer against stress and anxiety through psychosocial support from one's peers in a resource-constraint urban setting. Our findings also suggest incorporating a social network and community ties in designing mental health policies and interventions. PMID- 30012783 TI - Who teaches medical billing? A national cross-sectional survey of Australian medical education stakeholders. AB - IMPORTANCE: Billing errors and healthcare fraud have been described by the WHO as 'the last great unreduced health-care cost'. Estimates suggest that 7% of global health expenditure (US$487 billion) is wasted from this phenomenon. Irrespective of different payment models, challenges exist at the interface of medical billing and medical practice across the globe. Medical billing education has been cited as an effective preventative strategy, with targeted education saving $A250 million in Australia in 1 year from an estimated $A1-3 billion of waste. OBJECTIVE: This study attempts to systematically map all avenues of medical practitioner education on medical billing in Australia and explores the perceptions of medical education stakeholders on this topic. DESIGN: National cross-sectional survey between April 2014 and June 2015. No patient or public involvement. Data analysis-descriptive statistics via frequency distributions. PARTICIPANTS: All stakeholders who educate medical practitioners regarding clinical practice (n=66). 86% responded. RESULTS: There is little medical billing education occurring in Australia. The majority of stakeholders (70%, n=40) did not offer/have never offered a medical billing course. 89% thought medical billing should be taught, including 30% (n=17) who were already teaching it. There was no consensus on when medical billing education should occur. CONCLUSIONS: To our knowledge, this is the first attempt of any country to map the ways doctors learn the complex legal and administrative infrastructure in which they work. Consistent with US findings, Australian doctors may not have expected legal and administrative literacy. Rather than reliance on ad hoc training, development of an Australian medical billing curriculum should be encouraged to improve compliance, expedite judicial processes and reduce waste. In the absence of adequate education, disciplinary bodies in all countries must consider pleas of ignorance by doctors under investigation, where appropriate, for incorrect medical billing. PMID- 30012784 TI - Phantom motor execution as a treatment for phantom limb pain: protocol of an international, double-blind, randomised controlled clinical trial. AB - INTRODUCTION: Phantom limb pain (PLP) is a chronic condition that can greatly diminish quality of life. Control over the phantom limb and exercise of such control have been hypothesised to reverse maladaptive brain changes correlated to PLP. Preliminary investigations have shown that decoding motor volition using myoelectric pattern recognition, while providing real-time feedback via virtual and augmented reality (VR-AR), facilitates phantom motor execution (PME) and reduces PLP. Here we present the study protocol for an international (seven countries), multicentre (nine clinics), double-blind, randomised controlled clinical trial to assess the effectiveness of PME in alleviating PLP. METHODS AND ANALYSIS: Sixty-seven subjects suffering from PLP in upper or lower limbs are randomly assigned to PME or phantom motor imagery (PMI) interventions. Subjects allocated to either treatment receive 15 interventions and are exposed to the same VR-AR environments using the same device. The only difference between interventions is whether phantom movements are actually performed (PME) or just imagined (PMI). Complete evaluations are conducted at baseline and at intervention completion, as well as 1, 3 and 6 months later using an intention-to treat (ITT) approach. Changes in PLP measured using the Pain Rating Index between the first and last session are the primary measure of efficacy. Secondary outcomes include: frequency, duration, quality of pain, intrusion of pain in activities of daily living and sleep, disability associated to pain, pain self efficacy, frequency of depressed mood, presence of catastrophising thinking, health-related quality of life and clinically significant change as patient's own impression. Follow-up interviews are conducted up to 6 months after the treatment. ETHICS AND DISSEMINATION: The study is performed in agreement with the Declaration of Helsinki and under approval by the governing ethical committees of each participating clinic. The results will be published according to the Consolidated Standards of Reporting Trials guidelines in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03112928; Pre-results. PMID- 30012782 TI - Quality indicators for responsible use of medicines: a systematic review. AB - OBJECTIVE: All healthcare systems require valid ways to evaluate service delivery. The objective of this study was to identify existing content validated quality indicators (QIs) for responsible use of medicines (RUM) and classify them using multiple frameworks to identify gaps in current quality measurements. DESIGN: Systematic review without meta-analysis. SETTING: All care settings. SEARCH STRATEGY: CINAHL, Embase, Global Health, International Pharmaceutical Abstract, MEDLINE, PubMed and Web of Science databases were searched up to April 2018. An internet search was also conducted. Articles were included if they described medication-related QIs developed using consensus methods. Government agency websites listing QIs for RUM were also included. ANALYSIS: Several multidimensional frameworks were selected to assess the scope of QI coverage. These included Donabedian's framework (structure, process and outcome), the Anatomical Therapeutic Chemical (ATC) classification system and a validated classification for causes of drug-related problems (c-DRPs; drug selection, drug form, dose selection, treatment duration, drug use process, logistics, monitoring, adverse drug reactions and others). RESULTS: 2431 content validated QIs were identified from 131 articles and 5 websites. Using Donabedian's framework, the majority of QIs were process indicators. Based on the ATC code, the largest number of QIs pertained to medicines for nervous system (ATC code: N), followed by anti-infectives for systemic use (J) and cardiovascular system (C). The most common c-DRPs pertained to 'drug selection', followed by 'monitoring' and 'drug use process'. CONCLUSIONS: This study was the first systematic review classifying QIs for RUM using multiple frameworks. The list of the identified QIs can be used as a database for evaluating the achievement of RUM. Although many QIs were identified, this approach allowed for the identification of gaps in quality measurement of RUM. In order to more effectively evaluate the extent to which RUM has been achieved, further development of QIs may be required. PMID- 30012785 TI - Experiences of returning to work and maintaining work 7 to 8 years after a stroke: a qualitative interview study in Sweden. AB - OBJECTIVE: To explore how persons experienced return to work (RTW) and their work situation 7 to 8 years after a stroke. DESIGN: An explorative qualitative design with individual interviews. The data analysis was inductive thematic and three researchers collaborated during the analysis process. PARTICIPANTS: The study population included five women and eight men who had a stroke during 2009-2010, received care at the Sahlgrenska University Hospital in Gothenburg, Sweden and RTW after stroke and it was a heterogenic sample based on age, occupation, stroke severity and time to RTW. RESULTS: The analysis led to four themes; motivated and RTW while struggling with impairments, mixed feelings in the RTW process, still at work though restricted and social support for a sustainable work situation. The themes revealed that participants were motivated to RTW while struggling with impairments. The RTW process evoked mixed feelings of worry and grief over lost functions but also acceptance and gratitude for being able to work. Although maintaining work 7 to 8 years after experiencing a stroke, most were restricted in some way. Fatigue and cognitive impairments meant having to set limits, omit work tasks and rest at work, but also rest during free time and refraining from social activities in order to manage work. Participants avoided work-related stress if they could because of aggravated symptoms and/or fear of a new stroke. Support from supervisors and colleagues was often crucial for a sustainable work situation. CONCLUSION: Maintaining work can be a continuous struggle with invisible impairments many years after a stroke. Strategies for managing work are dependent on each individual work situation, where support and understanding at work seem to be crucial for a sustainable work situation. PMID- 30012786 TI - Prevalence and risk factors of MRSA colonisations: a cross-sectional study among personnel in outpatient care settings in Hamburg, Germany. AB - OBJECTIVES: Healthcare workers frequently come into contact with infected individuals and are at a greater risk of infection than the general population due to their occupation. Multidrug-resistant organisms (MDROs) also pose a significant challenge for personnel and medical facilities. Currently, little is known about the occupational risk of methicillin-resistant Staphylococcus aureus (MRSA) in outpatient care settings. Therefore, a cross-sectional study was conducted in Hamburg to investigate MRSA colonisation among outpatient nursing staff. METHODS: MRSA screening with nasal swabs was carried out, the known risk factors for colonisation were determined and information on infection control was inquired. Where tests were positive, a control swab was taken; if this confirmed a positive result, decolonisation was offered. A molecular biological examination of the MRSA samples was performed. The occupational MRSA exposure and risk factors were compared with the situation for personnel in inpatient geriatric care. RESULTS: A total of 39 outpatient services participated in the study and 579 employees were tested. The MRSA prevalence was 1.2% in all and 1.7% in nursing staff. Most of the employees that tested positive had close or known contact with MRSA patients. Health personnel frequently reported personal protective measures and their application. Compared with inpatient care staff, outpatient staff were older and had worked in their profession for a longer time. CONCLUSION: This study marks the first time that data has been made available on the occupational MRSA risk of outpatient care personnel in Hamburg. The MRSA prevalence is low and provides a good basis for describing the MRSA risk of occupational exposure by health personnel in outpatient care. PMID- 30012787 TI - Neurodevelopment of 24 children born in Brazil with congenital Zika syndrome in 2015: a case series study. AB - OBJECTIVE: To describe the neurodevelopment of children with congenital Zika syndrome during the second year of life. DESIGN: Case series study. SETTING: Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Pernambuco, Brazil. PARTICIPANTS: 24 children with congenital Zika syndrome born with microcephaly during the Zika outbreak in Brazil in 2015 and followed up at the IMIP during their second year of life. MAIN OUTCOME MEASURE: Denver Developmental Screening Test II, head circumference and clinical neurological examination. RESULTS: All children presented neurodevelopmental delay: for an average chronological age of 19.9 months, language was equivalent to that of age 2.1 months, gross motor 2.7 months, fine motor/adaptive 3.1 months and personal/social 3.4 months. Head circumference remained below the third percentile for age and gender, and growth rate up to the second year of life was 10.3 cm (expected growth 13 cm). Muscle tone was increased in 23 (95.5%) of 24 children, musculotendinous reflexes were increased in the whole sample and clonus was present in 18 (77.3%) of 24 children. All children except one had epilepsy. CONCLUSION: Children born with microcephaly associated with congenital Zika virus have a significant neurodevelopmental delay. PMID- 30012788 TI - Mobile therapeutic attention for treatment-resistant schizophrenia (m-RESIST): a prospective multicentre feasibility study protocol in patients and their caregivers. AB - INTRODUCTION: Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. In the European Union, approximately 40% of people with schizophrenia have TRS. Factors such as the persistence of positive symptoms or higher risk of comorbidities leave clinicians with a complex scenario when treating these patients. Intervention strategies based on mHealth have demonstrated their ability to support and promote self-management-based strategies. Mobile therapeutic attention for treatment-resistant schizophrenia (m RESIST), an innovative mHealth solution based on novel technology and offering high modular and flexible functioning, has been developed specifically for patients with TRS and their caregivers. As intervention in TRS is a challenge, it is necessary to perform a feasibility study before the cost-effectiveness testing stage. METHODS AND ANALYSIS: This manuscript describes the protocol for a prospective multicentre feasibility study in 45 patients with TRS and their caregivers who will be attended in the public health system of three localities: Hospital Santa Creu Sant Pau (Spain), Semmelweis University (Hungary) and Gertner Institute & Sheba Medical Center (Israel). The primary aim is to investigate the feasibility and acceptability of the m-RESIST solution, configured by three mHealth tools: an app, wearable and a web-based platform. The solution collects data about acceptability, usability and satisfaction, together with preliminary data on perceived quality of life, symptoms and economic variables. The secondary aim is to collect preliminary data on perceived quality of life, symptoms and economic variables. ETHICS AND DISSEMINATION: This study protocol, funded by the Horizon 2020 Programme of the European Union, has the approval of the ethics committees of the participating institutions. Participants will be fully informed of the purpose and procedures of the study, and signed inform consents will be obtained. The results will be published in peer-reviewed journals and presented in scientific conferences to ensure widespread dissemination. TRIAL REGISTRATION NUMBER: NCT03064776; Pre-results. PMID- 30012789 TI - Randomised controlled feasibility trial of real versus sham repetitive transcranial magnetic stimulation treatment in adults with severe and enduring anorexia nervosa: the TIARA study. AB - OBJECTIVE: Treatment options for severe, enduring anorexia nervosa (SE-AN) are limited. Non-invasive neuromodulation is a promising emerging intervention. Our study is a feasibility randomised controlled trial of repetitive transcranial magnetic stimulation (rTMS) in individuals with SE-AN, which aims to inform the design of a future large-scale trial. DESIGN: Double-blind, parallel group, two arm, sham-controlled trial. SETTING: Specialist eating disorders centre. PARTICIPANTS: Community-dwelling people with anorexia nervosa, an illness duration of >=3 years and at least one previous completed treatment. INTERVENTIONS: Participants received 20 sessions (administered over 4 weeks) of MRI-guided real or sham high-frequency rTMS to the left dorsolateral prefrontal cortex in addition to treatment-as-usual. OUTCOMES: Primary outcomes were recruitment, attendance and retention rates. Secondary outcomes included body mass index (BMI), eating disorder symptoms, mood, quality of life and rTMS safety and tolerability. Assessments were conducted at baseline, post-treatment and follow-up (ie, at 0 month, 1 month and 4 months post-randomisation). RESULTS: Thirty-four participants (17 per group) were randomly allocated to real or sham rTMS. One participant per group was withdrawn prior to the intervention due to safety concerns. Two participants (both receiving sham) did not complete the treatment. rTMS was safe and well tolerated. Between-group effect sizes of change scores (baseline to follow-up) were small for BMI (d=0.2, 95% CI -0.49 to 0.90) and eating disorder symptoms (d=0.1, 95% CI -0.60 to 0.79), medium for quality of life and moderate to large (d=0.61 to 1.0) for mood outcomes, all favouring rTMS over sham. CONCLUSIONS: The treatment protocol is feasible and acceptable to participants. Outcomes provide preliminary evidence for the therapeutic potential of rTMS in SE-AN. Largest effects were observed on variables assessing mood. This study supports the need for a larger confirmatory trial to evaluate the effectiveness of multi-session rTMS in SE-AN. Future studies should include a longer follow-up period and an assessment of cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN14329415; Pre-results. PMID- 30012790 TI - Episiotomy practice in six Palestinian hospitals: a population-based cohort study among singleton vaginal births. AB - OBJECTIVE: To explore the rates, characteristics and indications for episiotomy among women delivering vaginally for the first time, as well as parous women. STUDY DESIGN: A prospective, population-based birth cohort study. SETTING: Obstetric departments in six Palestinian government hospitals. PARTICIPANTS: All women with singleton vaginal births (n=29 165) from 1 March 2015 until 1 March 2016. METHODS: All women were divided into two groups: first vaginal birth group (n=9108), including primiparous women and women with their first vaginal birth after one caesarean section, and the parous group (n=20 057). Each group was analysed separately. Data were presented as numbers and percentages or range. Differences in rates were assessed by the p values of chi2 test, or Fisher's exact test if there are cell counts less than 5. MAIN OUTCOME MEASURES: Episiotomy rates and indications among women of singleton births. RESULTS: The overall episiotomy rate was 28.7%: 78.8% for women with first vaginal birth (range 56.6%-86.0%) and 5.9% for parous women (range 1.0%-9.5%). The most common indications for episiotomy were 'primiparity' in the first vaginal birth group (69.9%) and 'protecting the perineum' in the parous group (59.5%). The least common indications were prolonged second stage (1.5%) and fetal distress (6.9%), respectively. CONCLUSION: In Palestine, the majority of women who delivered vaginally for the first time had an episiotomy. Education of birth attendants, clinical audits, educational interventions and adherence to the updated guidelines may help to decrease the routine overuse of episiotomy. PMID- 30012791 TI - Publication status of completed registered studies in paediatric appendicitis: a cross-sectional analysis. AB - OBJECTIVE: Appendicitis is considered the most frequent surgical emergency in children. While the management of paediatric appendicitis is evolving, the precise amount of unpublished completed trials, potentially introducing bias into meta-analyses, is unknown. Controversial issues include the appropriate choice of surgical procedures, criteria for diagnosis of appendicitis, the role of antibiotic treatment and pain management. Selective reporting may introduce bias into evidence-based clinical decision-making, and the current, precise extent of unpublished results in paediatric appendicitis is unknown. We therefore assessed the publication status of completed clinical studies involving children registered on ClinicalTrials.gov. DESIGN: Cross sectional analysis. STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. SETTING AND PARTICIPANTS: ClinicalTrials.gov was queried for completed studies which were matched to publications on ClinicalTrials.gov, PubMed or Google Scholar. If no publication could be identified, principal investigators were contacted. INTERVENTIONS/EXPOSURE: Observational analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The proportion of published and unpublished studies was calculated. Subgroup analysis included studies on surgical procedures, diagnosis, antibiotic treatment and pain management. RESULTS: Out of n=52 completed clinical studies involving children with appendicitis, n=33 (63%) were published and n=19 (37%) were unpublished. Eighty three per cent (n=43/52) of clinical trials assessed the above-listed controversial issues. Diagnostic studies were most rigorously published (91% of trials reported), data on surgical procedures, antibiotic and pain management were less transparent. Sixty-six per cent of interventional studies and 60% of randomised studies were published. Median time-to-publication, for example, the delay between completion of the trial until public availability of the results was 24 (IQR 12-36), range 2-92 months. CONCLUSION: Despite the importance of appendicitis in clinical practice for the paediatric surgeon, there remains scientific uncertainty due to unpublished clinical trial results with room for improvement in the future. These data are helpful in framing the shifting paradigms in paediatric appendicitis because it adds transparency to the debate. PMID- 30012792 TI - Interrupted time-series analysis of the impact of generic market entry of antineoplastic products in China. AB - OBJECTIVES: The rapid growth of pharmaceutical costs is a major healthcare issue all over the world. The high prices of new drugs, especially those for cancer, are also a concern for stakeholders. Generic drugs are a major price-reducing opportunity and provide more societal value. The aim of this research is to analyse the impact of generic entry on the volume and cost of antineoplastic agents in China. METHODS: An interrupted time-series design examined monthly sales of three antineoplastic drugs (capecitabine, decitabine, imatinib) from 699 public hospitals during January 2011 to June 2016. The first generic entry times (December 2013, December 2012, August 2013, respectively) were regarded as the intervention time points. We estimated changes in volume and cost following the generic entry. RESULTS: We found that generic entry was associated with increases in the volume of three antineoplastic agents and decreases in their costs. In terms of volume, generic entry was associated with increases in use of capecitabine, decitabine and imatinib by 815.0 (95% CI -66.5 to 1696.5, p>0.05), 11.0 (95% CI 3.7 to 18.3, p=0.004) and 2145.5 (95% CI 1784.1 to 2506.9, p<0.001) units. The entry of generic antineoplastic drugs reduced the monthly cost trend of three agents by Y3.1 (95% CI -Y3.6 to -Y2.6, p<0.001), Y84.7 (95% CI -Y104.7 to -Y64.6, p<0.001) and Y21.3 (95% CI -Y24.2 to -Y18.4, p<0.001), respectively. The entry of generic drugs attenuated the upward trend in volume of three brand name drugs and even triggered reductions in the volume of brand-name capecitabine. The entry of generics was accompanied by significant increase of Y2.6 in monthly brand-name decitabine cost (95% CI Y0.2 to Y5.1, p=0.04). CONCLUSION: Our findings suggested that entry of generic drugs impacted use and cost of antineoplastic medicines in China. Generic drugs may improve the availability and the affordability of antineoplastic agents, which would benefit more patients. PMID- 30012793 TI - How do Australian women cope with pelvic girdle pain during pregnancy? A qualitative study protocol. AB - INTRODUCTION: Pelvic girdle pain is commonly experienced during pregnancy and results in significant physical, psychosocial and work-related challenges. Few studies have investigated the lived experiences of pregnant women with pelvic girdle pain and their coping strategies. There is a need to develop a greater understanding of this prevalent condition among Australian women. Thus, this study seeks to gain information about the impact of pelvic girdle pain on daily life and how women cope with this condition during pregnancy. METHODS AND ANALYSIS: A qualitative research design, situated within a phenomenological framework, is adopted. The participants will be invited to describe their lived experiences of pregnancy-related pelvic girdle pain, the impact on their daily life and the strategies they use to cope with the condition. A stratified purposive sample will be undertaken to ensure the sample provides information rich cases representative of women with pregnancy-related pelvic girdle pain. Face-to-face, individual, semistructured interviews will be conducted with participants at Westmead Hospital, Sydney, Australia. A solicited diary will be offered to any participants who may find attending the interview difficult. All participants will also be invited to attend a focus group session. The different methods of data collection used in this study will allow for triangulation, thereby increasing the trustworthiness of findings. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Human Research Ethics Committees of Westmead Hospital, Sydney, and Western Sydney University, Sydney. Dissemination of results will be via journal articles and conference presentations. PMID- 30012794 TI - Defining the risk factors for acute, subacute and chronic cough: a cross sectional study in a Finnish adult employee population. AB - OBJECTIVES: Chronic cough is linked to various long-standing risk factors like asthma, chronic rhinitis and oesophageal reflux disease. On the contrary, acute and subacute cough are usually considered to be caused by acute respiratory infections. Little is known about the possible long-standing risk factors for acute and subacute cough. In this study, we have identified the long-standing risk factors for acute, subacute and chronic cough in order to identify the risk factors specifically associated with chronic cough. DESIGN: A comprehensive 80 item questionnaire was sent via email to the participants. SETTING: A community based study to all public service employees of two towns in central Finland. PARTICIPANTS: There were 13 980 employees, of them 3697 responded (26.4%). Among the responders, there were 199 subjects with current daily acute cough (duration <3 weeks, prevalence 5.4%), 126 subjects with current daily subacute cough (duration 3-8 weeks, prevalence 3.4%) and 267 subjects with current daily chronic cough (duration >8 weeks, prevalence 7.2%). PRIMARY OUTCOME MEASURES: The risk factors that associated with each cough subtype. The subjects without any cough formed the reference group. RESULTS: Several risk factors were associated with both short and long cough subtypes namely family history of chronic cough, moisture damage exposure and number of reported somatic symptoms. Furthermore, allergy was associated with acute and subacute cough. Current asthma and chronic rhinitis were associated with subacute and chronic cough. Oesophageal reflux disease and advanced age were associated with chronic cough. CONCLUSIONS: The specific risk factors for chronic cough were oesophageal reflux disease and advanced age. Acute and subacute cough should not be regarded merely as symptoms of acute respiratory infections but possible manifestations of long-standing risk factors. A new risk factor for all cough types was family history of chronic cough. PMID- 30012795 TI - Prognostic implications of left ventricular strain by speckle-tracking echocardiography in population-based studies: a systematic review protocol of the published literature. AB - INTRODUCTION: Left ventricular (LV) strain by speckle-tracking echocardiography (STE) is a comparatively new prognostic marker. Meta-analyses relating LV strain by STE to outcomes have been conducted in selected patient-based populations with established or suspected cardiovascular (CV) diseases. However, the evidence related to population-based studies of community-dwelling individuals is uncertain. The aim of this study is to provide a comprehensive systematic review and analysis of the current available literature regarding LV strain by STE as a predictor of adverse outcomes in population-based studies. METHODS AND ANALYSES: Thesaurus and text-word searching will be used to search two online databases (MEDLINE and EMBASE) and additional sources will be identified from citation metrics and reference lists' search. Dual search results' screening, data extraction and quality assessment will be performed. Cohort studies of community/population-based samples who have had STE and followed up longitudinally for mortal and morbid events, and published in English and peer reviewed journals will be included. Primary outcome will be all-cause mortality whereas secondary outcomes will be composite cardiac and CV end points. Risk of bias will be assessed using Newcastle-Ottawa Quality Assessment Scale of cohort studies that will be modified as appropriate. Any arising discrepancies will be discussed and resolved through consensus. ETHICS AND DISSEMINATION: Ethical approval is not required as this is a protocol for a systematic review. The findings of this study will be presented at scientific conferences and published in a peer-reviewed journal. Any amendments to the protocol will be documented and updated in the PROSPERO registry. PROSPERO REGISTRATION NUMBER: CRD42018090302. PMID- 30012796 TI - Effectiveness of early assessment and intervention by interdisciplinary teams including health and social care professionals in the emergency department: protocol for a systematic review. AB - INTRODUCTION: Finding cost-effective strategies to improve patient care in the emergency department (ED) is an increasing imperative given growing numbers of ED attendees. Encouraging evidence indicates that interdisciplinary teams including health and social care professionals (HSCPs) enhance patient care across a variety of healthcare settings. However, to date no systematic reviews of the effectiveness of early assessment and/or interventions carried by such teams in the ED exist. This systematic review aims to explore the impact of early assessment and/or intervention carried out by interdisciplinary teams including HSCPs in the ED on the quality, safety and cost-effectiveness of care, and to define the content of the assessment and/or intervention offered by HSCPs. METHODS AND ANALYSIS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standardised guidelines, we will conduct a systematic review of randomised controlled trials (RCTs), non-RCTs, controlled before-after studies, interrupted time series and repeated measures studies that report the impact of early assessment and/or intervention provided to adults aged 18+ by interdisciplinary teams including HSCPs in the ED. Searches will be carried in Cumulative Index of Nursing and Allied Health Literature, Embase, Cochrane Library and MEDLINE from inception to March 2018. We will also hand-search the reference lists of relevant studies. Following a two-step screening process, two independent reviewers will extract data on the type of population, intervention, comparison, outcomes and study design. The quality of the studies will be appraised using the Cochrane Risk of Bias Tool. The findings will be synthesised in a narrative summary, and a meta-analysis will be conducted where appropriate. ETHICS AND DISSEMINATION: Ethical approval will not be sought since it is not required for systematic reviews. The results of this review will be disseminated through publication in a peer-review journal and presented at relevant conferences. TRIAL REGISTRATION NUMBER: CRD42018091794. PMID- 30012797 TI - Comparison of self-reported measures of alcohol-related dependence among young Swiss men: a study protocol for a cross-sectional controlled sample. AB - INTRODUCTION: Short screenings of alcohol-related dependence are needed for population-based assessments. A clinical interview constitutes a reliable diagnosis often seen as gold standard, but it is costly and time consuming and as such, not suitable for population-based assessments. Therefore, self-reported questionnaires are needed (eg, alcohol use disorder (AUD) as in the Diagnostic and Statistic Manual of Mental Disorders (DSM) 5), but their reliability is questionable. Recent studies called for more evidence-based measurements for population-based screening (eg, heavy alcohol use over time (HAU)). This study aims to test the reliability of different self-reported measures of alcohol use. METHODS AND ANALYSIS: Based on stratified random selection, 280 participants will be recruited from the French-speaking subgroup of the Swiss National Science Foundation-supported Cohort Study on Substance Use and Risk Factors (C-SURF). This cohort is a population-based sample of young Swiss men in their mid-20s (n=2668). The sample size calculation is based on a proportion non-inferiority test (alpha=5%, power=80%, margin of equivalence=10%, difference in sensitivity between self-reported AUD and HAU=5%, correlation between AUD and HAU=0.35, and drop-outs=15%). Assessment will include a clinical interview as the gold standard of alcohol-related dependence, self-reported alcohol measures (HAU, AUD and drinking patterns), biomarkers as gold standards of chronic excessive drinking, and health outcomes. To assess the validity of the self-reported alcohol measures, sensitivity analyses will be run. The associations between alcohol related measures and health outcomes will be tested. A non-response analysis will be run using the previous waves of the C-SURF study using logistic regressions. ETHICS AND DISSEMINATION: The study protocol has been approved by the Human Research Ethics Committee of the Canton of Vaud, Switzerland (no. 2017-00776). The results will be submitted for publication in peer-reviewed journals and presented at national and international conferences. PMID- 30012798 TI - Protocol for process evaluation of CIVIC randomised controlled trial: Community based InterVentions to prevent serIous Complications following spinal cord injury in Bangladesh. AB - INTRODUCTION: People with spinal cord injuries in low-income and middle-income countries are highly vulnerable to life-threatening complications in the period immediately after discharge from hospital. We are conducting a randomised controlled trial in Bangladesh to determine whether all-cause mortality at 2 years can be reduced if health professionals regularly ring and visit participants in their homes following discharge. We will conduct a process evaluation alongside the trial to explain the trial results and determine the feasibility of scaling this intervention up in low-income and middle-income countries if it is found to be effective. METHODS AND ANALYSIS: Our process evaluation is based on the Realist and Reach, Effectiveness, Adoption, Implementation and Maintenance frameworks. We will use a mixed methods approach that uses both qualitative and quantitative data. For example, we will audit a sample of telephone interactions between intervention participants and the healthcare professionals, and we will conduct semistructured interviews with people reflective of various interest groups. Quantitative data will also be collected to determine the number and length of interactions between the healthcare professionals and participants, the types of issues identified during each interaction and the nature of the support and advice provided by the healthcare professionals. All quantitative and qualitative data will be analysed iteratively before the final analysis of the trial results. These data will then be triangulated with the final results of the primary outcome. ETHICS AND DISSEMINATION: Ethics approval was obtained from the institutional ethics committee at the site in Bangladesh and from the University of Sydney, Australia. The study will be conducted in compliance with all stipulations of its protocol, the conditions of ethics committee approval and the relevant regulatory bodies. The results of the trial will be disseminated through publications in peer reviewed scientific journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12615000630516. PMID- 30012799 TI - Minimizing length of hospital stay for women's reproductive care. PMID- 30012800 TI - Sex differences in outcomes of heart failure in an ambulatory, population-based cohort from 2009 to 2013. AB - BACKGROUND: Heart failure remains a substantial cause of morbidity and mortality in women. We examined the sex differences in heart failure incidence, mortality and hospital admission in a population-based cohort. METHODS: All Ontario residents who were diagnosed with heart failure in an ambulatory setting between Apr. 1, 2009, and Mar. 31, 2014, were included in this study. Incident cases of heart failure were captured through physician billing using a validated algorithm. Outcomes were mortality and hospital admission for heart failure within 1 year of the diagnosis. Probability of death and hospital admission were calculated using the Kaplan-Meier method. The hazard of death was assessed using a multivariable Cox proportional hazard model. RESULTS: A total of 90 707 diagnoses of heart failure were made in an ambulatory setting during the study period (47% women). Women were more likely to be older and more frail, and had different comorbidities than men. The incidence of heart failure decreased during the study period in both sexes. The mortality rate decreased in both sexes, but remained higher in women than men. The female age-standardized mortality rate was 89 (95% confidence interval [CI] 80-100) per 1000 in 2009 and 85 (95% CI 75-95) in 2013, versus male age-standardized mortality rates of 88 (95% CI 80-97) in 2009 and 83 (95% CI 75-91) in 2013. Conversely, the rates of incident heart failure hospital admissions after heart failure diagnosis decreased in men and increased in women. INTERPRETATION: Despite decreases in overall heart failure incidence and mortality in ambulatory patients, mortality rates remain higher in women than in men, and rates of hospital admission for heart failure increased in women and declined in men. Further studies should focus on sex differences in health-seeking behaviour, medical therapy and response to therapy to provide guidance for personalized care. PMID- 30012801 TI - The mobile stroke unit and management of acute stroke in rural settings. PMID- 30012802 TI - Physicians who object to medical assistance in dying. PMID- 30012803 TI - Extended-release naltrexone overlooked in opioid use disorders guideline. PMID- 30012804 TI - Association versus causation. PMID- 30012805 TI - Call for family doctors to have more emergency medicine training sparks debate. PMID- 30012806 TI - Should medical students volunteer to help during emergencies in public settings? PMID- 30012807 TI - Health professionals decry detention of migrant children in Canada. PMID- 30012808 TI - Allthosesyllables. PMID- 30012809 TI - Differences between GP perception of delivered empathy and patient-perceived empathy: a cross-sectional study in primary care. AB - BACKGROUND: Empathy has positive effects on a range of healthcare outcomes. It is therefore an important skill for a GP. However, the correlation between GP perception of delivered empathy and patient perception of GP empathic communication during consultations is still unclear. AIM: To investigate the correlation between GP perception of delivered empathy and patient-perceived empathy. DESIGN AND SETTING: Cross-sectional study in primary care in the Netherlands, between December 2016 and February 2017. METHOD: GPs and their patients were asked to fill in an empathy questionnaire directly after a consultation. Patient perception of received empathy during the consultation was measured through the Dutch version of the Consultation and Relational Empathy (CARE) questionnaire. GP perception of delivered empathy during the consultation was measured with an adapted version of the CARE questionnaire. RESULTS: The authors obtained questionnaires from 147 consultations by 34 different GPs in 16 primary care practices. A total of 143 consultations were eligible for inclusion in the analysis. Mean patient-perceived empathy score was significantly higher than mean GPs' empathy score (42.1, range 20.0 to 50.0 and 31.6, range 24.0 to 41.0, respectively, P<0.0001). Furthermore, a low correlation (r = 0.06) was found between GP empathy score and patient-perceived empathy score. CONCLUSION: GPs rate the delivered empathy during consultations consistently and significantly lower than their patients experience empathy during consultations. Moreover, GPs' impressions of the empathy delivered during the consultation do not predict the actual amount of empathy perceived by their patients. Patients experience a great deal of empathy during their clinical encounter. GPs' self reports on empathy delivered gives an inaccurate reflection, and underestimates patient-perceived empathy. PMID- 30012810 TI - Now Gosport: what next? PMID- 30012811 TI - Chronic kidney disease and cause-specific hospitalisation: a matched cohort study using primary and secondary care patient data. AB - BACKGROUND: Although chronic kidney disease (CKD) is associated with various outcomes, the burden of each condition for hospital admission is unknown. AIM: To quantify the association between CKD and cause-specific hospitalisation. DESIGN AND SETTING: A matched cohort study in primary care using Clinical Practice Research Datalink linked to Hospital Episode Statistics in England. METHOD: Patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 for >=3 months) and a comparison group of patients without known CKD (matched for age, sex, GP, and calendar time) were identified, 2004-2014. Outcomes were hospitalisations with 10 common conditions as the primary admission diagnosis: heart failure; urinary tract infection; pneumonia; acute kidney injury (AKI); myocardial infarction; cerebral infarction; gastrointestinal bleeding; hip fracture; venous thromboembolism; and intracranial bleeding. A difference in the incidence rate of first hospitalisation for each condition was estimated between matched patients with and without CKD. Multivariable Cox regression was used to estimate a relative risk for each outcome. RESULTS: In a cohort of 242 349 pairs of patients, with and without CKD, the rate difference was largest for heart failure at 6.6/1000 person-years (9.7/1000 versus 3.1/1000 person-years in patients with and without CKD, respectively), followed by urinary tract infection at 5.2, pneumonia at 4.4, and AKI at 4.1/1000 person-years. The relative risk was highest for AKI with a fully adjusted hazard ratio of 4.90, 95% confidence interval (CI) = 4.47 to 5.38, followed by heart failure with 1.66, 95% CI = 1.59 to 1.75. CONCLUSION: Hospitalisations for heart failure, infection, and AKI showed strong associations with CKD in absolute and(or) relative terms, suggesting targets for improved preventive care. PMID- 30012813 TI - World Cancer Research Fund's campaign helps people take control of cancer risk. PMID- 30012812 TI - Nurse-led psychological intervention for type 2 diabetes: a cluster randomised controlled trial (Diabetes-6 study) in primary care. AB - BACKGROUND: Suboptimal glycaemic control in type 2 diabetes (T2D) is common and associated with psychological barriers. AIM: To investigate whether it was possible to train practice nurses in six psychological skills (Diabetes-6 [D6]) based on motivational interviewing (MI) and basic cognitive behaviour therapy (CBT), and whether integrating these with diabetes care was associated with improved glycaemic control over 18 months compared with standard care. DESIGN AND SETTING: Two-arm, single-blind, parallel cluster randomised controlled trial in primary care. METHOD: Adult participants (n = 334) with T2D and persistent HbA1c >=69.4 mmol/mol were randomised to receive 12 sessions of either the D6 intervention or standard care over 12 months. Practice nurses were trained in the six psychological skills and their competencies were measured by standardised rating scales. Primary outcome was a change in HbA1c level at 18 months from randomisation. Secondary outcomes were changes in systolic and diastolic blood pressure, body mass index, waist circumference, depressive symptoms, harmful alcohol intake, diabetes-specific distress, and cost-effectiveness. RESULTS: Using intention-to-treat analysis, there was no significant difference between D6 intervention and standard care in HbA1c (mean difference -0.79 mmol/mol, 95% confidence interval [CI] = -5.75 to 4.18) or for any of the secondary outcomes. The competency level of D6 nurses was below the beginner proficiency level and similar to the standard-care nurses. CONCLUSION: Training nurses in MI and basic CBT to support self-management did not lead to improvements in glycaemic control or other secondary outcomes in people with T2D at 18 months. It was also unlikely to be cost-effective. Furthermore, the increased contact with standard-care nurses did not improve glycaemic control. PMID- 30012814 TI - Advancing health through research partnerships in Latin America. PMID- 30012815 TI - Age and Risk of Stroke in Asians With Atrial Fibrillation. PMID- 30012816 TI - Prediction Models for Clinical Outcome After a Carotid Revascularization Procedure. AB - Background and Purpose- Prediction models may help physicians to stratify patients with high and low risk for periprocedural complications or long-term stroke risk after carotid artery stenting or carotid endarterectomy. We aimed to evaluate external performance of previously published prediction models for short and long-term outcome after carotid revascularization in patients with symptomatic carotid artery stenosis. Methods- From a literature review, we selected all prediction models that used only readily available patient characteristics known before procedure initiation. Follow-up data from 2184 carotid artery stenting and 2261 carotid endarterectomy patients from 4 randomized trials (EVA-3S [Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis], SPACE [Stent-Protected Angioplasty Versus Carotid Endarterectomy], ICSS [International Carotid Stenting Study], and CREST [Carotid Revascularization Endarterectomy Versus Stenting Trial]) were used to validate 23 short-term outcome models to estimate stroke or death risk <=30 days after the procedure and the original outcome measure for which the model was developed. Additionally, we validated 7 long-term outcome models for the original outcome measure. Predictive performance of the models was assessed with C statistics and calibration plots. Results- Stroke or death <=30 days after the procedure occurred in 158 (7.2%) patients after carotid artery stenting and in 84 (3.7%) patients after carotid endarterectomy. Most models for short-term outcome after carotid artery stenting (n=4) or carotid endarterectomy (n=19) had poor discriminative performance (C statistics ranging from 0.49-0.64) and poor calibration with small absolute risk differences between the lowest and highest risk groups and overestimation of risk in the highest risk groups. Long-term outcome models (n=7) had a slightly better performance with C statistics ranging from 0.59 to 0.67 and reasonable calibration. Conclusions- Current models did not reliably predict outcome after carotid revascularization in a trial population of patients with symptomatic carotid stenosis. In particular, prediction of short term outcome seemed to be difficult. Further external validation of existing prediction models or development of new prediction models is needed before such models can be used to support treatment decisions in individual patients. PMID- 30012817 TI - Cost-Effectiveness of Quantitative Magnetic Resonance Angiography Screening and Submaximal Angioplasty for Symptomatic Vertebrobasilar Disease. AB - Background and Purpose- The VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) study demonstrated posterior circulation distal flow status, determined by quantitative magnetic resonance angiography, is a robust predictor of vertebrobasilar stroke risk in patients with symptomatic atherosclerotic vertebrobasilar disease. Flow-compromised high-risk patients may benefit from flow-restoring endovascular procedures, such as submaximal angioplasty. In this study, we examine the cost-effectiveness of quantitative magnetic resonance angiography screening to identify patients who may benefit from submaximal angioplasty to restore vertebrobasilar flow. Methods- A Markov model was created comparing a no screening strategy with standard medical management alone and a screening strategy involving quantitative magnetic resonance angiography imaging and submaximal angioplasty for treatable patients with low vertebrobasilar flow for a 30-year time horizon. Outcomes included quality-adjusted life years (QALY) and lifetime costs. Rates of stroke and death were obtained from VERiTAS data, and disability rates and costs were derived from VERiTAS and the literature. A sensitivity analysis was performed with periprocedural stroke rate from angioplasty the primary variable of interest. Results- At a 6% periprocedural stroke risk, the screening strategy saved an average of 0.364 QALYs per patient and a lifetime cost savings of $7312 versus the no screening strategy. Among patients with low flow suitable for intervention, the benefit was substantially higher, averaging 1.485 QALYs saved and lifetime cost savings of $21 294. Across the entire cohort, QALY savings were observed at the end of the first year and economic savings at year 6. The benefit of screening declined at higher periprocedural risk. Conclusions- Quantitative magnetic resonance angiography screening and submaximal angioplasty with 6% periprocedural risk in suitable patients are cost effective both in terms of QALY and lifetime costs for patients with symptomatic vertebrobasilar occlusive disease. With potential health and economic savings, a clinical trial examining the periprocedural risk of submaximal angioplasty is warranted. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00590980. PMID- 30012818 TI - Significance of Nonfocal Symptoms in Patients With Transient Ischemic Attack. AB - Background and Purpose- Patients with transient ischemic attack (TIA) occasionally show nonfocal symptoms, such as unconsciousness, amnesia, and unsteadiness. The purpose of this study was to clarify the characteristics and prognosis of patients with TIA with nonfocal symptoms, using data from the PROMISE-TIA (Prospective Multicenter Registry to Identify Subsequent Cardiovascular Events After Transient Ischemic Attack). Methods- Patients with TIA within 7 days of onset were consecutively enrolled in the Japanese nationwide registry. Factors associated with nonfocal symptoms and 1-year risks of ischemic stroke and coronary artery diseases were assessed in multivariate-adjusted models. Results- We studied 1362 patients with TIA (879 men; mean age, 69+/-12 years), including 219 (16%) with nonfocal symptoms. Patients with TIA with nonfocal symptoms were more likely to show acute ischemic lesions in the posterior circulation on diffusion-weighted imaging (multivariate-adjusted odds ratio, 3.07; 95% confidence interval, 1.57-5.82) and arterial stenosis or occlusion in the posterior circulation on vascular examination (odds ratio, 1.94; 95% confidence interval, 1.19-3.09) than those without nonfocal symptoms. Although 1-year risk of ischemic stroke did not differ significantly between groups (adjusted hazard ratio, 0.79; 95% confidence interval, 0.42-1.37), risk of coronary artery disease was higher in patients with TIA with nonfocal symptoms (hazard ratio, 3.37; 95% confidence interval, 1.14-9.03). Conclusions- Both acute ischemic lesions and arterial stenosis and occlusion in the posterior circulation were more frequently observed in patients with TIA with nonfocal symptoms. PMID- 30012819 TI - Trajectory Groups of 24-Hour Systolic Blood Pressure After Acute Ischemic Stroke and Recurrent Vascular Events. AB - Background and Purpose- Blood pressure dynamics in patients with acute ischemic stroke may serve as an important modifiable and prognostic factor. Methods- A total of 8376 patients with acute ischemic stroke were studied from a prospective multicenter registry. Patients were eligible if they had been admitted within 24 hours of symptom onset and had >=5 systolic blood pressure (SBP) measurements during the first 24 hours of hospitalization. SBP trajectory groups in the first 24 hours were identified using the TRAJ procedure in SAS software with delta Bayesian Information Criterion and prespecified modeling parameters. Vascular events, including recurrent stroke, myocardial infarction, and death, were prospectively collected. The risk of having vascular events was calculated using the frailty model to adjust for clustering by hospital. Results- The group-based trajectory model classified patients with acute ischemic stroke into 5 SBP trajectory groups: low (22.3%), moderate (40.8%), rapidly stabilized (11.9%), acutely elevated (18.5%), and persistently high (6.4%) SBP. The risk of having vascular events was increased in the acutely elevated (hazard ratio, 1.28 [95% confidence interval, 1.12-1.47]) and the persistently high SBP groups (hazard ratio, 1.67 [95% confidence interval, 1.37-2.04]) but not in the rapidly stabilized group (hazard ratio, 1.13 [95% confidence interval, 0.95-1.34]), when compared with the moderate SBP group. Conclusions- SBP during the first 24 hours after acute ischemic stroke may be categorized into distinct trajectory groups, which differ in relation to stroke characteristics and frequency of subsequent recurrent vascular event risks. The findings may help to recognize potential candidates for future blood pressure control trials. PMID- 30012820 TI - Age Threshold for Ischemic Stroke Risk in Atrial Fibrillation. AB - Background and Purpose- Although older age is one of the most important risk factor for stroke in atrial fibrillation (AF), the appropriate age threshold (eg, CHA2DS2-VASc score [congestive heart failure, hypertension, age >=75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74 years, female], 1 point for age 65-74 years, 2 points for age >=75 years) for increased risk is controversial because actual age thresholds may differ between countries and ethnic groups. We investigated the age threshold for ischemic stroke risk among Asian AF patients. Methods- Using National Health Insurance Service database, including 426 650 oral anticoagulant-naive nonvalvular AF patients from 2005 to 2015, with <=2 nongender related CHA2DS2-VASc risk scores (CHA2DS2-VASc score 0-2 in males, 1-3 in females), we assessed the risk of ischemic stroke in AF patients according to the age. Results- Patients who fulfill the age risk criterion (age, 65-74 years) without other risk factors showed a significantly higher risk of stroke (4.76 per 100 person-years [100PY]; adjusted hazard ratio, 2.25; 95% confidence interval [CI], 2.17-2.36) compared with patients with 1 risk score other than age (1.87/100PY). Patients aged 55 to 59 years with no risk factors showed similar risk of stroke (1.94/100PY; adjusted hazard ratio, 0.95; 95% confidence interval, 0.90-1.00) than patients with 1 risk score (2.06/100PY). Patients aged 65 to 69 years and no other risk factors had similar stroke risk (4.08/100PY; adjusted hazard ratio, 0.93; 95% confidence interval, 0.90-0.97) than patients with 2 nongender-related risk scores (4.42/100PY). Conclusions- Older age is the most important predictor of ischemic stroke in AF, particularly for patients with low to intermediate risk of stroke. These nationwide data suggest lowering the current age threshold (age, >=65 years) in the CHA2DS2-VASc score to age >=55 years might be appropriate among Asian patients with AF. PMID- 30012822 TI - Increased Blood Pressure Variability Contributes to Worse Outcome After Intracerebral Hemorrhage. AB - Background and Purpose- Increased systolic blood pressure variability (BPV) is associated with worse outcome after acute ischemic stroke and may also have a negative impact after intracerebral hemorrhage. We sought to determine whether increased BPV was detrimental in the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage II) trial. Methods- The primary outcome of our study was a 3 month follow-up modified Rankin Scale of 3 to 6, and the secondary outcome was a utility-weighted modified Rankin Scale. We calculated blood pressure mean and variability using systolic blood pressure from the acute period (2-24 hours postrandomization) and subacute period (days 2, 3, and 7). Results- The acute period included 913 patients and the subacute included 877. For 5 different statistical measures of systolic BPV, there was a consistent association between increased BPV and worse neurological outcome in both the acute and subacute periods. This association was not found for systolic blood pressure mean. Conclusions- In this secondary analysis of ATACH-2, we show that increased systolic BPV is associated with worse long-term neurological outcome. Additional research is needed to find techniques that allow early identification of patients with an expected elevation of BPV and to study pharmacological or protocol-based approaches to minimize BPV. PMID- 30012821 TI - Perivascular Spaces Volume in Sporadic and Hereditary (Dutch-Type) Cerebral Amyloid Angiopathy. AB - Background and Purpose- Magnetic resonance imaging visible perivascular spaces in the centrum semiovale (CSO-PVS) have been associated with cerebral amyloid angiopathy (CAA).We aimed to further confirm this link by evaluating CSO-PVS volume in pathologically-demonstrated sporadic and genetically-demonstrated hereditary forms of the disease. Methods- We studied a retrospective hospital based cohort consisting of 63 individuals aged >55 having brain magnetic resonance imaging and pathological assessment of CAA (mean age, 73.6+/-8.5; 46% female), and a separate cohort consisting of 26 carriers, and 28 noncarriers of the hereditary cerebral hemorrhage with amyloidosis-Dutch type (mean age, 46.7+/ 12.8; 61.1% female). CSO-PVS volume was quantified on a single magnetic resonance imaging slice using a computer-assisted segmentation method and expressed as the relative volume of the intracranial volume in that particular slice (CSO-PVS relative volume). We compared CSO-PVS relative volume (1) between subjects with and without the disease in both cohorts; (2) between non-CAA, CAA without hemorrhage, and CAA with hemorrhage cases in the sporadic CAA cohort. All variables reaching P<0.1 in bivariate analyses were entered in logistic regression models. Results- In both sporadic and Dutch cohorts, cases with CAA had significantly higher CSO-PVS relative volume than cases without (median [IQR]: 3.7% [2.5-5.3] versus 1.8% [1.2-2.4], P<0.0001; 3.8% [0.6-6.2] versus 0.7% [0.4-1.6], P=0.007; respectively). In linear regression models, sporadic CAA was associated with higher CSO-PVS relative volume ( P=0.008). In the sporadic CAA cohort, compared with non-CAA cases, CSO-PVS relative volume was higher in both CAA with hemorrhage and without hemorrhage (4.4% [2.6-6.1] and 3% [2.4-3.6] versus 1.8% [1.2-2.4], P<0.001 and P=0.005, respectively). Higher CSO-PVS relative volume was associated with CAA in regression models, both when hemorrhage was present (odds ratio, 2.63; [95% confidence interval, 1.33-5.18]; P=0.005) and absent (odds ratio, 4.55; [95% confidence interval, 0.98-21.04]; P=0.05). Conclusions- Increased CSO-PVS volume is a consistent magnetic resonance imaging marker of cerebrovascular amyloid deposition and a promising diagnostic tool for sporadic CAA without hemorrhagic manifestations. PMID- 30012823 TI - Prognostic Value of Serial Echocardiography in Hypoplastic Left Heart Syndrome. AB - BACKGROUND: Hypoplastic left heart syndrome (HLHS) carries a high mortality. The prognostic value of echocardiographic variables at presentation and the importance of serial data are poorly explored. METHODS AND RESULTS: We retrospectively analyzed longitudinal clinical and echocardiographic parameters of children with hypoplastic left heart syndrome. The primary outcome was time to death or transplant after stage-1 surgery, right censored at stage 3 surgery, accounting for sequential surgical procedures. Univariable and multivariable analysis identified risk factors for transplant or mortality. Time-dependent trends in echo parameters stratified by patient survival were explored using nonparametric methods. In total 67 children with hypoplastic left heart syndrome were included. The 10-week, 20-week, and 1-year survival proportions were 77.6% (66-86), 68.7% (56-78), and 54.1% (41-65), respectively. At presentation, multivariable analysis identified a thicker interventricular septum (hazard ratio [HR], 1.64; P=0.007) to be associated with increased risk for transplant/death, whereas higher tricuspid valve annular planar systolic excursion z score (HR, 0.61; P=0.003) was associated with reduced risk of mortality/transplant. After stage-1, higher body surface area-indexed right ventricular end-systolic area (HR, 1.52; P=0.02), lower fractional area change (HR, 1.18; P=0.01), and qualitatively decreased right ventricular function (HR, 2.55; P=0.08) were associated with increased risk of transplant-free mortality, censored at stage 3. Higher body surface area-indexed right ventricular end-diastolic area (HR, 0.76; P=0.04) and better tricuspid valve annular planar systolic excursion z score (HR, 0.49; P=0.01) were associated with lower mortality/transplant. During follow-up, right ventricular dilation, dysfunction, and tricuspid regurgitation improved in transplant-free survivors and worsened in those transplanted or who died. CONCLUSIONS: Conventional echocardiographic parameters at presentation and during follow-up are potential markers for transplant-free survival in children with hypoplastic left heart syndrome. PMID- 30012824 TI - Is There an Age When Myocardial Perfusion Imaging May No Longer Be Prognostically Useful? AB - BACKGROUND: Heart disease continues to be the leading cause of death, and the prevalence of coronary artery disease is expected to increase as the population ages. It is important to understand the clinical utility of medical tests, or its lack thereof, in the aging population. The objective of this study was to understand the incremental prognostic value of positron emission tomographic (PET) myocardial perfusion imaging in the elderly (>=85 years of age). METHODS AND RESULTS: A total of 3343 patients enrolled in a multicenter observational PET registry were analyzed. Participants were initially divided into 3 age categories: 65 to 74.9, 75 to 84.9, and >=85 years of age and followed for all cause death. Median follow-up time was 3 years. Of the total patient population, 248 patients (49% men) were >=85 years old. When compared with younger patients, individuals >=85 years had a higher prevalence of hypertension (79%) and a lower incidence of dyslipidemia (54%) and diabetes mellitus (24%). On multivariable analysis, %left ventricular stress defect and %left ventricular ischemia were predictors of patient outcome for those <85 years of age but was not statistically significant in those >=85 years of age. The prognostic value of PET (%left ventricular stress defect and %left ventricular ischemia) appeared to decrease with advancing age. CONCLUSIONS: The elderly is a high-risk population irrespective of PET myocardial perfusion imaging results, and incremental prognostic value of PET myocardial perfusion imaging appears to wane in those >=85 years of age. Although PET myocardial perfusion imaging may be diagnostically useful in the elderly, its prognostic value in this population requires further evaluation. PMID- 30012827 TI - Coronary Atheroma Burden Is the Main Determinant of Patient Outcome: But How Much Detail Is Needed? PMID- 30012825 TI - Quantification of Coronary Atherosclerosis in the Assessment of Coronary Artery Disease. AB - BACKGROUND: Diagnosis of coronary artery disease and management strategies have relied solely on the presence of diameter stenosis >=50%. We assessed whether direct quantification of plaque burden (PB) and plaque characteristics assessed by coronary computed tomography angiography could provide additional value in terms of predicting rapid plaque progression. METHODS AND RESULTS: From a 13 center, 7-country prospective observational registry, 1345 patients (60.4+/-9.4 years old; 57.1% male) who underwent repeated coronary computed tomography angiography >2 years apart were enrolled. For conventional angiographic analysis, the presence of stenosis >=50%, number of vessel involved, segment involvement score, and the presence of high-risk plaque feature were determined. For quantitative analyses, PB and annual change in PB (?PB/y) in the entire coronary tree were assessed. Clinical outcomes (cardiac death, nonfatal myocardial infarction, and coronary revascularization) were recorded. Rapid progressors, defined as a patient with >=median value of ?PB/y (0.33%/y), were older, more frequently male, and had more clinical risk factors than nonrapid progressors (all P<0.05). After risk adjustment, addition of baseline PB improved prediction of rapid progression to each angiographic assessment of coronary artery disease, and the presence of high-risk plaque further improved the predictive performance (all P<0.001). For prediction of adverse outcomes, adding both baseline PB and ?PB/y showed best predictive performance (C statistics, 0.763; P<0.001). CONCLUSIONS: Direct quantification of atherosclerotic PB in addition to conventional angiographic assessment of coronary artery disease might be beneficial for improving risk stratification of coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02803411. PMID- 30012826 TI - Diagnostic Performance of Extracellular Volume, Native T1, and T2 Mapping Versus Lake Louise Criteria by Cardiac Magnetic Resonance for Detection of Acute Myocarditis: A Meta-Analysis. AB - BACKGROUND: The Lake Louise Criteria (LLC) were established in 2009 and are the recommended cardiac magnetic resonance imaging criterion for diagnosing patients with suspected myocarditis. Subsequently, newer parametric imaging techniques which can quantify T1, T2, and the extracellular volume (ECV) have been developed and may provide additional utility in the diagnosis of myocarditis. However, whether their diagnostic accuracy is superior to LLC remains unclear. In this meta-analysis, we compared the diagnostic performance of native T1, T2, ECV to LLC in diagnosing acute myocarditis. METHODS AND RESULTS: We searched PubMed for published studies of LLC, native T1, ECV, and T2 diagnostic criteria used to diagnose acute myocarditis. Seventeen studies were included, with a total of 867 myocarditis patients and 441 control subjects. Pooled sensitivity, specificity, and diagnostic odds ratio of all diagnostic tests were assessed by bivariate analysis. LLC had a pooled sensitivity of 74%, specificity of 86%, and diagnostic odds ratio of 17.7. Native T1 had a significantly higher sensitivity than LLC (85% versus 74%, P=0.025). Otherwise, there was no significant difference in sensitivity, specificity, and diagnostic odds ratio when comparing LLC to native T1, T2, or ECV. CONCLUSIONS: Native T1, T2, and ECV mapping provide comparable diagnostic performance to LLC. Although only native T1 had significantly better sensitivity than LLC, each technique offers distinct advantages for evaluating and characterizing myocarditis when compared with the LLC. PMID- 30012828 TI - Prognostic Value of Serial Echocardiography in Hypoplastic Left Heart Syndrome: Smaller Hearts, Better Results. PMID- 30012829 TI - Cardiovascular Magnetic Resonance for Myocardial Inflammation: Lake Louise Versus Mapping? PMID- 30012831 TI - In This Issue of the Journal. PMID- 30012830 TI - Prognosticating in the Very Elderly. PMID- 30012832 TI - Echocardiographic assessment of pulmonary hypertension: a guideline protocol from the British Society of Echocardiography. AB - Pulmonary hypertension is defined as a mean arterial pressure of >=25 mmHg as confirmed on right heart catheterisation. Traditionally, the pulmonary arterial systolic pressure has been estimated on echo by utilising the simplified Bernoulli equation from the peak tricuspid regurgitant velocity and adding this to an estimate of right atrial pressure. Previous studies have demonstrated a correlation between this estimate of pulmonary arterial systolic pressure and that obtained from invasive measurement across a cohort of patients. However, for an individual patient significant overestimation and underestimation can occur and the levels of agreement between the two is poor. Recent guidance has suggested that echocardiographic assessment of pulmonary hypertension should be limited to determining the probability of pulmonary hypertension being present rather than estimating the pulmonary artery pressure. In those patients in whom the presence of pulmonary hypertension requires confirmation, this should be done with right heart catheterisation when indicated. This guideline protocol from the British Society of Echocardiography aims to outline a practical approach to assessing the probability of pulmonary hypertension using echocardiography and should be used in conjunction with the previously published minimum dataset for a standard transthoracic echocardiogram. PMID- 30012833 TI - Balanced Rac1 activity controls formation and maintenance of neuromuscular acetylcholine receptor clusters. AB - Rac1, an important Rho GTPase that regulates the actin cytoskeleton, has long been suggested to participate in acetylcholine receptor (AChR) clustering at the postsynaptic neuromuscular junction. However, how Rac1 is regulated and how it influences AChR clusters have remained unexplored. This study shows that breaking the balance of Rac1 regulation, by either increasing or decreasing its activity, led to impaired formation and maintenance of AChR clusters. By manipulating Rac1 activity at different stages of AChR clustering in cultured myotubes, we show that Rac1 activation was required for the initial formation of AChR clusters, but its persistent activation led to AChR destabilization, and uncontrolled hyperactivation of Rac1 even caused excessive myotube fusion. Both AChR dispersal and myotube fusion induced by Rac1 were dependent on its downstream effector Pak1. Two Rac1 GAPs and six Rac1 GEFs were screened and found to be important for normal AChR clustering. This study reveals that, although general Rac1 activity remains at low levels during terminal differentiation of myotubes and AChR cluster maintenance, tightly regulated Rac1 activity controls normal AChR clustering. PMID- 30012834 TI - Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells. AB - Metastasis of breast cancer cells to distant organs is responsible for ~50% of breast cancer-related deaths in women worldwide. SHIP2 (also known as INPPL1) is a phosphoinositide 5-phosphatase for phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2]. Here we show, through depletion of SHIP2 in triple negative MDA-MB-231 cells and the use of SHIP2 inhibitors, that cell migration appears to be positively controlled by SHIP2. The effect of SHIP2 on migration, as observed in MDA-MB-231 cells, appears to be mediated by PI(3,4)P2. Adhesion on fibronectin is always increased in SHIP2 depleted cells. Apoptosis measured in MDA-MB-231 cells is also increased in SHIP2 depleted cells as compared to control cells. In xenograft mice, SHIP2-depleted MDA-MB-231 cells form significantly smaller tumors than those formed by control cells and less metastasis is detected in lung sections. Our data reveal a general role for SHIP2 in the control of cell migration in breast cancer cells and a second messenger role for PI(3,4)P2 in the migration mechanism. In MDA-MB-231 cells, SHIP2 has a function in apoptosis in cells incubated in vitro and in mouse tumor-derived cells, which could account for its role on tumor growth determined in vivo. PMID- 30012836 TI - Acidic cell elongation drives cell differentiation in the Arabidopsis root. AB - In multicellular systems, the control of cell size is fundamental in regulating the development and growth of the different organs and of the whole organism. In most systems, major changes in cell size can be observed during differentiation processes where cells change their volume to adapt their shape to their final function. How relevant changes in cell volume are in driving the differentiation program is a long-standing fundamental question in developmental biology. In the Arabidopsis root meristem, characteristic changes in the size of the distal meristematic cells identify cells that initiated the differentiation program. Here, we show that changes in cell size are essential for the initial steps of cell differentiation and that these changes depend on the concomitant activation by the plant hormone cytokinin of the EXPAs proteins and the AHA1 and AHA2 proton pumps. These findings identify a growth module that builds on a synergy between cytokinin-dependent pH modification and wall remodeling to drive differentiation through the mechanical control of cell walls. PMID- 30012835 TI - A comprehensive characterization of cis-acting splicing-associated variants in human cancer. AB - Although many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here, we developed a statistical framework to systematically identify SAVs disrupting or newly creating splice site motifs and applied it to matched whole-exome and transcriptome sequencing data from 8976 samples across 31 cancer types, generating a catalog of 14,438 SAVs. Such a large collection of SAVs enabled us to characterize their genomic features, underlying mutational processes, and influence on cancer driver genes. In fact, ~50% of SAVs identified were those disrupting noncanonical splice sites (non-GT-AG dinucleotides), including the third and fifth intronic bases of donor sites, or newly creating splice sites. Mutation signature analysis revealed that tobacco smoking is more strongly associated with SAVs, whereas ultraviolet exposure has less impact. SAVs showed remarkable enrichment of cancer-related genes, and as many as 14.7% of samples harbored at least one SAVs affecting them, particularly in tumor suppressors. In addition to intron retention, whose association with tumor suppressor inactivation has been previously reported, exon skipping and alternative splice site usage caused by SAVs frequently affected tumor suppressors. Finally, we described high-resolution distributions of SAVs along the gene and their splicing outcomes in commonly disrupted genes, including TP53, PIK3R1, GATA3, and CDKN2A, which offers genetic clues for understanding their functional properties. Collectively, our findings delineate a comprehensive portrait of SAVs, novel insights into transcriptional de-regulation in cancer. PMID- 30012837 TI - Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees. AB - BACKGROUND: We have previously described 19 pedigrees with apparent lamin (LMNA) related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family's LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families. METHODS: Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregating LMNA variants. RESULTS: In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family's nonsegregating LMNA variant. CONCLUSIONS: Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated. PMID- 30012838 TI - Additional Genetic Variants in Inherited Dilated Cardiomyopathy: Just Another Brick in the Wall? PMID- 30012839 TI - It's like another world: the perceived beneficial effects of an artistically designed multisensory environment. AB - Self-management strategies have been identified as having a key role in supporting mental health and preventing mental illness. Evidence suggests that spending time in nature, experiencing or viewing artwork and accessing sensory rooms all support self-management and positive mental health among varied clinical populations. This evidence informed the design of the sensory-art space (SAS), an artistically designed multisensory environment, which drew on themes and images of nature.The aim of this study was to explore the experiences and perceived benefits of the SAS among members of a university community.A maximum variation approach to sampling was used, and 18 participants were included in this qualitative study. Data were gathered via semi-structured interviews, which were audio-recorded and transcribed verbatim for thematic analysis.The findings presented six themes. The two core themes were: it's like another world, and easy to focus and describe how the SAS produced the beneficial effects described in the four remaining themes of: emotionally nutritious, meditative effects, relaxation and therapeuticParticipants identified beneficial effects of the SAS that were consistent with the evidence for other self-management strategies. The identified benefits also aligned with existing theories suggesting that the SAS functioned as a restorative environment. This study is the first to explore the experience of art in a multisensory and multidimensional capacity, which further contributes to the growing field of receptive engagement with the arts for health outcomes. PMID- 30012840 TI - Twenty years of management of care in Chile: what we know, what we do not know, what is yet to come. An analysis of arguments. AB - For over 20 years, the notion of 'management of care' has been foregrounded as key in the jurisdiction of the nursing profession, with the aim of detaching itself from the wider medical umbrella. A number of voices have advocated such centrality. These include juridical, academic and occupational perspectives. Critical stances, although peripheral, have also been voiced. These have been received, at best, with a 'polite silence' in mainstream circles.By looking at the arguments surrounding the 'management of care' circulated in these two decades, this article reports the various forms of discursive practice that participate in the political process of autonomy building. Particularly, we focus on the validity of the arguments as well as the cohesion across arguments within the knowledge system. In doing so, we evaluate its main premises and foundations, the reach of the conceptualisation and its disjointed, differing and incomplete bases. Similarly, we used an inferential technique for the reconstruction of omitted and unexpressed assertions.The article introduces an approach of the humanities that is seldom seen in healthcare. It also proposes a research agenda in regard to management of care for the upcoming decades. PMID- 30012841 TI - PLC and IP3-evoked Ca2+ release initiate the fast block to polyspermy in Xenopus laevis eggs. AB - The prevention of polyspermy is essential for the successful progression of normal embryonic development in most sexually reproducing species. In external fertilizers, the process of fertilization induces a depolarization of the egg's membrane within seconds, which inhibits supernumerary sperm from entering an already-fertilized egg. This fast block requires an increase of intracellular Ca2+ in the African clawed frog, Xenopus laevis, which in turn activates an efflux of Cl- that depolarizes the cell. Here we seek to identify the source of this intracellular Ca2+ Using electrophysiology, pharmacology, bioinformatics, and developmental biology, we explore the requirement for both Ca2+ entry into the egg from the extracellular milieu and Ca2+ release from an internal store, to mediate fertilization-induced depolarization. We report that although eggs express Ca2+-permeant ion channels, blockade of these channels does not alter the fast block. In contrast, insemination of eggs in the presence of Xestospongin C-a potent inhibitor of inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release from the endoplasmic reticulum (ER)-completely inhibits fertilization-evoked depolarization and increases the incidence of polyspermy. Inhibition of the IP3 generating enzyme phospholipase C (PLC) with U73122 similarly prevents fertilization-induced depolarization and increases polyspermy. Together, these results demonstrate that fast polyspermy block after fertilization in X. laevis eggs is mediated by activation of PLC, which increases IP3 and evokes Ca2+ release from the ER. This ER-derived Ca2+ then activates a Cl- channel to induce the fast polyspermy block. The PLC-induced cascade of events represents one of the earliest known signaling pathways initiated by fertilization. PMID- 30012844 TI - Clinical trial transparency in the Americas: the need to coordinate regulatory spheres. PMID- 30012842 TI - The TMEM16A channel mediates the fast polyspermy block in Xenopus laevis. AB - In externally fertilizing animals, such as sea urchins and frogs, prolonged depolarization of the egg immediately after fertilization inhibits the entry of additional sperm-a phenomenon known as the fast block to polyspermy. In the African clawed frog Xenopus laevis, this depolarization is driven by Ca2+ activated Cl- efflux. Although the prominent Ca2+-activated Cl- currents generated in immature X. laevis oocytes are mediated by X. laevis transmembrane protein 16a (xTMEM16A) channels, little is known about the channels that contribute to the fast block in mature eggs. Moreover, the gamete undergoes a gross transformation as it develops from an immature oocyte into a fertilization competent egg. Here, we report the results of our approach to identify the Ca2+ activated Cl- channel that triggers the fast block. By querying published proteomic and RNA-sequencing data, we identify two Ca2+-activated Cl- channels expressed in fertilization-competent X. laevis eggs: xTMEM16A and X. laevis bestrophin 2A (xBEST2A). By exogenously expressing xTMEM16A and xBEST2A in axolotl cells lacking endogenous Ca2+-activated currents, we characterize the effect of inhibitors on currents mediated by these channels. None of the inhibitors tested block xBEST2A currents specifically. However, 2-(4-chloro-2 methylphenoxy)-N-[(2-methoxyphenyl)methylideneamino]-acetamide (Ani9) and N-((4 methoxy)-2-naphthyl)-5-nitroanthranilic acid (MONNA) each reduce xTMEM16A currents by more than 70% while only nominally inhibiting those generated by xBEST2A. Using whole-cell recordings during fertilization, we find that Ani9 and MONNA effectively diminish fertilization-evoked depolarizations. Additionally, these inhibitors lead to increased polyspermy in X. laevis embryos. These results indicate that fertilization activates TMEM16A channels in X. laevis eggs and induces the earliest known event triggered by fertilization: the fast block to polyspermy. PMID- 30012845 TI - Erratum for Szaloki et al., "Evidence for Homodimerization of the c-Fos Transcription Factor in Live Cells Revealed by Fluorescence Microscopy and Computer Modeling". PMID- 30012846 TI - Id3 Restricts gammadelta NKT Cell Expansion by Controlling Egr2 and c-Myc Activity. AB - gammadelta NKT cells are neonatal-derived gammadelta T lymphocytes that are grouped together with invariant NKT cells based on their shared innate-like developmental program characterized by the transcription factor PLZF (promyelocytic leukemia zinc finger). Previous studies have demonstrated that the population size of gammadelta NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote gammadelta NKT cell development and expansion remains to be determined. In this study, we report that the transcription factor Egr2, which also activates PLZF expression in invariant NKT cells, is essential for regulating gammadelta NKT cell expansion. We observed a higher expression of Egr family genes in gammadelta NKT cells compared with the conventional gammadelta T cell population. Loss of function of Id3 caused an expansion of gammadelta NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient gammadelta NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated gammadelta NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient gammadelta NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2-double-deficient gammadelta NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2-Id3-E2A, which normally restricts the population size of gammadelta NKT cells by adjusting Egr2 dosage and c-Myc expression. PMID- 30012847 TI - miR-340 Alleviates Psoriasis in Mice through Direct Targeting of IL-17A. AB - Th17 cell is a well-known lineage of CD4+ effector Th cells that selectively produce IL-17A and play critical roles during the pathogenesis of autoimmune disease. A microRNA (miRNA) is a small noncoding RNA molecule that functions in posttranscriptional regulation of gene expression. Recently, an increasing number of studies have demonstrated that multiple miRNAs are dysregulated in patients with various autoimmune diseases and mediate autoimmune disease pathologic condition at least in part through the regulation of Th17 response. However, among the few miRNAs identified so far that play possible roles in the differentiation of Th17 cells, they all regulate the Th17 response through targeting negative or positive regulators of Th17 differentiation. In the current study, we sought to identify new miRNAs that can directly regulate the expression of IL-17A, the most important cytokine produced by Th17 cells. Our results showed that the 3' untranslated region of mouse IL-17A can act as a negative regulatory element to downregulate gene expression. Further study revealed that miR-340 can specifically bind to the 3' untranslated region of mouse IL-17A and downregulate the expression of endogenous IL-17A. More importantly, we demonstrated that treatment with miR-340 alleviates the clinical severity of imiquimod-induced psoriasis in mice through the downregulation of IL-17A. These data indicate that miR-340 may be a useful therapeutic target for the treatment of psoriasis and other IL-17A-mediated autoimmune diseases. PMID- 30012848 TI - B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains. AB - Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2 In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2-/- mice. Nucleotide binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2-/- mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2-/- mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2-/- mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2 /- mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells. PMID- 30012849 TI - 2B4 Mediates Inhibition of CD8+ T Cell Responses via Attenuation of Glycolysis and Cell Division. AB - We recently showed that 2B4 expression on memory T cells in human renal transplant recipients was associated with reduced rates of rejection. To investigate whether 2B4 functionally underlies graft acceptance during transplantation, we established an experimental model in which 2B4 was retrogenically expressed on donor-reactive murine CD8+ T cells (2B4rg), which were then transferred into naive recipients prior to skin transplantation. We found that constitutive 2B4 expression resulted in significantly reduced accumulation of donor-reactive CD8+ T cells following transplantation and significantly prolonged graft survival following transplantation. This marked reduction in alloreactivity was due to reduced proliferation of CD8+ Thy1.1+ 2B4rg cells as compared with control cells, underpinned by extracellular flux analyses demonstrating that 2B4-deficient (2B4KO) CD8+ cells activated in vitro exhibited increased glycolytic capacity and upregulation of gene expression profiles consistent with enhanced glycolytic machinery as compared with wild type controls. Furthermore, 2B4KO CD8+ T cells primed in vivo exhibited significantly enhanced ex vivo uptake of a fluorescent glucose analogue. Finally, the proliferative advantage associated with 2B4 deficiency was only observed in the setting of glucose sufficiency; in glucose-poor conditions, 2B4KO CD8+ T cells lost their proliferative advantage. Together, these data indicate that 2B4 signals function to alter T cell glucose metabolism, thereby limiting the proliferation and accumulation of CD8+ T cells. Targeting 2B4 may therefore represent a novel therapeutic strategy to attenuate unwanted CD8+ T cell responses. PMID- 30012850 TI - Influenza A Virus Negative Strand RNA Is Translated for CD8+ T Cell Immunosurveillance. AB - Probing the limits of CD8+ T cell immunosurveillance, we inserted the SIINFEKL peptide into influenza A virus (IAV)-negative strand gene segments. Although IAV genomic RNA is considered noncoding, there is a conserved, relatively long open reading frame present in segment 8, encoding a potential protein termed NEG8. The biosynthesis of NEG8 from IAV has yet to be demonstrated. Although we failed to detect NEG8 protein expression in IAV-infected mouse cells, cell surface Kb SIINFEKL complexes are generated when SIINFEKL is genetically appended to the predicted C terminus of NEG8, as shown by activation of OT-I T cells in vitro and in vivo. Moreover, recombinant IAV encoding of SIINFEKL embedded in the negative strand of the neuraminidase-stalk coding sequence also activates OT-I T cells in mice. Together, our findings demonstrate both the translation of sequences on the negative strand of a single-stranded RNA virus and its relevance in antiviral immunosurveillance. PMID- 30012851 TI - Novel therapies for diabetes mellitus in pregnancy. AB - Diabetes is a common complication of pregnancy, and the prevalence of all types of the disease is increasing worldwide. Diabetes in pregnancy is associated with short term and long term adverse effects for mother and child. The goal of treatment of diabetes in pregnancy is to minimize maternal and fetal adverse events related to hyperglycemia. Treatment options vary by type of diabetes, from a focus on lifestyle modifications in gestational diabetes to continuous glucose monitoring and insulin pumps in pregestational diabetes. Nevertheless, given the commonality of hyperglycemia, considerable overlap exists in the treatment of different types of diabetes in pregnancy. Also, despite ongoing research on treatment of diabetes in pregnancy for decades, changes in the characteristics of the patient population have highlighted the limited effectiveness of different therapies. Specifically, despite the co-occurrence of obesity and diabetes, treatment recommendations including glycemic targets are not altered in such cases and a single optimal treatment strategy for each type of diabetes in pregnancy does not seem to exist. Rather, the approach to treating pregnant women with diabetes likely needs to be individualized to maximize the short term and long term health of mother and child. This article will review recent clinical studies to summarize established treatment strategies and introduce novel therapies for diabetes in pregnancy. PMID- 30012854 TI - CARs versus BiTEs: A Comparison between T Cell-Redirection Strategies for Cancer Treatment. AB - The redirection of T cells against tumors holds much promise for the treatment of cancer. Two main approaches for T-cell redirection involve their genetic modification with chimeric antigen receptors (CAR), or the use of recombinant proteins designated bispecific T-cell engagers (BiTE). These approaches have demonstrated dramatic effects in patients with hematologic cancers, although limited effect against solid cancers. Here, we review and compare the successes and challenges of these two types of immunotherapies, with special focus on their mechanisms, and discuss strategies to improve their efficacy against cancer.Significance: CAR and BiTE cancer therapies have generated much excitement, but although the therapies are potentially competitive, information directly comparing the two is difficult to obtain. Here, we present the fundamentals of each approach and compare the range and level of functions they can elicit from T cells, and their efficacy against cancers. Cancer Discov; 8(8); 924-34. (c)2018 AACR. PMID- 30012857 TI - Retraction: Histone Deacetylase Inhibitors Sensitize Prostate Cancer Cells to Agents that Produce DNA Double-Strand Breaks by Targeting Ku70 Acetylation. PMID- 30012852 TI - EDUCATIONAL SERIES IN CONGENITAL HEART DISEASE: Prenatal diagnosis of congenital heart disease. AB - This review article will guide the reader through the background of prenatal screening for congenital heart disease. The reader will be given insight into the normal screening views, common abnormalities, risk stratification of lesions and also recent advances in prenatal cardiology. PMID- 30012853 TI - CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD L1 Blockade. AB - Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNbeta in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.Significance: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. Cancer Discov; 8(9); 1156-75. (c)2018 AACR.See related commentary by Mittal et al., p. 1066This article is highlighted in the In This Issue feature, p. 1047. PMID- 30012855 TI - A Langendorff-like system to quantify cardiac pump function in adult zebrafish. AB - Zebrafish are increasingly used as a vertebrate model to study human cardiovascular disorders. Although heart structure and function are readily visualized in zebrafish embryos because of their optical transparency, the lack of effective tools for evaluating the hearts of older, nontransparent fish has been a major limiting factor. The recent development of high-frequency echocardiography has been an important advance for in vivo cardiac assessment, but it necessitates anesthesia and has limited ability to study acute interventions. We report the development of an alternative experimental ex vivo technique for quantifying heart size and function that resembles the Langendorff heart preparations that have been widely used in mammalian models. Dissected adult zebrafish hearts were perfused with a calcium-containing buffer, and a beat frequency was maintained with electrical stimulation. The impact of pacing frequency, flow rate and perfusate calcium concentration on ventricular performance (including end-diastolic and end-systolic volumes, ejection fraction, radial strain, and maximal velocities of shortening and relaxation) were evaluated and optimal conditions defined. We determined the effects of age on heart function in wild-type male and female zebrafish, and successfully detected hypercontractile and hypocontractile responses after adrenergic stimulation or doxorubicin treatment, respectively. Good correlations were found between indices of cardiac contractility obtained with high-frequency echocardiography and with the ex vivo technique in a subset of fish studied with both methods. The ex vivo beating heart preparation is a valuable addition to the cardiac function tool kit that will expand the use of adult zebrafish for cardiovascular research. PMID- 30012859 TI - Correction: Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer. PMID- 30012858 TI - Correction: Targeting Cyclin D-CDK4/6 Sensitizes Immune-refractory Cancer by Blocking the SCP3-NANOG Axis. PMID- 30012860 TI - Correction: Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma. PMID- 30012861 TI - Correction: MUC1 Oncoprotein Promotes Refractoriness to Chemotherapy in Thyroid Cancer Cells. PMID- 30012862 TI - Correction: Y-Box Binding Protein-1 Induces the Expression of CD44 and CD49f Leading to Enhanced Self-Renewal, Mammosphere Growth, and Drug Resistance. PMID- 30012863 TI - Ribosomal RACK1:Protein Kinase C betaII Phosphorylates Eukaryotic Initiation Factor 4G1 at S1093 To Modulate Cap-Dependent and -Independent Translation Initiation. AB - Eukaryotic ribosomes contain the high-affinity protein kinase C betaII (PKCbetaII) scaffold, receptor for activated C kinase (RACK1), but its role in protein synthesis control remains unclear. We found that RACK1:PKCbetaII phosphorylates eukaryotic initiation factor 4G1 (eIF4G1) at S1093 and eIF3a at S1364. We showed that reversible eIF4G(S1093) phosphorylation is involved in a global protein synthesis surge upon PKC-Raf-extracellular signal-regulated kinase 1/2 (ERK1/2) activation and in induction of phorbol ester-responsive transcripts, such as cyclooxygenase 2 (Cox-2) and cyclin-dependent kinase inhibitor (p21Cip1), or in 5' 7-methylguanosine (m7G) cap-independent enterovirus translation. Comparison of mRNA and protein levels revealed that eIF4G1 or RACK1 depletion blocked phorbol ester-induced Cox-2 or p21Cip1 expression mostly at the translational level, whereas PKCbeta inhibition reduced them both at the translational and transcript levels. Our findings reveal a physiological role for ribosomal RACK1 in providing the molecular scaffold for PKCbetaII and its role in coordinating the translational response to PKC-Raf-ERK1/2 activation. PMID- 30012864 TI - Ribosomal RACK1:Protein Kinase C betaII Modulates Intramolecular Interactions between Unstructured Regions of Eukaryotic Initiation Factor 4G (eIF4G) That Control eIF4E and eIF3 Binding. AB - The receptor for activated C kinase (RACK1), a conserved constituent of eukaryotic ribosomes, mediates phosphorylation of eukaryotic initiation factor 4G1(S1093) [eIF4G1(S1093)] and eIF3a(S1364) by protein kinase C betaII (PKCbetaII) (M. I. Dobrikov, E. Y. Dobrikova, and M. Gromeier, Mol Cell Biol 38:e00304-18, 2018, https://doi.org/10.1128/MCB.00304-18). RACK1:PKCbetaII activation drives a phorbol ester-induced surge of global protein synthesis and template-specific translation induction of PKC-Raf-extracellular signal-regulated kinase 1/2 (ERK1/2)-responsive genes. For unraveling mechanisms of RACK1:PKCbetaII-mediated translation stimulation, we used sequentially truncated eIF4G1 in coimmunoprecipitation analyses to delineate a set of autoinhibitory elements in the N-terminal unstructured region (surrounding the eIF4E-binding motif) and the interdomain linker (within the eIF3-binding site) of eIF4G1. Computer-based predictions of secondary structure, mutational analyses, and fluorescent titration with the beta-sheet dye thioflavin T suggest that eIF4G1(S1093) modulates a 4-stranded beta-sheet composed of antiparallel beta hairpins formed by the autoinhibitory elements in eIF4G1's unstructured regions. The intact beta-sheet "locks" the eIF4G configuration, preventing assembly with eIF3/40S ribosomal subunits. Upon PKC stimulation, activated RACK1:PKCbetaII phosphorylates eIF4G(S1093) in the tight 48S initiation complex, possibly facilitating dissociation/recycling of eIF4F. PMID- 30012865 TI - Identification of a novel enhancer/chromatin opening element associated with high level gamma-globin gene expression. AB - The organization of the five beta-type globin genes on chromosome 11 reflects the timing of expression during erythroid development, with the embryonic epsilon globin gene located at the 5'end, followed by the two fetal gamma-globin genes, and the adult beta- and delta- globin genes at the 3'end. Here, we functionally characterized a DNase I hypersensitive site located 4 kb upstream of the Ggamma globin gene (HBG-4kb HS). This site is occupied by transcription factors USF1, USF2, EGR1, MafK, and NF-E2 in the human erythroleukemia cell line K562 and exhibits histone modifications typical for enhancers. We generated a synthetic zinc finger DNA-binding domain (ZF) targeting the HBG-4kb HS. The HBG-4kb ZF interacted with the target site in vitro and in the context of cells with high affinity and specificity. Direct delivery of the HBG-4kb ZF to K562 and primary human erythroid cells caused a reduction in gamma-globin gene expression which was associated with decreased binding of transcription factors and active histone marks at and downstream of the HS site. The data demonstrate that the HBG-4kb HS site is important for fetal globin production and suggest that it may act by opening chromatin in a directional manner. PMID- 30012866 TI - Specific Afferent Renal Denervation Prevents Reduction in Neuronal Nitric Oxide Synthase Within the Paraventricular Nucleus in Rats With Chronic Heart Failure. AB - Renal denervation (RDN) has been shown to restore endogenous neuronal nitric oxide synthase (nNOS) in the paraventricular nucleus (PVN) and reduce sympathetic drive during chronic heart failure (CHF). The purpose of the present study was to assess the contribution of afferent renal nerves to the nNOS-mediated sympathetic outflow within the PVN in rats with CHF. CHF was induced in rats by ligation of the left coronary artery. Four weeks after surgery, selective afferent RDN (A RDN) was performed by bilateral perivascular application of capsaicin on the renal arteries. Seven days after intervention, nNOS protein expression, nNOS immunostaining signaling, and diaphorase-positive stained cells were significantly decreased in the PVN of CHF rats, changes that were reversed by A RDN. A-RDN reduced basal lumbar sympathetic nerve activity in rats with CHF (8.5%+/-0.5% versus 17.0%+/-1.2% of max). Microinjection of nNOS inhibitor L-NMMA (L-NG-monomethyl arginine citrate) into the PVN produced a blunted increase in lumbar sympathetic nerve activity in rats with CHF. This response was significantly improved after A-RDN (Delta lumbar sympathetic nerve activity: 25.7%+/-2.4% versus 11.2%+/-0.9%). Resting afferent renal nerves activity was substantially increased in CHF compared with sham rats (56.3%+/-2.4% versus 33.0%+/-4.7%). These results suggest that intact afferent renal nerves contribute to the reduction of nNOS in the PVN. A-RDN restores nNOS and thus attenuates the sympathoexcitation. Also, resting afferent renal nerves activity is elevated in CHF rats, which may highlight a crucial neural mechanism arising from the kidney in the maintenance of enhanced sympathetic drive in CHF. PMID- 30012867 TI - Impaired Trafficking of beta1 Subunits Inhibits BK Channels in Cerebral Arteries of Hypertensive Rats. AB - Hypertension is a risk factor for cerebrovascular diseases, including stroke and dementia. During hypertension, arteries become constricted and are less responsive to vasodilators, including nitric oxide (NO). The regulation of arterial contractility by smooth muscle cell (myocyte) large-conductance calcium (Ca2+)-activated potassium (BK) channels is altered during hypertension, although mechanisms involved are unclear. We tested the hypothesis that dysfunctional trafficking of pore-forming BK channel (BKalpha) and auxiliary beta1 subunits contributes to changes in cerebral artery contractility of stroke-prone spontaneously hypertensive rats (SP-SHRs). Our data indicate that the amounts of total and surface BKalpha and beta1 proteins are similar in unstimulated arteries of age-matched SP-SHRs and normotensive Wistar-Kyoto rats. In contrast, stimulated surface-trafficking of beta1 subunits by NO or membrane depolarization is inhibited in SP-SHR myocytes. PKCalpha (protein kinase C alpha) and PKCbetaII total protein and activity were both higher in SP-SHR than in Wistar-Kyoto rat arteries. NO or depolarization robustly activated Rab11, a small trafficking GTPase, in Wistar-Kyoto rat arteries but weakly activated Rab11 in SP-SHRs. Bisindolylmaleimide, a PKC inhibitor, and overexpression of a PKC phosphorylation deficient Rab11A mutant (Rab11A S177A) restored stimulated beta1 subunit surface trafficking in SP-SHR myocytes. BK channel activation by NO was inhibited in SP SHR myocytes and restored by Rab11A S177A expression. Vasodilation to NO and lithocholate, a BKalpha/beta1 channel activator, was inhibited in pressurized SP SHR arteries and reestablished by bisindolylmaleimide. In summary, data indicate that spontaneously active PKC inhibits Rab11A-mediated beta1 subunit trafficking in arterial myocytes of SP-SHRs, leading to dysfunctional NO-induced BK channel activation and vasodilation. PMID- 30012868 TI - Dec1 and CLOCK Regulate Na+/K+-ATPase beta1 Subunit Expression and Blood Pressure. AB - Blood pressure shows a circadian rhythm, and recent studies have suggested the involvement of a molecular clock system in its control. In the clock system, the CLOCK (circadian locomotor output cycles kaput):BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1) heterodimer enhances promoter activity of clock genes, and DEC1 (BHLHE40/STRA13/SHARP-2) represses CLOCK/BMAL1-enhanced promoter activity through competition for binding to the clock element, CACGTG E-box. However, the molecular mechanisms by which this system regulates blood pressure remain unclear. Here, we show that DEC1 suppressed the expression of ATP1B1, which encodes the beta1 subunit of the Na+/K+-ATPase and elevated blood pressure. Using chromatin immunoprecipitation and chromatin immunoprecipitation-on-chip analyses, we found that DEC1 and CLOCK bound to E-boxes in the ATP1B1 promoter. Luciferase assays revealed that CLOCK:BMAL1 heterodimer enhanced transcription from the ATP1B1 promoter, whereas DEC1 suppressed this transactivation. Accordingly, Atp1b1 mRNA and protein levels in mouse kidney, aorta, and heart showed a circadian rhythm that was antiphasic to the blood pressure rhythm. Furthermore, Dec1-deficient mice showed enhanced Atp1b1 expression in these tissues and reduced blood pressure. In contrast, Clock mutant mice showed reduced Atp1b1 expression and elevated blood pressure. Our results raise the possibility that transcriptional regulation of Atp1b1 by DEC1 and CLOCK:BMAL1 contributes to blood pressure. PMID- 30012869 TI - Hypertension, Microvascular Pathology, and Prognosis After an Acute Myocardial Infarction. AB - The rationale for our study was to investigate the pathophysiology of microvascular injury in patients with acute ST-segment-elevation myocardial infarction in relation to a history of hypertension. We undertook a cohort study using invasive and noninvasive measures of microvascular injury, cardiac magnetic resonance imaging at 2 days and 6 months, and assessed health outcomes in the longer term. Three hundred twenty-four patients with acute myocardial infarction (mean age, 59 [12] years; blood pressure, 135 [25] / 79 [14] mm Hg; 237 [73%] male, 105 [32%] with antecedent hypertension) were prospectively enrolled during emergency percutaneous coronary intervention. Compared with patients without antecedent hypertension, patients with hypertension were older (63 [12] years versus 57 [11] years; P<0.001) and a lower proportion were cigarette smokers (52 [50%] versus 144 [66%]; P=0.007). Coronary blood flow, microvascular resistance within the culprit artery, infarct pathologies, inflammation (C-reactive protein and interleukin-6) were not associated with hypertension. Compared with patients without antecedent hypertension, patients with hypertension had less improvement in left ventricular ejection fraction at 6 months from baseline (5.3 [8.2]% versus 7.4 [7.6]%; P=0.040). Antecedent hypertension was a multivariable associate of incident myocardial hemorrhage 2-day post-MI (1.81 [0.98-3.34]; P=0.059) and all-cause death or heart failure (n=47 events, n=24 with hypertension; 2.53 [1.28-4.98]; P=0.007) postdischarge (median follow-up 4 years). Severe progressive microvascular injury is implicated in the pathophysiology and prognosis of patients with a history of hypertension and acute myocardial infarction. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02072850. PMID- 30012871 TI - Role of Mitochondrial Dysfunction and Reactive Oxygen Species in Mediating Hypertension in the Reduced Uterine Perfusion Pressure Rat Model of Preeclampsia. AB - Placental ischemia is believed to be the initial event in the development of preeclampsia. Mitochondrial dysfunction is a cause of reactive oxygen species (ROS) generation and oxidative stress, however, there are not many studies examining the role of mitochondrial ROS in the pathology of preeclampsia. The purpose of this study was to not only examine the effect of placental ischemia on mitochondrial-mediated oxidative stress in reduced uterine perfusion pressure (RUPP) rat model of preeclampsia but to also examine the role of mitochondrial ROS in contributing to hypertension in response to placental ischemia. Female pregnant Sprague Dawley rats were used in this study. On gestational day 14, RUPP surgery was performed. On gestational day 19, blood pressure (mean arterial pressure) was measured, placentas and kidneys were collected from normal pregnant and RUPP rats and processed for mitochondrial respiration, ROS, and oxidative phosphorylation enzyme activities. Renal and placental complex activities, expressions and respiration rates were significantly reduced and mitochondrial ROS was increased in RUPP versus normal pregnant mitochondria. Mean arterial pressure was elevated in RUPP (n=6) compared with normal pregnant rats (n=5; 126+/-4 versus 103+/-4 mm Hg; P<0.05) and treatment with mitochondrial-specific antioxidants (MitoQ/MitoTEMPO) significantly reduced mean arterial pressure in RUPPs (n=5-10). Mitochondrial ROS was significantly elevated in endothelial cells incubated with RUPP serum compared from with normal pregnant rats, whereas serum from mito antioxidant-treated RUPP rats attenuated this response. Impaired mitochondrial function and vascular, placental, and renal mitochondrial ROS play an important role in hypertension and reduced fetal weight in response to placental ischemia during pregnancy. PMID- 30012872 TI - Slow Traffic Makes for Bad Circulation. PMID- 30012870 TI - Immunohistopathology and Steroid Profiles Associated With Biochemical Outcomes After Adrenalectomy for Unilateral Primary Aldosteronism. AB - Unilateral primary aldosteronism (PA) is the most common surgically curable form of hypertension that must be accurately differentiated from bilateral PA for therapeutic management (surgical versus medical). Adrenalectomy results in biochemical cure (complete biochemical success) in almost all patients diagnosed with unilateral PA; the remaining patients with partial or absent biochemical success comprise those with persisting aldosteronism who were misdiagnosed as unilateral PA preoperatively. To identify determinants of postsurgical biochemical outcomes, we compared the adrenal histopathology and the peripheral venous steroid profiles of patients with partial and absent or complete biochemical success after adrenalectomy for unilateral PA. A large multicenter cohort of adrenals from patients with absent and partial biochemical success (n=43) displayed a higher prevalence of hyperplasia (49% versus 21%; P=0.004) and a lower prevalence of solitary functional adenoma (44% versus 79%; P<0.001) compared with adrenals from age- and sex-matched patients with PA with complete biochemical success (n=52). We measured the peripheral plasma steroid concentrations in a subgroup of these patients (n=43) and in a group of patients with bilateral PA (n=27). Steroid profiling was associated with histopathologic phenotypes (solitary functional adenoma, hyperplasia, and aldosterone-producing cell clusters) and classified patients according to biochemical outcome or diagnosis of bilateral PA. If validated, peripheral venous steroid profiling may be a useful tool to guide the decision to perform surgery based on expectations of biochemical outcome after the procedure. PMID- 30012873 TI - Risk Stratification of Type 2 Long-QT Syndrome Mutation Carriers With Normal QTc Interval: The Value of Sex, T-Wave Morphology, and Mutation Type. AB - BACKGROUND: Long-QT (LQT) syndrome mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T-wave morphology may reflect penetrance of LQT syndrome mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. METHODS: LQT2 mutation carriers with QTc <460 ms in men and <470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age >=18 years underwent blinded assessment. Flat, notched, or negative T waves in leads II or V5 were considered abnormal. Cox regression analysis was performed to assess the association between T-wave morphology, the presence of mutations in the pore region of KCNH2, and the risk of cardiac events defined as syncope, aborted cardiac arrest, defibrillator therapy, or sudden cardiac death. Sex-specific associations were estimated using interactions terms. RESULTS: LQT2 female carriers with abnormal T-wave morphology had significantly higher risk of cardiac events compared with LQT2 female carriers with normal T waves (hazard ratio, 3.31; 95% confidence interval, 1.68-6.52; P=0.001), whereas this association was not significant in men. LQT2 men with pore location of mutations have significantly higher risk of cardiac events than those with nonpore mutations (hazard ratio, 6.01; 95% confidence interval, 1.50-24.08; P=0.011), whereas no such association was found in women. CONCLUSIONS: The risk of cardiac events in LQT2 carriers with normal QTc is associated with abnormal T-wave morphology in women and pore location of mutation in men. The findings further indicate sex specific differences in phenotype and genotype relationship in LQT2 patients. PMID- 30012874 TI - Year in Review in Cardiac Electrophysiology. PMID- 30012875 TI - Seminoma with Neoplastic Meningitis Treated with Craniospinal Irradiation. AB - Pure seminoma is a histological subtype of testicular cancer that accounts for 50% of testicular germ cell tumors. It has a very low rate of metastasis to the central nervous system, with only one previously reported case of neoplastic meningitis (cancer that has spread to the cerebrospinal fluid). Traditionally, neoplastic meningitis has an ominous prognosis when associated with primary tumors that commonly spread to the leptomeninges, like breast and lung. This article highlights a unique case of pure seminoma with neoplastic meningitis and illustrates the effectiveness of craniospinal irradiation as a treatment modality. PMID- 30012876 TI - Disparities in the Use of Programmed Death 1 Immune Checkpoint Inhibitors. AB - Amid growing excitement for immune checkpoint inhibitors of programmed death protein 1 (anti-PD1 agents), little is known about whether race- or sex-based disparities exist in their use. In this observational study, we constructed a large and mostly community-based cohort of patients with advanced stage cancers, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, to compare the odds of receiving systemic treatment with or without anti-PD1 agents by race and by sex. In multivariable models that adjusted for age, stage, and number of prior anticancer therapies, we found no significant race-based disparities in anti-PD1 treatment. However, among patients with NSCLC, males had significantly higher odds of receiving anti-PD1 treatment compared with females (odds ratio 1.13, 95% confidence interval 1.02-1.24, p = .02). This finding suggests that as anti-PD1 agents enter the market to transform patient care, it will be critical to monitor for disparities in the use of these drugs. PMID- 30012877 TI - In Reply. PMID- 30012878 TI - Predictability matters: role of the hippocampus and prefrontal cortex in disambiguation of overlapping sequences. AB - Previous research has demonstrated that areas in the medial temporal lobe and prefrontal cortex (PFC) show increased activation during retrieval of overlapping sequences. In this study, we designed a task in which degree of overlap varied between conditions in order to parse out the contributions of hippocampal and prefrontal subregions as overlap between associations increased. In the task, participants learned sequential associations consisting of a picture frame, a face within the picture frame, and an outdoor scene. The control condition consisted of a single frame-face-scene sequence. In the low overlap condition, each frame was paired with two faces and two scenes. In the high overlap condition, each frame was paired with four faces and four scenes. In all conditions the correct scene was chosen among four possible scenes and was dependent on the frame and face that preceded the choice point. One day after training, participants were tested on the retrieval of learned sequences during fMRI scanning. Results showed that the middle and posterior hippocampus (HC) was active at times when participants acquired information that increased predictability of the correct response in the overlapping sequences. Activation of dorsolateral PFC occurred at time points when the participant was able to ascertain which set of sequences the correct response belonged to. The ventrolateral PFC was active when inhibition was required, either of irrelevant stimuli or incorrect responses. These results indicate that areas of lateral PFC work in concert with the HC to disambiguate between overlapping sequences and that sequence predictability is key to when specific brain regions become active. PMID- 30012879 TI - Preserved capacity for scene construction and shifts in perspective after hippocampal lesions. AB - The hippocampus has long been recognized as important for the formation of long term memory. Recent work has suggested that the hippocampus might also be important for certain kinds of spatial operations, as in constructing scenes, shifting perspective, or perceiving the geometry of scenes and their boundaries. We explored this proposal using a task similar to one used previously that related hippocampal activity to scenes and their boundaries. In our study, participants viewed scenes from above that displayed walls and towers. After viewing each scene, participants saw a scene from ground level and judged whether it was the same as or different from the scene just presented. The number of towers and walls in each scene was manipulated so that it was possible to assess how the structure of the scene affected performance. Patients with hippocampal lesions performed similarly to controls in all task conditions and had no special difficulty as a function of the layout of a scene and its boundaries. In contrast, a patient with large medial temporal lobe (MTL) lesions was impaired. Taken together, our findings suggest that the hippocampus is not needed for scene construction, shifts in perspective, or perceiving the geometry of scenes. The impairment associated with large MTL lesions may result from damage in or near parahippocampal cortex. PMID- 30012880 TI - Beneficial and detrimental effects of schema incongruence on memory for contextual events. AB - Mental schemas provide a framework into which new information can easily be integrated. In a series of experiments, we examined how incongruence that stems from a prediction error modulates memory for multicomponent events that instantiated preexisting schemas as noted in a previous study. Each event consisted of four stimulus pairs with overlapping components, presented in four blocks (A-B, B-C, C-D, D-A). A-B pairs elicited contextual expectations (A: Farm, B: Tractor) that were either met by a congruent C component (C: Farmer) or violated by an incongruent one (C: Lawyer). The baseline condition included unrelated pairs, where the C component was neither congruent nor incongruent. In experiment 2, events were presented in successive trials instead of blocks, and eye movements were recorded to analyze allocation of attention. Memory was tested through old-new item recognition followed by cued recall. Across experiments, recognition and recall performance for incongruent components was reduced compared to congruent components. Incongruent items were in some cases more accurately retrieved compared to unrelated ones, depending on task demands. Additionally, better recall was observed in the incongruent D-A pairs, compared to congruent and unrelated ones, because of reduced interference from C components. Eye-tracking revealed an increased number of fixations on C components in the incongruent and unrelated conditions. These results suggest that the integration of incongruent items into an episode is impaired, compared to congruent items, despite the contextual surprise and increased attention they elicited at encoding. However, there was a beneficial effect of prediction error on memory performance, compared to a baseline, depending on the task used. PMID- 30012881 TI - bFGF expression is differentially regulated by cocaine seeking versus extinction in learning-related brain regions. AB - In cocaine use disorder, relapse can be elicited by drug-associated cues despite long periods of abstinence. The persistence of drug-associated cues in eliciting drug seeking suggests enduring changes in structural and functional plasticity, which may be mediated by basic fibroblast growth factor (bFGF, FGF2). Stimulant drug use increases bFGF expression in reward- and learning-related brain regions, such as the infralimbic medial-prefrontal cortex (IL-mPFC), and we previously found that this increase was reversed by extinction. However, whether bFGF expression is similarly modified in other brain regions is unknown. Therefore, we used the conditioned place preference (CPP) paradigm to assess bFGF expression following cocaine-associated CPP or extinction of that CPP within the mPFC, nucleus accumbens (NAc), hippocampus (Hipp), and basolateral amygdala (BLA). bFGF expression was increased in IL-mPFC and NAc-Core and -Shell following a cocaine associated CPP, an effect reversed by extinction. Conversely, bFGF expression was increased in BLA following extinction, but no significant changes were observed in PL-mPFC or either dorsal or ventral Hipp. These results demonstrate differential regulation of bFGF following cocaine-associated CPP or extinction of that CPP in discrete brain regions. Changes in bFGF expression may regulate long lasting drug-induced plasticity that underlies persistent drug-associated memories, and therefore present potential prophylactic targets. PMID- 30012882 TI - Surprise and destabilize: prediction error influences episodic memory reconsolidation. AB - Through the process of "reconsolidation," reminders can temporarily destabilize memories and render them vulnerable to change. Recent rodent research has proposed that prediction error, or the element of surprise, is a key component of this process; yet, this hypothesis has never before been extended to complex episodic memories in humans. In our novel paradigm, we used naturalistic stimuli to demonstrate that prediction error enables adaptive updating of episodic memories. In Study 1, participants (N = 48) viewed 18 videos, each depicting an action-outcome event. The next day, we reactivated these memories by presenting the videos again. We found that incomplete reminders, which interrupted videos before the outcome, made memories vulnerable to subsequent interference from a new set of videos, producing false memories. In Study 2 (N = 408), an independent sample rated qualities of the stimuli. We found that videos that were more surprising when interrupted produced more false memories. Last, in Study 3 (N = 24), we tested competing predictions of reconsolidation theory and the Temporal Context Model, an alternative account of source confusion. Consistent with the mechanistic time-course of reconsolidation, our effects were crucially time dependent. Overall, we synthesize prior animal and human research to present compelling evidence that prediction error destabilizes episodic memories and drives dynamic updating in the face of new information. PMID- 30012883 TI - The posterior parietal cortex and subjectively perceived confidence during memory retrieval. AB - Functional neuroimaging studies suggest a role for the left angular gyrus (AG) in processes related to memory recognition. However, results of neuropsychological and transcranial magnetic stimulation (TMS) studies have been inconclusive regarding the specific contribution of the AG in recollection, familiarity, and the subjective experience of memory. To obtain further insight into this issue, 20 healthy right-handed volunteers performed a memory task in a single-blind within-subject controlled TMS study. Neuronavigated inhibitory repetitive TMS (rTMS) was applied over the left AG and the vertex in a randomized and counterbalanced order. Prior to rTMS participants were presented with a list of words. After rTMS participants were shown a second list of words and instructed to indicate if the word was already shown prior to rTMS ("old") or was presented for the first time ("new"). In addition, subjectively perceived memory confidence was assessed. Results showed that recollection was unaffected following inhibitory left AG rTMS. In contrast, rTMS over the left AG improved both familiarity and the subjectively perceived confidence of participants that demonstrated low baseline memory recognition. Our study highlights the importance of taking into account individual differences in experimental designs involving noninvasive brain stimulation. PMID- 30012884 TI - Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. AB - Cellular heme is thought to be distributed between a pool of sequestered heme that is tightly bound within hemeproteins and a labile heme pool required for signaling and transfer into proteins. A heme chaperone that can hold and allocate labile heme within cells has long been proposed but never been identified. Here, we show that the glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) fulfills this role by acting as an essential repository and allocator of bioavailable heme to downstream protein targets. We identified a conserved histidine in GAPDH that is needed for its robust heme binding both in vitro and in mammalian cells. Substitution of this histidine, and the consequent decreases in GAPDH heme binding, antagonized heme delivery to both cytosolic and nuclear hemeprotein targets, including inducible nitric-oxide synthase (iNOS) in murine macrophages and the nuclear transcription factor Hap1 in yeast, even though this GAPDH variant caused cellular levels of labile heme to rise dramatically. We conclude that by virtue of its heme-binding property, GAPDH binds and chaperones labile heme to create a heme pool that is bioavailable to downstream proteins. Our finding solves a fundamental question in cell biology and provides a new foundation for exploring heme homeostasis in health and disease. PMID- 30012885 TI - Obesity-induced protein carbonylation in murine adipose tissue regulates the DNA binding domain of nuclear zinc finger proteins. AB - In obesity-linked insulin resistance, oxidative stress in adipocytes leads to lipid peroxidation and subsequent carbonylation of proteins by diffusible lipid electrophiles. Reduction in oxidative stress attenuates protein carbonylation and insulin resistance, suggesting that lipid modification of proteins may play a role in metabolic disease, but the mechanisms remain incompletely understood. Herein, we show that in vivo, diet-induced obesity in mice surprisingly results in preferential carbonylation of nuclear proteins by 4-hydroxy-trans-2,3-nonenal (4-HNE) or 4-hydroxy-trans-2,3-hexenal (4-HHE). Proteomic and structural analyses revealed that residues in or around the sites of zinc coordination of zinc finger proteins, such as those containing the C2H2 or MATRIN, RING, C3H1, or N4-type DNA binding domains, are particularly susceptible to carbonylation by lipid aldehydes. These observations strongly suggest that carbonylation functionally disrupts protein secondary structure supported by metal coordination. Analysis of one such target, the nuclear protein estrogen-related receptor gamma (ERR-gamma), showed that ERR-gamma is modified by 4-HHE in the obese state. In vitro carbonylation decreased the DNA-binding capacity of ERR-gamma and correlated with the obesity-linked down-regulation of many key genes promoting mitochondrial bioenergetics. Taken together, these findings reveal a novel mechanistic connection between oxidative stress and metabolic dysfunction arising from carbonylation of nuclear zinc finger proteins, such as the transcriptional regulator ERR-gamma. PMID- 30012886 TI - Functional proteasome complex is required for turnover of islet amyloid polypeptide in pancreatic beta-cells. AB - Human islet amyloid polypeptide (hIAPP) is the principal constituent of amyloid deposits and toxic oligomers in the pancreatic islets. Together with hyperglycemia, hIAPP-derived oligomers and aggregates are important culprits in type 2 diabetes mellitus (T2DM). Here, we explored the role of the cell's main proteolytic complex, the proteasome, in hIAPP turnover in normal and stressed beta-cells evoked by chronic hyperglycemia. Moderate inhibition (10-35%) of proteasome activity/function in cultured human islets by the proteasome inhibitor lactacystin enhanced intracellular accumulation of hIAPP. Unexpectedly, prolonged (>1 h) and marked (>50%) impairment of proteasome activity/function had a strong inhibitory effect on hIAPP transcription and secretion from normal and stressed beta-cells. This negative compensatory feedback mechanism for controlling IAPP turnover was also observed in the lactacystin-treated rat insulinoma beta-cell line (INS 832/13), demonstrating the presence of an evolutionarily conserved mechanism for IAPP production. In line with these in situ studies, our current ex vivo data showed that proteasome activity and hIAPP expression are also down regulated in islets isolated from T2DM subjects. Gene expression and promoter activity studies demonstrated that the functional proteasome complex is required for efficient activation of the hIAPP promoter and for full expression of IAPP's essential transcription factor, FOXA2. ChIP studies revealed that promoter occupancy of FoxA2 at the rat IAPP promoter region is an important and limiting factor for amylin expression in proteasome-impaired murine cells. This study suggests a novel regulatory pathway in beta-cells involving proteasome, FOXA2, and IAPP, which can be possibly targeted to regulate hIAPP levels and islet amyloidosis in T2DM. PMID- 30012888 TI - Should Technical and Anatomical Difficulties Discourage Operators From Embarking on Transradial Access for Percutaneous Coronary Intervention? AB - BACKGROUND: Use of the radial approach for PCI procedures is increasing due to lower rates of access-site complications/bleeding, and patient preference. However, femoral operators switching may be discouraged by the learning curve and by anatomical issues that may complicate the procedure. We aimed to define the frequency of anatomic variants and success rates during transradial access for PCI. METHODS: We retrospectively analyzed 2588 cases of PCI attempted by the radial route; radial/brachial and subclavian angiography was performed when obstructions were encountered. Presence of anatomical variants, spasm, and ability to complete the procedure were noted. RESULTS: Radial procedures were successfully completed in 2741/2588 cases (98.2%); in the remainder, switching to femoral approach was necessary. Local arteriography was performed in 221/2588 cases (8.5%) due to difficulties encountered; of these, 131/221 difficulties (59%) were due to problems at the radial arterial level, 58/221 (26%) were due to problems at the subclavian level, and 32/221 (15%) were due to problems at brachial arterial sites. Extreme radial tortuosity (18%) and radial loop (20%) had relatively lower rates of success followed by subclavian tortuosity (73%). Females had significantly higher incidences of radial spasm (6% vs 1.9% in men; P<.001), radial tortuosity (3.4% vs 1.7% in men; P=.01), and subclavian tortuosity (3.8% vs 1.8% in men; P<.01). CONCLUSION: Inability to successfully complete invasive procedures via the radial approach is uncommon. Even when encountered, most difficulties can be overcome with the use of vasodilators and hydrophilic wires. These data provide reassurance for would-be radial converts that the learning curve may not be as steep as envisaged. PMID- 30012887 TI - A non-canonical GTPase interaction enables ORP1L-Rab7-RILP complex formation and late endosome positioning. AB - Endosomal transport represents the primary mode for intracellular trafficking and signaling transduction and thus has to be tightly controlled. The molecular processes controlling the endosomal positioning utilize several large protein complexes, one of which contains the small GTPase Rab7, Rab-interacting lysosomal protein (RILP), and oxysterol-binding protein-related protein 1 (ORP1L). Rab7 is known to interact with RILP through a canonical binding site termed the effector interacting switch region, but it is not clear how Rab7 interacts with ORP1L, limiting our understanding of the overall process. Here, we report structural and biochemical investigation of the Rab7-ORP1L interaction. We found that, contrary to prior studies, the interaction between Rab7 and the N-terminal ankyrin repeat domain (ARDN) of ORP1L is independent of Rab7's GTP- or GDP-binding state. Moreover, we show that Rab7 interacts with ORP1L ARDN via a unique region consisting of helix3 (alpha3) and 310-helix 2 (eta2). This architecture leaves the canonical effector-interacting switch regions available for RILP binding and thus allows formation of the ORP1L-Rab7-RILP tripartite complex. Mutational disruption of the interacting interface between ORP1L and Rab7 compromised the ability of ORP1L-Rab7-RILP to regulate the late endosome positioning. Collectively, our results again manifested the versatility in the interaction between GTPase and its effector. PMID- 30012889 TI - Safety of Percutaneous Coronary Intervention Without P2Y12 Inhibitor Pretreatment From a Cohort of Unselected Patients. AB - OBJECTIVES: Recent studies have challenged systematic pretreatment with a P2Y12 inhibitor before percutaneous coronary intervention (PCI) in elective and non-ST segment elevation myocardial infarction (NSTEMI) patients. The aim of this study was to assess outcomes after performing PCI immediately after coronary angiography with an exclusive "on-the-table" P2Y12 inhibitor loading dose, by evaluating ischemic and bleeding complications in unselected patients. METHODS: Consecutive patients admitted for elective PCI or NSTEMI were included in this two-center, prospective, observational study, and received a P2Y12 inhibitor after coronary angiography when PCI was decided. The primary composite endpoint was first occurrence of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or use of bail-out glycoprotein IIb/IIIa inhibitors at 30 days after PCI. Stent thrombosis and bleeding criteria (Bleeding Academic Research Consortium [BARC]) were evaluated. RESULTS: Among 299 included patients, a total of 188 were admitted for elective PCI and 111 for NSTEMI. The incidence of the primary endpoint was 8.5% (95% confidence interval [CI], 5.7-12.4). No definite stent thrombosis occurred. Three independent predictive factors were associated with the primary endpoint: NSTEMI setting (odds ratio [OR], 5.61; 95% CI, 1.75-17.98), thrombotic coronary lesion (OR, 4.26; 95% CI, 1.45-12.54), and longer procedure duration (OR, 1.06; 95% CI, 1.03-1.09). Clinically relevant bleedings (BARC 2, 3, or 5) occurred in 5.4% of patients. CONCLUSIONS: In an unselected population admitted for elective PCI or NSTEMI in real-world clinical practice, administration of a P2Y12 inhibitor only after coronary angiography is associated with a low rate of ischemic and bleeding events at 30 days. PMID- 30012890 TI - Transfemoral Implantation of the Acurate neo for the Treatment of Aortic Regurgitation. AB - OBJECTIVES: We report an international experience of transfemoral transcatheter aortic valve replacement (TAVR) using the self-expanding Acurate neo valve (Boston Scientific) in aortic regurgitation. METHODS: This series comprises 20 patients with pure aortic regurgitation undergoing transfemoral TAVR with the Acurate neo prosthesis at nine centers in Europe and Israel. RESULTS: Mean age was 79 +/- 8 years and mean STS score was 8.3 +/- 9.3%. Leaflet calcification was none/minimal in 19 patients (95%). Prosthesis size selection was based on perimeter-derived annular diameter, with a tendency to over-size in cases of borderline annuli. One patient required implantation of a second valve. Device success rate was 18/20 (90%). At discharge, aortic regurgitation was none in 14 patients (70%), mild in 5 patients (25%), and moderate in 1 patient (5%). Left ventricular end-diastolic diameter decreased from 58 +/- 7 mm at baseline to 53 +/- 7 mm before discharge (P<.001). At 30-day follow-up, there was no mortality, no stroke, and 3 patients (15%) had received a permanent pacemaker. New York Heart Association class had improved significantly compared to baseline (85% in class I/II compared to 15% at baseline; P<.001). CONCLUSIONS: In a selected patient population, transfemoral TAVR using the Acurate neo transcatheter heart valve was successful in treating aortic regurgitation, significantly reduced left ventricular dimensions, and improved clinical symptoms. PMID- 30012891 TI - WITHDRAWN: Underlying etiology determines the outcome in atraumatic chylous ascites. AB - Ahead of Print article withdrawn by publisher. This withdrawal is for above article due to the misoperation of advance online publication. PMID- 30012892 TI - WITHDRAWN: Assessment of the impact of an exercise program on the physical and functional capacity in patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay: An exploratory study. AB - Ahead of Print article withdrawn by publisher. This withdrawal is for above article due to the misoperation of advance online publication. PMID- 30012893 TI - Optimization of Alkyldiethanolamides Synthesis from Terminalia catappa L. Kernel Oil through Enzymatic Reaction. AB - Alkyldiethanolamides (fatty acid diethanolamides) synthesis from Terminalia catappa L. kernel oil was optimized using lypozyme as a catalyst. The result showed that the optimal reaction conditions were 2 hours reaction time, with a ratio of oil mass (g) to diethanolamine (mmol) of 1:5, a ratio of oil mass to enzyme (g) of 1: 0.075, and a temperature of 40 degrees C. The percentage of alkyldiethanolamides at optimum condition was 56-60%. The synthesis results were also analyzed by FTIR. FTIR spectra revealed specific absorption at several wave numbers (3434 cm-1, 1655 cm-1, 1280 cm-1), indicating that amide and alcohol bonds (C=O, C-N, and O-H) were formed. GC-MS was employed to identify the types of fatty acid diethanolamides that were successfully synthesized. The fatty acid diethanolamides formed were palmitoyldiethanolamide (Rt = 32.96 min) and oleyldiethanolamide (Rt = 35.57 min). The total nitrogen content of alkyldietanolamides was 0.26%, or 0.19 mmol of the amide group in 1 g of sample. PMID- 30012894 TI - Phytochemical Compositions and Antidiabetic Potentials of Salvia sclarea L. Essential Oils. AB - Salvia sclarea (SS) is characterized by its valuable essential oils (Eos) and potent biological activities. This study aimed at investigating the phytochemical composition of SS Eos collected in within the same week, from two different regions in Lebanon, Beirut (SS-Bt) and Taanayel (SS-Tl), utilizing GC-MS methods, and to explore their acute and subchronic antidiabetic potentials. Moreover, studying the phytochemical diversity of twenty SS Eos established on our work and literature descriptions in order to recognize the origin of the Lebanese active chemotype(s). The Eos have been obtained by hydro-distillation and identified via GC-MS analyses. Five chemotypes of SS Eos have been identified. The Lebanese Eos, SS-Bt and SS-Tl, studied here have shown evidence to belong to two different chemotypes 1 and 5, respectively. SS-Bt has shown to belong to chemotype 1, which is characterized by high linalool (LL) concentration (average 40.2%). On the other hand, SS-Tl has shown to belong to chemotype 5, which is characterized by high linalyl acetate (LA) concentration (average 50.4%). The acute and subchronic antidiabetic activities of these EOs have been monitored along with LL and LA, in order to find the most active chemotype. Chemotypes 1 (owned to high LL content), present at low altitude places of Lebanon and Poland, has shown significantly higher acute and subchronic antidiabetic activities than that of chemotype 5 (owned to high LA content). In conclusion, Salvia sclarea Eos have shown potential antidiabetic activities, and their Eos might be used in the future as a complementary or an alternative medicine in the management of diabetes and related complications. PMID- 30012895 TI - Contact Toxicity and Repellency of the Essential Oils of Evodia lenticellata Huang and Evodia rutaecarpa (Juss.) Benth. Leaves against Three Stored Product Insects. AB - The essential oils (EOs) extracted from Evodia lenticellata Huang and Evodia rutaecarpa (Juss.) Benth. leaves are screened to evaluate their contact toxicity and repellency towards Tribolium castaneum (Coleoptera: Tenebrionidae), Lasioderma serricorne (Coleoptera: Anobiidae) and Liposcelis bostrychophila (Psocoptera: Liposcelididae) adults. The EOs are obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS). The principal components in the E. lenticellata EO are identified to be caryophyllene oxide (28.5%), beta-caryophyllene (23.1%), beta-elemene (14.5%), and beta-cubebene (4.7%), while the main components of the E. rutaecarpa EO are alpha-pinene (39.4%), beta-elemene (13.5%), alpha-ocimene (7.6%), and alpha-selinene (4.0%). These two kinds of EOs and their individual compounds all showed different levels of contact toxicity and repellent activity against three stored-product insects. PMID- 30012896 TI - Simple Quantification of Lactones in Milk Fat by Solvent Extraction Using Gas Chromatography-Mass Spectrometry. AB - The analysis of lactones as an indicator of milk quality is important in food manufacturing. However, the extraction of lactones requires sensitive conditions due to their volatility. In this study, the parameters for resolution of lactone standards were evaluated by gas chromatography-electron ionization/mass spectrometry (GC-EI/MS) to develop a rapid and simple method for the quantification and compositional analysis of lactones in edible fats, especially milk fat. Fourteen lactone standards consisting of 6-16 carbon atoms were analyzed and their correction factors (CFs) were obtained by using delta undecalactone as an internal standard. The CFs of the lactone standards followed the same trend for delta-lactones and gamma-lactones. Three volume equivalents of organic solvent per unit sample yielded the best recovery in the lactone analysis. Notably, 91-114% lactone recovery for the standards was achieved with methanol as the extractant. This method was also applicable to other fat samples, such as virgin coconut oil that is thought to contain large amounts of lactones. The recovery of lactones from virgin coconut oil was in the range of 87-104%, indicating that the developed method is also applicable to solid or semi-solid fat samples. The lactone content of butter oil, coconut oil, and butter samples was calculated by using the obtained CFs and the results were in good agreement with those of previous reports. Consequently, the GC-EI/MS method developed in this study is deemed applicable for the quantification of lactones in fat samples. PMID- 30012897 TI - Optimization of Quercetin loaded Palm Oil Ester Based Nanoemulsion Formulation for Pulmonary Delivery. AB - In this research, the palm oil ester (POE)- based nanoemulsion formulation containing quercetin for pulmonary delivery was developed. The nanoemulsion formulation was prepared by high energy emulsification method and then further optimized using D-optimal mixture design. The concentration effects of the mixture of POE:ricinoleic acid (RC), ratio 1:1 (1.50-4.50 wt.%), lecithin (1.50 2.50 wt.%), Tween 80 (0.50-1.00 wt.%), glycerol (1.50-3.00 wt.%), and water (88.0 94.9 wt.%) towards the droplet size were investigated. The results showed that the optimum formulation with 1.50 wt.% POE:RC, 1.50 wt.% lecithin, 1.50 wt.% Tween 80, 1.50 wt.% glycerol and 93.90 % water was obtained. The droplet size, polydispersity index (PDI) and zeta potential of the optimized formulation were 110.3 nm, 0.290 and -37.7 mV, respectively. The formulation also exhibited good stability against storage at 4C for 90 days. In vitro aerosols delivery evaluation showed that the aerosols output, aerosols rate and median mass aerodynamic diameter of the optimized nanoemulsion were 99.31%, 0.19 g/min and 4.25 um, respectively. The characterization of physical properties and efficiency for aerosols delivery results suggest that POE- based nanoemulsion containing quercetin has the potential to be used for pulmonary delivery specifically for lung cancer treatment. PMID- 30012898 TI - Wound Healing Study of Eucalyptus Essential Oil Containing Nanoemulsion in Rat Model. AB - The objective of this investigation was to develop nanoemulsion formulations of Eucalyptus essential oil (EEO) and to evaluate its wound healing effects in comparison with standard gentamycin in rat model. Various nanoemulsionns of EEO were prepared using aqueous phase titration method and the zones of nanoemulsion were identified by the construction of phase diagrams. EEO nanoemulsions were investigated in terms of physical stability, self-nanoemulsification efficiency and physicochemical characterization. Optimized nanoemulsion of EEO was selected for wound healing study, collagen estimation and histopathological evaluation in rats in comparison with pure EEO and standard gentamycin. Optimized nanoemulsion presented significant would healing activity in rats as compared with pure EEO upon oral administration. The wound healing activity of optimized nanoemulsion was comparable with standard gentamycin. Optimized EEO nanoemulsion also presented significant enhancement in collagen content as compared with pure EEO and negative control. However, the collagen contents of optimized nanoemulsion treated animals were comparable with standard gentamycin-treated animals. Histopathological studies of optimized nanoemulsion treated rats showed no signs of inflammatory cells which suggested the safety and non-toxicity of EEO nanoemulsion. This study suggested the potential of nanoemulsion in enhancing the wound healing activity of EEO upon oral administration. PMID- 30012899 TI - Paradoxical Bactericidal Effects of Hydrophobic Lung Surfactant Proteins and Their Peptide Mimics Using Liposome Molecular Trojan. AB - Lung surfactant, besides alveolar stability, also provides defence against pathogens by surfactant proteins (SP), SP-A and SP-D. The hydrophobic proteins SP B and SP-C enhance surface activity. An unusual and paradoxical effect of bovine LS and synthetic model LS with SP-B/-C was bactericidal to Staphylococcus aureus and Escherichia coli. Bacterial proliferation were investigated with bovine lung surfactant extract (BLES), dipalmitoylphosphatdylcholine, palmitooleylglycerol, in combination with SP-B/-C using standard microbiological colony forming unit (CFU) counts and structural imaging. BLES and other surfactant-SP-B/-C mixtures inhibit bacterial growth in the concentration range of 0 -7.5 mg/mL, at > 10 mg/mL paradoxical growth of both the bacterial species suggest antibiotic resistance. The lipid only LS have no effect on bacterial proliferation. Smaller peptide mimics of SP-B or SP-B1-25, were less efficient than SP-Cff. Ultra structural studies of the bacterial CFU using electron and atomic force microscopy suggest some membrane damage of S. aereus at inhibitory concentration of BLES, and some structural alteration of E. coli at dividing zones, suggesting utilization and incorporation of surfactant lipid species by both bacteria. The results depicted from in vitro studies are also in agreement with protein-protein interactions obtained from PatchDock, FireDock and ClasPro algorithm. The MD simulation decipher a small range fluctuation of gyration radius of the LS proteins and their peptide mimics. The studies have alarming implications in the use of high dosages (100 mg/mL/kg body weight) of exogenous surfactant for treatment of respiratory distress syndrome, genetic knock-out abnormalities associated with these proteins, and the novel roles played by SP-B/C as bactericidal agents. PMID- 30012900 TI - Aggregation Behavior and Thiol-Thioester Exchange for Cationic Surfactants with Propylthioacetate Side Chain. AB - A series of cationic surfactants containing the thioacetate group, [CnH2n+1N(CH3)2(CH2)3SCOCH3] Cl (Cn3SAc, n = 12, 14, 16), were prepared and their properties in aqueous solution were investigated by conductivity, fluorescence, and dynamic light scattering measurements. The critical micelle concentrations (CMCs) of Cn3SAc decreased to about half the value of the corresponding alkyltrimethylammonium chloride. Thioacetate was eliminated with the addition of dithiothreitol (DTT) as well as NaOH. HPLC (high performance liquid chromatography) analysis and NMR (nuclear magnetic resonance) spectroscopy showed that thiol surfactants, [CnH2n+1N(CH3)2(CH2)3SH]Cl (Cn3SH), were generated upon the addition of DTT in aqueous solution via thiol-thioester exchange, whereas gemini surfactants, [CnH2n+1N(CH3)2(CH2)3SS(CH2)3N(CH3)2CnH2n+1]2Cl (2Cn3SS), were generated upon incubation in alkaline solution via hydrolysis and air oxidation. PMID- 30012901 TI - Tricaprin Rescues Myocardial Abnormality in a Mouse Model of Triglyceride Deposit Cardiomyovasculopathy. AB - Triglyceride deposit cardiomyovasculopathy (TGCV) is an intractable cardiovascular disease for which a specific treatment is urgently required. In TGCV, adipose triglyceride lipase (ATGL) deficiency results in the abnormal intracellular metabolism of long-chain fatty acid (LCFA) which leads to TG deposition. Medium-chain triglycerides have been used as an important functional food for various human diseases. To address the potential activities of tricaprin, a medium-chain triglyceride, on cardiac dysfunctions of TGCV, we examined the effects of tricaprin diet on Atgl knock out (KO) mice, an animal model for TGCV. Cardiac imaging tests showed that the tricaprin diet reduced TG accumulation, resulting from improvement of LCFA metabolism, and improved left ventricular function in Atgl KO mice compared to that in mice fed the control diet. In conclusion, tricaprin improved myocardial abnormality in the TGCV model, thus, it may be useful for the treatment of patients with TGCV. PMID- 30012902 TI - Lipid Nanodisc Formation using Pxt-5 Peptide Isolated from Amphibian (Xenopus tropicalis) Skin, and its Altered Form, Modify-Pxt-5. AB - Nanodiscs are self-assembled discoidal nanoparticles composed of amphiphilic alpha-helical scaffold proteins or peptides that accumulate around the circumference of a lipid bilayer. In this study, Pxt-5, which is an antimicrobial peptide isolated from the skin of Xenopus tropicalis, and its modified peptide (Modify-Pxt-5) were synthesized by solid-phase peptide synthesis (SPPS).Their surface properties, which are an important factor in inducing nanodisc formation, were investigated by circular dichroism (CD) spectroscopy, surface tension measurement, phospholipid vesicle clearance assay, and negative-staining transmission electron microscopy (NS-TEM). The alpha-helicity of Pxt-5 (8.4%) improved drastically to 45.6% by four amino-acid substitutions (Modify-Pxt-5). Both the peptides, having hydrophobic and hydrophilic faces, behaved like general surfactants, and the surface activity of Modify-Pxt-5 (CAC: 9.5*10-5 M, gammaCAC: 30.3 mN.m-1) was much higher than that of Pxt-5 (CAC: 7.9*10-5 M, gammaCAC: 38.1 mN.m-1). A turbid L-alpha-dimyristoylphosphatidylcholine (DMPC) vesicle solution (T = 0.3%) quickly turned transparent upon addition of Pxt-5 or Modify-Pxt-5. After twelve hours, the transmittance of vesicle solution with Modify-Pxt-5 (T = 96.2%) was found to be higher than that of vesicle solution with Pxt-5 (T = 83.5%), and then the micro-solubilized solutions were observed by NS-TEM. Interestingly, nanodisc structures were found in the vicinity of DMPC vesicles in both the images, and the average diameter of the nanodiscs was 11.2 +/- 6.0 nm for those containing Pxt-5 and 10.8 +/- 5.8 nm for those containing Modify-Pxt-5. It was also found that Modify-Pxt-5 effectively self-assembles into nanodiscs compared to Pxt-5 without any substitutions. PMID- 30012903 TI - 11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome. AB - 11-oxygenated C19 steroids (11oxC19s) are newly specified human androgens. Although median serum levels of 11oxC19 were reported to be higher in patients with polycystic ovary syndrome (PCOS) than in unaffected women, inter-individual variations in androgen levels among PCOS patients have poorly been investigated. Here, we quantified four 11oxC19s, i.e., 11-ketotestosterone (11KT), 11beta hydroxytestosterone (11OHT), 11beta-hydroxyandrostenedione (11OHDelta4A), and 11 ketoandrostenedione (11KDelta4A), in blood samples of 28 PCOS patients and 31 eumenorrheic women using liquid chromatography-tandem mass spectrometry. We referred to our previous data of classic androgens in these individuals. We found that 11OHT levels were higher in the PCOS group than in the eumenorrheic group. Moreover, although the median values of 11KT, 11KDelta4A, and 11OHDelta4A were comparable between the two groups, these steroids were markedly increased in some patients. Of the 28 patients, 8 had high levels of both 11oxC19s and classic androgens, whereas 4 had an increase only in 11oxC19 levels, and 12 had an increase only in classic androgen levels. Intragroup variations in androgen levels were relatively large in the PCOS group. Levels of 11OHT and 11KT were significantly higher in overweight/obese patients than in normal weight patients and correlated with body mass indexes. These results highlight the clinical significance of 11oxC19s as circulating androgens in PCOS patients and indicate that the accumulation of 11oxC19s and/or classic androgens is an essential feature of PCOS. The profiles of circulating androgens appear to vary among patients. In particular, overweight/obesity likely enhances the 11oxC19s accumulation in PCOS, although this notion awaits further validation. PMID- 30012904 TI - Neutrophil-lymphocyte ratio correlates with limited joint mobility of hand in patients with type 2 diabetes. AB - Limited joint mobility (LJM) of hand, which is one of the complications of diabetic hand, is associated with diabetic micro- and macroangiopathy although the precise pathogenesis is not completely understood. Neutrophil-lymphocyte ratio (NLR), a simple and novel inflammatory marker, has been reported to have a predictive effect to some diabetic complications in recent years. However, it is not elucidated about the relationship between LJM of hand and NLR in patients with type 2 diabetes. We evaluated the relationships between LJM of hand and NLR in 335 consecutive patients with type 2 diabetes in this cross-sectional study. LJM of hand was diagnosed by a 'prayer sign' or 'table test'. LJM of hand was present in 80 patients. The patients with LJM of hand had significantly older age, longer duration of diabetes, worse renal function, and higher proportion of diabetic neuropathy, retinopathy and nephropathy. NLR in patients with LJM of hand was higher than that in patients without LJM of hand (2.54 +/- 1.46 vs. 2.11 +/- 1.04, p = 0.004). Multivariate logistic regression analysis revealed that LJM of hand was positively correlated with NLR (odds ratio, 1.31; 95% confidence interval 1.03-1.69, p = 0.027) after adjustment for age, sex, duration of diabetes, body mass index, hemoglobin A1c, hypertension and dyslipidemia. Our results demonstrate a positive relation between LJM of hand and NLR in patients with type 2 diabetes. PMID- 30012905 TI - How to Improve the Conspicuity of Breast Tumors on Computed High b-value Diffusion-weighted Imaging. AB - PURPOSE: The aim of this study was to compare the tumor conspicuity on actual measured diffusion-weighted images (aDWIs) and computed DWI (cDWI) of human breast tumors and to examine, by use of a phantom, whether cDWI improves their conspicuity. MATERIALS AND METHODS: We acquired DWIs (b-value 0, 700, 1400, 2100, 2800, and 3500 s/mm2) of 148 women with breast tumors. cDWIs with b-values of 1400, 2100, 2800, and 3500 s/mm2 were calculated from aDWI scans where b = 0 and 700 s/mm2; the tumor signal-to-noise ratio (SNR) was compared at each b-value. We also subjected a phantom harboring a breast tumor and mammary glands to DWI. For reference we used two models. The model with b = 0, 1000, 1500, 2000, 2500, and 3000 s/mm2 was our multiple b-value model. In the single b-value model, we applied b = 0 and 1000 s/mm2 and changed the number of excitations (NEX). cDWIs were generated at b = 0 and 1000 and used to compare the SNR, the contrast ratio (CR), and the contrast-to-noise ratio (CNR). RESULTS: In the phantom study, the CNR of cDWI generated from high SNR images obtained at lower b-values and a high NEX was outperformed aDWI. However, the CR and CNR on cDWI obtained using the same scanning parameters were inferior to aDWI scans. Similarly, in the clinical study, breast tumor conspicuity was worse on high b-value cDWIs than aDWIs. CONCLUSION: To improve tumor conspicuity on cDWI, the quality of the source images must be improved. It may easily cause inferior conspicuity to aDWIs if high b-value cDWIs were generated from insufficient SNR images. PMID- 30012906 TI - The Validity and Reproducibility of Dietary Non-enzymatic Antioxidant Capacity Estimated by Self-administered Food Frequency Questionnaires. AB - BACKGROUND: High dietary non-enzymatic antioxidant capacity (NEAC) has been inversely related to the incidence of degenerative diseases. However, few studies have investigated the validity and reproducibility of dietary NEAC estimated from a food frequency questionnaire (FFQ). We assessed the validity and reproducibility of FFQ-based dietary NEAC against a dietary record (DR). METHODS: Participants were 244 men and 253 women who completed a 28-day DR and FFQs. NEAC for each food item was estimated according to available databases of antioxidant capacity, as measured by ferric reducing-antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and total radical-trapping antioxidant parameter (TRAP). Using Spearman's rank correlation coefficients (CCs), we assessed the validity for dietary NEACs from a 28-day DR and a FFQ, and the reproducibility for them from two FFQs administered at a 1-year interval. Additionally, joint classification and the Bland-Altman method were applied to assess agreement between the two methods. RESULTS: Regarding validation, deattenuated CCs for the energy-adjusted overall dietary NEACs between FFQ and DR for FRAP, ORAC, and TRAP were 0.52, 0.54, and 0.52, respectively, for all subjects. Extreme miscategorization rates by joint classification analysis were 2% for FRAP and ORAC and 1% for TRAP. Regarding reproducibility, CCs between the energy-adjusted dietary NEACs from two FFQs were 0.64 for FRAP and 0.65 for ORAC and TRAP. CONCLUSION: The validity and reproducibility of dietary NEAC of total food from the FFQ were moderate. Estimations of dietary NEAC using FFQ would be useful in studying disease relationships by categorizing habitual dietary NEAC. PMID- 30012907 TI - Prevalence and Correlates of Dyslipidemia Among Men and Women in Palau: Findings of the Palau STEPS Survey 2011-2013. AB - BACKGROUND: Epidemiological evidence of dyslipidemia in Pacific Island countries is limited despite the knowledge that non-communicable diseases have a high burden in the region. We aimed to examine the prevalence and correlates of dyslipidemia among residents of Palau. METHODS: The Palau STEPwise approach to Surveillance (STEPS), which was conducted from 2011 through 2013, comprised three parts: behavioral risk factors; physical measurements; and biochemical tests, covering areas such as blood lipids. We used STEPS-generated data to perform a cross-sectional study of 2,184 randomly selected Palau residents, comprising Palauans and non-Palauans aged 25-64 years. RESULTS: The age-adjusted mean BMI was 29.3 kg/m2 in men and 29.9 kg/m2 in women; age-adjusted mean triglycerides value was 182 mg/dL in men and 166 mg/dL in women; and age-adjusted mean cholesterol was 178 mg/dL in men and 183 mg/dL in women. The prevalence of overweight/obesity (BMI >=25 kg/m2) was 75% in men and 76% in women, and those of hypertriglyceridemia (triglycerides >=150 mg/dL) and hypercholesterolemia (total cholesterol >=200 mg/dL) were 48% in men and 41% in women and 18% in men and 23% in women, respectively. Mean values of total cholesterol were 177 mg/dL in Palauan men and 182 mg/dL in non-Palauan men. Mean values of triglycerides were 171 mg/dL in Palauan women and 150 mg/dL in non-Palauan women. Women living in rural areas showed a higher mean value of total cholesterol than those in urban areas. CONCLUSION: We found a high mean BMI and high prevalence of overweight/obesity and hypertriglyceridemia, but low mean total cholesterol and a low prevalence of hypercholesterolemia in Palau. Lipid profiles varied by age, ethnicity, and living area. PMID- 30012908 TI - Impact of Comorbidities on Survival in Gastric, Colorectal, and Lung Cancer Patients. AB - BACKGROUND: The presence of comorbidities in cancer patients may influence treatment decisions and prognoses. This study aimed to examine the impact of comorbidities on overall survival in Japanese patients diagnosed with major solid tumors. METHODS: To obtain patient-level information on clinical conditions and vital status, we performed a record linkage of population-based cancer registry data from Osaka Prefecture, Japan and administrative data produced under the Diagnosis Procedure Combination (DPC) system. The study population comprised patients who received a primary diagnosis of gastric, colorectal, or lung cancer between 2010 and 2012 at any of five cancer centers. We employed the Charlson Comorbidity Index (CCI) score to quantify the impact of comorbidities on survival. The association between CCI score and survival for each cancer site was analyzed using Cox proportional hazards regression models for all-cause mortality, after adjusting for patient sex, age at cancer diagnosis, and cancer stage. RESULTS: A total of 2,609 patients with a median follow-up duration of 1,372 days were analyzed. The most frequent CCI score among the patients was 0 (77.7%), followed by 2 (14.3%). After adjusting for the covariates, we detected a significant association between CCI score and all-cause mortality. The hazard ratios per one-point increase in CCI score were 1.12 (95% confidence interval [CI], 1.02-1.23), 1.20 (95% CI, 1.08-1.34), and 1.14 (95% CI, 1.04-1.24) for gastric, colorectal, and lung cancer, respectively. CONCLUSIONS: Comorbidities have a negative prognostic impact on overall survival in cancer patients, and should be assessed as risk factors for mortality when reporting outcomes. PMID- 30012909 TI - Analgesic Effect of Double-Level Retrolaminar Paravertebral Block for Breast Cancer Surgery in the Early Postoperative Period: A Placebo-Controlled, Randomized Clinical Trial. AB - Thoracic epidural anesthesia (TEA) and paravertebral block (PVB) have been performed for perioperative regional anesthesia in the trunk. However, TEA and PVB are associated with a risk of serious complications, such as pneumothorax, hypotension, or nerve damage. Retrolaminar paravertebral block (RLB) was introduced as a new alternative to PVB. This new approach might lower the risk of serious complications, but its use has not been well established yet. Therefore, we conducted a double-masked, placebo-controlled, randomized clinical trial to evaluate the efficacy of a double-level RLB for postoperative analgesia after breast cancer surgery. A total of 122 women who underwent breast cancer surgery with axillary lymph node dissection under general anesthesia were allocated into RLB group (60 patients) and Control group (62 patients). RLB was performed upon surgery completion with 15 ml ropivacaine (0.5%) for each lamina of the T2 and T4 vertebrae. In Control group, the same volume of normal saline was injected at each level. The time to first postoperative analgesic administration was significantly longer in RLB group than that in Control group (161.5 min vs. 64.0 min). The pain score in RLB group was significantly lower immediately after surgery. However, the number of patients requiring analgesics during the 12-hour post-surgical period was similar between RLB group (20 patients) and Control group (22 patients). In conclusion, the double-level RLB could delay the time to initial administration of analgesics, but this technique may be insufficient to reduce the analgesic requirement within the 12-hour postoperative period following breast cancer surgery. PMID- 30012910 TI - Newly Identified t(2;17)(p15;q24.2) Chromosomal Translocation Is Associated with Dysgenetic Gonads and Multiple Somatic Anomalies. AB - Campomelic dysplasia (CD) is a skeletal dysplasia characterized by shortened and bowed long bones, airway instability, the potential for disorders of sexual differentiation (DSD), and Pierre Robin Sequence (PRS) with cleft palate, midface hypoplasia and laryngotrachemomalacia. CD is caused by alterations in the Sex determining region of the Y chromosome (SRY)-related-box 9 (SOX9), which has important roles in tissue and sexual differentiation. The SOX9 gene and the enhancer regions of SOX9 are located at chromosome 17q24.3. We report a 6-year old phenotypically female referred to our department because of precocious puberty. The patient was born with Tetralogy of Fallot (TOF) and PRS. Skeletal X ray examination showed only 11 pairs of ribs and bilateral bowed radiuses. Endocrine evaluations showed that increased levels of serum testosterone, and chromosomal analysis revealed a 46, XY, t(2;17)(p15;q24.2) karyotype. The patient was diagnosed with peripheral precocious puberty caused by over-secretion of testosterone by gonadoblastoma originating from dysgenetic gonads with Y chromosome-related DSD. Multiple somatic abnormalities and DSD indicated that the patient might have CD. Laparoscopy revealed bilateral dysgenetic gonads, and these were removed in the successive operation to prevent malignant transformation and virilization, caused by dysgenetic gonads with Y chromosomal materials. It is highly suggestive that the chromosomal translocation of 17q 24.2 may cause DSD and multiple somatic abnormalities, including CD, although the identified 17q breakpoint was located outside of known SOX9 enhancer regions. Thus, a hitherto unknown enhancer may be present at 17q24.2. This is the first reported case of CD with a translocation breakpoint at 17q24.2. PMID- 30012911 TI - Mesoporous Silica Nanoparticles Rescue H2O2-induced Inhibition of Cardiac Differentiation. AB - The anti-oxidative property of mesoporous silica nanoparticles (MSNs) has been proposed previously, which prompted us to investigate the potential protective effect of MSNs on human embryonic stem cells (hESCs) against oxidative stress. To this purpose, the cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl) 2,5-diphenyl-2-H-tetrazolium bromide assay. Apoptosis was analyzed by Annexin V/propidium iodide double-staining method. The intracellular glutathione, superoxide dismutase and malondialdehyde were measured with commercial assay kits. The reactive oxygen species was detected by staining with fluorescent dye DCFH-DA. The relative levels of Nkx2.5, Mef2c, Tbx5, dHand and alpha-MHC transcripts were measured by real-time polymerase chain reaction. The protein levels of Connexin 43, Troponin C1 and GAPDH were determined by immunoblotting. The beating behavior of embryoid bodies (EBs) was visually examined. Our results demonstrated that MSNs reversed hydrogen peroxide (H2O2)-inhibited cell viability and ameliorated H2O2-induced cell apoptosis in vitro. The H2O2-elicited intracellular oxidative stress was significantly relieved in the presence of MSNs. Furthermore, MSNs improved H2O2-suppressed differentiation of hESC-derived EBs and the maturation of the cardiomyocytes. In addition, MSNs treatment enhanced the beating properties of EBs. MSNs effectively conferred protection on hESCs against oxidative stress with respect to cardiac differentiation.Key words: Mesoporous silica nanoparticles, hydrogen peroxide, human embryonic stem cells, differentiation. PMID- 30012912 TI - Effects of surgical treatment for acromegaly on knee MRI structural features. AB - Acromegalic arthropathy is a common complication of acromegaly and harms the quality of life of the patients even after acromegaly is in long-term remission. A recent study demonstrated by knee MRI the characteristic structural features of acromegalic arthropathy. However, the effects of treatment for acromegaly on such structural features are almost unknown. This study was undertaken to analyze the effects of transsphenoidal surgery (TSS) on acromegalic arthropathy and elucidate whether knee MRI findings are reversible or irreversible. We analyzed 22 patients with acromegaly (63.7% females, median age 58 years) by knee MRI at diagnosis. Out of these 22 patients, 16 who underwent TSS (68.9% female, median age 58 years) were also subjected to knee MRI 2 months after TSS. As for X-ray undetectable findings, MRI detected synovial thickening, bone marrow lesion, ligament injury and meniscus injury in 22.7%, 22.7%, 4.7% and 59.1% of the patients, respectively. With respect to the 16 patients who underwent TSS, clinical and structural improvements were observed respectively in 100%, 66.7% and 66.7% of the patients who showed knee joint pain, synovial thickening and bone marrow lesion before TSS. However, no patient showed structural improvement of meniscus injury after TSS. In acromegalic arthropathy, synovial thickening and bone marrow lesions are reversible while meniscus injury is irreversible. Because all those findings are associated with the exacerbation of arthropathy, they may be therapeutic targets for preventing the progression of arthropathy by endocrinological and orthopedic intervention. PMID- 30012913 TI - An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics. AB - Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo-, radio-, or targeted-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by these therapies. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides an update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics. First, some Chinese herbal medicines (e.g. Astragalus, Ginseng, Scutellaria barbata, TJ 41, TJ-48, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used for treating the cancer and/or reducing the toxicity induced by chemo-, radio-, or targeted-therapy are discussed. These Chinese herbal medicines have been shown to possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo-, radio-, or targeted therapeutics, improving an organism's immune system function, and lessening the damage caused by these therapeutics. Second, some clinical trials using Chinese herbal medicines as adjuvant improving cancer treatment related side effects and complications are reviewed. Some Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving peripheral neuropathy and gastrointestinal side effects including diarrhea, nausea, and vomiting, decrease the incidence of bone marrow suppression, protecting anthracycline-induced cardiotoxicity and radiation-induced pneumonitis, and relieving EGFR-TKIs related acneiform eruptions and other side effects. This review of those medicines should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs. However, rigorously designed trials on potential Chinese herbal medicine must be further examined involving cancer treatment especially molecular targeted-therapy in the future. PMID- 30012914 TI - Genotyping of single nucleotide polymorphisms using the SNP-RFLP method. AB - Genetic polymorphisms, including single nucleotide polymorphisms (SNPs), are responsible for inter-individual variability in susceptibility to cancer and other disorders. Both environmental factors (e.g., smoking or carcinogen exposure) and genetic variation underlie the development of cancer; however, studies of twins suggest that genetic variation is more important. Hence, the identification of SNPs makes an important contribution to cancer research. In this study, 13 SNPs in 12 genes were genotyped in HEK 293 and HeLa cells using the simple and inexpensive SNP-RFLP method. Sanger sequencing was performed for one SNP to validate the SNP-RFLP results. Of the 13 SNPs, 10 were homozygous and three were heterozygous (rs10937405, rs12296850, and rs3814113) in HEK 293 cells, while 12 were homozygous and one was heterozygous (rs995030) in HeLa cells. The cells carried eight disease-associated risk alleles (32% of typed alleles), including rs2853677, rs995030, rs2736100, and rs6010620 in HEK 293 cells, and rs10937405, rs3814113, rs4767364, and rs6010620 in HeLa cells. Four SNP loci were homozygous for different alleles in each cell line, with HEK 293 cells having a CC genotype at rs2853677, GG at rs2736100 and rs4767364, and TT at rs3819197, while HeLa cells had TT genotypes at rs2853677 and rs2736100, AA at rs4767364, and CC at rs3819197. In conclusion, these results are potentially applicable for testing of novel gene therapeutic approaches in future experiments where the non risk alleles of the eight identified risk alleles are substituted into HEK 293 or HeLa cells. PMID- 30012915 TI - Sargassum serratifolium attenuates RANKL-induced osteoclast differentiation and oxidative stress through inhibition of NF-kappaB and activation of the Nrf2/HO-1 signaling pathway. AB - Sargassum serratifolium C. Agardh is a marine brown alga that has long been used as an ingredient for food and medicine by many people living along Asian coastlines. Recently, various beneficial effects of extracts or compounds isolated from S. serratifolium have been reported, but their efficacies against bone destruction are unclear. Therefore, in this study, we investigated the inhibitory property of an ethanol extract of S. serratifolium (EESS) on osteoclast differentiation by focusing on the receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated osteoclastogenesis model using RAW 264.7 macrophages. Our results demonstrated that EESS reduced RANKL-induced osteoclast differentiation in RAW 264.7 cells, by inhibiting tartrate-resistant acid phosphatase (TRAP) activity and destroying the F-actin ring formation. EESS also attenuated RANKL-induced expressions of key osteoclast-specific genes, such as nuclear factor of activated T cells cytoplasmic 1 (NFATC1), TRAP, cathepsin K and matrix metalloproteinase-9. These effects were mediated by impaired nuclear translocation of nuclear factor (NF)-kappaB and suppression of IkappaB-alpha degradation. In addition, EESS effectively inhibited the production of reactive oxygen species (ROS) by RANKL, which was associated with enhanced expression of nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Overall, our findings provide evidence that EESS suppresses RANKL-induced osteoclastogenesis and oxidative stress through suppression of NF-kappaB and activation of Nrf2/HO-1 signaling pathway, indicating that S. serratifolium has a potential application the prevention and treatment of osteoclastogenic bone disease. PMID- 30012916 TI - An ethanolic extract of the aerial part of Siegesbeckia orientalis L. inhibits the production of inflammatory mediators regulated by AP-1, NF-kappaB and IRF3 in LPS-stimulated RAW 264.7 cells. AB - Herba Siegesbeckiae (HS, the dried aerial part of Siegesbeckia orientalis L.) is a commonly used traditional Chinese medicinal herb for treating inflammatory diseases. HS has been reported to exert anti-inflammatory effects by inhibiting the MAPKs and NF-kappaB pathways, the downstream effectors of TLR4 signalling. This study aims to further investigate the involvement of TLR4 signalling cascades in the effects of an ethanolic extract of HS (HS for short) on inflammatory mediators in murine macrophages. HS was extracted using 50% ethanol. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were used as the cell model. ELISA was used to detect cytokine/chemokine secretion. Real time-PCR and immunoblotting were used to examine mRNA and protein levels, respectively. We observed that HS dose-dependently inhibited the secretion of PGE2, MCP-1, MIP 1alpha and RANTES, and down-regulated mRNA levels of iNOS, COX-2, IL-1beta, IL-6, TNF-alpha, mPGES-1, MCP-1, MIP-1alpha and RANTES in LPS-stimulated RAW264.7 cells. HS did not affect the protein levels of TAK1, TBK1, PI3K, Akt, IKK, c-Jun, c-Fos and IRF3, while, dose-dependently decreased levels of their phosphorylated forms. The protein levels of IRAK1 and IRAK4 were upregulated, while those of TRAF6 and TRAF3 were downregulated by HS. Moreover, the nuclear protein levels of AP-1, NF-kappaB and IRF3 were dose-dependently decreased by HS. These results indicate that suppression of the IRAK4/MAPKs/AP-1, IRAK4/MAPKs/NF-kappaB, IRAK4/PI3K/NF-kappaB and TRAF3/TBK1/IRF3 pathways is associated with the inhibitory effects of HS on inflammatory mediators in LPS-stimulated RAW264.7 cells. This study provides a pharmacological basis for the clinical application of this herb in the treatment of inflammatory disorders. PMID- 30012917 TI - The proangiogenic role of polymorphonuclear myeloid-derived suppressor cells in mice infected with Echinococcus granulosus. AB - The aim of this study was to first evaluate the proangiogenic activity of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in mice infected with Echinococcus granulosus. PMN-MDSCs derived from experimentally infected mice were collected and cultured in vitro, and their effect on angiogenesis was investigated using a human umbilical vein endothelial cell (HUVEC) tube-formation assay stimulated with the supernatant by microscope and the Angiogenesis module of the software NIH Image J. In addition, the expression levels of several functional factors related to proangiogenic activity were analyzed. The results showed that vascular endothelial growth factor (VEGF) was increased in the serum from infected mice, and the PMN-MDSCs expressed VEGF directly. The culture supernatant from PMN-MDSCs significantly promoted HUVECs to form tubes. VEGF mRNA was higher and soluble fms-like tyrosine kinase-1 levels were lower, in PMN-MDSCs from infected mice than in those from control mice. In conclusion, host angiogenesis in mice infected with E. granulosus appeared to be promoted by PMN MDSCs. Other specific angiogenic factors derived from PMN-MDSCs and parasites in the microenvironment of infection foci should be clarified in further studies, in order to provide more information for the prophylaxis and treatment of echinococcosis. PMID- 30012918 TI - Comparison of plasma propofol concentration for apnea, response to mechanical ventilation, and airway device between endotracheal tube and supraglottic airway device in Beagles. AB - The relationships between propofol plasma concentrations and the pharmacodynamic endpoints may differ according to a type of airway device. To clarify these relationships in different airway devices would be useful to avoid the complication such as apnea and intraoperative awareness. The aim of this study was to investigate the influence of difference of airway device on propofol requirement during maintenance of anesthesia in dogs. We compared the influence of airway devices on the plasma propofol concentrations for apnea, response to mechanical ventilation, and response to airway device between endotracheal tube (ETT) and supraglottic airway device (SGAD) in Beagles. The pharmacodynamic effects were repeatedly assessed at varying propofol concentrations. The plasma concentrations (mean +/- SD) of propofol in the ETT and SGAD groups were 10.2 +/- 1.8 and 10.9 +/- 2.4 ug/ml for apnea (P=0.438), 7.9 +/- 1.2 and 7.4 +/- 1.5 ug/ml for response to mechanical ventilation (P=0.268), and 5.2 +/- 0.7 and 5.4 +/- 1.5 ug/ml for response to airway device (P=0.580), respectively. Required propofol concentration during maintenance of anesthesia may be similar between ETT and SGAD. Without moderate to strong stimuli such as airway device insertion or painful stimulation during surgery, the type of airway device may have little impact on required propofol concentration during maintenance of anesthesia in dogs. PMID- 30012919 TI - Pathophysiological abnormalities in the brains of Spontaneously Diabetic Torii Lepr fa (SDT fatty) rats, a novel type 2 diabetic model. AB - In recent years, a relationship between diabetes and neurodegenerative diseases, such as Parkinson's disease, Alzheimer disease or depression, has been proposed. In this study, pathophysiological changes in the brain, especially in the hippocampus, of male SDT fatty rats with obesity and hyperglycemia were investigated. Brains of SD rats and SDT fatty rats were collected at 32 and 58 weeks of age, and parietal cortical thickness and number of pyramidal cells in the hippocampal cornu ammonis 1 and 3 (CA1 and CA3) regions were measured. At 58 weeks of age, the parietal cortical thickness and number of pyramidal cells in the hippocampal CA1 and CA3 regions were lower in SDT fatty rats than in age matched SD rats. Measurements of mRNA in rat brains at 58 weeks of age showed that the expression of genes related to inflammatory responses (S100a9, TNFalpha, NF-kappaB) was elevated in SDT fatty rats. From the aforementioned results, changes suggestive of brain atrophy and impairment in cognitive function were observed in male SDT fatty rat brains. PMID- 30012920 TI - Transformation of double-hit follicular lymphoma to plasmablastic lymphoma: a partial role of MYC gene rearrangement. AB - Follicular lymphoma (FL) is genetically characterized by BCL2/IGH translocation. Some FL cases histologically transform to high-grade lymphoma, and the majority of cases transform to diffuse large B-cell lymphoma. We report herein an unusual FL case that transformed to plasmablastic lymphoma (PBL) with MYC gene rearrangement as early as 12 months after FL diagnosis. IGH/MYC translocation, the most common cytogenetic abnormality seen in de novo PBL, was also detected in the transformed tumor (double-hit lymphoma). The patient became resistant to chemotherapy and died 4 months after transformation. We speculate that the "second hit" of MYC rearrangement played a crucial role in PBL transformation (PBL-T) in this case. Highly specific three-color FISH analysis demonstrated the presence of BCL2/IGH/MYC triple fusion signals on a single chromosome as we expected, but BCL2/IGH and IGH/MYC fusion signals also coexisted in a single nucleus. The PBL-T tumor was genetically heterogeneous, despite being histologically quite homogeneous PBL. Surprisingly, three-color FISH analysis revealed that the preceding FL tumor was also genetically heterogeneous, simultaneously harboring BCL2/IGH, IGH/MYC and BCL2/IGH/MYC fusion signals (i.e. double-hit lymphoma), despite being histologically quite homogeneous FL. This suggests that MYC rearrangement played a partial role in PBL-T. Genetic instability including MYC rearrangement in the preceding FL tumor would contribute to PBL-T and poor outcome in this case. This study will broaden our understanding of the pathogenesis of high-grade transformation of FL and help improve patient outcome. PMID- 30012921 TI - A case of chronic lymphocytic leukemia complicated by autoimmune hemolytic anemia due to ibrutinib treatment. AB - Ibrutinib (IBR) covalently binds to the active site of Bruton's tyrosine kinase (BTK) and is used for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). Approximately 5-10% of CLL is complicated by autoimmune cytopenia (AIC), such as autoimmune hemolytic anemia (AIHA). Several cases of AIC have reportedly demonstrated improvement during IBR treatment. However, in our case, the patient developed AIHA during oral IBR treatment. As AIHA is exacerbated by the increased number of CLL cells in the peripheral blood, it may have developed because of disease progression rather than IBR use. This phenomenon may also be attributed to the production of autoantibodies due to increased number of CD5+ B cells. In this case, withdrawal of IBR and administration of rituximab improved hemolysis. If AIHA develops during treatment, its etiology must be examined to confirm the effects of treatment. PMID- 30012922 TI - Characteristic Histological Findings of Asymptomatic EBV-associated Lymphoproliferative Disorders in Tonsils. AB - Recently, an in situ hybridization (ISH) and immunohistochemical study demonstrated that Epstein-Barr virus (EBV) infection may be involved in tonsillar hypertrophy and recurrent tonsillitis in children and young adolescents. The present study was based on 630 consecutive specimens from tonsillectomies performed at the Dokkyo University School of Medicine between 2002 and May 2017. Clinical findings were obtained from hospital records. Histologically, a "pale clear zone" was characterized by hyperplastic germinal centers with ill-defined borders and interfollicular expansion. Immunohistologically, the majority of immunoblasts were CD20-positive, whereas medium to large lymphoid cells usually expressed CD3. Among 14 lesions, numerous EBV-encoded small RNA (EBER)-positive cells were detected in 10. In 7 of these 10 lesions, EBER-positive cells were detected in germinal centers as well as in the interfollicular area. Based on our results, the "pale clear zone" suggests asymptomatic EBV infection of the tonsil. The present study demonstrated that "pale clear zones" should be taken into consideration when diagnosing asymptomatic EBV-associated LPDs in the tonsils of children and young adolescents as well as in middle-aged patients. PMID- 30012923 TI - Transcatheter Closure of a Huge Ductus Arteriosus in a Severely Ill Neonate. AB - Hemodynamically significant patent ductus arteriosus (PDA) in preterm infants increases morbidity and mortality. Here we describe a 12-day-old neonate with a huge PDA who developed pulmonary hemorrhage following disseminated intravascular clotting and multiple organ failure. Medical treatment or surgical ligation could not be performed because of the patient's poor condition. Transcatheter closure using a commercially available device (Amplatzer Vascular Plug II) successfully treated the huge PDA without major complications. The Amplatzer Vascular Plug II approach might become a new option for PDA closure in small infants, including those who are critically ill. PMID- 30012924 TI - Early Transfer of Patients with Acute Heart Failure from a Core Hospital to Collaborating Hospitals and Their Prognoses. AB - Japan is facing problems associated with "heart failure (HF) pandemics" and bed shortages in core hospitals that can accommodate patients with acute HF. The prognosis is currently unknown for acute HF patients who were transferred from core hospitals to collaborating hospitals during the very early treatment phase and whose treatment strategies are in place.We enrolled 166 acute HF patients who were hospitalized between January 1, 2015, and December 31, 2015, and compared the conditions of transferred patients (n = 53, median duration before transfer = 6 days) and nontransferred patients (n = 113). The transferred and nontransferred patients had similar one-year mortality rates (24.5% versus 19.5%, log-rank P = 0.27) and composite one-year mortality and HF readmission rates (35.8% versus 31.0%, log-rank P = 0.32). Multivariate analysis determined that patient transfers were not associated with a higher composite endpoint (hazard ratio, 1.08; 95% confidence interval, 0.58-1.99, P = 0.82). Transferred patients with low composite congestion scores (CCSs) had significantly lower composite endpoints than those with high CCSs (23.5% versus 57.9%, log-rank P = 0.005).Acute HF patients who were transferred did not have inferior prognoses compared with nontransferred patients when the treatment strategies were correctly assumed by cardiologists. The implementation of early and strict decongestion strategies before transfer may be important for reducing cardiovascular events. PMID- 30012925 TI - Successful Transcatheter Diagnosis and Medical Treatment of Right Atrial Involvement in IgG4-related Disease. AB - IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder characterized by lymphoplasmacytic infiltration of numerous IgG4-positive plasma cells, leading to fibrous thickening in the affected tissue. Typical cardiovascular manifestations of IgG4-RD are periaortitis, coronary arteritis, and pericarditis. Rare cases of myocardial involvement in IgG4-RD have been reported, but surgical resection or open biopsy was required for the diagnosis in those cases. Here, we report a case in which percutaneous transcatheter biopsy under the guidance of intracardiac echocardiography was useful for diagnosis of IgG4-RD manifested as an intracavitary right atrial mass, extending into the superior vena cava. Successful transcatheter diagnosis of myocardial involvement of IgG4-RD led to immediate favorable response to steroid therapy. Including the present case, previous IgG4-RD cases with myocardial involvement are reviewed to delineate its clinical characteristics. PMID- 30012927 TI - Characteristics of Bone Strength and Metabolism in Type 2 Diabetic Model Nagoya Shibata Yasuda Mice. AB - We evaluated the suitability of Nagoya Shibata Yasuda (NSY) mice as an animal model for examining the influence of a glucose metabolism disorder on bone integrity, using Institute of Cancer Research (ICR) mice as controls. We selected six NSY and ICR mice each that were matched for weight, and measured serum glucose levels, serum insulin levels, and conducted an oral glucose tolerance test. Histological sections of the femurs of both mouse lines were prepared, and the bone strength, mass, and microstructure of the femur were compared, along with bone metabolism. Serum glucose levels were significantly higher in the NSY mice than in the control mice, but body weight and serum insulin levels did not differ between the groups. Bone mass, microstructure, and strength of the femur, and bone metabolism were lower in the NSY mice than in the control mice. In the cortical bone of the femur in the NSY mice, several parts were not stained with eosin, demonstrating a strong negative correlation between serum glucose levels and bone mineral density; however, there was a negative correlation between serum glucose levels and bone metabolic markers. The bone turnover rate in the NSY mice was decreased by hyperglycemia, resulting in a thinner and shorter femur, reduced cortical and trabecular areas, and lower bone mass compared to those of the control mice. Collectively, these results suggest deteriorated bone strength of the femur in NSY mice, serving as a useful model for studying the link between glucose metabolism and bone integrity. PMID- 30012926 TI - In-Stent Restenosis with "Inflammatory" Neointima Following Everolimus-Eluting Stent Implantation. AB - A 53-year-old male presented with acute myocardial infarction and was subsequently implanted with a 4.0 * 28 mm everolimus-eluting platinum chromium stent in his proximal left anterior descending artery. Eight months after the implantation, he developed exertional angina and underwent coronary angiography, which revealed significant in-stent restenosis (ISR). Percutaneous coronary intervention was performed 1 month later, and the pre-procedural optical coherence tomography (OCT) revealed a diffusely bordered and rapidly attenuated signal-poor region with invisible stent struts at ISR site, potentially indicating a "lipid-laden" neointima. The ISR lesion was excised using a novel directional coronary atherectomy catheter. The histological analysis of the retrieved restenotic tissues revealed substantial inflammation characterized by abundant foamy macrophages and T-cell infiltration. This "inflammatory" neointimal tissue with numerous macrophages (without a necrotic core) detected on OCT was not expected owing to the absence of a known feature of macrophages on OCT (i.e., high backscattering with remarkable attenuation). The current histological confirmation of in vivo OCT findings of restenotic neointima indicated that a "lipid-laden" neointima on OCT may not necessarily reflect necrotic core accumulation, and this could be attributed to substantial inflammation with abundant macrophages. PMID- 30012928 TI - Length and Cost of Hospital Stay in Poor-Risk Patients With Critical Limb Ischemia Undergoing Revascularization. AB - BACKGROUND: The aim of the current study was to identify the distribution of length and cost of hospital stay and their associated risk factors in poor-risk Japanese critical limb ischemia (CLI) patients undergoing revascularization. Methods and Results: We analyzed prospectively collected data from 507 CLI patients who required assistance in their daily lives due to disability in activities of daily living and/or cognitive function impairment and who underwent revascularization. The median length and cost of hospital stay were 23 days (IQR, 9-52 days) and Y2.25m (IQR, Y1.33m-3.58m), respectively. Reduced albumin, tissue loss, infection, surgical reconstruction, and bilateral revascularization were associated with prolonged hospital stay (P=0.012, 0.019, <0.001, <0.001, and <0.001, respectively). Doubling the length of the hospital stay was associated with a 44% increase in hospital cost. Regular dialysis, surgical reconstruction, and bilateral revascularization were independently associated with an approximately 20% increase in the cost of hospital stay (all P<0.001). CONCLUSIONS: Length and cost of hospital stay varied considerably between patients. Low serum albumin, tissue loss, infection, surgical reconstruction, and bilateral revascularization were associated with longer hospital stay. Regular dialysis, surgical reconstruction, and bilateral revascularization were independently associated with an approximately 20% increase in the cost of hospital stay. PMID- 30012929 TI - Mandibular vascular hamartoma in a cat. AB - A 10-year-old cat presented for evaluation with a 1-month history of salivation and oral bleeding. A right mandibular mass was palpated and computed tomography examination revealed entire bone proliferation. Mandibular bone biopsy was performed, and histopathological diagnosis was vascular hamartoma. The cat suddenly died on day 140. PMID- 30012930 TI - Impact of Recurrent Ventricular Tachyarrhythmia on Outcome in Japanese Heart Transplant Candidates With a Left Ventricular Assist Device. AB - BACKGROUND: Recurrent ventricular tachyarrhythmias (VTA) are "A factor" modifiers in the Interagency Registry for Mechanically Assisted Circulatory Support profile. The effect of recurrent VTA on clinical outcome, however, is controversial. We evaluated the impact of recurrent VTA on outcome in Japanese heart transplant candidates with a left ventricular assist device (LVAD). Methods and Results: Sixty-six adult patients with advanced heart failure who were listed for heart transplantation between January 2005 and October 2017 were enrolled in the study. Recurrent VTA (modifier A status) was defined as a sustained ventricular tachycardia or fibrillation that required implantable cardioverter defibrillator shocks or an external defibrillator more than twice weekly. The primary outcome was death from any cause. The secondary outcomes were the first occurrence of VTA and recurrent VTA after LVAD implantation. Sixteen patients (24%) met the criteria for modifier A status, and 15 patients had an LVAD implanted. During a median follow-up of 1,124 days, 21 of 60 patients with an LVAD died. There was a significantly higher mortality rate in LVAD patients with modifier A status than in those who did not meet the modifier A criteria. On multivariate analysis, patients with modifier A status had an increased risk of mortality (HR, 3.43; 95% CI: 1.30-8.61, P=0.001). CONCLUSIONS: Recurrent VTA might be a marker for worse outcome in Japanese heart transplant candidates with an LVAD. PMID- 30012931 TI - The Vicious Combination of Left Ventricular Diastolic Dysfunction and Frailty. PMID- 30012932 TI - Message From the Editor-in-Chief. PMID- 30012933 TI - Rat polyomavirus 2 infection in a colony of X-linked severe combined immunodeficiency rats in Japan. AB - Polyomaviruses (PyVs) infect a wide range of animals and provoke wasting diseases, particularly in immunosuppressed hosts. Recently, a novel Rattus norvegicus polyomavirus 2 (RatPyV2) has been identified in a colony of X-linked severe combined immunodeficiency (X-SCID) rats in the United States. Here, we describe the first report of the RatPyV2 infection in an X-SCID rat colony in Japan. The affected rats exhibited adult-onset wasting. Histologically, we observed large basophilic intranuclear inclusion bodies within the hyperplastic or dysplastic epithelial cells in the salivary glands, Harderian glands, extraorbital lacrimal glands, and in respiratory and reproductive tissues. Among these organs, the parotid salivary, Harderian, and extraorbital lacrimal glands were most obviously affected. In particular, the parotid salivary glands were the most severely and diffusely affected and atrophic lesions were prominent even at 1 month of age, which suggested that the parotid salivary glands would be highly susceptible to RatPyV2 in X-SCID rats. RatPyV2 inclusion bodies were also detected in the tail of the epididymis and deferent duct. Such reproductive lesions developed significantly in the later stage of breeding age, and therefore may be associated with the reduced fecundity observed in the infected X-SCID rats. We also established a simple, rapid, and non-invasive diagnostic method based on the Amp-FTA method, using buccal swabs for the detection of RatPyV2 in immunodeficient rats. Our findings contribute to the early detection and diagnosis of RatPyV2 infections. PMID- 30012934 TI - Molecular and histopathological characterization of Cryptosporidium and Eimeria species in bats in Japan. AB - Bats are potential reservoirs of Cryptosporidium and Eimeria. The genus Cryptosporidium infects various vertebrates and causes a diarrheal disease known as cryptosporidiosis. Many epidemiological studies in wild animals have been performed; however, most of them relied on only PCR-based detection because of the difficulty of performing pathological analyses. Accordingly, the natural host and pathogenicity of Cryptosporidium bat genotypes remain unclear. In this study, we captured Eptesicus nilssonii (Northern bats) in Hokkaido, Japan. Of the three intestinal samples obtained, two were positive for Cryptosporidium spp. and one was positive for Eimeria spp. The corresponding microorganisms were also confirmed histopathologically. We detected the novel Cryptosporidium bat genotype XII and Eimeria rioarribaensis in bat intestine. PMID- 30012935 TI - Enzymatic and molecular characterization of alpha-1,3-glucanase (AglST2) from Streptomyces thermodiastaticus HF3-3 and its relation with alpha-1,3-glucanase HF65 (AglST1). AB - Extracellular alpha-1,3-glucanase HF90 (AglST2), with a sodium dodecyl sulfate (SDS)-PAGE-estimated molecular mass of approximately 91 kDa, was homogenously purified from the culture filtrate of Streptomyces thermodiastaticus HF3-3. AglST2 showed a high homology with mycodextranase in an amino acid sequence and demonstrated specificity with an alpha-1,3-glycosidic linkage of homo alpha-1,3 glucan. It has been suggested that AglST2 may be a new type of alpha-1,3 glucanase. The optimum pH and temperature of AglST2 were pH 5.5 and 60 degrees C, respectively. AglST2 action was significantly stimulated in the presence of 5-20% (w/v) NaCl, and 1 mM metal ions Mn2+ and Co2+. On the other hand, it was inhibited by 1 mM of Ag+, Cu2+, Fe2+ and Ni2+. Regarding the stability properties, AglST2 retained more than 80% of its maximum activity over a pH range of 5.0-7.0 at up to 60 degrees C and in the presence of 0-20% (w/v) NaCl. Based on these results, the properties of AglST2 were comparable with those of AglST1, which had been previously purified and characterized from S. thermodiastaticus HF3-3 previously. The N-terminal amino acid sequence of AglST2 showed a good agreement with that of AglST1, suggesting that AglST1 was generated from AglST2 by proteolysis during cultivation. MALDI-TOF mass analysis suggested that AglST1 might be generated from AglST2 by the proteolytic removal of C-terminus polypeptide (approximately 20 kDa). Our investigation thus revealed the properties of AglST2, such as tolerance against high temperature, salts, and surfactants, which have promising industrial applications. PMID- 30012936 TI - Electroporation-mediated genome editing in vitrified/warmed mouse zygotes created by IVF via ultra-superovulation. AB - Recently, genome editing in mouse zygotes has become convenient and scalable, in association with various technological developments and improvements such as novel nuclease tools, alternative delivery methods, and contemporary reproductive engineering techniques. We have so far demonstrated the applicability of ultra superovulation, in vitro fertilization (IVF), and vitrification/warming of zygotes in microinjection-mediated mouse genome editing. Moreover, an electroporation-mediated method has rapidly become established for simple gene knockout and small precise modifications including single amino acid substitutions. Here, we present an updated example of an application coupling the following three latest technologies: 1) CRISPR-Cas9 ribonucleoprotein as the most convenient genome-editing reagent, 2) electroporation as the most effortless delivery method, and 3) cryopreserved oocytes created by IVF via ultra superovulation as the most animal welfare- and user-friendly strategy. We successfully created gene knockout and knock-in mice carrying insertion/deletion mutations and single amino acid substitutions, respectively, using the streamlined production system of mouse genome editing described above, referred to as the CREATRE (CARD-based Reproductive Engineering-Assisted Technology for RNP Electroporation) system. Owing to its accessibility, robustness, and high efficiency, we believe that our CREATRE protocol will become widely used globally for the production of genome-edited mice. PMID- 30012937 TI - Feasibility of skin acetone analysis in patients with cardiovascular diseases. AB - BACKGROUND: Breath acetone is reported to be a noninvasive biomarker for heart failure. However, the measurement of this metabolite requires expertize and is not standardized yet. Acetone is also released from the skin; thus, measuring acetone as a skin gas may be easier than breath analysis. METHODS: We analyzed skin acetone collected from 41 hospitalized patients with cardiovascular diseases. Passive samplers were used to measure skin acetone emission. Passive sampler was softly fixed on the surface of forearm skin for 10 hour at night. RESULTS: Skin acetone emission ranged from 0.00 to 2.70 ng/cm2/h, and was significantly correlated with blood ketone bodies (r = 0.377, p = 0.017). CONCLUSIONS: This is the first study to analyze skin gas in patients with cardiovascular diseases. Skin acetone emission was found to reflect blood ketone bodies. It is feasible to measure skin acetone emission for reflecting blood ketone bodies in patients with cardiovascular diseases. PMID- 30012938 TI - Comparisons between the efficacy of limaprost alfadex and pregabalin in cervical spondylotic radiculopathy : design of a randomized controlled trial. AB - BACKGROUND: Cervical spondylotic radiculopathy (CSR) is a relatively common neurological disease caused by the mechanical compression of nerve roots. Limaprost, a prostaglandin E1 derivative, functions as a vasodilator and has been used in the treatment of lumbar spinal stenosis in Japan. However, the effects of limaprost in cervical radiculopathy remain unclear. Our aim was to compare the efficacy of limaprost with that of pregabalin, which is widely used for the treatment of neuropathic pain. METHODS: In this randomized trial, patients with CSR received either limaprost or pregabalin orally for 8 weeks, along with nonsteroidal anti-inflammatory drugs. The primary outcomes were assessed using a numerical rating scale of pain and numbness, both at rest and during movement. Secondary outcomes were assessed using Short Form-36, provocation tests, painDETECT questionnaire, and subjective global assessment. The obtained data were evaluated according to the per-protocol analysis principle. RESULTS: A total of 46 patients were enrolled in this study, and 35 were available for analysis. A greater reduction in pain score was observed in neck pain during movement, and scapular and arm pain both at rest and during movement in the pregabalin-treated group up to 4 weeks. In the limaprost-treated group, numbness of the arm during movement showed a marked alleviation compared to the pregabalin-treated group at 8 weeks. There were no apparent differences between the two groups in terms of the secondary outcomes. CONCLUSIONS: Although pregabalin provided an earlier pain relief than limaprost, limaprost was superior to pregabalin in treating arm numbness. Limaprost might be one of the effective therapeutic options for CSR in primary care settings. PMID- 30012939 TI - Prognostic impact of preoperative lymphocyte-to-monocyte ratio in patients with colorectal cancer with special reference to myeloid-derived suppressor cells. AB - AIMS: We aimed to investigate the relationship of colorectal cancer prognosis and inflammatory parameters, including neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR), with reference to circulating myeloid-derived suppressor cells (MDSCs) in the current study. PATIENTS AND METHODS: Thirty-five patients who underwent curative-intent surgery were enrolled. A receiver operating characteristic curve (ROC) was used to assess the usefulness of candidates for prognostic factors. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method, and the candidates for prognostic factors were assessed by a Cox proportional hazard model. RESULTS: ROC curve analyses determined cutoff values for NLR and LMR as 2.9 and 2.4, respectively. The percentage of MDSCs in patients with LMR <= 2.4 was statistically higher than in those with LMR > 2.4 (p = 0.012). The patients with LMR <= 2.4 exhibited a statistically lower RFS than those with LMR > 2.4 (p = 0.008). These results were also observed in patients with stage II + III disease. LMR was an independent prognostic factor of RFS in colorectal cancer patients (hazard ratio: 7.757, 95% confidence interval: 1.462-41.152, p = 0.016). CONCLUSION: Lower LMR was associated with poor prognosis in colorectal cancer patients; whereas, higher circulating MDSCs were observed in patients with lower LMR. PMID- 30012940 TI - Causal Discovery Combining K2 with Brain Storm Optimization Algorithm. AB - Exploring and detecting the causal relations among variables have shown huge practical values in recent years, with numerous opportunities for scientific discovery, and have been commonly seen as the core of data science. Among all possible causal discovery methods, causal discovery based on a constraint approach could recover the causal structures from passive observational data in general cases, and had shown extensive prospects in numerous real world applications. However, when the graph was sufficiently large, it did not work well. To alleviate this problem, an improved causal structure learning algorithm named brain storm optimization (BSO), is presented in this paper, combining K2 with brain storm optimization (K2-BSO). Here BSO is used to search optimal topological order of nodes instead of graph space. This paper assumes that dataset is generated by conforming to a causal diagram in which each variable is generated from its parent based on a causal mechanism. We designed an elaborate distance function for clustering step in BSO according to the mechanism of K2. The graph space therefore was reduced to a smaller topological order space and the order space can be further reduced by an efficient clustering method. The experimental results on various real-world datasets showed our methods outperformed the traditional search and score methods and the state-of-the-art genetic algorithm-based methods. PMID- 30012941 TI - The Impact of the Australasian 'Health Star Rating', Front-of-Pack Nutritional Label, on Consumer Choice: A Longitudinal Study. AB - Front-of-pack (FoP) nutrition labels are a widely deployed tool in public good marketing. This article reports on a field experimental test of the impact of one of these systems, the Australasian Health Star Rating system (HSR), on consumer choice in the breakfast cereals category in New Zealand. This study forms part of a time-series replication stream of research on this topic. The research applied a 2 * 2 factorial design with multiple replications to retail food consumers exiting from supermarkets in New Zealand. The first part of the time series, undertaken shortly after the HSR's initiation in 2014, indicated that the HSR was ineffective. Between 2014 and 2016, commercial brands in the category within New Zealand massively promoted the HSR as a basis for consumer choice. The research presented in this article forms part of the second part of the series, undertaken in 2016, using an identical experimental methodology to the 2014 study. The results indicate that the HSR may be beginning to influence consumer choice as it was predicted to, but the impact of the system is still small, and statistically sub-significant, relative to other consumer decision inputs presented on the package. PMID- 30012942 TI - Anticancer Activity Evaluation of New Thieno[2,3-d]pyrimidin-4(3H)-ones and Thieno[3,2-d]pyrimidin-4(3H)-one Derivatives. AB - Anticancer screening of several novel thienopyrimidines has been performed. The thienopyrimidine derivatives were synthesized from available starting materials according to the convenient synthetic procedures using a one-pot solvent-free reaction which gave a wide access to thienopyrimidine-derivative production. The synthesized compounds were preselected via molecular docking to be tested for their anticancer activity in NCI 60 cell lines. It was observed that some compounds showed remarkable anticancer activity. It was found that the most active compound among thieno[2,3-d]pyrimidine-4(3H)-ones is 2-(benzylamino)-5,6 dimethylthieno[2,3-d]pyrimidin-4(3H)-one, which possesses cytotoxic activity on almost all cancer cell lines with mean growth 51.01%, where the most sensitive was the melanoma cell line MDA-MB-435 with GP (Growth Percent) = -31.02%. The patterns of structure-activity that are important for further optimization of the structure and the creation of more selective and active anticancer agents were proposed. PMID- 30012943 TI - The Effect of Cyanobacterial LPS Antagonist (CyP) on Cytokines and Micro-RNA Expression Induced by Porphyromonas gingivalis LPS. AB - Lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg-LPS) is a key bacterial structure involved in the maintenance of a chronic pro-inflammatory environment during periodontitis. Similar to other gram-negative LPS, Pg-LPS induces the release of pro-inflammatory cytokines through interaction with Toll Like Receptor 4 (TLR4) and is able to stimulate negative TLR4 regulatory pathways, such as those involving microRNA (miRNA). In this work, we employed CyP, an LPS with TLR4-MD2 antagonist activity obtained from the cyanobacterium Oscillatoria planktothrix FP1, to study the effects on pro-inflammatory cytokine production and miRNA expression in human monocytic THP-1 cells stimulated with Pg LPS or E. coli LPS (Ec-LPS). Results showed that CyP inhibited TNF-alpha, IL 1beta and IL-8 expression more efficiently when co-incubated with Pg-LPS rather than with Ec-LPS. The inhibition of pro-inflammatory cytokine production was maintained even when CyP was added 2 h after LPS. The analysis of the effects of CyP on miRNA expression showed that, although being an antagonist, CyP did not inhibit miR-146a induced by Pg-LPS or Ec-LPS, whereas it significantly inhibited miR-155 only in the cultures stimulated with Ec-LPS. These results suggest that CyP may modulate the pro-inflammatory response induced by Pg-LPS, not only by blocking TLR4-MD2 complex, but also by preserving miR-146a expression. PMID- 30012944 TI - Extended Near-Infrared Photoactivity of Bi6Fe1.9Co0.1Ti3O18 by Upconversion Nanoparticles. AB - Bi6Fe1.9Co0.1Ti3O18 (BFCTO)/NaGdF4:Yb3+, Er3+ (NGF) nanohybrids were successively synthesized by the hydrothermal process followed by anassembly method, and BFCTO 1.0/NGF nanosheets, BFCTO-1.5/NGF nanoplates and BFCTO-2.0/NGF truncated tetragonal bipyramids were obtained when 1.0, 1.5 and 2.0 M NaOH were adopted, respectively. Under the irradiation of 980 nm light, all the BFCTO samples exhibited no activity in degrading Rhodamine B (RhB). In contrast, with the loading of NGF upconversion nanoparticles, all the BFCTO/NGF samples exhibited extended near-infrared photoactivity, with BFCTO-1.5/NGF showing the best photocatalytic activity, which could be attributed to the effect of {001} and {117} crystal facets with the optimal ratio. In addition, the ferromagnetic properties of the BFCTO/NGF samples indicated their potential as novel, recyclable and efficient near-infrared (NIR) light-driven photocatalysts. PMID- 30012945 TI - High Vitamin C Status Is Associated with Elevated Mood in Male Tertiary Students. AB - Micronutrient status is thought to impact on psychological mood due to the role of nutrients in brain structure and function. The aim of the current study was to investigate the association of vitamin C status with mood state in a sample of male tertiary students. We measured fasting plasma vitamin C levels as an indicator of vitamin C status, and subjective mood was determined using the Profile of Mood States (POMS) questionnaire. One hundred and thirty-nine male students aged 18 to 35 years were recruited from local tertiary institutes in Christchurch, New Zealand. The average plasma vitamin C concentration was 58.2 +/ 18.6 (SD) umol/L and the average total mood disturbance score was 25.5 +/- 26.6 (possible score -32 to 200 measuring low to high mood disturbance, respectively). Plasma vitamin C concentration was inversely correlated with total mood disturbance as assessed by POMS (r = -0.181, p < 0.05). Examination of the individual POMS subscales also showed inverse associations of vitamin C status with depression, confusion, and anger. These findings suggest that high vitamin C status may be associated with improved overall mood in young adult males. PMID- 30012946 TI - Solvent Extraction and Identification of Active Anticariogenic Metabolites in Piper cubeba L. through 1H-NMR-Based Metabolomics Approach. AB - The aim of this study was to determine the effects of different solvents for extraction, liquid-liquid partition, and concentrations of extracts and fractions of Piper cubeba L. on anticariogenic; antibacterial and anti-inflammatory activity against oral bacteria. Furthermore, 1H-Nuclear Magnetic Resonance (NMR) coupled with multivariate data analysis (MVDA) was applied to discriminate between the extracts and fractions and examine the metabolites that correlate to the bioactivities. All tested bacteria were susceptible to Piper cubeba L. extracts and fractions. Different solvents extraction, liquid-liquid partition and concentrations of extracts and fractions have partially influenced the antibacterial activity. MTT assay showed that P. cubeba L. extracts and fractions were not toxic to RAW 264.7 cells at selected concentrations. Anti-inflammatory activity evaluated by nitric oxide (NO) production in lipopolysaccharide (LPS) stimulated cells showed a reduction in NO production in cells treated with P. cubeba L. extracts and fractions, compared to those without treatment. Twelve putative metabolites have been identified, which are (1) cubebin, (2) yatein, (3) hinokinin, (4) dihydrocubebin, (5) dihydroclusin, (6) cubebinin, (7) magnosalin, (8) p-cymene, (9) piperidine, (10) cubebol, (11) d-germacrene and (12) ledol. Different extraction and liquid-liquid partition solvents caused separation in principal component analysis (PCA) models. The partial least squares (PLS) models showed that higher anticariogenic activity was related more to the polar solvents, despite some of the active metabolites also present in the non-polar solvents. Hence, P. cubeba L. extracts and fractions exhibited antibacterial and anti-inflammatory activity and have potential to be developed as the anticariogenic agent. PMID- 30012947 TI - Chrysanthemum DgWRKY2 Gene Enhances Tolerance to Salt Stress in Transgenic Chrysanthemum. AB - WRKY transcription factors (TFs) play a vital part in coping with different stresses. In this study, DgWRKY2 was isolated from Dendranthema grandiflorum. The gene encodes a 325 amino acid protein, belonging to the group II WRKY family, and contains one typical WRKY domain (WRKYGQK) and a zinc finger motif (C-X4-5-C-X22 23-H-X1-H). Overexpression of DgWRKY2 in chrysanthemum enhanced tolerance to high salt stress compared to the wild type (WT). In addition, the activities of antioxidant enzymes (superoxide dismutase (SOD), peroxidase (POD), catalase (CAT)), proline content, soluble sugar content, soluble protein content, and chlorophyll content of transgenic chrysanthemum, as well as the survival rate of the transgenic lines, were on average higher than that of the WT. On the contrary, hydrogen peroxide (H2O2), superoxide anion (O2-), and malondialdehyde (MDA) accumulation decreased compared to WT. Expression of the stress-related genes DgCAT, DgAPX, DgZnSOD, DgP5CS, DgDREB1A, and DgDREB2A was increased in the DgWRKY2 transgenic chrysanthemum compared with their expression in the WT. In conclusion, our results indicate that DgWRKY2 confers salt tolerance to transgenic chrysanthemum by enhancing antioxidant and osmotic adjustment. Therefore, this study suggests that DgWRKY2 could be used as a reserve gene for salt-tolerant plant breeding. PMID- 30012948 TI - Intravenous Vitamin C Administration Improved Blood Cell Counts and Health Related Quality of Life of Patient with History of Relapsed Acute Myeloid Leukaemia. AB - A 52-year-old female presented to Integrated Health Options Clinic in October 2014 with a history of relapsed acute myeloid leukaemia (AML, diagnosed in 2009 and relapsed in 2014). Intravenous(IV) vitamin C therapy was initiated (in 2014) following completion of chemotherapy as an alternative to haematopoietic stem cell transplantation. IV vitamin C was administered twice weekly at a dose of 70 g/infusion. Within 4 weeks of initiation of IV vitamin C therapy, there was a dramatic improvement in the patient's blood indices with platelet cell counts increasing from 25 * 108/L to 196 * 108/L and white blood cell counts increasing from 0.29 * 108/L to 4.0 * 108/L, with further improvements observed over the next 18 months. Furthermore, there was a clear and sustained improvement in the patient's health-related quality of life scores assessed using a validated questionnaire. She has remained healthy and in complete remission until the present day. This case study highlights the benefits of IV vitamin C as a supportive therapy for previously relapsed AML. PMID- 30012949 TI - Morphomechanical Alterations Induced by Transforming Growth Factor-beta1 in Epithelial Breast Cancer Cells. AB - The Epithelial to mesenchymal transition (EMT) is the process that drives epithelial tumor cells to acquire an invasive phenotype. The role of transforming growth factor-beta1 (TGF-beta1) in EMT is still debated. We used confocal laser scanning microscopy and scanning force spectroscopy to perform a morphomechanical analysis on epithelial breast cancer cells (MCF-7), comparing them before and after TGF-beta1 exogenous stimulation (5 ng/mL for 48 h). After TGF-beta1 treatment, loss of cell-cell adherence (mainly due to the reduction of E-cadherin expression of about 24%) and disaggregation of actin cortical fibers were observed in treated MCF-7. In addition, TGF-beta1 induced an alteration of MCF-7 nuclei morphology as well as a decrease in the Young's modulus, owing to a rearrangement that involved the cytoskeletal networks and the nuclear region. These relevant variations in morphological features and mechanical properties, elicited by TGF-beta1, suggested an increased capacity of MCF-7 to migrate, which was confirmed by a wound healing assay. By means of our biophysical approach, we highlighted the malignant progression of breast cancer cells induced by TGF-beta1 exposure. We are confirming TGF-beta1's role in EMT by means of morphomechanical evidence that could represent a turning point in understanding the molecular mechanisms involved in cancer progression. PMID- 30012950 TI - Label-Free Optical Detection of Mycotoxins Using Specific Aptamers Immobilized on Gold Nanostructures. AB - This work focuses on the development of the novel label-free optical apta-sensors for detection of mycotoxins. A highly sensitive analytical method of total internal reflection ellipsometry (TIRE) combined with Localized Surface Plasmon Resonance (LSPR) phenomenon in nano-structured gold films was exploited here for the first time for detection of aflatoxin B1 and M1 in direct assay with specific aptamers immobilized on the surface of gold. The achieved detection of low molecular weight molecules, such as aflatoxin B1 and M1, in a wide range of concentrations from 100 ng/mL down to 0.01 ng/mL is remarkable for the LSPR method. The study of binding kinetics of aflatoxin molecules to their respective aptamers using dynamic TIRE measurements yielded the values of affinity constants in the range of 10-8-10-7 mol, which is characteristic for highly specific aptamer/target interactions similar to that for monoclonal antibodies. The effect of aptamers' DNA chain length on their binding characteristics was analyzed. PMID- 30012951 TI - Potentiometric Sensors for Iodide and Bromide Based on Pt(II)-Porphyrin. AB - Pt(II) 5,10,15,20-tetra(4-methoxy-phenyl)-porphyrin (PtTMeOPP) was used in the construction of new ion-selective sensors. The potentiometric response characteristics (slope and selectivity) of iodide and bromide-selective electrodes based on (PtTMeOPP) metalloporphyrin in o-nitrophenyloctylether (NPOE), dioctylphtalate (DOP) and dioctylsebacate (DOS) plasticized poly(vinyl chloride) membranes are compared. The best results were obtained for the membranes plasticized with DOP and NPOE. The sensors have linear responses with near-Nernstian slopes toward bromide and iodide ions and good selectivity. The membrane plasticized with NPOE was electrochemically characterized using the EIS method to determine its water absorption and the diffusion coefficient into the membrane. PMID- 30012952 TI - Design and Synthesis of 99mTcN-Labeled Dextran-Mannose Derivatives for Sentinel Lymph Node Detection. AB - BACKGROUND: New approaches based on the receptor-targeted molecular interaction have been recently developed with the aim to investigate specific probes for sentinel lymph nodes. In particular, the mannose receptors expressed by lymph node macrophages became an attractive target and different multifunctional mannose derivate ligands for the labeling with 99mTc have been developed. In this study, we report the synthesis of a specific class of dextran-based, macromolecular, multifunctional ligands specially designed for labeling with the highly stable [99mTc=N]2+ core. METHODS: The ligands have been obtained by appending to a macromolecular dextran scaffold pendant arms bearing a chelating moiety for the metallic group and a mannosyl residue for allowing the interaction of the resulting macromolecular 99mTc conjugate with specific receptors on the external membrane of macrophages. Two different chelating systems have been selected, S-methyl dithiocarbazate [H2N-NH-C(=S)SCH3=HDTCZ] and a sequence of two cysteine residues, that in combination with a monophosphine coligand, are able to bind the [99mTc=N]2+ core. CONCLUSIONS: High-specific-activity labeling has been obtained by simple mixing and heating of the [99mTc=N]2+ group with the new mannose-dextran derivatives. PMID- 30012953 TI - The Cartesian Product and Join Graphs on Edge-Version Atom-Bond Connectivity and Geometric Arithmetic Indices. AB - The Cartesian product and join are two classical operations in graphs. Let dL(G)(e) be the degree of a vertex e in line graph L(G) of a graph G. The edge versions of atom-bond connectivity (ABCe) and geometric arithmetic (GAe) indices of G are defined as ?ef?E(L(G))dL(G)(e)+dL(G)(f)-2dL(G)(e)*dL(G)(f) and ?ef?E(L(G))2dL(G)(e)*dL(G)(f)dL(G)(e)+dL(G)(f), respectively. In this paper, ABCe and GAe indices for certain Cartesian product graphs (such as Pn?Pm, Pn?Cm and Pn?Sm) are obtained. In addition, ABCe and GAe indices of certain join graphs (such as Cm+Pn+Sr, Pm+Pn+Pr, Cm+Cn+Cr and Sm+Sn+Sr) are deduced. Our results enrich and revise some known results. PMID- 30012954 TI - Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma. AB - Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARgamma modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARgamma expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPARgamma in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPARgamma is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPARgamma have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPARgamma in renal metabolism as a likely key factor in the maintenance of systemic homeostasis. PMID- 30012955 TI - Studying Smaller and Neglected Organisms in Modern Evolutionary Venomics Implementing RNASeq (Transcriptomics)-A Critical Guide. AB - Venoms are evolutionary key adaptations that species employ for defense, predation or competition. However, the processes and forces that drive the evolution of venoms and their toxin components remain in many aspects understudied. In particular, the venoms of many smaller, neglected (mostly invertebrate) organisms are not characterized in detail, especially with modern methods. For the majority of these taxa, even their biology is only vaguely known. Modern evolutionary venomics addresses the question of how venoms evolve by applying a plethora of -omics methods. These recently became so sensitive and enhanced that smaller, neglected organisms are now more easily accessible to comparatively study their venoms. More knowledge about these taxa is essential to better understand venom evolution in general. The methodological core pillars of integrative evolutionary venomics are genomics, transcriptomics and proteomics, which are complemented by functional morphology and the field of protein synthesis and activity tests. This manuscript focuses on transcriptomics (or RNASeq) as one toolbox to describe venom evolution in smaller, neglected taxa. It provides a hands-on guide that discusses a generalized RNASeq workflow, which can be adapted, accordingly, to respective projects. For neglected and small taxa, generalized recommendations are difficult to give and conclusions need to be made individually from case to case. In the context of evolutionary venomics, this overview highlights critical points, but also promises of RNASeq analyses. Methodologically, these concern the impact of read processing, possible improvements by perfoming multiple and merged assemblies, and adequate quantification of expressed transcripts. Readers are guided to reappraise their hypotheses on venom evolution in smaller organisms and how robustly these are testable with the current transcriptomics toolbox. The complementary approach that combines particular proteomics but also genomics with transcriptomics is discussed as well. As recently shown, comparative proteomics is, for example, most important in preventing false positive identifications of possible toxin transcripts. Finally, future directions in transcriptomics, such as applying 3rd generation sequencing strategies to overcome difficulties by short read assemblies, are briefly addressed. PMID- 30012956 TI - Comparative and Expression Analysis of Ubiquitin Conjugating Domain-Containing Genes in Two Pyrus Species. AB - Ripening affects the nutritional contents and quality of fleshy fruits, and it plays an important role during the process of fruit development. Studies have demonstrated that ubiquitin-conjugating (UBC or E2) genes can regulate fruit ripening, but the characterization of UBCs in pear is not well documented. The recently published genome-wide sequences of Pyrus bretschneideri and Pyrus communis have allowed a comprehensive analysis of this important gene family in pear. Using bioinformatics approaches, we identified 83 (PbrUBCs) and 84 (PcpUBCs) genes from P. bretschneideri and P. communis, respectively, which were divided into 13 subfamilies. In total, 198 PbrUBC paralogous, 215 PcpUBC paralogous, and 129 orthologous gene pairs were detected. Some paralogous gene pairs were found to be distributed on the same chromosome, suggesting that these paralogs may be caused by tandem duplications. The expression patterns of most UBC genes were divergent between Pyrus bretschneideri and Pyrus communis during pear fruit development. Remarkably, the transcriptome data showed that UBC genes might play a more important role in fruit ripening for further study. This is the first report on the systematic analysis of two Pyrus UBC gene families, and these data will help further study the role of UBC genes in fruit development and ripening, as well as contribute to the functional verification of UBC genes in pear. PMID- 30012958 TI - Adolescent Connectedness with Parents Promotes Resilience among Homeless Youth. AB - Youth who experience homelessness have worse health and well-being than housed youth. Internal assets, including social competency and positive self-identity, are factors that promote healthy development. This study compared internal assets between homeless and housed youth, and examined whether connectedness with parents moderates the association between homelessness and internal assets. Using data from a large population-based survey of middle- and high-school aged youth, we found that homelessness was associated with lower levels of internal assets. However, having high connectedness with a parent significantly predicted the strength of these assets, suggesting opportunities to promote health equity among homeless youth. PMID- 30012957 TI - Lamins in Lung Cancer: Biomarkers and Key Factors for Disease Progression through miR-9 Regulation? AB - Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or metastatic cancers. In this context, the identification of new biomarkers is essential to improve the differential diagnosis between cancer subtypes, to select the most appropriate therapy, and to establish prognostic correlations. Nuclear abnormalities are hallmarks of carcinoma cells and are used as cytological diagnostic criteria of malignancy. Lamins (divided into A- and B-types) are localized in the nuclear matrix comprising nuclear lamina, where they act as scaffolding protein, involved in many nuclear functions, with regulatory effects on the cell cycle and differentiation, senescence and apoptosis. Previous studies have suggested that lamins are involved in tumor development and progression with opposite results concerning their prognostic role. This review provides an overview of lamins expression in lung cancer and the relevance of these findings for disease diagnosis and prognosis. Furthermore, we discuss the link between A-type lamins expression in lung carcinoma cells and nuclear deformability, epithelial to mesenchymal transition, and metastatic potential, and which mechanisms could regulate A-type lamins expression in lung cancer, such as the microRNA miR-9. PMID- 30012959 TI - A Scale for the Management of Aggressive and Violent Behaviour (C_MAVAS): Psychometric Properties Testing in Mental Health Nurses. AB - Background: This study set out to examine the psychometric properties of C_MAVAS, a newly Chinese-translated version of MAVAS, a 27-item scale assessing healthcare professionals' attitudes to the management of patient violence. Method: The English version of the MAVAS was translated and back-translated to come up with C_MAVAS. A convenience sample of 262 qualified mental health nurses working in a local psychiatric hospital was recruited. Exploratory factor analysis tested C_MAVAS's construct validity. Results: Content validity of the C_MAVAS was very satisfactory with validity indices of 97.4% for the overall scale and 90% to 100% for individual items. Exploratory factor analysis yielded a four-factor solution: 'interactional perspectives on patient violence', 'best ways perceived for violence management', 'internal or biomedical perspectives on patient violence', and 'external perspectives on patient aggression and violence', were important in shaping their attitudes towards managing violence and patient disruptiveness. Internal consistency of the Chinese version was barely satisfactory (Cronbach's alpha = 0.51-0.67) for the four factors/subscales and its test-retest reliability was good (Pearson's coefficient = 0.84). Conclusion: The findings suggest the C_MAVAS is a valid and reliable tool to measure mental health nurses' attitudes towards patient violence/aggression in a mental hospital setting. PMID- 30012960 TI - Sensors for Enhanced Detection of Acetone as a Potential Tool for Noninvasive Diabetes Monitoring. AB - Measurement of blood-borne volatile organic compounds (VOCs) occurring in human exhaled breath as a result of metabolic changes or pathological disorders is a promising tool for noninvasive medical diagnosis, such as exhaled acetone measurements in terms of diabetes monitoring. The conventional methods for exhaled breath analysis are based on spectrometry techniques, however, the development of gas sensors has made them more and more attractive from a medical point of view. This review focuses on the latest achievements in gas sensors for exhaled acetone detection. Several different methods and techniques are presented and discussed as well. PMID- 30012961 TI - Composite Bonding Pre-Treatment with Laser Radiation of 3 um Wavelength: Comparison with Conventional Laser Sources. AB - To use the full potential of composite parts, e.g., to reduce the structural weight of cars or airplanes, a greater focus is needed on the joining technology. Adhesive bonding is considered favorable, superior joining technology for these parts. Unfortunately, to provide a structural and durable bond, a surface pre treatment is necessary. Due to its high integration potential in industrial process chains, laser radiation can be a very efficient tool for this purpose. Within the BMBF-funded (German Federal Ministry of Education and Research) project GEWOL, a laser source that emits radiation at 3 um wavelength (which shows significant advantages in theory) was developed for a sensitive laser-based bonding pre-treatment. Within the presented study, the developed laser source was compared with conventional laser sources emitting radiation at 355 nm, 1064 nm, and 10,600 nm in terms of application for a composite bonding pre-treatment. With the different laser sources, composites were treated, analytically tested, subsequently bonded, and mechanically tested to determine the bonding ability of the treated specimens. The results show a sensitive treatment of the surface with the developed laser source, which resulted in a very effective cleaning, high bonding strengths (over 32 MPa), and a good effectiveness compared with the conventional laser sources. PMID- 30012964 TI - Sensitivity Tests of Pellets Made from Manganese Antimonate Nanoparticles in Carbon Monoxide and Propane Atmospheres. AB - Nanoparticles of manganese antimonate (MnSb2O6) were prepared using the microwave assisted colloidal method for its potential application as a gas sensor. For the synthesis of the oxide, manganese nitrate, antimony chloride, ethylenediamine and ethyl alcohol (as a solvent) were used. The precursor material was calcined at 800 degrees C in air and analyzed by X-ray diffraction. The oxide crystallized into a hexagonal structure with spatial group P321 and cell parameters a = b = 8.8054 A and c = 4.7229 A. The microstructure of the material was analyzed by scanning electron microscopy (SEM), finding the growth of microrods with a size of around ~10.27 MUm and some other particles with an average size of ~1.3 MUm. Photoacoustic spectroscopy (PAS) studies showed that the optical energy band (Eg) of the oxide was of ~1.79 eV. Transmission electron microscopy (TEM) analyses indicated that the size of the nanoparticles was of ~29.5 nm on average. The surface area of the powders was estimated at 14.6 m2/g by the Brunauer-Emmett Teller (BET) method. Pellets prepared from the nanoparticles were tested in carbon monoxide (CO) and propane (C3H8) atmospheres at different concentrations (0-500 ppm) and operating temperatures (100, 200 and 300 degrees C). The pellets were very sensitive to changes in gas concentration and temperature: the response of the material rose as the concentration and temperature increased. The results showed that the MnSb2O6 nanoparticles can be a good candidate to be used as a novel gas sensor. PMID- 30012962 TI - The Biological and Biophysical Properties of the Spider Peptide Gomesin. AB - This review summarises the current knowledge of Gomesin (Gm), an 18-residue long, cationic anti-microbial peptide originally isolated from the haemocytes of the Brazilian tarantula Acanthoscurria gomesiana. The peptide shows potent cytotoxic activity against clinically relevant microbes including Gram-positive and Gram negative bacteria, fungi, and parasites. In addition, Gm shows in-vitro and in vivo anti-cancer activities against several human and murine cancers. The peptide exerts its cytotoxic activity by permeabilising cell membranes, but the underlying molecular mechanism of action is still unclear. Due to its potential as a therapeutic agent, the structure and membrane-binding properties, as well as the leakage and cytotoxic activities of Gm have been studied using a range of techniques. This review provides a summary of these studies, with a particular focus on biophysical characterisation studies of peptide variants that have attempted to establish a structure-activity relationship. Future studies are still needed to rationalise the binding affinity and cell-type-specific selectivity of Gm and its variants, while more pre-clinical studies are required to develop Gm into a therapeutically useful peptide. PMID- 30012963 TI - Betaine Improves Intestinal Functions by Enhancing Digestive Enzymes, Ameliorating Intestinal Morphology, and Enriching Intestinal Microbiota in High salt stressed Rats. AB - To investigate the role of betaine in the intestinal functions of high-salt stressed rats, 32 four-week-old male Sprague-Dawley rats weighing 128.0 (SD 5.06) g were randomly allotted to four groups. The control group was fed with standard chow diet (0.4% NaCl), while the treatment groups were fed a high-salt diet (4.0% NaCl) supplemented with betaine at 0.0%, 0.5%, and 1.0%, respectively. The experiment lasted 28 days. The results showed that rats in the high-salt stressed groups had a significant increase in both water intake and kidney index (p < 0.05). The level of cortisol (COR) was increased in the high-salt stressed rats (p < 0.05), and returned to normal levels with betaine supplementation (p < 0.05). Aldosterone (ALD) was decreased in all high-salt diet groups (p < 0.05). Betaine supplementation decreased antidiuretic hormone (ADH) levels significantly (p < 0.05). High salt stress decreased the activities of amylase, lipase, trypsin, and chymotrypsin in the small intestinal luminal contents (p < 0.05), however, these activities increased with betaine supplementation (p < 0.05). The gut villus height of small intestine was significantly decreased in the high-salt diet group (p < 0.05). However, they were higher in the betaine supplementation groups than in the control group (p < 0.05). A similar result was observed in the ratio of villus height to crypt depth (p < 0.05). Both alpha diversity indexes and beta diversity indexes showed that high salt stress decreased the diversity of intestinal microbiota, while supplementation with betaine counteracted the negative effect. In conclusion, the results indicate that betaine improves intestinal function by enhancing the digestive enzymes, ameliorating intestinal morphology, and enriching intestinal microbiota of high-salt stressed rats. PMID- 30012965 TI - Mining of Brassica-Specific Genes (BSGs) and Their Induction in Different Developmental Stages and under Plasmodiophora brassicae Stress in Brassica rapa. AB - Orphan genes, also called lineage-specific genes (LSGs), are important for responses to biotic and abiotic stresses, and are associated with lineage specific structures and biological functions. To date, there have been no studies investigating gene number, gene features, or gene expression patterns of orphan genes in Brassica rapa. In this study, 1540 Brassica-specific genes (BSGs) and 1824 Cruciferae-specific genes (CSGs) were identified based on the genome of Brassica rapa. The genic features analysis indicated that BSGs and CSGs possessed a lower percentage of multi-exon genes, higher GC content, and shorter gene length than evolutionary-conserved genes (ECGs). In addition, five types of BSGs were obtained and 145 out of 529 real A subgenome-specific BSGs were verified by PCR in 51 species. In silico and semi-qPCR, gene expression analysis of BSGs suggested that BSGs are expressed in various tissue and can be induced by Plasmodiophora brassicae. Moreover, an A/C subgenome-specific BSG, BSGs1, was specifically expressed during the heading stage, indicating that the gene might be associated with leafy head formation. Our results provide valuable biological information for studying the molecular function of BSGs for Brassica-specific phenotypes and biotic stress in B. rapa. PMID- 30012966 TI - Phytotoxic Activity of Metabolites Isolated from Rutstroemia sp.n., the Causal Agent of Bleach Blonde Syndrome on Cheatgrass (Bromus tectorum). AB - A fungal pathogen soon to be described as Rutstroemia capillus-albis (Rutstroemiaceae, Helotiales, Leotiomycetes) has been identified as the causal agent of 'bleach blonde syndrome' on the invasive annual grass weed Bromus tectorum (cheatgrass) in western North America. This apparently common but previously undescribed disease causes premature senescence and sterility, but does not affect seed germination or seedling emergence and growth. This study investigated whether the new species produces phytotoxins that could be implicated in pathogenesis. The compounds 9-O-methylfusarubin, 9-O methylbostrycoidin, 5-O-methylnectriafurone, trans-methyl-p-coumarate and terpestacin were isolated from the solid culture of this fungus. The undescribed absolute stereochemistry at C-3 of 9-O-methylfusarubin and at C-1' of 5-O methylnectriafurone were assigned by applying electronic and vibrational circular dichroism (ECD and VCD) combined with computational methods and the advanced Mosher's method, respectively. The first three listed compounds are naphtoquinone pigments, while terpestacin is a sesterterpene, and trans-methyl-p-coumarate could be the product of an unusual fungal phenylpropanoid biosynthesis pathway. In a juvenile plant immersion bioassay, both 9-O-methylfusarubin and terpestacin proved to be highly toxic at 10-4 M, causing wilting and plant death within 10 days. This finding suggests that these two compounds could play a role in pathogenesis on B. tectorum. PMID- 30012967 TI - Synthesis of Nitrogen-Rich Polymers by Click Polymerization Reaction and Gas Sorption Property. AB - Microporous organic polymers (MOPs) are promising materials for gas sorption because of their intrinsic and permanent porosity, designable framework, and low density. The introduction of nitrogen-rich building block in MOPs will greatly enhance the gas sorption capacity. Here, we report the synthesis of MOPs from the 2,4,6-tris(4-ethynylphenyl)-1,3,5-triazine unit and aromatic azides linkers by click polymerization reaction. Fourier transform infrared (FTIR) and solid-state 13C CP-MAS (Cross Polarization-Magic Angle Spinning) NMR confirm the formation of the polymers. CMOP-1 and CMOP-2 exhibit microporous networks with a BET (Brunauer Emmett-Teller) surface area of 431 m2.g-1 and 406 m2.g-1 and a narrow pore size distribution under 1.2 nm. Gas sorption isotherms including CO2 and H2 were measured. CMOP-1 stores a superior CO2 level of 1.85 mmol.g-1 at 273 K/1.0 bar, and an H2 uptake of up to 2.94 mmol.g-1 at 77 K/1.0 bar, while CMOP-2, with its smaller surface area, shows a lower CO2 adsorption capacity of 1.64 mmol.g-1 and an H2 uptake of 2.48 mmol.g-1. In addition, I2 vapor adsorption was tested at 353 K. CMOP-1 shows a higher gravimetric load of 160 wt%. Despite the moderate surface area, the CMOPs display excellent sorption ability for CO2 and I2 due to the nitrogen-rich content in the polymers. PMID- 30012968 TI - Nanostructure Formation on Diamond-Like Carbon Films Induced with Few-Cycle Laser Pulses at Low Fluence from a Ti:Sapphire Laser Oscillator. AB - This study reports the results of experiments on periodic nanostructure formation on diamond-like carbon (DLC) films induced with 800 nm, 7-femtosecond (fs) laser pulses at low fluence from a Ti:sapphire laser oscillator. It was demonstrated that 7-fs laser pulses with a high power density of 0.8-2 TW/cm2 at a low fluence of 5-12 mJ/cm2 can form a periodic nanostructure with a period of 60-80 nm on DLC films. The period decreases with increasing fluence of the laser pulses. The experimental results and calculations for a model target show that 7-fs pulses can produce a thinner metal-like layer on the DLC film through a nonlinear optical absorption process compared with that produced with 100-fs pulses, creating a finer nanostructure via plasmonic near-field ablation. PMID- 30012969 TI - DCO-MAC: A Hybrid MAC Protocol for Data Collection in Underwater Acoustic Sensor Networks. AB - In underwater acoustic sensor networks (UASNs), medium access control (MAC) is an important issue because of its potentially significant effect on the network performance. However, designing a suitable MAC protocol for the UASN is challenging because of the specific characteristics of the underwater acoustic channel and network, such as limited available bandwidth, long propagation delay, high bit-error-rate, and sparse network topology. In addition, as the traffic load is non-uniformly distributed in a UASN for data collection, it is essential to consider the application feature for the MAC protocol. In this paper, we propose a MAC protocol in a data-collection-oriented UASN, abbreviated as the DCO MAC protocol. In the proposed protocol, the network is partitioned into two kinds of sub-networks according to the traffic load. A contention-based MAC protocol is used in the sub-network with a light traffic load, while a reservation-based MAC protocol is used in the sub-network with a heavy traffic load. Meanwhile, the DCO MAC protocol supports the access of mobile nodes. The theoretical analysis and simulation results demonstrate that, in a UASN for data collection, the proposed MAC protocol outperforms the other existing MAC protocols, in terms of the network throughput, end-to-end packet delay, energy overhead, and fairness. PMID- 30012971 TI - Subwavelength Nanostructuring of Gold Films by Apertureless Scanning Probe Lithography Assisted by a Femtosecond Fiber Laser Oscillator. AB - Optical methods in nanolithography have been traditionally limited by Abbe's diffraction limit. One method able to overcome this barrier is apertureless scanning probe lithography assisted by laser. This technique has demonstrated surface nanostructuring below the diffraction limit. In this study, we demonstrate how a femtosecond Yb-doped fiber laser oscillator running at high repetition rate of 46 MHz and a pulse duration of 150 fs can serve as the laser source for near-field nanolithography. Subwavelength features were generated on the surface of gold films down to a linewidth of 10 nm. The near-field enhancement in this apertureless scanning probe lithography setup could be determined experimentally for the first time. Simulations were in good agreement with the experiments. This result supports near-field tip-enhancement as the major physical mechanisms responsible for the nanostructuring. PMID- 30012970 TI - Programmed Cell Death in the Pathogenesis of Influenza. AB - Influenza is a respiratory disease induced by infection by the influenza virus, which is a member of Orthomyxoviridae family. This infectious disease has serious impacts on public health systems and results in considerable mortality and economic costs throughout the world. Based on several experimental studies, massive host immune reaction is associated with the disease severity of influenza. Programmed cell death is typically induced during virus infection as a consequence of host immune reaction to limit virus spread by eliminating niches for virus propagation without causing inflammation. However, in some viral infectious diseases, such as influenza, in the process of immune reaction, aberrant induction of programmed cell death disturbs the maintenance of organ function. Current reports show that there are different types of programmed cell death that vary in terms of molecular mechanisms and/or associations with inflammation. In addition, these novel types of programmed cell death are associated with pathogenesis rather than suppressing virus propagation in the disease course. Here, we review our current understanding of mechanisms of programmed cell death in the pathogenesis of influenza. PMID- 30012972 TI - Psychosocial Problems, Indoor Air-Related Symptoms, and Perceived Indoor Air Quality among Students in Schools without Indoor Air Problems: A Longitudinal Study. AB - The effect of students' psychosocial problems on their reporting of indoor air quality (subjective IAQ) and indoor air-related (IA-related) symptoms has not been studied in schools in a longitudinal setting. Therefore, we analyzed whether changes in students' psychosocial problems (socioemotional difficulties and perceived teacher-student relations) between the beginning of seventh grade (age 12-13 years) and the end of ninth grade (15-16 years) predicted subjective IAQ and IA-related symptoms at the end of ninth grade. In order to explore the independent effect of psychosocial factors, we focused only on students in schools without observed indoor air problems. The analysis was of longitudinal data (N = 986 students) using latent change modelling. Increased socioemotional difficulties were related to more IA-related symptoms (standardized beta = 0.20) and deteriorated subjective IAQ (standardized beta = 0.20). Increased problems in teacher-student relations were related to deteriorated subjective IAQ (standardized beta = 0.21). Although students' psychosocial problems explained only 9-13% of the total variances, our findings support the notion that psychosocial factors also need to be taken into account in the evaluation of IAQ and the prevalence of IA-related symptoms in schools. PMID- 30012974 TI - Interband Absorption in Few-Layer Graphene Quantum Dots: Effect of Heavy Metals. AB - Monolayer, bilayer, and trilayer graphene quantum dots (GQDs) with different binding abilities to elemental heavy metals (HMs: Cd, Hg, and Pb) were designed, and their electronic and optical properties were investigated theoretically to understand deeply the optical response under heavy metal exposure. To gain insight into the nature of interband absorption, we performed density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations for thickness-varying GQDs. We found that the interband absorption in GQDs can be efficiently tuned by controlling the thickness of GQDs to attain the desirable coloration of the interacting complex. We also show that the strength of the interaction between GQDs and Cd, Hg, and Pb is strongly dependent on the number of sp2-bonded layers. The results suggest that the thickness of GQDs plays an important role in governing the hybridization between locally-excited (LE) and charge-transfer (CT) states of the GQDs. Based on the partial density-of-states (DOS) analysis and in-depth knowledge of excited states, the mechanisms underlying the interband absorption are discussed. This study suggests that GQDs would show an improved sensing performance in the selective colorimetric detection of lead by the thickness control. PMID- 30012975 TI - Zoonotic Fecal Pathogens and Antimicrobial Resistance in Canadian Petting Zoos. AB - This study aimed to better understand the potential public health risk associated with zoonotic pathogens in agricultural fairs and petting zoos in Canada. Prevalence of Salmonella, Shiga toxin-producing Escherichia coli (STEC) O157:H7, and top six non-O157 STEC serogroups in feces (n = 88), hide/feather (n = 36), and hand rail samples (n = 46) was assessed, as well as distributions of antimicrobial resistant (AMR) broad and extended-spectrum beta-lactamase (ESBL) producing E. coli. Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in pig nasal swabs (n = 4), and Campylobacter, Cryptosporidium, and Giardia in feces was also assessed. Neither Salmonella nor MRSA were detected. Campylobacter spp. were isolated from 32% of fecal samples. Cryptosporidium and Giardia were detected in 2% and 15% of fecal samples, respectively. Only one fecal sample was positive for STEC O157, whereas 22% were positive for non-O157 STEC. Multi-drug resistance (MDR) to antibiotics classified as critically and highly important in human medicine was proportionally greatest in E. coli from cattle feces. The beta-lactamase-producing E. coli from pig, horse/donkey feces, and hand rail samples, as well as the STEC E. coli from handrail swabs were MDR. The diversity and prevalence of zoonotic pathogens and AMR bacteria detected within agricultural fairs and petting zoos emphasize the importance of hygienic practices and sanitization with respect to reducing associated zoonotic risks. PMID- 30012973 TI - Curcumin for the Management of Periodontitis and Early ACPA-Positive Rheumatoid Arthritis: Killing Two Birds with One Stone. AB - We propose curcumin as a preventive measure to avoid/manage periodontitis (PD), and as a natural immunosuppressant for rheumatoid arthritis (RA). PD, mainly caused by Porphyromonas gingivalis forming biofilm and leading to tooth decay, is a major public health issue and a risk factor for the development of RA in humans. P. gingivalis is able to trigger experimental autoimmune arthritis in animal models and in humans can induce citrullinated peptides, which not only are a source of anti-citrullinated antibodies (ACPAs), but also participate in autoreactive responses and disease development. Curcumin appears to have efficient anti-bacterial activity against P. gingivalis infection and biofilm formation. In addition to antibacterial, anti-oxidant, and anti-inflammatory action, curcumin exerts unique immunosuppressant properties via the inhibition of Th17 pro-inflammatory responses and promotion of regulatory T cells, thus suppressing autoimmunity. We introduce curcumin as a natural product for the management of both PD and RA-related autoreactivity, possibly also as a preventive measure in early RA or individuals at high risk to develop RA. PMID- 30012978 TI - Surface-Acoustic-Wave Sensor Design for Acceleration Measurement. AB - We suggest a concept design of a SAW-based microaccelerometer with an original triangular-shaped console-type sensing element. Our design is particularly optimized to increase the robustness against positioning errors of the SAW resonators on the opposite sides of the console. We also describe the results of computer simulations and laboratory tests that are in a perfect agreement with each other and present the sensitivity characteristics of a manufactured experimental design device. PMID- 30012976 TI - Role of Arginine 117 in Substrate Recognition by Human Cytochrome P450 2J2. AB - The influence of Arginine 117 of human cytochrome P450 2J2 in the recognition of ebastine and a series of terfenadone derivatives was studied by site-directed mutagenesis. R117K, R117E, and R117L mutants were produced, and the behavior of these mutants in the hydroxylation of ebastine and terfenadone derivatives was compared to that of wild-type CYP2J2. The data clearly showed the importance of the formation of a hydrogen bond between R117 and the keto group of these substrates. The data were interpreted on the basis of 3D homology models of the mutants and of dynamic docking of the substrates in their active site. These modeling studies also suggested the existence of a R117-E222 salt bridge between helices B' and F that would be important for maintaining the overall folding of CYP2J2. PMID- 30012977 TI - The Role of Resilience in the Sibling Experience of Pediatric Palliative Care: What Is the Theory and Evidence? AB - Siblings of children with life limiting conditions (LLC) are an important part of the broader family system and require consideration in the holistic care of the family. There can be considerable variation in the functioning and adjustment of these siblings. The current paper explores the resilience paradigm, particularly in the context of siblings of children with LLC and serious medical conditions. The potential impact of children living with a seriously ill brother or sister will be overviewed, and a range of functional outcomes considered. Factors contributing to sibling resilience are detailed, including individual, family, and broader external and social factors. Given the limited research with siblings of children with LLC, literature has also been drawn from the siblings of children with serious and/or chronic medical conditions. Implications for clinical practice and future research are considered. Pediatric palliative care services may be well placed to contribute to this body of research as they have commonly extended relationships with the families of children with LLC, which span across the child's disease trajectory. PMID- 30012979 TI - Mechanical Modelling of the Plastic Flow Machining Process. AB - A new severe plastic deformation process, plastic flow machining (PFM), was introduced recently to produce sheet materials with ultrafine and gradient structures from bulk samples in one single deformation step. During the PFM process, a part of a rectangular sample is transformed into a thin sheet or fin under high hydrostatic pressure. The obtained fin is heavily deformed and presents a strain gradient across its thickness. The present paper aims to provide better understanding about this new process via analytical modelling accompanied by finite element simulations. PFM experiments were carried out on square commercially pure aluminum (CP Al) billets. Under pressing, the material flowed from the horizontal channel into a narrow 90 degrees oriented lateral channel to form a fin sheet product, and the remaining part of the sample continued to move along the horizontal channel. At the opposite end of the bulk sample, a back-pressure was applied to increase the hydrostatic pressure in the material. The experiments were set at different width sizes of the lateral channel under two conditions; with or without applying back-pressure. A factor called the lateral extrusion ratio was defined as the ratio between the volume of the produced fin and the incoming volume. This ratio characterizes the efficiency of the PFM process. The experimental results showed that this ratio was greater when back-pressure was applied and further, it increased with the rise of the lateral channel width size. Finite element simulations were conducted in the same boundary conditions as the experiments using DEFORM-2D/3D software, V11.0. Two analytical models were also established. The first one used the variational principle to predict the lateral extrusion ratio belonging to the minimum total plastic power. The second one employed an upper-bound approach on a kinematically admissible velocity field to describe the deformation gradient in the fin. The numerical simulations and the analytical modelling successfully predicted the experimental tendencies, including the deformation gradient across the fin thickness. PMID- 30012980 TI - Bioactive Compounds and Extracts from Traditional Herbs and Their Potential Anti Inflammatory Health Effects. AB - The inflammatory processes associated with several chronic illnesses like cardiovascular disease and cancer have been the focus of mechanistic studies of the pathogenicity of these diseases and of the use of different pharmacological and natural methods to prevent them. In this study we review the current evidence regarding the effectiveness of natural extracts from as-yet little-studied traditional botanical species in alleviating the inflammation process associated with several chronic diseases. Additionally, the intention is to expose the known pathways of action and the potential synergistic effects of the constituent compounds of the discussed extracts. It is noted that the here-studied extracts, which include black garlic rich in S-allylcystein, polyphenols from cat's claw (Uncaria tomentosa), devil's claw (Harpagophytum procumbens), camu-camu (Myrciaria dubia), and blackcurrant (Ribes nigrum), and citrus fruit extracts rich in hesperidin, have similar or greater effects than other, more extensively studied extracts such as tea and cocoa. The combined use of all of these extracts can give rise to synergetic effects with greater biological relevance at lower doses. PMID- 30012982 TI - Characterisation of the Mycobiota on the Shell Surface of Table Eggs Acquired from Different Egg-Laying Hen Breeding Systems. AB - Microbial safety is an important factor contributing to the egg quality. During egg acquisition, there is significant risk of contamination of the eggshell surface with microscopic fungi. Mycelial hyphae may grow on the eggshell surface and penetrate into the egg content. However, there is no information on the populations of microscopic fungi on the eggshell surface and, consequently, on possible production of mycotoxins. Therefore, the aim of the study was to identify the species of microscopic fungi present on the eggshell surface acquired from different breeding systems and to measure the number of selected mycotoxins. The qualitative analysis resulted in the identification of 41 isolates on the surface of eggs. There were 7 isolates from the organic production system, 11 from the free-range production system, 14 from the deep litter indoor housing system and 9 from the cage farming production system. The research proved that the diversification in the population of mycobiota on the eggshells depended on the egg-laying hen breeding system. The microscopic fungi isolated from the eggshells included toxigenic and pathogenic species such as Fusarium culmorum and F. equiseti. As the egg storage time increased, fungi, including the pathogenic species, penetrated through the eggshells. In consequence, mycotoxins were identified in the egg whites. Type-A and type-B trichothecenes were found in the eggshell samples containing F. culmorum. PMID- 30012981 TI - Effectiveness of a Locally Produced, Fish-Based Food Product on Weight Gain among Cambodian Children in the Treatment of Acute Malnutrition: A Randomized Controlled Trial. AB - Cambodia continues to have a high prevalence of acute malnutrition. Low acceptability has been found for standard ready-to-use-therapeutic-food (RUTF) products. Therefore, NumTrey, a locally-produced fish-based RUTF, was developed. The objective was to evaluate the effectiveness of NumTrey compared to an imported milk-based RUTF for weight gain among children aged 6-59 months in the home-treatment for acute malnutrition. Effectiveness was tested in a single blinded randomized controlled trial with weight gain as the primary outcome. Anthropometry was assessed at baseline and bi-weekly follow-ups until endline at Week 8. In total, 121 patients were randomized into BP-100TM (n = 61) or NumTrey (n = 60). There was no statistical difference in mean weight gain between the groups (1.06 g/kg/day; 95% CI (0.72, 1.41) and 1.08 g/kg/day; 95% CI (0.75, 1.41) for BP-100TM and NumTrey, respectively). In addition, no statistically significant differences in secondary outcomes were found. Although the ability to draw conclusions was limited by lower weight gain than the desired 4 g/kg/day in both groups, no superiority was found for eitherRUTF. A locally produced RUTF is highly relevant to improve nutrition interventions in Cambodia. A locally produced fish-based RUTF is a relevant alternative to imported milk-based RUTF for the treatment of SAM in Cambodia. PMID- 30012983 TI - A Novel Class of tRNA-Derived Small Non-Coding RNAs Respond to Myocardial Hypertrophy and Contribute to Intergenerational Inheritance. AB - tRNA-derived fragments (tRFs) are a new class of non-coding RNA that play an important role in regulating cellular RNA processing and protein translation. However, there is currently no study reporting the influence of tRFs on myocardial hypertrophy. In this study, we used an isoproterenol (ISO)-induced myocardial hypertrophy rat model. Small RNA (<40 nts) transcriptome sequencing was used to select differentially expressed tRFs. We also compared the tRFs expression pattern in F0 sperm and the hearts of F1 offspring between the myocardial hypertrophy group (Hyp) and the control group (Con). Isoproterenol successfully induced a typical cardiac hypertrophy model in our study. Small RNA seq revealed that tRFs were extremely enriched (84%) in the Hyp heart. Overexpression of tRFs1 and tRFs2 both enlarged the surface area of cardiac cells and increased expression of hypertrophic markers (ANF, BNP, and beta-MHC). Luciferase reporter assay identified that tRFs1 directly target 3'UTR of Timp3. tRFs1, tRFs2, tRFs3, and tRFs4 were also highly expressed in Hyp F0 sperm and in Hyp F1 offspring hearts, but there was no differential expression of tRFs7, tRFs9, and tRFs10. Compared to Con F1 offspring, Hyp F1 offspring had elevated expression levels of beta-MHC and ANP genes, and they had increased fibrosis and apoptosis in their hearts. These results demonstrated that tRFs are involved in regulating the response of myocardial hypertrophy. Besides, tRFs might serve as novel epigenetic factors that contribute to the intergenerational inheritance of cardiac hypertrophy. PMID- 30012984 TI - Study on the Photoluminescent and Thermal Properties of Zinc Complexes with a N6O4 Macrocyclic Ligand. AB - Reactions between a N6O4 macrocyclic ligand (L1) and several Zn(II) salts (trifluoromethane sulfonate, p-toluenesulfonate, acetate, benzoate, o-, m- or p hydroxybenzoate) led to the formation of seven complexes, [Zn2L1 (DMSO)4](OSO2CF3)4 (1), [Zn2(p-OSO2PhCH3)4L1] (2), [Zn2(OCOCH3)4L1] (3), [Zn2(OCOPh)4L1] (4), [Zn2(o-OCOPhOH)4L1] (5), [Zn2(m-OCOPhOH)4 L1] (6) and [Zn2(p OCOPhOH)4 L1] (7), which were characterized by elemental analysis, 1H-NMR, 13C NMR, IR, fluorescence spectroscopies and single crystal X-ray diffraction. In 1, the Zn atom is pentacoordinated with a N3O2 irregular trigonal bipyramidal coordination environment, like the geometries in compounds 3-7, whereas in structure 2 the metal atom is envisaged as possessing a distorted N3O3 octahedronal environment. All the compounds show interesting photoluminescent properties in solid states and solutions in DMF and DMSO, which are reported along with their TG-DTA thermal decomposition processes, UV-vis absorption spectroscopy and fluorescence quantum yields in DMF and DMSO. PMID- 30012985 TI - Upon Rejection: Psychiatric Emergencies of Failed Asylum Seekers. AB - Background: The status of a refugee or asylum seeker is only recognised after legal processes. The uncertainty of these procedures or the rejection itself may severely impact mental well-being. Methods: We surveyed the patterns of psychiatric services used by patients whose applications for asylum had been rejected. In a retrospective investigation of admissions to the University Emergency Department in Bern, Switzerland between 1 March 2012 and 28 February 2017, we studied patients receiving a psychiatric consultation after their applications had been rejected. The primary endpoint was based on the comparison of these individuals with controls who were asylum seekers with pending asylum applications using the Mann-Whitney U test and the chi-square test (chi2) with a significance level of 0.05. Results: Thirty-eight cases were identified. There were more men than women and the mean age was 30.08 +/- 9.62 years. Patients predominantly presented as walk-in patients (n = 16, 42.1%), most frequently due to suicidal ideation (n = 16, 42.1%). Stress-related disorders were the most common diagnosis (n = 29, 76.3%) and patients were mainly referred to inpatient treatment (n = 28, 73.7%). Patients with rejected applications were less likely to be living in reception centres than patients with a pending application (chi2 = 17.98, p < 0.001). Conclusion: The profile of asylum seekers whose applications had been rejected reflects individuals with high-stress levels, potentially aggravated by the negative asylum decision. PMID- 30012986 TI - Discrepancy between Self-Reported and Urine Cotinine-Verified Environmental Tobacco Smoke Exposure among Rural Pregnant Women in China. AB - Prenatal exposure to environmental tobacco smoke (ETS) is the most modifiable risk factor associated with adverse child-health outcomes. However, few longitudinal studies are implemented to compare the rates of discrepancy between self-reported (SR) and urinary cotinine (UC)-verified ETS exposure during the three trimesters of pregnancy, especially in rural areas. The objectives of this study were to assess the discrepancy between SR and UC-verified ETS exposure among rural women employing three measures throughout pregnancy, and to explore predictors related to these differences. This study used a prospective prenatal cohort consisting of 420 pregnant women whose ETS exposure was entirely evaluated by both SR and UC verification across three trimesters of pregnancy. Environmental tobacco exposure was assessed via SR verification, and was validated using the limit of detection for UC. The discrepancy rates were determined for each trimester. Multivariate logistic regression was used to assess the predictors associated with these differences. The discrepancy rates between SR and UC verification were 25.2%, 17.1%, and 20.5% (first, second, and third trimester, respectively). The highest inconsistency occurred in the first trimester. After adjusting for confounding factors, the following variables were found to have statistically significant associations with the discrepancy rate between SR and UC-verified ETS exposure: the number of smokers in the family and household income for all three trimesters, township site for the second and third trimester, and gravidity for the last trimester. The SR rate of ETS exposure among rural pregnant women is underreported, while the UC-verified rate is higher. More smokers in the family and gravidity may increase the risk of ETS exposure for pregnant women. Biochemical validation is warranted throughout pregnancy for the adoption of home-smoking bans and the promotion of community based smoke-free programs. PMID- 30012988 TI - Synthesis of Non-Stoichiometric (TiNb)C0.5 with High Hardness and Fracture Toughness under HTHP. AB - Nonstoichiometric TiC0.5 and (TiNb)0.5 powders were prepared by the mechanical alloying process using Ti, Nb, and TiC powders as raw materials. Furthermore, the as-prepared TiC0.5 and (TiNb)0.5 powders were used as initial materials to fabricate TiC0.5 and (TiNb)0.5 compacts under high pressures and high temperatures (HTHP) of 5.5 GPa and 1200-1550 degrees C for 5 min. Phase identification and microstructure of the mechanical-alloyed powders and the sintered TiC0.5 and (TiNb)0.5 compacts were realized by an X-ray diffractometer and scanning electron microscope. The results indicate that the as-prepared TiC0.5 and (TiNb)0.5 powders have a similar crystal structure of face-centered cubic (FCC) to TiC. The sintered (TiNb)0.5 compact has good Vickers hardness (~16 GPa), and notably, excellent fracture toughness (~7.3 MPa.m1/2). The non stoichiometric compound not only reduced the sintering temperature of covalent compounds, but also greatly enhanced the mechanical properties of the materials. Thus, we have provided a novel synthetic strategy for the production of a compound with high-strength covalent bonds. PMID- 30012987 TI - Effects of a Gluten-Containing Meal on Gastric Emptying and Gallbladder Contraction. AB - The ingestion of gluten has been associated with gastrointestinal symptoms even in the absence of detectable immune responses. Little is known about the pathophysiological effects of gluten on the upper gastrointestinal tract. We aimed to assess whether the ingestion of gluten leads to an impairment of the physiological mechanisms of gastric emptying, gallbladder contraction and relaxation. A total of 17 healthy subjects underwent ultrasound evaluation of gastric emptying dynamics and gallbladder contractions at baseline and every 30 min after a standard gluten-containing and gluten-free meal (250 kcal, 70% carbohydrates). The pattern of gastric emptying was similar after a standard meal with or without gluten, but differed in terms of the peak of the antral filling curve, which was wider (mean area 5.69, median 4.70, range 3.71-9.27 cm2 vs. mean 4.89, median 4.57, 2.27-10.22 cm2, p = 0.023) after the gluten-containing meal. The pattern of gallbladder contractions was different after the gluten-free meal (p < 0.05), with higher gallbladder volumes in the late refilling phases. The results of this study show that gluten ingestion exerts objective effects on gastric and gallbladder motility. Although the underlying pathophysiological mechanism remains unknown, these results could account for some of the gluten related symptoms reported by patients with celiac disease and non-celiac gluten sensitivity. PMID- 30012989 TI - Near Real-Time Detection of E. coli in Reclaimed Water. AB - Advanced treatment of reclaimed water prior to potable reuse normally results in the inactivation of bacterial populations, however, incremental treatment failure can result in bacteria, including pathogens, remaining viable. Therefore, potential microorganisms need to be detected in real-time to preclude potential adverse human health effects. Real-time detection of microbes presents unique problems which are dependent on the water quality of the test water, including parameters such as particulate content and turbidity, and natural organic matter content. In addition, microbes are unusual in that: (i) viability and culturability are not always synonymous; (ii) viability in water can be reduced by osmotic stress; and (iii) bacteria can invoke repair mechanisms in response to UV disinfection resulting in regrowth of bacterial populations. All these issues related to bacteria affect the efficacy of real-time detection for bacteria. Here we evaluate three different sensors suitable for specific water qualities. The sensor A is an on-line, real-time sensor that allows for the continuous monitoring of particulates (including microbial contaminants) using multi-angle light scattering (MALS) technology. The sensor B is a microbial detection system that uses optical technique, Mie light scattering, for particle sizing and fluorescence emission for viable bacteria detection. The last sensor C was based on adenosine triphosphate (ATP) production. E. coli was used a model organism and out of all tested sensors, we found the sensor C to be the most accurate. It has a great potential as a surrogate parameter for microbial loads in test waters and be useful for process control in treatment trains. PMID- 30012990 TI - Efficient 3D Objects Recognition Using Multifoveated Point Clouds. AB - Technological innovations in the hardware of RGB-D sensors have allowed the acquisition of 3D point clouds in real time. Consequently, various applications have arisen related to the 3D world, which are receiving increasing attention from researchers. Nevertheless, one of the main problems that remains is the demand for computationally intensive processing that required optimized approaches to deal with 3D vision modeling, especially when it is necessary to perform tasks in real time. A previously proposed multi-resolution 3D model known as foveated point clouds can be a possible solution to this problem. Nevertheless, this is a model limited to a single foveated structure with context dependent mobility. In this work, we propose a new solution for data reduction and feature detection using multifoveation in the point cloud. Nonetheless, the application of several foveated structures results in a considerable increase of processing since there are intersections between regions of distinct structures, which are processed multiple times. Towards solving this problem, the current proposal brings an approach that avoids the processing of redundant regions, which results in even more reduced processing time. Such approach can be used to identify objects in 3D point clouds, one of the key tasks for real-time applications as robotics vision, with efficient synchronization allowing the validation of the model and verification of its applicability in the context of computer vision. Experimental results demonstrate a performance gain of at least 27.21% in processing time while retaining the main features of the original, and maintaining the recognition quality rate in comparison with state-of-the-art 3D object recognition methods. PMID- 30012991 TI - Preparation of Poly (dl-Lactide-co-Glycolide) Nanoparticles Encapsulated with Periglaucine A and Betulinic Acid for In Vitro Anti-Acanthamoeba and Cytotoxicity Activities. AB - Poly (dl-lactide-co-glycolide) (PLGA) microspheres were synthesized as delivery system for the natural anti-parasitic compounds, Periglaucine A (PGA) and Betulinic acid (BA). Periglaucine A and Betulinic acid were encapsulated in PLGA nanoparticles by single emulsion method with an average particle size of approximately 100-500 nm. Periglaucine A and Betulinic acid encapsulation efficiency was observed to be 90% and 35% respectively. Anti-Acanthamoeba property of Periglaucine A and Betulinic acid remained intact after encapsulation. PGA-PLGA and BA-PLGA nanoparticles demonstrated inhibition in viability of Acanthamoeba triangularis trophozoites by 74.9%, 59.9%, 49.9% and 71.2%, 52.2%, 88% respectively at concentration of 100 ug/mL, 50 ug/mL and 25 ug/mL. Cytotoxicity of PGA-PLGA and BA-PLGA nanoparticles has been evaluated against lung epithelial cell line and showed dose dependent cytotoxicity value of IC50 2 ug/mL and 20 ug/mL respectively. Futher, increased viability was observed in lung epithelial cell line in higher doses of synthesized polymeric nanoparticles. Results indicate that poly (dl-lactide-co-glycolide) (PLGA) nanoparticles could be exploratory delivery systems for natural products to improve their therapeutic efficacy. PMID- 30012992 TI - A Consistent Procedure Using Response Surface Methodology to Identify Stiffness Properties of Connections in Machine Tools. AB - Accurate finite element models of mechanical systems are fundamental resources to perform structural analyses at the design stage. However, uncertainties in material properties, boundary conditions, or connections give rise to discrepancies between the real and predicted dynamic characteristics. Therefore, it is necessary to improve these models in order to achieve a better fit. This paper presents a systematic three-step procedure to update the finite element (FE) models of machine tools with numerous uncertainties in connections, which integrates statistical, numerical, and experimental techniques. The first step is the gradual application of fractional factorial designs, followed by an analysis of the variance to determine the significant variables that affect each dynamic response. Then, quadratic response surface meta-models, including only significant terms, which relate the design parameters to the modal responses are obtained. Finally, the values of the updated design variables are identified using the previous regression equations and experimental modal data. This work demonstrates that the integrated procedure gives rise to FE models whose dynamic responses closely agree with the experimental measurements, despite the large number of uncertainties, and at an acceptable computational cost. PMID- 30012993 TI - Evaluation of Commercial Prototype Bacteriophage Intervention Designed for Reducing O157 and Non-O157 Shiga-Toxigenic Escherichia coli (STEC) on Beef Cattle Hide. AB - Microbiological safety of beef products can be protected by application of antimicrobial interventions throughout the beef chain. This study evaluated a commercial prototype antimicrobial intervention comprised of lytic bacteriophages formulated to reduce O157 and non-O157 Shiga-toxigenic Escherichia coli (STEC) on beef cattle hide pieces, simulating commercial pre-harvest hide decontamination. STEC reduction in vitro by individual and cocktailed phages was determined by efficiency of plating (EOP). Following STEC inoculation onto hide pieces, the phage intervention was applied and hide pieces were analyzed to quantify reductions in STEC counts. Phage intervention treatment resulted in 0.4 to 0.7 log10 CFU/cm2 (p < 0.01) E. coli O157, O121, and O103 reduction. Conversely, E. coli O111 and O45 did not show any significant reduction after application of bacteriophage intervention (p > 0.05). Multiplicity of infection (MOI) evaluation indicated E. coli O157 and O121 isolates required the fewest numbers of phages per host cell to produce host lysis. STEC-attacking phages may be applied to assist in preventing STEC transmission to beef products. PMID- 30012994 TI - Exposures and Health Risks from Volatile Organic Compounds in Communities Located near Oil and Gas Exploration and Production Activities in Colorado (U.S.A.). AB - The study objective was to use a preliminary risk based framework to evaluate the sufficiency of existing air data to answer an important public health question in Colorado: Do volatile organic compounds (VOCs) emitted into the air from oil and gas (OG) operations result in exposures to Coloradoans living at or greater than current state setback distances (500 feet) from OG operations at levels that may be harmful to their health? We identified 56 VOCs emitted from OG operations in Colorado and compiled 47 existing air monitoring datasets that measured these VOCs in 34 locations across OG regions. From these data, we estimated acute and chronic exposures and compared these exposures to health guideline levels using maximum and mean air concentrations. Acute and chronic non-cancer hazard quotients were below one for all individual VOCs. Hazard indices combining exposures for all VOCs were slightly above one. Lifetime excess cancer risk estimates for benzene were between 1.0 * 10-5-3.6 * 10-5 and ethylbenzene was 7.3 * 10-6. This evaluation identified a small sub-set of VOCs, including benzene and n-nonane, which should be prioritized for additional exposure characterization in site-specific studies that collect comprehensive time-series measurements of community scale exposures to better assess community exposures. PMID- 30012995 TI - Smart Meter Data Collection Using Public Taxis. AB - The advent of wireless sensor networks (WSN) has opened up an array of applications. Due to the ad-hoc nature of WSN and the small size of wireless nodes, multiple system configurations are possible. In order to collect data from WSN, some systems utilize static nodes with a network setup that consists of multiple relays to facilitate the dissemination of data to a gateway. Other WSN architectures consist of a mixture of static and mobile nodes. Mobile nodes are able to collect data from the WSN when in close proximity to a static node. Such nodes are referred to as data mules. Data mules presents multiple advantages including the improvement of the network life as communication usually takes place via a single hop. In order to collect smart meter data, we propose the usage of mini-bus taxis carrying a data collector node as an alternative to traditional GSM models where data collected is directly uploaded from a data concentrator to a server. Using the vast network of mini-bus taxis in South Africa, data collection in areas lacking GSM network will be possible. This paper will attempt to present all the relevant parameters required for such data collection scheme to be successful. PMID- 30012997 TI - Novel Composite Electrolytes of Zr0.92Y0.08O2-alpha(8YSZ)-Low Melting Point Glass Powder for Intermediate Temperature Solid Oxide Fuel Cells. AB - In this study, Zr0.92Y0.08O2-alpha(8YSZ) powders were synthesized by the sol-gel method. The chemical physics changes and phase formation temperature of 8YSZ crystal were determined by thermogravimetry analysis and differential scanning calorimetry (TGA-DSC). 8YSZ-low melting point glass powder (8YSZ-glass) composite electrolytes with various weight ratios were prepared and calcined at different temperatures. The X-ray diffraction (XRD) patterns of the composite electrolytes were tested. The effects of synthesis temperature, weight ratio, test temperature, and oxygen partial pressure on the conductivities of 8YSZ-glass composite electrolytes, were also investigated at 400-800 degrees C. The result of the logsigma ~ log(pO2) plot indicates that the 8YSZ-20% glass (700 degrees C) is almost a pure ionic conductor. The oxygen concentration discharge cell illustrates that the 8YSZ-20% glass (700 degrees C) composite electrolyte is a good oxygen ion conductor. PMID- 30012996 TI - Quick Multi-Class Determination of Residues of Antimicrobial Veterinary Drugs in Animal Muscle by LC-MS/MS. AB - On the basis of the highly sensitive and selective liquid chromatography-tandem mass spectrometry technique, a generic extraction solvent and a sample dilution method was developed for the residue analysis of different polar veterinary drugs known as fluoroquinolones, sulfonamides, macrolides, and tiamulin in chicken muscle. The results showed that the matrix-matched calibration curves of all 10 compounds were in an effective linear relationship (r2 >= 0.997) in the range of 0.2-100 MUg L-1. At three spiking levels of 2 (5), 50, and 100 MUg kg-1, average recoveries of analytes were between 67.1% and 96.6% with relative standard deviations of intra-day and inter-day below 20%. The limits of detection and limits of quantification of the method were in the range of 0.3-2.0 MUg kg-1 and 2.0-5.0 MUg kg-1, respectively, which were significantly lower than their maximum residue limits. In addition, the intensity of the target analytes and its corresponding matrix effects were obviously related to the sample dilution times (matrix concentration). There were no significant differences (p > 0.05) in the average content of almost any of the analytes in medicated chickens between this method and the method in the literature for determining analytes. Lastly, the proposed method was successfully applied for the simultaneous analysis of 10 common veterinary drugs in food animal muscle tissues. PMID- 30012998 TI - PerLE: An "Open Source", ELearning Moodle-Based, Platform. A Study of University Undergraduates' Acceptance. AB - The implementation of innovative eLearning platforms offers numerous benefits, but it is important to understand individual acceptance and use of new technological systems in the educational setting. This study adopts a modified version of the Technology Acceptance Model (TAM), including three service quality constructs as external variables, to assess students' acceptance of PerLE, a Moodle-based eLearning platform developed at the University of Calabria (Italy). A six-section questionnaire, which was based on previous studies, was administered to 293 undergraduate students. Results show that the quality of online courses is the main construct that affects students' acceptance of PerLE. We found also that the PerLE user interface was a critical issue, requiring improvements to facilitate ease of use. In addition, the study underlines the important influence of Technical Support as an antecedent to the two main constructs of the TAM: PerLE Usefulness and PerLE Ease of Use. PMID- 30012999 TI - Inhibitory Effects and Killing Kinetics of Lactic Acid Rice Gel Against Pathogenic Bacteria Causing Bovine Mastitis. AB - Staphylococcus aureus and S. epidermidis are the major teat skin bacteria and lead to severe bovine mastitis. Teat antiseptic is an important tool for controlling intramammary infection. The antibacterial activity of lactic acid (LA) against one reference strain of S. aureus ATCC 25923 and two field strains including S. aureus and S. epidermidis was investigated using the broth microdilution method. Its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were 0.5% for strains belonging to both species. An antiseptic preparation containing 5% LA with modified rice gel (LA-RG) was successfully prepared. Rheological behavior of LA-RG was found to be a pseudoplastic flow with thixotropy with viscosity of approximately 0.007 Pas. LA RG exhibited a sufficient adhesive property in the rolling ball test with a length of 9.67 +/- 0.04 cm. Killing kinetic studies of LA-RG showed that the killing rate of LA-RG was significantly faster than that of LA. After 32 min of exposure to LA-RG, approximately 86% and 60% of S. aureus and S. epidermidis were reduced, respectively. Abnormal bacterial cell surface after exposure to LA-RG was observed by scanning electron microscopy. It is concluded that LA-RG is a promising preparation as an alternative product for preventing mastitis in dairy cattle. PMID- 30013000 TI - Transcriptome Analyses in Different Cucumber Cultivars Provide Novel Insights into Drought Stress Responses. AB - Drought stress is one of the most serious threats to cucumber quality and yield. To gain a good understanding of the molecular mechanism upon water deficiency, we compared and analyzed the RNA sequencing-based transcriptomic responses of two contrasting cucumber genotypes, L-9 (drought-tolerant) and A-16 (drought sensitive). In our present study, combining the analysis of phenotype, twelve samples of cucumber were carried out a transcriptomic profile by RNA-Seq under normal and water-deficiency conditions, respectively. A total of 1008 transcripts were differentially expressed under normal conditions (466 up-regulated and 542 down-regulated) and 2265 transcripts under drought stress (979 up-regulated and 1286 down-regulated). The significant positive correlation between RNA sequencing data and a qRT-PCR analysis supported the results found. Differentially expressed genes (DEGs) involved in metabolic pathway and biosynthesis of secondary metabolism were significantly changed after drought stress. Several genes, which were related to sucrose biosynthesis (Csa3G784370 and Csa3G149890) and abscisic acid (ABA) signal transduction (Csa4M361820 and Csa6M382950), were specifically induced after 4 days of drought stress. DEGs between the two contrasting cultivars identified in our study provide a novel insight into isolating helpful candidate genes for drought tolerance in cucumber. PMID- 30013001 TI - Design of the Fall-Block Sensing of the Railway Line Pantograph Based on 3D Machine Vision Sensors. AB - As an important part of the electric locomotive in railway transportation, the sensing and inspection of the pantograph has a significant effect on the safe operation of the train. In general, the pantograph carbon slip detection items include slide wear detection, slip strip crack detection, carbon slip fall-block detection and slip strip wear detection. The emergence and development of structured light measurement technology with 3D sensors provide new technical means for the acquisition of spatial 3D information. The three-dimensional data can not only obtain more information but also reduce the data deviation, thereby improving the measurement accuracy and work efficiency. At present, few studies have been conducted on the slide block and partial wear of the carbon slide. Therefore, this paper studies the detection of the pantograph slide block based on 3D sensor measurement technology. The experimental results indicate that it is feasible to adopt 3D measurement technology to detect the fall-block of the pantograph slide. In addition, a sound detection effect can also be obtained. PMID- 30013003 TI - The Analysis of the Physicochemical Properties of Benzocaine Polymorphs. AB - The study was a pioneering attempt to assess the influence of the structural polymorphism (forms I, II, III) of benzocaine on its solubility, apparent solubility, and chemical stability, which are vital parameters for preformulation and formulation work. The impact of differences in the solubility of selected polymorphs of benzocaine on their permeability through artificial biological membranes (PAMPA system) was evaluated. The polymorphs of benzocaine were obtained by means of techniques commonly used for the preparation of various pharmaceutical dosage forms: ball milling, micro milling, and cryogenic grinding, which allowed for the appearance or preservation of form III, the initial conformation of benzocaine. Ball milling resulted in the conversion of form III to I, whereas micro milling yielded form II. As a result of cryogenic grinding, form III of benzocaine was preserved. The identification of all polymorphic forms of benzocaine was confirmed via X-ray powder diffraction (PXRD) supported by FT IR spectroscopy coupled with density functional theory (DFT) calculations. The differences in solubility, dissolution, and permeability through artificial biological membranes resulting from the polymorphic forms of benzocaine were established by using chromatographic determinations. Accelerated stability tests indicated that all polymorphic forms were chemically stable at a required level. PMID- 30013002 TI - Genome-Guided Characterization of Ochrobactrum sp. POC9 Enhancing Sewage Sludge Utilization-Biotechnological Potential and Biosafety Considerations. AB - Sewage sludge is an abundant source of microorganisms that are metabolically active against numerous contaminants, and thus possibly useful in environmental biotechnologies. However, amongst the sewage sludge isolates, pathogenic bacteria can potentially be found, and such isolates should therefore be carefully tested before their application. A novel bacterial strain, Ochrobactrum sp. POC9, was isolated from a sewage sludge sample collected from a wastewater treatment plant. The strain exhibited lipolytic, proteolytic, cellulolytic, and amylolytic activities, which supports its application in biodegradation of complex organic compounds. We demonstrated that bioaugmentation with this strain substantially improved the overall biogas production and methane content during anaerobic digestion of sewage sludge. The POC9 genome content analysis provided a deeper insight into the biotechnological potential of this bacterium and revealed that it is a metalotolerant and a biofilm-producing strain capable of utilizing various toxic compounds. The strain is resistant to rifampicin, chloramphenicol and beta-lactams. The corresponding antibiotic resistance genes (including blaOCH and cmlA/floR) were identified in the POC9 genome. Nevertheless, as only few genes in the POC9 genome might be linked to pathogenicity, and none of those genes is a critical virulence factor found in severe pathogens, the strain appears safe for application in environmental biotechnologies. PMID- 30013004 TI - The Natural Product 6-Gingerol Inhibits Inflammation-Associated Osteoclast Differentiation via Reduction of Prostaglandin E2 Levels. AB - The natural product 6-gingerol, a major bioactive component of the rhizome of ginger (Zingiber officinale), is known to have several beneficial effects on health, including anti-inflammatory activity. The present study aimed to investigate the effects of 6-gingerol on osteoclast differentiation associated with inflammation. 6-Gingerol inhibited osteoclast differentiation in co-cultures of osteoblasts and osteoclast precursor cells in response to the pro-inflammatory cytokine, interleukin (IL)-1. However, it did not affect osteoclast precursor differentiation into osteoclasts induced by the receptor activator of nuclear factor-kappaB ligand (RANKL), a key cytokine causing osteoclast differentiation. 6-Gingerol inhibited IL-1-induced RANKL expression in osteoblasts, and the addition of RANKL to the co-cultures overcame 6-gingerol-mediated inhibition of osteoclast differentiation. It also suppressed IL-1-induced prostaglandin E2 (PGE2) production in osteoblasts, and the addition of exogenous PGE2 reversed 6 gingerol-mediated inhibition of IL-induced RANKL expression in osteoblasts and osteoclast differentiation in the co-cultures. We found that 6-gingerol reduced PGE2 levels by suppressing enzymatic activities of cyclooxygenase and PGE synthase, which cooperatively catalyze the conversion of arachidonic acid to PGE2. Our findings demonstrate that 6-gingerol inhibits IL-1-induced osteoclast differentiation via suppression of RANKL expression in osteoblasts though reduction of PGE2 levels, suggesting its potential use in treating inflammatory bone destruction associated with excessive PGE2 production. PMID- 30013005 TI - Multi-Mycotoxin Occurrence in Dairy Cattle Feeds from the Gauteng Province of South Africa: A Pilot Study Using UHPLC-QTOF-MS/MS. AB - The indispensable nature of toxigenic fungi and mycotoxins in agricultural systems is of worldwide concern, hence the need for surveillance studies to preserve public health. Thirteen dairy farms were surveyed and 40 dairy feeds of varying nature collected and analyzed for mycotoxins. Estimated levels of aflatoxins (AFs), fumonisin B1 (FB1), ochratoxin A (OTA), citrinin (CIT), zearalenone (ZEN), alpha-zearalenol (alpha-ZEL), beta-zearalenol (beta-ZEL), deoxynivalenol (DON), 3- and 15-acetyl-deoxynivalenol (ADONs), HT-2 toxin (HT-2), and beauvericin (BEA) were established using liquid chromatography-tandem mass spectrometry. Highest frequencies (40/40) were found for AFG2 (range: 15.07%). Minimal inhibition concentration (MIC) and minimal bactericidal/fungicidal concentration (MBC/MFC) demonstrated that water extracts had the best antimicrobial activity by a weak to moderate inhibition of growth of all eight tested microorganisms in addition to having a bactericidal effect on three of them. The quaking aspen methanol extract also displayed antimicrobial activity but to a lower level than the water extract. Ultra-performance liquid chromatography quadrupole time-of flight mass spectrometry (UPLC-QTOF-MS) analysis led to the identification of 92 compounds, mainly polyphenols in both extracts, with 22 molecules previously known for their antimicrobial properties. According to the relative abundance, 4 hydroxybenzaldehyde (5.44% in methanol extract) and kaempferol (5.03% in water extract) were the most abundant antimicrobial compounds. Among antimicrobial molecules identified, nine were from the flavonoid family. The results of our study demonstrate the interest of using quaking aspen as source of antimicrobial compounds. PMID- 30013008 TI - Update on FXR Biology: Promising Therapeutic Target? AB - Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor 15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut-liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development. PMID- 30013011 TI - A Topology Control with Energy Balance in Underwater Wireless Sensor Networks for IoT-Based Application. AB - As part of the IoT-based application, underwater wireless sensor networks (UWSN), which are typically self-organized heterogeneous wireless network, are one of the research hot-spots using various sensors in marine exploration and water environment monitoring application fields, recently. Due to the serious attenuation of radio in water, acoustic or hybrid communication is a usual way for transmitting information among nodes, which dissipates much more energy to prevent the network failure and guarantee the quality of service (QoS). To address this issue, a topology control with energy balance, namely TCEB, is proposed for UWSN to overcome time-delay and other interference, as well as make the entire network load balance. With the given underwater network model and its specialized energy consumption model, we introduce the non-cooperative-game-based scheme to select the nodes with better performance as the cluster-heads. Afterwards, the intra-cluster and inter-cluster topology construction are, respectively, to form the effective communication links of the intra-cluster and inter-cluster, which aim to build energy-efficient topology to reduce energy consumption. With the demonstration of the simulation, the results show the proposed TCEB has better performance on energy-efficiency and throughput than three other representative algorithms in complex underwater environments. PMID- 30013010 TI - Influence of Menopause on Inflammatory Cytokines during Murine and Human Bone Fracture Healing. AB - Postmenopausal females display a chronic inflammatory phenotype with higher levels of circulating pro-inflammatory cytokines. Furthermore, the inflammatory response to injury may be altered under estrogen-deficiency, because it was shown previously that estrogen-deficient mice displayed increased levels of the inflammatory cytokines Midkine (Mdk) and Interleukin-6 (IL-6) in the early fracture hematoma. Because a balanced immune response to fracture is required for successful bone regeneration, this might contribute to the delayed fracture healing frequently observed in osteoporotic, postmenopausal fracture patients. In this study, we aimed to investigate whether further cytokines in addition to Mdk and IL-6 might be affected by estrogen-deficiency after fracture in mice and whether these cytokines are also relevant during human fracture healing. Additionally, we aimed to investigate whether serum from male vs. female fracture patients affects osteogenic differentiation of human mesenchymal stem cells (MSCs). To address these questions, female mice were either sham-operated or ovariectomized (OVX) and subjected to standardized femur osteotomy. A broad panel of pro- and anti-inflammatory cytokines was determined systemically and locally in the fracture hematoma. In a translational approach, serum was collected from healthy controls and patients with an isolated fracture. Mdk and IL-6 serum levels were determined at day 0, day 14 and day 42 after fracture. Subgroup analysis was performed to investigate differences between male and female fracture patients after menopause. In an in vitro approach, human MSCs were cultured with the collected patient serum and osteogenic differentiation was assessed by qPCR and alkaline-phosphatase staining. Our results suggest an important role for the pro-inflammatory cytokines Mdk and IL-6 in the response to fracture in estrogen-deficient mice among all of the measured inflammatory mediators. Notably, both cytokines were also significantly increased in the serum of patients after fracture. However, only Mdk serum levels differed significantly between male and female fracture patients after menopause. MSCs cultivated with serum from female fracture patients displayed significantly reduced osteogenic differentiation, which was attenuated by Mdk-antibody treatment. In conclusion, our study demonstrated increased Mdk levels after fracture in OVX mice and female fracture patients after menopause. Because Mdk is a negative regulator of bone formation, this might contribute to impaired osteoporotic fracture healing. PMID- 30013012 TI - Data Privacy Protection Based on Micro Aggregation with Dynamic Sensitive Attribute Updating. AB - With the rapid development of information technology, large-scale personal data, including those collected by sensors or IoT devices, is stored in the cloud or data centers. In some cases, the owners of the cloud or data centers need to publish the data. Therefore, how to make the best use of the data in the risk of personal information leakage has become a popular research topic. The most common method of data privacy protection is the data anonymization, which has two main problems: (1) The availability of information after clustering will be reduced, and it cannot be flexibly adjusted. (2) Most methods are static. When the data is released multiple times, it will cause personal privacy leakage. To solve the problems, this article has two contributions. The first one is to propose a new method based on micro-aggregation to complete the process of clustering. In this way, the data availability and the privacy protection can be adjusted flexibly by considering the concepts of distance and information entropy. The second contribution of this article is to propose a dynamic update mechanism that guarantees that the individual privacy is not compromised after the data has been subjected to multiple releases, and minimizes the loss of information. At the end of the article, the algorithm is simulated with real data sets. The availability and advantages of the method are demonstrated by calculating the time, the average information loss and the number of forged data. PMID- 30013013 TI - Morphological Stasis and Proteome Innovation in Cephalochordates. AB - Lancelets, extant representatives of basal chordates, are prototypic examples of evolutionary stasis; they preserved a morphology and body-plan most similar to the fossil chordates from the early Cambrian. Such a low level of morphological evolution is in harmony with a low rate of amino acid substitution; cephalochordate proteins were shown to evolve slower than those of the slowest evolving vertebrate, the elephant shark. Surprisingly, a study comparing the predicted proteomes of Chinese amphioxus, Branchiostoma belcheri and the Florida amphioxus, Branchiostoma floridae has led to the conclusion that the rate of creation of novel domain combinations is orders of magnitude greater in lancelets than in any other Metazoa, a finding that contradicts the notion that high rates of protein innovation are usually associated with major evolutionary innovations. Our earlier studies on a representative sample of proteins have provided evidence suggesting that the differences in the domain architectures of predicted proteins of these two lancelet species reflect annotation errors, rather than true innovations. In the present work, we have extended these studies to include a larger sample of genes and two additional lancelet species, Asymmetron lucayanum and Branchiostoma lanceolatum. These analyses have confirmed that the domain architecture differences of orthologous proteins of the four lancelet species are because of errors of gene prediction, the error rate in the given species being inversely related to the quality of the transcriptome dataset that was used to aid gene prediction. PMID- 30013014 TI - Effect of Environmental Enrichment and Herbal Compounds-Supplemented Diet on Pig Carcass, Meat Quality Traits, and Consumers' Acceptability and Preference. AB - Animal welfare can be considered an ethical attribute of product quality, but consumers should appreciate its added value. The aim of this study was to evaluate consumer's acceptability, preference, and the meat and carcass quality of pigs reared with two stress-reducing strategies: supplementation of an herbal compound (HC) containing Valeriana officinalis and Passiflora incarnata, and environmental enrichment (EE) by the provision of hemp ropes, sawdust, and rubber balls. A total of 56 pigs were divided in four treatments in two pens of seven pigs per treatment (2 * 2 factorial design). Meat and carcass quality were evaluated. Consumer's acceptability and preference were analysed with a sensory test and a conjoint analysis in 110 consumers. Before slaughter, control pigs (no EE and no HC) presented lower live weight compared with other treatments (p = 0.0009). Although acceptance was the same for all of the treatments, consumers preferred systems aiming to increase pig welfare. The most important factor was production system, with a preference for those improving welfare, followed by feeding system, with a preference for those with natural herbs supplementation. Although price was the least important factor, a segment of consumers showed a clear preference for lower prices. These results suggest that welfare improvements could be appreciated by particular consumer segments. PMID- 30013015 TI - RFAmyloid: A Web Server for Predicting Amyloid Proteins. AB - Amyloid is an insoluble fibrous protein and its mis-aggregation can lead to some diseases, such as Alzheimer's disease and Creutzfeldt-Jakob's disease. Therefore, the identification of amyloid is essential for the discovery and understanding of disease. We established a novel predictor called RFAmy based on random forest to identify amyloid, and it employed SVMProt 188-D feature extraction method based on protein composition and physicochemical properties and pse-in-one feature extraction method based on amino acid composition, autocorrelation pseudo acid composition, profile-based features and predicted structures features. In the ten fold cross-validation test, RFAmy's overall accuracy was 89.19% and F-measure was 0.891. Results were obtained by comparison experiments with other feature, classifiers, and existing methods. This shows the effectiveness of RFAmy in predicting amyloid protein. The RFAmy proposed in this paper can be accessed through the URL http://server.malab.cn/RFAmyloid/. PMID- 30013017 TI - Constrained Multi-Sensor Control Using a Multi-Target MSE Bound and a delta-GLMB Filter. AB - The existing multi-sensor control algorithms for multi-target tracking (MTT) within the random finite set (RFS) framework are all based on the distributed processing architecture, so the rule of generalized covariance intersection (GCI) has to be used to obtain the multi-sensor posterior density. However, there has still been no reliable basis for setting the normalized fusion weight of each sensor in GCI until now. Therefore, to avoid the GCI rule, the paper proposes a new constrained multi-sensor control algorithm based on the centralized processing architecture. A multi-target mean-square error (MSE) bound defined in our paper is served as cost function and the multi-sensor control commands are just the solutions that minimize the bound. In order to derive the bound by using the generalized information inequality to RFS observation, the error between state set and its estimation is measured by the second-order optimal sub-pattern assignment metric while the multi-target Bayes recursion is performed by using a delta-generalized labeled multi-Bernoulli filter. An additional benefit of our method is that the proposed bound can provide an online indication of the achievable limit for MTT precision after the sensor control. Two suboptimal algorithms, which are mixed penalty function (MPF) method and complex method, are used to reduce the computation cost of solving the constrained optimization problem. Simulation results show that for the constrained multi-sensor control system with different observation performance, our method significantly outperforms the GCI-based Cauchy-Schwarz divergence method in MTT precision. Besides, when the number of sensors is relatively large, the computation time of the MPF and complex methods is much shorter than that of the exhaustive search method at the expense of completely acceptable loss of tracking accuracy. PMID- 30013016 TI - Genome Mining of Non-Conventional Yeasts: Search and Analysis of MAL Clusters and Proteins. AB - Genomic clustering of functionally related genes is rare in yeasts and other eukaryotes with only few examples available. Here, we summarize our data on a nontelomeric MAL cluster of a non-conventional methylotrophic yeast Ogataea (Hansenula) polymorpha containing genes for alpha-glucosidase MAL1, alpha glucoside permease MAL2 and two hypothetical transcriptional activators. Using genome mining, we detected MAL clusters of varied number, position and composition in many other maltose-assimilating non-conventional yeasts from different phylogenetic groups. The highest number of MAL clusters was detected in Lipomyces starkeyi while no MAL clusters were found in Schizosaccharomyces pombe and Blastobotrys adeninivorans. Phylograms of alpha-glucosidases and alpha glucoside transporters of yeasts agreed with phylogenesis of the respective yeast species. Substrate specificity of unstudied alpha-glucosidases was predicted from protein sequence analysis. Specific activities of Scheffersomycesstipitis alpha glucosidases MAL7, MAL8, and MAL9 heterologously expressed in Escherichia coli confirmed the correctness of the prediction-these proteins were verified promiscuous maltase-isomaltases. alpha-Glucosidases of earlier diverged yeasts L. starkeyi, B. adeninivorans and S. pombe showed sequence relatedness with alpha glucosidases of filamentous fungi and bacilli. PMID- 30013018 TI - A Multi-Parameter Perturbation Solution for Functionally Graded Piezoelectric Cantilever Beams under Combined Loads. AB - In this study, we use a multi-parameter perturbation method to solve the problem of a functionally graded piezoelectric cantilever beam under combined loads, in which three piezoelectric coefficients are selected as the perturbation parameters. First, we derive the two basic equations concerning the Airy stress function and electric potential function. By expanding the unknown Airy stress function and electric potential function with respect to three perturbation parameters, the two basic equations were decoupled, thus obtaining the corresponding multi-parameter perturbation solution under boundary conditions. From the solution obtained, we can see clearly how the piezoelectric effects influence the behavior of the functionally graded piezoelectric cantilever beam. Based on a numerical example, the variations of the elastic stresses and displacements as well as the electric displacements of the cantilever beam under different gradient exponents were shown. The results indicate that if the pure functionally graded cantilever beam without a piezoelectric effect is regarded as an unperturbed system, the functionally graded piezoelectric cantilever beam can be looked upon as a perturbed system, thus opening the possibilities for perturbation solving. Besides, the proposed multi-parameter perturbation method provides a new idea for solving similar nonlinear differential equations. PMID- 30013019 TI - Mitochondrial HTRA2 Plays a Positive, Protective Role in Dictyostelium discoideum but Is Cytotoxic When Overexpressed. AB - HTRA2 is a mitochondrial protein, mutations in which are associated with autosomal dominant late-onset Parkinson's disease (PD). The mechanisms by which HTRA2 mutations result in PD are poorly understood. HTRA2 is proposed to play a proteolytic role in protein quality control and homeostasis in the mitochondrial intermembrane space. Its loss has been reported to result in accumulation of unfolded and misfolded proteins. However, in at least one case, PD-associated HTRA2 mutation can cause its hyperphosphorylation, possibly resulting in protease hyperactivity. The consequences of overactive mitochondrial HTRA2 are not clear. Dictyostelium discoideum provides a well-established model for studying mitochondrial dysfunction, such as has been implicated in the pathology of PD. We identified a single homologue of human HTRA2 encoded in the Dictyostelium discoideum genome and showed that it is localized to the mitochondria where it plays a cytoprotective role. Knockdown of HTRA2 expression caused defective morphogenesis in the multicellular phases of the Dictyostelium life cycle. In vegetative cells, it did not impair mitochondrial respiration but nonetheless caused slow growth (particularly when the cells were utilizing a bacterial food source), unaccompanied by significant defects in the requisite endocytic pathways. Despite its protective roles, we could not ectopically overexpress wild type HTRA2, suggesting that mitochondrial HTRA2 hyperactivity is lethal. This toxicity was abolished by replacing the essential catalytic serine S300 with alanine to ablate serine protease activity. Overexpression of protease-dead HTRA2 phenocopied the effects of knockdown, suggesting that the mutant protein competitively inhibits interactions between wild type HTRA2 and its binding partners. Our results show that cytopathological dysfunction can be caused either by too little or too much HTRA2 activity in the mitochondria and suggest that either could be a cause of PD. PMID- 30013020 TI - Possible Drug-nutraceutical Interaction leading to Unexpected Sequelae after Inguinal Hernia Repair. AB - BACKGROUND Nutraceutical formulations are an area in which physicians should be increasingly aware of their side effects. This case study shows the adverse effects that ginkgo biloba can have when combined with tadalafil following an inguinal hernia repair. CASE REPORT A 74-year-old male presented for repair of a recurrent inguinal hernia and for which the procedure was performed without complication. Upon follow-up, it was noted that he had significant ecchymosis not only in the inguinal region but in the ventral aspect of his penis. Upon further questioning, he reported that he had been taking ginkgo biloba that was stopped 5 days prior to the operation and restarted postoperative day 1. This, combined with tadalafil, was thought to be the reason for the unexpected induration and ecchymosis at the shaft of the penis. After discontinuing both medications, the ecchymosis and induration did resolve. CONCLUSIONS While ecchymosis and induration are expected in the inguinal region, the appearance of significant ecchymosis and induration down the shaft of the penis was unexpected in this case, and therefore we thought it could be due to nutraceutical use of ginkgo biloba combined with tadalafil, which were started postoperatively. PMID- 30013021 TI - Graft Regeneration and Functional Recovery in Patients with Early Allograft Dysfunction After Living-Donor Liver Transplantation. AB - BACKGROUND Successful graft regeneration is important in living-donor liver transplantation (LDLT) because partial liver grafts are used. Early allograft dysfunction (EAD) is an intermediate outcome that affects the long-term postoperative course in liver transplantation. The aim of the present study was to investigate liver graft regeneration under EAD development in LDLT. MATERIAL AND METHODS The data of 226 patients who underwent LDLT from September 2010 to July 2014 were retrospectively analyzed. The patients were classified into 2 groups: one with and one without EAD. Graft regeneration, functional recovery, and long-term patient survival were compared between the 2 groups. RESULTS The grafts grew more vigorously in the EAD group than in the non-EAD group, as evidenced by the larger absolute (ALV) and relative liver volumes (RLV) of the former on postoperative days (POD) 7 and 21. The median (interquartile range) RLVs of the non-EAD group versus the EAD group were as follows: 55.2 (47.9-65.8) vs. 53.7 (46.6-64.5)% preoperatively, p>0.05; 76.1 (66.9-85.7) vs. 86.7 (73.9 96.8)% on POD 7, p<0.01; 79.6 (69.3-91.2) vs. 93.7 (79.6-101.6)%, p<0.01 on POD 21. In the early postoperative period, hepatic function, measured as total bilirubin and international normalized ratio, was higher in the EAD group; however, after EAD development, graft function recovered in these patients. In the follow-up period, overall patient survival was comparable between the 2 groups. CONCLUSIONS The liver grafts of EAD patients steadily regenerated, such that the development of EAD did not affect long-term patient survival after LDLT. PMID- 30013022 TI - Dexmedetomidine Protects Against Traumatic Brain Injury-Induced Acute Lung Injury in Mice. AB - BACKGROUND Traumatic brain injury (TBI) leads to acute lung injury (ALI), in which the inflammatory response plays an important role in its pathophysiology. Recent studies suggest that dexmedetomidine (Dex) plays a protective role in acute inflammatory diseases. However, whether Dex has a protective effect on TBI induced ALI is not clear. The aim of this study was to investigate the effect of Dex on TBI-induced ALI in mice. MATERIAL AND METHODS Mice were randomly divided into 5 groups: 1) sham group; 2) TBI group; 3) TBI+Dex group; 4) TBI+atipamezole (Atip) group; and 5) TBI+Dex+Atip group. Dex (50 MUg/kg) was intraperitoneal injected immediately after TBI. The alpha2 adrenergic antagonist Atip (250 MUg/kg) was intraperitoneal injected 15 minutes prior to Dex treatment. Then 24 hours later, the protein concentration in the bronchoalveolar lavage fluid (BALF), lung wet to dry weight ratio, hematoxylin and eosin (H&E) staining of lungs, the level of high-mobility group box protein 1(HMGB1) in serum, and the receptor for advanced glycation end products (RAGE) expression in lung were detected. RESULTS Dex ameliorated the score of lung histological examination, as well as the severity of pulmonary edema and permeability. Moreover, Dex was observed to significantly suppress the expression of HMGBI and RAGE. However, the protective effects of Dex were partially reversed by the administration of Atip. CONCLUSIONS Dex may protect against TBI-induced ALI via the HMGB1-RAGE signal pathway, and this protective effect is partly dependent on its alpha2 adrenoceptor agonist action. PMID- 30013023 TI - Correction: Deficiency of pigment epithelium-derived factor in nasopharyngeal carcinoma cells triggers the epithelial-mesenchymal transition and metastasis. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.Correction to: Cell Death Dis. 5, e1484 (2014); https://doi.org/10.1038/cddis.2014.408 ; published online 23 October 2014. PMID- 30013025 TI - Correction Alternative mechanisms of miR-34a regulation in cancer. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30013024 TI - Differential cell-intrinsic regulations of germinal center B and T cells by miR 146a and miR-146b. AB - Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a controls GC responses by targeting multiple CD40 signaling pathway components in B cells; by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity. PMID- 30013026 TI - Molecular Dynamics of Lithium Ion Transport in a Model Solid Electrolyte Interphase. AB - Li+ transport within a solid electrolyte interphase (SEI) in lithium ion batteries has challenged molecular dynamics (MD) studies due to limited compositional control of that layer. In recent years, experiments and ab initio simulations have identified dilithium ethylene dicarbonate (Li2EDC) as the dominant component of SEI layers. Here, we adopt a parameterized, non-polarizable MD force field for Li2EDC to study transport characteristics of Li+ in this model SEI layer at moderate temperatures over long times. The observed correlations are consistent with recent MD results using a polarizable force field, suggesting that this non-polarizable model is effective for our purposes of investigating Li+ dynamics. Mean-squared displacements distinguish three distinct Li+ transport regimes in EDC - ballistic, trapping, and diffusive. Compared to liquid ethylene carbonate (EC), the nanosecond trapping times in EDC are significantly longer and naturally decrease at higher temperatures. New materials developed for fast charging Li-ion batteries should have a smaller trapping region. The analyses implemented in this paper can be used for testing transport of Li+ ion in novel battery materials. Non-Gaussian features of van Hove self -correlation functions for Li+ in EDC, along with the mean-squared displacements, are consistent in describing EDC as a glassy material compared with liquid EC. Vibrational modes of Li+ ion, identified by MD, characterize the trapping and are further validated by electronic structure calculations. Some of this work appeared in an extended abstract and has been reproduced with permission from ECS Transactions, 77, 1155 1162 (2017). PMID- 30013027 TI - Mechanically tunable conductive interpenetrating network hydrogels that mimic the elastic moduli of biological tissue. AB - Conductive and stretchable materials that match the elastic moduli of biological tissue (0.5-500 kPa) are desired for enhanced interfacial and mechanical stability. Compared with inorganic and dry polymeric conductors, hydrogels made with conducting polymers are promising soft electrode materials due to their high water content. Nevertheless, most conducting polymer-based hydrogels sacrifice electronic performance to obtain useful mechanical properties. Here we report a method that overcomes this limitation using two interpenetrating hydrogel networks, one of which is formed by the gelation of the conducting polymer PEDOT:PSS. Due to the connectivity of the PEDOT:PSS network, conductivities up to 23 S m-1 are achieved, a record for stretchable PEDOT:PSS-based hydrogels. Meanwhile, the low concentration of PEDOT:PSS enables orthogonal control over the composite mechanical properties using a secondary polymer network. We demonstrate tunability of the elastic modulus over three biologically relevant orders of magnitude without compromising stretchability ( > 100%) or conductivity ( > 10 S m-1). PMID- 30013028 TI - Low total and free triiodothyronine levels are associated with insulin resistance in non-diabetic individuals. AB - This study examined associations of thyroid hormone levels and insulin resistance (IR) in non-diabetic individuals. Using a cross-sectional design, 2007-2008 data from the National Health and Nutrition Examination Survey (NHANES) were analyzed. NHANES participants >=20 years of age with complete data of interest were included. The homeostatic model assessment (HOMA) was used to quantify IR, and treated as a continuous variable. Self-reported diabetes or a fasting glucose >=7 mmol/L were used as criteria to exclude diabetic subjects. Race, liver function, obesity, hypertension, dyslipidemia, smoking, physical activity, vigorous recreational activity, 2-hour glucose, hemoglobin A1C (HbA1C), high-density lipoprotein, triglyceride, vitamin D and C-reactive protein were covariates significantly associated with HOMA-IR. A total of 1,560 non-diabetic subjects were included in the analysis. When adjusted for all factors significant in the univariate analysis (race, liver function, obesity, hypertension, dyslipidemia, smoking, physical activity, vigorous recreational activity, 2-hour glucose, HbA1C, high-density lipoprotein, triglyceride, vitamin D, and CRP) low total triiodothyronine (TT3) and low free T3 (FT3) were significantly associated with decreased HOMA-IR (adjusted coefficient = -0.486, 95% confidence interval [CI]: 0.936, -0.036; adjusted coefficient = -1.151, 95% CI: -1.952, -0.350, respectively). Insulin resistance is associated with low thyroid hormone levels in non-diabetic individuals. PMID- 30013029 TI - Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission. AB - Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response. PMID- 30013030 TI - Unique subgingival microbiota associated with periodontitis in cirrhosis patients. AB - Liver cirrhosis is a severe disease with major impact on the overall health of the patient including poor oral health. Lately, there has been increasing focus on oral diseases as cirrhosis-related complications due to the potential impact on systemic health and ultimately mortality. Periodontitis is one of the most common oral diseases in cirrhosis patients. However, no studies have investigated the composition of the subgingival microbiome in patients suffering from periodontitis and liver cirrhosis. We analysed the subgingival microbiome in 21 patients with periodontitis and cirrhosis using long-reads Illumina sequencing. The subgingival microbiota was dominated by bacteria belonging to the Firmicutes phylum and to a lesser extend the Actinobacteria and Bacteroidetes phyla. Bacteria usually considered periodontal pathogens, like Porhyromonas ginigivalis, Tannerella forsythia, Treponema denticola, generally showed low abundancy. Comparing the microbiota in our patients with that of periodontitis patients and healthy controls of three other studies revealed that the periodontitis associated subgingival microbiota in cirrhosis patients is composed of a unique microbiota of bacteria not normally associated with periodontitis. We hypothesise that periodontitis in cirrhosis patients is a consequence of dysbiosis due to a compromised immune system that renders commensal bacteria pathogenic. PMID- 30013032 TI - CircRNAFisher: a systematic computational approach for de novo circular RNA identification. AB - Circular RNAs (circRNAs) are emerging species of mRNA splicing products with largely unknown functions. Although several computational pipelines for circRNA identification have been developed, these methods strictly rely on uniquely mapped reads overlapping back-splice junctions (BSJs) and lack approaches to model the statistical significance of the identified circRNAs. Here, we reported a systematic computational approach to identify circRNAs by simultaneously utilizing BSJ overlapping reads and discordant BSJ spanning reads to identify circRNAs. Moreover, we developed a novel procedure to estimate the P-values of the identified circRNAs. A computational cross-validation and experimental validations demonstrated that our method performed favorably compared to existing circRNA detection tools. We created a standalone tool, CircRNAFisher, to implement the method, which might be valuable to computational and experimental scientists studying circRNAs. PMID- 30013033 TI - EGFR-targeting, beta-defensin-tailored fusion protein exhibits high therapeutic efficacy against EGFR-expressed human carcinoma via mitochondria-mediated apoptosis. AB - Defensins play an essential role in innate immunity. In this study, a novel recombinant beta-defensin that targets the epidermal growth factor receptor (EGFR) was designed and prepared. The EGFR-targeting beta-defensin consists of an EGF-derived oligopeptide (Ec), a beta-defensin-1 peptide (hBD1) and a lidamycin derived apoprotein (LDP), which serves as the "scaffold" for the fusion protein (Ec-LDP-hBD1). Ec-LDP-hBD1 effectively bound to EGFR highly expressed human epidermoid carcinoma A431 cells. The cytotoxicity of Ec-LDP-hBD1 to EGFR highly expressed A431 cells was more potent than that to EGFR low-expressed human lung carcinoma A549 and H460 cells (the IC50 values in A431, A549, and H460 cells were 1.8 +/- 0.55, 11.9 +/- 0.51, and 5.19 +/- 1.21 MUmol/L, respectively); in addition, the cytotoxicity of Ec-LDP-hBD1 was much stronger than that of Ec-LDP and hBD1. Moreover, Ec-LDP-hBD1 suppressed cancer cell proliferation and induced mitochondria-mediated apoptosis. Its in vivo anticancer action was evaluated in athymic mice with A431 and H460 xenografts. The mice were administered Ec-LDP hBD1 (5, 10 mg/kg, i.v.) two times with a weekly interval. Administration of Ec LDP-hBD1 markedly inhibited the tumor growth without significant body weight changes. The in vivo imaging further revealed that Ec-LDP-hBD1 had a tumor specific distribution with a clear image of localization. The results demonstrate that the novel recombinant EGFR-targeting beta-defensin Ec-LDP-hBD1 displays both selectivity and enhanced cytotoxicity against relevant cancer cells by inducing mitochondria-mediated apoptosis and exhibits high therapeutic efficacy against the EGFR-expressed carcinoma xenograft. This novel format of beta-defensin, which induces mitochondrial-mediated apoptosis, may play an active role in EGFR targeting cancer therapy. PMID- 30013031 TI - Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. AB - Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) deficient mice develop spontaneous SLE- and Sjogren's-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1-STAT3 complex, deficiency of Act1 (but not Il17ra-, Il17rc-, or Il17rb) results in hyper IL-23- and IL-21 induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjogren's-like diseases in Act1-/- mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL 21 expression, which promotes T-B cell interaction for B cell expansion and antibody production. Moreover, anti-IL-21 ameliorates the SLE- and Sjogren's-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjogren's-like syndrome in patients containing Act1 mutation. PMID- 30013034 TI - Activation of natural killer T cells contributes to triptolide-induced liver injury in mice. AB - Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 MUg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP induced liver injury when their NKT cells were depleted by injection of anti NK1.1 mAb (200 MUg, i.p.) on days -2 and -1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-gamma, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury. PMID- 30013035 TI - Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. AB - Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-alpha, IL-1beta, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 MUM). We further revealed that IAL suppressed LPS-induced NF-kappaB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-kappaB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI. PMID- 30013036 TI - Intestinal Lymphatic Endothelial Cells Produce R-Spondin3. AB - The R-Spondin (R-Spo) family regulates WNT signaling and stimulates the proliferation and differentiation of intestinal stem cells (ISCs). R-Spo plays a critical role in maintaining intestinal homeostasis, but endogenous producers of R-Spo in the intestine remain to be investigated. We found that R-Spo3 was the major R-Spo family member produced in the intestine and it was predominantly produced by CD45-CD90+CD31+ lymphatic endothelial cells (LECs) in the lamina propria of the intestinal mucosa. Transcriptome analysis demonstrated that LECs highly expressed R-Spo receptor, Lgr5, suggesting an autocrine stimulatory loop in LECs. LECs were significantly reduced in number, and their R-Spo3 production was impaired in intestinal graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. The impaired production of R-Spo3 in the intestine may be a novel mechanism of delayed tissue repair and defective mucosal defense in intestinal GVHD. We demonstrate a novel role of intestinal LECs in producing R-Spondin3 to maintain intestinal homeostasis. PMID- 30013038 TI - Correction: Tenovin-6 impairs autophagy by inhibiting autophagic flux. AB - This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly. PMID- 30013037 TI - The AHR represses nucleotide excision repair and apoptosis and contributes to UV induced skin carcinogenesis. AB - Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR-/- mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumorigenic functions in UVB-exposed skin. In fact, AHR-/- mice developed 50% less UVB induced cutaneous squamous cell carcinomas in a chronic photocarcinogenesis study than their AHR+/+ littermates. Taken together, our data reveal that AHR influences DNA damage-dependent responses in UVB-irradiated KC and critically contributes to skin photocarcinogenesis in mice. PMID- 30013039 TI - Identification of RNA-binding protein targets with HyperTRIBE. AB - RNA-binding proteins (RBPs) accompany RNA from birth to death, affecting RNA biogenesis and functions. Identifying RBP-RNA interactions is essential to understanding their complex roles in different cellular processes. However, detecting in vivo RNA targets of RBPs, especially in a small number of discrete cells, has been a technically challenging task. We previously developed a novel technique called TRIBE (targets of RNA-binding proteins identified by editing) to overcome this problem. TRIBE expresses a fusion protein consisting of a queried RBP and the catalytic domain of the RNA-editing enzyme ADAR (adenosine deaminase acting on RNA) (ADARcd), which marks target RNA transcripts by converting adenosine to inosine near the RBP binding sites. These marks can be subsequently identified via high-throughput sequencing. In spite of its usefulness, TRIBE is constrained by a low editing efficiency and editing-sequence bias from the ADARcd. Therefore, we developed HyperTRIBE by incorporating a previously characterized hyperactive mutation, E488Q, into the ADARcd. This strategy increases the editing efficiency and reduces sequence bias, which markedly increases the sensitivity of this technique without sacrificing specificity. HyperTRIBE provides a more powerful strategy for identifying RNA targets of RBPs with an easy experimental and computational protocol at low cost, that can be performed not only in flies, but also in mammals. The HyperTRIBE experimental protocol described below can be carried out in cultured Drosophila S2 cells in 1 week, using tools available in a common molecular biology laboratory; the computational analysis requires 3 more days. PMID- 30013040 TI - Swimming of peritrichous bacteria is enabled by an elastohydrodynamic instability. AB - Peritrichously-flagellated bacteria, such as Escherichia coli, self-propel in fluids by using specialised motors to rotate multiple helical filaments. The rotation of each motor is transmitted to a short flexible segment called the hook which in turn transmits it to a flagellar filament, enabling swimming of the whole cell. Since multiple motors are spatially distributed on the body of the organism, one would expect the propulsive forces from the filaments to push against each other leading to negligible swimming. We use a combination of computations and theory to show that the swimming of peritrichous bacteria is enabled by an elastohydrodynamic bending instability occurring for hooks more flexible than a critical threshold. Using past measurements of hook bending stiffness, we demonstrate how real bacteria are safely on the side of the instability that promotes systematic swimming. PMID- 30013041 TI - Microscale ecology regulates particulate organic matter turnover in model marine microbial communities. AB - The degradation of particulate organic matter in the ocean is a central process in the global carbon cycle, the mode and tempo of which is determined by the bacterial communities that assemble on particle surfaces. Here, we find that the capacity of communities to degrade particles is highly dependent on community composition using a collection of marine bacteria cultured from different stages of succession on chitin microparticles. Different particle degrading taxa display characteristic particle half-lives that differ by ~170 h, comparable to the residence time of particles in the ocean's mixed layer. Particle half-lives are in general longer in multispecies communities, where the growth of obligate cross feeders hinders the ability of degraders to colonize and consume particles in a dose dependent manner. Our results suggest that the microscale community ecology of bacteria on particle surfaces can impact the rates of carbon turnover in the ocean. PMID- 30013042 TI - Enhanced visible light photodegradation activity of RhB/MB from aqueous solution using nanosized novel Fe-Cd co-modified ZnO. AB - A series of novel Fe-Cd co-doped ZnO nanoparticle based photocatalysts are successfully synthesized by sol-gel route and characterized using scanning electron microscopy (SEM), energy dispersive X-ray emission (EDX), transmission electron microscopy (TEM), X-ray diffraction (XRD), UV-Vis spectroscopy, X-ray photoelectron spectroscopy (XPS), and Brunauer-Emmett-Teller (BET) techniques. The photocatalytic activity of ZnO nanoparticles doped with various atomic weight fraction of Fe and Cd has been investigated under visible light irradiation using the Methylene Blue and Rhodamine B dye in aqueous solution. The FeCd (2%):ZnO (ZFC-1) exhibit the highest photocatalytic activity in terms of rate constant as KMB = 0.01153 min-1 and KRhB = 0.00916 min-1). Further, the re-usability of the ZFC-1 photocatalyst is studied which confirms that it can be reused up to five times with nearly negligible loss of the photocatalytic efficiency. Moreover, the role of photoactive species investigated using a radical scavenger technique. The present investigations show that the doping concentration plays significant role in photocatalytic performance. The visible light absorption shown by Fe-Cd co doped ZnO nanoparticles is much higher than that of undoped body probably due to co-doping, and the charge carrier recombination is decreased effectively which yields a higher photocatalytic performance. The mechanism for the enhancement of photocatalytic activity under visible light irradiation is also proposed. PMID- 30013043 TI - Tescalcin/c-Src/IGF1Rbeta-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1. AB - Tescalcin (TESC; also known as calcineurin B homologous protein 3, CHP3) has recently reported as a regulator of cancer progression. Here, we showed that the elevation of TESC in non-small cell lung cancer (NSCLC) intensifies epithelial mesenchymal transition (EMT) and cancer stem cell (CSC) properties, consequently enhancing the cellular resistance to gamma-radiation. TESC expression and the phosphorylation (consequent activation) of signal transducer and activator of transcription 3 (STAT3) were upregulated in CSC-like ALDH1high cells than in ALDH1low cells sorted from A549 NSCLC cells. Knockdown of TESC suppressed CSC like properties as well as STAT3 activation through inhibition of insulin-like growth factor 1 receptor (IGF1R), a major signaling pathway of lung cancer stem cells. TESC activated IGF1R by the direct recruitment of proto-oncogene tyrosine kinase c-Src (c-Src) to IGF1Rbeta complex. Treatment of IGF1R inhibitor, AG1024, also suppressed c-Src activation, implicating that TESC mediates the mutual activation of c-Src and IGF1R. STAT3 activation by TESC/c-Src/IGF1R signaling pathway subsequently upregulated ALDH1 expression, which enhanced EMT-associated CSC-like properties. Chromatin immunoprecipitation and luciferase assay demonstrated that STAT3 is a potential transcription activator of ALDH1 isozymes. Ultimately, targeting TESC can be a potential strategy to overcome therapeutic resistance in NSCLC caused by augmented EMT and self-renewal capacity. PMID- 30013044 TI - A synthetic-diploid benchmark for accurate variant-calling evaluation. AB - Existing benchmark datasets for use in evaluating variant-calling accuracy are constructed from a consensus of known short-variant callers, and they are thus biased toward easy regions that are accessible by these algorithms. We derived a new benchmark dataset from the de novo PacBio assemblies of two fully homozygous human cell lines, which provides a relatively more accurate and less biased estimate of small-variant-calling error rates in a realistic context. PMID- 30013046 TI - High-precision automated reconstruction of neurons with flood-filling networks. AB - Reconstruction of neural circuits from volume electron microscopy data requires the tracing of cells in their entirety, including all their neurites. Automated approaches have been developed for tracing, but their error rates are too high to generate reliable circuit diagrams without extensive human proofreading. We present flood-filling networks, a method for automated segmentation that, similar to most previous efforts, uses convolutional neural networks, but contains in addition a recurrent pathway that allows the iterative optimization and extension of individual neuronal processes. We used flood-filling networks to trace neurons in a dataset obtained by serial block-face electron microscopy of a zebra finch brain. Using our method, we achieved a mean error-free neurite path length of 1.1 mm, and we observed only four mergers in a test set with a path length of 97 mm. The performance of flood-filling networks was an order of magnitude better than that of previous approaches applied to this dataset, although with substantially increased computational costs. PMID- 30013045 TI - An enhanced CRISPR repressor for targeted mammalian gene regulation. AB - The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits. PMID- 30013048 TI - Strelka2: fast and accurate calling of germline and somatic variants. AB - We describe Strelka2 ( https://github.com/Illumina/strelka ), an open-source small-variant-calling method for research and clinical germline and somatic sequencing applications. Strelka2 introduces a novel mixture-model-based estimation of insertion/deletion error parameters from each sample, an efficient tiered haplotype-modeling strategy, and a normal sample contamination model to improve liquid tumor analysis. For both germline and somatic calling, Strelka2 substantially outperformed the current leading tools in terms of both variant calling accuracy and computing cost. PMID- 30013047 TI - Active PSF shaping and adaptive optics enable volumetric localization microscopy through brain sections. AB - Application of single-molecule switching nanoscopy (SMSN) beyond the coverslip surface poses substantial challenges due to sample-induced aberrations that distort and blur single-molecule emission patterns. We combined active shaping of point spread functions and efficient adaptive optics to enable robust 3D-SMSN imaging within tissues. This development allowed us to image through 30-MUm-thick brain sections to visualize and reconstruct the morphology and the nanoscale details of amyloid-beta filaments in a mouse model of Alzheimer's disease. PMID- 30013049 TI - Arylic C-X Bond Activation by Palladium Catalysts: Activation Strain Analyses of Reactivity Trends. AB - We have quantum chemically explored arylic carbon-substituent bond activation via oxidative insertion of a palladium catalyst in C6H5X + PdLn model systems (X = H, Cl, CH3; Ln = no ligand, PH3, (PH3)2, PH2C2H4PH2) using relativistic density functional theory at ZORA-BLYP/TZ2P. Besides exploring reactivity trends and comparing them to aliphatic C-X activation, we aim at uncovering the physical factors behind the activity and selectivity. Our results show that barriers for arylic C-X activation are lower than those for the corresponding aliphatic C-X bonds. However, trends along bonds or upon variation of ligands are similar. Thus, bond activation barriers increase along C-Cl < C-H < C-C and along Pd < Pd(PH3) or Pd(PH2C2H4PH2) < Pd(PH3)2. Activation strain analyses in conjunction with quantitative molecular orbital theory trace these trends to the rigidity and bonding capability of the various C-X bonds, model catalysts, and ligands. PMID- 30013050 TI - Non-viral-mediated suppression of AMIGO3 promotes disinhibited NT3-mediated regeneration of spinal cord dorsal column axons. AB - After injury to the mature central nervous system (CNS), myelin-derived inhibitory ligands bind to the Nogo-66 tripartite receptor complex expressed on axonal growth cones, comprised of LINGO-1 and p75NTR/TROY and induce growth cone collapse through the RhoA pathway. We have also shown that amphoterin-induced gene and open reading frame-3 (AMIGO3) substitutes for LINGO-1 and can signal axon growth cone collapse. Here, we investigated the regeneration of dorsal root ganglion neuron (DRGN) axons/neurites after treatment with a short hairpin RNA (sh) AMIGO3 plasmid delivered with a non-viral in vivo-jetPEI vector, and the pro survival/axogenic neurotrophin (NT) 3 in vitro and in vivo. A bicistronic plasmid, containing both shAMIGO3 and NT3 knocked down >75% of AMIGO3 mRNA in cultured DRGN and significantly overexpressed NT3 production. In vivo, intra-DRG injection of in vivo-jetPEI plasmids containing shAMIGO3/gfp and shAMIGO3/nt3 both knocked down AMIGO3 expression in DRGN and, in combination with NT3 overexpression, promoted DC axon regeneration, recovery of conduction of compound action potentials across the lesion site and improvements in sensory and locomotor function. These findings demonstrate that in vivo-jetPEI is a potential non-viral, translatable DRGN delivery vehicle in vivo and that suppression of AMIGO3 disinhibits the growth of axotomised DRGN enabling NT3 to stimulate the regeneration of their DC axons and enhances functional recovery. PMID- 30013051 TI - Metabolomic Profiles Reveal Potential Factors that Correlate with Lactation Performance in Sow Milk. AB - Sow milk contains necessary nutrients for piglets; however, the relationship between the levels of metabolites in sow milk and lactation performance has not been thoroughly elucidated to date. In this study, we analysed the metabolites in sow milk from Yorkshire sows with high lactation (HL) or low lactation (LL) performance; these categories were assigned based on the weight gain of piglets during the entire lactation period (D1 to D21). The concentration of milk fat in the colostrum tended to be higher in the HL group (P = 0.05), the level of mannitol was significantly lower in the HL group (P < 0.05) and the level of glucuronic acid lactone was significantly higher in the HL group (P < 0.05) compared to those in LL group. In mature milk, the levels of lactose, creatine, glutamine, glutamate, 4-hydroxyproline, alanine, asparagine, and glycine were significantly higher (P < 0.05) in the HL group than those in LL group. The level of fatty acids showed no significant difference between the two groups in both the colostrum and mature milk. This study suggested that lactation performance may be associated with the levels of lactose and several amino acids in sow milk, and these results can be used to develop new feed additives to improve lactation performance in sows. PMID- 30013053 TI - Intermixing and periodic self-assembly of borophene line defects. AB - Two-dimensional (2D) boron (that is, borophene) was recently synthesized following theoretical predictions1-5. Its metallic nature and high in-plane anisotropy combine many of the desirable attributes of graphene6 and monolayer black phosphorus7. As a synthetic 2D material, its structural properties cannot be deduced from bulk boron, which implies that the intrinsic defects of borophene remain unexplored. Here we investigate borophene line defects at the atomic scale with ultrahigh vacuum (UHV) scanning tunnelling microscopy/spectroscopy (STM/STS) and density functional theory (DFT). Under suitable growth conditions, borophene phases that correspond to the v1/6 and v1/5 models are found to intermix and accommodate line defects in each other with structures that match the constituent units of the other phase. These line defects energetically favour spatially periodic self-assembly that gives rise to new borophene phases, which ultimately blurs the distinction between borophene crystals and defects. This phenomenon is unique to borophene as a result of its high in-plane anisotropy and energetically and structurally similar polymorphs. Low-temperature measurements further reveal subtle electronic features that are consistent with a charge density wave (CDW), which are modulated by line defects. This atomic-level understanding is likely to inform ongoing efforts to devise and realize applications based on borophene. PMID- 30013052 TI - Propolis potentiates the effect of cranberry (Vaccinium macrocarpon) against the virulence of uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC), the most prevalent bacteria isolated in urinary tract infections (UTI), is now frequently resistant to antibiotics used to treat this pathology. The antibacterial properties of cranberry and propolis could reduce the frequency of UTIs and thus the use of antibiotics, helping in the fight against the emergence of antibiotic resistance. Transcriptomic profiles of a clinical UPEC strain exposed to cranberry proanthocyanidins alone (190 ug/mL), propolis alone (102.4 ug/mL) and a combination of both were determined. Cranberry alone, but more so cranberry + propolis combined, modified the expression of genes involved in different essential pathways: down-expression of genes involved in adhesion, motility, and biofilm formation, and up-regulation of genes involved in iron metabolism and stress response. Phenotypic assays confirmed the decrease of motility (swarming and swimming) and biofilm formation (early formation and formed biofilm). This study showed for the first time that propolis potentiated the effect of cranberry proanthocyanidins on adhesion, motility, biofilm formation, iron metabolism and stress response of UPEC. Cranberry + propolis treatment could represent an interesting new strategy to prevent recurrent UTI. PMID- 30013054 TI - Structural evolution of titanium dioxide during reduction in high-pressure hydrogen. AB - The excellent photocatalytic properties of titanium oxide (TiO2) under ultraviolet light have long motivated the search for doping strategies capable of extending its photoactivity to the visible part of the spectrum. One approach is high-pressure and high-temperature hydrogenation, which results in reduced 'black TiO2' nanoparticles with a crystalline core and a disordered shell that absorbs visible light. Here we elucidate the formation mechanism and structural features of black TiO2 using first-principles-validated reactive force field molecular dynamics simulations of anatase TiO2 surfaces and nanoparticles at high temperature and under high hydrogen pressures. Simulations reveal that surface oxygen vacancies created upon reaction of H2 with surface oxygen atoms diffuse towards the bulk material but encounter a high barrier for subsurface migration on {001} facets of the nanoparticles, which initiates surface disordering. Besides confirming that the hydrogenated amorphous shell has a key role in the photoactivity of black TiO2, our results provide insight into the properties of the disordered surface layers that are observed on regular anatase nanocrystals under photocatalytic water-splitting conditions. PMID- 30013055 TI - Surface distortion as a unifying concept and descriptor in oxygen reduction reaction electrocatalysis. AB - Tuning the surface structure at the atomic level is of primary importance to simultaneously meet the electrocatalytic performance and stability criteria required for the development of low-temperature proton-exchange membrane fuel cells (PEMFCs). However, transposing the knowledge acquired on extended, model surfaces to practical nanomaterials remains highly challenging. Here, we propose 'surface distortion' as a novel structural descriptor, which is able to reconciliate and unify seemingly opposing notions and contradictory experimental observations in regards to the electrocatalytic oxygen reduction reaction (ORR) reactivity. Beyond its unifying character, we show that surface distortion is pivotal to rationalize the electrocatalytic properties of state-of-the-art of PtNi/C nanocatalysts with distinct atomic composition, size, shape and degree of surface defectiveness under a simulated PEMFC cathode environment. Our study brings fundamental and practical insights into the role of surface defects in electrocatalysis and highlights strategies to design more durable ORR nanocatalysts. PMID- 30013056 TI - Large anomalous Hall current induced by topological nodal lines in a ferromagnetic van der Waals semimetal. AB - Topological semimetals host electronic structures with several band-contact points or lines and are generally expected to exhibit strong topological responses. Up to now, most work has been limited to non-magnetic materials and the interplay between topology and magnetism in this class of quantum materials has been largely unexplored. Here we utilize theoretical calculations, magnetotransport and angle-resolved photoemission spectroscopy to propose Fe3GeTe2, a van der Waals material, as a candidate ferromagnetic (FM) nodal line semimetal. We find that the spin degree of freedom is fully quenched by the large FM polarization, but the line degeneracy is protected by crystalline symmetries that connect two orbitals in adjacent layers. This orbital-driven nodal line is tunable by spin orientation due to spin-orbit coupling and produces a large Berry curvature, which leads to a large anomalous Hall current, angle and factor. These results demonstrate that FM topological semimetals hold significant potential for spin- and orbital-dependent electronic functionalities. PMID- 30013057 TI - Design rules for minimizing voltage losses in high-efficiency organic solar cells. AB - The open-circuit voltage of organic solar cells is usually lower than the values achieved in inorganic or perovskite photovoltaic devices with comparable bandgaps. Energy losses during charge separation at the donor-acceptor interface and non-radiative recombination are among the main causes of such voltage losses. Here we combine spectroscopic and quantum-chemistry approaches to identify key rules for minimizing voltage losses: (1) a low energy offset between donor and acceptor molecular states and (2) high photoluminescence yield of the low-gap material in the blend. Following these rules, we present a range of existing and new donor-acceptor systems that combine efficient photocurrent generation with electroluminescence yield up to 0.03%, leading to non-radiative voltage losses as small as 0.21 V. This study provides a rationale to explain and further improve the performance of recently demonstrated high-open-circuit-voltage organic solar cells. PMID- 30013060 TI - The evolving interface between synthetic biology and functional metagenomics. AB - Nature is a diverse and rich source of bioactive pathways or novel building blocks for synthetic biology. In this Perspective, we describe the emerging research field in which metagenomes are functionally interrogated using synthetic biology. This approach substantially expands the set of identified biological activities and building blocks. In reviewing this field, we find that its potential for new biological discovery is dramatically increasing. Functional metagenomic mining using genetic circuits has led to the discovery of novel bioactivity such as amidases, NF-kappaB modulators, naphthalene degrading enzymes, cellulases, lipases and transporters. Using these genetic circuits as a template, improvements are made by designing biosensors, such as in vitro-evolved riboswitches and computationally redesigned transcription factors. Thus, powered by the rapidly expanding repertoire of biosensors and streamlined processes for automated genetic circuit design, a greater variety of complex selection circuits can be built, with resulting impacts on drug discovery and industrial biotechnology. PMID- 30013061 TI - Optical control of L-type Ca2+ channels using a diltiazem photoswitch. AB - L-type Ca2+ channels (LTCCs) play a crucial role in excitation-contraction coupling and release of hormones from secretory cells. They are targets of antihypertensive and antiarrhythmic drugs such as diltiazem. Here, we present a photoswitchable diltiazem, FHU-779, which can be used to reversibly block endogenous LTCCs by light. FHU-779 is as potent as diltiazem and can be used to place pancreatic beta-cell function and cardiac activity under optical control. PMID- 30013059 TI - Mechanical architecture and folding of E. coli type 1 pilus domains. AB - Uropathogenic Escherichia coli attach to tissues using pili type 1. Each pilus is composed by thousands of coiled FimA domains followed by the domains of the tip fibrillum, FimF-FimG-FimH. The domains are linked by non-covalent beta-strands that must resist mechanical forces during attachment. Here, we use single molecule force spectroscopy to measure the mechanical contribution of each domain to the stability of the pilus and monitor the oxidative folding mechanism of a single Fim domain assisted by periplasmic FimC and the oxidoreductase DsbA. We demonstrate that pilus domains bear high mechanical stability following a hierarchy by which domains close to the tip are weaker than those close to or at the pilus rod. During folding, this remarkable stability is achieved by the intervention of DsbA that not only forms strategic disulfide bonds but also serves as a chaperone assisting the folding of the domains. PMID- 30013058 TI - In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer. AB - Genetic aberrations driving pro-oncogenic and pro-metastatic activity remain an elusive target in the quest of precision oncology. To identify such drivers, we use an animal model of KRAS-mutant lung adenocarcinoma to perform an in vivo functional screen of 217 genetic aberrations selected from lung cancer genomics datasets. We identify 28 genes whose expression promoted tumor metastasis to the lung in mice. We employ two tools for examining the KRAS-dependence of genes identified from our screen: 1) a human lung cell model containing a regulatable mutant KRAS allele and 2) a lentiviral system permitting co-expression of DNA barcoded cDNAs with Cre recombinase to activate a mutant KRAS allele in the lungs of mice. Mechanistic evaluation of one gene, GATAD2B, illuminates its role as a dual activity gene, promoting both pro-tumorigenic and pro-metastatic activities in KRAS-mutant lung cancer through interaction with c-MYC and hyperactivation of the c-MYC pathway. PMID- 30013062 TI - Facile target validation in an animal model with intracellularly expressed monobodies. AB - Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals. As a genetically encoded reagent, the monobody inhibited proliferation of an MLL-AF9 cell line in vitro, suppressed its leukemogenesis and conferred a survival benefit in an in vivo mouse leukemia model. The capacity of this approach to readily bridge biochemical, structural, cellular characterization and tests in animal models may accelerate discovery and validation of druggable sites. PMID- 30013063 TI - Acetylation blocks DNA damage-induced chromatin ADP-ribosylation. AB - Recent studies report serine ADP-ribosylation on nucleosomes during the DNA damage response. We unveil histone H3 serine 10 as the primary acceptor residue for chromatin ADP-ribosylation and find that specific histone acetylation marks block this activity. Our results provide a molecular explanation for the well documented phenomenon of rapid deacetylation at DNA damage sites and support the combinatorial application of PARP and HDAC inhibitors for the treatment of PARP dependent cancers. PMID- 30013064 TI - Correction: Mechanisms of bystander effects in retinal pigment epithelium cell networks. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30013065 TI - Anterior cingulate cortex and its input to the basolateral amygdala control innate fear response. AB - Prefrontal brain areas are implicated in the control of fear behavior. However, how prefrontal circuits control fear response to innate threat is poorly understood. Here, we show that the anterior cingulate cortex (ACC) and its input to the basolateral nucleus of amygdala (BLA) contribute to innate fear response to a predator odor in mice. Optogenetic inactivation of the ACC enhances freezing response to fox urine without affecting conditioned freezing. Conversely, ACC stimulation robustly inhibits both innate and conditioned freezing. Circuit tracing and slice patch recordings demonstrate a monosynaptic glutamatergic connectivity of ACC-BLA but no or very sparse ACC input to the central amygdala. Finally, our optogenetic manipulations of the ACC-BLA projection suggest its inhibitory control of innate freezing response to predator odors. Together, our results reveal the role of the ACC and its projection to BLA in innate fear response to olfactory threat stimulus. PMID- 30013066 TI - Root exudate metabolites drive plant-soil feedbacks on growth and defense by shaping the rhizosphere microbiota. AB - By changing soil properties, plants can modify their growth environment. Although the soil microbiota is known to play a key role in the resulting plant-soil feedbacks, the proximal mechanisms underlying this phenomenon remain unknown. We found that benzoxazinoids, a class of defensive secondary metabolites that are released by roots of cereals such as wheat and maize, alter root-associated fungal and bacterial communities, decrease plant growth, increase jasmonate signaling and plant defenses, and suppress herbivore performance in the next plant generation. Complementation experiments demonstrate that the benzoxazinoid breakdown product 6-methoxy-benzoxazolin-2-one (MBOA), which accumulates in the soil during the conditioning phase, is both sufficient and necessary to trigger the observed phenotypic changes. Sterilization, fungal and bacterial profiling and complementation experiments reveal that MBOA acts indirectly by altering root associated microbiota. Our results reveal a mechanism by which plants determine the composition of rhizosphere microbiota, plant performance and plant-herbivore interactions of the next generation. PMID- 30013067 TI - A diuranium carbide cluster stabilized inside a C80 fullerene cage. AB - Unsupported non-bridged uranium-carbon double bonds have long been sought after in actinide chemistry as fundamental synthetic targets in the study of actinide ligand multiple bonding. Here we report that, utilizing Ih(7)-C80 fullerenes as nanocontainers, a diuranium carbide cluster, U=C=U, has been encapsulated and stabilized in the form of UCU@Ih(7)-C80. This endohedral fullerene was prepared utilizing the Kratschmer-Huffman arc discharge method, and was then co crystallized with nickel(II) octaethylporphyrin (NiII-OEP) to produce UCU@Ih(7) C80.[NiII-OEP] as single crystals. X-ray diffraction analysis reveals a cage stabilized, carbide-bridged, bent UCU cluster with unexpectedly short uranium carbon distances (2.03 A) indicative of covalent U=C double-bond character. The quantum-chemical results suggest that both U atoms in the UCU unit have formal oxidation state of +5. The structural features of UCU@Ih(7)-C80 and the covalent nature of the U(f1)=C double bonds were further affirmed through various spectroscopic and theoretical analyses. PMID- 30013068 TI - Serotonin concentration enhancers at clinically relevant doses reduce [11C]AZ10419369 binding to the 5-HT1B receptors in the nonhuman primate brain. AB - The serotonin (5-HT) system plays an important role in the pathophysiology and treatment of several major psychiatric disorders. Currently, no suitable positron emission tomography (PET) imaging paradigm is available to assess 5-HT release in the living human brain. [11C]AZ10419369 binds to 5-HT1B receptors and is one of the most 5-HT-sensitive radioligands available. This study applied 5-HT concentration enhancers which can be safely studied in humans, and examined their effect on [11C]AZ10419369 binding at clinically relevant doses, including amphetamine (1 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA; 1 mg/kg) or 5 hydroxy-L-tryptophan (5-HTP; 5 mg/kg). Twenty-six PET measurements (14 for amphetamine, 6 for MDMA and 6 for 5-HTP) using a bolus and constant infusion protocol were performed in four cynomolgus monkeys before or after drug administration. Binding potential (BPND) values were determined with the equilibrium method (integral interval: 63-123 min) using cerebellum as the reference region. BPND values were significantly decreased in several examined brain regions after administration of amphetamine (range: 19-31%), MDMA (16-25%) or 5-HTP (13-31%). Reductions in [11C]AZ10419369 binding were greater in striatum than cortical regions after administration of 5-HTP, while no prominent regional differences were found for amphetamine and MDMA. In conclusion, [11C]AZ10419369 binding is sensitive to changes in 5-HT concentration induced by amphetamine, MDMA or 5-HTP. The robust changes in BPND, following pretreatment drugs administered at clinically relevant doses, indicate that the applied PET imaging paradigms hold promise to be successfully used in future human studies. PMID- 30013069 TI - TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. AB - Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, therefore necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify TMEM106B as a primary robust driver of lung cancer metastasis. Ectopic expression of TMEM106B could significantly promote the synthesis of enlarged vesicular lysosomes that are laden with elevated levels of active cathepsins. In a TFEB-dependent manner, TMEM106B could modulate the expression of lysosomal genes of the coordinated lysosomal expression and regulation (CLEAR) pathway in lung cancer cells and patient samples. We also demonstrate that TMEM106B-induced lysosomes undergo calcium-dependent exocytosis, thereby releasing active lysosomal cathepsins necessary for TMEM106B-mediated cancer cell invasion and metastasis in vivo, which could be therapeutically prevented by pharmacological inhibition of cathepsins. Further, in TCGA LUAD data sets, 19% of patients show elevated expression of TMEM106B, which predicts for poor disease-free and overall survival. PMID- 30013070 TI - Quantitative proteomic characterization of cellular pathways associated with altered insulin sensitivity in skeletal muscle following high-fat diet feeding and exercise training. AB - Regular exercise elicits advantageous metabolic adaptations in skeletal muscle, such as improved insulin sensitivity. However, the underpinning molecular mechanisms and the effect of diet on muscle exercise training benefits are unclear. We therefore characterized the skeletal muscle proteome following exercise training (ET) in mice fed chow or high-fat diet (HFD). ET increased exercise performance, lowered body-weight, decreased fat mass and improved muscle insulin action in chow- and HFD-fed mice. At the molecular level, ET regulated 170 muscle proteins in chow-fed mice, but only 29 proteins in HFD-fed mice. HFD per se altered 56 proteins, most of which were regulated in a similar direction by ET. To identify proteins that might have particular health-related bearing on skeletal muscle metabolism, we filtered for differentially regulated proteins in response to ET and HFD. This yielded 15 proteins, including the major urinary protein 1 (MUP1), which was the protein most decreased after HFD, but increased with ET. The ET-induced Mup1 expression was absent in mouse muscle lacking functional AMPK. MUP1 also potentiated insulin-stimulated GLUT4 translocation in cultured muscle cells. Collectively, we provide a resource of ET-regulated proteins in insulin-sensitive and insulin-resistant skeletal muscle. The identification of MUP1 as a diet-, ET- and AMPK-regulated skeletal muscle protein that improves insulin sensitivity in muscle cells demonstrates the usefulness of these data. PMID- 30013072 TI - Bioprospection of Basidiomycetes and molecular phylogenetic analysis using internal transcribed spacer (ITS) and 5.8S rRNA gene sequence. AB - Macrofungi belonging to the phylum Basidiomycota are mostly used as medicinal mushrooms in many countries. In the present study, hundred basidiocarp of macrofungi were collected from Tamilnadu during rainy season. The basidiocarp was found in association with root/trunk of living trees, wood log and decayed matter. Among the hundred basidiocarp, 49 were grown into axenic cultures. Notable variations in the macroscopic characteristics of the basidiome and culture morphology were observed. To study the genetic diversity, the molecular taxonomy of the isolates was carried out using internal transcribed spacer (ITS) and 5.8S rRNA gene sequence marker. Thirty-two strains belonging to the order Polyporales, Hymenochataeles and Russuales under the division Basidiomycota were classified based on phylogeny analysis. This study provides first evidence for the occurrence of species Fulvifomes fastuosus (LDCMY39 and LDCMY43) and Ganoderma wiiroense (LDCMY02, LDCMY08, LDCMY11, LDCMY17 and LDCMY19) from southern India. Molecular evidence for the existence of Phellinus badius was given for the first time as well. These data enhance our understanding on the diversity of macrofungi in India, which could be further exploited for biomedical applications. PMID- 30013071 TI - Fe-N system at high pressure reveals a compound featuring polymeric nitrogen chains. AB - Poly-nitrogen compounds have been considered as potential high energy density materials for a long time due to the large number of energetic N-N or N=N bonds. In most cases high nitrogen content and stability at ambient conditions are mutually exclusive, thereby making the synthesis of such materials challenging. One way to stabilize such compounds is the application of high pressure. Here, through a direct reaction between Fe and N2 in a laser-heated diamond anvil cell, we synthesize three ironnitrogen compounds Fe3N2, FeN2 and FeN4. Their crystal structures are revealed by single-crystal synchrotron X-ray diffraction. Fe3N2, synthesized at 50 GPa, is isostructural to chromium carbide Cr3C2. FeN2 has a marcasite structure type and features covalently bonded dinitrogen units in its crystal structure. FeN4, synthesized at 106 GPa, features polymeric nitrogen chains of [N42-]n units. Based on results of structural studies and theoretical analysis, [N42-]n units in this compound reveal catena-poly[tetraz-1-ene-1,4 diyl] anions. PMID- 30013073 TI - Correction: Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30013075 TI - The acoustic phase resonances and surface waves supported by a compound rigid grating. AB - We study the radiative and bound acoustic modes supported by a rigid grating formed of three same-depth, narrow grooves per unit cell. One of the grooves is twice the width of the other two, forming a 'compound' grating. The structure supports so-called 'phase' resonances where the phase difference of the pressure field between the grooves on resonance varies by multiples of pi. We explore the dispersion of these modes experimentally by monitoring the specularly reflected signal as a function of the angle of incidence. In addition, by near-field excitation, the dispersion of the non-radiative surface modes has been characterised. Our results are compared with the predictions of a finite element method model. PMID- 30013076 TI - Correction: Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30013074 TI - Gabrb2-knockout mice displayed schizophrenia-like and comorbid phenotypes with interneuron-astrocyte-microglia dysregulation. AB - Intronic polymorphisms of the GABAA receptor beta2 subunit gene (GABRB2) under adaptive evolution were associated with schizophrenia and reduced expression, especially of the long isoform which differs in electrophysiological properties from the short isoform. The present study was directed to examining the gene dosage effects of Gabrb2 in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes with respect to possible schizophrenia-like and comorbid phenotypes. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition (PPI) deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol (PTZ)-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the behavioral phenotypes showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, and the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin (PV)-positive interneuron dystrophy, astrocyte dystrophy, and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation indicated by microglial activation was accompanied by elevated brain levels of oxidative stress marker malondialdehyde (MDA) and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). These extensive schizophrenia-like and comorbid phenotypes brought about by Gabrb2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, support a pivotal role of GABRB2 in schizophrenia etiology. PMID- 30013079 TI - A narcotic-narcoleptic link. PMID- 30013077 TI - Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment. AB - Enhancement of hematopoietic stem cell (HSC) homing and engraftment is clinically critical, especially for cord blood (CB) hematopoietic cell transplantation. Here we report that specific HDAC5 inhibition highly upregulates CXCR4 surface expression in human CB HSCs and progenitor cells (HPCs). This results in enhanced SDF-1/CXCR4-mediated chemotaxis and increased homing to the bone marrow environment, with elevated SCID-repopulating cell (SRC) frequency and enhanced long-term and secondary engraftment in NSG mice. HDAC5 inhibition increases acetylated p65 levels in the nucleus, which is important for CXCR4 transcription. Inhibition of nuclear factor-kappaB (NF-kappaB) signaling suppresses HDAC5 mediated CXCR4 upregulation, enhanced HSC homing, and engraftment. Furthermore, activation of the NF-kappaB signaling pathway via TNFalpha also results in significantly increased CXCR4 surface expression, enhanced HSC homing, and engraftment. These results demonstrate a previously unknown negative epigenetic regulation of HSC homing and engraftment by HDAC5, and allow for a new and simple translational strategy to enhance HSC transplantation. PMID- 30013080 TI - Bringing back early memories. PMID- 30013078 TI - Hippocampal projections to the anterior olfactory nucleus differentially convey spatiotemporal information during episodic odour memory. AB - The hippocampus is essential for representing spatiotemporal context and establishing its association with the sensory details of daily life to form episodic memories. The olfactory cortex in particular shares exclusive anatomical connections with the hippocampus as a result of their common evolutionary history. Here we selectively inhibit hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually cued odour recall. We find that spatial odour memory and temporal odour memory are independently impaired following inhibition of distinct, topographically organized hippocampal-AON pathways. Our results not only reveal a longstanding unknown function for the AON but offer new mechanistic insights regarding the representation of odours in episodic memory. PMID- 30013081 TI - ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage. AB - Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 localization to the lesion through MDC1 following DNA damage. ZNF506, in turn, recruits the protein phosphatase EYA, resulting in dephosphorylation of H2AX at Y142, which further facilitates the recruitment of MDC1 and other downstream repair factors. Thus, ZNF506 regulates the early dynamic signaling in the DNA damage response (DDR) pathway and controls progressive downstream signal amplification. Cells lacking ZNF506 or harboring mutations found in cancer patient samples are more sensitive to radiation, offering a potential new therapeutic option for cancers with mutations in this pathway. Taken together, these results demonstrate how the DDR pathway is orchestrated by ZNF506 to maintain genomic integrity. PMID- 30013082 TI - A spike-modified Middle East respiratory syndrome coronavirus (MERS-CoV) infectious clone elicits mild respiratory disease in infected rhesus macaques. AB - The recurrence of new human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) underscores the need for effective therapeutic countermeasures. Nonhuman primate models are considered the gold standard for preclinical evaluation of therapeutic countermeasures. However, MERS-CoV-induced severe respiratory disease in humans is associated with high viral loads in the lower respiratory tract, which may be difficult to achieve in nonhuman primate models. Considering this limitation, we wanted to ascertain the effectiveness of using a MERS-CoV infectious clone (icMERS-0) previously shown to replicate to higher titers than the wild-type EMC 2012 strain. We observed respiratory disease resulting from exposure to the icMERS-0 strain as measured by CT in rhesus monkeys with concomitant detection of virus antigen by immunohistochemistry. Overall, respiratory disease was mild and transient, resolving by day 30 post infection. Although pulmonary disease was mild, these results demonstrate for the first time the utility of CT imaging to measure disease elicited by a MERS-CoV infectious clone system in nonhuman primate models. PMID- 30013083 TI - Transient and Persistent UP States during Slow-wave Oscillation and their Implications for Cell-Assembly Dynamics. AB - The membrane potentials of cortical neurons in vivo exhibit spontaneous fluctuations between a depolarized UP state and a resting DOWN state during the slow-wave sleeps or in the resting states. This oscillatory activity is believed to engage in memory consolidation although the underlying mechanisms remain unknown. Recently, it has been shown that UP-DOWN state transitions exhibit significantly different temporal profiles in different cortical regions, presumably reflecting differences in the underlying network structure. Here, we studied in computational models whether and how the connection configurations of cortical circuits determine the macroscopic network behavior during the slow-wave oscillation. Inspired by cortical neurobiology, we modeled three types of synaptic weight distributions, namely, log-normal, sparse log-normal and sparse Gaussian. Both analytic and numerical results suggest that a larger variance of weight distribution results in a larger chance of having significantly prolonged UP states. However, the different weight distributions only produce similar macroscopic behavior. We further confirmed that prolonged UP states enrich the variety of cell assemblies activated during these states. Our results suggest the role of persistent UP states for the prolonged repetition of a selected set of cell assemblies during memory consolidation. PMID- 30013084 TI - The influence of ontogenetic diet variation on consumption rate estimates: a marine example. AB - Consumption rates are the foundation of trophic ecology, yet bioenergetics models used to estimate these rates can lack realism by not incorporating the ontogeny of diet. We constructed a bioenergetics model of a marine predatory fish (tailor, Pomatomus saltatrix) that incorporated high-resolution ontogenetic diet variation, and compared consumption estimates to those derived from typical bioenergetics models that do not consider ontogenetic diet variation. We found tailor consumption was over- or under-estimated by ~5-25% when only including the most common prey item. This error was due to a positive relationship between mean prey energy density and predator body size. Since high-resolution diet data isn't always available, we also simulated how increasing dietary information progressively influenced consumption rate estimates. The greatest improvement in consumption rate estimates occurred when diet variation of 2-3 stanzas (1-2 juvenile stanzas, and adults) was included, with at least 5-6 most common prey types per stanza. We recommend increased emphasis on incorporating the ontogeny of diet and prey energy density in consumption rate estimates, especially for species with spatially segregated life stages or variable diets. A small-moderate increase in the resolution of dietary information can greatly benefit the accuracy of estimated consumption rates. We present a method of incorporating variable prey energy density into bioenergetics models. PMID- 30013085 TI - Dentinogenic effects of extracted dentin matrix components digested with matrix metalloproteinases. AB - Dentin is primarily composed of hydroxyapatite crystals within a rich organic matrix. The organic matrix comprises collagenous structural components, within which a variety of bioactive molecules are sequestered. During caries progression, dentin is degraded by acids and enzymes derived from various sources, which can release bioactive molecules with potential reparative activity towards the dentin-pulp complex. While these molecules' repair activities in other tissues are already known, their biological effects are unclear in relation to degradation events during disease in the dentin-pulp complex. This study was undertaken to investigate the effects of dentin matrix components (DMCs) that are partially digested by matrix metalloproteinases (MMPs) in vitro and in vivo during wound healing of the dentin-pulp complex. DMCs were initially isolated from healthy dentin and treated with recombinant MMPs. Subsequently, their effects on the behaviour of primary pulp cells were investigated in vitro and in vivo. Digested DMCs modulated a range of pulp cell functions in vitro. In addition, DMCs partially digested with MMP-20 stimulated tertiary dentin formation in vivo, which exhibited a more regular tubular structure than that induced by treatment with other MMPs. Our results indicate that MMP-20 may be especially effective in stimulating wound healing of the dentin-pulp complex. PMID- 30013086 TI - Probiotics into outer space: feasibility assessments of encapsulated freeze-dried probiotics during 1 month's storage on the International Space Station. AB - Suppression of immune function during long spaceflights is an issue that needs to be overcome. The well-established probiotic Lactobacillus casei strain Shirota (LcS) could be a promising countermeasure, and we have launched a project to investigate the efficacy of its use on the International Space Station (ISS). As a first step, we developed a specialist probiotic product for space experiments, containing freeze-dried LcS in capsule form (Probiotics Package), and tested its stability through 1 month of storage on the ISS. The temperature inside the ISS ranged from 20.0 to 24.5 degrees C. The absorbed dose rate of the flight sample was 0.26 mGy/day and the dose equivalent rate was 0.52 mSv/day. The number of live LcS was 1.05 * 1011 colony-forming units/g powder (49.5% of the initial value) 6 months after the start of the study; this value was comparable to those in the two ground controls. Profiles of randomly amplified polymorphic DNA, sequence variant frequency, carbohydrate fermentation, reactivity to LcS-specific antibody, and the cytokine-inducing ability of LcS in the flight sample did not differ from those of the ground controls. We can therefore maintain the viability and basic probiotic properties of LcS stored as a Probiotics Package on the ISS. PMID- 30013087 TI - Dispersion-Solvent Control of Ionomer Aggregation in a Polymer Electrolyte Membrane Fuel Cell. AB - In this study, we examined the influence of the dispersion solvent in three dipropylene-glycol/water (DPG/water) mixtures, with DPG contents of 0, 50, and 100 wt%, on ionomer morphology and distribution, using dynamic light scattering (DLS) and molecular-dynamics (MD) simulation techniques. The DLS results reveal that Nafion-ionomer aggregation increases with decreasing DPG content of the solvent. Increasing the proportion of water in the solvent also led to a gradual decrease in the radius of gyration (Rg) of the Nafion ionomer due to its strong backbone hydrophobicity. Correspondingly, MD simulations predict Nafion-ionomer solvation energies of -147 +/- 9 kcal/mol in water, -216 +/- 21 kcal/mol in the DPG/water mixture, and -444 +/- 9 kcal/mol in DPG. These results suggest that higher water contents in mixed DPG/water solvents result in increased Nafion ionomer aggregation and the subsequent deterioration of its uniform dispersion in the solvent. Moreover, radial distribution functions (RDFs) reveal that the ( CF2CF2-) backbones of the Nafion ionomer are primarily enclosed by DPG molecules, whereas the sulfonate groups (SO3-) of its side chains mostly interact with water molecules. PMID- 30013088 TI - A CpG-adjuvanted intranasal enterovirus 71 vaccine elicits mucosal and systemic immune responses and protects human SCARB2-transgenic mice against lethal challenge. AB - Enterovirus 71 (EV71) is an aetiological agent responsible for seasonal epidemics of hand-foot-and-mouth disease, which causes considerable mortality among young children. Mucosal vaccines can efficiently induce secretory IgA at mucosal surfaces and thereby prevent or limit infection at the site of virus entry. CpG oligodeoxynucleotides (ODNs), which resemble bacterial DNA, can induce the innate immune response through activation of Toll-like receptor 9. Here, we used CpG ODNs as adjuvants to investigate an EV71 mucosal vaccine in mice. In the EV71 + CpG group, the EV71-specific IgG and IgA titres in the serum, nasal wash, bronchoalveolar lavage fluid, and faeces were substantially higher than those in the EV71- and phosphate-buffered saline-treated groups. Moreover, the number of EV71-specific IgG- and IgA-producing cells was also higher in the EV71 + CpG group. Furthermore, T-cell proliferative responses and interleukin-17 secretion were markedly increased when CpG-adjuvanted EV71 was delivered intranasally. More importantly, the induced antibodies neutralised infection by EV71 of the C2 genotype and crossneutralised infection by EV71 of the B4 and B5 genotypes. Lastly, human scavenger receptor class B, member 2-transgenic mice intranasally immunised with the CpG-adjuvanted EV71 vaccine resisted a subsequent lethal challenge with EV71, indicating that CpG was an effective intranasal adjuvant for EV71 mucosal-vaccine development. PMID- 30013089 TI - Decreased expression of bone morphogenetic protein-2 is correlated with biochemical recurrence in prostate cancer: Immunohistochemical analysis. AB - We evaluated the prognostic value of BMP-2 expression in prostate cancer tissue via immunohistochemistry in prostate cancer patients. From July 2007 to August 2010, radical prostatectomy specimens from 90 patients with clinically localized prostate cancer (mean age, 62.7 years, mean follow-up 90.4 months) were assessed for BMP-2 expression using immunohistochemistry. We used stepwise multivariate Cox regression models stratified by study to assess the independent effects of the predictive factors and estimated hazard ratios (HRs). There were significant differences in the baseline characteristics of Gleason score (GS) and biochemical recurrence (BCR) between the groups with decreased and normal BMP-2 expression. Univariate analysis revealed GS, T stage (>=T3), and decreased BMP-2 expression as significant predictive determinants of BCR. In addition, GS (7: HR 2.836, p = 0.022; >=8: HR 3.506, p = 0.048) and decreased BMP-2 expression (HR 2.007, p = 0.047) were significantly correlated with BCR in multivariate analysis. Overall five-year BCR-free survival rates in the group with decreased BMP-2 expression were worse than those in the group with normal expression. Therefore, decreased BMP-2 expression in prostate cancer tissue was correlated with the prognostic factors for BCR-free survival in patients with prostate cancer. PMID- 30013090 TI - Outcome and prognostic factors in 593 non-metastatic rectal cancer patients: a mono-institutional survey. AB - This retrospective study was undertaken to provide more modern data of real-life management of non-metastatic rectal cancer, to compare therapeutic strategies, and to identify prognostic factors of overall survival (OS) in a large cohort of patients. Data on efficacy and on acute/late toxicity were retrospectively collected. Patients were diagnosed a non-metastatic rectal cancer between 2004 and 2015, and were treated at least with radiotherapy. OS was correlated with patient, tumor and treatment characteristics with univariate and multivariate analyses. Data of 593 consecutive non-metastatic rectal cancer patients were analyzed. Median follow-up was 41 months. Median OS was 9 years. Radiotherapy was delivered in pre-operative (n = 477, 80.5%), post-operative (n = 75, 12.6%) or exclusive (n = 41, 6.9%) setting. In the whole set of patients, age, nutritional condition, tumor stage, tumor differentiation, and surgery independently influenced OS. For patients experiencing surgery, OS was influenced by age, tumor differentiation and nodal status. Surgical resection is the cornerstone treatment for locally-advanced rectal cancer. Poor tumor differentiation and node involvement were identified as major predictive factor of poor OS. The research in treatment intensification and in identification of radioresistance biomarkers should therefore probably be focused on this particular subset of patients. PMID- 30013091 TI - Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab therapy: retrospective analyses of the PRIME and PEAK clinical trials. AB - BACKGROUND: Data from two trials of panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival. METHODS: Patients with RAS wild type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a >=30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed. RESULTS: A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival. CONCLUSIONS: First-line panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to panitumumab. PMID- 30013092 TI - Structural dynamics of calmodulin-ryanodine receptor interactions: electron paramagnetic resonance using stereospecific spin labels. AB - We have used electron paramagnetic resonance, with rigid and stereospecific spin labels, to resolve structural states in calmodulin (CaM), as affected by binding of Ca and a CaM-binding peptide (RyRp) derived from the ryanodine receptor (RyR), the Ca channel that triggers muscle contraction. CaM mutants containing a pair of cysteines in the N-lobe and/or C-lobe were engineered and labeled with a stereospecifically bound bifunctional spin label (BSL). RyRp was synthesized with and without TOAC (a stereospecifically attached spin-labeled amino acid) substituted for a single amino acid near the N-terminus. Intramolecular DEER distance measurements of doubly-labeled BSL-CaM revealed that CaM exists in dynamic equilibrium among multiple states, consistent with open, closed, and compact structural models. Addition of RyRp shifted the equilibrium partially toward the compact state in the absence of Ca, and completely toward the compact state in the presence of Ca, supporting a conformational selection model. Inter protein distance measurements show that Ca stabilizes the compact state primarily by inducing ordered binding of the CaM N-lobe to RyRp, while only slightly affecting the C-lobe. The results provide insight into the structural mechanism of CaM-mediated RyR regulation, while demonstrating the power of using two types of rigidly and stereospecifically bound spin labels. PMID- 30013093 TI - The Roles of Serotonin in Decision-making under Social Group Conditions. AB - People in a social group often have to make decisions under conflict, for instance, to conform to the group or obey authority (subjects at higher social rank in the group). The neural mechanisms underlying how social group setting affects decision-making have largely remained unclear. In this study, we designed novel behavioral tests using food access priority and fear conditioning paradigms that captured decision-making under conflict associated with social group environments in mice and examined the roles of serotonin (5-HT) on these processes. Using these behavioral tests, administration of the selective 5-HT reuptake inhibitor, which increased 5-HT transmission, was found to attenuate conflicts in decision-making that may be associated with human cases of social obedience and conformity in mice under group housing. The results suggest that 5 HT plays important roles in the regulation of individual behaviors that organize social group dynamics. PMID- 30013094 TI - Amelioratory Effects of Testosterone Propionate on Age-related Renal Fibrosis via Suppression of TGF-beta1/Smad Signaling and Activation of Nrf2-ARE Signaling. AB - Androgen plays a pivotal role in the progression of renal fibrosis. However, whether exogenous androgen treatment to aged male rats can improve the age related renal fibrosis was not explored. In our study, the changes of morphological structure, renal fibrosis, ultrastructure and renal function, the expressions of extracellular matrix (ECM), matrix metalloproteinases (MMPs) and its tissue inhibitors of metalloproteinases (TIMPs), the expressions of tumor growth factor beta1 (TGF-beta1)/Smad signaling and oxidative stress parameters as well as nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling were tested in kidney of aged male Wistar rats after subcutaneous testosterone propionate (TP, 2 mg/kg/d, 84-day) injection. Aged rats showed significantly renal histopathological changes, increased renal fibrosis, increased thickening of the glomerular basement membrane and the Bowman's capsule basement membrane, declined renal functional, increased ECM, lower expressions of MMP-2 and MMP-9 and higher expressions of TIMP-1 and TIMP-2 in renal tissues and higher expressions of TGF-beta1/Smad signaling, as well as lower expressions of Nrf2-ARE signaling compared to young rats. TP treatment significantly improved age-related above indexes. These results suggested that TP supplement may alleviate age-related renal fibrosis via suppression of TGF-beta1/Smad signaling and activation of Nrf2-ARE signaling in aged rats. PMID- 30013095 TI - A Novel Multi-Gene Detection Platform for the Analysis of miRNA Expression. AB - The study of miRNAs and their roles as non-invasive biomarkers has been intensely conducted in cancer diseases over the past decade. Various platforms, ranging from conventional qPCRs to Next Generation Sequencers (NGS), have been widely used to analyze miRNA expression. Here we introduced a novel platform, PanelChipTM Analysis System, which provides a sensitive solution for the analysis of miRNA levels in blood. After conducting miRQC analysis, the system's analytical performance compared favorably against similar nanoscale qPCR-based array technologies. Because PanelChipTM requires only a minimal amount of miRNA for analysis, we used it to screen for potential diagnostic biomarkers in the plasma of patients with oral cavity squamous cell carcinoma (OSCC). Combining the platform with a machine learning algorithm, we were able to discover miRNA expression patterns capable of separating healthy subjects from patients with OSCC. PMID- 30013096 TI - Gene expression drives the evolution of dominance. AB - Dominance is a fundamental concept in molecular genetics and has implications for understanding patterns of genetic variation, evolution, and complex traits. However, despite its importance, the degree of dominance in natural populations is poorly quantified. Here, we leverage multiple mating systems in natural populations of Arabidopsis to co-estimate the distribution of fitness effects and dominance coefficients of new amino acid changing mutations. We find that more deleterious mutations are more likely to be recessive than less deleterious mutations. Further, this pattern holds across gene categories, but varies with the connectivity and expression patterns of genes. Our work argues that dominance arises as a consequence of the functional importance of genes and their optimal expression levels. PMID- 30013097 TI - TCM visualizes trajectories and cell populations from single cell data. AB - Profiling single cell gene expression data over specified time periods are increasingly applied to the study of complex developmental processes. Here, we describe a novel prototype-based dimension reduction method to visualize high throughput temporal expression data for single cell analyses. Our software preserves the global developmental trajectories over a specified time course, and it also identifies subpopulations of cells within each time point demonstrating superior visualization performance over six commonly used methods. PMID- 30013098 TI - Disentangling vehicular emission impact on urban air pollution using ethanol as a tracer. AB - The Sao Paulo Metropolitan Area is a unique case worldwide due to the extensive use of biofuel, particularly ethanol, by its large fleet of nearly 8 million cars. Based on source apportionment analysis of Organic Aerosols in downtown Sao Paulo, and using ethanol as tracer of passenger vehicles, we have identified primary emissions from light-duty-vehicles (LDV) and heavy-duty-vehicles (HDV), as well as secondary process component. Each of those factors mirror a relevant primary source or secondary process in this densely occupied area. Using those factors as predictors in a multiple linear regression analysis of a wide range of pollutants, we have quantified the role of primary LDV or HDV emissions, as well as atmospheric secondary processes, on air quality degradation. Results show a significant contribution of HDV emissions, despite contributing only about 5% of vehicles number in the region. The latter is responsible, for example, of 40% and 47% of benzene and black carbon atmospheric concentration, respectively. This work describes an innovative use of biofuel as a tracer of passenger vehicle emissions, allowing to better understand the role of vehicular sources on air quality degradation in one of most populated megacities worldwide. PMID- 30013100 TI - Cardiorenal complications of immune checkpoint inhibitors. AB - The development of immune checkpoint inhibitors (ICIs) has driven a revolutionary change in cancer treatment. Although traditional chemotherapeutic agents remain the first-line option for most cancers, targeted immune therapies are emerging as standard treatments for advanced-stage cancers. These agents target cell surface checkpoint proteins to stimulate the recognition and destruction of cancer cells by the immune system. Clinical studies have demonstrated these immunotherapeutics to elicit favourable antitumour responses in a variety of chemotherapy-refractory malignancies. However, use of these agents can also induce immune-related adverse events (irAEs) in off-target organs, including the heart and kidney. The most common manifestations of heart and kidney damage are myocarditis and acute interstitial nephritis, respectively, but other manifestations have been reported and, although rare, these off-target effects can be life threatening. Available data suggest that ICIs induce their off-target effects through several mechanisms, including direct binding to cell surface proteins expressed in healthy tissue, activation of T cells that cross-react with off-target tissues, generation of autoantibodies or by increasing levels of pro-inflammatory cytokines. Greater understanding of the adverse effects of cancer immunotherapies and the underlying mechanisms will facilitate the development of biomarkers to identify at-risk patients and approaches to prevent these irAEs. PMID- 30013099 TI - Structural basis for the regulation of inositol trisphosphate receptors by Ca2+ and IP3. AB - Inositol trisphosphate receptors (IP3Rs) are ubiquitous Ca2+-permeable channels that mediate release of Ca2+ from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP3Rs are jointly activated by inositol trisphosphate (IP3) and their permeant ion, Ca2+. At high concentrations, however, Ca2+ inhibits activity, ensuring precise spatiotemporal control over intracellular Ca2+. Despite extensive characterization of IP3R, the mechanisms through which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP3Rs in ligand-bound and ligand-free states. Multiple IP3-bound structures demonstrate that the large cytoplasmic domain provides a platform for propagation of long-range conformational changes to the ion-conduction gate. Structures in the presence of Ca2+ reveal two Ca2+ binding sites that induce the disruption of numerous interactions between subunits, thereby inhibiting IP3R. These structures thus provide a mechanistic basis for beginning to understand the regulation of IP3R. PMID- 30013101 TI - Suppression of AURKA alleviates p27 inhibition on Bax cleavage and induces more intensive apoptosis in gastric cancer. AB - Bax is a key molecule in mitochondria-apoptosis pathway, however it is not always an efficient apoptosis inducer in chemotherapeutic agents-treated cancer cells. Here, we found that specific inhibition of AURKA by MLN8237-induced calpain mediated Bax cleavage at N-terminal 33th asparagine (c-Bax) to promote apoptosis. The c-Bax, as Bax, could also efficiently located to mitochondria but c-Bax is a stronger apoptosis inducer than Bax. Morever, c-Bax-induced apoptosis could not be blocked by the canonical Bax inhibitor, Bcl-2. Further study found p27 was degraded and subsequently Bax was transformed to c-Bax through calpain. Also, p27 efficiently inhibited Bax cleavage and p27 knockdown sensitized apoptosis through Bax cleavage when cancer cells were treated with MLN8237. It is also demonstrated that the anti-apoptotic role of p27 lies its cytoplasmic localization. Finally, we found that the positive correlation between AURKA and p27 in advanced gastric cancer patients. In conclusion, we found that MNL8237 suppressed cell growth by regulating calpain-dependent Bax cleavage and p27 dysregulation in gastric cancer cells. PMID- 30013103 TI - Gut microbiota as gatekeeper of anti-tumour responses in the liver. PMID- 30013102 TI - Correction: Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30013104 TI - FIB-FESEM and EMPA results on Antoninianus silver coins for manufacturing and corrosion processes. AB - A set of ancient Antoninianus silver coins, dating back between 249 and 274 A.D. and minted in Rome, Galliae, Orient and Ticinum, have been characterized. We use, for the first time, a combination of nano-invasive (focused ion beam-field emission scanning electron microscopy-X-ray microanalysis (FIB-FESEM-EDX), voltammetry of microparticles (VIMP)) and destructive techniques (scanning electron microscopy (SEM-EDX) and electron microprobe analysis (EMPA)) along with non-invasive, i.e., micro-Raman spectroscopy. The results revealed that, contrary to the extended belief, a complex Ag-Cu-Pb-Sn alloy was used. The use of alloys was common in the flourishing years of the Roman Empire. In the prosperous periods, Romans produced Ag-Cu alloys with relatively high silver content for the manufacture of both the external layers and inner nucleus of coins. This study also revealed that, although surface silvering processes were applied in different periods of crisis under the reign of Antoninii, even during crisis, Romans produced Antoninianus of high quality. Moreover, a first attempt to improve the silvering procedure using Hg-Ag amalgam has been identified. PMID- 30013105 TI - CD32 expression is associated to T-cell activation and is not a marker of the HIV 1 reservoir. AB - CD32 has been shown to be preferentially expressed in latently HIV-1-infected cells in an in vitro model of quiescent CD4 T cells. Here we show that stimulation of CD4+ T cells with IL-2, IL-7, PHA, and anti-CD3/CD28 antibodies induces T-cell proliferation, co-expression of CD32 and the activation of the markers HLA-DR and CD69. HIV-1 infection increases CD32 expression. 79.2% of the CD32+/CD4+ T cells from HIV+ individuals under antiretroviral treatment were HLA DR+. Resting CD4+ T cells infected in vitro generally results in higher integration of provirus. We observe no difference in provirus integration or replication-competent inducible latent HIV-1 in CD32+ or CD32- CD4+ T cells from HIV+ individuals. Our results demonstrate that CD32 expression is a marker of CD4+ T cell activation in HIV+ individuals and raises questions regarding the immune resting status of CD32+ cells harboring HIV-1 proviruses. PMID- 30013106 TI - Molecular architecture of fungal cell walls revealed by solid-state NMR. AB - The high mortality of invasive fungal infections, and the limited number and inefficacy of antifungals necessitate the development of new agents with novel mechanisms and targets. The fungal cell wall is a promising target as it contains polysaccharides absent in humans, however, its molecular structure remains elusive. Here we report the architecture of the cell walls in the pathogenic fungus Aspergillus fumigatus. Solid-state NMR spectroscopy, assisted by dynamic nuclear polarization and glycosyl linkage analysis, reveals that chitin and alpha 1,3-glucan build a hydrophobic scaffold that is surrounded by a hydrated matrix of diversely linked beta-glucans and capped by a dynamic layer of glycoproteins and alpha-1,3-glucan. The two-domain distribution of alpha-1,3-glucans signifies the dual functions of this molecule: contributing to cell wall rigidity and fungal virulence. This study provides a high-resolution model of fungal cell walls and serves as the basis for assessing drug response to promote the development of wall-targeted antifungals. PMID- 30013107 TI - NKX3-1 is required for induced pluripotent stem cell reprogramming and can replace OCT4 in mouse and human iPSC induction. AB - Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is now routinely accomplished by overexpression of the four Yamanaka factors (OCT4, SOX2, KLF4, MYC (or OSKM))1. These iPSCs can be derived from patients' somatic cells and differentiated toward diverse fates, serving as a resource for basic and translational research. However, mechanistic insights into regulators and pathways that initiate the pluripotency network remain to be resolved. In particular, naturally occurring molecules that activate endogenous OCT4 and replace exogenous OCT4 in human iPSC reprogramming have yet to be found. Using a heterokaryon reprogramming system we identified NKX3-1 as an early and transiently expressed homeobox transcription factor. Following knockdown of NKX3 1, iPSC reprogramming is abrogated. NKX3-1 functions downstream of the IL-6-STAT3 regulatory network to activate endogenous OCT4. Importantly, NKX3-1 substitutes for exogenous OCT4 to reprogram both mouse and human fibroblasts at comparable efficiencies and generate fully pluripotent stem cells. Our findings establish an essential role for NKX3-1, a prostate-specific tumour suppressor, in iPSC reprogramming. PMID- 30013108 TI - IRE1alpha governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A. AB - Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a signalling network known as the unfolded protein response (UPR). Here, we identified filamin A as a major binding partner of the ER stress transducer IRE1alpha. Filamin A is an actin crosslinking factor involved in cytoskeleton remodelling. We show that IRE1alpha controls actin cytoskeleton dynamics and affects cell migration upstream of filamin A. The regulation of cytoskeleton dynamics by IRE1alpha is independent of its canonical role as a UPR mediator, serving instead as a scaffold that recruits and regulates filamin A. Targeting IRE1alpha expression in mice affected normal brain development, generating a phenotype resembling periventricular heterotopia, a disease linked to the loss of function of filamin A. IRE1alpha also modulated cell movement and cytoskeleton dynamics in fly and zebrafish models. This study unveils an unanticipated biological function of IRE1alpha in cell migration, whereby filamin A operates as an interphase between the UPR and the actin cytoskeleton. PMID- 30013109 TI - Differential regulation of transition zone and centriole proteins contributes to ciliary base diversity. AB - Cilia are evolutionarily conserved structures with many sensory and motility related functions. The ciliary base, composed of the basal body and the transition zone, is critical for cilia assembly and function, but its contribution to cilia diversity remains unknown. Hence, we generated a high resolution structural and biochemical atlas of the ciliary base of four functionally distinct neuronal and sperm cilia types within an organism, Drosophila melanogaster. We uncovered a common scaffold and diverse structures associated with different localization of 15 evolutionarily conserved components. Furthermore, CEP290 (also known as NPHP6) is involved in the formation of highly diverse transition zone links. In addition, the cartwheel components SAS6 and ANA2 (also known as STIL) have an underappreciated role in basal body elongation, which depends on BLD10 (also known as CEP135). The differential expression of these cartwheel components contributes to diversity in basal body length. Our results offer a plausible explanation to how mutations in conserved ciliary base components lead to tissue-specific diseases. PMID- 30013110 TI - Effect of surface and porosity of biochar on water holding capacity aiming indirectly at preservation of the Amazon biome. AB - As part of efforts to reduce pressure on the Amazon and other biomes, one approach considered by Brazilian authorities and scientists is more intensive use of the soils of the interior of the northeast of the country, which are generally sandy, with low contents of organic matter and low water holding capacity and are frequently affected by severe droughts. In this work, biochars produced from waste biomasses were tested for the improvement of these soils. The highest BET (Brunauer-Emmett-Teller) specific surface areas were observed for all biochars. In the pH range studied, the water hyacinth plants (WH) sample showed the most negative zeta potentials, as well as the highest water holding capacity (WHC) values, while the zeta potentials of two quartzarenic neosol soils were consistent with their WHC values. The results suggested that despite the effect of porosity on water retention, the zeta potential could be associated with the presence of negative charges by which hydrated cationic counterions were absorbed and retained. The surface energy and its polar and dispersive components were associated with water retention, with sugar cane bagasse, orange peel, and water hyacinth biochars presenting higher SE values and larger polar components. PMID- 30013111 TI - Nanoscale imaging of charge carrier transport in water splitting photoanodes. AB - The performance of energy materials hinges on the presence of structural defects and heterogeneity over different length scales. Here we map the correlation between morphological and functional heterogeneity in bismuth vanadate, a promising metal oxide photoanode for photoelectrochemical water splitting, by photoconductive atomic force microscopy. We demonstrate that contrast in mapping electrical conductance depends on charge transport limitations, and on the contact at the sample/probe interface. Using temperature and illumination intensity-dependent current-voltage spectroscopy, we find that the transport mechanism in bismuth vanadate can be attributed to space charge-limited current in the presence of trap states. We observe no additional recombination sites at grain boundaries, which indicates high defect tolerance in bismuth vanadate. These findings support the fabrication of highly efficient bismuth vanadate nanostructures and provide insights into how local functionality affects the macroscopic performance. PMID- 30013112 TI - The Consequences of Biofilm Dispersal on the Host. AB - Chronic infections are often associated with the presence of a biofilm, a community of microorganisms coexisting within a protective matrix of extracellular polymeric substance. Living within a biofilm can make resident microbes significantly more tolerant to antibiotics in comparison to planktonic, free-floating cells. Thus, agents that can degrade biofilms are being pursued for clinical applications. While biofilm degrading and dispersing agents may represent attractive adjunctive therapies for biofilm-associated chronic infections, very little is known about how the host responds to the sudden dispersal of biofilm cells. In this study, we found that large-scale, in vivo dispersal of motile biofilm bacteria by glycoside hydrolases caused lethal septicemia in the absence of antibiotic therapy in a mouse wound model. However, when administered prudently, biofilm degrading enzymes had the potential to potentiate the efficacy of antibiotics and help resolve biofilm-associated wound infections. PMID- 30013113 TI - Correction: DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues. AB - Correction to:Cell Death & Disease8, e2816 (2017); https://doi.org/10.1038/cddis.2017.222 ; published online 25 May 2017. PMID- 30013114 TI - The first plastid genome of a filamentous taxon 'Bangia' sp. OUCPT-01 in the Bangiales. AB - Red algae are important primary photosynthetic organisms. The Bangiales comprise a morphologically diverse order of red algae. Until now, complete plastid genomes of the Bangiales were only mapped for foliose species. To date, no filamentous plastomes have been published. The aim of this study was to determine and analyze the complete plastid genome of the filamentous marine species 'Bangia' sp. OUCPT 01. It is a circular molecule, 196,913 bps in length with a guanine-cytosine (GC) content of 33.5%. It has a quadripartite structure with two single copy regions separated by two direct non-identical repeats. It has 205 protein-coding genes, 37 tRNAs, and 6 rRNAs. Therefore, it has a high coding capacity and is highly similar to other Bangiales species in terms of content and structure. In particular, it reveals that the genera in the Bangiales have highly conserved gene content and plastome synteny. This plastome and existing data provide insights into the phylogenetic relationships among the Bangiales genera of the Rhodophyta. According to its plastid- and mitochondrial genomes, 'Bangia 2' is a sister group to Porphyra. However, the position of Wildemania schizophylla in the Bangiales is still controversial. Our results show that the Bangiales divergence time was ~225 million years ago. PMID- 30013116 TI - Efficacy and Tolerability of Guanylate Cyclase-C Agonist: Encouraging Results With Insignificant Clinical Importance. PMID- 30013115 TI - Intrinsically ionic conductive cellulose nanopapers applied as all solid dielectrics for low voltage organic transistors. AB - Biodegradability, low-voltage operation, and flexibility are important trends for the future organic electronics. High-capacitance dielectrics are essential for low-voltage organic field-effect transistors. Here we report the application of environmental-friendly cellulose nanopapers as high-capacitance dielectrics with intrinsic ionic conductivity. Different with the previously reported liquid/electrolyte-gated dielectrics, cellulose nanopapers can be applied as all solid dielectrics without any liquid or gel. Organic field-effect transistors fabricated with cellulose nanopaper dielectrics exhibit good transistor performances under operation voltage below 2 V, and no discernible drain current change is observed when the device is under bending with radius down to 1 mm. Interesting properties of the cellulose nanopapers, such as ionic conductivity, ultra-smooth surface (~0.59 nm), high transparency (above 80%) and flexibility make them excellent candidates as high-capacitance dielectrics for flexible, transparent and low-voltage electronics. PMID- 30013117 TI - Blast-induced cochlear synaptopathy in chinchillas. AB - When exposed to continuous high-level noise, cochlear neurons are more susceptible to damage than hair cells (HCs): exposures causing temporary threshold shifts (TTS) without permanent HC damage can destroy ribbon synapses, permanently silencing the cochlear neurons they formerly activated. While this "hidden hearing loss" has little effect on thresholds in quiet, the neural degeneration degrades hearing in noise and may be an important elicitor of tinnitus. Similar sensory pathologies are seen after blast injury, even if permanent threshold shift (PTS) is minimal. We hypothesized that, as for continuous-noise, blasts causing only TTS can also produce cochlear synaptopathy with minimal HC loss. To test this, we customized a shock tube design to generate explosive-like impulses, exposed anesthetized chinchillas to blasts with peak pressures from 160-175 dB SPL, and examined the resultant cochlear dysfunction and histopathology. We found exposures that cause large >40 dB TTS with minimal PTS or HC loss often cause synapse loss of 20-45%. While synaptopathic continuous noise exposures can affect large areas of the cochlea, blast-induced synaptopathy was more focal, with localized damage foci in midcochlear and basal regions. These results clarify the pathology underlying blast-induced sensory dysfunction, and suggest possible links between blast injury, hidden hearing loss, and tinnitus. PMID- 30013118 TI - Genome-centric view of carbon processing in thawing permafrost. AB - As global temperatures rise, large amounts of carbon sequestered in permafrost are becoming available for microbial degradation. Accurate prediction of carbon gas emissions from thawing permafrost is limited by our understanding of these microbial communities. Here we use metagenomic sequencing of 214 samples from a permafrost thaw gradient to recover 1,529 metagenome-assembled genomes, including many from phyla with poor genomic representation. These genomes reflect the diversity of this complex ecosystem, with genus-level representatives for more than sixty per cent of the community. Meta-omic analysis revealed key populations involved in the degradation of organic matter, including bacteria whose genomes encode a previously undescribed fungal pathway for xylose degradation. Microbial and geochemical data highlight lineages that correlate with the production of greenhouse gases and indicate novel syntrophic relationships. Our findings link changing biogeochemistry to specific microbial lineages involved in carbon processing, and provide key information for predicting the effects of climate change on permafrost systems. PMID- 30013119 TI - Complex silica composite nanomaterials templated with DNA origami. AB - Genetically encoded protein scaffolds often serve as templates for the mineralization of biocomposite materials with complex yet highly controlled structural features that span from nanometres to the macroscopic scale1-4. Methods developed to mimic these fabrication capabilities can produce synthetic materials with well defined micro- and macro-sized features, but extending control to the nanoscale remains challenging5,6. DNA nanotechnology can deliver a wide range of customized nanoscale two- and three-dimensional assemblies with controlled sizes and shapes7-11. But although DNA has been used to modulate the morphology of inorganic materials12,13 and DNA nanostructures have served as moulds14,15 and templates16,17, it remains challenging to exploit the potential of DNA nanostructures fully because they require high-ionic-strength solutions to maintain their structure, and this in turn gives rise to surface charging that suppresses the material deposition. Here we report that the Stober method, widely used for producing silica (silicon dioxide) nanostructures, can be adjusted to overcome this difficulty: when synthesis conditions are such that mineral precursor molecules do not deposit directly but first form clusters, DNA-silica hybrid materials that faithfully replicate the complex geometric information of a wide range of different DNA origami scaffolds are readily obtained. We illustrate this approach using frame-like, curved and porous DNA nanostructures, with one-, two- and three-dimensional complex hierarchical architectures that range in size from 10 to 1,000 nanometres. We also show that after coating with an amorphous silica layer, the thickness of which can be tuned by adjusting the growth time, hybrid structures can be up to ten times tougher than the DNA template while maintaining flexibility. These findings establish our approach as a general method for creating biomimetic silica nanostructures. PMID- 30013120 TI - Publisher Correction: Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. AB - In this Letter, the received date should have been 23 March 2017 instead of 13 April 2018. Authors R.M.K. and O.D.K. were incorrectly denoted as 'equally contributing' authors. The labels for 'control' and 'IFNgamma' in Extended Data Fig. 4g were reversed. These have been corrected online. PMID- 30013121 TI - Publisher Correction: Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. AB - In this Letter, affiliation number 1 was originally missing from the HTML; the affiliations were missing for author Ming-Yow Hung in the HTML; and the Fig. 4 legend erroneously referred to panels a-h, instead of a-g. These errors have been corrected online. PMID- 30013123 TI - A wavelength-convertible quantum memory: Controlled echo. AB - Quantum coherence control is reinvestigated for a new physical insight in quantum nonlinear optics and applied for a wavelength-convertible quantum memory in a solid ensemble whose spin states are inhomogeneously broadened. Unlike typical atomic media whose spin decays are homogeneous, a spin inhomogeneously broadened solid ensemble requires a counter-intuitive quantum coherence control to avoid spontaneous emission-caused quantum noises. Such a quantum coherence control in a solid ensemble satisfying both near perfect retrieval efficiency and ultralong photon storage offers a solid framework to quantum repeaters, scalable qubit generations, quantum cryptography, and highly sensitive magnetometry. Here, the basic physics of the counter-intuitive quantum coherence control is presented not only for a fundamental understanding of collective ensemble phase control but also for a coherence conversion mechanism between optical and spin states involving Raman rephasing. PMID- 30013122 TI - Moderate levels of dietary arachidonic acid reduced lipid accumulation and tended to inhibit cell cycle progression in the liver of Japanese seabass Lateolabrax japonicus. AB - To investigate the physiological roles of dietary arachidonic acid (ARA) in fish, a feeding trial with Japanese seabass was conducted, followed by a hepatic transcriptome assay. Six experimental diets differing basically in ARA level (0.05%, 0.22%, 0.37%, 0.60%, 1.38% and 2.32% of dry matter) were used in the feeding trial. Liver samples from fish fed diets with 0.05% and 0.37% ARA were subjected to transcriptomic assay, generating a total of 139 differently expressed unigenes, which were primarily enriched in lipid metabolism and cell cycle-related signaling pathways. Then, qRT-PCR validation on lipid metabolism and cell cycle-related genes as well as corresponding enzyme-linked immunosorbent assay of selected proteins were conducted with liver samples from all six groups. Moderated ARA levels reduced lipogenesis and stimulated beta-oxidation concurrently, but high ARA levels seemed to affect lipid metabolism in complicated ways. Both gene expression and protein concentration of cell cycle related proteins were decreased by moderate levels of dietary ARA. The lipid content and fatty acid composition in fish confirmed the transcription and protein concentration results related to lipid metabolism. In conclusion, moderate levels of dietary ARA (0.37% and 0.60%) reduced lipid accumulation and tended to inhibit cell cycle progression in the liver of Japanese seabass. PMID- 30013124 TI - Testing the feasibility of the startle-first route to deimatism. AB - Many prey species perform deimatic displays that are thought to scare or startle would-be predators, or elicit other reflexive responses that lead to attacks being delayed or abandoned. The form of these displays differs among species, but often includes prey revealing previously-hidden conspicuous visual components. The evolutionary route(s) to deimatism are poorly understood, but it has recently been suggested that the behavioural component of the displays evolves first followed by a conspicuous visual component. This is known as the "startle-first hypothesis". Here we use an experimental system in which naive domestic chicks forage for artificial deimatic prey to test the two key predictions of this hypothesis: (1) that movement can deter predators in the absence of conspicuously coloured display components; and, (2) that the combination of movement and conspicuously coloured display components is more effective than movement alone. We show that both these predictions hold, but only when the movement is fast. We thus provide evidence for the feasibility of 'the startle-first hypothesis' of the evolution of deimatism. PMID- 30013125 TI - Growth of mountain belts in central Asia triggers a new collision zone in central India. AB - Several unusual strong earthquakes occurred in central India along the Narmada Son Lineament (NSL) zone, far from active plate boundaries. To understand the role of collisional processes in the origin of this seismicity, we develop a numerical thermomechanical model of shortening between the Indian Plate and Asia. We show that at the final stage of collision, the shortening rate of the high mountain areas slows. The continuing convergence of India and Asia triggers the initiation of a new collision zone in continental part of India. Various geological and geophysical observations indicate that the NSL is a weakest zone with northward thrusting of the thinner central Indian lithosphere underneath the thicker northern part of the Indian Plate. We hypothesize that the NSL was reactivated during the final stage of the India Asia convergence and it will possibly form a new mountain belt within the Indian continent. PMID- 30013127 TI - Design principles of the paradoxical feedback between pancreatic alpha and beta cells. AB - Mammalian glucose homeostasis is controlled by the antagonistic hormones insulin and glucagon, secreted by pancreatic beta and alpha cells respectively. These two cell types are adjacently located in the islets of Langerhans and affect each others' secretions in a paradoxical manner: while insulin inhibits glucagon secretion from alpha cells, glucagon seems to stimulate insulin secretion from beta cells. Here we ask what are the design principles of this negative feedback loop. We systematically simulate the dynamics of all possible islet inter cellular connectivity patterns and analyze different performance criteria. We find that the observed circuit dampens overshoots of blood glucose levels after reversion of glucose drops. This feature is related to the temporal delay in the rise of insulin concentrations in peripheral tissues, compared to the immediate hormone action on the liver. In addition, we find that the circuit facilitates coordinate secretion of both hormones in response to protein meals. Our study highlights the advantages of a paradoxical paracrine feedback loop in maintaining metabolic homeostasis. PMID- 30013126 TI - Structural determinants of specificity and regulation of activity in the allosteric loop network of human KLK8/neuropsin. AB - Human KLK8/neuropsin, a kallikrein-related serine peptidase, is mostly expressed in skin and the hippocampus regions of the brain, where it regulates memory formation by synaptic remodeling. Substrate profiles of recombinant KLK8 were analyzed with positional scanning using fluorogenic tetrapeptides and the proteomic PICS approach, which revealed the prime side specificity. Enzyme kinetics with optimized substrates showed stimulation by Ca2+ and inhibition by Zn2+, which are physiological regulators. Crystal structures of KLK8 with a ligand-free active site and with the inhibitor leupeptin explain the subsite specificity and display Ca2+ bound to the 75-loop. The variants D70K and H99A confirmed the antagonistic role of the cation binding sites. Molecular docking and dynamics calculations provided insights in substrate binding and the dual regulation of activity by Ca2+ and Zn2+, which are important in neuron and skin physiology. Both cations participate in the allosteric surface loop network present in related serine proteases. A comparison of the positional scanning data with substrates from brain suggests an adaptive recognition by KLK8, based on the tertiary structures of its targets. These combined findings provide a comprehensive picture of the molecular mechanisms underlying the enzyme activity of KLK8. PMID- 30013128 TI - A community-based study on the association between Helicobacter pylori Infection and obesity. AB - Helicobacter pylori (H. pylori) infection can induce chronic inflammation and is associated with insulin resistance, metabolic syndrome and body mass index (BMI, kg/m2) changes. This study aimed to evaluate the association between H. pylori infection and overweight/obesity. This research was a cross-sectional study conducted from March 2014 to November 2016, using data from the three districts in the northeastern region of Taiwan. The inclusion criteria were an age >30 years and the absence of pregnancy. Ultimately, 2686 subjects (1713 women) were included in this study. Among the subjects aged less than 50 years, the subjects with H. pylori infection had higher mean BMI values than those without H. pylori infection (40-49 years: 25.7 +/- 4.4 vs. 24.7 +/- 3.8, P = 0.025; 30-39 years: 24.9 +/- 4.4 vs. 24.0 +/- 4.1, P = 0.063). H. pylori infection increased the risk of being obese 2 (BMI >=30) (odds ratio, OR = 1.836, 95% CI = 1.079-3.125, P = 0.025) with adjustments for demographic factors in subjects aged less than 50 years. In conclusions, subjects with H. pylori infection and age less than 50 years may increase a risk of being obesity (BMI >=30) compared to those without this type of infection. PMID- 30013129 TI - Incineration of Nanoclay Composites Leads to Byproducts with Reduced Cellular Reactivity. AB - Addition of nanoclays into a polymer matrix leads to nanocomposites with enhanced properties to be used in plastics for food packaging applications. Because of the plastics' high stored energy value, such nanocomposites make good candidates for disposal via municipal solid waste plants. However, upon disposal, increased concerns related to nanocomposites' byproducts potential toxicity arise, especially considering that such byproducts could escape disposal filters to cause inhalation hazards. Herein, we investigated the effects that byproducts of a polymer polylactic acid-based nanocomposite containing a functionalized montmorillonite nanoclay (Cloisite 30B) could pose to human lung epithelial cells, used as a model for inhalation exposure. Analysis showed that the byproducts induced toxic responses, including reductions in cellular viability, changes in cellular morphology, and cytoskeletal alterations, however only at high doses of exposure. The degree of dispersion of nanoclays in the polymer matrix appeared to influence the material characteristics, degradation, and ultimately toxicity. With toxicity of the byproduct occurring at high doses, safety protocols should be considered, along with deleterious effects investigations to thus help aid in safer, yet still effective products and disposal strategies. PMID- 30013131 TI - Ecological consequences of post-Columbian indigenous depopulation in the Andean Amazonian corridor. AB - European colonization of South America instigated a continental-scale depopulation of its indigenous peoples. The impact of depopulation on the tropical forests of South America varied across the continent. Furthermore, the role that indigenous peoples played in transforming the biodiverse tropical forests of the Andean-Amazonian corridor before AD 1492 remains unknown. Here, we reconstruct the past 1,000 years of changing human impact on the cloud forest of Ecuador at a key trade route, which connected the Inkan Empire to the peoples of Amazonia. We compare this historical landscape with the pre-human arrival (around 44,000-42,000 years ago) and modern environments. We demonstrate that intensive land-use within the cloud forest before European arrival deforested the landscape to a greater extent than modern (post-AD 1950) cattle farming. Intensive indigenous land-use ended abruptly around AD 1588 following a catastrophic population decline. Forest succession then took around 130 years to establish a structurally intact forest-one comparable to that which occurred before the arrival of the first humans to the continent. We show that nineteenth-century descriptions of the Andean-Amazonian corridor as a pristine wilderness record a shifted ecological baseline-one that less than 250 years earlier had consisted of a heavily managed and cultivated landscape. PMID- 30013130 TI - The exercise sex gap and the impact of the estrous cycle on exercise performance in mice. AB - Exercise physiology is different in males and females. Females are poorly studied due to the complexity of the estrous cycle and this bias has created an exercise sex gap. Here, we evaluated the impact of sexual dimorphism and of the estrous cycle on muscle strength and running power of C57BL/6 mice. Like men, male mice were stronger and more powerful than females. Exercise-induced increase of O2 consumption ([Formula: see text]O2) and CO2 production ([Formula: see text]CO2) were equal between sexes, indicating that running economy was higher in males. Thermoregulation was also more efficient in males. In females, proestrus increased exercise [Formula: see text]O2 and [Formula: see text]CO2 at low running speeds (30-35% female [Formula: see text]O2max) and estrus worsened thermoregulation. These differences translated into different absolute and relative workloads on the treadmill, even at equal submaximal [Formula: see text]O2 and belt speeds. In summary, our results demonstrate the better muscle strength, running power and economy, and exercise-induced thermoregulation of males compared to females. Proestrus and estrus still undermined the running economy and exercise-induced thermoregulation of females, respectively. These results demonstrate an important exercise sex gap in mice. PMID- 30013132 TI - Logarithmic scales in ecological data presentation may cause misinterpretation. AB - Scientific communication relies on clear presentation of data. Logarithmic scales are used frequently for data presentation in many scientific disciplines, including ecology, but the degree to which they are correctly interpreted by readers is unclear. Analysing the extent of log scales in the literature, we show that 22% of papers published in the journal Ecology in 2015 included at least one log-scaled axis, of which 21% were log-log displays. We conducted a survey that asked members of the Ecological Society of America (988 responses, and 623 completed surveys) to interpret graphs that were randomly displayed with linear linear or log-log axes. Many more respondents interpreted graphs correctly when the graphs had linear-linear axes than when they had log-log axes: 93% versus 56% for our all-around metric, although some of the individual item comparisons were even more skewed (for example, 86% versus 9% and 88% versus 12%). These results suggest that misconceptions about log-scaled data are rampant. We recommend that ecology curricula include explicit instruction on how to interpret log-scaled axes and equations, and we also recommend that authors take the potential for misconceptions into account when deciding how to visualize data. PMID- 30013134 TI - Hydrology and the future of the Greenland Ice Sheet. AB - Detection, attribution and projection of mass loss from the Greenland Ice Sheet has been a central focus of the glaciological community, with surface meltwater thought to play a key role in feedbacks that could accelerate sea-level rise. While the prospect of runaway sliding has faded, much remains uncertain when it comes to the role of surface runoff and subglacial discharge in Greenland's future. PMID- 30013133 TI - Patchy field sampling biases understanding of climate change impacts across the Arctic. AB - Effective societal responses to rapid climate change in the Arctic rely on an accurate representation of region-specific ecosystem properties and processes. However, this is limited by the scarcity and patchy distribution of field measurements. Here, we use a comprehensive, geo-referenced database of primary field measurements in 1,840 published studies across the Arctic to identify statistically significant spatial biases in field sampling and study citation across this globally important region. We find that 31% of all study citations are derived from sites located within 50 km of just two research sites: Toolik Lake in the USA and Abisko in Sweden. Furthermore, relatively colder, more rapidly warming and sparsely vegetated sites are under-sampled and under recognized in terms of citations, particularly among microbiology-related studies. The poorly sampled and cited areas, mainly in the Canadian high-Arctic archipelago and the Arctic coastline of Russia, constitute a large fraction of the Arctic ice-free land area. Our results suggest that the current pattern of sampling and citation may bias the scientific consensuses that underpin attempts to accurately predict and effectively mitigate climate change in the region. Further work is required to increase both the quality and quantity of sampling, and incorporate existing literature from poorly cited areas to generate a more representative picture of Arctic climate change and its environmental impacts. PMID- 30013135 TI - What treating Ebola means for pandemic influenza. AB - Almost all new treatments being developed for the next influenza pandemic target the virus. During the Ebola crisis in West Africa, patients were treated with an inexpensive generic statin/angiotensin receptor blocker combination that appeared to greatly improve survival. These drugs target the host response, not the virus, and probably reverse endothelial dysfunction. Scientists and health officials have shown little interest in this idea. Yet, during the early months of the next pandemic, vaccines will be unavailable and treatment options will be limited. Physicians should be prepared to undertake clinical trials of widely available generic drugs to determine whether they improve survival in patients with seasonal influenza, other emerging virus diseases, and other forms of acute critical illness. Public health officials should give these studies their strong support. If successful, they will suggest a 'bottom up' approach to patient care that could be implemented worldwide on the first pandemic day. PMID- 30013136 TI - Completing the global strategy: a missing element in preparation for pandemic influenza. PMID- 30013137 TI - Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis. AB - Insulin stimulates lipogenesis but insulin resistance is also associated with increased hepatic lipogenesis in obesity. However, the underlying mechanism remains poorly characterized. Here, we show a noncanonical insulin-Snail1 pathway that suppresses lipogenesis. Insulin robustly upregulates zinc-finger protein Snail1 in a PI 3-kinase-dependent manner. In obesity, the hepatic insulin-Snail1 cascade is impaired due to insulin resistance. Hepatocyte-specific deletion of Snail1 enhances insulin-stimulated lipogenesis in hepatocytes, exacerbates dietary NAFLD in mice, and attenuates NAFLD-associated insulin resistance. Liver specific overexpression of Snail1 has the opposite effect. Mechanistically, Snail1 binds to the fatty acid synthase promoter and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27, thereby repressing fatty acid synthase promoter activity. Our data suggest that insulin pathways bifurcate into canonical (lipogenic) and noncanonical (anti-lipogenesis by Snail1) two arms. The noncanonical arm counterbalances the canonical arm through Snail1-elicited epigenetic suppression of lipogenic genes. Impairment in the insulin-Snail1 arm may contribute to NAFLD in obesity. PMID- 30013138 TI - Genetic characterization and pathogenic potential of H10 avian influenza viruses isolated from live poultry markets in Bangladesh. AB - Fatal human cases of avian-origin H10N8 influenza virus infections have raised concern about their potential for human-to-human transmission. H10 subtype avian influenza viruses (AIVs) have been isolated from wild and domestic aquatic birds across Eurasia and North America. We isolated eight H10 AIVs (four H10N7, two H10N9, one H10N1, and one H10N6) from live poultry markets in Bangladesh. Genetic analyses demonstrated that all eight isolates belong to the Eurasian lineage. HA phylogenetic and antigenic analyses indicated that two antigenically distinct groups of H10 AIVs are circulating in Bangladeshi live poultry markets. We evaluated the virulence of four representative H10 AIV strains in DBA/2J mice and found that they replicated efficiently in mice without prior adaptation. Moreover, H10N6 and H10N1 AIVs caused high mortality with systemic dissemination. These results indicate that H10 AIVs pose a potential threat to human health and the mechanisms of their transmissibility should be elucidated. PMID- 30013140 TI - Correction: C-X-C motif chemokine ligand 10 produced by mouse Sertoli cells in response to mumps virus infection induces male germ cell apoptosis. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30013139 TI - Gene expression profiles of germ-free and conventional piglets from the same litter. AB - Germ-free (GF) pigs have clear microbiological backgrounds, and are extensively used as large animal models in the biomedical sciences. However, investigations of the transcriptomic differences between GF and cesarean-derived conventional (CV) piglets are limited. To improve our understanding of GF pigs, and to increase the utility of pigs as an alternative non-rodent model, we used RNA sequencing to profile gene expression in five tissues (the oral mucosae, jejunum, colon, liver, and spleen) of four male GF piglets and four male CV piglets from the same litter. We identified 14 genes that were differentially expressed in all five tissues. Seven of these common differentially expressed genes (DEGs) were interferon-inducible genes, and all 14 were consistently downregulated in the GF piglets as compared to the CV piglets. Compared to the other tissues tested, the expression of transcription factors (TFs) in the colon was most affected by the absence of a microbiota. The expression patterns of immune-related genes were downregulated in the GF piglets as compared to the CV piglets, indicating that the intestinal microbiota influenced gene expression in other tissues besides the gut. Gene Ontology (GO) analysis indicated that, in pigs, the intestinal microbiota affected the expression of genes related to immune system function and development. PMID- 30013142 TI - The paradigm shift in Antarctic ice sheet modelling. AB - The Antarctic ice sheet is one of the largest potential contributors to future sea level rise. Predicting its future behaviour using physically-based ice sheet models has been a bottleneck for the past decades, but major advances are ongoing. PMID- 30013141 TI - Circulating microRNAs are associated with Pulmonary Hypertension and Development of Chronic Lung Disease in Congenital Diaphragmatic Hernia. AB - Pulmonary hypertension (PH) contributes to high mortality in congenital diaphragmatic hernia (CDH). A better understanding of the regulatory mechanisms underlying the pathology in CDH might allow the identification of prognostic biomarkers and potential therapeutic targets. We report the results from an expression profiling of circulating microRNAs (miRNAs) in direct post-pulmonary blood flow of 18 CDH newborns. Seven miRNAs differentially expressed in children that either died or developed chronic lung disease (CLD) up to 28 days after birth, compared to those who survived without developing CLD during this period, were identified. Target gene and pathway analyses indicate that these miRNAs functions include regulation of the cell cycle, inflammation and morphogenesis, by targeting molecules responsive to growth factors, cytokines and cellular stressors. Furthermore, we identified hub molecules by constructing a protein protein interaction network of shared targets, and ranked the relative importance of the identified miRNAs. Our results suggest that dysregulations in miRNAs let 7b-5p, -7c-5p, miR-1307-3p, -185-3p, -8084, -331-3p and -210-3p may be detrimental for the development and function of the lungs and pulmonary vasculature, compromise cardiac function and contribute to the development of CLD in CDH. Further investigation of the biomarker and therapeutic potential of these circulating miRNAs is encouraged. PMID- 30013144 TI - gammadelta T cells and IgE team up to prevent tumors. PMID- 30013143 TI - TCRs are randomly distributed on the plasma membrane of resting antigen experienced T cells. AB - The main function of T cells is to identify harmful antigens as quickly and precisely as possible. Super-resolution microscopy data have indicated that global clustering of T cell antigen receptors (TCRs) occurs before T cell activation. Such pre-activation clustering has been interpreted as representing a potential regulatory mechanism that fine tunes the T cell response. We found here that apparent TCR nanoclustering could be attributed to overcounting artifacts inherent to single-molecule-localization microscopy. Using complementary super resolution approaches and statistical image analysis, we found no indication of global nanoclustering of TCRs on antigen-experienced CD4+ T cells under non activating conditions. We also used extensive simulations of super-resolution images to provide quantitative limits for the degree of randomness of the TCR distribution. Together our results suggest that the distribution of TCRs on the plasma membrane is optimized for fast recognition of antigen in the first phase of T cell activation. PMID- 30013145 TI - CD8+ T cells have commitment issues. PMID- 30013147 TI - Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific. AB - The functions and transcriptional profiles of dendritic cells (DCs) result from the interplay between ontogeny and tissue imprinting. How tumors shape human DCs is unknown. Here we used RNA-based next-generation sequencing to systematically analyze the transcriptomes of plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 conventional DCs (cDC1s), type 2 conventional DCs (cDC2s), CD14+ DCs and monocytes-macrophages from human primary luminal breast cancer (LBC) and triple-negative breast cancer (TNBC). By comparing tumor tissue with non-invaded tissue from the same patient, we found that 85% of the genes upregulated in DCs in LBC were specific to each DC subset. However, all DC subsets in TNBC commonly showed enrichment for the interferon pathway, but those in LBC did not. Finally, we defined transcriptional signatures specific for tumor DC subsets with a prognostic effect on their respective breast-cancer subtype. We conclude that the adjustment of DCs to the tumor microenvironment is subset specific and can be used to predict disease outcome. Our work also provides a resource for the identification of potential targets and biomarkers that might improve antitumor therapies. PMID- 30013148 TI - T cell cytolytic capacity is independent of initial stimulation strength. AB - How cells respond to myriad stimuli with finite signaling machinery is central to immunology. In naive T cells, the inherent effect of ligand strength on activation pathways and endpoints has remained controversial, confounded by environmental fluctuations and intercellular variability within populations. Here we studied how ligand potency affected the activation of CD8+ T cells in vitro, through the use of genome-wide RNA, multi-dimensional protein and functional measurements in single cells. Our data revealed that strong ligands drove more efficient and uniform activation than did weak ligands, but all activated cells were fully cytolytic. Notably, activation followed the same transcriptional pathways regardless of ligand potency. Thus, stimulation strength did not intrinsically dictate the T cell-activation route or phenotype; instead, it controlled how rapidly and simultaneously the cells initiated activation, allowing limited machinery to elicit wide-ranging responses. PMID- 30013146 TI - Epithelial damage and tissue gammadelta T cells promote a unique tumor-protective IgE response. AB - IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by gammadeltaTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that gammadelta T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcepsilonRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcepsilonRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development. PMID- 30013149 TI - Validation of reference genes for quantitative real-time PCR in tiger beetles across sexes, body parts, sexual maturity and immune challenge. AB - Reference genes are frequently used as normalizers for expression studies despite not being previously verified to present suitable stabilities. Considering the interest that tiger beetles have generated in the past years, resulting in a variety of studies, it is crucial to dispose of a validated reference gene panel for expression studies. Nine candidate genes were tested in Cicindela campestris and Calomera littoralis across several conditions and their transcription levels were assessed with geNorm, NormFinder, BestKeeper and DeltaCT method algorithms. Results showed high stabilities across sexes, immune challenge and gonad developmental stages for all genes tested, while body parts comparison presented less constant expression values. Only two genes are sufficient to perform a proper normalization for most of the conditions tested, except for the body parts comparison in C. littoralis, which requires the use of at least three reference genes. On the whole, no universal gene is found to be suitable for all situations, but according to the acceptable range of values, NADH, B-t, Vatpase and ArgKin seem to present the most constant expression stability, indicating their suitability as reference genes in most of the conditions. This is the first report evaluating the stability of housekeeping genes in adephagan beetles. PMID- 30013150 TI - Fully automatic liver segmentation combining multi-dimensional graph cut with shape information in 3D CT images. AB - Liver segmentation is an essential procedure in computer-assisted surgery, radiotherapy, and volume measurement. It is still a challenging task to extract liver tissue from 3D CT images owing to nearby organs with similar intensities. In this paper, an automatic approach integrating multi-dimensional features into graph cut refinement is developed and validated. Multi-atlas segmentation is utilized to estimate the coarse shape of liver on the target image. The unsigned distance field based on initial shape is then calculated throughout the whole image, which aims at automatic graph construction during refinement procedure. Finally, multi-dimensional features and shape constraints are embedded into graph cut framework. The optimal liver region can be precisely detected with a minimal cost. The proposed technique is evaluated on 40 CT scans, obtained from two public databases Sliver07 and 3Dircadb1. The dataset Sliver07 is considered as the training set for parameter learning. On the dataset 3Dircadb1, the average of volume overlap is up to 94%. The experiment results indicate that the proposed method has ability to reach the desired boundary of liver and has potential value for clinical application. PMID- 30013151 TI - Developing core outcome set for women's, newborn, and child health: the CROWN Initiative. PMID- 30013152 TI - Circulatory changes during gestational development of the sheep and human fetus. AB - BACKGROUND: Circulatory changes during gestational development of the human fetus have been considered to be similar to those noted in studies of the lamb fetus. METHODS: Blood flow measurements derived by Doppler ultrasound and magnetic resonance imaging techniques in human fetuses at various stages of gestation have been compared with those in the lamb. RESULTS: Combined ventricular output relative to fetal body weight does not change significantly with growth in the lamb or human. However, the proportion of cardiac output to the brain increases markedly in the human, but only slightly in the lamb fetus in the latter half of gestation. Cardiac output distribution to other organs also changes little in the lamb, but in the human, there is a marked decrease in the proportion distributed to the placenta and an increase in pulmonary flow. CONCLUSION: The developmental changes in the distribution of combined ventricular output in the human fetus may modify the responses to circulatory disturbances, such as congenital cardiovascular malformations, dependent on gestation. PMID- 30013154 TI - The USPSTF screening recommendation: a swinging pendulum. PMID- 30013153 TI - Small near-infrared photochromic protein for photoacoustic multi-contrast imaging and detection of protein interactions in vivo. AB - Photoacoustic (PA) computed tomography (PACT) benefits from genetically encoded probes with photochromic behavior, which dramatically increase detection sensitivity and specificity through photoswitching and differential imaging. Starting with a DrBphP bacterial phytochrome, we have engineered a near-infrared photochromic probe, DrBphP-PCM, which is superior to the full-length RpBphP1 phytochrome previously used in differential PACT. DrBphP-PCM has a smaller size, better folding, and higher photoswitching contrast. We have imaged both DrBphP PCM and RpBphP1 simultaneously on the basis of their unique signal decay characteristics, using a reversibly switchable single-impulse panoramic PACT (RS SIP-PACT) with a single wavelength excitation. The simple structural organization of DrBphP-PCM allows engineering a bimolecular PA complementation reporter, a split version of DrBphP-PCM, termed DrSplit. DrSplit enables PA detection of protein-protein interactions in deep-seated mouse tumors and livers, achieving 125-um spatial resolution and 530-cell sensitivity in vivo. The combination of RS SIP-PACT with DrBphP-PCM and DrSplit holds great potential for noninvasive multi contrast deep-tissue functional imaging. PMID- 30013155 TI - Structural Insight into Substrate Specificity of 3-Hydroxypropionyl-Coenzyme A Dehydratase from Metallosphaera sedula. AB - Metallosphaera sedula is a thermoacidophilic autotrophic archaeon known to utilize the 3-hydroxypropionate/4-hydroxybutyrate cycle (3-HP/4-HB cycle) as carbon fixation pathway. 3-Hydroxypropionyl-CoA dehydratase (3HPCD) is an enzyme involved in the 3-HP/4-HB cycle by converting 3-hydroxypropionyl-CoA to acryloyl CoA. To elucidate the molecular mechanism of 3HPCD from M. sedula (Ms3HPCD), we determined its crystal structure in complex with Coenzyme A (CoA). Ms3HPCD showed an overall structure and the CoA-binding mode similar to other enoyl-CoA hydratase (ECH) family enzymes. However, compared with the other ECHs, Ms3HPCD has a tightly formed alpha3 helix near the active site, and bulky aromatic residues are located at the enoyl-group binding site, resulting in the enzyme having an optimal substrate binding site for accepting short-chain 3-hydroxyacyl CoA as a substrate. Moreover, based on the phylogenetic tree analysis, we propose that the 3HPCD homologues from the phylum Crenarchaeota have an enoyl-group binding pocket similar to that of bacterial short-chain ECHs. PMID- 30013157 TI - Evaluation of serum and ocular levels of membrane attack complex and C-reactive protein in CFH-genotyped human donors. AB - BACKGROUND: There is a considerable body of evidence demonstrating a link between the membrane attack complex (MAC) and age-related macular degeneration (AMD), and between C-reactive protein (CRP) and AMD. Both the MAC and the monomeric form of CRP (mCRP) accumulate within the choriocapillaris in AMD. However, the precise contribution of these species to AMD pathophysiology has not been fully elucidated. METHODS: We sought to directly assess CRP and MAC levels between human serum and ocular tissues from the same CFH Y402H genotyped donors using ELISA of serum and RPE/choroid proteins. RESULTS: The Y402H polymorphism was associated with significantly increased MAC in RPE/choroid samples, but not in the serum, in a previously unstudied cohort. While MAC levels in the choroid were independent of circulating levels, choroidal CRP was correlated to serum levels. CONCLUSIONS: These data provide further evidence for local activation of complement within the choriocapillaris in AMD. PMID- 30013156 TI - The management of macular hole retinal detachment and macular retinoschisis in pathological myopia; a UK collaborative study. AB - PURPOSE: To study UK practice patterns for the management of retinal detachment secondary to macular hole (MHRD) and macular retinoschisis (MRS) in pathological myopia (PM). To review the anatomical and visual outcomes of the surgically managed cases. METHODS: A prospective observational case series for the management of MHRD was undertaken in association with the British Ophthalmological Surveillance Unit (BOSU). The results were combined with retrospective data, collected by the COllaboration of British RetinAl Surgeons (COBRA), on the management of both MHRD and MRS in PM in the UK. A total of 20 cases of MHRD and 53 cases of MRS (27 surgical cases and 26 cases managed conservatively) are reported in this combined study. RESULTS: MHRD: Mean baseline best corrected visual acuity (BCVA) was 1.60 logMAR. All cases underwent pars plana vitrectomy (PPV). Mean post-operative BCVA was 1.49 logMAR (p = 0.674). The macular hole was closed in 5/20 (25%) cases, open/flat in 10/20 (50%) cases and open/elevated in 4/20 cases (20%). MRS: Mean baseline BCVA was 0.87 logMAR in the surgical group and 0.45 logMAR in the conservatively managed group (p = 0.002). All eyes that had surgical intervention underwent PPV. Mean post-operative BCVA was 0.68 logMAR (p = 0.183). Anatomical outcomes demonstrated a persistent MRS in 2/27 (7.4%) cases, partial resolution in 7/27 (25.9%) cases and complete resolution in 16/27 (59.2%) cases. CONCLUSIONS: PPV is the only surgical procedure performed for the management of MHRD and MRS amongst the study participants. Success rates and visual outcomes are limited for MHRD and consistent with the current literature for MRS. PMID- 30013159 TI - Population authentication of the traditional medicinal plant Cassia tora L. based on ISSR markers and FTIR analysis. AB - Cassia tora is a plant of medicinal importance. Medicinal plants from different localities are believed to differ in their therapeutic potency. In this study, six populations of C. tora with different eco-geographical origins were investigated genotypically (ISSR) and phytochemically (FTIR) to establish an integrated approach for population discrimination and authentication of the origin of this medicinal herb. CHS gene expression analysis and determination of flavonoid content were carried out to substantiate the study. A total of 19 population-specific authentication bands were observed in 11 ISSR fingerprints. Authentication codes were generated using six highly polymorphic bands, including three authentication bands. FTIR spectra revealed that the peaks at wavenumber 1623 cm-1 (carbonyl group) and 1034 cm-1 (>CO- group) were powerful in separating the populations. These peaks are assigned to flavonoids and carbohydrates, respectively, were more intense for Ranchi (highland) population. Variation in the transcript level of CHS gene was observed. The findings of FTIR and RT-PCR analyses were in agreement with the TFC analysis, where, the lowest amount of flavonoids observed for Lucknow (lowland) population. All the populations of C. tora have been authenticated accurately by ISSR analyses and FTIR fingerprinting, and the Ranchi site was observed to be more suitable for the potential harvesting of therapeutic bioactive compounds. PMID- 30013161 TI - Insights into global planktonic diatom diversity: The importance of comparisons between phylogenetically equivalent units that account for time. AB - Metabarcoding has offered unprecedented insights into microbial diversity. In many studies, short DNA sequences are binned into consecutively lower Linnaean ranks, and ranked groups (e.g., genera) are the units of biodiversity analyses. These analyses assume that Linnaean ranks are biologically meaningful and that identically ranked groups are comparable. We used a metabarcode dataset for marine planktonic diatoms to illustrate the limits of this approach. We found that the 20 most abundant marine planktonic diatom genera ranged in age from 4 to 134 million years, indicating the non-equivalence of genera because some have had more time to diversify than others. However, species richness was largely independent of genus age, suggesting that disparities in species richness among genera were better explained by variation in rates of speciation and extinction. Taxonomic classifications often do not reflect phylogeny, so genus-level analyses can include phylogenetically nested genera, further confounding rank-based analyses. These results underscore the indispensable role of phylogeny in understanding patterns of microbial diversity. PMID- 30013158 TI - Retinopathy of prematurity in the United Kingdom: retreatment rates, visual and structural 1-year outcomes. AB - AIMS: To evaluate retreatment rates, visual and anatomical outcomes at 1-year postnatal age in infants treated for retinopathy of prematurity (ROP) METHODS: Longitudinal national surveillance study of infants treated for ROP in the United Kingdom between December 2013 and December 2014, supported by the British Ophthalmic Surveillance Unit. Here we report retreatment rates, anatomical, visual and refractive outcomes at 1-year follow-up. RESULTS: One-year follow-up forms were completed for 168 children of the original cohort of 327 (51.4%). Twenty-two had at least one retreatment: 17/153 right eyes (REs, 11.1%) after initial diode laser, and 5/14 REs (35.7%) after initial injection of anti vascular endothelial growth factor (VEGF) antibody. Median (interquartile range) RE best-corrected visual acuity was 0.6 (0.4-1.0) (n = 46 REs), and median acuity both eyes open 0.4 (0.3-0.7) logMAR (n = 89). Median spherical equivalent (RE) was 0.44 (-1.3 to 1.3) dioptre (D) (n = 116). Median astigmatism (RE) was 0.5 (0 1.0) D (n = 111), and median anisometropia 0.125 (0-0.75) D (n = 116). Twenty four children (20.5%) had been prescribed glasses. Sight impairment certification eligibility information was available for 131 children: 11 (8.4%) were eligible to be certified as sight impaired, and 5 (3.8%) as severely sight impaired. CONCLUSIONS: Retreatment rates are in line with previous reports, and appear higher after initial anti-VEGF antibody than after initial diode laser. Refractive outcomes are in line with previous studies, with a trend towards early emmetropia and myopia following diode laser, particularly in more severe ROP. PMID- 30013160 TI - Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. AB - ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms. PMID- 30013163 TI - Latitudinal variation in soil biota: testing the biotic interaction hypothesis with an invasive plant and a native congener. AB - Soil biota community structure can change with latitude, but the effects of changes on native plants, invasive plants, and their herbivores remain unclear. Here, we examined latitudinal variation in the soil biota community associated with the invasive plant Alternanthera philoxeroides and its native congener A. sessilis, and the effects of soil biota community variation on these plants and the beetle Agasicles hygrophila. We characterized the soil bacterial and fungal communities and root-knot nematodes of plant rhizospheres collected from 22 degrees N to 36.6 degrees N in China. Soil biota community structure changed with latitude as a function of climate and soil properties. Root-knot nematode abundance and potential soil fungal pathogen diversity (classified with FUNGuild) decreased with latitude, apparently due to higher soil pH and lower temperatures. A greenhouse experiment and lab bioassay showed native plant mass, seed production, and mass of beetles fed native foliage increased with soil collection latitude. However, there were no latitudinal patterns for the invasive plant. These results suggest that invasive and native plants and, consequently, their herbivores have different responses to latitudinal changes in soil-borne enemies, potentially creating spatial variation in enemy release or biotic resistance. This highlights the importance of linking above- and below-ground multitrophic interactions to explore the role of soil biota in non-native plant invasions with a biogeographic approach. PMID- 30013162 TI - The evolution of ecological facilitation within mixed-species biofilms in the mouse gastrointestinal tract. AB - The eco-evolutionary interactions among members of the vertebrate gut microbiota that ultimately result in host-specific communities are poorly understood. Here we show that Lactobacillus reuteri coexists with species that belong to the Lactobacillus johnsonii cluster (L. johnsonii, L. gasseri, and L taiwanensis) in a taxonomically wide range of rodents, suggesting cohabitation over evolutionary times. The two dominant Lactobacillus species found in wild mice establish a commensalistic relationship in gastric biofilms when introduced together into germ-free mice in which L. reuteri facilitates colonization of L. taiwanensis. Genomic analysis revealed allopatric diversification in strains of both species that originated from geographically separated locations (Scotland and France). Allopatry of the strains resulted in reduced formation of mixed biofilms in vitro, indicating that interspecies interactions in gastric Lactobacillus biofilms are the result of an adaptive evolutionary process that occurred in a biogeographical context. In summary, these findings suggest that members within the vertebrate gut microbiota can evolve inter-dependencies through ecological facilitation, which could represent one mechanism by which host-specific bacterial communities assemble across vertebrate species and an explanation for their spatial and biogeographic patterns. PMID- 30013167 TI - Referee acknowledgement for 2017. AB - In this issue, we publish the names of those who reviewed the manuscripts for us in 2017. The Editor-in-Chief, Subject Editors and everyone involved in publishing BJC would like to extend our sincere thanks to the referees for contributing their expertise and time. PMID- 30013165 TI - Identification and expression characterization of the Phloem Protein 2 (PP2) genes in ramie (Boehmeria nivea L. Gaudich). AB - Phloem protein 2 (PP2) is one of the most abundant and enigmatic proteins in sieve elements and companion cells, which play important roles in the maintenance of morphology, photoassimilate transportation and wound protection in higher plants, but to date, no PP2 (BnPP2) genes had been identified in ramie. Here, a total of 15 full-length BnPP2 genes were identified. These BnPP2 genes exhibited different responses to abiotic stresses. Interestingly, the BnPP2 genes are more sensitive to insect pests than to other stresses. A study of the BnPP2-15 promoter revealed that pBnPP2-15 could drive specific GUS expression in the petiole, root and stamen and could also be induced by mechanical wounding and aphid infection in transgenic Arabidopsis lines. The subcellular localization of six BnPP2 proteins showed that GFP-BnPP2-1, GFP-BnPP2-6, GFP-BnPP2-7, GFP-BnPP2 9, GFP-BnPP2-11 and GFP-BnPP2-12 were predominantly located in the cytoplasm. These results provide useful information elucidating the functions of BnPP2 genes in ramie. PMID- 30013164 TI - Metagenomics reveals functional synergy and novel polysaccharide utilization loci in the Castor canadensis fecal microbiome. AB - The North American beaver (Castor canadensis) has long been considered an engineering marvel, transforming landscapes and shaping biological diversity through its dam building behavior. While the beaver possesses conspicuous morphological features uniquely adapted for the use of woody plants as construction materials and dietary staples, relatively little is known about the specialized microorganisms inhabiting the beaver gastrointestinal tract and their functional roles in determining host nutrition. Here we use a combination of shotgun metagenomics, functional screening and carbohydrate biochemistry to chart the community structure and metabolic power of the beaver fecal microbiome. We relate this information to the metabolic capacity of other wood feeding and hindgut fermenting organisms and profile the functional repertoire of glycoside hydrolase (GH) families distributed among and between population genome bins. Metagenomic screening revealed novel mechanisms of xylan oligomer degradation involving GH43 enzymes from uncharacterized subfamilies and divergent polysaccharide utilization loci, indicating the potential for synergistic biomass deconstruction. Together, these results open a functional metagenomic window on less conspicuous adaptations enabling the beaver microbiome to efficiently convert woody plants into host nutrition and point toward rational design of enhanced enzyme mixtures for biorefining process streams. PMID- 30013166 TI - Non-adaptive strategy selection in adults with high mathematical anxiety. AB - Participants with mathematical anxiety (MA) tend to show particular difficulty in mathematical operations with high working memory (WM) demands compared to operations with lower WM demands. Accordingly, we examined strategy selection to test the cognitive mechanism underlying the observed weakness of high MA participants in mathematical operations with high WM demands. We compared two groups of college students with high or low MA, in the solution of simple non carry addition problems (e.g., 54 + 63) and complex carryover addition problems (e.g., 59 + 63). The results indicated that high MA participants showed particular difficulty in the harder carry condition. Testing the strategy selection mechanism among high MA participants, we found in the carry condition 1) they used the common strategy less often compared to low MA participants and 2) employed unusual strategies more often compared to low MA participants. Therefore, high MA participants were less efficient in their strategy selection, which may be due to weaker spatial representations, numerical difficulties, or less experience solving complex problems. These primitive representations are not adaptive, and can negatively impact performance in math tasks with high WM demands. PMID- 30013168 TI - Transcriptional profiling and genes involved in acquired thermotolerance in Banana: a non-model crop. AB - Banana is a non- model crop plant, and one of the most important crops in the tropics and sub tropics. Heat stress is the major abiotic stress affecting banana crop production because of its long growth period and is likely to become a threat due to global warming. To understand an acquired thermotolerance phenomenon at the molecular level, the RNA-seq approach was employed by adapting TIR method. A total of 136.38 million high quality reads were assembled. Differentially expressed genes under induction (I) was 3936, I + L was 2268 and lethal stress was 907 compared to control. Gene ontology and DGE analysis showed that genes related to heat shock factors, heat shock proteins, stress associated proteins, ROS scavenging, fatty acid metabolism, protein modification were significantly up regulated during induction, thus preparing the organism or tissue at molecular and cellular level for acquired thermotolerance. KEGG pathway analysis revealed the significant enrichment of pathways involved in protein processing, MAPK signaling and HSPs which indicates that these processes are conserved and involved in thermo tolerance. Thus, this study provides insights into the acquired thermotolerance phenomena in plants especially banana. PMID- 30013169 TI - Author Correction: PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation. AB - In the version of this article initially published, the right panel in Fig. 2b was duplicated from the corresponding panel in Fig. 2c, and some data points in Fig. 3b were duplicated from Fig. 3a. None of the conclusions in the paper are affected. The errors have been corrected in the HTML and PDF versions of the article, and source data have been posted for the revised panels. The original and corrected figures are shown in the accompanying Author Correction. PMID- 30013170 TI - Publisher Correction: Tuned thalamic excitation is amplified by visual cortical circuits. AB - In the published version of this article, a data point is missing from Fig. 4f, and the y-axis label reads "RFpre"; it should read "RFpref." The original article has not been corrected. The original and corrected figures are shown in the accompanying Publisher Correction. PMID- 30013172 TI - FRETting over postsynaptic PKC signaling. PMID- 30013171 TI - PKCalpha integrates spatiotemporally distinct Ca2+ and autocrine BDNF signaling to facilitate synaptic plasticity. AB - The protein kinase C (PKC) enzymes have long been established as critical for synaptic plasticity. However, it is unknown whether Ca2+-dependent PKC isozymes are activated in dendritic spines during plasticity and, if so, how this synaptic activity is encoded by PKC. Here, using newly developed, isozyme-specific sensors, we demonstrate that classical isozymes are activated to varying degrees and with distinct kinetics. PKCalpha is activated robustly and rapidly in stimulated spines and is the only isozyme required for structural plasticity. This specificity depends on a PDZ-binding motif present only in PKCalpha. The activation of PKCalpha during plasticity requires both NMDA receptor Ca2+ flux and autocrine brain-derived neurotrophic factor (BDNF)-TrkB signaling, two pathways that differ vastly in their spatiotemporal scales of signaling. Our results suggest that, by integrating these signals, PKCalpha combines a measure of recent, nearby synaptic plasticity with local synaptic input, enabling complex cellular computations such as heterosynaptic facilitation of plasticity necessary for efficient hippocampus-dependent learning. PMID- 30013173 TI - Structural cortical network reorganization associated with early conversion to multiple sclerosis. AB - Brain structural covariance networks (SCNs) based on pairwise statistical associations of cortical thickness data across brain areas reflect underlying physical and functional connections between them. SCNs capture the complexity of human brain cortex structure and are disrupted in neurodegenerative conditions. However, the longitudinal assessment of SCN dynamics has not yet been explored, despite its potential to unveil mechanisms underlying neurodegeneration. Here, we evaluated the changes of SCNs over 12 months in patients with a first inflammatory-demyelinating attack of the Central Nervous System and assessed their clinical relevance by comparing SCN dynamics of patients with and without conversion to multiple sclerosis (MS) over one year. All subjects underwent clinical and brain MRI assessments over one year. Brain cortical thicknesses for each subject and time point were used to obtain group-level between-area correlation matrices from which nodal connectivity metrics were obtained. Robust bootstrap-based statistical approaches (allowing sampling with replacement) assessed the significance of longitudinal changes. Patients who converted to MS exhibited significantly greater network connectivity at baseline than non converters (p = 0.02) and a subsequent connectivity loss over time (p = 0.001 0.02), not observed in non-converters' network. These findings suggest SCN analysis is sensitive to brain tissue changes in early MS, reflecting clinically relevant aspects of the condition. However, this is preliminary work, indicated by the low sample sizes, and its results and conclusions should be treated with caution and confirmed with larger cohorts. PMID- 30013174 TI - Self-hydrogenated shell promoting photocatalytic H2 evolution on anatase TiO2. AB - As one of the most important photocatalysts, TiO2 has triggered broad interest and intensive studies for decades. Observation of the interfacial reactions between water and TiO2 at microscopic scale can provide key insight into the mechanisms of photocatalytic processes. Currently, experimental methodologies for characterizing photocatalytic reactions of anatase TiO2 are mostly confined to water vapor or single molecule chemistry. Here, we investigate the photocatalytic reaction of anatase TiO2 nanoparticles in water using liquid environmental transmission electron microscopy. A self-hydrogenated shell is observed on the TiO2 surface before the generation of hydrogen bubbles. First-principles calculations suggest that this shell is formed through subsurface diffusion of photo-reduced water protons generated at the aqueous TiO2 interface, which promotes photocatalytic hydrogen evolution by reducing the activation barrier for H2 (H-H bond) formation. Experiments confirm that the self-hydrogenated shell contains reduced titanium ions, and its thickness can increase to several nanometers with increasing UV illuminance. PMID- 30013175 TI - In utero gene expression in the Slc39a8(neo/neo) knockdown mouse. AB - Slc39a8 encodes ZIP8, a divalent cation/bicarbonate symporter expressed in pluripotent mouse embryonic stem cells, and therefore ubiquitous in adult tissues; ZIP8 influxes Zn2+, Mn2+ and Fe2+. Slc39a8(neo/neo) knockdown mice exhibit 10-15% of wild-type ZIP8 mRNA and protein levels, and show pleiotropic phenotype of stunted growth, neonatal lethality, multi-organ dysmorphogenesis, and dysregulated hematopoiesis manifested as severe anemia. Herein we performed RNA-seq analysis of gestational day (GD)13.5 yolk sac and placenta, and GD16.5 liver, kidney, lung, heart and cerebellum, comparing Slc39a8(neo/neo) with Slc39a8(+/+) wild-type. Meta-data analysis of differentially-expressed genes revealed 29 unique genes from all tissues - having enriched GO categories associated with hematopoiesis and hypoxia and KEGG categories of complement, response to infection, and coagulation cascade - consistent with dysregulated hematopoietic stem cell fate. Based on transcription factor (TF) profiles in the JASPAR database, and searching for TF-binding sites enriched by Pscan, we identified numerous genes encoding zinc-finger and other TFs associated with hematopoietic stem cell functions. We conclude that, in this mouse model, deficient ZIP8-mediated divalent cation transport affects zinc-finger (e.g. GATA proteins) and other TFs interacting with GATA proteins (e.g. TAL1), predominantly in yolk sac. These data strongly support the phenotype of dysmorphogenesis and anemia seen in Slc39a8(neo/neo) mice in utero. PMID- 30013177 TI - Removal of Mn (II) by Sodium Alginate/Graphene Oxide Composite Double-Network Hydrogel Beads from Aqueous Solutions. AB - After the successful preparation of empirical double network hydrogel beads from graphene oxide/sodium alginate(GO/SA), its cationic metal adsorption performance in aqueous solutions were investigated. Taking Mn(II) as an example, the contribution of several factors including pH, bead dosage, temperature, contact time and initial concentration ions to adsorption efficiency were examined. The Transmission Electron Microscopy (TEM) results indicate that the GO/SA double (GAD) network hydrogel bead strongly interpenetrate and the adsorption of Mn(II) is mainly influenced by solution pH, bead dose and temperature. The GAD beads exhibit an excellent adsorption capacity of 56.49 mg g-1. The adsorption process fit both Pseudo-second order kinetic model (R2 > 0.97) and the Freundlich adsorption isotherm (R2 > 0.99) and is spontaneous. After seven rounds of adsorption-desorption cycle, the adsorption capacity of GAD hydrogel remained unchanged at 18.11 mg/g. PMID- 30013176 TI - Hyperthermia induces therapeutic effectiveness and potentiates adjuvant therapy with non-targeted and targeted drugs in an in vitro model of human malignant melanoma. AB - In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 degrees C) and high (45 degrees C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of non-targeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia's therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction. PMID- 30013178 TI - Common variation near IRF6 is associated with IFN-beta-induced liver injury in multiple sclerosis. AB - Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-beta (IFN-beta). Up to 60% of IFN-beta-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-beta-induced liver injury using a two-stage genome wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 * 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-beta-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 * 10-5) and alkaline phosphatase (P = 4.9 * 10-4). We show that these findings may be applicable to predicting IFN-beta-induced liver injury, offering insight into its safer use. PMID- 30013179 TI - Genome doubling shapes the evolution and prognosis of advanced cancers. AB - Ploidy abnormalities are a hallmark of cancer, but their impact on the evolution and outcomes of cancers is unknown. Here, we identified whole-genome doubling (WGD) in the tumors of nearly 30% of 9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wild-type tumors and in such cases was associated with an E2F-mediated G1 arrest defect, although neither aberration was obligate in WGD tumors. The variability of WGD across cancer types can be explained in part by cancer cell proliferation rates. WGD predicted for increased morbidity across cancer types, including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers, independently of established clinical prognostic factors. We conclude that WGD is highly common in cancer and is a macro-evolutionary event associated with poor prognosis across cancer types. PMID- 30013180 TI - Deep learning sequence-based ab initio prediction of variant effects on expression and disease risk. AB - Key challenges for human genetics, precision medicine and evolutionary biology include deciphering the regulatory code of gene expression and understanding the transcriptional effects of genome variation. However, this is extremely difficult because of the enormous scale of the noncoding mutation space. We developed a deep learning-based framework, ExPecto, that can accurately predict, ab initio from a DNA sequence, the tissue-specific transcriptional effects of mutations, including those that are rare or that have not been observed. We prioritized causal variants within disease- or trait-associated loci from all publicly available genome-wide association studies and experimentally validated predictions for four immune-related diseases. By exploiting the scalability of ExPecto, we characterized the regulatory mutation space for human RNA polymerase II-transcribed genes by in silico saturation mutagenesis and profiled > 140 million promoter-proximal mutations. This enables probing of evolutionary constraints on gene expression and ab initio prediction of mutation disease effects, making ExPecto an end-to-end computational framework for the in silico prediction of expression and disease risk. PMID- 30013182 TI - Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. AB - The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively1-3. Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic. PMID- 30013181 TI - Biallelic loss of human CTNNA2, encoding alphaN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration. AB - Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding alphaN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The alphaN catenin paralog, alphaE-catenin, acts as a switch regulating the balance between beta-catenin and Arp2/3 actin filament activities1. Loss of alphaN-catenin did not affect beta-catenin signaling, but recombinant alphaN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of alphaN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons. PMID- 30013183 TI - High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction. AB - Genome-wide association studies (GWAS) have identified many disease-associated noncoding variants, but cannot distinguish functional single-nucleotide polymorphisms (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by three disease-associated fSNPs via four regulatory proteins, RBPJ, RSRC2 and FUBP-1/TRAP150. Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2. Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism. PMID- 30013186 TI - More expansive gene transfer to the rat CNS: AAV PHP.EB vector dose-response and comparison to AAV PHP.B. AB - Engineered recombinant adeno-associated virus (AAV) vectors have advanced the transduction of neurons in the CNS on an expansive, wide-scale basis since the papers first using AAV9 for this purpose. Wide-scale CNS expression is relevant to gene therapy as well as indispensable for basic studies such as disease modeling. For example, the wide-scale gene transfer approach could expedite hypothesis testing in vivo relative to the generation of germ-line transgenic mice for all of the genes of interest. Wide-scale gene transfer is more efficient in neonates than in adults, so improving gene transfer efficiency in adults is an important goal. Here we characterized the relatively novel AAV PHP.EB vector for expansive gene transfer in the CNS of adult rats at three doses. The dose response data were consistent; expression levels can be controlled in a reproducible manner in the rat from moderate to robust levels. Within the CNS, the AAV PHP.EB-derived expression was neuron-selective to neuron-specific, while outside the CNS, organs such as the liver and heart were transduced by the parenteral gene delivery. Though we demonstrated graded expression levels, only the high dose, 1.2 * 1014 vector genomes/kg, yielded efficient expression in spinal cord motor neurons of the adult rat, so this vector dose would be required for models of spinal cord motor neuron disease. The neuronal expression in the rat CNS was greater with AAV PHP.EB than the previous engineered vector AAV PHP.B. AAV PHP.EB is thus one of the most efficient AAV vectors in the field for CNS gene transfer. PMID- 30013185 TI - Evolutionary dynamics of mycorrhizal symbiosis in land plant diversification. AB - Mycorrhizal symbiosis between soil fungi and land plants is one of the most widespread and ecologically important mutualisms on earth. It has long been hypothesized that the Glomeromycotina, the mycorrhizal symbionts of the majority of plants, facilitated colonization of land by plants in the Ordovician. This view was recently challenged by the discovery of mycorrhiza-like associations with Mucoromycotina in several early diverging lineages of land plants. Utilizing a large, species-level database of plants' mycorrhiza-like associations and a Bayesian approach to state transition dynamics we here show that the recruitment of Mucoromycotina is the best supported transition from a non-mycorrhizal state. We further found that transitions between different combinations of either or both of Mucoromycotina and Glomeromycotina occur at high rates, and found similar promiscuity among combinations that include either or both of Glomeromycotina and Ascomycota with a nearly fixed association with Basidiomycota. Our results portray an evolutionary scenario of evolution of mycorrhizal symbiosis with a prominent role for Mucoromycotina in the early stages of land plant diversification. PMID- 30013187 TI - Characterization of a replicating expanded tropism oncolytic reovirus carrying the adenovirus E4orf4 gene. AB - While the mammalian orthoreovirus type 3 dearing (reovirus T3D) infects many different tumour cells, various cell lines resist the induction of reovirus mediated cell death. In an effort to increase the oncolytic potency, we introduced transgenes into the S1 segment of reovirus T3D. The adenovirus E4orf4 gene was selected as transgene since the encoded E4orf4 protein induces cell death in transformed cells. The induction of cell death by E4orf4 depends in part on its binding to phosphatase 2A (PP2A). In addition to the S1-E4orf4 reovirus, two other reoviruses were employed in our studies. The reovirus rS1-RFA encodes an E4orf4 double-mutant protein that cannot interact with PP2A and the rS1-iLOV virus encoding the fluorescent marker iLOV as a reporter. The replacement of the codons for the junction adhesion molecule-A (JAM-A) binding head domain of the truncated spike protein blocks the entry of these recombinant viruses via the reovirus receptor JAM-A. Instead these viruses rely on internalization via binding to sialic acids on the cell surface. This expands their tropism and allows infection of JAM-A-deficient tumour cells. Here we not only demonstrate the feasibility of this approach but also established that the cytolytic activity of these recombinant viruses is largely transgene independent. PMID- 30013184 TI - Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis. AB - Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis. PMID- 30013188 TI - Different population dynamics in the supplementary motor area and motor cortex during reaching. AB - Neural populations perform computations through their collective activity. Different computations likely require different population-level dynamics. We leverage this assumption to examine neural responses recorded from the supplementary motor area (SMA) and motor cortex. During visually guided reaching, the respective roles of these areas remain unclear; neurons in both areas exhibit preparation-related activity and complex patterns of movement-related activity. To explore population dynamics, we employ a novel "hypothesis-guided" dimensionality reduction approach. This approach reveals commonalities but also stark differences: linear population dynamics, dominated by rotations, are prominent in motor cortex but largely absent in SMA. In motor cortex, the observed dynamics produce patterns resembling muscle activity. Conversely, the non-rotational patterns in SMA co-vary with cues regarding when movement should be initiated. Thus, while SMA and motor cortex display superficially similar single-neuron responses during visually guided reaching, their different population dynamics indicate they are likely performing quite different computations. PMID- 30013191 TI - Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis. AB - The histone methyltransferase multiple myeloma SET domain protein (MMSET/WHSC1) is highly expressed in diverse tumor types, and its expression appears to be involved in cell proliferation. In this study, we report that MMSET interacts with and methylates Aurora kinase A (AURKA). We show that MMSET-mediated methylation of AURKA induces interaction with p53 as well as enhanced kinase activity of AURKA, which results in the proteasomal degradation of p53. MMSET mediated p53 degradation increases cell proliferation and results in oncogenic activity. Furthermore, knockdown of MMSET potently inhibits tumorigenic cells and renders them sensitive to growth inhibition by the therapeutic drug, alisertib (AURKA inhibitor). Taken together, our results suggest that MMSET is a regulator of p53 stability via methylation of AURKA in proliferating cells and might be a potential therapeutic target in solid tumors. PMID- 30013190 TI - Bruton's tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma. AB - Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton's tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse-free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination. Both ALKWT and ALKF1174L can induce BTK phosphorylation and higher capacity of ALKF1174L is observed. Furthermore, the BTK inhibitor ibrutinib can effectively inhibit the growth of neuroblastoma xenograft in nude mice, and the combination of ibrutinib and the ALK inhibitor crizotinib further enhances the inhibition. Our study provides strong rationale for clinical trial of ALK-positive neuroblastoma using ibrutinib or the combination of ibrutinib and ALK inhibitors. PMID- 30013192 TI - Accelerating proton-coupled electron transfer of metal hydrides in catalyst model reactions. AB - Metal hydrides are key intermediates in catalytic proton reduction and dihydrogen oxidation. There is currently much interest in appending proton relays near the metal centre to accelerate catalysis by proton-coupled electron transfer (PCET). However, the elementary PCET steps and the role of the proton relays are still poorly understood, and direct kinetic studies of these processes are scarce. Here, we report a series of tungsten hydride complexes as proxy catalysts, with covalently attached pyridyl groups as proton acceptors. The rate of their PCET reaction with external oxidants is increased by several orders of magnitude compared to that of the analogous systems with external pyridine on account of facilitated proton transfer. Moreover, the mechanism of the PCET reaction is altered by the appended bases. A unique feature is that the reaction can be tuned to follow three distinct PCET mechanisms-electron-first, proton-first or a concerted reaction-with very different sensitivities to oxidant and base strength. Such knowledge is crucial for rational improvements of solar fuel catalysts. PMID- 30013189 TI - FMNL1 mediates nasopharyngeal carcinoma cell aggressiveness by epigenetically upregulating MTA1. AB - It has been suggested that formin-like protein 1 (FMNL1) plays an important role in the pathogenic process of several hematopoietic malignancies. In this study, we performed a series of in vivo and in vitro assays to elucidate the biological functions of FMNL1 and underlying mechanisms in human nasopharyngeal carcinoma (NPC) pathogenesis. Herein, we report that high expression of FMNL1 in NPC is positively associated with an aggressive disease and/or poor patient survival. Ectopic overexpression of FMNL1 in NPC cells substantially promoted cell invadopodia formation, epithelial-mesenchymal transition (EMT) and invasiveness, whereas depletion of FMNL1 potently suppressed NPC cells invadopodia formation, EMT, and invasive/metastatic capacities. We further show that FMNL1 could enhance NPC cell aggressiveness by increasing a key downstream target, the metastasis associated protein 1 (MTA1) gene. Importantly, ectopic overexpression of FMNL1 in NPC cells markedly improved the binding of HDAC1 with Profilin2 in the cytoplasm and suppressed the enrichment of HDAC1 on the promoter of MTA1 and thereby, leading to an increased MTA1 transcription and expression. Furthermore, in addition to the amplification of FMNL1 gene, decreased level of miR-16 in NPCs is another critical mechanism to upregulate FMNL1 expression. These results, collectively, provide first-line of evidences that high expression of FMNL1, resulted from decreased miR-16 and/or MTA1 amplification, has a potent oncogenic role to drive the development and aggressive process of NPC by upregulating MTA1, and FMNL1 might be employed as a new prognostic biomarker and therapeutic target for human NPC. PMID- 30013193 TI - Concerted nucleophilic aromatic substitutions. AB - Nucleophilic aromatic substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addition-elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds. PMID- 30013194 TI - Dopant-induced electron localization drives CO2 reduction to C2 hydrocarbons. AB - The electrochemical reduction of CO2 to multi-carbon products has attracted much attention because it provides an avenue to the synthesis of value-added carbon based fuels and feedstocks using renewable electricity. Unfortunately, the efficiency of CO2 conversion to C2 products remains below that necessary for its implementation at scale. Modifying the local electronic structure of copper with positive valence sites has been predicted to boost conversion to C2 products. Here, we use boron to tune the ratio of Cudelta+ to Cu0 active sites and improve both stability and C2-product generation. Simulations show that the ability to tune the average oxidation state of copper enables control over CO adsorption and dimerization, and makes it possible to implement a preference for the electrosynthesis of C2 products. We report experimentally a C2 Faradaic efficiency of 79 +/- 2% on boron-doped copper catalysts and further show that boron doping leads to catalysts that are stable for in excess of ~40 hours while electrochemically reducing CO2 to multi-carbon hydrocarbons. PMID- 30013195 TI - Control of neural systems at multiple scales using model-free, deep reinforcement learning. AB - Recent improvements in hardware and data collection have lowered the barrier to practical neural control. Most of the current contributions to the field have focus on model-based control, however, models of neural systems are quite complex and difficult to design. To circumvent these issues, we adapt a model-free method from the reinforcement learning literature, Deep Deterministic Policy Gradients (DDPG). Model-free reinforcement learning presents an attractive framework because of the flexibility it offers, allowing the user to avoid modeling system dynamics. We make use of this feature by applying DDPG to models of low-level and high-level neural dynamics. We show that while model-free, DDPG is able to solve more difficult problems than can be solved by current methods. These problems include the induction of global synchrony by entrainment of weakly coupled oscillators and the control of trajectories through a latent phase space of an underactuated network of neurons. While this work has been performed on simulated systems, it suggests that advances in modern reinforcement learning may enable the solution of fundamental problems in neural control and movement towards more complex objectives in real systems. PMID- 30013196 TI - Author Correction: Nociceptor sensory neurons suppress neutrophil and gammadelta T cell responses in bacterial lung infections and lethal pneumonia. AB - In the version of this article initially published, the line graph showing TNF alpha levels in Fig. 2d was inadvertently duplicated. A graph of IL-6 levels should be shown in place of the duplication.These results were also incorrectly described in the main text, which originally stated: "At an early time point of infection (6 h), RTX-treated mice showed higher induction of total inflammatory protein levels in the bronchoalveolar lavage fluid (BALF) (Fig. 2c), as well as levels of the cytokines TNF-alpha and IL-6, and the chemokine CXCL-1 (Fig. 2d)". This should instead read: "At an early time point of infection (6 h), RTX-treated mice showed higher induction of total inflammatory-protein levels in the bronchoalveolar lavage fluid (BALF) (Fig. 2c), as well as levels of the cytokine TNF-alpha and the chemokine CXCL-1 (Fig. 2d)".In the supplementary information initially posted online, incorrect bar graphs were presented in Supplementary Fig. 1b (VG, TRPV1+ data, top panel) and Supplementary Fig. 4b (DRG, CGRP+ data, middle panel). PMID- 30013197 TI - Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. AB - Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value >=1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition. PMID- 30013198 TI - Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. AB - Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse. PMID- 30013199 TI - Fetal gene therapy for neurodegenerative disease of infants. AB - For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains. PMID- 30013200 TI - Activation of basal forebrain purinergic P2 receptors promotes wakefulness in mice. AB - The functions of purinergic P2 receptors (P2Rs) for extracellular adenosine triphosphate (ATP) are poorly understood. Here, for the first time, we show that activation of P2Rs in an important arousal region, the basal forebrain (BF), promotes wakefulness, whereas inhibition of P2Rs promotes sleep. Infusion of a non-hydrolysable P2R agonist, ATP-gamma-S, into mouse BF increased wakefulness following sleep deprivation. ATP-gamma-S depolarized BF cholinergic and cortically-projecting GABAergic neurons in vitro, an effect blocked by antagonists of ionotropic P2Rs (P2XRs) or glutamate receptors. In vivo, ATP-gamma S infusion increased BF glutamate release. Thus, activation of BF P2XRs promotes glutamate release and excitation of wake-active neurons. Conversely, pharmacological antagonism of BF P2XRs decreased spontaneous wakefulness during the dark (active) period. Together with previous findings, our results suggest sleep-wake regulation by BF extracellular ATP involves a balance between excitatory, wakefulness-promoting effects mediated by direct activation of P2XRs and inhibitory, sleep-promoting effects mediated by degradation to adenosine. PMID- 30013202 TI - Resistance to prostate-cancer treatment is driven by immune cells. PMID- 30013203 TI - Coronary artery development, one cell at a time. PMID- 30013201 TI - Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson's disease. AB - We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) -mediated dopaminergic neurodegeneration. The use of GLP-1 or Exendin-4 for Parkinson's disease (PD) patients is limited by their short half-lives. The purpose of this study was to evaluate a new extended release Exendin-4 formulation, PT302, in a rat model of PD. Subcutaneous administration of PT302 resulted in sustained elevations of Exendin-4 in plasma for >20 days in adult rats. To define an efficacious dose within this range, rats were administered PT302 once every 2 weeks either before or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamine-induced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Exendin-4 levels and brain tyrosine hydroxylase immunoreactivity (TH-IR). PT302 significantly increased TH-IR in the lesioned substantia nigra and striatum. There was a significant correlation between plasma Exendin-4 levels and TH-IR in the substantia nigra and striatum on the lesioned side. Our data suggest that post-treatment with PT302 provides long-lasting Exendin-4 release and reduces neurodegeneration of nigrostriatal dopaminergic neurons in a 6-hydroxydopamine rat model of PD at a clinically relevant dose. PMID- 30013204 TI - Speciation far from the madding crowd. PMID- 30013205 TI - Beat protectionism and emissions at a stroke. PMID- 30013206 TI - Can resveratrol supplement change inflammatory mediators? A systematic review and meta-analysis on randomized clinical trials. AB - BACKGROUND: Resveratrol as a polyphenolic compound might be able to reduce inflammatory mediators. Change in inflammatory state is identified by the measurement of inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). The objective of this study is to conduct a systematic review and meta-analysis on randomized controlled trials that assessed the effect of resveratrol on concentration of serum inflammatory mediators. METHOD: Systematic search was performed up to October 2017 using ISI web of science, PubMed, Scopus, EMBASE, and Google scholar. Weighted mean difference was estimated either by subtracting baseline values from post-intervention value or as the post-intervention values. Fixed effect model was applied to analyze data where heterogeneity was <25%; otherwise, random effects models were applied. The protocol was registered with PROSPERO (No. CRD42018085098). RESULTS: The meta-analysis and systematic review considered 15 trials, involving 658 adults aged 18-75 years. Resveratrol significantly reduced serum CRP levels (WMD = -0.54; 95% CI: -0.78, -0.30; I2 = 77.7%; P < 0.0001), but it had no significant effect on serum IL-6 (WMD = -0.06; 95% CI: 0.27, 0.14; I2 = 62.0%; P = 0.005) and TNF-alpha levels (WMD = -0.20; 95% CI: 0.55, 0.16; I2 = 87.2%; P < 0.0001). Resveratrol intake reduced TNF-alpha in young subjects (WMD = -0.34; 95% CI: -0.57, -0.12; I2 = 60.5%; P = 0.038) and obese individuals (WMD = -1.52; 95% CI: -2.87, -0.16; I2 = 74.1%; P = 0.004). CONCLUSION: The analysis indicated possible decreasing effect of resveratrol on CRP, but it might not be able to change IL-6 and TNF-alpha concentrations. More studies, separately on males and females with obesity, and varied age, are necessary. PMID- 30013207 TI - Suppressing insulin feedback to improve efficacy of cancer therapeutics. PMID- 30013209 TI - Fabrication of graphene film composite electrochemical biosensor as a pre screening algal toxin detection tool in the event of water contamination. AB - In this work, we fabricated a novel graphene film composite biosensor for microcystin-LR detection as an alternative to time-consuming, expensive, non portable and often skills-demanding conventional methods of analysis involved in water quality monitoring and assessment. Excellent linear correlation (R2 = 0.99) of the electron-transfer resistance was achieved over a wide range of microcystin LR (MC-LR) concentration, i.e. 0.005-10 MUg/L. As-prepared graphene film composite biosensors can specifically detect MC-LR with remarkable sensitivity and detection limit (2.3 ng/L) much lower than the World Health Organization (WHO) provisional guideline limit of microcystin-LR concentration (i.e. 1 MUg/L) in different water sources. Their great potential can be attributed to large active surface area of graphene film and efficient charge transfer process enabled by their high conductivity. Developed graphene film composite biosensors were also successfully applied to determination of MC-LR in several environmental water samples with high detection recovery, which offers a promising possibility of large-scale manufacture of sensor tips due to their macroscopic free-standing nature, the scalable fabrication route and easily tunable size. PMID- 30013208 TI - O2-inducible H2O2-forming NADPH oxidase is responsible for the hyper O2 sensitivity of Bifidobacterium longum subsp. infantis. AB - Bifidobacteria are beneficial anaerobes, and their O2 sensitivity levels differ among species as a function of unknown molecular mechanisms. Bifidobacterium longum subspecies infantis (B. infantis), a predominant colonizer of the gastrointestinal tract of infants, showed a hyper O2-sensitive growth profile with accompanying a production of H2O2. In this study, we characterized an NADPH oxidase as a key enzyme responsible for this microbe's hyper O2 sensitivity. A dominant active elution peak of H2O2-forming NADPH oxidase activity was detected in the first step of column chromatography, and the purified NADPH oxidase (NPOX) was identified as a homolog of nitroreductase family proteins. The introduction of the gene encoding B. infantis NPOX (npoxA) into O2-tolerant Bifidobacterium minimum made the strain O2 sensitive and allowed it to produce H2O2. Knockout of the npoxA gene in B. infantis decreased the production of H2O2 and mitigated its B. infantis hyper O2 sensitivity. A transcript of B. infantis npoxA is induced by O2, suggesting that the aerobic production of toxic H2O2 is functionally conserved in B. infantis. PMID- 30013210 TI - Forecasting Events in the Complex Dynamics of a Semiconductor Laser with Optical Feedback. AB - Complex systems performing spiking dynamics are widespread in Nature. They cover from earthquakes, to neurons, variable stars, social networks, or stock markets. Understanding and characterizing their dynamics is relevant in order to detect transitions, or to predict unwanted extreme events. Here we study, under an ordinal patterns analysis, the output intensity of a semiconductor laser with feedback in a regime where it develops a complex spiking behavior. We unveil that, in the transitions towards and from the spiking regime, the complex dynamics presents two competing behaviors that can be distinguished with a thresholding method. Then we use time and intensity correlations to forecast different types of events, and transitions in the dynamics of the system. PMID- 30013213 TI - Fluorinated interphases. PMID- 30013211 TI - Maternal auxin supply contributes to early embryo patterning in Arabidopsis. AB - The angiosperm seed is composed of three genetically distinct tissues: the diploid embryo that originates from the fertilized egg cell, the triploid endosperm that is produced from the fertilized central cell, and the maternal sporophytic integuments that develop into the seed coat1. At the onset of embryo development in Arabidopsis thaliana, the zygote divides asymmetrically, producing a small apical embryonic cell and a larger basal cell that connects the embryo to the maternal tissue2. The coordinated and synchronous development of the embryo and the surrounding integuments, and the alignment of their growth axes, suggest communication between maternal tissues and the embryo. In contrast to animals, however, where a network of maternal factors that direct embryo patterning have been identified3,4, only a few maternal mutations have been described to affect embryo development in plants5-7. Early embryo patterning in Arabidopsis requires accumulation of the phytohormone auxin in the apical cell by directed transport from the suspensor8-10. However, the origin of this auxin has remained obscure. Here we investigate the source of auxin for early embryogenesis and provide evidence that the mother plant coordinates seed development by supplying auxin to the early embryo from the integuments of the ovule. We show that auxin response increases in ovules after fertilization, due to upregulated auxin biosynthesis in the integuments, and this maternally produced auxin is required for correct embryo development. PMID- 30013212 TI - Generalized lattice Wilson-Dirac fermions in (1 + 1) dimensions for atomic quantum simulation and topological phases. AB - The Dirac fermion is an important fundamental particle appearing in high-energy physics and topological insulator physics. In particular, a Dirac fermion in a one-dimensional lattice system exhibits the essential properties of topological physics. However, the system has not been quantum simulated in experiments yet. Herein, we propose a one-dimensional generalized lattice Wilson-Dirac fermion model and study its topological phase structure. We show the experimental setups of an atomic quantum simulator for the model, in which two parallel optical lattices with the same tilt for trapping cold fermion atoms and a laser-assisted hopping scheme are used. Interestingly, we find that the model exhibits nontrivial topological phases characterized by gapless edge modes and a finite winding number in the broad regime of the parameter space. Some of the phase diagrams closely resemble those of the Haldane model. We also discuss topological charge pumping and a lattice Gross-Neveu model in the system of generalized Wilson-Dirac fermions. PMID- 30013214 TI - Dissipative adaptation in driven self-assembly leading to self-dividing fibrils. AB - Out-of-equilibrium self-assembly of proteins such as actin and tubulin is a key regulatory process controlling cell shape, motion and division. The design of functional nanosystems based on dissipative self-assembly has proven to be remarkably difficult due to a complete lack of control over the spatial and temporal characteristics of the assembly process. Here, we show the dissipative self-assembly of FtsZ protein (a bacterial homologue of tubulin) within coacervate droplets. More specifically, we show how such barrier-free compartments govern the local availability of the energy-rich building block guanosine triphosphate, yielding highly dynamic fibrils. The increased flux of FtsZ monomers at the tips of the fibrils results in localized FtsZ assembly, elongation of the coacervate compartments, followed by division of the fibrils into two. We rationalize the directional growth and division of the fibrils using dissipative reaction-diffusion kinetics and capillary action of the filaments as main inputs. The principle presented here, in which open compartments are used to modulate the rates of dissipative self-assembly by restricting the absorption of energy from the environment, may provide a general route to dissipatively adapting nanosystems exhibiting life-like behaviour. PMID- 30013215 TI - Non-flammable electrolyte enables Li-metal batteries with aggressive cathode chemistries. AB - Rechargeable Li-metal batteries using high-voltage cathodes can deliver the highest possible energy densities among all electrochemistries. However, the notorious reactivity of metallic lithium as well as the catalytic nature of high voltage cathode materials largely prevents their practical application. Here, we report a non-flammable fluorinated electrolyte that supports the most aggressive and high-voltage cathodes in a Li-metal battery. Our battery shows high cycling stability, as evidenced by the efficiencies for Li-metal plating/stripping (99.2%) for a 5 V cathode LiCoPO4 (~99.81%) and a Ni-rich LiNi0.8Mn0.1Co0.1O2 cathode (~99.93%). At a loading of 2.0 mAh cm-2, our full cells retain ~93% of their original capacities after 1,000 cycles. Surface analyses and quantum chemistry calculations show that stabilization of these aggressive chemistries at extreme potentials is due to the formation of a several-nanometre-thick fluorinated interphase. PMID- 30013216 TI - Surface chemistry and buried interfaces in all-inorganic nanocrystalline solids. AB - Semiconducting nanomaterials synthesized using wet chemical techniques play an important role in emerging optoelectronic and photonic technologies. Controlling the surface chemistry of the nano building blocks and their interfaces with ligands is one of the outstanding challenges for the rational design of these systems. We present an integrated theoretical and experimental approach to characterize, at the atomistic level, buried interfaces in solids of InAs nanoparticles capped with Sn2S64- ligands. These prototypical nanocomposites are known for their promising transport properties and unusual negative photoconductivity. We found that inorganic ligands dissociate on InAs to form a surface passivation layer. A nanocomposite with unique electronic and transport properties is formed, that exhibits type II heterojunctions favourable for exciton dissociation. We identified how the matrix density, sulfur content and specific defects may be designed to attain desirable electronic and transport properties, and we explain the origin of the measured negative photoconductivity of the nanocrystalline solids. PMID- 30013217 TI - Direct observation of noble metal nanoparticles transforming to thermally stable single atoms. AB - Single noble metal atoms and ultrafine metal clusters catalysts tend to sinter into aggregated particles at elevated temperatures, driven by the decrease of metal surface free energy. Herein, we report an unexpected phenomenon that noble metal nanoparticles (Pd, Pt, Au-NPs) can be transformed to thermally stable single atoms (Pd, Pt, Au-SAs) above 900 degrees C in an inert atmosphere. The atomic dispersion of metal single atoms was confirmed by aberration-corrected scanning transmission electron microscopy and X-ray absorption fine structures. The dynamic process was recorded by in situ environmental transmission electron microscopy, which showed competing sintering and atomization processes during NP to-SA conversion. Further, density functional theory calculations revealed that high-temperature NP-to-SA conversion was driven by the formation of the more thermodynamically stable Pd-N4 structure when mobile Pd atoms were captured on the defects of nitrogen-doped carbon. The thermally stable single atoms (Pd-SAs) exhibited even better activity and selectivity than nanoparticles (Pd-NPs) for semi-hydrogenation of acetylene. PMID- 30013219 TI - The need for levering heat. PMID- 30013218 TI - High Purcell factor generation of indistinguishable on-chip single photons. AB - On-chip single-photon sources are key components for integrated photonic quantum technologies. Semiconductor quantum dots can exhibit near-ideal single-photon emission, but this can be significantly degraded in on-chip geometries owing to nearby etched surfaces. A long-proposed solution to improve the indistinguishablility is to use the Purcell effect to reduce the radiative lifetime. However, until now only modest Purcell enhancements have been observed. Here we use pulsed resonant excitation to eliminate slow relaxation paths, revealing a highly Purcell-shortened radiative lifetime (22.7 ps) in a waveguide coupled quantum dot-photonic crystal cavity system. This leads to near-lifetime limited single-photon emission that retains high indistinguishablility (93.9%) on a timescale in which 20 photons may be emitted. Nearly background-free pulsed resonance fluorescence is achieved under pi-pulse excitation, enabling demonstration of an on-chip, on-demand single-photon source with very high potential repetition rates. PMID- 30013220 TI - Order from disorder through dissipation of free energy. PMID- 30013221 TI - A quantum-dot heat engine operating close to the thermodynamic efficiency limits. AB - Cyclical heat engines are a paradigm of classical thermodynamics, but are impractical for miniaturization because they rely on moving parts. A more recent concept is particle-exchange (PE) heat engines, which uses energy filtering to control a thermally driven particle flow between two heat reservoirs1,2. As they do not require moving parts and can be realized in solid-state materials, they are suitable for low-power applications and miniaturization. It was predicted that PE engines could reach the same thermodynamically ideal efficiency limits as those accessible to cyclical engines3-6, but this prediction has not been verified experimentally. Here, we demonstrate a PE heat engine based on a quantum dot (QD) embedded into a semiconductor nanowire. We directly measure the engine's steady-state electric power output and combine it with the calculated electronic heat flow to determine the electronic efficiency eta. We find that at the maximum power conditions, eta is in agreement with the Curzon-Ahlborn efficiency6-9 and that the overall maximum eta is in excess of 70% of the Carnot efficiency while maintaining a finite power output. Our results demonstrate that thermoelectric power conversion can, in principle, be achieved close to the thermodynamic limits, with direct relevance for future hot-carrier photovoltaics10, on-chip coolers or energy harvesters for quantum technologies. PMID- 30013222 TI - Publisher Correction: Factors that make an impact. AB - In the final paragraph of the version of this Editorial previously published, the surname of Hagan Bayley was misspelt as 'Baley'; this has now been corrected in the online versions. PMID- 30013225 TI - Concentrating on intrinsic disorder. PMID- 30013224 TI - Novel In-situ Precipitation Process to Engineer Low Permeability Porous Composite. AB - Inspired by the natural precipitation of minerals in soil and rocks, a novel, simple and industrially scalable in-situ precipitation process to produce low permeability porous composites is presented. This process relies on capillary flow in wettable porous composites to absorb and store liquid. In this process, a porous composite first absorbs a salt solution, after which the composite is dipped in a second salt solution. Salts are selected such as they react to form an insoluble precipitate. As big pores absorb more liquid than small pores, the precipitated particles are formed specifically for each pore. In this paper, precipitation of CaCO3 nanoparticles in cellulose nanofibre (CNF) films was demonstrated as an example. Precipitation of 1 wt% of CaCO3 nanoparticles in the CNF film reduced the pore volume by 50%, without changing the density. This reduced the water vapour and oxygen transmission rates by one order of magnitude to 4.7 g/m2.day and 2.7 cc/m2.day, respectively. The barrier properties of in situ precipitated composites showed superior performance to previously reported CNF films in literature. The concept is general and of very high industrial interest as it can easily be retrofitted to current continuous industrial processes. PMID- 30013223 TI - A V-to-F substitution in SK2 channels causes Ca2+ hypersensitivity and improves locomotion in a C. elegans ALS model. AB - Small-conductance Ca2+-activated K+ (SK) channels mediate medium afterhyperpolarization in the neurons and play a key role in the regulation of neuronal excitability. SK channels are potential drug targets for ataxia and Amyotrophic Lateral Sclerosis (ALS). SK channels are activated exclusively by the Ca2+-bound calmodulin. Previously, we identified an intrinsically disordered fragment that is essential for the mechanical coupling between Ca2+/calmodulin binding and channel opening. Here, we report that substitution of a valine to phenylalanine (V407F) in the intrinsically disordered fragment caused a ~6 fold increase in the Ca2+ sensitivity of SK2-a channels. This substitution resulted in a novel interaction between the ectopic phenylalanine and M411, which stabilized PIP2-interacting residue K405, and subsequently enhanced Ca2+ sensitivity. Also, equivalent valine to phenylalanine substitutions in SK1 or SK3 channels conferred Ca2+ hypersensitivity. An equivalent phenylalanine substitution in the Caenorhabditis elegans (C. elegans) SK2 ortholog kcnl-2 partially rescued locomotion defects in an existing C. elegans ALS model, in which human SOD1G85R is expressed at high levels in neurons, confirming that this phenylalanine substitution impacts channel function in vivo. This work for the first time provides a critical reagent for future studies: an SK channel that is hypersensitive to Ca2+ with increased activity in vivo. PMID- 30013226 TI - Physical and chemical assessment of 1,3 Propanediol as a potential substitute of propylene glycol in refill liquid for electronic cigarettes. AB - Electronic cigarette has the potential to serve as a tobacco cessation aid if the prerequisites which are safety and efficacy in term of nicotine delivery are achieved. The nicotine-based liquids are mainly composed by propylene glycol and glycerol playing the important role of airborne carriers. 1,3 propanediol is proposed as a propylene glycol substitute to potentially improve the thermal stability, nicotine delivery and to decrease inhaled flavors concentrations. We have implemented various thermal, physicochemical and computational methods to evaluate the use of 1,3 propanediol as a substitute (or additional ingredient) to propylene glycol in e-liquids compositions. Our results indicate that 1,3 propanediol is stable upon heating when electronic cigarette are used in recommended conditions. We demonstrate that 1,3 propanediol gave better thermic profile compared to propylene glycol and glycerol, showing less thermal decomposition by-products. In addition, 1,3 propanediol gives to nicotine a more basic environment ensuring a high level of free base nicotine form. We have also established a quantum mechanical based computational method to validate e-liquids as flavor enhancer. Our findings showed that globally 1,3 propanediol seems to have better flavoring properties than glycerol and propylene glycol. Finally, 1,3 propanediol seems to induce quite similar aerodynamic properties compared to propylene glycol and glycerol. PMID- 30013227 TI - Phenotype of p53 wild-type epitope-specific T cells in the circulation of patients with head and neck cancer. AB - CD8+ cytotoxic T-cell (CTL) specific for non-mutated, wild type (wt) sequence p53 peptides derived from wt or mutant p53 molecules expressed in head and neck squamous cell carcinomas (HNSCC) have been detected in the circulation of patients with this disease. The frequency and differentiation/maturation phenotypes of these anti-tumor specific CTL can reflect the host's immunologic response. Therefore, we investigated the frequency and phenotypes of wt sequence p53 peptide-specific CTL in patients with HNSCC (n = 33) by flow cytometric analysis using HLA-A*0201 tetrameric peptides (tet) complexed with the wt sequence p53264-272 or p53149-157 peptide and co-staining with phenotypic markers. One main finding was that increasing frequencies of tet+ CD8+ T cells in patients' circulation correlated with increased frequencies of inactive naive tet+ cells, while those with effector memory and terminally differentiated phenotypes, which are associated with positive anti-tumor immune responses, decreased. We also found that the frequency of circulating tet+ CD8+ T cells negatively correlated with p53 expression in tumor tissues and tumor stage. Our findings support further clinical-based investigations to define the frequencies and phenotypes of wt sequence p53 peptide-specific CD8+ T cells to predict disease severity, enhance selection of patients for inclusion in vaccination trials and highlight prerequisites to enhance immune susceptibility by activation of inactive naive tet+ T cells and/or enhancing circulating effector T cell activity by checkpoint blockage. PMID- 30013228 TI - Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events. AB - The vasculature undergoes changes in diameter, permeability and blood flow in response to specific stimuli. The dynamics and interdependence of these responses in different vessels are largely unknown. Here we report a non-invasive technique to study dynamic events in different vessel categories by multi-photon microscopy and an image analysis tool, RVDM (relative velocity, direction, and morphology) allowing the identification of vessel categories by their red blood cell (RBC) parameters. Moreover, Claudin5 promoter-driven green fluorescent protein (GFP) expression is used to distinguish capillary subtypes. Intradermal injection of vascular endothelial growth factor A (VEGFA) is shown to induce leakage of circulating dextran, with vessel-type-dependent kinetics, from capillaries and venules devoid of GFP expression. VEGFA-induced leakage in capillaries coincides with vessel dilation and reduced flow velocity. Thus, intravital imaging of non invasive stimulation combined with RVDM analysis allows for recording and quantification of very rapid events in the vasculature. PMID- 30013229 TI - Assessing pediatric tobacco exposure using parent report: comparison with hair nicotine. AB - INTRODUCTION: The purpose of this study was to examine the relationships between screening questions for secondhand smoke (SHS) exposure and biomarker results using hair nicotine levels. Our ultimate goal was to develop sensitive and valid screening tools in pediatric clinical settings for SHS exposure. METHODS: Investigators developed a core set of questions regarding exposure. Data from two separate ongoing studies of well children and those with bronchopulmonary dysplasia (BPD) were used to assess the concordance between responses and hair nicotine levels. Sensitivity, a positive predictive value, and accuracy were examined. RESULTS: There was no single question with similar sensitivity in both populations. The question with the highest positive predictive value (90.8% well cohort and 84.6% BPD cohort) for both the groups was whether the child had been exposed to in-home smoking in the last 7 days. The question with the highest accuracy for both groups was the number of smokers at home (0 vs >= 1), with an accuracy of 72.4% for well children and 79.0% for the BPD cohort. CONCLUSIONS: There was a wide variability in the performance of specific questions. These data demonstrate that a "one-size-fits-all" approach to screening for secondhand tobacco smoke exposure may not be appropriate for all pediatric populations. PMID- 30013230 TI - A lower dose of intravitreal conbercept effectively treats retinopathy of prematurity. AB - Intravitreal Conbercept (IVC) is the latest applied and effective treatment for the management of retinopathy of prematurity (ROP). However, conbercept escapes from the vitreous into the general circulation and reduce systemic VEGF concentrations. Thus, there are concerns about systemic complications, in these premature infants who are developing vital organ systems. This study is to determine whether a low dosage (0.15 mg/0.015 mL) of IVC is effective in the treatment of Zone II Stage 2/3 + ROP. A total of 38 eyes of 20 infants were analyzed retrospectively. We identified treatment effectiveness as complete regression of retinopathy and retinal vascularisation to zone III. The mean gestational age (GA), postmenstrual age (PMA) at treatment and birth weights (BW) were 28.6 +/- 2.2 weeks, 39.3 +/- 3.0 weeks and 1297.5 +/- 429.2 g respectively. Primary effectiveness (react to IVC 0.15 mg alone) was found in 32/38 eyes (84.2%). Secondary effectiveness (a second IVC was required) was found in 6/38 eyes (15.8%). Follow-up continued until 90 weeks' postmenstrual age and showed no recurrences of plus disease or neovascularization. The study suggests 0.15 mg IVC is effective for Zone II Stage 2/3 + ROP, and there is no adverse ocular outcomes during the follow-up period. PMID- 30013231 TI - Iodine k-edge dual energy imaging reveals the influence of particle size distribution on solute transport in drying porous media. AB - Increasing salinity in groundwater and soil poses a threat to water and land resources. With the expectation of major changes to the hydrological cycle through climate change, the need for understanding the fundamental processes governing solute transport through soil has grown significantly. We provide experimentally verified insights into the influence of particle size distribution on solute transport in porous media during evaporation at the pore- and macro scales. To do so, we utilized four-dimensional (space plus time) synchrotron X ray tomography for iodine k-edge dual energy imaging to obtain solute concentration profiles in every single pore during saline water evaporation from coarse- and fine-grained sands. Close to the surface of the coarse-grained sand significantly higher salt concentrations were observed when compared to fine grained sand with the same porosity under similar cumulative evaporative mass losses. The physics behind this behaviour was delineated using the recorded data with high spatial and temporal resolutions. Moreover, the measured data enabled us to quantify the variations of the effective dispersion coefficient during evaporation and how it is influenced by the particle size distribution. We show that, contrary to common assumption in modelling of solute transport during evaporation, the effective dispersion coefficient varies as a function of liquid saturation and the length of the invaded zone during evaporation from porous media, and that it increases as liquid saturation decreases. PMID- 30013232 TI - The prescience of paleoclimatology and the future of the Antarctic ice sheet. AB - The emerging view that the West Antarctic ice sheet is in the early stage of collapse owes as much to paleoclimatology as to contemporary observations. PMID- 30013233 TI - Food Patterns are Associated with Likelihood of CKD in US Adults. AB - We investigated the association between dietary patterns and prevalent chronic kidney diseases (CKD), in participants of the 2005-2012 US National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2012, who had measured data on dietary intake and kidney function. Analyse of covariance (ANCOVA) and logistic regression models were employed to account for the survey design and sample weights. A total of 21,649 eligible participants (634 with and 20,015 without prevalent CKD) were included in the final analysis. Three food patterns together explained 50.8% of the variance of the dietary nutrients consumption. The first food pattern was representative of a diet containing high levels of saturated and mono-unsaturated fatty acids; the second food pattern comprised vitamins and trace elements; and the third food pattern was mainly representative of polyunsaturated fatty acids. The odd of prevalent CKD decreased across increasing quarters of vitamins and trace elements, so that the top quarter was associated with a 53% (95%CI: 42-62%) lower odds of CKD in age, sex and race adjusted logistic regression models. These results suggest that vitamins and trace elements intake are associated with lower risk of prevalent CKD. PMID- 30013234 TI - Timing correlations between cerebellar interpositus neuronal firing and classically conditioned eyelid responses in wild-type and Lurcher mice. AB - Classical eyeblink conditioning is an experimental model widely used for the study of the neuronal mechanisms underlying the acquisition of new motor and cognitive skills. There are two principal interpretations of the role of the cerebellum in the learning of eyelid conditioned responses (CRs). One considers that the cerebellum is the place where this learning is acquired and stored, while the second suggests that the cerebellum is mostly involved in the proper performance of acquired CRs, implying that there must be other brain areas involved in the learning process. We checked the timing of cerebellar interpositus nucleus (IPN) neurons' firing rate with eyelid CRs in both wild-type (WT) and Lurcher (a model of cerebellar cortex degeneration) mice. We used delay and trace conditioning paradigms. WT mice presented a better execution for delay vs. trace conditioning and also for these two paradigms than did Lurcher mice. IPN neurons were activated during CRs following the activation of the orbicularis oculi muscle. Firing patterns of IPN neurons were altered in Lurcher mice. In conclusion, the cerebellum seems to be mostly related with the performance of conditioned responses, rather than with their acquisition. PMID- 30013235 TI - Predicting El Nino in 2014 and 2015. AB - Early in 2014 several forecast systems were suggesting a strong 1997/98-like El Nino event for the following northern hemisphere winter 2014/15. However the eventual outcome was a modest warming. In contrast, winter 2015/16 saw one of the strongest El Nino events on record. Here we assess the ability of two operational seasonal prediction systems to forecast these events, using the forecast ensembles to try to understand the reasons underlying the very different development and outcomes for these two years. We test three hypotheses. First we find that the continuation of neutral ENSO conditions in 2014 is associated with the maintenance of the observed cold southeast Pacific sea surface temperature anomaly; secondly that, in our forecasts at least, warm west equatorial Pacific sea surface temperature anomalies do not appear to hinder El Nino development; and finally that stronger westerly wind burst activity in 2015 compared to 2014 is a key difference between the two years. Interestingly, in these years at least, this interannual variability in wind burst activity is predictable. ECMWF System 4 tends to produce more westerly wind bursts than Met Office GloSea5 and this likely contributes to the larger SST anomalies predicted in this model in both years. PMID- 30013236 TI - Host-linked soil viral ecology along a permafrost thaw gradient. AB - Climate change threatens to release abundant carbon that is sequestered at high latitudes, but the constraints on microbial metabolisms that mediate the release of methane and carbon dioxide are poorly understood1-7. The role of viruses, which are known to affect microbial dynamics, metabolism and biogeochemistry in the oceans8-10, remains largely unexplored in soil. Here, we aimed to investigate how viruses influence microbial ecology and carbon metabolism in peatland soils along a permafrost thaw gradient in Sweden. We recovered 1,907 viral populations (genomes and large genome fragments) from 197 bulk soil and size-fractionated metagenomes, 58% of which were detected in metatranscriptomes and presumed to be active. In silico predictions linked 35% of the viruses to microbial host populations, highlighting likely viral predators of key carbon-cycling microorganisms, including methanogens and methanotrophs. Lineage-specific virus/host ratios varied, suggesting that viral infection dynamics may differentially impact microbial responses to a changing climate. Virus-encoded glycoside hydrolases, including an endomannanase with confirmed functional activity, indicated that viruses influence complex carbon degradation and that viral abundances were significant predictors of methane dynamics. These findings suggest that viruses may impact ecosystem function in climate-critical, terrestrial habitats and identify multiple potential viral contributions to soil carbon cycling. PMID- 30013238 TI - A gated relaxation oscillator mediated by FrzX controls morphogenetic movements in Myxococcus xanthus. AB - Dynamic control of cell polarity is of critical importance for many aspects of cellular development and motility. In Myxococcus xanthus, MglA, a G protein, and MglB, its cognate GTPase-activating protein, establish a polarity axis that defines the direction of movement of the cell and that can be rapidly inverted by the Frz chemosensory system. Although vital for collective cell behaviours, how Frz triggers this switch has remained unknown. Here, we use genetics, imaging and mathematical modelling to show that Frz controls polarity reversals via a gated relaxation oscillator. FrzX, which we identify as a target of the Frz kinase, provides the gating and thus acts as the trigger for reversals. Slow relocalization of the polarity protein RomR then creates a refractory period during which another switch cannot be triggered. A secondary Frz output, FrzZ, decreases this delay, allowing rapid reversals when required. Thus, this architecture results in a highly tuneable switch that allows a wide range of reversal frequencies. PMID- 30013239 TI - Entrustable Professional Activities as a Novel Framework for Pharmacy Education. AB - Entrustable professional activities (EPAs) are units of measure for a particular profession that describe the professional's unique abilities and work. EPAs can be used in two ways: as a link between individual competencies for mastery and overall professional responsibilities in practice; and as a mechanism for faculty to assess the student's progression using levels of decreasing supervision. Currently used in medical education, implementation and utilization of EPAs within pharmacy education has potential benefits and challenges. This article will describe, highlight benefits of, and share mitigation strategies for implementing EPAs within pharmacy education. PMID- 30013237 TI - Human skin commensals augment Staphylococcus aureus pathogenesis. AB - All bacterial infections occur within a polymicrobial environment, from which a pathogen population emerges to establish disease within a host. Emphasis has been placed on prevention of pathogen dominance by competing microflora acting as probiotics1. Here we show that the virulence of the human pathogen Staphylococcus aureus is augmented by native, polymicrobial, commensal skin flora and individual species acting as 'proinfectious agents'. The outcome is pathogen proliferation, but not commensal. Pathogenesis augmentation can be mediated by particulate cell wall peptidoglycan, reducing the S. aureus infectious dose by over 1,000-fold. This phenomenon occurs using a range of S. aureus strains and infection models and is not mediated by established receptor-mediated pathways including Nod1, Nod2, Myd88 and the NLPR3 inflammasome. During mouse sepsis, augmentation depends on liver-resident macrophages (Kupffer cells) that capture and internalize both the pathogen and the proinfectious agent, leading to reduced production of reactive oxygen species, pathogen survival and subsequent multiple liver abscess formation. The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in the initiation of disease by an invading pathogen. As the human microflora is ubiquitous2, its role in increasing susceptibility to infection by S. aureus highlights potential strategies for disease prevention. PMID- 30013240 TI - A Comparison of Approaches to Student Pharmacist Business Planning in Pharmacy Practice Management. AB - Objective. To compare second-year student pharmacists' perspectives on two approaches for completing a pharmacy practice management business planning project. Methods. A mixed-methods approach was used to compare two options (traditional and experimental) for completing business plan projects that were offered to teams of second-year student pharmacists as part of a required pharmacy management course. Teams who chose the traditional project were required to develop a unique, pharmacy-related business plan while those who chose the experimental concept were paired with a pharmacy-focused firm within Tennessee and tasked with designing a potential service for the firm's consideration. At semester's end, all students were asked to complete a brief survey to provide insight on their experiences with either of the group projects. Students and firm stakeholders were also asked to participate in a group and individual interview, respectively. Results. Student group comparisons indicated that the experimental project provided a more real-world, business planning experience. Additionally, groups that did the experimental project were more likely to report seeing how business and pharmacy practice were connected, indicate a better understanding of the principles of pharmacy management, and be perceived as more marketable for a future pharmacy career. Firm representatives indicated that insight provided by the students was valuable and that they had plans to implement what was proposed. Conclusion. Connecting student pharmacists with a pharmacy-focused firm provided a real-world management experience that better complemented the course's principles, and created a mutually beneficial innovation-focused partnership. PMID- 30013241 TI - Effects of a Multicourse, Composite Examination Method on the Performance of PharmD Students in a Basic Pharmacokinetics Course. AB - Objective. To investigate the effects of multicourse, composite examinations on student performance in a pharmacokinetics course. Methods. A linear, mixed effects model was used to analyze student performance in identical daily quiz and examination questions in a pharmacokinetics course at two pharmacy schools. The same instructor taught the entire course at both institutions. The only difference between the two courses was the method of administration of examinations between the two school cohorts. Results. Students' scores on identical daily quizzes that were administered similarly to students in both schools were the same. However, student grades on multicourse examinations were significantly lower than those administered as individual course examinations in the other school group. The effect size was 1.15, indicating a large difference between the two cohorts in terms of their examination scores. The mixed-effects model revealed a negligible difference (0.622%) between the two student cohorts in terms of their academic abilities but showed a substantial effect (9.40%) for the examination format in favor of single course assessment. Conclusion. When compared to traditional, individual course examination, multicourse, composite examinations may significantly lower student grades in a pharmacokinetics course. PMID- 30013242 TI - Evaluation of an Evidence-Based Medicine Curriculum in a PGY1 Pharmacy Residency Program Using the Fresno Test. AB - Objective. To assess the effectiveness of a longitudinal evidence-based medicine (EBM) curriculum to improve pharmacy resident knowledge and skills in evidence based practice as measured by the Fresno Test. Methods. Residency program director and clinical pharmacist preceptors in a community teaching hospital developed a longitudinal EBM curriculum for a postgraduate year one (PGY1) pharmacy practice residency. The program was offered as a yearlong series of 1 hour meetings to train residents in evidence-based practice. A pre/post study design was used to evaluate the program. The full 12-item Fresno Test was used to measure specific EBP skills: Ask, Acquire, Appraise, Apply and Assess. Pre/post composite and item mean scores were compared using Student's paired t-test. Results. Forty-three residents completed pre- and post-Fresno Test evaluations between 2008 and 2014 with a mean increase in pre- and post-training scores from 125.9 (SD 32.9) to 138.5 (SD 33.6), p=.02. Conclusion. A longitudinal training program in EBM in a pharmacy residency demonstrated improvement in core evidence based practice abilities as measured by the Fresno Test. PMID- 30013243 TI - Pharmacy Student Knowledge, Confidence and Attitudes Toward Medical Cannabis and Curricular Coverage. AB - Objective. To assess pharmacy student confidence in their knowledge of qualifying conditions for medical cannabis use in the US and their attitudes toward curricular coverage of medical cannabis. Methods. Students were asked to complete an electronic survey to measure knowledge and confidence in various domains of medical cannabis treatment, including qualifying conditions, adverse effects, and other patient care skills. Results. There were 238 students who completed the survey. Responses to all domains and their corresponding confidence levels displayed a lack in confidence. The only domain wherein students had confidence in was their ability to retrieve related drug information. Nearly 80% of students felt that the topic of medical cannabis should be added to existing curricula within the next five years. Conclusion. With the prevalence of cannabis programs and knowledge gap, pharmacy schools should consider coverage of medical cannabis in the curricula. PMID- 30013244 TI - The Social Psychology of Biased Self-Assessment. AB - Objective: To describe the psychological mechanisms that underlie biased self assessment and suggest pedagogical techniques to counter them. Findings: Since the psychological mechanisms that underlie bias self-assessment occur below awareness, strategies that attempt to address bias directly are unlikely to succeed. A more effective approach may be to structure students' learning experiences in ways that prevent the unconscious biasing mechanisms from operating efficiently. Summary: Given the importance of accurate self-knowledge for professional students and clinicians, as well as its difficulty to attain, an understanding of the psychological mechanisms that contribute the most common forms of biased self-assessment is essential for creating and implementing effective mitigation strategies. PMID- 30013245 TI - Incorporation of Professionalism Expectations and Evaluative Processes Within a College of Pharmacy. AB - Objective. To determine professionalism factors of interest to the University of South Florida (USF) College of Pharmacy (COP) and develop a programmatic plan to monitor the professionalization of students, faculty, preceptors and staff. Methods. In 2013, the USF COP began investigating how best to incorporate processes to capture professionalism across all aspects of the program. A Professionalism Task Force was convened to identify key professionalism factors valued by faculty and preceptors to be incorporated in pharmacy practice experiences, didactic courses, faculty, and preceptor performance evaluations. A factor analysis was performed to identify items for inclusion in professional practice experience evaluations, course syllabi, faculty, preceptor and staff evaluations. Results. The analysis identified 11 factors for practice experiences, three for syllabi, and five for performance evaluations. The information from the factor analysis spurred additional discussion that led to the development of a programmatic plan for professionalization. Conclusion. A brief description of the programmatic professionalization plan is provided, including possible assessment processes. The goal of this endeavor was to ensure appropriate support and development of professionalization across the COP community. PMID- 30013246 TI - A Pilot Comparison of In-Room and Video Ratings of Team Behaviors of Students in Interprofesional Teams. AB - Objective. To examine concordance between in-room and video faculty ratings of interprofessional behaviors in a standardized team objective structured clinical encounter (TOSCE). Methods. In-room and video-rated student performance scores in an interprofessional 2-station TOSCE were compared using a validated 3-point scale assessing six team competencies. Scores for each student were derived from two in-room faculty members and one faculty member who viewed video recordings of the same team encounter from equivalent visual vantage points. All faculty members received the same rigorous rater training. Paired sample t-tests were used to compare individual student scores. McNemar's test was used to compare student pass/fail rates to determine the impact of rating modality on performance scores. Results. In-room and video student scores were captured for 12 novice teams (47 students) with each team consisting of students from four professions (medicine, pharmacy, physician assistant, nursing). Video ratings were consistently lower for all competencies and significantly lower for competencies of roles and responsibilities, and conflict management. Using a criterion of an average score of 2 out of 3 for at least one station for passing, 56% of students passed when rated in-room compared with 20% when rated by video. Conclusion. In room and video ratings are not equal. Educators should consider scoring discrepancies based on modality when assessing team behaviors. PMID- 30013247 TI - Practical Tips for Integrating Clinical Relevance into Foundational Science Courses. AB - The integration of foundational science and clinical science education is a hallmark of educational reform within the health professions, and an increasing number of pharmacy schools are implementing integrated curricula in professional pharmacy programs. Although the foundational sciences serve as an essential framework for understanding clinical knowledge, instructors may face challenges when integrating clinical science into foundational science courses. Here we present practical learner-centered teaching tips to address these challenges. PMID- 30013248 TI - A Meta-Analysis of Outcomes Comparing Flipped Classroom and Lecture. AB - Objective. To examine the evidence of the effectiveness of flipped classroom compared to traditional lecture. Methods. Experimental and observational studies were included and obtained through searches of PubMed, Education Resources Information Center (ERIC), and Google Scholar. Publications from January 1, 2000 through July 1, 2017 were included. Studies were eligible for this research if: (a) the study compared student outcomes using flipped classroom versus lecture and (b) at least one outcome measure was final examination score or final course score. This analysis used a random effects model with weighted mean difference (WMD) as the outcome. Results. Six studies were included in the qualitative synthesis and five were included in the quantitative synthesis. To date, there has only been one prospective randomized comparison of flipped classroom to lecture in student pharmacist education. When comparing final examination scores, there was no significant difference between flipped classroom and lecture based instruction. Only two studies examined the effect of flipped classroom compared to lecture on final course score. This analysis also found no significant difference. Conclusion. Despite a lack of prospective randomized studies, findings from this meta-analysis suggest that flipped classroom may be associated with minimal gains in student knowledge compared to lecture. These findings are important because previous research has estimated that the flipped classroom requires more time to develop and implement. Future studies using prospective randomized designs need to be conducted before widespread adoption. PMID- 30013249 TI - It's Time to Dismantle CE and Build a CPI System. PMID- 30013250 TI - It's Time We Fix the Peer Review System. PMID- 30013251 TI - 119th Annual Meeting of the American Association of Colleges of Pharmacy, Boston, Massachusetts, July 21-25, 2018. PMID- 30013252 TI - Address of the President-elect at the 2017 AACP Annual Meeting. PMID- 30013253 TI - Hepatitis C virus infection in Ghana: time for action is now. PMID- 30013254 TI - Audit of antenatal steroid use in mothers of preterms admitted to a neonatal intensive care unit in Ghana. AB - Background: Antenatal corticosteroids (ACS) are established as an effective method of reducing preterm morbidity and mortality. At the Korle Bu Teaching Hospital (KBTH), a tertiary referral centre in Ghana, it is recommended that a course of ACS should be given to mothers before delivery between 24 weeks to 34 weeks gestation. Objectives: The study was performed primarily to determine the level of adherence to guidelines on administration of ACS. Methods: All babies with gestational ages up to 34 weeks admitted to the neonatal unit (NICU) during the period of the study were eligible for inclusion. Results: There were 214 eligible admissions during the study period, of which 93 babies (43%) were studied due to poor access to medical records. Dexamethasone was the only steroid used, and mothers of 65 (70%) of the 93 babies received at least one dose; 17 (18%) received only one dose, 35 (38%) - 2 doses, 9 (10%) - 3 doses, and 4 (4%) - 4 doses. Conclusions: This study has shown a low uptake of antenatal corticosteroids, similar to other low-income and middle-income countries. To improve preterm survival and morbidity, there is an urgent need to increase the use of corticosteroids before preterm deliveries in Ghana and other low-income and middle-income countries. Funding: Not indicated. PMID- 30013255 TI - Where do delays occur when women receive antenatal care? A client flow multi-site study in four health facilities in Nigeria. AB - Objectives: The objective of the study was to identify where delays occur when women present for antenatal care in four Nigerian referral hospitals, and to make recommendations on ways to reduce delays in the course of provision of antenatal care in the hospitals. Design: Prospective observational study. Setting: Four Nigerian (1 tertiary and 3 secondary) Hospitals. Participants: Women who presented for antenatal care. Interventions: A process mapping. The National Health Service (NHS) Institute Quality and Service Improvement Tool was used for the assessment. Main outcome measures: The time women spent in waiting and receiving antenatal care in various departments of the hospitals. Results: Waiting and total times spent varied significantly within and between the hospitals surveyed. Mean waiting and total times spent were longest in the outpatients' departments and shortest in the Pharmacy Departments. Total time spent was an average of 237.6 minutes. chi2= 21.074; p= 0.0001. Conclusion: There was substantial delay in time spent to receive care by women seeking routine antenatal health services in the four secondary and tertiary care hospitals. We recommend managers in health facilities include the reduction of waiting times in the strategic plans for improving the quality of antenatal care in the hospitals. This should include the use of innovative payment systems that excludes payment at time of service delivery, adoption of a fast-track system such as pre-packing of frequently used commodities and the use of new tech informational materials for the provision of health education. Funding: The Alliance for Health Policy and Systems Research, World Health Organization, Geneva; Protocol ID A65869. PMID- 30013256 TI - Knowledge of spacer device, peak flow meter and inhaler technique (MDIs) among health care providers: an evaluation of doctors and nurses. AB - Background: Metered dose inhalers are cornerstone in effective management of bronchial asthma when correctly used. Most studies hitherto have focused on assessing patient's knowledge of inhaler technique. We sought to assess the knowledge of inhaler technique, spacer device and peak flow meter among doctors and nurses in a tertiary healthcare institution in Nigeria. Method: A cross sectional survey of nurses and doctors from emergency department, family and internal medicine; who were attending a continuous professional development lecture, was carried out. From a total of 100 questionnaires administered, we retrieved 87 of which 75 were completed, giving a response rate of 75%. It was a self-administered questionnaire. Data was analysed with SPSS version 21.0. Descriptive statistics were done. Association was examined using chi-square test. Result: Mean age of respondent was 35.8 years +/- 8.7, 47(62.7%) were < 40 years, 33(44%) were male, nurses were 30(40.0%). Only 28(37.3%) had ever used a peak flow meter. Only 4(14.3%) used peak flow meter frequently, while 12(26.7%) checked patient's inhaler technique often. Only 9 out of the 75 (12%) participants all of who are doctors knew at least 3 essential steps of the techniques in using the metered dose inhaler correctly. None of the participants got all the steps for the use of pMDI totally correct. Conclusion: Knowledge regarding the use of the metered dose inhaler and spacer device was poor. Health practitioners should have constant reminders in the form of continuous medical education to update their knowledge regarding correct inhaler technique. Funding: self-funded. PMID- 30013257 TI - Depression and quality of life in patients on long term hemodialysis at a nationalhospital in Ghana: a cross-sectional study. AB - : The study examined quality of life and prevalence of depressive symptoms in patients on long term hemodialysis. Further, it explored the impact of socio demographic characteristics on depression and quality of life. Design: Study design was cross-sectional. Setting: Study was conducted in the two renal dialysis units of the Korle-Bu Teaching hospital in Accra, Ghana. Participants and study tools: One hundred and six participants on haemodialysis were recruited for the study. The Patient Health Questionnaire and the World Health Organization Quality of Life instrument were used to assess depression and quality of life. Results: Forty five percent of participants screened positive for symptoms of depression. Approximately 19% obtained low scores on overall quality of life. There were significant negative correlations between the following: Depression and overall QoL, Depression and duration of dialysis treatment and Depression and income level. There was positive correlation between overall QoL and duration of dialysis, treatment and income. Conclusion: Depressive symptoms were common amongst patients on long term hemodialysis. Haemodialysis patients who obtained low scores on quality of life measures were more likely to screen positive for depressive symptoms. Screening for depressive symptoms among these patients is critical as early treatment may improve their general wellbeing. Funding: Not indicayed. PMID- 30013258 TI - Changes in antioxidant status associated with haemodialysis in chronic kidney disease. AB - : Oxidative stress has been implicated in the pathogenesis, progression of chronic kidney disease (CKD) and development of cardiovascular complications. Hemodialysis (HD) has also been described to contribute significantly to oxidative stress in CKD patients, though reports are conflicting. Objective: We evaluated the effects of one session of HD on the antioxidant capacity and lipid peroxidation in CKD patients. Method: Thirty-six CKD patients requiring HD were recruited into this study. Participants were naive to HD and each completed a session of three hours using polysulfone membrane dialyzers. Blood samples were collected before and after dialysis. Total antioxidant capacity (TAC) was measured by ferric reducing antioxidant power (FRAP) while malondialdehyde (MDA) was measured using thiobarbituric acid-reactive substance (TBARS). Comparison was made between pre-HD and post-HD values of TAC and MDA respectively, p value of <0.05 was taken as significant. Result: Mean age and estimated glomerular filtration rate of subjects were 45 +/-15 years and 6.3+/- 4.7mls/1.73m2 respectively. There was significant decrease in the mean TAC from 1232.2 +/- 495.6 umol Trolox equiv/ to 832.4 +/- 325.7 umol Trolox equiv/L post-dialysis (p< 0.001) while MDA values were similar before and after HD (11.8 +/- 1.8 vs 11.8 +/ 2.331)umol/L (p> 0.05). There was no significant association between changes in antioxidant status following HD with blood flow rate, ultrafiltration volume nor dialyzer per size. Conclusion: A session of HD in patients with CKD is associated with significant reduction of the total antioxidants capacity; and no effect on MDA levels. Funding: No external funding received. PMID- 30013259 TI - Traumatic tympanic membrane perforations: characteristics and factors affecting outcome. AB - Objective: To characterize traumatic tympanic membrane perforation (TTMP) in terms of distribution, mechanisms, and outcome of treatment. To assess the factors influencing such outcome. Study design: Prospective analytical study, assessing outcomes post-injuries. Setting: Clinical department of a tertiary referral hospital. Participants: Patients with TTMP based on history of trauma to the ear, and otoscopic examination confirming tympanic membrane (TM) perforation. Interventions: Conservative, inactive treatment. Main Outcome Measures: Distribution and healing of perforations. Results: There were 53 patients, Male: Female ratio =1.5:1, age 8-71years (Mean +/-SD= 33.8 +/-12.9). Median duration of injury before presentation was 3 days. 11 patients had both ears traumatized. 46.9% of perforations were in the antero-inferior part of the TM. Median size of perforations was 33.0%; Patients main complaints were blockage of the ears/ hearing loss and tinnitus. Common causes of perforations were domestic assault (28.3%), self-inflicted/ accidental injuries (20.8%), and road traffic accidents (18.9%). There was a significant difference in the mechanism/cause of injuries between the sexes (X2 =15.607, p=0.005). Traumatic perforation was caused by penetrating injuries in 22 (34.4%) ears. The outcome of TTMP was poor in 18.7%. Big sized perforations (t=2.630; p=0.011), penetrating injuries (X2 =9.263; p=0.005), and postero-superior location (X2=6.326;p=0.009) had negative impacts on the healing. Conclusions: TTMP was common in young adult males, caused often by assaults, presented with ear hearing loss and tinnitus, perforations were located in antero-inferior part of TM and most healed well. Factors associated with poor healing were postero-superior location, large size and penetrating injuries to the TM. Funding: Not indicated. PMID- 30013262 TI - The Global Adoption of National Policies Protecting Children from Violent Discipline in Schools and Homes, 1950-2011. AB - With a focus on the relationship between women's and children's rights and theories of globalization, we conduct an event history analysis of more than 150 countries between 1950 and 2011 to assess the factors associated with policies banning corporal punishment in schools and homes. Our research reveals that formal condemnation of corporal punishment in schools is becoming a global norm; policies banning corporal punishment in the home, in contrast, are being adopted more slowly. We find that the percentage of women in parliament is associated with the adoption of anti-corporal punishment policies in both schools and homes, suggesting a nexus between women's and children's issues. Countries with more ethnic diversity are slower to adopt home policies, however. We propose that groups in these countries may be resistant to laws because of the risk of selective or prejudicial enforcement. In terms of globalization, more aid is associated with both school and home policies, and countries that have ratified the Convention on the Rights of the Child are more likely to adopt home policies. Surprisingly, international nongovernmental organizations are not significantly associated with either type of policy adoption. PMID- 30013263 TI - Letters to the Editor. PMID- 30013260 TI - Impact of structured education on glucose control and hypoglycaemia in Type-2 diabetes: a systematic review of randomized controlled trials. AB - : Evidence for the use of structured education in diabetes management is accumulating and has shown positive influence in the management of Type-2 diabetes. Objective: To assess the impact of structured education on glucose control and hypoglycaemia in the management of Type-2 diabetes. Methods: A systematic review was done using Medline via Ovid and EMBASE databases of published English literature between 1980 and 2014. Included studies were randomized control trials that assessed the impact of structured education on glucose control and hypoglycaemia. Results: Out of the 12,086 full text articles were identified, 36 full text articles were finally considered for this review after applying both inclusion and exclusion criteria, of which 34 were exclusively on the effect of structured diabetes education on glucose control whilst 2 were studies on the effects of structured diabetes education on glucose control and hypoglycaemia. Majority of the studies included a predominant Caucasian population. There was heterogeneity in the included studies such as intervention methods and intensity as well as follow up periods. Group based education was preferred over individual education by most studies. Overall, most of the studies showed a significant positive effect on glycaemic control compared with control groups. One study showed a significant impact of structured education on hypoglycaemia. Conclusion: Structured education has positive impact on glucose control and hypoglycaemia in Type-2 diabetes and must be incorporated in routine care. Funding: The study was funded by the authors. PMID- 30013261 TI - Sjogren's and plasma cell variant Castleman disease: a case report. AB - Castleman disease is a rare cause of lymphoid hyperplasia and may result in localized symptoms or an aggressive, multisystem disorder. It can mimic other diseases like lymphoma or tuberculosis. It classically presents as a mediastinal mass that involves the lymphatic tissue primarily but can also affect extra lymphatic sites including the lungs, larynx, parotid glands, pancreas, meninges, and muscles. In HIV and HHV8-negative patients with idiopathic multi-centric Castleman disease, pathogenesis may involve autoimmune mechanisms. We highlight and report a case of a 34-year-old Ghanaian female who was successfully diagnosed and managed for Sjogren's as well as plasma cell variant Castleman disease with combination chemotherapy and rituximab followed by eighteen months maintenance therapy with pulse chlorambucil and prednisolone and three monthly rituximab. PMID- 30013264 TI - The Moral Obligation of Nutrition and Hydration in the Tradition and Magisterium of the Catholic Church: A Look at the Debate in the United States of America. AB - The recent publication of the fifth edition of the Ethical and Religious Directives for Catholic Health Care Services on November 17, 2009, by mandate of the United States bishops, witnessed the eruption of a controversy in the U.S. with regard to nutrition and hydration for the seriously ill and dying. Among the major philosophical and moral thinkers in the field, there are some on the one hand who-out of respect for the wishes of the patient as expressed in normal situations-see no need for nutrition and hydration if such are the patient's wishes, even though they may have been expressed before the patient became ill. On the other hand, there are those who-out of respect for human dignity and with the understanding that any act of euthanasia is morally unacceptable-do not see how the interruption of life support can be acceptable unless it comes to be a burden and no longer a benefit under end-of-life conditions. In light of all this, the present article aims to provide reflections on the nature of assisted nutrition and hydration (ANH) and the obligation to use it in cases where clinical evidence requires it, with a particular focus on the ongoing bioethical debate in the U.S. PMID- 30013265 TI - The Missing Premise in the HIV-Condom Debate. AB - In a recent article in this journal, "Condoms and HIV: The State of the Debate," William Newton argues that there are basically two issues around which parties dispute. The first is whether the use of a condom by a discordant couple amounts to performing a contraceptive act. At issue here is whether a couple's use of a condom to prevent disease transmission renders the act a contraceptive act. The second issue pertains to whether the use of a condom, apart from whatever the intentions of the agents are, is itself a failure to consummate a marital act. It is the second issue that I wish to address in this paper. I aim to argue that the Canon-Law argument, as I will call it, wishes to argue that because condomistic sex fails to consummate a marriage, the sexual act performed is immoral. I argue against this inference on two grounds: the first is that the conclusion succumbs to counterexamples, and second, the inference must rely on a premise that I show is false. PMID- 30013266 TI - The Catholic Church in America, the Discipline of Bioethics, and the Culture of Life: Looking to the Encyclical Evangelium Vitae for Guidance. AB - In this paper, I will first briefly discuss why the Catholic Church has always had and continues to have such a great concern for bioethics or health-care ethics, while I also highlight the biblical roots of this concern. Secondly, I will describe some of the ways in which the Catholic Church in America has exercised a positive influence in the field of bioethics, or what was in the mid twentieth century often called medical ethics. Thirdly, I will sketch how and why the Church has to a large extent lost this influence, tracing how secularization both inside and outside the Church contributed to the destruction of the so called "Catholic ghetto" and to the assimilation of ideas from the culture that were often alien to the Gospel and sound moral reasoning. Finally, I will offer some general reflections on how the Church can regain her influence in this area especially with the goal in mind of building a culture of life in American society-and how Catholic scholars in particular can contribute to this effort by following the lead of the late Pope John Paul II's 1995 encyclical on bioethics, Evangelium vitae, whose twentieth anniversary is fast approaching. PMID- 30013267 TI - Spirituality and the Health-Care Professional. AB - The Church and the clinic, theology and medicine, mutually support one another when the good of the other is justly pursued within an organic context of interdependency. In the midst of rapid change in health care, Catholic health care workers have much to offer the industry as they bring their spirituality of interdependency into their work environments. Due attention to spiritual nourishment received in the Church via the Eucharist is thus encouraged if Catholic health care is to have the leavening impact it is intended to have in culture. After revisiting Pope John Paul II's social encyclical Laborem exercens (On Human Work, 1981), a spirituality of work is offered for Catholic health-care professionals with particular focus on the Eucharist. Accordingly, this essay presents a theology of the Eucharist that shows how Catholics are bound closely together so that the poverty attending loneliness can be lessened and our mutual efforts at enhancing health may be strengthened. The Church and the clinic, theology and medicine, mutually support one another when the good of the other is justly pursued within an organic context of interdependency bolstered by the Eucharist. Our vocation is unity. Our affliction is to be in a state of duality, and affliction due to an original contamination of pride and of injustice.... Love is thus the right physician for our original illness.... We have lost this unity, we whose religion should be the most incarnate of any. We must recover it. -Simone Weil. PMID- 30013268 TI - Current Medical Research Winter 2010-Spring 2011. PMID- 30013269 TI - The 'Checkmate' for Iron Between Human Host and Invading Bacteria: Chess Game Analogy. AB - Iron is an essential nutrient for all living organisms with critical roles in many biological processes. The mammalian host maintains the iron requirements by dietary intake, while the invading pathogenic bacteria compete with the host to obtain those absorbed irons. In order to limit the iron uptake by the bacteria, the human host employs numerous iron binding proteins and withholding defense mechanisms that capture iron from the microbial invaders. To counteract, the bacteria cope with the iron limitation imposed by the host by expressing various iron acquisition systems, allowing them to achieve effective iron homeostasis. The armamentarium used by the human host and invading bacteria, leads to the dilemma of who wins the ultimate war for iron. PMID- 30013271 TI - An Approach to In Silico Dissection of Bacterial Intelligence Through Selective Genomic Tools. AB - All the genetic potential and the intelligence a bacteria can showcase in a given environment are embedded in its genome. In this study, we have presented systematic guidelines to understand a bacterial genome with the relevant set of in silico tools using a novel bacteria as an example. This study presents a multi dimensional approach from genome annotation to tracing genes and their network of metabolism operating in an organism. It also shows how the sequence can be used to mine the enzymes and construction of its 3-dimensional structure so that its functional behavior can be predicted and compared. The discriminating algorithm allows analysis of the promoter region and provides the insight in the regulation of genes in spite of the similarity in its sequences. The ecological niche specific bacterial behavior and adapted altered physiology can be understood through the presence of secondary metabolite, antibiotic resistance genes, and viral genes; and it helps in the valorization of genetic information for developing new biological application/processes. This study provides an in silico work plan and necessary steps for genome analysis of novel bacteria without any rigorous wet lab experiments. PMID- 30013270 TI - New Insights on Cyclization Specificity of Fungal Type III Polyketide Synthase, PKSIIINc in Neurospora crassa. AB - Type III polyketide synthases (PKSs) biosynthesize varied classes of metabolites with diverse bio-functionalities. Inherent promiscuous substrate specificity, multiple elongations of reaction intermediates and several modes of ring-closure, confer the proteins with the ability to generate unique scaffolds from limited substrate pools. Structural studies have identified crucial amino acid residues that dictate type III PKS functioning, though cyclization specific residues need further investigation. PKSIIINc, a functionally and structurally characterized type III PKS from the fungus, Neurospora crassa, is known to biosynthesize alkyl resorcinol, alkyl-triketide- and alkyl-tetraketide-alpha-pyrone products. In this study, we attempted to identify residue positions governing cyclization specificity in PKSIIINc through comparative structural analysis. Structural comparisons with other type III PKSs revealed a motif with conserved hydroxyl/thiol groups that could dictate PKSIIINc catalysis. Site-directed mutagenesis of Cys120 and Ser186 to Ser and Cys, respectively, altered product profiles of mutant proteins. While both C120S and S186C proteins retained wild type PKSIIINc product activity, S186C favoured lactonization and yielded higher amounts of the alpha-pyrone products. Notably, C120S gained new cyclization capability and biosynthesized acyl-phloroglucinol in addition to wild-type PKSIIINc products. Generation of alkyl-resorcinol and acyl-phloroglucinol by a single protein is a unique observation in fungal type III PKS family. Mutation of Cys120 to bulky Phe side-chain abrogated formation of tetraketide products and adversely affected overall protein stability as revealed by molecular dynamics simulation studies. Our investigations identify residue positions governing cyclization programming in PKSIIINc protein and provide insights on how subtle variations in protein cores dictate product profiles in type III PKS family. PMID- 30013272 TI - Effect of Homocysteine on Biofilm Formation by Mycobacteria. AB - Mycobacteria show peculiar aggregated outgrowth like biofilm on the surface of solid or liquid media. Biofilms harbor antibiotic resistant bacteria in a self produced extracellular matrix that signifies the bacterial fate to sedentary existence. Despite years of research, very little is known about the mechanisms that contribute to biofilm formation. LuxS has been previously known to play a role in biofilm formation in Autoinducer-2 dependent manner. We here show the effect of LuxS product-homocysteine, on the biofilm forming ability of non tuberculous mycobacteria, Mycobacterium smegmatis and Mycobacterium bovis BCG showing AI-2 independent phenotypic effect of LuxS. Exogenous supplementation of homocysteine in the culture media leads to aberrant cording, pellicle outgrowth, and biofilm formation. Thus, our study contributes to the better understanding of the mechanism of mycobacterial biofilm formation and sheds light on the role of LuxS product homocysteine. In addition, we highlight the contribution of activated methyl cycle in bacterial quorum sensing. PMID- 30013273 TI - S9A Serine Protease Engender Antigenic Gluten Catabolic Competence to the Human Gut Microbe. AB - The human gut microbiome has a significant role in host physiology; however its role in gluten catabolism is debatable. Present study explores the role of human gut microbes in gluten catabolism and a native human gut microbe Cellulomonas sp. HM71 was identified. SSU rDNA analysis has described human gut microbiome structure and also confirmed the permanent residentship of Cellulomonas sp. HM71. Catabolic potential of Cellulomonas sp. HM71 to cleave antigenic gluten peptides indicates presence of candidate gene encoding biocatalytic machinery. Genome analysis has identified the presence of gene encoding S9A serine protease family prolyl endopeptidase, with Ser591, Asp664 and His685 signature residues. Cellulomonas sp. HM71 prolyl endopeptidase activity was found optimal at pH 7.0 and 37 degrees C with a KM of 35.53 MUmol and specifically cleaves at proline residue. Current study describes the gluten catabolism potential of Cellulomonas sp. HM71 depicting possible role of human gut microbes in gluten catabolism to confer resistance mechanisms for the onset of celiac diseases in populations with gluten diet. PMID- 30013274 TI - Comparison of Antimicrobial Properties of Silver Nanoparticles Synthesized from Selected Bacteria. AB - Green silver nanoparticle (AgNP) biosynthesis is facilitated by the enzyme mediated reduction of Ag ions by plants, fungi and bacteria. The antimicrobial activity of green AgNPs is useful to overcome the challenge of antimicrobial resistance. Antimicrobial properties of biosynthesized AgNPs depend on multiple factors including culture conditions and the microbial source. The antimicrobial activity of AgNPs biosynthesized by Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Acinetobacter baumannii (confirmed clinical isolate) were investigated in this study. Biosynthesis conditions (AgNO3 concentration, pH, incubation temperature and incubation time) were optimized to obtain the maximum AgNP yield. Presence of AgNPs was confirmed by observing a characteristic UV-Visible absorbance peak in 420-435 nm range. AgNP biosynthesis was optimal at 0.4 g/L AgNO3 concentration under alkaline conditions at 60-70 degrees C. The biosynthesized AgNPs showed higher stability compared to chemogenized AgNPs in the presence of electrolytes. AgNPs synthesized by P. aeruginosa were the most stable while NPs of S. aureus were the least stable. AgNPs synthesized by P. aeruginosa and S. aureus showed good antimicrobial potential against E. coli, P. aeruginosa, S. aureus, MRSA and Candida albicans. AgNPs synthesized by S. aureus had greater antimicrobial activity. The antimicrobial activity of NPs may vary depending on the size and the morphology of NPs. PMID- 30013275 TI - Oral Intake of Lactobacillus helveticus NS8 Alleviates Ovalbumin-Induced Atopic Dermatitis in SKH-1 Hairless Mice. AB - Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and is driven by strong type 2 immune responses. Lactobacillus helveticus NS8 (NS8), a probiotic strain isolated from Mongolian koumiss, has anti-inflammatory activities. Here, we evaluated the therapeutic potential of NS8 on AD-like skin lesions by using SKH-1 hairless mice that underwent three cycles of epicutaneous sensitization (EC) with ovalbumin (OVA). NS8 (5 * 108 CFU/day) was orally administered to mice from 2 weeks before the first sensitization until the end of the study. NS8 attenuated the symptoms and pathological changes in the skin of AD mice. For example, NS8 reduced epidermal and dermal thickening and significantly restrained the infiltration of mast cells, eosinophils, and CD4+ T cells into the dermis. By analysing the Th1/Th2 cytokines produced in skin lesions, we found that NS8 significantly suppressed the expression of IL-4, IL-5, and IL-13 (P < 0.05), while it had no discernible effect on the expression of IFN-gamma. Systemically, NS-8 reduced the total IgE and OVA-specific IgE levels in serum (P < 0.05). Our study demonstrates that oral administration of L. helveticus NS8 effectively alleviates AD severity in mice by suppressing the Th2 immune response. NS8 may be a promising candidate for prophylactic and therapeutic treatments of allergic diseases, such as AD. PMID- 30013276 TI - Investigating the Role of Endophytic Fungi in Gentiana scabra bge. by Cross Growth Period Inoculation. AB - Gentiana scabra Bge. (gentian) is a Chinese medicinal plant. Endophytic fungi from the roots of gentian were isolated and cross-growth period inoculation was performed to study the roles of three Trichoderma spp. strains (F1, F2, and F9) in their original host plant. In treatments inoculated with F1, F2, and F9, gentiopicroside content increased 33.6, 23.7 and 13% than that in the control. Strains F1, F2, and F9 could also improve polysaccharide content by more than 6.6, 18.7 and 30% compared to the control. The incidence of spot blight in gentian inoculated with F1, F2, and F9 decreased by 31.2, 26.7 and 8.5%. Inconsistent changes in the activity of the three enzymes (superoxide dismutase, catalase and peroxidase) were observed when the plants were attacked by pathogens or inoculated with fungi. High enzymatic activity did not reflect mild disease. Cross-growth period inoculation, which takes into account the original living environment (gentian plant as "substrate" and different microorganisms as symbionts) of endophytic fungi, provides a new idea for studying effects of endophytes on their original hosts. This is the first research about the role of endophytic fungi in Gentiana scabra bge. in vivo. PMID- 30013277 TI - Designing a Novel Recombinant HN Protein with Multi Neutralizing Antigenic Sites and Auto Tag Removal Ability Based on NDV-VIIj for Diagnosis and Vaccination Application. AB - Hemagglutinin-neuraminidase (HN) protein besides its mediation in viral pathogenesis, is composed of various antigenic sites which stimulate production of host's antibodies. Thus, application of this protein in serological tests and vaccination plays a major role in biosecurity and control programs. In the present study, we designed a recombinant HN protein containing different neutralizing antigenic sites with velogenic patterns, and sub-cloned it into pET 43.1a+ expression vector. The expression of NusA-HN recombinant protein was induced. Affinity chromatography protein purification using HisPurTM Ni-NTA was then conducted. Moreover, we performed western-blot technique using HRP conjugated Anti His-Tag. Results revealed that following induction of recombinant protein, two distinct bands of HN-61 kDa and NusA-63 kDa were purified and identified by western-blotting. We recommend further analysis should be carried out to determine the functional role of this recombinant protein in enzyme-linked immunosorbent assays for Newcastle disease diagnosis. This HN protein containing multi neutralizing antigenic sites might also be applicable in vaccination programs to increase vaccines potency. PMID- 30013278 TI - Molecular Cloning and Identification of the 2'-5' Oligoadenylate Synthetase 2 Gene in Chinese Domestic Pigs Through Bioinformatics Analysis, and Determination of Its Antiviral Activity Against Porcine Reproductive and Respiratory Syndrome Virus Infection. AB - An interferon-mediated antiviral protein, 2'-5' oligoadenylate synthetase 2, plays an important role in the antiviral response of interferons. In this study, 2'-5' oligoadenylate synthetase 2 genes were cloned from Chinese domestic pigs. Bioinformatics analysis revealed that the 2024-bp long open reading fame encodes 707 amino acids. There are two conserved regions in this protein: the nucleotidyltransferase domain, and the 2'-5' oligoadenylate synthetase domain (OAS). Genetic evolution analysis showed that the 2'-5' oligoadenylate synthetase 2 gene in domestic pigs is closely related to that of cattle. There are multiple antigenic sites, no signal peptide, and no transmembrane region in the gene, which is predicted to be a hydrophilic protein. Secondary structures were found to be mainly alpha helix-based; its tertiary structure is close to that of humans and cattle, but not that of mice. Tissue distribution results indicated that this protein is distributed in multiple organs, with high distribution in the liver; it is mainly localized in the cytoplasm. PRRSV infection, interferon-beta, and Poly(I: C) treatment all promoted 2'-5' oligoadenylate synthetase 2 gene expression. Overexpression and RNA silencing of porcine OAS2 inhibited and promoted PRRSV replication in cells, respectively. The inhibitory effect of porcine OAS2 was mainly dependent on RNase L, similar to what was predicted. This study has laid the foundation for future antiviral studies in pig, and provided a new way of preventing and treating PRRSV in the future. PMID- 30013280 TI - Antifungal and Biocontrol Evaluation of Four Lysobacter Strains Against Clubroot Disease. AB - The effect of crude extract (Ce), seed coating agent (SCA) and whole bacterial broth culture (WBC) of Lysobacter strains was evaluated against the causal agent of clubroot formation in Cruciferous vegetables. The ability of four Lysobacter strains (L. antibioticus 6-B-1, L. antibioticus 6-T-4, L. antibioticus 13-B-1 and L. capsici ZST1-2) inhibited Plasmodiophora brassicae of resting spores and disease. Application of WBC of four Lysobacter strains inhibited clubroot disease, indicating that the disease suppression was due to antifungal compounds produced by the biocontrol bacterium in the culture. Development of clubroot on Chinese cabbage was inhibited when the WBC and SCA were applied before P. brassicae inoculation. Crude extract (Ce) of culture filtrate was effective in arresting the germination of resting spores of P. brassicae on slides. However, Lysobacter strains differed in their biocontrol effects, the strain L. capsci ZST1-2 recorded a high level of disease limiting effect. PMID- 30013279 TI - SIV-Specific Antibodies are Elicited by a Recombinant Fowlpox Virus Co-expressing SIV Gag and envT. AB - Given the failures of past HIV-1 vaccine clinical trials, potential HIV-1 vaccine candidates should be rigorously screened in preclinical models including simian immunodeficiency virus (SIV) primate models and small animal models. In this study, we tested the immunogenicity of a recombinant fowlpox virus (rFPV) expressing the SIV gag and SIV envT (rFPVsg-se) proteins in BALB/c mice, to establish a foundation for further development. rFPVsg-se was constructed through homologous recombination techniques and purified through plaque screening assays using enhanced green fluorescent protein as the reporter gene. The integration, transcription, and translation of the SIV genes were measured by PCR (genomic DNA), RT-PCR (RNA), Western-blot, respectively. The levels of SIV-specific antibodies were assessed by ELISA following a single immunization (n = 18/group) or a prime-boost strategy (n = 24/group) with rFPVsg-se and compared to FPV and PBS controls. Residual virus was measured in distant organs following immunization using PCR. SIV-specific IgG titers against gag and gp120 were detected following single vaccination and the prime-boost. As expected the titers were higher following the prime-boost approach. The levels of Gag- and gp120 specific antibodies were significantly higher than controls (p < 0.01) 14 days after the booster immunization. Residual rFPVSg-Se was detected in the muscle at the site of injection, but not in distant organs, from day 1-7 post immunization. In summary, rFPVsg-se induced high levels of SIV-specific antibodies suggesting it may be a viable candidate for further development. PMID- 30013281 TI - Variability in Protein Expression in Marine-Derived Purpureocillium lilacinum Subjected to Salt and Chromium Stresses. AB - Abiotic factors can cause substantial limitation of growth of microbes. A combination of salinity stress along with chromium (Cr+6), one of the carcinogen, can pose an immediate threat to any living system. To understand how salinity (0, 35 and 100 PSU) and Cr(VI) stress (0, 100 and 500 ppm), affects cells at the molecular level, the cellular response of Purpureocillium lilacinum to the individual as well the combination of both the stresses were studied by peptide mass fingerprinting technique. The study reports 1412 proteins, of which 105 proteins were found to be present across all conditions. The most prevalent functional class expressed was genetic information processing. Proteins involved in free radical scavenging were up-regulated in response to the oxidative stress generated due to both the applied stresses while expression of metal chelators, transporters systems, indicated towards multiple stress tolerance mechanisms to combat synergistic effects of salt and Cr stress. PMID- 30013282 TI - Development of T3SS Mutants (hrpB- and hrcV-) of Ralstonia solanacearum, Evaluation of Virulence Attenuation in Brinjal and Tomato-A Pre-requisite to Validate T3Es of R. solanacearum. AB - Ralstonia solanacearum is an important plant pathogen which infects a large number of agriculturally important crops. The Type Three Secretion System (T3SS) plays a major role in its pathogenicity by secreting type III effectors (T3Es) which overthrow the host defence mechanism. The secretion of T3Es is transcriptionally regulated by hrpB and its secretion is dependent on the pili formed by hrcV gene. In this study, two T3SS mutants of R. solanacearum strain Rs 09-161 viz. Rs-HrpB- and Rs-HrcV- were developed through insertional mutagenesis. The method of development of insertional mutant is quite simple and reliable. The plasmid integrates through homologous recombination and in vitro studies have proved that the integration was stable for several generations. The mutants are non-pathogenic on its highly susceptible hosts, brinjal and tomato inoculated by soil drench method and by petiole inoculation directly into the vascular system. Further it was observed that the colonisation ability of the mutants was also highly reduced in the susceptible host. These mutants will be useful in validating putative T3E through translocation studies. PMID- 30013283 TI - Rapid Detection Device for Salmonella typhi in Milk, Juice, Water and Calf Serum. AB - A limit of detection of 200 CFU/mL of Salmonella typhi spiked in various sample matrices were achieved in 30 min. The sample matrices were raw/unprocessed milk, commercially available milk, juice from packed bottles, fresh juice from carts, potable water, turbid water and calf serum. The complete protocol comprised of three steps: (a) cell lysis (b) nucleic acid amplification and (c) an in situ optical detection. The cell lysis was carried out using a simple heating based protocol, while the loop-mediated isothermal amplification of DNA was carried out by an in-house designed and fabricated system. The developed system consists of an aluminum block fitted with two cartridge heaters along with a thermocouple. The system was coupled to a light source and spectrometer for a simultaneous in situ detection. Primers specific for STY2879 gene were used to amplify the nucleic acid sequence, isolated from S. typhi cells. The protocol involves 15 min of cell lysis and DNA isolation followed by 15 min for isothermal amplification and simultaneous detection. No cross-reactivity of the primers were observed at 106 CFU/mL of Escherichia coli, Vibrio cholerae, Salmonella typhimurium, Salmonella paratyphi A, Pseudomonas aeruginosa, Bacillus cereus, Lysteria monocytogenes, Clostridium botulinum, Staphylococcus aureus and Salmonella havana. In addition, the system was able to detect S. typhi of 200 CFU/mL in a concoction of 106 CFU/mL of E. coli, 106 CFU/mL of V. cholerae, and 106 CFU/mL of hepatocyte-derived cellular carcinoma HUH7 cells. The proposed rapid diagnostic system shows a promising future in the field of food and medical diagnostics. PMID- 30013284 TI - Aloe Emodin Reduces Phthiodiolone Dimycocerosate Potentiating Vancomycin Susceptibility on Mycobacteria. AB - Treatment of tuberculosis still represent a major public health issue. The emergence of multi-and extensively-drug resistant (MDR and XDR) Mycobacterium tuberculosis clinical strains further pinpoint the urgent need for new anti tuberculous drugs. We previously showed that vancomycin can target mycobacteria lacking cell wall integrity, especially those lacking related phthiocerol and phthiodolone dimycocerosates, PDIM A and PDIM B, respectively. As aloe emodin was previously hypothesized to be able to target the synthesis of mycobacterial cell wall lipids, we tested its ability to potentiate glycopeptides antimycobacterial activity. The aloe emodin with the vancomycin induced a combination effect beyond simple addition, close to synergism, at a concentration lower to reported IC50 cytotoxic value, on M. bovis BCG and on H37Rv M. tuberculosis. Interestingly, out of six MDR and pre-XDR clinical strains, one showed a strong synergic susceptibility to the drug combination. Mycobacterial cell wall lipid analyses highlighted a selective reduction of PDIM B by aloe emodin. PMID- 30013285 TI - Motivating rural older residents to prepare for disasters: moving beyond personal benefits. AB - In the United States of America (USA), older adults in rural areas are at increased risk for adverse outcomes of disasters, partly due to medical needs, limited or long geographic distances from community resources, and less knowledge and motivation about preparedness steps. Older residents and ageing service providers in a rural community in the USA were interviewed regarding their perceptions about disasters and preparedness, and their reactions to the preparedness training programme using the concepts of the Extended Parallel Process Model. Participants generally indicated low motivation to engage in preparedness behaviours despite perceptions of personal risk and beliefs that preparedness behaviours were easy and could improve disaster outcomes. A theme of social relationships emerged from the data, with participants identifying social relationships as resources, barriers and motivators. People surrounding older adults can support or deter their preparedness behaviours, and sometimes elicit a desire to protect the wellbeing of others. Findings suggest two potential strategies to facilitate preparedness behaviours by moving beyond personal benefits: highlighting older adults' increased ability to protect the wellbeing of younger generations and their community by being prepared themselves, and engaging family, friends and neighbours in preparedness programmes to enhance the resilience of their social groups. Older adults in many cultures have a desire to contribute to their society. Novel and effective approaches to increase preparedness could target their social groups. PMID- 30013286 TI - Towards monitoring conformational changes of the GPCR neurotensin receptor 1 by single-molecule FRET. AB - Neurotensin receptor 1 (NTSR1) is a G protein-coupled receptor that is important for signaling in the brain and the gut. Its agonist ligand neurotensin (NTS), a 13-amino-acid peptide, binds with nanomolar affinity from the extracellular side to NTSR1 and induces conformational changes that trigger intracellular signaling processes. Our goal is to monitor the conformational dynamics of single fluorescently labeled NTSR1. For this, we fused the fluorescent protein mNeonGreen to the C terminus of NTSR1, purified the receptor fusion protein from E. coli membranes, and reconstituted NTSR1 into liposomes with E. coli polar lipids. Using single-molecule anisotropy measurements, NTSR1 was found to be monomeric in liposomes, with a small fraction being dimeric and oligomeric, showing homoFRET. Similar results were obtained for NTSR1 in detergent solution. Furthermore, we demonstrated agonist binding to NTSR1 by time-resolved single molecule Forster resonance energy transfer (smFRET), using neurotensin labeled with the fluorophore ATTO594. PMID- 30013287 TI - What Are Men Doing While Women Perform Extra Unpaid Labor? Leisure and Specialization at the Transition to Parenthood. AB - Marriage has significantly changed since Becker proposed his specialization model yet some scholars maintain that specialization characterizes modern couples. Specialization occurs when one partner, traditionally the man, concentrates on market work while the other partner, traditionally the woman, focuses on nonmarket work such as housework or childcare. Using innovative time diary data from primarily highly-educated, White, dual-earner U.S. couples, we examine how couples manage their time in market and household work and leisure across a momentous, gendered life course turning point-the transition to parenthood. We find little evidence of specialization, but stronger evidence of nonspecialization where both partners concurrently engaged in market work or leisure. Yet gender still mattered. Men enjoyed more leisure time, particularly on nonworkdays, whereas their partners performed more nonmarket work. Our study is the first known to uncover exactly what men were doing while women performed additional minutes of housework and childcare. On nonworkdays, fathers engaged in leisure 47% and 35% of the time during which mothers performed childcare and routine housework, respectively. Mothers engaged in leisure only about 16% to 19% of the time that fathers performed childcare and routine housework. In sum, although our study challenges economic theories of specialization by showing that nonspecialization is the norm for new parents' time among highly-educated, dual earner couples, persistent gender inequalities continue to characterize family work and leisure time. PMID- 30013288 TI - When Visual Cues Activate Moral Foundations: Unintended Effects of Visual Portrayals of Vaping within Electronic Cigarette Video Advertisements. AB - Within multimodal persuasive messages, the roles of visual cues in producing unintended effects have been understudied. In an experiment on a sample of former and current smokers (N = 991), we manipulated the presence of visual vaping cues within electronic cigarette video advertisements (N = 25) to evaluate opinions towards vape-free policies. Such cues diminished the effects of pro-vaping arguments to increase support for vape-free policies, inadvertently benefiting public health. Consistent with the moral foundations theory (MFT), endorsement of the care/harm moral foundation strengthened message effects. Furthermore, cognitions and emotions related to moral intuitions mediated the effects of visual vaping cues. These findings suggest that MFT can help explain unintended effects of visual cues when outcomes are related to morality. PMID- 30013289 TI - The 3-dot circle: A reliable method for safe and efficient digital templating of the acetabular component. AB - Background: Templating for preoperative planning of joint arthroplasty has followed the evolution of digital templating software. Objective: This study aims to provide a safe, reliable and reproducible method for prediction of acetabular component size based on measurement of the radiographic femoral head diameter, with the aid of templating software. Methods: A defined methodology for femoral head measurement was applied to 97 consecutive, calibrated digital pelvic radiographs. Based on radiographic femoral head diameter, the minimum acetabular shell diameter was calculated and then compared to the size of the implanted acetabular shells. Results: This method predicted safe minimum acetabular component size with an accuracy of 95.9% with a high inter-observer reliability of 97.6%. Conclusions: This study presents a simple, reproducible and accurate method for templating of the minimum safest acetabular component diameter. PMID- 30013290 TI - Functional outcome of arthroscopic double row repair for Bankart lesion. AB - Introduction: The shoulder joint is the most common major joint to dislocate. Population aged younger than 20 years, recurrent dislocation rates have been reported to be as high as 90%. For those individuals that continue to experience dislocations surgery is often a good decision. The goal of the Bankart surgery is to reconnect the torn labrum to the glenoid fossa. Double-row Bankart repair can both achieve anatomic reduction and enhance fixation stability. The purpose of our study is to assess the clinical outcome of arthroscopic double row repair. Methods: 49 cases with Bankart lesion operated by double row repair were studied. Functional outcome and retear were assessed after at least 6 months of surgery using scores and MRI. Results: Significant improvement in functional outcome after repair by double row Bankart repair. No retear or redislocation seen. Conclusion: Double row repair technique improves function of shoulder significantly and potentially minimizes future re-injury or recurrence risk. PMID- 30013292 TI - A Successful ENFit Launch Still Won't Stop All Incidents of Oral Medications Given Intravenously. AB - Preventing incidents of oral meds given intravenously. PMID- 30013291 TI - Mortality in patients sustaining a periprosthetic fracture following a hemiarthroplasty. AB - Periprosthetic fractures of the proximal femur after hip hemiarthroplasty are an increasing concern. The aim of this study was to analyse the 30 day mortality of periprosthetic fractures around a hip hemiarthroplasty. A retrospective case review at a single institution. 32 patients. Mean age 76.5, 16 males and 16 females. 13% underwent non-operative treatment, 50% open reduction internal fixation and 38% revision arthroplasty. 30 day mortality was 12.5% and 1 year mortality 28.1%. Time to surgery was the only significant risk factor for 30 day mortality Periprosthetic fractures following a hip hemiarthroplasty have high 30 day mortality. PMID- 30013294 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 30013293 TI - Hospitals Search for IV Opioids: Has the DEA Been Fast and Flexible Enough? AB - Hospitals search for IV opioids. PMID- 30013295 TI - Pharmaceutical Approval Update. AB - Fostamatinib (Tavalisse) for thrombocytopenia in adults with chronic immune thrombocytopenia; coagulation factor Xa (recombinant), inactivated-zhzo (Andexxa) for the reversal of anticoagulation; epoetin alfa-epbx (Retacrit), a biosimilar for the treatment of anemia. PMID- 30013296 TI - Etelcalcetide (Parsabiv) for Secondary Hyperparathyroidism in Adults With Chronic Kidney Disease on Hemodialysis. AB - Etelcalcetide (Parsabiv) for hyperparathyroidism in adults with chronic kidney disease on hemodialysis. PMID- 30013297 TI - Medicare Quietly Forces Changes To Federal Formulary Requirements: Changes Nibble Around the Edge of Drug Pricing, But Bigger Bites May Be Coming. AB - Quiet changes in federal health programs make minor but significant consumer friendly changes in the way drugs are priced for seniors in 2019. The author considers how this lays the groundwork for more radical changes in the future. PMID- 30013298 TI - Metastatic Soft Tissue Sarcomas: A Review Of Treatment and New Pharmacotherapies. AB - Soft tissue sarcomas represent a group of heterogeneous mesenchymal tumors that occur rarely in adults. While a variety of histological subtypes exist, some of the most common are leiomyosarcoma and liposarcoma. For eligible patients, standard first-line treatment of metastatic disease has typically comprised anthracycline-containing regimens. While traditional cytotoxic chemotherapy has been the mainstay of treatment in metastatic soft tissue sarcoma, emerging targeted and novel therapies are creating new frontiers of treatment for a variety of histological subtypes. Olaratumab (Lartruvo, Eli Lilly) in combination with doxorubicin represents a new potential first-line treatment option. Second line therapy is often histology-driven, and novel treatment options include trabectedin (Yondelis, Janssen) and eribulin (Halaven, Eisai). This review discusses the diagnosis, role of chemotherapy in unresectable and metastatic disease, and role of emerging therapies in the treatment of metastatic soft tissue sarcoma. PMID- 30013299 TI - Review of Medication Therapy for the Prevention of Sickle Cell Crisis. AB - This article reviews the clinical data concerning the uses of hydroxyurea, L glutamine, and crizanlizumab in treating pain crises associated with sickle cell disease. PMID- 30013300 TI - Satisfaction With Medication Reconciliation Completed by Pharmacy Technicians in an Emergency Department. AB - Purpose: To survey advanced nurse practitioners, physician assistants, nurses, physicians, and resident physicians involved with collecting and reconciling medication histories in the emergency department (ED) to measure their satisfaction with the current process involving pharmacy technicians. Methods: Two sites within a large health system with pharmacy technician-driven medication reconciliation processes asked health care professionals to complete a survey of 20 multiple-choice questions. The data collected determined resources used and barriers faced when collecting medication histories, satisfaction before and after the involvement of pharmacy technicians in the ED, and the impact technology may have on this process in the future. Results: Of 144 health care providers surveyed, 69.4% reported collecting medication histories through patient interviews. The most common barrier reported was the lack of time (44%) to spend on this step. After implementing the pharmacy technician-driven program, satisfaction with health care providers' required time improved from 18.8% to 68.9%. Similarly, satisfaction with the accuracy of medication histories improved from 40.3% to 75.4%. When asked about the use of technology if available, 65.2% of respondents reported they would almost always use technology. However, 61.6% of respondents preferred investing health care resources in adding more pharmacy technicians in the ED rather than adding technology. Conclusion: Pharmacy technicians have positively impacted the medication reconciliation process at the sites surveyed. Health care professionals report greater satisfaction with their time demands and perceived accuracy of medication histories, giving them more time to focus on other patient care tasks. Those surveyed reported interest in using technology to collect medication histories if it was available, but they would prefer more pharmacy technicians to assist with the process. PMID- 30013301 TI - Research Briefs. PMID- 30013302 TI - American Association for Cancer Research And American College of Obstetricians and Gynecologists. AB - We report on sessions on immunotherapies for non-small-cell lung cancer and pancreatic cancer from AACR and on endometriosis, hypoactive sexual desire disorder, neonatal abstinence syndrome, and more from ACOG. PMID- 30013303 TI - Modeling Cumulative Biological Phenomena with Suppes-Bayes Causal Networks. AB - Several diseases related to cell proliferation are characterized by the accumulation of somatic DNA changes, with respect to wild-type conditions. Cancer and HIV are 2 common examples of such diseases, where the mutational load in the cancerous/viral population increases over time. In these cases, selective pressures are often observed along with competition, co-operation, and parasitism among distinct cellular clones. Recently, we presented a mathematical framework to model these phenomena, based on a combination of Bayesian inference and Suppes' theory of probabilistic causation, depicted in graphical structures dubbed Suppes-Bayes Causal Networks (SBCNs). The SBCNs are generative probabilistic graphical models that recapitulate the potential ordering of accumulation of such DNA changes during the progression of the disease. Such models can be inferred from data by exploiting likelihood-based model selection strategies with regularization. In this article, we discuss the theoretical foundations of our approach and we investigate in depth the influence on the model selection task of (1) the poset based on Suppes' theory and (2) different regularization strategies. Furthermore, we provide an example of application of our framework to HIV genetic data highlighting the valuable insights provided by the inferred SBCN. PMID- 30013304 TI - A Functional Spatial Analysis Platform for Discovery of Immunological Interactions Predictive of Low-Grade to High-Grade Transition of Pancreatic Intraductal Papillary Mucinous Neoplasms. AB - Intraductal papillary mucinous neoplasms (IPMNs), critical precursors of the devastating tumor pancreatic ductal adenocarcinoma (PDAC), are poorly understood in the pancreatic cancer community. Researchers have shown that IPMN patients with high-grade dysplasia have a greater risk of subsequent development of PDAC in the remnant pancreas than do patients with low-grade dysplasia. In this study, we built a computational prediction model that encapsulates the spatial cellular interactions in IPMNs that play key roles in the transformation of low-grade IPMN cysts to high-grade cysts en route to PDAC. Using multiplex immunofluorescent images of IPMN cysts, we adopted algorithms from spatial statistics and functional data analysis to create metrics that summarize the spatial interactions in IPMNs. We showed that an ensemble of models learned using these spatial metrics can robustly predict, with high accuracy, (1) the dysplasia grade (low vs high grade) and (2) the risk of a low-grade cyst progressing to a high grade cyst. We obtained high classification accuracies on both tasks, with areas under the curve of 0.81 (95% confidence interval: 0.71-0.9) for task 1 and 0.81 (95% confidence interval: 0.7-0.94) for task 2. To the best of our knowledge, this is the first application of an ensemble machine learning approach for discovering critical cellular spatial interactions in IPMNs using imaging data. We envision that our work can be used as a risk assessment tool for patients diagnosed with IPMNs and facilitate greater understanding and investigation of the cellular interactions that cause transition of IPMNs to PDAC. PMID- 30013305 TI - Computational Model for Predicting the Relationship Between Micro-RNAs and Their Target Messenger RNAs in Breast and Colon Cancers. AB - Motivation: Uncovering the relationship between micro-RNAs (miRNAs) and their target messenger RNAs (mRNAs) can provide critical information regarding the mechanisms underlying certain types of cancers. In this context, we have proposed a computational method, referred to as prediction analysis by optimization method (PAOM), to predict miRNA-mRNA relations using data from normal and cancer tissues, and then applying the relevant algorithms to colon and breast cancers. Specifically, we used 26 miRNAs and 26 mRNAs with 676 (= 26 * 26) relationships to be recovered as unknown parameters. Results: Optimization methods were used to detect 61 relationships in breast cancer and 32 relationships in colon cancer. Using sequence filtering, we detected 18 relationships in breast cancer and 15 relationships in colon cancer. Among the 18 relationships, CD24 is the target gene of let-7a and miR-98, and E2F1 is the target gene of miR-20. In addition, the frequencies of the target genes of miR-223, miR-23a, and miR-20 were significant in breast cancer, and the frequencies of the target genes of miR-17, miR-124, and miR-30a were found to be significant in colon cancer. Availability: The numerical code is available from the authors on request. PMID- 30013306 TI - A Supervised Learning Tool for Prostate Cancer Foci Detection and Aggressiveness Identification using Multiparametric magnetic resonance imaging/magnetic resonance spectroscopy imaging. AB - Prostate cancer is the most frequently diagnosed cancer in men in the United States. The current main methods for diagnosing prostate cancer include prostate specific antigen test and transrectal biopsy. Prostate-specific antigen screening has been criticized for overdiagnosis and unnecessary treatment, and transrectal biopsy is an invasive procedure with low sensitivity for diagnosis. We provided a quantitative tool using supervised learning with multiparametric imaging to be able to accurately detect cancer foci and its aggressiveness. A total of 223 specimens from patients who received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging prior to the surgery were studied. Multiparametric imaging included extracting T2-map, apparent diffusion coefficient (ADC) using diffusion-weighted MRI, Ktrans using dynamic contrast enhanced MRI, and 3-dimensional-MR spectroscopy. A pathologist reviewed all 223 specimens and marked cancerous regions on each and graded them with Gleason scores, which served as the ground truth to validate our prediction model. In cancer aggressiveness prediction, the average area under the receiver operating characteristic curve (AUC) value was 0.73 with 95% confidence interval (0.72 0.74) and the average sensitivity and specificity were 0.72 (0.71-0.73) and 0.73 (0.71-0.75), respectively. For the cancer detection model, the average AUC value was 0.68 (0.66-0.70) and the average sensitivity and specificity were 0.73 (0.70 0.77) and 0.62 (0.60-0.68), respectively. Our method included capability to handle class imbalance using adaptive boosting with random undersampling. In addition, our method was noninvasive and allowed for nonsubjective disease characterization, which provided physician information to make personalized treatment decision. PMID- 30013308 TI - Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. AB - Cardiovascular disease (CVD) is the leading cause of death in the world and our approach to the control and management of CVD mortality is limited. Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in CVD mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to CVD. It outlines the advantages of NK and the outstanding issues pertaining to NK pharmacokinetics. Available evidence suggests that NK is a unique natural compound that possesses several key cardiovascular beneficial effects for patients with CVD and is therefore an ideal drug candidate for the prevention and treatment of CVD. Nattokinase is a promising alternative in the management of CVD. PMID- 30013309 TI - In Vitro Studies of the Antimicrobial and Free-Radical Scavenging Potentials of Silver Nanoparticles Biosynthesized From the Extract of Desmostachya bipinnata. AB - The aim of this study was to perform green synthesis of silver nanoparticles (AgNPs) from the leaf extract of Desmostachya bipinnata (Dharba), a medicinally important herb which is widely used across India. Synthesized AgNPs were analyzed by UV-Visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and energy dispersive X ray spectroscopy (EDAX). The results have confirmed that green synthesis of AgNPs leads to the fabrication of sphere-shaped particles with a diameter of 53 nm. Furthermore, these AgNPs were subjected to antioxidant and antimicrobial studies against gram-negative and gram-positive bacteria, where AgNPs at a concentration of 20 mg/mL showed highest zone of inhibition. Synthesized AgNPs were evaluated for their antioxidant activity by 1, 1-diphenyl-2-picryl hydrazyl radical (DPPH), H2O2, and superoxide inhibiting assays; increasing concentration has showed increase in scavenging ability. Cell toxicity was assessed on HepG2 cell lines, and synthesized nanoparticles at a concentration of 128 MUg/mL produced significant reduction in viability of Hep cells (P < .05). The availability of Dharba throughout the year and the eco-friendly approach in the synthesis of AgNPs coupled with bioactivity has demonstrated its potential as a novel biomaterial which can be used for various biomedical applications. PMID- 30013307 TI - Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives. AB - Multiple endocrine neoplasia (MEN) syndromes are infrequent inherited disorders in which more than one endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors. There are 3 famous and well-known forms of MEN syndromes (MEN 1, MEN 2A, and MEN 2B) and a newly documented one (MEN4). These syndromes are infrequent and occurred in all ages and both men and women. Usually, germ line mutations that can be resulted in neoplastic transformation of anterior pituitary, parathyroid glands, and pancreatic islets in addition to gastrointestinal tract can be an indicator for MEN1. The medullary thyroid cancer (MTC) in association with pheochromocytoma and/or multiple lesions of parathyroid glands with hyperparathyroidism can be pointer of MEN2 which can be subgrouped into the MEN 2A, MEN 2B, and familial MTC syndromes. There are no distinct biochemical markers that allow identification of familial versus nonfamilial forms of the tumors, but familial MTC usually happens at a younger age than sporadic MTC. The MEN1 gene (menin protein) is in charge of MEN 1 disease, CDNK1B for MEN 4, and RET proto-oncogene for MEN 2. The focus over the molecular targets can bring some hope for both diagnosis and management of MEN syndromes. In the current review, we look at this disease and responsible genes and their cell signaling pathway involved. PMID- 30013311 TI - DRESS Syndrome and Daclizumab Failure-Were Potentially Dangerous Signs Missed in Clinical Trials? AB - The US Food and Drug Administration (FDA) approved Zinbryta, an interleukin-2 receptor blocking antibody (daclizumab; Biogen and AbbVie) for the treatment of adults with relapsing forms of multiple sclerosis (MS) in May, 2016. It was also approved by the European Union in July, 2016. Zinbryta is a long-acting, self administered monthly injection that was branded as a new MS drug for patients who needed a "new option for treatment." It blocks interleukin-2 receptor alpha (CD25) and modulates T-cell expansion. The drug was withdrawn from the market in March, 2018 following 12 reports from Germany (9), United States (2), and Spain (1) following the development of "inflammatory encephalitis and meningoencephalitis" in patients on Zinbryta. Although cases of hepatotoxicity made news with Zinbryta earlier along this drug's postmarketing journey in the treatment of patients with MS, the European Medicines Agency (EMA) ordered a review of the risks of hepatotoxicity with Zinbryta use June, 2017; this analysis will focus on the pharmacovigilance data concerning the central nervous system (CNS) complications. The details of the CNS complications have been elucidated by EMA. Every drug failure provides an opportunity for learning, but it is also noteworthy that no FDA-approved MS drug in modern times has met with such an untimely, sudden, and inglorious exit. This should serve as a cautionary tale for all clinicians who use "newer MS drugs" that have mushroomed in recent memory following a flurry of recent FDA approvals. PMID- 30013310 TI - Valacyclovir Neurotoxicity and Nephrotoxicity in an Elderly Patient Complicated by Hyponatremia. AB - A 66-year-old women with no history of renal disease was admitted due to a coma and acute kidney injury with a serum creatinine level of 7.44 mg/dL which were ascribed to valacyclovir neurotoxicity and nephrotoxicity, respectively. She had received valacyclovir at a standard dosage for the treatment of herpes zoster and was finally discharged, having fully returned to her normal baseline mental status with a recovered serum creatinine level of 0.68 mg/dL. We feel that awareness of this pathology remains a challenge for physicians and therefore strongly recommend the further accumulation of experiences similar to our own. Our experience underscores the pitfalls of administering valacyclovir to elderly patients who barely appear to have a favorable renal function. Several concerns regarding the therapeutic management, including blood purification strategies, that emerged in this case are also discussed. PMID- 30013312 TI - Effect of clinical parameters on the ocular surface microbiome in children and adults. AB - Purpose: To perform a pilot study to characterize the effect of clinical parameters on the ocular surface microbiome (OSM) in children and adults using 16s ribosomal RNA sequencing. Methods: Prospective, cross-sectional study using 16s sequencing to evaluate the OSM. Comparisons were made in bacterial composition by 1) age, 2) gender, 3) sampling location of the ocular and periocular surfaces, and 4) topical drop use. 16s sequencing was performed using Illumina MiSeq 250 and analyzed using Qiime. Results: Thirty patients (15 children [mean 3.7 years], 15 adults [mean 60.4 years]) were sampled. Both principal coordinate analysis and unifrac distance analysis showed significant differences in the composition between the pediatric and adult OSMs (both p=0.001). The eyelid margin microbiota did not show any distinct clustering compared to conjunctiva within the pediatric samples but tended to show a distinction between anatomic sites in adult samples. No differences in OSM were noted by topical drop use. Conclusion: 16s sequencing is a useful tool in evaluating the OSM in patients of all ages, showing a distinct difference between pediatric and adult microbiomes. PMID- 30013313 TI - Macular edema resolution assessment with implantable dexamethasone in diabetic retinopathy (MERIT): a pilot study. AB - Purpose: This study aimed to evaluate the effect of dexamethasone implantation on the hard exudates (HEX) in patients with diabetic macular edema (DME). Study design: This was a nonrandomized open-label single-center prospective trial. Methods: This study included 15 eyes of 11 subjects with DME. Key inclusion criteria were naive eyes with DME with HEX within 3 mm of fovea with center involving DME; central macular thickness (CMT) >250 MUm at baseline; best corrected visual acuity (BCVA) between 20/400 and 20/40. Key exclusion criteria were previous intraocular surgery and history of panretinal photocoagulation (PRP) in past 4 months. The primary outcome measure was change in total HEX area at the macula (in mm2) measured by semiautomated algorithm. Secondary outcome measures were change in visual acuity, low-contrast visual acuity (LCVA), retinal sensitivity (RS) on macular microperimetry, and CMT. Results: The total HEX area reduced from 1.5 mm2 (+/-1.46 mm2) at baseline to 0.89 mm2 (+/-1.062 mm2) at the final visit (p=0.185). The CMT improved significantly (p=0.03) from 488.67 MUm (+/-240.66 MUm) to 326.93 MUm (+/-135.84 MUm) at the final visit. Mean BCVA remained stable (p=0.95) (50.93+/-16.65 at baseline and 50.6+/-18.95 at final visit). The mean LCVA and RS showed insignificant improvement (p=0.31 and p=0.28, respectively). Conclusion: Our pilot study demonstrated an improving trend in reduction of total HEX area and other anatomical outcomes, with limited functional outcomes. Larger randomized studies with a larger sample size with a control group are warranted to establish management protocols for DME with significant subfoveal HEX. PMID- 30013314 TI - Retinal nerve fiber layer thickness after laser-assisted subepithelial keratomileusis and femtosecond LASIK: a prospective observational cohort study. AB - Purpose: Based on the assumption that high levels of intraocular pressure (IOP) during femtosecond laser-assisted in situ keratomileusis (FS-LASIK) may compromise the retinal nerve fiber layer (RNFL), newer femtosecond platforms that operate without causing significant IOP elevation have been developed in recent years. However, this assumption has not been adequately tested. The aim of the current study was to evaluate possible changes in RFNL thickness in nonglaucomatous myopic patients undergoing FS-LASIK using the 60 KHz IntraLase(r) device that significantly elevates the IOP for an appreciable period of time vs an advanced surface ablation technique (laser-assisted subepithelial keratomileusis, LASEK) that does not induce any IOP elevation. Methods: This was a prospective, observational, controlled cohort study. One randomly selected eye of 114 consecutive eligible patients was analyzed. Inclusion criteria were myopia up to -6.00 diopters and astigmatism up to -2.00 diopters. As clinically indicated, 50 patients underwent LASEK and 64 underwent FS-LASIK. The RNFL thickness was determined with a spectral-domain optical coherence tomography device preoperatively and 3 months postoperatively by the same masked observer. Results: There was no significant difference in preoperative refractive error, age, or sex between the groups. Preoperatively, central corneal thickness was significantly lower in the LASEK group (529.1+/-36.1 vs 562.4+/-31.6 um, P=0.001). For the LASEK group, there was no significant difference between preoperative and postoperative RNFL thickness in the studied sectors (superior temporal, temporal, inferior-temporal, average). For the FS-LASIK group, compared to preoperative RNFL measures, statistically significant thicker postoperative values were found for the average RNFL (mean difference: 0.67 um, 0.7% increase, P=0.008) and the inferior-temporal sector (mean difference: 0.92 um, 0.6% increase, P=0.02). Conclusion: LASIK with a femtosecond platform that induces high intraoperative IOP did not cause RNFL thinning. The observed differences between preoperative and postoperative values are below the axial resolution limit of optical coherence tomography devices. PMID- 30013315 TI - Long-term clinical results and scanning electron microscopic analysis of the aspheric, hydrophobic, acrylic intraocular lens CT LUCIA 611P(Y). AB - Purpose: The aim of this study was to evaluate the clinical outcomes of a novel designed hydrophobic, acrylic, monofocal, fully preloaded intraocular lens (IOL; CT LUCIA 611P) 1 year after implantation. Scanning electron microscopic analysis regarding the optic-haptic junction and sharp edges of the IOL was performed. Patients and methods: This is a noninterventional, observational prospective study of cataract patients who underwent implantation of the CT LUCIA 611P. Ninety-six eyes of 54 subjects were enrolled. Follow-up included visual acuity assessment, slit lamp examination with special focus on appearance of glistenings and evaluation of posterior capsule opacification (PCO). Scanning electron microscopic analysis of the new designed optic-haptic junction and edges of the IOL was performed. Results: Best-corrected distance visual acuity increased from mean 0.48 logMAR (range 0.86-0.34) preoperatively to mean 0.02 logMAR (range 0.14 to -0.10) 1 year after surgery. Thirty-eight of 42 subjects' eyes (90.5%), which underwent bilateral surgery with implantation of the IOL, never required glasses for distance again, while 4 (9.5%) required glasses only in rare cases (eg, driving at night). The spherical equivalent was within +/-0.50 D in 88 of 96 subjects (91.7%) and within +/-0.75 D in 96.9% of cases. Target refraction +/ 1.00 D was achieved in 100% of subject eyes. No glistenings were reported in any case. From the surgeons' perspective, the wider, thicker optic-haptic transition of the IOL resulted in significantly increased stiffness, which enabled improved centering of the IOL and enhanced rotational stability and refractive predictability and stability and PCO prevention. Conclusion: The results of this long-term observational study demonstrate the safety and efficacy of the IOL. Because of the completely new designed thicker and stiffer optic-haptic junction regarding improved characteristics of the IOL (stability in the capsular bag), some special attention has to be addressed to the slightly different behavior of the lens during implantation and unfolding process. PMID- 30013316 TI - Comparison between intravitreal bevacizumab and posterior sub-tenon injection of triamcinolone acetonide in macular edema secondary to retinal vein occlusion. AB - Aim: To compare the efficacy and safety between posterior sub-tenon injection of triamcinolone acetonide (PSTA) and intravitreal injection of bevacizumab (Avastin) (IVIA) in the treatment of macular edema secondary to retinal vein occlusion. Patients and methods: A total of 45 eyes were retrospectively enrolled (23 eyes with intravitreal bevacizumab and 22 eyes with posterior sub-tenon triamcinolone acetonide). Main endpoints included logMAR of best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) before and after treatment at 6 months. Results: The mean logMAR improved from 0.78 to 0.56 at 6 months for intravitreal bevacizumab (p=0.001), and from 0.91 to 0.79 and 0.87 at 3 and 6 months (p=0.038 and 0.13), respectively, for sub-tenon triamcinolone acetonide. At 6 months, the BCVA was significantly better in the bevacizumab group (p=0.02). Both groups' mean CMT significantly improved, from 478 um at baseline to 295 um at 6 months in IVIA group (p<0.001) and from 419 um at baseline to 350 um in PSTA group (p=0.012); however, this was not different between the groups at 6 months (p=0.065). Recurrence of macular edema was not different between the groups either (p=0.08). Poorer final vision was associated with poorer baseline BCVA and diagnosis of central retinal vein occlusion after adjustment for age and sex (p<0.001 and 0.012, respectively). Significant elevation of IOP was noted at 3 months in the PSTA group, but declined at 6 months compared with baseline (p=0.002 and 0.41, respectively). Conclusion: Intravitreal bevacizumab seemed to achieve better visual acuity compared with posterior sub-tenon injections of triamcinolone acetonide at 6 months, while CMT was comparable. PSTA still resulted in transient IOP elevation. PMID- 30013317 TI - Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits. AB - Introduction: Human placental protein 13 (PP13) is a galectin predominantly expressed by the placenta. Low serum concentrations of PP13 in early pregnancy indicate a higher risk of developing preeclampsia. Methods: The pharmacokinetic disposition and bioavailability of PP13 were determined by single intravenous and subcutaneous administration to 12 healthy New Zealand White rabbits. The serum pharmacokinetic values were determined by enzyme-linked immunosorbent assay, and are best described by a two-compartment model. Results: Both volume of distribution and the area under the curve were dose dependent for the intravenous group (p<0.01). PP13 elimination half-life was also found to be different between the groups (p<0.01). The bioavailability of PP13 following subcutaneous administration was found to be 57%. Conclusion: This study shows that the concentration of total PP13 released into the maternal circulation during pregnancy might be much higher than previously estimated. PMID- 30013319 TI - The possibility of healing alveolar bone defects with simvastatin thermosensitive gel: in vitro/in vivo evaluation. AB - Background: In this study, simvastatin (SVT) in situ gels were successfully produced by our group. Methods: The preparations were characterized in the following aspects: in vitro gelation, drug release, stability and pharmacodynamics. Results: In this study, drug content of prepared gels was found to be in the range between 89 and 92%. The pH value was in the range between 6.5 and 7.0. The gelation temperature of the prepared thermogelling solutions was 37 degrees C. In vitro release showed that the release of SVT from in situ gels was slow with burst effects at an early stage. Researches indicated that intraorally slow release SVT in situ gels could effectively promote bone regeneration repair of alveolar bone defect. Conclusion: This drug delivery system could prove to be a novel form able to prolong the residence time and to control the release of drug when administered into the oral cavity. PMID- 30013318 TI - Antiangiogenic cytokines as potential new therapeutic targets for resveratrol in diabetic retinopathy. AB - Diabetes mellitus (DM) affects >350 million people worldwide. With many complications that can reduce the patient's quality of life, vision loss is one of the most debilitating disorders it can cause. Active research in the field of diabetes includes microvascular complications in diabetic retinopathy (DR). Disturbances in the balance of pro-angiogenesis and anti-angiogenesis factors can lead to the progression of DR. The retinal pigment epithelium (RPE) is the outermost layer of the retina, and it is essential in maintaining the visual function. The RPE produces and secretes growth factors as well as protective agents which maintain structural integrity of the retina. Small natural molecules, such as resveratrol, may influence neurotrophic factors of the retina. The pigment epithelium-derived factor (PEDF) and thrombospondin-1 (TSP-1) are secreted by RPE cells. These two proteins inhibit angiogenesis and inflammation in RPE cells. An alteration of their production contributes to various eye diseases. There is a critical balance between two important factors secreted on opposite sides of the RPE: at the basal side, vascular endothelial growth factor (VEGF; acts on the choroidal endothelium) and, on the apical side, PEDF (acts on neurons and photoreceptors). Resveratrol inhibits VEGF expression in human adult RPE cells and limits the development of proliferative vitreoretinopathy, by attenuating transforming growth factor-beta2-induced wound closure and cell migration. Possible new mechanisms could include PEDF and TSP-1 expression alterations under physiological and pathological conditions. Resveratrol is currently of interest due to its capacity to influence the cell's secretory activity. Some limitations arise from its low bioavailability. Several drug delivery systems are currently tested, promising to improve tissue concentrations. This article reviews biological pathways involved in the pathogenesis of DR that could be influenced by resveratrol. A study of these pathways could identify new potential targets for the reduction of diabetic complications. PMID- 30013320 TI - Efficacy and safety of adalimumab in the treatment of non-infectious uveitis: a meta-analysis and systematic review. AB - Objective: To summarize updated evidences on the efficacy and safety of adalimumab (ADA) in the treatment of patients with non-infectious uveitis. Patients and methods: A systematic search between January 2000 and September 2017 was conducted using PubMed, Embase, and Cochrane libraries. We investigated control of inflammation, improvement of visual acuity (VA), corticosteroid sparing effect, and adverse events (AEs) or serious adverse events. Results: Three randomized clinical trials (RCTs) and 20 non-RCTs were included and analyzed. The pooled proportions of inflammation control were 74% (95% CI 64% 82%) and 79% (95% CI 69%-87%) in groups of <=6- and >=12-months follow-up durations. No significant difference was found between the two groups (chi2 = 0.920, p = 0.337). Analysis of subgroups classified by degree of being treatment naive for anti-TNFalpha agents showed the inflammation control reached a high of 87% (95% CI 80%-92%) when subjects were "almost naive" to anti-TNFalpha before ADA treatment. VA was improved by three or more lines in 41.3% (52/126) eyes, and was equal to or better than the baseline in 88.8% (142/160) eyes. Corticosteroid sparing was observed in 82.0% (91/111) of the patients; among them, 48.8% (40/82) discontinued use of corticosteroid completely. Minor drug-related adverse events were reported. The treatment effects of ADA were generally consistent in the three RCTs, and ADA reduced the risk of treatment failure by 43%-75%. Conclusion: The current review provided evidences that ADA might be a promising choice in reducing inflammatory activity, gaining VA, and sparing corticosteroid use with minor AEs when applied in treating non-infectious uveitis. PMID- 30013321 TI - Comparison of nocturnal symptoms in advanced Parkinson's disease patients with sleep disturbances: pramipexole sustained release versus immediate release formulations. AB - Background: Nocturnal symptoms are common in Parkinson's disease (PD), which greatly affect the quality of life but are often overlooked in clinical settings. Treatment strategies that provide sustained dopaminergic stimulation may have sleep benefits. Objective: To investigate the treatment effects of pramipexole (PPX) sustained release (SR) versus PPX immediate release (IR) on nocturnal symptoms in advanced PD patients with sleep disturbances. Materials and methods: In this study, the PPX clinical trial (NCT00466167) was retrospectively analyzed for PD Sleep Scale (PDSS) total and domain scores in patients with advanced idiopathic PD receiving either PPX SR or PPX IR, who experienced motor fluctuations while on stable levodopa with a baseline PDSS total score of <90, indicating sleep disturbances. Analysis of covariance test was used to compare the adjusted mean changes at week 18 from baseline between treatment groups, after adjusting for pooled country and baseline scores. Results: A total of 119 patients with PD reported sleep disturbances at baseline (PDSS <90; SR, n=59; IR, n=60). At week 18, patients receiving PPX SR reported numerically greater improvement of sleep disturbance than those receiving PPX IR, although the difference of 6.8 points was not statistically significant (adjusted mean changes in PDSS total score, SR=28.5 versus IR=21.7 points, P=0.165). Patients receiving PPX SR observed a numerically greater adjusted mean change in all PDSS domains compared with PPX IR. The overall proportions of patients with any adverse event were similar between both PPX SR and IR groups (62.7% versus 70.0%). Conclusion: Both the PPX formulations showed improvements in nocturnal symptoms in advanced PD patients with sleep disturbances and were generally well tolerated. Given the known pharmacokinetic profile of an SR formulation and numerical advantage in PDSS mean change over IR formulation, these preliminary evidences support future prospectively designed studies to investigate the effects of PPX SR for improved sleep. PMID- 30013322 TI - Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus ipilimumab alone in patients with cancer: a meta-analysis of outcomes. AB - Background: Recent clinical studies have shown that initial therapy with combined cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and granulocyte macrophage colony-stimulating factor (GM-CSF)-based immunotherapies can enhance the antitumor efficacy of this approach. A key unanswered question is whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this study was taking a meta-analysis of randomized controlled trials to compare the effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response, overall survival, and progression-free survival, as well as the risk of adverse events (AEs) in patients with cancer. Materials and methods: Searches were made in electronic databases PubMed and Embase, and conference abstracts published by the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses were carried out using either random-effects or fixed-effects models according to the heterogeneity of eligible studies. Results: Six trials comprising of 445 patients were included in the meta-analysis. Combination group was superior to the ipilimumab alone in overall response rate, progression-free survival, and overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45, P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI: 0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03), colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab alone. Conclusion: These data suggested that the combination of ipilimumab and GM CSF was associated with a significant improvement in overall survival and lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion. PMID- 30013323 TI - Effect of preoperative loading dose ticagrelor and clopidogrel on no-reflow phenomenon during intervention in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis. AB - Background: Previous studies have shown that ticagrelor is more effective than clopidogrel in platelet inhibition. However, this conclusion remains controversial. Therefore, we performed this meta-analysis to assess the effect of preoperative loading dose ticagrelor and clopidogrel on no-reflow (NRF) during intervention in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). Materials and methods: Randomized controlled trials and observational studies were reviewed. The retrieval time was limited from inception to October 1, 2017. The retrieved databases included PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, the VIP database, and the Wang Fang database. RevMan 5.3 software was used for data analysis. Results: Fourteen randomized controlled trials and one observational study, including 4,162 patients, were included. In these articles, 1,521 patients were in the ticagrelor group (180 mg) and 2,641 patients were in the clopidogrel group (600 mg). The meta-analysis showed that compared with clopidogrel group, preoperative loading dose ticagrelor: 1) significantly reduced the incidence of NRF during PPCI (95% confidence interval [CI]: 0.15, 0.39, P<0.05) as well as the level of postoperative corrected thrombolysis in myocardial infarction frame count (95% CI: -8.89, -6.91, P<0.05); 2) significantly reduced the incidence of major adverse cardiovascular events during hospitalization, including 30 and 180 days after PPCI (95% CI: 0.41, 0.82, P<0.05; 95% CI: 0.15, 0.46, P<0.05, respectively); and 3) significantly improved thrombolysis in myocardial infarction flow after PPCI (95% CI: 1.40, 2.45, P<0.05). No significant difference was observed in terms of bleeding events within 30 and 180 days after PPCI (95% CI: 0.71, 1.54, P=0.82; 95% CI: 0.81, 3.19, P=0.18, respectively). Conclusion: Compared with clopidogrel, loading dose ticagrelor effectively reduced both the occurrence of NRF during PPCI and the incidence of major adverse cardiovascular event in patients with ST-segment elevation myocardial infarction undergoing PPCI. Furthermore, it did not increase the risk of bleeding after PPCI. PMID- 30013325 TI - Different doses of tenecteplase vs alteplase in thrombolysis therapy of acute ischemic stroke: evidence from randomized controlled trials. AB - Background: Recent studies showed inconsistent results of tenecteplase vs alteplase for acute ischemic stroke (AIS) with safety and efficacy. Methods: A meta-analysis was performed to explore the value of tenecteplase and alteplase in AIS treatment. Medline, Embase, and Cochrane Library from January 2001 to April 2018 were searched for randomized controlled trials (RCTs) with tenecteplase vs alteplase for AIS. Results: The primary outcomes were early neurological improvement at 24 h and functional outcome at 3 months. We pooled 1,390 patients from four RCTs. Tenecteplase showed a significant early neurological improvement (P=0.035) compared with alteplase. In addition, tenecteplase showed a neutral effect on excellent outcome (P=0.309), good functional outcome (P=0.275), and recanalization (P=0.3). No significant differences in safety outcomes were demonstrated. In subgroup analysis, 0.25 mg/kg dose of tenecteplase showed a significantly increased early neurological improvement (P<0.001). In serious stroke at baseline (National Institutes of Health Stroke Scale [NIHSS] >12) subgroup, tenecteplase showed a dramatic early neurological improvement (P=0.002) and low risks of any intracranial hemorrhage (ICH) (P=0.027). Conclusion: Tenecteplase provided better early neurological improvement than alteplase. The 0.25 mg/kg dose of tenecteplase subgroup specially showed better early neurological improvement and lower any ICH tendency than that of alteplase. In addition, in serious stroke at baseline subgroup, tenecteplase showed a lower risk of any ICH. PMID- 30013324 TI - Self-nanomicellizing solid dispersion of edaravone: part I - oral bioavailability improvement. AB - Background: Edaravone (EDR) is known for its free radical scavenging, antiapoptotic, antinecrotic, and anticytokine effects in neurological and non neurological diseases. It is currently available clinically as Radicava(r) and Radicut(r), intravenous medications, recently approved for the treatment of amyotrophic lateral sclerosis and cerebral infarction. However, the oral use of EDR is still restricted by its poor oral bioavailability (BA) due to poor aqueous solubility, stability, rapid metabolism, and low permeability. The present study reports the development of novel EDR formulation (NEF) using self-nanomicellizing solid dispersion (SNMSD) strategy with the aim to enable its oral use. Materials and methods: The selection of a suitable carrier for the development of NEF was performed based on the miscibility study. The optimization of EDR-to-carrier ratio was conducted via kinetic solubility study after preparing SNMSDs using solvent evaporation technique. The drug-polymer carrier interaction and self nanomicellizing properties of NEF were investigated with advanced characterization studies. In vitro permeation, metabolism, and dissolution study was carried out to examine the effect of the presence of a carrier on physico chemical properties of EDR. Additionally, the dose-dependent pharmacokinetic study of NEF was conducted and compared with the EDR suspension. Results: Soluplus(r) (SOL) as a carrier was selected based on the potential for improving aqueous solubility. The NEF containing EDR and SOL (1:5) resulted in the highest enhancement in aqueous solubility (17.53-fold) due to amorphization, hydrogen bonding interaction, and micellization. Moreover, the NEF demonstrated significant improvement in metabolism, permeability, and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2-, 16.1-, and 14.8-fold enhancement compared to EDR suspension at 46, 138, and 414 umol/kg doses. Conclusion: The results demonstrated that SNMSD strategy could serve as a promising way to enhance EDR oral BA and NEF could be a potential candidate for the treatment of diseases in which oxidative stress plays a key role in their pathogenesis. PMID- 30013326 TI - Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. AB - Introduction: The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of PubMed, Embase, and related articles was performed. Safety data were analyzed using Comprehensive Meta-Analysis software program version 2. Ultimately, 17 studies with 1,529 patients were included in our analysis. Results: The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. Higher PD-L1 expression was associated with a superior objective response rate. Conclusion: Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. PD-L1 expression is a biomarker of the efficacy of durvalumab. PMID- 30013327 TI - Medication adherence and persistence in patients with autoimmune rheumatic diseases: a narrative review. AB - Background: Several drugs are available for the treatment of autoimmune rheumatic diseases; however, their effectiveness may be negatively influenced by inappropriate adherence. Low adherence and persistence rates have a significant impact on patient quality of life and are associated with health-related expenses. Purpose: To provide an up-to-date narrative review on treatment adherence and persistence rates, and discuss the factors that influence them, in patients with autoimmune rheumatic diseases. Materials and methods: We searched the PubMed database for studies among patients with a diagnosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), or psoriatic arthritis (PsA), published from January 2015 to February 2017. Only studies with a well-defined measurement of adherence/persistence and those that carried out an evaluation of the influencing factors were included. Results: Fifteen relevant studies that evaluated adherence and/or persistence were included. Adherence rates varied between 9.3% and 94%, and persistence rates between 23% and 80%. Most of the studies used one method to evaluate adherence or persistence (different questionnaire scores, proportion of days covered, and mean treatment duration). A high concordance was found between the adherence measurements of the Medication Event Monitoring System and Visual Analog Scale. Factors of economic, demographic, and clinical nature were only moderately linked to treatment adherence or persistence. However, patient-related factors - such as positive and increased beliefs in medication necessity, strong views of the chronic nature of the diseases, and increased knowledge of the disease - were related to better treatment adherence. Conclusion: Owing to the heterogeneity of the study results, we consider that the use of more than one method to assess adherence/persistence should yield more comprehensive and accurate data about patient adherence behavior. Patient-related factors should be included and analyzed more often in adherence studies as the former may be modified to improve patient adherence. PMID- 30013328 TI - The Healthy Weights Initiative: results from the first 2,000 participants. AB - Background: A free, comprehensive, adult obesity reduction program was initiated in the cities of Moose Jaw and Regina, Saskatchewan, Canada. Objective: This study aimed to determine the short-term and long-term adherence outcomes, identify factors that impact long-term adherence, and measure health outcomes. Methods: The Healthy Weights Initiative (HWI) attendance was determined by using an electronic swipe card. An on-site exercise therapist also documented physical activity, duration, and intensity, as well as attendance of dietary and cognitive behavioral therapy education classes. Logistic regression determined which factors were associated with long-term adherence (exercising three times per week at 1 year) and various health outcomes. Results: In this study, 2,167 participants started and 2,000 completed the 24-week program (92.3%). Upon 24 week completion, the majority of the participants in Moose Jaw (59.0%) and Regina (63.1%) purchased 1-year fitness memberships at the YMCA. At 1 year, 79.8% of the participants were exercising three times a week or more at the Moose Jaw YMCA. Logistic regression revealed that participants who did not exercise three times a week at 1 year at the YMCA were more likely to have a spouse/partner who did not support the program (OR=2.01; 95% CI=1.81-2.22) and more likely to have a medical comorbidity (OR=1.22; 95% CI=1.03-1.49). At 24 weeks, average weight loss was modest (12.7 pounds) and regressed slightly at 1 year (10.4 pounds). However, at 24 weeks, many health gains were statistically significant and were maintained for 1 year. For example, the prevalence of depressed mood reduced from 49.0% at baseline to 13.0% at 24 weeks and increased to 19.0% at 1 year (P=0.000). Conclusion: We found that the availability of a community-based weight management program (Healthy Weights Initiative) demonstrated good adherence, modest weight loss, and positive health outcomes. PMID- 30013330 TI - Preference for a prefilled syringe or an auto-injection device for delivering golimumab in patients with moderate-to-severe ulcerative colitis: a randomized crossover study. AB - Purpose: Simponi(r) (golimumab, MSD) is a fully human monoclonal antibody against tumor necrosis factor alpha administered subcutaneously using an autoinjector or a prefilled syringe. This study examined preference for administration of golimumab by autoinjector or prefilled syringe in patients with moderate-to severe ulcerative colitis (UC). Patients and methods: This was a multicenter, open-label, randomized crossover trial (EudraCT no 2014-000656-29). Patients with moderate-to-severe UC were randomized 1:1 to receive 2 subcutaneous injections of 50 mg golimumab with the autoinjector followed by 2 injections of 50 mg with the prefilled syringe or the same 4 injections administered in the opposite order. Patients assessed preference, ease of use, and discomfort immediately after the injections and 2 weeks later. Results: Ninety-one patients were included (median age=42.7 years [range, 19.7-93.7]; 58% male). The autoinjector was preferred by 76.9% of patients immediately after injections and by 71.4% 2 weeks later. The autoinjector was more often considered extremely easy or easy to use (94.5%) than the prefilled syringe (73.6%). Moderate discomfort or worse was reported by more patients when using the prefilled syringe (20.9%) than when using the autoinjector (5.5%), and severe discomfort or discomfort preventing injection of future doses was reported by 8.8% for the pre-filled syringe but not at all when using the autoinjector. A favorable or extremely favorable overall impression was reported by 89.0% for the autoinjector and 72.5% for the prefilled syringe. Conclusion: Most patients with moderate-to-severe UC preferred to self-administer golimumab with the autoinjector over a prefilled syringe. PMID- 30013329 TI - Phosphate-control adherence in hemodialysis patients: current perspectives. AB - Objectives: This review summarizes factors relevant for adherence to phosphate control strategies in dialysis patients, and discusses interventions to overcome related challenges. Methods: A literature search including the terms "phosphorus", "phosphorus control", "hemo-dialysis", "phosphate binder medications", "phosphorus diet", "adherence", and "nonadherence" was undertaken using PubMed, PsycInfo, CINAHL, and Embase. Results: Hyperphosphatemia is associated with cardiovascular and all-cause mortality in dialysis patients. Management of hyperphosphatemia depends on phosphate binder medication therapy, a low-phosphorus diet, and dialysis. Phosphate binder therapy is associated with a survival benefit. Dietary restriction is complex because of the need to maintain adequate protein intake and, alone, is insufficient for phosphorus control. Similarly, conventional hemodialysis alone is insufficient for phosphorus control due to the kinetics of dialytic phosphorus removal. Thus, all three treatment approaches are important contributors, with dietary restriction and dialysis as adjuncts to the requisite phosphate binder therapy. Phosphate-control adherence rates are suboptimal and are influenced directly by patient, provider, and phosphorus-control strategy-related factors. Psychosocial factors have been implicated as influential "drivers" of adherence behaviors in dialysis patients, and factors based on self-motivation associate directly with adherence behavior. Higher-risk subgroups of nonadherent patients include younger dialysis patients and non-whites. Provider attitudes may be important - yet unaddressed - determinants of adherence behaviors of dialysis patients. Conclusion: Adherence to phosphate binders, low-phosphorus diet, and dialysis prescription is suboptimal. Multicomponent strategies that concurrently address therapy-related factors such as side effects, patient factors targeting self-motivation, and provider factors to improve attitudes and delivery of culturally sensitive care show the most promise for long-term control of phosphorus levels. Moreover, it will be important to identify patients at highest risk for lack of control, and for programs to be ready to deliver flexible person-centered strategies through training and dedicated resources to align with the needs of all patients. PMID- 30013331 TI - Prognostic ability of cystatin C and homocysteine plasma levels for long-term outcomes in very old acute myocardial infarction patients. AB - Background and aims: This study sought to evaluate the prognostic powers of combined use of cystatin C (Cys C) and homocysteine (Hcy) at predicting adverse events of patients >80 years old with acute myocardial infarction (AMI). Patients and methods: The analysis involved 753 patients >80 years old undergoing coronary angiography for chest pain in China from January 2006 to December 2012. Kaplan Meier method was used for survival and major adverse cardiac events (MACE) rates. Multivariate Cox regression was performed to identify mortality predictors. Receiver operating characteristic curve analysis was performed to predict the cutoff values of Cys C and Hcy for all-cause mortality. Results: The duration of follow-up was 40-116 months (median, 63 months; interquartile range, 51-74 months). The long-term survival and event-free survival rates of AMI patients were significantly lower than those of unstable angina pectoris patients (P<0.05), and were significantly different according to the tertile concentration of Cys C of AMI patients (P<0.01). Cys C and Hcy were independent risk factors for long-term all-cause mortality (odds ratio [OR] =3.72 [2.27-6.09]; OR =1.59 [1.04-2.61]) and MACE (OR =2.83 [1.82-4.40]; OR =1.09 [1.04-1.21]) of AMI patients. The predictive cutoff value of Cys C was 1.815 mg/L (82.8%, 86.4%) and that of Hcy was 15.06 MUmol/L (84.4%, 83.1%) in AMI patients. Combined use of both biomarker's cutoff values further increased the sensitivity and specificity of all-cause mortality. Conclusion: Cys C is a strong independent predictor of long-term all-cause death and MACE in very old AMI patients. The combined use of Cys C and Hcy further improves the predictive accuracy. PMID- 30013332 TI - The effect of positive changes during intraoperative monitoring of the functional improvement in patients with cervical compressive myelopathy. AB - Background: Cervical compressive myelopathy (CCM) is a progressive, degenerative spine disease and the most common cause of spinal cord dysfunction in older individuals. Current clinical guidelines for spinal surgery recommend multimodal intraoperative monitoring (IOM) during spinal surgery as a reliable and valid diagnostic adjunct to assess spinal cord integrity. The aim of this study was to evaluate the effect of positive changes during IOM on the functional status in patients with CCM. Methods: Patients who underwent spinal surgery with IOM due to CCM were enrolled. During the surgery, patients underwent IOM using motor evoked potential (MEP) and somatosensory evoked potential (SEP). MEP and SEP were checked before and immediately after decompression. A decrease in latency >10% or an increase in amplitude >50% was regarded as a "positive changes". Subjects were divided according to the presence of positive changes. Motor scores of American Spinal Injury Association (ASIA) impairment scale and Korean version of Modified Barthel Index (K-MBI) were evaluated before and after operation. Results: Twenty nine patients underwent spinal surgery due to CCM. Eleven patients showed positive changes in MEP during IOM. When the two groups were compared, improvement rate in the ASIA motor score and K-MBI were significantly higher in patients with positive changes than in patients without positive changes at 1 month after surgery. However, 6 months after surgery, there were no significance differences between the groups. Regardless of positive change, nearly all patients suffered from neuropathic pain after operation. Conclusion: Positive changes in MEP during IOM may affect functional improvement 1 month after operation and early discharge without significant complications in CCM patients. However, they do not affect the neuropathic pain and long-term functional outcome. Thus, tailored proper management is needed to achieve maximal functional recovery in each patient after cervical spinal decompression surgery. PMID- 30013333 TI - Thyroid function tests before prescribing anti-dementia drugs: a retrospective observational study. AB - Purpose: Treatable causes of cognitive dysfunction, such as hypothyroidism, should be excluded by physicians before prescribing anti-dementia drugs. Many clinical guidelines for dementia recommend a thyroid function test (TFT) as one of the standard screening tests for cognitive dysfunction. This study aimed to investigate the national implementation rate of TFTs during the 365 days before the initiation of anti-dementia drugs. Patients and methods: In this retrospective observational study, using Japan's nationwide claim database, we enrolled >=65-year-old patients who were newly prescribed anti-dementia drugs between April 2015 and March 2016. The outcome of this study was the implementation of TFTs in the 365 days prior to the index date. We used demographic data, including age, sex, comorbidities, home-based/institutional care, and provider type, as covariates. Results: We identified 262,279 patients newly prescribed anti-dementia drugs; of these, only 32.6% underwent TFTs before the initiation of anti-dementia drug treatment. Patients treated in dementia care centers were twice as likely to undergo TFTs as those treated in clinics (57% vs 26%; adjusted risk ratio: 2.17; 95% confidence interval: 2.01-2.33). Conclusion: In Japan, patients with dementia often do not undergo TFTs before being prescribed anti-dementia drugs, particularly in a primary care setting. This suggests that the practice of screening treatable cognitive dysfunction should be audited. PMID- 30013334 TI - Community pharmacists' knowledge of COPD, and practices and perceptions of medication counseling of COPD patients. AB - Background and purpose: COPD is one of the leading causes of morbidity and mortality worldwide. Although medication counseling interventions by pharmacists have been found to support the management of COPD, little is known about pharmacists' knowledge concerning COPD and regular practices and perceptions concerning medication counseling of COPD patients. The purpose of this study was to research these topics among Finnish community pharmacists. Materials and methods: In January 2017, an electronic survey was e-mailed to Finnish community pharmacies (n=741) via the Association of the Finnish Pharmacies. One pharmacist from each pharmacy, preferably a specialist in asthma, was invited to answer the survey. Results: Completed responses were received from 263 pharmacists (response rate =35%), of whom 196 pharmacists were specialists in asthma. Response rate among asthma pharmacists was 42%. Pharmacists were positive about their role in medication counseling and in support of the self-management of COPD patients. COPD-related knowledge was self-assessed as being good and was on a good level in respect of basic facts. However, almost half (46%) of the pharmacists did not know that COPD is considered a national public health issue, and ~50% of the pharmacists were not familiar with the current care guideline on COPD. Medication counseling was found to be more medicinal product-driven and less advisory concerning lifestyle changes such as smoking cessation and physical exercise. Conclusion: Although the pharmacists' knowledge of COPD was good on general topics, there were some gaps in their knowledge on the current care guideline and status of the disease. Pharmacists should more systematically individually target medication counseling according to patients' needs. In addition, lifestyle treatments, including smoking cessation and physical exercise, should be part of the medication counseling. PMID- 30013335 TI - COPD transitions in health and self-management: service users' experiences from everyday life. AB - Purpose: To explore how persons living with COPD experience transitions related to health, self-management, and follow-up from the healthcare services. Patients and methods: This study is part of a participatory research project. Six males and five females living with COPD, with a COPD assessment test score of 21-29, participated; all the participants were living at home. Data were collected in qualitative research interviews and analyzed using qualitative content analysis highlighting the participants' experiences. Results: The findings showed two main themes: "The struggle to keep going" and "The need for continuity and competent facilitation". The participants reported complex health transitions, with changes in roles and function, demanding exacerbations and critical events, and challenges with learning needed self-management. They expressed a great need for and had great benefit from, education, rehabilitation, and follow-up in their management of everyday life. Not all received offers in line with current guidelines. Conclusion: In-depth knowledge of patients' experienced COPD transitions offers clinicians guidance for the timing and quality of follow-up services. Life with COPD entails challenging transitions in health and self management. Good rehabilitation and follow-up from the healthcare services are needed throughout the disease trajectory. Participation in self-management education and rehabilitation that include psychosocial aspects may facilitate health-enhancing transitions and improve self-management skills. Experienced lack of competence and flexibility among healthcare providers hinders trust and collaboration. Access to stable and competent follow-up in the primary health services may facilitate cohesive services and collaborative self-management. PMID- 30013337 TI - Impact of air pollution on severe acute exacerbation of COPD. PMID- 30013336 TI - Overuse of inhaled corticosteroids in COPD: five questions for withdrawal in daily practice. AB - Evidence and guidelines are becoming increasingly clear about imbalance between the risks and benefits of inhaled corticosteroids (ICSs) in patients with COPD. While selected patients may benefit from ICS-containing regimens, ICSs are often inappropriately prescribed with - according to Belgian market research data - up to 70% of patients in current practice receiving ICSs, usually as a fixed combination with a long-acting beta2-adrenoreceptor agonist. Studies and recommendations support withdrawal of ICSs in a large group of patients with COPD. However, historical habits appear difficult to change even in the light of recent scientific evidence. We have built a collaborative educational platform with chest physicians and primary care physicians to increase awareness and provide guidance and support in this matter. PMID- 30013338 TI - Preparation of ginsenoside compound-K mixed micelles with improved retention and antitumor efficacy. AB - Introduction: Ginsenoside compound K (CK) has effects on cell-cycle regulation, tumor growth inhibition, and apoptosis induction. However, it has limited applications in clinical settings because of its low solubility and poor absorption. Methods: To overcome these limitations, we aimed to develop a mixed micellar system composed of phosphatidylcholine (PC) and 1,2-distearoyl-sn glycero-3-phosphoethanolamine polyethylene glycol 2000 (DSPE PEG 2000; DP). CK encapsulated in PC/DP mixed micelles had enhanced solubility, permeability, and retention effects. Results: Compared to free CK, the CK PC/DP micellar system exhibited improved anticancer effects in vitro, including cell-cycle arrest, apoptosis, and anti-invasion in human lung carcinoma A549 cells. The significant proapoptotic effect was reflected by increased chromosomal condensation, annexin V/propidium iodide staining, and related protein expression. In vitro cellular uptake and optical mouse imaging in vivo suggested that the improved antitumor effect was caused primarily by enhanced uptake and tumor targeting. Furthermore, an in vivo antitumor efficacy study indicated that the CK mixed micelles significantly inhibited tumor growth, thereby decreasing tumor volume at the end of the experiment as compared with that in the control mice. Histological analysis confirmed the antitumor effect with low toxicity. Conclusion: The PC/DP micellar system was an effective drug delivery system for CK in tumor therapy. PMID- 30013339 TI - Improved sensitivity of cellular MRI using phase-cycled balanced SSFP of ferumoxytol nanocomplex-labeled macrophages at ultrahigh field. AB - Purpose: The purpose of this study was to investigate the feasibility and sensitivity of cellular magnetic resonance imaging (MRI) with ferumoxytol nanocomplex-labeled macrophages at ultrahigh magnetic field of 7 T. Materials and methods: THP-1-induced macrophages were labeled using self-assembling heparin + protamine + ferumoxytol nanocomplexes which were injected into a gelatin phantom visible on both microscope and MRI. Susceptibility-weighted imaging (SWI) and balanced steady-state free precession (bSSFP) pulse sequences were applied at 3 and 7 T. The average, maximum intensity projection, and root mean square combined images were generated for phase-cycled bSSFP images. The signal-to-noise ratio and contrast-to-noise ratio (CNR) efficiencies were calculated. Ex vivo experiments were then performed using a formalin-fixed pig brain injected with100 and ~1,000 labeled cells, respectively, at both 3 and 7 T. Results: A high cell labeling efficiency (.90%) was achieved with heparin + protamine + ferumoxytol nanocomplexes. Less than 100 cells were detectable in the gelatin phantom at both 3 and 7 T. The 7 T data showed more than double CNR efficiency compared to the corresponding sequences at 3 T. The CNR efficiencies of phase-cycled bSSFP images were higher compared to those of SWI, and the root mean square combined bSSFP showed the highest CNR efficiency with minimal banding. Following co-registration of microscope and MR images, more cells (51/63) were detected by bSSFP at 7 T than at 3 T (36/63). On pig brain, both100 and ~1,000 cells were detected at 3 and 7 T. While the cell size appeared larger due to blooming effects on SWI, bSSFP allowed better contrast to precisely identify the location of the cells with higher signal-to-noise ratio efficiency. Conclusion: The proposed cellular MRI with ferumoxytol nanocomplex-labeled macrophages at 7 T has a high sensitivity to detect, 100 cells. The proposed method has great translational potential and may have broad clinical applications that involve cell types with a primary phagocytic phenotype. PMID- 30013340 TI - Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted PEGylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance. AB - Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%-30% 5-year survival rate when metastasized. We aimed to create dual targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Materials and methods: Cationic liposomes contained N-[1-(2,3 dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and distearoyl phosphatidylethanolamine-methyl-poly(ethylene glycol) (DSPE-mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE-mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels. Conclusion: Our dual targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS. PMID- 30013341 TI - Nanoscaled and microscaled parallel topography promotes tenogenic differentiation of ASC and neotendon formation in vitro. AB - Background: Topography at different scales plays an important role in directing mesenchymal stem cell differentiation including adipose-derived stem cells (ASCs) and the differential effect remains to be investigated. Purpose: This study aimed to investigate the similarity and difference between micro- and nanoscaled aligned topography for inducing tenogenic differentiation of human ASCs (hASCs). Methods: Parallel microgrooved PDMS membrane and a parallel aligned electrospun nanofibers of gelatin/poly-epsilon-caprolactone mixture were employed as the models for the study. Results: Aligned topographies of both microscales and nanoscales could induce an elongated cell shape with parallel alignment, as supported by quantitative cell morphology analysis (cell area, cell body aspect, and cell body major axis angle). qPCR analysis also demonstrated that the aligned topography at both scales could induce the gene expressions of various tenogenic markers at the 7th day of in vitro culture including tenomodulin, collagen I and collagen VI, decorin, tenascin-C and biglycan, but with upregulated expression of scleraxis and tenascin-C only in microscaled topography. Additionally, tenogenic differentiation at the 3rd day was confirmed only at microscale. Furthermore, microscaled topography was confirmed for its tenogenic induction at tissue level as neotendon tissue was formed with the evidence of mature type I collagen fibers only in parallel aligned polyglycolic acid (PGA) microfibers after in vitro culture with mouse ASCs. Instead, only fat tissue was formed in random patterned PGA microfibers. Conclusion: Both microscaled and nanoscaled aligned topographies could induce tenogenic differentiation of hASCs and micro-scaled topography seemed better able to induce elongated cell shape and stable tenogenic marker expression when compared to nanoscaled topography. The microscaled inductive effect was also confirmed at tissue level by neotendon formation in vitro. PMID- 30013342 TI - Nanoporous diopside modulates biocompatibility, degradability and osteogenesis of bioactive scaffolds of gliadin-based composites for new bone formation. AB - Introduction: It is predicted that with increased life expectancy in the whole world, there will be a greater demand for synthetic biomedical materials to repair or regenerate lost, injured or diseased tissues. Natural polymers, as biomedical materials, have been widely applied in the field of regenerative medicine. Materials and methods: By incorporation of nanoporous diopside bioglass (nDPB) into glia-din (GL) matrix, macro-nanoporous scaffolds of nDPB/GL composites (DGC) were fabricated by method of solution compressing and particles leaching. Results: The results revealed that the DGC scaffolds possessed well interconnected macropores of 200-500 MUm and nanopores of 4 nm, and the porosity and degradability of DGC scaffolds remarkably increased with the increase in nDPB content. In addition, in vitro cell experiments revealed that the adhesion and growth of MC3T3-E1 cells on DGC scaffolds were significantly promoted, which depended on nDPB content. Moreover, the results of histological evaluations confirmed that the osteogenic properties and degradability of DGC scaffolds in vivo significantly improved, which were nDPB content dependent. Furthermore, the results of immunohistochemical analysis demonstrated that, with the increase in nDPB content, the type I collagen expression in DGC scaffolds in vivo obviously enhanced, indicating excellent osteogenesis. Discussion and conclusion: The results demonstrated that the DGC scaffolds containing 30 wt% nDPB (30nDGC) exhibited good biocompatibility and new bone formation ability, which might have a great potential for applications in bone regeneration. PMID- 30013343 TI - Stimulation of wound healing using bioinspired hydrogels with basic fibroblast growth factor (bFGF). AB - Introduction: The objective of this study is to stimulate wound healing using bioinspired hydrogels with basic fibroblast growth factor (bFGF). Materials and methods: Inspired by the crosslinking mechanism in algae-based adhesives, hydrogels were fabricated with gum arabic, pectin, and Ca2+. The physical properties of the bioinspired hydrogels were characterized, and the in vitro release of bFGF was investigated. Then, the in vitro scratch assay for wound healing and in vivo wound healing experiment in a full-thickness excision wound model were performed for the bioinspired hydrogels with bFGF. Finally, histological examinations and organ toxicity tests were conducted to investigate the wound healing applications of the bioinspired hydrogels with bFGF. Results: The in vitro and in vivo results showed that the bioinspired hydrogels with bFGF could significantly enhance cell proliferation, wound re-epithelialization, collagen deposition, and contraction without any noticeable toxicity and inflammation compared with the hydrogels without bFGF and commercial wound healing products. Conclusion: These results suggest the potential application of bioinspired hydrogels with bFGF for wound healing. PMID- 30013344 TI - Phase-shift, targeted nanoparticles for ultrasound molecular imaging by low intensity focused ultrasound irradiation. AB - Purpose: Ultrasound (US) molecular imaging provides a non-invasive way to visualize tumor tissues at molecular and cell levels and could improve diagnosis. One problem of using US molecular imaging is microbubbles challenges, including instability, short circulation time, and poor loading capacity and penetrability. It is urgent to design new acoustic contrast agents and new imaging methods to facilitate tumor-targeted imaging. In this study, phase-shift poly lactic-co glycolic acid (PLGA) nanoparticles modified with folate as an efficient US molecular probe were designed and the long-term targeted imaging was achieved by low-intensity focused US (LIFU) irradiation. Methods: A new 5-step method and purification procedure was carried out to obtain uniform folic acid polyethylene glycol PLGA (PLGA-PEG-FA), the structure of which was confirmed by 1H nuclear magnetic resonance spectroscopy and thin-layer chromatography. Perflenapent (PFP) was wrapped in PLGA-PEG-FA by a double emulsion solvent evaporation method to obtain PFP/PLGA-PEG-FA nanoparticles. The targeted ability of the resulting nanoparticles was tested in vivo and in vitro. LIFU irradiation can irritate nanoparticle phase-shift to enhance tumor imaging both in vivo and in vitro. Results: PLGA-PEG-FA was a light yellow powder with a final purity of at least 98%, the structure of which was confirmed by 1H nuclear magnetic resonance spectroscopy and thin-layer chromatography. Highly dispersed PFP/PLGA-PEG-FA nanoparticles with spherical morphology have an average diameter of 280.9+/-33.5 nm, PFP load efficiency of 59.4%+/-7.1%, and shells, thickness of 28+/-8.63 nm. The nanoparticles can specifically bind to cells expressing high folate receptor both in vivo and in vitro. Ultrasonic imaging was significantly enhanced in vitro and in vivo by LIFU irradiation. The retention time was significantly prolonged in vivo. Conclusion: Phase-shift PFP/PLGA-PEG-FA nanoparticles induced by LIFU can significantly enhance ultrasonic imaging, specifically targeting tumors expressing folate receptor. As a potential targeting acoustic molecular probe, PFP/PLGA-PEG-FA nanoparticles can be used to achieve targeted localization imaging. PMID- 30013345 TI - Application of active targeting nanoparticle delivery system for chemotherapeutic drugs and traditional/herbal medicines in cancer therapy: a systematic review. AB - Patients treated with conventional cancer chemotherapy suffer from side effects of the drugs due to non-selective action of chemotherapeutic drugs to normal cells. Active targeting nanoparticles that are conjugated to targeting ligands on the surface of nanoparticles play an important role in improving drug selectivity to the cancer cell. Several chemotherapeutic drugs and traditional/herbal medicines reported for anticancer activities have been investigated for their selective delivery to cancer cells by active targeting nanoparticles. This systematic review summarizes reports on this application. Literature search was conducted through PubMed database search up to March 2017 using the terms nanoparticle, chemotherapy, traditional medicine, herbal medicine, natural medicine, natural compound, cancer treatment, and active targeting. Out of 695 published articles, 61 articles were included in the analysis based on the predefined inclusion and exclusion criteria. The targeting ligands included proteins/peptides, hyaluronic acid, folic acid, antibodies/antibody fragments, aptamer, and carbohydrates/polysaccharides. In vitro and in vivo studies suggest that active targeting nanoparticles increase selectivity in cellular uptake and/or cytotoxicity over the conventional chemotherapeutic drugs and non-targeted nanoparticle platform, particularly enhancement of drug efficacy and safety. However, clinical studies are required to confirm these findings. PMID- 30013347 TI - Preschool-onset obsessive-compulsive disorder with complete remission. AB - Early-onset obsessive-compulsive disorder (OCD) is more severe than later-onset OCD. There are no reports of any early-onset OCD patients being cured, especially with respect to preschoolers. In this case report, we describe the successful treatment and cure of a 6-year-old preschool girl with severe OCD since the age of 3. At the age of 3, the patient began to fear contamination and danger to herself and her family, leading to excessive hand-washing, and several months later, ritualized checking. The OCD symptoms waxed and waned for about 3 years and thereafter worsened gradually over a few weeks, culminating in a refusal to eat and dress. At the age of 6, after a week of inpatient pediatric treatment with no improvement, the patient was transferred to Osaka City University Hospital to seek psychiatric treatment. The patient fully recovered from OCD following family-based cognitive-behavioral therapy (CBT) and short-term use of low-dose fluvoxamine in an inpatient setting. After treatment, the OCD symptoms disappeared with complete remission for over 3 years. Now, aged 9, the patient has good global functioning and is well adjusted in her daily life with no need for any treatment. To the best of our knowledge, this is the first report of preschool-onset OCD with long-term complete remission with inpatient treatment in a preschooler with severe OCD. Some preschoolers with very early-onset OCD may have good prognosis without continuous pharmacotherapy, although the symptoms with the onset are severe enough to require hospitalization. Preschool-onset OCD is likely to be misdiagnosed as separation anxiety disorder. Our findings suggest that family-based CBT, which is the treatment of choice for preschool-onset OCD, can be applicable to inpatient treatment. Early detection and intensive intervention of OCD in preschoolers may improve the chance of remission. PMID- 30013346 TI - Intravenously-injected gold nanoparticles (AuNPs) access intracerebral F98 rat gliomas better than AuNPs infused directly into the tumor site by convection enhanced delivery. AB - Background: Intravenously (IV)-injected gold nanoparticles (AuNPs) powerfully enhance the efficacy of X-ray therapy of tumors including advanced gliomas. However, pharmacokinetic issues, such as slow tissue clearance and skin discoloration, may impede clinical translation. The direct infusion of AuNPs into the tumor might be an alternative mode of delivery. Materials and methods: Using the advanced, invasive, and difficult-to-treat F98 rat glioma model, we have studied the biodistribution of the AuNPs in the tumor and surrounding brain after either IV injection or direct intratumoral infusion by convection-enhanced delivery using light microscopy immunofluorescence and direct gold visualization. Results: IV-injected AuNPs localize more specifically to intracerebral tumor cells, both in the main tumor mass and in the migrated tumor cells as well as the tumor edema, than do the directly infused AuNPs. Although some of the directly infused AuNPs do access the main tumor region, such access is largely restricted. Conclusion: These data suggest that IV-injected AuNPs are likely to have a greater therapeutic benefit when combined with radiation therapy than after the direct infusion of AuNPs. PMID- 30013349 TI - Interstitial deletion within 7q31.1q31.3 in a woman with mild intellectual disability and schizophrenia. AB - We report the case of a Japanese woman with an interstitial deletion within the 7q31.1q31.3 region, she presented with mild intellectual disability since infancy, and later developed characteristic psychiatric manifestations, including abnormal behavior, delusions, and hallucinations. She was diagnosed with paranoid schizophrenia (F20.0, International Statistical Classification of Diseases and Related Health Problems 10th Revision). Array comparative genomic hybridization examination revealed the deletion involving several important genes for neurodevelopment. Particularly, FOXP2, DOCK4, MET, and WNT2 in this region are suggested to be related to language impairment, autistic disorders, and cognitive disorders, via the WNT pathway. In addition, the WNT signal pathway has been suggested to be implicated in the pathogenesis of psychiatric disorders such as schizophrenia and bipolar disorder. However, there is no case report regarding schizophrenia associated with a 7q31 microdeletion. We suspect that the disruptions of these one or plural genes among the interstitial deletion of 7q31.1q31.3 may be involved in the development of schizophrenia in this woman. This is the first report on schizophrenia associated with a 7q31 microdeletion. PMID- 30013348 TI - Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex. AB - Introduction: Although recombinant tissue plasminogen activator (rtPA) is a widely used therapy in patients with acute ischemic stroke, rtPA-induced toxicity or its adverse effects have been reported in our previous studies. However, Ginkgo biloba extract (GBE) may provide neuroprotective effects against rtPA induced toxicity. Thus, in the present study, we investigated whether a single administration of rtPA caused neurotoxicity in the prefrontal cortex (PFC) of rats and determined whether GBE or its diterpene ginkgolide (DG) constituents were neuroprotective against any rtPA-induced toxicity. Materials and methods: We randomly divided adult Sprague-Dawley rats into four groups that were intravenously administered saline, rtPA, rtPA+DG, or rtPA+GBE. The rats were sacrificed 24 hours later and the whole brain removed. A gas chromatography-mass spectrometry metabolomic approach was used to detect molecular changes in the PFC among the groups. Multivariate statistical and pathway analyses were used to determine the relevant metabolites as well as their functions and pathways. Results: We found 32 metabolites differentially altered in the four groups that were primarily involved in neurotransmitter, amino acid, energy, lipid, and nucleotide metabolism. Our results indicated that a single rtPA administration caused metabolic disturbances in the PFC. Both GBE and DG effectively ameliorated these rtPA-induced disturbances, although DG better controlled the rtPA-induced glutamate and aspartate excitotoxicity and the activation of NMDA receptor. Conclusion: Our results provide important novel mechanistic insights into the adverse effects of rtPA and offer directions for future exploration on the thrombolytic effects of rtPA combined with the administration of DG or GBE for the treatment of acute ischemic stroke in humans. PMID- 30013350 TI - The abnormal activation of D1R/Shp-2 complex involved in levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson's rats. AB - Background: Levodopa-induced dyskinesia (LID) is a troublesome problem in the treatment of Parkinson's disease (PD). The mechanisms of LID are still mysterious. Recently, the interaction between Shp-2 and D1 dopamine receptor (D1R) has been identified to be indispensable in the D1R-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the occurrence of LID. However, the role of Shp-2 in the D1R-mediated signaling pathway of dyskinetic rat models is not fully clear. We designed this study with the purpose of exploring the role of D1R/Shp-2 complex in the D1R-mediated signaling pathway in the occurrence of LID. Materials and methods: The 6-hydroxydopamine (6-OHDA) was injected unilaterally to produce the rat models of PD. Successful PD rat models were randomly divided into three groups to receive the treatment with L-3,4 dihydroxyphenylalanine (l-DOPA) + benserazide, l-DOPA + benserazide + D1R antagonist (SCH23390) or D1R agonist (SKF38393). Abnormal involuntary movements were assessed in different groups during the treatment. The interaction between D1R and Shp-2 was confirmed in the sham and LID rats through the methods of coimmunoprecipitation. In addition, the levels of p-Shp-2, p-ERK1/2 and p-mTOR were determined by Western blot in different groups. Results: After the treatment with l-DOPA + benserazide for 22 days, PD rats presented with dyskinesia. D1R agonist, SKF38393, induced similar involuntary movements in PD rats. In contrast, the dyskinetic movements were not induced by coadministration of l-DOPA + D1R antagonist (SCH23390). The interaction between D1R and Shp-2 in the normal rats was kept stable after the long-term use of l-DOPA. Moreover, we found that the pulsatile levodopa administration induced hyperphosphorylation of Shp-2, ERK1/2 and mTOR, while the coadministration of l-DOPA and D1R antagonist, SCH23390, did not induce the hyperphosphorylation of these proteins. Conclusion: These data verified the existence of D1R/Shp-2 complex and its crucial role in the D1R mediated signaling pathway in dyskinetic rats. Focus on the D1R/Shp-2 complex might be a potential treatment of LID in the future. PMID- 30013351 TI - Network meta-analysis of treatment regimens for inoperable advanced hepatocellular carcinoma with portal vein invasion. AB - Purpose: We assessed the efficacy and safety of different modalities using the network meta-analysis for inoperable hepatocellular carcinoma (HCC) with portal vein invasion. The interested modalities included stereotactic body radiotherapy (SBRT) combined with transarterial chemoembolization (TACE), three-dimensional radiotherapy (3D-RT) combined with hepatic arterial infusion chemotherapy (HAIC) or TACE, TACE plus sorafenib, and use of SBRT, HAIC, sorafenib, and TACE alone. Methods: PubMed and Cochrane Library electronic databases were systematically searched for eligible studies published up to June 2017. We used network meta analysis to compare the disease control rate (DCR) and severe adverse events for the eight interested regimens included in this analysis. Study quality was assessed following the Grading of Recommendations, Assessment, Development and Evaluations method. Results: Fifteen studies published between 2010 and 2016 involving a total of 2,359 patients were enrolled in this network meta-analysis. With indirect comparison of DCR and overall safety, the pooled results showed that RT plus HAIC was the most effective regimen in treating advanced HCC with portal vein tumor thrombosis, followed by RT plus TACE. HAIC alone and sorafenib combined with HAIC appeared least effective intervention regimens. The incidence of treatment-related adverse events of grade 3 or 4 occurred less in the patients who received SBRT alone compared with other interested regimens. Conclusion: 3D RT combined with HAIC or TACE showed more favorable treatment responses compared with other regimens in advanced HCC patients with portal vein tumor thrombosis. PMID- 30013352 TI - Effect of a 12-hour natural drainage technique on decreasing blood loss after total knee arthroplasty: a case-control study. AB - Background: Different methods of drainage have been used in patients with osteoarthritis after total knee arthroplasty (TKA), but the ideal strategy is controversial. This retrospective case-control study reported a technique of 12 hour natural drainage and aimed to confirm its efficacy and safety in the treatment for blood loss following TKA. Methods: There were 231 patients divided into three groups who underwent TKA from January 2014 to July 2017: 76 patients underwent 12-hour natural drainage in Group A, 80 patients underwent 4-hour clamping drainage in Group B, and 75 patients underwent continuous drainage in Group C. All perioperative clinical data were reviewed for statistical analysis. Results: The drainage volume and total blood loss after TKA were significantly lower in Group A than that in the other two groups (P<0.05), and serum level of hemoglobin was significantly higher in Group A than that in the other two groups (P<0.05). The maximum of active motion of the knee was greater in Group C at 2 days (P<0.05). Significantly more patients in Group C required blood transfusions (P<0.05). No difference was found in the complication rate among the three groups. Conclusion: The 12-hour natural drainage is an effective technique for reducing blood loss for patients following TKA. Compared with temporary clamping drainage and continuous negative pressure drainage, 12-hour natural drainage decreases blood loss, reduces post-operative transfusion requirements, and does not increase the risk of complications. Therefore, this technique of 12-hour natural drainage is recommended to be used in patients after TKA. PMID- 30013354 TI - Tech Has It's Place. PMID- 30013353 TI - Pulse pressure variation and pleth variability index as predictors of fluid responsiveness in patients undergoing spinal surgery in the prone position. AB - Background: This study investigated the ability of pulse pressure variation (PPV) and pleth variability index (PVI) to predict fluid responsiveness of patients undergoing spinal surgery in the prone position. Patients and methods: A total of 53 patients undergoing posterior lumbar spinal fusion in the prone position on a Jackson table were studied. PPV, PVI, and hemodynamic and respiratory variables were measured both before and after the administration of 6 mL/kg colloid in both the supine and prone positions. Fluid responsiveness was defined as a 15% or greater increase in stroke volume index, as assessed by esophageal Doppler monitor after fluid loading. Results: In the supine position, 40 patients were responders. The areas under the receiver operating characteristic (ROC) curves for PPV and PVI were 0.783 [95% CI 0.648-0.884, P<0.001] and 0.814 (95% CI 0.684 0.908, P<0.001), respectively. The optimal cut-off values of PPV and PVI were 10% (sensitivity 75%, specificity 62%) and 8% (sensitivity 78%, specificity 77%), respectively. In the prone position, 27 patients were responders. The areas under the ROC curves for PPV and PVI were 0.781 (95% CI 0.646-0.883, P<0.001) and 0.756 (95% CI 0.618-0.863, P<0.001), respectively. The optimal cut-off values of PPV and PVI were 7% (sensitivity 82%, specificity 62%) and 8% (sensitivity 67%, specificity 69%), respectively. Conclusion: Both PPV and PVI were able to predict fluid responsiveness; their predictive abilities were maintained in the prone position. PMID- 30013355 TI - Experiences of Donating Personal Data to Mental Health Research: An Explorative Anthropological Study. AB - Technological developments, such as the advent of social networking sites, apps, and tracking 'cookies', enable the generation and collection of unprecedented quantities of rich personal and behavioural data, opening up a vast new resource for mental health research. Despite these non-traditional health-related data already forming a vital foundation of many new research avenues, little analysis has been done focusing on the experiences, motivations, and concerns of the individuals already engaged in data sharing and donation practices. This explorative study aims to investigate the experiences of individuals voluntarily donating their data to mental health research, specifically through the open data initiative OurDataHelps.org, which aims to develop effective suicide prevention tools. Qualitative semi-structured interviews and participant observation were used on a small sample of participants, yielding 3 key findings: (1) The relationship between participants and their data traces fluctuated between unconscious agency and hyper awareness through curatorship. (2) Despite having concerns about privacy and surveillance, participants were driven by altruistic motivations to engage with health researchers valued by their community, in the hope that their personal information could be of some benefit to future avenues of research. (3) In most cases represented in this sample group, motivation was found to stem from personal experiences with mental health, suicide, and loss. In the suicide survivor community, the experience of data donation is often valued as a method for emotional processing of a loss, connecting with the experiences of others, or as a way of regaining a sense of 'purpose'. By understanding the motivations of individual participants, future projects can ensure that data donation processes are a positive experience and ultimately, increase and sustain the huge potential resources for health researchers worldwide. PMID- 30013357 TI - Reablement teams' roles: a qualitative study of interdisciplinary teams' experiences. AB - Introduction: Reablement is a service for home-dwelling older people experiencing a decline in health and function. The focus of reablement is the improvement of the person's function and coping of his or he valued daily activities. The health care professionals and the home care personnel are working together with the older person toward his goals. In reablement, health care personnel are organized in an interdisciplinary team and collaborate with the older person in achieving his goals. This organizing changes the roles of home care personnel from working almost alone to collaborating with different health care professionals. There is little scientific knowledge describing the roles of different health care professionals and home care personnel in the context of reablement. This study's objective is to explore and describe the roles of interdisciplinary teams in reablement services in a Norwegian setting. Method: Two interdisciplinary teams consisting of 17 health care professionals (i.e. occupational therapists, physiotherapists, nurses, and social educators) and ten home care personnel (auxiliary nurses and nursing assistants) participated in three focus group discussions. In addition, three interviews were conducted with occupational therapists, physiotherapists, nurses, and auxiliary nurses. The focus group discussions and the interviews were all digitally recorded, transcribed verbatim and analyzed using the qualitative content analysis. Results: The health care professionals' main role was to be consultants and advisors, consisting of (1) planning, adjusting, and conducting follow-ups of the intervention; (2) delegating tasks; and (3) supervising the home care personnel. The home care personnel's main role was to be personal trainers, consisting of (1) encouraging and counseling the older adults to perform everyday activities; and (2) conveying a sense of security while they performed everyday activities. The role of interdisciplinary collaboration was a common role for both the health care professionals and the home care personnel. Conclusion: The health care professionals established the setting, and had the main roles of supervision, delegating tasks, and main responsibility for the intervention. The home care personnel accepted the delegations and had a main role as personal trainers. Their work changed from body care to encouraging and counseling the older person to perform activities themselves in a safe way. The health care professionals and the home care personnel collaborated closely across roles. The home care personnel experienced a shift in role from home care to a person-centered care. This was perceived as strengthening the health care identity of their role. PMID- 30013356 TI - Survival Outcomes of Retreatment with Trastuzumab and Cytotoxic Chemotherapy for HER2-Positive Recurrent Patients With Breast Cancer Who Had Been Treated with Neo/adjuvant Trastuzumab Plus Multidrug Chemotherapy: A Japanese Multicenter Observational Study. AB - Background: There are little data on the usefulness of trastuzumab (TZM) retreatment as the first-line treatment for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer recurrence after perioperative treatment with TZM. Aim: To clarify the outcome and safety of TZM retreatment in patients with recurrent HER2-positive breast cancer. Method: An observational study was conducted on patients who relapsed after primary systemic therapy with TZM using the central registration system. The primary end point was progression free survival (PFS). Secondary end points consisted of the response rate, overall survival (OS), and safety. Result: In total, 34 patients were registered between July 2009 and June 2012. The median follow-up time was 23.7 months (2-24 months). The 1- and 2-year PFS rates were 46.9% (95% confidence interval (95% CI): 29.2% 62.9%) and 29.8% (95% CI: 15.0%-46.3%), respectively (median 10.6 months). The median PFS time for patients receiving TZM combined with CTx was 13.9 months. The 1-and 2-year OR rates were 93.9 (95% CI: 77.9%-98.4%) and 84.8% (95% CI: 67.4% 93.4%). Trastuzumab-induced grade 3/4 adverse events were not observed. Conclusions: This study suggests that the PFS and OS in Japanese patients who relapsed after perioperative TZM therapy improved or were similar to those in previous reports. Differences in patient backgrounds and treatments must be considered when interpreting the results. Trastuzumab should be used combination with CTx and/or HTx for retreatment. Retreatment with TZM is safe.Trial registration: UMIN000002738. PMID- 30013358 TI - "Breaking breast cancer news" with ethnic minority: a UK experience. AB - Breaking bad news is a challenge in medicine. It requires good communication skills, understanding, and empathy on the part of a clinician. Communication has both verbal and non-verbal components. The requirement for non-verbal communication varies with various diverse groups, depending upon their cultural and religious beliefs. Breaking bad news in an ethnically diverse group is complex where cultural, religious, and language barriers may exist. The National Health Service was established in 1948. Ethnic minority comprised of only 0.2% (53,000) of the total population. The health care professionals shared the same cultural backgrounds as their patients at that time. Census in 2011 indicates that the number of the ethnically diverse group has increased to 14% (2 million) in England and Wales. Eighty-six percent of the population was white British. Asians (Pakistani, Indian, Bangladeshi, and other) "groups" made up 7.5% of the population; black groups 3.4%; Chinese groups 0.7%; Arab groups 0.4%; and other groups 0.6%. This figure is expected to increase by 20%-30% in 2050. It is, therefore, important that a doctor working within the National Health Service in the UK, should be prepared to deal with patients who may have a different culture, faith, language, and set of beliefs. In this article, I have highlighted the various challenges/issues in communication with such patients, available resources, and recommendations of strategies to improve their care. Unfortunately, no one single strategy can be applied to all as each patient should be recognized individually and as such, different factors have different weightings on each consultation. It is, therefore, important that hospitals raise cultural and religious awareness so that the doctors can be more understanding toward their patients. This will not only improve the patient's experience, medical staff would also feel professionally satisfied. PMID- 30013359 TI - Analysis of Temporal Changes in Growth and Gene Expression for Commensal Gut Microbes in Response to the Polyphenol Naringenin. AB - In this study, the effect of the flavanone naringenin on the growth and genetic expression of the commensal gut microbes, Ruminococcus gauvreauii, Bifidobacterium catenulatum, and Enterococcus caccae, was analyzed. Analysis of growth curves revealed that Ruminococcus gauvreauii was unaffected by naringenin, Bifidobacterium catenulatum was slightly enhanced by naringenin, and Enterococcus caccae was severely inhibited by naringenin. Changes in genetic expression due to naringenin were determined using single-molecule RNA sequencing. Analysis revealed the following responses to naringenin: Ruminococcus gauvreauii upregulated genes involved in iron uptake; Bifidobacterium catenulatum upregulated genes involved in cellular metabolism, DNA repair and molecular transport, and downregulated genes involved in thymidine biosynthesis and metabolism; Enterococcus caccae upregulated pathways involved in transcription and protein transport and downregulated genes responsible for sugar transport and purine synthesis. For the first time, changes in growth and gene expression for commensal gut bacteria in response to naringenin were documented. PMID- 30013360 TI - By blocking hexokinase-2 phosphorylation, limonin suppresses tumor glycolysis and induces cell apoptosis in hepatocellular carcinoma. AB - Introduction: The purpose of present study was to investigate the effect of limonin on tumor glycolysis and the underlying mechanisms in hepatocellular carcinoma (HCC). Methods: Cell proliferation and colony formation assays were performed to evaluate the potency of limonin against HCC cells in vitro. The glucose consumption and lactate production after limonin treatment was determined. The effect of limonin on hexokinase-2 (HK-2) activity was assessed and the mitochondrial location of HK-2 was studied by immunoprecipitation. Cell apoptosis and protein expression were detected by flow cytometry and western blotting respectively. Protein overexpression by plasmid transfection was adopted to investigate the molecular mechanisms. Results: HCC proliferation and colony formation were inhibited by limonin in vitro. With the suppression of HK-2 activity, the glycolytic level in HCC cells was substantially reduced, which was evidenced by the decrease of glucose consumption and lactate production. The phosphorylation of HK-2 was substantially inhibited by limonin, which resulted in the disassociation of HK-2 from mitochondria. Due to the reduction of HK-2 in mitochondria, increasing Bax were shifted to the mitochondria and gave rise to the release of cytochrome C, which induced HCC cells to subject to mitochondria mediated apoptosis. Mechanism investigations revealed that the decrease of HK-2 phosphorylation was mainly due to the inhibition of Akt activity. In Akt exogenously overexpressed HCC cells, limonin-mediated cell proliferation inhibition, glycolysis suppression and apoptosis induction were significantly impaired. Conclusion: Limonin inhibited the tumor glycolysis in hepatocellular carcinoma by suppressing HK-2 activity, and the suppression of HK-2 was closely related to the decrease of Akt activity. PMID- 30013361 TI - Silencing of c-jun decreases cell migration, invasion, and EMT in radioresistant human nasopharyngeal carcinoma cell line CNE-2R. AB - Background: Previously, we found that c-jun was highly expressed in radiation resistant human nasopharyngeal carcinoma cells (CNE-2R) compared with human nasopharyngeal carcinoma cells (CNE-2). Materials and methods: In this study, we first used the scratch assays and transwell assays to detect the migration and invasion of CNE-2R and CNE-2 cells and tested the epithelial mesenchymal transformation (EMT)-related proteins E-cadherin and N-cadherin by Western blot analysis. Subsequently, c-jun was knocked down to establish the effect of c-jun on EMT, migration, and invasion of CNE-2R cells both in vitro and in vivo. Results: A high EMT level, CNE-2R cells were more capable of migration and invasion than CNE-2 cells. Moreover, silencing of c-jun has upregulated the expression of E-cadherin and downregulated N-cadherin in CNE-2R cells, and subsequently the migration and invasion capacity of the cells was decreased. Consistent with in vitro results, in vivo studies indicated that the c-jun silencing reduced pulmonary migration of CNE-2R cells. Immunohistochemistry of lung metastatic tumor tissue showed that E-cadherin was upregulated, and N cadherin was downregulated. Conclusion: These findings suggest that silencing of c-jun in CNE-2R cells reduces cells migration, invasion, and EMT both in vitro and in vivo. PMID- 30013363 TI - Overexpression of Beclin1 inhibits proliferation and promotes apoptosis of human laryngeal squamous carcinoma cell Hep-2. AB - Objective: Beclin1 was previously found to be downregulated in human laryngeal cancer (LC) tissues, and it results in poor prognosis. This study aimed to further confirm the antitumor effects of Beclin1 in LC cell line Hep-2. Materials and methods: Beclin 1 was overexpressed in Hep-2 cells using liposomal transfection and confirmed using reverse transcription polymerase chain reaction and Western blotting. Then, cell proliferation and apoptosis were determined in control (untransfected), empty vector transfected, and Beclin1 overexpressed groups using MTT and flow cytometry procedure, respectively. Results: The expression of the Beclin1 gene in Hep-2 cells was significantly increased after vector transfection compared with control (1.173+/-0.046 vs 0.453+/-0.016, P<0.01) and empty vector (1.173+/-0.046 vs 0.440+/-0.021, P<0.01). Overexpression of Beclin1 inhibited proliferation at 4 days (0.619+/-0.051 vs 0.891+/-0.081 and 0.619+/-0.051 vs 0.878+/-0.105, P<0.01), 5 days (0.684+/-0.078 vs 1.127+/-0.094 and 0.684+/-0.078 vs 1.162+/-0.117, P<0.01), and 6 days (0.725+/-0.069 vs 1.168+/ 0.103 and 0.725+/-0.069 vs 1.194+/-0.097, P<0.01) and promoted apoptosis (14.48%+/-1.42% vs 4.07%+/-0.66% and 14.48%+/-1.42% vs 4.39%+/-0.80%, P<0.01) in Hep-2 cells in comparison with the control and empty vector groups, respectively. Conclusion: Beclin1 may be an underlying target for the treatment of LC. This study has provided some experimental basis for the gene therapy of LC. PMID- 30013364 TI - miR-106b-5p inhibits the invasion and metastasis of colorectal cancer by targeting CTSA. AB - Background: Although miR-106b-5p has been reported to play a pivotal role in various human malignancies, its role in colorectal cancer (CRC) remains unknown. In this study, we comprehensively investigated miR-106b-5p expression and biologic functions in CRC and the molecular mechanism involved. Patients and methods: miR-106b-5p expression was detected in CRC tissues and cell lines by quantitative reverse transcription-polymerase chain reaction. The effects of miR 106b-5p on metastasis were determined in vitro using transwell assays, and in vivo effects were evaluated using a mouse tail vein injection model. Downstream targets of miR-106b-5p were confirmed using bioinformatics programs, luciferase assays, and rescue experiments. Target gene expression and clinicopathologic parameters were also analyzed. Results: miR-106b-5p expression was lower in CRC tissues than in corresponding nontumorous tissues (P=0.009), and miR-106b-5p downregulation was negatively associated with lymph node metastasis (P=0.006). Functional assays demonstrated that miR-106b-5p overexpression suppressed CRC cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, luciferase assays confirmed that miR-106b-5p directly bound to the 3' untranslated region of cathepsin A (CTSA) and that miR-106b-5p suppressed CRC cell migration and invasion by targeting CTSA. Clinicopathologic analysis showed that CTSA was significantly upregulated in CRC, and increased CTSA was negatively associated with lymph node metastasis (P=0.012). Conclusion: Our findings revealed that miR-106b-5p inhibits CRC metastasis by upregulating CTSA expression, which may lead to novel therapeutic strategies for CRC patients. PMID- 30013362 TI - Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial-mesenchymal transition. AB - Cancer stem cells are a small population of cells with the potential for self renewal and multi-directional differentiation and are an important source of cancer initiation, treatment resistance, and recurrence. Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells lose their epithelial phenotype and convert to mesenchymal cells. Recent studies have shown that cancer cells undergoing EMT can become stem-like cells. Many kinds of tumors are associated with chronic inflammation, which plays a role in tumor progression. Among the various immune cells mediating chronic inflammation, macrophages account for ~30%-50% of the tumor mass. Macrophages are highly infiltrative in the tumor microenvironment and secrete a series of inflammatory factors and cytokines, such as transforming growth factor (TGF)-beta, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha, which promote EMT and enhance the stemness of cancer cells. This review summarizes and discusses recent research findings on some specific mechanisms of tumor-associated macrophage-derived cytokines in EMT and cancer stemness transition, which are emerging targets of cancer treatment. PMID- 30013365 TI - The role of histone lysine methyltransferase NSD3 in cancer. AB - The growing number of findings demonstrate that nuclear receptor suppressor of variegation, enhancer of zeste, and trithorax domain-containing 3 (NSD3) is amplified and overexpressed in multiple cancer types. Nevertheless, the biological roles of NSD3 in carcinogenesis have not been well understood. In this review, we summarize the current knowledge on the mechanisms underlying NSD3 regulation in different cancers. In addition, NSD3 may serve as a potential druggable target for selective cancer therapy in the future. PMID- 30013366 TI - Loss of miR-516a-3p mediates upregulation of ABCC5 in prostate cancer and drives its progression. AB - To gain a comprehensive understanding of whether ABCC5 can regulate prostate cancer (PCa) progression, we performed microarray data analyses and identified that ABCC5 was drastically increased in primary PCa relative to normal samples, metastatic PCa relative to primary PCa, and castration-resistant PCa relative to hormone naive PCa, respectively. Multivariate Cox regression analysis suggested that ABCC5 overexpression in PCa was an independent prognostic factor for both poor biochemical recurrence-free and overall survival. We demonstrated that ABCC5 knockdown significantly inhibits PCa cell proliferation, migration, and invasion in vitro and suppresses tumor growth and metastasis in vivo. We also demonstrated that miR-516a-3p was significantly downregulated in PCa. We finally demonstrated that ABCC5 was a direct target of miR-516a-3p. miR-516a-3p overexpression can phenotypically copy ABCC5 knockdown-induced phenotypes, whereas forced expression of ABCC5 can drastically reverse the inhibitory effects of miR-516a-3p. miR-516a 3p may modulate the sensitivity of cancer cells to adriamycin and docetaxel by targeting ABCC5 with important implications in the design of new therapeutic agents. Taken together, our results indicated that loss of miR-516a-3p expression and thus uncontrolled ABCC5 upregulation might drive PCa progression and influence chemosensitivity. PMID- 30013367 TI - Bortezomib-based therapy for transplant-ineligible East Asian patients with newly diagnosed mantle-cell lymphoma. AB - Introduction: This subgroup analysis of the LYM-3002 Phase III study (NCT00722137) investigated whether substituting bortezomib for vincristine in frontline R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy could improve outcomes in East Asian patients with newly diagnosed mantle-cell lymphoma (MCL). Materials and methods: A total of 121 East Asian patients from China, Taiwan, Japan, and the Republic of Korea with stage II IV MCL who were ineligible or not considered for stem-cell transplantation were enrolled to six to eight 21-day cycles of R-CHOP or VR-CAP (R-CHOP with bortezomib replacing vincristine). Results: The primary end point was progression free survival. After a median follow-up of 42.4 months, median progression-free survival in East Asian patients was 13.9 (R-CHOP) versus 28.6 (VR-CAP) months (HR 0.7, P=0.157; 43% improvement with VR-CAP). Secondary end points (R-CHOP vs VR CAP), including complete response rate (47% vs 63%), duration of complete response (median 16.6 vs 46.7 months), and treatment-free interval (median 21 vs 46.5 months), were improved with VR-CAP. VR-CAP was associated with increased but manageable toxicity. The most frequent adverse events were hematologic toxicities. Conclusion: VR-CAP was effective in East Asian patients with newly diagnosed MCL, and could be considered for patients in whom stem-cell transplantation is not an option. PMID- 30013368 TI - The clinical usefulness of natural killer cell activity in patients with suspected or diagnosed prostate cancer: an observational cross-sectional study. AB - Purpose: To investigate the clinical usefulness of natural killer cell activity (NKA) for detection of prostate cancer (PCa) and prediction of Gleason grade. Patients and methods: We prospectively enrolled 221 patients who underwent transrectal ultrasound-guided prostate biopsy for suspected PCa due to elevated prostate-specific antigen (PSA) >2.5 ng/mL or abnormal findings on digital rectal examination (n=146), or who were diagnosed with PCa (n=75) between 2016 and 2017. The NKA was compared according to PCa and Gleason grade. Correlation analysis was used to evaluate associations among NKA, PCa, and Gleason grade, and expressed using distribution dot plots. The absolute risk and relative risk of PCa, and odds ratios at different cut-off values of NKA were calculated. Results: Of the total 221 patients, PCa was identified in 135 (61.9%) patients. When patients were divided according to PCa, there was no significant difference in NKA (1,267.6 vs 1,198.9 pg/mL, P=0.491). Furthermore, in 135 patients with PCa, the NKA was not significantly different according to Gleason grade (P=0.893). These results were not changed when confined to the patients with PSA between 2.5 and 10.0 ng/mL (P=0.654 and P=0.672, respectively). In addition, there was no significant difference in the risk of PCa at different cut-off values of NKA. Conclusion: These results indicate that NKA does not appear to be very useful for detection of PCa and prediction of Gleason grade. Further large multi institutional studies are required to verify the role of NKA in PCa detection and Gleason grade prediction. PMID- 30013369 TI - MicroRNAs as potential biomarkers for diagnosis, therapy and prognosis of gastric cancer. AB - Despite the widespread use of endoscopy and conventional tumor biomarkers, gastric cancer (GC) remains one of the most frequent causes of cancer-related deaths worldwide due to its late diagnosis and poor response to treatment. Valuable and practical biomarkers are urgently needed to screen patients with a high risk of GC that can complement endoscopic diagnosis. Such biomarkers will enable the efficient prediction of therapeutic response and prognosis of GC patients and favor the establishment of an effective treatment strategy for each and every patient. MicroRNAs (miRNAs) are a class of small non-coding RNA sequences that play important roles in modulating key biological processes by regulating the expression of target genes. Expectedly, miRNAs are abnormally expressed within the tumor tissue and in associated biological fluids of GC patients including their blood, gastric juice, and urine. Accumulating evidence indicates that miRNAs are potential biomarkers with multiple diagnostic functions for GC. Here, we review recent advances and challenges in using miRNAs, particularly biofluid miRNAs, as GC biomarkers with potential clinical applications including diagnosing, clinically staging, and predicting malignant behaviors, therapy response, recurrence after surgery and survival time. PMID- 30013370 TI - Predictive value of single nucleotide polymorphisms in XRCC1 for radiation induced normal tissue toxicity. AB - Purpose: X-Ray Repair Cross Complementing 1 (XRCC1) functioning in the base excision repair pathway plays an important role in the repair of DNA single strand breaks caused by ionizing radiation. The relationship between XRCC1 polymorphisms and the risk of radiation-induced side effects on normal tissues remains controversial. Therefore, we performed a comprehensive meta-analysis to elucidate these associations. Materials and methods: A systematic literature search was carried out in PubMed, Medline (Ovid), Embase, Web of Science, Cochrane database, and the references of relevant studies. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Results: A total of 40 studies including 6,682 patients were eventually identified in this meta-analysis. Pooled results suggested that rs25487 Arg399Gln polymorphism significantly increased the risk of acute radiation-induced side effects (OR=1.29, 95% CI: 1.10-1.52, P=0.002), especially acute mucositis (OR=1.91, 95% CI: 1.17-3.11, P=0.01) and acute gastrointestinal and genitourinary toxicity (OR=1.49, 95% CI: 1.04-2.11, P=0.03). Furthermore, patients who received head and neck irradiation with rs25487 Arg399Gln polymorphism were more likely to experience radiotherapy (RT) induced side effects (OR=1.46, 95% CI: 1.12-1.90, P=0.005). However, no statistically significant correlations were identified between rs25487 polymorphism and any late side effects and other irradiation areas. Likewise, no significant associations were detected between rs25489, rs1799782, or rs3213245 polymorphism and RT-induced toxicity. Conclusion: Our meta-analysis demonstrated that XRCC1 rs25487 Arg399Gln polymorphism had a significant predictive value and might predict a risk of severely acute RT-induced adverse effects, especially in acute mucositis and acute gastrointestinal and genitourinary toxicity, or in patients with head and neck irradiation. However, large-scale and well-designed studies are required to further evaluate the predictive value of XRCC1 variations on radiation-induced side effects in order to identify radiosensitive patients and predict radiotoxicity. PMID- 30013371 TI - Integrated omics and gene expression analysis identifies the loss of metabolite metabolite correlations in small cell lung cancer. AB - Background and objective: Small cell lung cancer (SCLC) is the most aggressive type of lung carcinoma with high metastatic potential and chemoresistance upon relapse. Cancer cells remodel the existing metabolic pathways for their benefits and the perturbations in cellular metabolism are the hallmark of cancer. However, the extent of these changes remains largely unknown for SCLC. Materials and methods: We characterized the metabolic perturbations in SCLC cells (SCLCC) by metabolomics. Large-scale correlation analysis was performed between metabolites. Targeted proteomics and gene expression analysis were employed to investigate the changes of key enzymes and genes in the disturbed pathways. Results: We found dramatic decrease of metabolite-metabolite correlations in SCLCC compared with normal control cells and non-small cell lung cancer cells. Pathway analysis revealed that the loss of correlations was associated with the alternations of fatty acid oxidation, urea cycle, and purine salvage pathway in SCLCC. Targeted proteomics and gene expression analysis confirmed significant changes of the expression for the key enzymes and genes in the pathways in SCLCC including the upregulation of carbamoyl phosphate synthase 1 (urea cycle) and carnitine palmitoyltransferase 1A (fatty acid oxidation), and the downregulation of hypoxanthine-guanine phosphoribosyltransferase and adenine phosphoribosyltransferase in purine salvage pathway. Conclusion: We demonstrated the loss of metabolite-metabolite correlations in SCLCC associated with the upregulation of fatty acid oxidation and urea cycle and the downregulation of purine salvage pathways. Our findings provide insights into the metabolic reprogramming in SCLCC and highlight the potential therapeutic targets for the treatment of SCLC. PMID- 30013372 TI - Cryostorage of immature and mature human testis tissue to preserve spermatogonial stem cells (SSCs): a systematic review of current experiences toward clinical applications. AB - While the survival rate of children with cancer is increasing, preserving fertility for prepubertal boys is still a challenge. Although intracytoplasmic sperm injection (ICSI) using frozen sperms has revolutionized infertility treatment, it is not applicable for the patients who undergo chemotherapy before puberty since spermatogenesis has not begun. Therefore, preserving spermatogonial stem cells (SSCs) as an experimental option can be provided to prepubertal patients at a risk of damage or loss of their SSCs due to cancer treatments and developmental or genetic disorders. Using frozen SSCs in testicular tissue, successful SSC autotransplantation in mouse and nonhuman primates has shown a promising future for SSC-based cell therapy. Cryopreservation of testicular tissue containing SSCs is the first step to translate SSC-based cell therapy into clinical male infertility treatment, and in the investigation into SSCs, it is very important to evaluate their quantity and functionality during this process. This systematic review summarizes the published data on cryopreservation techniques in human testis tissue for potential utilization in future clinical applications. PMID- 30013373 TI - Current trends to control fungal pathogens: exploiting our knowledge in the host pathogen interaction. AB - Human fungal infections remain a major challenge in medicine. Only a limited number of antifungal drugs are available, which are often related to severe adverse effects. In addition, there is an increased emergence related to resistant strains, which makes imperative to understand the host-pathogen interactions as well as to develop alternative treatments. Host innate and adaptive immunity play a crucial role controlling fungal infections; therefore, vaccines are a viable tool to prevent and treat fungal pathogens. Innate immunity is triggered by the interaction between the cell surface pattern recognition receptors (PRRs) and the pathogen-associated molecular patterns (PAMPs). Such an initial immunological response is yet little understood in fungal infections, in part due to the complexity and plasticity of the fungal cell walls. Described host cell-fungus interactions and antigenic molecules are addressed in this paper. Furthermore, antigens found in the cell wall and capsule, including peptides, glycoproteins, glycolipids, and glycans, have been used to trigger specific immune responses, and an increased production of antibodies has been observed when attached to immunogenic molecules. The recent biotechnological advances have allowed the development of vaccines against viral and bacterial pathogens with positive results; therefore, this technology has been applied to develop anti-fungal vaccines. Passive immunization has also emerged as an appealing alternative to treat disseminated mycosis, especially in immunocompromised patients. Those approaches have a long way to be seen in clinical cases. However, all studies discussed here open the possibility to have access to new therapies to be applied alone or in combination with current antifungal drugs. Herein, the state of the art of fungal vaccine developments is discussed in this review, highlighting new advances against Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Paracoccidioides brasiliensis, and Sporothrix spp. PMID- 30013374 TI - Efficiency of gold nanoparticles coated with the antimicrobial peptide indolicidin against biofilm formation and development of Candida spp. clinical isolates. AB - Background: This article examines the use of a novel nano-system, gold nanoparticles coated with indolicidin (AuNPs-indolicidin), against pathogenic Candida albicans biofilms. Candida species cause frequent infections owing to their ability to form biofilms, primarily on implant devices. Materials and methods: We used an integrated approach, evaluating the effect of AuNPs indolicidin on prevention and eradication of Candida biofilms formed in multi well polystyrene plates, with relative gene expression assays. Four biofilm associated genes (FG1, HWP1, ALS1 and ALS3, and CDR1 and CDR2) involved in efflux pump were analyzed using reverse transcription polymerase chain reaction. Results: Treatment with the nano-complex significantly inhibits the capacity of C. albicans to form biofilms and impairs preformed mature biofilms. Treatment with AuNPs-indolicidin results in an increase in the kinetics of Rhodamine 6G efflux and a reduction in the expression of biofilm-related genes. Conclusion: These data provide a chance to develop novel therapies against nosocomially acquired refractory C. albicans biofilms. PMID- 30013375 TI - Epidemiology and molecular characterization of multidrug-resistant Escherichia coli isolates harboring blaCTX-M group 1 extended-spectrum beta-lactamases causing bacteremia and urinary tract infection in Manhica, Mozambique. AB - Background: The emergence and spread of extended-spectrum beta-lactamases (ESBLs), especially CTX-M, is an important public health problem with serious implications for low-income countries where second-line treatment is often unavailable. Knowledge of the local prevalence of ESBL is critical to define appropriate empirical therapeutic strategies for multidrug-resistant (MDR) organisms. This study aimed to assess and characterize the presence of ESBL and especially CTX-M-producing Escherichia coli MDR isolates from patients with urinary tract infections (UTIs) and bacteremia in a rural hospital in Mozambique. Materials and methods: One hundred and fifty-one E. coli isolates from bacteremia and UTI in children were screened for CTX-M, TEM, SHV and OXA beta-lactamases by polymerase chain reaction and sequencing. Isolates carrying CTX-M group 1 beta lactamases were further studied. The resistance to other antibiotic families was determined by phenotypic and genotypic methods, the location of the blaCTX-M gene and the epidemiology of the isolates were studied, and extensive plasmid characterization was performed. Results: Approximately 11% (17/151) of E. coli isolates causing bacteremia and UTI were ESBL producers. CTX-M-15 was the most frequently detected ESBL, accounting for 75% of the total isolates characterized. The blaCTX-M gene is located in different plasmids belonging to different incompatibility groups and can be found in non-epidemiologically related isolates, indicating the high capacity of this resistance determinant to spread widely. Conclusion: Our data suggest the presence of a co-selection of third generation cephalosporin-resistant determinants in the study area despite limited access to these antibiotics. This highlights the importance of continuous surveillance of antimicrobial resistance of both genetic elements of resistance and resistant isolates in order to monitor the emergence and trends of ESBL producing isolates to promote adequate therapeutic strategies for the management of MDR bacterial infections. PMID- 30013376 TI - Effect of ethanol pretreatment in Acanthamoeba keratitis: a long-term follow-up study. AB - Purpose: The aim of this study was to evaluate the long-term outcomes of ethanol pretreatment in Acanthamoeba keratitis (AK). Patients and methods: This single center, retrospective, interventional study included 22 patients (24 eyes) who developed AK and underwent ethanol pretreatment between 2009 and 2015. Samples for smears, polymerase chain reaction, and culture for evidence of Acanthamoeba were collected. After ethanol pretreatment, the patients were treated with corneal epithelial debridement, topical 0.02% polyhexamethylene biguanide, and 0.1% propamidine isethionate. The primary outcomes were a clinically stable ocular surface, complete recovery from corneal infection, and acceptable corneal haze. The secondary outcome measure was improvement in best-corrected visual acuity. Complications and predictors of the visual outcome were also recorded. Results: Ethanol pretreatment was successful in 20 (83.3%) of the 24 eyes, and no further optical keratoplasty was required. Four eyes required rescue therapeutic keratoplasty because of rapid progression of AK. Patients in whom ethanol pretreatment was successful achieved good final visual outcomes regardless of sex, age, or causative Acanthamoeba species. Patients with worse initial best corrected visual acuity and rigid gas permeable lens-related AK had better improvement in vision. Conclusion: Ethanol as a pretreatment for AK is safe and effective. Combined with corneal epithelial debridement, ethanol pretreatment may preclude the need for optical and therapeutic keratoplasty. This technique is suitable for all stages of AK presenting within 3 weeks of symptom onset and achieves favorable results especially in early AK. PMID- 30013377 TI - Effects of glucosyl-hesperidin and physical training on body weight, plasma lipids, oxidative status and vascular reactivity of rats fed with high-fat diet. AB - Objective: The aim of the study was to evaluate the effects of supplementation with glucosyl hesperidin (GH), with or without physical training, on body weight, fat depot, glucose and plasma lipids, oxidative status and vascular function of rats fed with high-fat diet (HFD). Methods: After weaning, male Wistar rats were fed with an HFD plus fructose for 12 weeks and started receiving oral antioxidant supplementation and/or physical training after the fourth week of diet for eight further weeks. Body weight, epididymal and retroperitoneal fat, plasma glucose and lipids, oxidative status and mesenteric artery reactivity were evaluated. Results: Rats fed with HFD presented higher body weight gain and fat accumulation compared to control rats, while GH supplementation did not influence these parameters. Physical training reduced the body weight gain and fat accumulation and modulated the oxidative status by increasing superoxide dismutase activity and total antioxidant capacity and reducing lipid peroxidation. GH alone decreased lipid peroxidation. However, when given to exercised rats, it impaired the response elicited by physical training. HFD caused endothelial dysfunction, and neither GH nor physical exercise prevented it. Potency of sodium nitroprusside was increased in exercised animals but not in GH-supplemented rats. Conclusion: Physical exercise partially decreased the body fat accumulation, decreased plasma levels of glucose and lipids and improved general oxidative status and endothelium-independent relaxation in mesenteric arteries of rats fed with HFD. GH exhibited benefits only in the oxidative status. However, GH given in association with physical exercise did not cause further changes in addition to those promoted by physical exercise. On the contrary, in exercised animals, GH prevented those changes elicited by physical training in plasma glucose and lipids, oxidative status and endothelium-independent relaxation. PMID- 30013378 TI - Assessing the response of morphea and limited scleroderma to tranilast: a small prospective study comparing topical corticosteroids to a combination of topical corticosteroids and tranilast. AB - Background: Scleroderma is traditionally managed with immunomodulatory agents such as methotrexate, mycophenolate mofetil and corticosteroids. There are anecdotal reports for, and theoretical reasons why, the anti-fibrotic agent tranilast may provide an additional treatment modality. Objective: The objective of the current study was to demonstrate if the addition of topical tranilast to an established regime resulted in an improvement in the Localized Scleroderma Assessment Tool (LoSCAT) and modified Rodnan score. Patients and methods: A small double-blinded randomized prospective study of 11 pairs of treatment sites in four patients; three with morphea and one with limited scleroderma was performed. All patients continued with their prescribed treatment and applied 0.1% betamethasone valerate in PCCA PracaSilTM (B) to the control site with 0.1% betamethasone valerate and 1% tranilast (B/T) to the comparator site over a period of 3 months. Photographs and monthly LoSCAT scores were performed on the morphea patients and a modified Rodnan score on the limited scleroderma patient. Statistical analysis was via sign test. Results: The mean baseline LoScat score at the B treated sites was 6.6 which improved to 4.3 (p= 0.16). The mean baseline LoScat score at the B/T treated sites was 5.75 which improved to 2.8 following treatment. (p=0.04). Limitations: This was a small single center study. The ideal concentration of tranilast is unknown. As all patients continued with standard management the expected response may be less than would have been anticipated in a single agent trial. Conclusion: The role of tranilast in the management in scleroderma warrants further investigation in larger trials. PMID- 30013379 TI - Comparison of botulinum neurotoxin type A formulations in Asia. AB - Results: All protein-based therapeutics, such as botulinum neurotoxin type A (BoNT/A), are potentially immunogenic and can lead to anaphylaxis, autoimmunity, or diminished or complete absence of therapeutic efficacy, especially if administered repeatedly. Therefore, the protein quantity in BoNT/A products is an important consideration when selecting products for treatment. However, essential formulation data are not always publicly accessible. Materials and methods: The neurotoxin protein content of products newly introduced in Asia, such as (listed alphabetically) Botulax(r), Meditoxin(r), Nabota(r), and Relatox(r), was measured by sandwich enzyme-linked immunosorbent assay with antisera directed against BoNT/A compared to Xeomin(r). Results: Compared to Xeomin with no inactive neurotoxin, although Botulax and Nabota contained 844 and 754 pg of neurotoxin protein, respectively, the percentage of inactive neurotoxin was calculated to be 103 and 81, respectively, while the potency per pg of neurotoxin was 0.118 and 0.133 U, respectively. Meditoxin and Relatox had 575 and 578 pg of neurotoxins, respectively, marginally higher than that of Xeomin, while the percentage of inactive neurotoxins was 38 and 33, respectively, and the potency per pg of neurotoxin was 0.174 and 0.173 U, respectively. However, Xeomin, which has 416 pg/vial of purified neurotoxin and 0.240 U of efficacy per pg of neurotoxin, has the lowest neurotoxin protein content and consequently the highest specific potency compared to the four Asian BoNT/A preparations in this study. Conclusion: Although Botulax and Nabota had more neurotoxin than Xeomin in an equivalent volume, they contained greater amounts of inactive neurotoxin. In addition, although Meditoxin and Relatox had slightly more neurotoxin than Xeomin, both contained greater amounts of inactive neurotoxin. PMID- 30013380 TI - Prenatal diagnosis and molecular cytogenetic characterization of a de novo duplication of 15q24.3-q26.1. AB - Reported cases of distal 15q interstitial duplications are uncommon and do not result in a recognizable pattern of abnormalities. Some studies report prenatal overgrowth, while others describe growth retardation. We present molecular cytogenetic characterization of a 14 Mb interstitial duplication, encompassing 81 Online Mendelian Inheritance in Man (OMIM) genes, in a fetus with single umbilical artery and short limbs. We propose that growth restriction, previously described and present in our patient, may be due to duplication of a gene or genes contained in the 15q24 region. PMID- 30013381 TI - Evaluating the use of corticosteroids in preventing and treating bronchopulmonary dysplasia in preterm neonates. AB - Approximately 15 million babies worldwide are born premature, and complications of prematurity are one of the leading causes of death in neonates. Neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD) are two of the most common and serious consequences of prematurity. Synthetic corticosteroids, including dexamethasone, have been central in efforts to treat and prevent BPD. There is strong evidence to show that prenatal corticosteroids reduce infant mortality and the incidence of NRDS, leading to their widespread use in obstetric units. However, data suggest that they are not as effective in reducing the incidence of BPD as NRDS, which may be due to the multifactorial pathogenesis of BPD. On the other hand, the use of postnatal corticosteroids in preterm infants is much more controversial. They have been shown to improve lung function and help in reducing the need for mechanical ventilation. These benefits, however, are associated with a range of adverse short- and long-term effects. This review will discuss the benefits and consequences of corticosteroids in treating BPD and will examine alternative treatments and future research that may improve the understanding of BPD and inform clinical practice. PMID- 30013382 TI - Development of a nasal spray containing xylometazoline hydrochloride and iota carrageenan for the symptomatic relief of nasal congestion caused by rhinitis and sinusitis. AB - Introduction: Xylometazoline hydrochloride (HCl) is a nasal decongestant that causes vasoconstriction in the nasal submucosa. It has been used for more than 50 years for the treatment of nasal congestion caused by rhinitis/sinusitis. Iota carrageenan is effective against a broad variety of respiratory viruses, which are the most common cause of infections of the upper respiratory tract. Therefore, it is used as the active component in the antiviral nasal spray Coldamaris prophylactic (1.2 mg/mL iota-carrageenan in 0.5% NaCl) and other medical device nasal sprays that are approved and marketed in the EU. Recently, we developed a nasal spray formulation containing both xylometazoline HCl (0.05%) and iota-carrageenan (0.12%) that provides decongestion and antiviral protection of the nasal mucosa at the same time. Results: A set of in vitro experiments revealed that the vasoconstrictive properties of xylometazoline HCl and the antiviral effectiveness of iota-carrageenan against human rhinovirus (hRV) 1a, hRV8 and human coronavirus OC43 were maintained in the formulation containing these two compounds. Permeation experiments using bovine nasal mucosa showed that iota-carrageenan had no significant influence on the permeation of xylometazoline HCl. Finally, in the local tolerance and toxicity study, it was shown that the formulation was well tolerated at the application site with no occurrence of erythema or edema in the nostrils of all rabbits or any signs of toxicity in any of the organs and tissues inspected. Conclusion: Investigations on compatibility of xylometazoline HCl and iota-carrageenan demonstrated that the substances do not influence each other, allowing both to fulfill their known specific clinical efficacy (xylometazoline HCl) and effectiveness (iota-carrageenan). PMID- 30013383 TI - Altered levels of cytokines in patients with irritable bowel syndrome are not correlated with fatigue. AB - Introduction: A considerable number of patients with gastrointestinal complaints attributable to irritable bowel syndrome (IBS) have shown evidence of immune activation. Fatigue is also frequently reported by IBS patients and the condition is considered as a common comorbidity of IBS. Therefore, it is interesting to see whether these two conditions share the same pathophysiological mechanism. Aims: To investigate the potential role of cytokine profiles in patients with IBS and the relationship between cytokine profiles and fatigue. Materials and methods: Thirty-eight patients with IBS (32 females, 6 males, age range 18-70 years) and 22 healthy individuals (control group) (17 females, 5 males, age range 24-42 years) were included. IBS was diagnosed according to Rome III criteria, and severity of IBS symptoms and fatigue were evaluated using the Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS) and Fatigue Impact Scale (FIS), respectively. FIS scores of 25 or higher were defined as fatigue. Blood samples were also taken, and the Luminex(r) platform (Cytokine Human Ultrasensitive Magnetic 10-Plex Panel) was used for quantifying human cytokines' profile (granulocyte-macrophage colony-stimulating factor, interferon-gamma, interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor [TNF] alpha) in serum. Results: The serum levels of IL-5, IL-6, IL-10, and TNF-alpha were significantly higher in patients with IBS compared to healthy controls (p=0.003, p=0.011, p=0.007, and p=0.02, respectively). Conversely, serum levels of cytokine IL-1beta were significantly higher in the control group (p=0.03). The findings were consistent when comparing nonatopic patients with controls. Fatigue was demonstrated in 84.2% of the IBS patients. Scores of IBS-SSS were not significantly correlated with FIS scores (r=0.2, p=0.19), and they were not significantly different in patients with FIS scores >25 compared to patients with FIS scores <25 (p=0.11). None of the cytokine levels were significantly different in IBS patients with FIS scores >25 compared to IBS patients with FIS scores <25. Moreover, the cytokine levels in participants did not vary significantly between patients with diarrhea, constipation, or mixed bowel habits in multiple comparisons of patients. Conclusions: The cytokines IL-5, IL-6, IL-10, and TNF alpha may contribute to the development of IBS. However, serum levels of cytokines were not significantly different in IBS patients with fatigue compared with IBS patients without fatigue. Thus, the significance of cytokine levels may be less important than anticipated in search of common underlying mechanisms, and other factors should be explored in future studies. PMID- 30013384 TI - Kinesiology taping reduces the pain of finger osteoarthritis: a pilot single blinded two-group parallel randomized trial. AB - Objectives: Osteoarthritis (OA) is the most common arthropathy of the hand, and current treatments carry risks of adverse events. Supportive (kinesiology) tape may be analgesic and provide functional improvement, with a low risk of adverse outcomes. We experimented with supportive tape for OA of the proximal interphalangeal joint (PIPJ) of the finger in this pilot randomized trial. Methods: This two-group parallel randomized trial recruited adults with OA of the PIPJ of the finger. We excluded patients lacking capacity or the ability to safely apply the tape. Participants were randomized to receive kinesiology tape on the dorsum of the finger, blind to grouping. Pain was the primary outcome, which was recorded on a visual analog scale (VAS). Secondary outcomes were hand function and adverse reactions. Bootstrapped between-group analyses are reported. Results: Ten patients were included and randomized and provided complete data. There was no significant difference in pain between the groups (mean difference of 0.4 VAS units [95% confidence interval {CI} -1.6, 0.7], p=0.4). Overall, the application of kinesiology tape reduced reported pain by 6% (mean reduction of 0.6 VAS units [95% CI 0, 1.2], p=0.04). Taping did not affect hand function or digital range of motion. There were difficulties in recruiting individuals owing to the lack of dedicated research staff. Conclusion: Kinesiology taping may reduce the pain of OA in the finger; however, whether this is a true effect, placebo effect, Hawthorne phenomenon, or due to a statistical error (ie, type 1 error due to underpowering) is unclear. Hence, further trials are required. PMID- 30013385 TI - Recovery characteristics of total intravenous anesthesia with propofol versus sevoflurane anesthesia: a prospective randomized clinical trial. AB - Background: Pediatric dental procedures are performed under anesthesia because children may be uncooperative in the dental clinic due to their young age. Emergence delirium (ED), which involves a variety of behavioral disturbances that are frequently observed in children following emergence from general anesthesia, remains an unclear phenomenon. The aim of this randomized controlled trial is to compare the incidence of ED in children who underwent full mouth dental rehabilitation under either sevoflurane (SEVO) anesthesia or propofol-based total intravenous anesthesia (TIVA). Patients and methods: One hundred and twenty children with American Society of Anesthesiologists status I-II, aged >=3 and <=6 years, undergoing dental rehabilitation were assigned to receive either TIVA or SEVO. ED and postoperative pain were evaluated by a blinded investigator using the Pediatric Anesthesia Emergence Delirium scale and the Face, Legs, Activity, Cry, Consolability scale every 5 min. The recovery time, satisfaction levels of parents or guardians, extubation time, duration of the operation, and type of dental procedure were also recorded. Results: Data of 116 subjects were analyzed. The incidence of ED was higher after SEVO than after TIVA (65.5 vs 3.4%, P=0.00). Greater postoperative pain was observed in the SEVO group (median 3 vs 1, P=0.000). A statistically significant, moderate correlation (rs=0.46, P<0.0001) was found between the Face, Legs, Activity, Cry, Consolability and Pediatric Anesthesia Emergence Delirium scores. A higher parental satisfaction level was observed in the TIVA group. Conclusion: A lower incidence of ED and a higher parental satisfaction level were observed after TIVA. Moreover, TIVA resulted in a more comfortable postoperative period due to reduced postoperative pain, and the extubation time and recovery time were not increased. PMID- 30013386 TI - Strong Circadian Rhythms in the Choroid Plexus: Implications for Sleep Independent Brain Metabolite Clearance. AB - Cerebrospinal fluid (CSF) is a fluidic part of the brain's microenvironment that isolates the brain from the rest of the body. CSF dilutes metabolites from neuronal activities and removes them from the brain. Its production and resorption are regulated dynamically and are central to maintaining brain homeostasis. We discovered that the major CSF source, the choroid plexus (CP), harbors the brain's strongest circadian clock. Here, we consider some implications of the CP circadian clock for metabolite clearance in the brain. If the circadian clock contributes to timed production of the CSF, its synchronization with sleep timing can maximize clearance efficiency and help prevent neurodegenerative diseases such as Alzheimer's disease. PMID- 30013387 TI - Homeostatic Regulation of Interneuron Apoptosis During Cortical Development. AB - The mammalian cortex consists of two main neuronal types: the principal excitatory pyramidal neurons (PNs) and the inhibitory interneurons (INs). The interplay between these two neuronal populations - which drive excitation and inhibition (E/I balance), respectively - is crucial for controlling the overall activity in the brain. A number of neurological and psychiatric disorders have been associated with changes in E/I balance. It is not surprising, therefore, that neural networks employ several different mechanisms to maintain their firing rates at a stable level, collectively referred as homeostatic forms of plasticity. Here, we share our views on how the size of IN populations may provide an early homeostatic checkpoint for controlling brain activity. In a recent paper published in Cell Reports, we demonstrate that the extent of IN apoptosis during a critical early postnatal period is plastic, cell type specific, and can be reduced in a cell-autonomous manner by acute increases in neuronal activity. We propose that a critical interplay between the physiological state of the network and its cellular units fine-tunes the size of IN populations with the aim of stabilizing network activity. PMID- 30013389 TI - Testing the Protein Propagation Hypothesis of Parkinson Disease. AB - One of the most exciting recent hypotheses in neurology is that most neurodegenerative diseases are caused by the neuron to neuron propagation of prion-like misfolded proteins. In Parkinson disease, the theory initially emerged from postmortem studies demonstrating a caudal-rostral progression of pathology from lower brainstem to neocortex. Later, animal studies showed that the hallmark protein of PD, alpha-synuclein, exhibited all the characteristics of a prion. Here, we describe our work using human neuroimaging to test the theory that PD pathology advances via a propagating process along the connectome. We found that the pattern and progression of brain atrophy follow neuronal connectivity, correlate with clinical features, and identify an epicenter in the brainstem. PMID- 30013388 TI - Regional Cerebrovascular Reactivity and Cognitive Performance in Healthy Aging. AB - Cerebrovascular reactivity (CVR) reflects the response of brain blood vessels to vasoactive stimuli, such as neural activity. The current research assessed age related changes in regional CVR to 5% CO2 inhalation in younger (n = 30, range: 21-45 years) and older (n = 29, range: 55-75 years) adults, and the contribution of regional CVR to cognitive performance using blood-oxygen-level dependent contrast imaging (BOLD) functional magnetic resonance imaging (fMRI) at 3T field strength. CVR was measured by inducing hypercapnia using a block-design paradigm under physiological monitoring. Memory and attention were assessed with a comprehensive computerized aging battery. MRI data analysis was conducted using MATLAB(r) and SPM12. Memory and attention performance was positively associated with CVR in the temporal cortices. Temporal lobe CVR influenced memory performance independently of age, gender, and education level. When analyzing age groups separately, CVR in the hippocampus contributed significantly to memory score in the older group and was also related to subjective memory complaints. No associations between CVR and cognition were observed in younger adults. Vascular responsiveness in the brain has consequences for cognition in cognitively healthy people. These findings may inform other areas of research concerned with vaso protective approaches for prevention or treatment of neurocognitive decline. PMID- 30013390 TI - CYP17 polymorphisms are associated with decreased risk of breast cancer in Chinese Han women: a case-control study. AB - Introduction: CYP17 is the second most important enzyme in estradiol synthesis. Epidemiological studies have shown the associations between CYP17 polymorphisms and cancer risk. We conducted a case-control study to evaluate the relationship between CYP17 polymorphisms (rs743572 and rs2486758) and breast cancer (BC) risk. Patients and methods: This case-control study included 560 BC patients and 583 age-matched healthy controls from Northwest China. Two polymorphisms (rs743572 and rs2486758) of CYP17 were genotyped by using Sequenom MassARRAY. ORs and 95% CIs were used to evaluate the relationship. Results: Compared with the wild genotype of rs743572, we found a significantly reduced risk of BC associated with the variant genotypes (heterozygote model: OR=0.69, 95% CI=0.53-0.89; homozygote model: OR=0.68, 95% CI=0.49-0.95; dominant model: OR=0.69, 95% CI=0.54-0.87; overdominant model: OR=0.78, 95% CI=0.62-0.98; allele model: OR=0.79, 95% CI=0.66 0.93). For rs2486758 polymorphism, we did not find any difference in any of the genetic models. Further stratification analysis by clinical characteristics showed rs743572 was associated with estrogen receptor status (heterozygote model: OR=2.13, 95% CI=1.47-3.08; homozygote model: OR=3.29, 95% CI=1.94-5.58; dominant model: OR=2.39, 95% CI=1.69-3.37) and progesterone receptor status (homozygote model: OR=3.17, 95% CI=1.82-5.55), but there was no association between rs2486758 and clinical characteristics of BC. Haplotype analysis showed that Grs743572Crs2486758 haplotype was a protective factor of BC (OR=0.52, 95% CI=0.40 0.67). Survival analysis did not find that CYP17 rs743572 polymorphism was associated with triple-negative BC, either in terms of overall survival or progression-free survival. Conclusion: Our results suggest that CYP17 polymorphisms may reduce the susceptibility to BC in Chinese women. PMID- 30013392 TI - Clinical usefulness of 18F-FDG PET/CT for the detection of distant metastases in patients with non-small cell lung cancer at initial staging: a meta-analysis. AB - Background: We undertook a meta-analysis to evaluate the clinical usefulness of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for the detection of distant metastases in patients with non-small cell lung cancer (NSCLC) at initial staging. Materials and methods: All topic-related studies were comprehensively searched in the MEDLINE and Embase databases. We obtained the summary estimates and constructed the summary receiver operating characteristic curve for 18F-FDG PET/CT using the bivariate regression model. Results: Across 10 studies (1333 patients), the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for 18F-FDG PET/CT were 0.81 (95% confidence interval [CI] = 0.63-0.92), 0.96 (95% CI = 0.94-0.98), 22.9 (95% CI = 13.3-39.5), and 0.20 (95% CI = 0.09-0.42), respectively. Overall weighted area under the curve was 0.97 (95% CI = 0.96-0.98). Conclusion: 18F-FDG PET/CT has a good diagnostic performance for distant metastasis staging in patients with NSCLC at initial staging. PMID- 30013393 TI - The effect of HIF-1alpha and PKM1 expression on acquisition of chemoresistance. AB - Background: In patients with gastric cancer, one of the greatest obstacles to effective chemotherapy is the development of chemoresistance. It has been previously reported that hypoxia-inducible factor-1 alpha (HIF-1alpha) is associated with acquisition of chemoresistance, and more recent studies have also noted an association of pyruvate kinase muscle 1 (PKM1) and chemoresistance. The purpose of this study was to identify the effect of HIF-1alpha and PKM1 expression on the development of acquired chemoresistance using a paclitaxel (PTX)-resistant gastric cancer cell line. Materials and methods: A cancer cell line resistant to PTX was established from MKN45 cells by stepwise exposure to drug (rMKN45-PTX). The expressions of HIF-1alpha, apoptosis, vascular endothelial growth factor (VEGF), multidrug transporters and glycolytic enzyme were examined by Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry. We also assessed the tumor proliferation by subcutaneous tumor and peritoneal dissemination of mouse xenograft model. Results: The resistance index was 6.1 by determining as the ratio of the 50% growth inhibition (IC50) of rMKN45-PTX/IC50 of MKN45. Expression of nuclear factor kappa B and HIF-1alpha was increased in rMKN45-PTX cells compared with the parent cells. Expression of Bax and caspase-3 was significantly downregulated, whereas expression of Bcl-xL, P-glycoprotein, multidrug resistance-associated protein and VEGF was increased in rMKN45-PTX. The expression level of PKM1 was upregulated in rMKN45-PTX, leading to an increase in the PKM1/PKM2 ratio. Using xenograft models, we demonstrated that mouse subcutaneous tumors derived from rMKN45-PTX were significantly larger than those derived from MKN45 cells. Conclusion: Under the stress of chemotherapeutic agent exposure, high expression of HIF-1alpha affects various downstream genes. Although the underlying mechanism is unknown, our data suggest that PKM1 is also a molecular target for gastric cancer treatment. PMID- 30013391 TI - Recent advances in antiemetics: new formulations of 5HT3-receptor antagonists. AB - Purpose: To discuss new therapeutic strategies for chemotherapy-induced nausea and vomiting (CINV) involving 5-hydroxytryptamine type 3 (5HT3)-receptor antagonists (RAs). Summary: CINV remains poorly controlled in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC); nausea and delayed-phase CINV (24-120 hours after chemotherapy) are the most difficult to control. National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) antiemesis-guideline recommendations for HEC include a four-drug regimen (5HT3 RA, neurokinin 1 [NK1] RA, dexamethasone, and olanzapine). For some MEC regimens, a three-drug regimen (5HT3 RA, NK1 RA, and dexamethasone) is recommended. While 5HT3 RAs have dramatically improved CINV in the acute phase (0-24 hours after chemotherapy), their efficacy declines in the delayed phase. Newer formulations have been developed to extend 5HT3-RA efficacy into the delayed phase. Granisetron extended-release subcutaneous (GERSC), the most recently approved 5HT3 RA, provides slow, controlled release of therapeutic granisetron concentrations for >=5 days. GERSC is included in the NCCN and ASCO guidelines for MEC and HEC, with NCCN-preferred status for MEC in the absence of an NK1 RA. Efficacy and safety of 5HT3 RAs in the context of guideline recommended antiemetic therapy are reviewed. Conclusion: Recent updates in antiemetic guidelines and the development of newer antiemet-ics should help mitigate CINV, this dreaded side effect of chemotherapy. GERSC, the most recently approved 5HT3-RA formulation, is indicated for use with other antiemetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of MEC and anthracycline-cyclophosphamide combination-chemotherapy regimens. PMID- 30013394 TI - Prognostic and predictive value of the macroscopic growth pattern in patients undergoing curative resection of colorectal cancer: a single-institution retrospective cohort study of 4,080 Chinese patients. AB - Purpose: The purpose of this study was to determine whether macroscopic growth patterns had an impact on the prognosis of colorectal cancer (CRC) patients with different tumor-node-metastasis (TNM) stages and responses to chemotherapy in stage III patients. Patients and methods: We retrospectively recruited 4,080 stage I-III CRC patients who underwent curative resection at Shandong Provincial Hospital affiliated to Shandong University. All patients were grouped by macroscopic growth patterns (expansive, infiltrative and ulcerative subtypes), and stage III patients were further divided into chemotherapy and nonchemotherapy groups. Kaplan-Meier methods, univariate and multivariate analyses and subset analyses were performed to assess the overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Results: Kaplan-Meier survival curves and univariate analyses revealed better OS (HR=0.731; 95% CI=0.584-0.916), CSS (HR=0.714; 95% CI=0.548-0.932) and DFS (HR=0.722; 95% CI=0.602-0.864) in the expansive subtype and worse OS (HR=2.121; 95% CI=1.457-3.088), CSS (HR=2.499; 95% CI=1.664-3.753) and DFS (HR=2.360; 95% CI=1.756-3.170) in the infiltrative subtype. Subset analyses based on the tumor-node-metastasis stage showed that the infiltrative subtype was associated with inferior DFS in stage II (HR=2.357; 95% CI=1.210-4.595) and stage III patients (HR=1.941; 95% CI=1.394-2.702) and inferior OS and CSS in stage III patients (HR=1.805; 95% CI=1.210-2.693 and HR=1.981, 95% CI=1.280-3.065, respectively). In addition, multivariate Cox proportional hazard regression models revealed similar results. Furthermore, in stage III patients, the OS, CSS and DFS in both the expansive and ulcerative subtypes were significantly extended after the administration of chemotherapy (all, P<0.001). However, the OS, CSS and DFS in the infiltrative subtype did not change significantly after the administration of chemotherapy (P=0.486, 0.290 and 0.731, respectively). Conclusion: The macroscopic growth pattern was an independent prognostic factor among stage I-III CRC patients. The infiltrative subtype had the worst prognosis in stage III patients and did not display survival benefits from chemotherapy. PMID- 30013396 TI - Safety and efficacy of denosumab in the treatment of pulmonary metastatic giant cell tumor of bone. AB - Background: Giant cell tumor (GCT) of bone is an intermittent and locally aggressive tumor with increasing pulmonary metastatic potential. In this study, we evaluated the interim clinical outcome of denosumab in patients with pulmonary metastatic GCT. Materials and methods: We retrospectively reviewed seven patients with pulmonary metastatic GCT who received denosumab treatment after local tumor surgery during January 2014 and July 2016. Denosumab treatment for all patients lasted for at least 12 months. Serial chest computerized tomography scan was used to monitor the drug response and RECIST 1.1 standard was used to evaluate the therapeutic efficacy. Results: All patients experienced chest pain relief in the first month of treatment. Three patients showed partial response. Four patients got stable disease after denosumab treatment. Adverse events included one patient with hypocalcemia and two patients with fever. No treatment-related deaths were reported. No patient with metastatic disease progression was found during an average of 28.6 months follow-up period. Conclusion: We presented a promising interim clinical outcome using denosumab to treat patients with pulmonary metastatic GCT. Denosumab might be considered as the first-line treatment for patients with inoperable metastatic pulmonary GCT. However, Phase II clinical study with larger number of patients and longer follow-up period is needed to detect the further efficacy and safety of this drug for lung metastatic GCT. PMID- 30013395 TI - Modern management for brain metastasis patients using stereotactic radiosurgery: literature review and the authors' gamma knife treatment experiences. AB - Historically, whole brain radiotherapy was administered to most patients with brain metastases. However, over the past three decades, stereotactic radiosurgery (SRS), targeted at individual cranial lesions, has been accepted widely. In this study, based on the authors' experiences along with published data, recent trends in SRS for brain metastases are discussed. This article focuses on the following issues: 1) How many tumors can or should be treated with SRS? 2) Two-/three staged SRS for relatively large tumors, 3) post- or preoperative SRS, and 4) repeat SRS. PMID- 30013397 TI - Benefit from the inclusion of surgery in the treatment of patients with stage III pancreatic cancer: a propensity-adjusted, population-based SEER analysis. AB - Purpose: In the past 20 years, surgical resection has been a secure and applicable procedure for pancreatic cancer (PC), but it remains controversial for stage III PC with data evaluating its efficacy mostly derived from small randomized trials. Hence, we designed this study to further evaluate its benefit using surveillance, epidemiology, and end results dataset. Patients and methods: Patients with stage III PC were identified in the surveillance, epidemiology, and end results registries from 2004 to 2014. The effect of surgery on cancer specific survival was assessed by risk-adjusted Cox proportional hazard regression modeling and propensity score matching. Results: Overall, 6,138 patients with stage III PC were included. Of these, 608 patients underwent primary tumor surgery. On multivariable analyses, surgery was independently associated with improved cancer-specific survival (HR=0.580; 95% CI=0.523-0.643, p<0.001). The survival benefit with surgery was also observed in the propensity score-matched cohort (HR=0.501; 95% CI=0.438-0.573, p<0.001). Conclusion: Primary tumor surgery is associated with improved survival in stage III PC. Prospective randomized trials are needed to confirm these results, and further efforts are required to address patient selection. PMID- 30013398 TI - Prognostic significance of Ki67 expression and the derived neutrophil-lymphocyte ratio in nasopharyngeal carcinoma. AB - Purpose: To investigate the association of pretreatment Ki67 expression and the derived neutrophil-lymphocyte ratio (dNLR) with clinical outcomes in nasopharyngeal carcinoma (NPC). Patients and methods: For the study, 46 patients diagnosed with NPC at our hospital were recruited between April 2013 and December 2015. All patients were histologically confirmed to have non-keratinizing undifferentiated NPC. The expression of Ki67 proteins in NPC tissue was analyzed immunohistochemically, and the dNLR was assessed in the peripheral blood, both before treatment. Stage I and II disease was treated with radiotherapy with or without concurrent chemotherapy, and stage III and IV disease was treated with cisplatin-based radiochemotherapy and neoadjuvant chemotherapy regimens. Results: Forty-five of the 46 patients met the criteria, and the median follow-up period was 41 months (15-56 months). The cutoff values for Ki67 and dNLR were 77.5% and 2.01%, respectively. The 3-year overall survival (OS) and progression-free survival rates in the high versus low Ki67 expression groups were 62.5% vs. 93.1% (P = 0.009) and 56.3% vs. 93.1% (P = 0.003), respectively. The 3-year OS rate of patients with high dNLR vs. low dNLR was 64.3% vs. 90.3% (P = 0.023). In the Cox risk ratio model, Ki67 expression and dNLR were independent prognostic factors for OS. Patients were then divided into three groups based on Ki67 expression and dNLR (high risk, both factors were high; intermediate risk, one factor was high; and low risk, neither factor was high). The 3-year OS rates were 20%, 85%, and 95% for the high, intermediate, and low risk groups, respectively (P < 0.001). Conclusion: Pretreatment Ki67 and dNLR levels can be used as independent prognostic markers in NPC, and elevated values are associated with poor prognosis. Concurrently, high Ki67 expression and dNLR predict a significantly adverse outcome. PMID- 30013399 TI - Recurrence risk after preoperative biopsy in patients with resected early-stage non-small-cell lung cancer: a retrospective study. AB - Background: Tumor cell dissemination after needle biopsy has been reported in a variety of malignancies, including non-small-cell lung cancer (NSCLC). However, there is little clinical evidence in regard to whether preoperative biopsy increases the risk of recurrence in completely resected NSCLC. Patients and methods: A total of 322 patients diagnosed as pathological stage I NSCLC using intraoperative biopsy (IOB) (control group), preoperative percutaneous needle biopsy (PNB) or bronchoscopic biopsy were included in this study. Baseline characteristics were collected and compared. The disease-free survival (DFS) of patients was analyzed using Kaplan-Meier method. Subgroup analysis and Cox regression were performed to evaluate the effect of preoperative biopsy on recurrence risk with adjustment for potential confounders. Results: Among these patients, 202 (63%) underwent IOB, 66 (20%) underwent PNB, and 54 (17%) underwent bronchoscopic biopsy. DFS of patients who had preoperative PNB or bronchoscopic biopsy was similar to those who had IOB (P=0.514 and 0.869). Neither preoperative PNB nor transbronchial biopsy significantly affected recurrence incidence across all the relevant subgroups. Furthermore, multivariate analysis showed that preoperative biopsy was not associated with increased recurrence risk in NSCLC patients with adjustment for confounders, while squamous cell carcinoma and adjuvant chemotherapy were associated with prolonged DFS. Conclusion: Neither preoperative PNB nor bronchoscopic biopsy increased the recurrence risk in patients with resected stage I NSCLC, indicating that these procedures could be safely used for diagnosis of early-stage NSCLC. PMID- 30013401 TI - Knowledge on management of traumatic dental injuries among Saudi mothers. AB - Objective: This study investigated the knowledge of Saudi mothers regarding the management of traumatic dental injuries (TDIs) in children. Materials and methods: A cross-sectional study using structured questionnaires was employed for mothers chosen by stratified-cluster random sampling technique from primary health care centers in Riyadh, Saudi Arabia, over a period of 12 months (July 2016-June 2017). The questionnaire surveyed mothers' background and knowledge on management of tooth fracture and avulsion using photographs of TDI cases. Results: The sample consisted of 3,367 Saudi mothers. More than half of the mothers (55.3%) gave the correct response, which was to send the child with tooth fracture immediately to the dentist (p<0.01). The majority of mothers (41.6%) gave the correct response for the immediate mode of action, which was to save the avulsed tooth in storage medium and send the child to the dentist immediately (p<0.001). However, they prioritized the immediate management of TDIs, and most reported saline as a suitable storage medium (p<0.001). The mothers expressed a positive interest in further education. Conclusion: Educational programs and TDI protocols must be implemented to increase mothers' awareness and improve the prognosis of children with TDIs. PMID- 30013400 TI - Automated data-adaptive analytics for electronic healthcare data to study causal treatment effects. AB - Background: Decision makers in health care increasingly rely on nonrandomized database analyses to assess the effectiveness, safety, and value of medical products. Health care data scientists use data-adaptive approaches that automatically optimize confounding control to study causal treatment effects. This article summarizes relevant experiences and extensions. Methods: The literature was reviewed on the uses of high-dimensional propensity score (HDPS) and related approaches for health care database analyses, including methodological articles on their performance and improvement. Articles were grouped into applications, comparative performance studies, and statistical simulation experiments. Results: The HDPS algorithm has been referenced frequently with a variety of clinical applications and data sources from around the world. The appeal of HDPS for database research rests in 1) its superior performance in situations of unobserved confounding through proxy adjustment, 2) its predictable efficiency in extracting confounding information from a given data source, 3) its ability to automate estimation of causal treatment effects to the extent achievable in a given data source, and 4) its independence of data source and coding system. Extensions of the HDPS approach have focused on improving variable selection when exposure is sparse, using free text information and time-varying confounding adjustment. Conclusion: Semiautomated and optimized confounding adjustment in health care database analyses has proven successful across a wide range of settings. Machine-learning extensions further automate its use in estimating causal treatment effects across a range of data scenarios. PMID- 30013402 TI - Diagnostic discrepancy between bronchoalveolar lavage and transbronchial biopsy from bronchoscopies of HIV patients with pneumonia: toward an integral diagnosis. AB - Background: The key diagnostic method for the evaluation of lung diseases associated with HIV infection is bronchoscopy, with bronchoalveolar lavage (BAL) being the most commonly used sampling technique. Transbronchial biopsy (TBB) is often complementary. Setting: This is a retrospective cross-sectional study to determine the diagnostic usefulness of bronchoscopy with simultaneous samples obtained through BAL and TBB in HIV-infected patients with pneumonia at the National Institute of Respiratory Diseases Ismael Cosio Villegas. Methods: In this cross-sectional study (January 2014-December 2015), the diagnostic yield of bronchoscopic samples from all HIV-positive patients with pneumonia aged >18 years, from procedures performed in the Interventional Pulmonology Unit, was analyzed and recorded in its database. The diagnostic yield concordance between BAL and TBB samples was evaluated by kappa index calculation. Results: A total of 198 procedures on 189 HIV-infected patients with pneumonia were performed. A total of 167/189 (88.4%) patients were male, and the mean age was 34.7 years (SD +/-9.0). Overall, the diagnostic yield for either technique was 87.9% (174/198), but it was higher for TBB, its yield being 78.8% (156/198). In contrast, that of BAL was 62.1% (123/198) (P=0.001). The overall diagnostic yield concordance between TBB and BAL was insignificant (k=0.213, P<0.001). It improved for fungal infections, pneumocystosis, and tuberculosis (k=0.417, 0.583, and 0.462, respectively, all P<0.001). Conclusion: Our results show that the simultaneous obtainment of BAL and TBB samples is useful and complementary in the diagnosis of infections and malignancies in HIV-infected patients. Additionally, they are safe procedures in this group of patients. PMID- 30013403 TI - Clinical significance of anatomical urethral length on stress urinary incontinence women. AB - Objective: To evaluate the association between the length of the female urethra and urodynamic study (UDS) parameters in patients presenting with stress urinary incontinence (SUI). Patients and methods: We retrospectively enrolled 391 women who underwent a transobturator adjustable tape sling implantation for the management of SUI between April 2009 and March 2016. All patients underwent a physical examination and UDS. Filling cystometry data that were evaluated included the Valsalva leak point pressure, and the cough leak point pressure. The maximal urethral closure pressure, the functional urethral length (FUL), and the length of the continence zone (LCZ) were measured using the urethral profile obtained from the UDS. The anatomical urethral length (AUL) was measured intraoperatively using a Foley catheter. We calculated the LCZ/FUL ratio to determine the anatomical continence length for this study. Results: We noted that 299 patients completed the study. The mean AUL was 26.25+/-3.59 mm. The mean FUL and LCZ were 41.37+/-15.05 mm and 24.15+/-13.90 mm, respectively. The mean LCZ/FUL was 0.57+/-0.19. Using the Pearson correlation coefficient, we observed that the AUL showed a correlation with the FUL (0.168, P=0.034), the LCZ (0.212, P=0.007), the LCZ/FUL ratio (0.190, P=0.016), the Valsalva leak point pressure (0.223, P=0.005), the cough leak point pressure (0.215, P=0.006), and the maximal urethral closure pressure (0.178, P=0.043). Conclusion: Our results show that the AUL in women is associated with UDS parameters relating to SUI. PMID- 30013404 TI - Effects of blackberry (Morus nigra) fruit juice on levodopa-induced dyskinesia in a mice model of Parkinson's disease. AB - Background and objective: Levodopa-induced dyskinesia (LID) is a movement disorder that occurs due to levodopa consumption for a long period to attenuate Parkinsonism. Plants have been the basis for medical treatments in human history and still widely practiced. Blackberry (Morus nigra) is one of the fruits rich in anthocyanin. The present study examined the effect of blackberry fruit juice on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. Materials and methods: In this study, 42 male mice were used, which were divided into six groups equally: one control group and five groups receiving MPTP injection. After confirmation of Parkinsonism in MPTP groups, one group was preserved without treatment and four other groups were treated with levodopa (50 mg/kg ip). After the onset of LID (2 weeks), one group was kept without additional treatment and three other groups were treated with three different doses of blackberry fruit juice (5, 10, and 15 mL/kg) with levodopa orally for 7 days. Abnormal involuntary movement scale (AIMS) and cylinder behavioral test were carried out according to the schedule. The collected data were analyzed using the SPSS software with the significant level of P<0.05. Results: Parkinson's disease was confirmed with AIMS test on the fourth day after MPTP injection. The onset of LID was observed after 2 weeks of levodopa treatment using both behavioral tests. The result of administration of M. nigra fruit juice for 1 week showed that this addition is useful in hindering LID. These effects were more pronounced at doses 10 and 15 mL/kg with nearly the same results on attenuating AIMS. Low dose of the fruit juice does not seem to affect LID significantly. Conclusion: M. nigra fruit juice is effective to attenuate LID in an MPTP-induced Parkinson mice model. PMID- 30013407 TI - Treatment of rheumatoid arthritis in the USA: premature use of tumor necrosis factor inhibition and underutilization of concomitant methotrexate. AB - Purpose: The objective of this study was to assess the treatment for patients with rheumatoid arthritis (RA) in the USA. Patients and methods: This study entailed analysis of claims data for patients with RA who initiated treatment with oral methotrexate (MTX) or a biologic in 2009 (n=48,910) or 2012 (n=107,636) and had follow-up for 4 years (2009 cohort) or 2 years (2012 cohort). Results: A biologic was initiated before MTX for 27% of the 2009 cohort and 36% of the 2012 cohort. Concomitant use of MTX and a biologic declined from 74.1% (2009 cohort) to 45.4% (2012 cohort). Conclusion: MTX is underused in the treatment of RA in the USA. PMID- 30013406 TI - Pediatric rheumatology: addressing the transition to adult-orientated health care. AB - The transition from pediatric to adult health care is often a challenging process due to multiple interwoven complexities, especially for children with chronic medical conditions. Health care transition (HCT) is a process of moving from a pediatric to an adult model of health care with or without a transfer to a new clinician. This paper focuses on what is known about HCT for youth and young adults (Y/YA) with rheumatic diseases within a larger context of HCT recommendations. HCT barriers for youth, families, and providers and current evidence for a structured HCT processes are reviewed. Practical advice is offered on how to approach transition for Y/YA, what tools are available to assist in a successful transition process, and what are the areas of future research that are needed to improve the HCT evidence base. PMID- 30013405 TI - Management of refractory cirrhotic ascites: challenges and solutions. AB - Among the various risky complications of liver cirrhosis, refractory ascites is associated with poor survival of cirrhotics and persistently worsens their quality of life (QOL). Major clinical guidelines worldwide define refractory ascites as ascites that cannot be managed by medical therapy either because of a lack of response to maximum doses of diuretics or because patients develop complications related to diuretic therapy that preclude the use of an effective dose of diuretics. Due to the difficulty in receiving a liver transplantation (LT), the ultimate solution for refractory ascites, most cirrhotic patients have selected the palliative therapy such as repeated serial paracentesis, transjugular intrahepatic portosystemic shunt, or peritoneovenous shunt to improve their QOL. During the past several decades, new interventions and methodologies, such as indwelling peritoneal catheter, peritoneal-urinary drainage, and cell-free and concentrated ascites reinfusion therapy, have been introduced. In addition, new medical treatments with vasoconstrictors or vasopressin V2 receptor antagonists have been proposed. Both the benefits and risks of these old and new modalities have been extensively studied in relation to the pathophysiological changes in ascites formation. Although the best solution for refractory ascites is to eliminate hepatic failure either by LT or by causal treatment, the selection of the best palliative therapy for individual patients is of utmost importance, aiming at achieving the longest possible, comfortable life. This review briefly summarizes the changing landscape of variable treatment modalities for cirrhotic patients with refractory ascites, aiming at clarifying their possibilities and limitations. Evolving issues with regard to the impact of gut-derived systemic and local infection on the clinical course of cirrhotic patients have paved the way for the development of a new gut microbiome-based therapeutics. Thus, it should be further investigated whether the early therapeutic approach to gut dysbiosis provides a better solution for the management of cirrhotic ascites. PMID- 30013408 TI - Quality of life in coeliac disease: qualitative interviews to develop candidate items for the Coeliac Disease Assessment Questionnaire. AB - Background: Coeliac-specific measures have been criticized for not complying with current guidance on the development of patient-reported outcome measures (PROMs). The aim of this study was to develop a measure to assess health-related quality of life in adults with coeliac disease (CD), in accordance with current guidance for PROM development. Methods: In-depth qualitative interviews were conducted with adults with CD. A thematic analysis was undertaken to develop a coding framework. All interviews were analyzed according to this framework. Interviewing continued until data saturation was achieved. Candidate items were developed on the basis of the interview findings. Results: The analysis revealed 6 themes: 1) symptoms, 2) gluten-free diet, 3) emotional health, 4) impact on activities, 5) relationships, and 6) financial issues. Data saturation was reached after 8 interviews, but a total of 23 interviews were conducted to include a wide enough range of diverse participants. From the themes, 64 candidate items (9 for symptoms, 15 for emotional health, 16 for gluten-free diet, 7 for relationships, 12 for impact on activities, and 5 for financial issues) were developed to form the first draft of the Coeliac Disease Assessment Questionnaire (CDAQ). Conclusion: The 64 items reflect all the issues of importance to people with CD. Next, these items will be pretested and refined to lead to a shorter draft version of the CDAQ before it is administered in a survey to produce a final version with subscales. PMID- 30013409 TI - A novel method of proxy reporting questionnaire based measures of health-related quality of life of people with dementia in residential care: a psychometric evaluation. AB - Background: In research in residential care, health-related quality of life (HRQL) is usually measured using either observational methods or standardized questionnaires. DEMQOL-Proxy is a standardized questionnaire measuring HRQL of people with dementia and is usually reported by a family carer. However, not all residents have a family carer who visits often enough to act as a proxy. Objectives: We evaluated the psychometric performance of DEMQOL-Proxy when reported on behalf of people with dementia in residential care by a "trained proxy" (DEMQOL-Proxy-TP). Participants: We recruited a sample of 87 people with dementia living in care homes around the UK. Methods: We used modern psychometric methods (based on the Rasch model) to evaluate DEMQOL-Proxy-TP (on behalf of 85 residents) in a cross-sectional study. We evaluated scale-to-sample targeting, ordering of item thresholds, item fit to the model and differential item functioning (sex, age, type of dementia), local independence, unidimensionality and reliability on the full set of items (31 items) and also a smaller item set (26 items). Results: The smaller item set (DEMQOL-Proxy-TP-26) performed better than the original item set and was found to fit the model (p = 0.68). Nevertheless, 17 items were found to have disordered thresholds, and 24 pairs of items showed local dependency (residual correlations >0.3). There were also some areas where scale-to-sample targeting could be improved. Conclusion: After resolving the identified anomalies, DEMQOL-Proxy-TP can provide adequate measurement of HRQL of people with dementia living in residential care, particularly when no family carer is available. This can be interpreted at the group level but is not yet robust enough for use at the individual level. Future work will compare these results with the psychometric performance of DEMQOL-Proxy reported by family carers and DEMQOL self-reported by the residents. PMID- 30013410 TI - Patient Discomfort and Resident Confidence After Knee Intra-articular Injection Simulation Training: A Randomized Control Trial Study. AB - Teaching primary care providers how to perform musculoskeletal procedures has become increasingly important as more and more patients with orthopedic conditions present in primary care clinics. This study aims to evaluate whether targeted simulation model training in residency can increase residents' comfort level in performing intra-articular knee injections and decrease the pain of the procedure, as reported by patients injected. Residents were randomized into intervention and control groups. The comfort level of the residents as well as the pain levels from the procedures, as reported by patients, was recorded. The mean comfort level for the intervention group was 1.2, compared with that in the control group, which was 2.13; P value was .047. The mean pain level in the intervention group was 1.8, whereas in the control group was 3.63; P value was .156. Simulation training may boost residents' comfort level, but not necessarily decrease patient discomfort during intra-articular knee injections. PMID- 30013411 TI - Influence of HLA-B27 Subtypes on Ankylosing Spondylitis Phenotype: Comment on the Article by Akassou et al. PMID- 30013412 TI - Anterior Midline Glossotomy Approach for Large Schwannoma of the Tongue: Case Report. AB - Schwannoma corresponds to a benign neurogenic tumor, derived from neural crest cells. It accounts for approximately 5% of all benign soft tissue tumors. These are the most common cause of peripheral nerve neoplasms of the oral cavity and oropharynx representing 1%. Isolated or solitary neurofibromas of the oral cavity usually involve the tongue or the labial mucosa. They appear as soft, painless, slow-growing masses that are tender to depression or palpation. The case of a 40 year-old woman is studied because of the presence of painless swelling, slow, and progressive growth of the oral language. Complete removal of the lesion was performed and primary closure was performed. It had a satisfactory evolution, maintaining adequate sensory and sensory mobility and innervation. PMID- 30013413 TI - Should Symptoms Be Considered an Indication for Parathyroidectomy in Primary Hyperparathyroidism? AB - Asymptomatic primary hyperparathyroidism is a very common endocrine condition, yet management of this disease process remains controversial. Primary hyperparathyroidism can lead to a myriad of symptoms which not only decreases the quality of life of patients but also increases the risk of cardiovascular disease, osteoporosis, and kidney stones. Parathyroidectomy is the only known cure for the disease. This review explores the definition of asymptomatic primary hyperparathyroidism, the burden of disease, and the overwhelming benefits of parathyroidectomy. PMID- 30013414 TI - Combination of Empagliflozin and Metformin Therapy: A Consideration of its Place in Type 2 Diabetes Therapy. AB - Type 2 diabetes mellitus (T2DM) is characterized by multiple metabolic abnormalities and current approaches to treatment involve a stepwise approach, frequently involving the use of combination therapy. The addition of the sodium glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin, to metformin therapy has been shown to be effective and well tolerated in patients with T2DM and is 1 of the several recommended treatment options. The publication of the EMPA-REG OUTCOME study, which showed that empagliflozin is associated with cardiovascular (CV) and renal benefits, has resulted in changes in treatment guidelines for T2DM. Because many patients with T2DM will require treatment with more than 1 glucose-lowering agent, consideration of the role of empagliflozin in combination therapy is relevant. The clinical data reviewed show that the combination of empagliflozin/metformin offers the potential to improve glycemic control in T2DM and reduces body weight and blood pressure, vs each agent individually, with a manageable risk profile. This combination could be suitable for patients with T2DM who are inadequately controlled by metformin, in particular, for patients who would benefit from modest reductions in blood pressure and body weight or who have risk factors for CV disease or declining renal function. Empagliflozin/metformin is also available as a single-pill combination, which has the potential to provide a simplified treatment regimen and could lead to improved clinical outcomes compared with coadministration of individual tablets. PMID- 30013415 TI - Successful Endoscopic Treatment of Post-esophagectomy Refractory Reflux Using OverStitch: The First Clinical Case. AB - Aims: The reflux of duodeno-gastric contents into the remnant esophagus (gastric tube-esophageal reflux: GTER) is a significant issues in long-term esophageal cancer survivors after radical esophagectomy. We attempted endoscopic valve (funnel) creation for prevention for GTER using OverStitch endoscopic suturing system. Methods: The OverStitch was mounted onto a standard double-channel endoscope. Under general anesthesia, the funnel creation was attempted by placing semi-full thickness sutures on the gastric wall, at 3 cm distal to the primary esophago-gastric anastomosis. The postoperative outcomes were also evaluated. Results: In total, 4 sutures were needed and the operating time was 62 minutes without complication. The endoscopic and swallowing studies, as well as pH profile, were all improved postoperatively. The patient's quality of life was dramatically improved with complete disappearance of night-time reflux in spine position. Conclusions: Endoscopic antireflux funnel creation was feasible and safe. This procedure may become a useful treatment for patients with severe GTER after esophagectomy. PMID- 30013416 TI - An Evidence-Based Review of Statin Use in Patients With Nonalcoholic Fatty Liver Disease. AB - Background: Nonalcoholic fatty liver disease (NAFLD) is a common complication in patients with metabolic syndrome. The role of statin therapy specifically for the treatment of NAFLD remains unknown. The aim of this review is to discuss outcomes of recent articles analyzing statin therapy in patients with NAFLD. Findings: A total of 12 trials met the inclusion criteria. Statins were not found to increase the prevalence of NAFLD once confounding variables were considered. Statins were also found to be beneficial in treating dyslipidemia and improving liver function. Histological liver outcomes in patients with NAFLD were controversial. One trial found a reduction in the incidence of hepatocellular carcinoma associated with the use of statins. Conclusions: Overall, therapy with statins appears to be safe for use in patients with NAFLD. Several trials have validated the use of statins for the treatment of dyslipidemia; however, it remains unknown as to whether statins should be used to specifically treat NAFLD. PMID- 30013418 TI - Re: An evaluation of medical student-led podcasts: what are the lessons learnt? PMID- 30013417 TI - Unraveling of Central Nervous System Disease Mechanisms Using CRISPR Genome Manipulation. AB - The complex structure and highly variable gene expression profile of the brain makes it among the most challenging fields to study in both basic and translational biological research. Most of the brain diseases are multifactorial and despite the rapidly increasing genomic data, molecular pathways and causal links between genes and central nervous system (CNS) diseases are largely unknown. The advent of an easy and flexible CRISPR-Cas genome editing technology has rapidly revolutionized the field of functional genomics and opened unprecedented possibilities to dissect the mechanisms of CNS disease. CRISPR-Cas allows a plenitude of applications for both gene-focused and genome-wide approaches, ranging from original "gene scissors" making permanent modifications in the genome to the regulation of gene expression and epigenetics. CRISPR technology provides a unique opportunity to establish new cellular and animal models of CNS diseases and holds potential for breakthroughs in the CNS research and drug development. PMID- 30013420 TI - First healthy baby by anonymous oocyte donation in Japan. PMID- 30013419 TI - Asking what do residents value most: a recent overview of internal medicine residents' learning preferences. AB - Background: Little is known about the preferred learning experiences of today's internal medicine residents. We conducted a survey of the educational experiences in an internal medicine residency to determine the learning opportunities internal medicine residents value most and why. Methods: An online, anonymous survey of 182 internal medicine residents was performed, with each resident receiving a survey each day over nine days. Participants were asked to state their most valuable learning experience over the past day, describe why it was valuable, and rank it on a 5-point Likert-type scale. Resident free-text responses were coded and grouped into themes. The location of and participants in the experience were also examined. Results: The 182 residents completed a total of 303 surveys. Of the 303 surveys, 92% (N=277) of the responses noted their chosen learning experience was useful. An attending was involved in 50% (N=152) of experiences; the patient was noted as a participant in 8% (N=25) of experiences. Free-text responses were coded into five thematic groups descriptive of why residents found their learning experiences to be valuable: Repetition in Learning, Effective Pedagogy, Clinical Problem Solving as an Individual or Collaboratively, Opportunity for Active Engagement, and Bedside Learning. Conclusion: Our data provide a broader framework for designing and implementing future faculty development and resident curricula that emphasize interprofessional education and the patient as a key educational figure. PMID- 30013422 TI - Modulation of bone morphogenetic protein activity by melatonin in ovarian steroidogenesis. AB - Background: Melatonin regulates circadian and seasonal rhythms and the activities of hormones and cytokines that are expressed in various tissues, including the ovary, in which melatonin receptors are expressed. In the ovary, follicular growth occurs as a result of complex interactions between pituitary gonadotropins and autocrine and paracrine factors, including bone morphogenetic proteins (BMPs) that are expressed in the ovary. Methods: The effects of melatonin and BMPs on steroidogenesis were examined by using the primary cultures of rat granulosa cells. Main findings Results: It was shown that melatonin has antagonistic effects on BMP-6 actions in the granulosa cells, suggesting that melatonin is likely to contribute to balancing the biological activity of endogenous BMPs that maintain progesterone production and luteinization in the growing follicles. Similar interactions between melatonin and BMP-smad signaling also were shown in the mechanism of controlling ovarian steroidogenesis by other ligands. Conclusion: A new role of melatonin in the regulation of endocrine homeostasis in relation to BMP activity is introduced in this review. PMID- 30013421 TI - Decidualization of the human endometrium. AB - Background: Decidualization of the human endometrium, which involves a dramatic morphological and functional differentiation of human endometrial stromal cells (ESCs), is essential for the establishment of a successful pregnancy. Decidualization results from a complex interplay of transcription factors, morphogens, cytokines, cell cycle regulators, and signaling pathways. Methods: Based on a literature review, the regulation of, and the molecular mechanisms involved in, the decidualization of the endometrium are described. Main findings: Progesterone, together with proteins that are regulated by progesterone and/or cyclic adenosine monophosphate, including homeobox A10, forkhead box O1, signal transducers and activators of transcription, and heart and neural crest derivatives expressed transcript 2, forms a critical network for ESC decidualization and is a prerequisite to successful implantation. Decidualized ESCs contribute to the microenvironment at the feto-maternal interface and its direct or indirect influence on extracellular matrix remodeling, regulation of the local immune response, anti-oxidative stress, and angiogenesis (vascular maturation). Impairment of this process is associated with a variety of pregnancy disorders, including infertility, recurrent miscarriages, and uteroplacental disorders. Conclusion: A deeper understanding of the process of decidualization is expected to provide new insights into the fields of reproductive biology and reproductive medicine. PMID- 30013424 TI - Effectiveness of high-dose transvaginal progesterone supplementation for women who are undergoing a frozen-thawed embryo transfer. AB - Purpose: To evaluate the effectiveness of high-dose progesterone supplementation for women who are undergoing a frozen-thawed embryo transfer (FET). Methods: Among the 2010 FET cycles that were included in the present study, 1188 were 1200 mg/d of vaginal progesterone, while 822 were 900 mg/d. The dose of progesterone that was used was decided by the treatment period and additional progesterone supplementation was used when the serum progesterone levels were <9 ng/mL on luteal day 5. Results: The clinical pregnancy rate was higher in the 1200 mg group than in the 900 mg group. The mean serum progesterone level on luteal day 5 in the 1200 mg and 900 mg groups was 12.6 ng/mL and 13.4 ng/mL, respectively. The rate of additional progesterone supplementation was higher in the 1200 mg group. A logistic regression analysis identified a younger age (<=37 years) and the use of 1200 mg progesterone as independent predictive factors for the clinical pregnancy outcome. The analysis of the infant outcomes revealed no significant difference in the distribution of birth ages and weights. Conclusion: High-dose transvaginal progesterone of 1200 mg/d as luteal support contributed to good pregnancy outcomes. PMID- 30013425 TI - Morphologically poor blastocysts could affect the implantation rate of a morphologically good blastocyst during a double-blastocyst transfer for patients who have experienced repeated implantation failures. AB - Purpose: Increasing the number of transferred blastocysts sometimes is selected for patients with repeated implantation failure (RIF). To confirm this strategy, the pregnancy rates (PRs) were compared among the groups who had transferred either a single morphologically good blastocyst (MGB group), double blastocysts with both a MGB and a morphologically poor blastocyst (MGB + MPB group), or a double-BT with 2 MGBs (two-MGB group). Methods: This study was performed between April, 2009 and September, 2014, including 634 cycles for 354 patients with RIF. All the patients received cryopreserved blastocysts in either hormone replacement or natural ovulatory cycles. The included MGBs were at more than the Gardner grade 3BB stage. The PR and implantation rates (IRs) among the three groups were statistically evaluated by the chi-square test. Statistical significance was set at P < .01. Results: Although the PRs were similar in these three groups, the IR in the MGB + MPB group was significantly lower than that of the MGB group. The rate in the two-MGB group also was significantly lower than that of the MGB group. Conclusion: A double-BT with a MGB and a MPB does not increase the pregnancy rate, compared with a single-BT with a MGB among patients with RIF. PMID- 30013423 TI - Role of pituitary adenylate cyclase-activating polypeptide in modulating hypothalamic-pituitary system. AB - Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional peptide that is isolated and identified from the ovine hypothalamus, whose effects and mechanisms have been elucidated in numerous studies. The PACAP and its receptor are widely expressed, not only in the hypothalamus but also in peripheral organs. Methods: The studies on the role of PACAP in the hypothalamic-pituitary system, including those by the authors, were summarized. Results: In the pituitary gonadotrophs, PACAP increases the gonadotrophin alpha-, luteinizing hormonebeta-, and follicle-stimulating hormone beta-subunit expression and the expression of gonadotropin-releasing hormone (GnRH) receptor and its own receptor, PAC1R. Moreover, a low-frequency GnRH pulse increases the expression of PACAP and PAC1R more than a high-frequency GnRH pulse in the gonadotrophs. The PACAP stimulates prolactin synthesis and secretion and increases PAC1R in the lactotrophs. In the hypothalamus, PACAP increases the expression of the GnRH receptors, although it is unable to increase the expression of GnRH in the GnRH-producing neurons. Conclusion: The PACAP not only acts directly in each hormone-producing cell, it possibly might regulate hormone synthesis via the expression of its own receptors or those of other hormones. PMID- 30013426 TI - Prediction of pregnancy after frozen-thawed embryo transfer via in vivo intrauterine oxidation-reduction potential measurements: a pilot study. AB - Purpose: During the implantation period, the uterus goes through many complex, orchestrated changes, including alterations of the glycocalyx that are due to sialylation, sulfation, and fucosylation. A previous mouse study showed that the in vivo intrauterine oxidation-reduction potential (ORP) aided in determining the alterations in the uterine endometrium that are suitable for implantation and for evaluating prospective uterine receptivity, while the in vivo intrauterine pH did not. It was assessed if the in vivo intrauterine ORP could be a useful parameter to predict pregnancy in women. Methods: A prospective cohort study was conducted for patients who had received a frozen-thawed single embryo transfer in a programmed, hormonally controlled cycle. The in vivo intrauterine ORP was measured 3 times during the treatment cycle, at cycle days 9-10, 1 day before progesterone administration and immediately before the embryo transfer. Results: The amount of in vivo intrauterine ORP at 9-10 days after the start of menstrual bleeding was significantly lower in the pregnant group than in the non-pregnant group. A receiver-operator characteristic curve analysis of the intrauterine ORP as a predictor of non-conception showed an area under the curve of 0.80. Conclusion: The in vivo intrauterine ORP could be a useful parameter to predict pregnancy for the frozen-thawed embryo transfer treatment cycle. PMID- 30013427 TI - Effects of cyclophosphamide administration on the in vitro fertilization of mice. AB - Purpose: To evaluate the oocyte fertilization ability and embryo growth after cyclophosphamide (CPA) treatment in mice. Methods: Mice were treated with CPA at different doses (0-800 mg/kg body weight). The oocytes then were retrieved and evaluated for their in vitro fertilization efficiency. Results: The average number of metaphase II (MII) oocytes significantly decreased by >=400 mg/kg CPA administration. The fertilization rate also decreased in the group that was treated with >=400 mg/kg CPA. However, after fertilization, the embryos demonstrated normal growth ability. Two weeks after CPA administration, the number of mice from which the oocytes could be retrieved markedly decreased, but the fertilization rate and development of morphological features in the embryos were similar to those of the controls. One month after CPA administration, the number of mice from which the oocytes could be retrieved, fertilization rate, and development of the morphological features in the embryos were similar to those of the controls. Conclusion: The number of oocytes decreased as the CPA administration level increased; however, the oocytes' potential for fertilization and development to the blastocyst stage was not significantly affected. One month after CPA administration, the number of oocytes and the potential for development into blastocysts were recovered. PMID- 30013428 TI - Meiotic spindle size is a strong indicator of human oocyte quality. AB - Purpose: To investigate the relationship between the meiotic spindle size in human metaphase II oocytes and embryo developmental potential after intracytoplasmic sperm injection (ICSI). Methods: Analyzed were 1302 oocytes with a visible meiotic spindle from 281 patients aged under 40 years undergoing ICSI cycles. The meiotic spindle was imaged by using PolScope before ICSI. The oocytes were classified into three groups, according to spindle size: group A (<90 MUm2), group B (90-120 MUm2), and group C (>120 MUm2). Results: Overall, 389 (29.9%) oocytes were classified into group A, 662 (50.8%) into group B, and 251 (19.3%) into group C. The fertilization rate of the group B oocytes was significantly higher than for the A and C oocytes. The blastocyst formation rate in group B was significantly higher than in group A. In addition, the pregnancy rate in group B was significantly higher than in the other two groups. Conclusion: The oocytes with a spindle size of 90-120 MUm2 showed higher fertilization, blastocyst formation, and clinical pregnancy rates than those with larger or smaller spindles. The measurement of the meiotic spindle size thus has a positive predictive value for identifying human embryo developmental potential clinically. PMID- 30013429 TI - Relationship between the mode of conception and depressive symptoms during the first 6 months post-partum in Japan. AB - Purpose: To determine whether conventional treatment and assisted reproductive technology for infertility are associated with depressive symptoms and to identify the predictors of depressive symptoms during the first 6 months' post partum. Methods: A prospective cohort design was used, with the participants being recruited from 13 Japanese hospitals. Using self-report questionnaires, a total of 2709 women (response rate: 71.9%) provided longitudinal data at five time points: during their hospital stay and at 1, 2, 4, and 6 months' post partum. The depressive symptoms were measured by using the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS). A logistic regression analysis was used to examine the association between the mode of conception and depressive symptoms and to identify the predictors of the depressive symptoms. Results: There was no significant association between the mode of conception and the depressive symptoms at any time point. Six factors that were associated with the EPDS score were first-time childbirth, emergency cesarean delivery, infant feeding, financial burden, having a male infant, and dissatisfaction with social support. Conclusion: There was no significant relationship between the mode of conception and depressive symptoms. Nursing care should be based on individual assessments that focus on parity, the delivery method, infant feeding method, financial burden, the infant's sex, and social support, rather than on the mode of conception. PMID- 30013430 TI - Association of follicular fluid volume with membrane stretchability of human metaphase II oocytes following the gonadotropin-releasing hormone agonist protocol during intracytoplasmic sperm injection. AB - Purpose: The authors previously revealed the association of the follicular fluid (FF) volume with oolemma stretchability following the gonadotropin-releasing hormone (GnRH) antagonist protocol during intracytoplasmic sperm injection (ICSI). However, the impact of the GnRH agonist protocol on oolemma stretchability remains unclear. Methods: Data that were obtained from 74 ICSI cycles were reviewed retrospectively. Controlled ovarian stimulation was performed in accordance with the short GnRH agonist protocol. Each follicle was individually aspirated and assigned to one of six groups, according to the FF volume. The oolemma stretchability during ICSI was evaluated by using a mechanical stimulus for oolemma penetration; that is, oolemma penetration with or without aspiration (high vs low stretchability, respectively). Results: The incidence of low oolemma stretchability was significantly higher in the <1.0 mL group than that in the >=1.0 mL group. The normal fertilization rate was significantly lower in the <1.0 mL group than that in the 2.0-<3.0 mL group. The rate of blastocyst development was lower in the <1.0 mL group than that in the 3.0-<4.0 mL group. Conclusion: The FF volume potentially was associated with metaphase II oolemma stretchability, fertilization, and blastocyst development. PMID- 30013431 TI - Prediction of the in vitro developmental competence of early-cleavage-stage human embryos with time-lapse imaging and oxygen consumption rate measurement. AB - Purpose: To assess an embryo's ability to develop into a good-quality blastocyst during the early-cleavage stage using time-lapse imaging and the oxygen consumption rate. Methods: In total, 942 zygotes had their oxygen consumption rates measured. In total, 282 zygotes were assessed by using time-lapse imaging. In total, 121 zygotes were examined by using both their oxygen consumption rate and time-lapse imaging. Results: The embryos with moderate respiration rates of between 0.41 and 0.61 (*1014/mol s-1) on day 3 had a 22.1% chance of becoming good-quality blastocysts; those outside that range had a 14.3% chance. With the time-lapse system, when the first division was within 24 hours, 22.3% of the embryos grew to good blastocysts. After 24 hours, the rate dropped to 8.6%. The intervals between two consecutive cleavages were calculated and the duration of the second cell cycle was defined. When the time was between nine hours and 13 hours, there was a higher rate of good blastocysts. Regarding both criteria, when the embryos had progressed in the optimal range, a high percentage of them had become good blastocysts; it was 8.0% outside of that range. Conclusion: Individual embryos with the potential to develop into good-quality blastocysts could be selected at day 3 of culture using these systems. PMID- 30013432 TI - Analysis of endometrial microbiota by 16S ribosomal RNA gene sequencing among infertile patients: a single-center pilot study. AB - Purpose: The present study aimed to analyze the endometrial and vaginal microbiome among a Japanese infertile population by sequencing and the impact of the endometrial and vaginal environment on implantation. Methods: In total, 102 infertile (79 in vitro fertilization [IVF] and 23 non-IVF) patients and seven healthy volunteers were recruited from August to December, 2017. Endometrial fluid and vaginal discharge samples for sequencing were collected by using an intrauterine insemination catheter. The bacterial status of the endometrium and vagina were analyzed. Results: The Lactobacillus-dominated microbiota (>90% Lactobacillus spp.) in the endometrium vs vagina was 38% (30/79) vs 44.3% (44/79) in the IVF patients, 73.9% (17/23) vs 73.9% (17/23) in the non-IVF patients, and 85.7% (6/7) vs 85.7% (6/7) in the healthy volunteers. The percentage of endometrial Lactobacillus in the healthy volunteers was highly stable within the same menstrual cycle and even in the following cycle. The major taxonomies were Gardnerella, Streptococcus, Atopobium, Bifidobacterium, Sneathia, Prevotella, and Staphylococcus. Fifteen patients achieved pregnancy by a single vitrified-warmed blastocyst transfer during this study; the median percentage of Lactobacillus in the pregnant women was 96.45 +/- 33.61%. Conclusion: A considerable percentage of non-Lactobacillus-dominated (NLD) microbiota was found in the endometrium of Japanese infertile women. Increasing the endometrial level of the Lactobacilli to >90% might favor the implantation outcome of NLD infertile patients. PMID- 30013433 TI - Identifying a possible factor for the increased newborn size in singleton pregnancies after assisted reproductive technology using cryopreserved embryos, in comparison with fresh embryos. AB - Purpose: To determine whether the cycle regimens that are used for endometrial preparation are associated with the birthweight (BW) after assisted reproductive technology (ART) using frozen-thawed embryo transfer (FET). Methods: The BW of singletons who were born by ART using FET was compared retrospectively, according to whether a FET was conducted in a hormone replacement therapy cycle (HRT, n = 403) or an ovulatory cycle (OVL, n = 117). The BW after timed intercourse (NAT, n = 162) also was investigated. Results: There were no significant differences in the age of the mothers, percentage of primiparas, gestational periods, Body Mass Index, and sex ratio between the HRT and OVL cycles. The average BW from HRT was significantly greater than that of OVL. The BW from HRT was also greater, compared with NAT, while statistical significance was not achieved between OVL and NAT. The putative factors affecting the BW, such as ovarian stimulation protocols, endometrial thickness, and the stage and quality of embryos, could not explain the difference in the BW between the HRT and OVL cycles. Conclusion: An increased BW from ART using FET seems to be ascribable to conditions of the endometrium, but not cryopreservation procedures per se, which might provide a mechanistic framework for understanding heavier neonates who are born by FET. PMID- 30013434 TI - Pilot study of the optimal protocol of low dose step-up follicle stimulating hormone therapy for infertile women. AB - Purpose: To evaluate the optimized protocol of low dose follicle-stimulating hormone (FSH) therapy that has a starting dose of 50 IU/62.5 IU with a small increment dose (12.5 IU) for women with World Health Organization (WHO) II ovulatory disorder and unexplained infertility. Methods: Anovulatory women with WHO group II ovulatory disorder (ovulation induction [OI] patients, n = 29), and with an unexplained infertility (ovarian stimulation [OS] patients, n = 21) were enrolled. The protocol of low dose step-up FSH therapy was optimized for the starting dose as 50 IU (body mass index [BMI] < 20 group) and 62.5 IU (BMI >= 20 group) with the increment dose of 12.5 IU. Study outcomes were ovulation, monofollicular development and other variables. Results: In the OIpatients, the ovulation rate was 100% (BMI < 20 group) and 90.9% (BMI >= 20 group). Monofollicular development was 80.0% (BMI < 20) and 77.3% (BMI >= 20). The pregnancy rate was 60% (3/5 BMI < 20) and 18.2% (4/22 BMI >= 20). There was no multiple pregnancy. In the OSpatients, the ovulation rate was 100%. Monofollicular development was 85.7% (BMI < 20) and 76.6% (BMI >= 20). No pregnancy was achieved in the OSpatients. Conclusion: Optimized protocol of low dose FSH therapy setting a starting dose 50 IU/62.5 IU by BMI with an increment dose of 12.5 IU was safe and highly effective in WHO group II anovulatory patients. However, this protocol seemed uneffective for patients with unexplained infertility. PMID- 30013435 TI - Pregnancy outcomes of women who received conservative therapy for endometrial carcinoma or atypical endometrial hyperplasia. AB - Case: Approximately 3%-25% of cases of endometrial carcinoma (EC) or atypical endometrial hyperplasia (AH) occur in women aged <40 years and conservative treatment with high-dose medroxyprogesterone acetate (MPA) is administered to women who wish to preserve their fertility. Here is reported the pregnancy outcomes of patients with EC or AH who received MPA therapy at Tokushima University Hospital, Tokushima, Japan. The frequency of pregnancy and live births among the patients with EC or AH who received conservative treatment, followed by fertility treatment, were analyzed retrospectively. Outcome: Twelve patients underwent fertility examinations and received fertility treatment immediately after the completion of conservative treatment for EC or AH. One patient had the complication of severe diabetes and total embryo cryopreservation was performed before her diabetes was treated. Among the other 11 patients, 8 (72.7%) became pregnant at least once and 6 (54.5%) experienced at least 1 live birth. Three patients (25.0%) suffered disease recurrence during or after the infertility treatment and all of the recurrences occurred in the EC cohort. Conclusion: When patients with EC or AH wish to preserve their fertility, it is recommended that prompt and effective fertility treatment, including assisted reproductive technology, should be initiated just after conservative treatment because EC and AH exhibit relatively high recurrence rates among conservatively treated patients. PMID- 30013436 TI - Efficacy of Palonosetron-Dexamethasone Combination Versus Palonosetron Alone for Preventing Nausea and Vomiting Related to Opioid-Based Analgesia: A Prospective, Randomized, Double-blind Trial. AB - Background: The efficacy of dexamethasone plus palonosetron for postoperative nausea and vomiting (PONV) prophylaxis is not firmly established. This randomized, double-blind, controlled study evaluated whether the combination was superior to palonosetron alone in preventing PONV in patients receiving intravenous patient-controlled analgesia (IV-PCA) after upper extremity surgery. Methods: A total of 202 patients undergoing upper extremity surgery were randomly assigned to group P (palonosetron alone) or group PD (palonosetron plus dexamethasone). Group P patients received palonosetron 0.075 mg and normal saline 1.6 mL; group PD patients received palonosetron 0.075 mg and dexamethasone 8 mg. In both groups, palonosetron was added to the IV-PCA opioid infusion, which was continued for 48 h postoperatively. Incidence and severity of nausea, incidence of vomiting, rescue antiemetic requirements, pain intensity, and rescue analgesic requirements were evaluated for 72 h postoperatively. Quality of recovery was assessed using the quality of recovery-15 (QoR-15) questionnaire. Results: The incidence of PONV was significantly lower in group PD than in group P at 0-48 h postoperatively (61.5% vs 77.1%; p = 0.019). Severity of nausea at 0-6 h postoperatively was significantly less in group PD compared with group P (none/mild/moderate/severe: 49/22/15/10 vs. 36/16/25/19, p = 0.008). The incidence of vomiting and rescue antiemetic requirements were similar between groups. Pain intensity was significantly less in group PD than in group P at 0-48 h and 48-72 h postoperatively. Global QoR-15 was similar 24 h postoperatively between groups. Conclusions: Dexamethasone-palonosetron combination therapy reduced PONV incidence and postoperative pain in patients receiving opioid-based analgesia after upper extremity surgery. PMID- 30013437 TI - RANKL Reduces Body Weight and Food Intake via the Modulation of Hypothalamic NPY/CART Expression. AB - The receptor activator of nuclear factor-kappaB ligand (RANKL) modulates energy metabolism. However, how RANKL regulates energy homeostasis is still not clear. This study aims to investigate the central mechanisms by which central administration of RANKL inhibits food intake and causes weight loss in mice. We carried out a systematic and in-depth analysis of the neuronal pathways by which RANKL mediates catabolic effects. After intracerebroventricle (i.c.v.) injection of RANKL, the expression of neuropeptide Y (NPY) mRNA in the Arc was significantly decreased, while the CART mRNA expression dramatically increased in the Arc and DMH. However, the agouti-related protein (AgRP) and pro opiomelanocortin (POMC) mRNA had no significant changes compared with control groups. Together, the results suggest that central administration of RANKL reduces food intake and causes weight loss via modulating the hypothalamic NPY/CART pathways. PMID- 30013438 TI - Endothelial-cell inflammation and damage by reactive oxygen species are prevented by propofol via ABCA1-mediated cholesterol efflux. AB - Background: Cholesterol efflux efficiency, reactive oxygen species, and inflammation are closely related to cardiovascular diseases. Our aim was to investigate the effect of propofol on cholesterol-loaded rat aortic endothelial cells after high-density lipoprotein treatment in vitro. Methods and Results: The results showed that propofol promoted cholesterol efflux and ameliorated inflammation and reactive oxygen species overproduction according to the analysis of p65 nuclear translocation and a 2',7'-dichlorofluorescin diacetate assay, respectively. Conclusions: These results provide a possible explanation for the anti-inflammatory, antioxidant, and cholesterol efflux-promoting effects of propofol on rat aortic endothelial cells after incubation with high-density lipoprotein. PMID- 30013439 TI - Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis. AB - Silicosis is an incurable lung disease affecting millions of workers in hazardous occupations. It is caused by chronic exposure to the dust that contains free crystalline silica. Silica-induced lung damage occurs by several main mechanisms including cell death by apoptosis, fibrosis and production of cytokines. However, the signal pathways involved in these mechanisms are not fully characterized. In this study, the toll-like receptor 4 (TLR4)-related signal pathway was examined in silica-treated U937-differentiated macrophages. The expression level of TLR4 was measured by both quantitative PCR and Western blot. Confirmation of the involvement of MyD88/TIRAP and NFkappaB p65 cascade was performed by Western blot. The secretion of cytokines IL-1beta, IL-6, IL-10 and TNFalpha was measured by enzyme-linked immunosorbent assay. Our results showed that TLR4 and related MyD88/TIRAP pathway was associated with silica-exposure in U937-differentiated macrophages. Protein expression of TLR4, MyD88 and TIRAP was upregulated when the U937-differentiated macrophages were exposed to silica. However, the upregulation was attenuated when TLR4 inhibitor, TAK-242 was present. At different incubation times of silica exposure, it was found that NFkappaB p65 cascade was activated at 10-60 minutes. Release of cytokines IL-1beta, IL-6, IL-10 and TNFalpha was induced by silica exposure and the induction of IL-1beta, IL-6 and TNFalpha was suppressed by the addition of TAK-242. In conclusion, our study demonstrated that TLR4 and related MyD88/TIRAP pathway was involved in silica-induced inflammation in U937-differentiated macrophages. Downstream NFkappaB p65 cascade was activated within 1 hour when the U937-differentiated macrophages were exposed to silica. The better understanding of early stage of silica-induced inflammatory process may help to develop earlier diagnosis of silicosis. PMID- 30013440 TI - CDKN3 expression is an independent prognostic factor and associated with advanced tumor stage in nasopharyngeal carcinoma. AB - Background: Through data mining from the public transcriptome of NPC, cyclin dependent kinase inhibitor 3 (CDKN3) was identified as a significantly upregulated gene in NPC. CDKN3 functions as a key factor in cell cycle regulation. This study was aimed to investigate the expression of CDKN3 in NPC tissues and its prognostic significance. Methods: Immunohistochemistry was performed for 124 NPC patients to assess the protein expression of CDKN3. The stainings of CDKN3 were scored by using H-score method. The relationships between CDKN3 expression status and clinicopathological parameters, disease-specific survival (DSS), distant metastasis-free survival (DMeFS), and local recurrence free survival (LRFS) were statistically analyzed. Results: High expression of CDKN3 was significantly associated with higher primary nodal status (P=0.030) and higher TNM stage (P=0.019). In univariate analysis, high expression of CDKN3 predicted worse DSS (P<0.0001), DMeFS (P<0.0001), and LRFS (P<0.0001). In multivariate analysis, CDKN3 overexpression still acted as an independent prognostic factor for worse DSS (P<0.001; hazard ratio [HR]=11.999, 95% CI: 5.378 26.771), DMeFS (P<0.001; HR=15.069, 95% CI: 5.884-38.592), and LRFS (P<0.001; HR=5.000, 95% CI: 2.312-10.815). Conclusion: High expression of CDKN3 was an independent negative prognostic factor for NPC and was associated with advanced disease status. It might serve as potential therapeutic target and aid in risk stratification for patients with NPC. PMID- 30013441 TI - AKAP11 gene polymorphism is associated with bone mass measured by quantitative ultrasound in young adults. AB - Background: Due to the increased prevalence of osteoporosis and direct health care cost of osteoporosis-related fractures, there is a growing interest in identifying genetic markers associated with osteoporosis phenotypes in order to develop genetic screening strategies. We aimed to analyze the possible associations between calcaneal Quantitative ultrasound (QUS), a valuable screening tool for assessing bone status in clinical practice, and ZBTB40 (rs7524102, rs6426749), SP7 (rs2016266) and AKAP11 (rs9533090) genes. Methods: A cross-sectional study was conducted on 550 healthy individuals of Caucasian ancestry (381 females and 169 males, median age 20.46+/-2,69). Bone mass was assessed through QUS to determine broadband ultrasound attenuation (BUA, dB/MHz). Single-nucleotide polymorphisms (SNPs) in ZBTB40 (rs7524102, rs6426749), SP7 (rs2016266) and AKAP11 (rs9533090) were selected as genetic markers and genotyped using TaqMan OpenArray(r) technology. Results: Linear regression analysis revealed that rs7524102 and rs6426749 in ZBTB40, and rs9533090 in AKAP11 were significantly associated with the calcaneal QUS parameter after adjustments for age, sex, weight, height, physical activity, and calcium intake (p=0.038, p=0.012 and p=0.008, respectively). After applying the Bonferroni correction for multiple testing (p=0.012), only the association of rs9533090 in AKAP11 remained significant. Conclusion:AKAP11 gene (rs9533090) influences QUS trait in a population of Caucasian young adults. The rs9533090 SNP may be considered a factor affecting peak bone mass acquisition. PMID- 30013442 TI - Relationship of genetic variant distributions of WW domain-containing oxidoreductase gene with uterine cervical cancer. AB - To our knowledge, no study investigates the association of genetic variant distributions of WW domain-containing oxidoreductase (WWOX) gene with development of invasive cancer, clinicopathologic variables and patient survival in uterine cervical cancer for Taiwanese women. We therefore conducted this study to explore the clinical involvements of WWOX single nucleotide polymorphisms (SNPs) in cervical cancer. One hundred and thirty-one patients with cervical invasive cancer and 93 patients with precancerous lesions as well as 316 control women were consecutively enrolled. The genotypic frequencies of WWOX genetic variants rs73569323, rs383362, rs11545028, rs3764340 and rs12918952 were determined by real-time polymerase chain reaction. The results revealed that only WWOX SNP rs3764340 was associated between patients with cervical invasive cancer and normal controls among 5 WWOX genetic variants. Cervical cancer patients with genotypes GA/AA in WWOX SNP rs12918952 were associated with parametrium invasion and pelvic lymph node metastasis. Univariate analysis found that WWOX SNPs rs73569323 and rs11545028 were associated with patient survival, whereas multivariate analysis revealed CT/TT in rs11545028 was the only genetic variant, which could predict better overall survival, among 5 WWOX SNPs in Taiwan. In conclusion, Taiwanese women with CG/GG in WWOX SNP rs3764340 are susceptible to cervical invasive cancer. Cervical cancer patients with GA/AA in rs12918952 tend to have more risk to develop parametrium invasion and pelvic lymph node metastasis. Among 5 WWOX SNPs, rs11545028 is the only genetic variant associated with patient survival, in which CT/TT could predict better overall survival in Taiwanese women. PMID- 30013443 TI - Trehalose inhibits H2O2-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation. AB - Autophagy is a catabolic process to maintain intracellular homeostasis via removal of cytoplasmic macromolecules and damaged cellular organelles through lysosome-mediated degradation. Trehalose is often regarded as an autophagy inducer, but we reported previously that it could prevent ischemic insults induced autophagic death in neurons. Thus, we further investigated in this study whether trehalose could protect human dopaminergic SH-SY5Y cells against H2O2 induced lethal autophagy. We found pretreatment with trehalose not only prevented H2O2-induced death in SH-SY5Y cells, but also reversed H2O2-induced upregulation of LC3II, Beclin1 and ATG5 and downregulation of p62. Then, we proved that either autophagy inhibitor 3MA or genetic knockdown of ATG5 prevented H2O2-triggered death in SH-SY5Y cells. These indicated that trehalose could inhibit H2O2-induced autophagic death in SH-SY5Y cells. Further, we found that trehalose inhibited H2O2-induced AMPK activation and endoplasmic reticulum (ER) stress. Moreover, inhibition of AMPK activation with compound C or alleviation of ER stress with chemical chaperone 4-PBA obviously attenuated H2O2-induced changes in autophagy related proteins. Notably, we found that trehalose inhibited H2O2-induced increase of intracellular ROS and reduction in the activities of CAT and SOD. Consistently, our data revealed as well that mitigation of intracellular ROS levels with antioxidant NAC markedly attenuated H2O2-induced AMPK activation and ER stress. Therefore, we demonstrated in this study that trehalose prevented H2O2 induced autophagic death in SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation. PMID- 30013444 TI - The Combination Of Weak Expression Of PRDX4 And Very High MIB-1 Labelling Index Independently Predicts Shorter Disease-free Survival In Stage I Lung Adenocarcinoma. AB - Background: Oxidative stress plays pivotal roles in the progression of lung adenocarcinoma (LUAD) through cell signaling related closely to cancer growth. We previously reported that peroxiredoxin 4 (PRDX4), a secretory-type antioxidant enzyme, can protect against the development of various diseases, including potential malignancies. Since many patients with early-stage LUAD develop recurrence, even after curative complete resection, we investigated the association of the PRDX4 expression with the clinicopathological features and recurrence/prognosis using post-surgical samples of stage I-LUAD. Methods: The expression of PRDX4 and MIB-1, a widely accepted Ki67 protein, was immunohistochemically analysed in 206 paraffin-embedded tumour specimens of patients with stage I-LUAD. The PRDX4 expression was considered to be weak when less than 25% of the adenocarcinoma cells showed positive staining. Results: A weak PRDX4+ expression demonstrated a significantly close relationship with pathologically poor differentiation, highly invasive characteristics and recurrence. The decrease in PRDX4-positivity potentially induced cell growth in LUAD, which was correlated significantly with a very high MIB-1 labelling index (>=17.3%). Univariate/multivariate analyses revealed that the subjects with both weak PRDX4+ expression and a very high MIB-1 index had significantly worse disease-free survival rates than other subjects. Conclusions: The combination of weak PRDX4 expression and a very high MIB-1 index can predict high proliferating activity and recurrence with a potential poor prognosis, especially in post operative stage I-LUAD patients. PMID- 30013445 TI - IGF1 Gene Is Associated With Triglyceride Levels In Subjects With Family History Of Hypertension From The SAPPHIRe And TWB Projects. AB - Chromosome 12q23-q24 has been linked to triglyceride (TG) levels by previous linkage studies, and it contains the Insulin-like growth factor 1 (IGF1) gene. We investigated the association between IGF1 and TG levels using two independent samples collected in Taiwan. First, based on 954 siblings in 397 families from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe), we found that rs978458 was associated with TG levels (beta = -0.049, p = 0.0043) under a recessive genetic model. Specifically, subjects carrying the homozygous genotype of the minor allele had lower TG levels, compared with other subjects. Then, a series of stratification analyses in a large sample of 13,193 unrelated subjects from the Taiwan biobank (TWB) project showed that this association appeared in subjects with a family history (FH) of hypertension (beta = -0.045, p = 0.0000034), but not in subjects without such an FH. A re examination of the SAPPHIRe sample confirmed that this association appeared in subjects with an FH of hypertension (beta = -0.068, p = 0.0025), but not in subjects without an FH. The successful replication in two independent samples indicated that IGF1 is associated with TG levels in subjects with an FH of hypertension in Taiwan. PMID- 30013446 TI - A Review on the Effects of Bisphenol A and Its Derivatives on Skeletal Health. AB - Bisphenol A (BPA) is an endocrine disruptor which can bind to the oestrogen receptor. It also possesses oestrogenic, antiandrogenic, inflammatory and oxidative properties. Since bone responds to changes in sex hormones, inflammatory and oxidative status, BPA exposure could influence bone health in humans. This review aimed to summarize the current evidence on the relationship between BPA and bone health derived from cellular, animal and human studies. Exposure to BPA (0.5-12.5 uM) decreased the proliferation of osteoblast and osteoclast precursor cells and induce their apoptosis. Bisphenol AF (10 nM) enhanced transforming growth factor beta signalling but bisphenol S (10 nM) inhibited Wnt signalling involved in osteoblast differentiation in vitro. In animals, BPA and its derivatives demonstrated distinct effects in different models. In prenatal/postnatal exposure, BPA increased femoral bone mineral content in male rats (at 25 ug/kg/day) but decreased femoral mechanical strength in female mice (at 10 ug/kg/day). In oestrogen deficiency models, BPA improved bone mineral density and microstructures in aromatase knockout mice (at very high dose, 0.1% or 1.0% w/w diet) but decreased trabecular density in ovariectomized rats (at 37 or 370 ug/kg/day). In contrast, bisphenol A diglycidyl ether (30 mg/kg/day i.p.) improved bone health in normal male and female rodents and decreased trabecular separation in ovariectomized rodents. Two cross-sectional studies have been performed to examine the relationship between BPA level and bone mineral density in humans but they yielded negligible association. As a conclusion, BPA and its derivatives could influence bone health and a possible gender effect was observed in animal studies. However, its effects in humans await verification from more comprehensive longitudinal studies in the future. PMID- 30013447 TI - Migration of mesenchymal stem cells to tumor xenograft models and in vitro drug delivery by doxorubicin. AB - Mesenchymal stem cells (MSCs) show therapeutic effects in various types of diseases. MSCs have been shown to migrate towards inflamed or cancerous tissues, and visualized after sacrificing the animal. MSCs are able to deliver drugs to target cells, and are an ideal candidate for cancer therapy. The purpose of this study was to track the migration of MSCs in tumor-bearing mice; MSCs were also used as drug delivery vehicles. Human breast cancer cells (MDA-MB-231) and anaplastic thyroid cancer cells (CAL62) were transduced with lentiviral particles, to express the Renilla luciferase and mCherry (mCherry-Rluc) reporter genes. Human bone marrow-derived MSCs were transduced with lentiviral particles, to express the firefly luciferase and enhanced green fluorescence protein (Fluc2 eGFP) reporter genes (MSC/Fluc). Luciferase activity of the transduced cells was measured by bioluminescence imaging (BLI). Further in vitro migration assays were performed to confirm cancer cells conditioned medium dependent MSC and doxorubicin (DOX) treated MSC migration. MSCs were loaded with DOX, and their therapeutic effects against the cancer cells were studied in vitro. In vivo MSC/Fluc migration in mice having thyroid or breast cancer xenografts was evaluated after systemic injection. Rluc activity of CAL62/Rluc (R2=0.911), MDA MB-231/Rluc (R2=0.934) cells and Fluc activity of MSC/Fluc (R2=0.91) cells increased with increasing cell numbers, as seen by BLI. eGFP expression of MSC/Fluc was confirmed by confocal microscopy. Similar migration potential was observed between MSC/Fluc and naive MSCs in migration assay. DOX treated MSCs migration was not decreased compared than MSCs. Migration of the systemically injected MSC/Fluc cells into tumor xenografts (thyroid and breast cancer) was visualized in animal models (p<0.05) and confirmed by ex vivo (p<0.05) BLI. Additionally, MSCs delivered DOX to CAL62/Rluc and MDA-MB-231/Rluc cells, thereby decreasing their Rluc activities. In this study, we confirmed the migration of MSCs to tumor sites in cancer xenograft models using both in vivo and ex vivo BLI imaging. DOX-pretreated MSCs showed enhanced cytotoxic effects. Therefore, this noninvasive reporter gene (Fluc2)-based BLI may be useful for visualizing in vivo tracking of MSCs, which can be used as a drug delivery vehicle for cancer therapy. PMID- 30013448 TI - Rac1 promotes the survival of H9c2 cells during serum deficiency targeting JNK/c JUN/Cyclin-D1 and AKT2/MCL1 pathways. AB - Rac1, known as a "molecular switch", plays a crucial role in plenty of cellular processes. Rac1 aggravates the damage of myocardial cells in the process of myocardial ischemia-reperfusion during myocardial infarction through activating the NADPH oxidase and bringing about the reactive oxygen species(ROS) generation. Myocardial ischemia and hypoxia are the basic pathogenesis of myocardial infarction and the underlying mechanisms are intricate and varied. Moreover, the regulatory effect of Rac1 on myocardial cells in the condition of serum starvation and the potential mechanisms are still incompletely undefined. Therefore, heart-derived H9c2 cells cultured in 0% serum were used to mimic ischemic myocardial cells and to clarify the role of Rac1 in H9c2 cells and the underlying mechanisms during serum deficiency. After Rac1 was knocked down using specific siRNA, cell apoptosis was assessed by flow cytometry assay and cell proliferation was detected by CCK-8 assay and EdU assay. In addition, the expression and activation of protein in related signaling pathway were detected by Western blot and siRNAs was used to testify the signaling pathways. Our results indicated that Rac1 inhibited apoptosis, promoted proliferation and cell cycle progression of H9c2 cells during serum deficiency. We concluded that Rac1 inhibited apoptosis in an AKT2/MCL1 dependent way and promoted cell proliferation through JNK/c-JUN/Cyclin-D1. PMID- 30013449 TI - Clinical and Basic Evaluation of the Prognostic Value of Uric Acid in Traumatic Brain Injury. AB - Background: As a major antioxidant in serum, uric acid (UA) was once considered only as the leading cause of gout; however, recent studies have validated its neuroprotective role in ischemic stroke. Because the potential protective effects of UA in traumatic brain injury (TBI) remain largely unknown, this study investigated the role of UA in TBI in both clinical patients and experimental animals. Methods: In TBI patients, serum UA concentrations were measured within 3 days after injury. Clinical outcomes at discharge were classified according to the Glasgow Outcome Scale: good outcome (4-5) and poor outcome (1-3). Risk factors for good outcome were identified via backward logistic regression analysis. For the animal study, a controlled cortical impact (CCI) injury model was established in mice. These mice were given UA at different doses intraperitoneally, and subsequent UA concentrations in mouse serum and brain tissue were determined. Neurological function, oxidative stress, inflammatory response, neuronal maintenance, cerebral blood flow, and lesion size were also assessed. Results: The serum UA level was significantly lower in TBI patients who had a good outcome (P<0.01), and low serum UA was an independent predictor of good outcome after TBI (P<0.01; odds ratio, 0.023; 95% confidence interval, 0.006 0.082). Consistently, decreased levels of serum UA were observed in both TBI patients and CCI animals (P<0.05), whereas the UA concentration was increased in CCI brain tissue (P<0.05). Administration of UA further increased the UA level in brain tissue as compared to that in control animals (P<0.05). Among the different doses administered, 16 mg/kg UA improved sensorimotor functional recovery, spatial learning, and memory in CCI mice (P<0.05). Moreover, oxidative stress and the inflammatory response were inhibited by UA treatment (P<0.05). UA treatment also improved neuronal maintenance and cortical blood flow (P<0.05) but not lesion size (P>0.05). Conclusions: UA acted to attenuate neuronal loss, cerebral perfusion impairment and neurological deficits in TBI mice through suppression of neuronal and vascular oxidative stress. Following TBI, active antioxidant defense in the brain may result in consumption of UA in the serum, and thus, a decreased serum UA level could be predictive of good clinical recovery. PMID- 30013450 TI - Melatonin alleviates oxidative stress-inhibited osteogenesis of human bone marrow derived mesenchymal stem cells through AMPK activation. AB - Oxidative stress plays an important role in the pathogenesis of aging-related osteoporosis through the increased bone resorption or reduced bone formation. Melatonin, which can exert beneficial actions through antioxidant, anti inflammatory, and bone-preserving effects, shows promise in preventing oxidative stress-inhibited osteogenesis. However, specific mechanisms by which melatonin rescues oxidative stress-inhibited osteogenesis of human mesenchymal stem cells (MSCs) have not been fully elucidated yet. We therefore investigated whether activation of AMPK by melatonin regulates the antagonistic crosstalk between oxidative stress and osteogenic differentiation in human MSCs. Melatonin treatment significantly enhanced osteogenic differentiation of human MSCs through activation of AMPK and upregulation of FOXO3a and RUNX2 which were known as master transcription factors responsible for the mechanistic link between oxidative stress and osteogenic phenotype. Osteogenic differentiation determined by calcium deposition was significantly increased by melatonin treatment against oxidative stress. In addition, melatonin treatment reconstituted activation of AMPK and expression of FOXO3a and RUNX2 inhibited by oxidative stress. Overall, these results demonstrate that melatonin enhances osteogenic differentiation of human MSCs and restores oxidative stress-inhibited osteogenesis through AMPK activation in human MSCs, suggesting that activation of AMPK by melatonin may represent a promising new therapeutic strategy for treating metabolic bone diseases such as osteoporosis. PMID- 30013451 TI - A Snake Venom-Secreted Phospholipase A2 Induces Foam Cell Formation Depending on the Activation of Factors Involved in Lipid Homeostasis. AB - MT-III, a snake venom GIIA sPLA2, which shares structural and functional features with mammalian GIIA sPLA2s, activates macrophage defense functions including lipid droplet (LDs) formation, organelle involved in both lipid metabolism and inflammatory processes. Macrophages (MPhis) loaded with LDs, termed foam cells, characterize early blood vessel fatty-streak lesions during atherosclerosis. However, the factors involved in foam cell formation induced by a GIIA sPLA2 are still unknown. Here, we investigated the participation of lipid homeostasis related factors in LD formation induced by MT-III in macrophages. We found that MT-III activated PPAR-gamma and PPAR-beta/delta and increased the protein levels of both transcription factors and CD36 in macrophages. Pharmacological interventions evidenced that PPAR-gamma, PPAR-beta/delta, and CD36 as well as the endoplasmic reticulum enzymes ACAT and DGAT are essential for LD formation. Moreover, PPAR-beta/delta, but not PPAR-gamma, is involved in MT-III-induced PLIN2 protein expression, and both PPAR-beta/delta and PPAR-gamma upregulated CD36 protein expression, which contributes to MT-III-induced COX-2 expression. Furthermore, production of 15-d-PGJ2, an activator of PPARs, induced by MT-III, was dependent on COX-1 being LDs an important platform for generation of this mediator. PMID- 30013452 TI - Cytokines Produced by Lymphocytes in the Incompetent Great Saphenous Vein. AB - The pathogenesis of chronic venous disease (CVD) remains unclear, but lately inflammation is suggested to have an important role in its development. This study is aimed at assessing cytokines released by lymphocytes in patients with great saphenous vein (GSV) incompetence. In 34 patients exhibiting oscillatory flow (reflux) in GSV, blood was derived from the cubital vein and from the incompetent sapheno-femoral junction. In 12 healthy controls, blood was derived from the cubital vein. Lymphocyte culture with and without stimulation by phytohemagglutinin (PHA) was performed. Interleukins (IL) 1beta, 2, 4, 10, 12 (p70), and 17A; interleukin 1 receptor alpha (IL-1ra); tumor necrosis factor alpha (TNF-alpha); interferon-gamma (IFN-gamma); and RANTES were assessed in culture supernatants by the Bio-Plex assay. In both stimulated and unstimulated samples, in the examined group, IL-1beta and IFN-gamma had higher concentrations and RANTES had lower concentrations when compared to those in the control group. In the examined group, IL-4 and IL-17A had higher concentrations without stimulation and TNF-alpha had higher concentrations with stimulation. The GSV samples had higher IL-2, IL-4, IL-12 (p70), and IFN-gamma concentrations without stimulation and lower IL-2 and TNF-alpha concentrations with stimulation when compared to those of the upper limb in the examined group. These observations indicate that the oscillatory flow present in incompetent veins causes changes in the cytokine production by lymphocytes, promoting a proinflammatory profile. However, the relations between immunological cells, cytokines, and the endothelium require more insight. PMID- 30013453 TI - Heme Oxygenase-1 Reduces Sepsis-Induced Endoplasmic Reticulum Stress and Acute Lung Injury. AB - Background: Sepsis leads to severe acute lung injury/acute respiratory distress syndrome (ALI/ARDS) that is associated with enhanced endoplasmic reticulum (ER) stress. Heme oxygenase-1 (HO-1), an ER-anchored protein, exerts antioxidant and protective functions under ALI. However, the role of HO-1 activation in the development of endoplasmic reticulum (ER) stress during sepsis remains unknown. Methods: Cecal ligation and puncture (CLP) model was created to induce septic ALI. Lung tissue ER stress was measured 18 hours after CLP. The effects of HO-1 on ER stress during septic ALI were investigated in vivo using HO-1 agonist hemin and antagonist ZnPP. Results: Compared with the sham group, ER stress in septic lung increased significantly 18 hours after CLP, which was significantly reduced by pretreatment with the ER inhibitor 4-phenylbutyrate (4-PBA). The lung injury score and the lung wet to dry (W/D) ratio in lungs were significantly reduced in septic rats after ER stress inhibition. Similarly, lung ER stress-related genes' (PERK, eIF2-alpha, ATF4, and CHOP) levels were attenuated after ER stress inhibition. Furthermore, HO-1 activation by hemin reduced p-PERK, p-eIF2-alpha, ATF4, and CHOP protein expression and oxidative stress and lung cell apoptosis. Additionally, HO-1 antagonist could aggregate the ER stress-related ALI. Conclusions: ER stress was activated during CLP-induced ALI, which may represent a mechanism by which CLP induces ALI. HO-1 activation could inhibit CLP-induced lung ER stress and attenuate CLP-induced ALI. PMID- 30013454 TI - The anticancer effects of ferulic acid is associated with induction of cell cycle arrest and autophagy in cervical cancer cells. AB - Background: Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) is a hydroxycinnamic acid derived from a rich polyphenolic compound. This study aimed to investigate the effect of ferulic acid (4-hydroxy-3-methoxycinnamic acid; FA) on cell proliferation, invasion, apoptosis, and autophagy in Hela and Caski cervical carcinoma cell lines. Methods: The cell proliferation of FA in Hela and Caski cells were detected by MTT assay. The cell invasion of FA in Hela and Caski cells were detected by Transwell assay. Subsequently, MMP-9 mRNA expression for cell invasion was detected by RT-PCR. Additionally, cell cycle and apoptosis were assayed using flow cytometry. Expression levels of 7 proteins for both cell cycle and autophagy were measured by Western blot analysis. Results: After treated with FA (2.0 mM) for 48 h, the inhibition rates of FA in Hela and Caski cells were 88.3 and 85.4%, respectively. In addition, FA inhibited cell invasion through reducing MMP-9 mRNA expression. FA induced arrest in G0/G1 phase of the cell cycle in Hela and Caski cells with dose dependent (P < 0.05). Meanwhile, FA induced the cell cycle-related proteins expression such as p53 and p21, and reduced Cyclin D1 and Cyclin E levels. Moreover, FA decreased the autophagy related proteins such as LC3-II, Beclin1 and Atg12-Atg5 in a dose-dependent manner. Conclusion: FA can significantly inhibit cell proliferation and invasion in Hela and Caski cells. It might be acted as an anti-cancer drug through inhibiting the autophagy and inducing cell cycle arrest in human cervical carcinoma cells. PMID- 30013455 TI - Dose-Response Effect of Antibodies to S100 Protein and Cannabinoid Receptor Type 1 in Released-Active Form in the Light-Dark Test in Mice. AB - Earlier studies have shown that combination of antibodies to S100 protein and to cannabinoid receptor type 1 in released-active form (Brizantin) may possess anxiolytic properties and decrease nicotine dependence. Released-active form of antibodies is a novel approach that permits to modify natural functions of the target molecule (antigen) under investigation. The aim of the present study was to evaluate the anxiolytic-like effect of Brizantin in the light-dark test in mice, according to its ability to influence the number of entries into the lit compartment and the total time spent there. Three doses of Brizantin (2.5, 5, and 10 mL/kg) were compared with diazepam (1 mg/kg), placebo, and vehicle control. Anxiolytic-like effect of the tested drug was shown to be dose dependent, with an increasing trend from 2.5 to 10 mL/kg. Brizantin in its highest dose significantly increased studied behavioral parameters, although its effect was less pronounced than that of the reference drug diazepam (1 mg/kg). PMID- 30013456 TI - Radiophobia: 7 Reasons Why Radiography Used in Spine and Posture Rehabilitation Should Not Be Feared or Avoided. AB - Evidence-based contemporary spinal rehabilitation often requires radiography. Use of radiography (X-rays or computed tomography scans) should not be feared, avoided, or have their exposures lessened to decrease patient dose possibly jeopardizing image quality. This is because all fears of radiation exposures from medical diagnostic imaging are based on complete fabrication of health risks based on an outdated, invalid linear model that has simply been propagated for decades. We present 7 main arguments for continued use of radiography for routine use in spinal rehabilitation: (1) the linear no-threshold model for radiation risk estimates is invalid for low-dose exposures; (2) low-dose radiation enhances health via the body's adaptive response mechanisms (ie, radiation hormesis); (3) an X-ray with low-dose radiation only induces 1 one-millionth the amount of cellular damage as compared to breathing air for a day; (4) radiography is below inescapable natural annual background radiation levels; (5) radiophobia stems from unwarranted fears and false beliefs; (6) radiography use leads to better patient outcomes; (7) the risk to benefit ratio is always beneficial for routine radiography. Radiography is a safe imaging method for routine use in patient assessment, screening, diagnosis, and biomechanical analysis and for monitoring treatment progress in daily clinical practice. PMID- 30013458 TI - Recovery From Rheumatoid Arthritis Following 15 Months of Therapy With Low Doses of Ionizing Radiation: A Case Report. AB - Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that occurs commonly in old people. Hot spring radon therapy is widely practiced in Central Europe and Japan for relief from the painful symptoms. The usual duration of a spa treatment is a week or two, and the relief is temporary. This article reports on the near-complete recovery of a patient who had been suffering from RA for 10 years. The patient received 15 months of low-dose radon and gamma-radiation therapy in a room that reproduced the conditions of a radon spa. The daily 40 minute exposure in the therapy room was supplemented by ten 6-minute radio nebulizer treatments. The inflammation markers C-reactive protein and matrix metalloproteinase 3 declined strongly to the normal level of 0.07 mg/dL and the near-normal level of 48.9 ng/mL, respectively. After the patient's return to good health, the frequency of the visits was reduced to twice each month. The patient's protection systems appear to have adapted to stimulated conditions, sufficiently to sustain the recovery from RA. Such a long-term course of treatments and follow-up maintenance could be carried out in any hospital that has these low-dose radiation therapy rooms. The therapy could be scheduled to suit patient availability. PMID- 30013457 TI - It Is Time to Move Beyond the Linear No-Threshold Theory for Low-Dose Radiation Protection. AB - The US Environmental Protection Agency (USEPA) is the primary federal agency responsible for promulgating regulations and policies to protect people and the environment from ionizing radiation. Currently, the USEPA uses the linear no threshold (LNT) model to estimate cancer risks and determine cleanup levels in radiologically contaminated environments. The LNT model implies that there is no safe dose of ionizing radiation; however, adverse effects from low dose, low-dose rate (LDDR) exposures are not detectable. This article (1) provides the scientific basis for discontinuing use of the LNT model in LDDR radiation environments, (2) shows that there is no scientific consensus for using the LNT model, (3) identifies USEPA reliance on outdated scientific information, and (4) identifies regulatory reliance on incomplete evaluations of recent data contradicting the LNT. It is the time to reconsider the use of the LNT model in LDDR radiation environments. Incorporating the latest science into the regulatory process for risk assessment will (1) ensure science remains the foundation for decision making, (2) reduce unnecessary burdens of costly cleanups, (3) educate the public on the real effects of LDDR radiation exposures, and (4) harmonize government policies with the rest of the radiation scientific community. PMID- 30013461 TI - Neuromorphic Event-Based Generalized Time-Based Stereovision. AB - 3D reconstruction from multiple viewpoints is an important problem in machine vision that allows recovering tridimensional structures from multiple two dimensional views of a given scene. Reconstructions from multiple views are conventionally achieved through a process of pixel luminance-based matching between different views. Unlike conventional machine vision methods that solve matching ambiguities by operating only on spatial constraints and luminance, this paper introduces a fully time-based solution to stereovision using the high temporal resolution of neuromorphic asynchronous event-based cameras. These cameras output dynamic visual information in the form of what is known as "change events" that encode the time, the location and the sign of the luminance changes. A more advanced event-based camera, the Asynchronous Time-based Image Sensor (ATIS), in addition of change events, encodes absolute luminance as time differences. The stereovision problem can then be formulated solely in the time domain as a problem of events coincidences detection problem. This work is improving existing event-based stereovision techniques by adding luminance information that increases the matching reliability. It also introduces a formulation that does not require to build local frames (though it is still possible) from the luminances which can be costly to implement. Finally, this work also introduces a methodology for time based stereovision in the context of binocular and trinocular configurations using time based event matching criterion combining for the first time all together: space, time, luminance, and motion. PMID- 30013460 TI - Metabolomic analysis of serum from rats following long-term intake of Chinese sausage. AB - Introduction: Owing to the contamination of chemical pollutants, especially nitrosamines and their precursors, in Chinese sausage, long-term intake of Chinese sausage may have potential health effects. Objection: This study investigated the effects of long-term intake of Chinese sausage with different contaminations of N-nitrosodimethylamine (NDMA) on rat liver and the potential biomarkers in the serum. Methods: Serum metabolomic analysis was performed by gas chromatography-mass spectrometry at weeks 7, 17, 25, and 33; simultaneously, liver histopathological examination was conducted and its relationship with the serum metabolomics was also investigated. Results: In the study, long-term intake of Chinese sausage with different NDMA contents induced significant changes in serum metabolites and liver histopathology in rats. Metabonomic analysis showed that seven metabolites - beta-alanine, 3-aminoisobutyric acid, aminooxyacetic acid, D-alanyl-D-alanine, pelargonic acid, palmitic acid (PA), and linoleic acid (LA) - in three sausage diet groups were significantly decreased at four time points, where three other metabolites were notably increased, which included putrescine, ethanolamine phosphate, and taurine. Among the various treatments, the NDMA (sausage-free) group demonstrated the most remarkable changes. Phenylalanine was decreased followed by an increase, and tyrosine persistently declined, both of which were elevated in the NDMA group. In addition, the histopathological result was consistent with that of the serum metabolomic analysis, and the changes in serum metabolites in each sausage diet group and the NDMA group were consistently associated with disorders of lipids, amino acid, and energy metabolism. Conclusion: This work indicates that excessive NDMA content in sausage may cause liver damage. PMID- 30013459 TI - Protective Effects of Methanol Extract of Vernonia amygdalina (del.) Leaf on Aspirin-Induced Gastric Ulceration and Oxidative Mucosal Damage in a Rat Model of Gastric Injury. AB - This study investigated the quantitative polyphenolic constituents and gastroprotective effects of methanol extract of Vernonia amygdalina leaf (MEVA) against aspirin-induced gastric ulcer in rats. Ulceration was induced by 3 days' oral administration of aspirin (150 mg/kg body weight). Wistar rats were pretreated with cimetidine (reference drug) at a dose of 100 mg/kg body weight and MEVA at 200, 300, and 400 mg/kg body weight once daily for 28 days prior to ulcer induction. At the end of the experiment, gastric secretions, antioxidant status, and histopathological alteration were evaluated. We observed that the significantly increased ulcer index, gastric volume, free and total acidity, malondialdehyde level, and pepsin activity were effectively reduced following treatment with 200 and 300 mg/kg MEVA. The extract also markedly attenuated the reduced activity of superoxide dismutase and reduced glutathione level as well as pH and mucin content in the ulcerated rats. Administration of the extract also significantly attenuates necrosis of the stomach tissue of the ulcerated rats. The results suggested that the MEVA leaf, preferably at 200 and 300 mg/kg body weight, ameliorated aspirin-induced gastric ulceration via antioxidative and H2 receptor antagonist. PMID- 30013462 TI - Altered Gene Expression in Prefrontal Cortex of a Fabry Disease Mouse Model. AB - Fabry disease is an X-chromosome linked hereditary disease that is caused by loss of function mutations in the alpha-galactosidase A (alpha-Gal A) gene, resulting in defective glycolipid degradation and subsequent accumulation of globotriaosylceramide (Gb3) in different tissues, including vascular endothelial cells and neurons in the peripheral and central nervous system. We recently reported a differential gene expression profile of alpha-Gal A(-/0) mouse dorsal root ganglia, an established animal model of Fabry disease, thereby providing new gene targets that might underlie the neuropathic pain related symptoms. To investigate the cognitive symptoms experienced by Fabry patients, we performed one-color based hybridization microarray expression profiling of prefrontal cortex samples from adult alpha-Gal A(-/0) mice and age-matched wildtype controls, followed by protein-protein interaction and pathway analyses for the differentially regulated mRNAs. We found that from a total of 381 differentially expressed genes, 135 genes were significantly upregulated, whereas 246 genes were significantly downregulated between alpha-Gal A(-/0) mice and wildtype controls. Enrichment analysis for downregulated genes revealed mainly immune related pathways, including immune/defense responses, regulation of cytokine production, as well as signaling and transport regulation pathways. Further analysis of the regulated genes revealed a large number of genes involved in neurodegeneration. The current analysis for the first time presents a differential gene expression profile of central nervous system tissue from alpha-Gal A(-/0) mice, thereby providing novel knowledge on the deregulation and a possible contribution of gene expression to Fabry disease related brain pathologies. PMID- 30013463 TI - Association Between Programed Cell Death-1 and CD4+ T Cell Alterations in Different Phases of Ischemic Stroke Patients. AB - Objective: We aimed to analyze alterations in T cell subgroups during different post-ischemic stroke (IS) phases to explore the possible mechanisms underlying stroke-induced immune depression (SIID). Methods: Sixty-four IS patients who met the entry criteria were divided into three groups: an acute phase group, a sub acute phase group and a stable phase group. Fourteen healthy individuals were selected as normal controls. The phenotype distribution of T cells in patient peripheral blood was analyzed, and the immune checkpoint receptors programed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) were detected in different T cell phenotypes. Results: Compared with the control group, the absolute number of CD4+ T cells and CD4+ T central memory (TCM) cells was significantly increased in the acute phase group but decreased in the sub-acute phase and stable phase groups compared with that in the acute phase group. PD-1 expression in CD4+ T cells in the stable phase group showed a significant increase compared with that in the acute phase group. The expression of PD-1 on CD4+ TCM cells and CD4+ T effector memory (TEM) cells showed significant decreases in the acute phase compared with control cells; however, in the sub acute phase and the stable phase, PD-1 expression was significantly increased compared with that in the acute phase. Conclusions: T cell dysfunction, especially CD4+ T cell dysfunction, occurred during different IS phases. PD-1 was highly expressed in CD4+ T cells of different phenotypes after the acute phase and was associated with alterations in CD4+ T cells. Particularly, PD-1 was negatively correlated with the absolute number of TCM cells among different CD4+ T cell phenotypes, which may be one of the possible mechanisms of SIID. PMID- 30013464 TI - Screening Mammalian Cochlear Hair Cells to Identify Critical Processes in Aminoglycoside-Mediated Damage. AB - There is considerable interest in discovering drugs with the potential to protect inner ear hair cells (HCs) from damage. One means of discovery is to screen compound libraries. Excellent screening protocols have been developed employing cell lines derived from the cochlea and zebrafish larvae. However, these do not address the differentiated mammalian hair cell. We have developed a screening method employing micro-explants of the mammalian organ of Corti (oC) to identify compounds with the ability to influence aminoglycoside-induced HC loss. The assay is based on short segments of the neonatal mouse oC, containing ~80 HCs which selectively express green fluorescent protein (GFP). This allows the screening of hundreds of potential protectants in an assay that includes both inner and outer HCs. This review article describes various screening methods, including the micro explant assay. In addition, two micro-explant screening studies in which antioxidant and kinase inhibitor libraries were evaluated are reviewed. The results from these screens are related to current models of HC damage and protection. PMID- 30013466 TI - Elevated Aggression and Reduced White Matter Integrity in Mild Traumatic Brain Injury: A DTI Study. AB - Mild traumatic brain injury (mTBI) remains the most commonly reported head injury in the United States, and is associated with a wide range of post-concussive symptoms including physical, cognitive and affective impairments. Elevated aggression has been documented in mTBI; however, the neural mechanisms associated with aggression at the chronic stage of recovery remain poorly understood. In the present study, we investigated the association between white matter integrity and aggression in mTBI using diffusion tensor imaging (DTI). Twenty-six age-matched adults participated in the study, including 16 healthy controls (HCs) and 10 individuals in the chronic stage of recovery (either 6-months or 12 months post mTBI). Psychological measures of aggression included the Buss-Perry Aggression Questionnaire and the Personality Assessment Inventory (PAI). Axonal pathways implicated in affective processing were studied, including the corpus callosum, anterior thalamic radiation, cingulum and uncinate fasciculus, and measures of white matter integrity included fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). We found that adults with mTBI in the chronic stage of recovery had higher levels aggression. Individuals with mTBI also had greater RD in the corpus callosum compared to HCs, indicating reduced fiber integrity. Furthermore, we observed a significant association between reduced white matter integrity in the corpus callosum and greater aggression. Our findings provide additional evidence for underlying neuroanatomical mechanisms of aggression, although future research will be necessary to characterize the specific relationship between aggression and the white matter pathways we identified. PMID- 30013465 TI - Apical Function in Neocortical Pyramidal Cells: A Common Pathway by Which General Anesthetics Can Affect Mental State. AB - It has been argued that general anesthetics suppress the level of consciousness, or the contents of consciousness, or both. The distinction between level and content is important because, in addition to clarifying the mechanisms of anesthesia, it may help clarify the neural bases of consciousness. We assess these arguments in the light of evidence that both the level and the content of consciousness depend upon the contribution of apical input to the information processing capabilities of neocortical pyramidal cells which selectively amplify relevant signals. We summarize research suggesting that what neocortical pyramidal cells transmit information about can be distinguished from levels of arousal controlled by sub-cortical nuclei and from levels of prioritization specified by interactions within the thalamocortical system. Put simply, on the basis of the observations reviewed, we hypothesize that when conscious we have particular, directly experienced, percepts, thoughts, feelings and intentions, and that general anesthetics affect consciousness by interfering with the subcellular processes by which particular activities are selectively amplified when relevant to the current context. PMID- 30013467 TI - The Action Representation Elicited by Different Types of Drug-Related Cues in Heroin-Abstinent Individuals. AB - Drug related cue-induced reactivity plays a significant role in maintaining drug use and relapse in addicted individuals. The activation of Dorsolateral striatum Sensorimotor system (DLS-SM) has been suggested as an important route through which drug cues may induce automatic drug using behavior. The current study used fMRI to investigate the reactivity of heroin abstinent individuals to different types of cues, to clarify the characteristics of the cues that induce the activation of the sensorimotor area. Forty heroin-dependent abstinent individuals and 29 healthy subjects were recruited to perform the heroin cue-reactivity task during fMRI. The participants' subjective craving and physical signs were evaluated before and after scanning. Whole-brain analysis showed that compared to drug use tool and drug cues, cues related to drug use action were more likely to activate posterior central gyrus, para-hippocampus, supra marginal gyrus, superior parietal lobule (SPL) and inferior parietal lobule (IPL). These areas are involved in motor preparation and output, indicating that the sensorimotor area is also an important neural basis of craving and automatic drug using behavior, and may mediate craving and drug seeking behavior. Our findings thus suggest that cues related to drug using action may induce automatic drug seeking behavior more than cues related only to the drug itself. PMID- 30013468 TI - Frequency-Resolved Dynamic Functional Connectivity Reveals Scale-Stable Features of Connectivity-States. AB - Investigating temporal variability of functional connectivity is an emerging field in connectomics. Entering dynamic functional connectivity by applying sliding window techniques on resting-state fMRI (rs-fMRI) time courses emerged from this topic. We introduce frequency-resolved dynamic functional connectivity (frdFC) by means of multivariate empirical mode decomposition (MEMD) followed up by filter-bank investigations. In general, we find that MEMD is capable of generating time courses to perform frdFC and we discover that the structure of connectivity-states is robust over frequency scales and even becomes more evident with decreasing frequency. This scale-stability varies with the number of extracted clusters when applying k-means. We find a scale-stability drop-off from k = 4 to k = 5 extracted connectivity-states, which is corroborated by null models, simulations, theoretical considerations, filter-banks, and scale-adjusted windows. Our filter-bank studies show that filter design is more delicate in the rs-fMRI than in the simulated case. Besides offering a baseline for further frdFC research, we suggest and demonstrate the use of scale-stability as a possible quality criterion for connectivity-state and model selection. We present first evidence showing that connectivity-states are both a multivariate, and a multiscale phenomenon. A data repository of our frequency-resolved time-series is provided. PMID- 30013469 TI - Brain States That Encode Perceived Emotion Are Reproducible but Their Classification Accuracy Is Stimulus-Dependent. AB - The brain state hypothesis of image-induced affect processing, which posits that a one-to-one mapping exists between each image stimulus and its induced functional magnetic resonance imaging (fMRI)-derived neural activation pattern (i.e., brain state), has recently received support from several multivariate pattern analysis (MVPA) studies. Critically, however, classification accuracy differences across these studies, which largely share experimental designs and analyses, suggest that there exist one or more unaccounted sources of variance within MVPA studies of affect processing. To explore this possibility, we directly demonstrated strong inter-study correlations between image-induced affective brain states acquired 4 years apart on the same MRI scanner using near identical methodology with studies differing only by the specific image stimuli and subjects. We subsequently developed a plausible explanation for inter-study differences in affective valence and arousal classification accuracies based on the spatial distribution of the perceived affective properties of the stimuli. Controlling for this distribution improved valence classification accuracy from 56% to 85% and arousal classification accuracy from 61% to 78%, which mirrored the full range of classification accuracy across studies within the existing literature. Finally, we validated the predictive fidelity of our image-related brain states according to an independent measurement, autonomic arousal, captured via skin conductance response (SCR). Brain states significantly but weakly (r = 0.08) predicted the SCRs that accompanied individual image stimulations. More importantly, the effect size of brain state predictions of SCR increased more than threefold (r = 0.25) when the stimulus set was restricted to those images having group-level significantly classifiable arousal properties. PMID- 30013470 TI - Incorporation of Multiple-Days Information to Improve the Generalization of EEG Based Emotion Recognition Over Time. AB - Current studies have got a series of satisfying accuracies in EEG-based emotion classification, but most of the classifiers used in previous studies are totally time-limited. To produce generalizable results, the emotion classifier should be stable over days, in which the day-to-day variations of EEG should be appropriately handled. To improve the generalization of EEG-based emotion recognition over time by learning multiple-days information which embraces the day-to-day variations, in this paper, 17 subjects were recruited to view several video clips to experience different emotion states, and each subject was required to perform five sessions in 5 days distributed over 1 month. Support vector machine was built to perform a classification, in which the training samples may come from 1, 2, 3, or 4 days' sessions but have a same number, termed learning 1 days information (L1DI), learning 2-days information (L2DI), learning 3-days information (L3DI), and learning 4-days information (L4DI) conditions, respectively. The results revealed that the EEG variability could impair the performance of emotion classifier dramatically, and learning more days' information to construct a classifier could significantly improve the generalization of EEG-based emotion recognition over time. Mean accuracies were 62.78, 67.92, 70.75, and 72.50% at L1DI, L2DI, L3DI, and L4DI conditions, respectively. Features at L4DI condition were ranked by modified RFE, and features providing better contribution were applied to obtain the performances of all conditions, results showed that the performance of SVMs trained and tested with the feature subset were all improved for L1DI, L2DI (*p < 0.05), L3DI (**p < 0.01), and L4DI (*p < 0.05) conditions. It could be a substantial step forward in the development of emotion recognition from EEG signals because it may enable a classifier trained on one time to handle another. PMID- 30013471 TI - The Dynamics of Balanced Spiking Neuronal Networks Under Poisson Drive Is Not Chaotic. AB - Some previous studies have shown that chaotic dynamics in the balanced state, i.e., one with balanced excitatory and inhibitory inputs into cortical neurons, is the underlying mechanism for the irregularity of neural activity. In this work, we focus on networks of current-based integrate-and-fire neurons with delta pulse coupling. While we show that the balanced state robustly persists in this system within a broad range of parameters, we mathematically prove that the largest Lyapunov exponent of this type of neuronal networks is negative. Therefore, the irregular firing activity can exist in the system without the chaotic dynamics. That is the irregularity of balanced neuronal networks need not arise from chaos. PMID- 30013472 TI - Predicting Age From Brain EEG Signals-A Machine Learning Approach. AB - Objective: The brain age gap estimate (BrainAGE) is the difference between the estimated age and the individual chronological age. BrainAGE was studied primarily using MRI techniques. EEG signals in combination with machine learning (ML) approaches were not commonly used for the human age prediction, and BrainAGE. We investigated whether age-related changes are affecting brain EEG signals, and whether we can predict the chronological age and obtain BrainAGE estimates using a rigorous ML framework with a novel and extensive EEG features extraction. Methods: EEG data were obtained from 468 healthy, mood/anxiety, eating and substance use disorder participants (297 females) from the Tulsa-1000, a naturalistic longitudinal study based on Research Domain Criteria framework. Five sets of preprocessed EEG features across channels and frequency bands were used with different ML methods to predict age. Using a nested-cross-validation (NCV) approach and stack-ensemble learning from EEG features, the predicted age was estimated. The important features and their spatial distributions were deduced. Results: The stack-ensemble age prediction model achieved R2 = 0.37 (0.06), Mean Absolute Error (MAE) = 6.87(0.69) and RMSE = 8.46(0.59) in years. The age and predicted age correlation was r = 0.6. The feature importance revealed that age predictors are spread out across different feature types. The NCV approach produced a reliable age estimation, with features consistent behavior across different folds. Conclusion: Our rigorous ML framework and extensive EEG signal features allow a reliable estimation of chronological age, and BrainAGE. This general framework can be extended to test EEG association with and to predict/study other physiological relevant responses. PMID- 30013473 TI - Chuanxiong Formulae for Migraine: A Systematic Review and Meta-Analysis of High Quality Randomized Controlled Trials. AB - Objective: Migraine is a complex, prevalent and disabling neurological disorder characterized by recurrent episodes of headache without ideal treatment. We aim to assess the current available evidence of herbal Chuanxiong (Ligusticum chuanxiong Hort. root) formulae for the treatment of migraine according to the high-quality randomized controlled trials (RCTs). Methods: English and Chinese electronic databases were searched from their inceptions until March 2017. The methodological quality of included study was assessed by the Cochrane Collaboration risk of bias tool. RCTs with Cochrane risk of bias (RoB) score >=4 were included in the analyses. Meta-analysis was conducted using RevMan 5.3 software. Publication bias was assessed by funnel plot analysis and Egger's test. Results: Nineteen RCTs with 1832 participants were identified. The studies investigated the Chuanxiong formulae vs. placebo (n = 5), Chuanxiong formulae vs. conventional pharmacotherapy (CP) (n = 13 with 15 comparisons), and Chuanxiong formulae plus CP vs. CP (n = 1). Meta-analysis indicated that Chuanxiong formulae could reduce frequency, duration, days and pain severity of migraine and improve the total clinical efficacy rate (P < 0.05). Adverse event monitoring was reported in 16 out of 19 studies and occurrence rate of adverse event was low. Conclusion: The findings of present study indicated that Chuanxiong formulae exerted the symptom reliefs of for migraine. PMID- 30013474 TI - Retinal Protection and Distribution of Curcumin in Vitro and in Vivo. AB - Diabetic retinopathy (DR), a secondary complication of diabetes, is a leading cause of irreversible blindness accounting for 5% of world blindness cases in working age. Oxidative stress and inflammation are considered causes of DR. Curcumin, a product with anti-oxidant and anti-inflammatory properties, is currently proposed as oral supplementation therapy for retinal degenerative diseases, including DR. In this study we predicted the pharmacodynamic profile of curcumin through an in silico approach. Furthermore, we tested the anti-oxidant and anti-inflammatory activity of curcumin on human retinal pigmented epithelial cells exposed to oxidative stress, human retinal endothelial and human retinal pericytes (HRPCs) cultured with high glucose. Because currently marketed curcumin nutraceutical products have not been so far evaluated for their ocular bioavailability; we assessed retinal distribution of curcumin, following oral administration, in rabbit eye. Curcumin (10 MUM) decreased significantly (p < 0.01) ROS concentration and TNF-alpha release in retinal pigmented epithelial cells and retinal endothelial cells, respectively. The same curcumin concentration significantly (p < 0.01) protected retinal pericytes from high glucose damage as assessed by cell viability and LDH release. Among the tested formulations, only that containing a hydrophilic carrier provided therapeutic levels of curcumin in rabbit retina. In conclusion, our data suggest that curcumin, when properly formulated, may be of value in clinical practice to manage retinal diseases. PMID- 30013476 TI - Inhibition of RAGE Attenuates Cigarette Smoke-Induced Lung Epithelial Cell Damage via RAGE-Mediated Nrf2/DAMP Signaling. AB - The oxidative stress and cellular apoptosis by environmental factor including cigarette smoke induces alveolar airway remodeling leading to chronic obstructive pulmonary disease (COPD). Recently, the receptor for advanced glycan end products (RAGE) which is highly expressed in alveolar epithelium is emerging as a biomarker for COPD susceptibility or progression. However, it still remains unknown how RAGE plays a role in cigarette smoke extract (CSE)-exposed human alveolar type II epithelial cell line. Therefore, we determined the efficacy of RAGE-specific antagonist FPS-ZM1 in response to CSE-induced lung epithelial cells. CSE induced the elevated generation of RONS and release of pro inflammatory cytokines, and impaired the cellular antioxidant defense system. Further, CSE induced the alteration of RAGE distribution via the activation of redox-sensitive DAMP (Damage-associated molecular patterns) signaling through Nrf2 in cells. Although pre-treatment with SB202190 (p38 inhibitor) or SP600125 (JNK inhibitor) failed to recover the alteration of RAGE distribution, treatment of FPS-ZM1 significantly exhibited anti-inflammatory and anti oxidative/nitrosative effects, also inhibited the activation of redox-sensitive DAMP signaling through Nrf2 (nuclear factor erythroid 2-related factor 2) migration in the presence of CSE. Taken together, our data demonstrate that RAGE and Nrf2 play a pivotal role in maintenance of alveolar epithelial integrity. PMID- 30013475 TI - Trace Amine-Associated Receptors as Novel Therapeutic Targets for Immunomodulatory Disorders. AB - Trace amines and their receptors (trace amine-associated receptors; TAARs) are an emerging pharmacological target for the treatment of human disorders. While most studies have focused on their therapeutic potential for neurologic and psychiatric disorders, TAARs are also expressed throughout the periphery, including prominent expression in human leukocytes. Furthermore, recent independent, unbiased metabolomic studies have consistently identified one or more TAAR ligands as potential etiologic factors in inflammatory bowel disease (IBD). The putative role of TAARs in diseases such as IBD that are associated with hyperactive immune responses has not, however, previously been systematically addressed. Here, we review the current state of the knowledge of the effects of TAARs on leukocyte function, in particular in the context of mucosal epithelial cells that interface with the environment; developing a model whereby TAARs may be considered as a novel therapeutic target for disorders associated with dysregulated immune responses to environmental factors. In this model, we hypothesize that altered trace amine homeostasis results in hyperactivity of the immune system. Such loss of homeostasis can occur through many different mechanisms including TAAR polymorphisms and altered trace amine load due to changes in host synthesis and/or degradative enzymes, diet, or microbial dysbiosis. The resulting alterations in TAAR functioning can then lead to a loss of homeostasis of leukocyte chemotaxis, differentiation, and activation, as well as an altered ability of members of the microbiota to adhere to and penetrate the epithelial cell layers. Such changes would generate a pro inflammatory state at mucosal epithelial barrier layers that can manifest as clinical symptomatology such as that seen in IBD. These alterations may also have the potential to induce systemic effects, which could possibly contribute to immunomodulatory disorders in other systems, including neurological diseases. PMID- 30013477 TI - The IGF2/IGF1R/Nanog Signaling Pathway Regulates the Proliferation of Acute Myeloid Leukemia Stem Cells. AB - Acute myeloid leukemia is an aggressive disease characterized by clonal proliferation and differentiation into immature hematopoietic cells of dysfunctional myeloid precursors. Accumulating evidence shows that CD34+CD38- leukemia stem cells (LSCs) are responsible for drug resistance, metastasis, and relapse of leukemia. In this study, we found that Nanog, a transcription factor in stem cells, is significantly overexpressed in CD34+ populations from patients with acute myeloid leukemia and in LSCs from leukemia cell lines. Our data demonstrate that the knockdown of Nanog inhibited proliferation and induced cell cycle arrest and cell apoptosis. Moreover, Nanog silencing suppressed the leukemogenesis of LSCs in mice. In addition, we found that these functions of Nanog were regulated by the insulin-like growth factor receptor (IGF1R) signaling pathway. Nanog overexpression rescued the colony formation ability of LSCs treated with picropodophyllin (PPP), an IGF1R inhibitor. By contrast, knockdown of Nanog abolished the effects of IGF2 on the colony formation ability of these LSCs. These findings suggest that the IGF2/IGF1R/Nanog signaling pathway plays a critical role in LSC proliferation. PMID- 30013479 TI - Phenotype-Based and Self-Learning Inter-Individual Sleep Apnea Screening With a Level IV-Like Monitoring System. AB - Purpose: We propose a phenotype-based artificial intelligence system that can self-learn and is accurate for screening purposes and test it on a Level IV-like monitoring system. Methods: Based on the physiological knowledge, we hypothesize that the phenotype information will allow us to find subjects from a well annotated database that share similar sleep apnea patterns. Therefore, for a new arriving subject, we can establish a prediction model from the existing database that is adaptive to the subject. We test the proposed algorithm on a database consisting of 62 subjects with the signals recorded from a Level IV-like wearable device measuring the thoracic and abdominal movements and the SpO2. Results: With the leave-one-subject-out cross validation, the accuracy of the proposed algorithm to screen subjects with an apnea-hypopnea index greater or equal to 15 is 93.6%, the positive likelihood ratio is 6.8, and the negative likelihood ratio is 0.03. Conclusion: The results confirm the hypothesis and show that the proposed algorithm has potential to screen patients with SAS. PMID- 30013478 TI - How Tumor Cells Choose Between Epithelial-Mesenchymal Transition and Autophagy to Resist Stress-Therapeutic Implications. AB - Tumor cells undergo epithelial-mesenchymal transition (EMT) or macroautophagy (hereafter autophagy) in response to stressors from the microenvironment. EMT ensues when stressors act on tumor cells in the presence of nutrient sufficiency, and mechanistic target of rapamycin (mTOR) appears to be the crucial signaling node for EMT induction. Autophagy, on the other hand, is induced in the presence of nutrient deprivation and/or stressors from the microenvironment with 5' adenosine monophosphate-activated protein kinase (AMPK) playing an important, but not exclusive role, in autophagy induction. Importantly, mTOR and EMT on one hand, and AMPK and autophagy on the other hand, negatively regulate each other. Such regulation occurs at different levels and suggests that, in many instances, these two stress responses are mutually exclusive. Nevertheless, EMT and autophagy are able to interconvert and we suggest that this may depend on spatiotemporal changes in the tumor microenvironment and/or on duration/intensity of the stressor signal(s). Eventually, we propose a three-pronged therapeutic approach aimed at targeting these three major tumor cell populations. First, cytotoxic drugs that act on differentiated and proliferating tumor cells and which, per se, may promote induction of EMT or autophagy in surviving tumor cells. Second, inhibitors of mTOR in order to prevent EMT induction. Third inducers of autophagic cell death (autosis) in order to deplete tumor cells that are constitutively in an autophagic state or are induced to enter an autophagic state in response to antitumor therapy. PMID- 30013480 TI - Higher Training Frequency Is Important for Gaining Muscular Strength Under Volume Matched Training. AB - Background: This study investigated the effect of volume-matched strength training programs with different frequency and subsequent detraining on muscle size and strength. Methods: During a training period of 11 weeks, untrained subjects (age: 22.3 +/- 0.9 years, height: 173.1 +/- 4.8 cm and body mass: 66.8 +/- 8.4 kg) performed knee-extension exercise at 67% of their estimated one repetition maximum either one session per week (T1 group: 6 sets of 12 repetitions per session; n = 10) or three sessions per week (T3 group: 2 sets of 12 repetitions per session; n = 10). Rating of perceived exertion (RPE) and muscle stiffness were measured as an index of muscle fatigue and muscle damage, respectively. The magnitude of muscle hypertrophy was assessed with thigh circumference and the quadriceps muscle thickness. The changes in muscle strength were measured with isometric maximum voluntary contraction torque (MVC). Results: During the training period, RPE was significantly higher in the T1 than in the T3 (p < 0.001). After 11 weeks of training, both groups exhibited significant improvements in thigh circumference, muscle thickness, and MVC compared with baseline values. However, there was a significant group difference in MVC improvement at week 11 (T1: 43.5 +/- 15.5%, T3: 65.2 +/- 23.2%, p < 0.05). After 6 weeks of detraining, both groups showed the significant decreases in thigh circumference and muscle thickness from those at the end of training period, while no significant effect of detraining was observed in MVC. Conclusion: These results suggest that three training sessions per week with two sets are recommended for untrained subjects to improve muscle strength while minimizing fatigue compared to one session per week with six sets. PMID- 30013481 TI - The Importance of Connexin 43 in Enamel Development and Mineralization. AB - During enamel development, formation of hydroxyapatite crystals and regulation of pH in the enamel matrix require massive transport of ions. Both ameloblasts and adjacent dental epithelial cells in the stellate reticulum co-express several transmembrane cotransporters/ion-exchangers for transport of ions across plasma membranes. Gap junctions (GJs) enable intercellular exchanges of ions between neighboring cells. This suggests that the ameloblasts and other cell layers of the enamel organ, form a functional unit. During the bell stage of tooth formation, the non-ameloblast dental epithelium highly expresses the Na-K-Cl cotransporter (Nkcc1). Nkcc1-null mice are associated with enamel hypomineralization and increased expression of GJ protein connexin 43 (Cx43), suggesting that reduced ion transport in the Nkcc1-null mouse is in part compensated by increased intercellular ion transport through GJs. To understand the role of GJs in ion transport and its effect on pH regulation, we examined in a mouse strain in which Cx43 was ablated selectively in DMP1 expressing cells (Cx43flox/flox mice crossed with DMP1-8kb-Cre mice), including ameloblasts. Micro CT analysis showed that the mineral density at late maturation stage incisal enamel of the Cx43-null mice was 10% less than in controls, whereas that in dentin was unchanged. Maturation stage ameloblasts of mice lacking the pH regulating sodium/bicarbonate transporter NBCe1 (Nbce1-null), or chloride channel Cftr (Cftr-null) were found to have increased Cx43-immunostaining. These results support the possibility that GJs in the ameloblast-papillary complex at the maturation stage contribute to ion transport by enabling passage of ions directly from cells of the papillary layer into ameloblast layer. Increasing the number of GJs may partly compensate the reduction of ion-cotransporters and ion exchangers in dental epithelium. PMID- 30013483 TI - A Mouse Model of Creatine Transporter Deficiency Reveals Impaired Motor Function and Muscle Energy Metabolism. AB - Creatine serves as fast energy buffer in organs of high-energy demand such as brain and skeletal muscle. L-Arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase are responsible for endogenous creatine synthesis. Subsequent uptake into target organs like skeletal muscle, heart and brain is mediated by the creatine transporter (CT1, SLC6A8). Creatine deficiency syndromes are caused by defects of endogenous creatine synthesis or transport and are mainly characterized by intellectual disability, behavioral abnormalities, poorly developed muscle mass, and in some cases also muscle weakness. CT1 deficiency is estimated to be among the most common causes of X-linked intellectual disability and therefore the brain phenotype was the main focus of recent research. Unfortunately, very limited data concerning muscle creatine levels and functions are available from patients with CT1 deficiency. Furthermore, different CT1-deficient mouse models yielded conflicting results and detailed analyses of their muscular phenotype are lacking. Here, we report the generation of a novel CT1-deficient mouse model and characterized the effects of creatine depletion in skeletal muscle. HPLC-analysis showed strongly reduced total creatine levels in skeletal muscle and heart. MR-spectroscopy revealed an almost complete absence of phosphocreatine in skeletal muscle. Increased AGAT expression in skeletal muscle was not sufficient to compensate for insufficient creatine transport. CT1-deficient mice displayed profound impairment of skeletal muscle function and morphology (i.e., reduced strength, reduced endurance, and muscle atrophy). Furthermore, severely altered energy homeostasis was evident on magnetic resonance spectroscopy. Strongly reduced phosphocreatine resulted in decreased ATP/Pi levels despite an increased inorganic phosphate to ATP flux. Concerning glucose metabolism, we show increased glucose transporter type 4 expression in muscle and improved glucose clearance in CT1-deficient mice. These metabolic changes were associated with activation of AMP-activated protein kinase - a central regulator of energy homeostasis. In summary, creatine transporter deficiency resulted in a severe muscle weakness and atrophy despite different compensatory mechanisms. PMID- 30013482 TI - Physical Activity, Immune System, and the Microbiome in Cardiovascular Disease. AB - Cardiovascular health is a primary research focus, as it is a leading contributor to mortality and morbidity worldwide, and is prohibitively costly for healthcare. Atherosclerosis, the main driver of cardiovascular disease, is now recognized as an inflammatory disorder. Physical activity (PA) may have a more important role in cardiovascular health than previously expected. This review overviews the contribution of PA to cardiovascular health, the inflammatory role of atherosclerosis, and the emerging evidence of the microbiome as a regulator of inflammation. PMID- 30013486 TI - The Olympic Biathlon - Recent Advances and Perspectives After Pyeongchang. AB - The biathlon, combining cross-country ski skating with rifle marksmanship, has been an Olympic event since the Winter Games in Squaw Valley, United States, in 1960. As a consequence of replacing the classical with the skating technique in the 1980s, as well as considerable improvements in equipment and preparation of ski tracks and more effective training, the average biathlon skiing speed has increased substantially. Moreover, the mass-start, pursuit, and sprint races have been introduced. Indeed, two of the four current individual Olympic biathlon competitions involve mass-starts, where tactics play a major role and the outcome is often decided during the last round of shooting or final sprint. Biathlon is a demanding endurance sport requiring extensive aerobic capacity. The wide range of speeds and slopes involved requires biathletes to alternate continuously between and adapt different skating sub-techniques during races, a technical complexity that places a premium on efficiency. Although the relative amounts of endurance training at different levels of intensity have remained essentially constant during recent decades, today's biathletes perform more specific endurance training on roller skis on terrain similar to that used for competition, with more focus on the upper-body, systematic strength and power training and skiing at higher speeds. Success in the biathlon also requires accurate and rapid shooting while simultaneously recovering from high-intensity skiing. Many different factors, including body sway, triggering behavior, and even psychology, influence the shooting performance. Thus, the complexity of biathlon deserves a greater research focus on areas such as race tactics, skating techniques, or shooting process. PMID- 30013485 TI - miR-21 Protects Against Ischemia/Reperfusion-Induced Acute Kidney Injury by Preventing Epithelial Cell Apoptosis and Inhibiting Dendritic Cell Maturation. AB - Renal tubular injury and innate immune responses induced by hypoxia contribute to acute kidney injury. Accumulating evidence suggests that miR-21 overexpression protects against kidney ischemia injury. Additionally, miR-21 emerges as a key inhibitor in dendritic cell maturation. Thus, we hypothesized that miR-21 protects the kidney from IR injury by suppressing epithelial cell damage and inflammatory reaction. In this study, we investigated effects of miR-21 and its signaling pathways (PTEN/AKT/mTOR/HIF, PDCD4/NFkappa-B) on kidney ischemia/reperfusion (IR) injury in vitro and in vivo. The results revealed that IR increased miR-21, HIF1alpha, and 2alpha expression in vivo and in vitro. MiR 21 interacted with HIF1alpha and 2alpha through the PTEN/AKT/mTOR pathway. Moreover, inhibition of miR-21 activated PDCD4/NFkappa-B pathways, which are critical for dendritic cell maturation. Renal IR triggers local inflammation by inducing the dendritic cell maturation and promoting the secretion of IL-12, IL 6, and TNF-alpha cytokines. Knockdown of miR-21 intensified the effect of IR on tubular epithelial cell apoptosis and dendritic cell maturation. Our results suggested that IR-inducible miR-21 protects epithelial cells from IR injury via a feedback interaction with HIF (PTEN/AKT/mTOR/HIF/miR-21) and by inhibiting maturation of DCs through the PDCD4/NF-kappaB pathway. These findings highlight new therapeutic opportunities in AKI. PMID- 30013484 TI - Central Respiration and Mechanical Ventilation in the Gating of Swallow With Breathing. AB - Swallow-breathing coordination safeguards the lower airways from tracheal aspiration of bolus material as it moves through the pharynx into the esophagus. Impaired movements of the shared muscles or structures of the aerodigestive tract, or disruptions in the interaction of brainstem swallow and respiratory central pattern generators (CPGs) result in dysphagia. To maximize lower airway protection these CPGs integrate respiratory rhythm generation signals and vagal afferent feedback to synchronize swallow with breathing. Despite extensive study, the roles of central respiratory activity and vagal feedback from the lungs as key elements for effective swallow-breathing coordination remain unclear. The effect of altered timing of bronchopulmonary vagal afferent input on swallows triggered during electrical stimulation of the superior laryngeal nerves or by injection of water into the pharyngeal cavity was studied in decerebrate, paralyzed, and artificially ventilated cats. We observed two types of single swallows that produced distinct effects on central respiratory-rhythm across all conditions: post-inspiratory type swallows disrupted central-inspiratory activity without affecting expiration, whereas expiratory type swallows prolonged expiration without affecting central-inspiratory activity. Repetitive swallows observed during apnea reset the E2 phase of central respiration and produced facilitation of swallow motor output nerve burst durations. Moreover, swallow initiation was negatively modulated by vagal feedback and was reset by lung inflation. Collectively, these findings support a novel model of reciprocal inhibition between the swallow CPG and inspiratory or expiratory cells of the respiratory CPG where lung distension and phases of central respiratory activity represent a dual peripheral and central gating mechanism of swallow-breathing coordination. PMID- 30013488 TI - Transcriptional and Translational Relationship in Environmental Stress: RNAseq and ITRAQ Proteomic Analysis Between Sexually Reproducing and Parthenogenetic Females in Moina micrura. AB - Moina micrura is a kind of small-bodied water flea within the family Moinidae. Similar to Daphnia, M. micrura could also switch its reproduction mode from parthenogenetic female (PF) to sexual female (SF) to adapt to the external environment. To uncover the mechanisms of reproductive switching in M. micrura, we used both RNA-Seq and iTRAQ analyses to investigate the differentially expressed genes (DEGs) and their protein products between SF and PF in M. micrura. A total of 1665 DEGs (702 up-regulated, 963 down-regulated) and 600 differentially expressed proteins (DEPs) (102 up-regulated, 498 down-regulated) were detected in SF. Correlation analyses indicated that 31 genes were expressed significantly differentially at both transcriptomic and proteomic levels, including 15 up-regulated genes and 16 down-regulated genes in SF. Meanwhile, our data also showed that 528 DEPs have discordant expression at transcript level, implying post-transcriptional (including translational) regulation. These top up regulated genes and their protein products in SF were mainly grouped into the globin-related family, vitellogenin-related family, cuticle-related family, Hsp related family and methyltransferases-related family, which were all involved in the reproductive switching in Daphnia. In contrast, a cluster of orthologous groups revealed that up-regulated genes and their protein products in PF were strongly associated with the metabolic process, which may be responsible for rapid population proliferation in M. micrura. PMID- 30013487 TI - Evidence That Calcium Entry Into Calcium-Transporting Dental Enamel Cells Is Regulated by Cholecystokinin, Acetylcholine and ATP. AB - Dental enamel is formed by specialized epithelial cells which handle large quantities of Ca2+ while producing the most highly mineralized tissue. However, the mechanisms used by enamel cells to handle bulk Ca2+ safely remain unclear. Our previous work contradicted the dogma that Ca2+ is ferried through the cytosol of Ca2+-transporting cells and instead suggested an organelle-based route across enamel cells. This new paradigm involves endoplasmic reticulum (ER)-associated Ca2+ stores and their concomitant refilling by store-operated Ca2+ entry (SOCE) mediated by Ca2+ release activated Ca2+ (CRAC) channels. Given that Ca2+ handling is maximal during the enamel-mineralization stage (maturation), we anticipated that SOCE would also be elevated then. Confirmation was obtained here using single-cell recordings of cytosolic Ca2+ concentration ([Ca2+]cyt) in rat ameloblasts. A candidate SOCE agonist, cholecystokinin (CCK), was found to be upregulated during maturation, with Cck transcript abundance reaching 30% of that in brain. CCK-receptor transcripts were also detected and Ca2+ imaging showed that CCK stimulation increased [Ca2+]cyt in a dose-responsive manner that was sensitive to CRAC-channel inhibitors. Similar effects were observed with two other SOCE activators, acetylcholine and ATP, whose receptors were also found in enamel cells. These results provide the first evidence of a potential regulatory system for SOCE in enamel cells and so strengthen the Ca2+ transcytosis paradigm for ER-based transport of bulk Ca2+. Our findings also implicate enamel cells as a new physiological target of CCK and raise the possibility of an auto/paracrine system for regulating Ca2+ transport. PMID- 30013491 TI - Differences in Parental Burnout: Influence of Demographic Factors and Personality of Parents and Children. AB - Parental burnout is a syndrome related to parenthood and characterized by three dimensions: emotional and physical exhaustion, emotional distancing of parents from their children, and loss of parental accomplishment. Many factors can explain the interindividual differences in parental burnout (Roskam et al., 2017). In a study conducted among 372 French parents, we examined the relationship between parental burnout, demographic factors (age of parent and child(ren), age of parent at first birth, total number of children, and number of children present in the family home) and parent-assessed dispositional factors (personality traits of parent and child(ren)). Results for demographic factors showed that the younger the parents we surveyed, the higher their reported sense of parental accomplishment, although they also tended to feel more exhausted. We observed a similar pattern of results when we looked at the children's ages. In addition, the number of children at home slightly increased the emotional distance between parent and child(ren). Results for the parents' dispositional factors showed that all three personality traits we investigated, as well as their different facets (lack of emotional control and lack of impulse control for neuroticism, meticulousness and perseverance for conscientiousness, and cooperation and friendliness for agreeableness), were related to parental burnout and its three dimensions. More specifically, parental meticulousness and lack of emotional control were both risk factors for developing parental burnout. By contrast, agreeableness and perseverance were protective factors. With regard to the children, the same three personality traits were linked to the three dimensions of parental burnout. Having children they perceived as having a high level of neuroticism reduced parents' sense of parental accomplishment and increased their emotional exhaustion and distancing. The opposite relationships were found for agreeableness and conscientiousness. There were no significant relationships between parental assessments of their children' extraversion and openness and parental burnout and its three dimensions. The parent's personality explained 42.3% of the variance in parental burnout, and the child(ren)'s personality (parent-assessed) explained 13.8%. Taken together, these results demonstrate the importance of considering the personality of both parents and children in the study of parental burnout. PMID- 30013489 TI - A Bout of High Intensity Interval Training Lengthened Nerve Conduction Latency to the Non-exercised Affected Limb in Chronic Stroke. AB - Objective: Evaluate intensity-dependent effects of a single bout of high intensity interval training (HIIT) compared to moderate intensity constant-load exercise (MICE) on corticospinal excitability (CSE) and effects on upper limb performance in chronic stroke. Design: Randomized cross-over trial. Setting: Research laboratory in a tertiary rehabilitation hospital. Participants: Convenience sample of 12 chronic stroke survivors. Outcome measures: Bilateral CSE measures of intracortical inhibition and facilitation, motor thresholds, and motor evoked potential (MEP) latency using transcranial magnetic stimulation. Upper limb functional measures of dexterity (Box and Blocks Test) and strength (pinch and grip strength). Results: Twelve (10 males; 62.50 +/- 9.0 years old) chronic stroke (26.70 +/- 23.0 months) survivors with moderate level of residual impairment participated. MEP latency from the ipsilesional hemisphere was lengthened after HIIT (pre: 24.27 +/- 1.8 ms, and post: 25.04 +/- 1.8 ms, p = 0.01) but not MICE (pre: 25.49 +/- 1.10 ms, and post: 25.28 +/- 1.0 ms, p = 0.44). There were no significant changes in motor thresholds, intracortical inhibition or facilitation. Pinch strength of the affected hand decreased after MICE (pre: 8.96 +/- 1.9 kg vs. post: 8.40 +/- 2.0 kg, p = 0.02) but not after HIIT (pre: 8.83 +/- 2.0 kg vs. post: 8.65 +/- 2.2 kg, p = 0.29). Regardless of type of aerobic exercise, higher total energy expenditure was associated with greater increases in pinch strength in the affected hand after exercise (R2 = 0.31, p = 0.04) and decreases in pinch strength of the less affected hand (R2 = 0.26 p = 0.02). Conclusion: A single bout of HIIT resulted in lengthened nerve conduction latency in the affected hand that was not engaged in the exercise. Longer latency could be related to the cross-over effects of fatiguing exercise or to reduced hand spasticity. Somewhat counterintuitively, pinch strength of the affected hand decreased after MICE but not HIIT. Regardless of the structure of exercise, higher energy expended was associated with pinch strength gains in the affected hand and strength losses in the less affected hand. Since aerobic exercise has acute effects on MEP latency and hand strength, it could be paired with upper limb training to potentiate beneficial effects. PMID- 30013493 TI - The Altered States Database: Psychometric Data of Altered States of Consciousness. PMID- 30013492 TI - The Central Executive Mediates the Relationship Between Children's Approximate Number System Acuity and Arithmetic Strategy Utilization in Computational Estimation. AB - Studies investigating the relationship between working memory (WM) and approximate number system (ANS) acuity in the area of arithmetic strategy utilization are scarce. The choice/no choice method paradigm was used in the present study to determine whether and how ANS acuity and WM components affected strategy utilization. The results showed that the central executive (CE) mediated the relationship between ANS acuity and strategy utilization. Furthermore, quantile regression analyses revealed that the association between CE and strategy choice was robust from the first to highest quantile. Notably, the relationship between ANS acuity and strategy choice was significant at the median and higher quantiles (i.e., 0.5, 0.75, and 0.85 quantiles), but not significant at lower quantiles (i.e., 0.15 and 0.25 quantiles). These results suggest that domain-general skills play a crucial role in the relationship between children's ANS acuity and mathematical ability. The impact of ANS acuity and CE on strategy choice was dependent on the distribution of the strategy utilization level. These results provide a further understanding of the utilization of cognitive strategies. PMID- 30013494 TI - Nature Experiences and Adults' Self-Reported Pro-environmental Behaviors: The Role of Connectedness to Nature and Childhood Nature Experiences. AB - This cross-sectional study aims to improve our understanding of the psychological pathways behind the commonly reported link between experiences in nature and pro environmentalism. Particularly, we explore whether nature experiences lead to self-reported pro-environmental behaviors (PEBs) and whether this relation is mediated by connectedness to nature. Additionally, we examine the possible lasting effect of childhood experiences with nature on adults' PEB. Most studies reporting on the link between contact with nature and pro-environmentalism have been conducted in developed countries, limiting the generalization of the results. To address this gap in the literature, the current study was conducted in a developing country (Brazil) with a sample of 224 young adults. According to our findings, greater contact with nature during childhood is associated with greater contact with nature as an adult, which, in turn, is positively associated with connectedness to nature and PEB. The stimulation of pleasant experiences while in direct contact with nature during childhood seems to trigger interactions with nature in adulthood and consequently, adults embrace pro environmental actions. PMID- 30013490 TI - Effects of Adolescent THC Exposure on the Prefrontal GABAergic System: Implications for Schizophrenia-Related Psychopathology. AB - Marijuana is the most commonly used drug of abuse among adolescents. Considerable clinical evidence supports the hypothesis that adolescent neurodevelopmental exposure to high levels of the principal psychoactive component in marijuana, delta-9-tetrahydrocanabinol (THC), is associated with a high risk of developing psychiatric diseases, such as schizophrenia later in life. This marijuana associated risk is believed to be related to increasing levels of THC found within commonly used marijuana strains. Adolescence is a highly vulnerable period for the development of the brain, where the inhibitory GABAergic system plays a pivotal role in the maturation of regulatory control mechanisms in the central nervous system (CNS). Specifically, adolescent neurodevelopment represents a critical period wherein regulatory connectivity between higher-order cortical regions and sub-cortical emotional processing circuits such as the mesolimbic dopamine (DA) system is established. Emerging preclinical evidence demonstrates that adolescent exposure to THC selectively targets schizophrenia-related molecular and neuropharmacological signaling pathways in both cortical and sub cortical regions, including the prefrontal cortex (PFC) and mesolimbic DA pathway, comprising the ventral tegmental area (VTA) and nucleus accumbens (NAc). Prefrontal cortical GABAergic hypofunction is a key feature of schizophrenia-like neuropsychopathology. This GABAergic hypofunction may lead to the loss of control of the PFC to regulate proper sub-cortical DA neurotransmission, thereby leading to schizophrenia-like symptoms. This review summarizes preclinical evidence demonstrating that reduced prefrontal cortical GABAergic neurotransmission has a critical role in the sub-cortical DAergic dysregulation and schizophrenia-like behaviors observed following adolescent THC exposure. PMID- 30013495 TI - Individuality in the Early Number Skill Components Underlying Basic Arithmetic Skills. AB - Early number skills underlie success in basic arithmetic. However, very little is known about the skill profiles among children in preprimary education and how the potential profiles are related to arithmetic development. This longitudinal study of 440 Finnish children in preprimary education (mean age: 75 months) modeled latent performance-level profile groups for the early number skill components that are proposed to be key predictors of arithmetic (symbolic number comparison, mapping, and verbal counting skills). Based on three assessment time points (September, January, and May), four profile groups were found: the poorest performing (6%), low-performing (16%), near-average-performing (33%), and high average-performing children (45%). Although the differences between the groups were statistically significant in all three number skill components and in basic arithmetic, the poorest-performing children seemed to have serious difficulties in accessing the semantic meaning of symbolic numbers that was required in the number comparison and mapping tasks in this study. Interestingly, the tasks demanding processing between quantities and symbols also most differentiated the poorest-performing children from the low-performing children. Due to remarkable and stable individual differences in early number skill components, the findings suggest systematic support and progress monitoring practices in preeducational settings to diminish and avoid potential difficulties in arithmetic and mathematics in general. PMID- 30013496 TI - Enhancing the Prediction of Emotionally Intelligent Behavior: The PAT Integrated Framework Involving Trait EI, Ability EI, and Emotion Information Processing. AB - Emotional Intelligence (EI) has been conceptualized in the literature either as a dispositional tendency, in line with a personality trait (trait EI; Petrides and Furnham, 2001), or as an ability, moderately correlated with general intelligence (ability EI; Mayer and Salovey, 1997). Surprisingly, there have been few empirical attempts conceptualizing how the different EI approaches should be related to each other. However, understanding how the different approaches of EI may be interwoven and/or complementary is of primary importance for clarifying the conceptualization of EI and organizing the literature around it. We introduce a theoretical framework explaining how trait EI, ability EI, and emotion information processing - a novel component related to EI recently introduced in the literature (e.g., Fiori and Vesely Maillefer, 2018) - may contribute to effective emotion-related performance and provide initial evidence supporting its usefulness in predicting EI-related outcomes. More specifically, we show that performance in a task in which participants had to infer the mental and emotional states of others, namely a Theory of Mind task, was predicted jointly (e.g., interaction effects) by trait EI, ability EI, and emotion information processing, after controlling for personality and IQ (N = 323). Our results argue for the importance of investigating the joint contribution of different aspects of EI in explaining variability in emotionally laden outcomes. PMID- 30013497 TI - The Moderating Role of Vertical Collectivism in South-Korean Adolescents' Perceptions of and Responses to Autonomy-Supportive and Controlling Parenting. AB - Research increasingly demonstrates that associations between autonomy-relevant parenting and adolescent adjustment generalize across cultures. Yet, there is still an ongoing debate about the role of culture in these effects of autonomy relevant parenting. The current study aimed to contribute to a more nuanced perspective on this debate by addressing cultural variability in micro-processes involved in autonomy-relevant parenting and, more specifically, in adolescents' appraisals of and responses to parental behavior. In this vignette-based experimental study, involving 137 South-Korean adolescents (54% female, mean age = 16 years), we examined whether individual differences in vertical collectivism affect the association between descriptions of potentially autonomy-supportive and controlling parenting practices and (a) appraisals of these practices (in terms of perceived autonomy support and control and experiences of autonomy need satisfaction and frustration), and (b) anticipated responses to these practices (i.e., negotiation, submissive compliance, and oppositional defiance). Participants in the autonomy-supportive condition reported more perceived autonomy support and autonomy satisfaction and lower perceived control and autonomy need frustration than participants in the controlling condition. Collectivism moderated between-vignette effects on perceived control and autonomy need frustration such that the differences between the autonomy-supportive and controlling vignettes were less pronounced (yet still significant) among adolescents scoring higher on collectivism. Collectivism did not moderate effects of the vignettes on the responses to parenting, but yielded a main effect, with collectivism relating to more submissive compliance and less oppositional defiance. Overall, the results suggest that both universal and culture-specific processes are involved in autonomy-relevant socialization. PMID- 30013498 TI - Promoting Innovative Performance in Multidisciplinary Teams: The Roles of Paradoxical Leadership and Team Perspective Taking. AB - Although many researches recognize the role of team expertise diversity in providing different ideas, it remains unclear how and under which conditions these various ideas are elaborated and integrated to fuel team innovation. To address this question, we develop a model theorizing that paradoxical leadership helps diverse teams overcome the differentiating-integrating paradox to promote innovation. Moreover, we further theorize that paradoxical leadership will cultivate perspective taking among team members. Analyses of the multi-time and multi-source data from 98 teams suggest that teams with expertise diversity exhibit better innovative performance when paradoxical leadership is prevalent. Furthermore, team perspective taking mediates the positive moderating effects of paradoxical leadership on the relationship between expertise diversity and innovative performance. Through these analyses, this study not only addresses the innovation paradox of expertise diverse teams from the perspective of leader influence, but also enriches the understanding of the effects of paradoxical leadership. PMID- 30013499 TI - Relative Age Effects and Gender Differences in the National Test of Numeracy: A Population Study of Norwegian Children. AB - Relative age effect (RAE) refers to the phenomenon by which children born early in their year of birth perform more highly than children born later in the same cohort. The purpose of this study was to evaluate whether an RAE exists in the Norwegian numeracy test for 5th, 8th, and 9th graders (National sample of 175,760). The results showed that the RAE is consistent across 5th, 8th, and 9th graders for both boys and girls. Mean scores decreased systematically with month of birth for both genders, and the mean scores for boys were higher compared with girls. The most interesting result and novelty is the gender difference in RAE observed analyzing high- vs. low scorers. Boys born early in the year were overrepresented as high scorers (RAE advantage), whereas girls born late in the year were overrepresented as low scorers (RAE disadvantage). It would be beneficial for researchers, teachers and education policymakers to be aware of RAE, both in terms of the practical use and implications of test results and to help identify strategies to adjust for relative age differences in national tests. PMID- 30013500 TI - The Power of Good: A Leader's Personal Power as a Mediator of the Ethical Leadership-Follower Outcomes Link. AB - The study's goal was to examine the socially responsible power use in the context of ethical leadership as an explanatory mechanism of the ethical leadership follower outcomes link. Drawing on the attachment theory (Bowlby, 1969/1982), we explored a power-based process model, which assumes that a leader's personal power is an intervening variable in the relationship between ethical leadership and follower outcomes, while incorporating the moderating role of followers' moral identity in this transformation process. The results of a two-wave field study (N = 235) that surveyed employees and a scenario experiment (N = 169) fully supported the proposed (moderated) mediation models, as personal power mediated the positive relationship between ethical leadership and a broad range of tested follower outcomes (i.e., leader effectiveness, follower extra effort, organizational commitment, job satisfaction, and work engagement), as well as the interactive effects of ethical leadership and follower moral identity on these follower outcomes. Theoretical and practical implications are discussed. PMID- 30013501 TI - Why You Should Report Bayes Factors in Your Transcranial Brain Stimulation Studies. PMID- 30013502 TI - Cross-Cultural Revision and Psychometric Properties of the Chinese Version of the Autism Spectrum Rating Scale (2-5 Years). AB - Background: No sufficient biomarkers are available for early identification of autism in the general population. Currently, the diagnosis of ASD depends on behavioral assessments. A useful screening tool can help to detect early autistic symptoms and provide children an early opportunity for ASD-related interventions. This research aimed to assess cross-cultural adaptation and psychometric properties of the autism spectrum rating scale (ASRS) under the Chinese cultural environment. Methods: Participants were recruited from 17 kindergartens and 5 special education schools across five cities (Shanghai, Guangzhou, Changsha, Chengdu, and Harbin) in China. A total of 2,181 kindergarten children and 207 ASD cases participated in this study. Mplus 7.03 was utilized to conduct exploratory factor analysis, followed by adaptive modifications to construct the revised Chinese version of the ASRS (RC_ASRS). Results: The result showed that 62 items comprised a two-factor structure; Factor 1 (social communication, SC) included 21 items, and Factor 2 (unusual behavior, UB) included 41 items. Cronbach's alpha ranged from 0.87 to 0.91 within the RC_ASRS. The total score and the SC and UB scores were significantly higher in ASD cases than in kindergarten samples (Cohen's d ranged from 0.82 to 2.72). The total RC_ASRS score showed an area under the curve (AUC) of 0.95 (95% CI: 0.93-0.97). With a total score cut-off >= 60, the RC_ASRS is an excellent tool to identify ASD cases from Chinese kindergarten children (sensitivity = 88.6%, specificity = 84.5%). Conclusions: The RC_ASRS has excellent psychometric properties and is a reliable, useful tool for early ASD screening among Chinese children. PMID- 30013503 TI - The Electrophysiological Features in X-Linked Charcot-Marie-Tooth Disease With Transient Central Nervous System Deficits. AB - Background: Electrophysiological examination plays an important role in the diagnosis of X-linked Charcot-Marie-Tooth disease (CMTX1) with transient central nervous system deficits. However, the electrophysiological features are seldom reported. Methods: We reviewed and analyzed published reports to determine the electrophysiological features of CMTX1 patients with transient central nervous system deficits. Results: A total of 21 CMTX1 patients with transient central nervous system deficits were found in 17 published case reports/series. The age of onset ranged from 0.5 to 18 years (mean 12.02 +/- 0.78 years). All patients were male. Recurrent episodes of central nervous system deficits were reported in all 21 cases and resolved in periods ranging from several minutes to 3 days. All 20 patients who had MRIs at presentation had bilaterally symmetrical abnormal T2/Diffusion signals in the white matter without enhancement of gadolinium. All subsequent MRIs showed improvement or were within normal limits. The median motor nerve conduction velocity (MNCV), motor latencies, and compound muscle action potential (CMAP) amplitude were the most commonly measurable electrophysiological parameters (85.7%). All cases that had MNCV at presentation had slower and significantly decreased MNCV compared with the normal value (34.1 +/- 1.10 m/s vs. 46.8+/-2.05 m/s, P < 0.0001; 95% CI, -17.4 to -7.92). The average variations of MNCV in median nerve, ulnar nerve, peroneal nerve, and tibial nerve were 22.0 +/- 5.96%, 27.6 +/- 11.9%, 25.9 +/- 4.36%, and 27.3 +/- 4.30%, respectively. All cases with measured sensory nerve conduction velocity (SNCV) at presentation had slower and significantly decreased SNCV compared with the normal value (35.3 +/- 1.33 m/s vs. 47.7 +/- 2.40 m/s, P < 0.001; 95% CI -18.2 to -6.46). The average variations of SNCV in median nerve, ulnar nerve, and sural nerve were 19.9 +/- 8.24%, 25.2 +/- 7.75%, and 23.2 +/- 3.95%, respectively. Conclusion: This case series serves as a reminder that electrophysiological examination should be included in the diagnosis of recurrent and episodic neurological deficit with white matter lesions. Median MNCV is a sensitive and valuable parameter to support the diagnosis of CMTX1 with transient central nervous system deficits. PMID- 30013505 TI - Efficacy of Repositioning Therapy in Patients With Benign Paroxysmal Positional Vertigo and Preexisting Central Neurologic Disorders. AB - With the exception of migraines, benign paroxysmal positional vertigo (BPPV) in patients with preexisting central neurologic disorders (CND) is rarely discussed in the literature. Demographic features of this patient group and the efficacy of repositioning therapy are still unknown. We hypothesized that a CND may alter the function of the central vestibular pathway, thus changing the pattern of BPPV and outcomes of repositioning. In this study, we enrolled 93 consecutive idiopathic BPPV patients and categorized them into two groups according to the presence or absence of a CND. In our series, 31.2% of BPPV cases had a CND. The most common associated CNDs were cerebrovascular disease and migraines. The two groups showed similar age distributions, canal involvement, success rates of repositioning, and cycles of treatment used to achieve complete resolution. The major differences were the proportion of females (89.7%) and a right-side predominance (75.9%) in the CND group. There was a trend of more residual dizziness (RD) after successful repositioning in the CND group, but the difference was not significant. The reason for the female and right-side predominance in the CND group is unclear. We concluded that the efficacy of repositioning therapy was excellent (with a success rate of 80.6% with one cycle and 93.5% within two cycles of treatment) for BPPV with or without a preexisting CND. Clinicians are encouraged to diagnose and treat BPPV in patients with a preexisting CND as early as possible to improve patients' quality of life, avoid complications, and reduce medical costs. PMID- 30013507 TI - An Inexpensive 6D Motion Tracking System for Posturography. AB - Computerized posturography is most often performed with a force plate measuring center-of-pressure (COP). COP is related to postural control actions but does not monitor the outcome of those actions, i.e., center-of-mass (COM) stability. For a more complete analysis of postural control COM should also be measured; however, existing motion tracking technology is prohibitively expensive and overcomplicated for routine use. The objective of this work was to create and validate an inexpensive and convenient stereo vision system which measured a trunk-fixed target's 3D position and orientation relating to COM. The stereo vision system would be complementary to typical force plate methods providing precise 6D position measurements under laboratory conditions. The developed system's measurement accuracy was worst in the inferior-superior axis (depth) and pitch coordinates with accuracy measures 1.1 mm and 0.8 degrees , respectively. The system's precision was worst in the depth and roll coordinates with values 0.1 mm and 0.15 degrees , respectively. Computer modeling successfully predicted this precision with 11.3% mean error. Correlation between in vivo target position (TP) and COP was above 0.73 with COP generally demonstrating larger excursions oscillating around TP. Power spectral analysis of TP revealed 99% of the signal was bound below 1.1 Hz matching expectations for COM. The new complementary measurement method enables identification of postural control strategies and as a result more complete analysis. Stereo vision is a useful complement to typical force plate equipment. The system presented here is inexpensive and convenient demonstrating potential for routine use in clinic and research. In order to use this system in clinic, future work is required in interpretation of this system's data and normal reference values must be established across gender and age in a healthy population followed by values from patients with different pathologies. PMID- 30013506 TI - CSF Biomarkers of Neurodegeneration in Progressive Non-fluent Aphasia and Other Forms of Frontotemporal Dementia: Clues for Pathomechanisms? AB - Frontotemporal Dementia (FTD) encompasses distinct pathophysiologically heterogenous disorders with different genetic and cellular disease mechanisms. The objective of this study is to compare the constellation of biomarkers of neurodegeneration in the cerebrospinal fluid (CSF) to the FTD type categorized by clinical symptoms. We investigated the levels of Phospho181-tau, Total-tau, Beta amyloid1-42, Neurofilament light chain, and Progranulin in the CSF of n = 99 FTD patients regarding to the different subtypes of FTD, including semantic dementia (SD), progressive non-fluent aphasia (PNFA), behavioral variant FTD (bvFTD). We compared these groups to patients without neurodegenerative disorders and another cohort encompassing tauopathies with distinct clinical syndromes (Cortico basal syndrome and progressive supranuclear palsy) and logopenic PNFA (lPPA) as another disorder with predominant speech disturbance. CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (p < 0.05). Also, neurofilament light chain was significantly higher (p < 0.036) in all FTD patients especially in SD patients (p < 0.01). CSF-Nfl levels also distinguished SD patients from logopenic Alzheimers patients (p < 0.05). In sum, CSF-Neurofilament light chain and CSF-Progranulin seem to be promising biomarkers for FTD, the latter predominantly for assumed TDP43-mediated FTD. PMID- 30013504 TI - The Contributions of Vestibular Evoked Myogenic Potentials and Acoustic Vestibular Stimulation to Our Understanding of the Vestibular System. AB - Vestibular-evoked myogenic potentials (VEMPs) are short-latency muscle reflexes typically recorded from the neck or eye muscles with surface electrodes. They are used clinically to assess otolith function, but are also interesting as they can provide information about the vestibular system and its activation by sound and vibration. Since the introduction of VEMPs more than 25 years ago, VEMPs have inspired animal and human research on the effects of acoustic vestibular stimulation on the vestibular organs, their projections and the postural muscles involved in vestibular reflexes. Using a combination of recording techniques, including single motor unit recordings, VEMP studies have enhanced our understanding of the excitability changes underlying the sound-evoked vestibulo collic and vestibulo-ocular reflexes. Studies in patients with diseases of the vestibular system, such as superior canal dehiscence and Meniere's disease, have shown how acoustic vestibular stimulation is affected by physical changes in the vestibule, and how sound-evoked reflexes can detect these changes and their resolution in clinical contexts. This review outlines the advances in our understanding of the vestibular system that have occurred following the renewed interest in sound and vibration as a result of the VEMP. PMID- 30013508 TI - Novel Functional MRI Task for Studying the Neural Correlates of Upper Limb Tremor. AB - Introduction: Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardized protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. Objective: This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. Methods: Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a "brick-breaker" joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analyzed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. Results: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531-0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p = 0.01) during PLAY, but not during MOVE. Conclusion: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options. PMID- 30013509 TI - Noninvasive Relative Quantification of [11C]ABP688 PET Imaging in Mice Versus an Input Function Measured Over an Arteriovenous Shunt. AB - Impairment of the metabotropic glutamate receptor 5 (mGluR5) has been implicated with various neurologic disorders. Although mGluR5 density can be quantified with the PET radiotracer [11C]ABP688, the methods for reproducible quantification of [11C]ABP688 PET imaging in mice have not been thoroughly investigated yet. Thus, this study aimed to assess and validate cerebellum as reference region for simplified reference tissue model (SRTM), investigate the feasibility of a noninvasive cardiac image-derived input function (IDIF) for relative quantification, to validate the use of a PET template instead of an MRI template for spatial normalization, and to determine the reproducibility and within subject variability of [11C]ABP688 PET imaging in mice. Blocking with the mGluR5 antagonist MPEP resulted in a reduction of [11C]ABP688 binding of 41% in striatum (p < 0.0001), while no significant effect could be found in cerebellum (-4.8%, p > 0.99) indicating cerebellum as suitable reference region for mice. DVR-1 calculated using a noninvasive IDIF and an arteriovenous input function correlated significantly when considering the cerebellum as the reference region (striatum: DVR-1, r = 0.978, p < 0.0001). Additionally, strong correlations between binding potential calculated from SRTM (BPND) with DVR-1 based on IDIF (striatum: r = 0.980, p < 0.0001) and AV shunt (striatum: r = 0.987, p < 0.0001). BPND displayed higher discrimination power than VT values in determining differences between wild-types and heterozygous Q175 mice, an animal model of Huntington's disease. Furthermore, we showed high agreement between PET- and MRI based spatial normalization approaches (striatum: r = 0.989, p < 0.0001). Finally, both spatial normalization approaches did not reveal any significant bias between test-retest scans, with a relative difference below 5%. This study indicates that noninvasive quantification of [11C]ABP688 PET imaging is reproducible and cerebellum can be used as reference region in mice. PMID- 30013510 TI - Abnormal Blink Reflex and Intermuscular Coherence in Writer's Cramp. AB - Background: Writer's cramp (WC) is a task-specific focal hand dystonia presenting with pain, stiffness and/or tremor while writing. We explored the involvement of cortical and brainstem circuits by measuring intermuscular coherence (IMC) and pre-pulse inhibition (PPI) of the blink reflex. Methods: IMC was measured in 10 healthy controls and 20 WC patients (10 with associated tremor) while they performed a precision grip task at different force levels. Blink responses were evaluated in 9 healthy controls and 10 WC patients by stimulating the right supraorbital nerve and recording surface EMG from the orbicularis oculi muscles bilaterally. PPI involved conditioning this stimulation with a prior shock to the right median nerve (100 ms interval), and measuring the reduction in the R2 component of the blink reflex. Results: Significant IMC at 3-7 Hz was present in WC patients, but not in healthy controls. Compared to healthy controls, in WC patients the R2 component of the blink reflex showed significantly less PPI. IMC at 3-7 Hz could reliably discriminate WC patients from healthy controls. Conclusion: Cortical or sub-cortical circuits generating theta (3-7 Hz) oscillations might play an important role in the pathogenesis of WC. Moreover, the lack of PPI implicates abnormalities in brainstem inhibition in the emergence of WC. IMC may merit further development as an electrodiagnostic test for focal dystonia. PMID- 30013511 TI - Fat Mass Follows a U-Shaped Distribution Based on Estradiol Levels in Postmenopausal Women. AB - Objective: Estradiol (E2) regulates adipose tissue resulting in increased fat mass (FM) with declining E2. However, increased visceral fat and hyperestrogenemia are features of obese individuals. It is possible that adipocytes in obese individuals are less sensitive to E2 resulting in higher FM. Our objective is to identify the range of serum E2 for which postmenopausal women have the lowest FM and best body composition. Methods: Cross-sectional data from 252 community-dwelling postmenopausal women, 42-90 years old. Subjects were stratified into categories of E2 (pg/ml): (1) <=10.5; (2) 10.6-13.9; (3) 14.0 17.4; and (4) >=17.5. Body composition by dual-energy X-ray absorptiometry. Serum E2 by radioimmunoassay. Between-group comparisons by analysis of covariance. Results: E2 linearly increased with increasing body weight and body mass index (r = 0.15 and p = 0.01 for both), but not with total FM (kg) or % FM (r = 0.07, p = 0.34 and r = -0.04, p = 0.56, respectively). However, total FM (kg) followed a U shaped distribution and was significantly lower in group 3 (27.6 +/- 10.6), compared with groups 1: (34.6 +/- 12.5), 2: (34.0 +/- 12.4), and 4: (37.0 +/- 10.6), p = 0.005. % FM was also lowest in group 3. While fat-free mass (FFM, kg) increased with increasing E2 (p < 0.001), % FFM was highest in group 3. Conclusion: In our population of postmenopausal women, FM followed a U-shaped distribution according to E2 levels. E2 between 14.0 and 17.4 pg/ml is associated with the best body composition, i.e., lowest total and % FM and highest % FFM. Given the role of E2 in regulating body fat, high FM at the high end of the E2 spectrum may suggest reduced E2 sensitivity in adipocytes among obese postmenopausal women. Clinical Trials: ClinicalTrials.gov identifier: NCT00146107. PMID- 30013512 TI - Bone Marrow Adipocyte: An Intimate Partner With Tumor Cells in Bone Metastasis. AB - The high incidences of bone metastasis in patients with breast cancer, prostate cancer and lung cancer still remains a puzzling issue. The "seeds and soil" hypothesis suggested that bone marrow (soil) may provide a favorable "niche" for tumor cells (seed). When seeking for effective ways to prevent and treat tumor bone metastasis, most researchers focus on tumor cells (seed) but not the bone marrow microenvironment (soil). In reality, only a fraction of circulating tumor cells (CTCs) could survive and colonize in bone. Thus, the bone marrow microenvironment could ultimately determine the fate of tumor cells that have migrated to bone. Bone marrow adipocytes (BMAs) are abundant in the bone marrow microenvironment. Mounting evidence suggests that BMAs may play a dominant role in bone metastasis. BMAs could directly provide energy for tumor cells, enhance the tumor cell proliferation, and resistance to chemotherapy and radiotherapy. BMAs are also known for releasing some inflammatory factors and adipocytokines to promote or inhibit bone metastasis. In this review, we made a comprehensive summary for the interaction between BMAs and bone metastasis. More importantly, we discussed the potentially promising methods for the prevention and treatment of bone metastasis. Genetic disruption and pharmaceutical inhibition may be effective in inhibiting the formation and pro-tumor functions of BMAs. PMID- 30013514 TI - Ulipristal Acetate Interferes With Actin Remodeling Induced by 17beta-Estradiol and Progesterone in Human Endometrial Stromal Cells. AB - Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) used for emergency contraception and for the medical management of symptomatic uterine fibroids (UF). Treatment with UPA turns in amenorrhea and UF volume reduction. Treatment with UPA is associated with the frequent development of benign, transitory endometrial changes known as SPRM-associated endometrial changes (PAECs). Why PAECs develop and their biological or cellular basis is unknown. Sex steroids, including estrogen and progesterone, are established modulators of the actin cytoskeleton in various cells, including endometrial cells. This explains several morphological and functional changes in endometrial cells. We thus hypothesized that UPA may alter the appearance of the endometrium by interfering with the actions of 17beta-estradiol (E2) or progesterone (P4) on actin dynamics. We isolated and cultured human endometrial stromal cells (ESC) from endometrial biopsies from healthy fertile women. Treatment with E2 or P4 stimulated visible actin rearrangements with actin remodeling toward the membrane. Activation through phosphorylation of the actin regulatory proteins, Moesin, and focal adhesion kinase (FAK), hacked actin remodeling induced by E2 and P4. Membrane re-localization of Paxillin and Vinculin were also induced by E2 and P4, showing the formation of focal adhesion complexes. All these E2 and P4 actions were inhibited by co-treatment with UPA, which was otherwise inactive if given alone. The cytoskeletal changes induced by E2 and P4 turned into increased motility of ESC, and UPA again blocked the actions E2 and P4. In conclusion, we find that UPA interferes with the cytoskeletal actions of E2 and P4 in ESC. This finding helps understanding the mode of actions of SPRMs in the endometrium and may be relevant for other potential clinical applications of UPA. PMID- 30013515 TI - FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator? AB - Fibroblast growth factor-23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical "mineral metabolism" actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered. PMID- 30013516 TI - Hidden MODY-Looking for a Needle in a Haystack. PMID- 30013517 TI - Corrigendum: Regulation of multiple carbon monoxide consumption pathways in anaerobic bacteria. AB - [This corrects the article on p. 147 in vol. 2, PMID: 21808633.]. PMID- 30013519 TI - Reincarnation of Bacteriocins From the Lactobacillus Pangenomic Graveyard. AB - Bacteria commonly produce narrow spectrum bacteriocins as a means of inhibiting closely related species competing for similar resources in an environment. The increasing availability of genomic data means that it is becoming easier to identify bacteriocins encoded within genomes. Often, however, the presence of bacteriocin genes in a strain does not always translate into biological antimicrobial activity. For example, when analysing the Lactobacillus pangenome we identified strains encoding ten pediocin-like bacteriocin structural genes which failed to display inhibitory activity. Nine of these bacteriocins were novel whilst one was identified as the previously characterized bacteriocin "penocin A." The composition of these bacteriocin operons varied between strains, often with key components missing which are required for bacteriocin production, such as dedicated bacteriocin transporters and accessory proteins. In an effort to functionally express these bacteriocins, the structural genes for the ten pediocin homologs were cloned alongside the dedicated pediocin PA-1 transporter in both Escherichia coli and Lactobacillus paracasei heterologous hosts. Each bacteriocin was cloned with its native leader sequence and as a fusion protein with the pediocin PA-1 leader sequence. Several of these bacteriocins displayed a broader spectrum of inhibition than the original pediocin PA-1. We show how potentially valuable bacteriocins can easily be "reincarnated" from in silico data and produced in vitro despite often lacking the necessary accompanying machinery. Moreover, the study demonstrates how genomic datasets such as the Lactobacilus pangenome harbor a potential "arsenal" of antimicrobial activity with the possibility of being activated when expressed in more genetically amenable hosts. PMID- 30013520 TI - Degradation of Chrysene by Enriched Bacterial Consortium. AB - Chrysene is a high molecular weight (HMW), polycyclic aromatic hydrocarbon (PAH) known for its recalcitrance and carcinogenic properties and sparsely soluble (0.003 mg/L) in aqueous medium. Due to these refractory properties, bioavailability of chrysene is very low and therefore is persistence in the environment escaping the metabolism by microorganisms. However, few bacterial and fungal strains are reported to degrade chrysene, but with lower efficiency, requiring additional/extraneous carbon sources (co-substrates) for it's complete mineralization. In this study, development, enrichment and characterization of bacterial consortium ASDC, consisting of Rhodococcus sp., ASDC1; Bacillus sp. ASDC2; and Burkholderia sp. ASDC3 were reported. Chrysene was utilized as a sole source of carbon and energy by the consortium, having maximum degradation rate of 1.5 mg/L/day and maximum growth rate of 0.125/h, under optimized conditions of pH 7.0, 37 degrees C under aeration of 150 rpm on gyrating shaking. Chrysene degradation was unaffected in presence of other PAHs like pyrene, fluoranthene, naphthalene, phenanthrene, benzene, toluene and xylene, individually as well as in mixture. The results revealed that peptone, ammonium nitrate, sodium succinate have enhanced the chrysene degradation rate during first 24 h of experimentation, which was later on inhibited with increase in incubation time. The chrysene degradation was inhibited by mercury even at lower concentration (1 mM). The results also revealed that SDS has enhanced its degradation by 5.2-fold for initial 24 h of growth, but with increasing in the incubation period, it decreases by 1.2-fold on 7th day of experimentation. The HPLC studies suggested that chrysene was degraded through phthalic acid pathway by the consortium ASDC and the stoichiometric measurements indicated the complete mineralization of chrysene. The flask scale results were validated at simulated microcosm models, where enriched consortium ASDC exhibited maximum degradation (96%) in polluted, non-sterile soil sediment, indicating that consortial strains along with indigenous metabolism showed synergistic metabolism for degradation of chrysene. Thus, the above study revealed the useful enrichment of bacterial community for synergistic degradation of PAHs (chrysene) which could be further exploited for in situ remediation of PAH contaminated sites. PMID- 30013518 TI - Gene Expression Patterns in Roots of Camelina sativa With Enhanced Salinity Tolerance Arising From Inoculation of Soil With Plant Growth Promoting Bacteria Producing 1-Aminocyclopropane-1-Carboxylate Deaminase or Expression the Corresponding acdS Gene. AB - Camelina sativa treated with plant growth-promoting bacteria (PGPB) producing 1 aminocyclopropane-1-carboxylate deaminase (acdS) or transgenic lines expressing acdS exhibit increased salinity tolerance. AcdS reduces the level of stress ethylene to below the point where it is inhibitory to plant growth. The study determined that several mechanisms appear to be responsible for the increased salinity tolerance and that the effect of acdS on gene expression patterns in C. sativa roots during salt stress is a function of how it is delivered. Growth in soil treated with the PGPB (Pseudomonas migulae 8R6) mostly affected ethylene- and abscisic acid-dependent signaling in a positive way, while expression of acdS in transgenic lines under the control of the broadly active CaMV 35S promoter or the root-specific rolD promoter affected auxin, jasmonic acid and brassinosteroid signaling and/biosynthesis. The expression of genes involved in minor carbohydrate metabolism were also up-regulated, mainly in roots of lines expressing acdS. Expression of acdS also affected the expression of genes involved in modulating the level of reactive oxygen species (ROS) to prevent cellular damage, while permitting ROS-dependent signal transduction. Though the root is not a photosynthetic tissue, acdS had a positive effect on the expression of genes involved in photosynthesis. PMID- 30013513 TI - Inflammatory Signaling in Hypertension: Regulation of Adrenal Catecholamine Biosynthesis. AB - The immune system is increasingly recognized for its role in the genesis and progression of hypertension. The adrenal gland is a major site that coordinates the stress response via the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal system. Catecholamines released from the adrenal medulla function in the neuro-hormonal regulation of blood pressure and have a well established link to hypertension. The immune system has an active role in the progression of hypertension and cytokines are powerful modulators of adrenal cell function. Adrenal medullary cells integrate neural, hormonal, and immune signals. Changes in adrenal cytokines during the progression of hypertension may promote blood pressure elevation by influencing catecholamine biosynthesis. This review highlights the potential interactions of cytokine signaling networks with those of catecholamine biosynthesis within the adrenal, and discusses the role of cytokines in the coordination of blood pressure regulation and the stress response. PMID- 30013522 TI - Amastigote Synapse: The Tricks of Trypanosoma cruzi Extracellular Amastigotes. AB - To complete its life cycle within the mammalian host, Trypanosoma cruzi, the agent of Chagas' disease, must enter cells. Trypomastigotes originating from the insect vector (metacyclic) or from infected cells (bloodstream/tissue culture derived) are the classical infective forms of the parasite and enter mammalian cells in an actin-independent manner. By contrast, amastigotes originating from the premature rupture of infected cells or transformed from swimming trypomastigotes (designated extracellular amastigotes, EAs) require functional intact microfilaments to invade non-phagocytic host cells. Earlier work disclosed the key features of EA-HeLa cell interplay: actin-rich protrusions called 'cups' are formed at EA invasion sites on the host cell membrane that are also enriched in actin-binding proteins, integrins and extracellular matrix elements. In the past decades we described the participation of membrane components and secreted factors from EAs as well as the actin-regulating proteins of host cells involved in what we propose to be a phagocytic-like mechanism of parasite uptake. Thus, regarding this new perspective herein we present previously described EA-induced 'cups' as parasitic synapse since they can play a role beyond its architecture function. In this review, we focus on recent findings that shed light on the intricate interaction between extracellular amastigotes and non-phagocytic HeLa cells. PMID- 30013521 TI - Arbuscular Mycorrhizal Symbiosis Leads to Differential Regulation of Drought Responsive Genes in Tissue-Specific Root Cells of Common Bean. AB - Arbuscular mycorrhizal fungi (AMF) colonization in plants promotes both local and systemic changes in the gene expression profiles of the host that might be relevant for drought-stress perception and response. Drought-tolerant common bean plants (cv. BAT 477), colonized by a mixture of AMF (Glomus clarum, Acaulospora scrobiculata, and Gigaspora rosea), were exposed to a water deprivation regime of 96 h during pre-flowering. Root transcriptomes were accessed through RNA-Seq revealing a set of 9,965 transcripts with significant differential regulation in inoculated plants during a water deficit event, and 10,569 in non-inoculated. These data include 1,589 transcripts that are exclusively regulated by AMF inoculation, and 2,313 under non-inoculation conditions. Relative gene expression analyses of nine aquaporin-related transcripts were performed in roots and leaves of plants harvested at initial stages of treatment. Significant shifts in gene expression were detected in AM water deficit-treated roots, in relation to non inoculated, between 48 and 72 h. Leaves also showed significant mycorrhizal influence in gene expression, especially after 96 h. Root cortical cells, harboring or not arbuscules, were collected from both inoculation treatments through a laser microdissection-based technique. This allowed the identification of transcripts, such as the aquaporin PvPIP2;3 and Glucan 1,3 beta-Glucosidase, that are unique to arbuscule-containing cells. During the water deficit treatment, AMF colonization exerted a fine-tune regulation in the expression of genes in the host. That seemed to initiate in arbuscule-containing cells and, as the stressful condition persisted, propagated to the whole-plant through secondary signaling events. Collectively, these results demonstrate that arbuscular mycorrhization leads to shifts in common bean's transcriptome that could potentially impact its adaptation capacity during water deficit events. PMID- 30013524 TI - SAV4189, a MarR-Family Regulator in Streptomyces avermitilis, Activates Avermectin Biosynthesis. AB - The bacterial species Streptomyces avermitilis is an important industrial producer of avermectins, which are widely utilized as effective anthelmintic and insecticidal drugs. We used gene deletion, complementation, and overexpression experiments to identify SAV4189, a MarR-family transcriptional regulator (MFR) in this species, as an activator of avermectin biosynthesis. SAV4189 indirectly stimulated avermectin production by altering expression of cluster-situated activator gene aveR, and directly repressed the transcription of its own gene (sav_4189) and adjacent cotranscribed gene sav_4190 (which encodes an unknown transmembrane efflux protein). A consensus 13-bp palindromic sequence, 5' TTGCCYKHRSCAA-3' (Y = T/C; K = T/G; H = A/C/T; R = A/G; S = C/G), was found within the SAV4189-binding sites of its own promoter region, and shown to be essential for binding. The SAV4189 regulon was thus predicted based on bioinformatic analysis. Night new identified SAV4189 targets are involved in transcriptional regulation, primary metabolism, secondary metabolism, and stress response, reflecting a pleiotropic role of SAV4189. sav_4190, the important target gene of SAV4189, exerted a negative effect on avermectin production. sav_4189 overexpression and sav_4190 deletion in S. avermitilis wild-type and industrial strains significantly increased avermectin production. SAV4189 homologs are widespread in other Streptomyces species. sav_4189 overexpression in the model species S. coelicolor also enhanced antibiotic production. The strategy of increasing yield of important antibiotics by engineering of SAV4189 homologs and target gene may potentially be extended to other industrial Streptomyces species. In addition, SAV4189 bound and responded to exogenous antibiotics hygromycin B and thiostrepton to modulate its DNA-binding activity and transcription of target genes. SAV4189 is the first reported exogenous antibiotic receptor among Streptomyces MFRs. PMID- 30013523 TI - Clinical Staphylococcus argenteus Develops to Small Colony Variants to Promote Persistent Infection. AB - Staphylococcus argenteus is a novel staphylococcal species (also considered as a part of Staphylococcus aureus complex) that is infrequently reported on, and clinical S. argenteus infections are largely unstudied. Here, we report a persistent and recurrent hip joint infection case in which a S. argenteus strain and its small colony variants (SCVs) strain were successively isolated. We present features of the two S. argenteus strains and case details of their pathogenicity, explore factors that induce S. argenteus SCVs formation in the course of anti-infection therapy, and reveal potential genetic mechanisms for S. argenteus SCVs formation. S. argenteus strains were identified using phenotypic and genotypic methods. The S. argenteus strain XNO62 and SCV strain XNO106 were characterized using different models. S. argenteus SCVs were induced by the administration of amikacin and by chronic infection course based on the clinical case details. The genomes of both strains were sequenced and aligned in a pair wise fashion using Mauve. The case details gave us important insights on the characteristics and therapeutic strategies for infections caused by S. argenteus and its SCVs. We found that strain XNO62 and SCV strain XNO106 are genetically related sequential clones, the SCV strain exhibits reduced virulence but enhanced intracellular persistence compared to strain XNO62, thus promoting persistent infection. The induction experiments for S. argenteus SCVs demonstrated that high concentrations of amikacin greatly induce S. argenteus XNO62 to form SCVs, while a chronic infection of S. argenteus XNO62 slightly induces SCVs formation. Potential genetic mechanisms for S. argenteus SCVs formation were revealed and discussed based on genomic alignments. In conclusion, we report the first case of infection caused by S. argenteus and its SCVs strain. More attention should be paid to infections caused by S. argenteus and its SCVs, as they constitute a challenge to current therapeutic strategies. The problem of S. argenteus SCVs should be noticed, in particular when amikacin is used or in the case of a chronic S. argenteus infection. PMID- 30013526 TI - Extra-Chromosomal DNA Sequencing Reveals Episomal Prophages Capable of Impacting Virulence Factor Expression in Staphylococcus aureus. AB - Staphylococcus aureus is a major human pathogen with well-characterized bacteriophage contributions to its virulence potential. Recently, we identified plasmidial and episomal prophages in S. aureus strains using an extra-chromosomal DNA (exDNA) isolation and sequencing approach, uncovering the plasmidial phage phiBU01, which was found to encode important virulence determinants. Here, we expanded our extra-chromosomal sequencing of S. aureus, selecting 15 diverse clinical isolates with known chromosomal sequences for exDNA isolation and next generation sequencing. We uncovered the presence of additional episomal prophages in 5 of 15 samples, but did not identify any plasmidial prophages. exDNA isolation was found to enrich for circular prophage elements, and qPCR characterization of the strains revealed that such prophage enrichment is detectable only in exDNA samples and would likely be missed in whole-genome DNA preparations (e.g., detection of episomal prophages did not correlate with higher prophage excision rates nor higher excised prophage copy numbers in qPCR experiments using whole-genome DNA). In S. aureus MSSA476, we found that enrichment and excision of the prophage phiSa4ms into the cytoplasm was temporal and that episomal prophage localization did not appear to be a precursor to lytic cycle replication, suggesting phiSa4ms excision into the cytoplasm may be part of a novel lysogenic switch. For example, we show that phiSa4ms excision alters the promoter and transcription of htrA2 , encoding a stress-response serine protease, and that alternative promotion of htrA2 confers increased heat-stress survival in S. aureus COL. Overall, exDNA isolation and focused sequencing may offer a more complete genomic picture for bacterial pathogens, offering insights into important chromosomal dynamics likely missed with whole-genome DNA-based approaches. PMID- 30013525 TI - A Multiplex Asymmetric Reverse Transcription-PCR Assay Combined With an Electrochemical DNA Sensor for Simultaneously Detecting and Subtyping Influenza A Viruses. AB - The reliable and rapid detection of viral pathogens that cause respiratory infections provide physicians several advantages in treating patients and managing outbreaks. The Luminex respiratory virus panel (RVP) assay has been shown to be comparable to or superior to culture/direct fluorescent-antibody assays (DFAs) and nucleic acid tests that are used to diagnose respiratory viral infections. We developed a multiplex asymmetric reverse transcription (RT)-PCR assay that can simultaneously differentiate all influenza A virus epidemic subtypes. The amplified products were hybridized with an electrochemical DNA sensor, and the results were automatically acquired. The limits of detection (LoDs) of both the Luminex RVP assay and the multiplex RT-PCR-electrochemical DNA sensor were 101 TCID50 for H1N1 virus and 102 TCID50 for H3N2 virus. The specificity assessment of the multiplex RT-PCR-electrochemical DNA sensor showed no cross-reactivity among different influenza A subtypes or with other non influenza respiratory viruses. In total, 3098 respiratory tract specimens collected from padiatric patients diagnosed with pneumonia were tested. More than half (43, 53.75%) of the specimens positive for influenza A viruses could not be further subtyped using the Luminex RVP assay. Among the remaining 15 specimens that were not subtyped, not degraded, and in sufficient amounts for the multiplex RT-PCR-electrochemical DNA sensor test, all (100%) were H3N2 positive. Therefore, the sensitivity of the Luminex RVP assay for influenza A virus was 46.25%, whereas the sensitivity of the multiplex RT-PCR-electrochemical DNA sensor for the clinical H1N1 and H3N2 specimens was 100%. The sensitivities of the multiplex RT-PCR-electrochemical DNA sensor for the avian H5N1, H5N6, H9N2, and H10N8 viruses were 100%, whereas that for H7N9 virus was 85.19%. We conclude that the multiplex RT-PCR-electrochemical DNA sensor is a reliable method for the rapid and accurate detection of highly variable influenza A viruses in respiratory infections with greater detection sensitivity than that of the Luminex xTAG assay. The high mutation rate of influenza A viruses, particularly H3N2 during the 2014 to 2016 epidemic seasons, has a strong impact on diagnosis. A study involving more positive specimens from all influenza A virus epidemic subtypes is required to fully assess the performance of the assay. PMID- 30013527 TI - Origin of Cave Fungi. AB - Karst caves are obviously characterized by darkness, constantly low temperature, high humidity, and oligotrophy. Previous studies revealed that Karst caves have a high and specific bio-diversity. A large number of troglobiont animals had been discovered and their evolution and speciation have been well investigated. However, the origin and evolution of cave fungi remain unknown. In a previous study, we have identified 20 new species, which accounted for 49% of the total number of new species of fungi ever described from caves. In this study, we inferred the divergence times of these 20 new species and compared to the cave formation geologic age. The fossil-calibrated molecular clock showed that the divergence times of these 20 suspected troglobitic fungi are between late Miocene (7.2 Mya for Metapochonia variabilis) and late Jurassic (158 Mya for Gymnoascus exasperates). While based on the historical geological movement and the paleoclimate of Guizhou, it has been estimated that the development of caves in this area was later than middle Pliocene (3.5-4 Mya). It is therefore concluded that the new species described from these caves are unlikely troglobitic fungi but travelers from other environments. The geographic history of caves appeared to be too short for fungal speciation. PMID- 30013528 TI - Expression Profiles of mRNA and lncRNA in HCT-8 Cells Infected With Cryptosporidium parvum IId Subtype. AB - Cryptosporidium parvum is one of the most important enteric protozoan pathogens, responsible for severe diarrhea in immunocompromised human and livestock. However, few effective agents were available for controlling this parasite. Accumulating evidences suggest that long non-coding RNA (lncRNA) played key roles in many diseases through regulating the gene expression. Here, the expression profiles of lncRNAs and mRNAs were analyzed in HCT-8 cells infected with C. parvum IId subtype using microarray assay. A total of 821 lncRNAs and 1,349 mRNAs were differentially expressed in infected cells at 24 h post infection (pi). Of them, all five types of lncRNAs were identified, including 22 sense, 280 antisense, 312 intergenic, 44 divergent, 33 intronic lncRNAs, and 130 lncRNAs that were not found the relationship with mRNAs' location. Additionally, real time polymerase chain reactions of 10 lncRNAs and 10 mRNAs randomly selected were successfully confirmed the microarray results. The co-expression and target prediction analysis indicated that 27 mRNAs were cis-regulated by 29 lncRNAs and 109 were trans-regulated by 114 lncRNAs. These predicted targets were enriched in several pathways involved in the interaction between host and C. parvum, e.g., hedgehog signaling pathway, Wnt signaling pathway, and tight junction, suggesting that these differentially expressed lncRNAs would play important regulating roles during the infection of C. parvum IId subtype. PMID- 30013529 TI - Humic Substances Alter Ammonia Production and the Microbial Populations Within a RUSITEC Fed a Mixed Hay - Concentrate Diet. AB - Humic substances are a novel feed additive which may have the potential to mitigate enteric methane (CH4) production from ruminants as well as enhance microbial activity in the rumen. The aim of this study was to examine the effects of humic substances on fermentation characteristics and microbial communities using the rumen stimulation technique (RUSITEC). The experiment was conducted as a completely randomized design with 3 treatments duplicated in 2 runs (a 15-day period each run) with 2 replicates per run. Treatments consisted of a control diet (forage:concentrate; 60:40) without humic substances or humic substances added at either 1.5 g/d or 3.0 g/d. Dry matter disappearance, pH, fermentation parameters and gas production were measured from day 8 to 15. Samples for microbial profiling were taken on day 5, 10, and 15 using the digested feed bags for solid- associated microbes (SAM) and fermenter fluid for liquid- associated microbes (LAM). The inclusion of humic substances had no effect (P >= 0.19) on DM disappearance, pH or the concentrations of VFA. The production of NH3 was linearly decreased (P = 0.04) with increasing levels of humic substances in the diet. There was no effect (P >= 0.43) of humic substances on total gas, CO2 or CH4 production. The number of OTUs was significantly reduced in the 3.0 g/d treatment compared to the control on d 10 and 15; however, the microbial community structure was largely unaffected (P > 0.05). In the SAM samples, the genera Lachnospiraceae XPB1014 group, Succiniclasticum, and Fibrobacter were reduced in the 3.0 g/d treatment and Anaeroplasma, Olsenella, and Pseudobutyrivibrio were increased on day 5, 10, and 15. Within the LAM samples, Christensenellaceae R-7 and Succiniclasticum were the most differentially abundant genera between the control and 3.0 g/d HS treatment samples (P < 0.05). This study highlights the potential use of humic substances as a natural feed additive which may play a role in nitrogen metabolism without negatively affecting the ruminal microbiota. PMID- 30013530 TI - Endosymbionts Alter Larva-to-Nymph Transstadial Transmission of Babesia microti in Rhipicephalus haemaphysaloides Ticks. AB - Maternally inherited endosymbionts inhabit a variety of arthropods. Some of them can protect the arthropod host against a wide range of pathogens. However, very little is known about the association between endosymbionts and pathogen susceptibility in ticks. The present study investigated the effect of endosymbionts on larva-to-nymph transstadial transmission of Babesia microti by Rhipicephalus haemaphysaloides ticks. Engorged female ticks were injected with PBS, ciprofloxacin or kanamycin. The offspring larvae were used to infest B. microti-positive mice. Prevalence of B. microti among the nymphs in different treatment groups and its association with endosymbiont density in the larvae were analyzed. The results showed that the prevalence of B. microti in the kanamycin treated group (63.9%, 95% confidence interval (CI): 52.8-75.0%) was higher than that in the PBS (23.6%, 95% CI: 13.8-33.4%) or ciprofloxacin-treated (25.0%, 95% CI: 15.0-35.0%) groups. This increased prevalence was associated with reduced density of Coxiella-like endosymbiont but was not related to the density of Rickettsia-like endosymbiont. No direct evidence has previously been reported about the impact of Coxiella-like endosymbiont on pathogen susceptibility in ticks. This study reveals that endosymbionts are potentially important defensive symbionts of R. haemaphysaloides which may influence the colonization or susceptibility of B. microti in the tick host. PMID- 30013531 TI - Detection and Investigation of Eagle Effect Resistance to Vancomycin in Clostridium difficile With an ATP-Bioluminescence Assay. AB - Vancomycin was bactericidal against Clostridium difficile at eightfold the minimum inhibitory concentration (MIC) using a traditional minimum bactericidal concentration (MBC) assay. However, at higher concentrations up to 64 * MIC, vancomycin displayed a paradoxical "more-drug-kills-less" Eagle effect against C. difficile. To overcome challenges associated with performing the labor-intensive agar-based MBC method under anaerobic growth conditions, we investigated an alternative more convenient ATP-bioluminescence assay to assess the Eagle effect in C. difficile. The commercial BacTiter-GloTM assay is a homogenous method to determine bacterial viability based on quantification of bacterial ATP as a marker for metabolic activity. The ATP-bioluminescence assay was advantageous over the traditional MBC-type assay in detecting the Eagle effect because it reduced assay time and was simple to perform; measurement of viability could be performed in less than 10 min outside of the anaerobic chamber. Using this method, we found C. difficile survived clinically relevant, high concentrations of vancomycin (up to 2048 MUg/mL). In contrast, C. difficile did not survive high concentrations of metronidazole or fidaxomicin. The Eagle effect was also detected for telavancin, but not for teicoplanin, dalbavancin, oritavancin, or ramoplanin. All four pathogenic strains of C. difficile tested consistently displayed Eagle effect resistance to vancomycin, but not metronidazole or fidaxomicin. These results suggest that Eagle effect resistance to vancomycin in C. difficile could be more prevalent than previously appreciated, with potential clinical implications. The ATP-Bioluminescence assay can thus be used as an alternative to the agar-based MBC assay to characterize the Eagle effect against a variety of antibiotics, at a wide-range of concentrations, with much greater throughput. This may facilitate improved understanding of Eagle effect resistance and promote further research to understand potential clinical relevance. PMID- 30013532 TI - EPS Glycoconjugate Profiles Shift as Adaptive Response in Anaerobic Microbial Granulation at High Salinity. AB - Anaerobic granulation at elevated salinities has been discussed in several analytical and engineering based studies. They report either enhanced or decreased efficiencies in relation to different Na+ levels. To evaluate this discrepancy, we focused on the microbial and structural dynamics of granules formed in two upflow anaerobic sludge blanket (UASB) reactors treating synthetic wastewater at low (5 g/L Na+) and high (20 g/L Na+) salinity conditions. Granules were successfully formed in both conditions, but at high salinity, the start-up inoculum quickly formed larger granules having a thicker gel layer in comparison to granules developed at low salinity. Granules retained high concentrations of sodium without any negative effect on biomass activity and structure. 16S rRNA gene analysis and Fluorescence in Situ Hybridization (FISH) identified the acetotrophic Methanosaeta harundinacea as the dominant microorganism at both salinities. Fluorescence lectin bar coding (FLBC) screening highlighted a significant shift in the glycoconjugate pattern between granules grown at 5 and 20 g/L of Na+, and the presence of different extracellular domains. The excretion of a Mannose-rich cloud-like glycoconjugate matrix, which seems to form a protective layer for some methanogenic cells clusters, was found to be the main distinctive feature of the microbial community grown at high salinity conditions. PMID- 30013533 TI - Experimental Warming Differentially Influences the Vulnerability of Phototrophic and Heterotrophic Periphytic Communities to Copper Toxicity. AB - Aquatic ecosystems are generally subjected to multiple perturbations due to simultaneous or successive combinations of various natural and anthropogenic environmental pressures. To better assess and predict the resulting ecological consequences, increasing attention should be given to the accumulation of stresses on freshwater ecosystems and its effects on the vulnerability of aquatic organisms, including microbial communities, which play crucial functional roles. Here we used a microcosm study to assess the influence of an experimental warming on the vulnerability of phototrophic and heterotrophic periphytic communities to acute and chronic copper (Cu) toxicity. Natural periphytic communities were submitted for 4 weeks to three different temperatures (18, 23, and 28 degrees C) in microcosms contaminated (at about 15 MUg L-1) or not with Cu. The vulnerability of both phototrophic and heterotrophic microbial communities to subsequent acute Cu stress was then assessed by measuring their levels of sensitivity to Cu from bioassays targeting phototrophic (photosynthetic activity) and heterotrophic (beta-glucosidase and leucine aminopeptidase extracellular enzymatic activities) microbial functions. We postulated that both the increase in temperature and the chronic Cu exposure would modify microbial community structure, thus leading to changes in the capacity of phototrophic and heterotrophic communities to tolerate subsequent acute exposure to Cu. Our results demonstrated that the influence of temperature on the vulnerability of phototrophic and heterotrophic microbial communities to Cu toxicity can vary greatly according to function studied. These findings emphasize the importance of considering different functional compartments and different functional descriptors to better assess the vulnerability of periphyton to multiple stresses and predict the risks induced by multiple stressors for ecosystem balance and functioning. PMID- 30013534 TI - Effect of Early Weaning on the Intestinal Microbiota and Expression of Genes Related to Barrier Function in Lambs. AB - Weaning stress has been reported to impair intestinal health. The gut microbiota plays a vital role in the long-term health of the host. However, our understanding of weaning stress on gut microbiota and barrier function is very limited in livestock species, especially lambs. We investigated the effects of early weaning stress on intestinal bacterial communities and intestinal barrier function in lambs. A total of 24 neonatal male Hu lambs were randomly allocated into two groups, one weaned on day 28 and the other weaned on day 56. At 42 and 84 days, six lambs from each group were randomly selected and sacrificed. Ileal tissue and ileal digesta were collected to compare the differences in ileal microbiota and the mRNA levels of Toll-like receptors (TLRs) and tight junction proteins between the early weaning group and the control group at day 42 when the early weaning group have been weaned for 14 days, and at day 84 when the 28 and 56 days weaning groups had been weaned for 56 and 28 days, respectively. 16S rRNA gene sequencing of ileal samples revealed that the ileal microbiota was very different between the two groups, even at 84 days of age. Early weaning significantly increased alpha diversity and altered the relative abundance of several bacterial taxa. The expression of genes related to intestinal barrier function was affected by early weaning. Early weaning significantly increased ileal mRNA levels of TLR1 on days 42 and 84; TLR2, TLR4, and TLR5 on day 84; claudin1 and claudin4 on day 42; and occludin on day 84. We demonstrate that early weaning not only altered the ileal microbiota on day 42 (compared with lambs that were not weaned), but also had lasting effects on the ileal microbiota at day 84; furthermore, early weaning impacts expression levels of genes related to intestinal barrier function. PMID- 30013535 TI - Unprecedented in Vitro Antitubercular Activitiy of Manganese(II) Complexes Containing 1,10-Phenanthroline and Dicarboxylate Ligands: Increased Activity, Superior Selectivity, and Lower Toxicity in Comparison to Their Copper(II) Analogs. AB - Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2].4H2O (1) and {[Mn(3,6,9 tdda)(phen)2].3H2O.EtOH}n (3) (odaH2 = octanedioic acid, phen = 1,10 phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)].4H2O (6), [Mn2(isoph)2(phen)3].4H2O (7), {[Mn(phen)2(H2O)2]}2(isoph)2(phen).12H2O (8) and [Mn(tereph)(phen)2].5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu2(oda)(phen)4](ClO4)2.2.76H2O.EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, {[Cu(3,6,9-tdda)(phen)2].3H2O.EtOH}n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents. PMID- 30013536 TI - The Potential Correlation Between Bacterial Sporulation and the Characteristic Flavor of Chinese Maotai Liquor. AB - The relationship between the formation of characteristic Maotai-flavor substances (MTFS) and the dominant bacteria in Maotai Daqu (MTDQ) has long been a topic of research interest in the field of liquor brewing in China. To investigate the connection between MTFS and the Bacillus subtilis (one of dominant bacteria in MTDQ) cultured on solid plates of wheat extract medium at, temperatures of 37, 46, and up to 55 degrees C (Group A), and at a constant 37 degrees C (Group B), the transcriptomes of the bacteria grown in the two groups were studied. About 10 out of 84 differentially expressed genes (DEGs) were related to promoting sporulation. Furthermore, observations made with transmission electron microscopy (TEM) showed that a thicker spore cortex appeared in Group A. The content of 2, 6 pyridinedicarboxylic acid (DPA), an important component of the spore, was 49.77 (+/-2.50) and 38.23 (+/-3.96) MUg/mg of dried spores from the bacteria cultured in Groups A and B, respectively. Combined with the production process of Maotai liquor, more DPA accumulates in the high-temperature fermentation stage and is then released by spore germination during the subsequent temperature-drop stage. We suggest that DPA (or its derivatives) can then be transformed into MTFS by the Maillard reaction after many rounds of microbial fermentation. The viewpoint that there is a potential correlation between bacterial sporulation and the production of MTFS is proposed. PMID- 30013537 TI - DNA Damage Repair and Drug Efflux as Potential Targets for Reversing Low or Intermediate Ciprofloxacin Resistance in E. coli K-12. AB - Ciprofloxacin is a potent antibacterial drug that is widely used in human clinical applications. As a consequence of its extensive use, resistance has emerged in almost all clinically relevant bacterial species. A mean to combat the observed ciprofloxacin resistance is by reversing it via co-administration of a potentiating compound, also known as a helper drug. Here, we report on the current advances in identifying ciprofloxacin helper drugs, and put them into perspective of our own findings. We searched for potential helper drug targets in Escherichia coli strains with different levels of ciprofloxacin resistance using transcriptomics i.e., RNAseq and by deletion of genes associated with hyper susceptibility to ciprofloxacin. Differential gene expression analysis of the highly ciprofloxacin resistant uropathogenic E. coli strain, ST131 UR40, treated with a clinically relevant concentration of ciprofloxacin (2 MUg/mL), showed that the transcriptome was unaffected. Conversely, genetic screening of 23 single gene deletions in the high-level ciprofloxacin resistant laboratory derived E. coli strain, LM693, led to a significant decrease in the minimal inhibitory concentration for several genes, including genes encoding the AcrAB-TolC efflux pump, SOS-response proteins and the global regulator Fis. In addition, deletion of acrA, tolC, recA, or recC rendered two E. coli strains with intermediate susceptibility to ciprofloxacin fully susceptible according to the CLSI recommended breakpoint. Our results corroborate the AcrAB-TolC efflux pump and the SOS response proteins, RecA and RecC, as potential targets for ciprofloxacin helper drugs in treatment of human bacterial infections caused by E. coli strains with intermediate sensitivity to ciprofloxacin. PMID- 30013538 TI - Lactobacillus acidophilus Attenuates Salmonella-Induced Stress of Epithelial Cells by Modulating Tight-Junction Genes and Cytokine Responses. AB - Scope: Salmonellosis is a prevalent food-borne illness that causes diarrhea in over 130 million humans yearly and can lead to death. There is an urgent need to find alternatives to antibiotics as many salmonellae are now multidrug resistant. As such, specific beneficial bacteria and dietary fibers can be an alternative as they may prevent Salmonella Typhimurium (STM) infection and spreading by strengthening intestinal barrier function. Methods and Results: We tested whether immune active long-chain inulin-type fructans and/or L. acidophilus W37, L. brevis W63, and L. casei W56 can strengthen barrier integrity of intestinal Caco 2 cells in the presence and absence of a STM. Effects of the ingredients on intestinal barrier function were first evaluated by quantifying trans-epithelial electric resistance (TEER) and regulation of gene expression by microarray. Only L. acidophilus had effects on TEER and modulated a group of 26 genes related to tight-junctions. Inulin-type fructans, L. brevis W63 and L. casei W56 regulated other genes, unrelated to tight-junctions. L. acidophilus also had unique effects on a group of six genes regulating epithelial phenotype toward follicle associated epithelium. L. acidophilus W37 was therefore selected for a challenge with STM and prevented STM-induced barrier disruption and decreased secretion of IL-8. Conclusion:L. acidophilus W37 increases TEER and can protect against STM induced disruption of gut epithelial cells integrity in vitro. Our results suggest that selection of specific bacterial strains for enforcing barrier function may be a promising strategy to reduce or prevent STM infections. PMID- 30013540 TI - Suspended Materials in River Waters Differentially Enrich Class 1 Integron- and IncP-1 Plasmid-Carrying Bacteria in Sediments. AB - Aquatic ecosystems are frequently considered as the final receiving environments of anthropogenic pollutants such as pharmaceutical residues or antibiotic resistant bacteria, and as a consequence tend to form reservoirs of antibiotic resistance genes. Considering the global threat posed by the antibiotic resistance, the mechanisms involved in both the formation of such reservoirs and their remobilization are a concern of prime importance. Antibiotic resistance genes are strongly associated with mobile genetic elements that are directly involved in their dissemination. Most mobile genetic element-mediated gene transfers involve replicative mechanisms and, as such, localized gene transfers should participate in the local increase in resistance gene abundance. Additionally, the carriage of conjugative mobile elements encoding cell appendages acting as adhesins has already been demonstrated to increase biofilm forming capability of bacteria and, therefore, should also contribute to their selective enrichment on surfaces. In the present study, we investigated the occurrence of two families of mobile genetic elements, IncP-1 plasmids and class 1 integrons, in the water column and bank sediments of the Orne River, in France. We show that these mobile elements, especially IncP-1 plasmids, are enriched in the bacteria attached on the suspended matters in the river waters, and that a similar abundance is found in freshly deposited sediments. Using the IncP-1 plasmid pB10 as a model, in vitro experiments demonstrated that local enrichment of plasmid-bearing bacteria on artificial surfaces mainly resulted from an increase in bacterial adhesion properties conferred by the plasmid rather than an improved dissemination frequency of the plasmid between surface-attached bacteria. We propose plasmid-mediated adhesion to particles to be one of the main contributors in the formation of mobile genetic element-reservoirs in sediments, with adhesion to suspended matter working as a selective enrichment process of antibiotic resistant genes and bacteria. PMID- 30013541 TI - Microbial Community Shifts in Response to Acid Mine Drainage Pollution Within a Natural Wetland Ecosystem. AB - Natural wetlands are known to play an important role in pollutant remediation, such as remediating acid mine drainage (AMD) from abandoned mine sites. However, many aspects of the microbiological mechanisms underlying AMD remediation within wetlands are poorly understood, including the role and composition of associated microbial communities. We have utilized an AMD-polluted river-wetland system to perform rRNA sequence analysis of microbial communities that play a role in biogeochemical activities that are linked to water quality improvement. Next generation sequencing of bacterial 16S rRNA gene amplicons from river and wetland sediment samples identified variation in bacterial community structure and diversity on the basis of dissolved and particulate metal concentrations, sediment metal concentrations and other water chemistry parameters (pH and conductivity), and wetland plant presence. Metabolic reconstruction analysis allowed prediction of relative abundance of microbial metabolic pathways and revealed differences between samples that cluster on the basis of the severity of AMD pollution. Global metabolic activity was predicted to be significantly higher in unpolluted and wetland sediments in contrast to polluted river sediments, indicating a metabolic stress response to AMD pollution. This is one of the first studies to explore microbial community structure dynamics within a natural wetland exposed to AMD and our findings indicate that wetland ecosystems play critical roles in maintaining diversity and metabolic structure of sediment microbial communities subject to high levels of acidity and metal pollution. Moreover, these microbial communities are predicted to be important for the remediation action of the wetland. PMID- 30013542 TI - Human Endogenous Retrovirus K in the Crosstalk Between Cancer Cells Microenvironment and Plasticity: A New Perspective for Combination Therapy. AB - Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed. PMID- 30013543 TI - Microbial Delivery Vehicles for Allergens and Allergen-Derived Peptides in Immunotherapy of Allergic Diseases. AB - Allergen-specific immunotherapy represents the only available curative approach to allergic diseases. The treatment has proven effective, but it requires repetitive administrations of allergen extracts over 3-5 years and is often associated with adverse events. This implies the need for novel therapeutic strategies with reduced side effects and decreased treatment time, which would improve patients' compliance. Development of vaccines that are molecularly well defined and have improved safety profile in comparison to whole allergen extracts represents a promising approach. Molecular allergy vaccines are based on major allergen proteins or allergen-derived peptides. Often, such vaccines are associated with lower immunogenicity and stability and therefore require an appropriate delivery vehicle. In this respect, viruses, bacteria, and their protein components have been intensively studied for their adjuvant capacity. This article provides an overview of the microbial delivery vehicles that have been tested for use in allergy immunotherapy. We review in vitro and in vivo data on the immunomodulatory capacity of different microbial vehicles for allergens and allergen-derived peptides and evaluate their potential in development of allergy vaccines. We also discuss relevant aspects and challenges concerning the use of microbes and their components in immunotherapy of allergic diseases. PMID- 30013539 TI - Nano-Strategies to Fight Multidrug Resistant Bacteria-"A Battle of the Titans". AB - Infectious diseases remain one of the leading causes of morbidity and mortality worldwide. The WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. Therefore, the antibiotic resistance crisis is one of the most pressing issues in global public health. Associated with the rise in antibiotic resistance is the lack of new antimicrobials. This has triggered initiatives worldwide to develop novel and more effective antimicrobial compounds as well as to develop novel delivery and targeting strategies. Bacteria have developed many ways by which they become resistant to antimicrobials. Among those are enzyme inactivation, decreased cell permeability, target protection, target overproduction, altered target site/enzyme, increased efflux due to over-expression of efflux pumps, among others. Other more complex phenotypes, such as biofilm formation and quorum sensing do not appear as a result of the exposure of bacteria to antibiotics although, it is known that biofilm formation can be induced by antibiotics. These phenotypes are related to tolerance to antibiotics in bacteria. Different strategies, such as the use of nanostructured materials, are being developed to overcome these and other types of resistance. Nanostructured materials can be used to convey antimicrobials, to assist in the delivery of novel drugs or ultimately, possess antimicrobial activity by themselves. Additionally, nanoparticles (e.g., metallic, organic, carbon nanotubes, etc.) may circumvent drug resistance mechanisms in bacteria and, associated with their antimicrobial potential, inhibit biofilm formation or other important processes. Other strategies, including the combined use of plant-based antimicrobials and nanoparticles to overcome toxicity issues, are also being investigated. Coupling nanoparticles and natural-based antimicrobials (or other repurposed compounds) to inhibit the activity of bacterial efflux pumps; formation of biofilms; interference of quorum sensing; and possibly plasmid curing, are just some of the strategies to combat multidrug resistant bacteria. However, the use of nanoparticles still presents a challenge to therapy and much more research is needed in order to overcome this. In this review, we will summarize the current research on nanoparticles and other nanomaterials and how these are or can be applied in the future to fight multidrug resistant bacteria. PMID- 30013544 TI - Comparative Genomics of Pseudomonas sp. Strain SI-3 Associated With Macroalga Ulva prolifera, the Causative Species for Green Tide in the Yellow Sea. AB - Algae-bacteria associations occurred widely in marine habitats, however, contributions of bacteria to macroalgal blooming were almost unknown. In this study, a potential endophytic strain SI-3 was isolated from Ulva prolifera, the causative species for the world's largest green tide in the Yellow Sea, following a strict bleaching treatment to eliminate epiphytes. The genomic sequence of SI-3 was determined in size of 4.8 Mb and SI-3 was found to be mostly closed to Pseudomonas stutzeri. To evaluate the characteristics of SI-3 as a potential endophyte, the genomes of SI-3 and other 20 P. stutzeri strains were compared. We found that SI-3 had more strain-specific genes than most of the 20 P. stutzeri strains. Clusters of Orthologous Groups (COGs) analysis revealed that SI-3 had a higher proportion of genes assigned to transcriptional regulation and signal transduction compared with the 20 P. stutzeri strains, including four rhizosphere bacteria, indicating a complicated interaction network between SI-3 and its host. P. stutzeri is renowned for its metabolic versatility in aromatic compounds degradation. However, significant gene loss was observed in several aromatic compounds degradation pathways in SI-3, which may be an evolutional adaptation that developed upon association with its host. KEGG analysis revealed that dissimilatory nitrate reduction to ammonium (DNRA) and denitrification, two competing dissimilatory nitrate reduction pathways, co-occurred in the genome of SI-3, like most of the other 20 P. stutzeri strains. We speculated that DNRA of SI-3 may contribute a competitive advantage in nitrogen acquisition of U. prolifera by conserving nitrogen in NH4+ form, as in the case of microalgae bloom. Collectively, these data suggest that Pseudomonas sp. strain SI-3 was a suitable candidate for investigation of the algae-bacteria interaction with U. prolifera and the ecological impacts on algal blooming. PMID- 30013546 TI - Corrigendum: Differential Characteristics of Viral siRNAs Between Leaves and Roots of Wheat Plants Naturally Infected with Wheat Yellow Mosaic Virus, a Soil Borne Virus. AB - [This corrects the article on p. 1802 in vol. 8, PMID: 28979249.]. PMID- 30013545 TI - Structural Insight Into Conformational Changes Induced by ATP Binding in a Type III Secretion-Associated ATPase From Shigella flexneri. AB - Gram-negative bacteria utilize the type III secretion system (T3SS) to inject effector proteins into the host cell cytoplasm, where they subvert cellular functions and assist pathogen invasion. The conserved type III-associated ATPase is critical for the separation of chaperones from effector proteins, the unfolding of effector proteins and translocating them through the narrow channel of the secretion apparatus. However, how ATP hydrolysis is coupled to the mechanical work of the enzyme remains elusive. Herein, we present a complete description of nucleoside triphosphate binding by surface presentation antigens 47 (Spa47) from Shigella flexneri, based on crystal structures containing ATPgammaS, a catalytic magnesium ion and an ordered water molecule. Combining the crystal structures of Spa47-ATPgammaS and unliganded Spa47, we propose conformational changes in Spa47 associated with ATP binding, the binding of ATP induces a conformational change of a highly conserved luminal loop, facilitating ATP hydrolysis by the Spa47 ATPase. Additionally, we identified a specific hydrogen bond critical for ATP recognition and demonstrated that, while ATPgammaS is an ideal analog for probing ATP binding, AMPPNP is a poor ATP mimic. Our findings provide structural insight pertinent for inhibitor design. PMID- 30013547 TI - Metabolic Profiling of Human Eosinophils. AB - Immune cells face constant changes in their microenvironment, which requires rapid metabolic adaptation. In contrast to neutrophils, which are known to rely near exclusively on glycolysis, the metabolic profile of human eosinophils has not been characterized. Here, we assess the key metabolic parameters of peripheral blood-derived human eosinophils using real-time extracellular flux analysis to measure extracellular acidification rate and oxygen consumption rate, and compare these parameters to human neutrophils. Using this methodology, we demonstrate that eosinophils and neutrophils have a similar glycolytic capacity, albeit with a minimal glycolytic reserve. However, compared to neutrophils, eosinophils exhibit significantly greater basal mitochondrial respiration, ATP linked respiration, maximum respiratory capacity, and spare respiratory capacity. Of note, the glucose oxidation pathway is also utilized by eosinophils, something not evident in neutrophils. Furthermore, using a colorimetric enzymatic assay, we show that eosinophils have much reduced glycogen stores compared to neutrophils. We also show that physiologically relevant levels of hypoxia (PO2 3 kPa), by suppressing oxygen consumption rates, have a profound effect on basal and phorbol myristate-acetate-stimulated eosinophil and neutrophil metabolism. Finally, we compared the metabolic profile of eosinophils purified from atopic and non-atopic subjects and show that, despite a difference in the activation status of eosinophils derived from atopic subjects, these cells exhibit comparable oxygen consumption rates upon priming with IL-5 and stimulation with fMLP. In summary, our findings show that eosinophils display far greater metabolic flexibility compared to neutrophils, with the potential to use glycolysis, glucose oxidation, and oxidative phosphorylation. This flexibility may allow eosinophils to adapt better to diverse roles in host defense, homeostasis, and immunomodulation. PMID- 30013548 TI - Recognition of Lipopolysaccharide and Activation of NF-kappaB by Cytosolic Sensor NOD1 in Teleost Fish. AB - Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram negative bacteria. This molecule can induce strong immune response and various biological effects. In mammals, TLR4 can recognize LPS and induce inflammatory response. However, the innate receptor in fish for recognizing LPS remains ambiguous. LPS can invade the cytoplasm via outer membrane vesicles produced by Gram-negative bacteria and could be detected by intracellular receptor caspase-11 in mammals, so, there may also exist the intracellular receptors that can recognize LPS in fish. NOD1 is a member of NOD-like receptors family and can recognize the iE-DAP in the cytoplasm in mammals. In fish, NOD1 can also respond to infection of Gram-negative bacteria and may play an important role in the identification of bacterial components. In this study, to study whether NOD1 is a recognition receptor for LPS, we detected the expression of NOD1 and several cytokines at transcript levels to determine whether LPS can induce inflammatory response in teleost fish and NOD1 can respond to LPS. Then, we perform the binding analysis between NOD1 and ultrapure LPS by using Streptavidin pulldown assay and enzyme-linked immunosorbent assay to prove that NOD1 can be combined with LPS, and using dual luciferase reporter gene assay to verify the signal pathways activated by NOD1. Next, through cell viability analysis, we proved that LPS-induced cytotoxicity can be mediated by NOD1 in fish. The results showed that NOD1 can identify LPS and activate the NF-kappaB signal pathway by recruiting RIPK2 and then promoting the expression of inflammatory cytokines to induce the resistance of organism against bacterial infection. PMID- 30013549 TI - The Ebola-Glycoprotein Modulates the Function of Natural Killer Cells. AB - The Ebola virus (EBOV) uses evasion mechanisms that directly interfere with host T-cell antiviral responses. By steric shielding of human leukocyte antigen class 1, the Ebola glycoprotein (GP) blocks interaction with T-cell receptors (TCRs), thus rendering T cells unable to attack virus-infected cells. It is likely that this mechanism could promote increased natural killer (NK) cell activity against GP-expressing cells by preventing the engagement of NK inhibitory receptors; however, we found that primary human NK cells were less reactive to GP-expressing HEK293T cells. This was manifested as reduced cytokine secretion, a reduction in NK degranulation, and decreased lysis of GP-expressing target cells. We also demonstrated reduced recognition of GP-expressing cells by recombinant NKG2D and NKp30 receptors. In accordance, we showed a reduced monoclonal antibody-based staining of NKG2D and NKp30 ligands on GP-expressing target cells. Trypsin digestion of the membrane-associated GP led to a recovery of the recognition of membrane-associated NKG2D and NKp30 ligands. We further showed that membrane associated GP did not shield recognition by KIR2DL receptors; in accordance, GP expression by target cells significantly perturbed signal transduction through activating, but not through inhibitory, receptors. Our results suggest a novel evasion mechanism employed by the EBOV to specifically avoid the NK cell immune response. PMID- 30013550 TI - Granulocyte-Colony Stimulating Factor-Overexpressing Mesenchymal Stem Cells Exhibit Enhanced Immunomodulatory Actions Through the Recruitment of Suppressor Cells in Experimental Chagas Disease Cardiomyopathy. AB - Genetic modification of mesenchymal stem cells (MSCs) is a promising strategy to improve their therapeutic effects. Granulocyte-colony stimulating factor (G-CSF) is a growth factor widely used in the clinical practice with known regenerative and immunomodulatory actions, including the mobilization of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Here we evaluated the therapeutic potential of MSCs overexpressing G-CSF (MSC_G-CSF) in a model of inflammatory cardiomyopathy due to chronic Chagas disease. C57BL/6 mice were treated with wild-type MSCs, MSC_G-CSF, or vehicle (saline) 6 months after infection with Trypanosoma cruzi. Transplantation of MSC_G-CSF caused an increase in the number of circulating leukocytes compared to wild-type MSCs. Moreover, G CSF overexpression caused an increase in migration capacity of MSCs to the hearts of infected mice. Transplantation of either MSCs or MSC_G-CSF improved exercise capacity, when compared to saline-treated chagasic mice. MSC_G-CSF mice, however, were more potent than MSCs in reducing the number of infiltrating leukocytes and fibrosis in the heart. Similarly, MSC_G-CSF-treated mice presented significantly lower levels of inflammatory mediators, such as IFNgamma, TNFalpha, and Tbet, with increased IL-10 production. A marked increase in the percentage of Tregs and MDSCs in the hearts of infected mice was seen after administration of MSC_G-CSF, but not MSCs. Moreover, Tregs were positive for IL-10 in the hearts of T. cruzi infected mice. In vitro analysis showed that recombinant hG-CSF and conditioned medium of MSC_G-CSF, but not wild-type MSCs, induce chemoattraction of MDSCs in a transwell assay. Finally, MDSCs purified from hearts of MSC_G-CSF transplanted mice inhibited the proliferation of activated splenocytes in a co-culture assay. Our results demonstrate that G-CSF overexpression by MSCs potentiates their immunomodulatory effects in our model of Chagas disease and suggest that mobilization of suppressor cell populations such as Tregs and MDSCs as a promising strategy for the treatment of chronic Chagas disease. Finally, our results reinforce the therapeutic potential of genetic modification of MSCs, aiming at increasing their paracrine actions. PMID- 30013551 TI - Regulation of Leukocytes by TspanC8 Tetraspanins and the "Molecular Scissor" ADAM10. AB - A disintegrin and metalloproteinase 10 (ADAM10) is a ubiquitous transmembrane protein that functions as a "molecular scissor" to cleave the extracellular regions from its transmembrane target proteins. ADAM10 is well characterized as the ligand-dependent activator of Notch proteins, which control cell fate decisions. Indeed, conditional knockouts of ADAM10 in mice reveal impaired B-, T , and myeloid cell development and/or function. ADAM10 cleaves many other leukocyte-expressed substrates. On B-cells, ADAM10 cleavage of the low-affinity IgE receptor CD23 promotes allergy and asthma, cleavage of ICOS ligand impairs antibody responses, and cleavage of the BAFF-APRIL receptor transmembrane activator and CAML interactor, and BAFF receptor, reduce B-cell survival. On microglia, increased ADAM10 cleavage of a rare variant of the scavenger receptor triggering receptor expressed on myeloid cells 2 may increase susceptibility to Alzheimer's disease. We and others recently showed that ADAM10 interacts with one of six different regulatory tetraspanin membrane proteins, which we termed the TspanC8 subgroup, comprising Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. The TspanC8s are required for ADAM10 exit from the endoplasmic reticulum, and emerging evidence suggests that they dictate ADAM10 subcellular localization and substrate specificity. Therefore, we propose that ADAM10 should not be regarded as a single scissor, but as six different scissors with distinct substrate specificities, depending on the associated TspanC8. In this review, we collate recent transcriptomic data to present the TspanC8 repertoires of leukocytes, and we discuss the potential role of the six TspanC8/ADAM10 scissors in leukocyte development and function. PMID- 30013552 TI - Evaluation of Blood-Based Antibody Rapid Testing for HIV Early Therapy: A Meta Analysis of the Evidence. AB - Background: Western blot (WB) assay is considered the gold standard test for HIV infection confirmation. However, it requires technical expertise and is quite time-consuming. WHO recommends blood-based rapid diagnosis to achieve same-day test and treatment. However, this rapid testing strategy has not been promoted worldwide due to inadequate research evaluating the effectiveness of rapid tests (RTs) as an alternative confirmatory HIV test for WB. This study aims to compare the diagnostic performance of rapid HIV tests compared with WB. Methods: PubMed and Web of Science were searched for publications on rapid HIV tests using blood specimen. A meta-analysis was performed to quantitatively evaluate the diagnostic performance of rapid HIV tests compared with the WB assay in terms of pooled sensitivity, specificity, area under summary receiver operating characteristic (SROC) curve, and diagnostic odds ratio (DOR). Results: Twenty articles involving 27,343 fresh specimens for rapid HIV tests were included in the meta-analysis. Regarding Capillus HIV-1/HIV-2, the pooled sensitivity, specificity, area under SROC curve, and DOR derived from six studies were 0.999 (95% CI, 0.956-1.000), 0.999 (95% CI, 0.991-1.00), 1.00 (95% CI, 0.99-1.00), and 1.0 * 106 (95% CI, 2.6 * 104-3.9 * 107) compared with the WB assay, respectively. With respect to Determine HIV-1/2, the pooled sensitivity, specificity area under SROC, and DOR derived from eight studies were 1.00 (95% CI, 0.789-1.000), 0.992 (95% CI, 0.985 0.996), 1.00 (95% CI, 0.99-1.00), and 1.8 * 106 (95% CI 406.049-7.8 * 109) compared with the WB assay, respectively. Regarding two-step serial RTs, the pooled sensitivity, specificity area under SROC, and DOR derived from eight studies were 0.998 (95% CI, 0.991-1.000), 0.998 (95% CI, 0.994-0.999), and 1.00 (95% CI 0.99-1.00) compared with the WB assay, respectively. Conclusion: Our meta analysis results may provide evidenced-based support for substituting RT for WB. Blood-based rapid HIV tests have comparable sensitivity and specificity to WB for HIV early therapy. PMID- 30013553 TI - Helicobacter pylori Outer Membrane Vesicle Size Determines Their Mechanisms of Host Cell Entry and Protein Content. AB - Gram-negative pathogens ubiquitously shed outer membrane vesicles (OMVs) that play a central role in initiating and regulating pathogenesis in the host. Due to their highly inflammatory nature, OMVs are extensively being examined for their role in mediating disease in addition to their applications in innovative vaccines. A key mechanism whereby OMVs mediate inflammation and disease progression is dependent on their ability to enter host cells. Currently, the role of OMV size on determining their mechanism of cellular entry and their protein composition remains unknown. In this study, we examined the mechanisms whereby OMV size regulates their mode of entry into epithelial cells, in addition to their protein cargo and composition. We identified that a heterogeneous sized population of Helicobacter pylori OMVs entered epithelial cells via macropinocytosis, clathrin, and caveolin-dependent endocytosis. However, smaller OMVs ranging from 20 to 100 nm in size preferentially entered host cells via caveolin-mediated endocytosis. Whereas larger OMVs ranging between 90 and 450 nm in size entered host epithelial cells via macropinocytosis and endocytosis. Most importantly, we identified the previously unknown contribution that OMV size has on determining their protein content, as fewer and less diverse bacterial proteins were contained within small OMVs compared to larger OMVs. Collectively, these findings identify the importance of OMV size in determining the mechanisms of OMV entry into host cells, in addition to regulating their protein cargo, composition, and subsequent immunogenicity. These findings have significant implications in broadening our understanding of the bacterial regulation of virulence determinants and immunogenic proteins associated with OMVs, their role in mediating pathogenesis and in refining the design and development of OMV-based vaccines. PMID- 30013554 TI - Photoconversion of Alloreactive T Cells in Murine Peyer's Patches During Acute Graft-Versus-Host Disease: Tracking the Homing Route of Highly Proliferative Cells In Vivo. AB - The regulation of immune cell migration throughout the body is essential to warrant immunosurveillance and to maintain immune homeostasis. Marking and tracking of these cells has proven important to study mechanisms of immune cell trafficking and cell interaction in vivo. Photoconversion is a well-suited technique for intravital application because it enables contactless time- and location-specific marking of cells in the tissue without surgically manipulating the microenvironment of the cells in question. However, in dividing cells the converted fluorescent protein may decline quickly. Here, we provide a detailed description of the photoconversion technique and its applicability to tracking highly proliferating T cells from the priming site of T cell activation to peripheral target organs of effector function in a preclinical model. Dendra2+ T cells were photoconverted in the Peyer's patches during the initiation phase of acute graft-versus-host disease (GvHD) and tracked through the mesenteric lymph nodes and the peripheral blood to the small intestine with flow cytometry and intravital two-photon microscopy. Photoconverted alloreactive T cells preserved the full proliferative capacity, homing, and migration of alloreactive T cells in the intestinal lamina propria. We conclusively proved that photoconversion of highly proliferative alloreactive T cells in the Peyer's patches is an effective tool to study trafficking of alloreactive T cells under physiologic conditions and to GvHD target tissues. This technique can also be applied to the study of immune cell tracking under inflammatory and non-inflammatory conditions. PMID- 30013555 TI - Predicting the Effectiveness of Hepatitis C Virus Neutralizing Antibodies by Bioinformatic Analysis of Conserved Epitope Residues Using Public Sequence Data. AB - Hepatitis C virus (HCV) is a global health issue. Although direct-acting antivirals are available to target HCV, there is currently no vaccine. The diversity of the virus is a major obstacle to HCV vaccine development. One approach toward a vaccine is to utilize a strategy to elicit broadly neutralizing antibodies (bNAbs) that target highly-conserved epitopes. The conserved epitopes of bNAbs have been mapped almost exclusively to the E2 glycoprotein. In this study, we have used HCV-GLUE, a bioinformatics resource for HCV sequence data, to investigate the major epitopes targeted by well-characterized bNAbs. Here, we analyze the level of conservation of each epitope by genotype and subtype and consider the most promising bNAbs identified to date for further study as potential vaccine leads. For the most conserved epitopes, we also identify the most prevalent sequence variants in the circulating HCV population. We examine the distribution of E2 sequence data from across the globe and highlight regions with no coverage. Genotype 1 is the most prevalent genotype worldwide, but in many regions, it is not the dominant genotype. We find that the sequence conservation data is very encouraging; several bNAbs have a high level of conservation across all genotypes suggesting that it may be unnecessary to tailor vaccines according to the geographical distribution of genotypes. PMID- 30013558 TI - CLA+ T Cell Response to Microbes in Psoriasis. AB - Streptococcus pyogenes throat infection is a clinically relevant trigger of both guttate and chronic plaque psoriasis, and it provides an ideal context in which to study the pathogenesis of these diseases using an antigen-dependent approach. Circulating cutaneous lymphocyte-associated antigen (CLA) positive (+) memory T cells are a subset of peripheral lymphocytes whose phenotype and function are related to immunological mechanisms in the skin. These cells are considered peripheral biomarkers of T-cell-mediated skin diseases. The coculture of autologous epidermal cells with CLA+ T cells from psoriasis patients activated by S. pyogenes allows the reproduction of the ex vivo initial molecular events that occur during psoriatic lesion formation. With cooperation of autologous epidermal cells, S. pyogenes selectively activates CLA+ T cells both in guttate and plaque psoriasis, inducing key mediators, including an IL-17 response. Here, we explore potential new mechanisms of psoriasis development including the influence of HLA Cw6 on S. pyogenes CLA+ T cell activation in guttate psoriasis, the relevance of IL-9 on microbe induced IL-17 response in guttate and plaque psoriasis, and novel effector functions of Candida albicans. This review will summarize recent knowledge of psoriatic mechanisms elicited by microbes that have been studied through an innovative translational perspective based on CLA+ T cell-mediated cutaneous immune response. PMID- 30013557 TI - The Hurdles From Bench to Bedside in the Realization and Implementation of a Universal Influenza Vaccine. AB - Influenza viruses circulate worldwide causing annual epidemics that have a substantial impact on public health. This is despite vaccines being in use for over 70 years and currently being administered to around 500 million people each year. Improvements in vaccine design are needed to increase the strength, breadth, and duration of immunity against diverse strains that circulate during regular epidemics, occasional pandemics, and from animal reservoirs. Universal vaccine strategies that target more conserved regions of the virus, such as the hemagglutinin (HA)-stalk, or recruit other cellular responses, such as T cells and NK cells, have the potential to provide broader immunity. Many pre-pandemic vaccines in clinical development do not utilize new vaccine platforms but use "tried and true" recombinant HA protein or inactivated virus strategies despite substantial leaps in fundamental research on universal vaccines. Significant hurdles exist for universal vaccine development from bench to bedside, so that promising preclinical data is not yet translating to human clinical trials. Few studies have assessed immune correlates derived from asymptomatic influenza virus infections, due to the scale of a study required to identity these cases. The realization and implementation of a universal influenza vaccine requires identification and standardization of set points of protective immune correlates, and consideration of dosage schedule to maximize vaccine uptake. PMID- 30013559 TI - Vgamma9Vdelta2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression. AB - Vgamma9Vdelta2 T cells are non-conventional T cells with a natural inclination to recognize and kill cancer cells. Malignant B cells, including myeloma cells, are privileged targets of Vgamma9Vdelta2 T cells in vitro. However, this inclination is often lost in vivo due to multiple mechanisms mediated by tumor cells and local microenvironment. Multiple myeloma (MM) is a paradigm disease in which antitumor immunity is selectively impaired at the tumor site. By interrogating the immune reactivity of bone marrow (BM) Vgamma9Vdelta2 T cells to phosphoantigens, we have revealed a very early and long-lasting impairment of Vgamma9Vdelta2 T-cell immune functions which is already detectable in monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even in clinical remission after autologous stem cell transplantation. Multiple cell subsets [MM cells, myeloid-derived suppressor cells, regulatory T cells, and BM derived stromal cells (BMSC)] are involved in Vgamma9Vdelta2 T-cell inhibition via several immune suppressive mechanisms including the redundant expression of multiple immune checkpoints (ICPs). This review will address some aspects related to the dynamics of ICP expression in the BM of MM patients in relationship to the disease status (MGUS, diagnosis, remission, and relapse) and how this multifaceted ICP expression impairs Vgamma9Vdelta2 T-cell function. We will also provide some suggestions how to rescue Vgamma9Vdelta2 T cells from the immune suppression operated by ICP and to recover their antimyeloma immune effector functions at the tumor site. PMID- 30013560 TI - Neoantigen Vaccine Delivery for Personalized Anticancer Immunotherapy. AB - Cancer neoantigens derived from random somatic mutations in tumor tissue represent an attractive type of targets for the cancer immunotherapies including cancer vaccine. Vaccination against the tumor-specific neoantigens minimizes the potential induction of central and peripheral tolerance as well as the risk of autoimmunity. Neoantigen-based cancer vaccines have recently showed marked therapeutic potential in both preclinical and early-phase clinical studies. However, significant challenges remain in the effective and faithful identification of immunogenic neoepitopes and the efficient and safe delivery of the subunit vaccine components for eliciting potent and robust anticancer T cell responses. In this mini review, we provide a brief overview of the recent advances in the development of neoantigen-based cancer vaccines focusing on various vaccine delivery strategies for targeting and modulating antigen presenting cells. We discuss current delivery approaches, including direct injection, ex vivo-pulsed dendritic cell vaccination, and biomaterial-assisted vaccination for enhancing the efficiency of neoantigen vaccines and present a perspective on future directions. PMID- 30013556 TI - Insights Into Mucosal-Associated Invariant T Cell Biology From Studies of Invariant Natural Killer T Cells. AB - Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells are innate-like T cells that function at the interface between innate and adaptive immunity. They express semi-invariant T cell receptors (TCRs) and recognize unconventional non-peptide ligands bound to the MHC Class I-like molecules MR1 and CD1d, respectively. MAIT cells and iNKT cells exhibit an effector-memory phenotype and are enriched within the liver and at mucosal sites. In humans, MAIT cell frequencies dwarf those of iNKT cells, while in laboratory mouse strains the opposite is true. Upon activation via TCR- or cytokine dependent pathways, MAIT cells and iNKT cells rapidly produce cytokines and show direct cytotoxic activity. Consequently, they are essential for effective immunity, and alterations in their frequency and function are associated with numerous infectious, inflammatory, and malignant diseases. Due to their abundance in mice and the earlier development of reagents, iNKT cells have been more extensively studied than MAIT cells. This has led to the routine use of iNKT cells as a reference population for the study of MAIT cells, and such an approach has proven very fruitful. However, MAIT cells and iNKT cells show important phenotypic, functional, and developmental differences that are often overlooked. With the recent availability of new tools, most importantly MR1 tetramers, it is now possible to directly study MAIT cells to understand their biology. Therefore, it is timely to compare the phenotype, development, and function of MAIT cells and iNKT cells. In this review, we highlight key areas where MAIT cells show similarity or difference to iNKT cells. In addition, we discuss important avenues for future research within the MAIT cell field, especially where comparison to iNKT cells has proven less informative. PMID- 30013561 TI - The Effect of C-Reactive Protein Isoforms on Nitric Oxide Production by U937 Monocytes/Macrophages. AB - Inflammation is regulated by many endogenous factors including estrogen, a steroid hormone that declines with increasing age, leading to excessive inflammation in the elderly. C-reactive protein (CRP) is an acute phase inflammatory protein that exists in two forms, native CRP (nCRP) and monomeric CRP (mCRP), which mediate distinct biological activities. It is unclear how each CRP isoform mediates nitric oxide (NO), a signaling molecule generated by NO synthase (NOS). This study investigated whether CRP isoforms have distinct effects on NO production by unstimulated and lipopolysaccharide (LPS)-activated monocytes/macrophages and whether estrogen mediates CRP-induced NO production in an in vitro model of aging. NO and inducible NOS (iNOS) were measured (n = 12) by the Griess assay and an enzyme-linked immunosorbent assay, respectively following incubation (24 h) of human-derived U937 monocytes/macrophages with CRP isoforms [(nCRP) = 500 and 1,000 ug/ml; (mCRP) = 100 and 250 ug/ml] in the absence or presence of 17 beta-estradiol (1 * 10-7, 1 * 10-8, and 1 * 10-9 M). The response to each CRP isoform and estrogen was dependent on the differentiation and activation status of cells. Monocytes with or without prior LPS-activation significantly increased (P < 0.01) NO/iNOS production when treated with mCRP. The mCRP isoform had no effect (P > 0.05) on NO/iNOS production by unactivated or LPS activated macrophages, whereas nCRP significantly (P < 0.05) reduced NO/iNOS production by macrophages, with or without prior LPS-activation. The nCRP isoform had opposing actions on monocytes, significantly (P < 0.01) increasing and reducing NO/iNOS by unactivated and LPS-activated monocytes, respectively. Estrogen significantly (P < 0.01) reversed nCRP-mediated NO inhibition by unactivated macrophages but decreased CRP-induced NO by unactivated monocytes treated with nCRP or mCRP and LPS-activated monocytes treated with mCRP. NO was differentially mediated by CRP isoforms in a cell-type/state-specific manner, with production corresponding to concomitant changes in iNOS levels. Collectively, the findings indicate nCRP and estrogen predominantly reduce NO production, whereas mCRP increases NO production. This supports growing evidence that mCRP exacerbates inflammation while nCRP and estrogen dampen the overall inflammatory response. Therapeutic strategies that restore estrogen levels to those found in youth and promote the stability of nCRP or/and prevent the formation of mCRP may reduce NO production in age-related inflammatory conditions. PMID- 30013562 TI - Development and Selection of the Human Vgamma9Vdelta2+ T-Cell Repertoire. AB - Vgamma9Vdelta2+ lymphocytes are among the first T-cells to develop in the human fetus and are the predominant peripheral blood gammadelta T-cell population in most adults. Capable of broad polyclonal responses to pyrophosphate antigens (pAg), they are implicated in immunity to a diverse range of infections. Previously Vgamma9Vdelta2+ development was thought to involve postnatal selection and amplification of public Vgamma9 clonotypes in response to microbial stimuli. However, recent data indicate the Vgamma9Vdelta2+ T-cell receptor (TCR) repertoire, which is generated early in gestation, is dominated by public Vgamma9 clonotypes from birth. These chains bear highly distinct features compared to Vgamma9 chains from Vdelta1+ T-cells, due either to temporal differences in recombination of each subset and/or potentially prenatal selection of pAg reactive clonotypes. While these processes result in a semi-invariant repertoire featuring Vgamma9 sequences preconfigured for pAg recognition, alterations in TCRdelta repertoires between neonate and adult suggest either peripheral selection of clonotypes responsive to microbial antigens or altered postnatal thymic output of Vgamma9Vdelta2+ T-cells. Interestingly, some individuals demonstrate private Vgamma9Vdelta2+ expansions with distinct effector phenotypes, suggestive of selective expansion in response to microbial stimulation. The Vgamma9Vdelta2+ T-cell subset, therefore, exhibits many features common to mouse gammadelta T-cell subsets, including early development, a semi-invariant TCR repertoire, and a reliance on butyrophilin-like molecules in antigen recognition. However, importantly Vgamma9Vdelta2+ T-cells retain TCR sensitivity after acquiring an effector phenotype. We outline a model for Vgamma9Vdelta2+ T-cell development and selection involving innate prenatal repertoire focusing, followed by postnatal repertoire shifts driven by microbial infection and/or altered thymic output. PMID- 30013563 TI - Pectin Oligosaccharides Ameliorate Colon Cancer by Regulating Oxidative Stress- and Inflammation-Activated Signaling Pathways. AB - Colon cancer (CC) is the third common neoplasm worldwide, and it is still a big challenge for exploring new effective medicine for treating CC. Natural product promoting human health has become a hot topic and attracted many researchers recently. Pectin, a complex polysaccharide in plant cell wall, mainly consists of four major types of polysaccharides: homogalacturonan, xylogalacturonan, rhamnogalacturonan I and II, all of which can be degraded into various pectin oligosaccharides (POS) and may provide abundant resource for exploring potential anticancer drugs. POS have been regarded as a novel class of potential functional food with multiple health-promoting properties. POS have antibacterial activities against some aggressive and recurrent bacterial infection and exert beneficial immunomodulation for controlling CC risk. However, the molecular functional role of POS in the prevention of CC risk and progression remains doubtful. The review focuses on antioxidant and anti-inflammatory roles of POS for promoting human health by regulating some potential oxidative and inflammation-activated pathways, such as ATP-activated protein kinase (AMPK), nuclear factor erythroid-2 related factor-2 (Nrf2), and nuclear factor-kappaB (NF-kappaB) pathways. The activation of these signaling pathways increases the antioxidant and antiinflammatory activities, which will result in the apoptosis of CC cells or in the prevention of CC risk and progression. Thus, POS may inhibit CC development by affecting antioxidant and antiinflammatory signaling pathways AMPK, Nrf2, and NF-kappaB. However, POS also can activate signal transduction and transcriptional activator 1 and 3 signaling pathway, which will reduce antioxidant and anti inflammatory properties and promote CC progression. Specific structural and structurally modified POS may be associated with their functions and should be deeply explored in the future. The present review paper lacks the important information for the linkage between the specific structure of POS and its function. To further explore the effects of prebiotic potential of POS and their derivatives on human immunomodulation in the prevention of CC, the specific POS with a certain degree of polymerization or purified polymers are highly demanded to be performed in clinical practice. PMID- 30013564 TI - No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency. AB - Immunoglobulin class-switch recombination (CSR) and somatic hypermutations (SHMs) are prerequisites for antibody and immunoglobulin receptor maturation and adaptive immune diversity. The mismatch repair (MMR) machinery, consisting of homologs of MutSalpha, MutLalpha, and MutSbeta (MSH2/MSH6, MLH1/PMS2, and MSH2/MSH3, respectively) and other proteins, is involved in CSR, primarily acting as a backup for nonhomologous end-joining repair of activation-induced cytidine deaminase-induced DNA mismatches and, furthermore, in addition to error-prone polymerases, in the repair of SHM-induced DNA breaks. A varying degree of antibody formation defect, from IgA or selective IgG subclass deficiency to common variable immunodeficiency and hyper-IgM syndrome, has been detected in a small number of patients with constitutional mismatch repair deficiency (CMMRD) due to biallelic loss-of-function mutations in one of the MMR genes (PMS2, MSH6, MLH1, or MSH2). To elucidate the clinical relevance of a presumed primary immunodeficiency (PID) in CMMRD, we systematically collected clinical history and laboratory data of a cohort of 15 consecutive, unrelated patients (10 not previously reported) with homozygous/compound heterozygous mutations in PMS2 (n = 8), MSH6 (n = 5), and MLH1 (n = 2), most of whom manifested with typical malignancies during childhood. Detailed descriptions of their genotypes, phenotypes, and family histories are provided. Importantly, none of the patients showed any clinical warning signs of PID (infections, immune dysregulation, inflammation, failure to thrive, etc.). Furthermore, we could not detect uniform or specific patterns of laboratory abnormalities. The concentration of IgM was increased in 3 out of 12, reduced in 3 out of 12, and normal in 6 out of 12 patients, while concentrations of IgG and IgG subclasses, except IgG4, and of IgA, and specific antibody formation were normal in most. Class-switched B memory cells were reduced in 5 out of 12 patients, and in 9 out of 12 also the CD38hiIgM plasmablasts were reduced. Furthermore, results of next generation sequencing based analyses of antigen-selected B-cell receptor rearrangements showed a significantly reduced frequency of SHM and an increased number of rearranged immunoglobulin heavy chain (IGH) transcripts that use IGHG3, IGHG1, and IGHA1 subclasses. T cell subsets and receptor repertoires were unaffected. Together, neither clinical nor routine immunological laboratory parameters were consistently suggestive of PID in these CMMRD patients, but previously shown abnormalities in SHM and rearranged heavy chain transcripts were confirmed. PMID- 30013566 TI - Upregulation of Heme Oxygenase-1 Endues Immature Dendritic Cells With More Potent and Durable Immunoregulatory Properties and Promotes Engraftment in a Stringent Mouse Cardiac Allotransplant Model. AB - Heme oxygenase-1 (HO-1) is critical for the ability of immature dendritic cells (imDCs) to suppress T-cell responses. Induction of high HO-1 expression may markedly improve the tolerogenic capacity of imDCs. Here, we generated bone marrow-derived DCs (BMDCs) from BALB/c mice with low doses of GM-CSF and IL-4. The adherent BMDCs were obtained as imDCs. Upregulation of HO-1 in imDCs (HO-1hi imDCs) was achieved by cobalt protoporphyrin treatment. HO-1hi-imDCs proved to be more maturation-resistant than conventional imDCs, with an enhanced ability to inhibit allogeneic T-cell proliferation stimulated by anti-CD3/CD28 antibodies. When donor-derived DC adoptive transfer was performed in a stringent mouse cardiac allotransplant model, the extent of graft prolongation observed with HO 1hi imDCs was superior to that obtained with conventional imDCs. T-cell activation and proliferation in cardiac allograft recipients was more strongly suppressed in the HO-1hi imDC transfusion group than that in the untreated imDC group. Furthermore, donor HO-1hi imDCs were able to maintain a status of high HO 1 expression and survived longer in the recipient spleens than did untreated imDCs after adoptive transfer. In vitro-generated HO-1hi imDCs had an enhanced tolerogenic capacity to modulate alloimmune responses both in vitro and in vivo, and thus may offer a novel antigen-specific and cost-effective strategy to induce transplant tolerance. PMID- 30013565 TI - Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome. AB - Dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death. Some patients rapidly recover from sepsis, but many develop chronic critical illness (CCI), a debilitating condition that impacts functional outcomes and long-term survival. The "Persistent Inflammation, Immunosuppression, and Catabolism Syndrome" (PICS) has been postulated as the underlying pathophysiology of CCI. We propose that PICS is initiated by an early genomic and cytokine storm in response to microbial invasion during the early phase of sepsis. However, once source control, antimicrobial coverage, and supportive therapies have been initiated, we propose that the persistent inflammation in patients developing CCI is a result of ongoing endogenous alarmin release from damaged organs and loss of muscle mass. This ongoing alarmin and danger-associated molecular pattern signaling causes chronic inflammation and a shift in bone marrow stem cell production toward myeloid cells, contributing to chronic anemia and lymphopenia. We propose that therapeutic interventions must target the chronic organ injury and lean tissue wasting that contribute to the release of endogenous alarmins and the expansion and deposition of myeloid progenitors that are responsible for the propagation and persistence of CCI. PMID- 30013567 TI - Inhibition of Angiopoietin-2 Production by Myofibrocytes Inhibits Neointimal Hyperplasia After Endoluminal Injury in Mice. AB - Fibrocytes are myeloid lineage cells implicated in wound healing, repair, and fibrosis. We previously showed that fibrocytes are mobilized into the circulation after vascular injury, including the immune-mediated injury that occurs after allogeneic transplantation. A common response to inflammatory vascular injury is intimal hyperplasia (IH), which, alongside vascular remodeling, results in progressive loss of blood flow, downstream ischemia, and end-organ fibrosis. This forms the pathological basis of transplant arteriosclerosis and other diseases including post-angioplasty re-stenosis. In investigating whether fibrocytes contribute to IH, we previously showed that subpopulations expressing smooth muscle actin and CD31 are recruited to the site of injury and accumulate in the neointima. Expression of tissue factor (TF) by these "CD31+ myofibrocytes" is needed for progressive neointimal expansion, such that TF inhibition limits the neointima to a single layer of cells by day 28 post-injury. The aim of this study was to determine pathophysiological mediators downstream of TF that contribute to myofibrocyte-orchestrated IH. We first show that myofibrocytes make up a significant component of the neointima 28 days following injury. Using a previously defined adoptive transfer model, we then show that CD31+ myofibrocytes get recruited early to the site of injury; this model allows manipulations of the adoptively transferred cells to study how IH develops. Having confirmed that inhibition of TF on adoptively transferred cells prevents IH, we then show that TF, primarily through the generation of thrombin, induces secretion of angiopoietin-2 by myofibrocytes and this directly stimulates proliferation, inhibits apoptosis, and induces CXCL-12 production by neointimal cells, including non-fibrocytes, all of which promote progressive IH in vivo. Prior incubation to inhibit angiopoietin-2 secretion by or block TIE-2 signaling on adoptively transferred fibrocytes inhibits IH. These novel data indicate that angiopoietin-2 production by early recruited myofibrocytes critically influences the development of IH after vascular injury and suggest new therapeutic avenues for exploration. PMID- 30013568 TI - Glycyrrhizin Protects Mice Against Experimental Autoimmune Encephalomyelitis by Inhibiting High-Mobility Group Box 1 (HMGB1) Expression and Neuronal HMGB1 Release. AB - The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE). Glycyrrhizin (GL), a glycoconjugated triterpene extracted from licorice root, has the ability to inhibit the functions of HMGB1; however, GL's function against EAE has not been thoroughly characterized to date. To determine the benefit of GL as a modulator of neuroinflammation, we used an in vivo study to examine GL's effect on EAE along with primary cultured cortical neurons to study the GL effect on HMGB1 release. Treatment of EAE mice with GL from onset to the peak stage of disease resulted in marked attenuation of EAE severity, reduced inflammatory cell infiltration and demyelination, decreased tumor necrosis factor-alpha (TNF-alpha), IFN-gamma, IL 17A, IL-6, and transforming growth factor-beta 1, and increased IL-4 both in serum and spinal cord homogenate. Moreover, HMGB1 levels in different body fluids were reduced, accompanied by a decrease in neuronal damage, activated astrocytes and microglia, as well as HMGB1-positive astrocytes and microglia. GL significantly reversed HMGB1 release into the medium induced by TNF-alpha stimulation in primary cultured cortical neurons. Taken together, the results indicate that GL has a strong neuroprotective effect on EAE mice by reducing HMGB1 expression and release and thus can be used to treat central nervous system inflammatory diseases, such as MS. PMID- 30013569 TI - CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: alpha Galactosylceramide and Beyond. AB - CD1d-restricted invariant natural killer T (iNKT) cells are considered an attractive target for cancer immunotherapy. Upon their activation by glycolipid antigen and/or cytokines, iNKT cells can induce direct lysis of tumor cells but can also induce an antitumor immune response via their rapid production of proinflammatory cytokines that trigger the cytotoxic machinery of other components of the innate and adaptive immune system. Here, we provide an overview of various therapeutic approaches that have been evaluated or that are currently being developed and/or explored. These include administration of alpha-GalCer or alternative (glyco) lipid antigens, glycolipid-loaded antigen-presenting cells and liposomes, strategies that enhance CD1d expression levels or are based on ligation of CD1d, adoptive transfer of iNKT cells or chimeric antigen receptor iNKT cells, and tumor targeting of iNKT cells. PMID- 30013571 TI - Commentary: Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation. PMID- 30013570 TI - Evaluating the Vaccine Potential of a Tetravalent Fusion Protein (rBmHAXT) Vaccine Antigen Against Lymphatic Filariasis in a Mouse Model. AB - Lymphatic filariasis (LF) is a tropical parasitic infection of human transmitted by mosquitoes. Chronic infection results in severe physical disability in the infected patients. Although several potential vaccine antigens were identified by several groups, there are no licensed prophylactic vaccine to date against this infection in the human. Previous attempts from our laboratory to develop a trivalent prophylactic vaccine against LF showed that >90% protection could be achieved in rodent models. However, this trivalent vaccine gave only 35% protection in non-human primates. The major focus of this study was to develop a tetravalent prophylactic vaccine (rBmHAXT) and test the vaccine potential in a mouse model. We evaluated three different adjuvant formulations; alum, glucopyranosyl lipid adjuvant in stable emulsion (GLA/SE) alum (AL019), and mannosylated chitosan (MCA) to determine the optimum adjuvant formulation for rBmHAXT. Results presented in this study show that rBmHAXT + AL019 gave the highest rate of protection (>88%) against challenge infection, compared to rBmHAXT + AL007 (79%), rBmHAXT + MCA (79%) and controls. Analysis of the immune correlates of protection showed that all three adjuvants elicited high titer of antigen-specific IgG1, IgG2a, and IgG2b antibodies. High number of IFN-gamma producing antigen-specific memory cells were generated in the vaccinated animals irrespective of the adjuvants used. Similarly, spleen cells from rBmHAXT vaccinated animals secreted IL-4, IL-10, and IFN-gamma in response to rBmHAXT suggesting the generation of a balanced Th1/Th2 response. There was also an increase in IL-17-secreting cells in rBmHAXT-vaccinated animals. These findings thus suggest that rBmHAXT + AL019 is a better prophylactic formulation for LF. PMID- 30013572 TI - A Single Microorganism Epitope Attenuates the Development of Murine Autoimmune Arthritis: Regulation of Dendritic Cells via the Mannose Receptor. AB - A single epitope of Leishmania analog of the receptors for activated C kinase (LACK) from Leishmania major, the polypeptide LACK156-173, is recognized by Vbeta4+/Valpha8+ T cells, and activate these cells that drives the subsequent T helper (Th)2 response. This study was undertaken to investigate the therapeutic potential of the LACK156-173 epitope in murine autoimmune arthritis models. To explore the influence of the LACK156-173 epitope on murine collagen antibody induced arthritis, as well as its immunological mechanism, we vaccinated or treated mice with a LACK156-173 epitope expression plasmid or polypeptide. The effect of LACK156-173 epitope was then evaluated by clinical scores, histopathology, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Using flow cytometry, we measured the subsets and maturity of CD11c+ dendritic cells (DCs), as well as T cell polarization, in co-culture experiments. We also measured cytokine gene expression and production. The murine macrophage like cell line RAW264.7 was used to identify the receptor for the epitope. Vaccination or treatment of the mice with the LACK156-173 epitope expression plasmid or polypeptide ameliorated the severity of arthritis. qRT-PCR analysis revealed that the LACK156-173 epitope improved the balance of effector T cells in synovial tissue compared to that in untreated arthritis controls. Toll-like receptor (TLR) 4 expression was diminished by LACK156-173. The epitope also influenced T cell polarization by regulating the differentiation, maturation, and functions of CD11c+ DCs and upregulating Jagged1 ligand expression. Blocking the mannose receptor (MR) significantly attenuated LACK156-173 epitope-induced macrophage activation. Our data indicate that vaccination or treatment with a single microorganism epitope, LACK156-173, is a highly efficient therapy for murine autoimmune arthritis. The therapeutic effects are mediated by the regulation of the differentiation, maturation, and functions of DCs via MR, resulting in the upregulation of Jagged1 expression and Th2 cell polarization. Our results demonstrate the therapeutic potential of the LACK156-173 epitope in rheumatoid arthritis. PMID- 30013573 TI - Elevated IgG Responses in Infants Are Associated With Reduced Prevalence of Mycobacterium tuberculosis Infection. AB - Background: It is unclear whether antibodies can prevent Mycobacterium tuberculosis (Mtb) infection. In this study, we examined the relationship between total plasma IgG levels, IgG elicited by childhood vaccines and soil-transmitted helminths, and Mtb infection prevalence, defined by positive QuantiFERON (QFT) test. Methods: We studied 100 Mtb uninfected infants, aged 4-6 months. Ten infants (10%) converted to positive QFT test (QFT+) within 2 years of follow-up for Mtb infection. Antibody responses in plasma samples acquired at baseline and tuberculosis investigation were analyzed by enzyme-linked immunosorbent assay and ImmunoCAP(r) assay. Results: QFT- infants displayed a significant increase in total IgG titers when re-tested, compared to IgG titers at baseline, which was not observed in QFT+ infants. Bacille Calmette-Guerin (BCG) vaccine-specific IgG2 and live-attenuated measles vaccine-specific IgG were raised in QFT- infants, and infants who acquired an Mtb infection did not appear to launch a BCG-specific IgG2 response. IgG titers against the endemic helminth Ascaris lumbricoides increased from baseline to QFT re-testing in all infants. Conclusion: These data show raised IgG associates with a QFT-status. Importantly, this effect was also associated with a trend showing raised IgG titers to BCG and measles vaccine. Our data suggest a possible protective association between raised antibody titers and acquisition of Mtb infection, potentially mediated by exposure to antigens both related and unrelated to Mtb. PMID- 30013574 TI - IFN-gamma Regulates the Expression of MICA in Human Corneal Epithelium Through miRNA4448 and NFkappaB. AB - Purpose: Major histocompatibility complex class I-related chain A (MICA), a non classical major histocompatibility complex molecule, can stimulate or co stimulate CD8+ T cells or natural killer (nk) cells, thus affecting cornea allograft survival. This study investigated IFN-gamma regulation of MICA expression levels in human corneal epithelium by miRNA4448. Methods: MICA expression levels in human corneal epithelial cells (HCECs) stimulated with IFN gamma were detected by qRT-PCR and an enzyme-linked immunosorbent assay, and differential miRNA expression levels were measured. qRT-PCR, Western blotting, and immunofluorescence staining revealed nuclear factor kappa B (NFkappaB)/P65 expression in IFN-gamma-treated and miRNA4448-overexpressed HCECs. A luciferase reporter assay was used to predict the interaction between NFkappaB and MICA. Additionally, HCECs were transfected with MICA plasmid or treated with IFN-gamma and NKG2D-mAb and cocultured with NK cells and CD8+ T cells. Cell apoptosis was measured using Annexin V/PI staining. qRT-PCR detected the expression of anti apoptosis factor Survivin and apoptosis factor Caspase 3 in MICA-transfected and IFN-gamma-treated HCECs after co-culturing with NK cells and CD8+ T cells. Results: IFN-gamma (500 ng/ml, 24 h) upregulated MICA expression in HCECs in vitro. Among six differentially expressed microRNAs, miRNA4448 levels decreased the most after IFN-gamma treatment. The overexpression of miRNA4448 decreased MICA expression. miRNA4448 downregulated NFkappaB/P65 expression in IFN-gamma induced HCEC, and it was determined that NFkappaB/P65 directly targeted MICA by binding to the promotor region. A coculture with NK cells and CD8+ T cells demonstrated that MICA overexpression enhanced HCEC apoptosis, which could be inhibited by NKG2D-mAb. Simultaneously, Survivin mRNA expression decreased and Caspase3 mRNA expression increased upon the interaction between MICA and NK (CD8+ T) cells in HCECs. Conclusion: IFN-gamma enhances the expression of MICA in HCECs by modulating miRNA4448 and NFkappaB/P65 levels, thereby contributing to HCEC apoptosis induced by NK and CD8+ T cells. This discovery may lead to new insights into the pathogenesis of corneal allograft rejection. PMID- 30013575 TI - Unexpected Help: Follicular Regulatory T Cells in the Germinal Center. AB - Follicular helper T (Tfh) cells are necessary for germinal center (GC) formation and within the GC, provide key signals to B cells for their differentiation into plasmablasts and plasma cells that secrete high-affinity and isotype-switched antibody (Ab). A specialized subset of Foxp3+ T cells termed T follicular regulatory (Tfr) cells, also regulate the differentiation of Ab-secreting cells from the GC. Tfr-cell function in the GC is not well understood, however, the dominant paradigm currently is that Tfr cells repress excessive Tfh and GC B cell proliferation and help promote stringent selection of high-affinity B cells. A mouse model where the Bcl6 gene is specifically deleted in Foxp3+ T cells (Bcl6FC mice) allows the study of Tfr cell function with more precision than other approaches. Studies with this model have shown that Tfr cells play a key role in maintaining GC B cell proliferation and Ab levels. Part of the mechanism for this positive "helper" effect of Tfr cells on the GC is Tfr cell-derived IL-10, which can promote B cell growth and entry into the dark zone of the GC. Recent studies on Tfr cells support a new paradigm for Tfr cell function in the GC reaction. Here, we review studies on Tfr cell functions and discuss the evidence that Tfr cells can have a major helper role in the GC-dependent Ab response. PMID- 30013576 TI - Functional Analysis of Genetic Variations in Surfactant Protein D in Mycobacterial Infection and Their Association With Tuberculosis. AB - Surfactant proteins (SPs)-A and -D are C-type lectins of the collectin family and function in the clearance of infectious particles in the lungs. Some polymorphisms of SPs that give rise to amino acid changes have been found to affect their function. Several SP-A gene polymorphisms have been reported to be associated with respiratory infection diseases, such as tuberculosis (TB). However, the relationship between surfactant proteins D (SP-D) polymorphisms and TB is still unclear. To study the associations between SP-D polymorphisms and TB, the correlations of SP-D polymorphisms with TB were examined in a case-control study, which included 364 patients with TB and 177 control subjects. In addition, we cloned two major SP-D exonic polymorphism C92T (rs721917) and A538G (rs2243639) constructs and used these for in vitro assays. The effects of SP-D polymorphisms on agglutination and other interactions with Mycobacterium bovis bacillus Calmette-Guerin (M. bovis BCG) were evaluated. In comparison with SP-D 92C (amino acid residue 16, Threonine), our results showed that SP-D 92T (amino acid residue 16, Methionine) had a lower binding ability to M. bovis BCG, a lower capacity to inhibit phagocytosis, lesser aggregation, poorer survival of bacillus Calmette-Guerin (BCG)-infected MH-S cells, and less inhibition of intracellular growth of M. bovis BCG. The case-control association study showed that the 92T homozygous genotype was a risk factor for TB. However, a lesser effect was seen for polymorphism A538G. In conclusion, the results of functional and genetic analyses of SP-D variants consistently showed that the SP-D 92T variant increased susceptibility to TB, which further confirmed the role of SP-D in pulmonary innate immunity against mycobacterial infection. PMID- 30013577 TI - IL-17A+GM-CSF+ Neutrophils Are the Major Infiltrating Cells in Interstitial Lung Disease in an Autoimmune Arthritis Model. AB - Objective: To gain a better understanding of the pathogenesis of autoimmune arthritis-associated interstitial lung disease (ILD), we sought to identify the characteristics of lung-infiltrating cells in SKG mice with ILD. Methods: We injected curdlan in SKG mice at 8 weeks of age, and identified the presence of ILD by PET-MRI at 20 weeks post-injection and histological analysis at 22 weeks post-injection. Lung-infiltrating cells were examined by flow cytometry. Analysis of serum cytokines by the Luminex multiplex cytokine assay was performed at 14 and 22 weeks post-injection, and cytokine profiles before and after the development of ILD were compared. Opal multiplexed immunofluorescent staining of lung tissue was also performed. Results: At 20 weeks post-injection, curdlan treated SKG mice developed not only arthritis but also lung inflammation combined with fibrosis, which was identified by PET-MRI and histological analysis. The majority of inflammatory cells that accumulated in the lungs of curdlan-treated SKG mice were CD11b+Gr1+ neutrophils, which co-express IL-17A and GM-CSF, rather than TNF-alpha. Compared with 14 weeks post-injection, serum levels of GM-CSF, MCP1, IL-17A, IL-23, TSLP, and soluble IL-7Ralpha had increased at 22 weeks post injection, whereas those of IFN-gamma, IL-22, IL-6, and TNF-alpha remained unchanged. Furthermore, IL-23, CXCL5, IL-17A, and GM-CSF, but not TNF-alpha, were observed in immunofluorescent-stained lung tissue. Conclusion: We found that IL 17A+GM-CSF+ neutrophils represented the major inflammatory cells in the lungs of curdlan-treated SKG mice. In addition, GM-CSF and IL-17A appear to play a more important role than TNF-alpha in ILD development. PMID- 30013578 TI - Integrated Transcript and Metabolite Profiles Reveal That EbCHI Plays an Important Role in Scutellarin Accumulation in Erigeron breviscapus Hairy Roots. AB - Scutellarin, a flavonoid 7-O-glucuronide, is an essential bioactive compound of Erigeron breviscapus (Vaniot) Hand.-Mazz. used for the treatment of cerebrovascular diseases. However, due to overexploitation and overuse, E. breviscapus is facing the problems of extinction and habitat degradation. In this study, a correlation analysis between the transcript and metabolite profiles of methyl jasmonate (MeJA)-treated E. breviscapus at different time points indicated that chalcone isomerase (EbCHI) was the primary contributor to scutellarin accumulation during flavonoid biosynthesis. EbCHI was then further characterized as a chalcone isomerase that efficiently converted chalcone to naringenin in vitro. Optimal parameters derived by comparing different culture conditions were successfully used to establish hairy root cultures of E. breviscapus with a maximum transformation rate of 60% in B5 medium. Furthermore, overexpression of EbCHI significantly enhanced scutellarin accumulation in E. breviscapus hairy roots with a maximum content of 2.21 mg g-1 (dw), 10-fold higher than that of natural roots (0.21 mg g-1 dw). This study sheds new light on a method of effective gene-based metabolic engineering by accurate and appropriate strategies and provides a protocol for hairy root cultures that accumulate high levels of scutellarin, providing a promising prospect for relieving the overexploitation and unavailability of E. breviscapus in the future. PMID- 30013579 TI - Long Term Management of Rhizomania Disease-Insight Into the Changes of the Beet necrotic yellow vein virus RNA-3 Observed Under Resistant and Non-resistant Sugar Beet Fields. AB - Rhizomania disease, caused by the Beet necrotic yellow vein virus (BNYVV), is considered as one of the major constraints for sugar beet production, worldwide. As a result of the introgression of major resistance genes (Holly, Rz2) in commercially available sugar beet varieties, the virus has endured strong selection pressure since the 90s'. Understanding the virus response and diversity to sugar beet resistance is a key factor for a sustainable management of only few resistance genes. Here we report rhizomania surveys conducted in a rhizomania hot spot, the Pithiviers area (France) during a 4-year period and complementary to the study of Schirmer et al. (2005). The study aimed at evaluating the intra- and inter-field BNYVV diversity in response to different sources of resistance and over the growing season. To follow rhizomania development over the sugar beet growing season, extensive field samplings combined with field assays were performed in this study. The evolution of the BNYVV diversity was assessed at intra- and inter-field levels, with sugar beet cultivars containing different resistance genes (Rz1, Rz1 + Heterodera schachtii resistance and Rz1Rz2). Intra field diversity was analyzed at the beginning and the end of the growing season of each field. From more than one thousand field samples, the simultaneous presence of the different A, B and P types of BNYVV was confirmed, with 21 variants identified at positions 67-70 of the p25 tetrad. The first variant, AYHR, was found most commonly followed by SYHG. Numerous mixed infections (9.93% of the samples), mostly of B-type with P-type, have also been evidenced. Different tetrads associated with the A- or B-type were also found with a fifth RNA-genome component known to allow more aggressiveness to BNYVV on sugar beet roots. Cultivars with Rz1+Rz2 resistant genes showed few root symptoms even if the BNYVV titre was quite high according to the BNYVV type present. The virus infectious potential in the soil at the end of the growing season with such cultivars was also lower despite a wider diversity at the BNYVV RNA3 sequence level. Rz1+Rz2 cultivars also exhibited a lower presence of Beet soil-borne virus (BSBV), a P. betae-transmitted Pomovirus. Cultivars with Rz1 and nematode (N) resistance genes cultivated in field infected with nematodes showed lower BNYVV titre than those with Rz1 or Rz1+Rz2 cultivars. Overall, the population structure of BNYVV in France is shown to be different from that previously evidenced in different world areas. Implications for long-term management of the resistance to rhizomania is discussed. PMID- 30013580 TI - Calmodulin 1 Regulates Senescence and ABA Response in Arabidopsis. AB - Cellular calcium acts as a second messenger and regulates diverse developmental events and stress responses. Cytosolic calcium has long been considered as an important regulator of senescence, however, the role of Ca2+ in plant senescence has remained elusive. Here we show that the Calmodulin 1 (CaM1) gene, which encodes Ca2+-binding protein calmodulin 1, positively regulates leaf senescence in Arabidopsis. Yellowing of leaves, accumulation of reactive oxygen species (ROS), and expression of the senescence-associated gene 12 (SAG12) were significantly enhanced in CaM1 overexpression plants. In contrast, abscisic acid (ABA)-triggered ROS production and stomatal closure were reduced in amiRNA-CaM1 plants. We found a positive-feedback regulation loop among three signaling components, CaM1, RPK1, and RbohF, which physically associate with each other. RPK1 positively regulates the expression of the CaM1 gene, and the CaM1 protein, in turn, up-regulates RbohF gene expression. Interestingly, the expression of CaM1 was down-regulated in rbohD, rbohF, and rbohD/F mutants. We show that CaM1 positively regulates ROS production, leaf senescence, and ABA response in Arabidopsis. PMID- 30013581 TI - Flammability of Two Mediterranean Mixed Forests: Study of the Non-additive Effect of Fuel Mixtures in Laboratory. AB - In the Mediterranean region, wildfires are a major disturbance, determined by ecosystem and forest species characteristics. Both the flammability and resistance to fire of a mixed forest may vary from those of the individual species. Two mixed Mediterranean woodlands, a Cupressus sempervirens and Quercus ilex stand in Italy; and a Juniperus thurifera and Quercus faginea stand in Spain were investigated. Laboratory flammability tests were conducted on live foliage, litter samples and on litter beds from individual and mixed species to evaluate: (i) the flammability traits of the mixtures of live foliage and litter samples; (ii) whether the flammability of the two-species mixtures are non-additive, i.e., differ from expected flammability based on arithmetic sum of the single effects of each components species in monospecific fuel; (iii) the ignition success and initial fire propagation in litter beds. Flammability tests were also conducted on bark samples to estimate the resistance of the tree species to fire. The ignitibility of live foliage was lower and the combustibility was higher in Cupressaceae than in Quercus. Non-additive effects were observed in some flammability components of live foliage and litter, especially in the mixtures of C. sempervirens and Q. ilex. Ignitability and combustibility were higher and lower than expected, respectively, and tended to be driven by Quercus), while the consumability was lowered more than expected by both Cupressaceae. The ignition success in the litter beds was low, especially for the presence of Cupressaceae that increase the bulk density of the mixtures. Cupressaceae, which have a thinner bark, suffered more damage to the cambium after shorter exposure to the heat source than Quercus species. In all the species studied, time to reach lethal temperatures in the cambium was dependent on thickness rather than on flammability of the bark. The study findings revealed that tree species may influence flammability of mixed fuels disproportionately to their load. The studied species showed to exert a contrasted effect on flammability of the mixtures, increasing ignitability and decreasing combustibility and consumability well out of their proportion in the mixture. This may potentially influence fire dynamics in mixed forests. PMID- 30013582 TI - Simultaneous Editing of Two Copies of Gh14-3-3d Confers Enhanced Transgene-Clean Plant Defense Against Verticillium dahliae in Allotetraploid Upland Cotton. AB - Gossypium hirsutum is an allotetraploid species, meaning that mutants that are difficult to be generated by classical approaches due to gene redundancy. The CRISPR/Cas9 genome editing system is a robust and highly efficient tool for generating target gene mutants, by which the genes of interest may be functionally dissected and applied through genotype-to-phenotype approaches. In this study, the CRISPR/Cas9 genome editing system was developed in G. hirsutum through editing the Gh14-3-3d gene. In T0 transgenic plants, lots of insertions and deletions (indels) in Gh14-3-3d at the expected target site were detected in the allotetraploid cotton At or Dt subgenomes. The results of the PCR, T7EI digestion and sequencing analyses showed that the indels in Gh14-3-3d gene can be stably transmitted to the next generation. Additionally, the indels in the At and Dt subgenomes were segregated in the T1 transgenic plants following Mendelian law, independing on the T-DNA segregation. Two homozygous Gh14-3-3d-edited plants free of T-DNA were chosen by PCR and sequencing assays in the T1 plants, which were called transgene-clean editing plants and were designated ce1 and ce2 in the T2 lines showed higher resistance to Verticillium dahliae infestation compared to the wild-type plants. Thus, the two transgene-clean edited lines can be used as a germplasm to breed disease-resistant cotton cultivars, possibly avoiding complex and expensive safety assessments of the transgenic plants. PMID- 30013584 TI - Genome-Wide Association Mapping for Cold Tolerance in a Core Collection of Rice (Oryza sativa L.) Landraces by Using High-Density Single Nucleotide Polymorphism Markers From Specific-Locus Amplified Fragment Sequencing. AB - Understanding the genetic mechanism of cold tolerance in rice is important to mine elite genes from rice landraces and breed excellent cultivars for this trait. In this study, a genome-wide association study (GWAS) was performed using high-density single nucleotide polymorphisms (SNPs) obtained using specific-locus amplified fragment sequencing (SLAF-seq) technology from a core collection of landraces of rice. A total of 67,511 SNPs obtained from 116,643 SLAF tags were used for genotyping the 150 accessions of rice landraces in the Ting's rice core collection. A compressed mixed liner model was used to perform GWAS by using the high-density SNPs for cold tolerance in rice landraces at the seedling stage. A total of 26 SNPs were found to be significantly (P < 1.48 * 10-7) associated with cold tolerance, which could explained phenotypic variations ranging from 26 to 33%. Among them, two quantitative trait loci (QTLs) were mapped closely to the previously cloned/mapped genes or QTLs for cold tolerance. A newly identified QTL for cold tolerance in rice was further characterized by sequencing, real time polymerase chain reaction, and bioinformatics analyses. One candidate gene, i.e., Os01g0620100, showed different gene expression levels between the cold tolerant and sensitive landraces under cold stress. We found the difference of coding amino acid in Os01g0620100 between cold tolerant and sensitive landraces caused by polymorphism within the coding domain sequence. In addition, the prediction of Os01g0620100 protein revealed a WD40 domain that was frequently found in cold tolerant landraces. Therefore, we speculated that Os01g0620100 was highly important for the response to cold stress in rice. These results indicated that rice landraces are important sources for investigating rice cold tolerance, and the mapping results might provide important information to breed cold-tolerant rice cultivars by using marker-assisted selection. PMID- 30013585 TI - Variable Patterning of Chromatin Remodeling, Telomere Positioning, Synapsis, and Chiasma Formation of Individual Rye Chromosomes in Meiosis of Wheat-Rye Additions. AB - Meiosis, the type of cell division that halves the chromosome number, shows a considerable degree of diversity among species. Unraveling molecular mechanisms of the meiotic machinery has been mainly based on meiotic mutants, where the effects of a change were assessed on chromosomes of the particular species. An alternative approach is to study the meiotic behavior of the chromosomes introgressed into different genetic backgrounds. As an allohexaploid, common wheat tolerates introgression of chromosomes from related species, such as rye. The behavior of individual pairs of rye homologues added to wheat has been monitored in meiotic prophase I and metaphase I. Chromosome 4R increased its length in early prophase I much more than other chromosomes studied, implying chromosome specific patterns of chromatin organization. Chromosome conformation affected clustering of telomeres but not their dispersion. Telomeres of the short arm of submetacentric chromosomes 4R, 5R, and 6R failed more often to be included in the telomere cluster either than the telomeres of the long arms or telomeres of metacentrics such as 2R, 3R, and 7R. The disturbed migration of the telomeres of 5RS and 6RS was associated with failure of synapsis and chiasma formation. However, despite the failed convergence of its telomere, the 4RS arm developed normal synapsis, perhaps because the strong increase of its length in early prophase I facilitated homologous encounters in intercalary regions. Surprisingly, chiasma frequencies in both arms of 4R were reduced. Similarly, the short arm of metacentric chromosome 2R often failed to form chiasmata despite normal synapsis. Chromosomes 1R, 3R, and 7R showed a regular meiotic behavior. These observations are discussed in the context of the behavior that these chromosomes show in rye itself. PMID- 30013587 TI - Legume Intercropping With the Bioenergy Crop Sida hermaphrodita on Marginal Soil. AB - The cultivation of perennial biomass plants on marginal soils can serve as a sustainable alternative to conventional biomass production via annual cultures on fertile soils. Sida hermaphrodita is a promising species to be cultivated in an extensive cropping system on marginal soils in combination with organic fertilization using biogas digestates. In order to enrich this cropping system with nitrogen (N) and to increase overall soil fertility of the production system, we tested the potential of intercropping with leguminous species. In a 3 year outdoor mesocosm study, we intercropped established S. hermaphrodita plants with the perennial legume species Trifolium pratense, T. repens, Melilotus albus, and Medicago sativa individually to study their effects on plant biomass yields, soil N, and above ground biomass N. As a control for intercropping, we used a commercial grass mixture without N2-fixing species as well as a no-intercropping treatment. Results indicate that intercropping in all intercropping treatments increased the total biomass yield, however, grass species competed with S. hermaphrodita for N more strongly than legumes. Legumes enriched the cropping system with fixed atmospheric nitrogen (N2) and legume facilitation effects varied between the legume species. T. pratense increased the biomass yield of S. hermaphrodita and increased the total biomass yield per mesocosm by 300%. Further, the total above ground biomass of S. hermaphrodita and T. pratense contained seven times more N compared to the mono-cropped S. hermaphrodita. T. repens also contributed highly to N facilitation. We conclude that intercropping of legumes, especially T. pratense and T. repens can stimulate the yield of S. hermaphrodita on marginal soils for sustainable plant biomass production. PMID- 30013586 TI - Genetic and Molecular Regulation of Seed Storage Proteins (SSPs) to Improve Protein Nutritional Value of Oilseed Rape (Brassica napus L.) Seeds. AB - The world-wide demand for additional protein sources for human nutrition and animal feed keeps rising due to rapidly growing world population. Oilseed rape is a second important oil producing crop and the by-product of the oil production is a protein rich meal. The protein in rapeseed meal finds its application in animal feed and various industrial purposes, but its improvement is of great interest, especially for non-ruminants and poultry feed. To be able to manipulate the quality and quantity of seed protein in oilseed rape, understanding genetic architecture of seed storage protein (SSPs) synthesis and accumulation in this crop species is of great interest. For this, application of modern molecular breeding tools such as whole genome sequencing, genotyping, association mapping, and genome editing methods implemented in oilseed rape seed protein improvement would be of great interest. This review examines current knowledge and opportunities to manipulate of SSPs in oilseed rape to improve its quality, quantity and digestibility. PMID- 30013583 TI - A Plant Biologist's Toolbox to Study Translation. AB - Across a broad range of species and biological questions, more and more studies are incorporating translation data to better assess how gene regulation occurs at the level of protein synthesis. The inclusion of translation data improves upon, and has been shown to be more accurate than, transcriptional studies alone. However, there are many different techniques available to measure translation and it can be difficult, especially for young or aspiring scientists, to determine which methods are best applied in specific situations. We have assembled this review in order to enhance the understanding and promote the utilization of translational methods in plant biology. We cover a broad range of methods to measure changes in global translation (e.g., radiolabeling, polysome profiling, or puromycylation), translation of single genes (e.g., fluorescent reporter constructs, toeprinting, or ribosome density mapping), sequencing-based methods to uncover the entire translatome (e.g., Ribo-seq or translating ribosome affinity purification), and mass spectrometry-based methods to identify changes in the proteome (e.g., stable isotope labeling by amino acids in cell culture or bioorthogonal noncanonical amino acid tagging). The benefits and limitations of each method are discussed with a particular note of how applications from other model systems might be extended for use in plants. In order to make this burgeoning field more accessible to students and newer scientists, our review includes an extensive glossary to define key terms. PMID- 30013588 TI - Multiple Consequences Induced by Epidermally-Located Anthocyanins in Young, Mature and Senescent Leaves of Prunus. AB - Anthocyanic morphs are generally less efficient in terms of carbon gain, but, in turn, are more photoprotected than anthocyanin-less ones. To date, mature leaves of different morphs or leaves at different developmental stages within the same species have generally been compared, whereas there is a lack of knowledge regarding different stages of development of red vs. green leaves. Leaves (1-, 7 , and 13-week-old) of red- (RLP) and green-leafed (GLP) Prunus in terms of photosynthetic rate, carbon metabolism and photoprotective mechanisms were compared to test whether anthocyanin-equipped leaves perform better than anthocyanin-less leaves and whether photoprotection is the primary role of epidermally-located anthocyanins, using for the first time a recently-developed parameter of chlorophyll fluorescence (qPd). GLP leaves had a higher photosynthetic rate in 1- and 7-week-old leaves, but RLP leaves performed better at an early stage of senescence and had a longer leaf lifespan. Anthocyanins contributed to leaf photoprotection throughout the leaf development, but were tightly coordinated with carotenoids. Besides photoprotecting, we propose that epidermal anthocyanins may be principally synthetized to maintain an efficient carbon-sink strength in young and senescent leaves, thus extending the RLP leaf lifespan. PMID- 30013591 TI - Corrigendum: The Glycerate and Phosphorylated Pathways of Serine Synthesis in Plants: The Branches of Plant Glycolysis Linking Carbon and Nitrogen Metabolism. AB - [This corrects the article DOI: 10.3389/fpls.2018.00318.]. PMID- 30013589 TI - Differential Shape of Geminivirus Mutant Spectra Across Cultivated and Wild Hosts With Invariant Viral Consensus Sequences. AB - Geminiviruses (family Geminiviridae) possess single-stranded circular DNA genomes that are replicated by cellular polymerases in plant host cell nuclei. In their hosts, geminivirus populations behave as ensembles of mutant and recombinant genomes, known as viral quasispecies. This favors the emergence of new geminiviruses with altered host range, facilitating new or more severe diseases or overcoming resistance traits. In warm and temperate areas several whitefly transmitted geminiviruses of the genus Begomovirus cause the tomato yellow leaf curl disease (TYLCD) with significant economic consequences. TYLCD is frequently controlled in commercial tomatoes by using the dominant Ty-1 resistance gene. Over a 45 day period we have studied the diversification of three begomoviruses causing TYLCD: tomato yellow leaf curl virus (TYLCV), tomato yellow leaf curl Sardinia virus (TYLCSV) and tomato yellow leaf curl Malaga virus (TYLCMaV, a natural recombinant between TYLCV and TYLCSV). Viral quasispecies resulting from inoculation of geminivirus infectious clones were examined in plants of susceptible tomato (ty-1/ty-1), heterozygous resistant tomato (Ty-1/ty-1), common bean, and the wild reservoir Solanum nigrum. Differences in virus fitness across hosts were observed while viral consensus sequences remained invariant. However, the complexity and heterogeneity of the quasispecies were high, especially in common bean and the wild host. Interestingly, the presence or absence of the Ty-1 allele in tomato did not lead to differences in begomovirus mutant spectra. However, the fitness decrease of TYLCSV and TYLCV in tomato at 45 dpi might be related to an increase in CP (Coat protein) mutation frequency. In Solanum nigrum the recombinant TYLCMaV, which showed lower fitness than TYLCSV, at 45 dpi actively explored Rep (Replication associated protein) ORF but not the overlapping C4. Our results underline the importance of begomovirus mutant spectra during infections. This is especially relevant in the wild reservoir of the viruses, which has the potential to maintain highly diverse mutant spectra without modifying their consensus sequences. PMID- 30013590 TI - Genetic Basis and Breeding Perspectives of Grain Iron and Zinc Enrichment in Cereals. AB - Micronutrient deficiency, also known as "hidden hunger," is an increasingly serious global challenge to humankind. Among the mineral elements, Fe (Iron) and Zn (Zinc) have earned recognition as micronutrients of outstanding and diverse biological relevance, as well as of clinical importance to global public health. The inherently low Fe and Zn content and poor bioavailability in cereal grains seems to be at the root of these mineral nutrient deficiencies, especially in the developing world where cereal-based diets are the most important sources of calories. The emerging physiological and molecular understanding of the uptake of Fe and Zn and their translocation in cereal grains regrettably also indicates accumulation of other toxic metals, with chemically similar properties, together with these mineral elements. This review article emphasizes breeding to develop bioavailable Fe- and Zn-efficient cereal cultivars to overcome malnutrition while minimizing the risks of toxic metals. We attempt to critically examine the genetic diversity regarding these nutritionally important traits as well as the progress in terms of quantitative genetics. We sought to integrate findings from the rhizosphere with Fe and Zn accumulation in grain, and to discuss the promoters as well as the anti-nutritional factors affecting Fe and Zn bioavailability in humans while restricting the content of toxic metals. PMID- 30013593 TI - Commentary: Likelihood Ratio as Weight of Forensic Evidence: A Closer Look. PMID- 30013592 TI - Screening of the LAMB2, WT1, NPHS1, and NPHS2 Genes in Pediatric Nephrotic Syndrome. AB - Mutations in the NPHS1, NPHS2, LAMB2, and the WT1 genes are responsible for causing nephrotic syndrome (NS) in two third of the early onset cases. This study was carried out to assess the frequencies of mutations in these genes in a cohort of pediatric NS patients. A total of 64 pediatric familial or sporadic SRNS cases were recruited. Among these, 74% had a disease onset of up to 3 years of age. We found one homozygous frameshift mutation in the NPHS1 gene in one CNS case and two homozygous mutations in the NPHS2 gene. Six mutations in four cases in the LAMB2 gene were also identified. No mutation was detected in the WT1 gene in isolated SRNS cases. LAMB2 gene missense mutations were segregating in NS cases with no extra-renal abnormalities. Analysis of the population genomic data (1000 genome and gnomAD databases) for the prevalence estimation revealed that NS is more prevalent than previously determined from clinical cohorts especially in Asian population compared with overall world populations (prevalence worldwide was 1in 189036 and in South-Asian was 1in 56689). Our results reiterated a low prevalence of mutations in the NPHS1, NPHS2, LAMB2, and WT1 genes in the studied population from Pakistan as compared to some European population that showed a high prevalence of mutations in these genes. This is a comprehensive screening of the genes causing early onset NS in sporadic and familial NS cases suggesting a more systematic and robust approach for mutation identification in all the 45 disease-causing genes in NS in our population is required. PMID- 30013594 TI - Polygenic Basis and Variable Genetic Architectures Contribute to the Complex Nature of Body Weight -A Genome-Wide Study in Four Chinese Indigenous Chicken Breeds. AB - Body weight (BW) is one of the most important economic traits for animal production and breeding, and it has been studied extensively for its phenotype genotype associations. While mapping studies have mostly aimed at finding as many loci as possible that contributed to the variation in BW, the role of other factors in its genetic architecture, including their frequencies in the population and their interactions, have been largely overlooked. To comprehensively characterized the genetic architecture of BW, we performed a genome-wide association study (GWAS) both at the single-marker and haplotype level on birds from four indigenous Chinese chicken breeds (Chahua, Silkie, Langshan, and Beard), rather than studying crosses between two founder lines. Additionally, samples from two more breeds (Red Junglefowl and Recessive White) were included to better reflect variable genetic characteristics across populations. Six loci were mapped in this study, revealing the polygenic basis underlying BW. Moreover, by further examining the frequencies of the significantly associated haplotypes in each subpopulation and their effect sizes, most of the loci were found to affect BW in the Beard chicken breed alone. Two loci in GGA9 and GGA27, however, had a common effect on BW across subpopulations, showing that different underlying genetic mechanisms contribute to the phenotypic variability. These findings, particularly the variable genetic architectures found in different loci, improve our understanding of the overall genetic contributions to the large variability in BW among Chinese indigenous chicken breeds. These findings thus will have important implications for future chicken breeding. PMID- 30013595 TI - The Neural Basis of Fear Promotes Anger and Sadness Counteracts Anger. AB - In contrast to cognitive emotion regulation theories that emphasize top-down control of prefrontal-mediated regulation of emotion, in traditional Chinese philosophy and medicine, different emotions are considered to have mutual promotion and counteraction relationships. Our previous studies have provided behavioral evidence supporting the hypotheses that "fear promotes anger" and "sadness counteracts anger"; this study further investigated the corresponding neural correlates. A basic hypothesis we made is the "internal versus external orientation" assumption proposing that fear could promote anger as its external orientation associated with motivated action, whereas sadness could counteract anger as its internal or homeostatic orientation to somatic or visceral experience. A way to test this assumption is to examine the selective involvement of the posterior insula (PI) and the anterior insula (AI) in sadness and fear because the posterior-to-anterior progression theory of insular function suggests that the role of the PI is to encode primary body feeling and that of the AI is to represent the integrative feeling that incorporates the internal and external input together. The results showed increased activation in the AI, parahippocampal gyrus (PHG), posterior cingulate (PCC), and precuneus during the fear induction phase, and the activation level in these areas could positively predict subsequent aggressive behavior; meanwhile, the PI, superior temporal gyrus (STG), superior frontal gyrus (SFG), and medial prefrontal cortex (mPFC) were more significantly activated during the sadness induction phase, and the activation level in these areas could negatively predict subsequent feelings of subjective anger in a provocation situation. These results revealed a possible cognitive brain mechanism underlying "fear promotes anger" and "sadness counteracts anger." In particular, the finding that the AI and PI selectively participated in fear and sadness emotions was consistent with our "internal versus external orientation" assumption about the different regulatory effects of fear and sadness on anger and aggressive behavior. PMID- 30013596 TI - Prolactin Is a Strong Candidate for the Regulation of Luteal Steroidogenesis in Vizcachas (Lagostomus maximus). AB - Prolactin (PRL) is essential for the maintenance of the corpora lutea and the production of progesterone (P4) during gestation of mice and rats, which makes it a key factor for their successful reproduction. Unlike these rodents and the vast majority of mammals, female vizcachas (Lagostomus maximus) have a peculiar reproductive biology characterized by an ovulatory event during pregnancy that generates secondary corpora lutea with a consequent increment of the circulating P4. We found that, although the expression of pituitary PRL increased steadily during pregnancy, its ovarian receptor (PRLR) reached its maximum in midpregnancy and drastically decreased at term pregnancy. The luteinizing hormone receptor (LHR) exhibited a similar profile than PRLR. Maximum P4 and LH blood levels were recorded at midpregnancy as well. Remarkably, the P4-sinthesizing enzyme 3beta HSD accompanied the expression pattern of PRLR/LHR throughout gestation. Instead, the luteolytic enzyme 20alpha-HSD showed low expression at early and midpregnancy, but reached its maximum at the end of gestation, when PRLR/LHR/3beta-HSD expressions and circulating P4 were minimal. In conclusion, both the PRLR and LHR expressions in the ovary would define the success of gestation in vizcachas by modulating the levels of 20alpha-HSD and 3beta-HSD, which ultimately determine the level of serum P4 throughout gestation. PMID- 30013598 TI - Changes in Uterine Cancer Incidence Rates in Egypt. AB - Background: Uterine cancer is one of the top-ranking cancers in women with wide international variations in incidence rates. Developed countries have higher incidence rates than the developing countries. Egypt has significantly lower incidence of uterine cancer than other countries in the Middle East. This study aimed at verifying the incidence rate of uterine cancer and characterizing the demographic and clinical profiles of patients residing in the Gharbiah province in the Nile delta region of Egypt. Methods: Data from 660 uterine cancer patients diagnosed during the period of 1999 to 2010 were abstracted from the Gharbiah Cancer Registry, the only population-based registry in Egypt. The data included age, marital status, number of children, residence, smoking, occupation, date and basis of diagnosis, tumor topography, morphology, stage and grade, and treatment. Crude rate, age-standardized rate (ASR), and age-specific rate were calculated and associated with demographic and clinical characteristics of patients. Results: The study confirmed the low ASR of uterine cancer in Egypt, (4.1 per 100,000 (95% CI: 3.8-4.4)). The incidence rate increased significantly over the 12-year period. The crude rate (CR) was 1.95, 95% CI (1.64-2.25) in 1999-2002; 2.9, 95% CI (2.5-3.2) in 2003-2006; and 3.5, 95% CI (3.1-3.9) in 2007-2010. The rate ratio was 1.5, 95% CI (1.2-1.8) in 2003-2006 and 1.8, 95% CI (1.5-2.2) in 2007-2010 compared to 1999-2002. The majority of patients (83%) were postmenopausal with the highest age-specific rate in the 60-69-year age group (22.07 per 100,000 (95% CI: 19.3-25.2). The majority of patients were diagnosed at early stages (60% localized and 5% regional), had adenocarcinoma (68%), and resided in urban areas (54%). Conclusions: The study confirmed the low incidence rate of uterine cancer in the Gharbiah province of Egypt and significant increase in incidence in recent years. Future studies should focus on verifying the possible effect of hysterectomy on lowering the incidence, the factors related to the changes in rates between rural and urban areas, and the possible impact of nutritional and epidemiologic transitions on the increasing rates. PMID- 30013599 TI - Herpes Simplex Virus Colitis in a Patient with Newly Diagnosed Crohn's Disease. AB - Herpesvirus colitis is a known cause of morbidity and mortality amongst immunosuppressed individuals. We present a case of HSV colitis following a diagnosis of Crohn's Disease and methylprednisolone therapy. Diagnosis was confirmed by immunohistochemical staining and supported by polymerase chain reaction (PCR) of cutaneous vesicles. The patient recovered following three weeks of acyclovir. PMID- 30013597 TI - The Roles of Thyroid and Thyroid Hormone in Pancreas: Physiology and Pathology. AB - It is widely accepted that thyroid hormones (THs), secreted from the thyroid, play important roles in energy metabolism. It is also known that THs also alter the functioning of other endocrine glands; however, their effects on pancreatic function have not yet been reviewed. One of the main functions of the pancreas is insulin secretion, which is altered in diabetes. Diabetes, therefore, could be related to thyroid dysfunction. Earlier research on this subject focused on TH regulation of pancreas function (such as insulin secretion) or on insulin function through TH-mediated increase of energy metabolism. Afterwards, epidemiological investigations and animal test research found a link between autoimmune diseases, thyroid dysfunction, and pancreas pathology; however, the underlying mechanisms remain unknown. Furthermore, recent studies have shown that THs also play important roles in pancreas development and on islet pathology, both in diabetes and in pancreatic cancer. Therefore, an overview of the effects of thyroid and THs on pancreas physiology and pathology is presented. The topics contained in this review include a summary of the relationship between autoimmune thyroid dysfunction and autoimmune pancreas lesions and the effects of THs on pancreas development and pancreas pathology (diabetes and pancreatic cancer). PMID- 30013601 TI - User-Friendly Genetic Conditional Knockout Strategies by CRISPR/Cas9. AB - Loss-of-function studies are critically important in gene functional analysis of model organisms and cells. However, conditional gene inactivation in diploid cells is difficult to achieve, as it involves laborious vector construction, multifold electroporation, and complicated genotyping. Here, a strategy is presented for generating biallelic conditional gene and DNA regulatory region knockouts in mouse embryonic stem cells by codelivery of CRISPR-Cas9 and short homology-arm targeting vectors sequentially or simultaneously. Collectively, a simple and rapid method was presented to knock out any DNA element conditionally. This approach will facilitate the functional studies of essential genes and regulatory regions during development. PMID- 30013602 TI - Glycoprotein Ibalpha Kozak polymorphism in patients presenting with early-onset acute coronary syndrome. AB - Introduction: Glycoprotein Ibalpha (GPIbalpha) receptor is the chief molecule responsible for initial platelet adhesion to the subendothelium. A thymidine to cytosine single nucleotide substitution at position -5 from the ATG start codon characterizes the Kozak sequence polymorphism. The Kozak sequence polymorphism may increase the surface expression of GPIbalpha and contribute to thrombogenesis. We evaluated the allele frequencies of GPIbalpha Kozak sequence polymorphism in the Turkish population and examined the relationship between GPIbalpha Kozak sequence polymorphism and early-onset acute coronary syndrome (ACS). Material and methods: This study enrolled 200 patients (122 male, 78 female, mean age: 39 +/-5 years) and 200 healthy control subjects (110 male, 90 female, 41 +/-4 years). The patient group was composed of patients admitted to our coronary care unit with early-onset ACS and patients who attended to our cardiology outpatient clinic after hospital discharge with a diagnosis of early onset ACS. Results: Kozak polymorphism frequencies in patients and control subjects did not differ significantly (23% versus 22.5%, p = 0.812, respectively). In patients who presented with non-ST elevation myocardial infarction (NSTEMI), the frequency of GPIbalpha Kozak polymorphism was borderline significantly higher when compared with patients who presented with ST elevation myocardial infarction (STEMI) (35% vs. 20%, p = 0.05, respectively). Allele frequencies of T and C were calculated to be 0.873 and 0.128. Conclusions: Although the frequency of GPIbalpha Kozak polymorphism did not differ significantly in early-onset ACS patients versus control subjects, Kozak polymorphism frequency was borderline significantly higher in patients who presented with NSTEMI when compared to patients with STEMI. PMID- 30013600 TI - Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application. AB - Mesenchymal stem cells (MSCs) are multipotent stem cells characterized by self renewal, production of clonal cell populations, and multilineage differentiation. They exist in nearly all tissues and play a significant role in tissue repair and regeneration. Additionally, MSCs possess wide immunoregulatory properties via interaction with immune cells in both innate and adaptive immune systems, leading to immunosuppression of various effector functions. Numerous bioactive molecules secreted by MSCs, particularly cytokines, growth factors, and chemokines, exert autocrine/paracrine effects that modulate the physiological processes of MSCs. These invaluable virtues of MSCs provide new insight into potential treatments for tissue damage and inflammation. In particular, their extensive immunosuppressive properties are being explored for promising therapeutic application in immune disorders. Recently, clinical trials for MSC-mediated therapies have rapidly developed for immune-related diseases following reports from preclinical studies declaring their therapeutic safety and efficacy. Though immunotherapy of MSCs remains controversial, these clinical trials pave the way for their widespread therapeutic application in immune-based diseases. In this review, we will summarize and update the latest research findings and clinical trials on MSC-based immunomodulation. PMID- 30013603 TI - Acupuncture on Obesity: Clinical Evidence and Possible Neuroendocrine Mechanisms. AB - Objective: Acupuncture, as one of the complementary and alternative medicines, represents an efficient therapeutic option for obesity control. We conducted a meta-analysis to investigate the effectiveness of acupuncture in obesity and also summarized the available studies on exploring the mechanisms. Design: We searched six databases from the inception to April 2017 without language restriction. Eligible studies consisted of acupuncture with comparative controls ((1) sham acupuncture, (2) no treatment, (3) diet and exercise, and (4) conventional medicine). The primary outcomes consisted of BMI, body weight reduction, and incidence of cardiovascular events (CVD). Secondary outcomes included waist circumference (WC), waist-to-hip ratio (WHR), body fat mass percent, body fat mass (kg), total cholesterol (TC), triglyceride (TG), glucose, low density lipoprotein cholesterol (LDL-c) reduction, high density lipoprotein cholesterol (HDL-c) increase, and adverse effects. The quality of RCTs was assessed by the Cochrane Risk of Bias Tool. Subgroup analyses were performed according to types of acupuncture. A random effects model was used to adjust for the heterogeneity of the included studies. Publication bias was assessed using funnel plots. Main Results: We included 21 studies with 1389 participants. When compared with sham acupuncture, significant reductions in BMI (MD=-1.22, 95%CI=-1.87 to -0.56), weight (MD=-1.54, 95%CI=-2.98 to -0.11), body fat mass (kg) (MD=-1.31, 95%CI= 2.47 to -0.16), and TC (SMD=-0.63, 95%CI=-1.00 to -0.25) were found. When compared with no treatment group, significant reductions of BMI (MD=-1.92, 95%CI= 3.04 to -0.79), WHR (MD=-0.05, 95%CI=-0.09 to -0.02), TC (MD=-0.26, 95%CI=-0.48 to -0.03), and TG (MD=-0.29 95%CI=-0.39 to -0.18) were found. When compared with diet and exercise group, significant reduction in BMI (MD=-1.24, 95%CI=-1.87 to 0.62) and weight (MD=-3.27 95%CI=-5.07 to -1.47) was found. Adverse effects were reported in 5 studies. Conclusions: We concluded that acupuncture is an effective treatment for obesity and inferred that neuroendocrine regulation might be involved. PMID- 30013605 TI - The Construction of Sham Dry Needles and Their Validity. AB - Appropriate control interventions are necessary to show the treatment effect of dry needling. Different control procedures, such as dry needling of the contralateral side, and sham treatments, such as random and superficial needle insertion, have been utilized in trials. However, those methods might elicit a physiological response and are subsequently not ideal for use as a control. This descriptive study illustrates the construction of low-cost sham dry needles and evaluates their validity. Forty-two healthy asymptomatic subjects received either sham or real dry needling intervention to their right gluteal muscles and reported if they felt that the needle pierced the skin. They also graded the severity and qualified (sharp or dull) the pain associated with the intervention. The results showed that most of the subjects in both groups believed the needle penetrated the skin. The quantity of pain associated with the treatment was similar in both groups, but the quality assigned was different. The authors conclude that sham dry needling can be accomplished and used as a valid control treatment in dry needling research using these low-cost sham needles. PMID- 30013604 TI - A Brief Body-Mind-Spirit Group Therapy for Chinese Medicine Stagnation Syndrome: A Randomized Controlled Trial. AB - Background: Stagnation syndrome, a diagnostic entity in traditional Chinese medicine (TCM), is characterized by mind-body obstruction-like symptoms. Although TCM has long-established symptom-relief treatments, a comprehensive mind-body intervention was called for. Purpose: The study evaluated the efficacy of a six session body-mind-spirit (BMS) group therapy for persons with stagnation syndrome. Method: A 2-arm randomized controlled trial design was adopted. The control group received a parallel general TCM instruction course. Both groups completed a pretest (T0), posttest (T1), and 2-month follow-up assessment (T2). The measures included self-report scales on stagnation, depression, anxiety, physical distress, daily functioning, and positive and negative affect; the other measure was of salivary cortisol, a biological marker of stress. Results: Data on 111 adults with stagnation syndrome were included in the analysis. Completion rates were high (over 87%) for both the intervention and control groups. Repeated measures multivariate MANOVA revealed a significant combined effect with large effect size (eta-squared = 0.42). Repeated-measures ANOVA further revealed that the intervention group showed significant improvements in stagnation, the primary outcome, with medium effect size (eta-squared = 0.11). The intervention group also showed significant improvements in depression, physical distress, everyday functioning, and negative affect (eta-squared = 0.06 to 0.13). Post hoc analysis revealed that the intervention group showed significant improvements over the control group in cortisol level at 2-month follow-up assessment (T0 versus T2) with small effect size (eta-squared = 0.05), but not at posttest (T0 versus T1). Conclusions: Overall, the findings indicate that our brief BMS group therapy intervention for stagnation syndrome is efficacious. Moreover, the intervention resulted in a number of substantial improvements in the physical and mental health domains. PMID- 30013606 TI - Editorial. PMID- 30013607 TI - Fetal growth surveillance - Current guidelines, practices and challenges. AB - Antenatal surveillance of fetal growth is an essential part of good maternity care, as lack of detection of fetal growth restriction is directly associated with stillbirth and perinatal morbidity. New algorithms and guidelines provide care pathways which rely on regular third trimester ultrasound biometry and plotting of estimated fetal weight in pregnancies considered to be at increased risk, and their implementation has increased pressures on ultrasound resources. Customised growth charts have improved the distinction between constitutional and pathological smallness and reduced unnecessary referrals. Their introduction, together with clinicians' training, e-learning and audit as the key elements of the growth assessment protocol, has resulted in increased antenatal detection of small for gestational age babies and a reduction in avoidable stillbirths. However, missed case audits highlight that further improvements are needed, and point to the need to address quality assurance and resource issues in ultrasound services. PMID- 30013609 TI - Single centre audit of early impact of inclusion of the three vessel and trachea view in obstetric screening. AB - Detection rates of congenital cardiac malformations have traditionally remained low. The NHS Fetal Anomaly Screening Programme (FASP) aims to increase these detection rates for various reasons, including influencing perinatal management and aiding parental decision making. The inclusion of the three vessel view and trachea (3VT) view in 2015 aimed to improve detection rates of arch abnormalities in particular. This study evaluated the early impact of the new initiative at one NHS Trust. Departmental screen-positive rates were compared for a full year before and after implementation. Referrals to, and opinions of, the foetal medicine unit (FMU) were assessed; as were undetected congenital heart defects for the two time periods. Compared with the pre-implementation (pre-3VT) period, the number of completed anomaly scans performed after implementation (post-3VT) increased by 3% and the number of FMU referrals increased by 625%. Departmental screen-positive rates for cardiac abnormalities increased from 40% (pre-3VT) to 91% (post-3VT). Over half (52%) of the FMU referrals were made due to a suspected abnormal 3VT view. Early evaluation of 3VT implementation at this NHS Trust indicates that it has been a success. Departmental screen-positive rates for congenital cardiac malformations have risen. However, this performance has come at a cost: Some abnormalities now being detected, such as loose vascular ring and PLSVC, are frequently asymptomatic and likely to be clinically insignificant. The implementation of 3VT achieves the aims of FASP but may begin to exceed what is expected from a low risk population screening programme. PMID- 30013608 TI - Computer-assisted detection of tardus parvus waveforms on Doppler ultrasound. AB - Objective: To determine if a novel computer-generated metric, effective acceleration time, improves accuracy for detecting tardus parvus waveforms on spectral Doppler ultrasound. Methods: Patients with echocardiography-confirmed aortic valve stenosis (n = 132; 60 mild, 44 moderate, 28 severe) and matched controls (n = 48) who underwent carotid Doppler ultrasound were identified through an imaging database search at a single medical center. A custom-built spectral analysis computer program generated effective acceleration time values for spectral Doppler waveforms in the carotid arteries and a receiver operating characteristic analysis was performed to determine the optimal median effective acceleration time cutoff value to detect tardus parvus waveforms. Two radiologists, blinded to subject disease status, reviewed and rated all carotid sonograms for presence of tardus parvus waveforms. Inter-rater variability was measured, and the accuracy of aortic valve stenosis detection with and without use of the effective acceleration time cutoff was calculated. Results: Receiver operating characteristic analysis revealed an optimal effective acceleration time cutoff of >= 48 ms with a corresponding area under the curve of 0.77 (95% CI: 0.70-0.84). Use of the effAT cutoff demonstrated an accuracy of 74%. Accuracy of visual waveform interpretation by raters ranged from 43% to 61%. Inter-rater agreement in detection of tardus parvus waveforms was 76% (136/180 cases, K = 0.44, p < 0.001). Conclusions: Detection of tardus parvus waveforms through visual interpretation of spectral Doppler waveform morphology is limited by low accuracy and moderate inter-rater variability. Use of a computer-generated median effective acceleration time cutoff value markedly improves diagnostic accuracy and avoids observer variability. PMID- 30013610 TI - Levels of agreement in the measurements of carotid artery ultrasound across a regional vascular network. AB - Introduction: Duplex ultrasound is often the sole imaging modality used in diagnosing carotid artery disease. However, the reproducibility and repeatability of scientists in determining the peak systolic velocity and end diastolic velocity of the internal carotid artery and common carotid artery (CCA) is widely debated. Study aim: To investigate intra- and inter-operator variability in diagnostic ultrasound of the carotid arteries across a centralised vascular network using a healthy test subject. To identify potential causes of variability and highlight areas for improvement. Methods: Fifteen vascular scientists across four hospital Trusts in the Bristol, Bath and Weston vascular network measured the peak systolic velocity and end diastolic velocity of the internal carotid artery and common carotid artery in a subject using a single portable ultrasound machine. A double blind assessment of spectral Doppler images was performed by two vascular clinical scientists for optimal caliper placement, spectral gain and angle correction. Results were compared for intra- and inter-operator variability. Results: Initial quality assessment of the Doppler images revealed that three out of 15 scientists produced suboptimal results. Box plot analysis of the common carotid artery and internal carotid artery for each scientist revealed significant variance (ANOVA p < 0.05). However, a Levene's test revealed no single operator who consistently produced highly variable results (p = 0.569). Conclusion: This study highlights the difficulty in obtaining consistent velocity measurements from a subject. Despite the variability in absolute peak systolic velocity and end diastolic velocity, scientists were generally consistent in obtaining an optimal spectral Doppler trace. Some issues with consistency were, however, identified which were subsequently addressed. PMID- 30013611 TI - A retrospective review of the role of B-mode and color Doppler ultrasonography in the investigation of primary hyperparathyroidism: Features that differentiate benign from malignant lesions. AB - Purpose: To identify the variant features encountered in parathyroid abnormalities and document those suggesting malignant change. Materials and methods: Data were collected from a cohort of patients who underwent investigation for primary hyperparathyroidism over a 10-year period. Ultrasonographic features: shape, presence of calcification, cystic changes, heterogeneous echogenicity, vascularity, capsular thickening, local invasion, and vascularity were reviewed retrospectively and were used to correlate with final histological findings. Results: One hundred forty-seven patients with histology and concurrent ultrasonographic scans were reviewed, and divided into benign parathyroid lesions (nodular hyperplasia (n = 44), adenoma (n = 93)) and parathyroid carcinoma (n = 10). Parathyroid carcinomas were significantly larger than benign parathyroid lesions (P = 0.030). Benign parathyroid lesions showed variant sonographic features: irregular shape (16.8%), heterogenous echogenicity (24.1%), calcification (1.5%), capsular thickening (1.5%), and cystic change (19.7%). A significantly higher proportion of parathyroid carcinomas demonstrated heterogenous echogenicity (P = 0.022), capsular thickening (P = 0.023), and infiltrative margin (P < 0.0001) than benign parathyroid lesions. Of the 137 benign parathyroid lesions, 38 (27.7%), 76 (55.5%), 23 (16.8%) were avascular, vascular, and hypervascular, respectively. Of the 10 parathyroid carcinomas, 4 (40%), 3 (30%), and 3 (30%) of lesions were avascular, vascular, and hypervascular, respectively. The vascularity of the lesions did not differ significantly between the parathyroid carcinoma and benign parathyroid lesions (P = 0.281). Conclusion: Ultrasonographic features such as irregular shape, heterogeneous echogenicity, cystic change, and vascularity are nondiscriminatory features between benign or malignant lesions. Large lesion size together with the presence of calcification, capsular thickening, or infiltrative margin strongly raises the suspicion of a malignant parathyroid lesion, and management should be altered. PMID- 30013612 TI - The reliability of carotid ultrasound in determining the return of pulsatile flow: A pilot study. AB - Manual palpation of pulses is unreliable in detecting pulsatile flow in human participants, complicating the assessment of return of spontaneous circulation after cardiac arrest. Ultrasound may offer an alternative. This study's objective was to investigate whether return of pulsatile flow in humans can be reliably assessed by common carotid artery ultrasound. We conducted a single-blinded randomised study of common carotid artery ultrasound using 20 cardiopulmonary bypass patients to model the return of pulsatile flow. Synchronised time-stamped videos of radial artery invasive blood pressure and 10 two-dimensional or 10 colour Doppler ultrasounds were recorded. Three independent reviewers recorded the timestamp where they considered pulsatile flow was first visible on ultrasound. Ultrasound times were compared to the onset of arterial line pulsatile flow and reliability assessed by intraclass correlation coefficient. The median difference between radial artery and ultrasound flow time (interquartile range (range)) was 24 seconds (5-40 (0-93)) for two-dimensional and 5 seconds (2-17 (-28 to 188)) for colour Doppler. The intraclass correlation coefficient for two-dimensional ultrasound was 0.86 (95%CI 0.63-0.96) and 0.32 (95%CI -0.01 to 0.71) for colour Doppler. The median (interquartile range (range)) mean arterial pressure where ultrasound flow occurred for two dimensional ultrasound was 62 mmHg (49-74 (33-82)) and 56 mmHg (52-73 (43-83)) for colour Doppler. In our pilot study, two-dimensional ultrasound was reliable in detecting the return of pulsatile flow. Colour Doppler detected pulsatile flow earlier and at lower mean arterial pressure but was not reliable, although a larger study is needed to determine colour Doppler's utility. PMID- 30013613 TI - Vasa praevia: Should we routinely screen high-risk women for this rare but serious condition? AB - Vasa praevia is described as the unprotected fetal vessels traversing through the placental membranes over the cervical os, below the fetal presenting part and unprotected by placental tissue or the umbilical cord. It is often not detected antenatally and presents with painless bleeding and rapid fetal compromise after spontaneous or artificial rupture of the membranes, which causes trauma to these vessels. It is a rare condition affecting one in 2500 pregnancies and has a reported perinatal mortality rate of up to 60%. More than 80% of cases of vasa praevia have at least one risk factor for the condition and it has been shown that identification of vasa praevia antenatally results in fetal survival rates of up to 97%. Risk factors include placenta praevia, velamentous cord insertion, bi-lobed placenta, succenturiate lobe, assisted reproduction and multiple pregnancy. Screening for vasa praevia with transvaginal ultrasound has been shown to be sensitive and cost effective when used in a targeted population where risk factors are present. Here, we present the antenatal assessment and management of a case of vasa praevia detected during the routine 20-week anatomy scan of a healthy primigravida, which resulted in elective caesarean section delivery of a healthy baby at 36 weeks' gestation. The pathophysiology of vasa praevia is discussed and the methods and role of screening for this rare but serious condition are appraised. PMID- 30013614 TI - Automatic Optic Disc Detection in Color Retinal Images by Local Feature Spectrum Analysis. AB - The optic disc is a key anatomical structure in retinal images. The ability to detect optic discs in retinal images plays an important role in automated screening systems. Inspired by the fact that humans can find optic discs in retinal images by observing some local features, we propose a local feature spectrum analysis (LFSA) that eliminates the influence caused by the variable spatial positions of local features. In LFSA, a dictionary of local features is used to reconstruct new optic disc candidate images, and the utilization frequencies of every atom in the dictionary are considered as a type of "spectrum" that can be used for classification. We also employ the sparse dictionary selection approach to construct a compact and representative dictionary. Unlike previous approaches, LFSA does not require the segmentation of vessels, and its method of considering the varying information in the retinal images is both simple and robust, making it well-suited for automated screening systems. Experimental results on the largest publicly available dataset indicate the effectiveness of our proposed approach. PMID- 30013615 TI - Structure Optimization for Large Gene Networks Based on Greedy Strategy. AB - In the last few years, gene networks have become one of most important tools to model biological processes. Among other utilities, these networks visually show biological relationships between genes. However, due to the large amount of the currently generated genetic data, their size has grown to the point of being unmanageable. To solve this problem, it is possible to use computational approaches, such as heuristics-based methods, to analyze and optimize gene network's structure by pruning irrelevant relationships. In this paper we present a new method, called GeSOp, to optimize large gene network structures. The method is able to perform a considerably prune of the irrelevant relationships comprising the input network. To do so, the method is based on a greedy heuristic to obtain the most relevant subnetwork. The performance of our method was tested by means of two experiments on gene networks obtained from different organisms. The first experiment shows how GeSOp is able not only to carry out a significant reduction in the size of the network, but also to maintain the biological information ratio. In the second experiment, the ability to improve the biological indicators of the network is checked. Hence, the results presented show that GeSOp is a reliable method to optimize and improve the structure of large gene networks. PMID- 30013617 TI - Biomimetic Actuation and Artificial Muscle. PMID- 30013616 TI - Effect of Da-Cheng-Qi decoction for treatment of acute kidney injury in rats with severe acute pancreatitis. AB - Background: The traditional Chinese formula Da-Cheng-Qi-decoction (DCQD) has been used to treat acute pancreatitis for decades. DCQD could ameliorate the disease severity and the complications of organ injuries, including those of the liver and lungs. However, the pharmacological effects in the kidney, a target organ, are still unclear. This study aimed to investigate the herbal tissue pharmacology of DCQD for acute kidney injury (AKI) in rats with severe acute pancreatitis (SAP). Methods: Rats were randomly divided into the sham-operation group (SG), the model group (MG) and the low-, medium- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Sodium taurocholate (3.5%) was retrogradely perfused into the biliopancreatic duct to establish the model of SAP in rats. Different doses of DCQD were administered to the treatment groups 2 h after the induction of SAP. The major components of DCQD in kidney tissues were detected by HPLC MS/MS. Inflammatory mediators in the kidney tissues, as well as serum creatinine (Scr), blood urea nitrogen (BUN) and pathologic scores, were also evaluated. Results: Ten components of DCQD were detected in the kidneys of the treatment groups, and their concentrations increased dose-dependently. Compared with the SG, the levels of inflammatory mediators, Scr, BUN and pathological scores in the MG were obviously increased (p < 0.05). The high dose of DCQD showed a maximal effect in downregulating the pro-inflammatory mediators interleukin-6 (IL)-6 and tumour necrosis factor-alpha (TNF-alpha), upregulating anti-inflammatory mediators IL-4 and IL-10 in the kidney and alleviating the pathological damages. DCQD decreased the pancreas and kidney pathological scores of rats with SAP, especially in the HDG (p < 0.05). Compared with the MG, the level of Scr in the HDG was significantly decreased (p < 0.05). Conclusions: DCQD ameliorated AKI in rats with SAP via regulating the inflammatory response, which might be closely related to the distribution of its components in the kidney. PMID- 30013619 TI - Using surveillance to change practice. PMID- 30013620 TI - Establishing catheter-related bloodstream infection surveillance to drive improvement. AB - Background: Catheter-related blood stream infections (CRBSI) are an important complication of central venous access devices but are often poorly measured. This article describes the journey of one hospital trust to set up a surveillance process for CRBSI across all specialties of the trust and to reduce CRBSI. Method: Using a locally adapted CRBSI criteria and root cause analysis (RCA) for investigation we identified a number of opportunities for a quality improvement programme. Findings: Over a 5-year period we saw a significant and sustained reduction in the rate of CRBSI from 5 per 1000 catheter days to 0.23 per 1000 catheter days. Conclusions: The surveillance enabled rates of CRBSI to be monitored across the trust and the success of our improvements to be measured. PMID- 30013618 TI - The controversial role of Enterococcus faecalis in colorectal cancer. AB - Colorectal cancer (CRC) is a complex and widespread disease, currently ranked as the third most frequent cancer worldwide. It is well known that the gut microbiota has an essential role in the initiation and promotion of different cancer types, particularly gastrointestinal tumors. In fact, bacteria can trigger chronic inflammation of the gastric mucosal, which can induce irreversible changes to intestinal epithelial cells, thus predisposing individuals to cancer. Some bacterial strains, such as Helicobacter pylori, Streptococcus bovis, Bacteroides fragilis, Clostridium septicum and Fusobacterium spp. have a well established role in CRC development. However, the role of Enterococcus faecalis still remains controversial. While part of the literature suggests a harmful role, other papers reported E. faecalis as an important probiotic microorganism, with great applicability in food products. In this review we have examined the vast majority of published data about E. faecalis either in CRC development or concerning its protective role. Our analysis should provide some answers regarding the controversial role of E. faecalis in CRC. PMID- 30013622 TI - Surgical site infection after trans urethral resection of the prostate (TURP): 2008-2013 French national SSI surveillance ISO-RAISIN. AB - Objective: To describe surgical site infection (SSI) after transurethral resection of prostate (TURP) from the French national database. Methods: A national SSI surveillance system was implemented in 1999. Each year, the network included urology departments that included at least two months plus one month follow-up, or at least 100 consecutive targeted surgical procedures. A dataset of patients who underwent urology procedures during the six-year period 2008-2013 was made available. SSI diagnosis was made according to standardised CDC criteria. Descriptive analyses were performed using SAS software version 9.4. Results: A total of 12,897 TURPs were performed by 89 urology departments. The crude incidence SSI rate was 2.43 (95% confidence interval = 2.16-2.79). The mean delay for diagnosis was 11.9 +/- 8.9 days. The treatment of the SSI required a new surgical intervention in 1.35%. In the multilevel multivariate analysis, ASA score and duration of follow-up were the only parameters correlated with the SSI rate. Conclusions: On more than 12,000 TURPs surveyed, the SSI rate was 2.43. ASA score and duration of follow-up were the only parameters correlated with the SSI rate. PMID- 30013621 TI - Impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional approach on rates of ventilator-associated pneumonia in intensive care units of two hospitals in Kuwait. AB - Objective: To analyse the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional approach (IMA) on ventilator associated pneumonia (VAP) rates in three intensive care units (ICUs) from two hospitals in Kuwait City from January 2014 to March 2015. Design: A prospective, before-after study on 2507 adult ICU patients. During baseline, we performed outcome surveillance of VAP applying CDC/NHSN definitions. During intervention, we implemented the IMA through the INICC Surveillance Online System (ISOS), which included: (1) a bundle of infection prevention interventions; (2) education; (3) outcome surveillance; and (4) feedback on VAP rates and consequences. Logistic regression analysis was performed to estimate the effect of the intervention on VAP, controlling for potential bias. Results: During baseline, 1990 mechanical ventilator (MV)-days and 14 VAPs were recorded, accounting for 7.0 VAPs per 1000 MV-days. During intervention, 9786 MV-days and 35 VAPs were recorded, accounting for 3.0 VAPs per 1000 MV-days. The VAP rate was reduced by 57.1% (incidence density ratio = 0.51; 95% CI = 0.28-0.93; p = 0.042). Logistic regression showed a significant reduction in VAP rate during the intervention phase (OR = 0.39, 95% CI = 0.18-0.83), with 61% effectiveness. Conclusions: Implementing IMA through ISOS was associated with a significant reduction in the VAP rate in Kuwait ICUs. PMID- 30013624 TI - Impact of an antimicrobial stewardship program on healthcare-associated Clostridium difficile rates at a community-based teaching hospital. AB - We conducted a pre-intervention/post-intervention study to assess the rate of healthcare-associated Clostridium difficile infections (HA-CDI) before and after the implementation of an antimicrobial stewardship program (ASP). Upon implementation of our ASP, the usage of targeted antimicrobials, including ceftriaxone, clindamycin, fluoroquinolones and carbapenem antibiotics, were significantly reduced. There was also a significant reduction in HA-CDI/1000 patient-days following ASP implementation (0.84 vs. 0.28; P = 0.035). PMID- 30013623 TI - Post-exposure prophylaxis following occupational exposure to HIV and hepatitis B: an analysis of a 12-year record in a Nigerian tertiary hospital. AB - Background: Healthcare workers (HCWs) have an increased risk of occupational exposure to blood-borne pathogens. Aims/objectives: We aim to examine the utilisation and outcome of post-exposure prophylaxis (PEP) for both HIV and hepatitis B (HBV) among HCWs. Methods: This was a retrospective study conducted in a tertiary hospital in North-Western Nigeria. We reviewed data on HIV or HBV PEP given to HCWs between 2004 and 2016. Results: A total of 115 HCWs presented for PEP during the study period. Intern doctors were the most exposed group (40/115; 34.8%). There were 86/115 (74.8%) needle stick exposures. While 53/115 (46.1%) of the sources of exposure were HIV-positive, 9/115(7.83%) were HBV positive. Zidovudine-based regimen (40/70) was the most commonly prescribed. No seroconversion occurred among those that completed PEP treatment and follow-up. Discussion: No seroconversion occurred among those that received either or both HIV and HBV PEP and completed PEP treatment. PMID- 30013625 TI - Antimicrobial resistance: A biopsychosocial problem requiring innovative interdisciplinary and imaginative interventions. AB - To date, antimicrobials have been understood through largely biomedical perspectives. There has been a tendency to focus upon the effectiveness of pharmaceuticals within individual bodies. However, the growing threat of antimicrobial resistance demands we reconsider how we think about antimicrobials and their effects. Rather than understanding them primarily within bodies, it is increasingly important to consider their effects between bodies, between species and across environments. We need to reduce the drivers of antimicrobial resistance (AMR) at a global level, focusing on the connections between prescribing in one country and resistance mechanisms in another. We need to engage with the ways antimicrobials within the food chain will impact upon human healthcare. Moreover, we need to realise what happens within the ward will impact upon the environment (through waste water). In the future, imaginative interventions will be required that must make the most of biomedicine but draw equally across a wider range of disciplines (e.g. engineering, ecologists) and include an ever-increasing set of professionals (e.g. nurses, veterinarians and farmers). Such collective action demands a shift to working in new interdisciplinary, inter-professional ways. Mutual respect and understanding is required to enable each perspective to be combined to yield synergistic effects. PMID- 30013626 TI - Candida autovaccination: A new strategy to prevent antifungal resistance? PMID- 30013627 TI - Diary. PMID- 30013628 TI - Cytoplasmic expression of estrogen receptor beta may predict poor outcome of EGFR TKI therapy in metastatic lung adenocarcinoma. AB - There is growing evidence that estrogen receptors (ER) are expressed in lung cancer cells, and are able to interact with the epidermal growth factor receptor (EGFR) signaling pathway. However, data on the association between cytoplasmic ER expression and the response to EGFR-tyrosine kinase inhibitors (TKI) treatment are limited. The aim of the present study was to investigate the associations between ERalpha/ERbeta expression and EGFR mutational status and response to TKI treatment in metastatic lung adenocarcinoma. A retrospective study of 126 consecutive patients with lung adenocarcinoma who were diagnosed with stage IV disease and had received EGFR-TKI treatment was conducted. ER expression was detected by immunohistochemistry. EGFR and GTPase KRas (KRAS) mutational statuses were evaluated by denaturing high performance liquid chromatography and PCR restriction fragment length polymorphism, respectively. In the overall cohort of 126 lung adenocarcinoma samples analyzed, ERalpha expression in the nucleus of tumor cells was identified in 17 (18.9%) patients, whereas ERbeta expression was identified in the nucleus (22/126, 17.5%) and cytoplasm (17/126, 13.5%). The nuclear expression of ERbeta was positively associated with the degree of tumor differentiation (P=0.010). EGFR-sensitizing mutations were significantly associated with improved objective response rates (ORR), disease control rates (DCR), median progression-free survival (mPFS) and median overall survival (mOS) (P<0.001; P<0.001; P=0.003; and P=0.026, respectively). Patients with cytoplasmic ERbeta expression exhibited non-significant poorer ORR, DCR, mPFS and mOS compared with patients without cytoplasmic ERbeta expression (P=0.082; P=0.106; P=0.084; and P=0.119, respectively). However, the significant decrease of ORR, DCR and mPFS was observed in patients with coexisting cytoplasmic ERbeta expression and EGFR-sensitizing mutations (P=0.030; P=0.009; and P=0.018, respectively) in comparison with the subgroup with EGFR sensitizing mutations but negative expression of cytoplasmic ERbeta. A trend towards shorter mOS was also observed in patients with coexisting cytoplasmic ERbeta expression and EGFR sensitizing mutations (P=0.071). No KRAS mutations were identified in patients with cytoplasmic ERbeta expression. Subsequent to adjusting for sex, smoking status and EGFR mutation status, the Cox repression analysis indicated that cytoplasmic expression of ERbeta was a negative independent predictor for mPFS in the whole patient cohort (HR=1.870; 95% confidence interval 1.058-3.305; P=0.031). Cytoplasmic ERbeta expression was negatively correlated with the efficacy of EGFR-TKI treatment for metastatic lung adenocarcinoma, particularly for patients with coexisting cytoplasmic ERbeta expression and EGFR-sensitizing mutations. Cytoplasmic ERbeta may be a promising marker to predict the outcome of EGFR-TKI treatment. PMID- 30013629 TI - Identification of common differentially-expressed miRNAs in ovarian cancer cells and their exosomes compared with normal ovarian surface epithelial cell cells. AB - The aim of the present study was to identify common microRNAs (miRNAs) in ovarian cancer (OC) cells and their exosomes using microarray data (accession number GSE76449) available from the Gene Expression Omnibus database, including exosomal samples from 3 OC cell lines, 1 normal ovarian surface epithelial cell line and their original cell samples. Differentially-expressed miRNAs (DE-miRNAs) were identified using the Linear Models for Microarray data method, and mRNA targets of DE-miRNAs were predicted using the miRWalk2 database. The potential functions of the target genes of the DE-miRNAs were analyzed using the Database for Annotation, Visualization and Integrated Discovery tool. The association between crucial miRNAs and target genes, and their clinical associations, were validated using The Cancer Genome Atlas data. As a result, 12 upregulated and 12 downregulated DE-miRNAs were shared by the 3 OC cell lines compared with normal controls in the exosomal samples, while 5 upregulated and 65 downregulated DE miRNAs were shared between the original cells. Among them, 9 downregulated DE miRNAs were shared between exosomal and original cells. The target genes of 4 common DE-miRNAs between exosomal and original cells (miR-127-3p, miR-339-5p, miR 409-3p and miR-654-3p) were predicted. Functional enrichment analysis indicated that these target genes may be involved in the Wnt signaling pathway (miR-409-3p CTBP1 and miR-339-5p-CHD8) and Proteoglycans in cancer (miR-127-3p-PPP1CA). The negative associations between these 3 miRNAs and target genes were confirmed by a Pearson's correlation analysis. miR-127 was negatively associated with tumor grade. In conclusion, our results describe a set of miRNAs involved in OC development, in exosomal and non-exosomal manners, by regulating their target genes. They may be potential targets for treatment of OC. PMID- 30013630 TI - BRAF V600E mutation and BRAF VE1 immunoexpression profiles in different types of glioblastoma. AB - Abnormalities in proto-oncogene B-Raf (BRAF) are typical in several subgroups of gliomas, including pilocytic astrocytomas, optic nerve gliomas, pleomorphic xanthoastrocytomas (PXA), anaplastic PXAs and gangliogliomas. However, they are rarely reported in adult gliomas. BRAF alterations are frequent in a distinct variant of glioblastomas (GBMs) known as epithelioid GBMs (E-GBMs). There are limited studies on whether immunohistochemistry (IHC) can be used to determine the presence of BRAF VE1 mutations in these tumors. The aim of the current study was to examine BRAF V600E mutations in 20 GBMs, including GBMs with epithelioid features, giant cell GBMs and conventional GBMs. V600 mutations were detected using the Cobas 4800 BRAF V600 Mutation Test, and IHC analysis was also performed. Of the 6 cases of GBM with epithelioid features, 1 exhibited a BRAF V600E mutation, while the other cases did not. IHC staining was positive in 3 out of the 8 conventional GBMs. Vemurafenib is a targeted therapy that has mainly been used for the treatment of melanoma patients for several years, and as a possible alternative treatment for cases of GBM harboring BRAF mutations, its existence may make testing for BRAF status important. PMID- 30013631 TI - Hypermethylation of normal mucosa of esophagus-specific 1 is associated with an unfavorable prognosis in patients with non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-associated mortality due to high incidence and poor survival rates, irrespective of global variations in its biology and treatment. Changes in DNA methylation are frequent in cancer and constitute an important mechanism in tumorigenesis. Normal mucosa of esophagus specific 1 (NMES1) is expressed in epithelial tissue and is believed to be a tumor suppressor gene. The present study investigated the methylation status of the NMES1 promoter in 178 cases of primary non-small cell lung cancer (NSCLC) by pyrosequencing and evaluated the prognostic value of this methylation. NMES1 methylation-positive tumors above the background threshold for non-malignant tissue were found in 15 cases (8.4%) and were detected exclusively in malignant tissues. In addition, univariate and multivariate analyses showed that methylation-positive patients experienced worse overall survival rate (OSR) compared with methylation-negative patients (adjusted hazard ratio, 2.62; 95% confidence interval, 1.20-5.69; P=0.02). Notably, within the methylation-positive group, patients with strong methylation tended to experience worse OSR compared with those with weak methylation (adjusted hazard ratio, 2.45 vs. 3.05; Ptrend=0.02). These findings suggest that NMES1 may serve an important role in lung cancer pathogenesis, and its methylation could be considered a prognostic marker for NSCLC. Further studies with large numbers of samples are required to confirm this conclusion. PMID- 30013632 TI - Expression of miR-30c and BCL-9 in gastric carcinoma tissues and their function in the development of gastric cancer. AB - microRNA-30c (miR-30c) is a member of the miR-30s family, which is known to serve important roles in the occurrence and development of numerous tumor types. Our previous microarray analysis of extracted RNA from tissue samples was conducted to examine the expression of miR-30c and predict miR-30c target genes. In the present study, it was determined that the expression of miR-30c was differentially expressed in 82 paired gastric cancer (GC) and paracancerous tissues. Cellular expression of miR-30c in two GC cell lines MKN-45, MKN-74 and one non-cancer cell line GES-1 was modified using the miR-30c-mimic and miR-30c inhibitor reagents, in a series of transfection experiments. Following transfection of cancer and non-cancer cell lines with the miR-30c-mimic, cell proliferation and apoptosis rates were increased. Compared with the NC group, MKN 74 cell proliferation was significantly inhibited (P<0.05) following transfection with the miR-30c-mimic at 48 and 24 h, GES-1 was significantly inhibited (P<0.05) at 24 and 48 h, and apoptosis was significantly reduced in transfected MKN-74 cells (P<0.05). The clinicopathological data and the expression of BCL-9 and miR 30c in patients with GC were used to identify associations. The expression levels of miR-30c were associated with age. Western blot analysis demonstrated that the BCL-9 expression levels in MKN-74 cells were higher following transfection with the miR-30c-mimic, and were lower following transfection with the miR-30c inhibitor, both compared with the negative control group. It was concluded that compared with the negative control group, the expression of miR-30c was low in GC tissues and may be involved in GC development via regulation of proliferation, apoptosis and the cell cycle. PMID- 30013633 TI - DRAM1 regulates the migration and invasion of hepatoblastoma cells via autophagy EMT pathway. AB - DNA-damage regulated autophagy modulator 1 (DRAM1) is known as a target of TP53 mediated autophagy, and has been reported to promote the migration and invasion abilities of glioblastoma stem cells. However, the precise contribution of DRAM1 to cancer cell invasion and migration, and the underlying mechanisms remain unclear. In the present study, small interfering (si)RNA or short hairpin RNA mediated knockdown of DRAM1 was performed in hepatoblastoma cells and the migration and invasion abilities were detected in vitro and in vivo. To investigate the underlying mechanisms, western blotting and immunofluorescence were used to detect the expression of autophagy-associated proteins and epithelial-mesenchymal-transition (EMT)-associated markers. The results showed that DRAM1 knockdown by specific siRNA abrogated cell autophagy, as well as inhibited the migration and invasion of HepG2 cells in Transwell assays, which may be reversed by rapamycin treatment. In addition, DRAM1 knockdown increased the expression of E-Cadherin while decreased the expression of vimentin in HepG2 cells, which was also be reversed by rapamycin treatment. Taken together, these results suggest that DRAM1 is involved in the regulation of the migration and invasion of HepG2 cells via autophagy-EMT pathway. PMID- 30013634 TI - Application of contrast-enhanced ultrasound and enhanced CT in diagnosis of liver cancer and evaluation of radiofrequency ablation. AB - This study investigated the application effect of contrast-enhanced ultrasound (CEUS) and enhanced CT in diagnosis of liver cancer and response evaluation of radiofrequency ablation (RFA). A total of 60 patients with liver cancer were selected in Dongying People's Hospital from April 2016 to May 2017. All patients were subjected to CEUS and enhanced CT. With pathological examination as the gold standard, diagnostic consistency of the two methods was compared. After RFA, patients were subjected to CEUS and enhanced CT to assess the efficacy, and the consistency was compared. There was no significant difference in diagnostic accuracy between CEUS and CT (p>0.05). Area under the ROC curve of CEUS was 0.896, with a sensitivity of 91.2% and a specificity of 88.7%. The area under the ROC curve for enhanced CT diagnosis was 0.907, with a sensitivity of 91.8% and a specificity of 89.7%. No significant difference in the maximal cross sectional area of lesions was found between CEUS and enhanced CT, and there was no significant difference in evaluation of therapeutic efficiency between the methods (p>0.05) before and 1 and 3 months after treatment. Bland-Altman test showed that there was a strong consistency between CEUS and enhanced CT in the measured maximum cross-sectional area of lesions at 1 and 3 months after treatment. Linear regression analysis showed that maximum section cross-sectional area measured by CEUS was significantly correlated with that detected by enhanced CT (r2=0.617). The results suggested that diagnostic efficiency of CEUS was similar to that of enhanced CT, and both showed high sensitivity and specificity. Two methods showed high consistency in evaluating the curative effect of RFA. CEUS can achieve real-time observation of focal blood flow perfusion, and was more economically affordable and convenient. PMID- 30013635 TI - Correlation of CT signs with lymphatic metastasis and pathology of neuroblastoma in children. AB - Correlation between computed tomography (CT) signs, lymphatic metastasis and pathological features of neuroblastoma (NB) in children was investigated. A total of 374 child patients diagnosed with NB via CT scan and pathological section in Department of Pediatric of Xuzhou Children's Hospital from March 2011 to January 2017 were collected, and their clinical data were retrospectively analyzed. According to CT signs, NB calcification and invasion to surrounding tissues were evaluated, and the tumor site, tumor size, lymphatic metastasis, pathological types and clinical prognosis were analyzed. In plain CT scan, 160 cases showed clear tumor mass, and 214 cases showed blurred mass; 78 cases of tumors were uniform in density, and 296 cases were not uniform in density. Besides, there were 351 cases of calcification in mass. There were 106 cases of axial rotation of kidney, 53 cases of enlargement of renal calyce and renal pelvis, 66 cases of elevation of liver position, 71 cases of pancreas translocation, 26 cases of gastrointestinal tract translocation, 17 cases of vascular translocation and 12 cases of bladder translocation, besides 23 of the cases showed no significantly abnormal changes. Moreover, 211 cases had retroperitoneal lymphatic metastasis with soft tissue swelling in phrenic angle, abdominal aorta and renal hilum in image, and non-uniform annular enhancement or uniform enhancement in enhanced scanning. NB in right adrenal gland invaded the liver in 53 cases, invaded the kidney in 26 cases, invaded the psoas in 40 cases and blood vessels in 32 cases, and the remaining cases showed no invasion. A total of 68 cases were accompanied by pleural thickening, 34 cases by pleural effusion, 36 cases by tracheal compression, 38 cases by rib compression, and 40 cases by tumor invading into vertebral canal. Bone metastasis occurred in 182 cases; liver metastases occurred in 28 cases, and brain metastases in 35 cases. NB calcification was significantly correlated with pathological type, tumor site and lymphatic metastasis (p<0.05), but not correlated with tumor size (p>0.05); NB invasion to surrounding tissues was associated with pathological type, tumor site and clinical prognosis (p<0.05), but was not correlated with the tumor size (p>0.05). We concluded that patients with distal mediastinal mass identified by CT examination, accompanied by calcification, and invasion to surrounding tissues may suffer from NB. Tumor growth is closely correlated with tumor differentiation degree. PMID- 30013636 TI - MicroRNA-155-5p suppresses the migration and invasion of lung adenocarcinoma A549 cells by targeting Smad2. AB - Lung cancer is one of the major causes of cancer-related deaths worldwide. Notably, miR-155-5p is one of the most amplified miRNAs in non-small cell lung carcinoma (NSCLC). However, the role of miR-155-5p in lung cancer metastasis has not been fully evaluated. In the present study, miR-155-5p mimic and inhibitor were used to investigate the effects of miR-155-5p on the metastasis of human lung carcinoma A549 cells. The study indicated that transfection of miR-155-5p mimic significantly suppressed cell proliferation, migration and invasion of A549 cells, whereas its inhibition significantly promoted cell proliferation, migration and invasion of A549 cells, suggesting a potential therapeutic application of miR-155-5p in controlling lung cancer metastasis. Moreover, transfection of miR-155-5p mimic suppressed the expression of Smad2/3, ZEB1, ZEB2 and N-cadherin and induced that of E-cadherin, whereas its inhibition significantly upregulated the expression of Smad2/3, ZEB1, ZEB2 and N-cadherin and downregulated that of E-cadherin. Collectively, the findings suggest that miR 155-5p suppresses the proliferation, migration and invasion of A549 cells. Therefore, loss of miR-155-5p may serve an essential role in tumorigenesis and tumour progression in lung cancers. PMID- 30013637 TI - Identification of potential target genes in pancreatic ductal adenocarcinoma by bioinformatics analysis. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most complicated and fatally pathogenic human malignancies. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of PDAC. The aim of the present study was to identify the key genes and signaling pathways associated with PDAC using bioinformatics analysis. Four transcriptome microarray datasets (GSE15471, GSE55643, GSE62165 and GSE91035) were acquired from Gene Expression Omnibus datasets, which included 226 PDAC samples and 65 normal pancreatic tissue samples. We screened differentially expressed genes (DEGs) with GEO2R and investigated their biological function by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analysis. The overall survival data was obtained from UALCAN, which calculated the data shared with The Cancer Genome Atlas. In addition, a protein-protein interaction (PPI) network of the DEGs was constructed by STRING and Cytoscape software. The four sets of DEGs exhibited an intersection consisting of 205 genes (142 up-regulated and 63 down-regulated), which may be associated with PDAC. GO analysis showed that the 205 DEGs were significantly enriched in the plasma membrane, cell adhesion molecule activity and the Energy pathways, and glycine, serine, threonine metabolism were the most enriched pathways according to KEGG pathway analysis. Kaplan-Meier survival analysis revealed that 22 of 205 common genes were significantly associated with the overall survival of pancreatic cancer patients. In the PPI network and sub network, DKK1 and HMGA2 were considered as hub genes with high connectivity degrees. DKK1 and HMGA2 are strongly associated with WNT3A and TP53 separately, which indicates that they may play an important role in the Wnt and P53 signaling pathways. Using integrated bioinformatics analysis, we identified DKK1 and HMGA2 as candidate genes in PDAC, which may improve our understanding of the mechanisms of the pathogenesis and integration; the two genes may be therapeutic targets and prognostic markers for PDAC. PMID- 30013638 TI - Role of miR-23a/Zeb1 negative feedback loop in regulating epithelial-mesenchymal transition and tumorigenicity of intraocular tumors. AB - Role of the two-way negative feedback regulation channel formed by miR-23a and Zeb1 in epithelial-mesenchymal transition (EMT), tumorigenic ability, and migration and metastasis capacity of the intraocular malignant tumor cells was investigated. Molecular biological methods such as real time-quantitative PCR (RT qPCR), immunoblotting method, and immunofluorescence were used to detect the expression levels of mRNA and protein in the Zeb1 factor in OCM-1, WERI-RB1, and Y79 cells before and after miR-23a transfection. Transwell cells were used to detect the in vitro membrane permeation and migration ability in OCM-1, WERI-RB1, and Y79 cells (non-transfection group, blank control transfection group, mimic transfection group, inhibitor transfection group). The results revealed that the relative expression of miR-23a in the cells in the miR-23a mimic transfection group increased significantly compared with that in the control group (p<0.05). There were significant differences in the relative expression of mRNA between the mimic transfection and control group (p<0.05). RT-qPCR detection showed that the relative expression of mRNA of the epithelial-labeled factor E-cadherin increased significantly in the miR-23a mimics group (p<0.05). Expression of the protein E cadherin increased while the expression of the mesenchyme-labeled proteins of vimentin and N-cadherin decreased in the mimics group. Zeb1 has a negative feedback effect on miR-23a. They can form a negative feedback loop. The results showed that miR-23a and Zeb1 form a bidirectional inhibitory negative feedback loop, which plays an important role in regulating EMT. In conclusion, the significant changes in the mesenchymal phenotype of the stable strains with Zeb1 overexpressed in the OCM-1 cells cannot be completely explained with the changes in cytoskeleton caused by EMT. PMID- 30013639 TI - Pathological tumor volume predicts survival outcomes in oral squamous cell carcinoma. AB - The present study examined whether the pathological tumor volume (PTV) was correlated with the survival outcomes in patients with oral squamous cell carcinoma (SCC) and clinical lymph node metastasis. Forty-seven patients who underwent radical surgery without preoperative treatment were enrolled. The PTV of the primary tumor, which was surgically resected without preoperative treatment, was calculated based on the diameters in three dimensions. A survival analysis was performed using a Cox proportional hazards model. A PTV of >=18 cm3 was significantly correlated with shorter overall survival (P<0.01) and local recurrence-free survival (P<0.01) in a univariate analysis. A multivariate analysis with adjustment for the pathological stage (stage I-II/III-IV), primary site (tongue/others) and positive surgical margin and/or extracapsular extension (absent/present) showed that a PTV of >=18 cm3 was significantly correlated with shorter overall survival (P<0.01) and local recurrence-free survival (P<0.01). The present findings suggested that PTV in oral SCC provides a prognostic parameter that may predict shorter or longer overall and local recurrence-free survival. PMID- 30013640 TI - Effects of miRNA-130a on the proliferation and apoptosis of glioma cell lines. AB - Regulatory ability of micro-ribose nucleic acid-130a (miRNA-130a) in the proliferation and invasive growth of human brain glioma cells and its mechanism were investigated. RT-qPCR was used to analyze expression of miRNA-130a in U-87MG glioma specimens; lipidosome was used to mediate miRNA-130a mimic transfecting glioma cells and the expression of miRNA-130a was detected by using RT-qPCR after transfection; methyl thiazolyl tetrazolium (MTT) assay and flow cytometry (FCM) were adopted to evaluate the changes in biological characteristics of cell growth and proliferation; the migration and invasion abilities of tumor cells were measured through scratch assay and Transwell in vitro cell migration assay. In miRNA-130a mimic-transfected U-87MG cells, RT-qPCR showed that the expression of miRNA-130a was upregulated; MTT assay and FCM revealed that the cell growth was strengthened; scratch assay and Transwell in vitro cell migration assay verified that the migration and invasion abilities of cells were enhanced. In conclusion, the high expression of miRNA-130a can promote growth and invasion, indicating that miRNA-130a can be considered as a candidate target of gene therapy for glioma. PMID- 30013641 TI - Analysis of risk factors for stage I lung adenocarcinoma using low-dose high resolution computed tomography. AB - Risk factors for stage I lung adenocarcinoma were analyzed using low-dose high resolution computed tomography (CT). The patients were divided into case group (stage I lung adenocarcinoma patients) and control group (benign pulmonary nodules patients). All patients were subjected to low-dose high-resolution CT. Multiple linear regression was performed to analyze the CT imaging features of the two groups. Stage I lung adenocarcinoma patients were significantly associated with nodular site (X3, upper left lobe) [95% CI (1.796, 54.695), p=0.008], nodule type (X4) (p<0.001), nodule size (X5) [95% CI (0.614, 0.803), p<0.001], spicule sign (X7) [95% CI (0.029, 0.580), p=0.008], lobulation sign (X8) [95% CI (0.048, 0.673), p=0.011]. The stepwise regression equation is: Logistic (p) =-12.009 + 2.294X3 - 0.327X4 - 0.354X5 - 2.042X7 - 1.713X8. Risk factors of low-dose and high-resolution CT imaging for patients with stage I lung adenocarcinoma are nodular site (upper left lobe), nodule type, nodule size, spicule sign, and lobulation sign. PMID- 30013642 TI - FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis and lung cancer. AB - The aim of this study was to investigate the expression of FGF2 and FGFR2 in patients with idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) as well as their clinical significance. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were used to detect FGF2 and FGFR2 expression in LC and adjacent normal tissues of LC patients and lavage fluid of idiopathic pulmonary fibers patients and normal controls (confirmed by bronchoalveolar lavage examination). The expression levels of FGF2 mRNA and protein in the non-small cell LC tissues were significantly higher than those in the adjacent normal tissues (P<0.001). The expression level of FGF2 protein in lavage fluid of patients with IPF was higher than that of the control group (P<0.001). The expression level of FGFR2 mRNA in the non-small cell LC tissues was significantly higher than that in the adjacent normal tissues (P<0.001). The expression level of FGFR2 protein in the non-small cell LC tissues was higher than that in the adjacent normal lung tissues (P<0.001). The expression levels of FGF2 mRNA and FGFR2 mRNA in cancer tissues were not significantly correlated with age, sex and history of smoking (P>0.05), but were significantly correlated with lymph node metastasis, tumor differentiation and TNM staging. FGF2 and FGFR2 proteins were highly expressed in cancer tissues of LC patients and lavage fluid of patients with IPF. The expression of FGF2 mRNA and FGFR2 mRNA was correlated with lymph node metastasis and TNM stage. The high expression levels of FGF2 mRNA and FGFR2 mRNA were associated with tumor metastasis and poor prognosis of LC patients. PMID- 30013643 TI - Salinomycin may inhibit the cancer stem-like populations with increased chemoradioresistance that nasopharyngeal cancer tumorspheres contain. AB - Tumor recurrence and metastasis of nasopharyngeal cancer (NPC) often result in the failure of treatment due to chemoradioresistance. Cancer stem cells (CSCs) have been observed to drive tumor initiation and tumor chemoradioresistance. Therefore, the poor prognosis of advanced NPC is likely to result from the failure to kill CSCs. Sphere formation may be used as an experimental method to enrich potential CSC subpopulations. At present, there are few reports on NPC tumorspheres. The present study focused on examining the cancer stem-like properties of NPC tumorspheres from NPC cell lines. Western blot analysis revealed that NPC tumorspheres had a higher expression of stem cell markers Nanog homeobox and SRY-box 2, compared with parental cells. It was additionally verified that NPC tumorspheres contained a high aldehyde dehydrogenase (ALDH) enzymatic activity compared with parental cells. ALDH+ cells were amplified by 9- to 10-fold in tumorspheres, compared with parental cells (1.8 vs. 16.9%). The tumorsphere cells exhibited an increased half maximal inhibitory concentration value of >10-fold with cisplatin compared with the control parental cells. Compared with the parental cells, the percentage of side population cells in the tumorsphere cell population increased significantly (10.3 vs. 2.3%; P<0.05). NPC tumorsphere cells demonstrated enhanced resistance to radiation. Further investigation verified that salinomycin inhibited NPC CSCs by selectively targeting its stem cells. Altogether, the data revealed that NPC tumorspheres contain cancer stem-like populations with increased chemoradioresistance. It was suggested that the serum-free culture of NPC cells may provide an appropriate model for researching the sensitivity of CSCs to therapeutic agents. It was additionally revealed that salinomycin is an efficient inhibitor of NPC CSCs, supporting the hypothesis that salinomycin may eliminate CSCs and imply a need for further clinical evaluation. PMID- 30013644 TI - Intracerebral schwannoma: A case report and literature review. AB - Intracranial schwannoma accounts for between 5 and 8% of intracranial tumors, whereas intracerebral schwannoma, a rare disease, accounts for <1% of intracranial schwannomas. In addition to the present case report, a total of 84 cases reported within China and elsewhere were reviewed and summarized, and the age of the tumor onset, the site of disease, imaging results, clinical presentation, pathological classification and prognosis were analyzed. The present case report described a 12-year-old female with an intracerebral schwannoma in the brainstem, who was followed-up for 5 years using magnetic resonance imaging after a surgical resection without recurrence, and clinical symptoms were reported to have completely resolved. The incidence of intracerebral schwannoma was low among cases, and the correct diagnosis was not able to be made preoperatively, and the majority of cases were diagnosed on the basis of postoperative pathology. The majority of cases analyzed were supratentorial, occurring at an age <=40 according to previous literature. In addition, 33% of patients presented with subtentorial schwannoma, occurring at an age >40. The prognosis was classified as good (patient can live independently) for the majority of patients if surgery was able to completely resect the lesion. PMID- 30013645 TI - Follow-up study of HPV58 variants in women with incident HPV58 infection from a Colombian cohort. AB - Certain variants of human papillomavirus (HPV)type 58 are associated with an increased risk of high grade squamous intraepithelial lesions and cervical cancer. However, little is known about the persistence of HPV58 E6/E7 variants in women with incident HPV58 infections. The aim of the present study was to evaluate the presence and persistence of HPV58 E6/E7 variants in 71 women with incident HPV58 infection throughout their follow-up. These women belonged to a cohort examined in a longitudinal study of 1,610 Colombian women, who were HPV negative and had normal baseline cytology. E6/E7 DNA regions of HPV58-positive samples were amplified and sequenced using automated direct sequencing. A total of 639 samples were analyzed from the 71 women, and 117 samples (18.3%) were HPV58-positive. HPV58 E6/E7 variants were detected in 85.5% of the samples. The T307/A694/G744/A761 variant was identified in 88% of the samples, the T307/G744 variant was identified in 9% of samples and the T187/T307/A367/G744/G793/T798/A801/T840/C852 was identified in 3% of the samples. Overall, 50% of the HPV58 infections were present after 1 year of follow-up and all infections were cleared after 7 years. Women who had first sexual intercourse at >15 years of age had a lower clearance rate than those who had sexual intercourse for the first time at <=15 years of age [hazard ratio (HR)=0.29; 95% confidence interval (CI)=0.09-0.92]. Likewise, parous women had a higher clearance rate than nulliparous women (HR=3.43, 95% CI=1.23-9.60). There was no difference in clearance rates between HPV58 E6/E7 variants. In conclusion, HPV58 variants were not associated with persistence of the infection in this group of women. PMID- 30013646 TI - Pachymic acid inhibits growth and induces cell cycle arrest and apoptosis in gastric cancer SGC-7901 cells. AB - The aim of the present study was to elucidate the anticancer effect of pachymic acid (PA) in gastric cancer SGC-7901 cells and the potential molecular mechanisms involved. Cell Count kit-8 assay was performed to examine the effect of PA on the cell proliferation of SGC-7901 cells. Cell cycle, cell apoptosis, mitochondria membrane potential (Dpsim) and reactive oxygen species (ROS) analysis were assessed by flow cytometry, respectively. DNA fragmentation assay was performed by Hoechst 33258 staining. Western blotting was performed to detect the effect of various concentrations of PA on the levels of BCL2 associated X protein (Bax) expression as well as B-cell lymphoma 2 (Bcl-2), cytochrome C (cyt-c) and caspase 3 in SGC-7901 cells. It was demonstrated that PA was able to significantly inhibit the viability and induce G0/G1 cell cycle arrest of SGC-7901 cells in a concentration-dependent manner. The apoptotic rate and ROS generation were markedly increased, while Dpsim was decreased following the treatment of SGC-7901 cells with various concentrations of PA. Moreover, the expression of Bax, cytochrome c and caspase-3 were markedly increased and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was significantly inactivated and BCL-2 expression was decreased following PA treatment in SGC-7901 cells. Notably, JAK2 inhibitor (AG490) mimics the effects of PA on the viability and apoptosis of SGC-7901 cells. Further in vivo study indicated that treatment with PA significantly inhibited the growth of tumor in nude mice that were transplanted with SGC-7901 cells in a concentration-dependent manner. These results may advance the current understanding of the anticancer mechanisms of PA in gastric cancer. PMID- 30013647 TI - Delayed cognitive deficits can be alleviated by calcium antagonist nimodipine by downregulation of apoptosis following whole brain radiotherapy. AB - Radiation therapy is important for the comprehensive treatment of intracranial tumors. However, the molecular mechanisms underlying the pathogenesis of delayed cognitive dysfunction are not well-defined and effective treatments or prevention measures remain insufficient. In the present study, 60 adult male Wistar rats were randomly divided into three groups, which included a control, whole brain radiotherapy (WBRT) (single dose of 30 Gy of WBRT) and nimodipine (single dose of 30 Gy of WBRT followed by nimodipine injection intraperitoneally) groups. The rats were sacrificed 7 days or 3 months following irradiation. At 3 months, the Morris water maze test was used to assess spatial learning and memory function in rats. The results demonstrated that the WBRT group demonstrated a significantly impaired cognitive performance, decreased numbers of hippocampal Cornu Ammonis (CA)1 neurons and upregulated expression of caspase-3 in the dentate gyrus compared with those in the control and nimodipine groups. Reverse transcription quantitative polymerase chain reaction analysis demonstrated that the WBRT group exhibited increased ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 compared with that in control and nimodipine groups on day 7 following irradiation. However, the WBRT group exhibited decreased levels of brain-derived neurotrophic factor (BDNF) compared with that in control and nimodipine groups at 3 months following brain irradiation. The levels of growth associated protein 43 and amyloid precursor protein between the nimodipine group and WBRT group were not statistically significant. The present study demonstrated that neuron apoptosis may lead to delayed cognitive deficits in the hippocampus, in response to radiotherapy. The cognitive impairment may be alleviated in response to a calcium antagonist nimodipine. The molecular mechanisms involved in nimodipine-mediated protection against cognitive decline may involve the regulation of Bax/Bcl-2 and BDNF in the hippocampus. PMID- 30013648 TI - Clinical research of individualized therapy in advanced esophageal cancer based on the ERCC1 C8092A genotype. AB - The present study aimed to explore the role and clinical value of the detection of Excision repair cross-complementing 1(ERCC1) C8092A polymorphisms in individualized therapy of patients with advanced esophageal cancer. A total of 127 patients with advanced esophageal cancer were enrolled between January 2010 and January 2014 in Anhui Provincial Hospital. Patients were randomly assigned in a 1:2 ratio to a standard treatment group or an individualized treatment group, respectively, prior to ERCC1 C8092A assessment. Patients in the standard treatment group were treated with paclitaxel and cisplatin. The DNA was obtained from the peripheral blood of individualized treatment patients, amplified by PCR and sequenced to determine the ERCC1 C8092A polymorphism prior to the administration of chemotherapies. Patients with the ERCC1 C8092A genotype of A/A or A/C received paclitaxel and cisplatin, and those with the genotype of C/C received paclitaxel and fluorouracil. The primary endpoint was response rate (RR). The secondary endpoints included toxicity of chemotherapy, progression-free survival (PFS) and overall survival (OS) times. Differences between the groups were evaluated by chi2 test. Differences in survival were analyzed by Kaplan Meier survival curves. The survival rate was analyzed by log-rank test. Follow-up data was obtained until December 2015. The RR was obtained for 15 patients (34.8%) in the standard treatment group and 45 patients (53.6%) in the individualized treatment group (chi2=3.095; P=0.046). For adverse events, nausea and vomiting and anemia were significantly decreased in the individualized treatment group compared with the standard treatment group (P=0.001 and P=0.004, respectively). The median progression free survival time was 4.4 months [95% confidence interval (CI)3.8-5.0 months] in the standard treatment group and 6.6 months (95% CI, 5.8-7.4 months) in the individualized treatment group (P=0.018). The median overall survival time was 11.4 months (95% CI, 10.1-12.7 months) in the standard treatment group and 14.2 months (95% CI, 13.2-15.2 months) in the individualized treatment group (P=0.008). The RR, toxicity of chemotherapy, PFS and OS were significantly improved in the individualized treatment group compared with the standard treatment group. Detection of ERCC1 gene polymorphisms maybe performed for patients with advanced esophageal cancer to improve individualized therapy, which requires additional study. PMID- 30013649 TI - Identification of differentially expressed genes in cervical cancer by bioinformatics analysis. AB - Cervical cancer is the most common gynecological malignancy. In recent years, the incidence of cervical cancer has had a younger trend. Cervical cancer morbidity and mortality rates have been significantly reduced due to recent decades of cervical cytology screening leading to the early detection and treatment of cervical cancer and precancerous lesions. There are a number of methods used to treat cervical cancer and improve the survival rate. However, the prevalence and recurrence rates of cervical cancer are increasing every year. There is an urgent requirement for a better understanding of the molecular mechanism cervical cancer development. The present study used scientific information retrieval from the Gene Expression Omnibus database to download the GSE26511 dataset, which contained 39 samples, including 19 cervical cancer lymph node-positive samples and 20 cervical cancer lymph node-negative samples. Using Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and weighted gene co-expression network analysis, 1,263 differentially expressed genes were found that affected the biological processes, including 'cell cycle process', 'signaling pathways', 'immune response', 'cell activation', 'regulation of immune system process' and 'inflammatory response'. These areas should be the focus of study for cervical cancer in the future. PMID- 30013650 TI - Expression of galectin-7 in vulvar lichen sclerosus and its effect on dermal fibroblasts. AB - Lichen sclerosus is a chronic and inflammatory disease. Extensive studies have focused on the epidermis, with the dermis or epidermis-dermis receiving less attention. To investigate the role of galectin-7, a keratinocyte protein, in vulvar lichen sclerosus (VLS) and its potential effects on dermal fibroblasts, immunohistochemical staining was performed with VLS tissue samples and normal control samples. The expression of galectin-7 was determined by evaluating the galectin-7 integrated density analysis, and further assessed by western blot analysis. Dermal fibroblasts were isolated from the normal tissue of the female anogenital region following sexual plastic surgery. A cell viability assay was performed on isolated dermal fibroblast cells in the presence or absence of galectin-7. Reverse transcription-quantitative polymerase chain reaction (RT qPCR) was performed to determine the transcriptional level of collagen I and collagen III in the response to different doses of galectin-7. In the immunohistochemical analysis, galectin-7 demonstrated a significantly elevated level in VLS, compared to control tissues, which was confirmed by western blot analysis. In the analysis of primary dermal fibroblast cells, galectin-7 significantly inhibited the viability rate of fibroblasts in a dose-dependent manner. RT-qPCR data revealed that the transcription level of collagen I and collagen III were positively associated with the galectin-7 treatment concentration. The overexpression of galectin-7 is associated with the progression of VLS in the epidermis, a high concentration of galectin-7 inhibits the viability of the primary vulvar dermal fibroblasts, and stimulates the accumulation of collagen I and collagen III in dermal fibroblast cultures, thus galectin-7 may serve as a drug target during VLS progression. PMID- 30013651 TI - Gene-expression signature predicts survival benefit from postoperative chemoradiotherapy in head and neck squamous cell carcinoma. AB - Postoperative radiotherapy or concurrent chemoradiotherapy are routine clinical options for the treatment of head and neck squamous cell carcinoma (HNSCC). However, the benefit of adding chemotherapy to radiotherapy is contested. The present study aimed to develop a gene signature to predict the clinical benefit of postoperative chemoradiotherapy using public data from The Cancer Genome Atlas. A 22-gene signature was established, which demonstrated the best predictive value. Patients were separated into low-score and high-score subgroups based on the expression score of the 22-gene signature. In the high-score subgroup, patients who received chemoradiotherapy demonstrated improved overall survival, relapse-free survival and local regional control compared with those who received radiotherapy alone. However, in the low-score subgroup adding chemotherapy to radiotherapy was associated with worse patient outcomes. The predictive value of the 22-gene signature was independent of the conventional clinical variables. Gene set enrichment analysis revealed that the expression signatures of hypoxia phenotype and stem-like traits were significantly enriched in the low-score subgroup. In addition, the low-score subgroup was associated with the gene sets involved in resistance to anticancer drugs. In conclusion, hypoxia- or stem-like gene expression properties are associated with chemotherapy resistance in HNSCC. The 22-gene signature may be useful as a predictive marker to help distinguish patients who will benefit from postoperative concurrent chemoradiotherapy. PMID- 30013652 TI - Juglone suppresses epithelial-mesenchymal transition in prostate cancer cells via the protein kinase B/glycogen synthase kinase-3beta/Snail signaling pathway. AB - Epithelial-mesenchymal transition (EMT) serves an important role in the metastasis of prostate cancer. Juglone is a natural compound isolated from plants that is reported to possess potent cytotoxic properties. However, there are no studies on the anti-EMT effect of juglone in prostate cancer, or its potential underlying mechanisms of action. In the present study, the effect of juglone on the EMT of prostate cancer cells was investigated. Transwell assays were used to demonstrate that juglone inhibits the migration and invasion of the prostate cancer (PC) LNCaP and LNCaP-AI cell lines. Results from western blot analysis demonstrated that juglone increases the expression of the epithelial marker E cadherin while decreasing the expression of mesenchymal markers (N-cadherin and Vimentin) in a dose-dependent manner. The data from the present study also revealed that juglone downregulates the expression of Snail, a repressor of E cadherin and an inducer of EMT. Furthermore, juglone prevented inactivation of glycogen synthase kinase-3beta (GSK-3beta), an endogenous inhibitor of Snail in a dose-dependent manner. Lithium chloride (LiCl), a GSK-3beta inhibitor, prevented juglone-mediated downregulation of Snail expression and upregulation of E cadherin. In addition, phosphorylation and subsequent activation of protein kinase B (Akt), which is known to phosphorylate GSK-3beta at serine 9 (Ser9), leading to its inhibition, were significantly decreased by juglone in LNCaP and LNCaP-AI cells. Inhibition of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway by LY294002 augmented juglone-mediated GSK-3beta activity by inhibiting Ser9 phosphorylation. These findings indicated that juglone suppresses EMT via the Akt/GSK-3beta/Snail pathway, consequently decreasing the invasiveness of PC cells. PMID- 30013653 TI - GINS2 regulates cell proliferation and apoptosis in human epithelial ovarian cancer. AB - Go-Ichi-Ni-San 2 (GINS2), also known as partner of Sld five 2, is involved in the initiation of DNA replication and cell cycle progression. GINS2 is abundantly expressed in a number of malignant solid tumors, including breast cancer, melanoma and hepatic carcinoma. However, the functions of GINS2 in epithelial ovarian cancer (EOC) remain unclear. The aim of the present study was to investigate these functions. GINS2 expression was detected in EOC and normal ovarian tissues using immunohistochemistry. To investigate the functions of GINS2 in EOC, GINS2 expression was stably knocked down in SKOV-3 cells using lentiviral short hairpin RNA (shRNA). The expression of GINS2 mRNA and protein in SKOV-3 cells was examined using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses, respectively. Cell proliferation was determined using high-content screening and MTT assays. Cell cycle progression and apoptosis were detected using flow cytometry. Compared with normal ovarian tissues, EOC tissues expressed increased levels of GINS2 expression (16.7 vs. 58.3%). Increased expression of GINS2 mRNA was also observed in SKOV-3 and OVCAR3 cells. In the investigation of GINS2 functions in EOC, GINS2 expression at the mRNA and protein levels was significantly inhibited by specific GINS2 shRNA. GINS2 knockdown significantly inhibited the proliferation and viability of SKOV-3 cells and induced cell cycle arrest in S phase. Furthermore, GINS2 knockdown in SKOV-3 cells significantly increased cell apoptosis. GINS2 is markedly expressed in EOC tissues and cell lines. Stable GINS2 knockdown in SKOV 3 cells significantly inhibited cell proliferation and induced cell cycle arrest and cell apoptosis. Therefore, GINS2 may be involved in EOC progression. PMID- 30013654 TI - CCR7 regulates ANO6 to promote migration of pancreatic ductal adenocarcinoma cells via the ERK signaling pathway. AB - The increase in migratory ability of pancreatic ductal adenocarcinoma cells is a key event in the development of metastasis to the lymph nodes and distant organs. Although the C-C motif chemokine receptor 7 (CCR7) and its ligand, C-C motif chemokine ligand 21 (CCL21), have been revealed to serve an important role in tumor migration, their precise roles and potential underlying mechanisms remain largely unknown. The present study revealed that overexpression of CCR7 significantly promoted BxPC-3 cell migration, accompanied by the induction of anoctamin 6 (ANO6) expression, indicating that ANO6 is a downstream target of CCR7 signaling. Furthermore, the level of phosphorylated extracellular signal regulated kinase (ERK) was significantly increased in CCR7-overexpressing BxPC-3 cells, indicating that ERK may be a potential mediator of CCR7-regulated ANO6 expression in BxPC-3 cells. To characterize the receptor-mediated pathway, a specific ERK inhibitor, U0126, was used, which reduced BxPC-3 cell migration and the expression of ANO6. In summary, the results of the present study demonstrate that CCR7 promoted BxPC-3 cell migration by regulating ANO6 expression perhaps via activation of the ERK signaling pathway. PMID- 30013655 TI - Fusobacterium nucleatum promotes the progression of colorectal cancer by interacting with E-cadherin. AB - Increasing evidence suggests that Fusobacterium nucleatum is involved in colorectal carcinogenesis. Previous studies have explored whether F. nucleatum may trigger colonic epithelial-mesenchymal transition. The results of the present study demonstrated that F. nucleatum enhances the proliferation and invasion of NCM460 cells compared with that of normal control and DH5alpha cells. Furthermore, F. nucleatum significantly increased the phosphorylation of p65 (a subunit of nuclear factor-kappaB), as well as the expression of interleukin (IL) 6, IL-1beta and matrix metalloproteinase (MMP)-13. Additionally, F. nucleatum infection did not affect the expression levels of epithelial (E-)cadherin and beta-catenin. E-cadherin knockdown in NCM460 cells did not induce the activation of inflammatory responses in response to F. nucleatum infection, whereas it increased inflammation in response to beta-catenin silencing. F. nucleatum infection could not increase the proportion of cells at S phase when E-cadherin was silenced. Nevertheless, F. nucleatum infection enhanced the proportion of NCM460 cells at S phase when transfected with small interfering RNAs to knock down beta-catenin expression. In conclusion, the results of the present study demonstrated that F. nucleatum infection interacted with E-cadherin instead of beta-catenin, which in turn enhances the malignant phenotype of colorectal cancer cells. PMID- 30013656 TI - Dihydroartemisinin suppresses the proliferation of Epstein-Barr virus-associated gastric carcinoma cells via downregulation of latent membrane protein 2A. AB - Treatment of recurrent and metastatic Epstein-Barr virus-associated gastric carcinoma (EBVaGC) remains a challenge, particularly in developing countries, due to lack of efficient screening programs. Latent membrane protein 2A (LMP2A) has been reported to serve an important function in the development of EBVaGC. In previous years dihydroartemisinin (DHA), traditionally used as an anti-malarial agent, has been demonstrated to inhibit tumor growth with low toxicity to normal cells. In the present study, the anti-tumor effect of DHA in EBVaGC was investigated. The MTT assay was used to compare the viability of untreated and DHA-treated EBVaGC GT-38 cells. Flow cytometry was applied to determine the percentage of GT-38 cells at each stage of the cell cycle. Reverse transcription polymerase chain reaction and western blotting were used to determine the expression of the LMP2A gene. The effect of DHA treatment in vivo was evaluated in nude mice bearing GT-38 tumors. The results of the present study revealed that DHA-treated cells exhibited a time- and dose-dependent inhibition of viability. DHA significantly increased the apoptotic rate of GT-38 cells following treatment with 20 ug/ml DHA for 48 h. DHA-treated GT-38 cells were blocked in the G0/G1 phase, resulting in an accumulation of G0/G1 phase cells and a significant decrease of G2/M phase cells. In vivo, the results of the present study revealed that DHA significantly inhibited the growth of GT-38 cell-transplanted tumors. The mRNA and protein levels of LMP2A were significantly downregulated in the DHA treated group compared with the control group. The present data indicated that DHA inhibited cell growth and induced cell apoptosis of the EBVaGC GT-38 cell line via downregulation of LMP2A. DHA may therefore be a potential therapeutic candidate for the treatment of EBVaGC. PMID- 30013657 TI - miR-214-3p promotes the proliferation, migration and invasion of osteosarcoma cells by targeting CADM1. AB - Although osteosarcoma (OS) is the most common type of primary bone tumor in adolescents and young adults, its mechanism remains unclear. A previous study by the authors demonstrated that miR-214-3p was upregulated in OS patients. Therefore, the present study aimed to investigate the effect and molecular mechanism of miR-214-3p in OS cells. OS cell lines, U2OS and MNNG/HOS Cl#5, were transiently transfected with miR-214-3p mimics, a control mimic, miR-214-3p inhibitors and a control inhibitor. Subsequent assays revealed that elevated miR 214-3p promoted the proliferative, migratory and invasive abilities of OS cells, while the opposite effects were observed in cells that were transfected with miR 214-3p inhibitors. The interaction between miR-214-3p and cell adhesion molecule 1 (CADM1) 3'untranslated region (UTR) was verified by a dual luciferase assay, which indicated that the relative luciferase activity was decreased in 293T cells that were co-transfected with miR-214-3p mimic and psiCHECK2-CADM1-3'UTR compared with cells that were co-transfected with psiCHECK2-CADM1-3'UTR and control mimic. The knockdown of CADM1 using small-interfering RNA enhanced the proliferative, migratory and invasive abilities of OS cells. Furthermore, downregulated CADM1 expression increased the expression of phosphorylated P44/42 mitogen activated kinase (MAPK). In conclusion, miR-214-3p was able to directly target CADM1 and decrease its expression. This resulted in the activation of the P44/42 MAPK signaling pathway, and thereby promoted the proliferation, migration and invasion of OS cells. PMID- 30013658 TI - Role of the tumour protein P53 gene in human cervical squamous carcinoma cells: Discussing haematopoietic cell-specific protein 1-associated protein X-1-induced survival, migration and proliferation. AB - The haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1), as a mitochondrial membrane protein, induces cancer progression and metastasis. The present study aimed to investigate the role of HAX-1-induced survival, migration and proliferation of human cervical squamous carcinoma cells and to elucidate its potential molecular mechanisms. The level of HAX-1 was examined by quantitative polymerase chain reaction and western blot analyses. The survival, migration and proliferation of the human cervical squamous carcinoma SiHa cell line were measured by the water-soluble tetrazolium salt (WST-1) assay, Transwell assay and 3H-thymidine incorporation into DNA (3H-TdR) assay, respectively. The intracellular reactive oxygen species (ROS) was estimated by the fluorescence of H2DCFDA, and the mitochondrial membrane potential was tested using a JC-1 probe. The expression of the HAX-1 gene was significantly increased in human cervical carcinoma tissues relative to non-cancerous cervix tissues. Overexpression of HAX 1 increased the survival, migration and proliferation ability of SiHa cells, decreased the production of ROS, and maintained the integrity of the mitochondrial membrane and morphology. The effect brought on these cells could be abrogated by the addition of wild-type tumour protein P53 (p53) or carbonyl cyanide-p-trifluoro methoxyphenylhydrazone-induced mitochondrial dysfunction. In summary, these data support the notion that HAX-1 induced the survival, migration and proliferation of human cervical squamous carcinoma cells by inhibiting its downstream regulatory factor p53 in SiHa cells. PMID- 30013659 TI - miRNA-29a inhibits colon cancer growth by regulation of the PTEN/Akt/GSK3beta and Wnt/beta-catenin signaling pathways. AB - In the present study, the effects of microRNA-29a (miRNA-29a) on colon cancer cell viability and the molecular mechanisms underlying the effects were investigated. The expression of miRNA-29a in colon cancer serum samples was notably downregulated, compared with in the normal group. First, miRNA-29a mimic was used to increase the expression of miRNA-29a in HCT-116 cells. Furthermore, upregulation of miRNA-29a suppressed cell viability, increased lactate dehydrogenase levels and apoptosis, and promoted caspase-3/9 activities and B cell lymphoma 2-associated X protein and phosphatase and tensin homolog (PTEN) protein expression in colon cancer cells. Furthermore, upregulation of miRNA-29a decreased phosphoinositide 3-kinase, phosphorylated (p)-protein kinase B (Akt) and p-glycogen synthase kinase 3beta (GSK3beta) protein expression and suppressed the Wnt/beta-catenin signaling pathway in colon cancer cells. The results of the present study verified that the protective effects of miRNA-29a suppress the PTEN/Akt/GSK3beta and Wnt/beta-catenin signaling pathways in colon cancer. PMID- 30013660 TI - Overexpression of ROD1 inhibits invasion of breast cancer cells by suppressing the translocation of beta-catenin into the nucleus. AB - The incidence of breast cancer is increasing throughout the world. Although significant progress has been made in diagnostic techniques and targeted therapies, the prognosis of breast cancer remains poor. Regulator of differentiation 1 (ROD1) may inhibit the development of several types of cancer. However, the role of ROD1 in breast cancer cells remains unknown. In the present study, western blot analysis and reverse transcription-quantitative polymerase chain reaction revealed that expression of ROD1 was significantly reduced in breast cancer cells. Overexpression of ROD1 reduced the proliferation rate, demonstrated using a Cell Counting Kit-8 assay. Additionally, the overexpression of ROD1 decreased the invasiveness of breast cancer cells, indicating that ROD1 may serve as a tumor suppressor. Additionally, the data suggested that ROD1 significantly suppressed the activity of Wnt luciferase reporter (TOP Flash) in MDA-MB-231 cells. Furthermore, it was demonstrated that ROD1 may interact with beta-catenin by using co-immunoprecipitation, resulting in suppression of beta catenin migration into the nucleus. Notably, ROD1 demonstrated its anticancer effect by decreasing beta-catenin (Y333) phosphorylation in a nude mouse xenograft model. Overexpression of ROD1 may downregulate Ki67 protein levels, as determined by immunohistochemistry. These results indicated that ROD1 may be used as a therapeutic target in patients with breast cancer. PMID- 30013661 TI - Cell-free DNA and chemoembolization in patients with liver metastases from colorectal cancer. AB - : Transarterial chemoembolization with irinotecan loaded beads (DEBIRI-TACE) represents an investigative treatment option for patients with metastatic colorectal cancer (mCRC). The present study examined DEBIRI-TACE with concomitant mFOLOFX6-bevacizumab as a first-line treatment for mCRC and explored the clinical value of circulating cell-free DNA (cfDNA). Patients with limited mCRC of the liver who had not been treated with chemotherapy received up to 4 biweekly DEBIRI TACE treatments. The endpoints examined included the response rate, survival, toxicity and translational analysis. Due to toxicity and lack of feasibility, the study closed prematurely. Total cfDNA was measured with a direct fluorescent assay. Between December 2012 and February 2014, 14 patients underwent a total of 49 DEBIRI-TACE treatments. With a median follow-up of 1.7 years, the median progression free survival and overall survival (OS) were 240 days [95% confidence interval (CI): 161-357] and 522 days (95% CI: 174-1,054), respectively. The response rate was 50%. Twelve patients experienced grade 3 toxicity or above. Dynamics of cfDNA showed biological variations in relation to therapy. To conclude, the present results indicated a response rate of 50% and median OS of 522 days for 14 patients with mCRC undergoing DEBIRI-TACE, but unacceptable toxicity and lack of feasibility with the applied schedule. The findings suggest that the level of cfDNA may be associated with the disease course, response to treatment and outcome. TRIAL REGISTRATION: The European Clinical Trials database (EudraCT no. 2012-000987-11) at 05-14-2012. PMID- 30013662 TI - Expression of AQP3 and AQP5 as a prognostic marker in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a common type of breast malignancy with high a propensity for metastasis and locoregional recurrence. The aim of the present study was to investigate the expression of aquaporin (AQP) 3 and AQP5, analyze their association with clinicopathological parameters and explore their clinical significance in tissue samples from patients with TNBC. Immunohistochemistry was performed to detect the expression patterns of AQP3 and AQP5 in 96 patients with TNBC who underwent surgery between 2007 and 2012. AQP3 and AQP5 were expressed primarily in the membrane and cytoplasm of tumor cells within TNBC tissues. AQP3 and AQP5 expression was notably stronger in carcinoma tissue compared with adjacent normal tissue. Overexpression of AQP3 and AQP5 was significantly associated with tumor size, lymph node status and local relapse/distant metastasis. In addition, aberrant overexpression of AQP5 was observed more frequently in TNBC tissues with higher Ki-67 expression than in those with lower Ki-67 expression. In univariate analysis, patients with TNBC with high AQP3 and AQP5 expression demonstrated poorer 5-year disease-free survival and overall survival compared with patients with low AQP3 and AQP5 expression. In multivariate analysis, the combined expression of AQP3 and AQP5 was an independent prognostic marker in patients with TNBC. The results of the present study suggest that the overexpression of AQP3 and AQP5 may serve as a novel therapeutic marker in patients with TNBC. PMID- 30013663 TI - Effect of Period 2 on the proliferation, apoptosis and migration of osteosarcoma cells, and the corresponding mechanisms. AB - Period 2 (per2) is a core circadian clock gene. Dysregulation of the per2 gene has been identified in a number of types of human cancer and may be associated with a poor prognosis. To confirm the influence of per2 gene on MNNG/HOS human osteosarcoma cells, small interfering (si)RNA against per2 or plasmids containing per2 were transfected into MNNG/HOS cells, and the proliferation, apoptosis and migration were observed. The present study demonstrated that per2 knockdown significantly enhanced MNNG/HOS cell proliferation and migration and protected MNNG/HOS cells from apoptosis. Per2 overexpression inhibited MNNG/HOS cell proliferation and migration and promoted apoptosis. Furthermore, the protein expression of phosphorylated (p)-protein kinase B (Akt) and Bcl-2 were inhibited in per2-overexpressing cells, while the expression of p27, p21 and cleaved caspase-3 was promoted. In contrast, the expression of p-Akt and Bcl-2 was promoted in per2-knockdown cells, and p27, p21 and cleaved caspase-3 were decreased. This initial study may provide an alternative therapeutic strategy for the treatment of osteosarcoma. PMID- 30013664 TI - Clinicopathological characteristics of malignant melanomas of the skin and gastrointestinal tract. AB - The present study examined the differences between gastrointestinal melanoma (GM) and skin melanoma (SM). The clinicopathological characteristics, the expression of melanoma stem cell markers nestin, sex determining region Y-box 2 and ATP binding cassette sub-family B member 5, and the presence of the BRAFV600E mutation were evaluated in 10 cases of GM and 31 cases of SM. Patients with GM had an increased mean age compared with those with SM (76 vs. 68 years). In addition, GMs were significantly more likely than SMs to be amelanotic (50 vs. 7%; P=0.001) and display round cells (70 vs. 23%; P=0.02). The mitosis rate was also significantly higher in GM compared with SM (P<0.05). The incidence of lymph node metastasis (60 vs. 32%; P<0.05) and distant metastasis (10 vs. 6.5%, P=0.02) was significantly higher in GMs compared with SMs. The expression of stem cell markers did not differ significantly between groups, however, in the SM group advanced-stage disease was associated with a significantly higher expression of nestin than early-stage disease (P<0.05). Immunohistochemically, the expression of BRAFV600E was significantly lower in GMs compared with in SMs (1.0 vs. 3.3; P=0.01). These findings indicate that the identification of these features may aid in the diagnosis of GM and SM, as well as contribute to the development of novel targeted therapies against GM. PMID- 30013665 TI - MicroRNA-539 inhibits colorectal cancer progression by directly targeting SOX4. AB - Colorectal cancer (CRC) is the third most prevalent cancer and the fourth most common cause of cancer-associated mortality in males and females globally. Aberrant expression of microRNA-539 (miR-539) has been reported in multiple types of cancer. However, miR-539 expression, function and underlying mechanisms have not been clearly elucidated in CRC. In the present study, miR-539 expression was detected by reverse transcription-quantitative polymerase chain reaction (RT qPCR) in CRC tissues and cell lines. The effects of miR-539 on CRC cells were further examined in in vitro studies. In addition, the direct targets of miR-539 in CRC were investigated using bioinformatics, luciferase reporter assays, RT qPCR and western blotting. miR-539 was revealed to be significantly downregulated in CRC cell lines and tissues. Decreased miR-539 expression was associated with lymph node metastasis and tumor-node-metastasis stage in patients with CRC. Functional assays revealed that the rescue of miR-539 expression attenuated CRC cell proliferation and invasion in vitro. Additionally, SRY-box 4 (SOX4) was validated as a direct target gene of miR-539 in CRC. Furthermore, SOX4 was revealed to be upregulated in CRC tissues at the mRNA and protein level. A significant negative correlation between miR-539 and SOX4 mRNA expression levels was observed in CRC tissues. Furthermore, upregulation of SOX4 partially restored the tumor suppressive effects of miR-539 on CRC cell proliferation and invasion. Taken together, this suggests that miR-539 may serve tumor-suppressive functions in CRC during the process of malignant transformation, by directly targeting SOX4. miR-539/SOX4-based targeted therapy may represent a potential novel treatment for patients with CRC. PMID- 30013666 TI - Ecotropic viral integration site 1 regulates the progression of acute myeloid leukemia via MS4A3-mediated TGFbeta/EMT signaling pathway. AB - Acute myeloid leukemia (AML) is a type of malignant tumor that is caused by malignant clone hematopoietic stem cells. The ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is highly expressed in AML, and its expression level has been associated with poor prognosis of AML. Previous studies have indicated that Evi1 may regulate cell proliferation, differentiation and apoptosis by inhibiting the membrane-spanning-4-domains subfamily-A member-3 (MS4A3) gene in AML. The aim of the present study was to investigate the role of Evi1 in the progression of AML. The results revealed that Evi1 was overexpressed in leukemia cells compared with normal T lymphocytes. MicroRNAs (miR)-133 and 431 that target Evi1 were investigated, and it was observed that there was a low expression of miR-431 in AML. The transfection of miR-431 was able to decrease the promoter methylation levels of the Evi1 gene in AML cells. The transfection of miR-431 also suppressed the migration and invasion of AML cells. The present study revealed that the transfection of miR-431 mimic was able to downregulate MS4A3 expression in AML cells. Furthermore, the expression levels of transforming growth factor beta (TGFbeta) and epithelial-to-mesenchymal transition (EMT) markers fibronectin, alpha-smooth muscle actin, and vimentin were downregulated following the transfection of miR-431 in AML cells. The overexpression of MS4A3 was also able to suppress miR-431-mediated inhibition of the expression of TGFbeta and EMT markers in AML cells. The addition of TGFbeta inhibited the downregulation of EMT markers by transfection of miR-431 in AML cells. The transfection of miR-431 suppressed the migration and invasion of AML cells, which was also abolished by the addition of TGFbeta. In conclusion, the results of the present study indicated that Evi1 may be a potential molecular target of leukemia therapy via MS4A3-mediated TGFbeta/EMT signaling pathway. PMID- 30013667 TI - Synergistic antitumor activity of aspirin and erlotinib: Inhibition of p38 enhanced aspirin plus erlotinib-induced suppression of metastasis and promoted cancer cell apoptosis. AB - High-dose erlotinib is effective for non-small cell lung cancer patients with brain metastases. The aim of the present study was to investigate whether aspirin could increase the anti-proliferative and anti-metastatic effects of regular erlotinib treatment. The data demonstrated that combining aspirin with erlotinib significantly induced apoptosis and inhibited tumor cell proliferation in several human cancer types. Furthermore, aspirin plus erlotinib significantly induced the activation of E-cadherin and suppression of p38. The data also indicated that the p38/E-cadherin pathway may be involved in the apoptosis caused by the combination of aspirin and erlotinib. As p38 and E-cadherin also serve a key role in epithelial-to-mesenchymal transition (EMT) and cancer metastasis, we hypothesized that the combination of aspirin and erlotinib may significantly inhibit tumor metastasis. First, aspirin plus erlotinib achieved potent inhibition of cancer cell migration and invasion, which are crucial for cancer metastasis. Next, the results demonstrated that aspirin plus erlotinib inhibited angiogenesis by suppressing endothelial cell migration and invasion. Moreover, it was confirmed that aspirin plus erlotinib exerted synergistic anti-angiogenic effects. Finally, the synergistic anti-proliferative and anti-metastatic effects of the combination of aspirin with erlotinib were further validated in an A549 xenograft model in vivo. In conclusion, aspirin plus erlotinib may be an effective combination regimen for patients with metastatic cancer. PMID- 30013668 TI - The impact of inflammation and cytokine expression of PM2.5 in AML. AB - Environmental and health issues have become a major focus of research worldwide in recent years. Particulate matter with diameter <=2.5 um (PM2.5) is a common air pollutant that has been demonstrated to be associated with various diseases, including acute myeloid leukemia (AML). In the present study, the effects of PM2.5 on the proliferation and inflammation were assessed using three human acute myeloid cell lines (U937, HL-60 and KG-1a) in vitro. Additionally, the levels of several cytokines [interleukin (IL)-2, IL-10, IL-17A and tumor necrosis factor (TNF)alpha] in AML cells and Sprague Dawley rats were evaluated to investigate the effects of PM2.5 on cytokine expression in AML. The results revealed that PM2.5 was capable of enhancing inflammatory responses in AML cells, and increasing IL-2, IL-10, IL-17A and TNFalpha mRNA expression in AML cells to different degrees. Furthermore, PM2.5 increased IL-2 and IL-10 contents in rats following 12 weeks of exposure. These results suggested that PM2.5 may serve a role in promoting the occurrence and progression of leukemia by affecting cytokine expression, and that there may be various mechanisms active in different AML subtypes. PMID- 30013669 TI - Association between rectal bleeding and the absolute dose volume of the rectum following image-guided radiotherapy for patients with prostate cancer. AB - The association between rectal bleeding and the received dose relative to the volume of the rectum is well established in prostate cancer patients who have undergone radiotherapy. The relative volume of the rectum is affected by the rectal anatomical volume, which depends on the definition of rectal length. Compared with the relative rectal volume, the absolute volume of the rectum may be more associated with rectal bleeding. The present study investigated the absolute volume of the rectum that may be used to predict late rectal bleeding following intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT). The cases of 82 patients of prostate cancer, who underwent IMRT and IGRT, were retrospectively evaluated by evaluating dose volume histograms. The median patient age was 73.4 years (range, 51.3-85.9 years). The median total prescribed dose was 76 Gy given in 38 fractions. The absolute and relative dose volumes of the rectum were evaluated by multivariate analysis, and the optimal dose to prevent rectal bleeding was determined. The actuarial >=grade 1 rectal bleeding rate at 4 years was 4.5% (95% confidence interval, 1.5-13.4%) with a median observation period of 45.3 months. The absolute rectal volume (ml) treated with 60 Gy was the only significant risk factor for rectal bleeding (P<0.05), but the relative rectal volume (%) was not identified as a significant factor by the multivariate analysis. When the rectal volume of 5 or 10 ml received 60 Gy (D5cc and D10cc), rectal bleeding was expected to occur in 3.3 and 7.3% of the patients, respectively. Rectal D5cc <=60 Gy is recommended to prevent late >=grade 1 rectal bleeding in IGRT. PMID- 30013670 TI - Identification of long non-coding RNA CCAT1 as an oncogene in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a common type of cancer worldwide. Long non coding RNAs (lncRNAs) have been demonstrated to be associated with the development of multiple types of human cancer. The present study aimed to identify the potential role of lncRNA colon cancer associated transcript 1 (CCAT1) in NPC. Reverse transcription-quantitative polymerase chain reaction (RT qPCR) was used to detect the expression levels of CCAT1 in NPC tissues and cell lines. The function of CCAT1 in the proliferation, migration, invasion and apoptosis of NPC cells was detected by MTT, cell scratch, Transwell, flow cytometry and caspase-3 ELISA assays, respectively. The results indicated that the expression levels of CCAT1 were significantly upregulated in NPC tissues compared with normal nasopharyngeal epithelial tissues. CCAT1 expression was also higher in SUNE-1 and C666-1 cells compared with NP69 cells. Furthermore, the knockdown of CCAT1 was indicated to inhibit growth, migration and invasion, and induce apoptosis in NPC cells. In conclusion, the present study is, to the best of our knowledge, the first to provide new findings that support an oncogenic role of CCAT1 in NPC. Further research is required to define the potential molecular mechanism of CCAT1 in the development of NPC. PMID- 30013671 TI - Elucidating feed-forward apoptosis signatures in breast cancer datasets: Higher FOS expression associated with a better outcome. AB - Overstimulation of pro-proliferative pathways and high level expression of pro proliferative transcription factors (TFs) can lead to apoptosis. This is likely due to TF binding sites for pro-proliferative TFs common to pro-proliferative and pro-apoptosis-effector genes. Certain clinical datasets have indicated that molecular markers associated with higher proliferation rates lead to improved outcomes for patients with cancer. These observations have been extensively assessed on a general basis, however there has been little work dissecting feed forward apoptosis signaling pathways that may represent specific distinctions between a pro-proliferative mechanism and a pro-apoptotic mechanism in samples from patients with cancer. Using The Cancer Genome Atlas datasets and bioinformatic approaches, the present study reports that higher FOS expression levels, along with higher FOS target apoptosis-effector gene expression, is associated with an increased survival, while higher POU2F1 expression is associated with a reduced survival (average difference of 25.9 months survival). In summary, in the datasets examined FOS represents an apoptosis-driver and high POU2F1 represents a driver mechanism for cancer development. PMID- 30013672 TI - The link between FOXJ1 expression level in bladder carcinoma and tumor recurrence. AB - [This retracts the article DOI: 10.3892/ol.2017.7504.]. PMID- 30013673 TI - Improved ovarian cancer EMT-CTC isolation by immunomagnetic targeting of epithelial EpCAM and mesenchymal N-cadherin. AB - Epithelial cell adhesion molecule (EpCAM)-targeted capture remains the most common isolation strategy for circulating tumor cells (CTCs). However, epithelial to-mesenchymal transition (EMT) leads to decreased epithelial EpCAM expression affecting the optimal CTC capture. In this study, we tested a cohort of ovarian cancer cell lines using flow cytometry to identify N-cadherin as the additional immunomagnetic cell surface target for ovarian cancer cell isolation. Combined immunomagnetic targeting of mesenchymal N-cadherin and epithelial EpCAM enriched CTCs from advanced ovarian cancer patient blood approximately three times more efficiently than targeting of EpCAM alone. We also show that more EMT-phenotype CTCs are captured by including N-cadherin targeting into CTC isolation protocols. However, after N-cadherin-based CTC isolation, in some blood samples of healthy individuals, we also observed the presence of cells expressing markers common to CTCs. Our data show that these "false positives" can be largely distinguished from CTCs as circulating endothelial cells (CECs) by vascular endothelial cadherin co-staining. CEC counts are highly variable in patients and healthy controls. Our data demonstrate that a combination of EpCAM with N-cadherin targeted isolation can improve CTC detection and widen the EMT-phenotype spectrum of captured CTCs. PMID- 30013674 TI - Recent advances in phosphorescent platinum complexes for organic light-emitting diodes. AB - Phosphorescent organometallic compounds based on heavy transition metal complexes (TMCs) are an appealing research topic of enormous current interest. Amongst all different fields in which they found valuable application, development of emitting materials based on TMCs have become crucial for electroluminescent devices such as phosphorescent organic light-emitting diodes (PhOLEDs) and light emitting electrochemical cells (LEECs). This interest is driven by the fact that luminescent TMCs with long-lived excited state lifetimes are able to efficiently harvest both singlet and triplet electro-generated excitons, thus opening the possibility to achieve theoretically 100% internal quantum efficiency in such devices. In the recent past, various classes of compounds have been reported, possessing a beautiful structural variety that allowed to nicely obtain efficient photo- and electroluminescence with high colour purity in the red, green and blue (RGB) portions of the visible spectrum. In addition, achievement of efficient emission beyond such range towards ultraviolet (UV) and near infrared (NIR) regions was also challenged. By employing TMCs as triplet emitters in OLEDs, remarkably high device performances were demonstrated, with square planar platinum(II) complexes bearing pi-conjugated chromophoric ligands playing a key role in such respect. In this contribution, the most recent and promising trends in the field of phosphorescent platinum complexes will be reviewed and discussed. In particular, the importance of proper molecular design that underpins the successful achievement of improved photophysical features and enhanced device performances will be highlighted. Special emphasis will be devoted to those recent systems that have been employed as triplet emitters in efficient PhOLEDs. PMID- 30013675 TI - Steric "attraction": not by dispersion alone. AB - Non-covalent interactions between neutral, sterically hindered organic molecules generally involve a strong stabilizing contribution from dispersion forces that in many systems turns the 'steric repulsion' into a 'steric attraction'. In addition to London dispersion, such systems benefit from electrostatic stabilization, which arises from a short-range effect of charge penetration and gets bigger with increasing steric bulk. In the present work, we quantify this contribution for a diverse set of molecular cores, ranging from unsubstituted benzene and cyclohexane to their derivatives carrying tert-butyl, phenyl, cyclohexyl and adamantyl substituents. While the importance of electrostatic interactions in the dimers of sp2-rich (e.g., pi-conjugated) cores is well appreciated, less polarizable assemblies of sp3-rich systems with multiple short range CH...HC contacts between the bulky cyclohexyl and adamantyl moieties are also significantly influenced by electrostatics. Charge penetration is drastically larger in absolute terms for the sp2-rich cores, but still has a non negligible effect on the sp3-rich dimers, investigated herein, both in terms of their energetics and equilibrium interaction distances. These results emphasize the importance of this electrostatic effect, which has so far been less recognized in aliphatic systems compared to London dispersion, and are therefore likely to have implications for the development of force fields and methods for crystal structure prediction. PMID- 30013676 TI - Metal-free formal synthesis of phenoxazine. AB - A transition metal-free formal synthesis of phenoxazine is presented. The key step of the sequence is a high-yielding O-arylation of a phenol with an unsymmetrical diaryliodonium salt to provide an ortho-disubstituted diaryl ether. This species was cyclized to acetylphenoxazine in moderate yield. The overall yield in the three-step sequence is 72% based on recovered diaryl ether. An interesting, unusually stable iodine(III) intermediate in the O-arylation was observed by NMR and could be converted to the product upon longer reaction time. PMID- 30013677 TI - Hyper-reticulated calixarene polymers: a new example of entirely synthetic nanosponge materials. AB - New calixarene-based nanosponges (CaNSs), i.e., hyper-reticulated polymers constituted by calixarene monomer units joined by means of bis(1,2,3 trialzolyl)alkyl linkers, were synthesized, characterized and subjected to preliminary tests to assess their supramolecular absorption abilities towards a set of suitable organic guests, selected as pollutant models. The synthesis was accomplished by means of a CuAAC reaction between a tetrakis(propargyloxy)calix[4]arene and an alkyl diazide. The formation of the polymeric network was assessed by means of FTIR and 13C{1H} CP-MAS solid-state NMR techniques, whereas morphological characterization was provided by SEM microghaphy. The materials were proved to possess pH-dependent sequestration abilities, due to the presence of the weakly basic triazole linkers. Sequestration efficiency indeed depends on the effective occurrence of both electrostatic and hydrophobic interactions between the guest and the polymer lattice. Thus, our CaNS nanosponges can be considered as a new class of purely synthetic smart absorbent materials. PMID- 30013679 TI - Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions. AB - We recently reported a novel hybrid batch-flow synthesis of the antipsychotic drug clozapine in which the reduction of a nitroaryl group is described under flow conditions using sodium dithionite. We now report the expansion of this method to include the reduction of aldehydes. The method developed affords yields which are comparable to those under batch conditions, has a reduced reaction time and improved space-time productivity. Furthermore, the approach allows the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process. PMID- 30013678 TI - Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis. AB - Most of the polyvalent organoiodine compounds derive from iodoarenes, which are released in stoichiometric amounts in any reaction mediated by lambda3- or lambda5-iodanes. In parallel to the development of solid-supported reagents or reactions catalytic in iodine, a third strategy has emerged to address this issue in terms of sustainability. The atom-economy of transformations involving stoichiometric amounts of lambda3- or lambda5-iodanes, thus, has been improved by designing tandem reactions that allows for incorporating the aryl motif into the products through a subsequent one-pot nucleophilic addition or catalytic coupling reaction. This review summarizes the main achievements reported in this area. PMID- 30013680 TI - Cobalt-catalyzed C-H cyanations: Insights into the reaction mechanism and the role of London dispersion. AB - Carboxylate-assisted cobalt(III)-catalyzed C-H cyanations are highly efficient processes for the synthesis of (hetero)aromatic nitriles. We have now analyzed the cyanation of differently substituted 2-phenylpyridines in detail computationally by density functional theory and also experimentally. Based on our investigations, we propose a plausible reaction mechanism for this transformation that is in line with the experimental observations. Additional calculations, including NCIPLOT, dispersion interaction densities, and local energy decomposition analysis, for the model cyanation of 2-phenylpyridine furthermore highlight that London dispersion is an important factor that enables this challenging C-H transformation. Nonbonding interactions between the Cp* ligand and aromatic and C-H-rich fragments of other ligands at the cobalt center significantly contribute to a stabilization of cobalt intermediates and transition states. PMID- 30013682 TI - Lanyamycin, a macrolide antibiotic from Sorangium cellulosum, strain Soce 481 (Myxobacteria). AB - Lanyamycin (1/2), a secondary metabolite occurring as two epimers, was isolated from the myxobacterium Sorangium cellulosum, strain Soce 481. The structures of both epimers were elucidated from HRESIMS and 1D and 2D NMR data and the relative configuration of their macrolactone ring was assigned based on NOE and vicinal 1H NMR coupling constants and by calculation of a 3D model. Lanyamycin inhibited HCV infection into mammalian liver cells with an IC50 value of 11.8 uM, and exhibited a moderate cytotoxic activity against the mouse fibroblast cell line L929 and the human nasopharyngeal cell line KB3 with IC50 values of 3.1 and 1.5 MUM, respectively, and also suppressed the growth of the Gram-positive bacterium Micrococcus luteus. PMID- 30013681 TI - Thiocarbonyl-enabled ferrocene C-H nitrogenation by cobalt(III) catalysis: thermal and mechanochemical. AB - Versatile C-H amidations of synthetically useful ferrocenes were accomplished by weakly-coordinating thiocarbonyl-assisted cobalt catalysis. Thus, carboxylates enabled ferrocene C-H nitrogenations with dioxazolones, featuring ample substrate scope and robust functional group tolerance. Mechanistic studies provided strong support for a facile organometallic C-H activation manifold. PMID- 30013683 TI - Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA. AB - TEMPO spin labels protected with 2-nitrobenzyloxymethyl groups were attached to the amino residues of three different nucleosides: deoxycytidine, deoxyadenosine, and adenosine. The corresponding phosphoramidites could be incorporated by unmodified standard procedures into four different self-complementary DNA and two RNA oligonucleotides. After photochemical removal of the protective group, elimination of formic aldehyde and spontaneous air oxidation, the nitroxide radicals were regenerated in high yield. The resulting spin-labeled palindromic duplexes could be directly investigated by PELDOR spectroscopy without further purification steps. Spin-spin distances measured by PELDOR correspond well to the values obtained from molecular models. PMID- 30013684 TI - A conformationally adaptive macrocycle: conformational complexity and host-guest chemistry of zorb[4]arene. AB - Large amplitude conformational change is one of the features of biomolecular recognition and is also the basis for allosteric effects and signal transduction in functional biological systems. However, synthetic receptors with controllable conformational changes are rare. In this article, we present a thorough study on the host-guest chemistry of a conformationally adaptive macrocycle, namely per-O ethoxyzorb[4]arene (ZB4). Similar to per-O-ethoxyoxatub[4]arene, ZB4 is capable of accommodating a wide range of organic cations. However, ZB4 does not show large amplitude conformational responses to the electronic substituents on the guests. Instead of a linear free-energy relationship, ZB4 follows a parabolic free-energy relationship. This is explained by invoking the influence of secondary C-H...O hydrogen bonds on the primary cation...pi interactions based on the information obtained from four representative crystal structures. In addition, heat capacity changes (DeltaCp) and enthalpy-entropy compensation phenomena both indicate that solvent reorganization is also involved during the binding. This research further deepens our understanding on the binding behavior of ZB4 and lays the basis for the construction of stimuli-responsive materials with ZB4 as a major component. PMID- 30013685 TI - Direct electrochemical generation of organic carbonates by dehydrogenative coupling. AB - Organic carbonates are an important source for polycarbonate synthesis. However, their synthesis generally requires phosgene, sophisticated catalysts, harsh reaction conditions, or other highly reactive chemicals. We present the first direct electrochemical generation of mesityl methyl carbonate by C-H activation. Although this reaction pathway is still challenging concerning scope and efficiency, it outlines a new strategy for carbonate generation. PMID- 30013686 TI - Drug targeting to decrease cardiotoxicity - determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells. AB - Background: Cardiomyopathy induced by the chemotherapeutic agents doxorubicin and daunorubicin is a major limiting factor for their application in cancer therapy. Chemotactic drug targeting potentially increases the tumor selectivity of drugs and decreases their cardiotoxicity. Increased expression of gonadotropin releasing hormone (GnRH) receptors on the surface of tumor cells has been reported. Thus, the attachment of the aforementioned chemotherapeutic drugs to GnRH-based peptides may result in compounds with increased therapeutic efficacy. The objective of the present study was to examine the cytotoxic effect of anticancer drug-GnRH-conjugates against two essential cardiovascular cell types, such as cardiomyocytes and endothelial cells. Sixteen different previously developed GnRH-conjugates containing doxorubicin, daunorubicin and methotrexate were investigated in this study. Their cytotoxicity was determined on primary human cardiac myocytes (HCM) and human umbilical vein endothelial cells (HUVEC) using the xCELLigence SP system, which measures impedance changes caused by adhering cells on golden electrode arrays placed at the bottom of the wells. Slopes of impedance-time curves were calculated and for the quantitative determination of cytotoxicity, the difference to the control was analysed. Results: Doxorubicin and daunorubicin exhibited a cytotoxic effect on both cell types, at the highest concentrations tested. Doxorubicin-based conjugates (AN 152, GnRH-III(Dox-O-glut), GnRH-III(Dox-glut-GFLG) and GnRH-III(Dox=Aoa-GFLG) showed the same cytotoxic effect on cardiomyocytes. Among the daunorubicin-based conjugates, [4Lys(Ac)]-GnRH-III(Dau=Aoa), GnRH-III(Dau=Aoa-YRRL), {GnRH III(Dau=Aoa-YRRL-C)}2 and {[4N-MeSer]-GnRH-III(Dau-C)}2 had a significant but decreased cytotoxic effect, while the other conjugates - GnRH-III(Dau=Aoa), GnRH III(Dau=Aoa-K(Dau=Aoa)), [4Lys(Dau=Aoa)]-GnRH-III(Dau=Aoa), GnRH-III(Dau=Aoa GFLG), {GnRH-III(Dau-C)}2 and [4N-MeSer]-GnRH-III(Dau=Aoa) - exerted no cytotoxic effect on cardiomyocytes. Mixed conjugates containing methotrexate and daunorubicin - GnRH-III(Mtx-K(Dau=Aoa)) and [4Lys(Mtx)]-GnRH-III(Dau=Aoa) - showed no cytotoxic effect on cardiomyocytes, as well. Conclusion: Based on these results, anticancer drug-GnRH-based conjugates with no cytotoxic effect on cardiomyocytes were identified. In the future, these compounds could provide a more targeted antitumor therapy with no cardiotoxic adverse effects. Moreover, impedimetric cytotoxicity analysis could be a valuable technique to determine the effect of drugs on cardiomyocytes. PMID- 30013687 TI - Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates. AB - To synthesize nucleoside and oligosaccharide derivatives, we often use a glycosylation reaction to form a glycoside bond. Coupling reactions between a nucleobase and a sugar donor in the former case, and the reaction between an acceptor and a sugar donor of in the latter are carried out in the presence of an appropriate activator. As an activator of the glycosylation, a combination of a Lewis acid catalyst and a hypervalent iodine was developed for synthesizing 4' thionucleosides, which could be applied for the synthesis of 4'-selenonucleosides as well. The extension of hypervalent iodine-mediated glycosylation allowed us to couple a nucleobase with cyclic allylsilanes and glycal derivatives to yield carbocyclic nucleosides and 2',3'-unsaturated nucleosides, respectively. In addition, the combination of hypervalent iodine and Lewis acid could be used for the glycosylation of glycals and thioglycosides to produce disaccharides. In this paper, we review the use of hypervalent iodine-mediated glycosylation reactions for the synthesis of nucleosides and oligosaccharide derivatives. PMID- 30013688 TI - Anomeric modification of carbohydrates using the Mitsunobu reaction. AB - The Mitsunobu reaction basically consists in the conversion of an alcohol into an ester under inversion of configuration, employing a carboxylic acid and a pair of two auxiliary reagents, mostly triphenylphosphine and a dialkyl azodicarboxylate. This reaction has been frequently used in carbohydrate chemistry for the modification of sugar hydroxy groups. Modification at the anomeric position, leading mainly to anomeric esters or glycosides, is of particular importance in the glycosciences. Therefore, this review focuses on the use of the Mitsunobu reaction for modifications of sugar hemiacetals. Strikingly, unprotected sugars can often be converted regioselectively at the anomeric center, whereas in other cases, the other hydroxy groups in reducing sugars have to be protected to achieve good results in the Mitsunobu procedure. We have reviewed on the one hand the literature on anomeric esterification, including glycosyl phosphates, and on the other hand glycoside synthesis, including S- and N-glycosides. The mechanistic details of the Mitsunobu reaction are discussed as well as this is important to explain and predict the stereoselectivity of anomeric modifications under Mitsunobu conditions. Though the Mitsunobu reaction is often not the first choice for the anomeric modification of carbohydrates, this review shows the high value of the reaction in many different circumstances. PMID- 30013689 TI - Visible light-mediated difluoroalkylation of electron-deficient alkenes. AB - A method for the reductive difluoroalkylation of electron-deficient alkenes using 1,1-difluorinated iodides mediated by irradiation with blue light is described. The reaction involves radical addition of 1,1-difluorinated radicals at the double bond followed by hydrogen atom transfer from sodium cyanoborohydride. PMID- 30013691 TI - Heterogeneous acidic catalysts for the tetrahydropyranylation of alcohols and phenols in green ethereal solvents. AB - The application of heterogeneous catalysis and green solvents to the set up of widely employed reactions is a challenge in contemporary organic chemistry. We applied such an approach to the synthesis and further conversion of tetrahydropyranyl ethers, an important class of compounds widely employed in multistep syntheses. Several alcohols and phenols were almost quantitatively converted into the corresponding tetrahydropyranyl ethers in cyclopentyl methyl ether or 2-methyltetrahydrofuran employing NH4HSO4 supported on SiO2 as a recyclable acidic catalyst. Easy work up of the reaction mixtures and the versatility of the solvents allowed further conversion of the reaction products under one-pot reaction conditions. PMID- 30013690 TI - The phenyl vinyl ether-methanol complex: a model system for quantum chemistry benchmarking. AB - The structure of the isolated aggregate of phenyl vinyl ether and methanol is studied by combining a multi-spectroscopic approach and quantum-chemical calculations in order to investigate the delicate interplay of noncovalent interactions. The complementary results of vibrational and rotational spectroscopy applied in molecular beam experiments reveal the preference of a hydrogen bond of the methanol towards the ether oxygen (OH???O) over the pi docking motifs via the phenyl and vinyl moieties, with an additional less populated OH???P(phenyl)-bound isomer detected only by microwave spectroscopy. The correct prediction of the energetic order of the isomers using quantum chemical calculations turns out to be challenging and succeeds with a sophisticated local coupled cluster method. The latter also yields a quantification as well as a visualization of London dispersion, which prove to be valuable tools for understanding the role of dispersion on the docking preferences. Beyond the structural analysis of the electronic ground state (S0), the electronically excited (S1) state is analyzed, in which a destabilization of the OH???O structure compared to the S0 state is observed experimentally and theoretically. PMID- 30013692 TI - Synthesis of diamido-bridged bis-pillar[5]arenes and tris-pillar[5]arenes for construction of unique [1]rotaxanes and bis-[1]rotaxanes. AB - The pillar[5]arene mono- and di(oxyalkoxy)benzoic acids were successfully prepared in high yields by sequential alkylation of omega-bromoalkoxy-substituted pillar[5]arenes with methyl or ethyl p-hydroxybenzoate followed by a hydrolytic reaction under basic conditions. Under catalysis of HOBt/EDCl, the amidation reaction of pillar[5]arene mono(oxybutoxy)benzoic acid with monoamido functionalized pillar[5]arenes afforded diamido-bridged bis-pillar[5]arenes. 1H NMR and 2D NOESY spectra clearly indicated that [1]rotaxanes were formed by insertion of longer diaminoalkylene unit into the cavity of one pillar[5]arene with another pillar[5]arene acting as a stopper. The similar catalysed amidation reaction of pillar[5]arene di(oxybutoxy)benzoic acid with monoamido functionalized pillar[5]arenes resulted in the diamido-bridged tris pillar[5]arenes, which successfully form the unique bis-[1]rotaxanes bearing longer than diaminopropylene diamido bridges. PMID- 30013693 TI - beta-Hydroxy sulfides and their syntheses. AB - Sulfur-containing natural products are ubiquitous in nature, their most abundant source being marine organisms since sulfur, in the form of the sulfate ion, is the second most abundant anion in sea water after chloride. As part of natural products, sulfur can appear in a multitude of combinations and oxidation states: thiol, sulfide (acyclic or heterocyclic), disulfide, sulfoxide, sulfonate, thioaminal, hemithioacetal, various thioesters, thiocarbamate and isothiocyanate. This review article focuses on beta-hydroxy sulfides and analogs; their presence in natural products, general protocols for their synthesis, and examples of their application in target oriented synthesis. PMID- 30013694 TI - Natural and redesigned wasp venom peptides with selective antitumoral activity. AB - About 1 in 8 U.S. women (~12%) will develop invasive breast cancer over the course of their lifetime. Surgery, chemotherapy, radiotherapy, and hormone manipulation constitute the major treatment options for breast cancer. Here, we show that both a natural antimicrobial peptide (AMP) derived from wasp venom (decoralin, Dec-NH2), and its synthetic variants generated via peptide design, display potent activity against cancer cells. We tested the derivatives at increasing doses and observed anticancer activity at concentrations as low as 12.5 MUmol L-1 for the selective targeting of MCF-7 breast cancer cells. Flow cytometry assays further revealed that treatment with wild-type (WT) peptide Dec NH2 led to necrosis of MCF-7 cells. Additional atomic force microscopy (AFM) measurements indicated that the roughness of cancer cell membranes increased significantly when treated with lead peptides compared to controls. Biophysical features such as helicity, hydrophobicity, and net positive charge were identified to play an important role in the anticancer activity of the peptides. Indeed, abrupt changes in peptide hydrophobicity and conformational propensity led to peptide inactivation, whereas increasing the net positive charge of peptides enhanced their activity. We present peptide templates with selective activity towards breast cancer cells that leave normal cells unaffected. These templates represent excellent scaffolds for the design of selective anticancer peptide therapeutics. PMID- 30013695 TI - Magnetic-field-induced phase separation via spinodal decomposition in epitaxial manganese ferrite thin films. AB - In this study, we report about the occurrence of phase separation through spinodal decomposition (SD) in spinel manganese ferrite (Mn ferrite) thin films grown by Dynamic Aurora pulsed laser deposition. The driving force behind this SD in Mn ferrite films is considered to be an ion-impingement-enhanced diffusion that is induced by the application of magnetic field during film growth. The phase separation to Mn-rich and Fe-rich phases in Mn ferrite films is confirmed from the Bragg's peak splitting and the appearance of the patterned checkerboard like domain in the surface. In the cross-sectional microstructure analysis, the distribution of Mn and Fe-signals alternately changes along the lateral (x and y) directions, while it is almost homogeneous in the z-direction. The result suggests that columnar-type phase separation occurs by the up-hill diffusion only along the in-plane directions. The propagation of a quasi-sinusoidal compositional wave in the lateral directions is confirmed from spatially resolved chemical composition analysis, which strongly demonstrates the occurrence of phase separation via SD. It is also found that the composition of Mn-rich and Fe rich phases in phase-separated Mn ferrite thin films deposited at higher growth temperature and in situ magnetic field does not depend on the corresponding average film composition. PMID- 30013696 TI - Understanding the Use of Composite Endpoints in Clinical Trials. AB - Clinicians, institutions, healthcare networks, and policymakers use outcomes reported in clinical trials as the basis for medical decision-making when managing individual patients or populations. Therefore, the choice of a valid primary endpoint is crucial for randomized controlled trials (RCT) to demonstrate efficacy of new therapies. Recent improvements in treatment, however, have led to a decline in the morbidity and mortality of several common diseases, resulting in a reduction in relevant outcomes that can be used as clinical trial endpoints. Composite endpoints have been used as a solution to maintain the feasibility of RCTs, particularly when facing low event rates, high cost, and long follow-up. However, the benefits of using composite endpoints must be weighed against the risks of misinterpretation by clinicians and policymakers, as incorrect interpretation may have a detrimental effect on patients and populations. This paper defines a composite endpoint, discusses the rationale for its use, and provides a practical approach to interpreting results to aid in medical decision making. PMID- 30013697 TI - Emergency Department Time Course for Mild Traumatic Brain Injury Workup. AB - Introduction: Mild traumatic brain injury (mTBI) is a common cause for visits to the emergency department (ED). The actual time required for an ED workup of a patient with mTBI in the United States is not well known. National emergency medicine organizations have recommended reducing unnecessary testing, including head computed tomography (CT) for these patients.10. Methods: To examine this issue, we developed a care map that included each step of evaluation of mTBI (Glasgow Coma Scale Score 13-15) - from initial presentation to the ED to discharge. Time spent at each step was estimated by a panel of United States emergency physicians and nurses. We subsequently validated time estimates using retrospectively collected, real-time data at two EDs. Length of stay (LOS) time differences between admission and discharged patients were calculated for patients being evaluated for mTBI. Results: Evaluation for mTBI was estimated at 401 minutes (6.6 hours) in EDs. Time related to head CT comprised about one-half of the total LOS. Real-time data from two sites corroborated the estimate of median time difference between ED admission and discharge, at 6.3 hours for mTBI. Conclusion: Limiting use of head CT as part of the workup of mTBI to more serious cases may reduce time spent in the ED and potentially improve overall ED throughput. PMID- 30013698 TI - Geospatial Clustering of Opioid-Related Emergency Medical Services Runs for Public Deployment of Naloxone. AB - Introduction: The epidemic of opioid use disorder and opioid overdose carries extensive morbidity and mortality and necessitates a multi-pronged, community level response. Bystander administration of the opioid overdose antidote naloxone is effective, but it is not universally available and requires consistent effort on the part of citizens to proactively carry naloxone. An alternate approach would be to position naloxone kits where they are most needed in a community, in a manner analogous to automated external defibrillators. We hypothesized that opioid overdoses would show geospatial clustering within a community, leading to potential target sites for such publicly deployed naloxone (PDN). Methods: We performed a retrospective chart review of 700 emergency medical service (EMS) runs that involved opioid overdose or naloxone administration in Cambridge, Massachusetts, between October 16, 2016 and May 10, 2017. We used geospatial analysis to examine for clustering in general, and to identify specific clusters amenable to PDN sites. Results: Opioid-related emergency medical services (EMS) runs in Cambridge, Massachusetts (MA), exhibit significant geospatial clustering, and we identified three clusters of opioid-related EMS runs in Cambridge, MA, with distinct characteristics. Models of PDN sites at these clusters show that approximately 40% of all opioid-related EMS runs in Cambridge, MA, would be accessible within 200 meters of PDN sites placed at cluster centroids. Conclusion: Identifying clusters of opioid-related EMS runs within a community may help to improve community coverage of naloxone, and strongly suggests that PDN could be a useful adjunct to bystander-administered naloxone in stemming the tide of opioid-related death. PMID- 30013699 TI - Systemwide Clinical Ultrasound Program Development: An Expert Consensus Model. AB - Clinical ultrasound (CUS) is integral to the practice of an increasing number of medical specialties. Guidelines are needed to ensure effective CUS utilization across health systems. Such guidelines should address all aspects of CUS within a hospital or health system. These include leadership, training, competency, credentialing, quality assurance and improvement, documentation, archiving, workflow, equipment, and infrastructure issues relating to communication and information technology. To meet this need, a group of CUS subject matter experts, who have been involved in institution- and/or systemwide clinical ultrasound (SWCUS) program development convened. The purpose of this paper was to create a model for SWCUS development and implementation. PMID- 30013700 TI - Paramedic Out-of-hospital Cardiac Arrest Case Volume Is a Predictor of Return of Spontaneous Circulation. AB - Introduction: Many factors contribute to the survival of out-of-hospital cardiac arrest (OHCA). One such factor is the quality of resuscitation efforts, which in turn may be a function of OHCA case volume. However, few studies have investigated the OHCA case volume-survival relationship. Consequently, we sought to develop a model describing the likelihood of return of spontaneous circulation (ROSC) as a function of paramedic cumulative OHCA experience. Methods: We conducted a statewide retrospective study of cardiac arrest using the North Carolina Prehospital Care Reporting System. Adult patients suffering a witnessed, non-traumatic cardiac arrest between January 2012 and June 2014 were included. Using logistic regression, we calculated an adjusted odds ratio (OR) for the influence of the preceding five-year paramedic OHCA case volume on ROSC while controlling for the potentially confounding variables identified a priori as patient age, gender, and non-Caucasian race; shockable presenting rhythm; layperson/first responder cardiopulmonary resuscitation (CPR); and emergency medical services (EMS) response time. Results: Of the 6,405 patients meeting inclusion criteria, 3,155 (49.3%) experienced ROSC. ROSC was more likely among patients treated by paramedics with >= 15 OHCA experiences during the preceding five years (OR [1.21], p<0.01). ROSC was also more likely among patients with shockable initial rhythms (OR [2.35], p<0.01) and who received layperson/first responder CPR (OR [1.77], p<0.01). Increasing patient age (OR [0.996], p=0.02), male gender (OR [0.742], p<0.01), and increasing EMS response time (OR [0.954], p<0.01) were associated with a decreased likelihood of ROSC. Non-Caucasian race was not an independent predictor of ROSC. Conclusion: We found that a paramedic five-year OHCA case volume of >= 15 is significantly associated with ROSC. Further study is needed to determine the specific actions of these more experienced paramedics who are responsible for the increased likelihood of ROSC, as well as the influence of case volume on the longer-term outcome measures of hospital discharge and neurological function. PMID- 30013701 TI - A Randomized Comparison of In-hospital Rescuer Positions for Endotracheal Intubation in a Difficult Airway. AB - Introduction: Emergency endotracheal intubation (ETI) is a common and critical procedure performed in both prehospital and in-hospital settings. Studies of prehospital providers have demonstrated that rescuer position influences ETI outcomes. However, studies of in-hospital rescuer position for ETI are limited. While we adhere to strict standards for the administration of ETI, we posited that perhaps requiring in-hospital rescuers to stand for ETI is an obstacle to effectiveness. Our objective was to compare in-hospital emergency medicine (EM) trainees' performance on ETI delivered from both the seated and standing positions. Methods: EM residents performed ETI on a difficult airway mannequin from both a seated and standing position. They were randomized to the position from which they performed ETI first. All ETIs were recorded and then scored using a modified version of the Airway Management Proficiency Checklist. Residents also rated the laryngeal view and the difficulty of the procedure. We analyzed comparisons between ETI positions with paired t-tests. Results: Forty-two of our 49 residents (85.7%) participated. Fifteen (35.7%) were female, and all three levels of training were represented. The average number of prior ETI experiences among our subjects was 44 (standard deviation=34). All scores related to ETI performance were statistically equivalent across the two positions (performance score, number of attempts, time to intubation success, and ratings of difficulty and laryngeal view). We also observed no differences across levels of training. Conclusion: The position of the in-hospital provider, whether seated or standing, had no effect on the provider's ETI performance. Since environmental circumstances sometimes necessitate alternative positioning for effective ETI administration, our findings suggest that there may be value in training residents to perform ETI from both positions. PMID- 30013702 TI - Simple Changes to Emergency Department Workflow Improve Analgesia in Mechanically Ventilated Patients. AB - Introduction: In 2013 the Society for Critical Care Medicine (SCCM) published guidelines for the management of pain and agitation in the intensive care unit (ICU). These guidelines recommend using an analgesia-first strategy in mechanically ventilated patients as well as reducing the use of benzodiazepines. Benzodiazepines increase delirium in ICU patients thereby increasing ICU length of stay. We sought to determine whether a simple educational intervention for emergency department (ED) staff, as well as two simple changes in workflow, would improve adherence to the SCCM guidelines. Methods: This was a cohort study that took place from 2014-2016. All patients who were intubated in the ED by an emergency physician (EP) during this time were eligible for inclusion in this study. In January 2015, we began an educational campaign with the ED staff consisting of a series of presentations and online trainings. The impetus for our educational campaign was to have best practices in place for our new emergency medicine residency program starting in July 2016. We made two minor changes in our ED workflow to support this educational objective. First, fentanyl infusions were stocked in the ED. Second, we instituted a medication order set for mechanically ventilated patients. This order set nudged EPs to choose medications consistent with the SCCM guidelines. We then evaluated the use of opioids and benzodiazepines in mechanically ventilated patients from 2014 through 2016 using Fisher's exact test. All analyses were conducted in the overall sample (n=509) as well as in subgroups after excluding patients with seizures/status epilepticus as their primary admission diagnosis (n=461). Results: In 2014 prior to the interventions, 41% of mechanically ventilated patients received an opioid, either as an intravenous (IV) push or IV infusion. In 2015 immediately after the intervention, 71% of patients received an opioid and 64% received an opioid in 2016. The use of benzodiazepine infusions decreased from 22% in 2014 to 7% in 2015 to 1% in 2016. Conclusion: A brief educational intervention along with two simple changes in ED workflow can improve compliance with the SCCM guidelines for the management of pain and agitation in mechanically ventilated patients. PMID- 30013703 TI - Using the Natural Experiment Study Design to Evaluate the Effect of a Change in Doctor's Roster on Patient Flow in an Emergency Department. AB - Introduction: The effect of changes in doctors' rosters is rarely subjected to scientific evaluation. We describe how a natural experiment (NE) study design can be used to evaluate if a managerial decision about doctors' rosters has an effect on patient flow in an emergency department (ED). We hypothesized that an extra doctor each morning from 6 a.m. (i.e., a modified "casino shift") might improve the productivity of a hospital's ED. Methods: This was an NE observational study using data on patient flow in the ED of Zealand University Hospital, Denmark, between April 1, 2016, and April 1, 2017. We compared days on which the 6 a.m. emergency physician called in sick (case days) with data from the same weekday a week later where staffing was as scheduled (control days). Results: Patient caseload did not did differ significantly on days with and without the extra doctor from 6 a.m. (measured by number of admissions, triage scores and mean patient age). Door-to-doctor time was 70 minutes (mean, standard deviation [SD], 49) on days without the extra doctor and 56 minutes (mean, SD 41) on days with the early-morning doctor present (p > 0.05). ED length of stay was 250 minutes (mean, SD 119) on days without the extra doctor and 209 minutes (mean, SD 109) on days with the early-morning doctor present (p > 0.05). Conclusion: In our setting, an extra doctor in the ED from 6 a.m. did not change patient flow. These results suggest that the workflow in the ED should be viewed as a connected supply chain. The study also demonstrates that a natural experiment study design can be used to evaluate ED managerial decisions. PMID- 30013705 TI - Cost of Routine Herpes Simplex Virus Infection Visits to U.S. Emergency Departments 2006-2013. AB - Introduction: Little is known about emergency department (ED) utilization for herpes simplex viruses (HSV) types 1 and 2 in the United States. Our goal was to determine the utilization and cost burden associated with HSV infection visits to U.S. EDs in recent years from 2006-2013. Methods: We analyzed the Nationwide Emergency Department Sample (NEDS) database, the largest national database of hospital-based ED visits in the U.S., to determine the number of visits and the cost associated with HSV visits from 2006-2013. We also analyzed trends across years. Results: From 2006-2013, there were 704,728 ED visits with a primary diagnosis of HSV infection. Of these, 658,805 (93.5%) resulted in routine discharges without inpatient admission, amounting to a total ED charge of $543.0 million. After adjusting for inflation, there was a doubling of total ED spending for HSV from 2006 to 2013 ($45.0 million to $90.7 million) and a 24% increase in number of visits (73,227 visits in 2006, vs. 90,627 visits in 2013). ED visits for genital herpes have increased while visits for herpes gingivostomatitis have decreased. Conclusion: HSV-associated ED use and associated costs have increased between 2006-2013. Most of these cases could likely be managed in non-emergent outpatient settings as 93.5% of visits resulted in routine discharges without admission. Our findings add to knowledge regarding HSV utilization and epidemiology in the U.S. and highlight the need for continued prevention, patient education, and emphasis of care in non-emergency settings to prevent unnecessary ED utilization. PMID- 30013704 TI - Opioid Administration and Prescribing in Older Adults in U.S. Emergency Departments (2005-2015). AB - Introduction: We assess trends in opioid administration and prescribing from 2005 2015 in older adults in United States (U.S.) emergency departments (ED). Methods: We analyzed data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) survey from 2005 to 2015. ED visits for painful conditions were selected and stratified by age (18-64, 65-74, 75-84, >= 85 years). We analyzed trends in opioid administration in the ED and prescribing at discharge to encounters >= 65 and assessed predictors of use using survey-weighted chi-square tests and logistic regression. Trends in the use of five commonly prescribed opioids were also explored. Results: Opioid administration in the ED and prescribing at discharge for encounters with patients >= 65 years fell overall, but not significantly. By contrast, opioid administration in the ED and prescribing at discharge significantly declined for adult encounters 18-64 by 20% and 32%, respectively. A similar proportion of adult encounters >= 65 were administered opioids in the ED as 18-64, but adult encounters >= 85 had the lowest rates of administration. A smaller proportion of adult encounters >= 65 years with painful conditions were prescribed opioids at discharge compared to <65. However, this age-related disparity in prescribing narrowed over the study period. There were shifts in the specific types of opioids administered and prescribed in adult encounters >= 65 years over the study period, with the most notable being a 76% increase in hydromorphone administration comparing 2005-06 to 2014-15. Conclusion: From 2005-15, 1 in 4 to 1 in 10 ED patients with painful conditions were administered or prescribed an opioid in U.S. EDs. Opioids prescribing increased from 2005-11 and then declined from 2012-15, more so among visits in the 18-64 age group compared to >= 65 years. Opioid administrating demonstrated a gradual rise and decline in all adult age groups. Age consistently appears to be an important consideration, where opioid prescribing declines with advancing age. Given the nationwide opioid crisis, ED providers should remain vigilant in limiting opioids, particularly in older adults who are at higher risk for adverse effects. PMID- 30013706 TI - Anaphylaxis-related Malpractice Lawsuits. AB - Introduction: Anaphylaxis continues to cause significant morbidity and mortality. Healthcare providers struggle to promptly recognize and appropriately treat anaphylaxis patients. The goal of this study was to characterize anaphylaxis related malpractice lawsuits. Methods: We collected jury verdicts, settlements, and court opinions regarding alleged medical malpractice involving anaphylaxis from May 2011 through May 2016 from an online legal database (Thomson Reuters Westlaw). Data were abstracted onto a standardized data form. Results: We identified 30 anaphylaxis-related malpractice lawsuits. In 80% of cases, the trigger was iatrogenic (40% intravenous [IV] contrast, 33% medications, 7% latex). Sixteen (53%) cases resulted in death, 7 (23%) in permanent cardiac and/or neurologic damage, and 7 (23%) in less severe outcomes. Fourteen (47%) of the lawsuits were related to exposure to a known trigger. Delayed recognition or treatment was cited in 12 (40%) cases and inappropriate IV epinephrine dosing was reported in 5 (17%) cases. Defendants were most commonly physicians (n=15, 50%) and nurses (n=5, 17%). The most common physician specialties named were radiology and primary care (n=3, 10% each), followed by emergency medicine, anesthesiology, and cardiology (n=2, 7% each). Among the 30 cases, 14 (47%) favored the defendant, 8 (37%) resulted in findings of negligence, 3 (10%) cases settled, and 5 (17%) had an unknown legal outcome. Conclusion: Additional anaphylaxis education, provision of epinephrine autoinjectors or other alternatives to reduce dosing errors, and stronger safeguards to prevent administration of known allergens would all likely reduce anaphylaxis-related patient morbidity and mortality and providers' legal vulnerability to anaphylaxis-related lawsuits. PMID- 30013707 TI - Initial Standardized Framework for Reporting Social Media Analytics in Emergency Care Research. AB - The use of social media platforms to disseminate information, translate knowledge, change clinical care and create communities of practice is becoming increasingly common in emergency and critical care. With this adoption come new lines and methods of inquiry for research in healthcare. While tools exist to standardize the reporting of clinical studies and systematic reviews, there is no agreed framework for examining social media-based research. This article presents a publication and appraisal checklist for such work and invites further collaboration in the form of a Delphi technique to clarify, expand, improve, and validate the proposal. PMID- 30013708 TI - Suffocation Injuries in the United States: Patient Characteristics and Factors Associated with Mortality. AB - Introduction: Asphyxiation or suffocation injuries can result in multi-organ damage and are a major cause of morbidity and mortality among different age groups. This study aims to describe characteristics of patients presenting with suffocation injuries to emergency departments (EDs) in the United States (U.S.) and to identify factors associated with mortality in this population. Methods: We conducted a retrospective cross-sectional study using the 2013 U.S National Emergency Department Sample database. ED visits with primary diagnoses of intentional or accidental suffocation injury, and injury by inhalation and aspiration of foreign bodies or food (ICD-9-CM codes) were included. We performed descriptive statistics to describe the study population. This was followed by multivariate analyses to identify factors associated with mortality. Results: We included a total of 27,381 ED visits for suffocation injuries. Most suffered from either inhalation and ingestion of food causing obstruction of respiratory tract or suffocation (51.6%), or suicide and self-inflicted injury by hanging, strangulation, and suffocation (39.4%). Overall mortality was 10.9%. Over half (54.7%) of the patients were between 19 and 65 years old. Males were more common than females (59.1% vs. 40.9%). Over half of the patients (54.9%) were treated and released from the ED. Factors associated with increased mortality included male gender, young age (4-18 years), diseases of the cardiac, respiratory, genitourinary and neurologic systems, intentional self-harm, and self-payer status. Conclusion: Mortality from suffocation injuries remains high with significant burden on children and adolescents and on patients with intentional injuries. Tailored initiatives targeting identified modifiable factors through implementation of behavioral and environmental change can reduce the risk of suffocation injury and improve clinical outcomes of affected victims. PMID- 30013709 TI - Computed Tomography Risk Disclosure in the Emergency Department: A Survey of Pediatric Emergency Medicine Fellowship Program Leaders. AB - Introduction: Given the potential malignancy risks associated with computed tomography (CT), some physicians are increasingly advocating for risk disclosure to patients/families. Our goal was to evaluate the practices and attitudes of pediatric emergency medicine (PEM) fellowship program leaders' regarding CT radiation-risk disclosure. Methods: We conducted a cross-sectional survey study of the United States and Canadian PEM fellowship directors and associate/assistant directors. We developed a web-based survey using a modified Dillman technique. Primary outcome was the proportion who "almost always" or "most of the time" discussed potential malignancy risks from CT prior to ordering this test. Results: Of 128 physicians who received the survey, 108 (86%) responded. Of those respondents, 73%, 95% confidence interval (CI) [64-81] reported "almost always" or "most of the time" discussing potential malignancy risks when ordering a CT for infants; proportions for toddlers, school-age children, and teenagers were 72% (95% CI [63-80]), 66% (95% CI [56-75]), and 58% (95% CI [48-67]), respectively (test for trend, p=0.008). Eighty percent reported being "extremely" or "very" comfortable discussing radiation risks. Factors of "high" or "very high" importance in disclosing risks included parent request for a CT not deemed clinically indicated for 94% of respondents, and parent-initiated queries about radiation risks for 79%. If risk disclosure became mandatory, 82% favored verbal discussion over written informed consent. Conclusion: PEM fellowship program leaders report frequently disclosing potential malignancy risks from CT, with the frequency varying inversely with patient age. Motivating factors for discussions included parental request for a CT deemed clinically unnecessary and parental inquiry about risks. PMID- 30013710 TI - Patient Preference for Pain Medication in the Emergency Department Is Associated with Non-fatal Overdose History. AB - Introduction: Opioid overdose is a major public health problem. Emergency physicians need information to better assess a patient's risk for overdose or opioid-related harms. The purpose of this study was to determine if patient reported preference for specific pain medications was associated with a history of lifetime overdose among patients seeking care in the emergency department (ED). Methods: ED patients (18-60 years) completed a screening survey that included questions on overdose history, ED utilization, opioid misuse behaviors as measured by the Current Opioid Misuse Measure (COMM), and analgesic medication preferences for previous ED visits for pain with specific responses for preference for hydromorphone (Dilaudid(r)), morphine, ketorolac (Toradol(r)), "no preference" or "never visited the ED for pain." We compared individuals who reported a lifetime history of overdose descriptively to those without a lifetime history of overdose. Logistic regression was used to determine factors associated with a history of overdose. Results: We included 2,233 adults in the analysis (71.5% response rate of patients approached) with 532 reporting at least one lifetime overdose. In the univariate analysis, medication preference was significantly associated with overdose history (p < .001); more patients in the overdose group reported preferring morphine and hydromorphone and those without a history of overdose were more likely to have no preference or say they had never visited the ED for pain. In the logistic regression analysis, patients with higher odds of overdose included those of Caucasian race, participants with a higher COMM score, preference for ketorolac, morphine or hydromorphone. Those who were younger, female and reported never having visited the ED for pain had lower odds of reporting a lifetime overdose. Having "any preference" corresponded to 48% higher odds of lifetime overdose. Conclusion: Patients with a pain medication preference have higher odds of having a lifetime overdose compared to patients without a specific pain medication preference, even after accounting for level of opioid misuse. This patient-reported preference could cue emergency physicians to identifying high-risk patients for overdose and other substance-related harms. PMID- 30013712 TI - Proceed with Caution Before Assigning "Red Flags" in Residency Applications. PMID- 30013711 TI - Transaminase and Creatine Kinase Ratios for Differentiating Delayed Acetaminophen Overdose from Rhabdomyolysis. AB - Introduction: Rhabdomyolysis and delayed acetaminophen hepatotoxicity may be associated with elevated serum transaminase values. Establishing the cause of elevated transaminases may be especially difficult because of limited or inaccurate histories of acetaminophen ingestion. We hypothesized that the comparative ratios of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) can differentiate acetaminophen hepatotoxicity from rhabdomyolysis. Methods: A retrospective chart review of patients in four hospitals from 2006 to 2011 with a discharge diagnosis of acetaminophen toxicity or rhabdomyolysis was performed. Subjects were classified into three groups: rhabdomyolysis, acetaminophen overdose (all), and acetaminophen overdose with undetectable serum acetaminophen concentrations [acetaminophen(delayed)]. Ratios of AST, ALT, and CK were compared using non-parametric statistical methods. Results: 1,353 subjects were identified and after applying our exclusion criteria there were 160 in the rhabdomyolysis group, 68 in the acetaminophen overdose (all) group, and 29 in the acetaminophen (delayed) group. The AST/ALT ratio for the rhabdomyolysis group was 1.66 (Interquartile range: 1.18-2.22), for the acetaminophen overdose (all) group was 1.38 (1.08-1.69, statistically lower than the rhabdomyolysis group, p = 0.018), and for the acetaminophen (delayed)group was 1.30 (1.06-1.63, p = 0.037). CK/AST ratios were 21.3 (12.8-42.2), 5.49 (2.52 15.1, p < 0.001), and 3.80 (1.43-13.8, p < 0.001) respectively. CK/ALT ratios were 37.1 (16.1-80.0), 5.77 (2.79-25.2, p < 0.001), and 5.03 (2.20-17.4, p < 0.001) respectively. Increasing CK to transaminase ratio cutoffs resulted in increasing test sensitivity but lower specificity. Conclusion: AST/ALT, CK/AST and CK/ALT ratios are significantly larger in rhabdomyolysis when compared to patients with acetaminophen toxicity. This result suggests that the ratios could be used to identify patients with rhabdomyolysis who otherwise might have been diagnosed as delayed acetaminophen toxicity. Such patients may not require treatment with N-acetylcysteine, resulting in cost savings and improved resource utilization. PMID- 30013713 TI - Closing the Gap Between Entrustment and Resuscitation. PMID- 30013714 TI - Scholarship in Emergency Medicine: A Primer for Junior Academics: Part II: Promoting Your Career and Achieving Your Goals. AB - Scholarship is an important component of success for academic emergency physicians. Scholarship can take many forms, but all require careful planning. In this article, we provide expert consensus recommendations for improving junior faculty's scholarship in emergency medicine (EM). Specific focus is given to promoting your research career, obtaining additional training opportunities, networking in EM, and other strategies for strategically directing a long-term career in academic medicine. PMID- 30013716 TI - Teaching Methods Utilized During Medical Resuscitations in an Academic Emergency Department. AB - Introduction: One important skill that an emergency medicine trainee must learn is the resuscitation of the critically ill patient. There is research describing clinical teaching strategies used in the emergency department (ED), but less is known about specific methods employed during actual medical resuscitations. Our objective was to identify and describe the teaching methods used during medical resuscitations. Methods: This was a prospective study involving review of 22 videotaped, medical resuscitations. Two teams of investigators first each reviewed and scored the amount and types of teaching observed for the same two videos. Each team then watched and scored 10 different videos. We calculated a Cohen's kappa statistic for the first two videos. For the remaining 20 videos, we determined means and standard deviations, and we calculated independent two tailed t-tests to compare means between different demographic and clinical situations. Results: The Cohen's kappa statistic was K=0.89 with regard to number of teaching events and K=0.82 for types of teaching observed. Of the resuscitations reviewed, 12 were in coding patients. We identified 148 episodes of teaching, for an average of 7.4 per resuscitation. The amount of teaching did not vary with regard to whether the patient was coding or not (p=0.97), nor based on whether the primary learner was a junior or senior resident (p=0.59). Questioning, affirmatives and advice-giving were the most frequently observed teaching methods. Conclusion: Teachers use concise teaching methods to instruct residents who lead medical resuscitations. Further research should focus on the effectiveness of these identified strategies. PMID- 30013715 TI - Journal Club in Residency Education: An Evidence-based Guide to Best Practices from the Council of Emergency Medicine Residency Directors. AB - Journal clubs are an important tool for critically appraising articles and keeping up-to-date with the current literature. This paper provides a critical review of the literature on the design and structure of journal clubs in residency education with a focus on preparation, topic selection, implementation, and integration of technology. Recommendations for preparation include developing clearly defined goals and objectives that are agreed upon by all journal club participants; mentorship from experienced faculty members to ensure appropriate article selection, maintenance of structure, and applicability to objectives; distribution of articles to participants 1-2 weeks prior to the scheduled session with reminders to read the articles at predetermined intervals; and the use of a structured critical appraisal tool for evaluating the articles. Recommendations for topic selection include selecting a primary objective of either critical appraisal or informing clinical practice and ensuring that the articles align with the objective; involving learners in the topic- and article-selection process; and having the article selection driven by a specific clinical question. Recommendations for implementation include hosting sessions in the evening and away from the hospital environment; providing food to participants; hosting meetings on a monthly basis at regularly scheduled intervals; mandating journal club attendance; and using theories of adult learning. Recommendations for integration of technology include using previously established, effective strategies and determining the feasibility of creating an online journal club versus joining an established journal club. It is the authors' intention that after reading this paper readers will have new strategies and techniques for implementing and running a journal club at their home institutions. PMID- 30013717 TI - A Targeted Mindfulness Curriculum for Medical Students During Their Emergency Medicine Clerkship Experience. AB - Introduction: Despite high rates of burnout in senior medical students, many schools provide the majority of their wellness training during the first and second preclinical years. Students planning a career in emergency medicine (EM) may be at particularly high risk of burnout, given that EM has one of the highest burnout rates of all the specialties in the United States We developed an innovative, mindfulness-based curriculum designed to be integrated into a standard EM clerkship for senior medical students to help students manage stress and reduce their risk of burnout. Methods: The curriculum included these components: (1) four, once-weekly, 60-minute classroom sessions; (2) prerequisite reading assignments; (3) individual daily meditation practice and journaling; and (4) the development of a personalized wellness plan with the help of a mentor. The design was based on self-directed learning theory and focused on building relatedness, competence, and autonomy to help cultivate mindfulness. Results: Thirty students participated in the curriculum; 20 were included in the final analysis. Each student completed surveys prior to, immediately after, and six months after participation in the curriculum. We found significant changes in the self-reported behaviors and attitudes of the students immediately following participation in the curriculum, which were sustained up to six months later. Conclusion: Although this was a pilot study, our pilot curriculum had a significantly sustained self-reported behavioral impact on our students. In the future, this intervention could easily be adapted for any four-week rotation during medical school to reduce burnout and increase physician wellness. PMID- 30013718 TI - Persistent Increased Frequency of Genomic Instability in Women Diagnosed with Breast Cancer: Before, during, and after Treatments. AB - This study aimed to evaluate DNA damage in patients with breast cancer before treatment (background) and after chemotherapy (QT) and radiotherapy (RT) treatment using the Comet assay in peripheral blood and the micronucleus test in buccal cells. We also evaluated repair of DNA damage after the end of RT, as well as the response of patient's cells before treatment with an oxidizing agent (H2O2; challenge assay). Fifty women with a mammographic diagnosis negative for cancer (control group) and 100 women with a diagnosis of breast cancer (followed up during the treatment) were involved in this study. The significant DNA damage was observed by increasing in the index and frequency of damage along with the increasing of the frequency of micronuclei in peripheral blood and cells of the buccal mucosa, respectively. Despite the variability of the responses of breast cancer patients, the individuals presented lesions on the DNA, detected by the Comet assay and micronucleus Test, from the diagnosis until the end of the oncological treatment and were more susceptible to oxidative stress. We can conclude that the damages were due to clastogenic and/or aneugenic effects related to the neoplasia itself and that they increased, especially after RT. PMID- 30013719 TI - Mangiferin and Morin Attenuate Oxidative Stress, Mitochondrial Dysfunction, and Neurocytotoxicity, Induced by Amyloid Beta Oligomers. AB - Amyloid beta- (Abeta-) mediated ROS overproduction disrupts intraneuronal redox balance and exacerbates mitochondrial dysfunction which leads to neuronal injury. Polyphenols have been investigated as therapeutic agents that promote neuroprotective effects in experimental models of brain injury and neurodegenerative diseases. The aim of this study was to identify the neuroprotective effects of morin and mangiferin against Abeta oligomers in cultured cortical neurons and organotypic slices as well as their mechanisms of action. Cell death caused by Abeta oligomers in neuronal cultures was decreased in the presence of micromolar concentrations of mangiferin or morin, which in turn attenuated oxidative stress. The neuroprotective effects of antioxidants against Abeta were associated with the reduction of Abeta-induced calcium load to mitochondria; mitochondrial membrane depolarization; and release of cytochrome c from mitochondria, a key trigger of apoptosis. Additionally, we observed that both polyphenols activated the endogenous enzymatic antioxidant system and restored oxidized protein levels. Finally, Abeta induced an impairment of energy homeostasis due to a decreased respiratory capacity that was mitigated by morin and mangiferin. Overall, the beneficial effects of polyphenols in preventing mitochondrial dysfunction and neuronal injury in AD cell models suggest that morin and mangiferin hold promise for the treatment of this neurological disorder. PMID- 30013720 TI - Exposure to Ti4Al4V Titanium Alloy Leads to Redox Abnormalities, Oxidative Stress, and Oxidative Damage in Patients Treated for Mandible Fractures. AB - Due to the high biotolerance, favourable mechanical properties, and osseointegration ability, titanium is the basic biomaterial used in maxillofacial surgery. The passive layer of titanium dioxide on the surface of the implant effectively provides anticorrosive properties, but it can be damaged, resulting in the release of titanium ions to the surrounding tissues. The aim of our work was to evaluate the influence of Ti6Al4V titanium alloy on redox balance and oxidative damage in the periosteum surrounding the titanium miniplates and screws as well as in plasma and erythrocytes of patients with mandibular fractures. The study included 31 previously implanted patients (aged 21-29) treated for mandibular fractures and 31 healthy controls. We have demonstrated increased activity/concentration of antioxidants both in the mandibular periosteum and plasma/erythrocytes of patients with titanium mandibular fixations. However, increased concentrations of the products of oxidative protein and lipid modifications were only observed in the periosteum of the study group patients. The correlation between the products of oxidative modification of the mandible and antioxidants in plasma/erythrocytes suggests a relationship between the increase of oxidative damage at the implantation site and central redox disorders in patients with titanium miniplates and screws. PMID- 30013721 TI - The Effects of Buckwheat Leaf and Flower Extracts on Antioxidant Status in Mouse Organs. AB - This study was undertaken to investigate the effects of the extracts of buckwheat leaf and flower on the antioxidant status of the brain and liver tissue. The administration of buckwheat extracts (both concentrations were 10%) to mice (at the dose 10 mL/kg of body weight) for 21 days significantly decreased superoxide dismutase (SOD) activity and reduced the amount of glutathione (GSH) and malondialdehyde (MDA) in the mouse brain, while catalase (CAT) activity significantly increased. In the mouse liver, the amount of GSH and activity of SOD increased, while the CAT activity after administering buckwheat leaf and flower extracts was lower in experimental mice than in the control group. However, the administration of 10% ethanol (for 21 days) to control animals also had a significant effect on the antioxidant system in brain and liver cells. Experimental animals demonstrated rather marked changes in the activities of the antioxidant enzymes SOD and CAT in their liver and brain cells, and changes in the levels of GSH and MDA were observed when compared with the control group. PMID- 30013722 TI - Evaluation of the Protective Effect of Olive Leaf Extract on Cisplatin-Induced Testicular Damage in Rats. AB - In the present investigation, the effect of olive leaf extract (OLE) on testicular damage induced in rats by an intraperitoneal injection of cisplatin (cis-diamminedichloroplatinum (CDDP)) at a dose of 5 mg/kg was tested. Rats were randomly divided into 4 groups: control, CDDP, OLE, and OLE + CDDP. After 5 days of CDDP treatment, body and testicular weights, histopathological alteration, and serum male sex hormone levels were determined. In addition to the biochemical and immunohistochemical changes in the testes, CDDP caused the disorganization of germinal epithelium and apoptosis by inducing Bax and inhibiting Bcl-2 protein expression. Testicular weights, catalase, serum testosterone, testicular enzymatic (including glutathione peroxidase, glutathione reductase, and superoxide dismutase) along with nonenzymatic (glutathione) antioxidants, and levels of luteinizing and follicle-stimulating hormones were significantly reduced in addition to a significant increase in testicular malondialdehyde and nitrite/nitrate levels when compared with the control group. OLE treatment markedly attenuated both biochemical and histopathological changes. The reproductive beneficial effects of OLE were mediated, at least partly, by inducing the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. PMID- 30013723 TI - Characterization of oral microbiota and acetaldehyde production. AB - Background: Neisseria has been reported to be a high producer of acetaldehyde (ACH), a carcinogen, from ethanol in vitro, but no information exists regarding whether the ACH production depends on oral microbiota profiles. Objective and Design: To explore the salivary microbiota profiles with respect to ACH production ability in the oral cavity using a cross-sectional design. Results: Using 16S rRNA gene amplicon sequencing, we classified 100 saliva samples into two types of communities (I and II). Salivary ACH production ability from ethanol was measured using gas chromatography and was found to vary over a 30-fold range. ACH production ability was significantly higher in the type I community, wherein the relative abundance of Neisseria species was significantly lower. Multivariate logistic regression analysis showed that the subjects with the type I community exhibited significantly higher probability of high ACH production ability than those with the type II community (P = 0.014). Moreover, the relative abundance of Neisseria species was inversely correlated with the ACH production ability (P = 0.002). Conclusion: The salivary microbiota profile with a lower relative abundance of Neisseria species was independently associated with high ACH production ability, despite Neisseria species are dominant producers of ACH in vitro. PMID- 30013724 TI - Deployment-related trauma and post-traumatic stress disorder: does gender matter? AB - Objective: Military research has attempted to identify whether women have an increased vulnerability to mental health issues following deployment-related trauma, but findings have been mixed. Most studies have controlled for childhood abuse, but not other non-deployment trauma (e.g. life-threatening illness), which may partly explain previous mixed results. This study assessed gender differences in the association between deployment-related trauma and post-traumatic stress disorder (PTSD) while controlling for non-deployment trauma. Methods: Data came from the 2013 Canadian Forces Mental Health Survey. Regular or reserve personnel who had been deployed at least once were included in this study (n = 5980). Logistic regression was used to examine the interaction between gender and deployment-related trauma in predicting lifetime PTSD. Results: After controlling for non-deployment trauma, the association of gender with PTSD went from being significant to being marginally significant. The interaction between gender and deployment-related trauma was not significant. Conclusion: Though controlling for non-deployment trauma did not completely dissipate gender differences in PTSD, such differences were greatly reduced, indicating that these may be partly related to traumatic experiences outside deployment. As gender did not moderate the link between deployment-related trauma and PTSD, the findings suggest that trauma experienced while on deployment does not disproportionately affect women compared to their male counterparts. PMID- 30013725 TI - Perceived danger during deployment: a Rasch validation of an instrument assessing perceived combat exposure and the witnessing of combat consequences in a war zone. AB - The potential stressors associated with military deployment are related to an increased risk of adverse mental health outcomes. Perceived exposure to combat has been found to be proportional to the severity of post-deployment posttraumatic stress disorder (PTSD). However, other perceived adversities during deployment, such as witnessing danger, distress, and hardship in the war zone, have been less systematically studied, but might play an equally substantial role for post-deployment mental health. The development and validation of scales that assess these related constructs are needed to distinguish their contribution to post-deployment risk of PTSD. We evaluated the validity of 10 items measuring perceived danger distributed to all deployed personnel with the Danish Defense since 1998. We hypothesize two scales: Exposure to Danger and Combat (EDC) and Witnessing Consequences of War (WCW). Two military cohorts deployed to Afghanistan in 2009 (Cohort 1, N = 276) and 2013 (Cohort 2, N = 273) were included. Questionnaire data was collected six months after homecoming, including deployment experiences and post-deployment reactions. We tested the construct validity of the 10 items of perceived danger with Rasch models (RM), focusing specifically on presence of subscales, and differential item functioning (DIF) across cohorts. We confirmed the existence of two separate subscales, EDCS and WCWS, both with adequate reliability. None of the subscales fitted a pure RM, but adequate fit was found for graphical log-linear RMs with evidence of DIF for the ECDS. However, adjusting the score to account for DIF had practically no effect, suggesting that the total non-adjusted mean score can be used in future cohort comparisons. Perceived exposure to combat and danger and witnessing consequences of war are related, but essentially distinct, concepts, each providing unique information about deployment adversities. Future studies should evaluate their shared and unique contribution to the risk of post-deployment PTSD. PMID- 30013727 TI - ECG with alternating electric axis in relation to left-sided tension pneumothorax: a case report and review of the literature. AB - The incidence of spontaneous pneumothorax has been estimated to 7.4-18.0/100,000 for men and 1.2-6.0/100,000 for women. The most common symptoms are sudden chest pain and dyspnoea. Due to chest pain many patients have an electrocardiogram (ECG) done in the acute setting. We present a case of unusual findings of electric alternans in the electrocardiogram (ECG) in a patient with a left-sided spontaneous pneumothorax. Reviewing the literature we found five former cases of pneumothoraxes with electric alternans in the ECG, all occurring in relation to left-sided pneumothorax. PMID- 30013726 TI - Effectiveness of an intensive treatment programme combining prolonged exposure and eye movement desensitization and reprocessing for severe post-traumatic stress disorder. AB - Background: There is room for improvement regarding the treatment of severe post traumatic stress disorder (PTSD). Intensifying treatment to increase patient retention is a promising development. Objective: The aim of this study was to determine the effectiveness of an intensive trauma-focused treatment programme over 8 days for individuals suffering from severe PTSD. Method: Treatment was provided for 347 PTSD patients (70% women; mean age = 38.32 years, SD = 11.69) and consisted of daily sessions of prolonged exposure and eye movement desensitization and reprocessing (EMDR) therapy (16 sessions in total), physical activity, and psycho-education. All participants had experienced multiple traumas, including sexual abuse (74.4%), and suffered from multiple comorbidities (e.g. 87.5% had a mood disorder). Suicidal ideation was frequent (73.9%). PTSD symptom severity was assessed by both clinician-rated [Clinician Administered PTSD Scale (CAPS)] and self-report [PTSD Symptom Scale Self Report (PSS-SR) and Impact of Event Scale (IES)] inventories. For a subsample (n = 109), follow-up data at 6 months were available. Results: A significant decline in symptom severity was found (e.g. CAPS intention-to-treat sample Cohen's d = 1.64). At post-treatment, 82.9% showed a clinically meaningful response and 54.9% a loss of diagnosis. Dropout was very low (2.3%). Conclusions: Intensive trauma-focused treatment programmes including prolonged exposure, EMDR therapy, and physical activity can be effective for patients suffering from severe PTSD and are associated with low dropout rates. PMID- 30013728 TI - Three principles for radiation safety: time, distance, and shielding. PMID- 30013729 TI - Challenges in fibromyalgia diagnosis: from meaning of symptoms to fibromyalgia labeling. AB - Fibromyalgia (FM) is a contested illness with ill-defined boundaries. There is no clearly defined cut-point that separates FM from non-FM. Diagnosis of FM has been faced with several challenges that occur, including patients' health care-seeking behavior, symptoms recognition, and FM labeling by physicians. This review focuses on important but less visible factors that have a profound influence on under- or over-diagnosis of FM. FM shows different phenotypes and disease expression in patients and even in one patient over time. Psychosocial and cultural factors seem to be a contemporary ferment in FM which play a major role in physician diagnosis even more than having severe symptom levels in FM patients. Although the FM criteria are the only current methods which can be used for classification of FM patients in surveys, research, and clinical settings, there are several key pieces missing in the fibromyalgia diagnostic puzzle, such as invalidation, psychosocial factors, and heterogeneous disease expression. Regarding the complex nature of FM, as well as the arbitrary and illusory constructs of the existing FM criteria, FM diagnosis frequently fails to provide a clinical diagnosis fit to reality. A physicians' judgment, obtained in real communicative environments with patients, beyond the existing constructional scores, seems the only reliable way for more valid diagnoses. It plays a pivotal role in the meaning and conceptualization of symptoms and psychosocial factors, making diagnoses and labeling of FM. It is better to see FM as a whole, not as a medical specialty or constructional scores. PMID- 30013730 TI - Chronic postsurgical pain: current evidence for prevention and management. AB - Chronic postsurgical pain (CPSP) is an unwanted adverse event in any operation. It leads to functional limitations and psychological trauma for patients, and leaves the operative team with feelings of failure and humiliation. Therefore, it is crucial that preventive strategies for CPSP are considered in high-risk operations. Various techniques have been implemented to reduce the risk with variable success. Identifying the risk factors for each patient and applying a timely preventive strategy may help patients avoid the distress of chronic pain. The preventive strategies include modification of the surgical technique, good pain control throughout the perioperative period, and preoperative psychological intervention focusing on the psychosocial and cognitive risk factors. Appropriate management of CPSP patients is also necessary to reduce their suffering. CPSP usually has a neuropathic pain component; therefore, the current recommendations are based on data on chronic neuropathic pain. Hence, voltage-dependent calcium channel antagonists, antidepressants, topical lidocaine and topical capsaicin are the main pharmacological treatments. Paracetamol, NSAIDs and weak opioids can be used according to symptom severity, but strong opioids should be used with great caution and are not recommended. Other drugs that may be helpful are ketamine, clonidine, and intravenous lidocaine infusion. For patients with failed pharmacological treatment, consideration should be given to pain interventions; examples include transcutaneous electrical nerve stimulation, botulinum toxin injections, pulsed radiofrequency, nerve blocks, nerve ablation, neuromodulation and surgical management. Physical therapy, cognitive behavioral therapy and lifestyle modifications are also useful for relieving the pain and distress experienced by CPSP patients. PMID- 30013731 TI - Orexin-A inhibits capsaicin-induced changes in cyclooxygenase-2 and brain-derived neurotrophic factor expression in trigeminal nucleus caudalis of rats. AB - Background: The trigeminal nucleus caudalis (Vc) is a primary central site for trigeminal transmitting. Noxious stimulation of the trigeminal nociceptors alters the central synaptic releases and neural expression of some inflammatory and trophic agents. Orexin-A and the orexin 1 receptor (OX1R) are expressed in pain pathways including trigeminal pain transmission. However, the the mechanism(s) underling orexin-A effects on trigeminal pain modulation have not been fully clarified. Methods: Trigeminal pain was induced by subcutaneous injection of capsaicin in the upper lip in rats. The effect of trigeminal pain on cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) expression in the Vc of animals was determined by immunofluorescence. Subsequently, OX1R agonist (orexin-A) and antagonist (SB-334867-A) was administrated in the Vc to investigate the possible roles of the Vc OX1R on changes in COX-2 and BDNF levels following pain induction. Results: The data indicated an increase in COX-2 and decrease in BDNF immuno-reactivity in the Vc of capsaicin, and capsaicin- pretreated with SB-334867-A (80 nM), groups of rat. However, the effect of capsaicin on COX-2 and BDNF expressions was reversed by a Vc microinjection of orexin-A (100 pM). Conclusions: Overall, the present data reveals that orexin-A can attenuate capsaicin-induced trigeminal pain through the modulation of pain effects on COX-2 and BDNF expressions in the Vc of rats. PMID- 30013732 TI - A randomized, open labeled study comparing the serum levels of cobalamin after three doses of 500 mcg vs. a single dose methylcobalamin of 1500 mcg in patients with peripheral neuropathy. AB - Background: Vitamin B12 deficiency has been associated with peripheral neuropathy, loss of sensation in the peripheral nerves, and weakness in the lower extremities. Methylcobalamin is the most effective analogue of vitamin B12 used to treat or prevent the complications associated with vitamin B12 deficiency. The current study aimed to compare the serum cobalamin levels after administration of two different regimes of methylcobalamin in peripheral neuropathy patients. Methods: The present study was a prospective, randomized, comparative study. The study consisted of two parallel groups, group A (methylcobalamin 500 ug injection intramuscularly three times a week) and group B (methylcobalamin 1500 ug injection intramuscularly once a week). A control group of healthy volunteers was also included. Results: A total of 24 patients (12 in each group) were included in the study. Five healthy volunteers were also included as a control in each group. At the end of treatment, serum cobalamin levels were significantly (P = 0.028) higher in group A (1892.08 +/- 234.50) as compared with group B (1438.5 +/ 460.32). The serum cobalamin levels in Group A healthy volunteers were also two times higher than that of group B (P = 0.056). Both the LANSS scale and DN4 questionnaire reported similar results at end of treatment. Conclusions: The 500 ug methylcobalamin thrice weekly regime is more effective in increasing the serum cobalamin levels as compared to the 1500 ug methylcobalamin once weekly regime. PMID- 30013733 TI - Comparison of patient-controlled epidural analgesia with patient-controlled intravenous analgesia for laparoscopic radical prostatectomy. AB - Background: Patient-controlled epidural analgesia (PCEA) is known to provide good postoperative analgesia in many types of surgery including laparoscopic surgery. However, no study has compared PCEA with patient-controlled intravascular analgesia (PCIA) in laparoscopic radical prostatectomy (LARP). In this study, the efficacy and side effects of PCEA and PCIA after LARP were compared. Methods: Forty patients undergoing LARP were randomly divided into two groups: 1) a PCEA group, treated with 0.2% ropivacaine 3 ml and 0.1 mg morphine in the bolus; and 2) a PCIA group, treated with oxycodone 1 mg and nefopam 1 mg in the bolus. After the operation, a blinded observer assessed estimated blood loss (EBL), added a dose of rocuronium, performed transfusion, and added analgesics. The numeric rating scale (NRS), infused PCA dose, and side effects were assessed at 1, 6, 24, and 48 h. Results: EBL, added rocuronium, and added analgesics in the PCEA group were less than those in the PCIA group. There were no significant differences in side-effects after the operation between the two groups. Patients were more satisfied with PCEA than with PCIA. The NRS and accumulated PCA count were lower in PCEA group. Conclusions: Combined thoracic epidural anesthesia could induce less blood loss during operations. PCEA showed better postoperative analgesia and greater patient satisfaction than PCIA. Thus, PCEA may be a more useful analgesic method than PICA after LARP. PMID- 30013734 TI - The effect of stabilization exercise on pain-related disability, sleep disturbance, and psychological status of patients with non-specific chronic low back pain. AB - Background: Sleep disturbance and depression are becoming more recognized as important symptoms among individuals with chronic low back pain. This study evaluated the effect of stabilization exercise on pain-related disability, sleep disturbance and the psychological status of patients with non-specific chronic low back pain (NSCLBP). Methods: A total of 26 patients (M/F = 17/9) with NSCLBP with a mean age of 50.0 +/- 15.5 took part in this study. Participants were recruited from selected hospitals in Lagos state. Ethical approval was sought and obtained from the health research and ethics committee of Lagos University Teaching Hospital Idi-araba, Lagos, Nigeria. Participants performed stabilization exercise for eight weeks consecutively and were assessed for pain-related disability, anxiety, depression, and sleep disturbance using the pain-disability index, hospital anxiety and depression scale, and the insomnia severity index at baseline, the 4th week, and the 8th week, post-intervention. Results: The participants studied recorded significant reduction in pain-related disability (P = 0.001). There was also improvement in the sleep quality (P = 0.001), depression level (P = 0.001), and anxiety level (P = 0.001), post intervention. Conclusions: This study revealed that stabilization exercise is very useful in the management of sleep disturbance, pain-related disability, depression, and anxiety in NSCLBP patients. PMID- 30013735 TI - The impact of caudally administrated tramadol on immune response and analgesic efficacy for pediatric patients: a comparative randomized clinical trial. AB - Background: Immune responses appear to be affected by anesthetics and analgesics. We investigated the effects of caudal tramadol on the postoperative immune response and pain management in pediatric patients. Methods: Sixty ASA-I pediatric patients aged 3-10 years undergoing lower abdominal surgery. Patients were randomly assigned either to a caudal bupivacaine (0.25%) group (group B), or a group that received caudal tramadol (1 mg/kg) added to the bupivacaine (0.25%) (group T). Both were diluted in a 0.9% NaCl solution to a total volume of 1ml/kg. The systemic immune response was measured by collecting blood samples preoperatively, at the end of anesthesia, and at 24 and 72 hours postoperatively, and studied for interleukin IL-6, C-reactive proteins (CRP) cortisol levels, and leucocytes with its differential count. Postoperative pain was assessed along with sedation scales. Results: Postoperative production of IL-6 was significantly higher in group B at the end of anesthesia, than at the 24th hour, and at the 72nd hour in group B and group T, respectively. The immune response showed leukocytosis with increased percentages of neutrophil and monocytes, and a decreased lymphocyte response rate within both groups with no significant differences between the groups. Cortisol and CRP were significantly higher in group B. Conclusions: Adding tramadol to a caudal bupivacaine block can attenuate the pro-inflammatory cytokine response, Cortisol, and CRP in children undergoing lower abdominal surgery. PMID- 30013737 TI - Stensen's duct sialolith in a geriatric patient. PMID- 30013736 TI - Extended duration pulsed radiofrequency for the management of refractory meralgia paresthetica: a series of five cases. AB - Meralgia paresthetica (MP) is a sensory mononeuropathy, caused by compression of the lateral femoral cutaneous nerve (LFCN) of thigh. Patients refractory to conservative management are treated with various interventional procedures. We report the first use of extended duration (8 minutes) pulsed radiofrequency of the LFCN in a case series of five patients with refractory MP. Four patients had follow up for 1-2 years, and one had 6 months follow up. All patients reported remarkable and long lasting symptom relief and an increase in daily life activities. Three patients came off medications and two patients required minimal doses of neuropathic medications. No complications were observed. PMID- 30013738 TI - The serological diagnosis of adult coeliac disease - a cautious step forward? PMID- 30013739 TI - Seronegative coeliac disease: Are they coeliac? When biopsy in adult can be avoided? PMID- 30013741 TI - Role of biopsy in diagnosis and treatment of adult celiac disease. AB - Celiac disease (CD) is an immune-mediated enteropathy that characteristically responds to treatment with a gluten-free diet. In most, clinical features improve with resolution of diarrhea and weight loss. Serological studies also tend to normalize. Small intestinal biopsies from the duodenum reveal a severe to moderately severe architectural disturbance showing crypt epithelial hyperplasia with increased numbers of epithelial cell mitotic figures along with villous "flattening", increased numbers of lamina propria plasma cells and lymphocytes and increased numbers of intra-epithelial lymphocytes in untreated disease. With a gluten-free diet, these changes can be expected to resolve to normal. In some patients, this mucosal inflammatory process may persist, especially in the proximal small intestine for variable periods of time. In CD, resolution of histopathological changes can occur within 6 months, but often, more than a year is required, and sometimes, 2 years or more. Changes are not only time-dependent, but appear to be gender-dependent with resolution more readily achieved in females compared to males, and age-dependent with more persistence of the inflammatory process in the elderly compared to younger patients. Future studies need to take into account the individual nature of the normal mucosal healing process in CD treated with a gluten-free diet. PMID- 30013740 TI - Exploring the villus. AB - The small intestinal villus and its associated epithelium includes enterocytes as the main cell type and differentiated goblet and argentaffin cells, while the invaginated crypt epithelium is the site of cell division and hence the origin of all epithelial components. Enterocytes form a cohesive monolayer which acts both as a permeability barrier between lumen and the interior, and an important gateway for nutrient digestion, absorption and transport. Differentiation and polarisation of enterocytes depends on cytoskeletal proteins that control cell shape and maintain functionally specialised membrane domains; extracellular matrix (ECM) receptors; channels and transporters regulating ion/solute transfer across the cell. The mesenchymally-derived basement membrane dynamically controls morphogenesis, cell differentiation and polarity, while also providing the structural basis for villi, crypts and the microvasculature of the lamina propria so that tissue morphology, crucially, is preserved in the absence of epithelium. Mucosal re-organisation requires immense cooperation between all elements within the lamina, including marked revisions of the microvasculature and extensive alterations to all basement membranes providing support for endodermal and mesenchymal components. In this context, subepithelial myofibroblasts fulfil important regulatory activities in terms of tissue morphogenesis; remodelling; control of epithelial cell development, polarity and functional attributes; and an intimate involvement in repair, inflammation and fibrosis. This paper reviews the main structural and functional aspects of the villus, including the epithelium and its outer glycocalyx and microvillous border; and subjacent to the epithelium, the basement membrane with its attached web of myo-fibroblasts together with the lamina propria core of the villi, and its microvasculature and lacteals. Finally, some comments on the rapidity with which the overall structure of the villi changes in their response to both external, and internal, influences. PMID- 30013742 TI - Non celiac gluten sensitivity and diagnostic challenges. AB - Non-celiac gluten sensitivity (NCGS), also referred to as non-celiac wheat sensitivity (NCWS), is a clinical syndrome characterized by both intestinal and extra-intestinal symptoms responsive to the withdrawal of gluten-containing food from the diet. The aim of this review is to summarize recent advances in research and provide a brief overview of the history of the condition for the benefit of professionals working in gastroenterology. Academic databases such as PubMed and Google Scholar were searched using key words such as "non-celiac gluten sensitivity", "gluten related disorders", and the studies outlined in reference page were selected and analysed. Most of the analysed studiers agree that NCGS would need to be diagnosed only after exclusion of celiac disease and wheat allergy, and that a reliable serological marker is not available presently. The mechanisms causing symptoms in NCGS after gluten ingestion are largely unknown, but recent advances have begun to offer novel insights. The estimated prevalence of NCGS, at present, varies between 0.6 and 6%. There is an overlap between irritable bowel syndrome and NCGS with regard to the similarity of gastrointestinal symptoms. The histologic characteristics of NCGS are still under investigation, ranging from normal histology to slight increase in the number of T lymphocytes in the superficial epithelium of villi. Positive response to gluten free diet for a limited period (e.g., 6 weeks), followed by the reappearance of symptoms after gluten challenge appears, at this moment, to be the best approach for confirming diagnosis. The Salerno expert criteria may help to diagnose NCGS accurately in particular for research purposes but it has limited applicability in clinical practice. PMID- 30013743 TI - Biological markers for non-celiac gluten sensitivity: a question awaiting for a convincing answer. AB - Non Celiac Gluten Sensitivity (NCGS) is characterized by immunological, morphological or symptomatic manifestations precipitated by gluten ingestion in individuals without celiac disease (CD). The most important challenge in NCGS is the diagnosis, currently based only on clinical observation. The "Salerno criteria" have been pointed out to achieve a reliable diagnosis even if they lack immediacy and practicality, thus making questionable patient's adherence. Therefore, biological indicators supporting the clinical diagnosis of NCGS are advisable. For these reasons, many attempts have been performed in order to identify possible serological, immunological, histopathological, immunohistochemical and pathophysiological aspects characterizing this condition with the aim of using them for diagnostic purposes. In the present narrative review, we carried out an update of the current scenario of potential markers of NCGS. The main fault of available studies is that, in most cases investigations have been pointed out towards molecules, which cannot be searched in the current laboratories of clinical analysis. Therefore, the matter has been confined within basic research. Additionally, in these studies, sensitivity and specificity of biological markers were not computable. This is a relevant limit, since an ideal test for NCGS should have a good discriminative power against both CD and other causes of microscopic enteritis. Until now, serological tests have failed, while the search for a soluble marker indicative of activation of innate immune system as well as immunohistochemistry could be the promising bases for the development of appropriate investigations in the future. PMID- 30013744 TI - The serological diagnosis of coeliac disease - a step forward. AB - The development of highly performing serological tests to identify patients with coeliac disease (CD), allowed large scale screening studies to be carried out and the results transformed our understanding of the prevalence of the condition in the general population. The next logical step was to ask whether CD could be reliably diagnosed by these tests without the need for small intestinal biopsies. This was shown to be the case. Studies from Derby, UK, indicated that about half of adult patients can be diagnosed in this way and similar figures have been provided for children. When considering this approach, it is essential that laboratories only use highly performing test kits that they have validated to measure tissue transglutaminase antibodies because all kits do not function to the same high standard. There remains a place for biopsy when criteria for serological diagnosis are not met, if the diagnosis of CD is strongly suspected but serological tests are negative or in patients not showing the expected responses to gluten free diet or otherwise causing concern, when not only small bowel biopsy will be indicated but also other investigations. Those with refractory CD should not be compromised by this diagnostic strategy. As serological tests become more refined and information accumulates, it is likely that this mode of diagnosis will gather momentum for the benefit of patients and carers. This brief review looks at the evidence for making the diagnosis of CD in some cases by serological tests alone. PMID- 30013745 TI - Celiac disease microarray analysis based on System Biology Approach. AB - Aim: Aim of this study is screen of the large numbers of related genes of CD to find the key ones. Background: Celiac disease (CD) is known as a gluten sensitive and immune system dependent disease. There are several high throughput investigations about CD but it is necessary to clarify new molecular aspects mechanism of celiac. Methods: Whole-genome profile (RNA) of the human peripheral blood mononuclear cells (PBMCs) as Gene expression profile GSE113469 was retrieved Gene Expression Omnibus (GEO) database. The significant genes were selected and analyzed via protein-protein interaction (PPI) network by Cytoscape software. The key genes were introduced and enriched via ClueGO to find the related biochemical pathways. Results: Among 250 significant genes 47 genes with expressed change above 2 fold change (FC) were interacted and the constructed network were analyzed. The network characterized by poor connections so it was promoted by addition 50 related nodes and 18 crucial nodes were introduced. Two clusters of biochemical pathways were identified and discussed. Conclusion: There is an obvious conflict between microarray finding and the well-known related genes of CD. This problem can be solve by more attention to the interpretation of PPI ntwork analysis results. PMID- 30013746 TI - Pentraxin 3 and biopsy status in celiac patients. AB - Aim: In our study we explored a possible relationship between PTX3 and CD. Background: Gluten sensitivity is known as a hallmark of celiac disease (CD). The diagnosis of CD requires demonstration of a typical enteropathy, and positive serology supports the diagnosis. The CD immune response involves the adaptive, as well as the innate immunity and is characterized by the presence of anti-gliadin (AGA) and anti-transglutaminase 2 antibodies (tTGA), lymphocytic infiltration in the intestinal epithelial membrane and expression of multiple cytokines. The long pentraxin 3 (PTX3), an acute-phase inflammatory molecule, plays an important role in innate immunity. Methods: 108 CD patients were divided according to Marsh Histological grade following Marsh criteria classification in three groups: Group 1: Marsh 0, patients with a known history of CD under gluten free diet, complete remission; Group 2: Marsh1 and Marsh 2; Group 3: Marsh 3. Healthy age-matched controls without a known history of CD or gastrointestinal symptoms (n=30) served as controls. PTX3 serum levels were measured by sandwich ELISA on an automated platform. Results: PTX3 serum levels were significantly elevated in group 3 and group 2 compared with HC (mean 3.31+/- 1.27 ng/mL and 3.97 +/- 0.54 ng/mL versus 1.06 +/- 0.59 ng/mL; P < 0.005), with group 1 (0.76+/-0.31 ng/mL). No statistically significant differences were found between group 1 and HC group. We found a strong linear correlation between PTX3 serum levels and AGA levels in group 2 (r=0.78, P <0.0001), and group 3 (r =0.63, P < 0.005) but no correlations were detected between PTX3 serum levels and tTGA levels (group 2, r= 0.04; group 3, r=0.24). Serological data revealed that PTX3 correlated with major gastrointestinal damage patients. Conclusion: PTX3 is a component of the humoral arm of the innate immune system. Our data showed that PTX3 serum levels were high in active disease patients with pathological levels of AGA. We also demonstrated that patients with normal AGA IgA levels had PTX3 serum levels compared to healthy control. We hypothesized that PTX3 is able to modulate the innate response to gliadin in CD and it could regulate the adaptive immune response. PMID- 30013747 TI - The influences of dried Chicory root and White lupine added to food on jejunal morphology: experimental study. AB - Aim: The objective of this work was to test the effects of adding dried Chicory root and White lupine food on small bowel morphology and compare it to a standard commercial diet. Background: Various commercial gluten-free products, gluten-free raw materials and gluten-free plants are this time available on the food market, but there are still not enough information about their effect on the small bowel morphology. Methods: Altogether thirty rabbits were used in this study. The control diet (C) contained common feed components. The first experimental diet (E1) contained (per kg) 60 g of dried chicory roots instead of barley, whereas the second experimental diet (E2) was based on white lupine seeds (cv. Amiga; 120 g per kg diet) instead of the soybean meal used in the control diet. The experiment started when the rabbits were 34-days old and lasted until they were 55-days old. At the end, one jejunal small bowel tissue was sampled, and both the heights and depths of the villi and crypts were measured. Results: The highest villi were measured in the E1 (598.99 um) group, mean in the C (590.30 um) group and the lowest were in the E2 (563.74 um) group. The most intense mucin villous positivity was observed in the E2 group, followed by the E1 group, and the weakest positivity was found in the visible C group. Conclusion: Chicory root has practical uses in gluten-free industries. PMID- 30013748 TI - Prevalence of celiac disease in Iranian patients with rheumatologic disorders. AB - Aim: Patients with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Fibromyalgia (FM) may have underlying non-diagnosed celiac disease (CD). Background: The aim of this study was to determine the prevalence of CD in patients with these underlying diseases in Iran. Methods: This cross-sectional study was performed among 300 consecutive patients with SLE, RA, and FM (each group 100 patients) since 2015 to 2017. The blood samples were collected and serum IgA anti-tissue trans-glutaminase (Anti-tTG) level was assessed for all patients. The seropositive patients underwent endoscopy and duodenal/jejunal biopsy according to the Marsh classification. Results: Out of 300 investigated patients with mean age of 41.2 years old, 92% of patients with SLE, RA and fibromyalgia were women. Among 100 patients with SLE, only 1 subject (1%), out of 100 patients with RA 3 subjects (3%), and none of the patients with fibromyalgia were seropositive for CD (with overall prevalence 1.4). All four patients were female and categorized as Marsh III. Conclusion: The results of the study indicated that patients with lupus have the same prevalence, but subjects with RA had three times higher prevalence rate than normal population for CD. Therefore, CD investigation in these individuals can improve their quality of life. PMID- 30013749 TI - Prevalence of celiac disease serological markers in a cohort of Italian rheumatological patients. AB - Aim: To assess the prevalence of celiac disease (CD) serological markers in a cohort of patients referred to an Italian rheumatological outpatient clinic. Background: Current guidelines do not suggest CD screening in patients with rheumatological diseases and these subjects are not considered to be at high risk for CD. Methods: A total of 230 sera of rheumatological patients referred to the Division of Internal Medicine at the Department of Medical and Surgical Sciences between January 2005 and December 2013 were screened for CD by testing IgA antitransglutaminase (TTG IgA), IgG deamidated gliadin peptides (DGP IgG) and IgA antiendomysium (EMA) antibodies. Of the 230 patients tested, 67 had a diagnosis of rheumatoid arthritis (RA), 52 Sjogren's syndrome (SjS), 42 systemic sclerosis (SCL), 35 systemic lupus erythematosus (SLE), 15 mixed connective tissue disease, 11 polymyositis and 10 dermatomyositis. Results: TTG IgA antibodies were identified in 7/230 cases (3%), 3 in SjS (3/42 - 5.8%), 2 in SCL (2/42 - 4.8%), 1 in RA (1/67 - 1.5%) and 1 in SLE sera (1/35 - 2.8%). All the seven sera were also positive for DGP IgG and EMA IgA. DGP IgG were the most frequent antibody detected, being found in 16 (7%) sera. Conclusion: This study identified a high prevalence of CD antibodies in adult patients referred to a rheumatology outpatient clinic. These results highlight the importance of CD screening in subjects presenting with rheumatological features. PMID- 30013750 TI - A rapid and sensitive assay to identify HLA-DQ2/8 risk alleles for celiac disease using real-time PCR method. AB - Aim: To perform a simple, rapid and sensitive Real-time PCR based SYBR Green method to determine the human leukocyte antigen (HLA)-DQ 2/8 alleles in celiac disease (CD) patients. Background: Many molecular techniques are available to determine the HLA-DQ2 and DQ8 alleles, but they are too expensive and have many steps that make them difficult to use. Methods: To determine the HLA-DQ 2/8 alleles we have developed a new real-time PCR assay, using SYBR Green technique with melting curve analysis on genomic DNA isolated from 75 CD patients and 94 healthy controls. The specific primers to examine HLA-DQA1*05, HLA-DQB1*02 and HLA-DQB1*0302 alleles were used and results were compared with commercially available kits. Results: Using this method, the presence of HLA-DQ2 and HLA-DQ8 alleles were determined with sensitivity and specificity 80% and 100% respectively and compared to low resolution commercially available kits, the results of this method were more efficient. The frequency of DQ2 and DQ8 in patients was 76% and 29%, respectively and overall 96% of patients were carries DQ2 and/or DQ8 alleles. Conclusion: The result of this study showed that Real time PCR using SYBR Green method with melting curve analysis has good efficiency to identify the HLA-DQ2/8 risk alleles. PMID- 30013751 TI - An exploration into the motivation for gluten avoidance in the absence of coeliac disease. AB - Aim: To explore the motivation for gluten avoidance in the absence of coeliac disease (CD) and ascertain what symptoms are triggered by gluten and what beliefs/reasons influence this decision. Background: Links between physical/psychological symptoms and gluten in CD are well known but less is known about those who self-select a gluten-free diet (GFD) in the absence of CD. Methods: An empirical study using responses to an anonymous on-line questionnaire. Closed questions were used as a screening tool to exclude participants who had CD, wheat allergy or were following a low FODMAP diet. Data from participants using a GFD in the absence of a medical diagnosis was then analysed using thematic analysis. Results: 120 initial responses, 87 were completed in full. 23 respondents fulfilled the inclusion criteria for thematic analysis. 7 different themes emerged, including one for signs/symptoms. Other themes identified included difficulties of a GFD, health beliefs, feelings and influence on decision to follow a GFD. Responses indicate that the reasons for gluten avoidance are in the most part reasoned and logical and were based around participants' self-management of symptoms. Conclusion: Symptoms included those typical of irritable bowel syndrome (IBS), but also infertility, low mood/energy, immune function and weight management and visual and auditory hallucinations. It appears the majority of responses analysed thematically could fit into the spectrum of non-coeliac gluten sensitivity (NCGS). Findings also suggest more support at all levels of medical care may help patients establish if it is gluten, rather than wheat or FODMAPs particularly fructans that are contributing to signs/symptoms. PMID- 30013752 TI - Detection of asymptomatic celiac disease in two siblings from a mother with non celiac gluten sensitivity. AB - Non-celiac gluten sensitivity and celiac disease are known to be two distinct clinical entities, however, non-celiac gluten sensitivity has been detected in a proportion of first-degree relatives of celiac patients. Herein for the first time we describe the occurrence of asymptomatic celiac disease in two siblings, a girl and a boy, whose mother suffered from a proven non-celiac gluten sensitivity. Both the 12-year old girl and 9-year old boy were positive for anti endomysial and anti-tissue transglutaminase antibodies of IgA class at a very high and low titer, respectively. Duodenal biopsy confirmed the diagnosis of active celiac disease (severe villous flattening) in the girl, whereas her brother had Marsh 1 lesion consistent with a potential celiac disease. This case report indicates that antibody screening for celiac disease can be recommended in any symptomatic or asymptomatic first-degree relatives of patients with non celiac gluten sensitivity. PMID- 30013753 TI - Post pancreatitis/cholecystectomy gluten intolerance. AB - This case report describes the journey of a patient who suffered from life limiting gastrointestinal symptoms after an acute bout of pancreatitis following ERCP for cholelithiasis bile following a ductal stone, and subsequent cholecystectomy. She was diagnosed and treated for IBS with medication without significant improvement. On implementation of a simple gluten and lactose exclusion diet she recovered to her premorbid state, and trials of gluten challenge triggered flares of symptoms. This case report will go on to discuss current evidence for use of gluten and lactose exclusion diets in some gluten sensitive patients misdiagnosed with IBS. PMID- 30013754 TI - Liver Transplantation: What Every Gastroenterologist Should Know about It. AB - Liver Transplantation (LT) is the treatment of choice for patients with end-stage liver disease. Improvement in outcomes (allograft and patient survival) has led to widespread use of LT worldwide. This success is due to improvement in patient selection, transplantation surgery, anesthesia/postoperative care, and immunosuppression management. This review will focus on different aspects of LT, which every physician should know to provide better patient care. PMID- 30013755 TI - Prevalence of Chronic Constipation and Its Associated Factors in Pars Cohort Study: A Study of 9000 Adults in Southern Iran. AB - BACKGROUND Chronic constipation is one of the most common gastrointestinal disorders. It has negative effects on the patients' quality of life, and their productivity, and results in a high economic burden on the healthcare services. The aim of the present study was to estimate the prevalence of chronic constipation and its associated factors in pars cohort study (PCS). METHODS A cross-sectional study was conducted on the baseline data of the PCS. Data gathering was done by structured questionnaire and physical examination. A total of 9264 subjects aged between 40 and 75 years were enrolled in the PCS. Diagnosis of chronic constipation was done using Rome IV criteria. Multivariable binary logistic regression was applied for data analysis. RESULTS A total of 752 (8.1%) participants were diagnosed as having chronic constipation (9.3% of female and 6.7% of male participants). Older age (OR: 1.55, 95% CI: 1.31-1.83), physical activity (OR: 0.56, 95% CI: 0.46-0.68), opium consumption (OR: 2.06, 95% CI: 1.63 2.60) , anxiety (OR: 1.38, 95% CI: 1.15-1.65), depression (OR: 1.22, 95% CI: 1.01 1.48), back pain or arthralgia (OR: 1.38, 95% CI: 1.14-1.67), insomnia (OR: 1.62, 95% CI: 1.36-1.93) and gastroesophageal reflux disease (OR: 1.51, 95% CI: 1.28 1.78) were associated with the prevalence of constipation in the multivariable analysis. CONCLUSION Chronic constipation was a common problem in the PCS population. Decreasing modifiable risk factors associated with constipation such as opium consumption and physical inactivity can reduce its prevalence and decrease burden of the disease. PMID- 30013756 TI - Vitamin D Status and Its Relation to Inflammatory Markers in Patients with Mild to Moderate Ulcerative Colitis. AB - BACKGROUND Inflammatory bowel disease (IBD), Crohn's disease (CD), and Ulcerative colitis (UC) are autoimmune inflammatory diseases of the alimentary tract, which seems to be caused by the interaction of environmental and genetic factors as well as diet and nutritional factors such as vitamin D. The aim of this study was to assess the vitamin D status and its associations with erythrocyte sedimentation rate (ESR), and high-sensitivity C-reactive protein (hs-CRP) as inflammatory markers in patients with UC. METHODS In this analytical cross sectional study 90 patients with mild to moderate UC who were resident of Tehran were assessed. 25(OH)D, parathyroid hormone (PTH), ESR and hs-CRP were measured. Dietary intake was assessed by 3-day 24h diet recall. Statistical analyses were performed using STATA (Version 12). RESULTS The average serum 25-OH-vitamin D3 was 33.1 +/- 8.3 ng/mL and 38.9% of the patients were vitamin D deficient or insufficient (37.3% of men and 41% of women). No significant correlation between serum 25(OH)D and hs-CRP, ESR, body mass index (BMI), and disease duration was found. There were no significant differences in serum 25(OH)D between men and women. Mean daily dietary vitamin D and calcium intakes were 189.5 Iu (95% CI: 176.0 - 203.1) and 569.5 mg (95% CI: 538.8 - 600.2) respectively. CONCLUSION In this cross-sectional study 38.9% of the patients with mild to moderate UC were vitamin D deficient or insufficient and vitamin D level was not correlated to ESR and/or hs-CRP. More studies are needed to investigate the effect of vitamin D in the pathogenesis of UC or as a part of its treatment. PMID- 30013757 TI - Correlation between Serum Ferritin Level and Histopathological Disease Severity in Non-alcoholic Fatty Liver Disease. AB - BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. Recently several parameters, such as serum ferritin, have emerged as possible predictors for the severity of NAFLD and insulin sensitivity. We aimed to investigate the value of serum ferritin level as a useful biomarker for the prediction of histopathological disease severity in non-alcoholic steatohepatitis (NASH), the necro-inflammatory form of NAFLD. METHODS This was a prospective cross sectional study in which demographic, clinical, histological, laboratory, and anthropometric data of 30 adult patients with biopsy-proven NAFLD/NASH were analyzed. RESULTS In our patients population with mean age of 37.9 years and mean BMI of 26.5, statistical analysis did not show a significant difference between the three grades of steatosis in the mean ferritin levels (p = 0.559). It was also observed that ferritin level did not have a significant correlation with the stage of fibrosis (p = 0.228). The mean transferrin saturation did not show significant difference in different stages and grades of NASH (p = 0.260 and 0.944, respectively), either. CONCLUSION Serum ferritin level may not be useful as a single marker for the prediction of histopathological severity of disease in young patients with NASH who are not morbidly obese. PMID- 30013759 TI - Increased Expression of Aryl Hydrocarbon Receptor in Peripheral Blood Mononuclear Cells of Patients with Autoimmune Hepatitis. AB - BACKGROUND Previous studies have indicated an elevated level of serum Interleukin (IL)-22 in patients with autoimmune hepatitis (AIH). However, there are no experimental data on the master transcription factor (aryl hydrocarbon receptor) that plays an important role in the development of T helper type 22 (Th22) cells as major producers of IL-22. The aim of the present study was to examine the expression of aryl hydrocarbon receptor in patients with AIH and in normal controls. METHODS Levels of mRNA transcripts were measured in the peripheral blood mononuclear cells of 18 patients with AIH and compared with 18 normal controls by a quantitative real-time polymerase chain reaction. RESULTS mRNA expression of aryl hydrocarbon receptor was significantly higher in patients with AIH compared with the healthy control group (P = 0.006). CONCLUSION Th22 cells may play an important role in the pathogenesis of AIH. PMID- 30013758 TI - The Association between Angiotensin II Type 1 Receptor Gene A1166C Polymorphism and Non-alcoholic Fatty Liver Disease and Its Severity. AB - BACKGROUND Genetic predisposition may have important role in pathogenesis of non alcoholic fatty liver disease (NAFLD). Angiotensin II type I receptor (AGTR1) has been known to involve in the process of liver steatosis and fibrosis. This study aimed to investigate the association between AGTR1 A1166C polymorphism and NAFLD. METHODS A cross-sectional study was conducted during May 2014-May 2015 among healthy adults referring to our radiology clinic for abdominal sonography. AGTR1 A1166C polymorphism was evaluated in subjects with NAFLD and healthy individuals using allelic discrimination method. RESULTS 58 subjects with NAFLD were compared with 88 healthy individuals without NAFLD. The frequency of AA and CC genotypes of AGTR1 was significantly higher in patients with NAFLD compared with controls (p = 0.029 and 0.042, respectively). C allele was more detected in subjects with NAFLD compared with the healthy controls (OR: 2.1; 95% CI: 1.23-3.61, p = 0.006). CC genotype (OR: 10.62; 95% CI: 1.05-106.57, p = 0.045) and C allele (OR: 6.81; 95% CI: 1.42- 32.48, p = 0.016) were also predictors of severe fatty liver disease in our study population. CONCLUSION Our results provide the first evidence that AGTR1 gene A1166C polymorphism not only is associated with NAFLD and but also may predict its severity. PMID- 30013760 TI - Role of Hepatobiliary Scintigraphy in the Diagnosis of Gallbladder Agenesis; A Case Report and Brief Review of Literature. AB - Gallbladder agenesis (GA) is a rare congenital anomaly. Only 50% of the cases with GA are symptomatic, presenting mostly in the 4th or 5th decade of life. The clinical presentation of GA and imaging findings are non-specific and often misinterpreted as other diseases such as ectopic gall bladder. This can lead to unnecessary surgery when the final diagnosis is usually made. Although GA can cause an identical pattern to acute cholecystitis in hepatobiliary scintigraphy, in certain clinical settings, scintigraphy can be helpful as a confirmatory study, especially to rule out the possibility of ectopic gall bladder. In our case, the combination of imaging findings including ultrasonography, computed tomography, and hepatobiliary scintigraphy led to accurate diagnosis avoiding further surgeries. PMID- 30013761 TI - Appendectomy Scar Endometriosis: A Case Report. AB - Scar endometriosis is one of the rare cases of surgery, which specifically occurs in gynecological surgeries. It is important to do a correct diagnosis in such rare cases to have an efficient treatment. The disease is commonly observed in child-bearing women with clinical manifestations such as acute abdomen or chronic and cyclic pelvic pain. Herein we reported a case of appendectomy scar endometriosis. PMID- 30013762 TI - Obstructive Jaundice in a Patient with Polycystic Liver. PMID- 30013763 TI - Association between Gastrointestinal Functional Disorders and Migraine Headache: A Therapeutic Link. PMID- 30013764 TI - The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia. AB - Recurrent mutations affecting cellular metabolism and epigenetic regulation are implicated in the pathogenesis of acute myeloid leukemia (AML). Isocitrate dehydrogenase 2 (IDH2) gene mutations are described in 12% of patients with AML and 5% of patients with myelodysplastic syndromes. IDH2 enzyme is involved in the Krebs cycle, catalyzing alpha-ketoglutarate from isocitrate. Mutant IDH2 enzymes acquire a neomorphic enzymatic activity with the ability to produce 2 hydroxyglutarate from alpha-ketoglutarate, inhibiting multiple alpha ketoglutarate-dependent dioxygenase reactions; leading to aberrant DNA hypermethylation and differentiation block in myeloid precursors and ultimately promoting leukemogenesis. Enasidenib (formerly AG-221) is an oral small molecule selective targeted inhibitor of the mutant IDH2 enzyme, approved in August 2017 by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory (R/R) IDH2-mutated AML. Preclinical studies showed the effectiveness of enasidenib in inhibiting the production of 2 hydroxyglutarate with high potency, and alleviating the mutant IDH2-induced differentiation block. In the original AG221-001 phase I/II trial, patients with R/R AML were treated with enasidenib single agent therapy at escalating doses up to 650 mg daily, with the 100 mg dose level identified to be safe and effective for further evaluation. Overall, 113 patients were treated in the dose-escalation and 126 in the dose-expansion cohorts. The overall response rate for R/R patients was 40%, including a complete remission of 19%. At a median follow up of 7.7 months, the median overall survival was 9.3 months, and reached 19.7 months in responders. Enasidenib was well tolerated, although adverse events of clinical interest include indirect hyperbilirubinemia and IDH-inhibitor-induced differentiation syndrome, which can be life threatening if not identified and treated promptly. Ongoing clinical trials evaluating enasidenib in combination with intensive chemotherapy and hypomethylating agents in newly diagnosed AML, and in rational combinations for R/R AML patients are underway. PMID- 30013766 TI - BAY 81-8973, a full-length recombinant factor VIII for the treatment of hemophilia A: product review. AB - BAY 81-8973 (Kovaltry(r)) is an unmodified, full-length recombinant factor VIII (rFVIII) approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. The amino acid sequence for BAY 81-8973 is identical to that of sucrose-formulated rFVIII (rFVIII-FS; Kogenate(r) FS/KOGENATE(r), Bayer), but the two products differ in their manufacturing approaches. The manufacture of BAY 81-8973 includes several modifications and enhancements, such as the introduction of the gene for human heat shock protein 70, a molecular chaperone protein that facilitates folding of proteins; no addition of human- or animal-derived proteins in the cell culture, purification process, or final formulation; and use of a 20-nm filter to remove any potential aggregates and pathogens. BAY 81-8973 was extensively studied in the LEOPOLD clinical development program, which enrolled participants of all age groups (children, adolescents, and adults) with severe hemophilia A. The pharmacokinetic profile of BAY 81-8973 was shown to be noninferior to, and for some variables more favorable than, rFVIII-FS and another commercial full-length rFVIII product. BAY 81-8973 was shown to be efficacious when used for prophylaxis, on-demand treatment, and perioperative hemostasis. The efficacious prophylaxis dose of BAY 81-8973 was approximately 20-40 IU/kg given two or three times per week, which achieved low annualized bleeding rates. Either the one-stage or the chromogenic assay provides accurate measurements for postinfusion monitoring of BAY 81-8973 levels, with no product-specific calibration standard needed. The incidence of treatment-related adverse events was ?7% across all LEOPOLD studies, and no previously treated patient developed anti-BAY 81-8973 inhibitors in the completed primary studies. PMID- 30013765 TI - Update on the role of lenalidomide in patients with multiple myeloma. AB - Lenalidomide is a derivative of thalidomide and belongs to the class of drugs known as the immunomodulatory drugs (IMiDs). The IMiDs have played a large role in improving the survival outcomes of patients with multiple myeloma. In particular, lenalidomide is currently standard of care in the newly diagnosed setting, in the maintenance setting post-autologous stem cell transplant, as well as in the relapsed/refractory setting. While the combination of lenalidomide and various proteasome inhibitors has proven particularly effective, there are emerging data demonstrating the effectiveness of lenalidomide in combination with other important classes of drugs including the monoclonal antibodies. Recent studies have provided insight into the molecular target of lenalidomide and the other IMiDs, although there is still much to be learned regarding the mechanisms by which lenalidomide affects the myeloma cell and the immune system. Here we review the molecular mechanisms of action, side effects, and the results of the clinical trials which have led to the widespread incorporation of lenalidomide into the myeloma therapeutic armamentarium. PMID- 30013767 TI - A case series of Kimura's disease: a diagnostic challenge. AB - Kimura's disease (KD) is a rare, benign disorder characterized by subcutaneous masses with regional lymph-node enlargement. It is considered to be due to chronic inflammation of unclear etiology. Most cases have been reported in young, 20-30-year-old men of Asian descent. The diagnosis of KD is based on pathological features and elevated immunoglobulin E levels. Characteristic pathological features include intact lymph-node architecture, florid germinal center hyperplasia, extensive eosinophilic infiltrates, and proliferation of postcapillary venules. However, these features can also be seen in Hodgkin's disease or T-cell lymphoma, therefore, cases presenting as KD pose a diagnostic challenge. We report a case series of two cases with suspected KD at initial presentation, with one patient eventually diagnosed with Hodgkin's disease after clinical progression. The first case was a 45-year-old Asian man who presented with bilateral thigh masses and significantly enlarged inguinal lymph nodes. The histopathology was characteristic and the patient had stable disease on treatment with cetirizine for 20 months. The second case was a 29-year-old African-American man who had progressive enlargement of the right neck lymph nodes extending into the mediastinum, with the original biopsy suggestive of KD. An initial search for Reed-Sternberg cells using immunohistochemical staining for CD15 and CD30 was negative. However, the patient developed neurological symptoms corresponding to tumor extension to the cervical and thoracic neural foramina. A repeat biopsy showed a lack of nodal structure and atypical large cells that were positive for CD30 staining. The patient was treated with chemotherapy with good response. We emphasize the importance of following the clinical course to render an accurate diagnosis. Both cases showed extensive eosinophilic infiltration and other KD like pathological features. However, KD is rare; not missing a malignant diagnosis lies in high clinical suspicion and repeated exhaustive work up. PMID- 30013768 TI - Long non-coding RNA CASC15 promotes melanoma progression by epigenetically regulating PDCD4. AB - Background: Long non-coding RNAs (LncRNAs) have been identified as critical regulators in a variety of cancer types. Cancer susceptibility candidate 15 (CASC15), a lncRNA located at chromosome 6p22.3, has been discovered to participate in melanoma progression and phenotype switching. Nevertheless, the roles and molecular mechanisms of CASC15 in melanoma are far from being understood. Results: We found that CASC15 expression was up-regulated in melanoma tissues and associated with advanced pathological stages. Function experiments displayed that CASC15 knockdown hindered proliferation, facilitated apoptosis and suppressed invasion, while CASC15 overexpression facilitated proliferation and invasion in melanoma cells. Further mechanistic analysis showed that CASC15 epigenetically silenced the expression of programmed cell death 4 (PDCD4) by recruiting EZH2 and increasing H3K27me3 level at the promoter region of PDCD4. Additionally, PDCD4 overexpression inhibited proliferation, enhanced apoptosis and decreased invasion of melanoma cells. Moreover, CASC15-knockdown-induced anti cancer effects were abated by PDCD4 down-regulation. Furthermore, depletion of CASC15 blocked tumor growth of melanoma by up-regulating PDCD4 in vivo. Conclusions: CASC15 acts as an oncogene by negatively regulating PDCD4 expression via recruiting EZH2 and subsequently increasing H3K27me3 level. Together, our study indicates that CASC15/EZH2/PDCD4 may serve as a promising therapeutic target for melanoma intervention. PMID- 30013769 TI - Nasopharyngeal adenoid cystic carcinoma, suggestion of therapeutic innovations: A case report and review of literature. AB - Introduction: Nasopharyngeal adenoid cystic carcinoma is a rare tumor. Compared with others nasopharyngeal tumors, it is characterised by slow evolution but it is locally aggressive and has a high tendency to recurrences. Due to the rarity of cases, no consensus exists about treatment approaches. Presentation of the case: We report the case of a 55-year-old-woman, with a locally advanced adenoid cystic carcinoma. The patient was operated by endoscopic surgery, received radiation and had a good objective response. The follow-up showed no local recurrence after one year. Conclusion: The aim of this work is to review the literature concerning this rare malignancy, and discusses treatment approaches in initial situations and during recurrences.We supported the interest of the intraoperative neuronavigation system for surgical safety. PMID- 30013770 TI - Limited distal duodenal resection: Surgical approach and outcomes. A case series. AB - Introduction: Tumours involving the duodenum are usually treated with pancreaticoduodenectomy, which may be associated with considerable morbidity. Limited distal duodenal resection, a relatively smaller procedure, can be done in some of these patients. We describe our experience with this operation for such lesions. Methods: We retrospectively analyzed, from prospectively collected data 10 consecutive patients who underwent limited duodenal and proximal jejunal resection between March 2011 and Nov 2015. Results: There were 8 males and 2 females who had a median age of 47 years. Their common presentations were abdominal pain (50%) and upper gastrointestinal bleeding (40%). Five had malignancy (adenocarcinoma: 2, neuroendocrine tumours: 2, non Hodgkin's lymphoma 1). Three had gastrointestinal stromal tumours (GISTs) and 2 had other benign tumours (lipoma 1, ectopic pancreas 1). The 30-day post-operative morbidity rate was 60% (n = 6) with mostly minor complications (Clavien grade 1 or 2). Median post-operative stay was 9 (range, 6-13) days. All ten patients were alive without recurrence after a median follow up of 26.5 months. Conclusion: Limited distal duodenal resection is a feasible surgical alternative to a pancreaticoduodenectomy in carefully selected patients with benign and some malignant tumours of the third and fourth part of the duodenum. PMID- 30013771 TI - Massive ameloblastoma: A case report of difficult fiberoptic intubation. AB - Introduction: Intubation can sometimes be difficult in patients with lesions in the mouth floor. Ameloblastoma is a frequently encountered tumor of the maxillofacial area. An extensive lesion might occupy the floor of the mouth, prevent displacement of the tongue, limiting the space for inserting a laryngoscope blade and resulting in difficult intubation even with fiberoptic bronchoscopy. Case presentation: A 66-year-old man (67 kg; 171 cm) with a mental swelling was diagnosed with ameloblastoma and scheduled for surgical resection. The tumor was extensive, occupying most of the anterior floor of the mouth. We were concerned about impossible direct laryngoscopy because the massive tumor in the floor of the mouth compressed the base of the tongue against the posterior wall of the pharynx, restricting the space for inserting the laryngoscope blade. Therefore, we planned to perform awake nasal fiberoptic intubation to secure the airway. Although the procedure was complicated by the massive tumor, successful intubation was achieved by hand-assisted alteration of the direction of the endotracheal tube (ETT) under direct laryngoscopy. Discussion: Awake fiberoptic intubation was complicated by the tumor protrusion to deviate the ETT. Discovering of the ETT deviation by the insufficient blade insertion facilitated visualizing the vocal cords with the fiberoptic scope. Conclusion: Identification of ETT deviation even with insufficient blade insertion and hand-assisted alteration of the direction of the ETT might raise the chances of successful fiberoptic intubation. The anesthesiologist should be aware of the likelihood of failed fiberoptic intubation and plan for alternative approaches to secure the airway. PMID- 30013772 TI - Nurses and physicians' viewpoints about decision making of do not attempt resuscitation (DNAR). AB - Background: Despite advances with regard to "do not attempt resuscitation order", physicians are still reluctant to implement it. In fact, while the nurses could be of great help in making decision about "do not attempt resuscitation order," they are mostly neglected in this process. The current study was conducted to determine the nurses and physicians' viewpoints about decision making process of "do not attempt resuscitation order". Methods: A descriptive analytical study was carried out with participation of 152 physicians and 152 nurses. The participants were selected through stratified quota sampling from three educational hospitals affiliated with Kermanshah University of Medical Sciences. Data gathering tools were a demographics checklist and a researcher-designed questionnaire with 20 statements for measuring the attitudes of the respondents about the decision making process and implementation of "do not attempt resuscitation order" of incurable patients. Results: Totally, 304 respondents (152 nurses and 152 physicians) participated in the study. The nurses' attitude score about the consent of the competent patients to "do not attempt resuscitation" was significantly lower in comparison with the physicians, (p < 0.001). However, the nurses' attitude was more positive than the physicians attitude about the belief that "taking the patient's consent is the physician's responsibility" (p < 0.001). Moreover, the nurses' attitude was more negative compared with the physicians' attitude about the idea that "obtaining the patient's consent is the nurse's responsibility" (p < 0.001). Both groups believed that the nurses cannot recommend "do not attempt resuscitation order" (p < 0.770). Both groups of the respondents believed that the nurses were not qualified to issue the "do not attempt resuscitation order" (physicians' mean score = 2.85, nurses' mean score = 2.89). The physicians' believe in "necessity to negotiate with the nurses about the order" was less deep than that of the nurses (p = 0.035). Conclusions: Given the different attitudes of the nurses and the physicians about the decision making process of "do not attempt resuscitation," it is necessary to codify a medical guideline and clarify the decision making and implementation process. The guideline needs to clearly state physician's, nurse's, patient's, and other medical team members' responsibilities and roles, respectively. PMID- 30013773 TI - A study of antibiotic prescription pattern in patients referred to tertiary care center in Northern India. AB - Background: Tremendous infectious disease burden and rapid emergence of multidrug resistant pathogens continues to burden our healthcare system. Antibiotic stewardship program often implements antibiotic policies that help in preventing unnecessary use of antibiotics and in optimizing management. To develop such a policy for management of infections in the emergency unit, it is important to analyze the information regarding antibiotic prescription patterns in patients presenting to the emergency room referred from various healthcare settings. This study was conducted with the aforementioned background. Methods: We conducted a prospective observational study in triage area of emergency unit of a tertiary care hospital. All the referred patients were screened for antibiotic prescription. Data extraction form was used to capture information on patient demographics, diagnosis and antibiotics prescribed. Antibiotic prescription details with regard to dosage, duration and frequency of antimicrobial administration were also recorded. Data were summarized using descriptive statistics as appropriate. Results: Out of 517 screened patients, 300 were prescribed antimicrobials. Out of 29 antibiotics prescribed, 12 were prescribed in more than 90% of patients. Broad spectrum antibiotics accounted for 67.3% of prescriptions. In 129 out of 300 patients, no evidence of infectious etiology was found. Conclusion: Our study highlights some common but serious lapses in antibiotic prescription patterns in patients referred from various healthcare settings. This emphasizes the need to provide training for rational use of antibiotics across healthcare settings. PMID- 30013774 TI - Mycobacterial chylous ascites: report of three cases and systematic review. AB - Background: Chylous ascites is an uncommon presentation of mycobacterial infection. Methods: We report three cases of tubercular chylous ascites, and in addition, we performed a systematic review of the published literature for the clinical presentation, treatment, and outcomes of mycobacterial chylous ascites. We followed the PRISMA guidelines for the systematic review. Results: A total of 33 cases (including three of ours) were included. The mean age of the reported cases was 32.54 +/- 17.56 years, and a male predominance (76%) was noted. The predominant clinical features were abdominal distension, abdominal pain, fever and loss of appetite and weight. Mycobacterium tuberculosis (MTB) and Mycobacterium avium-intracellulare (MAC) infection were responsible for 16 and 15 cases, respectively. All patients with MAC related chylous ascites had HIV infection. The mechanisms were related to lymph nodal enlargement, constrictive pericarditis and remote scrofuloderma. Overall, there was 29% mortality. Use of anti-mycobacterial therapy with use of total parenteral nutrition, octreotide and medium chain triglyceride-based diet resulted in improvement in the rest of the cases. The cause of death in our case was anti-tubercular therapy-induced hepatitis; three deaths were due to disseminated mycobacterial infection, one due to cardiopulmonary failure and unknown in four patients. Conclusion: Chylous ascites due to mycobacterial infection is uncommon and associated with poor outcome. However, early diagnosis and nutritional management along with antimycobacterial therapy can improve outcome. PMID- 30013775 TI - Changes in gene expression as one of the key mechanisms involved in radiation induced bystander effect. AB - The radiation-induced bystander effect (RIBE) refers to the manifestation of responses by non-targeted/non-hit cells or tissues situated in proximity to cells and tissues directly exposed to ionizing radiation (IR). The RIBE is elicited by agents and factors released by IR-hit cells. The growing body of data suggests that the underlying mechanisms of the RIBE are multifaceted depending both on the biological (characteristics of directly IR-exposed cells, bystander cells, intercellular milieu) and the physical (dose, rate and type of IR, time after exposure) factors/parameters. Although the exact identity of bystander signal(s) is yet to be identified, the published data indicate changes in gene expression for multiple types of RNA (mRNA, microRNA, mitochondrial RNA, long non-coding RNA, small nucleolar RNA) as being one of the major responses of cells and tissues in the context of the RIBE. Gene expression profiles demonstrate a high degree of variability between distinct bystander cell and tissue types. These alterations could independently, or in a signaling cascade, result in the manifestation of readily observable endpoints, including changes in viability and genomic instability. Here, the relevant publications on the gene candidates and signaling pathways involved in the RIBE are reviewed, and a framework for future studies, both in vitro and in vivo, on the genetic aspect of the RIBE is provided. PMID- 30013777 TI - Phenotypic spectrum of SLC25A4 mutations. AB - There is no comprehensive overview concerning the phenotypic variability in patients carrying SLC25A4 mutations available. Therefore, the aim of the present review was to summarise and discuss recent findings concerning the clinical presentation and phenotypic heterogeneity of SLC25A4 mutations. The study was conducted by systematically reviewing the literature using the search terms 'mitochondrial', "myopathy', 'nuclear DNA', 'mitochondrial DNA', in combination with 'SLC25A4' or 'AAC1'. The results indicated that the phenotypic heterogeneity in patients carrying a SLC25A4 mutation is broader than so far anticipated. Patients carrying a SLC25A4 mutation not only manifest as encephalo-myo cardiomyopathy but also with scoliosis, cataract, depression, headache, hydrocephalus or arterial hypertension. SLC25A4 mutations may result in mtDNA depletion or multiple mitochondrial (mt)DNA deletions. SLC25A4-associated mtDNA depletion presents with the more severe phenotype and the worse outcome than patients with multiple mtDNA deletions. Depletion syndrome due to SLC25A4 mutations is associated with congenital respiratory insufficiency requiring mechanical ventilation with poor prognosis in the majority of the cases. Mutations in the SLC25A4 gene manifest phenotypically with multiorgan abnormalities in addition to encephalo-myo-cardiomyopathy. SLC25A4 mutations, causing mtDNA depletion, present with a more severe phenotype, including respiratory insufficiency and more widespread cerebral disease than mutations causing multiple mtDNA deletions. PMID- 30013776 TI - Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary. AB - Targeting non-oncogenes may result in the selective death of cancer cells. Clear cell carcinoma of the ovary (CCC) may exhibit resistance against conventional chemotherapy and is associated with poor prognosis. The aim of the present report was to review synthetic lethality-based therapies for CCC. Previous English language studies were reviewed to accumulate preclinical and clinical data on targeting synthetic lethal partners. Synthetic lethal interactions have a variety of types, involving components of a backup or parallel pathway with overlapping functions, components encoded by paralogous pairs, subunit components that form heteromeric complexes and components that are arranged in a single linear pathway. A set of candidate gene targets potentially resulting in synthetic lethality have been previously identified. HNF class homeobox, AT-rich interaction domain 1A, ATR serine/threonine kinase, ATM serine/threonine kinase, checkpoint kinase 1 and phosphatase and tensin homolog may be the key partner genes. A variety of loss of function genes in CCC are driver or passenger events and may function as synthetic lethal pairs under replication stress conditions. Further clinical studies will be required to investigate the safety and therapeutic effect of synthetic lethality pairs in CCC tumor types with replication stress. PMID- 30013778 TI - miR-124-3p acts as a potential marker and suppresses tumor growth in gastric cancer. AB - miR-124-3p has been implicated in a variety of cancers. The purpose of the present study was to investigate the expression, prognostic roles and functions of miR-124-3p in gastric cancer. Functional studies indicated that ectopic overexpression of miR-124-3p in gastric cancer cells suppressed cell viability and plate colony formation in vitro and tumor growth in vivo. In situ hybridization analysis demonstrated that decreased expression of miR-124-3p was associated with clinical stage and lymph node metastasis, as well as shorter overall survival and disease-free survival rates. Furthermore, it was observed that miR-124-3p repressed the carcinogenesis of gastric cancer by targeting Ras related C3 botulinum toxin substrate 1 (Rac1) and specificity protein 1 (SP1). Collectively, these results indicate a potential underlying mechanism for the regulation of gastric cancer by miR-124-3p involving targeting of Rac1 and SP1. Thus, miR-124-3p may be an independent indicator of survival and treatment strategy for patients with gastric cancer. PMID- 30013779 TI - Second-line triple therapy in failures with vonoprazan-based triple therapy for eradication of Helicobacter pylori. AB - Gastric acid inhibition during treatment is important for the eradication of Helicobacter pylori (H. pylori) infection. A novel potassium-competitive acid blocker, vonoprazan (VPZ), has been demonstrated to achieve high eradication rates; however, the efficacy of second-line treatment in failures of VPZ-based triple therapy has not been well studied. The aim of the current study was to determine the efficacy of VPZ in a first-line regimen for H. pylori eradication, and the efficacy of a second-line regimen using metronidazole (MTZ) in failures with the first-line regimen. Of 580 subjects enrolled in the study, 524 patients completed first-line treatment (275 patients who received VPZ and 249 patients who received LPZ). First-line regimens consisted of a combination of clarithromycin (CAM) 200 or 400 mg twice a day, amoxicillin (AMPC) 750 mg twice a day, and either LPZ 30 mg or VPZ 20 mg twice a day, administered orally for 7 days. CAM and VPZ/LPZ were replaced with metronidazole (MTZ) 250 mg and rabeprazole 10 mg in the second-line regimens. The eradication of H. pylori was assessed by the H. pylori stool antigen test. The overall first-line eradication rate with VPZ was significantly higher than that with LPZ [91.0% (250/275) vs. 84.7% (211/249), respectively, P=0.030]. The dose of CAM (400 vs. 800 mg) did not affect the eradication rate in either the VPZ or LPZ regimens. The overall eradication rates of the second-line regimens with MTZ did not differ significantly between the VPZ-failure and LPZ-failure groups [87.0% (20/23) vs. 87.9% (29/33), respectively, P=0.700]. Therefore, VPZ was significantly more effective than LPZ for first-line treatment. In patients with failure of first line eradication therapy, successful results of second-line eradication therapy did not differ between the VPZ- and LPZ-failure groups. In conclusion, VPZ-based triple therapy should be recommended for eradication of H. pylori. PMID- 30013780 TI - Anti-proliferative effect of ridaifen-B on hepatoma cells. AB - Ridaifens (RIDs), a novel series of tamoxifen derivatives, exhibit a potent growth-inhibitory effect against numerous tumor cells regardless of the expression of estrogen receptors, and are thus promising candidates as novel anti tumor drugs. RID-B is a first generation RIDs, and inhibits the proliferation of several tumor cell lines. However, the potentially growth inhibitory effect of RID-B against hepatoma cells, and the detailed mechanism underlying RID-B mediated tumor cell death remain to be elucidated. The purpose of the current study was to evaluate the anti-proliferative effect of RID-B against hepatoma cells. The anti-proliferative effect of RID-B against human hepatoma Huh-7 cells was investigated by cell proliferation assay using WST-1 reagent, and caspase-3 activity was evaluated by using specific fluorescent substrate. In addition, DNA fragmentation in Huh-7 cells induced by RID-B was estimated by terminal deoxynucleotidyl transferase dUTP nick-end labelling assay, and binding of RID-B to double-stranded DNA was confirmed by mass spectrometry. RID-B (0.5, 1 and 2 uM) inhibited the growth of Huh-7 cells, seemingly dose-dependently, but did not inhibit the growth of normal primary rat hepatocytes in the same concentration range. Furthermore, the caspase-3 activity of Huh-7 cells was increased by RID-B (0.5 and 5 uM), and the anti-proliferative effect of RID-B (1 uM) on Huh-7 cells was partially suppressed by the addition of the caspase inhibitor, Z-VAD-FMK. Additionally, RID-B (10 uM) directly bound to double-stranded DNA, and the addition of DNA suppressed RID-B-mediated cell growth inhibition and DNA fragmentation in Huh-7 cells. From these data, it may be concluded that RID-B inhibited cell growth and induced apoptosis via activating caspase-3 and binding to DNA directly, leading to DNA fragmentation in hepatoma cells. PMID- 30013781 TI - Impact of relative dose intensity in gemcitabine-cisplatin chemotherapy for metastatic urothelial carcinoma. AB - Objectives: To evaluate the impact of relative dose intensity for gemcitabine cisplatin chemotherapy in patients with metastatic urothelial carcinoma. Methods: We retrospectively reviewed the medical records of 18 patients with metastatic urothelial carcinoma, who received gemcitabine-cisplatin regimen as the first line chemotherapy between 2009 and 2015. The doses of gemcitabine and cisplatin were reduced or the intervals between treatment cycles were prolonged according to the treatment efficacy and adverse events during the first and second cycles. The individually optimal relative dose intensity was set as the actual dose per the standard dose in the first and second cycles. From the third course onward, patients received the gemcitabine-cisplatin chemotherapy with the same relative dose intensity. Overall survival was compared with the groups according to the value of relative dose intensity. Results: The median age was 72.5 (range, 56-79) years and 15 men and 3 women were enrolled in the study. The median number of cycles of first-line gemcitabine-cisplatin chemotherapy was 8 (range, 2-17), and the median survival time from initiation of first-line chemotherapy was 20.1 (range, 3.5-32.8) months. The total median relative dose intensity of gemcitabine cisplatin chemotherapy was 56.1%. The median survival time of 10 patients in the group with the relative dose intensity of less than 60% was significantly longer than that of 8 patients in the group with the relative dose intensity of more than 60% (19.2 and 11.0 months, respectively, p = 0.04). Conclusion: Individual low relative dose intensity management in the first-line gemcitabine-cisplatin chemotherapy may be an acceptable option for patients with metastatic urothelial carcinoma. PMID- 30013782 TI - Determinants of hospitalizations for pneumonia among Finnish drug users. AB - Objective: The study examined the determinants of being hospitalized for pneumonia in a large cohort of drug users. Methods: Information of 4817 clients seeking treatment for illicit drug use was linked with the Finnish hospital discharge register to identify those who were hospitalized with main/primary diagnoses of pneumonia during 1997-2013. Cox regression models were used to examine the association between age, gender, homelessness, and route of drug administration of the primary drug at initial clinical consultation and pneumonia hospitalization. Findings were presented as adjusted hazard ratios and 95% confidence intervals. Results: There were 354 persons diagnosed with pneumonia, with a total of 522 hospitalizations at the end of 2013. The univariate Cox models revealed that being over 44 years of age, male gender, homelessness, and intravenous drug use at initial clinical consultation increased the risk of being hospitalized for pneumonia. In the fully adjusted multivariate model, being over 44 years was the strongest factor independently associated with pneumonia hospitalization (adjusted hazard ratio: 2.67, 95% confidence interval: 1.56-4.57, p < 0.001), followed by homelessness (adjusted hazard ratio: 1.75, 95% confidence interval: 1.38-2.22, p < 0.001) and intravenous drug use (adjusted hazard ratio: 1.27, 95% confidence interval: 1.01-1.59, p = 0.041). Of the 354 clients hospitalized for pneumonia, 31.9% (n = 113) were rehospitalized within 30 days of being discharged. One-third of the reasons for the 30-day rehospitalization were pneumonia-related. Conclusion: Vaccination, measures addressing housing instability, safe injecting and good hygienic practices, and treating underlying drug use problems could help to reduce morbidity for pneumonia in this cohort. PMID- 30013783 TI - Hemoglobin spray as adjunct therapy in complex wounds: Meta-analysis versus standard care alone in pooled data by wound type across three retrospective cohort controlled evaluations. AB - Objectives: Low tissue oxygenation is a predictor of healing outcomes in complex wounds. Adjunct hemoglobin to aid oxygen diffusion has been demonstrated to achieve superior healing outcomes; however, the relative healing benefit across different wound types and evaluations has not yet been estimated. This article does this for the first time. Methods: Data were pooled from previously published real world controlled evaluations, three retrospective cohort controlled studies of a variety of wounds within standard care across hospital and primary care in the North of England in patients with diabetic foot ulcers (n = 40), chronic wounds (n = 100), and sloughy wounds (n = 200). Wounds were equally distributed between adjunct hemoglobin and control and the hemoglobin spray was used as per instructions for use and applied twice weekly, mostly for the duration of the wounds in all three evaluations. Wound healing over 26 weeks was the primary outcome in each of the evaluations, with additional healing and quality of life indicators including pain, wound size, slough coverage, wound exudate levels, adverse events, and dressing regimen used, over time. Each wound type with 10 or more patients in both the standard care alone and adjunctive hemoglobin groups (n = 257/73% of patients) was evaluated. Results: Cox proportional hazards log-rank regressions demonstrated significantly higher weekly chance of healing in each wound type (beta, 95% range, sample, p): trauma 1.55 (1.23-1.96, n = 110, p < 0.001), diabetic foot ulcers 2.39 (1.52-3.75, n = 60, p = 0.01), venous leg ulcers 4.98 (1.69-14.7, n = 33, p = 0.04), burns 1.82 (1.11-2.99, n = 30, p = 0.02), and post-surgical wounds 2.75 (1.53-4.96, n = 24, p = 0.001). Results on additional healing indicators were consistent with the main findings. Notably, controlling for ischemia in diabetic foot ulcers resulted in an increased beta of 5.68 (2.33-13.86, n = 29, p < 0.001). Conclusion: Adjunct hemoglobin spray, when implemented within standard care, is likely to achieve substantial healing benefits to patients, in particular for diabetic foot ulcers, venous leg ulcers, and post-surgical wounds. PMID- 30013784 TI - Association between physical health and cardiovascular diseases: Effect modification by chronic conditions. AB - Objectives: This study assessed whether the physical component summary score of the RAND-36 health-related quality-of-life survey was associated with incidence of coronary heart disease, stroke, congestive heart failure, angina, or peripheral arterial disease, and whether baseline chronic conditions modified these associations. Methods: Analysis was limited to 69,155 postmenopausal women (50-79 years) in the Women's Health Initiative Study who had complete data on the RAND-36, the outcomes, and covariates. Chronic conditions were defined as blood pressure ?140/90 mm or self-reported heart disease, diabetes, hypertension, arthritis, asthma, emphysema, cancer, and/or cholesterol-reducing medication use. Outcomes data were ascertained during follow-up (1993-2005) with medical records. Results: There were 2451 coronary heart disease, 1896 stroke, 1533 congestive heart failure, 1957 angina, and 502 peripheral arterial disease events during follow-up (median 8.2 years). Participants in the lowest physical component summary quintile, compared to the highest, had a significantly higher risk of developing coronary heart disease (hazard ratio (95% confidence interval) 2.0 (1.7, 2.3)), stroke (1.8 (1.5, 2.2)), angina (2.4(2.0, 2.9)), and peripheral arterial disease (3.0 (2.0, 4.4)), irrespective of chronic conditions. Interactions between physical component summary and existing chronic conditions were not significant for any outcome except congestive heart failure (p = 0.005); after adjustment, participants in the lowest physical component summary quintile and with any chronic condition had nearly a twofold higher risk of congestive heart failure (Yes = 4.4 (3.3, 5.8) vs No = 2.4 (1.2, 4.3)). Conclusion: We found a low physical component summary score was a significant risk factor for individual cardiovascular disease incidence in postmenopausal women. PMID- 30013785 TI - Iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders: Results from a phase 3, randomized open-label study. AB - Objectives: The recent availability of iron-based phosphate binders has raised some concerns about iron overload in patients with end-stage renal disease. This study evaluated iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders. Methods: This analysis used 2-year follow-up data from an open-label, multicentre, randomized, active-controlled, parallel-group, phase 3 trial of lanthanum carbonate (SPD405-307). After a washout period, if patients' serum phosphate levels exceeded 5.9 mg/dL, they were randomized 1:1 to receive lanthanum carbonate (375-3000 mg/day) or non-iron-based standard therapy during a 6-week dose titration period. Patients achieving control of serum phosphate levels (?5.9 mg/dL) received maintenance therapy with lanthanum carbonate or standard therapy for up to 24 months. Results: No clinically relevant changes in mean (standard deviation) iron parameters between the treatment groups (lanthanum carbonate, n = 682; standard therapy, n = 677) from baseline to month 24/final visit were observed: iron (ug/dL), -1.1 (41.8) versus 1.0 (38.7); ferritin (ng/mL), 208.4 (445.1) versus 262.4 (505.5); transferrin saturation (%), 2.8 (18.0) versus 2.8 (17.3); and haemoglobin (g/dL), 0.4 (1.9) versus 0.3 (1.7), respectively (all, p > 0.1). There were no clinically relevant changes in the percentage of patients receiving any anti-anaemic preparation in either treatment group (pre- vs post randomization: lanthanum carbonate, 94.9% vs 97.8%; standard therapy, 95.1% vs 98.8%, respectively). This is in contrast to the study by Lewis and colleagues, which found significant increases in ferritin and transferrin saturation levels in patients receiving ferric citrate versus active control (calcium acetate and/or sevelamer carbonate) after 52 weeks of therapy. Although serum ferritin and transferrin saturation are the recommended iron indices by the Kidney Disease Outcome Quality Initiative, they are indirect indicators of iron status. Longer term studies are required to understand fully the potential risks associated with iron overload. Conclusion: No evidence of iron accumulation was found in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron based binders. PMID- 30013786 TI - Use of autologous bone grafting from the calcaneus and interconnected porous hydroxyapatite ceramic for bone transplantation in rheumatoid foot surgery. AB - Cancellous bone grafts from the calcaneus have been used for the foot and ankle as well as iliac bone graft; however, there is a sparse report for calcaneal bone transplantation in the field of rheumatoid foot surgery. In this study, safety and usefulness of calcaneal bone grafts, and combination with interconnected porous hydroxyapatite ceramic, was evaluated in rheumatoid arthritis foot surgeries. Of six rheumatoid arthritis cases, three (talo-navicular joint fusion) used a calcaneal bone graft alone, and the remaining three cases (subtalar joint and talo-navicular joint fusion) used a combination of calcaneal bone graft and interconnected porous hydroxyapatite ceramic augmented with dense calcium hydroxyapatite for subtalar bony defect (1.5-2.0 cm) after the correction. Pre- and postoperative Japanese Society for Surgery of the Foot rheumatoid arthritis foot ankle scale scores were obtained for the clinical assessment. As radiographic assessment, tibio-calcaneal angle, calcaneal pitch, talo-1st metatarsal angle, and pronated foot index were also evaluated. After starting weight-bearing or walking, there was no pain and skin trouble at the fusion and harvesting sites. All cases achieved bony fusion within 6-10 weeks. Japanese Society for Surgery of the Foot rheumatoid arthritis foot ankle score was improved in all six cases. Furthermore, tibio-calcaneal angle, talo-1st metatarsal angle, and pronated foot index were also improved at latest follow-up in all cases. In conclusion, autologous bone grafting from the calcaneus was safe and convenient even in rheumatoid foot surgeries. For larger bony defects (1.5 2.0 cm), combination use with interconnected porous hydroxyapatite ceramic augmented with dense calcium hydroxyapatite was also useful. PMID- 30013787 TI - Septic pulmonary emboli causing recurrent bilateral pneumothoraces in a patient with right sided endocarditis: A case report and review of literature. AB - Patients with a history of drug abuse and right sided endocarditis are prone to develop septic pulmonary emboli. Pneumothorax is a rare complication of septic pulmonary emboli reported in the literature, likely due to the rupture of thin walled septic cavitary lesions resembling pneumatoceles into the pleural space. Only seven cases (including our case) of pneumothorax from septic pulmonary emboli due to right sided endocarditis have been described in the literature. Our patient is the first reported case of recurrent bilateral pneumothorax due to septic pulmonary emboli and tricuspid valve endocarditis. PMID- 30013788 TI - Old syndrome-new approach: Mauriac syndrome treated with continuous insulin delivery. AB - Mauriac syndrome has rarely been reported in children and adolescents with a poorly controlled diabetes mellitus type 1. However, it still occurs despite the worldwide improvements of metabolic control. The risks have not been elucidated. We present a 13.5-year-old boy with a typical clinical presentation of Mauriac syndrome consisting of growth delay, cushingoid appearance, hepatomegaly, and delayed puberty. A stepwise correction of glycemic control was introduced using continuous insulin delivery. All symptoms improved during the 2.5-year follow-up. No retinopathy occurred. This patient with Mauriac syndrome followed with continuous glucose monitoring and treated with continuous insulin delivery, resulting in no retinopathy after 2.5 years of follow-up. We suggest that this approach should be recommended in patients with Mauriac syndrome. PMID- 30013789 TI - Spinal neuraxial anaesthesia for caesarean section in a parturient with type I Arnold Chiari malformation and syringomyelia. AB - Introduction: Type 1 Arnold Chiari malformation is associated with prolapse of the cerebellar tonsils into or below the level of the foramen magnum and is usually diagnosed in adults. There are no current guidelines for the management of patients with a residual type I Arnold Chiari malformation, planned for a caesarean section under spinal neuraxial anaesthesia. The paucity in the literature on this topic presents as a management dilemma. Case report: We report a case of a term parturient with type 1 Arnold Chiari malformation, following surgical decompression 4 years earlier, with a residual syringomyelia that underwent an elective caesarean section under spinal neuraxial anaesthesia. Conclusion: This case highlights that multidisciplinary management and early anaesthetic consult are of paramount importance in the outcome of the patient, and that spinal neuraxial anaesthesia can be considered as a safe anaesthetic option. PMID- 30013790 TI - Uridine triacetate for severe 5-fluorouracil toxicity in a patient with thymidylate synthase gene variation: Potential pharmacogenomic implications. AB - Adverse drug reactions can be unpredictable. However, pharmacogenomic testing can help identify patients who may be more susceptible to the toxic effects of certain drugs. Genetic variations in the dihydropyrimidine dehydrogenase and thymidylate synthase genes have been shown to increase the risk of 5-fluorouracil toxicity. 5-Fluorouracil toxicity can be life threatening. Fortunately, there is treatment available for 5-fluorouracil toxicity, called uridine triacetate. Although, the indications for its use limit its administration to within 96 h of receiving 5-fluorouracil, we report a case of effective therapy in a patient started on uridine triacetate beyond the recommended 96 h, who was found to carry a thymidylate synthase gene variation but no dihydropyrimidine dehydrogenase mutations. This provides important implications for pharmacogenomic testing. PMID- 30013791 TI - HbA1c and hypoglycaemia in intensively treated type 2 diabetes: a retrospective cohort study in primary care. AB - Objective: To establish whether low HbA1c is associated with clinical hypoglycaemia among people with type 2 diabetes prescribed insulins or sulphonylureas. Design: Retrospective cohort study using routine electronic GP health records collected between January 2013 and December 2015. Setting: Three east London Clinical Commissioning Groups. Participants: Two cohorts of adults with type 2 diabetes prescribed either (i) insulins with or without other oral antidiabetic medication (n = 6788, 36.4%) or (ii) sulphonylureas with or without other oral antidiabetic medications excluding insulins (n = 11,840, 63.6%). Main outcome measures: First clinically recorded hypoglycaemia and all-cause mortality. Hazard ratios (HR) adjusting for age, ethnicity, renal function and comorbidities were calculated using Cox regression models. Results: Compared with an HbA1c of 53-63 mmol/mol, the adjusted HR of hypoglycaemia in those with a low HbA1c, below 53 mmol/mol, in the insulin and sulphonylurea cohorts were 1.26 (95% CI, 0.97 to 1.62) and 1.54 (95% CI, 1.27 to 1.87), respectively. Adjusted HRs of all-cause mortality from low HbA1c in the insulin and sulphonylurea cohorts were 1.54 (95% CI, 1.15 to 2.07) and 1.42 (95% CI, 1.11 to 1.81), respectively. Increasing age and renal impairment were also associated with increased hypoglycaemic risk in both cohorts. Conclusions: HbA1c below 53 mmol/mol was associated with episodes of clinical hypoglycaemia among people with type 2 diabetes prescribed sulphonylureas, and all-cause mortality in those prescribed insulins and sulphonylureas. These findings support the need for reviewing glycaemic targets and the intensities of treatment in those with low HbA1c prescribed insulins or sulphonylureas to reduce the risk of hypoglycaemia. PMID- 30013792 TI - Single-phase bilateral low dose contrast medium injection for diagnosing occlusions of the thoracic venous system: a case report. AB - Occlusion of the thoracic venous system and/or occlusion of central venous catheters (CVC) of unknown cause can, in selected cases, require advanced imaging. Here, we describe a case study of a patient with a failing central dialysis catheter (CDC) which was diagnosed by computed tomography (CT) in connection with a single-phase bilateral low-dose contrast medium (CM) injection using only 3.6 g of iodine. By injecting a low CM dose, the risk of streak artifacts from first-pass of high intravascular concentrations of CM can be avoided. Therefore, the technique described here should be beneficial also to patients with normal renal function. PMID- 30013793 TI - Variable size of aortic subvalvular pseudoaneurysm. AB - Aortic subvalvular pseudoaneurysms (PSA) are particularly subjected to strain and shear stress forces from blood flow and therefore their size can vary along the heart cycle. Here we describe a case of an aortic subvalvular PSA that shows significant variation in size between systolic and diastolic phase during retrospective ECG-triggered cardiac computed tomography angiography. PMID- 30013794 TI - Extraocular muscle sampled volume in Graves' orbitopathy using 3-T fast spin-echo MRI with iterative decomposition of water and fat sequences. AB - Background: Current magnetic resonance imaging (MRI) techniques for measuring extraocular muscle (EOM) volume enlargement are not ideally suited for routine follow-up of Graves' ophthalmopathy (GO) because the difficulty of segmenting the muscles at the tendon insertion complicates and lengthens the study protocol. Purpose: To measure the EOM sampled volume (SV) and assess its correlation with proptosis. Material and Methods: A total of 37 patients with newly diagnosed GO underwent 3-T MRI scanning with iterative decomposition of water and fat (IDEAL) sequences with and without contrast enhancement. In each patient, the three largest contiguous coronal cross-sectional areas (CSA) on the EOM slices were segmented using a polygon selection tool and then summed to compute the EOM-SV. Proptosis was evaluated with the Hertel index (HI). The relationships between the HI value and EOM-SV and between HI and EOM-CSA were compared and assessed with Pearson's correlation coefficient and the univariate regression coefficient. Inter-observer and intra-observer variability were calculated. Results: HI showed a stronger correlation with EOM-SV (P < 0.001; r = 0.712, r2 = 0.507) than with EOM-CSA (P < 0.001; r = 0.645 and r2 = 0.329). The intraclass correlation coefficient indicated that the inter-observer agreement was high (0.998). The standard deviation between repeated measurements was 1.9-5.3%. Conclusion: IDEAL sequences allow for the measurement EOM-SV both on non-contrast and contrast enhanced scans. EOM-SV predicts proptosis more accurately than does EOM-CSA. The measurement of EOM-SV is practical and reproducible. EOM-SV changes of 3.5-8.3% can be assumed to reflect true volume changes. PMID- 30013795 TI - Diffusion-weighted imaging in acute pulmonary embolism: a feasibility study. AB - Background: Magnetic resonance imaging (MRI) can be an alternative method to computed tomography angiography (CTA) for pulmonary embolism. Purpose: To evaluate the feasibility of diffusion-weighted imaging (DWI) detecting acute pulmonary embolism (PE) in free-breathing humans. Material and Methods: Twenty patients with PE verified by CTA and 20 controls were investigated with MRI (1.5 Aera, Siemens Healthcare). All sequences were performed in the transversal plane using free-breathing without gating. The protocol consisted of a two-dimensional steady-state free precession (SSFP) and a single-shot DWI echo-planar imaging sequence with a voxel resolution of 2 * 2 * 5 mm. Three b values were used: 50, 400, and 800 s/mm2. Images were analyzed in two orders: an open source analysis (OSA); and a blinded only DWI analysis (BDA) simulating clinical work. Results: OSA of corresponding images showed 370 findings on CTA (i.e. one elongated emboli could be represented in multiple images). SSFP identified 237 of those (64%). DWI with b values of 50, 400, and 800 identified 327 (88%), 245 (66%), and 138 (37%), respectively. In BDA we found 160 true emboli (according to CTA) on b50, 78 on b400, and 54 on b800. Fifty-two of these findings at the subsegmental level could be correlated to PE on CTA but were not visible on SSFP. Conclusions: DWI has a high sensitivity for detecting PE but suffers from poor specificity. It could potentially be used as an eye catcher, i.e. where to look for PE in other MRI sequences. PMID- 30013797 TI - The Global Precipitation Climatology Project (GPCP) Monthly Analysis (New Version 2.3) and a Review of 2017 Global Precipitation. AB - The new Version 2.3 of the GPCP Monthly analysis is described in terms of changes made to improve the homogeneity of the product, especially after 2002. These changes include corrections to cross calibration of satellite data inputs and updates to the gauge analysis. Over ocean, changes starting in 2003 result in an overall precipitation increase of 1.8% after 2009. Updating the gauge analysis to its final, high quality version increases the global land total by 1.8% for the post-2002 period. These changes correct a small, incorrect dip in the estimated global precipitation over the last decade in the earlier Version 2.2. The GPCP analysis is also used to describe global precipitation for 2017. The general La Nina pattern for 2017 is noted and the evolution from the early 2016 El Nino pattern is described. The 2017 global value is one of the highest for the 19792017 period, exceeded only by 2016 and 1998 (both El Nino years) and reinforces the small positive trend. Results for 2017 also reinforce significant trends in precipitation intensity (on a monthly scale) in the tropics. These results for 2017 indicate the value of the GPCP analysis for climate monitoring in addition to research. PMID- 30013798 TI - Development and Evaluation of a Loop-Mediated Isothermal Amplification Assay for Diagnosis of Schistosoma mansoni Infection in Faecal Samples. AB - Human intestinal schistosomiasis is caused by the blood fluke, Schistosoma mansoni. With intensified efforts to control schistosomiasis by mass drug administration using praziquantel (PZQ), there is an urgent need to have accessible, quality-assured diagnostic tests for case detection and disease surveillance and for monitoring efficacy of treatment and other interventions. Current diagnostic tools are limited by suboptimal sensitivity, slow turn-around time, affordability, and inability to distinguish current from past infections. We describe a simple and rapid diagnostic assay, based on the loop-mediated isothermal amplification (LAMP) technology for diagnosis of S. mansoni infection in human faecal samples. The LAMP primers used in this assay were previously described and they target a 121-bp DNA repeat sequence in S. mansoni. The LAMP assay was optimized at an isothermal temperature of 63 degrees C for 1 hour. The amplified DNA was either visualized under ultraviolet light after electrophoresis or by directly observing the color change after staining the amplicons with CYBR Green dye. The LAMP assay was evaluated against the microscopy-based procedure and the results were analysed using Cohen's kappa coefficient to determine the degree of agreement between the two techniques. The LAMP assay reliably detected S. mansoni ova DNA in faecal samples and parasite DNA in amounts as low as 32fg. When the assay was tested for specificity against other faecal-based soil transmitted helminths (STH), no cross-reactivity was observed. The LAMP assay was superior to the Kato-Katz assay with a 97% specificity; a high positivity score reliably detecting S. mansoni and a Kappa Coefficient of 0.9 suggested an exceptional agreement between the two techniques. The LAMP assay developed has great potential for application in field settings to support S. mansoni control and elimination campaigns. PMID- 30013799 TI - Mechanism and rate constant of proline-catalysed asymmetric aldol reaction of acetone and p-nitrobenzaldehyde in solution medium: Density-functional theory computation. AB - In search of new ways to improve catalyst design, the current research focused on using quantum mechanical descriptors to investigate the effect of proline as a catalyst for mechanism and rate of asymmetric aldol reaction. A plausible mechanism of reaction between acetone and 4-nitrobenzaldehyde in acetone medium was developed using highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies calculated via density functional theory (DFT) at the 6-31G*/B3LYP level of theory. New mechanistic steps were proposed and found to follow, with expansion, the previously reported iminium enamine route of typical class 1 aldolase enzymes. From the elementary steps, the first step which involves a bimolecular collision of acetone and proline was considered as the rate-determining step, having the highest activation energy of 59.07 kJ mol-1. The mechanism was used to develop the rate law from which the overall rate constant was calculated and found to be 4.04*10-8dm3mol-1s-1 . The new mechanistic insights and the explicit computation of the rate constant further improve the kinetic knowledge of the reaction. PMID- 30013800 TI - Smear Microscopy for Diagnosis of Pulmonary Tuberculosis in Eastern Sudan. AB - Background: In Sudan, tuberculosis diagnosis largely relies on clinical symptoms and smear microscopy as in many other low- and middle-income countries. The aim of this study was to investigate the positive predictive value of a positive sputum smear in patients investigated for pulmonary tuberculosis in Eastern Sudan. Methods: Two sputum samples from patients presenting with symptoms suggestive of tuberculosis were investigated using direct Ziehl-Neelsen (ZN) staining and light microscopy between June to October 2014 and January to July 2016. If one of the samples was smear positive, both samples were pooled, stored at -20 degrees C, and sent to the National Reference Laboratory (NRL), Germany. Following decontamination, samples underwent repeat microscopy and culture. Culture negative/contaminated samples were investigated using polymerase chain reaction (PCR). Results: A total of 383 samples were investigated. Repeat microscopy categorized 123 (32.1%) as negative, among which 31 were culture positive. This increased to 80 when PCR and culture results were considered together. A total of 196 samples were culture positive, of which 171 (87.3%), 14 (7.1%), and 11 (5.6%) were M. tuberculosis, M. intracellulare, and mixed species. Overall, 15.6% (57/365) of the samples had no evidence of M. tuberculosis, resulting in a positive predictive value of 84.4%. Conclusions: There was a discordance between the results of smear microscopy performed at local laboratories in the Sudan and at the NRL, Germany; besides, a considerable number of samples had no evidence of M. tuberculosis. Improved quality control for smear microscopy and more specific diagnostics are crucial to avoid possible overtreatment. PMID- 30013801 TI - A Young Male with Severe Myocarditis and Skeletal Muscle Myositis. AB - A 34-year-old male presented with retrosternal chest pain, fatigue, shortness of breath, and a history of a previous episode of myocarditis four years prior. He had elevated troponin T, normal skeletal muscle enzymes, and negative inflammatory markers. Cardiac magnetic resonance imaging (MRI) confirmed active myocarditis with extensive myocardial fibrosis and normal left ventricular ejection fraction (LVEF). His myocarditis symptoms resolved with steroids and anti-inflammatory treatment, but on closer questioning, he reported a vague history of long-standing calf discomfort associated with episodes of stiffness, fatigue, and flu-like symptoms. MRI of the lower legs consequently demonstrated active myositis in the calf muscles. Immunomodulatory therapy was commenced with good effect. The patient is undergoing regular follow-up in both cardiology and rheumatology outpatient departments. Repeated MRI of the legs showed significant interval improvement in his skeletal muscle myositis, and repeat cardiac MRI demonstrated the resolution of myocarditis along with persistent stable extensive myocardial fibrosis and preserved LVEF. The patient has returned to full-time work. PMID- 30013802 TI - Sepsis, Endocarditis, and Purulent Arthritis due to a Rare Zoonotic Infection with Streptococcus equi Subspecies zooepidemicus. AB - Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) is mostly known as an opportunistic pathogen found in horses and as a rare human zoonosis. An 82 year-old male, who had daily contact with horses, was admitted in a septic condition. The patient presented with dyspnea, hemoptysis, impaired general condition, and severe pain in a swollen left shoulder. Synovial fluid from the affected joint and blood cultures showed growth of S. equi subsp. zooepidemicus. Transesophageal echocardiography showed a vegetation on the aortic valve consistent with endocarditis. Arthroscopic revision revealed synovitis and erosion of the rotator cuff. Technetium-99m scintigraphy showed intense increased activity in the left shoulder, suspicious of osteitis. The infection was treated with intravenous antibiotics over a period of five weeks, followed by oral antibiotics for another two months. The patient recovered without permanent sequelae. PMID- 30013796 TI - Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer. AB - Protein methyltransferases have been shown to methylate histone and non-histone proteins, leading to regulation of several biological processes that control cell homeostasis. Over the past few years, the histone-lysine N-methyltransferase SETD7 (SETD7; also known as SET7/9, KIAA1717, KMT7, SET7, SET9) has emerged as an important regulator of at least 30 non-histone proteins and a potential target for the treatment of several human diseases. This review discusses current knowledge of the structure and subcellular localization of SETD7, as well as its function as a histone and non-histone methyltransferase. This work also underlines the putative contribution of SETD7 to the regulation of gene expression, control of cell proliferation, differentiation and endoplasmic reticulum stress, which indicate that SETD7 is a candidate for novel targeted therapies with the aim of either stimulating or inhibiting its activity, depending on the cell signaling context. PMID- 30013803 TI - A Rare Presentation of Stage IV Large Cell Neuroendocrine Carcinoma of the Cervix with Metastasis to the Cranium. AB - Neuroendocrine tumors (NETs) are aggressive diseases developing from neuroendocrine cells that most frequently involve the gastro-entero-pancreatic tract and the lung, but more rarely are found in almost all body tissues. Limited biological and clinical data are currently available for NETs in uncommon sites, such as female genital tract. NETs represent 0.9% to 1.5% of the tumors of the uterine cervix. This case is reported on a 75-year-old Caucasian woman, presenting with dental and generalized pain for two weeks. Later during her admission, facial droop and diplopia were noticed. Radiological findings ruled out cerebrovascular accident but revealed multiple bone marrow lesions involving the left and the right clivus, right Meckel's cave, and posterior margin of the right cavernous sinus. Findings also included pulmonary nodules and adenopathy supporting diagnosis of likely stage IV metastatic carcinoma. Further imaging revealed homogeneous enhancement of the uterus suggestive of diffusely infiltrative carcinoma; pathology results confirmed large cell neuroendocrine carcinoma of the uterine cervix (LCNEC) giving her a 1.5-month median survival range. PMID- 30013804 TI - Unsuspected Diagnosis of Uterine Leiomyosarcoma after Laparoscopic Myomectomy in an Isolated Bag. AB - Minimally invasive techniques are generally applied for patients suspected of having benign fibroids if medical treatment is insufficient. On the other hand, sometimes some occult carcinomas of uterus like leiomyosarcomas may be reported for the patients' applied morcellation. This condition is rare but outcomes are clinically significant. Fragmentation of occult sarcoma in the abdominal cavity without isolation bag results in widespread and poor survival. In this article, we report a case of 37-year-old woman suffering from pain due to unexpected leiomyosarcoma. Laparoscopic myomectomy was performed with power morcellation in an isolated bag. Although isolation bag is generally reported to be preventive, recurrence of sarcoma was seen at 5th month of follow-up. Even though morcellation within a bag seems to block wide spreading, dispersion of tumor cannot be stopped and more investigations have to be done. PMID- 30013805 TI - Total Hip Lithiasis: A Rare Sequelae of Spilled Gallstones. AB - Laparoscopic cholecystectomy is a surgical treatment for acute cholecystitis or symptomatic cholelithiasis. One potential complication, the spillage of gallstones into the peritoneal cavity, can form a nidus for infection and may be associated with hepatic, retroperitoneal, thoracic, and abdominal wall abscesses. We report a case of a patient presenting with a right iliopsoas abscess and an infected right hip prosthesis status postlaparoscopic cholecystectomy. A CT demonstrated that the acetabular shell was overmedialized and perforated through the medial wall. The patient was taken to the operating room for explantation of components. A collection of gallstones was identified deep to the acetabulum during the explantation. The case highlights the importance of avoiding overmedialization of the acetabular component, which can provide a direct route for infection into the hip joint. PMID- 30013806 TI - Management of Psychosis in a Patient with Probable Dopa-Responsive Dystonia. AB - Dopa-responsive dystonia is a rare childhood neurological disorder characterized by asymmetric dystonia, predominantly of the lower limb, that responds excellently to levodopa replacement therapy. Although it is known that behavioral changes, such as depression, anxiety disorders, and sleep disturbances, typically follow onset of motor symptoms, there is limited literature on the psychiatric symptoms of this disorder. This report describes a novel case of a 20-year-old male with a history of dopa-responsive dystonia and schizoaffective disorder who presented with both dystonia and psychosis after a period of medication noncompliance. This case provides a reference for the management of psychosis in patients with dopa-responsive dystonia and highlights the need for more research on the nonmotor symptoms that accompany this neurological disorder. PMID- 30013807 TI - Benzo[g]coumarin-Based Fluorescent Probes for Bioimaging Applications. AB - Benzo[g]coumarins, which consist of coumarins fused with other aromatic units in the linear shape, have recently emerged as an interesting fluorophore in the bioimaging research. The pi-extended skeleton with the presence of electron donating and electron-withdrawing substituents from the parent coumarins changes the basic photophysical parameters such as absorption and fluorescence emission significantly. Most of the benzo[g]coumarin analogues show red/far-red fluorescence emission with high two-photon absorbing property that can be applicable for the two-photon microscopy (TPM) imaging. In this review, we summarized the recently developed benzo[g]coumarin analogues including photophysical properties, synthesis, and applications for molecular probes that can sense biologically important species such as metal ions, cell organs, reactive species, and disease biomarkers. PMID- 30013808 TI - SRM-MS Method Development for Hepcidin-25 Peptide. AB - As advanced mass spectrometry- (MS-) based hepcidin analysis offers to overcome the limitations in analytical methods using antihepcidin, further improvement of MS detection sensitivity for the peptide may enhance the diagnostic value of the hepcidin for various iron-related disorders. Here, improved MS detection sensitivity of hepcidin has been achieved by reducing the disulfide bonds in hepcidin, by which proton accessibility increased, compared to the intact hepcidin peptide. Comparing the ionization efficiencies of reduced and nonreduced forms of hepcidin, the reduced form of hepcidin showed an increase in ionization efficiency more than two times compared to the nonreduced form of hepcidin. We also demonstrated improved detection sensitivity of the peptide in SRM assay. We observed a significant improvement of detection sensitivity at the triple quadrupole MS platform, that the ionization efficiency increased at least twice more, and that the limit of detection (LOD) increased more than 10 times in the concentration ranges of 1 fmol to 10 fmol of hepcidin. In this study, we demonstrated the usefulness of the hepcidin modification for overall enhancement of the ionization efficiencies of the hepcidin peptide in the MS-based quantitative measurement assay. PMID- 30013809 TI - Weekend Admission of Intracapsular Femoral Neck Fractures Not Associated With a Greater Rate of Mortality or Morbidity. AB - Introduction: For a number of emergency conditions, admission over the weekend has been associated with rising morbidity and mortality rates. However, different studies have provided conflicting results regarding the increased rates of mortality and morbidity for patients with intracapsular femoral fracture who were admitted over the weekend, compared to weekdays. This study investigated the effect of weekend admissions on the surgical outcomes of patients with intracapsular femoral neck fractures. Materials and Methods: We conducted a retrospective cohort study of all the patients who were admitted to our level-II trauma center with an intracapsular femoral neck fracture between January 2009 and June 2011. Admission was classified as at the weekend if it took place between 18:00 pm on Friday until midnight on Sunday or on bank holidays. We compared the mortality rates within 30 days and 6 months after surgery for weekday and weekend admissions. Secondary outcomes considered included length of hospital stay, postoperative complications, and reoperation rates. Statistical analysis was performed using logistic regression models, which were adjusted for patient and surgical characteristics. Results: In total, 315 patients met our inclusion criteria. The mean age of this group was 77.9 years (standard deviation +/-13) and the female to male ratio was 5:2. The average follow-up period was 49 months. Under logistic regression analysis, weekend admission was not a significant independent risk factor for the 30-day mortality rate (odds ratio 1.85, 95% confidence interval, 0.74-4.62; P = .19). Seventy-seven patients admitted over the weekend were treated within 24 hours versus 125 patients for the weekday group (80.2% vs 57.9%; P = .005). There were no differences between the sample groups in relation to implant-related complications (24.9% vs 25.8%, respectively, P = .89) nor in relation to general complications (12% vs 18.6%, respectively, P = .06). The mean hospital stay of patients operated on during weekends or holidays was significantly shorter compared to patients operated on during weekdays (6.7 vs 8.5 days; P = .009). Conclusion: Patients with intracapsular femoral neck fractures who were admitted over the weekend at our trauma center did not have a higher risk of mortality or morbidity. Furthermore, temporary preoperative care provided over the weekend by an internal medical consultant can be safe and efficient even in the circumstances where there is a lack of dedicated geriatric support. The absence of an elective operating list at the weekend could be a potential factor in shortening waiting times for surgery for intracapsular femoral neck fracture at weekends and holidays. PMID- 30013810 TI - Is There a Role for Early Palliative Intervention in Frail Older Patients With a Neck of Femur Fracture? AB - Background: Patients with a neck of femur fracture have a high mortality rate. National outcomes have improved significantly as the management of this patient group is prioritized. In 2016, however, 4398 (6.7%) patients died within 30 days of admission. Objective: To investigate whether palliative care could be integrated early in the care plan for high-risk patients. Methods: All cases of inpatient mortality following neck of femur fracture at North Bristol Major Trauma Centre over a 24-month period were reviewed. A comprehensive assessment of care was performed from the emergency department until death. All investigations, interventions, and management decisions were recorded. A consensus decision regarding expected mortality was made for each case at a multidisciplinary meeting which included surgical, orthogeriatric, nursing, and anesthetic team input. Results: A total of 1033 patients were admitted following a neck of femur fracture. There were 74 inpatient deaths, and 82% were considered predictable at our multidisciplinary meeting. The mean length of stay was 18 days (range: 0-85, median 14). In 42% of cases, mortality was considered predictable on admission, and 40% were considered predictable following acute deterioration. These patients received on average 28 blood tests (range: 4-114) and 6.8 X-rays and computed tomographies (range: 2-20). Of this, 66% received end-of-life care; mean duration 2.3 days (range: 0-17). Conclusions: Mortality rates remain high in a subset of patients. This study demonstrates that intensive investigation and medical management frequently continues until death, including in patients with predictably poor outcomes. Early palliative care input has been integrated successfully into patient management in other specialties. We demonstrate that it is feasible to identify patients with hip fracture who may benefit from this expertise. PMID- 30013812 TI - KRATOM AND THE OPIOID CRISIS. PMID- 30013811 TI - Ten years of EMS Fall Calls in a Community: An Opportunity for Injury Prevention Strategies. AB - Objective: To determine whether fall calls, lift assists, and need for transport to the hospital over the past 10 years in one emergency medical services (EMS) system have altered coincident with demographic changes and to estimate health care cost for lift assists. Methods: We conducted a retrospective chart review of EMS fall-related care. The HealthEMS database for a suburban community surveyed was queried from March 1, 2007, to March 1, 2017. Fall-related calls in patients 60 years or older were identified and determined to be either lift assists (calls that do not result in transport) or fall calls that resulted in transport to the hospital. Results: Of the 38 237 EMS care responses in patients 60 years or older, 11.5% were related to falls. Fall calls increased by 268% over the past 10 years (P = .0006), yet the number of transports to the hospital significantly decreased over time (P = .02). Lift assists increased significantly (P = .0003), nearly doubling over the decade. At the same time, fall calls that did not result in transport to the hospital cost the community an estimated US$1.5 million over a 10-year period. Discussion: There has been a dramatic shift in fall-related calls to EMS in older individuals with more frequent calls for lesser acuity needs. Utilization of EMS for lift assists has substantial financial consequences and diverts care from calls that need immediate triage and transport to care. Conclusion: Future work to reduce the frequency and increase the impact of EMS lift assists could have a significant cost benefit and provide opportunity for enrollment in appropriate community services and fall prevention programs. PMID- 30013813 TI - EFFECTIVE PAIN CONTROL IN HUTCHINSON-GILFORD PROGERIA SYNDROME. PMID- 30013814 TI - Valbenazine and Deutetrabenazine for Tardive Dyskinesia. AB - Tardive dyskinesia (TD) is a medication-induced permanent movement disorder with no United States Food and Drug Administration (FDA)-approved treatments prior to 2017. Although TD is medication-induced, patients who have responded well to antipsychotics might not be candidates for dose reduction or discontinuation due to a risk of psychiatric decompensation. Valbenazine and deutetrabenazine were recently approved by the FDA for the treatment of TD. They offer a unique mechanism of action by inhibiting vesicular monoamine transporter type 2. The objective of this review is to discuss the efficacy, tolerability, dosing, drug interactions, and precautions for valbenazine and deutetrabenazine. PMID- 30013815 TI - Combination Phentermine-Topiramate Extended Release for the Treatment of Binge Eating Disorder: An Open-Label, Prospective Study. AB - Objective: The goal of this study was to obtain preliminary data on the usefulness of the combination of phentermine and topiramate extended release (phentermine-topiramate) in binge-eating disorder (BED) associated with obesity or overweight. Design: Ten participants with BED and obesity or overweightness with at least one weight-related complication received phentermine-topiramate in an open-label, prospective, 12-week trial. The primary outcome measure was change in weight. The study was registered under the identifier NCT02659475 at ClinicalTrials.gov. Results: Seven participants completed the study. Phentermine topiramate treatment was associated with significant reductions in weight, body mass index, binge-eating episode frequency, and measures of global clinical severity, eating disorder psychopathology, and obsessive-compulsive symptoms. Mean daily dose of phentermine-topiramate at endpoint was 6.8 to 41.4mg per day. The most common adverse event (AE) was dysgeusia. There were no serious AEs, and no participants displayed symptoms of medication misuse or withdrawal. Conclusion: Phentermine-topiramate could be helpful for weight loss and reduction of binge-eating symptoms in patients with obesity or overweight in addition to BED. Controlled studies are warranted. PMID- 30013816 TI - Effects of Lisdexamfetamine Dimesylate on Functional Impairment Measured on the Sheehan Disability Scale in Adults With Moderate-to-severe Binge Eating Disorder: Results from Two Randomized, Placebo-controlled Trials. AB - Objective: In two Phase III, randomized, placebo-controlled trials (NCT01718483 and NCT01718509 at ClinicalTrials.gov), lisdexamfetamine dimesylate (LDX) reduced binge eating days/week in adults with moderate-to-severe binge eating disorder (BED). We describe the effects of LDX (50mg and 70mg) on the Sheehan Disability Scale (SDS; exploratory endpoint) from both studies. Design: The SDS was assessed at baseline, Week 6, and Week 12/early termination. Analyses included mixed effects models for repeated measures for the examination of SDS total and domain score changes and a generalized estimating equation model to assess dichotomized remission status (remission [total score <=6] versus nonremission [total score >6]). Results: Least squares (95% confidence interval [CI]) mean treatment differences for SDS total score change from baseline at Week 12 were -2.80 ( 3.98, -1.61) in Study 1 and -3.70 (-4.81, -2.58) in Study 2 (both p<0.001). Least squares (95% CI) mean treatment differences across SDS domains favored LDX over placebo in both studies for the change from baseline at Week 12 (work/school: 0.8 [-1.2, -0.4] and -1.1 [-1.5, -0.7], both p<0.001; social life/leisure activities: -1.0 [-1.4, -0.5] and -1.4 [-1.8, -1.0], both p<0.001; and family life/home responsibilities: -1.0 [-1.4, -0.5] and -1.3 [-1.7, -0.9], both p<0.001). Odds ratios (95% CI) for SDS remission versus nonremission favored LDX over placebo at Week 12 (Study 1: 2.39 [1.44, 3.96]; p<0.001 and Study 2: 5.12 [2.80, 9.33]; p<0.001). Conclusion: These findings indicate that LDX treatment is associated with improvement on the SDS in adults with moderate-to-severe BED. PMID- 30013817 TI - Delirium and Psychotic Symptoms Associated with Hyperglycemia in a Patient with Poorly controlled Type 2 Diabetes Mellitus. AB - Delirium, acute confusional states, and secondary psychosis have been associated with several medical conditions, including endocrine disorders. In the context of diabetes mellitus (DM), it has been mostly related to hypoglycemia and rarely occurs in association with hyperglycemia, outside of the context of a hyperglycemic hyperosmolar state or diabetic ketoacidosis. Here, we describe a case of delirium and psychotic symptoms associated with hyperglycemia in a patient with poorly controlled Type 2 DM as an attempt to alert clinicians to this rare association. We also review the pathophysiological mechanisms that might lead to the onset of delirium in the context of hyperglycemia. PMID- 30013818 TI - Development of a Behavioral Health Stigma Measure and Application of Machine Learning for Classification. AB - Objective: Given the growing public health importance of measuring the change in mental health stigma over time, the goal of this study was to demonstrate the potential for using machine learning as a tool to analyze patterns of social stigma as a complement to traditional research methods. Methods: A total of 1,904 participants were recruited through Sona Systems, Ltd (Tallinn, Estonia), an experiment management system for online research, to complete a self-reported survey. The collected data were used to develop a new measure of mental (behavioral) health stigma. To build a classification predictive model of stigma, a decision tree was used as the data mining tool, wherein a set of classification rules was generated and tested for its ability to examine the prevalence of stigma. Results: A three-factor stigma model was supported and confirmed. Results indicate that the measure is content-valid and internally consistent. Performance evaluation of the machine learning-based classification algorithm revealed a sufficient inter-rater reliability with a predictive accuracy of 92.4 percent. Conclusion: This study illustrates the potential for applying machine learning to derive a data-driven understanding of the extent to which stigma is prevalent in society. It establishes a framework for the development of an index to track stigma over time and to assist healthcare decision-makers with improving the health of populations and the experience of care for patients. PMID- 30013819 TI - Atrial Fibrillation and Injected Aripiprazole: A Case Report. AB - Background: Aripiprazole is a widely clinically employed antipsychotic drug for a range of indications. It has unusual pharmacodynamics as a dopamine D2 receptor partial-agonist with complex interactions with serotonin receptors and, a relatively unusual long elimination half-life. Although other atypical antipsychotics have been associated with an increased risk of atrial fibrillation, aripiprazole is considered to be relatively neutral in regard to its cardiac risk. We report a case of a 45-year-old Caucasian patient with schizoaffective disorder who developed acute atrial fibrillation (AF) several days after an intramuscular injection of a large long-acting dose of the drug after low oral doses had been well-tolerated. The patient responded to intravenous metoprolol and amiodarone and converted back to normal sinus rhythm within 24 hours, after having his oral aripiprazole dose lowered. The timing and dose-dependent effect of aripiprazole administration suggests an association between aripiprazole and the new onset of AF in this case, which calls for added clinical vigilance in patients with risk factors for stroke and in younger patients who could have predisposing factors for arrhythmias. PMID- 30013820 TI - A Pilot Randomized Clinical Trial Comparing Three Brief Group Interventions for Individuals With Tinnitus. AB - Background: Tinnitus (ie, ear or head noises not caused by external sounds) is common among the general population and is the most prevalent service-connected disability in the United States' Department of Veterans Affairs system. While numerous clinical interventions have been created to systematically address the range of issues caused by tinnitus, only a few tinnitus interventions have focused on both teaching and assessing coping strategies. The present pilot study involved a randomized clinical trial comparing 3 brief group interventions to a usual-care (UC) group (ie, a wait-list control group): the first intervention based on acceptance and commitment therapy (ACT), a second based on cognitive behavioral therapy (CBT), and a third based on coping effectiveness training (CET). Each intervention group also received tinnitus-related audiological education. Participants: Forty individuals met the eligibility requirements and were randomized into 1 of the 4 groups (ACT, CBT, CET, or UC). An intent-to-treat analysis was used in this study. Measures: The Brief COPE scale was used to assess coping. Coping was assessed at 3 time points (pre-intervention, post intervention, and at 4-week follow-up). The outcomes were 3 coping factors (engagement coping, disengagement coping, and social support coping). Results: When examining differences among the groups on mean coping scores over time, significant group differences were found on social support coping, with the CET group scores significantly higher than the UC group. Discussion: While all 3 brief interventions teach stress-reduction techniques, ACT and CBT focus primarily on managing one's unwanted thoughts and emotions. CET teaches participants both a range of coping strategies (eg, stress-management approaches) to more effectively manage stressors that cannot be changed, as well as coping strategies (eg, such as problem-solving) that can be used to eliminate stressors that can be changed. CET also teaches communication skills for telling others about one's tinnitus-related issues. CET instructs individuals on how to select coping strategies that are appropriate for different kinds of stressors and how to seek social support, which is a skill not explicitly taught by ACT or CBT. Results of this study were derived from a small sample size, and thus, future research should focus on replicating the results among a larger sample. In addition, future research could focus on adapting the CET intervention to a different delivery format. PMID- 30013822 TI - Correction: Resurrecting a subgenus to genus: molecular phylogeny of Euphyllia and Fimbriaphyllia (order Scleractinia; family Euphylliidae; clade V). AB - [This corrects the article DOI: 10.7717/peerj.4074.]. PMID- 30013821 TI - Total Lifestyle Coaching: A Pilot Study Evaluating the Effectiveness of a Mind Body and Nutrition Telephone Coaching Program for Obese Adults at a Community Health Center. AB - Background: Stress and obesity are interrelated and common among low-income adults. Mind-body interventions have been shown to reduce psychological distress and have been incorporated into many weight loss interventions. However, few of these programs have incorporated a telephone coaching component. Objective: We designed and piloted a novel weight loss telephone coaching intervention for this population and examined its effectiveness on weight loss and improvements in health behaviors in obese community health center patients. Methods: This was a 6 month, single-arm, prospective, pre-post pilot study. The study took place at a community health center near Boston, Massachusetts. Participants were 27 overweight and obese community health center patients. The intervention consisted of one in-person intake with the registered dietitian, trained in mind-body approaches, and approximately 1 phone coaching session every 2 weeks for 6 consecutive months. Anthropometric data consisted of weight, body mass index (BMI), and blood pressure. Questionnaires consisted of the Perceived Stress Scale 10 item, the CIGNA Healthy Eating Survey, Section H: Behavioral Eating, a physical activity questionnaire, and a nutritional habits questionnaire. We used paired samples t tests to assess pre-post changes in weight, BMI, blood pressure, perceived stress, behavioral eating, and physical activity. We also conducted semistructured exit interviews to learn about participants' experiences in this program. Results: There was a trend toward weight reduction (P < .1, Cohen's d = 0.33) and significant improvements in systolic blood pressure (P = .001, Cohen's d = 0.72), perceived stress (P = .001, Cohen's d = 0.75), and behavioral eating (P = .009, Cohen's d = 0.54). Improvements in weight were sustained 6 months after completion of the intervention. Conclusion: Results suggest that a telephone nutrition health coaching intervention is feasible and may facilitate weight loss in obese community health center patients. Future randomized controlled studies are warranted to better understand these improvements. Clinicaltrialsgov registration: NCT03025217. PMID- 30013823 TI - Correction: Proceraea exoryxae sp. nov. (Annelida, Syllidae, Autolytinae), the first known polychaete miner tunneling into the tunic of an ascidian. AB - [This corrects the article DOI: 10.7717/peerj.3374.]. PMID- 30013824 TI - A Pan-Amazonian species delimitation: high species diversity within the genus Amazophrynella (Anura: Bufonidae). AB - Amphibians are probably the most vulnerable group to climate change and climate change associate diseases. This ongoing biodiversity crisis makes it thus imperative to improve the taxonomy of anurans in biodiverse but understudied areas such as Amazonia. In this study, we applied robust integrative taxonomic methods combining genetic (mitochondrial 16S, 12S and COI genes), morphological and environmental data to delimit species of the genus Amazophrynella (Anura: Bufonidae) sampled from throughout their pan-Amazonian distribution. Our study confirms the hypothesis that the species diversity of the genus is grossly underestimated. Our analyses suggest the existence of eighteen linages of which seven are nominal species, three Deep Conspecific Lineages, one Unconfirmed Candidate Species, three Uncategorized Lineages, and four Confirmed Candidate Species and described herein. We also propose a phylogenetic hypothesis for the genus and discuss its implications for historical biogeography of this Amazonian group. PMID- 30013825 TI - High expression level of MMP9 is associated with poor prognosis in patients with clear cell renal carcinoma. AB - Matrix metallopeptidase 9 (MMP9) was found to be associated with tumor aggressiveness. In this study, we focused on the correlation between MMP9 expression and clear cell renal carcinoma (ccRCC). Through the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) staining, we observed that compared with adjacent normal renal tissues, in ccRCC tissues the mRNA and protein levels of MMP9 were enhanced, and the mRNA levels of GTP-binding protein smg p21B(RAP1B), B rapidly accelerated fibrosarcoma (RAF), methyl ethyl ketone2 (MEK2), extracellular regulated protein kinases1 (ERK1), ERK2, v-ets avian erythroblastosis virus E26 oncogene homolog1 (ETS1) and ETS2 also increased. The Kaplan-Meier survival analysis suggested that high MMP9 expression was an unfavorable prognostic biomarker for ccRCC patients. Our results indicated that the increased expression level of MMP9 in ccRCC may be due to the activation of the Mitogen-activated protein kinases (MAPK)/ERK signaling pathway, and MMP9 may be an attractive target for ccRCC therapy. PMID- 30013826 TI - Reproducible research and GIScience: an evaluation using AGILE conference papers. AB - The demand for reproducible research is on the rise in disciplines concerned with data analysis and computational methods. Therefore, we reviewed current recommendations for reproducible research and translated them into criteria for assessing the reproducibility of articles in the field of geographic information science (GIScience). Using this criteria, we assessed a sample of GIScience studies from the Association of Geographic Information Laboratories in Europe (AGILE) conference series, and we collected feedback about the assessment from the study authors. Results from the author feedback indicate that although authors support the concept of performing reproducible research, the incentives for doing this in practice are too small. Therefore, we propose concrete actions for individual researchers and the GIScience conference series to improve transparency and reproducibility. For example, to support researchers in producing reproducible work, the GIScience conference series could offer awards and paper badges, provide author guidelines for computational research, and publish articles in Open Access formats. PMID- 30013827 TI - corseq: fast and efficient identification of favoured codons from next generation sequencing reads. AB - Background: Optimization of transgene expression can be achieved by designing coding sequences with the synonymous codon usage of genes which are highly expressed in the host organism. The identification of the so-called "favoured codons" generally requires the access to either the genome or the coding sequences and the availability of expression data. Results: Here we describe corseq, a fast and reliable software for detecting the favoured codons directly from RNAseq data without prior knowledge of genomic sequence or gene annotation. The presented tool allows the inference of codons that are preferentially used in highly expressed genes while estimating the transcripts abundance by a new kmer based approach. corseq is implemented in Python and runs under any operating system. The software requires the Biopython 1.65 library (or later versions) and is available under the 'GNU General Public License version 3' at the project webpage https://sourceforge.net/projects/corseq/files. Conclusion: corseq represents a faster and easy-to-use alternative for the detection of favoured codons in non model organisms. PMID- 30013828 TI - Volatile profiling in Rhus coriaria fruit (sumac) from three different geographical origins and upon roasting as analyzed via solid-phase microextraction. AB - Rhus coriaria (sumac) is a fruit grown worldwide for its culinary use as a flavoring agent and for its health benefits. Despite several studies on R. coriaria non-volatile metabolites, much less is recognized concerning volatile composition within that genus. In an effort to expand on flavor profile sumac and its food products, we report on volatile profiling from three accessions of different origins including Palestine, Jordan and Egypt in addition to its cold tea and post roasting via headspace solid-phase microextraction (SPME). Under optimized conditions, 74 volatile components were identified belonging to alcohols, aromatics, esters, ethers, furan/aldehyde, hydrocarbons, ketones, monoterpenes, oxides and sesquiterpene hydrocarbons. Major identified components included alpha-pinene, naphthalene and o-cymene in Palestinian, Jordanian and Egyptian sumac, respectively. Whereas sesquiterpenes amounted for the major volatile class in fresh R. coriaria at ca. 40-58%, furan/aldehydes were the predominant classes in roasted fruits (58%). Volatile abundance data was further subjected to multivariate data analyses revealing furfural and nonanal enrichment in roasted compared to fresh fruits and their cold tea preparation. Seeds exhibited no aroma components which justified their removal in R. coriaria prior to its use as a food flavor. Such knowledge is expected to be the key for understanding the olfactory and taste properties of R. coriaria and its several food products. PMID- 30013829 TI - Preliminary study on phosphate solubilizing Bacillus subtilis strain Q3 and Paenibacillus sp. strain Q6 for improving cotton growth under alkaline conditions. AB - Background: Low phosphorus availability limits crop production in alkaline calcareous soils in semi-arid regions including Pakistan. Phosphate solubilizing bacteria may improve crop growth on alkaline calcareous soils due to their ability to enhance P availability. Methods: Twenty rhizobacterial isolates (Q1 Q20) were isolated from rhizosphere of cotton and characterized for their growth promoting attributes in vitro. The selected phosphate solubilizing isolates were further screened for their ability to improve cotton growth under axenic conditions (jar trial). The phosphorus solubilization capacities of selected strains were quantified and these strains were identified through 16S rDNA sequencing. Results: Isolates Q2, Q3, Q6, Q7, Q8, Q13 and Q14 were able to solubilize phosphate from insoluble sources. Most of these isolates also possessed other traits including catalase activity and ammonia production. The growth promotion assay showed that Q3 was significantly better than most of the other isolates followed by Q6. Maximum root colonization (4.34 * 106 cfu g-1) was observed in case of isolate Q6 followed by Q3. The phosphorus solubilization capacities of these strains were quantified, showing a maximum phosphorus solubilization by Q3 (optical density 2.605 +/- 0.06) followed by the Q6 strain. The strain Q3 was identified as Bacillus subtilis (accession # KX788864) and Q6 as Paenibacillus sp. (accession # KX788865) through 16S rDNA sequencing. Discussion: The bacterial isolates varied in their abilities for different growth promoting traits. The selected PGPR Bacillus subtilis strain Q3 and Paenibacillus sp. strain Q6 have multifarious growth promoting traits including ability to grow at higher EC and pH levels, and phosphorus solubilizing ability. These strains can efficiently colonize cotton roots under salt affected soils and help plants in phosphorus nutrition. It is concluded that both strains are potential candidates for promoting cotton growth under alkaline conditions, however further investigation is required to determine their potential for field application. PMID- 30013830 TI - Back to beaked: Zea mays subsp. mays Rostrata Group in northern Italy, refugia and revival of open-pollinated maize landraces in an intensive cropping system. AB - Crop landraces are fundamental resources to increase the eroded genepool of modern crops in order to adapt agriculture to future challenges; plus, they are of immeasurable heritage and cultural value. Between the 1940s and the 1960s open pollinated varieties (OPVs) of flint and semi-flint maize in Europe were almost completely replaced by high-yielding hybrid dent cultivars selected in North America. No comprehensive assessment was performed after the 1950s to understand which maize genetic resources survived genetic erosion in northern Italy, an area characterized by a high degree of landraces extinction and introgression, intensive hybrid dent monocultures, as well as being one of the hotspots of maize cultivation at a continental level. Among these landraces, beaked maize represents a peculiar case study for assessing the survival of OPVs in intensive cropping systems. By means of ethnobotanical and literature surveys, the history of Zea mays subsp. mays Rostrata Group and its current distribution were reconstructed. It emerged that beaked maize originated in the study area and it is one of the oldest genepools available not subjected to formal crop improvement. We identified 28 landraces of beaked maize currently cultivated, 18 here recorded for the first time. The cultivation of more than half of the 28 landraces has continued throughout the last 80 years in a few fragmented localities that can be regarded as "refugia". The survival of these landraces from substitution with high-yielding cultivars and unidirectional introgression has been mainly due to active on-farm conservation performed by custodian farmers and secondarily to cultivation in isolated areas (e.g., mountain valleys). After decades of genetic erosion, beaked maize has since the late 1990s experienced a revival, in terms of an increasing number of cultivation localities and the level of product commercialization. This process is mostly spontaneous and only occasionally mediated by governmental institutions; it is linked to the rediscovery of local food products, in this case mainly polenta, a dish made of corn flour, which used to be the staple food across northern Italy. The ex situ conservation of beaked maize and on-farm measures put in place by the farmers to prevent introgression are also assessed. Further research and collecting missions are needed to provide an inventory of open-pollinated landraces of other landrace groups that have survived genetic erosion in Europe. To meet this aim, extensive ethnobotanical surveys, such as the one performed here, are very powerful tools in detecting these genetic resources. PMID- 30013832 TI - Assessing population changes of historically overexploited black corals (Order: Antipatharia) in Cozumel, Mexico. AB - Black corals (Antipatharians) are crucial structural and ecological components of many mesophotic coral ecosystems (MCEs; reefs 30-150 m depth). In Mexico, black corals are harvested for the jewellery industry, which has historically led to population depletion. Harvesting began in the early 1960s and was concentrated around Cozumel Island until 1995. Since then, harvesting permits have been granted only for the mainland coast. Here we compare Cozumel populations between 1998 and 2016 for the two black coral species targeted by the jewellery industry. We found that densities of Plumapathes pennacea in 2016 were substantially lower than in 1998. However, the 2016 P. pennacea population has shifted to be dominated by larger colonies, suggesting disproportionate juvenile mortality or recruitment failure. Low numbers of Antipathes caribbeana were recorded, and no change in population density or colony size was detected between 1998 and 2016. Despite harvesting occurring for almost 70 years in the Mexican Caribbean, no information on reproduction, recruitment and other dynamics of the targeted species is available. We advocate for harvesting permits to be based on scientific evidence, and for implementation of future restrictions to prevent total depletion of black corals in the area. PMID- 30013831 TI - Molecular dynamics ensemble refinement of the heterogeneous native state of NCBD using chemical shifts and NOEs. AB - Many proteins display complex dynamical properties that are often intimately linked to their biological functions. As the native state of a protein is best described as an ensemble of conformations, it is important to be able to generate models of native state ensembles with high accuracy. Due to limitations in sampling efficiency and force field accuracy it is, however, challenging to obtain accurate ensembles of protein conformations by the use of molecular simulations alone. Here we show that dynamic ensemble refinement, which combines an accurate atomistic force field with commonly available nuclear magnetic resonance (NMR) chemical shifts and NOEs, can provide a detailed and accurate description of the conformational ensemble of the native state of a highly dynamic protein. As both NOEs and chemical shifts are averaged on timescales up to milliseconds, the resulting ensembles reflect the structural heterogeneity that goes beyond that probed, e.g., by NMR relaxation order parameters. We selected the small protein domain NCBD as object of our study since this protein, which has been characterized experimentally in substantial detail, displays a rich and complex dynamical behaviour. In particular, the protein has been described as having a molten-globule like structure, but with a relatively rigid core. Our approach allowed us to describe the conformational dynamics of NCBD in solution, and to probe the structural heterogeneity resulting from both short- and long-timescale dynamics by the calculation of order parameters on different time scales. These results illustrate the usefulness of our approach since they show that NCBD is rather rigid on the nanosecond timescale, but interconverts within a broader ensemble on longer timescales, thus enabling the derivation of a coherent set of conclusions from various NMR experiments on this protein, which could otherwise appear in contradiction with each other. PMID- 30013833 TI - Speciation among sympatric lineages in the genus Palythoa (Cnidaria: Anthozoa: Zoantharia) revealed by morphological comparison, phylogenetic analyses and investigation of spawning period. AB - Zoantharians are sessile marine invertebrates and colonial organisms possessing sexual and asexual reproductive ability. The zooxanthellate zoantharian genus Palythoa is widely distributed in coral reef ecosystems. In the Ryukyu Archipelago, Japan, sympatric Palythoa tuberculosa and P. mutuki are the dominant species of this genus in the intertidal zone. Previous phylogenetic analyses have shown that these two species are closely related, and additionally revealed a putative sympatric hybrid species (designated as Palythoa sp. yoron). In this study, we attempted to delineate Palythoa species boundaries and to clarify the relationships among these three groups plus another additional putative sympatric species (P. aff. mutuki) by multiple independent criteria. The morphology of these four lineages was clearly different; for example the number of tentacles was significantly different for each species group in all pairwise comparisons. From observations of gonadal development conducted in 2010 and 2011, P. sp. yoron and P. aff. mutuki appear to be reproductively isolated from P. tuberculosa. In the phylogenetic tree resulting from maximum likelihood analyses of the ITS-rDNA sequence alignment, P. tuberculosa and P. sp. yoron formed a very well supported monophyletic clade (NJ = 100%, ML = 95%, Bayes = 0.99). This study demonstrates that despite clear morphological and/or reproductive differences, P. tuberculosa and P. sp. yoron are phylogenetically entangled and closely related to each other, as are P. mutuki and P. aff. mutuki. Additionally, no single molecular marker was able to divide these four lineages into monophyletic clades by themselves, and a marker that has enough resolution to solve this molecular phylogenetic species complex is required. In summary, the morphological and reproductive results suggest these lineages are four separate species, and that incomplete genetic lineage sorting may prevent the accurate phylogenetic detection of distinct species with the DNA markers utilized in this study, demonstrating the value of morphological and reproductive data when examining closely related lineages. PMID- 30013834 TI - Identification of SNPs potentially related to immune responses and growth performance in Litopenaeus vannamei by RNA-seq analyses. AB - Litopenaeus vannamei is one of the most important shrimp species for worldwide aquaculture. Despite this, little genomic information is available for this penaeid and other closely related taxonomic crustaceans. Consequently, genes, proteins and their respective polymorphisms are poorly known for these species. In this work, we used the RNA sequencing technology (RNA-seq) in L. vannamei shrimp evaluated for growth performance, and exposed to the White Spot Syndrome Virus (WSSV), in order to investigate the presence of Single Nucleotide Polymorphisms (SNPs) within genes related to innate immunity and growth, both features of great interest for aquaculture activity. We analyzed individuals with higher and lower growth rates; and infected (unhealthy) and non-infected (healthy), after exposure to WSSV. Approximately 7,000 SNPs were detected in the samples evaluated for growth, being 3,186 and 3,978 exclusive for individuals with higher and lower growth rates, respectively. In the animals exposed to WSSV we found about 16,300 unique SNPs, in which 9,338 were specific to non-infected shrimp, and 7,008 were exclusive to individuals infected with WSSV and symptomatic. In total, we describe 4,312 unigenes containing SNPs. About 60% of these unigenes returned GO blastX hits for Biological Process, Molecular Function and Cellular Component ontologies. We identified 512 KEGG unique KOs distributed among 275 pathways, elucidating the majority of metabolism roles related to high protein metabolism, growth and immunity. These polymorphisms are all located in coding regions, and certainly can be applied in further studies involving phenotype expression of complex traits, such as growth and immunity. Overall, the set of variants raised herein enriches the genomic databases available for shrimp, given that SNPs originated from nextgen are still rare for this relevant crustacean group, despite their huge potential of use in genomic selection approaches. PMID- 30013835 TI - Major medical causes by breed and life stage for dogs presented at veterinary clinics in the Republic of Korea: a survey of electronic medical records. AB - Background: Age and breed are considered the greatest risk factors for disease prevalence and mortality in companion dogs. Understanding the prevalence of diseases, in relation to age and breed, would support appropriate guidance for future health care strategies and provide useful information for the early diagnosis of diseases. The purpose of this study was to investigate the major medical causes for dogs visiting primary-care veterinary clinics in the Republic of Korea, stratified by age and breed. Methods: A total of 15,531 medical records of canine patients were analyzed from 11 veterinary clinics who shared data from January 1, 2016 to December 31, 2016. An electronic medical record (EMR) system was used for data collection, which included the animal identification number, age, breed, gender, neuter status, clinical information, and diagnosis. EMR data were classified using the International Classification of Disease system from the World Health Organization; presenting signs or diagnoses were identified according to breed and life stage. Results: Within the age groups, preventive medicine (16.7% confidence intervals (CI) [15.9-17.5]) was the most common cause for clinic visits for the <1 year and 1-3 year groups. Additionally, neutering surgery (6.6% CI [6.0-7.1]) and patella luxation (1.4% CI [1.8-2.7]) were frequently performed in these age groups. In the 4-6 year group, otitis externa (8.8% CI [7.8-10.0]) and dermatitis or eczema (8.5% CI [7.5-9.6]) were common medical problems. In older dogs (>10 year), the prevalences of heart disease, kidney disease, Cushing's disease, and mammary tumors were higher than in the other age groups. Small and toy breed dogs comprised 67.7% of all dogs in this analysis. For all breeds, otitis externa, dermatitis or eczema, vomiting, and diarrhea were common medical problems. Discussion: This study identified the most common medical disorders and differences in prevalences of diseases, according to age and breeds. The information from EMRs for dogs visiting primary-care veterinary clinics can provide background knowledge that is required to enable a better understanding of disease patterns and occurrence by age and breeds. The information from this study could enable the creation of strategies for preventing diseases and enable the identification of health problems for more effective disease management in companion dogs. PMID- 30013836 TI - Differences in electromyographic activity of biceps brachii and brachioradialis while performing three variants of curl. AB - Background: Dumbbell curl (DC) and barbell curl in its two variants, straight (BC) or undulated bar (EZ) are typical exercises to train the elbow flexors. The aim of the study was to verify if the execution of these three variants could induce a selective electromyographic (EMG) activity of the biceps brachii (BB) and brachioradialis (BR). Methods: Twelve participants performed one set of ten repetitions at 65% of their 1-RM for each variant of curl. Pre-gelled electrodes were applied with an inter-electrode distance of 24 mm on BB and BR. An electrical goniometer was synchronously recorded with EMG signals to determine the concentric and eccentric phases of each variant of curl. Results: We detected higher activation profile of both BB (P < 0.05) and BR (P < 0.01) during the EZ compared to the DC. Higher levels of activation was found during the concentric phase for only the BR performed with an EZ compared to DC (P < 0.001) and performing BC compared to DC (P < 0.05). The eccentric phase showed a higher activation of the BB muscle in EZ compared to DC (P < 0.01) and in BC compared to DC (P < 0.05). The BR muscle showed a higher activation performing EZ compared to DC (P < 0.01). Discussion: The EZ variant may be preferred over the DC variant as it enhances BB and BR EMG activity during the whole range of motion and only in the eccentric phase. The small difference between BC and EZ variants of the BB and BR EMG activity makes the choice between these two exercises a matter of subjective comfort. PMID- 30013837 TI - Minimizing confounders and increasing data quality in murine models for studies of the gut microbiome. AB - Murine models are widely used to explore host-microbe interactions because of the challenges and limitations inherent to human studies. However, microbiome studies in murine models are not without their nuances. Inter-individual variations in gut microbiota are frequent even in animals housed within the same room. We therefore sought to find an efficient and effective standard operating procedure (SOP) to minimize these effects to improve consistency and reproducibility in murine microbiota studies. Mice were housed in a single room under specific pathogen free conditions. Soiled cage bedding was routinely mixed weekly and distributed among all cages from weaning (three weeks old) until the onset of the study. Females and males were separated by sex and group-housed (up to five mice/cage) at weaning. 16S rRNA gene analyses of fecal samples showed that this protocol significantly reduced pre-study variability of gut microbiota amongst animals compared to other conventional measures used to normalize microbiota when large experimental cohorts have been required. A significant and consistent effect size was observed in gut microbiota when mice were switched from regular chow to purified diet in both sexes. However, sex and aging appeared to be independent drivers of gut microbial assemblage and should be taken into account in studies of this nature. In summary, we report a practical and effective pre study SOP for normalizing the gut microbiome of murine cohorts that minimizes inter-individual variability and resolves co-housing problems inherent to male mice. This SOP may increase quality, rigor, and reproducibility of data acquisition and analysis. PMID- 30013838 TI - Phylogeny and divergence times of suckers (Cypriniformes: Catostomidae) inferred from Bayesian total-evidence analyses of molecules, morphology, and fossils. AB - Catostomidae ("suckers") is a diverse (76 species) and broadly distributed family of Holarctic freshwater fishes with a rich fossil record and a considerable number (~35%) of threatened and imperiled species. We integrate DNA sequences (three mitochondrial genes, three nuclear genes), morphological data, and fossil information to infer sucker phylogenetic relationships and divergence times using Bayesian "total-evidence" methods, and then test hypotheses about the temporal diversification of the group. Our analyses resolved many nodes within subfamilies and clarified Catostominae relationships to be of the form ((Thoburniini, Moxostomatini), (Erimyzonini, Catostomini)). Patterns of subfamily relationships were incongruent, but mainly supported two placements of the Myxocyprininae; distinguishing these using Bayes factors lent strongest support to a model with Myxocyprininae sister to all remaining sucker lineages. We improved our Bayesian total-evidence dating analysis by excluding problematic characters, using a clock partitioning scheme identified by Bayesian model selection, and employing a fossilized birth-death tree prior accommodating morphological data and fossils. The resulting chronogram showed that suckers evolved since the Late Cretaceous Eocene, and that the Catostomini and Moxostomatini clades have accumulated species diversity since the early to mid-Miocene. These results agree with the fossil record and confirm previous hypotheses about dates for the origins of Catostomide and catostomine diversification, but reject previous molecular hypotheses about the timing of divergence of ictiobines, and between Asian-North American lineages. Overall, our findings from a synthesis of multiple data types enhance understanding of the phylogenetic relationships, taxonomic classification, and temporal diversification of suckers, while also highlighting practical methods for improving Bayesian divergence dating models by coupling phylogenetic informativeness profiling with relaxed-clock partitioning. PMID- 30013839 TI - Ecological and molecular characterization of a coral black band disease outbreak in the Red Sea during a bleaching event. AB - Black Band Disease (BBD) is a widely distributed and destructive coral disease that has been studied on a global scale, but baseline data on coral diseases is missing from many areas of the Arabian Seas. Here we report on the broad distribution and prevalence of BBD in the Red Sea in addition to documenting a bleaching-associated outbreak of BBD with subsequent microbial community characterization of BBD microbial mats at this reef site in the southern central Red Sea. Coral colonies with BBD were found at roughly a third of our 22 survey sites with an overall prevalence of 0.04%. Nine coral genera were infected including Astreopora, Coelastrea, Dipsastraea, Gardineroseris, Goniopora, Montipora, Pavona, Platygyra, and Psammocora. For a southern central Red Sea outbreak site, overall prevalence was 40 times higher than baseline (1.7%). Differential susceptibility to BBD was apparent among coral genera with Dipsastraea (prevalence 6.1%), having more diseased colonies than was expected based on its abundance within transects. Analysis of the microbial community associated with the BBD mat showed that it is dominated by a consortium of cyanobacteria and heterotrophic bacteria. We detected the three main indicators for BBD (filamentous cyanobacteria, sulfate-reducing bacteria (SRB), and sulfide oxidizing bacteria (SOB)), with high similarity to BBD-associated microbes found worldwide. More specifically, the microbial consortium of BBD-diseased coral colonies in the Red Sea consisted of Oscillatoria sp. (cyanobacteria), Desulfovibrio sp. (SRB), and Arcobacter sp. (SOB). Given the similarity of associated bacteria worldwide, our data suggest that BBD represents a global coral disease with predictable etiology. Furthermore, we provide a baseline assessment of BBD disease prevalence in the Red Sea, a still understudied region. PMID- 30013840 TI - Patterns of triclosan resistance in Vibrionaceae. AB - The antimicrobial additive triclosan has been used in personal care products widely across the globe for decades. Triclosan resistance has been noted among Vibrio spp., but reports have been anecdotal and the extent of phenotypic triclosan resistance across the Vibrionaceae family has not been established. Here, triclosan resistance was determined for Vibrionaceae strains across nine distinct clades. Minimum inhibitory concentrations (MIC) were determined for 70 isolates from clinical (n = 6) and environmental sources (n = 64); only two were susceptible to triclosan. The mean MIC for all resistant Vibrionaceae was 53 ug mL-1 (range 3.1-550 ug mL-1), but was significantly different between clades (p < 0.001). The highest mean triclosan MIC was observed in the Splendidus clade (200 ug mL-1; n = 3). Triclosan mean MICs were 68.8 ug mL-1 in the Damselae clade and 45.3 ug mL-1 in the Harveyi clade. The lowest mean MIC was observed in the Cholerae clade with 14.4 ug mL-1, which was primarily represented by clinical strains. There were no significant differences in triclosan MIC among individual species or among environmental strains isolated from different locations. Overall, phenotypic triclosan resistance appears to be widespread across multiple clades of Vibrionaceae. PMID- 30013841 TI - Demographics, perceptions, and socioeconomic factors affecting influenza vaccination among adults in the United States. AB - Objective: The study objective is to analyze influenza vaccination status by demographic factors, perceived vaccine efficacy, social influence, herd immunity, vaccine cost, health insurance status, and barriers to influenza vaccination among adults 18 years and older in the United States. Background: Influenza vaccination coverage among adults 18 years and older was 41% during 2010-2011 and has increased and plateaued at 43% during 2016-2017. This is below the target of 70% influenza vaccination coverage among adults, which is an objective of the Healthy People 2020 initiative. Methods: We conducted a survey of a nationally representative sample of adults 18 years and older in the United States on factors affecting influenza vaccination. We conducted bivariate analysis using Rao-Scott chi-square test and multivariate analysis using weighted multinomial logistic regression of this survey data to determine the effect of demographics, perceived vaccine efficacy, social influence, herd immunity, vaccine cost, health insurance, and barriers associated with influenza vaccination uptake among adults in the United States. Results: Influenza vaccination rates are relatively high among adults in older age groups (73.3% among 75 + year old), adults with education levels of bachelor's degree or higher (45.1%), non-Hispanic Whites (41.8%), adults with higher incomes (52.8% among adults with income of over $150,000), partnered adults (43.2%), non-working adults (46.2%), and adults with internet access (39.9%). Influenza vaccine is taken every year by 76% of adults who perceive that the vaccine is very effective, 64.2% of adults who are socially influenced by others, and 41.8% of adults with health insurance, while 72.3% of adults without health insurance never get vaccinated. Facilitators for adults getting vaccinated every year in comparison to only some years include older age, perception of high vaccine effectiveness, higher income and no out-of-pocket payments. Barriers for adults never getting vaccinated in comparison to only some years include lack of health insurance, disliking of shots, perception of low vaccine effectiveness, low perception of risk for influenza infection, and perception of risky side effects. Conclusion: Influenza vaccination rates among adults in the United States can be improved towards the Healthy People 2020 target of 70% by increasing awareness of the safety, efficacy and need for influenza vaccination, leveraging the practices and principles of commercial and social marketing to improve vaccine trust, confidence and acceptance, and lowering out-of-pocket expenses and covering influenza vaccination costs through health insurance. PMID- 30013842 TI - Assessing metacognitive beliefs about worry: validation of German versions of the Why Worry Scale II and the Consequences of Worry Scale. AB - Background: Metacognitive beliefs have been proposed to play a key role in initiating and maintaining worry. The Why Worry-Scale-II (WW-II) and Consequences of Worry Scale (COWS) are self-report questionnaires assessing positive and negative metacognitive beliefs. The main goal of this study was to validate German versions of these two questionnaires. Method: N = 603 participants completed a questionnaire battery, including the two self-report measures of metacognitive beliefs. We conducted confirmatory factor analyses, calculated internal consistencies, and examined convergent and divergent validity. In addition, the questionnaires' power in predicting worry, repetitive negative thinking (RNT) and generalized anxiety disorder (GAD) symptoms were investigated. Results: The factor structure of the original versions could be replicated for both measures. Furthermore, the translated questionnaires demonstrated excellent internal consistency and evidence of convergent and divergent validity. Importantly they also possessed predictive power in explaining worry, RNT and GAD symptoms, even over and above the Metacognitions Questionnaire-30 (MCQ-30) as the current gold standard. Conclusions: Overall, our findings suggest that the WW-II and COWS show solid psychometric properties and are useful in measuring metacognitive beliefs independently from the MCQ-30. PMID- 30013843 TI - Stability of important antibodies for kidney disease: pre-analytic methodological considerations. AB - Background: The importance of circulating antibodies as biomarkers of kidney disease has recently been recognized. However, no study has systematically described the methodology of sample preparation and storage regarding antibodies as biomarkers of kidney disease. It remains unknown whether repetitive freeze thaw cycles, physical disturbances, storage at different temperatures or for different periods of time, or haemolytic or turbid serum samples affect antibody measurements. The aim of this study was to investigate the stabilities of antibodies associated with kidney disease in serum samples under various relevant clinical and research conditions. Methods: We stored serum samples in the following different conditions: repetitive freeze-thaw cycles (1, 6 or 12 times), long-term storage (7 or 12 months at -80 degrees C), physical disturbance (1 or 8 h), and storage at 4 degrees C (1, 3 or 6 weeks) and room temperature (1 or 7 days). The stabilities of the anti-phospholipase A2 receptor (anti-PLA2R), anti glomerular basement membrane, anti-myeloperoxidase and anti-proteinase 3 antibodies were evaluated with enzyme-linked immunosorbent assays (ELISA). Results: We found that repetitive freeze-thaw cycles did not have a significant effect on the stabilities of the abovementioned antibodies in clear serum samples. The ELISA readings of haemolytic and turbid serum samples tended to increase and decrease, respectively. Neither long-term storage at -80 degrees C nor physical disturbance had a significant effect on anti-PLA2R antibody stability in sealed serum samples. The concentrations of most of these antibodies increased in unsealed serum samples that were stored at 4 degrees C for more than 6 weeks or at room temperature for more than 7 days. Discussion: Our findings revealed that the abovementioned circulating antibodies that are used as biomarkers for kidney disease had stable physicochemical properties, structures and immunoreactivities such that they were not influenced by repetitive freeze thaw cycles, physical disturbances or long-term storage at -80 degrees C. However, the ELISA readings tended to change for haemolytic, turbid and unsealed serum samples. PMID- 30013844 TI - Do triceps surae muscle dynamics govern non-uniform Achilles tendon deformations? AB - The human Achilles tendon (AT) consists of sub-tendons arising from the gastrocnemius and soleus muscles that exhibit non-uniform tissue displacements thought to facilitate some independent actuation. However, the mechanisms governing non-uniform displacement patterns within the AT, and their relevance to triceps surae muscle contractile dynamics, have remained elusive. We used a dual probe ultrasound imaging approach to investigate triceps surae muscle dynamics (i.e., medial gastrocnemius-GAS, soleus-SOL) as a determinant of non-uniform tendon tissue displacements in the human AT. We hypothesized that superficial versus deep differences in AT tissue displacements would be accompanied by and correlate with anatomically consistent differences in GAS versus SOL muscle shortening. Nine subjects performed ramped maximum voluntary isometric contractions at each of five ankle joint angles spanning 10 degrees dorsiflexion to 30 degrees plantarflexion. For all conditions, SOL shortened by an average of 78% more than GAS during moment generation. This was accompanied by, on average, 51% more displacement in the deep versus superficial region of the AT. The magnitude of GAS and SOL muscle shortening positively correlated with displacement in their associated sub-tendons within the AT. Moreover, and as hypothesized, superficial versus deep differences in sub-tendon tissue displacements positively correlated with anatomically consistent differences in GAS versus SOL muscle shortening. We present the first in vivo evidence that triceps surae muscle dynamics may precipitate non-uniform displacement patterns in the architecturally complex AT. PMID- 30013845 TI - Applying sequential pattern mining to investigate cerebrovascular health outpatients' re-visit patterns. AB - Background and Objective: Increases in outpatients seeking medical check-ups are expanding the number of health examination data records, which can be utilized for medical strategic planning and other purposes. However, because hospital visits by outpatients seeking medical check-ups are unpredictable, those patients often cannot receive optimal service due to limited facilities of hospitals. To resolve this problem, this study attempted to predict re-visit patterns of outpatients. Method: Two-phase sequential pattern mining (SPM) and an association mining method were chosen to predict patient returns using sequential data. The data were grouped according to the outpatients' personal information and evaluated by a discriminant analysis to check the significance of the grouping. Furthermore, SPM was employed to generate frequency patterns from each group and extract a general association pattern of return. Results: Results of sequence patterns and association mining in this study provided valuable insights in terms of outpatients' re-visit behaviors for regular medical check-ups. Cosine and Jaccard are two symmetric measures which were used in this study to indicate the degree of association between two variables. For instance, Jaccard values of variable abnormal blood pressure associated with an abnormal body-mass index (BMI) and/or abnormal blood sugar were respectively 47.5% and 100%, for the two visit and three-visit behavior patterns. These results indicated that the corresponding pair of variables was more reliable when covering the three-visit behavior pattern than the two-visit behavior. Thus, appropriate preventive measures or suggestions for other medical treatments can be prepared for outpatients that have this pattern on their third visit. The higher degree of association implies that the corresponding behavior pattern might influence outpatients' intentions to regularly seek medical check-ups concerning the risk of stroke. Furthermore, a radiology diagnosis (i.e., magnetic resonance imaging or neck vascular ultrasound) plays an important role in the association with a re visit behavior pattern with respective 50% and 70% Cosine and Jaccard values in general behavior {f11}?{f01}. These findings can serve as valuable information to increase the quality of medical services and marketing, by suggesting appropriate treatment for the subsequent visit after learning the behavior patterns. Conclusions: The proposed method can provide valuable information related to outpatients' re-visit behavior patterns based on hidden knowledge generated from sequential patterns and association mining results. For marketing purposes, medical practitioners can take behavior patterns studied in this paper into account to raise patients' awareness of several possible medical conditions that might arise on subsequent visits and encourage them to take preventive measures or suggest other medical treatments. PMID- 30013846 TI - Kinematic characteristics of barefoot sprinting in habitually shod children. AB - Background: Anecdotally, a wide variety of benefits of barefoot running have been advocated by numerous individuals. The influence of the alterations in the properties of the shoe on the running movement has been demonstrated in adults at submaximal jogging speeds. However, the biomechanical differences between shod and barefoot running in children at sprinting speeds and the potential developmental implications of these differences are still less examined. The purpose was to determine the potential differences in habitually shod children's sprint kinematics between shod and barefoot conditions. Methods: Ninety-four children (51 boys and 43 girls; 6-12 years-old; height, 135.0 +/- 0.12 m; body mass, 29.0 +/- 6.9 kg) performed 30 m maximal sprints from standing position for each of two conditions (shod and barefoot). To analyze sprint kinematics within sagittal plane sprint kinematics, a high-speed camera (300 fps) was set perpendicular to the runway. In addition, sagittal foot landing and take-off images were recorded for multiple angles by using five high-speed cameras (300 fps). Spatio-temporal variables, the kinematics of the right leg (support leg) and the left leg (recovery leg), and foot strike patterns: rear-foot strike (RFS), mid-foot strike (MFS), and fore-foot strike (FFS) were investigated. The paired t-test was used to test difference between shod and barefoot condition. Results: Barefoot sprinting in habitually shod children was mainly characterized by significantly lower sprint speed, higher step frequency, shorter step length and stance time. In shod running, 82% of children showed RFS, whereas it decreased to 29% in barefoot condition. The touch down state and the subsequent joint movements of both support and recovery legs during stance phase were significantly altered when running in condition with barefoot. Discussion: The acute effects of barefoot sprinting was demonstrated by significantly slower sprinting speeds that appear to reflect changes in a variety of spatiotemporal parameters as well as lower limb kinematics. It is currently unknown whether such differences would be observed in children who typically run in bare feet and what developmental benefits and risks may emerge from increasing the proportion of barefoot running and sprinting in children. Future research should therefore investigate potential benefits that barefoot sprinting may have on the development of key physical fitness such as nerve conduction velocity, muscular speed, power, and sprinting technique and on ways to minimize the risk of any acute or chronic injuries associated with this activity. PMID- 30013847 TI - Experimental evolution of UV resistance in a phage. AB - The dsDNA bacteriophage T7 was subjected to 30 cycles of lethal ultraviolet light (UV) exposure to select increased resistance to UV. The exposure effected a 0.9999 kill of the ancestral population, and survival of the ending population was nearly 50-fold improved. At the end point, a 2.1 kb deletion of early genes and three substitutions in structural-genes were the only changes observed at high frequency throughout the 40 kb genome; no changes were observed in genes affecting DNA metabolism. The deletion accounted for only a two-fold improvement in survival. One possible explanation of its benefit is that it represents an error catastrophe, whereby the genome experiences a reduced mutation rate. The mechanism of benefit provided by the three structural-gene mutations remains unknown. The results offer some hope of artificially evolving greater protection against sunlight damage in applications of phage therapy to plants, but the response of T7 is weak compared to that observed in bacteria selected to resist ionizing radiation. Because of the weak response, mathematical analysis of the selection process was performed to determine how the protocol might have been modified to achieve a greater response, but the greatest protection may well come from evolving phages to bind materials that block the UV. PMID- 30013848 TI - Socioeconomic status is not associated with health-related quality of life in a group of overweight middle-aged men. AB - Socioeconomic status is a known determinant of health. In secondary data analyses, we assessed whether socioeconomic status affected health-related quality of life in a group of overweight (body mass index 25-30 kg/m2) middle aged (45.9 +/- 5.4 years) men, recruited in Auckland (New Zealand). Health related quality of life was assessed with SF-36v2 three times: at baseline, and 12 and 30 weeks later. Socioeconomic status was determined by geo-coded deprivation scores derived from current address using the New Zealand Index of Deprivation 2006 (NZDep2006), as well as capital value of residence. Univariable and multivariable analyses showed no associations between measures of socioeconomic status and any mental or physical health domains. Our findings may reflect the fact that these men are not currently experiencing comorbidities associated with overweight. PMID- 30013849 TI - Searching for best lower dimensional visualization angles for high dimensional RNA-Seq data. AB - The accumulation of RNA sequencing (RNA-Seq) gene expression data in recent years has resulted in large and complex data sets of high dimensions. Exploratory analysis, including data mining and visualization, reveals hidden patterns and potential outliers in such data, but is often challenged by the high dimensional nature of the data. The scatterplot matrix is a commonly used tool for visualizing multivariate data, and allows us to view multiple bivariate relationships simultaneously. However, the scatterplot matrix becomes less effective for high dimensional data because the number of bivariate displays increases quadratically with data dimensionality. In this study, we introduce a selection criterion for each bivariate scatterplot and design/implement an algorithm that automatically scan and rank all possible scatterplots, with the goal of identifying the plots in which separation between two pre-defined groups is maximized. By applying our method to a multi-experiment Arabidopsis RNA-Seq data set, we were able to successfully pinpoint the visualization angles where genes from two biological pathways are the most separated, as well as identify potential outliers. PMID- 30013850 TI - Molecular characterization of clonal lineage and staphylococcal toxin genes from S. aureus in Southern Nigeria. AB - Background: Staphylococcus aureus is a human colonizer with high potential for virulence, and the spread of the virulent strains from the colonized hosts to non carriers in the community is on the increase. However, there are few reports on comprehensive analysis of staphylococcal enterotoxin (SE) genes with clonal lineage in S. aureus in Africa. This is essential because of diversity of cultures and habits of the people. This study analyzed spa types and enterotoxin genes in S. aureus strains previously isolated from the human nostrils, poultry and clinical samples in Southern Nigeria. Methods: Forty-seven S. aureus isolates were obtained from humans nostrils (n = 13), clinical strains (n = 21) and poultry (n = 13) from previous studies in Southern Nigeria. The strains were analyzed for mecA gene, selected toxins genes (sea, seb, sec, sed, see, seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq, ser, seu) and Panton-Valentine leukocidin (PVL) gene (lukS-PV/lukF-PV) by PCR. Population structures of the strains were detected by Staphylococcal protein A (spa) typing. Results: Twenty different spa types were obtained with the highest percentages, 17% observed in spa type t091 from clinical, nasal and poultry samples while t069 was the most prevalent spa type in poultry. Two MRSA were only detected in human strains. The poultry strains had the highest occurrence of SE genes (18%) followed by nasal strains (15%) and clinical strains (10%). Eighty-nine percent of all tested isolates harbored at least one SE gene; seo was the most prevalent (34%) followed by seg (30%) and sea (21%), while sec, see and sej were absent in all strains. Spa type t355 was associated with lukS-PV/lukF-PV gene and complete absence of all studied SE. Sea, seq, seb, sek were associated with spa type t069; sea was associated with t127 while sep was associated with spa type t091. There were coexistences of seo/seg and sei/seg. Conclusions: The higher carriage of staphylococci enterotoxin genes by the nasal and poultry S. aureus strains suggests a high potential of spread of staphylococcal food poisoning through poultry and healthy carriers in the community. This is the first report of high occurrence of staphylococcal enterotoxins genes in poultry from Nigeria. PMID- 30013851 TI - Association of circulating microRNA-122 with presence and severity of atherosclerotic lesions. AB - Objective: MicroRNA (miR)-122 is highly expressed in the liver, where it has been implicated as a regulator of fatty-acid metabolism. A recent study reported that miR-122 plays a role in pathogenesis of atherosclerosis; however, whether it connects with severity of atherosclerotic lesion is still controversial. We therefore investigated the association between miR-122 expression and presence and severity of coronary atherosclerotic plaque. Methods: During January-November 2017, we included 300 patients with coronary heart disease (CHD) and 100 subjects as the control group. MiR-122 content was detected by quantitative real-time polymerase chain reaction. MiR-122 level was identified in all subjects, and the Spearman correlation between miR-122 and severity of atherosclerosis was analyzed. Results: Patients with CHD had higher miR-122 expression than in control group (2.61, 0.91-8.86 vs. 1.62, 0.71-3.45, p < 0.001). Gensini score was significantly associated with miR-122 expression (r = 0.7964, p < 0.001). The odds ratio of miR-122 solely was 0.12 (95% CI [0.05-0.43]) and factors such as cholesterol, triglyceride together with miR-122 level were closely associated with atherosclerosis (all p < 0.001). Conclusions: The serum level of miR-122 may be used to differentiate between mild and severe coronary atherosclerotic lesion. Use of this marker might allow non-invasive diagnosis the degree of coronary atherosclerosis. PMID- 30013852 TI - Protected areas' effectiveness under climate change: a latitudinal distribution projection of an endangered mountain ungulate along the Andes Range. AB - Background: Climate change is one of the greatest threats to biodiversity, pushing species to shift their distribution ranges and making existing protected areas inadequate. Estimating species distribution and potential modifications under climate change are then necessary for adjusting conservation and management plans; this is especially true for endangered species. An example of this issue is the huemul (Hippocamelus bisulcus), an endemic endangered deer from the southern Andes Range, with less than 2,000 individuals. It is distributed in fragmented populations along a 2,000 km latitudinal gradient, in Chile and Argentina. Several threats have reduced its distribution to <50% of its former range. Methods: To estimate its potential distribution and protected areas effectiveness, we constructed a species distribution model using 2,813 huemul presence points throughout its whole distribution range, together with 19 bioclimatic layers and altitude information from Worldclim. Its current distribution was projected for years 2050 and 2070 using five different Global Climate Models estimated for scenarios representing two carbon Representative Concentration Routes (RCP)-RCP4.5 and RCP6.0. Results: Based on current huemul habitat variables, we estimated 91,617 km2 of suitable habitat. In future scenarios of climate change, there was a loss of suitable habitat due to altitudinal and latitudinal variation. Future projections showed a decrease of 59.86-60.26% for the year 2050 and 58.57-64.34% for the year 2070 according to RCP4.5 and RCP6.0, respectively. Protected areas only covered only 36.18% of the present distribution, 38.57-34.94% for the year 2050 and 30.79-31.94% for 2070 under climate change scenarios. Discussion: Modeling current and future huemul distributions should allow the establishment of priority conservation areas in which to focus efforts and funds, especially areas without official protection. In this way, we can improve management in areas heavily affected by climate change to help ensure the persistence of this deer and other species under similar circumstances worldwide. PMID- 30013853 TI - Selection of reference genes for quantitative real-time PCR analysis in halophytic plant Rhizophora apiculata. AB - Rhizophora apiculata is a halophytic, small mangrove tree distributed along the coastal regions of the tropical and subtropical areas of the world. They are natural genetic reservoirs of salt adaptation genes and offer a unique system to explore adaptive mechanisms under salinity stress. However, there are no reliable studies available on selection and validation of reference genes for quantitative real-time polymerase chain reaction (qRT-PCR) in R. apiculata physiological tissues and in salt stress conditions. The selection of appropriate candidate reference gene for normalization of qRT-PCR data is a crucial step towards relative analysis of gene expression. In the current study, seven genes such as elongation factor 1alpha (EF1alpha), Ubiquitin (UBQ), beta-tubulin (beta-TUB), Actin (ACT), Ribulose1,5-bisphosphate carboxylase/oxygenase (rbcL), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and 18S rRNA (18S) were selected and analyzed for their expression stability. Physiological tissues such as leaf, root, stem, and flower along with salt stress leaf samples were used for selection of candidate reference genes. The high-quality expression data was obtained from biological replicates and further analyzed using five different programs such as geNorm, NormFinder, BestKeeper, Delta Ct and RefFinder. All algorithms comprehensively ranked EF1alpha followed by ACT as the most stable candidate reference genes in R. apiculata physiological tissues. Moreover, beta TUB and 18S were ranked as moderately stable candidate reference genes, while GAPDH and rbcL were least stable reference genes. Under salt stress, EF1alpha was comprehensively recommended top-ranked candidate reference gene followed by ACT and 18S. In order to validate the identified most stable candidate reference genes, EF1alpha, ACT, 18S and UBQ were used for relative gene expression level of sodium/proton antiporter (NHX) gene under salt stress. The expression level of NHX varied according to the internal control which showed the importance of selection of appropriate reference gene. Taken together, this is the first ever systematic attempt of selection and validation of reference gene for qRT-PCR in R. apiculata physiological tissues and in salt stress. This study would promote gene expression profiling of salt stress tolerance related genes in R. apiculata. PMID- 30013854 TI - Cloning, purification and characterization of trehalose-6-phosphate synthase from Pleurotus tuoliensis. AB - Pleurotus tuoliensis, a kind of valuable and favorable edible mushroom in China, is always subjected to high environmental temperature during cultivation. In our previous study with P. tuoliensis, trehalose proved to be effective for tolerating heat stress. Trehalose-6-phosphate synthase (TPS; EC2.4.1.15) plays a key role in the biosynthesis of trehalose in fungi. In this study, a full-length of cDNA with 1,665 nucleotides encoding TPS (PtTPS) in P. tuoliensis was cloned. The PtTPS amino acid was aligned with other homologues and several highly conserved regions were analyzed. Thus, the TPS protein was expressed in Escherichia coli and purified by affinity chromatography to test its biochemical properties. The molecular mass of the enzyme is about 60 kDa and the optimum reaction temperature and pH is 30 degrees C and 7, respectively. The UDP-glucose and glucose-6-phosphate were the optimum substrates among all the tested glucosyl donors and acceptors. Metal cations like Mg2+, Co2+, Mn2+, Ni2+, K+, Ag+ stimulated PtTPS activity significantly. Metal chelators such as sodium citrate, citric acid, EDTA, EGTA and CDTA inhibited enzyme activity. Polyanions like heparin and chondroitin sulfate were shown to stimulate TPS activity. PMID- 30013855 TI - Sex change in scallop Patinopecten yessoensis: response to population composition? AB - Sex structure is very labile between populations and specific for each population because it is a result of genetic, ontogenetic and biocenotic influences on the mollusks. In this study, the age frequency distribution, age-sex structure, and sex ratio were assessed in the wild populations of the Yeso scallop Patinopecten yessoensis (Jay) observed at fifteen sites in the northwestern Sea of Japan (=East Sea). The sex ratio varied between the populations from 0.83:1 to 1.52:1 (males/females), with the mean sex ratio being 1.03 +/- 0.05:1. Within a population, the proportions of males and females in term of number differed between age classes. Males were more numerous than females in the younger age classes, and females prevailed over males in the older age classes. It was found that in different scallop populations the sex change occurred at different ages. In the populations that predominantly consisted of young (two- to four-year-old) individuals, males prevailed over females in the age class 2 yr.; the equal male/female proportion was found in the age class 3 yr.; and in older age classes, females prevailed over males. Another pattern was observed in the populations that consisted mainly of middle-aged (five- to six-year-old) individuals. Here, the age-sex ratio became equal at an age of 4-6 years. In the old populations (mainly 6-12-year-olds) the equal male/female proportion was observed at an age of 8-10 years. Thus, the age of sex change was not uniform for the scallop populations. It depended on the age structure of the population and, thus, was socially controlled. The greater number of females in the older age classes suggests a protandric sex change. PMID- 30013856 TI - Stop signals delay synchrony more for finger tapping than vocalization: a dual modality study of rhythmic synchronization in the stop signal task. AB - Background: A robust feature of sensorimotor synchronization (SMS) performance in finger tapping to an auditory pacing signal is the negative asynchrony of the tap with respect to the pacing signal. The Paillard-Fraisse hypothesis suggests that negative asynchrony is a result of inter-modal integration, in which the brain compares sensory information across two modalities (auditory and tactile). The current study compared the asynchronies of vocalizations and finger tapping in time to an auditory pacing signal. Our first hypothesis was that vocalizations have less negative asynchrony compared to finger tapping due to the requirement for sensory integration within only a single (auditory) modality (intra-modal integration). However, due to the different measurements for vocalizations and finger responses, interpreting the comparison between these two response modalities is problematic. To address this problem, we included stop signals in the synchronization task. The rationale for this manipulation was that stop signals would perturb synchronization more in the inter-modal compared to the intra-modal task. We hypothesized that the inclusion of stop signals induce proactive inhibition, which reduces negative asynchrony. We further hypothesized that any reduction in negative asynchrony occurs to a lesser degree for vocalization than for finger tapping. Method: A total of 30 participants took part in this study. We compared SMS in a single sensory modality (vocalizations (or auditory) to auditory pacing signal) to a dual sensory modality (fingers (or tactile) to auditory pacing signal). The task was combined with a stop signal task in which stop signals were relevant in some blocks and irrelevant in others. Response-to-pacing signal asynchronies and stop signal reaction times were compared across modalities and across the two types of stop signal blocks. Results: In the blocks where stopping was irrelevant, we found that vocalization (-61.47 ms) was more synchronous with the auditory pacing signal compared to finger tapping (-128.29 ms). In the blocks where stopping was relevant, stop signals induced proactive inhibition, shifting the response times later. However, proactive inhibition (26.11 ms) was less evident for vocalizations compared to finger tapping (58.06 ms). Discussion: These results support the interpretation that relatively large negative asynchrony in finger tapping is a consequence of inter-modal integration, whereas smaller asynchrony is associated with intra modal integration. This study also supports the interpretation that intra-modal integration is more sensitive to synchronization discrepancies compared to inter modal integration. PMID- 30013857 TI - Effects of two-week e-learning on eHealth literacy: a randomized controlled trial of Japanese Internet users. AB - Background: The Internet is widely used as a source of information by people searching for medical or healthcare information. However, information found on the Internet has several drawbacks, and the ability to consume accurate health information on the Internet (eHealth literacy) is increasingly important. This study's goal was to clarify the extent to which eHealth literacy is improved after e-learning in a randomized controlled trial. Methods: Data were collected on 301 Japanese adults through an online survey. Participants were assigned to the intervention (e-learning about eHealth literacy) group or the control group in a 1:1 ratio. The intervention group included 148 participants, and 153 participants were in the control group. The participants provided information at baseline on demographic characteristics, self-rated health, and frequency of Internet searching. The eHealth Literacy Scale (eHEALS), which was the main measure of eHealth literacy, and data on secondary outcomes (the Healthy Eating Literacy Scale and skill for evaluating retrieved search results) were obtained at baseline and at follow-up. The score difference was calculated by subtracting the score at baseline from the score at follow-up. Linear regression analysis and multinomial regression analysis were performed using the differences in score as the dependent variables and the intervention as the explanatory variable. Intention-to-treat analysis was employed. Results: The results from participants who responded to all of the questions both times were analyzed (134 in the intervention group and 148 in the control group). eHEALS increased 1.57 points due to the intervention effect (Delta score change = 1.57; 95% CI [0.09-3.05]; p = 0.037). Skills for evaluating retrieved search results improved more in the intervention group than in the control group (relative risk ratio = 2.47; 95% Confidence Interval: 1.33, 4.59; p = 0.004). There were no large differences at baseline between the intervention and control groups in the eHEALS, Healthy Eating Literacy scale, or skill for evaluating retrieved search results. However, at follow-up, the intervention group had improved more than the control group on both the eHEALS and skill for evaluating retrieved search results. Discussion: eHealth literacy improved after the e-learning, as evidenced by the change to the eHEALS scores and increased skill for evaluating retrieved search results. There was no significant effect of e-learning, which did not include content on healthy eating, on the Healthy Eating Literacy Scale scores. This indicates that scores did not increase much due to effects other than e-learning, as is sometimes seen with the Hawthorne effect. Although it was statistically significant, the effect size was small. Therefore, future research is necessary to verify the clinical implications. In sum, this study suggests that e-learning is an effective way to improve eHealth literacy. PMID- 30013858 TI - Staphylococcus aureus viewed from the perspective of 40,000+ genomes. AB - Low-cost Illumina sequencing of clinically-important bacterial pathogens has generated thousands of publicly available genomic datasets. Analyzing these genomes and extracting relevant information for each pathogen and the associated clinical phenotypes requires not only resources and bioinformatic skills but organism-specific knowledge. In light of these issues, we created Staphopia, an analysis pipeline, database and application programming interface, focused on Staphylococcus aureus, a common colonizer of humans and a major antibiotic resistant pathogen responsible for a wide spectrum of hospital and community associated infections. Written in Python, Staphopia's analysis pipeline consists of submodules running open-source tools. It accepts raw FASTQ reads as an input, which undergo quality control filtration, error correction and reduction to a maximum of approximately 100* chromosome coverage. This reduction significantly reduces total runtime without detrimentally affecting the results. The pipeline performs de novo assembly-based and mapping-based analysis. Automated gene calling and annotation is performed on the assembled contigs. Read-mapping is used to call variants (single nucleotide polymorphisms and insertion/deletions) against a reference S. aureus chromosome (N315, ST5). We ran the analysis pipeline on more than 43,000 S. aureus shotgun Illumina genome projects in the public European Nucleotide Archive database in November 2017. We found that only a quarter of known multi-locus sequence types (STs) were represented but the top 10 STs made up 70% of all genomes. methicillin-resistant S. aureus (MRSA) were 64% of all genomes. Using the Staphopia database we selected 380 high quality genomes deposited with good metadata, each from a different multi-locus ST, as a non-redundant diversity set for studying S. aureus evolution. In addition to answering basic science questions, Staphopia could serve as a potential platform for rapid clinical diagnostics of S. aureus isolates in the future. The system could also be adapted as a template for other organism-specific databases. PMID- 30013859 TI - Genetic diversity and population structure of the endangered basal angiosperm Brasenia schreberi (Cabombaceae) in China. AB - Brasenia schreberi J.F. Gmelin (Cabombaceae), an aquatic herb that occurs in fragmented locations in China, is rare and endangered. Understanding its genetic diversity and structure is crucial for its conservation and management. In this study, 12 microsatellite markers were used to estimate the genetic diversity and variation in 21 populations of B. schreberi in China. A total of 61 alleles were found; assessment of allelic richness (Ar = 1.92) and observed and expected heterozygosity (HO = 0.200, HE = 0.256) suggest lower genetic diversity compared to some endangered species, and higher variation was observed within populations (58.68%) rather than among populations (41.32%). No significant correlation between geographical and genetic distance among populations was detected (Mantel test, r = 0.0694; P = 0.7985), which may have likely resulted from barriers to gene flow (Nm = 0.361) that were produced by habitat fragmentation. However, Bayesian and neighbor-joining cluster analyses suggest a population genetic structure consisting of two clusters (I and II) or four subclusters (I-1, 2 and II-1, 2). The genetic structure and distribution of B. schreberi in China may have involved glacial refugia that underwent range expansions, introgression, and habitat fragmentation. The findings of the present study emphasize the importance for both in situ and ex situ conservation efforts. PMID- 30013860 TI - Comparing the Results of Written Testing for Advanced Cardiac Life Support Teaching Using Team-based Learning and the "Flipped Classroom" Strategy. AB - Objectives We sought to further determine whether cognitive test results changed for advanced cardiac life support (ACLS) taught in the team-based learning/flipped classroom format (TBL/FC) versus a lecture-based (LB) control. Methods We delivered 2010 ACLS to two classes of fourth-year medical students in the TBL/FC format (2015-2016), compared to three classes in the LB format (2012 2014). There were 27.5 hours of instruction for the TBL/FC model (TBL - 10.5 hours, podcasts - nine hours, small-group simulation - eight hours), and 20 hours (lectures - 12 hours, simulation - eight hours) in LB. We taught TBL for 13 cardiac cases while LB had none. Didactic content and seven simulated cases were the same in lecture (2012-2014) or in podcast formats (2015-2016). Testing was the same using 50 multiple-choice (MC) format questions, 20 rhythm-matching questions, and seven fill-in management of simulated cases. Results Some 468 students enrolled in the course 259 (55.4%) in the LB format in 2012-2014, and 209 (44.6%) in the TBL/FC format in 2015-2016. The scores for two out of three tests (MC and fill-in) increased with TBL/FC. Combined, median scores increased from 93.5% (IQR 90.6, 95.4) to 95.1% (92.5, 96.8, p = 0.0001). More students did not pass one of three tests with LB versus TBL/FC (24.7% versus 18.2%), and two or three parts of the test (8.1% versus 4.3%, p = 0.01). On the contrary, 77.5% passed all three with TBL/FC versus 67.2% with LB (change 10.3%, 95% CI 2.2% 18.2%). Conclusion TBL/FC teaching for ACLS improved written test results compared with the LB format. PMID- 30013861 TI - Wernicke's Encephalopathy as a Rare Complication of Hyperemesis Gravidarum: A Case Report and Review of Literature. AB - Wernicke's encephalopathy (WE) is a rare neurological syndrome that presents in the setting of thiamine deficiency. Though alcoholism is the most common cause of this condition, a few other etiologies include malnutrition from other causes, hemodialysis, and hyperemesis gravidarum. In this case report, we aim to report a case of a young woman who developed WE in the setting of hyperemesis gravidarum (HG) that improved with thiamine replacement. This manuscript details her presentation and clinical examination and includes a spontaneous upbeat nystagmus and goes over the condition along with a review of the literature. PMID- 30013863 TI - Bradycardia and Syncope in a Patient Presenting With Loperamide Abuse. AB - Loperamide is an antidiarrheal agent available as an inexpensive over-the-counter (OTC) medication. In general, it is considered to be safe, but lately, loperamide drug abuse has been reported due to its opioid properties. When used in high doses, several harmful effects including cardiotoxicity, central nervous system (CNS) and respiratory depression have been reported. This prompted the FDA to release a warning in 2016 regarding the arrhythmogenic potential of loperamide. We present a case of a 32-year-old male with a history of polysubstance abuse who presented to the emergency department (ED) requesting "detoxification" from loperamide. The patient complained of opiate withdrawal symptoms including chills, nausea, vomiting, constipation, and abdominal cramps thought to be secondary to the abuse of loperamide. He was found to have right bundle branch block (RBBB) and bradycardia with a heart rate (HR) of 51 beats per min (bpm). He also reported an unexplained syncopal episode, one day prior to visiting the ED. In the current case report, we discuss loperamide abuse, its harmful effects, and management. PMID- 30013862 TI - Evaluation of CyberKnife Radiosurgery for Recurrent Trigeminal Neuralgia. AB - Stereotactic radiosurgery (SRS) has evolved as an accepted treatment for medication resistant trigeminal neuralgia. Initial results are very good but follow-up over three to five years shows a gradual return of pain in up to 50% of treated patients, often requiring further treatment. The results with repeat SRS using the isocentric Gamma Knife (GK) (Elekta, Stockholm, Sweden), especially in patients having initially good results, are very similar to the outcomes after the initial treatment although there is an increased risk of residual facial numbness secondary to the additional radiation dose to the trigeminal nerve. However, after 2000, non-isocentric SRS systems began to be used for treating trigeminal neuralgia including the CyberKnife (CK) (Accuray, Sunnyvale, California) as well as various linear accelerator (LINAC) based systems. This report specifically examines a series of recurrent trigeminal cases treated by the same group of physicians with the CK system. Similar doses and locations on the trigeminal nerve and/or the root entry zone were used for both initial and repeat SRS treatment regardless of system used. Although there are numerous series reporting the use of GK for recurrent treatment for recurrent trigeminal neuralgia, there are no series reviewing the results and long-term effectiveness using CK for repeat SRS for recurrent trigeminal pain. We reviewed 23 cases that had initial treatment for trigeminal neuralgia either surgically or with SRS with either the GK or CK and then a later second procedure only with CK. The follow-up after the second CK SRS ranged from three to 13 years found that the results are very similar to the multiple reports in the literature describing second or third SRS treatments with the GK. Results of repeat radiosurgery treatment of recurrent trigeminal neuralgia appear to be independent of the system used and are primarily based on proper target and dose to the trigeminal nerve. PMID- 30013864 TI - Impact of Hypothyroidism on Outcomes of Percutaneous Coronary Intervention with Coronary Atherectomy for Calcified Coronary Lesions: A Propensity-matched Analysis. AB - Overt and subclinical hypothyroid states have been depicted as risk factors for a more prominent level of coronary calcification. The utilization of coronary atherectomy with percutaneous coronary intervention (PCI) is on the ascent over the past few years as lesions that are more complex are now attempted with a percutaneous approach. However, the real-world data on hypothyroid status influencing PCI with coronary atherectomy outcomes is very limited. Therefore, we proposed to investigate the outcomes of percutaneous coronary intervention with coronary atherectomy in hypothyroid patients using the largest inpatient database in the United States (US), the National Inpatient Sample (NIS). To minimize the selection bias, we surveyed and compared the outcomes in both the unmatched and propensity-score matched euthyroid and hypothyroid cohorts. Concisely, this propensity-matched analysis, using the largest population-based sample in the US, has established higher cardiovascular comorbidities and worse clinical outcomes of PCI with coronary atherectomy owing to clinical hypothyroidism. PMID- 30013865 TI - Effect of Comprehensive Surgical Safety System on Patients' Outcome: A Prospective Clinical Study. AB - Background Patient safety has become an integral part of hospital management to prevent catastrophic events which adversely affects the patients, care providers and the hospital. Surgical Checklists are an easy and simple way to prevent surgical errors and complications. Objective This prospective study is to evaluate the effect of SURPASS (Surgical Patient Safety System) checklist on the outcome of the patients who underwent surgery in our hospital. Methods All the patients who underwent surgery in the sixth unit of Department of Surgery from April 2014 to May 2015 were included in the study excluding those aged above 13 years and day care surgery cases. For the control group (initial six months) no checklist was implemented whereas for the study group (next six months) SURPASS checklist was implemented. Data collected on age, sex, diagnosis, surgical procedure, type of anaesthesia, number and type of postoperative complications, need of second surgery because of complications, length of hospital stay and outcome (discharge, disability or death). Mann-Whitney U test and Fisher's exact test were used for analysis. Results Of the total 372 patients operated, 200 were before and 172 were after implementation of SURPASS checklist. Before implementation of the checklist, complications were noticed in 66.66% of elective and 77.23% of emergency cases. Whereas after implementation of checklist the complications in elective cases were found to be 51.09% (p-value = 0.008) and 67.50% (p-value = 0.024) in emergency cases. Conclusion Implementation of SURPASS checklist is effective in reducing the rate of postoperative complications in both elective and emergency surgeries. PMID- 30013866 TI - Probable Lewy Body Dementia with a Predilection for Auditory Hallucinations. AB - The patient was a 60-year-old male who initially presented to the emergency room with extreme agitation aggravated by internal stimuli as well as visual hallucinations, paranoia, and grandiose delusions. He was diagnosed with nonspecific schizophrenia and treated with risperidone, trazodone, and lithium. Approximately 16 months later, he was readmitted to the hospital trying to enter a stranger's car that he thought was his. He was confused and was unable to give an accurate history. His psychomotor retardation and confusion were thought to be due to risperidone. When his dose was decreased, he displayed involuntary movements of the mouth and extremities, restlessness, and a patting of his head. The risperidone was switched to zyprexa in an effort to decrease extrapyramidal symptoms. About two months later, he was found unresponsive and catatonic in his car. During his stay, the patient had a fluctuation in the latency of his responses on a daily basis. He would be aware of where he was but was unable to explain why or for how long. He had a difficult time remembering names and was still exhibiting abnormal involuntary movements around the mouth and extremities. The patient's course of initial predominantly auditory and visual hallucinations that progressed to extrapyramidal symptoms and fluctuating cognition one year later may suggest Lewy body dementia. PMID- 30013867 TI - Brachial Artery Coiling: Report of a Rare Case. AB - Nowadays, the transradial approach is increasingly used for performing percutaneous coronary interventions and is preferred over the transfemoral approach. In the latest European Society of Cardiology guidelines (2017) for management of acute myocardial infarction in patients presenting with ST-segment elevation, the transradial approach is recommended over the transfemoral one if performed by an experienced radial operator (MATRIX study). Transradial procedure failures may be related to puncture failure, artery spasm, or to anatomical variations that require specific catheter handling or changing with a contralateral or transfemoral approach. Herein we report a failure of transradial heart catheterization due to brachial artery coiling. PMID- 30013868 TI - Variant Distal Ulnar Nerve Loop: A Previously Undescribed Anatomical Finding. AB - A previously undescribed variant ulnar nerve loop was discovered during the routine anatomic forearm and hand dissection of an adult female. The major finding was that of a large loop traveling around the distal tendon of the flexor carpi ulnaris. The variation presented here appears to be unique. The exact function of such derailed anatomy is not clear but, if found during surgery, might confound normal dissection methods or, when present, could result in varied clinical presentations regarding the sensory or motor examination of the hand. PMID- 30013869 TI - Acute Psychosis After Treatment of Epididymitis with Ciprofloxacin. AB - Ciprofloxacin is a broad-spectrum antibiotic that is generally well-tolerated and widely used in clinical practice to treat various forms of infection. There have been several case reports detailing the development of psychosis and other neuropsychiatric symptoms secondary to use of this antibiotic. This case report details the history of an acute paranoid psychosis that developed in a patient treated with ciprofloxacin for epididymitis. PMID- 30013870 TI - Piriformis Syndrome and Wallet Neuritis: Are They the Same? AB - Piriformis syndrome (PS) involves the piriformis muscle and adjacent sciatic nerve, producing features similar to true sciatica of lumbar spine origin, for example, lumbar disc prolapse, thereby confusing pain physicians about the diagnosis. Synonyms that are used frequently for PS are deep gluteal syndrome, extra-spinal sciatica, wallet neuritis, etc. Commonly presenting symptoms of PS include gluteal pain which increases with affected side sitting/per-rectal manoeuvre, and improves with ambulation/intra-lesional steroid, etc. Among various PS associations, wallet neuritis is one of them. However, the latter condition can present with even without the typical features for PS, such as positive flexion adduction internal rotation (FAIR) test, pace sign, etc. In a situation like this, mere discontinuation with fatty buttock wallet is often sufficient for relieving patients' discomfort, making other approaches unnecessary for the patient (though these approaches are warranted for many PS manifestations). Thus, it would not be wise to use piriformis syndrome and wallet neuritis terminology interchangeably as depicted in many published papers. PMID- 30013871 TI - Long-term Survival After Treating Cardiac Metastasis With Radiation and Immune Therapy: A Case Report. AB - Cardiac metastases are a rare clinical entity and they generally portend a poor prognosis. Management is generally directed toward symptom control and maintaining cardiac function; however, long-term survival is rare. Here, we report a case of isolated metastatic urothelial cell carcinoma to the right ventricle that was functionally limiting the patient. The metastasis was successfully palliated for 17 months following radiation and immune therapy; however, disease progression in and around his heart ultimately led to a cardiac arrest. PMID- 30013872 TI - The Emergence of a Forgotten Entity: Dermatomyositis-like Presentation of Lyme Disease in Rural Wisconsin. AB - Dermatomyositis (DM) is one of the rare clinical manifestations of tickborne related autoimmune presentations; we report an uncommon case of Borrelia-related DM-like presentation from rural Wisconsin. A 76-year-old female presented with fatigue, malaise, weight loss and progressive proximal muscle weakness after a flare-up of shoulder arthritis. She had a heliotrope rash and a Shawl sign in addition to generalized cutaneous erythema with edema. There was no history of tick bite, Lyme disease (LD) or DM. The physical exam revealed erythema migrans (EM) and DM-like musculocutaneous findings. Enzyme-linked immunosorbent assay and western blot were positive for LD. The patient received intravenous ceftriaxone and doxycycline for five days, leading to the resolution of EM lesions and improvement in her muscle weakness. In addition, DM-like features resolved with antiborrelial treatment and required no steroids or immunosuppressants. Workup including electromyography, skin or muscle biopsy could not be performed as the patient improved clinically. At six months post-treatment, she remained in remission. PMID- 30013873 TI - Impact of a Canadian Pediatric Society Position Statement on Trampoline-related Injuries at IWK Health Centre, Halifax, Nova Scotia. AB - INTRODUCTION: In 2007, the Canadian Pediatric Society (CPS) advised against the recreational use of trampolines at home and reaffirmed that statement in 2013. We evaluated the impact of this position statement on trampoline-related injuries at the IWK Health Centre in Halifax, Nova Scotia. METHODS: We completed a retrospective analysis (2001-2015) using the IWK Health Centre's Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) database. The time frame was divided into a pre-statement, post-statement, and post-reaffirmed statement. We included data on captured emergency department visits for children aged 0-16 years with trampoline-related injuries. Demographics, location, and injury mechanism were compared using the chi-squared and z tests. The proportions of trampoline injuries for pre-, post-, and post-reaffirmed statements were compared via analysis of variance (ANOVA). RESULTS: Since the CPS statement, trampoline-related injuries significantly increased at the IWK Health Centre from 0.9% to 1.6% (p<0.001). Injuries increased in children under four years old and decreased in children 10-14 years (p=0.009). Recreational use at home (93%) remained the most common location of the incident (p<0.001). Fractures (n=277) and sprains/soft tissue injuries (n=232) to the ankle, head/neck, or elbow remained the most common injuries and did not significantly change post-statement or post-reaffirmed statement (p>0.05). CONCLUSIONS: Despite the CPS statement, trampoline-related injuries remain an important source of injuries at the IWK Health Centre. The types of injury did not significantly change during this time frame. PMID- 30013874 TI - A Left-sided Azygos Vein in a Cadaver: Anatomical and Surgical Considerations. AB - Despite the wide-spread knowledge among anatomists and surgeons that the azygos vein lies on the right side of the vertebral column, various scientific works have been conducted which suggest the existence of left-sided azygos veins. The displacement of the vessel seems to be related with aging, due to crossover veins and the development of osteophytes on the thoracic vertebrae. The current case report confirms the variation of the azygos vein's course, highlights the awareness of the relatively unusual left-sided location of the azygos vein for the surgeon of the region, and underlines the clinical significance of such knowledge to the modern internist-radiologist, general surgeon and thoracic surgeon, as well. PMID- 30013876 TI - Tunable fractional Fourier transform implementation of electronic wave functions in atomically thin materials. AB - A tunable fractional Fourier transform of the quantum wave function of electrons satisfying either the Schrodinger or the Dirac equation can be implemented in an atomically thin material by a parabolic potential distribution applied on a direction transverse to that of electron propagation. The difference between the propagation lengths necessary to obtain a fractional Fourier transform of a given order in these two cases could be seen as a manifestation of the Berry phase. The Fourier transform of the electron wave function is a particular case of the fractional Fourier transform. If the input and output wave functions are discretized, this configuration implements in one step the discrete fractional Fourier transform, in particular the discrete Fourier transform, and thus can act as a coprocessor in integrated logic circuits. PMID- 30013875 TI - Improving the catalytic activity for hydrogen evolution of monolayered SnSe2(1 x)S2x by mechanical strain. AB - Exploring efficient electrocatalysts for hydrogen production with non-noble metals and earth-abundant elements is a promising pathway for achieving practical electrochemical water splitting. In this work, the electronic properties and catalytic activity of monolayer SnSe2(1-x)S2x (x = 0-1) under compressive and tensile strain were investigated using density functional theory (DFT) computations. The results showed SnSe2(1-x)S2x alloys with continuously changing bandgaps from 0.8 eV for SnSe2 to 1.59 eV for SnS2. The band structure of a SnSe2(1-x)S2x monolayer can be further tuned by applied compressive and tensile strain. Moreover, tensile strain provides a direct approach to improve the catalytic activity for the hydrogen evolution reaction (HER) on the basal plane of the SnSe2(1-x)S2x monolayer. SnSeS and SnSe0.5S1.5 monolayers showed the best catalytic activity for HER at a tensile strain of 10%. This work provides a design for improved catalytic activity of the SnSe2(1-x)S2x monolayer. PMID- 30013877 TI - Numerical analysis of single-point spectroscopy curves used in photo-carrier dynamics measurements by Kelvin probe force microscopy under frequency-modulated excitation. AB - In recent years, the investigation of the complex interplay between the nanostructure and photo-transport mechanisms has become of crucial importance for the development of many emerging photovoltaic technologies. In this context, Kelvin probe force microscopy under frequency-modulated excitation has emerged as a useful technique for probing photo-carrier dynamics and gaining access to carrier lifetime at the nanoscale in a wide range of photovoltaic materials. However, some aspects about the data interpretation of techniques based on this approach are still the subject of debate, for example, the plausible presence of capacitance artifacts. Special attention shall also be given to the mathematical model used in the data-fitting process as it constitutes a determining aspect in the calculation of time constants. Here, we propose and demonstrate an automatic numerical simulation routine that enables to predict the behavior of spectroscopy curves of the average surface photovoltage as a function of a frequency-modulated excitation source in photovoltaic materials, enabling to compare simulations and experimental results. We describe the general aspects of this simulation routine and we compare it against experimental results previously obtained using single point Kelvin probe force microscopy under frequency-modulated excitation over a silicon nanocrystal solar cell, as well as against results obtained by intensity modulated scanning Kelvin probe microscopy over a polymer/fullerene bulk heterojunction device. Moreover, we show how this simulation routine can complement experimental results as additional information about the photo-carrier dynamics of the sample can be gained via the numerical analysis. PMID- 30013878 TI - Quantitative comparison of wideband low-latency phase-locked loop circuit designs for high-speed frequency modulation atomic force microscopy. AB - A phase-locked loop (PLL) circuit is the central component of frequency modulation atomic force microscopy (FM-AFM). However, its response speed is often insufficient, and limits the FM-AFM imaging speed. To overcome this issue, we propose a PLL design that enables high-speed FM-AFM. We discuss the main problems with the conventional PLL design and their possible solutions. In the conventional design, a low-pass filter with relatively high latency is used in the phase feedback loop, leading to a slow response of the PLL. In the proposed design, a phase detector with a low-latency high-pass filter is located outside the phase feedback loop, while a subtraction-based phase comparator with negligible latency is located inside the loop. This design minimizes the latency within the phase feedback loop and significantly improves the PLL response speed. In addition, we implemented PLLs with the conventional and proposed designs in the same field programmable gate array chip and quantitatively compared their performances. The results demonstrate that the performance of the proposed PLL is superior to that of the conventional PLL: 165 kHz bandwidth and 3.2 MUs latency in water. Using this setup, we performed FM-AFM imaging of calcite dissolution in water at 0.5 s/frame with true atomic resolution. The high-speed and high resolution imaging capabilities of the proposed design will enable a wide range of studies to be conducted on various atomic-scale dynamic phenomena at solid liquid interfaces. PMID- 30013879 TI - The role of the Ge mole fraction in improving the performance of a nanoscale junctionless tunneling FET: concept and scaling capability. AB - In this paper, a new nanoscale double-gate junctionless tunneling field-effect transistor (DG-JL TFET) based on a Si1-x Ge x /Si/Ge heterojunction (HJ) structure is proposed to achieve an improved electrical performance. The effect of introducing the Si1-x Ge x material at the source side on improving the subthreshold behavior of the DG-JL TFET and on suppressing ambipolar conduction is investigated. Moreover, the impact of the Ge mole fraction in the proposed Si1 x Ge x source region on the electrical figures of merit (FoMs) of the transistor, including the swing factor and the ION/IOFF ratio is analyzed. It is found that the optimized design with 60 atom % of Ge offers improved switching behavior and enhanced derived current capability at the nanoscale level, with a swing factor of 42 mV/dec and an ION/IOFF ratio of 115 dB. Further, the scaling capability of the proposed Si1-x Ge x /Si/Ge DG-HJ-JL TFET structure is investigated and compared to that of a conventional Ge-DG-JL TFET design, where the optimized design exhibits an improved switching behavior at the nanoscale level. These results make the optimized device suitable for designing digital circuit for high performance nanoelectronic applications. PMID- 30013880 TI - Electrical characterization of single nanometer-wide Si fins in dense arrays. AB - This paper demonstrates the development of a methodology using the micro four point probe (MU4PP) technique to electrically characterize single nanometer-wide fins arranged in dense arrays. We show that through the concept of carefully controlling the electrical contact formation process, the electrical measurement can be confined to one individual fin although the used measurement electrodes physically contact more than one fin. We demonstrate that we can precisely measure the resistance of individual ca. 20 nm wide fins and that we can correlate the measured variations in fin resistance with variations in their nanometric width. Due to the demonstrated high precision of the technique, this opens the prospect for the use of MU4PP in electrical critical dimension metrology. PMID- 30013881 TI - Synthesis of hafnium nanoparticles and hafnium nanoparticle films by gas condensation and energetic deposition. AB - In this work we study the fabrication and characterization of hafnium nanoparticles and hafnium nanoparticle thin films. Hafnium nanoparticles were grown in vacuum by magnetron-sputtering inert-gas condensation. The as deposited nanoparticles have a hexagonal close-packed crystal structure, they possess truncated hexagonal biprism shape and are prone to surface oxidation when exposed to ambient air forming core-shell Hf/HfO2 structures. Hafnium nanoparticle thin films were formed through energetic nanoparticle deposition. This technique allows for the control of the energy of charged nanoparticles during vacuum deposition. The structural and nanomechanical properties of the nanoparticle thin films were investigated as a function of the kinetic energy of the nanoparticles. The results reveal that by proper adjustment of the nanoparticle energy, hexagonal close-packed porous nanoparticle thin films with good mechanical properties can be formed, without any additional treatment. It is shown that these films can be patterned on the substrate in sub-micrometer dimensions using conventional lithography while their porosity can be well controlled. The fabrication and experimental characterization of hafnium nanoparticles is reported for the first time in the literature. PMID- 30013883 TI - Synthesis of carbon nanowalls from a single-source metal-organic precursor. AB - In this work, the deposition of carbon nanowalls (CNWs) by inductively coupled plasma enhanced chemical vapor deposition (ICP-PECVD) is investigated. The CNWs are electrically conducting and show a large specific surface area, which is a key characteristic to make them interesting for sensors, catalytic applications or energy-storage systems. It was recently discovered that CNW films can be deposited by the use of the single-source metal-organic precursor aluminium acetylacetonate. This precursor is relatively unknown in combination with the ICP PECVD deposition method in literature and, thus, based on our previous publication is further investigated in this work to better understand the influence of the various deposition parameters on the growth. Silicon, stainless steel, nickel and copper are used as substrate materials. The CNWs deposited are characterized by scanning electron microscopy (SEM), Raman spectroscopy and Auger electron spectroscopy (AES). The combination of bias voltage, the temperature of the substrate and the substrate material had a strong influence on the morphology of the graphitic carbon nanowall structures. With regard to these results, a first growth model for the deposition of CNWs by ICP-PECVD and aluminium acetylacetonate is proposed. This model explains the formation of four different morphologies (nanorods as well as thorny, straight and curled CNWs) by taking the surface diffusion into account. The surface diffusion depends on the particle energies and the substrate material and thus explains the influence of these parameters. PMID- 30013882 TI - Synthesis of rare-earth metal and rare-earth metal-fluoride nanoparticles in ionic liquids and propylene carbonate. AB - Decomposition of rare-earth tris(N,N'-diisopropyl-2-methylamidinato)metal(III) complexes [RE{MeC(N(iPr)2)}3] (RE(amd)3; RE = Pr(III), Gd(III), Er(III)) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)europium(III) (Eu(dpm)3) induced by microwave heating in the ionic liquids (ILs) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm][BF4]), 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([BMIm][NTf2]) and in propylene carbonate (PC) yield oxide-free rare-earth metal nanoparticles (RE-NPs) in [BMIm][NTf2] and PC for RE = Pr, Gd and Er or rare-earth metal-fluoride nanoparticles (REF3-NPs) in the fluoride-donating IL [BMIm][BF4] for RE = Pr, Eu, Gd and Er. The crystalline phases and the absence of significant oxide impurities in RE-NPs and REF3-NPs were verified by powder X-ray diffraction (PXRD), selected area electron diffraction (SAED) and high-resolution X-ray photoelectron spectroscopy (XPS). The size distributions of the nanoparticles were determined by transmission electron microscopy (TEM) and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) to an average diameter of (11 +/- 6) to (38 +/- 17) nm for the REF3-NPs from [BMIm][BF4]. The RE-NPs from [BMIm][NTf2] or PC showed diameters of (1.5 +/- 0.5) to (5 +/- 1) nm. The characterization was completed by energy-dispersive X-ray spectroscopy (EDX). PMID- 30013884 TI - The inhibition effect of water on the purification of natural gas with nanoporous graphene membranes. AB - Molecular dynamics simulations are used to investigate the inhibiting effect of water on the natural gas separation with nanoporous graphene. The membrane separation process involves CH4 + N2 mixtures with and without the addition of water. The results show that water is able to form hydrogen bonds with nitrogen atoms located in a nanopore rim. This effect causes a decrease of separation selectivity as well as a reduction of gas permeation. In the extreme case, when the nanopore rim contains only nitrogen atoms, water agglomerates at the center of the nanopore and effectively closes down the permeation path. The conclusions are confirmed by the analysis of stability and kinetics of hydrogen bonds. PMID- 30013885 TI - Nonlinear effect of carrier drift on the performance of an n-type ZnO nanowire nanogenerator by coupling piezoelectric effect and semiconduction. AB - In piezoelectric semiconductors, electric fields drive carriers into motion/redistribution, and in turn the carrier motion/redistribution has an opposite effect on the electric field itself. Thus, carrier drift in a piezoelectric semiconducting structure is essentially nonlinear unless the induced fluctuation of carrier concentration is very small. In this paper, the nonlinear governing equation of carrier concentration was established by coupling both piezoelectric effect and semiconduction. A nonlinear carrier-drift effect on the performance of a ZnO nanogenerator was investigated in detail and it was elucidated that carrier motion/redistribution occurs in the ZnO nanowire (ZNW) cross section while there is no carrier motion in the axial direction. At the same time, we noted that the amplitude of boundary electric charge grows with increasing deformation, but the peaks of boundary electric charge do not appear at the cross-section endpoints. Thus, in order to effectively improve the performance of the ZNW nanogenerator, the effect of electrode configuration on the piezoelectric potential difference and output power was analyzed in detail. The electrode size for the optimal performance of a ZnO nanowire generator was proposed. This analysis that couples electromechanical fields and carrier concentration as a whole has some referential significance to piezotronics. PMID- 30013886 TI - A differential Hall effect measurement method with sub-nanometre resolution for active dopant concentration profiling in ultrathin doped Si1-x Ge x and Si layers. AB - In this paper, we present an enhanced differential Hall effect measurement method (DHE) for ultrathin Si and SiGe layers for the investigation of dopant activation in the surface region with sub-nanometre resolution. In the case of SiGe, which constitutes the most challenging process, we show the reliability of the SC1 chemical solution (NH4OH/H2O2/H2O) with its slow etch rate, stoichiometry conservation and low roughness generation. The reliability of a complete DHE procedure, with an etching step as small as 0.5 nm, is demonstrated on a dedicated 20 nm thick SiGe test structure fabricated by CVD and uniformly doped in situ during growth. The developed method is finally applied to the investigation of dopant activation achieved by advanced annealing methods (including millisecond and nanosecond laser annealing) in two material systems: 6 nm thick SiGeOI and 11 nm thick SOI. In both cases, DHE is shown to be a uniquely sensitive characterisation technique for a detailed investigation of dopant activation in ultrashallow layers, providing sub-nanometre resolution for both dopant concentration and carrier mobility depth profiles. PMID- 30013887 TI - Synthesis of a MnO2/Fe3O4/diatomite nanocomposite as an efficient heterogeneous Fenton-like catalyst for methylene blue degradation. AB - Heterogeneous Fenton-like catalysts with the activation of peroxymonosulfate (PMS), which offer the advantages of fast reaction rate, wide functional pH range and cost efficiency, have attracted great interest in wastewater treatment. In this study, a novel magnetic MnO2/Fe3O4/diatomite nanocomposite is synthesized and then used as heterogeneous Fenton-like catalyst to degrade the organic pollutant methylene blue (MB) with the activation of PMS. The characterization results show that the Fe3O4 nanoparticles and nanoflower-like MnO2 are evenly distributed layer-by-layer on the surface of diatomite, which can be readily magnetically separated from the solution. The as-prepared catalyst, compared with other Fenton-like catalysts, shows a superb MB degradation rate of nearly 100% in 45 min in the pH range of 4 to 8 and temperature range of 25 to 55 degrees C. Moreover, the nanocomposite shows a good mineralization rate of about 60% in 60 min and great recyclability with a recycle efficiency of 86.78% after five runs for MB. The probable mechanism of this catalytic system is also proposed as a synergistic effect between MnO2 and Fe3O4. PMID- 30013888 TI - Arthroscopic Treatment of a Posterior Labral Interposition after a Pediatric Hip Dislocation-A Case Report. AB - We report the case of a 13-year-old boy, who suffered a posterior hip dislocation from playing soccer. Closed reduction was performed urgently. Because of a nonconcentric hip after closed reduction, further imaging was done. An intra articular bony fragment was identified. Arthroscopic treatment was performed. Through an anterior portal we were able to locate the intra-articular bony fragment, which was located within the region of the fovea. After lifting of the caudal enfolded labral complex, we were able to remove the fragment. Evidence of a grade 3 cartilage defect was present at the femoral head. We were able to reduce the enfolded posterior labral complex, which was stable afterwards without the necessity of additional suture fixations. The concentric hip reduction was confirmed on an anteroposterior view of the hip postoperatively. The patient was instructed to toe tip weight-bearing for 6 weeks with limited range of motion to 60 degrees of hip flexion. Eight weeks after surgery, he was free of pain and discomforts. From our experience, the arthroscopic intervention after pediatric hip dislocation associated with intra-articular bony fragments or posterior labral complex injuries, represents to be a preferred minimally invasive method in contrast to open surgical procedures. PMID- 30013889 TI - Neonatal Intrathoracic Gastric Volvulus in Marfan's Syndrome. AB - We report a 12-day-old male who was admitted with vomiting because of an unusual early complication of Marfan's syndrome (MS): a sliding hiatal hernia. Initial ultrasound showed no stomach at its normal position and the chest X-ray presented an intrathoracic gas bubble with the nasogastric tube inside. An upper gastrointestinal contrast study confirmed the complete herniation of the stomach into the thorax. Via an exploratory laparotomy it was carefully reintroduced into the abdomen, following a hiatal reconstruction. A Thal fundoplication and a gastrostomy were also performed to guarantee its fixation. Although characterized by cardiac/aortic abnormalities, MS should be considered in any infant with hiatal/paraesophageal hernia, which should be repaired early to avoid gastric ischemia/volvulus. PMID- 30013892 TI - Prosthesis retention after an infected hip prosthesis: hip fractures versus primary total hip prosthesis, data from 1998 - 2015. AB - Background: A prosthetic joint infection (PJI) is a serious complication and specifically a burden for patients after hip fracture surgery, as they are mostly frail elderly patients with multiple comorbidities. Since treatment protocols are lacking there is a need to evaluate current practice. Aim: To evaluate the difference in prosthesis retention after an infected primary total hip replacement (THR) compared to PJI after hip prosthesis surgery performed for a hip fracture. Methods: We retrospectively collected data of patients who developed PJI after primary THR or after hip fracture surgery (THR or hemiarthroplasty) in the Westfriesgasthuis Hospital between 1998 and 2015. Main outcome variables were DAIR treatment and prosthesis retention. Findings: A PJI developed in 48 patients after primary THR and in 23 patients after hip fracture surgery. DAIR was performed in all patients after primary THR and in 87.0% of patients after hip fracture surgery (p<0.05). In 11.4% of patients after primary THR, revision surgery was performed within 1 year after PJI compared to 34.8% after hip fracture surgery (p<0.05). Only 2.1% of patients deceased within 1 year after infection of primary THR compared to 34.8% after hip fracture surgery (p<0.05). Conclusion: Our results showed that prosthesis retention in patients with a PJI after hip fracture surgery is 23% lower than in patients with a PJI after primary THR. This is probably due to the fact that patients who experience a hip fracture are mostly frail elderly with multiple comorbidities and therefore less able to conquer a PJI. PMID- 30013890 TI - Using animal models to improve the design and application of transcranial electrical stimulation in humans. AB - Purpose of Review: Transcranial electrical stimulation (tES) is a non-invasive stimulation technique used for modulating brain function in humans. To help tES reach its full therapeutic potential, it is necessary to address a number of critical gaps in our knowledge. Here, we review studies that have taken advantage of animal models to provide invaluable insight about the basic science behind tES. Recent Findings: Animal studies are playing a key role in elucidating the mechanisms implicated in tES, defining safety limits, validating computational models, inspiring new stimulation protocols, enhancing brain function and exploring new therapeutic applications. Summary: Animal models provide a wealth of information that can facilitate the successful utilization of tES for clinical interventions in human subjects. To this end, tES experiments in animals should be carefully designed to maximize opportunities for applying discoveries to the treatment of human disease. PMID- 30013893 TI - Antibiotic resistance profiles of deep surgical site infections in hip hemiarthroplasty; comparing low dose single antibiotic versus high dose dual antibiotic impregnated cement. AB - Objectives: The incidence of fractured neck of femur (FNOF) is increasing yearly. Many of these patients undergo hip hemiarthroplasty. High dose dual-antibiotic cement (HDDAC) has been shown to reduce rates of deep surgical site infection (SSI) when compared to the current standard low dose single-antibiotic cement (LDSAC) in a quasi-randomised controlled trial. Some concerns exist regarding the use of HDDAC and the development of antibiotic resistance. We reviewed cases of infection in LDSAC and HDDAC bone cement with regard to causative organism and resistance profile. Methods: A retrospective analysis was undertaken of all hemiarthroplasties within our trust from April 2008 to December 2014. We identified all patients in this time period who acquired a deep SSI. The infecting organisms and susceptibility patterns were collated for each cement. Results: We identified 1941 hemiarthroplasties. There were 38 deep surgical site infections representing an infection rate of 3.4% in LDSAC patients and 1.2% in HDDAC patients. The majority of infections were polymicrobial. Staphylococcus epidermidis was the most commonly isolated organism. It accounted for a larger proportion of HDDAC than LDSAC infections (p<0.05). Infection with Corynebacterium species and S. aureus, including MRSA, was eradicated completely with the use of HDDAC. There was no significant change in the proportion of Gram negative and Gram positive infections between the two cements. In Gram positive organisms, there was no significant change in resistance to most antibiotics. Although fewer resistant infections overall, there were significant increases in the proportion of resistance to ciprofloxacin and clindamycin with HDDAC. We observed no resistance to daptomycin or linezolid in either cement and levels of resistance remained low to rifampicin and teicoplanin. In Gram negative organisms, no significant change in resistance was observed. Conclusions: We observed a significantly lower infection rate with the use of HDDAC compared to LDSAC. Such was this reduced infection rate that there was a trend to a lower rate of resistance with the use of HDDAC. However, there were increases in the proportion of resistant cases, most notably to clindamycin and ciprofloxacin in Gram positive organisms, possibly reflecting the higher number of S. epidermidis in the HDDAC group. Whilst the differences in our study were not found to be statistically significant, it is reassuring for teams using HDDAC to prevent SSI in hip hemiarthroplasty. PMID- 30013891 TI - Treatment of Prosthetic Joint Infection with Debridement, Antibiotics and Irrigation with Implant Retention - a Narrative Review. AB - Prosthetic joint infection usually requires combined medical and surgical therapy. While revision surgery is widely considered to be the gold standard surgical procedure, debridement, antibiotics and irrigation with implant retention is a very appealing alternative. There is however great controversy regarding its real worth with success rates ranging from 0% to over 90%. A number of different patient and host related variables as well as specific aspects of surgical and medical management have been described as relevant for the final outcome. Along this paper, the authors will provide the readers with a critical narrative review of the currently available literature while trying to provide concise and practical treatment recommendations regarding adequate patient selection criteria, proper surgical technique and optimal antibiotic therapy. PMID- 30013894 TI - Limited Predictive Value of Serum Inflammatory Markers for Diagnosing Fracture Related Infections: results of a large retrospective multicenter cohort study. AB - Introduction: Diagnosing Fracture-Related Infections (FRI) based on clinical symptoms alone can be challenging and additional diagnostic tools such as serum inflammatory markers are often utilized. The aims of this study were 1) to determine the individual diagnostic performance of three commonly used serum inflammatory markers: C-Reactive Protein (CRP), Leukocyte Count (LC) and Erythrocyte Sedimentation Rate (ESR), and 2) to determine the diagnostic performance of a combination of these markers, and the additional value of including clinical parameters predictive of FRI. Methods: This cohort study included patients who presented with a suspected FRI at two participating level I academic trauma centers between February 1st 2009 and December 31st 2017. The parameters CRP, LC and ESR, determined at diagnostic work-up of the suspected FRI, were retrieved from hospital records. The gold standard for diagnosing or ruling out FRI was defined as: positive microbiology results of surgically obtained tissue samples, or absence of FRI at a clinical follow-up of at least six months. The diagnostic accuracy of the individual serum inflammatory markers was assessed. Analyses were done with both dichotomized values using hospital thresholds as well as with continuous values. Multivariable logistic regression analyses were performed to obtain the discriminative performance (Area Under the Receiver Operating Characteristic, AUROC) of (1) the combined inflammatory markers, and (2) the added value of these markers to clinical parameters. Results: A total of 168 patients met the inclusion criteria and were included for analysis. CRP had a 38% sensitivity, 34% specificity, 42% positive predictive value (PPV) and 78% negative predictive value (NPV). For LC this was 39%, 74%, 46% and 67% and for ESR 62%, 64%, 45% and 76% respectively. The diagnostic accuracy was 52%, 61% and 80% respectively. The AUROC was 0.64 for CRP, 0.60 for LC and 0.58 for ESR. The AUROC of the combined inflammatory markers was 0.63. Serum inflammatory markers combined with clinical parameters resulted in AUROC of 0.66 as opposed to 0.62 for clinical parameters alone. Conclusion: The added value of CRP, LC and ESR for diagnosing FRI is limited. Clinicians should be cautious when interpreting the results of these tests in patients with suspected FRI. PMID- 30013895 TI - Cerclages after Femoral Osteotomy Are at Risk for Bacterial Colonization during Two-Stage Septic Total Hip Arthroplasty Revision. AB - Aims: In cases of a two-stage septic total hip arthroplasty (THA) exchange a femoral osteotomy with subsequent cerclage stabilization may be necessary to remove a well-fixed stem. This study aims to investigate the rate of bacterial colonization and risk of infection persistence associated with in situ cerclage hardware in two-stage septic THA exchange. Patients and Methods: Twenty-three patients undergoing two-stage THA exchange between 2011 and 2016 were included in this retrospective cohort study. During the re-implantation procedure synovial fluid, periprosthetic tissue samples and sonicate fluid cultures (SFC) of the cerclage hardware were acquired. Results: Seven of 23 (30%) cerclage-SFC produced a positive bacterial isolation. Six of the seven positive cerclage-SFC were acquired during THA re-implantation. Two of the seven patients (29%) with a positive bacterial isolation from the cerclage hardware underwent a THA-revision for septic complications. The other five patients had their THA in situ at last follow-up. Conclusions: Despite surgical debridement and antimicrobial therapy, a bacterial colonization of cerclage hardware occurs and poses a risk for infection persistence. All cerclage hardware should be removed or exchanged during THA reimplantation. PMID- 30013896 TI - Results and Patient Reported Outcome Measures (PROMs) after One-Stage Revision for Periprosthetic Joint Infection of the Hip: A Single-centre Retrospective Study. AB - Background: Little is known about functional outcome and quality of life (QoL) after one-stage revision for periprosthetic joint infection (PJI) of the hip. Methods: a cohort of 30 subjects treated with one-stage revision between 2011 and 2015 was identified, and questionnaires on functional outcome and QoL were distributed. Results: 28 subjects were successfully treated (93%). Most subjects were referred from other hospitals. Coagulase-negative Staphylococcus was found in 50% of the cases, and 40% of all cultured bacteria were multidrug-resistant. 25% had subsequent revision surgery, unrelated to PJI. Functional outcome was good and QoL scores were high, comparable to prosthetic joint revision surgery in general. Conclusion: Although the cohort was small and statistical analysis was not performed, this study showed that excellent results can be obtained with one stage revision for hip PJI. Functional outcome and QoL was comparable to prosthetic joint revision surgery in general. PMID- 30013897 TI - Candida auris colonization in an immunocompetent patient: A new threat in medical ICU. AB - Candida auris has become a great challenge in diagnostic, therapeutic and hospital environmental adaptation. With a prevalence of 5.3% in intensive care unit (ICU) acquired candidemia in India, its colonization is very rapid which hastens hospital transmission. Strict surveillance and preventive measures need to be adopted in ICU as it can persist on dry, inanimate object, prompt adaptation and antifungal resistance can pose a future threat of a new drug hospital acquired pathogen. PMID- 30013898 TI - Vascular pythiosis of carotid artery with meningitis and cerebral septic emboli: A case report and literature review. AB - Vascular Pythiosis caused by Pythium insiodiosum rarely involves carotid artery. A case of concealed ruptured pseudoaneurysm of the carotid artery with neck abscesses, and cerebral septic emboli is described. Patient presented with large pulsatile neck mass that failed to response to surgery, antifungals and immunotherapeutic vaccine. Residual unresectable disease leads to death in the patient. Pythiosis should be considered as a differential diagnosis of head and neck infection. PMID- 30013899 TI - A promoter variant of lncRNA GAS5 is functionally associated with the development of osteosarcoma. AB - Background: Previous studies showed that genetic variant rs145204276 in the promoter region of GAS5 was associated with the development of human cancer including colorectal cancer and hepatocellular cancer. This study aimed to investigate the role of rs145204276 in the development of osteosarcoma (OS). Methods: 132 OS patients and 1270 healthy controls were recruited for the genotyping analysis of rs145204276. Promoter methylation level of GAS5 was determined for all patients. The tumor tissues and the adjacent normal tissue were collected from 42 patients during surgery and the relative expression of GAS5 was then quantified by Real-time PCR. The Chi-square test was used to determine the difference of genotype and allele frequency between the patients and the controls. The gene expression and the percentage of methylation alleles were compared among different genotypes of rs145204276 with One-way ANOVA test. Results: Compared with the controls, patients were found to have significantly lower rate of genotype del/del (7.6% vs. 8.7%, p = 0.024). The frequency of allele del was significantly lower in the patients than in the controls (23.5% vs. 30.1%, p = 0.021). Compared with than patients with genotype ins/ins, those with genotype del/del had remarkably higher expression of GAS5 (0.0033 +/- 0.0019 vs. 0.0018 +/- 0.0006, p < 0.001). Patients with genotype del/del were found to have obviously hypermethylation at the 7th CpG site as compared with those with genotype ins/ins (38.7% +/- 21.1% vs. 20.5% +/- 8.2%, p < 0.001). Conclusions: The genetic variant rs145204276 is functionally associated with the susceptibility of OS, which can function as a protective factor in the incidence of OS possibly through the regulation of GAS5. PMID- 30013900 TI - Patella Footprint Technique-A Surgical Method for Medial Patellofemoral Ligament Reconstruction. AB - Recurrent patella instability is a common condition that may potentiate substantial knee dysfunction resulting in loss of time from work and sports. There are numerous factors that contribute to recurrent patella instability including tearing of the medial patellofemoral ligament (MPFL), shallow trochlea, valgus alignment, externally rotated tibia tubercle, ligamentous laxity, elevated Q angle, and increased tibial tuberosity trochlear groove distance. Reconstruction of the MPFL has been shown to restore patella stability where concomitant pathology is within acceptable limits. Major complications include recurrence from inadequate MPFL reconstruction or failure to address other pathology, patella femoral pain from over constrained MPFL or unaddressed cartilage defects to the patella femoral compartment, or patella fracture. This technique provides a reproducible method of restoring patella stability through MPFL reconstruction while minimizing stress risers in the patella by using suture anchor fixation that creates a ligamentous footprint instead of tendon healing into a socket on the patella. PMID- 30013901 TI - How to Rapidly Abolish Knee Extension Deficit After Injury or Surgery: A Practice Changing Video Pearl From the Scientific Anterior Cruciate Ligament Network International (SANTI) Study Group. AB - Knee extension deficit is frequently observed after anterior cruciate ligament reconstruction or rupture and other acute knee injuries. Loss of terminal extension often occurs because of hamstring contracture and quadriceps inactivation rather than mechanical intra-articular pathology. Failure to regain full extension in the first few weeks after anterior cruciate ligament reconstruction is a recognized risk factor for adverse long-term outcomes, and therefore, it is important to try to address it. In this Technical Note, a simple, rapid, and effective technique to help regain full knee extension and abolish quadriceps activation failure is described. PMID- 30013902 TI - Anatomic Medial Patellofemoral Ligament Reconstruction Without Bone Tunnels or Anchors in the Patella. AB - Medial patellofemoral ligament reconstruction is an essential component of surgical treatment for recurrent dislocation of the patella. Various techniques have been described, most of which potentially increase the risk of patellar fracture. We present a new technique for anatomic medial patellofemoral ligament reconstruction without using suture anchors or patellar tunnels, therefore, eliminating the risk of iatrogenic patellar fracture and making a revision procedure easier in case of failure. PMID- 30013903 TI - Fresh Osteochondral Patellar Allograft Resurfacing. AB - The treatment of articular cartilage lesions in young patients is certainly a complex matter and subject of continuous research, particularly for those located at the patellofemoral joint, given its peculiar biomechanical characteristics. Osteochondral grafts can be of relatively small size when the defect is focal and in an area that allows good stability and consequently the graft's integration. In case of large or multifocal lesions, it is possible to consider an osteochondral transplantation of the entire articular surface of the patella. We present a simple and reproducible technique to perform a patellar fresh osteochondral allograft resurfacing attempting to reduce the symptoms and delay a prosthetic implant in young patients with advanced patellar chondral injuries. PMID- 30013904 TI - Hybrid Achilles Tendon Repair. AB - In the treatment of acute Achilles tendon rupture, recent studies demonstrate that conservative treatment with functional rehabilitation provides good results, with nearly identical postoperative rerupture rates when compared with surgical treatment. Surgical treatment is indicated in patients with particular conditions, such as patients who are young active athletes who require early return to play or those who wish to avoid the muscle atrophy associated with conservative methods. If surgery is the selected option for treatment, the postoperative complications of each type of surgery must be considered. In conventional open repair, the most common complication is soft-tissue infection due to the high tension of soft tissue affected from the bowstring of the repaired tendon being kept in the equinus position of the ankle. For percutaneous methods, sural nerve entrapment and injury are the most commonly reported complications. Other methods, including endoscopy, require technical expertise as well as special equipment. Several types of combination approaches have been explored in the literature. We describe a combined open and percutaneous technique to repair the Achilles tendon, called the hybrid Achilles tendon repair. This technique has been developed to provide a simplified and reproducible method of hybrid repair in which the complications of previous methods are avoided and which can be done without special equipment. PMID- 30013905 TI - Extra-articular Debridement of Hip Joint for Management of Anterior Hip Pain. AB - Groin pain is a common problem that is known to be a complex issue. The wide variety of possible pathologies in numerous anatomical structures contributes to this complexity. For patients who have anterior hip pain in Patrick's test and tenderness at Scarpa's triangle, we perform periarticular debridement based on the hypothesis that rectus femoris tendinosis, subacute/chronic fibrosis of the anterior inferior iliac spine fat pad, and gluteal muscle adhesion are responsible for such anterior hip pain. This Technical note illustrates the surgical procedure of periarticular debridement for extra-articular pathology associated anterior hip pain. Repair of the injured labrum and correction of femoroacetabular impingement deformity have never been performed in this cohort. Arthroscopic periarticular debridement is a reliable surgical technique that can relieve anterior hip pain and provide a rapid to return to normal activities. PMID- 30013906 TI - Arthroscopic Synovectomy of the Interphalangeal Joint of the Great Toe. AB - Synovitis of the interphalangeal joint of the great toe can occur in patients with rheumatoid arthritis, seronegative arthritides, or gouty arthritis or after a penetrating injury to the joint. Complete synovectomy of the joint usually requires a lengthy incision and extensive soft-tissue dissection. The purpose of this Technical Note is to describe the surgical details of arthroscopic synovectomy of the hallucal interphalangeal joint, which can reduce the surgical trauma. PMID- 30013907 TI - Fresh Osteochondral and Meniscus Allografting for Post-traumatic Tibial Plateau Defects. AB - Large post-traumatic osteochondral defects of the proximal tibia in young active patients can be challenging because total or partial arthroplasties are to be avoided. The use of a fresh osteochondral allograft including its meniscus is one of the few options to biologically treat these injuries. Although the use of a fresh allograft is not easily accessible in some places and carries considerable logistical limitations, it is an alternative that provides viable chondrocytes to the defect. The inclusion of the meniscus in the osteochondral graft improves the results but also makes the technique even more demanding. We present a thorough description of this allograft transplantation to make it as reproducible as possible. PMID- 30013908 TI - Arthroscopic Posterolateral Corner Stabilization With Popliteus Tenodesis. AB - The injuries of the posterolateral corner (PLC) of the knee often remain misdiagnosed. Because most structures in this anatomical region have low potential to heal, the posterolateral rotational instability results in a deterioration in patient quality of life, impaired biomechanics of the knee, and increased tension on other ligaments and the meniscus. Many open and a few arthroscopic techniques have been developed to repair or reconstruct the damaged structures of the PLC. Creating an additional midlateral arthroscopic portal on the lateral side of the knee was the key to developing the technique to recreate a static stabilizer against external rotational instability of the PLC by fixing the popliteus tendon as a native, vascularized material to the tibia. PMID- 30013909 TI - Endoscopic Proximal Adductor Lengthening for Chronic Adductor-Related Groin Pain. AB - Proximal adductor injuries are relatively common groin injuries in athletes. Various tenotomy techniques have been described including open, partial, and percutaneous approaches. Current techniques help most athletes return to sport; however, many develop adductor weakness. Moreover, the procedures lack full visualization of the tendon and do not allow for return to athletes' preinjury level of play. We describe an endoscopic z-lengthening of the proximal adductor tendon with the potential to minimize complications associated with open procedures such as incisional pain and neurovascular injury while affording a more complete tenotomy than current percutaneous techniques. This is a safe and reproducible technique that allows for release of tension as a result of pathologic adductor tendon pathologies. PMID- 30013910 TI - Is It Safe to Perform an Early Arthroscopy After a Traumatic Hip Dislocation With an Associated Pelvic Ring Injury? Report of Our Technique. AB - Hip arthroscopy is useful in the treatment of several intra-articular pathologies, however, its use in high-energy hip and pelvis injuries raises concerns about fluid extravasion and stability of the pelvic ring. We present our arthroscopic surgical technique (initial access to the peripheral compartment) to remove intra-articular loose bodies and treat associated lesions, as well as our concerns with the technique, in case of a traumatic hip dislocation associated with a contralateral pelvic ring injury. PMID- 30013911 TI - Beware of hemopneumothorax following core needle breast biopsy. AB - Minimal diagnostic procedures are conducted regularly by the radiologists for several lesions within the body. The usual methodology is biopsy with a needle, either fine needle aspiration or core biopsy. The guidance is under CT or U/S. Fine needle aspiration has usually small diameter in comparison to the core biopsy. In any case the radiologist will choose the appropriate method based on the site of the lesion and safety of the patient. Pneumothorax and hemothorax are adverse effects that can be managed either on site with the help of a small catheter, however; there are cases where video-assisted thoracic surgery is needed in order to manage a more severe case. In the current study we present such a case where video-assisted surgery was necessary. PMID- 30013912 TI - Retrospective analysis of primary plasma cell leukemia in Kansai Myeloma Forum registry. AB - We retrospectively analyzed twenty-six patients with primary plasma cell leukemia (pPCL) registered from May 2005 until April 2015 by the Kansai Myeloma Forum. Twenty patients received novel agents (bortezomib or lenalidomide), and their median survival of was 34 months. The median survival of patients who underwent autologous stem cell transplantation (SCT) was 40 months, those undergoing allogeneic SCT 55 months, and those undergoing both types of SCT (auto-allo) 61 months; whereas for those who did not undergo SCT it was 28 months (p = 0.845). The only statistically significant risk factor identified by multivariate analysis was hypercalcemia. PMID- 30013913 TI - Which of the branched-chain amino acids increases cerebral blood flow in hepatic encephalopathy? A double-blind randomized trial. AB - Branched-chain amino acids increase the brain perfusion of patients with hepatic encephalopathy (HE), but the amino acid and the mechanisms involved are still unknown. This study compared brain perfusion and clinical improvement during leucine or isoleucine supplementation. After randomization, 27 subjects with cirrhosis and HE received leucine or isoleucine supplements for one year. Brain single Photon Emission Computed Tomography (SPECT) and dynamic brain scintigraphy (DBS) were performed pretreatment and at 1, 8 and 12 months of supplementation. Brain perfusion was increased only in the isoleucine group at 8 months of treatment by both SPECT and DBS (p < 0.001 and p = 0.05, respectively) and by SPECT at the 12th month (p < 0.05). This was associated with hepatic encephalopathy improvement at 8 and 12 months (p = 0.008 and 0.004, respectively), which was not observed in the leucine group (p = 0.313 and 0.055, respectively). Isoleucine supplementation achieved a better impact on brain perfusion restoration in HE. PMID- 30013914 TI - Patients with a severe prolonged Disorder of Consciousness can show classical EEG responses to their own name compared with others' names. AB - Patients in Vegetative State (VS), also known as Unresponsive Wakefulness State (UWS) are deemed to be unaware of themselves or their environment. This is different from patients diagnosed with Minimally Conscious state (MCS), who can have intermittent awareness. In both states, there is a severe impairment of consciousness; these disorders are referred to as disorders of consciousness (DOC) and if the state is prolonged, pDOC. There is growing evidence that some patients who are behaviourally in VS/UWS can show neural activation to environmental stimuli and that this response can be detected using functional brain imaging (fMRI/PET) and electroencephalography (EEG). Recently, it has also been suggested that a more reliable detection of brain responsiveness and hence a more reliable differentiation between VS/UWS and MCS requires person-centred and person-specific stimuli, such as the subject's own name stimulus. In this study we obtained event related potential data (ERP) from 12 healthy subjects and 16 patients in pDOC, five of whom were in the VS/UWS and 11 in the Minimally Conscious State (MCS). We used as the ERP stimuli the subjects' own name, others' names and reversed other names. We performed a sensor level analysis using Statistical Parametric Mapping (SPM) software. Using this paradigm in 4 DOC patients (3 in MCS, and 1 in VS/UWS) we detected a statistically significant difference in EEG response to their own name versus other peoples' names with ERP latencies (~300 ms and ~700 ms post stimuli). Some of these differences were similar to those found in a control group of healthy subjects. This study shows the feasibility of using self-relevant stimuli such as a subject's own name for assessment of brain function in pDOC patients. This neurophysiological test is suitable for bed-side/hospital based assessment of pDOC patients. As it does not require sophisticated scanning equipment it can feasibly be used within a hospital or care setting to help professionals tailor medical and psycho-social management for patients. PMID- 30013915 TI - Aberrant hemodynamic responses in autism: Implications for resting state fMRI functional connectivity studies. AB - Functional MRI (fMRI) is modeled as a convolution of the hemodynamic response function (HRF) and an unmeasured latent neural signal. However, HRF itself is variable across brain regions and subjects. This variability is induced by both neural and non-neural factors. Aberrations in underlying neurochemical mechanisms, which control HRF shape, have been reported in autism spectrum disorders (ASD). Therefore, we hypothesized that this will lead to voxel specific, yet systematic differences in HRF shape between ASD and healthy controls. As a corollary, we also hypothesized that such alterations will lead to differences in estimated functional connectivity in fMRI space compared to latent neural space. To test these hypotheses, we performed blind deconvolution of resting-state fMRI time series acquired from large number of ASD and control subjects obtained from the Autism Brain Imaging Data Exchange (ABIDE) database (N = 1102). Many brain regions previously implicated in autism showed systematic differences in HRF shape in ASD. Specifically, we found that precuneus had aberrations in all HRF parameters. Consequently, we obtained precuneus-seed-based functional connectivity differences between ASD and controls using fMRI as well as using latent neural signals. We found that non-deconvolved fMRI data failed to detect group differences in connectivity between precuneus and certain brain regions that were instead observed in deconvolved data. Our results are relevant for the understanding of hemodynamic and neurochemical aberrations in ASD, as well as have methodological implications for resting-state functional connectivity studies in Autism, and more generally in disorders that are accompanied by neurochemical alterations that may impact HRF shape. PMID- 30013917 TI - Feeling excluded no matter what? Bias in the processing of social participation in borderline personality disorder. AB - Background: Patients with Borderline Personality Disorder (BPD) feel ostracized even when they are included. This might be due to a biased processing of social participation in BPD. We examined whether patients with BPD also process social overinclusion in a biased manner, i.e., whether they feel ostracized even when the degree of social participation is increased. Methods: An EEG-compatible version of Cyberball was used to investigate the effects of inclusion and overinclusion (33% vs. 45% ball receipt) on perceived ostracism, need threat and P3 amplitude, an EEG indicator for expectancy violation. Twenty-nine patients with BPD, 28 patients with Social Anxiety Disorder (SAD) and 28 healthy controls (HC) participated. Results: The P3 amplitude was enhanced for patients with BPD and SAD compared to HCs independent of condition. Both patient groups reported more perceived ostracism relative to HCs in the inclusion but not in the overinclusion condition. Only patients with BPD reported stronger need threat in both conditions. Conclusions: The EEG results imply that being socially included violates the expectations of patients with BPD, irrespective of the actual degree of social participation. However, when overincluded, patients with BPD no longer feel ostracized. Except for need threat, patients with SAD might show a comparable bias in the processing of social participation as patients with BPD. PMID- 30013916 TI - Connectome-derived diffusion characteristics of the fornix in Alzheimer's disease. AB - The fornix bundle is a major white matter pathway of the hippocampus. While volume of the hippocampus has been a primary imaging biomarker of Alzheimer's disease progression, recent research has suggested that the volume and microstructural characteristics of the fornix bundle connecting the hippocampus could add relevant information for diagnosing and staging Alzheimer's disease. Using a robust fornix bundle isolation technique in native diffusion space, this study investigated whether diffusion measurements of the fornix differed between normal older adults and Alzheimer's disease patients when controlling for volume measurements. Data were collected using high gradient multi-shell diffusion weighted MRI from a Siemens CONNECTOM scanner in 23 Alzheimer's disease and 23 age- and sex-matched control older adults (age range = 53-92). These data were used to reconstruct a continuous fornix bundle in every participant's native diffusion space, from which tract-derived volumetric and diffusion metrics were extracted and compared between groups. Diffusion metrics included those from a tensor model and from a generalized q-sampling imaging model. Results showed no significant differences in tract-derived fornix volumes but did show altered diffusion metrics within tissue classified as the fornix in the Alzheimer's disease group. Comparisons to a manual tracing method indicated the same pattern of results and high correlations between the methods. These results suggest that in Alzheimer's disease, diffusion characteristics may provide more sensitive measures of fornix degeneration than do volume measures and may be a potential early marker for loss of medial temporal lobe connectivity. PMID- 30013918 TI - Identifying first-episode drug naive patients with schizophrenia with or without auditory verbal hallucinations using whole-brain functional connectivity: A pattern analysis study. AB - Many studies have focused on patients with schizophrenia with or without auditory verbal hallucinations (AVHs), but due to the complexity of schizophrenia, biologically based diagnosis of patients with schizophrenia remains unsolved. The objectives of this study are to classify between first-episode drug-naive patients with schizophrenia and healthy controls, and to classify between patients with and without AVHs. Resting state fMRI data from 41 patients with schizophrenia (22 with and 19 without AVHs) and 23 normal controls (NC) were included to compute functional connectivity between brain regions. Classifiers based on support vector machine (SVM) were developed to classify patients with schizophrenia from NC, as well as between the two subgroups of patients. The classification accuracy was evaluated with a leave-one-out cross-validation (LOOCV) strategy. The accuracy in discriminating both subgroups of patients from NC was 81.3%, with 92.0% (sensitivity) and 65.2% (specificity) for the patients and NC, respectively. The classification accuracy in discriminating patients with and without AVHs was 75.6%, with 77.3% (sensitivity) and 73.9% (specificity) for patients with and without AVHs, respectively. The results suggest that functional connectivity provided good discriminative power not only for identifying patients with schizophrenia among NC, but also in discriminating patients with schizophrenia with and without AVHs. PMID- 30013919 TI - Advanced diffusion imaging for assessing normal white matter development in neonates and characterizing aberrant development in congenital heart disease. AB - Background: Elucidating developmental trajectories of white matter (WM) microstructure is critically important for understanding normal development and regional vulnerabilities in several brain disorders. Diffusion Weighted Imaging (DWI) is currently the method of choice for in-vivo white matter assessment. A majority of neonatal studies use the standard Diffusion Tensor Imaging (DTI) model although more advanced models such as the Neurite Orientation Dispersion and Density Imaging (NODDI) model and the Gaussian Mixture Model (GMM) have been used in adult population. In this study, we compare the ability of these three diffusion models to detect regional white matter maturation in typically developing control (TDC) neonates and regional abnormalities in neonates with congenital heart disease (CHD). Methods: Multiple b-value diffusion Magnetic Resonance Imaging (dMRI) data were acquired from TDC neonates (N = 16) at 38 to 47 gestational weeks (GW) and CHD neonates (N = 19) aged 37 weeks to 41 weeks. Measures calculated from the diffusion signal included not only Mean Diffusivity (MD) and Fractional Anisotropy (FA) derived from the standard DTI model, but also three advanced diffusion measures, namely, the fiber Orientation Dispersion Index (ODI), the isotropic volume fraction (Viso), and the intracellular volume fraction (Vic) derived from the NODDI model. Further, we used two novel measures from a non-parametric GMM, namely the Return-to-Origin Probability (RTOP) and Return-to-Axis Probability (RTAP), which are sensitive to axonal/cellular volume and density respectively. Using atlas-based registration, 22 white matter regions (6 projection, 4 association, and 1 callosal pathways bilaterally in each hemisphere) were selected and the mean value of all 7 measures were calculated in each region. These values were used as dependent variables, with GW as the independent variable in a linear regression model. Finally, we compared CHD and TDC groups on these measures in each ROI after removing age-related trends from both the groups. Results: Linear analysis in the TDC population revealed significant correlations with GW (age) in 12 projection pathways for MD, Vic, RTAP, and 11 pathways for RTOP. Several association pathways were also significantly correlated with GW for MD, Vic, RTAP, and RTOP. The right callosal pathway was significantly correlated with GW for Vic. Consistent with the pathophysiology of altered development in CHD, diffusion measures demonstrated differences in the association pathways involved in language systems, namely the Uncinate Fasciculus (UF), the Inferior Fronto-occipital Fasciculus (IFOF), and the Superior Longitudinal Fasciculus (SLF). Overall, the group comparison between CHD and TDC revealed lower FA, Vic, RTAP, and RTOP for CHD bilaterally in the a) UF, b) Corpus Callosum (CC), and c) Superior Fronto-Occipital Fasciculus (SFOF). Moreover, FA was lower for CHD in the a) left SLF, b) bilateral Anterior Corona Radiata (ACR) and left Retrolenticular part of the Internal Capsule (RIC). Vic was also lower for CHD in the left Posterior Limb of the Internal Capsule (PLIC). ODI was higher for CHD in the left CC. RTAP was lower for CHD in the left IFOF, while RTOP was lower in CHD in the: a) left ACR, b) left IFOF and c) right Anterior Limb of the Internal Capsule (ALIC). Conclusion: In this study, all three methods revealed the expected changes in the WM regions during the early postnatal weeks; however, GMM outperformed DTI and NODDI as it showed significantly larger effect sizes while detecting differences between the TDC and CHD neonates. Future studies based on a larger sample are needed to confirm these results and to explore clinical correlates. PMID- 30013920 TI - Neural correlates of cognitive function and symptoms in attention deficit/hyperactivity disorder in adults. AB - While gray matter (GM) anomalies have been reported for attention deficit/hyperactivity disorder (ADHD), investigating their associations with cognitive deficits and individual symptom domains can help pinpoint the neural underpinnings critical for the pathology of ADHD, particularly the persist form of ADHD. In this work, we performed both independent component analysis and voxel based morphometry analysis on whole brain GM of 486 adults including 214 patients, 96 unaffected siblings, and 176 healthy controls, in relation to cognition and symptoms. Independent component analysis revealed that higher GM volume in inferior semilunar lobule, inferior frontal gyri, and superior and middle frontal gyri was associated with better working memory performance, and lower GM volume in cerebellar tonsil and culmen was associated with more severe inattention symptoms. Consistently, voxel-based morphometry analysis showed that higher GM volume in multiple regions of frontal lobe, cerebellum and temporal lobe was related to better working memory performance. Focusing on the networks derived from ICA, our results integrated prefrontal regions and cerebellar regions through associations with working memory and inattention symptoms, lending support for the theory of 'cool'-cognition dysfunction being mediated by inferior fronto-striato-cerebellar networks in ADHD. Siblings showed intermediate cognitive impairments between patients and controls but presented GM anomalies in unique focal regions, suggesting they are a separate group potentially affected by the shared genetic and environmental risks with ADHD patients. PMID- 30013921 TI - Baseline biomarkers of connectome disruption and atrophy predict future processing speed in early multiple sclerosis. AB - The development of accurate prognoses in multiple sclerosis is difficult, as the disease is characterized by heterogeneous patterns of brain abnormalities that relate in an unclear way to future impairments. Here, we use a statistical modeling approach to determine if the baseline pattern of connectome disruption due to T2-FLAIR lesions could predict a patient's future processing speed, as measured using the Symbol Digits Modality Test scores. Imaging data, demographics and Symbol Digits Modality Test scores were collected from 61 early relapsing remitting multiple sclerosis patients. The Network Modification Tool was used to estimate damage to the connectome by quantifying white matter abnormalities' effects on 1) global network properties, 2) regional connectivity and 3) connectivity between pairs of regions. MS subjects showed significant improvement of processing speed between baseline and follow-up (t = -2.6, p = 0.0096); however, both baseline (t = -4.01, p = 0.00012) and follow-up (t = -2.10, p = 0.038) processing speed were significantly lower than age-matched healthy controls. Partial Least Squares Regression was used to create models that predict future processing speed from between baseline imaging metrics and demographics. The model based on region-pair disconnection and gray matter atrophy had the lowest AIC and highest prediction accuracy (R2 = 0.79) compared to models based on global (R2 = 0.41) or regional (R2 = 0.66) disconnection and gray matter atrophy, overlap with an ROI-based atlas and gray matter atrophy (R2 = 0.73) or gray matter atrophy alone (R2 = 0.71). We found that baseline measures of connectivity disruption in various parietal, temporal, occipital and subcortical regions and atrophy in the putamen were important predictors of future processing speed. We conclude that information about disruptions to pairwise brain connections is more informative of future processing speed than regional or global metrics or gray matter atrophy alone. The combination of quantitative disconnectome metrics, gray matter atrophy and statistical modeling approaches could enable clinicians in developing more accurate, individualized prognoses of future cognitive status in multiple sclerosis patients. PMID- 30013922 TI - Syntactic processing in music and language: Parallel abnormalities observed in congenital amusia. AB - Evidence is accumulating that similar cognitive resources are engaged to process syntactic structure in music and language. Congenital amusia - a neurodevelopmental disorder that primarily affects music perception, including musical syntax - provides a special opportunity to understand the nature of this overlap. Using electroencephalography (EEG), we investigated whether individuals with congenital amusia have parallel deficits in processing language syntax in comparison to control participants. Twelve amusic participants (eight females) and 12 control participants (eight females) were presented melodies in one session, and spoken sentences in another session, both of which had syntactic congruent and -incongruent stimuli. They were asked to complete a music-related and a language-related task that were irrelevant to the syntactic incongruities. Our results show that amusic participants exhibit impairments in the early stages of both music- and language-syntactic processing. Specifically, we found that two event-related potential (ERP) components - namely Early Right Anterior Negativity (ERAN) and Left Anterior Negativity (LAN), associated with music- and language syntactic processing respectively, were absent in the amusia group. However, at later processing stages, amusics showed similar brain responses as controls to syntactic incongruities in both music and language. This was reflected in a normal N5 in response to melodies and a normal P600 to spoken sentences. Notably, amusics' parallel music- and language-syntactic impairments were not accompanied by deficits in semantic processing (indexed by normal N400 in response to semantic incongruities). Together, our findings provide further evidence for shared music and language syntactic processing, particularly at early stages of processing. PMID- 30013924 TI - Isolated focal dystonia phenotypes are associated with distinct patterns of altered microstructure. AB - Objective: Isolated adult-onset focal dystonia is considered a network disorder with disturbances to the motor basal ganglia and cerebellar circuits playing a pathophysiological role, but why specific body regions become affected remains unknown. We aimed to use diffusion tensor imaging to determine if the two most common phenotypes of focal dystonia are associated with distinguishing microstructural changes affecting the motor network. Methods: Fifteen blepharospasm patients, 20 cervical dystonia patients, and 30 age- and sex matched healthy controls were recruited. Maps of fractional anisotropy and mean diffusivity were analyzed using a voxel-based approach and an automated region-of interest technique to evaluate deep gray matter nuclei. Correlations between diffusion measures and dystonia severity were tested, and post hoc discriminant analyses were conducted. Results: Voxel-based analyses revealed significantly reduced fractional anisotropy in the right cerebellum and increased mean diffusivity in the left caudate of cervical dystonia patients compared to controls, as well as lower fractional anisotropy in the right cerebellum in cervical dystonia patients relative to blepharospasm patients. In addition to reduced fractional anisotropy in the bilateral caudate nucleus of cervical dystonia patients relative to controls and blepharospasm patients, region-of interest analyses revealed significantly reduced fractional anisotropy in the right globus pallidus internus and left red nucleus of blepharospasm patients compared to both controls and cervical dystonia patients. Diffusivity measures in the red nucleus of blepharospasm patients correlated with disease severity. In a three-group discriminant analysis, participants were correctly classified with only modest reliability (67-75%), but in a two-group discriminant analysis, patients could be distinguished from each other with high reliability (83-100%). Conclusions: Different focal dystonia phenotypes are associated with distinct patterns of altered microstructure within constituent regions of basal ganglia and cerebellar circuits. PMID- 30013923 TI - Neural responses to emotional involuntary memories in posttraumatic stress disorder: Differences in timing and activity. AB - Background: Involuntary memories are a hallmark symptom of posttraumatic stress disorder (PTSD), but studies of the neural basis of involuntary memory retrieval in posttraumatic stress disorder (PTSD) are sparse. The study of the neural correlates of involuntary memories of stressful events in PTSD focuses on the voluntary retrieval of memories that are sometimes recalled as intrusive involuntary memories, not on involuntary retrieval while being scanned. Involuntary memory retrieval in controls has been shown to elicit activity in the parahippocampal gyrus, precuneus, inferior parietal cortex, and posterior midline regions. However, it is unknown whether involuntary memories are supported by the same mechanisms in PTSD. Because previous work has shown that both behavioral and neural responsivity is slowed in PTSD, we examined the spatiotemporal dynamics of the neural activity underlying negative and neutral involuntary memory retrieval. Methods: Twenty-one individuals with PTSD and 21 non-PTSD, trauma-exposed controls performed an involuntary memory task, while undergoing a functional magnetic resonance imaging scan. Environmental sounds served as cues for well associated pictures of negative and neutral scenes. We used a finite impulse response model to analyze temporal differences between groups in neural responses. Results: Compared with controls, participants with PTSD reported more involuntary memories, which were more emotional and more vivid, but which activated a similar network of regions. However, compared to controls, individuals with PTSD showed delayed neural responsivity in this network and increased vmPFC/ACC activity for negative > neutral stimuli. Conclusions: The similarity between PTSD and controls in neural substrates underlying involuntary memories suggests that, unlike voluntary memories, involuntary memories elicit similar activity in regions critical for memory retrieval. Further, the delayed neural responsivity for involuntary memories in PTSD suggests that factors affecting cognition in PTSD, like increased fatigue, or avoidance behaviors could do so by delaying activity in regions necessary for cognitive processing. Finally, compared to neutral memories, negative involuntary memories elicit hyperactivity in the vmPFC, whereas the vmPFC is typically shown to be hypoactive in PTSD during voluntary memory retrieval. These patterns suggest that considering both the temporal dynamics of cognitive processes as well as involuntary cognitive processes would improve existing neurobiological models of PTSD. PMID- 30013925 TI - Age of gray matters: Neuroprediction of recidivism. AB - Age is one of the best predictors of antisocial behavior. Risk models of recidivism often combine chronological age with demographic, social and psychological features to aid in judicial decision-making. Here we use independent component analyses (ICA) and machine learning techniques to demonstrate the utility of using brain-based measures of cerebral aging to predict recidivism. First, we developed a brain-age model that predicts chronological age based on structural MRI data from incarcerated males (n = 1332). We then test the model's ability to predict recidivism in a new sample of offenders with longitudinal outcome data (n = 93). Consistent with hypotheses, inclusion of brain-age measures of the inferior frontal cortex and anterior medial temporal lobes (i.e., amygdala) improved prediction models when compared with models using chronological age; and models that combined psychological, behavioral, and neuroimaging measures provided the most robust prediction of recidivism. These results verify the utility of brain measures in predicting future behavior, and suggest that brain-based data may more precisely account for important variation when compared with traditional proxy measures such as chronological age. This work also identifies new brain systems that contribute to recidivism which has clinical implications for treatment development. PMID- 30013926 TI - Comparison between simultaneously acquired arterial spin labeling and 18F-FDG PET in mesial temporal lobe epilepsy assisted by a PET/MR system and SEEG. AB - Objective: In the detection of seizure onset zones, arterial spin labeling (ASL) can overcome the limitations of positron emission tomography (PET) with 18F fluorodeoxyglucose (18F-FDG), which is invasive, expensive, and radioactive. PET/magnetic resonance (MR) systems have been introduced that allow simultaneous performance of ASL and PET, but comparisons of these techniques with stereoelectroencephalography (SEEG) and comparisons among the treatment outcomes of these techniques are still lacking. Here, we investigate the effectiveness of ASL compared with that of SEEG and their outcomes in localizing mesial temporal lobe epilepsy (MTLE) and assess the correlation between simultaneously acquired PET and ASL. Methods: Between October 2016 and August 2017, we retrospectively studied 12 patients diagnosed with pure unilateral MTLE. We extracted and quantitatively computed values for ASL and PET in the bilateral hippocampus. SEEG findings and outcome were considered the gold standard of lateralization. Finally, the bilateral asymmetry index (AI) was calculated to assess the correlation between PET and ASL. Results: Our results showed that hypoperfusion in the hippocampus detected using ASL matched the SEEG-defined epileptogenic zone in this series of patients. The mean normalized voxel value of ASL in the contralateral hippocampus was 0.97 +/- 0.19, while in the ipsilateral hippocampus, it was 0.84 +/- 0.14. Meanwhile, significantly decreased perfusion and metabolism were observed in these patients (Wilcoxon, p < 0.05), with a significant positive correlation between the AI values derived from PET and ASL (Pearson's correlation, r = 0.74, p < 0.05). Significance: In our SEEG- and outcome-defined patients with MTLE, ASL could provide significant information during presurgical evaluation, with the hypoperfusion detected with ASL reliably lateralizing MTLE. This non-invasive technique may be used as an alternative diagnostic tool for MTLE lateralization. PMID- 30013927 TI - Acute trajectories of neural activation predict remission to pharmacotherapy in late-life depression. AB - Pharmacological treatment of major depressive disorder (MDD) typically involves a lengthy trial and error process to identify an effective intervention. This lengthy period prolongs suffering and worsens all-cause mortality, including from suicide, and is typically longer in late-life depression (LLD). Our group has recently demonstrated that during an open-label venlafaxine (serotonin norepinephrine reuptake inhibitor) trial, significant changes in functional resting state connectivity occurred following a single dose of treatment, which persisted until the end of the trial. In this work, we propose an analysis framework to translate these perturbations in functional networks into predictors of clinical remission. Participants with LLD (N = 49) completed 12-weeks of treatment with venlafaxine and underwent functional magnetic resonance imaging (fMRI) at baseline and a day following a single dose of venlafaxine. Data was collected at rest as well as during an emotion reactivity task and an emotion regulation task. Remission was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) <=10 for two weeks. We computed eigenvector centrality (whole brain connectivity) and activation during the emotion regulation and emotion reactivity tasks. We employed principal components analysis, Tikhonov-regularized logistic classification, and least angle regression feature selection to predict remission by the end of the 12-week trial. We utilized ten-fold cross-validation and Receiver Operator Curves (ROC) curve analysis. To determine task-region pairs that significantly contributed to the algorithm's ability to predict remission, we used permutation testing. Using the fMRI data at both baseline and after the first dose of treatment yielded a sensitivity of 72% and a specificity of 68% (AUC = 0.77), a 15% increase in accuracy over baseline MADRS. In general, the accuracy at baseline was further improved by using the change in activation following a single dose. Activation of the frontal cortex, hippocampus, parahippocampus, caudate, thalamus, medial temporal cortex, middle cingulate, and visual cortex predicted treatment remission. Acute, dynamic trajectories of functional imaging metrics in response to a pharmacological intervention are a valuable tool for predicting treatment response in late-life depression and elucidating the mechanism of pharmacological therapies in the context of the brain's functional architecture. PMID- 30013928 TI - Brain lesion scores obtained using a simple semi-quantitative scale from MR imaging are associated with motor function, communication and cognition in dyskinetic cerebral palsy. AB - Purpose: To characterise brain lesions in dyskinetic cerebral palsy (DCP) using the semi-quantitative scale for structural MRI (sqMRI) and to investigate their relationship with motor, communication and cognitive function. Materials and methods: Thirty-nine participants (19 females, median age 21y) with DCP were assessed in terms of motor function, communication and a variety of cognitive domains. Whole-head magnetic resonance imaging (MRI) was performed including T1 MPRAGE, T2 turbo spin echo (axial plane), and fluid attenuated inversion recovery images (FLAIR). A child neurologist visually assessed images for brain lesions and scored these using the sqMRI. Ordinal, Poisson and binomial negative regression models identified which brain lesions accounted for clinical outcomes. Results: Brain lesions were most frequently located in the ventral posterior lateral thalamus and the frontal lobe. Gross (B = 0.180, p < .001; B = 0.658, p < .001) and fine (B = 0.136, p = .003; B = 0.540, p < .001) motor function were associated with global sqMRI score and parietal involvement. Communication functioning was associated with putamen involvement (B = 0.747, p < .028). Intellectual functioning was associated with global sqMRI score and posterior thalamus involvement (B = -0.018, p < .001; B = -0.192, p < .001). Selective attention was associated with global sqMRI score (B = -0.035, p < .001), parietal (B = -0.063, p = .023), and corpus callosum involvement (B = -0.448, p < .001). Visuospatial and visuoperceptive abilities were associated with global sqMRI score (B = -0.078, p = .007) and medial dorsal thalamus involvement (B = -0.139, p < .012), respectively. Conclusions: Key clinical outcomes in DCP are associated with specific observable brain lesions as indexed by a simple lesion scoring system that relies only on standard clinical MRI. PMID- 30013930 TI - Responsive neurostimulation for treatment of pediatric drug-resistant epilepsy. AB - Responsive neurostimulation for epilepsy involves an implanted device that delivers direct electrical brain stimulation in response to detection of incipient seizures. Responsive neurostimulation is a safe and effective treatment for adults with drug-resistant epilepsy, but although novel treatments are critically needed for younger patients, responsive neurostimulation is currently not approved for children with drug-resistant epilepsy. Here, we report a 16-year old patient with seizures arising from eloquent cortex, who was successfully treated with responsive neurostimulation. This case highlights the potential utility of this therapy for pediatric patients and underscores the need for larger studies. PMID- 30013929 TI - Functional and structural brain networks in posterior cortical atrophy: A two centre multiparametric MRI study. AB - This study identified structural and functional brain connectivity alterations in two independent samples of patients along the posterior cortical atrophy (PCA) disease course. Twenty-one PCA patients and 44 controls were recruited from two expert centres. Microstructural damage of white matter (WM) tracts was assessed using probabilistic tractography; resting state (RS) functional connectivity of brain networks was explored using a model free approach; grey matter (GM) atrophy was investigated using voxel-based morphometry. Compared with controls, common patterns of damage across PCA patients included: GM atrophy in the occipital temporal-parietal regions; diffusion tensor (DT) MRI alterations of the corpus callosum and superior (SLF) and inferior longitudinal fasciculi (ILF) bilaterally; and decreased functional connectivity of the occipital gyri within the visual network and the precuneus and posterior cingulum within the default mode network (DMN). In PCA patients with longer disease duration and greater disease severity, WM damage extended to the cingulum and RS functional connectivity alterations spread within the frontal, dorsal attentive and salience networks. In PCA, reduced DMN functional connectivity was associated with SLF and ILF structural alterations. PCA patients showed distributed WM damage. Altered RS functional connectivity extends with disease worsening from occipital to temporo parietal and frontostriatal regions, and this is likely to occur through WM connections. Future longitudinal studies are needed to establish trajectories of damage spreading in PCA and whether a combined DT MRI/RS functional MRI approach is promising in monitoring the disease progression. PMID- 30013931 TI - Intracarotid amobarbital disrupts synchronous and nested oscillatory activity ipsilateral to injection. AB - The mechanism of amobarbital action during the intracarotid amobarbital procedure is poorly understood. We report a patient case who underwent IAP while implanted with bilateral stereo-EEG. We analyzed the spectral power, phase amplitude coupling, and cluster-phase group synchrony during the procedure. Delta and gamma power increased bilaterally. By contrast, phase amplitude coupling increased only ipsilateral to the injection. Similarly, 4-30 Hz cluster-phase group synchrony declines and gamma cluster-phase group synchrony increases only ipsilateral to the injection. These results suggest that a possible additional mechanism for amobarbital action in the IAP is by altering the precise timing of oscillatory activity. PMID- 30013932 TI - Seizures in HIV: The case for special consideration. AB - Purpose: This study aimed to determine the rate, cause and management of seizures in the context of potential ART-ASD interactions in a cohort of HIV + individuals. Methods: Records of 604 HIV + patients were reviewed and those reporting epilepsy/seizure diagnosis were further evaluated. Results: This cohort exhibited a seizure rate of 2.4%. HIV + patients treated for epilepsy displayed low serum ASD levels and failed to achieve seizure control. They were more likely to disengage from Neurology follow-up. Conclusion: For HIV + patients presenting with seizures/epilepsy the ASD prescription and the provision of supplementary support services needs to be carefully considered. PMID- 30013933 TI - Extra-muscular manifestations of TK2 deficiency. PMID- 30013935 TI - Long-term outcomes in Amish patients diagnosed with propionic acidemia. AB - Propionic acidemia (PA) occurs at a higher incidence within the Amish; however, sensitivity of newborn screening and its impact on long-term clinical outcomes has not been reported in this population. This study reviewed screening data and health records of 20 Wisconsin Amish patients diagnosed with PA. Newborn screening did not identify all cases; however, early detection did offer appreciable long-term protection from neurological sequelae. This is the first report summarizing PA cases within the Amish. PMID- 30013934 TI - Neurocognitive assessments and long-term outcome in an adult with 2-methyl-3 hydroxybutyryl-CoA dehydrogenase deficiency. AB - Background: 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBDD) is a rare X-linked disorder associated with the accumulation of 2-methyl-3 hydroxybutyric acid in body fluids as a consequence of a disruption in isoleucine metabolism. The clinical presentation is heterogeneous, including a neurodegenerative course with retinopathy and cardiomyopathy leading to death in early childhood and a slowly progressive disease associated with learning disability and survival into adulthood. The condition is often diagnosed in childhood. Results: This paper outlines the long-term neurocognitive outcomes in a 38-year old man with MHBDD. Several psychometric tests were used to assess his cognitive ability and adaptive functioning in childhood during an acute illness and in adulthood when the patient showed deterioration in the ability to walk or speak. Conclusions: There is an increasing demand for an accurate and objective measure of cognitive functioning that can be used to follow the natural progression of MHBDD. Psychological assessment may enable the identification of organic problems. The application and interpretation of psychometric tests used in children may vary from those used in adults. PMID- 30013937 TI - Bimodal glucose distribution in Asian Indian pregnant women: Relevance in gestational diabetes mellitus diagnosis. AB - Aims: Presence of bimodality in plasma glucose distribution (BPG) and its relevance for gestational diabetes mellitus (GDM) diagnosis were studied in Asian Indian pregnant women. Methods: Fasting (FPG) and two hour plasma glucose (2-h PG) values of oral glucose tolerance tests performed in 36,530 pregnant women for GDM screening (2006-16 period), were analyzed for BPG. A unimodal normal and a mixture of two normal distributions were fitted to log-transformed FPG and 2-h PG data. The mixture model was compared to unimodal model for BPG using likelihood ratio test (LRT) and the comparison was further verified by bootstrapping. The cut points of the two normal distribution curves in the mixture models of FPG and 2-h PG were noted. Results: Fasting and 2-h PG distribution was bimodal in all pregnant women. The comparison of mixture and unimodal models using LRT revealed p value <0.001 in all age groups. The cut points for FPG and 2-h PG were 5.81 mmol/L (95% CI: 5.69-5.92) and 8.41 mmol/l (95% CI: 8.09-8.75) respectively. Conclusion: BPG is noted for both FPG and 2-hPG in Asian Indian pregnant women. The cutpoints of normal distribution curves are close to threshold values for FPG and 2-h PG proposed in NICE (National Institute for health and Care Excellence) and IADPSG (International Association of Diabetes and Pregnancy Study Group) GDM diagnostic criteria respectively. Further research on BPG in pregnant women of racial groups with high GDM prevalence, is likely to be of value in GDM diagnosis. PMID- 30013936 TI - Influence of peroxisome proliferator-activated receptor-gamma exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome. AB - Background and objective: The Pro12Ala (exon 2) and His447His (exon 6) polymorphisms of PPAR-gamma, and Gly972Arg polymorphism of IRS-1 have been implicated in insulin resistance (IR) and adiposity. Our aim was to investigate the influence of these polymorphisms on metabolic features of polycystic ovary syndrome (PCOS). Methods: Fifty-three PCOS women and 26 control women underwent a clinical and biochemical evaluation, including a 75-g oral glucose tolerance test. Insulin secretion and insulin sensitivity indices were calculated. Results: Frequencies of PPAR-gamma polymorphisms did not differ from those predicted by the Hardy-Weinberg equilibrium. Instead, the IRS-1 Gly972Arg allele was significantly more frequent in the PCOS group compared to controls. The most frequent allelic combinations were IRS1+/exon2-/exon6- (which prevailed in PCOS) and IRS-1-/exon2-/exon6- (which prevailed in controls). Among PCOS women, compared with the wild type patients, carriers of the Gly972Arg IRS-1 allele had lower E2 levels, while carriers of the Pro12Ala PPAR-gamma (exon 2) allele had lower free testosterone levels. No other significant relationships were noted. When compared with the wild type, in PCOS group IR and beta-cell function were: (i) trendwise greater in carriers of the variant IRS-1 allele; (ii) trendwise lower in carriers of the variant PPAR-gamma exon 6 allele; (iii) significantly lower in carriers of the variant PPAR-gamma exon 2 allele. Conclusions: Our data support the protective influence of PPAR-gamma-exon 2 and exon 6 variants on IR and beta cell function, whereas IRS-1 polymorphism is associated with an unfavorable metabolic profile. However, these associations do not fully explain the high metabolic risk associated with PCOS. PMID- 30013938 TI - Crosstalk between GSK-3, c-Fos, NFkappaB and TNF-alpha signaling pathways play an ambitious role in Chitosan Nanoparticles Cancer Therapy. AB - Nanotechnology is a promising era of medicine for developing targeted drug delivery system. Chitosan nanoparticles (CNPs) have attracted increasing attention for their wide applications as anticancer drugs. This article is concerned with the therapeutic index of chitosan nanoparticles against diethyl nitrosamine (DEN) induced hepatocellular carcinoma (HCC). HCC was induced in rats via repeated DEN administration in a dose of 200 mg/kg BW IP, 2 weeks later rats received (2 ml/kg BW) CCl4 orally for 2 months followed by daily treatment with chitosan nanoparticles in an oral dose of 12 mg/kg for 1 month. Then the gene expression of glycogen synthase kinase-3 (GSK-3), (c-FOS), nuclear factor kappa-B (NFkappaB) and tumor necrosis factor- alpha (TNF-alpha) were reported in rats sera and the correlation between GSK-3, C-Fos, NFKB and TNF-alpha and liver tumorigenesis was investigated. The results elucidated that DEN significantly increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Marked increments in serum malondialdehyde (MDA) and nitric oxide (NOx) levels along with a slight reduction of glutathione (GSH) level were evidenced in HCC. Liver injury triggered an inflammatory response by enhancing the mRNA gene expression of NFkappaB and TNF-alpha. DEN effectively activated apoptotic markers GSK-3 and c-FOS. Oral administration of CNPs alleviated the oxidative, inflammatory and apoptotic hazards induced via DEN. The histopathological examination reinforced these results. The present study highlights the anti-inflammatory and anti-apoptotic potentials of CNPs against DEN-induced HCC. PMID- 30013939 TI - Contamination by neonicotinoid insecticides and their metabolites in Sri Lankan black tea leaves and Japanese green tea leaves. AB - Tea is one of the world's most popular beverages due to health promoting effects. Despite these, there have been concerns about the adverse effects of tea contamination by neonicotinoid insecticides. Only a handful of studies on neonicotinoid insecticides in tea have been carried out and this study was therefore performed to determine the concentrations of seven neonicotinoid insecticides and 20 metabolites in Japanese green tea leaves, and black tea leaves from Sri Lanka; and assess the Maximum Daily Intake (MDI) of neonicotinoid insecticides. From the results, the seven parent compounds were detected in Japanese tea leaves and beverages. Dinotefuran (3004 ng/g) was found at the highest level in green tea leaves. Ten of the 20 metabolites were detected in Japanese tea products. Dinotefuran-urea (92%) and thiacloprid-amide (89%) were most frequently detected in Japanese tea leaves. Clothianidin-urea (100 ng/g) was found at the highest level in green tea leaves. Neonicotinoid insecticides and metabolites were not detected in Sri Lankan black tea leaves. The concentrations and MDI of neonicotinoid insecticides in tea leaves were below the Maximum Residual Levels (MRLs) and Acceptable Daily Intakes (ADIs), respectively. PMID- 30013940 TI - Refinement of a colostrum-deprived pig model for infectious disease research. AB - Well-defined pig models are useful to study the pathogenicity of newly recognized pathogens or strains in pigs and serve as animal models for some human diseases. The conventional pig model, where research pigs are sourced from commercial high health production systems, is commonly used due to the easiness of getting pigs in a timely manner. However, freedom of the pig for the pathogen of interest is important at study start and serological assays to screen pigs for antibodies against newly identified pathogens or molecular assays detecting all possible circulating pathogen variants may not yet exist. Using colostrum-deprived (CD) pigs is a good alternative strategy to circumvent passively-acquired immunity against the pathogen of interest or exposure to pathogens shortly after birth. However, CD pigs are difficult to rear as they are highly susceptible to infections, and mortality rates in the first few days of life are often very high. Herein we report on refinement of a CD pig model with consistent survival rates of 90-100% of the piglets. *Step-by-step protocol to derive and rear CD piglets with higher expected survival rates.*Pig housing improvement minimizes the risk of disease transmission.*Infectious virus disease research pig model purpose. PMID- 30013941 TI - Site-specific fluorescence double-labeling of proteins and analysis of structural changes in solution by Fluorescence Resonance Energy Transfer (FRET). AB - Fluorescence Resonance Energy Transfer (FRET) is a well-known methodology for detection and quantitation of structural changes of proteins in solution. FRET requires site-specific protein labeling with two fluorophores, one of which functions as an energy donor and the other one as an energy acceptor. However, the site-specific labeling of protein is often complex and difficult, particularly when inserting two fluorophores in specific sites. We have examined several protein labeling approaches with a varying degree of success. Described here is a dual labeling strategy that worked reproducibly in a number of protein targets and we believe will be applicable to a variety of proteins, which have few or no native cysteine (Cys) residues. We have successfully double-labeled DnaA protein of Bacillus anthracis, which lacks intrinsic Cys residues. A cysteine residue was inserted at the N-terminus by in vitro mutagenesis and a Cys Cys-Phe-Gly-Cys-Cys (CCPGCC) sequence at the C-terminus by PCR. This protein was labeled site-specifically with a fluorescein derivative, FlAsH, at the CCPGCC sequence followed by Alexa568 maleimide at the N-terminus Cys residue. Structural changes of the protein with nucleotide, DNA and an inhibitor protein binding were determined by FRET analysis of the double-labeled protein. This comprehensive novel methodology for site-specific protein labeling with different fluorophores is applicable for understanding different in vitro proteomic structural studies. Here, we describe a verified technique used for FRET spectral analysis and quantitative evaluation of structural changes using fluorophore labeled DnaA protein constructs as an example. PMID- 30013942 TI - Air-drying of cells enables visualization of antiparallel microtubule overlaps in the spindle midzone. AB - Immunofluorescence staining is used extensively to examine various types of cellular events. However, even when an antibody can detect its epitopes in western blotting, it sometimes fails to detect its epitopes when used for immunofluorescence staining. One example is the antiparallel microtubule overlaps in the anaphase and telophase spindle midzone, which functions as a signaling scaffold for cleavage furrow specification. It has been believed that it cannot be visualized by immunofluorescence staining due to the highly dense structure of microtubule overlaps (Ifuji et al., 2017). Here, we show a simple method for visualization of antiparallel microtubule overlaps in the anaphase and telophase spindle midzone. *Air-drying cells before fixation enables visualization of antiparallel microtubule overlaps in the anaphase and telophase spindle midzone, which cannot be visualized by the conventional method.*Simple method that requires minimal usage of equipment.*Commonly used anti-tubulin antibodies can be used in this method. PMID- 30013943 TI - Combining ancillary soil data with VisNIR spectra to improve predictions of organic and inorganic carbon content of soils. AB - While traditional laboratory methods of determining soil organic carbon (SOC) content are generally simple, this becomes more challenging when carbonates are present in the soil; such is commonly found in semi-arid areas. Additionally, soil inorganic carbon (SIC) content itself is difficult to determine. This study uses visible near infrared (VisNIR) spectra to predict SOC and SIC contents of samples, and the impact of including soil pH and soil total carbon (STC) data as predictor variables was evaluated. The results indicated that combining available soil pH and STC content data with VisNIR spectra dramatically improved prediction accuracy of the Cubist models. Using the full suite of predictor variables, Cubist models trained on the calibration dataset (75%) could predict the validation dataset (25%) for SOC content with a Lin's concordance correlation coefficient (LCCC) of 0.94, and an LCCC of 0.83 for SIC content. This is compared to an LCCC of 0.81 and 0.35 for SOC and SIC content, respectively, when no ancillary soil data was included with VisNIR spectra as predictor variables. These results suggest that there may be promise for using other readily available soil data in combination with VisNIR spectra to improve the predictions of different soil properties. *It can be laborious and expensive to measure soil organic and inorganic carbon content with traditional laboratory methods, and there has been recent focus on using spectroscopic techniques to overcome this.*This study demonstrates that combining ancillary soil data (pH and total carbon content) with these spectroscopic techniques can considerably improve predictions of SOC and SIC content. PMID- 30013944 TI - Methods of determining titanium dioxide nanoparticles enhance inorganic arsenic bioavailability and methylation in two freshwater algae species. AB - We developed the effect of titanium dioxide nanoparticles (nano-TiO2) on the bioaccumulation and biotransformation of arsenic (As), which remain largely unknown. We thus exposed two freshwater algae (Microcystis aeruginosa and Scenedesmus obliquus) to inorganic As with the aim of increasing our understanding on As bioaccumulation and methylation in the presence of nano-TiO2. Direct evidence of TEM and EDX image showed that nano-TiO2 (anatase) entered the exposed algae. Thus, nano-TiO2 as carriers boosted arsenic accumulation and methylation in these two algae species, which varied with both inorganic As speciation and algae species. Specifically, nano-TiO2 could enhance markedly arsenate accumulation in M. aerugginosa and arsenite accumulation in S. obliquus. Similarly, we found higher content of As methylation in M. aeruginosa of arsenite with 2 mg L-1 of nano-TiO2 treatment and in S. obliquus of arsenate treatment. Additionally, S. obliquus exhibited higher As methylation compared to M. aeruginosa, being more sensitive to As associated with nano-TiO2 than M. aeruginosa. Due to changes in pH levels inside these exposed algae, the As dissociation from nano-TiO2 inside algal cell enhanced As methylation. Accordingly, the potential influence of nanoparticles on the bioaccumulation and biotransformation of their co-contaminants deserves more attention. *Nano-TiO2 entry is assumed to promote As accumulation into exposed algae.*Nano-TiO2 had different carrying capacities for different forms of As and algae.*As dissociation from nano-TiO2 is assumed to enhance As methylation in algae. PMID- 30013945 TI - Beam position monitor gate functionality implementation and applications. AB - We introduce a novel technique to implement gate functionality for the beam position monitors (BPM) at the National Synchrotron Light Source II (NSLS-II). The functionality, now implemented in FPGA, allows us to acquire two separated bunch-trains' synchronized turn-by-turn (TBT) data simultaneously with the NSLS II in-house developed BPM system. The gated position resolution is improved about 3 times by narrowing the sampling width. Experimentally we demonstrated that the machine lattice could be transparently characterized with the gated TBT data of a short diagnostic bunch-train Cheng et al., 2017; Li et al., 2017. Other applications, for example, precisely characterizing storage ring impedance/wake field through recording the beam positions of two separated bunch trains has been experimentally demonstrated. *Gated BPM signal processing improves the position resolution.*Transparent lattice measurement using the gate function with diagnostic bunches.*Collective effect study with simultaneous position measurement from two gates. PMID- 30013946 TI - Deconstruction: the qualitative methodology for the analysis of sustainability assessment tools of agri-system. AB - As sustainability is a philosophical concept, the evaluation of sustainability of an agri-system is underpinned by a philosophical understanding. Deconstruction is the qualitative methodology derived from philosophical science that allows to show what is hidden, to reveal the implicit meaning of a sustainability assessment tool. *Qualitative methodology of analysis.*Applicable to all kind of qualitative analysis.*Suitable for review article. PMID- 30013947 TI - Two alternative chromatography methods assisted by the sulfonic acid moeity for the determination of furosine in milk. AB - N6-(2-(2-Furanyl-2-oxoethyl))-l-lysine (furosine) is a deteriorative reaction product that is produced during heat treatment and storage of milk. This compound affects the quality of commercial dairy products. Accurate determination of furosine is necessary as it may serve as a measure of the degree of protein degradation in dairy products. In this article, two HPLC based methods (1. a novel ion-pairing reagent 2. a strong cation exchange column) are proposed to quantify furosine. These methods were optimized and validated for their application to analyze fluid milk and dried milk powder. *Two methods that can be used for routine milk quality control, including heat damage and adulteration, were developed.*Compared to previous methods, the modified procedures herein using aromatic sulfonic acids (a pairing agent or covalently bound to a matrix on a strong cation exchange column) provide less expensive and more sensitive determinations.*The identification and quantification of the furosine chromatographic signal was successfully achieved during analysis of commercial and spiked samples. PMID- 30013948 TI - Urinary Lead Concentration Is an Independent Predictor of Cancer Mortality in the U.S. General Population. AB - Lead is a ubiquitous pollutant that constitutes an environmental hazard worldwide. Although lead has been known as a carcinogenic factor in animal models, its role in human carcinogenesis is still a topic of debate with limited epidemiological evidence. Moreover, the association between urinary lead, as the most non-invasive and accessible way for lead measurement in human, and cancer mortality in general population has never been explored. We addressed this subject using continuous National Health and Nutrition Examination Survey 1999 2010 data and its Mortality Follow-Up Study. Of 5,316 subjects in study population, 161 participants died due to cancer. Cancer-specific mortality was associated with urinary lead levels after multivariable adjustment. Kaplan-Meier survival curve and cubic regression spline analyses indicated that high concentration of urinary lead exhibited significant association with raised death rate of cancer. Despite the marked decrease in environmental lead levels over the past three decades, lead exposure is still the significant determinant of cancer mortality in general population in U.S., and quantification of urinary lead may serve as a non-invasive approach to facilitate biomarker discovery and clinical translational research. PMID- 30013949 TI - Diagnostic Value of Methylated Septin9 for Colorectal Cancer Detection. AB - Background: Methylated Septin9 (mSEPT9) has been suggested as a reliable biomarker in colorectal cancer (CRC) detection. We aimed to determine the diagnostic value of mSEPT9 for CRC detection in Chinese patients. In addition, we compared the diagnostic efficacy of mSEPT9 to traditional screening method [fecal occult blood test (FOBT)] and two biomarkers [carcinoembryonic antigen (CEA) and carbohydrate antigen-199 (Ca-199)]. Methods: Overall 248 subjects including 123 patients with CRC and 125 controls were included. Plasma and fecal samples were collected for CEA, Ca-199, mSEPT9, and FOBT tests. Sensitivity and specificity were calculated to evaluate the diagnostic efficacy of each method; receiver operating characteristic (ROC) curve was plotted for the assessment of diagnostic accuracy, and comparisons among FOBT, mSEPT9, and the combination were assessed through area under the ROC curve (AUC). Results: mSEPT9 achieved overall sensitivity and specificity of 61.8% [95% confidence interval (CI): 53.0-69.9%] and 89.6% (83.0-93.8%), respectively, with an AUC value of 0.757 (95% CI: 0.701 0.807), superior to FOBT [sensitivity: 61.4% (50.9-70.9%); specificity: 70.3% (59.1-79.5%); AUC: 0.658 (0.578-0.723)], CEA [sensitivity: 35.0% (27.1-43.7%); specificity: 62.6% (53.8-70.7%); AUC: 0.485 (0.411-0.559)], and Ca-199 [sensitivity: 17.9% (12.1-25.6%); specificity: 55.7% (48.9-64.1%); AUC: 0.353 (0.283-0.423)]. The combination of mSEPT9 and FOBT further improved sensitivity and AUC value of 84.1% (75.1-90.3%) and 0.807 (0.752-0.863), respectively, while specificity was declined to 62.2% (50.8-72.4%). Conclusion: mSEPT9 demonstrated best diagnostic ability in CRC detection compared with FOBT, CEA, and Ca-199. The combination of mSEPT9 and FOBT further improved diagnostic sensitivity especially for early stage disease, which may provide a new approach for future CRC screening, though further investigations are warranted. PMID- 30013951 TI - Hypoxia-Inducible Factor-1alpha Activity as a Switch for Glioblastoma Responsiveness to Temozolomide. AB - Rationale: The activity of the transcription factor, hypoxia-inducible factor (HIF)-1alpha, is a common driver of a number of the pathways involved in the aggressiveness of glioblastomas (GBMs), and it has been suggested that the reduction in this activity observed, soon after the administration of temozolomide (TMZ), can be a biomarker of an early response in GBM models. As HIF 1alpha is a tightly regulated protein, studying the processes involved in its downregulation could shed new light on the mechanisms underlying GBM sensitivity or resistance to TMZ. Methods: The effect of HIF-1alpha silencing on cell responsiveness to TMZ was assessed in four genetically different human GBM cell lines by evaluating cell viability and apoptosis-related gene balance. LAMP-2A silencing was used to evaluate the contribution of chaperone-mediated autophagy (CMA) to the modulation of HIF-1alpha activity in TMZ-sensitive and TMZ-resistant cells. Results: The results showed that HIF-1alpha but not HIF-2alpha activity is associated with GBM responsiveness to TMZ: its downregulation improves the response of TMZ-resistant cells, while blocking CMA-mediated HIF-1alpha degradation induces resistance to TMZ in TMZ-sensitive cells. These findings are in line with the modulation of crucial apoptosis-related genes. Conclusion: Our results demonstrate the central role played by HIF-1alpha activity in determining the sensitivity or resistance of GBMs to TMZ, and we suggest that CMA is the cellular mechanism responsible for modulating this activity after TMZ treatment. PMID- 30013950 TI - Unraveling the Role of Angiogenesis in Cancer Ecosystems. AB - Activation of the tumor and stromal cell-driven angiogenic program is one of the first requirements in the tumor ecosystem for growth and dissemination. The understanding of the dynamic angiogenic tumor ecosystem has rapidly evolved over the last decades. Beginning with the canonical sprouting angiogenesis, followed by vasculogenesis and intussusception, and finishing with vasculogenic mimicry, the need for different neovascularization mechanisms is further explored. In addition, an overview of the orchestration of angiogenesis within the tumor ecosystem cellular and molecular components is provided. Clinical evidence has demonstrated the effectiveness of traditional vessel-directed antiangiogenics, stressing on the important role of angiogenesis in tumor establishment, dissemination, and growth. Particular focus is placed on the interaction between tumor cells and their surrounding ecosystem, which is now regarded as a promising target for the development of new antiangiogenics. PMID- 30013953 TI - Evaluating New Compounds to Treat Burkholderia pseudomallei Infections. AB - Burkholderia pseudomallei is the causative agent of melioidosis, a disease that requires long-term treatment regimens with no assurance of bacterial clearance. Clinical isolates are intrinsically resistant to most antibiotics and in recent years, isolates have been collected that display resistance to frontline drugs. With the expanding global burden of B. pseudomallei, there is a need to identify new compounds or improve current treatments to reduce risk of relapse. Using the Pathogen Box generated by Medicines for Malaria Venture, we screened a library of 400 compounds for bacteriostatic or bactericidal activity against B. pseudomallei K96243 and identified seven compounds that exhibited inhibitory effects. New compounds found to have function against B. pseudomallei were auranofin, rifampicin, miltefosine, MMV688179, and MMV688271. An additional two compounds currently used to treat melioidosis, doxycycline and levofloxacin, were also identified in the screen. We determined that the minimal inhibitory concentrations (MIC) for levofloxacin, doxycycline, and MMV688271 were below 12 MUg/ml for 5 strains of B. pseudomallei. To assess persister frequency, bacteria were exposed to 100x MIC of each compound. Auranofin, MMV688179, and MMV688271 reduced the bacterial population to an average of 4.53 * 10-6% compared to ceftazidime, which corresponds to 25.1% survival. Overall, our data demonstrates that auranofin, MMV688197, and MMV688271 have the potential to become repurposed drugs for treating melioidosis infections and the first evidence that alternative therapeutics can reduce B. pseudomallei persistence. PMID- 30013952 TI - Transcriptional Profiling of Immune-Related Genes in Leishmania infantum-Infected Mice: Identification of Potential Biomarkers of Infection and Progression of Disease. AB - Leishmania spp. is a protozoan parasite that affects millions of people around the world. At present, there is no effective vaccine to prevent leishmaniases in humans. A major limitation in vaccine development is the lack of precise understanding of the particular immunological mechanisms that allow parasite survival in the host. The parasite-host cell interaction induces dramatic changes in transcriptome patterns in both organisms, therefore, a detailed analysis of gene expression in infected tissues will contribute to the evaluation of drug and vaccine candidates, the identification of potential biomarkers, and the understanding of the immunological pathways that lead to protection or progression of disease. In this large-scale analysis, differential expression of 112 immune-related genes has been analyzed using high-throughput qPCR in spleens of infected and naive Balb/c mice at four different time points. This analysis revealed that early response against Leishmania infection is characterized by the upregulation of Th1 markers and M1-macrophage activation molecules such as Ifng, Stat1, Cxcl9, Cxcl10, Ccr5, Cxcr3, Xcl1, and Ccl3. This activation doesn't protect spleen from infection, since parasitic burden rises along time. This marked difference in gene expression between infected and control mice disappears during intermediate stages of infection, probably related to the strong anti inflammatory and immunosuppresory signals that are activated early upon infection (Ctla4) or remain activated throughout the experiment (Il18bp). The overexpression of these Th1/M1 markers is restored later in the chronic phase (8 wpi), suggesting the generation of a classical "protective response" against leishmaniasis. Nonetheless, the parasitic burden rockets at this timepoint. This apparent contradiction can be explained by the generation of a regulatory immune response characterized by overexpression of Ifng, Tnfa, Il10, and downregulation Il4 that counteracts the Th1/M1 response. This large pool of data was also used to identify potential biomarkers of infection and parasitic burden in spleen, on the bases of two different regression models. Given the results, gene expression signature analysis appears as a useful tool to identify mechanisms involved in disease outcome and to establish a rational approach for the identification of potential biomarkers useful for monitoring disease progression, new therapies or vaccine development. PMID- 30013954 TI - Screening and Identification of B-Cell Epitopes in the P61 Protein of Nocardia brasiliensis. AB - The P61 protein is an immunodominant antigen of Nocardia brasiliensis that is observed in the sera from patients infected with the bacterium. However, the B cell epitopes of N. brasiliensis are still unresolved. To identify the antigenic determinants of P61, we screened seven monoclonal antibodies (mAbs) against P61 protein that was expressed in the Escherichia coli system. A series of truncated peptides of P61 were then generated and the mAbs were used to screen these peptides by Western blot analyses. Three B-cell epitopes were recognized by the P61 specific mAbs: 461-FEYWTKVDPEIGKRIEEG-478, 427-LVREVFNDAQRDRLVSNVVGGVQEPV. LSRVFEYWTKVDPEIGKRIEEGVRAG-482, and 447-HVLGGVQEPVLSRVFEY WTKVDPEI GKRIEEGVRAGLD 484. The latter two epitopes were further identified by N. brasiliensis-infected mouse serum. These results facilitate future investigations of serodiagnostic methods to identify Nocardia infections. PMID- 30013955 TI - Activation of Interleukin-1beta Release by the Classical Swine Fever Virus Is Dependent on the NLRP3 Inflammasome, Which Affects Virus Growth in Monocytes. AB - Classical swine fever virus (CSFV) is a classic Flavivirus that causes the acute, febrile, and highly contagious disease known as classical swine fever (CSF). Inflammasomes are molecular platforms that trigger the maturation of proinflammatory cytokines to engage innate immune defenses that are induced upon cellular infection or stress. However, the relationship between the inflammasome and CSFV infection has not been thoroughly characterized. To understand the function of the inflammasome response to CSFV infection, we infected porcine peripheral blood monocytes (PBMCs) with CSFV. Our results indicated that CSFV infection induced both the generation of pro-interleukin-1beta (pro-IL-1beta) and its processing in monocytes, leading to the maturation and secretion of IL-1beta through the activation of caspase 1. Moreover, CSFV infection in PBMCs induced the production and cleavage of gasdermin D (GSDMD), which is an inducer of pyroptosis. Additional studies showed that CSFV-induced IL-1beta secretion was mediated by NLRP3 and that CSFV infection could sufficiently activate the assembly of the NLRP3 inflammasome in monocytes. These results revealed that CSFV infection inhibited the expression of NLRP3, and knockdown of NLRP3 enhanced the replication of CSFV. In conclusion, these findings demonstrate that the NLRP3 inflammasome plays an important role in the innate immune response to CSFV infection. PMID- 30013956 TI - Prevention and management of urosepsis triggered by ureteroscopy. AB - Urosepsis is a potentially life-threatening phenomenon that may occur after an ureteroscopic procedure. With the increasingly widespread adoption of ureteroscopy, there is a concern that the rates of urosepsis may increase. This review examines the current work being undertaken to minimize postprocedure infections both in the field of device development and in clinical care. Guidelines for the diagnosis and management of urosepsis will be discussed. PMID- 30013957 TI - Percutaneous Radiofrequency Ablation of Small (1-2 cm) Hepatocellular Carcinomas Inconspicuous on B-Mode Ultrasonographic Imaging: Usefulness of Combined Fusion Imaging with MRI and Contrast-Enhanced Ultrasonography. AB - Purpose: To assess usefulness of adding contrast-enhanced ultrasonography (CEUS) to fusion imaging (FI) for percutaneous radiofrequency ablation (RFA) of hepatocellular carcinomas (HCCs) inconspicuous on FI alone. Therapeutic outcomes of RFA under CEUS-added FI guidance for HCCs inconspicuous on FI alone were also evaluated. Methods: This prospective study was approved by the institutional review board and informed consent was obtained from all patients. Planning US was performed with FI for 126 patients with a single HCC (1-2 cm) to evaluate the feasibility of RFA by grading lesion conspicuity score using a four-point scale. RFA was performed under CEUS-added FI guidance for HCCs inconspicuous on FI alone. We evaluated how many HCCs initially inconspicuous on FI became conspicuous after adding CEUS. After CEUS-added FI-guided RFA, therapeutic outcomes including rates of technical success, primary technique efficacy, major complications, and local tumor progression were assessed. Results: After adding CEUS, 90.5% (19/21) of all tumors initially inconspicuous on FI became conspicuous, thus enabling direct targeting for RFA. Technical success and primary technique efficacy rates were 94.7% (18/19) and 100% (19/19), respectively. No major complications were observed after RFA. Cumulative local tumor progression rates after RFA were estimated to be 5.3%, 10.8%, and 10.8% at 1, 2, and 3 years, respectively. Conclusion: Adding CEUS to FI is useful for improving the conspicuity of HCCs inconspicuous on FI alone, thus enabling successful percutaneous RFA with excellent therapeutic outcomes. PMID- 30013959 TI - Parental Time of Returning Home From Work and Child Mental Health Among First Year Primary School Students in Japan: Result From A-CHILD Study. AB - Introduction: Child mental health is known to be influenced by parental work hours. Although literature suggests that parent-child interaction mediates the association, few studies have directly measured the parental time of returning home from work. We analyzed data from a school-based survey to examine the association between parental time of returning home from work and child mental health. Methods: We used a sample of 2,987 first-year primary school students derived from the Adachi Child Health Impact of Living Difficulty (A-CHILD) study that examined the impact of family environment and lifestyle on child health in Adachi City, Tokyo, Japan. We analyzed the associations between reported parental time of returning home and the continuous Strengths and Difficulties Questionnaire (SDQ) scores using multivariable regression modeling. Results: Children whose parents both returned home late (later than 6 p.m. for the mother and later than 8 p.m. for the father), or at irregular times, had higher scores in total difficulties (beta = 1.20, 95% CI: 0.55 to 1.85), the "conduct problems" subscale (beta = 0.37, 95% CI: 0.13 to 0.60), and the hyperactivity/inattention subscale (beta = 0.53, 95% CI: 0.24 to 0.82) compared with children whose parents both returned home earlier. Mediation analyses indicated that the percentage of the total association between parental time of returning home and the SDQ scores, which was mediated by parent-child interaction, was 20% (95% CI: 10 to 46) for total difficulties, 17% (95% CI: 7 to 49) for conduct problems, and 23% (95% CI: 11 to 52) for hyperactivity/inattention. Conclusions: Late or irregular returning home times for both parents had an adverse effect on child mental health, and the relationship was partly mediated by reduced frequency of parent-child interaction. PMID- 30013958 TI - Improving Long-Term Outcomes After Extracorporeal Membrane Oxygenation: From Observational Follow-Up Programs Toward Risk Stratification. AB - Since the introduction of extracorporeal membrane oxygenation (ECMO), more neonates and children with cardiorespiratory failure survive. Interest has therefore shifted from reduction of mortality toward evaluation of long-term outcomes and prevention of morbidity. This review addresses the changes in ECMO population and the ECMO-treatment that may affect long-term outcomes, the diagnostic modalities to evaluate neurological morbidities and their contributions to prognostication of long-term outcomes. Most follow-up data have only become available from observational follow-up programs in neonatal ECMO survivors. The main topics are discussed in this review. Recommendations for long term follow up depend on the presence of neurological comorbidity, the nature and extent of the underlying disease, and the indication for ECMO. Follow up should preferably be offered as standard of care, and in an interdisciplinary, structured and standardized way. This permits evaluation of outcome data and effect of interventions. We propose a standardized approach and recommend that multiple domains should be evaluated during long-term follow up of neonates and children who needed extracorporeal life support. PMID- 30013960 TI - Measuring Airway Obstruction in Severe Asthma in Children. AB - Lung function is an important tool in the diagnosis and monitoring of patients with asthma at all ages. Airway obstruction is a typical feature of asthma and it can be assessed with several lung function techniques. Spirometry, respiratory resistance and reactance, and lung volumes are available to measure it at different ages and in children. The assessment of a bronchodilator response is always recommended to show the reversibility of the obstruction. Poor lung function is a predictor of poor asthma outcome and a low Forced Expiratory Volume in the first second of expiration percent predicted measured with spirometry, has been shown to be associated with a higher risk of having an exacerbation during the following year independently of the presence of asthma symptoms. In severe asthma lung function assessment is used to distinguish different phenotypes, children with severe asthma have worse airflow limitation prior to administration of a bronchodilator than children with non severe asthma. Airway resistance and reactance are indirect measurements of airway obstruction and they can be measured with the forced oscillation technique, which is feasible also in non collaborative children. This technique can be more informative in discriminating patients with asthma from healthy controls and is able to indicate a more peripheral involvement of the airways. The role of this technique in severe asthma is still debated. In conclusion lung function is useful in the clinical management of children with severe asthma. PMID- 30013962 TI - HHV-6 Specific T-Cell Immunity in Healthy Children and Adolescents. AB - Objective: Primary infection with human herpes virus 6 (mainly HHV-6B) commonly occurs in the first 2 years of life leading to persistence and the possibility of virus reactivation later in life. Consequently, a specific cellular immune response is essential for effective control of virus reactivation. We have studied cell-mediated immune response to HHV-6 (U54) in healthy children and adolescents. Materials and Methods: By flow cytometry, the amount of cytokine (interferon gamma-IFN- gamma, interleukin 2-IL-2, tumor necrosis factor alpha-TNF alpha) secreting T-cells were measured after 10 days of pre-sensitization and 6 h of re-stimulation with mixtures of pooled overlapping peptides from U54, staphylococcal enterotoxin B (SEB, positive control), or Actin (negative control) in healthy children and adolescents without any underlying immune disorder or infectious disease. Results: All individuals showed a virus-specific response for at least one cytokine in either CD4+ or CD8+ cells. Percentages of individuals with HHV-6-specific TNF-alpha response in CD4+ (48% of individuals) as well as CD8+ (56% of individuals) were always the highest. Our data show significantly higher frequencies of HHV-6-specific TNF-alpha producing CD8+ T-cells in individuals older than 10 years of life (p = 0.033). Additionally, the frequency of HHV-6 specific TNF-alpha producing CD8+ T-cells positively correlated with the age of the individuals. Linear regression analysis showed a positive relation between age and frequency of HHV-6-specific TNF-alpha producing CD8+ T-cells. Conclusion: Results indicate that T-cell immune response against HHV-6 is commonly detectable in healthy children and adolescents with higher frequencies of antigen-specific T-cells in older children and adolescents possibly reflecting repeated stimulation by viral persistence and subclinical reactivation. PMID- 30013963 TI - Synthesis and Characterization of Photoresponsive Macromolecule for Biomedical Application. AB - Azobenzene, a photo switcher, has attracted increasing interest due to its structural response to photo stimulus in the field of information science and chemical sensing in the recent decades. However, limited water solubility and cytotoxicity restrained their applications in the biomedical field. In research, HA-AZO has been designed as a water soluble photo switcher in biomedical application. Synthesized HA-AZO had good water-solubility and a stable pi-pi* transition absorbance peak trans-isomer. With exposure to UV, transformation from trans-isomer to cis-isomer of HA-AZO could be realized according to UV spectra. Reversely, trans-isomer could be gradually recovered from cis-isomer in the dark. Simultaneously, quick response and slow recovery could be detected in the process of structural change. Moreover, repeated illumination was further used to detect the antifatigue property of HA-AZO, which showed no sign of fatigue during 20 circles. The influence of pH value on UV spectrum for HA-AZO was investigated in the work. Importantly, in acid solution, HA-AZO no longer showed any photoresponsive property. Additionally, the status of HA-AZO under the effect of UV light was investigated by DLS results and TEM image. Finally, in vitro cytotoxicity evaluations were performed to show the effects of photoresponsive macromolecule on cells. PMID- 30013961 TI - Immunological Effects of Human Milk Oligosaccharides. AB - Human milk oligosaccharides (HMOs) comprise a group of structurally complex, unconjugated glycans that are highly abundant in human milk. HMOs are minimally digested in the gastrointestinal tract and reach the colon intact, where they shape the microbiota. A small fraction of HMOs is absorbed, reaches the systemic circulation, and is excreted in urine. HMOs can bind to cell surface receptors expressed on epithelial cells and cells of the immune system and thus modulate neonatal immunity in the infant gut, and possibly also sites throughout the body. In addition, they have been shown to act as soluble decoy receptors to block the attachment of various microbial pathogens to cells. This review summarizes the current knowledge of the effects HMOs can have on infections, allergies, auto immune diseases and inflammation, and will focus on the role of HMOs in altering immune responses through binding to immune-related receptors. PMID- 30013964 TI - In Silico Workflow for the Discovery of Natural Products Activating the G Protein Coupled Bile Acid Receptor 1. AB - The G protein-coupled bile acid receptor (GPBAR1) has been recognized as a promising new target for the treatment of diverse diseases, including obesity, type 2 diabetes, fatty liver disease and atherosclerosis. The identification of novel and potent GPBAR1 agonists is highly relevant, as these diseases are on the rise and pharmacological unmet therapeutic needs are pervasive. Therefore, the aim of this study was to develop a proficient workflow for the in silico prediction of GPBAR1 activating compounds, primarily from natural sources. A protocol was set up, starting with a comprehensive collection of structural information of known ligands. This information was used to generate ligand-based pharmacophore models in LigandScout 4.08 Advanced. After theoretical validation, the two most promising models, namely BAMS22 and TTM8, were employed as queries for the virtual screening of natural product and synthetic small molecule databases. Virtual hits were progressed to shape matching experiments and physicochemical clustering. Out of 33 diverse virtual hits subjected to experimental testing using a reporter gene-based assay, two natural products, farnesiferol B (27) and microlobidene (28), were confirmed as GPBAR1 activators reaching more than 50% receptor activation at 20 MUM with EC50s of 13.53 MUM and 13.88 MUM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid (1). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 MUM, including new scaffolds from natural and synthetic origin. PMID- 30013965 TI - Huanglongmycin A-C, Cytotoxic Polyketides Biosynthesized by a Putative Type II Polyketide Synthase From Streptomyces sp. CB09001. AB - Three natural products of nonaketide biosynthetic origin, probably biosynthesized from nine molecules of malonyl-CoA, have been isolated. Herein we described the isolation and structure elucidation of huanglongmycin (HLM) A-C and identification of the putative hlm biosynthetic gene cluster from Streptomyces sp. CB09001, isolated from a karstic cave in Xiangxi, China. Albeit previously isolated, HLM A was reported for the first time to exhibit moderate cytotoxicity against A549 lung cancer cell line (IC50 = 13.8 +/- 1.5 MUM) and weak antibacterial activity against gram-negative clinical isolates. A putative biosynthetic pathway for HLM A, featuring a nonaketide-specific type II polyketide synthase, was proposed. It would be consistent with the isolation of HLM B and C, which are two new natural products and likely shunt metabolites during HLM A biosynthesis. PMID- 30013967 TI - Dynamic Surface Wetting and Heat Transfer in a Droplet-Particle System of Less Than Unity Size Ratio. AB - Dynamic surface wetting of particles in contact with droplet is a complex phenomenon ubiquitously encountered in many multiphase systems of industrial importance. In this study, we address this aspect by investigating impact behavior of a water droplet (diameter = 2.9 +/- 0.1 mm) in the Weber number (We) range from ~4 to 104 on a stationary spherical brass particle (diameter = 10 mm) with and without heat transfer using a combination of high speed imaging and computational fluid dynamics (CFD) modeling approach. In cold state interactions (20 degrees C), droplet exhibited oscillatory interfacial motion comprising periodic spreading and recoiling motion. Interactions involving heat transfer were studied in film boiling regime (350 degrees C) and two outcomes were noted droplet rebound and disintegration. A coupled Level Set and Volume of Fluid (VOF) approach based multiphase CFD model was utilized to predict the dynamic spread ratio and transient evolution of droplet shape during the interaction. To capture the complex contact line motion realistically, a continuous time varying profile of experimentally measured dynamic contact angles was used as a wall boundary condition for the cold interactions which provided good agreement with experimentally measured droplet spread ratio. In film boiling regime, droplet spread ratio was correlated to impact Weber number and a power law trend was obtained. Rebound and disintegration outcomes were characterized by the droplet particle contact time. For simulating interactions in film boiling regime, a constant contact angle in the limit of super-hydrophobic surface was implemented in the CFD model to account for the apparent non-wetting effect due to vapor film formation at the contact area. A sensitivity analysis was performed involving three different contact angle boundary conditions (theta s = 150, 160, and 170 degrees ) to represent the surface hydrophobicity. CFD model predicted interaction outcomes and droplet spread ratios were in reasonable agreement with the experiment at different impact Weber numbers. Increase in spherical surface heat flux and corresponding rise in droplet temperature at different impact Weber numbers were also quantified which showed an increasing trend up to a critical Weber number for droplet disintegration. PMID- 30013966 TI - Ag3VO4 Nanoparticles Decorated Bi2O2CO3 Micro-Flowers: An Efficient Visible-Light Driven Photocatalyst for the Removal of Toxic Contaminants. AB - Semiconductor-based photocatalysis is of great potential for tackling the environmental pollution. Herein, a novel hierarchical heterostructure of Bi2O2CO3 micro-flowers in-situ decorated with Ag3VO4 nanoparticles was developed by a facile method. Various characterization techniques have been employed to study the physical and chemical property of the novel catalyst. The novel catalyst was utilized for the photocatalytic removal of industrial dyes (rhodamine B, methyl orange) and tetracycline antibiotic under visible-light irradiation. The results indicated that Ag3VO4/Bi2O2CO3 heterojunctions showed a remarkably enhanced activity, significantly higher than those of bare Ag3VO4, Bi2O2CO3, and the physical mixture of Ag3VO4 and Bi2O2CO3 samples. This could be ascribed to an enhanced visible-light harvesting capacity and effective separation of charge carriers by virtue of the construction of hierarchical Ag3VO4/Bi2O2CO3 heterojunction. Moreover, Ag3VO4/Bi2O2CO3 also possesses an excellent cycling stability. The outstanding performance of Ag3VO4/Bi2O2CO3 in removal of toxic pollutants indicates the potential of Ag3VO4/Bi2O2CO3 in real environmental remediation. Highlights Novel architectures of Ag3VO4 nanoparticles modified Bi2O2CO3 micro-flowers were constructed.Novel Ag3VO4/Bi2O2CO3 exhibited excellent photocatalytic activity and stability.Ag3VO4/Bi2O2CO3 heterojunctions significantly promote the charge separation. PMID- 30013968 TI - Two Novel Small Molecule Donors and the Applications in Bulk-Heterojunction Solar Cells. AB - Two novel small molecules DTRDTQX and DTIDTQX, based on ditolylaminothienyl group as donor moiety and quinoxaline as middle acceptor moiety with different terminal acceptor groups were synthesized and characterized in this work. In order to study the photovoltaic properties of DTRDTQX and DTIDTQX, bulk-heterojunction solar cells with the configuration of FTO/c-TiO2/DTRDTQX(or DTIDTQX):C70/MoO3/Ag were fabricated, in which DTRDTQX and DTIDTQX acted as the donors and neat C70 as the acceptor. When the weight ratio of DTRDTQX:C70 reached 1:2 and the active layer was annealed at 100 degrees C, the optimal device was realized with the power conversion efficiency (PCE) of 1.44%. As to DTIDTQX:C70-based devices, the highest PCE of 1.70% was achieved with the optimal blend ratio (DTIDTQX:C70 = 1:2) and 100 degrees C thermal annealing treatment. All the experimental data indicated that DTRDTQX and DTIDTQX could be employed as potential donor candidates for organic solar cell applications. PMID- 30013969 TI - Effects of Zirconium Doping Into a Monoclinic Scheelite BiVO4 Crystal on Its Structural, Photocatalytic, and Photoelectrochemical Properties. AB - Effects of zirconium (Zr) doping into BiVO4 powder on its structural properties and photocatalytic activity for O2 evolution were examined. The formation of BiVO4 powder crystallized in a monoclinic scheelite structure (ms-BiVO4) was achieved when the sample was doped with a relatively small amount of Zr. The photocatalytic activity of Zr-doped ms-BiVO4 powder was much higher than that of non-doped ms-BiVO4. However, further doping caused a reduction of photocatalytic activity for O2 evolution due to the occurrence of structural alterations into tetragonal scheelite and tetragonal zircon structures. Similar effects of Zr doping were also observed for the photoelectrochemical (PEC) system based on BiVO4 thin films doped with various amounts of Zr. Thus, Zr doping was confirmed to be effective for improvements of photocatalytic and PEC functions of BiVO4 for water oxidation. PMID- 30013970 TI - Progress of Research in Negative Thermal Expansion Materials: Paradigm Shift in the Control of Thermal Expansion. AB - To meet strong demands for the control of thermal expansion necessary because of the advanced development of industrial technology, widely various giant negative thermal expansion (NTE) materials have been developed during the last decade. Discovery of large isotropic NTE in ZrW2O8 has greatly advanced research on NTE deriving from its characteristic crystal structure, which is now classified as conventional NTE. Materials classified in this category have increased rapidly. In addition to development of conventional NTE materials, remarkable progress has been made in phase-transition-type NTE materials using a phase transition accompanied by volume contraction upon heating. These giant NTE materials have brought a paradigm shift in the control of thermal expansion. This report classifies and reviews mechanisms and materials of NTE to suggest means of improving their functionality and of developing new materials. A subsequent summary presents some recent activities related to how these giant NTE materials are used as practical thermal expansion compensators, with some examples of composites containing these NTE materials. PMID- 30013971 TI - Serum Antibodies Against Simian Virus 40 Large T Antigen, the Viral Oncoprotein, in Osteosarcoma Patients. AB - Human osteosarcoma (OS) is a rare human cancer, mostly occurring in children and adolescents. Simian virus 40 (SV40 = Macaca mulatta polyomavirus 1) sequences have been detected in different human cancers, including osteosarcoma. SV40 is an oncogenic virus in vivo, whereas it transforms different kinds of mammalian cells, as well as distinct human cell types. SV40 injected in rodents induces tumors of different histotypes, such as bone and brain tumors. Herein, the association between OS and SV40 large T antigen (Tag) was studied by employing indirect ELISAs using synthetic peptides that mimic different epitopes of the SV40 Tag, the viral oncoprotein. Indirect ELISAs were used to detect serum IgG antibodies against this oncogenic virus in samples from OS patients. Controls were sera from healthy subjects (HS) and oncological patients affect by breast cancer (BC), which is not associated with SV40. It turned out that sera of OS patients had a higher prevalence of SV40 Tag antibodies, 35%, compared to HS, 20% and BC, 19%, respectively. The different prevalence of SV40 Tag antibodies revealed in OS vs. HS and vs. BC is statistically significant with P < 0.05 and P < 0.01, respectively. Our immunological data indicate a significantly higher prevalence of antibodies against SV40 Tag epitopes in serum samples from OS patients compared to HS and BC, the controls. These results suggest an association between OS and SV40 Tag, indicating that this oncogenic virus may be a cofactor in OS development. PMID- 30013972 TI - The Management of Patients With Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF), the most common form of fibrosing idiopathic interstitial pneumonia, is an inexorably progressive disease with a 5-year survival of ~20%. In the last decade, our understanding of disease pathobiology has increased significantly and this has inevitably impacted on the approach to treatment. Indeed, the paradigm shift from a chronic inflammatory disorder to a primarily fibrotic one coupled with a more precise disease definition and redefined diagnostic criteria have resulted in a massive increase in the number of clinical trials evaluating novel candidate drugs. Most of these trials, however, have been negative, probably because of the multitude and redundancy of cell types, growth factors and profibrotic pathways involved in disease pathogenesis. As a consequence, until recently IPF has lacked effective therapies. Finally, in 2014, two large phase 3 clinical trials have provided robust evidence that pirfenidone, a compound with anti-fibrotic, anti-oxidant and anti-inflammatory properties, and nintedanib, a tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors are able to slow down functional decline and disease progression with an acceptable safety profile. While this is a major achievement, neither pirfenidone nor nintedanib cures IPF and most patients continue to experience disease progression and/or exacerbation despite treatment. Therefore, in recent years increasingly more attention has been paid to preservation of quality of life and, in the advanced phase of the disease, palliation of symptoms. Lung transplantation, the only curative treatment, remains a viable option for only a minority of highly selected patients. The unmet medical need in IPF remains high, and more efficacious and better tolerated drugs are urgently needed. However, a truly effective therapeutic approach should also address quality of life and highly prevalent concomitant conditions and complications of IPF. PMID- 30013974 TI - The Effectiveness of Cognitive Behavioral Therapy With Mindfulness and an Internet Intervention for Obesity: A Case Series. AB - : It is difficult for obese (body mass index of more than 30) and overweight (body mass index of 25-30) people to reduce and maintain their weight. The aim of this case series was to examine the effectiveness of a new cognitive behavioral therapy (CBT) program that combines mindfulness exercises (e.g., the raisin exercise and breathing exercises) and an online intervention to prevent dropout and subsequent weight gain in overweight participants. This case series included three participants, for whom previous weight reduction programs had been unsuccessful. All participants completed the program (60-min, group sessions provided weekly for 9 weeks) and an 18-month follow-up assessment. Results showed that all participants succeeded in losing weight (loss ranged from 5.30 to 8.88% of their total body weight). Although rebound weight gain is commonly observed in the first year following initial weight loss, the follow-up assessment showed that participants achieved further weight loss during the 18-month follow-up period. These results suggest that a CBT program that comprises mindfulness and an online intervention may be an effective method for weight loss and maintenance, and may prevent dropout in obese and overweight individuals. TRIAL REGISTRATION: This case series was registered at www.umin.ac.jp with identifier UMIN000029664. PMID- 30013973 TI - A Perspective on the Use of NB-UVB Phototherapy vs. PUVA Photochemotherapy. AB - Narrowband UVB (NB-UVB) phototherapy and psoralen-UVA (PUVA) photochemotherapy are widely used phototherapeutic modalities for a range of skin diseases. The main indication for NB-UVB and PUVA therapies is psoriasis, and other key diagnoses include atopic eczema, vitiligo, cutaneous T-cell lymphoma (CTCL), and the photodermatoses. The decision on choice of phototherapy is important and NB UVB is usually the primary choice. NB-UVB phototherapy is a safe and effective therapy which is usually considered when topical agents have failed. PUVA requires prior psoralen sensitization but remains a highly effective mainstay therapy, often used when NB-UVB fails, there is rapid relapse following NB-UVB or in specific indications, such as pustular or erythrodermic psoriasis. This review will provide a perspective on the main indications for use of NB-UVB and PUVA therapies and provide comparative information on these important dermatological treatments. PMID- 30013976 TI - Peguero Electrocardiographic Left Ventricular Hypertrophy Criteria and Risk of Mortality. AB - Background: Peguero electrocardiographic left ventricular hypertrophy (ECG-LVH) criteria are newly developed criteria that have shown better diagnostic performance than the traditional Cornell-voltage and Sokolow-Lyon criteria. However, prediction of poor outcomes rather than detection of increased left ventricular mass is becoming the primary use for ECG-LVH criteria which requires investigating any new ECG-LVH criteria in terms of prediction. Aims: To examine the prognostic significance of the newly developed Peguero ECG-LVH criteria. Methods: We compared the prognostic significance of Peguero ECG-LVH with Cornell voltage and Sokolow-Lyon ECG-LVH criteria in 7,825 participants (age 59.8 +/- 13.4 years; 52.7% women) from the third National Health and Nutrition Examination Survey who were free of major intraventricular conduction defects. ECG-LVH criteria were derived from digital ECG tracings processed at a central core laboratory. Results: At baseline, ECG-LVH was detected in 11.8% by Peguero; in 4.3% by Cornell voltage and in 6.4% by Sokolow-Lyon. During a median follow up of 13.8 years, 2,796 all-cause mortality events occurred. In multivariable models adjusted for demographics and cardiovascular risk factors, presence of Peguero ECG-LVH was associated with increased risk of all-cause mortality [HR (95% CI): 1.29 (1.16, 1.44)]. This association was not significantly different from the associations of Cornell voltage-LVH or Sokolow-Lyon LVH with all-cause mortality [HR (95%CI): 1.32 (1.12, 1.55) and 1.24 (1.07, 1.43), respectively; p-values for comparisons of these HRs with the HR of Peguero ECG-LVH 0.817 and 0.667, respectively]. Similar patterns of associations were observed with cardiovascular, ischemic heart disease and heart failure mortalities. Conclusion: Peguero ECG-LVH is predictive of increased risk of death similar to the traditional ECG-LVH criteria. PMID- 30013978 TI - Opinions of Health Professionals on Tailoring Reproductive Health Services to the Needs of Adolescents. AB - Introduction: Tailoring sexual and reproductive health programs and services to the needs of adolescents will help adolescents make informed decisions and choices regarding their sexual and reproductive health. Objective: To assess the opinions of service providers on tailoring sexual and reproductive health services to the needs of adolescents. Method: A qualitative study using indepth interviews was held among eight decision-makers and service providers in two hospitals within the Kintampo North Municipality and Kintampo South District as well as the Municipal and District Health Directorates in Kintampo North and South between April and May 2011. Results: All respondents expressed the opinion that it is a good idea to tailor sexual and reproductive health services to the needs of adolescents. They admitted that very limited sexual and reproductive health programs targeting adolescent needs were available in the study area. Service providers also reported very low levels of health facilities use by adolescents for sexual and reproductive health information and services. Health professionals attributed the poor sexual and reproductive health services utilization by adolescents to stigma from the society and attitudes of service providers. Conclusion: There are no targeted sexual and reproductive health programmes and services for adolescents. Services providers indicated that it is important to tailor sexual and reproductive health services to the needs of adolescents to prevent stigma, unwanted pregnancy, abortion, and sexually transmitted infections. PMID- 30013977 TI - Zinc Nanoparticles Enhance Brain Connectivity in the Canine Olfactory Network: Evidence From an fMRI Study in Unrestrained Awake Dogs. AB - Prior functional Magnetic Resonance Imaging (fMRI) studies have indicated increased neural activation when zinc nanoparticles are added to odorants in canines. Here we demonstrate that zinc nanoparticles up-regulate directional brain connectivity in parts of the canine olfactory network. This provides an explanation for previously reported enhancement in the odor detection capability of the dogs in the presence of zinc nanoparticles. In this study, we obtained fMRI data from awake and unrestrained dogs while they were being exposed to odorants with and without zinc nanoparticles, zinc nanoparticles suspended in water vapor, as well as just water vapor alone. We obtained directional connectivity between the brain regions of the olfactory network that were significantly stronger for the condition of odorant + zinc nanoparticles compared to just odorants, water vapor + zinc nanoparticles and water vapor alone. We observed significant strengthening of the paths of the canine olfactory network in the presence of zinc nanoparticles. This result indicates that zinc nanoparticles could potentially be used to increase canine detection capabilities in the environments of very low concentrations of the odorants, which would have otherwise been undetected. PMID- 30013979 TI - Enhancing Epitranscriptome Module Detection from m6A-Seq Data Using Threshold Based Measurement Weighting Strategy. AB - To date, with well over 100 different types of RNA modifications associated with various molecular functions identified on diverse types of RNA molecules, the epitranscriptome has emerged to be an important layer for gene expression regulation. It is of crucial importance and increasing interest to understand how the epitranscriptome is regulated to facilitate different biological functions from a global perspective, which may be carried forward by finding biologically meaningful epitranscriptome modules that respond to upstream epitranscriptome regulators and lead to downstream biological functions; however, due to the intrinsic properties of RNA molecules, RNA modifications, and relevant sequencing technique, the epitranscriptome profiled from high-throughput sequencing approaches often suffers from various artifacts, jeopardizing the effectiveness of epitranscriptome modules identification when using conventional approaches. To solve this problem, we developed a convenient measurement weighting strategy, which can largely tolerate the artifacts of high-throughput sequencing data. We demonstrated on real data that the proposed measurement weighting strategy indeed brings improved performance in epitranscriptome module discovery in terms of both module accuracy and biological significance. Although the new approach is integrated with Euclidean distance measurement in a hierarchical clustering scenario, it has great potential to be extended to other distance measurements and algorithms as well for addressing various tasks in epitranscriptome analysis. Additionally, we show for the first time with rigorous statistical analysis that the epitranscriptome modules are biologically meaningful with different GO functions enriched, which established the functional basis of epitranscriptome modules, fulfilled a key prerequisite for functional characterization, and deciphered the epitranscriptome and its regulation. PMID- 30013981 TI - The Associations between Biochemical and Microbiological Variables and Taste Differ in Whole Saliva and in the Film Lining the Tongue. AB - The objective of this work was to investigate whether the biological film lining the tongue may play a role in taste perception. For that purpose, the tongue film and saliva of 21 healthy subjects were characterized, focusing on microorganisms and their main metabolic substrates and products. In parallel, taste sensitivity was evaluated using a test recently developed by our group, and the links between biological and sensory data were explored by a correlative approach. Saliva and tongue film differed significantly in biochemical composition (proportions of glucose, fructose, sucrose, and lactic, butyric, and acetic acids) and in microbiological profiles: compared to saliva, tongue film was characterized by significantly lower proportions of Bacteroidetes (p<0.001) and its main genus Prevotella (p<0.01) and significantly higher proportions of Firmicutes (p<0.01), Actinobacteria (p<0.001), and the genus Streptococcus (p<0.05). Generic taste sensitivity was linked to biological variables in the two compartments, but variables that appeared influent in saliva (flow, organic acids, proportion of Actinobacteria and Firmicutes) and in tongue film (sugars and proportions of Bacteroidetes) were not the same. This study points to two interesting areas in taste research: the oral microbiome and the specific characterization of the film lining the tongue. PMID- 30013980 TI - Effect of Chronic Kidney Disease on Changes in Vasopressin System Expression in the Kidney Cortex in Rats with Nephrectomy. AB - It is believed that the vasopressinergic system plays an important role in the pathogenesis of chronic kidney disease (CKD). The aim of this study was to evaluate the effect of CKD on changes in vasopressin system expression in the kidney cortex in rats with nephrectomy. The study was performed on 4 groups of Sprague Dawley (SPRD) rats: a control group (CN), 1/2 nephrectomy (N1/2), 2/3 nephrectomy (N2/3), and 5/6 nephrectomy (N5/6). Blood and the kidney cortex were collected to evaluate plasma copeptin concentrations and mRNA expressions of V1a vasopressin receptors (V1aR) and V2 vasopressin receptors (V2R) and V1aR, V2R, and aquaporin 2 (AQP2) protein levels. V1aR and V2R mRNA expression in the kidney cortex was significantly lower in the CN group compared with the other groups. In contrast, the V1aR, V2R, and AQP2 protein levels were significantly higher in the CN group compared with all of the nephrectomized groups. Plasma copeptin concentration was significantly lower in the CN group than in the nephrectomized groups. CKD caused significant changes in the expression of the vasopressinergic system. Further research is needed to explain the mechanisms of the impact of the vasopressinergic system on the kidney in CKD. PMID- 30013982 TI - Advances and Challenges at the Waste-to-Bioenergy/Biorefinery Nexus. PMID- 30013983 TI - 16S rRNA Long-Read Sequencing of the Granulation Tissue from Nonsmokers and Smokers-Severe Chronic Periodontitis Patients. AB - Smoking has been associated with increased risk of periodontitis. The aim of the present study was to compare the periodontal disease severity among smokers and nonsmokers which may help in better understanding of predisposition to this chronic inflammation mediated diseases. We selected deep-seated infected granulation tissue removed during periodontal flap surgery procedures for identification and differential abundance of residential bacterial species among smokers and nonsmokers through long-read sequencing technology targeting full length 16S rRNA gene. A total of 8 phyla were identified among which Firmicutes and Bacteroidetes were most dominating. Differential abundance analysis of OTUs through PICRUST showed significant (p>0.05) abundance of Phyla-Fusobacteria (Streptobacillus moniliformis); Phyla-Firmicutes (Streptococcus equi), and Phyla Proteobacteria (Enhydrobacter aerosaccus) in nonsmokers compared to smokers. The differential abundance of oral metagenomes in smokers showed significant enrichment of host genes modulating pathways involving primary immunodeficiency, citrate cycle, streptomycin biosynthesis, vitamin B6 metabolism, butanoate metabolism, glycine, serine, and threonine metabolism pathways. While thiamine metabolism, amino acid metabolism, homologous recombination, epithelial cell signaling, aminoacyl-tRNA biosynthesis, phosphonate/phosphinate metabolism, polycyclic aromatic hydrocarbon degradation, synthesis and degradation of ketone bodies, translation factors, Ascorbate and aldarate metabolism, and DNA replication pathways were significantly enriched in nonsmokers, modulation of these pathways in oral cavities due to differential enrichment of metagenomes in smokers may lead to an increased susceptibility to infections and/or higher formation of DNA adducts, which may increase the risk of carcinogenesis. PMID- 30013984 TI - Serum Folate Correlates with Severity of Guillain-Barre Syndrome and Predicts Disease Progression. AB - The aim of this study was to determine the associations between serum folate level and the clinical course and severity of Guillain-Barre syndrome (GBS). We retrospectively enrolled 112 pairs of GBS patients and age- and sex-matched healthy controls with measured serum folate levels. On admission, 21 (18.9%) GBS patients had folate deficiency, of which only two were female patients. Patients with normal folate levels had a shorter disease progression than those with folate deficiency (median progression duration: 6 versus 13 days, p < 0.001). Serum folate levels on admission were correlated with progression duration and Medical Research Council (MRC) sum score in the upper limbs at nadir (r = -0.261, p = 0.005; r = -0.208, p = 0.03) but not with the duration of hospital stay or GBS disability score (p > 0.05). Logistic regression analysis revealed that normal folate levels on admission were an independent predictor of faster GBS progression, along with younger age, intact deep sensation, and a lower MRC sum score on admission. These results show that serum folate levels are correlated with the progression duration and severity of GBS. Further studies are required to confirm the potential of folate level as a biomarker for GBS prognosis. PMID- 30013985 TI - Microbiota Composition in Upper Respiratory Tracts of Healthy Children in Shenzhen, China, Differed with Respiratory Sites and Ages. AB - The upper respiratory tract (URT) is home to various microbial commensals, which function as competitors to pathogens and help train the immune system. However, few studies have reported the normal microbiota carriage in the URT of healthy Chinese children. In this study, we performed a 16S rDNA gene sequencing analysis of 83 anterior nares (ANs), 60 nasopharynx (NP), and 97 oropharynx (OP) samples from 98 healthy children in Shenzhen, China (<=12 years of age). The microbiota in ANs and NP is the same at different ages and typical species in these sites include Moraxella, Staphylococcus, Corynebacterium, Streptococcus, and Dolosigranulum. By contrast, the OP is primarily colonized by Streptococcus, Prevotella, Neisseria, Veillonella, Rothia, Leptotrichia, and Haemophilus. Streptococcus and Rothia keep low abundance in OP microbiota of children <=1 year old, whereas Prevotella, Neisseria, Haemophilus, and Leptotrichia amass significantly in individuals >1 year old. This work furnishes an important reference for understanding microbial dysbiosis in the URT of Chinese paediatric patients. PMID- 30013975 TI - Deciphering Non-coding RNAs in Cardiovascular Health and Disease. AB - After being long considered as "junk" in the human genome, non-coding RNAs (ncRNAs) currently represent one of the newest frontiers in cardiovascular disease (CVD) since they have emerged in recent years as potential therapeutic targets. Different types of ncRNAs exist, including small ncRNAs that have fewer than 200 nucleotides, which are mostly known as microRNAs (miRNAs), and long ncRNAs that have more than 200 nucleotides. Recent discoveries on the role of ncRNAs in epigenetic and transcriptional regulation, atherosclerosis, myocardial ischemia/reperfusion (I/R) injury and infarction (MI), adverse cardiac remodeling and hypertrophy, insulin resistance, and diabetic cardiomyopathy prompted vast interest in exploring candidate ncRNAs for utilization as potential therapeutic targets and/or diagnostic/prognostic biomarkers in CVDs. This review will discuss our current knowledge concerning the roles of different types of ncRNAs in cardiovascular health and disease and provide some insight on the cardioprotective signaling pathways elicited by the non-coding genome. We will highlight important basic and clinical breakthroughs that support employing ncRNAs for treatment or early diagnosis of a variety of CVDs, and also depict the most relevant limitations that challenge this novel therapeutic approach. PMID- 30013986 TI - Localization of Glucose Transporter 10 to Hair Cells' Cuticular Plate in the Mouse Inner Ear. AB - This study aimed to investigate the localization pattern of glucose transporters (Gluts) in mouse cochlea. Genome-wide gene expression analysis using CodeLinkTM bioarrays indicated that Glut1 and Glut10 were highly expressed (~10-fold) in mouse cochlea compared with the other members of glucose transporters (Glut2-6, Glut8, and Glut9). Semiquantitative RT-PCR and western blotting confirmed that Glut10 expression in mouse cochlea was high throughout the embryogenesis and postnatal development. Immunofluorescent staining showed that Glut10 protein was localized in the cuticular plate of the outer and inner cochlear hair cells and in the ampullary crest of the vestibular system. Based on these results, it was supposed that Glut10 may contribute to glucose transport from the endolymph to the hair cells across the cuticular plate. PMID- 30013987 TI - Association between VEGF Gene Polymorphisms and the Susceptibility to Lung Cancer: An Updated Meta-Analysis. AB - Background and Objective: The association between vascular endothelial growth factor (VEGF) gene polymorphisms (-2578C/A, +936C/T, and -460C/T) and lung cancer risk has been extensively studied in the last decades, but currently available results remain controversial or ambiguous. Therefore, we conducted a meta analysis to assess whether the relationship between the VEGF gene and lung cancer susceptibility exists. Methods: The meta-analysis was conducted by searching the databases PubMed, Embase, and Web of Science covering all eligible studies published up to October 1, 2017. The pooled odds ratios (ORs) as well as their 95% confidence intervals (CIs) were utilized to evaluate the possible associations. Publication bias of relevant studies was examined via Begg's funnel plots and Egger's regression tests. Results: This meta-analysis included 13 published case-control studies covering 4477 patients with lung cancer and 4346 healthy controls, who had been accrued from December 1992 to July 2012. For the overall eligible data collected in our meta-analysis, it indicated that VEGF +936C/T, -460C/T, and -2578C/A polymorphisms did not correlate with the elevated lung cancer risk in all genetic comparison models. Moreover, VEGF +460T/C polymorphism was found to be significantly associated with susceptibility to lung cancer in these models (allele model: pooled OR = 1.12, 95% CI: 1.00-1.26, P = 0.184; homozygote model: pooled OR = 1.51, 95% CI: 1.12-2.03, P = 0.821), but no significant results were detected in Caucasian populations. Conclusions: VEGF +936C/T, -460C/T, and -2578C/A polymorphisms were not associated with the risk of lung cancer. The VEGF +460T/C polymorphism might be a risk factor for lung cancer only in Asian populations. PMID- 30013988 TI - The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases. AB - Orphan nuclear receptor 4A1 (NR4A1) is a transcriptional factor of the nuclear orphan receptor (NR4A) superfamily that has sparked interest across different research fields in recent years. Several studies have demonstrated that ligand independent NR4A1 is an immediate-early response gene and the protein product is rapidly induced by a variety of stimuli. Hyperfunction or dysfunction of NR4A1 is implicated in various metabolic processes, including carbohydrate metabolism, lipid metabolism, and energy balance, in major metabolic tissues, such as liver, skeletal muscle, pancreatic tissues, and adipose tissues. No endogenous ligands for NR4A1 have been identified, but numerous compounds that bind and activate or inactivate nuclear NR4A1 or induce cytoplasmic localization of NR4A1 have been identified. This review summarizes recent advances in our understanding of the molecular biology and physiological functions of NR4A1. And we focus on the physiological functions of NR4A1 receptor to the development of the metabolic diseases, with a special focus on the impact on carbohydrate and lipid metabolism in skeletal muscle, liver, adipose tissue, and islet. PMID- 30013989 TI - The Imbalance of FOXP3/GATA3 in Regulatory T Cells from the Peripheral Blood of Asthmatic Patients. AB - Background: Treg cells play an important role in the pathogenic progress of asthma. Objective: To address the alterations of Treg cells in asthma. Methods: Proliferation-and function-associated markers of Treg cells along with the percentage of Treg cells producing some cytokine from asthmatics and healthy subjects were analyzed by flow cytometry. Besides, the expressions of USP21 and PIM2 in Treg cells were measured by cell immunochemistry after Treg cells were sorted. Results: Treg cells from asthmatic patients showed lower proliferation activity and were more likely to be apoptotic. These cells expressed lower levels of GITR, CTLA-4, Nrp-1, and IL-10 compared to those from the healthy control. Th2 like Treg cells increased in asthmatic patients, while the percentage of IFN-r+ Treg cells was similar between two groups. Moreover, the percentage of IL-4+ Treg cells is related to the asthma control. Treg cells from asthmatic patients expressed more FOXP3 as well as GATA3; the expression level of GATA3 negatively correlated with FEV1%pred. Increased expressions of USP21 and PIM2 in Treg cells from asthmatic patients were found. Conclusion: Treg cells decreased in asthmatic patients, with an impaired immunosupression function and a Th2-like phenotype, which may be due to overexpression of GATA3 and FOXP3, regulated by USP21 and PIM2, respectively. PMID- 30013990 TI - Poly-L-Arginine Induces Apoptosis of NCI-H292 Cells via ERK1/2 Signaling Pathway. AB - Cationic protein is a cytotoxic protein secreted by eosinophils and takes part in the damage of airway epithelium in asthma. Poly-L-arginine (PLA), a synthetic cationic protein, is widely used to mimic the biological function of the natural cationic protein in vitro. Previous studies demonstrated the damage of the airway epithelial cells by cationic protein, but the molecular mechanism is unclear. The purpose of this study aimed at exploring whether PLA could induce apoptosis of human airway epithelial cells (NCI-H292) and the underlying mechanism. Methods. The morphology of apoptotic cells was observed by transmission electron microscopy. The rate of apoptosis was analyzed by flow cytometry (FCM). The expressions of the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), Bcl-2/Bax, and cleaved caspase-3 were assessed by western blot. Results. PLA can induce apoptosis in NCI-H292 cells in a concentration-dependent manner. Moreover, the phosphorylation of the ERK1/2 and the unbalance of Bcl2/Bax, as well as the activation of caspase-3, were involved in the PLA induced apoptosis. Conclusions. PLA can induce the apoptosis in NCI-H292 cells, and this process at least involved the ERK1/2 and mitochondrial pathway. The results could have some indications in revealing the apoptotic damage of the airway epithelial cells. Besides, inhibition of cationic protein-induced apoptotic death in airway epithelial cells could be considered as a potential target of anti-injury or antiremodeling in asthmatics. PMID- 30013992 TI - STAT5 and TET2 Cooperate to Regulate FOXP3-TSDR Demethylation in CD4+ T Cells of Patients with Colorectal Cancer. AB - The tumor-infiltrating Tregs are linked to colorectal cancer progression and outcome. FOXP3 is regarded as a critical developmental and functional factor for Tregs. FOXP3-TSDR demethylation is required for stable expression of FOXP3 and maintenance of Treg function. In our study, we found specific DNA hypomethylation of FOXP3-TSDR in CD4+ T cells from colon tumor tissues as compared with normal colonic tissues. Moreover, we also found that the expression of STAT5 and TET2 was increased in CD4+ T cells from colon tumor tissues, and the superfluous STAT5 and TET2 binding to FOXP3-TSDR resulted in DNA hypomethylation. In conclusion, we have demonstrated that excessive amounts of STAT5 may bind more TET2 to the FOXP3 TSDR and upregulate FOXP3 expression via DNA demethylation. Our study improved the mechanism of FOXP3-TSDR hypomethylation in tumor-infiltrating CD4+ T cells of CRC patients. PMID- 30013993 TI - Reflection for the undergraduate on writing in the portfolio: where are we now and where are we going? AB - Introduction: The portfolio can be seen as a tool for assessment of a variety of learning activities that differ in content, usage, and assessment. The portfolio not only meets the learner's educational needs but also the political and public reassurance demand that the health professional has achieved the required competency of the curriculum that allows him or her to practice safely with or without supervision in the health organization. Methods: An in-depth search on Google Scholar, Medline and PubMed was conducted using the terms "reflection and portfolio" with especial emphasis on undergraduates. All the manuscripts collected were critically reviewed regardless of the date of publication. Results: Even though the systematic review showed the limited effect of the educational impact of the portfolio on the undergraduate, numerous benefits can be seen, e.g. improvement in the relationship between students and tutors, an increase in general knowledge, awareness and reflection. Reflection for medical undergraduates in portfolio per se was associated with improvement in communications skills, professionalism and better achievement in postgraduate studies and increase in experiential learning. Interestingly, the portfolio was shown to be useful for undergraduate and tutors in filling the gaps of learning in clinical surgery, urology and geriatric medicine. In addition, for dental and nursing students it was associated with an increase in professionalism, clinical competency, and self-confidence. Lack of integration of reflection throughout the curriculum of the medical school was considered one of the main problems. Conclusion: Further research is needed to address the following questions (i) it will be of interest to assess if there is any difference in reflective portfolio between students from problem-based learning (PBL) curriculum and those from traditional curriculum. (ii) Assess the difference in reflective portfolio between community-oriented and PBL curriculum and PBL and traditional curriculum (iii) if there is any difference in the reflective portfolio in these three curriculums, it will be of interest how this can alter the evidence base of the educational effects of the portfolio. In other words, is there any curriculum that will consistently produce evidence based educational effects of the portfolio? PMID- 30013991 TI - Immunological Mechanisms in Allergic Diseases and Allergen Tolerance: The Role of Treg Cells. AB - The immune system regulates itself to establish an appropriate immune response to potentially harmful pathogens while tolerating harmless environmental antigens and self-antigens. A central role in this balance is played by regulatory T cells (Tregs) through various ways of actions. By means of molecule secretion and cell cell contact mechanisms, Tregs may have the capacity to modulate effector T cells and suppress the action of proinflammatory cytokines across a broad range of cell types. As a result, abnormal regulatory T cell function has been pointed as a main cause in the development of allergic diseases, a major public health problem in industrialized countries, with a high socioeconomic impact. This prevalence and impact have created an international interest in improving the allergy diagnosis and therapy. Additionally, research has sought to gain a better understanding of the molecular mechanisms underlining this kind of disease, in order to a better management. At this respect, the role of Treg cells is one of the most promising areas of research, mainly because of their potential use as new immunotherapeutical approaches. Therefore, the aim of this review is to update the existing knowledge of the role of Tregs in this pathology deepening in their implication in allergen-specific therapy (AIT). PMID- 30013994 TI - Conflict management strategies in coping with students' disruptive behaviors in the classroom: Systematized review. AB - Introduction: Classroom management is leading the class by setting the class schedule, organizing the procedures, supervising the learners' progress, and predicting and solving their problems. Students' disruptive behaviors and classroom management are the most important challenges and concerns of the teachers. The current review aimed to analyze the classroom management techniques and strategies used to cope with the students' disruptive behaviors. Methods: The present study was systematic review. The articles in Science Direct, PubMed and Scopus databases and Google Scholar search engine were searched using the keywords of classroom management, students' disruptive behaviors, difficult students, and confrontation strategies during 2000-2017. A total of 31 articles were included in the study for analysis. Results: The results showed all the techniques and strategies used and teachers' challenges in dealing with students' disruptive behaviors were included in conflict management strategies, which were classified into three categories, i.e. cooperative and problem solving strategies, avoidance strategies and punishment strategies. Moreover, the studies mostly emphasized the use of cooperative and problem solving strategies, and the most highlighted methods were making effective mutual communication with students to correct their negative behavior, training and preparing the teachers for dealing with the students' disruptive behaviors and using various teaching methods and approaches based on the classroom situation. Conclusion: To cope with the challenges of students' disruptive behaviors, the teachers can use different strategies. Also, sufficient knowledge and skills about teaching, familiarity with the relevant and influential disciplines in dealing with students and making effective communication in the class can be helpful in developing and enjoying more effective skills in classroom management. PMID- 30013995 TI - Pedagogical mediation using the virtual learning environment and the new generation: A search for improved performance in medical education. AB - Introduction: Medical schools face increasing challenges to accommodate new health care needs. However, little has changed regarding the students' education. In addition, educators face the challenge of improving their teaching approach, making it suitable and effective for the new generation. The purpose of this work was to describe and contextualize the application of active pedagogical methodologies using the virtual learning environment (VLE) as a tool to improve the students' performance. Methods: This research is a quantitative and qualitative case study, carried out in one faculty of medicine in the state of Amazonas. Given a total population of senior students in this faculty, the number of participants corresponds to a proportion of 75% in the period of two years. This work required a paradigm shift, by focusing on interactive and technological teaching, professionalism, mentoring, communication, and feedback. Courses using virtual learning environment (VLE) should be prone to interaction, dialogue, collaboration and, asynchronously, autonomy. One of the key aspects of VLE content production is to select appropriate subject matters and texts to be discussed. It is through the VLE contents that the mediation of knowledge construction process and the participants' interaction takes place. Results: The improvement over the pre-test evaluation was evident, ranging between 12.59 and 50.9%, depending on the subject matter, to 81.31% in the final evaluation. In addition, the students expressed consistently positive opinions regarding the use of VLE. Conclusion: The use of VLE as a pedagogical tool, in an interactive format and appropriate to the transmission of information and knowledge construction, was adequate for an evident improvement in the cognitive performance of the senior students of medicine. In addition, the positive evaluation of the students regarding the pedagogical methodology used constitutes an added value of this approach. PMID- 30013996 TI - The Applications of Virtual Reality Technology in Medical Groups Teaching. AB - Introduction: Virtual reality is a new method for training different medical groups. Based on this technology, professionals and students of various medical sciences can determine their level of competence for medical treatment before any performance on the patient. Therefore, the aim of this study was to identify the applications of virtual reality technology for training the medical groups. Methods: This is a scoping review study conducted in 2016. Articles were retrieved through the search of related keywords in databases such as Pub Med, Scopus, Web of Sciences, Springer, and Google scholar. Then, after applying the entry criteria, 21 papers were selected from a total of 1343. Data extraction was done by a data collection form. The collected data were summarized and reported using content analysis technique according to the study purpose. Results: The findings of the study indicated that 11 cases (48%) have used virtual education technology for laparoscopic surgery training. Using virtual reality has improved learning in 17 (74%) studies. A higher accuracy in medical practice by people trained through VR has been reported in 20 (87%) studies. Conclusion: The results indicate that the application of virtual reality capabilities plays an important role in improving the performance of different medical groups. According to the results, it can be suggested that virtual reality capabilities should be used to train different medical groups based on their individual and collective needs. PMID- 30013997 TI - Using Modified Direct Observation of Procedural Skills (DOPS) to assess undergraduate medical students. AB - Introduction: Nowadays according to competency based curriculum, selecting an appropriate assessment method is inevitable. This study aimed to investigate application of Direct Observation of Procedural Skills (DOPS) in undergraduate medical students. Methods: This is a cross sectional study conducted during emergency ward rotation in last year medical students using consensus sampling method. Each student performed 2 procedures at least twice under the observation of 2 assessors using modified DOPS rating scales designed for each procedure simultaneously. Correlation between DOPS score and final routine exam was measured. Face and content validity was determined by the panel of experts. Moreover, through the test-retest and inter-rater reliability, the correlation of each score and total score was investigated. The spent time was calculated too. The statistical analysis was carried out using SPSS version 18. Results: Totally 60 students did 240 procedures under DOPS. The face and content validity confirmed by an expert panel. The findings showed that there was a significant correlation between the scores of each test and the total DOPS score (r1=0.736**, r2=0.793**, r3=0.564**, r4=0.685**; p<0.001). There was a significant correlation between the first and second scores of doing the same procedure (Pearson Cor.=0.74, p<0.001) and also between the scores of the two individual examiners when observing the same procedure (Pearson Cor.=0.84-0.94 p<0.001). The results showed that there was no correlation (Pearson Correlation =0.018, p<0.89) between the scores of this test and the final routine ward exam scores. The average time for doing DOPS test and the average time for providing feedback were 11.17 Max and 9.2 4.5 Min, respectively. Conclusion: The use of novel performance assessment methods such as DOPS is highly beneficial in order to ensure the adequacy of learning in medical students and assess their readiness for accepting professional responsibilities. DOPS as a practical and reliable test with acceptable validation can be used to assess clinical skills of undergraduate medical students. PMID- 30013998 TI - Implementation of standardized patient program using local resources in Avalon School of Medicine. AB - Introduction: The standardized Patient Program (SPP) is a standard educational training method which provides the pre-clinical students a better clinical foundation by linking the realm of clinical medicine to basic sciences. It incorporates a modern simulation technique and enhances the ability of the students wherein they can practice, apply and learn the basics of patient encounter. The main objective of this study was to analyze the implementation and efficiency of the SPP in Avalon University School of Medicine (AUSOM). Methods: A quasi-experimental "before-and-after" study design was conducted among the 3rd Semester (MD3) medical students at AUSOM. 24 students voluntarily participated in the study. The effectiveness of the program was evaluated after comparing the summative examination scores before and after implementation of the SPP (graded in 100 points system). Mean scores were calculated and a comparison of the change in scores was made, using a paired t-test in Stata (OStata corp). Results: The mean final summative clinical skills examination scores of the students before and after the introduction of the SPP were 78.46 +/- 6.62 (SEM: 1.35, range: 89 70) and 86.54+/-6.41 (SEM: 1.31, range: 98-65), respectively. There was a statistically significant increment (t=5.5058, p=0.0001) in the scores of the students after the introduction of the SPP. Conclusion: Introduction and implementation of SPP at AUSOM at preclinical years increased the overall students' performance in clinical skills. It is necessary that medical schools implement SPP early in preclinical years to strengthen learning and inoculate necessary clinical skills in medical students. PMID- 30013999 TI - Smart Phones in Research: A tool for data capture by undergraduate medical students during Re-Orientation of Medical Education (ROME) training. PMID- 30014000 TI - Develop Talents to Increase Productivity: Report of the Ninth National Medical Science Olympiad in Islamic Republic of Iran in year 2017. PMID- 30014001 TI - Emergence of Resistance to Colistin During the Treatment of Bloodstream Infection Caused by Klebsiella pneumoniae Carbapenemase-Producing Klebsiella pneumoniae. AB - We report the emergence of colistin resistance in Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae after 8 days of colistin based therapy, resulting in relapse of bloodstream infection and death. Disruption of the mgrB gene by insertion of a mobile genetic element was found to be the mechanism, which was replicated in vitro after exposure to subinhibitory concentrations of colistin and meropenem. PMID- 30014002 TI - Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression. AB - Background: The infectious cycle of varicella-zoster virus (VZV) after reactivation from the dorsal root ganglia includes replication and assembly of complete enveloped virions in the human skin to cause the characteristic herpes zoster (shingles). Methods: To pursue studies of innate immunity to VZV infection, we have adapted a fetal skin organ culture model to a human neonatal foreskin explant model. Results: Abundant expression of VZV IE62, gE, and gC was visualized by confocal microscopy while numerous enveloped virions were observed by electron microscopy in infected skin organ cultures. Microarray experiments demonstrated that the patterns of upregulated transcripts differed between VZV infected cells and VZV-infected skin explants. One result stood out, namely a >30 fold elevated interleukin (IL)-6 level in the infected skin explant that was not present in the infected monolayer culture. The IL-6 results in the polyermase chain reaction (PCR) assay were reproduced by quantitative PCR testing with newly designed primers. To determine if increased transcription was accompanied by increased IL-6 expression, we quantitated the levels of IL-6 protein in the explant media at increasing intervals after infection. We found a statistically significant increase in IL-6 protein levels secreted into the media from VZV infected skin explants as compared with mock-infected explants. Conclusions: The cellular stress response to VZV infection in neonatal skin explants included highly elevated levels of IL-6 transcription and expression. This skin organ model could be adapted to other viruses with a skin tropism, such as herpes simplex virus. PMID- 30014004 TI - Using Video-Reflexive Ethnography to Engage Hospital Staff to Improve Dementia Care. AB - In this article, we discuss how video-reflexive ethnography may be useful in engaging staff to improve dementia care in a hospital medical unit. Seven patients with dementia were involved in the production of patient-story videos, and fifty members of staff (nurses, physicians, and allied health practitioners) participated in video-reflexive groups. We identified five substantial themes to describe how video-reflexive groups might contribute to enacting person-centered care for improving dementia care: (a) seeing through patients' eyes, (b) seeing normal strange and surprised, (c) seeing inside and between, (d) seeing with others inspires actions, and (e) seeing with the team builds a culture of learning. Our findings suggest that video reflexivity is not only useful for staff engagement but also effective in enhancing team capacity to enact person centered care in the hospital setting. PMID- 30014003 TI - "They Should Be Asking Us": A Qualitative Decisional Needs Assessment for Women Considering Cervical Cancer Screening. AB - In this study, we examine from multiple perspectives, women's shared decision making needs when considering cervical screening options: Pap testing, in-clinic human papillomavirus (HPV) testing, self-collected HPV testing, or no screening. The Ottawa Decision Support Framework guided the development of the interview schedule. We conducted semi-structured interviews with seven screen-eligible women and five health care professionals (three health care providers and two health system managers). Women did not perceive that cervical screening involves a "decision," which limited their knowledge of options, risks, and benefits. Women and health professionals emphasized how a trusted primary care provider can support women making a choice among cervical screening modalities. Having all cervical screening options recommended and funded was perceived as an important step to facilitate shared decision making. Supporting women in making preference based decisions in cervical cancer screening may increase screening among those who do not undergo screening regularly and decrease uptake in women who are over screened. PMID- 30014005 TI - The Association Between Filial Piety and Depressive Symptoms Among U.S. Chinese Older Adults. AB - Background: Depressive symptoms are detrimental to the overall health and well being of older adults. This study aimed to examine the association between filial piety and depressive symptoms among U.S. Chinese older adults. Method: Data were derived from the Population Study of Chinese Elderly in Chicago (PINE), a community-engaged, population-based epidemiological study of U.S. Chinese older adults aged 60 years and above in the Greater Chicago area. The Patient Health Questionnaire-9 (PHQ-9) was adopted to measure depressive symptoms. Six domains of filial piety were evaluated, involving respect, happiness, care, greeting, obedience, and financial support. Regression analyses were performed. Results: After adjusting for age, sex, education, annual personal income, marital status, living arrangement, number of children, years in the United States, years in the community and medical comorbidities, every one point lower in filial piety expectation score was associated with increased risk of depressive symptoms (RR [rate ratio] = .96, .95-.98). And every one point lower in filial piety receipt score was associated with increased risk of depressive symptoms (RR = .94, .93 .95). Discussion: This study provides insights to research on filial piety and depressive symptoms by examining expectation and perceived receipt of filial piety. Future studies are needed to investigate the association between filial discrepancy and depressive symptoms. PMID- 30014006 TI - Achieving Health Equity in Asian Populations. AB - Research about Asian Americans and Asian health equity issues have significant gaps, in part, due to lack of funding and support for minority investigators and examinations of health in this population. This special issue is designed to further our understanding of Asian health equity, especially within the context of global Chinese populations to examine how sociocultural contexts impact aging and health. Through the findings reported in this special issue, we call for increased funding and support to minority research scholars to conduct research toward improving Asian health equity, with an emphasis on nuanced cultural contexts of this population. PMID- 30014007 TI - A Case Report of Acute Abdominal Pain From a Rare Infectious Etiology. PMID- 30014008 TI - Recurrent Encephalopathy During Febrile Illnesses in a 6-Year-Old Boy. AB - Acute onset of encephalopathy is often due to infections or intoxications, but a high index of suspicion should exist for metabolic or autoimmune causes particularly in recurrent cases. A 6-year-old previously healthy Caucasian male presented with confusion and somnolence. He had several days of fever, myalgia, headaches, and rhinorrhea and was influenza-A positive. He was noted to have new urinary incontinence, inability to follow commands, and was responsive only to noxious stimuli. His neurological examination revealed bilateral ankle clonus. Laboratory results were significant for hypoglycemia and high anion gap metabolic acidosis. Cerebrospinal fluid was unremarkable and cultures remained negative. A magnetic resonance imaging (MRI) of the brain showed diffuse gray matter restricted diffusion. His presentation was attributed to acute influenza-A encephalitis. Four months later, he presented with emesis, abdominal pain, dehydration, and hypoglycemia. He subsequently developed dysarthria and confusion. A brain MRI was similar to his previous presentation. A repeat lumbar puncture was normal. A urine organic acid profile showed elevations of ketones and branched chain ketoacids, with mild elevations of N-acetylleucine and N acetyl isoleucine. This pattern is consistent with maple syrup urine disease (MSUD). Genetic testing revealed that he is a heterozygote for 2 pathogenic variants in the BCKDHB gene (P200X and G278S), confirming MSUD. This case highlights the importance of broadening workup to include inborn errors of metabolism in cases of unexplained encephalopathy. Providers should be aware that diseases such as MSUD can occur in intermittent forms that may not be detected until early childhood. PMID- 30014009 TI - A Single-Center Study of Viral Respiratory Tract Infections in Hospitalized Children From the Kurdistan Region of Iraq. AB - Viral respiratory infections are among the most common causes of disease in humans, particularly in young children, and remain a major public health problem worldwide. For many geographic regions, there is limited epidemiological information on the main causative agents of these diseases. In this article, we investigated, in a prospective study, the viral agents leading to acute respiratory disease in children younger than 15 years of age who were admitted to the pediatric emergency unit of a major teaching hospital in Erbil City, capital of the Kurdistan region, Iraq. Nasopharyngeal samples obtained from 269 hospitalized children were analyzed for viral respiratory pathogens using the xTAG Respiratory Virus Panel Fast assay, and the data were correlated with the clinical and demographic information available for these patients. One or more respiratory virus(es) were detected in 203 out of 269 (75.5%) samples. The most frequent viruses were enterovirus/rhinovirus (n = 88; 32.7%), respiratory syncytial virus (n = 55; 20.4%), and human metapneumovirus (n = 36; 13.4%). In 42 samples (15.6%), coinfections with 2 or more respiratory viruses were detected, with enterovirus/rhinovirus, respiratory syncytial virus, human metapneumovirus, and adenovirus being identified as the most common agents in viral coinfections in these patients. PMID- 30014010 TI - American Football Sets Players' Body Mass Index. AB - Objectives. Document American football, National Football League (NFL), Lean State (LS) or Heavy State (FS) Public High School (PHS), sets similar player position mean body mass indexes (BMI). Review health risks related to BMI. Methods. Public accessible 2014-2015 football rosters were used to calculate individual player's BMI for four PHS teams about each LS and FS Capital City and 32 NFL teams. Mean BMI were compared for male player positions: quarterback (Q), backfield (B), and line (L) players. Results. Q, B, and L mean BMI were not significantly different for LS and FS PHS and NFL, but mean BMI was significantly (P < .01) different for Q or B versus L. Conclusion. Football sets similar BMI for player positions with PHS line prone to obese BMI (considered healthy for NFL players) regardless of regional BMI trends. We propose PHS football set player BMI upper limit 30 to support public health and sports safety goals. PMID- 30014011 TI - Headache in an Obese Adolescent Male: A Nonclassical Presentation of an Uncommon Disease. AB - Background. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a diagnosis of exclusion in the clinical scenario of increased intracranial pressure without an identifiable cause. This case report provides a brief review of current literature on IIH, important differential considerations to rule out prior to diagnosis, and relevant imaging findings of IIH. Case Presentation. An 18-year-old male presenting with headache and blurry vision was found to have signs of increased intracranial pressure on imaging without other abnormalities to explain the cause, suggesting IIH as a diagnosis. Conclusion. IIH is classically seen in overweight females of childbearing age but should be considered in all obese patients, including the pediatric population given the increasing rate of childhood obesity. PMID- 30014012 TI - Is external compression on the IVC a risk factor for IVC filter abutment? A single center experience of 141 infrarenal celect filter insertions. AB - Objectives: To investigate risk factors for inferior vena cava (IVC) filter abutment, including external compression on the IVC wall, using venous phase computed tomography (CT). Methods: One-hundred-forty-one cases of Celect IVC filter insertion between January 2009 and April 2017 were retrospectively reviewed. On pre-procedural CT, IVC diameter and morphological classifications were measured. Filter tilt angle, IVC angle, vertical position, and filter tip abutment to the IVC wall were analyzed on post-procedural CT. IVC compression was examined by pre- and post-procedural CT analysis. Multiple logistic regression analysis was conducted to find factors related to IVC filter abutment. Results: Of 141 IVC filter insertion cases, 52 were classified in the filter tip abutment group and 89 in the non-abutting group. IVC tilt angle (11.7 +/- 5.5 degrees vs. 6.4 +/- 5.4 degrees ), presence of external compression (14/52, 27% vs. 9/89, 9%), and IVC morphology were different between the groups (p < 0.05). In multiple logistic regression analysis, filter-tilt angle over 9.25 degrees and external compression on the IVC were found to be independent predictors of filter abutment (odds ratios: 4.56, 10.18, respectively). Conclusion: IVC filter tilt, external compression on IVC wall, and IVC morphology were significantly different between the filter tip abutment and non-abutment groups. External compression and filter tilt over 9.25 degrees were risk factors for filter tip abutment in multiple logistic regression analysis. By identifying these factors, we may be able to reduce filter tilting by preventing the filter from being deployed in a dangerous area. PMID- 30014013 TI - Use of ophthalmic B-scan ultrasonography in determining the causes of low vision in patients with diabetic retinopathy. PMID- 30014014 TI - Sex Differences in the Neuroimmune System. AB - While sex differences in the peripheral immune response have been studied extensively, sex differences in the neuroimmune response, including glial activation and associated cytokine production in the brain, is a recently emerging field. Advances in our understanding of sex differences in the neuroimmune response have important implications for understanding how neural circuits are shaped during early brain development, how activation of the immune system may impact cognitive function and behavior, and how inflammation may be associated with the risk of mental health disorders that have strong sex-biases. The goal of this mini review is to highlight recent work in the field of sex differences in neuroimmune function, with a particular focus on how microglia function is influenced by age and sex hormone exposure. PMID- 30014016 TI - Amino acid analyses of the exosome-eluted fractions from human serum by HPLC with fluorescence detection. AB - Objectives: Amino acid levels in serum or plasma are used for early detection and diagnosis of several diseases. The objective of this study was to analyze amino acid levels in serum exosomes, which have not been previously reported. Design and methods: We investigated the amino acid composition of exosomes from human serum using HPLC with fluorescence detection. Results: The composition ratios of His, Arg, Glu, Cys-Cys, Lys, and Tyr were significantly increased in the exosomes compared with those in the corresponding native serum. d-Ser, an endogenous co agonist of the N-methyl-d-aspartate receptor, was also enriched in the exosome eluted fraction. Conclusions: Our results suggest that certain amino acids are enriched in the exosome-eluted fraction from human serum. These differences could have future diagnostic potential. PMID- 30014017 TI - Polymyositis as a presentation of advanced carcinoma of Mullerian origin: A case report and discussion. AB - *Ovarian cancer of Mullerian origin may have paraneoplastic features as a first presenting symptom.*Presentations of polymyositis may be associated with underlying carcinomas of Mullerian origin.*Our patient demonstrated clinical improvement in symptoms after initiation of steroids, IVIG and chemotherapy. PMID- 30014015 TI - Multi-centre evaluation of recent troponin assays for the diagnosis of NSTEMI. AB - Objectives: We aimed to compare the use of nine different cardiac troponin (cTn) assays (2 cTnT and 7 cTnI) for the diagnosis of NSTEMI in a single multi-centre population. Design and methods: One hundred and fifty-eight patients were included (mean age 60 years, SD 17 years), including 23 patients (14%) with NSTEMI. Results: The analytical comparison highlighted a large heterogeneity of cTn assays, as reflected by percentages of patients with detectable cTn, correlation coefficients, Passing-Bablok comparisons and concordance coefficients. Correlations within cTnI assays were good and correlation within cTnT assays was excellent. Diagnostic performances demonstrated that each cTn assay has specific threshold values. Furthermore, some assays (HS-cTnI and T, cTnI-Pathfast and cTnI-Centaur) indicated high sensitivity and negative predictive value using the limit of detection (LoD) diagnostic strategy. For the latter assays, a significant increase in specificity was found when using the 99th percentile or the H0-H3 strategies, in comparison to the LoD strategy. When applying the European Society of Cardiology H0-H3 algorithm, comparable diagnostic performances were obtained. Conclusion: All 9 cTn assays indicated overall good diagnostic performances for the diagnosis of NSTEMI in emergency departments when the recommended algorithm based on the variation of cTn value between two measurements at admission and 3 h later was used. PMID- 30014018 TI - Florid cystic endosalpingiosis with uterine preservation and successful assisted reproductive therapy. AB - *While endosalpingiosis is often asymptomatic & incidental, florid cystic endosalpingiosis can have a variable presentation*Cystic endosalpingiosis can be difficult to differentiate from other non-neoplastic peritoneal inclusion cysts*Although associated with serous pelvic neoplasms, there is no evidence for oophorectomy at the completion of fertility*There is no strong evidence that hysterectomy along with cyst resection leads to improved outcomes if pathology is benign*This is the first reported case of successful assisted-reproductive therapy after resected florid cystic endosalpingiosis. PMID- 30014019 TI - Ovarian microcystic stromal tumor: Radiologic-pathologic correlation. AB - Ovarian microcystic stromal tumor (MST) is characterized by microcysts, solid cellular regions with lobulated growth, and collagenous or fibrous stroma forming hyaline plaques. While several reports have evaluated the unique pathologic and immunohistochemical profile of these tumors, there has been limited description of the radiologic findings of ovarian microcystic stromal tumor in the literature. We present a case of a 66 year old female who presented for evaluation of a new cystic pelvic mass found to have ovarian microcystic stromal tumor. To our knowledge, this is one of the first reports to evaluate the radiologic features associated with this tumor. An enhanced understanding of the correlation between imaging appearance and specific histopathologic findings may aid in the early recognition of this rare neoplasm. PMID- 30014020 TI - Mullerian carcinosarcoma arising from atypical pelvic endometriosis. AB - *Mullerian Carcinosarcoma (MC) is one of the rarest endometriosis associated malignancies (EAM).*Atypical endometriosis can undergo variety of metaplastic changes causing diagnostic dilemma.*Atypical endometriosis possibly represents a precursor lesion in the development of EAM. PMID- 30014021 TI - Advancing clinical research globally: Cervical cancer research network from Mexico. AB - Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer. PMID- 30014022 TI - Second primary rhabdomyosarcoma of the uterine cervix presenting with synchronous ovarian Sertoli-Leydig cell tumor: An illustrative case of DICER1 syndrome. AB - *Embryonal rhabdomyosarcoma of the uterine cervix and ovarian Sertoli-Leydig cell tumors are associated with DICER1 mutation*DICER1-associated tumors should prompt genetic counseling and testing*Somatic and germline genetic mutation profiles can be used to differentiate second primary from recurrent tumors. PMID- 30014023 TI - Cardiac arrest after tourniquet deflation in upper limb. AB - Pneumatic tourniquet is a technique widely used in orthopedic surgery, in particular, for reducing intraoperative bleeding and facilitation of surgery. That said, it may cause local and systemic complications which can be life threatening. The description of this kind of complications is usually made after lower limb utilization. We report the case of a patient, operated for fractures of the two upper limbs, who presented after the second tourniquet deflation, a cardiac arrest with a good recovery after cardio-pulmonary resuscitation. The most likely cause of this cardiac arrest, is the ischemia reperfusion syndrome caused by successive excessively inflated tourniquet, since pulmonary embolism and myocardial infarction are eliminated. In the light of this exceptional clinical observation, we insist on the respect of usual recommendations of use, such as duration and inflation pressure, especially when successive upper limbs tourniquets are used. PMID- 30014024 TI - Open liver trauma causing hepatico caval fistula successfully treated by embolization. AB - Introduction: Traumatic arteriovenous fistula results from a breach of vascular integrity between a vein and an adjacent artery. Hepato caval fistula is a rare entity. Open surgical approaches have increasingly given way to radiological embolization techniques in the treatment of these arteriovenous fistulae, especially in intrahepatic locations. Case report: We report the case of a patient diagnosed with a fistula, from the right branch of the liver artery to the right hepatic vein, developed following an open liver trauma. Successful embolization through the transarterial route was achieved with simple outcomes. Conclusion: The interventional radiology for endovascular management has revolutionized the treatment of hepatic liver traumas. The conservative treatment is henceforth the common approach even if hepatic artery or hepatic veins are involved in case of arteriovenous fistula. PMID- 30014025 TI - A case report and technical tip of chronic subdural hematoma treated by the placement of a subdural peritoneal shunt. AB - Background: Chronic subdural hematomas (CSDH) tend to occur most commonly in the elderly population, usually resulting from minor or insignificant head trauma. The pathophysiology behind CSDH is often directly associated with cerebral atrophy, and other causes of cerebral atrophy such as alcoholism or dementia. Other predisposing factors include diabetes, coagulopathy, use of anticoagulants (including aspirin), seizure disorders, and CSF shunts. Considerable evidence supporting the use of external drainage after evacuation of primary CSDH is readily available in the literature. Case report: We report the case of a 72 year old male with a history of recurrent left subdural hematoma presenting to the neurosurgical clinic with a two-day history of personality changes, difficulty speaking, urinary incontinence, and headaches. Burr hole evacuation was performed with the placement of a subdural peritoneal shunt. At the one-month follow-up appointment, the patient had complete resolution of symptoms and CT scan showed no new recurrence of the subdural hematoma. Conclusions: Although several treatment options are available for the management of CSDH, recurrence of hematoma is a major and very common complication that may result in re-injury due to mass effect caused by chronic hematoma. However, placement of subdural peritoneal shunt for the treatment of CSDH can reduce the recurrence rate of CSDH and therefore, reduce the risk of brain re-injury. PMID- 30014026 TI - Resuscitative endovascular balloon occlusion of the aorta with a low profile, wire free device: A game changer? AB - A 24 year old male arrived to our hospital after a motor cycle crash with evidence of a traumatic brain injury and in hemorrhagic shock not responsive to volume administration. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) was performed in a timely fashion using a new, low profile, wire free device. This lead to rapid reversal of hypotension while his bleeding source was sought and controlled. Recently, REBOA has emerged as an adjunct in the hypotensive trauma patient with noncompressible torso hemorrhage. As first described, this procedure makes use of commonly available vascular surgery and endovascular products requiring large introducer sheaths (12-14 French) and long guidewires. Concerns regarding this technique center around the safety and feasibility of using such equipment in the emergency setting outside an angiography suite. This has likely limited widespread adoption of this technique. To address these concerns, newer products designed to be placed through a smaller sheath (7 French) and without the use of guidewires have been developed. Here we report on our first clinical use of such a device that we believe represents a significant advance in the care of the trauma patient. PMID- 30014027 TI - Conservative treatment using an endoscopic pancreatic stent in a patient with delayed diagnosis of pancreatic injury after blunt trauma: A case report. AB - The diagnostic evaluation of pancreatic injuries has improved dramatically in recent years. However, it is sometimes difficult to diagnose pancreatic injuries. Surgical treatment after delayed diagnosis is associated with increased risks of mortality and morbidity. A 47-year-old man was referred to our emergency department after experiencing blunt abdominal trauma 5 d earlier. The patient was diagnosed with a grade-III pancreatic injury. His hemodynamic status remained stable. He was managed successfully using endoscopic pancreatic stenting and percutaneous drainage catheter insertion. PMID- 30014028 TI - A case of renal vein branch injury identified by multidetector computed tomography. AB - A 39-year-old male fell from a forklift and was urgently transported to our hospital. His vital signs were stable at the initial visit. Contrast imaging computed tomography (CT) showed extravasation (Ev) of contrast medium emigrating outside of the renal capsule and hematoma around the right kidney, and he was diagnosed with traumatic right renal injury, Grade IV laceration [American Association for the Surgery of Trauma classification]. When imaging the inferior renal artery branch extremity perfusing the area where Ev was found in the following blood vessel contrast imaging, obvious Ev was not found in the arterial phase; however, massively spreading Ev was found in the area adjacent to the renal laceration in the venous phase after taking a contrast image of the renal parenchyma. Thus, he was diagnosed with a renal vein branch injury. The transcatheter arterial embolization (TAE) was performed to the area, resulting in the disappearance of Ev. The effectiveness of TAE for renal injury has been established; however, it is only performed for arterial hemorrhage. TAE for venous injury has not previously been considered because a tamponade is supposedly effective for hemostasis of venous hemorrhage due to the anatomy surrounding Gerota's fasciae. This is an extremely rare case in which only venous injury was identified, without obvious arterial hemorrhage. Gerota's fasciae were broken and hemostasis treatment was required. Because the renal artery is the end artery, the venous hemorrhage was controlled with arterial embolization. In our case, renal vein branch injury was identified on CT and hemorrhage was terminated using TAE for the renal artery branch. TAE can be used as a non-operative management for the successful treatment of renal vein branch injury. PMID- 30014029 TI - Inequalities in socio-emotional development and positive parenting during childhood: Evidence from China 2010-2014. AB - Socio-emotional development (SED) is a critical dimension of early childhood development (ECD). However, little research has been conducted thus far regarding inequalities across family income status in children's SED and positive parenting scores in China, which has the second largest population of children in the world. Using nationally representative data from the China Family Panel Survey (CFPS), we addressed this knowledge gap by assessing the levels and trends of inequalities in children's SED scores and positive parenting scores across wealth quintiles between 2010 and 2014. Positive parenting was measured for (1) children aged two and younger (PP_younger) and (2) children between the ages of three and five (PP_older). We adopted five inequality measures, including both absolute and relative measures. We found that, between 2010 and 2014, SED scores significantly increased for all five wealth quintiles, with the first quintile (Q1, the lowest income) growing the fastest. Consequently, observed inequalities in SED scores between Q1 and the fifth wealth quintile (Q5, the highest income) no longer existed in 2014. For the two parenting scores, we observed a significant reduction in inequality between Q1 and Q5, from 1.03 (95% CI: 0.71-1.35) in 2010 to 0.51 (95% CI: 0.27-0.74) in 2014 for PP_younger and from 1.28 (95% CI: 1.09 1.47) in 2010 to 0.53 (95% CI: 0.37-0.70) in 2014 for PP_older. These changes are due to larger increases in scores for children in Q1 compared to Q5 during this time period. These results are highly consistent over different inequality measurements and indicate that both the absolute level and the equality status of young children's SED score and parenting score experienced improvement during the study period. This suggests that China's large investments since 2010 in pre primary education may have yielded their desired results. Future research should further investigate the association between positive parenting and SED. PMID- 30014030 TI - Occupational inequalities in female cancer incidence in Japan: Hospital-based matched case-control study with occupational class. AB - Background: Socioeconomic inequalities in female cancer incidence have previously been undocumented in Japan. Methods: Using a nationwide inpatient dataset (1984 2016) in Japan, we identified 143,806 female cancer cases and 703,157 controls matched for sex, age, admission date, and admitting hospital, and performed a hospital-based matched case-control study. Based on standardized national classification, we categorized patients' socioeconomic status (SES) by occupational class (blue-collar, service, professional, manager), cross classified by industry sector (blue-collar, service, white-collar). Using blue collar workers in blue-collar industries as the reference group, we estimated the odds ratio (OR) for each cancer incidence using conditional logistic regression with multiple imputation, adjusted for major modifiable risk factors (smoking, alcohol consumption). Results: We identified lower risks among higher-SES women for common and overall cancers: e.g., ORs for managers in blue-collar industries were 0.67 (95% confidence interval [CI], 0.46-0.98) for stomach cancer and 0.40 (95% CI, 0.19-0.86) for lung cancer. Higher risks with higher SES were evident for breast cancer: the OR for professionals in service industries was 1.60 (95% CI, 1.29-1.98). With some cancers, homemakers showed a similar trend to subjects with higher SES; however, the magnitude of the OR was weaker than those with higher SES. Conclusions: Even after controlling for major modifiable risk factors, socioeconomic inequalities were evident for female cancer incidence in Japan. PMID- 30014031 TI - Socioeconomic status, gender and dementia: The influence of work environment exposures and their interactions with APOE E4. AB - It is a well-established fact that unfavourable social and economic conditions have a negative impact on health and longevity. Recent findings suggest that this is also true of age-related dementias. Yet most common indicators of socioeconomic status (SES) say very little about the actual mechanisms at play in disease development. The present paper explores five work exposure characteristics, all of which have a clear social gradient, that could potentially shed further light on the relationship between SES and dementia. Specifically, it investigates whether these exposures could moderate the impact of a well-known genetic risk factor: the APOE E4 allele. The empirical analyses are based on data from a Swedish population study (n = 1019). Main occupation was linked to The Job Exposure Matrix to estimate the individuals' exposure to the following work environment factors: work control, support, psychological demands, physical demands and job hazards. All analyses were conducted using binary logistic regression and focused specifically on gene-work exposure interactions. A significant main effect of work control on dementia risk was detected for males (OR = 0.68; p< 0.05), but not for females. However, control was found to significantly moderate the effect of APOE E4 in both genders, albeit in different ways. These findings do not only underscore the importance of considering interactions between social and genetic risk factors to better understanding multifactorial diseases such as dementia. They also propose that gender- and class-based inequities interact, and hence must be considered simultaneously, also in relation to this particular disease. PMID- 30014032 TI - The use of Centiloids for applying [11C]PiB classification cutoffs across region of-interest delineation methods. AB - Introduction: Centiloid standardization was developed to establish a quantitative outcome measure of amyloid burden that could accommodate the integration of different amyloid positron emission tomography radiotracers or different methods of quantifying the same tracer. The goal of this study was to examine the use of Centiloids for establishing amyloid classification cutoffs for differing region of-interest (ROI) delineation schemes. Methods: Using ROIs from hand-drawn delineation in native space as the gold standard, we compared standard uptake value ratios obtained from the 6 hand-drawn ROIs that determine amyloid positivity classification with standard uptake value ratio obtained from 3 different automated techniques (FreeSurfer, Statistical Parametric Mapping, and superimposed hand-drawn ROIs in Pittsburgh Compound B template space). We tested between-methods reliability using repeated measures models and intraclass correlation coefficients. Results: We found high reliability between the hand drawn standard method and other methods for almost all the regions considered. However, small differences in standard uptake value ratio were found to lead to unreliable classifications when the hand-drawn native space-derived cutoffs were used across other ROI delineation methods. Discussion: The use of Centiloid standardization greatly improved the agreement of Pittsburgh Compound B classification across methods and may serve as an alternative method for applying cutoffs across methodologically different outcomes. PMID- 30014033 TI - Retinal oxygen metabolism in patients with mild cognitive impairment. AB - Introduction: We have previously reported that retinal vessel oxygen saturation is increased in mild-to-moderate dementia of Alzheimer's type when compared with healthy individuals. Mild cognitive impairment (MCI) is the predementia stage of the disease. The main purpose was to investigate if these changes are seen in MCI. Methods: Retinal vessel oxygen saturation was measured in 42 patients with MCI and 42 healthy individuals with a noninvasive retinal oximeter, Oxymap T1. The groups were paired according to age. Results: Arteriolar and venular oxygen saturation was increased in MCI patients compared to healthy individuals (arterioles: 93.1 +/- 3.7% vs. 91.1 +/- 3.4%, P = .01; venules: 59.6 +/- 6.1% vs. 54.9 +/- 6.4%, P = .001). Arteriovenous difference was decreased in MCI compared to healthy individuals (33.5 +/- 4.5% vs. 36.2 +/- 5.2%, P = .01). Discussion: Increased retinal vessel oxygen saturation and decreased arteriovenous difference in MCI could reflect less oxygen extraction by retinal tissue. This indicates that retinal oxygen metabolism may be affected in patients with MCI. PMID- 30014034 TI - Understanding hallucinations in probable Alzheimer's disease: Very low prevalence rates in a tertiary memory clinic. AB - Introduction: Averaging at 13.4%, current literature reports widely varying prevalence rates of hallucinations in patients with probable Alzheimer's disease (AD), and is still inconclusive on contributive factors to hallucinations in AD. Methods: This study assessed prevalence, associated factors and clinical characteristics of hallucinations in 1227 patients with probable AD, derived from a tertiary memory clinic specialized in early diagnosis of dementia. Hallucinations were assessed with the Neuropsychiatric Inventory. Results: Hallucination prevalence was very low, with only 4.5% (n = 55/1227) affected patients. Hallucinations were mostly visual (n = 40/55) or auditory (n = 12/55). Comorbid delusions were present in over one-third of cases (n = 23/55).Hallucinations were associated with increased dementia severity, neuropsychiatric symptoms, and a lifetime history of hallucination-evoking disease (such as depression and sensory impairment), but not with age or gender. Discussion: In the largest sample thus far, we report a low prevalence of hallucinations in probable AD patients, comparable to rates in non-demented elderly. Our results suggest that hallucinations are uncommon in early stage AD. Clinicians that encounter hallucinations in patients with early AD should be sensitive to hallucination-evoking comorbidity. PMID- 30014035 TI - Development of Professionalism in Graduate Medical Education: A Case-Based Educational Approach From the College of American Pathologists' Graduate Medical Education Committee. AB - Professionalism and physician well-being are important topics in academic medicine. Lapses in professional judgment may lead to disciplinary action and put patient's health at risk. Within medical education, students and trainees are exposed to professionalism in the institution's formal curriculum and hidden curriculum. Development of professionalism starts early in medical school. Trainees entering graduate medical education already have developed professional behavior. As a learned behavior, development of professional behavior is modifiable. In addition to role modeling by faculty, other modalities are needed. Use of case vignettes based on real-life issues encountered in trainee and faculty behavior can serve as a basis for continued development of professionalism in trainees. Based on the experience of program directors and pathology educators, case vignettes were developed in the domains of service, research, and education and subdivided into the areas of duty, integrity, and respect. General and specific questions pertaining to each case were generated to reinforce model behavior and overcome professionalism issues encountered in the hidden curriculum. To address physician burnout, cases were generated to provide trainees with the skills to deal with burnout and promote well-being. PMID- 30014036 TI - Quantification of the Effectiveness of a Residency Program Using the Resident In Service Examination. AB - This study describes a quantitative tool in the assessment of residency programs, in which national ranking of residents after the resident in-service examination in postgraduate year 4 is compared to that in postgraduate year 1. The relationship between training and changes in ranking, resident in-service examination results before and after training in specific areas are also compared. To illustrate the use of this novel approach, data from a large residency program were analyzed. The 70 residents were ranked as a postgraduate year 1 group at the 50th national percentile. As postgraduate year 4 residents, they were ranked at the 59th percentile, a significant (P < .003) improvement. There was moderate correlation between performance in postgraduate year 1 and that in postgraduate year 4 (0.61); however, initial ranking was no indication of the final (R2 = .34), with the exception of high performers. Training in specific areas improved ranking, demonstrating association between training and performance. In conclusion, the effectiveness of training provided by a residency program can be quantified using the resident in-service examination. This should provide a quantitative tool in the assessment of postgraduate programs. PMID- 30014037 TI - Plasticity reveals hidden resistance to extinction under climate change in the global hotspot of salamander diversity. AB - Extinction rates are predicted to rise exponentially under climate warming, but many of these predictions ignore physiological and behavioral plasticity that might buffer species from extinction. We evaluated the potential for physiological acclimatization and behavioral avoidance of poor climatic conditions to lower extinction risk under climate change in the global hotspot of salamander diversity, a region currently predicted to lose most of the salamander habitat due to warming. Our approach integrated experimental physiology and behavior into a mechanistic species distribution model to predict extinction risk based on an individual's capacity to maintain energy balance with and without plasticity. We assessed the sensitivity of extinction risk to body size, behavioral strategies, limitations on energy intake, and physiological acclimatization of water loss and metabolic rate. The field and laboratory experiments indicated that salamanders readily acclimatize water loss rates and metabolic rates in ways that could maintain positive energy balance. Projections with plasticity reduced extinction risk by 72% under climate warming, especially in the core of their range. Further analyses revealed that juveniles might experience the greatest physiological stress under climate warming, but we identified specific physiological adaptations or plastic responses that could minimize the lethal physiological stress imposed on juveniles. We conclude that incorporating plasticity fundamentally alters ecological predictions under climate change by reducing extinction risk in the hotspot of salamander diversity. PMID- 30014038 TI - A Cross-Sectional Study of Cannabidiol Users. AB - Introduction: Preclinical and clinical studies suggest that cannabidiol (CBD) found in Cannabis spp. has broad therapeutic value. CBD products can currently be purchased online, over the counter and at Cannabis-specific dispensaries throughout most of the country, despite the fact that CBD is generally deemed a Schedule I controlled substance by the U.S. Drug Enforcement Administration and renounced as a dietary supplement ingredient by the U.S. Food and Drug Administration. Consumer demand for CBD is high and growing, but few studies have examined the reasons for increasing CBD use. Materials and Methods: A self selected convenience sample (n = 2409) was recruited via an online survey designed to characterize whom, how, and why individuals are currently using CBD. The anonymous questionnaire was accessed from October 25, 2017 to January 25, 2018. Participants were recruited through social media. Results: Almost 62% of CBD users reported using CBD to treat a medical condition. The top three medical conditions were pain, anxiety, and depression. Almost 36% of respondents reported that CBD treats their medical condition(s) "very well by itself," while only 4.3% reported "not very well." One out of every three users reported a nonserious adverse effect. The odds of using CBD to treat a medical condition were 1.44 (95% confidence interval, 1.16-1.79) times greater among nonregular users of Cannabis than among regular users. Conclusion: Consumers are using CBD as a specific therapy for multiple diverse medical conditions-particularly pain, anxiety, depression, and sleep disorders. These data provide a compelling rationale for further research to better understand the therapeutic potential of CBD. PMID- 30014039 TI - Marijuana Use in Adults Living with Sickle Cell Disease. AB - Introduction: Legal access to marijuana, most frequently as "medical marijuana," is becoming more common in the United States, but most states do not specify sickle cell disease as a qualifying condition. We were aware that some of our patients living with sickle cell disease used illicit marijuana, and we sought more information about this. Materials and Methods: We practice at an urban, academic medical center and provide primary, secondary, and tertiary care for ~130 adults living with sickle cell disease. We surveyed our patients with a brief, anonymous, paper-and-pen instrument. We reviewed institutional records for clinically driven urine drug testing. We tracked patient requests for certification for medical marijuana. Results: Among 58 patients surveyed, 42% reported marijuana use within the past 2 years. Among users, most endorsed five medicinal indications; a minority reported recreational use. Among 57 patients who had at least one urine drug test, 18% tested positive for cannabinoids only, 12% tested positive for cocaine and/or phencyclidine only, and 5% tested positive for both cannabinoids and cocaine/phencyclidine. Subsequent to these studies, sickle cell disease became a qualifying condition for medical marijuana in our state. In the interval ~1.5 years, 44 patients have requested certification. Conclusion: Our findings and those of others create a rationale for research into the possible therapeutic effects of marijuana or cannabinoids, the presumed active constituents of marijuana, in sickle cell disease. Explicit inclusion of sickle cell disease as a qualifying condition for medical marijuana might reduce illicit marijuana use and related risks and costs to both persons living with sickle cell disease and society. PMID- 30014040 TI - "Tiptoeing Around the System": Alternative Healthcare Navigation Among Gender Minorities in New Orleans. AB - Purpose: Gender Minority (GM) individuals experience healthcare access barriers, including financial concerns and discrimination, which influence their health seeking behaviors. This study explores the alternative navigation strategies used by GM individuals to cope with these barriers and access care, both biomedical and complementary and alternative medicine (CAM). Methods: In-depth interviews were conducted with GM individuals (n=18) and healthcare providers (n=5) identified through purposive sampling. Semistructured guides were used to elicit information about healthcare seeking strategies and experiences. Transcribed interview data were coded, sorted, and analyzed for key themes. Results: Commonly discussed healthcare access barriers included the following: identifying a competent provider, costs and insurance obstacles, and anticipated discrimination. Respondents expressed a need for gender-affirming care within the biomedical system, and alternative navigation strategies to overcome access barriers, including travelling abroad for surgical procedures, ordering hormones online, and sharing with friends. Respondents discussed CAM principally related to emotional health, preferring CAM to biomedical offerings. Utilizing social networks to access all care modalities was common. Conclusions: The healthcare seeking behavior of GM individuals demonstrates great resilience. This population is committed to accessing gender-affirming care regardless of the associated risks of care outside of provider supervision. The healthcare community needs to eliminate access barriers and support harm reduction strategies. CAM for emotional health support and the role of social networks in accessing care resources should be better integrated into care for this population. PMID- 30014041 TI - Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer. AB - Background and purpose: In this study we have combined fractionated radiation treatment (RT) with two molecular targeted agents active against key deregulated signaling pathways in head and neck cancer. Materials and methods: We used two molecularly characterized, low passage HNSCC cell lines of differing biological characteristics to study the effects of binimetinib and buparlisib in combination with radiation in vitro and in vivo. Results: Buparlisib was active against both cell lines in vitro whereas binimetinib was more toxic to UT-SCC-14. Neither agent modified radiation sensitivity in vitro. Buparlisib significantly inhibited growth of UT-SSC-15 alone or in combination with RT but was ineffective in UT-SCC 14. Binimetinib did cause a significant delay with RT in UT-SCC-14 and it significantly reduced growth of the UT-SCC-15 tumors both alone and with RT. The tri-modality treatment was not as effective as RT with a single effective agent. Conclusions: No significant benefit was gained by the combined use of the two agents with RT even though each was efficacious when used alone. PMID- 30014043 TI - The influence on survival of glucocorticoid induced diabetes in cancer patients with metastatic spinal cord compression. AB - Background and purpose: The influence of glucocorticoid induced hyperglycemia on survival in patients with metastatic spinal cord compression (MSCC) is unknown. Materials and methods: In a prospective, observational cohort study 131 patients with MSCC referred to radiotherapy, 30 Gray (Gy) in 10 fractions, and treated with >=100 mg prednisolone a day were followed with daily blood glucose measurements during radiotherapy. Results: During follow-up a total of 56 patients 43% (95% CI = 35-52%) presented plasma glucose values diagnostic of diabetes. Sixteen patients who developed diabetes were treated with insulin, 12% (95% CI = [6%; 18%]) of the total population. The patients developing diabetes with need for insulin therapy during glucocorticoid therapy had a significantly increased mortality compared to those with normal glucose metabolism and with diabetes without need for therapy, hazard ratio = 2.1 (95% CI = 1.08-4.09, p = 0.0285). Discussion: To our knowledge this is the first prospective study to describe the influence of glucocorticoid induced diabetes on survival in patients with MSCC from different primary tumors. Conclusions: The results indicate that development of diabetes during high-dose glucocorticoid therapy needing insulin treatment in patients with MSCC from different primary tumors is associated with reduced survival. PMID- 30014042 TI - Prospective in silico study of the feasibility and dosimetric advantages of MRI guided dose adaptation for human papillomavirus positive oropharyngeal cancer patients compared with standard IMRT. AB - Purpose: We aim to determine the feasibility and dosimetric benefits of a novel MRI-guided IMRT dose-adaption strategy for human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC). Materials/methods: Patients with locally advanced HPV+ OPC underwent pre-treatment and in-treatment MRIs every two weeks using RT immobilization setup. For each patient, two IMRT plans were created (i.e. standard and adaptive). The prescription dose for the standard plans was 2.12 Gy/fx for 33 fractions to the initial PTV. For adaptive plans, a new PTVadaptive was generated based on serial MRIs in case of detectable tumor shrinkage. Prescription dose to PTVadaptive was 2.12 Gy/fx to allow for maximum dose to the residual disease. Any previously involved volumes received minimally a floor dose of 50.16 Gy. Uninvolved elective nodal volumes were prescribed 50.16 Gy in 1.52 Gy/fx. Dosimetric parameters of organs at risk (OARs) were recorded for standard vs. adaptive plans. Normal tissue complication probability (NTCP) for toxicity endpoints was calculated using literature-derived multivariate logistic regression models. Results: Five patients were included in this pilot study, 3 men and 2 women. Median age was 58 years (range 45-69). Three tumors originated at the tonsillar fossa and two at the base of tongue. The average dose to 95% of initial PTV volume was 70.7 Gy (SD,0.3) for standard plans vs. 58.5 Gy (SD,2.0) for adaptive plans. The majority of OARs showed decrease in dosimetric parameters using adaptive plans vs. standard plans, particularly swallowing related structures. The average reduction in the probability of developing dysphagia >= grade2, feeding tube persistence at 6-month post-treatment and hypothyroidism at 1-year post-treatment was 11%, 4%, and 5%, respectively. The probability of xerostomia at 6-month was only reduced by 1% for adaptive plans vs. standard IMRT. Conclusion: These in silico results showed that the proposed MRI-guided adaptive approach is technically feasible and advantageous in reducing dose to OARs, especially swallowing musculature. PMID- 30014044 TI - Salvage radiotherapy after radical prostatectomy: Long-term results of urinary incontinence, toxicity and treatment outcomes. AB - Purpose: For patients with local recurrent disease after radical prostatectomy (35-54%) salvage radiotherapy (SRT) is the treatment of choice. In the post prostatectomy setting, SRT may impose risk at increased toxicity. As data on long term toxicity, especially on urinary incontinence, are scarce, we report on the long-term treatment outcomes, toxicity and urinary incontinence rates after SRT. Materials and methods: Patients with biochemically recurrent prostate cancer after radical prostatectomy, who were treated with SRT (3D-CRT) at our institution between 1998 and 2012, were included in this retrospective cohort analysis. Primary endpoint was urinary incontinence rate. Secondary endpoints were acute and late grade >=2 genitourinary (GU) and gastrointestinal (GI) toxicity rates, biochemical progression-free survival (bPFS), distant metastasis free survival (DMFS), disease specific survival (DSS), and overall survival (OS). Results: 244 patients were included. Median follow-up after SRT was 50 months (range: 4-187 months). Before start of SRT 69.7% of patients were continent for urine. After SRT de novo urinary incontinence complaints (grade >= 1) occurred in the respective acute and late phase in 6.1% and 17.6% of patients. Respective acute grade >=2 GU and GI toxicity was 19.2% and 17.6%. Late grade >=2 toxicity for GU was 29.9% and for GI was 21.3%, respectively. The respective 5-year bPFS, OS, DSS and DMFS rates were 47.6%, 91.8%, 98.8% and 80.5%. Conclusions: Experience at our institution with SRT demonstrates that this results in good long-term biochemical control. However, toxicity and urinary incontinence rates were high. PMID- 30014045 TI - Medical egg freezing: How cost and lack of insurance cover impact women and their families. AB - Medical egg freezing (MEF) is being recommended increasingly for women at risk of losing their reproductive ability due to cancer chemotherapy or other fertility threatening medical conditions. This first, binational, ethnographic study of women who had undergone MEF sought to explore women's experiences under two different funding systems: (i) the USA, where the cost of MEF is rarely covered by private or state health insurance; and (ii) Israel, where the cost of MEF is covered by national health insurance. Women were recruited from four American and two Israeli in-vitro fertilization clinics where MEF is offered. In-depth, semi structured interviews were conducted with 45 women (33 Americans, 12 Israelis) who had completed at least one cycle of MEF. All of the Israeli women had cancer diagnoses, but were not faced with the additional burden of funding an MEF cycle. In marked contrast, the American women - 23 with cancer diagnoses and 10 with other fertility-threatening medical conditions - struggled, along with their families, to 'piece together' MEF funding, which added significant financial pressure to an already stressful situation. Given the high priority that both American and Israeli women in this study placed on survival and future motherhood, it is suggested that insurance funding for MEF should be mandated in the USA, as it is in Israel. This article concludes by describing new state legislative efforts in this regard. PMID- 30014046 TI - Exploring students' use of online sources in small groups with an augmented reality-based activity - group dynamics negatively affect identification of authentic online information. AB - In this study initially, we wanted to explore students' use of online sources and how they use online information to try to persuade each other when they get the group assignment to identify misleading from correct information. We grounded our concept on "OnLife" (Floridi, 2015) in which students used online information to find arguments for their actions. We created an AR-based campus tour for mobile devices in which students discussed content, identified correctness of online information and were asked to made a group decision. Four groups have been studied. Video-recorded observation and interviews were applied. During data analysis we found results that point to four distinctive patterns of relationships between social in-group dynamics and the identification of authentic online information: a) network of equal members, b) omission of one person, c) one person guides the others, d) no collaborative reasoning. The result is a 'Happy Surprise', it shows that social dynamics affected group performance stronger than equal access to online sources. Equal access to online information did not lead to a reasonable based-on-facts discussion. Group dynamics diminished the advantage of equal access and impacted decision-making more than the information itself. Because of the small study size, generalization of results is limited, but lays a foundation for follow-up or experimental studies. PMID- 30014047 TI - Removal of chromium (VI) from aqueous solution using vesicular basalt: A potential low cost wastewater treatment system. AB - In this study, vesicular basalt volcanic rock was taken and its application for adsorption of chromium (VI) from aqueous solution was investigated. Different physical and chemical properties of the powdered rock was studied using Fourier transform infrared spectroscopy (FT-IR), Powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). A series of batch experiments were carried out to study the effect of various experimental parameters (pH, ionic strength and contact time) on chromium (VI) adsorption. It was found that the removal efficiency of chromium (VI) decreased with increasing pH and ionic strength. The adsorption process was optimal at pH 2. The maximum adsorption capacity was 79.20 mg kg-1 at an initial concentration of 5.0 mg L-1 and adsorbent dosage of 50 g L 1. In individual adsorption tests, Pseudo-second-order kinetic and Freundlich isotherm models could better describe chromium (VI) adsorption on the vesicular basalt. This study indicated that vesicular basalt, which is inexpensive, has the potential to remove chromium (VI) from polluted water. PMID- 30014048 TI - Modified halloysite nanoclay as a vehicle for sustained drug delivery. AB - This paper presents the effect of modified halloysite nanotubes on the sustained drug release mechanisms of sodium salicylate. Acid treatment and composite polymer-halloysite modification techniques were adopted in this study. After each modification, sodium salicylate drug was loaded, and in vitro release properties were evaluated and compared with the raw unmodified halloysite nanotubes. The results obtained from SEM, TEM and FTIR analyses indicate that both acid treatment and composite formation have no effect on the tubular structure and morphology of halloysite. However, modification of the halloysite nanotubes did influence the drug release rate. In the acid treatment modification, there was an improved loading of sodium salicylate drug which resulted in the sustain release of large amount of the sodium salicylate. In the polymer/halloysite composite formation, a consistent layer of polymer was formed around the halloysite during the composite formation and thus delayed release providing sustained release of sodium salicylate drug over a longer period of time as compared to the acid treated and unmodified halloysite. The results from the invitro release were best fitted with the Higuchi and the Koresymer-Peppas models. PMID- 30014049 TI - Non-arteritic ischemic optic neuropathy and supplemental nitric oxide usage. AB - Purpose: To report a case of Non-Arteritic Ischemic Optic Neuropathy (NAION) in a middle-aged bodybuilder in excellent physiological condition without any signs or symptoms of vasculopathy and a history of nitric oxide supplement usage. Observations: The patient had visual acuity of 20/25 in the right eye, and 20/30 in the left eye, with a relative afferent pupillary defect and dyschromatopsia in the right eye. Visual field testing with Humphrey perimetry demonstrated an inferior altitudinal field defect OD. Fundus examination showed a small cupless disc OD with mild pallor, and a small cupless disc OS. He denied usage of sildenafil or other phosphodiesterase (PDE) inhibitor medications but frequently ingested megadoses of nitric oxide (NO) as part of his bodybuilding regimen. Conclusions: Nitric oxide supplements act through the same pharmacologic pathway as PDE inhibitors, and this case is suggestive that other vasodilating agents may be similarly associated with NAION. PMID- 30014050 TI - Intraocular lens dystrophic calcification after trans-scleral diode laser treatment for a cyclodialysis cleft. AB - Purpose: To describe a case of intraocular lens (IOL) dystrophic calcification as a complication of trans-scleral diode laser successfully used to treat a post trabeculectomy cyclodialysis cleft. Observations: A 76-year-old male with primary open angle glaucoma and pseudophakia (+19.0D Akreos M160L, Bausch & Lomb) was evaluated for vision impairment 4 months post-trabeculectomy complicated by a cyclodialysis cleft of his right eye. The patient was successfully treated with trans-scleral diode laser. After this treatment IOL opacification developed. Slit lamp examination and color photography of the anterior segment was performed prior to exchange of the opacified IOL. The explanted IOL underwent star testing, macroscopic imaging, phase contrast and scanning electron microscopy in addition to energy dispersive x-ray spectroscopy.Confluent IOL deposits developed 4 months after trans-scleral diode laser treatment requiring IOL exchange. Star optical testing of the explanted IOL showed disruption of the diffraction image. An asymmetric pattern of deposition was congruent with the laser treatment quadrant. The subsurface location and discrete nature of the deposits were seen on phase contrast and electron microscopy. Energy dispersive x-ray spectroscopy demonstrated a predominance of calcium/phosphate in the deposits. We are unaware of previous reports in the literature of IOL dystrophic calcification occurring as a complication of trans-scleral diode laser treatment for a post trabeculectomy cyclodialysis cleft. Conclusion and importance: Delayed postoperative IOL dystrophic calcification in our case may have been from a combination of IOL biomaterial susceptibility to diode laser energy; damaged IOL material providing a nidus for calcific nucleation; and blood ocular barrier breakdown altering aqueous composition. We suggest that pseudophakia should influence the consideration of diode laser as treatment of a cyclodialysis cleft. PMID- 30014051 TI - Transient myopic shift due to ciliary body detachment as the sole ocular manifestation of hypertensive emergency - A case report. AB - Purpose: Hypertensive emergency usually presents to ophthalmologists in the form of hypertensive retinopathy. We present a case of hypertensive emergency that presented as bilateral transient myopic shift due to ciliary body detachment in the absence of any retinal pathology. The purpose of this paper is to showcase another ocular manifestation of hypertensive emergency. Observations: A 35 year old female with a blood pressure of 192/114 mmHg presented to the emergency department with headache and acute onset blurry vision. Computed Tomography (CT) of the head, and lumbar puncture were within normal limits. Visual acuity was counting fingers in the right eye and 6/90 in the left eye, both of which improved to 6/9 with -5.00 diopters spherical correction in the right eye, and 4.75 diopters correction in the left eye. Intraocular pressures were normal. Anterior chambers were shallow, and there were no retinal changes on dilated fundus examination. Enhanced-depth optical coherence tomography (EDI-OCT) showed bilateral increased choroidal thickness and ultrasound biomicroscopy (UBM) showed 360 degrees ciliary body detachment with angle closure. With improved blood pressure control, her ciliary body detachment resolved and her refractive error returned to baseline. Conclusions: & Importance: Hypertensive emergency may present with choroidal thickening with anterior ciliary body rotation and detachment. A review of medications is important, as this presentation has also been reported as a rare side effect of sulphonamide drugs. In the absence of retinopathy, UBM and EDI-OCT imaging should be considered in the acutely hypertensive patient presenting with myopic shift. PMID- 30014052 TI - Recurrence of paraproteinemic keratopathy after penetrating keratoplasty and its assessment with confocal microscopy. AB - Purpose: To report on a case of recurrence of paraproteinemic keratopathy (PPK) associated with monoclonal gammopathy after bilateral penetrating keratoplasty. Observations: Penetrating keratoplasty was performed on both eyes of a 45-year old man due to bilateral progressive corneal stromal clouding. Recurrence of the corneal stromal opacities accompanied by a decrease in visual acuity was observed on slit-lamp examination already two years after penetrating keratoplasty. Confocal laser scanning microscopy (CLSM) of the corneal grafts performed three years after penetrating keratoplasty showed bilateral morphological changes identical to that found in the patient's corneas prior to penetrating keratoplasty. A hematological work-up revealed monoclonal gammopathy of type IgG kappa. The histochemical examination of the explanted corneas confirmed the diagnosis of PPK. Conclusions and importance: Paraproteinemic keratopathy is an underdiagnosed ophthalmological condition, which may be associated with potentially life-threatening hematologic disorders. A hematological workup should be performed in patients with corneal opacities of uncertain etiology. Penetrating keratoplasty should be performed with caution in patients with monoclonal gammopathy due to the possibility of a very fast recurrence of PPK in the corneal graft. This is the first presentation of the recurrence of flake-like PPK after penetrating keratoplasty assessed with CLSM. PMID- 30014053 TI - Enhancement of polaron-hopping-based a.c. conduction in semiconducting STS (Se-Te Sn) glass by silver incorporation. AB - In the present work, we have synthesized novel Se78-xAgxTe20Sn2 (0 <= x <= 6) semiconducting glasses for improving thermally activated a.c. conduction in STS glass (x = 0). The results of the experimental analysis of thermally activated a.c. conduction have been reported in terms of frequency and temperature of Se78 xAgxTe20Sn2 (0 <= x <= 6) glasses. The frequency dependent experimental data of a.c. conductivity sigmaac show that sigmaac follows the Jonscher universal power law. Variation of a.c. conductivity with temperature obeys the Arrhenius relation. Further analysis confirms that the density of defect states can be determined on the basis of a correlated barrier hopping model using the frequency/temperature dependence of a.c. conductivity sigmaac (T,omega). The analysis of composition dependence of various electric parameters like potential barrier height Wm, hopping distances Rmin and Romega, dielectric constant (epsilon') and the density of defect states N shows that hopping conduction is improved after silver incorporation into the parent glass. This is explained in terms of a dipolar model by considering the dipoles of Ag+ ions with negatively charged defect states. PMID- 30014054 TI - Imaging the confined surface oxidation of Ni3Al(111) by in situ high temperature scanning tunneling microscopy. AB - The initial oxidation of Ni3Al(111) was imaged by in situ scanning tunneling microscopy (STM) at 700-750 K. At 740 K +/- 10 K a moire structure is formed as the major surface phase: high resolution STM data atomically resolve a top hexagonal lattice with a lattice constant of 2.93 +/- 0.01 A aligned or slightly rotated with respect to the substrate. Auger electron spectra acquired from the surface phase identify Al atoms in an oxidic environment together with Ni atoms unaffected by the oxidation of the Ni3Al(111) surface. A special mass balance analysis applied to STM images recorded during formation of the moire structure allowed to extract the metal content of the surface phase. The moire phase can be attributed to a single O/Al double layer of alpha-Al2O3 ontop of the Ni3Al(111) crystal. The surface double layer is laterally expanded by ~7% with respect to alpha-Al2O3 and, relating to the next nearest neighbor distance of the substrate of 2.52 A, it contains 0.73 ML oxygen and 0.49 ML aluminium atoms. The building principle of the surface phase is almost identical to the one of the reported Oi/Ali interface layer of the so called surface oxide, except for its rotational alignment with respect to the substrate as shown in a careful moire analysis. It could be shown that this thinnest possible surface aluminum oxide layer is formed due to kinetic restrictions: the oxide grows within the first layer of the Ni3Al(111) surface ejecting 0.5 ML surface metal atoms, which are then converted into the surface oxide laterally separated at the ascending step edge of the same terrace. While the formation of the surface oxide is kinetically hindered most likely by the availability of Al adatoms, all rearrangement processes required for the surface oxide formation on each terrace are not rate limiting as identified by in situ STM. Instead, the local oxide growth rather follows the kinetics driven by the adsorption probability of the impinging oxygen molecules and provides the possibility to entirely cover whole Ni3Al(111) surface. PMID- 30014055 TI - ARGET-ATRP synthesis and swelling response of compositionally varied poly(methacrylic acid-co-N,N-diethylaminoethyl methacrylate) polyampholyte brushes. AB - Modifying the composition of polyampholytes, which are comprised of charge positive and charge-negative repeat units, directly contributes to trade-offs between charge and structure, which are externally regulated by solution pH and added salt. Here, the relative ratio of anionic and cationic comonomers is varied to tailor the stimuli-responsiveness of poly(methacrylic acid-co-N,N diethylaminoethyl methacrylate) (P(MAA-co-DEAEMA)) brushes to changes in solution pH and an added zwitterion. These systems display a strong dependence on excess repeating units of either type and the random incorporation appears to facilitate self-neutralization of charges. Pseudo-living growth with smooth comonomer incorporation is achieved using activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP), creating well-defined brushes. In situ ellipsometry measurements of solvated brush thickness indicate that at low and high pH, the brushes display polyelectrolyte behavior with a strong compositional dependence, but at intermediate pH values, the brushes show the characteristic collapse attributed to self-neutralization of polyampholytes. The polyampholyte brushes maintain these patterns of behavior across all compositions and in the presence of an added zwitterion, which contributes additional hydrophobic character as evidenced by decreases in the swollen layer thicknesses. The response of the P(MAA-co-DEAEMA) brushes to the organic osmolyte betaine is consistent with its tendency to stabilize proteins and peptides in a kosmotropic fashion. These studies add perspective to efforts to manipulate sequence in polyampholytic polymers, support broader efforts to tailor interfacial soft films for applications in biotechnology and sensing, and understand aggregation and stability of biological polymers. PMID- 30014056 TI - Immuno-modified superparamagnetic nanoparticles via host-guest interactions for high-purity capture and mild release of exosomes. AB - The study of exosomes has great significance for cancer diagnosis and prognosis, in which damage-free isolation of exosomes is a critically important step due to their extremely low concentration in body fluids. Herein, immunoaffinitive superparamagnetic nanoparticles (IS-NPs) were successfully constructed by combining antibodies with superparamagnetic nanoparticles through host-guest interactions between beta-cyclodextrin (beta-CD) and 4-aminoazobenzene (AAB). Exosomes in cell-culture supernatants or body fluids can be efficiently captured by IS-NPs and then mildly eluted by competitive host molecules, alpha-CD. Approximately 80% of the exosomes were captured by the IS-NPs from the model samples containing varied concentrations of exosomes (1011-107 exosomes per mL). After elution, the release efficiency of the captured exosomes was as high as 86.5%, as calculated from the extracted RNA content. A comparison between the exosomes isolated by our IS-NPs, conventional ultracentrifugation (UC), polyethylene glycol (PEG)-based precipitation, and a commercial kit was conducted to examine the performance of the IS-NP exosome isolation. The particle-to protein ratio of IS-NP captured exosomes (8.8 +/- 1.3 * 109) was eight-fold higher than that of the UC (1.1 +/- 0.4 * 109) and more than two-fold that of the PEG-based precipitation (3.7 +/- 0.8 * 109) and commercial kit (3.2 +/- 0.8 * 109) isolated ones, revealing that IS-NPs yielded more exosomes with higher purity than all the other three approaches. Cellular uptake experiments demonstrated that the exosomes captured by IS-NPs have retained their structural and functional integrities, and their broad applications in biomedical areas could therefore be expected. Promisingly, this host-guest interaction involving immunoaffinity magnetic particle system could offer a new way for fast, high efficiency and high-purity exosome isolation and elution, further benefitting exosomes' applications in desired areas. PMID- 30014057 TI - Coordination, reactivity, and structural properties of electron-rich ethoxy- and dimethylamino-substituted 1,3-diketiminate ligands and their complexes. AB - In this paper we describe the synthesis, characterization, and X-ray crystal structures of two ligands, diethyl-N,N'-bis(p-tolyl)malonimidate and 1,3 bis(dimethylamino)-N,N'-bis(p-tolyl)propanediimidate. Their corresponding rhodium(i) dicarbonyl, dimethylaluminium, and bis-ligated zinc complexes have also been prepared and characterized. The donor properties of the ligands have been studied and have been compared to those of the traditional anionic N,N' chelating ligand nacnac. PMID- 30014059 TI - Black phosphorus quantum dots: synthesis, properties, functionalized modification and applications. AB - Zero-dimensional (0D) black phosphorus quantum dots (BPQDs) are emerging functional nanomaterials. 0D BPQDs are a new form of black phosphorus (BP) nanostructures that were first prepared in 2015; they are different from typical two-dimensional (2D) BP layered nanosheets and one-dimensional (1D) BP nanoribbons. Since 2015, numerous studies have been devoted to exploring various synthetic methods, properties and modifications of BPQDs, which exhibit a broad range of applications. This review systematically summarizes PBQDs for the first time. Different synthetic methods are reviewed, including ultrasonic and electrochemical exfoliation, solvothermal treatment, blender breaking, milling crushing and pulsed laser irradiation. We highlight the physicochemical properties of BPQDs from theoretical models and discuss their experimentally observed properties. The surface modifications and functionalized combination of BPQDs with other substances are summarized by illustrating different hybrid structures, such as BPQDs/nanosheets hybrids, BPQDs-doping films, BPQDs-molecules complexes, polymers-modified BPQDs, and the assembly of BPQDs in devices. The potential applications of BPQDs are demonstrated in current research fields, including bioimaging, fluorescence sensing, nonlinear optical absorbers, cancer therapy, intelligent electronics, photovoltaics, optoelectronics and flexible devices. The current status, challenges and future perspectives of PBQDs are discussed rationally. This timely overall review should be desirable for broad scientists and facilitate the further development of layered nanostructures derived QDs and other low-dimensional nanomaterials. PMID- 30014058 TI - A protein@metal-organic framework nanocomposite for pH-triggered anticancer drug delivery. AB - We have synthesized a core@shell nanocomposite using biocompatible bovine serum albumin (BSA) as the core and a pH-sensitive metal-organic framework (MOF) as the shell. Doxorubicin (DOX)/BSA nanoparticles as cores have been prepared. A zeolitic imidazolate framework-8 (ZIF-8) layer has been coated on the outer surface of the DOX/BSA core. The ZIF layer acts as a capsule for the safe storage of DOX under physiological conditions. An efficient pH-responsive drug delivery system using a BSA/DOX@ZIF, in which the drug is not released in PBS at pH 7.4 but is released at low pH (5.0-6.0), has been constructed. Compared to the pure ZIF, a better biocompatibility has been obtained using the BSA/DOX@ZIF. The BSA/DOX@ZIF shows a much higher efficacy than free DOX against the breast cancer cell line MCF-7. The positive charges on the outer surface of the BSA/DOX@ZIF also improve its cellular uptake. PMID- 30014061 TI - A novel route to prepare N-graphene/SnO2 composite as a high-performance anode for lithium batteries. AB - In this study, we report a simple method to prepare nitrogen-doped graphene, with which a nitrogen-doped graphene/SnO2 composite was successfully fabricated and employed as a lithium battery anode. Electrochemical test results indicated that the as-prepared nitrogen-doped graphene/SnO2 electrode possesses high reversible capacity and outstanding charging and discharging capabilities, which would make it possible to meet the requirements for portable electronic devices in the future. These super electrochemical properties could benefit from the synergistic effect of SnO2 nanoparticles that contribute to the high capacity and nitrogen doped graphene that could enhance the electroconductivity. Moreover, the graphene nanosheet provides a large specific surface area for SnO2 nanoparticles to anchor on, which could efficiently overcome the structure destruction of SnO2-based electrodes during continuous charging and discharging tests. This concept can offer a general approach toward designing anode materials with better performance. PMID- 30014062 TI - Modelling mass balance of cadmium in paddy soils under long term control scenarios. AB - A simple mathematical model on the basis of the mass balance principle was developed to simulate the long-term changes of Cd in paddy soils. The model predicted the dynamics of cadmium concentration in soils under six alternative control scenarios, including rice straw incorporation into fields (A), removing straw from fields (B), irrigating paddies with groundwater (C), reducing atmospheric Cd deposition (D), liming (E), and integrating measures (F), which were used for Cd contaminated paddy fields in the central subtropical areas of China. The uncertainty of parameters was analyzed using Monte Carlo methods. Scenario simulation results showed that atmospheric deposition was the main external source of Cd, contributing 70% of the total inputs, and plant uptake was an important output pathway, responsible for 92% of the total outputs. Removing straw from fields was more effective than other single control scenarios, and integrating measures were more effective in lowering Cd concentration in contaminated paddy soils. The Cd concentration in soils can meet the critical value (0.3 mg kg-1) in a low-level Cd contaminated paddy field (0.68 mg kg-1) with integrating measures through 40 years of cultivation. In the same case, a high-level Cd contaminated field (1.48 mg kg-1) was converted to a low-level Cd contaminated field (0.54 mg kg-1). However, long term use of lime can increase the Cd concentration in paddy soils. Controllable factors that affected Cd accumulation in paddy soils were plant uptake factors, and the atmospheric deposition flux and irrigation water flux of Cd. Therefore, integrating measures including removing rice straw and preventing the emission of Cd into the atmosphere and irrigation water was the optimal approach to lower Cd concentration in contaminated paddy soils. PMID- 30014063 TI - Prediction of DNA and RNA structure with the NARES-2P force field and conformational space annealing. AB - A physics-based method for the prediction of the structures of nucleic acids, which is based on the physics-based 2-bead NARES-2P model of polynucleotides and global-optimization Conformational Space Annealing (CSA) algorithm has been proposed. The target structure is sought as the global-energy-minimum structure, which ignores the entropy component of the free energy but spares expensive multicanonical simulations necessary to find the conformational ensemble with the lowest free energy. The CSA algorithm has been modified to optimize its performance when treating both single and multi-chain nucleic acids. It was shown that the method finds the native fold for simple RNA molecules and DNA duplexes and with limited distance restraints, which can easily be obtained from the secondary-structure-prediction servers, complex RNA folds can be treated with using moderate computer resources. PMID- 30014064 TI - Nalpha-Amino acid containing privileged structures: design, synthesis and use in solid-phase peptide synthesis. AB - Fmoc-protected Nalpha-amino acid containing heterocyclic privileged structures, O (1-methyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-l-serine and O-((S)-5-oxo-2,3,5,7a tetrahydro-1H-pyrrolizin-7-yl)-l-serine, were synthesized on the solid phase from simple commercially available building blocks under mild conditions. The amino acid side-chain is composed of tetramic acid, a natural product derived privileged structure. The key transformation was the formation of cyclic enol ethers via nonclassical Wittig olefinations of the esters. Solid-phase synthesis represents a method of choice, particularly for the synthesis of peptides. This route is compatible with traditional Merrifield solid-phase peptide synthesis (SPPS), as documented on the preparation of the pentapeptide Leu-enkephalin amide H-Tyr-Gly-Gly-Phe-Leu-NH2 with Phe or Tyr replaced by a novel amino acid. PMID- 30014065 TI - Harnessing volatile luminescent lanthanide complexes to visualise latent fingermarks on nonporous surfaces. AB - Two commercially-available terbium and europium complexes, EuFOD and TbTMHD, provide luminescent visualisation of latent fingermarks placed on nonporous surfaces via sublimation. This is demonstrated using UV radiation from a forensic light source. The method was optimised on metal foil, with other archetypal nonporous surfaces (i.e. glass, ceramic) also suited to this method. PMID- 30014066 TI - The novel synthesis of a continuous tube with laminated g-C3N4 nanosheets for enhancing photocatalytic activity and oxygen evolution reaction performance. AB - Novel tubular graphitic carbon nitride has been successfully prepared via electrospinning technology, high temperature calcination technology, a vapor deposition reaction method and the method of acid removal, and in this process, Al2O3 fibers used as a template can help achieve the controllable preparation of GCNTs. Structural characterization results reveal that the as-prepared sample has the same composition as bulk graphitic carbon nitride and verify the well-defined tubular morphology of the graphitic carbon nitride tubes, which have a diameter of about 270 nm and a wall thickness of 30 nm. With regard to the photocatalytic activity of the sample, the degradation of organic dyes under visible light irradiation was carried out and cycling experiments were conducted, and the results indicated that the prepared sample has visible light catalytic activity and great stability. The specific tubular structure of graphitic carbon nitride will provide more active sites and higher reaction efficiency with potential application to waste treatment. When applied as an electrocatalyst in the oxygen evolution reaction (OER), GCNTs deliver a current density of 10 mA cm-2 at an overpotential of 360 mV with a Tafel slope of only 40 mV dec-1, and demonstrate excellent long term durability. PMID- 30014068 TI - A plausible model correlates prebiotic peptide synthesis with the primordial genetic code. AB - Aminoacyladenylates (5'-aa-AMPs) are key intermediates in peptide synthesis. Here we report analogs of 5'-aa-AMPs, namely nucleotide amidates (aa-N-NMPs), obtained under Hadean conditions. Significantly, dipeptides were detected from the above reactions and their yields varied with different nucleosides through the formation of different aa-N-NMPs. This model provides both prebiotic peptides and the primordial version of the genetic code through reactions that occurred under potentially prebiotic conditions. PMID- 30014069 TI - The new diphosphanylphosphido complexes of tungsten(vi) and molybdenum(vi). Their synthesis, structures and properties. AB - We report on the reactivity of R2P-P(Li)-PR'2 (R = tBu, iPr, R' = NEt2, iPr) towards diimido complexes [(dippN)2MCl2.dme] (M = Mo, W and dipp = 2,6-iPr2C6H3). A series of new complexes with diphosphanylphosphido ligands R2P-P-PR'2 were isolated. The solid-state structures of [(dippN)2M(Cl)(1,2-eta-iPr2P-P-PiPr2)] (2Mo and 2W) and [(dippN)2M(Cl){1,2-eta-tBu2P-P-P(NEt2)2}] (3Mo and 3W) were established by single-crystal X-ray diffraction analysis and indicate a side-on geometry of the R2P-P-PR'2 moiety. 3W and 3Mo are the first triphosphorus complexes with the amido ligand NEt2 on the P atom. [(dippN)2M(Cl)(1,2-eta-tBu2P P-PtBu2)] (1Mo and 1W) and 3Mo and 3W display similar side-on geometry in solution and in the solid state. By contrast, 2Mo and 2W reveal a dynamic behavior in solution. For the first time, the reactivity of diphosphanylphosphido complexes towards different nucleophiles was studied. The complexes react with the phosphorus nucleophile Ph2PLi, yielding phosphanylphosphinidene complexes [(dippN)2M(Cl)(eta2-P-PR2)]- Li+ (M = Mo, W) together with related diphosphanes R'2P-PPh2. Carbon nucleophile MeLi does not yield [(dippN)2M(Cl)(eta2-P-PR2)]- Li+ but substitutes a Cl ligand at the metal center. Moreover, we compare the coordination of the R2P-P-PR'2 moiety to different metal centers based on DFT methods. PMID- 30014070 TI - Assembly of three-dimensional binary superlattices from multi-flavored particles. AB - Binary superlattices constructed from nano- or micron-sized colloidal particles have a wide variety of applications, including the design of advanced materials. Self-assembly of such crystals from their constituent colloids can be achieved in practice by, among other means, the functionalization of colloid surfaces with single-stranded DNA sequences. However, when driven by DNA, this assembly is traditionally premised on the pairwise interaction between a single DNA sequence and its complement, and often relies on particle size asymmetry to entropically control the crystalline arrangement of its constituents. The recently proposed "multi-flavoring" motif for DNA functionalization, wherein multiple distinct strands of DNA are grafted in different ratios to different colloids, can be used to experimentally realize a binary mixture in which all pairwise interactions are independently controllable. In this work, we use various computational methods, including molecular dynamics and Wang-Landau Monte Carlo simulations, to study a multi-flavored binary system of micron-sized DNA-functionalized particles modeled implicitly by Fermi-Jagla pairwise interactions. We show how self-assembly of such systems can be controlled in a purely enthalpic manner, and by tuning only the interactions between like particles, demonstrate assembly into various morphologies. Although polymorphism is present over a wide range of pairwise interaction strengths, we show that careful selection of interactions can lead to the generation of pure compositionally ordered crystals. Additionally, we show how the crystal composition changes with the like-pair interaction strengths, and how the solution stoichiometry affects the assembled structures. PMID- 30014071 TI - High-precision digital droplet pipetting enabled by a plug-and-play microfluidic pipetting chip. AB - Emerging demands for handling minute liquid samples and reagents have been constantly growing in a wide variety of medical and biological areas. This calls for low-volume and high-precision liquid handling solutions with ease-of-use and portability. In this article, a new digital droplet pipetting method is introduced for the first time, derived from the microfluidic impact printing principle. Configured as a conventional handheld pipette, the prototype device consists of a plug-and-play and disposable microfluidic pipetting chip, driven by a programmable electromagnetic actuator for on-demand dispensing of nanoliter droplets. In particular, the impact-driven microfluidic pipetting chip, in place of the traditional disposable pipette tips, offers both liquid loading and droplet generation. The printing nozzle has been micro-fabricated using a femtosecond laser with a super-hydrophobic structure, in order to minimize the dispensing residues. As a result of the high-precision droplet dispensing principle, the variations of the dispensed volume have been successfully reduced from 49.5% to 0.6% at 0.1 MUL, as compared to its commercial counterparts. A proof-of-concept study for concentration dilution and quantitative analysis of cell drug resistance has been carried out by using the digital droplet pipetting system, demonstrating its potential in a broad range of biomedical applications which require both high precision and low-volume processing. PMID- 30014073 TI - Mobility of hydrous species in amorphous calcium/magnesium carbonates. AB - Amorphous calcium carbonate (ACC) is commonly found in many biological materials. As ACC readily crystallizes into calcite, stabilizers, such as anions, cations or macromolecules, often occur to avoid or delay unwanted crystallization. In biogenic ACC, magnesium is commonly present as one of the stabilizing agents. It is generally thought that the presence of mobile water in ACC is responsible for its limited stability and that the strong interaction of Mg2+ with water stabilizes the amorphous structure by retarding dehydration of ACC. To test this hypothesis, we studied the mobility of hydrous species in the model materials ACC, amorphous magnesium carbonate (AMC) and amorphous calcium/magnesium carbonate (ACMC), using quasi elastic neutron scattering (QENS) which is highly sensitive to the dynamics of H atoms. We discovered that hydrous species in the considered amorphous materials consist of water and hydroxide ions, as magnesium ions are incorporated in a ratio of 1 to about 0.6 with OH-. Surprisingly, we found that there is no evidence of translational diffusion of water and hydroxides when calcium is present in the samples, showing that hydrous species are highly static. However, we did observe diffusion of water in AMC with similar dynamics to that found for water in clays. Our results suggest that Mg2+-water interactions alone are not the only reason for the high stability of AMC and ACMC. The stabilizing effect of Mg ions, in addition to Mg-water binding, is likely to be caused by binding to hydroxide in amorphous calcium carbonates. In fact, the incorporation of hydroxides into the amorphous phase results in a mineral composition that is incompatible with any of the known Ca/Mg-carbonate crystal phases, requiring large scale phase separation to reach the composition of even the basic magnesium carbonate minerals artinite and hydromagnesite. PMID- 30014074 TI - Effect of spectrin network elasticity on the shapes of erythrocyte doublets. AB - Red blood cell (RBC) aggregates play an important role in determining blood rheology. RBCs in plasma or polymer solution interact attractively to form various shapes of RBC doublets, where the attractive interactions can be varied by changing the solution conditions. A systematic numerical study on RBC doublet formation is performed, which takes into account the shear elasticity of the RBC membrane due to the spectrin cytoskeleton, in addition to the membrane bending rigidity. RBC membranes are modeled by two-dimensional triangular networks of linked vertices, which represent three-dimensional cell shapes. The phase space of RBC doublet shapes in a wide range of adhesion strengths, reduced volumes, and shear elasticities is obtained. The shear elasticity of the RBC membrane changes the doublet phases significantly. Experimental images of RBC doublets in different solutions show similar configurations. Furthermore, we show that rouleau formation is affected by the doublet structure. PMID- 30014075 TI - Combined solid-state NMR, FT-IR and computational studies on layered and porous materials. AB - Understanding the structure-property relationship of solids is of utmost relevance for efficient chemical processes and technological applications in industries. This contribution reviews the concept of coupling three well-known characterization techniques (solid-state NMR, FT-IR and computational methods) for the study of solid state materials which possess 2D and 3D architectures and discusses the way it will benefit the scientific communities. It highlights the most fundamental and applied aspects of the proactive combined approach strategies to gather information at a molecular level. The integrated approach involving multiple spectroscopic and computational methods allows achieving an in depth understanding of the surface, interfacial and confined space processes that are beneficial for the establishment of structure-property relationships. The role of ssNMR/FT-IR spectroscopic properties of probe molecules in monitoring the strength and distribution of catalytic active sites and their accessibility at the porous/layered surface is discussed. Both experimental and theoretical aspects will be considered by reporting relevant examples. This review also identifies and discusses the progress, challenges and future prospects in the field of synthesis and applications of layered and porous solids. PMID- 30014076 TI - Sensitive and rapid detection of pathogenic bacteria from urine samples using multiplex recombinase polymerase amplification. AB - Bacterial infections may cause severe diseases such as tuberculosis, sepsis, nephritis and cystitis. The rapid and sensitive detection of bacteria is a prerequisite for the treatment of these diseases. The current gold standard for bacterial identification is bacteriological culture. However, culture-based identification takes 3-7 days, which is time-consuming and laborious. In this study, bacteria in urine samples were enriched using a portable filter-based pipette. Then, a centrifugal chip was constructed to detect multiple pathogenic bacteria from urine samples by integrating the DNA extraction, multiplex recombinase polymerase amplification (RPA) and fluorescent detection together. This eliminated the time-consuming cultivation step, and thus accelerated the diagnosis of the urinary tract infections (UTIs). The five major pathogenic bacteria in UTIs were detected in this study, which are Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Salmonella typhimurium. Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Staphylococcus aureus were successfully detected with limits of detection of 100 CFU mL-1 from urine samples within 40 min. Salmonella typhimurium was successfully detected with a limit of detection of 1000 CFU mL-1 from urine samples. The chip-based bacteria detection proposed in this study is a promising tool for sensitive, accurate, and multiplex identification of bacteria in clinical urine samples of UTIs and bacteriuria. PMID- 30014077 TI - Surface aging investigation by means of an AFM-based methodology and the evolution of conservative nanoscale interactions. AB - The divergence in physical properties of surfaces exposed to airborne contaminants in the atmosphere has been widely investigated in recent years, but agreement regarding the role that airborne hydrocarbons and water contamination have on surface property evolution remains elusive. Here we investigate the evolution of a freshly grown highly oriented pyrolytic graphite (HOPG) surface exposed to a controlled environment solely containing airborne water contamination, i.e. water vapor. Our approach combines standard electromagnetic spectrum-based spectrometry methods and atomic force microscopy based techniques to provide a holistic view of the surface properties. We provide evidence of the affect that water adsorption kinetics has on surface properties, interpreting time dependent force-distance profiles and force of adhesion maps directly obtained from the standard observables in a bimodal AFM. To demonstrate the generality of our approach we also apply it to aged calcite surfaces, proving its advantages in providing comprehensive transient characterization of surfaces with sufficient spatial resolution. PMID- 30014079 TI - Tailoring the components and morphology of discharge products towards highly rechargeable Li-CO/CO2 batteries. AB - A new non-aqueous Li-CO/CO2 battery with the main discharge products being Li2CO3 and carbon is introduced for the first time. Our findings demonstrate that with the addition of CO, the components and morphology of the discharge products are skillfully tailored, becoming more uniform, with poorer crystallinity and better conductivity. Thanks to these features, the utilization of a cathode in the Li CO/CO2 battery system is increased and the discharge products are more easily decomposed. These positive effects caused by CO endow the Li-CO/CO2 battery with enhanced electrochemical performances. PMID- 30014082 TI - Facile incorporation of technetium into magnetite, magnesioferrite, and hematite by formation of ferrous nitrate in situ: precursors to iron oxide nuclear waste forms. AB - The fission product, 99Tc, presents significant challenges to the long-term disposal of nuclear waste due to its long half-life, high fission yield, and to the environmental mobility of pertechnetate (TcO4-), the stable Tc species in aerobic environments. Migration of 99Tc from disposal sites can potentially be prevented by incorporating it into durable waste forms based on environmentally stable minerals. Since Tc(iv) and Fe(iii) have the same ionic radius, Tc(iv) can replace Fe(iii) in iron oxides. Environmentally durable iron oxides include goethite (alpha-FeOOH), hematite (alpha-Fe2O3), and magnesioferrite (MgFe2O4). The incorporation of Tc into two of these, hematite and magnesioferrite, as well as magnetite (Fe3O4) by means of simple, aqueous chemistry is presented starting from TcO4- in 5 M nitric acid. A combination of X-ray diffraction and X-ray absorption fine structure spectroscopy reveals that Tc(iv) replaces Fe(iii) within the iron oxide structures. Following incorporation, Tc doped samples were suspended in deionized water under aerobic conditions, and the release rates of Tc were determined. The results of this work show that Tc leaches more quickly from Fe3O4 than from alpha-Fe2O3 or MgFe2O4. Modeling the leach rates and comparison with the leach rate of Tc from TiO2 indicate that release of Tc is controlled by solid state diffusion. PMID- 30014083 TI - Unexpectedly efficient SO2 capture and conversion to sulfur in novel imidazole based deep eutectic solvents. AB - An innovative strategy for sustainable SO2 capture and conversion in novel imidazole-based deep eutectic solvents (DESs) is demonstrated in this work. These DESs exhibit an extremely high SO2 loading capacity (up to 1.39 g g-1) and excellent reversibility (15 recycles). The absorbed SO2 can be rapidly converted in situ to sulphur (up to 99% conversion) in the presence of H2S at room temperature without any additives. PMID- 30014081 TI - Ion mobility action spectroscopy of flavin dianions reveals deprotomer-dependent photochemistry. AB - The intrinsic optical properties and photochemistry of flavin adenine dinucleotide (FAD) dianions are investigated using a combination of tandem ion mobility spectrometry and action spectroscopy. Two principal isomers are observed, the more stable form being deprotonated on the isoalloxazine group and a phosphate (N-3,PO4 deprotomer), and the other on the two phosphates (PO4,PO4 deprotomer). Ion mobility data and electronic action spectra suggest that photo induced proton transfer occurs from the isoalloxazine group to a phosphate group, converting the PO4,PO4 deprotomer to the N-3,PO4 deprotomer. Comparisons of the isomer selective action spectra of FAD dianions and flavin monoanions with solution spectra and gas-phase photodissociation action spectra suggests that solvation shifts the electronic absorption of the deprotonated isoalloxazine group to higher energy. This is interpreted as evidence for significant charge transfer in the lowest optical transition of deprotonated isoalloxazine. Overall, this work demonstrates that the site of deprotonation of flavin anions strongly affects their electronic absorptions and photochemistry. PMID- 30014084 TI - Major compounds of red ginseng oil attenuate Abeta25-35-induced neuronal apoptosis and inflammation by modulating MAPK/NF-kappaB pathway. AB - beta-Amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD) is associated with complex mechanisms. Thus, a multi-target approach might be suitable for AD treatment. Following our previous study on the neuroprotective effects of red ginseng oil extract, its major compounds, including linoleic acid (LA), beta-sitosterol (BS), and stigmasterol (SS), were examined to elucidate the mechanism of anti-apoptosis and anti-inflammation in Abeta25-35-stimulated PC12 cells. The results showed that the three compounds mitigated Abeta25-35 toxicity by regulating oxidative stress, apoptotic responses, and pro-inflammatory mediators. LA and SS strongly regulated intrinsic apoptosis markers, such as mitochondrial membrane potential, intracellular Ca2+, Bax/Bcl-2 ratio, and caspases-9, -3, and -8. However, BS blocked only the intrinsic apoptotic pathway, particularly by suppressing Ca2+ accumulation. Furthermore, all three compounds downregulated iNOS and phospho-nuclear factor-kappaB, but only LA and SS inhibited the expression of cyclooxygenase-2 and phospho-IkappaB. In assays to evaluate MAPK expression for confirming upstream signal pathways, BS decreased the phosphorylation of p38 and ERK, but not JNK, while SS markedly decreased the phosphorylation of all three MAPKs, and LA clearly decreased the phosphorylation of ERK and JNK, but not p38. These results indicate that LA, BS, and SS act as neuroprotectives against Abeta25-35-induced injury by distinct molecular mechanisms, indicating their preventive and/or therapeutic potential to treat AD. PMID- 30014085 TI - Single-file transport of water through membrane channels. AB - Water at interfaces governs many processes on the molecular scale from electrochemical and enzymatic reactions to protein folding. Here we focus on water transport through proteinaceous pores that are so narrow that the water molecules cannot overtake each other in the pore. After a short introduction into the single-file transport theory, we analyze experiments in which the unitary water permeability, pf, of water channel proteins (aquaporins, AQPs), potassium channels (KcsA), and antibiotics (gramicidin-A derivatives) has been obtained. A short outline of the underlying methods (scanning electrochemical microscopy, fluorescence correlation spectroscopy, measurements of vesicle light scattering) is also provided. We conclude that pf increases exponentially with a decreasing number NH of hydrogen bond donating or accepting residues in the channel wall. The variance in NH is responsible for a more than hundredfold change in pf. The dehydration penalty at the channel mouth has a smaller effect on pf. The intricate link between pf and the Gibbs activation energy barrier, DeltaG?t, for water flow suggests that conformational transitions of water channels act as a third determinant of pf. PMID- 30014086 TI - Effects of intramolecular hydrogen bonding and sterically forced non-coplanarity on organic donor/acceptor two-photon-absorbing molecules. AB - Two photon absorption (2PA) is of great interest across many disciplines and there has been a large effort to increase the two-photon cross section (sigma2) via synthetic modification, especially by enhancing intramolecular charge transfer (ICT). This work takes the previously studied (7-benzothiazol-2-yl-9,9 diethylfluoren-2-yl)diphenylamine (AF240), an asymmetric D-pi-A chromophore, and intentionally appends a functional group (-OH, AF240-OH or -OCH3, AF240-OMe) to the 6-position of the fluorenyl pi-bridge of the new chromophores. Electrochemical results in both dichloromethane and acetonitrile support stabilization of the highest occupied molecular orbital in the derivatives due to inductive electron donating effects of the hydroxy and methoxy groups. The lowest unoccupied molecular orbital is stabilized via intramolecular hydrogen bonding to the benzothiazole moiety in the case of AF240-OH. As previously observed for AF240, the steady-state emission spectra show significant solvatochromism as they broaden and red shift with increasing solvent polarity. The fluorescence lifetimes and quantum yields show that the non-radiative rate constant is increased for AF240-OH in all solvents, especially in nonpolar media. The results suggest there is forced intramolecular hydrogen bonding to the benzothiazole in nonpolar solvents because the solvent poorly solubilizes the hydroxy group. This increases the non-radiative decay rate constant (knr) via additional vibrational decay pathways. While not as dramatic, the increase in knr in polar solvents supports some deactivation via hydrogen bonding to the solvent. Steric effects are also observed in the methoxy derivative, which inhibits planarization of the benzothiazole with the fluorene, increasing the energy of the excited state. Ultrafast transient absorption spectroscopy in tetrahydrofuran solution supports stabilization of the excited state in a few ps as solvent and structural reorganizations occur. In the case of AF240-OH, no evidence of proton transfer is observed. The decrease in emission energies in the case of AF240-OH support increased ICT driven by higher degree of coplanarity and the quinoidal structure in the excited state. However, a moderate increase in the intrinsic 2PA cross section is resulted. It is likely because of the two possible and competing solvent-stabilized ICT processes (PICT and TICT) in AF240-OH. Nevertheless, the strategic presence of a hydroxide group capable of intramolecular hydrogen bonding in AF240-OH provides a much broader 2PA sensitivity window than AF240. PMID- 30014087 TI - Understanding mode-specific dynamics in the local mode representation. AB - Mode specificity is a main characteristic of transition state control of reaction dynamics. The normal mode representation has been widely employed to describe the mode specificity in elementary chemical reactions. However, spectroscopists have demonstrated that the local mode representation has advantages in analyzing the overtone and combination band spectra. In this work, the mode-specific reaction dynamics between the hydrogen atom and the molecules H2S and H2O is studied using a full-dimensional quantum scattering model in the (2 + 1) Radau-Jacobi coordinates. The mode specificities in the reactions that violates our physical intuition in the normal mode representation are well rationalized in the local mode representation. The energy flow between different XH bonds resulting from the intramolecular interaction and/or intermolecular interaction is unveiled, together with its impacts on dynamics of the abstraction and exchange reactions. PMID- 30014088 TI - Need for Further Analysis in Cognitive Outcomes of Children Born Preterm. PMID- 30014089 TI - Reforming Payment for Primary Care-It's Not Just the Money, It's the Payment System. PMID- 30014090 TI - Additional Factors Regarding Clinical Outcomes of General Anesthesia and Conscious Sedation for Acute Ischemic Stroke. PMID- 30014092 TI - Review: In adults with type 1 diabetes, SGLT-2 inhibitors reduce HbA1c but increase diabetic ketoacidosis. PMID- 30014091 TI - Review: In type 2 diabetes, SGLT-2 inhibitors or GLP-1 agonists reduce mortality vs control or DPP-4 inhibitors. PMID- 30014093 TI - Review: In uncontrolled, persistent asthma, adding LAMAs to inhaled corticosteroids reduce exacerbations. PMID- 30014094 TI - Review: SMART reduces asthma exacerbations compared with other controller and relief therapy regimens. PMID- 30014095 TI - Review: More-intensive vs less-intensive LDL-cholesterol lowering reduces mortality. PMID- 30014096 TI - Review: In noncardiac surgery, amiodarone, beta-blocker, or statin prophylaxis reduces postoperative AF. PMID- 30014097 TI - Review: After PCI in AF, OAC plus single vs dual antiplatelets reduces major bleeding; no difference for MACE. PMID- 30014099 TI - Review: Postdischarge home interventions can increase or decrease falls in older adults. PMID- 30014098 TI - Review: Evidence is inconclusive on metabolic surgery vs medical treatment for microvascular complications in T2DM. PMID- 30014100 TI - In IBS with constipation, plecanatide reduced abdominal pain and increased bowel movements at 12 wk. PMID- 30014101 TI - Scrutiny-Dependent Cancer and Self-fulfilling Risk Factors. PMID- 30014102 TI - Scrutiny-Dependent Cancer and Self-fulfilling Risk Factors. PMID- 30014103 TI - An Adventure in Open Payments. PMID- 30014104 TI - An Adventure in Open Payments. PMID- 30014105 TI - An Adventure in Open Payments. PMID- 30014106 TI - Whole-Exome Sequencing in Adults With Chronic Kidney Disease. PMID- 30014107 TI - Whole-Exome Sequencing in Adults With Chronic Kidney Disease. PMID- 30014108 TI - Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease. PMID- 30014109 TI - Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease. PMID- 30014110 TI - The Letter. PMID- 30014111 TI - unforgotten. PMID- 30014113 TI - Web Exclusive. Annals Story Slam - Seeing the Body, or Two Sparks. PMID- 30014112 TI - Web Exclusive. Annals for Hospitalists Inpatient Notes - Bedrest Is Toxic-Why Mobility Matters in the Hospital. PMID- 30014114 TI - Web Exclusive. Annals Story Slam - Getting to Know My People. PMID- 30014115 TI - Web Exclusive. Annals Story Slam - Death of a Patient. PMID- 30014116 TI - Web Exclusive. Annals Story Slam - Who Knew? PMID- 30014117 TI - Web Exclusive. Annals Story Slam - Only at Temple. PMID- 30014118 TI - Web Exclusive. Annals Story Slam - A Time to Die. PMID- 30014119 TI - Web Exclusive. Annals Story Slam - The Gift. PMID- 30014120 TI - Web Exclusive. Annals Story Slam - The Little Things. PMID- 30014121 TI - Web Exclusive. Annals Story Slam - But You Used to Be a Man. PMID- 30014122 TI - Web Exclusive. Annals Story Slam - Clerks, Codes, and Culture, or "We Weren't Even Supposed to Be Here!" PMID- 30014123 TI - Annals for Educators - 17 July 2018. PMID- 30014125 TI - Correction: Issues Surrounding Age-Adjusted D-Dimer Cutoffs. PMID- 30014124 TI - Annals for Hospitalists - 17 July 2018. PMID- 30014126 TI - Web Exclusive. Annals Consult Guys - A Stumper: How Much Spent for How Much Prevention? PMID- 30014127 TI - Early Experiences With Journal Data Sharing Policies: A Survey of Published Clinical Trial Investigators. PMID- 30014128 TI - Comparison of Antibiotic Prescribing in Retail Clinics, Urgent Care Centers, Emergency Departments, and Traditional Ambulatory Care Settings in the United States. PMID- 30014129 TI - Association Between Marketplace Policy and Public Coverage Among Medicaid or Children's Health Insurance Program-Eligible Children and Parents. PMID- 30014130 TI - Overprescription in Urgent Care Clinics-The Fast and the Spurious. PMID- 30014131 TI - Introducing JAMA Internal Medicine Patient Pages. PMID- 30014132 TI - Errors in the Table and Results. PMID- 30014133 TI - Associations Between the Patient Protection and Affordable Care Act Medicaid Primary Care Payment Increase and Physician Participation in Medicaid. AB - Importance: The Patient Protection and Affordable Care Act (ACA) increased 2013 to 2014 Medicaid payment rates for qualifying primary care physicians (PCPs) and services to higher Medicare payment levels, with the goal of improving primary care access for Medicaid enrollees. Objectives: To evaluate the payment increase policy and to assess whether it was associated with changes in Medicaid participation rates or Medicaid service volume among PCPs. Design, Setting, and Participants: This study used 2012 to 2015 IMS Health aggregated medical claims and encounter data from PCPs eligible for the payment increase practicing in all states except Alaska and Hawaii and included 20 723 PCPs with observations in each month from January 1, 2012, to December 31, 2015. Data are for professional services performed in ambulatory settings, including office, hospital outpatient department, and emergency department. Regression models were used to test whether outcomes differed in months subject to higher payment rates relative to months before the increase and after the expiration of the increase in some states. The models controlled for time-invariant physician characteristics and time-varying characteristics, such as Medicaid enrollment. Interaction terms were included to estimate differential associations in subgroups of states (eg, by Medicaid managed care penetration) and physicians (eg, by specialty). Main Outcomes and Measures: Physician-month records subject to higher Medicaid payment rates were flagged using state-specific implementation and end dates for the payment increase. Five outcomes were measured for each physician-month observation, including (1) an indicator for seeing any patients enrolled in Medicaid, (2) an indicator for seeing more than 5 patients enrolled in Medicaid, (3) the Medicaid share of total patients, (4) a count of new patient evaluation and management visits furnished to patients enrolled in Medicaid, and (5) a count of existing patient evaluation and management visits furnished to patients enrolled in Medicaid. Results: Among 20 723 PCPs, the payment increase had no association with PCP participation in Medicaid or Medicaid service volume. The estimated average marginal effects for all 5 outcomes were not statistically distinguishable from 0. This null result was robust to sensitivity analyses, including different time trend specifications and analyses focusing on the payment increase implementation and expiration time frames. Descriptively, the Medicaid share of patients increased by about 25% from 2012 to 2015, although the share did not increase differentially in states and months subject to higher payment rates. Conclusions and Relevance: The limited duration and design of the payment increase may have dampened its effectiveness. Future efforts to improve access through payment changes or other means can benefit from better understanding of the outcomes of this policy. PMID- 30014134 TI - I Have a Cold-What Do I Need to Know? PMID- 30014135 TI - Additional Factors Regarding Clinical Outcomes of General Anesthesia and Conscious Sedation for Acute Ischemic Stroke. PMID- 30014136 TI - Perinatal Marijuana Use and the Developing Child. PMID- 30014137 TI - Assessment of Patterns of Potentially Unsafe Use of Zolpidem. PMID- 30014138 TI - Need for Further Analysis in Cognitive Outcomes of Children Born Preterm. PMID- 30014140 TI - Making the Voices of Female Trainees Heard. PMID- 30014142 TI - A New Tool for Clinical Neuroscience-Synaptic Imaging. PMID- 30014141 TI - Association of Self-regulation With Obesity in Boys vs Girls in a US National Sample. AB - Importance: Poor self-regulation in childhood is associated with increased risk of obesity. However, studies have assumed that greater self-regulation is associated with a lower obesity risk and have rarely examined differences in the association by sex. Objectives: To examine how different levels of toddler self regulation are associated with the prevalence of obesity at kindergarten age and whether the pattern of association is different between boys and girls. Design, Setting, and Participants: This was a prospective cohort study using data from the Early Childhood Longitudinal Study, Birth Cohort, a nationally representative sample of 10 700 US children born in 2001 and followed up through kindergarten entry (2006-2007). The analytic sample included 6400 children with observed toddler self-regulation. Data collection occurred in children's homes and consisted of a parent interview and direct assessment of the child. Data analysis took place between May 2016 and March 2018. Exposures: During a standardized, in home, developmental assessment at 24 months of age, observers scored 4 dimensions of children's self-regulation: adaptability, attention, persistence, and frustration tolerance. Self-regulation scores ranging from a low of 4 to a high of 20 were grouped into quartiles. Main Outcomes and Measures: With use of measured heights and weights at 5.5 years, obesity was defined as a body mass index for age in the 95th percentile or greater. Results: The analytic sample consisted of 6400 children (3250 boys [50.6%, weighted]), with a median age of 24.1 months (interquartile range, 23.4-24.7 months) and 64.5 months (interquartile range, 61.7-67.6 months) at the self-regulation and body mass index assessments, respectively. Self-regulation scores were lower for boys than for girls (mean, 13.7 [95% CI, 13.4-13.9] vs 14.9 [95% CI, 14.7-15.1]), and the lowest self-regulation quartile comprised more boys than girls (weighted percentages, 66.5% vs 33.5%). The prevalence of obesity at 5.5 years was 19.2% among boys and 16.5% among girls. The pattern of association between toddler self regulation and obesity at 5.5 years was different for boys and girls (P = .008 for interaction). Among boys, the adjusted prevalence of obesity was 19.7%, 18.3%, 20.3%, and 15.9% from lowest to highest quartile of self-regulation. In contrast, among girls, there was a U-shaped association (adjusted prevalence of obesity from lowest to highest self-regulation quartile, 17.0%, 10.3%, 10.7%, and 15.0%). Conclusions and Relevance: In a large national cohort of US children, there were differences between boys and girls in the pattern of the association between self-regulation at 24 months and obesity at 5.5 years of age. Obesity prevention efforts aimed at improving self-regulation may have different results for girls and boys. PMID- 30014139 TI - Quality and Quantity of Sleep and Factors Associated With Sleep Disturbance in Hospitalized Patients. AB - Importance: Although inadequate sleep has a proven negative association with health care outcomes, to date, no large-scale studies have examined sleep in general hospital wards. Objectives: To assess the subjective quantity and quality of sleep and to identify the hospital-related factors associated with sleep disturbances in hospitalized patients. Design: For this nationwide, single-day, multicenter, cross-sectional, observational study, which took place on February 22, 2017, all hospitals in the Netherlands were encouraged by word of mouth and conventional and social media to participate in this study. A total of 39 hospitals participated. Included patients were at least 18 years of age, were able to give informed consent, and had spent at least 1 night in a regular-care hospital ward. Exposures: Hospitalization in a regular-care ward. Main Outcomes and Measures: Quantity and quality of last night's sleep in the hospital compared with habitual sleep at home the month before hospitalization. The Consensus Sleep Diary and the Dutch-Flemish Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance item bank were used. Complementary questions assessed sleep-disturbing factors. Results: A total of 2005 patients were included (median age, 68 years; interquartile range, 57-77 years; 994 of 1935 [51.4%] were male [70 patients did not identify their sex]). Compared with habitual sleep at home, the total sleep time in the hospital was 83 minutes (95% CI, 75-92 minutes; P < .001) shorter. The mean number of nocturnal awakenings was 2.0 (95% CI, 1.9-2.1) times at home vs 3.3 (95% CI, 3.2-3.5) times during hospitalization (P < .001). Patients woke up 44 minutes (95% CI, 44-45 minutes; P < .001) earlier than their habitual wake-up time at home. A total of 1344 patients (70.4%) reported having been awakened by external causes, which in 718 (35.8%) concerned hospital staff. All aspects of sleep quality measured using PROMIS questions were rated worse during hospitalization than at home. The most reported sleep-disturbing factors were noise of other patients, medical devices, pain, and toilet visits. Conclusions and Relevance: This study demonstrated that the duration and quality of sleep in hospitalized patients were significantly affected and revealed many potentially modifiable hospital-related factors negatively associated with sleep. Raising awareness about the importance of adequate sleep in the vulnerable hospital population and introducing interventions to target sleep-disturbing factors may improve healing. PMID- 30014143 TI - Data Sharing Statements for Clinical Trials: One Step Down the Road. PMID- 30014144 TI - Zika in 2018: Advising Travelers Amid Changing Incidence. PMID- 30014146 TI - Need for Further Analysis in Cognitive Outcomes of Children Born Preterm. PMID- 30014147 TI - Fertility Preservation Discussions With Male Adolescents With Cancer and Their Parents: "Ultimately, It's His Decision". PMID- 30014145 TI - Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging. AB - Importance: Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective: To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants: This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5 trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as 11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (11C-PiB) for beta-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures: Outcomes were 11C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results: Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] beta-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] beta-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by 11C-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 0.56; P = .01). Conclusions and Relevance: To our knowledge, this is the first study to investigate synaptic density in vivo in AD using 11C-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses. PMID- 30014149 TI - Minimizing Sleep Disruption for Hospitalized Patients: A Wake-up Call. PMID- 30014148 TI - Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders. AB - Importance: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. Objective: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. Design, Setting, and Participants: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. Main Outcomes and Measures: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. Results: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P = .04) in children and 5.5 (95% CI, 1.4-22.5; P = .02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity. Conclusions and Relevance: Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy. PMID- 30014150 TI - Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota: A Systematic Review. AB - Background: Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood. Purpose: To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics. Data Sources: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018. Study Selection: RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition. Data Extraction: 4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results. Data Synthesis: Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators. Limitation: Journal publication processes may have affected the completeness of reporting; only English-language publications were examined. Conclusion: Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data. Primary Funding Source: No specific funding. PMID- 30014151 TI - Is the Over-the-Counter Availability of Human Insulin in the United States Good or Bad? PMID- 30014152 TI - Media Dissemination of the Montreal Cognitive Assessment After President Donald Trump's Medical Evaluation. PMID- 30014153 TI - Additional Factors Regarding Clinical Outcomes of General Anesthesia and Conscious Sedation for Acute Ischemic Stroke-Reply. PMID- 30014154 TI - Limbic Encephalitis in Patients with Epilepsy-is Quantitative MRI Diagnostic? AB - PURPOSE: Limbic encephalitis (LE) is an immune-related disease with limbic symptoms, variable and asymmetric magnetic resonance imaging (MRI) aspects and antibody profiles. This study investigated the diagnostic value of quantitative relaxation times T2 (qT2) and MRI signal intensities (SI) in LE. METHODS: The prospective 3T-MRI study included 39 epilepsy patients with initially suspected LE and 20 healthy controls. Values and asymmetry indices of qT2, T2-weighted (T2 w) and proton density (PD)-w SI of manually delineated and automatically segmented amygdala and hippocampus were measured. Additionally, two raters made a blinded visual analysis on FLAIR (fluid attenuation inversion recovery) and T2-w images. RESULTS: According to diagnostic guidelines, 22 patients had probable LE and 17 patients had possible LE. The qT2 was higher (p < 0.01) in patients than in controls (mean +/- SD, amygdala 98 +/- 7 ms vs. 90 +/- 5 ms, hippocampus 101 +/- 7 ms vs. 92 +/- 3 ms), but was not different between probable and possible LE or between sides (left and right). The PD-w SI and T2-w SI were lower in patients than in controls but were not different between patient subgroups or between sides. Diagnostic performance of visual analysis was relatively poor. CONCLUSIONS: Epilepsy patients with suspected LE had elevated qT2 in amygdala and hippocampus, whereas the expected T2-w SI increase was not found; however, the diagnostic value of qT2 remains questionable since it did not discriminate probable from possible LE. PMID- 30014156 TI - Bisphosphonate use after clinical fracture and risk of new fracture: response to comments by Wu et al. PMID- 30014157 TI - Role of musculoskeletal disorders in falls of postmenopausal women. AB - : We aimed to investigate the role of musculoskeletal disorders (MSDs) as risk factors for falls among postmenopausal women. Our results indicate that MSDs are common and are associated with increased falling risk, especially nonslip falls. Excess number of falls due to MSDs is greater than that due to any other disease class. PURPOSE: Falls are a major public health problem worldwide. The aim of the study was to investigate the role of MSDs as risk factors for falls among postmenopausal women. METHODS: This cohort study utilized data from a population based, prospective cohort study (OSTPRE). The study population consisted of 8656 women aged 57-66 years (in 1999) living in Kuopio Province, Eastern Finland, who responded to postal enquiries in 1999 and 2004. Information on MSDs and other morbidities was obtained from the 1999 enquiry and information on falls from the 2004 enquiry. Women were classified as fallers or non-fallers according to their falling events in the preceding 12 months. The fallers were further divided into women with slip and nonslip falls. RESULTS: Of the study sample, 53.3% reported a MSD and 39.2% reported a fall during the preceding 12 months. MSDs predicted falls (OR = 1.38; 95% CI 1.26-1.50) and the association was stronger for nonslip (OR = 1.56; 95% CI 1.39-1.75) than slip falls (OR 1.22; 95% CI 1.08-1.38) compared to the women without MSDs. The risk of falls increased with increasing number (1, 2, >= 3) of MSDs: 1.25 (95%CI 1.13-1.38), 1.48 (95%CI 1.30-1.68), and 1.92 (95%CI 1.60-2.31), respectively. After adjustments, the risk of falling related to MSDs reduced by about 5% (adjusted p < 0.001). The population attributable fraction of falls due to MSDs was 10.3% of all falls, greater than that due to any other disease class. CONCLUSION: MSDs are common and an important risk factor for falls and especially nonslip falls among postmenopausal women. The number of excess falls due to MSDs in this population group is greater than that due to any other disease class. PMID- 30014155 TI - Phosphate wasting disorders in adults. AB - A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments. PMID- 30014158 TI - Nonlinear association between bone mineral density and all-cause mortality: the Dong-gu study. AB - : There was a U-shaped association between hip BMD and all-cause mortality, with the lowest mortality in the 90th percentile in males. However, there was an inverse linear relationship in females. In contrast, the association between lumbar spine BMD and mortality was less evident in males, with no association in females. INTRODUCTION: Bone mineral density (BMD) is reported inversely associated with mortality. Although some previous studies provided evidence for nonlinear associations, these were not adequately assessed in most previous works. METHODS: We evaluated the nonlinear relationship between BMD and mortality in Asians. Our study involved 8629 participants in the Dong-gu study from 2007 to 2010. Cox proportional hazard regression was used to calculate hazard ratios (HRs) according to BMD categories after adjusting for potential confounders. During a follow-up of 6.7 +/- 1.4 years, 712 participants died. RESULTS: There was a U-shaped association between hip BMD and all-cause mortality, with the lowest mortality in the 90th percentile in males. However, there was an inverse linear relationship in females. In males, compared with the 75th to 95th percentile group, the < 2.5th percentile group had a 3.89 (95% CI 2.41-6.28)-fold higher risk and the 2.5th to 5th percentile group had a 2.51 (95% CI 1.25-5.04) fold higher risk. The HR was 2.51 (95% CI 1.25, 5.04) in the > 97.5th percentile group. In females, compared with that in the 75th to 95th percentile group, the HR was 2.33 (95% CI 1.24, 4.39) in the < 2.5th percentile group. In contrast, the association between lumbar spine BMD and mortality was less evident in males, with no association in females. CONCLUSION: In conclusion, this study shows that the association between BMD and mortality varies by gender and that high and low BMD are predictors of all-cause mortality in males. PMID- 30014160 TI - Following the crowd: patterns of crowdsourcing on Twitter among urologists. AB - PURPOSE: To examine patterns of crowdsourcing on the social media platform Twitter among urologists. METHODS: Urologists' public Twitter accounts were reviewed for original posts seeking clinical advice or feedback, and associated reply posts, before and after the 140-character-limit expansion in 2017. Predictors of responses to crowdsourcing requests were determined using multivariable regression. When patient data were posted, we noted whether consent was documented. RESULTS: A total of 276 posts in 23 crowdsourcing requests prior to character-limit expansion were analyzed. Reasons for crowdsourcing included requesting solutions to a clinical dilemma (82 posts, 30%); advice seeking about a surgical plan (77 posts, 28%); surveying colleagues' experiences with a new product (64 posts, 23%); and soliciting feedback about a proposed course of action (53 posts, 19%). Recent completion of training (as a proxy for inexperience) did not appear to disproportionately motivate crowdsourcing; authors' median time in practice was 7 years, and authors practicing for <= 7 years initiated 57% of requests. 22 (96%) crowdsourcing requests received >= 1 reply. Of 15 requests about a specific patient, eight included imaging, but only one cited patient consent. A second analysis of 184 posts in 17 crowdsourcing requests initiated after character-limit expansion demonstrated significantly more authors replying per request (P = 0.01), but no change in the frequency of patient-specific crowdsourcing or citation of consent. CONCLUSIONS: Urologists are leveraging Twitter for crowdsourcing clinical guidance and experiential knowledge. Nearly all requests were answered, suggesting low barriers to entry for novice users. Even after character-limit expansion, dissemination of potentially identifiable patient data remains a concern. PMID- 30014162 TI - Study of a reactor model for enzymatic reactions in continuous mode coupled to an ultrasound bath for esters production. AB - The main objective of this work was to investigate the enzymatic production of ethyl esters in continuous mode coupled to an ultrasound bath. For esterification reactions soybean free fatty acids (FFA) and ethanol were used as substrates, and Novozym 435 and Lipozyme TL IM, as catalysts. The experimental system consisted of a packed bed glass reactor immersed in an ultrasound bath and the following variables were studied: ethanol to FFA molar ratio of 1:1, 1:3 and 1:6, substrates flow rate of 2.5 and 5 mL/min, at 65 degrees C and 132 W ultrasound power output. It was noticed that the excess alcohol favored the esterification reaction with the best conversions observed, 95%, at 6 min reaction for 1:6 FFA to ethanol molar ratio, 2.5 mL/min feeding flow rate. Increasing the substrates feeding flow rate decreased the conversion down to 87% and replacing the Novozym 435 by Lipozyme TL IM no satisfactory conversions were achieved. This type of reactor demonstrated good performance for ethyl esters production, opening promising perspectives for use in the production of other types of esters such as those aromatic and others with high value. PMID- 30014161 TI - Occupational emphysema in South African miners at autopsy; 1975-2014. AB - PURPOSE: To determine the associations between exposure duration, measured by employment tenure, and emphysema presence and severity in black and white South African miners at autopsy. METHODS: We examined the association between mining tenure and emphysema presence or severity using the Pathology Automation (PATHAUT) database, 1975-2014. We used logistic regression models adjusted for age, tuberculosis, HIV status, and year of death. The effect of smoking on the presence and severity of emphysema was assessed in a sub-analysis of white miners. RESULTS: Mining tenure was significantly associated with increased odds of emphysema presence in black and white miners. For every 10-year increase in tenure, black miners had a 17% increase in odds of emphysema [ORblack = 1.17 (95% CI 1.12, 1.22)] and white miners had a 7% increase in odds of the disease [ORwhite = 1.07 (95% CI 1.04, 1.10)]. Tenure was significantly associated with emphysema severity among black miners [ORseverity = 1.16 (95% CI 1.06, 1.28)]. In a subset of white miners with smoking status, we found that for every 10 years of tenure, there is a significant increase in odds of emphysema presence and severity [ORpresence = 1.14 (95% CI 1.09, 1.19); ORseverity = 1.06 (95% CI 1.00, 1.10)] after adjusting for smoking. CONCLUSIONS: We observed a significant relationship between mining tenure and emphysema severity among South African miners in PATHAUT between 1975 and 2014. This relationship was evident in multi variable analyses adjusted for smoking among white miners. Hazards from long term exposure to inhaled mineral dust leading to lung damage (silicosis, fibrosis, COPD) is evident and warrants further improvement of working conditions and prevention measures in South African mines especially for black workers. Further research is needed to determine if there is an effect of TB and HIV co-infection on the development of emphysema. PMID- 30014159 TI - AtDIV2, an R-R-type MYB transcription factor of Arabidopsis, negatively regulates salt stress by modulating ABA signaling. AB - KEY MESSAGE: AtDIV2 integrates ABA signaling to negatively regulate salt stress in Arabidopsis. AmDIV (DIVARICATA) is a functional MYB transcription factor (TF) that regulates ventral identity during floral development in Antirrhinum. There are six members of DIV homologs in Arabidopsis; however, the functions of these proteins are largely unknown. Here, we characterized an R-R-type MYB TF AtDIV2, which is involved in salt stress responses and abscisic acid (ABA) signaling. Although universally expressed in tissues, the nuclear-localized AtDIV2 appeared not to be involved in seedling development processes. However, upon exposure to salt stress and exogenous ABA, the transcripts of AtDIV2 are markedly increased in wild-type (Wt) plants. The loss-of-function mutant div2 displayed much more tolerance to salt stress, and several salt-responsive genes were up-regulated. In addition, the div2 mutant showed higher sensitivity to ABA during seed germination. And the germination variance between the Wt and div2 mutant cannot be rectified by treatment with both ABA and sodium tungstate at the same time. ELISA results showed that the endogenous ABA content in the div2 mutant is clearly increased than that in Wt plants. Furthermore, the transcriptional expressions of several ABA-related genes, including ABA1 and ABI3, were elevated. Taken together, our results suggest that the R-R-type MYB TF AtDIV2 plays negative roles in salt stress and is required for ABA signaling in Arabidopsis. PMID- 30014163 TI - Selective capture and sensitive fluorometric determination of Pseudomonas aeruginosa by using aptamer modified magnetic nanoparticles. AB - A fluorometric assay is described for the detection of the food pathogen Pseudomonas aeruginosa (P. aeruginosa). It is based on the hybridization of aptamer and fluorescein-labeled complementary DNA (FAM-cDNA) in combination with magnetic separation. In the absence of P. aeruginosa, FAM-cDNA is assembled on the surface of aptamer modified magnetic particles (MNPs) via hybridization between aptamer and cDNA. Upon addition of P. aeruginosa, FAM-cDNA is replaced by the bacteria and released from the MNPs since the aptamer preferentially binds to bacteria. After magnetic separation, the amount of bacteria can be quantified by determination of the fluorescence intensity (lambdaexc/em = 494/525 nm) of the supernatant containing the released FAM-cDNA. This kind of assay allows for both selective enrichment and sensitive fluorometric determination of bacteria in a single step. The assay has a response to the logarithm of P. aeruginosa concentration that is linear in the range between 10 and 108 cfu.mL-1, with a detection limit as low as 1 cfu.mL-1. The detection process can be finished within <1.5 h. The feasibility of the assay was verified by detecting P. aeruginosa in spiked food samples. Graphical abstract Hybridization of aptamer and carboxyfluorescein labeled complementary DNA is combined with magnetic separation for detection of as low as 1 cfu.mL-1 Pseudomonas aeruginosa. This kind of assay allows for both selective enrichment and sensitive fluorometric determination of bacteria in a single step. PMID- 30014164 TI - The yield of full BRCA1/2 genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations. AB - PURPOSE: BRCA1 and BRCA2 genotyping results have clinical implications for cancer risk assessment and targeted therapy. Current practice in Israel is to genotype for the predominant BRCA1/2 mutations first, followed by full gene analysis in eligible mutation-negative individuals. This work assessed the rate of non predominant mutations in BRCA1/2 in ethnically diverse high-risk cases. METHODS: Breast and/or ovarian cancer patients who tested negative for the predominant BRCA1/2 mutations were referred for comprehensive BRCA1/2 genotyping if calculated risk for carrying a BRCA mutation was >= 10%. RESULTS: Of 1258 eligible patients, 41 (3.3%) carried one of 38 mutations: 3% of Ashkenazi Jews and 3.4% of mixed ethnicities. Detection rate was < 5% among patients diagnosed with cancer younger than 40 or with bilateral breast cancer, and was 5.5% of ovarian cancer patients. Three of the carriers (7.3%) carried gene rearrangements. Three mutations were reported in more than one case. CONCLUSIONS: The overall yield of comprehensive BRCA1/2 testing in ethnically diverse high risk Israeli individuals is 3.3%. This is lower than expected by probability models. A slightly higher rate of BRCA1/2 carriers was seen among ovarian cancer cases. These data should guide BRCA1/2 optimal testing strategy in Israel. PMID- 30014165 TI - A comparison of orofacial profiles in 5- and 10-year-old Swedish children with and without cleft lip and/or palate. AB - OBJECTIVES: The objectives of this study were to assess orofacial profiles in 5- and 10-year-old children with cleft lip and/or palate (CL/P) compared to controls and to estimate a possible association between orofacial dysfunction and caries frequency. MATERIALS AND METHODS: A total of 133 children with CL/P (77 5-year olds and 56 10-year-olds) and 308 controls (142 5-year-olds and 166 10-year-olds) were included in the study. Orofacial function was evaluated with Nordic Orofacial Test-Screening (NOT-S), and caries were scored according to the International Caries Detection and Assessment System (ICDAS). RESULTS: The total NOT-S score was higher in children with CL/P compared to controls (mean 3.2 vs 0.9, p < 0.001). The domains frequently scored in CL/P children were speech (82%), face at rest (72%), and facial expression (58%). There was a significantly positive correlation between NOT-S scores and caries frequency. CONCLUSIONS: Children with CL/P have impaired orofacial function compared to controls. There seems to be a correlation between orofacial function and caries. CLINICAL RELEVANCE: Impaired orofacial function seen in children with CL/P can be one of many risk factors for caries development, and it is suggested to be a part of caries risk assessment. PMID- 30014166 TI - Is the pneumatisation of the maxillary sinus following tooth loss a reality? A retrospective analysis using cone beam computed tomography and a customised software program. AB - OBJECTIVES: To compare the dimensions of maxillary sinuses in dentate and edentulous patients using cone beam computed tomography (CBCT) scans and a customised software program. MATERIALS AND METHODS: This study comprised CBCTs of 50 dentate and 50 edentulous posterior maxillae. The observers drew two planar curves in all included sinuses in the frontal, sagittal and axial planes of the respective CBCT scans. The volume (mm3), surface (mm2) and maximum diameter (mm) of the sinuses were calculated using a custom-made software program. The variables analysed were the influence of the state of dentition on sinus dimensions (primary outcome) and the influence of age, gender and side on sinus dimensions; the time needed for analysis; and the intra- and inter-observer agreement (secondary outcomes). RESULTS: There was no difference in sinus dimensions between dentate and edentulous posterior maxillae. Males had significantly (p < 0.05) greater volume, surface and diameter than females. Strong intra- and inter-observer agreement (Pearson correlation) was found for the calculated sinus dimensions. The time needed per analysis was less than 4 min for both observers. CONCLUSIONS: Being edentulous did not have an impact on the sinus dimensions, suggesting that there is no ongoing pneumatisation in the sinus after tooth loss. Males had larger sinuses than females in a population older than 30 years. CLINICAL RELEVANCE: Following tooth loss in the posterior maxilla, vertical bone height is primarily lost due to resorption of the alveolar crest, and not due to pneumatisation of the maxillary sinus. The customised software program was found to be user-friendly and efficient. PMID- 30014167 TI - Perspective pinhole model with planar source for augmented reality surgical navigation based on C-arm imaging. AB - PURPOSE: For augmented reality surgical navigation based on C-arm imaging, accuracy of the overlaid augmented reality onto the X-ray image is imperative. However, overlay displacement is generated when a conventional pinhole model describing a geometric relationship of a normal camera is adopted for C-arm calibration. Thus, a modified model for C-arm calibration is proposed to reduce this displacement, which is essential for accurate surgical navigation. METHOD: Based on the analysis of displacement pattern generated for three-dimensional objects, we assumed that displacement originated by moving the X-ray source position according to the depth. In the proposed method, X-ray source movement was modeled as variable intrinsic parameters and represented in the pinhole model by replacing the point source with a planar source. RESULTS: The improvement which represents a reduced displacement was verified by comparing overlay accuracy for augmented reality surgical navigation between the conventional and proposed methods. The proposed method achieved more accurate overlay on the X-ray image in spatial position as well as depth of the object volume. CONCLUSION: We validated that intrinsic parameters that describe the source position were dependent on depth for a three-dimensional object and showed that displacement can be reduced and become independent of depth by using the proposed planar source model. PMID- 30014168 TI - Metabolic engineering strategies for enhanced shikimate biosynthesis: current scenario and future developments. AB - Shikimic acid is an important intermediate for the manufacture of the antiviral drug oseltamivir (Tamiflu(r)) and many other pharmaceutical compounds. Much of its existing supply is obtained from the seeds of Chinese star anise (Illicium verum). Nevertheless, plants cannot supply a stable source of affordable shikimate along with laborious and cost-expensive extraction and purification process. Microbial biosynthesis of shikimate through metabolic engineering and synthetic biology approaches represents a sustainable, cost-efficient, and environmentally friendly route than plant-based methods. Metabolic engineering allows elevated shikimate production titer by inactivating the competing pathways, increasing intracellular level of key precursors, and overexpressing rate-limiting enzymes. The development of synthetic and systems biology-based novel technologies have revealed a new roadmap for the construction of high shikimate-producing strains. This review elaborates the enhanced biosynthesis of shikimate by utilizing an array of traditional metabolic engineering along with novel advanced technologies. The first part of the review is focused on the mechanistic pathway for shikimate production, use of recombinant and engineered strains, improving metabolic flux through the shikimate pathway, chemically inducible chromosomal evolution, and bioprocess engineering strategies. The second part discusses a variety of industrially pertinent compounds derived from shikimate with special reference to aromatic amino acids and phenazine compound, and main engineering strategies for their production in diverse bacterial strains. Towards the end, the work is wrapped up with concluding remarks and future considerations. PMID- 30014169 TI - Identification and characterization of oxidoreductase component (NdmD) of methylxanthine oxygenase system in Pseudomonas sp. NCIM 5235. AB - Pseudomonas sp. NCIM 5235 is a caffeine-degrading bacterial strain that metabolizes caffeine by sequential demethylation using methylxanthine demethylases. These enzymes belong to the class of two-component Rieske oxygenases and require an oxidoreductase, NdmD, for efficient catalysis. NdmD in Pseudomonas sp. has a unique domain fusion in its N-terminal that is not observed in any other Rieske oxygenase reductases reported so far. In this report, a ~ 1.7 kb ndmD gene from the gDNA of Pseudomonas sp. has been isolated and has been cloned in a pET28a expression vector. Soluble NdmD was over-expressed in Escherichia coli BL21 cells and purified by Ni2+ NTA chromatography. Monomeric molecular mass of the protein was found to be ~ 65 kDa and optimal activity was observed at 35 degrees C and pH 8.0. It showed broad substrate specificity with highest Kcat/km of 490.8 +/- 17.7 towards cytochrome c. To determine the role of N-terminal Rieske domain in its reductase activity, two deletion constructs Delta114NdmD and Delta250NdmD were made. Cytochrome c reductase (ccr) activity of the NdmD constructs and demethylase activity of NdmA in the presence of NdmD constructs showed that there is no significant difference in the catalytic activity of NdmD upon deletion of its N-terminal Rieske domain. However, there might be some functional and evolutionary significance for the fusion of Rieske domain to NdmD and we hypothesize that this domain fusion is an intermediate phase of evolution towards the development of a more efficient enzyme system for xenobiotic degradation. PMID- 30014170 TI - Exito!: Making an Impact in Training Latinos for Doctorates and Cancer Research. AB - Latinos lag behind other racial/ethnic groups in pursuit of master's and doctoral degrees in public health and the health sciences. Exito! is modeled after the Minority Training Program in Cancer Control Research (MTPCCR), which found that Latino participants went on to doctoral programs at a lower rate (12%) than African American (36%) and Asian participants (33%). Exito! Latino Cancer Research Leadership Training is designed to increase the number of Latinos who pursue doctoral degrees and careers in cancer health disparity (CHD) research. The program has three components: recruitment with partnering universities and associations, an ethnically tailored intensive 5-day summer institute (SI), and 6 month paid internships offered on a competitive basis. Up to 20 master's level students/master's level health professionals are selected annually to participate in the SI; faculty are leaders in Latino CHD research. Funded by the National Cancer Institute (NCI) from 2011 to 2015, Exito! recruited 101 summer institute participants and awarded 21 internships. Analyses of pre- and post-institute surveys showed significant increases in confidence to apply to a doctoral program and academic self-efficacy among summer institute participants, and significantly increased research skills among interns. Forty-three percent of Exito! program alumni applied to a doctoral program (our main outcome) and 29.7% were currently enrolled. This is nearly double the rate for MTPCCR Latino participants (17%) for the corresponding time period. Exito! is a model pipeline program for encouragement of Latinos on to doctoral programs (e.g., PhD and DrPH) with the potential to increase the pool of cancer health disparity researchers. PMID- 30014171 TI - Development of a Cancer Self-management Education Programme for Women with Breast Cancer at the End of Primary Treatment. AB - Breast cancer survivors have specific healthcare needs. As a result of their disease and treatment, they have to adapt to different physical and psychosocial late effects. Unfortunately, several studies have documented insufficiency in the survivorship healthcare system. The aim of this paper was to describe the process of development and testing of a novel Cancer Self-management Education programme (CSME programme) to improve patient-reported self-management and self-efficacy for patients with breast cancer who were at the end of primary treatment. The development of the educational programme was inspired by the Plan-Do-Study-Act (PDSA) circle and based on person-centred principles. It was conducted at a Danish university hospital. Nine oncology healthcare providers, two external experts in patient education and five patients were involved in the development and testing of the education programme. Implementation of dialogue-based tools was used as an educational learning instrument in the SCME programme. The PDSA approach to the development of the CSME programme resulted in a person-centred programme that could improve self-management and self-efficacy in the survivorship phase of patients with breast cancer. PMID- 30014173 TI - Cellular self-assembly into 3D microtissues enhances the angiogenic activity and functional neovascularization capacity of human cardiopoietic stem cells. AB - While cell therapy has been proposed as next-generation therapy to treat the diseased heart, current strategies display only limited clinical efficacy. Besides the ongoing quest for the ideal cell type, in particular the very low retention rate of single-cell (SC) suspensions after delivery remains a major problem. To improve cellular retention, cellular self-assembly into 3D microtissues (MTs) prior to transplantation has emerged as an encouraging alternative. Importantly, 3D-MTs have also been reported to enhance the angiogenic activity and neovascularization potential of stem cells. Therefore, here using the chorioallantoic membrane (CAM) assay we comprehensively evaluate the impact of cell format (SCs versus 3D-MTs) on the angiogenic potential of human cardiopoietic stem cells, a promising second-generation cell type for cardiac repair. Biodegradable collagen scaffolds were seeded with human cardiopoietic stem cells, either as SCs or as 3D-MTs generated by using a modified hanging drop method. Thereafter, seeded scaffolds were placed on the CAM of living chicken embryos and analyzed for their perfusion capacity in vivo using magnetic resonance imaging assessment which was then linked to a longitudinal histomorphometric ex vivo analysis comprising blood vessel density and characteristics such as shape and size. Cellular self-assembly into 3D-MTs led to a significant increase of vessel density mainly driven by a higher number of neo capillary formation. In contrast, SC-seeded scaffolds displayed a higher frequency of larger neo-vessels resulting in an overall 1.76-fold higher total vessel area (TVA). Importantly, despite that larger TVA in SC-seeded group, the mean perfusion capacity (MPC) was comparable between groups, therefore suggesting functional superiority together with an enhanced perfusion efficacy of the neo vessels in 3D-MT-seeded scaffolds. This was further underlined by a 1.64-fold higher perfusion ratio when relating MPC to TVA. Our study shows that cellular self-assembly of human cardiopoietic stem cells into 3D-MTs substantially enhances their overall angiogenic potential and their functional neovascularization capacity. Hence, the concept of 3D-MTs may be considered to increase the therapeutic efficacy of future cell therapy concepts. PMID- 30014172 TI - PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF induced endothelial proliferation. AB - VEGF induces normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo. This transition depends on the balance between VEGF-induced endothelial stimulation and PDGF-BB-mediated pericyte recruitment, and co-expression of PDGF-BB normalizes aberrant angiogenesis despite high VEGF doses. We recently found that VEGF over-expression induces angiogenesis in skeletal muscle through an initial circumferential vascular enlargement followed by longitudinal splitting, rather than sprouting. Here we investigated the cellular mechanism by which PDGF-BB co-expression normalizes VEGF-induced aberrant angiogenesis. Monoclonal populations of transduced myoblasts, expressing similarly high levels of VEGF alone or with PDGF BB, were implanted in mouse skeletal muscles. PDGF-BB co-expression did not promote sprouting and angiogenesis that occurred through vascular enlargement and splitting. However, enlargements were significantly smaller in diameter, due to a significant reduction in endothelial proliferation, and retained pericytes, which were otherwise lost with high VEGF alone. A time-course of histological analyses and repetitive intravital imaging showed that PDGF-BB co-expression anticipated the initiation of vascular enlargement and markedly accelerated the splitting process. Interestingly, quantification during in vivo imaging suggested that a global reduction in shear stress favored the initiation of transluminal pillar formation during VEGF-induced splitting angiogenesis. Quantification of target gene expression showed that VEGF-R2 signaling output was significantly reduced by PDGF-BB co-expression compared to VEGF alone. In conclusion, PDGF-BB co expression prevents VEGF-induced aberrant angiogenesis by modulating VEGF-R2 signaling and endothelial proliferation, thereby limiting the degree of circumferential enlargement and enabling efficient completion of vascular splitting into normal capillary networks despite high VEGF doses. PMID- 30014174 TI - Optimization of alkaline pretreatment and enzymatic hydrolysis for the extraction of xylooligosaccharide from rice husk. AB - Rice husk (RH) is the major agricultural waste obtained during rice hulling process, which can be a sustainable source of xylooligosaccharide (XOS). The current study deals with the production of XOS from Thai rice husk using alkaline pretreatment and enzyme hydrolysis method. The response surface methodology consisted of central composite design and Box-Behnken design was employed to achieve the maximum response in alkaline pretreatment and XOS production, respectively. The optimum conditions for alkaline pretreatment to recover maximum xylan yield were 12-18% of alkaline concentration, the temperature at 110-120 degrees C, and steaming time for 37.5-40 min. The FTIR results suggested that the extracted sample was the xylan fraction. The maximum XOS production of 17.35 +/- 0.31 mg XOS per mL xylan was observed in the run conditions of 6.25 mg enzyme per g xylan, 9 h of incubation time, and 5% of xylan. The results revealed that the xylan extracted from RH by using an effective base couple with the steam application and the enzymatic hydrolysis help to maximize the yield of XOS, which can be further used in functional foods and dietary supplements. PMID- 30014176 TI - Incidence of diarrhea and associated risk factors in patients with traumatic brain injury and enteral nutrition. AB - To determine the occurrence of diarrhea and associated factors in critically ill patients with traumatic brain injury (TBI) in use of nutritional therapy. Prospective cohort study conducted in an Intensive Care Unit (ICU) of a General Hospital reference in trauma. We evaluated TBI patients who stayed less than 72 h in the ICU, who were using EN for at least 48 h. Definition of diarrhea it was considered three or more episodes of liquid stools or semi-liquid at 24 h. For analysis were evaluated demographic, epidemiological, clinical and nutritional data. Twenty-three patients were evaluated, being 86.9% male, median 33 years old (IQR = 25-52 years) and 16-day ICU stay (IQR = 10-26 days). Diarrhea occurred in 69.6% of the patients and they had a longer time in the ICU (p = 0.007). All patients who used combination prokinetic therapy (metoclopramide and erythromycin) and used antibiotics for more than 8 days had diarrhea (p = 0.057 and p = 0.007, respectively). The incidence of diarrhea was high in TBI patients with enteral nutrition and was associated with the use of antibiotics for more than one week. PMID- 30014177 TI - Calorie restriction protects against apoptosis, mitochondrial oxidative stress and increased calcium signaling through inhibition of TRPV1 channel in the hippocampus and dorsal root ganglion of rats. AB - The TRPV1 channel is activated in neurons by capsaicin, oxidative stress, acidic pH and heat factors, and these factors are attenuated by the antioxidant role of calorie restriction (CR). Hence, we investigated the hypothesis that the antioxidant roles of CR and food frequency (FF) may modulate TRPV1 activity and apoptosis through inhibition of mitochondrial oxidative stress in hippocampal (HIPPON) and dorsal root ganglion neurons (DRGN). We investigated the contribution of FF and CR to neuronal injury and apoptosis through inhibition of TRPV1 in rats. We assigned rats to control, FF and FF + CR groups. A fixed amount of food ad libitum was supplemented to the control and FF groups for 20 weeks, respectively. FF + CR group were fed the same amount of food as the control group but with 20% less calories during the same period. In major results, TRPV1 currents, intracellular Ca2+ levels, apoptosis, reactive oxygen species, mitochondrial depolarization, PARP-1 expression, caspase 3 and 9 activity and expression values were found to be increased in the HIPPON and DRGN following FF treatment, and these effects were decreased following FF + CR treatment. The FF induced decrease in cell viability of HIPPO and DRGN, and vitamin E concentration of brain, glutathione peroxidase, vitamin A, and beta-carotene values of the HIPPO, DRGN, plasma, liver and kidney were increased by FF + DR treatment, although lipid peroxidation levels in the same samples were decreased. In conclusion, CR reduces FF-induced increase of oxidative stress, apoptosis and Ca2+ entry through TRPV1 in the HIPPON and DRGN. Our findings may be relevant to the etiology and treatment of obesity following CR treatment. PMID- 30014178 TI - In vitro biocompatibility of orthodontic miniscrews with human gingival fibroblast and SAOS-2 osteoblast cultures. AB - PURPOSE: Miniscrews are an important choice for orthodontic anchorage. Yet reports on failures do exist, and attempts have been made to elucidate the causes. Clinical outcomes may be compromised not only by the mechanical implications of miniscrew design and the location of anchorage but also by poor biocompatibility. Hence, this study deals with the surface roughness and elemental composition of miniscrews and how these properties may affect the in vitro biocompatibility of four commercially available miniscrews. METHODS: Most of the currently available miniscrews are made of TiAl6V4, an alloy widely considered to be biocompatible. The samples tested in this study included four similarly dimensioned TiAl6V4 products from different manufacturers: tomas(r) by Dentaurum, OrthoEasy(r) by Forestadent(r), Dual TopTM by Jeil Medical/Promedia, and LOMAS by Mondeal(r). The surface properties of these products were characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and agar overlay assays according to ISO 10993 5. RESULTS: The miniscrew products were found to show variations in surface finish quality pertaining to topography and chemical composition, with the latter departing slightly from the manufacturers' specifications. MTT assays yielded rates of cell culture viability in excess of 90%, and agar overlay assays did not reveal decoloration beyond the specimen outlines in any of the experimental groups tested. CONCLUSIONS: The four miniscrew products exhibited some minor, but statistically significant, differences in microtopography, alloy composition, and biological inertness. Cytotoxicity testing revealed that all four products should be considered non-cytotoxic, thus, ruling out poor biocompatibility as a cause of miniscrew failure. PMID- 30014175 TI - IDO and TDO as a potential therapeutic target in different types of depression. AB - Depression is highly prevalent worldwide and a leading cause of disabilty. However, the medications currently available to treat depression fail to adequately relieve depressive symptoms for a large number of patients. Research into the aberrant overactivation of the kynurenine pathway and the production of various active metabolites has brought new insight into the progression of depression. IDO and TDO are the first and rate-limiting enzymes in the kynurenine pathway and regulate the production of active metabolites. There is substantial evidence that TDO and IDO enzyme are activated during depression, and therefore, IDO and TDO inhibitors have been identified as ideal therapeutic targets for depressive disorder. Hence, this review will focus on the kynurenine branch of tryptophan metabolism and describe the role of IDO and TDO in the pathology of depression. In addition, this review will compare the relative imbalance between KYNA and neurotoxic kynurenine metabolites in different psychiatric disorders. Finally, this review is also directed toward assessing whether IDO and TDO are potential therapeutic target in depression associated with other diseases such as diabetes and/or cancer, as well as the development of potent IDO and TDO inhibitors. PMID- 30014180 TI - What Differentiates Underserved Smokers Who Successfully Quit From Those Who Do Not. AB - Poor persons continue to smoke at high rates and suffer grave health effects. We have been working with our community partners since 2008 to help poor people in the surrounding neighborhoods stop smoking through a multi-phase CBPR intervention known as CEASE. Our study used qualitative methods to identify factors that characterized those who successfully quit smoking (doers) and those who did not (non-doers). Both doers and non-doers identified social pressure as the main reason for starting to smoke, and health as the main motivator for quitting. Although they were similar in many ways, the doers seemed to have more social support for cessation-i.e., more people in their lives who wanted them to quit and whom they wanted to protect from secondhand smoke. The non-doers offered more feedback on how to improve the cessation classes, including making them longer, reducing the class size, adding extra counseling, and using quitting partners. Both doers and non-doers reported increased self-confidence, appreciation for the cessation support they received from CEASE, and a desire that the group classes continue. Cessation is a social event and smokers with more social support appear to be more successful at quitting. Showing interest in and offering social support to poor underserved smokers in their own communities is a powerful way to help them. PMID- 30014179 TI - Biomechanical properties of CAD/CAM-individualized nickel-titanium lingual retainers: an in vitro study. AB - PURPOSE: This study aimed to determine and compare the mechanical properties of novel CAD/CAM(computer-aided design/manufacturing)-individualized nickel-titanium (NiTi) and conventional twisted wires. METHODS: Seven NiTi wires (angular, 0.20 * 0.20 mm up to 0.50 * 0.50 mm) and two twisted steel wires (round, 0.40 mm and 0.44 mm) were investigated in three-point (3PBT) and four-point bending tests (4PBT) using the Orthodontic Measurement and Simulation System. All wires were loaded up to a distance of 3.3 mm, and resulting forces were measured. Additionally, in the biomechanical test (BMT), CAD/CAM-individualized NiTi retainers (0.35 * 0.35 mm) were subjected to intrusive and extrusive deformation of 0.1, 0.2, and 0.4 mm. RESULTS: For twisted wires, typical plastic deformations were found in 3PBT (0.40 mm: 0.3 mm; 0.44 mm: 0.4 mm), and maximum resulting forces for these reached 1.3 N and 3.2 N for the 0.40 mm and 0.44 mm wires, respectively. Corresponding values in the 4PBT totaled 0.8 N for the 0.40 mm and 1.9 N for the 0.44 mm twisted wire. The NiTi samples showed plastic deformations in the 3PBT for the 0.25 * 0.25 mm dimension and in 4PBT for the 0.35 mm * 0.35 mm version. At a deflection of 1.5 mm, both tests revealed significantly different forces for the NiTi wires of different dimensions (p <= 0.001). In the BMT, no remarkable loading plateau or plastic deformation was observed. The resulting forces were significantly higher for extrusive than for intrusive deformation (p <= 0.001). CONCLUSIONS: Individualized NiTi retainers feature specific elasticity and dimensional stability, and more deflection is necessary to achieve permanent deformations. The CAD/CAM production process did not significantly influence the biomechanical properties of the NiTi wires. PMID- 30014181 TI - Health Perception According to the Lifestyle of University Students. AB - University students are characterized by having inadequate eating habits, along with an unhealthy lifestyle, which, among other factors, can affect the perception they have of their state of health. The aim of the study was to evaluate the health perception of a group of university students according to lifestyle. A cross-sectional observational study was carried out on 214 university students from different universities and branches of knowledge. Anthropometric data were collected. Three questionnaires were administered: PREDIMED (Mediterranean Diet (MD) adherence), SF-36 (perception of health state) and GPAQ (physical activity (PA)). The differences between variables were analyzed using Student-t or Mann-Whitney U, Kruskal-Wallis and Pearson Chi-Square tests. Statistical significance was reached at p < 0.05. Most students were found to be normal weighted. The subjects presented an moderate MD adherence, this being better in Health Sciences students. 75.7% practiced light PA. The health perception is worse for most of the subscales analyzed than that of the reference population (except physical-function, physical-role, and emotional-role). There is an association between PA and health perception: students with intense PA have less body pain and better physical function; the less active, the less vitality. The more physically active subjects the greater MD adherence. Lifestyle and eating habits of health sciences students are healthier than that of students from other branches of knowledge. The physically active subjects have a better perception of quality of life-related to health and greater MD adherence. PMID- 30014182 TI - Impact of quantitative index derived from 123I-FP-CIT-SPECT on reconstruction with correction methods evaluated using a 3D-striatum digital brain phantom. AB - We evaluated quantitation accuracy of the specific binding ratio (SBR) and specific uptake ratio (SUR) of dopamine transporter for various correction methods by using a novel three-dimensional striatum digital brain (3D-SDB) phantom comprised of segments containing the striatum, ventricle, brain parenchyma, and skull bone extracted from T2-weighted MR images. A process image was reconstructed by projection data sets with blurring, scatter, and attenuation from 3D-SDB phantom data. A 3D-iterative reconstruction algorithm was used without correction (OSEM), or with scatter (SC), attenuation (AC), AC + SC (ACSC), AC + resolution recovery (RR; ACRR), SC + RR (SCRR), AC + SC + RR (ACSCRR), AC + SC + RR + partial volume (PVC; ACSCRRP), and AC + SC + RR + PVC + ventricle (ACSCRRPV). Data were then quantified using SBR and SUR. Differences between measured and true SBR values were (in order): ACSCRR < ACSC < ACRR < AC < SCRR < SC < OSEM: the maximal error was 45.3%. The trend of differences between measured and true SUR values was similar to that of SBR; maximal error was 65%. The ACSCRR-corrected SUR, which was closer to the true value, was underestimated by 30.4%. However, the ACSCRRP-corrected SUR was underestimated by a maximum of 22.5%. The SUR in the ACSCRRPV was underestimated by 6.2%. The accuracy of quantitation was improved using various types of compensation and correction. Accuracy improved more for the SUR when PVC and ventricle correction were added. PMID- 30014183 TI - How Harvard Defined Irreversible Coma. AB - The Harvard criteria for the definition of irreversible coma or brain death were a product of a multidisciplinary committee chaired by anesthesiologist Beecher. The Harvard criteria included unreceptivity, unresponsiveness, no movements or breathing, no reflexes with further delineation of brainstem reflexes, and a flat electroencephalogram (repeated after 24 h with no change). The apnea test involved disconnection of the ventilator for 3 min. Hypothermia or any other central nervous system depressant had to be excluded. The Harvard criteria (and what followed) have been a bane for bioethicists from day one. This historical vignette explains, criticizes, and celebrates this landmark publication for its courage to tackle the topic. The Harvard criteria resulted in more studies and more criteria gradually complicating matters until the American Academy of Neurology in 1995 provided the necessary simplicity. PMID- 30014184 TI - Clinical Trial Protocol: Phase 3, Multicenter, Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Efficacy, and Safety Study Comparing EG-1962 to Standard of Care Oral Nimodipine in Adults with Aneurysmal Subarachnoid Hemorrhage [NEWTON-2 (Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After SubarachNoid Hemorrhage)]. AB - BACKGROUND: Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the PrecisaTM platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. RESULTS: A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2-4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine. CONCLUSIONS: The primary endpoint is the proportion of subjects with favorable outcome (6-8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632. PMID- 30014185 TI - Revision anterior cruciate ligament reconstruction restores knee laxity but shows inferior functional knee outcome compared with primary reconstruction. AB - PURPOSE: To evaluate and compare knee laxity and functional knee outcome between primary and revision anterior cruciate ligament (ACL) reconstruction in the same cohort of patients. METHODS: Patients who underwent primary and revision ACL reconstruction (ACLR) at Capio Artro Clinic, Stockholm, Sweden, from 2000 to 2015, were identified in our local database. Inclusion criteria were: same patients who underwent primary hamstring tendons (HT) and revision bone-patellar tendon-bone (BPTB) autograft ACLR, no associated ligament injuries and no contralateral ACL injuries/reconstructions. The cause of revision ACLR was graft rupture for all patients. The KT-1000 arthrometer, with an anterior tibial load of 134-N, was used to evaluate knee laxity preoperatively and 6-month postoperatively. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was collected preoperatively and at the 1-year follow-up. RESULTS: A total of 118 patients with primary and revision ACLR arthrometric laxity measurements were available (51.0% males; mean age at primary ACLR 21.7 +/- 7.1 years and revision ACLR 24.3 +/- 7.5 years). The mean preoperative and postoperative anterior side to-side (STS) difference values were not significantly different between primary and revision ACLR. However, primary ACLR showed a significantly higher frequency of postoperative anterior STS difference > 5 mm compared with revision ACLR (8.4 vs 5.0%; P = 0.02). The KOOS was available for primary and revision ACLR for 73 patients (55.4% males; mean age at primary ACLR 21.6 +/- 7 years and revision ACLR 24.7 +/- 7.3 years). Preoperatively, revision ACLR showed significantly higher scores in all KOOS subscales, except for the activity of daily living (ADL) subscale. For the primary ACLR, the improvement from preoperatively to the 1-year follow-up was significantly greater in all KOOS subscales and, the postoperative scores were superior for Pain, ADL and Sports subscales compared with revision ACLR. CONCLUSIONS: The findings of this study showed that anterior knee laxity is restored with revision BPTB autograft ACLR after failed primary HT autograft ACLR, in the same cohort of patients. However, revision ACLR showed a significantly inferior functional knee outcome compared with primary ACLR. It is important for clinicians to inform and set realistic expectations for patients undergoing revision ACLR. Patients must be aware of the fact that having revision ACLR their knee function will not improve as much as with primary ACLR and the final postoperative functional outcome is inferior. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 30014186 TI - Would program performance indicators and a nationally coordinated response accelerate the elimination of tuberculosis in Canada? AB - Twenty years ago, a National Consensus Conference on Tuberculosis (TB) recommended that the provinces and territories of Canada jointly declare a commitment to TB elimination with national coordination and assured funding, executed by a committee of federal and provincial/territorial representatives. Canada has committed to the global TB elimination targets set forth by the World Health Organization but lacks a coordinated response. In particular, with the exception of one published and implemented by Indigenous Services Canada, there has been no national monitoring and performance framework. Herein, we provide a commentary on the importance, to TB elimination in Canada, of developing such a framework. We invite a debate about whether more can and should be done to monitor and report for action at every jurisdictional level. Of utmost importance will be the need to achieve consensus from stakeholders about what is measured, among whom, how often, who collects and processes data, and how to respond to the successes and failures those data indicate. Insofar, as performance targets are well defined and implemented, national progress towards tuberculosis elimination should accelerate. PMID- 30014187 TI - China: concurring regulation of cross-border genomic data sharing for statist control and individual protection. AB - This paper reviews the major legal instruments and self-regulations that bear heavily on the cross-border sharing of genomic data in China. It first maps out three overlapping frameworks on genomic data and analyzes their underpinning policy goals. Subsequent sections examine the regulatory approaches with respect to five aspects of responsible use and sharing of genomic data, namely, consent, privacy, security, compatible processing, and oversight. It argues that substantial centralised control exerted by the state is, and would probably remain, the dominant feature of genomic data governance in China, though concerns of individual protection are gaining momentum. Rather than revolving around a simplistic antinomy between privacy preservation and open science, the regulatory landscape is mainly shaped by the tension between government desires for national security, state competitiveness, and public health benefits. PMID- 30014188 TI - Canada: will privacy rules continue to favour open science? AB - Canada's regulatory frameworks governing privacy and research are generally permissive of genomic data sharing, though they may soon be tightened in response to public concerns over commercial data handling practices and the strengthening of influential European privacy laws. Regulation can seem complex and uncertain, in part because of the constitutional division of power between federal and provincial governments over both privacy and health care. Broad consent is commonly practiced in genomic research, but without explicit regulatory recognition, it is often scrutinized by research or privacy oversight bodies. Secondary use of health-care data is legally permissible under limited circumstances. A new federal law prohibits genetic discrimination, but is subject to a constitutional challenge. Privacy laws require security safeguards proportionate to the data sensitivity, including breach notification. Special categories of data are not defined a priori. With some exceptions, Canadian researchers are permitted to share personal information internationally but are held accountable for safeguarding the privacy and security of these data. Cloud computing to store and share large scale data sets is permitted, if shared responsibilities for access, responsible use, and security are carefully articulated. For the moment, Canada's commercial sector is recognized as "adequate" by Europe, facilitating import of European data. Maintaining adequacy status under the new European General Data Protection Regulation (GDPR) is a concern because of Canada's weaker individual rights, privacy protections, and regulatory enforcement. Researchers must stay attuned to shifting international and national regulations to ensure a sustainable future for responsible genomic data sharing. PMID- 30014189 TI - [Becoming breastfeeding friendly in Germany-an international research project to assess the readiness to scale up breastfeeding]. AB - Despite known positive effects for breastfed children and their mothers, only one third of children under four months of age are breastfed exclusively. In addition, an overview of structures, actors, and measures to promote breastfeeding in Germany is missing. In a two-year international research project entitled Becoming Breastfeeding Friendly (BBF), the current status of German breastfeeding support is systematically evaluated on the basis of the Breastfeeding Gear Model (BFGM) which was developed by the Yale School of Public Health. Therefore, committee members with expertise in the healthcare sector, science, policy, and communication evaluate 54 benchmarks of the eight relevant gears: advocacy, political will, legislation & policies, funding & resources, training & program delivery, promotion, research & evaluation, coordination, and goals & monitoring. Based on the identified strengths and needs, concrete calls to action for scaling up breastfeeding promotion are derived and prioritized. BBF started in September 2017 and is conducted in cooperation with the Yale School of Public Health by the Healthy Start - Young Family Network as well as the National Breastfeeding Committee as an initiative of the Federal Ministry of Nutrition and Agriculture. The project assesses the framework conditions for breastfeeding and thus makes a valuable contribution to the health promotion of mother and child and to breastfeeding protection in Germany. PMID- 30014190 TI - [Medication safety in children : What role do dosing and formulations play?] AB - Medication errors are more common in children compared to adults due to often missing efficacy evidence and limited or missing regulatory approvals for paediatric drugs.Roots of errors are located at different levels. They result, for example, from missing clinical studies that particularly investigate efficacy and correct dosing in younger age groups, the lack of age-appropriate dosage forms, the use of harmful ingredients, as well as the complicated and high-risk prescribing process.Electronic systems may improve the quality of drug prescriptions and reduce medication errors. The basic assumption is valid, evidence-based data behind such a system. In contrast to other countries, such a database is not yet available in Germany. The Plan of Action for the improvement of medication safety in Germany 2016-2019 (Aktionsplan) contains an action point "Creation of a database for dosing of paediatric medicines". Initial funding for 2 years has been granted for its implementation.Through systematic literature searches and the availability and provision of up-to-date knowledge on paediatric medicines, medication safety for children and adolescents can be improved. A database with relevant information to support more correct prescriptions within the paediatric population appears productive. The Aktionsplan has paved the way for the dissemination of evidence-based drug information for the country's paediatric population. PMID- 30014191 TI - The prevalence and determinants of return to work in head and neck cancer survivors. AB - PURPOSE: To determine the prevalence of and factors associated with the reduction or complete cessation of employment following treatment in head and neck cancer survivors. METHODS: This cross-sectional study was conducted among head and neck cancer survivors visiting outpatient clinics at the Princess Margaret Cancer Centre over a period of 18 months. Participants at any point along their survivorship course completed a survey that included demographic information, the Radiation Therapy Oncology Group (RTOG) Work Status Questionnaire, the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), the M.D. Anderson Symptom Inventory-Head and Neck (MDASI-HN), the Cancer Survivors' Unmet Needs Measure (CaSUN), and the EuroQol EQ-5D-5L utility scale. RESULTS: Among 130 participants, 64 were employed at diagnosis. At the time of study, 31 (48%) had reduced their work, among whom, 21 (32.8%) had not returned to work at all following treatment. Pre-treatment employment status, cancer-related symptoms, quality of life, and health utility were associated with employment outcomes. CONCLUSION: A high proportion of head and neck cancer survivors reduced their work capacity and many did not return following cancer treatment. Further research is needed to understand the barriers to work return in these survivors and to explore strategies to encourage resumption of employment and employment satisfaction. PMID- 30014192 TI - Knowledge, fatigue, and cognitive factors as predictors of lymphoedema risk reduction behaviours in women with cancer. AB - OBJECTIVE: To identify social-cognitive factors predicting lymphoedema risk reduction behaviours (hereafter, self-care) after discharge among patients in Japan with breast or gynaecological cancers, using the extended model of the theory of planned behaviour. METHODS: A cross-sectional questionnaire study was conducted in an oncology hospital. Items measured were (1) knowledge about self care; (2) the Cancer Fatigue Scale; (3) social-cognitive factors in the theory of planned behaviour (attitudes, subjective norms, and perceived behavioural control); (4) self-care (limb hygiene, observation, articular movement, recommended risk-reduction behaviours in daily life, and diet and weight control); and (5) demographics. Of 202 respondents, 147 who had not been diagnosed with lymphoedema were eligible for statistical analysis (65.3% with gynaecological cancer, 34.7% with breast cancer). RESULTS: Structural equation modelling was used to examine a hypothesised model based on the theory of planned behaviour. The results revealed that a longer time since surgery, higher levels of fatigue, less knowledge, higher expected efficacy of self-care, and lower perceived behavioural control directly and significantly predicted less self-care behaviour. CONCLUSIONS: Besides education about self-care behaviour, levels of fatigue and perceived behavioural control should be taken into account to encourage female patients with cancer to perform self-care after discharge. Continuous psycho-educational programmes after discharge may help to facilitate self-care behaviours among long-term female cancer survivors. PMID- 30014193 TI - Quality of care in hospitalized cancer patients before and after implementation of a systematic prevention program for delirium: the DELTA exploratory trial. AB - BACKGROUND: We evaluated whether the DELirium Team Approach (DELTA) program-a systematic management program aimed at screening high-risk groups and preventing delirium-would improve quality of care in patients hospitalized with cancer. METHODS: A retrospective before-after study was conducted during a pre intervention period (between October 2012 and March 2013) and a post-intervention period (between October 2013 and March 2014) at a Japanese hospital providing specialized treatments for cancer. A total of 4180 inpatients were evaluated before the implementation of the DELTA program and 3797 inpatients were evaluated after implementation. RESULTS: After program implementation, the incidence of delirium decreased from 7.1 to 4.3% (odds ratio [OR], 0.52; 95% CI, 0.42-0.64). The incidence of adverse events, including falls or self-extubation, also decreased, from 3.5 to 2.6% (OR, 0.71; 95% CI, 0.54-0.92). There was a significant decrease in the prescription of benzodiazepines (OR, 0.79; 95% CI, 0.71-0.87), increase in the level of independence in activities of daily living at discharge (OR, 1.94; 95% CI, 1.11-3.38), and decrease in the length of stay (risk ratio 0.90; 95% CI, 0.90-0.90). CONCLUSIONS: The systematic management program for delirium decreased the incidence of delirium and improved several clinical outcomes. These data suggest that this simple cost-effective program is feasible and implementable as routine care in busy wards. PMID- 30014194 TI - Examining trajectories of anxiety in men with prostate cancer faced with complex treatment decisions. AB - PURPOSE: To examine changes in anxiety over time (trajectories) in men with prostate cancer faced with a decision to participate in a clinical trial and to identify demographic and study variables that predict these trajectories. METHODS: Our data come from a larger study examining the efficacy of a decision aid on decisional conflict in men with prostate cancer who were deciding whether to participate in a prostate cancer clinical trial. We used latent growth mixture models to identify 'classes' (i.e. groups) of participants with different trajectories of anxiety, as assessed by the State-Trait Anxiety Inventory state scale, and binary logistic regression to determine predictors of anxiety 'class'. RESULTS: In 128 men with prostate cancer (mean age = 63), growth mixture modelling identified two classes defined by different anxiety trajectories. One class (n = 27) started with a higher mean anxiety score and did not change over time (stable high), whereas the second class (n = 101) started with lower anxiety and significantly reduced over time (low and recovering). None of the demographic and study variables (including age, education, marital status, and decision to join the trial) was predictive of anxiety class. CONCLUSIONS: Men treated for prostate cancer who have high levels of anxiety after surgery may continue to have persistent high anxiety levels which do not reduce naturally over time. Patient or disease characteristics do not appear to predict anxiety. It is important, therefore, to monitor for anxiety in this population and refer for psychological interventions where required. PMID- 30014196 TI - Impact of East Coast fever on Grande Comore: assessment taking a participatory epidemiology approach. AB - East Coast fever (ECF), one of the most serious tick-borne diseases in sub Saharan and eastern Africa, was introduced to the island of Grande Comore in 2002 through zebu import from Tanzania, resulting in at least a 10% loss of livestock. A participatory epidemiology initiative was launched in 2015 to gain a better understanding of ECF epidemiology. Thirty-six villages were investigated involving 36 focus group sessions and 120 individual questionnaires. Farmers' knowledge of ECF and of priority diseases affecting the country was assessed, and the impacts of ECF and other major diseases were compared by a scoring method. The results showed that 69.4% (95% CI [51.3, 87.5%]) of the farmers had good to very good knowledge of ECF. The most important cattle diseases on Grande Comore were considered to be East Coast fever, heartwater, babesiosis, and cutaneous diseases. About 58% of the farmers (95% CI [49.2, 66.8%]) use curative treatments when cattle were sick. Between January and September 2015, the ECF incidence was estimated at 18.5% (95% CI [15.5, 21.4%]), and 87.5% (95% CI [72.7, 100%]) of the cattle infected by ECF died. The ECF incidence estimated in our study was found to be less when compared to that observed in Tanzania even though the climatic conditions in the Union of the Comoros are suitable for the biological vector of ECF, the tick species Rhipicephalus appendiculatus. Access to chemical treatment and its effectiveness against ECF, as well as controlling borders and organizing quarantine, are discussed. PMID- 30014195 TI - Contemporary perspectives of core stability training for dynamic athletic performance: a survey of athletes, coaches, sports science and sports medicine practitioners. AB - BACKGROUND: Core stability training has grown in popularity over 25 years, initially for back pain prevention or therapy. Subsequently, it developed as a mode of exercise training for health, fitness and sport. The scientific basis for traditional core stability exercise has recently been questioned and challenged, especially in relation to dynamic athletic performance. Reviews have called for clarity on what constitutes anatomy and function of the core, especially in healthy and uninjured people. Clinical research suggests that traditional core stability training is inappropriate for development of fitness for heath and sports performance. However, commonly used methods of measuring core stability in research do not reflect functional nature of core stability in uninjured, healthy and athletic populations. Recent reviews have proposed a more dynamic, whole body approach to training core stabilization, and research has begun to measure and report efficacy of these modes training. The purpose of this study was to assess extent to which these developments have informed people currently working and participating in sport. METHODS: An online survey questionnaire was developed around common themes on core stability training as defined in the current scientific literature and circulated to a sample population of people working and participating in sport. Survey results were assessed against key elements of the current scientific debate. RESULTS: Perceptions on anatomy and function of the core were gathered from a representative cohort of athletes, coaches, sports science and sports medicine practitioners (n = 241), along with their views on effectiveness of various current and traditional exercise training modes. Most popular method of testing and measuring core function was subjective assessment through observation (43%), while a quarter (22%) believed there was no effective method of measurement. Perceptions of people in sport reflect the scientific debate, and practitioners have adopted a more functional approach to core stability training. There was strong support for loaded, compound exercises performed upright, compared to moderate support for traditional core stability exercises. Half of the participants (50%) in the survey, however, still support a traditional isolation core stability training. CONCLUSION: Perceptions in applied practice on core stability training for dynamic athletic performance are aligned to a large extent to the scientific literature. PMID- 30014197 TI - Screening genetic diseases prevalence in Braunvieh cattle. AB - Heritable abnormalities can cause a reduction in productive performance, structural defects, or death of the animal. There are reports of hereditary abnormalities in Braunvieh cattle from several countries, but no evidence was found on their existence in Mexico. In this study, 28 genes associated with hereditary diseases were screened with the GGP-LD 30K array (GeneSeek(r)) in 300 Mexican registered Braunvieh animals. Allelic frequencies of the markers associated with illness were obtained for the following: citrullinaemia, spinal dysmyelination, spinal muscular atrophy, Brows Swiss fertility haplotype 2, congenital muscular dystonia, epidermolysis bullosa, Pompes, maple syrup urine, syndactyly, Weaver syndrome, crooked tail, deficiency of uridine monophosphate synthase, hypotrichosis, Marfan syndrome, and weak calf syndrome. The allelic frequency values were low for all the analysed loci (from 0.0015 to 0.0110), with exception of syndactyly (0.4145). Although homozygous animals for these genetic conditions were detected, no physical or physiological abnormalities associated with the clinical form of the diseases were observed in the sampled animals. Markers associated with a crooked tail, deficiency of uridine monophosphate synthase, hypotrichosis, Marfan syndrome, and weak calf syndrome were absent. The studied Mexican Braunvieh population does not present clinical or subclinical effects for ten diseases in homozygous animals. However, since the assessed animals are considered as breeding stock, the monitoring of carrier animals might be periodically necessary. PMID- 30014198 TI - [Physical medical aspects of early rehabilitation after proximal femoral fractures]. AB - Proximal femoral fractures in old age are known as fragility fractures. They are the sequelae of osteoporosis and an expression of a general reduced capacity and an increase in sensory and functional deficits against the background of multimorbidity. They are often caused by reduced compensation strategies. Simultaneously, for many older people they represent a life event. Despite modern osteosynthesis techniques and less stressful anesthesia procedures, the occurrence of a proximal femoral fracture shakes the labile equilibrium of those affected. Proximal femoral fractures are associated with a high risk of mortality. Only some 50% of those affected achieve the pretraumatic functional level again. Therefore, a comprehensive, multiprofessional and interdisciplinary management of these patients is required. The rehabilitation has to start at the time of diagnosis and at the latest after the operation with a comprehensive interdisciplinary management. Pain and complaints during the rehabilitation have to be clarified and targeted, mostly multimodal interventions, must be included. PMID- 30014199 TI - Meconium peritonitis: the role of postnatal radiographic and sonographic findings in predicting the need for surgery. AB - BACKGROUND: The role of imaging in meconium peritonitis is not limited to establishing a diagnosis; rather, it might also be helpful in determining which neonates require surgery. However, few data in the literature correlate the postnatal radiographic and sonographic findings with the need for surgery. OBJECTIVE: To compare the role of postnatal radiographic and sonographic findings in predicting the need for surgery in neonates with meconium peritonitis. MATERIALS AND METHODS: We conducted a retrospective analysis of clinical, imaging and surgical findings in all neonates with meconium peritonitis in the period 1999-2014. We divided the children into operative or non-operative groups and then correlated each group with the presence or absence of the following findings on both the radiographs and sonograms: peritoneal calcification, meconium pseudocyst, intestinal obstruction, volvulus, ascites and pneumoperitoneum. RESULTS: Thirty-seven neonates (22 males, 15 females) had meconium peritonitis in this period, of whom 23 (62%) required surgery and 14 (38%) were successfully treated non-surgically. None had an antenatal infection and three had cystic fibrosis (8%). Bowel obstruction identified on radiography (12/23, P=0.01) and sonography (9/23, P=0.04) and ascites identified with sonography (7/23, P=0.01) were associated with the need for surgical intervention. The presence of pneumoperitoneum and volvulus were also associated with surgical intervention. There was no significant statistical difference in the number of neonates with diffuse peritoneal calcification who were treated operatively or non-operatively. Four (33%) of the 12 neonates with meconium pseudocysts were successfully treated non-operatively. CONCLUSION: Imaging findings that predicted the need for surgery were intestinal obstruction, ascites, volvulus and pneumoperitoneum. Neonates with meconium pseudocysts did not require surgery if they were not associated with the described findings. The findings in our patients also indicate that those with diffuse peritoneal calcification as an isolated finding can be successfully treated non-operatively. PMID- 30014200 TI - Significance of pleural effusion at diagnosis in pediatric Hodgkin lymphoma: a report from Children's Oncology Group protocol AHOD0031. AB - BACKGROUND: Pleural effusion at presentation in Hodgkin lymphoma has been associated with inferior outcome but has not been systematically evaluated. OBJECTIVE: To determine whether pleural effusion at presentation in children with Hodgkin lymphoma is a primary indicator of poor prognosis or secondary to associated factors. MATERIALS AND METHODS: Children's Oncology Group (COG) AHOD0031, a randomized, response-based, centrally reviewed protocol, enrolled 1,712 eligible patients <22 years of age with initial presentation of intermediate risk, biopsy-proven Hodgkin lymphoma; 1,423 had available imaging for retrospective review. We coded effusions as fluid-only or with associated pleural nodule or adjacent lung or bone involvement and correlated this with disease stage, tumor response, large mediastinal adenopathy, and mass effect on the superior vena cava (SVC) and left innominate vein. We recorded change in size and character of effusions post-chemotherapy. RESULTS: Pleural effusions were present in 217, with 204 having fluid-only and 13 having associated solid components. Patients with effusions were more likely to have large mediastinal adenopathy (P<0.0001), be slow early responders (P<0.0001) and have higher relapse rate (P<0.0001). Vascular compression was not significantly correlated with pleural effusion. Of 121 patients with adequate [F-18]2-fluoro-2 deoxyglucose (FDG) positron emission tomography (PET)/CT imaging, no FDG PET avidity was seen in any pleural effusion but was present in solid components. The side of the pleural effusion in those with moderate or large effusions was highly associated with the side of large mediastinal adenopathy (P<0.0001). Statistical analysis indicates that pleural effusion is an independent risk factor for poorer response and relapse. CONCLUSION: Pleural effusion in Hodgkin lymphoma is an important independent poor prognostic indicator for response and relapse. PMID- 30014201 TI - Semiparametric sieve maximum likelihood estimation under cure model with partly interval censored and left truncated data for application to spontaneous abortion. AB - This work was motivated by observational studies in pregnancy with spontaneous abortion (SAB) as outcome. Clearly some women experience the SAB event but the rest do not. In addition, the data are left truncated due to the way pregnant women are recruited into these studies. For those women who do experience SAB, their exact event times are sometimes unknown. Finally, a small percentage of the women are lost to follow-up during their pregnancy. All these give rise to data that are left truncated, partly interval and right-censored, and with a clearly defined cured portion. We consider the non-mixture Cox regression cure rate model and adopt the semiparametric spline-based sieve maximum likelihood approach to analyze such data. Using modern empirical process theory we show that both the parametric and the nonparametric parts of the sieve estimator are consistent, and we establish the asymptotic normality for both parts. Simulation studies are conducted to establish the finite sample performance. Finally, we apply our method to a database of observational studies on spontaneous abortion. PMID- 30014202 TI - Association of paraspinal muscle water-fat MRI-based measurements with isometric strength measurements. AB - OBJECTIVES: Chemical shift encoding-based water-fat MRI derived proton density fat fraction (PDFF) of the paraspinal muscles has been emerging as a surrogate marker in subjects with sarcopenia, lower back pain, injuries and neuromuscular disorders. The present study investigates the performance of paraspinal muscle PDFF and cross-sectional area (CSA) in predicting isometric muscle strength. METHODS: Twenty-six healthy subjects (57.7% women; age: 30 +/- 6 years) underwent 3T axial MRI of the lumbar spine using a six-echo 3D spoiled gradient echo sequence for chemical shift encoding-based water-fat separation. Erector spinae and psoas muscles were segmented bilaterally from L2 level to L5 level to determine CSA and PDFF. Muscle flexion and extension maximum isometric torque values [Nm] at the back were measured with an isokinetic dynamometer. RESULTS: Significant correlations between CSA and muscle strength measurements were observed for erector spinae muscle CSA (r = 0.40; p = 0.044) and psoas muscle CSA (r = 0.61; p = 0.001) with relative flexion strength. Erector spinae muscle PDFF correlated significantly with relative muscle strength (extension: r = -0.51; p = 0.008; flexion: r = -0.54; p = 0.005). Erector spinae muscle PDFF, but not CSA, remained a statistically significant (p < 0.05) predictor of relative extensor strength in multivariate regression models (R2adj = 0.34; p = 0.002). CONCLUSIONS: PDFF measurements improved the prediction of paraspinal muscle strength beyond CSA. Therefore, chemical shift encoding-based water-fat MRI may be used to detect subtle changes in the paraspinal muscle composition. KEY POINTS: * We investigated the association of paraspinal muscle fat fraction based on chemical shift encoding-based water-fat MRI with isometric strength measurements in healthy subjects. * Erector spinae muscle PDFF correlated significantly with relative muscle strength. * PDFF measurements improved prediction of paraspinal muscle strength beyond CSA. PMID- 30014203 TI - Chemical shift imaging for evaluation of adrenal masses: a systematic review and meta-analysis. AB - OBJECTIVES: To perform a systematic review and meta-analysis of published data to evaluate the utility of chemical shift imaging (CSI) for differentiating between adrenal adenomas and non-adenomas. METHODS: A systematic search of the MEDLINE, Web of Science Core Collection, EMBASE and Cochrane Central Register of Controlled Trials electronic databases was performed. The methodological quality of the included studies was assessed by using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. A bivariate random effect model was used to determine summary and subgroup sensitivity and specificity and calculate summary receiver operating characteristic curves (SROC). RESULTS: Eighteen studies with 1138 patients and 1280 lesions (859 adenomas, 421 non-adenomas) in total were included. In addition to summary analysis, quantitative analyses of the adrenal signal intensity index (SII, 978 lesions, 14 studies), adrenal-to-spleen ratio (ASR; 394 lesions, 7 studies) and visual analysis (560 lesions, 5 studies) were performed. The resultant data showed considerable heterogeneity (inconsistency index I2 of 94%, based on the diagnostic odds ratio, DOR). The pooled sensitivity of CSI for adenoma was 0.94 [95% confidence interval (CI) 0.88-0.97] and pooled specificity was 0.95 (95% CI 0.89-0.97). The area (AUC) under the SROC curve was 0.98 (95% CI 0.96-0.99). The corresponding AUCs were 0.98, 0.99 and 0.95 for SII, ASR and visual evaluation, respectively. CONCLUSION: CSI has high sensitivity, specificity and accuracy for adrenal adenoma. Diagnostic performance does not improve when quantitative indices are used. KEY POINTS: * Inclusion of CSI in abdominal MRI protocols provides an effective solution for classifying adrenal masses discovered on MR exams * Visual evaluation of adrenal CSI is sufficient; use of quantitative indices does not improve diagnostic accuracy. PMID- 30014204 TI - Prospective comparison of diffusion-weighted MRI and dynamic Gd-EOB-DTPA-enhanced MRI for detection and staging of hepatic fibrosis in primary sclerosing cholangitis. AB - PURPOSE: To assess the diagnostic value of multiparametric magnetic resonance imaging (MRI) including dynamic Gd-EOB-DTPA-enhanced (DCE) and diffusion-weighted (DW) imaging for diagnosis and staging of hepatic fibrosis in primary sclerosing cholangitis (PSC) using transient elastography as a standard reference. MATERIAL AND METHODS: Multiparametric MRI was prospectively performed on a 3.0-Tesla scanner in 47 patients (age 43.9+/-14.3 years). Transient elastography derived liver stiffness measurements (LSM), DCE-MRI derived parameters (hepatocellular uptake rate (Ki), arterial (Fa), portal venous (Fv) and total (Ft) blood flow, mean transit time (MTT), and extracellular volume (Ve)) and the apparent diffusion coefficient (ADC) were calculated. Correlation and univariate analysis of variance with post hoc pairwise comparison were applied to test for differences between LSM derived fibrosis stages (F0/F1, F2/3, F4). ROC curve analysis was used as a performance measure. RESULTS: Both ADC and Ki correlated significantly with LSM (r= -0.614; p<0.001 and r= -0.368; p=0.01). The ADC significantly discriminated fibrosis stages F0/1 from F2/3 and F4 (p<0.001). Discrimination of F0/1 from F2/3 and F4 reached a sensitivity/specificity of 0.917/0.821 and 0.8/0.929, respectively. Despite significant inter-subject effect for classification of fibrosis stages, post hoc pairwise comparison was not significant for Ki (p>0.096 for F0/1 from F2/3 and F4). LSM, ADC and Ki were significantly associated with serum-based liver functional tests, disease duration and spleen volume. CONCLUSION: DW-MRI provides a higher diagnostic performance for detection of hepatic fibrosis and cirrhosis in PSC patients in comparison to Gd-EOB-DTPA-enhanced DCE-MRI. KEY POINTS: * Both ADC and hepatocellular uptake rate (Ki) correlate significantly with liver stiffness (r= 0.614; p<0.001 and r= -0.368; p=0.01). * The DCE-imaging derived quantitative parameter hepatocellular uptake rate (Ki) fails to discriminate pairwise intergroup differences of hepatic fibrosis (p>0.09). * DWI is preferable to DCE imaging for discrimination of fibrosis stages F0/1 to F2/3 (p<0.001) and F4 (p<0.001). PMID- 30014205 TI - Interpolating hourly temperatures for computing agroclimatic metrics. AB - Calculating many agroclimatic metrics, e.g., chill or heat accumulation in orchards, requires continuous records of hourly temperature. Such records are often unavailable, with farm managers and researchers relying on daily data or hourly records with gaps. While procedures for generating idealized temperature curves exist, interpolating hourly records has long been a challenge. The SolveHours procedure combines measured hourly temperatures, idealized daily temperature curves and proxy data to fill gaps in such records. It first determines daily temperature extremes by solving systems of linear equations that express the typical relationships between hourly temperatures and daily temperature extremes for every hour. After filling gaps in this record with bias corrected data from proxy stations or by linear interpolation, SolveHours uses these data to generate an idealized temperature curve. Deviations of recorded hourly temperatures from this curve are calculated, linearly interpolated, and added to the idealized curve to obtain a gapless record. The procedure was compared to alternative gap-filling algorithms using an 8-month dataset from an orchard near Winters, CA, in which half the records were replaced by 500 gaps of random length. The SolveHours procedure achieved ratio of performance to interquartile distance (RPIQ) values of 6.7 (when using temperature extremes from a proxy station) and 8.2 (with temperature extremes measured on site), with root mean square errors of 1.6 and 1.3 degrees C, respectively. It outperformed all other algorithms in reproducing recorded accumulation of Chill Portions and Growing Degree Hours. The SolveHours procedure is implemented in the chillR package for the R programming environment ( https://cran.r project.org/web/packages/chillR/vignettes/hourly_temperatures.html ). PMID- 30014206 TI - Interactions of zearalenone and its reduced metabolites alpha-zearalenol and beta zearalenol with serum albumins: species differences, binding sites, and thermodynamics. AB - Zearalenone (ZEN) is a mycotoxin produced by Fusarium species. ZEN mainly appears in cereals and related foodstuffs, causing reproductive disorders in animals, due to its xenoestrogenic effects. The main reduced metabolites of ZEN are alpha zearalenol (alpha-ZEL) and beta-zearalenol (beta-ZEL). Similarly to ZEN, ZELs can also activate estrogen receptors; moreover, alpha-ZEL is the most potent endocrine disruptor among these three compounds. Serum albumin is the most abundant plasma protein in the circulation; it affects the tissue distribution and elimination of several drugs and xenobiotics. Although ZEN binds to albumin with high affinity, albumin-binding of alpha-ZEL and beta-ZEL has not been investigated. In this study, the complex formation of ZEN, alpha-ZEL, and beta ZEL with human (HSA), bovine (BSA), porcine (PSA), and rat serum albumins (RSA) was investigated by fluorescence spectroscopy, affinity chromatography, thermodynamic studies, and molecular modeling. Our main observations are as follows: (1) ZEN binds with higher affinity to albumins than alpha-ZEL and beta ZEL. (2) The low binding affinity of beta-ZEL toward albumin may result from its different binding position or binding site. (3) The binding constants of the mycotoxin-albumin complexes significantly vary with the species. (4) From the thermodynamic point of view, the formation of ZEN-HSA and ZEN-RSA complexes are similar, while the formation of ZEN-BSA and ZEN-PSA complexes are markedly different. These results suggest that the toxicological relevance of ZEN-albumin and ZEL-albumin interactions may also be species-dependent. PMID- 30014207 TI - A chemiluminescence-based catalase assay using H2O2-sensitive CdTe quantum dots. AB - A method is described for the chemiluminescence based determination of the activity of catalase (CAT) using H2O2-sensitive CdTe quantum dots (QDs). It is based on the finding that the chemiluminescence (CL) of the CdTe/H2O2 system is reduced due to the consumption of H2O2 by the catalytic action of CAT. The Michaelis constant is calculated to be 519 +/- 27 mM, showing the potential of the method to accurately measure the Km compared to the standard method. The method does not require QDs to be conjugated to biological/organic molecules and therefore is considered to be a rapid and convenient method for determination of CAT in real samples. At an incubation time of 2 s, the LOD was calculated to be 4.5 unit/mL, with a linear range from 6 to 400 unit/mL. The assay is sensitive, simple, and suitable for practical applications. Graphical abstract Schematic representation of chemiluminescence-based catalase U(CAT) assay using the CdSe QD/H2O2 system. The reduction of H2O2 is reflected by the chemiluminescence of the QDs. A mechanism is put forward based on the changes in chemiluminescence intensity of the QDs by the consumption of H2O2 due to the catalytic action of CAT. PMID- 30014209 TI - Cellular neurometabolism: a tentative to connect cell biology and metabolism in neurology. AB - It has become increasingly evident that inborn errors of metabolism (IEMs) are particularly prevalent as diseases of the nervous system and that a broader, more inclusive definition of IEM is necessary. In fact, as long as biochemistry is involved, any kind of monogenic disease can become an IEM. This new, extended definition includes new categories and mechanisms, and as a general trend will go beyond a single biochemical pathway and/or organelle, and will appear as a connection of multiple crossroads in a system biology approach.From one side, a simplified and updated classification of IEM is presented that mixes elements from the diagnostic approach with pathophysiological considerations into three large categories based on the size of molecules ("small and simple" or "large and complex") and their implication in energy metabolism. But from another side, whatever their size, metabolites involved in IEM may behave in the brain as signalling molecules, structural components and fuels, and many metabolites have more than one role. Neurometabolism is becoming more relevant, not only in relation to these new categories of diseases but also as a necessary way to explain the mechanisms of brain damage in classically defined categories of IEM. Brain metabolism, which has been largely disregarded in the traditional approach to investigating and treating neurological diseases, is a major clue and probably the next imminent "revolution" in neurology and neuroscience. Biochemistry (metabolism) and cell neurobiology need to meet. Additionally, the brain should be studied as a system (connecting different levels of complexity). PMID- 30014208 TI - Emerging Treatments in Episodic Migraine. AB - PURPOSE OF REVIEW: The purpose of this review is to evaluate and describe recent and emerging treatment options for episodic migraine. RECENT FINDINGS: Recent advances have been made in better understanding the pathophysiology of migraine, which has led to further investigation of potential new pharmacologic and non pharmacologic treatment options. A number of new medications are emerging for the acute and preventive treatment of migraine, including CGRP monoclonal antibodies, CGRP receptor antagonists, serotonin 5-HT1F agonists, and PACAP receptor monoclonal antibodies. Additionally, newer studies on existing non-invasive neuromodulation devices including transcranial magnetic stimulation, supraorbital transcutaneous nerve stimulation, and transcutaneous vagus nerve stimulation have recently received FDA approval for use in migraine. Neuromodulation devices including percutaneous mastoid electrical stimulation, non-painful remote electrical stimulation, and caloric vestibular stimulation are undergoing further investigation and have shown promising results thus far. These new developments are expected to contribute to better treatment and decreased disability in migraine. PMID- 30014210 TI - Synaptic metabolism: a new approach to inborn errors of neurotransmission. AB - To date, inborn errors of neurotransmitters have been defined based on the classic concept of inborn error of metabolism (IEM), and they include defects in synthesis, catabolism, and transport pathways. However, the omics era is bringing insights into new diseases and is leading to an extended definition of IEM including new categories and mechanisms. Neurotransmission takes place at the synapse, the most specialized tight junction in the brain. The concept of "synaptic metabolism" would point to the specific chemical composition and metabolic functions of the synapse. Based on these specialized functions, we aim to provide a tentative overview about the major categories of IEM susceptible to affect neurotransmission. Small molecule defects (biogenic amines and amino acids) and energy defects are amongst the most prevalent diseases reported to disturb the concentration of CSF neurotransmitters. In these IEM, the neurological phenotypes have been largely described. Disorders of complex molecules are not typically considered as diseases affecting neurotransmission. However, most of them have been recently discovered and are involved in intracellular vesiculation, trafficking, processing, and quality control mechanisms. In this large group, neurotransmission is affected in disorders of chaperones and autophagy, disorders of the synaptic vesicle, and diseases affecting pre-synaptic membranes (synthesis and remodeling of complex lipids, defects of glycosylation). Disorders of the vesicle pools, receptor trafficking, and the chronobiology of neurotransmission are potentially emerging new categories. Finally, although not considered as IEM, channelopathies are a large group of diseases disturbing neurotransmitter homeostasis. New CSF biomarkers will probably contribute to improve the diagnosis of these disorders and find new therapeutic targets. PMID- 30014211 TI - Correction to: Prophylactic negative pressure wound therapy after lower extremity fracture surgery: a pilot study. AB - The published online version contain mistake in the author list for the name of the author "J. Carel Goslings" was incorrectly presented in the HTML version. PMID- 30014212 TI - The continuing relevance of "older" mycorrhiza literature: insights from the work of John Laker Harley (1911-1990). AB - To new generations of scientists beginning their careers in research, we strongly recommend the practice of reading older literature. To illustrate the value of doing so, we highlight six insights of one of the most influential mycorrhiza researchers of the twentieth century, Jack Harley. These insights concerning mycotrophy, the new niche, the sheath, C cycling, N cycling, and mutualism were published prior to 1975 and so may have escaped the notice of many, but they laid the groundwork for some of the most important research of today. PMID- 30014213 TI - Assessment of Cardiovascular Health among Community-Dwelling Men with Incarceration History. AB - Returning to the community after incarceration is a particularly vulnerable time with significantly increased risk of death in the first 2 weeks. The elevated risk of death persists as long as 2 years, with cardiovascular disease (CVD) among the leading causes. African-Americans, especially African-American men, have higher rates of incarceration and community supervision (e.g., probation and parole) and an earlier onset of hypertension compared to Whites. Few studies have objectively assessed the cardiovascular health profile of criminal justice involved individuals. This study is designed to determine the cardiovascular health profile among men in community corrections and/or transitional housing, identify the prevalence of key CVD risk factors, and assess if risk varies by race/ethnicity. We recruited 100 adult men (mean age = 42.7, SD = 11.35, 60% White, 40% non-Hispanic White) with a history of incarceration in jail or prison of >= 6 months during their most recent incarceration and enrolled in a community corrections program. Using the American Heart Association's Life's Simple 7TM (LS 7), measures of each of the LS-7 components (body mass index, blood pressure, lipids, blood glucose, smoking, diet, and physical activity) were obtained, and LS-7 scores were generated for each measure using AHA-defined categories of poor (1 point), intermediate (2 points), and ideal (3 points) and summed to yield a total score ranging from poor for all (7 points) to ideal for all (21 points). Mann-Whitney U tests were performed to assess differences in LS-7 scores (poor, intermediate, ideal) by race/ethnicity. Additionally, an independent samples t test was conducted for race/ethnicity and LS-7 total score. Mann-Whitney U tests for LS-7 categories and race/ethnicity indicated a greater number of non-Whites had poor blood pressure (p < .01) and diet (p < .05) as compared to Whites. The independent samples t test demonstrated significantly lower LS-7 scores for non Whites compared to Whites. To our knowledge, this is the first study to evaluate cardiovascular health among individuals with a history of incarceration using the LS-7 metric, which included objective measures for four of the seven LS-7 metrics. Non-Whites, which included African-Americans, Hispanics, and American Indians, were more likely than Whites to fall into the poor category for both diet and blood pressure and had significantly lower total LS-7 scores than Whites, indicating they have worse scores across all seven of the LS-7 measures. Similar to what is found among non-incarcerated samples, non-Whites with incarceration histories are at elevated risk for cardiovascular events relative to their White peers. PMID- 30014214 TI - Forecasting Migraine Attacks and the Utility of Identifying Triggers. AB - PURPOSE OF REVIEW: This review synthesizes the utility of measuring migraine triggers for the purpose of forecasting future headache attacks. The nature of forecasting models, headache triggers as inputs to such models, and how these trigger exposures can be measured for forecasting are reviewed. A critical evaluation of the existing forecasting models in the context of their potential application for preemptive treatment is considered. RECENT FINDINGS: A substantial pool of candidate trigger factors could be considered in the creation of forecasting models. However, because mechanistic information about causal factors that precede a migraine attack is not well understood, and such factors are difficult to measure, empirical models that are based on trigger factors that are merely associated with the onset of headache activity are likely to be the focus of forecasting efforts in the near future. Of such factors, stress has considerable empirical support and has been used to successfully forecast future headache attacks within individuals over time. However, at present, existing models possess only modest levels of discrimination and lack strong resolution in generated predictions. Current headache forecasting models represent an important first step in accurately predicting future headache activity. However, to utilize these models in a preemptive treatment paradigm where the risk of headache is treated prior to the actual experience of pain, these models must achieve greater precision with good calibration and generate predictions that are clinically actionable by individuals in their real-time home environments. PMID- 30014215 TI - Laser pulpotomy-an effective alternative to conventional techniques-a systematic review of literature and meta-analysis. AB - The aim of this systematic review and subsequent meta-analysis was to elaborate the efficacy of laser pulpotomy over the formocresol pulpotomy of human primary teeth. Published materials in the MedLine were looked for through "PUBMED" and "PUBMED CENTRAL". The MESH terms of "Laser", "Pulpotomy", "Primary teeth", and "Children" were used to carry the search from the years 1999 to 2017. Collected data were assessed by four investigators using inclusion and exclusion criteria in order to select those studies with precise method targeted. Only clinical trials on all types of lasers were included for this systematic reviews but only four articles were used for the meta-analysis as the rest did not meet the requirements. Statistical analysis was conducted to see the differences. Seventeen articles completely fulfilled the inclusion criteria of this study. In general, high clinical, radiographic, and histopathological success rates were reported in laser groups in comparison to other assessed methods. Meta-analysis indicated that except at 36 months, in all other time intervals, Laser proved better or close results to formocresol. At 36 months, laser showed better clinical results. Laser may be considered as an adjuvant alternative for vital pulp therapy on human primary teeth but due to the limited number of high-quality clinical research articles on laser-assisted pulpotomy, various types of laser application methods, and different follow-up periods, reaching a net consensus is still challenging. PMID- 30014217 TI - [Erratum to: Operative treatment of the degenerative cervical spine]. PMID- 30014216 TI - Effect of preoperative balloon dilation on treatment outcomes of laparoscopic Heller-Dor surgery for achalasia: a propensity score matched study. AB - PURPOSE: There is some debate about whether preoperative balloon dilation influences the outcomes of laparoscopic Heller-Dor surgery (LHD), with no consensus opinion as yet. Thus, we investigated if preoperative dilation influences the treatment outcomes of LHD for achalasia. METHODS: The subjects of this study were 526 patients with achalasia who underwent LHD as an initial treatment between August 1994 and February 2017. The patients were roughly classified by the status of preoperative balloon dilation and matched with propensity scores for age, sex, BMI, morphologic type, and maximum esophageal transverse diameter. Consequently, 94 subjects each were assigned to the balloon dilation (BD) group and to the non-balloon dilation (non-BD) group. We evaluated patient backgrounds, surgical outcomes, and incidence of postoperative reflux esophagitis. RESULTS: No differences were found in surgical time, intraoperative blood loss, incidence of intraoperative mucosal injury, or postoperative hospital stay between the BD and non-BD groups. The mean patient satisfaction was significantly higher in the non-BD group (4.9) than in the BD group (4.7) and the incidence of postoperative esophagitis was significantly lower in the non-BD group (1.1%) than in the BD group (7.4%). CONCLUSIONS: Preoperative balloon dilation had no effect on intraoperative complications but did increase the incidence of postoperative reflux esophagitis in patients undergoing LHD for achalasia. PMID- 30014218 TI - Impact of Gender and Age on the Prognosis of Differentiated Thyroid Carcinoma: a Retrospective Analysis Based on SEER. AB - The incidence of thyroid cancer in females is significantly higher than that in males; however, females are more likely to have more favorable outcomes. We aimed to determine the characteristics of differentiated thyroid carcinoma (DTC) subtypes in males and females, and to compare their clinical behavior and survival. A total of 68,337 cases were recruited from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. The disease-specific survival (DSS) of follicular variant papillary thyroid carcinoma (FVPTC) and follicular thyroid carcinoma (FTC) were similar to that of classical variant papillary thyroid carcinoma (CPTC) in male patients (FVPTC vs. CPTC, adjusted hazard ratio (aHR) = 0.947, P = 0.776; FTC vs. CPTC, aHR = 1.512, P = 0.104). In premenopausal female (< 55 years old), FVPTC had better DSS than CPTC (aHR = 0.321, P = 0.038) while FTC had worse DSS than CPTC (aHR = 3.272, P = 0.013); in postmenopausal female, FTC had poorer prognosis than CPTC (aHR = 2.145, P = 0.002), no statistical difference was found between CPTC and FVPTC (aHR = 0.724, P = 0.087). For patients younger than 55 years, women had significantly better DSS compared with men with CPTC (aHR = 0.376, P < 0.001) and FVPTC (aHR = 0.102, P < 0.001). However, no difference was observed in patients older than 55 years. Interestingly, outcomes of FTC were not affected by gender in patients of all ages. These results suggested that different clinical behaviors and outcomes of DTC subtypes should be considered in patients with different genders. PMID- 30014219 TI - Correlation between polar surface area and bioferroelectricity in DNA and RNA nucleobases. AB - We have performed computational molecular modelling to study the polarization switching and hysteresis loop behaviours of DNA and RNA nucleobases using the PM3 semi-empirical quantum mechanical approaches. All the nucleobases: adenine (A), thymine (T), guanine (G), cytosine (C), and uracil (U) were modelled. Our study indicates that all the nucleobases exhibit a zero-field polarization due to the presence of polar atoms or molecules such as amidogen and carbonyl. The shape of polarization P versus an applied electric field E hysteresis loop is square, implying typical ferroelectrics behaviour. The total energy U as a function of an applied electric field E exhibits a butterfly-like loop. The presence of zero field polarization and ferroelectrics hysteresis loop behaviours in nucleobases may support the hypothesis of the existence of bioferroelectricity in DNA and RNA. We also found an interesting relationship between the minimum electric field required for switching [Formula: see text] and the ratio of the topological polar surface area (TPSA) to the total surface area (TSA) of a nucleobase. In particular, the [Formula: see text] of a nucleobase is inversely proportional to the TPSA/TSA ratio. This work may provide useful information for understanding the possible existence of ferroelectricity in biomaterials. PMID- 30014220 TI - The utrophin-beta 2 syntrophin complex regulates adipocyte lipid droplet size independent of adipogenesis. AB - Utrophin is a widely expressed cytoskeleton protein and is associated with lipid droplets (LDs) in adipocytes. The scaffold protein beta 2 syntrophin (SNTB2) controls signaling events by recruiting distinct membrane and cytoskeletal proteins, and binds to utrophin. Here we show that SNTB2 forms a complex with utrophin in adipocytes. SNTB2 protein is strongly diminished when utrophin is low. Of note, knock-down of utrophin or SNTB2 enhances LD growth during adipogenesis. SNTB2 reduction has no effect on basal and induced lipolysis, and insulin-stimulated phosphorylation of Akt is normal. The antilipolytic activity of insulin is enhanced in adipocytes with low SNTB2, while knock-down of utrophin has no effect. Uptake of exogenously supplied oleate and linoleate is comparable in scrambled and SNTB2 siRNA-treated cells. In the fibroblasts, diminished SNTB2 is associated with lower proliferation. CCAAT/enhancer-binding protein alpha and sterol regulatory element-binding proteins which are critical transcription factors for adipogenesis are normally expressed. Consequently, maturation of cells with SNTB2 knock-down is not grossly impaired. In fibroblasts, SNTB2 is localized to filamentous and vesicular structures which are distinct from beta actin, alpha tubulin, endoplasmic reticulum, early endosomes, lysosomes and mitochondria. Collectively, our data provide evidence that the utrophin-SNTB2 complex regulates LD size without affecting adipogenesis. PMID- 30014221 TI - Structural effects of methylglyoxal glycation, a study on the model protein MNEI. AB - The reaction of free amino groups in proteins with reactive carbonyl species, known as glycation, leads to the formation of mixtures of products, collectively referred to as advanced glycation endproducts (AGEs). These compounds have been implicated in several important diseases, but their role in pathogenesis and clinical symptoms' development is still debated. Particularly, AGEs are often associated to the formation of amyloid deposits in conformational diseases, such as Alzheimer's and Parkinson's disease, and it has been suggested that they might influence the mechanisms and kinetics of protein aggregation. We here present the characterization of the products of glycation of the model protein MNEI with methylglyoxal and their effect on the protein structure. We demonstrate that, despite being an uncontrolled process, glycation occurs only at specific residues of the protein. Moreover, while not affecting the protein fold, it alters its shape and hydrodynamic properties and increases its tendency to fibrillar aggregation. Our study opens the way to in deep structural investigations to shed light on the complex link between protein post-translational modifications, structure, and stability. PMID- 30014222 TI - Correction to: A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer. AB - The original version of this article unfortunately contained a mistake. The co authors' names were incorrect. PMID- 30014223 TI - Differences Between the Intestinal Lumen Microbiota of Aberrant Crypt Foci (ACF) Bearing and Non-bearing Rats. AB - BACKGROUND: Multiple factors including host-microbiota interaction could contribute to the conversion of healthy mucosa to sporadic precancerous lesions. An imbalance of the gut microbiota may be a cause or consequence of this process. AIM: The goal was to investigate and analyze the composition of gut microbiota during the genesis of precancerous lesions of colorectal cancer. METHODS: To analyze the composition of gut microbiota in the genesis of precancerous lesions, a rat model of 1, 2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) was established. The feces of these rats and healthy rats were collected for 16S rRNA sequencing. RESULTS: The diversity and density of the rat intestinal microbiota were significantly different between ACF-bearing and non-bearing group. ACF were induced in rats treated with DMH and showed increased expression of the inflammatory cytokines IL-6, IL-8, and TNF-alpha. Firmicutes was the most predominant phylum in both ACF-bearing and non-bearing group, followed by Bacteroidetes. Interestingly, although the density of Bacteroidetes decreased from the fifth week to the 17th week in both groups, it was significantly reduced in ACF-bearing group at the 13th week (P < 0.01). At the genus level, no significant difference was observed in the most predominant genus, Lactobacillus. Instead, Bacteroides and Prevotella were significantly less abundant (P < 0.01), while Akkermansia was significantly more abundant (P < 0.05) in ACF-bearing group at the 13th week. CONCLUSION: Imbalance of the intestinal microbiota existed between ACF-bearing and non-bearing rats, which could be used as biomarker to predict the genesis of precancerous lesions in the gut. PMID- 30014224 TI - Relationship Between Meal Frequency and Gastroesophageal Reflux Disease (GERD) in Iranian Adults. AB - BACKGROUND: The association between frequency of meals and snacks and gastroesophageal reflux disease (GERD) is less studied in Middle-Eastern countries. AIM: We aimed to determine the relationship between meal and snack frequency with GERD symptoms in a large sample of Iranian adults. METHODS: In this cross-sectional study, 4669 individuals filled out a questionnaire about their number of meals and snacks. Frequency of total meals was defined by summing up the frequency of main meals and snacks, and participants were categorized into four categories: < 3, 3-5, 6-7 and >= 8 meals/day. GERD was defined as having heartburn sometimes or more during the last 3 months. The severity of disease was assessed. RESULTS: The prevalence of GERD in the study population was 23.7%. There was no significant association between meal or snack frequency and GERD symptoms in the whole population. However, after adjustment of all potential confounders, we found that women who consumed 1-2 or 3-5 snacks per day, compared with those who never had snacks, had a 41% (OR 0.59; 95% CI 0.42-0.84) and 51% (OR 0.49; 95% CI 0.32-0.75) reduced risk of having GERD, respectively. Women who consumed 6-7 or >= 8 snacks and meals per day had a 38% (OR 0.62; 95% CI 0.41 0.96) and 43% (OR 0.57; 95% CI 0.34-0.95) risk reduction for GERD compared with those who ate < 3 snacks and meals per day. CONCLUSION: We found no significant association between meal frequency and GERD symptoms in the whole population. Gender-specific analysis revealed inverse associations between meal and snack frequency and GERD in Iranian women. Further prospective studies are required to confirm these associations. PMID- 30014225 TI - Quality Improvement in Gastroenterology: A Systematic Review of Practical Interventions for Clinicians. AB - BACKGROUND: Quality improvement (QI) identifies practical methods to improve patient care; however, it is not always widely known which QI methods are successful. We sought to create a primer of QI in gastroenterology for the practicing clinician. METHODS: We performed a systematic review of QI literature in gastroenterology. We included search terms for inflammatory bowel disease, irritable bowel syndrome, celiac disease, gastroesophageal reflux disease, pancreatitis, liver disease, colorectal cancer screening, endoscopy, and gastrointestinal bleeding. We used general search terms for QI as well as specific terms to capture established quality metrics for each GI disease area. RESULTS: We found 33 studies that met our definitions for QI. There were 17 studies of endoscopy including screening colonoscopy, six on liver disease, four on IBD, two on GERD, three on GI bleeding, and one on celiac disease. Education was the most common intervention, although most successful studies combined education with another intervention. Other effective interventions included retraining sessions to reach ADR goals in colonoscopy, nursing protocols to increase HCC screening, and EMR decision support tools to prompt reassessment of PPI therapy. Many studies showed improved compliance to metrics, but few were able to show differences in length of stay, readmissions, or mortality. CONCLUSIONS: Our review of quality improvement literature in gastroenterology revealed common themes of successful programs: Education was frequently used but often insufficient, the EMR may be underutilized in guiding decision making, and patient-reported outcomes were infrequently assessed. Further research may be needed to compare QI strategies directly. PMID- 30014226 TI - Ledipasvir/Sofosbuvir Effectively Treats Hepatitis C Virus Infections in an Underserved Population. AB - BACKGROUND: Underserved populations have an unequal burden of HCV infections and poor outcomes with interferon-based treatments. Direct-acting antivirals have the potential to reduce these inequalities. AIMS: We aimed to estimate sustained virologic response (SVR) following treatment with sofosbuvir-based regimens for HCV infections among underserved individuals and summarize the frequency of SVR across published studies of underserved populations. METHODS: We used data from a clinical cohort of patients aged >= 18 years who initiated sofosbuvir-based regimens for HCV infection between February 2014 and June 2016 at an urban public hospital network that serves as the healthcare safety-net for Tarrant County, Texas. We estimated SVR with corresponding 95% confidence limits (CL). In addition, we systematically reviewed the evidence to identify other studies of direct-acting antivirals among underserved populations. RESULTS: Our study population comprised 435 patients. The majority of patients were aged >= 50 years (76%), male (52%), non-Hispanic White (54%), HCV genotype 1 (79%) and treated with ledipasvir/sofosbuvir (69%). Overall SVR was 89% (95% CL 86, 92%) and highest for ledipasvir/sofosbuvir (SVR = 95%, 95% CL 92, 97%). The reported SVR following direct-acting antivirals among 837 underserved patients from three other studies ranged between 90 and 99%. CONCLUSIONS: Our results suggest that direct-acting antivirals, particularly ledipasvir/sofosbuvir, are generally effective for achieving SVR among underserved patients with HCV infections and may help reduce inequalities in HCV prevalence and outcomes for this vulnerable population. PMID- 30014227 TI - Comparison of HHV-6 DNA detection in plasma and whole blood in allogeneic hematopoietic stem cell transplant recipients: frequent false-positive results for active HHV-6 infection using whole blood samples. AB - In this prospective observational study, we compared the human herpesvirus-6 (HHV 6) DNA load in serially collected paired plasma and whole blood (WB) samples from allogeneic hematopoietic stem cell transplantation (HSCT) recipients. A total of 721 paired samples were collected from 68 recipients. The positive rate for HHV-6 DNA was 9.7 and 35.0% in plasma and WB samples, respectively (P < 0.001). The correlation of HHV-6 DNA load between plasma and WB was poor (R2 = 0.250). After reaching peak levels, HHV-6 DNA showed a delayed decrease in WB in comparison with plasma (median, 28 versus 7 days, P < 0.001). We additionally tested HHV-6 mRNA status in 95 samples from eight patients. To identify positive HHV-6 mRNA, plasma HHV-6 DNA showed 55.0% sensitivity and 100% specificity, whereas WB HHV-6 DNA showed 90.0% sensitivity and 68.0% specificity. The false-positive rate for identifying positive HHV-6 mRNA was 0% for plasma HHV-6 DNA and 32.0% for WB HHV 6 DNA. Although WB was more sensitive than plasma for detecting HHV-6 reactivation, the rates of false positivity for active HHV-6 infection were higher for WB than for plasma. PMID- 30014228 TI - Environmental Noise Exposure and Neurodevelopmental and Mental Health Problems in Children: a Systematic Review. AB - PURPOSE OF REVIEW: We systematically summarized and evaluated evidence on association between traffic noise exposure and indicators of neurodevelopmental and mental health problems. RECENT FINDINGS: Twelve studies on 10 unique populations were reviewed. Different outcomes, mostly measured by the Strength and Difficulties Questionnaire (SDQ) and its subscales, were reported. Overall bias in each study was acceptable, but the quality of evidence for specific outcomes was "low" to "very low," according to the Grading of Recommendations Assessment, Development and Evaluation system. Data supporting the harmful effect of noise on neurodevelopmental and mental health in children are heterogeneous and limited. Direction of potentially harmful effect was most consistent for road traffic noise and total SDQ score and hyperactivity/inattention. At this point, there is only suggestive evidence that road traffic noise might lead to neurodevelopmental problems in children. PMID- 30014229 TI - A Study of the Variability in Contact Resistive Random Access Memory by Stochastic Vacancy Model. AB - Variability in resistive random access memory cell has been one of the critical challenges for the development of high-density RRAM arrays. While the sources of variability during resistive switching vary for different transition metal oxide films, the stochastic oxygen vacancy generation/recombination is generally believed to be the dominant cause. Through analyzing experimental data, a stochastic model which links the subsequent switching characteristics with its initial states of contact RRAM cells is established. By combining a conduction network model and the trap-assisted tunneling mechanism, the impacts of concentration and distribution of intrinsic oxygen vacancies in RRAM dielectric film are demonstrated with Monte Carlo Simulation. The measurement data on contact RRAM arrays agree well with characteristics projected by the model based on the presence of randomly distributed intrinsic vacancies. A strong correlation between forming characteristics and initial states is verified, which links forming behaviors to preforming oxygen vacancies. This study provides a comprehensive understanding of variability sources in contact RRAM devices and a reset training scheme to reduce the variability behavior in the subsequent RRAM states. PMID- 30014230 TI - Delayed intra-articular pseudoaneurysm of the dorsalis pedis artery following arthroscopic Brostrom results in an unusual clinical presentation. AB - Pseudoaneurysms of the dorsalis pedis artery are rare complications following arthroscopic surgery. This manuscript reports a case of an intra-articular pseudoaneurysm presenting nearly 5 months following an arthroscopic Brostrom procedure. The rarity of this complication and the patient's unusual clinical presentation prompted the use of imaging to diagnose the problem and guide management. Although imaging artifacts are often a nuisance, recognition of clinically relevant artifacts can help make a diagnosis. This case illustrates such a situation. PMID- 30014232 TI - The Pannexin-1 Channel Inhibitor Probenecid Attenuates Skeletal Muscle Cellular Energy Crisis and Histopathological Injury in a Rabbit Endotoxemia Model. AB - This study aimed to investigate the effect of probenecid (Pro) as an inhibitor of the pannexin-1 (Panx-1) channel-mediated release of intracellular ATP to the extracellular compartment on inflammation, cellular energy crisis, and organ injury in a rabbit sepsis model induced by Escherichia coli lipopolysaccharides (LPS). A total of 24 anesthetized and ventilated rabbits were randomly assigned to receive one of four treatments: infusion of LPS without Pro (LPS group), infusion of LPS with Pro (LPS + Pro group), sham operation without Pro (normal group), and sham operation with Pro (normal + Pro group). The LPS group had significantly higher serum ATP levels, serum inflammatory factor levels (TNF alpha, IL-6, and IL-1beta), and lower ATP concentrations and ATP/ADP ratios in the skeletal muscle tissue than the normal group. Compared to that at baseline, the expression of Panx-1 in peripheral blood cells increased significantly after the infusion of LPS (fluorescence intensity of Panx-1: T0 (baseline) vs. T1 (post LPS) = 10 +/- 1.2 vs. 84 +/- 48, P < 0.0001; paired differences 73 +/- 46, P = 0.024). Moreover, the LPS group exhibited higher expression of Panx-1 in the skeletal muscle tissue than the normal group. The serum ATP level was significantly positively correlated with IL-1beta (R = 0.602, P = 0.001), IL-6 (R = 0.381, P = 0.033), and TNF-alpha (R = 0.514, P = 0.005) in 24 paired measurements. Compared to the LPS group, the LPS + Pro group had significantly lower levels of inflammatory factors (TNF-alpha, IL-6, and IL-1beta) and serum ATP. In the skeletal muscle tissue, the LPS + Pro group also had a higher ATP concentration (1.1 +/- 0.15 vs. 1.33 +/- 0.17, P = 0.041) and ATP/ADP ratio (0.37 +/- 0.03 vs. 0.51 +/- 0.06, P = 0.002) and a lower histopathological damage score (4.67 +/- 0.52 vs. 3 +/- 0.63, P = 0.004). An overexpression of Panx-1 channel might be responsible for the strong inflammatory response, high serum ATP level, and skeletal muscle cellular energy crisis and histopathological damages in sepsis. Inhibiting Panx-1 channel-mediated release of intracellular ATP could decrease the above-mentioned injuries, and Panx-1 might be a potential therapeutic target in sepsis. PMID- 30014233 TI - Simulated management of urinary tract injury during robotic pelvic surgery utilizing the porcine model. AB - Urologic injury is an infrequent but serious complication of pelvic surgery. Training in the assessment and management of this injury might be enhanced through animated simulation. Our objective was to assess the intraoperative management of urologic injury with robotic pelvic surgery using a simulated injury animal model. We used a female domestic pig to create three types of urologic injury, which we then managed with robotically assisted surgery. An edited video of the model was assessed by 14 senior learners and 10 attending faculty. The assessments included key competencies and domains of fidelity. A scale of poor, fair, or good was utilized. The defects and repairs simulated those seen in humans, both anatomically and surgically, although deficiencies were noted. Related to fidelity of the anatomy of the ureter and bladder, lower ratings were given for some of the key competencies (determining the relationship to the trigone, ureteral mobilization, repair of all 3 injuries). The porcine model for simulation of urologic injury during robotically assisted pelvic surgery may be useful for training purposes. PMID- 30014231 TI - Resolvin D1 Promotes SIRT1 Expression to Counteract the Activation of STAT3 and NF-kappaB in Mice with Septic-Associated Lung Injury. AB - Resolvin D1 (RvD1) is a novel endogenous docosahexaenoic acid (DHA)-derived lipid mediators, which possesses a dual role of anti-inflammation and promotes inflammation resolution. The aim of the present study was to assess the effects of RvD1 on cecal ligation and puncture (CLP) model of sepsis and explore the underlying mechanism. Six-to-eight-week-old male C57BL/6 mice were randomly divided into following three groups: sham-operated group (SO), CLP model group (CLP), and CLP+RvD1 group (RvD1). The SO group underwent the sham operation. The RvD1 groups were administered RvD1 (10-ng/g body weight) by penile vein injection, but the CLP groups were administered the same volume of vehicle (PBS) after CLP. We assessed the survival benefit of RvD1 in CLP-induced septic mice for 7 days. After 24 h, mice were sacrificed, bronchoalveolar lavage fluids (BALF) was collected for proinflammatory cytokines assay, and albumin assay and the lung tissues were harvested for histologic analysis, myeloperoxidase (MPO) activity and the expression of Sirtuin 1 (SIRT1), signal transducers, and activators of transcription 3 (STAT3), nuclear factor-kappaB (NF-kappaB), and mitogen-activated protein kinases (MAPKs). RvD1 treatment increased the survival time in mice with sepsis induced by CLP, reducing the MPO activity and albumin level at 24 h. The levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-6 (IL-6) in BALF were significantly decreased by RvD1. RvD1 promoted SIRT1 expression and suppressed the activation of NF-kappaB, STAT3, ERK, and p38 in lung tissues of septic mice. These results suggest that RvD1 may improve survival and attenuate the degree of lung inflammation reaction in mice with CLP by suppressing STAT3, NF-kappaB, ERK, and p38 expressions through a mechanism partly dependent on SIRT1. PMID- 30014234 TI - Biochemically diagnosed hypothyroidism and postoperative complications after cardiac surgery: a retrospective cohort analysis. AB - PURPOSE: To determine whether hypothyroidism is associated with cardiovascular complications and surgical wound infections after cardiac surgery. METHODS: Patients were categorized as: (1) hypothyroid [patients with increased TSH concentrations (? 5.5 mIU/L) within 6 months prior to surgery]; (2) corrected hypothyroid [diagnosis of hypothyroidism any time before surgery or on preoperative thyroid supplementation and normal TSH concentration (0.4 [Formula: see text] TSH [Formula: see text] 5.5 mIU/L]; and (3) euthyroid [no hypothyroid diagnosis and not on preoperative thyroid supplementation and normal TSH concentrations (0.4-5.5 mIU/L)]. We conducted pairwise comparisons among the three groups using inverse probability of treatment weighting. We compared the groups on postoperative myocardial infarction, cardiac arrest, atrial fibrillation, and a composite of surgical wound infections and postoperative vasopressor use using multivariable logistic regression models. We compared the groups on ICU and hospital length of stay using Cox proportional hazards regression. RESULTS: Hypothyroidism was associated with a lower risk of atrial fibrillation than euthyroidism, with an estimated relative risk (99.4% CI) of 0.71 (0.56, 0.89); P < 0.001. However, none of the other pairwise comparisons on myocardial infarction, cardiac arrest, and atrial fibrillation were significant. Corrected hypothyroid patients were slightly more likely to be discharged from hospital at any given time than euthyroid patients (hazard ratios (99.6% CI), 1.18 (1.07, 1.30); P < 0.001), but no other pairwise comparisons for secondary outcomes were significant. CONCLUSIONS: Hypothyroidism was associated with lower risk of atrial fibrillation than euthyroidism, and corrected hypothyroidism was associated with a shorter length of stay than euthyroidism. PMID- 30014235 TI - Prognostic factors in stereotactic body radiotherapy of lung metastases. AB - PURPOSE: The aim of this study was to evaluate prognostic factors in patients with lung metastases who undergo lung stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: A total of 87 patients with 129 lung metastases who underwent SBRT between November 2004 and May 2012 were enrolled in this retrospective study. The patient collective consisted of 54 men (62.1%) and 33 women (37.9%); the median age was 65 years (range 36-88). The Karnofsky performance index was >=70% (median 90%) for all cases, but one (60%). Adverse effects were categorized using the CTCAE 4.0 classification system. Retrospective analyses regarding patients' characteristics, progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS), and local tumor control rates (LTC) were performed. RESULTS: On univariate and multivariate analysis OS, DSS, and PFS were significantly (p < 0.05) better for patients with <=3 lung metastases; no extrathoracic metastases at the time of the SBRT; a gross tumor volume (GTV) <7.7 cm3 and patients that received a staging that included positron emission tomography with fluorine 18 fluorodeoxyglucose/computed tomography (FDG PET/CT) imaging. Furthermore, a longer OS was observed if newly diagnosed metastases during follow-up were limited to the lung (median survival: 43.7 months versus 21.7 months; p = 0.023). CONCLUSION: The number and pattern of metastases, and the size of the target volume are strong predictors for the outcome of patients receiving SBRT of lung tumors. FDG-PET/CT should be part of pretherapeutic staging before SBRT. PMID- 30014236 TI - Radiation-induced morphea-a rare but severe late effect of adjuvant breast irradiation : Case report and review of the literature. AB - BACKGROUND: Radiation-induced morphea (RIM) is a circumscribed localized scleroderma that occurs most often in the breast. After an asymptomatic period of one month to several years, the symptoms (circumscribed inflammation, edema, sclerosis) often arise suddenly and cannot be clinically distinguished from a local recurrence in the form of inflammatory carcinoma. CASE: We present a case of a 74-year-old woman who developed this rare and serious local side-effect in connective tissue following neoadjuvant CDK 4/6 inhibitor abemaciclib (Verzenio(r)) and aromatase inhibitor anastrozole (Arimidex(r)) therapy and subsequent radiation therapy of the breast. CONCLUSIONS: Little is known about risk factors and pathogenesis of RIM. Here we describe the first case of RIM following immunotherapy. The diagnosis is based on clinical appearance and histopathological examination. Treatment should be initiated in the inflammatory stage in order to prevent or delay irreversible fibrosis and atrophy of the breast. PMID- 30014238 TI - Laparoscopic Sleeve Gastrectomy Is Associated with Lower 30-Day Morbidity Versus Laparoscopic Gastric Bypass: an Analysis of the American College of Surgeons NSQIP. AB - PURPOSE: Laparoscopic sleeve gastrectomy (LSG) has rapidly gained popularity as a single-stage operation for the treatment of morbid obesity, as patients undergoing LSG have been shown to achieve similar weight loss and resolution of obesity-related comorbidities in comparison to those undergoing Roux-en-Y gastric bypass (RYGB), the "gold standard" bariatric operation. Although LSG poses fewer technical challenges than RYGB, little is known about differences in short-term outcomes among patients undergoing LSG and RYGB. We hypothesized that LSG is associated with lower 30-day risk-adjusted serious morbidity. METHODS: Preoperative characteristics and 30-day outcomes from the American College of Surgeons National Surgical Quality Improvement Program (ACSNSQIP) Participant Use Files (PUF) 2010-2014 were selected for all patients who underwent LSG or RYGB. Descriptive comparisons were performed using chi-square and Wilcoxon's rank-sum tests as appropriate. The primary outcome was a risk-adjusted composite measure of 30-day serious morbidity and mortality. RESULTS: We analyzed records for 47,982 (42.0%) and 66,380 (58.0%) patients undergoing LSG and RYGB, respectively. On univariate analysis, LSG patients had a lower rate of organ space infection (0.45% vs. 0.68%, p < 0.001), lower rate of bleeding requiring transfusions (1.00% vs. 1.60%, p < 0.001), lower rate of sepsis (0.34% vs. 0.49%, p < 0.001), and septic shock (0.12% vs. 0.22%, p < 0.001) and required fewer unplanned reoperations (1.34% vs. 2.56%, p < 0.001) than RYGB patients. Both groups had similar rates of deep venous thrombosis (0.33% vs. 0.28%, p = 0.15) and pulmonary embolism (0.17% vs. 0.21%, p = 0.15). Mortality was lower among LSG patients (0.09% vs. 0.14%, p = 0.01). On multivariate analysis, RYGB was associated with higher risk-adjusted 30-day serious morbidity than LSG (odds ratio 1.61; 95% CI 1.52-1.71, p < 0.001). Older age, female gender, higher BMI, and insulin dependent diabetes were also associated with risk of serious morbidity (C statistic = 0.60). CONCLUSION: Serious morbidity following bariatric surgery is uncommon; however, LSG may be associated with modest protection from adverse 30 day outcomes in comparison to RYGB. Our conclusion is limited by the difference in baseline risk factors of the populations studied. PMID- 30014237 TI - Preclinical evaluation of an innovative anti-TAM approach based on zoledronate loaded erythrocytes. AB - In tumor microenvironment, tumor-associated macrophages (TAMs) are implicated in cancer sustainment, metastasis, and drug resistance, raising a growing interest as targets in cancer therapy. Since the bisphosphonate zoledronate has proven to affect TAMs' functions, the anti-tumor effect of single or repeated administrations of red blood cells (RBCs) encapsulating zoledronate was evaluated in a mouse model of mammary carcinoma. The obtained results showed that loaded RBCs, but not free zoledronate, caused a significant (p < 0.01) and time-lasting reduction of TAMs' extent in tumor mass of Balb/C mice inoculated with murine mammary carcinoma T41 cells; in addition, a significant reduction (p < 0.05) of tumor growth rate has been obtained only following repeated administrations of zoledronate-loaded RBCs. The anti-tumor effect was secondary to the early depletion of spleen macrophages. Moreover, by assessing the IgG2a/IgG1 ratio, a prevalence of Th1 cytotoxic response in tumor-bearing mice receiving zoledronate by means of RBCs has been observed. These encouraging findings provide further evidence for the central role played by macrophages in tumor setting and highlight the suitability of zoledronate-loaded RBCs as pharmacological agents in depleting, even if indirectly, TAMs and, thus, their eligibility as part of a therapeutic strategy in cancer treatment. PMID- 30014239 TI - The intraventricular-spot sign: prevalence, significance, and relation to hematoma expansion and outcomes. AB - BACKGROUND: The presence of the spot sign on computed tomography angiogram (CTA) is considered a sign of active bleeding, and studies have shown it can predict hematoma expansion in intraparenchymal hemorrhage (IPH). The spot sign in intraventricular hemorrhage (IVH) has not been explored yet. The purpose of this study is to estimate the prevalence of the intraventricular-spot sign, and its prediction of hematoma expansion and clinical outcomes. METHODS: We retrieved data of hemorrhagic stroke patients seen at our medical center from January 2013 to January 2018. A total of 321 subjects were filtered for the prevalence analysis (PA). We further excluded 114 subjects without a follow-up CT-head for the hematoma expansion analysis (HEA). Patients were grouped based on the location of hemorrhage into three groups: isolated IPH with the spot sign always in IPH (i-IPH), isolated IVH with the spot sign always in IVH (i-IVH), and combined IPH and IVH which would be further sub-grouped according to the location of the spot sign: in IPH only (IPH+/IVH) and in IVH only (IPH/IVH+). The prevalence, demographics, and incidence of hematoma expansion were compared between the groups using Pearson's chi-square test and Student's t test. RESULTS: The prevalence of the spot sign was 8, 20, 17, 5% in (i-IPH), (i-IVH), (IPH+/IVH), and (IPH/IVH+) groups, respectively. The rate of hematoma expansion were (42 vs. 13%), (33 vs. 31%), (80 vs. 22%), and (25 vs. 22%) in spot sign positive vs. negative subjects in each group, respectively (p values = 0.023, = 1, <0.001, and = 1). CONCLUSION: We studied the prediction of spot sign on hematoma expansion and clinical outcomes in the different subtypes of ICH. Our study showed that spot sign is a good predictor in IPH but not IVH. Despite the rarity of IVH; the prevalence of spot sign was higher in IVH than IPH. This might be due to anatomical and physiological variations. PMID- 30014240 TI - Step length predicts executive dysfunction in Parkinson's disease: a 3-year prospective study. AB - Cognition and gait appear to be closely related. The chronological interplay between cognitive decline and gait dysfunction is not fully understood. The aim of the present prospective study is investigating whether the dysfunction of specific gait parameters, during specific task and medication conditions, may predict subsequent cognitive impairment in Parkinson's disease (PD). We evaluated cognition and gait in 39 Parkinsonian patients at an initial assessment and after 3 years. Cognitive performance was evaluated with a neuropsychological battery designed to assess memory, executive/attention, and visuospatial domains. Gait was investigated using a gait analysis system during both the off and on states in the following conditions: (1) normal gait; (2) motor dual task; and (3) cognitive dual task. We used regression models to determine whether gait predicts subsequent cognitive dysfunction. Overall, the cognitive test scores were stable over time with the exception of the executive/attention scores, whereas all gait parameters declined. The step length during the cognitive dual task during the on state at the initial evaluation was the only significant predictor of executive/attention domain dysfunction at follow up. The results were confirmed when executive/attention dysfunction at the initial assessment evaluation was included in the regression model as a covariate. Our longitudinal study offers additional insight into the progression of gait dysfunction, and its chronological relationship with cognitive dysfunction in PD patients. In particular, the present study indicates that step length during a cognitive task when on medication is an independent predictor of future executive/attention decline. PMID- 30014241 TI - Abundance and diversity of prokaryotes in ephemeral hypersaline lake Chott El Jerid using Illumina Miseq sequencing, DGGE and qPCR assays. AB - Chott El Jerid is the largest hypersaline ephemeral lake in southern Tunisian Sahara desert and is one of the biggest depressions at the North of Africa. This study aimed to investigate the diversity and abundance of microbial communities inhabiting Chott El Jerid during wet season (when it was flooded), using molecular methods [Illumina Miseq sequencing, DGGE and qPCR (qPCR)]. 16S rRNA gene analyses revealed that bacterial community was dominated by Proteobacteria (especially Ralstonia species), followed by Firmicutes, Bacteroidetes, Cyanobacteria, Actinobacteria and Verrucomicrobia. The results obtained using prokaryotic universal primers showed low relative abundance of Archaea dominated by few OTUs related to Methanosarcinaceae and Methanomassiliicoccaceae families and the presence of sulfate-reducing Archaea affiliated with Archaeoglobus. However, the results obtained using Archaea-specific primers showed that archaeal community was mainly composed of aerobic Halobacteria (especially Halorubrum species) and anaerobic members of Methanomicrobia. These results also provided evidence for the presence of members of the genus Halohasta in this environment. qPCR results revealed that Archaea were more abundant in studied samples than Bacteria. The sulfate-reducing Bacteria were also found abundant (~ one-third of the bacterial community) and outnumbered methanogens, suggesting their potential important role in this sulfate-rich and hypersaline ecosystem. PMID- 30014243 TI - A Systematic Review of Ultrasound-Detected Lipohypertrophy in Insulin-Exposed People with Diabetes. AB - INTRODUCTION: Lipohypertrophy (LH) is a common complication occurring in diabetes individuals. The most common methods used include palpation, visual examination and/or ultrasound (US). To date, there is limited information on the detection sensitivity among the different techniques used to identify LH. This systematic review aimed to identify studies that examined insulin-related LH using US detection to identify the prevalence, characteristics and morphology of LH, and to compare US and clinical palpation methods for detecting LH. METHODS: Three electronic databases were systematically searched for studies detecting LH using US in insulin users. Articles were screened for eligibility and included studies were appraised using quality assessment tools. The quality of the evidence was evaluated using Grading of Recommendations Assessment, Development and Evaluation, and the extracted data was synthesised narratively. RESULTS: Sixteen articles were included in the review providing data on 1722 patients. The prevalence of LH prevalence varied from 14.5% to 88% (median 56.6%). Identified risk factors for the development of included insulin injection behaviour such as a lack of injection site rotation and social factors such as low education level. Four studies compared LH detection by US to palpation, providing inconsistent results. One study showed that palpation detected 64% more LH, whilst two studies demonstrated that US identified 50% more sites and extended areas of LH (additional ~ 5 cm2). Another study provided comparable estimates between palpation and US in clinicians trained to detect LH (97%). CONCLUSION: The evidence highlights a lack of congruence in results pertaining to the detection sensitivity of US and palpation for LH sites. More research with robust study design is needed to verify whether clinically palpation is sufficient to detect LH, or whether US would increase the precision of LH assessment to help address this common clinically significant problem. PMID- 30014242 TI - Characterization of esterase activity from an Acetomicrobium hydrogeniformans enzyme with high structural stability in extreme conditions. AB - The biotechnological and industrial uses of thermostable and organic solvent tolerant enzymes are extensive and the investigation of such enzymes from microbiota present in oil reservoirs is a promising approach. Searching sequence databases for esterases from such microbiota, we have identified in silico a potentially secreted esterase from Acetomicrobium hydrogeniformans, named AhEst. The recombinant enzyme was produced in E. coli to be used in biochemical and biophysical characterization studies. AhEst presented hydrolytic activity on short-acyl-chain p-nitrophenyl ester substrates. AhEst activity was high and stable in temperatures up to 75 degrees C. Interestingly, high salt concentration induced a significant increase of catalytic activity. AhEst still retained ~ 50% of its activity in 30% concentration of several organic solvents. Synchrotron radiation circular dichroism and fluorescence spectroscopies confirmed that AhEst displays high structural stability in extreme conditions of temperature, salinity, and organic solvents. The enzyme is a good emulsifier agent and is able to partially reverse the wettability of an oil-wet carbonate substrate, making it of potential interest for use in enhanced oil recovery. All the traits observed in AhEst make it an interesting candidate for many industrial applications, such as those in which a significant hydrolytic activity at high temperatures is required. PMID- 30014244 TI - Phase I trial of Lipovaxin-MM, a novel dendritic cell-targeted liposomal vaccine for malignant melanoma. AB - INTRODUCTION: In this phase I study using a 3 + 3 dose escalation design, the safety, dose-limiting toxicity (DLT), immunogenicity and efficacy of intravenous Lipovaxin-MM-a multi-component dendritic cell-targeted liposomal vaccine against metastatic melanoma-was investigated. METHODS: Twelve subjects with metastatic cutaneous melanoma were recruited in three cohorts. Patients in Cohort A (n = 3) and Cohort B (n = 3) received three doses of 0.1 and 1 mL of Lipovaxin-MM, respectively, every 4 weeks. Patients in Cohort C (n = 6) received four doses of 3 mL vaccine weekly. Immunologic assessments of peripheral blood were made at regular intervals and included leukocyte subsets, cytokine levels, and Lipovaxin MM-specific T-cell and antibody reactivities. Tumor responses were assessed by RECIST v1.0 at screening, then 8 weekly in Cohorts A and B and 6 weekly in Cohort C. RESULTS: Of a total of 94 adverse events (AEs) reported in ten subjects, 43 AEs in six subjects were considered to be possibly or probably vaccine-related. Most (95%) vaccine-related AEs were grade 1 or 2, two (5%) grade 3 vaccine related AEs of anemia and lethargy were recorded, and higher grade AEs and DLTs were not observed. No consistent evidence of vaccine-specific humoral or cellular immune responses was found in post-immunization blood samples. One patient had a partial response, two patients had stable disease, and the remaining patients had progressive disease. CONCLUSIONS: Lipovaxin-MM was well tolerated and without clinically significant toxicity. Immunogenicity of Lipovaxin-MM was not detected. Partial response and stable disease were observed in one and two patients, respectively. PMID- 30014246 TI - In recognition of Ireland's doctor scientists: Carel le Roux, Seamas Donnelly and Michael P Keane. PMID- 30014247 TI - A novel role for estrogen-induced signaling in the colorectal cancer gender bias. AB - Colorectal cancer (CRC) is a malignancy whose incidence is increasing globally, and there is a gender difference in the increasing risk. Evidence from hormone replacement therapy studies points to a role for circulating estrogens in suppressing the development of CRC. Estrogen receptor-beta has been identified as a tumor suppressor, but other actions of estrogen may also contribute to the difference in CRC incidence between men and women. The KCNQ1/KCNE3 potassium channel is regulated by estrogen in order to modulate chloride secretion during the menstrual cycle; the effect of estrogen on the colon is to promote fluid conservation during the implantation window. KCNQ1 is also a tumor suppressor in CRC, and its sustained expression has been linked to suppression of the Wnt/beta catenin signaling pathway that contributes to CRC tumor progression. KCNQ1 regulation may represent a link between the normal physiological actions of estrogen in the colon and the hormone's apparent tumor-suppressive effects in CRC development. PMID- 30014248 TI - Brief Report: Cross-Modal Capture: Preliminary Evidence of Inefficient Filtering in Children with Autism Spectrum Disorder. AB - This study investigates how task-irrelevant auditory information is processed in children with autism spectrum disorder (ASD). Eighteen children with ASD and 19 age- and IQ-matched typically developing (TD) children were presented with semantically-congruent and incongruent picture-sound pairs, and in separate tasks were instructed to attend to only visual or both audio-visual sensory channels. Preliminary results showed that when required to attend to both modalities, both groups were equally slowed for semantically-incongruent compared to congruent pairs. However, when asked to attend to only visual information, children with ASD were disproportionally slowed by incongruent auditory information, suggesting that they may have more difficulty filtering task-irrelevant cross-modal information. Correlational analyses showed that this inefficient cross-modal attentional filtering was related to greater sociocommunicative impairment. PMID- 30014245 TI - Methylation of Cdkn1c may be involved in the regulation of tooth development through cell cycle inhibition. AB - Cdkn1c, a member of the Cip/Kip cyclin-dependent kinase inhibitor family, is critically involved in regulating cell cycle and cellular differentiation during development in mammals. However, the functional role of Cdkn1c and the underlying mechanisms by which Cdkn1c affects odontogenesis remain largely unknown. In our study, we found that Cdkn1c expression dynamically changes from embryonic day 11.5 (E11.5) to postnatal day 3 (P3), and exhibits tissue-specific expression profiles. Evaluation of CDKN1C protein by immunohistochemistry and western blot, revealed that CDKN1C protein expression peaks at P3 and then is reduced at P5 and P7. Interestingly, we observed that CDKN1C expression is higher in immature odontoblasts than preodontoblasts, is lower in mature odontoblasts, and is practically absent from ameloblasts. We evaluated cell cycle progression to further investigate the mechanisms underlying CDKN1C-mediated regulation of odontogenesis, and found that pRB, cyclin D1 and CDK2 expression decreased from P1 to P3, and reduced at P5 and P7. In addition, we observed increased methylation of KvDMR1 at P1 and P3, and reduced KvDMR1 methylation at P5 and P7. However, the methylation levels of Cdkn1c-sDMR were relatively low from P1 to P7. In summary, we demonstrated that Cdkn1c expression and methylation status may be involved in early postnatal tooth development through regulating the cell cycle inhibition activity of Cdkn1c. Notably, Cdkn1c expression and methylation may associate with cell cycle exit and differentiation of odontoblasts. PMID- 30014249 TI - Sunk Cost Effect in Individuals with Autism Spectrum Disorder. AB - The sunk cost effect, an interesting and well-known decision bias, is pervasive in real life and has been studied in various disciplines. In this study, we modified a task exemplifying the sunk cost effect and used it to evaluate this behavior in individuals with autism spectrum disorder (ASD). The control group exhibited a typical sunk cost effect in our task. We found that the sunk cost effect was lower in the ASD group than in the control group. The results agree with previous evidence of reduced sensitivity to context stimuli in individuals with ASD and extend this finding to the context of the sunk cost effect. Our findings are useful in addressing the practical implications on their socioeconomic behavior. PMID- 30014250 TI - Movement Disorders and Syndromic Autism: A Systematic Review. AB - Movement disorders are reported in idiopathic autism but the extent to which comparable movement disorders are found in syndromic/co-morbid autism is unknown. A systematic search of Medline, Embase, PsychINFO and CINAHL on the prevalence of specific movement disorder in syndromic autism associated with specific genetic syndromes identified 16 papers, all relating to Angelman syndrome or Rett syndrome. Prevalence rates of 72.7-100% and 25.0-27.3% were reported for ataxia and tremor, respectively, in Angelman syndrome. In Rett syndrome, prevalence rates of 43.6-50% were reported for ataxia and 27.3-48.3% for tremor with additional reports of dystonia, rigidity and pyramidal signs. However, reliable assessment measures were rarely used and recruitment was often not described in sufficient detail. PMID- 30014251 TI - Transjugular Intrahepatic Portosystemic Shunt Through the Strut of a Previously Placed Stent: Technical Feasibility and Long-Term Follow-Up Results. AB - AIMS AND OBJECTIVES: To evaluate technical feasibility, long-term primary patency and clinical outcome of the transjugular intrahepatic portosystemic shunt (TIPS) through the struts of the previously placed stents. MATERIALS AND METHODS: Retrospective evaluation of seven consecutive patients (three male and four female, age range 13-65 years, median 28) out of a total 95 patients, who underwent TIPS through the strut of the previously placed stents of hepatic vein (HV), inferior vena cava (IVC) or TIPS in a single tertiary care hospital. Six of the patients were diagnosed with Budd-Chiari syndrome (BCS) and one with alcohol induced chronic liver disease (CLD). Kaplan-Meier test was used to calculate 18- and 60-month primary patency rate of TIPS stent. RESULTS: TIPS through the strut of a previously placed stent was technically successful in all the patients (100%). The TIPS was direct intrahepatic portosystemic shunt (DIPS) in 5/7 cases, due to occluded HV. Mean portosystemic pressure gradient (PPG) reduced from 24 mmHg +/- 5.9 (range, pre-TIPS 15-31 mmHg) to 8.57 mmHg +/- 4.4 (range, post-TIPS, 3-14 mmHg). One patient required three sessions of TIPS revisions. Another patient needed TIPS revision after 5 years of TIPS creation. All the patients showed improvement in clinical symptoms and in mean Child-Turcotte-Pugh (CTP) score and modified end-stage liver disease (MELD) score during mean follow-up period 40.57 month +/- 34.9 (range 3-100 month). Primary patency rates of TIPS stent measured with Kaplan-Meier estimate at 18- and 60-month follow-up were 80% (95% CI, 37-97%) and 40% (95% CI, 10-97%), respectively. CONCLUSION: TIPS through the strut of a previously placed stent is technically feasible with good long term primary patency and clinical outcome. PMID- 30014252 TI - Intra-caval Percutaneous Radiofrequency Ablation for a Neuroendocrine Tumor (NET) Metastasis in Transplanted Liver. AB - Less than 1% of patients with liver metastases from neuroendocrine tumors (NETs) are susceptible to liver transplantation. We report a case of a patient transplanted 13 years ago for NET metastases, with a lesion histologically proved for NET metastasis located at the cava vein anastomosis. He was treated with percutaneous radiofrequency ablation (RFA) after a first failed attempt of endovascular approach. The vascular heat sink, which RFA is susceptible to, was considered an advantage in this case, since it restricted the propagation of heat only to the tissue located in the very proximity of the RFA antenna, protecting the inferior vena cava vessel walls. This positive result may suggest an additional use of RFA in selected challenging cases. PMID- 30014254 TI - Right infraaxillary thoracotomy approach for upper thoracic vertebral decompression and fusion at T2-T6 levels: a technical note. AB - PURPOSE: Disorders of the upper thoracic spine can lead to serious disability and morbidity. However, operating on the upper thoracic vertebrae T2-T5 remains challenging because of the anatomical features of the thoracic spine. We describe a novel anterolateral upper thoracic approach, which is safe and reproducible and allows direct access to the upper thoracic spine from T2 to T6 inclusive, obviating the risk of damaging complex anatomical structures inherent in the anterior trans-sternal approach. METHODS: Three patients with upper thoracic spinal-related spinal cord compression disease, presented with progressive thoracic myelopathy and upper back pain. Magnetic resonance imaging showed direct spinal cord compression due to upper thoracic vertebral destruction. In addition preoperative computed tomography also revealed vertebral erosion and collapse. The surgical management of the three patients involved decompression and reconstruction via the right infraaxillary thoracotomy approach, and fixation with a titanium mesh cage and an anterior plate in each. RESULTS: Clinical outcome measures including pre- and postoperative radiographic parameters were assessed. There were no complications associated with this technique. The back pain and neural function gradually improved, and plate placement was achieved in all patients. None of the patients experienced clinical symptoms or screw loosening or breakage in this study. CONCLUSIONS: The technique described is a safe and novel right infraaxillary thoracotomy approach to provide direct access from vertebral bodies T2-T6 and to provide adequate room for upper thoracic vertebral decompression and fusion surgery. However, a suitable fixation implant should be designed. These slides can be retrieved under Electronic Supplementary Material. PMID- 30014253 TI - Identification of genome-wide binding sites of heat shock factor 1, Hsf1, under basal conditions in the human pathogenic yeast, Candida albicans. AB - The master regulator of thermal stress response, Hsf1, is also an essential determinant for viability and virulence in Candida albicans. Our recent studies highlighted that apart from ubiquitous roles of Hsf1 at higher temperatures, it also has myriad non-heat shock responsive roles essential under iron deprivation and drug defense. Here, we further explored its implications in the normal cellular functioning, by profiling its genome-wide occupancy using chromatin immuno-precipitation coupled to high-density tiling arrays under basal and iron deprived conditions. Hsf1 recruitment profiles revealed that it binds to promoters of 660 genes of varied functions, under both the conditions, however, elicited variability in intensity of binding. For instance, Hsf1 binding was observed on several genes of oxidative and osmotic stress response, cell wall integrity, iron homeostasis, mitochondrial, hyphal and multidrug transporters. Additionally, the present study divulged a novel motif under basal conditions comprising, -GTGn3GTGn3GTG- where, Hsf1 displays strong occupancy at significant number of sites on several promoters distinct from the heat induced motif. Hence, by binding to and regulating major chaperones, stress responsive genes and drug resistance regulators, Hsf1 is imperative in regulating various cellular machineries. The current study provides a framework for understanding novel aspects of how Hsf1 coordinates diverse cellular functions. PMID- 30014255 TI - [Influence of tumor-free resection margins on overall and disease-free survival after resection of colorectal liver metastases]. PMID- 30014256 TI - Low dosage of arsenic trioxide (As2O3) inhibits angiogenesis in epithelial ovarian cancer without cell apoptosis. AB - Arsenic trioxide (As2O3) induces cell apoptosis and reduces the invasive and metastatic activities in various cancer types. However, the role of As2O3 in ovarian cancer angiogenesis remains unclear. In this study, we investigated the role of As2O3 in ovarian cancer angiogenesis and found that a low concentration of As2O3 causes no effects on epithelial ovarian cancer cell viability or apoptosis. Moreover, we found that As2O3-treated epithelial ovarian cancer cells demonstrate a reduced tube formation of endothelial cells in Matrigel. In addition, As2O3-treated epithelial ovarian cancer cells show a decreased VEGFA, VEGFR2 and CD31 mRNA expression. As per the underlying mechanisms involved in As2O3 treatment, we found that As2O3 inhibits VEGFA and VEGFR2 expression that thereby inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway. This leads to a suppression in both VEGFA synthesis and angiogenesis-related gene expression. A decreased VEGFA synthesis and secretion also inhibits the VEGFA-VEGFR2-PI3K/ERK signaling pathway in human umbilical vein endothelial cells (HUVECs). In summary, our results may provide strategies for the use of As2O3 in the prevention of tumor angiogenesis. PMID- 30014257 TI - A reevaluation of iron binding by Mycobactin J. AB - The complex stability constant (log beta110) and the free iron concentration (pM) are used to compare the relative strength of iron binding by siderophores. Direct measurements of these thermodynamic parameters are often not possible for siderophores due to very large log beta110 values ranging from 30 to 50. Instead, siderophore iron(III)-binding constants are determined by competitive experiments with other strong chelators with known values, such as EDTA. Iron(III) binding constants of water-insoluble siderophores, such as the mycobactins produced by the mycobacterium family, have never been directly measured. Since mycobactins contain two hydroxamic acid binding motifs, their log beta110 values have been assumed to be comparable to those of other hydroxamate-based siderophores like desferrioxamine B, at ~ 30. However, exochelin MN, another mycobacterial siderophore that contains two hydroxamic acid moieties, has a log beta110 of 39.1 and a pM of 31.1, which makes it among the strongest siderophores known. We have found that mycobactin J, the amphiphilic siderophore of Mycobacterium paratuberculosis, can remove iron(III) from TrenCAM (log beta110 = 43.6) within 1 min in methanol. This surprising result indicates that log beta110 for mycobactin J is ~ 43 and the ligand exchange kinetics in methanol is fast. The results imply that mycobactins are capable of removing iron quickly from very strongly binding siderophores in a cellular milieu. We propose a model mechanism for iron acquisition by pathogenic mycobacteria in vivo. This model explains how the host iron captured by siderophores can be returned to the invading pathogen even in the absence of active uptake mechanisms. PMID- 30014258 TI - An EMS-induced new sequence variant, TEMS5032, in the coding region of SRS3 gene leads to shorter grain length in rice (Oryza sativa L.). AB - Grain shape and size influence yield and consumer preferences in rice. In the present study, we characterized and mapped a short and bold grained mutant and named it as TEMS5032, as the mutant is a result of EMS-induced transition from C to T at the 5032nd bp of SRS3 gene, which is known to affect grain size in rice. The substitution led to creation of a stop codon in the motor domain of SRS3, a kinesin 13 family gene, translating into a truncated protein product. However, transcription of this gene remained unaffected in TEMS5032 compared to the wild type, N22. Further, the mutation was found to affect 13 of the 25 cell cycle related genes as they showed differential expression with respect to N22. Based on rate of grain filling, dry matter accumulation in the endosperm and histological studies, the effect of mutation in TEMS5032 was found to be similar to a known variant, TCM758, but less severe than sar1 mutant. Sequencing of 88 rice germplasm lines in the kinesin motor domain region did not reveal the presence of this mutation, establishing it as a new variant of SRS3 gene. PMID- 30014259 TI - Comparative Profiling of Three Atheris Snake Venoms: A. squamigera, A. nitschei and A. chlorechis. AB - A proteomic and transcriptomic comparative analysis of the venoms of three Atheris species (A. squamigera, A. nitschei and A. chlorechis) was carried out by size exclusion liquid chromatography, gel electrophoresis, mass spectrometry, and mRNA sequencing. The improved proteomic profiling utilised in this work was combined with transcript studies, advancing our insights into venom composition, protein distribution and inter-species variation among the three bush vipers. Crude venoms of all three samples contained at least 10-20 protein components, ranging in size from <= 3 to > 98 kDa. Both approaches yielded converging overall information, pointing to phospholipases, disintegrins, serine proteases and metalloproteases as the major toxin classes, which are likely to explain the local and systemic symptoms observed in envenomation by Atheris genus. Being considered as the main factors involved in the distinct venom-induced pathologies, these identified snake venom proteins are of particular interest in terms of understanding their physiological and biological function as well as for their contribution in potential medical treatments. PMID- 30014262 TI - Duodenal Invasion of Pancreatic Cancer Resulting in Hematemesis. PMID- 30014260 TI - Fatigue in early, intensively treated and tight-controlled rheumatoid arthritis patients is frequent and persistent: a prospective study. AB - Fatigue has a large impact on quality of life and is still unmanageable for many patients. Study aims were describe (1) the prevalence and pattern of fatigue over time in patients with early rheumatoid arthritis under a treat-to-target strategy and (2) identify predictive factors for worsening and recovering of fatigue over time. Data from the tREACH study were used, comparing different treatment strategies with fatigue as secondary objective. Patient outcomes on fatigue, quality of life, depression, and coping were obtained every 6 months and clinically assessed every 3 months. Prediction of fatigue at 12 months was investigated with an ROC curve. Analysis was stratified into non-fatigue and fatigue at baseline. Logistic regression was used for the evolution of fatigue in relation with the covariates over time. Almost half of all patients (n = 246) had high fatigue levels at baseline, decreasing slightly over time. At 12 months, 43% of patients were fatigued; while 23% of the initially fatigued patients showed lower levels of fatigue, the fatigue level had increased in 15% of the initially non-fatigued patients. The strongest predictor of fatigue was the previous fatigue levels (AUC 0.89). Higher score on the depression scale and coping with limitations was associated with developing fatigue over time in the initially non fatigued group. Despite a strict treat-to-target strategy, fatigue remained an overall problem during the first year of treatment, and was mainly predicted by its baseline status. In subgroups, a small additional effect of depression was seen. Monitoring fatigue and depression may be important in managing fatigue. PMID- 30014261 TI - Charging and Charge Switching of Unsaturated Lipids and Apolar Compounds Using Paterno-Buchi Reactions. AB - The ability to control the charge state and ionization efficiency of lipids and hydrocarbons by means of in-source Paterno-Buchi functionalization in nano electrospray ionization mass spectrometry experiments is investigated. Ultraviolet light irradiation of acetylpyridine filled nano-electrospray emitter tips, containing unsaturated analytes, generates protonated lipid and hydrocarbon ions. Comparison of reaction yields and fragment ion abundances of functionalized unsaturated fatty acids indicate that acetylpyridine Paterno-Buchi functionalization allows to readily detect fatty acids and determine double bond positions, but fragmentation efficiency and reactivity depend on double bond position and varies between different acetylpyridine isomers. Results for methyl oleate and olefins suggest that fragment ion abundances of unsaturated compounds depend on interactions between acetylpyridine and nearby functional groups. Paterno-Buchi functionalization with acetylpyridine was used to detect and assign double bond positions of mono- and polyunsaturated fatty acid, cholesterol ester, triglyceride, and hydrocarbon standards with ion abundances that are up to 631 times higher than abundances of the same compounds prior Paterno-Buchi reaction. To demonstrate the scope and analytical robustness of the newly developed method, free fatty acids in mouse brain as well as male Schistosoma mansoni extracts and hydrocarbons in an olefin mixture are investigated. For this complex set of analytes, charging and charge switching using acetylpyridine Paterno-Buchi functionalization enable double bond position assignment and relative quantification in positive ion mode. Graphical Abstract. PMID- 30014263 TI - [Syncope in prehospital emergency medicine]. AB - Loss of consciousness is a frequent cause for an emergency call to the emergency medical services (EMS). It can be associated with life-threatening conditions. A distinction must be made between transient loss of consciousness (TLOC) and syncope, which is of cardiovascular origin by definition. Initial assessment in prehospital emergency care should follow the ABCDE algorithm including a 12-lead ECG. The presence of important risk factors such as occurrence in supine position, physical stress, palpitations, history of heart diseases, and any abnormalities in the ECG warrants hospital admission. Initial treatment without admission to an emergency department may only be acceptable for healthy patients without any risk factors and injuries, when vital signs are normal and an orthostatic etiology seems most likely. PMID- 30014264 TI - Effect of Morphology and Crystal Structure on the Thermal Conductivity of Titania Nanotubes. AB - Titania nanotubes (TNTs) with different morphology and crystal structure are prepared by chemical processing and rapid breakdown anodization (RBA) methods. The nanotubes are studied in terms of thermal conductivity. The TNTs with variable wall thickness below 30 nm have significantly reduced thermal conductivity than bulk titania, due to the phonon confinement, smaller phonon mean free path, and enhanced phonon boundary scattering. The amorphous nanotubes (TNTAmor) have comparatively thicker walls than both crystalline nanotubes. The TNTAmor has a thermal conductivity of 0.98 W m-1 K-1, which is slightly less than the thermal conductivity of crystalline anatase nanotubes (TNTA; 1.07 W m-1 K-1). However, the titania nanotubes with mixed structure (TNTA,T) and the smallest dimensions have the lowest thermal conductivity of 0.75 W m-1 K-1, probably due to the phonon confinement. The experimental results are compared with the theoretical study considering the size confinement effect with different wall dimensions of TNTs and surface scattering. The results agree well with the surface roughness factor (p) of 0.26 for TNTA,T, 0.18 for TNTA, and 0.65 for TNTAmor, indicating diffusive phonon scattering and rougher surfaces for TNTA. Interestingly, the present results together with those presented in literature suggest that thermal conductivity reduction with respect to the wall thickness occurs also for the amorphous nanotubes. This is ascribed to the role of propagons in the thermal transport of disordered structures. PMID- 30014265 TI - Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals. AB - AIMS/HYPOTHESIS: Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and optic atrophy and is caused by bi allelic mutations in the WFS1 gene. In a recent sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the WFS1 gene. The aim of this study was to perform the genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome. METHODS: We analysed the allele frequency of the missense variant in multiple variant databases. We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes. We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls. RESULTS: The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3, p = 3.4 * 10-15). The age at diagnosis of diabetes for these eight individuals (17.8 +/- 8.3 years) was several times greater than for typical Wolfram syndrome (5 +/- 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had the Wolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case-control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81, p = 0.004). CONCLUSIONS/INTERPRETATION: We have identified a low-frequency coding variant in the WFS1 gene that is enriched in Ashkenazi Jewish individuals and causes a mild form of Wolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels. PMID- 30014266 TI - Sensitive and early detection of mitochondrial dysfunction in the liver of NASH model mice by PET imaging with 18F-BCPP-BF. AB - BACKGROUND: Nonalcoholic fatty liver disease is a common disorder that progresses from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH). It is thought that mitochondrial dysfunction plays a critical role in the progression of NASH. In this study, we developed a non-invasive method for early diagnosis and staging of NASH that directly measures mitochondrial complex-I (MC-I) activity in the liver of NASH model mice by positron emission tomography (PET) imaging using the novel tracer 2-tert-butyl-4-chloro-5-[6-(4-[18F]fluorobutoxy) pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF). Liver uptake of 18F-BCPP BF in NASH and age-matched control mice was measured as a standard uptake value over a period of 1 to 12 weeks. Histopathological evaluation of the liver tissue was performed by haematoxylin and eosin staining, and fibrosis was assessed by Masson's trichrome staining. RESULTS: Significant mitochondrial dysfunction was detected as early as 1 week after commencing the diet, and MC-I activity in the liver measured by PET was reduced by > 50% relative to that in age-matched control mice after 6 weeks. Liver uptake of 18F-BCPP-BF was low throughout the 12 week experimental period. Histopathological examination revealed that steatosis, inflammation, and ballooning progressed from 1 to 6 weeks, with fibrosis observed from 6 to 12 weeks. CONCLUSIONS: PET scans and histopathological analysis revealed that mitochondrial dysfunction in the liver contributed to the progression of NASH. PET imaging with 18F-BCPP-BF is a useful tool for detecting NASH at early stages and for monitoring therapeutic response. PMID- 30014267 TI - Framework for Evaluating and Implementing Inpatient Portals: a Multi-stakeholder Perspective. AB - Inpatient portals are emerging as an important tool to support patient care and are increasingly being adopted in hospitals. However, best practices concerning the implementation, use, and impact of these portals are poorly understood. To improve evaluation and implementation efforts, this paper develops a logic model that can help researchers and hospital managers in deploying and assessing the impact of inpatient portals. Guided by the Systems Engineering Initiative for Patient Safety (SEIPS) framework, we held a series of two focus groups (n = 12 and n = 8, respectively) and an online forum (n = 14) including hospital administrators, clinicians, patients, and information technology team members to learn from these stakeholders about the system-wide implementation and evaluation of an inpatient portal at an academic medical center in the United States. These sessions were supplemented with a Nominal Group process to assess the relative importance and feasibility of evaluation areas. Our Logic Model highlights that patients are at the center of the multi-stakeholder context within which inpatient portals are being implemented, and that collaborative work is necessary for successful implementation and evaluation of the tool. The Model also identifies priority areas for evaluation, and it suggests measures and data sources applicable for quality improvement and research. Applying the SEIPS 2.0 framework, this Logic Model captures the multiple relevant stakeholder perspectives by describing the organizational structures, processes, and outcomes that pertain to inpatient portals. This Model provides specific evaluation suggestions for hospital managers seeking to implement inpatient portals as well as for researchers seeking to evaluate this new technology. PMID- 30014269 TI - A longitudinal study of the association of the eicosapentaenoic acid/arachidonic acid ratio derived from fish consumption with the serum lipid levels: a pilot study. AB - : It has been demonstrated that regular fish consumption is associated with a reduced mortality from atherosclerotic cardiovascular disease (ASCVD). However, data are scarce regarding the correlation between the changes in the serum eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio associated with regular fish consumption and the changes in the serum lipid profile variables. This study was designed as a hospital-based longitudinal study to investigate the relationship between the changes in the serum EPA/AA ratio and changes of the serum lipid levels in patients with one or more risk factors for ASCVD. In 475 patients followed-up for at least 1 year, univariable and multivariable regression analyses conducted after adjustments for the risk factors of ASCVD revealed that the absolute change of the EPA/AA ratio (?EPA/AA ratio) was independently and significantly associated with the changes of the serum levels of low-density lipoprotein cholesterol (LDL-C) (beta = - 0.129, p = 0.005), triglyceride (TG) (beta = - 0.108, p = 0.019), non-high-density lipoprotein cholesterol (non-HDL-C) (beta = - 0.149, p = 0.001), and TG/HDL-C ratio, a marker of the LDL particle size (beta = - 0.104, p = 0.02), while not being correlated with any other lipid parameters. On the other hand, while the ? docosahexaenoic acid (DHA)/AA ratio was inversely correlated with the changes of the serum HDL-C level and positively correlated with the changes of the TG/HDL-C ratio, possibly serving to promote development of atherosclerosis. The results suggest that an increase of the EPA/AA ratio might be associated with decrease of the serum levels of LDL-C, TG and non-HDL-C levels, as well as with an increase of the TG/HDL-C ratio, which represents increased LDL particle size, all of which play a role in the development of ASCVD. A high EPA/AA ratio, but not DHA/AA ratio, derived from fish consumption might reduce the risk of ASCVD through reducing the risk of development of atherosclerosis. CLINICAL TRIAL REGISTRATION INFORMATION: UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603. PMID- 30014270 TI - Pre-hospital rescue times and interventions in severe trauma in Germany and the Netherlands: a matched-pairs analysis. AB - PURPOSE: The aim of this study was to compare the pre-hospital treatment of major trauma patients with similar injury patterns in Germany and the Netherlands. PATIENTS AND METHODS: This matched-pairs analysis is based on the TraumaRegister DGU(r). The authors compared major trauma patients (ISS >= 16) from 2009 to 2015 treated in Dutch and German Level 1 trauma centers (TC). Endpoints were the pre hospital times and interventions performed until hospital admission. Additional endpoints included hospital mortality, 24-h mortality and standardized mortality ratio (SMR) which was calculated using the Revised Injury Severity Classification, version II (RISC II). Patients were matched by age, gender, injury pattern, vital status on-scene and involvement into a traffic accident. Three subgroups were formed according to the mode of transportation and level of care provided during transport: Ambulance/Physician, Helicopter/Physician and Ambulance/Emergency Medical Technician. RESULTS: Patients were matched into 1094 pairs. German patients arrived at the TC after a mean pre-hospital time of 65.6 (+/- 29.6) min while Dutch patients arrived after 61.4 (+/- 28.7) min. Pre hospital intubation rate was slightly higher in the Netherlands (44.1% GER vs 50.5% NL). Chest tubes were placed in 3.0% of German patients and 8.3% of Dutch patients. 63.5% of the German patients received analgesia/sedation which was below the rate of Dutch patients (71.1%). The hospital mortality was for 17.6% for German patients and 19.8% for Dutch patients. The SMR was about 1.0 for both groups. CONCLUSION: Multiple differences and some similarities in the treatment of major trauma patients with similar injury patterns were found but no clinically relevant differences in the chosen outcome parameters could be observed. PMID- 30014271 TI - Non-invasive cardiac output monitoring device "ICON" in trauma patients: a feasibility study. AB - PURPOSE: Assessment of hemodynamics is crucial for the evaluation of major trauma patients. Cardiac output (CO) monitoring provides additional information and may improve volume resuscitation. The goal of this prospective pilot study was to evaluate the feasibility of a new non-invasive CO monitoring (NICOM) device in the emergency department (ED). METHODS: Single-center prospective observational pilot study including 20 trauma patients admitted to a level 1 trauma center. CO was continuously monitored for 60 min after ED admission using the new NICOM device ICON(r). This device measures changes of the thoracic bioimpedance to calculate CO. Conventional vital signs were recorded simultaneously. Feasibility, safety, reliability, user-friendliness, and impact of the device on standard ED procedures were assessed. RESULTS: Thirteen (65%) patients were male, median age was 57.5 (IQR 25), and median ISS was 10.5 (IQR 14.8). Median CO over time was 9.8 l/min (IQR 4.6). No adverse effects were recorded. The device proved to be user-friendly with no negative impact on routine ED care. In four patients, detachment of electrodes was observed, and in four patients, the CO recording was temporary discontinued. Short-term changes of the CO were observed 44 times after the placement of electrodes and during patient transfers. CONCLUSIONS: Non invasive CO monitoring proved to be feasible and safe for the initial hemodynamic evaluation of trauma patients. Problems with the NICOM device were detachment of electrodes and temporary signal loss. Due to the small sample size and relatively low injury burden of the patients included in this study, further prospective investigation is warranted. PMID- 30014268 TI - Centrally Acting Agents for Obesity: Past, Present, and Future. AB - For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate, which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/naltrexone, naltrexone blocks the feed-back inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in Phase III trials for obesity, and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide, is a melanocortin-4 receptor agonist, which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues. PMID- 30014272 TI - Comparison of lower extremity fasciotomy wound closure techniques in children: vacuum-assisted closure device versus temporary synthetic skin replacement. AB - PURPOSE: No clear consensus on the optimal treatment of fasciotomy wounds due to acute compartment syndrome of the lower leg in children exists. We therefore compared two commonly used methods to close fasciotomy wounds, Epigard, a temporary synthetic skin replacement (SSR) and the vacuum-assisted closure (V.A.C.) device, in respect of treatment duration and complication rates. METHODS: We studied the cases of 27 patients who were treated at our institution for acute compartment syndrome of the lower leg with a fasciotomy over a 10-year period. The fasciotomy wound was either treated with SSR or V.A.C. device. We recorded the number of procedures to definitive wound closure, days to wound closure, hospitalization days and sequelae rate. RESULTS: In the V.A.C. device group (18 patients) the mean number of procedures until definitive wound closure was 3.1, mean days until wound closure was 9.4 and mean days of hospitalization was 16.2. One patient suffered from a wound infection and one patient required a full thickness skin graft. In the SSR group (9 patients), the mean number of procedures was 1.8, mean days until definitive wound closure was 4.9 and mean days of hospitalization was 9.9. No sequelae were recorded. There was a statistically significant smaller number of procedures (p value 0.018), fewer days to definitive wound closure (p value 0.002) and fewer hospitalization days (p value 0.005) in the SSR group. CONCLUSIONS: Both SSR and V.A.C. device are safe and reliable for closure of fasciotomy wounds in children, whereas SSR seems to lead to shorter time until definitive wound closure. PMID- 30014273 TI - Comparative analysis of non-simultaneous bilateral fractures of the proximal femur. AB - PURPOSE: We performed a monocenter cohort study to determine surgical revision and mortality after sustaining an initial and a non-simultaneous contralateral proximal femoral fracture. METHODS: We identified all patients surgically treated for a contralateral femoral fracture between 2006 and 2015. Patient demographic characteristics and follow-up were identified by our electronic database; failed information regarding revision and mortality were obtained by telephone, as well as the evaluation of the mobility for all alive patients. The endpoint of the study was set for every patient at least 2 years postoperatively. RESULTS: Within a total of 2296 patients, we identified 250 patients (10.8%) treated for a contralateral fracture. The mean interval between the two occurrences was 5.2 years and the mean age at the time of contralateral fracture was 84.4 years. Almost every third fracture occurred later than 5 years after the initial fracture, and even every tenth fracture later than 10 years. More than 50% of the patients also had dementia at this time. The total surgical revision rate was 17.2% after initial, and 20.4% after contralateral fracture, but this difference was statistically not significant (p = 0.31). However, revisions for infection or hematoma were more than twice after contralateral fracture (p = 0.006). The 1 year mortality rate was 36%, and dementia (log rank p < 0.001) and male gender (log rank p < 0.001) were significant negative predictors for the survival rate. After a mean of 42 months, the follow-up of the 67 alive patients recorded a mean Parker Score of 5.2 items. CONCLUSION: Contralateral femoral fracture was accompanied by a higher revision and mortality rate-but patients were also 5 years older. Dementia and male gender were significant negative variables for the survival time. In the future, the highest priority will be the prophylaxis of falling to avoid or at least to decline the number of these fractures in geriatric patients. PMID- 30014274 TI - Green Emitting Cerium Doped CaS Whiskers Grown by Solid State Diffusion Method. AB - Undoped and cerium doped Calcium sulfide (CaS) phosphors were synthesized using solid state diffusion method. The X-ray diffraction pattern revealed that both undoped and doped CaS crystallites have cubic structure with average crystallite size varying from 20 to 30 nm. Scanning electron micrographs indicated that Ce doped CaS phosphors were composed of whiskers with different dimensions and orientations. The optical properties of undoped and Ce doped particles were characterized using Photoluminescence (PL) and UV-Vis absorption spectroscopy. The PL emission spectrum of cerium doped CaS phosphors for an excitation wavelength 465 nm showed a main peak at 500 nm and a shoulder peak at 556 nm due to 5d -> 4f transition in Ce3+ ions. The variation of PL intensity with cerium concentration was investigated and the maximum PL intensity was obtained for a doping concentration of 3 wt.%. The optical band gap of the samples was estimated from the diffuse reflectance spectrum and was found to increase with increase in cerium concentration. The enhanced optical properties of these phosphors can be exploited in various optoelectronic devices including displays and bioimaging techniques. PMID- 30014275 TI - Synthesis, Photophysical Properties and Application of New Porphyrin Derivatives for Use in Photodynamic Therapy and Cell Imaging. AB - New derivatives of tetrakis(4-carboxyphenyl) porphyrin were designed, synthesized and characterized by IR, proton NMR and mass spectroscopy. The ground and excited state nature of new derivatives were examined using UV-Vis. absorption and fluorescence spectroscopy, fluorescence quantum yield and fluorescence lifetime studies. The singlet oxygen quantum yield of each synthesized derivative of porphyrin was estimated for their further efficacy as potential photosensitizer in biological studies. The significant photophysical data of all synthesized derivatives was supplementary accessed to examine the cell imaging and cytotoxicity against two cancer cell lines viz. MBA-MD-231 and A375. The fluorescence lifetime, fluorescence quantum yield and efficiency of singlet oxygen generation suggests alkyl amine and alkyl hydrazide linked new porphyrin photosensitizers can be useful for PDT agent in cancer treatment. PMID- 30014277 TI - [Segmental testicular infarction]. AB - Segmental testicular infarction is a rare cause of acute scrotum and only a few cases have been reported. Torsion of the testis, testicular tumor and infection are important differential diagnoses. The present case report describes a 61-year old man with left-sided testicular pain increasing over 24 h. The diagnosis of segmental testicular infarction was considered after color Doppler ultrasound of the left scrotum and it was confirmed by surgical exploration and pathological examination. Although it is uncommon, segmental testicular infarction should be taken into consideration when acute scrotal pain is encountered, especially for younger patients, since a testis-sparing treatment strategy can be performed. PMID- 30014278 TI - Capability assessment and tourism development model verification of Haraz watershed using analytical hierarchy process (AHP). AB - The present study aimed at assessing tourism potential of a place to meet requirements of sustainable development policies. We studied the Haraz watershed because of its particular environmental characteristics and a high potential for ecotourism. The required data for this descriptive-analytical research were collected by combining field and desktop studies. First, the ecotourism capability assessment of the area was done using Arc GIS 10.3 software based on the Hyrcanian Forest Tourism Development Model for concentrated tourism and extensive tourism. Next, the most important effective indices included (i.e., 19 indices) were determined by Delphi questionnaire and SPSS 17. Finally, AHP technique was applied to analyze the body mass of the indices in order to verify the validity of the model. The results show that 0.0044, 01.3, 3.52, and 37.71% of the study area is suitable for concentrated ecotourism (grade 1), concentrated ecotourism (grade 2), extensive ecotourism (grade 1), and extensive ecotourism (grade 2), respectively. Based on the model applied, slope, direction, and fundamentals (infrastructure) with the body masses of 0.232, 0.116, and 0.115 were identified as the first priorities. Comparing the results of this model and AHP confirms the validity of the model. To strengthen the tourism development potential of the watershed and protect its ecosystems and biodiversity, it is necessary to choose a proper development model. Failure to identify the existing capacities and the field's sensitivities can cause dissatisfaction of local residents and also damage to the ecosystem of the area. PMID- 30014279 TI - Towards Differential Connectomics with NeuroVIISAS. AB - The comparison of connectomes is an essential step to identify changes in structural and functional neuronal networks. However, the connectomes themselves as well as the comparisons of connectomes could be manifold. In most applications, comparisons of connectomes are applied to specific sets of data. In many studies collections of scripts are applied optimized for certain species (non-generic approaches) or diseases (control versus disease group connectomes). These collections of scripts have a limited functionality which do not support functional and topographic mappings of connectomes (hemispherical asymmetries, peripheral nervous system). The platform-independent and generic neuroVIISAS framework is built to circumvent limitations that come with variants of nomenclatures, connectivity lists and connectional hierarchies as well as restrictions to structural connectome analyses. A new analytical module is introduced into the framework to compare different types of connectomes and different representations of the same connectome within a unique software environment. As an example a differential analysis of the partial connectome of the laboratory rat that is based on virus tract tracing with the same regions of non-virus tract tracing has been performed. A relatively large connectional coherence between the two different techniques was found. However, some detected connections are described by virus tract-tracing only. PMID- 30014276 TI - [Recommendations for extracorporeal cardiopulmonary resuscitation (eCPR) : Consensus statement of DGIIN, DGK, DGTHG, DGfK, DGNI, DGAI, DIVI and GRC]. AB - Extracorporeal cardiopulmonary resuscitation (eCPR) may be considered as a rescue attempt for highly selected patients with refractory cardiac arrest and potentially reversible etiology. Currently there are no randomized, controlled studies on eCPR, and valid predictors of benefit and outcome which might guide the indication for eCPR are lacking. Currently selection criteria and procedures differ across hospitals and standardized algorithms are lacking. Based on expert opinion, the present consensus statement provides a proposal for a standardized treatment algorithm for eCPR. PMID- 30014280 TI - Epidemiology, etiology, and types of severe adult brachial plexus injuries requiring surgical repair: systematic review and meta-analysis. AB - The literature describing epidemiology, etiology, and types of serious brachial plexus injuries (BPIs) is sparse. The aim of this review was to investigate the epidemiological and etiopathogenetical data of serious BPIs undergoing surgical reconstruction. A systematic search was conducted from January 1985 to December 2017. All studies that reported data about prevalence of specific types and causes of BPIs in adults treated surgically were included and cumulatively analyzed. Ten studies including 3032 patients were identified. The pooled prevalence of closed BPIs was 93% (95% CI: 87-97%), lacerations accounted for 3% (95% CI: 1-6%), and gunshot wounds (GSWs) for 3% (95% CI: 0-7%). The prevalence of male patients was 93% (95% CI: 90-96%) and female cases 7% (95% CI: 4-10%). The most common cause of closed BPI was motorcycle accidents with 67% (95% CI: 49 82%) prevalence followed by car crashes with 14% (95% CI: 8-20%). Other causes were rare. Ninety percent (95% CI: 78-98%) of patients suffered from a supraclavicular or combined supra-/infraclavicular trauma, while 10% (95% CI: 2 22%) from isolated infraclavicular injury. The prevalence of complete lesions was 53% (95% CI: 47-58%) followed by upper plexus lesion with 39% (95% CI: 31-48%) and lower plexus injury with 6% (95% CI: 1-12%). This meta-analysis demonstrates that the typical patient suffering from severe BPI is a male after motorcycle accident with closed supraclavicular injury causing complete or slightly less commonly upper plexus palsy. Lacerations and GSWs of brachial plexus are rare. PMID- 30014281 TI - Sources and Levels of Trace Elements Influence Some Blood Parameters in Murrah Buffalo (Bubalus bubalis) Calves. AB - Sources of supplemental minerals in the diet of animals are of important significance. Bio-availability of organic sources is believed to be more in the body as compared to regularly used inorganic sources and hence environment friendly due to reduced mineral excretion, which in turn reduces their requirements in the diet as well. Twenty-four male Murrah buffalo (Bubalus bubalis) calves (about 18-20 months of age and 318.54 +/- 8.85 kg body weight) were divided randomly into four groups of six animals each. In the control group (C, InOrg100) zinc (Zn), copper (Cu), and manganese (Mn) were supplemented through an inorganic source, while in treatment groups, organic source at the rate of 50, 75, or 100% (in groups T1 (Org50), T2 (Org75), and T3 (Org100), respectively) was fed at level as supplemented in the control group. Feeding was continued for a period of 180 days with blood sampling at day 0 followed by a regular interval of 45 days. Plasma samples were analyzed for trace elements Cu, Mn, Zn, and iron (Fe), total antioxidant status, ceruloplasmin, and superoxide dismutase (SOD) with cell-mediated and humoral immune response. Plasma levels of different trace minerals like Fe, Mn, and Cu remained unaffected with two sources and different levels of organic minerals, except the level of Zn, which showed higher (P < 0.05) levels in the group Org100 compared to others, and remained indicative of higher bio-availability through the organic source. The concentration of plasma total antioxidants indicated no adverse effect on the reduction of supplemental levels up to half of these minerals. Also, the level of plasma SOD was high (P < 0.05) at each level of the organic source as compared to the 100% level of the inorganic source. Immune response in respect of cell mediated as well as humoral immunity did not show any reduction in different groups. The study indicated beneficial impacts of the organic source in the form of superior plasma Zn level as well as SOD concentrations. In addition, no negative effect on most of the studied parameters was observed after reducing supplemental trace minerals to half indicating higher bio-availability of organic trace minerals. PMID- 30014282 TI - The Effect of Zinc Sulfate on miR-122, miR-34a, Atioxidants, Biochemical and Histopathological Parameters Following Hepatic Ischemia/Reperfusion Injury in Rats. AB - Liver ischemia-reperfusion (IR) injury is a situation which occurs in various conditions such as pringle maneuver and liver transplantation. The regulatory effect of zinc sulfate (ZnSO4) is an important trace element on several liver disorders well known, but its effects on microRNAS (miR-122 and miR-34a) have not been evaluated. The goal of this study was to identify the protective effects of ZnSO4 on IR-induced liver injury, in particular, microRNAS in rats. Thirty-two male Wistar rats were randomly assigned into four groups (eight each group): sham, IR, ZnSO4 pretreatment, and ZnSO4 + IR groups. In sham and ZnSO4 pretreatment groups, animals received normal saline (N/S, 2 ml/kg) and ZnSO4 (5 mg/kg) for 7 consecutive days intraperitoneally (ip), then only laparotomy was performed. In IR and ZnSO4 + IR groups, N/S and ZnSO4, respectively, were given with the same dose, time, and route, before induction of ischemia for 45 min followed by reperfusion for 60 min. Blood sample was taken for biochemical and microRNAs analysis. Tissue specimens also were obtained for the measurements of antioxidant activities and histopathological evaluations. Our results showed that ZnSO4 pretreatment ameliorated histopathological changes decreased the increased serum levels of liver enzymes, miR-122 and miR-34a, and enhanced the decreased activity of antioxidant enzymes following hepatic IR injury. The present study indicated that ZnSO4 had potential hepatoprotective action against IR-induced injury. Therefore, it has been suggested that it can be administered as an anti miR before elective hepatic surgeries for prevention of this complication. PMID- 30014283 TI - Genistein and Silicon Synergistically Protects Against Ovariectomy-Induced Bone Loss Through Upregulating OPG/RANKL Ratio. AB - We have reported that genistein (Gen) and silicon (Si) have synergistic effects on ovariectomy-induced bone loss in rat; however, the potential mechanisms behind this effect were not fully clarified yet. This study was performed to evaluate the bone protective mechanisms of concomitant intake of genistein and silicon in ovariectomized rat by OPG/RANKL axis. Three-month-old Sprague-Dawley female rats were subjected to ovariectomy (OVX) or sham surgery; after surgery, the OVX rats were randomly divided into five groups: OVX-Gen, OVX-Si, OVX-Gen-Si, OVX-E, and OVX. Genistein, silicon, and 17beta-estradiol supplementation were started after ovariectomy and continued for 10 weeks. The results showed that genistein and silicon treatment increased the bone mineral density (BMD) of ovariectomized rats. In addition, the BMD of the tibia and femur were highest in the OVX-Gen-Si group compared with OVX-Gen and OVX-Si group (p < 0.05). After 10 weeks treatment with genistein and silicon, the bone structure of ovariectomized rats was recovered, there was no difference of bone histomorphometric parameters between OVX-Gen-Si, OVX-E, and SHAM group (p > 0.05), and there was no difference in the concentration of serum ALP, Ca, P, OPG, and RANKL between OVX-Gen-Si, SHAM, and OVX-E groups (p > 0.05). RT-PCR showed that genistein and silicon treatment could effectively increase the OPG mRNA expression and decreased the RANKL mRNA expression compared to that of the OVX group (p < 0.05), the OPG/RANKL mRNA ratios were significantly decreased in the OVX group (p < 0.05), and it was nearly to normal in the OVX-Gen-Si group. Immunohistochemical staining results showed that genistein and silicon supplementation could effectively increase the protein expression of OPG and decrease the protein expression of RANKL in bone tissues; there were no significant differences in OPG and RANKL positive expression areas between OVX-Gen-Si, SHAM, and OVX-E group (p > 0.05). The results above indicate that genistein and silicon supplementation can effectively reduce RANKL, increase OPG levels, and OPG/RANKL ratios in the serum and bone tissue of ovariectomized rats; this is the main mechanism by which genistein and silicon play a bone protective role in ovariectomized rats. PMID- 30014284 TI - Evaluation of Plasma Trace Elements in Different Stages of Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. Its global prevalence is estimated between 25 and 45%, occurring mainly in overweight individuals with unhealthy dietary habits and low levels of physical activity. Many studies have investigated the association of trace elements with liver diseases, though not with NAFLD. In this work, we investigated trace element levels in plasma of patients and not-patients and their possible association with various stages of the disease. Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the determination of As, Ba, Cd, Co, Cs, Cu, Fe, Rb, Sr, Tl, and Zn in the plasma of 189 free-living residents of Athens, Greece, either healthy or patients with mild, moderate, or severe NAFLD. The disease was diagnosed by abdominal ultrasound; blood samples were analyzed for total, HDL and LDL cholesterol, triglycerides, fasting glucose, fasting insulin, and liver enzymes, namely aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyltransferase (Gamma-GT); insulin resistance was determined by the homeostatic model assessment (HOMA-IR). Zinc exhibited a statistically significant negative association with the severity of the disease, while cesium showed a statistically significant positive association. Moreover, thallium and iron were inversely associated with insulin levels. Trace element determination in plasma could be useful for establishing relationships with NAFLD status of patients. Further research is required for the verification and interpretation of these findings. PMID- 30014285 TI - Calculation of an Adequate Intake (AI) Value and Safe Range of Selenium (Se) for Chinese Infants 0-3 Months Old Based on Se Concentration in the Milk of Lactating Chinese Women with Optimal Se Intake. AB - The required selenium intake for optimal health in Chinese residents was published in 2014. However, the adequate intake (AI) value for Chinese infants 0 3 months old is not established. This study assessed the current selenium nutritional status of 264 lactating Chinese women from three geographical locations with different Se levels (Liangshan in Sichuan province, Enshi in Hubei province, and Xicheng District in Beijing), to screen mothers with optimal Se intake, and to modify the AI value of Se for Chinese infants 0-3 months old. Milk and plasma Se concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) and glutathione peroxidase 3 (GPx3), and plasma selenoprotein P (SEPP1) was measured by ELISA. Daily Se intake (Y, MUg/day) in lactating Chinese woman was calculated from plasma Se concentrations (X, MUg/L) using the formula logY = 1.623 log(X) + 3.433. Plasma Se concentrations in lactating Chinese women were 78.19 +/- 25.71, 112.48 +/- 24.57, and 183.83 +/- 45.81 MUg/L from Se-deficient, Se-moderate, and seleniferous areas, respectively. Se intakes calculated from concentrations of plasma Se were 45.6 +/- 21.69, 80.03 +/- 27.69, and 223.10 +/- 50.95 MUg/day, respectively. An optimal dietary Se intake is not lower than the recommended nutrient intake (RNI) but not more than the tolerable upper intake level (UL). A range of 78-400 MUg Se/day was defined as the optimal daily Se intake for lactating Chinese women. The percentages of mothers within this range in Sichuan, Beijing, and Enshi were 8.11, 45.13, and 6.06%, respectively. Based on milk Se concentrations of mothers with optimal daily Se intake, the adequate Se intake value and a safe range for Chinese infants 0-3 months of age were calculated as 15.29 and 8-35 MUg Se/day, respectively. The Se status of Chinese lactating women has improved, particularly in traditionally Se-deficient and Se-toxic regions. A safe range for daily Se intake in Chinese infants may be regarded as a guideline for infant formula. PMID- 30014288 TI - Immunohistochemistry for PAX7 is a useful confirmatory marker for Ewing sarcoma in decalcified bone marrow core biopsy specimens. AB - PAX7 has been recently demonstrated to be a highly sensitive marker for Ewing sarcoma, and thus far has only been shown to label a relatively small set of other mesenchymal neoplasms. Because the processing of bone marrow core biopsies can often hinder the performance of immunohistochemical stains, we set out to determine if our laboratory's PAX7 staining protocol effectively detects Ewing sarcoma in Bouin's fixed, decalcified bone marrow core biopsies. We stained ten core biopsies involved by Ewing sarcoma, nine non-involved core biopsies, and 13 core biopsies involved by histologic mimics of Ewing sarcoma. Only the ten biopsies involved by Ewing sarcoma and four biopsies with rhabdomyosarcoma showed strong nuclear PAX7 staining. None of the other tumors demonstrated PAX7 expression. This study demonstrates that the PAX7 staining protocol used in our laboratory is a useful marker for Ewing sarcoma and other PAX7-positive tumors in decalcified bone marrow core biopsies. PMID- 30014287 TI - Region-Specific Microstructure in the Neonatal Ventricles of a Porcine Model. AB - The neonate transitions from placenta-derived oxygen, to supply from the pulmonary system, moments after birth. This requires a series of structural developments to divert more blood through the right heart and onto the lungs, with the tissue quickly remodelling to the changing ventricular workload. In some cases, however, the heart structure does not fully develop causing poor circulation and inefficient oxygenation, which is associated with an increase in mortality and morbidity. This study focuses on developing an enhanced knowledge of the 1-day old heart, quantifying the region-specific microstructural parameters of the tissue. This will enable more accurate mathematical and computational simulations of the young heart. Hearts were dissected from 12, 1 day-old deceased Yorkshire piglets (mass: 2.1-2.4 kg, length: 0.38-0.51 m), acquired from a breeding farm. Evans blue dye was used to label the heart equator and to demarcate the left and right ventricle free walls. Two hearts were used for three-dimensional diffusion-tensor magnetic resonance imaging, to quantify the fractional anisotropy (FA). The remaining hearts were used for two-photon excited fluorescence and second-harmonic generation microscopy, to quantify the cardiomyocyte and collagen fibril structures within the anterior and posterior aspects of the right and left ventricles. FA varied significantly across both ventricles, with the greatest in the equatorial region, followed by the base and apex. The FA in each right ventricular region was statistically greater than that in the left. Cardiomyocyte and collagen fibre rotation was greatest in the anterior wall of both ventricles, with less dispersion when compared to the posterior walls. In defining these key parameters, this study provides a valuable insight into the 1-day-old heart that will provide a valuable platform for further investigation the normal and abnormal heart using mathematical and computational models. PMID- 30014286 TI - Toward Improving Safety in Neurosurgery with an Active Handheld Instrument. AB - Microsurgical procedures, such as petroclival meningioma resection, require careful surgical actions in order to remove tumor tissue, while avoiding brain and vessel damaging. Such procedures are currently performed under microscope magnification. Robotic tools are emerging in order to filter surgeons' unintended movements and prevent tools from entering forbidden regions such as vascular structures. The present work investigates the use of a handheld robotic tool (Micron) to automate vessel avoidance in microsurgery. In particular, we focused on vessel segmentation, implementing a deep-learning-based segmentation strategy in microscopy images, and its integration with a feature-based passive 3D reconstruction algorithm to obtain accurate and robust vessel position. We then implemented a virtual-fixture-based strategy to control the handheld robotic tool and perform vessel avoidance. Clay vascular phantoms, lying on a background obtained from microscopy images recorded during petroclival meningioma surgery, were used for testing the segmentation and control algorithms. When testing the segmentation algorithm on 100 different phantom images, a median Dice similarity coefficient equal to 0.96 was achieved. A set of 25 Micron trials of 80 s in duration, each involving the interaction of Micron with a different vascular phantom, were recorded, with a safety distance equal to 2 mm, which was comparable to the median vessel diameter. Micron's tip entered the forbidden region 24% of the time when the control algorithm was active. However, the median penetration depth was 16.9 MUm, which was two orders of magnitude lower than median vessel diameter. Results suggest the system can assist surgeons in performing safe vessel avoidance during neurosurgical procedures. PMID- 30014289 TI - Dendriform pulmonary ossification leading to bilateral lung transplant: a case report. AB - Metaplastic ossification within the lung is seen in a variety of diseases, usually as sequela of either a separate primary pulmonary parenchymal disease or an underlying cardiac disorder such as valvular disease. Primary intraalveolar ossification or ossification within the alveolar septa is a rare entity. Similarly, it is unusual to see overt, diffuse disease affecting the lung to the point of respiratory failure leading to lung transplant. We present a case of an adult male who underwent bilateral lung transplantation, with the native lung pathology showing diffuse, severe dendriform ossification of the bilateral upper and lower lung lobes. The gross and histologic findings along with the radiographic imaging are reviewed herein. Overall, primary ossification of the lung leading to lung transplant is a rare condition that pulmonologists caring for patients with interstitial lung disease should be aware of as a possible cause of the patient's symptoms and lung dysfunction. PMID- 30014291 TI - Postoperative Small Bowel Obstruction Following Laparoscopic or Open Fundoplication in Children: A Retrospective Analysis Using a Nationwide Database. AB - BACKGROUND: Postoperative small bowel obstruction (SBO) is one of the most serious adverse events resulting in deteriorated quality of life in children. Numerous studies have shown that laparoscopic surgery significantly reduces the occurrence of SBO compared with open surgery in adults. However, evidence of the advantages of laparoscopic surgery over open surgery in terms of reducing SBO is lacking in children. Fundoplication is a common abdominal procedure in children. This study was performed to compare the occurrence of SBO after laparoscopic fundoplication (LF) versus open fundoplication (OF). METHODS: Using the Diagnosis Procedure Combination database, a national inpatient database in Japan, we retrospectively identified patients aged 0-18 years who underwent LF or OF from July 2010 to March 2016. Propensity score adjustment was used to compare the occurrence of SBO between the groups. RESULTS: We identified 1838 eligible patients who underwent LF (n = 1362) or OF (n = 476). The median age at surgery was 4.0 and 1.5 years in the LF and OF group, respectively (P < 0.001). The median weight at admission was 11.4 and 7.5 kg, respectively (P < 0.001). Nineteen (1.4%) patients in the LF group and 13 (2.7%) in the OF group had at least one episode of SBO (P = 0.11, log-rank test). In the propensity score adjusted Cox regression analysis, SBO was significantly less likely to occur in the LF than OF group (hazard ratio, 0.36; 95% confidence interval 0.16-0.82; P = 0.01). CONCLUSIONS: In this retrospective nationwide study, LF was significantly associated with a reduction in SBO compared with OF in children. PMID- 30014290 TI - Surgical jejunostomy and radiological gastro-jejunostomy tube feeding in children: risks, benefits and nutritional outcomes. AB - PURPOSE: Radiologically inserted gastrojejunal tubes (RGJ) and surgical jejunostomy (SJ) are established modes of jejunal feeding. The aim of the study is to review nutritional outcomes, complications and the practical consideration to enable patients and carers to make informed choice. METHODS: Retrospective review of patient notes with a RGJ or SJ in 2010, with detailed follow-up and review of the literature. RESULTS: Both RGJ and SJ are reliable modes to provide stable enteral nutrition. Both have complications and their own associated limitations. CONCLUSIONS: The choice has to be tailored to the individual patient, the social care available, the inherent medical disease and risk/benefit of repeated anaesthetic and radiation exposure. RGJ and SJ are important tools for nutritional management that achieve and maintain growth in a complex group of children. The risk and benefits should be reviewed for each individual patient. PMID- 30014293 TI - A Comparison of Two Preoperative Frailty Models in Predicting Postoperative Outcomes in Geriatric General Surgical Patients. AB - BACKGROUND: Frailty in a surgical geriatric population may identify patients at increased risk of complications. However, the optimal method to diagnose it remains to be identified. This study aims to compare two common frailty models and assess their association with postoperative adverse outcomes in elderly patients undergoing general surgical procedures. METHODS: Prospective study including 298 patients age 65 years or older undergoing elective general surgical operations in a tertiary hospital. Frailty phenotype (FP) was classified using a validated scale which included weight loss, weakness, exhaustion, slowed walking speed and low physical activity. A preoperative comprehensive geriatric assessment (CGA) was performed including managing daily activities (ADL), instrumental ADL, cognitive status, comorbidities, polypharmacy and nutritional status. Main outcomes measures were postoperative complications and length of stay. RESULTS: There were 135 (46%), 114 (38%) and 46 (15%) minor/intermediate, major and major + procedures, respectively. The agreement between the FP and CGA was moderate (kappa index: 0.45). FP was significantly associated with postoperative complications with an odds ratio (OR) of 2.3, (95% confidence interval 1.4-3.8, p < 0.01). The association of CGA with postoperative complications did not reach statistical significance (p = 0.07). Postoperative hospital stay was significantly longer in both CGA frailty (p < 0.001) and FP (p = 0.001) groups compared to the fit population. In the multivariate analysis adjusted for ASA and POSSUM category, FP retained its significance as a predictor of postoperative complications (OR: 1.9, 95% CI 1.03-3.3, p = 0.038). CONCLUSIONS: FP was associated more consistently than CGA with adverse postoperative outcomes in elderly patients undergoing general surgical procedures. PMID- 30014292 TI - The Prognostic Value of Preoperative Neutrophil-to-Lymphocyte Ratio in Resected Patients with Pancreatic Adenocarcinoma. AB - PURPOSE: This research aims to analyze neutrophil-to-lymphocyte ratio (NLR) for resectable pancreatic ductal adenocarcinoma (PDAC) patients and reveal its predictive value. METHODS: We enrolled 389 pancreatic adenocarcinoma patients who had undergone curative surgery between January 1, 2008 and August 15, 2015 in Jiangsu Provincial People's Hospital, and they were followed up until December 20, 2016. Among them, 219 patients had definite recurrence record in our hospital. The appropriate cutoff value for the NLR was obtained from X-tile software. The association between qualitative variables and NLR was analyzed by Chi-square test or Fisher's exact test, and for quantitative values, the association was analyzed by independent Student's t test. Additionally, survival analysis was performed by Kaplan-Meier plots. Independent prognostic factors were found according to Cox regression analysis. RESULTS: Based on univariate analysis, the elevated preoperative NLR had an important influence on the decreased recurrence-free survival (RFS) (8.2 vs. 14.9 months) and overall survival (OS) (13.7 vs. 22 months), and this result also counted in the multivariate analysis. Regarding OS, both patients with or without postoperative chemotherapy can obtain benefits from low NLR according to subgroup analysis. Stage I and II pancreatic adenocarcinoma patients can get longer OS and RFS from low NLR, while patients with stage III cancer cannot. Regarding recurrence site, high NLR level was also related to distant metastasis (P = 0.02). CONCLUSION: Preoperative NLR level could be a useful prognostic indication for resectable pancreatic adenocarcinoma patients. PMID- 30014295 TI - Regioselective glucuronidation of daidzein in liver and intestinal microsomes of humans, monkeys, rats, and mice. AB - Daidzein, one of the major soy isoflavones, has a number of beneficial bioactivities for human health. It is mainly metabolized into 7- and/or 4' glucuronides by UDP-glucuronosyltransferase (UGT) enzymes in mammals, including humans. The present study was conducted to examine the regioselective glucuronidation of daidzein at the 7- and 4'-hydroxyl groups in the liver and intestinal microsomes of humans, monkeys, rats, and mice. Daidzein glucuronidation activities at substrate concentrations of 1.0-200 uM were assessed, and Eadie-Hofstee plots were constructed. The kinetics for 7- and 4' glucuronidation in the liver microsomes fit the Michaelis-Menten model, except for an atypical model for 7-glucuronidation in rats and a biphasic model for 4' glucuronidation in monkeys. These kinetics in the intestinal microsomes followed the Michaelis-Menten model, except for a biphasic model for 7-glucuronidation in mice. The CLint values for 7-glucuronidation were in the order of monkeys (49) ? rats (5.3) > humans (1.0) > mice (0.7) for liver microsomes, and rats (2.4) >= monkeys (2.2) > humans (1.0) >= mice (0.8) for intestinal microsomes. On the other hand, the CLint values for 4'-glucuronidation were in the order of monkeys (4.0) > mice (1.0) ~ humans (1.0) > rats (0.4) for liver microsomes, and humans (1.0) ? monkeys (0.08) >= mice (0.07) > rats (0.05) for intestinal microsomes. These results demonstrated that the metabolic abilities of UGT enzymes toward daidzein in the liver and intestines markedly differed among humans, monkeys, rats, and mice, and suggest that species and regioselective differences are closely associated with the bioactivities of soy isoflavones. PMID- 30014296 TI - Research Progresses in Cancer Stem Cells of Three Common Fertility-Related Female Malignancies. AB - With abilities to renew themselves and lead to heterogeneity of tumors, cancer stem cells (CSCs) are similar to stem cells. As three leading causes of death that endanger women's health, breast cancer, ovarian cancer and cervical cancer are characterized by high degree of malignancy, metastasis and recurrence. Associated with women's fertility, these three malignancies are common and representative among females. These years, research findings have suggested that CSCs are closely connected with many cancers (including aforementioned three malignancies) and several processes of tumors such as their genesis and development. CSCs have become great concerns for current cancer treatment and interventions. This paper does not only summarize roles of CSCs in genesis, development, drug resistance, metastasis and recurrence of breast cancer, ovarian cancer and cervical cancer, but also proposes potential methods of treatment and intervention, in hope of inspiring readers and researchers. PMID- 30014294 TI - Superior adaptation of aerobic rice under drought stress in Iran and validation test of linked SSR markers to major QTLs by MLM analysis across two years. AB - Drought is one of the biggest challenges for rice (Oryza sativa L.) production in rainfed areas. Developing "aerobic rice" cultivars could be a valuable alternative to irrigated/rainfed areas. During 2010-2013, 115 rice genotypes, including non-local cultivars and aerobic rice genotypes, were evaluated and 31 rice genotypes were screened, while 21 Iranian lowland rice cultivars (52 genotypes) were investigated under non-stress and drought conditions at the University of Guilan, Rasht, Iran, in 2014 and 2017. The results revealed the superiority of high yielding genotypes, namely Neda (6.202 t ha- 1), IR82639-B-B 140-1 (6.020 t ha- 1), and IR82635-B-B-82-2 (5.75 t ha- 1) under non-stress, Panda (4.512 t ha- 1), and IR82639-B-B-140-1 (4.08 t ha- 1), under drought stress conditions. Based on the molecular markers evaluation using identified SSR markers linked to major QTLs different important traits specially drought stress, IR 82639-B-B-140-1 showed the highest genetic distance with high-quality Iranian lowland cultivars, which could be considered as a donor for the development of new cultivars. Moreover, the assignment of rice genotypes based on Jaccard distance clustering was in agreement with the grouping of structure analysis. The validation test using MLM analysis in this natural population revealed the most important significant associations that were identified under drought conditions. These are: the associations between RM306, RM319, RM511, RM28166, and RM11943 with different grain yield (GY)-related traits simultaneously and stable across both years. These markers, which were verified in a natural population across 2 years, could be considered as the potential markers for use in marker-assisted breeding and to improve the grain yield of rice. PMID- 30014297 TI - Accumulation of microdamage at complete and incomplete fracture sites in a patient with bilateral atypical femoral fractures on glucocorticoid and bisphosphonate therapy. PMID- 30014298 TI - Impact of vitamin C on teriparatide treatment in the improvement of bone mineral density, strength, and quality in vitamin C-deficient rats. AB - Age-related decreases in serum levels of vitamin C (VC) may negatively affect the efficacy of anti-osteoporotic pharmacotherapy. The purpose of this study was to evaluate the effects of VC and teriparatide (TPTD) on bone mineral density (BMD), strength, and quality in VC-deficient osteogenic disorder Shionogi (ODS) rats. Six-month-old female ODS rats were divided into an untreated ODS control group, a VC group, a TPTD group, and a VC + TPTD group, based on the administration of VC and TPTD (n = 10 each). VC was given as 2.0 mg/ml supplemented water. TPTD was administered subcutaneously once a week at 30 ug/kg body weight. After 12 weeks of treatment, BMDs of the femur and lumbar spine, bone strengths of the femoral diaphysis and metaphysis, and cancellous bone quality of proximal tibiae as estimated by Fourier transform infrared spectroscopy (FTIR) were compared between groups. Compared to the ODS control group, the VC group showed significantly higher total femoral BMD, but the TPTD group showed significantly higher femoral and lumbar spinal BMD, maximum load of femoral metaphysis, and hydroxyapatite (HA) crystallinity by FTIR (p < 0.05). In addition to the increases shown in the TPTD group, the VC + TPTD group also showed significantly higher stiffness of the femoral diaphysis and breaking energy of the femoral metaphysis compared to the ODS control group (p < 0.05). These results indicated that TPTD alone increased cancellous/cortical BMD and cancellous bone strength with improvement of HA crystallinity in ODS rats, but addition of VC supplementation further improved cortical bone strength. PMID- 30014299 TI - Residual vein obstruction in patients diagnosed with acute isolated distal deep vein thrombosis associated with active cancer. AB - After acute proximal deep vein thrombosis (DVT) the thrombotic mass decreases, especially during the first months of anticoagulation. The persistence of residual vein obstruction (RVO) may predict future recurrence in patients with cancer-associated DVT. We aimed to evaluate the proportion of patients with RVO after an episode of cancer associated isolated distal DVT (IDDVT), to identify variables associated with RVO, and to provide initial evidence of its association with recurrent VTE. We performed a post-hoc analysis of a multicenter cohort study of patients with isolated cancer-associated acute IDDVT. We included patients who underwent a control ultrasonography at the end of the anticoagulant treatment between day 30 and day 365 after index IDDVT, given that no recurrent VTE had already occurred on anticoagulant treatment. A total of 153 patients had ultrasonographic follow-up after a median of 92 days from index IDDVT: 45.8% had RVO and 54.2% exhibited complete recanalization. Female sex, Body Mass Index > 30 Kg/m2 and involvement of axial calf veins showed the strongest association with RVO. The risk of recurrence was twofold higher in patients with (versus without) RVO. RVO persisted in approximately half of patients with an episode of cancer associated IDDVT at anticoagulant discontinuation. Patients with RVO appeared to be at a higher risk for recurrent events. PMID- 30014300 TI - Incidence and outcomes of catheter related thrombosis (CRT) in patients with acute leukemia using a platelet-adjusted low molecular weight heparin regimen. AB - Patients with acute leukemia frequently develop catheter-related thrombosis (CRT) despite concurrent thrombocytopenia. The incidence, treatment and outcomes of this complication are poorly documented. We undertook this study to determine the incidence of CRT in patients with acute leukemia and assess the safety and effectiveness of a treatment strategy using a platelet-adjusted low molecular weight heparin (LMWH) dosing protocol. Patients (18 years and older) with newly diagnosed acute leukemia from January 2014 to December 2015 who received central venous catheters were included. The clinical data were reviewed up to 12 months from acute leukemia diagnosis to capture objectively documented CRT events. The outcome events including recurrent venous thromboembolism (VTE), bleeding events, infectious or mechanical complications, and death were reported up to 3 months from the time of CRT diagnosis. The incidence of CRT among 214 patients was 10.7% (23 patients) in the first 12 months after acute leukemia diagnosis. Among 18 patients who were treated with anticoagulation, 14 (78%) received reduced LMWH dosing due to concurrent thrombocytopenia. There were no recurrent VTE episodes, but 3 patients experienced bleeding events while on anticoagulation. Fifteen patients (83%) completed a minimum of 3 months anticoagulation. Twelve patients (52%) experienced an infectious complication, which was the main reason for catheter removal. Deaths occurred in 2 patients, related to underlying acute leukemia during 3 months period following CRT. Symptomatic CRT is frequent in patients with acute leukemia. Platelet-adjusted LMWH dosing may be effective and well tolerated despite thrombocytopenia. PMID- 30014301 TI - Increased Alternative Splicing as a Host Response to Edwardsiella ictaluri Infection in Catfish. AB - Alternative splicing is the process of generating multiple transcripts from a single pre-mRNA used by eukaryotes to regulate gene expression and increase proteomic complexity. Although alternative splicing profiles have been well studied in mammalian species, they have not been well studied in aquatic species, especially after biotic stresses. In the present study, genomic information and RNA-Seq datasets were utilized to characterize alternative splicing profiles and their induced changes after bacterial infection with Edwardsiella ictaluri in channel catfish (Ictalurus punctatus). A total of 27,476 alternative splicing events, derived from 9694 genes, were identified in channel catfish. Exon skipping was the most abundant while mutually exclusive exon was the least abundant type of alternative splicing. Alternative splicing was greatly induced by E. ictaluri infection with 21.9% increase in alternative splicing events. Interestingly, genes involved in RNA binding and RNA splicing themselves were significantly enriched in differentially alternatively spliced genes after infection. Sequence analyses of splice variants of a representative alternatively spliced gene, splicing factor srsf2, revealed that certain spliced transcripts may undergo nonsense-mediated decay (NMD), suggesting functional significance of the induced alternative splicing. Although statistical analysis was not possible with such large datasets, results from quantitative real-time PCR from representative differential alternative splicing events provided general validation of the bacterial infection-induced alternative splicing. This is the first comprehensive study of alternative splicing and its changes in response to bacterial infection in fish species, providing insights into the molecular mechanisms of host responses to biotic stresses. PMID- 30014302 TI - A 26-week, randomized trial of insulin detemir versus NPH insulin in children and adolescents with type 2 diabetes (iDEAt2). AB - : There are limited studies evaluating the safety and efficacy of treatments in young people with type 2 diabetes (T2D). This study compared the efficacy and safety of insulin detemir versus neutral protamine Hagedorn (NPH) insulin, both in combination with metformin and lifestyle intervention, in children and adolescents with T2D. This randomized, open-label, phase 3 trial recruited patients (n = 42) aged 10-17 years diagnosed with T2D already receiving metformin +/- other oral antidiabetic drugs +/- basal insulin. Patients were randomized (1:1) to receive either insulin detemir or NPH insulin, both with the maximum tolerated dose of metformin, and lifestyle intervention, over 26 weeks. Enrollment terminated prematurely after 17 months due to a very slow recruitment rate (12% of the target met). After 26 weeks, the observed mean HbA1c value had decreased by 0.61% points in the insulin detemir group vs. 0.84% points in the NPH insulin group. The rate of symptomatic blood glucose-confirmed hypoglycemic episodes was 0.4 episodes/patient-year of exposure (PYE) for insulin detemir vs. 1.1 episodes/PYE for NPH insulin. CONCLUSION: No safety issues were revealed with either basal insulin. Due to the low number of patients recruited, no efficacy conclusions could be drawn. ClinicalTrials.gov identifier: NCT02131272. What is known: * There is a growing worldwide epidemic of type 2 diabetes in children and adolescents. * There is a lack of research and limited treatment options currently available in this population. What is new: * No safety issues with insulin detemir or neutral protamine Hagedorn insulin in children and adolescents with type 2 diabetes were observed. * Improving clinical trial recruitment, along with providing early, efficacious, and safe treatment options, in this population is critical. PMID- 30014303 TI - Unhealthy eating habits and participation in organized leisure-time activities in Czech adolescents. AB - : A healthy lifestyle habits in adolescents consist of healthy eating patterns and active ways of spending leisure time. This study aimed to examine the relationship between organized leisure-time activities (OLTA) and eating habits in adolescence. Data from the 2013/2014 Health Behaviour in School-aged Children (HBSC) study on 10,494 Czech adolescents aged 11-15 years was used. The associations of participation in OLTA with ten specific eating habits were analyzed using logistic regression. Involvement in any type of OLTA was associated with higher consumption of daily breakfast, fruit, and vegetables and a lower intake of soft drinks. Participants in non-sport and sport and other activity reported lower rates of unhealthy eating habits (e.g., lower rates of eating crisps and eating in front of the TV or computer). Participation only in sport was related to more frequent eating at fast food restaurants but less frequent snacking in front of the computer and intake of crisps. CONCLUSION: Participation in OLTA was associated with healthier eating habits (e.g., consumption of fruit and vegetables) and a lower occurrence of unhealthy eating habits (e.g., consumption of soft drinks). Alternatively, our findings indicate that non-participation in OLTA can serve as an indicator of an unhealthy lifestyle in adolescence. What is Known * Unhealthy eating habits in youth tend to persist into adulthood and are related to adverse health consequences later in life. * The type of the leisure-time activity (participation in sport, non-sport, sport, and other activities) affects the strength of developmental outcomes in adolescents. What is New * Youth participating in non-sport activity and sport and other activity concurrently reported lower rates of unhealthy eating habits (e.g., eating junk food, eating in front of the TV/computer). * Non-participation in OLTA could be viewed as a potential risk factor for an unhealthy lifestyle in adolescents. PMID- 30014304 TI - Health-related quality of life in Spanish coeliac children using the generic KIDSCREEN-52 questionnaire. AB - : The aim of this study is to assess the impact of coeliac disease (CD) on health related quality of life (HRQOL) using the generic KIDSCREEN-52 questionnaire in a group of Spanish children aged 8-18 years and their parents. For this cross sectional study, coeliac children in the targeted age range, who are members of the Madrid Coeliac Association (MCA), were invited to participate. The Spanish version of the generic KIDSCREEN-52 questionnaire was administered via e-mail. Scores (on a scale from 1 to 100) were expressed as the mean and standard deviation (SD). Demographic and clinical variables related to HRQOL were also assessed. The questionnaire was completed by 434 children and/or their parents. Respondents gave scores of over 50 to seven quality of life domains. Mean scores were significantly higher in children than in their parents for six out of ten domains. In contrast, parents awarded significantly higher scores to the "social support and peers" domain than children did. Significantly lower QOL scores were reported by girls, children aged 16-18 years, children older than 7 years at the time of CD diagnosis, and respondents who did not adhere to the prescribed diet or had difficulty in doing so. CONCLUSION: Overall, the KIDSCREEN-52 questionnaire revealed that CD had no substantial negative impacts on the children's QOL. However, some concerns from the children's perspective were identified, such as issues regarding relationships with their peers. These issues will need to be addressed in order to improve QOL in children with CD. What is Known: * According to the Spanish version of the specific CDDUX, parents and children felt CD had no substantial negative impacts on their HRQOL. What is New: * According to the generic KIDSCREEN-52 questionnaire, QOL in Spanish coeliac children does not seem to be negatively affected by the disease in most general aspects of life. * Parents have a worse perception of their children's HRQOL than their children themselves. PMID- 30014306 TI - Classification of thyroid hormone receptor agonists and antagonists using statistical learning approaches. AB - In silico models are presented for modeling and predicting thyroid hormone receptor (TR) agonists and antagonists. A data set consisting of 258 compounds is used in the present work. The C4.5, random forest (RF) and support vector machine (SVM) statistical methods were used for evaluation. The performance of the quantitative structure-activity relationships was further validated with fivefold cross-validation and an independent external test set. The C4.5 model is slightly weak, and the prediction accuracies of the agonists and antagonists are 93.2 and 57.8% for cross-validation, respectively, averaging 83.1% of correctly classified compounds in the test set. The RF model possesses an average prediction accuracy of 84.0 and 87.1% for the cross-validation and external validation, respectively. Furthermore, the overall prediction accuracy and the external prediction accuracy are 96.6 and 97.2%, respectively, for the SVM model. The results would validate the reliability of the derived models, further demonstrating that RF and SVM models are useful tools capable of classifying TR-binding ligands as agonists or antagonists. PMID- 30014305 TI - Systemic administration of strontium ranelate to enhance the osseointegration of implants: systematic review of animal studies. AB - The literature states that Strontium (Sr) is able to simultaneously stimulate bone formation and suppress bone resorption. Recent animal studies suggest that the systemic administration of Sr, in the form of strontium ranelate (SRAN), would enhance the osseointegration of implants. The purpose of the present study was to undertake a systematic review on animal studies evaluating the systemic administration of Sr to enhance the osseointegration of titanium implants and the remodeling of bone grafts. The MEDLINE (PubMed) and Scopus bibliographic databases were searched from 1950 to October 2017 for reports on the use of systemic and non-radioactive Sr to enhance the osseointegration of titanium implants and the remodeling of bone grafts in animals. The search strategy was restricted to English language publications using the combined terms: "strontium" and "implant or graft or biomaterial or bone substitute". Five studies were included, all related to the systemic administration of Sr in the form SRAN, and its effects on osseointegration of titanium implants. No studies on the use of SRAN-based therapy to enhance the remodeling of bone grafts were found. The studies differed notably with respect to the study population (healthy female rats, healthy male rats, and female rats with induced osteoporosis) and SRAN dose (ranging from 500 to 1000 mg/kg/day). Results were diverse, but a tendency suggesting positive influence of systemic SRAN administration on the osseointegration of titanium implants was observed. No major side-effects due to strontium administration were reported. Systemic Sr administration, in the form of SRAN, seems to enhance peri-implant bone quality and implant osseointegration in animals, however, at a moderate extent. Further studies, evaluating both the effects of this drug on implant osseointegration and the risk/benefit of its use, are needed to provide a rationale of this therapeutic approach. PMID- 30014307 TI - Subdural empyema in children. AB - BACKGROUND: Subdural empyema denotes the collection of purulent material in the subdural spaceand is commonly seen in infants and older children. In infants, the most common cause is bacterialmeningitis. In older children, sinusitis and otitis media are usually the source for subdural empyema. Theclinical symptomatology is varied and has a wide range including prolonged or recurrent fever, seizures,meningeal irritation, and raised intracranial pressure. It can mimic as well as complicate meningitis and aheightened clinical awareness is therefore paramount. AIMS AND OBJECTIVES: The clinical profile, etiopathogenesis, imaging features and management of subdural empyema in children is discussed and the relevant literature is reviewed. CONCLUSION: Subdural empyema is a neurosurgical emergency and rapid recognition and treatment canavoid life-threatening complications. In most cases, surgical decompression through burr hole or craniotomyis warranted. Near complete evacuation of the purulent material and appropriate long-term intravenous antibiotics are necessary for a gratifying outcome. PMID- 30014308 TI - Isolation of right internal carotid artery, persistent proatlantal 1 artery and rete mirabile in a child with 22q11 deletion syndrome. AB - We report a case of a 2-year-old girl with 22q11 deletion syndrome who underwent studies for cardiac murmur. Ultrasound, computed tomography angiography and digital subtraction angiography revealed an aberrant right subclavian artery and an isolated right internal carotid artery (ICA) originating from the right pulmonary artery. A right carotid rete mirabile (CRM) and a proatlantal (Pa) type 1 artery were also found. We hypothesize that Pa type 1 persistence and CRM development are secondary to the reversal of flow of the isolated ICA. PMID- 30014310 TI - Power Talk: Communication Styles, Vocalization Rates and Dominance. AB - Humans are social beings that form hierarchies to gain and maintain resources. Dominant positions are often obtained through resource control strategies, displayed through language. Language can be examined in a number of ways including number of vocalizations and pragmatic skills. The benefit of pragmatic skills, in relationship to popularity (group dominance), can be explained by virtue signalling and the sociometer theory. The current study examined the relationship of individuals in a novel group setting. Results revealed that popularity within the group was related to the number of vocalizations and increased pragmatic skills. Taken together, it appears that vocalizations and pragmatic skills may help individuals signal their position within the hierarchy, while monitoring the social communications of others. PMID- 30014309 TI - Spectral Ripples in Round-Window Cochlear Microphonics: Evidence for Multiple Generation Mechanisms. AB - The cochlear microphonic (CM) results from the vector sum of outer hair cell transduction currents excited by a stimulus. The classical theory of CM generation-that the response measured at the round window is dominated by cellular sources located within the tail region of the basilar membrane (BM) excitation pattern-predicts that CM amplitude and phase vary little with stimulus frequency. Contrary to expectations, CM amplitude and phase-gradient delay measured in response to low-level tones in chinchillas demonstrate a striking, quasiperiodic pattern of spectral ripples, even at frequencies > 5 kHz, where interference with neurophonic potentials is unlikely. The spectral ripples were reduced in the presence of a moderate-level saturating tone at a nearby frequency. When converted to the time domain, only the delayed CM energy was diminished in the presence of the saturator. We hypothesize that the ripples represent an interference pattern produced by CM components with different phase gradients: an early-latency component originating within the tail region of the BM excitation and two delayed components that depend on active cochlear processing near the peak region of the traveling wave. Using time windowing, we show that the early, middle, and late components have delays corresponding to estimated middle-ear transmission, cochlear forward delays, and cochlear round trip delays, respectively. By extending the classical model of CM generation to include mechanical and electrical irregularities, we propose that middle components are generated through a mechanism of "coherent summation" analogous to the production of reflection-source otoacoustic emissions (OAEs), while the late components arise through a process of internal cochlear reflection related to the generation of stimulus-frequency OAEs. Although early-latency components from the passive tail region typically dominate the round-window CM, at low stimulus levels, substantial contributions from components shaped by active cochlear processing provide a new avenue for improving CM measurements as assays of cochlear health. PMID- 30014311 TI - Joint Contributions of Multilevel Linguistic Knowledge to Character Meaning Retention in L2 Chinese. AB - Character learning is a key issue for second language (L2) Chinese learners. However, our understanding is limited regarding the extent to which the multilevel linguistic knowledge simultaneously works for learning characters, particularly for L2 compound character meaning retention. To fill these gaps, two research questions were addressed. (1) What are the relationships among L2 learners' radical knowledge, character knowledge, and character meaning retention? (2) To what extent do radical knowledge and character knowledge independently and jointly contribute to character meaning retention? Fifty-six English-speaking L2 Chinese collegiate participants in the U.S. completed a character retention scale and four linguistic knowledge tasks (radicals and characters) after two character-learning sessions. The main findings showed that radical knowledge and character knowledge independently accounted for 23% and 34% of the variance of character meaning retention, respectively. Their joint contributions explained 41% of the outcome variance. The results suggest a combinational character-teaching approach when learning new compound characters. PMID- 30014312 TI - Correction to: Preparation and Optimization of Fast-Disintegrating Tablet Containing Naratriptan Hydrochloride Using D-Optimal Mixture Design. AB - During the production process, an editorial error occurred where the typesetter placed the +/- symbol on the right side of the values in Table IV, whereas the symbol should be placed on the left side. The original article has been corrected. PMID- 30014313 TI - Visualization of ischemic stroke-related changes on 18F-THK-5351 positron emission tomography. AB - BACKGROUND: The 18F-THK-5351 radiotracer has been used to detect the in vivo tau protein distribution in patients with tauopathy, such as Alzheimer's disease and corticobasal syndrome. In addition, 18F-THK-5351 can also monitor neuroinflammatory process due to high affinity to astrogliosis. We aimed to explore 18F-THK-5351 distribution patterns and characteristics in patients with recent ischemic stroke. RESULTS: Fifteen patients received 18F-THK-5351 positron emission tomography (PET) and diffusion tensor imaging (DTI) approximately 3 months after ischemic stroke. A region of interest (ROI) was placed in the peri ischemic area and was mirrored on the contralateral side as the control, and a proportional value was derived from the ratio of the peri-ischemic ROI value over the mirrored ROI value. Increased 18F-THK-5351 retention was observed in the areas around and remote from the stroke location. The proportional 18F-THK-5351 values were negatively correlated with the proportional fractional anisotropy values (r = - 0.39, P = 0.04). CONCLUSION: 18F-THK-5351 PET imaging provides a potential tool for in vivo visualization of the widespread ischemia-related changes associated with a microstructural disruption in recent ischemic stroke patients. PMID- 30014314 TI - Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: A Network Meta-Analysis. AB - BACKGROUND: A broad range of disease-modifying therapies (DMTs) for relapsing remitting multiple sclerosis (RRMS) is available. However, the efficacy and safety of traditional DMTs compared with the recently developed DMTs remain unclear. OBJECTIVE: Therefore, we have synthesised available evidence of clinical outcomes for DMTs in adults with RRMS. METHODS: PubMed, Scopus and a manual search were performed. Bayesian network meta-analyses of randomised clinical trials assessing DMTs as monotherapies were conducted. SUCRA and GRADE were used to rank therapies and to assess quality of general evidence, respectively. RESULTS: Thirty-three studies were included in the meta-analyses. The most effective therapies for the outcome of annualised relapse rate were alemtuzumab (96% probability), natalizumab (96%) and ocrelizumab (85%), compared with all other therapies (hazard ratio versus placebo, 0.31, 0.31 and 0.37, respectively; p < 0.05 for all comparisons) (high-quality evidence). However, no significant differences among these three therapies were found. Discontinuation due to adverse events revealed similarity across all therapies, except for alemtuzumab, which showed less discontinuation when compared with interferon-1a intramuscular (relative risk 0.37; p < 0.05). CONCLUSION: High-quality evidence shows that alemtuzumab, natalizumab and ocrelizumab present the highest efficacy among DMTs, and other meta-analyses are required regarding adverse events frequency, to better understand the safety of therapies. Based on efficacy profile, guidelines should consider a three-category classification (i.e. high, intermediate and low efficacy). PMID- 30014316 TI - How social is social inhibition of return? AB - A number of studies have shown that the motor actions of one individual can affect the attention of an observer. In one notable example, "social inhibition of return," observers are relatively slow to initiate a response to a location where another individual has just responded. In the present article we examine the degree to which this phenomenon can be considered a social effect. We find that unlike the related social, or "joint," Simon effect, social inhibition of return is not influenced by competitive versus cooperative interaction, nor by live versus recorded interaction. We do find however that co-actors need to turn take in order for the effect to occur. Thus, so-called "social" inhibition of return only reaches a minimal threshold to be considered a social phenomenon. PMID- 30014315 TI - Association Between Psychotropic Medication Polypharmacy and an Objective Measure of Balance Impairment Among Middle-Aged Adults: Results from the US National Health and Nutrition Examination Survey. AB - OBJECTIVE: Psychotropic medications (e.g., antidepressants, anxiolytics, and neuroleptics) are increasingly prescribed with two or more taken concurrently (polypharmacy), and have been associated with an increased risk of falling. The aim of this study was to examine the association between psychotropic medication use and balance impairment using an objective balance measure. METHODS: We derived data from participants aged 40 years and older in the US National Health and Nutrition Examination Survey (1999/00-2003/04) who completed the Modified Clinical Trial of Sensory Interaction and Balance and indicated current medications (n = 3090). Balance impairment was defined as failing the Modified Clinical Trial of Sensory Interaction and Balance condition 4 (standing on foam surface, eyes closed). Medication use included specific psychotropic classes, a count of psychotropic medications, and a count of non-psychotropic medications taken concurrently. Nested multiple logistic regression assessed relationships between medication use and balance impairment, adjusting for covariates and complex sampling. RESULTS: One third of participants had balance impairment. After accounting for medical comorbidities, there was no relationship between individual classes of psychotropic medications and balance impairment. After adjusting for all covariates, there was a dose-response relationship between the number of psychotropic medications taken and balance impairment, with every additional medication associated with a 35% higher odds (odds ratio = 1.35; 95% confidence interval 1.07-1.70). In comparison, there was no increase in the odds of balance impairment associated with each additional medication taken for participants only taking non-psychotropic medications. CONCLUSIONS: Psychotropic medication polypharmacy is associated with an increased odds of balance impairment. Clinicians should exercise caution when prescribing combinations of psychotropic medications, and refer to physical therapy for assessment and treatment if balance impairment is detected. PMID- 30014317 TI - Effect of contextual knowledge on spatial layout extrapolation. AB - Boundary extension (BE) refers to the tendency to remember a previously perceived scene with a greater spatial expanse. This phenomenon is described as resulting from different sources of information: external (i.e., visual) and internally driven (i.e., amodal, conceptual, and contextual) information. Although the literature has emphasized the role of top-down expectations to account for layout extrapolation, their effect has rarely been tested experimentally. In this research, we attempted to determine how visual context affects BE, as a function of scene exposure duration (long, short). To induce knowledge about visual context, the memorization phase of the camera distance paradigm was preceded by a preexposure phase, during which each of the to-be-memorized scenes was presented in a larger spatial framework. In an initial experiment, we examined the effect of contextual knowledge with presentation duration, allowing for in-depth processing of visual information during encoding (i.e., 15 s). The results indicated that participants exposed to the preexposure showed decreased BE, and displayed no directional memory error in some conditions. Because the effect of context is known to occur at an early stage of scene perception, in a second experiment we sought to determine whether the effect of a preview occurs during the first fixation on a visual scene. The results indicated that BE seems not to be modulated by this factor at very brief presentation durations. These results are discussed in light of current visual scene representation theories. PMID- 30014318 TI - Visual statistical learning at basic and subordinate category levels in real world images. AB - Visual statistical learning (VSL) has been proposed as a powerful mechanism underlying the striking ability of human observers to handle complex visual environments. Previous studies have shown that VSL can occur when statistical information is embedded at multiple levels of abstraction, such as at semantically different category levels. In the present study, we further examined whether statistical regularities at a basic category level (e.g., a regular sequence of a bird, then a car, and then a dog) could influence the ability to extract statistical regularities at the subordinate level (e.g., a regular sequence of a parrot, then a sports car, and then an Eskimo dog). In the familiarization phase, participants were exposed to a stream of real-world images whose semantic categories had temporal regularities. Importantly, the temporal regularities existed at both the basic and subordinate levels, or the regularities existed at only the subordinate level, depending on the experimental condition. After completing the familiarization, participants performed a surprise two-alternative forced choice (2AFC) task for a familiarity judgment between two triplets in which the temporal regularities were either preserved or not preserved. Our results showed that the existence of statistical regularities at the basic level did not influence VSL at the subordinate level. The subsequent experiments showed these results consistently even when the basic-level categories had to be explicitly recognized and when the stimuli were not easily categorized at their subordinate level. Our results suggest that VSL is constrained to learn a particular level of patterns when patterns are presented across multiple levels. PMID- 30014320 TI - Sarcopenic obesity. AB - Sarcopenic obesity, a chronic condition, is today a major public health problem with increasing prevalence worldwide, which is due to progressively aging populations, the increasing prevalence of obesity, and the changes in lifestyle during the last several decades. Patients usually present to healthcare facilities for obesity and related comorbidities (type 2 diabetes mellitus, non alcoholic fatty liver disease, dyslipidemia, hypertension, and cardiovascular disease) or for non-specific symptoms related to sarcopenia per se (e.g., fatigue, weakness, and frailty). Because of the non-specificity of the symptoms, sarcopenic obesity remains largely unsuspected and undiagnosed. The pathogenesis of sarcopenic obesity is multifactorial. There is interplay between aging, sedentary lifestyle, and unhealthy dietary habits, and insulin resistance, inflammation, and oxidative stress, resulting in a quantitative and qualitative decline in muscle mass and an increase in fat mass. Myokines, including myostatin and irisin, and adipokines play a prominent role in the pathogenesis of sarcopenic obesity. It has been suggested that a number of disorders affecting metabolism, physical capacity, and quality of life may be attributed to sarcopenic obesity, although it is not as yet established whether sarcopenia and obesity act synergistically. There is to date no approved pharmacological treatment for sarcopenic obesity. The cornerstones of its management are weight loss and adequate protein intake combined with exercise, the latter in order to reduce the loss of muscle mass observed during weight loss following diet unpaired with exercise. A consensus on the definition of sarcopenic obesity is considered essential to facilitate the performance of mechanistic studies and clinical trials aimed at deepening our knowledge, thus enabling improved management of affected individuals in the near future. PMID- 30014319 TI - Evaluation of Antiproliferative Activity, Safety and Biodistribution of Oxaliplatin and 5-Fluorouracil Loaded Lactoferrin Nanoparticles for the Management of Colon Adenocarcinoma: an In Vitro and an In Vivo Study. AB - PURPOSE: Colon adenocarcinoma is the most common form of gastro intestinal tract cancer, predominantly in ageing population. Chemotherapy with 5-Fluorouracil and oxaliplatin is an indispensable treatment regimen, nevertheless having limitation of systemic toxicity and lower therapeutic index. The present study is based on evaluation of anti-proliferative potential, pharmacokinetics parameters, safety profile, biodistribution and efficacy of 5-FU/oxaliplatin loaded lactoferrin nanoparticles in cell lines and wistar rats in order to overcome the above limitation. METHODS: Nanoparticles were prepared by Water-in-oil process. The anti-proliferative efficacy and mode of cellular entry was evaluated in COLO-205 cells. The pharmacokinetics and biodistribution analysis were performed in healthy rats while efficacy and safety assay were performed in ACF induced rats. RESULTS: 5-FU and oxaliplatin loaded nanoparticles shows enhanced antiproliferative activity as compare to free drugs in COLO-205 cells. Lactoferrin nanoparticles also improve the pharmacokinetics profile, safety parameters and efficacy of 5-FU and Oxaliplatin. CONCLUSION: Lactoferrin nanoparticles demonstrated an attractive drug delivery module to manage the colon adenocarcinoma as it has improved the antiproliferative activity of 5-FU and Oxaliplatin against colon adenocarcinoma cells. Moreover, it also improves the pharmacokinetic profile and safety parameters of the same drug in wistar rat. PMID- 30014322 TI - Stores, Channels, Glue, and Trees: Active Glial and Active Dendritic Physiology. AB - Glial cells and neuronal dendrites were historically assumed to be passive structures that play only supportive physiological roles, with no active contribution to information processing in the central nervous system. Research spanning the past few decades has clearly established this assumption to be far from physiological realities. Whereas the discovery of active channel conductances and their localized plasticity was the turning point for dendritic structures, the demonstration that glial cells release transmitter molecules and communicate across the neuroglia syncytium through calcium wave propagation constituted path-breaking discoveries for glial cell physiology. An additional commonality between these two structures is the ability of calcium stores within their endoplasmic reticulum (ER) to support active propagation of calcium waves, which play crucial roles in the spatiotemporal integration of information within and across cells. Although there have been several demonstrations of regulatory roles of glial cells and dendritic structures in achieving common physiological goals such as information propagation and adaptability through plasticity, studies assessing physiological interactions between these two active structures have been few and far. This lacuna is especially striking given the strong connectivity that is known to exist between these two structures through several complex and tightly intercoupled mechanisms that also recruit their respective ER structures. In this review, we present brief overviews of the parallel literatures on active dendrites and active glial physiology and make a strong case for future studies to directly assess the strong interactions between these two structures in regulating physiology and pathophysiology of the brain. PMID- 30014321 TI - Evolution of Caste-Specific Chemical Profiles in Halictid Bees. AB - Chemical communication is crucial for the maintenance of colony organization in eusocial insects and chemical signals are known to mediate important aspects of their social life, including the regulation of reproduction. Sociality is therefore hypothesized to be accompanied by an increase in the complexity of chemical communication. However, little is known about the evolution of odor signals at the transition from solitary living to eusociality. Halictid bees are especially suitable models to study this question as they exhibit considerable variability in social behavior. Here we investigated whether the dissimilarities in cuticle chemical signals in females of different castes and life stages reflect the level of social complexity across halictid bee species. Our hypothesis was that species with a higher social behavior ergo obligate eusocial species possess a more distinct chemical profile between castes or female life stages. We analyzed cuticular chemical profiles of foundresses, breeding females and workers of ancestrally solitary species, facultative and obligate eusocial halictid species. We also tested whether social complexity was associated with a higher investment in chemical signals. Our results revealed higher chemical dissimilarity between castes in obligate than in facultative eusocial species, especially regarding macrocyclic lactones, which were the single common compound class overproduced in queens compared with workers. Chemical dissimilarities were independent of differences in ovarian status in obligate eusocial species but were dependent on ovarian status in facultative eusocial species, which we discuss in an evolutionary framework. PMID- 30014324 TI - Simulation-based mastery learning significantly reduces gender differences on the Fundamentals of Endoscopic Surgery performance exam. AB - BACKGROUND: Analysis of the Fundamentals of Endoscopic Surgery (FES) performance exam showed higher scores for men than women. Gender differences have been reduced with task-specific practice. We assessed the effect of simulation-based mastery learning (SBML) on FES performance exam differences by gender. METHODS: Forty-seven surgical trainees [29 men (m), 18 women (w)] completed a SBML curriculum and were assessed by FES. Fourteen trained on the GI Mentor 2, 18 on the Endoscopy Training System, and 15 using the Surgical Training for Endoscopic Proficiency curriculum. Performance of male and female trainees was compared. RESULTS: On the pre-training assessment, there were large differences between genders in FES pass rates (m 77%, w 15%, p < 0.001), total scores (m 69 +/- 11, w 50 +/- 12; p < 0.001), and in four of five FES sub-task scores (Navigation, m 73 +/- 19, w 55 +/- 22, p = 0.02; Loop reduction, m 34 +/- 29, w 14 +/- 22, p = 0.02; Retroflexion, m 81 +/- 17, w 47 +/- 27, p < 0.001; Targeting, m 89 +/- 10, w 66 +/- 23, p = 0.002). No differences were discernible post training (Pass rate, m 100%, w 94%, p = 0.4; Total score, m 77 +/- 8, w 72 +/- 12, p = 0.2; Navigation, m 91 +/- 13, w 80 +/- 13, p = 0.009; Loop reduction, m 49 +/- 26, w 46 +/- 36, p = 0.7; Retroflexion, m 82 +/- 18, w 81 +/- 15, p = 0.9; Targeting, m 92 +/- 15, w 86 +/- 12, p = 0.12). Time needed to complete curricula was not discernably different by gender (m 3.8 +/- 1.7 h, w 5.0 +/- 2.6 h, p = 0.17). CONCLUSIONS: Gender-based differences are nearly eliminated through task-specific SBML training. This lends further evidence to the validity argument for the FES performance exam as a measure of basic endoscopic skills. PMID- 30014325 TI - Comparison of robotic- and laparoscopic-assisted gastrectomy in advanced gastric cancer: updated short- and long-term results. AB - BACKGROUND: Emerging evidence has demonstrated that either laparoscopic-assisted gastrectomy (LAG) or robotic-assisted gastrectomy (RAG) could be adopted as standard treatment for early gastric cancer. However, the long-term survival and recurrence rate after LAG or RAG for locally advanced gastric cancer (AGC) has seldom been reported. METHODS: We retrospectively analyzed the data from 339 patients who underwent LAG and 163 patients who underwent RAG from a prospectively established database in the Chinese People's Liberation Army General Hospital. We compared the short- and long-term oncological outcomes of the RAG group versus the LAG group in the entire cohort, and in a propensity score-matched cohort. RESULTS: Before propensity score matching (PSM), the two groups revealed comparable 3-year overall survival rates (OS, RAG vs. LAG: 76.1 vs. 81.7%, p = 0.118), and recurrence-free survival rates (RFS, RAG vs. LAG: 73.0 vs. 67.6%, p = 0.297). Similar results were obtained in the propensity score matched cohort; the respective overall survival rates in the propensity score matched RAG and LAG groups were 76.1 and 79.8% (p = 0.552), and the respective RFS rates were 73.0 and 68.7% (p = 0.386). After PSM, RAG was still associated with a significantly longer mean operating time (249.46 +/- 63.26 vs. 232.17 +/- 65.39 min, p = 0.008) and higher total costs (133.38 +/- 41.62 vs. 95.34 +/- 29.39 103 RMB, p < 0.001) than LAG; the two groups did not significantly differ in other surgical and oncological characteristics. CONCLUSION: Although there were some differences in the outcomes of RAG versus LAG in AGC patients, both RAG and LAG were similar in short-term recovery and long-term oncological outcomes. PMID- 30014326 TI - Facilitating endoscopic submucosal dissection: double balloon endolumenal platform significantly improves dissection time compared with conventional technique (with video). AB - BACKGROUND: Flexible endoscopes ability to manipulate the intestinal environment is limited. As a result, complex endolumenal procedures are often technically demanding and result in long procedure times, impacting institutional resources. Single- and double-balloon add-on endoscopic devices have been employed throughout the GI tract to facilitate tissue control e.g., small bowel enteroscopy, with recent reports suggesting a possible colonic utility for complex procedures e.g., ESD. Our objective was to objectively analyze the efficacy of a new double-balloon device in performing ESD. METHODS: Ex vivo-12 simulated colonic lesions were created in porcine rectum using a standard 40 mm diameter template. Two categories were evaluated, standard cap technique ESD and double-balloon assisted ESD with retraction (ESD-R). Cases were performed sequentially. In vivo-Six, 40 mm lesion ESD-R's were performed in a porcine model. The primary outcomes of this study were total procedure and dissection times. RESULTS: In ex vivo studies, the median total procedure time with the double-balloon platform was significantly shorter than the traditional ESD technique (29 +/- 18 vs. 57 +/- 21 min, p = 0.03). In the in vivo studies, lesions were successfully removed in a mean time of 48 min, with a dissection time of 20 min with no significant complications. Balloon-clip retraction and specimen retrieval capabilities were used in all double-balloon assisted cases. After 6 cases, times were significantly shorter (ex vivo 47 vs. 17 min; in vivo 57 vs. 27 min). CONCLUSIONS: We have demonstrated the development of a unique technical ESD method facilitated by a new double-balloon device. Ex and in vivo investigation demonstrated superiority of ESD-R over the conventional ex vivo method. The DB device provided increased stability, improved visualization and tissue traction, which significantly reduced dissection time. Such an approach may increase safety, improve patient outcomes, and may prevent unnecessary surgeries for benign conditions. PMID- 30014327 TI - Endoscopic treatment of nonmalignant tracheoesophageal and bronchoesophageal fistula: results and prognostic factors for its success. AB - BACKGROUND: Nonmalignant esophago-respiratory fistulas (ERF) are frightening clinical situations, involving surgery with high morbi-mortality rate. We described the endoscopic management of benign ERF. The aim of the study was to describe outcomes of endoscopic treatment of nonmalignant ERF and to analyze factors associated with its success. METHODS: This is a retrospective study involving patients managed for benign ERF in our center between 2012 and 2016. The ERFs were classified into three groups of sizes: (I) punctiform, (II) medium, and (III) large. The primary aim was to document the endoscopic success (= fistula's healing after 6 months). The secondary objectives were characteristics of endoscopic treatment, the functional success and death, and identifying factors associated with success and death. RESULTS: 22 patients were included. The etiologies of ERF were surgery in 12 patients, esophageal dilatation in 3, invasive ventilation in 3, radiation therapy in 2, and tracheostomy in 2. Ninety three procedures were performed (mean of number: 4.2 +/- 4.5/patient). Twenty-one patients had stent placement, eight over-the-scope clips (OTSC), and seven a combined therapy. The endoscopic success rate was 45.5% (n = 10; 67% in punctiform, 50% in medium, and 14% in large ERF), and the functional success was 55% (n = 12). Serious adverse events occurred in 9 patients (40.9%). Six patients died (27%). The persistence of the orifice after 6 months of endoscopic treatment was associated with failure (OR 44; IC95: 3.38-573.4; p = 0.004 multivariate analysis). The orifice's size was associated with mortality [71% of death if large fistulas (p = 0.001) univariate analysis]. CONCLUSION: Endoscopic treatment of ERF leads to 45.5% of successful endoscopic closure and 55.5% of functional success, depending on fistula's orifice size. After 6 months without healing, the chances for success dramatically decrease. PMID- 30014328 TI - Implementation of 3D printed superior mesenteric vascular models for surgical planning and/or navigation in right colectomy with extended D3 mesenterectomy: comparison of virtual and physical models to the anatomy found at surgery. AB - BACKGROUND: Three-dimensional (3D) printing technology has recently been well approved as an emerging technology in various fields of medical education and practice; e.g., there are numerous studies evaluating 3D printouts of solid organs. Complex surgery such as extended mesenterectomy imposes a need to analyze also the accuracy of 3D printouts of more mobile and complex structures like the diversity of vascular arborization within the central mesentery. The objective of this study was to evaluate the linear dimensional anatomy landmark differences of the superior mesenteric artery and vein between (1) 3D virtual models, (2) 3D printouts, and (3) peroperative measurements. METHODS: The study included 22 patients from the ongoing prospective multicenter trial "Safe Radical D3 Right Hemicolectomy for Cancer through Preoperative Biphasic MDCT Angiography," with preoperative CT and peroperative measurements. The patients were operated in Norway between January 2016 and 2017. Their CT datasets underwent 3D volume rendering and segmentation, and the virtual 3D model produced was then exported for stereolithography 3D printing. RESULTS: Four parameters were measured: distance between the origins of the ileocolic and the middle colic artery, distance between the termination of the gastrocolic trunk and the ileocolic vein, and the calibers of the middle colic and ileocolic arteries. The inter-arterial distance has proven a strong correlation between all the three modalities implied (Pearson's coefficient 0.968, 0.956, 0.779, respectively), while inter-venous distances showed a weak correlation between peroperative measurements and both virtual and physical models. CONCLUSION: This study showed acceptable dimensional inter-arterial correlations between 3D printed models, 3D virtual models and authentic soft tissue anatomy of the central mesenteric vessels, and weaker inter venous correlations between all the models, reflecting the highly variable nature of veins in situ. PMID- 30014329 TI - Comparison of early experience of robotic and transanal total mesorectal excision using propensity score matching. AB - BACKGROUND: Robotic surgery and transanal minimally invasive surgery are the two recently developed techniques, which can overcome the difficult pelvic dissection in conventional laparoscopy. This study aimed to compare the early cases of robotic and transanal total mesorectal excision (taTME) using propensity score matching. METHODS: The first 40 cases of taTME and the first 80 sphincter-saving robotic total mesorectal resection for rectal cancer were selected from the prospectively collected database. Using propensity score matching, the outcomes of 40 matched cases of robotic TME were compared with the 40 cases of taTME. RESULTS: Before matching, patients in the taTME group were significantly younger. The tumors were smaller but more distally located. Significantly more patients in the taTME group received preoperative chemoradiation. After matching, the two groups did not show any differences in gender, age, comorbidity, the level of tumors, and incidences of preoperative chemoradiation. The operating time was significantly shorter (254 vs. 170 min, p < 0.05) and the blood loss was less (50 vs. 150 ml, p = 0.002) in the taTME group. Conversion rate was 5% in both groups. There was no difference in the hospital stay, overall morbidity, the anastomotic leakage rate, and the urinary complication rate between the two groups. More patients in the taTME group did not require a separate abdominal incision. The distal margin, the number of lymph nodes examined, and the rate positive circumferential margin (0 vs. 5%, p = 0.494) were also similar between the two groups. CONCLUSIONS: Both taTME and robotic surgery can achieve favorable outcomes in the rectal cancer resection. Comparison of the early experience of the two procedures with propensity score matching showed the taTME was associated with a shorter operating time, less blood loss, and a higher rate of transanal extraction of the specimen. Further evaluation by randomized trials is warranted. PMID- 30014330 TI - Clinicopathological characteristics of patients with pain after endoscopic submucosal dissection for gastric epithelial neoplasm. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is widely used for large superficial gastrointestinal tumors. Epigastric pain is a frequent complication of ESD. However, little is known about its incidence and associated factors. This study evaluated pain incidence and characteristics of patients with pain after gastric ESD. METHODS: We retrospectively analyzed a prospectively collected registry of clinical, endoscopic, and pathologic results of patients who underwent ESD for gastric adenoma or cancer from January 2010 to December 2015. A Visual Analogue Scale (VAS) was used to assess pain immediately after, and 2, 12, and 24 h after ESD. The primary outcome was the use of painkillers (VAS score > 4). Analyzed data included age, sex, pathology, specimen and tumor size, procedure time, and tumor location. RESULTS: Of 1226 patients, 461 (36.4%) needed a painkiller at least once after ESD (pain group). Compared with the no pain group, the pain group had more females, less alcohol consumption, larger tumor and specimen size, and more antral lesions. In multivariate analysis, female sex (OR 1.559, 95% CI 1.217-1.996, p < 0.001), antral tumor location (OR 1.780, 95% CI 1.398-2.265, p < 0.001), and procedure time over 30 min (OR 1.443, 95% CI 1.130-1.842, p = 0.003) were predictive factors for pain. CONCLUSION: This study showed that a considerable number of patients needed one or more painkiller doses after gastric ESD. The factors affecting pain included sex, procedure time, and lesion location. Endoscopists should use preemptive or aggressive pain management in high-risk patients after ESD. PMID- 30014331 TI - Comparison of impacts of intraperitoneal saline instillation with and without pulmonary recruitment maneuver on post-laparoscopic shoulder pain prevention: a randomized controlled trial. AB - BACKGROUND: Intraperitoneal isotonic saline instillation (SI) and pulmonary recruitment maneuver (RM) were indicated to alleviate post-laparoscopic shoulder pain (PLSP) effectively. The aim of this study was to compare the effects of the single strategy using SI alone and the combined strategy using SI and RM on PLSP reduction. METHODS: Subjects undergoing elective gynecologic laparoscopy were randomly allocated to a control group (no intervention, n = 48) and two intervention groups (single strategy of SI alone, n = 48; combined strategy of SI and RM, n = 48). In the control group, carbon dioxide was removed only via passive evacuation through the port sites at the completion of the laparoscopic procedure. In the saline instillation group, 20-mL/kg of body weight SI was performed. In the combined strategy group, RM using five pulmonary inflations was performed, in addition to SI. The PLSP scores, which were the primary outcome, were recorded using a visual analog scale postoperatively. RESULTS: The PLSP scores 24 and 48 h after surgery were significantly lower in the two intervention groups than in the control group (P = 0.014 and P = 0.001, respectively), while no significant differences were observed between the two intervention groups. CONCLUSIONS: The single strategy using SI alone is as effective as the combined strategy of SI and RM for removing residual carbon dioxide and consequently preventing PLSP. Therefore, considering the potential risks of pulmonary or hemodynamic complications associated with RM, the single strategy using SI alone might be a better choice than the combined strategy. PMID- 30014332 TI - Comment on: "Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review". PMID- 30014333 TI - Author's Reply to Kitic: Comment on: "Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review". PMID- 30014334 TI - Warning from constricted and wrinkled internal jugular vein. PMID- 30014335 TI - Efficient Production of Polymalic Acid by a Novel Isolated Aureobasidium pullulans Using Metabolic Intermediates and Inhibitors. AB - Polymalic acid (PMA) is a linear anionic polyester composed of L-malic acid monomers, which have potential applications as drug carriers, surgical suture, and biodegradable plastics. In this study, a novel strain of Aureobasidium pullulans var. melanogenum GXZ-6 was isolated and identified according to the morphological observation and deoxyribonucleic acid internal-transcribed spacer sequence analysis, and the product of PMA was characterized by FT-IR, 13C-NMR, and 1H-NMR spectra. The PMA titer of GXZ-6 reached 62.56 +/- 1.18 g L-1 with productivity of 0.35 g L-1 h-1 using optimized medium with addition of metabolic intermediates (citrate and malate) and inhibitor (malonate) by batch fermentation in a 10-L fermentor. Besides that the malate for PMA synthesis in GXZ-6 might mainly come from the glyoxylate cycle, based on results, citrate, malate, malonate, and maleate increased while succinate and fumarate inhibited the production of PMA, which was different from that of other A. pullulans. This study provided a potential strain and a simple metabolic control strategy for high-titer production of PMA and shared novel information on the biosynthesis pathway of PMA in A. pullulans. PMID- 30014336 TI - An Organizational Framework for Sexual Media's Influence on Short-Term Versus Long-Term Sexual Quality. AB - Although research has suggested a net negative influence of sexual media on sexual quality, enough researchers have found results suggesting that sexual media has no effect or a positive influence that the matter warrants further investigation. We present an organizational framework utilizing primarily the acquisition, activation, application model (3AM), and the Antecedents-Context Effects model (ACE) to reconcile these apparently contradictory claims. By synthesizing these theories, we suggest that to truly understand the impact of sexual media on sexual quality, four factors must be taken into account: (1) the content of the sexual media being viewed, (2) the difference between short-term and long-term sexual quality, (3) the influence of exclusivity, formativeness, resonance, and reinforcement in moderating the extent to which the portrayed sexual script is applied (influences attitudes and behavior), and (4) the couple context for congruency of use, script application, and moral paradigms. While acknowledging the many nuances that should be considered, we ultimately argue that when considering these factors simultaneously, the overall scripts presented in sexual media are congruent with pursuing factors for short-term sexual quality and incongruent with pursuing factors for long-term sexual quality. PMID- 30014337 TI - Viewing Time and Self-Report Measures of Sexual Attraction in Samoan Cisgender and Transgender Androphilic Males. AB - Across cultures, androphilic males (natal males who are predominantly sexually attracted to adult men, not women) tend to present in one of two forms: cisgender or transgender. Previous research has shown that, although their gender presentation and identities are distinct, the two forms are similar in many other ways. The present study examined whether cisgender and transgender androphilic males exhibit a similar pattern of self-reported sexual attraction and viewing time response to images of men and women, and one that is directly inverse to that of cisgender gynephilic males (natal males who are predominately sexually attracted to adult women, not men). Using measures of self-reported sexual attraction and viewing time, we compared the response patterns of Samoan cisgender males who self-identified as men, were predominantly attracted to men, and had sex only with men (N = 16) and Samoan transgender males who self identified as fa'afafine, were predominantly attracted to men, and had sex only with men (N = 30). Samoan cisgender males who self-identified as men, were predominantly attracted to women, and had sex only with women (N = 31) served as a comparison group. Androphilic men and fa'afafine reported greater sexual attraction to men than women and viewed the images of men longer than those of women. Gynephilic men showed the inverse pattern. Viewing time discrepancies between participant's preferred gender and their non-preferred gender were greater for gynephilic men compared to the two androphilic groups. The implications of these preliminary findings for the use of viewing time measures of male sexual orientation across different cultural contexts are discussed. PMID- 30014338 TI - Gay Circuit Parties in Barcelona and Their Impact on Gonorrhea Incidence. AB - This study explored the role of circuit parties on the incidence of gonorrhea among men who have sex with men (MSM) in Barcelona (Spain). Specifically, it aimed to detect cyclic peaks in the number of reported diagnoses of gonorrhea after gay circuit parties. We analyzed monthly cases of gonorrhea reported from January 2007 through December 2016 after the main annual gay circuit parties in Barcelona. We used the integer autoregressive model for time series with discrete values. The performance of the model was tested in heterosexual men and women, in whom the circuit parties could be expected to have no impact. A sensitivity analysis was conducted, changing post-event diagnosis windows to 1 week later/1 week before. In the study period, a total of 4182 of gonorrhea cases were detected, of which 74.8% (n = 2181) occurred in men who identified themselves as MSM. The average annual increase in gonorrhea cases reported among MSM was 32.57%. In an independent analysis of each gay circuit party, cases increased significantly in two of them. The results were also similar for same-sex practices among men only. On controlling for the increasing trend over the study period and the seasonal effect, an average of 1.16 gonorrhea cases in MSM (95% CI: 0.68, 1.64) were attributable to the celebration of one of the gay circuit parties considered. During the expected outbreak, an average of 13 gonorrhea cases were detected and between 5 and 13% were attributable to one of the circuit parties. In view of these findings, participants should consider seeking advice from their healthcare provider and practice safer sex using condoms to prevent sexually transmitted infections. Local public health services should be reinforced to ensure care for participants during and after gay circuit parties. More research is needed to design and implement preventive programs. PMID- 30014339 TI - How Do College Experience and Gender Differentiate the Enactment of Hookup Scripts Among Emerging Adults? AB - Empirical attention to "hooking up" has expanded over time, yet limited attention has been devoted to understanding the hookup experiences of emerging adults (ages 18-25) who have not attended college and how they may differ from those who have attended college. Guided by life course and scripting theories, we used a storytelling methodology to content analyze the hookup stories of a large sample of college-attending and non-college emerging adults (N = 407). We also compared stories based on gender, as several studies report gender differences but have yet to consider how hookup scripts may differ between men and women. Overall, we found that college-attending and non-college emerging adults reported using similar hookup scripts in their most recent hookup experience, as did emerging adult men and women. However, we found that greater proportions of non-college emerging adults reported sexual touch, meeting in an "other location," and positive reactions to their most recent hookup. Greater proportions of college attending emerging adults reported their hookup occurred in a house/apartment. In terms of gender, greater proportions of women reported "having sex" and deep kissing, hooking up with an acquaintance, partner characteristics as a reason to hookup, and negative reactions to their most recent hookup. Greater proportions of men reported hooking up with a stranger, meeting at a bar/club, hooking up at a party, and hooking up at an "other location." Implications for future research and sexual health education and intervention are discussed. PMID- 30014340 TI - Taxometric Analysis of the Latent Structure of Pedophilic Interest. AB - The present study examined the latent structure of pedophilic interest. Using data from phallometric tests for pedophilic interest across four samples of offenders (ns = 805, 632, 531, 261), taxometric analyses were conducted to identify whether pedophilic interest is best characterized as taxonic or dimensional. Across the samples, the majority of analyses supported taxonic latent structure in pedophilic interest. Visual inspection of taxometric curves indicated trichotomous latent structure (i.e., three-ordered classes) may characterize pedophilic interest in these samples. In a second step of taxometric analysis, the results supported trichotomous latent structure, indicating the presence of a complement taxon and two pedophilic taxa. In comparison with the complement taxon, the men in the first pedophilic taxon were non-exclusively pedophilic and had similar rates of sexual recidivism and sexual compulsivity. The men in the second pedophilic taxon were exclusively pedophilic, had more child victims and total victims, sexually re-offended at a higher rate, and were more sexually compulsive. The finding of trichotomous latent structure in pedophilic interest is both consistent and inconsistent with previous taxometric studies and has implications for research, assessment, and treatment of pedophilic interest. PMID- 30014341 TI - Autonomic dysfunction in multiple sclerosis and other updates on recent autonomic research. PMID- 30014342 TI - Pituitary tumour apoplexy within prolactinomas in children: a more aggressive condition? AB - OBJECTIVES: To evaluate clinical presentations, diagnosis and management of paediatric patients presenting with pituitary apoplexy. METHODS: A retrospective case series describing a cohort of paediatric patients presenting with this condition from 2010-2016 to a tertiary referral children's hospital in the United Kingdom. RESULTS: Pituitary apoplexy is a rare condition that seems to have a higher relative incidence in children than adults. Our series suggests that pituitary apoplexy in paediatric patients with adenomas appears more common than previously described. All our patients required surgery, either as an acute or delayed procedure, for visual compromise. Two patients had commenced growth hormone (GH) for GH deficiency two weeks prior to the onset of pituitary apoplexy. CONCLUSIONS: With only a limited number of published case reports surrounding this topic our case series contributes to help further understand and manage this condition. PMID- 30014343 TI - Editorial: The Life and Contributions of Thomas Dishion. PMID- 30014345 TI - Pre-therapy Somatostatin Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy. AB - PURPOSE: Early identification of aggressive disease could improve decision support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR) positron emission tomography (PET) before PRRT was analyzed. PROCEDURES: Thirty one patients with G1/G2 pNET were enrolled (G2, n = 23/31). Prior to PRRT with [177Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET computed tomography was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUVmean/max), imaging-based TF, and clinical parameters (Ki67, CgA) for prediction of both progression-free survival (PFS) and overall survival (OS) after PRRT were evaluated. RESULTS: Within a median follow-up of 3.7 years, tumor progression was detected in 21 patients (median, 1.5 years) and 13/31 deceased (median, 1.9 years). In ROC analysis, the TF entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff = 6.7, AUC = 0.71, p = 0.02). Of note, increasing entropy could predict a longer survival (> 6.7, OS = 2.5 years, 17/31), whereas less voxel-based derangement portended inferior outcome (< 6.7, OS = 1.9 years, 14/31). These findings were supported in a G2 subanalysis (> 6.9, OS = 2.8 years, 9/23 vs. < 6.9, OS = 1.9 years, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using entropy (n = 31, p < 0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n = 31, p = 0.04). Ki67 was negatively associated with PFS (p = 0.002); however, SUVmean/max failed in prognostication (n.s.). CONCLUSIONS: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification. PMID- 30014346 TI - Contamination Level, Source Identification and Risk Assessment of Potentially Toxic Elements (PTEs) and Polycyclic Aromatic Hydrocarbons (PAHs) in Street Dust of an Important Commercial Center in Iran. AB - The geochemical nature and health hazards of potentially toxic elements (PTEs) and polycyclic aromatic hydrocarbons (PAHs) in the street dust of Bandar Abbas, Iran, are investigated in this study based on 27 street dust samples. Mean concentrations of Cu, Pb, Zn, As, Sb, and Hg revealed elevated concentrations as compared to the world soil average. Calculated enrichment factors (EFs) indicated that there is very high contamination in dust particles owing to anthropogenic emissions. Two main sources of PTEs are traffic emissions (Cu, Pb, Zn, Co, Mn, Fe, As, Cd, Sb, and Hg) and resuspended soil particles (Al, Ti, Ni, and Cr). Statistical analysis shows that Al, Mn, Ni, Ti, Cr, Fe, and Co are geogenic, whereas PAHs are mainly derived from traffic emissions. Values of incremental lifetime cancer risk (ILCR), as derived from a modified model of the United State Environmental Protection Agency (USEPA), indicate that Bandar Abbas residents are potentially exposed to high cancer risk, especially via dust ingestion and dermal contact, whereas the level of hazard index (HI), hazard quotients (HQ), and cancer risk associated with exposure to the elements in street dust fall lower than threshold values representative of health risks. PMID- 30014344 TI - Cerebral Metabolic Changes During Sleep. AB - PURPOSE OF REVIEW: The goal of the present paper is to review current literature supporting the occurrence of fundamental changes in brain energy metabolism during the transition from wakefulness to sleep. RECENT FINDINGS: Latest research in the field indicates that glucose utilization and the concentrations of several brain metabolites consistently change across the sleep-wake cycle. Lactate, a product of glycolysis that is involved in synaptic plasticity, has emerged as a good biomarker of brain state. Sleep-induced changes in cerebral metabolite levels result from a shift in oxidative metabolism, which alters the reliance of brain metabolism upon carbohydrates. We found wide support for the notion that brain energetics is state dependent. In particular, fatty acids and ketone bodies partly replace glucose as cerebral energy source during sleep. This mechanism plausibly accounts for increases in biosynthetic pathways and functional alterations in neuronal activity associated with sleep. A better account of brain energy metabolism during sleep might help elucidate the long mysterious restorative effects of sleep for the whole organism. PMID- 30014348 TI - Supportive Role of Probiotic Strains in Protecting Rats from Ovariectomy-Induced Cortical Bone Loss. AB - Osteoporosis is a major health problem that occurs as a result of an imbalance between bone formation and bone resorption. Different approaches have been established for treating osteoporosis. Recently, because of their health benefits and also low adverse reaction, probiotics have been receiving considerable attention. In this study, we compared the effectiveness of five probiotic strains, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei, Bifidobacterium longum, and Bacillus coagulans, in protecting rats from ovariectomized (OVX)-induced bone loss. Forty-nine adult female Sprague-Dawley rats were allocated into seven groups as follows: group 1, control; group 2, OVX; group 3, OVX + Lactobacillus acidophilus; group 4, OVX + Lactobacillus casei; group 5, OVX + Bacillus coagulans; group 6, OVX + Bifidobacterium longum; and group 7, OVX + Lactobacillus reuteri. Probiotics were fed to OVX groups at the concentration of (1 * 109 CFU/ml/day) for 4 weeks. Then, biochemical parameters, including vitamin D, calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP), were assessed. Dual-energy X-ray absorptiometry (DEXA) scans were used that assess bone mineral density (BMD), bone marrow concentration (BMC), and area of global, femur, spine, and tibia. Lactobacillus acidophilus and Lactobacillus casei significantly increased Ca and ALP and decreased P in treated groups. Lactobacillus casei, Lactobacillus reuteri, and Bifidobacterium longum increased vitamin D significantly. Lactobacillus acidophilus and Lactobacillus casei indicated the most effects on BMD. In terms of BMC, and bone area, Lactobacillus acidophilus, Lactobacillus reuteri, and Lactobacillus casei demonstrated the significant enhancement in OVX groups treated with. Among the probiotics used in this study, Lactobacillus acidophilus and Lactobacillus casei showed the most effects in terms of BMD, BMC, bone area, and biochemical parameters. It seems that probiotics effects on bone health are strain dependent, but further studies should be done to prove these findings. PMID- 30014349 TI - Cardiovascular risk prediction models with myocardial perfusion imaging in chronic kidney disease: ACCESSing digits or focusing on the patient? PMID- 30014347 TI - Visual Fixation Assessment in Patients with Disorders of Consciousness Based on Brain-Computer Interface. AB - Visual fixation is an item in the visual function subscale of the Coma Recovery Scale-Revised (CRS-R). Sometimes clinicians using the behavioral scales find it difficult to detect because of the motor impairment in patients with disorders of consciousness (DOCs). Brain-computer interface (BCI) can be used to improve clinical assessment because it directly detects the brain response to an external stimulus in the absence of behavioral expression. In this study, we designed a BCI system to assist the visual fixation assessment of DOC patients. The results from 15 patients indicated that three showed visual fixation in both CRS-R and BCI assessments and one did not show such behavior in the CRS-R assessment but achieved significant online accuracy in the BCI assessment. The results revealed that electroencephalography-based BCI can detect the brain response for visual fixation. Therefore, the proposed BCI may provide a promising method for assisting behavioral assessment using the CRS-R. PMID- 30014350 TI - Comparison of Characteristics of Benign Prostatic Hyperplasia (BPH) Patients Treated with Finasteride and Alpha Blocker Combination Therapy Versus Alpha Blocker Monotherapy in China: An Analysis of Electronic Medical Record Data. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is commonly treated with 5-alpha reductase inhibitor/alpha blocker combination therapy or with alpha blocker monotherapy. However, in China, the characteristics of BPH patients receiving 5 alpha-reductase inhibitor/alpha blocker combination therapy or alpha blocker monotherapy remain largely unknown. Therefore, this study compared the characteristics of BPH patients receiving either the 5-alpha-reductase inhibitor finasteride in combination with an alpha blocker or an alpha blocker as monotherapy in clinical practice in China. METHODS: Data were obtained from a large electronic medical record database from four tertiary hospitals in major cities in China (2009-2016). BPH patients aged >= 50 years with >= 1 alpha blocker fill on/after the first BPH diagnosis were selected. Patients were further classified as receiving combination therapy (>= 1 overlapping day of supply for finasteride and an alpha blocker) or alpha blocker monotherapy (did not receive any 5-alpha-reductase inhibitor). Patient characteristics, visit type (in- vs. outpatient) at treatment initiation, and comorbidities were evaluated during the 6-month baseline period and compared between the two groups using two sample t tests and chi-square tests/Fisher's exact tests. RESULTS: A total of 2666 and 2738 patients received combination therapy and monotherapy, respectively. The combination group was older (70.3 vs. 67.3 years, p < 0.0001) and had more patients initiated in an inpatient setting (46.0% vs. 26.4%, p < 0.0001). Compared with the monotherapy group, the combination group had more comorbidities, such as hypertension (48.3% vs. 35.6%, p < 0.0001), cardiovascular disease (65.3% vs. 48.0%, p < 0.0001), and diabetes (21.1% vs. 15.7%, p < 0.0001), and a higher Charlson comorbidity index (0.9 vs. 0.7, p < 0.0001). CONCLUSION: Chinese BPH patients using finasteride/alpha blocker combination therapy were older and had a higher comorbidity burden than those using alpha blocker monotherapy. These findings provide Chinese healthcare decision-makers with a better understanding of the patient characteristics generally associated with BPH combination therapy vs. alpha blocker monotherapy. FUNDING: Merck Sharp and Dohme (China) Co., Ltd., Shanghai, China. PMID- 30014351 TI - Ferrous and ferric differentially deteriorate proliferation and differentiation of osteoblast-like UMR-106 cells. AB - The association between iron overload and osteoporosis has been found in many diseases, such as hemochromatosis, beta-thalassemia and sickle cell anemia with multiple blood transfusion. One of the contributing factors is iron toxicity to osteoblasts. Some studies showed the negative effects of iron on osteoblasts; however, the effects of two biological available iron species, i.e., ferric and ferrous, on osteoblasts are elusive. Since most intracellular ionized iron is ferric, osteoblasts was hypothesized to be more responsive to ferric iron. Herein, ferric ammonium citrate (FAC) and ferrous ammonium sulfate (FAS) were used as ferric and ferrous donors. Our results showed that both iron species suppressed cell survival and proliferation. Both also induced osteoblast cell death consistent with the higher levels of cleaved caspase 3 and caspase 7 in osteoblasts, indicating that iron induced osteoblast apoptosis. Iron treatments led to the elevated intracellular iron in osteoblasts as determined by atomic absorption spectrophotometry, thereby leading to a decreased expression of genes for cellular iron import and increased expression of genes for cellular iron export. Effects of FAC and FAS on osteoblast differentiation were determined by the activity of alkaline phosphatase (ALP). The lower ALP activity from osteoblast with iron exposure was found. In addition, ferric and ferrous differentially induced osteoblastic and osteoblast-derived osteoclastogenic gene expression alterations in osteoblast. Even though both iron species had similar effects on osteoblast cell survival and differentiation, the overall effects were markedly stronger in FAC-treated groups, suggesting that osteoblasts were more sensitive to ferric than ferrous. PMID- 30014352 TI - High Selenium Yeast mitigates aluminum-induced cerebral inflammation by increasing oxidative stress and blocking NO production. AB - High Selenium Yeast (SeY) serves many important roles with respect to the maintenance of normal nervous system functioning. Studies have reported the nerve inflammation induced by Aluminum (Al) was associated with the increase of mortality. However, in-depth studies are required to verify the hypothesized neuro-protective efficacy of SeY against Al-induced cerebral damage through modulation of the inflammatory response. Here, mice were treated with SeY (0.1 mg/kg) and/or Al (10 mg/kg) by oral gavage for 28 days. Inflammation was assessed by histopathological examination and expression of biomarkers for inflammation. Furthermore, the oxidation-reduction levels and the NO production were assessed using diagnostic kits and RT-PCR. The data indicated that SeY significantly protected cerebrum against Al-induced pathological changes, in addition to the disordered expression of biomarkers of inflammation, the imbalance of oxidation reduction, and the increase of NO production. Therefore, the chemoprotective potential of SeY against Al-induced cerebral inflammation via restore the levels of oxidation-reduction and the generation of NO was demonstrated. PMID- 30014354 TI - Variation on a theme: investigating the structural repertoires used by ferric uptake regulators to control gene expression. AB - In every living organism, the control of metal homoeostasis is a tightly regulated process coordinated by several intertwined biological pathways. In many bacteria, the ferric uptake regulator (Fur) family of transcriptional factors (TFs) are key factors in controlling the expression of genes involved in metal homeostasis and can also regulate the expression of genes involved in responses to oxidative stresses. Since the crystallization of Escherichia coli Fur DNA binding domain, the crystal structure of several metalloregulators have been reported. While the Fur family of proteins adopt similar structures, each contains unique structural features relating to their specific biological functions. Moreover, recent groundbreaking studies have provided additional insights into the mechanisms underlying the binding of DNA by these metalloregulators. In this review, we present a comprehensive overview of the crystal structure of Fur family metalloregulators with a specific focus on the new structures of these TFs bound to DNA. PMID- 30014353 TI - Chromium malate alleviates high-glucose and insulin resistance in L6 skeletal muscle cells by regulating glucose uptake and insulin sensitivity signaling pathways. AB - Previous study revealed that chromium malate improved the regulation of fasting blood glucose and insulin resistance in type 2 diabetic rats. In this study, the effect of chromium malate on anti-high-glucose and improve insulin resistance activities in L6 skeletal muscle cells with insulin resistance and its acting mechanism were investigated. Chromium malate showed direct anti-high-glucose activity in vitro. The glucose levels had a significant downward trend compared to chromium trichloride. Compared with model group, chromium malate could significantly promote the secretion levels of GLUT-4, Akt, Irs-1, PPARgamma, PI3K and p38-MAPK, promote AMPKbeta1 phosphorylation, and reduced the level of p-Irs-1 in L6 cells with insulin resistance. And the relate mRNA expression of chromium malate was significantly increased. Chromium malate is more effective at improving the related proteins and mRNA expression than those of chromium trichloride and chromium picolinate. Pretreatment with the specific p38MAPK inhibitor completely inhibited the GLUT-4 and Irs-1 proteins and mRNA expression induced by the chromium malate when compared with model group, but GLUT-4 and Irs 1 proteins and mRNA expression was partially inhibited after inhibiting p38MAPK/PI3K expression. The results suggested that chromium malate had a beneficial influence on the improvement of controlling glucose levels and insulin resistance in L6 cells with insulin resistance by regulating proteins production and genes expression in glucose uptake and insulin sensitivity signaling pathways. The signaling pathways of glucose uptake and insulin sensitivity. This study shown that chromium malate could significant increase in the production levels of GLUT-4, p-AMPKbeta1, Akt, Irs-1, PPARgamma, PI3K and p38-MAPK proteins and mRNA in L6 cells with insulin resistant. Pretreatment with the specific p38MAPK inhibitor completely inhibited the GLUT-4 and Irs-1 proteins and mRNA expression induced by the chromium malate compared to model group, but the proteins and mRNA were partially inhibited after inhibiting p38MAPK/PI3K. Therefore, chromium malate had beneficial influence on improvement of controlling glucose levels and insulin resistant in L6 cells by regulating proteins production and genes expression in glucose uptake and insulin sensitivity signaling pathways. The key proteins of glucose uptake and insulin sensitivity signaling pathways were p38MAPK, PI3K and PPARgamma. PMID- 30014355 TI - Oxidative stress and neurodegeneration: the involvement of iron. AB - Many evidences indicate that oxidative stress plays a significant role in a variety of human disease states, including neurodegenerative diseases. Iron is an essential metal for almost all living organisms due to its involvement in a large number of iron-containing proteins and enzymes, though it could be also toxic. Actually, free iron excess generates oxidative stress, particularly in brain, where anti-oxidative defences are relatively low. Its accumulation in specific regions is associated with pathogenesis in a variety of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis and Neurodegeneration with Brain Iron Accumulation). Anyway, the extent of toxicity is dictated, in part, by the localization of the iron complex within the cell (cytosolic, lysosomal and mitochondrial), its biochemical form, i.e., ferritin or hemosiderin, as well as the ability of the cell to prevent the generation and propagation of free radical by the wide range of antioxidants and cytoprotective enzymes in the cell. Particularly, ferrous iron can act as a catalyst in the Fenton reaction that potentiates oxygen toxicity by generating a wide range of free radical species, including hydroxyl radicals (.OH). The observation that patients with neurodegenerative diseases show a dramatic increase in their brain iron content, correlated with the production of reactive oxigen species in these areas of the brain, conceivably suggests that disturbances in brain iron homeostasis may contribute to the pathogenesis of these disorders. The aim of this review is to describe the chemical features of iron in human beings and iron induced toxicity in neurodegenerative diseases. Furthermore, the attention is focused on metal chelating drugs therapeutic strategies. PMID- 30014356 TI - Dyskinesia in Parkinson's disease: a clinical complication and an open scientific question. PMID- 30014357 TI - Serum 25-hydroxyvitamin D3 levels and flares of systemic lupus erythematosus: a longitudinal cohort analysis. AB - The aim of this study is to evaluate the relationship between baseline serum 25 hydroxyvitamin D3 levels and SLE activity/flares over time. This is a longitudinal study of 276 patients who fulfilled >= 4 ACR criteria for SLE and recruited in the year 2011. Serum samples were collected at baseline and assayed for 25-hydroxyvitamin D3 at the end of a mean follow-up of 32.5 months. Participants were stratified into three groups according to baseline 25 hydroxyvitamin D3 levels: group I (< 15 ng/ml, deficiency), group II (15-30 ng/ml, insufficiency), and group III (> 30 ng/ml, adequate). Baseline and summated SLE disease activity index (SLEDAI) score over time and the annual incidence of lupus flares were compared among these groups. 25-hydroxyvitamin D3 levels of < 15, 15-30, and > 30 ng/ml were present in 26, 54, and 20% of the recruited patients, respectively. Group I had significantly higher baseline SLEDAI scores. After a follow-up of 32.5 +/- 5.5 months, 153 mild/moderate and 91 severe flares developed. The mean summated SLEDAI was 3.2 +/- 2.0 in group I, 2.4 +/- 1.9 in group II and 2.7 +/- 2.1 in group III patients (P = 0.02). The annual incidence of mild/moderate and severe flares was 0.26 +/- 0.39 and 0.20 +/- 0.45 (group I); 0.20 +/- 0.33 and 0.09 +/- 0.22 (group II); and 0.20 +/- 0.32 and 0.14 +/- 0.46 (group III), respectively (P > 0.05). In a subgroup of 73 patients who were clinically and serologically quiescent at baseline, a similar trend of more flares was observed in group I patients. Vitamin D deficiency was frequent in Chinese SLE patients and was associated with more active disease at baseline and over time, as well as a trend of more severe lupus flares. PMID- 30014359 TI - Clinically important neutralizing anti-drug antibodies detected with an in-house competitive ELISA. AB - Therapeutic drug monitoring of TNF-alpha inhibitors is crucial for evaluating patients with inflammatory diseases on a personalized level. It has been clinically observed that many patients receiving TNF-alpha inhibitors, with negative drug and anti-drug antibody results from bridging ELISA (bELISA), lose their drug response over time, despite dose optimization. Our aims were to develop innovative in-house competitive ELISAs (cELISAs) for the detection of neutralizing antibodies against infliximab and adalimumab and compare their results to reporter gene assay (RGA) and in-house bELISA. Furthermore, we aimed to evaluate patient anti-drug antibody results in regard to their clinical records and potential benefits of therapeutic drug monitoring with the novel cELISAs. Sera of patients treated with infliximab (n = 46) or adalimumab (n = 31), having undetectable drug levels, were tested with our in-house cELISA. Briefly, samples were incubated with a fixed amount of drug and the neutralizing capacity of the samples was determined. The cELISA results were compared to RGA and bELISA results using Spearman's correlation coefficient. Additionally, patient clinical data were evaluated in line with the results of cELISA, bELISA, and RGA using the Kaplan-Meier analysis and the Log Rank test. Both anti infliximab and anti-adalimumab cELISAs showed very good correlation to RGA (r = 0.932, p < 0.0001 and r = 0.947, p < 0.0001, respectively). Furthermore, a positive result in anti-infliximab cELISA can predict treatment failure in 100% of patients with negative bELISA, while a positive result in anti-adalimumab cELISA can predict treatment failure in 80% of patients with negative bELISA. Taken together, we developed innovative cELISAs enabling quantification of functional and neutralizing anti-drug antibodies, comparable to RGA. The association between cELISA results and loss of drug response in patients identified clinically important anti-drug antibodies, as measured by cELISA. PMID- 30014360 TI - Serum IL 4 and its gene polymorphism (rs79071878) in Egyptian children with familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is an autoinflammatory disorder. It is caused by mutations in the MEFV gene encoding the pyrin protein, which regulates the innate inflammatory response. The aim of the current study was to investigate the relationship between serum Interleukin-4 (IL-4) and its gene polymorphism, namely rs79071878, and FMF occurrence, severity, and response to treatment in Egyptian children harboring the disease. Fifty Egyptian children diagnosed as having FMF were included in this study. They were divided equally into two groups according to disease activity. Forty controls, age- and gender-matched, were also included. Serum IL-4 levels were measured by enzyme-linked immunosorbent assay (ELISA). The IL-4 rs79071878 polymorphism was determined by polymerase chain reaction (PCR) analysis. There was no significant difference in genotype distribution of IL-4 gene rs79071878 between patients and controls (p = 0.286) and had no correlation with FMF severity or response to colchicine therapy. Serum IL-4 level had no significant difference between children with FMF attack and those in attack-free period compared to controls (p = 0. 794) and had no correlation with any of demographic, or clinical characteristics, disease severity, or response to colchicine therapy. Serum IL-4 level and its gene polymorphism were not found to have any increase risk of FMF occurrence, disease severity, or response to treatment in the Egyptian children. Further studies are needed to verify these results. PMID- 30014363 TI - Pulsatile versus non-pulsatile tinnitus in idiopathic intracranial hypertension. AB - INTRODUCTION: Tinnitus is a symptom commonly associated with idiopathic intracranial hypertension (IIH) that can have a profound effect on quality of life. We aim to determine tinnitus symptom response after dural venous sinus stenting (DVSS) or CSF diversion with a shunt, in patients with both pulsatile (PT) and non-pulsatile tinnitus (NPT). METHODS: Single-centre cohort of IIH patients (2006-2016) who underwent 24-h ICP monitoring (ICPM). An un-paired t test compared ICP and pulse amplitude (PA) values in IIH patients with PT vs. NPT. RESULTS: We identified 59 patients with IIH (56 F:3 M), mean age 32.5 +/- 9.49 years, 14 of whom suffered from tinnitus. Of these 14, seven reported PT and seven reported NPT. Patients with tinnitus had a mean 24-h ICP and PA of 9.09 +/- 5.25 mmHg and 6.05 +/- 1.07 mmHg respectively. All 7 patients with PT showed symptom improvement or resolution after DVSS (n = 4), secondary DVSS (n = 2) or shunting (n = 1). In contrast, of the 7 with NPT, only 1 improved post intervention (DVSS), despite 2 patients having shunts and 5 having DVSS. CONCLUSIONS: NPT and PT were equally as common in our group of IIH patients. DVSS appears to be an effective management option for IIH patients with a clear history of pulsatile tinnitus. However, non-pulsatile tinnitus was more persistent and did not respond well to either DVSS or CSF diversion. PMID- 30014361 TI - Assessment of left atrial function using speckle tracking echocardiography in ankylosing spondylitis: a case-control study. AB - The aim of this study is to assess the left atrium (LA) deformation parameters by using 2D speckle tracking echocardiography (2D-STE) in ankylosing spondylitis (AS) patients and to evaluate the relationship between these parameters and AS clinical indexes. 30 patients with AS (22 males, 8 females) and 30 healthy individuals (19 males, 11 females) were enrolled in this study. Transthoracic echocardiography was performed to both groups. Besides the conventional echocardiographic parameters, the LA strain parameters; including systolic reservoir (LA S-S), early diastolic-conduit (LA S-E), late diastolic-contraction (LA S-A) were measured. No significant difference was found between two groups in terms of conventional echocardiographic parameters except mean deceleration time (DT). Mean DT was prolonged in the AS patients compare with the control group (173.5 +/- 22.5 vs. 155.3 +/- 36.7, p = 0.025). In the AS patients, LA S-S (48.3 +/- 9.4 vs. 56.9 +/- 10.1, p = 0.001), LA S-E (26.4 +/- 6.4 vs. 31.6 +/- 7.3, p = 0.005) and LA S-A (21.9 +/- 4.7 vs. 25.4 +/- 5.7, p = 0.013) values were statistically lower than the control group. Also a negative correlation was observed between the Bath Ankylosing Spondylitis Metrology Index (BASMI) and LA S S (r = - 0.509, p = 0.004), LA S-E (r = - 0.501, p = 0.005). Our study demonstrated that 2D-STE is a useful method to determine the left atrial involvement in AS patients without the clinical evident of cardiovascular disease. PMID- 30014362 TI - 3D myocardial deformation analysis from cine MRI as a marker of amyloid protein burden in cardiac amyloidosis: validation versus T1 mapping. AB - Cardiac amyloidosis (CA) is a significant contributor to heart failure with preserved ejection fraction and is appreciating expanding therapeutic options. Non-invasive tools aimed at accurate identification and surveillance of therapeutic response are of immediate and expanding need. While native and post contrast T1 mapping quantify expansion of the extra-cellular compartment from amyloid protein deposition, 3D strain analysis of non-contrast cine images offers unique advantages relevant to high prevalence of renal insufficiency in this population and reduced dependency on field strength, pulse sequence, and vendor implementation. We aimed to evaluate global and segmental associations between 3D strain and T1 mapping in patients with cardiac amyloidosis. Twenty consecutive patients with confirmed CA were recruited and underwent a standardized cardiovascular magnetic resonance imaging protocol at 3 T including using multi planar cine imaging and T1 mapping using a shortened modified look-locker inversion recovery sequence. T1 mapping was performed pre- and (when permitted by renal function) post-contrast and measured for segmental T1 values. Spatially matched 3D strain-based measures were similarly calculated. Mean left ventricular ejection fraction was 61 +/- 21% (range 30-73%). Mean global native T1 was 1308 +/- 96 ms. Post-contrast T1 and partition coefficient were 558 +/- 104 ms and 0.85 +/- 0.31, respectively. Global myocardial strain values were 8.1 +/- 2.9% in the longitudinal direction, - 9.2 +/- 3.4% in the circumferential direction, and 41.7 +/- 22.8% in the maximum principal direction. Segmental analyses confirmed relative worsening in T1 values and reductions in strain values in the basal myocardial segments with relative sparing of the apical segments. Significant associations between T1 and strain-based measures were observed globally and segmentally, with the strongest associations found both globally and segmentally in the circumferential and minimum principal directions of deformation. This study identifies strong associations between 3D myocardial strain and T1-mapping based markers of regional amyloid protein deposition. These findings support expanded investigation of myocardial strain as a surrogate marker of response to novel therapeutic strategies in patients with cardiac amyloidosis. PMID- 30014364 TI - One For All, All For One? Collective Representation in Healthcare Policy. AB - Healthcare collectives, such as patient organizations, advocacy groups, disability organizations, professional associations, industry advocates, social movements, and health consumer organizations have been increasingly involved in healthcare policymaking. Such collectives are based on the idea that individual interests can be aggregated into collective interests by participation, deliberation, and representation. The topic of collectivity in healthcare, more specifically collective representation, has only rarely been addressed in (Western) bioethics. This symposium, entitled: "Collective Representation in Healthcare Policy" of the Journal of Bioethical Inquiry draws attention to this understudied topic from a variety of disciplines, within a variety of socio cultural contexts. We draw attention to important ethical, cultural, and social questions, and into the practices, justifications for, and implications of collective representation of patients in healthcare policy. PMID- 30014365 TI - Effect of petroleum-derived substances on life history traits of bird cherry-oat aphid (Rhopalosiphum padi L.) and on the growth and chemical composition of winter wheat. AB - The aim of the study was to determine the effects of various petroleum-derived substances (PDSs), namely petrol, diesel fuel, and spent engine oil, on life history traits of the bird cherry-oat aphid Rhopalosiphum padi L., and on the growth and chemical composition of its host plant-winter wheat Triticum aestivum L. Each substance was tested separately, using two concentrations (9 and 18 g kg 1). Plants were cultivated in both control and contaminated soils. In early October 2013, soil was contaminated and after 1 week, winter wheat seeds, 'Batuta' cultivar, were sown. In early June 2014, observations of the effect of petroleum-derived substances on traits of three successive generations of aphids were conducted. Aphids were inoculated separately on leaves using cylindrical cages hermetically closed on both sides. Contamination of aphid occurred through its host plant. Results showed that all of the applied petroleum-derived substances have a generally adverse effect on the developmental parameters in aphids, resulting in the decrease of its fecundity, shortening its average life span, and most often lowering of the population intrinsic growth rate. PDSs caused the limitation of growth in wheat plants; whereas, changes in nutrient contents and heavy metals depended on the part of the plant analysed, the substance applied, and on its dose. The negative relationships between the contents of both some macro-elements (Ca, K, P) and heavy metals (Mn, Cd, Cu, and Zn) and the developmental parameters of particular generations of R. padi were observed. The high susceptibility of R. padi to the presence of PDSs in the substrate for the host plant should be emphasised-the clear-cut changes in the life span and fecundity, with relatively small changes in the chemical composition of the plant, constitute an evident indication that the developmental parameters of aphids have the potential for the use as bio-indicator to evaluate the state of the environment contaminated by PDSs. PMID- 30014358 TI - From autoinflammation to autoimmunity: old and recent findings. AB - Autoimmune diseases and autoinflammatory diseases have a number of similar etiopathogenetic and clinical characteristics, including genetic predisposition and recurrent systemic inflammatory flares. The first phase of ADs involves innate immunity: by means of TLRs, autoantigen presentation, B and T cell recruitment and autoantibody synthesis. The second phase involves adaptive immunity, a self-sustaining process in which immune complexes containing nucleic acids and autoantibodies activate self-directed inflammation. The link between autoimmunity and autoinflammation is IL-1beta, which is crucial in connecting the innate immune response due to NLR activation and the adaptive immune responses of T and B cells. In conclusion, although ADs are still considered adaptive immunity mediated disorders, there is increasing evidence that innate immunity and inflammasomes are also involved. The aim of this review is to highlight the link between the innate and adaptive immune mechanisms involved in autoimmune diseases. PMID- 30014366 TI - Distribution of polybrominated diphenyl ethers in the atmosphere of the Pearl River Delta region, South China. AB - Air samples were collected from 26 air-monitoring stations located in the Pearl River Delta (PRD) and two in Shaoguan, South China, to investigate the spatial distribution and temporal changes in polybrominated diphenyl ethers (PBDEs) after the production and use of PBDE commercial formulations was restricted in China and the "dual transfer strategy" implemented by Guangdong Province. The spatial distribution of PBDEs was inhomogeneous in the PRD region, with concentrations ranging from 26.3 to 634 pg/m3 and a mean value of 105 pg/m3. The PBDE levels in the five western cities (Guangzhou, Foshan, Zhaoqing, Zhongshan, and Jiangmen) were markedly higher than those in the four eastern cities (Dongguan, Huizhou, Shenzhen, and Zhuhai). BDE-209 was the predominant congener, accounting for 57.3 89.8% of the total measured PBDEs in this study. The proportion of penta- and nona-BDE congeners in the four eastern cities was markedly higher than those in five western cities. Principal component analysis showed that this elevation might be related to the debromination of BDE-209 during the thermal treatment process of products when PBDEs are used as flame retardants. Although the PBDE levels found in this study were markedly lower than those reported in previous studies, further efforts are still needed to clarify if there was a decreasing trend for PBDEs in the atmosphere of the PRD, in view of the increasing trends of PBDEs found by other researchers in mangrove sediments from Hong Kong and the Pearl River estuary in 2014 and 2015. PMID- 30014368 TI - Beneficial effects of dietary silver nanoparticles and silver nitrate on broiler nutrition. AB - This study was conducted to investigate the growth modulatory effects of dietary supplementation with silver nanoparticles (Ag NPs) and Ag nitrate on broiler chickens. Thirty 15-day-old chicks were equally divided into the control group (fed basal diets), the Ag-nano group (fed basal diets supplemented with 50 ppm/kg of Ag NPs for 12 d), and the Ag nitrate group (fed basal diets supplemented with 100 ppm/kg Ag nitrate for 12 days). Chicks fed Ag NPs showed increased body weight gain and muscle weight, improved feed efficiency, and increased ash digestibility, while Ag digestibility tend to increase but not significant. Plasma triiodothyronine contents, and muscle Ag and nitrogen contents as well as a significant increase in the following mRNA levels in muscle tissue: insulin like growth factor-1 (IGF1), glucose transporters (Glut1, Glut3), citrate synthase (CS), and glutathione peroxidase (GPx), whereas the atrogin-1, fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), lactate dehydrogenase (LDH), and carnitine palmitoyl transferase 1A (CPT1A) mRNA levels were unchanged. However, these chicks exhibited decreased levels of plasma cholesterol, triglyceride, and glucose. Dietary supplementation with Ag NPs improved the growth performance of broiler chickens. PMID- 30014367 TI - Inactivation of influenza A virus via exposure to silver nanoparticle-decorated silica hybrid composites. AB - Influenza A virus (IFV-A) is one of the main cause of seasonal flu and can infect various of host species via the reassortment of segmented RNA genomes. Silver nanoparticles (AgNPs) have been known as excellent antiviral agent against IFV. However, the use of free AgNPs has several major drawbacks, including the inherent aggregation among AgNPs and unwanted cytotoxic or genotoxic damages for human body via inhalation or ingestion. In this study, we assessed the efficacy of our novel ~ 30-nm-diameter AgNP-decorated silica hybrid composite (Ag30-SiO2; ~ 400 nm in diameter) for IFV-A inactivation. Ag30-SiO2 particles can inhibit IFV A effectively in a clear dose-dependent manner. However, when real-time RT-PCR assay was used, merely 0.5-log10 reduction of IFV-A was observed at both 5 and 20 degrees C. Moreover, even after 1 h of exposure to Ag30-SiO2 particles, more than 80% of hemagglutinin (HA) damage and 20% of neuraminidase (NA) activities had occurred, and the infection of Madin-Darby Canine Kidney (MDCK) cells by IFV A was reduced. The results suggested that the major antiviral mechanism of Ag30 SiO2 particles is the interaction with viral components located at the membrane. Therefore, Ag30-SiO2 particles can cause nonspecific damage to various IFV-A components and be used as an effective method for inactivating IFV-A. PMID- 30014369 TI - Global trends and future prospects of food waste research: a bibliometric analysis. AB - The unregulated discharge reams of food waste (FW) causes severe resource loss and environmental pollution. In the present study, a bibliometric analysis was used for research activities and tendencies of food waste from 1991 to 2015. The results indicated that the amount of FW research continually grew by the years, and the number of publications rose significantly from 2012. Bioresource Technology and Waste Management were the two most frequently published journals in the field of FW research. China took a leading position and had a high h-index (38) out of 94 countries/territories, followed by the USA and South Korea. Presently, anaerobic digestion for methane and dark fermentation for hydrogen production are the mainstream techniques in FW disposal. Lactic and ethanol fermentation from FW received more and more attention in recent years. Life cycle assessment (LCA) was an ever-increasingly popular evaluation method for FW related research. Moreover, cluster analysis indicated microbial community structure, food security, leachate, and pathogens were also the research hotspots. PMID- 30014370 TI - Determining phytolith-occluded organic carbon sequestration using an upgraded optimized extraction method: indicating for a missing carbon pool. AB - Phytolith-occluded organic carbon (PhytOC) is considered one of the most promising terrestrial carbon (C) sinks. Different methods are used for phytolith extraction from wet-ashing techniques and the subsequent determination of PhytOC content from soil. This is in order to optimize the wet-ashing techniques and to improve estimation accuracy of C sequestration potential of phytoliths from soil. Results show that the organic matter removal and carbonate removal protocol, applying sonication, has a significant effect on phytolith extraction. Namely, the sequential removal of first organic matter and then carbonates applied to such methods could eliminate greater than 17.14, 46.68, and 26.17% extraneous material compared to other methods. Moreover, phytoliths extracted using methods that apply sonication eliminated 7.49, 42.70, and 17.57% more extraneous material than methods that did not. Additionally, the procedure associated with the second oxidation step significantly influenced the determination of PhytOC content, that is, 29.34, 33.75, 26.41, and 64.64% of excess organic C were oxidized during this step. The upgraded optimal method we recommend for phytolith extraction in association with wet-ashing techniques and the subsequent determination of PhytOC content is therefore to first apply sonication, then the second oxidation step, and finally the removal of organic matter. Using this optimal upgraded method, we estimated the C sequestration potential of phytoliths from the soil of slash pine in China at 0.51 Mt. C. Furthermore, using this upgraded optimal method increased the precision of the carbon sequestration potential of phytoliths from soil by up to 63.83%. PMID- 30014371 TI - Delta wave notching time is associated with accessory pathway localization in patients with Wolff-Parkinson-White syndrome. AB - PURPOSE: Our aim was to investigate the relation between delta wave notching time (DwNt) and accessory pathway location in patients with Wolff-Parkinson-White (WPW) syndrome. METHODS: The retrospective study included 149 WPW patients who underwent ablation therapy. DwNt was defined as the duration between the initial point of QRS and the notching in the delta wave. DwNt was divided by QRS duration to obtain the delta wave index (Dwi). RESULTS: Patients with left-sided accessory pathway (AP) had significantly higher DwNt (p < 0.001) and Dwi (p = 0.027) values. The R wave voltage in lead I (p = 0.037) and S wave voltage in lead V1 (p = 0.005) values were significantly higher in patients with right-sided AP compared to patients with left-sided AP. When 27 ms was taken as the DwNt cut-off value, higher durations determined the left-sided AP location with a sensitivity of 91% and a negative predictive value of 91.4%. Dwi cutoff values >= 0.29 were accepted to indicate a left-sided AP location with a sensitivity of 91.2% and a NPV of 91.4%. CONCLUSIONS: WPW patients with left-sided AP have longer DwNt values than patients with right-sided AP. PMID- 30014372 TI - Is Abortion Included in Maternal and Child Health Curricula in the United States? AB - Purpose The purpose of this study is to assess whether Maternal and Child Health (MCH) graduate programs address abortion content in their programs' foundational courses, elective courses, and general curricula. Description Between January and March 2017, we conducted a descriptive study with faculty from the 13 Centers of Excellence in Maternal and Child Health Education, Science and Practice (COEs). We reviewed syllabi and discussed foundational and elective course content via email and key informant interviews with COE faculty. We categorized abortion coverage in foundational courses as "transparent" or "tangential" depending on inclusion of the word "abortion" in course syllabi. We identified electives addressing abortion as "electives including abortion" and courses that focus on abortion as "abortion-specific electives." Assessment Evidence demonstrated that most programs do not transparently address abortion in required course curricula. Only one of 13 COEs transparently addresses abortion in the foundational course(s); seven COEs tangentially include abortion in foundational courses; and all programs address abortion in some capacity though no standard exists to ensure its inclusion. Despite barriers, including avoidance of controversy and fear of losing funding, COEs could address abortion by establishing shared curricular standards, facilitating values clarification and attitude transformation activities, utilizing information-sharing networks, strengthening relationships between MCH programs and abortion-related organizations, and using professional societies. The scope of our study does not allow us to conclude why abortion content is lacking nor the quality of current content. Conclusion MCH programs should transparently incorporate abortion content in foundational and electives courses to educate students on how to engage with complex and sometimes stigmatized public health issues. PMID- 30014373 TI - Patient-, Hospital-, and Neighborhood-Level Factors Associated with Severe Maternal Morbidity During Childbirth: A Cross-Sectional Study in New York State 2013-2014. AB - Background The incidence of severe maternal morbidity (SMM) during childbirth is increasing in the United States. A better characterization of risk factors for SMM may identify targets for improving maternal outcomes. This study aims to characterize patient-, hospital-, and neighborhood-level factors associated with SMM during childbirth. Methods SMM during childbirth was identified in the 2013 2014 State Inpatients Database for New York. Hospital and neighborhood characteristics were abstracted from the American Hospital Association and the Area Health Resources files. Multilevel modeling was used to identify factors associated with SMM, with and without blood transfusion, and its between-hospital variation. Results 403,116 delivery-related discharges from 139 hospitals were analyzed; 1557 (0.39%) recorded SMM without blood transfusion. In the final multilevel model, 7 patient-level factors were associated with a greater than fourfold increase in the risk of SMM: pulmonary hypertension, postpartum hemorrhage, placenta accreta, chronic kidney disease, cardiac conduction disorders, emergent cesarean delivery, and preeclampsia. Three hospital-level factors were associated with SMM: proportion of non-White patients, proportion of Medicaid beneficiaries, and coding intensity. No neighborhood-level factors were predictive of SMM. The proportion of variation in SMM explained by the model was 23.5 with 23.2% related to patient-level factors. The model explained 55% of the between-hospital variation, primarily related to patient-level factors. Similar results were observed for SMM with blood transfusion. Conclusions This study confirms the association between patient-level factors and SMM. It identifies patient-level factors as the major driver of between-hospital variation in SMM. Efforts to improve maternal outcomes should target patient-level factors. PMID- 30014374 TI - Evaluation of Community Programs for Early Childhood Development: Parental Perspectives and Recommendations. AB - Objectives Optimal early childhood development is crucial for promoting positive child health outcomes. Community programs supporting child development are available throughout the United States but general parental perceptions of such programs are not well understood. This study aimed to examine parental perceptions of community programs for early childhood development in a semi-urban city of the US. Methods Data were collected from focus groups (n = 4) composed of English-fluent parents from the local community with at least one child aged 0-5 years. After generation of verbatim transcripts, data were analyzed by two independent coders in order to identify themes. Results Parental perceptions were categorized into four areas: (1) Utilization of community services, (2) Helpful aspects of community services, (3) Negative aspects of community services and (4) Parental recommendations for improved resource utilization. Helpful aspects identified included social and economic support, provision of parental education, and developmental screening and medical support. Negative aspects included utilization of standardized assessment tools, awareness of agencies and resources, and access to services. In order to improve resource utilization, parents suggested improved communication with parents and the child's medical home, transparency, and translation of program information into other languages. Conclusions For Practice Overall, participants felt that community programs that support early childhood development and parenting were helpful. However, community agencies can improve on communication with parents and medical providers as well as translation of program information. PMID- 30014375 TI - Correction to: Barriers Faced by the Health Workers to Deliver Maternal Care Services and Their Perceptions of the Factors Preventing Their Clients from Receiving the Services: A Qualitative Study in South Sudan. AB - The original version of this article unfortunately contained a mistake in the funding statement. PMID- 30014376 TI - The Interprofessional/Family-Centered-Care Observation Rubric (I-FOR): Results of a Multicenter Study of a New Measure of Educational Outcomes. AB - Introduction The ability to provide family-centered care (FCC) and the ability to work in interprofessional care teams (IPC) are essential educational outcomes in graduate training programs. Lack of standardized measures leave programs to rely on idiosyncratic methods to monitor outcomes. We developed a faculty observation tool as part of an effort to create a national quality improvement database. We present evidence for the feasibility and validity of the faculty observation tool. Methods Trainees and faculty at four independent training programs participated. Nineteen maternal and child health disciplines were represented. Faculty supervisors rated trainees using the new measure (I-FOR), and trainees completed related subscales of a previously developed self-report measure, the core competency measure (CCM). Faculty provided qualitative feedback regarding the I-FOR in a separate questionnaire. Results Faculty (n = 78) completed the I FOR on 86 trainees (86/92 = 93%) and reported satisfaction with completing the measures. The I-FOR demonstrated good internal consistency (Cronbach's alpha > 0.930) and test-retest reliability (IPC r = 0.862, FCC r = 0.823, p < 0.001). Greater than 95% of participants reported that the I-FOR accurately addressed the relevant skills for each practice domain. The I-FOR showed no correlation with the CCM. Significant improvements over time in the I-FOR ratings were demonstrated in three out of four programs. Discussion The I-FOR demonstrated good internal consistency and test-retest reliability. Faculty responses provide evidence for the feasibility and validity of the instrument. Self-report and faculty-observation measures both increased with training but were not correlated with each other. PMID- 30014377 TI - Investigation of Predictors of Newborn Screening Refusal in a Large Birth Cohort in North Dakota, USA. AB - Objectives The objective of this study was to identify maternal and provider predictors of newborn screening (NBS) refusal in North Dakota between 2011 and 2014. Methods Records of 40,440 live resident births occurring in North Dakota between 2011 and 2014 were obtained from the North Dakota Department of Health and included in the study. Factor-specific percentages of NBS refusals and 95% confidence intervals were computed for each predictor. Since the outcome is rare, multivariable Firth logistic regression was used to investigate maternal and provider predictors of NBS refusal. Model goodness-of-fit test was evaluated using the Hosmer-Lemeshow test. All analyses were conducted in SAS 9.4. Results Of the 40,440 live births, 135 (0.33%) were NBS refusals. 97% of the refusals were to white women, 94% were homebirths, and 93% utilized state non-credentialed birth attendants. The odds of NBS refusals were significantly higher among non credentialed birth attendants (p < 0.0001), homebirths (p < 0.0001), and among those that refused Hepatitis B vaccination (HBV) at birth (p = 0.047). On the other hand, odds of NBS refusals were significantly (p < 0.0001) lower among women that had more prenatal visits. Conclusions for Practice This study provides preliminary evidence of association between NBS refusal and provider type, home births, and HBV refusal. Additional studies of obstetric providers, home births and women are needed to improve our understanding of the reasons for NBS refusal to better deliver preventive services to newborns. PMID- 30014378 TI - ? PMID- 30014379 TI - ? PMID- 30014380 TI - ? PMID- 30014381 TI - ? PMID- 30014382 TI - ? PMID- 30014384 TI - ? PMID- 30014383 TI - ? PMID- 30014385 TI - ? PMID- 30014386 TI - ? PMID- 30014387 TI - [Minimally invasive total hip arthroplasty: an overview]. PMID- 30014388 TI - [Essential principles for evaluation and management of upper airway stenoses in children and adults]. PMID- 30014389 TI - [Oral hygiene in the elderly - an interdisciplinary challenge]. PMID- 30014390 TI - [Diabetes mellitus and microbiome: How do you advise your patients?] PMID- 30014391 TI - [Otitis externa - A spectrum between annoying itching of the ear and lethal complications]. PMID- 30014392 TI - [Behavioural change and ataxia - think about hyponatremia]. PMID- 30014393 TI - [Proteinuria - what to do?] PMID- 30014394 TI - [Unexpected increase in serum-creatinine]. PMID- 30014395 TI - ? PMID- 30014396 TI - ? PMID- 30014397 TI - ? PMID- 30014398 TI - ? PMID- 30014399 TI - ? PMID- 30014400 TI - ? PMID- 30014401 TI - ? PMID- 30014402 TI - ? PMID- 30014403 TI - ? PMID- 30014404 TI - ? PMID- 30014405 TI - ? PMID- 30014407 TI - ? PMID- 30014406 TI - ? PMID- 30014408 TI - ? PMID- 30014409 TI - ? PMID- 30014410 TI - ? PMID- 30014411 TI - ? PMID- 30014412 TI - ? PMID- 30014413 TI - ? PMID- 30014414 TI - ? PMID- 30014415 TI - ? PMID- 30014417 TI - ? PMID- 30014416 TI - ? PMID- 30014418 TI - ? PMID- 30014419 TI - ? PMID- 30014420 TI - ? PMID- 30014421 TI - ? PMID- 30014422 TI - ? PMID- 30014424 TI - ? PMID- 30014423 TI - ? PMID- 30014425 TI - ? PMID- 30014426 TI - [Rendu-Osler-Weber Disease: A rare differential diagnosis of gastrointestinal bleeding]. PMID- 30014428 TI - ? PMID- 30014429 TI - ? PMID- 30014431 TI - ? PMID- 30014430 TI - ? PMID- 30014432 TI - [Cardiovascular prevention: from the guidelines to the family practice]. PMID- 30014434 TI - Artisanal, shell-based handicraft in Papua New Guinea: Challenges and opportunities for livelihoods development. AB - A thorough understanding of livelihoods is necessary to ensure development policies are compatible with both resource conservation and the social and economic goals of development. Few studies, however, focus on value-adding activities occurring post-harvest in artisanal fisheries. The transformation of mollusc shells and skeletal remains of other marine taxa into artistic jewellery and decorative items is becoming an increasingly important livelihood activity for rural, coastal communities across the Pacific. We examine the potential challenges facing the shell-based handicraft sector and opportunities for overcoming these challenges using a quantitative study of artisans among the Tigak Islands of Papua New Guinea. The major challenges facing this livelihood sector are perceptions of marine resource declines and a lack of livelihood flexibility, attributed to the specialisation of material assets and skills. Improving market heterogeneity and developing coastal aquaculture may facilitate sustainable development of this livelihood sector. PMID- 30014433 TI - Industrial wastewater treatment in internal circulation bioreactor followed by wetlands containing emergent plants and algae. AB - Wastewater treatment based on ecological principles is a low cost and highly desirable solution for the developing countries like Pakistan. The present study evaluated the effectiveness of biological treatment systems including Internal Circulation (IC) anaerobic bioreactor and constructed wetlands (CWs) containing macrophytes and mixed algal cultures for industrial wastewater treatment. The IC bioreactor reduced COD (52%), turbidity (89%), EC (24%) of the industrial wastewater. However, the effluents of IC bioreactor did not comply with National Environmental Quality Standards (NEQS) of Pakistan. Post-treatment of IC bioreactor effluents was accomplished in CW containing macrophytes (Arundo donax and Eichhornia crassipes) and mixed algal culture. The CWs planted with macrophytes lowered the concentrations of COD (89%) and turbidity (99%). CWs with algal biomass were not effective in further polishing the effluent. Inhibition of algal biomass growth was observed due to physicochemical characteristics of wastewater. The integrated treatment system consisting of IC bioreactor and macrophytes was found more suitable option for industrial wastewater treatment. PMID- 30014435 TI - Acute kidney injury in patients with cirrhosis of liver: Clinical profile and predictors of outcome. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication of liver cirrhosis and is associated with poor survival. We studied the clinical profile and predictors of in-hospital mortality in patients with cirrhosis of the liver with AKI. METHODS: This retrospective cohort study examined patients at a tertiary care hospital. AKI staging was done based on the new 2015 Ascites Club Criteria. Patients were grouped into three types of AKI: pre-renal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN). RESULTS: Data of 123 patients with cirrhosis and AKI were analyzed. Most patients had AKI stage 3 (57.7%). ATN (42.3%) and HRS (43.9) were the predominant types of AKI followed by PRA (13.8%). The overall in-hospital mortality in our study was 44.7%. The mortality increased with increasing severity of AKI (p = 0.0001) and was the highest in AKI stage 3 (p = 0.001) and those who required hemodialysis (p = 0.001). There was a significant in-hospital mortality in patients with ATN and HRS in comparison to PRA (p = 0.001). On multivariate analysis, the factors predicting in-hospital mortality were AKI stage 3, and oliguria (p = 0.0001). CONCLUSIONS: Acute kidney injury in cirrhosis of liver carries high in-hospital mortality. Pre-renal AKI has a better survival compared to ATN and HRS. The higher stage of AKI at presentation and the presence of oliguria are two important predictors of in-hospital mortality. PMID- 30014436 TI - [Recognition and correct classification of pressure ulcers: a position paper]. AB - BACKGROUND: Pressure ulcers comprise serious skin and tissue damage. The correct diagnosis and classification into different categories is often difficult in daily practice. QUESTION: What procedure can be recommended to correctly diagnose and classify pressure ulcers in practice? MATERIALS AND METHODS: The society Initiative Chronische Wunden (ICW) e. V. established a group of experts who developed practical recommendations for the diagnosis and classification of pressure ulcers based on the current literature and their own expertise. RESULTS: Pressure ulcers should only be diagnosed if skin and/or tissue damage is most likely due to prolonged pressure or pressure associated with shear forces. A complete anamnesis must be performed to detect periods of previous prolonged immobility. Pressure ulcers are usually located at typical predilection sites. For category I and "suspected deep tissue damage" the tissue damage occurs under (initially) intact skin. However, the diagnosis is uncertain and the classification should be made later. The category II pressure ulcer is usually an exclusion diagnosis. The categories III and IV are pressure ulcers in the proper sense. As long as the distinction between category III and IV is not possible, the lower category should be coded. CONCLUSIONS: Currently, a relevant classification should be used uniformly for the respective setting. In accordance with the clinical picture, a most suitable diagnosis is to be made. It does not matter which classification system is used. The future WHO ICD-11 version will allow better classification of pressure ulcers. PMID- 30014437 TI - Low trabecular bone score in postmenopausal women with differentiated thyroid carcinoma after long-term TSH suppressive therapy. AB - : The effect of thyroid suppression therapy (TST) on trabecular bone scores (TBS) and bone mineral density (BMD) in thyroidectomized women with differentiated thyroid carcinoma (DTC) on long-term follow-up is presently not conclusive. PATIENTS AND METHODS: We carried out a study in 61 premenopausal and 84 postmenopausal Caucasian women with DTC. Serum biochemistry, bone markers, TBS, BMD, and bone fractures were evaluated 1-3 months post surgery and after a median follow-up of 10 years. RESULTS: In the final study, patients belonged to Group I Premenopausal (n = 14) who remained in this status; Group II Premenopausal who became postmenopausal (n = 47); Group III patients who were and continued as postmenopausal (n = 84). Baseline premenopausal patients had a normal TBS mean value of 1.39 +/- 0.14 significantly higher than that found in postmenopausal 1.31 +/- 0.12 (p = 001). In the final study, premenopausal patients continued to have a normal TBS of 1.46 +/- 0.08 compared to the significantly lower value of postmenopausal patients 1.25 +/- 0.11 (p = 0.0009). Lumbar BMD (L-BMD) loss after the long-term study was significant in Group II (0.99 g/cm2 +/- 0.13 vs. 0.91 +/- 0.12 g/cm2, p < 0.0001) and there was a slight, but not significant, bone loss in Group I (1.00 +/- 0.12 vs. 0.98 +/- 0.11, p = 0.1936) and in Group III (0.86 +/- 0.12 vs. 0.84 +/- 0.15, p = 0.1924) compared with baseline values. CONCLUSION: Longer-term suppression therapy in female patients with DTC did not increase significantly the risk of bone loss, although we found in postmenopausal patients deterioration of bone microarchitecture. TBS study should be considered in the evaluation of postmenopausal DTC patients on long-term DTC for the evaluation of the risk of fractures. PMID- 30014438 TI - Metyrapone treatment in Cushing's syndrome: a real-life study. AB - INTRODUCTION AND AIM: Medical treatment is increasingly used in patients with Cushing's syndrome (CS). Metyrapone (MET) is an inhibitor of 11beta-hydroxylase: retrospective studies reported a decrease of cortisol secretion in 50% of cases. We evaluated the effectiveness of MET in an observational study, considering the normalization of urinary-free cortisol (UFC) and late-night salivary cortisol (LNSC) levels. MATERIALS AND METHODS: We enrolled 31 patients with CS, treated with MET for at least 1 month (16 for primary treatment and 15 after surgical failure). A planned dose-titration regimen considering baseline UFC levels was adopted; MET dose was uptitrated until UFC normalization, surgery, or side effect occurrence. UFC and LNSC levels were routinely measured by liquid chromatography tandem mass spectrometry. RESULTS: Patients were treated with a median dose of 1000 mg for 9 months. UFC and LNSC decreased quickly after the first month of treatment (-67 and -57% from baseline), with sustained UFC normalization up to 12 and 24 months (in 13 and 6 patients, respectively). UFC and LNSC normalized later (after 3-6 months) in patients with severe hypercortisolism (>5-fold baseline UFC). Regarding the last visit, 70 and 37% of patients normalized UFC and LNSC, respectively. Body weight reduction (-4 kg) was observed after UFC normalization. Severe side effects were not reported, half of the female patients complained of hirsutism, and blood pressure was not increased. CONCLUSIONS: MET therapy is a rapid-onset, long-term effective, and safe medical treatment in CS patients, achieving UFC normalization (in 70% of patients) more than cortisol rhythm recovery (in 37% of subjects). PMID- 30014439 TI - Detectability of residual invasive bladder cancer in delayed 18F-FDG PET imaging with oral hydration using 500 mL of water and voiding-refilling. AB - OBJECTIVE: 2-Fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) imaging is not considered useful for assessing bladder cancer due to the physiological uptake of 18F-FDG in the bladder. Despite reports of the detection of bladder cancer by washing out 18F-FDG from the bladder, such methods are invasive and impractical in the routine practice. The purpose of this study was to evaluate prospectively the utility of oral hydration with 500 mL of water and voiding-refilling, a minimally invasive method that we introduced to enable detection of residual invasive bladder cancer on delayed 18F-FDG PET imaging. METHODS: From January 2015 to December 2017, 267 consecutive patients with bladder cancer underwent 18F-FDG PET/computed tomography scans. Among these patients, 25 (19 men and 6 women; mean age, 72.0 +/- 11.3 years) were newly diagnosed as having muscle-invasive bladder cancer by transurethral resection of bladder tumor and T3b or T4 by magnetic resonance imaging (MRI). All patients were orally hydrated with only 500 mL of water and were then instructed to void frequently for 60 min before early 18F-FDG PET imaging. After the scans, they were instructed to hold their urine for 60 min. Then, delayed imaging was performed. Two radiologists evaluated the early and delayed 18F-FDG PET images to determine whether residual invasive bladder cancer could be detected. The maximum standardized uptake values (SUVmax) of the bladder urine and residual tumor site were also measured on early and delayed images. The maximum diameter of the primary bladder tumor was measured on MRI. RESULTS: The sensitivity for detecting residual invasive bladder cancer on early and delayed imaging were 24.0 and 92.0%, respectively (P < 0.001). The SUVmax of the bladder urine on the early and delayed imaging were 34.7 +/- 29.7 and 16.0 +/- 10.7 (mean +/- SD), respectively. The SUVmax of the residual tumor site on the early and delayed imaging were range 15.65-30.83 and 10.06-45.70, respectively. CONCLUSION: Delayed 18F-FDG PET imaging with oral hydration using only 500 mL of water and voiding-refilling is useful for detecting residual invasive bladder cancer. PMID- 30014440 TI - A systematic review of the prognostic value of texture analysis in 18F-FDG PET in lung cancer. AB - OBJECTIVE: The aim of this study was to perform a systematic review of the prognostic value of texture parameters derived by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in patients with lung cancer. METHODS: PubMed and EMBASE databases were searched up to March 12, 2018, for original articles involving texture analysis for the prediction of prognosis in patients with lung cancer. Risk of bias in the studies was critically assessed using the QUIPS tool. The results of survival analysis in the included studies were compared. RESULTS: Of the 446 articles retrieved, 17 studies were eligible for inclusion. Our review suggests that the prognostic value of texture parameters in lung cancer remains unproven. Most studies had a moderate to high risk of bias. Texture parameters that described prognosis were not replicated across studies. Conflicting results on hazard ratios were found among the studies. This discrepancy is partly explained by false-positive findings originating from statistical error and variability caused by different methodologies used for image acquisition and processing in the included studies. CONCLUSION: Based on currently available evidence, there is insufficient evidence to support the prognostic value of texture analysis in 18F-FDG PET in lung cancer. Further studies implementing well established methodologies and statistical evidence are warranted for proper validation of these promising imaging biomarkers. PMID- 30014441 TI - Design Principles for Nanoparticle Plasmon-Enhanced Organic Solar Cells. AB - Plasmonic metallic nanoparticles are coupled to the organic solar cells to overcome the trade-off between the light absorption and carrier collection. They are usually located inside or outside of the active layers. However, no detailed comparison was reported on the light absorption difference when nanoparticles are located inside or outside of the active layers. In this paper, we compare light trapping abilities of Ag nanospheres in organic solar cells when they are located inside and outside of the photoactive layer. We show that large-sized nanoparticles are preferred when they are placed outside of the active layer while small-sized nanoparticles are favored in the case of embedding nanoparticles in the homogenous active layer. PMID- 30014442 TI - 12-year changes in cardiovascular risk factors in people with major depressive or bipolar disorder: a prospective cohort analysis in Germany. AB - BACKGROUND: Major depressive disorder (MDD) and bipolar disorder are associated with certain cardiovascular risk factors (CVRFs), but it is unclear whether they are associated with unfavourable changes of clinically manifest CVRFs over time. METHODS: We used baseline and 12-year follow-up (n = 1887) data from the German Health Interview and Examination Survey 1998. Multivariable linear regression models assessed associations between lifetime CIDI-diagnosed mood disorders at baseline and continuous risk factor-related outcomes (blood pressure, HbA1c, LDL C, HDL-C, triglycerides, BMI) at follow-up. RESULTS: We did not find consistent deterioration of CVRFs in persons with compared to persons without MDD. Analyses pointed to severity of mood disorder as an important correlate of long-term changes of comorbid hypertension: while a history of mild MDD was not associated with changes in CVRFs, moderate MDD was associated with lower blood pressure [systolic: beta = - 7.5 (CI - 13.2; - 1.9); diastolic: beta = - 4.5 (CI - 7.8; - 1.3)] and a history of bipolar disorder was associated with higher systolic blood pressure at follow-up (beta = 14.6; CI 4.9-24.4). Further, severe MDD was weakly associated with a higher BMI at follow-up [beta = 1.2 (CI 0.0; 2.4)]. These outcomes were not mediated by use of psychotropic medication and remained statistically significant after adjusting for the use of antihypertensive medication. CONCLUSION: Since most investigated parameters showed no associations, participants with a lifetime history of MDD in this cohort did not carry a specific risk for a worsening of pre-existing clinically manifest CVRFs. Our findings extend evidence of MDD severity and bipolar disorder as important correlates of long-term changes of arterial hypertension and obesity. PMID- 30014443 TI - The moral brain and moral behaviour in patients with Parkinson's disease: a review of the literature. AB - Morality is a complex and versatile concept that necessitates the integrated activity of multiple interacting networks in the brain. Numerous cortical and subcortical areas, many of which are implicated in either emotional and cognitive control or Theory of Mind, are involved in the processing of moral behaviour. Different methods have been used to investigate various aspects of morality, which has lead to confusing and sometimes opposing results. Emotional, cognitive and personality changes have long been recognized in Parkinson's disease (PD) patients, suggesting a potential impact on moral aspects of behaviour in daily living situations. Alterations in social cognition have been described in all stages of PD but these are rather directly related to PD pathology and not to dopaminergic or DBS treatment. There are no convincing data supporting the hypothesis that dopaminergic treatment or deep brain stimulation of the STN per se interfere with morality in PD patients, although subgroups of patients may display socially unacceptable behaviour. Research in social cognition in PD patients is a fascinating topic that needs further attention in view of the impact on quality of life for PD patients and their caregivers. PMID- 30014444 TI - Reversible "ears of the lynx" sign in Marchiafava-Bignami disease. PMID- 30014445 TI - HIV-associated mild neurocognitive disorder (MND). PMID- 30014446 TI - A Review of Health Survey Research for People with Refugee Background Resettled from Africa: Research Gaps and Methodological Issues. AB - We reviewed 27 studies on adults with a refugee background resettled from Africa published between 1999 and 2017 to appraise their methodological issues for survey research. Out of 27 studies, eleven used a single sampling method (referral = 1, convenience = 10), and 16 relied on multiple sampling methods, many of which were combinations of referral and convenience. The two most salient recruitment strategies found were building trusted relationships with the community (n = 15), and using recruiters who were culturally and linguistically matched to the refugee communities of interest (n = 14). Fifteen studies used existing data collection instruments, while in 13 studies, researchers developed their own data collection instruments. In-person or phone interviews using bilingual interviewers (n = 21) were the most frequently used mode of data collection, followed by a self-administered survey (n = 7). Our review presents methodological gaps in current refugee health studies, such as limited use of probability sampling approach due to system barriers, lack of information in community engagement and recruitment processes, and insufficient considerations of unique culture and experiences of refugee communities when developing or adapting the instruments. Efforts can be made to guide and facilitate appropriate reporting and development of more scientifically robust survey methodologies for refugee health studies, as well as to improve registration system infrastructure that may help identify these hidden populations more effectively. PMID- 30014447 TI - A Health Professions Pipeline for Underrepresented Students: Middle and High School Initiatives. AB - The Department of Health Career Opportunity Programs at UConn Health has developed the Aetna Health Professions Partnership Initiative (Aetna HPPI), a formal education consortium offering a comprehensive program of educational enrichment and support activities for underrepresented and first-generation students. The purpose is to identify and develop a diverse applicant pool of students who will eventually enter a health professions career with a focus on medicine and dental medicine. Activities are conducted for students in middle school through college. The achievements of the middle and high school pipeline programs and their impact on producing a more diversified health professions workforce were examined. The students are recruited from the greater Hartford, CT area and come from backgrounds traditionally underrepresented in healthcare, first-generation college families and modest family means. Program elements include a 30-week academic year Saturday Academy and a 6-week summer academic enrichment program aimed at preparing students for successful entrance into college, and a Parental Seminar Series for parents. Some of the activities include science, math, language arts, PSAT, SAT and ACT preparation, college tours, career counseling, mentoring by health professionals, and cultural experiences. Data analysis and tracking of the students in the academy have revealed some significant achievements. All seniors in the academy have graduated from high school. The SAT scores of the academy students have consistently stood above the average for the rest of the Hartford School District. In addition, the graduating seniors have a high rate of college matriculation. PMID- 30014448 TI - Ovarian environment aging: follicular fluid lipidomic and related metabolic pathways. AB - PURPOSE: The decline in female fecundity with age may be caused by decreased oocyte quality, a factor that may be associated with the altered composition of follicular fluid (FF). METHODS: In an effort to better understand follicular aging and the role of lipids in a given biological system, we present a prospective study that compares lipid profiles of FF from women older than 35 years (aging group, n = 12) to women equal or younger than 35 years old (control group, n = 17). FF lipids were extracted, and mass spectra were generated using a Waters Synapt G1 Q-TOF in MS mode. MS data was evaluated for both multi- and univariate statistics. The lipids identified as potential biomarkers of follicle aging were attributed by the online databases Lipid Maps, followed by pathway network analysis using Cytoscape software. RESULTS: The in vitro fertilization (IVF) parameters showed significant differences in aging, number of follicles, total number of oocytes and oocytes in MII, and number of injected oocytes. Additionally, FF from the aging group revealed 11 lipids with higher abundance, while FF from the control group included 4 lipids with higher abundance. CONCLUSIONS: We suspect that aging may influence lipid metabolism in a downstream cascade leading, ultimately, to decreased oocyte quality. The discovery of target lipids may assist oocyte selection for IVF in the future. Furthermore, systems biology approach based on post-genomic medicine may help unravel a number of altered mechanisms not previously understood. PMID- 30014450 TI - Affiliation with Natural Products at KIB of Prof. Zhou Jun: On the Occasion of 80th Anniversary of Kunming Institute of Botany, CAS. AB - Prof. Zhou Jun, Academician of Chinese Academy of Sciences (1999), is a phytochemist and medicinal chemist of China. He is one of the pioneers of Kunming Institute of Botany, CAS and a major founder of the State Key Laboratory of Phytochemistry and Plant Resources in West China. The chemical compositions of some TCM from genus of Dioscorea, Aconitum, Panax, Paris, Cynanchum, Gastrodia, Dendrobium etc. and family Asclepiadaceae, Caryophyllaceae, Hypoxidaceae etc. have been explored by Prof. Zhou's team as steroids, triterpenoids, alkaloids, cyclic peptides and phenols etc., which revealed the main active composition of those TCM such as Panax notoginseng, Paris yunnanensis and Gastrodia elata. PMID- 30014449 TI - RNA Sequencing and Pathway Analysis Identify Important Pathways Involved in Hypertrichosis and Intellectual Disability in Patients with Wiedemann-Steiner Syndrome. AB - A growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous system. Among them, heterozygous de novo variants in KMT2A, a gene coding for histone methyltransferase, have been associated with Wiedemann-Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of KMT2A variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function KMT2A variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in KMT2A mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease. PMID- 30014453 TI - Is Prophylactic Central Compartment Neck Dissection Indicated for Clinically Node Negative Papillary Thyroid Cancer: The Answer is Dependent on How the Data are Interpreted and the Weight Given to the Risks and Benefits. PMID- 30014451 TI - [Basics and applications of Natural Language Processing (NLP) in radiology]. AB - BACKGROUND: Due to the increasing demands in radiology, applications that enable quality assurance and continuous process optimization are required. OBJECTIVE: The principles of Natural Language Processing (NLP) as a computer-based method for structuring of free text reports are explained and application scenarios are sketched. MATERIALS UND METHODS: The structuring of free texts succeeds by several theories, linguistic techniques (word meanings, word context, negations), statistical methods with rules and currently with deep learning approaches. Medical encyclopedias, such as RadLex(r), are suitable for coding findings. NLP was used in our own radiology clinic to check the quality of 3756 CT reports. RESULTS: In our case study, NLP proved to be a helpful, automated tool for internal quality testing. DISCUSSION: NLP offers numerous application scenarios for decision support and for quality management in radiology. PMID- 30014454 TI - Impact of Breast Reconstruction on Time to Definitive Surgical Treatment, Adjuvant Therapy, and Breast Cancer Outcomes. AB - BACKGROUND: Delays in surgery and adjuvant treatment for breast cancer are associated with decreased survival. However, the time between diagnosis and surgery is rising, partly attributed to the added complexity of immediate breast reconstruction (IBR). We sought to investigate time to treatment and survival outcomes in breast cancer patients undergoing IBR. METHODS: We performed a retrospective review of 2004-2014 California Cancer Registry data for stage 0-III breast cancer patients undergoing mastectomy. Time to surgery, adjuvant systemic therapy and radiation therapy, propensity score, and covariate-adjusted overall mortality hazard ratios (HRs) were assessed by IBR status. RESULTS: Of 56,782 patients, 13,738 (24.2%) underwent IBR, with a median follow-up of 68.8 months. Median time between diagnosis and surgery was increased for patients undergoing IBR compared with those without {49 days (interquartile range [IQR] 34-73) vs. 35 days (IQR 21-56), p < 0.001}. IBR did not affect the interval from surgery to adjuvant chemotherapy or radiation, but prolonged time to endocrine therapy by 5 days (p = 0.014). Significantly lower survival was observed when time to surgery exceeded 120 days (vs. 0-30 days; HR 1.14 [1.02-1.28], p = 0.023), and improved survival with IBR (vs. without; HR 0.67 [0.61-0.74], p < 0.001). The benefit associated with reconstruction persisted for all age groups except age 80 + years, while surgical delay > 120 days demonstrated significantly lower survival in women < 60 years of age. CONCLUSIONS: While IBR delays time to definitive surgery, its use did not substantially affect time to adjuvant treatment or survival outcomes. Further research is ongoing to mitigate the effects of potential selection bias in favor of IBR. PMID- 30014455 TI - Immunotherapy for Breast Cancer is Finally at the Doorstep: Immunotherapy in Breast Cancer. AB - BACKGROUND: Although immunotherapy is making rapid inroads as a major treatment method for melanoma, lung, bladder, and hereditary colon cancer, breast cancer (BC) remains one of the tumors yet to experience the cellular immunology explosion despite the fact that heavy lymphocyte responses in breast tumors improve response to therapy and can predict for long-term survival. RESULTS: Immunotherapies in the form of monoclonal antibodies such as trastuzumab and pertuzumab have had an impact on HER2-positive breast cancer (HER2+BC) treatment through antibody-dependent cellular cytotoxicity. Current evidence suggests that checkpoint inhibitors and other cellular therapies are at the doorstep of improving outcomes in triple-negative BC (TNBC) and HER2+BC, especially when combined with standard therapies. CONCLUSIONS: Although this approach has benefitted small numbers of patients to date, numerous clinical trials are underway to define the relative role immunotherapy may play in the treatment of BC. PMID- 30014452 TI - The effects of multi-stage exercise with and without concurrent cognitive performance on cardiorespiratory and cerebral haemodynamic responses. AB - INTRODUCTION: Studies of cerebral haemodynamics have shown changes with increased exercise intensity, but the patterns have been highly variable and reliable associations with cognitive performance have not been identified. The aim of this study was to examine whether exercise-induced changes in oxygenated haemoglobin (O2Hb) led to changes in concomitant cognitive performance. METHODS: This study examined cardiorespiratory and cerebral haemodynamics during multi-stage exercise from rest to exhaustion, with (Ex + C) and without (Ex) concurrent cognitive performance (Go/No-go task). RESULTS: The presence of the cognitive task affected both cardiorespiratory and cerebral haemodynamics. The patterns in the cerebral haemodynamics during Ex and Ex + C diverged above the respiratory compensation threshold (RCT), but differences were significant only at 100% [Formula: see text], displaying increased deoxygenated haemoglobin (HHb), decreased difference between oxygenated and deoxygenated haemoglobin (HbDiff), and decreased cerebral oxygenation (COx) during Ex + C. More complex haemodynamic trends against intensity during Ex + C suggested that the presence of a cognitive task increases cerebral metabolic demand at high exercise intensities. The levels of O2Hb, HHb, HbDiff and total haemoglobin increased most steeply at intensities around the RCT during both Ex and Ex + C, but these changes were not accompanied by improved cognitive performance. CONCLUSION: The primary hypothesis, that cognitive performance would match changes in O2Hb, was not supported. Small variations in reaction time and response accuracy across exercise intensities were not significant, suggesting that cognitive performance is unaffected by intense short duration exercise. Our results add further evidence that exercise-induced changes in cerebral haemodynamics do not affect cognitive performance. PMID- 30014456 TI - Chronic Pain After Breast Surgery: A Prospective, Observational Study. AB - BACKGROUND: Chronic pain is an important complication of breast surgery, estimated to affect 20-30% of patients. We prospectively examined surgical, demographic, and psychosocial factors associated with chronic pain 6 months after breast surgery. METHODS: Patients undergoing breast surgery for benign and malignant disease preoperatively completed validated questionnaires to assess baseline pain and psychosocial characteristics. Pain at 6 months was quantified as the Pain Burden Index (PBI), which encompasses pain locations, severity, and frequency. Surgical type was categorized as breast-conserving surgery (BCS), mastectomy, and mastectomy with reconstruction; axillary procedure was categorized as no axillary surgery, sentinel lymph node biopsy (SLNB), and axillary dissection. PBI was compared between groups using one-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA, and the relationship between baseline demographic and psychosocial factors and PBI was assessed using Spearman's Rank Correlation. p < 0.05 was considered significant. RESULTS: PBI was variable amongst patients reporting this endpoint (n = 216) at 6 months, but no difference was found between primary breast surgical types (BCS, mastectomy, and mastectomy with reconstruction) or with surgical duration. However, axillary dissection was associated with higher PBI than SLNB and no axillary procedure (p < 0.001). Younger age (< 0.001) and higher BMI (p = 0.010), as well as higher preoperative anxiety (p = 0.017), depression (p < 0.001), and catastrophizing scores (p = 0.005) correlated with higher 6-month PBI. CONCLUSIONS: Amongst surgical variables, only axillary dissection was associated with greater pain at 6 months after surgery. Patient characteristics that were associated with higher PBI included lower age and higher BMI, as well as higher baseline anxiety, depression, and catastrophizing. PMID- 30014457 TI - Correction to: Trials with patient-reported outcomes registered on the Australian New Zealand Clinical Trials Registry (ANZCTR). AB - In the original publication of the article, the sentence "The ANZCTR is the fifth largest trial registry internationally, with 21,330 registered trials as at January 2018 [5]" in the Introduction section was published incorrectly. PMID- 30014458 TI - Identification and assessment of health-related quality of life issues in patients with sporadic desmoid-type fibromatosis: a literature review and focus group study. AB - PURPOSE: Sporadic desmoid-type fibromatosis (DTF) is a rare, chronic, non metastasising, disease of the soft tissues. It is characterised by local invasive and unpredictable growth behaviour and a high propensity of local recurrence after surgery thereby often having a great impact on health-related quality of life (HRQL). This study aims to review currently used HRQL measures and to asses HRQL issues among DTF patients. METHODS: A mixed methods methodology was used consisting of (1) a systematic literature review, according to the PRISMA guidelines (2009), using search terms related to sporadic DTF and HRQL in commonly used databases (e.g. Embase, Medline Ovid, Web of science, Cochrane Central, Psyc Info, and Google scholar), to provide an overview of measures previously used to evaluate HRQL among DTF patients; (2) focus groups to gain insight into HRQL issues experienced by DTF patients. RESULTS: The search strategy identified thirteen articles reporting HRQL measures using a wide variety of cancer-specific HRQL tools, functional scores, symptom scales (e.g. NRS), and single-item outcomes (e.g. pain and functional impairment). No DTF specific HRQL tool was found. Qualitative analysis of three focus groups (6 males, 9 females) showed that participants emphasised the negative impact of DTF and/or its treatment on several HRQL domains. Six themes were identified: (1) diagnosis, (2) treatment, (3) follow-up and recurrence, (4) physical domain, (5) psychological and emotional domain, and (6) social domain. CONCLUSION: A DTF specific HRQL tool and consensus regarding the preferred measurement tool among DTF patients is lacking. Our study indicates that HRQL of DTF patients was negatively affected in several domains. A DTF-specific HRQL measure could improve our understanding of short- and long-term effects and, ideally, can be used in both clinic and for research purposes. PMID- 30014459 TI - Combination of three miRNA (miR-141, miR-21, and miR-375) as potential diagnostic tool for prostate cancer recognition. AB - PURPOSE: Prostate cancer (PCa) is a common tumor disease in western countries and a leading cause of cancer-driven mortality in men. Current methods for prostate cancer detection, like prostate-specific antigen screening, lead to significant overtreatment. The purpose of the study was to analyze circulating microRNAs in serum as non-invasive biomarkers in patients with diagnosis of prostate cancer and healthy individuals. METHODS: This preliminary study included a population of 20 patients with mean age of 68.6 years and mean PSA of 21.3 ng/ml. Eight healthy patients were used as control. MiRNAs were quantified in the total RNA fraction extracted from serum and levels of five microRNAs (miR-106b, miR-141, miR-21, mir 34a, and miR-375) were quantified by RT-qPCR. Statistical analyses evaluated correlation between clinicopathological data and miRNAs expression levels. RESULTS: Relative expression ratios of miR-106b, miR-141-3p, miR-21, and miR-375 were significantly increased (1.8-, 1.9-, 2.4-, and 2.6-fold, respectively) in the PCa group compared to healthy control. Using receiver operating characteristics, the highest area under the curve equal to 0.906 was obtained for miR-357 and indicates a very good diagnostic properties of this biomarker. We found expression level of mir-34a not related with PCa. CONCLUSIONS: Our results support previous findings on the possibility of discriminating prostate cancer patients from healthy controls by detecting miRNA (miR-141-3p, miR-21, and miR 375). Further insights into miRNA abundance and characteristics are necessary to validate the panel of miRNA as surrogate markers in diagnosis of prostate cancer. PMID- 30014460 TI - Dietary taurine supplementation improves breast meat quality in chronic heat stressed broilers via activating the Nrf2 pathway and protecting mitochondria from oxidative attack. AB - BACKGROUND: Chronic heat stress can induce oxidative impairment and decrease breast meat quality in broilers. Taurine is a beta-amino acid with antioxidant properties. To investigate the alleviative effects and molecular mechanisms of taurine supplementation on breast meat quality in broilers exposed to chronic heat stress, 144 28-day-old chickens (Arbor Acres) were randomly distributed to thermoneutral (TN, 22 degrees C, basal diet), heat stress (HS, consistent 32 degrees C, basal diet), or heat stress plus taurine (HS + T, consistent 32 degrees C, basal diet + 5.00 g kg-1 taurine) groups for a 14-day trial. RESULTS: Chronic heat stress did not affect the contents of moisture, crude protein and crude fat in breast muscle, but impaired breast meat quality in broilers. Taurine supplementation significantly alleviated the increase in lightness and drip loss and the decrease in pH45 min and shear force of breast meat in chronic heat stressed broilers. Compared with the HS group, taurine supplementation significantly decreased the levels of reactive oxygen species and malonaldehyde and increased the messenger RNA expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 and heme oxygenase 1 in the HS + T group. Meanwhile, taurine supplementation effectively alleviated mitochondrial damage caused by chronic heat exposure. CONCLUSION: Dietary taurine supplementation can effectively improve the quality of breast meat in chronic heat-stressed broilers via activating the Nrf2 pathway and protecting mitochondria from oxidative attack. (c) 2018 Society of Chemical Industry. PMID- 30014461 TI - Extensive somatosensory and motor corticospinal sprouting occurs following a central dorsal column lesion in monkeys. AB - The corticospinal tract (CST) forms the major descending pathway mediating voluntary hand movements in primates, and originates from ~nine cortical subdivisions in the macaque. While the terminals of spared motor CST axons are known to sprout locally within the cord in response to spinal injury, little is known about the response of the other CST subcomponents. We previously reported that following a cervical dorsal root lesion (DRL), the primary somatosensory (S1) CST terminal projection retracts to 60% of its original terminal domain, while the primary motor (M1) projection remains robust (Darian-Smith et al., J. Neurosci., 2013). In contrast, when a dorsal column lesion (DCL) is added to the DRL, the S1 CST, in addition to the M1 CST, extends its terminal projections bilaterally and caudally, well beyond normal range (Darian-Smith et al., J. Neurosci., 2014). Are these dramatic responses linked entirely to the inclusion of a CNS injury (i.e., DCL), or do the two components summate or interact? We addressed this directly, by comparing data from monkeys that received a unilateral DCL alone, with those that received either a DRL or a combined DRL/DCL. Approximately 4 months post-lesion, the S1 hand region was mapped electrophysiologically, and anterograde tracers were injected bilaterally into the region deprived of normal input, to assess spinal terminal labeling. Using multifactorial analyses, we show that following a DCL alone (i.e., cuneate fasciculus lesion), the S1 and M1 CSTs also sprout significantly and bilaterally beyond normal range, with a termination pattern suggesting some interaction between the peripheral and central lesions. PMID- 30014463 TI - Involvement of sonic hedgehog and notch signaling in regenerative neurogenesis in adult zebrafish optic tectum after stab injury. AB - Unlike humans and other mammals, adult zebrafish have the superior capability to recover from central nervous system (CNS) injury. We previously found that proliferation of radial glia (RG) is induced in response to stab injury in optic tectum and that new neurons are generated from RG after stab injury. However, molecular mechanisms which regulate proliferation and differentiation of RG are not well known. In the present study, we investigated Shh and Notch signaling as potential mechanisms regulating regeneration in the optic tectum of adult zebrafish. We used Shh reporter fish and confirmed that canonical Shh signaling is activated specifically in RG after stab injury. Moreover, we have shown that Shh signaling promotes RG proliferation and suppresses their differentiation into neurons after stab injury. In contrast, Notch signaling was down-regulated after stab injury, indicated by the decrease in the expression level of her4 and her6, a target gene of Notch signaling. We also found that inhibition of Notch signaling after stab injury induced more proliferative RG, but that inhibition of Notch signaling inhibited generation of newborn neurons from RG after stab injury. These results suggest that high level of Notch signaling keeps RG quiescent and that appropriate level of Notch signaling is required for generation of newborn neurons from RG. Under physiological condition, activation of Shh signaling or inhibition of Notch signaling also induced RG proliferation. In adult optic tectum of zebrafish, canonical Shh signaling and Notch signaling play important roles in proliferation and differentiation of RG in physiological and regenerative conditions. PMID- 30014462 TI - Development of a novel clustering tool for linear peptide sequences. AB - Epitopes identified in large-scale screens of overlapping peptides often share significant levels of sequence identity, complicating the analysis of epitope related data. Clustering algorithms are often used to facilitate these analyses, but available methods are generally insufficient in their capacity to define biologically meaningful epitope clusters in the context of the immune response. To fulfil this need we developed an algorithm that generates epitope clusters based on representative or consensus sequences. This tool allows the user to cluster peptide sequences on the basis of a specified level of identity by selecting among three different method options. These include the 'clique method', in which all members of the cluster must share the same minimal level of identity with each other, and the 'connected graph method', in which all members of a cluster must share a defined level of identity with at least one other member of the cluster. In cases where it is not possible to define a clear consensus sequence with the connected graph method, a third option provides a novel 'cluster-breaking algorithm' for consensus sequence driven sub-clustering. Herein we demonstrate the tool's clustering performance and applicability using (i) a selection of dengue virus epitopes for the 'clique method', (ii) sets of allergen-derived peptides from related species for the 'connected graph method' and (iii) large data sets of eluted ligand, major histocompatibility complex binding and T-cell recognition data captured within the Immune Epitope Database (IEDB) with the newly developed 'cluster-breaking algorithm'. This novel clustering tool is accessible at http://tools.iedb.org/cluster2/. PMID- 30014464 TI - Antioxidant activity and phenolic composition in pomegranate (Punica granatum L.) genotypes from south Italy by UHPLC-Orbitrap-MS approach. AB - BACKGROUND: Pomegranate fruits are a rich source of polyphenols with numerous health-promoting effects. Pomegranate juices of five genotypes ('Mollar', 'Kingdom', 'Dente di Cavallo', and two old populations 'Francofonte' and 'Santa Tecla') were evaluated regarding anthocyanin and non-anthocyanin phenolic contents using ultrahigh performance liquid chromatography (UHPLC)-Orbitrap-mass spectrometry (MS). Moreover, total antioxidant activity (TAA) was evaluated using a 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assay. RESULTS: Twenty-three phenolic compounds were identified. Cyanidin-3,5-O diglucoside and pelargonidin-3,5-O-diglucoside were the most representative anthocyanins in all genotypes; the Santa Tecla population had the highest content of these anthocyanins, 97.64 mg L-1 and 40.29 mg L-1 respectively. In the Francofonte population, ferulic acid hexoside was the most abundant compound (391.18 mg L-1 ). TAA values ranged between 221.5 and 36.73 umol Trolox equivalents/100 mL of juice. A high TAA value was recorded for the Santa Tecla pomegranate population. CONCLUSION: The UHPLC-Orbitrap-MS approach was employed for the first time to identify the phenolic compound profiling in five pomegranate genotypes. TAA was analysed using an ABTS assay, and the results showed a significant variability in nutraceutical potential of the pomegranate genotypes studied. The inclusion of phenolic information in the linear discriminant analysis allowed very good discriminations among genotypes to be obtained. (c) 2018 Society of Chemical Industry. PMID- 30014465 TI - Estimation of the diagnostic accuracy of clinical parameters for monitoring peri implantitis progression: An experimental canine study. AB - BACKGROUND: Lack of consensus on the clinical parameters of peri-implantitis may complicate accurate diagnosis of the disorder. Furthermore, the lack of reliable estimates of the diagnostic capacity of the clinical endpoints precludes the definition of an effective treatment protocol for peri-implantitis. The present canine study assesses the diagnostic accuracy of the clinical parameters for monitoring the peri-implant tissues in a controlled ligature-induced peri implantitis model followed by a spontaneous progression phase. METHODS: Six beagle dogs were followed-up on during three episodes of ligature-induced peri implantitis and a further episode of spontaneous progression. Probing depth (PD), bleeding on probing (BOP), mucosal recession (MR), and suppuration (SUP) were recorded at four sites per implant and at four study timepoints. Moreover, the implant mucosal index (IMI) was calculated at implant level. Marginal bone loss (MBL) was determined using computed tomography at four sites per implant. A linear regression model was used to estimate clinical and radiological parameters during peri-implantitis progression. RESULTS: Progressive peri-implant bone loss is characterized by an increase in PD, more profuse BOP, MR, and SUP in advanced cases (p < 0.001). However, even in the presence of severe bone loss, SUP was not a common finding, with an incidence of approximately 10% at the last timepoint. These clinical parameters were significantly correlated to MBL at most of the timepoints. The IMI, in turn, showed a positive correlation to MBL and the peri implant inflammatory signs (r = 0.39; p < 0.001), with a tendency to exhibit higher scores during ligature-induced peri-implantitis, followed by a slight decrease during the spontaneous progression period. CONCLUSION: The clinical features of peri-implantitis and spontaneous progression of the disorder may facilitate an accurate monitoring of peri-implant pathologic bone loss. PMID- 30014467 TI - Influence of freezing on the bioaccessibility of beetroot (Beta vulgaris) bioactive compounds during in vitro gastric digestion. AB - BACKGROUND: The effect of freezing (in liquid nitrogen at -196 degrees C , at 80 degrees C and at -20 degrees C) on the food matrix structure and the consequent effect on the bioaccessibility of total polyphenol content (TPC) and antioxidant activity (AA) of beetroot was investigated by an in vitro digestion method. The in vitro digestion involved incubation in simulated saliva followed by incubation in simulated gastric juice. Bioaccessibility of bioactive compounds was evaluated by measuring the TPC and the AA during in vitro digestion in both the beetroot matrix and the gastric juice. RESULTS: Release of TPC and AA of beetroot was higher in frozen samples (55 +/- 5% for TPC and 68 +/- 5% for AA) than in the fresh beetroot sample (~46% for TPC and ~53% for AA). The mass transfer kinetics were described by using a Weibull model with mean relative errors lower than 8.5% contributing to a better understanding of the influence of freezing on the bioaccessibility of bioactive compounds. CONCLUSIONS: From the treatments tested in this study, freezing with liquid nitrogen resulted in the greatest increase in bioaccessibility of the antioxidant and phenolic compounds of beetroots. (c) 2018 Society of Chemical Industry. PMID- 30014466 TI - Reduced expression of the RNA-binding protein HuD in pancreatic neuroendocrine tumors correlates with low p27Kip1 levels and poor prognosis. AB - For the majority of patients diagnosed with pancreatic neuroendocrine tumors (NETs), there is significant malignant potential with a poor prognosis; however, the molecular abnormalities and pathogenesis of pancreatic NETs have not been firmly established. Here, we report that loss of expression of the RNA-binding protein HuD correlates with low p27Kip1 (p27) levels and poor prognosis in pancreatic NETs. HuD expression was frequently lost in many human pancreatic NETs, and these pancreatic NETs showed aggressive clinicopathological phenotypes with low p27 levels, increased tumor size, higher World Health Organization grade and pT stage of the tumor, and the presence of angioinvasion. Furthermore, loss of HuD was an independent, progression-free prognostic factor in multivariate survival analysis. However, the level of HuR, a member of the same Hu protein family as HuD, was not significantly correlated with pancreatic NET size and progression. Mechanistically, HuD enhanced p27 mRNA translation by interacting with both the 5'-untranslated region (UTR) and the 3'-UTR of p27 mRNA, and consequently suppressed cell cycle progression and tumor growth. In addition, HuD competed with miR-30a-3p for binding to the 3'-UTR of p27 mRNA, suggesting an interplay between HuD and miR-30a-3p in controlling p27 translation. Our results identify HuD as a pivotal suppressor of pancreatic NET growth, and suggest that HuD has potential value as a prognostic factor of pancreatic NETs. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30014468 TI - Impact of thymoquinone on cyclosporine A pharmacokinetics and toxicity in rodents. AB - OBJECTIVES: Cyclosporine A (CsA) is an immunosupprsant drug used to prevent graft rejection and in the treatment of several autoimmune diseases. Thyomquinone (TQ), a bioactive component of Nigella sativa, has strong antioxidant properties and has been used in prevention of many toxicities, hence its protective effect and pharmacokinetic interactions with CsA was investigated in this study. METHODS: For bioavailability study, the rats were divided into four groups: TQ (PO, 10 mg/kg) was given alone for 7 days, then TQ plus CsA for another 5 days, CsA was given by two routes (po) and (IP) in a dose of 10 mg/kg 1 h after administration of TQ. Blood samples were taken at the 12th day at specified times, CsA level was determined by immune assays. The protective effect of TQ was studied. Blood samples for lab investigations and histopathology were taken at the 28th day. KEY FINDINGS: Thyomquinone reduced the bioavailability of oral CsA by around 32% (P > 0.05). However, bioavailability of IP administered CsA was not affected. Chronic administration of CsA increased concentrations of fasting glucose and Cystatin C and produced marked s kidney alteration of parenchyma which was reversed by concomitant administration of TQ. CONCLUSIONS: A potential drug interaction between TQ and CsA, which may reduced its oral bioavailability. Independently TQ caused significant attenuation of CsA induced renal toxicity and diabetogenic effect. PMID- 30014469 TI - Quantitative comparison of taxa and taxon concepts in the diatom genus Fragilariopsis: a case study on using slide scanning, multiexpert image annotation, and image analysis in taxonomy1. AB - Semiautomated methods for microscopic image acquisition, image analysis, and taxonomic identification have repeatedly received attention in diatom analysis. Less well studied is the question whether and how such methods might prove useful for clarifying the delimitation of species that are difficult to separate for human taxonomists. To try to answer this question, three very similar Fragilariopsis species endemic to the Southern Ocean were targeted in this study: F. obliquecostata, F. ritscheri, and F. sublinearis. A set of 501 extended focus depth specimen images were obtained using a standardized, semiautomated microscopic procedure. Twelve diatomists independently identified these specimen images in order to reconcile taxonomic opinions and agree upon a taxonomic gold standard. Using image analyses, we then extracted morphometric features representing taxonomic characters of the target taxa. The discriminating ability of individual morphometric features was tested visually and statistically, and multivariate classification experiments were performed to test the agreement of the quantitatively defined taxa assignments with expert consensus opinion. Beyond an updated differential diagnosis of the studied taxa, our study also shows that automated imaging and image analysis procedures for diatoms are coming close to reaching a broad applicability for routine use. PMID- 30014470 TI - Fermented goat milk consumption improves cardiovascular health during anemia recovery. AB - BACKGROUND: Iron (Fe) plays a crucial role in several fundamental processes, including erythropoiesis, cellular metabolism, and in cardiovascular disease. The aim of this work was to contribute to a better understanding of the physiology of and recovery from Fe deficiency by studying how fermented milk consumption affects vascular biomarkers during Fe repletion. RESULTS: The deleterious cardiovascular biomarkers cytokine-induced neutrophil chemoattractant 1, connective tissue growth factor (CTGF), interleukin-6, monocyte chemoattractant protein-1 (MCP-1), inhibitor of tissue plasminogen activator 1 total, metallopeptidase inhibitor 1 (TIMP-1), tumor necrosis factor alpha, vascular endothelial growth factor (VEGF), sE-selectin, and soluble intercellular adhesion molecule 1 (sICAM-1) decreased after fermented goat milk consumption in groups of fed animals either with normal Fe or Fe overload with respect to rats fed with fermented cow milk. The beneficial cardiovascular biomarkers caveolin-1 and adiponectin were higher in both control and anemic rats fed fermented goat milk either with normal Fe or Fe overload with respect to fermented cow milk. Anemia decreased TIMP-1 in rats fed fermented goat milk with Fe overload, whereas there was increased CTGF and MCP-1 in animals fed fermented cow milk with either normal or Fe overload. In addition, Fe overload increased VEGF. CONCLUSION: Fermented goat milk consumption improves hematological status and promotes beneficial metabolic responses, which may attenuate cardiovascular risk factors during anemia recovery and iron overload to lessen the inflammatory response, macrophages activation and atherosclerosis development. (c) 2018 Society of Chemical Industry. PMID- 30014471 TI - CRISPR-Cas9: A cornerstone for the evolution of precision medicine. AB - Modern genetic therapy incorporates genomic testing and genome editing. It is the finest approach for precision medicine. Genome editing is a state-of-the-art technology to manipulate gene expression thus generating a particular genotype. It encompasses multiple programmable nuclease-based approaches leading to genetic changes. Not surprisingly, this method triggered internationally a wide array of controversies in the scientific community and in the public since it transforms the human genome. Given its importance, the pace of this technology is exceptionally fast. In this report, we introduce one aspect of genome editing, the CRISPR/Cas9 system, highlight its potential to correct genetic mutations and explore its utility in clinical setting. Our goal is to enlighten health care providers about genome editing and incite them to take part of this vital debate. PMID- 30014473 TI - Rebuttal from Stephen M. Stick and Andre Schultz. PMID- 30014472 TI - Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by demyelination, inflammation and neurodegeneration throughout the central nervous system. Although spinal cord pathology is an important factor contributing to disease progression, few studies have examined MS lesions in the spinal cord and how they differ from brain lesions. In this study we have compared brain and spinal cord white (WM) and grey (GM) matter from MS and control tissues, focusing on small heat shock proteins (HSPB) and HSP16.2. Western blotting was used to examine protein levels of HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 in brain and spinal cord from MS and age-matched non-neurological controls. Immunohistochemistry was used to examine expression of the HSPs in MS spinal cord lesions and controls. Expression levels were quantified using ImageJ. Western blotting revealed significantly higher levels of HSPB1, HSPB6 and HSPB8 in MS and control spinal cord compared to brain tissues. No differences in HSPB5 and HSP16.2 protein levels were observed, although HSPB5 protein levels were higher in brain WM versus GM. In MS spinal cord lesions, increased HSPB1 and HSPB5 expression was observed in astrocytes, and increased neuronal expression of HSP16.2 was observed in normal-appearing GM and type 1 GM lesions. The high constitutive expression of several HSPBs in spinal cord and increased expression of HSPBs and HSP16.2 in MS illustrate differences between brain and spinal cord in health and upon demyelination. Regional differences in HSP expression may reflect differences in astrocyte cytoskeleton composition and influence inflammation, possibly affecting the effectiveness of pharmacological agents. PMID- 30014475 TI - Our flawed approach to undue inducement in medical research. AB - Some worry that offering too much money to participate in medical research can seduce people into participating against their better judgment. These overly attractive offers that impair judgment are often referred to as 'undue inducements'. The current approach to prevent undue inducement is to limit the size of such offers. The hope is that smaller offers will not be attractive enough to impair judgment. Even if this is true, I argue that we should reject this solution. In Section 1, I go over the problem of undue inducement, and our current approach to preventing it, in more detail. In Section 2, I argue that, like money, therapeutic benefits of medical research may also unduly induce. In Section 3, I argue that the current approach to preventing undue inducement is absurd in the case of therapeutic inducements. In Section 4, I argue that our current approach is analogously problematic in the case of monetary inducements. PMID- 30014476 TI - Conscientious objection in healthcare: How much discretionary space best supports good medicine? AB - Daniel Sulmasy has recently argued that good medicine depends on physicians having a wide discretionary space in which they can act on their consciences. The only constraints Sulmasy believes we should place on physicians' discretionary space are those defined by a form of tolerance he derives from Locke, whereby people can publicly act in accordance with their personal religious and moral beliefs as long as their actions are not destructive to society. Sulmasy also claims that those who would reject physicians' right to conscientious objection eliminate discretionary space, thus undermining good medicine and unnecessarily limiting religious freedom. I argue that, although Sulmasy is correct that some discretionary space is necessary for good medicine, he is wrong in thinking that proscribing conscientious objection entails eliminating discretionary space. I illustrate this using Julian Savulescu and Udo Schuklenk's system for restricting conscientious objections as a counter-example. I then argue that a narrow discretionary space constrained by professional ideals will promote good medicine better than Sulmasy's wider discretionary space constrained by his conception of tolerance. Sulmasy's version of discretionary space would have us tolerate actions that are at odds with aspects of good medicine, including aspects that Sulmasy himself explicitly values, such as fiduciary duty. Therefore, if we want the degree of religious freedom in the public sphere that Sulmasy favours then we must decide whether it is worth the cost to the healthcare system. PMID- 30014474 TI - Immunotoxicity of aflatoxin M1 : as a potent suppressor of innate and acquired immune systems in a subacute study. AB - BACKGROUND: Although, to date, there have been several in vitro and in vivo studies of immunomodulatory effects of aflatoxin M1 (AFB1 ), little is known about the effect of AFM1 on various aspects of innate and acquired immunity. In the present study, AFM1 was administered intraperitoneally, at doses of 25 and 50 MUg kg-1 , body mass for 28 days and various immunological parameters were measured. RESULTS: Several parameters related to immune function were suppressed: organ mass, cellularity of spleen, proliferation response to lipopolysaccaride and phytohemagglutinin-A, hemagglutination titer, delayed type of hypersensitivity response, spleen cell subtypes, serum hemolytic activity, serum immunoglobulin G level and cytokine production. AFM1 did not cause changes in body mass, hematological parameters or the concentration of immunoglobulin M in blood serum. CONCLUSIONS: Overall, the data suggested that AFM1 suppressed innate and acquired immunity. Therefore, with respect to consumer safety, it is extremely important to further control the level of AFM1 in milk, and this should be considered as a precedence for risk management actions. (c) 2018 Society of Chemical Industry. PMID- 30014478 TI - 4D robust optimization including uncertainties in time structures can reduce the interplay effect in proton pencil beam scanning radiation therapy. AB - PURPOSE: Interplay effects in proton radiotherapy can create large distortions in the dose distribution and severely degrade the plan quality. Standard methods to mitigate these effects include abdominal compression, gating, and rescanning. We propose a new method to include the time structures of the delivery and organ motion in the framework of four-dimensional (4D) robust optimization to generate plans that are robust against interplay effects. METHODS: The method considers multiple scenarios reflecting the uncertainties in the delivery and in the organ motion. In each scenario, the pencil beam scanning spots are distributed to different phases of the breathing cycle according to each individual spot time stamp, and a partial beam dose is calculated for each phase. The partial beam doses are accumulated on a reference phase through deformable image registrations. Minimax optimization is performed to take all scenarios into account simultaneously. For simplicity, the uncertainties in this proof of concept study are limited to variations in the breathing pattern. The method is evaluated for three different nonsmall cell lung cancer patients and compared to plans using conventional 4D robust optimization both with and without rescanning. We assess the ability of the method to mitigate distortions from the interplay effect over multiple evaluation scenarios using 4D dose calculations. This interplay evaluation is performed in an experimentally validated framework, which is independent of the optimization in the plan generation step. RESULTS: For the three studied patients, 4D optimization including time structures is efficient, especially for large tumor motions, where rescanning of conventional 4D robustly optimized plans is not sufficient to mitigate the interplay effect. The most efficient approach of the new method is achieved when it is combined with rescanning. For the patient with the largest motion, the mean V95% is 99.2% and mean V107% is 3.65% for the best rescanned 4D plan optimized with time structure. This can be compared to conventional 4D optimized plans with mean V95% of 92.7% and mean V107% of 13.1%. CONCLUSIONS: The current study shows the potential of reducing interplay effects in proton pencil beam scanning radiotherapy by incorporating organ motion and delivery characteristics in a 4D robust optimization. PMID- 30014477 TI - Neurofibromatosis type I: mutation spectrum of NF1 in spanish patients. AB - Neurofibromatosis type I (NF1) is one of the most common genetic disorders in humans. NF1, a tumor predisposition syndrome, is caused by heterozygous pathogenic variants in the NF1 gene. Molecular genetic testing of NF1 is complex, especially because of the presence of a high number of partial pseudogenes, some of them with a high percentage of sequence identity. In this study, we have analyzed the largest cohort of NF1 Spanish patients (150 unrelated individuals suspected of having NF1 and 53 relatives, making a total of 203 individuals). Mutation analysis of the entire coding region was performed in all unrelated index patients. Additionally, the Multiplex Ligation-dependent Probe Amplification (MLPA) test of the NF1 gene and SPRED1 gene analysis (sequencing and MLPA test) was performed in some of the negative patients for NF1 point mutations. When fulfilling the National Institutes of Health (NIH) criterion for the clinical diagnosis of NF1, the detection rate was 79%. Among the 80 genetically confirmed NF1 probands, we detected 69 different pathogenic variants. Two mutations (3%) were gross deletions of the whole gene, the remaining 78 mutations (97%) were small changes spread among all NF1 exons. Among these 69 different mutations detected, 42 mutations were described elsewhere, and 27 mutations were novel mutations. When segregation was studied, 67% of mutations resulted de novo variants. No genetic mosaicism was detected on patients' parents. PMID- 30014479 TI - Adverse drug reactions during hepatitis C treatment with direct-acting antivirals: The role of medication errors, their impact on treatment discontinuation and their preventability. New insights from the Campania Region (Italy) spontaneous reporting system. AB - WHAT IS KNOWN AND OBJECTIVE: Medication errors, such as unnecessary treatment discontinuation during treatment with direct-acting antivirals (DAAs), can lead to imbalances in the benefit-to-risk ratio. This risk is especially high when the medication error leads to adverse drug reactions (ADRs). However, to date, evidence on the frequency of this phenomenon is scarce. This study aims to provide better insight into ADRs possibly due to medication errors leading to DAA discontinuation and their preventability. METHODS: The Italian Pharmacovigilance Network database was used to extract individual case safety reports (ICSRs) generated from July 2012 to March 2017 via the Campania Region (Italy) spontaneous reporting system. ICSRs that included ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, dasabuvir, daclatasvir, sofosbuvir, simeprevir or elbasvir/grazoprevir as suspected drugs were included in this study. A preventability assessment was then performed utilizing the "P-Method," an algorithm that evaluates known risk factors due to medication errors that can be detected in ICSRs. RESULTS AND DISCUSSION: Of the 355 cases included in this study, 6 (1.69%) were classified as preventable and 52 (14.6%) were classified as potentially preventable. The most frequently identified critical criteria (risk factor) for preventable or potentially preventable cases were drug-drug interactions and incorrect drug dosing as part of the antiviral treatment scheme. In total, 89 of the 355 cases (25.1%) discontinued use of the DAAs due to ADRs, of which 20 of the 89 cases (22.5%) were due to an unimportant medical event as classified by the European Medicine Agency important medical event list. WHAT IS NEW AND CONCLUSION: This study found a proportion of preventable/potentially preventable ADRs involving DAA, which could be improved in the Campania Region (Italy). Additionally, the study identified a high proportion of seemingly unnecessary DAA discontinuations among patients who experienced ADRs. PMID- 30014480 TI - Rebuttal from Miriam F. Figueira, Megan J. Webster and Robert Tarran. PMID- 30014481 TI - Trust and responsibility in molecular tumour boards. AB - Molecular tumour boards (MTBs) offer recommendations for potentially effective, but potentially burdensome, molecularly targeted treatments to a patient's treating physician. In this paper, we discuss the question of who is responsible for ensuring that there is an adequate evidence base for any treatments recommended to a patient. We argue that, given that treating oncologists cannot usually offer a robust evaluation of the evidence underlying an MTB's recommendation, members of the MTB are responsible for ensuring that the evidence level is adequate. We explore two models for how to share responsibility between MTB members. According to the first model, each MTB member, as well as the treating physician, should be held maximally and equally responsible for the recommendations. We argue that this insufficiently accounts for differences in roles and expertise of MTB members. We propose instead that responsibility is delegated via relationships of trust. We argue if these relationships of trust are to be instances of reasonable trust, (a) MTBs should offer a clinical representative to whom a treating physician may delegate the responsibility of ensuring there is sufficient evidence for treatment recommendations, (b) the relationships of trust between the representative and the other MTB members should be clearly defined, and (c) MTB members should be carefully selected. Treating oncologists retain a responsibility to consider general limitations of the evidence for targeted treatments in assessing whether the treatment recommendation offered by an MTB's representative is adequate for a given clinical situation. PMID- 30014482 TI - Personality characteristics that are valued in teams: Not always "more is better"? AB - This study investigates the relationships between personality traits and contributions to teamwork that are often assumed to be linear. We use a theory driven approach to propose that extraversion, agreeableness and conscientiousness have inverted U-shaped relationships with contributions to teamwork. In a sample of 220 participants asked to perform a creative task in teams, we found that extraversion, agreeableness and conscientiousness were curvilinearly associated with peer-rated contributions to teamwork in such a way that the associations were positive, with a decreasing slope, up to a peak, and then they became negative as personality scores further increased. We replicated the results concerning the non-linear association between extraversion, conscientiousness and peer-rated contributions to teamwork in a sample of 314 participants engaged in a collaborative learning exercise. Our results support recent claims and empirical evidence that explorations of personality-work-related behaviours relationships should move beyond the linearity assumptions. We conclude by discussing the implications of our research for personnel selection. PMID- 30014483 TI - The mechanism of SO2 -induced stomatal closure differs from O3 and CO2 responses and is mediated by nonapoptotic cell death in guard cells. AB - Plants closing stomata in the presence of harmful gases is believed to be a stress avoidance mechanism. SO2 , one of the major airborne pollutants, has long been reported to induce stomatal closure, yet the mechanism remains unknown. Little is known about the stomatal response to airborne pollutants besides O3 . SLOW ANION CHANNEL-ASSOCIATED 1 (SLAC1) and OPEN STOMATA 1 (OST1) were identified as genes mediating O3 -induced closure. SLAC1 and OST1 are also known to mediate stomatal closure in response to CO2 , together with RESPIRATORY BURST OXIDASE HOMOLOGs (RBOHs). The overlaying roles of these genes in response to O3 and CO2 suggested that plants share their molecular regulators for airborne stimuli. Here, we investigated and compared stomatal closure event induced by a wide concentration range of SO2 in Arabidopsis through molecular genetic approaches. O3 - and CO2 -insensitive stomata mutants did not show significant differences from the wild type in stomatal sensitivity, guard cell viability, and chlorophyll content revealing that SO2 -induced closure is not regulated by the same molecular mechanisms as for O3 and CO2 . Nonapoptotic cell death is shown as the reason for SO2 -induced closure, which proposed the closure as a physicochemical process resulted from SO2 distress, instead of a biological protection mechanism. PMID- 30014484 TI - Transforming Growth Factor-beta and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma. AB - : Transforming growth factor (TGF)-beta suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-beta switch towards dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-beta. Both HCC models showed reduced proliferation and clonogenic growth behavior upon TGF-beta stimulation, however, exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of anti-oncogenic TGF-beta. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF-beta expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression suggesting that CXCL5 is a TGF-beta target gene collaborating with Axl signaling. Loss of either TGF-beta or Axl signaling abrogated CXCL5-dependent attraction of neutrophils. In mice, tumor formation of transplanted HCC cells relied on CXCL5 expression. In HCC patients, high levels of Axl and CXCL5 correlated with advanced tumor stages, recruitment of neutrophils into HCC tissue and reduced survival. CONCLUSION: The synergy of TGF-beta and Axl induces CXCL5 secretion causing the infiltration of neutrophils into HCC tissue. Intervention with TGF-beta/Axl/CXCL5 signaling may be an effective therapeutic strategy to combat HCC progression in TGF-beta positive patients. This article is protected by copyright. All rights reserved. PMID- 30014485 TI - The burden of adverse obstetric and perinatal outcomes from maternal smoking in an Australian cohort. AB - BACKGROUND: Maternal smoking is associated with a number of adverse outcomes with a dose-dependent increase in risk. The aim of this study was to evaluate the obstetric and perinatal outcomes in women who smoked during pregnancy. METHODS: This was a retrospective cohort study of women who smoked during pregnancy and birthed at a major perinatal centre in Australia between January 2000 and April 2017. The study cohort was compared to a cohort of women who did not smoke in pregnancy. Smoking status was ascertained on history and included all types of smoking. Demographic characteristics and obstetric, intrapartum and perinatal outcomes were compared between the two groups. RESULTS: The study cohort included 20 477 (14.6%) women who smoked during pregnancy and 119 396 controls. Women who smoked tended to be younger, of higher body mass index (BMI), Caucasian and Indigenous ethnicity. Smokers were less likely to be nulliparous, but more likely to be hypertensive and have a lower socioeconomic status compared to non-smokers. Women who smoked were more likely to have a caesarean section for non-reassuring fetal status (adjusted odds ratio (aOR) 1.16, 95%CI 1.07-1.26, P < 0.001). The infants of women who smoked were more likely to be born preterm, have a lower median birth weight and birth weights <10th (aOR 1.76, 95%CI 1.66-1.86, P < 0.001) and <5th centile (aOR 2.00, 95%CI 1.86-2.16, P < 0.001). Neonatal outcomes in the smoking cohort were worse with an increase in neonatal intensive care unit admission (aOR 1.34, 95%CI 1.27-1.43, P < 0.001), severe acidosis (aOR 1.41, 95%CI 1.27-1.43, P < 0.001) and a composite of severe neonatal outcomes (18.0% vs 12.0%, aOR 1.35, 95%CI 1.28-1.43, P < 0.001). CONCLUSION: Women who smoke in pregnancy have worse obstetric and perinatal outcomes compared to controls and should be managed as high risk. PMID- 30014486 TI - Characteristic morphological changes in anti-VEGF therapy-induced glomerular microangiopathy. AB - AIMS: Agents targeting vascular endothelial growth factor (VEGF) have increasingly been used for the treatment of advanced malignancies, and have been found to induce renal thrombotic microangiopathy (TMA) and proteinuria. However, histomorphological changes in human biopsies in this setting and the underlying mechanism are not yet fully understood. Therefore, we collected renal biopsy cases with a history of aVEGF therapy to review and compare morphological kidney changes in this context. METHODS AND RESULTS: Renal biopsies of 15 patients who had received anti-VEGF (aVEGF) therapy evaluated between 2013 and 2017 at a single centre were morphologically characterised with light microscopy, electron microscopy, and immunohistochemistry (IgA, IgG, IgM, C1q, and C3), and compared with cases with acute TMA caused by atypical haemolytic-uraemic syndrome or hypertension. Morphological overlap with immune complex and cryoglobulinaemic membranoproliferative glomerulonephritis, diabetic glomerulopathy and pre eclampsia-induced glomerulopathy are discussed. Segmental glomerular capillary microaneurysms and segmental hyalinosis were typical morphological features of aVEGF therapy-induced glomerular microangiopathy, whereas fibrin or platelet thrombi or fragmented erythrocytes were rarely found or were absent. aVEGF therapy-associated microangiopathy was diffusely distributed in the glomeruli, spared preglomerular vessels, and showed morphological characteristics of chronic TMA. In individual cases, aVEGF therapy-induced glomerular microangiopathy was accompanied by immune-complex glomerulonephritis. CONCLUSION: aVEGF therapy induced glomerular microangiopathy has a characteristic morphology and clinical presentation that helps to differentiate it from other causes of TMA. Awareness of these light microscopic findings allows identification of aVEGF therapy as a trigger of renal disease in critically ill cancer patients, and might therefore help in deciding on further therapy. PMID- 30014488 TI - The Utility of MR Elastography to Differentiate Nodular Regenerative Hyperplasia from Cirrhosis. AB - Nodular regenerative hyperplasia (NRH) is characterized by diffuse parenchymal nodularity of the liver with small regenerative nodules, leading to possible portal hypertension. Differentiating NRH from cirrhosis on standard imaging is difficult. We evaluated the potential utility of MRI and MR Elastography (MRE) in differentiating NRH and cirrhosis. This article is protected by copyright. All rights reserved. PMID- 30014487 TI - AKTions by Cytoplasmic lncRNA CASC9 Promote Hepatocellular Carcinoma Survival. PMID- 30014489 TI - Changing Trends in Etiology- and Ethnicity-Based Annual Mortality Rates of Cirrhosis and Hepatocellular Carcinoma in the United States. AB - : With recent improvements in the treatment of end-stage liver disease (ESLD), a better understanding of the burden of cirrhosis and hepatocellular carcinoma (HCC) is needed in the United States (US). A population-based study using the US Census and national mortality database was performed. We identified the age standardized etiology-specific mortality rates for cirrhosis and HCC among US adults aged >= 20 years from 2007 to 2016. We determined temporal mortality rate patterns by joinpoint analysis with estimates of annual percentage change (APC). Age-standardized cirrhosis-related mortality rates increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3% (95% CI 2.0 2.7). The APC in mortality rates for hepatitis C virus (HCV)-cirrhosis shifted from a 2.9% increase per year during 2007-2014 to a 6.5% decline per year during 2014-2016. Meanwhile, mortality for cirrhosis from alcoholic liver disease (ALD, APC 4.5%) and nonalcoholic fatty liver disease (NAFLD, APC 15.4%) increased over the same period, while mortality for hepatitis B virus (HBV)-cirrhosis decreased with an average APC of -1.1%. HCC-related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at an annual rate of 2.0% (95% CI 1.3-2.6). Etiology-specific mortality rates of HCC were largely consistent with cirrhosis related mortality. Minority populations had a higher burden of HCC-related mortality. CONCLUSION: Cirrhosis- and HCC-related mortality rates increased between 2007 and 2016 in the US. However, mortality rates in HCV-cirrhosis demonstrated a significant decline from 2014-2016, during the direct-acting antiviral era. Mortality rates for ALD/NAFLD-cirrhosis and HCC have continued to increase, while HBV-cirrhosis-related mortality declined during the 10-year period. Importantly, minorities had a disproportionately higher burden of ESLD related mortality. This article is protected by copyright. All rights reserved. PMID- 30014491 TI - Patients with compensated cirrhosis are also at risk of falling. AB - Some years ago, we observed that falling in the previous year was more frequent in patients with cirrhosis than in healthy controls, and showed for the first time that cirrhotic patients, mainly those with cognitive dysfunction, are predisposed to falling during follow-up. Since then, the relevance of falls in cirrhosis has been addressed in the context of their incidence, risk factors, related mortality, associated complications, health care needs, familial and social burden, and health-related quality of life deterioration. This article is protected by copyright. All rights reserved. PMID- 30014490 TI - Dual targeting of histone methyltransferase G9a and DNA-methyltransferase 1 for the treatment of experimental hepatocellular carcinoma. AB - : Epigenetic modifications like DNA and histone methylation functionally cooperate fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our new dual G9a histone-methyltransferase and DNA-methytransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1, along with that of their molecular adaptor ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was measured in human HCCs (n=268), peritumoral tissues (n=154) and HCC cell lines (n=32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cells growth by pharmacological and genetic approaches. The activity of our lead compound, CM-272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a, DNMT1 and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM 272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM-272 inhibited the metabolic adaptation of HCC cells to hypoxia, and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose-1,6-bisphosphatase (FBP1), epigenetically repressed in HCC, was restored by CM-272. CONCLUSION: Combined targeting of G9a/DNMT1 with compounds like CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC. This article is protected by copyright. All rights reserved. PMID- 30014493 TI - Acute localized exanthematous pustulosis caused by a herbal medicine, dai-kenchu to. PMID- 30014492 TI - Pathological features of total gastrectomy specimens from asymptomatic hereditary diffuse gastric cancer patients and implications for clinical management. AB - Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant syndrome characterised by multigenerational diffuse gastric cancer, and is mainly caused by germline alterations in the CDH1 gene. Currently, endoscopy has limited diagnostic accuracy, and total gastrectomy (TG) is the treatment of choice for asymptomatic CDH1 carriers. In this study, we aimed to obtain a better understanding of HDGC syndrome by exploring the histopathological findings of TG specimens from asymptomatic HDGC patients. A comprehensive literature review was carried out, searching for TGs performed in asymptomatic HDGC patients. Fourteen unpublished cases, analysed in our institution, were also included. The series encompassed 174 CDH1 carriers. Preoperative endoscopic biopsies were positive in 28.3%. A macroscopic lesion was apparent in 11.7% of TGs. Histopathological analysis revealed intraepithelial lesions and/or intramucosal signet ring cell carcinoma in 87.9% of TGs. When we explored the type of protocol used for handling the specimens, we found that microscopic cancer foci were detected in 95.3% of TGs when a total-embedding protocol (assessment of the totality of gastric mucosa) was applied, and only in 62.5% when no specific protocol was used (P < 0.001). Helicobacter pylori infection was found in 23.4% cases. In conclusion, a thorough histopathological examination of gastric mucosa remains the gold standard for detection of cancer foci in HDGC gastrectomy specimens, requiring experienced pathologists for an accurate diagnosis. A better understanding of the natural history of HDGC will enable better clinical management of HDGC patients, particularly regarding the optimal timing for the performance of TG. PMID- 30014494 TI - Age at HBeAg seroconversion and other factors for outcomes of chronic hepatitis B. AB - The large cohort study of Fung et al [1] in this Journal described 18-year outcomes of chronic HBV infection after HBeAg seroconversion (ESC) and constructed scores predicting HCC and HBsAg seroclearance. Although the number of patient and the duration of follow-up are impressive, several points require clarification or further discussion. First: Since the durability of spontaneous and antiviral therapy related ESC is different [2], it seems not appropriate to lump 219 patients who had received antiviral therapy and the 504 untreated patients together as a cohort. This article is protected by copyright. All rights reserved. PMID- 30014495 TI - MicroRNA Sequencing Identifies a Serum MicroRNA Panel, Which Combined With Aspartate Aminotransferase to Platelet Ratio Index Can Detect and Monitor Liver Disease in Pediatric Cystic Fibrosis. AB - Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on nonspecific assessments, whereas liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase (AST) to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical, and imaging assessments as follows: CFLD (n = 44), CF patients with no evidence of liver disease (CFnoLD; n = 40), and healthy controls (n = 40). Serum miRNAs were analyzed using miRNA sequencing (miRNA-Seq). Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p, and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, whereas miR-142 3p and let-7g-5p were down-regulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p, and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an area under the receiver operating characteristics curve (AUROC) = 0.91 (sensitivity = 83%, specificity = 92%; P < 0.0001). Expression levels of serum miR-18a-5p were correlated with increasing hepatic fibrosis (HF) stage in CFLD (rs = 0.56; P < 0.0001), showing good diagnostic accuracy for distinguishing severe (F3-F4) from mild/moderate fibrosis (F0-F2). A unit increase of miR-18a-5p showed a 7-fold increased odds of having severe fibrosis with an AUROC = 0.82 (sensitivity = 93%, specificity = 73%; P = 0.004), indicating its potential to predict fibrosis severity. Conclusion: We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF. PMID- 30014497 TI - Estimating individualized optimal combination therapies through outcome weighted deep learning algorithms. AB - With the advancement in drug development, multiple treatments are available for a single disease. Patients can often benefit from taking multiple treatments simultaneously. For example, patients in Clinical Practice Research Datalink with chronic diseases such as type 2 diabetes can receive multiple treatments simultaneously. Therefore, it is important to estimate what combination therapy from which patients can benefit the most. However, to recommend the best treatment combination is not a single label but a multilabel classification problem. In this paper, we propose a novel outcome weighted deep learning algorithm to estimate individualized optimal combination therapy. The Fisher consistency of the proposed loss function under certain conditions is also provided. In addition, we extend our method to a family of loss functions, which allows adaptive changes based on treatment interactions. We demonstrate the performance of our methods through simulations and real data analysis. PMID- 30014496 TI - Oogenesis is accompanied by cyclic morphological changes in hepatocytes of Neotropical freshwater fish Piabina argentea. AB - We determined for the first time the reproductive biology of Piabina argentea through macroscopic and microscopic analysis of ovaries and evaluated the morphological changes in hepatocytes. Two hundred and 46 specimens were collected, 204 females and 42 males, between March 2014 and February 2015. Biometrics data were obtained. From females, gonad and liver samples were conducted to histological, histochemical and immunohistochemical techniques. Mature ovaries were used to determine absolute and relative fecundity. Total length and body weight values indicated that females were larger than males. The estimated weight-length ratio showed negative allometric growth. The absolute fecundity average was 171.83 +/- 59.89 oocytes per ovary. In addition, females spawning capable and regressing stages were found throughout the sampling period and the presence of all oocyte types in regressing stage ovaries indicated asynchronous oocyte development and multiple spawning. From regenerating to spawning capable stage the oocytes accumulated yolk in cytoplasm became bigger. While in the liver hepatocytes with a larger cell area during regenerating stage and proliferative activity in the spawning capable stage were observed. Thus, our results indicate that P. argentea had an opportunistic reproductive strategy and cyclic morphological changes of hepatocytes occurred during the oogenesis. PMID- 30014498 TI - Consumption of a defined, plant-based diet reduces lipoprotein(a), inflammation, and other atherogenic lipoproteins and particles within 4 weeks. AB - BACKGROUND: Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein and is minimally effected by lifestyle changes. While some drugs can reduce Lp(a), diet has not consistently shown definitive reduction of this biomarker. The effect of consuming a plant-based diet on serum Lp(a) concentrations have not been previously evaluated. HYPOTHESIS: Consumption of a defined, plant-based for 4 weeks reduces Lp(a). METHODS: Secondary analysis of a previous trial was conducted, in which overweight and obese individuals (n = 31) with low-density lipoprotein cholesterol concentrations >100 mg/dL consumed a defined, plant-based diet for 4 weeks. Baseline and 4-week labs were collected. Data were analyzed using a paired samples t-test. RESULTS: Significant reductions were observed for serum Lp(a) (-32.0 +/- 52.3 nmol/L, P = 0.003), apolipoprotein B (-13.2 +/- 18.3 mg/dL, P < 0.0005), low-density lipoprotein (LDL) particles (-304.8 +/- 363.0 nmol/L, P < 0.0005) and small-dense LDL cholesterol (-10.0 +/- 9.2 mg/dL, P < 0.0005). Additionally, serum interleukin-6 (IL-6), total white blood cells, lipoprotein-associated phospholipase A2 (Lp-PLA2), high-sensitivity c-reactive protein (hs-CRP), and fibrinogen were significantly reduced (P <= 0.004). CONCLUSIONS: A defined, plant-based diet has a favorable impact on Lp(a), inflammatory indicators, and other atherogenic lipoproteins and particles. Lp(a) concentration was previously thought to be only minimally altered by dietary interventions. In this protocol however, a defined plant-based diet was shown to substantially reduce this biomarker. Further investigation is required to elucidate the specific mechanisms that contribute to the reductions in Lp(a) concentrations, which may include alterations in gene expression. PMID- 30014499 TI - Cerebellar atrophy and its contribution to cognition in frontotemporal dementias. AB - OBJECTIVE: Increasing evidence suggests that cerebellar damage impacts on cognitive functions. Frontotemporal dementias (FTDs) are neurodegenerative brain conditions, primarily affecting the frontal and/or temporal lobe. Three main phenotypes are recognized, each with a distinct clinical and cognitive profile: behavioral-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The severity of cerebellar changes and their relation to cognition in FTD, however, remain unclear. This study aimed to establish cerebellar gray matter changes on magnetic resonance imaging (MRI) and their relation to profiles of cognitive deficits in FTD subtypes. METHODS: Ninety-six FTD patients (45 bvFTD, 28 SD, and 23 PNFA), meeting current clinical diagnostic criteria, and 35 age-, sex-, and education-matched controls underwent brain MRI and cognitive assessment. Cerebral and cerebellar gray matter integrity were investigated using voxel-based morphometry. RESULTS: Compared with controls, widespread bilateral cerebellar changes were observed in all FTD subtypes, with the greatest atrophy present in bvFTD. Significant associations were found between cerebellar integrity and cognitive performance in attention and working memory in bvFTD, visuospatial function in SD, and language-motor function in PNFA. Bilateral atrophy of crus and lobule VI were most commonly associated with cognitive deficits, irrespective of FTD phenotype. INTERPRETATION: This study is the first to identify distinct patterns of cerebellar atrophy across FTD syndromes, which in turn relate to discrete cognitive dysfunctions, after accounting for the effect of cerebral atrophy. These findings extend our understanding of the cerebellum and point to its involvement across an array of processes beyond the domain of motor function. Ann Neurol 2018;83:98-109. PMID- 30014500 TI - Successful Treatment With Ledipasvir/Sofosbuvir in an Infant With Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency With HCV Allowed Gene Therapy with Strimvelis. PMID- 30014501 TI - Effect of quorum quenching bacteria on growth, virulence factors and biofilm formation of Yersinia ruckeri in vitro and an in vivo evaluation of their probiotic effect in rainbow trout. AB - Five N-acyl homoserine lactone-degrading bacteria (quorum quenching (QQ) strains) were selected to evaluate their impacts on growth, virulence factors and biofilm formation in Yersinia ruckeri in vitro. No difference was observed among the growth pattern of Y. ruckeri in monoculture and coculture with the QQ strains. To investigate the regulation of virulence factors by quorum sensing in Y. ruckeri, cultures were supplemented with 3oxo-C8-HSL. The results indicated that swimming motility and biofilm formation are positively regulated by QS (p < 0.05), whereas caseinase, phospholipase and haemolysin productions are not influenced by 3oxo-C8 HSL (p > 0.05). The QQs were able to decrease swimming motility and biofilm formation in Y. ruckeri. QQ bacteria were supplemented to trout feed at 108 CFU/g (for 40 days). Their probiotic effect was verified by Y. ruckeri challenge either by immersion or injection in trout. All strains could significantly increase fish survival with Bacillus thuringiensis and Citrobacter gillenii showing the highest and lowest relative percentage survival (RPS) values (respectively, 85% and 38%). Besides, there was no difference between the RPS values by either immersion or injection challenge expect for B. thuringiensis. The putative involvement of the QQ capacity in the protection against Yersinia is discussed. PMID- 30014502 TI - Mendelian randomization: Progressing towards understanding causality. PMID- 30014504 TI - Women in neurology: A WIN-Win. PMID- 30014505 TI - Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. AB - OBJECTIVE: To evaluate neurofilament light (NfL) as a biomarker of the presymptomatic phase of amyotrophic lateral sclerosis (ALS). METHODS: The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc), but who, at the time of enrollment, demonstrated no clinical symptoms or signs (including electromyographic evidence) of manifest disease. NfL in serum and cerebrospinal fluid (CSF) were quantified using an electrochemiluminescence immunoassay. RESULTS: Serum and CSF NfL are substantially higher in ALS patients compared to controls and at-risk individuals and remain relatively stable over time. Among phenoconverters, however, NfL levels were elevated (ie, above the range observed in controls) as far back as ~12 months preceding the emergence of the earliest clinical symptoms or signs of disease. INTERPRETATION: Serum (and CSF) NfL are informative biomarkers of presymptomatic ALS, providing a new tool to quantify presymptomatic disease progression and to potentially predict the timing of clinical phenoconversion. As such, quantification of NfL may aid the design and implementation of early therapeutic intervention for affected individuals and/or disease prevention trials for individuals at short-term risk of developing ALS. Ann Neurol 2018 Ann Neurol 2018;83:130-139. PMID- 30014506 TI - Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease. PMID- 30014508 TI - Plasma urate and risk of Parkinson's disease: A mendelian randomization study. AB - OBJECTIVE: Urate is a potent antioxidant, and high plasma urate has been associated with lower incidence of Parkinson's disease (PD) in epidemiological studies. We tested the hypothesis that high concentrations of plasma urate are associated with low incidence of PD. METHODS: We performed observational and genetic analyses using plasma urate and the urate SLC2A9 rs7442295 and ABCG2 rs2231142 genotype in >102,000 individuals from the CGPS (Copenhagen General Population Study). Information on PD and mortality was from national patient and death registries. Incidences of PD were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. RESULTS: In total, 398 individuals were diagnosed with PD, of which 285 were incident cases. The multivariable adjusted hazard ratio for PD was 0.56 (95% confidence interval [CI], 0.41-0.77) for the highest versus the lowest tertile of plasma urate (p for trend across 3 groups, 8 * 10-5 ). Each one-allele increase in the combined allele score was associated with 19MUmol/l (95% CI, 18.5-19.9) higher plasma urate. In observational analyses, a 50MUmol/l higher plasma urate was associated with a hazard ratio of 0.85 (0.77-0.92) for PD; in instrumental variable analyses, 50MUmol/l higher plasma urate was associated with an odds ratio of 1.20 (0.85-1.71) for PD. INTERPRETATION: High plasma urate was associated with lower risk of PD in observational analyses; however, in instrumental variable analysis, high plasma urate was not associated with low risk of PD. Thus, our data do not support a causal relationship between high plasma urate and low risk of PD. Ann Neurol 2018;84:178-190. PMID- 30014509 TI - Immunohistochemical study of Ki-67 protein, androgen receptor, and estrogen receptor beta in testicular tissues of male pigs immunocastrated with different times of GnRH vaccination. AB - This study aimed to investigate the immunoexpression of Ki-67 protein, androgen receptor (AR), and estrogen receptor beta (ERbeta) in testicular tissues of male pigs immunocastrated using GnRH vaccine (ImprovacTM, Zoetis Co., Ltd., Thailand) with different times. Totally, 30 male pigs were classified by castration protocol into three groups: T1 (n = 10) consisted of pigs immunocastrated at 14 and 18 weeks of age, T2 (n = 10) included pigs immunocastrated at 9 and 19 weeks of age, and C (n = 10) contained intact pigs. The results revealed that testicular length of pigs in C was longer than that of both T1 (8.1 +/- 0.76 vs 6.5 +/- 0.5 cm, p < 0.001) and T2 (8.1 +/- 0.76 vs 6.9 +/- 1.0, p = 0.007). Spearman correlation coefficients showed negative correlation between testicular length and H-score of AR (r = -0.38, p = 0.037), as well as positive correlation between testicular length and Ki-67 index (r = 0.602, p < 0.001). Generally, mean Ki-67 index and mean H-scores of AR and ERbeta of pigs in T1 were not different from those in T2 (p > 0.05). However, mean Ki-67 index and mean AR H-scores of T1 and T2 were significantly different from C group (p < 0.05). In summary, the immunocastration significantly affected testicular length, including expressions of Ki-67, AR, and ERbeta in pig testes. Moreover, the duration between two shots of GnRH vaccine could be extended from 4 to 10 weeks without difference in Ki-67 protein, AR, and ERbeta immunoexpressions. PMID- 30014507 TI - Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development. AB - OBJECTIVE: Developmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology. METHODS: We clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER. RESULTS: All 9 individuals harbored heterozygous null-allele variants in CUX1, encoding the Cut-homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age-related intelligence at ages 4, 6, and 8 years after a previous history of significant DD. INTERPRETATION: Our results suggest that null-allele variants, and thus haploinsufficiency of CUX1, cause an isolated phenotype of DD or ID with possible catch-up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200-207. PMID- 30014511 TI - Allogeneic Mesenchymal Stem Cells Therapy for the Treatment of Hepatitis B Virus Related Acute-on-Chronic Liver Failure. PMID- 30014510 TI - A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain. AB - OBJECTIVE: To identify novel autoantibodies for neuropathic pain (NeP). METHODS: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. RESULTS: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100beta-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti-small DRG neuron antibody-positive patients had anti-plexin D1 antibodies. Application of anti-plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti-plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. INTERPRETATION: Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208-224. PMID- 30014503 TI - Natural History of Vanishing White Matter. AB - OBJECTIVE: To comprehensively describe the natural history of vanishing white matter (VWM), aiming at improving counseling of patients/families and providing natural history data for future therapeutic trials. METHODS: We performed a longitudinal multicenter study among 296 genetically confirmed VWM patients. Clinical information was obtained via disease-specific clinical questionnaire, Health Utilities Index and Guy's Neurological Disability Scale assessments, and chart review. RESULTS: First disease signs occurred at a median age of 3 years (mode = 2 years, range = before birth to 54 years); 60% of patients were symptomatic before the age of 4 years. The nature of the first signs varied for different ages of onset. Overall, motor problems were the most common presenting sign, especially in children. Adolescent and adult onset patients were more likely to exhibit cognitive problems early after disease onset. One hundred two patients were deceased. Multivariate Cox regression analysis revealed a positive relation between age at onset and both preservation of ambulation and survival. Absence of stress-provoked episodes and absence of seizures predicted more favorable outcome. In patients with onset before 4 years, earlier onset was associated with more severe disability and higher mortality. For onset from 4 years on, disease course was generally milder, with a wide variation in severity. There were no significant differences for sex or for the 5 eIF2B gene groups. The results confirm the presence of a genotype-phenotype correlation. INTERPRETATION: The VWM disease spectrum consists of a continuum with extremely wide variability. Age at onset is a strong predictor for disease course. Ann Neurol 2018;84:274 288. PMID- 30014512 TI - Nodular Regenerative Hyperplasia Associated With Immune Checkpoint Blockade. PMID- 30014513 TI - Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease. AB - OBJECTIVE: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk. METHODS: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median (PWM)-based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments. RESULTS: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88 1.20) per 1-standard-deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83-1.17] and 0.99 [95% CI, 0.86-1.14], respectively). INTERPRETATION: We did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191 199. PMID- 30014515 TI - Sustainable method for Alzheimer dementia prediction in mild cognitive impairment: Electroencephalographic connectivity and graph theory combined with apolipoprotein E. AB - OBJECTIVE: Mild cognitive impairment (MCI) is a condition intermediate between physiological brain aging and dementia. Amnesic-MCI (aMCI) subjects progress to dementia (typically to Alzheimer-Dementia = AD) at an annual rate which is 20 times higher than that of cognitively intact elderly. The present study aims to investigate whether EEG network Small World properties (SW) combined with Apo-E genotyping, could reliably discriminate aMCI subjects who will convert to AD after approximately a year. METHODS: 145 aMCI subjects were divided into two sub groups and, according to the clinical follow-up, were classified as Converted to AD (C-MCI, 71) or Stable (S-MCI, 74). RESULTS: Results showed significant differences in SW in delta, alpha1, alpha2, beta2, gamma bands, with C-MCI in the baseline similar to AD. Receiver Operating Characteristic(ROC) curve, based on a first-order polynomial regression of SW, showed 57% sensitivity, 66% specificity and 61% accuracy(area under the curve: AUC=0.64). In 97 out of 145 MCI, Apo-E allele testing was also available. Combining this genetic risk factor with Small Word EEG, results showed: 96.7% sensitivity, 86% specificity and 91.7% accuracy(AUC=0.97). Moreover, using only the Small World values in these 97 subjects, the ROC showed an AUC of 0.63; the resulting classifier presented 50% sensitivity, 69% specificity and 59.6% accuracy. When different types of EEG analysis (power density spectrum) were tested, the accuracy levels were lower (68.86%). INTERPRETATION: Concluding, this innovative EEG analysis, in combination with a genetic test (both low-cost and widely available), could evaluate on an individual basis with great precision the risk of MCI progression. This evaluation could then be used to screen large populations and quickly identify aMCI in a prodromal stage of dementia. Ann Neurol 2018 Ann Neurol 2018;84:302-314. PMID- 30014514 TI - Subcellular origin of mitochondrial DNA deletions in human skeletal muscle. AB - OBJECTIVE: In patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain deficiency. This study aimed to identify the sub-cellular origin and potential mechanisms underlying this process. METHODS: Serial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis. RESULTS: We report respiratory chain-deficient perinuclear foci containing mtDNA deletions, which show local elevations of both mitochondrial mass and mtDNA copy number. These subcellular foci of respiratory chain deficiency are associated with a local increase in mitochondrial biogenesis and unfolded protein response signaling pathways. We also find that the commonly reported segmental pattern of mitochondrial deficiency is consistent with the three-dimensional organization of the human skeletal muscle mitochondrial network. INTERPRETATION: We propose that mtDNA deletions first exceed the biochemical threshold causing biochemical deficiency in focal regions adjacent to the myonuclei, and induce mitochondrial biogenesis before spreading across the muscle fiber. These subcellular resolution data provide new insights into the possible origin of mitochondrial respiratory chain deficiency in mitochondrial myopathy. Ann Neurol 2018;84:289-301. PMID- 30014516 TI - Clinical validation of blood/brain glutamate grabbing in acute ischemic stroke. AB - OBJECTIVE: Blood/brain-glutamate grabbing is an emerging concept in the treatment of acute ischemic stroke, where essentially the deleterious effects of glutamate after ischemia are ameliorated by coaxing glutamate to enter the bloodstream and thus reducing its concentration in the brain. Aiming to demonstrate the clinical efficacy of blood glutamate grabbers in patients with stroke, in this study, we resorted to a drug-repositioning strategy for the discovery of new glutamate grabbing drugs. METHODS: The glutamate-grabbing ability of 1,120 compounds (90% of which were drugs approved by the US Food and Drug Administration) was evaluated during an in vitro high-throughput screening campaign. Subsequently, the protective efficacy of the selected drugs was probed in an ischemic animal model and finally tested in stroke patients. RESULTS: Riboflavin (vitamin B2 ) was identified as the main hit compound. In ischemic animal models treated with riboflavin (1mg/kg), it was confirmed that blood glutamate reduction was associated with a significant reduction of infarct size. These results led to a randomized, double-blind, phase IIb clinical trial with patients with stroke. Fifty patients were randomized to 1 of the 2 study arms: the control group (placebo) and the experimental group (20mg of riboflavin [vitamin B2 Streuli@ ). Decrease in glutamate concentration was significantly greater (p < 0.029) in the treated group. Comparative analysis of the percentage improvement on the National Institutes of Health Stroke Scale score at discharge was slightly higher in the riboflavin-treated group than in the placebo group (33.7 +/- 43.7 vs 48.9 +/- 42.4%, p = 0.050). INTERPRETATION: This translational study represents the first human demonstration of the efficacy of blood glutamate grabbers in the treatment of patients with stroke, paving the way for the development of a promising novel protective therapy. Ann Neurol 2018;84:260-273. PMID- 30014517 TI - ADAPT: An algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. AB - BACKGROUND AND AIM: Given the high global prevalence of non-alcoholic fatty liver disease (NAFLD), the need for relevant non-invasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (>=F3) is the most crucial, as these individuals have the greatest risk of adverse, long-term, liver-related outcomes. We aimed to investigate the role of PRO-C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD. METHODS: We measured PRO-C3 by enzyme linked immunosorbent assay (ELISA) in two large independent cohorts with extensive clinical phenotyping and liver biopsy; 150 in the derivation and 281 in the validation cohort. A PRO-C3 based fibrosis algorithm that included Age, presence of DiAbetes, PRO-C3 (a marker of type III collagen formation), and plaTelet count ("ADAPT") was developed. RESULTS: PRO-C3 increased with fibrosis stage (rho 0.50 p<0.0001) and was independently associated with advanced fibrosis (OR=1.05, 95% CI 1.02-1.08, p= 0.003). ADAPT showed areas under the receiver operating characteristics curve (AUROC) of 0.86 (95% CI 0.79 to 0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83 to 0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase (AST) to platelet ratio index (APRI), FIB-4 and NAFLD fibrosis score (NFS) in most comparisons. CONCLUSION: PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3 based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4 and NFS. This article is protected by copyright. All rights reserved. PMID- 30014518 TI - Bronchial hyper-responsiveness in preterm-born subjects: A systematic review and meta-analysis. AB - BACKGROUND: Preterm-born survivors have increased respiratory symptoms and decreased lung function, but the nature of bronchial hyper-responsiveness (BHR) is unclear. We conducted a systematic review and meta-analysis for BHR in preterm born survivors including those with and without chronic lung disease in infancy (CLD) comparing results to term-born subjects. METHODS: We searched eight databases up to December 2016. Included articles compared BHR in preterm-born and term-born subjects. Studies reporting BHR as decreases in forced expiratory volume in 1 second (FEV1 ) after provocation stimuli were included. The analysis used Review Manager V5.3. RESULTS: From 10 638 titles, 265 full articles were screened, and 28 included in a descriptive analysis. Eighteen articles were included in a meta-analysis as they reported the proportion of subjects who had BHR. Pooled odds ratio (OR) estimates (95% confidence interval) for BHR comparing the preterm and term-born groups was 1.88 (1.32, 2.66). The majority of the studies reported BHR after a methacholine challenge or an exercise test. Odds ratio was 1.89 (1.12, 3.19) after methacholine challenge and 2.59 (1.50, 4.50) after an exercise test. Nine of fifteen articles reporting BHR in CLD subjects were included in a meta-analysis. Differences for BHR including for methacholine (OR 4.35; 2.36, 8.03) and exercise (OR 5.13; 1.82, 14.47) were greater in the CLD group compared to the term group. CONCLUSIONS: Preterm-born subjects especially those who had CLD had increased rates of BHR to direct (methacholine) and indirect (exercise) stimuli compared to term-born subjects suggesting subgroups might benefit from anti-inflammatory or bronchodilator therapies. PMID- 30014520 TI - A novel TGF-beta and H19 signaling axis in tumor-initiating hepatocytes that regulates hepatic carcinogenesis. AB - : The functions of TGF-beta in the liver vary depending on specific cell types and their temporal response to TGF-beta during different stages of hepatocarcinogenesis. Through analysis of tumor tissues from hepatocellular carcinoma (HCC) patients, we were able to cluster hepatic epithelial cell-derived TGF-beta gene signatures in association with distinct clinical prognoses. To delineate the role of hepatic epithelial TGF-beta signaling in HCC development, we employed a novel experimental system in which tumor-initiating hepatocytes (TICs) were isolated from TGF-beta receptor II floxed mice (Tgfbr2f/f ) and transplanted into the syngeneic C57BL/6J mice via splenic injection. The recipient mice were then administered Cre-expressing adenovirus to inactivate Tgfbr2 in the transplanted TICs. After latency, the Tgfbr2-inactivated TICs formed larger and more tumor nodules in the recipient livers compared to TICs without Tgfbr2 inactivation. In vitro analyses revealed that treatment of cultured TICs with TGF-beta inhibited the expression of progenitor cell factors (including Sox2). RNA-seq analysis identified H19 as one of the most upregulated long noncoding RNA (lncRNA) in association with Tgfbr2 inactivation in TICs. Tgfbr2 inactivation by Ad-Cre led to a 5-fold increase of H19 expression in TICs. Accordingly, TGF-beta treatment reduced H19 expression. We observed that forced overexpression of Sox2 in TICs increased the transcription of H19, whereas knockdown of Sox2 decreased it. Furthermore, depletion of H19 reduced the progenitor property of TICs in vitro and decreased their tumorigenic potential in vivo. Finally, we observed low level of H19 mRNA expression in human HCC tissues from patients with the epithelial TGF-beta gene signature in association with favorable prognosis. CONCLUSION: Our findings disclose a novel TGF-beta and H19 signaling axis via Sox2 in TICs that importantly regulates hepatocarcinogenesis. This article is protected by copyright. All rights reserved. PMID- 30014521 TI - School Dental Service in Sri Lanka: geo-spatial analysis of access to oral health care. AB - BACKGROUND: The School Dental Service contributes to the reduction of social inequalities in oral health among school children. AIM: To investigate the distribution of School Dental Clinics staffed by School Dental Therapists in Sri Lanka in relation to the distribution of the child population and socioeconomic status. DESIGN: School Dental Clinics were mapped using geographic information system (GIS) software and overlayed with population data of 3-13-year-old children (including poverty status). RESULTS: Overall, there was an uneven geographic distribution of the total 422 School Dental Clinics. Sri Lankan children have restricted access to school dental care in a few poverty stricken districts in the Northern, Eastern, North Central, and Uva provinces. When the geographic distribution of children by poverty status was analysed, it was found that in Sri Lanka, only 53% of the most socially disadvantaged children lived within 5 km from a School Dental Clinic, compared to 75% of the least disadvantaged. CONCLUSION: A coordinated national School Dental Service strategy is needed in response to identified areas of poor or inadequate accessibility to dental services for large parts of the child population, especially those from low socioeconomic backgrounds. PMID- 30014522 TI - Bone marrow iron score as an indicator for secondary iron overload in acute myeloid leukemia patients. AB - OBJECTIVES: Secondary iron overload due to red blood cell transfusions (RBCT) is associated with increased morbidity and mortality. However, attention for secondary iron overload and its side effects in patients with hematological malignancies may need improvement. The aim of this study was to determine the number of transfused RBCT needed to reach a maximum bone marrow iron score (BMIS). METHODS: Bone marrow iron score was independently assessed by two researchers on consecutive bone marrow samples of 35 acute myeloid leukemia (AML) patients. The slides were blinded to both researchers to prevent bias. A Kaplan Meier survival analysis was performed for estimation of the proportion of patients reaching a maximum BMIS. RESULTS: In total, 141 bone marrow specimens from 35 patients were included. The median number of RBCT to reach a maximum was 20 units (range 6-42, IQR 15-26), after a mean of 1.64 chemotherapy courses (SD 0.99). CONCLUSIONS: In conclusion, the cumulative RBCT number is associated with BMIS. Due to the considerable variation in number of RBCT to reach a maximum BMIS, BMIS instead of only considering the cumulative RBCT number may be a valuable indicator of secondary iron overload in AML patients. BMIS could guide iron-lowering therapy and/or transfusion strategies in an early stage. PMID- 30014519 TI - Preemptive-TIPS improves outcome in high-risk variceal bleeding: An observational study. AB - OBJECTIVE: Patients admitted with acute variceal bleeding (AVB) and Child Pugh C score (CP-C) or Child Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding and mortality. Preemptive TIPS (p TIPS) has been shown to improve survival in these patients but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high-risk patients. DESIGN: Multicenter, international, observational study including 671 patients from 34 centers admitted for AVB and high-risk of treatment failure. Patients were managed according to current guidelines and use of drugs and endoscopic therapy (D+E) or preemptive TIPS (p-TIPS) was based on individual center policy. RESULTS: p-TIPS in the setting of AVB is associated with a lower mortality in Child C patients compared to D+E (1 year mortality 22% vs 47% in D+E group; P=0.002). Mortality rate in CP-B+AB patients was low and p TIPS did not improve it. In CP-C and CP-B +AB patients, p-TIPS reduces treatment failure and rebleeding (1 year CIF-probability of remaining free of the composite endpoint: 92% vs 74% in the D+E group; P=0.017), development of "de novo" or worsening of previous ascites without increasing rates of hepatic encephalopathy. CONCLUSION: p-TIPS must be the treatment of choice in CP-C patients with AVB. Due to the strong benefit in preventing further bleeding and ascites, p-TIPS could be a good treatment strategy for CP-B+AB patients. This article is protected by copyright. All rights reserved. PMID- 30014523 TI - The Dual-State Luminescent Mechanism of 2,3,4,5-Tetraphenyl-1H-pyrrole. AB - 2,3,4,5-Tetraphenyl-1H-pyrrole (TePP) was synthesized by a simple one-step reaction. The compound showed a balanced emission in both the solution and solid state with the absolute quantum yield of PhiF/THF =65.6 % and PhiF/solid =74.3 %, respectively. Temperature and viscosity variation measurements demonstrated that the phenyl group at the 1-position (N-position) of the pyrrole core can act as a rotor in pyrrole-based molecules, which can consume the excited energy and reduce the molecular emission in solution. TePP without the phenyl group at the 1 position can effectively enhance the emission in solution. Single-crystal analysis showed that the phenyl groups at the 2,5-positions of pyrrole extend the molecular conjugation and lock the conformation. The phenyl groups at the 3,4 positions with a twisted conformation prevent their molecules from close packing and are helpful for aggregated emission. A delicate balance between the twisting conformation and rigid conjugation takes advantage of both ACQ and AIE luminogens. The strategy can tune the AIE, ACQ, or solution and solid dual-state emission properties of pyrrole-based molecules by simply altering the position of phenyl groups, which provides a great opportunity to explore the luminescent mechanism in greater detail and to facilitate practical applications. PMID- 30014524 TI - Predictive accuracy of serum total calcium for both critically high and critically low ionized calcium in critical illness. AB - BACKGROUND: The accuracy of total calcium and its corrected value for predicting critically high and critically low ionized calcium in critical illness is controversial. The aim of this study was to investigate whether the concentration of total serum calcium, either corrected for albumin or not, could predict critically high or low values in critical illness. METHODS: This report describes a retrospective study using the Medical Information Mart for Intensive Care (MIMIC) III database. Test panels that contained serum albumin, total calcium, and ionized calcium (named ATI panels) with order time intervals of less than one hour were extracted. The predictive accuracy of total calcium, either corrected for albumin or not, was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 12 118 ATIs with 103 critically low and 92 critically high ionized calcium results were extracted. The areas under ROC curves (AUCs) of corrected and uncorrected total calcium for predicting critically low ionized calcium were 0.69 (95% CI: 0.61-0.76) and 0.70 (95% CI: 0.63-0.78), respectively. For predicting critically high ionized calcium, the AUCs were 0.98 (95% CI: 0.97-1.00) and 0.97 (95% CI: 0.95-1.00), respectively. With positive predictive values (PPVs) of 0.05 and 0.10, the sensitivities (both corrected and uncorrected) were approximately 0.50 for predicting critically low ionized calcium and 0.95 for predicting critically high ionized calcium. CONCLUSIONS: Total calcium, either corrected for albumin or not, is not a reliable test to predict critically low ionized calcium in critical illness. Total calcium's predictive accuracy for critically high ionized calcium is high. PMID- 30014525 TI - Erectile dysfunction and atrial fibrillation: A systematic review and meta analysis. AB - OBJECTIVE: To investigate the pooled incidence or the prevalence of erectile dysfunction, and to assess the risk of erectile dysfunction in patients with atrial fibrillation. METHODS: A systematic review was carried out in the MEDLINE, EMBASE and Cochrane databases from inception through January 2018 to identify: (i) studies that reported the incidence and/or prevalence of erectile dysfunction in atrial fibrillation patients; or (ii) studies that assessed the association between atrial fibrillation and erectile dysfunction. Pooled odds ratios and 95% confidence intervals were calculated using a random effects model. RESULTS: Five observational studies (27 841 patients) were enrolled. The pooled estimated prevalence of erectile dysfunction in atrial fibrillation patients was 57% (95% confidence interval 50-64, I2 = 0). A study showed an incidence of newly diagnosed erectile dysfunction in atrial fibrillation patients of 0.96% during the mean follow-up duration of 4.67 +/- 3.20 years. There was a significant association of atrial fibrillation with an increased risk of erectile dysfunction, with a pooled odds ratio of 1.79 (95% confidence interval 1.44-2.23, I2 = 0%). The data on the risk of atrial fibrillation development in patients with erectile dysfunction were limited. A study showed the comparable risk of atrial fibrillation in patients with erectile dysfunction (odds ratio 1.03, 95% confidence interval 0.67-1.5), when compared with those without erectile dysfunction. CONCLUSIONS: The present study suggests a significant association between erectile dysfunction and atrial fibrillation. The overall estimated prevalence of erectile dysfunction among atrial fibrillation patients is 57%. However, despite limited data, the current evidence suggests a low incidence of new erectile dysfunction in atrial fibrillation patients. PMID- 30014526 TI - Structural signature of SCA3: From presymptomatic to late disease stages. AB - OBJECTIVE: Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)-based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12). METHODS: All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1-multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord. RESULTS: There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age- and sex-matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex. CONCLUSION: Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401-408. PMID- 30014527 TI - BRAF mutation leading to central nervous system rosai-dorfman disease. AB - Rosai-Dorfman disease (RDD) is an uncommon histiocytic proliferative disorder that can present in nodal, extranodal, or, extremely rarely, in central nervous system (CNS)-restricted form. RDD is characterized histologically as a non Langerhans cell histiocytosis composed of atypical CD68+ /S-100+ /CD1a- macrophages demonstrating prominent emperipolesis and effacement of the surrounding tissue. Previously thought to represent a reactive process, recent studies have raised the possibility that RDD and other histiocytic lesions, including Erdheim-Chester and Langerhans cell histiocytosis, are clonal processes linked to somatic mutations in the mitogen-activated protein (MAP) kinase pathway. Herein, we present a fatal case of RDD isolated to the CNS and used a next-generation targeted gene panel and Sanger sequencing to uncover a pathogenic deletion in the beta3-alphaC loop of the kinase domain in exon 12 of BRAF. This mutation, previously described in melanoma and Langerhans cell histiocytosis, represents the first BRAF mutation of this kind identified in RDD. These findings support the idea that RDD is a neoplastic condition and raise the possibility that inhibitors of the MAP kinase pathway may be effective in RDD. Ann Neurol 2018;83:147-152. PMID- 30014528 TI - Fetal fraction-based risk algorithm for non-invasive prenatal testing: screening for trisomies 13 and 18 and triploidy in women with low cell-free fetal DNA. AB - OBJECTIVE: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF). METHODS: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut off of >= 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively. RESULTS: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%). CONCLUSIONS: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. (c) 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. PMID- 30014529 TI - Molecular Probes for Imaging Fibrosis and Fibrogenesis. AB - Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common result of chronic tissue injury. Advances in the clinical management of fibrotic diseases have been hampered by the low sensitivity and specificity of noninvasive early diagnostic options, lack of surrogate end points for use in clinical trials, and a paucity of noninvasive tools to assess fibrotic disease activity longitudinally. Hence, the development of new methods to image fibrosis and fibrogenesis is a large unmet clinical need. Herein, an overview of recent and selected molecular probes for imaging of fibrosis and fibrogenesis by magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography is provided. PMID- 30014530 TI - The misjudgment of criminal responsibility. AB - Generally, a criminal statute must consist of two essential elements: a description of the forbidden act (actus reus) and a designation of a guilty mental state (mens rea). For a crime to be committed, an individual must commit the forbidden act with the culpable mental state. For any criminal act, both criminal liability and the possible punishment turn largely on retrospective judgments by legal decision-makers about what a defendant was or was not thinking at the time of committing the forbidden act. Given the central and foundational nature of this legal judgment, there is surprisingly little empirical study of how the mens rea construct functions. Shen and colleagues have studied the reliability of mock jurors' ability to distinguish between the various mental state categories defined in the Model Penal Code and have identified some support for jurors' ability to reliably sort "guilty minds" into their "correct" categories (Shen, Hoffman, Jones, Greene, & Marois, ). The present study builds on this work by examining mock jurors' ability to reliably and "accurately" judge a defendant's mens rea at the time of an offense under conditions reflecting how criminal jurors are tasked with judging a defendant's mens rea. It was hypothesized that folk psychology models of human behavior that generally presume a high degree of personal control and responsibility would bias individuals' judgments of others' criminal behavior in the direction of reflecting intentional and purposeful conduct. Overall, results demonstrate that, in a surprisingly high percentage of cases across many conditions, individual decision-makers are indeed likely to attribute the most culpable mental state (purpose) to defendants, even when the facts on the record are judged by legal experts to depict no more than negligent or reckless conduct. PMID- 30014531 TI - Alkali Metals-Based Energetic Coordination Polymers as Promising Primary Explosives: Crystal Structures, Energetic Properties, and Environmental Impact. AB - Coordination polymers (CPs) consisting of alkali metals (Na, K, Rb, and Cs) and a powerful nitrogen- and oxygen-rich energetic ligand (4,4'-bis(dinitromethyl)-3,3' bisnitramide-methylene-furazanate, DBMF2- ) were developed. Molecular structures of these CPs, confirmed by single-crystal X-ray diffraction analysis, indicated that the same ligand takes on a U-shaped state for Na and an N-shaped state for K, Rb, and Cs. Explosion tests demonstrated that both Na2 DBMF and K2 DBMF efficiently detonated the secondary explosive RDX. This indicates that they are both effective primary explosives. K2 DBMF exhibits better calculated detonation performance (D: 8227 m s-1 ; P: 32.5 GPa) than the primary explosive Pb(N3 )2 . In addition, toxicity tests and evaluation of their decomposition products reveal their low impact on the environment. Both experimental results and theoretical analyses indicate that the combination of alkali metals and a powerful energetic ligand can stimulate the development of primary explosives. PMID- 30014532 TI - Systematic review of psychosocial factors associated with evictions. AB - Evictions from rented accommodations are a common pathway to homelessness and can negatively impact the lives of individuals and communities worldwide. There have been only few interventions developed to address evictions, and it is important to first understand factors associated with evictions. This systematic review included all available peer-reviewed articles on the topic published in the international literature from 1900 to 2017 and identified 10 peer-reviewed studies of evictions conducted in the United States, Canada, Amsterdam and Britain. From these studies, four categories of factors associated with evictions were identified. These factors were financial hardships, sociodemographic characteristics, substance use and other health problems. While many studies had large sample sizes, the majority of studies were cross-sectional. Together, our review found that there were several salient factors known to be associated with evictions which may benefit from intervention. However, more prospective studies on evictions and development of interventions are needed. PMID- 30014533 TI - The Charcot-Marie-Tooth Health Index: Evaluation of a Patient-Reported Outcome. AB - OBJECTIVE: The development of a disease-specific patient-reported outcome for Charcot-Marie-Tooth disease is an important step in the preparation for therapeutic trials. This study describes the development of the Charcot-Marie Tooth Health Index (CMTHI). METHODS: Inherited Neuropathy Consortium Contact Registry participants were queried on the symptoms that most impacted their lives. The CMTHI was developed based on these responses. Factor analysis, assessment of test-retest reliability, known group validity, and patient interviews were utilized to refine the instrument. RESULTS: The final CMTHI contains 18 themes that capture Charcot-Marie-Tooth disease (CMT) burden. The CMTHI has a high internal consistency and test-retest reliability. The CMTHI was able to discriminate between patient groups expected to have different disease burden. The CMTHI was able to discriminate levels of disability as measured by the CMT examination score and the mobility-Disability Severity Index. INTERPRETATION: The CMTHI represents a valid and reliable outcome to assess patient-reported disease burden in CMT. Ann Neurol 2018;84:225-233. PMID- 30014534 TI - Management of phrenic nerve palsy following cardiac surgery. AB - Phrenic nerve palsy (PNP) is a potential complication of cardiac surgery. It may prolong ventilation and hospitalization and result in significant morbidity and mortality. The diagnosis and management of PNP following cardiac surgery is reviewed. PMID- 30014535 TI - Empowering elderly Iranians through a social group work intervention: A trial study to assess the effect of the intervention on participants' quality of life. AB - We designed and ran an empowerment-oriented social group work intervention to assess whether the intervention could improve the quality of life of older Iranians. The intervention consisted of nine group sessions that focused on capacity building and increasing individual competences, environmental resources and opportunities. Using a randomised controlled trial (RCT), 60 elderly people (30 men and 30 women in the intervention and control groups) from Social Services Centres in Tehran Municipality participated in this study. The WHOQOL-BREF instrument was used to measure quality of life, comparing before, after and follow-up measures between the groups and within each group. ANOVA and GEE tests were applied to analyse the data. The results showed significant progress in overall quality of life of the participants, particularly in the domains of physical health, psychological health, social relationships and environmental health. In pretest, there were no significant differences between the groups in terms of quality of life and its domains, but there were significant differences in the post- and follow-up tests. This study provides support for the empowerment oriented social group work intervention with Iranian elderly people. This kind of intervention can be a useful model for empowering older people, especially in countries where social support and health services for seniors are not yet freely available. PMID- 30014536 TI - Distinct modes of stress granule assembly mediated by the KH-type RNA-binding protein Rnc1. AB - We have previously identified the KH-type RNA-binding protein Rnc1 as an important regulator of the posttranscriptional expression of the MAPK phosphatase Pmp1 in fission yeast. Rnc1 localization in response to stress has not been elucidated thus far. Here, we report the dual roles of Rnc1 in assembly of stress granules (SGs), nonmembranous cytoplasmic foci composed of messenger ribonucleoproteins. Rnc1 can localize to poly(A)-binding protein (Pabp)-positive SGs upon various stress stimuli, including heat shock (HS) and arsenite treatment. Furthermore, Rnc1 deletion results in decreased SGs, indicating that Rnc1 is a new component and a regulator of SGs. Notably, Rnc1 translocates to the dot-like structures faster than Pabp, and this stress-induced Rnc1 translocation does not require its RNA-binding ability, as the Rnc1KH1,2,3GD mutant protein with impaired RNA-binding activity forms dots rather more efficiently than the wild-type Rnc1 upon HS. Interestingly, in the absence of stress, Rnc1 overproduction induced massive aggregation of Pabp-positive SGs and eIF2alpha phosphorylation. In clear contrast, overproduction of the Rnc1KH1,2,3GD mutant failed to induce Pabp aggregation and eIF2alpha phosphorylation, indicating that Rnc1 overproduction-induced SG assembly requires Rnc1 RNA-binding activity. Collectively, Rnc1 regulates SG assembly, dependently or independently of its RNA binding activity. PMID- 30014537 TI - Magnetic resonance imaging of masticatory muscles in basset hounds. AB - OBJECTIVES: To describe low- and high-field MRI characteristics of occult masticatory muscle lesions in basset hounds. MATERIALS AND METHODS: Retrospective review of the MR images of the heads of 44 basset hounds that had been imaged for reasons unrelated to suspected muscle disease. RESULTS: In most basset hounds, there was reduced bulk of the superficial part of the temporalis and masseter muscles together with bilaterally symmetrical T2W and T1W hyperintense signal with reduced contrast enhancement compared to normal muscle. Interpretation of various pulse sequences suggested that the affected muscle areas contained adipose tissue with no evidence of inflammation, and this was confirmed on biopsy in one dog. This pattern of changes is different from MRI changes in inflammatory myopathies. CLINICAL SIGNIFICANCE: Poor muscle bulk and MRI signal changes in the superficial parts of the temporalis and masseter muscles in basset hounds appear to be normal findings in this breed and should not be misinterpreted as evidence of an inflammatory myopathy. PMID- 30014538 TI - Hormonal influence on HIV-1 transmission in the female genital tract: New insights from systems biology. AB - Although anti-retroviral treatments have significantly slowed down the spread of the HIV-1 pandemic, approximately 2 million new infections occur every year. The majority of new infections are in sub-Saharan Africa where rates of infection are much higher in women than men. Young women are disproportionately affected and have higher susceptibility to HIV-1. The complex interactions between HIV-1 and the female genital tract (FGT) and the mechanisms regulating susceptibility in women remain incompletely understood. In this review, we focus on the current understanding of the acute events that occur in the FGT following HIV-1 exposure with a particular focus on the effect of endogenous and exogenous sex hormones on HIV-1 susceptibility. We highlight the contribution of the recent transcriptomic and proteomic studies in providing new insights. PMID- 30014539 TI - Underestimation of alcohol consumption in cohort studies and implications for alcohol's contribution to the global burden of disease. AB - BACKGROUND AND AIMS: Estimated alcohol consumption from national self-report surveys is often only 30-40% of official estimates based on sales or taxation data. Global burden of disease (GBD) estimates for alcohol adjust survey estimates up to 80% of total per capita consumption. This assumes that cohort studies needed to estimate relative risks for disease suffer less from under reporting than typical national surveys. However, there is limited evidence on which to base that assumption. This paper aims to assess the extent of underestimation of alcohol consumption in cohort studies concerning alcohol and mortality compared with official total consumption estimates. DESIGN: Comparisons of estimated per capita consumption from a comprehensive sample of cohort studies against official estimates by country and year. PARTICIPANTS: A total of 1 876 046 participants in 40 cohort studies from 18 countries on alcohol use and all cause mortality identified by systematic review. MEASUREMENTS: Alcohol consumption data from the cohort studies were converted into usual grams of ethanol per day and then to total age 15+ per capita consumption. Matched estimates were sourced from the World Health Organization (WHO) Global Health Observatory. FINDINGS: The cohort studies had mean coverages of age 15+ per capita alcohol consumption of 61.71% (ranging from 29.19% for Russia to 96.53% for Japan), after weighting estimates by sample size for within-country estimates and by number of studies per country for the overall estimate. Regional estimates were higher for the United States (66.22%) and lower for western European countries (55.35%). CONCLUSIONS: Underestimation of alcohol consumption in cohort studies is less than in typical population surveys. Because some under-coverage is caused by under-sampling heavier drinkers, the current practice of uplifting survey estimates to 80% of total population consumption in global burden of disease studies appears to be appropriate. PMID- 30014541 TI - Virtual reality objects improve learning efficiency and sustained abilities in fetal ultrasound. AB - OBJECTIVE: Virtual reality (VR) objects of fetal ultrasound (US) volumes have been proposed for teaching and learning diagnostic ultrasound. We hypothesized that VR objects improve learning efficiency and retention of diagnostic abilities. METHODS: Medical students and junior doctors were taught normal and abnormal sonographic fetal brain anatomy using conventional means (video lectures and review articles; control group) or additionally with selected VR objects from a novel fetal brain atlas (http://pb.fetal.ch; study group). Knowledge, speed of recognition and retention of diagnostic abilities were tested one and four months later. RESULTS: The study group answered significantly more questions correctly and solved the tests quicker than controls, both one and four months after the teaching. CONCLUSION: The use of VR objects significantly improves learning efficiency and knowledge retention in fetal ultrasound teaching. This article is protected by copyright. All rights reserved. PMID- 30014540 TI - Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis. AB - OBJECTIVE: Cortical spreading depolarizations (CSDs) are intense and ubiquitous depolarization waves relevant for the pathophysiology of migraine and brain injury. CSDs disrupt the blood-brain barrier (BBB), but the mechanisms are unknown. METHODS: A total of six CSDs were evoked over 1 hour by topical application of 300 mM of KCl or optogenetically with 470 nm (blue) LED over the right hemisphere in anesthetized mice (C57BL/6 J wild type, Thy1-ChR2-YFP line 18, and cav-1-/- ). BBB disruption was assessed by Evans blue (2% EB, 3 ml/kg, intra-arterial) or dextran (200 mg/kg, fluorescein, 70,000 MW, intra-arterial) extravasation in parietotemporal cortex at 3 to 24 hours after CSD. Endothelial cell ultrastructure was examined using transmission electron microscopy 0 to 24 hours after the same CSD protocol in order to assess vesicular trafficking, endothelial tight junctions, and pericyte integrity. Mice were treated with vehicle, isoform nonselective rho-associated kinase (ROCK) inhibitor fasudil (10 mg/kg, intraperitoneally 30 minutes before CSD), or ROCK-2 selective inhibitor KD025 (200 mg/kg, per oral twice-daily for 5 doses before CSD). RESULTS: We show that CSD-induced BBB opening to water and large molecules is mediated by increased endothelial transcytosis starting between 3 and 6 hours and lasting approximately 24 hours. Endothelial tight junctions, pericytes, and basement membrane remain preserved after CSDs. Moreover, we show that CSD-induced BBB disruption is exclusively caveolin-1-dependent and requires rho-kinase 2 activity. Importantly, hyperoxia failed to prevent CSD-induced BBB breakdown, suggesting that the latter is independent of tissue hypoxia. INTERPRETATION: Our data elucidate the mechanisms by which CSDs lead to transient BBB disruption, with diagnostic and therapeutic implications for migraine and brain injury. PMID- 30014542 TI - The judgements that evidence-based medicine adopts. AB - In "The evidence that evidence-based medicine omits", Brendan Clarke and colleagues argue that when establishing causal facts in medicine, evidence of mechanisms ought to be included alongside evidence of correlations. One of the reasons they provide is that correlations can be spurious and generated by unknown confounding variables. A causal mechanism can provide a plausible explanation for the correlation, and the absence of such an explanation is an indication that the correlation is not causal. Evidence-based medicine (EBM) proponents remain sceptical about this argument, one problem being that the formulation of a mechanism requires judgements that are external to the evaluation of data and experimental designs-for instance judgements of plausibility against, or derivability from, background knowledge. Because background knowledge is always incomplete and therefore unreliable, EBM proponents maintain that the plausibility of a hypothesis should be evaluated mainly by the quality of population data that yielded it. Here, I use the example of oestrogen replacement therapy's effect on coronary heart disease, an example that is often quoted in defence of the epistemic advantage of randomized controlled trials, to show that the evaluation of the most reliable study design necessarily implies the adoption of judgements that are external to the specific evidence of correlation. The exclusion of evidence of mechanism, therefore, is not effective in bypassing paradigm-dependent judgements, which are external to specific evidence. Because such judgements cannot be excluded by evidence evaluation, they can only be kept under scrutiny, or adopted uncritically. I propose that the latter option can hinder the maintenance of an active critical inquiry, as well as the analysis of experts' disagreement. PMID- 30014543 TI - The effects of variations in tissue microstructure from postmortem rat brain on the asymmetry of the water proton resonance. AB - PURPOSE: This work was performed to investigate the effects of tissue microstructure from postmortem rat brain on the shape of the water proton spectrum. METHODS: Perfusion-fixed, resected rat brains (N = 4) were imaged at 9.4T. 3D DTI and 3D echo-planar spectroscopic imaging (EPSI) data were acquired with 150 MUm isotropic resolution. DTI data were acquired over 60 directions with b = 3000 s/mm2 . Water spectra were produced from EPSI data acquired over 128 echoes, with 2.9 Hz spectral resolution. A voxel-wise metric reflecting spectral asymmetry about the peak of the resonance was computed and compared with orientation estimates from DTI data by fitting data with the susceptibility anisotropy model. RESULTS: Asymmetric broadening of the water resonance was computed for mixed populations of grey and/or white matter as determined by thresholding the fractional anisotropy. Asymmetry was shown to be differentially affected by tract orientation relative to B0 in high FA voxels, whereas low FA voxels exhibited little sensitivity. Anatomic structures in the hippocampus were also found to produce distinct changes in the water resonance. CONCLUSION: Present results demonstrate that structural variations in tissue architecture cause characteristic, reproducible changes in the water resonance shape. This suggests that water spectra are sensitive to cytoarchitectural variations in brain tissue. PMID- 30014544 TI - The impact of waiting time on patient outcomes: Evidence from early intervention in psychosis services in England. AB - Recently, new emphasis was put on reducing waiting times in mental health services as there is an ongoing concern that longer waiting time for treatment leads to poorer health outcomes. However, little is known about delays within the mental health service system and its impact on patients. We explore the impact of waiting times on patient outcomes in the context of early intervention in psychosis (EIP) services in England from April 2012 to March 2015. We use the Mental Health Services Data Set and the routine outcome measure the Health of the Nation Outcome Scale. In a generalised linear regression model, we control for baseline outcomes, previous service use, and treatment intensity to account for possible endogeneity in waiting time. We find that longer waiting time is significantly associated with a deterioration in patient outcomes 12 months after acceptance for treatment for patients that are still in EIP care. Effects are strongest for waiting times longer than 3 months, and effect sizes are small to moderate. Patients with shorter treatment periods are not affected. The results suggest that policies should aim to reduce excessively long waits in order to improve outcomes for patients waiting for treatment for psychosis. PMID- 30014545 TI - The distributed circuit within the piriform cortex makes odor discrimination robust. AB - Distributed circuits wherein connections between subcircuit components seem randomly distributed are common to the olfactory circuit, hippocampus, and cerebellum. In such circuits, activation patterns seem random too, showing no detectable spatial preference, and contrast with regions that have topographic connections between subcircuits and topographic activation patterns. Quantitative studies of topographic circuits in the neocortex have yielded common principles of organization. Whether distributed circuits share similar principles of organization is unknown because similar quantitative information is missing and understanding the way they encode information remains a challenge. We addressed these needs by providing a quantitative description of the mouse piriform cortex, a paleocortical distributed circuit that subserves olfaction. The quantitative information provided two insights. First, with a nearly parameter-free model of the olfactory circuit, we show that the piriform cortex robustly maintains odor information and discrimination ability present in the olfactory bulb. Second, the paleocortex is quantitatively different from the neocortex: it has a lower surface area density, which decreases from the anterior to posterior paleocortex contrasting with the uniform neuronal density of the neocortex. These insights might also apply to other distributed circuits. PMID- 30014546 TI - Illness perceptions of Chinese women with breast cancer and relationships with socio-demographic and clinical characteristics. AB - AIMS: The aim of the study is to explore the illness perceptions of Chinese women with breast cancer and relationships with their socio-demographic and clinical characteristics. METHODS: A descriptive, correlational, and exploratory design was used. The Chinese version of the Revised Illness Perception Questionnaire was modified and used to collect data. RESULTS: Of the 16 common symptoms of breast cancer, the participants recognized only 2.81 symptoms, on average. Of the 6 causal factors, "uncontrollable factors" had the highest mean score, while "behavioural factors" received the lowest score. Most of the participants knew little about the disease, perceived that this illness is cyclic in nature and would not last for a long time, believed that the illness could have serious consequences but could be controlled, and reported having negative emotional responses to this illness. Most of the dimensions of illness perception were significantly correlated with one another. Furthermore, some socio-demographic and clinical characteristics were confirmed to be predictors of illness perceptions. CONCLUSIONS: These findings suggest that illness perceptions should be regarded as a whole to guide the coping process of Chinese women with breast cancer and provide new clinical information to support care for this group. PMID- 30014547 TI - The vividness of imagining emotional feelings in positive situations is attenuated in non-clinical dysphoria and predicts the experience of positive emotional feelings. AB - OBJECTIVE: The vividness of imagining emotional feelings in positive situations (EFP) in non-clinically dysphoric and non-dysphoric individuals and its relation to dysphoric and positive feelings was examined. METHOD: Participants were university students in Study 1 (N = 106, 84 women; 18-45 years), in Study 2 (N = 43, 39 women; 20-47 years), in Study 3 (N = 109, 92 women; 18-50 years) who filled out a set of questionnaires assessing depressive symptoms, cognition measures, and then completed an affective imagery task, using a cross-sectional design. RESULTS: Non-clinically dysphoric participants imagined less vividly EFP than non-dysphoric participants. The vividness of imagining EFP accounted for group differences in positive feelings beyond positive and negative cognition and negative mood. CONCLUSIONS: In addition to deficits in the general imagery of positive events, the attenuation of vividness of EFP in non-clinical dysphoric individuals warrants attention as a separate pathway by which non-clinically dysphoric individuals develop deficiencies of conscious positive feelings. PMID- 30014548 TI - Medication adherence for resistant hypertension: Assessing theoretical predictors of adherence using direct and indirect adherence measures. AB - OBJECTIVES: This study examined theoretical predictors of long-term medication adherence (i.e., treatment-related beliefs, coherence of beliefs from experience with medication, habit strength, and pill burden) for patients with apparent treatment-resistant hypertension in primary care, using a composite adherence score derived from direct and indirect measures (i.e., prescription refill, self report, and bioanalytical assays of urine). DESIGN: Cross-sectional study. METHODS: Individual patient records were screened for prescription refill adherence. Patients provided a urine sample for adherence screening and completed a battery of psychometric scales, including two self-report adherence measures (N = 204). Convergence of adherence measures was assessed, a composite adherence score was calculated, and hierarchical multiple regression was used to examine the role of theoretical predictors of adherence. RESULTS: Non-adherence estimates ranged from 20.3 to 41.1%, depending on the assessment method used. Associations among adherence measures were weak to moderate (rho = .00-.53). Medication-taking habit strength was the strongest predictor of adherence, explaining 19% incremental variance in adherence beyond treatment-related beliefs. Beliefs and coherence did not predict adherence, even for patients with weaker habits. Pill burden was not associated with habit strength or adherence for this sample. CONCLUSIONS: Associations among unique adherence measures were weak overall, providing further evidence that multiple measures are necessary to accurately assess adherence. Habit strength is a key predictor of adherence for chronic conditions. Both habit strength and pill burden represent important intervention targets for improving long-term medication adherence. Longitudinal inception studies are needed to properly test Common-Sense Model propositions and elucidate the role of beliefs, coherence, and habits in predicting adherence at various stages of the chronic illness trajectory. Statement of contribution What is already known on this subject? Non-adherence to antihypertensives is a leading cause of apparent treatment-resistant hypertension (aTRH). Behaviour maintenance (vs. initiation) factors may be more predictive of long-term adherence. What does this study add? Associations among direct and indirect measures of adherence are generally weak. Habit strength is the strongest predictor of long-term adherence for aTRH in primary care. Inception studies are needed to further validate Common Sense Model propositions. PMID- 30014549 TI - Detecting introgression despite phylogenetic uncertainty: The case of the South American siskins. AB - Genetic introgression among closely related species is a widespread phenomenon across the Tree of Life and could be an important source of adaptive variation during early stages of diversification. In particular, genomic studies have revealed that many rapidly radiating clades tend to have complex, reticulate evolutionary histories. Although rapid radiations appear to be susceptible to introgression, they present special challenges for its detection because formal tests require accurate phylogenies, and paradoxically, introgression itself may obscure evolutionary relationships. To address this methodological challenge, we assessed introgression in a recent, rapid avian radiation in the Andes, the South American siskins (Spinus). Using ~45,000 SNPs, we estimated the Spinus phylogeny using multiple analytical approaches and recovered four strongly conflicting topologies. We performed a series of complimentary introgression tests that included valid tests for each of the likely species trees. From the consilience of test results, we inferred multiple introgression events among Andean Spinus in a way that was robust to phylogenetic uncertainty in the species tree. Positive tests for introgression were corroborated by independent population structure and ancestral assignment analyses, as well as a striking geographic pattern of mitochondrial haplotype sharing among species. The methodological approach we describe could be applied using any genomewide data, including SNP data, for clades without fully resolvable species trees. Our discovery of multiple introgression events within the Andean radiation of Spinus siskins is consistent with an emerging paradigm, that introgression tends to accompany the early stages of diversification. PMID- 30014550 TI - The SNP43 (G/A) polymorphism in CAPN10 gene confers an increased risk of cognitive impairment in cerebral small vessel disease. AB - BACKGROUND: Cognitive impairment, significantly reducing processing speed and executive function, is the critical consequence of cerebral small vessel disease (SVD), in which genetic variations have been studied. In this study, we explore the role of SNP43 (G/A) and SNP63 (C/T) polymorphism in the CAPN10 on cognitive impairment process in cerebral SVD. METHODS: Cerebral SVD patients (n = 224) and healthy controls (n = 187) were recruited. The relationship between frequency distribution of SNP43 (G/A) and SNP63 (T/C) genotype and allele in CAPN10 gene, and cognitive impairment was examined. The independent risk factors for cognitive impairment in SVD were determined by logistic regression analysis. RESULTS: Accordingly, the frequency distribution of genotype and allele at SNP43 (G/A) was significantly different between cerebral SVD patients and healthy controls. Cerebral SVD patients with GG genotype were more susceptible for cognitive impairment, whereas cerebral SVD patients with GA + AA genotype were less possible to suffer from cognitive impairment, compared with those with GG genotype. And also, cerebral SVD does not include SNP63 (C/T) to associate with cognitive impairment, and SNP43 (G/A), total cholesterol, triglyceride, low density lipoprotein, and high-density lipoprotein were independent risk factors for cognitive impairment in SVD. CONCLUSION: Our study provides evidence that SNP43 (G/A) in the CAPN10 gene increases the risk of cognitive impairment in SVD patients. Besides it is proven that, patients with G allele are more susceptible to suffer from cerebral SVD with worse cognitive impairment. PMID- 30014551 TI - Synthesis of a Structure-Definite alpha-Cyclodextrin-Based Macromolecular [3]Rotaxane Using a Size-Complementary Method. AB - The challenging synthesis of an alpha-cyclodextrin (CD)-based macromolecular rotaxane with definite structure was fulfilled using a size-complementary method. A new peracetylated (PAc) alpha-CD-based size-complementary [3]rotaxane was prepared and its thermal dissociation kinetics studied. The de-slippage mechanism was found to be different from that of the native alpha-CD-based system. PAcalpha CD-based size-complementary [3]rotaxanes were employed as initiators for a ring opening polymerization of epsilon-caprolactone to obtain the macromolecular [3]rotaxanes. Detailed investigation of component dissociation showed the highly movable character of the wheel on the polymer main chain. A general method for controlling the movement of wheels in rotaxane frameworks, even in polymer systems, was established. This will enable the development of new supramolecular architectures and molecular machines. PMID- 30014552 TI - Burroughs' 'Letter from a master addict to dangerous drugs': a forgotten classic. PMID- 30014554 TI - Site-Selective C-S Bond Formation at C-Br over C-OTf and C-Cl Enabled by an Air Stable, Easily Recoverable, and Recyclable Palladium(I) Catalyst. AB - This report widens the repertoire of emerging PdI catalysis to carbon-heteroatom, that is, C-S bond formation. While Pd0 -catalyzed protocols may suffer from the formation of poisonous sulfide-bound off-cycle intermediates and lack of selectivity, the mechanistically diverse PdI catalysis concept circumvents these challenges and allows for C-S bond formation (S-aryl and S-alkyl) of a wide range of aryl halides. Site-selective thiolations of C-Br sites in the presence of C-Cl and C-OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X-ray, and reactivity data support dinuclear PdI catalysis to be operative. Contrary to air-sensitive Pd0 , the active PdI species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling. PMID- 30014555 TI - Panobinostat inhibits the proliferation of CD34+ CD38- cells under stimulation of hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia. AB - BACKGROUND: Encouraging responses to histone deacetylase inhibitors have been reported for hematologic malignancies. Here, we report effects of panobinostat and 5-azacytidine on the proliferation of juvenile myelomonocytic leukemia (JMML) CD34+ cells. PROCEDURE: We previously reported that stimulation of JMML CD34+ cells with stem cell factor and thrombopoietin on irradiated murine AGM-S3 cells led to substantial expansion of JMML CD34+ cells that contained leukemic stem cells capable of transplantation into immunodeficient mice. Using this culture system, we evaluated effects of panobinostat and 5-azacytidine on the proliferation of JMML CD34+ cells. RESULTS: Panobinostat dose dependently reduced the numbers of day 7 CD34+ cells generated under stimulation of hematopoietic growth factors on AGM-S3 cells in all eight patients with JMML. These patients possessed various genetic and/or karyotypic abnormalities. CD34+ CD38- cells were substantially more sensitive to panobinostat at 10 and 20 nM than CD34+ CD38+ cells. Panobinostat, however, failed to influence the ability of AGM-S3 cells to stimulate JMML CD34+ cell production. In contrast to HL60 cells, apoptosis and cell cycle arrest in panobinostat-mediated inhibition were at low levels in JMML. The inhibitor also suppressed the factor-dependent proliferation of normal CD34+ cells on AGM-S3 cells. Meanwhile, no substantial inhibitory effects of 5 azacytidine on the growth of JMML CD34+ cells were observed. CONCLUSIONS: These results demonstrate that panobinostat directly suppresses the growth of JMML CD34+ cells, in particular CD34+ CD38- cells, regardless of the genetic abnormality type, suggesting that it is a useful antileukemic drug to target JMML stem cells at a pretransplant stage. PMID- 30014556 TI - Agomelatine, a novel therapeutic option for the management of irritable bowel syndrome. AB - WHAT IS KNOWN AND OBJECTIVE: Irritable bowel syndrome (IBS) is a complex and chronic, relapsing gastrointestinal condition that affects more than 10% of the population worldwide. There is a pressing need for new therapeutic strategies in the management of IBS. Increasing research has shed light on the modulatory functions of melatonin on pain, local inflammation and motility in the gastrointestinal tract. However, melatonin's effects are limited by its extensive first-pass metabolism and short half-life. COMMENT: Agomelatine, a naphthalene analog of melatonin, is a novel melatonergic drug with a longer half-life and a comparatively greater affinity for MT1 and MT2 melatonin receptors than melatonin itself. Agomelatine also shows serotonin 5-HT3 receptor antagonist activity, which is theoretically of benefit for patients with IBS with diarrhoea (IBS-D) as it regulates gastrointestinal motility and visceral sensory mechanisms. Although only one clinical study of agomelatine use in patients with IBS exists, we believe that agomelatine is a safe and efficacious multimodal agent with untapped potential in the management of IBS. WHAT IS NEW AND CONCLUSION: Numerous comorbidities are associated with IBS, including chronic pain syndromes and psychiatric disorders. Coupled with its antidepressant actions, agomelatine could serve as an effective adjunct therapeutic. Agomelatine should be considered in our therapeutic armamentarium for IBS management. PMID- 30014557 TI - Density Functional Characterization of the 4f-Relevant Electronic Transitions of Lanthanide-Doped Lu2 O3 Luminescence Materials. AB - Herein, we present a theoretical study on trivalent-lanthanide-substituted luminescence materials (Lu2 O3 : Ln; with Ln=Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb) by using first-principles calculations based on the Coulomb-corrected density functional theory (DFT+U). Large-scale calculations of electronic the structure are carried out with the goal of pinpointing the 4f-relevant electronic transition rule and optical features of Lu2 O3 : Ln systems. A characteristic double "zigzag" pattern for Ln3+ and Ln2+ energy levels is observed. Accordingly, four types of electric-dipole allowed transition modes are predicted in the lanthanide-doped Lu2 O3 family, with Lu2 O3 : Eu and Lu2 O3 : Yb showing superior absorption features. Finally, this 4f-controlled electronic transition image provides useful guidance for designing new luminescence materials with desired properties. PMID- 30014553 TI - Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease. AB - OBJECTIVE: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181 , and whether these increases are associated with accelerated brain volume loss and memory decline. METHODS: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. RESULTS: In mutation carriers, Met66 carriers showed faster memory decline (4*), hippocampal volume loss (16*), and CSF tau and ptau181 increases (6*) than Val66 homozygotes. BDNF did not influence rates of cortical beta-amyloid accumulation or change in CSF Abeta42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical beta-amyloid accumulation, or change in any CSF measures of tau, ptau181 , and CSF Abeta42 . INTERPRETATION: As in sporadic AD, the deleterious effects of beta-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424-435. PMID- 30014558 TI - A brief campaign to prevent diabetic ketoacidosis in children newly diagnosed with type 1 diabetes mellitus: The NO-DKA Study. AB - OBJECTIVE: New-onset diabetic ketoacidosis (NO-DKA) is entirely preventable with early recognition of the symptoms of type 1 diabetes mellitus (T1D). In this study, we aimed to assess whether a simple and easily delivered educational campaign could reduce the risk of DKA. METHODS: A poster highlighting key features of new-onset T1D was delivered once a year over 2 years to mailboxes of over 460 000 individual residential households in the Auckland region (New Zealand). In the first year, the campaign poster was also delivered to all general practices in the region. Families of all newly diagnosed cases of T1D in children answered a brief questionnaire to ascertain whether the campaign reached them. RESULTS: Over the 24-month period covered by this study, 132 new cases of T1D were diagnosed in children and adolescents in Auckland. There were 38 cases (28.8%) of DKA, which is similar to the average over the previous 5-year period (27.0%). The caregivers of three children reported both seeing the campaign poster and seeking medical attention as a result. None of these three children were in DKA at diagnosis; they were aged 6.3 to 9.7 years, and of New Zealand European ethnicity. CONCLUSIONS: A non-targeted campaign to raise awareness of diabetes symptoms in youth led only a few caregivers to seek timely medical attention. Overall, this once-yearly untargeted campaign to raise awareness of diabetes symptoms in youth had limited impact. More effective strategies are required, possibly involving sustained targeted education of medical practitioners. PMID- 30014559 TI - "Doubtful accepting": A grounded theory study of living with cardiac resynchronization therapy. AB - Heart failure is associated with low quality of life and a high mortality rate. There is limited information about patients' experiences of living with cardiac resynchronization therapy (CRT). In the present study, we sought to explore the process of living with CRT defibrillator. This qualitative study was completed from December 2014 to April 2016 using a grounded theory approach. Twenty semistructured interviews were held with 17 patients with heart failure. Data analysis was done via a previously-published approach. The core category of the process of living with the device is "doubtful accepting". This process includes three sequential phases: losing integrity, attempting to cope with the device, and coexisting. The process takes place in a context of barriers and facilitators, and results in a wide spectrum of outcomes, from frustration to empowerment. Nurses' awareness of this process can help them provide higher quality care, strengthen facilitators and reduce barriers to the process, and enable patients to effectively use coping strategies. PMID- 30014560 TI - Predicting complications in hepatic resection for colorectal liver metastasis: the lymphocyte-to-monocyte ratio. AB - BACKGROUND: Colorectal cancer is one of the most common malignancies worldwide; whilst approximately 20% of patients have hepatic disease at presentation. Hepatic resection remains the gold standard of care; however, it is associated with significant morbidity. We sought to establish whether the lymphocyte-to monocyte ratio (LMR) could help predict post-operative complications, thus improving patient outcomes. METHODS: We performed a retrospective cohort study of patients undergoing hepatic resection at a single centre. Baseline demographics and complications within 30 days following surgery were recorded. White blood cell counts and C-reactive protein (CRP) were recorded pre-operatively, and until post-operative day 7. RESULTS: A total of 188 operations were included. About 47.3% of resections had a complicated recovery, of which 31.46% were major. The median LMR was 1.29 across the cohort, 1.60 for uncomplicated procedures, 1.14 for those with complications and 0.85 in major complications. For detecting major complications versus an uncomplicated recovery, median LMR was the best parameter (area under the curve 0.78), whilst it was the only parameter to accurately predict such complications within 48 hours of surgery (area under the curve 0.72 on day 1). It was consistently the most accurate parameter at detecting uncomplicated versus complicated recovery, minor versus major complications, and major complications versus an uncomplicated recovery, at numerous timepoints over the post-operative period. CONCLUSION: The LMR appears better at predicting complications following hepatic resection for colorectal liver metastases, as opposed to conventionally measured parameters. PMID- 30014561 TI - A simple gold nanoplasmonic SERS method for trace Hg2+ based on aptamer regulating graphene oxide catalysis. AB - The as-prepared graphene oxide (GO) exhibited a strong catalytic effect on reduction of HAuCl4 by trisodium citrate to form gold nanoplasmons (AuNPs) with a strong surface-enhanced Raman scattering (SERS) effect at 1615 cm-1 in the presence of molecular probe Victoria blue 4R (VB4r). SERS intensity increased with nanocatalyst GO concentration due to the formation of more AuNP substrates. The aptamer (Apt) of Hg2+ can bind to GO to form Apt-GO complexes, which can strongly inhibit nanocatalysis. When target Hg2+ is present, the formed stable Hg2+ -Apt complexes are separated from the GO surface, which leads to GO catalysis recovery. The enhanced SERS signal was linear to Hg2+ concentration in the range 0.25-10 nmol/L, with a detection limit of 0.08 nmol/L Hg2+ . Thus, a new gold nanoplasmon molecular spectral analysis platform was established for detecting Hg2+ , based on Apt regulation of GO nanocatalysis. PMID- 30014562 TI - The sFlt-1/PlGF Ratio: ruling out pre-eclampsia for up to 4 weeks and the value of retesting. AB - OBJECTIVE: The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is mostly elevated some time before and at the clinical onset of preeclampsia. The PROGNOSIS study validated a ratio cut-off of <= 38 to rule out onset of preeclampsia for 1 week in women with suspected disease. This analysis assessed the mid-term predictive value of the sFlt-1/PlGF ratio and the effect of repeat measurement vs a single test. METHODS: An exploratory post-hoc analysis of data from PROGNOSIS was performed in pregnant women (>= 18 years, gestational weeks 24 + 0 to 36 + 6 days at Visit 1) with suspected preeclampsia. Serum samples were collected at first clinic visit and weekly thereafter; sFlt-1 and PlGF levels were measured using Elecsys(r) sFlt-1 and PlGF immunoassays. We examined whether the 1-week rule-out value of <= 38 sFlt-1/PlGF ratio could predict the absence of preeclampsia 2, 3, and 4 weeks post-baseline. We also assessed the value of repeat sFlt-1/PlGF testing by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first sample in women with/without preeclampsia/adverse fetal outcome. RESULTS: In an analysis of 550 women, preeclampsia was ruled out 2 and 3 weeks post-baseline with high negative predictive value (NPV; 97.9% and 95.7%, respectively). Within 4 weeks, preeclampsia was ruled out with high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Women who developed preeclampsia had significantly larger median increases in sFlt-1/PlGF ratio 2 and 3 weeks post initial visit, vs those who did not (2 weeks: Delta 31.22 vs Delta 1.45, P < 0.001; 3 weeks: Delta 48.97 vs Delta 2.39, P < 0.001). Women who developed preeclampsia and/or a fetal adverse outcome had a significantly greater median increase in sFLt-1/PlGF ratio over the same period (2 weeks: Delta 21.22 vs Delta 1.40, P < 0.001; 3 weeks: Delta 34.95 vs Delta 2.30, P < 0.001). CONCLUSION: The Elecsys(r) sFlt-1/PlGF immunoassay ratio can help to rule out preeclampsia for 4 weeks in women with suspected preeclampsia. This article is protected by copyright. All rights reserved. PMID- 30014563 TI - Ultrasonographic features of colonic B-cell lymphoma with mesenteric lymphomatosis in a cat. AB - A 10-year-old male neutered Domestic Shorthair cat was referred for chronic inappetence, weight loss, and hematochezia and an abdominal mass. Abdominal ultrasonography revealed a heterogeneously hypoechoic transmural colonic mass, which extended beyond the serosa and into the adjacent mesentery. Cytology and clonality assays of fine needle aspirates of the mass and mesenteric nodules yielded a diagnosis of B-cell lymphoma. Colonic lymphoma with mesenteric involvement can have a similar appearance to carcinomatosis, therefore a definitive diagnosis requires sampling and further testing of the mesenteric lesions. PMID- 30014564 TI - The impact of contextual information on the emotion recognition of children with an intellectual disability. AB - BACKGROUND: Research suggests that having relevant contextual information can help increase the accuracy of emotion recognition in typically developing (TD) individuals and adults with an intellectual disability. The impact of context on the emotion recognition of children with intellectual disability is unknown. METHOD: Emotion recognition tasks, which varied in terms of contextual information, were completed by 102 children (45 with and 57 without intellectual disability). RESULTS: There was a significant effect of age and group, with older and TD children performing better on average. There were significant group by condition interactions, whereby children with intellectual disability were more accurate at identifying emotions depicted by line drawings compared with photos with contextual information that was not directly related to the emotion being depicted. The opposite was found for TD children. CONCLUSIONS: These results have implications for socio-emotional interventions, such as universal school programmes. PMID- 30014566 TI - Clinical application of magnetic resonance elastography in chronic liver disease. AB - Recent evidence highlighted that the accurate assessment of liver fibrosis is important for evaluating the progression of chronic liver disease. During the past decade, many non-invasive methods have been developed to reduce the need for core-needle biopsy in fibrosis staging and to overcome its limitations, such as invasiveness, high cost, low reproducibility, and poor patient consent. The diagnostic performance of magnetic resonance elastography (MRE) is promising for use in clinical practice to evaluate not only liver fibrosis, but also survival and major clinical end-points such as liver decompensation, portal hypertension, development of hepatocellular carcinoma, and surgical outcomes. Together with other clinical markers, MRE can be used to better categorize patients with advanced fibrosis and cirrhosis, and assign them to different classes of risk for significant clinical outcomes. This review discusses clinical applications of MRE in the management strategy of patients with chronic liver disease. PMID- 30014565 TI - Randomized controlled trial of an oral appliance (SomnoDent) for sleep-disordered breathing and cardiac function in patients with heart failure. AB - In patients with heart failure (HF), sleep-disordered breathing (SDB) is a common comorbidity and a risk factor for poor clinical outcomes. SDB can be ameliorated by continuous positive airway pressure; however, inadequate adherence remains a major cause of treatment failure. On the other hand, the efficacy of oral appliance (OA) has been proved in orthodontics and otolaryngology, although the efficacy of OA in patients with HF remains to be elucidated. This trial aims to determine the efficacy of OA for SDB in patients with HF. Patients with HF undergoing optimal medical therapy who were diagnosed as having SDB (apnea hypopnea index [AHI] >= 10 and percentage of central AHI per total AHI <= 70%) by using polysomnography (PSG) will be enrolled in the present study. Either patients with HF with reduced ejection fraction (left ventricular ejection fraction [LVEF] <= 50%) or HF with preserved ejection fraction (history of hospitalization because of acute decompensated HF) or plasma B-type natriuretic peptide (BNP) level >= 100 pg/mL will be included. Each patient will be randomly assigned into active OA or sham OA. PSG, laboratory, and echocardiographic data will be obtained after 3 months of intervention. The main outcome measures are AHI, plasma BNP, and E/e' determined with echocardiography. Furthermore, overnight urinary catecholamine, 6-min walk distance, Epworth sleepiness scale, and health-related quality of life will be assessed simultaneously. This trial started on April 1, 2017, and the projected end date is March 31, 2019. This study was registered in the University Hospital Medical Information Network (UMIN000025731). PMID- 30014567 TI - High flow nasal cannulae versus non-invasive ventilation in moderate hypercapnic respiratory failure: Different roads, same destination but doubtful equality. PMID- 30014568 TI - Pet exposure in the family during pregnancy and risk for type 1 diabetes-The prospective ABIS study. AB - BACKGROUND: The autoimmune process later leading to type 1 diabetes (T1D) seems to start very early in life. Different viruses have been suspected to contribute to the development of T1D, some already during pregnancy. As viruses may be hosted by animals and from them transferred to humans we decided to investigate if exposure to pets during pregnancy is related to later development of T1D. METHODS: ABIS (All Babies in Southeast Sweden)-is a prospective population-based cohort study of unselected children born in southeast Sweden between Oct first 1997 to Oct first 1999. Parents of 16 384 children answered a questionnaire within 3 days after birth including information about exposure to different pets. The ABIS registry has been connected to the National Registry of diagnosis and also the national Registry of Drug prescriptions so we know that 137 children have got T1D, and they were compared with the non-diabetic population. RESULTS: During pregnancy, 45.5% of the mothers had pet animals at home. Most common were cats (25.0%) and dogs (18.7%). Neither exposure to dogs (OR = 1.27, P = 0.23) or cats (OR = 0.81, P = 0.31) were associated to later T1D risks. However, exposure to hamsters increased the T1D risk (OR 4.21, P = 0.0007). In a multiple regression this association remained (P = 0.005) when adjusted for other possible risk factors. CONCLUSIONS: Exposure to hamster during pregnancy seems to increase the risk of T1D in the child. One possibility could be infection by virus hosted by the pet. PMID- 30014570 TI - Objective measurements of the atlantoaxial joint on radiographs performed without flexion can increase the confidence of diagnosis of atlantoaxial instability in toy breed dogs. AB - Toy breed dogs are overrepresented for atlantoaxial instability. Radiography is a standard diagnostic test, however published toy breed-specific radiographic measurements are lacking and diagnosis remains largely subjective. Aims of this retrospective, diagnostic accuracy study were to describe normal values and determine whether some quantitative radiographic criteria strongly support a diagnosis of atlantoaxial instability specific to toy breed dogs. Neutral lateral and ventrodorsal radiographs of 102 toy breed dogs (92 control, 10 affected) were reviewed. The median C1-C2 overlap (the distance of overlap between the C2 spinous process and the dorsal arch of C1) was +4.65 mm in control dogs and -5.00 mm in atlantoaxial instability cases. A C1-C2 overlap <= +1.55 mm was the most sensitive (100%) and specific (94.5%) radiographic measurement in the diagnosis of atlantoaxial instability. Three relative measurements were performed: the ventral atlantodental interval to dorsal atlantodental interval ratio, the dens/C2 ratio, and the C1-C2 angle. These three relative measurements had good specificity (94.5, 86.9, and 98.9%, respectively), lower sensitivity (80.0, 66.7, and 60.0%, respectively), and were not influenced by body weight (P > 0.05). Absolute measurements (including absolute dens length and atlantoaxial distance) were significantly correlated with body weight (P < 0.05) diminishing their utility in the diagnosis of atlantoaxial instability. Decreased C1-C2 overlap strongly supports atlantoaxial instability. The ventral atlantodental interval/dorsal atlantodental interval ratio, dens/C2 ratio, and C1-C2 angle may provide further support but may be normal in individual cases. PMID- 30014569 TI - Blockade of receptors of advanced glycation end products ameliorates diabetic osteogenesis of adipose-derived stem cells through DNA methylation and Wnt signalling pathway. AB - OBJECTIVES: Diabetes mellitus-related osteoporosis is caused by the imbalance between bone absorption and bone formation. Advanced glycation end products (AGEs) are considered a cause of diabetic osteoporosis. Although adipose-derived stem cells (ASCs) are promising adult stem cells in bone tissue regeneration, the ability of osteogenesis of ASCs in diabetic environment needs to explore. This study aimed to investigate the influence of AGEs on the osteogenic potential of ASCs and to explore the signalling pathways involved in its effect. MATERIALS AND METHODS: ASCs were isolated from inguinal fat and cultured in osteogenic media with or without AGEs and FPS-ZM1, an inhibitor of receptor for AGEs (RAGE). Alizarin red-S, Oil Red-O and Alcian blue staining were used to confirm osteogenic, adipogenic and chondrogenic potential of ASCs, respectively. Immunofluorescence, western blotting and real-time PCR were used to measure changes in markers of osteogenic differentiation, DNA methylation and Wnt signalling. RESULTS: The multipotentiality of ASCs was confirmed. Treated with AGEs, OPN and RUNX2 expressions of ASCs were reduced and there was a noticeable loss of mineralization, concomitant with an increase in the expression of RAGE, 5 MC, DNMT1 and DNMT3a. AGEs treatment also led to a loss of Wnt signalling pathway markers, including beta-Catenin and LEF1, with an increase in GSK-3beta. Treatment with the RAGE inhibitor, FPS-ZM1, rescued AGEs-induced loss of osteogenic potential, modulated DNA methylation and upregulated Wnt signalling in ASCs. CONCLUSIONS: Our results demonstrate that AGEs-RAGE signalling inhibits the osteogenic potential of ASCs under osteoinductive conditions by modulating DNA methylation and Wnt signalling. FPS-ZM1 can rescue the negative effects of AGEs and provide a possible treatment for bone tissue regeneration in patients with diabetic osteoporosis. PMID- 30014571 TI - CrossTalk proposal: mucosal acidification drives early progressive lung disease in cystic fibrosis. PMID- 30014572 TI - Preliminary evaluation of quince (Cydonia oblonga Mill.) fruit as extraction source of antioxidant phytoconstituents for nutraceutical and functional food applications. AB - BACKGROUND: Quince (Cydonia oblonga) fruits can be considered as starting material for the extraction of health-promoting phytochemicals, to be exploited in food and nutraceuticals. In the present work, liquid chromatography coupled with diode array detection and tandem mass spectrometry analysis allowed the study of the phytochemical composition of quince fruits and to compare it with those of six commercial apple varieties. RESULTS: The distribution and quantification of secondary metabolites in peel and pulp were studied and compared with six commercial apple varieties. Furthermore the in vitro antioxidant activity was determined by 2,2-diphenyl-2-picrylhydrazyl (DPPH) assay. Quince fruit presented significant amounts of shikimic and quinic acid derivatives, as well as flavonoids and procyanidins. Compared with apple, quince fruit composition was characterized by the presence of 4-caffeoylshikimic acid, 4 caffeoyl quinic acid, quercetin-3,7-diglucoside, kaempferol-3-O-rhamnoside and kaempferol-7-O-glucoside, and the dihydrochalcones were not detectable. The peel showed the highest contents of phenolics, whereas 3-O-caffeoylquinic acid was the most abundant compound in the quince pulp. The Pearson correlation index was calculated considering the quantitative amount of the phenolic constituents and the radical scavenging activity toward DPPH. both for peel and pulp extracts. CONCLUSIONS: This study highlighted the presence of significant amounts of valuable secondary metabolites in quince fruit, in particular the procyanidins and caffeoyl esters with shikimic and quinic acid. Notably, owing to the higher content in phenolic compounds and the stronger antioxidant capacity compared with the other fruits considered, the use of C. oblonga as a source of antioxidant can be valuable in nutraceuticals, revealing new possible applications of quince fruit. (c) 2018 Society of Chemical Industry. PMID- 30014574 TI - Should I stay or should I go? Approach/avoidance conflict and emotional functioning. AB - Personality has long held a prevalent place in the pantheon of psychological research. In the last 40 years, neuropsychological models of personality have become a popular predictor of human behaviour and emotionality. With a particular focus on Gray's Reinforcement Sensitivity Theory, this study investigated the interaction of high Behavioural Activation System (BAS) and Behavioural Inhibition System (BIS) as a predictor of emotional functioning. Participants (n = 499) recruited from the community completed an online survey composed of questions on demographic information, behavioural inhibition and activation, emotional instability and indices of depression, anxiety and mixed depression anxiety. Consistent with our primary hypothesis, the interaction of high BAS * BIS predicted emotional instability using an observed variable path model. This was subsequently associated with depression, anxiety and mixed depression-anxiety symptoms. Future avenues for research using BIS/BAS monitoring in clinical practice and study limitations are discussed. (c) 2018 John Wiley & Sons, Ltd. PMID- 30014575 TI - Multiple imputation in Cox regression when there are time-varying effects of covariates. AB - In Cox regression, it is important to test the proportional hazards assumption and sometimes of interest in itself to study time-varying effects (TVEs) of covariates. TVEs can be investigated with log hazard ratios modelled as a function of time. Missing data on covariates are common and multiple imputation is a popular approach to handling this to avoid the potential bias and efficiency loss resulting from a "complete-case" analysis. Two multiple imputation methods have been proposed for when the substantive model is a Cox proportional hazards regression: an approximate method (Imputing missing covariate values for the Cox model in Statistics in Medicine (2009) by White and Royston) and a substantive model-compatible method (Multiple imputation of covariates by fully conditional specification: accommodating the substantive model in Statistical Methods in Medical Research (2015) by Bartlett et al). At present, neither accommodates TVEs of covariates. We extend them to do so for a general form for the TVEs and give specific details for TVEs modelled using restricted cubic splines. Simulation studies assess the performance of the methods under several underlying shapes for TVEs. Our proposed methods give approximately unbiased TVE estimates for binary covariates with missing data, but for continuous covariates, the substantive model-compatible method performs better. The methods also give approximately correct type I errors in the test for proportional hazards when there is no TVE and gain power to detect TVEs relative to complete-case analysis. Ignoring TVEs at the imputation stage results in biased TVE estimates, incorrect type I errors, and substantial loss of power in detecting TVEs. We also propose a multivariable TVE model selection algorithm. The methods are illustrated using data from the Rotterdam Breast Cancer Study. R code is provided. PMID- 30014573 TI - Interkingdom microbial consortia mechanisms to guide biotechnological applications. AB - Microbial consortia are capable of surviving diverse conditions through the formation of synergistic population-level structures, such as stromatolites, microbial mats and biofilms. Biotechnological applications are poised to capitalize on these unique interactions. However, current artificial co-cultures constructed for societal benefits, including biosynthesis, agriculture and bioremediation, face many challenges to perform as well as natural consortia. Interkingdom microbial consortia tend to be more robust and have higher productivity compared with monocultures and intrakingdom consortia, but the control and design of these diverse artificial consortia have received limited attention. Further, feasible research techniques and instrumentation for comprehensive mechanistic insights have only recently been established for interkingdom microbial communities. Here, we review these recent advances in technology and our current understanding of microbial interaction mechanisms involved in sustaining or developing interkingdom consortia for biotechnological applications. Some of the interactions among members from different kingdoms follow similar mechanisms observed for intrakingdom microbial consortia. However, unique interactions in interkingdom consortia, including endosymbiosis or interkingdom-specific cell-cell interactions, provide improved mitigation to external stresses and inhibitory compounds. Furthermore, antagonistic interactions among interkingdom species can promote fitness, diversification and adaptation, along with the production of beneficial metabolites and enzymes for society. Lastly, we shed light on future research directions to develop study methods at the level of metabolites, genes and meta-omics. These potential research methods could lead to the control and utilization of highly diverse microbial communities. PMID- 30014576 TI - Intracerebroventricular streptozotocin-induced Alzheimer's disease-like sleep disorders in rats: Role of the GABAergic system in the parabrachial complex. AB - AIM: Sleep disorders are common in Alzheimer's disease (AD) and assumed to directly influence cognitive function and disease progression. This study evaluated sleep characteristics in a rat model of AD that was induced by intracerebroventricular streptozotocin (STZ) administration and assessed the possible underlying mechanisms. METHODS: Cognition ability was assessed in the Morris water maze in rats. Sleep parameters were analyzed by electroencephalographic and electromyographic recordings. Neuronal activity in brain areas that regulate sleep-wake states was evaluated by double-staining immunohistochemistry. High-performance liquid chromatography with electrochemical detection was used to detect neurotransmitter levels. RESULTS: Fourteen days after the STZ injection, the rats exhibited sleep disorders that were similar to those in AD patients, reflected by a significant increase in wakefulness and decreases in nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. The c-Fos expression analysis indicated that neuronal activity and the number of neurons in the dorsal raphe nucleus and locus coeruleus decreased in STZ-injected rats. In the ventrolateral preoptic nucleus (VLPO), the activity of gamma-aminobutyric acid (GABA) neurons was suppressed. In the arousal-driving parabrachial nucleus (PBN), GABAergic activity was suppressed, whereas glutamatergic activity was promoted. The neurotransmitter analysis revealed a reduction in GABA in the VLPO and PBN and elevation of glutamate in the PBN. A direct injection of the GABAA receptor antagonist bicuculline in the PBN in normal rats induced a similar pattern of sleep disorder as in STZ-injected rats. A microinjection of GABA in the PBN improved sleep disorders that were induced by STZ. CONCLUSION: These results suggest that the reduction in GABAergic inhibition in the PBN and VLPO may be involved in sleep disorders that are induced by STZ. Our novel findings encourage further studies that investigate mechanisms of sleep regulation in sporadic AD. PMID- 30014577 TI - Supervised machine learning outperforms taxonomy-based environmental DNA metabarcoding applied to biomonitoring. AB - Biodiversity monitoring is the standard for environmental impact assessment of anthropogenic activities. Several recent studies showed that high-throughput amplicon sequencing of environmental DNA (eDNA metabarcoding) could overcome many limitations of the traditional morphotaxonomy-based bioassessment. Recently, we demonstrated that supervised machine learning (SML) can be used to predict accurate biotic indices values from eDNA metabarcoding data, regardless of the taxonomic affiliation of the sequences. However, it is unknown to which extent the accuracy of such models depends on taxonomic resolution of molecular markers or how SML compares with metabarcoding approaches targeting well-established bioindicator species. In this study, we address these issues by training predictive models upon five different ribosomal bacterial and eukaryotic markers and measuring their performance to assess the environmental impact of marine aquaculture on independent data sets. Our results show that all tested markers are yielding accurate predictive models and that they all outperform the assessment relying solely on taxonomically assigned sequences. Remarkably, we did not find any significant difference in the performance of the models built using universal eukaryotic or prokaryotic markers. Using any molecular marker with a taxonomic range broad enough to comprise different potential bioindicator taxa, SML approach can overcome the limits of taxonomy-based eDNA bioassessment. PMID- 30014578 TI - Artificial intelligence and machine learning in emergency medicine. AB - Interest in artificial intelligence (AI) research has grown rapidly over the past few years, in part thanks to the numerous successes of modern machine learning techniques such as deep learning, the availability of large datasets and improvements in computing power. AI is proving to be increasingly applicable to healthcare and there is a growing list of tasks where algorithms have matched or surpassed physician performance. Despite the successes there remain significant concerns and challenges surrounding algorithm opacity, trust and patient data security. Notwithstanding these challenges, AI technologies will likely become increasingly integrated into emergency medicine in the coming years. This perspective presents an overview of current AI research relevant to emergency medicine. PMID- 30014579 TI - Electron donor-driven bacterial and archaeal community patterns along forest ring edges in Ontario, Canada. AB - Forest rings are 50-1600 m diameter circular structures found in boreal forests around the globe. They are believed to be chemically reducing chimney features, having an accumulation of reduced species in the middle of the ring and oxidation processes occurring at the ring's edges. It has been suggested that microorganisms could be responsible for charge transfer from the inside to the outside of the ring. To explore this, we focused on the changes in bacterial and archaeal communities in the ring edges of two forest rings, the 'Bean' and the 'Thorn North' ring, in proximity to each other in Ontario, Canada. The drier samples from the methane-sourced Bean ring were characterized by the abundance of bacteria from the classes Deltaproteobacteria and Gemmatimonadetes. Geobacter spp. and methanotrophs, such as Candidatus Methylomirabilis and Methylobacter, were highly abundant in these samples. The Thorn North ring, centred on an H2 S accumulation in groundwater, had wetter samples and its communities were dominated by the classes Alphaproteobacteria and Anaerolineae. This ring's microbial communities showed an overall higher microbial diversity supported by higher available free energy. For both rings, the species diversity was highest near the borders of the 20-30 m broad ring edges. PMID- 30014580 TI - Language experience influences audiovisual speech integration in unimodal and bimodal bilingual infants. AB - Infants as young as 2 months can integrate audio and visual aspects of speech articulation. A shift of attention from the eyes towards the mouth of talking faces occurs around 6 months of age in monolingual infants. However, it is unknown whether this pattern of attention during audiovisual speech processing is influenced by speech and language experience in infancy. The present study investigated this question by analysing audiovisual speech processing in three groups of 4- to 8-month-old infants who differed in their language experience: monolinguals, unimodal bilinguals (infants exposed to two or more spoken languages) and bimodal bilinguals (hearing infants with Deaf mothers). Eye tracking was used to study patterns of face scanning while infants were viewing faces articulating syllables with congruent, incongruent and silent auditory tracks. Monolinguals and unimodal bilinguals increased their attention to the mouth of talking faces between 4 and 8 months, while bimodal bilinguals did not show any age difference in their scanning patterns. Moreover, older (6.6 to 8 months), but not younger, monolinguals (4 to 6.5 months) showed increased visual attention to the mouth of faces articulating audiovisually incongruent rather than congruent faces, indicating surprise or novelty. In contrast, no audiovisual congruency effect was found in unimodal or bimodal bilinguals. Results suggest that speech and language experience influences audiovisual integration in infancy. Specifically, reduced or more variable experience of audiovisual speech from the primary caregiver may lead to less sensitivity to the integration of audio and visual cues of speech articulation. PMID- 30014581 TI - Identifying a newly discovered HLA-C allele, HLA-C*02:138. AB - A new allele, now named HLA-C*02:138, was discovered during testing of a registry donor for possible stem cell transplantation. PMID- 30014582 TI - Effect of a salt-reduction strategy on blood pressure and acceptability among customers of a food concessionaire in Lima, Peru. AB - AIM: Limited information exists regarding the implementation of salt reduction strategies on collective food services, such as restaurants and food concessionaires. The present study aimed to assess the effect of a salt reduction strategy on blood pressure levels and food acceptability among customers of a food concessionaire. METHODS: A quasi-experimental study with two phases was conducted. In the pre-intervention phase, the amount of salt used in food preparation was determined. In the intervention phase, a reduction of 20% in salt added to food preparations was implemented. Four hedonic tests and two blood pressure measurements were performed before and after the intervention implementation using standardised techniques. In addition, an evaluation of uneaten food was conducted daily on all customers' plates. Mixed linear regression models were generated to assess the effect of the intervention on blood pressure and acceptability. RESULTS: A total of 71 workers were evaluated, mean age of 37.5 years, 57.8% females, who consumed the food of the concessionaire, on average, 4.4 (SD: 0.7) days per week. Systolic and diastolic blood pressure were reduced by 3.1 (P < 0.001) and 2.9 (P < 0.001) mmHg at the end of the study, respectively. The results of the hedonic tests and the uneaten food before and after the intervention did not vary significantly. CONCLUSIONS: The reduction of 20% of salt added to food from a concessionaire had a positive impact on the reduction of customers' blood pressure without reducing food acceptability. This strategy could be implemented in other contexts. PMID- 30014584 TI - Successful treatment of pulmonary mucormycosis in two pediatric hematopoietic stem cell transplant patients. AB - Pulmonary mucormycosis diagnosed immediately after hematopoietic stem cell transplantation frequently portends a poor prognosis. However, here we describe two cases in children that were treated successfully to highlight the efficacy of a multidisciplinary approach. Despite diagnosis in the immediate post-transplant period and requirement for ongoing immunosuppression to prevent or treat GVHD, both are long-term survivors due to early surgical debridement with transfusion support and prompt initiation of targeted antifungal therapy. In the absence of evidence-based treatment guidelines, survival of pulmonary mucormycosis is achievable even in high-risk patients with a multidisciplinary team to guide management. PMID- 30014585 TI - Oxidized Albumin-A Trojan Horse for p38 MAPK-Mediated Inflammation in Decompensated Cirrhosis. PMID- 30014583 TI - Frequency of HLA-DQ, susceptibility genotypes for celiac disease, in Brazilian newborns. AB - BACKGROUND: The frequency of HLA-DQ2 and DQ8 predisposing genotypes for celiac disease (CD) has shown significant variation among different world regions and has not been previously determined among the highly interbred Brazilian population. The aim of this study was to investigate the frequency of these genotypes among Brazilian newborns (NB). METHODS: We typed DQA1*05 - DQB1*02 (DQ2.5) and DQA1*03 - DQB1*03:02 (DQ8) alleles in 329 NB using qPCR technique. Subsequently we confirmed our results by PCR-SSP using a reference kit which further identified DQ2.2 (DQA1*02:01 - DQB1*02). RESULTS: Among the 329 NB, using qPCR technique: 5 (1.52%) carried both DQ2.5 and DQ8 variants; 58 (17.63%) carried only DQ2.5 (DQA1*05 and DQB1*02) and 47 (14.29%) carried only the DQ8 (DQA1*03 and DQB1*03:02) variant. The use of the PCR-SSP method yielded further information; among the 329 samples: 34 (10.34%) tested positive for DQ2.2 and among the 47 previously DQ8 positives samples, we found 10 (3.04%) that also tested positives for DQ2.2. CONCLUSION: 43.7% of the analyzed individual tested positive for at least one of the CD predisposing HLA-DQ genotypes in our group of Brazilian NB. The highest frequency was found for DQ2.5 positive subjects (17.6%) followed by DQ8 (11.3%); DQ2.2 (10.3%); DQ8 and DQ2.2 (3.0%); DQ2.5 and DQ8 (1.5%). We found no positive sample for DQ2.5 associated with DQ2.2. PMID- 30014586 TI - Liver Stiffness Measurements in Patients with Noncirrhotic Portal Hypertension The Devil Is in the Details. AB - Noncirrhotic portal hypertension (NCPH) is often a diagnostic challenge due to signs and symptoms of portal hypertension that overlap with cirrhosis. The etiology of NCPH is broadly classified as prehepatic, hepatic (presinusoidal and sinusoidal) and posthepatic. Some common etiologies of NCPH encountered in clinical practice include portal vein thrombosis (prehepatic) and nodular regenerative hyperplasia (hepatic). Liver histology, although considered gold standard to exclude cirrhosis in individuals with suspected NCPH, is often limited by subtle histologic features or inadequate sampling. Liver stiffness measurements (LSMs) by vibration-controlled transient elastography may provide clinically important information to distinguish NCPH from cirrhosis by revealing normal LSM in prehepatic and presinusoidal NCPH. PMID- 30014587 TI - Feasibility of using ultra-low pulse rate fluoroscopy during routine diagnostic coronary angiography. AB - INTRODUCTION: Coronary angiogram, while a powerful diagnostic tool in coronary artery disease, is not without an associated risk from ionising radiation. There are a number of factors that influence the amount of radiation the patient receives during the procedure, some of which are under the control of the operator. One of these is an adjustment of the fluoroscopic pulse rate. This study aims to assess the feasibility of using ultra-low pulse rate (3 pulses per second(pps)) fluoroscopy during routine diagnostic coronary angiogram procedures and the effect it has on fluoroscopy time, diagnostic clarity and radiation dose. METHODS: A retrospective study of three operators each undertaking 50 coronary angiogram procedures was performed. One of the operators used a pulse rate of 3 pps and 6 pps for fluoroscopic screening while the control groups used the standard 10 pps mode utilised at this centre. RESULTS: Results demonstrated no reduction of diagnostic clarity, up to a 58% reduction in Dose Area Product and no increase in fluoroscopy time with the 3 pps setting. CONCLUSIONS: Findings from this pilot study suggest that utilisation of ultra-low pulse rate fluoroscopy in routine transfemoral diagnostic coronary angiography in the catheterisation laboratory is feasible. PMID- 30014588 TI - Something fishy going on. PMID- 30014589 TI - Efficacy and safety of a fixed combination of insulin degludec/insulin aspart in children and adolescents with type 1 diabetes: A randomized trial. AB - BACKGROUND: Insulin degludec/insulin aspart (IDegAsp) is a fixed soluble co formulation of basal and bolus insulin. OBJECTIVE: To evaluate efficacy and safety of IDegAsp in pediatric patients with type 1 diabetes (T1D). SUBJECTS: Children and adolescents (aged 1 to <18 years) with T1D. METHODS: A 16-week, phase 3b, treat-to-target, parallel-group, open-label, non-inferiority trial was conducted at 63 sites in 14 countries from October 2013 to November 2014. Patients were randomized 1:1 (age stratified: 1-<6 years; 6-<12 years; 12-<18 years) to IDegAsp once daily (OD) plus insulin aspart (IAsp) for remaining meals (IDegAsp + IAsp), or IDet OD or twice daily plus mealtime IAsp (IDet + IAsp). The primary end-point was HbA1c change from baseline at week 16. RESULTS: A total of 362 participants were randomized to IDegAsp + IAsp (n = 182) or IDet + IAsp (n = 180). HbA1c decreased from baseline to week 16 by 0.3% in both groups (estimated treatment difference: -0.04%-points [-0.23; 0.15]95%CI (-0.45 mmol/mol [-2.51; 1.60]95%CI ), confirming non-inferiority. There were no significant differences between treatment groups in fasting or self-measured plasma glucose. Confirmed hypoglycemia rates did not significantly differ between groups. There was a significant reduction in basal and total insulin dose with IDegAsp + IAsp vs IDet + IAsp (post hoc analysis). Mean number of injections/day was 3.6 and 4.9 with IDegAsp + IAsp and IDet + IAsp, respectively (post hoc analysis). A non significant higher rate of severe hypoglycemia was observed with IDegAsp + IAsp vs IDet + IAsp. The most frequent adverse events in both groups were hypoglycemia, headache, and nasopharyngitis. CONCLUSIONS: IDegAsp + IAsp was non inferior to IDet + IAsp regarding HbA1c, had similar hypoglycemia rates and required fewer injections. PMID- 30014590 TI - The profile of abstract rule learning in infancy: Meta-analytic and experimental evidence. AB - Everyone agrees that infants possess general mechanisms for learning about the world, but the existence and operation of more specialized mechanisms is controversial. One mechanism-rule learning-has been proposed as potentially specific to speech, based on findings that 7-month-olds can learn abstract repetition rules from spoken syllables (e.g. ABB patterns: wo-fe-fe, ga-tu-tu...) but not from closely matched stimuli, such as tones. Subsequent work has shown that learning of abstract patterns is not simply specific to speech. However, we still lack a parsimonious explanation to tie together the diverse, messy, and occasionally contradictory findings in that literature. We took two routes to creating a new profile of rule learning: meta-analysis of 20 prior reports on infants' learning of abstract repetition rules (including 1,318 infants in 63 experiments total), and an experiment on learning of such rules from a natural, non-speech communicative signal. These complementary approaches revealed that infants were most likely to learn abstract patterns from meaningful stimuli. We argue that the ability to detect and generalize simple patterns supports learning across domains in infancy but chiefly when the signal is meaningfully relevant to infants' experience with sounds, objects, language, and people. PMID- 30014591 TI - Surveillance of drugs that most frequently induce acute kidney injury: A pharmacovigilance approach. AB - WHAT IS KNOWN AND OBJECTIVE: Acute kidney injury (AKI) often occurs in hospitalized patients, and it is an increasing problem worldwide. Recently, clinical studies have shown that there is a strong association between drug induced AKI and poor outcomes, including the progression of chronic kidney disease and end-stage renal disease; however, limited data are available on drug induced AKI. The purpose of this study was to clarify the rank-order of the association of all drugs with AKI using a spontaneous reporting system database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to Pharmaceuticals and Medical Devices Agency between April 2004 and January 2017 were analysed. RESULTS AND DISCUSSION: Based on 5 195 890 reports of all adverse events, we obtained 12 964 reports of AKI caused by all drugs and calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for AKI. The most frequently reported drugs were valaciclovir hydrochloride (ROR, 24.88; 95% CI: 23.1-26.8), eldecalcitol (ROR, 14.23; 95% CI, 11.68-17.33), edaravone (ROR, 14.03; 95% CI, 11.76-16.75), acyclovir (ROR, 11.17; 95% CI, 9.55-13.1), piperacillin-tazobactam (ROR, 9.23; 95% CI, 7.72-11.0), and spironolactone (ROR, 7.36; 95% CI, 6.12-8.86). WHAT IS NEW AND CONCLUSION: A comprehensive study using a pharmacovigilance database enabled us to identify the drugs that most frequently induce AKI, raising physicians' awareness of the drugs in use for patients with potentially decreased renal function. PMID- 30014592 TI - Viral shedding of clade 2.3.4.4 H5 highly pathogenic avian influenza A viruses by American robins. AB - American robins (Turdus migratorius) are commonly associated with farmsteads in the United States and have shown previous evidence of exposure to an H5 avian influenza A virus (IAV) near a poultry production facility affected by a highly pathogenic (HP) H5 virus in Iowa, USA during 2015. We experimentally infected American robins with three clade 2.3.4.4 HP H5 viruses (H5N2 and H5N8). A total of 22/24 American robins shed virus, and all three strains were represented. The highest virus titres shed were 104.3 , 104.3 and 104.8 PFU/ml, associated respectively with viruses isolated from poultry, a captive gyrfalcon (Falco rusticolus), and a Northern pintail (Anas acuta). Of those birds that shed, viral shedding was initiated 1 or 2 days post-infection (DPI) and shedding ceased in all birds by 7 DPI. This study adds an additional synanthropic wildlife species to a growing list of animals that can successfully replicate and shed IAVs. PMID- 30014593 TI - Simple models combining competition, defence and resource availability have broad implications in pelagic microbial food webs. AB - In food webs, interactions between competition and defence control the partitioning of limiting resources. As a result, simple models of these interactions contain links between biogeochemistry, diversity, food web structure and ecosystem function. Working at hierarchical levels, these mechanisms also produce self-similarity and therefore suggest how complexity can be generated from repeated application of simple underlying principles. Reviewing theoretical and experimental literature relevant to the marine photic zone, we argue that there is a wide spectrum of phenomena, including single cell activity of prokaryotes, microbial biodiversity at different levels of resolution, ecosystem functioning, regional biogeochemical features and evolution at different timescales; that all can be understood as variations over a common principle, summarised in what has been termed the 'Killing-the-Winner' (KtW) motif. Considering food webs as assemblages of such motifs may thus allow for a more integrated approach to aquatic microbial ecology. PMID- 30014594 TI - Identifying therapeutic targets from spontaneous beneficial brain lesions. AB - Brain damage can occasionally result in paradoxical functional benefit, which could help identify therapeutic targets for neuromodulation. However, these beneficial lesions are rare and lesions in multiple different brain locations can improve the same symptom. Using a technique called lesion network mapping, we show that heterogeneous lesion locations resulting in tremor relief are all connected to common nodes in the cerebellum and thalamus, the latter of which is a proven deep brain stimulation target for tremor. These results suggest that lesion network mapping can identify the common substrate underlying therapeutic lesions and effective therapeutic targets. Ann Neurol 2018;83:153-157. PMID- 30014595 TI - Carboplatin and vincristine neurotoxicity in the treatment of pediatric low-grade gliomas. AB - BACKGROUND: Pediatric low-grade gliomas (LGG) represent 30-50% of central nervous system pediatric tumors. Over the last decades, the combination of carboplatin and vincristine (CV) has become the first line of treatment in most centers. In a large clinical trial where the efficacy of CV was compared to another regimen, 19% presented grade III neurotoxicity. Despite the fact that CV therapy is widely used for pediatric patients with LGG, no study has reported detailed neurological adverse events and outcome with this treatment regimen. The purpose of this retrospective study is to better understand neurotoxicity associated with CV. PROCEDURE: We conducted a retrospective study to better evaluate the incidence and evolution of neurotoxicity associated with CV in patients with LGG. RESULTS: Twenty-one pediatric patients were treated with CV at our single institution over 16 years. Most patients had optic glioma. Peripheral neuropathy was present in most patients (86%). Eight patients (38%) had a dose reduction of vincristine due to grade III toxicity (three motor neuropathies, three sensory neuropathies, one constipation, and one dysphagia). Most neurotoxicity occurred during induction or the first maintenance cycle. No ototoxicity was observed during treatment or follow-up. CONCLUSIONS: In our study, neurotoxicity with vincristine occurred two times more frequently than in previously published literature. Careful neurological assessment is important to detect neurotoxicity, especially during induction. The high incidence of neurotoxicity should be considered when selecting a chemotherapy regimen for pediatric LGG. PMID- 30014596 TI - Epidermal grafting for leukoderma resulting from 1064-nm quality-switched neodymium-doped yttrium aluminium garnet laser toning. AB - Leukoderma secondary to Q-switched 1064-nm neodymium-doped yttrium aluminium garnet laser is usually refractory to treatment. The pathogenesis was cumulative phototoxic damage to melanocytes and eventually resulted in melanocytopenia. Wood's light or UV imaging can help observe early leukoderma before it becomes apparent clinically and determine the degree of melanocytopenia before conducting a biopsy. NB-UVB phototherapy and 308-nm excimer laser can potentially worsen the pre-existing melasma lesions and may not be effective if the lesions have already become melanocytopenic. Epidermal grafting can replenish the hypopigmented area with melanocytes without worsening melasma. PMID- 30014597 TI - CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence? AB - OBJECTIVE: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. METHODS: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression). RESULTS: We identified 3 new variants in cases, but only 1 was ALS-specific. Also, 1 control specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p = 0.86, p = 0.86, and p = 0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. INTERPRETATION: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants. Ann Neurol 2018;83:110-116. PMID- 30014598 TI - Population pharmacokinetics of serelaxin in patients with acute or chronic heart failure, hepatic or renal impairment, or portal hypertension and in healthy subjects. AB - AIMS: Serelaxin is a recombinant human relaxin-2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. METHODS: Serum concentration-time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed-effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. RESULTS: A three-compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady-state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady-state volume of distribution (Vss) was higher in patients with AHF (544 ml kg-1 ) or chronic heart failure (434 ml kg-1 ), compared with typical nonheart failure subjects (347 ml kg-1 ). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively. CONCLUSIONS: Patients with HF showed higher Vss but similar clearance (and therefore steady-state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady-state concentration was moderate and therefore unlikely to be clinically relevant. PMID- 30014599 TI - Prevalence of Group I Salmonella Kentucky in domestic food animals from Pennsylvania and overlap with human clinical CRISPR sequence types. AB - Although infrequently associated with illness in humans, Salmonella enterica, subsp. enterica serovar Kentucky is the most common non-clinical, non-human serovar reported in the United States, being largely found in poultry and poultry products, as well as being associated with cattle. This serovar is polyphyletic and can be separated into two groups, Group I and II, based on CRISPR-typing analysis. In Salmonella Kentucky isolates from human clinical samples in Pennsylvania, both lineages are equally represented. The goal of this study was to determine whether both groups were also represented in domestic food animals in Pennsylvania. We analysed the CRISPR arrays from 67 Salmonella Kentucky isolates used PCR and sequencing of CRISPR arrays or analysis of whole genome sequences to analyse the CRISPR arrays and Across a collection of 67 Salmonella Kentucky isolates that includes those collected from farms, veterinary clinical samples as well as isolates from retail meats, we show that Group I Salmonella Kentucky are the exclusive lineage present. We reveal that the specific subtype of over a quarter of these animal isolates are also found to be responsible for causing human salmonellosis in the same region over the same time period. PMID- 30014600 TI - CrossTalk opposing view: mucosal acidification does not drive early progressive lung disease in cystic fibrosis. PMID- 30014601 TI - Simultaneous determination of total homocysteine, cysteine, glutathione, and N acetylcysteine in brain homogenates by HPLC. AB - We have developed a simple, fast, accurate, and cheap method for the simultaneous determination of total cysteine, homocysteine, glutathione, and N-acetylcysteine in brain homogenates based on the reduction of disulfide bonds by tris(2 carboxyethyl) phosphine, pre-column derivatization of free thiol groups with 2 chloro-1-methylquinolinium tetrafluoroborate followed by ion-pair reversed-phase high-performance liquid chromatography separation with ultraviolet detection. The separation of thiol derivatives was achieved in 10 min. Linearity was observed in the range of 10-300, 0.7-10, 2-30, and 3-20 MUmol/L homogenate with a limit of detection of 3.7, 0.2, 0.8, and 1.2 MUmol/L homogenate for cysteine, homocysteine, glutathione, and N-acetylcysteine, respectively. The precision, calculated as relative standard deviation, was in the range of 1.21-4.77, 1.53 14.35, 0.47-1.92, and 1.61-8.95% for cysteine, homocysteine, glutathione, and N acetylcysteine, respectively. The presented method was successfully applied to the selective determination of total amino thiols in pig brain tissue samples. PMID- 30014602 TI - Notch3ECD immunotherapy improves cerebrovascular responses in CADASIL mice. AB - OBJECTIVE: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by dominant mutations in the NOTCH3 receptor, is the most aggressive small vessel disease of the brain. A key feature of its pathogenesis is accumulation of the extracellular domain of NOTCH3 receptor (Notch3ECD ) in small vessels, with formation of characteristic extracellular deposits termed granular osmiophilic material (GOM). Here, we investigated the therapeutic potential of a mouse monoclonal antibody (5E1) that specifically recognizes Notch3ECD . METHODS: The binding affinity of 5E1 toward purified NOTCH3 was assessed using Octet analysis. The ability of 5E1 to bind Notch3ECD deposits in brain vessels and its effects on disease-related phenotypes were evaluated in the CADASIL mouse model, which overexpresses a mutant rat NOTCH3. Notch3ECD and GOM deposition, white matter lesions, and cerebral blood flow deficits were assessed at treatment initiation (10 weeks) and study completion (30 weeks) using quantitative immunohistochemistry, electron microscopy, and laser-Doppler flowmetry. RESULTS: 5E1 antibody bound recombinant rat NOTCH3 with an average affinity of 317nM. A single peripheral injection of 5E1 robustly decorated Notch3ECD deposits in the brain vasculature. Chronic administration of 5E1 did not attenuate Notch3ECD or GOM deposition and was not associated with perivascular microglial activation. It also failed to halt the development of white matter lesions. Despite this, 5E1 treatment markedly protected against impaired cerebral blood flow responses to neural activity and topical application of vasodilators and normalized myogenic responses of cerebral arteries. INTERPRETATION: This study establishes immunotherapy targeting Notch3ECD as a new avenue for disease-modifying treatment in CADASIL that warrants further development. Ann Neurol 2018;84:246-259. PMID- 30014603 TI - Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. AB - OBJECTIVE: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the central nervous system (CNS). We analyzed their pathogenic activity by affinity purifying these antibodies (Abs) from patients and transferring them to experimental animals. METHODS: Patients with Abs to MOG were identified by cell based assay. We determined the cross-reactivity to rodent MOG and the recognized MOG epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in 2 models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically. RESULTS: We identified 17 patients with MOG Abs from our outpatient clinic and selected 2 with a cross-reactivity to rodent MOG; both had recurrent optic neuritis. Affinity-purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the 2 patients recognized different epitopes on MOG, the CC' and the FG loop. In both patients, these Abs persisted during our observation period of 2 to 3 years. The anti-MOG Abs from both patients were pathogenic upon intrathecal injection in 2 different rat models. Together with cognate MOG-specific T cells, these Abs enhanced T-cell infiltration; together with myelin basic protein-specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology. INTERPRETATION: MOG-specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon cotransfer with myelin-reactive T cells, suggesting that these Abs are similarly pathogenic in patients. Ann Neurol 2018;84:315-328. PMID- 30014604 TI - Vitamin K1 and Vitamin K2 immunopharmacological effects on the peripheral lymphocytes of healthy subjects and dialysis patients, as estimated by the lymphocyte immunosuppressant sensitivity test. AB - WHAT IS KNOWN AND OBJECTIVE: Renal transplant recipients receive immunosuppressive therapy to prevent acute rejection. We evaluated the immunopharmacological efficacy of vitamin K1 (VK1) and vitamin K2 (VK2) on T-cell mitogen-activated-peripheral lymphocytes of dialysis patients and healthy subjects. METHODS: The effects of VK1 and VK2 on the T-cell mitogen-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) obtained from 12 healthy subjects and 12 dialysis patients were estimated. Seven cytokines produced from the activated PBMCs were measured by a BD Cytometric Beads Array kit. Regulatory T cells (Tregs) in PBMCs were analysed as CD4 + CD25 + FoxP3 + lymphocytes by flow cytometry. RESULTS: VK2 dose-dependently suppressed the concanavalin A-stimulated proliferation of PBMCs from healthy subjects and dialysis patients, whereas VK1 had no significant effect on the PBMC proliferation. VK1 and VK2 did not influence the production of most of the Th1/Th2/Th17 cytokines from the activated PBMCs of these subjects, although VK2 increased the IL-4 production from PBMCs of healthy subjects. The Treg percentages in the PBMCs of dialysis patients were markedly decreased compared to healthy PBMCs after the treatment with relatively low concentrations of VK2. WHAT IS NEW AND CONCLUSION: The present data suggest that VK2 has immunosuppressive efficacy. VK2 may enhance the immunosuppressive efficacies of glucocorticoids while preventing osteoporosis caused by glucocorticoids. PMID- 30014605 TI - Health inequalities between male and female immigrants in Spain after the beginning of the economic crisis. AB - The aim of this study was to analyse health inequalities in the immigrant population in Spain in 2014, while differentiating between immigrant and native born men and women. We have designed a cross-sectional study on the population aged over 15 years resident in Spain and the data were obtained from the 2014 European Health Survey in Spain (n = 22,842). Among immigrant men and women, we observed a lower risk of having a Chronic Physical Problem (CPP) or a Mental Health Problem (MHP) and a lower consumption of psychiatric drugs. We also observed a higher risk of lack of medical care in immigrant men compared to native-born. The country of origin was not significantly related to self perception of health or use of Primary Care (PC) and Emergency Care services. In conclusion, we observed that now that the peak of the crisis has passed it seems that the "healthy immigrant" effect is being recovered, although the gender inequalities observed in the general population are transferred to the immigrant population. We need to approach the feminisation of migration from a new perspective and understand how inequalities affect immigrant women. PMID- 30014606 TI - Working alliance and outcome effectiveness in videoconferencing psychotherapy: A systematic review and noninferiority meta-analysis. AB - Videoconferencing psychotherapy (VCP)-the remote delivery of psychotherapy via secure video link-is an innovative way of delivering psychotherapy, which has the potential to overcome many of the regularly cited barriers to accessing psychological treatment. However, some debate exists as to whether an adequate working alliance can be formed between therapist and client, when therapy is delivered through such a medium. The presented article is a systematic literature review and two meta-analyses aimed at answering the questions: Is working alliance actually poorer in VCP? And is outcome equivalence possible between VCP and face-to-face delivery? Twelve studies were identified which met inclusion/exclusion criteria, all of which demonstrated good working alliance and outcome for VCP. Meta-analyses showed that working alliance in VCP was inferior to face-to-face delivery (standardized mean difference [SMD] = -0.30; 95% confidence interval [CI] [-0.67, 0.07], p = 0.11; with the lower bound of the CI extending beyond the noninferiority margin [-0.50]), but that target symptom reduction was noninferior (SMD = -0.03; 95% CI [-0.45, 0.40], p = 0.90; CI within the noninferiority margin [0.50]). These results are discussed and directions for future research recommended. PMID- 30014608 TI - Authoritarian parenting style predicts poorer glycemic control in children with new-onset type 1 diabetes. AB - OBJECTIVE: To examine cross-sectional and longitudinal associations among parenting styles (ie, authoritative, authoritarian, and permissive) and youth glycated hemoglobin (HbA1c) in a cohort of families of children with new-onset type 1 diabetes (T1D). METHODS: One-hundred two parents completed a baseline measure of parenting style, and we collected child HbA1c values at baseline and at three- and six-month follow-ups. We examined correlations among use of different parenting strategies and child HbA1cs. We conducted multiple regressions to assess the impact of these strategies on child HbA1c at three month and six-month follow-ups, while controlling for baseline HbA1c, family income, and T1D duration. RESULTS: Correlational analyses showed negative associations between authoritative strategies and child HbA1c at baseline, three month, and six-month assessments and positive associations between authoritarian strategies and child HbA1c at three-month and six-month assessments. Regression analyses found use of authoritarian-like strategies were the only parenting strategies associated with child HbA1c at three-month and six-month follow-ups, while controlling for baseline HbA1c, family income, and T1D duration. CONCLUSION: Parents' use of authoritarian-like strategies may negatively impact glycemic control over the course of six-month in children with new-onset T1D. PMID- 30014607 TI - Dermatofibrosarcoma protuberans with a novel COL6A3-PDGFD fusion gene and apparent predilection for breast. AB - Dermatofibrosarcoma protuberans is a locally aggressive superficial mesenchymal neoplasm. It typically occurs in adulthood, and has been reported to have a slight male predilection. Tumors have a characteristic histopathologic appearance, including: storiform architecture, infiltrative "honeycomb" growth within subcutaneous adipose tissue, and immunoreactivity for CD34. Virtually all molecularly characterized cases to date have been found to harbor a COL1A1-PDGFB fusion product. Following identification of an index patient with a novel COL6A3 PDGFD fusion gene, we undertook a molecular investigation, using a combination of RNA sequencing and fluorescence in situ hybridization (FISH), to assess the prevalence of PDGFD rearrangement in dermatofibrosarcoma protuberans (N = 63). Three additional patients were found to have balanced PDGFD rearrangements. Interestingly, all 4 tumors arose on the breast of females. As a result, we subsequently examined 16 additional cases of primary breast dermatofibrosarcoma protuberans, identifying 2 additional tumors with PDGFD rearrangement. The morphology and immunophenotype of all 6 cases was analogous to those with the canonical COL1A1-PDGFB fusion; none of the cases showed fibrosarcomatous transformation. This study illustrates that the COL6A3-PDGFD fusion product is rare in dermatofibrosarcoma protuberans, and associated with an apparent predilection for breast. An awareness of this variant is important for pathologists, as it will not be detected using conventional reverse transcription polymerase chain reaction or FISH-based diagnostic assays for dermatofibrosarcoma protuberans. PMID- 30014609 TI - Hybrid Nanoreactors: Enabling an Off-the-Shelf Strategy for Concurrently Enhanced Chemo-immunotherapy. AB - Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off-the-shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation. PMID- 30014610 TI - Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease. AB - Aminoacyl-tRNA synthetases (ARSs) canonical function is to conjugate specific amino acids to cognate tRNA that are required for the first step of protein synthesis. Genetic mutations that cause dysfunction or absence of ARSs result in various neurodevelopmental disorders. The human phenylalanine-tRNA synthetase (PheRS) is a tetrameric protein made of two subunits coded by FARSA gene and two subunits coded by FARSB gene. We describe eight affected individuals from an extended family with a multisystemic recessive disease manifest as a significant growth restriction, brain calcifications, and interstitial lung disease. Genome wide linkage analysis and whole exome sequencing identified homozygosity for a FARSB mutation (NM_005687.4:c.853G > A:p.Glu285Lys) that co-segregate with the disease and likely cause loss-of-function. This study further implicates FARSB mutations in a multisystem, recessive, neurodevelopmental phenotype that share clinical features with the previously known aminoacyl-tRNA synthetase-related diseases. PMID- 30014611 TI - Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disease caused by loss-of-function dystrophin (DMD) mutations in boys, who typically suffer loss of ambulation by age 12. Previously, we reported that coding variants in latent transforming growth factor beta (TGFbeta)-binding protein 4 (LTBP4) were associated with reduced TGFbeta signaling and prolonged ambulation (p = 1.0 * 10-3 ) in DMD patients; this result was subsequently replicated by other groups. In this study, we evaluated whether additional DMD modifier genes are observed using whole-genome association in the original cohort. METHODS: We performed a genome-wide association study (GWAS) for single nucleotide polymorphisms (SNPs) influencing loss of ambulation (LOA) in the same cohort of 253 DMD patients used to detect the candidate association with LTBP4 coding variants. Gene expression and chromatin interaction databases were used to fine-map association signals above the threshold for genome-wide significance. RESULTS: Despite the small sample size, two loci associated with prolonged ambulation met genome-wide significance and were tagged by rs2725797 (chr15, p = 6.6 * 10-9 ) and rs710160 (chr19, p = 4.7 * 10-8 ). Gene expression and chromatin interaction data indicated that the latter SNP tags regulatory variants of LTBP4, whereas the former SNP tags regulatory variants of thrombospondin-1 (THBS1): an activator of TGFbeta signaling by direct binding to LTBP4 and an inhibitor of proangiogenic nitric oxide signaling. INTERPRETATION: Together with previous evidence implicating LTBP4, the THBS1 modifier locus emphasizes the role that common regulatory variants in gene interaction networks can play in mitigating disease progression in muscular dystrophy. Ann Neurol 2018;84:234-245. PMID- 30014612 TI - Exploring bioactive peptides from bacterial secretomes using PepSAVI-MS: identification and characterization of Bac-21 from Enterococcus faecalis pPD1. AB - As current methods for antibiotic drug discovery are being outpaced by the rise of antimicrobial resistance, new methods and innovative technologies are necessary to replenish our dwindling arsenal of antimicrobial agents. To this end, we developed the PepSAVI-MS pipeline to expedite the search for natural product bioactive peptides. Herein we demonstrate expansion of PepSAVI-MS for the discovery of bacterial-sourced bioactive peptides through identification of the bacteriocin Bac-21 from Enterococcus faecalis pPD1. Minor pipeline modifications including implementation of bacteria-infused agar diffusion assays and optional digestion of peptide libraries highlight the versatility and wide adaptability of the PepSAVI-MS pipeline. Additionally, we have experimentally validated the primary protein sequence of the active, mature Bac-21 peptide for the first time and have confirmed its identity with respect to primary sequence and post translational processing. Successful application of PepSAVI-MS to bacterial secretomes as demonstrated herein establishes proof-of-principle for use in novel microbial bioactive peptide discovery. PMID- 30014614 TI - Hepatitis E virus in archived sera from wild boars (Sus scrofa), Czech Republic. AB - To determine whether hepatitis E virus (HEV) was distributed in the population of wild boars in South Moravia between 1990 and 2008, a total of 366 samples of archived sera from wild boars were investigated using serological (commercial ELISA) and molecular (RT-qPCR) methods. A total of 31 (8.5%) wild boars were seropositive, and from two of them, RNA sequences were recovered by nested RT PCR. The presented results, with one of the oldest animal's HEV-positive serum (collected in 1990), suggest that wild boars may be a reservoir of HEV in the Czech Republic and that this virus has been circulating in studied areas for more than 20 years. PMID- 30014613 TI - A comprehensive comparison of the fifth-wave highly pathogenic and low-pathogenic H7N9 avian influenza viruses reveals potential threat posed by both types of viruses in mammals. AB - Before 2013, zoonotic influenza infections were dominated by H5N1 viruses in China. However, the emergence of the H7N9 viruses in early 2013 changed this dominance greatly, and more than 1,600 laboratory-confirmed human cases of H7N9 infections have been reported since then. To understand the underlying mechanism of the emergence of the fifth epidemic wave that shows an unexpected sharp increase, we systematically investigated the biological characteristics of the highly pathogenic (HP) and low-pathogenic (LP) H7N9 AIVs during this period. We first systematically analysed the haemagglutination assay gene of all the isolates available from the website and found that the HP and LP viruses differed a little in the well-established receptor binding sites and in other potentially important sites. Phylogenetic analysis showed that both the HP and LP viruses belong to the branch of the Yangtze River Delta, whereas they diverged to different small branches. To further compare the biological variations in the HP and LP viruses, we selected six HP and six LP strains for in-depth analysis, including receptor binding characteristics, thermal stability, viral replication and virulence in mice. The three major findings of this study were as follows: (a) Other potential site/sites may affect the receptor binding property of the H7N9 viruses; (b) the HP viruses displayed a higher thermostability than did the LP viruses, quite consistent with the epidemiological data during the summer period; and (c) one-third of the HP viruses were moderately pathogenic in mice, whereas all the LP viruses were nonpathogenic in this animal model. However, the LP viruses replicated more efficiently in the mouse lung and can spread to the extrarespiratory organs (spleen, kidney and brain). Taken together, our results suggest that both the HP and LP H7N9 viruses can pose a potential threat to public health, highlighting the importance of the continual surveillance of the H7N9 AIVs. PMID- 30014615 TI - Next-generation sequencing of HLA-G based on long-range polymerase chain reaction. AB - Clarifying the functional roles of HLA-G and the variation in the HLA-G gene that affects the expression are increasingly important in reproduction, cancer, organ transplantation, and autoimmune diseases. The homology between HLA genes and the genetic variability within each gene complicates the design of HLA gene-specific genotyping assays. We have designed a high-throughput, cost-efficient, robust, and specific assay for sequencing the full HLA-G gene including the 5'-upstream regulatory region, introns, and the 3'-untranslated region, using the next generation sequencing (NGS) platform Ion Torrent PGM (Thermo Fisher Scientific, Waltham, Massachusetts). Conventional sequencing methods require the design of multiple primer pairs in order to cover the entire HLA-G gene. Designing multiple primer pairs specific for the HLA-G gene that also target all known alleles is difficult. Here, we present a setup that by the use of long-range polymerase chain reaction amplifies the whole HLA-G gene in a single reaction, which only requires a single HLA-G-specific primer pair. Enzymatic DNA shearing is used to break the long-range PCR product into shorter fragments ranging from 75 to 200 bp in length that are sequenced by NGS. PMID- 30014616 TI - ACI-1 beta-lactamase is widespread across human gut microbiomes in Negativicutes due to transposons harboured by tailed prophages. AB - Antibiotic resistance is increasing among pathogens, and the human microbiome contains a reservoir of antibiotic resistance genes. Acidaminococcus intestini is the first Negativicute bacterium (Gram-negative Firmicute) shown to be resistant to beta-lactam antibiotics. Resistance is conferred by the aci1 gene, but its evolutionary history and prevalence remain obscure. We discovered that ACI-1 proteins are phylogenetically distinct from beta-lactamases of Gram-positive Firmicutes and that aci1 occurs in bacteria scattered across the Negativicute clade, suggesting lateral gene transfer. In the reference A. intestini RyC-MR95 genome, we found transposons residing within a tailed prophage context are likely vehicles for aci1's mobility. We found aci1 in 56 (4.4%) of 1,267 human gut metagenomes, mostly hosted within A. intestini, and, where could be determined, mostly within a consistent mobile element constellation. These samples are from Europe, China and the USA, showing that aci1 is distributed globally. We found that for most Negativicute assemblies with aci1, the prophage observed in A. instestini is absent, but in all cases aci1 is flanked by varying transposons. The chimeric mobile elements we identify here likely have a complex evolutionary history and potentially provide multiple complementary mechanisms for antibiotic resistance gene transfer both within and between cells. PMID- 30014617 TI - Building a Thermostable Metabolon for Facilitating Coenzyme Transport and In Vitro Hydrogen Production at Elevated Temperature. AB - To facilitate coenzyme transport and in vitro enzymatic hydrogen production, a multi-enzyme metabolon comprising a miniscaffoldin containing three cohesins, a dockerin-containing mutant dehydrogenase, a dockerin-containing diaphorase, and a Histidine-tagged (His-tagged) NiFe hydrogenase was constructed. As the NiFe hydrogenase has very complicated structure and cannot be fused directly with a dockerin, a bifunctional peptide was designed. The bifunctional peptide, in which one terminus contains a modified dockerin binding the cohesin of the miniscaffoldin and the other, after chemical modification, binds the His-tag of NiFe hydrogenase, enabled His-tagged proteins to be integrated into the cohesin dockerin-based metabolon. The metabolon exhibited an initial reaction rate 4.5 times that of the enzyme cocktail at the same enzyme loading, which indicated enhanced coenzyme transport of the metabolon. However, this metabolon was unstable owing to the degradation of the miniscaffoldin at elevated temperature. Glutaraldehyde was used to cross-link the metabolon for locking its spatial organization. The cross-linked metabolon not only exhibited 2.5 times the reaction rate of the enzyme cocktail, but also retained its stability at 70 degrees C. The amount of hydrogen production catalyzed by the cross-linked metabolon was nearly twice that of the metabolon without glutaraldehyde cross linking and four times that of the enzyme cocktail at 70 degrees C after 22 h of reaction. PMID- 30014619 TI - Transcriptome-Wide Analysis Reveals the Landscape of Aberrant Alternative Splicing Events in Liver Cancer. AB - : Alternative splicing (AS) is assumed to be a pivotal determinant for the generation of diverse transcriptional variants in cancer. However, the comprehensive dysregulation of AS and the prospective biological and clinical relevance in hepatocellular carcinoma (HCC) remain obscure. Here, we identified and depicted the AS landscape in HCC by performing reference-based assembly of sequencing reads from over 600 RNA-seq libraries. We detected various differentially spliced ASEs across patients, covering not only protein-coding genes but also considerable numbers of non-coding genes. Strikingly, alternative transcription initiation was found to frequently occur in HCC. These differential ASEs were highly related to "cancer hallmarks", and involved in metabolism related pathways in particular. In addition, 243 differential ASEs were identified as risk predictors for HCC patient survival. The isoform switch of metabolism-related gene UGP2 might play an essential role in HCC. We further constructed regulatory networks between RNA binding protein (RBP) genes and the corresponding ASEs. Further analysis demonstrated that the regulated networks were enriched in a variety of metabolism-related pathways. CONCLUSION: Differential ASEs are prevalent in HCC, where alternative transcription initiation was found to frequently occur. We found that genes having differential ASEs were significantly enriched in metabolism-related pathways. The expression variations, binding relations and even mutations of RBP genes largely influenced differential ASEs in HCC. This article is protected by copyright. All rights reserved. PMID- 30014618 TI - T-cell subset differentiation and antibody responses following antiretroviral therapy during simian immunodeficiency virus infection. AB - Antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection represents a major breakthrough in the treatment of HIV/acquired immune-deficiency syndrome. However, it remains unclear how ART influences virus specific immune responses and understanding this is important for developing novel cure and eradication interventions for HIV-1. In the present study, we evaluate how ART impacts T-cell and antibody responses in simian immunodeficiency virus (SIV) -infected rhesus macaques. We evaluated CD4 and CD8 T-cell responses by multiparameter flow cytometry, viral loads by quantitative RT-PCR by a two step process using SIV-specific primers and antibody neutralization function by luciferase-based TZM-bl assays. We demonstrate that macaques treated with ART exhibit phenotypic and qualitative effects on T-cell and antibody responses. Macaques on ART exhibited low numbers of virus-specific T-cell responses, and these responses appeared to be partially biased towards central memory subsets. More importantly, there were significantly reduced neutralizing antibody responses in macaques treated with ART. Collectively, these data improve the understanding of how virus-specific immune responses are generated during ART, and suggest the potential importance of therapeutic vaccines to maintain adaptive immunity during treated infection. PMID- 30014620 TI - Clinical Manifestations and Outcomes of Patients with Sarcomatoid Hepatocellular Carcinoma. AB - : Hepatocellular carcinoma (HCC) is the fifth common cancer and the second leading cause of cancer-related deaths worldwide. Sarcomatoid HCC is a rare histological subtype of HCC, with largely unclear clinical manifestations and outcomes. Thus, we evaluated the clinical manifestations and outcomes of patients with sarcomatoid HCC. We identified 5047 patients with histologically proven HCC from the Cancer Registry Database (1996-2016) of National Taiwan University Hospital. Among them, 40 patients with sarcomatoid HCC were identified from the pathology database of National Taiwan University Hospital. We included 160 patients with non-sarcomatoid HCC through propensity score matching according to sex, age, and Barcelona Clinic Liver Cancer stage. The majority of these patients with sarcomatoid HCC were men (75%); their median age was 58 years. Only 47.5% of the patients with sarcomatoid HCC presented with typical image patterns of HCC. The pathological grading of sarcomatoid HCC was more advanced compared with that of non-sarcomatoid HCC (42.5% vs. 23.8% in grade III and IV, P < 0.0001). The sarcomatoid group had significantly shorter median recurrence-free (13.3 vs. 84.2 months, log-rank P < 0.0001) and overall (8.3 vs. 69.3 months, log-rank P < 0.0001) survival than did the non-sarcomatoid group. The results of the multivariable Cox proportional hazard model revealed histological sarcomatoid subtype as an independent factor for all-cause mortality (hazard ratio [HR], 6.47; 95% confidence interval [CI], 3.12-13.43; P < 0.0001) and tumor recurrence (HR, 4.08; 95% CI, 1.72-9.66; P = 0.001). CONCLUSION: Compared with non sarcomatoid HCC, sarcomatoid HCC was associated with more advanced histological grades and atypical image patterns. Histological sarcomatoid subtype is an independent predictor of tumor recurrence after curative treatment and all-cause mortality in patients with HCC. This article is protected by copyright. All rights reserved. PMID- 30014621 TI - Choreographing Death: A Social Phenomenology of Medical Aid-in-dying in the United States. AB - This article draws on ethnographic research on the implementation of Vermont's 2013 medical aid-in-dying (AID) law to explore a fundamental paradox: While public discourse characterizes AID as a mechanism for achieving an individually controlled autonomous death, the medico-legal framework that organizes it enlists social support and cultivates dependencies. Therefore, while patients pursuing AID may avoid certain types of dependency-such as those involved in bodily care the process requires them to affirm and strengthen other bureaucratic, material, and affective forms. By tracing the social phenomenology of several AID deaths, I illustrate how AID results in distinctive forms of sociality and dependency that require terminally ill people and caregivers to embrace a collaborative stance toward choreographing death. I argue that assisted dying offers an opportunity to resist dominant U.S. cultural narratives that view dependency in purely negative terms and reimagine the relationships between disability, dependency, and care at the end of life. PMID- 30014622 TI - Successful treatment of primary donor-derived human herpesvirus-8 infection and hepatic Kaposi Sarcoma in an adult liver transplant recipient. AB - Kaposi sarcoma (KS) may rarely occur in transplant recipients through primary human herpesvirus-8 (HHV-8) infection from a seropositive donor. This report describes a patient who developed hepatic KS after receiving a split liver transplant from an HHV-8-positive donor. The recipient was treated with liposomal doxorubicin after reduction in immunosuppression led to acute cellular rejection. This treatment achieved regression of KS while preserving allograft function, demonstrating a successful therapeutic strategy for this malignancy. PMID- 30014623 TI - Honouring the role of community in community health work with Cambodian Americans. AB - Despite surviving extreme forms of violence, torture and other traumas during the Khmer Rouge genocide and forced migration, Cambodian Americans experience devastating health inequities and barriers to health access in the United States (U.S.). From the perspective of Cambodian American community health workers (CHWs), we explored three aims in this community-based participatory research (CBPR), qualitative study: Cambodian Americans' understanding of health, community health work strategies that improve health access of Cambodian Americans, and action steps that improve health access for Cambodian Americans. From 2014 to 2016, our two-phased study spanned seven U.S. states, which included a focus group (n = 5) and 16 semistructured interviews. Participants identified an indigenous concept of health, and micro-level (e.g. service navigation, peer education) and mezzo-level interventions (e.g. community building, coalition work) to improve health access. Finally, Khmer Health Advocates, a community based health advocacy organisation, served as a vital study partner in this CBPR study. PMID- 30014624 TI - Impact of an emergency department-run clinical decision unit on access block, ambulance ramping and National Emergency Access Target. AB - OBJECTIVE: ED access block is an ongoing significant problem and has been associated with excess mortality. Multiple models of care have been studied in an effort to improve access block and other key performance indicators (KPIs) of ED. METHODS: This present study describes the impact of a new model of care using an ED led, consultant run clinical decision unit (CDU) on performance, using a retrospective analysis of data for 9 month periods before and after the introduction of the CDU model of care. Primary outcomes were access block (percentage of patients admitted >8 h), discharge National Emergency Access Target (NEAT) adherence and Queensland Ambulance Service level three escalations. RESULTS: After the implementation of the CDU, access block significantly improved. There was a significant improvement in NEAT adherence. Total ambulance ramping time fell by 58% and ambulance service level three escalations fell from 21 to 5 post-CDU implementation. Overall there was no change to hospital mortality numbers. The percentage of patients that did not wait and 30 day representations showed a small but statistically significant decrease. CONCLUSION: In summary, this ED led, consultant run CDU model of care resulted in significantly improved performance on a range of KPIs, including improvement in access block and NEAT figures. The substantial improvements in ambulance ramping and escalations also indicated that the department was able to cope better with periods of high activity. PMID- 30014625 TI - Accuracy, satisfaction and usability of a flash glucose monitoring system among children and adolescents with type 1 diabetes attending a summer camp. AB - BACKGROUND: The study aimed to assess accuracy, satisfaction and usability of a flash glucose monitoring system (FGM) in children and adolescents with type 1 diabetes mellitus (T1DM) attending a diabetes summer camp. METHODS: Sixty-six children and adolescents with T1DM aged 6 to 17 years participating in a 7-day medically supervised summer camp were enrolled. Capillary blood glucose (BG) and flash glucose (FG) values were measured simultaneously at breakfast, lunch, and dinner and for any given FG value <72 mg/dL (<4.0 mmol/L) during daytime, <108 mg/dL (<6.0 mmol/L) at nighttime, >270 mg/dL (>15.0 mmol/L) or when patient symptoms were discordant with sensor readings. Sensor-related issues were documented and patients' and healthcare professionals' (HCPs) satisfaction was evaluated. RESULTS: FGM demonstrated satisfactory clinical accuracy compared to reference capillary BG values with 98.8% of values falling within the clinically acceptable zones (A and B) of the consensus error grid. Overall mean absolute relative difference (MARD) was 16.7% +/- 16.1%. Specific calculations of mean absolute difference (MAD), mean relative difference (MRD), and mean difference (MD) demonstrated that FGM overestimated BG values across all glycemic ranges. Overall satisfaction with the FGM was high in 91.7% participants and 95.0% HCPs, although confidence in the system was low in 18.0% participants and 40.0% HCPs. CONCLUSIONS: The FGM exhibited satisfactory clinical accuracy. However, based on the present data, we conclude that no decision should be taken on the basis of a single, non-verified, FGM value alone. Our study highlights the need for revised therapeutic education for patients/families and further investigation on the integration of sensor readings in clinical decision-making. PMID- 30014626 TI - Longer-Period Effects of Bicarbonate/Lactate-Buffered Neutral Peritoneal Dialysis Fluid in Patients Undergoing Peritoneal Dialysis. AB - High concentrations of lactate are considered to contribute to impairment of the peritoneal membrane. We investigated the longer-period effects of bicarbonate/lactate-buffered neutral peritoneal dialysis fluid (PDF) in patients undergoing PD for about 2 years. Patients undergoing PD were changed from a lactate-buffered neutral PDF to a bicarbonate/lactate-buffered neutral PDF. We then investigated the patients' clinical outcomes and peritoneal membrane functions as well as the surrogate markers in the drained dialysate. Fourteen patients undergoing PD were enrolled. Peritonitis was observed in one patient. No other adverse events were observed. Peritoneal function did not change as the ultrafiltration volume decreased. Fibrin degradation products and vascular endothelial growth factor in the drained dialysate decreased while the interleukin level increased. These results suggest that bicarbonate/lactate buffered neutral PDF may have beneficial effects in terms of peritoneal preservation and can be safely used in patients undergoing PD. PMID- 30014627 TI - [Effect of the Expression of iNOS Induced by Mycobacterium tuberculosis CRISPR associated Csm4 (Rv2820c) on Intracellular Viability of Mycobacterium smegmatis]. AB - OBJECTIVE: To determine how Csm4 protein expression affects intracellular survival of Mycobacterium smegmatis(MS). METHODS: Csm 4 gene was amplified by PCR to construct pMV261-Csm4 shuttle expression plasmid. The Csm4 protein expression in MS_Csm4 was detected by Western blot after electroporation of the recombinant plasmid into MS. The growth kinetics of MS_Csm4 in vitro and the influence of reactive N,O species on the growth of MS_Csm4were observed. The intracellular survival of MS_Csm4 and expressions of inducible nitric oxide synthase gene (iNOS) and nitric oxide production (NO) were detected after infection with THP-1 macrophages. RESULTS: Csm4 protein was successfully expressed in MS_Csm4,which did not affect the growth of the recombinant MS. Reactive N,O species decreased MS_Csm4 colony forming unit (CFU) in vitro. THP-1 increased the expression of iNOS and NO production and decreased intracellular survival of MS_Csm4. CONCLUSION: Recombinant MS_Csm4 is susceptible to reactive N,O species in vitro. THP-1 promotes NO release and thus discourages intracellular survival of MS. PMID- 30014628 TI - [Investigation of Lentiviral Vectors Based Integrin beta8 RNAi System in Neonatal Rats' Brain]. AB - OBJECTIVE: To construct lentiviral vectors expressing pSicoR-beta8 shRNA and evaluate its efficiency of RNA interference in neonatal rats' brain. METHODS: Plasmid vectors pSicoR-beta8 shRNA and pSicoR-control,as well as lentiviral packaging system pDM2G,g/p RRE and pRSV Rev were amplified respectively and plasmid DNA was identified by restriction enzyme digestion. Lentiviral packaging system and expressing vector pSicoR-beta8 shRNA/pSicoR-control were co transfected into packaging cell line 293T. Lentiviral particles expressing beta8 shRNA or control sequence packaged and secreted by 293T were collected,concentrated by PEG-it,and viral titers were assayed by 50% tissue culture infective dose (TCID50). RNAi for integrin beta8 in neonatal rats' brain was performed by intraventricular injection of lentivirus expressing beta8-shRNA and rats received lentivirus expressing beta8-shRNA were served as control. Green fluorescent protein (GFP) expression after intraventricular injection of GFP Lentivirus was observed under fluorescence microscope,beta8 mRNA and beta8 protein expression were detected by RT-PCR and Western blot respectively,all of which were performed to evaluate the RNAi efficiency and to choose the optimal time for intervention. RESULTS: Restrictive endonuclease digestion and agarose gel electrophoresis showed plasmids as same as the expected size. Lentiviral titers for LV-control after concentration was 1.0*108 PFU/mL,and for LV-beta8 shRNA 5.0*108 PFU/mL.One day after intraventricular injection of lentiviral vectors containing GFP sequence,lenticivirus genome was integrated into host cells and emitted green fluorescence. A relatively strong green fluorescence could be observed in brain slides 2 d,3 d and 5 d after intraventricular injection. Western blot and RT-PCR demonstrated a maximum inhibition happened 3 d after intraventricular injection of LV-beta8 shRNA,the inhibitory rate for beta8 mRNA and beta8 protein were 56% and 51%,respectively. CONCLUSION: Lentiviral vectors expressing beta8-shRNA are successfully constructed and lentiviral mediated beta8-RNAi is successfully applied for in vivo use. PMID- 30014629 TI - [The Expression and Biological Function of claudin-23 in Colorectal Cancer]. AB - OBJECTIVE: To determine the expression of claudin-23 in colorectal cancer and paracarcinoma tissues,and its effects on the proliferation and migration of colorectal cancer cells. METHODS: Six pairs of samples of colorectal cancer and corresponding paracarcinoma tissues were collected from the West China Hospital of Sichuan University. Quantitative real time PCR was performed to determine the expression of claudin-23 in the tissue samples. Colorectal cancer cell lines with stable overexpression of claduin-23 were constructed using lentivirus. CCK-8 and migration assays were conducted to identify the effects of claudin-23 on cell proliferation and migration. RESULTS: The expression of claudin-23 in colorectal cancer tissues decreased compared with their adjacent normal tissues (P<0.05). claudin-23 decreased cell adhesion and increased cell proliferation in HCT15 cells. RKO and HCT15 cells with over expressed claudin-23 had increased ability of migration. CONCLUSION: claudin-23 facilitates the migration ability of colorectal cancer cells and may participate in the metastasis of colorectal cancer. PMID- 30014630 TI - [Study on the Relationship Between XIAP Gene and Resistance of Taxol in Ovarian Cancer]. AB - OBJECTIVE: To research the expression of X-linked inhibitor of apoptosis protein gene (XIAP) on paclitaxel resistance in ovarian cancer. METHODS: A2780 and A2780/T cells were treated with paclitaxel respectively at the concentrations of 5 ng/mL,10 ng/mL,20 ng/mL , 40 ng/mL,80 ng/mL,160 ng/mL,320 ng/mL,then the inhibition rate of cells were detected by MTT assay. The expression of XIAP mRNA and protein among the A2780 and A2780/T cells treated respectively with paclitaxel at the concentration of 100 ng/mL was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot. The A2780/T cells were divided into blank group,empty group,small interfering RNA (siRNA) XIAP group and siRNA-non-specific group. The expression of XIAP mRNA and protein of four groups were detected by RT-qPCR and Western blot. Apoptotic rate of these groups with addition of paclitaxel at the concentrations of 0 ng/mL,1 000 ng/mL,1 500 ng/mL,2 000 ng/mL and 2 500 ng/mL were detected by flow cytometry. RESULTS: After the treatments on A2780 and A2780/T cells with the different concentrations of paclitaxel,the inhibition rate of A2780 cells were gradually increased with the increased paclitaxel concentrations (P<0.05),while there were no obvious differences in A2780/T cells (P>0.05). After the treatment on these cells with paclitaxel at the concentration of 100 ng/mL,the expression of XIAP mRNA was lower than that non-treatment with paclitaxelin A2780 cells (P<0.05),and the expression of XIAP mRNA in the A2780/T cells were no statistical significance between the treatment group and non treatment group with paclitaxel (P>0.05). However,the expression of A2780/T cells'XIAP mRNA and protein treated with paclitaxel were higher than A2780 cells' (P<0.05). The expression of XIAP mRNA and protein in siRNA-XIAP group was lower than those of other groups (P<0.05). The apoptotic rate of siRNA-XIAP group was higher than those of other groups treated with the paclitaxel at concentrations of 2 000 ng/mL and 2 500 ng/mL (P<0.05). CONCLUSION: XIAP's high expression on mRNA and protein was correlated with ovarian cancer paclitaxel resistance,specific siRNA can promote cell apoptosis by reducing the expression of XIAP,and increase the sensitivity of drug-resistant cancer cells to paclitaxel. PMID- 30014631 TI - [Influence of Acidosis on Electrophysiological Characteristics of Cortical GABAergic Neurons in Mice]. AB - OBJECTIVE: To investigate the influences of extracellular acidosis on spike encoding and synaptic transmission of cortical GABAergic neurons in mice. METHODS: Twenty mice aged 27-30 d mice were selected to prepare coronary cortical slices and then divided into control group and extracellular acidosis group. In control group,the coronal slices were perfused with artificial cerebrospinal fluid at pH7.4,the action potential threshold potential,absolute refractory period and action potential peak spacing were recorded with the patch-clamp all cell current clamp mode; the spontaneous excitatory postsynaptic current was recorded with the voltage clamp mode extracellular acidosis group,the artificial cerebrospinal fluid was adjusted at pH6.5,mimicking extracellular acidosis. Recorded neurons action potential and spontaneous excitatory postsynaptic currents again,comparing the difference of the above indexes between the two groups. RESULTS: Compared with the control group,the extracellular acidosis significantly prolonged the inter-spike intervals and absolute refractory periods (P<0.01),increased the voltage of threshold potentials and the amplitude and frequency of spontaneous excitatory postsynaptic currents (P<0.01). CONCLUSION: Extracellular acidosis leads to the dysfunction of cortical GABAergic neurons by breaking the inter-characteristics and synaptic transmission,contributing one of the possible mechanisms to acidosis-induced brain damage. PMID- 30014632 TI - [Expression and Regulatory Effect of miR-30b on Dynamin in Cochlear Hair Cells]. AB - OBJECTIVE: To determine the expression of miR-30b in hair cells of mice,and its regulatory effect on the target gene DNM1 and expression of Dynamin,the key protein of synaptic endocytosis in inner hair cells. METHODS: The basilar membrane of cochlear in adult C57 mice was obtained. The expression of miR-30b in the hair cells was detected by in situ hybridization. Luciferase vector was constructed and transfected into 293T cells with miR-30b. Changes in luciferase activity were measured to verify whether DNM1 was the target gene of miR-30b. Adeno-associated virus carrying miR-30b were micro-injected into cochlear via the round window membrane. mRNA expressions of DNM1 and miR-30b were detected by RT PCR 14 days later. The expression of Dynamin was detected by Western blot. RESULTS: miR-30b expressed in the inner and outer hair cells scattered in the region of the nucleus and cytoplasm. miR-30b reduced luciferase activity from the reporter vector containing DNM11 (P<0.05),but not in its mutants. Increased expressions of miR-30b and decreased mRNA expressions of DNM1 and Dynamin were observed following transfection of AAV-miR-30b. CONCLUSION: miR-30b expresses in inner and outer hair cells,which is consistent with the morphological orientation of dynamin. miR-30b inhibits the expression of Dynamin by targeting DNM11 gene. PMID- 30014633 TI - [Effects of Targeting lncRNA HOTAIR on the Invasion and Nude Mouse Tumorigenicity of Epithelial Ovarian Cancer Cells]. AB - OBJECTIVE: To explore the effects of shRNA-mediated downregulating lncRNA HOTAIR on the invasion,nude mouse tumorigenicity and snail expression of epithelial ovarian cancer SKOV3 cells. METHODS: The expression of lncRNA HOTAIR was detected by RT-PCR in SKOV3 cells. The shRNA targeting the lncRNA HOTAIR gene was cloned into RNA interference plasmid. The construction shHOTAIR vector was transfected into ovarian cancer SKOV3 cells by lipofectamine 2000,and the stably transfected cells were isolated by G418 and single clone selection. The downregulating expression of lncRNA HOTAIR was detected by quantitative real time PCR(qRT-PCR). The characteristics of shHOTAIR transfected SKOV3 cells were analyzed from the assays of invasion and nude mouse tumorigenicity,as well as the expression of snail and E-cadherin mRNA detected by qRT-PCR,and snail detected by immunohistochemistry and Western blot methods in xenograft tumor,respectively. RESULTS: The lncRNA HOTAIR expression was proved by RT-PCR in SKOV3 cells. The lncRNA HOTAIR expression in shHOTAIR transfected SKOV3 cells was significantly lower than the scramble control (P<0.01). The shHOTAIR transfected SKOV3 cells show that the invasion ability was significantly decreased compared with the scramble control (P<0.01). The nude mouse tumorigenicity,including tumorigenicity mouse number and tumor volume,was significantly decreased compared with the control group (P<0.01). The snail protein expression detected by IHC and Western blot in shHOTAIR-SKOV3 xenograft tumor was significantly decreased compared with the control scramble- SKOV3 group (P<0.05). The lncRNA HOTAIR low expression resulted in increasing E-cadherin and decreasing snail expression detected by qRT PCR in the shHOTAIR transfected SKOV3 cells of xenograft tumor,compared with the scramble control (P<0.05). CONCLUSION: Targeting lncRNA HOTAIR expression in SKOV3 cells with RNA interference can decrease snail,increase E-cadherin and significantly reduce the invasion and tumorigenicity of epithelial ovarian cancer SKOV3 cells. These results suggest that the lncRNA HOTAIR could be an effective therapeutic target for human epithelial ovarian caner treatment. PMID- 30014634 TI - [Interference of Lumican Regulates the Invasion and Migration of Liver Cancer Cells]. AB - OBJECTIVE: To explore the effect of silencing lumican on the invasion and migration of liver cancer cells. METHODS: Lumican was silenced by shRNA in liver cancer cells (HepG2 and MHCC97H). The mRNA levels of lumican were detected by qRT PCR. Cell invasion was measured by Transwell. Cell migration was tested via wound healing. The protein levels of lumican,MMP-9,VEGF,ERK1,JNK,p-ERK1 and p-JNK were measured by Western blot. RESULTS: Liver cancer cells (HepG2 and MHCC97H) had higher levels of mRNA and protein of lumican compared with normal hepatocyte L02 (P<0.01). shRNA lowered the levels of mRNA and protein of lumican (P<0.01),and weakened the invasion and migration of cancer cells (P<0.01). The expressions of MMP-9 and VEGF decreased with the shRNA silence (P<0.01). shRNA also reduced the protein level of p-ERK1 and p-JNK (P<0.01). CONCLUSION: Silencing lumican by shRNA attenuates the invasion and migration of liver cancer cells via inhibiting the activation of ERK1/JNK pathway. PMID- 30014635 TI - [Gender-dependent Expression of ERbeta in AEC II of Fetal Mice Exposed to Arsenic and Estrogen Receptor Antagonist]. AB - OBJECTIVE: To determine the effects of arsenic and estrogen receptor antagonist (ICI182, 780) on the expression of estrogen receptor beta (ERbeta) in alveolar II epithelial cells (AECII) of female and male mice. METHODS: Nineteen or twenty day fetus mice were obtained through caesarean section of ICR mice. Purified AECII cells were separated from the female and male fetus,respectively,and confirmed using immunofluorescence staining. The cells were exposed to sodium arsenite (NaAsO2) at a low,medium,or high dosage determined by MTT and cultured for 24 h. The NaAsO2 (5 MUmol/L) exposed cells were compared with those treated (for 24 h) with dimethyl sulfoxide (DMSO) or ICI182, 780 (1*10-4 mol/L). Apoptosis rates of the cells were measured by flow cytometry. Real-time fluorescence quantitative PCR method and Western blot technique were used to detect the expression ofERbetamRNA and protein in AECII. RESULTS: Purity of AECII cells reached (87.0+/ 2.5)%. NaAsO2 exposure was set at a concentration of 0.5 (low),1.25 (medium),and 5 (high) MUmol/L. The cells exposed to medium and high dosage of NaAsO2 had higher apoptosis rates than the blank controls (P<0.05),without sex differences. Female cells exposed to medium and high dosage of NaAsO2 had higher levels of expressions ofERbetamRNA and protein than the blank controls (P<0.05) and male cells exposed to the same dosage of NaAsO2 (P<0.05). No significant differences were found in the expressions ofERbetamRNA and protein between the exposed male cells and the blank controls. ICI182, 780 lowered the expression levels ofERbetamRNA and protein in the female exposed cells (P<0.01). CONCLUSION: Arsenic exposure increases expressions of AECII's ERbeta,more so in female cells than in male cells. This can be blocked by estrogen receptor antagonists. PMID- 30014636 TI - [Effects of Phenylalanine on Glucose Uptake in Mouse Myoblast Cell Line C2C12 and Its Relationship with mTOR-p70S6K Pathway]. AB - OBJECTIVE: To investigate the influence of phenylalanine(Phe) on glucose uptake in mouse myoblast cell line C2C12 and to explore its relationship with mTOR p70S6K pathway. METHODS: C2C12 cells were cultured to promote formation of multinucleated myotubes in vitro.The cells were deprived and incubated with Phe at different concentrations (1.25,2.5,5,10,20 mmol/L).Krebs-Ringer buffer (KRB) was used as control.The 2-NBDG was used to measure glucose uptake of C2C12.The expression of mTOR,p70S6K,IRS-1,and Akt protein were evaluated by Western blot. RESULTS: Compared with KBP treatment,glucose uptake of the cells incubated with 5 mmol/L leucine (Leu) was decreased by 30% (P=0.001), while a 40% increase was detected in the cells incubated with 5 mmol/L Phe (P<0.01).The promotion of glucose uptake was Phe concentration-dependent.Phe stimulation had no effect on the phosphorylation of mTOR at Ser2448. Phosphorylation of p70S6K at Thr389 was inhibited in the cells incubated with Phe at concentration higher than 1.25 mmol/L, but the difference was not significant (P=0.815). Leu stimulated but Phe over 1.25 mmol/L inhibited phosphorylation of IRS-1 at Ser636/639, although the difference was not significant (P=0.381).Neither Leu nor Phe affected the expression of phospho-Akt (Ser473) significantly. CONCLUSION: Phenylalanine inhibits phosphorylation of IRS-1 at Ser636/639 possibly through inhibiting the activation of p70S6K.The effect of Phe on mTOR-p70S6K pathway is Akt-independent. PMID- 30014637 TI - [Effect of Flavonoids from Wang Zaizi on Adjuvant Arthritis in Rats and Its Mechanism]. AB - OBJECTIVE: The therapeutic effect and mechanism of total flavonoids in Isodon amethystoides (Ben-th) Cy Wu et Hsuan (TFIA) on adjuvant arthritis (AA) were investigated. METHODS: AA model rats were set and complete Freund's adjuvant injection,randomly divided into 4 groups: AA group,AA+TFIA 50 mg/kg group,AA+TFIA 100 mg/kg group,AA+TFIA 150 mg/kg group,and each group has 10 rats. Blank control group was set without modeling (n=10). Four days post-modeling rats in each TFIA groups were treated once a day with TFIA at 50 mg/kg,100 mg/kg and 150 mg/kg for 24 d,and rats in blank control and AA groups were given saline as control. At the 12th day,16th day,20th day and 24th day of treatment,the effect of TFIA on AA rats was evaluated by rat arthritis score. Then the rats were sacrificed on the 24th day of treatment,and the synovial tissue of rats was isolated and the fibroblast-like synoviocytes (FLS) were primary cultured. The expressions of IL-1 in FLS was detected by ELISA,the FLS proliferation activity was detected by MTT assay,and the expression of miR-152,beta-catenin and cyclin D1 gene (ccnd1) were detected by real time qPCR. MiR-152 mimics and NC mimics (control) were transfected into FLS in AA rats,and miR-152 inhibitors and NC inhibitors (control) were transfected into FLS in AA+TFIA 100 mg/kg group rats. The expressions of miR-152,beta-catenin, ccnd1, IL-1 and FLS proliferation were detected 36 h post-transfection. RESULTS: TFIA significantly inhibited the arthritis socre of rats and the expressions of beta-catenin, ccnd1, IL-1 and the proliferation of FLS in AA rats (P<0.05). There was no significant difference between the dose groups,all of which were significant when compared with the blank control group (P<0.05). Compared with the control group,the expression of miR-152 in AA group was significantly decreased (P<0.05). After transfection of miR-152 mimics into AA FLS,overexpression of miR-152 significantly inhibited the expressions of beta-catenin, ccnd1, IL-1 and the proliferation of FLS (P<0.05). After transfection of miR-152 inhibitors into FLS from AA+TFIA 100 mg/kg group,inhibition of miR-152 significantly promoted the expressions of beta catenin, ccnd1, IL-1 and the proliferation of FLS. CONCLUSION: TFIA has a certain therapeutic effect on AA rats via the up-regulation of miR-152 expression,possibly affecting the classical Wnt signaling pathway. PMID- 30014638 TI - [Effects of Thapsigargin on Intracellular Ca2+ and Caspase-3 Protein Expression in Mouse Lung Fibroblast]. AB - OBJECTIVE: To explore the effects of calcium pump inhibitor thapsigargin (TG) on intracellular Ca2+ and the expression of caspase-3 protein in mouse lung fibroblast. METHODS: Mice lung fibroblast cells were divided into three groups: the blank control group,transforming growth factor-beta1 (TGF-beta1) group and TG treated group. The cells were induced by 5 ng/mL TGF-beta1 for 24 h in TGF-beta1 group and TG group,4 MUmol/L TG was added in TG group for 24 h. After 48 h,the cells were collected,and the cell structure was observed by transmission electron microscope,intracellular Ca2+ level was detected with laser confocal microscope,the protein expression of caspase-3 was examined using immunohistochemistry method. RESULTS: Transmission electron microscopy showed that the cells in the blank control group had obvious nucleolus,complete organelles and less apoptosis. In TGF-beta1 group,the cell morphology was intact,chromatin was evenly distributed,and no apoptotic cells were found. In TG group,there were a large number of apoptosis of fibroblasts,chromatin clumps in nuclei and a small amount of collagen fibers. The level of Ca2+ in TGF-beta1 group was significantly lower than that in control group (P<0.05),and which in TG group was significantly higher (P<0.05 ). The protein expression of caspase-3 in TGF-beta1 group were significantly lower than that in blank control group (P<0.05),which in TG group increased obviously (P<0.05). CONCLUSION: TG could cause intracellular calcium dysregulation in mouse lung fibroblasts,increase caspase-3 protein expression and promote cell apoptosis. PMID- 30014639 TI - [Effect of Rutin on Liver Function and Morphology in Type 1 Diabetes Mice Induced by Streptozotocin]. AB - OBJECTIVE: To investigate the effect of Rutin on the function and morphology of liver in type 1 diabetes mice induced by streptozotocin (STZ). METHODS: Type 1 diabetic mice model was established with the treatment of STZ by a 5 d intraperitoneal administration to male Kunming mice. Normal group had 12 mice without treatment of STZ,the mice with DM after STZ treated were randomly divided into DM group,low-dose (50 mg/kg) Rutin group and high-dose (100 mg/kg) Rutin group,each group had 12 mice. The mice in normal and DM group were given sodium carboxymethyl cellulose (10 mg/kg). Each mice was given above drugs by intragastric administration for 8 weeks. Postprandial random blood glucose was measured at 4 weeks and 8 weeks and the levels of alanine aminotransferase (ALT),aspartate aminotransferase (AST),lactate dehydrogenase (LDH),total protein (TP) and albumin (ALB) in serum were detected by automatic biochemical analyzer after 8 weeks. The morphology of liver was observed by HE and Masson staining. The ultrastructure of liver tissue was observed by electron microscope. RESULTS: After a continuous small-dose injection of STZ,the success rate of diabetes model mice were up to 98%. The blood glucose of the model group was significantly increased (P<0.01),and the levels of ALT,AST and LDH in serum were significantly higher,and TP and ALB were lower than those in normal group (P<0.05,P<0.01). Compared to the DM group,the levels of blood glucose were lower (P<0.05) at 4 weeks and 8 weeks,the contents of ALT,AST and LDH were significantly decreased,and TP and ALB were improved in both Rutin dose group. High-dose group performed more obvious (P<0.05,P<0.01). Morphological observation showed the tissue morphology of Rutin treatment group were improved obviously,and the effect was more significant in high-dose Rutin group. CONCLUSION: Rutin may improve the liver function and reduce the damage of liver tissue in STZ-induced type 1 diabetic mice. PMID- 30014640 TI - [The Research on the Anti-glioma Effect and Mechanism of Cinobufagin]. AB - OBJECTIVE: To study the effect of cinobufagin (CB) on the proliferation inhibition and induction of apoptosis in glioblastoma cell lines U87 and its molecular mechanism. METHODS: A gradient concentration (0-20 MUmol/L) of CB was used to treat the U87 glioma cells for 6 h,12 h,24 h and 48 h,respectively. Cell viabilities were determined by CCK-8 assay to discover the effects of different concentrations of CB on the proliferation of glioma cells. Different concentrations (1-20 MUmol/L) of CB were used to treat the U87 glioma cells for 12 h and 24 h,hochest33342 staining assay was used to assess the apoptosis levels. Immunofluorescence staining was used to determine the expression of growth related proteins phospho-protein kinase B(T308)[ p-AKT(T308)] in U87 glioma cells after being treated with CB for 24 h. Western blot was used to determine the apoptotic related proteins (BAX,cleaved-caspase 3,cleaved-caspase 9) and growth related proteins [phospho-inositide 3-kinase (p-PI3K),p-AKT(T308),p AKT(S473),phospho-ribosomal protein S6 kinase (PS6),phospho-4E-binding protein 1 (p-4EBP1)]. RESULTS: A significant effect of CB on the proliferation inhibition and induction of apoptosis in U87 glioma cells in a time- and dose-dependent manner was observed. Treatment with CB induced the expression levels of apoptosis related protein,cleaved-caspase 3 and BAX,and the PI3K-AKT-4EBP1 signaling pathway related proteins p-AKT(T308) and p-4EBP1 were decreased. CONCLUSION: CB can inhibit U87 glioma cells growth and induce apoptosis,which may involve the PI3K-AKT-4EBP1 and BAX-caspase signaling pathways. PMID- 30014641 TI - [The Study of Protective Effect of Paeoniflorin on Lung Injury in MRL/lpr Mice]. AB - OBJECTIVE: To investigate the protective effects of paeoniflorin on the lung injury in systemic lupus erythematosus with mouse model. METHODS: Ten wild type mice and 40 MRL/lpr mice were used in this study. MRL/lpr mice were randomly assigned to MRL/lpr group,MRL/lpr + dexamethasone (1.5 mg/kg) group,MRL/lpr + paeoniflorin (20 mg/kg) group,and MRL/lpr + paeoniflorin (40 mg/kg). The levels of malondialdehyde (MDA) , superoxide dismutase (SOD) ,catalase (CAT) ,glutathione peroxidase (GSH-Px) in serum were detected. The serum levesl of inflammatory cytokines were measured. Lung pathological changes were determined by HE staining. The protein level of phospho-phosphatidylinositol-3 kinase (P PI3K),phospho-serine-threonine kinase B(P-Akt) ,phospho-nuclear factor kappa B (P NF-kappaB),phospho-inhibitor of nuclear factor kappa Balpha (P-IkappaBalpha) were detected by Western blot. RESULTS: Paeoniflorin decreased serum level of MDA and increased the levels of SOD,CAT,GSH-PX,and decreased the levels of inflammatory cytokines. Paeoniflorin improved lung pathological changes and inhibited the protein levels of P-PI3K,P-Akt,P-NF-kappaBp65,and P-IkappaBalpha in the lung tissue of MRL/lpr mice. CONCLUSION: Paeoniflorin may be beneficial for the prevention of lung injury in systemic lupus erythematosus. PMID- 30014642 TI - [The Value of Circulating Exsomal miR-451a to Monitor Therapy Response in Diffuse Large B Cell Lymphoma]. AB - OBJECTIVE: To investigate the expression level of circulating exsomal miR-451a and its significances in therapy monitoring in diffuse large B cell patients. METHODS: We isolated exsomal RNAs fractions from serum of 56 DLBCL patients before treatment,during treatment and after treatment. The serum of 56 healthy controls was collected at the same time. Quantitative real time polymerase chain reaction (qRT-PCR) were performed to detected the expression level of circulating exsomal miR-451a. Receive operater characteristic (ROC) curve was performed to comfirm the diagnostic efficiency of miR-451a. Chemotherapy effect corresponding with miR-451a was analyzed. RESULTS: Circulating exsomal miR-451a was down expression in DLBCL compared with healthy controls (P<0.000 1), and the area under the ROC curve (AUC) was 0.737 (95%CI0.645-0.816) . In 43 patients who had complete follow-up information,the patients who obtained remission,including complete remission (CR) and partial remission (PR) ,had the levels of circulating exsomal miR-451a gradually increased. While in patients who did not get remission, including stable disease (SD) and progression disease (PD) ,had no significant changes of circulating exsomal miR-451a. CONCLUSION: Circulating exsomal miR-451a may be an potential indicator for therapy response monitoring in DLBCL. PMID- 30014643 TI - [The Relationship of Clinicopathology of p16 in Non-small Cell Lung Cancer and 5 nitrogen impurity-2'-deoxycytidine-nitrogen Impurity on the Influence of p16 Expression in Lung Cancer A549 Cells]. AB - OBJECTIVE: To investigate the relationship between expression of tumor suppressor gene p16 in non-small cell lung cancer (NSCLC) tissues and clinicopathological parameters,to further study on DNA methyltransferase inhibitors 5-nitrogen impurity-2'-deoxycytidine (5-Aza-CdR) in human lung cancer cell line A549 in regulating the expression of p16. METHODS: The expression of p16 protein in 76 cases of NSCLC tissues and normal tissue adjacent to carcinoma were detect by immunohistochemical SP method and the differences of p16 protein expression were analyzed. p16 gene promoter region of DNA methylation status were detect by MSP method in 5-Aza-CdR processing A549 cells,the expression of p16 in A549 lung cancer cell and effect of 5-Aza-CdR were detect by Western blot method. RESULTS: 32 cases (42.11%) of p16 protein expression was positive,significantly lower than that of the normal tissue adjacent to carcinoma (positive expression in 59 cases,77.63%) in 76 cases of NSCLC tissues; There were statistically significant differences (P<0.05) in the positive expression rates of p16 in NSCLC tissues with different pathological tissue grading,tumor differentiation degree,clinical TNM stage and lymph node metastasis. In A549 cells,p16 protein expression and non methylated products were both in low expression states. After treated with 5-Aza CdR,the expression of p16 protein and its non-methylated products were up regulated,with the increase of 5-Aza-CdR concentration. CONCLUSION: The low expression of p16 in NSCLC tissues with squamous cell carcinomas,low differentiation,lymph node metastasis and phase III-IV,which may prompt the deactivation and cause further progression of NSCLC,5-Aza-CdR could induce the expression of p16 protein and non-methylated products in A549 cells. PMID- 30014644 TI - [Preliminary Study on Association Between Intestine Microbiota and Blood Glucose,Blood Lipid Metabolism in Middle-aged and Elderly People in Chengdu]. AB - OBJECTIVE: To investigate the possible relationship between the gut microbiota and hyperlipidemia,hyperglycemia in middle-aged and elderly people in Chengdu. METHODS: 51 of middle-aged and elderly people participated in this study. The concentration of blood glucose and lipid,and the other physiological parameters of the subjects were analyzed,and their fecal microbiota was also profiled by Illumina high-throughput sequencing technique. RESULTS: The fecal microbiota in the middle-aged and elderly were mainly Firmicutes,Bacteroidetes,Proteobacteria,Fusobacteria,Actinobacteria,Verrucomicrob a. The diversity offecalmicrobiota was significantly lower in the subjects with higher blood glucose (P<0.05),while it did not exhibited relationship with changes in blood lipids. At the bacterial phyla: Proteobacteria and Bacteroidetes were respectively significantly higher in middle-aged and elderly women with higher blood glucose (P<0.05). At the bacterial genus: Faecalibacterium was significantly lower in the hyperglycemic subjects (P<0.05),its abundance and blood glucose levels were negatively correlated (r=-0.278,P=0.048); Prevotella and Paraprevotella were significantly lower in the high blood lipids group (P<0.05),and both of them were negatively correlated with blood lipid levels (r= 0.357,P=0.10; r=-0.365,P=0.008). CONCLUSION: The fecal microbiota in the tested middle-aged and elderly subjects varied with blood glucose and blood lipid concentration. Intestinal microbes might posses close relationship with blood glucose and lipid metabolism in middle-aged and elderly people. PMID- 30014645 TI - [Association of Serum Soluble CD36 with Clinical Variables in Diabetic Patients with Chronic Kidney Diseas]. AB - OBJECTIVE: To investigate the levels of serum soluble CD36 (sCD36) in patients of diabetes mellitus (DM) with chronic kidney disease (CKD),and to analyze its correlation with clinical indicators. METHODS: A total of 161 patients with CKD were enrolled in this study. The patients were divided into two groups according to whether they had DM or not: DM+CKD group and non-DM CKD group. The levels of carotid intima-media thickness (IMT) and the combination of atherosclerotic plaques were measured by color Doppler ultrasonography. Serum fasting serum samples were collected and serum sCD36 level was measured by ELISA. the status of serum sCD36 was analyzed with the progress of renal disease,and the correlation of sCD36 level with clinical indicators were analyzed. RESULTS: Among the 161 patients,87 (54%) were DM+CKD and 74 (46%) were non-DM CKD. There was no significant difference in the levels of urea nitrogen (BUN),serum creatinine (sCr),estimated glomerular filtration rate (eGFR),cystatin C (Cys-C),triglyceride (TG),cholesterol (Chol),low density lipoprotein-chol (LDL-C),urinary albumin/creatinine and IMT in the two groups (P>0.05). Compared with non-DM CKD group,the serum sCD36 level (U/L) in DM+CKD group was lower (4.58+/-1.06 vs. 4.97+/-1.28,P<0.05). In DM+CKD group,serum sCD36 was negatively correlated with BUN,sCr and Cys-C (r=-0.355,-0.336,-0.323; P<0.01),and positively correlated with eGFR (r= 0.399; P<0.01),but not with TG,Chol,LDL-C or IMT (P>0.05). In non-DM CKD group,there was a positive correlation between sCD36 and TG,Chol and LDL-C (r= 0.251, 0.298, 0.292; P<0.05),and negatively correlated with Cys-C (r=-0.287; P<0.05),but not with eGFR,BUN,sCr or IMT (P>0.05). With the progress of CKD,serum sCD36 levels gradually decreased (P>0.05). CONCLUSION: Serum sCD36 level is associated with renal function in the patients with DM complicated with CKD,but not with lipid indicators. PMID- 30014646 TI - [IL-8 Induces Epithelial-to-mesenchymal Transition of Ovarian Carcinoma Cells: a Preliminary Study]. AB - OBJECTIVE: To explore the effect of IL-8 on the epithelial-to-mesenchymal transition (EMT) in ovarian cancer,which will provide experimental basis for revealing related molecular mechanism in malignant metastasis of ovarian cancer. METHODS: The migration of ovarian cancer cell line SKOV3 cells was explored with Real time label free cell analysis (RTCA) after treatment with recombinant human IL-8.SKOV3 cells were co-cultured with IL-8 for 48 h,proteins involved in EMT were investigated via Western blot to explore the effect of IL-8 on the activation of the EMT. Invasion of SKOV3 cells after treatment with IL-8 were evaluated by transwell assay. RESULTS: According to the results of RTCA,after treatment with IL-8 for 48 h,the migration of SKOV3 cells was in platform phase. The treatment of IL-8 unregulated vimentin and snail and downregulated E cadherin,which suggested that IL-8 induced EMT in ovarian cancer. The results of transwell test showed that invasive ability of IL-8 pretreated SKOV3 cells was enhanced (P<0.05). CONCLUSION: IL-8 can induce the EMT of ovarian cancer and enhance the invasion and migration of ovarian cancer. PMID- 30014647 TI - [Validity of the Inpatient Satisfaction Questionnaire]. AB - OBJECTIVE: To assess the validity of the self-designed inpatient satisfaction questionnaire using Structural Equation Model (SEM). METHODS: The questionnaire survey was conducted in a tertiary hospital in Sichuan in April 2016,with participants selected through a systematical sampling approach. The structural validity of the inpatient satisfaction questionnaire was assessed using SEM. The statistical analyses were performed using Lisrel8.70. RESULTS: About 98.5% of returned questionnaires were valid for data analyses,which resulted in a total sample of 2562. A good model fit was achieved: df=8.36,root mean square error of appoximation (RMSEA)=0.054,root mean square residual (RMR)=0.021,goodness-of-fit index (GFI)=0.93,adjusted GFI (AGFI)=0.91,com-parative fit index (CFI)=0.98,non normed fit index (NNFI)=0.98,parsimony GFI(PGFI) =0.74. Factor loadings on exogenous latent variables ranged from 0.59 to 0.94,with 0.52-0.87 AVE. CONCLUSION: The questionnaire has a good construct validity,which can be used for evaluating inpatient satisfaction in tertiary hospitals. PMID- 30014648 TI - [Missing Data Replacement Methods in Different Scenarios]. AB - OBJECTIVE: To compare the effect of different approaches of missing data replacement on the regression coefficient estimates r of "length of stay" on "hospital expenditure". METHODS: Data were extracted from the medical records of patients with head and neck neoplasms who were admitted to Sichuan Cancer Hospital. R 3.4.1 was used for generating and processing simulated datasets. Various scenarios were established by setting up different proportions of missing data and missing mechanisms using Monte Carlo method. Three strategies were tested for replacing missing data: Complete Case method,Expectation Maximization (EM),and Markov Chain Monte Carlo method (MCMC). The regression coefficient estimates r of standardized "length of stay" on standardized logarithmic "hospital expenditure" were calculated using these strategies and compared with that of the original complete dataset,in terms of their accuracy (magnitude of differences in r) and precision (differences in the standard error of r). RESULTS: The three replacement methods were all acceptable (within the limit rc+/ 0.5 sc) when missing data were generated using MAR (2?1) mechanism,or less than 30% data were simulated as missing using the MCAR and MAR (1?2) mechanism. The EM method had the best estimation precision. CONCLUSION: Missing data replacement should consider the proportion of missing data and potential mechanisms involved. PMID- 30014649 TI - [Three-dimensional Ultrasound Assessment on Apical Vertebral Rotation in Patients with Adolescent Idiopathic Scoliosis:Reliability and Validity Analyses]. AB - OBJECTIVE: To assess reliability and validity of the three-dimensional (3-D) ultrasound measurement of apical vertebral rotation in patients with adolescent idiopathic scoliosis (AIS). METHODS: Sixteen female AIS patients were recruited. Ultrasound examinations were performed using a 3-D ultrasound unit with a SonixGPS system,which were compared with magnetic resonance imaging (MRI) examinations conducted on the same day. Two raters performed 3-D ultrasound scanning in supine position on angle measurements for vertebral rotation in the transverse plane three times,respectively. The center of laminae (COL) method was used to measure apical vertebral rotation in the 3-D ultrasound image,compared with the Aaro-Dahlborn results of MRI. Reliability of the 3-D ultrasound measurements was assessed using intra-class correlation coefficients (ICC),mean absolute deviation (MAD),standard deviation (SD) and standard error of measurement (SEM). Validity of the 3-D ultrasound measurements was assessed using paired Student t-tests,Bland-Altman statistics and Pearson correlation coefficients. The level of significance was set as 0.05. RESULTS: 3-D ultrasound had high intra- and inter-rater reliabilities (ICC [2,k]>0.9,P<0.05) for assessing vertebral rotation. There was no significant difference between the Aaro-Dahlborn results in MRI and the COL Results in 3-D ultrasound (P>0.05). High consistencies (Bland-Altman) and correlations (Pearson) were demonstrated between the two methods. CONCLUSION: Radiation-free 3-D ultrasound is a reliable and valid method for measuring apical vertebral rotation in the transverse plane of patients with AIS. PMID- 30014650 TI - [Quantitative Assessment of Skin Thickness using High Frequency Ultrasound in Systemic Sclerosis]. AB - OBJECTIVE: To investigate the performance of high frequency ultrasound in the assessment of skin thickness in patients with systemic sclerosis (SSc). METHODS: The study included 82 SSc (SSc group) and 67 healthy volunteers (control group) from 2014 to 2016. The skin thickness at bilateral middle fingers and forearms,anterior chest and abdominal wall was measured using high frequency ultrasound. All the patients with SSc underwent the modified rodnan skin score (mRSS) over 17 anatomical sites by an experienced dermatologist. The differences in age,sex,height,body mass,body mass index (BMI) and skin thickness between SSc patients and healthy controls were compared. Receiver operating characteristic (ROC) curve analysis was performed to determine the performance of high frequency ultrasound in the differentiation of SSc from healthy skin,and the correlation of mRSS with skin thickness were analyzed. RESULTS: SSc patients and healthy controls shared similar demographic features (age,sex ratio,height,body mass,BMI) (P>0.05). Skin thickness values in SSc patients were increased significantly at fingers and forearms compared with healthy controls (P<0.05). The area under the curve (AUC) was 0.938, 0.905, 0.608, 0.586, 0.398, 0.321 at right and left finger,right and left forearm,chest and abdominal wall. Among them,AUC>0.9 of right and left fingers can be used for diagnosis,The skin thickness cut-off value for determining the diagnosis of SSc were as follows: 1.35 mm at the right finger with 84.1% sensitivity and 95.5% specificity,1.26 mm at the right forearm with 86.6% sensitivity and 89.6% specificity,respectively. Skin thickness increased significantly with mRSS. The correlation of total mRSS scores with total skin thickness was 0.599 (P<0.001),and the correlation of local mRSS score with local skin thickness were 0.400-0.623 (P<0.001),with the highest correlation coefficient at right finger and the lowest at abdomen. CONCLUSION: High frequency ultrasound may reflect extent of skin involvement of SSc,and skin thickness assessed with high frequency ultrasound appeared to be highly specific and sensitive at fingers. PMID- 30014651 TI - [Clinical Comparative Analysis of Cryptococcus neoformans Meningitis Between Patients with and without AIDS]. AB - OBJECTIVE: To compare clinical characteristics and therapeutic outcomes between HIV and non-HIV patients with Cryptococcus neoformans meningitis (CNM). METHODS: A total of 73 patients with CNM (30 patients without HIV and 43 with HIV) were admitted from January 2012 to January 2017. The clinical manifestations,biochemical and microbiological characteristics of cerebrospinal fluid (CSF) were collected and analyzed. RESULTS: The patients in the two group displayed non-specific symptoms such as headache,fever,nausea and vomiting. Non HIV CNM patients had more serious inflammatory reaction with higher karyocytes and protein level (P=0.000,P=0.041,respectively),while had lowere positive rate of primary ink staining in cerebrospinal fluid (70.0% vs. 93.0%,P=0.009),higher misdiagnosis rate (43.3% vs. 14.0%,P=0.005),longer hospitalization duration [(112.27+/-105.42) d vs. (52.64+/-39.17) d,P=0.021],higher adverse reactions rate of antifungal treatment was (80.0% vs. 30.2%,P=0.000). However,in HIV CNM patients,40 (93.0%) patients did not receive antiviral therapy before and were diagnosed as AIDS for the first time; the therapeutic effect in this group was very poor with higher mortality (30.2% vs. 13.4%,P=0.000). CONCLUSION: Immunity status should be considered in the diagnosis and treatment of CNM,since it is difficult to diagnose with long treatment period and poor prognosis. PMID- 30014652 TI - [Drug Knowledge of Middle School Students in HIV-prone Areas of Liangshan]. AB - OBJECTIVE: To investigate drug knowledge of middle school students in HIV prone areas in Liangshan of Sichuan Province. METHODS: Students were randomly selected from the middle schools located in the HIV prone areas in Liangshan. A questionnaire survey was conducted. Drug knowledge of the respondents and associated factors were analyzed. RESULTS: Of the 10 749 respondents,10.1% had wrong knowledge about drugs. The respondents of male gender and minority ethnicity in the region and those who were in a lower grade,had poor academic records,more sisters,and a schoolmate taking drugs,and lived in a family with HIV infected member were more likely to had poor drug knowledge. By contrast,the respondents who had a peasant father,lived with both parents,resided in a city or township,self-rated in the middle and low 1/3 of wealth,lived in a community with >50% school attendance,and had a family member taking drugs were less likely to have wrong drug knowledge. CONCLUSION: Middle school students in the HIV prone areas in Liangshan have poor drug knowledge. Socioeconomic factors influence the drug knowledge of students,which require systematic interventions. PMID- 30014653 TI - [Efficacy of Screening and Confirmatory Tests of Primary Aldosteronism in Diagnosing Aldosterone Producing Adenoma]. AB - OBJECTIVE: To assess the efficacy of screening and confirmatory tests of primary aldosteronism (PA) in diagnosing aldosterone producing adenoma (APA). METHODS: Clinical data of 167 hypertensive patients were retrospectively reviewed,including 93 patients with APA and 74 patients with essential hypertension (EH). The area under curves (AUC) of receiver operating characteristic (ROC) curves were compared among the five indicators: supine plasma aldosterone concentration (PAC),absolute PAC values and PAC drop rates post saline infusion test (SIT) and captopril challenge test (CCT). RESULTS: APA patients had higher supine PAC,higher percentage of third degree hypertension,and lower serum potassium level than EH patients (P<0.05). Compared with EH patients,APA patients had lower PAC change rates,post posture change and SIT (P<0.05),but similar post CCT (P>0.05). The AUC of supine PAC reached 0.975. Higher AUC was found in absolute PAC values post SIT compared with PAC droop rates (0.984 vs. 0.680,P<0.001). Similar results were also found with CCT (0.949 vs. 0.538,P<0.001). A cut-off of supine aldosterone renin ratio (ARR) >30 and supine PAC>17.8 ng/dL had 96.8% sensitivity and 90.5% specificity. A cut-off of 14.59 ng/dL PAC post SIT had 90.2% sensitivity and 97.3% specificity. A cut-off of 19.11 ng/dL PAC post CCT had 88.8% sensitivity and 95.9% specificity. CONCLUSION: Screening tests using supine ARR>30 plus supine PAC>17.83 ng/dL are preferred with high sensitivity and specificity. The absolute values of PAC post SIT and CCT are recommended for confirming APA. PMID- 30014654 TI - [Clinical Report of 128 Cases of Meticulous Thoracoscopic Lobectomy in Children]. AB - OBJECTIVE: To investigate the feasibility and effect of precise thoracoscopic lobectomy in children. METHODS: The clinical data of precise thoracoscopic lobectomy in infants and children were analyzed retrospectively in West China Hospital of Sichuan University. RESULTS: There were total 128 cases (male 69,female 59) of precise thoracoscopic lobectomy in infants and children from Oct,2013 to March,2017,which including 62 cases of congenital cyst of lungs,47 cases of cystic adenomatoid malformations,17 cases of pulmonary sequestrations,and 2 cases of lung tumors. The lesions cvere located in upper lobe of lung in 28 cases,lower lobe in 98 cases and middle lobe in 2 cases. Intraoperative pulmonary arteriovenous,bronchial and interlobar fissure tissues were precisely treated. One case was converted to open surgery because of the thoracic adhesions due to repeated infection,the remaining cases were successfully completed under the endoscopic procedure. Intraoperative bleeding was 3-5 mL,operation time was 35-120 min,mean 55 min. The closed thoracic drainage tubes were removed within 24 h postoperatively; No atelectasis,bleeding,bronchial pleural fistula,pulmonary infection and other complications occurred. The post-operative hospital day ranged 3-4 d. During the follow-up for 6-36 months,all cases were recovered well,and no recurrence occurred. CONCLUSION: Meticulous thoracoscopic lobectomy is feasible in children,and it is effective in avoiding common postoperative complications,accelerating the recovery and shortening the hospitalization time. PMID- 30014655 TI - [Effects of Restrictive Transfusion on the Outcome of Mitral Valve Replacement]. AB - OBJECTIVE: To investigate effects of restrictive transfusion on the outcome of mitral valve replacement. METHODS: We selected 120 continuous patients of mitral valve replacement from June 2011 to June 2016. Based on the different blood transfusion strategy,the patients were divided into two groups: liberal blood transfusion group and restrictive blood transfusion strategy group. The blood routine test,liver and kidney function,coagulation function,full examination before blood transfusion,blood types,echocardiography and so on were examined when the patients were admitted to hospital,also the clinical data of perioperative patients were recorded,and blood transfusion volume,major complication and mortality were compared between the two groups. RESULTS: The transfusion volume of red blood cells decreased from (3.2+/-1.1) to (1.8+/-1.5) U with restrictive transfusion,the difference was statistically significant (P=0.01),while plasma volume increased from (325.7+/-96.5) mL to (385.2+/-86.2) mL (P=0.04). There were differences in major complications between the two groups (39.2% vs. 31.7%,P=0.04),especially for respiratory-related complications such as the proportion of using ventilator >24 h (P=0.03),total time using ventilator (P=0.03),lung infection rate (P=0.04). The restrictive transfusion group had better outcome with less cost of hospitalization. The mortality was not different (P>0.05). CONCLUSION: Restrictive transfusion strategy reduces the incidence of major complications in patients of mitral valve replacement with less cost. PMID- 30014656 TI - [The Clinical Evaluation of Prosthetic Valve in Patients with Dysfunction Valve Endocarditis]. AB - OBJECTIVE: To evaluate the outcomes of valve replacement of endocarditis using bioprothetic and mechanical valves. METHODS: This study comprised 52 patients [mean age (47+/-18) yr.,mean follow-up time (6.2+/-3.8) years] underwent valve endocarditis with bioprotheses,The control group were matched (3?1) with 156 patients of endocarditis underwent mechanical valves replacement using the following variables: age+/-5 yr.,body mass index (BMI)+/-20%,time of operation+/ 1 year,replacement position and sex ratio. And evaluate the effects of using bioprothetic and mechanical valves on perioperative and long-term outcomes of valve replacement of endocarditis. RESULTS: The perioperative mortality of the patients receiving bioprothetic and mechanical valves were 17.3%+/-2.2% and 19.9%+/-1.8%,respectively,which was independent of valve type (P=0.27). Long-term survival were 56.1%+/-5.2% and 61.2%+/-8.1%,respectively (P=0.58). Meanwhile,long term complication-free survival were 75.0%+/-3.2% and 82.3%+/-4.4%,respectively (P=0.29). For the patients younger than or equal to 60 yr.,long-term reoperation rates for bioprothetic and mechanical valves were 41.4%+/-7.2% and 30.5%+/-5.4% (P=0.02). For the patients older than 60 yr.,however,reoperation rates were 24.1%+/-8.5% and 14.7%+/-5.7% (P=0.36). CONCLUSION: Perioperative mortality and long-term survival are independent to valve types in patients with endocarditis. Mechanical valve shows potential advantage compared with bioprothetic valve in the patients younger than 60-year-old. PMID- 30014657 TI - [Home-based Rehabilitation of Stroke Patients]. AB - OBJECTIVE: To assess the physical,psychological and social functioning of stroke patients with home-based rehabilitation. METHODS: Convenient sampling strategy was adopted to select 234 stroke patients discharged from a tertiary hospital rehabilitation center. The patients were assessed using Barthel index (BI),instrumental activities of daily living (IADL) scale,modified rivermead mobility index (mRMI),self-perceived burden scale (SPBS),self-rating depression scale,and Zarit caregiver burden interview (ZBI) during their outpatient visits,household visits,or telephone interviews. RESULTS: The patients had an average BI score of 61.77+/-22.83,61.11% had mild dependence on daily life. Their IADL score was low at an average of 7.25+/-6.26. They had 28.90+/-10.22 in MRMI score and 29.26+/-7.07 in SPB score. More than 90% had a feeling of self-burden. The caregiver burden score reached 43.97+/-12.28. Male patients and those with cerebral infarction had better functioning than female patients and those with cerebral hemorrhage. Better physical functioning was demonstrated in those who were younger than 60 yr.,experienced more than one year home-based rehabilitation,were cared by relatives,and had a female caregiver. But such differences were not significant in SPBS and ZBI scores. CONCLUSION: Home-based rehabilitation of stroke has failed to achieve anticipated results. The outcomes vary across those with different age,gender,and type of stroke. PMID- 30014658 TI - [Component Changes of Metabolic Syndrome in Pre-elderly People with Healthy Obese Phenotype]. AB - OBJECTIVE: To determine component changes of metabolic syndrome in pre-elderly people with healthy obese phenotype. METHODS: A total of 1 686 adults aged between 45-59 yr. who underwent health examinations from 2010 to 2016 in West China Hospital of Sichuan University participated in this study. The participants had healthy obese phenotype at the baseline but no history of diabetes,high blood pressure,high cholesterol and cardiovascular disease. Component changes of metabolic syndrome (MS) and associated factors over the seven-year period were analysed using logistic regression modeling. RESULTS: The number of MS components increased over the years in centrally obese individuals,and 11.0% developed MS,including 118 men [(53.29+/-4.00) years old,66.95% current smokers,5.93% past smokers,24.58% alcohol drinkers] and 67 women [(52.01+/-4.06) years old,26.87% current smokers,1.49% past smokers,11.94% alcohol drinkers]. The most frequently presented MS components included higher fasting glucose,higher blood pressure and higher triglyceride. Healthy status (0 MS component) resumed in 44 participants who had abdominal obesity (1 MS component) at the baseline: 27 women and 17 men. Age (OR=1.732, 95%CI:1.594-1.882, P<0.000 1),smoking (OR=7.188, 95%CI:4.311 11.986, P<0.000 1) and drinking (OR=3.986, 95%CI:2.283-6.959, P<0.000 1) were identified as risk factors of MS. CONCLUSION: MS components increase over years in both men and women. Smoking and drinking are the main risk factors of MS progression. Regular MS surveillance and behavioral interventions are recommended for pre-elderly people with healthy obese phenotype. PMID- 30014659 TI - [Effect of acupuncture and moxibustion on severe obesity complicated with hyperlipidemia in different genders]. AB - OBJECTIVE: To explore the effect of acupuncture and moxibustion on severe obesity complicated with hyperlipidemia in different genders and their comprehensive effect, lipid indexes, and obesity indexes. METHODS: A total of 264 patients of severe obesity complicated with hyperlipidemia were assigned into a male group (106 cases) and a female group (158 cases).According to their clinical symptoms and patterns, acupuncture and moxibustion differentiation therapies were applied for stomach and intestine heat type, spleen deficiency and dampness resistance type, phlegm-dampness internal resistance type, liver depression and spleen deficiency type, spleen and kidney yang deficiency type and yin deficiency and blood stasis type.The obesity indexes were weight (W), obesity degree (A), body mass index (BMI) and body fat percentage (F); the blood lipid indexes were total cholesterol (TC),triglyceride (TG),low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C). The comprehensive effect, obesity and blood lipid indexes were observed.. RESULTS: The total effective rate of the male group was 91.5% (97/106), and the total effective rate of the female group was 85.4% (135/158) , without statistical significance (R>0.05). After treatment, the obesity indexes of W, A, BMI and F and the blood lipid levels of TC, TG, LDL-C decreased, the levels of HDL-C increased compared with those before treatment in the two groups (P<0.05, P<0.01). The different values before and after treatment of the above all indexes in the male group were higher than those in the female group (all P<0.05). CONCLUSION: Acupuncture and moxibustion can both improve the obesity and blood lipid indexes for the patients with obesity complicated with hyperlipidemia. The effect is better for male than for female. The methods can prevent and treat hyperlipidemia. PMID- 30014660 TI - [Effects of acupuncture and moxibustion at different times on the nausea and vomiting induced with chemotherapy: a self cross control study]. AB - OBJECTIVE: To investigate acupuncture-moxibustion intervention during the different times for chemotherapy-induced nausea and vomiting (CINV) symptoms. METHODS: Eighty patients received cisplatin chemotherapy with nausea and vomiting were assigned into an AB group and a BA group. Self cross control study was carried out. In the AB group, acupuncture and moxibustion were used during the intermission and there were no acupuncture-moxibustion during chemotherapy period in the first chemotherapy cycle; acupuncture and moxibustion were not applied during the intermission and acupuncture-moxibustion intervention were used during chemotherapy in the third cycle of chemotherapy. The intervention times were different correspondingly in the BA group. Acupuncture and moxibustion were not used to in the second cycle of elution period. The vomiting incidence, nausea, vomiting and retching scale (R-INVR), patient satisfaction and compliance during different chemotherapy times after acupuncture and moxibustion intervention were compared. RESULTS: On the first and second days of chemotherapy, the nausea incidences of patients treated with acupuncture and moxibustion during the intermittent period was less than those during chemotherapy period (both P<0.05), but continuous 4 days after the third day of chemotherapy, the numbers had no significant difference (all P>0.05). The scores of R-INVR were not significantly different between intervention in the chemotherapy period and intermittent period (P>0.05), with decreasing trend. The patients were more satisfied with acupuncture and moxibustion in the intermittent period (P<0.05). CONCLUSION: Acupuncture and moxibustion in the intermittent period can prevent vomiting induced by the chemotherapy of cisplatin, with satisfaction and compliance. Acupuncture and moxibustion intervention during chemotherapy period have the potential to improve nausea and vomiting. PMID- 30014661 TI - [Effect of moxibustion on prevention and treatment of nausea and vomiting caused by cisplatin in lung cancer]. AB - OBJECTIVE: To observe the clinical effects between moxibustion combined with 5 hydroxy tryptamine (5-HT) receptor antagonist and simple 5-HT receptor antagonist in the prevention and treatment of nausea and vomiting caused by cisplatin chemotherapy in patients with lung cancer. METHODS: Fifty-eight patients with lung cancer who were treated with cisplatin chemotherapy were randomly assigned into an observation group and a control group, 29 cases in each one. The patients in the two groups were applied by 5-HT receptor antagonist to prevent nausea and vomiting on the 1st through 3rd days of chemotherapy. Moxibustion at Baihui (GV 20) and Zhongwan (CV 12) was used in the observation group 1-3 days before chemotherapy for 1 course, 3 days as 1 course, 5 cones each acupoint and once a day. Rhodes's index of nausea and vomiting and retching (INVR) was recorded in 0 24 h, 24-48 h, 48-72 h and 72-96 h of chemotherapy. The rates of nausea and vomiting, as well as fatigue degree were observed in the above 4 time periods. The safety was assessed. RESULTS: After treatment, the scores of nausea and vomiting in 0-24 h, 24-48 h, 48-72 h and 72-96 h of chemotherapy in the observation group were lower than those in the control group (all P<0.01). The nausea rates in the above 4 time periods in the observation group were 37.9% (11/29), 62.1% (18/29), 60.7% (17/28) and 17.4% (4/23), which were lower than 93.1% (27/29), 89.7% (26/29), 89.3% (25/28), 52.0% (13/25) in the control group respectively (all P<0.05). The vomiting rates in the above 4 time periods in the observation group were 10.3% (3/29), 31.0% (9/29), 32.1% (9/28) and 13.0% (3/23), which were better than 37.9% (11/29), 79.3% (23/29), 82.1% (23/28) and 44.0% (11/25) in the control group (all P<0.05). The fatigue scores in the observation group in 0-24 h, 24-48 h, 48-72 h and 72-96 h of chemotherapy were lower than those in the control group (all P<0.01). There was no adverse reactions in the two groups during chemotherapy, such as skin toxicity, diarrhea, fever, allergy, etc. CONCLUSION: Moxibustion combined with 5-HT receptor antagonist can obviously reduce the rates and degrees of nausea and vomiting caused by cisplatin chemotherapy in patients with lung cancer, which are better than simple 5-HT receptor antagonist, without apparent adverse reactions. PMID- 30014662 TI - [Efficacy of acupuncture combined with computer-aided movable and measurable ankle-foot orthosis (CMM-AFO) on injury of nervus peroneus communis]. AB - OBJECTIVE: To observe the efficacy difference among medication, medication plus rehabilitation training and medication plus rehabilitation training plus acupuncture on injury of nervus peroneus communis. METHODS: A total of 81 patients were randomly divided into a control group, an observation 1 group and an observation 2 group; three patients dropped out and 78 patients were included into statistical analysis, 26 patients in each group. The patients in the control group were treated with oral administration of mecobalamin, 500 MUg per time, 3 times a day for 60 days. Based on the treatment of control group, the patients in the observation 1 group were treated with rehabilitation training by computer aided movable and measurable ankle-foot orthosis (CMM-AFO). Based on the treatment of observation 1 group, the patients in the observation 2 group were treated with acupuncture at Jiexi (ST 41), Fenglong (ST 40), Yanglingquan (GB 34) and Zusanli (ST 36), etc, 30 min per treatment, once a day for 60 days. After 60 day treatment, the clinical efficacy was evaluated; the muscle strengths of foot dorsal stretch and digital flexion were evaluated; the motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) were recorded. RESULTS: After treatment, 20 patients were cured in the observation 2 group, which was significantly higher than 8 patients in the control group and 15 patients in the observation 1 group (both P<0.05). The muscle strengths, SCV and MCV in the observation 2 group were significantly higher than those in the control group and the observation 1 group (all P<0.05). CONCLUSION: Acupuncture combined with CMM-AFO have significant efficacy on injury of nervus peroneus communis, and improve muscle strengths, SCV and MCV, which are superior to medication alone and medication plus rehabilitation training. PMID- 30014663 TI - [Retrospective study on incomplete intestinal obstruction treated with the adjuvant therapy of acupuncture and moxibustion]. AB - OBJECTIVE: To evaluate the clinical effects on incomplete intestinal obstruction treated with the adjuvant therapy of acupuncture and moxibustion. METHODS: Using the retrospective analysis, 80 patients of incomplete intestinal obstruction were divided into an observation group and a control group, 40 cases in each one. In the control group, the routine treatment was given, such as fasting, gastrointestinal decompression, parenteral nutrition, infection prevention with antibiotics and enema laxative. In the observation group, on the basis of the treatment as the control group, acupuncture was applied at bilateral Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39); moxibustion was used at left Yangchi (TE 4), Zhongwan (CV 12), Qihai (CV 6) and Guanyuan (CV 4). The treatment was given once a day, 30 min each time. The average days of treatment, the surgical transfer rate, the time to first flatus, the recovery time of defecation and the time of solid food intake were observed in the patients of the two groups. RESULTS: The average days of treatment in the observation group was obviously less than that in the control group (P<0.05). The surgical transfer rate in the observation group was obviously lower than that in the control group (P<0.05). The time to first flatus, the recovery time of defecation and the time of solid food intake were all obviously earlier than those in the control group (all P<0.05). CONCLUSION: The adjuvant therapy of acupuncture and moxibustion achieves the significant therapeutic effects on incomplete intestinal obstruction, shortens the treatment duration and reduces the surgical transfer rate and the patient's economic burden. PMID- 30014664 TI - [Effect of transcutaneous electrical acupoint stimulation on postoperative analgesia of ureteroscopic holmium laser lithotripsy]. AB - OBJECTIVE: To explore the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative analgesia of ureteroscopic holmium laser lithotripsy. METHODS: One hundred and twenty adult patients, American Association of Anesthesiologists (ASA) Class I or II, scheduled to ureteroscopic holmium laser lithotripsy, were randomly assigned into an observation group and a control group, 60 cases in each one. The patients in the observation group were treated with TEAS for postoperative analgesia. TEAS was implemented at bilateral Shenshu (BL 23) and Yinlingquan (SP 9) at the time of back ward and postoperative 4 h, 8 h, 12 h. TEAS at 7:00, 11:00 and 15:00 at the above acupoints were used on the second and third days; while placebo (twice a day, 100 mg a time) was used. Tramadol hydrochloride tablets for postoperative analgesia were applied in the contnol group, twice a day, 100 mg a time, and electrode sheets without stimulation were put on Shenshu (BL 23) and Yinlingquan (SP 9). When analgesia was insufficient with the score of visual analogue scale (VAS)>=3, the patients were treated with tramadol tablets for remedy analgesia. The VAS score, the concentrations of serotonin (5-HT) and substance P (SP) in 3 mL venous blood at the time of back ward (T0), postoperative 4 h (T1), 12 h (T2), 24 h (T3), and 48 h (T4) were detected respectively. The total amount of medication for remedy analgesia and the incidence of adverse reactions, such as nausea and vomiting within postoperative 48 h were compared between the two groups. RESULTS: The VAS scores at T1 through T4 were lower than those at T0 in the two groups (all P<0.05). Compared with the control group, the VAS scores at T1 through T3 in the observation group were lower (all P<0.05). The total dose of remedy analgesic medicine within 48 h after operation in the observation group was lower than that in the control group (P<0.05). Compared with the control group, the concentrations of 5-HT at T1, T2, T4 and SP at T1 through T4 were lower (all P<0.05). The numbers of constipation, nausea and vomiting in the observation group were less than those in the control group (both P<0.05). CONCLUSION: TEAS can relieve the pain and reduce the total amount of analgesic medicine, the levels of substance causing pain and the incidence of adverse reactions after ureteroscopic holmium laser lithotripsy. PMID- 30014665 TI - [Effects of mild moxibustion on the uterine microcirculation in patients of primary dysmenorrhea]. AB - OBJECTIVE: To observe the effects of mild moxibustion on the uterine microcirculation in patients of primary dysmenorrhea (PD) and explore the potential mechanism of mild moxibustion in the treatment of PD. METHODS: A total of 30 patients were randomized into a treatment group and a waiting list group, 15 cases in each one. Additionally, 15 healthy people were collected in the healthy group. In the treatment group, the mild moxibustion was used at Guanyuan (CV 4) and Sanyinjiao (SP 6). The treatment was given once a day since 5 to 7 days before menstruation until menses, 20 min each time. The treatment lasted for 3 menstrual cycles. No any intervention was provided in the waiting list group and the healthy group. The three-dimensional Doppler ultrasound test was adopted to observe the changes of the relevant indexes of uterine arterial blood, such as the systolic velocity (Vs), the diastolic velocity (Vd), the mean velocity (Vm), peak systolic velocity/end diastolic velocity (S/D), pulsatility index (PI) and the resistance index (RI) before treatment and at the end of 3-menstrual-cycle treatment. RESULTS: Before treatment, as compared with the healthy group, Vs, Vd and Vm reduced in the treatment group and the waiting list group, S/D, PI and RI increased in the treatment group (all P<0.05). The differences were not significant in S/D, PI and RI between the waiting list group and the healthy group (all P>0.05). After treatment for 3 menstrual cycles, Vs, Vd and Vm increased in the treatment group (all P<0.05), S/D, PI and RI reduced (all P<0.05). The difference was not significant in every index before and after trial in the waiting list group and the healthy group (all P>0.05). After treatment, Vs, Vd and Vm in the treatment group were higher than those in the waiting list group (all P<0.05) and the difference was not significant as compared with those in the healthy group (all P>0.05). S/D, PI and RI in the treatment group were lower than those in the waiting list group and the healthy group (all P<0.05). CONCLUSION: The mild moxibustion remarkably improves the uterine microcirculation in PD patients, which is achieved possibly by increasing blood velocity and reducing vascular resistance. PMID- 30014666 TI - [Effects of scalp acupuncture on brain injury in premature infants with different months of age]. AB - OBJECTIVE: To explore the clinical efficacy differences of scalp acupuncture on brain injury in premature infants with different months of age. METHODS: According to the corrected months of age, 90 cases of premature infants with brain injury were divided into a group A (3 through 6 corrected months of age), a group B (7 through 9 corrected months of age) and group C (10 through 12 corrected months of age), 30 patients in each one. Based on the conventional early intervention, the infants in the group A were treated with scalp acupuncture at Zhiqizhen, motor area; the infants in the group B were treated with scalp acupuncture at Zhiqizhen, motor area and foot motor sensory area; the infants in the group C were treated with scalp acupuncture at Zhiqizhen, motor area, foot motor sensory area and balance area. All the treatment was given once every other day, and totally 30 treatments were given. The Alberta infant motor scale (AIMS), development quotient (DQ) of each function indexes in Gesell developmental scale (GDS) were observed before and after treatment; the clinical efficacy of each group was compared and the correlation between clinical efficacy and months of age was analyzed. RESULTS: Compared before treatment, the total score of AIMS and DQ of each function indexes of GDS were all improved in the three groups after treatment (all P<0.01). After treatment, the differences of total score of AIMS and DQ of each function indexes of GDS among the three groups were significant (P<0.05, P<0.01), and the results in the group A were higher than those in the group B and the group C (P<0.05, P<0.01). The total effective rate was 96.3% (26/27) in the group A, which was higher than 89.7% (26/29) in the group B and 83.3% (25/30) in the group C. The correlation analysis indicated less months of age was significantly corelated with better efficacy (P<0.05). CONCLUSION: Scalp acupuncture has superior improvement on the recovery of brain damage in premature infants, especially for those with 6 months of age or less. PMID- 30014667 TI - [Relativity and integrality of the acupoint effect specificity]. AB - The researches on the acupoint effect specificity were summarized to explore whether the integrality of the acupoint effect specificity existed and analyze the connection between the relativity and integrality of the acupoint effect specificity. The literature on the clinical and experimental researches relevant with the acupoint effect specificity was retrieved through CNKI from January 2007 to October 2017. A total of 39 papers met the retrieving criteria. Separately, in terms of the holism of TCM theory, the holism of meridian theory and modern research, the integrality of acupoint effect specificity was analyzed. The relativity and the integrality are indicated in the acupoint effect specificity. The integrality of acupoint effect specificity is closely related to the holism of TCM theory as well as the meridians. Just because of its integrality, the acupoint effect specificity is relative, rather than absolute. PMID- 30014668 TI - [The discovery, application and enlightenment of Lanwei (EX-LE 7)]. AB - The discovery and application of Lanwei (EX-LE 7) was reviewed to elaborate its enlightenment on the inheritance and innovation of acupuncture. Literature published before April of 2017 was searched in CNKI and VIP database with"Lanwei (EX-LE 7)"and"acupuncture"as key words. Related references and publications were retrieved. According to the purpose, literature was screened and key information was extracted to perform systematic review and analysis. The results indicated Lanwei (EX-LE 7), reflection of relationship between organ and body surface under the guidance of acupuncture and meridians theory, was not a point, but an area. The discovery and application of Lanwei (EX- LE 7) was the product of western and Chinese combination. The best indication was simple appendicitis, but operation should be applied once adhesion, purulent and perforation occurred. It is indicated to improve clinical efficacy and avoid accident, the reasoned core of theory system should be insisted and the communication with modern medicine should be reinforced. PMID- 30014669 TI - [Effects of electroacupuncture at "Zusanli" (ST 36) on expression of mitophagy related proteins in skeletal muscle in rats with spleen deficiency syndrome]. AB - OBJECTIVE: To observe the expression change of mitophagy-related proteins in skeletal muscle in rats with spleen deficiency syndrome and to explain the partial action mechanism of acupuncture at Zusanli (ST 36) for spleen deficiency syndrome. METHODS: Forty male SD rats, after normal feeding, were randomly divided into a normal group, a spleen deficiency group, a Zusanli group and a non acupoint group, ten rats in each group. Except the normal group, the three factors modeling method was used for 14 days to establish the model of spleen deficiency syndrome on the other 3 groups. The rats in the Zusanli group were treated with EA at bilateral "Zusanli" (ST 36), while the rats in the non acupoint group were treated with EA at bilateral non acupoint (dense-sparse wave, frequency of 2 Hz/100 Hz, 20 min per treatment, once a day for 10 days). The rats in the normal group and spleen deficiency group were treated with immobilization for 20 min per day, and no EA was given. The HPLC method was applied to measure the content of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) in skeletal muscle. The Western blotting method was applied to measure the expression of adenosine monophosphate activated protein kinase (AMPK), p-AMPK, ULK1, p-ULK1,LC3-Iand LC3-II in skeletal muscle. RESULTS: The ATP content in the spleen deficiency group was significantly lower than that in the normal group (P<0.01); the ATP content in the Zusanli group was significantly higher than that in the spleen deficiency group (P<0.05) but lower than that in the normal group (P<0.05), there was no significant difference between the non-acupoint group and the spleen deficiency group (P>0.05). Compared with the normal group, the AMP/ATP in the spleen deficiency group and the Zusanli group were significantly up regulated (P<0.01, P<0.05). The differences of p-AMPK/AMPK between the spleen deficiency group and the normal group was not significant (P>0.05). Compared with the normal group and spleen deficiency group, the p-AMPK/AMPK in the Zusanli group was significantly up-regulated (both P<0.05). The p-ULK1/ULK1 and LC3 II/LC3-Iin the Zusanli group was higher than those in the normal group and spleen deficiency group (all P<0.01). CONCLUSION: EA at "Zusanli" (ST 36) might activate AMPK and produce stable ULK1/AMPK compound and increase the mitochondrial autophagy, which could regulate spleen-stomach and treat spleen deficiency. PMID- 30014670 TI - [Time-effect relationship and molecular mechanism of electroacupuncture for repair of gastric mucosal lesion]. AB - OBJECTIVE: To dynamically observe the effects of electroacupuncture (EA) on repair of gastric mucosal lesion in rats with gastric ulcer, and to explore the time-effect relationship and molecular mechanism of EA for gastric ulcer. METHODS: A total of 72 SD rats were randomly assigned to a normal group, a model group, a acupoint group and a sham acupoint group, and each group were further divided into a 1-day subgroup, a 4-day subgroup and a 7-day subgroup, 6 rats in each subgroup. The rat model of gastric ulcer was established by using intragastric administration of ethyl alcohol. The rats in the acupoint group were treated with EA at"Zusanli"(ST 36) and"Liangmen"(ST 21); the rats in the sham acupoint group were treated with EA at points 5 mm next to"Zusanli"(ST 36) and"Liangmen"(ST 21); the EA was given 30 min per treatment, once a day. The rats in the normal group and model group were treated with immobilization for 30 min per day, and no EA was given. PR-PCR method was applied to test the expression of proliferating cell nuclear antigen (PCNA) and substance P (SP); Western blot method was applied to test the expression of neurotensin (NT). RESULTS: After 1 day treatment, the ulcer index in the model group was higher than that in the normal group (P<0.01), and the expression of PCNA, SP and NT was decreased (P<0.01, P<0.05); compared with the model group and sham acupoint group, the ulcer index was decreased in the acupoint group (both P<0.05), and the expression of PCNA and SP was up-regulated (all P<0.05) while that of NT was up-regulated (both P<0.01). After 4-day treatment, the ulcer index in the model group was reduced but still higher than that in the normal group (P<0.05), and the expression of PCNA, SP and NT was up-regulated and higher than that in the normal group (all P<0.01); the ulcer index in the acupoint group was similar to that in the normal group (P>0.05), and the expression of PCNA and SP was lower than that in the model group (P<0.01, P<0.05), and the expression of NT was not significantly different from that in the model group (P>0.05). After 7-day treatment, the differences of indexes above were not significant among the four groups (all P>0.05). CONCLUSION: EA at acupoints of stomach meridian has two-way regulation on PCNA and SP and improve the expression of NT in different pathological state of gastric ulcer, which could further improve the repair of gastric ulcer. PMID- 30014671 TI - [Acupuncture combined with local anesthesia for percutaneous vertebroplasty]. AB - OBJECTIVE: To observe the analgesic and sedative effects of acupuncture combined with local anesthesia for percutaneous vertebroplasty (PVP). METHODS: Sixty patients of single segmental osteoporotic vertebral compression fractures who were prepared to receive PVP were randomly divided into an observation group, a control 1 group, a control 2 group, 20 cases in each group. The patients in the observation group were treated with electroacupuncture (EA) at Hegu (LI 4), Neiguan (PC 6) and Zusanli (ST 36) 20 min before operation; during operation, EA was given combined with regular anesthesia. The patients in the control 1 group were treated with intramuscular injection of parecoxib sodium (40 mg), combined with regular anesthesia. The patients in the control 2 group were treated with intravenous injection of dezocine (5 mg), combined with regular anesthesia. Visual analogue scale (VAS) and Ramesy sedation score were compared among the three groups. RESULTS: In the observation group and control 2 group, the VAS during puncture and bone cement placement was higher than that before acupuncture (all P<0.01); the VAS during bone cement placement was higher than that before puncture (P<0.05, P<0.01); the VAS after operation was lower than that during puncture and bone cement placement (P<0.05, P<0.01). In the control 1 group, the VAS during puncture and bone cement placement and after operation was higher than that before acupuncture (P<0.01, P<0.05), the VAS after operation was lower than that during puncture and bone cement placement (P<0.05, P<0.01). There was no significant difference in VAS and Ramesy score among three groups at all time points (all P>0.05). CONCLUSION: Compared with local anesthesia and analgesics, acupuncture combined with local anesthesia has similar analgesic and sedative effect for PVP, which could be considered a better method for PVP anesthesia. PMID- 30014672 TI - [Professor WU Lianzhong's experience in the treatment of oculomotor nerve palsy with acupuncture based on the interactions of twelve muscle regions and opposing needling theory]. AB - It was to introduce professor WU Lianzhong's experience in the treatment of oculomotor nerve palsy with acupuncture based on the interactions of twelve muscle regions and opposing needling theory. In the treatment, the TCM syndrome differentiation is taken as the general principle, the theory of the interactions of twelve muscle regions and opposing needling as the specific feature. The contrary needling is used at Hanyan (GB 4) and Juliao (ST 3) on the healthy side. The meridian-collateral and the exterior-interior differentiations are adopted to identify the syndromes. At the early stage of the disease, the treating principle focuses on expelling wind, eliminating cold and promoting the circulations of meridians and collaterals. The shallow needling, less acupoints and gentle stimulation are required. At the middle and late stage, the treating principle concentrates on strengthening the antipathogenic qi and harmonizing qi and blood. The deep needling, the multiple acupoints and the strong stimulation are applied. Additionally, the four-needling technique at Fengchi (GB 20), the multiple shallow needling at the eyelid margin, the opposing needling and the quantity of needling sensation are used in combination, which were developed by professor WU. With those comprehensivemethods, the symptoms of oculomotor nerve palsy are relieved and the significant clinical therapeutic effects achieved. PMID- 30014673 TI - [Evolution of filiform needle insertion methods in multi-edition of Acupuncture and Moxibustion]. AB - This paper reviewed the filiform needle insertionmethods in multi-edition of Acupuncture and Moxibustion, explored its evolution and reasons, and analyzed its development trend. By referring multi-edition of Acupuncture and Moxibustion and related literature regarding acupuncture manipulation published after 1940s, combined with acupuncture manipulation characteristics of modern and contemporary acupuncture masters, it was found that the definition of needle insertion methods needed to be improved after several changes. The classification of needle insertion methods was stable over development. The thrusting method of needle insertion was previously included, and then disappeared. The description of needle insertion methods was improving. These evolutions were mainly influenced by the academic and clinical background, the academic thought of writers and acupuncture masters, the internationalization and standardization of acupuncture and so on. The twist-inserting method and some other needle-inserting instrument meet the safe, sterile, painless and convenient development trend, which might be included in Acupuncture and Moxibustion in the future. PMID- 30014674 TI - [Illustration of the characteristics and enlightenments of the development of Acupuncture and Moxibustion Hospital of CACMS]. AB - The issue on the acupuncture clinical service mode has been early proposed by the scholars. The acupuncture clinical service mode is still existed as the department of acupuncture in TCM hospital nowadays. But this pattern has brought the inconvenience and issues between physicians and patients. In the study, through reviewing briefly the history of acupuncture hospital since the foundation of the People's Republic of China, the authors explained why taking the Hospital of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (CACMS) as the object. By integrating the relevant achievements of the scholars on the study of acupuncture hospital, the historical development of acupuncture-moxibustion hospital was reviewed. By comparing with the development mode of TCM hospital, the differences were generalized between the two hospitals in terms of the purpose of hospital establishment, the development mode of treatment, education and research, modernization mode, the relationship with western medicine and the hospital scale. It was analyzed by the authors that the development characteristics of acupuncture-moxibustion hospital were determined by the accidental and the inevitable factors. By the comprehensive analysis, the enlightenments to the future development of acupuncture-moxibustion hospital were explored. PMID- 30014675 TI - [Analysis on the diversity and refactoring of acupuncture-moxibustion theory based on the polymorphism of clinical thought]. AB - By analyzing the acupuncture clinical thinking polymorphism in the ancient and modern time,it is shown that the guidance theory systems of acupuncture and moxibustion therapy are on the diversity. Classic meridian system is part of the important composition of acupuncture theory system,and it is not the only one guidance for clinical acupuncture. In the ancient time, acupoints were according to local lesion, classical meridian therory, acupoint indication and effect, the disease, the syndrome, cold-hot and deficiency-excess features, pulse, time and season, meridian's Biao- ben Genjie, and needling instrument, etc. In the modern clinical practice, the points are selected according to the above theories and the modern theories such as western medicine anatomy,as well as various micro acupuncture systems and the new method theories. Through the analysis of the diversity of ancient and modern acupuncture theory, a preliminary idea of the acupuncture-moxibustion theory system is suggested including traditional theory system (classical meridian system, classical non-meridian system and classical TCM system), and modern theory system [nervous system (linear contact system) and non-nervous system (nonlinear contact system)]. PMID- 30014676 TI - [Understanding of the trigger points of myalgia: acupuncture and dry needling exploration and modern acupuncture mechanism]. AB - The similarities and differences between trigger points of myalgia and acupoints were explored. Nodules could be detected by B-ultrasound at trigger points of myalgia, but not acupoints. In clinical symptoms, the referred pain pathway of trigger points of myalgia is similar with the pathway of acupuncture meridian. Therefore, the location of trigger points of myalgia should take referred pain as pathway, which is similar with locating acupoints as meridian. Acupuncture at trigger points of myalgia takes jumping feeling as criterion, while acupuncture at acupoints are mainly based on acid swelling and numbness. From clinical observation to basic experimental research, a lot of pathophysiological evidence is provided for trigger point of myalgia. It is believed that the trigger point of myalgia might be the precise acupoint in modern scientific research, and the meridian is the synthesis of the mechanics of nerve, blood vessel and fascia. Although acupuncture and dry needling are different in theory, but the scientific foundation of TCM and western medicine is coherent. PMID- 30014677 TI - [Exploration of phenomena and regularity of heat-sensitive acupoints based on bibliometrics]. AB - OBJECTIVE: To explore the phenomena and regularity of heat-sensitive acupoints for clinic and further study. METHODS: Modern literature before May 11st, 2017 on heat-sensitive phenomena was retrieved from CNKI, VIP, WANFANG database, and SinoMED. The research trend of heat-sensitive acupoints and interventions, heat sensitive region, detection indexes, and diseases were analyzed by bibliometrics. RESULTS: Among 201 included papers, 35 papers on healthy person was the highest, which were mainly related to Mingmen (GV 4) with 8 papers. As to the detection indexes, 125 papers on the individual, saturated and sensation vanishing moxibustion quantity accounted for the largest part, which were most relevant to the points in the bladder meridian of foot-taiyang (66 papers) and soft tissue injury (29 papers), and the second part was infrared radiation feature (61 papers), which were most relevant to healthy person (23 papers). CONCLUSION: Heat sensitive phenomena own regularity, and the detection indexes are specific to heat-sensitive points in healthy person or patients with different diseases. PMID- 30014678 TI - [Clinical curative effect research status and analysis of acupuncture treatment for primary insomnia]. AB - OBJECTIVE: To grasp the clinical efficacy of acupuncture in the treatment of primary insomnia (PI), and analyze its future research directions. METHODS: A total of 41 prospective randomized controlled trials (RCTs) were conducted in which the clinical efficacy of acupuncture for treatment of PI was compared with sedative and hypnotic drugs in recent six years by searching databases of CNKI, WANFANG database, PubMed, and BioMed Central (BMC), the aspects of diagnostic criteria, efficacy standards, observation time, control drugs, characteristics of acupoint selection and regularity were used to review and analyse. RESULTS: Acupuncture treatment for PI was mainly based on acupoints in the head, combined with selecting the points according to the different syndrome, showing short-term efficacy and safety advantages, but it was not well-established in many aspects such as diagnostic criteria, efficacy evaluation, observation time, and control drugs. CONCLUSION: Current evidence shows that acupuncture treatment is effective, but it is necessary to add more stringent RCTs, and introduce objective monitoring indicators to strengthen the evidence and enhance the overall level of research. PMID- 30014679 TI - Neuroprotective measures throughout the TAVI pathway. AB - Aortic stenosis (AS) is the most common clinical valvular heart disorder that warrants active treatment. Symptomatic and severe AS is associated with increased morbidity and mortality if left untouched. Transcatheter aortic valve implantation (TAVI) is an innovative therapeutic modality approved initially for patients with prohibitive surgical risk and subsequently became a mainstream practice and the preferred treatment modality for many patients with severe AS at high and moderate surgical risk. Consistently global TAVI volumes have increased and indications continue to widen toward younger and lower-risk patients. However, peri-procedural stroke is one of the most feared complications of TAVI, and when clinically evident, it is often associated with significant increase in mortality, physical disability, social isolation and financial costs. Furthermore, even when clinically overt stroke is not evident following TAVI, highly sensitive imaging modalities have demonstrated new post-procedural ischemic lesions in most patients. Although little is known about the long-term clinical significance of these lesions, there are strong signals showing they might be related with reduced subsequent neurocognitive function. This review provides a comprehensive contemporary insight of the definitions, incidence and temporal trends of stroke in TAVI patients, as well as the mechanisms, etiologies and risk factors for such neurological events. Furthermore, an integrated approach of neuroprotective measures targeted to reduce the incidence of stroke during each phase of the peri-procedural TAVI pathway is suggested with a special focus on the role of embolic protective devices. PMID- 30014680 TI - Postoperative soft-tissue infection due to multidrug-resistant Pseudomonas aeruginosa: usefulness of ceftolozane-tazobactam. PMID- 30014682 TI - Wound odor: current methods of treatment and need for objective measures. AB - Chronic wounds are an enormous burden to society, costing billions of dollars annually in the US alone. Despite the extensive research into methods to heal chronic wounds, many remain unhealed for months to years. There is a need to focus on patient reported outcomes to improve quality of life in patients with non-healing wounds. Wound odor has a significant impact on patient quality of life; however, relatively little information is available on the management of wound odor. We review the current data available on wound odor and discuss the need for standardized objective measures of odor to improve research quality. An independent search of the Pubmed and Embase databases was conducted using combinations of the following words or phrases: wounds, chronic wounds, diabetic ulcers, venous leg ulcers (VLUs), malignant ulcers, odor, odour, smell, malodor, artificial olfaction, electronic nose, and e-nose. Article references were also searched for significance. There are few overall studies on wound odor, and fewer randomized controlled trials. Current trials on odor have consistent weaknesses such as subjective measures and poor methodology. No single odor treatment modality has been demonstrated to be widely effective for wound odor or superior to other methods. Future research should incorporate objective measures of odor such as electronic noses into clinical trials. PMID- 30014681 TI - Staphylococcus aureus bacteremia in a secondary level Spanish hospital: clinical implications of high vancomycin MIC. AB - OBJECTIVE: One of the most controversial issues in recent years has been the clinical significance of high vancomycin MIC in Staphylococcus aureus bacteremia. The aim of this study was to elucidate the clinical implication that this parameter has in the staphylococcal bacteremia of a second level hospital. METHODS: Retrospective descriptive study between January 2014 and September 2016 with 138 records from the blood culture Severo Ochoa University Hospital registry. A total of 98 cases were finally analized. Microbiological analysis of vancomycin MIC was performed using micro dilution technique. RESULTS: The mean age was 71.4 +/- 12.45 and 63.26% of the patients had a Charlson index >=6. A 30.61% were carriers of a venous central catheter. The most frequent source was venous central catheter (26.53%). There were 14.24% metastatic events. Global mortality rate at 30 days was 25.51%. The 43.87% of strains had a vancomycin MIC >= 2 mg/L. High vancomycin MIC was significantly associated with persistent bacteremia (OR 3.12 [1.13-8.93]), maintaining this statistical significance in methicillin-resistant S. aureus (MRSA) group (p =0.001) but no in methicillin susceptible S. aureus (MSSA) group (p = 0.13). Persistent bacteremia was also significantly related with permanent catheter carriers (OR 4.18 [1.38-12.61]), peripheric catheter source (OR 5.18 [1.13-8.93]) and metastatic complications (OR 3.82 [1.03- 12.81]). There was no significant association between high vancomycin MIC and mortality. CONCLUSIONS: High vancomycin MIC may be useful in daily clinical practice as a marker of poor clearance of S. aureus bacteremia, specially when is due to MRSA strains. PMID- 30014683 TI - Cutaneous relapse after allogenic hematopoietic stem cell transplantation for acute myeloid leukemia: a clinical and immunophenotype study of seven patients. PMID- 30014684 TI - Anti-TNFalpha-induced psoriasis under treatment of hidradenitis suppurativa. PMID- 30014685 TI - Cutaneous complications of immunosuppression in 812 transplant recipients: a 40 year single center experience. AB - BACKGROUND: As a consequence of the improvement in survival after solid organ transplantation, to visit transplant recipients with neoplastic and non neoplastic skin disorders due to immunosuppressive treatment has become common for dermatologists. METHODS: Our endpoints were: to investigate (i) the most common skin diseases in a population of transplant recipients, (ii) their associations with the type of immunosuppressant or transplant received; (iii) to compare our single centre 40-year experience with the literature data. We retrospectively analyzed the clinical details of the adult patients transplanted in the years 1974-2014, visited for consultation in the Dermatology Unit of our hospital. RESULTS: Pathologic conditions were observed in more than 3/4 of 812 adults during the followup (mean 12.1 years): nonmelanoma skin cancers or actinic keratoses were seen in 44.0% (n = 357) of patients, non-neoplastic events in 55.2% (n = 448). Heart transplant had the statistically significant highest rate of NMSC and AK (52.6%, p=0.0352). Patients receiving cyclosporine A developed at least one non-melanoma skin cancer or actinic keratosis in 57.7% of cases (p=0.0001), while tacrolimus showed a lower risk (33%, p=0.0001). CONCLUSIONS: As transplant recipients are susceptible to skin changes, especially after immunosuppressant treatments, a dermatological follow-up should be scheduled for each patient. PMID- 30014686 TI - Immunotherapy and potential molecular targets for the treatment of pituitary adenomas resistant to standard therapy: a critical review of potential therapeutic targets and current developments. AB - INTRODUCTION: Pituitary adenomas (PAs) are primary central nervous system (CNS) tumors, accounting for as much as 25% of intracranial neoplasms. Although existing remedies show success in treating most PAs, treatment of invasive and non-functioning PAs, in addition to functioning PAs unresponsive to standard therapy, remains challenging. With the continually increasing understanding of biochemical pathways involved in tumorigenesis, immunotherapy stands as a promising alternative therapy for pituitary tumors that are resistant to standard therapy. METHODS: A literature search was conducted of the PubMed database for immunotherapies of PAs. The search yielded a total of 2,621 articles, 26 of which were included in our discussion. RESULTS: Several pathologically expressed molecules could potentially serve as promising targets of current or future immunotherapies for PAs. Programmed death ligand-1 (PD-1/PD-L1), matrix metalloproteinases (MMPs), EpCAM (Trop1) and Trop2, cancer-testis antigen MAGE A3, epidermal growth factor receptor (EGFR), folate receptor alpha (FRalpha), vascular endothelial growth factor (VEGF), and galectin-3 (Gal-3) have all been implicated as crucial factors involved with tumor survival and invasion. Inhibition of these pathways may prove efficacious in the management of invasive and treatment-resistant PAs. CONCLUSIONS: Rapid advancements in tumor immunology may increase the probability of successful treatment of PAs by exploitation of the normal immune response or by targeting novel proteins. Current research on many of the targets reviewed in this article are successfully being utilized to manage various neoplastic disease including CNS tumors. These therapies may eventually play a key role in the treatment of PAs that do not respond to standard therapy. PMID- 30014687 TI - The impact of Type 2 Diabetes on the peri- and postoperative outcomes of minimally invasive fusion techniques in the lumbar spine. AB - BACKGROUND: The impact of diabetes on spinal surgery has been studied extensively, but very few studies have focused on minimal access spinal technologies (MAST) and complication rates in patients suffering from Type 2 Diabetes (T2DM). Diabetes increases the risk of wound healing disorders, complication rate and length of stay in the hospital. We focused on the peri- and postoperative complications of MAST in an unselected consecutive population of 187 patients suffering from degenerative disorders lumbar spine disorders. Since mostly older patients are affected by degenerative lumbar changes, we concentrated on T2DM. METHODS: We evaluated perioperative and postoperative complication rates associated with MAST fusion techniques in lumbar spine surgery in patients suffering from T2DM compared to patients without diabetes. Lumbar fusion was performed using interbody and posterolateral fusion. RESULTS: 18 female and 16 male patients suffered from T2DM (15.65% and 22.22% respectively). No differences between patients with and without T2DM concerning surgeryrelated complications including infections, severe wound healing disorders or length of inhospital stay were noted. Peri- or postoperative complication rates, as well as blood loss volumes, were evenly distributed between the two groups. CONCLUSIONS: T2DM is not a risk factor for the occurrence of complications in MAST. PMID- 30014688 TI - Fluorescent tracers in neurosurgical procedures: an European survey. AB - BACKGROUND: In recent years several techniques have been proposed with the aim of improving tumors visualization and extent of resection and, among them, the use of photosensitive dyes is gaining great interest. Regarding the application of the two most used dyes, 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SF), there is still a lack of shared and established protocols among different centers. The main objective of the present study was to evaluate the current practice of fluorescence-guided techniques in neuro-oncological surgery in Europe. METHODS: An online questionnaire consisting of 33 questions was completed by 136 European Association of Neurosurgical Societies neurosurgeons. Responses were entered into a database and subsequently analyzed. RESULTS: Data were analyzed from 136 out of 1476 active European neurosurgeons which had been contacted, with a 9,2% response rate. Based on the data from the questionnaire, Germany was the most responsive country (15% of the total respondents) and the main indication for 5-ALA and SF utilization were high-grade gliomas. 5-ALA was mainly used as defined in Gliolan(r) datasheet, while SF as off-label technique with a 5 mg/kg dose of injection at the end of patient intubation. Both the dyes were mainly used in adult population, more frequently by neurosurgeons with less than 20 cases per year expertise. Mean price per patient were 817,6 ? and 7,7 ? for 5-ALA and SF, respectively. CONCLUSIONS: 5-ALA acid is still the preferred and more established fluorescent dye used during high-grade gliomas resection, with SF as a gaining-attention, really cheaper and more ductile alternative. PMID- 30014689 TI - Energy Level Alignment of Molybdenum Oxide on Colloidal Lead Sulfide (PbS) Thin Films for Optoelectronic Devices. AB - Interfacial charge transport in optoelectronic devices is dependent on energetic alignment that occurs via a number of physical and chemical mechanisms. Herein, we directly connect device performance with measured thickness-dependent energy level offsets and interfacial chemistry of 1,2-ethanedithiol-treated lead sulfide (PbS) quantum dots and molybdenum oxide. We show that interfacial energetic alignment results from partial charge transfer, quantified via the chemical ratios of Mo5+ relative to Mo6+. The combined effect mitigates leakage current in both the dark and the light, relative to a metal contact, with an overall improvement in open circuit voltage, fill factor, and short circuit current. PMID- 30014690 TI - Application of Displacement Chromatography to Online Two-Dimensional Liquid Chromatography Coupled to Tandem Mass Spectrometry Improves Peptide Separation Efficiency and Detectability for the Analysis of Complex Proteomes. AB - The complexity of mammalian proteomes is a challenge in bottom-up proteomics. For a comprehensive proteome analysis, multidimensional separation strategies are necessary. Online two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) combining strong cation exchange (SCX) in the first dimension with reversed-phase (RP) chromatography in the second dimension provides a powerful approach to analyze complex proteomes. Although the combination of SCX with RP chromatography provides a good orthogonality, only a moderate separation is achieved in the first dimension for peptides with two (+2) or three (+3) positive charges. The aim of this study was to improve the performance of online SCX-RP MS/MS by applying displacement chromatography to the first separation dimension. Compared to gradient chromatography mode (GCM), displacement chromatography mode (DCM) was expected to improve the separation of +2-peptides and +3-peptides, thus reducing complexity and increasing ionization and detectability. The results show that DCM provided a separation of +2-peptides and +3-peptides in remarkably sharp zones with a low degree of coelution, thus providing fractions with significantly higher purities compared to GCM. In particular, +2-peptides were separated over several fractions, which was not possible to achieve in GCM. The better separation in DCM resulted in a higher reproducibility and significantly higher identification rates for both peptides and proteins including a 2.6-fold increase for +2-peptides. The higher number of identified peptides in DCM resulted in significantly higher protein sequence coverages and a considerably higher number of unique peptides per protein. Compared to conventionally used salt-based GCM, DCM increased the performance of online SCX-RP-MS/MS and enabled comprehensive proteome profiling in the low microgram range. PMID- 30014691 TI - Fused Fluorenylindolenine-Donor-Based Unsymmetrical Squaraine Dyes for Dye Sensitized Solar Cells. AB - A series of four unsymmetrical squaraine dyes, XSQ1-4, were synthesized using a fused fluorenylindolenine-based donor unit for dye-sensitized solar cells (DSSCs). The fused structure of fluorenylindolenine helped in moving the absorption toward the near-infrared (NIR) region, and the two sp3-C centers available on this donor were utilized to incorporate out-of-plane alkyl chains in opposite directions to control the dye-dye interactions on the TiO2 surface. High extinction coefficient (epsilon >= 105 M-1 cm-1) for absorbing NIR photons and suitable highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels with respect to the conduction band of TiO2 and electrolyte for charge injection and dye regeneration processes, respectively, make these dyes potential sensitizers for DSSCs. Introduction of branched alkyl groups in the pi-framework helped in controlling dye aggregation to reduce exciton quenching and assisted in TiO2 surface passivation to avoid the charge recombination process. Furthermore, having a naphthyl group on the indole part of the anchoring group containing segment helped to red-shift the absorption spectrum of dyes 15 nm toward the NIR region (XSQ3-4). Among all of the dyes under investigation, XSQ2 gave the best photovoltaic performance, having a short circuit current density ( JSC) of 13.99 mA cm-2, open-circuit voltage ( VOC) of 0.66 V, and a fill factor (ff) of 0.71, with a device performance (eta) of 6.57%. Electrochemical impedance spectroscopy revealed higher electron lifetime on TiO2 for XSQ2, which helps to avoid the charge recombination process. PMID- 30014692 TI - Biodegradable Cyclomatrix Polyphosphazene Nanoparticles: A Novel pH-Responsive Drug Self-Framed Delivery System. AB - Traditional drug delivery systems suffer from low drug-loading and relatively weak therapeutic efficacy, therefore, development of new drug delivery systems with high-efficiency has become more urgent. In this report, a novel-innovative drug delivery strategy, namely drug self-framed delivery system (DSFDS), is prepared via using anticancer drugs as polymer frame without using any carriers. The drug molecules (exemplified by doxorubicin) containing more than two nucleophilic functional groups (diols/diamines) directly reacted with hexachlorocyclotriphosphazene via mild precipitation polycondensation under ambient conditions, forming biocompatible drug self-framed delivery nanoparticles. Because of the covalent bonding of the drug molecules, DSFD nanoparticles (DSFDs) with super high drug-loading were stable in the circulation during delivery. However, sustained release of drug in the acidic environment within cells endowed DSFDs with long-term anticancer therapeutic efficacy. This strategy is applicable for diverse hydrophilic and hydrophobic drugs and may be a new platform for designing high drug-loading and release-controllable drug delivery systems. PMID- 30014693 TI - Absorbent Filaments from Cellulose Nanofibril Hydrogels through Continuous Coaxial Wet Spinning. AB - A continuous and scalable method for the wet spinning of cellulose nanofibrils (CNFs) is introduced in a core/shell configuration. Control on the interfacial interactions was possible by the choice of the shell material and coagulant, as demonstrated here with guar gum (GG) and cellulose acetate (CA). Upon coagulation in acetone, ethanol, or water, GG and CA formed supporting polymer shells that interacted to different degrees with the CNF core. Coagulation rate was shown to markedly influence the CNF orientation in the filament and, as a result, its mechanical strength. The fastest coagulation noted for the CNF/GG core/shell system in acetone led to an orientation index of ~0.55 (Herman's orientation parameter of 0.40), Young's modulus of ~2.1 GPa, a tensile strength of ~70 MPa, and a tenacity of ~8 cN/tex. The system that underwent the slowest coagulation rate (CNF/GG in ethanol) displayed a limited CNF orientation but achieved an intermediate level of mechanical resistance, owing to the strong core/shell interfacial affinity. By using CA as the supporting shell, it was possible to spin CNF into filaments with high water absorption capacity (43 g water/g dry filament). This was explained by the fact that water (used as the coagulant for CA) limited the densification of the CNF core structure, yielding filaments with high accessible area and pore density. PMID- 30014694 TI - Rox-DNA Functionalized Silicon Nanodots for Ratiometric Detection of Mercury Ions in Live Cells. AB - A ratiometric fluorescent sensor for mercury ions (Hg2+) has been constructed via covalent functionalization of silicon nanodot (SiND) with Hg2+-specific 6-carboxy X-rhodamine (Rox)-tagged DNA. For the Rox-DNA functionalized SiND, the red fluorescence of Rox can be quenched by the blue-emitting SiND in the presence of Hg2+ due to structural change in DNA, which serves as the response signal. Meawhile, the fluorescence of SiND is insensitive to Hg2+ and acts as the reference signal. The wavelength difference in the optimal emission peak is as large as 190 nm between SiND (422 nm) and Rox (612 nm), which can efficaciously exclude the interference of the two emission peaks, and facilitates dual-color visualization of Hg2+ ions. The biofunctionalization of SiND improves the acid base stability of SiND significantly, which is favorable for its application in the intracellular environment. Accordingly, a sensitive, simple, precise and rapid method for tracing Hg2+ was proposed. The limit of detection and precision of this method for Hg2+ was 9.2 nM and 8.8% (50 nM, n = 7), respectively. The increase of Hg2+ concentration in the range of 10-1500 nM was in accordance with linearly increase of the I422/ I612 ratio. As for practical application, the recoveries in spiked human urine and serum samples were in the range of 81-107%. Moreover, this fluorescent nanosensor was utilized to the ratiometric detection of Hg2+ in HeLa cells. PMID- 30014695 TI - Synthesis and Properties of 2'-OMe-RNAs Modified with Cross-Linkable 7 Deazaguanosine Derivatives. AB - Cross-linkable 7-deaza-6-vinylguanosine (ADVP) and 7-propynyl-7-deaza-6 vinylguanosine (ADpVP) derivatives were synthesized and successfully incorporated into 2'-OMe-RNA oligonucleotides by solid-phase oligonucleotide synthesis. Analysis of their cross-link properties revealed that the 7-propynyl substituent on ADpVP induces a significant enhancement of the cross-link kinetics of the proximal 6-vinyl group to the complementary uracil base in the target RNA compared to that of ADVP. In addition, the 2'-OMe-RNA oligonucleotide containing ADpVP exhibited a higher antisense effect on luciferase production in the cell lysate than that of ADVP. These results suggested that the 7-substituted 7-deaza 6-vinylguanosine derivatives can be used as potent cross-linkers to target mRNA inside of cells. PMID- 30014697 TI - Discovery of a Potent alpha-Galactosidase Inhibitor by in Situ Analysis of a Library of Pyrrolizidine-(Thio)urea Hybrid Molecules Generated via Click Chemistry. AB - The parallel synthesis of a 26-membered-library of aromatic/aliphatic-(thio)urea linked pyrrolizidines followed by in situ biological evaluation toward alpha galactosidases has been carried out. The combination of the (thio)urea-forming click reaction and the in situ screening is pioneer in the search for glycosidase inhibitors and has allowed the discovery of a potent coffee bean alpha galactosidase inhibitor (IC50 = 0.37 MUM, Ki = 0.12 MUM) that has also showed inhibition against human lysosomal alpha-galactosidase (alpha-Gal A, IC50 = 5.3 MUM, Ki = 4.2 MUM). PMID- 30014696 TI - Supramolecular Regulation of Anions Enhances Conductivity and Transference Number of Lithium in Liquid Electrolytes. AB - Achieving high ionic conductivity in lithium-ion battery (LIB) electrolytes requires dissociation of Li-salts; however, though the generation of free Li+ from salt dissociation is advantageous, the presence of freely diffusing anions may reduce the Li+ transference number. The use of supramolecular anion recognition to regulate and modify ion-pairing and diffusion of anions in battery electrolytes is yet to be deeply understood. Herein, we demonstrate that addition of a selective and strong PF6--binding macrocycle to a solution of LiPF6 in low dielectric media leads to enhanced ion pair dissociation and an increased Li+ transference number. This work provides a well-defined model system to study the effects of anion binding in battery electrolytes. PMID- 30014698 TI - Nanocarbon-Based Glycoconjugates as Multivalent Inhibitors of Ebola Virus Infection. AB - SWCNTs, MWCNTs, and SWCNHs have been employed as virus-mimicking nanocarbon platforms for the multivalent presentation of carbohydrates in an artificial Ebola virus infection model assay. These carbon nanoforms have been chemically modified by the covalent attachment of glycodendrons and glycofullerenes using the CuAAC "click chemistry" approach. This modification dramatically increases the water solubility of these structurally different nanocarbons. Their efficiency in blocking DC-SIGN-mediated viral infection by an artificial Ebola virus has been tested in a cellular experimental assay, finding that glycoconjugates based on MWCNTs functionalized with glycofullerenes are potent inhibitors of viral infection. PMID- 30014699 TI - Mesoionic and Related Less Heteroatom-Stabilized N-Heterocyclic Carbene Complexes: Synthesis, Catalysis, and Other Applications. AB - Mesoionic carbenes are a subclass of the family of N-heterocyclic carbenes that generally feature less heteroatom stabilization of the carbenic carbon and hence impart specific donor properties and reactivity schemes when coordinated to a transition metal. Therefore, mesoionic carbenes and their complexes have attracted considerable attention both from a fundamental point of view as well as for application in catalysis and beyond. As a follow-up of an earlier Chemical Reviews overview from 2009, the organometallic chemistry of N-heterocyclic carbenes with reduced heteroatom stabilization is compiled for the 2008-2017 period, including specifically the chemistry of complexes containing 1,2,3 triazolylidenes, 4-imidazolylidenes, and related 5-membered N-heterocyclic carbenes with reduced heteratom stabilization such as (is)oxazolylidenes, pyrrazolylidenes, and thiazolylidenes, as well as pyridylidenes as 6-membered N heterocyclic carbenes with reduced heteroatom stabilization. For each ligand subclass, metalation strategies, electronic and steric properties, and applications, in particular, in metal-mediated catalysis, are compiled. Mesoionic carbenes demonstrate particularly high activity in (water) oxidation, hydrogen transfer reactions, and cyclization reactions. Unique features of these ligands are identified such as their dipolar structure, their specific donor properties, as well as stability aspects of the ligand and the complexes, which provides opportunities for further research. PMID- 30014700 TI - Proteomic Analysis of Charcoal-Stripped Fetal Bovine Serum Reveals Changes in the Insulin-like Growth Factor Signaling Pathway. AB - Charcoal-stripped fetal bovine serum (CS-FBS) is commonly used to study androgen responsiveness and androgen metabolism in cultured prostate cancer (CaP) cells. Switching CaP cells from FBS to CS-FBS may reduce the activity of androgen receptor (AR), inhibit cell proliferation, or modulate intracellular androgen metabolism. The removal of proteins by charcoal stripping may cause changes in biological functions and has not yet been investigated. Here we profiled proteins in FBS and CS-FBS using an ion-current-based quantitative platform consisting of reproducible surfactant-aided precipitation/on-pellet digestion, long-column nanoliquid chromatography separation, and ion-current-based analysis. A total of 143 proteins were identified in FBS, among which 14 proteins including insulin like growth factor 2 (IGF-2) and IGF binding protein (IGFBP)-2 and -6 were reduced in CS-FBS. IGF-1 receptor (IGF1R) and insulin receptor were sensitized to IGFs in CS-FBS. IGF-1 and IGF-2 stimulation fully compensated for the loss of AR activity to maintain cell growth in CS-FBS. Endogenous production of IGF and IGFBPs was verified in CaP cells and clinical CaP specimens. This study provided the most comprehensive protein profiles of FBS and CS-FBS and offered an opportunity to identify new protein regulators and signaling pathways that regulate AR activity, androgen metabolism, and proliferation of CaP cells. PMID- 30014701 TI - Correction to Ga-Doped Pt-Ni Octahedral Nanoparticles as a Highly Active and Durable Electrocatalyst for Oxygen Reduction Reaction. PMID- 30014702 TI - Silicon Substitution in Oxazine Dyes Yields Near-Infrared Azasiline Fluorophores That Absorb and Emit beyond 700 nm. AB - Exchanging the bridging oxygen atom in rhodamine dyes with a dimethylsilyl group red-shifts their excitation and emission spectra, transforming orange fluorescent rhodamines into far-red Si-rhodamines. To study the effect of this substitution in other dye scaffolds, synthetic approaches to incorporate silicon into the bridging position of oxazine dyes were developed. The fluorescence of the compact azasiline dyes ASiFluor710 and ASiFluor730 is red-shifted by 57-83 nm from that of Oxazine 1. PMID- 30014703 TI - Direct Regioselective [3 + 2] Cycloaddition Reactions of Masked Difluorodiazoethane with Electron-Deficient Alkynes and Alkenes: Synthesis of Difluoromethyl-Substituted Pyrazoles. AB - Phenylsulfone difluorodiazoethane (PhSO2CF2CHN2), an easy-to-prepare and bench stable masked CF2-building block, has been developed. The synthetic utility of this reagent is demonstrated by a direct regioselective [3 + 2] cycloaddition with electron-deficient alkynes and alkenes. This protocol enables facile construction of an array of difluoromethyl-substituted pyrazoles in good to high yields under mild reaction conditions. PMID- 30014704 TI - Hormesis and immunity: A review. AB - The hormesis concept demonstrates that in contrast to the toxic effect of high doses of materials, irradiation, etc., low doses of them are beneficial and, in addition, help to eliminate (prevent) the deleterious effect of high doses given after it. By this effect, it is an important factor of (human) evolution protecting man from harmful impacts, similarly to the role of immunity. However, immunity is also continuously influenced by hormetic effects of environmental [chemical (pollutions), physical (background irradiations and heat), etc.] and medical (drugs and therapeutic irradiations) and food interactions. In contrast to earlier beliefs, the no-threshold irradiation dogma is not valid in low-dose domains and here the hormesis concept is valid. Low-dose therapeutic irradiation, as well as background irradiations (by radon spas or moderately far from the epicenter of atomic bomb or nuclear facilities), is rather beneficial than destructive and the fear from them seems to be unreasonable from immunological point of view. Practically, all immune parameters are beneficially influenced by all forms of low-dose radiations. PMID- 30014706 TI - A Systematic Review of Race/Ethnicity and Parental Treatment Decision-Making. AB - Patient race/ethnicity affects health care utilization, provider trust, and treatment choice. It is uncertain how these influences affect pediatric care. We performed a systematic review (PubMed, Scopus, Web of Science, PsycINFO, Cochrane, and Embase) for articles examining race/ethnicity and parental treatment decision-making, adhering to PRISMA methodology. A total of 9200 studies were identified, and 17 met inclusion criteria. Studies focused on treatment decisions concerning end-of-life care, human papillomavirus vaccination, urological surgery, medication regimens, and dental care. Findings were not uniform between studies; however, pooled results showed (1) racial/ethnic minorities tended to prefer more aggressive end-of-life care; (2) familial tradition of neonatal circumcision influenced the decision to circumcise; and (3) non-Hispanic Whites were less likely to pursue human papillomavirus vaccination but more likely to complete the vaccine series if initiated. The paucity of studies precluded overarching findings regarding the influence of race/ethnicity on parental treatment decisions. Further investigation may improve family-centered communication, parent engagement, and shared decision-making. PMID- 30014707 TI - Accuracy of High-Frequency Endoluminal Ultrasonography for Clinical Staging of Upper Tract Urothelial Carcinoma. AB - INTRODUCTION: Staging of upper tract urothelial carcinoma (UTUC) remains a dilemma due to imaging and biopsy limitations leading to understaging. We seek to determine the accuracy of endoluminal ultrasound (ELUS) for clinical staging of UTUC. MATERIALS AND METHODS: Patients evaluated for UTUC underwent retrograde pyelography, ureteroscopy, and ELUS. ELUS was performed using mechanical radial scanning at 20 MHz in B-mode with a 5F probe. Cine clips were evaluated by 2 radiologists blinded to ureteroscopic and pathology findings. Results were compared to pathology from nephroureterectomy. Inclusion criteria were patients who underwent nephroureterectomy without pretreatment or managed endoscopically for cTa-1 disease and were without recurrence for >1 year. RESULTS: From 2008 to 2013, 53 patients underwent ELUS without complication. Twenty-seven patients met inclusion criteria with conclusive ELUS imaging. ELUS accurately identified 16 of 21 patients with non-muscle invasive (MI) disease (18 pTa, 2 pT1, 1 CIS) and 1 of 6 patients with at least MI disease (2 pT2, 4 pT3). For MI disease, the positive predictive value (PPV), negative predictive value, and accuracy was 76.2%, 16.7%, and 63%, respectively, while for non-organ confined (OC) disease results were 0%, 81.8%, and 66.7%, respectively. CONCLUSIONS: With current technique and instrumentation, ELUS may prove useful in select cases to confirm findings of non MI and OC disease. However, it has insufficient PPV for stage pT2-3 disease. Further studies and better instrumentation are needed before incorporation into clinical practice. PMID- 30014708 TI - Accuracy of two Generic Prediction Equations and One Population-Specific Equation for Resting Energy Expenditure in Individuals with Spinal Cord Injury. AB - PURPOSE: The primary aim was to assess the accuracy of common prediction equations, the Harris-Benedict (HB) and the Mifflin St. Jeor (MSJ) equations, for estimating resting energy expenditure (REE) among people with spinal cord injury (SCI) against actual REE measurements. The secondary aim was to cross-validate the Buchholz et al. energy prediction equation created for people with SCI. METHODS: A metabolic cart with canopy was used to measure the actual REE. The HB, MSJ, and the Buchholz et al. equations were used for the prediction of REE. RESULTS: Thirty-nine participants (31 males and 8 females) were enrolled in this cross-sectional study. The REEs significantly differed from one another, F(1.52, 57.68) = 52.04, P < 0.001, where both the HB (M = 1703.06, SD = 265.1) and the MSJ (M = 1628.92, SD = 233.8) energy predictions were significantly higher (P < 0.001) than the measured REE (M = 1394.05, SD = 298.7). In contrast, the Buchholz et al. equation did not differ from the measured REE. CONCLUSIONS: Our data show that the HB and MSJ equations do not accurately predict the energy needs of this community. Using a SCI-specific equation would improve estimates of REE, such as the Buchholz et al. equation. More research into energy equations for this population may help health care professionals better tailor dietary requirements for weight management. PMID- 30014709 TI - Chemical constituents from the culture of the fungus Hericium alpestre. AB - Two new compounds herialpins A-B (1-2), along with eleven known compounds, were isolated from the culture of fungus Hericium alpestre. The structures were elucidated by 1D and 2D NMR data, ESI-MS and X-ray crystallographic analysis. Compounds 1-2 were assayed for their cytotoxicity against three tumor cell lines compared with the known compound 3. Compounds 1 and 2 were found with modest activity, while compound 3 exhibits stronger selective inhibitory activity against A549 and HT-29 cells with IC50 values of 15.1 and 20.1 MUmol/L, respectively. The pyrano[3,4-g]chromene-4,6-dione moiety in compound 3 should be responsible for the stronger selective inhibitory activity. PMID- 30014711 TI - New steroidal glycosides from the fibrous roots of Ophiopogon japonicus. AB - Two new steroidal glycosides (named fibrophiopogonins A, B), along with one known glycoside, were isolated from the fibrous roots of Ophiopogon japonicus (Liliaceae). Comprehensive spectroscopic analysis, including 2D NMR spectroscopy, and the results of acid hydrolysis allowed the chemical structure of the compounds to be assigned as 26-[(O-beta-D-glucopyranosyl-(1 -> 6)-D glucopyranosyl)]-barogenin- 3-O-[alpha-L-rhamnopyranosyl-(1->2)]-beta-D glucopyranoside and (25R)-26-[(O- beta-D-glucopyranosyl-(1->6)-beta-D glucopyranosyl)]- 3beta,22alpha,26- trihydroxyfurost- 5-ene-3-O-[alpha-L rhamnopyranosyl-(1->2)]-beta-D-glucopyranoside. This is the first isolation of a cholestane glycoside with disaccharide moiety from a Ophiopogon species. The cytotoxic activities of 1~3 against A375 and MCF-7 cells are described. PMID- 30014710 TI - Lactobacillus acidophilus and Clostridium butyricum ameliorate colitis in murine by strengthening the gut barrier function and decreasing inflammatory factors. AB - Ulcerative colitis is a type of chronic inflammation present in the intestines for which the aetiology is not yet clear. The current therapies for ulcerative colitis cannot be considered to be long-term management strategies due to their significant side effects. Therefore, it is essential to identify an alternative therapeutic strategy for ulcerative colitis. The present study focused on the evaluation of the anti-inflammatory activities of Lactobacillus acidophilus CGMCC 7282 and Clostridium butyricum CGMCC 7281. The roles of both single and combination of L. acidophilus CGMCC 7282 and C. butyricum CGMCC 7281 in ulcerative colitis were investigated in 2,4,6-trinitrobenzenesulfonic acid induced acute colitis (Th1-type colitis) in Sprague-Dawley rats and oxazolone induced chronic colitis (Th2-type colitis) in BALB/c mice. The in vivo studies showed that the administration of L. acidophilus CGMCC 7282, C. butyricum CGMCC 7281 and L. acidophilus CGMCC 7282 plus C. butyricum CGMCC 7281 could reduce the Th1-type colitis as well as the Th2-type colitis, and the combination of the two strains exhibited the most notable effects, as indicated by the reduced mortality rates, the suppressed disease activity indices, the improved body weights, the reduced colon weight/colon length and colon weight/body weight ratios, and the improved gross anatomic characteristics and histological features (ameliorations of neutrophil infiltration and ulceration in the colon). It was found that the alterations of the gut microbiome, the barrier function changing and the selected inflammation-related cytokines are observed in the ulcerative colitis rats/mice treated with L. acidophilus CGMCC 7282 and C. butyricum CGMCC 7281. The combination of L. acidophilus CGMCC 7282 plus C. butyricum CGMCC 7281 also exerted a stronger anti-inflammatory effect than either of the single strains alone in vitro. These findings provide evidence that the administration of L. acidophilus CGMCC 7282 plus C. butyricum CGMCC 7281 may be a promising therapy for ulcerative colitis. PMID- 30014712 TI - Effects of feeding diets containing essential oils and betaine to heat-stressed growing-finishing pigs. AB - This study was to evaluate the effects of dietary essential oils (EO) and betaine on growth performance, nutrient digestibility and serum hormones in growing finishing pigs under heat stress conditions. A total of 96 crossed pigs [(Landrace * Yorkshire) * Duroc] with an initial body weight (BW) of 24.7 +/- 0.27 kg were used in an 18-week trial. Pigs were randomly allocated to four treatments according to BW and gender. There were six replication pens in each treatment, with four pigs (two barrows and two gilts) per pen. Treatment groups were: (1) control group (CON), basal diet + 23 degrees C for 24 h; (2) heat stress group (HC) with basal diet + 37 degrees C for 9 h, 23 degrees C for 15 h; (3) group HEO, HC with 0.01% EO; (4) group HBE, HC with 0.1% betaine. During the overall period, groups HEO and HBE had higher (p < 0.05) average daily gain than group HC. At week 6, group HC had a lower apparent total tract digestibility (ATTD) of dry matter (DM) (p < 0.05), but at week 12, this group had lower ATTD of DM, nitrogen and gross energy than group HEO (p < 0.05). At week 12 and 18, dietary EO decreased (p < 0.05) serum cortisol and norepinephrine concentration. At week 18, dietary EO and betaine decreased (p < 0.05) epinephrine concentration. Conclusively, dietary EO may be a potential nutritional strategy to alleviate heat stress in growing-finishing pigs. PMID- 30014713 TI - The association of serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy in Asians with type 2 diabetes: A nested case-control study. AB - BACKGROUND:: Fluctuation of kidney function may signify intra-glomerular microvascular hemodynamic instability. We aim to examine the association of long term serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy. METHODS:: We included type 2 diabetes mellitus patients who attended the Diabetes Centre in 2011-2014 and were followed up (median = 3.2 years). Digital colour fundus photographs were assessed for diabetic retinopathy at follow-up. Diabetic retinopathy severity was categorized into non proliferative diabetic retinopathy and proliferative diabetic retinopathy. We conducted a nested case-control study involving 177 diabetic retinopathy (118 non proliferative diabetic retinopathy, 50 proliferative diabetic retinopathy) and 327 age- and gender-matched non-diabetic retinopathy. Serum creatinine measured before follow-up visit was obtained (?3 readings/patient). Variability was calculated as intra-individual standard deviation/? n/( n - 1). RESULTS:: Diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-diabetic retinopathy [9.1 (4.9-21.6) vs 5.4 (3.4-10.1) uM, p < 0.001]. After multivariable adjustment, adjusted-serum creatinine-standard deviation was associated with diabetic retinopathy [odds ratio = 1.47, 95% confidence interval (1.02-2.10), p = 0.04]. The area under the curve increased significantly after adding adjusted-serum creatinine-standard deviation [0.70 (0.65-0.75) vs 0.72 (0.68-0.77), p < 0.03]. Proliferative diabetic retinopathy have higher adjusted serum creatinine-standard deviation than non-proliferative diabetic retinopathy [15.5 (6.6-39.7) vs 7.47 (4.52-17.8) uM, p < 0.001]. After adjustment, adjusted serum creatinine-standard deviation remained associated with non-proliferative diabetic retinopathy [1.48 (1.04-2.12), p = 0.03] and proliferative diabetic retinopathy [2.43 (1.34-4.39), p = 0.003; p-trend = 0.002]. Similar findings were observed for estimated glomerular filtration rate variability. CONCLUSION:: Serum creatinine and estimated glomerular filtration rate variability is associated with the presence and severity of diabetic retinopathy independent of intra individual means. This may inform novel therapeutic strategies aiming to achieve stable renal function in type 2 diabetes mellitus. PMID- 30014714 TI - Perceptions of self and other: Social judgments and gaze patterns to videos of adolescents with and without autism spectrum disorder. AB - Neurotypical adults often form negative first impressions of individuals with autism spectrum disorder and are less interested in engaging with them socially. In contrast, individuals with autism spectrum disorder actively seek out the company of others who share their diagnosis. It is not clear, however, whether individuals with autism spectrum disorder form more positive first impressions of autistic peers when diagnosis is not explicitly shared. We asked adolescents with and without autism spectrum disorder to watch brief video clips of adolescents with and without autism spectrum disorder and answer questions about their impressions of the individuals in the videos. Questions were related to participants' perceptions of the social skills of the individuals in the video, as well as their own willingness to interact with that person. We also measured gaze patterns to the faces, eyes, and mouths of adolescents in the video stimuli. Both participant groups spent less time gazing at videos of autistic adolescents. Regardless of diagnostic group, all participants provided more negative judgments of autistic than neurotypical adolescents in the videos. These data indicate that, without being explicitly informed of a shared diagnosis, adolescents with autism spectrum disorder form negative first impressions of autistic adolescents that are similar to, or lower than, those formed by neurotypical peers. PMID- 30014715 TI - Improving Documentation of Pediatric Height, Weight, and Body Mass Index by Primary Care Providers. AB - The regular documentation of anthropometric data in an electronic medical record (EMR) is one tracking method used by primary care providers to follow the growth trajectory and development of children in their health care practices. EMR reminders have been proposed as a method to increase recording of pediatric height and weight by primary care providers, leading to potentially better detection and management of children classified as overweight or obese. The aim of this pre-post study was to improve a Family Health Team's physician documentation of pediatric height and weight through the implementation of an EMR reminder alert tool. The documentation rate for children 4-7 years old in the 6 months before intervention was 36% of children seen. After implementation of EMR reminder alerts, primary care physicians' documentation rate rose to 45% (9% increase; P < 0.01), but it was below the 15% target increase. Better documentation of pediatric height and weight by family physicians is needed to improve monitoring of children's growth trajectories. Additional strategies to increase documentation rates are needed. PMID- 30014716 TI - The risk association of plasma total homocysteine with acute myocardial infarction is modified by serum vitamin A. AB - Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the potential interaction between plasma tHcy and serum Vit-A in relation to incident acute myocardial infarction. Methods Cox proportional hazards models were used to assess the prospective relationships between tHcy and acute myocardial infarction in 2205 patients from Western Norway undergoing elective coronary angiography for suspected stable angina pectoris. Results are reported as hazard ratio per standard deviation increase in log-transformed tHcy. An interaction term for tHcy * Vit-A was added to multivariate models including age, sex, smoking, apolipoprotein B fasting, statin and aspirin prescription and estimated glomerular filtration rate. Results Geometric mean (geometric standard deviation) age of the participants (64.3% men) was 62.3 (1.24) years. Plasma tHcy was higher among participants in the upper versus lower Vit-A tertile. During 7 (2.4) years of follow-up, 15.1% suffered an AMI. A significant association of plasma tHcy with AMI in the total study population was observed. When we stratified the population according to Vit-A tertiles, plasma tHcy was associated with acute myocardial infarction only in the upper Vit-A tertile (hazard ratio per SD: 1.25, 95% confidence interval: 1.04-1.53, pinteraction = 0.03). Conclusions The risk relationship between plasma tHcy and acute myocardial infarction was modified by serum concentrations of Vit-A in patients with suspected stable angina pectoris. This finding may clarify the relationship between tHcy and cardiovascular disease. PMID- 30014717 TI - Moving from Policy to Practice: A Report of School Nutrition Policy Adherence in Nova Scotia. AB - PURPOSE: School food and nutrition policies have the potential to encourage healthier eating among children and youth to address rising concerns of poor diet quality. Despite their widespread implementation, there is little reported monitoring of policy adherence. This short report describes adherence to the provincial school food and nutrition policy in Nova Scotia (NS) that was implemented in 2006. METHODS: An online survey was distributed to NS public schools in 2014-2015 to assess adherence to the directives and guidelines of the policy. Descriptive information was obtained for schools and indicators for policy adherence were explored. RESULTS: A total of 242 schools completed the survey (73% response rate) and policy adherence was variable across the different components. Few schools adhered to the policy standard related to the sale of unhealthy foods and there was inconsistency in school adherence reported for other policy indicators. CONCLUSIONS: This research suggests that further action is need to ensure "minimum nutrition" food and beverages are not available in schools and that healthy eating is reinforced through prioritizing key policy actions like pricing strategies, discontinuing fundraising with unhealthy food, and ensuring food programs are available in a nonstigmatizing manner. PMID- 30014718 TI - Educating the MSTEM Workforce to Address the Needs of Aging Societies: A Call for Best Practices. PMID- 30014719 TI - Mood state as a blood glucose modulator in a patient with bipolar disorder and diabetes mellitus: A case report. PMID- 30014720 TI - Sleep and Gastrointestinal Symptoms in a Community-Based Survey of Children. AB - We examined whether gastrointestinal (GI) symptoms were associated with sleep disturbances in a community-based sample of 337 school-aged children from Ypsilanti, Michigan. Parents completed the sleep-related breathing disorder scale of the Pediatric Sleep Questionnaire and the Conners' parents rating scale, which included questions concerning GI symptoms. One fifth of the children screened positive for sleep-disordered breathing; the same fraction had sleepiness, and one-quarter snored more than half the time. Similarly, one quarter of children had 2 or more GI symptoms. Children with positive sleep-disordered breathing scores were 2.22 times as likely to have 2 or more GI symptoms in the past month after confounder adjustment (95% confidence interval = 1.39-3.55). In particular, this relationship appeared to be driven by daytime sleepiness, as children with sleepiness had about a 2-fold higher prevalence of 2 or more GI symptoms (adjusted prevalence ratio = 1.96, 95% confidence interval = 1.18-3.26). Neither snoring nor sleep duration were associated with GI symptoms. PMID- 30014721 TI - Dietetic Staffing and Workforce Capacity Planning in Primary Health Care. AB - The addition of Registered Dietitians (RD) to primary health care (PHC) teams has been shown to be effective in improving health and economic outcomes with reported savings of $5 to $99 New Zealand dollars for every $1 spent on nutrition interventions. Despite proven benefits, very few Canadians have access to dietitians in PHC. This paper summarizes the literature on dietetic staffing ratios in PHC in Canada and other countries with similar PHC systems. Examples are shared to demonstrate how dietitians and others can utilize published staffing ratios to review dietitian services within their settings, identify gaps, and advocate for additional positions to meet population needs. The majority of published dietetic staffing ratios describe ranges of 1 RD: 15 000-18 500 patients, 1 RD for every 4-14 family physicians, or 1 RD for every 300-500 patients with diabetes. These staffing ratios may be inadequate as surveys report ongoing issues of limited access to dietetic counseling, under-serviced populations, and a shortage of dietitians to meet current population needs in PHC. Newer projection models based on specific population needs and ongoing workforce data are required to identify professional practice issues and accurately estimate dietetic staffing requirements in PHC. PMID- 30014722 TI - Changes in Energy Metabolism from Prepregnancy to Postpartum: A Case Report. AB - PURPOSE: Energy metabolism is at the core of maintaining healthy body weights. Likewise, the assessment of energy needs is essential for providing adequate dietary advice. We explored differences in energy metabolism of a primigravid woman (age: 30 years) at 1 month prepregnancy ("baseline"), during pregnancy (33 weeks), and at 3 and 9 months postpartum. Measured versus estimated energy expenditure were compared using equations commonly used in clinical practice. METHODS: Energy metabolism was measured using a state-of-the-art whole body calorimetry unit (WBCU). Body composition (dual-energy X-ray absorptiometry), energy intake (3-day food records), physical activity (Baecke questionnaire), and breastmilk volume/breastfeeding energy expenditure (24-hours of infant test retest weighing) were assessed. RESULTS: This case report is the first to assess energy expenditure in 3 different stages of a woman's life (prepregnancy, pregnancy, and postpartum) using WBCU. We noticed that weight and energy needs returned to prepregnancy values at 9 months postpartum, although a pattern of altered body composition emerged (higher fat/lean ratio) without changes in physical activity and energy intake. For this woman, current recommendations for energy overestimated actual needs by 350 kcal/day (9 months postpartum). CONCLUSION: It is likely that more accurate approaches are needed to estimate energy needs during and postpregnancy, with targeted interventions to optimize body composition. PMID- 30014723 TI - Size Matters: Package Size Influences Recognition of Serving Size Information. AB - PURPOSE: To identify the impact of package size on an individual's use of serving size information. The hypothesis was that participants would make more serving size assumption errors on a nutrition facts table (NFT) interpretation task when assessing packages that appear as a single serving but contain multiple servings, compared with products that appear as a multi-serving and contain multiple servings. METHODS: Sixty participants were randomized into 1 of 3 conditions (n = 20 each); products that appeared as a single serving and contain a single serving (SSSS), products that appeared as a single serving and contain multiple servings (SSMS), and products that both appear as a multi-serving and contain multiple servings (MSMS). All 3 conditions were tested on a NFT interpretation task while participants were being presented food items that were appropriate to their given condition. RESULTS: Participants in the SSMS (9.55 +/- 7.78) condition made significantly more serving size assumption errors than the SSSS (0.00 +/- 0.00; P < 0.001) and MSMS (0.40 +/- 0.75; P < 0.001) conditions. CONCLUSIONS: Participants did not address serving size information when they perceived a product to be a single serving. This resulted in people misinterpreting nutritional and caloric content of foods that were single unit foods with multiple servings. PMID- 30014724 TI - Profile of evolocumab and its cost-effectiveness in patients with high cardiovascular risk: literature review. AB - INTRODUCTION: Evolocumab is fully human monoclonal antibody which binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), and prevents its blocking effect on recycling of liver low-density lipoprotein (LDL) receptors. Areas covered: The aim of this review is to assess efficacy, safety, and cost effectiveness of evolocumab in adult patients with high cardiovascular risk. Major research databases MEDLINE, EBSCO, and CENTRAL were systematically searched for relevant study reports. Expert commentary: Even when given in full doses, statins augmented with ezetimibe and cholesterol-binding resins could not reduce cholesterol baseline level for more than 66%, while evolocumab reduces cholesterol level for 75% or even more. Up to now, evolocumab showed good safety profile, and patents tolerate it very well. The abovementioned advantages of evolocumab made it almost ideal drug for hypercholesterolemia, and probably in the future the best drug for secondary prevention of major cardiovascular events. Evolocumab is borderline cost-effective for the treatment of patients with high cardiovascular risk in European countries, while in the U.S.A. it is under debate where the underlying assumption (risk of cardiovascular disease events) determine the true value. PMID- 30014726 TI - Characterization of tomato processing by-product for use as a potential functional food ingredient: nutritional composition, antioxidant activity and bioactive compounds. AB - Tomato pomace, a by-product generated during tomato processing, was collected at a large tomato processing industry. The by-product was mainly constituted of tomato skin (61.5%), and presented high moisture content (66.58 g.100g-1 wet basis). Among the nutrients, the highest content was of dietary fibre, followed by proteins and fat (50.74, 20.91, 14.14 g.100g-1 d.w., respectively). The pomace has high in vitro antioxidation capacity, especially when measured with the TEAC assay (224.81 MUmol Trolox equivalent 100g-1 d.w.). This is due especially to the high amount of lycopene remaining in the by-product after processing (446.9 MUg.g 1 d.w). The waste was fractioned into skin and seed fractions by sedimentation, resulting in the increase of lycopene yield by 55%, when using skin fraction as the source material in place of the whole pomace. This by-product shows great potential for being used as a source of the ingredients of high nutritional value, especially dietary fibre and lycopene. PMID- 30014725 TI - Ongoing activities to optimize the quality and efficiency of lipid-lowering agents in the Scottish national health service: influence and implications. AB - BACKGROUND: Prescribing of lipid-lowering agents (LLAs) has increased worldwide including in Scotland with increasing prevalence of coronary heart disease, and higher dose statins have been advocated in recent years. There have also been initiatives to encourage prescribing of generic versus patented statins to save costs without compromising care. There is a need to document these initiatives and outcomes to provide future direction. METHOD: Assessment of utilization (items dispensed) and expenditure of key LLAs (mainly statins) between 2001 and 2015 in Scotland alongside initiatives. RESULTS: Multiple interventions over the years have increased international nonproprietary name prescribing (99% for statins) and preferential prescribing of generic versus patented statins, and reduced inappropriate prescribing of ezetimibe. This resulted in a 50% reduction in expenditure of LLAs between 2001 and 2015 despite a 412% increase in utilization, increased prescribing of higher dose statins (71% in 2015) especially atorvastatin following generic availability, and reduced prescribing of ezetimibe (reduced by 72% between 2010 and 2015). As a result, the quality of prescribing has improved. CONCLUSION: Generic availability coupled with multiple measures has resulted in appreciable shifts in statin prescribing behavior and reduced ezetimibe prescribing, resulting in improvements in both the quality and efficiency of prescribing. PMID- 30014727 TI - Management of ventilator-associated pneumonia: Need for a personalized approach. AB - INTRODUCTION: Optimizing management of ventilator-associated pneumonia (VAP) should focus on the accurate identification of true lung infection, determination of the etiological agent, and early institution of adequate empirical therapy and de-escalation. Local adaptation of the standard guidelines leads to favorable outcome in the management of VAP Areas covered: In this review, we present the concepts of early adequate therapy and the key considerations such as patient characters, clinical and etiological diagnosis, and assessment of patients for de escalation that favor optimization of therapy. We highlight the issues that need a personalized approach in the management of VAP emphasizing on various patient categories for reassessment and tailoring the therapy. Expert commentary: Rapid diagnostic techniques and non-invasive metabolomics will identify phenotypes which will shift the traditional paradigm based on conventional cultures. A personalized approach taking into account baseline resistance epidemiology, underlying disease (and comorbidities), duration of hospitalization, and prior antimicrobial exposure should guide targeted therapy. PMID- 30014728 TI - The association of hyperuricemia and immediate postpartum hypertension in women without a diagnosis of chronic hypertension. AB - Our objective was to determine if elevated uric acid (UA) is associated with postpartum hypertension (PP HTN) in women without chronic hypertension. This is a secondary analysis of a randomized trial. We compared those with elevated UA to those with normal UA. Logistic regression was conducted to determine the association of elevated UA with PP HTN. Five hundred and fifty-six women met criteria. An UA level >= 5.2 mg/dL was associated with immediate PP HTN (adjusted odds ratio 2.44, 95% CI 1.63-3.64). The association was stronger among overweight and obese women. We conclude that hyperuricemia is associated with PP HTN, especially among obese women. PMID- 30014729 TI - Tebipenem, the first oral carbapenem antibiotic. AB - INTRODUCTION: Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, have become increasingly challenging to successfully treat. The beta-lactam antibiotic subclass, the carbapenems, have proven valuable for the treatment of such Gram-negative bacterial infections due to their spectrum and beta-lactamase stability properties. However, all marketed carbapenems to date are parenterally administered to adult patients. Areas covered: One carbapenem, tebipenem-pivoxil (TBPM-PI), is an oral prodrug that was approved in Japan for pediatric use only in 2009. This review summarizes preclinical and clinical data for TBPM-PI, which is now in clinical development again this time for use as the first oral carbapenem available for treatment of bacterial infections in adult patients. Expert commentary: There is an urgent unmet need with an increasing prevalence of fluoroquinolone-resistant and ESBL producing Gram-negative pathogens in the hospital and community setting. Carbapenems have traditionally been considered the drugs of choice for infections caused by enterobacteria producing ESBL and AmpC enzymes because they are not affected by these resistance mechanisms. The carbapenem, TBPM-PI, offers an oral option, particularly as step-down therapy, for use of this class in the treatment of serious Gram-negative infections. PMID- 30014730 TI - Generation of Flp-intm-ready DG44 and Lec 3.2.8.1 CHO cell lines for quick and easy constitutive protein expression. AB - The well-characterized cell line Chinese hamster ovary (CHO) has been used to produce numerous biopharmaceuticals and is an important tool for basic research. However, introducing foreign DNA into specially modified CHO cells such as DG44 and Lec 3.2.8.1 can sometimes be an arduous process. Here we show that the Flp intm plasmid can be modified to produce a fluorescent tracer protein tag (mCherrytm) as a fusion reporter, to allow for the rapid selection of single-cell sorted, isogenic Flp-intm-ready DG44 and Lec 3.2.8.1 cell lines. These two cell lines are stable and viable and may be useful for applications such as antibody production and crystallographic studies. Here we provide key details on how the modified pFRT/CherryZeo plasmid may be used to incorporate Flp-intm technology into virtually any desired target cell line in a fast, safe and reliable manner. PMID- 30014731 TI - Inorganic lanthanides induce PCR bias towards shorter amplicons. AB - Rare earth elements have many uses, and are frequently included in products such as fluorescent materials, hydride batteries, catalytic materials and lasers. In this study, it was observed that trivalent lanthanide ions (Ln[III] ions) appeared to inhibit the synthesis of large fragments in PCR assays, thus resulting in the preferential amplification of shorter sequences. It is therefore speculated that this Ln(III) ion-mediated bias could be utilized to improve the success rates for amplification of shorter products. PMID- 30014732 TI - Could closing the gender gap in STEMM really take a quarter of a millennium? PMID- 30014733 TI - Microgels and apparatus for PAGE of nucleic acids in one or two dimensions. AB - We describe a system for horizontal 1D or 2D PAGE comprising an apparatus and microgels. There is no buffer outside the gel, making handling and sample loading easy. Specially designed electrodes on all four sides allow 2D electrophoresis without gel rotation. Electrophoresis is completed within 20 min and sensitivity is in the subnanogram range. The system is temperature controlled for speed, denaturation of nucleic acid molecules and maintaining molecules single-stranded. The system allows characterization of structure, conformation and damage in complex nucleic acid preparations. Besides quick 1D PAGE, 2D applications include characterization of efficiency of complex molecular procedures, checking quality of biosamples and detecting DNA damage in cells and body fluids. The system should also run protein gels. PMID- 30014735 TI - Designer microbiomes. AB - To what extent can your microbiome define you and how can it be altered to optimize your health? PMID- 30014734 TI - Luciferase complementation based-detection of G-protein-coupled receptor activity. AB - Protein complementation assays (PCA) are used as pharmacological tools, enabling a wide array of applications, ranging from studies of protein-protein interactions to second messenger effects. Methods to detect activities of G protein-coupled receptors (GPCRs) have particular relevance for drug screening. Recent development of an engineered luciferase NanoLuc created the possibility of generating a novel PCA, which in turn could open a new avenue for developing drug screening assays. Here we identified a novel split position for NanoLuc and demonstrated its use in a series of fusion constructs to detect the activity of GPCRs. The split construct can be applied to a variety of pharmacological screening systems. PMID- 30014736 TI - Non-lethal method for the preparation of metaphase spreads using cultured mantle tissue from live adult abalone. AB - Metaphase spread preparation in adult abalone has not been successful, which has restricted the applications of karyotyping-based technologies. Here, we present a non-lethal method to enable preparation of metaphase spreads from live adult abalone using a tissue culture method. Mantle tissue fragments from live adult abalone were cultured in vitro and the cultured cells were used for metaphase spread preparation. To retrieve a sufficient number of proliferating cells required for metaphase spread preparation, at least 14 days of culture was required, and culturing the marginal zone of mantle was more optimal than culturing other areas. Additionally, it was shown that simple medium consisting of basal medium, fetal bovine serum and antibiotics could stimulate cellular proliferation followed by metaphase spread preparation. PMID- 30014737 TI - Long-term imaging of calcium dynamics using genetically encoded calcium indicators and automatic tracking of cultured cells. AB - Calcium dynamics is crucial for many signaling pathways and cell functions. Understanding how calcium regulates cell function often requires long-term imaging of calcium dynamics. Here we report a methodological approach of long term (5-10 h) imaging of calcium dynamics in cultured cells. The approach links calcium imaging using genetically encoded calcium indicators and semi-automatic tracking of individual cells. It can be used in a large variety of situations, ranging from the role of calcium in biological processes to cell heterogeneity and screening of drugs modifying signaling pathways. PMID- 30014738 TI - A bioinformatics approach to identify telomere sequences. AB - Conventional approaches to identify a telomere motif in a new genome are laborious and time-intensive. An efficient new methodology based on next generation sequencing (NGS), de novo sequence repeat finder (SERF) and fluorescence in situ hybridization (FISH) is presented. Unlike existing heuristic approaches, SERF utilizes an exhaustive analysis of raw NGS reads or assembled contigs for rapid de novo detection of conserved tandem repeats representing telomere motifs. SERF was validated using the NGS data from Ipheion uniflorum and Allium cepa with known telomere motifs. The analysis program was then used on NGS data to investigate the telomere motifs in several additional plant species and together with FISH proved to be an efficient approach to identify as yet unknown telomere motifs. PMID- 30014739 TI - Osteogenesis of osteogenic matrix cell sheets preserved in culture medium in a rat model. AB - Osteogenic matrix cell sheets (OMCSs) are ideal for bone regeneration. Transportation of OMCSs may be necessary, during which their osteogenic ability must be maintained. Here, we evaluated different media and temperatures for OMCS preservation. Bone marrow stromal/stem cells (BMSCs) were obtained from Fischer rats and analyzed for stem cell markers by flow cytometry. OMCSs were prepared from BMSCs by treatment with dexamethasone and ascorbic acid phosphate. After OMCS collection, they were stored in minimum essential medium (MEM) or Hank's balanced salt solution (HBSS) at 37, 22, or 4 degrees C for 24 hours. Cell viability and cytotoxic effects in the preservation conditions were determined by adenosine triphosphate (ATP) contents and lactate dehydrogenase (LDH) release, respectively. Osteogenesis was assessed by subcutaneously implanting preserved OMCSs around beta-tricalcium phosphate ceramic disks into syngeneic rats. Implants were evaluated by alkaline phosphatase (ALP) activities, osteocalcin contents, and histology. Mesenchymal stem cells comprised 51% of primary cultured BMSCs. ATP contents were significantly different in OMCSs stored in MEM or HBSS at 22 degrees C and 4 degrees C. LDH release was significantly different in OMCSs stored in HBSS at 22 degrees C and 4 degrees C. The highest LDH release was observed in OMCSs stored in HBSS at 37 degrees C. ALP activities and osteocalcin contents were the lowest in implanted OMCSs stored in HBSS at 37 degrees C at four weeks after subcutaneous implantation. There was a significant difference in the osteocalcin levels of implanted OMCSs stored in MEM at 37 degrees C and HBSS at 4 degrees C. Abundant bone tissue around and inside disks was found in histological sections of OMCSs stored in all preservation conditions except for MEM and HBSS at 37 degrees C. Maintaining the osteogenic ability of OMCSs during transport is important, and preservation of OMCSs in MEM or HBSS at 4 degrees C or 22 degrees C is a simple and inexpensive method. PMID- 30014743 TI - Assessing the effectiveness of nutrition interventions implemented among US college students to promote healthy behaviors: A systematic review. AB - BACKGROUND:: Nutrition interventions are used to increase knowledge, change attitudes and beliefs about healthy eating, to increase skills, and promote healthy eating. AIMS:: To review the effectiveness of published nutrition interventions implemented among college students to promote healthy behaviors. METHODS:: The authors explored multiple electronic databases, such as ERIC, Science Direct, and EBSCOhost. Search criteria included nutritional interventions implemented among students attending US colleges, written in English, and published in peer-reviewed journals between 2000 and 2015. The authors conducted a systematic search of 1413 articles, and an in-depth review of 30 articles. The authors evaluated the following: (a) participants; (b) research design; (c) assessment instruments; (d) outcome measures; (e) results; and (f) methodological issues. RESULTS:: Short-term interventions showed promise in promoting positive dietary changes, which can serve as a protective factor for developing overweight and obesity. Methodological issues related to lack of comparison groups and minimal long-term follow-up do not allow researchers to determine if the interventions were the cause of the change, or if these changes are sustained over time. Studies that have a comparison group, use visual displays, or have longer durations, may maximize outcomes, improving long-term effects. CONCLUSIONS:: Nutrition interventions can effectively change dietary habits among college students. This can lead to healthy weight management and reduce the risk for overweight and obesity. Future research should consider the highlighted methodological issues to improve the quality of nutrition interventions. PMID- 30014745 TI - Effects of Sound Change on the Weighting of Acoustic Cues to the Three-Way Laryngeal Stop Contrast in Korean: Diachronic and Dialectal Comparisons. AB - Both segmental and suprasegmental properties of the South Kyungsang dialect of Korean have changed under the influence of standard Seoul Korean. This study examines how such sound change affects acoustic cues to the three-way laryngeal contrast among Korean stops across Kyungsang generations through a comparison with Seoul Korean. Thirty-nine female Korean speakers differing in dialect (Kyungsang, Seoul) and age (older, younger) produced words varying in initial stops and lexical accent patterns, for which voice onset time and fundamental frequency (F0) at vowel onset were measured. This study first confirms previous findings regarding age and dialectal variation in distinguishing the three Korean stops. In addition, we report age variation in the use of voice onset time and F0 for the stops in Kyungsang Korean, with younger speakers using F0 more than older speakers as a cue to the stop distinction. This age variation is accounted for by the reduced lexical tonal properties of Kyungsang Korean and the increased influence of Seoul Korean. A comparison of the specific cue weighting across speaker groups also reveals that younger Kyungsang speakers pattern with Seoul speakers who arguably follow the enhancing F0 role of the innovative younger Seoul speakers. The shared cue weighting pattern across generations and dialects suggests that each speaker group changes the acoustic cue weighting in a similar direction. PMID- 30014744 TI - miR-149-5p inhibits cell growth by regulating TWEAK/Fn14/PI3K/AKT pathway and predicts favorable survival in human osteosarcoma. AB - MicroRNAs (miRNAs) as small non-coding RNAs act as either tumor suppressors or oncogenes in human cancers, of which miR-149-5p (miR-149) is involved in tumor growth and metastasis, but its role and molecular mechanisms underlying osteosarcoma growth are poorly understood. The correlation of miR-149 expression with clinicopathological characteristics and prognosis in patients with sarcoma was analyzed by The Cancer Genome Atlas (TCGA) RNA-sequencing data. Osteosarcoma cell growth affected by miR-149 was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and colony formation assays. As a result, we found that the expression level of miR-149 was markedly downregulated in human sarcoma samples and were negatively associated with tumor size, acting as an independent prognostic factor for overall survival of the sarcoma patients. Restoration of miR-149 expression suppressed osteosarcoma cell growth, while its knockdown reversed these effects. Furthermore, we identified TNFRSF12A (TNF receptor superfamily member 12A), also called fibroblast growth factor-inducible 14 (Fn14) as a direct target of miR-149, and TNFRSF12A and its ligand TNFSF12 (TNF superfamily member 12), also called tumor necrosis factor-related weak inducer of apoptosis (TWEAK), were both negatively correlated with miR-149 expression in sarcoma samples. Knockdown of TNFRSF12A suppressed cell growth, but its overexpression weakened the antiproliferative effects of miR-149 via the PI3K/AKT (AKT serine/threonine kinase) signaling pathway. Altogether, our findings show that miR-149 functions as a tumor suppressor in osteosarcoma via inhibition of the TWEAK-Fn14 axis and represents a potential therapeutic target in patients with osteosarcoma. PMID- 30014746 TI - Erratum. PMID- 30014747 TI - Structural abnormalities detected by knee magnetic resonance imaging are common in middle-aged subjects with and without risk factors for osteoarthritis. AB - Background and purpose - Few data are available regarding structural changes present in knees without radiographically evident osteoarthritis (OA). We evaluated the prevalence of findings suggestive of knee OA by magnetic resonance imaging (MRI) in middle-aged subjects without radiographic OA with or without OA risk factors. Patients and methods - 340 subjects from the Osteoarthritis Initiative, aged 45-55 years (51% women) with Kellgren-Lawrence grade 0 in both knees, who had 3T knee MR images were eligible. 294 subjects had risk factors and 46 were without risk factors. MR images were assessed using the MOAKS scoring system. Results - At least 1 MR-detected feature was found in 96% (283/294) of subjects with risk factors and in 87% (40/46) of those without. Cartilage damage (82%), bone marrow lesions (60%), osteophytes (45%), meniscal body extrusion (32%), and synovitis-effusion (29%) were the most common findings in subjects with risk factors, while cartilage damage (67%), osteophytes (46%), meniscal body extrusion (37%), and bone marrow lesions (35%) were most common in subjects without. The prevalence of any abnormality was higher in subjects with OA risk factors than in subjects without (prevalence ratio adjusted for age and sex 1.3 [95% CI 1.1-1.6]), so was prevalence of subchondral cysts and bone marrow lesions. MR-detected structural changes were more frequent in patellofemoral joints. Interpretation - Our findings highlight the great challenge in distinguishing pathological features of early knee OA from what could be considered part of "normal ageing." Bone marrow lesions were more frequently found in subjects with multiple OA risk factors. PMID- 30014748 TI - Cerebral monitoring of anaesthesia on reducing cognitive dysfunction and postoperative delirium: a systematic review. AB - Objective To assess the efficacy of cerebrally monitoring the depth of anaesthesia in reducing postoperative cognitive dysfunction and postoperative delirium (POD). Methods MEDLINE, EMBASE, and Cochrane Library databases were searched following PRISMA statement guidelines. We included randomized clinical trials (RCTs) comparing electroencephalogram-based and routine care-guided titration of anaesthesia in a systematic review. The risk estimate from each RCT was pooled in a meta-analysis. The primary outcome was POD and long-term cognitive dysfunction. Subgroup analyses were conducted for the subtypes of intervention group and surgery. We identified five RCTs with a total sample size of 2,868 and with bispectral index (BIS) or auditory evoked potential (AEP) as interventions. Results The odds ratio (OR) for POD and long-term cognitive decline was 0.51 (95%CI: 0.35-0.76) and 0.69 (95%CI: 0.49-0.97), respectively. Significant heterogeneity was identified in the POD data. There was no significant difference between BIS- and AEP-based titration of anaesthesia in reducing the risk of POD. Extensive heterogeneity for cardiac and thoracic surgery was identified in the study population, and significant publication bias was found among the POD results. Conclusions BIS- and AEP-guided anaesthesia are associated with significantly reduced risk of POD and long-term cognitive dysfunction. PMID- 30014750 TI - Nummular eczema of the breast following surgery and reconstruction in breast cancer patients. PMID- 30014749 TI - IAPP/amylin deposition, which is correlated with expressions of ASC and IL-1beta in beta-cells of Langerhans' islets, directly initiates NLRP3 inflammasome activation. AB - Recent findings revealed that type 2 diabetes mellitus (T2D) is a chronic inflammatory disease and an islet amyloid polypeptide (IAPP)/amylin, is deposited within pancreatic islets. IAPP/amylin has been reported to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been shown to recognize pathogens and/or metabolites and complexes with the adopter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC to form a huge complex, called an inflammasome, an interleukin (IL)-1beta processing platform. Although reactive oxygen species (ROS) were reported to be involved in activation of NLRP3 inflammasome, we were hypothesized that IAPP could directly activate NLRP3 inflammasome, leading to islets beta-cell death. We analyzed expression of the inflammasome components ASC, NLRP3, caspase-1, IL 1beta, IAPP/amylin, and insulin immunohistochemically in Langerhans' islets of autopsy cases. The initial event of NLRP3 inflammasome activation was assessed using a cell-free system consisting of NLRP3 and ASC with the amplified luminescent proximity homogeneous assay. IAPP/amylin deposition in Langerhans' islets was detected and significantly correlated with expressions of IL-1beta and ASC. IAPP/amylin directly interacted with NLRP3 and initiated an interaction between NLRP3 and ASC in a cell-free system. The deposition of IAPP/amylin in beta-cells of Langerhans' islets may act together with the expression level of an inflammasome component, ASC, to regulate IL-1beta processing, and directly lead to the dysfunction of beta-cells. The interaction between IAPP/amylin and NLRP3 could be an attractive drug target to avoid both inflammation and beta-cell death for T2D therapy. PMID- 30014751 TI - Estradiol to Androstenedione Ratios Moderate the Relationship between Neurological Injury Severity and Mortality Risk after Severe Traumatic Brain Injury. AB - Early declines in gonadotropin production, despite elevated serum estradiol, among some individuals with severe traumatic brain injury (TBI) suggests amplified systemic aromatization occurs post-injury. Our previous work identifies estradiol (E2) as a potent mortality marker. Androstenedione (A), a metabolic precursor to E2, estrone (E1), and testosterone (T), is a steroid hormone substrate for aromatization that has not been explored previously as a biomarker in TBI. Here, we evaluated serum A, E1, T, and E2 values for 82 subjects with severe TBI. Daily hormone values were calculated, and E2:A and E1:T ratios were generated and then averaged for days 0-3 post-injury. After data inspection, mean E2:A values were categorized as above (high aromatization) and below (low aromatization) the 50th percentile for 30-day mortality assessment using Kaplan Meier survival analysis and a multivariable Cox proportional hazard model adjusting for age, and Glasgow Coma Scale (GCS) to predict 30-day mortality status. Daily serum T, E1, and E2 were graphed by E2:A category. Serum E1 and E2 significantly differed over time (p < 0.05); the high aromatization group had elevated levels and a significantly lower probability of survival within the first 30 days (p = 0.0274). Multivariable Cox regression showed a significant E2:A*GCS interaction (p = 0.0129), wherein GCS predicted mortality only among those in the low aromatization group. E2:A may be a useful mortality biomarker representing enhanced aromatization after TBI. E2:A ratios may represent non neurological organ dysfunction after TBI and may be useful in defining injury subgroups in which GCS has variable capacity to serve as an accurate early prognostic marker. PMID- 30014752 TI - An energy efficiency routing protocol for wireless body area networks. AB - The wireless body area networks (WBANs) play an important role in monitoring and minimising the duration of patients stays at the hospital. The aim of our study was to design an energy efficient routing protocol for WBANs taking into consideration the minimisation of energy and maximisation of the network lifetime, such as that the routing is recognised as a resource hungry operation. In this protocol, to confront the different constraints, we use the concept of the gateway body sensor which is responsible for sending data to the base station. Some biosensors transmit data directly while some use clustering technique to send data, it depends on the type of transferred information. Simulation results showed that clustering based routing protocol for wireless body area network (CRPBA) improves the quality of our network by minimising the energy consumption and enhances the stability period. PMID- 30014753 TI - Investigating the Influence of Social Media Consumption on Punitive Attitudes Among a Sample of U.S. University Students. AB - Prior research suggests that media consumption influences attitudes toward punitiveness. Traditionally, prior efforts have generally examined television news and crime-related programming. However, less is known whether more contemporary forms of media consumption, such as social media, are related to punitive attitudes. Using a multisite sample of more than 900 mostly young adults, the current study examines (a) the relationship between four types of social media consumption (overall, general news, crime-specific content, and punishment-specific content) on penal attitudes and (b) whether these relationships vary based on key characteristics. Results reveal that individuals who consume punishment-specific content on social media are significantly more likely to have stronger attitudes regarding the use of punishment and this relationship varies by fear of crime. Findings and directions for future research are discussed. PMID- 30014754 TI - Reflections of Men of Mexican Origin: A Grounded Theory Study of Intimate Partner Violence Risk Factors. AB - Intimate partner violence (IPV) is a societal problem with many repercussions for the health care and judicial systems. In the United States, women of color are frequently affected by IPV and experience negative, physical, and mental ramifications. Increasing IPV perpetration and perpetration recurrence rates among men of Mexican origin (MMO) warrants a better understanding of unique risk factors that can only be described by these men. Qualitative studies regarding MMO and distinct IPV risk factors among this populace are few and infrequent. The purpose of this study was to describe IPV risk factors among men of MMO and to describe the process by which these men are able to overcome IPV perpetration risk factors. Fifty-six men of Mexican origin from a low-income housing community in far-west Texas were recruited for participation in audiotaped focus groups. Grounded theory (GT) methodology techniques were utilized to analyze, translate, and transcribe focus group data. Data collection ended when saturation occurred. Participants described risk factors for IPV. Emerging themes included: environment as a context, societal view of MMO, family of origin, normalcy, male and female contributing factors to IPV, and breaking through. Theme abstractions led to the midrange theory of Change Through Inspired Self-Reflection which describes the process of how MMO move from IPV perpetration to nonviolence. The results of the study provide insight on what MMO believe are IPV risk factors. There are implications for clinicians who provide services to MMO, and provide the impetus for future research among this population. PMID- 30014755 TI - Helicobacter pylori infection is not associated with rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is an autoinflammatory disease caused by genetic susceptibility and environmental triggers, which include infectious agents. Helicobacter pylori, a bacterium that frequently colonizes the stomach, is associated with the development of certain autoinflammatory disorders. This study examined a possible association between H. pylori infection and RA. METHOD: This cohort study was performed in the Central Denmark Region. Patients were enrolled from primary healthcare centres after a urea breath test (UBT) for H. pylori and followed for a median of 8 years. Nationwide administrative registries provided information about the patients' diagnoses, country of birth, and gender. Comorbidity was determined using the Charlson Comorbidity Index. We compared the prevalence of RA via odds ratios (ORs) and incidences using Cox regression to calculate the hazard ratios (HRs) by comparing H. pylori-positive and H. pylori negative individuals and adjusting for confounding variables. RESULTS: A total of 56 000 people diagnosed as H. pylori positive or negative had similar rates of comorbidity. No link was found between H. pylori and RA. There was no difference in RA prevalence until time of UBT [OR = 0.91, 95% confidence interval (CI) 0.70 1.19)] or incidence of new RA cases after UBT (HR = 0.80, 95% CI 0.56-1.13) between H. pylori-positive and -negative subjects. Validation via four other RA definitions provided similar results. CONCLUSION: This study found no association between H. pylori infection and RA. This result does not support the involvement of H. pylori in a gut-joint axis of importance for RA development. PMID- 30014757 TI - A Small Molecule Spinogenic Compound Enhances Functional Outcome and Dendritic Spine Plasticity in a Rat Model of Traumatic Brain Injury. AB - The tetra (ethylene glycol) derivative of benzothiazole aniline (SPG101) has been shown to improve dendritic spine density and cognitive memory in the triple transgenic mouse model of Alzheimer disease (AD) when administered intraperitoneally. The present study was designed to investigate the therapeutic effects of SPG101 on dendritic spine density and morphology and sensorimotor and cognitive functional recovery in a rat model of traumatic brain injury (TBI) induced by controlled cortical impact (CCI). Young adult male Wistar rats with CCI were randomly divided into the following two groups (n = 7/group): (1) Vehicle, and (2) SPG101. SPG101 (30 mg/kg) dissolved in vehicle (1% dimethyl sulfoxide in phosphate buffered saline) or Vehicle were intraperitoneally administered starting at 1 h post-injury and once daily for the next 34 days. Sensorimotor deficits were assessed using a modified neurological severity score and adhesive removal and foot fault tests. Cognitive function was measured by Morris water maze, novel object recognition (NOR), and three-chamber social recognition tests. The animals were sacrificed 35 days after injury, and their brains were processed for measurement of dendritic spine density and morphology using ballistic dye labeling. Compared with the vehicle treatment, SPG101 treatment initiated 1 h post-injury significantly improved sensorimotor functional recovery (days 7-35, p < 0.0001), spatial learning (days 32-35, p < 0.0001), NOR (days 14 and 35, p < 0.0001), social recognition (days 14 and 35, p < 0.0001). Further, treatment significantly increased dendritic spine density in the injured cortex (p < 0.05), decreased heterogeneous distribution of spine lengths in the injured cortex and hippocampus (p < 0.0001), modifications that are associated with the promotion of spine maturation in these brain regions. In summary, treatment with SPG101 initiated 1 h post-injury and continued for an additional 34 days improves both sensorimotor and cognitive functional recovery, indicating that SPG101 acts as a spinogenic agent and may have potential as a novel treatment of TBI. PMID- 30014756 TI - Bicyclic eremophilane-type petasite sesquiterpenes potentiate peroxisome proliferator-activated receptor gamma activator-mediated inhibition of dendritic cells. AB - Dendritic cell (DC) activation induces expression of co-stimulatory surface molecules, as well as migration into secondary lymphoid organs, where they activate naive T-cells. A family of plant derivatives, eremophilane-type petasite sesquiterpenes, can regulate the immune system through DC targeting due to their anti-inflammatory effects. Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in inhibition of inflammatory responses and induction of DCs to acquire a mucosal phenotype. Since mucosal DCs are central in innate immune responses, we hypothesized that eremophilane-type petasite sesquiterpenes exerted their anti-inflammatory effects by inhibiting DC maturation and activation through PPARgamma. This study assessed the bicyclic eremophilane-type petasite sesquiterpene compounds Fukinone and 10betaH-8alpha,12-Epidioxyeremophil 7(11)-en-8beta-ol (ZYFDC21 and ZYFDC22) in the maturation and activation of mouse DC. We measured surface expression of co-stimulatory molecules by flow cytometry and cell-free supernatant cytokine production upon lipopolysaccharide stimulation by enzyme-linked immunosorbent assays (ELISAs) in the presence or absence of PPARgamma agonists. DCs were generated from C57BL/6 mice bone marrow cells and harvested. Cells were exposed to bicyclic eremophilane-type petasite sesquiterpenes ZYFDC21 or ZYFDC22 in the presence or absence of synthetic PPARgamma agonists (GW1929 and TGZ) or the natural PPARgamma ligand 15d-PGJ2, followed by overnight activation with LPS. We observed differences in the upregulation of surface expression of CD86, along with TNF, IL-6, and IL-12p70 released by DCs stimulated with LPS, when using combinations of bicyclic eremophilane-type petasite sesquiterpenes ZYFDC21 or ZYFDC22, and PPARgamma agonists, in particular the PPARgamma ligand 15d-PGJ2. Our results indicate that bicyclic eremophilane-type petasite sesquiterpenes ZYFDC21 or ZYFDC22 inhibit maturation and activation of DC, and this activity is augmented upon PPARgamma activation. PMID- 30014758 TI - Functional Magnetic Resonance Imaging and Oculomotor Dysfunction in Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) is a significant cause of disability, especially when symptoms become chronic. This chronicity is often linked to oculomotor dysfunction (OMD). To our knowledge, this is the first prospective study to localize aberrations in brain function between mTBI cohorts, by comparing patients with mTBI with OMD with an mTBI control group without OMD, using task and resting-state functional magnetic resonance imaging (fMRI). Ten subjects with mTBI who had OMD (OMD group) were compared with nine subjects with mTBI who had no findings of OMD (control group). These groups were determined by a developmental optometrist using objective testing for OMD. The (convergence) task fMRI data demonstrated significantly decreased brain activity, measured as decreases in the blood oxygen level dependent (BOLD) signal, in the OMD group compared with the control group in three brain regions: the left posterior lingual gyrus, the bilateral anterior lingual gyrus and cuneus, and the parahippocampal gyrus. When doing a seed-based resting state fMRI analysis in the lingual/parahippocampal region, a large cluster covering the left middle frontal gyrus and the dorsolateral pre-frontal cortex (Brodmann areas 9 and 10), with decreased functional correlation in the OMD group, was identified. Together these observations provide evidence for neural networks of interactions involving the control of eye movement for visual processing, reading comprehension, spatial localization and navigation, and spatial working memory that appear to be decreased in mTBI patients with OMD compared with mTBI patients without OMD. The clinical symptomatology associated with post-traumatic OMD correlates well with these MRI findings. PMID- 30014759 TI - Cortical Neuromodulation of Remote Regions after Experimental Traumatic Brain Injury Normalizes Forelimb Function but is Temporally Dependent. AB - Traumatic brain injury (TBI) results in well-known, significant alterations in structural and functional connectivity. Although this is especially likely to occur in areas of pathology, deficits in function to and from remotely connected brain areas, or diaschisis, also occur as a consequence to local deficits. As a result, consideration of the network wiring of the brain may be required to design the most efficacious rehabilitation therapy to target specific functional networks to improve outcome. In this work, we model remote connections after controlled cortical impact injury (CCI) in the rat through the effect of callosal deafferentation to the opposite, contralesional cortex. We show rescue of significantly reaching deficits in injury-affected forelimb function if temporary, neuromodulatory silencing of contralesional cortex function is conducted at 1 week post-injury using the gamma-aminobutyric acid (GABA) agonist muscimol, compared with vehicle. This indicates that subacute, injury-induced remote circuit modifications are likely to prevent normal ipsilesional control over limb function. However, by conducting temporary contralesional cortex silencing in the same injured rats at 4 weeks post-injury, injury-affected limb function either remains unaffected and deficient or is worsened, indicating that circuit modifications are more permanently controlled or at least influenced by the contralesional cortex at extended post-injury times. We provide functional magnetic resonance imaging (MRI) evidence of the neuromodulatory effect of muscimol on forelimb-evoked function in the cortex. We discuss these findings in light of known changes in cortical connectivity and excitability that occur in this injury model, and postulate a mechanism to explain these findings. PMID- 30014760 TI - Relationship Between White Matter Abnormalities and Neuropsychological Measures in Children With ADHD. AB - OBJECTIVE: Using Diffusion Tensor Imaging (DTI), to investigate microstructural white matter differences between ADHD and typically developing children (TDC), and their association with inhibition and working memory performance usually impaired in ADHD. METHOD: Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in 36 noncomorbid children with a Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) diagnosis of combined type ADHD and 20 TDC. Correlations between FA/MD and Stop Signal Task and N-Back performance parameters were computed. RESULTS: Working memory performance was significantly associated with MD in the superior longitudinal fasciculus (SLF) and the cingulum in the ADHD group. No between-group differences in FA/MD reached significance, after controlling for between-group head motion differences. CONCLUSION: The association between white matter integrity in the cingulum and the SLF and working memory performance confirms previous studies. Our results also show that when critical conditions are controlled (age, comorbidity, head motion), no ADHD-related structural abnormality (FA/MD) are observed, in line with prior suggestions. PMID- 30014761 TI - Resting State Electroencephalography and Sports-Related Concussion: A Systematic Review. AB - Sports-related concussion is associated with a range of short-term functional deficits that are commonly thought to recover within a two-week post-injury period for most, but certainly not all, persons. Resting state electroencephalography (rs-EEG) may prove to be an affordable, accessible, and sensitive method of assessing severity of brain injury and rate of recovery after a concussion. This article presents a systematic review of rs-EEG in sports related concussion. A systematic review of articles published in the English language, up to June 2017, was retrieved via PsychINFO, Medline, Medline In Process, Embase, SportDiscus, CINAHL, and Cochrane Library, Reviews, and Trials. The following key words were used for database searches: electroencephalography, quantitative electroencephalography, qEEG, cranio-cerebral trauma, mild traumatic brain injury, mTBI, traumatic brain injury, brain concussion, concussion, brain damage, sport, athletic, and athlete. Observational, cohort, correlational, cross sectional, and longitudinal studies were all included in the current review. Sixteen articles met inclusion criteria, which included data on 504 athletes and 367 controls. All 16 articles reported some abnormality in rs-EEG activity after a concussion; however, the cortical rhythms that were affected varied. Despite substantial methodological and analytical differences across the 16 studies, the current review suggests that rs-EEG may provide a reliable technique to identify persistent functional changes in athletes after a concussion. Because of the varied approaches, however, considerable work is needed to establish a systematic methodology to assess its efficacy as a marker of return-to-play. PMID- 30014763 TI - Chemogenomics Systems Pharmacology Mapping of Potential Drug Targets for Treatment of Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is associated with high mortality and morbidity. Though the death rate of initial trauma has dramatically decreased, no drug has been developed to effectively limit the progression of the secondary injury caused by TBI. TBI appears to be a predisposing risk factor for Alzheimer's disease (AD), whereas the molecular mechanisms remain unknown. In this study, we have conducted a research investigation of computational chemogenomics systems pharmacology (CSP) to identify potential drug targets for TBI treatment. TBI induced transcriptional profiles were compared with those induced by genetic or chemical perturbations, including drugs in clinical trials for TBI treatment. The protein-protein interaction network of these predicted targets were then generated for further analyses. Some protein targets when perturbed, exhibit inverse transcriptional profiles in comparison with the profiles induced by TBI, and they were recognized as potential therapeutic targets for TBI. Drugs acting on these targets are predicted to have the potential for TBI treatment if they can reverse the TBI-induced transcriptional profiles that lead to secondary injury. In particular, our results indicated that TRPV4, NEUROD1, and HPRT1 were among the top therapeutic target candidates for TBI, which are congruent with literature reports. Our analyses also suggested the strong associations between TBI and AD, as perturbations on AD-related genes, such as APOE, APP, PSEN1, and MAPT, can induce similar gene expression patterns as those of TBI. To the best of our knowledge, this is the first CSP-based gene expression profile analyses for predicting TBI-related drug targets, and the findings could be used to guide the design of new drugs targeting the secondary injury caused by TBI. PMID- 30014762 TI - The levels of NF-kappaB p50 and NF-kappaB p65 play a role in thyroid carcinoma malignancy in vivo. AB - Background To investigate the relationship between the levels of nuclear factor (NF)-kappaB p50 and NF-kappaB p65 and tumour characteristics in patients with thyroid carcinoma. Methods This prospective study enrolled consecutive patients with thyroid carcinoma. Tumour samples were collected and the levels of NF-kappaB p50 and NF-kappaB p65 protein and mRNA were measured using immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (qRT PCR). Results A total of 73 patients with thyroid carcinoma were included in the study (20 males; 53 females; mean +/- SD age, 44.8 +/- 12.7 years, range, 18-76 years). There were no significant differences in sex, age and pathological type between the NF-kappaB p50 positive group and the NF-kappaB p50 negative group, but tumour diameter and lymph node metastasis were significantly higher in the NF kappaB p50 positive group compared with the NF-kappaB p50 negative group. Similar findings were observed for NF-kappaB p65. The levels of NF-kappaB p50 were positively correlated with NF-kappaB p65 in samples of thyroid carcinoma ( rs = 0.653). Conclusion The levels of NF-kappaB p50 and NF-kappaB p65 in samples of thyroid carcinoma were positively associated with tumour diameter and the presence of lymph node metastasis. PMID- 30014764 TI - Epilepsy in Propionic Acidemia: Case Series of 14 Saudi Patients. AB - Propionic acidemia is an inborn error of metabolism that is inherited in an autosomal recessive manner. It is characterized by a deficient propionyl-CoA carboxylase due to mutations in either of its beta or alpha subunits. In the literature, there is a clear association between propionic acidemia and epilepsy. In this cohort, we retrospectively reviewed the data of 14 propionic acidemia patients in Saudi Arabia and compared the findings to those of former studies. Six of the 14 (43%) patients developed epileptic seizure, mainly focal seizures. All patients were responsive to conventional antiepileptic drugs as their seizures are controlled. The predominant electroencephalographic (EEG) findings were diffuse slowing in 43% and multifocal epileptiform discharges in 14% of the patients. In 1 patient, burst suppression pattern was detected, a pattern never before reported in patients with propionic acidemia. Brain magnetic resonance imaging (MRI) findings mainly consisted of signal changes of the basal ganglia (36%), generalized brain atrophy (43%), and delayed myelination (43%).The most common genotype in our series is the homozygous missense mutation in the PCCA gene (c.425G>A; p. Gly142Asp). However, there is no clear genotype-seizure correlation. We conclude that seizure is not an uncommon finding in patients with propionic acidemia and not difficult to control. Additional studies are needed to further elaborate on genotype-seizure correlation. PMID- 30014765 TI - Labeling Theory and Life Stories of Juvenile Delinquents Transitioning Into Adulthood. AB - Labeling theory contends that an acquisition of a criminal status can be very problematic for offenders navigating into adulthood. This article examines this assertion with the life story of 23 juvenile delinquents. The objective of the study was to gain insight into how the negative reactions of friends, families, and society worked to change and reinforced their offending behavior. The qualitative data which resulted from the use of semi-structured interview guide revealed that self-motivation of offenders to move into "new" neighborhoods and the lack of labeling triggered a turning point among those who desisted than the persistent offenders. The theoretical implication of this finding is that labeling per se may not necessarily explain persistence in crime considering how those who desisted from crime maneuvered their labeling status in the face of discrimination. In formulating a desistance theory of crime and delinquency, criminologists need to revise and evaluate traditional labeling theory with life histories of offenders in the desistance process. This shift in paradigm will inform the coping mechanism of more offenders, as well as the appropriate techniques and strategies to reduce recidivism. Strengthening prison aftercare programs, provision of institutional and social support, and the integration of residential change into post offenders' treatment therapy will be in the right direction for policy makers. PMID- 30014766 TI - Improved conceptual generation and selection with transcranial direct current stimulation in older adults. AB - INTRODUCTION: Normal aging is associated with deficits in various aspects of spoken language production, including idea generation and selection, and involves activity in frontal brain areas including left inferior frontal cortex (LIFG). These conceptual preparation processes, largely involving executive control, precede formulation and articulation stages and are critical for language production. Noninvasive brain stimulation (e.g., transcranial direct current stimulation, tDCS) has proven beneficial for age-related fluency and naming deficits, but this has not been extended to conceptual preparation mechanisms. METHOD: We investigated whether tDCS could facilitate idea generation and selection in 24 older adults aged 60-80 years. In the first phase, participants completed an idea generation test and a selection test with no stimulation. In the second phase they completed an alternate version of the tests in conjunction with either active or sham stimulation. Active stimulation applied 1-mA anodal tDCS over LIFG for the test duration (10 min). RESULTS: Responses were faster following active stimulation than following sham. Furthermore, improvements were specific to test conditions involving novel generation (p = .030) and selection (p = .001) and were not observed in control conditions for which these mechanisms were minimally involved. CONCLUSIONS: We concluded that tDCS benefits conceptual preparation mechanisms. This preliminary evidence is an important step for addressing age-related decline in propositional language generation, which is integral to conversational speech. This approach could also be extended toward rehabilitation in neurological patients with deficits in these processes. PMID- 30014767 TI - Bone Marrow-Derived Monocytes Drive the Inflammatory Microenvironment in Local and Remote Regions after Thoracic Spinal Cord Injury. AB - Spinal cord injury (SCI) produces a toxic inflammatory microenvironment that negatively affects plasticity and recovery. Recently, we showed glial activation and peripheral myeloid cell infiltration extending beyond the epicenter through the remote lumbar cord after thoracic SCI. The presence and role of infiltrating monocytes is important, especially in the lumbar cord where locomotor central pattern generators are housed. Therefore, we compared the inflammatory profile of resident microglia and peripheral myeloid cells after SCI. Bone marrow chimeras received midthoracic contusive SCI, and trafficking was determined 1-7 days later. Fluorescence-activated cell (FAC) sorting showed similar infiltration timing of both neutrophils and macrophages in epicenter and lumbar regions. While neutrophil numbers were attenuated by day 3, macrophages remained unchanged at day 7, suggesting that macrophages have important long-term influence on the microenvironment. Nanostring gene array identified a strong proinflammatory profile of infiltrating macrophages relative to microglia at both epicenter and lumbar sites. Macrophages had elevated expression of inflammatory cytokines (IL 1beta, IFNgamma), chemokines (CCL2, CXCL2), mediators (COX-1, MMP-9), and receptors (CCR2, Ly6C), and decreased expression of growth promoting genes (GDNF, BDNF). Importantly, lumbar macrophages had elevated expression of active trafficking genes (CCR2, l-selectin, MMP-9) compared with epicenter macrophages. Further, acute rehabilitation exacerbated the inflammatory profile of infiltrated macrophages in the lumbar cord. Such high inflammatory potential and negative response to rehabilitation of infiltrating macrophages within lumbar locomotor central pattern generators likely impedes activity-dependent recovery. Therefore, limiting active trafficking of macrophages into the lumbar cord identifies a novel target for SCI therapies to improve locomotion. PMID- 30014768 TI - Stocks and environmental release of mercury in backlight cold cathode fluorescence lamps. AB - Cold cathode fluorescent lamps (CCFLs), with mercury as their essential component, were widely used as backlight in liquid crystal display (LCD) appliances before 2008. Since 2008, the mercury-free light emitting diode started to be used as a substitute for CCFLs and the replacement finished in about 2014. Nowadays, CCFLs are obsolete products from the viewpoint of manufacture but they are important as waste. In recent years, large amounts of CCFLs are flowing to waste phase for treatment and this has become a major issue in most countries. To better understand and control the risk of CCFLs, the stock of mercury in CCFLs, its flow to waste phase and mercury emission with the life cycle of CCFLs in mainland China were estimated in this study. Results showed that there was 15.2 tons of mercury stocked in CCFLs in main LCD appliances (i.e., LCD televisions, LCD monitors, and laptop monitors) from 2003-2015. CCFLs and mercury started to flow to waste phase around the year 2007 and will likely peak in 2018 with an annual flow of 324.8 million units and 1.5 tons respectively, then will likely decline dramatically till 2030. Dismantling and production were the two main life stages of CCFLs with mercury vapor release, during which approximately 2.1 tons and 1.2 tons of mercury were released to the atmosphere respectively. The research also indicates that mercury recycling in specialized facilities was another life stage with high mercury emission risk in which the processes of shredding, separation, and residue disposal are inevitably accompanied by mercury release. PMID- 30014769 TI - Corrigendum. PMID- 30014770 TI - Perceived Barriers to Physical Activity Among Low-Income Latina Women at Risk for Type 2 Diabetes. AB - Purpose The purpose of this study was to examine perceived barriers to physical activity among low-income Latina women who were at risk for type 2 diabetes, as well as the demographic factors that influence these perceived barriers. Methods Recruited in the waiting room of a community health center in a low-income neighborhood (n = 160), Latina women between the ages of 18 and 49 years completed a survey to assess demographic characteristics and perceived barriers to physical inactivity. Descriptive statistics, chi-square tests, and multivariate regression analyses were conducted to identify barriers to physical activity and the associations between demographic factors and perceived barriers. Results The most commonly perceived barriers to physical activity in the study sample were lack of willpower and lack of energy. After adjusting for other characteristics, overweight/obese participants were more likely than women of normal weight to report social influence and fear of injury as important barriers to exercise. In addition, women whose preferred language was Spanish were more likely than women whose preferred language was English to perceive lack of time, and social influence as important barriers. Conclusions The effective encouragement of physical activity among Latina women at risk for type 2 diabetes must address the perceived barriers of lack of willpower and lack of energy. Although all women at risk for type 2 diabetes could benefit from counseling and other strategies to encourage physical activity, these efforts should be targeted toward Spanish-speaking overweight/obese women, who are more likely to perceive barriers to exercise. PMID- 30014771 TI - Intracellular Ca2+ Release and Synaptic Plasticity: A Tale of Many Stores. AB - Ca2+ is an essential trigger for most forms of synaptic plasticity. Ca2+ signaling occurs not only by Ca2+ entry via plasma membrane channels but also via Ca2+ signals generated by intracellular organelles. These organelles, by dynamically regulating the spatial and temporal extent of Ca2+ elevations within neurons, play a pivotal role in determining the downstream consequences of neural signaling on synaptic function. Here, we review the role of three major intracellular stores: the endoplasmic reticulum, mitochondria, and acidic Ca2+ stores, such as lysosomes, in neuronal Ca2+ signaling and plasticity. We provide a comprehensive account of how Ca2+ release from these stores regulates short- and long-term plasticity at the pre- and postsynaptic terminals of central synapses. PMID- 30014772 TI - WITHDRAWN: Using Trunk Posture to Monitor Heat Strain at Work. AB - Ahead of Print article withdrawn by publisher. PMID- 30014773 TI - Mitral Intervention With Left Ventricular Assist Device: Preparing for Recovery. AB - Left ventricular assist device (LVAD) insertion is an increasingly common treatment of advanced heart failure. Insertion guidelines suggest regurgitant lesions of the mitral valve should not be addressed. However, recent evidence suggests that mitral regurgitation may not necessarily improve with LVAD insertion, and such patients may have worse outcomes. Thus, practice variability is high given the discrepancy between traditional thinking and new evidence that unrepaired mitral regurgitation may increase perioperative mortality. Additionally, the challenges of LVADs can make transesophageal echocardiography evaluation and assessment of mitral valve pathology difficult. PMID- 30014775 TI - Reactive Attachment Disorder and Attachment theory from infancy to adolescence: review, integration, and expansion. AB - In reviewing the preceding articles, I emphasize the predominance of relational theories in the study of development as a way of demonstrating the evolutionary and relational extremity of reactive attachment disorder (RAD). The lack (or distortion?) of mutuality, RAD's defining feature, has implications for all aspects of development, not least of which is self-regulation. I review each article in this special issue, emphasizing important features, integrating across studies, expanding their links to attachment theory, and recommending future directions. Finally, I conduct two meta-analyses of the samples in this special issue, one meta-analysis addressing convergent validity of RAD assessment instrumentation developed by authors represented here and the other addressing the links between RAD and internalizing and externalizing behaviors. This special issue exploits the disaggregation of reactive attachment and disinhibited social engagement disorders to move the field forward in remarkable ways, both methodologically and substantively. PMID- 30014774 TI - Addition of hyaluronic acid improves tolerance to 7% hypertonic saline solution in bronchiectasis patients. AB - BACKGROUND: The excessive retention of sputum in the airways, leading to pulmonary infections, is a common consequence of bronchiectasis. Although inhalation of 7% hypertonic saline (HS) has proven an effective method to help remove the mucus, many patients are intolerant of this treatment. The addition of 0.1% hyaluronic acid to HS (HS+HA) could increase tolerance to HS in these patients. The main objective of this study was to evaluate the tolerability of HS+HA in bronchiectasis patients who are intolerant to HS. METHODS: This prospective, observational, open-label study analysed the outcomes of two groups of bronchiectasis patients previously scheduled to start HS therapy. Patients were assessed for tolerance to HS by a questionnaire, spirometry and clinical evaluation. Patients who were intolerant were evaluated for tolerance to HS+HA approximately one week later. All patients were evaluated for their tolerance to HS or HS+HA 4 weeks after the start of their treatment. Patients were also assessed with quality-of-life and adherence questionnaires, and all adverse events were registered. RESULTS: A total of 137 bronchiectasis patients were enrolled in the study (age = 63.0 +/- 14.7 years; 63.5% women). Of these, 92 patients (67.1%) were tolerant and 45 patients (32.9%) were intolerant to HS. Of the 45 patients intolerant to HS, 31 patients (68.9%) were tolerant and 14 patients (31.1%) intolerant to HS+HA. Of these 31 tolerant patients, 26 (83.9%) could complete the 4-week treatment with HS+HA. CONCLUSIONS: Two-thirds of bronchiectasis patients that presented intolerance to inhaled HS alone are tolerant to inhaled HS+HA, suggesting that HA improves tolerance to HS therapy. PMID- 30014777 TI - Altered chemical evolution in landfill leachate post implementation of biodegradable waste diversion. AB - Within the UK implementation of the European Union Landfill Directive (1999) has led to the diversion of biodegradable waste (BW) from municipal solid wastes away from landfills. It has been widely anticipated, but thus far not verified, that the diversion of BW and consequent reduction in BW reaching landfill would lead to a change in the degradation processes occurring within landfills and that this would be reflected in an altered evolution in leachate chemistry compared to pre Directive landfills. This paper provides evidence based on leachate chemistry from two operational landfills together with calculations of the reduced BW content, that demonstrate the acetogenic phase that characterised pre-Directive landfill leachates is missing and is now more typical of methanogenic phase leachate. The paper demonstrates how data from national datasets and detailed landfill records can be used to constrain likely and upper estimates of the amount of BW going into post-Directive landfills, and the observed change in the evolution of leachate chemistry which has resulted from a decrease in BW content from typical values of BW (pre-Landfill Directive) of 22% to an inferred 12% in the case-study landfills. Data provided here add to the growing literature that estimates the amount of BW in recent post-Directive landfills which importantly allow the quantitative linkage between a decrease in landfilled BW and observed changes in leachate chemistry to be established such that future landfill operators can increase confidence in the effect of Directive implementation on landfill operational parameters. PMID- 30014778 TI - Computer-aided design-based guided endodontic: A novel approach for root canal access cavity preparation. AB - In cases of teeth with unusual morphology like calcified pulp canal, guided endodontic treatment is suggested. An endodontic guide which navigates burs according to a preplanned path is used. Existing approaches of endodontic guide design are based on visual observation and analysis of tomographic scan of teeth. Hence, they are time-consuming and expert-dependent. Computer-aided design-based methodology was employed to design and fabricate a customized endodontic guide. A cone beam computed tomographic scan with MIMICS software was used to create a solid model of the teeth. The solid model generated was sliced through the developed program in MATLAB. The geometric centers of consecutive slices were joined to plot the root canals central axis. To gauge the optimum bur angulation for guide design, a straight line fitted in the data set of the geometric center helped create minimally invasive access. Methodology involved simulated verification of the drill path to judge the accuracy and feasibility of root canal access cavity preparation. Next, endodontic guides for extracted teeth were designed and fabricated using a three-dimensional printer, followed by guided root canal access cavity preparation for extracted teeth. To validate the proposed methodology, using a MATLAB image processing tool box, the deviation between the prepared root canal access cavity axis and root canal axis was analyzed in radiographs of post-treated teeth. The deviation between the tool path axis and root canal axis in simulated root canals was found to be not more than 0.210 +/- 0.04 mm. The deviation between the axis of the planned root canal access cavity and the prepared root canal access cavity was 0.07 +/- 0.02 mm. The proposed method reveals encouraging results for endodontic guide design. PMID- 30014776 TI - 'We just dilute sugar and give' health workers' reports of management of paediatric hypoglycaemia in a referral hospital in Malawi. AB - BACKGROUND: Acutely sick children in resource-constrained settings who present with hypoglycaemia have poor outcomes. Studies have questioned the current hypoglycaemia treatment cut-off level of 2.5 mmol/l. Improved knowledge about health workers' attitudes towards and management of hypoglycaemia is needed to understand the potential effects of a raised cut-off level. OBJECTIVE: This research explored health workers' perceptions about managing acutely ill children with hypoglycaemia in a Malawian referral hospital. A secondary objective was to explore health workers' opinions about a potential increase in the hypoglycaemia cut-off level. METHODS: We used a qualitative design with semi-structured individual interviews performed with health workers in the Paediatric Accident and Emergency Unit at Queen Elizabeth Central Hospital, Malawi, in October 2016. Data were analysed using latent content analysis. Ethical approval was obtained from the University of Malawi, College of Medicine Research and Ethics Committee P.01/16/1852. RESULTS: Four themes were formed that described the responses. The first, 'Critical and difficult cases need easy treatment', showed that health workers perceived hypoglycaemia as a severe condition that was easily manageable. The second, 'Health system issues', revealed challenges relating to staffing and resource availability. The third, 'From parental reluctance to demand', described a change in parents' attitudes regarding intravenous treatments. The fourth, 'Positive about the change but need more information', exposed health workers' concerns about potential risks of a raised cut-off level for hypoglycaemia treatment, as well as benefits for the patients. CONCLUSIONS: Health workers perceived hypoglycaemia as a severe condition that is easy to manage when the required equipment and supplies are available. Due to the common lack of test equipment and dextrose supplies, health workers have adopted alternative strategies to diagnose and manage hypoglycaemia. A change to the hypoglycaemia treatment cut-off level raised concerns about potential risks, but was also thought to be of benefit for some patients. PMID- 30014779 TI - Impact of education and training course for ECMO patients based on high-fidelity simulation: a pilot study dedicated to ICU nurses. AB - INTRODUCTION: Medical and para-medical education is one of the key points of healthcare strategy. Training and education based on high-fidelity simulation is one of the gold standards in modern healthcare institutions. We describe a model of training dedicated to ICU nurses in charge of patients with ECMO. The aim of our educational tool was to teach ICU nurses ECMO basic knowledge and skills. METHODS: An ECMO Specialist Course Committee implemented the training programme. It was on two consecutive days and consisted of theoretical, practical and high fidelity, simulation-based teaching. A content expert implemented each scenario and learning objectives were defined. Participants were assessed pre- and post test (Group 1 and Group 2). RESULTS: In two years, seven sessions took place and 40 volunteers were enrolled. High-fidelity, simulation-based teaching consisted of seven scenarios. There was a significant improvement in mean score between pre and post-test. Moreover, we noticed that the basic level (pre-test) of participants was improving over the time. The mean pre-test scores of Group 2 were significantly higher than Group1. CONCLUSION: The implementation of education and training course for ICU nurses in charge of patients on ECMO is feasible and reliable. It improves nurse personal levels, but also shares in improving the global level of the team to which they belong. PMID- 30014780 TI - Onset-to-alarm time in patients with acute stroke: Results from a Mexican population. PMID- 30014781 TI - The politics of a natural laboratory: Claiming territory and governing life in the Galapagos Islands. AB - The Galapagos Islands are often called a natural laboratory of evolution. This metaphor provides a powerful way of understanding space that, through scientific research, conservation and tourism, has shaped the archipelago over the past century. Combining environmental histories of field science with political ecologies of conservation biopower, this article foregrounds the territorial production of the archipelago as a living laboratory. In the mid-twentieth century, foreign naturalists used the metaphor to make land claims as they campaigned to create the Galapagos National Park and Charles Darwin Research Station. Unlike earlier 'parks for science', these institutions were not established under colonial rule, but through postwar institutions of transnational environmental governance that nonetheless continued colonial approaches to nature protection. In the following decades, the metaphor became a rationale for territorial management through biopolitical strategies designed to ensure isolation by controlling human access and introduced species. This article's approach extends the scope of what is at stake in histories of field science: not only the production of knowledge and authority of knowledge claims, but also the foundation of global environmental governance and authority over life and death in particular places. Yet while the natural laboratory was a powerful geographical imagination, analysis shows that it was also an unsustainable goal. PMID- 30014782 TI - Cow milk protein allergy and other common food allergies and intolerances. AB - The prevalence of food allergy and food intolerance is increasing and it is an important public health problem affecting children. Food allergy results from an immunological reaction to certain food(s) and affects numerous organs in the body. Food intolerances are non-immunological reactions including metabolic, toxic, pharmacological and undefined mechanisms. Cow milk is the most common cause of food allergy and food intolerance, especially in young children. Food intolerance can present with similar symptoms to those of food allergy. Health care personnel, patients and their caregivers often confuse food intolerance with food allergy. This review focuses on the clinical manifestations, diagnostic evaluation, treatment and prevention of food allergy and food intolerance. PMID- 30014784 TI - Improving care for acute in-hospital ischemic strokes-A narrative review. AB - In-hospital strokes, that is new strokes occurring among hospitalized patients, account for 6.5-15% of all strokes. Compared to community-onset stroke patients, in-hospital stroke patients tend to have worse functional and mortality outcomes. This review addresses the characteristics of acute in-hospital ischemic strokes, reasons these patients have worse outcomes compared to community-onset stroke patients, and future steps to improve outcomes. PMID- 30014785 TI - Prehospital idarucizumab prior to intravenous thrombolysis in a mobile stroke unit. AB - Background Administration of intravenous idarucizumab to reverse dabigatran anticoagulation prior to thrombolysis for patients with acute ischemic stroke has been previously described, but not in the prehospital setting. The speed and predictability of idarucizumab reversal is well suited to prehospital treatment in a mobile stroke unit and allows patients with recent dabigatran intake to access reperfusion therapy. Aims To describe feasibility of prehospital idarucizumab administration prior to thrombolysis on the Melbourne mobile stroke unit. Methods The Melbourne mobile stroke unit is a specialized stroke ambulance servicing central metropolitan Melbourne, Australia and provides prehospital assessment, scanning and treatment with an integrated CT scanner and multidisciplinary stroke team. All cases were identified through the mobile stroke unit treatment registry since launch in November 2017. Results Of a total of n = 20 thrombolysis cases in the first 4 months of operation, three patients (15%) received intravenous idarucizumab 5 g for dabigatran reversal prior to thrombolysis. Mean time between idarucizumab administration and thrombolysis was approximately 10 minutes. Two of the three patients were shown to have large vessel occlusion on CTA in the mobile stroke unit and proceeded to endovascular thrombectomy. At 24 hours, only one patient had a small amount of asymptomatic petechial hemorrhage on follow-up imaging. All patients demonstrated substantial neurological recovery and were discharged to inpatient rehabilitation. Conclusions Rapid treatment with prehospital administration of idarucizumab prior to thrombolysis using a mobile stroke unit is feasible and facilitates hyperacute treatment. PMID- 30014783 TI - Advances in proton therapy in lung cancer. AB - Lung cancer remains the leading cause of cancer deaths in the United States (US) and worldwide. Radiation therapy is a mainstay in the treatment of locally advanced non-small cell lung cancer (NSCLC) and serves as an excellent alternative for early stage patients who are medically inoperable or who decline surgery. Proton therapy has been shown to offer a significant dosimetric advantage in NSCLC patients over photon therapy, with a decrease in dose to vital organs at risk (OARs) including the heart, lungs and esophagus. This in turn, can lead to a decrease in acute and late toxicities in a population already predisposed to lung and cardiac injury. Here, we present a review on proton treatment techniques, studies, clinical outcomes and toxicities associated with treating both early stage and locally advanced NSCLC. PMID- 30014787 TI - ? PMID- 30014786 TI - Attachment disorder behavior in early and middle childhood: associations with children's self-concept and observed signs of negative internal working models. AB - Most research on attachment in childhood is based on observation. In contrast, research on reactive attachment disorder (RAD) is mainly based on caregiver reports. Moreover, little is known about self-concept or internal working models (IWMs) of self and others in children with RAD. The present study examined whether caregiver reports and the frequency of observed signs of RAD reveal differences between children at risk for developing RAD symptoms and healthy controls in middle childhood. In addition, children's self-concept, observable signs of negative IWMs, and mental health were assessed. Results revealed that the RAD risk group showed increased reported and observed signs of RAD, a more negative self-concept, and more signs of negative IWMs compared to healthy controls. Signs of RAD in middle childhood were expressed trans-relational to both caregivers and strangers. Moreover, RAD symptoms were associated with negative self-concept, observed signs of negative IWMs, and poor mental health. PMID- 30014788 TI - [Youth in foster care: which kind of support do they really need? Future research perspectives]. PMID- 30014790 TI - [How can we raise public awareness of child and youth psychiatry and psychotherapy?] PMID- 30014789 TI - ? PMID- 30014791 TI - A stochastic multi-agent system for Internet of Things-enabled waste management in smart cities. AB - The population of the Earth is moving towards urban areas forming smart cities (SCs). Waste management is a component of SCs. We consider a SC which contains a distribution of waste bins and a distribution of waste trucks located in the SC sectors. Bins and trucks are enabled with Internet of Things (IoT) sensors and actuators. Prior approaches focus mainly on the dynamic scheduling and routing issues emerging from IoT-enabled waste management. However, less research has been done in the area of the stochastic reassignment process during the four seasons of the year over a period of two years. In this paper we aim to stochastically reassign trucks to collect waste from bins through time. We treat this problem with a multi-agent system for stochastic analyses. PMID- 30014792 TI - Evolution as a fact? A discourse analysis. AB - Since the middle of the twentieth century, there has been a heated debate between evolutionists and antievolutionists regarding whether or not evolution is a 'fact'. The debate has spawned a number of court cases involving antievolutionists describing evolution as a 'theory, not a fact'. An analysis of the 'fact of biological evolution' discourse reveals several overarching agreements among its advocates, but also a contradictory morass of positions regarding how scientific theories, hypotheses and facts interrelate, how these terms are related to biological evolution, what a scientific fact is, and how science popularizers use the scientific and public vernaculars. The formation, structure and development of the discourse is assessed through a Foucauldian discourse analysis, as well as through the lens of Gieryn's conceptions of public science and cultural cartography. PMID- 30014793 TI - Potassium Channels: A Big Family, Many Different Targets, Great Pharmacological Opportunities. PMID- 30014794 TI - Pancreatic Cancer Chemoprevention: Challenges and Opportunities. PMID- 30014795 TI - Perspectives on Rational Drug Design and Therapy for Pediatric Precision Medicine. PMID- 30014796 TI - M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets. AB - The process of inflammation is orchestrated by macrophages, according to their state of differentiation: thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2 phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN), both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis. A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor. Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein, and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models of diabetes. This review discusses the concept that Nrf2/HO-1 acts as a 'therapeutic funnel' through which a range of natural and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has presented intriguing potential drug targets for DN, such as eotaxin/CCR3. PMID- 30014797 TI - Mycoplasmas and Novel HO-1 Inducers: Recent Advances. AB - Inflammation and the ways for its regulation: The development of an effective system for the treatment of inflammatory diseases requires comprehensive studies of the cellular signaling molecular networks comprising responses to various stressors, including pathogenic and non-pathogenic microorganisms. Significant attention on fundamental and applied research has recently focused on inducers of heme oxygenase-1 (HO-1) and inhibitors of the expression of this enzyme, which regulates expression of this and other cytoprotective molecules and modulation of inflammation. Recent studies indicate that mycoplasmas (a major group of human pathogens of the Mollicutes) are capable of modulating inflammatory responses through the activation of the Nrf2 and the expression of HO-1. In vitro experiments demonstrate that the membrane lipoproteins (LAMPs), along with lipoprotein derivatives (lipopeptide MALP-2) in mycoplasmas cause a "cross-talk" between the pro- and antiinflammatory signaling pathways. Importantly, lipopeptide/lipoprotein - induced expression of HO-1 tends to suppress inflammation. Conclusion: The study of the molecular network that causes the corresponding outcome can facilitate the development of new approaches for the treatment of inflammatory processes. The derivatives of LAMPs and MALP-2 and of their analogues may prove promising for the treatment of diseases associated with chronic inflammation. PMID- 30014798 TI - Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke. AB - Stroke is the second-leading cause of death and a leading cause of serious long term disability worldwide, with an increasing global burden due to the growing and aging population. However, strict eligibility criteria for current treatment opportunities make novel therapeutic approaches desirable. Oxidative stress plays a pivotal role during cerebral ischemia, eventually leading to neuronal injury and cell death. The significant correlation between redox imbalance and ischemic stroke has led to various treatment strategies targeting the endogenous antioxidant system in order to ameliorate the adverse prognosis in patients with cerebral infarction. One of the most extensively investigated cellular defense pathway in this regard is the Nrf2-heme oxygenase-1 (HO-1) axis. In this review, our aim is to focus on the potential clinical relevance of targeting the HO-1 pathway in ischemic stroke. PMID- 30014799 TI - Recent advances in probiotics as live biotherapeutics against gastrointestinal diseases. AB - : Back ground: Gastrointestinal (GI) diseases are a major cause of emergency department visits requiring hospitalizations leading to considerable burden on global economy. Several factors contribute to the onset of gastrointestinal diseases such as pathogens (parasites, bacteria, virus, toxins etc.), autoimmune disorders and severe inflammation of intestine. OBJECTIVE: One common feature among all these diseases is the dysentery and alteration of gut microbiota composition (gut dysbiosis). Apart from conventional therapies such as antibiotics and ORS supplementation, gut microbiota modulation with probiotic supplementation has emerged as a successful and healthy alternative in mitigating GI diseases. In this review our goal is to discuss the causes of gastrointestinal diseases and the present state of various therapeutic strategies such as probiotics as live biotherapeutics and fecal microbial transplants (FMT's). CONCLUSIONS: Several reports and clinical trials point out to the beneficial effects of probiotics in modulating the gut microbiota and improving the side effects of gastrointestinal diseases. Live biotherapeutics and FMT's could be suitable and successful alternatives to conventional therapies in mitigating the gastrointestinal pathogens. PMID- 30014800 TI - Metallothionein: a Novel Therapeutic Target for Treatment of Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic inflammation within the gastrointestinal tract. It is a multifactorial disease associated with immune-cell mediated oxidative damage to the intestinal mucosa. There is no cure for IBD, but anti-cytokine therapy can limit target inflammation and disease progression. Unfortunately, many patients are nonresponsive or develop resistance to anti-cytokine therapy over time creating a need for new therapeutic agents. Metallothionein (MT) is a small, highly conserved stress response protein that has been shown to modulate the immune response as a pro inflammatory agent, regulate divalent heavy metal homeostasis, and act as a reactive metabolite scavenger. Our research, as well as other groups studying MT, has described MT induction and release during IBD inflammatory stress response. The release of MT results in activation of inflammatory responses leading to progressive inflammation and subsequent expansion of MT synthesis. A monoclonal antibody specific for MT has been used in murine models of IBD and should only target the extracellular pool of MT, thus representing a novel therapeutic approach to this disease. PMID- 30014801 TI - Cyclic Peptides for Protein-Protein Interaction Targets. PMID- 30014802 TI - Controlled Growth and Characterization Ag/ZnO Nanotetrapods for Humidity Sensing. AB - AIM AND OBJECTIVE: Ultrafine Ag/ZnO nanotetrapods (AZNTP) have been prepared successfully using silver (I)-bis (oxalato) zinc complex and 1, 3-diaminopropane (DAP) with a phase separation system, and have been injected into a diethyl/water solution. MATERIALS AND METHODS: This crystal structure and lattice constant of the AZNTP obtained were investigated by means of a SEM, XRD, TEM and UV-vis spectrum. RESULTS: The results of the present study demonstrated the growth and characterization AZNTP for humidity sensing and DAP plays a key role in the determination of particle morphology. AZNTP films with 23 nm in arm diameter have shown highly sensitive, quick response sensor material that works at room temperature. PMID- 30014803 TI - Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke Patients Receiving Thrombectomy: Standard or Low Dose Therapy? AB - BACKGROUND: We compared the clinical outcomes of low and standard dose recombinant tissue Plasminogen Activator (rtPA) treatment in Acute Ischemic Stroke (AIS) patients receiving Endovascular Mechanical Thrombectomy (EVT). METHODS: Between April 01, 2015 and September 30, 2017, all AIS patients admitted to the Linkou and Chiayi Chang Gung Memorial Hospital were retrospectively reviewed. Patients with large vessel occlusions, who underwent bridging therapy with rtPA and EVT, were further enrolled. The enrolled patients were categorized into low (0.6-0.7 mg/kg; LD) or standard dose (0.9 mg/kg; SD) group based on the dose of rtPA they received. Baseline characteristics, reperfusion status, and clinical outcomes were compared between the two groups. RESULTS: Forty-two patients were enrolled in the final analyses, including 13 in the LD and 29 in the SD group. In all groups analyzed, the frequencies of moderate to severe and severe stroke at discharge were significantly decreased compared to those at stroke onset (p < 0.01). Compared to the SD group, patients of the LD group had a similar rate of mortality (LD vs. SD; 0% vs. 3.4%, p = 1.00), and comparable frequencies of functional independence at 3 months after stroke onset (LD vs. SD; 33.3% vs. 44.8%, p = 0.50). The rates of symptomatic intracerebral hemorrhage were also similar between the two groups (LD vs. SD; 0% vs. 6.9%, p =1.00). CONCLUSIONS: Compared to standard dose treatment, low dose rtPA may have similar clinical efficacy and safety outcomes in AIS patients receiving bridging therapy. PMID- 30014804 TI - Comparison of Demographic, Epidemiological, Immunological, and Clinical Characteristics of Patients with HIV Mono-infection Versus Patients Co-infected with HCV or/and HBV: A Serbian Cohort Study. AB - OBJECTIVE: The study aimed to correlate the status of hepatitis C (HCV) and hepatitis B virus (HBV) co-infection in patients with human immunodeficiency virus (HIV) infection with clinical and demographic data prior to starting highly active antiretroviral therapy (HAART) and assess the impact of HCV and HBV co infection on the natural history of HIV infection. PATIENTS AND METHODS: The study involved a total of 836 treatment-naive patients with available serological status for HBV and HCV at the point of therapy initiation. Patients were stratified into four groups: HIV mono-infection, HIV/HCV, HIV/HBV, and HIV/HCV/HBV co-infection. Demographic, epidemiological, immunological and clinical characteristics were analyzed in order to assess the possible impact of HCV and HBV co-infection on HIV - related immunodeficiency and progression to AIDS. RESULTS: The prevalence of HCV and HBV co-infection in our cohort was 25.7% and 6.3%, respectively. Triple HIV/HCV/HBV infection was recorded in 1.7% of the patients. In comparison with those co-infected with HCV, patients with HIV mono infection had lower levels of serum liver enzymes activity and higher CD4 cell counts, and were less likely to have CD4 cell counts below100 cells/uL and clinical AIDS, with OR 0.556 and 0.561, respectively. No difference in the development of advanced immunodeficiency and/or AIDS was recorded between patients with HIV monoinfection and those co-infected with HBV, or both HCV/HBV. CONCLUSION: HIV/HCV co-infection was found to be more prevalent than HIV/HBV co infection in a Serbian cohort. Co-infection with HCV was related to more profound immunodeficiency prior to therapy initiation, reflecting a possible unfavorable impact of HCV on the natural history of HIV infection. PMID- 30014805 TI - Subcutaneous implantable cardioverter defibrillators: an overview of implantation techniques and clinical outcomes. AB - Sudden cardiac death (SCD) is a significant health problem worldwide. Multiple randomized controlled trials have shown that implantable cardioverter defibrillators (ICDs) are effective life-saving management option for individuals at risk of SCD in both primary and secondary prevention. Although the conventional transvenous ICDs (TV-ICDs) are safe and effective, there are potential complications associated with its use, including localized pocket or wound infection or systematic infection, a vascular access related complication such as pneumothorax, and venous thrombosis, and lead related complications such as dislodgement, malfunction, and perforation. Furthermore, transvenous leads placement may not be feasible in certain patients like those with venous anomaly or occlusion, or with the presence of intracardiac shunts. Transvenous leads extraction, when needed, is associated with considerable morbidity & mortality and requires significant skills and costs. Totally subcutaneous ICD (S-ICD) is designed to afford the same life-saving benefit of the conventional TV-ICDs while avoiding the shortcomings of the TV-leads and to simplify the implant techniques and hence expand the use of ICDs in clinical practice. It becomes commercially available after receiving CE mark in 2009, and it is use increased significantly after its FDA approval in 2012. This review aims to give an overview of the S-ICD system components, implantation procedure, clinical indications, safety, efficacy, and future directions. PMID- 30014806 TI - Synthesis and anticancer activity of 9-O-pyrazole alkyl substituted berberine derivatives. AB - BACKGROUND: Berberine (BBR), an isoquinoline plant alkaloid isolated from plants such as Coptis chinensis and Hydrastis canadensis, own multiple pharmacological activities. OBJECTIVE: In this study, seven BBR derivatives were synthesized and their anticancer activity against HeLa cervical and A549 human lung cancer cell lines were evaluated in vitro. METHODS: The anti-cancer activity was measured by MTT assay, and apoptosis was demonstrated by the annexin V-FITC/PI staining assay. The intracellular oxidative stress was investigated through DCFH-DA assay. The molecular docking study was carried out in molecular operating environment (MOE). RESULTS: Compound B3 and B5 showed enhanced anti-cancer activity compared with BBR, the IC50 for compound B3 and B5 were significant lower than BBR, and compound B3 at the concentration of 64 or 128 MUM induced apoptosis in HeLa and A549 cell lines. The reactive oxygen species (ROS) was generated in both cell lines when treated with 100 MUM of all the compounds, and Compound B3 and B5 induced higher activity in the generation of ROS, while compound B3 exhibited the highest activity, these results are in according with the cytotoxicity results, indicating the cytotoxicity were mostly generated from the oxidative stress. In addition, molecular docking analysis showed that compound B3 had the greatest affinity with Hsp90. Upon binding, the protective function of Hsp90 was lost, which might explain its higher cytotoxicity from molecular interaction aspect. CONCLUSION: All the results demonstrated that compound B3 and B5 showed significant higher anti-cancer ability than BBR, and compound B3 is a promising anticancer drug candidate. PMID- 30014807 TI - Malaria, antimalaria drugs, drug/parasite interactions, and the brain: a review of impacts on behaviour, neurochemistry and structure. AB - BACKGROUND: Recorded history shows that malaria has plagued mankind for centuries, if not millennia, with the disease infecting and affecting several body tissues, organs and systems; including the central nervous system. Cerebral malaria is a severe form of malaria that may be associated with acute and chronic general behavioural, neurological or neuropsychiatric manifestations. The observation that the use of certain antimalaria drugs may also be associated with behavioural, neurochemical and structural brain changes complicates the picture, as both the infection and its treatment may cause significant changes in brain structure/function and behaviour. However, scientific literature appears to have made only a limited (if any) attempt at distinguishing the central nervous system effects of malaria infection from those of antimalaria drugs, and those that may occur due to possible interactions between the parasite and the drugs; as it relates to behaviour, brain neurochemistry, and neuromorphology. In this narrative review, we examine available literature dealing with the subject of the central effects of: the plasmodium parasite, antimalaria drugs, and interactions between drugs and the parasite; with a view to delineating the behavioural, neurochemical and neuromorphological changes that may occur due the infection, the drugs, and with the interactions of the drugs with the parasites inside the host. CONCLUSION: While research examining this subject matter continues to advance our understanding of the interactions amongst parasite/drug and the brain; for now, there are more questions than answers in relation to the effects of antimalaria drug/parasite interactions on the brain. PMID- 30014808 TI - Validation of AfiTagII, a device for automatic measuring of lying behaviour in Holstein and Jersey cows on two different bedding materials. AB - Lying behaviour is important for the welfare of the cow. Therefore, reliable electronic devices may improve the management of the cows, and the devices can be used as a tool in research. However, accelerometer-based devices measure acceleration, and an algorithm is therefore necessary for the calculation of lying behaviour. Thus, validation of such devices is imperative prior to use. The objective of this study was to validate the use of the AfiTagII device for measurements of the lying time and frequency of lying bouts of Danish Holstein (DH) and Danish Jersey (DJ) cows in a loose-house system on two different bedding materials. The validation included correlations and linear regression analyses of data collected by the AfiTagII compared with data collected both by direct observations and recordings from a previously validated device (IceQube). In total, 40 cows were observed directly with primiparous and multiparous DJ and DH cows, equally represented. Furthermore, 21 cows were monitored with both AfiTagII and IceQube devices, and data from both devices were collected simultaneously. The devices were attached to the hind leg of the cow. The estimates of the lying time from the AfiTagII device was highly correlated with the recordings from direct observations (r=0.98), and there was a linear relation between these with an intercept equal to 0 and a slope close to 1. The estimates of the lying time from the AfiTagII device was also highly correlated with the IceQube recordings (r=0.94). However, the intercept deviated from 0. The frequency of lying bouts recorded by the AfiTAgII compared to direct observations showed a positive predictive value of 0.96 for lactating cows on the slatted floor and of 0.85 for the dry cows on the deep bedding. The correlations between frequency of lying bouts recorded with the two devices were high (r=0.94), but the intercept deviated from 0. In conclusion, the AfiTagII has a high accuracy for the measurements of lying behaviour in both DH and DJ cows kept on different bedding materials. PMID- 30014809 TI - Stage-specific differential DNA methylation data analysis during human erythropoiesis in chromosome 16. AB - Previous studies have generated controversial findings regarding the correlation between DNA methylation in the human genome and gene expression. Some reports have indicated that promoter methylation is negatively correlated with gene expression levels; however, in some cases, a poor or positive correlation was reported. Most previous findings were based on general trends observed with whole genome data analysis. Here, we present a novel chromosome-specific statistical analysis design of empirical Bayes differential tests for five phases of erythroid development. To better understand the common methylation patterns of differentially methylated regions (DMRs) during specific stages, we defined differential phases for each CpG locus, based on a maximum log2 fold change. Analyzing hypermethylated and hypomethylated CpG loci separately showed variations in methylation patterns during erythropoiesis in the gene body, promoter and enhancer regions. Hypomethylated DMRs showed stronger associations with erythroid-specific enhancers at the differentiation start phase and with exons in the intermediate phase. To investigate the hypomethylated DMRs further, transcription factor binding site-enrichment analysis was conducted. This analysis highlighted novel transcription factors during each differentiation stage that were not detected by previous differential methylation data analysis. In contrast, hypermethylated DMRs showed a consistent methylation pattern over the different genomic regions. Thus, a closer examination of DNA methylation patterns in a single chromosome during each developmental stage can contribute to verify the association nature between gene expression and DNA methylation. PMID- 30014811 TI - Salmonella enterica serovars Panama and Arechavaleta: Risk Factors for Invasive Non-Typhoidal Salmonella Disease in Guadeloupe, French West Indies. AB - A retrospective study was conducted to identify the risk factors associated with Salmonella enterica bacteremia in infants and children in Guadeloupe, French West Indies. The 171 patients with S. enterica infection seen between 2010 and 2014 included 155 (90.6%) with acute gastroenteritis, of whom 42 (27.1%) had concomitant bacteremia, and 16 (9.4%) with primary bacteremia. Most cases (97.7%) were in infants and children with no underlying health condition. Two subspecies were recovered: enterica (N = 161, 94.2%) and houtenae (N = 10, 5.8%). All but one (serovar Typhi) were non-typhoidal Salmonella. The most common serovars were Panama (N = 57, 33.3% of isolates) and Arechavaleta (N = 28, 16.4%). Univariate analysis showed a strong association only between age > 6 months and infection with the Panama or Arechavaleta serovar (P = 0.002). The rate of resistance to all classes of antibiotics during the study period was low (< 15%); however, the detection of one extended-spectrum beta-lactamase-producing S. enterica strain highlights the need for continued monitoring of antimicrobial drug susceptibility. Infection with Panama (P < 0.001) or Arechavaleta (P < 0.001) serovar was significantly associated with bacteremia in a multivariate analysis. These serovars are probably poorly adapted to humans or are more virulent. A delay between onset of symptoms and hospital admission > 5 days (P = 0.01), vomiting (P = 0.001), and increased respiratory rate (P = 0.001) contributed independently to bacteremia in the multivariate analysis. Thus, if non-typhoidal infection is suspected, blood should be cultured and antibiotic treatment initiated in all patients who meet these criteria. PMID- 30014810 TI - Epidemiology of Plasmodium vivax Malaria Infection in Nepal. AB - Malaria is endemic in the southern plain of Nepal which shares a porous border with India. More than 80% cases of malaria in Nepal are caused by Plasmodium vivax. The main objective of this study was to review the epidemiology of P. vivax malaria infections as recorded by the national malaria control program of Nepal between 1963 and 2016. National malaria data were retrieved from the National Malaria program in the Ministry of Health, Government of Nepal. The epidemiological trends and malariometric indicators were analyzed. Vivax malaria has predominated over falciparum malaria in the past 53 years, with P. vivax malaria comprising 70-95% of the annual malaria infections. In 1985, a malaria epidemic occurred with 42,321 cases (82% P. vivax and 17% Plasmodium falciparum). Nepal had experienced further outbreaks of malaria in 1991 and 2002. Plasmodium falciparum cases increased from 2005 to 2010 but since then declined. Analyzing the overall trend between 2002 (12,786 cases) until 2016 (1,009 cases) shows a case reduction by 92%. The proportion of imported malaria cases has increased from 18% of cases in 2001 to 50% in 2016. The current trends of malariometric indices indicate that Nepal is making a significant progress toward achieving the goal of malaria elimination by 2025. Most of the cases are caused by P. vivax with imported malaria comprising an increasing proportion of cases. The malaria control program in Nepal needs to counter importation of malaria at high risk areas with collaborative cross border malaria control activities. PMID- 30014813 TI - Case Report: Corneal Coinfection with Fungus and Amoeba: Report of Two Patients and Literature Review. AB - We report two cases of corneal coinfection with Acanthamoeba and Fusarium sp. along with the review of published literature. A 35-year-old woman and 65-year old man presented to the institute with corneal ulcer refractory for treatment with topical antibiotics. Microbiological examination revealed the presence of Acanthamoeba cysts along with septate, hyaline fungal filaments. After emergency therapeutic penetrating keratoplasty (TPK) in both, the corneal tissue was sent for histopathologic examination, which confirmed the presence of Acanthamoeba and fungal coinfection. One patient had a recurrence of fungal infection after TPK. In subjects with a rapid progression of mycotic ulcer, coinfection with other microorganisms including Acanthamoeba should be suspected. The two cases presented here emphasize the importance of microbiology in making prompt diagnosis and appropriate management of these cases at an early stage. PMID- 30014812 TI - Comprehensive Assessment of a Hotspot with Persistent Bancroftian Filariasis in Coastal Sri Lanka. AB - The Sri Lankan Anti-Filariasis campaign distributed five rounds of mass drug administration (MDA with diethylcarbamazine plus albendazole) to some 10 million people in eight districts between 2002 and 2006. Sri Lanka was recognized by the WHO for having eliminated lymphatic filariasis (LF) as a public health problem in 2016. However, recent studies by our group documented pockets with persistent LF in coastal Sri Lanka, especially in Galle district. The present study was performed to reexamine an area previously identified as a potential hotspot for persistent LF (Balapitiya Public Health Inspector area, population 17,500). A community survey documented high rates for circulating filarial antigenemia (3%, confidence interval [CI]: 1.8-4.9) and microfilaremia (1%, CI: 0.5-2.5%). Circulating filarial antigenemia rates were 2.8-fold higher in males than females. High prevalence was also observed for anti-filarial antibodies in young children (5.7%, CI: 3.7-8.4%) and for filarial DNA in vector mosquitoes (5.2%, CI: 4.2-6.3%). Spatial data showed that persistent LF was dispersed across the entire study area. Other studies showed that persistent LF was not limited to Balapitiya and not solved by additional rounds of MDA. Molecular xenomonitoring studies conducted in 2016 in 22 of 168 Public Health Midwife areas in the coastal Galle evaluation unit (approximate population 600,000) found that 179 of 660 (27%) pools of Culex collected from all areas were positive for Wuchereria bancrofti DNA by quantitative polymerase chain reaction; the estimated infection rate in mosquitoes was 1.26%, CI: 1.0-1.5%. Interventions other than routine MDA will be required to remove LF hotspots in Balapitiya and in other areas in coastal Sri Lanka. PMID- 30014814 TI - Anthropometry and Malaria among Children in Niger: A Cross-Sectional Study. AB - The complex relationship between malnutrition and malaria affects morbidity and mortality in children younger than 5 years, particularly in parts of sub-Saharan Africa where these conditions occur together seasonally. Previous research on this relationship has been inconclusive. Here, we examine the association between anthropometric indicators and malaria infection in a population-based sample of children younger than 5 years in Niger. This cross-sectional study is a secondary analysis of a cluster-randomized trial comparing treatment strategies for trachoma in Niger. We included children aged 6-60 months residing in the 48 communities enrolled in the trial who completed anthropometric and malaria infection assessments at the final study visit. We evaluated the association between anthropometric indicators, including height-for-age z-score (HAZ) and weight-for-age z-score (WAZ) and indicators of malaria infection, including malaria parasitemia and clinical malaria. In May 2013, we collected data from 1,649 children. Of these, 780 (47.3%) were positive for malaria parasitemia and 401 (24.3%) had clinical malaria. In models of malaria parasitemia, the adjusted odds ratio (aOR) was 1.05 (95% confidence interval [CI]: 1.00-1.10) for HAZ and 1.07 (95% CI: 0.99, 1.15) for WAZ. In models of clinical malaria, the aOR was 1.07 (95% CI: 1.02-1.11) for HAZ and 1.09 (95% CI: 1.01-1.19) for WAZ. Overall, we did not find evidence of an association between most anthropometric indicators and malaria infection. Greater height may be associated with an increased risk of clinical malaria. PMID- 30014815 TI - Mentoring in Global Health: Formative Evaluation of Tuberculosis Research Training Programs in Ethiopia and Georgia. AB - Mentoring is a critical component of career development for research scientists and is related to mentee success both in terms of career selection and advancement. However, there are limited data on the role of mentoring in low- and middle-income countries (LMICs). Cross-cultural mentorship programs have the potential to foster the transfer of knowledge and the development of capacity to resource-poor settings. This formative evaluation explores the cultural context of mentoring in the countries of Georgia and Ethiopia. Results were used to build culturally relevant mentor training programs for two Global Infectious Disease Research Training Programs focused on tuberculosis funded by the Fogarty International Center at the US National Institutes of Health. Four focus group discussions were conducted with research trainees and mentors to explore the perceptions of mentorship, identify obstacles for successful mentoring, and generate recommendations to strengthen mentoring in each program situated in a LMIC. Data revealed the barriers to mentoring in Ethiopia and Georgia included gaps in knowledge about mentoring roles and responsibilities, lack of knowledge about the responsibilities of the trainee in a mentoring relationship, and the need to set clear expectations between mentors and trainees. All of the focus group participants desired formal mentor training. These data informed six key components of the development and implementation of the mentor training programs in both countries. The topics included the following: a foundation in mentoring, establishing expectations between mentees and mentors, increasing interactions between mentees and mentors, additional mentor training, a case study curriculum, and methods of evaluating mentoring relationships. PMID- 30014816 TI - Controlled Human Malaria Infection with Graded Numbers of Plasmodium falciparum NF135.C10- or NF166.C8-Infected Mosquitoes. AB - Controlled human malaria infections (CHMIs) with Plasmodium falciparum (Pf) parasites are well established. Exposure to five Pf (NF54)-infected Anopheles mosquitoes results in 100% infection rates in malaria-naive volunteers. Recently Pf clones NF135.C10 and NF166.C8 were generated for application in CHMIs. Here, we tested the clinical infection rates of these clones, using graded numbers of Pf-infected mosquitoes. In a double-blind randomized trial, we exposed 24 malaria naive volunteers to bites from one, two, or five mosquitoes infected with NF135.C10 or NF166.C8. The primary endpoint was parasitemia by quantitative polymerase chain reaction. For both strains, bites by five infected mosquitoes resulted in parasitemia in 4/4 volunteers; 3/4 volunteers developed parasitemia after exposure to one or two infected mosquitoes infected with either clone. The prepatent period was 7.25 +/- 4.0 days (median +/- range). There were no serious adverse events and comparable clinical symptoms between all groups. These data confirm the eligibility of NF135.C10 and NF166.C8 for use in CHMI studies. PMID- 30014817 TI - Hepatitis B Surface Antigen Seroprevalence among Prevaccine and Vaccine Era Children in Bangladesh. AB - Bangladesh introduced hepatitis B vaccine in a phased manner during 2003-2005 into the routine childhood vaccination schedule. This study was designed to evaluate the impact of the introduction of hepatitis B vaccine in Bangladesh by comparing hepatitis B surface antigen (HBsAg) prevalence among children born before and after vaccine introduction and to estimate the risk of vertical transmission of chronic hepatitis B virus (HBV) infection from mother to infant. We also evaluated the field sensitivity and specificity of an HBsAg point-of-care test strip. We selected a nationally representative sample of 2,100 prevaccine era and 2,100 vaccine era children. We collected a 5-mL blood sample from each child. One drop of blood was used to perform rapid HBsAg testing. If a child had a positive HBsAg test result with the rapid test, a blood sample was collected from the mother of the HBsAg-positive child and from the mothers of two subsequently enrolled HBsAg-negative children. All samples were tested for serologic markers of HBV infection using standard enzyme-linked immunosorbent assay. One (0.05%) child in the vaccine era group and 27 (1.2%; 95% confidence interval [CI]: 0.8-1.7%) children in the prevaccine era group were HBsAg positive. Mothers of HBsAg-positive children were more likely to be HBsAg positive than mothers of HBsAg-negative children (odds ratios = 4.7; 95% CI: 1.0 21.7%). Sensitivity of the HBsAg rapid test was 91.2% (95% CI: 76.6-98.1%) and specificity was 100% (95% CI: 99.9-100%). The study results suggest that even without a birth dose, the hepatitis B vaccine program in Bangladesh was highly effective in preventing chronic HBV infection among children. PMID- 30014818 TI - Accuracy, Ease of Use, Safety, and Acceptability of a 23-MUL Conical Cup Blood Transfer Device for Use with Rapid Diagnostic Tests. AB - Devices to safely transfer fixed amounts of finger prick blood to rapid diagnostic tests (RDTs) pose a significant challenge, especially in non laboratory settings. Following the success of an "inverted cup device" for transfer of 5 MUL blood, a prototype with a conical cup shape was developed for transfer of 20 MUL blood, the amount needed for human immunodeficiency virus or human African trypanosomiasis (HAT) RDTs. This study determined the volume of blood transferred by this new blood transfer device (BTD) and compared its ease of use, safety, and acceptability with that of a plastic pipette when used by health workers (HWs) for HAT RDTs in northwestern Uganda. After a half-day training, 48 HWs had used the two BTDs with at least 10 patients. The conical cup BTD effectively transferred a mean of 22.76 MUL of blood (standard deviation 3.31 MUL). A significantly higher proportion of HWs were able to collect the full amount of blood using the conical cup BTD, as compared with the pipette (92.4% versus 74.2%, P < 0.001). In HW questionnaires, the conical cup BTD scored higher than the pipette in various aspects of ease of use and safety. In addition, HWs preferred the conical cup BTD (79%), indicating that it was easy to handle, made work faster, and increased their confidence in front of the patient. These findings suggest that the design of the conical cup BTD may be adapted for RDTs requiring 20 MUL of blood to facilitate safe and accurate blood transfer. PMID- 30014820 TI - Case Report: First Report of Autochthonous Human Cutaneous Myiasis Caused by Hypoderma lineatum in Europe. AB - We report a case of human cutaneous myiasis by Hypoderma lineatum, contracted by a farmer who never traveled outside Italy. Identification at species level has been performed by both morphological examination and sequencing of cytochrome c oxidase subunit I gene. This is the first description of human hypodermosis by H. lineatum contracted in Europe. PMID- 30014819 TI - Cost-Effectiveness of Indoor Residual Spraying of Households with Insecticide for Malaria Prevention and Control in Tanzania. AB - Using a decision-tree approach, we examined the cost-effectiveness of indoor residual spraying (IRS) of households with insecticide combined with insecticide treated bed net (ITN) distribution (IRS + ITN), compared with ITN distribution alone in the programmatic context of mainland Tanzania. The primary outcome of our model was the expected economic cost to society per case of malaria averted in children <= 5 years of age. Indoor residual spraying of households with insecticide data came from a program implemented in northwest Tanzania from 2008 to 2012; all other data originated from the published literature. Through sensitivity and scenario analyses, the model also examined the effects of variations in insecticide resistance, malaria prevalence, and different IRS modalities. In the base case, IRS + ITN is expected to be more expensive and more effective than the ITN-only intervention (incremental cost-effectiveness ratio [ICER]: $152.36). The number of IRS rounds, IRS insecticide costs, ITN use, malaria prevalence, and the probability that a child develops symptoms following infection drove the interventions' cost-effectiveness. Compared with universal spraying, targeted spraying is expected to lead to a higher number of malaria cases per person targeted (0.211-0.256 versus 0.050-0.076), but the incremental cost per case of malaria averted is expected to be lower (ICER: $41.70). In a scenario of increasing pyrethroid resistance, the incremental expected cost per case of malaria averted is expected to increase compared with the base case (ICER: $192.12). Tanzania should pursue universal IRS only in those regions that report high malaria prevalence. If the cost per case of malaria averted of universal IRS exceeds the willingness to pay, targeted spraying could provide an alternative, but may result in higher malaria prevalence. PMID- 30014821 TI - Operational Performance of the Onchocerca volvulus "OEPA" Ov16 ELISA Serological Assay in Mapping, Guiding Decisions to Stop Mass Drug Administration, and Posttreatment Surveillance Surveys. AB - Onchocerciasis is a neglected tropical disease targeted for elimination. The World Health Organization (WHO) has developed guidelines for the verification of onchocerciasis elimination that include entomological and epidemiological criteria. The latter require demonstrating with statistical confidence that the infection prevalence in children is less than 0.1%, necessitating an assay with a high degree of specificity. We present an analysis of the performance of the Onchocerciasis Elimination Program for the Americas (OEPA) version of the Ov16 enzyme-linked immunosorbant assay (ELISA) when used under operational conditions. In Africa and Latin America, the assay demonstrated 99.98% specificity in 69,888 children in 20 foci where transmission was believed to be interrupted. The assay produced a prevalence estimate equal to that of skin snip microscopy when applied in putatively hypo-endemic zones of Ethiopia. The OEPA Ov16 ELISA demonstrated the specificity required to be effectively deployed to verify transmission elimination under the WHO guidelines, while exhibiting a sensitivity equivalent to skin snip microscopy to identify hypo-endemic areas. PMID- 30014822 TI - Melioidosis is in the Americas: A Call to Action for Diagnosing and Treating the Disease. AB - Melioidosis, a disease caused by the pathogen Burkholderia pseudomallei, is a significant underreported endemic disease found in tropical countries worldwide. Recent studies have demonstrated that human melioidosis cases have been increasingly recognized in the Americas. Therefore, the first Scientific Reunion of Melioidosis in the Americas was organized in Colombia, with the participation of health authorities of 11 Latin American countries and the United States. This report summarizes the topics reviewed during the meeting, including how to identify human infections and properly diagnose them, with the goal of increasing recognition of the disease in the Americas. PMID- 30014823 TI - Case Report: Delayed Diagnosis of Congenital Malaria by Plasmodium vivax in a Newborn of an Eritrean Woman with Varicella Infection. AB - Congenital malaria (CM) is uncommon in both malaria-endemic and non-endemic countries. It may be caused by any Plasmodium spp., although Plasmodium falciparum and Plasmodium vivax are the more frequent etiologic agents. We report a case of delayed diagnosis of CM by P. vivax in a newborn of an Eritrean primigravida. The mother developed pregnancy-related immunodepression and varicella-zoster viral infection 9 days before natural delivery; therefore, the child was admitted in the neonatal intensive care unit (NICU) to administer specific varicella-zoster immunoglobulin prophylaxis and for clinical monitoring. During the NICU stay, the newborn presented a febrile syndrome with vomiting, anemia, and thrombocytopenia. A P. vivax severe malaria diagnosis was made by detecting trophozoites in the thick and thin blood smears. The infant was successfully treated with intravenous artesunate and clindamycin. Our experience suggests that malaria diagnostic tests need to be included in routine blood analyses in newborns with febrile syndrome from mothers with an epidemiologic link to malaria-endemic areas. PMID- 30014824 TI - Case Report: A Cluster of Plasmodium falciparum Malaria Cases among Thai Workers in Gembu, Nigeria. AB - Although falciparum malaria is an important risk among travelers to sub-Saharan Africa, many travelers remain unaware of this risk. In October 2015, we found a cluster of imported Plasmodium falciparum malaria cases among Thai gem mine workers in Nigeria; none had received malaria chemoprophylaxis or information regarding malaria risk. The index case developed fever and visited our hospital on arrival day in Thailand after his 3-week stay in Nigeria. Plasmodium falciparum was found in his blood. He recovered completely 3 days post-admission. After we requested he contact his colleagues in Nigeria regarding malaria risk, we found that three of his five colleagues currently had fever, were diagnosed with malaria, and were being treated in a local hospital. Two were successfully treated in Nigeria. Although their blood films were negative for malaria, we could confirm that they recently had malaria because the polymerase chain reaction (PCR) was still positive for P. falciparum. Tragically, the last febrile case died in Nigeria 6 days post-admission, after developing jaundice and alteration of consciousness. The two colleagues without fever symptoms were also tested by PCR, which was negative for malaria. In conclusion, we found that four of six workers had malaria in this cluster, which was equal to 66.7% attack rate. There is an urgent need to raise awareness of malaria among workers in highly endemic areas. Clinical practice for travelers who are ill on their return should not only focus on individual cases but also consider potential disease clusters. PMID- 30014825 TI - First Report of Trypanosoma cruzi Infection in Salivary Gland of Bats from the Peruvian Amazon. AB - In the Americas, 8 million people are infected with Chagas disease, and an additional 90 million people are at risk for infection. Little is known about the role bats play in the sylvatic transmission cycle of Trypanosoma cruzi, the parasite causing Chagas disease. Here, we captured bats in the villages of Palmiche, Pachacutec, Nuevo San Martin, and Mayuriaga located in the Datem del Maranon Province in Loreto, Peru. Venous blood samples were collected by cardiac puncture or from the upper extremities, and trypanosomatids were identified by microscopy and molecularly. We collected blood samples from 121 bats on filter paper for molecular studies and 111 slides for microscopic examination of thin and thick blood smears from 16 different bat species. The prevalence of trypanosomatids in all bats species was 34.7% (42/121) and the prevalence of T. cruzi was 4.1% (5/121). In hematophagous bat species, the prevalence of trypanosomatids and T. cruzi was 36.9% (27/73) and 2.7% (2/73), respectively. In non-hematophagous bats, the prevalences of trypanosomatids and T. cruzi were 31.2% (15/48) and 6.2% (3/48), respectively. Also, we confirm the presence of T. cruzi in salivary glands of hematophagous bats Diaemus youngi. These results suggest a sylvatic cycle of trypanosomatid transmission in which bats may harbor infectious T. cruzi parasites that could be transmitted to humans via hematophagous bat bites or salivary contamination by non-hematophagous bats of vegetables consumed by humans. PMID- 30014826 TI - Antibiotic Therapy in Adults with Malaria (ANTHEM): High Rate of Clinically Significant Bacteremia in Hospitalized Adults Diagnosed with Falciparum Malaria. AB - It has been believed that concomitant bacteremia is uncommon in adults hospitalized with falciparum malaria. Accordingly, the World Health Organization treatment guidelines presently only recommended additional antibacterial therapy in these patients if they have a clinical syndrome compatible with serious bacterial infection. Admission blood cultures were collected from 20 consecutive adults in Myanmar, hospitalized with a positive immunochromatographic test and blood film, suggesting a diagnosis of falciparum malaria; four (20%) had bacteremia with a clinically significant pathogen. These case series' data were pooled with a previously published multicenter study from Myanmar which had also collected blood cultures in adults hospitalized with a diagnosis of falciparum malaria. Among 87 patients in the two studies, 13 (15%) had clinically significant bacteremia on admission, with Gram-negative organisms in 10 (77%) and Staphylococcus aureus in the remaining three (23%). Bacteremic patients had more severe disease than non-bacteremic patients (median [interquartile range] respiratory coma acidosis malaria score 2 [1-4] versus 1 [1-2], P = 0.02) and were more likely to die (2/13 [15%] versus 1/74 [1%], P = 0.01). However, bacterial coinfection was suspected clinically in a minority of bacteremic patients (5/13 [38%] compared with 13/70 [19%] of non-bacteremic patients, P = 0.11). Concomitant bacteremia in adults diagnosed with falciparum malaria may be more common than previously believed and is difficult to identify clinically in resource-poor settings. Death is more common in these patients, suggesting that clinicians should have a lower threshold for commencing empirical antibacterial therapy in adults diagnosed with falciparum malaria in these locations than is presently recommended. PMID- 30014827 TI - Antibiotic Prophylaxis for Melioidosis in Patients Receiving Hemodialysis in the Tropics? One Size Does Not Fit All. AB - Melioidosis has a high case fatality rate and is more common in patients with chronic kidney disease. Some authors recommended trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis for all hemodialysis (HD) patients during the wet season in melioidosis-endemic regions. Historical data were reviewed to determine if TMP/SMX prophylaxis was warranted in the HD population of Far North Queensland, Australia. Between 1997 and 2017, there were 242 culture-confirmed cases of melioidosis in the region, three (1.2%) occurred in HD patients; all survived without intensive care support. During the study period, there were 843 HD patients in the region with 3,024 cumulative patient years of risk. Even assuming 100% efficacy, it would have been necessary to prescribe TMP/SMX for 1,008 patient years to prevent one case of melioidosis. Given the significant additional cost and potentially life-threatening side effects of TMP/SMX therapy, clinicians should review the local epidemiology of melioidosis before the implementation of universal TMP/SMX prophylaxis in their HD population. PMID- 30014829 TI - Characterizing Pediatric Tuberculosis with and without Human Immunodeficiency Virus Coinfection in Harare, Zimbabwe. AB - Pediatric tuberculosis (TB) represents a major barrier to reducing global TB mortality, especially in countries confronting dual TB and human immunodeficiency virus (HIV) epidemics. Our study aimed to characterize pediatric TB epidemiology in the high-burden setting of Harare, Zimbabwe, both to fill the current knowledge gap around the epidemiology of pediatric TB and to indicate areas for future research and interventions. We analyzed de-identified data of 1,051 pediatric TB cases (0-14 years) found among a total of 11,607 TB cases reported in Harare, Zimbabwe, during 2011-2012. We performed Pearson's chi2 test and multivariate logistic regression analysis to characterize pediatric TB and to assess predictors of HIV coinfection. Pediatric TB cases accounted for 9.1% of all TB cases reported during 2011-2012. Approximately 50% of pediatric TB cases were children younger than 5 years. Almost 60% of the under-5 age group were male, whereas almost 60% of the 10-14 age group were female. The overall HIV coinfection rate was 58.3%. Odds for HIV coinfection was higher for the 5-9 age group (adjusted odds ratio [AOR]: 2.77, 95% confidence interval [CI]: 1.97-3.94), the 10-14 group (AOR: 3.57, 95% CI: 2.52-5.11), retreatment cases (AOR: 6.17, 95% CI: 2.13, 26.16), and pulmonary TB cases (AOR: 2.39, 95% CI: 1.52, 3.75). In conclusion, our study generated evidence that pediatric TB, compounded by HIV coinfection, significantly impacts children in high-burden settings. The findings of our study indicate a critical need for targeted interventions. PMID- 30014830 TI - Abnormal Helminth Egg Development, Strange Morphology, and the Identification of Intestinal Helminth Infections. AB - Occasionally, abnormal forms of parasitic helminth eggs are detected during routine diagnostics. This finding can prove problematic in diagnosis because morphologic analysis based on tightly defined measurements is the primary method used to identify the infecting species and molecular confirmation of species is not always feasible. We describe instances of malformed nematode eggs (primarily from members of the superfamily Ascaridoidea) from human clinical practice and experimental trials on animals. On the basis of our observations and historical literature, we propose that unusual development and morphology of nematode and trematode eggs are associated with early infection. Further observational studies and experimentation are needed to identify additional factors that might cause abnormalities in egg morphology and production. Abnormal egg morphology can be observed early in the course of infection and can confound accurate diagnosis of intestinal helminthiases. PMID- 30014828 TI - Effect of Antibiotics on Short-Term Growth among Children in Burkina Faso: A Randomized Trial. AB - Antibiotics improve both weight and height gain in randomized trials of preschool children with preexisting morbidity. Here, we assess the effect of a short course of three different antibiotics (amoxicillin, azithromycin, and cotrimoxazole) on short-term linear and ponderal growth in a population-based sample of preschool children in rural Burkina Faso. We randomized households with at least two children in the Nouna district, Burkina Faso, to a 5-day course of amoxicillin, azithromycin, cotrimoxazole, or placebo. Within each antibiotic-randomized household, one child was randomly assigned to receive the antibiotic and the other to receive the placebo. Weight and height measurements were taken at baseline and 30 days following the last study medication dose. Weight-for-height Z (WHZ), height-for-age Z (HAZ), and weight-for-age Z (WAZ) scoreswere calculated based on the 2006 World Health Organization standards. Of the 124 households and 248 children enrolled, 229 had anthropometry measurements at 1 month and were analyzed. Children randomized to amoxicillin gained significantly more weight compared with both the placebo household (mean difference 317 g, 95% confidence interval [CI]: 115-519 g) and placebo sibling (mean difference 315 g, 95% CI: 147 482 g) controls. Growth velocity in g/kg/day, and WHZ and WAZ scores were higher in amoxicillin-treated children compared with placebo households and siblings. There were no differences in weight gain in children randomized to azithromycin or cotrimoxazole compared with placebo households or placebo siblings. There were no differences in height gain or HAZ across any of the study arms. Amoxicillin may have short-term growth-promoting effects in healthy children. PMID- 30014831 TI - Brucellosis in Dogs and Public Health Risk. AB - Brucella canis infects dogs and humans. In dogs, it can cause reproductive failure; in humans, it can cause fever, chills, malaise, peripheral lymphadenomegaly, and splenomegaly. B. canis infection in dogs is underrecognized. After evaluating serologic data, transmission patterns, and regulations in the context of brucellosis in dogs as an underrecognized zoonosis, we concluded that brucellosis in dogs remains endemic to many parts of the world and will probably remain a threat to human health and animal welfare unless stronger intervention measures are implemented. A first step for limiting disease spread would be implementation of mandatory testing of dogs before interstate or international movement. PMID- 30014833 TI - Dual Genotype Orientia tsutsugamushi Infection in Patient with Rash and Eschar, Vietnam, 2016. AB - We report a dual genotype Orientia tsutsugamushi infection in Vietnam in 2016. The patient had fever, rash, and an eschar. The Kawasaki genotype was identified in the eschar specimen and Karp genotype in the whole blood specimen. The genotype co-infection rate for scrub typhus is unknown and should be further evaluated. PMID- 30014832 TI - Hypoglycemic Toxins and Enteroviruses as Causes of Outbreaks of Acute Encephalitis-Like Syndrome in Children, Bac Giang Province, Northern Vietnam. AB - We investigated the cause of seasonal outbreaks of pediatric acute encephalitis like syndrome associated with litchi harvests (May-July) in northern Vietnam since 2008. Nineteen cerebrospinal fluid samples were positive for human enterovirus B, and 8 blood samples were positive for hypoglycemic toxins present in litchi fruits. Patients who were positive for hypoglycemic toxins had shorter median times between disease onset and admission, more reports of seizures, more reports of hypoglycemia (glucose level <3 mmol/L), lower median numbers of leukocytes in cerebrospinal fluid, and higher median serum levels of alanine aminotransferase and aspartate transaminase than did patients who were positive for enteroviruses. We suggest that children with rapidly progressing acute encephalitis-like syndrome at the time of the litchi harvest have intoxication caused by hypoglycemic toxins, rather than viral encephalitis, as previously suspected. These children should be urgently treated for life-threatening hypoglycemia. PMID- 30014835 TI - Anncaliia algerae Microsporidial Myositis, New South Wales, Australia. AB - We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention. PMID- 30014834 TI - Ancylostoma ceylanicum Hookworm in Myanmar Refugees, Thailand, 2012-2015. AB - During 2012-2015, US-bound refugees living in Myanmar-Thailand border camps (n = 1,839) were surveyed for hookworm infection and treatment response by using quantitative PCR. Samples were collected at 3 time points: after each of 2 treatments with albendazole and after resettlement in the United States. Baseline prevalence of Necator americanus hookworm was 25.4%, Ancylostoma duodenale 0%, and Ancylostoma ceylanicum (a zoonosis) 5.4%. Compared with N. americanus prevalence, A. ceylanicum hookworm prevalence peaked in younger age groups, and blood eosinophil concentrations during A. ceylanicum infection were higher than those for N. americanus infection. Female sex was associated with a lower risk for either hookworm infection. Cure rates after 1 dose of albendazole were greater for A. ceylanicum (93.3%) than N. americanus (65.9%) hookworm (p<0.001). Lower N. americanus hookworm cure rates were unrelated to beta-tubulin single nucleotide polymorphisms at codons 200 or 167. A. ceylanicum hookworm infection might be more common in humans than previously recognized. PMID- 30014836 TI - Hospitalized Patient as Source of Aspergillus fumigatus, 2015. AB - Hospital-acquired aspergillosis is usually associated with environmental contamination. In 2015, continuous monitoring of airborne fungi and multilocus variable-number tandem-repeat analysis identified the source of Aspergillus fumigatus as the airway of a patient. Therefore, patients colonized with Aspergillus spp. should be treated in airborne infection isolation rooms. PMID- 30014837 TI - Enhanced Surveillance for Coccidioidomycosis, 14 US States, 2016. AB - Although coccidioidomycosis in Arizona and California has been well characterized, much remains unknown about its epidemiology in states where it is not highly endemic. We conducted enhanced surveillance in 14 such states in 2016 by identifying cases according to the Council of State and Territorial Epidemiologists case definition and interviewing patients about their demographic characteristics, clinical features, and exposures. Among 186 patients, median time from seeking healthcare to diagnosis was 38 days (range 1-1,654 days); 70% had another condition diagnosed before coccidioidomycosis testing occurred (of whom 83% were prescribed antibacterial medications); 43% were hospitalized; and 29% had culture-positive coccidioidomycosis. Most (83%) patients from nonendemic states had traveled to a coccidioidomycosis-endemic area. Coccidioidomycosis can cause severe disease in residents of non-highly endemic states, a finding consistent with previous studies in Arizona, and less severe cases likely go undiagnosed or unreported. Improved coccidioidomycosis awareness in non-highly endemic areas is needed. PMID- 30014838 TI - Novel Enterobacter Lineage as Leading Cause of Nosocomial Outbreak Involving Carbapenemase-Producing Strains. AB - We investigated unusual carbapenemase-producing Enterobacter cloacae complex isolates (n = 8) in the novel sequence type (ST) 873, which caused nosocomial infections in 2 hospitals in France. Whole-genome sequence typing showed the 1 year persistence of the epidemic strain, which harbored a blaVIM-4 ST1-IncHI2 plasmid, in 1 health institution and 2 closely related strains harboring blaCTX-M 15 in the other. These isolates formed a new subgroup in the E. hormaechei metacluster, according to their hsp60 sequences and phylogenomic analysis. The average nucleotide identities, specific biochemical properties, and pangenomic and functional investigations of isolates suggested isolates of a novel species that had acquired genes associated with adhesion and mobility. The emergence of this novel Enterobacter phylogenetic lineage within hospitals should be closely monitored because of its ability to persist and spread. PMID- 30014839 TI - Case Series of Severe Neurologic Sequelae of Ebola Virus Disease during Epidemic, Sierra Leone. AB - We describe a case series of 35 Ebola virus disease (EVD) survivors during the epidemic in West Africa who had neurologic and accompanying psychiatric sequelae. Survivors meeting neurologic criteria were invited from a cohort of 361 EVD survivors to attend a preliminary clinic. Those whose severe neurologic features were documented in the preliminary clinic were referred for specialist neurologic evaluation, ophthalmologic examination, and psychiatric assessment. Of 35 survivors with neurologic sequelae, 13 had migraine headache, 2 stroke, 2 peripheral sensory neuropathy, and 2 peripheral nerve lesions. Of brain computed tomography scans of 17 patients, 3 showed cerebral and/or cerebellar atrophy and 2 confirmed strokes. Sixteen patients required mental health followup; psychiatric disorders were diagnosed in 5. The 10 patients who experienced greatest disability had co-existing physical and mental health conditions. EVD survivors may have ongoing central and peripheral nervous system disorders, including previously unrecognized migraine headaches and stroke. PMID- 30014840 TI - Susceptibility of Human Prion Protein to Conversion by Chronic Wasting Disease Prions. AB - Chronic wasting disease (CWD) is a contagious and fatal neurodegenerative disease and a serious animal health issue for deer and elk in North America. The identification of the first cases of CWD among free-ranging reindeer and moose in Europe brings back into focus the unresolved issue of whether CWD can be zoonotic like bovine spongiform encephalopathy. We used a cell-free seeded protein misfolding assay to determine whether CWD prions from elk, white-tailed deer, and reindeer in North America can convert the human prion protein to the disease associated form. We found that prions can convert, but the efficiency of conversion is affected by polymorphic variation in the cervid and human prion protein genes. In view of the similarity of reindeer, elk, and white-tailed deer in North America to reindeer, red deer, and roe deer, respectively, in Europe, a more comprehensive and thorough assessment of the zoonotic potential of CWD might be warranted. PMID- 30014841 TI - Human Norovirus Replication in Human Intestinal Enteroids as Model to Evaluate Virus Inactivation. AB - Human noroviruses are a leading cause of epidemic and endemic acute gastroenteritis worldwide and a leading cause of foodborne illness in the United States. Recently, human intestinal enteroids (HIEs) derived from human small intestinal tissue have been shown to support human norovirus replication. We implemented the HIE system in our laboratory and tested the effect of chlorine and alcohols on human norovirus infectivity. Successful replication was observed for 6 norovirus GII genotypes and was dependent on viral load and genotype of the inoculum. GII.4 viruses had higher replication levels than other genotypes. Regardless of concentration or exposure time, alcohols slightly reduced, but did not completely inactivate, human norovirus. In contrast, complete inactivation of the 3 GII.4 viruses occurred at concentrations as low as 50 ppm of chlorine. Taken together, our data confirm the successful replication of human noroviruses in HIEs and their utility as tools to study norovirus inactivation strategies. PMID- 30014842 TI - Poverty and Community-Acquired Antimicrobial Resistance with Extended-Spectrum beta-Lactamase-Producing Organisms, Hyderabad, India. AB - The decreasing effectiveness of antimicrobial agents is a global public health threat, yet risk factors for community-acquired antimicrobial resistance (CA-AMR) in low-income settings have not been clearly elucidated. Our aim was to identify risk factors for CA-AMR with extended-spectrum beta-lactamase (ESBL)-producing organisms among urban-dwelling women in India. We collected microbiological and survey data in an observational study of primigravidae women in a public hospital in Hyderabad, India. We analyzed the data using multivariate logistic and linear regression and found that 7% of 1,836 women had bacteriuria; 48% of isolates were ESBL-producing organisms. Women in the bottom 50th percentile of income distribution were more likely to have bacteriuria (adjusted odds ratio 1.44, 95% CI 0.99-2.10) and significantly more likely to have bacteriuria with ESBL producing organisms (adjusted odds ratio 2.04, 95% CI 1.17-3.54). Nonparametric analyses demonstrated a negative relationship between the prevalence of ESBL and income. PMID- 30014844 TI - Clonal Expansion of Macrolide-Resistant Sequence Type 3 Mycoplasma pneumoniae, South Korea. AB - To investigate the genetic background for the emergence of macrolide resistance, we characterized the genetic features of Mycoplasma pneumoniae using multilocus sequence typing. Of the 146 M. pneumoniae strains collected during the 5 consecutive outbreaks of M. pneumoniae pneumonia during 2000-2016 in South Korea, macrolide resistance increased from 0% in the first outbreak to 84.4% in the fifth. Among the 8 sequence types (STs) identified, ST3 (74.7%) was the most prevalent, followed by ST14 (15.1%). Macrolide-susceptible strains comprised 8 different STs, and all macrolide-resistant strains were ST3 (98.3%) except 1 with ST14. The proportion of macrolide-resistant strains in ST3 remained 2.2% (1/46) until the 2006-2007 outbreak and then markedly increased to 82.6% (19/23) during the 2010-2012 outbreak and 95.0% (38/40) during the 2014-2016 outbreak. The findings demonstrated that clonal expansion of ST3 M. pneumoniae was associated with the increase in macrolide resistance in South Korea. PMID- 30014843 TI - Toxoplasmosis in Transplant Recipients, Europe, 2010-2014. AB - Transplantation activity is increasing, leading to a growing number of patients at risk for toxoplasmosis. We reviewed toxoplasmosis prevention practices, prevalence, and outcomes for hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT; heart, kidney, or liver) patients in Europe. We collected electronic data on the transplant population and prevention guidelines/regulations and clinical data on toxoplasmosis cases diagnosed during 2010-2014. Serologic pretransplant screening of allo-hematopoietic stem cell donors was performed in 80% of countries, screening of organ donors in 100%. SOT recipients were systematically screened in 6 countries. Targeted anti-Toxoplasma chemoprophylaxis was heterogeneous. A total of 87 toxoplasmosis cases were recorded (58 allo-HSCTs, 29 SOTs). The 6-month survival rate was lower among Toxoplasma-seropositive recipients and among allo-hematopoietic stem cell and liver recipients. Chemoprophylaxis improved outcomes for SOT recipients. Toxoplasmosis remains associated with high mortality rates among transplant recipients. Guidelines are urgently needed to standardize prophylactic regimens and optimize patient management. PMID- 30014845 TI - Wnt/beta-catenin regulates an ancient signaling network during zebrafish scale development. AB - Understanding how patterning influences cell behaviors to generate three dimensional morphologies is a central goal of developmental biology. Additionally, comparing these regulatory mechanisms among morphologically diverse tissues allows for rigorous testing of evolutionary hypotheses. Zebrafish skin is endowed with a coat of precisely patterned bony scales. We use in-toto live imaging during scale development and manipulations of cell signaling activity to elucidate core features of scale patterning and morphogenesis. These analyses show that scale development requires the concerted activity of Wnt/beta-catenin, Ectodysplasin (Eda) and Fibroblast growth factor (Fgf) signaling. This regulatory module coordinates Hedgehog (HH) dependent collective cell migration during epidermal invagination, a cell behavior not previously implicated in skin appendage morphogenesis. Our analyses demonstrate the utility of zebrafish scale development as a tractable system in which to elucidate mechanisms of developmental patterning and morphogenesis, and suggest a single, ancient origin of skin appendage patterning mechanisms in vertebrates. PMID- 30014846 TI - Thioredoxin shapes the C. elegans sensory response to Pseudomonas produced nitric oxide. AB - Nitric oxide (NO) is released into the air by NO-producing organisms; however, it is unclear if animals utilize NO as a sensory cue. We show that C. elegans avoids Pseudomonas aeruginosa (PA14) in part by detecting PA14-produced NO. PA14 mutants deficient for NO production fail to elicit avoidance and NO donors repel worms. PA14 and NO avoidance are mediated by a chemosensory neuron (ASJ) and these responses require receptor guanylate cyclases and cyclic nucleotide gated ion channels. ASJ exhibits calcium increases at both the onset and removal of NO. These NO-evoked ON and OFF calcium transients are affected by a redox sensing protein, TRX-1/thioredoxin. TRX-1's trans-nitrosylation activity inhibits the ON transient whereas TRX-1's de-nitrosylation activity promotes the OFF transient. Thus, C. elegans exploits bacterially produced NO as a cue to mediate avoidance and TRX-1 endows ASJ with a bi-phasic response to NO exposure. PMID- 30014847 TI - Cytokinin transfer by a free-living mirid to Nicotiana attenuata recapitulates a strategy of endophytic insects. AB - Endophytic insects provide the textbook examples of herbivores that manipulate their host plant's physiology, putatively altering source/sink relationships by transferring cytokinins (CK) to create 'green islands' that increase the nutritional value of infested tissues. However, unambiguous demonstrations of CK transfer are lacking. Here we show that feeding by the free-living herbivore Tupiocoris notatus on Nicotiana attenuata is characterized by stable nutrient levels, increased CK levels and alterations in CK-related transcript levels in attacked leaves, in striking similarity to endophytic insects. Using 15N-isotope labeling, we demonstrate that the CK N6-isopentenyladenine (IP) is transferred from insects to plants via their oral secretions. In the field, T. notatus preferentially attacks leaves with transgenically increased CK levels; plants with abrogated CK-perception are less tolerant of T. notatus feeding damage. We infer that this free-living insect uses CKs to manipulate source/sink relationships to increase food quality and minimize the fitness consequences of its feeding. PMID- 30014849 TI - KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site. AB - The voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate KV7.1 via an electrostatic mechanism. The activating effect was abolished when KV7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of KV7.1 restored PUFA effects on KV7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of KV7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on KV7.1. This mechanistic understanding of how KCNE1 alters KV7.1 pharmacology is essential for development of drugs targeting the IKs channel. PMID- 30014848 TI - Introgression of regulatory alleles and a missense coding mutation drive plumage pattern diversity in the rock pigeon. AB - Birds and other vertebrates display stunning variation in pigmentation patterning, yet the genes controlling this diversity remain largely unknown. Rock pigeons (Columba livia) are fundamentally one of four color pattern phenotypes, in decreasing order of melanism: T-check, checker, bar (ancestral), or barless. Using whole-genome scans, we identified NDP as a candidate gene for this variation. Allele-specific expression differences in NDP indicate cis-regulatory divergence between ancestral and melanistic alleles. Sequence comparisons suggest that derived alleles originated in the speckled pigeon (Columba guinea), providing a striking example of introgression. In contrast, barless rock pigeons have an increased incidence of vision defects and, like human families with hereditary blindness, carry start-codon mutations in NDP. In summary, we find that both coding and regulatory variation in the same gene drives wing pattern diversity, and post-domestication introgression supplied potentially advantageous melanistic alleles to feral populations of this ubiquitous urban bird. PMID- 30014850 TI - Genetics of trans-regulatory variation in gene expression. AB - Heritable variation in gene expression forms a crucial bridge between genomic variation and the biology of many traits. However, most expression quantitative trait loci (eQTLs) remain unidentified. We mapped eQTLs by transcriptome sequencing in 1012 yeast segregants. The resulting eQTLs accounted for over 70% of the heritability of mRNA levels, allowing comprehensive dissection of regulatory variation. Most genes had multiple eQTLs. Most expression variation arose from trans-acting eQTLs distant from their target genes. Nearly all trans eQTLs clustered at 102 hotspot locations, some of which influenced the expression of thousands of genes. Fine-mapped hotspot regions were enriched for transcription factor genes. While most genes had a local eQTL, most of these had no detectable effects on the expression of other genes in trans. Hundreds of non additive genetic interactions accounted for small fractions of expression variation. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail. PMID- 30014851 TI - Arid1a restrains Kras-dependent changes in acinar cell identity. AB - Mutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the mouse pancreas in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis. PMID- 30014853 TI - To be or not to be. AB - Chromatin remodeling processes can drive acinar cell fate decisions. PMID- 30014852 TI - A selective gut bacterial bile salt hydrolase alters host metabolism. AB - The human gut microbiota impacts host metabolism and has been implicated in the pathophysiology of obesity and metabolic syndromes. However, defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging due to the complexity of the microbiome-host ecosystem. Here, we identify strains from the abundant gut bacterial phylum Bacteroidetes that display selective bile salt hydrolase (BSH) activity. Using isogenic strains of wild-type and BSH-deleted Bacteroides thetaiotaomicron, we selectively modulated the levels of the bile acid tauro-beta-muricholic acid in monocolonized gnotobiotic mice. B. thetaiotaomicron BSH mutant-colonized mice displayed altered metabolism, including reduced weight gain and respiratory exchange ratios, as well as transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver. Our results demonstrate that metabolites generated by a single microbial gene and enzymatic activity can profoundly alter host metabolism and gene expression at local and organism-level scales. PMID- 30014855 TI - Whole-genome sequence analysis reveals unique SNP profiles to distinguish vaccine and wild-type strains of bovine herpesvirus-1 (BoHV-1). AB - Bovine herpesvirus-1 (BoHV-1) is a major pathogen affecting cattle worldwide causing primarily respiratory illness referred to as infectious bovine rhinotracheitis (IBR), along with reproductive disorders including abortion and infertility in cattle. While modified live vaccines (MLVs) effectively induce immune response against BoHV-1, they are implicated in disease outbreaks in cattle. Current diagnostic methods cannot distinguish between MLVs and field strains of BoHV-1. We performed whole genome sequencing of 18 BoHV-1 isolates from Pennsylvania and Minnesota along with five BoHV-1 vaccine strains using the Illumina Miseq platform. Based on nucleotide polymorphisms (SNPs) the sequences were clustered into three groups with two different vaccine groups and one distinct cluster of field isolates. Using this information, we developed a novel SNP-based PCR assay that can allow differentiation of vaccine and clinical strains and help accurately determine the incidence of BoHV-1 and the association of MLVs with clinical disease in cattle. PMID- 30014854 TI - Viral dedication to vigorous destruction of interferon receptors. AB - Interferons (IFNs) exhibit forceful inhibitory activities against numerous viruses by inducing synthesis of anti-viral proteins or promoting immune cell functions, which help eradicate the vicious microbes. Consequently, the degree to which viruses evade or counterattack IFN responses influences viral pathogenicity. Viruses have developed many strategies to interfere with the synthesis of IFNs or IFN receptor signaling pathway. Furthermore, multiple viruses decrease levels of IFN receptors via diverse tactics, which include decreasing type I IFN receptor mRNA expression, blocking post-translational modification of the receptor, and degrading IFN receptors. Recently, influenza virus was found to induce CK1alpha-induced phosphorylation and subsequent degradation of the receptor for type I and II IFNs. In this review, viral mechanisms that remove IFN receptors are summarized with an emphasis on the mechanisms for virus-induced degradation of IFN receptors. PMID- 30014856 TI - Receptor-binding properties of influenza viruses isolated from gulls. AB - Ducks, gulls and shorebirds represent the major hosts of influenza A viruses (IAVs) in nature, but distinctions of IAVs in different birds are not well defined. Here we characterized the receptor specificity of gull IAVs with HA subtypes H4, H6, H14, H13 and H16 using synthetic sialylglycopolymers. In contrast to duck IAVs, gull IAVs efficiently bound to fucosylated receptors and often preferred sulfated and non-sulfated receptors with Galbeta1-4GlcNAc cores over the counterparts with Galbeta1-3GlcNAc cores. Unlike all other IAVs of aquatic birds, H16 IAVs showed efficient binding to Neu5Acalpha2-6Gal-containing receptors and bound poorly to Neu5Acalpha2-3Galbeta1-3-terminated (duck-type) receptors. Analysis of HA crystal structures and amino acid sequences suggested that the amino acid at position 222 is an important determinant of the receptor specificity of IAVs and that transmission of duck viruses to gulls and shorebirds is commonly accompanied by substitutions at this position. PMID- 30014857 TI - Cyclophilins and cyclophilin inhibitors in nidovirus replication. AB - Cyclophilins (Cyps) belong to the family of peptidyl-prolyl isomerases (PPIases). The PPIase activity of most Cyps is inhibited by the immunosuppressive drug cyclosporin A and several of its non-immunosuppressive analogs, which can also block the replication of nidoviruses (arteriviruses and coronaviruses). Cyclophilins have been reported to play an essential role in the replication of several other RNA viruses, including human immunodeficiency virus-1, hepatitis C virus, and influenza A virus. Likewise, the replication of various nidoviruses was reported to depend on Cyps or other PPIases. This review summarizes our current understanding of this class of nidovirus-host interactions, including the potential function of in particular CypA and the inhibitory effect of Cyp inhibitors. Also the involvement of the FK-506-binding proteins and parvulins is discussed. The nidovirus data are placed in a broader perspective by summarizing the most relevant data on Cyp interactions and Cyp inhibitors for other RNA viruses. PMID- 30014858 TI - Characterizaton of gamma delta T cells in Marek's disease virus (Gallid herpesvirus 2) infection of chickens. AB - Immunity against Marek's disease (MD), caused by Gallid herpesvirus 2 (GaHV-2), in chickens is mediated by both innate and adaptive responses. The present study evaluated the effects of GaHV-2 infection on distribution and frequency of gammadelta T cells in tissues, as well as their expression of cytokines. We found that the infected chickens had significantly higher number of gammadelta T cells in their spleens by 10 and 21 days post-infection (d.p.i.) and nearly 100% of these gammadelta T cells were CD8+ at 21 d.p.i. Conversely, the number of gammadelta T cells in the cecal tonsils of GaHV-2-infected birds decreased compared to uninfected birds. Splenic gammadelta T cells had up-regulated expression of interferon-gamma early in infection followed by simultaneous gene expression of interleukin-10 during the later phases. In conclusion, these results suggest a potential role for gammadelta T cells in host response to GaHV 2 and further elucidate the underlying immunological mechanisms of interactions between this virus and its host. PMID- 30014859 TI - Monoclonal antibody against N2 neuraminidase of cold adapted A/Leningrad/134/17/57 (H2N2) enables efficient generation of live attenuated influenza vaccines. AB - Cold adapted influenza virus A/Leningrad/134/17/57 (H2N2) is a reliable master donor virus (Len/17-MDV) for preparing live attenuated influenza vaccines (LAIV). LAIVs are 6:2 reasortants that contain 6 segments of Len/17-MDV and the hemagglutinin (HA) and neuraminidase (NA) of contemporary circulating influenza A viruses. The problem with the classical reassortment procedure used to generate LAIVs is that there is limited selection pressure against NA of the Len/17-MDV resulting in 7:1 reassortants with desired HA only, which are not suitable LAIVs. The monoclonal antibodies (mAb) directed against the N2 of Len/17-MDV were generated. 10C4-8E7 mAb inhibits cell-to-cell spread of viruses containing the Len/17-MDV N2, but not viruses with the related N2 from contemporary H3N2 viruses. 10C4-8E7 antibody specifically inhibited the Len/17-MDV replication in vitro and in ovo but didn't inhibit replication of H3N2 or H1N1pdm09 reassortants. Our data demonstrate that addition of 10C4-8E7 in the classical reassortment improves efficiency of LAIV production. PMID- 30014860 TI - Viral RNA load and histological changes in tissues following experimental infection with an arterivirus of possums (wobbly possum disease virus). AB - Tissues from Australian brushtail possums (Trichosurus vulpecula) that had been experimentally infected with wobbly possum disease (WPD) virus (WPDV) were examined to elucidate pathogenesis of WPDV infection. Mononuclear inflammatory cell infiltrates were present in livers, kidneys, salivary glands and brains of WPD-affected possums. Specific staining was detected by immunohistochemistry within macrophages in the livers and kidneys, and undefined cell types in the brains. The highest viral RNA load was found in macrophage-rich tissues. The detection of viral RNA in the salivary gland, serum, kidney, bladder and urine is compatible with transmission via close physical contact during encounters such as fighting or grooming, or by contact with an environment that has been contaminated with saliva or urine. Levels of viral RNA remained high in all tissues tested throughout the study, suggesting that on-going virus replication and evasion of the immune responses may be important in the pathogenesis of disease. PMID- 30014862 TI - The benefits and risks of asking research participants about suicide: A meta analysis of the impact of exposure to suicide-related content. AB - One obstacle potentially hindering research on suicide is the assumption that assessing suicide may make individuals more likely to engage in suicidal thoughts or behaviours; a concern expressed by ethics committees, researchers, and clinicians. However, decisions which are overly cautious and restrictive when approving research proposals will hinder important research in this area. The present aim was to conduct a meta-analysis to examine whether asking about suicide or exposure to suicide-related content in research studies led to changes in participants' levels of distress, suicidal ideation, or suicide attempts. A systematic search of peer-reviewed and unpublished literature from 2000 to 2017 identified 18 studies. Exposure to suicide-related content led to significant, albeit small, reductions in suicidal ideation (g = -0.13, p < .001) and a lower likelihood of engaging in suicidal behaviour (OR = 0.714, p < .05). The reduction in suicidal ideation was moderated by age such that adolescents showed nearly twice as large a reduction in suicidal ideation from pre- to post-exposure as adults did. Thus, evidence to date suggests that asking research participants about suicide does not increase risk, and may be associated with small benefits. Ethics review boards should calibrate their consideration of the risks associated with participation based on the available evidence and relative to the cost of depriving potential participants of any benefits that participation may offer. PMID- 30014863 TI - Comparing palm oil tocotrienol rich fraction with alpha-tocopherol supplementation on oxidative stress in healthy older adults. AB - Vitamin E is a fat-soluble compound and powerful antioxidant that have been shown to protect the cell membranes against damage caused by free radicals. Human vitamin E supplementation studies are usually limited to alpha-tocopherol but currently tocotrienols are also available. This study aims to compare the effects of tocotrienol rich fraction (TRF) with alpha-tocopherol (alpha-TF) supplementation on oxidative stress in healthy male and female older adults aged 50-55 years old. A total of 71 subjects both male and female aged between 50 and 55 years were divided into groups receiving placebo (n = 23), alpha-TF (n = 24) and TRF (n = 24) for six months. Blood was taken at baseline (month 0), 3 months and 6 months osf supplementation for determination of plasma malondialdehyde (MDA), protein carbonyl, total DNA damage, vitamin D concentration and vitamin E isomers. alpha-TF supplementation reduced plasma MDA and protein carbonyl in female subjects after 3 and 6 months. TRF supplementation reduced MDA levels in both males and females as early as 3 months while DNA damage was reduced in females only at 6 months. Supplementation with alpha-TF and TRF increased plasma vitamin D concentration in both males and females after 6 months, but vitamin D concentration in male subjects were significantly higher compared to female subjects in TRF group. Vitamin E isomer determination showed alpha-TF, alpha tocotrienol and gamma-tocotrienol were increased in both male and female subjects. In conclusion, TRF supplementation effects were different from alpha-TF in reducing oxidative stress markers and vitamin D levels with a more pronounced effect in female subjects. PMID- 30014864 TI - Serum homocysteine and cysteine levels and changes in the lipid profile of children and adolescents over a 12-month follow-up period. AB - INTRODUCTION: There is evidence of associations between high serum homocysteine (Hcy) and cysteine (Cys) levels and changes in the lipid profile of adults; however, little information is available with respect to these associations in the pediatric age group. OBJECTIVE: To identify the effect of high baseline serum Hcy and Cys levels, alone or in conjunction, on the lipid profile of children and adolescents over a 12-month follow-up period. METHODS: A cohort study involving 540 boys and girls of 7-15 years of age was conducted over 12 months. The outcome variables were the lipid indicators and the principal exposure variable was serum Hcy and Cys levels. A generalized estimating equation (GEE) approach was used to identify the associations of interest. RESULTS: Irrespective of age, sex, socioeconomic status, diet or anthropometric status, when serum Hcy levels were above the 5th quintile of distribution at baseline, HDL-cholesterol decreased by a mean of 2.91 mg/dl (p < 0.01), while triglyceride levels increased by a mean of 1.58 mg/dl (p < 0.01) over the 12-month follow-up period. In individuals with high baseline Cys levels, there was a reduction of 1.95 mg/dl (p < 0.01) and an increase of 1.76 mg/dl (p < 0.01) in mean serum HDL-cholesterol and triglyceride levels, respectively, over the 12-month period. When serum Hcy and Cys levels were both above the 5th quintile of distribution at baseline, there was a reduction of 3.65 mg/dl (p < 0.01) in mean HDL-cholesterol and an increase of 3.53 mg/dl (p < 0.01) in mean triglyceride levels in the 12 months of follow-up. CONCLUSIONS: High baseline serum Hcy and Cys levels resulted in a reduction in mean HDL-cholesterol levels and an increase in mean triglycerides levels over the 12 months of follow-up in children and adolescents, with these alterations being greater when these two biochemical parameters were simultaneously high at baseline. PMID- 30014865 TI - Flavonoid rich dark cocoa may improve fatigue in people with multiple sclerosis, yet has no effect on glycaemic response: An exploratory trial. AB - CONTEXT: Current research suggests that dark cocoa may reduce fatigue; however, the effect on fatigue in people with MS (pwMS) has never been established. The objective of this feasibility study was to explore the acute effect of high flavonoid cocoa on measures of fatigue and glycaemic response. METHODS: This was a randomised crossover participant blind exploratory study in 12 participants (2 male and 10 female) with MS-related fatigue (>4 on the Fatigue Severity Scale; FSS). After fasting overnight, participants consumed the high flavonoid cocoa drink (350 mg gallic acid equivalents {GAE}/g) or a low flavonoid cocoa control (120 mg GAE/g), consuming the alternative drink on the next visit. Fatigue was self-reported on a 100 mm visual analogue scale at 30-min time intervals for 2 h post cocoa consumption and every 2 h for the rest of the day. Fatigability was monitored using a 6 min walk test (6MWT) at the end of the visit (2 h), and activity monitors worn for 24 h commencing at 12 noon on the day of testing. The feasibility of performing the trial including outcome measures was documented. RESULTS: A moderate effect was found in self-reported fatigue throughout the day in favour of the high flavonoid group (Cohen's d 0.32, 95% non-central t CI -0.57 to 1.20). Fatigability measures did not change. Participants consumed and enjoyed the cocoa, all participants completed the study and outcome measures were accepted. CONCLUSION: The results of this study support further trials to investigate the feasibility and efficacy of pure cocoa as a dietary supplement for fatigue in pwMS. PMID- 30014866 TI - Time to revisit the strategy of massive vitamin A prophylaxis dose administration to the under five children in India - An analysis of available evidence. AB - Childhood blindness due to corneal ulceration has historically been prevalent among poor Indian children. To tackle this situation the National Institute of Nutrition (NIN), Hyderabad, India, launched (after field-testing) massive dose based national vitamin A (Vit-A) prophylaxis program. Over a period of time reduction in childhood mortality was also hailed as a beneficial effect of the program. Data from the Indian Council for Medical Research (ICMR) indicate that in most Indian states there has been a gradual reduction in the prevalence of Bitot's spots. However, it was not attributed to the prophylaxis program because of its low and patchy coverage. It was, rather, attributed to the control of malnutrition, along with measles vaccination and improvement in healthcare access. Various studies have concluded that massive dose vitamin A prophylaxis does not reduce childhood mortality; this may have been due to the Hawthorne effect; whereby beneficial effects arose from frequent contact of health workers with community members. Paradoxically, harmful effects of massive doses of Vit-A are documented, e.g. acute toxicity in certain groups of children, ranging from increased intracranial pressure, mental retardation (postnatal period), and even death. Vit-A also intensifies bone demineralization, and increased levels can lead to calcium deficiency and, hence, growth retardation in vulnerable children. According to the present authors, for children who have Bitot's spots or who have just recovered from an attack of measles, the best approach is to give Vit-A in therapeutic doses along with adequate daily intake of vegetables and fruits. Public-spirited citizens, along with the scientific community, must ensure the scrapping of the universal massive dose Vit-A prophylaxis approach, to avoid Vit A toxicity and reduce economic burden to the health system. PMID- 30014861 TI - Strength in diversity: Understanding the pathways to herpes simplex virus reactivation. AB - Herpes simplex virus (HSV) establishes a latent infection in peripheral neurons and can periodically reactivate to cause disease. Reactivation can be triggered by a variety of stimuli that activate different cellular processes to result in increased HSV lytic gene expression and production of infectious virus. The use of model systems has contributed significantly to our understanding of how reactivation of the virus is triggered by different physiological stimuli that are correlated with recrudescence of human disease. Furthermore, these models have led to the identification of both common and distinct mechanisms of different HSV reactivation pathways. Here, we summarize how the use of these diverse model systems has led to a better understanding of the complexities of HSV reactivation, and we present potential models linking cellular signaling pathways to changes in viral gene expression. PMID- 30014867 TI - Malnutrition in the elderly and its effects on bone health - A review. AB - This article aims to provide an overview of the prevalence, causes and risk factors associated with malnutrition in the elderly. It includes the clinical consequences and economic impact of malnutrition in the elderly and in particular the osteoporotic population. It encompasses the significance of dietary protein and its effects on bone health. PMID- 30014868 TI - Undernutrition and obesity among elderly people living in two cities of developing countries: Prevalence and associated factors in the EDAC study. AB - BACKGROUND: Nutritional status among elderly people living in Sub-Saharan Africa is poorly studied, even though undernutrition and obesity are known to cause many complications and are risk factors for progression and death in several diseases. The aims of this study were to assess the nutritional status of the elderly in Central Africa and to study the factors associated with nutritional disorders (undernutrition and obesity). METHODS: Two cross-sectional population-based studies were carried out in the capitals of Central African Republic (CAR) and Republic of Congo (ROC) between 2008 and 2009. Participants were aged >=65 years old and underwent nutritional assessment including the following measurements: weight, height, body mass index (BMI), waist circumference (WC). Diet was also investigated. Nutritional status was defined according to the WHO BMI classification (<18.5 = undernutrition; >=30 = obesity). Multinomial regression analysis was performed in order to identify factors associated with nutritional status. RESULTS: 990 elderly people underwent nutritional assessment (482 in CAR and 508 in ROC). Mean BMI was 22.7 +/- 4.8 kg/m2. The prevalence of undernutrition was 19.2% and was lower in ROC than in CAR (9.5% vs. 29.5%; p < 0.0001). The prevalence of obesity was 8.8% and was higher in ROC than in CAR (14.6% vs. 2.7%; p < 0.0001). The mean WC was 85.3 +/- 28.4 cm. Adjusted on study site, increasing age (OR = 1.6 [95% CI: 1.1-2.3] for 75-84 years, OR = 2.6 [95% CI: 1.4-4.8] for 85+ years), occupation as farmer/breeder (OR = 2.2 [95% CI: 1.1 4.2]), smoking (OR = 1.71 [95% CI: 1.14-2.56]) and low sugar consumption (OR = 1.7 [95% CI: 1.1-2.7]) were positively associated with undernutrition whereas only female sex was positively associated with obesity (OR = 5.0 [95% CI: 2.2 11.0]). CONCLUSIONS: The prevalence of undernutrition is high in the elderly population of these countries, in contrast to obesity. Undernutrition and obesity are associated with different socio-economic factors and food consumption. Simple nutritional advice could contribute to improving the nutritional status of elderly people in Central Africa. PMID- 30014869 TI - Comprehensive comparison of malnutrition and its associated factors between nursing home and community dwelling elderly: A case-control study from Northwestern Iran. AB - BACKGROUND & AIMS: Only a limited number of studies have compared nursing home and community residing elderly in terms of health-related issues. The present study aimed to compare nutritional status and its associated factors between nursing home residents and community-dwelling seniors. METHODS: In this case control, age- and gender-matched study in Tabriz (East Azarbaijan, Iran), elderly subjects aged 65 years and older were recruited from nursing homes (n = 76) and community (n = 88). Anthropometric, blood pressure and dietary intake measurements, as well as biochemical assays were performed. Nutritional status (Mini Nutritional Assessment: MNA), cognitive function (Mini Mental State Examination: MMSE) and physical performance (Barthel Index) were assessed and compared between the two settings. RESULTS: Nursing home residents had significantly lower body mass index (BMI), limbs, waist and hip circumferences, and diastolic blood pressure. Caloric and protein intake of the groups were similar, while nursing home residents received lower amounts of many micronutrients and saturated fats and higher polyunsaturated fats. MNA, MMSE and Barthel index scores were significantly different between the groups, all of them in favor of the free living elderly (p < 0.001, p < 0.001 and p = 0.014, respectively). Laboratory tests revealed significantly lower levels of hemoglobin, folate, fasting blood sugar, insulin, albumin, prealbumin, creatinine and uric acid in the nursing home group; however, mean cell volume (MCV) and HDL cholesterol were higher in this group. CONCLUSION: Elderly people living in nursing homes have lower BMI, suffer from many nutritional deficiencies and are predisposed to malnutrition, impaired cognition and deteriorating physical performance, compared to community dwelling seniors. PMID- 30014870 TI - Removal of percutaneous endoscopic gastrostomy tubes in adults using the "cut and push" method: A systematic review. AB - BACKGROUND: PEG tubes are inserted for long term enteral feeding and may need to be removed at some point post insertion. A recognized method to remove the PEG is the cut and push method (CP). Some studies have suggested that CP is safe whilst others have reported complications and death. Subsequently the use of CP is not uniform but, if safe, could provide a cost effective, minimally invasive, alternative to gastroscopy. The aim of this study was to locate and critically appraise all publications relevant to CP in adult patients using a systematic approach. METHOD: Systematic searching of electronic databases Embase, Medline and Cinahl, using keywords in title and abstracts. Exclusions were: non-human, under 18 years of age, English language. Time limits were not applied. Preliminary searching gave 538 hits that were then hand reviewed for relevance. Selected studies were critically appraised and data summarized into tables for use in the review. RESULTS: 27 records were included in the review spanning from 1990-2014. A total of 21 case reports detailing complications in 24 individuals, including 5 deaths. There were 5 cohort studies and 1 case report detailing the safe use of CP, with 3 complications. Cases totalled 373 with 27 complications (7%). Most common complication was gastrointestinal obstruction, usually occurring in the first 6 months post CP. A history of bowel surgery was evident in some cases where obstruction occurred. The majority of cohort studies reported the use of assessment criteria to exclude those at risk of obstruction and reported low complication rates. CONCLUSIONS: The quality and quantity of the evidence on CP is insufficient to make recommendations for clinical practice. Further research is needed to evaluate the effectiveness of CP. PMID- 30014871 TI - Seasonality of nutrient intake - An analysis including over 44,000 participants in 4 countries. AB - BACKGROUND AND AIMS: Dietary intake is believed to follow a seasonal pattern, so adjusting for seasonality in nutritional epidemiology is usually requested. The aim of this study was to assess the seasonality of energy and macronutrients intake (expressed as % of total caloric intake) using a large set of population based studies. METHODS: Cross-sectional data from 9 population-based studies from 4 countries (3 in the Northern Hemisphere and 1 in Southern Hemisphere), with a total sample size of 44,611 subjects. Data were derived from FFQ or repeated 24 h recalls. Dietary markers included total energy intake, protein, carbohydrates, fat, alcohol, sugars and fatty acids (saturated, mono and poly-unsaturated). Seasonality was assessed using the cosinor method stratifying on hemisphere and gender. RESULTS: Most nutrients did not show a significant seasonal variation. When individual studies were considered, the number of nutrients showing significant seasonal variations varied from 5 to none in men and from 6 to none in women. Jointly, in the Northern hemisphere, significant seasonal variations were found for sugar intake in both genders and for alcohol consumption in men only; in the Southern Hemisphere, significant seasonal variations were found for fat and monounsaturated fatty acids in women. Analysis of the three consecutive periods of the Bus Sante study in Switzerland showed that the number of significant seasonal variations decreased from 5 in 1993-1999 to 1 in 2006-2012 in men, and from 6 in 1993-1999 to none in 2006-2012 in women. Seasonal variation decreased over time for most nutrients, with the exception of monounsaturated fatty acids in men. CONCLUSIONS: Seasonality of energy and macronutrients intake varies considerably according to study, with no common pattern and small magnitude of variation. Its amplitude appears to be declining over time. Systematic adjustment for season might not be necessary when assessing the effects of total energy and macronutrient intake on disease. PMID- 30014873 TI - Lower skeletal muscle attenuation and high visceral fat index are associated with complicated disease in patients with Crohn's disease: An exploratory study. AB - BACKGROUND AND AIMS: The prognostic value of body composition analysis in patients with Crohn's disease (CD) is poorly explored. The aims of the present study were to assess fat and skeletal muscle compartments including muscle radiation attenuation (MA) in patients with CD, and to analyze its predictive value to identify complicated phenotypes. METHODS: Seventy one patients with CD who have had an abdominal CT within one month of clinical, laboratory, and endoscopic evaluation were included. Skeletal muscle area (SMA) and index (SMI), visceral fat area (VFA) and index (VFI), subcutaneous fat area (SFA), and mean MA were measured using appropriate software. Sarcopenia, as defined by Martin's criteria was assessed. Montreal classification was used to characterize disease phenotype. RESULTS: Mean MA was lower in patients >40 years (p = 0.001), L2 (p = 0.09) and stricturing/penetrating disease (p = 0.03) whereas SMA and SMI were significantly lower in patients with positive C-reactive protein and previous hospital admissions (p < 0.01). On multivariate analysis, higher MA was protective against the complicated disease phenotype (stricturing/penetrating disease and/or previous surgeries) (OR 0.81; p = 0.002) whereas a high visceral fat index increased such risk (OR 26.1; p = 0.02). A ROC curve showed a 82.4% sensibility, 90.3% specificity, 17.6% positive predictive value, 9.7% negative predictive value and an area under the curve (AUC) of 0.91 for body composition analysis to predict complicated disease. CONCLUSIONS: A lower muscle attenuation and a high visceral fat index seem to be associated with more severe phenotypes in patients with CD. PMID- 30014874 TI - Corrigendum to "Association between adductor pollicis muscle thickness, anthropometric and immunological parameters in HIV-positive patients" [Clin Nutr ESPEN 17 (2017) 105-109]. PMID- 30014875 TI - Measures of adiposity differentially correlate with C-reactive protein among persons with multiple sclerosis. AB - BACKGROUND: While MS is considered, in part, an inflammatory disease, the relationship between measures of adiposity and MS have not been well studied. This is important considering the strength of the association between adiposity and inflammation reported in the general population, and the resultant increased risk for cardiovascular and metabolic disease. Evidence demonstrates MS is associated with higher prevalence rates of cardiovascular disease than the general population, which provides an impetus to examine how measures of adiposity and systemic inflammation are related in individuals with MS. OBJECTIVE: To examine the association between measures of adiposity and systemic inflammation, specifically using the global marker C-reactive protein (CRP), among persons with MS compared with a control group without MS. METHODS: Persons with MS and a control group (n = 33/group) had measures of adiposity (body mass index, total body fat, and trunk fat) correlated and regressed to CRP. RESULTS: Differential relationships between CRP and adiposity measures were observed between the MS group and the control group. Within the MS group, when adjusted for sex, age, and physical activity level, only whole body percent fat explained a significant portion of the variance in CRP (adjusted R2 = 0.095, p < 0.05), whereas all of the adiposity measures explained a significant degree of variance within the control group (p < 0.05), with trunk fat mass having the strongest correlation. CONCLUSIONS: The differential relationships observed between the MS and control groups suggests that whole body fat may be a more important factor related to whole body inflammation in MS, rather than other adiposity markers, such as BMI or trunk fat. This differential association should be taken into account in future research examining body fatness/obesity and CRP. PMID- 30014872 TI - Italian pediatric nutrition survey. AB - INTRODUCTION: the prevalence of malnutrition in children and its impact on clinical outcomes is underrecognized by clinicians in Italy as well as worldwide. A novel definition of pediatric malnutrition has been recently proposed by a working group of the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), based on the correlation between illness and the use of zscores of anthropometric measurements. AIM: to investigate the prevalence of malnutrition and related nutritional support among hospitalized children in Italy, in a nationwide survey performed in a single day (16/4/2015). METHODS: an open access website (http://nday.biomedia.net) was used to collected data from 73 hospitals and 101 wards in 14 Italian regions (1994 patients). Anonymous information was collected on hospitals' characteristics, patient's anthropometry, admission diagnosis, presence of chronic diseases and use of nutritional support: oral nutritional supplements (ONS), enteral nutrition (EN) or parenteral nutrition (PN). Z-scores of anthropometric measurements, calculated with Epi Info 7.1.5, defined nutritional status: wasting was identified by BMI or Weight-for-Length z-score (<-1 mild, <-2 moderate, <-3 severe), stunting by Height-for-Age Z-score <-2. WHO 2006 and CDC 2000 growth charts were used respectively for children younger and older than 2 years old. RESULTS: 1790 complete records were obtained for hospitalized patients aged 0-20 years, with median age 6.16 (0.1-20 years and 53.3% males). 52.9% were aged 0-6 years and 58.8% of children suffered from chronic diseases. Wasting was detected in 28.7% of the total sample with higher occurrence observed in age ranges 0-6 and 14-20 years, while 17.3% of patients showed stunting; surprisingly almost 27% of them were aged 0-2. A ranking of the admission diagnosis with the highest rate of malnutrition was complied. The prevalence of wasting was significantly (p < 0.005) higher amongst children with chronic diseases (34.1% vs. 27.1%); stunting prevalence tripled in patients with chronic disease (24.5% vs. 8.3%). Only 23.5% of malnourished children (17%, 25.6% and 36.7%, respectively mild, moderate and severe malnutrition) received nutritional support: 11.7% received oral nutrition supplements (ONS, modular or complete), 11.5% enteral nutrition (EN, 6.4% via nasogastric tube, 5.1% via gastrostomy) and 6.8 % received parenteral nutrition (PN); in some patients a combination of two. Nutritional support is more commonly used among stunting patients, 39.5% of children under treatment. CONCLUSION: Malnutrition of any grade was observed in nearly 1/3 and stunting in 17% of the reported hospitalized children, and it is likely to be underrecognized as the nutritional support reached only a small part of the malnourished children. PMID- 30014876 TI - Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis. AB - BACKGROUND: There is limited evidence about the optimal length of washout when switching from natalizumab to fingolimod. OBJECTIVE: To study if a washout period of 4 weeks is associated with less disease activity compared to 8 weeks. METHODS: 25 patients with Relapsing Remitting Multiple Sclerosis were included in an open label, prospective study with a follow-up of 108 weeks. The primary endpoint (PE) was defined as "time to first relapse or MRI disease activity up to week 56". In addition, a recurrent event analysis (REA) was performed up to week 108. RESULTS: The PE was not met (HR 0.67, 95% CI [0.22,1.97], p = 0.462). Number of relapses before stopping natalizumab was positively associated with the hazard of relapse (HR 3.91, p = 0.0117, 95% CI [1.36, 11.28]). The REA showed a reduction of the hazard to develop a relapse by 77% (HR 0.23, 95% CI [0.08, 0.69], p = 0.00854) in favor of the cohort with 4 weeks washout. CONCLUSIONS: Our study suggests that switching from natalizumab to fingolimod with a shorter washout of 4 weeks might reduce the risk of disease reactivation after switching. PMID- 30014877 TI - Cardiovascular conditions in persons with multiple sclerosis, neuromyelitis optica and transverse myelitis. AB - BACKGROUND: Cardiovascular conditions are associated with poorer outcomes in multiple sclerosis (MS). Whether the burden of cardiovascular conditions differs between those with demyelinating disease and unaffected controls is not clear. The objective of this study is to investigate the burden and age of onset of cardiovascular conditions in a US population with MS, neuromyelitis optica spectrum disorder (NMOSD), or transverse myelitis (TM) to unaffected controls adjusting for likely confounders. METHODS: Using a case-control study design, we compared the burden of self-reported diabetes mellitus type 2, heart disease, hyperlipidemia, and hypertension in cases with MS (N = 1,548), NMOSD (N = 306), and TM (N = 145) to controls (N = 677), adjusting for demographics, smoking history, obesity, family history of individual cardiovascular conditions, and presence of other cardiovascular conditions. The age of onset for individual cardiovascular conditions were also compared between cases and controls. RESULTS: MS cases were 48% more likely to have ever had hypertension than controls (p = 0.01). The prevalence of other cardiovascular conditions did not differ across cases and controls. There were also no differences in the age of cardiovascular disease onset between cases and controls. CONCLUSION: Cardiovascular conditions are as common in those with demyelinating diseases compared to unaffected individuals, with hypertension being more common among those with MS. PMID- 30014878 TI - Protective effects of hydro-ethanolic extract of Terminalia chebula on primary microglia cells and their polarization (M1/M2 balance). AB - Teminalia chebula (TC) has been traditionally used in the Iranian traditional medicine (ITM) and Ayurvedic medicine primarily for neurologic disorders and inflammation. Mainly, its fruits have been applied for CNS disorders. The effects of Terminalia chebula as herbal medicine with anti-inflammatory and anti-oxidant properties were aimed on lipopolysaccharide (LPS)-induced microglial inflammation. Cytotoxicity of TC extract (0-80) ug/ml on microglial cells was evaluated using the MTT assay. Also, the protective effect of TC extract concentrations with specified amount of LPS-induced mice microglial cells was studied. The concentrations of TNF-alpha (Tumor Necrosis Factor-alpha), IL-1beta (Interleukin-1beta), IL-6 and PGE-2 (Prostaglandin-E2) were evaluated using ELISA. Gene expression of TNF-alpha, IL-1beta, IL-6, COX-2 (Cyclooxygenase-2), iNOS and arginase-1 was also evaluated using the Real-Time PCR method. Nitrite oxide and urea were measured using biochemical methods. The studied concentrations of TC extract did not affect the viability of microglial cells but significantly protected the viability after treatment with LPS. The concentrations and expression levels of pro-inflammatory factors (TNF-alpha, IL 1beta, IL-6, PGE-2, COX-2) were significantly decreased after TC extract treatment in LPS-induced microglial cells with dose dependent manner. The extract also significantly decreased the levels of nitric oxide, increased urea and down regulated the expression of nitric oxide synthesis while arginase-1 expression was enhanced. Our results suggest that TC extract reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system inflammatory diseases. PMID- 30014879 TI - Streptococcus suis serotype 3 and serotype 18 capsular polysaccharides contain di N-acetyl-bacillosamine. AB - Streptococcus suis serotype 3 is counted among the S. suis serotypes causing clinical disease in pigs. Yet, limited information is available on this serotype. Here we determined for the first time the chemical composition and structure of serotype 3 capsular polysaccharide (CPS), a major bacterial virulence factor and the antigen at the origin of S. suis classification into serotypes. Chemical and spectroscopic data gave the repeating unit sequence for serotype 3: [4)D-GlcA (beta1-3)d-QuiNAc4NAc(beta1-]n. To the best of our knowledge, this is the first report of di-N-acetyl-d-bacillosamine (QuiNAc4NAc) containing polysaccharides in Streptococci and the second time this rare diamino sugar has been observed in a Gram-positive bacterial species since its initial report. This led to the identification of homologues of UDP-QuiNAc4NAc synthesis genes in S. suis serotype 18. Thus, the repeating unit sequence for serotype 18 is: [3)d GalNAc(alpha1-3)[d-Glc (beta1-2)]d-GalA4OAc(beta1-3)d-GalNAc(alpha1-3)d QuiNAc4NAc(alpha1-]n. A correlation between S. suis serotypes 3 and 18 CPS sequences and genes of these serotypes' cps loci encoding putative glycosyltransferases and polymerase responsible for the biosynthesis of the repeating unit was tentatively established. Knowledge of CPS structure and composition will contribute to better dissect the role of this bacterial component in the pathogenesis of S. suis serotypes 3 and 18. PMID- 30014880 TI - The level of reporting of neurocognitive outcomes in randomised controlled trials of brain tumour patients: A systematic review. AB - BACKGROUND: Neurocognitive impairment is frequently present in brain tumour patients and is therefore considered an important outcome in brain tumour research. To use neurocognitive outcomes (NCO) in clinical decision-making, neurocognitive evidence should be of sufficiently high quality. We aimed to investigate the level of neurocognitive functioning reporting in randomised controlled trials (RCTs) in brain tumour patients. METHODS: We conducted a systematic literature search in several databases up to August 2017. Of the selected relevant RCTs, the following data were retrieved: basic trial demographics and NCO characteristics, quality of NCO reporting and risk of bias. We also analysed studies that should impact clinical decision-making based on their quality of reporting. RESULTS: We identified 65 RCTs, of which NCO was the primary end-point in 14 (22%). Important methodological limitations were related to the documentation of statistical approaches for dealing with missing data and to discussing limitations and generalisability issues uniquely related to the NCO components. Risk of bias was high regarding blinding of personnel and incomplete outcome data. Twenty RCTs (31%), eight with NCO as primary end-point and 12 as secondary end-point, satisfied a sufficient number of criteria to be classified as 'high-quality' NCO evidence. Most of these studies did contribute to clinical decision-making. CONCLUSION: Investigators involved in brain tumour research should give attention to methodological challenges related to NCO reporting as identified in this review, as 'high-quality' reporting of NCO evidence can be of value in clinical decision-making. PMID- 30014881 TI - Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme. AB - AIM: This analysis evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous non small-cell lung cancer (NSCLC) enrolled in the expanded access programme (EAP) in Italy. METHODS: Nivolumab was available on physician request. Safety data included adverse events (AEs). Efficacy data included investigator-assessed tumour response, progression date and survival information. Results were analysed for patients aged <65, 65-<75 and >=75 years and for the overall population. RESULTS: A total of 371 patients with squamous NSCLC were enrolled at 96 centres between April 2015 and September 2015; 34% (n = 126), 47% (n = 175) and 19% (n = 70) were aged <65, 65-<75 and >=75 years, respectively. Efficacy was similar among patients aged <65, 65-<75 and >=75 years and the overall population (objective response rates: 18%, 18%, 19% and 18%, respectively; disease control rates: 49%, 47%, 43% and 47%, respectively). Median overall survival was reduced in patients aged >=75 years (5.8 months) versus patients aged <65; years (8.6 months), patients aged 65-<75 years (8.0 months) and the overall population (7.9 months). The incidence of grade 3-4 treatment-related AEs was low in patients aged 65, 65-<75 and >=75 years and the overall population (3%, 9%, 3%, 6%, respectively). Discontinuation rates due to treatment-related AEs were low irrespective of age (4-5%). CONCLUSIONS: These EAP results suggest that elderly patients with advanced squamous NSCLC benefit from nivolumab, with tolerability similar to that in the overall population. PMID- 30014883 TI - Mapping the European cancer research landscape: An evidence base for national and Pan-European research and funding. AB - BACKGROUND: Cancer research is among the most active biomedical research domains for the European Union (EU). However, little quantitative empirical evidence is available to guide the decisions on the choice of disease site to study, specific research domain focus or allocation of research resources. To inform national/supranational cancer research policy, high-resolution intelligence is needed. METHODS: We performed a bibliometric analysis of European cancer research papers in the Web of Science from 2002 to 2013 to quantify research activity in each of the 28 EU Member States, along with Iceland, Norway and Switzerland (EUR31), which cancer sites/research domains they addressed, and their sources of financial support (2009-2013). FINDINGS: Cancer research papers from EUR31 correlated well with national Gross Domestic Products (r2 = 0.94). However, certain cancer sites (lung, oesophagus and pancreas) were under-researched relative to their disease burden, whereas central nervous system and blood cancers were more generously supported than their burden would warrant. An analysis of research domains indicated a paucity of research on radiotherapy (5%), palliative care (1.2%) and quality of life (0.5%). European cancer research funding in 2012-2013 amounted to ~?7.6 billion and came from diverse sources, especially in western Europe/Scandinavia, where in nine countries the charitable sector outspent the government but not in Eastern Europe where charitable research funding barely exists. INTERPRETATION: Several countries need to increase their cancer research outputs substantially, and/or alter their research portfolios to better match their growing (and changing) cancer burden. More co ordination among funding agencies is required, so that resources can be attuned to align activities to research gaps and perceived clinical needs. In Eastern Europe, the charitable funding sector needs to be developed, so that both public and patient advocacy can have an active role in research. PMID- 30014882 TI - Predicting early death in older adults with cancer. AB - BACKGROUND: Predicting early death after a comprehensive geriatric assessment (CGA) is very difficult in clinical practice. The aim of this study was to develop a scoring system to estimate risk of death at 100 days in elderly cancer patients to assist the therapeutic decision. METHODS: This was a multicentric, prospective cohort study approved by an ethics committee. Elderly cancer patients aged older than 70 years were enrolled before the final therapeutic decision. A standardised CGA was made before the treatment decision at baseline. Within 100 days, event (death), oncologic and geriatric data were collected. Multivariate logistic regression was used to select the risk factors for the overall population. Score points were assigned to each risk factor using the beta coefficient. Internal validation was performed by a bootstrap method. Calibration was assessed with the Hosmer-Lemeshow goodness of fit test and accuracy with the mean c-statistic. FINDINGS: One thousand fifty patients (mean age: 82 years) joined the study from April 2012 to December 2014. The independent predictors were metastatic cancers (odds ratio [OR] 2.5; 95% confidence interval [CI], [1.7 3.5] p<0 .001); gait speed<0.8 m/s (OR 2.1; 95% CI [1.3-3.3] p=0.001); Mini Nutritional Assessment (MNA) < 17 (OR 8; 95% CI; [3.7-17.3] p<0.001), MNA <=23.5 and >= 17 (OR 4.4; 95% CI, [2.1-9.1) p<0.001); performance status (PS) > 2 (OR 1.7; 95% CI, [1.1-2.6)] p=0.015) and cancers other than breast cancer (OR 4; 95% CI, [2.1-7.9] p<0.001). We attributed 4 points for MNA<17, 3 points for MNA between <=23.5 and >= 17, 2 points for metastatic cancers, 1 point for gait speed <0.8 m/s, 1 point for PS > 2 and 3 points for cancers other than breast cancer. The risk of death at 100 days was 4% for 0 to 6 points, 24% for 7 to 8 points, 39% for 9 to 10 points and 67% for 11 points. INTERPRETATION: To our knowledge, this is the first score which estimates early death in elderly cancer patients. The system could assist in the treatment decision for elderly cancer patients. PMID- 30014884 TI - Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis. AB - INTRODUCTION: Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin-bound paclitaxel and gemcitabine (nab P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia. METHODS: We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of >=1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2-3 mg/dl, B: >3-5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed. RESULTS: Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41-79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8-14.0) months; for A: 11.8 (95% CI: 6.5-16.5), B: 9.2 (95% CI: 1.1 - NA) months and C 11.8 (95% CI: 5.9-20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13). CONCLUSION: Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting. PMID- 30014885 TI - Peritoneal and extraperitoneal relapse after previous curative treatment of peritoneal metastases from colorectal cancer: What survival can we expect? AB - INTRODUCTION: Over the last 20 years, complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) dramatically increased the survival of patients with colorectal peritoneal metastases (CRPM). However, despite better knowledge of the disease, around 70% of patients relapse after CRS with HIPEC. This study was designed to analyse the pattern of recurrence and the outcomes of different treatment modalities. METHODS: Patients relapsing after CRS plus HIPEC for CRPM were selected from a prospective database. The impact of iterative curative-intent treatments was analysed using Kaplan-Meier estimates and multivariate Cox regression models. RESULTS: Between April 1993 and December 2014, 190 of 274 (69%) patients previously treated by CRS plus HIPEC developed relapse, as an isolated peritoneal recurrence (31%), isolated distant recurrence (35%), or multisite recurrence (34%). The curative intent treatment rate was 48% for isolated peritoneal recurrences, 49% for isolated distant recurrences and 22% for multisite recurrences (p = 0.002). From the diagnosis of relapse, 3- and 5-year overall survival were 77% and 46% after curative-intent treatment and 14% and 4.7% after non-curative treatment, with median survival of 59.7 and 18.3 months (log-rank p < 0.0001), respectively. Regression analysis identified the initial extent of CRPM (hazard ratio [HR]: 2.25; p < 0.0001), iterative curative-intent treatment (HR: 0.22; p < 0.0001) and disease-free interval (HR: 1.77; p = 0.01) as independent predictors of prolonged survival. CONCLUSIONS: Iterative curative-intent treatment can be performed in up to 40% of patients with relapse after CRS and HIPEC for CRPM, and is associated with prolonged survival in selected patients. PMID- 30014886 TI - Corrigendum to "Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study" [Drug Alcohol Depend. 162 (2016) 245-250]. PMID- 30014889 TI - SUMOylation: re-wiring the plant nucleus during stress and development. AB - Conjugation of small ubiquitin-related modifier (SUMO) to intracellular proteins provides a dynamic regulatory mechanism that enables plants to rapidly defend against environmental challenges. SUMOylation of mostly nuclear proteins is among the fastest stress responses observed but precisely how this post-translational modification provides stress resilience remains unclear. Here, we describe the plant SUMO system and its expanding target catalog, which implicates this modification in DNA repair, chromatin modification/remodeling, transcriptional activation/repression, epigenetics, and RNA metabolism, with a likely outcome being extensive nuclear re-wiring to withstand stress. In parallel, studies have linked SUMO to developmental programs such as gametogenesis and gene silencing. The accumulating data support the notion that SUMOylation substantially influences the transcriptional and epigenetic landscapes to promote stress tolerance and developmental progression. PMID- 30014887 TI - Factors associated with perceived loss of libido in people who inject opioids: Results from a community-based survey in France. AB - BACKGROUND: Regular consumption of opioids exposes individuals to several side effects. One of these is a loss of libido, which has a negative impact on quality of life. We used a cross-sectional community-based survey of people who inject opioids to study factors associated with loss of libido, and more particularly the impact of the type of opioid injected. METHODS: This secondary study was conducted throughout France in 2015 and involved 514 people who inject opioids. Self-reported sociodemographic characteristics, drug consumption, injection related data and loss of libido were collected using a brief questionnaire administered either through face-to-face interviews or online. Two different models were used to identify factors associated with loss of libido: simple logistic regression and a two-step Heckman model. RESULTS: Forty-three percent of the participants reported a loss of libido. The first model showed that filling in the questionnaire online (OR[95%CI] = 2.55[1.64;3.96]; p < 0.001), reporting that morphine sulfate (OR[95%CI] = 2.67[1.56;4.58]; p < 0.001) or methadone (OR[95%CI] = 2.50[1.13;5.56]; p = 0.030) was the opioid they injected most (versus buprenorphine), and reporting benzodiazepine use (OR[95%CI] = 1.62[1.07;2.44]; p = 0.033) were factors strongly associated with loss of libido. In the two-step, Heckman model which corrected for selection bias, along with these factors, reporting heroin as the opioid injected most was also strongly associated. CONCLUSION: Our findings showed that full-opioid agonists could have a negative impact on libido when injected regularly. Libido can improve quality of life and should be routinely discussed through counseling in prevention services with people who inject drugs. PMID- 30014888 TI - From signals to stem cells and back again. AB - During plant development, organ morphology and body architecture are dynamically adjusted in response to a changing environment. This developmental plasticity is based on precisely controlled maintenance of primary, as well as programmed initiation of pluripotent stem cell populations during secondary- and de novo meristem formation (reviewed in [1-3]). Plant stem cells are found exclusively in specific locations that are defined by relative position within the growing tissue. It follows that stem cell fate is primarily instructed by endogenous signals that dynamically define the stem cell niche in response to tissue topography [4]. Furthermore, plant stem cell activity is strongly dependent on developmental stage, suggesting that they are sensitive to long range signaling from distant organs, including the root [5,6**]. And finally, environmental signals exert a major influence allowing plants to cope with the plethora of highly variable environmental parameters during their life-cycle [7]. Integrating tissue level positional information with long range developmental cues, as well as environmental signals requires intricate molecular mechanisms that allow to filter, classify, and balance diverse inputs and translate them into appropriate local cell behavior. In this short review, we aim to highlight advances in identifying the relevant signals, their mode of action, as well as the mechanisms of information processing in stem cells of the shoot apical meristem (SAM). PMID- 30014890 TI - Irreversible strigolactone recognition: a non-canonical mechanism for hormone perception. AB - Unveiling of hormone perception is central to comprehending hormone action. It is generally recognized that an active hormone molecule binds its receptor to initiate hormone signaling, subsequently dissociates from its receptor without being changed, and then initiates the next round of hormone perception. However, recent studies discovered that the alpha/beta hydrolase DWARF14 serves as a non canonical receptor for the plant hormone strigolactone (SL) to generate the active form of SL which remains covalently bound in an irreversible manner, triggering SL signal transduction. In this short review, we will discuss the recent advances in uncovering this unprecedented non-canonical mechanism for hormone perception. PMID- 30014891 TI - Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding. AB - Klotho is an anti-aging protein that is engaged in the suppression of canonical WNT signaling. In this study, we investigated the expression pattern of human WNTs and Klotho in the pancreatic cancer. In the cancerous cells, WNT-1 exhibited much higher expression as compared to other WNTs, while no WNT expression was detected in the normal tissue. In contrast, Klotho expression was significantly low in the cancerous tissue. Based on these observations, we intended to explore Klotho binding to WNT-1 and cystein-rich domains (CRDs) of Frizzled (FZD) homologs through molecular docking and dynamics simulation assays. Interestingly, similar region of WNT-1 was detected in binding with Klotho and CRDs of FZD-1/2. FZD-CRDs were grasped by the association of peripheral hydrophobic residues of WNT-1 U-shaped cavity. Subsequently, WNT-1-bound Klotho-peptides were isolated and reevaluated for their binding abilities against WNT-1 and FZD-CRDs., The conformational readjustements of these complexes were deeply analyzed by calculating the size of WNT-1 U-shaped cavity. In comparison to apo-WNT-1, cavity opening was markedly enhanced (8.2 A to 15.64 A, 32.89 A and 35.11 A) in WNT-1-a, WNT-1-c and WNT-1-e complexes, respectively. Thus Klotho-derived peptides may facilitate distinct conformational changes in the WNT-1-FZD associated region. As a result, aberrant loss of FZD binding may lead to augment WNT signaling. Overall, current study opens up new avenues in the pancreatic cancer therapeutics through antagonizing WNT-1 by Klotho. PMID- 30014892 TI - The hydrolysis of 6-phosphogluconolactone in the second step of pentose phosphate pathway occurs via a two-water mechanism. AB - Hydrolysis reaction marks the basis of life yet the mechanism of this crucial biochemical reaction is not completely understood. We recently reported the mechanisms of hydrolysis of nucleoside triphosphate and phosphate monoester. These two reactions hydrolyze P-O-P and P-O-C linkages, respectively. Here, we present the mechanism of hydrolysis of delta-6-phosphogluconolactone, which is an important precursor in the second step of the pentose phosphate pathway. Its hydrolysis requires the cleavage of C-O-C linkage and its mechanism is hitherto unknown. We report three mechanisms of hydrolysis of delta-6 phosphogluconolactone based on density functional computations. In the energetically most favorable mechanism, two water molecules participate in the hydrolysis reaction and the mechanism is sequential, i.e., activation of the attacking water molecule (OH bond breaking) precedes that of the cleavage of the CO bond of the C-O-C linkage. The rate-limiting energy barrier of this mechanism is comparable to the reported experimental free energy barrier. This mechanism has similarities with the mechanism of triphosphate hydrolysis and that of hydrolytic cleavage of DNA in EcoRV enzyme. This two-water sequential hydrolysis mechanism could be the unified mechanism required for the hydrolysis of other hydrolysable species in living cells. PMID- 30014893 TI - On the outdoor thermal perception and comfort of a Mediterranean subject across other Koppen-Geiger's climate zones. AB - The climatic conditions characterizing the troposphere affect the outdoor activities of the population which, in turn, characterize the anthroposphere. Over the past years recent studies examined a possible analytical definition of the outdoor thermal comfort for different types of population acclimatized to their specific residency area. Thanks to the use of the MOCI (Mediterranean Outdoor Comfort Index: an index used to predict the thermal perception of the Mediterranean population in an outdoor environment), the present study aimed at analyzing the psychophysiological response of a Mediterranean subject with respect to climatic conditions different from the original ones after having experienced a quick change. Indeed, thermal stress and discomfort might affect deeply the ability of the subject to carry out outdoor activities. This condition determines the necessity of possessing useful information to plan the best period to perform a journey in distant places and/or perform useful actions that will make the outdoor activity as much comforting as possible (choosing the proper clothes with the right thermal insulation). For this reason, the worldwide environmental conditions during an average year were examined. To be more specific, this study focused its attention on the editing of seasonal spatial maps with the MOCI level curves and on the temporal analysis of the MOCI values characterizing those 6 different cities (one for each continent) reporting the higher number of foreign arrivals. PMID- 30014894 TI - Increased prevalence of essential hypertension in areas previously exposed to fallout due to nuclear weapons testing at the Semipalatinsk Test Site, Kazakhstan. AB - This study examines the association between environmental radiation exposure and essential hypertension in a series of investigated geographical districts adjacent to the Semipalatinsk nuclear test site in Kazakhstan. The sample consists of 2000 volunteers participants in screening examinations in three administrative districts close to the nuclear test site, which was carried out as part of the Government Programs on Environmental Health Hazard. The cross sectional study compares prevalence ratios in a population sample with long-term exposure in the low and intermediate dose range. Age-adjusted odds ratios for hypertension were found significantly increased with higher exposure groups. After accounting for main cardiovascular risk factors into the model and stratifying by gender, the prevalence odds ratios for radiation remained significantly increased, with a significant dose-response effect observed for some but not all subgroups. The results support existing evidence of cardiovascular health effects of radiation exposure and of persisting environmental health issues that require attention in both epidemiological surveys and healthcare provision. PMID- 30014895 TI - Exposure to tetrachloroethylene-contaminated drinking water and time to pregnancy. AB - BACKGROUND: The synthetic solvent tetrachloroethylene (PCE), commonly used in dry cleaning operations, is a human neurotoxicant and carcinogen. However, its effect on reproduction is poorly understood, as prior studies have been limited to small occupational cohorts. We examined the association between PCE exposure from contamination of the public drinking water supply and time-to-pregnancy (TTP) in a cohort of mothers from Cape Cod, Massachusetts. METHODS: The Cape Cod Family Health Study is a retrospective cohort study designed to examine the reproductive and developmental health effects of exposure to PCE-contaminated drinking water. Our analysis included 1565 women who reported 3826 planned pregnancies from 1949 to 1990. Women completed self-administered questionnaires that ascertained TTP for each of her pregnancies, regardless of the outcome, as well as residential history and demographic information. We utilized EPANET water distribution system modeling software and a leaching and transport model to assess PCE exposure for each pregnancy. We used log-binomial regression models to estimate relative risks (RR) and 95% confidence intervals (CI), adjusting for potential confounders. We performed a probabilistic bias analysis to examine the effect of outcome misclassification on our results. RESULTS: Any cumulative PCE exposure before pregnancy was associated with a 15% reduction in risk of TTP > 12 months (RR = 0.85, 95% CI: 0.70, 1.03). However, women with the highest average monthly PCE exposure around the time of the pregnancy attempt (>= 2.5 g) had increased risk of TTP > 12 months (RR = 1.36, 95% CI: 1.06, 1.76). CONCLUSIONS: We found little evidence for long-term, cumulative adverse effects of PCE exposure on TTP, but high levels of PCE exposure around the time of the pregnancy attempt were associated with longer TTP. These associations may be underestimated due to the exclusion of unsuccessful pregnancy attempts from our study population, and may be biased by outcome and exposure misclassification given the long-term recall of TTP and use of a leaching and transport model to estimate PCE exposure. PMID- 30014896 TI - Ambient air pollution and pregnancy outcomes: A comprehensive review and identification of environmental public health challenges. AB - There is a growing number of studies on the association between ambient air pollution and adverse pregnancy outcomes, but their results have been inconsistent. Consequently, a comprehensive review of this research area is needed. There was a wide variability in studied pregnancy outcomes, observed gestational windows of exposure, observed ambient air pollutants, applied exposure assessment methods and statistical analysis methods Gestational duration, preterm birth, (low) birth weight, and small for gestational age/intrauterine growth restriction were most commonly investigated pregnancy outcomes. Gestational windows of exposure typically included were whole pregnancy period, 1st, 2nd, 3rd trimester, first and last gestational months. Preterm birth was the outcome most extensively studied across various gestational windows, especially at the beginning and at the end of pregnancy. Particulate matter, nitrogen dioxide, ozone, and carbon monoxide were the most commonly used markers of ambient air pollution. Continuous monitoring data were frequently combined with spatially more precisely modelled estimates of exposure. Exposure to particulate matter and ozone over the entire pregnancy was significantly associated with higher risk for preterm birth: the pooled effect estimates were 1.09 (1.03-1.16) per 10 MUg/m3 increase in particulate matter with an aerodynamic diameter of 10 um or less (PM10),1.24 (1.08-1.41) per 10 MUg/m3 increase in particulate matter with an aerodynamic diameter of 2.5 um or less (PM2.5), and 1.03 (1.01-1.04) per 10 ppb increase in ozone. For pregnancy outcomes other than PTB, ranges of observed effect estimates were reported due to smaller number of studies included in each gestational window of exposure. Further research is needed to link the routine pregnancy outcome data with spatially and temporally resolved ambient air pollution data, while adjusting for commonly defined confounders. Methods for assessing exposure to mixtures of pollutants, indoor air pollution exposure, and various other environmental exposures, need to be developed. PMID- 30014897 TI - Adipose tissue levels of polybrominated diphenyl ethers and breast cancer risk in Chinese women: A case-control study. AB - Polybrominated diphenyl ethers (PBDEs) are suspected to be associated with breast cancer risk because of their estrogenic potencies. Epidemiological studies of PBDEs and breast cancer are scarce. Our study aimed to estimate the association between adipose-tissue PBDE concentrations and breast cancer risk. A total of 209 breast cancer cases and 165 controls were recruited from hospitals between January 2014 and May 2016 in Shantou, Chaoshan area, China. Concentrations of 14 PBDE congeners were measured in adipose tissues obtained from the breast for cases and the abdomen/breast for controls during surgery. Demographic and clinicopathologic characteristics were obtained from medical records. Breast cancer risk as well as clinicopathologic characteristics were evaluated by adipose-tissue PBDE level. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk associated with levels of PBDE congeners were estimated from logistic regression models for all cases and stratified by estrogen receptor (ER) status. Level of total PBDEs (?PBDE) and most individual PBDE congeners were higher in breast cancer cases than controls (median ?PBDE, 94.99 vs 73.72 ng/g lipid). In the adjusted univariate model for all cases, breast cancer risk was increased with both 2nd and 3rd tertiles versus the 1st tertile of BDE-47 level (OR 2.05 [95% CI 1.08-3.92]; 5.47 [2.96-10.11]) and BDE 209 level (2.48 [1.30-4.73]; 4.72 [2.52-8.83]) with trend (both P < 0.001) and with the 3rd tertile of BDE-28 level (2.83 [1.63-4.92]), BDE-99 (3.22 [1.85 5.60]), BDE-100 (5.45 [2.90-10.23]), BDE-138 (2.40 [1.37-4.20]), BDE-153 (1.74 [1.02-2.97]), BDE-154 (1.84 [1.05-3.22]), and ?PBDE levels (1.83 [1.07-3.14]) but decreased with the 3rd tertile of BDE-71 level (0.38 [0.22-0.65]) with trend (all P < 0.01). After stratifying by ER-positive or -negative status, the adjusted results were similar for ER-positive patients except for BDE-153 and BDE-154, with no statistical significance. In the multivariate model for all cases, age, menarche age, BDE-47, 71, 99, 100, 183 and 209 were independent factors associated with breast-cancer risk. ?PBDE and most individual PBDE congeners investigated were positively associated with breast cancer risk in women from the Chaoshan area, China. PBDE may play a role in the occurrence and development of breast cancer. PMID- 30014898 TI - Estimation of TETRA radio use in the Airwave Health Monitoring Study of the British police forces. AB - BACKGROUND: The Airwave Health Monitoring Study aims to investigate the possible long-term health effects of Terrestrial Trunked Radio (TETRA) use among the police forces in Great Britain. Here, we investigate whether objective data from the network operator could be used to correct for misreporting in self-reported data and expand the radio usage availability in our cohort. METHODS: We estimated average monthly usage of personal radio in the 12 months prior to enrolment from a missing value imputation model and evaluated its performance against objective and self-reported data. Factors associated with TETRA radio usage variables were investigated using Chi-square tests and analysis of variance. RESULTS: The imputed data were better correlated with objective than self-reported usage (Spearman correlation coefficient = 0.72 vs. 0. 52 and kappa 0.56 [95% confidence interval 0.55, 0.56] vs. 0.46 [0.45, 0.47]), although the imputation model tended to under-estimate use for higher users. Participants with higher personal radio usage were more likely to be younger, men vs. women and officer vs. staff. The median average monthly usage level for the entire cohort was estimated to be 29.3 min (95% CI: [7.2, 66.6]). CONCLUSION: The availability of objective personal radio records for a large proportion of users allowed us to develop a robust imputation model and hence obtain personal radio usage estimates for ~50,000 participants. This substantially reduced exposure misclassification compared to using self-reported data and will allow us to carry out analyses of TETRA usage for the entire cohort in future work. PMID- 30014899 TI - Preconception seminal plasma concentrations of endocrine disrupting chemicals in relation to semen quality parameters among male partners planning for pregnancy. AB - BACKGROUND: Some non-persistent endocrine disruptors (EDCs) are adversely associated with semen quality and few studies have measured those EDCs in seminal plasma. OBJECTIVE: To find an association between EDCs in seminal plasma and semen quality parameters. METHODS: Five chemical classes of non-persistent EDCs were quantified in seminal plasma from 339 male partners who participated in a prospective pregnancy study. Bisphenols, benzophenone UV-filters, antimicrobials and phthalate diesters and their monoester metabolites were measured using high performance liquid chromatography-tandem mass spectrometry and gas chromatography mass spectrometry. Semen samples underwent next day analysis using a standardized protocol for the quantification of 35 endpoints. Linear mixed-effects models of EDCs that were log transformed and rescaled by their standard deviations or dichotomized at the 75th percentile for each exposure and outcomes with covariate adjustment were performed. EDCs in seminal plasma were also assessed relative to clinical reference values of semen quality endpoints using logistic regression or generalized estimating equations. RESULTS: The most consistent findings supporting adverse associations between seminal EDCs and semen quality were observed for some phthalate metabolites. For example, seminal plasma mono-ethyl, mono-n-butyl, mono-2-isobutyl and mono-benzyl phthalate concentrations were associated with decreased odds of having semen volume above clinical reference values (mEP: aOR=0.46; 95%CI= 0.32, 0.66; mBP: aOR=0.40; 95%CI= 0.28, 0.57; miBP: aOR=0.39; 95%CI= 0.27, 0.56), and mBzP: aOR= 0.34; 95%CI= 0.24, 0.49). CONCLUSIONS: Environmentally relevant concentrations of specific phthalates in seminal plasma were associated with diminished semen volume, sperm motility, viability, and morphological alterations in sperm heads such that semen volume and sperm viability fall below reference values. PMID- 30014900 TI - Volcanic ash from Puyehue-Cordon Caulle Volcanic Complex and Calbuco promote a differential response of pro-inflammatory and oxidative stress mediators on human conjunctival epithelial cells. AB - Volcanic ash could pose a hazard to the ocular surface as it is constantly exposed to environmental particles. We exposed conjunctival cells to Puyehue Cordon Caulle volcanic complex (PCCVC) or Calbuco ash particles and evaluated proliferation, viability, apoptosis, MUC1 expression, pro-inflammatory cytokines, and oxidative stress markers. Ash particles from these volcanoes vary in size, composition, and morphology. Our results demonstrate that PCCVC but not Calbuco ash particles induce cytotoxicity on human conjunctival epithelial cells viewed as a decrease in cell proliferation and the transmembrane mucin MUC1 expression; a pro-inflammatory response mediated by IL-6 and IL-8; and an imbalance of the redox environment leading to protein oxidative damage. This is the first in vitro study that assesses the biological effect of volcanic ash particles on human conjunctival epithelial cells and the involvement of inflammatory mediators and oxidative stress as the mechanisms of damage. Our results could provide a better understanding of the ocular symptoms manifested by people living near volcanic areas. PMID- 30014901 TI - An air quality index-based multistage type-2-fuzzy interval-stochastic programming model for energy and environmental systems management under multiple uncertainties. AB - In this study, a multistage type-2-fuzzy interval-stochastic programming (MTIP) method is developed, which extends upon the existing multistage stochastic programming (MSP) by allowing uncertainties expressed as probabilistic distributions, interval values and type-2 fuzzy sets to be effectively incorporated within the optimization framework. Through coupling air quality index (AQI) with MTIP, an AQI-MTIP model is formulated for energy and environmental systems (EES) management of Tianjin. A number of scenarios based on changed AQIs are examined to analyze the impacts of environmental requirements on the city's energy system. Results indicate that (i) with the improvement of environmental requirement, utilization of clean energies (especially natural gas) is provoked markedly; (ii) PM2.5 is the primary pollutant, 64.50% of which should be reduced each period to maintain the city's air quality at a health-safe level. These findings can help decision makers adjust energy structure, make effective mitigation strategy, and gain deep insight into the relationship between energy consumption and environmental requirement. PMID- 30014902 TI - Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway. AB - Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4',5-trihydroxy-stilbene-3 beta-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-alpha (PPAR-alpha), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase 1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition. PMID- 30014905 TI - Effects of microplastics on the uptake, distribution and biotransformation of chiral antidepressant venlafaxine in aquatic ecosystem. AB - In this study, we investigated the enantioselective environmental behaviors of the chiral antidepressant venlafaxine (VFX) in lab-scale aquatic ecosystems in the presence of microplastics (MPs). To determine the bioaccumulation, distribution, and metabolism as well as the effects of MPs on aquatic ecosystems, water-sediment, water-Lemna.minor (L.minor), water-Misgurnus.anguillicaudatus (M.anguillicaudatus), and water-sediment-L.minor-M.anguillicaudatus ecosystems were set up and exposed to venlafaxine and two levels of microplastics over a 90 day period. The removal efficiencies of VFX ranged from 58 to 96% in different ecosystems, and VFX degraded significantly faster in the complex water-sediment L.minor-M.anguillicaudatus ecosystem with S-enantiomer preferentially enriched. The main metabolite O-desmethylvenlafaxine (O-DVFX) was also observed in ecosystems, displaying similar enantioselectivity. When exposed to 50 mg L-1 of microplastics, the amount of venlafaxine in sediment and loach (M.anguillicaudatus) were significantly higher than that in the 1 mg L-1 microplastics treatments, and enhanced accumulation of O-DVFX was observed in loach. The present study for the first time assessed the combined effects of venlafaxine and microplastics in simulated aquatic microcosms, which could help gain an insight into the potential ecological impacts of chiral pollutants and microplastic, and evaluate their environment risks more accurately in future. PMID- 30014903 TI - Melatonin protects mouse granulosa cells against oxidative damage by inhibiting FOXO1-mediated autophagy: Implication of an antioxidation-independent mechanism. AB - Oxidative stress has been described as a prime driver of granulosa cell (GCs) death during follicular atresia. Increasing evidence suggests potential roles of melatonin in protecting GCs from oxidative injury, though the underlying mechanisms remain largely undetermined. Here we first proposed that the inhibition of autophagy through some novel regulators contributes to melatonin mediated GCs survival under conditions of oxidative stress. Oxidant-induced loss of GCs viability was significantly reduced after melatonin administration, which was correlated with attenuated autophagic signals upon oxidative stimulation both in vivo and in vitro. Compared with melatonin treatment, suppression of autophagy displayed similar preventive effect on GCs death during oxidative stress, but melatonin provided no additional protection in GCs pretreated with autophagy inhibitors. Notably, we found that melatonin-directed regulation of autophagic death was independent of its antioxidation/radical scavenging ability. Further investigations identified FOXO1 as a critical downstream effector of melatonin in promoting GCs survival from oxidative stress-induced autophagy. Specifically, suppression of FOXO1 via the melatonin-phosphatidylinositol 3-kinase (PI3K)-AKT axis not only improved GCs resistance to oxidative stress, but also abolished the autophagic response, from genes expression to the formation of autophagic vacuoles. Moreover, the activation of SIRT1 signaling was required for melatonin mediated deacetylation of FOXO1 and its interaction with ATG proteins, as well as the inhibition of autophagic death in GCs suffering oxidative stress. These findings reveal a brand new mechanism of melatonin in defense against oxidative damage to GCs by repressing FOXO1, which may be a potential therapeutic target for anovulatory disorders. PMID- 30014906 TI - An innovative wastewater treatment technology based on UASB and IFAS for cost efficient macro and micropollutant removal. AB - An innovative process based on the combination of a UASB reactor and an IFAS system is proposed in order to combine different redox conditions and biomass conformations to promote a high microbial diversity. The objective of this configuration is to enhance the biological removal of organic micropollutants (OMPs) as well as to achieve the abatement of nitrogen by using the dissolved methane as an inexpensive electron donor. Results showed high removals of COD (93%) and dissolved methane present in the UASB effluent (up to 85%) was biodegraded by a consortium of aerobic methanotrophs and heterotrophic denitrifiers. Total nitrogen removal decreased slightly along the operation (from 44 to 33%), depending on the availability of electron donor, biomass concentration, and configuration (floccules and biofilm). A high removal was achieved in the hybrid system (>80%) for 6 of the studied OMPs. Sulfamethoxazole, trimethoprim, naproxen, and estradiol were readily biotransformed under anaerobic conditions, whereas ibuprofen or bisphenol A were removed in the anoxic-aerobic compartment. Evidence of the cometabolic biotransformation of OMPs has been found, such as the influence of nitrification activity on the removal of bisphenol A, and of the denitrification activity on ethinylestradiol removal. PMID- 30014907 TI - A label-free aptasensor for ultrasensitive Pb2+ detection based on electrochemiluminescence resonance energy transfer between carbon nitride nanofibers and Ru(phen)32. AB - A label-free aptasensor was developed for ultrasensitive detection of Pb2+ based on electrochemiluminescence resonance energy transfer (ECL-RET) from graphitic carbon nitride nanofibers (CNNFs) to Ru(phen)32+. The CNNFs synthesized via a facile two-step hydrolysis-electrolysis strategy showed intense and stable ECL signal by taking advantages of amplifying and stabilizing effect of carbon nanotubes and Au nanoparticles. After the specific hybridation between capture DNA and Pb2+ specific aptamer, Ru(phen)32+ could be captured onto CNNFs modified electrode by effectively intercalating into the grooves of double-strand DNA, thus triggering the ECL-RET and leading to highly enhanced ECL intensity. The presence of Pb2+ would result in the detachment of Ru(phen)32+ and then the inhibition of ECL-RET. Then Pb2+ concentration could be quantified based on ECL change before and after introduction of Pb2+. The target recycling based on exonuclease I (Exo I) mediated digestion of Pb2+-aptamer complex was implemented to further improve the sensitivity. These synergistic amplification strategies enabled the aptasensor to be ultrasensitive for Pb2+ determination with a detection limit of 0.04 pM. The proposed probe was utilized to analyze environmental samples with satisfactory results. PMID- 30014904 TI - Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway. AB - Cellular oxidative stress plays a vital role in the pathological process of neural damage in cerebral ischemia/reperfusion (I/R). The breast cancer susceptibility protein 1 (BRCA1), a tumor suppressor, can modulate cellular antioxidant response and DNA repair. Yet the role of BRCA1 in cerebral I/R injury has not been explored. In this study, we observed that BRCA1 was mainly expressed in neurons and was up-regulated in response to I/R insult. Overexpression of BRCA1 attenuated reactive oxygen species production and lipid peroxidation. Enhanced BRCA1 expression promoted DNA double strand break repair through non homologous end joining pathway. These effects consequently led to neuronal cell survival and neurological recovery. Mechanically, BRCA1 can interact with the nuclear factor (erythroid-derived 2)-like 2 (NRF2) through BRCA1 C-terminal (BRCT) domain. The cross-talk between BRCT and NRF2 activated the NRF2/Antioxidant Response Element signaling pathway and thus protected injured neurons during cerebral I/R. In conclusion, enhanced BRCA1 after cerebral I/R injury may attenuate or prevent neural damage from I/R via NRF2-mediated antioxidant pathway. The finding may provide a potential therapeutic target against ischemic stroke. PMID- 30014908 TI - Novel mechanisms of selenate and selenite reduction in the obligate aerobic bacterium Comamonas testosteroni S44. AB - Selenium oxyanion reduction is an effective detoxification or/and assimilation processes in organisms, but little is known the mechanisms in aerobic bacteria. Aerobic Comamonas testosteroni S44 reduces Se(VI)/Se(IV) to less-toxic elemental selenium nanoparticles (SeNPs). For Se(VI) reduction, sulfate and Se(VI) reduction displayed a competitive relationship. When essential sulfate reducing genes were respectively disrupted, Se(VI) was not reduced to red-colored SeNPs. Consequently, Se(VI) reduction was catalyzed by enzymes of the sulfate reducing pathway. For Se(IV) reduction, one of the potential periplasm molybdenum oxidoreductase named SerT was screened and further used to analyze Se(IV) reduction. Compared to the wild type and the complemented mutant strain, the ability of Se(IV) reduction was reduced 75% in the deletion mutant DeltaserT. Moreover, the Se(IV) reduction rate was significantly enhanced when the gene serT was overexpressed in Escherichia coli W3110. In addition, Se(IV) was reduced to SeNPs by the purified SerT with the presence of NADPH as the electron donor in vitro, showing a Vmax of 61 nmol/min.mg and a Km of 180 MUmol/L. A model of Se(VI)/Se(IV) reduction was generated in aerobic C. testosteroni S44. This work provides new insights into the molecular mechanisms of Se(VI)/Se(IV) reduction activities in aerobic bacteria. PMID- 30014909 TI - Microparticles based on ionic and organosolv lignins for the controlled release of atrazine. AB - Lignins are natural polymers of the lignocellulosic biomass. Nowadays, there is a growing interest in developing value-added products based on lignins due to their renewability, low cost and abundance. In this work, lignin microspheres from organosolv and ionic isolation processes were prepared for the controlled release of atrazine. Microspheres were prepared by the solvent extraction/evaporation technique. The controlled release of atrazine from organosolv and ionic lignins microparticles was studied in water. Mobility experiments were performed in an agricultural soil from Argentina. The results showed that microparticles prepared using dichloromethane as the dispersed phase were spherical, while lignins dispersed in ethyl acetate produce irregular microparticles. Organosolv lignin microparticles presented higher encapsulation efficiency for all herbicide loads. About 98% and 95% of atrazine was released in 24 and 48 h approximately from organosolv and ionic lignin microparticles, respectively. The release profiles of atrazine from both lignin microparticles were not affected by the herbicide load. Atrazine mobility experiments in soil showed that about 80% of free atrazine was leached in 37 days, while 65.0% and 59.7% of the herbicide was leached from ionic and organosolv lignin microparticles, respectively. Thus, atrazine-loaded microparticles could reduce leaching compared to a commercial formulation of free atrazine. PMID- 30014910 TI - Preparation of the CNTs/AG/ITO electrode with high electro-catalytic activity for 2-chlorophenol degradation and the potential risks from intermediates. AB - A novel carbon nanotubes (CNTs)/agarose (AG)/ITO electrode with high electro catalytic activity was prepared using a simple sol-gel method. Characterization results showed that the prepared CNTs/AG membrane, coated on the ITO conductive glass, was consisted of C and O. The electro-catalytic degradation for 2 chlorophenol (2-CP) and the influence factors were investigated. The results meant that electro-catalytic degradation for 2-CP was highly dependent on pH, bias voltage, and catalyst dosage. At pH 2, 4 V bias voltage, and 5 wt% CNTs dosage, the electro-catalytic efficiency of CNTs/AG/ITO electrode for 2-CP (20 mg/L) achieved 98% within 180 min. Afterwards, the electro-catalytic properties of recycling electrode, roles of the generated reactive oxygen species, and the reaction pathways were also investigated and proposed. In addition, the toxicities of the generated intermediates from the electro-catalytic degradation were calculated by easy methods. The results indicated that the toxicities of some intermediates were higher than the parent pollutant, especially the formation of 2-CP dimer which was seldom reported in the advanced oxidation process. The findings of using AG as the carrier and conductive adhesive for catalytic material and the assessment methods for the possible increasing risks from the intermediates were reported firstly in this paper. PMID- 30014911 TI - Facile synthesis of smartaminosilane modified- SnO2/porous silica nanocomposite for high efficiency removal of lead ions and bacterial inactivation. AB - The aim of the present study is to synthesize a new and proficient nanoadsorbent for rapid removal of heavy metals and disinfection of microorganisms. The proposed nanoadsorbent was fabricated using SnO2 nanoparticles as the core, coated with mesoporous silica and further modified with 3-Aminopropyl triethoxysilane to render SnO2/PSi/NH2 nanocomposite. The nanocomposite was characterized using Fourier Transform Infrared (FTIR), X-Ray diffraction (XRD), Scanning Electron Microscopy (SEM) and Nitrogen adsorption-desorption analysis. The potential of the resultant SnO2/PSi/NH2 nanocomposite for the convenient removal of Lead ions in a batch systems was investigated as a function of solution pH, contact time, adsorbent dosage, temperature and metal ion concentration. The adsorption behavior was in good agreement with Sips and Langmuir isotherm models. The maximum adsorption capacity of SnO2/PSi/NH2 was 653.62 mg g-1. Furthermore, the desorption experiments demonstrated that the proposed nanocomposite could be used frequently for at least three consecutive cycles with minor losses in adsorption performance. The bacterial inactivation ability of SnO2/PSi/NH2 toward E-Coli and S. aureus bacteria was also evaluated using disk diffusion and linear cultivation tests, according to which the SnO2/PSi/NH2 nanocomposite possessed exceptional disinfection ability toward both bacteria, specifically S. aureus. PMID- 30014912 TI - Simulation and experimental study on the mechanism of the chlorination of azithromycin. AB - Azithromycin (AZI) has been listed as an emerging contaminant by the US EPA since 2009 because it is frequently detected in wastewater, surface water, and drinking water. In this paper, the chlorination of AZI in drinking water was simulated and studied. The results indicated that new compounds were generated in the chlorination of AZI. The byproducts were identified by liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-Q-TOF), and four of the byproducts were detected in real water samples. The kinetic studies demonstrated that the reaction rates of AZI chlorination were dependent on the initial concentration of free chlorine and the pH value. The potential toxicities of the byproducts were assessed by quantitative structure-activity relationship software and investigated by the viability of Chinese hamster lung (CHL), Jurkat T and Hep G2 cells. PMID- 30014913 TI - Taurine provides a time-dependent amelioration of the brain damage induced by gamma-irradiation in rats. AB - Exposure to ionizing radiation (IR) is inevitable since over 80% of total average exposure comes from natural sources. Brain is vulnerable to the deleterious effects of IR. Therefore, scientists paid attention in identifying novel compounds to protect against radiation-induced brain injury. Adult male albino rats weighing 120-150 g were divided into five groups, 18 rats each. Group 1 served as control, group 2 received an oral daily dose of taurine (500 mg/kg) for 2 weeks. Group 3 was exposed to a whole body single dose of gamma-irradiation (6 Gy). Groups 4 and 5 received taurine before and after gamma-irradiation, respectively. Six rats from each group were sacrificed after 1, 2 or 3 weeks. Throughout the 3 weeks studied, there were significant increases in MDA, NO, TNF alpha levels, and Cytochrome-c and activities of Caspases -9 and -3 and significant decreases in GSH, SOD, CAT and GPx in the irradiated group when compared with the relevant control. Cerebral cortex of irradiated rats showed vacuolization and nuclear pyknosis in the neuronal cells and focal gliosis. Taurine administration pre- or post-irradiation significantly ameliorated all these previous effects. Taurine had antioxidant, anti-inflammatory, and anti apoptotic effects and ameliorated the histopathological changes in brain in a time-dependent mode. PMID- 30014914 TI - Natural attenuation of TiO2 nanoparticles in a fractured hard-rock. AB - Successive transport experiments of TiO2 nanoparticles (NP) suspension through fractured hard-rock column were done in laboratory. A low ionic strength (IS) water (0.8-1.3 10-3 M) at pH ~4.5 was used, corresponding to the chemical composition of groundwater where the rock was collected (Naizin, France). The surface charge of TiO2 NP was positive while that of rock was negative favoring NP deposition. SEM/EDX reveals that NP were retained on a broad distribution of mineral collectors along the preferential flow pathways (i.e., fractures). However, a non-negligible amount of NP (~10%) was transferred through the rock. Divalent cation (Ca2+) was responsible for the reduction of the negative charge of the rock and thus contributed to limit the NP deposition as attested by DLVO model. Blocking of rock surfaces by NP favored NP transfer while the ripening process and the size exclusion of aggregates decreased NP mobility. Decrease of water flow favored the exchange of solutes from the immobile to the mobile water in the porous medium, which in turn favored the aggregation of the NP and led to their natural attenuation. The result evidences how slight modifications of the environmental conditions can strongly influence the fate of NP in groundwater. PMID- 30014915 TI - Indoor air quality in health clubs: Impact of occupancy and type of performed activities on exposure levels. AB - Associations between indoor air quality (IAQ) and health in sport practise environments are not well understood due to limited knowledge of magnitude of inhaled pollutants. Thus, this study assessed IAQ in four health clubs (HC1-HC4) and estimated inhaled doses during different types of activities. Gaseous (TVOCs, CO, O3, CO2) and particulate pollutants (PM1, PM4) were continuously collected during 40 days. IAQ was influenced both by human occupancy and the intensity of the performed exercises. Levels of all pollutants were higher when clubs were occupied (p < 0.05) than for vacant periods, with higher medians in main workout areas rather than in spaces/studios for group activities. In all spaces, TVOCs highly exceeded legislative limit (600 MUg/m3), even when unoccupied, indicating possible risks for the respective occupants. CO2 levels were well correlated with relative humidity (rs 0.534-0.625) and occupancy due to human exhalation and perspiration during exercising. Clubs with natural ventilations exhibited twice higher PM, with PM1 accounting for 93-96% of PM4; both PM were highly correlated (rs 0.936-0.995) and originated from the same sources. Finally, cardio classes resulted in higher inhalation doses than other types of exercising (1.7-2.6). PMID- 30014916 TI - Simultaneous determination of paraquat and atrazine in water samples with a white light reflectance spectroscopy biosensor. AB - An optical immunosensor based on White Light Reflectance Spectroscopy for the simultaneous determination of the herbicides atrazine and paraquat in drinking water samples is demonstrated. The biosensor allows for the label-free real-time monitoring of biomolecular interactions taking place onto a SiO2/Si chip by transforming the shift in the reflected interference spectrum due to reaction to effective biomolecular layer thickness. Dual-analyte determination is accomplished by functionalizing spatially distinct areas of the chip with protein conjugates of the two herbicides and scanning the surface with an optical reflection probe. A competitive immunoassay format was adopted, followed by reaction with secondary antibodies for signal enhancement. The sensor was highly sensitive with detection limits of 40 and 50 pg/mL for paraquat and atrazine, respectively, and the assay duration was 12 min. Recovery values ranging from 90.0 to 110% were determined for the two pesticides in spiked bottled and tap water samples, demonstrating the sensor accuracy. In addition, the sensor could be regenerated and re-used at least 20 times without significant effect on the assay characteristics. Its excellent analytical performance and short analysis time combined with the small sensor size should be helpful for fast on-site determinations of these analytes. PMID- 30014917 TI - A new function of spent activated carbon in BAC process: Removing heavy metals by ion exchange mechanism. AB - To investigate the potential of the spent activated carbon (AC) on removing heavy metals, the spent ACs used 5 years were collected from a full-scale BAC water treatment plant of southern China. The study found that the spent ACs had very good adsorption capacity for Pb(II) and Cd(II) at low concentrations (about 200 MUg/L or less) with the maximum removal rates of more than 95% and 86% respectively (only 10-15% for virgin ACs), which will provide the theoretical basis for the disposal of spent AC (the hazardous waste) in BAC process or the combination reuse of spent AC and the virgin AC. Surface properties analyses showed that compared to virgin AC, the pH and PZC in the spent AC significantly decreased, and the relative abundance of surface carboxyl increased by 81% on average, which are essential for the adsorption of metals. To explore the adsorption mechanism, take Pb(II) for example, the adsorption isotherm and kinetics fittings were carried out, which can be well described by Freundlich model (R2 = 0.9356) and the pseudo-second-order kinetic model (R2 = 0.9276), respectively. Analyses of influencing factors, FT-IR and XPS before and after Pb(II) adsorption confirmed the ion exchange mechanism of spent AC for the removal of heavy metals. PMID- 30014918 TI - Metronidazole removal by means of a combined system coupling an electro-Fenton process and a conventional biological treatment: By-products monitoring and performance enhancement. AB - In order to mineralize Metronidazole (MTZ), a process coupling an electro-Fenton pretreatment and a biological degradation was implemented. A mono-compartment batch reactor containing a carbon-felt cathode and a platinum anode was employed to carry out the electro-Fenton pretreatment of MTZ. A total degradation of MTZ (100 mg L-1) was observed at 0.07 mA.cm-2 after only 20 min of electrolysis. Yet, after 1 and 2 h of electrolysis, the mineralization level remained low (16.2% and 32% respectively), guaranteeing a significant residual organic content for further biological treatment. LCMS/MS was used to determine the intermediates by products and hence to propose a plausible degradation pathway. An increase from 0 to 0.44 and 0.6 for 1 and 2 h of electrolysis was observed for the BOD5/COD ratio. Thus, from 1 h of electro-Fenton pretreatment, the electrolysis by products were considered biodegradable. A biological treatment of the electrolysis by-products after 1 and 2 h was then realized. The mineralization yields reached very close values, about 84% for 1 and 2 h of electrolysis after 504 h of biological treatment, namely close to 89% for the overall process, showing the pertinence of the proposed coupled process. PMID- 30014919 TI - Low-cost iron-doped catalyst for phenol degradation by heterogeneous Fenton. AB - The aim of this work was to study the feasibility of textile sludge as a precursor to prepare catalysts for catalytic wet peroxide oxidation (CWPO) by chemical and thermal treatments. Textile sludge was characterized by physical chemical and metal composition analyses. The chemical activation was evaluated using iron sulfate and the thermal treatment was carried out at 720 degrees C in a vacuum pyrolysis reactor. Two catalysts with iron contents of 1.5% and 5.6% were selected. Process parameters influence on CWPO of phenol were evaluated and a maximum removal of phenol and TOC was observed at pH 3 and 60 degrees C, using 3 g L-1 of the catalyst containing 5.6% of iron and 11.8 mmol L-1 of H2O2. Metal analysis indicated that the textile sludge is suitable to be employed as both iron catalyst and adsorbent. The catalysts characterization indicated a reasonable surface area with a well-developed microporosity and the presence of Hematite structures in the carbonaceous matrix. The degradation process achieved 98.2% of phenol conversion, 68.2% of mineralization and 2.11 mg L-1 of iron leaching in 150 min of reaction. The catalyst presented activity for up to 5 cycles of use, but with loss of efficiency. PMID- 30014920 TI - Bioactive secondary metabolites from the marine-associated fungus Aspergillus terreus. AB - Three new compounds, including a prenylated tryptophan derivative, luteoride E (1), a butenolide derivative, versicolactone G (2), and a linear aliphatic alcohol, (3E,7E)-4,8-dimethyl-undecane-3,7-diene-1,11-diol (3), together with nine known compounds (4-12), were isolated and identified from a coral-associated fungus Aspergillus terreus. Their structures were elucidated by HRESIMS, one- and two-dimensional NMR analysis, and the absolute configuration of 2 was determined by comparison of its electronic circular dichroism (ECD) spectrum with the literature. Structurally, compound 1 featured an unusual (E)-oxime group, which occurred rarely in natural products. Compounds 1-3 were evaluated for the alpha glucosidase inhibitory activity, and compound 2 showed potent inhibitory potency with IC50 value of 104.8 +/- 9.5 MUM, which was lower than the positive control acarbose (IC50 = 154.7 +/- 8.1 uM). Additionally, all the isolated compounds were evaluated for the anti-inflammatory activity against NO production, and compounds 1-3, 5-7, and 10 showed significant inhibitory potency with IC50 values ranging from 5.48 to 29.34 MUM. PMID- 30014921 TI - Novel benzotriazole N-acylarylhydrazone hybrids: Design, synthesis, anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis and FAK inhibition. AB - A series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC50 values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC50 values in nano-molar range between 25 and 130 nM. They showed 18-2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC50 values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC50 values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC50 = 32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism. PMID- 30014922 TI - Tetrahydroindolocarbazoles (THICZs) as new class of urokinase (uPA) inhibitors: Synthesis, anticancer evaluation, DNA-damage determination, and molecular modelling study. AB - Tetrahydroindolocarbazoles (THICZs) with versatile substituents, have been designed, synthesized, structure characterized, then investigated for their in vitro anticancer screening, urokinase inhibition (uPA) evaluated, DNA-damage determination was further explored. Compounds 5, 8, 10 and 17 displayed the most promising antitumor activities against the breast cancer cell line as compared to the standard drug, doxorubicin with IC50 = 5.24 +/- 0.37, 4.00 +/- 0.52, 7.20 +/- 0.90 and 9.60 +/- 1.10 ug/ml (versus 3.30 +/- 0.48 ug/ml for doxorubicin). Compounds 5, 8, 10 and 17 represents the most significant uPA inhibitors of our study with IC50 of 3.80, 2.70. 4.75, 10.80 (ng/ml) respectively. The expression levels of CDKN2A gene were decreased in 8, 10 and 17 cell lines as compared to those in positive control samples. Cell lines treated with 5, 8, 10 and 17 clearly observed a high score of damaged DNA cells. A deeper examination revealed that our hetroaromatics showed an extensive hydrogen bonding interactions that is required in the S pocket which is important for activity Arg 217, Gly 219, Gly 216, Lys 143 and Ser 190. So we present THICZs as promising uPA inhibitors expected as significant promise for further development as anti-invasiveness drugs. PMID- 30014923 TI - Promiscuous enzyme-catalyzed cascade reaction: Synthesis of xanthone derivatives. AB - Based on the screening of biocatalysts and reaction conditions including organic solvent, water content, lipase loading, reaction temperature and time, lipase TLIM exhibited the prominent promiscuity for the Knoevenagel-Michael cascade reactions of 1, 3-diketones with aromatic aldehydes to synthesize xanthone derivatives. This procedure provides satisfactory advantages such as environmental begin, simple work-up, generality, obtaining in excellent yields (80-97%), and potential for recycling of biocatalyst. PMID- 30014924 TI - Efficient synthesis of the ketone body ester (R)-3-hydroxybutyryl-(R)-3 hydroxybutyrate and its (S,S) enantiomer. AB - The ketone body ester (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate and its (S,S) enantiomer were prepared in a short, operationally simple synthetic sequence from racemic beta-butyrolactone. Enantioselective hydrolysis of beta-butyrolactone with immobilized Candida antarctica lipase-B (CAL-B) results in (R)-beta butyrolactone and (S)-beta-hydroxybutyric acid, which are easily converted to (R) or (S)-ethyl-3-hydroxybutyrate and reduced to (R) or (S)-1,3 butanediol. Either enantiomer of ethyl-3-hydroxybutyrate and 1,3 butanediol are then coupled, again using CAL-B, to produce the ketone body ester product. This is an efficient, scalable, atom-economic, chromatography-free, and low cost synthetic method to produce the ketone body esters. PMID- 30014925 TI - Enhanced photosynthetic linear electron flow in mixotrophic green microalga Ettlia oleoabundans UTEX 1185. AB - Basic understanding of the photosynthetic physiology of the oleaginous green microalga Ettlia oleoabundans is still very limited, including the modulation of the photosynthetic membrane upon metabolism conversion from autotrophy to mixotrophy. It was previously reported that, upon glucose supply in the culture medium, E. oleoabundans preserves photosystem II (PSII) from degradation by virtue of a higher packing of thylakoid complexes. In this work, it was investigated whether in the mixotrophic exponential growth phase the PSII activity is merely preserved or even enhanced. Modulated fluorescence parameters were then recorded under short-term treatments with increasing irradiance values of white light. It was found that the mixotrophic microalga down-regulated the chlororespiratory electron recycling from photosystem I (PSI), but enhanced the linear electron flow from PSII to PSI. Ability to keep PSII more open than in autotrophic growth conditions indicated that the respiration of the glucose taken up from the medium fed the carbon fixing reactions with CO2. The overall electron poise was indeed well regulated, with a lesser need for thermal dissipation of excess absorbed energy. It is proposed that the significant, though small, increase in PSII maximum quantum yield in mixotrophic cells just reflects an improved light energy use and an increased photochemical capacity as compared to the autotrophic cells. PMID- 30014926 TI - Physiological and molecular genetic studies on two elicitors for improving the tolerance of six Egyptian soybean cultivars to cotton leaf worm. AB - Cotton leaf worm (Spodoptera littoralis) is considered one of the most destructive agricultural pests in Egypt. Six soybean cultivars (Giza-21, Giza-22, Giza-35, Giza-82, Giza-83 and Giza-111) were grown under natural infection with cotton leaf worm. The effect of two elicitors, methyl jasmonate and sodium nitroprusside on enhancing the ability of susceptible cultivars to tolerate (Spodoptera littoralis) was studied. Giza-35 and Giza-111 showed tolerance performance under natural infection compared to Giza-22 and Giza-82 as sensitive ones, while Giza-83 and Giza-21 showed moderate tolerance. Both treatments positively affected seed yield and its components and fatty acid composition. Extracted fatty acids showed variable changes in treated plants compared with the untreated controls. Plants treated with the two elicitors showed an increase in Linoleic acid and Linolenic acid fatty acids and decrease in Palmitic acid and Palmitolic acid content. Treatment with methyl jasmonate was found to be more effective than sodium nitroprusside and enhanced resistance of the susceptible cultivars. Eight IRAP and iPBS retrotransposon-based markers were used to detect genetic differences among studied soybean cultivars and to develop molecular genetic markers for cotton leaf worm infestation. The technique successfully identified soybean genotypes in addition to nineteen molecular markers related to soybean tolerance. PMID- 30014928 TI - Evaluation of placental vascularization indices in monochorionic diamniotic and dichorionic diamniotic twin pregnancies. AB - OBJECTIVES: We aimed to investigate and compare placental vascularization indices between monochorionic-diamniotic, dichorionic-diamniotic normal twin pregnancies, and normal singular pregnancies. We hypothesized that there is correlation between placental three-dimensional power Doppler vascularization indices and birth weight in case of twin pregnancies, and that normal singular pregnancies have higher placental vascularization indices than normal twin pregnancies. STUDY DESIGN: Placental three-dimensional power Doppler vascularization indices, such as vascularization index, flow index, and vascularization-flow index were measured in monochorionic-diamniotic (N = 15) and dichorionic-diamniotic (N = 36) normal twin pregnancies, and in normal singular (N = 109) pregnancies. Correlations were analyzed between vascularization indices, and birth weight, APGAR score, umbilical pH, umbilical venous bicarbonate, lactate, and base excess. RESULTS: Vascularization indices and birth weight were significantly (p < 0.01) higher in normal singular gestations (vascularization index = 10.36, flow index = 46.08, vascularization-flow index = 4.08, average birth weight = 3377 g at 38.2 weeks average gestational age) compared to monochorionic-diamniotic and dichorionic-diamniotic normal twin pregnancies. No significant differences were found in vascularization indices between monochorionic-diamniotic and dichorionic diamniotic normal twins. There were no significant differences in APGAR score, umbilical pH, umbilical venous bicarbonate, lactate, and base excess between groups examined (p < 0.01). We found strong linear correlations between placental vascularization indices and birth weight in both twin groups. CONCLUSION: Placental three-dimensional power Doppler vascularization indices seem appropriate for predicting birth weight in monochorionic-diamniotic and dichorionic-diamniotic normal twin pregnancies. Our pilot study revealed reference values for vascularization indices in case of twin pregnancies examined. PMID- 30014927 TI - Upregulated structural and regulatory genes involved in anthocyanin biosynthesis for coloration of purple grains during the middle and late grain-filling stages. AB - Anthocyanin biosynthesis is controlled by structural and regulatory genes. Purple wheat grains accumulate anthocyanin during developmental processes. However, anthocyanin cannot accumulate at the beginning of grain formation. To understand the reason for this phenomenon, we performed observations and analyses of pigments, developmental stages, and the transcriptome of caryopsis in Triticum aestivum L. cv. Guizi 1 (GZ1). In the early grain-filling stage (10 dpa to 20 dpa), anthocyanin accumulated from nearly 0 mg.kg-1 (10 dpa) to 15.39 mg.kg-1 (20 dpa), and the expression levels of structural genes (except GzDFR) and main regulatory genes GzMYB-7D1 and GzMYC-2A1 were low. When the grains developed to the middle (20 dpa to 30 dpa) and late (30 dpa to 40 dpa) grain-filling stages, the anthocyanin content peaked at 197.31 mg.kg-1, and the expression levels of structural and regulatory genes at 25 dpa and 35 dpa were higher than that at 10 dpa. In particular, the expression levels of GzANS, Gz3GT, GzMYB-7D1, and GzMYC 2A1 were upregulated 45.74~28.54, 765.00~384.00, 419.00~574.00, and 5.34~29.05 times, respectively. Grains were also colored from green to purple. Anthocyanin accumulates in the pericarp and testa and is stored in vacuoles of epidermal and transverse cells. The major compositions are cyanidin and peonidin. These results revealed that the upregulated structural and regulatory genes in the middle and late grain-filling stages may result in the anthocyanin biosynthesis and coloration of grains, which provides new insights into anthocyanin biosynthesis and regulation mechanisms. PMID- 30014929 TI - In vitro probiotic properties of vaginal Lactobacillus fermentum MG901 and Lactobacillus plantarum MG989 against Candida albicans. AB - Candida albicans is the most important Candida species causing vulvovaginal candidiasis (VVC). We investigated the potential of the probiotic strains Lactobacillus fermentum MG901 and L. plantarum MG989 towards control of C. albiacns. Cell viability tests following co-culturing with lactobacilli revealed that C. albicans cells lost metabolic activity and were eventually killed. Further studies revealed that MG901 and MG989 had high surface hydrophobicity that enhanced its adhesion ability to epithelial cell. The MG901 and MG989 showed coaggregation with E. coli and C. albicans to affect their adhesion and colonization. The adhesion of MG901 and MG989 to HT-29 cell and its inhibition of E. coli and C. albicans adherence to these cells were demonstrated. These incidences provided evidence of the possible colonization of MG901 and MG989 that would prevent binding and growth of E. coli and C. albicans onto intestinal epithelial cells. Following daily administration of 108 CFU of viable MG901 and MG989 orally, the animals' feces were examined for bacterial excretion. The potential probiotic MG901 and MG989 were found to persist for up to 6 days in the feces of mice. In conclusion, L. fermentum MG901 and L. plantarum MG989 have the potential to inhibit the yeast growth, which could possibly have played an important role in helping to clear VVC in vivo. PMID- 30014930 TI - Association betweenGREM2 gene polymorphism with osteoporosis and osteopenia in postmenopausal women. AB - OBJECTIVE: Osteoporosis is a civilization disease, in which the dominant symptoms are the loss of bone mass and disturbances in bone structure. Gremlin-2 is one of the BMP (bone morphogenetic proteins) antagonists and participate in osteogenesis and osteoblast differentiation. The aim of the study was to analyze whether the GREM2 gene polymorphism is significantly more common in postmenopausal women than in healthy women and whether it is a predisposing factor for the osteoporosis development. STUDY DESIGN: The study consisted of 675 unrelated Polish postmenopausal women, including 109 with osteopenia, 333 with osteoporosis and 233 healthy women. The effect of the GREM2 polymorphism on T-score, Z-score, L2L4AM, L2L4YA, L2L4BMD, body mass, BMI, birth weight was statistically evaluated. RESULTS: Statistical significance was observed between the TT and TC genotypes and also between TT and CC genotypes in the case of birth weight in the control group and the group of women with osteoporosis. Analysis of body mass in women with osteoporosis showed the statistical significance between genotypes TT and CC, TT and TC. Analysis of the frequencies of TT, TC and CC genotypes of the rs4454537 polymorphism of the GREM2 gene showed no statistical significance between studied groups. CONCLUSION: Our study found that the most frequent genotype in the group of women with osteopenia and osteoporosis was TC while in the group of healthy women the protective TT genotype was dominant. Hence, it can be postulated that the TT genotype is a protective factor against the development of osteoporosis. PMID- 30014931 TI - Body fat index: A novel alternative to body mass index for prediction of gestational diabetes and hypertensive disorders in pregnancy. AB - OBJECTIVES: To evaluate the association of ultrasound measurement of maternal abdominal subcutaneous and pre-peritoneal fat thickness in relation to the subsequent diagnosis of gestational diabetes (GDM), and to assess the association of body fat index (BFI), compared to conventional body mass index (BMI), with respect to the development of some obstetric related complications. STUDY DESIGN: A prospective study included non-diabetic pregnant women who were scheduled for fetal anatomic survey. Women underwent fat measurements and BFI (pre-peritoneal fat x subcutaneous fat/height) was calculated. They underwent routine glucose screening and diagnostic tests for GDM. Obstetric complications, mode of delivery, and delivery related events were reported. Multivariable logistic regression was used to test potential predictors for development of obesity related complications. Primary outcome was development of GDM. Secondary outcomes included development of hypertensive disorders during pregnancy and need for cesarean delivery due to labor dystocia. The optimal cut-off points for continuous variables were obtained using a receiver operating characteristic (ROC) curve analyses. RESULTS: 389 women met study criteria. Median gestational age at time of ultrasound evaluation was 19.1 weeks. Positive family history of diabetes (adjusted odds ratio "OR" 2.30, 95% CI 1.35-3.92), history of GDM (adjusted OR 6.87, 95% CI 3.03-15.61), subcutaneous fat>=13 mm (adjusted OR 4.63, 95% CI 1.60-13.38) and pre-peritoneal fat>=12 mm (adjusted OR 3.32, 95% CI 1.06 10.42) were significant predictors for development of GDM. ROC analysis demonstrated that a BFI > 0.5 was statistically superior to a BMI > 25 or 30 as a predictor of gestational diabetes (adjusted OR 6.24, 95% CI 1.86-20.96). A Similar ROC analysis demonstrated that a BFI > 0.8 was associated with a higher risk for the development of hypertensive disorders of pregnancy (adjusted OR 2.70 [95% CI 1.60-4.55]), and need for cesarean delivery (adjusted OR 2.01[95% CI 1.23 3.28]) than a BMI > 25 or 30. CONCLUSION: Values obtained by ultrasound measurement of subcutaneous and pre-peritoneal fat are associated with development of GDM and hypertensive disorders in pregnancy. Our data suggest that BFI was a better predictor than BMI for development of GDM and hypertensive disorders in pregnancy and should be studied further. PMID- 30014932 TI - Food influence on lead relative bioavailability in contaminated soils: Mechanisms and health implications. AB - To determine the effects of dietary constituents on soil Pb oral bioavailability, Pb relative bioavailability (RBA) in 3 soils contaminated by zinc smelting (ZS), wire-rope production (WR), and metal mining (MM) was measured under fasted and fed states with 9 foods. Under fasted state, Pb-RBA was 84.4 +/- 10.3, 82.6 +/- 4.70, and 32.3 +/- 1.10% for ZS, WR, and MM soils; however, it decreased by 1.3 3.5 fold to 23.9-58.8, 25.6-49.9, and 14.8-24.2% under fed states with foods excluding Pb-RBA with egg in WR soil (97.3 +/- 4.46%), and with cabbage and egg in MM soil (40.0 +/- 8.62 and 44.4 +/- 0.96%). In the presence of foods, egg and pork with significantly higher protein and fat contents leaded to the highest soil Pb-RBA (44.4-97.3%), while Pb-RBA determined with mineral-rich mouse feed was 1.6-7.9 fold lower (9.41-13.5%), suggesting high fat and protein foods tended to increase soil Pb-RBA, while high mineral diets decreased soil Pb-RBA. The increased Pb-RBA of MM soil with cabbage compared to fasted state was due to high organic content in cabbage, which could increase soil Pb solubility by inhibiting Fe and Pb co-precipitation in the intestine. For accurate assessment of health risks of contaminated soils, dietary influence on soil Pb-RBA should be considered. PMID- 30014933 TI - Electrokinetically assisted oil-water phase separation in oily sludge with implementing novel controller system. AB - Upstream and downstream petroleum industry generate of significant amounts of oily sludge per day. On the other hand, a disposal of such sludge requires expensive pre-treatments following local regulations. Conventional processes, like centrifugal separation provide sludge volume reduction and water extraction. However, water-in-oil emulsion requires extra stages for phase separation, which overall increases the costs. Therefore, electrokinetically (EK) assisted oil water phase separation method was considered. In this study, a novel implemented controller, installed into the EK system, permitted to increase the length of exposure time to electrical field, while a significant decrease of energy consumption was observed. The controller, implemented based on Percolation Theory and applied to a linear horizontal EK system, showed enhanced sludge demulsification and improvement the quality of separated fractions. TGA analysis showed a superior quality of liquids extracted by EK with controller comparing to liquids without controller or generated by centrifuging process. A reaction rate with respect to temperature to assess the presence of water in the oil was also defined. The method, shown in this paper, advances the oil-water phase separation and permits for better oil recovery and sludge volume reduction. PMID- 30014934 TI - How important are maritime emissions for the air quality: At European and national scale. AB - Due to its dependence on fossil fuel combustion, emissions from the marine transport sector can significantly contribute to air pollution. This work aims to evaluate the impact of maritime transport emissions on air quality in Portugal using a numerical air quality modelling approach, with high-resolution emission data. Emissions from the European TNO inventory were compiled and pre-processed at hourly and high spatial (~3 * 3 km2) resolutions. Scenarios with and without these maritime emissions were then simulated with the WRF-CHIMERE modelling system, extensively tested and validated for Portugal domain, in order to evaluate their impact on air quality. A simulation was performed for one year (2016) and the resulting differences were analysed in terms of spatial distribution, time series and deltas. The main deltas for NO2 and PM10 are located over international shipping routes and major ports, while O3 concentrations are impacted in a larger area. The modelling results also indicate that shipping emissions are responsible for deltas in the concentration of NO2 higher than 20% over specific urban areas located in the west coast of Portugal, and less than 5% for PM10. For O3 the relative contribution is low (around 2%) but this contribution is also observed at locations more than 50 km from the coast. PMID- 30014935 TI - Seasonal and spatial distribution of antibiotic resistance genes in the sediments along the Yangtze Estuary, China. AB - Antibiotics resistance genes (ARGs) are considered as an emerging pollutant among various environments. As a sink of ARGs, a comprehensive study on the spatial and temporal distribution of ARGs in the estuarine sediments is needed. In the present study, six ARGs were determined in sediments taken along the Yangtze Estuary temporally and spatially. The sulfonamides, tetracyclines and fluoroquinolones resistance genes including sul1, sul2, tetA, tetW, aac(6')-Ib, and qnrS, were ubiquitous, and the average abundances of most ARGs showed significant seasonal differences, with relative low abundances in winter and high abundances in summer. Moreover, the relative high abundances of ARGs were found at Shidongkou (SDK) and Wusongkou (WSK), which indicated that the effluents from the wastewater treatment plant upstream and inland river discharge could influence the abundance of ARGs in sediments. The positive correlation between intI1 and sul1 implied intI1 may be related to the occurrence and propagation of sulfonamides resistance genes. Correlation analysis and redundancy discriminant analysis showed that antibiotic concentrations had no significant correlation to their corresponding ARGs, while the total extractable metal, especially the bioavailable metals, as well as other environmental factors including temperature, clay, total organic carbon and total nitrogen, could regulate the occurrence and distribution of ARGs temporally and spatially. Our findings suggested the comprehensive effects of multiple pressures on the distribution of ARGs in the sediments, providing new insight into the distribution and dissemination of ARGs in estuarine sediments, spatially and temporally. PMID- 30014936 TI - Microplastics in seawater and zooplankton from the Yellow Sea. AB - Marine plastic pollution is a worldwide problem. Microplastics (MPs) are the predominant form of marine plastic debris, a form small enough to be ingested by and potentially harm marine organisms. It is urgent to develop ecologically relevant metrics for the risk assessment of MPs based on in situ data, especially for coastal areas. For the first time, we performed a comprehensive study of the characteristics of MPs in seawater and zooplankton in the Yellow Sea. For MPs in seawater, the average concentration is 0.13 +/- 0.20 pieces/m3, dominated by fragments (42%). The average size is 3.72 +/- 4.70 mm, with the most frequent size appearing at 1200 MUm. The major polymer types are polypropylene and polyethylene, accounting for 88.13% in total. The distribution of MPs in seawater is patchy, with high MP concentrations close to the coastal cities. The average concentration of MPs in 11 total zooplankton groups is 12.24 +/- 25.70 pieces/m3. The average size is 154.62 +/- 152.90 MUm, with 90% being <500 MUm. Fiber is the dominant shape of MPs found in zooplankton, accounting for 46%, but the composition of the polymer type is diverse. The retention of MPs in zooplankton depends on the taxa and their abundance in the Yellow Sea. Siphonophorea, Copepoda, Euphausiacea and Amphipoda are the main repositories compared to other groups, achieving 3.57, 2.44, 1.41 and 1.36 pieces/m3, respectively. The high concentration area of MPs in zooplankton appeared near the adjacent waters of the Yangtze estuary. These results prove that zooplankton act as a repository for MPs in coastal waters. The retention of MPs in zooplankton is recommended as a key index for further ecological risk assessment of MPs. PMID- 30014937 TI - Characterizing benzene series (BTEX) pollutants build-up process on urban roads: Implication for the importance of temperature. AB - Benzene series (BTEX) pollutants which are generated by traffic can deposit (build-up) on urban road surfaces. When they are washed-off by stormwater runoff, BTEX are toxic to ecological and human health if the stormwater is reused. To understand the risk posed by BTEX, it is essential to have an in-depth investigation on BTEX build-up, one of the most important stormwater pollutant processes. This study analysed the relationship between BTEX build-up and BTEX build-up's influential factors. The outcomes confirmed an important role of climatic factors (particularly temperature) on influencing BTEX build-up. This has not been considered in previous stormwater studies although this has been widely focused in atmospheric pollution. BTEX build-up loads were generally higher and the variability was low in dry seasons with low temperature such as winter and spring. Additionally, the influence of temperature on BTEX build-up on urban road surfaces is more important in the case of larger particles (such as >75 MUm) than smaller particles. The study also showed that petrol station areas have a potential to export stormwater runoff with high BTEX concentrations, compared to typical urban roads. This is particularly applicable in winter and spring. These outcomes can provide useful guidance to improving stormwater quality modelling approaches, especially relevant to estimation of BTEX concentrations in the stormwater. PMID- 30014938 TI - Spatiotemporal patterns of PM10 concentrations over China during 2005-2016: A satellite-based estimation using the random forests approach. AB - BACKGROUND: Few studies have estimated historical exposures to PM10 at a national scale in China using satellite-based aerosol optical depth (AOD). Also, long-term trends have not been investigated. OBJECTIVES: In this study, daily concentrations of PM10 over China during the past 12 years were estimated with the most recent ground monitoring data, AOD, land use information, weather data and a machine learning approach. METHODS: Daily measurements of PM10 during 2014 2016 were collected from 1479 sites in China. Two types of Moderate Resolution Imaging Spectroradiometer (MODIS) AOD data, land use information, and weather data were downloaded and merged. A random forests model (non-parametric machine learning algorithms) and two traditional regression models were developed and their predictive abilities were compared. The best model was applied to estimate daily concentrations of PM10 across China during 2005-2016 at 0.10 (~10 km). RESULTS: Cross-validation showed our random forests model explained 78% of daily variability of PM10 [root mean squared prediction error (RMSE) = 31.5 MUg/m3]. When aggregated into monthly and annual averages, the models captured 82% (RMSE = 19.3 MUg/m3) and 81% (RMSE = 14.4 MUg/m3) of the variability. The random forests model showed much higher predictive ability and lower bias than the other two regression models. Based on the predictions of random forests model, around one third of China experienced with PM10 pollution exceeding Grade II National Ambient Air Quality Standard (>70 MUg/m3) in China during the past 12 years. The highest levels of estimated PM10 were present in the Taklamakan Desert of Xinjiang and Beijing-Tianjin metropolitan region, while the lowest were observed in Tibet, Yunnan and Hainan. Overall, the PM10 level in China peaked in 2006 and 2007, and declined since 2008. CONCLUSIONS: This is the first study to estimate historical PM10 pollution using satellite-based AOD data in China with random forests model. The results can be applied to investigate the long-term health effects of PM10 in China. PMID- 30014939 TI - Microplastic bacterial communities in the Bay of Brest: Influence of polymer type and size. AB - Microplastics (<5 mm) exhibit intrinsic features such as density, hydrophobic surface, or high surface/volume ratio, that are known to promote microbial colonization and biofilm formation in marine ecosystems. Yet, a relatively low number of studies have investigated the nature of microplastic associated bacterial communities in coastal ecosystems and the potential factors influencing their composition and structure. Here, we characterized microplastics collected in the Bay of Brest by manual sorting followed by Raman spectroscopy and studied their associated bacterial assemblages using 16S amplicon high-throughput sequencing. Our methodology allowed discriminating polymer type (polyethylene, polypropylene and polystyrene) within small size ranges (0.3-1 vs. 1-2 vs. 2-5 mm) of microplastics collected. Data showed high species richness and diversity on microplastics compared to surrounding seawater samples encompassing both free living and particle attached bacteria. Even though a high proportion of operational taxonomic units (OTU; 94 +/- 4%) was shared among all plastic polymers, polystyrene fragments exhibited distinct bacterial assemblages as compared to polyethylene and polypropylene samples. No effect of microplastic size was revealed regardless of polymer type, site and date of collection. The Vibrio genus was commonly detected in the microplastic fraction and specific PCR were performed to determine the presence of potentially pathogenic Vibrio strains (namely V. aestuarianus and the V. splendidus polyphyletic group). V. splendidus related species harboring putative oyster pathogens were detected on most microplastic pools (77%) emphasizing the need of further research to understand the role of microplastics on pathogen population transport and ultimate disease emergence. PMID- 30014940 TI - Stabilizing mixed fatty acid and phthalate ester monolayer on artificial seawater. AB - Phthalate esters which are widely used as industrial chemicals have become widespread contaminants in the marine environment. However, little information is available on the interfacial behavior of phthalate esters in the seawater, where contaminants generally occur at elevated concentrations and have the potential to transfer into the atmosphere through wave breaking on sea surface. We used artificial seawater coated with fatty acids to simulate sea surface microlayer in a Langmuir trough. The interactions of saturated fatty acids (stearic acid (SA) and palmitic acid (PA)) with one of the most abundant phthalate esters (di-(2 ethylhexyl) phthalate (DEHP)), were investigated under artificial seawater and pure water conditions. Pure DEHP monolayer was not stable, while more stable mixed monolayers were formed by SA and DEHP on the artificial seawater at relatively low surface pressure. Sea salts in the subphase can lower the excess Gibbs free energy to form more stable mixed monolayer. Among the ten components in the sea salts, Ca2+ ions played the major role in condensation of mixed monolayer. The condensed characteristic of the mixed SA (or PA)/DEHP monolayers suggested that the hydrocarbon chains were ordered on artificial seawater. By means of infrared reflection-absorption spectroscopy (IRRAS), we found that multiple sea salt mixtures induced deprotonated forms of fatty acids at the air water interface. Sea salts can improve the stability and lifetime of mixed fatty acid and phthalate ester monolayer on aqueous droplets in the atmosphere. Interfacial properties of mixed fatty acid and phthalate ester monolayers at the air-ocean interface are important to help understand their behavior and fate in the marine environment. PMID- 30014941 TI - Systematic characterization and proposed pathway of tetracycline degradation in solid waste treatment by Hermetia illucens with intestinal microbiota. AB - Antibiotics can effectively protect livestock from pathogen infection, but residual antibiotics in manure bring risks to ecosystems and public health. Here, we demonstrated that black soldier fly larvae (BSFL) could provide an environmentally friendly manure treatment based on their ability to effectively and rapidly degrade tetracycline (TC). Investigation of the biological mechanisms and degradation pathways of TC by BSFL indicated that nearly 97% of TC was degraded within 12 days in a non-sterile BSFL treatment system, which is up to 1.6-fold faster than that achieved by normal composting. Our results showed that rapid TC-degradation was largely carried out by the intestinal microbiota of the larvae, which doubled the TC-degradation rates compared to those achieved in sterile BSFL systems. This conclusion was further supported by highly-efficient TC-biodegradation both in vivo and in vitro by four larval intestinal isolates. Moreover, detailed microbiome analysis indicated that intestinal bacterial and fungal communities were modified along with significantly increased tet gene copy number in the gut, providing the means to tolerate and degrade TC. Through analysis of TC degradation in vitro, four possible biodegradation products, two hydrolysis products and three conceivable inactivation products were identified, which suggested TC degradation reactions including hydrolysis, oxygenation, deamination, demethylation, ring-cleavage, modification, etc. In conclusion, our studies suggested an estimation of the fate of TC antibiotics in manure treatment by BSFL colonized by gut microbes. These results may provide a strategy for accelerating the degradation of antibiotics by adjusting the intestinal microbiota of BSFL. PMID- 30014942 TI - Aptamer based electrochemical assay for protein kinase activity by coupling hybridization chain reaction. AB - The present work reported a simple, lable-free and sensitive electrochemical method for the detection of protein kinase A (PKA) activity. This method was based on the specific recognition of aptamer and the aptamer-induced hybridization chain reaction (HCR) amplification strategy. The aptasensor was constructed by immobilizing capture probe on a gold electrode via an Au-S bond. When adenosine triphosphate (ATP) aptamer was introduced, its one terminus hybridized with capture probe and the other hybridized with the complementary region of an auxiliary probe, which other region triggered HCR between two hairpin DNA (H1 and H2) to form a long DNA concatamer. At last a large number of electroactive methyle blue (MB) molecules were assembled on the dsDNA concatamer, which generated a significantly amplified electrochemical signal. In the presence of ATP, the HCR would not be performed because the aptamer specifically bond to ATP and the electrochemical response would decrease. However, when ATP and PKA coexisted, the electrochemical response would recovery because that ATP had been translated into ADP by PKA. So the activity of PKA could be effectively monitored according to the change of electrochemical signal. Based on the HCR amplification strategy, the aptasensor showed a wide linear range (4 - 4 *105 U L-1) and a low detection limit (1.5 U L-1) for the detection of PKA. Furthermore, the method was applied to study the inhibitory effect of H-89 on PKA activity. The developed aptasensor was also used to the analysis of drug-induced PKA activity in cell lysates, indicating the potential application of the developed method in the fields of clinical diagnostics and discovery of new targeted drugs. PMID- 30014943 TI - Early detection and monitoring of chronic wounds using low-cost, omniphobic paper based smart bandages. AB - The growing socio-economic burden of chronic skin wounds requires the development of new automated and non-invasive analytical systems capable of wirelessly monitoring wound status. This work describes the low-cost fabrication of single use, omniphobic paper-based smart bandages (OPSBs) designed to monitor the status of open chronic wounds and to detect the formation of pressure ulcers. OPSBs are lightweight, flexible, breathable, easy to apply, and disposable by burning. A reusable wearable potentiostat was fabricated to interface with the OPSB simply by attaching it to the back of the bandage. The wearable potentiostat and the OPSB can be used to simultaneously quantify pH and uric acid levels at the wound site, and wirelessly report wound status to the user or medical personnel. Additionally, the wearable potentiostat and the OPSBs can be used to detect, in an in-vivo mouse model, the formation of pressure ulcers even before the pressure induced tissue damage becomes visible, using impedance spectroscopy. Our results demonstrate the feasibility of using inexpensive single-use OPSBs and a reusable, wearable potentiostat that can be easily sterilized and attached to a new OPSB during the dressing change, to provide long term wound progression data to guide treatment decisions. PMID- 30014944 TI - An amperometric aptasensor for ultrasensitive detection of sulfadimethoxine based on exonuclease-assisted target recycling and new signal tracer for amplification. AB - The risks caused by veterinary drug residues in animal foodstuffs are of great concern to the public. Accordingly, this work reported an amperometric aptasensor for highly sensitive detection of sulfadimethoxine (SDM). Functionalised fullerene (C60)-doped graphene (C60-rGO) nanohybrid was designed and prepared to load electroactive toluidine blue (Tb) through the pi-pi stacking, forming a C60 rGO-Tb nanocomposite. Furthermore, the as-prepared nanocomposite was decorated with gold nanoparticles and used for the immobilization of signal probes to form a new signal tracer, which was coupled with exonuclease-catalyzed target recycling for amplification. To construct the aptasensor, a thiolated double stranded DNA (dsDNA) of aptamer-capture probe complex was immobilised on a gold electrode surface through strong Au-S bond. In the presence of SDM, the aptamer preferred to form an aptamer-SDM complex, which led to the dissociation of dsDNA. Then aptamer could be selectively digested by RecJf exonuclease, resulting in liberated SDM molecules to participate in the next reaction cycling and achieve signal amplification. Then, capture probes released from the cyclic processes were hybridized with the signal tracer, which could further enhance electrochemical signal responses. On the basis of cascade signal amplification strategies, the proposed aptasensor exhibited a wide linear range from 10 fg/mL to 10 ng/mL for SDM with high sensitivity, good selectivity and satisfactory stability. PMID- 30014945 TI - Water-dispersible molecularly imprinted nanohybrids via co-assembly of carbon nanotubes with amphiphilic copolymer and photocrosslinking for highly sensitive and selective paracetamol detection. AB - A novel kind of water-dispersible molecularly imprinted nanohybrids containing multi-walled carbon nanotubes (MWCNTs) was prepared via the combination of co assembly and photocrosslinking, and employed to construct an electrochemical sensor. A photo-crosslinkable amphiphilic copolymer (Poly(AA-co-VMc-co-EHA), PDHES) was firstly synthesized, which could co-assemble with MWCNTs in the presence of template molecule (paracetamol, PCM) in aqueous solution, generating photo-crosslinkable molecularly imprinted nanohybrids (MIP-MWCNTs). A robust MIP MWCNTs film was formed on the electrode surface via the deposition of MIP-MWCNTs nanohybrids and the subsequent photo-crosslinking. After extracting paracetamol molecules, an electrochemical MIP-MWCNTs sensor was successfully developed. The as-prepared MIP-MWCNTs sensor showed a significantly wide linear detection range (0.1-2500 MUM) and low detection limit (0.02 MUM), owing to the large surface area of MIP-MWCNTs nanohybrids and superior electrical conductivity of MWCNTs, which affords a direct channel for the electron transfer from the recognition cavities to the electrode surface and thus enhances the response signal. In addition, good selectivity toward paracetamol (the imprinting factor alpha is 7.5) and ultrafast response time (less than 180 s) of MIP-MWCNTs sensor have also been demonstrated. The MIP-MWCNTs sensor also exhibited satisfactory repeatability and stability, which has been successfully utilized to measure paracetamol in urine samples with good results, demonstrating a promising feature for applications in medical diagnostics. PMID- 30014946 TI - A highly selective electrochemical immunosensor based on conductive carbon black and star PGMA polymer composite material for IL-8 biomarker detection in human serum and saliva. AB - A new approach to enhance the electrochemical performance of biosensor was attempted by using Super P(c) carbon black/Star polymer composite material. In this study, we developed an electrochemical IL 8 biosensor by modification with a conductive composite including Super P, polyvinylidene fluoride (PVDF) and star polymer (SPGMA) of disposable ITO electrode surface. The Super P carbon black as carbonaceous material had a high conductivity and was used for the enhancement of electron transfer between electrode surface and electrolyte. Anti-IL 8 antibodies were utilized as biorecognition molecules and bound to epoxy groups of star polymer covalently. The chemical characterization of antibody immobilization on this composite was performed by using Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy. The characterizations of stepwise modification of this immunosensor were performed by electrochemical techniques such as Electrochemical Impedance Spectroscopy (EIS), Cyclic Voltammetry (CV) and Single Frequency Impedance (SFI); and morphological techniques such as Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Several variables that affect the immunosensor performance were optimized. Under optimum conditions, a wide linear range 0.01-3 pg/mL and low detection limit 3.3 fg/mL were obtained. Super P-star polymer composite modified immunosensor was easy, sensitive, cheap and reliable analytical method for IL 8 detection. The applicability of the proposed immunosensor to determine IL 8 in saliva and serum samples were examined. The results of biosensor and Enzyme-linked Immunosorbent Assay (ELISA) kit were in compatible. Consequently, it was concluded that the electrochemical immunosensor offers a potential approach for IL 8 detection in clinical applications. PMID- 30014947 TI - Cellular environment-responsive intelligent DNA logic circuits for controllable molecular sensing. AB - Here we report smart molecular logic circuits built on a well-designed H-shaped DNA nanostructure that can recognize cell-simulated bioenvironments and modulate the operations of a DNA nanosensor. By assembling a wild-type ATP aptamer and a parallel G-quadruplex into the H-shaped DNA scaffold, two intrinsic cellular components, ATP and K+, are utilized to activate the logic circuits, enabling fluorescent detection of the target DNA via toehold-mediated strand displacement. In this way, two logic circuits consisting of cascaded "AND-AND" and "OR-AND" gates are achieved, which are responsive to the ATP and/or K+ concentration change outside and inside cells, and therefore control whether or not the downstream DNA sensor works. This work illustrates a novel concept for developing new bioinspired DNA molecular devices for not only programmable molecular sensing but also targeted drug delivery. PMID- 30014948 TI - Cost-effective smartphone-based reconfigurable electrochemical instrument for alcohol determination in whole blood samples. AB - The determination of ethanol intoxication in whole blood samples may open the opportunity for a precise and quick point-of-measurement in the ambit of medical emergency or law enforcement. In contrast with traditional techniques based on breath sampling, direct blood measurements present greater immunity to errors specially in case of unconscious or non-collaborative patients. In this context, a portable, sensitive and easy-to-use instrument is highly desirable. In the current work we present a smartphone-based uPotentiostat which combines a novel circuital technique for sensor readout digitalization with a reusable lab-on-a chip (LoC) concept. Such system allows both chronoamperometric and cyclic voltammetry measurements with a reduced number of electronic components on a very compact PCB (38.5 * 22.5 mm2). Power, data-link and user interface are provided in combination with a standard smartphone, enabling cost-effectiveness and reconfigurability without sacrificing precision. The readout platform discussed in this work has been coupled to a LoC for point-of-care combining Pt electrodes microfabricated on silicon substrate for electrochemical measurement and a microfluidic structure of methacrylate for fluid management. Biosensing is enabled by in situ electrodeposition of a calcium alginate hydrogel containing horseradish peroxidase (HPR) and alcohol oxidase (AOx) for selective ethanol detection. Alginate membrane electrodeposition has been here optimized for rapid generation (2 min) and to retain the cellular fraction, thus allowing the measurement in whole blood samples. The uPotentiostat features a sensitivity of 36 nA/g L-1 to ethanol concentration in blood in the 0-1.25 g;L-1 range, with a limit of quantification (LoQ) of 4.5 nA, which is a suitable response for discerning the legal, illegal, severely illegal thresholds in a 40 uL sample of blood. PMID- 30014949 TI - Target-programmed and autonomous proximity binding aptasensor for amplified electronic detection of thrombin. AB - The development of sensitive and simple approaches capable of monitoring trace amounts of protein biomarkers is appealing for disease diagnosis and treatment. Towards this end, we have developed an electrochemical sensing platform for sensitive and simple detection of protein biomarkers by using thrombin as the model target molecules via a target-programmed proximity binding amplification approach. The binding of thrombin to the aptamer sequences in the partial dsDNA duplex probes induces the release of the ssDNA trigger strands, which catalyze subsequent assembly formation of many methylene blue (MB)-tagged proximate DNA motifs with the presence of the DNA fuel strands through cascaded toehold mediated strand displacement reactions. Due to the proximity-binding effect, these MB-tagged proximate DNA motifs anneal with the capture probes on the sensor surface with significantly enhanced stability against the corresponding single component counterpart, thereby pulling the MB tags close to the sensor surface and generating substantially amplified signal responses for sensitive determination of thrombin down to 23.6 pM. In addition, such aptasensor can specifically discriminate thrombin from other interference proteins, and can also be utilized to monitor thrombin in diluted serum samples, demonstrating its great potential for sensitive determination of proteins for early disease diagnosis. PMID- 30014950 TI - Radiomodulatory effects of Aloe vera on hepatic and renal tissues of X-ray irradiated mice. AB - The present study was aimed to explore the protective role of Aloe vera gel extract against hepatic and renal damage caused by X-ray exposure to mice. Male balb/c mice were divided into four groups: control, Aloe vera gel extract [AV] (50 mg/ kg b.w on alternate days for 30 days), X-ray (2 Gy) and AV + X-ray. X-ray irradiation enhanced the serum levels of liver function indices and chromosomal abnormalities in liver. Kidney function markers were found to be deranged and were accompanied by reduced glomerular filtration rate indicating renal dysfunction. Irradiation caused histopathological and biochemical alterations in both tissues which was associated with enhanced reactive oxygen species (ROS), lipid peroxidation (LPO) levels, lactate dehydrogenase (LDH) activity and enhanced apoptosis as revealed by TUNEL assay and DNA fragmentation. The administration of Aloe vera gel extract to X-ray exposed animals significantly improved their hepatic and renal function parameters which were associated with a reduction in ROS/LPO levels, LDH activity and chromosomal abnormalities as compared to their irradiated counterparts. In vitro assays revealed effective radical scavenging ability of Aloe vera gel extract, which may be linked to its potential in exhibiting antioxidant effects in in vivo conditions. This data suggested that Aloe vera may serve to boost the antioxidant system, thus providing protection against hepatic and renal damage caused by X-ray. PMID- 30014951 TI - Optimal sequence of adjuvant endocrine and radiation therapy in early-stage breast cancer - A systematic review. AB - IMPORTANCE: Clinical equipoise exists around the optimal time to start adjuvant endocrine therapy in patients who will receive post-operative radiotherapy for breast cancer. Concerns continue to exist regarding potential reduced efficacy, or increased toxicity, when radiation, and endocrine therapy are administered concurrently. OBJECTIVE: To perform a systematic review of studies comparing outcomes between sequential and concurrent adjuvant radiation and endocrine therapy in early-stage breast cancer. All modalities of radiation therapy were considered, and endocrine therapy could be either tamoxifen or an aromatase inhibitor. Outcomes of interest included; local, regional or distant recurrence, overall survival and treatment-related toxicities. EVIDENCE REVIEWED: PubMed, Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1946 to December 2017. Two reviewers independently assessed each citation using the criteria outlined above. Study quality was assessed using the Cochrane Collaboration's tool for prospective studies, and the Newcastle-Ottawa scale for retrospective studies. FINDINGS: Of 2137 unique citations identified, 13 met eligibility criteria. Eleven were unique studies (7569 patients), while 2 of the studies were updated analyses of previous studies. Studies evaluated the timing of adjuvant radiation, and tamoxifen (5 studies, 1550 patients), or aromatase inhibitors (6 studies, 6019 patients). We identified 1 complete randomized clinical trial (150 patients), and 5 retrospective studies (1580 patients), in addition to conference abstracts (5 studies, 5839 patients). Overall, none of the studies showed a significant difference in efficacy, or toxicity, with concurrent versus sequential treatment. However, given the significant heterogeneity of the study populations, it was not possible to conduct a meta-analysis. CONCLUSIONS AND RELEVANCE: In the absence of high quality data, adequately powered randomized trials are required to answer this important clinical question. PMID- 30014952 TI - Overview of the LUX-Lung clinical trial program of afatinib for non-small cell lung cancer. AB - Tyrosine kinase inhibitors (TKIs) have emerged as first-line treatment for the management of epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib were the initial TKIs to be approved for lung cancer and showed improved response rates compared with chemotherapy. Afatinib is an irreversible ErbB family blocker that has also been shown to be active in EGFR-mutated NSCLC. Afatinib has been tested as first-line treatment of advanced NSCLC in the LUX-Lung trial program, as well as in the second- and third-line settings. In this article, we will review the data from the 8 reported LUX-Lung trials. PMID- 30014953 TI - Does the association between mindful parenting and adolescents' dispositional mindfulness depend on the levels of anxiety and depression symptomatology in mothers? AB - The current study aims to investigate whether mindful parenting and adolescents' dispositional mindfulness differ as a function of maternal anxiety and depressive symptoms and to explore the moderating role of these symptoms on the relationship between mindful parenting and adolescents' dispositional mindfulness. A sample of 685 mother-adolescent dyads was collected in Portuguese public schools. Mothers completed self-reported measures of mindful parenting and symptoms of anxiety and depression, and adolescents (aged 10-18 years) completed a measure of dispositional mindfulness. Mothers with clinically significant symptomatology levels reported lower levels of mindful parenting than those with normal symptomatology. Almost all mindful parenting dimensions were significantly associated with adolescents' mindfulness, but only under lower or moderate levels of anxiety and depression symptomatology. These findings suggest that parental factors play a key role in adolescents' mindfulness skills and underline the detrimental effect of maternal psychopathology on mindful parenting and on its link with adolescents' mindfulness. PMID- 30014954 TI - Direct and indirect effects of father-daughter relationship on adolescent girls' psychological outcomes: The role of basic psychological need satisfaction. AB - Fathers play a salient role in the children's development, especially in daughters. In this study, we examined the direct and indirect effects of father daughter relationship on psychological outcomes of adolescent girls. A total of 310 adolescent girls aged between 14 and 18 (M = 15.88, SD = 0.89) of a Turkish population-based sample completed a battery of self-report surveys measuring perceptions related to father-daughter relationship, basic psychological need satisfaction, well-being, and ill-being. Structural equation modelling results indicated that father-daughter relationship is directly related to higher levels of well-being and lower levels of ill-being. Besides, results demonstrated that indirect effects of basic psychological need satisfaction on the link between father-daughter relationship and psychological outcomes were significant. These findings suggest that father-daughter relationship significantly influences mental health of adolescent girls and this effect is mediated by basic psychological need satisfaction. Implications for counseling interventions and recommendations for future research are discussed. PMID- 30014955 TI - Role of the IL-6-Receptor expression in CD14+ monocytes in modulating sleep in patients with bipolar disorder. AB - OBJECTIVE: Bipolar disorder is a severe mental disorder associated with persistent sleep disturbances and elevated levels of mRNA coding for pro inflammatory cytokines within peripheral monocytes. The mechanisms causing and sustaining a reduced sleep quality remain elusive. The pro-inflammatory cytokine receptor IL-6R is known to negatively affect sleep quality and architecture. Since elevations in IL-6R have repeatedly been demonstrated in bipolar disorder the association of sleep quality and architecture with levels of mRNA coding for IL-6R in monocytes was to be tested. METHODS: Euthymic patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all night polysomnography (PSG) and six day actigraphy. CD14+ monocytes were isolated on the evening of PSG assessment and levels of mRNA coding for IL-6R and other cytokines were determined using hybridization based assays. Interactions between IL-6R and sleep measures were calculated using linear regression models, adjusting for potential confounders. RESULTS: Patients with bipolar disorder were found to have a reduced subjective sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) and more frequent arousals and short changes to wake during sleep. Both PSQI and the frequency of arousals were significantly predicted by levels of IL-6R. Contrary to previous publications, elevated levels of mRNA coding for pro-inflammatory cytokines in peripheral CD14+ monocytes of patients with bipolar disorder could not be replicated. LIMITATIONS: Participants were only investigated with one night of PSG which may have given rise to first night effects. CONCLUSIONS: Reduced sleep quality in euthymic patients with bipolar disorder may be related to an increased expression of IL-6R by peripheral monocytes. PMID- 30014956 TI - Violent criminal behavior in the context of bipolar disorder: Systematic review and meta-analysis. AB - BACKGROUND: Despite the potential importance of understanding violent criminal behavior (VCB) in individuals suffering from bipolar disorder (BD), previous findings are conflicting. The aims of the present study are to clarify the association of VCB and BD in comparison to general population and other psychiatric conditions. METHODS: A systematic review of literature from January 1st, 1980 through January 16th, 2017 from 3 electronic databases (MEDLINE/PubMed, EMBASE and PsycInfo), following the PRISMA and the MOOSE statements. Original peer-reviewed studies reporting data on VCB in BD were included. A random-effects meta-analysis was performed. Potential sources of heterogeneity were examined through subgroup and meta-regression analyses. The protocol was registered in PROSPERO, CRD42017054070. RESULTS: Twelve studies providing data from 58,475 BD participants. The prevalence of VCB in BD was 7.1% (95%CI = 3.0-16.5%; k = 4). The association of BD and VCB compared to general population was not significant (OR = 2.784; 95% CI, 0.687-11.287, P = .152). The association was significant only in cross-sectional studies, in studies in which VCB was assessed through self-reported measures, and in studies conducted in the USA. BD was more likely to be associated with VCB when BD patients were compared to controls with depressive disorders, whilst it was found to be less associated with VCB when BD was compared to psychotic disorders. LIMITATIONS: 1. the methodological heterogeneity across the included studies. 2. causal inferences were precluded by the inclusion of cross-sectional studies. CONCLUSIONS: These findings might provide a more balance portrait of the association between BD and VCB to clinicians, law enforcement and general public. PMID- 30014957 TI - The associations between non-suicidal self-injury and first onset suicidal thoughts and behaviors. AB - BACKGROUND: Theoretical and empirical literature suggests that non-suicidal self injury (NSSI) is an important correlate of suicide risk. The present study was designed to evaluate: (a) whether NSSI is associated with increased odds of subsequent onsets of suicidal thoughts and behaviors (STB) independent of common mental disorders, (b) whether NSSI is associated with increased risk of transitioning from suicide ideation to attempt, and (c) which NSSI characteristics are associated with STB after NSSI. METHOD: Using discrete-time survival models, based on retrospective age of onset reports from college students (n = 6,393, 56.8% female), we examined associations of temporally prior NSSI with subsequent STB (i.e., suicide ideation, plan, and attempt) controlling mental disorders (i.e., MDD, Broad Mania, GAD, Panic Disorder, and risk for Alcohol Dependence). NSSI characteristics associated with subsequent STB were examined using logistic regressions. RESULTS: NSSI was associated with increased odds of subsequent suicide ideation (OR = 2.8), plan (OR = 3.0), and attempt (OR = 5.5) in models that controlled for the distribution of mental disorders. Further analyses revealed that NSSI was associated with increased risk of transitioning to a plan among those with ideation, as well as attempt among those with a plan (ORs = 1.7-2.1). Several NSSI characteristics (e.g., automatic positive reinforcement, earlier onset NSSI) were associated with increased odds of experiencing STB. LIMITATIONS: Surveys relied on self-report, and thus, there is the potential for recall bias. CONCLUSIONS: This study provides support for the conceptualization of NSSI as a risk factor for STB. Investigation of the underlying pathways accounting for these time-ordered associations is an important avenue for future research. PMID- 30014958 TI - A pilot investigation of differential neuroendocrine associations with fronto limbic activation during semantically-cued list learning in mood disorders. AB - BACKGROUND: Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. METHODS: In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18-65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. RESULTS: Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. LIMITATIONS: Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. CONCLUSIONS: Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders. PMID- 30014960 TI - The relevance of epigenetics to seasonal affective disorder. PMID- 30014959 TI - Heterogeneity in emotion regulation difficulties among women victims of domestic violence: A latent profile analysis. AB - BACKGROUND: Research over the past two decades supports emotion regulation as a transdiagnostic factor related to the etiology, maintenance, and treatment of a wide range of psychiatric difficulties and risky behaviors. However, prior investigations are limited by their focus on difficulties regulating negative (but not positive) emotions. Further, research has not accounted for the heterogeneity in difficulties regulating emotions. METHODS: Participants were 210 female victims of domestic violence (DV; M age = 36.14, 48.6% African American) who completed measures assessing emotion regulation (Difficulties in Emotion Regulation Scale; Difficulties in Emotion Regulation Scale - Positive), posttraumatic stress disorder (PTSD; Posttraumatic Stress Diagnostic Scale), depression (Center for Epidemiologic Studies-Depression Scale), alcohol misuse (Alcohol Use Disorder Identification Test) and drug misuse (Drug Abuse Screening Test). Latent profile analysis was utilized to identify subgroups of DV victimized women who were similar in endorsed difficulties in regulating negative and positive emotions. Differences in psychiatric difficulties (i.e., PTSD and depressive symptom severity) and risky behaviors (i.e., alcohol and drug misuse) were examined across these classes. RESULTS: Three classes of DV-victimized women differentiated by levels of difficulties regulating negative and positive emotions were identified. Greater psychiatric difficulties were found among classes defined by higher levels of difficulties regulating emotions, regardless of emotion valence. Risky behaviors were more prevalent among the class defined by higher levels of difficulties regulating both negative and positive emotions. LIMITATIONS: Although results add to the literature on difficulties regulating emotions and their correlates, findings must be interpreted in light of limitations present including use of a cross-sectional and correlation design, reliance on self-report measures, and assessment of a select sample of women victims of DV. CONCLUSIONS: Results highlight the potential importance of tailoring interventions accounting for the heterogeneity in negative and positive emotion regulation dimensions among DV-victimized women. PMID- 30014961 TI - Prevalence of major depressive disorder and association with personal and socio economic factors. Results for Spain of the European Health Interview Survey 2014 2015. AB - BACKGROUND: Depression is a prevalent and most burdensome mental disorder. The objectives of this study are: to assess the prevalence of major depressive disorder in the adult population of Spain; and to analyse its association with personal and socio-economic factors. METHODS: Data from the European Health Interview Survey in Spain (2014-2015) were analysed (n = 21,546). DSM-IV Major Depressive Disorder (MDD) was assessed with the PHQ-8. Personal (age, marital status, and country of birth) and socio-economic (educational level, residence area, employment status and occupational social class) factors were also measured. Prevalence by gender and by personal and socio-economic factors was estimated. Crude (OR) and adjusted (aOR) Odds Ratio and their 95% Confidence Intervals (95%CI) were calculated using logistic regression models. All analyses were stratified by gender. RESULTS: Prevalence of MDD was 8.0% (95%CI: 7.3-8.6) among women and 4.1% (95%CI: 3.7-4.6) among men. For both genders, MDD was more prevalent among unemployed and among those in more disadvantaged social classes. Among women only, MDD was more prevalent for those widowed or separated, those with lower educational level, those retired, pre-retired or homemakers and in older ages. Among men only, MDD was more prevalent among those that were born in Spain. LIMITATIONS: Data are cross-sectional and the sensitivity and specificity of PHQ-8 are not perfect. CONCLUSIONS: Prevalence of MDD in Spain is high, especially among women, and is strongly associated with personal variables and socio-economic disadvantage. Intersectoral interventions aimed at diminishing the impact of socio-economic disadvantage may help decreasing the societal burden of depression. PMID- 30014962 TI - Induced neuro-vascular interactions robustly enhance functional attributes of engineered neural implants. AB - Engineered neural implants have a myriad of potential basic science and clinical neural repair applications. Although there are implants that are currently undergoing their first clinical investigations, optimizing their long-term viability and efficacy remain an open challenge. Functional implants with pre vascularization of various engineered tissues have proven to enhance post implantation host integration, and well-known synergistic neural-vascular interplays suggest that this strategy could also be promising for neural tissue engineering. Here, we report the development of a novel bio-engineered neuro vascular co-culture construct, and demonstrate that it exhibits enhanced neurotrophic factor expression, and more complex neuronal morphology. Crucially, by introducing genetically encoded calcium indicators (GECIs) into the co culture, we are able to monitor functional activity of the neural network, and demonstrate greater activity levels and complexity as a result of the introduction of endothelial cells in the construct. The presence of this enhanced activity could putatively lead to superior integration outcomes. Indeed, leveraging on the ability to monitor the construct's development post implantation with GECIs, we observe improved integration phenotypes in the spinal cord of mice relative to non-vascularized controls. Our approach provides a new experimental system with functional neural feedback for studying the interplay between vascular and neural development while advancing the optimization of neural implants towards potential clinical applications. PMID- 30014963 TI - A fluorescent chemical probe CDy9 selectively stains and enables the isolation of live naive mouse embryonic stem cells. AB - Human and mouse embryonic stem cells (ESCs) differ in terms of their pluripotency status, i.e., naive vs. primed. This affects various biological properties and leads to several technical hurdles for future clinical applications, such as difficulties in chimera formation, single-cell passaging, and gene editing. In terms of generating functional human tissues and organs via mammalian interspecies chimerism, a fluorescent chemical probe that specifically labels naive ESCs would help to isolate these cells and monitor their conversion. This study demonstrates that the fluorescent chemical probe compound of designation yellow 9 (CDy9) selectively stains naive, but not primed, mouse ESCs (mESCs). CDy9 entered cells via Slc13a5, a highly expressed membrane transporter in naive mESCs. Fluorescence-based cell sorting based on CDy9 staining successfully separated naive mESCs from primed mESCs. Mice generated using CDy9+ cells isolated during the conversion of mouse epiblast stem cells into naive mESCs exhibited coat color chimerism. Furthermore, CDy9 specifically stained cells in the inner cell mass of mouse embryos. These findings suggest that CDy9 is a useful tool to isolate functional naive mESCs. PMID- 30014965 TI - Laminin-521 promotes quiescence in isolated stellate cells from rat liver. AB - The laminin alpha5 protein chain is an element of basement membranes and important to maintain stem cells. Hepatic stellate cells (HSC) are liver-resident mesenchymal stem cells, which reside in a quiescent state on a basement membrane like structure in the space of Disse. In the present study, laminin alpha5 chain was detected in the space of Disse of normal rat liver. Since HSC are critical for liver regeneration and can contribute to fibrosis in chronic liver diseases, the effect of laminins on HSC maintenance was investigated. Therefore, isolated rat HSC were seeded on uncoated polystyrene (PS) or PS coated with either laminin 521 (PS/LN-521) or laminin-211 (PS/LN-211). PS/LN-521 improved HSC adhesion and better preserved their retinoid stores as well as quiescence- and stem cell associated phenotype, whereas HSC on PS/LN-211 or PS developed into myofibroblasts-like cells. To improve the homogeneity as well as the presentation of laminin molecules on the culture surface to HSC, laminin-functionalized, gold nanostructured glass surfaces were generated. This approach further enhanced the expression of quiescence-associated genes in HSC. In conclusion, the results indicate that LN-521 supports the quiescent state of HSC and laminin alpha5 can be regarded as an important element of their niche in the space of Disse. PMID- 30014964 TI - Cellular interactions with hydrogel microfibers synthesized via interfacial tetrazine ligation. AB - Fibrous proteins found in the natural extracellular matrix (ECM) function as host substrates for migration and growth of endogenous cells during wound healing and tissue repair processes. Although various fibrous scaffolds have been developed to recapitulate the microstructures of the native ECM, facile synthesis of hydrogel microfibers that are mechanically robust and biologically active have been elusive. Described herein is the use of interfacial bioorthogonal polymerization to create hydrogel-based microfibrous scaffolds via tetrazine ligation. Combination of a trifunctional strained trans-cyclooctene monomer and a difunctional s-tetrazine monomer at the oil-water interface led to the formation of microfibers that were stable under cell culture conditions. The bioorthogonal nature of the synthesis allows for direct incorporation of tetrazine-conjugated peptides or proteins with site-selectively, genetically encoded tetrazines. The microfibers provide physical guidance and biochemical signals to promote the attachment, division and migration of fibroblasts. Mechanistic investigations revealed that fiber-guided cell migration was both F-actin and microtubule dependent, confirming contact guidance by the microfibers. Prolonged culture of fibroblasts in the presence of an isolated microfiber resulted in the formation of a multilayered cell sheet wrapping around the fiber core. A fibrous mesh provided a 3D template to promote cell infiltration and tissue-like growth. Overall, the bioorthogonal approach led to the straightforward synthesis of crosslinked hydrogel microfibers that can potentially be used as instructive materials for tissue repair and regeneration. PMID- 30014966 TI - Neural correlates of response bias: Larger hippocampal volume correlates with symptom aggravation in combat-related posttraumatic stress disorder. AB - The diagnosis of posttraumatic stress disorder (PTSD) is vulnerable to the simulation or exaggeration of symptoms as it depends on the individual's self report of symptoms. The use of symptom validity tests is recommended to detect malingering in PTSD. However, in neuroimaging research, PTSD diagnosis is often taken at face validity. To date, no neuroimaging study has compared credible PTSD patients with those identified as malingering, and the potential impacts of including malingerers along with credible patients on results is unclear. We classified male patients with combat-related PTSD as either credible (n = 37) or malingerers (n = 9) based on the Morel Emotional Numbing Test and compared structural neuroimaging and psychological questionnaire data. Patients identified as malingerers had larger gray matter volumes in the hippocampus, right inferior frontal gyrus and thalamus, and reported higher PTSD symptoms than credible PTSD patients. This is the first structural neuroimaging study to compare credible PTSD patients and malingerers. We find evidence of structural differences between these groups, in regions implicated in PTSD, inhibition and deception. These results emphasize the need for the inclusion of SVTs in neuroimaging studies of PTSD to ensure future findings are not confounded by an unknown mix of valid PTSD patients and malingerers. PMID- 30014967 TI - Altered landing mechanics are shown by male youth soccer players at different stages of maturation. AB - OBJECTIVES: Examine the effects of maturation on single leg jumping performance in elite male youth soccer players. DESIGN: Cross sectional. SETTING: Academy soccer clubs. PARTICIPANTS: 347 male youth players classified as either pre, circa or post-peak height velocity (PHV). MAIN OUTCOME MEASURES: Single leg countermovement jump (SLCMJ) height, peak vertical landing forces (pVGRF), knee valgus and trunk side flexion. RESULTS: Vertical jump height and absolute pVGRF increased with each stage of maturation (p < 0.001; d = 0.85-2.35). Relative to body weight, significantly higher landing forces were recorded on the left leg in circa versus post-PHV players (p < 0.05; d = -0.40). Knee valgus reduced with maturation but the only notable between-group differences were shown in post-PHV players (p < 0.05; d = 0.67); however, greater ipsilateral lateral trunk flexion angles was also present and these differences were significantly increased relative to circa-PHV players (p < 0.05; d = 0.85). CONCLUSION: Periods of rapid growth are associated with landing kinetics which may heighten injury risk. While reductions in knee valgus were displayed with maturation; a compensatory strategy of greater trunk lateral flexion was evident in post-PHV players and this may increase the risk of injury. PMID- 30014968 TI - Comparison of the acute perceptual and blood pressure response to heavy load and light load blood flow restriction resistance exercise in anterior cruciate ligament reconstruction patients and non-injured populations. AB - OBJECTIVES: To compare the acute perceptual and blood pressure responses to: 1) light load blood flow restriction resistance exercise (BFR-RE) in non-injured individuals and anterior cruciate ligament reconstruction (ACLR) patients; and 2) light load BFR-RE and heavy load RE (HL-RE) in ACLR patients. DESIGN: Between subjects, partially-randomised. METHODS: This study comprised 3 groups: non injured BFR-RE (NI-BFR); ACLR patients BFR-RE (ACLR-BFR); ACLR patients HL-RE (ACLR-HL). NI-BFR and ACLR-BFR performed 4 sets (30, 15, 15, 15 reps, total = 75 reps, 30s inter-set rest) of unilateral leg press exercise at 30% 1RM with continuous BFR at 80% limb occlusive pressure. ACLR-HL performed 3 * 10 reps (Total = 30 reps, 30s inter-set rest) of unilateral leg press exercise at 70% 1RM. Perceived exertion (RPE), muscle pain, knee pain and pre- and 5-min post exercise blood pressure were measured. RESULTS: RPE was higher in ACLR-BFR compared to NI-BFR (p < 0.05). Muscle pain was higher in NI-BFR and ACLR-BFR compared to ACLR-HL (p < 0.05). Knee pain was lower in ACLR-BFR compared to ACLR HL (p < 0.01). There were no differences in blood pressure. CONCLUSION: These responses to BFR exercise may not limit application and favourably influence knee pain throughout ACLR rehabilitation training programmes. These findings can help inform practitioners' decisions to utilise this tool. PMID- 30014969 TI - Successful conservative treatment for a subtotal proximal avulsion of the rectus femoris in an elite soccer player. PMID- 30014970 TI - Patient-reported symptoms after breast cancer diagnosis and treatment: A retrospective cohort study. AB - AIM: Breast cancer and its treatment are associated with varying symptoms. The province of Ontario (13.6 million) has implemented a provincial programme to screen for symptoms among cancer patients using the Edmonton Symptom Assessment System (ESAS). The purpose of this study was to describe symptom burden in the year after diagnosis among women with breast cancer. METHODS: This observational study linked cancer incidence, stage, treatment and demographic data with ESAS scores collected at cancer clinic visits. The cohort consisted of all adult women diagnosed with stage I-III breast cancer between 2007 and 2013 who received surgery as their primary treatment and had at least one symptom screening record. The prevalence and trajectory of moderate-to-severe and severe symptom scores in the year after diagnosis were described. Multivariable logistic regression models identified factors associated with moderate-to-severe and severe symptom scores. RESULTS: The cohort included 23,840 breast cancer patients and with 90,556 unique symptom assessments, within the first year from diagnosis. Tiredness had the highest incidence of moderate-to-severe scores; 60% reported at least one moderate-to-severe score in the 12 months after diagnosis, followed by impaired well-being (53%) and anxiety (44%). Elevated symptom scores were most commonly reported in 6 months after diagnosis. Higher comorbidity score (Aggregated Diagnosis Group >=10), more advanced stage at diagnosis, younger age, urban residence, lower income and treatment course were associated with moderate-to severe and severe symptom scores. CONCLUSION: These findings identify time points and patient subgroups at risk for elevated symptom scores and may benefit from personalised or targeted supportive care interventions. PMID- 30014971 TI - Indoleamine 2,3-dioxygenase 1 and programmed cell death-ligand 1 co-expression correlates with aggressive features in lung adenocarcinoma. AB - BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive effector, and its expression is associated with prognosis in several cancer types. Here, we investigated the relationship between IDO1 expression in lung adenocarcinoma and patient prognosis and clinicopathological features, including programmed cell death-ligand 1 (PD-L1) expression. MATERIALS AND METHODS: In this study, surgically resected primary lung adenocarcinoma specimens from 427 patients were evaluated for IDO1 and PD-L1 expression by immunohistochemistry, and lung adenocarcinoma cell lines were evaluated for IDO1 and PD-L1 protein expression by enzyme-linked immunosorbent assay and flow cytometry and for messenger RNA levels by real-time reverse-transcriptase polymerase chain reaction analysis. RESULTS: IDO1 was expressed in 260 patients (60.9%) at 1% cut-off and 63 patients (14.8%) at 50% cut-off. Tissues from 145 patients (34.0%) were positive for PD-L1 using the cut-off of 1%. Multivariate analysis showed that >=1% IDO1 positivity was significantly associated with higher tumour grade, vascular invasion and PD-L1 expression. IDO1 and PD-L1 proteins were co-expressed in 123 patients (28.8%), and co-expressing tumours exhibited significantly more malignant traits than those positive for one or neither protein. In multivariate analysis, co-expression of IDO1 and PD-L1 was significantly associated with shorter disease-free survival and overall survival. Both proteins were upregulated in lung adenocarcinoma cell lines by treatment with interferon-gamma and transforming growth factor-beta. CONCLUSION: These results suggest that IDO1 and PD-L1 co-expression may define an aggressive form of lung adenocarcinoma. PMID- 30014972 TI - Changes in treatment patterns and survival in elderly patients with stage I non small-cell lung cancer with the introduction of stereotactic body radiotherapy and video-assisted thoracic surgery. AB - BACKGROUND: The optimal treatment of elderly patients with early-stage non-small cell lung cancer (NSCLC) remains elusive. Still, the introduction of video assisted thoracic surgery (VATS) and stereotactic body radiotherapy (SBRT) may have led to more elderly receiving treatment and improved median overall survival (OS). MATERIALS AND METHODS: We analysed data from the Netherlands Cancer Registry of 2168 patients >=65 years with clinical stage I NSCLC and distinguished two periods: 2004-2008 (A) and 2009-2013 (B). The analyses focussed on treatment patterns and median OS for patients receiving surgery, radiotherapy or neither surgery nor radiotherapy. Furthermore, we explored the influence of the application of VATS and SBRT. RESULTS: The resection rate did not differ between the periods A and B (51% versus 53%; p = 0.37), despite significantly more VATS procedures in the latter period (0% versus 32%; p < 0.001). Application of radiotherapy increased (26% versus 33%; p = 0.001), especially SBRT (3% versus 63%; p < 0.001). The proportion of patients receiving neither therapy decreased (23% versus 14%; p < 0.001). Median OS for all patients significantly improved (31 versus 42 months; p = 0.001), and also for those receiving radiotherapy (23 versus 33 months; p = 0.02), but not significantly for surgical patients (65 versus 74 months; p = 0.16). Still, in multivariable analysis, surgical patients had an increased risk of death in period A compared with period B (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.01-1.43); this was not the case for patients receiving radiotherapy (HR 1.19; 95% CI, 0.99-1.43). Five-year OS was 57% for surgical patients and 23% for those receiving radiotherapy. CONCLUSION: In elderly patients with stage I NSCLC, the use of surgery remained constant, that of radiotherapy increased and fewer patients received neither treatment over the years. Median OS improved for all patients; surgery was associated with the highest long-term OS. PMID- 30014973 TI - Survival and mortality rates of Wilms tumour in Southern and Eastern European countries: Socioeconomic differentials compared with the United States of America. AB - BACKGROUND: Despite recent therapeutic advancements, Wilms tumour (WT) presents remarkable survival variations. We explored mortality and survival patterns for children (0-14 years) with WT in 12 Southern and Eastern European (SEE) countries in comparison with the United States of America (USA). METHODS: A total of 3966 WT cases (0-14 years) were registered by a network of SEE childhood cancer registries (N:1723) during available registration periods circa 1990-2016 and surveillance, epidemiology, and end results program (SEER) (N:2243; 1990-2012); mortality data were provided by the respective national statistical services. Kaplan-Meier curves and Cox proportional hazards models were used to assess the role of age, sex, year of diagnosis, urbanisation and Human Development Index (HDI) on overall survival (OS). RESULTS: Persisting regional variations shape an overall 78% 5-year OS in the participating SEE countries, lagging behind the USA figure (92%, p=0.001) and also reflected by higher SEE mortality rates. Worth mentioning is the gradually escalating OS in SEE (hazard ratio [HR]5-year increment:0.67, 95% confidence interval [CI]:0.60, 0.75) vs. a non-significant 10% improvement in the SEER data, which had a high starting value. OS differentials [two-fold less favourable among children aged 10-14 years, boys and those living in rural SEE areas (HR:1.37; CI:1.10-1.71) or countries with inferior HDI (2-3-fold)] were minimal in the USA. CONCLUSIONS: Children with WT residing in SEE countries do not equally enjoy the substantial survival gains, especially for those living in rural areas and in lower HDI countries. Noteworthy are steep and sizeable survival gains in SEE along with the newly presented Greek data pointing to achievable survival goals in SEE despite the financial crisis. PMID- 30014975 TI - Incorporating the influent cellulose fraction in activated sludge modelling. AB - Cellulose represents a significant fraction of domestic wastewater, but it is not considered as a separate state variable in the conventional Activated Sludge Models (ASM). Cellulose is a very slowly degradable substrate that in traditional wastewater characterisation methods would be characterised partly as slowly biodegradable and partly as inert material. This can be problematic when the same model is used under different temperature conditions or different solid retention times. Also with the emerging attention for cellulose recovery, inclusion of this compound in models helps to assess the impact of cellulose recovery on operations and on operational costs. But also in membrane bioreactors, sieves are used in order to remove fibrous material, mainly cellulose. In this study a modification of ASM1 is proposed, where cellulose is introduced as a separate state variable and it is supposed to degrade with a first order hydrolysis rate. With the aid of this model, the effect of fine sieves is simulated using two alternatives, by either sieving the influent or the activated sludge. The model proved to be useful for operational purposes, and illustrates the need for including cellulose as separate state variable. PMID- 30014976 TI - A four-year simulation of soil aquifer treatment using columns filled with San Gabriel Valley sand. AB - Two column pairs filled with 3.05-m of a sandy soil from the Upper San Gabriel Valley were operated for a period of four and 1/2 years on municipal effluent from the San Jose Creek Water Reclamation Plant operated by the Sanitation Districts of Los Angeles County (LACSD). One column pair was fed filtered, chlorinated effluent (tertiary effluent) for the entire period. The other pair was fed ozonated secondary effluent for 8-mo, ozonated secondary effluent filtered through biological activated carbon (O3/BAC) for 7-mo and tertiary effluent for 38-mo. Each column pair was operated in series, where the first column was operated for a shorter residence time and the second column for a longer residence time. Residence times tested were 5-d, 28-d, 30-d, 58-d, 60-d, 150-d and 180-d. For the last 38-mo, both pairs of columns had a residence time of 30-d in the first column and the total residence time of the two pairs was 150 and 180-d, respectively. Testing showed both of these pairs had the same long term performance. The column pairs with a 150 to 180-d residence time, which were both fed tertiary effluent, reached an effluent total organic carbon (TOC) of 1.8 mg/L. Column pairs with a 28 to 30-d residence time, which were fed tertiary, ozonated, and O3/BAC effluent, reached effluent TOCs of 2.3, 2.1 and 1.8 mg/L respectively. In the latter, some TOC removal was shifted from the soil columns to the BAC. During the last 38 months of testing, using tertiary effluent as the source water, a series of sampling events was performed throughout the soil column system for N-nitrosodimethylamine (NDMA) and chemicals of emerging concern (CECs). NDMA was substantially reduced in all the columns, with a median value of 3 ng/L after 30-d and <2 ng/L after both 150 and 180-d. Twenty-one CECs were found in the majority of tertiary effluent samples, twelve of which were attenuated by the soil columns and the remaining were not. Chemicals found to be recalcitrant were 4-nonylphenol, acesulfame-k, carbamazepine, lidocaine, primidone, simazine, sucralose, sulfamethoxazole, and TCEP. Using excitation emission matrix (EEM) techniques, soluble microbial products (SMP) peak characteristic of effluent organic matter (EfOM) is nearly eliminated after a 30 d hydraulic retention time (HRT) and completely eliminated in the 150/180-d samples. The intensity of the other peaks is significantly reduced as well, resulting in an EEM much like that of natural groundwater. PMID- 30014974 TI - Prevalence and risk factors for fatigue among breast cancer survivors on aromatase inhibitors. AB - PURPOSE: Fatigue is the most common and distressing symptom experienced by cancer survivors. This study sought to determine the prevalence and risk factors for fatigue among breast cancer (BC) survivors receiving aromatase inhibitors (AIs). MATERIAL AND METHODS: We conducted a cross-sectional survey study among postmenopausal women with stage 0 to III BC receiving adjuvant AI therapy at the outpatient breast oncology clinic of a large university hospital. Participants with a score >=4 on the 'worst fatigue' item of the Brief Fatigue Inventory were classified as having moderate or severe fatigue. Multivariate logistic regression analyses were performed to evaluate risk factors. RESULTS: Among 1103 participants, 616 (55.8%) had moderate or severe fatigue. In the multivariate logistic regression model, women younger than 55 years were significantly more likely to report moderate to severe fatigue than women older than 65 years (adjusted odds ratio [AOR] = 1.58, 95% confidence interval [CI] = 1.07-2.35; p = 0.023). Compared to women with high school or less education, women with college or more education were significantly more likely to report moderate to severe fatigue (AOR = 1.40, 95% CI = 1.02-1.91; p = 0.037). Increasing body mass index (BMI) was significantly associated with increased risk of experiencing moderate to severe fatigue (overweight: AOR = 1.37, 95% CI = 1.01-1.84, p = 0.042; obesity: AOR = 2.08, 95% CI = 1.53-2.81, p < 0.001). Fatigue was significantly correlated with pain severity (r = 0.48, p < 0.001) and insomnia (r = 0.62, p < 0.001). CONCLUSION: Moderate to severe fatigue complaints exceed 50% among AI users. Fatigue is highly related to younger age, higher education level, higher BMI, pain severity and insomnia. PMID- 30014977 TI - Bacterial growth through microfiltration membranes and NOM characteristics in an MF-RO integrated membrane system: Lab-scale and full-scale studies. AB - Biofilm formation on membrane surfaces causes many operational problems such as a decrease in permeate flux and an increase in hydraulic resistance. In this study, the ability of bacteria to pass through microfiltration (MF) membranes and the growth potential of microfilterable bacteria were investigated in order to understand biofouling in MF-reverse osmosis (RO) integrated membrane systems. Growth of microfilterable bacteria in MF permeate was observed, indicating that not all MF membranes can guarantee the total rejection of bacteria. Changes in natural organic matter (NOM) characteristics and growth potential of bacteria during the treatment process are important factors in the occurrence of biofilm development in water treatment systems. Analysis of protein-like and humic-like substances in NOM of two successive RO stages revealed an increase in the concentrations of both biopolymers and humic substances of RO concentrates. Unexpectedly, the use of antiscalants was seen to enhance the growth of bacteria in the RO feed water in this study. Bacterial 16s rRNA pyrosequencing revealed that passing source water through the MF membranes dramatically changed bacterial community structure. The bacterial communities that passed through the MF steps primarily belonged to the family Comamonadaceae. However, several bacteria groups including Flavobacteriaceae, Sphingobacteriaceae and Sphingomonadaceae selectively composed the biofilm community formed on the RO membranes. Thus, understanding the selectivity and filterability of MF towards microorganisms involved in biofouling on RO membrane surfaces is crucial for the improvement of membrane-related operational processes. PMID- 30014978 TI - Clogging vs. fouling in immersed membrane bioreactors. AB - Whilst the fouling of MBR membrane surfaces has been very extensively explored by the academic community, there is an increasingly widespread recognition by practitioners of the issue of clogging of membrane channels with sludge solids, sometimes termed "sludging". The study undertaken has quantified this phenomenon using a bespoke test cell allowing a flat sheet membrane channel to be viewed directly during operation and the accumulated solids determined by digital image processing. Sludging behaviour has then been correlated both with the sludge properties, from sludge samples taken from both an industrial and municipal MBR, and the permeability decline rate data. The work has revealed the expected trends in fouling propensity, as quantified by the exponent n of the Deltap/Deltat = m.exp(nJ) correlation from classical flux-step tests. With zero membrane aeration the industrial samples exhibited sludging, the filling of the complete thickness of the membrane channel with sludge solids, whereas for municipal sludge the solids formed a cake layer which did not fill the channel. In the absence of sludging the permeability decline followed the expected pattern of increasing at the elevated soluble COD and capillary suction time values of the industrial sludge, compared with municipal sludge at the same solids concentration range (8 12 g.L-1). However, there was no evident correlation between fouling (permeability decline without sludging) and sludging: incipient sludging did not appear to influence permeability, though can be assumed to negatively impact on long-term operation, or relate to the sCOD concentration. Sludging instead appeared to depend on the sludge physical properties, and primarily the viscosity: sludge samples at high viscosities were found to exhibit a different air-scour pattern to that at normal MLSS concentrations. Outcomes suggest that sludging is caused by rheological conditions promoting bubble coalescence and bubble stream constriction, reducing the exposure of the membrane surface to scouring air. PMID- 30014979 TI - The influence of land cover on the sensitivity of streams to metal pollution. AB - Identifying freshwater systems that are at risk from anthropogenic stressors is a pressing management problem. In particular, the detection of metal pollution is often constrained by data availability and resources. To address this challenge and develop a tool to identify susceptible systems, we tested whether land cover could be predictive of stream sensitivity to metal pollution, as determined by the biotic ligand model (BLM). We used water chemistry data from the conterminous United States to estimate metal sensitivity in streams using two BLMs (i.e., HydoQual, Bio-Met). Subsequently, we combined the sensitivity estimates with land cover and physiochemical data from the GAGES-II database to build predictive models of sensitivity to metals in streams. When combined, our predictor variables (e.g., land cover, mean annual temperature, mean annual precipitation) generally explained about half of the variation in our dataset. In each model, the percent of wetlands in a watershed was strongly correlated with reduced sensitivity to metals, likely due to increased concentrations of dissolved organic carbon associated with wetlands. To validate the utility of the models, we used them to predict metal sensitivity in sites where metal concentrations had been collected, but where the full suite of BLM parameters were unknown. We were able to classify several hundred sites which are likely at risk to metal pollution. Our work highlights the value in considering metal toxicity at the landscape-scale and describes a new approach to estimate metal sensitivity when site-specific chemical parameters are unknown. PMID- 30014980 TI - Ozone and chlorine reactions with dissolved organic matter - Assessment of oxidant-reactive moieties by optical measurements and the electron donating capacities. AB - Oxidation processes are impacted by the type, concentration and reactivity of the dissolved organic matter (DOM). In this study, the reactions between various types of DOM (Suwannee River fulvic acid (SRFA), Nordic Reservoir NOM (NNOM) and Pony Lake fulvic acid (PLFA)) and two oxidants (ozone and chlorine) were studied in the pH range 2-9 by using a combination of optical measurements and electron donating capacities. The relationships between residual electron donating capacity (EDC) and residual absorbance showed a strong pH dependence for the ozone-DOM reactions with phenolic functional groups being the main reacting moieties. Relative EDC and absorbance abatements (UV254 or UV280) were similar at pH 2. At pH 7 or 9, the relative abatement of EDC was more pronounced than for absorbance, which could be explained by the formation of UV-absorbing products such as benzoquinone from the transformation of phenolic moieties. An increase in fluorescence abatement with increasing pH was also observed during ozonation. The increase in fluorescence quantum yields could not be attributed to formation of benzoquinone, but related to a faster abatement of phenolic moieties relative to fluorophores with low ozone reactivity. The overall *OH yields as a result of DOM induced ozone consumption increased significantly with increasing pH, which could be related to the higher reactivity of phenolic moieties at higher pH. The *OH yields for SRFA and PLFA were proportional to the phenolic contents, whereas for NNOM, the *OH yield was about 30% higher. During chlorination of DOM at pH 7 an efficient relative EDC abatement was observed whereas the relative absorbance abatement was much less pronounced. This is due to the formation of chlorophenolic moieties, which exert a significant absorbance, and partly lose their electron donating capacity. Pre-ozonation of SRFA leads to a decrease of chloroform and haloacetic acid formation, however, only after a threshold of > ~50% abatement of the EDC and under conditions which are not precursor limited. The decrease in chloroform and haloacetic acid formation after the threshold EDC abatement was proportional to the relative residual EDC. PMID- 30014981 TI - Refinery and concentration of nutrients from urine with electrodialysis enabled by upstream precipitation and nitrification. AB - Human urine is a valuable resource for nutrient recovery, given its high levels of nitrogen, phosphorus and potassium, but the compositional complexity of urine presents a challenge for an energy-efficient concentration and refinery of nutrients. In this study, a pilot installation combining precipitation, nitrification and electrodialysis (ED), designed for one person equivalent (1.2 Lurine d-1), was continuously operated for ~7 months. First, NaOH addition yielded calcium and magnesium precipitation, preventing scaling in ED. Second, a moving bed biofilm reactor oxidized organics, preventing downstream biofouling, and yielded complete nitrification on diluted urine (20-40%, i.e. dilution factors 5 and 2.5) at an average loading rate of 215 mg N L-1 d-1. Batch tests demonstrated the halotolerance of the nitrifying community, with nitrification rates not affected up to an electrical conductivity of 40 mS cm-1 and gradually decreasing, yet ongoing, activity up to 96 mS cm-1 at 18% of the maximum rate. Next-generation 16S rRNA gene amplicon sequencing revealed that switching from a synthetic influent to real urine induced a profound shift in microbial community and that the AOB community was dominated by halophilic species closely related to Nitrosomonas aestuarii and Nitrosomonas marina. Third, nitrate, phosphate and potassium in the filtered (0.1 MUm) bioreactor effluent were concentrated by factors 4.3, 2.6 and 4.6, respectively, with ED. Doubling the urine concentration from 20% to 40% further increased the ED recovery efficiency by ~10%. Batch experiments at pH 6, 7 and 8 indicated a more efficient phosphate transport to the concentrate at pH 7. The newly proposed three-stage strategy opens up opportunities for energy- and chemical-efficient nutrient recovery from urine. Precipitation and nitrification enabled the long-term continuous operation of ED on fresh urine requiring minimal maintenance, which has, to the best of our knowledge, never been achieved before. PMID- 30014982 TI - Spatially explicit pollutant load-integrated in-stream E. coli concentration modeling in a mixed land-use catchment. AB - Pathogen contamination is a major cause of surface water impairment in the United States, and fecal bacteria levels are typically used to evaluate microbial loading in bodies of water. Environmental models are considered a useful tool for evaluating watershed management practices. In this study, we assessed E. coli contamination of the Upper Stroubles Creek, Virginia, USA using the Soil and Water Assessment Tool (SWAT) model. The study area has been declared an impaired body of water due to recent bacterial contamination. Bacterial source characterizations play a critical role in such modeling exercises and especially in the case of non-point sources. As the SWAT model involves bacteria load estimation at a Hydrological Response Unit (HRU) level, we use the Spatially Explicit Load Enrichment Calculation Tool (SELECT) for our E. coli load estimations. We also evaluate current approaches to the measurement of bacterial interactions of the sediment-water interface using SWAT and the frequent measurements of streambed E. coli concentrations. For the simulation of in-stream E. coli concentrations using estimates drawn from SELECT without (with) sediment bacteria resuspension-deposition, Nash-Sutcliffe Efficiency (NSE) values of -0.41 to 0.34 (-0.19 to 0.36) are found. Moreover, in-stream E. coli concentrations measured at flow duration intervals show that the model frequently overestimates mid-range flows while underestimating low-range flows even with model improvements. The use of high-resolution E. coli loads and the consideration of sediment bacteria resuspension-deposition processes, generated higher E. coli concentrations for forested areas compared to those of urban and pasture lands, suggesting the importance of using detailed bacteria load estimations and land use information when assessing E. coli distribution in the environment. PMID- 30014983 TI - Discursively framing physicians as leaders: Institutional work to reconfigure medical professionalism. AB - Physicians are well-known for safeguarding medical professionalism by performing institutional work in their daily practices. However, this study shows how opinion-making physicians in strategic arenas (i.e. national professional bodies, conferences and high-impact journals) advocate to reform medical professionalism by discursively framing physicians as leaders. The aim of this article is to critically investigate the use of leadership discourse by these opinion-making physicians. By performing a discursive analysis of key documents produced in these strategic arenas and additional observations of national conferences, this article investigates how leadership discourse is used and to what purpose. The following key uses of medical leadership discourses were identified: (1) regaining the lead in medical professionalism, (2) disrupting 'old' professional values, and (3) constructing the 'modern' physician. The analysis reveals that physicians as 'leaders' are expected to become team-players that work across disciplinary and organizational boundaries to improve the quality and affordability of care. In comparison to management that is negatively associated with NPM reform, leadership discourse is linked to positive institutional change, such as decentralization and integration of care. Yet, it is unclear to what extent leadership discourses are actually incorporated on the work floor and to what effect. Future studies could therefore investigate the uptake of leadership discourses by rank and file physicians to investigate whether leadership discourses are used in restricting or empowering ways. PMID- 30014984 TI - Consensus documents - past, present, and future. PMID- 30014985 TI - Method for preclinical pathology evaluation and analysis of cardiovascular implantable electronic device implant sites. AB - : Cardiovascular implantable electronic devices (CIEDs) typically incorporate leads that directly contact the endocardium. Post-explant pathology evaluation of formalin-fixed CIED lead implant sites and downstream organs (i.e., lungs) can provide useful safety data to the US Food and Drug Administration; however, current regulatory guidelines do not mandate how the safety data are collected. In this paper, we outline a protocol for preclinical pathology evaluation of leads associated with CIEDs, which includes formalin fixation of the heart and lungs, gross evaluation, and qualitative and quantitative histologic evaluation. We recommend fixation of the whole heart with leads in situ alongside intratracheal formalin infusion; this enables rapid and effective preservation of target tissues and increases histologic quality to allow for accurate qualitative and quantitative pathology evaluation. Overall, we believe that our approach to pathology evaluation of leads may maximize information acquired from preclinical studies, leading to more accurate safety assessments. SUMMARY: This article introduces an established method for pathology evaluation and analysis of cardiac leads recommended for companies and researchers that seek approval from a regulatory body. PMID- 30014986 TI - Subcellular partitioning of metals and metalloids (As, Cd, Cu, Se and Zn) in liver and gonads of wild white suckers (Catostomus commersonii) collected downstream from a mining operation. AB - In the present study, we examined the subcellular distribution of metals and metalloids (As, Cd, Cu, Se and Zn) in the liver and gonads of wild white suckers (Catostomus commersonii) collected downstream from a metal mining operation (exposure area) and in a reference area. Metal partitioning among potentially metal-sensitive fractions (heat-denatured proteins (HDP), mitochondria and microsomes) and potentially biologically detoxified fractions (heat-stable proteins (HSP) and metal-rich granules) within cells was determined after differential centrifugation, NaOH digestion and heat-denaturation steps. Metal handling strategies between liver and gonads, and between sexes, were examined. Hepatic metal concentrations were significantly higher in exposed compared to reference fish, especially for Se (14x), Cd (5x) and Cu (3x), and did not vary between sexes. In contrast, gonadal Cd, Cu, Se and Zn concentrations were consistently lower in testes than in ovaries; marked differences in Cd and Se concentrations between exposed and reference fish were observed for both sexes. Overall, metal-handling strategies were similar in both liver (male and female pooled) and female gonads, but differed from those in male gonads, likely due to the different functions assigned to ovaries and testes. Subcellular partitioning of As, Cd and Cu showed that the HSP fraction was most responsive to increased metal exposure, presumably reflecting Cu regulation, and possibly Cd and As detoxification. Zinc concentrations were tightly controlled and mainly found in the HDP fraction. Interestingly, changes in Cd-handling strategy in female gonads were particularly evident, with Cd shifting dramatically from the metal-sensitive HDP fraction in reference fish to the metal-detoxified HSP fraction in exposed fish. It seems that Cd detoxification in female gonads was not fully induced in the less contaminated fish, but became more effective above a threshold Cd concentration of 0.05 nmol/g dry weight. Partitioning of Se was different, with the largest contributor to the total liver and gonad Se burdens being the putative metal-sensitive HDP fraction, suggesting that excess Se in this fraction in exposed fish may lead to Se-related stress. The present subcellular partitioning results demonstrate that metal handling strategies vary among metals, between organs and (in some cases) as a function of metal exposure. They also show promise in identifying metals of potential concern in a risk assessment context. PMID- 30014987 TI - Gold Octahedra nanoparticles (Au_0.03 and Au_0.045): Synthesis and impact on marine clams Ruditapes decussatus. AB - The increased use of gold nanoparticles (AuNPs) in several applications has led to a rise in concerns about their potential toxicity to aquatic organisms. In addition, toxicity of nanoparticles to aquatic organisms is related to their physical and chemical properties. In the present study, we synthesize two forms of gold octahedra nanoparticles (Au_0.03 and Au_0.045) in 1.3-propandiol with polyvinyl-pyrrolidone K30 (PVPK30) as capping agent using polyol process. Shape, size and optical properties of the particles could be tuned by changing the molar ratio of PVP K30 to metal salts. The anisotropy in nanoparticles shape shows strong localized surface plasmon resonance (SPR) in the near infrared region of the electromagnetic spectrum. Environmental impact of Oct-AuNPs was determined in the marine bivalve, Ruditapes decussatus exposed to different concentrations of Au_0.03 and Au_0.045. The dynamic light scattering showed the stability and resistance of Au_0.03 and Au_0.045 in the natural seawater. No significant modification in vg-like proteins, MDA level and enzymatic activities were observed in treated clams with Au_0.03 even at high concentration. In contrast, Au_0.045 induced superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST) activities, in a concentration dependent manner indicating defense against oxidative stress. Enhanced lipid peroxidation represented by malondialdehyde content confirmed oxidative stress of Au_0.045 at high concentration. These results highlight the importance of the physical form of nanomaterials on their interactions with marine organisms and provide a useful guideline for future use of Oct-AuNPs. In addition, Vitellogenin is shown not to be an appropriate biomarker for Oct-AuNPs contamination even at high concentration. We further show that Oct-AuNPs exhibit an important antioxidant response without inducing estrogenic disruption. PMID- 30014988 TI - A novel two-stage biomass gasification concept: Design and operation of a 1.5 MWth demonstration plant. AB - To gasify the biofuel of low ash melting temperature and overcome the high content of tar in bio-gas, a novel two-stage gasification concept is proposed. This concept enables the tar-free bio-gas generated in the gasification process under thermal cracking. On that basis, a demonstration project is introduced. Rice husk acts as the feedstock for its accessibility on-site in the commissioning period. System reliability has been confirmed for the stable operation of more than 60 days. Tests have been performed under some typical operating conditions. As the results suggest, the bio-gas of 6.7 MJ/Nm3 LHV is generated with cold gas efficiency and carbon conversion of 67.5% and 87% respectively. Elementary economic evaluation of this concept is also made in accordance with the commissioning results. As a result, the annual net profit of 40.92 K USD is yielded without a subsidized price for biomass materials. PMID- 30014989 TI - The adsorption properties of endoglucanase to lignin and their impact on hydrolysis. AB - Nonproductive adsorption of cellulase to lignin dramatically influenced the hydrolysis efficiency of lignocellulose. By comparing the adsorption behaviors of CBH and EG, we found that the adsorption of EG to lignin showed lower adsorption velocity and capacity versus CBH. During the adsorption of EG to lignin, carbohydrate binding domain (CBM) and catalytic domain (CD) both played an important role by a two-step adsorption process, in which CD slowly bond on lignin and developed stronger interaction with lignin. The optimal binding position of EG on lignin was consistent with that on polysaccharide located in the open catalytic tunnel. So, the adsorption of EG to lignin not only limited the movement of enzyme, but also restricted the catalytic ability of enzyme, which dramatically influenced enzymatic hydrolysis. Increasing the proportion of EG in cellulase cocktails or engineering "weak lignin adsorbed" EG was necessary to relieve the influence of lignin adsorption on hydrolysis. PMID- 30014990 TI - Effects of digestion time in anaerobic digestion on subsequent digestate composting. AB - Digestion time (DT) in anaerobic digestion (AD) on performance of subsequent digestate composting regarding compost maturity and greenhouse gas (GHG) emission was investigated. Digestates for composting were obtained after anaerobically digested mixture of dairy manure, corn stalks, and tomato residues (48:32:20, volatile solids based) with DT of 15, 30, and 45 days, respectively. Digestates were composted with corn stalks (85:15, wet weight based). Results showed approximately 30% and 70% of biochemical methane potential (342.0 L/kg VSfeedstock) were obtained when DT of 15 and 30 days. Digestate co-composting with cornstalks could be initiated effectively and reduced GHG emissions by 18.9 29.0% compared to compost with raw materials. DT of 30 and 45 days digestate composting cause benefit on germination index. DT of 45 days had the highest net power production in combine AD and composting system. DT of 30 days digestate composting was optimum choice for compost maturity and GHG emissions. PMID- 30014991 TI - Effect of sodium chloride on polyhydroxyalkanoate production from food waste fermentation leachate under different organic loading rate. AB - Polyhydroxyalkanoate (PHA) production integrated with anaerobic digestion is promising for food waste recycle. However, effect of salinity and high organic load in waste fermentation leachate (FWFL) on PHA production is unknown. Effects of sodium chloride (NaCl, 0, 5.0, 10.0 and 15.0 g/L) and organic loading rate (OLR, 1350 and 8433 mg COD/(L.d)) on the enrichment of PHA-accumulating microorganisms and PHA accumulation using FWFL were investigated in this research. Stable operation and obvious effect were observed under lower OLR with increasing NaCl concentration, but effect of NaCl was concealed by the inhibition caused by high OLR. Paracoccus was the dominant bacteria in all treatments with NaCl. Microbial community at low OLR and 5.0 g/L NaCl had the best performance reflected by kinetic parameters. Real FWFL with different NaCl concentrations was used in batch assays to verify the optimized enrichment strategy, reaching the maximum PHA content of 33.4% at 2.5 g/L NaCl. PMID- 30014992 TI - Feasibility of enhancing short-chain fatty acids production from waste activated sludge after free ammonia pretreatment: Role and significance of rhamnolipid. AB - This study reported a new, renewable and high-efficient strategy for anaerobic fermentation, i.e., using free ammonia (FA) to pretreat waste activated sludge (WAS) for 1 d and then combining with rhamnolipid (RL), by which the short-chain fatty acids (SCFA) production was remarkably improved. Experimental results showed the maximal SCFA production of 324.7 +/- 13.9 mg COD/g VSS was achieved at 62.6 mg FA/L pretreatment combined with 0.04 g RL/g TSS, which was respectively 5.95-fold, 1.63-fold and 1.41-fold of that from control, FA pretreatment and RL pretreatment. Mechanism investigations revealed that FA + RL enhanced sludge solubilization and hydrolysis, providing more organics for subsequent SCFA production. It was also found that the combined method inhibited acidogenesis and methanogenesis, but the inhibition to methanogenesis was much severer than that to acidogenesis. Finally, the feasibility of NH4+-N and PO3-4-P, released in fermentation liquor, being recovered as magnesium ammonium phosphate (MAP) was confirmed. PMID- 30014993 TI - Development of denitrifying phosphate accumulating and anammox micro-organisms in anaerobic hybrid reactor for removal of nutrients from low strength domestic sewage. AB - Low strength domestic sewage was treated in an Anaerobic Hybrid Reactor. The first phase was focused on the enhancement of denitrifying phosphate accumulating organisms (DPAOs) for the concurrent removal of nitrogen and phosphate. 16S rRNA gene confirmed the presence of Flavobacterium spp. and Pseudomonasalcaligenes spp. which are dominant DPAOs. The second phase was the anaerobic ammonium oxidation (anammox) enrichment phase, and it exhibited much higher chemical oxygen demand (87%) and nitrogen removal (90%) as compared to the first phase. However, it had failed to remove the phosphate from the system. In case of anammox, the dominant specie detected was Candidatus Brocadia, along with minor counts of Candidatus Jettenia and Anammoxoglobus Propionicus. Apart from that, ammonia oxidizing bacteria (Nitrosomonas europaea, Nitrosomonas nitrosa) and methanogens (Methanosaeta, Methanobacterium) were also detected in the system. This study showed the feasibility of anammox species over DPAOs in treating domestic sewage. PMID- 30014994 TI - Dissipation characteristics of pyrene and ecological contribution of submerged macrophytes and their biofilms-leaves in constructed wetland. AB - The dissipation characteristics of pyrene and ecological contribution of submerged macrophytes (Vallisneria natans, Hydrilla verticillata and artificial plant) and their biofilms-leaves in constructed wetland system were investigated by high-throughput sequencing. Results showed a non-negligible ecological contribution of submerged macrophytes and their biofilms-leaves in dissipating pyrene in planted sediments (33.25-43.00%) in contrast with unplanted system (23.25-26.50%). Alpha and Beta diversity analysis indicated that bacterial community structures were influenced in order of attached surface > incubation time > spiking concentration of pyrene in sediment. Difference analysis suggested that attached surface tended to affect the rare genera up to significant level compared with incubation time. In addition, RDA analysis showed that PAH degrading bacteria in biofilms-leaves of submerged macrophytes were positively correlated with the dissipation ratios of pyrene. Interestingly, nitrogen transforming microorganisms were also influenced in the presence of pyrene, while submerged macrophytes contributed to alleviate the impact. PMID- 30014995 TI - Effects of aqueous phase recirculation in hydrothermal carbonization of sweet potato waste. AB - Aqueous phase recirculation was investigated in hydrothermal carbonization of sweet potato waste at 220 degrees C for 60 min. The result showed that the aqueous phase reuse significantly increased the hydrochar yield. The lower H/C and O/C ratios indicated that decarboxylation reaction was promoted. The CC vibration of the benzene backbone became intense, suggesting the occurrence of aromatization and polymerization reactions. Thus, the carbon content and HHV were improved. After recirculation, hydrochar showed a decrease in combustion ignition temperature whereas an increase in pyrolysis initial decomposition temperature. The burnout temperatures in combustion and terminated temperature in pyrolysis both showed an increase trend. The hydrochars obtained from the recirculation step possessed lower emissions of NOX or SO2 than that from reference step. The pyrolysis emission result showed that more high thermal stability components were formed during recirculation step. Overall, aqueous phase recirculation was a feasible way to improve hydrothermal carbonization process. PMID- 30014996 TI - Rapid selection of astaxanthin-hyperproducing Haematococcus mutant via azide based colorimetric assay combined with oil-based astaxanthin extraction. AB - The aim of this work was to develop a new approach for simple and high-throughput selection of astaxanthin-hyperproducing Haematococcus mutants through a sequential combination method of azide-based colorimetric assessment and oil based astaxanthin quantification. Randomly mutagenized cells were spotted on solid culture medium containing 50 uM of sodium azide to accelerate the biosynthesis of astaxanthin. After 3 days, highly-induced mutants were preliminarily isolated by visual inspection and their astaxanthin accumulations were rapidly quantified by soybean oil-based extraction method. On the whole, the selected mutants showed reduced vegetative growth rates but eventually exhibited higher astaxanthin productions than the parental strain owing to their improved inductive growths. Among them, M13 showed 174.7 +/- 5.69 mg L-1 of the highest astaxanthin production, which is 1.59-times higher than that of wild-type. This wide-scope screening method expedites both upstream and downstream astaxanthin quantification, making it a useful tool for isolating microalgae with high astaxanthin production. PMID- 30014997 TI - Effects of individual and complex ciprofloxacin, fullerene C60, and ZnO nanoparticles on sludge digestion: Methane production, metabolism, and microbial community. AB - Antibiotics and nanoparticles, emerging contaminants, present great environmental risks and human health concerns. Sludge adsorption, a biological wastewater treatment removal mechanism, targets ciprofloxacin (Cip) antibiotics, C60, and ZnO, leaving complex pollution in sludge anaerobic digestion. This study investigated the mechanisms through which individual and combined ZnO, Cip, and C60 affect sludge anaerobic digestion by studying their effects on CH4 production, metabolism, and microbial community. ZnO was generally more toxic to CH4 production than Cip. The ZnO + Cip complex was more influential (>29%) than ZnO or ZnO + C60, with short-lasting acute and additive toxicity effects on methanogenesis and degradation of protein and carbohydrate. ZnO + C60 and ZnO + Cip exerted apparent additional complex effects on Firmicutes, Aminicenantes, Chloroflexi, and Parcubacteria. These results would potentially aid toxicity control related to complex pollution, and improve energy production and reduce pollution risks when used in land applications. PMID- 30014998 TI - Kinetic analyses and synergistic effects of CO2 co-gasification of low sulphur petroleum coke and biomass wastes. AB - This study presents thermogravimetric analyses (TGA) of CO2 co-gasification of petroleum coke with low sulphur (PC) and various types of biomass wastes including agricultural (rice husk (RH), rice stalk (RS) and cotton straw (CS)) and by-product wastes (saw dust (SD) and sugar cane bagasse (SCB)). Their reactivities, synergistic effect and kinetics were studied and compared in detail. The homogeneous model (HM) and shrinking core models (SCM) were applied to estimate the kinetic parameters. The results indicated that obvious synergistic effect was observed during the co-gasification of the blends. The PC gasification reactivity was significantly improved by the addition of biomass wastes. The model of R2 was found to be most suitable for the co-gasification. The activation energy of PC was decrease from 293.72 kJ/mol to117.04 kJ/mol by the addition of SD. The co-gasification of PC and biomass waste is a promising way for the efficient utilization of PC and biomass wastes. PMID- 30014999 TI - Succession of bacterial community function in cow manure composing. AB - Succession of bacterial community, metabolism function and substrate utilization capacity in 60 days composting of cow manure were analyzed by 16S rRNA pyrosequencing, PICRUSt and Biolog method, respectively. The results showed that the number of bacterial OTUs increased from 176 in raw cow manure to 203 on Day 10, 220 on Day-30 and 313 on Day-60 of the composting, respectively. The PICRUSt analysis showed that the relative abundances of genes involved in lipid and carbohydrate metabolism increased by 28.5% and 22.4% during the incubation, respectively, but the abundances of the genes involved in nucleotide and amino acid metabolism decreased by 21.6% and 2.1%. Furthermore, the average well color development (AWCD) of carboxylic acids (0.99-0.48) and amino acids (1.61-0.89) in Biolog Eco-microplate displayed a steady downtrend through the composting process. Redundancy analysis showed that ORP, moisture and temperature could explain 68.1%, 17.6% and 14.2% of the variation in bacterial genera, respectively. PMID- 30015000 TI - Alkali/urea pretreatment of rice straw at low temperature for enhanced biological hydrogen production. AB - A pretreatment process using alkali/urea solution at low temperature was proposed for enhanced cellulosic biohydrogen production. Different alkaline solutions with both presence and absence of urea were studied. It can be found NaOH/Urea pretreatment exhibited excellent pretreatment performance at temperature from -8 degrees C to -20 degrees C. Microscopic structure observation combined FTIR analysis further demonstrated that NaOH/Urea pretreatment at low temperature could effectively disrupt the structure of rice straw and made more cellulose and hemicellulose available. The pretreated materials were then subjected for biohydrogen production by Thermoanaerobacterium thermosaccharolyticum M18. The maximum hydrogen production and energy conversion efficiency of 22.08 mmol/L and 9.76% were obtained from NaOH/Urea pretreated rice straw at low temperature. The results were 161.92% and 56.91% higher than the counterpart without pretreatment, respectively. This study provides a new direction to pretreat lignocellulose efficiently for enhanced biohydrogen production at cold climate region. PMID- 30015001 TI - CO2 conversion by the integration of biological and chemical methods: Spirulina sp. LEB 18 cultivation with diethanolamine and potassium carbonate addition. AB - The aim of this work was to evaluate if the addition of the chemical absorbents diethanolamine and potassium carbonate affects the CO2 biofixation, growth and biomass composition of Spirulina sp. LEB 18. The association of the diethanolamine (DEA) and potassium carbonate (K2CO3) absorbents increased the dissolved inorganic carbon concentration in the cultivation medium, allowing greater CO2 biofixation by the Spirulina. Higher biomass concentration (2.1 g L 1) and maximum productivity (174.2 mg L-1 d-1) were observed with the mixture of 1.64 mmol L-1 of DEA and 0.41 mmol L-1 of K2CO3. In this cultivation condition, Spirulina sp. LEB 18 showed high protein content (58.8 w w-1) and an increased carbohydrate concentration (23.7% w w-1). The addition of these absorbent concentrations may be applied in the cultivation of Spirulina sp. LEB 18 to increase CO2 biofixation and cell growth. PMID- 30015002 TI - Influence of sulfadimethoxine (SDM) and sulfamethazine (SM) on anammox bioreactors: Performance evaluation and bacterial community characterization. AB - The specific inhibitory effects of sulfonamides on anaerobic ammonium oxidation (anammox) process remain unknown. This study investigated the inhibitory characteristics of sulfadimethoxine (SDM) and sulfamethazine (SM) in two anammox bioreactors with NH4+-N (160 mg/L) and NO2--N (210 mg/L) in influent. Results indicate that anammox bacteria in both bioreactors adapted to low antibiotic concentrations (less than 3 mg/L). At concentrations between 5 and 7 mg/L, SDM inhibited the growth of anammox bacteria and resulted in a decrease of Candidatus Brocadia abundance from 2.57% to 0.39%. In contrast, at concentrations of 5-9 mg/L, SM inhibited the denitrification process more severely than SDM, resulting in higher accumulation of nitrite and nitrate. The purpose of this study was to elucidate the inhibitory effects of sulfonamides on the anammox process and to provide a reference for the stable operation of anammox bioreactors for the treatment of sulfonamide-containing wastewater. PMID- 30015003 TI - Insight into structure-reactivity relationships for the iron-catalyzed hydrotreatment of technical lignins. AB - The viability of several technical lignins as a source for biobased platform chemicals was investigated via hydrotreatment using a cheap Fe-based limonite catalyst and without using a solvent. In general, high-quality oils (up to 29 wt% total monomers) with an average relative composition of 55% alkylphenolics and 27% aromatics were obtained. Detailed structural investigations showed that the S G aromatic unit content of the lignins was the most important factor positively affecting overall oil yields. A second parameter was the lignocellulose processing method. Even though alkaline lignin isolation provides more recalcitrant lignins, their lower aliphaticity and methoxy group content partially limit char and gas formation. Finally, enhanced monomer yields could be obtained irrespective of the ether linkage content, and a high amount of beta-O-4 linkages actually showed a slightly negative effect on monomer yields. Overall, the results demonstrate that this route is particularly suitable for processing residual lignin streams. PMID- 30015004 TI - Anesthetic management of carcinoid heart disease after cardiac surgery. A possible use of veno-arterial extracorporeal membrane oxygenation support. PMID- 30015005 TI - Emotional and behavioral adjustment in 4 to 11-year-old boys and girls with classic congenital adrenal hyperplasia and unaffected siblings. AB - It has been suggested that atypical hormone environments during early development may contribute to subsequent development of psychopathology. Also, it has been suggested that individuals with the autosomal recessive genetic variant, classic congenital adrenal hyperplasia (CAH), might be at increased risk of psychopathology. The present study examined emotional and behavioral adjustment in young children with CAH and their unaffected siblings in the United Kingdom. The parent-reported version of the Strengths and Difficulties Questionnaire (SDQ) was employed to assess adjustment in children aged 4 to 11 years. There were 38 boys with CAH, 43 girls with CAH, 23 unaffected brothers, and 31 unaffected sisters. No differences in emotional or behavioral problems were found between boys or girls with CAH and unaffected same-sex siblings. In addition, affected and unaffected boys in the current sample generally did not differ from boys in the general population. However, compared with girls in the general population, girls with CAH had more difficulties related to conduct problems, hyperactivity/ inattention, and prosocial behavior, and unaffected sisters had more difficulties related to peer problems, conduct problems, and prosocial behavior. These findings suggest that both girls with CAH and unaffected sisters of girls or boys with CAH may be at increased risk of developing behavioral problems. Potential influences related to the early hormone environment, familial process, and social stigma are considered. PMID- 30015006 TI - Influence of pre-existing hypertension on neuroendocrine and cardiovascular changes evoked by chronic stress in female rats. AB - This study investigated neuroendocrine, autonomic, and cardiovascular changes evoked by daily exposure to the same type of stressor (homotypic) or different aversive stressor stimuli (heterotypic) in 60-days-old female normotensive Wistar rats and female spontaneously hypertensive rats (SHR). Both strains of rats were exposed for 10 consecutive days to either the homotypic stressor repeated restraint stress (RRS) or the heterotypic stressor chronic unpredictable stress (CUS). As expected, SHR had higher baseline blood pressure values and impaired baroreflex activity in relation to normotensive animals. Besides, SHR presented higher plasma corticosterone levels and decreased thymus weight. Both RRS and CUS increased baseline plasma corticosterone concentration and decreased body weight gain in both normotensive and SHR rats. In addition, both stress protocols caused hypertrophy of adrenal glands in normotensive rats. Regarding the cardiovascular effects, RRS increased basal heart rate in both rat strains, which was mediated by an increase in sympathetic tone to the heart. Besides, RRS increased baroreflex-mediated tachycardia in SHR animals, while CUS increased cardiac parasympathetic activity and pacemaker activity in normotensive rats. Taken together, these results indicate a stress type-specific effect, as identified by a vulnerability of both strains to the deleterious cardiovascular effects evoked by the homotypic stressor and a resilience to the impact of the heterotypic stressor. Vulnerability of hypertensive rats was evidenced by the absence of CUS evoked adaptive cardiovascular responses and an increase of baroreflex tachycardia in SHR animals subjected to RRS. The somatic and HPA axis changes were overall independent of the chronic stress regimen and pre-existing hypertension. PMID- 30015007 TI - A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice. AB - A polymorphism in the P2RX7 gene that encodes for the P2X7 ionotropic ATP-gated receptor (P2X7R) protein has been shown to be associated with an increased risk for developing depressive illnesses. However, the role of P2X7R in depression is still unclear. To better understand the role of P2X7R and its subsequent impact on microglial activation, we compared the effect of the P2X7R antagonist Brilliant Blue G (BBG) with that of fluoxetine in an unpredictable chronic mild stress (UCMS) model of depression in mice. Our results indicate that BBG (50 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day) successfully reversed the degradation of coat states and nest-building scores induced by exposure to UCMS, similar to the conventional antidepressant fluoxetine (15 mg/kg body weight in 0.9% NaCl, 10 ml/kg/day). BBG also reversed the UCMS-induced microglial activation in cortical and hippocampal regions and the basal nuclei of mouse brains and corrected the UCMS-induced hypothalamo-pituitary-adrenal (HPA) axis dysregulation. In contrast to fluoxetine, however, BBG treatment did not increase the density of doublecortin-positive cells in the dentate gyrus, indicating that BBG had no impact on hippocampal neurogenesis. These results suggest that P2X7R is involved in recovery from depressive-like states caused by exposure to UCMS in a mechanism that involves restoration of the HPA axis but not hippocampal neurogenesis. These results add to the evidence that P2X7R antagonist agents may have potential value in the pharmacological management of depression. PMID- 30015009 TI - Maternal parity and perinatal cortisol adaptation: The role of pregnancy-specific distress and implications for postpartum mood. AB - INTRODUCTION: Compared to women who have given birth before (i.e., multiparas), those giving birth for the first time (i.e., primiparas) show higher cortisol levels. Psychological factors may play a role; hypothalamic-pituitary-adrenal activation is a well-described stress response. Primiparity also predicts greater risk for postpartum depression, which may be related to greater correspondence between cortisol and mood following prenatal cortisol elevations. The current study examined associations among parity, perinatal cortisol adaptation, pregnancy-specific distress, and postpartum mood. METHODS: This longitudinal study assayed serum cortisol levels among 137 women at early, mid-, and late pregnancy and postpartum. Pregnancy-specific distress and depressive symptoms were assessed. Maternal age, race, body mass index, sleep quality, depressive symptoms, and sampling time of day were statistically controlled. RESULTS: Primiparous women showed higher cortisol levels than multiparous women during mid (chi2 = 11.8, p < 0.01) and late pregnancy (chi2 = 18.9, p < 0.01) and higher distress across pregnancy (F1,126 = 22.1, p < 0.01). Mediation analyses demonstrated that the association between parity and prenatal cortisol (per area under the curve; AUC) was partially accounted for by distress (ab = 1.0, 95%CI [0.05, 2.9]). Prenatal cortisol (per AUC) did not predict postpartum depressive symptoms (b* = 0.03, p = 0.81), with no difference by parity (b* = 0.03, p = 0.91). At postpartum, a significant interaction between parity and cortisol (b* = 0.40, p = 0.03) revealed no significant association between cortisol and mood among multiparas (b* = -0.11, p = 0.28) but a trend toward a positive association among primiparas (b* = 0.24, p = 0.06). DISCUSSION: Cortisol levels and pregnancy specific distress are higher in primiparas versus multiparas, with pregnancy specific distress partially mediating the association between parity and cortisol levels. Cortisol levels and mood display correspondence at postpartum in primiparous but not multiparous women. While observational studies must be interpreted with caution due to potential unmeasured confounders, these findings suggest that future studies examining mechanisms underlying perinatal and postpartum hypothalamic-pituitary-adrenal perturbations and designing interventions aimed at preventing related complications should carefully consider potential differences by parity. PMID- 30015008 TI - Sexual orientation and salivary alpha-amylase diurnal rhythms in a cohort of U.S. young adults. AB - Sexual minorities in the United States are at elevated risk of prejudice, discrimination, and violence victimization due to stigma associated with their sexual orientation. These stressors may contribute to physiological stress responses and changes in the regulation of the sympathetic nervous system (SNS). To date, no studies have examined the associations among minority sexual orientation, recent stressful events, and diurnal salivary alpha-amylase (sAA) patterns. The present study included 1663 young adults ages 18-32 years (31% men, 69% women) from the Growing Up Today Study, a prospective cohort of U.S. youth. Participants provided five saliva samples over the course of one day to estimate diurnal sAA patterns. Sexual orientation groups included completely heterosexual with no same-sex partners (CH; referent), mostly heterosexual/completely heterosexual with same-sex partners, and gay/lesbian/bisexual (LB or GB). Sex stratified multilevel models were fit to evaluate the association of sexual orientation with diurnal patterns of log sAA. The association of recent stressful events was also evaluated. Among women, sexual minorities scored significantly higher than CH on perceived stress and number of stressful events in the past month (p < 0.05). Among men, sexual minorities scored higher than CH on perceived stress but not recent stressful events. In multivariable models, recent stressful events were not associated with sAA patterns, but significant sexual orientation group differences in sAA diurnal rhythm were observed among women though not among men. Compared to CH women, LB showed a blunted awakening response and elevated sAA levels across the day, both indicators consistent with SNS dysregulation. Findings suggest dysregulation of stress physiology in LB women, but not other sexual minority women or men, relative to same-sex heterosexuals. Observed dysregulation may relate to exposure among LB women to chronic stressors associated with sexual orientation stigma, although these relations and differences by sex warrant further study. PMID- 30015010 TI - Prenatal and postnatal cortisol and testosterone are related to parental caregiving quality in fathers, but not in mothers. AB - Testosterone and cortisol have both been implicated in human parenting behavior. We investigated the relations between observed quality of caregiving during parent-child interactions and pre- and postnatal testosterone and cortisol levels, in both mothers (N = 88) and fathers (N = 57). Testosterone and cortisol were measured before and after interaction with an infant simulator (prenatal) and with their own child (postnatal) to index basal levels as well as steroid reactivity to the interaction. Our findings are that in fathers, interactions between cortisol and testosterone are related to quality of caregiving both pre- and postnatally. Prenatally there was a stronger negative relation between T and quality of caregiving in fathers with lower cortisol levels, and postnatally there was a stronger negative relation between cortisol and quality of caregiving in fathers high in testosterone levels. Furthermore, prenatal cortisol levels were related to paternal quality of caregiving during interaction with their own child. In mothers, no associations between quality of caregiving and our endocrine measures were observed. We interpret our findings in the context of hyperreactive physiological responses observed in parents at risk for insensitive caregiving, and in light of the dual-hormone hypothesis. The current findings contribute to the growing literature on the endocrine antecedents of human caregiving behavior. PMID- 30015011 TI - iAcet-Sumo: Identification of lysine acetylation and sumoylation sites in proteins by multi-class transformation methods. AB - MOTIVATION: Posttranslational modification (PTM) is a biological mechanism involved in the enzymatic modification of proteins after translation by ribosomes. Two or more modifications occurring at one residue can be transformed into a multi-label system. Two or more simultaneous modifications on a residue is more common than single PTMs. Lysine residues in proteins can be subjected to a variety of PTMs, such as ubiquitination, acetylation, sumoylation, methylation, and succinylation. Identification of uncharacterized sequences in proteins is a highly significant and state-of-the-art issue. Notably, in order to provide a method of processing multi-label sequences of lysine residues, it is highly desirable to develop computational methods to predict lysine acetylation and sumoylation modifications. RESULTS: In this paper, we first launched an integrated approach, known as the five-step prediction method (FSPM), to solve the problem effectively by (1) using one-sided selection (OSS) to deal with imbalanced data, (2) extracting binary features from protein sequences, (3) incorporating binary relevance, classifier chains and multi-class transformation methods to simplify multi-label problems, (4) constructing different classifiers, and (5) implementing cross-validation and evaluating these classifiers. In 10 fold cross-validation, FSPM achieved an accuracy of 61.49% and an absolute-true rate of 60.17%. The results showed that FSPM is accurate and could be used as a powerful engine in multi-label systems. We also conducted a variety of statistical analyses of the predicted results to discuss the biological functions of lysine acetylation and sumoylation. PMID- 30015012 TI - Automatized colon polyp segmentation via contour region analysis. AB - The increasing use of colorectal cancer screening programs has contributed to the growing number of colonoscopies performed by health centers. Hence, in recent years there has been a tendency to develop medical diagnosis support tools in order to assist specialists. This research has designed an automatized polyp detection system that allows a reduction in the rate of missed polyps that can lead to interval cancer; one of the main risks existing in colonoscopy. A characterization has therefore been made of the shape, color and curvature of edges and their regions, enabling the segmentation of polyps present in colonoscopy images. A 90.53% polyp detection rate has been achieved using the designed system, and 76.29% and 71.57% segmentation quality for the Annotated Area Covered and Dice Coefficient indicators respectively. This system aims to offer assistance with medical diagnosis that has a positive impact on patient health. PMID- 30015013 TI - Modeling the influence of co-localized intracellular calcium stores on the secretory response of bovine chromaffin cells. AB - Catecholamines secretion from chromaffin cells is mediated by a Ca2+-dependent process in the submembrane space where the exocytotic machinery is located and high-Ca2+ microdomains (HCMDs) are formed by the coordinated activity of a functional triad composed of Ca2+ channels, endoplasmic reticulum (ER) and mitochondria. It has been observed experimentally that subpopulations of cortical mitochondria and ER associate to secretory sites in bovine chromaffin cells. Here, we study the effect of the geometrical distribution of the co-localized cortical organelles both in the formation of HCMDs in the vicinity of Ca2+ channels and on the secretory activity of bovine chromaffin cells in response to a single voltage pulse. Our simulations indicate that co-localized organelles have a dual role in the formation of HCMDs, having, on the one hand, an amplification effect due to the Ca2+-induced Ca2+-release mechanism from the ER and, on the other, acting as physical barriers to Ca2+ diffusion. In addition, our simulations suggest that the increased levels of Ca2+ in the microdomain enhances the secretion of the vesicles co-localized to the Ca2+ channels. As a whole, our results support the idea that the functional triads formed by Ca2+ channels, subplasmalemma ER and mitochondria have a positive effect on the secretion of catecholamines in bovine chromaffin cells. PMID- 30015014 TI - RNAi-mediated antiviral immunity in mammals. AB - RNA interference (RNAi) was discovered in plants where it functions as the main antiviral pathway and this antiviral role was subsequently extended to invertebrates. But it remained hotly debated whether RNAi fulfils a similar role in mammals that already have a potent innate immune system based on interferon and an elaborate adaptive immune system. On the one hand, mammalian cells do encode most of the RNAi machinery, but this could be used exclusively to control cellular gene expression via micro RNAs (miRNAs). But on the other hand, virus derived small interfering RNAs, the hallmark of RNAi involvement, could not be readily detected upon virus infection of mammalian cells. However, recent studies have indicated that these signature molecules are generated in virus-infected embryonic cell types of mammals and that viruses actively suppress such responses by means of potent RNAi suppressor proteins. Thus, the tide seems to be changing in favor of RNAi as accessory antiviral defense mechanism in humans. Intriguingly, recent studies indicate that insects have also developed an additional innate immune system that collaborates with the RNAi response in the fight against invading viral pathogens. Thus, the presence of multiple antiviral response mechanisms seems standard outside the plant world and we will specifically discuss the interactions between these antiviral programs. PMID- 30015015 TI - A study of interface reaction zone in a SiC fibre/Ti-17 composite. AB - The interface reaction zone (RZ) in a unidirectional continuous carbon-coated SiC fibre reinforced Ti-17 titanium alloy composite is investigated. Micro-computed tomography (CT), scanning and transmission electron microscopy are employed to characterize the fibre/matrix interface. It is revealed that the interface RZ is a 400 nm thick titanium carbide (TiC) layer which is composed of two sublayers, a 60 nm thick fine-grained sublayer and an approximate 340 nm thick coarse-grained sublayer. The RZ is formed through chemical reaction between carbon coating on the SiC fibre surface and Ti, Zr and Sn in the alloy matrix. The reaction is controlled by atom diffusion occurring at the fibre/matrix interface. However, in the reaction process, Al, Cr and Mo in the matrix are rejected and piled up in front of the RZ on the matrix side. A structure model is proposed to describe the formation mechanism of the interface RZ. PMID- 30015016 TI - Multiple-ellipse fitting method to precisely measure the positions of atomic columns in a transmission electron microscope image. AB - In this paper, we propose a multiple-ellipse fitting method to accurately determine the atomic column positions in transmission electron microscopy (TEM) images. The column is enclosed by a series of ellipses fitted from contour lines at equidistant intensity levels, and each atomic column is shaped by an averaged elliptical shape to obtain its positions. In particular, the intensity profile of the atomic column can be obtained by an elliptically rotational average based on its shape; therefore, the intensities of the neighbouring atomic column can be subtracted for each atomic column during subsequent position refinement. This method can achieve precision in the picometre range, and we quantitatively measure this precision by analysing an image containing two Gaussian-shaped atoms and some simulated high-resolution transmission electron microscopy (HRTEM) images of SrTiO3. PMID- 30015017 TI - Synthesis, characterization, anti-diabetic potential and DFT studies of 7-hydroxy 4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime. AB - A new compound named 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime (7 Oxime) was synthesized and characterized by FT-IR, FT-Raman, 1H NMR and 13C NMR techniques. The conformer possibilities were studied to find the most stable conformer and its molecular geometry. Then, the dimer form of the most stable monomer was built and optimized. Density functional theory (DFT) B3LYP method with 6-311++G(d,p) basis set was applied to analyze the molecular electrostatic potential (MEP), HOMO and LUMO orbitals, the vibrational wavenumbers, the infrared intensities, the Raman scattering activities and several thermodynamic properties (at different temperatures). The stability of the molecule derived from hyperconjugative interactions and charge delocalization has been analyzed by using natural bond orbital (NBO) analysis. In order to find the possible inhibitory activity of 7-Oxime, an accurate molecular blind docking simulation was performed. The results indicated that the mentioned compound has a good binding affinity to interact with the active sites of human alpha-glucosidase and alpha-amylase. For the first time, our computational finding suggests that this compound has a potential to be used as a supplementary agent in the pre management of diabetes mellitus. PMID- 30015018 TI - Local-dependency of morphological and optical properties between breast cancer cell lines. AB - Breast cancer is the most malignant type of cancer in women and is a global health problem, with mortality by metastasis being the main factor among others. Currently, detection and diagnosis of breast cancer is achieved through a variety of procedures, such as clinical examination, medical imaging, biopsy, and histopathological analysis. In contrast, spectroscopic analysis has a variety of advantages such as being noninvasive, not destroying biological materials, and not requiring additional histological analysis. In this study, various approaches using Raman spectroscopy, atomic force microscopy (AFM), and optical microscopy were used together to differentiate between and characterize normal breast cell lines (MCF-10A) and breast cancer cell lines (MDA-MB-231, MDA-MB-453). Raman spectra of normal breast cell and breast cancer cell lines confirmed visual differences in the concentrations of various compounds. These spectra were also analyzed using principle component analysis (PCA), and the PCA results showed reliable separation of the three cell lines and the cancer cell lines (MDA-MB 231, MDA-MB-453). With these results, optically synchronizing the AFM morphology, the Raman spectroscopy, and the visible RGB optical transmission intensity provided contrasts for not only conformational differences but also intracellular variation between the normal and cancer cell lines. We observed the inherent characteristic that there is no local difference in cancer cells regardless of morphology in a wide range of optical properties such as absorption, scattering and inelastic scattering. PMID- 30015019 TI - Irreversible solvent-assisted structural transformation in 3D metal-organic frameworks: Structural modification and enhanced iodine-adsorption properties. AB - In this work, we demonstrate a solvent-assisted structural transformation between two 3D metal-organic frameworks (MOFs) ([Zn4(alpha-bptc)2(H2O)3]n (1) -> {[Zn2(alpha-bptc)(H2O)4].(pra)}n (2)) (alpha-H4bptc = 2,3,3',4'-biphenyl tetra carboxylic acid and pra = pyridin-2-amine) at room temperature by immersing complex 1 in a mother solution. The structural transformation involves not only solvent exchange but also the cleavage and formation of coordination bonds, which is confirmed by infrared spectroscopy, single-crystal X-ray diffraction analysis, powder X-ray diffraction patterns, and thermogravimetric analysis. Structural analyses revealed that significant modifications occurred during the transformation including the changes in lattice parameters, unit cell volume, space group, coordination number, secondary building units, and topological type. In the case of drastic structural transitions, significant changes in properties were also observed. Complex 2 displayed the interesting uptake and release of iodine with the changes in visible color, UV and fluorescence spectra, and fully reversible I2 uptake of 8.5 mg g-1, which further suggested about its future application as iodine absorbing material. PMID- 30015020 TI - Synthesis, spectral characterization, molecular modeling, antibacterial and antioxidant activities and stability study of binuclear Pd(II) and Ru(III) complexes with novel bis-[1-(2-[(2-hydroxynaphthalen-1 yl)methylidene]amino}ethyl)-1-ethyl-3-phenylthiourea] ligand: Application to detection of cholesterol. AB - A novel bis-[1-(2-[(2-hydroxynaphthalen-1-yl) methylidene]amino}ethyl)-1-ethyl-3 phenylthiourea] Schiff base (L) and its binuclear palladium and ruthenium complexes have been prepared and characterized by ESI-MS, elemental analysis, NMR (1H NMR, 13C NMR, COSY, NEOSY and HSQC), FT-IR, ATR, UV-Visible spectra, TGA measurements, conductivity and cyclic voltammetry. The experimental results and the molecular parameters calculated using DFT method revealed a square planar geometry around Pd and octahedral geometry around ruthenium metal. The antibacterial activity of the ligand L and its complexes was evaluated against different human bacteria. In addition, the formation constants of the synthesized Schiff base-metal complexes and the systems formed with these chelates and cholesterol were estimated using spectrophotometric technique. The detection of cholesterol using novel Pd and Ru Schiff base complexes was studied using fluorometric method, and the measurements showed that the sensitive fluorometric response towards cholesterol analysis was determined using palladium complex. The limit of detection (LOD) of cholesterol calculated using this complex (4.6 MUM) is lower (better) than LOD found using ruthenium complex (19.1 MUM) and different compounds previously published around linear range of 0-5 mM. PMID- 30015021 TI - Testing the purity of spectral profiles: Finger-print resolution of complex matrices and extraction of absorbance signals. AB - The application of spectrophotometric techniques has shown a tremendous development over the past few years, where it is possible to determine the concentrations of several components in complex matrix. A new feature will be introduced in this work where the application of spectrophotometric techniques will be enhanced to resolution and checking the purity of signals. The finger print resolution "ratio subtraction method" (RSM) was coupled with the novel complementary method "unified constant subtraction" (UCS); in addition to the methods: extended ratio subtraction method (EXRSM), constant multiplication (CM) or "spectrum subtraction" (SS). These techniques were applied for the determination of the complex matrix of the binary mixture of chloramphenicol and dexamethasone. By applying official spectrophotometric methods, direct determination of the components was allowed with no need for validation procedures. The spectrophotometric techniques were successfully applied to the laboratory prepared mixtures and the combined dosage form where the purity of the extracted signals were tested by calculating the spectral contrast angle (theta) and the spectral ratio factor (SRF) where the results were compared to show the capability to recover pure spectral profiles and detect the presence of impurities. The proposed methods proved that spectrophotometric techniques can be used for identification and separation of signals, similar to chromatographic techniques. PMID- 30015022 TI - UV-Vis, FTIR, 1H, 13C NMR spectra and thermal studies of charge transfer complexes formed in the reaction of Gliclazide with pi- and sigma-electron acceptors. AB - Charge transfer interactions (CT) between a gliclazide (GLC) donor and a picric acid (PA) pi acceptor or iodine sigma acceptor, were studied in a chloroform solution and in the solid state. UV-vis spectroscopy elucidated the formation of the complexes, and allowed determination of the stoichiometry, stability constants (K), and thermodynamic quantities (DeltaG degrees , DeltaH degrees , and DeltaS degrees ), and spectroscopic properties such as the molar extinction coefficient (epsilonCT), oscillator strength (f), transition dipole moment (MUEN), and ionization potential (Ip). Beer's law was obeyed over the 2-8 and 4 12 MUg mL-1 concentration ranges for GLC with PA (method A) and I2 (method B), respectively, with correlation coefficients of 0.9986 and 0.9989. The limits of detection (LOD) and limits of quantification (LOQ) have also been reported. The 1:1 stoichiometric CT complexes were synthesized and characterized by FTIR, 1H, and 13C NMR spectroscopy. The results indicated a favorable proton migration from PA to the donor molecule, and an interaction between the NH of GLC and iodine. Thermogravimetric analysis techniques (TGA/DTA) and differential scanning calorimetry (DSC) were used to determine the thermal stability of the synthesized CT complex. The kinetic parameters (DeltaG*, DeltaH*, and DeltaS*) were calculated from thermal decomposition data using the Coats-Redfern method. PMID- 30015023 TI - Krypton-methanol spectroscopic study: Assessment of the complexation dynamics and the role of the van der Waals interaction. AB - The Kr-CH3OH (Krypton-Methanol) system has several technological applications, such as the determination of diffusivity coefficients, their use in the development of detectors and combustion techniques among others. We report an extensive theoretical study concerning the stability of such complex. A mix between molecular dynamics, electronic structure calculations and solution of the nuclear Schrodinger equation lead to investigation of spectroscopic constants, lifetime of the complex and its Quantum Theory Atom in Molecules (QTAIM) properties. The study of the Potential Energy Curves (PEC) suggested three configurations to be stable as their potential well were able to harbor 9 vibrational levels. Properties from the curves also allowed us to obtain the lifetime of the complex, whose values were >1 ps regardless of the conformation. Furthermore, topological investigations of the charge density profile of the complex, in the scope of QTAIM properties, show that van der Waals type interactions takes place between the noble gas and the methanol molecule. These features are in consonance to the experimental fact that this complex is stable. PMID- 30015024 TI - Enhanced chemical and spatial recognition of fish bones in surimi by Tri-step infrared spectroscopy and infrared microspectroscopic imaging. AB - Surimi is an intermediate product with an increasing popularity worldwide. Discrimination of impurities like fish bones in surimi has become an urgent issue owing to the food safety and the improved requirements for assessment methods in identification of surimi quality and grades. A Tri-step infrared spectroscopy, including Fourier transform infrared spectroscopy (FT-IR), second derivative infrared spectroscopy (SD-IR) and two-dimensional correlation infrared spectroscopy (2DCOS-IR) has been applied to integrally discriminate different contents (1%-8%) of fish bones in surimi at macro-scale. Meanwhile, attenuated total reflection infrared spectroscopy (ATR-IR) microspectroscopic imaging has been employed to recognize and identify the location of fish bones (less than 1.0 mm in size) in micro-scale. Fishbone characteristic infrared absorption peak at 1011 cm-1 contributes to surimi peaks at 1045 cm-1 and 988 cm-1 confirmed by calculation of their peak heights and ratios of peak areas in original spectra. SD-IR spectra enhance the difference in range of 1440-500 cm-1, and specifically peak intensity at 599 cm-1 is significantly increased in surimi with 3%-8% fish bones. Moreover, 2DCOS-IR spectra reveal that surimi containing fish bones have increased intensity of auto-peaks at 525 cm-1, 519 cm-1, 512 cm-1 and 505 cm-1 mainly contributed by hydroxyapatite and collagen. In ATR-IR microspectroscopic images, a clear fishbone shape (800 * 200 MUm) corresponding to its visible image is clearly observed in principal component (PC) score image, which is confirmed as a fish bone by corresponding pixel spectra. Furthermore, the single-wavenumber image shows the spatial chemical distribution of various components for both the fish bone and surimi. Consequently, fish bones can be integrally recognized by physical and chemical imaging manners. It has been demonstrated that the developed Tri-step infrared spectroscopy and ATR-IR microspectroscopic imaging could be applicable for rapidly recognizing impurities and adulterants in surimi. PMID- 30015025 TI - Rapid production of cadmium infinite coordination polymer nanofiber via solvent induced precipitation method. AB - The precipitation synthesis of cadmium infinite coordination polymer (Cd-ICP) nanofibers with a high degree of uniformity is reported. The elemental analyses (CHN and ICP-OES), energy-dispersive X-ray spectroscopy (EDX) and thermogravimetric analysis (TGA) show that thermally robust monodisperse solid consists of bi-carboxylic acid linker and cadmium ion. The coordination between the Cd2+ ion and bi-carboxylic acid linker was investigated by Fourier transform infrared (FT-IR) spectroscopy. The photoluminescence (PL) properties of the Cd ICP were studied in comparison with those of the bi-carboxylic acid linker. It was shown that the emission intensity of the Cd-ICP is much stronger than linker due to the structural rigidity after the coordination of linker to Cd ions. The field emission scanning electron microscopy (FE-SEM) results show that after calcination of the Cd-ICP the morphology changed from fiber to hexagonal-like disc. Furthermore, the results of UV-Vis spectroscopy show larger band gap for obtained CdO relative to the bulk counterpart. PMID- 30015026 TI - Urea-based porous organic polymer/graphene oxide hybrid as a new sorbent for highly efficient extraction of bovine serum albumin prior to its spectrophotometric determination. AB - A 3D urea-based porous organic polymer (Urea-POP) was prepared via the reaction of tetrakis(4-aminophenyl)methane and 1,4-Phenylene diisocyanate. The polymer was subsequently reacted with 2D layered nanosheets of graphene oxide (GO) to prepare Urea-POP/GO as a novel and highly efficient sorbent for pre-concentration and extraction of serum albumin samples, prior to spectrophotometric determination. The hybrid material combines advantages of both POP and GO such as hydrophilicity, high dispersion stability, porosity, and having a large number of nitrogen- and oxygen-containing functional groups. Parameters which influence the extraction efficiency such as the amount of the adsorbent, pH of sample solution, ionic strength, adsorption and desorption time were investigated and optimized. For the method, detection limit of 0.068 mg L-1 and determination coefficient (R2) of 0.9991 were obtained. The intra- and inter-day was calculated with five replicates in the same day and seven consecutive days, respectively. Intra-day and inter-day precisions were 1.7% and 5.9%, respectively. The maximum sorption capacity was 357.1 mg g-1, which is higher than the other reported sorbents. The proposed method was demonstrated to be sensitive enough for determination of serum albumin from bio-samples. PMID- 30015027 TI - Comparison and application of fluorescence EEMs and DRIFTS combined with chemometrics for tracing the geographical origin of Radix Astragali. AB - Selection of the appropriate method for traceability may be of great interest for the characterization of food authenticity and to reveal falsifications. The possibility of tracing the geographical origins of Radix Astragali based on diffuse reflectance mid-infrared Fourier transform spectroscopy (DRIFTS) technique and fluorescence fingerprints (EEMs) technique was investigated in this work. DRIFTS technique combined with PCA and PLS-DA and EEMs technique combined with M-PCA and N-PLS-DA were used to determine the geographical origin of Radix Astragali samples, respectively. DRIFTS-PLS-DA provided total recognition rates of 98.4% for all Radix Astragali samples in the training sets and 94.6% in the predicted sets. Compared with the DRIFTS, EEMs combined with chemometrics obtained more accurate recognition results. The total recognition rates (RRs) of the training sets and prediction sets obtained with EEMs-N-PLS-DA were all 100%. The good classification results of fluorescence fingerprints technique should be attributed mainly to two reasons. One reason is that three-dimensional fluorescence spectrum can provide more information than two-dimensional DRIFTS, and the other reason is that fluorescence spectrum has higher sensitivity and selectivity than the DRIFTS. Therefore, fluorescence fingerprint (EEMs) technique combined with chemometrics results more adequate for tracing the food geographical origin. It should be noted that the more the analysis target contains fluorescent substances, the more accurate results are obtained by using the fluorescent fingerprint method. Conversely, if the classification object contains very few fluorescent substances, the classification result may not be as good as the DRIFTS method. Furthermore, due to relatively cumbersome operation of fluorescence method, EEMs fluorescence method is unsuitable for rapid analysis as compared to infrared method. PMID- 30015028 TI - Effect of temperature on the electrical properties of lanthanum ferrite. AB - Electric and dielectric properties of lanthanum ferrite were investigated by the alternating current impedance spectroscopy. Results reveal that LaFeO3 exhibits a non-Debye type relaxation. High values of epsilon' were obtained at low frequency. Such behavior was explained based on the Maxwell-Wagner polarization model. Furthermore, a low dielectric loss was obtained at high frequencies indicating that the obtained compound is an important candidate for nonlinear optical application. The variation of the AC conductivity with frequency at different temperatures obeys the universal Jonscher's power law. The decreasing trend of the exponent s with temperature increase suggests that the correlated barrier hopping model is adequate to describe the conduction mechanism in LaFeO3. Furthermore, the density of the localized states N(Ef) at the Fermi level was calculated at different temperatures. Results reveal an increase in N(Ef) with temperature increase. Such behavior explains the observed increase in sigmaac. PMID- 30015029 TI - Manganese-doped carbon quantum dots-based fluorescent probe for selective and sensitive sensing of 2,4,6-trinitrophenol via an inner filtering effect. AB - In the present work, a selective and sensitive method for detecting TNP using manganese doped carbon quantum dots (Mn-CDs) was developed. The Mn-CDs were prepared via a simple hydrothermal method using 1-(2-pyridinylazo)-2-naohthalenol naohthalenol (PAN) and MnCl2 as precursors. The as-prepared Mn-CDs have UV emission with high quantum yield (83.2%). Because of the strong characteristic absorption of TNP at 356 nm, which has good spectral overlap with the emission peak of Mn-CDs, the fluorescence intensity of Mn-CDs at 360 nm is linearly quenched in the presence of TNP in the concentration range of 0.1-200 MUM. The developing assay based on an inner filter effect (IFE) mechanism for detecting TNP is selective, convenient, and shows that the as-prepared Mn-CDs have application prospects for simple and specific analytical chemistry. PMID- 30015030 TI - Dual-channel fluorescence detection of mercuric (II) and glutathione by down- and up-conversion fluorescence carbon dots. AB - The fluorescent carbon dots (CDs) with high fluorescent quantum yield (phif = 62%) and down- and up-conversion fluorescence properties were synthesized by one pot hydrothermal treatment of citric acid and tris(hydroxymethyl)methyl aminomethane. The CDs displayed the capability to absorb excitation wavelength at 660 nm and 330 nm with fluorescence emission wavelength at 398 nm and 399 nm, respectively. The CDs showed high selectivity towards Hg2+ against various metal ions. Around 70% fluorescence was quenched by 40 MUM Hg2+ through dynamic and static quenching mechanisms. Because of stronger affinity between the thiol and Hg2+, over 90% fluorescence was recovered by adding 40 MUM glutathione to CDs Hg2+ system. The calibration curves exhibited wide linear region for Hg2+ (0-4 MUM) and glutathione (0-30 MUM). The limits of detection with down- and up conversion for Hg2+ were calculated to be 0.23 MUM and 0.25 MUM, and for glutathione were 0.28 MUM and 0.29 MUM, respectively. Inspired by the sensing results, logic gates with Hg2+ and glutathione as inputs were also established. Most importantly, this method was applied to detect Hg2+ and glutathione in tap water and lake water, and the recovery values were obtained to be 96.2%-110.4% and 93.4%-96.9%. PMID- 30015031 TI - Binding mechanism of five typical sweeteners with bovine serum albumin. AB - In this work, the interactions between bovine serum albumin (BSA) and five sweeteners including aspartame (APM), acesulfame (AK), sucralose (TGS), sodium cyclamate (SC), and rebaudioside-A (REB-A) have been studied by multispectroscopic techniques, and molecular simulation in order to provide much useful information for the application of new and safer artificial sweeteners. Fluorescence quenching assays indicated that the formation of complexes between sweeteners and BSA mainly induced the fluorescence quenching of protein and the binding site number were about 1 indicting that there is one mainly binding site of APM, AK, TGS, SC, or REB-A in domain of BSA with relatively weak interactions. Molecular modeling results indicated that hydrogen bonding interactions were the mainly binding forces of sweeteners with BSA. Circular dichroism spectra indicated that APM and REB-A obviously induced the secondary structure changes of BSA. The presence of APM increased the fraction of alpha-Helix of BSA from 65.4% to 73.8%, while the presence of REB-A resulted in decreasing the fraction of alpha-helix of BSA from 65.4% to 51.2%. The melting temperature studies showed that these five sweeteners except REB-A act as stabilizers to increase the thermal stability of BSA during the thermal denaturation process. In addition, AK, TGS, and SC obviously increased the esterase-like activity of BSA, and such loss of activity of BSA induced by APM and REB-A. PMID- 30015032 TI - Quantum cascade laser based absorption spectroscopy for direct monitoring of atmospheric N2O isotopes. AB - A compact high-resolution spectroscopic sensor using a thermoelectrically (TE) cooled continuous-wave (CW) room temperature (RT) quantum cascade laser (QCL) operating at 4.6 MUm, is employed for simultaneous detection of three main isotopic species (14N15N16O, 15N14N16O and 14N14N16O). To enable a high-precision analysis of N2O isotopic species at ambient mixing ratios, a liquid nitrogen-free preconcentration unit is built to trap and load atmospheric N2O. The absorption spectra of 14N15N16O, 15N14N16O, and 14N14N16O between 2188.6 cm-1 and 2189 cm-1 are measured, and the respective ratios of the rare to the abundant isotopologues abundances are demonstrated. Moreover, spectroscopic parameters of pressure broadening coefficient for selected absorption lines have been determined, and a good agreement is obtained by comparing with HITRAN database. PMID- 30015033 TI - Monazite, rhabdophane, xenotime & churchite: Vibrational spectroscopy of gadolinium phosphate polymorphs. AB - Rare-earth phosphates with the general formula REEPO4.nH2O belong to four distinct structural types: monazite, rhabdophane, churchite, and xenotime. We report herein the first direct comparison between vibrational spectra of these compounds for the same metal cation i.e. gadolinium. The four GdPO4.nH2O samples were prepared through wet chemistry methods and first characterized by X-ray diffraction. Three distinct spectral domains, associated to the deformation and stretching modes of phosphate tetrahedra (PO4) and to water molecules vibrations were then analyzed from FTIR and Raman data, and discussed regarding the structural characteristics of each sample. The most obvious differences between the spectra were associated to delta(H2O) and deltas(PO4) modes and led to propose a simple method to rapidly and unambiguously discriminate the four polymorphs. PMID- 30015034 TI - Synthesis of 5-(5-methyl-benzofuran-3-ylmethyl)-3H- [1, 3, 4] oxadiazole-2-thione and investigation of its spectroscopic, reactivity, optoelectronic and drug likeness properties by combined computational and experimental approach. AB - This paper reports the synthesis of 5-(5-methyl-benzofuran-3-ylmethyl)-3H- [1, 3, 4] oxadiazole-2-thione (5MBOT) and characterization by FT-IR, FT-Raman, 1H NMR, 13C NMR and UV spectral studies. The density functional theory (DFT) calculations have been executed for the 5MBOT using B3LYP/6-31++G (d, p) basis set. The fundamental modes of the vibrations were designated by the potential energy distribution (PED), and the computed and experimental values support each other. The 1H NMR and 13C NMR chemical shifts of 5MBOT were estimated by gauge-including atomic orbitals (GIAO) method and compared with the experimental chemical shifts. The UV-Vis method used to study the visible absorption maxima (lambdamax) by using Time-Dependent DFT. Further, the Mulliken population analysis (MPA), natural population analysis (NPA) charges, thermodynamic properties at different temperatures were presented. The calculated HOMO and LUMO energies show that charge transfer within the molecule. The natural bonds orbital (NBO) also computed. Optoelectronic properties have been carried out by combination of DFT calculations and molecular dynamics (MD) simulations, in order to assess the potential of this structure for applications in organic electronics. Further, the study encompassed calculations of reorganization energies for holes and electrons and charge transfer rates. DFT calculations have been also used in order to identify locations possibly sensitive towards the autoxidation mechanism, which correlates between bond dissociation energy for hydrogen abstraction and the mechanism. The MD simulations have been used to understand interaction of 5MBOT with water molecules. Molecular docking studies reveals the antifungal activity of 5MBOT may be due to hydrogen bonding and hydrophobic interactions with different antifungal proteins. PMID- 30015035 TI - Brain regional synchronous activity predicts tauopathy in 3*TgAD mice. AB - Alzheimer's disease (AD) is characterized by progressive cognitive impairment and by extensive neuronal loss associated with extracellular amyloid beta-peptide (Abeta) plaques and intraneuronal tau pathology in temporal and parietal lobes. AD patients are at increased risk for epileptic seizures, and data from experimental models of AD suggest that aberrant neuronal network activity occurs early in the disease process before cognitive deficits and neuronal degeneration. The contributions of Abeta and/or tau pathologies to dysregulation of neuronal network activity are unclear. Using a transgenic mouse model of AD (3*TgAD mice) in which there occurs differential age-dependent development of tau and Abeta plaque pathologies, we applied analysis of resting state functional magnetic resonance imaging regional homogeneity, a measure of local synchronous activity, to discriminate the effects of Abeta and tau on neuronal network activity throughout the brain. Compared to age-matched wild-type mice, 6- to 8-month-old 3*TgAD mice exhibited increased regional homogeneity in the hippocampus and parietal and temporal cortices, regions with tau pathology but not Abeta pathology at this age. By 18-24 months of age, 3*TgAD mice exhibited extensive tau and Abeta pathologies involving the hippocampus and multiple functionally related brain regions, with a spatial expansion of increased local synchronous activity to include those regions. Our findings demonstrate that age-related brain regional hypersynchronous activity is associated with early tau pathology in a mouse model, consistent with a role for early tau pathology in the neuronal circuit hyperexcitability that is believed to precede and contribute to neuronal degeneration in AD. PMID- 30015036 TI - Estimates of age-related memory decline are inflated by unrecognized Alzheimer's disease. AB - Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-beta status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-beta and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory. PMID- 30015037 TI - Rapid method to determine plutonium, neptunium, americium and curium in granite samples. AB - A fast method for determination of plutonium, neptunium, americium and curium isotopes in granite has been developed for use following a radiological event. Granite samples are fused with sodium hydroxide to achieve complete dissolution, critical if refractory particles are present. Rapid precipitation steps are utilized to preconcentrate the actinide isotopes and remove sample matrix interferences. Plutonium, neptunium, and americium/curium are separated using innovative extraction chromatography and measured by alpha spectrometry. The sample preparation time is less than four hours. PMID- 30015038 TI - Feasibility study on the use of 3D silicon microdosimeter detectors for microdosimetric analysis in boron neutron capture therapy. AB - This paper presents the feasibility study of a novel 3D mesa bridge microdosimeter and its use for BNCT dosimetry. The performance of the microdosimeter was studied using Monte Carlo simulation. The clinical BNCT field at Kyoto University Reactor (KUR) using both thermal and epithermal irradiation modes were used in this study. Results show that this microdosimeter can be utilised as an effective tool to measure microdosimetric spectrum in the BNCT field and experimental validation will follow once KUR is operational. PMID- 30015039 TI - Isomer ratios and cross sections for the isomeric pair 122mSb and 122gSb in the 123Sb(n,2n) reaction. AB - Cross-sections and their isomeric ratios sigmam/sigmag in the energy range of 13 15 MeV for isomeric pair 122mSb and 122gSb produced by the 123Sb(n,2n) reaction have been measured by activation and off-line gamma-ray spectrometric technique using the K-400 Neutron Generator at the Chinese Academy of Engineering Physics (CAEP). Specifically, the versatile stacked foil irradiation technique and a high resolution HPGe detector were employed. The 3H(d,n)4He reaction was used to produce the neutron beam. Partial cross sections sigmam and sigmag were derived from the absolute cross section of the metastable state and residual nuclear decay analysis. The 123Sb(n,2 n)122m,gSb reaction excitation functions and their isomeric cross section ratios were numerically calculated with TALYS-1.8 code with different level density options. Results are discussed and compared with corresponding literature data. PMID- 30015040 TI - Monte Carlo simulation-based design for an electron-linear-accelerator-driven subcritical neutron multiplier for boron neutron capture therapy. AB - Fuel configurations for a subcritical neutron multiplier, which was embedded in a beam-shaping assembly and irradiated by electrons from a linear accelerator, were examined to maximize the production of the epithermal neutron flux for boron neutron capture therapy. The epithermal neutron flux at the treatment position increased as the area per uranium fuel plate increased and was estimated to be 2 * 109 cm-2 s-1 when the subcritical neutron multiplier was irradiated by a 4.4 kW (0.22 mA) beam of 20 MeV electrons. PMID- 30015041 TI - Hereditary component of variation in 90Sr deposition in inbred mice under exogenous conditions that affect bone formation. AB - Bone-seeking radionuclides (specifically 90Sr) accumulate in the bone tissue and act as a long-term source of internal irradiation. Their behaviour in the body has been studied in detail, while the impact of inheritance has not been established. On one hand, the genetic determination of both skeletal morphology and calcium metabolism is indirect evidence that the kinetics of deposition of alkaline-earth radioisotopes in the skeleton also have a hereditary component. On the other hand, analysis of 90Sr kinetics in different inbred mouse strains did not reveal any differences between the mice. This study used a classical approach to evaluating the hereditary component of variation in quantitative traits, namely, a variant of familial analysis (the method of twin families). The growth of the skeleton is known to be accompanied by distinct changes in 90Sr accumulation. That is why the hereditary (familial) component of variation in 90Sr kinetics in the bone tissue of CBA mice was analyzed under the influences that modify growth processes Individual parameters of 90Sr accumulation differed between experimental groups by a factor of 2-4.5. At the same time, features of 90Sr accumulation proved to be characteristic of entire families. The results show that the intrafamilial correlation in 90Sr deposition in the skeleton is highly significant (R = 0.542, P <= 0.0001) and comparable to that of morphological parameters (R = 0.532-0.546, P <= 0.0001). The results confirm the existence of statistically significant intrafamilial correlations of weight and metabolic parameters, which is similarly expressed in different families, thereby providing evidence for hereditary determination of 90Sr metabolism. At the same time, the stability of 90Sr metabolism inheritance to changes in morphophysiology and environmental influences (including those close to pathogenic ones) is shown. This is evidence of its authenticity and significance. The results obtained can be extrapolated to humans instead of directly analyzing the role of hereditary factors in the metabolism of toxic compounds, which are difficult and unethical to perform in human subjects. PMID- 30015042 TI - Alpha particle counting system at SANAEM. Preliminary measurements as a part of validation studies. AB - Alpha-particle counting at a defined solid angle (DSA) is one of the most accurate methods used in the primary activity standardization of alpha-particle emitting radionuclides. The important features of the technique are geometrically calculated efficiency and low background energy spectra. This paper describes measurement conditions of the DSA counter installed at Turkish Atomic Energy Authority - Saraykoy Nuclear Research and Training Center (TAEK-SANAEM) and source preparation apparatus. Details of source preparation, preliminary work of measurement and solid angle calculations are explained. The standardization of the activity of 241Am sources with detailed uncertainty analysis is reported as part of a validation of the method. PMID- 30015043 TI - Towards the production of carrier-free 99Mo by neutron activation of 98Mo in molybdenum hexacarbonyl -Szilard-Chalmers enrichment. AB - The neutron irradiation of molybdenum hexacarbonyl has been systematically studied to identify possible improvements for the production of molybdenum-99. After irradiation, the targets were dissolved in dichloromethane, and Szilard Chalmers liquid-liquid extraction was carried out with aqueous extractants. The effects of the irradiation time, the aqueous phase composition and the irradiated mass were studied with a focus on the chemistry involved. Stable extraction yields of 20% were obtained with enrichment decreasing with target decomposition. Improved enrichment requires decreased decomposition. PMID- 30015044 TI - Absolute standardization of 57Co and analysis of the results obtained in two international comparisons. AB - The absolute standardization of Co-57 by the 4pi(PC)-gamma coincidence method, in efficiency extrapolation variant, is presented. An original, improved method, based on the use of the equivalent decay scheme, was applied; apart from the enhancement of efficiency, a diminution of extrapolation slope was obtained, lowering the extrapolation uncertainty. The results obtained in the participation at the supplementary comparison CCRI(II)-S6.Co-57 and at the key comparison code BIPM.RI(II)-K1.Co-57 are presented. The method allows to simplify the treatment of 56Co and 58Co impurities' correction, which influences significantly the measurements in a CENTRONIC type ionization chamber. An example of treatment of this mixture, where the influence of impurities on results was analyzed, will be presented. PMID- 30015045 TI - Study of the neutron field around ENSA-DPT spent fuel transport and storage casks. AB - Neutron field measurements around individual DPT type spent fuel transport and storage casks were performed at the storage installation of Trillo Nuclear Power Plant. Neutron spectra were determined at five different positions using a Bonner sphere system. These measurements were used to validate the dosimetry measurements of two neutron monitors. Axial and angular measurements were used to determine the ambient dose equivalent. The results are consistent with the cask design and no field correction is needed when using these monitors. PMID- 30015046 TI - The half-life of 129I. AB - The radionuclide 129I is a long-lived fission product that decays to 129Xe by beta-particle emission. It is an important tracer in geological and biological processes and is considered one of the most important radionuclides to be assessed in studies of global circulation. It is also one of the major contributors to radiation dose from nuclear waste in a deep geological repository. Its half-life has been obtained by a combination of activity and mass concentration measurements in the frame of a cooperation of 6 European metrology institutes. The value obtained for the half-life of 129I is 16.14 (12) * 106 a, in good agreement with recommended data but with a significant improvement in the uncertainty. PMID- 30015047 TI - A process to describe radiation damage at the molecular level. Application to the 125I seeds in water. AB - The correlation between the absorbed energy and the induced biological damage still has unclear aspects, especially in the low energy and low dose rate irradiation regimes. From the knowledge of the molecular-induced effects (dissociations), it would be possible to better understand the side effects of radiation, such as induced cancers or damage to healthy tissue. With this in view, this paper presents results of a simulation of a 125I-seed treatment with an event-by-event MC code (LEPTS) specifically designed to account for the low energy secondary particle interactions, such as electron attachment, vibro rotational and neutral dissociation interactions. This calculation allowed us to analyze the potential radiation damage not only in connection with the energy deposition, but also in terms of induced molecular dissociations by taking into account ionizing and non-ionizing dissociative processes. We propose that this description of the molecular level damage be the basis for nanodosimetric evaluations. PMID- 30015048 TI - Free clinic utilisation by immigrants after the introduction of a restrictive health policy in the Basque Country (Spain). AB - OBJECTIVES: Policies restricting healthcare access for immigrants were applied in times of reduced public funding for welfare in Spain. This study aimed to assess the impact of the implementation of a more restrictive health policy in the Basque Country region, Decree 114/2012, on the number of consultations attended at a free clinic, where the majority of patients are undocumented immigrants. STUDY DESIGN: Interrupted time series. METHODS: A negative binomial regression model was applied in two phases to the number of healthcare consultations during the period 2007-2017 (n = 9272) to estimate the level and trend changes associated with the implementation of the policy. Data were analysed separately by sex and adjusted for consultations' seasonality and unemployment rate and the sex-specific percentage of migrant population in Biscay province as confounding factors. RESULTS: Different trends of attendance between men and women were observed during the whole period, constituting 76.94% and 23.06% of all consultations, respectively. After the implementation of the decree, the number of consultations for women per trimester decreased and increased for men by 1%, although it was not statistically significant in either of the trends. CONCLUSIONS: No clear relationship between the implementation of the Basque Decree 114/2012 and an increase in the attendance of immigrants in a free clinic during the studied period was found. PMID- 30015049 TI - Quantum chemical calculation of free radical substitution reaction mechanism of camptothecin. AB - Free radical substitution reaction, which has low energy barrier and takes place in mild reaction conditions, is an important method for camptothecin's modification. The experimental data show that the free radical substitution reaction of camptothecin has high site selectivity, and prefers to take place at site 7. Up to now, few researches focus on the mechanism of it. In this study, the differences of the reaction rate constant (k) for the reactions at different sites, such as site of 7, 9, 10, 11, 12, were investigated with B3LYP of density functional theory at the 6-31 + G (d, p) base set level and CPCM aqueous solvent model. It was found that the substitution reaction can be carried out in two steps in acidic condition. First, the methyl radical attacks the corresponding site to form an intermediate having methyl radical combined with the camptothecin skeleton, and then a hydrogen atom was abstracted by the singlet oxygen to form methyl camptothecin, wherein the first step was the rate control step of the reaction. The results show that site 7 has the higherreaction rate constant (k) than other examined sites, indicating that the reaction tends to take place on site 7 position, which is in agreement with the experimental results. PMID- 30015050 TI - Molecular dynamics simulations on miscibility, glass transition temperature and mechanical properties of PMMA/DBP binary system. AB - Polymethyl methacrylate (PMMA) and dibutyl phthalate (DBP) binary system was simulated by molecular dynamics (MD) simulations with the COMPASS force field to predict properties of PMMA/DBP blends such as the miscibility, the glass transition temperature (Tg) and mechanical properties of polymer/plasticizer blends. Results show that PMMA/DBP is a miscible system, which can be predicted by comparing the difference of the solubility parameters value (|Deltadelta|<2.0 MPa0.5) between PMMA and DBP. The free volumes (VF) and density (rho) of PMMA/DBP system were simulated to study the Tg. It is found that the VF and rho of PMMA/DBP change regularly along with the increase of DBP mass fraction and the transition occurred at the turning point. We also predicted the effects of temperature and DBP on the mechanical properties of PMMA including Young's modulus (E), Bulk modulus (K), Shear modulus (G) and Poisson's ratio (v). The mechanical properties can be effectively improved by the temperature and the addition of DBP plasticizer, which may provide a more flexible mixture with a lower E, K, G and an increased ductility. Accordingly, the method used in this work is not only a useful tool to provide properties of a given polymer/plasticizer blend but also a promising technique to help screen the formulations of polymer bonded explosive (PBX) and propellants before experiments. PMID- 30015051 TI - Molecular mechanism of D816X mutation-induced c-Kit activation and -mediated inhibitor resistance in gastrointestinal stromal tumor. AB - The D816X (X = V, H, Y or F) missense mutation constitutively activates c-Kit kinase in gastrointestinal stromal tumor (GIST) and has been observed to cause acquired resistance against first-line and second-line kinase inhibitors. In the present study, the allosteric mechanism of D816X-induced c-Kit conformational change is investigated at molecular level. The Asp816 residue is located at the activation loop (A-loop) of c-Kit and the mutation can eliminate a negative formal charge from the loop region by substituting the acidic asparagic acid residue with neutral valine, histidine, tyrosine or phenylalanine. Here, we classify the c-Kit kinase into four states in terms of its mutation (wild type or mutant) and conformation (DFG-in or DFG-out). The wild-type kinase is electrostatically stabilized in inactive DFG-out conformation, whereas the D816X mutation can promote the conformational conversion to active DFG-in and then activate the kinase. Structural analysis reveals that the Asp816 residue in DFG out is surrounded by a number of polar and positively charged residues within its first and second shells of protein context, and kinase conformational change to DFG-in brings this residue into a negative electrostatic potential environment. Dynamics simulation characterizes that the c-Kit conformational conversion from DFG-out to DFG-in can cause local unfavorable effect to type-II inhibitor, while the mutation-induced global structural rearrangement would participate in the favorable interaction of c-Kit with type-I inhibitor. PMID- 30015052 TI - Relationship between vertebral morphology and the potential risk of spinal cord injury by pedicle screw in adolescent idiopathic scoliosis. AB - OBJECTIVE: We aimed to investigate the relative preoperative position of the spinal cord in AIS and explore the potential risk of spinal cord injury from placement of pedicle screws. PATIENTS AND METHODS: Twenty-seven patients with a mean age of 15 +/- 1.8 years (range, 12-19 years) classified as having Lenke type 1 AIS (1A: 15 cases, 1B: 8 cases, 1C: 4 cases) were analyzed. The mean Cobb angle of the main curve was 55.9 +/- 14.4 degrees . Axial CT myelography images were selected from the T4 to T12 vertebrae, and 243 images were analyzed. Outer cortical pedicle width, inner cortical pedicle width, pedicle length, chord length, transverse pedicle angle, the angle of rotation (RAsag) of the vertebra, and the distance between the spinal cord and concave (Dc) and convex pedicles (Dv) were calculated from landmark locations. RESULTS: The mean concave outer cortical pedicle width was larger than the mean convex outer cortical pedicle width at T4, T5, T11, and T12 (p < 0.05) and smaller than the mean convex outer cortical pedicle width around the apex of the curve from T7 to T9 (p < 0.05). The mean concave inner cortical pedicle width was larger than the mean convex inner cortical pedicle width at T4, T5, and T11 (p < 0.05) and smaller than the mean convex inner cortical pedicle width around the apex of the curve at T7 and T8 (p < 0.001). The mean Dc was smaller than the mean Dv around the apex of the curve from T6 to T11 (p < 0.05). Dv was significantly correlated with the convex outer cortical pedicle width (R = 0.286, p < 0.001), convex inner cortical pedicle width (R = 0.202, p = 0.002), convex transverse pedicle angle (R=-0.286, p < 0.001), and RAsag (R = 0.277, p < 0.001). Dc was significantly correlated with the concave outer (R = 0.269, p < 0.001) and inner cortical pedicle width (R = 0.230, p < 0.001). CONCLUSION: The distance from the spinal cord to the medial wall of the pedicle was significantly correlated with outer and inner cortical pedicle width, and the potential risk of spinal cord injury by pedicle screw is increased with insertion into a narrower pedicle, especially on the concave side around the apex. PMID- 30015053 TI - Management of leptomeningeal metastasis in breast cancer. AB - Leptomeningeal metastasis (LM), which occurs when malignant cells spread to the central nervous system, is becoming an increasingly common complication in patients with breast cancer. Diagnosis and treatment of LM is challenging. Moreover, prognosis of patients with LM is poor, with a median survival of 6 months after diagnosis. This review highlights the strengths and limitations of currently available diagnostic tools and therapies for LM. The current treatments for LM, including radiotherapy, systemic therapy, and intrathecal treatment, aim to maintain the quality of life of patients by correcting neurological deficits and arresting neurological degeneration. However, there is no standardized therapy for LM because of a lack of randomized trials on this condition. PMID- 30015054 TI - Not your average Saturday night palsy-High resolution nerve ultrasound resolves rare cause of wrist drop. AB - We present a case of a patient with acute wrist drop caused by radial nerve torsion. NCS showed axonal lesion of the radial nerve. High-resolution ultrasound was able to visualize a constriction of the radial nerve. Nerve torsion is a rare differential diagnosis to Saturday night palsy. The patient was subjected to early surgical intervention and showed a favorable outcome in follow-up. Thus, high-resolution ultrasound may subject these patients early to surgical therapy. PMID- 30015055 TI - Trends in the incidence of primary brain, central nervous system and intracranial tumors in Israel, 1990-2015. AB - BACKGROUND: The association between cellphone technology and brain, central nervous system (CNS) and intracranial tumors is unclear. Analysis of trends in incidence of such tumors for periods during which cellphone use increased dramatically may add relevant information. Herein we describe secular trends in the incidence of primary tumors of the brain and CNS from 1990 to 2015 in Israel, a period during which cellphone technology became extremely prevalent in Israel. METHODS: All cases of primary brain, CNS and intracranial tumors (excluding lymphomas) diagnosed in Israel from 1990 to 2015 were identified in the Israel National Cancer Registry database and categorized by behavior (malignant; benign/uncertain behavior) and histologic type. Annual age-standardized incidence rates by sex and population group (Jews; Arabs) were computed, and the annual percent changes and 95% confidence intervals per category were calculated using Joinpoint software. RESULTS: Over 26 years (1990-2015) no significant changes in the incidence of malignant brain, CNS and intracranial tumors were observed, except for an increase in malignant glioma incidence in Jewish women up to 2008 and Arab men up to 2001, which levelled off in both subgroups thereafter. The incidence of benign/uncertain behavior brain, CNS and intracranial tumors increased in most population groups up to the mid-2000s, a trend mostly driven by changes in the incidence of meningioma, but either significantly decreased (Jews) or stabilized (Arabs) thereafter. CONCLUSIONS: Our findings are not consistent with a discernable effect of cellphone use patterns in Israel on incidence trends of brain, CNS and intracranial tumors. PMID- 30015056 TI - Resting-state connectivity after visuo-motor skill learning is inversely associated with offline consolidation in Parkinson's disease and healthy controls. AB - Procedural memory refers to skills acquired through practice and depends on cortico-striatal and cortico-cerebellar circuits. These circuits are typically affected in Parkinson's disease (PD), leading to impaired skill learning, including defective offline consolidation, early in the course of the disease. Evidence points to a role of slow oscillations (<4 Hz) during sleep for offline consolidation. However recent studies showed consolidation over the course of the day, suggesting that consolidation may arise during wakefulness, too. Here we investigate whether functional connectivity (FC) at rest after visuo-motor skill learning is associated with the extent of offline improvements in healthy controls and PD patients. Nineteen participants (9 PD, 10 healthy controls) performed a mirror-drawing task. High-density 156-channel resting state EEG was recorded before and immediately after training. Performance on the task was measured again 24 h later to test for offline consolidation. Delta-band (1-3.5 Hz) FC centered on the left parietal cortex after training predicted offline consolidation. Weak FC was observed in most healthy controls and associated with marked overnight improvement, while strong FC was observed in most PD patients and associated with weak offline consolidation or loss of the skill. These findings indicate that offline consolidation starts immediately after visuo-motor skill learning in brain regions and frequencies typically involved in sleep related consolidation. PMID- 30015057 TI - Polypharmacy prevalence among older adults based on the survey of health, ageing and retirement in Europe. AB - Polypharmacy, a common condition among the elderly, is associated with adverse outcomes, including increased healthcare costs, due to higher mortality, falls and hospitalizations rates, adverse drug reactions, drug-drug reactions and medication nonadherence. This study aims to evaluate the prevalence and factors related to polypharmacy in older adults across 17 European countries, plus Israel. In this cross-sectional analysis, we used data from participants aged 65 or more years from Wave 6 of the Survey of Health, Ageing, and Retirement in Europe (SHARE) database. Polypharmacy was defined as the concurrent use of five or more medications. Age, gender, education, physical inactivity, number of limitations with activities of daily living, network satisfaction, quality of life, depression, number of chronic diseases and difficulty taking medication variables were found to be associated with polypharmacy. Our results showed a prevalence of polypharmacy ranging from 26.3 to 39.9%. Switzerland, Croatia and Slovenia were the countries with the lowest prevalence, whereas Portugal, Israel and the Czech Republic were the countries where the prevalence of polypharmacy was the highest. Age, gender, number of limitations with activities of daily living, number of chronic diseases, quality of life, depression, physical inactivity, network satisfaction, difficulty in taking medications, years of education and shortage of money were significant variables associated with polypharmacy. Polypharmacy is a highly prevalent condition in the elderly population. Identification of variables associated with polypharmacy, such as those identified in this study, is important to identify and monitor elderly groups, which are most vulnerable to polypharmacy. PMID- 30015058 TI - Implementation of long-term care and hospital utilization: Results of segmented regression analysis of interrupted time series study. AB - This population-based time series study aimed to examine the effects of the long term care insurance (LTCI) program on hospital utilization in Korea. Health insurance claim data and LTCI data were combined into a database of 92,596 individuals who were enrolled in Health Insurance at baseline. They were made of people who applied to LTCI program at least once since July 2008, and their hospital utilization records since 2002 were observed. Estimates of length of hospital stay (LOS) after the introduction of LTCI program were calculated using a segmented regression analysis. Although average LOS in hospitals implementation was lower pre-implementation period than post-implementation (16.865 days, SD: 4.864; 26.078 days, SD: 2.215, respectively, p < .0001), a decreasing trend was observed along the post-implementation period. The estimate for baseline trend, which reflect a trend in LOS before LTCI implementation, was 0.219 days (p < .0001). The estimate for Level change after intervention which is only indicated as the change of LOS was 2.821 days at the time of LTCI implementation, and was statistically significant (p < .0001). The estimate for Trend change after intervention, reflecting the trend in LOS after LTCI implementation, was -0.313, indicating a decreasing trend in LOS of -0.094 days (p = 0.0055), compared with the baseline trend. LTCI program was significantly associated with a decreasing trend in LOS. The results suggest that the introduction of LTCI program may have played a role in reducing LOS in older adults. PMID- 30015059 TI - General laryngeal mask airway anesthesia with lumbar plexus and sciatic block provides better outcomes than general anesthesia and endotracheal intubation in elderly patients undergoing hip surgery. AB - OBJECTIVE: To compare the perioperative outcomes and hemodynamic effects at induction of general laryngeal mask airway (LMA) anesthesia with lumbar plexus sciatic nerve block (LPSB) and general anesthesia with endotracheal intubation (ET) in elderly patients undergoing hip surgery. METHODS: A total of 63 patients having open reduction internal fixation of an intertrochanteric fracture were randomly assigned to receive LMA anesthesia with LPSB or general anesthesia with ET. Perioperative and postoperative outcomes were compared between the 2 groups. RESULTS: Compared with the LMA/block group, there were significant reductions in systolic blood pressure, diastolic blood pressure, and mean arterial pressure at induction in the general endotracheal group (all, P < 0.001). In the general ET group, 84% of the patients experienced at least one episode of significant hypotension, whereas no patient in the LMA/block group had significant hypotension (P < 0.001). There were no changes in cardiac output, cardiac index, stroke volume, and stroke volume index of the LMA/block group, whereas significant changes were noted in the general anesthesia ET group. Significantly fewer complications were noted in the LMA/block group, and LMA block was associated with shorter weaning time, fewer returns to the intensive care unit, and less postoperative pain. CONCLUSIONS: General LMA anesthesia with LPSB provides better outcomes that general ET anesthesia in elderly patients undergoing hip surgery. PMID- 30015060 TI - Biogenic synthesis of gold nanoparticles and their application in photocatalytic degradation of toxic dyes. AB - Plants and their extracts play an important role in the green synthesis of nanoparticles mainly because of their environmental benignity. Based on plant extracts number of metal nanoparticles have been synthesized. In our study, we report a green technique for the synthesis of gold nanoparticles using the aqueous extracts of Alpinia nigra leaves and their photocatalytic activities. The antioxidant, antibacterial and antifungal potential of the synthesized nanoparticles were also evaluated. The aqueous extract of the plant is rich in flavonoids with Total Flavonoid Content of 491mgRE/g extract. The presence of flavonoids was further confirmed through analytical High Performance Liquid Chromatography (HPLC) analysis. The A. nigra mediated syntheses of gold nanoparticles (ANL-AuNPs) were characterized by UV-Vis spectrophotometer, Fourier Transform Infrared (FTIR) Spectroscopy, X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM). The crystalline nature of the ANL-AuNPs was confirmed by the powder XRD analysis. The TEM micrographs showed that the ANL-AuNPs was predominantly spherical in shape and the average particle size was 21.52 nm. The polyphenolics and other functional groups present in the aqueous extract that acted as reducing and capping agent in the synthesis of the Au-NPs were identified via FTIR spectral analysis. These green synthesized nanoparticles exhibited antioxidant activity with IC50 value of 52.16 MUg/ml and showed inhibition in the growth of both gram-positive and gram-negative bacteria. The pathogenic fungus, Candida albicans was also susceptible to these nanoparticles. The ANL-AuNPs in the presence of sunlight catalyzed the degradation of the anthropogenic pollutant dyes, Methyl Orange and Rhodamine B with percent degradation of 83.25% and 87.64% respectively. The photodegradation process followed pseudo first order kinetic model. These results confirm that Alpinia nigra is a potential bioresource for the synthesis of Au-NPs with versatile applications. PMID- 30015061 TI - Solar energy at birth and human lifespan. AB - PURPOSE: The purpose of this paper is to examine the role of UVR at birth and its relationship to lifespan and determine whether there are significant differential effects on sex and race. We test if variation in UVR, as determined by solar cycles (long-term variation), is related to survival as measured by age at death. METHODS: The data used 78 million death records from the National Center for Health Statistics (NCHS) from 1979 to 2013 with accidents, suicides, and war casualties deleted resulted in ~63 million records. Records of persons <= 47 years old were also scrubbed because we could not show an effect on lifespan based upon the intensity of solar energy as reflected by sunspot number (SSN). This we hypothesize is due to the protective effect of the hormones associated with growth and reproduction. Also selected were persons afflicted with multiple sclerosis (MS). RESULTS: Males of all races born with a UVR intensity as estimated by sunspot number (SSN) <= 90 had an average lifespan of 74.4 years, for females of all races, 78.1 years; males born with >90 had an average lifespan of 66.3 years, for females of all races, 70.2 years, resulting in a lifespan decrease of 8.1 years for males and 8.5 years for females. For African-American males born <= 90 SSN, 70.8 years and for >90 SSN, 62.5 years, an 8.3-year decrease; similarly, for African-American females <= 90 SSN, 75.0, for >90 SSN, 65.4 years, a 9.6-year decrease. Higher solar energy at birth had an adverse effect on human lifespan. We also found that there were twice as many persons with MS born in >80-90 SSN as in the general population. CONCLUSIONS: There is a statistically significant inverse relationship between exposure to solar energy at birth and average human lifespan. Solar energy by some mechanism alters the epigenome at birth, but the effect of higher solar energy becomes apparent after the age of natural selection. PMID- 30015062 TI - Immunosenescence-like state is accelerated by constant light exposure and counteracted by melatonin or turmeric administration through DJ-1/Nrf2 and P53/Bax pathways. AB - The awareness of the interrelationship between immunosenescence and constant light exposure can provide new insights into the consequences of excessive exposure to light at night due to light pollution or shift work. Here, we investigated whether constant light exposure (LL) acts as an inducer of immunosenescence. We also determined the role of melatonin or turmeric in reversing the putative effects of constant light and explored for the first time the underlying molecular mechanisms. Young (3-4-month-old) rats were exposed daily to LL alone or in combination with each of melatonin and turmeric for 12 weeks. A group of aged rats (18-months old; n = 6) was used as a reference for natural immunosenescence. Constant light exposure resulted in remarkable pathophysiological alterations resembling those noticed in normal aged rats, manifested as apparent decreases in antioxidant activities as well as Nrf2 and DJ 1 expressions, striking augmentation in oxidative stress, proinflammatory cytokines and expression of TNFalpha, Bax, and p53 genes, and deleterious changes of lymphoid organs, Co-administration of melatonin or turmeric was able to reverse all alterations induced by LL through upregulation of Nrf2/DJ-1 and downregulation of p53/Bax pathways. These data suggest that LL accelerates immunosenescence via oxidative stress and apoptotic pathways. They also demonstrate for the first time that turmeric is comparable to melatonin in boosting the immune function and counteracting the LL-associated immunosenescence. These effects suggest that turmeric supplementation can be used as an inexpensive intervention to prevent circadian disruption-related immunosenescence. However, to validate the effects of turmeric on humans further studies are warranted. PMID- 30015063 TI - Photobiomodulation improved stereological parameters and sperm analysis factors in streptozotocin-induced type 1 diabetes mellitus. AB - The aim of this study was to evaluate the effect of photobiomodulation (PBM) on testicular tissues and fresh sperm analysis factors in streptozotocin (STZ) induced type one diabetes mellitus (T1DM) mice. T1DM was induced in 15 male Syrian mice by injection of 200 mg/kg STZ. After one month, mice were divided randomly into three groups, harboring 5 mice each: 1, control group; 2, first laser group (890 nm, 80 Hz, 0.03 J/cm2) and 3, second laser group (0.2 J/cm2). Then the mice were euthanized and testicles were dissected for stereological studies, and both epididymis and vas deferens were removed for fresh sperm analysis. Data were analyzed by statistical methods. A significant increase was observed in the Sertoli cell count in both PBM groups, compared to the control group. In addition, the second PBM group shows a significant increase in the Sertoli cell count, compared to the first PBM group. Both PBM groups show significant increase in the Leydig cell count, compared to the control group. There were significant increases of the length in the seminiferous tubules in both PBM groups, compared to the control group. In addition, the second PBM group showed a significant increase of the length in the seminiferous tubules, compared to the first PBM group. The second PBM group showed a significant increase in the sperm count, compared to the control, and first PBM groups. The first PBM group showed a significant increase in sperm count, compared to the control group. The sperm motility and count were significantly increased in the second PBM group, compared to the control and first PBM groups. The sperm motility was significantly increased in the first PBM group, compared to the control group. PBM with 0.2 J/cm2 and 0.03 J/cm2 energy densities significantly improved the stereological parameters and fresh sperm analysis factors, compared to the control group in STZ-induced T1DM in mice. Moreover, the PBM with 0.2 J/cm2 energy density was statistically more effective, compared to the 0.03 J/cm2. PMID- 30015064 TI - Safety and efficacy of non-vitamin K oral anticoagulant for atrial fibrillation patients after percutaneous coronary intervention: A bivariate analysis of the PIONEER AF-PCI and RE-DUAL PCI trial. AB - BACKGROUND: The tradeoff in safety versus efficacy in substituting a non-vitamin K antagonist oral anticoagulant for a vitamin K antagonist (VKA) in the stented atrial fibrillation patient has not been quantitatively evaluated. METHODS: Based on summary data from the PIONEER AF-PCI and RE-DUAL PCI trials, 4 antithrombotic regimens were compared with VKA-based triple therapy: (1) rivaroxaban (riva) 15 mg daily + P2Y12 inhibitor, (2) riva 2.5 mg twice daily + P2Y12 inhibitor + aspirin, (3) dabigatran (dabi) 110 mg twice daily + P2Y12 inhibitor, and (4) dabi 150 mg twice daily + P2Y12 inhibitor. A bivariate model with a noninferiority margin of 1.38 was used to simultaneously assess safety and efficacy. The safety end point was major or clinically relevant nonmajor bleeding by International Society on Thrombosis and Haemostasis definitions. The efficacy end point was a thromboembolic event (myocardial infarction, stroke, or systemic embolism), death, or urgent revascularization. The bivariate outcome, a measure of risk difference in the net clinical outcome, was compared between antithrombotic regimens. RESULTS: All 4 non-vitamin K antagonist oral anticoagulant regimens were superior in bleeding and noninferior in efficacy compared with triple therapy with VKA. Riva 15 mg daily and 2.5 mg twice daily were associated with bivariate combined risk reductions of 5.6% (2.3%-8.8%) and 5.5% (2.1%-8.7%), respectively, and dabi 110 mg twice daily and 150 mg twice daily reduced the bivariate risk by 3.8% (0.5%-7.0%) and 6.3% (2.4%-9.8%), respectively. CONCLUSIONS: A bivariate analysis that simultaneously characterizes both risk and benefit demonstrates that riva- and dabi-based regimens were both favorable over VKA plus dual antiplatelet therapy among patients with atrial fibrillation undergoing PCI. PMID- 30015065 TI - Patterns of glucose-lowering medication use in patients with type 2 diabetes and heart failure. Insights from the Diabetes Collaborative Registry (DCR). AB - BACKGROUND: Optimal glucose-lowering strategies in patients with both heart failure (HF) and type 2 diabetes mellitus (T2D) are not well defined, particularly as novel medication classes emerge.We sought to evaluate current patterns of glucose-lowering medication use in adults with T2D with and without HF. METHODS: The DCR is a US-based outpatient registry of adults with diabetes; currently includes 3074 providers in 203 practices. We used hierarchical, modified Poisson regression models to examine the relationship between concomitant HF with use of each glucose-lowering medication class, adjusting for other factors that could impact selection of one medication class over another: age, chronic kidney disease (CKD), coronary artery disease (CAD), number of glucose-lowering medications, and insurance. RESULTS: Among 456,106 adults with T2D, 125,161 (27%) had a diagnosis of HF (30% HFrEF, 15%HFmrEF, 55% HFpEF). Patients with T2D and HF were more likely to be older and male, and to have CAD, atrial fibrillation, and CKD. In the multivariable models, HF was associated with a greater use of insulin (RR 1.39, 95% CI 1.36-1.42) and lower use of thiazolidinediones (RR 0.79, 95% CI 0.74-0.83), SGLT2 inhibitors (RR 0.83, 95% CI 0.79-0.89), and metformin (RR 0.84, 95% CI 0.82-0.86). Among the subgroup of patients with HF, thiazolidinediones, GLP-1 receptor agonists, and SGLT2 inhibitors were used even less often in patients with lower ejection fraction, indicating that both the diagnosis of clinical HF and ejection fraction may influence the choice of glucose-lowering medications. CONCLUSION: In a large US based outpatient registry, we found that a quarter of adults with T2D had a diagnosis of HF, which was predominantly HFpEF. Although certain T2D medication use in patients with HF appeared consistent with evidence (less use of thiazolidinediones), others appeared contrary to evidence (less use of metformin and SGLT2 inhibitors). PMID- 30015066 TI - Harmony Outcomes: A randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus-Rationale, design, and baseline characteristics. AB - BACKGROUND: Albiglutide is a long-acting glucagon-like peptide-1 receptor agonist that improves glycemic control in patients with type 2 diabetes mellitus (T2DM). Harmony Outcomes is a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major adverse cardiovascular (CV) events in patients with T2DM and established CV disease. METHODS: The trial was designed to recruit 9,400 patients aged >=40 years with T2DM, prior atherosclerotic CV disease, and suboptimal glycemic control. Participants were assigned in a 1:1 ratio to albiglutide 30 mg (potentially increasing to 50 mg) or matching placebo administered once weekly by subcutaneous injection. The trial will continue until >=611 confirmed primary outcome events (CV death, myocardial infarction, or stroke) occur over a median follow-up of at least 1.5 years. RESULTS: A total of 9,463 patients were enrolled at 611 sites in 28 countries between July 2015 and December 2016. The mean age was 64.1 years; duration of T2DM, 13.8 years; and glycated hemoglobin, 8.7%. The percentage of patients with prior coronary artery disease was 70.5%; peripheral arterial disease, 25.0%; stroke, 17.7%; heart failure, 20.2%; and chronic kidney disease, 22.6%. CONCLUSIONS: Harmony Outcomes will assess the CV safety of albiglutide in patients with T2DM and CV disease. Trials of other agents in the glucagon-like peptide-1 receptor agonist class have shown CV benefit for only some of these medications, possibly due to differences in trial design or instead due to differences in drug structure or metabolism. Harmony Outcomes will provide information critical to our understanding of this heterogenous class of glucose-lowering agents. PMID- 30015067 TI - Long-term outcomes of mitral regurgitation by type and severity. AB - BACKGROUND: We aimed to determine the association of MR severity and type with all-cause death in a large, real-world, clinical setting. METHODS: We reviewed full echocardiography studies at Duke Echocardiography Laboratory (01/01/1995 12/31/2010), classifying MR based on valve morphology, presence of coronary artery disease, and left ventricular size and function. Survival was compared among patients stratified by MR type and baseline severity. RESULTS: Of 93,007 qualifying patients, 32,137 (34.6%) had >=mild MR. A total of 8094 (8.7%) had moderate/severe MR, which was primary myxomatous (14.1%), primary non-myxomatous (6.2%), secondary non-ischemic (17.0%), and secondary ischemic (49.4%). At 10 years, patients with primary myxomatous MR or MR due to indeterminate cause had survival rates of >60%; primary non-myxomatous, secondary ischemic, and non ischemic MR had survival rates <50%. While mild (HR 1.06, 95% CI 1.03-1.09), moderate (HR 1.31, 95% CI 1.27-1.37), and severe (HR 1.55, 95% CI 1.46-1.65) MR were independently associated with all-cause death, the relationship of increasing MR severity with mortality varied across MR types (P <= .001 for interaction); the highest risk associated with worsening severity was seen in primary myxomatous MR followed by secondary ischemic MR and primary non myxomatous MR. CONCLUSIONS: Although MR severity is independently associated with increased all-cause death risk for most forms of MR, the absolute mortality rates associated with worse MR severity are much higher for primary myxomatous, non myxomatous, and secondary ischemic MR. The findings from this study support carefully defining MR by type and severity. PMID- 30015068 TI - Cardiac systolic dysfunction in past illicit users of anabolic androgenic steroids. AB - Background: Illicit use of anabolic androgenic steroids (AAS) is associated with left ventricle (LV) systolic dysfunction and increased LV mass (LVM), but whether these findings persist in former AAS users has yet to be elucidated. The objective was to assess LV systolic function, LVM and myocardial fibrosis in current and former illicit AAS users compared with non-users. Methods: Community based cross-sectional study among men, aged 18-50 years, involved in recreational resistance training. We included 37 current and 33 former illicit AAS users, geometric mean (95%CI), 30 (21; 44) months since AAS cessation, and 30 non-users as controls. We assessed myocardial function and structure using advanced echocardiography and cardiac MRI with late-gadolinium enhancement. Results: Mean (SE) LV global longitudinal strain (GLS) was impaired in former AAS users compared with non-users, -16.7 (0.5) versus -18.2 (0.4) %, P < .05. Mean (SE) LV ejection fraction (EF) was decreased, 51 (1) versus 58 (1) %, P < .001 and LV GLS impaired, -14.5 (0.4)%, P < .001, in current AAS users compared with non-users. Measures of LVM were increased in current AAS users compared with the other two groups, P < .001. Plasma total testosterone was independently associated with reduced LVEF (P = .049) and increased LVM/body surface area (P = .005) in multivariate linear regressions. Focal myocardial fibrosis was not detected in any participants and diffuse myocardial fibrosis, assessed using post-contrast T1 mapping time, did not differ among the three groups. Conclusions: Past illicit AAS use is associated with impaired LV GLS, suggesting subclinical cardiac systolic dysfunction years after AAS cessation. PMID- 30015069 TI - Rationale and design of a cluster randomized trial of a multifaceted intervention in people with hypertension: The Heart Outcomes Prevention and Evaluation 4 (HOPE 4) Study. AB - BACKGROUND: Cardiovascular disease is the leading cause of death throughout the world, with the majority of deaths occurring in low- and middle-income countries. Despite clear evidence for the benefits of blood pressure reduction and availability of safe and low-cost medications, most individuals are either unaware of their condition or not adequately treated. OBJECTIVE: The primary objective of this study is to evaluate whether a community-based, multifaceted intervention package primarily provided by nonphysician health workers can improve long-term cardiovascular risk in people with hypertension by addressing identified barriers at the patient, health care provider, and health system levels. METHODS/DESIGN: HOPE-4 is a community-based, parallel-group, cluster randomized controlled trial involving 30 communities (1,376 participants) in Colombia and Malaysia. Participants >=50 years old and with newly diagnosed or poorly controlled hypertension were included. Communities were randomized to usual care or to a multifaceted intervention package that entails (1) detection, treatment, and control of cardiovascular risk factors by nonphysician health workers in the community, who use tablet-based simplified management algorithms, decision support, and counseling programs; (2) free dispensation of combination antihypertensive and cholesterol-lowering medications, supervised by local physicians; and (3) support from a participant-nominated treatment supporter (either a friend or family member). The primary outcome is the change in Framingham Risk Score after 12 months between the intervention and control communities. Secondary outcomes including change in blood pressure, lipid levels, and Interheart Risk Score will be evaluated. SIGNIFICANCE: If successful, the study could serve as a model to develop low-cost, effective, and scalable strategies to reduce cardiovascular risk in people with hypertension. PMID- 30015070 TI - Synthesis and anticancer activity of new dihydropyrimidinone derivatives. AB - A series of dihydropyrimidinone derivatives bearing various N-heterocyclic moieties was designed and synthesized. Twelve new compounds were screened for their cytotoxic activity using 60 cancer cell lines according to NCI (USA) protocol. Compound 19 showed a significant activity against NCI-H460, SK-MEL-5, and HL-60 (TB) cell lines with growth inhibition 88%, 86% and 85%, respectively, and was found to be more safe on normal cells when compared to doxorubicin. Enzyme inhibition assay was performed for compound 19 against mTOR (IC50 = 0.64 MUM) and VEGFR-2 (IC50 = 1.97 MUM) to show high potency in comparison to rapamycin (IC50 = 0.43 MUM) and sorafenib (IC50 = 0.3 MUM) as references, respectively. Cell cycle analysis of A549 cells treated with 19 showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining. PMID- 30015071 TI - Novel natural compounds from endophytic fungi with anticancer activity. AB - Plant endophytes are microorganisms that live in healthy plant tissues in part or all of their life history without causing obvious symptoms of infection in the host plants. Endophytes, a new type of microbial resource that can produce a variety of biological constituents, have great values for research and broad prospects for development. This article reviewed the research and development progress of endophytic fungi with cytotoxic activity between 2014 and 2017, including endophytic fungi sources, microbial taxonomy, compound classification and cytotoxic activity. The results showed that the 109 strains of endophytic fungi belong to 3 phyla, 7 classes and 50 genera. The secondary metabolites mainly contained alkaloids, terpenes, steroids, polyketides, quinones, isocoumarins, esters etc. The results of this study provide references for the development of new antitumor drugs and endophytes resources. PMID- 30015072 TI - Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131). AB - Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 MUM). In a mouse model of paclitaxel resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day. PMID- 30015073 TI - Mixed-ligand Cu(II) hydrazone complexes designed to enhance anticancer activity. AB - The ligand quantity, ligand type, and coordination geometry have important influences on the anticancer activity of metal-based complexes. On the basis of the structures of previously reported 1:1 Cu(II)/ligand complexes ([Cu(L1)Cl].2H2O 1a, [Cu(L2)Cl].H2O 2a, and [Cu(L2)NO3].H2O 3a), we subsequently designed, developed, and characterized a series of corresponding 1:1:1 Cu(II)/ligand/co-ligand complexes ([Cu(L1)(Py)Cl].H2O 1b, [Cu(L2)(Py)Cl] 2b, and [Cu(L2)(Py)NO3] 3b), where L1 = (E)-N'-(2-hydroxybenzylidene)acetohydrazide, L2 = (E)-N'-(2- hydroxybenzylidene)benzohydrazide, and Py = pyridine. All six Cu(II) complexes were assessed for their in vitro anticancer properties against a panel of human cancer cells, including cisplatin-resistant A549cisR cell lines. Interestingly, we observed that the 1:1:1 Cu/ligand/co-ligand mixed-ligand Cu(II) complexes exhibited higher anticancer activity than the corresponding 1:1 Cu(II)/ligand complexes. In particular, the 1:1:1 Cu(II)/ligand/co-ligand complex 3b displayed the greatest toxicity toward several cancer cells with better IC50 (1.12-3.77 MUM) than cisplatin. Further mechanistic explorations showed that the 3b complex induced DNA damage, thus resulting in mitochondria-mediated apoptotic cell death. Furthermore, the 3b complex displayed pronounced cytostatic effects in the MCF-7 3D spheroid model. PMID- 30015074 TI - Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression. AB - Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 MUM agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs. PMID- 30015075 TI - Current progress on antioxidants incorporating the pyrazole core. AB - The search of new antioxidants, as drugs candidates, is an active field of medicinal chemistry. The synthesis of compounds with antioxidant potential has increased in recent years and a high number of structurally diverse compounds have been published. This review aims to show the current state-of-the-art on the development of antioxidant compounds incorporating the pyrazole pharmacophore. It is a well-timed review driven by the increasing number of papers, on this issue, that have been published since the beginning of the 21st century (from 2000 to 2017). The aim is to look deeper into the structures already published in the literature containing the pyrazole core as the unique pharmacophore or combined with other pharmacophores and see the relationship between the presence of this five-membered nitrogen heterocycle and the behaviour of the compounds as potential antioxidant agents. An attempt was made to whenever possible establish structure-activity relationships that could help the design of new and more potent antioxidant agents containing this important pharmacophore. PMID- 30015076 TI - Discovery of potent anti-convulsant carbonic anhydrase inhibitors: Design, synthesis, in vitro and in vivo appraisal. AB - We report the design, synthesis and pharmacological assessment of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the synthesized compounds were screened for their CA inhibitory action against four isoforms of human origin (h), i.e. hCA I, hCA II, hCA VII and hCA IX. In-vitro carbonic anhydrase inhibition studies have shown that first series, 4-(2-(4-(4-substitutedpiperazin-1 yl)benzylidene)hydrazinyl)benzenesulfonamides (4a- 4i) bestowed low nanomolar range to medium nanomolar range inhibitors against hCA II and hCA VII, effectively involved in epileptogenesis. Furthermore, compounds belonging to the second series, 4-(2-(4-(4-substitutedpiperazin yl)benzylidene)hydrazinecarbonyl)benzenesulfonamides (8a-8k) showed effective inhibition against hCA VII, being less effective against other hCA isoforms. Inspiring with obtained CA inhibition results, we have chosen some of the potent hCA II and hCA VII inhibitors (4g, 4i and 8d) to test their anti-convulsant efficacy in MES and sc-PTZ seizure tests in Swiss Albino male mice. In result, these compounds significantly attenuated both electrical (MES) as well as chemical (sc-PTZ) induced seizures. Next, in advance anticonvulsant tests, compound 8d displayed long duration of action in time course study and successfully attenuated MES induced seizure in mice up to 6 h after drug administration without showing neurotoxicity in rotarod test. Moreover, this compound was also found to be orally active and effectively abolished generalized tonic-clonic seizures in male Wistar rats upon oral administration, being non toxic in sub acute toxicity studies. PMID- 30015077 TI - Potential targets for therapeutic intervention and structure based vaccine design against Zika virus. AB - Continuously increasing number of reports of Zika virus (ZIKV) infections and associated severe clinical manifestations, including autoimmune abnormalities and neurological disorders such as neonatal microcephaly and Guillain-Barre syndrome have created alarming situation in various countries. To date, no specific antiviral therapy or vaccine is available against ZIKV. This review provides a comprehensive insight into the potential therapeutic targets and describes viral epitopes of broadly neutralizing antibodies (bNAbs) in vaccine design perspective. Interactions between ZIKV envelope glycoprotein E and cellular receptors mediate the viral fusion and entry to the target cell. Blocking these interactions by targeting cellular receptors or viral structural proteins mediating these interactions or viral surface glycans can inhibit viral entry to the cell. Similarly, different non-structural proteins of ZIKV and un-translated regions (UTRs) of its RNA play essential roles in viral replication cycle and potentiate for therapeutic interventions. Structure based vaccine design requires identity and structural description of the epitopes of bNAbs. We have described different conserved bNAb epitopes present in the ZIKV envelope as potential targets for structure based vaccine design. This review also highlights successes, unanswered questions and future perspectives in relation to therapeutic and vaccine development against ZIKV. PMID- 30015078 TI - Exploration of carboxy pyrazole derivatives: Synthesis, alkaline phosphatase, nucleotide pyrophosphatase/phosphodiesterase and nucleoside triphosphate diphosphohydrolase inhibition studies with potential anticancer profile. AB - In the present work we report the synthesis of new aryl pyrazole derivatives using 1,3-dicarbonyl motifs. The reaction was proceeded by the cyclization of pentane-2,4-dione (1a), 3-chloropentane-2,4-dione (1b) or ethyl 3-oxobutanoate (1c) with different aryl hydrazines. The products, which can be regarded as 1H pyrazol-1-yl-one analogues (3a-f, 3g-o, 4a-c, 5a-b) and represent drug like molecules along with well-developed structure-activity relationships, were obtained in good to excellent yield. The structures of synthesized compounds were charcterized on the basis of FT-IR, 1H NMR, 13C NMR and mass spectroscopic data. Considering alkaline phosphatases (APs), nucleotide pyrophosphatases/phosphodiesterases (NPPs) and nucleoside triphosphate diphosphohydrolase as the molecular targets, the effects of these synthesized compounds were investigated on different isozymes of APs, NPPs and NTPDases. The data revealed that the synthesized compounds inhibited both enzymes but most of them inhibited tissue non-specific alkaline phosphatase (TNAP) more selectively. The antitumor activity results indicated that the synthesized derivatives have strong inhibitory effects on the growth of selected cell lines from different tissues such as breast, bone marrow and cervix (MCF-7, K-562 and Hela) but with varying intensities. Moreover the binding mode of interactions were explained on the basis of molecular docking and in-silico studies. PMID- 30015079 TI - Health utilities of patients with multiple sclerosis and neuromyelitis optica spectrum disorders in Thailand. AB - BACKGROUND: Multiple sclerosis (MS) and neuromyelitis optica spectrum (NMOSD) cause several symptoms that negatively impact on patient's quality of life. No study has ever conducted to examine the quality of life of MS and NMOSD patients, especially in terms of health utility, among the non-western population. This study aims to examine health utility among MS and NMOSD patients in Thailand. METHODS: A multicenter cross-sectional study including 104 MS and 186 NMOSD patients was conducted. Health utility was measured using EQ-5D questionnaire. Demographic data, clinical data and Expanded Disability Status Scales (EDSS) were also collected. RESULTS: Health utility scores of MS or NMOSD were 0.41 +/- 0.36 and 0.41 +/- 0.32, respectively. No significant difference between MS and NMOSD in term of health utility score was found. Pain, mobility, and anxiety/depression are the three most affected domains among both MS and NMOSD patients. Age at onset less than 40 years and EDSS score less than or equal to 2.5 were significantly associated with higher health utility score in MS and NMOSD patients. CONCLUSION: Our findings clearly demonstrated the negative impact of MS and NMOSD on patients' health-related quality of life. Effective interventions that target pain, mobility, and anxiety/depression should be provided to improve quality of life of these patients. Health utility estimates from this study can be used as an important input for economic evaluations of treatments for MS and NMOSD to inform resource-allocation decisions. PMID- 30015080 TI - Hypothesis: Multiple sclerosis is caused by three-hits, strictly in order, in genetically susceptible persons. AB - Multiple Sclerosis is a chronic, progressive and debilitating neurological disease which, despite extensive study for over 100 years, remains of enigmatic aetiology. Drawn from the epidemiological evidence, there exists a consensus that there are environmental (possibly infectious) factors that contribute to disease pathogenesis that have not yet been fully elucidated. Here we propose a three tiered hypothesis: 1) a clinic-epidemiological model of multiple sclerosis as a rare late complication of two sequential infections (with the temporal sequence of infections being important); 2) a proposal that the first event is helminthic infection with Enterobius Vermicularis, and the second is Epstein Barr Virus infection; and 3) a proposal for a testable biological mechanism, involving T Cell exhaustion for Epstein-Barr Virus protein LMP2A. We believe that this model satisfies some of the as-yet unexplained features of multiple sclerosis epidemiology, is consistent with the clinical and neuropathological features of the disease and is potentially testable by experiment. This model may be generalizable to other autoimmune diseases. PMID- 30015082 TI - Collective properties of viral infectivity. AB - Individual virions typically fail to infect cells. Such decoupling between virions and infectious units is most evident in multicomponent and other segmented viruses, but is also frequent in non-segmented viruses. Despite being a well-known observation, the causes and implications of low single-virion infectivity often remain unclear. In principle, this can originate from intrinsic genetic and/or structural virion defects, but also from host infection barriers that limit early viral proliferation. Hence, viruses may have evolved strategies to increase the per-virion likelihood of establishing successful infections. This can be achieved by adopting spread modes that elevate the multiplicity of infection at the cellular level, including direct cell-to-cell viral transfer, encapsulation of multiple virions in microvesicles or other intercellular vehicles, virion aggregation, and virion binding to microbiota. In turn, increasing the multiplicity of infection could favor the evolution of defective viruses, hence modifying the fitness value of these spread modes. PMID- 30015081 TI - Socio-economic inequalities in secondhand smoke exposure at home in the context of mother-child pairs in Bangladesh. AB - OBJECTIVES: This study aimed to examine socio-economic disparities in mother child pairs' self-reported and cotinine-measured secondhand smoke (SHS) exposure at home. STUDY DESIGN: This is a cross-sectional study. METHODS: This study was conducted in the Rajshahi district of Bangladesh from May to July 2017. A total of 541 mother-child pairs were interviewed for self-reported measured SHS; cotinine-measured saliva test was performed on 263 mothers and 236 children. Mother-child pairs' SHS exposure at home was the outcome of interest. RESULTS: Overall self-reported prevalence of SHS exposure at home was 49.0%. Self-reported SHS exposure among mothers (50.2%) and children (51.3%) were lower than the prevalence rate of cotinine-measured exposure for mothers (60.5%) and their children (58.9%). Maternal rich bands of wealth were found to be associated with lower likelihood of self-reported (adjusted odds ratio [AOR] = 0.59, 95% confidence interval [CI] = 0.35-0.99) and cotinine-measured SHS exposure among mothers (AOR = 0.17, 95% CI = 0.08-0.37). Maternal rich bands of wealth were also found to be associated with lower likelihood of cotinine-measured SHS exposure among children (AOR = 0.11, 95% CI = 0.07-0.26). CONCLUSIONS: Socio-economic inequalities exist in exposure to SHS at home. Interventional approaches aimed at reducing SHS at home are urgently needed at public health and healthcare service level, with special focus given to the socioeconomically disadvantaged groups. PMID- 30015083 TI - Adaptation by copy number variation in monopartite viruses. AB - Viruses evolve rapidly in response to host defenses and to exploit new niches. Gene amplification, a common adaptive mechanism in prokaryotes, archaea, and eukaryotes, has also contributed to viral evolution, especially of large DNA viruses. In experimental systems, gene amplification is one mechanism for rapidly overcoming selective pressures. Because the amplification generally incurs a fitness cost, emergence of adaptive point mutations within the amplified locus or elsewhere in the genome can enable collapse of the locus back to a single copy. Evidence of gene amplification followed by subfunctionalization or neofunctionalization of the copies is apparent by the presence of families of paralogous genes in many DNA viruses. These observations suggest that copy number variation has contributed broadly to virus evolution. PMID- 30015084 TI - Cervical dystonia: Normal auditory mismatch negativity and abnormal somatosensory mismatch negativity. AB - OBJECTIVE: Previous electrophysiological and psychophysical tests have suggested that somatosensory integration is abnormal in dystonia. Here, we hypothesised that this abnormality could relate to a more general deficit in pre-attentive error/deviant detection in patients with dystonia. We therefore tested patients with dystonia and healthy subjects using a mismatch negativity paradigm (MMN), where evoked potentials generated in response to a standard repeated stimulus are subtracted from the responses to a rare "odd ball" stimulus. METHODS: We assessed MMN for somatosensory and auditory stimuli in patients with cervical dystonia and healthy age matched controls. RESULTS: We found a significant group * oddball type interaction effect (F (1, 34) = 4.5, p = 0.04, rhoI = 0.63). A follow up independent t-test for sMMN data, showed a smaller sMMN amplitude in dystonic patients compared to controls (mean difference control-dystonia: -1.0 uV +/- 0.3, p < 0.00, t = -3.1). However the amplitude of aMMN did not differ between groups (mean difference control-dystonia: -0.2 uV +/- 0.2, p = 0.24, t = -1.2). We found a positive correlation between somatosensory MMN and somatosensory temporal discrimination threshold. CONCLUSION: These results suggest that pre-attentive error/deviant detection, specifically in the somatosensory domain, is abnormal in dystonia. This could underlie some previously reported electrophysiological and psychophysical abnormalities of somatosensory integration in dystonia. SIGNIFICANCE: One could hypothesize a deficit in pre-conscious orientation towards potentially salient signals might lead to a more conservative threshold for decision-making in dystonia. PMID- 30015085 TI - Temporal relationship between arousals and Cheyne-Stokes respiration with central sleep apnea in heart failure patients. AB - OBJECTIVE: The interplay between arousals and respiratory events during Cheyne Stokes respiration (CSR) with central sleep apnea (CSA) in heart failure (HF) patients is still not fully understood. We investigated the temporal relationship between arousals and CSR-CSA. METHODS: Episodes of CSR-CSA during sleep stages N1 N2 were analyzed in 22 HF patients with an apnea-hypopnea index >=15/h, dominant CSA and central apnea index >=5/h. For each CSR-CSA cycle (apnea + hyperpnea), we determined the onset (ARonset, relative to hyperpnea onset) and duration of detected arousals. RESULTS: Arousals (N = 2348) mostly occurred within the first half of the hyperpneic phase (42.6%, ARonset = 10.6 +/- 2.1 s; duration = 10.6 +/ 5.2 s) or close to hyperpnea onset (21.5%, ARonset = -0.1 +/- 0.6 s; duration = 13.9 +/- 5.4 s). Within-apnea arousals were less frequent (12.4%, ARonset = -16.0 +/- 4.7 s; duration = 3.8 +/- 1.4 s). The proportion of CSR-CSA cycles without any hyperpnea-related arousal was 27.5 +/- 18.2%. Hyperpnea-related arousability (total number of hyperpneic arousals/total duration of hyperpneas) and apnea related arousability were 63.4 +/- 21.0/h and 23.8 +/- 16.9/h, respectively (p < 0.0001). CONCLUSION: During CSR-CSA, a significant proportion of arousals occur at hyperpnea onset, indicating a low arousal threshold. Hyperpneic arousals are not essential for CSR-CSA. Arousability markedly increases during hyperpneas, likely due to the concurrent increase in chemoreceptor stimulation. SIGNIFICANCE: This study extends current knowledge on the interplay between sleep instability and respiratory events during CSR-CSA. PMID- 30015087 TI - Regulation of neutrophils in type 2 immune responses. AB - Type 2 immune responses contribute to the resistance to helminths and toxins as well as several physiological processes. Although they usually do not participate in type 2 immune responses, neutrophils have been shown in mice to enhance the anti-helminth response, but they also contribute to increased target tissue damage. Increased pathology and morbidity is also observed in type 2 immune mediated disorders, such as allergic asthma, when neutrophils become a predominant subset of the infiltrate. How neutrophil recruitment is regulated during type 2 immune responses is now starting to become clear, with recent data showing that signaling via the prototypic type 2 cytokine interleukin-4 receptor mediates direct and indirect inhibitory actions on neutrophils in mice and humans. PMID- 30015086 TI - Antiviral RNA interference in mammals. AB - Infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). Consistent with a major antiviral function of RNAi, productive virus infection in these eukaryotic hosts depends on the expression of virus-encoded suppressors of RNAi (VSRs). The eukaryotic RNAi pathway is highly conserved, particularly between insects and mammals. This review will discuss key recent findings that indicate a natural antiviral function of the RNAi pathway in mammalian cells. We will summarize the properties of the characterized mammalian vsiRNAs and VSRs and highlight important questions remaining to be addressed on the function and mechanism of mammalian antiviral RNAi. PMID- 30015088 TI - Discharge education delivered to general surgical patients in their management of recovery post discharge: A systematic mixed studies review. AB - BACKGROUND: Discharge education is essential for postoperative general surgery patients for their self-management of care at home post discharge. The first 30 days' post-surgery is pivotal to the post-operative recovery process as this is when most post-operative complications occur. Insufficient discharge education can compromise patients' recovery process causing postoperative complications and unplanned hospital readmissions. OBJECTIVES: To identify the discharge education provided to general surgery patients. DESIGN: Systematic mixed studies review. DATA SOURCES: Literature data sources were searched from December 2017 to January 2018 using the four databases: EBSCO CINAHL Plus, EBSCO MEDLINE, Ovid EMBASE and COCHRANE Library. Searches were supplemented with hand searching of reference lists. REVIEW METHODS: The relevance of the articles was reviewed using the inclusion and exclusion criteria; included data were extracted and presented in a summary table. Two reviewers appraised the methodological quality of the articles using the Mixed Methods Appraisal Tool. Discussions were held to examine emergent themes, quality scores of the studies, and agreement reached by consensus. Themes were derived through inductive analysis. RESULTS: A total of 468 records were screened for titles and abstracts and 7 studies met the inclusion criteria. There was a mix of qualitative and quantitative studies. The majority of the included sample were patients with one quantitative study including patients' family and nurses. Discharge education was delivered at various timing and at different doses during the surgical process. Education delivered was mostly standardised and some of the discharge interventions were tailored and included a checklist for stoma care and a discharge warning tool. Four themes were identified: quality of discharge education influences its uptake, health care professionals' perceptions of their role in the delivery of discharge education to patients, patients' preferences for education delivery and patients' participation in their self-care. CONCLUSIONS: The quality of discharge education has an influence on patient participation in their management of care post discharge. Assessing patients' preparedness for discharge is an essential component of discharge planning process. The presentation, timing and frequency of discharge education was important in the delivery of information. Tailored education reflecting the learning needs of patients using multiple media delivered in varying doses enhanced patients' overall knowledge for successful management of recovery post discharge. The scarcity of recent literature in discharge education indicates that the quantity of evidence regarding discharge education intervention in general surgery patients is low and further work in this area needs to be undertaken. PMID- 30015089 TI - Skin status for predicting pressure ulcer development: A systematic review and meta-analyses. AB - BACKGROUND: People with altered skin status are conventionally considered to have a higher risk of developing new ulcers. However, the evidence underpinning this potentially prognostic relationship is unclear. OBJECTIVES: To systematically review the evidence for the prognostic association of skin status with pressure ulcer risk. METHODS: We performed a comprehensive electronic database search in February 2017 to identify longitudinal studies that considered skin status in multivariable analysis for predicting pressure ulcer risk in any population. Study selection was conducted by two reviewers independently. We collected data on the characteristics of studies, participants, skin status, and results of multivariable analyses of skin status-pressure ulcer incidence associations. We applied the Quality In Prognosis Studies tool to assess risk of bias. We conducted meta-analyses using STATA where data were available from multivariable analyses. We used the Grades of Recommendation Assessment, Development and Evaluation approach to assess the certainty of evidence generated from each meta analysis. RESULTS: We included 41 studies (with 162,299 participants, and 7382 having new ulcers) that investigated 15 skin descriptors. Participants were predominantly hospitalised adults and long-term care residents (with a median age of 75.2 years). Studies had a median follow-up duration of 7.5 weeks. 61.0% (25/41) of studies were judged as being high risk of bias. 53.7% (22/41) of studies had small sample sizes. Subsequently, the certainty of evidence was rated as low or very low for all 13 meta-analyses that we conducted though all analyses showed statistically significant associations of specific skin descriptors pressure ulcer incidence. People with non-blanchable erythema may have higher odds of developing pressure ulcers than those without (Odds Ratio 3.08, 95% Confidence Interval 2.26-4.20 if pressure ulcer preventive measures were not adjusted in multivariable analysis; 1.99, 1.76-2.25 if adjusted) (both low certainty evidence). The evidence for other skin descriptors was judged as very low-certainty and their prognostic value is uncertain. CONCLUSIONS: There is low certainty evidence that people with non-blanchable erythema may be more likely to develop new pressure ulcers than those without non-blanchable erythema. The evidence for the prognostic effects of other skin descriptors (e.g., history of pressure ulcer) is of very low-certainty. The findings support regular skin assessment and preventive action being taken in the presence of non-blanchable erythema. Given the millions at risk of ulceration and the widely recommended use of skin status as part of risk assessment there is a need for more, high quality confirmatory studies. PMID- 30015091 TI - Semi-automated system for concentrating 68Ga-eluate to obtain high molar and volume concentration of 68Ga-Radiopharmaca for preclinical applications. AB - INTRODUCTION: 68Ga-radiopharmaceuticals are common in the field of Nuclear Medicine to visualize receptor-mediated processes. In contrast to straightforward labeling procedures for clinical applications, preclinical in vitro and in vivo applications are hampered for reasons like e.g. volume restriction, activity concentration, molar activity and osmolality. Therefore, we developed a semi automatic system specifically to overcome these problems. A difficulty appeared unexpectedly, as intrinsic trace metals derived from eluate (Zn, Fe and Cu) are concentrated as well in amounts that influence radiochemical yield and thus lower molar activity. METHODS: To purify Gallium-68 and to reduce the high elution volume of a 68Ga-generator, a NaCl-based method using a column containing PS-H+ was implemented in a low volume PEEK system. Influence on reducing osmolality, acidity and the amount of PS-H+ resin (15-50 mg) was investigated. [68Ga]Ga was desorbed from the PS-H+ resin with acidified 2-5 M NaCl (containing 0.05 M of HCl) and 68Ga-activity was collected. DOTA-TATE was used as a peptide model. All buffers and additives used for labeling were mixed with Chelex 100 (~1 g/50 mL) for >144 h and eventually filtered using a 0.22 MUm filter (Millipore). Quantification of metals was performed after labeling by HPLC (UV). RESULTS: Gallium-68 activity could be desorbed from PS-H+ cation column with 3 M NaCl, and >60% (120-180 MBq) of [68Ga]Ga was collected in <0.3 mL. Taking into account the used amount of 68Ga-eluate, buffer and other excipients, the overall amount of trace metal per labeling was <1.5 nmol. DOTA-TATE could be labeled with [68Ga]Ga with high radiochemical yield, >99% (ITLC), and a radiochemical purity of >95% (HPLC). CONCLUSION: With the here described concentration system and metal purification technique, a low activity containing 68Ga-generator can be used to label DOTA-peptide in preclinical applicable amounts >60 MBq/nmol (40-60 MBq/0.1 mL) and within 20 min. PMID- 30015092 TI - Establishment of a method for in-vivo SPECT/CT imaging analysis of 111In-labeled exendin-4 pancreatic uptake in mice without the need for nephrectomy or a secondary probe. AB - INTRODUCTION: Radiolabeled exendin derivatives have been developed to visualize and quantify pancreatic beta cells. However, there are currently no established methods for analyzing in-vivo SPECT/CT images to quantify probe accumulation in the pancreas in rodent models. In this study, we aimed to establish an analytical method for murine in-vivo SPECT/CT imaging. METHODS: First, we investigated the correlation between radioactivity measured by curiemeter and uptake calculated from SPECT/CT images of pancreata harvested after probe injection. Second, ROI volume necessary for reliable estimation of pancreatic uptake value was also examined. Third, the influence of high renal uptake on analysis was investigated with SPECT/CT imaging of harvested kidneys. Fourth, we compared pancreatic uptake values and ROI volumes estimated from in-vivo SPECT/CT images of pre- and post nephrectomy mice. Finally, we assessed the correlation between the pancreatic uptake values from in-vivo SPECT/CT image analysis and radioactivity of harvested pancreata determined with a curiemeter. RESULTS: Radioactivity of harvested pancreata measured by curiemeter and uptake values derived from SPECT/CT imaging of harvested pancreas showed an almost perfect correlation (r = 0.99, p < 0.001). Analysis using ROIs with >40% of the volume of the whole pancreas enabled reliable estimates of uptake (%CV < 10%). Exclusion of the perirenal space 2.7 mm from the kidney surface removed the influence of high renal uptake. Setting the uptake value of post-nephrectomy pancreatic ROIs as 100%, the uptake estimated from pre-nephrectomy images was comparable (102.9 +/- 2.2%). A strong correlation was observed between pancreatic radioactivity measured by curiemeter and the uptake value derived from in-vivo SPECT/CT imaging (r = 0.90, p < 0.001). CONCLUSION: Our analytical method without nephrectomy or additional probes enables reliable quantification of the pancreatic uptake of 111In-labeled exendin 4 using in-vivo SPECT/CT imaging. The quantification of rodent BCM with our method would be helpful to drug development. PMID- 30015090 TI - Evaluation of a chloride-based 89Zr isolation strategy using a tributyl phosphate (TBP)-functionalized extraction resin. AB - INTRODUCTION: The remarkable stability of the 89Zr-DOTA complex has been shown in recent literature. The formation of this complex appears to require 89Zr-chloride as the complexation precursor rather than the more conventional 89Zr-oxalate. In this work we present a method for the direct isolation of 89Zr-chloride from irradiated natY foils. METHODS: 89Zr, 88Zr, and 88Y were prepared by 16 MeV proton irradiation of natY foils and used for batch-extraction based equilibrium coefficient measurements for TBP and UTEVA resin. Radionuclidically pure 89Zr was prepared by 14 MeV proton-irradiation of natY foils. These foils were dissolved in concentrated HCl, trapped on columns of TBP or UTEVA resin, and 89Zr-chloride was eluted in <1 mL of 0.1 M HCl. For purposes of comparison, conventionally isolated 89Zr-oxalate was converted to 89Zr-chloride by trapping, rinsing, and elution from a QMA cartridge into 1 M HCl. Trace metal analysis was performed on the resulting 89Zr products. RESULTS: Equilibrium coefficients for Y and Zr were similar between UTEVA and TBP resins across all HCl concentrations. Kd values of <10-1 mL/g were observed for Y across all HCl concentrations. Kd values of >103 mL/g were observed at HCl concentrations >9 M for Zr, falling to Kd values of <100 mL/g at low HCl concentrations. 89Zr-chloride was recovered from small columns of TBP in <1 mL of 0.1 M HCl with an overall recovery efficiency of 89 +/ 3% (n = 3). An average Y/Zr separation factor of 1.5 * 105 (n = 3) was obtained. Trace metal impurities, notably Fe, were higher in TBP-isolated 89Zr-chloride compared with 89Zr-chloride prepared using the conventional two-step procedure. CONCLUSION: TBP-functionalized resin appears promising for the direct isolation of 89Zr-chloride from irradiated natY targets. Excellent 89Zr recovery efficiencies were obtained, and chemical purity was sufficient for proof-of concept chelation studies. PMID- 30015093 TI - One-pot enzymatic synthesis of l-[3-11C]lactate for pharmacokinetic analysis of lactate metabolism in rat brain. AB - INTRODUCTION: Lactate could serve as an energy source and signaling molecule in the brain, although there is insufficient in vivo evidence to support this possibility. Here we aimed to use a one-pot enzymatic synthetic procedure to synthesize l-[3-11C]lactate that can be used to evaluate chemical forms in the blood after intravenous administration, and as a probe for pharmacokinetic analysis of lactate metabolism in in vivo positron emission tomography (PET) scans with normal and fasted rats. METHODS: Racemic [3-11C]alanine obtained from 11C-methylation of a precursor and deprotection was reacted with an enzyme mixture consisting of alanine racemase, d-amino acid oxidase, catalase, and lactate dehydrogenase to yield l-[3-11C]lactate via [3-11C]pyruvate. The optical purity was measured by HPLC. Radioactive chemical forms in the arterial blood of Sprague Dawley rats with or without insulin pretreatment were evaluated by HPLC 10 min after bolus intravenous injection of l-[3-11C]lactate. PET scans were performed on normal and fasted rats administered with l-[3-11C]lactate. RESULTS: l-[3-11C]Lactate was synthesized within 50 min and had decay corrected radiochemical yield, radiochemical purity, and optical purity of 13.4%, >95%, and >99%, respectively. The blood radioactivity peaked immediately after l-[3 11C]lactate injection, rapidly decreased to the minimum value within 90 s, and slowly cleared thereafter. HPLC analysis of blood samples revealed the presence of [11C]glucose (78.9%) and l-[3-11C]lactate (12.1%) 10 min after administration of l-[3-11C]lactate. Insulin pretreatment partly inhibited glyconeogenesis conversion leading to 55.4% as [11C]glucose and 38.9% as l-[3-11C]lactate simultaneously. PET analysis showed a higher SUV in the brain tissue of fasted rats relative to non-fasted rats. CONCLUSIONS: We successfully synthesized l-[3 11C]lactate in a one-pot enzymatic synthetic procedure and showed rapid metabolic conversion of l-[3-11C]lactate to [11C]glucose in the blood. PET analysis of l-[3 11C]lactate indicated the possible presence of active lactate usage in rat brains in vivo. PMID- 30015094 TI - Influence of transport line material on the molar activity of cyclotron produced [18F]fluoride. AB - INTRODUCTION: Production of fluorine-18-labeled radiopharmaceuticals is always associated with the varying levels of the same compound containing stable fluorine-19. In practice, this affects the molar activity (Am), defined as amount of radioactivity divided by the molar quantity (Bq/mol). We have focused on studying how the material of the transport tubing connecting the cyclotron target chamber to the synthesis device affects the concentration of fluoride in the water arriving to the reaction vessel and subsequently the Am of the fluorine-18 labeled radiopharmaceuticals produced. METHODS: Batches of irradiated and non irradiated water were analyzed for fluoride content after being transported via non-fluorinated (PEEK, PP) and fluorinated (PTFE, ETFE) tubing or using no tubing at all. Am for the [18F]fluoride was determined and compared with the Am of [18F]fluciclatide, synthesized from the same [18F]fluoride containing batches of water. RESULTS: Significantly higher concentrations of fluoride were seen in irradiated water that was transported in fluorinated tubing compared to non irradiated water transported in tubing of the same material. This elevation of fluoride concentration is presumably caused by the interaction of ionizing radiation with the fluorinated tubing used between the target chamber and hot cell. Likewise, a significant difference was seen for PEEK tubing (non fluorinated). This could be due to the fact that fluorine containing compounds are used in the manufacture of PEEK. When using fluorinated tubing for transport of the irradiated water, the resulting fluciclatide concentrations were significantly higher compared to when using non-fluorinated tubing. No significant difference was seen between fluciclatide concentrations when PTFE or ETFE tubing was compared to each other. Using no tubing resulted in lowest fluciclatide concentration. CONCLUSIONS: Fluorinated tubing is a source of stable fluoride, and Am can be increased by using non-fluorinated transport tubing. Of all the tubing materials studied PP is preferred. PMID- 30015095 TI - HLA-G and anti-HCV in patients on the waiting list for kidney transplantation. AB - PURPOSE: Human leukocyte antigen (HLA)-G is a non-classic major histocompatibility complex HLA class I molecule. HLA-G may have tolerogenic properties which are linked to epigenetic-sensitive pathways. There is a correlation of sHLA-G levels and graft acceptance in transplantation studies. There are previous data on correlation of sHLA-G with graft rejection as well as with viral infections such as hepatitis C virus (HCV) in kidney transplanted patients. Here, we report the sHLA-G expression in patients on the waiting list for kidney transplantation, with and without anti-HCV compared to a control group. METHODS: Serum of 67 patients on the waiting list for kidney transplantation (n = 43 with anti-HCV and n = 24 without anti-HCV) was analyzed. Among these patients, n = 39 were on the waiting list for the first transplantation, while n = 28 were patients who returned in the list. The control group included n = 23 blood donors with anti-HCV (n = 13) and without anti-HCV (n = 10). RESULTS: The expression of sHLA-G was significantly lower in the control group (39.6 +/- 34.1 U/ml) compared to both - patients on the waiting list for the first transplantation (62.5 +/- 42.4 U/ml, p=0.031) and patients who returned in the list (76.7 +/- 53.9 U/ml, p=0.006). No significant differences were observed in all anti-HCV positive groups. A positive linear correlation between sHLA-G and TNF-alpha, and patient age was observed. CONCLUSIONS: Serum sHLA-G values were significantly increased in both - patients on the waiting list for the first transplantation and patients who returned in the list, as compared to control group. Our findings confirm the key tolerogenic role of sHLA-G levels as epigenetic-related marker for measuring the state of kidney allograft acceptance. PMID- 30015096 TI - Investigation of isochrony phenomenon based on the computational theory of human arm trajectory planning. AB - The isochrony principle is a well-known phenomenon whereby the speed of human arm movement is regulated to increase as its trajectory distance increases. However, the relationship between the trajectory planning and the isochrony phenomenon has never been sufficiently explained. One computational study derived the algorithm for estimating the optimal movement segmentation and its duration based on the framework of the minimum commanded torque change criterion. By extending this finding, we can consider the hypothesis that the human arm trajectory is generated based on the minimum commanded torque change criterion to ensure that the duration average of the commanded torque changes (DCTCs) are equivalent between certain movement segmentations, rather than to satisfy the isochrony phenomenon. To test this hypothesis, we measured the behavioral performance of hand movement tasks in which subjects write eight-shaped and double-elliptical shaped trajectories including two similar shaped arcs of different sizes (hereafter called large and small loops). Our results indicate that the human arm movement is planned in such a manner that the DCTCs for the large and small loops are equivalent during writing of the double-elliptical-shaped trajectories regardless of the arc size. A similar tendency was also observed for the data during the eight-shaped movements, although the ratio of the DCTCs slightly changed depending on the arc size conditions. Thus, our study provides experimental evidence that the isochrony phenomenon is ensured through the computational process of trajectory planning. PMID- 30015097 TI - Exposure to solar light reduces cytotoxicity of sewage effluents to mammalian cells: Roles of reactive oxygen and nitrogen species. AB - Sewage effluents can contain hundreds of toxic pollutants, making them a risk to humans when involved in drinking water. It is therefore important to evaluate the cytotoxicity of sewage effluents to mammalian cells. Solar light might influence the water quality of sewage effluents after their discharge into lakes or rivers, altering their cytotoxicity. In this study, natural solar light was found to lower the cytotoxicity of sewage effluents to Chinese hamster ovary (CHO) cells. Cytotoxicity of different samples decreased by 31%-65% after 12 h of simulated irradiation. Ultraviolet in sunlight was the major contributor to the cytotoxicity reduction. Aquatic reactive oxygen species (ROS), including singlet oxygen, superoxide anions, hydrogen peroxide, and hydroxyl radicals, were generated in the effluents under irradiation and they contributed to part of cytotoxicity reduction. Pollutants in sewage effluents induced cytotoxicity by simultaneously elevating the levels of intracellular ROS and intracellular reactive nitrogen species (RNS) in CHO cells. Solar light and the aquatic ROS formed under irradiation reduced the cytotoxicity because the transformed pollutants in sewage effluents increased lower intracellular ROS and RNS levels. These results help reveal the detoxification mechanism of sewage effluents in natural environment. PMID- 30015098 TI - Tradeoffs between pathogen inactivation and disinfection byproduct formation during sequential chlorine and chloramine disinfection for wastewater reuse. AB - Treatment of fully nitrified municipal wastewater effluents with chlorine followed by chloramines (i.e., sequential chlorine disinfection) upstream of advanced treatment trains can contribute pathogen inactivation credits for potable reuse while leaving a chloramine residual to control biofouling on membrane units in the advanced treatment train. However, free chlorine exposures must be optimized to maximize pathogen inactivation while minimizing the formation of disinfection byproducts (DBPs) that are challenging to remove in the advanced treatment train. Using a pilot-scale disinfection contactor receiving fully-nitrified, tertiary municipal wastewater effluent, this study found that a 3 mg * min/L free chlorine CT (i.e., the product of the chlorine residual "C" and the contact time "T") followed by a 140 mg * min/L chloramine CT could reliably achieve 5-log inactivation of MS2 bacteriophage and reduce median total coliform concentrations below 2.2 MPN/100 mL. Free chlorine disinfection was equally effective when chlorine was dosed to exceed the breakpoint for 1 mg/L of ammonia as N. At this free chlorine exposure, regulated trihalomethane (THM) and haloacetic acid (HAA) formation remained below their Maximum Contaminant Levels (MCLs), but NDMA concentrations of ~30 ng/L were above the 10 ng/L California Notification Level. Increasing the free chlorine exposure to ~30 mg * min/L increased THM and HAA formation, with regulated THMs approaching or exceeding the MCL. Although this free chlorine exposure prevented NDMA formation during chloramination, the ~10 ng/L background NDMA formation in the tertiary effluent remained. Increasing the free chlorine exposure also increased the formation of unregulated halogenated DBP classes that may be significant contributors to the DBP-associated toxicity of the disinfected wastewater. The results indicate that sequential chlorination can be used to optimize the benefits of free chlorine (virus and NDMA control) and chloramine disinfection (THM, HAA, and coliform control). PMID- 30015099 TI - Light-excited photoelectrons coupled with bio-photocatalysis enhanced the degradation efficiency of oxytetracycline. AB - Intimately coupled photocatalysis and biodegradation (ICPB) is a novel wastewater treatment technique that has potential applications in refractory degradation. This paper reports a synergistic degradation protocol that allowing the transfer of photoelectrons between photocatalysts and microbes without supplementary electron donors or improving the loading rate of the photocatalysts. As a result, a degradation rate of ~94% was sustained for 400 h in a perturbation setup with a hydraulic retention time of 4.0 h. We achieved the degradation of beta-apo oxytetracycline, a stable antimicrobial intermediate compound (half-life of 270 d in soil interstitial water), within 10 min, and no accumulation was observed. Moreover, the required loading rate of the photocatalyst was dramatically reduced to 18.3% compared to previous reports which mentioned much higher rates. The results of our study provided a new strategy to improve the degradation efficiency of oxytetracycline and give new insight into the degradation mechanism of the bio-photocatalytic degradation system. PMID- 30015100 TI - Chemical markers for quality control of bran-fried sulfur-fumigated Paeoniae Radix Alba. AB - In traditional Chinese medicine practice, crude herbs are often subjected to traditional processing (Paozhi in Chinese) for a special medicinal purpose. Bran frying is one of processing methods for Paeoniae Radix Alba (PRA). Previous studies found that paeoniflorin and paeoniflorin sulfonate, a principle bioactive compound and its sulfur-fumigation induced characteristic sulfur-containing derivative, could be used together with sulfur dioxide residue as chemical markers for the quality control of sulfur-fumigated PRA crude material. In this paper, the feasibility of these three markers used for the quality control of bran-fried sulfur-fumigated PRA was further investigated. First, homemade samples of sulfur-fumigated PRA with different sulfur-fumigation duration (0.5-6 h) were bran-fried, and stored for 12 months. Second, the contents of sulfur dioxide residue, paeoniflorin and paeoniflorin sulfonate were dynamically quantified respectively. Third, the variation of the marker contents and their correlation during bran-frying and storage was evaluated. A validation was conducted using commercial bran-fried PRA samples. The results showed that bran-frying caused an averaged reduction of 20% in the content of sulfur dioxide residue, and during the first two months of storage the content of sulfur dioxide residue was decreased by up to 27%, then the content was tending towards stability for the subsequent ten months of storage (RSD = 3.92%). Meanwhile, paeoniflorin and paeoniflorin sulfonate were relatively stable, the contents of which were not affected by bran-frying processing and 12 months of storage. The correlations between the contents of sulfur dioxide residue and paeoniflorin/paeoniflorin sulfonate were obviously influenced by storage duration. Since sulfur dioxide residue is a safety marker, while paeoniflorin and paeoniflorin sulfonate can reflect the inner quality and the impact extent of sulfur-fumigation on the quality of bran-fried PRA respectively, these three chemicals might be used together as markers for the quality control, and consequently to ensure the safety and efficacy of bran-fried PRA. PMID- 30015101 TI - Combining excitation-emission matrix fluorescence spectroscopy, parallel factor analysis, cyclodextrin-modified micellar electrokinetic chromatography and partial least squares class-modelling for green tea characterization. AB - In this study, an alternative analytical approach for analyzing and characterizing green tea (GT) samples is proposed, based on the combination of excitation-emission matrix (EEM) fluorescence spectroscopy and multivariate chemometric techniques. The three-dimensional spectra of 63 GT samples were recorded using a Perkin-Elmer LS55 luminescence spectrometer; emission spectra were recorded between 295 and 800 nm at excitation wavelength ranging from 200 to 290 nm, with excitation and emission slits both set at 10 nm. The excitation and emission profiles of two factors were obtained using Parallel Factor Analysis (PARAFAC) as a 3-way decomposition method. In this way, for the first time, the spectra of two main fluorophores in green teas have been found. Moreover, a cyclodextrin-modified micellar electrokinetic chromatography method was employed to quantify the most represented catechins and methylxanthines in a subset of 24 GT samples in order to obtain complementary information on the geographical origin of tea. The discrimination ability between the two types of tea has been shown by a Partial Least Squares Class-Modelling performed on the electrokinetic chromatography data, being the sensitivity and specificity of the class model built for the Japanese GT samples 98.70% and 98.68%, respectively. This comprehensive work demonstrates the capability of the combination of EEM fluorescence spectroscopy and PARAFAC model for characterizing, differentiating and analyzing GT samples. PMID- 30015102 TI - Simultaneous determination of five bioactive components of Gancao in rat plasma by UHPLC-MS/MS and its application to comparative pharmacokinetic study of incompatible herb pair Gansui-Gancao and Gansuibanxia Decoction. AB - Incompatible herb pair Gansui-Gancao is recorded in "eighteen incompatible" medicaments in many monographs of TCM (Traditional Chinese Medicine) which means the two herbs can not be co-used in most cases. However, Gansuibanxia decoction composed of Gansui(Kansui), Banxia(Pinellia), Shaoyao(Peony) and Gancao(Liquorice) is a traditional Chinese formula which has been clinically employed for the treatment of cancerous ascites, pleural effusion, peritoneal effusion, etc. The purpose of the study was to investigate the pharmacokinetics of main bioactive components in Gancao to explore the reasons why Gansui-Gancao can be used in Gansuibanxia decoction. A simple, rapid and sensitive UHPLC-MS/MS method for simultaneous determination of liquiritigenin, isoliquiritigenin, liquiritin, glycyrrhetinic acid and glycyrrhizic acid of liquorice in rat plasma was developed and validated. After extraction from plasma, the analytes and internal standard were separated on a C18 column with the mobile phase consisting of 0.1% acetic acid containing 0.2 mM ammonium acetate in water and acetonitrile via gradient elution. The electrospary ionization source was adopted under the multiple reaction monitoring mode. The method was succesfully applied to a comparative pharmacokinetic study of main bioactive components of Gancao in rat plasma after oral administration of the extracts of Gancao (GC), Gansui-Gancao (GS-GC), Shaoyao-Gancao (SY-GC), Gansui-Shaoyao-Gancao (GS-SY-GC) and Gansuibanxia decoction (GSBXD), respectively. The pharmacokinetic parameters had significant differences (P < 0.05) in different groups which showed that Gansui decreased the bioavailability of Gancao, while Shaoyao increased the bioavailability of Gancao. Hence, these may be the pharmacokinetic mechanism of incompatible herb pair Gansui-Gancao and the reasons why the herb pair can be used in Gansuibanxia decoction. PMID- 30015103 TI - Impedances of the inner and middle ear estimated from intracochlear sound pressures in normal human temporal bones. AB - For almost a decade, we have measured intracochlear sound pressures evoked by air conducted (AC) sound presented to the ear canal in many fresh human cadaveric specimens. Similar measurements were also obtained during round window (RW) mechanical stimulation in multiple specimens. In the present study, we use our accumulated data of intracochlear pressures and simultaneous velocity measurements of the stapes or RW to determine acoustic impedances of the cochlear partition, RW, and the leakage paths from scala vestibuli and scala tympani, as well as the reverse middle ear impedance. With these impedances, we develop a computational lumped-element model of the normal ear that illuminates fundamental mechanisms of sound transmission. To calculate the impedances for our model, we use data that passes strict inclusion criteria of: (a) normal middle-ear transfer function defined as the ratio of stapes velocity to ear-canal sound pressure, (b) no evidence of air within the inner ear, and (c) tight control of the pressure sensor sensitivity. After this strict screening, updated normal means, as well as individual representative data, of ossicular velocities and intracochlear pressures for AC and RW stimulation are used to calculate impedances. This work demonstrates the existence and the value of physiological acoustic leak impedances that can sometimes contribute significantly to sound transmission for some stimulation modalities. This model allows understanding of human sound transmission mechanisms for various sound stimulation methods such as AC, RW, and bone conduction, as well as sound transmission related to otoacoustic emissions. PMID- 30015104 TI - Prognostic impact of ASXL1 mutations in patients with myelodysplastic syndromes and multilineage dysplasia with or without ring sideroblasts. AB - INTRODUCTION: The 2016 World Health Organization (WHO) classification of myeloid neoplasms reclassified patients with myelodysplastic syndromes (MDS) with multilineage dysplasia (MLD) based on the presence or absence of ring sideroblasts (RS). We performed this study to validate this change in the context of relevant gene mutations. METHODS: WHO-defined MDS and MLD were identified with detailed clinical, cytogenetic and outcomes data. A 32-gene targeted exome sequencing panel was performed on bone marrow samples obtained at diagnosis. RESULTS: Ninety eight patients were included; 59 (60%) MDS-MLD and 39 (40%) MDS RS-MLD. There were no significant differences in the median overall survival (OS) in the two groups (25 months each, p = 0.6). Among the myeloid-relevant gene mutations, presence of ASXL1 (HR 2.5, p = 0.005) was identified as an adverse prognostic factor in a multivariate analysis. CONCLUSION: While segregation of MDS-MLD based on RS holds little prognostic relevance, ASXL1 mutational status significantly and independently predicts poor outcomes. PMID- 30015105 TI - Higher body mass index is associated with better survival in patients with myelodysplastic syndromes. PMID- 30015106 TI - Heterogeneity and its multiscale integration in plant morphogenesis. AB - Heterogeneity is observed at all levels in living organisms, but its role during the development of an individual is not well understood. Heterogeneity has either to be limited to ensure robust development or can be an actor of the biological processes leading to reproducible development. Here we review the sources of heterogeneity in plants, stress the interplay between noise in elementary processes and regulated biological mechanisms, and highlight how heterogeneity is integrated at multiple scales during plant morphogenesis. PMID- 30015107 TI - Relationship between economic stress factors and stress, anxiety, and depression: Moderating role of social support. AB - The economic crisis had a detrimental impact on the economies of several European countries, namely in Portugal. The literature emphasizes that periods of economic turmoil potentiate the appearance of mental health issues, such as stress, anxiety, and depression, and decrease populations' well-being. The present study, conducted in Portugal, was performed with a sample of 729 individuals, 33.9% males and 66.1% females, with an average age of 36.99 years old. Its' aim was to assess the relationship between economic stress factors (economic hardship, financial threat, and financial well-being) and stress, anxiety, and depression, as well as to test the moderating effect of social support on this relationship. Structural equation modeling (SEM) was used to examine the relationships defined. When comparing the results obtained in the models without and with social support as a moderator, statistically significant differences were observed on the relationships between financial threat and depression and between economic hardship and stress, anxiety, and depression. Regarding the association between financial threat and stress and anxiety, the effect of the economic stressor decreased in the presence of social support, but the differences were not statistically significant. The implications of these results are discussed and strategies to foster social support are proposed. PMID- 30015108 TI - Attachment and medically unexplained somatic symptoms: The role of mentalization. AB - Previous research has found an association between insecure attachment and increased somatization in adults. However, the mechanisms underlying this association are unknown. In the present study, we examined whether the association between attachment insecurity and somatization in psychiatric patients diagnosed with medically unexplained somatic symptoms (MUSS) is mediated by mentalization deficits. Attachment security of 58 outpatients diagnosed with MUSS was measured with the Experiences in Social Relationships Questionnaire (ECR). Difficulty with understanding own emotions was measured with the Toronto Alexithymia Scale-20. In addition, others' mental state comprehension was measured with the Reading the Mind in the Eyes Test (RMET). Somatic symptom severity experienced by MUSS patients was related to attachment anxiety and alexithymia. These associations remained significant after controlling for sex, age, medication use, and depressive symptoms. Moreover, alexithymia mediated the association between anxious attachment and severity of somatic symptoms. Somatic symptom severity was also related to better RMET performance, although this association was not significant after controlling for sex, age, medication use, and depressive symptoms. Our findings may indicate that individuals with an anxious attachment style have difficulties in clarifying own emotions. This may in turn result in somatic experience of emotional distress and risk for development of MUSS. PMID- 30015109 TI - The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review. AB - Approximately one-third of patients with schizophrenia have treatment-resistant schizophrenia (TR-SCZ), which is a condition characterized by suboptimal response to antipsychotics other than clozapine. Importantly, treatment with clozapine-the only antipsychotic with an indication for TR-SCZ-is often delayed, which could contribute to negative outcomes. Given that the specific impact of delay in clozapine initiation is not well understood, we aimed to conduct a systematic search of the Ovid Medline(r) database to identify English language publications exploring the impact of delay in clozapine initiation on treatment outcomes in patients with TR-SCZ. Additionally, clinico-demographic factors associated with clozapine delay were examined. Our search identified four retrospective studies that showed an association between longer delay in clozapine initiation and poorer treatment outcomes, even after including covariates, such as age, sex, and duration of illness. In addition, we found six studies that showed an association between age and clozapine delay, but results with regard to other clinico demographic variables were inconsistent. Overall, the available literature reveals a possible link between delay in clozapine use and poorer treatment outcomes in patients with TR-SCZ. However, given the relatively small number of studies on this clinically important topic, future research is warranted to draw more definitive conclusions. PMID- 30015110 TI - DNA methylation and gene expression of the chemokine (C-X-C motif) ligand 1 in patients with deficit and non-deficit schizophrenia. AB - This study detected the differences in gene expression and DNA methylation of CpG sites in CXCL1 gene and further investigated their associations with clinical symptoms in deficit schizophrenia (DS) and non-deficit schizophrenia (NDS). Pyrosequencing and RT-qPCR were separately used to determine DNA methylation and mRNA expression of CXCL1 gene. Both DNA methylation and expression were significantly different among DS, NDS and healthy control (HC) groups. Correlation analysis revealed that CXCL1 gene expression was associated with the negative syndrome in NDS patients, while no association in DS patients was observed. All together, these results suggest that DS may be a specific subgroup of schizophrenia with the characteristic abnormality of peripheral CXCL1 DNA methylation and gene expression. PMID- 30015111 TI - An ecological exploration of individual, family, and environmental contributions to parental quality of life in autism. AB - The aim of this study was to assess the respective weight of individual and environmental factors on quality of life (Qol) of parents of children with autism spectrum disorders (ASD). Few studies have investigated both individual and environmental predictors of Qol but to our knowledge, none of them has considered the child's and parents' characteristics, family context and services available in the same design. Participants were 115 parents (73 mothers and 42 fathers) of children with ASD aged from 3 to 10 years. Hierarchical regression analyses were conducted to investigate predictors of parental Qol among child-related, parent related and environmental factors. Findings indicate that a higher Qol is associated with a good quality of interaction in marital and parent-grandparents dyads, no family medical history and access to psycho-educational interventions for the child, regardless of child's developmental quotient, comorbidity, parent sex and working time. This final model best fits the data and explains 31.5% of the variance of parents' Qol. This study highlights that it is crucial to consider both individual and environmental variables as potential protective factors of parental adjustment. An ecological approach seems to be relevant to understand which parenting resources should be targeted in support programs. PMID- 30015112 TI - Functional remission in schizophrenia: A FROGS-based definition and its convergent validity. AB - Functional remission concerns only one third of schizophrenia patients who achieved symptomatic remission. We previously developed a scale devoted to functional remission, named the FROGS (Functional Remission Of General Schizophrenia). This instrument encompasses three clinically relevant dimensions. The aim of this study is to provide a threshold for functional remission relying on these three dimensions, and to compare its psychometric properties with other scales devoted to functional remission. We tested the characteristics of functional remission according to the FROGS. The FROGS was used in different European countries and compared to other valid scales (GAF, PSP and PSRS) in a sample of 295 schizophrenia patients. The association with different parameters as external validators was assessed, including clinical remission. A comparison of the classifying properties of each scale compared to the others was made. The four instruments were equally influenced by the PANSS score, the clinical remission according Andreassen's criteria, the number of past hospitalizations and the presence of a paid working activity. These findings provide a simple threshold for the FROGS, tightly linked to the definition of functional remission, with a good convergent validity. This instrument might be easily used to facilitate the assessment of functional remission in schizophrenia. PMID- 30015113 TI - Influence of ancient anthropogenic activities on the mangrove soil microbiome. AB - Mangroves are highly productive ecosystems located at the transition between the terrestrial and marine environments. Mangroves play an important role in carbon storage, nutrient cycling and support for the marine food web. Mangrove soils are formed by fine particles rich in organic carbon and are subject to constant fluctuations in oxygen, salinity and nutrient availability due to fresh water flux and tidal variations. Microbes play an important role in nutrient cycling in mangrove soils; however, studies on the mangrove soil microbiome are scarce. Here we compare the microbiome of pristine mangrove soil located in an environmentally protected area in Guaratuba, Southern Brazil, with the microbiome of mangrove soil affected by the presence of carbonaceaous debris eroding from an archeological site known as Sambaqui. We show that although the Sambaqui site has a major effect on soil chemistry, increasing the soil pH by 2.6 units, only minor changes in the soil microbiome were detected indicating resilience of the microbial community to pH variations. The high alpha diversity indexes and predicted metabolic potential suggest that the mangrove soil microbiome not only provides important ecological services but also may host a broad range of microbes and genes of biotechnological interest. PMID- 30015114 TI - Effects of water quality on aspects of reproductive biology of Cnesterodon decemmaculatus. AB - The Suquia River basin (Cordoba, Argentina) is under a strong negative impact due to multiple sources of anthropic pollution. The main goal of our study was to evaluate if variations in the water quality of Suquia river basin affect the reproductive biology of Cnesterodon decemmaculatus and determine if the responses provided by the species can be considered as biomarkers of river quality. This assessment was performed through the measurement of morphological, histological and somatic parameters in adult males collected at four sampling sites during the beginning and the end of the breeding season. The water quality evaluation carried out through the estimation of a water quality index (WQI) and pesticides concentrations in water, revealed a pollution gradient along the studied basin. The same variation pattern was registered for the somatic index. In addition, the analysis of the morphology of the male copulatory organ (gonopodium) showed that individuals collected at Cordoba city had the lowest Gonopodium-Somatic Index (Gonop-SI) value, while those sampled at the most polluted site showed abnormalities in the small structures of the gonopodium. On the other hand, few histological alterations were found in the liver whereas no alterations were found in gonads along the river. The results obtained allowed us to characterize the environmental conditions of the studied basin and demonstrated the water quality deterioration along the Suquia River. PMID- 30015115 TI - Single step synthesis of Janus nano-composite membranes by atmospheric aerosol plasma polymerization for solvents separation. AB - Solvent permeation across membranes is limited due to physical resistance to diffusion from the selective layer within the membrane and to plasticizing effects generated by the solvent molecules onto the polymeric macromolecular matrix. Nano-composite thin film membranes provide promising routes to generate controlled microstructural separation materials with higher selectivities and permeabilities. Here, the fabrication of nano-composite based on octamethyl polyhedral oligomeric silsesquioxane - hexamethyldisiloxane thin film membranes is demonstrated by aerosol assisted atmospheric plasma deposition onto pre-formed nano-porous membrane supports for the first time. Stable, atomically smooth and continuous solid films with controllable thickness down to 50 nm were achieved. The deposition process allowed for the control of the wettability of the surfaces to water and organic solvents, leading to the generation of hydrophobic but alcohol-philic surfaces. The liquid entry pressure of the films to water was found to be 8 bar from plasma polymerization as oppose to 3 bar for the bare nano porous support only. In addition, the ideal separation selectivity for ethanol to water, up to 6.5, highlight the impact of both the surface energy and level of cross-linking of the hexamethyldisiloxane nanostructures on the diffusion mechanisms. This new atmospheric plasma deposition strategy opens-up cost effective and environmentally friendly routes for the design of the smart Janus membrane with customizable properties and performance. PMID- 30015116 TI - Determination of glyphosate, AMPA and glufosinate in dairy farm water from Argentina using a simplified UHPLC-MS/MS method. AB - Argentina, together with the USA and Brazil, produces approximately 80% of the total worldwide glyphosate loadings. The development of a simplified ultra-high performance liquid chromatographic tandem mass spectrometric method (UHPLC-MS/MS) for the determination of glyphosate, aminomethylphosphonic acid (AMPA) and glufosinate in water is described, including studies of several alternatives of 9 fluorenylmethylchloroformate (FMOC-Cl) derivatization and pretreatment steps. The proposed method includes acidification and neutralization of a low sample volume (3 mL), 2 hours derivatization step, cleanup with dichloromethane, followed by reverse phase UHPLC-MS/MS determination of the analytes. Figures of merit were satisfactory in terms of linearity, selectivity, accuracy and intermediate precision (%REC 70-105% with RSD < 15%). Limits of quantification (LOQ) were suitable for monitoring purposes (0.6, 0.2, 0.1 MUg/L for glyphosate, AMPA and glufosinate respectively). The validated methodology was applied for the analysis of livestock wells waters from 40 dairy farms located in the central region of Argentina. Glyphosate and AMPA were quantified in 15% and 53% of the analyzed samples with concentrations ranging from 0.6-11.3 MUg/L and 0.2-6.5 MUg/L respectively. Greater concentrations of glyphosate were also verified in waters from open-reservoir tanks, which are directly exposed to the farm environment. In these cases glyphosate and AMPA occurrence increased, being quantified in the 33% and 61% of the samples with values ranging 0.6-21.2 MUg/L and 0.2-4.2 MUg/L respectively. Also in this case glufosinate was found in 52% samples at 0.996. This study gave significant insight into the HPSEC profiles of AOM, in which resolved peaks A and B (biopolymers) and peak C (humic substances) showed a strong correlation with the formation of carbonaceous-DBPs (C-DBPs). This likely resulted from the abundance of aromatic structures and conjugated CC double bonds in their chemical nature. Our results also indicated the importance of algal cells, including intra-cellular and cell-bound organic matter, over extra cellular organic matter as precursors to C-DBP formation. The application of the information extracted from HPSEC profiles associated with the fluorescent components of AOM showed great improvements in the predictability of THMs, HAAs, and C-DBPs with R2 > 0.7 and p < 0.05. The outcome of this study will significantly benefit effective control of AOM-derived DBP formation by the chlorination of eutrophic waters. PMID- 30015121 TI - Modulation of mitochondrial functions by xenobiotic-induced microRNA: From environmental sentinel organisms to mammals. AB - Mitochondria play a crucial role in energetic metabolism, signaling pathways, and overall cell viability. They are in the first line in facing cellular energy requirements in stress conditions, such as in response to xenobiotic exposure. Recently, a novel regulatory key role of microRNAs (miRNAs) in important signaling pathways in mitochondria has been proposed. Consequently, alteration in miRNAs expression by xenobiotics could outcome into mitochondrial dysfunction, reactive oxygen species overexpression, and liberation of apoptosis or necrosis activating proteins. The aim of this review is to show the highlights about mitochondria-associated miRNAs in cellular processes exposed to xenobiotic stress in different cell types involved in detoxification processes or sensitive to environmental hazards in marine sentinel organisms and mammals. PMID- 30015122 TI - Glyphosate and atrazine in rainfall and soils in agroproductive areas of the pampas region in Argentina. AB - The presence in the atmosphere of glyphosate (GLP) and atrazine (ATZ) was investigated-those pesticides dominating the market in Argentina-through rain, as the main climatic phenomenon associated with wet deposition, both through analyzing source-receptor relationships with soil along with the climatic influences that may condition that transport and through estimating the annual deposition on the surface of the Argentine pampas. Rainwater samples (n = 112) were collected throughout each rainfall in urban areas of the pampas having different degrees of land use and with extensive crop production plus subsurface soil samples (n = 58) from the relevant periurban sites. The herbicides-analyzed by liquid-chromatography-mass-spectrometry-were detected in >80% of the rain samples at median-to-maximum concentrations of 1.24-67.3 MUg.L-1 (GLP) and 0.22 26.9 MUg.L-1(ATZ), while aminomethylphosphonic acid (AMPA) was detected at 34% (0.75-7.91 MUg.L-1). In soils, GLP was more frequently registered (41%; 102-323 MUg.kg-1) followed by ATZ (32%; 7-66 MUg.kg-1) and then AMPA (22%; 223-732 MUg.kg 1). The maximum GLP concentrations quantified in rainwater exceeded the previously reported levels for the USA and Canada. No associations were observed between soil and rainwater concentrations in the same monitoring areas-despite the soil's action as a source, as evidenced through the AMPA present in rainwater. Median GLP concentrations were significantly associated with isohyets, in an increasing gradient from the east to the west-as such in an inverse pattern to that of the annual rainfall volumes; whereas ATZ-rainwater levels exhibited no characteristic spatial configuration. The estimated annual deposition of GLP by rainfall indicated that more than onc source of a herbicide can lead to its presence in the atmosphere and points out the relevance of rainfall's contribution to the surface levels of a pollutant. PMID- 30015123 TI - Capturing the applicability of in vitro-in silico membrane transporter data in chemical risk assessment and biomedical research. AB - Costs, scientific and ethical concerns related to animal tests for regulatory decision-making have stimulated the development of alternative methods. When applying alternative approaches, kinetics have been identified as a key element to consider. Membrane transporters affect the kinetic processes of absorption, distribution, metabolism and excretion (ADME) of various compounds, such as drugs or environmental chemicals. Therefore, pharmaceutical scientists have intensively studied transporters impacting drug efficacy and safety. Besides pharmacokinetics, transporters are considered as major determinant of toxicokinetics, potentially representing an essential piece of information in chemical risk assessment. To capture the applicability of transporter data for kinetic-based risk assessment in non-pharmaceutical sectors, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) created a survey with a view of identifying the improvements needed when using in vitro and in silico methods. Seventy-three participants, from different sectors and with various kinds of expertise, completed the survey. The results revealed that transporters are investigated mainly during drug development, but also for risk assessment purposes of food and feed contaminants, industrial chemicals, cosmetics, nanomaterials and in the context of environmental toxicology, by applying both in vitro and in silico tools. However, to rely only on alternative methods for chemical risk assessment, it is critical that the data generated by in vitro and in silico methods are scientific integer, reproducible and of high quality so that they are trusted by decision makers and used by industry. In line, the respondents identified various challenges related to the interpretation and use of transporter data from non-animal methods. Overall, it was determined that a combined mechanistically-anchored in vitro-in silico approach, validated against available human data, would gain confidence in using transporter data within an animal-free risk assessment paradigm. Finally, respondents involved primarily in fundamental research expressed lower confidence in non-animal studies to unravel complex transporter mechanisms. PMID- 30015124 TI - Safety and efficacy assessment of a GLP-1 mimetic: insulin glargine combination for treatment of feline diabetes mellitus. AB - A commonly used therapeutic strategy for type 2 diabetes mellitus (DM) in humans involves the use of synthetic incretin hormone-based therapies including exenatide, a glucagon-like pepetide-1 hormone agonist. Glucagon-like pepetide-1 agonists can be used alone or as an ancillary therapy with other agents, including insulin and oral antihyperglycemics. Little is known about the role of these therapies for DM in cats. Therefore, the primary objective of this study was to evaluate the safety and efficacy of short-acting exenatide combined with insulin, as compared to placebo and insulin for the treatment of DM in cats. Treatment with exenatide was well tolerated; only 2 cats developed side effects requiring dose reduction. Two cats (25%) went into diabetic remission while receiving exenatide and insulin, whereas remission was not reported during placebo treatment. The average change in the daily exogenous insulin dose was significant (beta = -0.56 U/kg, 95% confidence interval, -0.96 to -0.15, P = 0.007), and the dose of insulin administered was lower during exenatide treatment. The average weight loss experienced on exenatide was significantly higher than on placebo (beta = 0.65 kg, 95% confidence interval, 0.09-1.21, P = 0.02). There was no significant difference in any of the hormone concentrations evaluated for cats on exenatide vs placebo treatments. Overall, the treatment of diabetic cats with insulin and a fixed dose of exenatide was found to be safe. The weight loss and decreased exogenous insulin requirement experienced with exenatide treatment could be a significant benefit for overweight diabetic cats and warrants further evaluation. PMID- 30015125 TI - Multiparametric quantification of heterogeneity of metal ion concentrations, as demonstrated for [Mg2+] by way of 31P MRS. AB - Magnesium(II) is the second most abundant intracellular cation in mammals. Non invasive 31P MRS is currently used to measure intracellular free Mg2+ levels in studies of magnesium deficiency disorders. However, this technique only provides one [Mg2+] value for a given tissue volume (or voxel), based on the chemical shift of the ATP-beta (or NTP-beta) resonance. We present here an approach for quantifying tissue heterogeneity in regard to [Mg2+], by way of multiple 31P MRS derived descriptors characterizing the statistical intra-volume distribution of free [Mg2+] values. Our novel paradigm exploits the fact that the lineshape of the ATP-beta 31P MRS resonance reflects the statistical distribution of [Mg2+] values within the observed volume (or voxel). Appropriate lineshape analysis reveals multiple quantitative statistical parameters (descriptors) characterizing the [Mg2+] distribution. First, the ATP-beta 31P MRS resonance is transformed into a [Mg2+] curve that is used to construct a histogram with our specially developed algorithms. From this histogram, at least eight [Mg2+] descriptors are computed: weighted mean concentration and median concentration, standard deviation of concentration, range of concentration, concentration mode(s), concentration kurtosis, concentration skewness, and concentration entropy. Comprehensive evaluation based on in silico and experimental models demonstrates the validity of this new method. This basic feasibility study should open new avenues for future in vivo studies in physiology and medicine. PMID- 30015126 TI - Engineering spin Hamiltonians using multiple pulse sequences in solid state NMR spectroscopy. AB - Multiple pulse sequences are often used to manipulate spin Hamiltonians in solid state nuclear magnetic resonance spectroscopy. In this paper, we analyze multiple pulse sequences using the well-known average Hamiltonian theory. We first expand the resulting average Hamiltonian into a reachable set of sub-Hamiltonians and then develop a general procedure using both flip-angle and phase of the applied pulses as control variables to select any of those sub-Hamiltonians. We use this method to analyze solid-echo based sequences and to design new proton-proton homonuclear decoupling sequences in static solids. It is found that this newly designed decoupling scheme, in the presence of finite pulse length, effectively suppresses the 1H-1H homonuclear dipolar interactions while establishes variable scaling factors on the heteronuclear dipolar interactions and chemical shift interactions, depending on the flip-angle of the applied pulses. When the pulse flip-angle is close to 54.7 degrees , this sequence possesses a large scaling factor with relatively low average decoupling field. When the pulse flip-angle becomes ~120 degrees , the scaling factor is almost zero. A static 15N-acetyl valine crystal sample has been used as an example to confirm and validate the performance of this new decoupling scheme. PMID- 30015127 TI - Effect of high salinity in wastewater on surface properties of anammox granular sludge. AB - Bacterial surface properties fundamentally affect the stability and aggregation of anammox granular sludge. The variation in the surface properties of the granular sludge at different salinities were investigated to further clarify the effect of salinity on the aggregation of anammox granular sludge in this study. High anammox activity was obtained at a salinity of 30 g/L NaCl, and the average removal efficiency of NH4+N, NO2--N and TN reached 91.9% +/- 1.4%, 97.3% +/- 0.4% and 86.3% +/- 0.9%, respectively. The sludge particle size in Reactor 1 (with 0 g/L NaCl as control) and Reactor 2 (with 0, 15 and 30 g/L NaCl) increased from 1.62 +/- 0.16 mm and 1.59 +/- 0.12 mm to 2.71 +/- 0.23 mm and 2.44 +/- 0.19 mm, respectively, during total operation. PN gradually decreased from 30.58 +/- 2.5 mg/g to 18.11 +/- 2.1 mg/g, and PS sharply increased from 1.48 +/- 0.09 mg/g to 10.52 +/- 0.50 mg/g with the increase in salinity. The PS/PN ratio of extracellular polymeric substances (EPS) rapidly increased from 0.05 to 0.58 with an increase of salinity. Fourier transform infra-red spectroscopy (FTIR) and X ray photoelectron spectroscopy (XPS) results showed that salinity inhibited the expression of anammox sludge hydrophobicity by changing surface groups. Binding between multivalent metal ions and EPS was significantly hindered by the high Na+ concentration. The results of this study provided a better understanding of the effect of salinity on the stability and aggregation of anammox granular sludge in saline wastewater treatment. PMID- 30015128 TI - Metabolic enhancement of 2,3',4,4',5-pentachlorobiphenyl (CB118) using cytochrome P450 monooxygenase isolated from soil bacterium under the presence of perfluorocarboxylic acids (PFCAs) and the structural basis of its metabolism. AB - 2,3',4,4',5-Pentachlorobiphenyl (CB118) is one of the most abundant polychlorinated biphenyl (PCB) congeners in the environment, and perfluoroalkyl acids, including perfluorocarboxylic acids (PFCAs), are widely distributed in the environment. Although CB118 and perfluoroalkyl acids are present in all humans and biota, effects in the metabolic fate of CB118 leading to toxicity change are unclear. P450BM3, which is isolated from the soil bacterium Bacillus megaterium, metabolized CB118 to three different hydroxylated pentachlorobiphenyls (M1-M3). M2 was identified as 4'-OH-2,3',4,5,5'-pentachlorobiphenyl. These reactions were promoted by the presence of PFCAs, and perfluorooctanoic acid (PFCA-C8) was the most effective for accelerating these reactions among PFCAs with different carbon chain length. The production rate of M2 was accelerated by 25-times using PFCA C8. Furthermore, the docking models of P450BM3 with CB118 and PFCAs revealed that the conformational changes of the substrate-binding cavity of P450BM3 after binding of PFCAs to P450BM3 were important for selective production of CB118 metabolites. This study leads to the clarification of the different metabolic fates of PCBs under complex contamination with PFCAs. PMID- 30015129 TI - A disadvantageous effect of adsorption of barium by melanin on transforming activity. AB - At present, beneficial effects of melanin and harmful effects of barium have been reported. However, little is known about the adsorption of barium, and even less is known about the biological significance of adsorption of barium by melanin. In this study, we showed that there was a strong correlation between the digitalized level of skin pigmentation and barium level in murine skin compared to the correlations between skin pigmentation level and levels of homologous elements of barium (magnesium, calcium and strontium). The concentration of subcutaneously injected barium in skin with a high level of pigmentation was higher than that in skin with a low level of pigmentation. Our cell-free experiment using the Langmuir isotherm for adsorption of barium in synthetic melanin also provided direct evidence of adsorption of barium by melanin. We then investigated the biological significance of melanin-mediated barium adsorption. We found barium mediated increase in transforming activity in pigmented melanocytes (melan-a) but not in unpigmented melanocytes (melan-c) after confirming that the barium level in melan-a melanocytes was 3.4-fold higher than that in melan-c melanocytes after culture of 5 MUM barium for 24 h. Taken together, our results not only indicate adsorption of barium by melanin in mice, cells and cell-free systems but also suggest a disadvantageous effect of adsorption of barium by melanin on transforming activity in cultured cells. PMID- 30015130 TI - Macroscopic, theoretical simulation and spectroscopic investigation on the immobilization mechanisms of Ni(II) at cryptomelane/water interfaces. AB - In the present study, the macroscopic sorption behaviors and microscopic immobilization mechanisms of Ni(II) at cryptomelane/water interfaces were explored using the combination of batch sorption technique, desorption procedure, theoretical simulation, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and extended X-ray absorption fine structure (EXAFS) analyses. The good simulation of the pseudo second-order model on the sorption kinetics data suggests a driving force of chemical sorption rather than mass transport or physical interaction. The sorption trends and uptake mechanisms are obviously related to the solution pH, with cation exchange or outer-sphere surface complexation at an acidic pH of 4.0, inner-sphere surface complexation in both the edge-shared (ES) and double corner shared (DCS) modes at a neutral pH of 7.0, and precipitation of alpha-Ni(OH)2(s) phase at a highly alkaline pH of 10.0. The gradual increase of Ni(II) sorption amount with solution temperature rising from 293 K to 333 K is consistent with the increased ratio of the weak DCS configuration. The research findings herein can help us better understand the migration and transformation trends of Ni(II) in the manganese mineral-riched aquatic environment. PMID- 30015131 TI - Understanding and optimization of the flocculation process in biological wastewater treatment processes: A review. AB - In the operation of biological wastewater treatment processes, fast sludge settling during liquid-solids disengagement is preferred as it affects effluent quality, treatment efficiency and plant operation economy. An important property of fast settling biological sludge is the ability to spontaneously form big and dense flocs (flocculation) that readily separates from water. Therefore, there had been much research to study the conditions that promote biological sludge flocculation. However, reported findings have often been inconsistent and this has possibly been due to the complex nature of the biological flocculation process. Thus, it has been challenging for wastewater treatment plant operators to extract practical information from the literature. The aim of this review is to summarize the current state of understanding of the factors that affect sludge flocculation so that evaluation of such information can be facilitated and strategize for intervention in the sludge flocculation and deflocculation process. PMID- 30015132 TI - Effect of irradiation energy and residence time on decomposition efficiency of polycyclic aromatic hydrocarbons (PAHs) from rubber wood combustion emission using soft X-rays. AB - This research aims to investigate the effects of irradiation energy and residence time of soft X-ray irradiation in the decomposition of sixteen polycyclic aromatic hydrocarbons (PAHs) in smoke particles emitted from the Para rubber wood burning. The burning process was carried out in a tube furnace and the soft X-ray radiation used had a wave length of 0.13-0.41 nm. The irradiated (IR) and non irradiated (N-IR) smoke particles were collected simultaneously using a 10-stage Andersen sampler equipped with an inertial-filter stage (ANIF), in order to determine the physicochemical characteristic of both IR and N-IR smoke particles, including particle size distribution and concentration, and particle-bound PAHs concentration. Results show that the nano-size smoke particles contained the highest amount of PAHs and of carcinogenic potency equivalent (BaP-TEQ). About 75% of PAH compounds on the total smoke particles were decomposed at the highest irradiation energy. Moreover, 4-6 ring PAHs in nanoparticles (<70 nm) were decomposed of up to about 91% at the highest irradiation energy. The decomposition efficiency of PAHs was influenced by particle size, PAHs boiling temperature and irradiation energy. It was higher for PAHs with lower boiling temperature and smaller size particles, while the effect of residence time was not significant. PMID- 30015133 TI - Decline in sensorimotor systems explains reduced falls self-efficacy. AB - Physical performance including balance tasks is one of the main factors explaining the variance in falls self-efficacy in older adults. Balance performance is often measured by use of gross assessment scales, which assess the result of integration of all systems involved in postural control. We aimed to investigate which measurements of postural control correlate to falls self efficacy scores as measured by the FES-I instrument, and which sensory and motor systems best explain them. A cross sectional study was designed, in which 45 older adults performed quiet stance and limits of stability trials during which their center of pressure (CoP) excursion was recorded. Falls self-efficacy was measured using the Falls Efficacy Scale - International. Eyesight, vestibular function, proprioception, reaction time and strength were also measured. Hierarchical orthogonal projection of latent structures was used to model FES-I with the CoP trials and then with the sensory and muscle function data. Fes-I could be explained to 39%, with the eyes open trials and the limits of stability trials loading the heaviest. The base model could be explained to 40% using the sensory and muscle function data, with lower limb strength, leg proprioception, neck proprioception, reaction time and eyesight loading the heaviest. PMID- 30015134 TI - Global electromyographic signal characteristics depend on maximal isometric contraction method in the knee extensors. AB - OBJECTIVE: To determine if maximal isometric contraction (MVIC) method (i.e., ramp (MVICRAMP) versus traditional MVIC) influences (1) maximal voluntary isometric torque (MVIT) production of the knee extensors, (2) electromyographic signal amplitude (EMGAMP), and (3) EMG mean power frequency (EMGMPF) of the rectus femoris and vastus lateralis in moderately-to highly-activated subjects. We hypothesized that EMGAMP would be greater during the MVICRAMP than MVIC muscle contractions, but that there would be no difference in MVIT. APPROACH: Twenty five males (23.4 +/- 3.4 y; % voluntary activation = 93.9 +/- 5.1%) visited the laboratory and completed MVICRAMPs and MVICs. During all contractions, leg extensor torque and sEMG signals from the vastus lateralis (VL) and rectus femoris (RF) were recorded. MAIN RESULTS: There was no significant difference in the MVIT produced (p = 0.65) or in EMGMPF (p = 0.052) during MVICRAMP versus MVIC. However, EMGAMP was 18.1% higher during the MVICRAMP than MVIC (p = 0.004). SIGNIFICANCE: Maximal isometric muscle contraction method significantly influenced EMGAMP, and had a moderate effect on EMGMPF (d = 0.49). Investigators who utilize MVICs to determine maximal EMG signal amplitude and frequency to normalize their EMG signals should be aware of these differences. PMID- 30015135 TI - Comparison of chairs based on HDsEMG of back muscles, biomechanical and comfort indices, for violin and viola players: A short-term study. AB - This work investigates the effect of different seats on violin and viola players sitting postures using High-Density-surface-Electromyography techniques (HDsEMG), biomechanical and comfort indices. Five types of chairs were assessed on 18 violin and three viola players by comparing: (a) pelvic tilt and kyphosis and lordosis angles, (b) subjective comfort indices, and (c) EMG amplitude of erector spinae and trapezius. Sitting "as you like" on a standard orchestra chair is the condition with the highest subjective comfort (but not significantly different from other chairs). A saddle chair with low back support is associated to the lowest EMG of the erector spinae (p < 0.05) and a saddle stool is associated to the spinal angles closest to those of the standing posture. In 12 out of 21 (57%) musicians, the erector spinae was activated in an intermittent manner, regardless of the chair used. These findings justify further research on the selected chairs, on muscle fatigue and on the intermittent postural control strategy. PMID- 30015136 TI - Effects of rule uncertainty on cognitive flexibility in a card-sorting paradigm. AB - Cognitive flexibility has been studied in two separate research traditions. Neuropsychologists typically rely on rather complex assessment tools such as the Wisconsin Card Sorting Test (WCST). In contrast, task-switching paradigms are used in experimental psychology to obtain more specific measures of cognitive flexibility. We aim to contribute to the integration of these research traditions by examining the role of the key factor that differs between the WCST and experimental task-switching paradigms: rule uncertainty. In two experimental studies, we manipulated the degree of rule uncertainty after rule switches in a computerized version of the WCST. Across a variety of task parameters, reducing rule uncertainty consistently impaired the speed and accuracy of responses when the rule designated to be more likely turned out to be incorrect. Other performance measures such as the number of perseverative errors were not significantly affected by rule uncertainty. We conclude that a fine-grained analysis of WCST performance can dissociate behavioural indicators that are affected vs. unaffected by rule uncertainty. By this means, it is possible to integrate WCST results and findings obtained from task-switching paradigms that do not involve rule uncertainty. PMID- 30015137 TI - Dissociating decision strategies in free-choice tasks - A mouse tracking analysis. AB - Everyday life offers a variety of possible actions, from which we choose one that corresponds to our intended goals. How do these goals and actions interact within the mind? One way to investigate this question is free-choice tasks, where participants freely choose the action they want to perform on any given trial. Such tasks are used in research on voluntary actions and goal-driven behavior, such as ideomotor theory. However, these tasks leave participants with a substantial amount of freedom and allow for different response strategies. Such strategies can, though being hidden in the final data, influence the results, for example by hiding the effects of manipulations of interest. To better understand participants' behavior in free-choice tasks, we used mouse tracking in an ideomotor free-choice experiment, where participants learn the connection between an action and an effect. Subsequently, they have to freely choose between actions, while the former effect is presented as a stimulus. We identified two distinct groups that applied different decision strategies. The first group made the decision at the beginning of or before the trial, irrespective of the yet to be presented effect stimulus. The second group decided within the trial and was affected by the stimulus more often. This suggests that people handle free-choice tasks differently which is expressed in heterogeneous choice patterns and response times and an underestimation of the examined effects. These differences potentially limit the reliability of inferences from free-choice experiments and should be considered in the interpretation of their results. PMID- 30015138 TI - Scheduling styles. AB - To schedule activities and transition from one activity to the next, humans can rely on the external clock (clock-time style) or on their internal sense (event time style). This article discusses how relying on an external time cue versus an internal time cue can markedly shape the way people perceive the social world, beyond its mere purpose of organizing activities. First, research shows that individuals' reliance on clock-time or event-time is not a mere cultural artifact, but also constitutes a way to self-regulate. Second, each scheduling style is akin to different lenses through which people consider the world: each deeply and differently influences people's sensation of control and their ability to savor positive emotions. Downstream implications for the domains of creativity, consumer decision-making and management are discussed. PMID- 30015139 TI - Rapid mussel-inspired synthesis of PDA-Zn-Ag nanofilms on TiO2 nanotubes for optimizing the antibacterial activity and biocompatibility by doping polydopamine with zinc at a higher temperature. AB - Mussel-inspired deposition of polydopamine (PDA) is a green chemical method that has been used to load silver nanoparticles on titanium oxide nanotubes (TiO2 NTs) to kill bacteria. However, a long reaction time is required for both the polymerization of dopamine and the reaction between PDA and silver nitrate. In addition, the deposition of silver nanoparticles is difficult to control, which may increase the risk of cytotoxicity. In this study, a rapid polymerization of dopamine was achieved by performing the reaction in a water bath at 90 degrees C (PDA-H). Furthermore, the reduction of Ag+ ions was markedly accelerated by the PDA-Zn film that was formed on the surface of TiO2 NTs from a solution of dopamine and zinc nitrate under the same heating conditions. The reaction between the PDA-Zn film and silver nitrate was dramatically reduced to 10 min, and the silver nanoparticles deposited on the PDA-Zn film were more uniform than those by PDA-H film. This PDA-Zn-Ag-TiO2 NTs material exhibited good antibacterial activity, as evidenced by the inhibition zone. The WST-1 assay indicated that the PDA-Zn-Ag film possessed a lower cell cytotoxicity and better biocompatibility than other Ag containing PDA films. PMID- 30015140 TI - Monoolein liquid crystalline phases for topical delivery of crocetin. AB - The present investigation concerns the production and characterization of monoolein-water systems designed for cutaneous administration of crocetin. The different monoolein crystalline phases forming in the presence of crocetin as a function of added water have been investigated by x-ray and polarized light microscopy. Franz cell was employed to compare in vitro the crocetin diffusion from selected monoolein water systems containing 95, 90 or 75% w/w of monoolein, while to investigate the performance of monoolein-water as transdermal delivery systems, in vivo studies, based on tape stripping were performed. The presence of micellar, lamellar and Q230 phases was found in the case of systems containing monoolein 95, 90 and 75% w/w respectively, with a viscosity almost directly proportional to the amount of added water. The higher the amount of water, the longer the crocetin stability, while its diffusion was slower in the case of more viscous systems. Tape stripping results indicated a more rapid depletion of crocetin on stratum corneum in the case of systems characterized by cubic phases, followed by micellar and lamellar ones. This behaviour could be related to a more rapid drug penetration throughout the deeper skin strata. PMID- 30015141 TI - Preparation of self-assembled platinum nanoclusters to combat Salmonella typhi infection and inhibit biofilm formation. AB - In this work, phytoprotein functionalized platinum nanoparticles (PtNCs) were synthesized using the proteins from fresh green spinach leaves. Transmission electron microscopy showed that PtNCs were spherical shape with size ~5 nm, which self assembled into spherical platinum nanoclustures (PtNCs) with size within the range of 100-250 nm. The presence of elemental platinum was confirmed by EDX analysis. FTIR studies confirm that the PtNCs were stabilized by the protein. As prepared PtNCs inhibits the growth of the food borne pathogen, Salmonella typhi with minimum inhibitory concentration (MIC) of 12.5 MUM. Light microscopy evidenced that the PtNCs can damage the established biofilms. Antibacterial mechanistic study revealed that PtNCs damages the S. typhi membranes, which was confirmed by scanning electron microscopy and further by fluorescence microscopy using acridine orange/propidium iodide dual staining assay. Besides membrane damage, PtNCs also triggered the intracellular ROS-mediated oxidative damage over the antioxidant defense and kills S. typhi. The hemolytic test showed low cytotoxicity of PtNCs at 100 MUM (four times higher the MIC). Finally, the therapeutic efficacy of PtNCs was validated in S. typhi infected zebrafish animal model and the obtained results are discussed. PMID- 30015142 TI - Effects of the multilayer structures on Exenatide release and bioactivity in microsphere/thermosensitive hydrogel system. AB - Traditional polypeptide-loaded PLGA microspheres (PM) using emulsion electrospray techniques often exhibit unsteady release and limited bioactivity. To solve these two problems, an Exenatide (EXT)-loaded multilayer system composed ofPM and thermosensitive hydrogel was prepared by the emulsion electrospray technique in this study. Hydrogel mixture were loaded in PLGA microspheres as Depot-hydrogel to prepare Gel/PM. The PM/Gel and Gel/PM/Gel systems were obtained by dispersion of PM and Gel/PM into hydrogel mixture, respectively. EXT in Gel/PM/Gel showed a constantly in vitro release for 30 days, which was significantly enhanced in comparison of those in the PM/Gel and the Gel/PM. PM/Gel and Gel/PM/Gel showed diminished burst release and no platform period compared with PM and Gel/PM. And these could be because the introduced Matrix-hydrogel outside, as a buffer layer, inhibited burst releases and exhibited a sustained manner. The inner Depot hydrogelstructure slowed the PLGA degradation rate and drug release rate. As well, more than 15-day blood glucose levels in KKAy mice were greatly maintained at 7.50-9.50 mmol/L after a single subcutaneous injection of Gel/PM/Gel (4.95 MUg/kg). Spatial stability and further bioactivity of released EXT were well protected by EXT-hydrogel complexes, and undesirable uptake of EXT and microspheres via phagocytes were also decreased by PEG shell. Thus, the long acting microspheres/hydrogel multilayer system prepared by emulsion electrospray technique showed promising potentials for loading hydrophilic polypeptides and proteins. PMID- 30015143 TI - An antibody-based platform for melatonin quantification. AB - Melatonin, the 'chemical signal of darkness', is responsible to regulate biological rhythms and different physiological processes. It is mainly produced by the pineal gland as a hormone in a rhythmic daily basis, but it may also be synthesized by other tissues, such as immune cells, under inflammatory conditions. Its abnormal circulating levels have been related to several diseases such as type 2 diabetes, Alzheimer's disease and some types of cancer. Currently, melatonin is exclusively quantified by ELISA or radioimmunoassays, which although are very sensitive techniques and present low detection limits, usually require specialized personal and equipment, restricting the tests to a limited number of patients. To overcome such limitations, we developed a novel easy-to-use electrochemical immunosensor for rapid melatonin quantification. Anti-melatonin antibodies were immobilized into Indium tin oxide (ITO) platforms using (3 Aminopropyl)triethoxysilane (APTES), 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) crosslinkers. The platforms were assayed with synthetic and biologically-present melatonin containing samples. The developed device displayed a linear response in the concentration range from 0.75 to 7.5 MUmol/L and a limit of detection of 0.175 MUmol/L using Electrochemical Impedance Spectroscopy (EIS) (R2 = 0.989) and 0.513 MUmol/L using Cyclic Voltammetry (CV) (R2 = 0.953) for synthetic melatonin. Furthermore, the sensors exhibited a good stability and reproducibility (3.45% and 2.87% for EIS and CV, respectively, n = 3), maintaining adequate response even after 30 days of assembly. On biologically-present melatonin-containing samples the device displayed a similar performance when compared to ELISA technique (deviation of 13.31%). We expect that the developed device contributes significantly to the medical area allowing precise and complete diagnosis of the diseases related to abnormal levels of melatonin. PMID- 30015144 TI - Mitochondrial and metabolic adjustments during the final phase of follicular development prior to IVM of bovine oocytes. AB - In vitro maturation (IVM) leads to reduced developmental rates compared to the use of in vivo matured oocytes. This reduction can be attributed to the suboptimal environment experienced during IVM, but the use of incompetent oocytes also plays a significant role. The objective of this study has been to characterize the mitochondrial and metabolic differences between competent and incompetent bovine oocytes selected prior to IVM based on Brilliant Cresyl Blue (BCB) staining. BCB selection allowed to sort two populations of cumulus-oocyte complexes (COCs) exhibiting diverse developmental competence despite showing a similar size and thereby being morphologically undistinguishable otherwise. Nuclear maturation rates were similar in both populations, but cleavage and blastocysts rates were significantly higher in BCB+ compared with BCB-. Mitochondrial distribution was similar between both groups, but mtDNA content experienced a 1.9-fold increase between BCB- and BCB+ oocytes, suggesting that a significant mtDNA synthesis must occur at the last stages of follicular development to achieve full competence prior to IVM. Consistently, transcriptional analysis in cumulus cells revealed an upregulation of the mitochondrial transcription factor TFAM in BCB-. Transcriptional analysis also suggested a decrease in both anaerobic glycolysis and pentose phosphate pathway (PPP) in BCB+ COCs, as the anaerobic glycolysis enzymes GAPDH and LDHA and the positive regulator of G6PD activity SIRT2 were upregulated in BCB- cumulus cells. These results suggest that during the final stages of follicular development a significant mtDNA replication must occur to achieve full oocyte developmental competence, and that this replication may be linked to anaerobic glycolysis and PPP activities. PMID- 30015145 TI - Embryonic and fetal development of the white-lipped peccary (Tayassu pecari). AB - The white-lipped peccary (Tayassu pecari) is an endangered large-sized Neotropical ungulate that is one of the most hunted mammals in the Amazon. Here, we used two embryos and 102 white-lipped peccary fetuses originated from animals hunted for subsistence in the Peruvian and Brazilian Amazon to describe the intrauterine development of external and internal morphology of this Neotropical ungulate. Logistic regressions were used to estimate the probability of occurrence of main external characteristics in relation to the total dorsal length (TDL), while multiple linear and non-linear regressions were conducted to assess the relationship between external and visceral biometry with TDL. External characteristics appeared in the following chronological order: limbs, differentiated genitalia and opened eyelids (>=5.1 cm TDL), fused eyelids (>=6.2 cm TDL), hooves and outer ear (>=7.9 cm TDL), dorsal gland (>=9.4 cm TDL), skin (>=11.5 cm TDL); tactile pelage (>=13.8 cm TDL), covering pelage (>=20.9 cm TDL), tooth eruption (>=26.4 cm TDL) and opened eyelids (>=27.8 cm TDL). The formula of fetal age was ?W = 0.084 (t - 31.80), with a high linear relationship between TDL and gestational age. All external biometric parameters and absolute volume of visceral organs showed strong positive relationship with TDL. Except for the liver, we found differences in the relative volume of most visceral organs between advanced fetuses (>=34.2 cm TDL) and adults. The most important events during the intrauterine development in the white-lipped peccary show that, in contrast with the domestic pig, it is a highly precocial species producing newborns with a high fetal growth velocity which allows newborns to achieve an early autonomous functionality. Our results are relevant to improve imaging techniques and assist the reproductive and clinical management for the white lipped peccary both in captivity and in the wild. PMID- 30015146 TI - The use of female estrogenized goats as sexual stimulator of crossbred dairy males subsequently exposed to acyclic goats during two phases of the anestrous season. AB - This research evaluated the possible influence of exposure of male goats to estrogenized female goats ("female effect") upon males' sexual behavior [appetitive (ASB) & consummatory (CSB)], as well as the induction of reproductive activity of crossbred dairy female goats exposed to such treated males ("male effect") during the early and deep anestrous periods. Crossbred dairy adult male goats (n = 12; 24-48 mo. old) and 80 anovulatory crossbred dairy adult female goats (34-50 mo. old) were used during two experimental periods: March to April and April to May. First, males were separated into four groups (n = 3 each), roughly homogeneous regarding body weight and body condition score and randomly assigned to four experimental groups. The first two groups included males + estrogenized females, then such males were exposed to anestrous females either during March (group 1: three males; 20 females; EFEM-MAR), or during April (group 2: three males; 20 females; EFEM-APR). The second two groups were respective control groups: Males + non-treated-anestrous females, and then such males exposed to acyclic females either during March (group 3: three males; 20 females; CONT-MAR) or April (group 4: three males; 20 females; CONT-APR). Once the male-to female contact was established, both odor (ODT) and behavior (BEHT) tests (2 d * 2 h) were performed during both anestrous periods. On day 10 after introduction of the males, in both anestrous periods, one ultrasonography scanning ("US") was performed to quantify the presence, number and size of corpus luteum (US-CL) to determine the effectiveness of the "male effect" and indicators of ovarian activity. Then, on day 45 after introduction of the males, a second US was performed to evaluate pregnancy rate (US-PREG). The EFEM-males, regardless of the phase of the anestrous cycle, had an increased (P < 0.05) odor intensity with respect to the control groups. In addition, while an increased (P < 0.05) ASB occurred in the EFEM-males, no CSB differences (P > 0.05) arose when treatments were compared, neither in March-April nor in April-May. The EFEM-males exposed to acyclic goats in March-April (i.e. early anestrous period), promoted not only the largest estrus and ovulatory responses (P < 0.05), but also the largest pregnancy rate (P < 0.05) in these previously anestrus goats, suggesting that in April-May (i.e. profound anestrous), the presence of active males was not enough to completely suppress cyclic reproductive arrest. This study generates interesting out-of-season reproductive outcomes in a goat population with a large proportion of highly seasonal dairy breeds (i.e. Alpine, Saanen and Toggenburg), augmenting the possibility to expand milk production and the economic income of goat producers across the year. Besides, this practice may serve as an interesting reproductive tool to increase the sustainability of marginal goat production systems under semiarid conditions. PMID- 30015147 TI - An optimized controlled rate slow cooling protocol for bovine ovarian tissue cryopreservation by means of X-ray computed tomography. AB - Cryopreservation and subsequent transplantation of ovarian tissue is the only option to preserve fertility in certain patients facing gonadotoxic treatment. So far, cryopreservation of ovarian tissue has been carried out mostly by a controlled rate slow cooling process, typically known as slow freezing. Even though there are still some concerns about the iatrogenic damage on the follicle population, this technique has been used in the more than 100 live births reported to date. It is well known that the control of the cryoprotectant loading in the tissue is crucial to in a cryopreservation procedure. We have used the technology of X-ray computed tomography to assess the concentration and distribution of dimethyl sulfoxide (one of the cryoprotectants most used in fertility preservation) inside pieces of bovine ovarian tissue after its cryopreservation. The low voltage used in our device (75 kV) and the high electronic density of this cryoprotectant makes the X-ray attenuation proportional to its concentration. By assessing and comparing the permeation and homogeneity of the cryoprotectant inside ovarian tissue fragments subjected to a controlled rate slow cooling process, we have characterized the effect of variations in the main parameters involved in the process, with the goal of achieving an optimized protocol with higher permeation of the cryoprotectant in the tissue. The most promissory results were obtained by increasing the initial concentration of dimethyl sulfoxide in the vehicle solution from 10 to 20%v/v. PMID- 30015148 TI - BDNF Val66Met polymorphism is not related with temporal lobe epilepsy caused by hippocampal sclerosis in Brazilian population. AB - PURPOSE: Some variants of the brain derived neurotrophic factors (BDNF) gene, namely the Val66Met (rs6265), may contribute the risk for epilepsy development. We aimed to investigate if this polymorphism was associated with the risk for epilepsy development in TLE-HS and its correlation with epilepsy-related factors and the presence of psychiatric disorders. METHODS: We assessed 119 patients with unequivocal TLE-HS and 112 healthy controls. Individuals were genotyped for the polymorphisms of the gene encoding BDNF Val66Met. RESULTS: There was no difference between TLE-HS and healthy controls, for the genotypic distribution (p = 0.636) and allelic distribution (p = 0.471). There was no correlation between Val66Met and epilepsy-related factors and for psychiatric comorbidities (p = 0.888). CONCLUSIONS: Our findings demonstrated that polymorphism Val66Met is not associated with TLE-HS, epilepsy-related factors and psychiatric comorbidities in this selected group of patients. PMID- 30015149 TI - Association between HLA alleles and lamotrigine-induced cutaneous adverse drug reactions in Asian populations: A meta-analysis. AB - PURPOSE: The aim of this study was to assess the association between human leukocyte antigen (HLA) variants and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cARDs). METHODS: A comprehensive literature search was conducted on the relationship of HLA alleles with LTG-induced cADRs in Asian populations, through PubMed, Embase, and Cochrane Library. The last search was in February 2018. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to access the strength of the association between an HLA allele and LTG-induced cADRs. RESULTS: A total of 11 studies met the inclusion criteria and were enrolled in our meta- analysis, which were based on Chinese, Korean, and Thai populations. Among these populations, we observed that HLA-B*1502 is a risk allele for LTG-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Chinese populations (pooled OR 2.4, 95% CI: 1.20-4.78, P = 0.01), HLA-A*2402 was found to be a significant risk allele for both SJS/TEN (pooled OR 3.50, 95% CI: 1.61-7.59, P = 0.002) and maculopapular eruption (MPE) (pooled OR 2.14, 95% CI: 1.10-4.16, P = 0.03), and HLA-B*3303 was considered to be a protective marker for MPE in Chinese and Korean populations (pooled OR 0.2, 95% CI 0.06-0.64, P = 0.007). CONCLUSIONS: In Asian populations, HLA-B*1502 is a risk factor for LTG-induced bullous lesions such as SJS/TEN in Chinese populations, and HLA-A*2402 is associated with the susceptibility to either SJS/TEN or MPE. HLA-A*3303 is a protective allele against LTG-induced MPE in Chinese and Korean populations. PMID- 30015151 TI - Deconstructing the molecular mechanisms shaping the vertebrate body plan. AB - The large display of body shapes and sizes observed among vertebrates ultimately represent variations of a common basic body plan. This likely results from the use of homologous developmental schemes, just differentially tinkered both in amplitude and timing by natural selection. In this review, we will revisit, discuss and combine old ideas with new concepts to update our view on how the vertebrate body is built. Recent advances, particularly at the molecular level, will guide our deconstruction of the individual developmental modules that sequentially produce head, neck, trunk and tail structures, and the transitions between them. PMID- 30015150 TI - Prognosis of post-stroke status epilepticus: Effects of time difference between the two events. AB - PURPOSE: This study aimed to investigate the prognosis of patients with status epilepticus (SE) following stroke, focusing on the timing of SE after the event and other unexplored variables. METHODS: All consecutive patients experiencing post-stroke SE (PSSE) in our center were included (2011-2016). We analyzed SE- and stroke-related factors in relation to the patients' outcome. RESULTS: 95 patients with PSSE (54 ischemic and 41 hemorrhagic stroke) were analyzed; 40 were women (42.1%) and mean age was 72.7 +/- 13.56 years. 51(53.7%) showed prominent motor symptoms, 49(51.6%) needed >2 antiepileptic drugs, and 27(28.4%) required anesthetics. Median duration of SE was 12 h (1-240). Median time from stroke to SE was 15 days (0-532). At discharge, logistic regression identified SE within 72 h after stroke (p = 0.004), baseline mSTESS (p = 0.009), and lesion volume (p = 0.001) as independent factors predicting mortality. Female sex (p = 0.019), SE duration >12 h (p = 0.005), temporal lobe involvement (p = 0.029), and stroke-to SE time <90 days (p < 0.0001) were independent predictors of functional decline. At long-term follow-up, SE occurring within 72 h after stroke (p = 0.0001), SE duration (p = 0.004), and baseline mSTESS score (p = 0.012) remained as predictive of mortality. CONCLUSIONS: The timing of SE after stroke is associated with different consequences: mortality was higher when SE occurred within the first 72 h after stroke and this risk persisted at follow-up, whereas risk of functional decline was higher when SE occurred during the first 3 months. Other factors such as the mSTESS score and SE duration were associated with outcome at both discharge and long-term follow-up. PMID- 30015152 TI - Planar cell polarity in organ formation. AB - The planar cell polarity (PCP) pathway controls a variety of morphological events across many species. During embryonic development, the PCP pathway regulates coordinated behaviour of groups of cells to direct morphogenetic processes such as convergent extension and collective cell migration. In this review we discuss the increasingly prominent role of the PCP pathway in organogenesis, focusing on the lungs, kidneys and heart. We also highlight emerging evidence that PCP gene mutations are associated with adult diseases. PMID- 30015153 TI - Periodic energy conversion in an electric-double-layer capacitor. AB - Electrostatic conversion devices operate through periodic modulation of capacitance. Such devices have a wide range of configurations, involving either changes in permittivity, electrode-plate spacing or wetting area. The presented study examines, theoretically, a potential configuration of an electric-double layer capacitor (EDLC)-based transducer, as it converts concentration and temperature oscillations into an electric alternating current. A constant voltage applied at the EDLC electrodes results in the formation of two opposite-sign EDLs, and an electric current is generated when ionic charges pass from one EDL to the other. In the examined configuration, this ionic charge transfer is induced by boundary modulation of temperature and/or concentration. To capture the oscillating dynamics of the ion distribution and ion flux, we solve the full set of Poisson-Nernst-Planck (PNP) equations coupled with the energy equation. We find that the transducer's optimal conditions for conversion, for which the device's frequency response is maximized, are governed by three main factors: low irreversible Joule heating, confined geometry, where the capacitor thickness is a close as possible to the EDL's characteristic screening length, and, most importantly, 'tuning' the system to a resonance frequency dictated by the interplay between geometry and characteristic time scales for mass and heat diffusion. PMID- 30015154 TI - Surface and bulk properties of surfactants used in fire-fighting. AB - HYPOTHESIS: Reports on the colloidal and interfacial properties of fluorocarbon (FC) surfactants used in fire-fighting foam formulations are rare. This is primarily because these formulations are complex mixtures of different hydrocarbon (HC) and fluorocarbon (FC) surfactants. By developing a greater understanding of the individual properties of these commercial FC surfactants, links can be made between structure and respective surface/ bulk behaviour. Improved understanding of structure property relationships of FC surfactants will therefore facilitate the design of more environmentally responsible surfactant replacements. EXPERIMENTS: Surface properties of three partially fluorinated technical grade surfactants were determined using tensiometry and neutron reflection (NR), and compared with a research-grade reference surfactant (sodium perfluorooctanoate (NaPFO)). To investigate the bulk behaviour and self-assembly in solution, small-angle neutron (SANS) scattering was used. FINDINGS: All FC surfactants in this study generate very low surface tensions (< 20 mN m-1) which are comparable, and in some cases, lower than fully-fluorinated surfactant analogues. The complementary techniques (tensiometry and NR) allowed direct comparison to be made with NaPFO in terms of adsorption parameters such as surface excess and area per molecule. Surface tension data for these technical grade FC surfactants were not amenable to reliable interpretation using the Gibbs adsorption equation, however NR provided reliable results. SANS has highlighted how changes in surfactant head group structure can affect bulk properties. This work therefore provides fresh insight into the structure property relationships of some industrially relevant FC surfactants, highlighting properties which are essential for development of more environmentally friendly replacements. PMID- 30015155 TI - Electret nanofibrous membrane with enhanced filtration performance and wearing comfortability for face mask. AB - Airborne particulate matter (PM) pollution has become a serious threat to human health, thus it is highly desired for a high-filtration-performance and good wearing-comfort face mask. Herein, a highly breathable and thermal comfort filter medium consisting of electret polyethersulfone/barium titanate nanofibrous membrane (PES/BaTiO3 NFM) integrated on a nonwoven polypropylene substrate was developed. Benefiting from the high porosity and optimized injection charge energy, the PES/BaTiO3 membrane was endowed with a good air permeability of 743 mm s-1, a modest water vapor permeability of 6.24 kg m-2 d-1, and an enhanced charge storage stability. In addition, the electret PES/BaTiO3 NFM1.5 medium with a low basis weight of 4.32 g m-2 still shows a high filtration efficiency of 99.99% and a low pressure drop of 67 Pa after being treated at 200 degrees C for 45 min, which is better than that of commercial media. Moreover, 3D simulation based on the characters of composite membrane was processed to graphically express the airflow distribution during the filtration process. Significantly, the NFM1.5 with a high infrared (IR) transmittance of 93.4% led to an effective radiative cooling to human body radiation. This multifunctional fibrous medium design may provide new insights into the development of environmental adaptive protection materials. PMID- 30015156 TI - Superior adsorption of phosphate by ferrihydrite-coated and lanthanum-decorated magnetite. AB - Present study reports the successful development of a novel lanthanum (La)-based magnetic adsorbent and its use for phosphate removal from water. For its synthesis, natural magnetite (Mag), Fe3O4, was subjected to partial dissolution in HCl solution and the obtained suspension was mixed with an alkaline solution for in-situ synthesis of ferrihydrite (Fh)-coated Mag (Mag@Fh). Mag@Fh was then decorated with La (hydr)oxides followed by calcination to produce Fh-coated and La-decorated Mag (Mag@Fh-La). Obtained Mag@Fh-La represented high phosphate adsorption capacity (44.8 mg P/g at 15.7% La in its structure) and La usage efficiency. Moreover, Mag@Fh-La retained its high adsorption capacity (>35.0 mg P/g) over a wide range of equilibrium solution pH (3.2-10.7). The combination of FTIR, XPS analysis and adsorption experiments revealed that ligand exchange and electrostatic attraction were the main mechanisms that jointly facilitated the adsorption of phosphate. Adsorption-desorption cycle studies confirmed the well retained adsorption efficiency of regenerated Mag@Fh-La for repeated applications. Final experiments with real domestic wastewater (initial phosphate concentration of 1.7 mg/L) revealed that 0.2 g/L Mag@Fh-La efficiently reduced the phosphate concentration to below 0.02 mg/L. Overall, this work clearly highlights that the synthesized novel adsorbent has promising applications in phosphate removal from real wastewater. PMID- 30015158 TI - Telomerase-Mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance. AB - Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2' deoxyguanosine (6-thio-dG), to target telomerase-expressing non-small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy- and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer patients with minimal toxicities. PMID- 30015157 TI - Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis. AB - Aberrant glycosylation plays a critical role in tumor aggressiveness, progression, and metastasis. Emerging evidence associates cancer initiation and metastasis to the enrichment of cancer stem cells (CSCs). Several universal markers have been identified for CSCs characterization; however, a specific marker has not yet been identified for different cancer types. Specific glycosylation variation plays a major role in the progression and metastasis of different cancers. Interestingly, many of the CSC markers are glycoproteins and undergo differential glycosylation. Given the importance of CSCs and altered glycosylation in tumorigenesis, the present review will discuss current knowledge of altered glycosylation of CSCs and its application in cancer research. PMID- 30015160 TI - Reverse Phase Protein array for the quantification and validation of protein biomarkers of beef qualities: The case of meat color from Charolais breed. AB - Reverse Phase Protein Arrays (RPPA) were applied for the quantification and validation of protein biomarkers of beef qualities on M. longissimus thoracis sampled early post-mortem from young Charolais bulls. pHu was related to six proteins, three of which are glycolytic enzymes (ENO1, ENO3 and TPI1), while others belong to structural (TTN and alpha-actin) and proteolytic (MU-calpain) pathways. For color traits, several correlations were found, interestingly with structural proteins. The relationships were in some cases trait-dependent. To understand the mechanisms and explore animal variability, color data were categorized into three classes. alpha-actin and TTN allowed efficient separation of the classes and were strongly related with all color traits. Biomarkers belonging to heat stress and metabolism pathways were also involved. Two identified proteins, namely Four and a half LIM domains 1 (FHL1) and Tripartite motif-containing 72 (TRIM72), were for the first time related to beef color. Overall, these relationships could be used to develop muscle-specific processing strategies to improve beef color stability. PMID- 30015161 TI - Rabbit meat production and processing in China. AB - Rabbit meat has become increasingly popular in China; however, the main available products are still as cut-up parts or whole carcass due to a lack of processing. Currently, rabbit meat products do not fully meet the consumer demand for convenience, thus hindering the further development of the rabbit meat industry. As the biggest rabbit meat producer globally, China has conducted a series of studies on rabbit meat processing and the development of new products. This review presents rabbit breeds, meat importation, exportation, and meat production in China. The development of the rabbit meat industry and research on rabbit meat processing are discussed. The main problems, including a lack of leading enterprises and brand products, insufficient investment and research, and the weakness of fundamental studies on traditional products, are highlighted. Furthermore, current trends of rabbit meat production and processing of being centralized and regionalized, as well as being intelligentized and standardized, are discussed. PMID- 30015159 TI - Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer. AB - A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1-24 of KIF5B and exons 15-21 of MET. KIF5B MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients. PMID- 30015162 TI - Capybara meat: An extraordinary resource for food security in South America. AB - The available information on capybara (Hydrochoerus hydrochaeris) meat, an important resource for the subsistence of many traditional communities in several South American countries, is reviewed. Some features of the species, such as an herbivorous diet, high prolificacy, rapid growth rate, tameness, and social behaviour, which allow its commercial use through harvesting in Venezuela and farming in Brazil, where commercial hunting is not allowed, is discussed. Key characteristics of capybara meat, is low saturated fat and cholesterol content. Discussions about management and handling practices regarding animal welfare and capybara meat quality are also highlighted. After commenting on ethical, political, and economic implications of wildlife use it is concluded that capybara meat has an extraordinary potential to satisfy the growing demand for healthy and high-quality protein of animal origin for the subsistence of many people in the Neotropics. PMID- 30015163 TI - Variation in the FABP4 gene affects carcass and growth traits in sheep. AB - Fatty acid-binding protein 4 (FABP4) participates in fatty-acid transportation and variation in the gene has been reported to affect fat deposition in mammals. To assess the effects of variation in FABP4 on carcass and growth traits in sheep, two regions of the gene were investigated in 749 New Zealand Romney lambs. Five variants (A1 - E1) were found in region-1 (exon 2 - intron 2) and three variants (A2 - C2) were found in region-2 (exon 3 - intron 3). A1 was associated with a decrease in leg meat yield, loin meat yield and total meat yield, whereas A2 was associated with a decrease in weaning-weight and pre-weaning growth-rate. Haplotype A1-A2 was found to be associated with a decrease in birth-weight, pre weaning growth-rate, hot carcass weight, loin meat yield, shoulder meat yield and total meat yield, while haplotype A1-B2 was associated with increased fat depth at the 12th rib (V-GR). Taken together, this supports the contention that variation in FABP4 affects growth and meat production in sheep. PMID- 30015164 TI - Effects of pioglitazone hydrochloride and vitamin E on meat quality, antioxidant status and fatty acid profiles in finishing pigs. AB - To investigate the effects of pioglitazone hydrochloride (PGZ) and vitamin E (VE), 160 Duroc * Landrace * Large White pigs were randomly divided into a 2 * 2 factorial arrangement with 2 levels of PGZ (0 or 15 mg/kg) and 2 levels of VE (0 or 325 mg/kg) for 28 days. Each group had 5 replicates with 8 pigs, half males and half females. Feeding PGZ increased intramuscular fat and VE supplementation decreased cooking loss (P < 0.05). Feeding VE increased total polyunsaturated fatty acid (PUFA), C18:2n-6 and C18:3n-3 (P < 0.05). For 18:3n-3, the increase in C18:3n-3 due to VE was accentuated when combined with PGZ (P < 0.001). Additionally, VE tended to increase superoxide dismutase (P = 0.079) and glutathione peroxidase activity (P = 0.054). In summary, PGZ and VE had positive effects on pork quality by decreasing cooking loss and increasing intramuscular fat and antioxidant capacity, and may prove useful in improving the healthfulness of fatty acid profiles. PMID- 30015165 TI - Bioinspired synthesis of multiple-functional nanocomposite platform showing optically and thermally responsive affinity: Application to environmentally responsive separation membrane. AB - A tremendous effort has been made for the synthesis and multifunction of environmentally responsive and selective separation membranes. With the bioinspired design of polydopamine (pDA)-assisted inorganic film, we proposed a simple, yet efficient, thermo-responsive cell culture substrate. Herein, a Ag/TiO2/pDA-based nanocomposite structure was initially obtained, and the ciprofloxacin-imprinted membranes (MINCMs) with thermo-responsive recognition sites were then synthesized by using NIPAm as backbone monomer. The opto thermally responsive molecularly imprinted membranes (OT-MIMs) were obtained through in situ reduction of HAuCl4 on membrane surfaces, Au nanoparticles were used as the light-heat converters. The light-switching principle was elaborated as well as the energy conversions that took place in this system. These conformational changes finally allowed the constructions or destructions of ciprofloxacin-imprinted sites. Due to the formation of the opto-thermally responsive ciprofloxacin-imprinted sites, rapid adsorption dynamics and opto thermally responsive perm-selectivity toward templates were both achieved. Therefore, 58.65 mg/g of adsorption capacity and 4.91 of permselectivity factor from OT-MIMs were successfully obtained. Importantly, the as-designed bioinspired strategy led to a state-of-the-art design that was capable of reversibly controlling the flow rate (J) of ciprofloxacin from 12.10 to 4.93 mg min-1 cm-2 in less than a few minutes using light. PMID- 30015166 TI - Cyclodextrin-functionalized Ag/AgCl foam with enhanced photocatalytic performance for water purification. AB - The application of visible light-induced photocatalysts for photocatalytic pollution mitigation has become a promising strategy due to the inexhaustible solar energy. And how to improve pollutants degradation rate is still a meaningful work. Many researchers dealt with this issue by enhancing visible light absorption of photocatalysts. However, few studies focus on this issue by improving semiconductor's absorption property of organic pollutants. Hence, in this work, we prepared the Ag/AgCl foam coated per-6-thio-beta-cyclodextrin (SH beta-CD) to improve the photocatalytic activity of Ag/AgCl foam. Here, we chose SH-beta-CD because it has a special cavity that can effectively absorb and capture proper organic pollutants via host-guest interaction, which makes it an ideal pollutants surface adsorber when coated on the surface of Ag/AgCl particles. Hence, those trapped pollutants in the cavities can be attacked directly by those reactive oxidation species (ROS) that produced by Ag/AgCl particles under visible light irradiation, resulting in the significant promotion of pollution mitigation rate. The experimental results demonstrated the photodegradation rate constant of methyl orange (MO) by Ag/AgCl@beta-CD foam (k = 0.120 min-1) increased approximately 2.6 times compared with pure Ag/AgCl from (k = 0.048 min-1). We anticipate our SH-beta-CD modified Ag/AgCl foam would be a promising candidate for photodegradation of organic pollutants in wastewater remediation. PMID- 30015167 TI - Membrane-lytic actions of sulphonated methyl ester surfactants and implications to bactericidal effect and cytotoxicity. AB - Surfactants are multifunctional molecules widely used in personal care and healthcare formulations to cleanse, help disperse active ingredients (e.g., forming emulsions) and stabilise products. With increasing demands on improving biosafety, there is now mounting pressure to understand how different surfactants elicit toxicities at molecular and cellular levels. This work reports the membrane-lytic behaviour of a group of sulphonated methyl ester (SME) surfactants together with representative conventional surfactants. All surfactants displayed the clear rise of lysis of the model lipid bilayer membranes around their CMCs, but the two ionic surfactants SDS and C12TAB even caused measurable lysis below their CMCs, with membrane-lytic actions increasing with monomer concentration. Furthermore, whilst ionic and nonionic surfactants could achieve full membrane lysis once above their CMCs, this ability was weak from the SME surfactants and decreased with increasing the acyl chain length. In contrast to the conventional anionic surfactants such as SDS and SLES, the protein solubilizing capability of the SME surfactants was also low. On the other hand, MTT assays against 3T3 fibroblast cells and human chondrocyte cells revealed high toxicity from SDS and C12TAB against the other surfactants studied, but the difference between SME and the rest of conventional surfactants was small. Similar behaviour was also observed in their bactericidal effect against E. coli and S. aureus. The trend is broadly consistent with their membrane-lytic behaviour, indicating little selectivity in their cytotoxicity and bactericidal action. These results thus reveal different toxicities implicated from different surfactant head groups. Increase in acyl chain length as observed from SME surfactants could help improve surfactant biocompatibility. PMID- 30015168 TI - Synthesis of a g-C3N4-Cu2O heterojunction with enhanced visible light photocatalytic activity by PEG. AB - A g-C3N4-Cu2O was successfully synthesized in the presence of PEG-400 surfactant via a hydrothermal method and high-temperature calcination method. Based on the results of TEM, XPS, EPR, and other techniques, it was verified that a heterojunction was formed. The synthesized g-C3N4-Cu2O show excellent photocatalytic activity and stability was confirmed through cycling experiments, XRD and XPS. At a suitable addition amount, the value of band gap of g-C3N4-Cu2O is reduced to 1.87 eV, the PL intensity decreases effectively, the specific surface area is increased to 12.8114 m2/g, and the photocatalytic degradation rate is increased to 94%. Adding the surfactant PEG-400 in the precursor solutions leads to a reduction in the crystallite size, which can improve the morphology and specific surface area to form abundant heterojunction interfaces as channels for photo-generated carrier separation, and improve its light utilization and quantum efficiency. PMID- 30015169 TI - Do Silver Zones reduce auto-related elderly pedestrian collisions? Based on a case in Seoul, South Korea. AB - Inaugurated in 2007, in Seoul, South Korea, the Silver Zone is a designated pedestrian safety zone for the elderly that adopts speed limit measures such as traffic signage and road surface markings. In this study, we empirically investigate the effectiveness of the Silver Zone in two respects: first, whether the establishment of the Silver Zone has lowered the number of elderly pedestrian collisions, and second, whether Silver Zones are established in the appropriate areas, that is, those with the highest frequency of such collisions. From our quasi-experimental statistical analysis, Difference-in-Difference, we learn that the Silver Zone has no effects on reducing elderly pedestrian collisions. From our spatial statistical analyses-Kernel Density mapping and Bivariate Moran's I we found a spatial mismatch between the frequency of senior pedestrian-vehicular collisions and the location of Silver Zones. For better performance of the Silver Zone system, we suggest additional types of physical measures to be integrated into the Silver Zone system. Municipal-level comprehensive master plan for Silver Zone system is also necessary, under which local governments should use periodic surveys to inventory and prioritise the locations of highest elderly pedestrian vehicular collisions. PMID- 30015170 TI - A study on correlation of pedestrian head injuries with physical parameters using in-depth traffic accident data and mathematical models. AB - The objective of the present study is to predict brain injuries and injury severities from realworld traffic accidents via in-depth investigation of head impact responses, injuries and brain injury tolerances. Firstly, a total of 43 passenger car versus adult pedestrian accidents were selected from two databases of the In-depth Investigation of Vehicle Accidents in Changsha of China (IVAC) and the German In-Depth Accident Study (GIDAS). In a previous study the 43 accidents were reconstructed by using the multi-body system (MBS) model (Peng et al., 2013a) for determining the initial conditions of the head-windscreen impact in each accident. Then, a study of the head injuries and injury mechanisms is carried out via 43 finite element (FE) modelings of a head strike to a windscreen, in which the boundary and loading conditions are defined according to results from accident reconstructions, including impact velocity, position and orientation of the head FE model. The brain dynamic responses were calculated for the physical parameters of the coup/countercoup pressure, von Mises and maximum shear stresses at the cerebrum, the callosum, the cerebellum and the brain stem. In addition, head injury criteria, including the cumulative strain damage measure (CSDM) (with tissue level strain threshold 0.20) and the dilatational damage measure (DDM), were developed in order to predict the diffuse axonal injury (DAI) and contusions, respectively. The correlations between calculated parameters and brain injuries were determined via comparing the simulation results with the observed injuries in accident data. The regression models were developed for predicting the injury risks in terms of the brain dynamic responses and the calculated CSDM and DDM values. The results indicate that the predicted values of 50% probability causing head injuries in the Abbreviated Injury Scale (AIS) 2+ correspond to coup pressure 167 kPa, countercoup pressure -117 kPa, von Mises 16.3 kPa and shear stress 7.9 kPa respectively, and causing AIS 3+ head injuries were 227 kPa, -169 kPa, 24.2 kPa and 12.2 kPa respectively. The results also suggest that a 50% probability of contusions corresponds to CSDM value of 48% at strain levels of 0.2, and the 50% probability of contusions corresponds to a DDM value of 6.7%. PMID- 30015171 TI - Extractive from Hypericum ascyron L promotes serotonergic neuronal differentiation in vitro. AB - BACKGROUND: Plant natural products have many different biological activities but the precise mechanisms underlying these activities remain largely unknown. Hypericum longistylum has long been recorded in Chinese medicine as a cure for depression and related disorders, but how it repairs neural lineages has not been addressed. METHODS: We extracted compounds from Hypericum longistylum and determined their effect on neural differentiation of embryonic stem cells (ESCs) in vitro by using the Pax6-GFP reporter system. The amount of serotonin released during differentiation was measured by HPLC. The tail suspension test and forced swimming test was performed for determining the effect of compounds on depression like behaviors in mice. RESULTS: We found that one of the phloroglucinol derivatives not only facilitated differentiation of neural progenitor cells, but also increased the efficiency of differentiation into serotonergic neurons. This compound also improved the behaviors of mice placed in a stressful environment and reduced signs of depression. CONCLUSIONS: This is the first use of Chinese herb derived-natural products to promote neurogenesis of ESCs, including the generation of serotonergic neurons, and the first attempt to identify the active compound in Hypericum longistylum responsible for its beneficial effects on depressive diseases. PMID- 30015172 TI - Corrigendum to Generation of a human iPSC line by mRNA reprogramming. Stem Cell Res., Volume 28, April 2018, Pages 157-160. PMID- 30015173 TI - A fast method to reprogram and CRISPR/Cas9 gene editing from erythroblasts. AB - An efficient one-step procedure to reprogram fibroblasts into human induced pluripotent stem cells (hiPSC) and perform CRISPR/Cas9 gene editing simultaneously was recently reported. Here we show that such simultaneous reprogramming and gene editing can be efficiently done from erythroblasts. We successfully obtained human induced pluripotent stem cells colonies together with in frame and out of frame CAPN1 mutations in one or both alleles. We did not identify off-targets in edited cell lines. The entire process, from blood collection to mutated hiPSC took approximately 5 weeks, a much shorter period than standard multi-step methodologies using fibroblasts. Noteworthy, blood drawing is a less invasive procedure than a skin biopsy. PMID- 30015174 TI - Distinct requirements for the maintenance and establishment of mouse embryonic stem cells. AB - Mouse embryonic stem cells (ESCs) that maintain a sustainable pluripotent state are derived from the inner cell mass (ICM) of blastocysts, in which pluripotency is lost during differentiation in vivo. It is unclear when and how the ability to maintain pluripotency is acquired during the derivation of ESCs. We analyzed the required culture condition for the maintenance and establishment of ESCs in detail. Even at low concentration of the GSK3beta inhibitor and LIF (LowGiL), the expression levels of pluripotency markers and the chimera-producing ability of the cells were comparable with those of ESCs cultured in the presence of both inhibitors and LIF (2iL). However, blastocysts underwent spontaneous differentiation, and ESCs were not established under LowGiL condition. Time course analysis showed that 2iL condition for three days from the initiation of culture was sufficient for the acquisition of permanent pluripotency. Although X chromosome-linked pluripotent genes were significantly up-regulated during the culture of both male and female blastocysts in 2iL condition, no such up regulation was observed in LowGiL condition. In conclusion, 2iL-dependent activation of these X-linked genes at the earliest phase of ESC derivation is one of the molecular bases for the acquisition of permanent pluripotency. PMID- 30015175 TI - Computational investigation of TGF-beta receptor inhibitors for treatment of idiopathic pulmonary fibrosis: Field-based QSAR model and molecular dynamics simulation. AB - The discovery of drugs relevant to transforming growth factor beta (TGF-beta) receptor inhibitors have been considered as a considerable challenge during therapy idiopathic pulmonary fibrosis diseases. For the first time, herein we illustrate a field-based quantitative structure-activity relationship (QSAR) model and molecular dynamics (MD) simulations for novel 7-substituted-pyrazolo [4, 3-b] pyridine derivatives with biological activity for the TGF-beta receptor, with an attempt of elucidating the 3D structural features that are essential for the activity. Results demonstrate that the field-based model (Q2 = 0.548, R2training = 0.840, R2test = 0.750) are acceptable with good predictive capabilities. In addition, MD studies were also carried out on the training set with the aim of exploring their binding modes in the active pocket of TGF-beta receptor, resulting in some of the crucial structural fragments which are responsible for inhibitory activity. Therefore, we summarized the following features required for TGF-beta receptor inhibition: electronegative in region1, bulky groups in region2 and smaller groups in region3. Based on the model and related information, we hope the above information provides an important insight for understanding the interactions of the inhibitors and TGF-beta receptor, which may be useful in discovering novel potent inhibitors. PMID- 30015177 TI - Therapeutic potential of promiscuous targets in Mycobacterium tuberculosis. AB - In the field of tuberculosis drug development, the term 'promiscuous' was coined to collectively describe targets that repeatedly show up in whole-cell screenings. With the current climate leaning towards the exclusion of these targets in future drug screens, this review discusses and clarifies misconceptions surrounding this classification, the prospects of developing compounds targeting promiscuous targets, and their potential impact on tuberculosis drug development. The dominance of these targets in cell-based screens reflect not only bias introduced by experimental setup, but also some of the pathogen's greatest vulnerabilities. Coupled with favourable predictions of their in vivo efficacies and synergism with other TB drugs, these targets open opportunities to be explored for the development of rational drug combination for tuberculosis. PMID- 30015176 TI - Synthesis, thymidine phosphorylase inhibitory and computational study of novel 1,3,4-oxadiazole-2-thione derivatives as potential anticancer agents. AB - A series of novel 1,3,4-oxadiazole-2-thione derivatives were designed, synthesized and evaluated for in vitro anticancer activity against breast cancer (MCF-7) cell line and thymidine phosphorylase. The synthesis of target compounds was performed by cyclization reaction using aromatic amines and carbon disulphide to get mannich bases. The synthesized compound 2j exhibited the most potent anticancer activity against MCF-7 cell line. Compounds 2d, 2j, 2o and 2h showed potent thymidine phosphorylase inhibitory activity. The SAR study revealed that the substitution of phenyl ring with electron withdrawing group at R1 position and less bulky amines group at R2 position of 1,3,4-oxadiazole-2-thione ring showed significant growth inhibitory activity. Further in silico ADMET properties of synthesized compounds were calculated along with molecular docking to study the binding mode of the compounds in the active site of thymidine phosphorylase (TP). The molecular docking studies showed that amines group have good binding interaction on active site residues of TP such as compounds 2j and 2o exhibited hydrogen bond interaction with amino acid residues GLY152, THR151 and HIS116 of thymidine phosphorylase (PDB ID: 1UOU). The result of biological activity and docking study revealed that amines group at R2 point of 1,3,4-oxadiazole-2-thione moiety is essential for anticancer activity. PMID- 30015178 TI - Navigating and making choices about healthcare: The role of place. AB - In this paper, we examine the intersections between place and healthcare choice, drawing on Bourdieu's concepts of distinction and social space, and engaging with data from interviews with 78 Australians living in varied geographic locations. We find the status of an area is used to judge the quality of its healthcare services. Areas with high status are assumed to have better quality health services than areas of disadvantage. Where people live shapes the choices they make and their judgements about the status of a place. Moreover, having less choice is not necessarily problematic. Participants in regional and remote areas with less choice tend to report positive experiences with healthcare providers. Place can constrain people's ability to make good healthcare choices, yet participants have differing capacities to mobilise resources to overcome the constraints of place. PMID- 30015180 TI - Urban foodscape trends: Disparities in healthy food access in Chicago, 2007-2014. AB - We investigated changes in supermarket access in Chicago between 2007 and 2014, spanning The Great Recession, which we hypothesized worsened local food inequity. We mapped the average street network distance to the nearest supermarket across census tracts in 2007, 2011, and 2014, and identified spatial clusters of persistently low, high or changing access over time. Although the total number of supermarkets increased city-wide, extremely low food access areas in segregated, low income regions did not benefit. Among black and socioeconomically disadvantaged residents of Chicago, access to healthy food is persistently poor and worsened in some areas following recent economic shocks. PMID- 30015181 TI - Systematic review of the use of Google Street View in health research: Major themes, strengths, weaknesses and possibilities for future research. AB - We systematically reviewed the current use of Google Street View (GSV) in health research and characterized major themes, strengths and weaknesses in order to highlight possibilities for future research. Of 54 qualifying studies, we found that most used GSV to assess the neighborhood built environment, followed by health policy compliance, study site selection, and disaster preparedness. Most studies were conducted in urban areas of North America, Europe, or New Zealand, with few studies from South America or Asia and none from Africa or rural areas. Health behaviors and outcomes of interest in these studies included injury, alcohol and tobacco use, physical activity and mental health. Major strengths of using GSV imagery included low cost, ease of use, and time saved. Identified weaknesses were image resolution and spatial and temporal availability, largely in developing regions of the world. Despite important limitations, GSV is a promising tool for automated environmental assessment for health research. Currently untapped areas of health research using GSV include identification of sources of air, soil or water pollution, park design and usage, amenity design and longitudinal research on neighborhood conditions. PMID- 30015179 TI - Community change and resident needs: Designing a Participatory Action Research study in Metropolitan Boston. AB - The health implications of urban development, particularly in rapidly changing, low-income urban neighborhoods, are poorly understood. We describe the Healthy Neighborhoods Study (HNS), a Participatory Action Research study examining the relationship between neighborhood change and population health in nine Massachusetts neighborhoods. Baseline data from the HNS survey show that social factors, specifically income insecurity, food insecurity, social support, experiencing discrimination, expecting to move, connectedness to the neighborhood, and local housing construction that participants believed would improve their lives, identified by a network of 45 Resident Researchers exhibited robust associations with self-rated and mental health. Resident-derived insights into relationships between neighborhoods and health may provide a powerful mechanism for residents to drive change in their communities. PMID- 30015182 TI - Simulated wastewater reduced Klebsiella michiganensis strain LH-2 viability and corresponding antibiotic resistance gene abundance in bio-electrochemical reactors. AB - A previous study revealed that the electrolytic stimulation process in bio electrochemical reactors (BER) can accelerate growth of sulfadiazine (SDZ) antibiotic resistant bacteria (ARB) in nutrient broth medium. However, the influence of different medium nutrient richness on the fate of ARB and the relative abundance of their corresponding antibiotic resistance genes (ARGs) in this process is unknown. Specifically, it is not clear if the fate of ARB in minimal nutrition simulated wastewater is the same as in nutrient broth under electrolytic stimulation. Therefore, in this study, nutrient broth medium and the simulated wastewater were compared to identify differences in the relative abundance of Klebsiella michiganensis LH-2 ARGs in response to the electrolytic stimulation process, as well as the fate of the strain in simulated wastewater. Lower biomass, specific growth rates and viable bacterial counts were obtained in response to the application of increasing current to simulated wastewater medium. Furthermore, the percentage of ARB lethality, which was reflected by flow cytometry analysis, increased with current in the medium. A significant positive correlation of sul genes and intI gene relative abundance versus current was also observed in nutrient broth. However, a significant negative correlation was observed in simulated wastewater because of the higher metabolic burden, which may have led to decreased ARB viability. Further investigation showed that the decrease in ARGs abundance was responsible for decreased strain tolerance to SDZ in simulated wastewater. These results reveal that minimal nutrition simulated wastewater may reduce ARB and ARGs propagation in BER. PMID- 30015183 TI - Chronic excess fluoride uptake contributes to degenerative joint disease (DJD): Evidence from six marsupial species. AB - One of the manifestations of chronic fluoride toxicosis in mammals is skeletal fluorosis, which can include lesions of degenerative joint disease (DJD). Although DJD lesions have been less commonly studied than bone or dental lesions in relation to the pathology and epidemiology of fluoride toxicosis, there have been multiple independent studies in various species that have concluded that there appears to be an effect. The mechanisms by which fluoride affects the joints are not clear, but our data provide evidence that chronic excess dietary fluoride intake contributes to DJD. Our study is the first to specifically address the association between fluoride exposure and DJD in multiple species of free-ranging mammals. We describe levels of DJD in six marsupial species (Macropus giganteus, Notamacropus rufogriseus, Wallabia bicolor, Phascolarctos cinereus, Trichosurus vulpecula and Pseudocheirus peregrinus) inhabiting high and low fluoride environments. Lesions occurred to varying extents in all species, and lesion distribution varied with biomechanical differences in gait. In addition, we show an association (independent of age) between increasing bone fluoride concentration (as a measure of fluoride exposure) and increasing prevalence of moderate and severe DJD in five species of marsupial, which we propose does not persist at the highest levels of fluoride exposure due to selective survival bias. PMID- 30015184 TI - Assessment of mutagenicity caused by popular baby foods and baby plastic-ware products: An imperative study using microbial bioassays and migration analysis. AB - Specialized products for infants have become every parent's first choice. Although these products claim to be safe and mild for infant use, yet there is a need to monitor them using different tools for mutagenicity detection to ensure further safety. In this study, a range of popular ready to eat and powdered baby foods, formula milk powders and attractive plasticware for infants were picked from the Indian market and tested for their mutagenicity using two microbial bioassays based on Salmonella typhimurium, viz., Ames bacterial reversion assay and fluctuation assay. Furthermore, chemical migration analysis was done on the most toxic baby food and baby plasticware samples as shown by the bioassays to detect possible leaching of Bisphenol a (BPA), lead and Di-2 ethyl hexyl phthalate (DEHP). It was surprising to find that the products made for the most risk-prone group in the society, i.e., infants have a significant potential to cause mutagenicity. PMID- 30015185 TI - Impacts of silicon addition on arsenic fractionation in soils and arsenic speciation in Panax notoginseng planted in soils contaminated with high levels of arsenic. AB - Arsenic (As) is a well-known carcinogenic substance whose biological toxicity in soils and plants depends on its concentration and chemical forms. Silicon (Si) generally can alleviate biotic and abiotic stresses, including As stress. However, its effects vary depending on As chemical form, plant species and other factors. A pot experiment was performed to investigate the effects of Si addition on the content and forms of As in red soil and its uptake, transport and speciation in Panax notoginseng. The results showed that additions of 25 and 75 mg kg-1 of Si both significantly decreased the concentrations of water-soluble As and exchangeable As in soil and therefore decreased the bioavailability of soil As. However, the As uptake by Panax notoginseng (PN) was increased, which resulted in increases in As concentration by 18.5% and 2.3% in roots and by 56.7% and 58.3% in shoots, respectively, when compared with the control. Arsenate (As(V)) was the dominant As species in all the treatment soils (99.8-100%), whereas arsenite (As(III)) was prevalent in plant roots (75.2-92.4%), shoots (74.1-87.9%) and leaves (73.9-84.3%). Si addition (25 and 75 mg kg-1) significantly increased As(III) concentration in roots by 167.5% and 83.3%, respectively. Monomethylarsonic acid (MMA) was the only detected methylated As but at low concentrations (0.01-0.29 mg kg-1) and only in PN leaves. Si addition (25 and 75 mg kg-1) significantly increased the copy number of the arsenite methyltransferase (arsM) gene by 31.0% and 47.2% but did not increase the methylated As species content in PN leaves. The detected copy number of the arsM gene did not represent the capacity of soil to methylate As, and the sources of MMA in leaves need to be explored in further research. PMID- 30015186 TI - Toxicity of imidazoles ionic liquid [C16mim]Cl to Hela cells. AB - Our study aimed to evaluate the toxicity of 1-hexadecyl-3-methylimidazolium chloride ([C16min]Cl) on the human cervical carcinoma (Hela) cells. We evaluated toxicity, cell viability, genotoxicity, oxidative stress, apoptosis, and apoptosis-related gene expression in Hela cells following exposure to [C16min]Cl. The results indicated that [C16min]Cl inhibited the growth of Hela cells, decreased cell viability, induced DNA damage and apoptosis, inhibited superoxide dismutase, decreased glutathione content, as well as increased the cellular malondialdehyde level of Hela cells. Moreover, [C16min]Cl induced changes in the transcription of p53, Bax and Bcl-2, suggesting that the p53 and Bcl-2 family might have been involved in the cytotoxicity and apoptosis induced by [C16min]Cl in Hela cells. Taken together, these results revealed that [C16min]Cl imparts oxidative stress, genotoxicity, and induces apoptosis in Hela cells; hence, it is not a green solvent. PMID- 30015187 TI - Implications on the Pb bioaccumulation and metallothionein levels due to dietary and waterborne exposures: The Callinectes danae case. AB - This study aimed to assess the bioaccumulation of Pb and induction of metallothionein-like proteins (MT) in Callinectes danae through single and combined dietary and waterborne exposures. Male C. danae individuals were collected in the south area of the Cananeia-Iguape-Peruibe Protected Area (APA CIP), in Sao Paulo State, Brazil. After an acclimatization period, exposure assays were performed during 7 and 14 days, at two Pb concentrations (0.5 e 2.0 ug/g) in 4 treatments: 1) control; 2) contaminated water only; 3) contaminated food only; 4) contaminated water and food. The results indicate that C. danae is highly tolerant to Pb exposure at the evaluated concentrations. In gills, Pb bioaccumulation is more dependent of water efflux and time of exposure (higher Pb values). However, pathways act simultaneously in the induction of MT expression in this tissue. The decreases in Pb accumulation in the combined treatments and MT increases after 14 days in gills suggests that these proteins play a detoxification function in the presence of Pb. In hepatopancreas, depending on the predominance of a certain pathway or combined pathways, accumulation occured at different times. For muscle tissue, bioaccumulation was observed due to contaminated water exposure, but not dietary exposure, probably because Pb concentrations were low. PMID- 30015188 TI - Sub-lethal effects of six neonicotinoids on avoidance behavior and reproduction of earthworms (Eisenia fetida). AB - Avoidance behavior of earthworms (Eisenia fetida) against six neonicotinoids (NEOs) (acetamiprid, dinotefuram, clothianidin, thiacloprid, nitenpyram, imidacloprid) was studied following the protocol of ISO. The results showed obvious avoidance behavior of E. fetida against the tested insecticides, and the medium effective concentration for avoidance behavior (EC50) of the six pesticides was 0.14, 0.55, 0.91, 7.87, 1.32 and 0.77 mg/kg, respectively. Compared to the acute toxicity, avoidance behavior was more sensitive as an indicator of soil contamination with NEOs. Chronic toxicity of above six NEOs to E. fetida was also evaluated; cocoon production, hatchability, cocoon weight and adult weight were all affected in the test. Cocoon production and hatchability were more sensitive than cocoon weight and adult weight. The reproduction of earthworms were significantly reduced with a 56 d half-maximal effective hatchability concentration (EC50) of 0.37, 0.74, 1.30, 3.57, 1.20 and 0.70 mg/kg (acetamiprid, dinotefuram, clothianidin, thiacloprid, nitenpyram, imidacloprid), respectively. Most of the tested NEOs were highly toxic to E. fetida. Avoidance behavior and reproduction damage of E. fetida was observed at very low concentrations. The existing levels of pollution with NEOs in soil frequently exceed the lowest observed adverse effect concentrations, which are likely to have negative biological and ecological impacts on earthworms. PMID- 30015189 TI - Does ammonium nitrogen affect accumulation, subcellular distribution and chemical forms of cadmium in Kandelia obovata? AB - Heavy metals and nutrients are commonly found in mangrove sediments, but the effect of nutrients on heavy metals in mangrove plants is not clear. A study quantifying the effects of ammonium nitrogen (NH4+-N) on the accumulation, subcellular distribution and chemical forms of cadmium (Cd) in Kandelia obovata seedlings were conducted. The experiment consisted of four levels of NH4+-N (0, 10, 50 and 100 mg L-1) in each of which consisted of four Cd levels (0, 1, 5 and 10 mg L-1). The results showed that NH4+-N magnified the Cd toxicity due to reduced plant biomass, especially with 10 mg L-1 Cd and 100 mg L-1 NH4+-N supply. NH4+-N, especially at 100 mg L-1, enhanced the concentration and accumulation of Cd in root but its role on Cd translocation from root to stem and leaf was limited, probably due to low translocation factor. At subcellular level, Cd mainly accumulated in root cell wall but its fractionation depended on Cd levels. Under the stress of 1 and 5 mg L-1 Cd, 50 mg L-1 NH4+-N supply improved transfer of Cd from root cell wall into cell, and increased pectate and protein integrated forms of intracellular Cd to alleviate Cd toxicity. Under the stress of 10 mg L-1 Cd, NH4+-N supply promoted the deposition of Cd on root cell wall to restrain its transfer to root cell, which was verified by the reduced levels of pectate and protein integrated forms of Cd in root cell. Thus, NH4+-N supply improved immobilization of Cd in roots and alleviated Cd toxicity through integration with pectate and protein as well as cell wall combinations in root of K. obovata. PMID- 30015190 TI - The effects of continuous diazinon exposure on growth and reproduction in Japanese medaka using a modified Medaka Extended One Generation Reproduction Test (MEOGRT). AB - The Medaka Extended One Generation Reproduction Test (MEOGRT) is a Tier 2 test within U.S. Environmental Protection Agency's (USEPA) Endocrine Disruptor Screening Program (EDSP), designed to characterize the potential adverse effects to fish of exposure to chemical that can cause disruption of the endocrine system. The MEOGRT focuses primarily on adverse effects to reproduction while collecting information regarding effects on growth, survival, and endocrine related endpoints. However, the risk assessment process for fish, as mandated by legislation such as the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) or the Toxic Substances Control Act (TSCA), could benefit from a more detailed assessment of effects on growth. Typically, fish growth data in support of risk assessment are obtained from full life-cycle tests or early life stage tests using the fathead minnow. As an alternative to these tests, a modified MEOGRT was conducted to assess the effects of diazinon on the various parameters measured in the MEOGRT. Diazinon is an organophosphate insecticide that is detected in the environment, and whose efficacy is a result of inhibition of the acetylcholine esterase enzyme at neuromuscular junctions and synapses of the nervous system. Diazinon (2.9, 5.2, 10.3, 19.8, and 40.2 MUg/L) was tested with the MEOGRT protocol, and the lowest observable effect concentrations of 2.9 MUg/L for fecundity and 5.2 MUg/L for growth were determined. Additional growth measurements were added to the MEOGRT protocol to more robustly define growth rates and to determine the impact size has on reproductive performance. Fish size starting at the first measurement day (i.e. 21 days post-fertilization), and continuing through the duration of the test was reduced with exposure to 5.2 MUg/L and higher, and asymptotic size predicted from growth modeling was reduced at 10.3 MUg/L and higher. By simply adding non-destructive growth measurements at two additional time points, the MEOGRT provided enough data for the parameterization of growth models, which could be used to characterize the reproductive implications of growth impairment. PMID- 30015191 TI - Intensified nutrients removal in constructed wetlands by integrated Tubifex tubifex and mussels: Performance and mechanisms. AB - The synergy of Tubifex tubifex (T. tubifex) and mussels on SFCWs (named SFCW-MT) performance was well studied in laboratory throughout a year. The SFCW-MT were steady operated with high TN and TP treatment, with the removal efficiencies of 37.85 +/- 5.22% and 39.26 +/- 5.20% even in winter. The mussels had excellent NH4 N removal efficiency, and avoid the shortage of NH4-N removal with T. tubifex in winter. Simultaneously, the SFCW-MT improved the NO3-N treatment by 51% than that in control group. The plant growth was improved in SFCW-MT, which reflected in the improvement of total chlorophyll contents and plant heights. The N and P absorbed by wetland plants and adsorbed by substrate were both increased with mussels. Microbial analysis results revealed that, the mussels could keep the abundance of nitrifiers despite the negative effect of T. tubifex. On that basis, the improved proportions of denitrifiers (Firmicutes) have a significantly recognized role in NO3-N transformation in SFCW-MT. The gut and membrane sections of mussels, as well as T. tubifex, also has proportions of denitrifiers and part of nitrifiers, and thus changed the microbial community in substrate. This evidence indicated that the co-existence of T. tubifex and mussels have potential application for simultaneous removal of NH4-N and NO3-N in CWs. PMID- 30015192 TI - Insecticidal properties of Solanum nigrum and Armoracia rusticana extracts on reproduction and development of Drosophila melanogaster. AB - Plant-derived substances, because of high biological activity, arouse interest of many scientists. Thus, plant extracts and pure substances are intensively studied on various insects as potential insecticides. In such studies, D. melanogaster is one of the most important model organisms. In our studies, we analysed the contents of two plant extracts and tested the activity of their main components against fruit flies and compared observed effects to effects caused by crude extracts. Then, we assessed the development of the next, unexposed generation. The chemical analysis of extracts revealed the presence of numerous glycoalkaloids and glucosinolates in Solanum nigrum and Armoracia rusticana extracts. These extracts, as well as their main components, revealed lethal and sublethal effects, such as the altered developmental time of various life stages and malformations of imagoes. Interestingly, the results for the extracts and pure main compounds often varied. Some of the results were also observed in the unexposed generation. These results confirm that the tested plants produce a range of substances with potential insecticidal effects. The different effects of extracts and pure main components suggest the presence of minor compounds, which should be tested as insecticides. PMID- 30015193 TI - Feasibility of nanoscale zero-valent iron to enhance the removal efficiencies of heavy metals from polluted soils by organic acids. AB - Soil washing with natural chelators to remediate metal-contaminated soils has been gained attention by researchers. However, the abilities of the chelators to remediate the multiple metal polluted soils are less effective. This study employed zero-valent iron nanoparticle (nZVI) to enhance the removal efficiencies of citric (CA), tartaric (TA) and oxalic acids (OA), and evaluate their feasibility. Results showed that metal removal efficiencies increased with the increasing concentration of nZVI and soil-liquid ratio, decreased with the increasing solution pH. The kinetic simulation indicated that pseudo-first-order and pseudo-second-order models could be used for describing the washing processes. Additionally, metal removals were significantly improved by addition of nZVI (p < 0.05). The highest enhancements of soil Cd, Pb and Zn removals under solution pH of 4.0, soil-liquid ratio of 1:20 and washing time of 120 min reached 12.83% (OA- nZVI), 24.92% (CA-nZVI) and 11.64% (OA- nZVI) for mine soil, and 19.24% (TA- nZVI), 18.16% (CA-nZVI) and 8.93% (OA- nZVI) for farmland soil, respectively. After soil washing, the exchangeable forms and the environmental risks of residual metals were markedly diminished in soils. Therefore, the combinations of the organic acids and nZVI are the feasible practices to repair the soils contaminated by heavy metals. PMID- 30015195 TI - Proteome profile analysis of boron-induced alleviation of aluminum-toxicity in Citrus grandis roots. AB - Aluminum (Al)-toxicity and boron (B)-deficiency are two major factors limiting crop production in tropical and subtropical areas. Elevating B supply can alleviate the Al-induced inhibition of growth in Citrus grandis. Seedlings of C. grandis were irrigated for 18 weeks with nutrient solutions containing two B levels (2.5 and 20 MUM H3BO3) and two Al levels (0 and 1.2 mM AlCl3.6H2O). By using 2-dimensional electrophoresis (2-DE) based MALDI-TOF/TOF-MS method, this study successfully identified and quantified sixty-one differentially abundant proteins in Citrus roots in response to B-Al interactions. The mechanisms underlying the B-induced alleviation of Al-toxicity unveiled by 2-DE technique could be summarized as follows: a) remodeling of cell wall by reducing the synthesis of lignin (sugar ATP Binding Cassette (ABC) transporter ATPase and cinnamyl alcohol dehydrogenase) and increasing the modification of cell wall (UDP forming); b) enhancing the abundances of proteasomes and turnover of dysfunctional proteins (proteasome or protease); c) increasing the abundance of stress response proteins, such as alcohol dehydrogenase, S-adenosylmethionine synthetase (SAMS) and glycosyl hydrolase; d) reinforcing cellular biological regulation and signal transduction (calreticulin-1). For the first time, some proteins, such as cell division protein 48 (CDC48), calreticulin and phospholipase, which might be involved in the downstream signaling of Al in Citrus plants, were successfully identified. PMID- 30015196 TI - Toxic effects of pentachlorophenol and 2,2',4,4'-tetrabromodiphenyl ether on two generations of Folsomia candida. AB - The standard Folsomia candida test (ISO 11267), in which only the survival and reproduction of the parental generation (F0) were determined, is insufficient to assess the toxicity of chemicals, like endocrine disrupting chemicals (EDCs), since the effects of EDCs could last for several generations and sometimes can be transgenerational. It's necessary to assess the effects on subsequent generations to address the long-term consequences of these chemicals exposure. In this study, the effects of pentachlorophenol (PCP) and 2,2',4,4'-tetrabromodiphenyl (BDE47) were assessed on F0 and the first filial generation (F1) of F. candida after 28 day or 10-day exposure of F0. In the 28-day exposure method, F0 was exposed to PCP or BD47 for 28 days and F1 was exposed for about 21 days. In the 10-day exposure method, F0 was exposed for 10 days and F1 was not exposed. The F. candida reproduction of F0 and F1 can be assessed in both methods, while transgenerational effects can further be evaluated in the 10-day exposure method. The numbers of F1 and F2 (second filial generation) juveniles in the 28-day exposure method and F1 juveniles in the 10-day exposure method decreased significantly for the PCP treatment. For BDE47, only the number of F1 juveniles in the 28-day exposure method significantly decreased. The EC50 values of F0 reproduction (the number of F1 juveniles) in the 28-day exposure method were 89 and 306 mg/kg dry soil for PCP and BDE47, respectively. Results suggested that PCP could affect F. candida egg hatching or juvenile survival and adult reproductive capacity, while BDE47 was more likely to affect egg hatchability or juvenile survival rather than adult reproductive capacity. It also indicated that F. candida exposed to PCP or BDE47 could recover in clean soil. Transgenerational effects were not observed for neither PCP nor BDE47 in this study. PMID- 30015194 TI - Urban street dust bound 24 potentially toxic metal/metalloids (PTMs) from Xining valley-city, NW China: Spatial occurrences, sources and health risks. AB - Street dusts (SDs) were a significant tracer to understand the pollution status of potentially toxic metal/metalloids (PTMs) in local environment. In this study, a total of 157 SDs were collected in the valley-city of Xining, NW China, with the objective to systematically investigate the spatial occurrences, sources and health risk status of 24 PTMs bound in SDs. The basic datasets of pH and size fractions showed that the SDs with PTMs were more alkaline and dominated with the coarse particle sizes between PM10-50, respectively. Results of concentration levels and spatial status of 24 PTMs processed with multi-statistical tools well established the sources identification in monitored local areas. It was suggested that the principal elements, Al, Fe, Si, K, Ca, Na, Mg, coupled with the trace elements Bi, Ga, Nb, Ni, Rb, Sr, Th, U, Y, Zr, As, Mn, Ti, V, Ce and La would be possiblely predominated by geogenic source or nature material, whereas contamination of Ba, Cu, Pb and Zn was clearly related to traffic-related sources. Peculiar associations among Cr and Co were possiblely enriched in SDs very close to the alloy industries. However, Sb and Sn differed from other observed PTMs, which appeared to derive predominantly from the coal combustion other than sources of electronic and mechanical industries. Compared to the integrated potential ecological risk index (PERI) of all PTMs with considerable contamination level and ecological risk, the single PTM of Sb posed very high risk. Calculated Hazard Index (HI) suggested ingestion as the most important exposure pathway for the majority of PTMs in children and adults, and no significant health risks of non-carcinogenic to children and adults were found except Cr (2.78) exposured to children. However, the evaluated cancerous risk was in the acceptable range both to children and adults except for the case of Cr exposure to adults (1.55E-06) compared to other PTMs. Although the carcinogenic risk was found no significant level, the maps of spatial carcinogenic risks above the threshold for children and adults were observed in some local monitoring areas, which should be attention and not to be always ignored. PMID- 30015197 TI - Phytotoxicity of polymetallic mine wastes from southern Tuscany and Saxony. AB - Restoration potential of mine wastes or approaches to improve soil conditions and to ameliorate phytotoxicity on these sites may be simulated in standardized greenhouse experiments. Plants can be cultivated side by side on materials from different origins in dilution series with defined admixtures of certain aggregates. Mine wastes used in the present study originated from Fenice Capanne (FC, Tuscany, Italy) and Altenberg (ALT, Saxony, Germany). Tailings of the Italian site contain high concentrations of lead, zinc, arsenic and sulphur while tin, wolfram, molybdenum and lithium are highly elevated in the German mine waste. We tested growth responses of five crop species and analyzed concentrations of various metals and nutrients in the shoot to evaluate the toxicity of the FC mine waste and found oilseed rape being the most and corn the least resistant crop. Interestingly, oilseed rape accumulated seven times higher levels of lead than corn without showing adverse effects on productivity. In a subsequent comparison of FC and ALT mine waste, we cultivated different species of buckwheat (Fagopyrum spec.), a fast growing genus that evolved in mountain areas and that has been shown to be tolerant to low pH and high concentrations of metals. We found that the FC mine waste was more toxic than the ALT substrate in F. tataricum and F. esculentum. However, lower admixtures of FC material (10%) resulted in stronger growth reductions than higher proportions (25%) of the mine waste which was primarily related to the slightly lower pH and higher availability of essential metals due to the admixture of sand. These results confirm the importance of managing the soil chemical and physical characteristics of wastelands and call for the development of assisted reclamation to prepare sites for regular biomass production. PMID- 30015198 TI - The role of major functional groups: Multi-evidence from the binding experiments of heavy metals on natural fulvic acids extracted from lake sediments. AB - Fulvic acid (FA) plays a key role in governing the environmental geochemistry behavior of heavy metals. In this work, the roles of major functional groups were investigated based on binding experiments of heavy metals on natural FA extracted from lake sediments. The results showed that the adsorption capacities were ranked as Cu2+ > Pb2+ >Cd2+. The differences of peak area at 3412, 1713, 617and 2430 cm-1 pre- and post-binding reactions in FTIR spectra suggested that phenolic, carboxyl and nitrogen-containing groups were the major functional groups providing sites binding heavy metals. Moreover, the results of bi-Langmuir model and the ionic strength effects jointly indicated that electrostatic attraction was the key mechanism during the adsorption process. The fitted results of Ligand-binding model suggested that the major functional groups in FA were classified into two types binding sites: weak (i.e. phenolic and carboxyl groups) and strong binding sites (i.e. nitrogen-containing groups). Additionally, there might be p-benzoquinone-like formed in FA which were then reduced to hydroquinone during the adsorption process, corresponding to the changing of peak area at 1614 and 830 cm-1 in FTIR spectra, the occurrence of Peak C in Fluorescence excitation-emission matrix (EEM) spectra and the ratios of H/C (<1) and O/C (~1). The organic matter in sediments from Lake Wuliangsuhai presented similar characteristics with terrestrial plants due to the lake characterized by Phragmites australis and Potamogeton pectinatus L. being the dominant species, which shared large proportions of woody tissues as well as waxy hydrocarbons resembling that of terrestrial plants. This work is useful to insight the environmental effects of FA on heavy metals in environment. PMID- 30015199 TI - Assessment of gamma radiation and associated radiation hazards in coastal sediments of south east coast of Tamilnadu, India with statistical approach. AB - Gamma spectroscopy was performed to determine the concentrations of 226Ra, 232Th and 40K in sediment samples collected from Periyakalapet to Parangaipettai, East coast of Tamilnadu. The activity concentrations were determined by direct counting using a hyper pure germanium (HPGe) detector inter phased with a multi channel analyzer (MCA). The average activity concentrations of the corresponding nuclides were 30.81 Bq kg-1 for 226Ra, 85.67 Bq kg-1 for 232Th and 425.72 Bq kg-1 for 40K. The average activity concentration of 232Th and 40K are slightly higher and 226Ra is lower than world average values. The radiation hazard indices namely Radium Equivalent Activity (Raeq) Absorbed Gamma Dose Rate (DR), Annual Effective Dose Rate (HR), Representative Level Index (RLI), Annual Gonadal Dose Equivalent (AGDE), Internal Hazard Index (Hin) and External Hazard index (Hex) are calculated and compared with the previously reported data. The extracted values are comparable to the recommended values and they all fall within the safety limits. Hence harmful radiation effects are not posed to the public and tourists going to the beaches for recreation or to the fishermen involved in their activities in the area as a result of the natural radioactivity of sediments. Multivariate Statistical analyses were carried out between the parameters obtained from the radioactivity to know the existing relations and to study the spatial distribution of radionuclides. PMID- 30015201 TI - Ribosomes and cryo-EM: a duet. AB - Ribosomes and electron cryomicroscopy (cryo-EM) share a long, intertwined history. However, cryo-EM only recently usurped X-ray crystallography as the predominant structural method to study ribosomes in atomic detail. The main, but not only, reason for this succession was the introduction of direct-electron detectors enabling cryo-EM to achieve equally high resolutions. Here, we describe how cryo-EM sample preparation and data processing allows new types of structural analyses not possible by X-ray crystallography. Taking advantage of these approaches, cryo-EM structures have revealed unprecedented insights into the function of ribosomes from a wide range of biological sources and in numerous physiological contexts. These include the discovery of a new mechanism of polypeptide synthesis and the identification of the roles of ribosomes in functional supercomplexes. PMID- 30015200 TI - A microfluidic surface-enhanced Raman spectroscopy approach for assessing the particle number effect of AgNPs on cytotoxicity. AB - Silver nanoparticles (Ag NPs) have well-known antibacterial properties and are widely applied in various medical products and general commodities. Although many studies have addressed the toxicity of Ag NPs to mammalian cells, the direct relationship between the number of Ag NPs in living cells and the corresponding cell toxicity has not yet been explicitly demonstrated. In this work, a simple and reusable microfluidic device composed of a quartz cover slip and a glass plate with etched micro-channel and micro-wells was employed for separating and trapping single living cells. The device was silanized to render the surface hydrophobic. For simplicity, HeLa cells as the model cancer cells were used in the study, which were pipette-loaded into an array of micro wells based on dead end filling. Surface enhanced Raman spectroscopy (SERS) was then employed to examine the living cancer cells and assessed number and distribution of Ag NPs in the cells. Combined with the cell viability assay, we therefore correlated the number of Ag NPs in the cell with the toxicity to the cell directly. PMID- 30015202 TI - The cryo-EM resolution revolution and transcription complexes. AB - Direct electron detector technology combined with improved imaging processing procedures has dramatically increased the resolution that can be obtained by single-particle cryo-electron microscopy and cryo-electron tomography. These developments-often referred to as the 'resolution revolution' in cryo-EM-have had a profound impact on the structural biology of transcription as they allow the determination of atomic or near-atomic resolution structures of very large, flexible and often transient transcription complexes that in many cases had resisted crystal structure determination for decades. In this review, we will discuss recent advances and breakthroughs in the structural biology of transcription complexes enabled by the revolution in cryo-electron microscopy with particular focus on eukaryotic RNA polymerases and their pre-initiation complexes, but also chromatin remodelers and epigenetic regulators. PMID- 30015203 TI - Two-year gait analysis controls of the minimally invasive total hip arthroplasty by the direct anterior approach. AB - BACKGROUND: The purpose of the study was to determine the long-term functional outcome of two hip approaches by gait analysis. Patients were selected by prospective randomization, and operated on either by the anterolateral approach or by a minimally invasive direct anterior approach. METHODS: 33 patients (17 anterolateral approach; 16 direct anterior approach) were analyzed using a Vicon 870 system. Gait analysis was performed two years after total hip arthroplasty. Temporo-spatial and kinematic variables were obtained. FINDINGS: On chest and pelvic kinematics, no patient group demonstrated significant differences. The time-distance parameters showed significant differences with the anterior approach in cadence and stride time. INTERPRETATION: The study indicates that the direct anterior approach exerts positive effects compared with the anterolateral approach two years after surgery. The muscle-sparing concept of direct anterior approach results in significant differences in gait compared to the anterolateral approach 2 years after surgery. PMID- 30015204 TI - Is neuromuscular inhibition detectable in elite footballers during the Nordic hamstring exercise? AB - BACKGROUND: The presence of neuromuscular inhibition following injury may explain the high incidence of biceps femoris injury recurrence in elite (soccer) footballers. This phenomenon may be detectable in elite players during the Nordic hamstring exercise. Thus, the first purpose of this study was to assess biceps femoris muscle activation during this exercise in players with hamstring injury history. Additionally, following injury, observed increases in synergistic muscle activation may represent a protective mechanism to the presence of neuromuscular inhibition. Thus, the second purpose was to identify if the relative contributions of biceps femoris, and its synergists reflected a post-injury pattern of activation suggestive of these potentially compensatory neural mechanisms. METHODS: Ten elite players with a history of hamstring injury and ten elite players without a history of hamstring injury, completed six repetitions of the Nordic hamstring exercise. During each trial, biceps femoris, semitendinosus and gluteus maximus muscle activations were collected at 90-30 degrees and 30-0 degrees of knee flexion. FINDINGS: Biceps femoris activation was significantly higher at 90-30 degrees of knee flexion compared to 30-0 degrees (P < 0.001) but did not differ between the groups. In players with a history of injury, muscle activation ratios for the biceps femoris/semitendinosus (P = 0.001) and biceps femoris/gluteus maximus (P = 0.023) were significantly greater at 30-0 degrees of knee flexion than in the control group. INTERPRETATION: Neuromuscular inhibition of the biceps femoris was not detected during the exercise within elite footballers, yet the relative contributions of biceps femoris and its synergists appear to change following injury. PMID- 30015205 TI - Two-dimensional frontal plane projection angle can identify subgroups of patellofemoral pain patients who demonstrate dynamic knee valgus. AB - BACKGROUND: Identifying individuals with patellofemoral pain who demonstrate similar modifiable factors including dynamic knee valgus may be useful in establishing subgroups of patients that can undergo individualised management strategies. However, a lack of objective assessment criteria means that the findings are of limited value to clinicians aiming to distinguish between patients with and without altered frontal plane knee kinematics. Therefore, the aim of the study was to investigate dynamic knee valgus in individuals with and without patellofemoral pain by determining frontal plane knee alignment during functional activity. METHODS: Thirty recreationally active individuals with patellofemoral pain and 30 non-injured individuals had frontal plane knee alignment assessed via two-dimensional analysis of the frontal plane projection angle during single limb stance and single limb squats to 60 degrees of knee flexion. FINDINGS: Individuals with patellofemoral pain demonstrated excessive frontal plane knee alignment (P = .003; ES = 0.68) compared to uninjured participants during single limb squats. In addition, assessing frontal plane knee alignment using two-dimensional analysis had fair specificity and sensitivity of discriminating patellofemoral pain injury. INTERPRETATION: Clinical quantification of two-dimensional frontal plane knee alignment may be utilised to subgroup patients with patellofemoral pain that display dynamic knee valgus during single limb squats. Furthermore, this may be a useful clinical tool to determine individuals that may be at risk of developing pain in the future. PMID- 30015206 TI - Comparison of aneurysmal and non-pathologic human ascending aortic tissue in shear. AB - BACKGROUND: The mechanical properties of the aorta may provide some guidance to cardiovascular surgeons treating aortic disease. While tensile tests are traditional, recent work suggests that shear is important in aortic dissection. Characterizing the differences or similarities in the mechanical shear stress response of non-pathologic human ascending aortic tissue and of tissue that has remodeled to become aneurysmal contributes to understanding the differences in behavior of the two tissues. METHODS: Fresh non-pathological and aneurysmal tissue acquired from the operating room is deformed in translational shear at approximately physiological rates to 67% deformation followed by stress relaxation to allow comparison of their mechanical behavior. Aneurysmal tissue is tested at 1 mm/s or 12 mm/s and normal tissue at 12 mm/s. The deformation is either in the circumferential or longitudinal direction for a total of 48 specimens. FINDINGS: The shear response at 12 mm/s in non-pathological and aneurysmal tissue is similar in the circumferential direction but different in the longitudinal direction. Tissue type accounts for up to 30% of the variation in the longitudinal direction. The aneurysmal tissue response is rate-dependent. Both tissues exhibit significant shear stress relaxation. INTERPRETATION: Remodeling to create the aneurysm modifies the bond strength between collagen fibers and the extracellular matrix. The time-dependent response is probably due to interstitial fluid behavior. Thoracic surgeons must use caution in applying aortic stress values in the literature because they depend on the deformation rate. PMID- 30015207 TI - Steered molecular dynamics characterization of the elastic modulus and deformation mechanisms of single natural tropocollagen molecules. AB - Collagen is a common structural protein, providing mechanical integrity for various vertebrate connective tissues such as cartilage and bone. The mechanical behaviours of these tissues under physical stimulations are controlled by the hierarchical structure of collagen and its interactions with other extracellular matrix molecules. However, the mechanical properties and deformation mechanisms of natural collagen under physiological loading rates at the molecular level are not fully understood. In this study, comprehensive steered molecular dynamics (SMD) simulations were performed on the 2nd intact overlap region (d2ol) and the 2nd intact D-period (d2olgp) of an in-situ characterized collagen molecule, under a large range of strain rates (6.5 * 106% s-1 to 1.3 * 1012% s-1). The results show that, depending on the applied strain rates, tropocollagen molecules unfold in different ways. Particularly, at high and intermediate strain rates, the number of inter-chain hydrogen bonds decreases rapidly even at small deformations, leading to a dramatic increase in the force. This results in an increase in the estimated Young's modulus of collagen triple helices as the deformation rate goes up, which, together with the nonlinear mechanical behaviour, explains the broad range of the Young's modulus for collagen model peptides reported in earlier SMD studies. Atomistic-level analyses indicate that the elastic modulus of single tropocollagen molecules decreases as the strain rate becomes smaller. However, for strain rates below 1.3 * 108% s-1, the tangent Young's modulus of d2ol (d2olgp) converges to approximately 3.2 GPa (3.4 GPa), at the strain of 10.5% (12%) when the segment is fully uncrimped. Furthermore, for strain rates under 1.3 * 108% s-1, d2ol and d2olgp show identical deformation mechanisms (unwinding, uncoiling and backbone stretching), but the corresponding strain ranges are different. This study will aid in future studies on characterizing the mechanical properties of collagen molecules and collagen-like peptides by indicating the proper pulling strain rates and how to determine the suitable strain range used for evaluating the elastic modulus. PMID- 30015208 TI - Prediction of storage modulus in solid-like poly (lactic acid)/poly (ethylene oxide)/carbon nanotubes nanocomposites assuming the contributions of nanoparticles and interphase regions in the networks. AB - In this paper, Kolarik model for tensile modulus of co-continuous blends is developed to predict the storage modulus of poly (lactic acid) (PLA)/poly (ethylene oxide) (PEO)/carbon nanotubes (CNT) nanocomposites at low frequencies (solid-like region). The storage moduli of prepared samples are obtained by frequency sweep test and Kolarik model is expanded assuming the characteristics of interphase regions and CNT networks. The developed model takes into account the percolation threshold, the percentage of networked CNT and the volume fraction of interphase regions in the networks. The calculations of developed model are compared to the experimental data and the significances of main parameters on the storage modulus are justified. The calculations successfully agree with the experimental data at different PLA and CNT concentrations. The addition of CNT thickens and strengthens the interphase regions in the samples, but the different concentrations of PLA differently affect the properties of interphase regions. A thick and strong interphase enhances the storage modulus of nanocomposites. The high fraction of networked CNT and the significant modulus of nanoparticles considerably promote the storage modulus, but only small networks cause poor storage modulus for nanocomposites. PMID- 30015209 TI - On the atomistic-based continuum viscoelastic constitutive relations for axonal microtubules. AB - Mechanical response of brain's interior during traumatic brain injury is primarily governed by the cytoskeleton (CSK) and occurs over multiple length scales starting from the axonal substructure level. The axonal cytoskeleton can be viewed as a nanofiber reinforced nanocomposite structure where nano-fibrous microtubules (MTs) are arranged in staggered arrays and cross-linked by Tau proteins. Each MT is made of thirteen laterally connected protofilaments (PFs), each of which is formed via linear polymerization of alphabeta-heterodimer protein called tubulin. Recent studies suggest that the unique viscoelastic nature of axons governs the damage during traumatic brain injury. To understand how the internal substructures of axon influences the viscoelastic mechanical behavior of axon from a theoretical perspective, the viscoelastic properties of MTs need to be properly described. Since viscosity is a bulk property, the measurement methods are fairly consistent. On the other hand, the reported experimentally measured elastic properties of MTs vary by several orders of magnitude due to limitations of experimental tools. Alternatively, many have attempted to determine MT properties using theoretical and computational methods at different length scales ranging between the atomistic and the continuum level. The atomistic approaches capture the dynamics and interactions of a material at the atomic or atomic cluster level but these methods are computationally expensive and can model only a very small physical scale. On the other hand, the continuum theories lack finer scale details. Here, we present an atomistic-based continuum viscoelastic constitutive relation for microtubules (MTs) based on the interatomic potential for proteins and continuum homogenization method. The interaction potential includes both van der Waals and electrostatic interactions between the protein molecules. The calculated Young's modulus of 3.385 GPa agrees reasonably well with the range of experimentally measured value without any parameter fitting. We have then investigated the viscoelastic response of MT based on the estimated viscosity using atomistic simulation and evaluated Young's modulus using our method. The current theory suggests that MT behaves like a viscoelastic material when applied loading rate is extremely high, otherwise it acts like an elastic solid material. PMID- 30015210 TI - Not all those who wander are lost: Spatial exploration patterns and their relationship to gender and spatial memory. AB - When humans and animals navigate through environments, they form spatial memories important for supporting subsequent recall of locations relative to their own position and orientation, as well as to other object locations in the environment. The goal of the current study was to examine whether individual differences in initial exploration of a large-scale novel environment relate to subsequent spatial memories. A majority of studies examining spatial memory formed in large-scale spaces have constrained encoding of the environment by leading participants on pre-determined paths, thereby limiting their free exploration. We allowed participants to freely explore a large-scale, virtual environment to locate a set of objects within. We then tested their ability to navigate back to those objects as well as their ability to point to them from one another. Based on previous work suggesting gender differences in navigation strategies and spatial anxiety, we predicted that males and females would show different patterns of initial exploration and that these exploration patterns would account for gender differences in measures of spatial memory. We found that females revisited previous locations more often and showed lower rates of spreading through an area. These measures of exploration partially accounted for gender differences in efficiency in navigation and pointing accuracy to remembered locations. The results demonstrate the importance of exploration in spatial memory and provide a new perspective on gender differences in spatial cognition. PMID- 30015211 TI - Intuitive statistical inferences in chimpanzees and humans follow Weber's law. AB - Humans and nonhuman great apes share a sense for intuitive statistical reasoning, making intuitive probability judgments based on proportional information. This ability is of fundamental importance, in particular for inferring general regularities from finite numbers of observations and, vice versa, for predicting the outcome of single events using prior information. To date it remains unclear which cognitive mechanism underlies and enables this capacity. The aim of the present study was to gain deeper insights into the cognitive structure of intuitive statistics by probing its signatures in chimpanzees and humans. We tested 24 sanctuary-living chimpanzees in a previously established paradigm which required them to reason from populations of food items with different ratios of preferred (peanuts) and non-preferred items (carrot pieces) to randomly drawn samples. In a series of eight test conditions, the ratio between the two ratios to be discriminated (ROR) was systematically varied ranging from 1 (same proportions in both populations) to 16 (high magnitude of difference between populations). One hundred and forty-four human adults were tested in a computerized version of the same task. The main result was that both chimpanzee and human performance varied as a function of the log(ROR) and thus followed Weber's law. This suggests that intuitive statistical reasoning relies on the same cognitive mechanism that is used for comparing absolute quantities, namely the analogue magnitude system. PMID- 30015212 TI - Reconstruction of traumatic lumbar hernias: A case report. AB - BACKROUND: Traumatic lumbar hernias are not common hernias that are encountered by general or plastic surgery teams, however it is important to understand the anatomy of the hernia in order to be able to correct the flank defect. In our patient, the oblique muscles were sheared off the iliac crest periosteum, however the attachments to the ribs and spine were maintained. We were able to successfully place a pre-peritoneal polypropylene mesh which was secured to the musculature, and re-approximate the oblique muscles to the iliac crest using Mitek QUICKANCHOR(r) sutures. Our case study has been reported in line with the SCARE criteria ([8] Agha et al., 2016). CASE REPORT: The subject in our case was a 47-year-old gentleman who was involved in a motor vehicle accident, and sustained a traumatic lumbar hernia due to the 3-point seatbelt he was wearing. He was transported via ambulance to our trauma center. CONCLUSION: Understanding the anatomy and mechanism of injury is the key to reconstructing traumatic lumber hernias. Although not required, mesh reinforcement has significantly reduced the recurrence of all hernias. This is the simplest and most effective way, in our opinion, to return the flank muscles to their native position while providing mesh reinforcement. PMID- 30015213 TI - Mullerian cyst in posterior mediastinum: A report of a case. AB - INTRODUCTION: A Mullerian cyst is a recently defined rare benign tumor of the posterior mediastinum. It is necessary to distinguish it from neurogenic tumor or bronchogenic cyst arising in the posterior mediastinum. Herein, we have reported and reviewed a case of Mullerian cyst in the light of the existing literature. PRESENTATION OF A CASE: A 40-year-old woman was referred to our department for abnormal mediastinal tumor on computed tomography (CT). Chest CT revealed a 2-cm nodule in the left posterior mediastinum, while magnetic resonance imaging (MRI) T2-weighted scan revealed an elliptical, homogenous, and high-intensity neoplasm, and bronchogenic cyst or neurogenic tumor was suspected. She did not present with any symptoms. A thoracoscopic surgery was performed for the cyst removal. Histopathological examination revealed that the cyst wall was covered with a layer of columnar epithelium. Immunohistochemical staining revealed the presence of estrogen receptor (ER) and progesterone receptor (PgR). Therefore a diagnosis of mediastinal Mullerian cyst was made. DISCUSSION AND CONCLUSION: It is important to differentiate Mullerian cyst in the posterior mediastinal from other mediastinal cystic tumor for optimal decision-making in treatment. PMID- 30015214 TI - Surgical management of wide intrabony defect underlying midline diastema using Whale's tail flap technique: A Case Report. AB - INTRODUCTION: Management of wide midline diastemas accompanying an underlying osseous defect is cumbersome which sometimes yields unpredictable results. However, regenerative therapy of these highly aesthetic zones using a Whale's tail flap technique obtains a maximum papilla fill after placement of the bone graft. This case report illustrated the utilisation of Whale's tail technique of flap for a large interdental defect. CASE PRESENTATION: A young healthy 31-year old male patient presented with maxillary midline diastema. Probing depth of 6 mm was also noted over the mesial aspect of the same teeth with localised osseous defect radiographically which lead to a diagnosis of localized chronic periodontitis in relation to those teeth. A Whale's tail technique flap for papilla preservation was performed together with a regenerative procedure using bone graft and GTR membrane. DISCUSSION: Midline diastema is a common reported complaint in dentistry due to both aesthetic and functional reasons. Following the treatment, 12 months postoperatively, patient had a probing depth reduction of 3 mm and a gain in clinical attachment of 2 mm. The surgical technique allowed regeneration of wide intrabony defects involving the maxillary anterior teeth with notable interdental diastemas. CONCLUSION: This lead to significant improvement of the hard and soft tissue contour as well as it recreated a functional reattachment which was documented up to 12 months postoperatively. PMID- 30015215 TI - Percutaneous screw fixation of fractured neck of femur in a teenage girl with osteogenesis imperfecta. A case report. AB - INTRODUCTION: Neck of femur fracture in osteogenesis imperfecta is rarely reported. The management is uncertain and always reported as difficult. Clinical outcomes are not well described. CASE PRESENTATION: A teenage girl, who is known to have osteogenesis imperfecta, sustained neck of femur fracture in the presence of a previously inserted implant. She was treated by percutaneous screw fixation. In both immediate and long term follow up, our patient had satisfactory outcome and return to pre-fracture functional status. DISCUSSION: Dealing with fragility fracture in small abnormal hips is challenging especially, in the presence of a retained implant in- situ. Intra-operative difficulty were encountered during positioning, reduction, and screw insertion attempt. CONCLUSION: This rare case illustrates the anticipated difficulties in managing neck of femur fracture in osteogenesis imperfect patients. It also emphasize on the importance of surgical fixation to control pain and allow for healing in anatomically functional position. PMID- 30015216 TI - Total intracorporeal robotic renal auto-transplantation: A new minimally invasive approach to preserve the kidney after major ureteral injuries. AB - BACKGROUND: Renal auto-transplantation is a suitable option for managing patients with major ureteric injury. Conventional Renal auto-transplantation is however, underutilized because of its invasiveness. Completely intra-corporeal robotic renal auto-transplantation is a suitable option to decrease the morbidity. In this case, we report the first use of total intra-corporeal robotic renal auto transplantation outside of North America. CASE REPORT: A 30-year-old woman presented with an extensive upper left ureter defect, following a high kinetic energy trauma. She underwent 2 median laparotomies, with extensive resection of small intestine, and 1 transverse laparotomy to repair a massive rupture of abdominal muscles. The procedure was performed via a transperitoneal approach, with the assistance of the da Vinci Si robot (Intuitive Surgical Inc. Sunnyvale, CA, USA). The renal auto-transplantation was conducted entirely robotically, in 2 separate stages, using a 4 robotic arm approach. Total operative time was 300 min: 150 min to harvest the kidney including adhesiolysis, 20 min to reposition the patient, and 130 min for the robot assisted kidney transplantation (RAKT). The total ischemia time was 96 min (3 min of warm ischemia, no cold ischemia, 93 min of rewarming time). The estimated blood loss was 150 mL. CONCLUSION: To our knowledge, this is the first case successfully performed as a total robotic approach outside of North America. PMID- 30015217 TI - In silico analysis of virulence genes in an emerging dental pathogen A. baumannii and related species. AB - OBJECTIVES: Acinetobacter baumannii is an opportunistic pathogen which has recently been categorized as a high risk pathogen by World Health Organisation (WHO). The microbe has stealthily entered the oral cavity and has established itself as a potential pathogen by acquiring drug resistance and expression of several virulence genes. Surveillance on the type of virulence factors harboured by the organism will enable us to comprehend the mechanism of pathogenesis. The study was performed to screen for the presence of crucial virulence factors associated with Acinetobacter spp. as reviewed from the literature by employing computational tools. DESIGN: Nineteen genome sequences of Acinetobacter spp. with the predominance of different strains of A. baumannii were classified phylogenetically into clusters using in silico restriction digestion and pulse field gel electrophoresis (PFGE). Further, the frequency of common virulence genes in the genome of various Acinetobacter spp. was recorded using in silico PCR analysis. RESULTS: Based on PFGE pattern and phylogenetic tree the genomes of A. baumannii were clustered into 4 genotypes (G1-G4). Two species were excluded from the list since they were negative for almost all the virulence genes tested. Frequency of virulence genes in each of the 17 genomes analysed, found ompA and smpA to be the major virulence factors in A. baumannii and related species. Acinetobacter spp. belonging to genotypes 2 and 3 were found to harbour 1-15 and 6-10 potential genes encoding virulence factors respectively. CONCLUSIONS: The present study showed numerous virulence genes in genomes analysed. In silico analysis of these virulence genes can be used as candidates to build novel therapeutic targets against the pathogen. An extensive study on the functional role of these genes could aid in stalling the propagation and dissemination of A. baumannii among susceptible individuals. PMID- 30015218 TI - Effect of chitosan nanoparticles on the inhibition of Candida spp. biofilm on denture base surface. AB - OBJECTIVES: Chitosan nanoparticles (ChNPs) have antifungal effects, however there is a lack of information about the effects of ChNPs against Candida biofilm on denture base surface. This study investigated the ChNPs effect against C. albicans biofilm adhesion and formation, and against Candida spp. biofilm on heat cured acrylic resin. DESIGN: The ChNPs were synthetized (3800 MUg/mL) and characterized by infra-red spectrophotometry and transmission electron microscopy. The minimum inhibitory/fungicidal concentrations (MIC/MFC) against Candida spp. were determined. The time-kill assay and changes on C. albicans micromorphology were evaluated. The % inhibition of ChNPs on C. albicans biofilm formation and reduction were investigated using 1 min and 8 h exposure. Candida biofilm was developed on resin surfaces and ChNPs were applied every 8 h for 5 days. After, fungal cells were counted (CFU/mL) and the surface roughness (Ra) and vickers microhardness (HV) of resin were analysed. For all experiments, sodium hypochlorite (NaOCl) was used as control. Data were analyzed by ANOVA, Tukey and paired t-tests (alpha = 0.05). RESULTS: The MIC80% of ChNPs was 30.1 MUg/mL. ChNPs at 4 MIC showed complete inhibition in the time-kill assays. Blastoconidia cells were predominant after ChNPs application. The % inhibition ChNPs on C. albicans was proportional to its concentration, regardless of the exposure time. ChNPs decreased the CFU/mL of Candida spp. and showed lower alteration of HV and Ra values of resin surface compared to NaOCl. CONCLUSIONS: The ChNPs inhibited C. albicans biofilm, reduced Candida biofilm on resin and caused small changes in roughness and hardness of acrylic resin surface. PMID- 30015219 TI - Comparison of undergraduate educational environment in medical and nursing program using the DREEM tool. AB - INTRODUCTION: Educational environment (EE) in a health educational institute can bring about an enduring impact on the students' motivation, knowledge, critical thinking along with their social life. Therefore, identifying strengths and the need for change in the education environment is vital for the enhancement of the students' learning. OBJECTIVE: This study aimed to compare the perceptions of nursing and medical students about their EE in a private university, Karachi Pakistan. METHODOLOGY: Data from two cross-sectional studies of 884 students from both medical and nursing schools of Aga Khan University was acquired and analyzed. EE was measured by a well-known inventory i.e. 'Dundee' Reading Educational Environment Measure (DREEM). The scores were constructed using standardized guidelines. Mann-Whitney U test and two way ANOVA were used in statistical analysis. RESULTS: With 84.1% average response rate, the mean + SD DREEM score was measured as 126 +/- 20.3. Nursing students regarded more positive perception about their EE (127.3 +/- 19.3) as compared to medical students (124.6 +/- 21.3) and was found to be statistically significant (P = 0.027). Medical students scored higher in the domain of Perception of Atmosphere (PoA); whereas, nursing students scored higher in Academic Self Perception (ASP). Both of the groups have rated lower scores on the domain of Perception of Teaching (PoT). CONCLUSION: Both medical and nursing students appreciated the EE pertaining to Perception of Learning (PoA), Academic Self- Perception (ASP), Perception of learning (PoL) and Social Self-perception (SSP). The study showed that nursing students' perception on their EE was relatively more satisfactory than medical students. However, both medical and nursing students identified areas of improvement in the domain of Perception of Teaching (PoT). This finding indicates dire need to devise innovative teaching strategies both for medical & nursing education. PMID- 30015220 TI - The effect of mannequin fidelity on the achievement of learning outcomes for nursing, midwifery and allied healthcare practitioners: Systematic review and meta-analysis. AB - BACKGROUND: Simulation has demonstrated superiority over purely didactic instruction in multiple contexts, and educationalists have embraced this modality for enhancing access to clinical skills. However, there remains uncertainty if increasing the realism (fidelity) of simulation equipment heightens performance. To address this within nursing and allied health, this review examines if increasing equipment fidelity improves learning outcomes. METHODS: A systematic search of; CINAHL, Academic Search Complete, AMED; British Education Index, ERIC, MEDLINE, PsycARTICLES, PsycINFO, Maternity and Infant Care, INTERMID, Google Scholar, American Doctoral Dissertations, EThOS, ClinicalTrials.gov and ISRCTN registers was conducted for trials comparing two or more fidelity levels for knowledge, psychomotor or affective/non-technical outcomes. Data extraction and quality appraisal were performed and independently verified. Subgroup meta analyses were undertaken (where viable), at post-intervention, intermediate, and long-term assessment time-frames. RESULTS: 18 RCTs and quasi-experimental trials containing ~1192 participants met the inclusion criteria. Almost 3/4 of included trials exhibited high risk-of-bias. Training on higher-fidelity mannequins was associated with improved performance immediately post-intervention when compared with training on lower-fidelity mannequins for knowledge (p < 0.00001) and psychomotor outcomes (p < 0.00001). A similar directional effect for affective/non-technical skills was considered less robust due to substantial weaknesses in available studies. During follow-up testing at intermediate (1-3 weeks) and long-term (1-6 months) data points, there was insufficient evidence to determine any advantage in the use of higher fidelity mannequins. Repeated intervention training was also insubstantially reported. CONCLUSION: Higher fidelity mannequins exhibited modest advantages when testing closely followed training. However results need to be confirmed using a larger number of high quality RCTs. A greater body of research using repeated-interventions and extended time-frames is also required before the influence of sustained training with alternative mannequins can be fully elucidated. PMID- 30015221 TI - Burnout subtypes and associated factors among police officers in Sri Lanka: A cross-sectional study. AB - Even though policing is associated with very high levels of occupational stress and burnout, no studies have been conducted to explore burnout subtypes among police officers globally. Hence, this cross-sectional study was conducted among 750 police officers working in a police division in Sri Lanka to determine the distribution and associations of burnout subtypes using the Burnout Clinical Subtype Questionnaire. The police officers had high scores for frenetic and worn out subtypes in comparison to the underchallenged subtype. Multivariable analysis elicited a multitude of statistically significant associations with burnout subtypes (p < 0.05). Staff adequacy and fewer working hours were negatively associated with frenetic subtype. Younger police officers had a positive association, while, being married, satisfactory infrastructure facilities, frequent superior guidance, satisfactory higher official support, satisfactory allowances and the opportunity to serve public showed negative associations with underchallenged subtype. Being married, staff adequacy, frequent superior guidance, higher official support, satisfactory allowances, satisfactory social status and overall job satisfaction elicited significant negative associations with worn-out subtype. The findings are suggestive of high burnout subtype profile among the police officers in the study population and the associated factors of the three burnout subtypes are congruent with the characteristics of the burnout subtype profile. PMID- 30015222 TI - The neo-criminalization of stalking in the Portuguese legal system. AB - Despite the theme stalking was only being given attention in the final decades of the 20th century, the truth is that this phenomenon has always existed. It consists in a series of persistent harassment behaviour of which one person is the victim of another, there may exist or have existed a relationship between them or they may be unknown to each other. This behaviour may be of the most varied nature and, frequently, if seen in an isolated form, may appear to be simple acts of courtship and demonstrations of affection, which are not taken very seriously by society. One of the first countries that criminalized stalking was the United States of America, more specifically the State of California, in 1990. Several European countries also included stalking in their legal systems, making it independent of other crimes, especially the crime of domestic violence. In Portugal, this behaviour was criminalized in 2015, described in article 154-A of the Criminal Code, under the heading persecution. The aim of this work is to make a juridical analysis of the article 154-A of the Portuguese Criminal Code, to understand if there was truly the need to create a new type of crime for the behaviour of stalking, or if other previously typified legal measures would have been sufficient to protect the victims' interests. This study is also intended to indicate alternative forms of punishment for this phenomenon under the Portuguese jurisdiction. PMID- 30015224 TI - Insights from epigenetic studies on human health and evolution. AB - Epigenetic variation represents a unique aspect of human biological variation that can shed light on our evolutionary history as well as the etiology of human disease. DNA methylation is the most commonly studied type of epigenetic modification and can alter gene expression without changing the underlying DNA sequence. DNA methylation occurs throughout all living organisms although its function seems to have evolved from genome defense in fungi, bacteria and plants to a more complex role in gene regulation and cellular differentiation in animals. Human DNA methylation was originally studied in imprinting diseases and cancer, but more recently has been investigated as a mechanism to mediate the impact of environmental and psychosocial stressors on human health and disease. PMID- 30015223 TI - Poisoning due to household products: A ten years retrospective analysis of telephone calls to the National Poisons Information Centre, All India Institute of Medical Sciences, New Delhi, India. AB - Extensive use of different chemicals in various fields and their easy availability has led to an increased incidence of accidental and intentional poisoning in developing countries including India. A diverse range of household products commonly used for domestic purposes comprise pesticides, household cleaners, thermometer mercury, antiseptics, kerosene, paint thinners etc. Any of these products, if misused or mishandled can cause poisoning. In India, the National Poisons Centre (NPIC) at the All India Institute of Medical Sciences, New Delhi, provides information on management of poisoning to treating physicians. Analysis of data based on telephone calls received by the NPIC (April 2006-March 2016) has highlighted a high incidence of poisoning due to household products, followed by pharmaceuticals, agricultural pesticides and industrial chemicals. The objective of the present retrospective study was to determine the incidence of poisoning due to various household products as reported to the NPIC during the ten years period. The total number of calls received by the Centre was 16,420. There were 7114 calls (45.5%) due to household products with adults (>18yrs.) and children (<1-18yrs.) constituting 38.7% and 61.2% calls respectively. Males outnumbered females (M = 62.4%, F = 37.5%). The mode of poisoning was mainly unintentional (66.8%) followed by intentional mode (33.2%). The commonest route of exposure was oral (95.6%). Household pesticides were commonly implicated (43.7%) followed by household cleaners (21.8%), thermometer mercury (5.2%) naphthalene balls (5%), antiseptics (3%), kerosene (2%) and paint thinner (2%). Miscellaneous products comprising of camphor, silica gel, hair dye, nail polish remover, cosmetics, adhesives etc were also involved in poisoning (17.1%). The trend and pattern of poisoning varies in different parts of the country, because all calls on poisoning are not reported to the Centre. So the data as such may not be a true reflection of the scenario in India. However, the results do indicate an increasing incidence of poisoning due to household products especially in children. The probable reasons for high incidence could be careless storage, ignorance, non compliance with prescribed instructions for use and negligible parental supervision in case of children. The results of the study highlight, an urgent need to identify high risk circumstances, common toxic products involved and implementation of prevention and awareness programmes, to achieve poisons control at home. PMID- 30015225 TI - Meanings, measurements, and musings on the significance of patterns in human microbiome variation. AB - Variation of the human microbiome is a multidimensional value depending on the question of interest. Unlike traditional human genetics, which most often deals with variation at the level of genes or genetic sequences, microbiome variation may be most relevant at the functional level and can be interrogated a number of ways. Most common methods are marker gene metataxonomic surveys or shotgun metagenomic sequencing, however more direct indicators of microbial activity that are gaining popularity include metabolomic and metatranscriptomic surveys. With all these data and promise in human microbiome research, it requires that we reassess what is meant by variation of the human microbiome and how its significance impacts the ability of microbiome research to be informative on a range of topics from evolutionary theory to clinical outcomes. Learning from mistakes is essential to advancing the field, and new sophisticated analysis tools are helping to crystallize associations between microbiome variation and its drivers so that firm ground supports future explorations of mechanism. However, the body of current data suggests that these may be highly individualized due to the array of interactions between the host, the microbiome, and the environment. As a result, microbiome researchers need to be cognizant of population contexts and the limits these impose on conclusive outcomes. PMID- 30015226 TI - Characteristics and outcomes of venous thromboembolism in patients with hereditary hemorrhagic telangiectasia. PMID- 30015227 TI - Bleeding and venous thromboembolic events in patients with active cancer hospitalized for an acute medical illness. AB - BACKGROUND: Cancer patients hospitalized for an acute medical illness are considered to be at high risk of venous thromboembolism (VTE). Information on bleeding and symptomatic VTE in these patients remains scant. The objectives of this study were to evaluate the incidence of bleeding and VTE during hospitalization and after discharge in a prospective cohort of hospitalized medically-ill cancer patients. METHODS: Consecutive patients with active cancer admitted for an acute medical illness. The primary outcome was the incidence of clinically relevant bleeding. Secondary outcomes included symptomatic and incidentally detected VTE. Outcomes were recorded during hospitalization up to three months after discharge. RESULTS: The study population consisted of 330 patients with a mean age of 73.2 (+/-12.1) years. During a median hospitalization of eight days, six patients (1.8%) developed a clinically relevant bleeding. Pharmacological thromboprophylaxis was administered to four of these six patients (66.6%), and 108 of 324 (33.3%) patients without bleeding. Twelve (3.6%) were diagnosed with VTE, of whom two had received thromboprophylaxis. In ten patients, VTE was detected incidentally. After discharge, 11 patients experienced major bleeding and two developed symptomatic VTE during a median follow-up of 92 days (range 19-110). Two thirds of all major bleeding events were gastrointestinal, and 87% occurred in patients with gastrointestinal or genitourinary cancer. CONCLUSIONS: In patients with active cancer admitted for an acute medical illness, the risk of bleeding and symptomatic VTE appeared to be low during hospitalization. After discharge, the risk of bleeding was higher and significantly outweighed that of VTE. PMID- 30015228 TI - Associations between complement pathways activity, mannose-binding lectin, and odds of unprovoked venous thromboembolism. AB - INTRODUCTION: Deep vein thrombosis (DVT) originates in the valvular sinuses of large veins in a local milieu characterized by stasis and severe hypoxia. This may induce complement- and coagulation activation, which potentially increases the risk of venous thromboembolism (VTE). The aim of the present study was to investigate whether the activity of the complement pathways, the level of mannose binding lectin (MBL) and tissue-factor (TF) induced thrombin generation were associated with risk of unprovoked VTE. METHODS: A case-control study was performed in patients with unprovoked VTE (n = 24) and age- and sex-matched healthy controls (n = 24). Serum complement pathway activity was measured by the total complement screen assay (Wieslab(r)). MBL was quantified by ELISA. Plasma TF-induced thrombin generation was measured using the CAT-assay. RESULTS: Activity in the highest quintile of the classical pathway was associated with increased odds of unprovoked VTE (OR 4.5, 95% CI; 0.8-24.7). Moreover, MBL deficiency (<=100 ng/ml) was associated with unprovoked VTE (OR 3.5, 95% Cl; 0.8 15.3). VTE patients had shortened TF-induced lag-time (4.8 +/- 0.6 min vs. 5.8 +/ 2.1 min, p < 0.001) and a higher endogenous thrombin potential (ETP) (1383 +/- 267 nM*h vs. 1265 +/- 247 nM*h, p = 0.07) than controls. No association between the classical complement pathway activity or MBL deficiency, and parameters of TF induced thrombin generation was observed. CONCLUSION: Our findings suggest that high activity of the classical complement pathway, and MBL deficiency, might be associated with an increased odds of unprovoked VTE, independent of activation of TF-induced coagulation. PMID- 30015229 TI - Short closure time values in PFA-100(r) are related to venous thrombotic risk. Results from the RETROVE Study. AB - INTRODUCTION: Platelets play a role in the pathophysiology of venous thromboembolism (VTE). Some studies have not found an association between VTE and platelet aggregation. The PFA-100(r) analyser is an in vitro assay for assessing primary haemostasis. But, there are no studies to evaluate its association with VTE. We investigated the contribution of the global platelet function and aggregation in the development of VTE. MATERIAL AND METHODS: We analysed 800 individuals who were included in the RETROVE Study (Riesgo de Enfermedad TROmboembolica VEnosa). Global platelet function was evaluated as closure times (CT) with the agonists ADP and epinephrine using a PFA-100(r) analyser. Platelet aggregation was evaluated by MultiplateTM analyser. The VTE risk for all the parameters was calculated by unconditional logistic regression analyses considering the potential confounders: age, gender, body mass index (BMI), factor VIII (FVIII), the von Willebrand factor (vWF) and the ABO blood group system. RESULTS: The unadjusted odds ratio (OR) values <=10th percentile for the PFAadp and PFAepi were 4.02 (95% CI, 2.76-5.95) and 3.33 (2.27-4.97). Also, after adjusting for vWF, we obtained lower OR for the PFAadp and for PFAepi: 2.24 (1.44 3.49) and 1.63 (1.04-2.59). But, the whole blood aggregation parameters did not shown an association with VTE risk. CONCLUSION: We demonstrated an association between short CT and VTE risk. Although, the whole blood aggregation parameters did not show an association with the VTE risk. This striking contrast suggests that there are other platelet function mechanisms (e.g. adhesion) that are responsible of VTE risk. PMID- 30015230 TI - Murine models of vascular endothelial injury: Techniques and pathophysiology. AB - Vascular endothelial injury (VEI) triggers pathological processes in various cardiovascular diseases, such as coronary heart disease and hypertension. To further elucidate the in vivo pathological mechanisms of VEI, many animal models have been established. For the easiness of genetic manipulation and feeding, murine models become most commonly applied for investigating VEI. Subsequently, countless valuable information concerning pathogenesis has been obtained and therapeutic strategies for VEI have been developed. This review will highlight some typical murine VEI models from the perspectives of pharmacological intervention, surgery and genetic manipulation. The techniques, pathophysiology, advantages, disadvantages and the experimental purpose of each model will also be discussed. PMID- 30015231 TI - Pro-apoptotic activity of ruthenium 1-methylimidazole complex on non-small cell lung cancer. AB - Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1Meim)(dppb)(5,5'-DMbpy)]Cl (3) and [RuCl(1Meim)(dppb)(phen)]Cl (4) where, 1Meim = 1-methylimidazole, dppb = 1,4 Bis(diphenylphosphino)butane, bpy = 2,2'-bipyridine, 4,4'-DMbpy = 4,4'-dimethyl 2,2'-bipyridine, 5,5'-DMbpy = 5,5'-dimethyl-2,2'-bipyridine and phen = 1,10 phenanthroline. Additionally, crystal structures containing the cations of (1) and (3) were obtained when the counter ion was exchanged, leading to the formation of [RuCl(1Meim)(dppb)(bpy)]PF6 (5) and [RuCl(1Meim)(dppb)(5,5' DMbpy)]PF6 methanol solvate (6) where PF6 = hexafluorophosphate, showing one 1 methylimidazole molecule coordinated through the imidazole nitrogen, as expected. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, 1H, 13C{1H} and 31P{1H} NMR, mass spectrometry and cyclic voltammetry. The interactions of complexes 1-4 with DNA and human serum albumin (HSA) were evaluated, and the cytotoxicity profiles of compounds 1 4 were determined using four different tumor cell lines derived from human cancers (melanoma: HT-144, colon: HCT-8, breast: MDA-MB-231 and lung: A549). A higher cytotoxic activity was observed for compound (3) against non-small cell lung cancer (A549). Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation. Therefore, the data obtained in the present study support further investigations concerning molecular targets of complex (3) in non-small cell lung cancer. PMID- 30015232 TI - Nickel-pincer nucleotide cofactor. AB - A novel organometallic cofactor, nickel pyridinium-3,5-dithiocarboxylic acid mononucleotide, was recently discovered in lactate racemase (LarA) of Lactobacillus plantarum. This review summarizes the substantial progress made in uncovering the function of this cofactor as a transient hydride acceptor in the LarA mechanism. The latest developments related to cofactor biosynthesis reveal insights into a pathway in which LarB serves as a nicotinic acid adenine dinucleotide hydrolase/carboxylase, LarE acts as a sacrificial sulfur transferase, and LarC functions as a nickel insertase, forming the nickel-pincer nucleotide cofactor that becomes covalently tethered to LarA in some bacteria. Bioinformatic studies reveal a widespread occurrence of larA, larB, larC, and larE orthologs in microorganisms, and additional roles for the cofactor are considered. PMID- 30015233 TI - Electron transfer and transport through multi-heme proteins: recent progress and future directions. AB - I review recent experimental measurements probing electron transfer (ET) and electron transport (ETp) through multi-heme cytochromes (MHCs) as well as their theoretical interpretation. Examples include pump-probe spectroscopy of Ru labeled MHCs aimed at determining heme-heme ET rates in MHCs and the measurement of the I-V characteristics of MHCs in bioelectronic junctions. While the ET mechanism appears to be well established for MHCs in aqueous solution, the ETp mechanism in bioelectronic junctions such as STM remains elusive partly due to the complexities of the electrode-protein interface. PMID- 30015234 TI - Nature's conductors: what can microbial multi-heme cytochromes teach us about electron transport and biological energy conversion? AB - Microorganisms can acquire energy from the environment by extending their electron transport chains to external solid electron donors or acceptors. This process, known as extracellular electron transfer (EET), is now being heavily pursued for wiring microbes to electrodes in bioelectrochemical renewable energy technologies. Recent studies highlight the crucial role of multi-heme cytochromes in facilitating biotic-abiotic EET both for cellular electron export and uptake. Here we explore progress in understanding the range and function of these biological electron conduits in the context of fuel-to-electricity and electricity-to-bioproduct conversion. We also highlight emerging topics, including the role of multi-heme cytochromes in inter-species electron transfer and in inspiring the design and synthesis of a new generation of protein-based bioelectronic components. PMID- 30015235 TI - Switched memory B cells promote alveolar bone damage during periodontitis: An adoptive transfer experiment. AB - Periodontitis is a bacteria-induced disease that often leads to alveolar bone damage. We sought to determine the role and mechanism of switched memory B cells in alveolar bone destruction during periodontitis. Sensitized B cells were sorted and cultured, then their expression of receptor activator for nuclear factor kappaB ligand (RANKL), interleukin-6 (IL-6), and interleukin-12 (IL-12) was detected. Using these cells, we prepared adoptive transfer models in which we induced periodontitis. We found that switched memory B cells produced more RANKL in terms of both protein and mRNA levels than other subpopulations. Switched memory B cells expressed more IL-6 and IL-12 mRNA than other subpopulations, but differences in respective protein levels were not significant. Moreover, we found that switched memory B cell transfer resulted in increased alveolar bone loss and periodontal osteoclastogenesis. Moreover, switched memory B cell transfer increased the proportion of Th1 and Th17 cells as well as the expression of RANKL, osteoprotegerin (OPG), tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), IL-1beta, IL-6, IL-17A in gingiva, and cervical lymph nodes (CLNs). The outcomes of the present study indicate that switched memory B cells regulate alveolar bone homeostasis via enhancing cytokine expression and increasing proliferation of Th1 and Th17 cells. PMID- 30015236 TI - Effect of butylated hydroxyl toluene on the immune response of Rift Valley fever vaccine in a murine model. AB - The present study was planned to examine the effect of butylated hydroxy toluene (BHT) on the immune response of Rift Valley fever vaccine (RVFV) in Swiss mice. Animals were divided into four equal groups. The first group was kept as negative control. The 2nd group was orally administrated with the acceptable daily intake (ADI) of BHT 0.3 mg/kg b.wt. daily for 21 days and the 3rd group were vaccinated only by inactivated RVFV at a dose of 0.2 ml I/P two times. The 4th group was orally administrated BHT as in the 2nd group and vaccinated by inactivated RVFV as in the 4th group. Blood samples were collected from all groups two weeks from booster vaccination. The cellular immunity was determined by leucocytic indices and the neutrophil-lymphocyte ratio (NLR) whereas, humoral immunity was evaluated with IgG antibodies titer using enzyme-linked immune-sorbent assay (ELISA) test, serum neutralization test (SNT) and challenge test. BHT induced leucopenia, neutrophilia and marked lymphocytopenia in both non-vaccinated and vaccinated mice. Moreover, BHT significantly decreased the efficiency of vaccination by inducing 70% cytopathic effect (CPE) in the infected cell cultures and increasing the ED50 value of RVFV vaccine. The present study indicates that BHT possesses a potential for decreasing both cellular and humoral mediated mechanisms. PMID- 30015237 TI - Comparison of six cell penetrating peptides with different properties for in vitro and in vivo delivery of HPV16 E7 antigen in therapeutic vaccines. AB - The high risk human papillomavirus (HPV) types 16 and 18 are globally linked to >50% and 20% of all cervical cancers, respectively. The HPV E7 oncoprotein was determined as a therapeutic vaccine target due to its constitutive expression by HPV-infected cells. The findings demonstrated the efficiency of therapeutic HPV DNA- and protein-based vaccines in preclinical and clinical trials. However, there are limitations for penetration of DNA and protein constructs into the cells without a suitable delivery system. Recently, several cell penetrating peptides (CPPs) have been suggested for delivery of nucleic acids and proteins into cells through covalent or non-covalent fashion. In this study, we determined highly efficient CPPs for the controlled delivery of HPV16 E7 antigen, in vitro and in vivo. Our data indicated the effective delivery of E7 protein by Pep-1, Cady-2, P28 and hPP10, and E7 DNA by MPG and +36 GFP CPPs in HEK-293T cell line at certain ratios. Moreover, immunization with the heterologous MPG + E7 DNA prime/P28 + rE7 protein boost elicited a higher Th1 cellular immune response with a predominant IFN-gamma profile and strong Granzyme B secretion than those induced by other groups in a murine tumor model. Indeed, the groups vaccinated with rE7+ P28/rE7+ P28, MPG+ E7 DNA/P28+ rE7, and E7 DNA+ MPG/E7 DNA+ MPG nanovaccines displayed complete protection and remained tumor-free >60 days after treatment. These data suggest P28 and MPG as promising protein and gene delivery systems for development of HPV therapeutic vaccines. PMID- 30015238 TI - Sauchinone inhibits IL-1beta induced catabolism and hypertrophy in mouse chondrocytes to attenuate osteoarthritis via Nrf2/HO-1 and NF-kappaB pathways. AB - BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease for which currently no anti-inflammatory therapy is available. Sauchinone (SAU), a key bioactive compound derived from Saururus chinensis, which has shown remarkable anti-inflammatory effects. METHODS: To evaluate the effect of SAU on OA progression, mouse chondrocytes were pretreated with SAU and subsequently stimulated with interleukin (IL)-1beta. We found that SAU reduced the production of pro-inflammatory cytokines, such as nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), and IL-6. SAU also inhibited the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) at both the gene and protein level. Moreover, SAU promoted the expression of aggrecan, while inhibiting the expression of catabolic factors, such as matrix metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS-5) in mouse chondrocytes. Col X, vascular endothelial growth factor-A (VEGF)-A, and Runx2, major markers of hypertrophic chondrocytes, were markedly elevated following IL 1beta stimulation, and were reduced by SAU treatment while having the opposite effect on Col II. Mechanistically, we found that SAU inhibited nuclear factor kappa B (NF-kappaB) and activated the Nrf2/HO-1 pathway. The beneficial effects of SAU were also observed in vivo using a mouse OA model. CONCLUSIONS: Our findings indicate that SAU may be a potential novel therapeutic for the treatment of OA. PMID- 30015239 TI - Andrographolide ameliorates silica induced pulmonary fibrosis. AB - The purpose of this study was to investigate the protective effect of andrographolide in silica-induced pulmonary fibrosis (PF) in mice and its underlying mechanisms. Male Swiss albino mice were divided into five groups: Normal control group, disease control group (1.5 mg silica/60 MUL/mice) via oropharyngeal route, low dose (LD) group received silica + andrographolide (3 mg/kg), high dose (HD) group received silica + andrographolide (10 mg/kg), andrographolide per se group received 10 mg/kg andrographolide. Various bronchoalveolar lavage fluid (BALF) and biochemical parameters, inflammatory cytokines, histology and protein expression studies were carried out. Andrographolide significantly reduced total protein concentration, albumin, accumulation of inflammatory cells and lactate dehydrogenase (LDH) level in BALF. We found that andrographolide intervention led to decreased levels of the inflammatory cells including neutrophils, macrophages and lymphocytes in the BALF of the treated animals. In addition, andrographolide significantly reduced nitrite (p < 0.01 at HD), malondialdehyde (p < 0.01 at HD) and upregulated glutathione (p < 0.01 at HD) in silica challenged animals. Andrographolide showed anti-fibrotic activity by reducing collagen deposition and inflammation in lung. Histopathology revealed that andrographolide decreased irregular cellular nodules, inflammatory infiltration and fibrosis. Andrographolide intervention significantly reduced the expression of N-cadherin, alpha-SMA and vimentin (mesenchymal markers) and upregulated the expression of E-cadherin (an epithelial marker). Hence, andrographolide elicits its anti-pulmonary fibrotic effect by halting the progression of epithelial-to-mesenchymal transition (EMT) via affecting fibroblasts. We, to the best of our knowledge prove for the first time that andrographolide possesses potent antifibrotic activity by targeting inflammatory cells and EMT associated fibroblasts. PMID- 30015240 TI - ZIP8 induces monocyte adhesion to the aortas ex-vivo by regulating zinc influx. AB - Monocytes recruited and adhering to the inflamed arteries are crucial for atherosclerosis development. Here, we report the role of zinc (Zn2+) homeostasis in monocyte adhesion and recruitment. By comparing the expression levels of Zn2+ transporters between non-adhering and adhering monocytes, we found that the Zn2+ importer ZIP8 was specifically upregulated in monocytes adhering to the aortas ex vivo. Although the overexpression of ZIP8 increased the absorption of Zn2+, Fe2+ and Cd2+ in monocytes, only Zn2+ supplementation was demonstrated capable of promoting the adhesion of monocytes to endothelial monolayers in vitro. In addition, we confirmed the role of ZIP8-dependent Zn2+ influx in promoting monocyte adhesion to the aortas ex-vivo. More importantly, the enforced expression of ZIP8 increased monocyte adhesion and recruitment to the nascent atherosclerotic lesions in ApoE-/- mice. Overall, our results suggest that the Zn2+ influx in monocytes regulated by ZIP8 is a novel factor determining their adhesion and recruitment to atherosclerotic lesions, and that targeting ZIP8 or Zn2+ homeostasis may represent a novel strategy to interfere these activities. PMID- 30015241 TI - Epigallocatechin-3-gallate protects against the exacerbation of allergic eosinophilic inflammation associated with obesity in mice. AB - Obesity is linked to worse asthma symptoms. Epigallocatechin-3-gallate (EGCG) reduces airway inflammation, but no study investigated the effects of EGCG on obesity-associated asthma. We aimed here to evaluate the effects of EGCG on allergen-induced airway inflammation in high-fat diet-fed mice. Male C57Bl/6 mice maintained on either standard-chow or high-fat diet for 12 weeks were treated or not with EGCG (10 mg/kg/day, gavage, two weeks). Animals were intranasally challenged with ovalbumin (OVA). In lung tissue and bronchoalveolar lavage fluid (BALF), cell counting and markers of inflammation and oxidative stress were evaluated. High-fat diet-fed mice exhibited significantly higher body weight and epididymal fat mass compared with lean group. EGCG treatment reduced by 20% the epididymal fat mass in obese mice (P < 0.05). The OVA-induced increases of total cells and eosinophils in lung tissue of obese mice were significantly reduced EGCG treatment. The increased levels of TNF-alpha, IL-4, IL-5 and eotaxin in BALF of obese mice were normalized by EGCG. Likewise, the enhanced expression of inducible nitric oxide synthase (iNOS) and nitric oxide metabolite (NOx) levels in obese mice were normalized by EGCG. Reactive-oxygen species (ROS) and superoxide dismutase (SOD) levels were elevated and reduced, respectively, in lung tissue of obese mice, both of which were restored by EGCG. In lean mice, EGCG had no significant effect in evaluated parameter (body measures, and inflammatory and oxidative markers). EGCG turns to normal the levels of inflammatory and oxidative stress markers in lungs of obese mice, suggesting it could be an option to attenuate obesity-related asthma. PMID- 30015242 TI - When robots care: Public deliberations on how technology and humans may support independent living for older adults. AB - While assistive robots receive growing attention as a potential solution to support older adults to live independently, several scholars question the underlying social, ethical and health policy assumptions. One perplexing issue is determining whether assistive robots should be introduced to supplement caregivers or substitute them. Current state of knowledge indicates that users and caregivers consider that robots should not aim to replace humans, but could perform certain tasks. This begs the question of the nature and scope of the tasks that can be delegated to robots and of those that should remain under human responsibility. Considering that such tasks entail a range of actions that affect the meaning of caregiving and care receiving, this article offers sociological insights into the ways in which members of the public reason around assistive actions, be they performed by humans, machines or both. Drawing on a prospective public deliberation study that took place in Quebec (Canada) in 2014 with participants (n = 63) of different age groups, our findings clarify how they envisage what robots can and cannot do to assist older people, and when and why delegating certain tasks to robots becomes problematic. A better understanding of where the publics draw a limit in the substitution of humans by robots refocuses policymakers' attention on what good care entails in modern healthcare systems. PMID- 30015243 TI - Financial protection of households against health shocks in Greece during the economic crisis. AB - BACKGROUND: Harsh funding cutbacks along with measures shifting cost to patients have been implemented in the Greek health system in recent years. Our objective was to investigate the evolution of financial protection of Greek households against out-of-pocket payments (OOPP) during the economic crisis. METHODS: National representative data of 33,091 households were derived from the Household Budget Surveys for the period 2008-2015. Financial protection was assessed by applying the approaches of catastrophic (CHE) and impoverishing OOPP. The determinants of CHE and impoverishment were examined using binary logistic regressions. RESULTS: OOPP dropped by 23.5% in real values between 2008 and 2015, though their share in households' budget rose from 6.9% to 7.8%, with an increasing trend since 2012. These outcomes were driven by significant increases in medical products (20.2%) and inpatient (63%) OOPP, while outpatient expenses decreased considerably (-62%). Both incidence and overshoot of CHE were significantly exacerbated. The additional burden was distributed progressively, hence, financial risk inequalities decreased. Food poverty increased, but its incidence still remains at very low levels. Both incidence and intensity of relative poverty increased considerably in real terms. The poverty impact of OOPP is aggravating following 2012, and 1.9% of individuals were impoverished due to OOPP in 2015. Households of higher size, lower expenditure quintile, in urban areas, without disabled, elderly or young children members, and with younger or retired, better-educated breadwinners were significantly less vulnerable to CHE. Households in the lower-middle expenditure quintile, in rural regions, and with elderly members were facing higher risk, while wealthier families exhibited a considerable lower likelihood of impoverishment. CONCLUSIONS: The expansion of reliance of healthcare funding on OOPP has increased the financial risk and hardship of Greek households, which may disrupt their living conditions and create barriers to healthcare access. Cost-sharing policies should recognise the different social protection needs of households. PMID- 30015244 TI - Quantifying life: Understanding the history of Quality-Adjusted Life-Years (QALYs). AB - Quality-Adjusted Life-Years (QALYs) are central to healthcare decision-making in Britain and abroad, yet their history is poorly understood. In this paper, we argue that a more in-depth and political history of the QALY is needed to allow a critical evaluation of its current dominance. Exploiting rich data from archives and 44 semi-structured interviews conducted between 2015 and 2018, we employ Multiple Streams Analysis to construct a complex and dynamic picture of how the idea of QALYs emerged and was adopted within UK health policy. Through its historical and political approach, the paper illuminates the relative roles in the policy-making process of experts (especially economists) and politicians as 'entrepreneurs' in the development of new ideas; how these were influenced by negotiation within established and emerging institutional structures; and the role of serendipity and crisis. PMID- 30015245 TI - Neuronal calcium signaling via store-operated channels in health and disease. AB - Store-operated calcium entry (SOCE) is the flow of calcium ions (Ca2+) into cells in response to the depletion of intracellular Ca2+ stores that reside predominantly in the endoplasmic reticulum (ER). The role of SOCE has been relatively well understood for non-excitable cells. It is mediated mostly by the ER Ca2+ sensor STIM1 and plasma membrane Ca2+ channel Orai1 and serves to sustain Ca2+ signaling and refill ER Ca2+ stores. In contrast, because of the complexity of Ca2+ influx mechanisms that are present in excitable cells, our knowledge about the function of neuronal SOCE (nSOCE) is still nascent. This review summarizes the available data on the molecular components of nSOCE and their relevance to neuronal signaling. We also present evidence of disturbances of nSOCE in neurodegenerative diseases (namely Alzheimer's disease, Huntington's disease, and Parkinson's disease) and traumatic brain injury. The emerging important role of nSOCE in neuronal physiology and pathology makes it a possible clinical target. PMID- 30015246 TI - Dysfunction of SERCA pumps as novel mechanism of methylglyoxal cytotoxicity. AB - A novel pathway of methylglyoxal (MGX)-induced apoptosis via sarcoplasmic reticulum Ca2+-ATPase (SERCA) is presented. Interaction of SERCA1 with MGX was investigated by molecular docking and experimentally in a cell-free system. MGX concentration- and time-dependently decreased SERCA1 activity. A significant increase of sarcoplasmic reticulum (SR) carbonylation was found in the concentration range of 1-10 mM caused by MGX and a decrease of thiol groups at the concentrations of 5 and 40 mM. Affinities of SERCA1 to ATP and Ca2+ were not influenced by MGX, however decreases of Vmax related to both binding sites were observed. Molecular docking indicated binding of MGX at the cytosolic region of SERCA1, inducing conformational changes in the cytosolic-transmembrane interface. This interaction resulted in conformational changes in the cytosolic region (FITC fluorescence decrease) as well as in the transmembrane region of SERCA1 (Trp fluorescence decrease) without direct binding to the cytosolic ATP or transmembrane Ca2+ binding sites. Regarding the MGX inhibitory effect in a cell free system and similarities of SERCA1 to its other isoforms, proapoptotic properties of MGX may be expected in cellular systems. At cellular level, MGX induced a decrease of SERCA2b expression in the pancreatic INS-1E beta-cell line. This was accompanied by cell viability decrease, increase in apoptosis, impaired insulin secretion and elevation of basal intracellular Ca2+ levels. Decreased expression of SERCA2b may contribute to induction of apoptosis of pancreatic beta cells. PMID- 30015247 TI - Characterization and potential roles of calretinin in rodent spermatozoa. AB - Calretinin has been detected in various excitable cells but the presence and putative roles of such a calcium-binding protein has never been characterized in sperm. Epididymal spermatozoa were collected from C57Bl6 (wild-type, WT) or calretinin knockout (CR-/-) mice and Wistar rats. A specific staining for calretinin was detected by immunofluorescence in the principal piece of the flagellum, both in WT mouse and rat spermatozoa. Western blots confirmed the expression of calretinin in rat and WT spermatozoa as well as its absence in CR-/ mice. No significant difference was observed in the spontaneous acrosome reaction between WT and CR-/- sperm. The addition of the calcium-ionophore A 23187, Thapsigargin or Progesterone to WT or CR-/- incubated spermatozoa induced increases in the acrosome reaction but the stimulatory effects were identical in both genotypes. Motility measurements assessed by computer-assisted sperm analysis indicated that, under basal non-stimulatory conditions, CR-/- sperm exhibited a lower curvilinear velocity and a smaller lateral head movement amplitude, although no difference was observed for the beat cross frequency. After incubation with 25 mM NH4Cl, the curvilinear velocity, the amplitude of the lateral head movement and the hyperactivation were increased, while the beat cross frequency was decreased, in both genotypes. Evaluation of the in vivo fertility potential indicated that the CR-/- litter sizes were clearly reduced compared to the WT litter sizes. Our study describes, for the first time, the expression of calretinin in sperm. These data extend the potential implication of calcium-binding proteins in the sperm calcium-signaling cascade and bring new insights into the understanding of sperm physiology. PMID- 30015248 TI - Over and under-regulation in the Colorado Cannabis industry - A data-analytic perspective. AB - With the State of California legalizing recreational cannabis sales on January 1, 2018, the regulatory process is once more in the forefront of cannabis research. Colorado, often held up as a model of legalization policy, was the first state to implement retail sale of recreational cannabis on January 1st, 2014. However, a combination of subsequent under-regulation and over-regulation, inconsistently applied across issues such as retail licencing, chemical testing, cannabis derivatives, municipality approval for growers, and financing, have not only held back the industry in Colorado but also negatively impacted public health, oversight, and have potentially increased the availability of illegal cannabis. We argue that a data-analytic approach to the industry is potentially the most effective way to resolve these concerns, since in the absence of consistent and reliable data, policymakers are apt to satisfy individual policy concerns without considering the industry as a whole. In this paper we present a data-analytic framework for the cannabis industry, offering a theoretically-driven justification for our approach, and describe implications for research on drug and information policy. The framework may serve as a model for other states or countries contemplating cannabis legalisation. As four new states legalised recreational cannabis in 2016, the implications of this research for policymakers has dramatically increased. PMID- 30015249 TI - Microalgae hydrothermal liquefaction and derived biocrude upgrading with modified SBA-15 catalysts. AB - In this study, a novel route was proposed for microalgae biofuel production by catalytic upgrading of Chlorella hydrothermal liquefaction (HTL) derived biocrude. Al-SBA-15, CuO/Al-SBA-15, ZuO/Al-SBA-15, and CuO-ZnO/Al-SBA-15 catalysts were synthesized in a facile, one-pot way, and tested for methyl palmitate decarboxylation and biocrude upgrading without H2 addition. These modified SBA-15 catalysts enhanced alkane selectivity of methyl palmitate decarboxylation from 7.6 wt% up to 79.6 wt% at 340-350 degrees C. FT-IR, TG and GC-MS characterizations were employed to identify the composition and properties of the upgraded bio-oils. Compared with thermal upgrading, modified SBA-15 catalysts enriched the yield of low boiling point compounds, and the content of heavy bio-oil (>400 degrees C) declined from 9.57 wt% to 1.89 wt%. Hydrocarbon yield was greatly enriched on the catalysts, and aromatics predominant on Al-SBA 15 while aliphatics abundant on metal oxide(s) supported catalysts. The hydrocarbon yield was increased from 25.1 wt% (thermal) to 65.7 wt% on the CuO/Al SBA-15. PMID- 30015250 TI - Effect on blood pressure and eye health symptoms in a climate-financed randomized cookstove intervention study in rural India. AB - BACKGROUND: Air pollution from cooking with solid fuels is a potentially modifiable risk factor for increased blood pressure and may lead to eye irritation. OBJECTIVES: To evaluate whether a climate motivated cookstove intervention reduced blood pressure and eye irritation symptoms in Indian women. METHODS: Households using traditional stoves were randomized to receive a rocket stove or continue using traditional stoves. Systolic (SBP) and diastolic blood pressure (DBP), and self-reported eye symptoms were measured twice, pre intervention and at least 124 days post-intervention in women > 25 years old in control (N = 111) and intervention (N = 111) groups in rural Karnataka, India. Daily (24-h) fine particle (PM2.5) mass and absorbance (Abs) were measured in cooking areas at each visit. Mixed-effect models were used to estimate before-and after differences in SBP, DBP and eye symptoms. RESULTS: We observed a lower SBP (-2.0 (-4.5, 0.5) mmHg) and DBP (-1.1 (-2.9, 0.6) mmHg) among exclusive users of intervention stove, although confidence intervals included zero. Stacking or mixed use of intervention and traditional stoves contributed to a small increase in SBP 2.6 (-0.4, 5.7) mmHg) and DBP (1.2 (-0.9, 3.3) mmHg). Exclusive and mixed stove users experienced higher post-intervention reductions, on average, in self reported eye irritation symptoms for burning sensation in eyes, and eyes look red often compared to control. Median air pollutant concentrations increased post intervention in all stove groups, with the lowest median PM2.5 increase in the exclusive intervention stove group. CONCLUSIONS: Health benefits were limited due to stacking and lower-than-predicted efficiency of the intervention stove in the field. Stove adoption and use behavior, in addition to stove technology, affects achievement of health co-benefits. Carbon-financing schemes need to align with international guidelines that have been set based on health outcomes to maximize health co-benefits from cookstove interventions. PMID- 30015251 TI - The inhalation effects of by-products from chlorination of heated indoor swimming pools on spinal development in pup mice. AB - INTRODUCTION: It has been postulated that swimming in heated indoor swimming pools in the first year of life is associated with the development of spinal deformity in children. We explored in pup mice whether exposure to certain disinfection by-products resulting from chlorination of heated pools would affect the future development of the spinal column. METHODS: Mice, from birth and for 28 consecutive days, were exposed to chemicals known to be created by disinfection by-products of indoor heated swimming pools. The study made use of a body fluid analogue and a chlorine source to recreate the conditions found in municipal pools. A cohort of 51 wild-type C57B6 mice, male and female, were divided into two groups: experimental (n = 29) and controls (n = 22). 24 mice were observed for 8 months (32 weeks), with 27 culled at 4 months (16 weeks). Serial CT scanning was used to assess the spines. RESULTS: Exposure to disinfection by products resulted in an increase in the normal thoracic kyphotic spinal angle of the mice when compared with their controls at 10 weeks; experimental mice kyphosis range 35-82 degrees versus 29-38 degrees in controls. At 14 weeks the kyphosis of the experimental mice had reduced in size but never to that of the control group. CONCLUSION: We have demonstrated the ability to influence spinal development in pup mice through environmental factors and shown that the developmental deformity became evident only after a significant latent period. PMID- 30015252 TI - Diagnostic value of multiphase postmortem computed tomography angiography in selected cases of blunt traumatic deaths. AB - OBJECTIVES: Recently, multiphase postmortem computed tomography angiography (MPMCTA) has been proven as a reliable tool in the diagnosis of vascular pathology, while its potential efficiency in the detection of soft tissue lesions is ignored. In this study, we have evaluated the overall diagnostic value of MPMCTA in the diagnosis of blunt traumatic deaths in selected cases to determine its additional advantages and limitations in order to identify its potential applications. METHODS: This prospective study examined 14 decedents presented to the Department of Legal Medicine of Hamburg University that alleged death due to blunt trauma. For each case, MPMCTA and conventional autopsy findings were compared. Both radiological and autopsy findings are divided according to the body regions in addition to the detection of the cause of death. RESULTS: Both MPMCTA and the conventional autopsy showed the major findings but not all findings. MPMCTA was better in the demonstration of vascular and skeletal lesions, while the diagnosis of parenchymal injury remains autopsy-dependent. The efficiency of MPMCTA for detection of haemorrhage was relatively affected by the blood amount and the location of the bleeding source. The presented MPMCTA related artefacts interfered with the accurate diagnosis of certain injuries. CONCLUSION: The combination of MPMCTA with conventional autopsy appears to be the gold standard for investigation of blunt traumatic deaths. Depending on the death circumstances and the expected findings, MPMCTA can be performed alone in selected cases. PMID- 30015254 TI - Links between infant sleep and parental tolerance for infant crying: longitudinal assessment from pregnancy through six months postpartum. AB - BACKGROUND: Low parental tolerance for crying has been associated with infant sleep problems, yet the directionality of this link remained unclear. This longitudinal study aimed to assess the synchronous and prospective bidirectional links between parental cry-tolerance, soothing, and infant sleep from pregnancy through six months postpartum. METHODS: Sixty-five couples were recruited during pregnancy and assessed for cry-tolerance using a paradigm in which participants were shown a videotape of a crying infant and were asked to stop the video when they feel it is necessary to intervene. Infant sleep was assessed objectively using actigraphy for five nights at three and six months postpartum. Parental soothing techniques were reported by parents at both assessment points, and cry tolerance was reassessed at six months. RESULTS: Concomitant associations were found between maternal cry-tolerance and infant sleep at six months, indicating that lower maternal cry-tolerance was correlated with poorer actigraphic sleep quality. Furthermore, Structural Equation Modeling analyses yielded significant prospective associations, showing that lower cry-tolerance at pregnancy predicted better infant sleep at three months, whereas more disrupted sleep at three months predicted lower cry-tolerance at six months. Moreover, fathers showed higher cry tolerance compared to mothers, and parents became more similar to each other across time in their reactivity to infant crying. CONCLUSION: Consistent with the transactional model of infant sleep, the findings of this study highlight the role of parental cry-tolerance in infant sleep development, and demonstrate bidirectional links between this construct and infant sleep throughout the first six months of life. PMID- 30015253 TI - Structural insight into the optimization of ethyl 5-hydroxybenzo[g]indol-3 carboxylates and their bioisosteric analogues as 5-LO/m-PGES-1 dual inhibitors able to suppress inflammation. AB - The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3 carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3 carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway. PMID- 30015255 TI - Characterization of upper airway obstruction using cine MRI in children with residual obstructive sleep apnea after adenotonsillectomy. AB - OBJECTIVES/BACKGROUND: Tonsillectomy and adenoidectomy (T&A) lead to resolution of obstructive sleep apnea (OSA) in most children. However, OSA persists in about 25-40% of children. Cinematic magnetic resonance imaging (cine MRI) can aid the management of persistent OSA by localizing airway obstruction. We describe our experience in implementing and optimizing a cine MRI protocol by using a 3 Tesla MRI scanner, and the use of dexmedetomidine for sedation to improve reproducibility, safety, and diagnostic accuracy. PATIENTS/METHODS: Patients aged 3-18 years who underwent cine MRI for the evaluation of persistent OSA after T&A and failed positive airway pressure (PAP) therapy were included. Clinical data and the apnea-hyponea index were compared with quantitative and qualitative estimates of airway obstruction from imaging sequences. RESULTS: A total of 36 children were included with a mean age of 9.6 +/- 4.6 (SD) years with 40% over 12 years of age. Two-thirds of them were boys. Seventeen out of 36 children (47%) had Down syndrome. Single site and multilevel obstruction were identified in 21 of 36 patients (58%) and in 12 of 36 patients (33%), respectively. All cine MRIs were performed without complications. Multiple regression analysis demonstrated that a combination of the minimum airway diameter and body mass index z-score best predicted OSA severity (P = 0.002). CONCLUSIONS: Cine MRI is a sensitive, safe, and noninvasive modality for visualizing upper airway obstruction in children with persistent OSA after T&A. Accurate identification of obstruction can assist in surgical planning in children who fail PAP therapy. PMID- 30015256 TI - Dietary inflammatory index and cardiometabolic risk in US adults. AB - BACKGROUND AND AIMS: We investigated the association between Dietary Inflammatory Index (DII(r)) scores and cardio-metabolic risk factors singly and in combination as metabolic syndrome (MetS). METHODS: We used data from participants selected from the US National Health and Nutrition Examination Survey (NHANES). Analyses were restricted to participants with data available on dietary intake, biochemical data, and anthropometric measurements from 2005 to 2012. Statistical analyses used the SPSS(r) Complex Samples v22.0 (IBM Corp, Armonk, NY) and accounted for the survey design and sample weights. Energy-adjusted-DII (E DII(r)) expressed per 1000 kcal was calculated from 24-h dietary recalls. Of the 17,689 participants with evaluable data, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample, with men being slightly younger than women (44.9 vs. 46.5 years, p = 0.05). RESULTS: In multivariable-adjusted regression models, the odds of MetS, its components, as well as obesity, and elevated high sensitivity C-reactive protein (hsCRP) increased across increasing quartiles of E DII (p < 0.001). In age, sex, race, income-to-poverty ratio-adjusted models, these and other cardiovascular disease risk factors (triglycerides/high density lipoprotein cholesterol (HDL-C) ratio, apolipoprotein (B) and HbA1C) increased across quartiles of the E-DII (all p < 0.001), while HDL-C levels decreased (p < 0.001). CONCLUSIONS: This study suggests associations between MetS, its components, subclinical inflammation, and the DII. These results reinforce the view that diet plays an important role in the occurrence of cardiovascular diseases. PMID- 30015257 TI - Local control in young women with early-stage breast cancer treated with hypofractionated whole breast irradiation. AB - OBJECTIVE: To compare local control (LC) in young women with early-stage breast cancer (BC) treated with hypofractionated (HF) whole breast irradiation (WBI) vs conventional fractionation (CF) following breast-conserving surgery (BCS). MATERIALS AND METHODS: Women <50 years with pT1-2N0 BC following BCS treated with WBI, CF (50Gy/25 fractions) or HF (42.4Gy/16 fractions) followed by a tumor bed boost (10-16Gy/5-8 fractions) from 2009 to 2013 were identified from an institutional database. Median follow-up was 5.2 years (range 0.3-8.4). Kaplan Meier analysis was used to estimate 5-year LC. Logistic regression identified factors associated with receipt of CF vs HF WBI. RESULTS: Of 270 eligible women, 227 (84%) were treated with HF and 43 (16%) with CF WBI. A tumor bed boost of 10 Gy/5 fractions was given in 97% of patients, 53% received adjuvant chemotherapy and 94% (225/239) with estrogen-positive disease received endocrine therapy. Median age was 45 years (range 30-49) in HF and 40 years (range 19-49) in the CF group. The 5-year LC rate was 99.3% (95% CI 97.9-100%, p = 0.495) in the HF and 97.5% (95% CI 92.8-100%) in the CF group. On univariate analysis, age <= 40 years or triple negative BC was associated with a decreased likelihood of receiving HF WBI. Only age remained significant on multivariate analysis [OR 2.82 (95% CI 1.45 5.48, p = 0.002)]. CONCLUSIONS: HF WBI was associated with excellent LC rates in this study cohort, comparable to CF WBI. However, CF WBI was more likely to be recommended to women <40 years. PMID- 30015258 TI - Synthesis and characterization of a flexible fluorescent magnetic Fe3O4@SiO2/CdTe NH2 nanoprobe. AB - In this study, we designed and synthesized two novel fluorescent magnetic nanoparticles. Fe3O4@SiO2-NH-GSH-CdTe (FSGC) (GSH = glutathione) nanoparticles were synthesized using amino-functionalized Fe3O4@SiO2 nanoparticles and GSH stabilized CdTe quantum dots (CdTe QDs), while flexible Fe3O4@SiO2-NH-GSH-CdTe-NH NH2 (FSGCN) nanoparticles were synthesized using the FSGC precursor and 1,6 hexamethylenediamine. These two kinds of nanoprobes exhibited excellent magnetic and fluorescent properties. By comparing the fluorescence quenching effect of folic acid (FA) on FSGC and FSGCN, we found that the quenching effect of FA on FSGC was acute and the process was too fast to determine the FA content. However, the quenching effect of FA on flexible FSGCN was mild and hence it could be used as a nanoprobe to determine FA concentration. At physiological pH, the fluorescence quenching effect of FA on the FSGCN nanoprobes was fitted according to the Stern-Volmer equation with a linear response in the concentration range of 0.14 to 4.20 MUg mL-1 with a detection limit of 15.1 * 10-9 g mL-1 (S/N = 3) under optimized experimental conditions. The proposed flexible nanoprobe was successfully used to determine the content of FA in folic acid tablets. Recovery was found to be in the range of 92.7%-105.6% with a relative standard deviation of 1.12%-3.84%. Owing to their good stability, environment-friendly characteristics, high selectivity, and good optical properties and biocompatibility, these nanoprobes have potential for usage in practical applications. PMID- 30015259 TI - Kinetic and metabolic behaviour of the pectinolytic strain Aureobasidium pullulans GM-R-22 during pre-fermentative cold maceration and its effect on red wine quality. AB - Pectinolytic yeasts can be applied to winemaking with the purpose of improving sensory and technological properties of wine because of their enzymes secreted during vinification. In this work, the autochthonous yeast-like pectinolytic strain from D.O. San Rafael viticulture region, Aureobasidium pullulans GM-R-22, was used in co-culture with Saccharomyces cerevisiae IOC 18-2007 in microvinification trials with Malbec must applying pre-fermentative cold maceration (PCM). A. pullulans remained viable during PCM and S. cerevisiae growth and fermentative kinetics were not affected in mixed culture with respect to pure S. cerevisiae culture. High pectinolytic activity (9.13 U/mg) was detected in mixed A. pullulans vinification during PCM, in which conditions of low temperature (8 degrees C), low pH (3.8) and high sugar concentration (250.6 g/L) governed. Mixed A. pullulans wine showed enhanced colour compared with pure S. cerevisiae wine, characterised by higher colour index and percentage of red colour, lower tonality and percentage of yellow colour, and negative values of b* and h* indicating more bluish and purplish tonalities. Moreover, filtration time and turbidity diminished by a 40% in mixed A. pullulans wine. The presence of GM R-22 strain improved the production of desirable volatile compounds, such as esters and norisoprenoids, which displayed the maximum odour activity values (OAVs), whereas this strain reduced the total content of higher alcohols when compared to pure S. cerevisiae fermentation. Sensory analysis indicated that A. pullulans impacted on wine highlighting the violet hue, plum jam aroma, body and equilibrium that are distinctive features of Malbec variety. A. pullulans GM-R-22 seems to be promising for applying to low-temperature red winemaking as an adjunct culture to S. cerevisiae to improve the wine quality and vinification process. PMID- 30015260 TI - Inactivation of stress-resistant ascospores of Eurotiales by industrial sanitizers. AB - Different fungi, including the genera Aspergillus (Neosartorya), Paecilomyces (Byssochlamys) and Talaromyces, produce (asco)spores that survive pasteurization treatments and are regarded as the most stress-resistant eukaryotic cells. The sensitivity of the ascospores to treatments with industrial sanitizers containing chlorine dioxide and iodine (iodophors) has never been assessed before. Ascospores of 4 species of Eurotiales were tested and showed clear variations in sensitivity. The most resilient species, T. macrosporus and Pae. variotii (=B. spectabilis) survive 75, but not 200 ppm chlorine dioxide solution treatments. These species were able to survive 75 ppm iodine solution treatments, but relatively low amounts of ascospores (100-1000 spores) could be inactivated after 16 h of treatment. Inactivated spores did not show any sign of germination after 7 days following treatment on growth medium. As judged by microscopy, iodine inactivation resulted in visibly distorted ascospores. For the interpretation of results, the state of dormancy or activation of ascospores is highly important. PMID- 30015261 TI - Discrimination of non-typhoid Salmonella serogroups and serotypes by Fourier Transform Infrared Spectroscopy: A comprehensive analysis. AB - Simpler, quick and low-cost methods for routine Salmonella enterica typing are required for epidemiologic surveillance of this important zoonotic pathogen. In this study, using a comprehensive isolate collection, we investigated the potential of Fourier transform infrared spectroscopy (FTIRS) to discriminate the most clinically-relevant serogroups and serotypes of non-typhoid Salmonella. Moreover, the role of O-units composition on the FTIRS Salmonella discrimination was also explored. S. enterica isolates (n = 325; 2002-2015; different sources and countries), of 57 serotypes and 15 serogroups [including the most frequent ones, B-n = 122; C-n = 108; D-n = 43 and E-n = 33)] were analysed by FTIRS. Infrared spectra were analysed by Partial Least Square Discriminant Analysis (PLSDA) and/or Principal Component Analysis (PCA). The polysaccharides region provided the spectral sharpest differences being used in the subsequent Salmonella typing. Serogroups (B, C, D and E) discrimination was achieved with high accuracy (99.6% of correct assignments; PLSDA model). Differences in the O unit structures composition of those serogroups are likely justifying the discrimination achieved. Other serogroups (G, H, K, L, M, N, O, T, U, Y, Z) were correctly predicted as not belonging to serogroups B, C, D nor E, except for 3 isolates of serogroups H (S. Sundsvall, n = 1) and K (S. Cerro, n = 2). In fact, O-unit structure of serogroup H and K shows some similarity with sub-serogroup C1 with the remaining serogroups presenting marked differences in this cellular component. The sub-serogroups discrimination was successfully achieved for C1, C2 and C3 (using PCA), and for E1-E2-E3 and E4 (by PLSDA). Appropriate serotype discrimination was obtained for most of S. Rissen from the remaining C1 serotypes (91.5%-PLSDA), and S. Enteritidis (D1) from the remaining D1/D2 serotypes (93.4% PLSDA). The lack of available O-unit composition for particular serotypes prevents the elucidation of the role of this cellular component on the discrimination at serotype level obtained. FTIRS was able to discriminate relevant serogroups (B, C, D and E), sub-serogroups (C1, C2 and C3; E1-E2-E3 and E4) and particular important serotypes (S. Enteritidis, S. Rissen and S. Senftenberg). Further studies on O-antigen composition would clarify the fundaments of discrimination obtained by FTIRS. PMID- 30015262 TI - Development and Validation of a Nomogram for Predicting Overall Survival in Pancreatic NeuroendocrineTumors. AB - BACKGROUND: The objective of current study was to develop and validate a nomogram to predict overall survival in pancreatic neuroendocrine tumors (PNETs). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with PNETs between 2004 and 2015. Patients were randomly separated into the training set and the validation set. Cox regression model was used in training set to obtain independent prognostic factors to develop a nomogram for predicting overall survival (OS). The discrimination and calibration plots were used to evaluate the predictive accuracy of the nomogram. RESULTS: A total of 3142 patients with PNETs were collected from the SEER database. Sex, age, marital status, primary site, TNM stage, tumor grade, and therapy were associated with OS in the multivariate models. A nomogram was constructed based on these variables. The nomogram for predicting OS displayed better discrimination power than the Tumor-Node-Metastasis (TNM) stage systems 7th edition in the training set and validation set. The calibration curve indicated that the nomogram was able to accurately predict 3- and 5-year OS. CONCLUSIONS: The nomogram which could predict 3- and 5-year OS were established in this study. Our nomogram showed a good performance, suggesting that it could be served as an effective tool for prognostic evaluation of patients with PNETs. PMID- 30015263 TI - PET-based Treatment Response Assessment for Neoadjuvant Chemoradiation in Pancreatic Adenocarcinoma: An Exploratory Study. AB - PURPOSE: Performance of anatomical metrics of Response Evaluation Criteria in Solid Tumors (RECIST1.1) versus Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST1.0) for neoadjuvant chemoradiation (nCR) of pancreatic adenocarcinoma was evaluated based on the pathological treatment response (PTR) data. METHODS AND MATERIALS: The pre- and post-nCR CT and PET data for 14 patients with resectable or borderline resectable pancreatic head adenocarcinoma treated with nCR followed by surgery were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade 0, 1, 2 or 3 (G0, G1, G2 or G3) for complete, moderate, minimal and poor responses, respectively. Maximum standardized uptake value (SUVmax) was defined using body-weight (SUVbw). PERCIST1.0 was defined using lean body mass normalized SUV (SUVlb or SUL). RECIST1.1 was defined by contouring the whole pancreas head on the CT image. Pre- and post-SUL-peak and SUVmax, RECIST1.1 and PETRECIST1.0 were correlated with PTR using Pearson's correlation coefficient test. RESULTS: The average mean and SD in SUL-peak for all patients analyzed were lower in post-nCR (3.63+/-1.06) compared to those at pre-nCR (4.29+/-0.89). Using PERCIST1.0, 62% of patients showed stable metabolic disease (SMD), 23% partial metabolic response (PMR), and 15% progressive metabolic disease (PMD). Using RECIST1.1, 85% of patients showed stable disease (SD), 8% partial response (PR), and 7% progressive diseases (PD). A poor insignificant correlation was established between PRT and PERECIST1.0 (r=0.121), whereas no correlation was seen with RECIST1.1. CONCLUSIONS: PERCIST1.0 appears to increase the chance of detecting patients with progressive disease compared to the conventional anatomical-based assessment of RECIST1.1. The integration of these additional radiographic metrics in assessing treatment response to nCR for pancreatic adenocarcinoma may provide a promising strategy to better select patients that are most suitable for therapeutic intensification. PMID- 30015264 TI - Predictors of severe relapse in pregnant women with psychotic or bipolar disorders. AB - Pregnancy in women with severe mental illness is associated with adverse outcomes for mother and infant. There are limited data on prevalence and predictors of relapse in pregnancy. A historical cohort study using anonymised comprehensive electronic health records from secondary mental health care linked with national maternity data was carried out. Women with a history of serious mental illness who were pregnant (2007-2011), and in remission at the start of pregnancy, were studied; severe relapse was defined as admission to acute care or self-harm. Predictors of relapse were analysed using random effects logistic regression to account for repeated measures in women with more than one pregnancy in the study period. In 454 pregnancies (389 women) there were 58 (24%) relapses in women with non-affective psychoses and 25 (12%) in women with affective psychotic or bipolar disorders. Independent predictors of relapse included non-affective psychosis (adjusted OR = 2.03; 95% CI = 1.16-3.54), number of recent admissions (1.37; 1.03 1.84), recent self-harm (2.24; 1.15-4.34), substance use (2.15; 1.13-4.08), smoking (2.52; 1.26-5.02) and non-white ethnicity (black ethnicity: 2.37; 1.23 4.57, mixed/other ethnicity: 2.94; 1.32-6.56). Women on no regular medication throughout first trimester were also at greater risk of relapse in pregnancy (1.99; 1.05-3.75). There was no interaction between severity of illness and medication status as relapse predictors. Therefore, women with non-affective psychosis and higher number of recent acute admissions are at significant risk of severe relapse in pregnancy. Continuation of medication in women with severe mental illness who become pregnant may be protective. PMID- 30015265 TI - Excitation-inhibition dysbalance as predictor of autistic phenotypes. AB - Autistic traits are normally distributed across health and disease, with autism spectrum disorders (ASD) at the extreme end. As we learned from mutations of synaptic or synapse regulating genes, leading to monogenetic forms of autism, the heterogeneous etiologies of ASD converge at the synapse. They result in a mild synaptic dysfunction as the final common pathway, also addressed as synaptopathy. Based on genetic rodent models and EEG/MEG findings in autists, a neuronal excitation-inhibition dysbalance is considered autism-pathognomonic. We hypothesized that this objectively measurable consequence is not restricted to the diagnosis of ASD but transcends disease borders and is of quantitative rather than qualitative nature. For proof-of-principle, we conducted a transcranial magnetic stimulation (TMS) study, monitoring corticospinal excitability and intracortical inhibition of the motor cortex. Employing the GRAS data collection of N > 1200 deep-phenotyped schizophrenic subjects, we had the chance to select for this study N = 20 perfectly matched men. They differed highly significantly by autistic trait severity, as assessed using PANSS autism severity score (PAUSS), capturing the continuum of autistic behaviors. Applying TMS to these men, we provide first intriguing hints of a positive correlation of autistic phenotype severity with functional cortical correlates, mainly alterations in GABAergic system and ion channels. This 'dose-response relationship' between severity of autistic traits and excitation-inhibition ratio in non-ASD subjects underlines the biological basis of this continuous trait. Based on these data, TMS may evolve as new add-on biomarker of autistic traits across disease groups. Finally, common treatment strategies targeting the excitation-inhibition dysbalance in humans may develop. To ultimately achieve this goal, however, replication studies with larger numbers of individuals would be desirable. PMID- 30015266 TI - VEGF-B electrotransfer mediated gene therapy induces cardiomyogenesis in a rat model of cardiac ischemia. AB - Atherosclerosis induced myocardial infarction (MI) continues to be a major public health concern. Regenerative therapies that restore cardiac muscle cells are largely absent. The rate of cardiomyogenesis in adults is insufficient to compensate for MI damage. In this study, we explored the capacity of a gene therapy approach to promote cardiomyogenesis. We hypothesized that VEGF-B, critical during fetal heart development, could promote cardiomyogenesis in adult ischemic hearts. Gene electrotransfer (GET), a physical method of in vivo gene delivery, was adapted to the rat model of MI. Favorable pulsing parameters were then used for delivery of pVEGF-B and compared to a sham control in terms of infarct size, cardiomyocyte proliferation and presence of new cardiomyocytes. Ki67 immunoreactivity was used for proliferation analysis. Newly synthetized DNA was labeled with BrdU to identify new cells post-infarction. Cardiac troponin co localization indicated proliferating and new cardiomyocytes histologically. Eight weeks post-treatment, GET pVEGF-B treated hearts had significantly smaller infarcts than the sham control group (p < 0.04). Proliferating and new cardiomyocytes were only present in the GET of pVEGF-B group, and absent in the controls. In summary, GET pVEGF-B promoted cardiomyogenesis post-MI, demonstrating for the first time direct evidence of myocardial regeneration post infarction. PMID- 30015267 TI - Improved decolorization of dye wastewater in an electrochemical system powered by microbial fuel cells and intensified by micro-electrolysis. AB - Electrochemical decolorization is of particular importance for the efficient treatment of dye wastewater. A promising electrochemical system powered by microbial fuel cells (MFCs) and intensified by Fe-C micro-electrolysis is proposed and enhanced decolorization of methyl orange (MO) is realized in this study. The decolorization efficiency reached as high as 97.1 +/- 1.8% after 180 min of operation with initial MO concentration of 50 mg/L and applied voltage of 700 mV. Decolorization efficiency initially increased and then decreased with rising Fe-to-C ratio. In addition, efficiency was enhanced with the increase of aeration rate up to 6.0 L/min. Lower initial MO concentration and pH were also shown to facilitate MO decolorization. A study of mechanisms, with results from control tests and scavenger experiments indicated that MO decolorization was contributed by the indirect oxidation by various oxidizing substances, especially O2-, that were generated during the process. MO molecule was decomposed and low molecular weight compounds such as indolizine, hydrazide and thione were generated. This study advances the performance of MFC in dye wastewater treatment by combining with a standard technique. PMID- 30015268 TI - Using metabolic charge production in the tricarboxylic acid cycle (QTCA) to evaluate the extracellular-electron-transfer performances of Shewanella spp. AB - Using an electrochemical cell equipped with carbon felt electrodes (poised at +0.63 V vs. SHE), the current production capabilities of two Shewanella strains NTOU1 and KR-12-were examined under various conditions with lactate as an electron donor. The metabolic charge produced in the tricarboxylic acid cycle (QTCA) was calculated by mass-balance. The data showed a linear relation between the electric coulomb production (QEL) and QTCA with an R2 of 0.65. In addition, a large amount of pyruvate accumulation was observed at pH = 6, rendering QTCA negative. The results indicate an occurrence of an undesired cataplerotic reaction. It was also found that QTCA provides important information showing the oxygen-boosting TCA cycle and anodic-current generation of Shewanella spp. Linear dependence of the change in charge for biomass growth (4.52FDeltanCell) on QTCA was also found as expressed by 4.52FDeltanCell = 1.0428 QTCA + 0.0442, indicating that these two charge quantities are inherently identical under most of the experimental conditions. In the mediator-spiked experiments, the external addition of the mediators (ferricyanide, anthraquinone-2, 6-disulfonate, and riboflavin) beyond certain concentrations inhibited the activity of the TCA cycle, indicating that the oxidative phosphorylation is deactivated by excessive amounts of mediators, yet Shewanella spp. are constrained with regard to carrying out the substrate-level phosphorylation. PMID- 30015269 TI - Electrotaxis of tumor-initiating cells of H1975 lung adenocarcinoma cells is associated with both activation of stretch-activated cation channels (SACCs) and internal calcium release. AB - The metastatic potential of cancer cells is related to their migratory ability, which is influenced by in vivo microenvironment possessing specific physiochemical factors including electric properties. In the present study, we isolated two different subsets of lung adenocarcinoma H1975 cells, as side population (SP) and main population (MP). SP cells were demonstrated to have cancer stem cell characteristics. Using a microscale device to provide physiological direct-current electric field (dcEF), we investigated the electrotactic responses of the SP and MP cells. The results showed that both SP and MP cells exhibited enhanced cathodal migration ability with actin reorganization and transient intracellular calcium ions ([Ca2+]i) increase under dcEF stimulation. For SP cells, the treatment of either stretch-activated cation channels (SACCs) inhibitor or the blockage of intracellular Ca2+ release could partially inhibited dcEF-activated [Ca2+]i increase, and the concomitant treatment led to a complete inhibition. For MP cells, SACCs activation was entirely responsible for EF-activated increase of [Ca2+]i. All these results suggested that that intracellular Ca2+ activation may be associated with cancer cell tumorigenicity and metastasis. PMID- 30015270 TI - Subjective and objective evaluation of visual functions in dyslexic children with visual perceptual deficiency-Before and after ten-weeks of perceptual training. AB - AIMS: This pilot study investigated perceptual and electrophysiological characteristics of dyslexic children, and evaluated the immediate and prolonged effect of visual perceptual training on these characteristics in these children. METHODS AND PROCEDURES: Seven dyslexic children and seven controls aged 7-8 years were recruited and completed this study. All dyslexic children completed 10-weeks of visual perceptual training. The visual perceptual skills were assessed and binocular visual evoked potentials (VEP) were recorded with two different pattern stimulations initially (Baseline), 3 months after the first assessment (Evaluation I) and 6 months after first assessment (Evaluation II). OUTCOMES AND RESULTS: A significant reduction (p = 0.021) in VEP amplitudes in the dyslexic subjects in response to 15 Hz reversal frequency at 15% contrast stimulation was found, compared with controls, prior to perceptual training. A significant correlation (p = 0.005) was found between the VEP amplitude with 15 Hz reversal frequency and the total score of Test of Visual Perceptual Skills (non-motor) - revised (TVPS-R). After training, dyslexic subjects scored higher in some of the visual perceptual tasks and these improvements persisted for 3 months. However, the VEP amplitude in the dyslexics showed no significant change after perceptual training. PMID- 30015271 TI - Stability of bullying and internalizing problems among adolescents with ASD, ID, or typical development. AB - BACKGROUND: It is known that children with disabilities, especially adolescents with autism spectrum disorder (ASD), are at increased risk for victimization. However, little is known about the impact of victimization over time. AIMS: Primary aims included identifying to what extent risk factors (i.e., internalizing behavior problems and conflict in friendship) related to bullying victimization over time. METHODS AND PROCEDURES: In-depth interviews conducted separately with 15-year-olds with autism spectrum disorder (ASD), intellectual disability (ID), or typical development (TD) and their mothers investigated the experiences of victimization in a two-year follow up to an earlier study at adolescent age 13. OUTCOMES AND RESULTS: Findings at age 15 demonstrated that the highest rates of bullying continued to be endorsed by youth with ASD. However, youth with ID were found to experience and report the most severe bullying. Longitudinal examination revealed that internalizing behaviors at age 13 predicted victimization experiences at age 15. CONCLUSIONS AND IMPLICATIONS: During middle adolescence, youth with ASD continue to experience more frequent victimization. Thus, shifting the focus of interventions that not only target the salient social deficits of ASD, but also address comorbid conditions such as internalizing symptoms, may further contribute to reduction of social isolation and peer difficulties. PMID- 30015272 TI - A schoolwide approach to promoting student bystander behavior in response to the use of the word "retard". AB - BACKGROUND AND AIMS: The use of the word retard ("the r-word") among adolescents sheds light on societal views about individuals with intellectual disability and the need to address the colloquial use of this word and its underlying stigma. Schools provide an important platform for intervening to promote social change among youth. The present study examined the impact of a schoolwide social inclusion program on students' bystander behavior against the use of the r-word. METHODS AND PROCEDURES: 1233 students from 5 high schools were surveyed about the prevalence of the r-word in their school, the contexts in which it is used, and their bystander behavior in response to the word. Approximately 40% of surveyed students participated in an R-word Campaign, Unified Sports team, and/or Unified Club as part of the Special Olympics Unified Champion Schools (UCS) program. OUTCOMES AND RESULTS: Students' prosocialness, the context in which the r-word was used, and participation in UCS activities significantly predicted active bystander behavior in response to the r-word. CONCLUSIONS AND IMPLICATIONS: By empowering students to be active bystanders against the use of the r-word in school, school-based interventions provide a promising avenue for addressing both the use of the r-word and its underlying stigma. PMID- 30015273 TI - Comparison of children diagnosed with cerebral palsy in a private cord blood bank to an epidemiological sample. AB - BACKGROUND: Although cord blood (CB) stem cell research is being conducted for treatment of cerebral palsy (CP), little is known about children with CP and stored CB. AIMS: To compare demographic and clinical characteristics of children with CP and stored CB to children with CP identified in a population-based study. METHODS AND PROCEDURES: The Longitudinal Umbilical Stem cell monitoring and Treatment REsearch (LUSTRE(r)) Registry recruited children from the largest US private CB bank. Demographics, co-morbidities, and gross motor function (GMFCS level and walking ability) were collected and, where possible, compared with the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. OUTCOMES AND RESULTS: 114 LUSTRE participants were compared to 451 ADDM participants. LUSTRE participants were more likely to be white, but sex distribution was similar. Co-morbidities (autism and epilepsy) and functional mobility were also similar. CONCLUSIONS AND IMPLICATIONS: The results of this analysis suggest that while children diagnosed with CP and with access to stored CB differ from a broader population sample in terms of demographics, they have similar clinical severity and comorbidity profiles. As such, LUSTRE may serve as a valuable source of data for the characterization of individuals with CP, including individuals who have or will receive CB infusions. PMID- 30015274 TI - Study of the in vitro and in vivo metabolism of 4-HO-MET. AB - 4-Hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET) is a new psychoactive substance (NPS) of the chemical class of tryptamines. It shows structural similarities to the endogenous neurotransmitter serotonin, and is a serotonergic hallucinogen, affecting emotional, motoric, and cognitive functions. The knowledge about its biotransformation is mandatory to confirm the abuse of the substance by urine analysis in forensic cases. Therefore, phase I metabolites were generated by the use of the pooled human liver microsomes (pHLM) in vitro model and analyzed by high-performance liquid chromatography high-resolution tandem mass spectrometry with information-dependent acquisition (HPLC-IDA-HR-MS/MS). Furthermore, three authentic urine samples was analyzed and results were compared: 12 different in vitro and 4 in vivo metabolites were found. The predominant biotransformation steps observed in vitro were mono- or dihydroxylation of 4-HO-MET, besides demethylation, demethylation in combination with monohydroxylation, formation of a carboxylic acid, deethylation, and oxidative deamination. In vivo, monohydroxylation, and glucuronidation were detected. A metabolic pathway based on these results was proposed. For the analysis of urine samples in forensic cases, the N-oxide metabolite and the HO-alkyl metabolite are recommended as target compounds, besides the glucuronides of 4-HO-MET and the parent compound 4 HO-MET itself. PMID- 30015275 TI - Fatal zolpidem poisoning due to its intravenous self-injection: Postmortem distribution/redistribution of zolpidem and its predominant metabolite zolpidem phenyl-4-carboxylic acid in body fluids and solid tissues in an autopsy case. AB - We experienced a curious fatal case, in which a male in his 20s self-administered zolpidem intravenously. The victim was found dead lying on floor of his apartment room, with a tourniquet band and new injection marks on his right forearm. Nearby the body, a medical disposal syringe containing small-volume solution dissolving crushed zolpidem tablets was found. The postmortem interval was estimated at about two days. The direct cause of his death was judged as asphyxia due to the aspiration of stomach contents into the trachea and bronchi. The specimens dealt with were body fluids and solid tissues including femoral vein blood, right and left heart blood, pericardial fluid, urine, bile, stomach contents, the brain, lung, heart muscle, liver, spleen, kidney, pancreas and skeletal muscle. For the extractions of zolpidem, zolpidem phenyl-4-carboxylic acid, deuterated internal standards zolpidem-d7 and zolpidem phenyl-4-carboxylic acid-d4, a modified QuEChERS method was used, followed by the analysis by liquid chromatography tandem mass spectrometry. Because this study included various kinds of human matrices with quite different properties, the standard addition method was most preferable to overcome the matrix effects and recovery rates, and also did not need to use blank human matrices for validation experiments. The concentration of zolpidem and its phenyl-4-carboxylic acid metabolite in various specimens tested were generally extreme higher than those of reported fatal cases, supporting that the victim had died of intravenous zolpidem injection. The concentrations of zolpidem in femoral vein blood and right and left heart blood specimens in the present case were 9.55, 28.5 and 46.9MUg/mL, respectively, which far exceeded estimated fatal levels. The present study also showed the postmortem distribution/redistribution of zolpidem and its phenyl-4-carboxylic acid metabolite in 15 body fluid and solid tissue specimens including stomach contents. Although a number of published literatures dealt with zolpidem poisoning cases due to oral ingestion of the drug, this is the first report on fatal intravenous zolpidem injection case and postmortem distribution of zolpidem and its predominant metabolite. PMID- 30015276 TI - Can measurements of heroin metabolites in post-mortem matrices other than peripheral blood indicate if death was rapid or delayed? AB - BACKGROUND: In heroin-related deaths, it is often of interest to determine the approximate time span between intake of heroin and death, and to decide whether heroin or other opioids have been administered. In some autopsy cases, peripheral blood cannot be sampled due to decomposition, injuries or burns. The aim of the present study was to investigate whether measurements of heroin metabolites in matrices other than peripheral blood can be used to differentiate between rapid and delayed heroin deaths, and if morphine/codeine ratios measured in other matrices can separate heroin from codeine intakes. METHODS: In this study, we included 51 forensic autopsy cases where morphine was detected in peripheral blood. Samples were collected from peripheral and cardiac blood, pericardial fluid, psoas and lateral vastus muscles, vitreous humor and urine. The opioid analysis included 6-acetylmorphine (6-AM), morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G) and codeine. Urine was only used for qualitative detection of 6-AM. 45 heroin-intake cases were divided into rapid deaths (n=24), based on the detection of 6-AM in blood, or delayed deaths (n=21), where 6-AM was detected in at least one other matrix but not in blood. An additional 6 cases were classified as codeine-intake cases, based on a morphine/codeine ratio below unity (<1) in peripheral blood, without detecting 6 AM in any matrix. RESULTS: The median morphine concentrations were significantly higher in the rapid compared with the delayed heroin deaths in all matrices (p=0.004 for vitreous humor and p<0.001 for the other matrices). In the rapid heroin deaths, the M3G/morphine concentration ratios were significantly lower than in the delayed deaths both in peripheral and cardiac blood (p<0.001), as well as in pericardial fluid (p<0.001) and vitreous humor (p=0.006), but not in muscle. The morphine/codeine ratios measured in cardiac blood, pericardial fluid and the two muscle samples resembled the ratios in peripheral blood, although codeine was less often detected in other matrices than peripheral blood. CONCLUSIONS: Measurements of heroin-metabolites in cardiac blood, pericardial fluid and vitreous humor provide information comparable to that of peripheral blood regarding rapid and delayed heroin deaths, e.g. M3G/morphine ratios <2 indicate a rapid death while ratios >3 indicate a delayed death. However, considerable overlap in results from rapid and delayed deaths was observed, and measurements in muscle appeared less useful. Furthermore, matrices other than peripheral blood can be used to investigate morphine/codeine ratios, but vitreous humor seems less suited. PMID- 30015277 TI - Quantifying chemiluminescence of the forensic luminol test for ovine blood in a dilution and time series. AB - This study investigates the chemiluminescent reaction of whole ovine blood with a luminol solution in a time and dilution series. Replicate samples of both fresh and dried certified pathogen-free ovine blood were prepared and diluted. Seven dilution conditions from neat to 1:1000000 were created for testing. A luminol solution, created using the standard Weber protocol, was applied to all samples in controlled laboratory conditions. A SpectraMax(r) M3 microplate reader luminometer was used to quantify the chemiluminescence from the reactions as relative luminescence units (RLUs) every four seconds for three minutes. Trends within and amongst the times series, reaction half-lives, and maximum chemiluminescent intensities are discussed. Our research provides a comprehensive dataset derived from instrumental and visual observations on the chemiluminescence resulting from ovine blood's reaction to luminol. This study has implications in forensic bloodstain pattern analysis as it offers a mixed method approach to characterizing the reaction between blood and a commonly used presumptive testing reagent. PMID- 30015278 TI - Development and application of a new nose hairs sample collection device for GSR Particles by scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS). AB - When a firearm is discharged, a gaseous cloud containing characteristic particles of gunshot residue (GSR) are released forward and behind at high speed, depositing on clothing, hands, face and hair, as well as being inhaled and therefore retained in the nostrils of the person who fired the weapon. GSRs have characteristic sizes and morphologies and consist of a combination of lead, antimony and barium, as well as other elements. Scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDS) is a widely accepted technique for the analysis of these residues; however, little has been reported on samples taken from the nostrils of the suspect that discharged the shot. The analysis of residues found on hands has been more frequent. This article presents a device (Nasal Stub) developed by us for the non-invasive collection of GSR particles from the nostrils and a platform also developed by us to contain these devices that is compatible with SEM-EDS. To evaluate the effectiveness of our Nasal Stub to collect GSR particles from nose hairs, four types of firearms of different calibers were utilized. Nasal samples were collected at 0, 2, 4, 6, 8, and 20h after firing. The results show that the nasal device was able to recover GSR particles from nose hairs for all the weapons used, even, in some cases, over 20h after firing. It was concluded that Nasal Stub and its methodology proposed for the analysis of nasal GSR from nose hairs by SEM-EDS was effective and that it can complement other traditional analyses of GSR particles, increasing the amount of evidentiary support for the forensic analysis presented in a tribunal or court. PMID- 30015279 TI - Oxidized multiwalled carbon nanotubes coated fibers for headspace solid-phase microextraction of amphetamine-type stimulants in human urine. AB - Carbon nanotubes (CNTs) have attracted a lot of attention as effective sorbents due to their strong sorption properties and several potential applications in many fields. In this work, the acid oxidized multiwalled carbon nanotubes (MWCNTs COOH) was coated onto a stainless steel wire by a simple physical adhesion approach to develop solid-phase microextraction (SPME) fibers. By combination of the MWCNTs-COOH coated fiber-based headspace SPME and gas chromatography-mass spectrometry (GC-MS), the developed method demonstrates a good enhancement factor (288-651), low limits of detection (LODs, 0.2-1.3MUg/L) for determination of amphetamine-type stimulant drugs (ATSs) in urine samples. The recoveries of the spiked ATSs (5, 50 and 500MUg/L) were in the range of 88-107%, the calibration curve was linear for concentrations of analytes in the range from 0.5 to 1000MUg/L (R=0.963-0.999). Furthermore, single fiber repeatability and fiber-to fiber reproducibility were in the range of 2.3%-6.2% (n=6) and 5.7%-9.8% (n=3), respectively. The MWCNTs-COOH coated fiber is highly thermally stable and can be used over 150 times. The method was successfully applied to the forensic determination of amphetamine (AMP) and methamphetamine (MAMP) in human urine samples and satisfactory results were achieved. PMID- 30015280 TI - Determining the number of test fires needed to represent the variability present within firearms of various calibers. AB - The Association of Firearm and Toolmark Examiners recommends a minimum of two test fires be performed when an unknown firearm is submitted to a laboratory prior to doing a comparison with a cartridge case collected from a crime scene. Limited research has been performed to determine how many test fires are necessary to be representative of the match distribution of a firearm. Various makes and models of firearms comprising five calibers were tested using a hybrid equivalence test to determine how many cartridge cases were required to represent the match distribution of an unknown firearm based on both breech face and firing pin correlation scores from an IBIS(r) HeritageTM System. The same general trend was observed for each caliber of firearm where the equivalence percentage increased from 10 to 30 cartridge cases. Overall, 15 cartridge cases are sufficient for above an 80% probability of representing the full match distribution for an unknown firearm. To approach full equivalence, 25 cartridge cases are enough because 30 cartridge cases were not found to be significantly higher in equivalence percentage for any caliber of firearm tested. PMID- 30015281 TI - Forensic taphonomy: Vertebrate scavenging in the temperate southwestern Cape, South Africa. AB - Vertebrate scavenging can significantly accelerate the rate of decomposition, which can hinder estimating the post-mortem interval (PMI). Patterns of decomposition and scavenging are highly specific to different environments in a forensic context, with no known data for South Africa. A better understanding of local decomposition patterns, taking scavenging into account, could increase the accuracy of PMI estimation and improve identification of human remains. Using a porcine model in the forensically significant thicketed Cape Flats Dune Strandveld habitat, the effect of vertebrate scavenging on the decomposition process was examined. This part of Cape Town suffers from poor socioeconomic conditions and a high murder rate, which is due in part to the dense population. Human decomposition was simulated using three small (~20kg) domestic pig (Sus scrofa domesticus) carcasses, with ethical clearance. One pig served as a control and was caged to prevent vertebrate but not invertebrate access; the other two served as experimental treatments. They were deployed in Delft, Cape Town, and observed by motion-activated, time-lapse remote photography to record scavenger species and activity. A rapid increase in the decomposition rate was observed due to Cape grey mongoose (Galerella pulverulenta) scavenging, with early skeletonisation reached by both experimental pigs by day 14, compared to the control remaining in advanced decomposition after 93 days. Mongoose is the primary scavenger in this habitat, and showed notable patterns of feeding behaviour, exclusively within daylight hours. Scavenging activity was only influenced by rainfall later in the cycle. This research provides knowledge on locally relevant decomposition patterns and highlights the necessity for PMI estimation methods to consider vertebrate scavengers. This may improve human skeletal identification in forensic cases. There is scope for expansion of this study, with an investigation of seasonal effects, the interaction between invertebrate and vertebrate activity, as well as, the effect of clothing on scavenger access. PMID- 30015282 TI - Laryngohyoid fractures in suicidal hanging: A prospective autopsy study with an updated review and critical appraisal. AB - Laryngohyoid fractures in hanging victims are one of the most studied and paradoxically contradictory topics in forensic pathology. According to literary sources, the incidence of laryngohyoid fractures in hanging varies significantly, from 0% to 100%. To verify the diagnostic significance of these injuries in hanging, we prospectively and consecutively analyzed the occurrence of laryngohyoid fractures in a group of 178 suicidal hanging victims (M/F=150/28, aged 14-94years, mean age=50, complete suspension=111 cases, partial suspension=67 cases) in relation to selected variables (age, sex, weight, the completeness of body suspension, and ligature knot location). Altogether, we identified the following types of laryngohyoid fractures in 129 of 178 cases (72.5%): isolated fracture(s) to the thyroid cartilage in 60 cases (33.7%), combined thyrohyoid fractures in 41 cases (23.0%), isolated fracture(s) to the hyoid bone in 28 cases (15.7%), and no fractures to the cricoid cartilage or the cervical vertebrae. The highest frequency of laryngohyoid fractures was found in lateral hangings (right lateral: 26/34, 76.5%; left lateral: 31/37, 83.8%), whereas the lowest rate was found in anterior hangings (4/11, 36.4%). In lateral hangings, fractures more often occurred contralaterally to the suspension point. Statistical analysis revealed significant associations of the occurrence of laryngohyoid fractures with the age of the victim (p=0.028), with the position of the ligature knot on the neck (p=0.019) and with the age-corrected weight of the victim (p=0.026). In addition, we performed a systematic updated review and critical appraisal of relevant literary sources to report the incidence, fracture patterns, and contributing variables of laryngohyoid injuries in hanging. Both the results of our study and the provided literary synthesis show that if evaluated properly, laryngohyoid fractures in hanging may diagnostically offer far more than just evidence that injury to the neck occurred and may also present research opportunities regarding several issues that should be further analyzed and explained. PMID- 30015283 TI - Skeletal weathering in central Florida: A preliminary approach for developing a scoring protocol to estimate time since death. AB - Regardless of region, skeletal remains deposited in subaerial contexts are subjected to a progression of taphonomic alterations. However, there are limited postmortem interval (PMI) standards developed, particularly in environments where skeletonization can occur quickly. The research purpose was to evaluate the timing and progression of early weathering alterations in two microenvironments (shaded and open) using pig carcasses (Sus scrofa) in the subtropical humid environment of central Florida. Over nine months, sun bleaching was assessed using Munsell(r) Soil Color Charts (2009) and scored based on percentage of the bone sun bleached, while bone weathering was further evaluated using Behrensmeyer's (1978) stages. Results indicate that microenvironment has a significant influence, with the onset and progression of sun bleaching and Behrensmeyer's (1978) Stages 2 and 3 occurring earlier in the open microenvironment. Sun bleaching stages and Behrensmeyer's (1978) weathering stages can be utilized in conjunction for developing regionally specific PMI taphonomic models for different microenvironments. PMID- 30015284 TI - Sexual dimorphism of the first deciduous molar: A geometric morphometric approach. AB - Estimating the sex of immature skeletal remains is important when reconstructing the biological profile of unknown individuals in anthropological practice. Teeth have a distinct importance as they are the most frequently recovered physical elements of an individual. They persist after death due to their hardness and resistance to postmortem insults. The aim of this study was to analyse the sexual dimorphism of the occlusal surface of the first deciduous molar using geometric morphometric techniques. This study evaluated 38 first maxillary deciduous molars (21 males, 17 females) and 30 first mandibular deciduous molars (15 males, 15 females) from the Granada osteological collection of identified subadults (Granada, Spain). The landmark and semilandmark coordinates were analysed by principal components analysis, canonical variate analysis and discriminant analysis. Only the first maxillary deciduous molar showed a significant sexual dimorphism, with cross-validation values for shape variables of 93.23% for males and 83.17% for females, and 100% for males and 87.50% for females when both shape and size variables were considered. Despite there being acceptable cross validation classification for the first mandibular deciduous molar (82.35% for males and 92.31% for females for shape variables and 82.35% for males and 92.31% for females for shape and size variables), no significant differences indicating sexual dimorphism were identified. The results show that the first upper deciduous molar can assist in sex estimation, and that geometric morphometric analysis is a suitable technique to answer questions related to shape that cannot be observed with the naked eye. PMID- 30015285 TI - Combination random isothermal amplification and nanopore sequencing for rapid identification of the causative agent of an outbreak. AB - BACKGROUND: Outbreaks of fever of unknown origin start with nonspecific symptoms and case definition is only slowly developed and adapted, therefore, identifying the causative agent is crucial to ensure suitable treatment and control measures. As an alternative method for Polymerase Chain Reaction in molecular diagnostics diagnostic, metagenomics can be applied to identify the pathogen responsible for the outbreak through sequencing all nucleic acids present in a sample extract. Sequencing data obtained can identify new or variants of known agents. OBJECTIVES: To develop a rapid and field applicable protocol to allow the identification of the causative agent of an outbreak. STUDY DESIGN: We explored a sequencing protocol relying on multiple displacement isothermal amplification and nanopore sequencing in order to allow the identification of the causative agent in a sample. To develop the procedure, a mock sample consisting of supernatant from Zika virus tissue culture was used. RESULTS: The procedure took under seven hours including sample preparation and data analysis using an offline BLAST search. In total, 63,678 sequence files covering around 10,000 bases were extracted. BLAST search revealed the presence of Zika virus. CONCLUSION: In conclusion, the protocol has potential for point of need sequencing to identify RNA viruses. The whole procedure was operated in a suitcase laboratory. However, the procedure is cooling chain dependent and the cost per sequencing run is still high. PMID- 30015286 TI - Outcome of a hepatitis B vaccination program for clients of a drug consumption facility. AB - BACKGROUND: Intravenous drug users (IDUs) are a risk group for hepatitis B. In Germany, the hepatitis B virus (HBV) vaccination rates in IDUs are low. OBJECTIVES: In this study the implementation and success of HBV vaccination in a drug consumption facility (DCF) was evaluated. STUDY DESIGN: Clients attending a DCF were asked regarding their HBV status. In case of no known HBV infection and no previous vaccination, clients interested in HBV vaccination were offered a HBV blood testing. HBV vaccination was administered to susceptible clients in months 0, 1, 6. Booster vaccinations were offered to clients without seroconversion (anti-HBs < 100 U/l). RESULTS: 193 out of 364 clients reported on a known HBV infection or immunity after vaccination. 95 (55.6%) out of 171 eligible clients underwent a HBV serology. According to HBV serology 31 (32.6%) out of 95 clients were not susceptible for vaccination (mainly due to an unknown HBV infection). 47 (73.4%) out of 64 clients susceptible were administered 3 vaccinations. 10 clients received at least one further vaccination. For those showing up for testing (36 out of 47 clients) the seroconversion rate was 69.4% (> 100 IU/l) and 83.3% (> 10 IU/l), respectively. DISCUSSION: Only a minority of clients of a DCF was susceptible for HBV vaccination. 47 out of 64 (73.4%) susceptible clients underwent at least three administrations of the vaccine, mostly resulting in seroconversion. Even in IDUs attending a DCF, a clientele with unstable social and health conditions, HBV vaccination can be carried out successfully. PMID- 30015288 TI - Diagnosis, management, and prognosis of patients with acute kidney injury in Japanese intensive care units: The JAKID study. AB - PURPOSE: To determine the proportion of diagnosis and outcomes of critically ill patients with acute kidney injury (AKI), and its association with mortality using the complete Kidney Disease Improving Global Outcomes (KDIGO) classification and Sepsis-3 definition. METHODS: We conducted a multicenter prospective cohort study of 13 intensive care units (ICU) in Japan. Patients admitted to the ICUs during six months in 2016 were consecutively enrolled. RESULTS: Among 2292 patients, AKI was diagnosed in 1024 (44.7%) patients, using the KDIGO classification. Sepsis was diagnosed in 424 patients (18.5%), of whom 281 patients (66.3%) had AKI. Septic shock was diagnosed in 166 patients (7.2%), of whom 125 patients (75.3%) had AKI. Of 1024 patients with AKI, renal replacement therapy was applied to 171 patients (16.7% of AKI) during the ICU stay. The adjusted odds ratio (aOR) of AKI to hospital mortality was 1.66 (95% confidence intervals 1.26-2.18), while that among sepsis was 0.87 (95% confidence intervals 0.55-1.37). CONCLUSIONS: AKI accounted for >40% of ICU patients with the KDIGO classification and was associated with increased risk of hospital mortality. Septic AKI was diagnosed in three-fourths of patients with sepsis, while the impact of AKI on hospital mortality among sepsis was not observed. PMID- 30015289 TI - National incidence rates for Acute Respiratory Distress Syndrome (ARDS) and ARDS cause-specific factors in the United States (2006-2014). AB - PURPOSE: To estimate the incidence of Acute Respiratory Distress Syndrome (ARDS) and ARDS-related mortality rates. METHODS: We identified patients with a risk factor for ARDS in the National Inpatient Sample (NIS) (2006-2014). Using survey weighted descriptive statistics we estimated annual and overall proportions of ARDS cases. RESULTS: From over 69 million discharges, 1,151,969 ARDS discharges and 969,567 ARDS discharges with a risk factor were identified. Sepsis (46.8%), pneumonia (44.9%) and shock (44.4%) were the most common ARDS risk factor. Pancreatitis (3.4%), pulmonary contusion (1.4%) and drowning (0.2%) were the least frequently reported. Incidence rates increased from 180.7 (2006) to 220.8 (2011) and again from 182.8 (2012) to 193.4 (2014). Incidence for pneumonia, shock and sepsis-associated ARDS increased steadily, while transfusion and trauma associated ARDS declined. Trends for gastric aspiration and pancreatitis-related ARDS remained unchanged. Shock, sepsis and transfusion-associated ARDS had higher mortality rates compared to other factors. Except for transfusion and trauma associated ARDS, mortality rates for other factors declined. CONCLUSION: Although increasing incidence for ARDS was observed, mortality rates declined for most risk factors. Mortality for transfusion and trauma-associated ARDS increased in the later study period, research is needed to examine reasons for the increasing in-hospital deaths associated with these risk factors. PMID- 30015290 TI - Detection of invasive pulmonary aspergillosis in critically ill patients by combined use of conventional culture, galactomannan, 1-3-beta-D-glucan and Aspergillus specific nested polymerase chain reaction in a prospective pilot study. AB - : Invasive pulmonary aspergillosis (IPA) is an emerging and life-threatening infectious disease in patients admitted to the intensive care unit (ICU). Most diagnostic studies are conducted in hematological patients and results cannot readily be transferred to ICU patients lacking classical host factors. In a multicenter, prospective clinical trial including 44 ICU patients, hematological (n = 14) and non-hematological patients (n = 30), concurrent serum and bronchoalveolar lavage (BAL) samples were analyzed by conventional culture, galactomannan (GM), 1-3-beta-D-glucan (BDG) as well as an Aspergillus specific nested polymerase chain reaction (PCR). Nine patients (20%) had putative IPA according to AspICU classification. GM and PCR showed superior performance in BAL with sensitivity/specificity of 56%/94% and 44%/94% compared to 33%/97% and 11%/94% in serum. Despite better sensitivity of 89%, BDG showed poor specificity of only 31% (BAL) and 26% (serum). Combination of GM and PCR (BAL) with BDG (serum) resulted in 100% sensitivity, but also reduced specificity to 23%. Whereas mean GM levels were significantly higher in hematological patients BDG and PCR did not differ between hematological and non-hematological patients. Under present clinical conditions test combinations integrating both BAL and blood samples are advantageous. BDG might best serve as possible indicator for ruling out IPA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01695499. First posted: September 28, 2012, last update posted: May 8, 2017. PMID- 30015291 TI - Novel lipid tools and probes for biological investigations. AB - We present the latest advances in lipid tool development for studying cellular membrane trafficking and metabolism. We focus on chemical modifications that are introduced to natural lipid structures. The new functionalities are used to follow and interfere with lipid dynamics in intact cells. PMID- 30015292 TI - The effects of school desegregation on infant health. AB - This paper examines the effects of school desegregation on infant health using birth certificate data from 1970 to 2002 and a multiple difference-in-differences approach that exploits variation in the timing of desegregation across counties. Using cohort fixed effects and county fixed effects, I find that among black mothers in Southern regions, school desegregation reduces preterm births by 1.7 percentage points. These results are robust to county-specific cohort trends, county-specific year trends, and state-specific cohort fixed effects. In addition, school desegregation increases maternal education and prenatal care in the first trimester and decreases the likelihood of the child having a teenage father. These may be important pathways to improved infant health. This paper adds to the growing literature on the importance of school desegregation in areas beyond academic achievement. PMID- 30015293 TI - There is no such thing as a (gluten-)free lunch: Higher food prices and the cost for coeliac consumers. AB - A lifelong gluten-free diet is the only available treatment for coeliac disease at present. However, the high price of gluten-free substitute foods is likely to generate a welfare loss for consumers who drop gluten from their diet. Using original data on retail prices in four major UK supermarkets and consumption data from the UK Living Cost and Food Survey, we simulate the welfare change associated to a switch to the gluten-free diet. Within the "Bread and Cereals" category, retail price data show that the average price of gluten-free products is L1.12/100g relative to L 0.59/100g of gluten-containing products. Our estimates indicate that on average in the UK coeliac consumers have to pay an extra L 10 per week to maintain their utility levels prior to the dietary switch. This correspond to 29% of the weekly food budget. Results by income quartile are suggestive of regressive effects and the welfare loss for low-income consumers is estimated at 36% of their food budget compared to 24% of high-income consumers. PMID- 30015294 TI - The effect of unemployment insurance on alcohol use and abuse following job loss. AB - We investigate whether unemployment insurance (UI) policy affects the drinking behavior of the unemployed. Using NLSY data supplemented with Geocode data, we estimate the effect of benefit replacement rates on changes in individual alcohol consumption following job loss. Identification relies on variation in replacement rates across states and over time. Results indicate that a 100% increase in benefit replacement rate, roughly equivalent to a state moving from the lowest to the highest replacement rate, would, on average, result in unemployed individuals consuming 19.1 additional drinks a month. Looking at the change in an individual's binge drinking upon job loss, individuals receiving the highest level of benefits are 14.7% more likely to increase their binge drinking than those receiving the least generous benefits. We find that individuals' responsiveness to changes in replacement rates vary based on drinking history, industry labor market conditions, education, and age. PMID- 30015295 TI - Risk factors of pure leukoaraiosis and the association with preclinical carotid atherosclerosis. AB - BACKGROUND AND AIMS: The risk factors of cerebral large artery disease (carotid atherosclerosis) have been well recognized, but not of small artery disease, especially leukoaraiosis. In this study, we investigated the risk factors of pure leukoaraiosis (without stroke), and the association with preclinical carotid atherosclerosis. METHODS: Data from 384 subjects with leukoaraiosis and 379 controls with normal cerebral parenchyma were collected at the Beijing Tiantan Hospital from 1 January, 2009 to 31 December, 2015. Entry criteria: 1) age over 40 years; 2) not taking lipid lowering drugs and vitamin B; 3) normal cerebral parenchyma or leukoaraiosis on brain MRI scan; 4) intra- and extra-cranial large artery stenosis less than 50%. EXCLUSION CRITERIA: 1) any brain lesions except cerebral leukoaraiosis; 2) severe systemic diseases. Age, gender, well-known vascular risk factors, serum lipid profile, levels of total homocysteine, vitamin B12, folic acid were analyzed with multivariable logistic regression model. RESULTS: Age and hypertension, but not serum homocysteine, vitamin B12, folic acid, or serum lipid profile, were independently associated with leukoaraiosis. Furthermore, there was no significant association between pure leukoaraiosis and preclinical carotid atherosclerosis after adjusting for age. CONCLUSIONS: Only age and hypertension are independently related to pure leukoaraiosis, and there is no association between pure leukoaraiosis and preclinical carotid atherosclerosis. PMID- 30015297 TI - Disappearance of recurrent pancreatitis after splenectomy in familial chylomicronemia syndrome. AB - BACKGROUND AND AIMS: Recurrent pancreatitis is a severe complication of familial chylomicronemia syndrome (FCS) mainly secondary to lipoprotein lipase deficiency. The mechanism and interindividual variability of pancreatitis in FCS are not fully understood, but abnormalities in the drainage system of pancreatic veins could be involved. METHODS AND RESULTS: Two cases of typical FCS are described with a past history of recurrent pancreatitis that dramatically improved after splenectomy performed in both cases for reasons non-related to FCS. CONCLUSIONS: These are the first reports of the disappearance of pancreatitis after splenectomy in FCS and they should be considered of anecdotal nature at this time. The disappearance of pancreatitis following splenectomy could be in part due to subsequent improvements in pancreatic drainage. Extrahepatic portal hypertension induced by hypertriglyceridemic splenomegaly leading to pancreatic congestion could also be a contributing factor. PMID- 30015296 TI - Dietary 23-hydroxy ursolic acid protects against atherosclerosis and obesity by preventing dyslipidemia-induced monocyte priming and dysfunction. AB - BACKGROUND AND AIMS: We demonstrated that dietary ursolic acid (UA) reduces atherosclerotic lesion size and improves kidney function in diabetic mice. Based on structure-function analyses of naturally occurring UA analogs, we synthesized 23-hydroxy ursolic acid (23-OHUA), a compound with structural features predicted to enhance its bioavailability and anti-atherogenic properties compared to UA. The goal of this study was to determine the anti-obesogenic and atheroprotective properties of 23-OHUA and its mechanism of action. METHODS: We performed chemotaxis assays to determine IC50 of phytochemicals on primed THP-1 monocytes. We fed 12-week old female LDLR-/- mice a high-fat diet (HFD) or a HFD supplemented with either 0.05% UA or 0.05% 23-OHUA, and measured monocyte priming, weight gain and atherosclerotic lesion size after 6 and 20 weeks. RESULTS: Both dietary UA and 23-OHUA prevented dyslipidemia-induced loss of MKP-1 activity, and hyper-chemotactic activity, hallmarks of blood monocytes priming and dysfunction, but they did not affect plasma lipids or blood glucose levels nor WBC and monocyte counts. After 20 weeks, mice fed 23-OHUA showed 11% less weight gain compared to HFD-fed control mice and a 40% reduction in atherosclerotic plaque size, whereas UA reduced lesion size by only 19% and did not reduce weight gain. CONCLUSIONS: Dietary 23-OHUA reduces weight gain and attenuates atherogenesis in mice by protecting monocytes against metabolic stress induced priming and dysfunction. Based on its mechanism of action, 23-OHUA may represent a novel therapeutic approach for the prevention and treatment of obesity and atherosclerosis. PMID- 30015298 TI - Effect of gestational diabetes mellitus on newborn cholesterol metabolism. AB - BACKGROUND AND AIMS: Impaired glucose metabolism during pregnancy may associate with changes in fetal cholesterol metabolism. We investigated if gestational diabetes mellitus (GDM) affects newborn cholesterol metabolism as determined by cord blood squalene and non-cholesterol sterols. Furthermore, we examined potential correlations between cord blood and maternal serum non-cholesterol sterols. METHODS: Pregnant women at risk for GDM (BMI>30 kg/m2) were enrolled from maternity clinics in Finland. GDM was determined from the results of an oral glucose tolerance test. Serum samples were taken in the third trimester of pregnancy, and cord blood samples collected from their newborns at birth. Squalene and non-cholesterol sterols were analyzed from serum and cord blood by gas liquid chromatography. All women with GDM were in good glycaemic control. RESULTS: The ratios of squalene and non-cholesterol sterols to cholesterol (100 * MUmol/mmol of cholesterol) in cord blood did not differ between the infants born to mothers with GDM (n = 15) or mothers with normal glucose tolerance (n = 13). The ratios of sitosterol and campesterol to cholesterol in the cord blood correlated with the corresponding maternal serum ratios (r = 0.70, p < 0.0001) in both groups. CONCLUSIONS: In obese women under good glycaemic control, GDM did not affect newborn cholesterol metabolism. Cord blood sitosterol and campesterol ratios to cholesterol correlated with the corresponding maternal serum ratios thus potentially reflecting maternal-fetal cholesterol transport. PMID- 30015299 TI - Serum uric acid concentrations and risk of intracerebral hemorrhage: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: The relationship between serum uric acid (UA) and the risk of intracerebral hemorrhage (ICH) remains controversial. The aim of our systematic review and meta-analysis was to ascertain the association between serum UA concentrations and the risk of ICH. METHODS: We systematically searched databases of Embase, Pubmed, Web of Science and Cochrane Library up to December 30, 2017, and additional papers were identified through a manual search. Mean difference (MD) for serum UA levels with 95% confidence intervals (CI) was calculated. Six studies, including 345 ICH patients, 574 ischemic stroke patients and 535 healthy controls, were identified for meta-analysis. RESULTS: Our results revealed no statistically significant differences in the comparison of UA between ICH and healthy controls (95% CI = -9.04-15.61); UA levels in patients with ischemic stroke were significantly higher than those in healthy controls (95% CI = 3.91-56.32); further subgroup analysis of age showed higher UA levels in ICH patients over 65 years than healthy controls (age>=65: 95% CI = 1.44-35.96). Subgroup of ethnicity (Asians: CI = -9.06-21.00; Caucasians: 95% CI = -68.43 8.43), gender (Men: 95% CI = -56.08-4.73; Women: 95% CI = -27.19-35.91) and sample size (large samples: 95% CI = -20.54-41.05; small samples: 95% CI = -25.41 13.78) with respect to UA levels between ICH and healthy controls did not change these results. CONCLUSIONS: This meta-analysis showed that serum UA levels did not increase the risk of ICH probably because of the dual roles of UA, i.e. pro oxidant and antioxidant, in the progression of atherosclerosis. However, serum UA may be a potential risk factor for ICH in the elderly. There were no race specific differences in UA levels between Asians and Caucasians as well as gender related differences between men and women in the risk of ICH. PMID- 30015300 TI - Characterization of LncRNA expression profile and identification of novel LncRNA biomarkers to diagnose coronary artery disease. AB - BACKGROUND AND AIMS: Dysregulation of long non-coding RNAs (lncRNAs) has been proven to be involved in the pathogenesis of coronary artery disease (CAD). However, it remains to be extensively explored. Thus, the present study aims to study expression patterns, biological functions, and diagnostic value of lncRNAs in CAD. METHODS: Using microarray, we performed the transcriptome-wide lncRNA and mRNAs expression profile of peripheral blood mononuclear cells (PBMCs) of 93 CAD patients and 48 healthy controls. Gene Ontology (GO) and pathway analysis for differentially expressed mRNAs were used to investigate underlying biological associations of differentially expressed lncRNAs, and path-net was created to depict interactions of significant pathways. qRT-PCR was used to validate selected lncRNAs in 412 CAD patients and 295 healthy controls. Receiver operating characteristic (ROC) curve analysis was performed to evaluate whether lncRNAs could be used in the diagnosis of CAD patients. Finally, the functional significance of validated lncRNAs was determined in THP-1-derived macrophages. RESULTS: We identified 1210 lncRNAs and 890 mRNAs differentially expressed from the expression profile and validated 7 lncRNAs. Two novel lncRNA biomarkers, ENST00000444488.1 and uc010yfd.1, together with CAD risk factors, had the better performance for discrimination of CAD patients from healthy controls, and ENST00000444488.1 could diagnose acute myocardial infarction (AMI) patients. The knockdown of 20 ENST00000444488.1, uc010yfd.1, ASO3973 and ENST00000602558.1 affected the expression of inflammation-related genes and their nearby genes in THP-1-derived macrophages, respectively. CONCLUSIONS: We offered a transcriptome wide overview of aberrantly expressed lncRNAs in CAD patients, and identified two novel lncRNA biomarkers for diagnosing CAD. Loss of validated lncRNAs regulated the expression of inflammation-related genes and their nearby genes. PMID- 30015301 TI - Lipid management in ACS: Should we go lower faster? AB - Low-density lipoprotein-cholesterol (LDL-C) is a well-accepted causal risk factor for athero-thrombotic cardiovascular disease, as demonstrated in large epidemiological studies, including Mendelian randomization data. Several randomized controlled trials and meta-analyzes have shown that lipid lowering therapies, such as statins and more recently the non-statin agents ezetimibe and Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) monoclonal antibodies (mAb), reduce cardiovascular events across a broad range of baseline LDL-C levels. Over time, the recommended target for LDL-C has become more stringent, moving from 2.6 mmol/l to 1.8 mmol/l in very high-risk patients. It is currently recommended to start high intensity statin treatment immediately after acute coronary syndromes (ACS) to maximally and rapidly reduce LDL-C. The novel treatment options enable the achievement of very low LDL-C levels below 1 mmol/l, with no reported safety issues, in particular with regard to neurocognitive events. However, current evidence supports the use of PCSK9 mAb treatment in ACS patients only after an initial 2-3 month run-up treatment adaptation period with maximally tolerated statin. The use of PCSK9 mAb immediately in the acute phase of ACS (<1 month) remains to be studied. Some data suggest that circulating PCSK9 increases coronary plaque vulnerability, inflammation as well as platelet aggregation in the acute phase of ACS, potentially justifying earlier PSCK9 mAb treatment initiation. As the use of novel treatment combinations in ACS is further explored to widen the perspectives of a more personalized approach for the management of ACS based on individual patient risk profile and baseline LDL-C values, their relative cost-effectiveness will also need to be assessed. PMID- 30015302 TI - Assessing levels of student nurse learning in community based health placement with vulnerable families: Knowledge development for future clinical practice. AB - BACKGROUND: Community services work with vulnerable families to assist them to link with health, education and welfare services. Community placements provide nursing students with understandings of the health impacts of social circumstances on broad population's. Nurses provide health care for vulnerable populations so it is important for students to gain experience in dealing with various population groups in a variety of settings. Community placements can increase student confidence to provide care for all people in the acute care setting. OBJECTIVES: The research project explored the use of a community placement to assist nursing students in applying psychosocial theories to practice; determining the affect of nursing students to the community service; and if the learning achieved in the placement was applicable to their future nursing practice were also objectives of the research. DESIGN: The mixed methods design used placement suitability focused questionnaires, and student, staff and clinical supervisor one-to-one interviews. SETTINGS: In 2015 a community based homelessness service which provides a home visiting service approached the School of Nursing and Midwifery to provide a community placement for nursing students. The urban homelessness service caters for 350 homeless clients per month. PARTICIPANTS: Eight second year nursing students and six fulltime homelessness staff, mainly social workers, participated in the surveys and interviews. METHODS: Nursing students were 'buddied' with a social worker and visited individuals and families recently placed in emergency housing. The student nurses (8) and homelessness staff (6) were surveyed and interviewed about their knowledge, skills and perceptions about the value of community based placements. RESULTS: Findings indicate student's recognition of the skills to be learned in a non-acute setting are applicable to all clinical settings and enhance student knowledge and potential future care. The staff in the homelessness service espouse the enhancement provided by the expertise of the nursing students working with vulnerable populations. This paper highlights the benefits as perceived by students on often undervalued community based placements. CONCLUSIONS: It is essential that universities collaborate with industry and consumers to ensure that the undergraduate programs offer a high standard of care and address current trends in the health care industry. There is a growing need for workforce development in primary healthcare and an increased understanding about how adversity can lead to ill health. PMID- 30015303 TI - We don't miter the sheets on the bed: Understanding the preceptor role in the enculturation of nursing students. AB - Preceptors play key roles in nursing students' socialization or formation, and transition from academia to practice. Students still struggle with this transition. Viewing student socialization to nursing as enculturation has provided valuable insights into faculty perceptions of this process. This focused ethnography explored preceptors' perceptions about nursing's culture and their role in bringing students into that culture. Data included semi-structured interviews with preceptor participants from three hospitals in two cities in a single Midwestern state. Analysis of verbatim transcripts followed Leininger's four phases of qualitative data analysis. The following themes emerged: nursing has a unique, dynamic professional culture that is difficult to describe and varies based on many different factors; nursing students are part of this unique, dynamic and professional nursing culture; there are multifaceted influences to the culture of nursing; preceptors help nursing students learn the real culture as opposed to the ideal aspects of the culture taught in school; and nursing students and preceptors mutually benefit from preceptor mentorship and role modeling. Viewing professional socialization as enculturation integrates various perspectives on work place learning for clinical nursing education and invites nurse preceptors' attention to sociocultural factors in this process. PMID- 30015304 TI - Simulation as an educational tool in acute nursing care: A controlled intervention study. AB - Simulations have become a common educational tool among nursing students; however, the impact of clinical simulations as tested using an experimental design is not yet well established. In a controlled intervention study, nursing students received either traditional classroom lessons (C) or traditional classroom lessons combined with simulation-based lessons at the hospital (I). The primary outcome variable was the basic knowledge of acute nursing measured by a multiple-choice questionnaire. Secondary outcome variables were grade point average, the students' perception of the learning process, and self-efficacy. Seventy-four students participated in the study; C:n = 36 and I:n = 38. Regarding basic knowledge, there was no significant difference between the groups (I:11.8 +/- 0.4, C:12.1 +/- 0.4, p = 0.54). The I-group had a more positive perception of the learning process (Delta:6.0 +/- 1.1,p < 0.002) and rated their self-efficacy higher (Delta:8.5 +/- 2.3,p < 0.002). The students reported higher levels of self efficacy, when combining the traditional lessons and simulation-based lessons. When combining the two approaches, their fundamental knowledge is not improved. PMID- 30015305 TI - Continuing professional development in mental health: Promoting dialogue and reflection through art. AB - International policy mandates that mental health consumers and carers are involved in the continuing professional development of nurses. However, within the literature, continuing professional development of mental health nurses continues to be delivered in didactic formats, with few examples of mental health nurses and consumers engaging together in the process. Consumers and carers are often excluded from professional development programs because of structural discrimination. Where they are included, it is often through storytelling that has been sanitised of challenging practice issues. There are few opportunities for reflection on practice. The purpose of this discussion article is to create debate about the involvement of mental health consumers and carers in professional development. Educators should consider artmaking between mental health consumers, carers and clinicians as a useful participatory process to support professional development, co-learning, mutual dialogue and reflection on practice. PMID- 30015306 TI - Clinical nursing leadership educational intervention for first-year nursing students: A qualitative evaluation. AB - Clinical nursing leadership is critical for quality care. All nurses including students should receive clinical nursing leadership education. Research pertaining to educational strategies on clinical leadership for nursing students remains sparse. The aim of this paper is to report the qualitative evaluation of a co-constructed educational intervention on clinical nursing leadership, developed for 1st year preregistration nursing students. The research question was "what are the components of an educational intervention that support the development of clinical nursing leadership in 1st year nursing students?". The intervention included videos, brainstorming, journal entries on students' clinical leadership paired with the observation of a nurse's clinical leadership. A research and development model guided the study. Focus groups and individual interviews were conducted with 23 students and 6 educators who tested the intervention. Thematic analysis revealed three intervention components that supported learning: visual examples at the student's level, observation of role models and animated discussions in small groups. Visual examples and observation of role models supported learning by expanding student's initial views of nursing beyond a technical role to one that is embedded with clinical nursing leadership. Animated discussions in small groups helped students learn to speak up and be open to other's opinions. PMID- 30015307 TI - Electrochemical simulation of three novel cardiovascular drugs phase I metabolism and development of a new method for determination of them by liquid chromatography coupled with tandem mass spectrometry. AB - In this study electrochemistry (EC) coupled with electrospray ionization mass spectrometry (ESI-MS) was used to study the metabolic fate of three novel cardiovascular drugs: rivaroxaban (RIV), aliskiren (ALS), and prasugrel (PRS). Mimicry of the oxidative phase I metabolism was achieved in a simple amperometric thin-layer cell equipped with a boron-doped diamond (MD) working electrode. Structures of the electrochemically-generated metabolites were elucidated from MS/MS experiments. Additionally, a sensitive, specific, and rapid ultra-high performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS) method has been developed and validated for the selected drugs in human urine samples. Three different sample preparation methods were compared and finally, sample preparation was accomplished through an ultrasound-assisted emulsification microextraction process (USAEME). The drugs were detected using a triple quadrupole tandem mass spectrometer by multiple reaction monitoring via an electrospray ionization source with positive ionization mode (ESI(+)). The results obtained by EC-MS were compared with conventional in vivo studies by analyzing urine samples from patients. Data from in vivo experiments showed good agreement with the data from electrochemical oxidation. Thus, EC-MS is very well suited for the simulation of the oxidative metabolism of rivaroxaban, aliskiren, and prasugrel as well. Moreover, electrochemical conversion of target compounds appears to be a new in vitro technology for the prediction of potential metabolites. PMID- 30015308 TI - Affinity purification of the avidin protein family, based on crystal structures of avidin-HABA complexes. AB - Since the importance of the high affinity between avidin and biotin, Kd = 3 * 10 16 M, gained universal recognition, numerous chemical, biological and medical avidin-biotin based applications have been developed. However, in some cases the high affinity may be a disadvantage, as this interaction is irreversible under physiological conditions. The dye, 4'-hydroxyazobenzene-2-carboxylic acid (HABA), binds avidin, at the biotin binding site, as determined by X-ray, at a much lower affinity constant, Kd = 6 * 10-6 M. We prepared a HABA affinity column (amber colored). Avidin bound to the column at a pH between 4 and 8.5, causing a change of color to red, and it could be eluted at mild conditions with buffers containing biotin, HABA, 1.5 M potassium chloride or a pH lower than 4.0 or higher than 8.5. Avidin eluted with HABA, created a red avidin-HABA complex, which was visualized. HABA free avidin was obtained by dialysis, which was followed by the loss of red coloration. The novel and easy to use HABA-affinity column was employed in our lab to prepare pure, fully glycosylated avidin from egg white. Most importantly, it may serve as an ideal tool for educational purposes, illuminating concepts of molecular recognition, reversible molecular binding, structure-based molecular design and solid phase chemical synthesis, as it is a reliable and visible reagent. PMID- 30015310 TI - PRiME pass-through purification of lignans in Silybum marianum and UPLC-MS/MS analysis. AB - A PRiME (process, robustness, improvements, matrix effects, ease of use) pass through cleanup procedure was developed for the extraction and purification of silychristins A and B, silybins A and B, isosilybins A and B, and silydianin in Silybum marianum. After optimizing the extracting solvent types and the sample loading volume, the crude extract was diluted to 3 mL with 95% acetonitrile and then loaded on the PRiME cartridge. The eluate was analyzed by ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). All the target analytes were deprotonated as [M-H]- at m/z 481 by conducting collision-induced dissociation (CID), and the major fragment ions were m/z 463 ([M-H2O-H]-), 453 ([M-CO-H]-), 355 ([M-C6H6O3-H]-), 301 ([M355-CO2-H]-), and 179 ([C10H11O3]-). Afterwards, this method was validated in terms of linearity (R2 > 0.9990), intra day precision (1.02%-3.79%), inter-day precision (1.59%-4.87%), sensitivity (LOD <= 0.45 MUg.kg-1 and LOQ <= 1.50 MUg.kg-1), and recovery (76.9-103.4%, RSD < 8.90%). Finally, the proposed protocol was successfully applied to eight batches of S. marianum samples. The total content of the seven active compounds varied amongst the batches from different places of origin. PMID- 30015309 TI - Determination of methyl isopropyl hydantoin from rat erythrocytes by gas chromatography mass-spectrometry to determine methyl isocyanate dose following inhalation exposure. AB - Methyl isocyanate (MIC) is an important precursor for industrial synthesis, but it is highly toxic. MIC causes irritation and damage to the eyes, respiratory tract, and skin. While current treatment is limited to supportive care and counteracting symptoms, promising countermeasures are being evaluated. Our work focuses on understanding the inhalation toxicity of MIC to develop effective therapeutic interventions. However, in-vivo inhalation exposure studies are limited by challenges in estimating the actual respiratory dose, due to animal-to animal variability in breathing rate, depth, etc. Therefore, a method was developed to estimate the inhaled MIC dose based on analysis of an N-terminal valine hemoglobin adduct. The method features a simple sample preparation scheme, including rapid isolation of hemoglobin, hydrolysis of the hemoglobin adduct with immediate conversion to methyl isopropyl hydantoin (MIH), rapid liquid-liquid extraction, and gas-chromatography mass-spectrometry analysis. The method produced a limit of detection of 0.05 mg MIH/kg RBC precipitate with a dynamic range from 0.05-25 mg MIH/kg. The precision, as measured by percent relative standard deviation, was <8.5%, and the accuracy was within 8% of the nominal concentration. The method was used to evaluate a potential correlation between MIH and MIC internal dose and proved promising. If successful, this method may be used to quantify the true internal dose of MIC from inhalation studies to help determine the effectiveness of MIC therapeutics. PMID- 30015311 TI - Development and validation of analytical methodology by GC-FID using hexadecyl propanoate as an internal standard to determine the bovine tallow methyl esters content. AB - EN 14103:2003 and EN 14103:2011 were developed in order to determine fatty acid methyl ester (FAME) content of biodiesel. The internal standards (IS) of biodiesel include methyl heptadecanoate (MHD) and methyl nonadecanoate (MND), respectively. However, since these ISs are also present in bovine tallow methyl esters (BTME) or overlapping peaks, they have not been efficient. This work proposes an improved BTME determination method by using hexadecyl propanoate (HDP) as an IS. For this purpose, an analytical methodology by Gas Chromatography Flame Ionization Detector (GC-FID) was developed and validated, where HDP demonstrated selectivity in retention time between peaks C16:1 and C18:0 for coconut and soybeans methyl esters and BTME, as well as resolution >1.5 for the BTME in split mode 30:1. Trueness in the determination of BTME content using the HDP as an IS was statistically equivalent to confidence interval of 95% for the null hypothesis statistic test, even when only 20% of the HDP was utilized in comparison with the IS concentrations defined by EN 14103:2003 and EN 14103:2011. This allowed the biodiesel analysis to be performed five times more with 1 g of HDP. Furthermore, the method developed enabled us to reduce the analysis time by 21.6%, without prejudice to the integration of peaks (C6:0 to C24:1). Regarding the repeatability and intermediate precision tests, results of RSD (%) <= 2% were reached. Additionally, the method developed has proved to be robust. HDP is a long-chain fatty alcohol ester absent from feedstocks used in biodiesel synthesis. It presents all of the characteristics for a good IS, ideal for application via internal standardization method, as recommended by EN 14103. PMID- 30015312 TI - A multiplex PCR amplification strategy coupled with microchip electrophoresis for simultaneous and sensitive detection of three foodborne bacteria. AB - Foodborne bacteria are some of the most important human pathogens and can cause many diseases. In this study, multiplex PCR amplification combined with microchip electrophoresis (MCE) was studied to simultaneously and sensitively detect Staphylococcus aureus, Proteus mirabilis, and Enterobacter sakazakii. In order to simultaneously and accurately detect the aim bacteria, three pairs of primers were specially designed for the multiplex PCR amplification of the target genes of three bacteria, which were the specific genes corresponding to these bacteria respectively. After the DNA fragments of three bacteria were simultaneously extracted, the multiplex PCR amplification was performed by adding the three pairs of specific primers in the mixed DNA fragments solution. The multiplex PCR products of the three food-borne pathogens were analyzed by MCE and the limits of detection of target DNA fragments were 1.2-2.2ngMUL-1, (S/N=3). The limits of detection of the aim bacteria were calculated as 53CFUmL-1 for Enterobacter sakazakii, 32CFUmL-1 for Proteus mirabilis, 28CFUmL-1 for Staphylococcus aureus, respectively. Satisfactory results were obtained when this method was applied to detect the three foodborne bacteria in milk samples. The experimental results show that this method has the advantages of quickness, less sample consumption, high selectivity and high sensitivity. PMID- 30015313 TI - Prenatal and childhood exposure to perfluoroalkyl substances (PFAS) and measures of attention, impulse control, and visual spatial abilities. AB - BACKGROUND: Despite evidence from toxicological studies describing the potential neurotoxicity of perfluoroalkyl substances (PFAS), their role in neurodevelopment remains uncertain amid inconsistent findings from epidemiological studies. METHODS: Using data from 218 mother-child dyads from the Health Outcomes and Measures of the Environment Study, we examined prenatal and childhood (3 and 8 years) serum concentrations of four PFAS and inattention, impulsivity, and visual spatial abilities. At 8 years, we used the Conners' Continuous Performance Test II to assess attention and impulse control and the Virtual Morris Water Maze (VMWM) to measure visual spatial abilities. RESULTS: In multiple informant models, there was no evidence to indicate that prenatal or childhood PFAS are associated with attention. However, there was an inverse association between prenatal ln-perfluorooctanoate (PFOA) and errors of commission (beta = -2.0, 95% Confidence Interval [CI] -3.8, -0.3). Ln-perfluorononanoate (PFNA) at 3 years was associated with longer (poorer) VMWM completion times of 3.6 seconds (CI 1.6, 5.6). However, higher concurrent concentrations of ln-perfluorohexane sulfonate (PFHxS) (beta = -2.4 s, 95% CI -4.4, -0.3) were associated with shorter (better) times. Higher prenatal PFHxS was positively associated with percentage of traveling distance in the correct quadrant (beta = 4.2%, 95% CI 0.8, 7.7), indicating better performance. CONCLUSION: Findings were mixed for prenatal and childhood PFAS concentrations and visual spatial abilities. There is not enough evidence to support that PFAS are associated with visual spatial abilities as assessed by the VMWM or CPT-II measures of inattention or impulsivity in children at age 8 years. PMID- 30015314 TI - A radioligand receptor binding assay for ciguatoxin monitoring in environmental samples: Method development and determination of quality control criteria. AB - Ciguatoxins are algal toxins responsible for tens of thousands of human intoxications yearly, both in tropical and subtropical endemic regions as well as worldwide through fish exportation. Previously developed methods for biotoxin surveillance in the environment and seafood include analytical methods and in vivo and in vitro bioassays. The radioligand receptor binding assay (r-RBA) is among the in vitro methodologies currently used for the detection and quantification of marine biotoxins. For the ciguatoxin group, the r-RBA has been widely used as a means to characterize the mode of action and as detection method in various biological matrices. Yet, screening methods have not been standardized, and the details of the ciguatoxin-specific r-RBA are not well documented, which limit interlaboratory comparison and progress toward method validation. This work presents the development of an optimized r-RBA for ciguatoxins and provides guidance on its use and quality control checks for analysis of environmental samples. We focus on the analysis of critical parameters involved in determining assay acceptability. Calculation of toxin concentrations in fish samples is illustrated with four examples. Thus, this paper provides the detailed information required for a full validation of the r RBA, a necessary step toward the development and implementation of a regulatory monitoring programme for ciguatoxins in seafood products using the r-RBA. PMID- 30015315 TI - Permafrost thaw and implications for the fate and transport of tritium in the Canadian north. AB - Layers of permafrost developed during the 1950s and 1960s incorporated tritium from the atmosphere that originated from global nuclear weapons testing. In regions underlain by substantial permafrost, this tritium has been effectively trapped in ice since it was deposited and subject to radioactive decay alone, which has substantially lengthened its environmental half-life compared to areas with little or no permafrost where the weapons-test era precipitation has been subject to both decay and hydrodynamic dispersion. The Arctic is warming three times faster than other parts of the world, with northern regions incurring some of the most pronounced effects of climate change, resulting in permafrost degradation. A series of 23 waterbodies across the Canadian sub-Arctic spanning the continuous, discontinuous and isolated patches permafrost zones in northern Manitoba, Northwest Territories and Labrador were sampled. Surface water and groundwater seepage samples were collected from each lake and analyzed for tritium, stable isotopes (delta18O and delta2H) and general water chemistry characteristics. Measured tritium was significantly higher in surface waters (SW) and groundwater seepage (GW) in water bodies located in the sporadic discontinuous (64 +/- 15 T U. in SW and 52 +/- 9 T U. in GW) and extensive discontinuous (53 +/- 7 T U. in SW and 61 +/- 7 T U. in GW) permafrost regions of the Northwest Territories than in regions underlain by continuous permafrost in northern Manitoba (<12 T U. in both SW and GW) or those within isolated patches of permafrost in Labrador (16 +/- 2 T U. in SW and 21 +/- 4 T U. in GW). The greatest tritium enrichment (up to 128 T U.) was observed in lakes near Jean Marie River in the Mackenzie River valley, a region known to be experiencing extensive permafrost degradation. These results demonstrate significant permafrost degradation in the central Mackenzie River basin and show that tritium is becoming increasingly mobile in the sub-Arctic environment-at concentrations higher than expected-as a result of a warming climate. A better understanding of the cycling of tritium in the environment will improve our understanding of Arctic radioecology under changing environmental conditions. PMID- 30015316 TI - Relative comparison of tissue specific bioaccumulation and radiation dose estimation in marine and freshwater bivalve molluscs following exposure to phosphorus-32. AB - With respect to environmental protection, understanding radionuclide bioconcentration is necessary to relate exposure to radiation dose and hence to biological responses. Few studies are available on tissue specific accumulation of short-lived radionuclides in aquatic invertebrates. Short-lived radionuclides such as 32Phosphorus (32P), although occurring in small quantities in the environment, are capable of concentrating in the biota, especially if they are chronically exposed. In this study, we firstly compared tissue specific bioaccumulation and release (depuration) of 32P in adult marine (Mytilus galloprovincialis, MG) and freshwater bivalve molluscs (Dreissena polymorpha, DP). Secondly, using the Environmental Risk from Ionising Contaminants Assessment and Management (ERICA) tool, we calculated tissue specific doses following determination of radionuclide concentration. Marine and freshwater bivalves were exposed for 10 days to varying 32P concentrations to acquire desired whole body average dose rates of 0.10, 1.0 and 10 mGy d-1. Dose rates encompass a screening dose rate value of 10 MUGy h-1 (0.24 mGy d-1), in accordance with the ERICA tool. This study is the first to relate tissue specific uptake and release (via excretion) of 32P from two anatomically similar bivalve species. Results showed highly tissue specific accumulation of this radionuclide and similarity of accumulation pattern between the two species. Our data, which highlights preferential 32P accumulation in specific tissues such as digestive gland, demonstrates that in some cases, tissue-specific dose rates may be required to fully evaluate the potential effects of radiation exposure on non-human biota. Differential sensitivity between biological tissues could result in detrimental biological responses at levels presumed to be acceptable when adopting a 'whole body' approach. PMID- 30015317 TI - A Rare Cause of Inguinal Mass: Round Ligament Cyst. AB - Round ligament mesothelial cyst is a rare cause of inguinal mass. Round ligament cysts are generally diagnosed during operation in cases who are operated with a pre-diagnosis of inguinal hernia. In this study, we aim to present two cases, who have applied to our clinic with the complaint of a mass in inguinal region and who are diagnosed as round ligament cyst, together with their ultrasound, magnetic resonance images and operation images. PMID- 30015318 TI - Distribution of lip and/or palate clefts types among children form Lodz during years 1981-2015. AB - INTRODUCTION: Cleft lip and/or palate are the most common face malformations. Clinical picture of these anomalies is very variable. Cleft can include only lip and/or alveolus, palate or all of these structures can be clefted. AIM: The aim of this paper is to present all particular types of clefts, their relationship to sex and body side in the group of children from Lodz during the years 1981-2015. MATERIAL AND METHOD: The study group included 434 patients with facial clefts (218 males and 216 females) in the age between 4 weeks to 18 years. RESULTS: In the analyzed group there were 181 palate clefts (41.7%), 156 lip and palate clefts (36%) and 97 lip clefts (22.3%). Detailed analysis of clefts types showed that isolated palate clefts are definitely more frequent in females than males (112 vs 69), while lip and palate clefts in boys than girls (96 vs. 60). CONCLUSIONS: During 35 years in children form Lodz the most common type of anomaly were palate clefts, followed by lip and palate clefts and the less frequent were lip clefts. Palate clefts are more common in girls, while lip and palate clefts in boys. Left-sided clefts are two times more common than right clefts. PMID- 30015319 TI - Does abdominal ultrasound is a useful tool in appendicitis diagnosis? AB - INTRODUCTION: Acute appendicitis is the most common acute abdominal illness. Despite diagnosis progress there is still 20% negative appendectomy rate. The aim of the study was to determine the usefulness of abdominal sonography in diagnosis of acute appendicitis. MATERIALS AND METHODS: Data were collected retrospectively from 326 patients who were operated with suspected appendicitis and had abdominal ultrasound before surgery. Appendicitis was confirmed by pathologic reports. There were two variants of positive abdominal sonography. In the first variant, the positive ultrasound was visualized inflamed appendix. In the second variant, the sonographic diagnosis of appendicitis was based on visualized inflamed appendix or one of indirect signs of appendicitis - localized periappendiceal fluid collection, enlarged lymph nodes, thickening of intestinal wall in right iliac fossa. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were defined and compared. RESULTS: 83,74% patients has appendicitis in pathologic report. In 39,53% cases appendix was visualized in abdominal ultrasound. In 65,95% cases of sonography indirect signs occurred. In the first variant sensitivity, specificity, PPV and NPV was 47,99%, 79,25%, 92,25% and 22,83%. In the second variant 67,77%, 43,40%, 86,05% and 20,72%. In the second variant sensitivity was significantly higher (p<0,001) but specificity was significantly lower (p<0,001). CONCLUSION: Limited sensitivity and specificity cannot confirm appendicitis. Typical clinical course with negative ultrasound should not delay the correct diagnosis and early surgical treatment. PMID- 30015320 TI - Surgical treatment of extra-appendiceal colorectal neuroendocrine tumors. AB - BACKGROUND: Extra-appendiceal colorectal neuroendocrine tumors are rare neoplasms with a variable biological behavior. MATERIALS AND METHODS: The study group consisted of 15 patients with an extra-appendiceal colorectal neuroendocrine tumor who underwent surgical resection (M/F=3:12, mean age=62.9 years). Lower grade neuroendocrine tumors and neuroendocrine carcinomas were recognized in 5 and 10 patients, respectively. Data were evaluated retrospectively with regard to clinical and pathologic characteristics and outcomes. RESULTS: The median age of the patients with lower-grade NETs was significantly lower than that in patients with NECs (53 yr vs. 68 yr, p=0.03). NETs G1-G2 were significantly smaller than neuroendocrine carcinomas (4.0 cm vs. 6.4 cm, p=0.02). There were no differences between lower-grade NETs and NECs with regard to tumor location, rate of nodal involvement and distant metastases. All the patients underwent open segmental resection of the colon or rectum. Complete resection was achieved in 3 of 5 patients from the lower-grade NET group, and in 5 of 10 patients in the NEC group. Overall survival was significantly better for lower-grade NETs tumors (p=0.005). The median survival was 4.8 months in the NEC group. The median survival in the lower-grade NET group was not achieved after a median follow-up of 69 months. Three-year overall survival was 100% for lower-grade NETs, and only 27% for NECs. CONCLUSION: Lower-grade neuroendocrine tumors seem to exhibit comparable potential for dissemination as neuroendocrine carcinomas, but prognostic implications of metastases are distinct. PMID- 30015321 TI - Barrett's esophagus and gland cancer - the experience of one center. AB - OBJECTIVE: The aim of the study was to evaluate the prevalence and clinical aspects of Barrett's esophagus and adenocarcinoma of the lower part of esophagus in gastroscopy. MATERIAL AND METHODS: Retrospective review of 10000 upper gastrointestinal endoscopic examinations were performed at the Department of Oncology Endoscopy in Bydgoszcz from 2004 to 2014 in terms of incidence of Barrett's esophagus and adenocarcinoma in the lower part of esophagus. RESULTS: The medical records of 5378 (53.8%) women and 4622 (46.2%) men were analyzed. The average age of men and women was 62.4 and 62.7, respectively. Barrett's esophagus was diagnosed in 67 patients, including 38 (56.7%) of men where the average age of men and women was 56.9 and 60.2 years, respectively. The most commonly reported symptom was heartburn occurred in 45 (67.2%) of patients. During ten years of follow-up PB examination the adenocarcinomas were detected in 3 (4.47%) cases. Adenocarcinoma was diagnosed in 46 patients, of whom 37 in men. In the case of 27 patients (58.7%), esophageal cancer was treated with the intention of radicalization. The probability of 5-year survival in these patients was 10.2% for women and 9.2% for men. CONCLUSIONS: The number of Barrett's esophagus and adenocarcinoma are increasing at 0.67% and 0.46% annually, respectively. The risk of adenocarcinoma developed from Barrett's esophagus during endoscopic follow-up period was 4.47%. Barrett's esophagus is more common in men before the age of 60, and nearly half of them have intestinal metaplasia without dysplasia. Probability of 5-year survival in patients with adenocarcinoma was 9.7%. PMID- 30015322 TI - Risk factors and inflammatory predictors for Anastomotic Leakage following Total Mesorectal Excision with defunctioning stoma. AB - BACKGROUND: This study aims to examine the factors involved in anastomotic leak (AL) following low anterior resection and total mesorectal excision (LAR-TME) and to determine the usefulness of early measurement of the inflammatory biomarkers C Reactive Protein (CRP) and Procalcitonin (PCT). METHODS: One hundred patients undergoing LAR-TME with a proximal diverting stoma were analyzed between 2013 and 2016. Postoperative CRP and PCT levels were measured on the 3rd and the 6th postoperative days. RESULTS: There were 11 clinical leaks with a negative impact in univariate analysis on AL of male gender, larger and stenotic tumours, intraoperative blood loss > 200 mL, the need for perioperative blood transfusion, postoperative anaemia and an operating time exceeding 180 minutes. On multivariate analysis, only perioperative blood transfusion was an independent AL risk factor. Recorded CRP was higher in AL patients when compared with non-AL cases on both the 3rd postoperative day (152.4 mg/L vs. 93 mg/L, respectively; P < 0.0001) and the 6th postoperative day (130.5 mg/L vs. 68.2 mg/L; P < 0.0001). The PCT levels also significantly differed between AL and non-AL cases on the 3rd postoperative day (0.5 ng/mL vs. 0.2 ng/mL, respectively; P < 0.0001) and the 6th postoperative day (1.16 ng/mL vs. 0.1 ng/mL, respectively; P < 0.0001). Both CRP and PCT showed high negative predictive values (NPV) for the diagnosis of an AL on both postoperative days. CONCLUSION: Following low restorative proctectomy, the high NPV of CRP and PCT measurements for the diagnosis of anastomotic leaks may assist decision-making for early hospital discharge. PMID- 30015323 TI - Diagnosis and treatment of obscure small bowel bleedings - analysis of double balloon enteroscopy role in diagnosing and treatment algorythm on basis of own material. AB - Introduction Obscure gastrointestinal bleeding (OGIB) is defined as a reccurent bleeding to gastrointestinal tract without evaluated origin, despite detiled endoscopic and image diagnostics. Mots common reason of OGIB i small bowel bleeding (SBB). Methodology Retrospective analysis of patients hospitalised in Gastroenterology Department of 7 Szpital Marynarki Wojennej w Gdansku with suspicion of OIGB. Results Double balloon enteroscopy was performed in 31 cases. Origin of bleeding was founded in small bowel in 87% of cases and in 64 % successfull,simultaneous therapeutic procedure was performed. No clinically relevant complications were noticed. Conclusion According to actual diagnostic algorythms of OGIB, double balloon enteroscopy is highly effective also in polish medical care system. This tehnique is a safe and effective tool in diagnostics and treatment of SBB, but its availability is still limited in Poland. Abstrakt. PMID- 30015324 TI - Desmoid tumor of the mesentery in a patient after restorative proctocolectomy as a result of familial adenomatous polyposis - case reports. AB - Desmoid (desmoid tumor) is a cytologically benign fibrous tumor that originates from musculoskeletal structures of the entire body [1]. The term "desmoid", first introduced by Muller in 1838, derives from the Greek word desmos, which means tendinous [2]. The etiopathogenesis of desmoid is not fully understood, most reports of publications regarding its treatment are based on individual case reports. The prognosis is good, and healing is achieved mainly through surgical excision of the lesion. The aim of the paper is to present a case of a 33-year old woman with diagnosed familial polyposis in the colon, who has been identified with mesenteric desmoid.ic desmoid. PMID- 30015325 TI - Surgical teaching at the Medical School Otto-von-Guericke University of Magdeburg - basic conceptual description. AB - Teaching in surgery, one of the classical big clinical and main disciplines beside internal medicine, needs to be also associated with great attention in regard to a valuable final result at the end of the study of human medicine. In particular, surgery is not only the subject to a large number of lectures it also represents one third (four months) of the compulsory internship (practical year - in German, "Praktisches Jahr") at the end of the study of medicine. Therefore, medical teaching of students should be always part of serious and steady attempts to optimize course und contents as a component of guiding activities focussing onto the substantial improvement of the study of medicine. In detail, the classical and traditionally established type of teaching, the (oral) lecture, has to be further developed and reasonably completed by numerous interactive and practice-oriented teaching, learning and examining modalities (obligatory or facultative seminars / courses, training in [very] small groups of students, bed side teaching, individual practical exercises within the SkillsLab, groups of young researchers, research projects in teaching, scientific publications on topics and recommendable experiences ot teaching including students, "Teach-the teacher" projects etc.). Although many novel concepts have been inaugurated and considerable advances have been achieved, there is a steady need for further improvement. In the presented representative but medical school-specific overview, the current complex surgical teaching concept, which has been continuously optimized over the last couple of years, at the Otto-von-Guericke University Medical School with University Hospital of Magdeburg (Germany) is described as a scientific and systematizing document as well as a manuscript associated with the ongoing preparation of an institutional "Teaching Manual" on surgical teaching and training for medical students. It should - last but not least - provide the basis for a public discussion, which vice versa might hopefully and possibly result in further structural reforms of (surgical) teaching in the near future. PMID- 30015326 TI - Chylous complications of various severity and manifestations within diverse compartments in reconstructive vascular surgery #) #) The manuscript is dedicated to Prof. Dr. Z. Halloul. AB - INTRODUCTION: Chylous complications, which occur also in the profile of vascularsurgical interventions with considerable frequency, are challenging with regard to their adequate management. Aim & method: Compact short overview on epidemiological, classifying, symptomatic, diagnostic and therapeutic aspects of chylous complications in vascular surgery, based on i) own clinical experiences, ii) a current selection of relevant scientific references and iii) representative case reports from clinical practice. Results (complex patient- & clinical finding associated aspects): - Basic treatment of lymphedema / postreconstructive edema comprises the complex physical therapy to improve edematous swelling, which need to be usually performed over years. - In case of lymphocele, wait-and-see strategy can be initially pursued to observe spontaneous clinical course. If the lymphocele and its clinical complaints persist, puncture, placement of a drainage or temporary instillation of doxycyclin or ethanol can be attempted. - In case of lymphatic fistula, vacuum-assisted closure dressing, radiation and selective ligation of lymphatic vessels after previous application of methylen blue dye can be used. - Chylascites and chylothorax should be primarily treated - as have been widely established in the mean time - with a consequently conservative approach comprising initially paracentesis / thoracocentesis, protein-enriched and low-fat diet containing middle chain triglycerides (MCT) or total parenteral nutrition combined with the application of a somatostatin analogue (surgical approach as ultima ratio only aiming at ligation of the lesioned lymphatic vessel - if necessary, including preoperative consumption of cream). SUMMARY: Chylous complications can be primarily treated with conservatice measures, which should be exploited using a step-wise approach prior to surgical intervention as ultima ratio. CONCLUSION: The experienced vascular surgeon should be aquainted with a sufficient, finding-adapted management of chylous complications. This requires a well-experienced clinician and surgeon with great expertise regarding the interdisciplinary setting comprising of interventional radiology, vascular (abdominal) surgery and partially surgical intensive care. PMID- 30015327 TI - GaN-based vertical-cavity surface-emitting lasers with AlInN/GaN distributed Bragg reflectors. AB - This paper describes the status and prospects of gallium nitride-based vertical cavity surface-emitting lasers (VCSELs) with semiconductor-based distributed Bragg reflectors. These optoelectronic devices, which emit laser light from the violet to green region, are expected to be a superior light source for the next generation of displays and illumination, such as retinal scanning displays and adaptive headlights. The development status and prospects are discussed in comparison with already commercialized gallium arsenide-based infrared VCSELs. PMID- 30015328 TI - Manipulating the flow of light using Dirac-cone zero-index metamaterials. AB - Metamaterials with a refractive index of zero exhibit properties that are important for integrated optics. Possessing an infinite effective wavelength and zero spatial phase change, zero-index metamaterials may be especially useful for routing on-chip photonic processes and reducing the footprint of nonlinear interactions. Zero-index has only been achieved recently in an integrated platform through a Dirac-cone dispersion, enabling some of these more exciting applications in an integrated platform. This paper presents an overview of Dirac cone zero-index metamaterials, including the fundamental physics, history and demonstration in the optical regime, as well as current challenges and future directions. PMID- 30015329 TI - Temperature dependence of nonlinear susceptibilities in an infinite range interaction model. AB - We present a model to probe metamagnetic properties in systems with a variable number of interacting spins. Thermodynamic properties such as the magnetization per particle [Formula: see text], linear susceptibility [Formula: see text], and nonlinear susceptibilities [Formula: see text] and [Formula: see text] were calculated. The model produces a different magnetic response for N particles when comparing to N - 1 particles for small [Formula: see text]. For an even number of particles, the susceptibilities show maxima in their temperature dependence. An odd number produces an additional free spin response that dominates at low temperatures. This free spin response also produces a step in the field-dependent magnetization per particle at B = 0 for odd N. The magnetization shows N/2 steps at [Formula: see text] with integer n for even N and [Formula: see text] additional steps at [Formula: see text] with integer n for odd N. Small clusters respond with metamagnetism in an otherwise isotropic spin space, while the large clusters show no metamagnetism. PMID- 30015330 TI - Relaxation of nonequilibrium quasiparticles in mesoscopic size superconductors. AB - Rapid development of micro- and nanofabrication methods have provoked interest and enabled experimental studies of electronic properties of a vast class of (sub)micrometer-size solid state systems. Mesoscopic-size hybrid structures, containing superconducting elements, have become interesting objects for basic research studies and various applications, ranging from medical and astrophysical sensors to quantum computing. One of the most important aspects of physics, governing the behavior of such systems, is the finite concentration of nonequilibrium quasiparticles, present in a superconductor even well below the temperature of superconducting transition. Those nonequilibrium excitations might limit the performance of a variety of superconducting devices, like superconducting qubits, single-electron turnstiles and microrefrigerators. On the contrary, in some applications, like detectors of electromagnetic radiation, the nonequilibrium state is essential for their operation. It is therefore of vital importance to study the mechanisms of nonequilibrium quasiparticle relaxation in superconductors of mesoscopic dimensions, where the whole structure can be considered as an 'interface'. At early stages of research the problem was mostly studied in relatively massive systems and at high temperatures close to the critical temperature of a superconductor. We review the recent progress in studies of nonequilibrium quasiparticle relaxation in superconductors including the low temperature limit. We also discuss the open physical questions and perspectives of development in the field. PMID- 30015331 TI - Electrical contact resistance in graphite-graphene contacts from ab initio methods. AB - We study the ballistic transmission and the contact resistance (R c) of a graphite-graphene contact in a top contact geometry from first principles. We find that the calculated R c's depend on the amount of graphene-graphite overlap, but quickly saturate for transfer lengths of the order of a few tens of A. For contacts overlapping more than this transfer length, the R c can be lower than the 100 [Formula: see text] mark. On the other hand, edge graphite-graphene contacts are expected to have very low contact resistance. PMID- 30015332 TI - Influence of morphology on electrical and optical properties of graphene/Al-doped ZnO-nanorod composites. AB - The development of future 3D-printed electronics relies on the access to highly conductive inexpensive materials that are printable at low temperatures (<100 ?C). The implementation of available materials for these applications are, however, still limited by issues related to cost and printing quality. Here, we report on the simple hydrothermal growth of novel nanocomposites that are well suited for conductive printing applications. The nanocomposites comprise highly Al-doped ZnO nanorods grown on graphene nanoplatelets (GNPs). The ZnO nanorods play the two major roles of (i) preventing GNPs from agglomerating and (ii) promoting electrical conduction paths between the graphene platelets. The effect of two different ZnO-nanorod morphologies with varying Al-doping concentration on the nanocomposite conductivity and the graphene dispersity are investigated. Time dependent absorption, photoluminescence and photoconductivity measurements show that growth in high pH solutions promotes a better graphene dispersity, higher doping levels and enhanced bonding between the graphene and the ZnO nanorods. Growth in low pH solutions yields samples characterized by a higher conductivity and a reduced number of surface defects. These samples also exhibit a large persistent photoconductivity attributed to an effective charge separation and transfer from the nanorods to the graphene platelets. Our findings can be used to tailor the conductivity of novel printable composites, or for fabrication of large volumes of inexpensive porous conjugated graphene-semiconductor composites. PMID- 30015333 TI - Psychological Status of Volunteers in a Phase I Clinical Trial Assessed by Symptom Checklist 90 (SCL-90) and Eysenck Personality Questionnaire (EPQ). AB - BACKGROUND The psychological status of volunteers was investigated to provide a theoretical method for Phase I clinical trial management and result analysis. MATERIAL AND METHODS The Symptom Checklist 90 (SCL-90) and Eysenck Personality Questionnaire (EPQ) were used to assess the psychological status 200 healthy Chinese volunteers. RESULTS SCL-90 results indicate that the average value of positive factors is 10.32+/-14.26 by self-assessment of healthy volunteers, somatization factor is 1.13+/-0.13, compulsive symptom factor is 1.29+/-0.27, interpersonal sensitivity factor is 1.31+/-0.21, depression factor is 1.26+/ 0.33, anxiety factor is 1.21+/-0.21, hostility factor is 1.08+/-0.26, phobia factor is 1.05+/-0.18, paranoid factor is 1.12+/-0.23, and psychotic symptom factor is 1.17+/-0.26. CONCLUSIONS Compared to the norm in China, the score of each factor of healthy volunteers was relatively low, with a statistically significant difference (P<0.001). EPQ results show that P score was 4.59+/-2.33, E score is 13.13+/-4.32, N score was 6.89+/-5.26, and L score was 13.21+/-4.25 for the 200 healthy volunteers. Compared to the norm in China, the P and N scores were lower, and the E and L scores were higher, with a statistically significant difference (P<0.001). PMID- 30015335 TI - Palladium-catalyzed C(carbonyl)-C bond cleavage of amides: a facile access to phenylcarbamate derivatives with alcohols. AB - A sulfur-containing auxiliary enabled palladium-catalyzed C(carbonyl)-C bond activation of amides was reported to form phenylcarbamate derivatives with alcohols. Both alkyl and benzyl alcohols could be employed well with yields up to 85%. Derivations from phenylcarbamates to ureas and thiocarbamates illustrated the potential applications of this sequential C-C cleavage/C-O coupling reaction. PMID- 30015337 TI - Correction: Are current guidelines for sun protection optimal for health? Exploring the evidence. AB - Correction for 'Are current guidelines for sun protection optimal for health? Exploring the evidence' by Robyn M. Lucas et al., Photochem. Photobiol. Sci., 2018, DOI: 10.1039/c7pp00374a. PMID- 30015338 TI - Coincident modulation of lattice and electron thermal transport performance in MXenes via surface functionalization. AB - Efficiently modulating the thermal transport performance of materials including MXenes is highly desired as heat transfer is critical in a wide range of applications. However, the design principles for MXenes to achieve optimized thermal conductivity are not yet understood. Herein we highlight that the thermal conductivity modulation can be achieved by altering the surface fuctionalization, which also exhibits unexpected coincident effects on both the lattice and electron contribution to thermal transport. Our results indicate that the functionalization of O significantly decreases both the lattice and electron thermal conductivities of Ti2C MXenes because O will induce not only a shorter phonon relaxation time but also a metal-semiconductor transition, showing great potential for applications including thermoelectrics. In contrast to O, after being functionalized by F or OH both the lattice and electron thermal conductivities are increased, which will improve heat dissipation in electronics and batteries. Our findings will provide a fundamental guideline to the design of MXene-based devices with optimal thermal transport performance. PMID- 30015339 TI - Localization of transmembrane multiblock amphiphilic molecules in phase-separated vesicles. AB - A series of triblock amphiphilic molecules bearing hydrophilic PEG chains at both ends of the long aromatic hydrophobic moieties were obtained serendipitously. The molecules involve linearly connected diarylethyne and diarylbutadiyne units, which show characteristic emissions upon excitation by UV light. These emissions showed red-shifts upon an increase in the solvent polarity, where the shifts are larger for the molecules with longer aromatic moieties. The distribution of these molecules in phase-separated membranes consisting of DOPC/DPPC/cholesterol was studied by fluorescence microscopy. It was found that most compounds, except for that with the longest hydrophobic unit, were selectively distributed in the Ld phase consisting mainly of DOPC. Interestingly, some of them were suggested to encourage delocalization of cholesterol in both the Lo and Ld phases. PMID- 30015343 TI - Tunable spin states in the two-dimensional magnet CrI3. AB - The recent discovery of ferromagnetic single-layer CrI3 creates ample opportunities for studying the fundamental properties and the spintronic applications of atomically thin magnets. Through first-principles calculations and model Hamiltonian simulations, here we build for the first time a substantial magnetic phase diagram under lateral strain and charge doping, the two factors that are easily modulated in single-layer CrI3via substrate and gating controls. We demonstrate that both lateral strain and charge doping efficiently change the coupling between the local spins and thus have unexpected effects on the magnetic properties of CrI3. In particular, the strain tunes the magnetic order and anisotropy: a compressive strain leads to a phase transition from a ferromagnetic insulator to an antiferromagnetic insulator, while a tensile strain can flip the magnetic orientation from off-plane to in-plane. Furthermore, we find that the phase transition under compressive strain is insensitive to charge doping, whereas the phase transition under tensile strain is modulated by electron doping significantly. Our predicted magnetic phase diagram and rationalized analysis indicate the single-layer CrI3 to be an ideal system to harness both basic magnetic physics and building blocks for magnetoelastic applications. PMID- 30015344 TI - Plasmon-driven water splitting enhancement on plasmonic metal-insulator semiconductor hetero-nanostructures: unraveling the crucial role of interfacial engineering. AB - Understanding and controlling the charge transfer behavior across the interface/junction in hybrid nanostructures is essential for various plasmon enhanced catalytic reactions. The rational design of plasmonic nanostructures offers a unique capability for eliminating the daunting complexity of the electronic effect induced by interfacial interactions and maximizing the conversion efficiency of solar energy into chemical energy by surface coupling. Herein, we tactfully construct a new type of plasmon-driven photoanode based on plasmonic metal-insulator-semiconductor (PMIS) hetero-nanostructures (Au@SiO2NP decorated alpha-Fe2O3 nanorod array), by using Fe2O3 nanoarrays as model semiconductor structures and Au@SiO2 NPs as photosensitizers, for optimizing the photoelectrochemical (PEC) water splitting performance. The thin insulating layer (SiO2) of the hetero-nanostructure has been found to play a crucial role in significantly enhancing the plasmon-driven water splitting performance via eliminating the negative effect of surface states (resulting in Fermi level pinning and recombination) at the metal-semiconductor interface, suppressing the recombination of current carriers, as well as maximizing the metal-semiconductor barrier height. This study provides new insight into a novel plasmonic nanocatalyst design by rational interface engineering and will be of benefit for a better understanding of manipulating the interfacial electronic properties between plasmonic nanocrystals and semiconductors for catalytic applications. PMID- 30015347 TI - Sensitive and label-free discrimination of 5-hydroxymethylcytosine and 5 methylcytosine in DNA by ligation-mediated rolling circle amplification. AB - We develop a label-free fluorescence method for sensitive discrimination of 5 hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) based on the specific oxidation of 5hmC to 5-formylcytosine (5fC) and the subsequent conversion to uracil (U) in combination with ligation-mediated rolling circle amplification (RCA). This method exhibits high sensitivity with a detection limit of as low as 34.8 fM. It can discriminate as low as the 0.01% 5hmC level from the mixture, and exhibits good performance in serum sample analysis as well. PMID- 30015349 TI - Single lithium-ion polymer electrolytes based on poly(ionic liquid)s for lithium ion batteries. AB - A promising method of synthesizing a lithium-containing room temperature polymeric ionic liquid (PIL) by utilizing the zwitterionic effect to turn a lithium salt into a liquid for single lithium-ion conduction was proposed. In this work, the room temperature PIL was constructed by the equimolar monomer mixture of zwitterion 3-(1-vinyl-3-imidazolic)propanesulfonate (VIPS) and 4 styrenesulfnny(trifluoromethylsulfony)imde (LiSTFSI) based on intermolecular electrostatic interactions. In situ photopolymerization with flexible chain poly(ethylene glycol)methyl ether methacrylate (PEGM) and cross-linker poly(ethylene glycol)dimethacrylate (PEGDM) in the presence of propylene carbonate (PC) generated free-standing PIL electrolyte films. The PIL electrolytes with Li+-rich channels have an excellent lithium transference number approaching unity (0.93 at room temperature) while attaining comparable ionic conductivity (sigma ~ 1.31 * 10-4 S cm-1 at 30 degrees C). The charge-discharge performance of a Li/LiFePO4 half-cell equipped with this PIL electrolyte would provide a promising model system for novel single lithium ion conductors. PMID- 30015351 TI - Pathology and terminology of interstitial cystitis/bladder pain syndrome: A review. AB - Interstitial cystitis/bladder pain syndrome (IC/BPS) is an umbrella term of chronic debilitating conditions of unknown etiology characterized by symptoms of lower urinary tract hypersensitivity such as bladder pain/discomfort, urgency, and urinary frequency. The pathological features of IC/BPS have been generally reported as non-specific chronic inflammatory changes, with mast cell infiltration as a potential key finding. However, growing evidence reveals a histological distinction between IC/BPS with Hunner lesions and IC/BPS without Hunner lesions, and also sheds doubt on the diagnostic value of the mast cell count. Specifically, IC/BPS with Hunner lesions is an inflammatory disorder characterized by pancystitis with B cell abnormalities and epithelial denudation, while IC/BPS without Hunner lesions shows minimal histological changes. The umbrella term "IC/BPS" connects totally distinct clinical entities. Pathological evaluation thus plays an important role in the precise subtyping and clinical management of IC/BPS. In addition, terminology should be developed to refer separately to IC/BPS with Hunner lesions and IC/BPS without Hunner lesions. PMID- 30015353 TI - Sperm head morphology is associated with sperm swimming speed: A comparative study of songbirds using electron microscopy. AB - Sperm exhibit extraordinary levels of morphological diversification across the animal kingdom. In songbirds, sperm have a helically shaped head incorporating a distinct acrosomal membrane or "helical keel," the form and extent of which varies across species. The functional significance of this helical shape, however, remains unknown. Using scanning electron microscopy, we quantified inter and intraspecific variation in sperm head morphology across 36 songbird species (Passeriformes: Passerida). Using phylogenetic comparative methods, we investigated the relationship between sperm head morphology and both sperm swimming speed and the frequency of extra-pair young (EPY). We found that species whose sperm had a relatively more pronounced helical form (i.e., long acrosome, short nucleus, wide helical membrane, and a more pronounced waveform along the sperm head "core") had faster-swimming sperm. We found no evidence of a relationship between interspecific variation in sperm head morphology and EPY, although we did find that among- and within-male variation in sperm head traits were negatively correlated with EPY. Applying principles of fluid mechanics, we discuss how the helical form of the sperm head may influence swimming speed, and suggest that further studies considering aspects of sperm morphology beyond sperm length are needed to improve our understanding of sperm structure-function relationships. PMID- 30015352 TI - Reduction in the colonization of Staphylococcus aureus on the skin surface under calcium-/magnesium-depleted conditions. AB - : Excessive expansion of Staphylococcus aureus is associated with several skin diseases, including atopic dermatitis (AD). Recently, we have demonstrated that washing skins with ultra-pure soft water containing little bivalent metal ions improved skin conditions of atopic subjects. In this study, we investigated the roles of calcium or magnesium on the proliferation of S. aureus both in vitro and in vivo. Depletion of calcium and magnesium in the culture medium significantly suppressed the expansion of S. aureus growth. When S. aureus, diluted with water containing calcium/magnesium at the concentration of medium-hard water (83.0 mg l 1 as CaCO3 ) or the one that contains little calcium/magnesium, was applied onto the tape-stripped skin of Hos:HR-1 mice, growth of S. aureus in water without those minerals on the skin was suppressed. These results suggest that depletion of both calcium and magnesium abrogate the proliferation of S. aureus not only in the culture system but also on the skin surface of mice. Since colonization of S. aureus on the skin is well-known to exacerbate AD symptoms, usage of ultra-pure soft water containing less calcium and magnesium may improve the skin condition through the suppression of S. aureus growth on the skin of patients with skin problems. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the importance of calcium and magnesium for the colonization and growth of Staphylococcus aureus by using both in vitro culture systems and in vivo experiments on the murine skin. Our results indicate that the removal of these metal ions is probably beneficial for protecting the skin from S. aureus. Thus, using ultra-pure soft water without metal ions may improve the skin condition of patients with skin problems through the protection from S. aureus colonization. PMID- 30015354 TI - Novel mechanisms regulating endothelial barrier function in the pulmonary microcirculation. AB - The pulmonary epithelial and vascular endothelial cell layers provide two sequential physical and immunological barriers that together form a semi permeable interface and prevent alveolar and interstitial oedema formation. In this review, we focus specifically on the continuous endothelium of the pulmonary microvascular bed that warrants strict control of the exchange of gases, fluid, solutes and circulating cells between the plasma and the interstitial space. The present review provides an overview of emerging molecular mechanisms that permit constant transcellular exchange between the vascular and interstitial compartment, and cause, prevent or reverse lung endothelial barrier failure under experimental conditions, yet with a clinical perspective. Based on recent findings and at times seemingly conflicting results we discuss emerging paradigms of permeability regulation by altered ion transport as well as shifts in the homeostasis of sphingolipids, angiopoietins and prostaglandins. PMID- 30015355 TI - IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. AB - Human cancers, including hepatocellular carcinoma (HCC), are characterized by a high degree of drug resistance in chemotherapy. However, the underlying molecular mechanism remains unknown. To the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the regulation of macrophage polarization, M1-type and M2-type macrophages were separately induced using lipopolysaccharide and interleukin-4 (IL-4), and we found that the IL 6/STAT3 signaling pathway was inhibited in M1-type macrophages but activated in M2-type macrophages. After anti-IL-6-treated macrophages were separately induced by lipopolysaccharide and IL-4, we found that the inhibition of IL-6/STAT3 signaling pathway turned macrophages into M1-type. Co-culture with M1-type macrophages reduced HCC cell viability, proliferation, invasion, migration, drug resistance, but increased apoptosis. Co-culture with M2-type macrophages yielded reciprocal results. The inhibition of IL-6/STAT3 signaling pathway mediated by anti-IL6 was shown to significantly enhance the effects of M1-type macrophages on HCC cells and rescue HCC cells from co-culture with M2-type macrophages. Tumor xenografts of co-cultured HCC cells were established in nude mice and the results showed that the inhibition of IL-6/STAT3 signaling pathway mediated by anti-IL6 was found to reduce tumor formation of HCC cells co-cultured with M1- or M2-type macrophages and lung metastases. The current study reveals a novel mechanism of IL-6/STAT3 signaling pathway in the regulation of macrophage polarization, thus contributing to HCC metastasis and drug resistance in chemotherapy. PMID- 30015356 TI - Influence of infantile hemangioma severity and activity on QoL of patients and their parents: A cross-sectional study. AB - BACKGROUND: Quality of life (QoL) data are lacking in children with infantile hemangioma (IH) and their parents/caregivers. Available data are conflicting. OBJECTIVES: To determine QoL of (parents of) patients with IH in the proliferative phase related to IH-severity and activity. METHODS: Parents of 59 IH-patients (<= 6 months) were asked to fill in the Dutch IH-specific QoL questionnaire (D-IH-QoL) within 1 month after their first visit to our tertiary referral center. Hemangioma Severity Scale (HSS) score and Hemangioma Activity Score (HAS) were assessed. RESULTS: D-IH-QoL-scores were low; mean: 22.6 (range 1 56; max 116). Mean HSS score and HAS score were 8.4 (range 2-28) and 4.0 (range 1.5-6), respectively. Higher HSS scores correlated with worse QoL (rho = .358; P = .005). HAS scores did not correlate with QoL scores. CONCLUSION: An IH only seems to have limited influence on QoL in young children and their parents in the first month of their first doctor's visit. QoL is more affected in more severe IH. Physicians should be alert to the impact of IH, optionally guided by the HSS score. PMID- 30015357 TI - Improved Outcome in an Animal Model of Prolonged Cardiac Arrest Through Pulsatile High Pressure Controlled Automated Reperfusion of the Whole Body. AB - The reperfusion period after extracorporeal cardiopulmonary resuscitation has been recognized as a key player in improving the outcome after cardiac arrest (CA). Our aim was to evaluate the effects of high mean arterial pressure (MAP) and pulsatile flow during controlled automated reperfusion of the whole body. Following 20 min of normothermic CA, high MAP, and pulsatile blood flow (pulsatile group, n = 10) or low MAP and nonpulsatile flow (nonpulsatile group, n = 6) controlled automated reperfusion of the whole body was commenced through the femoral vessels of German landrace pigs for 60 min. Afterwards, animals were observed for eight days. Blood samples were analyzed throughout the experiment and a species-specific neurologic disability score (NDS) was used for neurologic evaluation. In the pulsatile group, nine animals finished the study protocol, while no animal survived postoperative day four in the nonpulsatile group. NDS were significantly better at any given time in the pulsatile group and reached overall satisfactory outcome values. In addition, blood analyses revealed lower levels of lactate in the pulsatile group compared to the nonpulsatile group. This study demonstrates superior survival and neurologic outcome when using pulsatile high pressure automated reperfusion following 20 min of normothermic CA compared to nonpulsatile flow and low MAP. This study strongly supports regulating the reperfusion period after prolonged periods of CA. PMID- 30015358 TI - Video modelling interventions improve social communication skills for individuals with Autism Spectrum Disorder. PMID- 30015359 TI - Protein kinase CK2 modulation of pyruvate kinase M isoforms augments the Warburg effect in cancer cells. AB - Protein kinase CK2 is active in cancer cells. Previously, we reported that increased CK2 activity could induce epithelial mesenchymal transition of cancer cells. CK2 also induced epithelial mesenchymal transition in colon cancer cell lines such as HT29 and SW620, and the transitioned cells (CK2alpha cells) became more proliferative than the controls. We assumed that CK2 could affect cancer cell growth by modulating their energy metabolism. Here, we examined the molecular effects of CK2 on the glucose metabolism of cancer cells. We found that CK2alpha cells consumed more glucose and produced more lactate than control cells did. An XF glycolysis stress test showed that aerobic glycolysis was augmented up to the cancer cell's maximal glycolytic capacity in CK2alpha cells. Molecular analysis revealed that pyruvate kinase M1 was downregulated and pyruvate kinase M2 was nuclear localized in CK2alpha cells. Consequently, the expression and activity of lactate dehydrogenase A (LDHA) were upregulated. Treatment with FX11 a specific LDHA inhibitor-or clustered regularly interspaced short palindromic repeats (CRISPR)-mediated knockout of LDHA inhibited the CK2-driven proliferation of cancer cells. We conclude that CK2 augments the Warburg effect, resulting in increased proliferation of cancer cells. PMID- 30015360 TI - Phenomenological contribution to understanding of vocally disruptive behaviour: A clinical case study in a patient with dementia. AB - BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) cause great suffering in patients and their families. Phenomenology can help clarify the diagnosis and propose some new therapeutic responses using Daseinsanalyse. Separation issues understood using the phenomenological description of the melancholic type (MT) by Tellenbach may further shed light on our understanding of depression in dementia. SUBJECT AND METHODS: In a 90-year-old woman presenting with advanced (Clinical Dementia Rating 3) mixed dementia and BPSD in the form of vocally disruptive behaviour (VDB), we discuss separation anxiety as the aetiopathogenic hypothesis. Depression and BPSD were assessed using the Neuropsychiatric Inventory, Cornell scale, and Montgomery-Asberg Depression Rating Scale to confirm our second phenomenological diagnostic hypothesis, ie, melancholy. The Big Five Inventory scale filled in by a proxy was also used to evaluate the patient's premorbid personality. We then propose an explanatory frame of VDB and depression through the standard phenomenological assessment of its relation to time, space, self, and other. RESULTS: Confirming MT, we found an inhibited temperament and low openness to experience in the patient, as well as a symbiotic relationship with a close relative (the other). CONCLUSION: Separation anxiety may well explain the patient's MT expressed by VDB. Melancholic type and her symbiotic relationship led to a situation unbearable to the patient and her close relative unable to delegate care to a specialized team. RUNNING HEAD: Phenomenology in vocally disruptive behaviour in dementia. We have found new explanations in similar clinical cases in dementia as follows. A patient presenting with vocally disruptive behaviour has a melancholic type, a behavioural-inhibited temperament, and marital violence in the past. Phenomenology may help explain this profile with neurobiological disorders. The life trajectory, from childhood into older age, must be taken into account to understand behavioural and psychological symptoms of dementia. PMID- 30015361 TI - Surgical Neuromodulation of Tinnitus: A Review of Current Therapies and Future Applications. AB - INTRODUCTION: Tinnitus is the conscious perception of an auditory sensation in the absence of external stimulus. Proposed theories are based on neuroplastic changes that occur due to sensory deprivation. The authors review the relevant literature on functional imaging and neuromodulation of tinnitus and describe potential targets for deep brain stimulation (DBS). MATERIALS AND METHODS: A MEDLINE keyword and Medical Subject Heading term literature search was performed using PubMed for tinnitus, neuromodulation, DBS, transcranial magnetic stimulation, epidural electrode stimulation, intradural electrode stimulation, functional imaging, and connectivity. Data from these reports were extracted and reviewed. RESULTS: Multiple imaging studies are employed to understand the pathophysiology of tinnitus. Abnormal regions and altered connectivity implicated in tinnitus include auditory pathway and limbic structures. Neuromodulation attempts to correct this hyperexcitable state by disrupting these aberrant oscillations and returning activity to baseline. Applied treatment modalities include transcranial magnetic stimulation, epidural/intradural electrode stimulation, and DBS. More recently, modulation of autonomic pathways through vagus nerve stimulation and paired auditory sounds has demonstrated tinnitus improvement via plasticity changes. CONCLUSIONS: DBS shows much promise as a therapeutic option for tinnitus. Stimulation of the auditory pathway, particularly the medial geniculate body, could counteract thalamocortical dysrhythmias and reduce gamma activity implicated in the tinnitus percept. Stimulation of the limbic pathway could decrease attention to and perception of tinnitus. Additional studies, focusing on the involvement of thalamic and limbic structures in the pathophysiology of tinnitus, are needed to support the use of DBS. PMID- 30015362 TI - Stuck in the Clinic: Vernacular Healing and Medical Anthropology in Contemporary sub-Saharan Africa. AB - While vernacular therapeutics had long been a topic of interest to many writing about medicine and healing in Africa, with a few exceptions most recent anthropological writings on medicine in Africa are focused on biomedicine. In this article, I trace this shift back to the turn of the millennium and the convergence of three events: the emergence of global health, the accession of the occult economies paradigm, and critiques of culturalism in medical anthropology. I argue that these three shifts led to research projects and priorities that looked different from those defined and undertaken as late as the late 1990s. While seeking to avoid the errors that could come with writing about vernacular therapeutic traditions in Africa as bounded comprehensive systems, I argue that there are empirical, political, and practical reasons why medical anthropologists may want to reconsider our collective research priorities. PMID- 30015363 TI - Performance and outcomes of noninvasive prenatal testing for twin pregnancies in Japan. AB - AIM: The purpose of this study was to describe the characteristics of women with twin pregnancies who undergo noninvasive prenatal testing (NIPT) as well as the post-partum and neonatal outcomes of such cases in Japan. METHODS: The study population consisted of women who were pregnant with twins and who underwent NIPT using massively parallel sequencing (MPS) at Nagoya City University Hospital between April 2013 and June 2016. Questionnaires were completed pre-NIPT and post partum. RESULTS: Among 4009 women who underwent NIPT during the study period, 75 women (1.9%) were pregnant with twins. Fifteen women (20%) experienced vanishing twin/intrauterine fetal deaths at <22 weeks, and 60 women (80%) had normal twin pregnancies at the time of genetic counseling for NIPT. The use of NIPT was correlated with increased proportions of women using assisted reproductive technology (ART). The test had a high performance, with a false-positive rate of 1.7% and no false negatives. CONCLUSION: In this study, NIPT had a high performance, with a false positive rate of 1.7% and no false negatives. When treating women with twin pregnancies, the efficacy of NIPT should be explained during genetic counseling. Further larger studies are required to assess the reliability and validity of NIPT in twin pregnancies. PMID- 30015364 TI - Mixed mold pulmonary infections in haematological cancer patients in a tertiary care cancer centre. AB - There is a paucity of data regarding mixed mold pulmonary infections (MMPIs) in patients with haematological malignancies with or without haematopoietic stem cell transplantation (HSCT). We retrospectively studied 27 such patients (2005 2015) and compared them to patients with invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus. Factors associated with the diagnosis of MMPIs were significant corticosteroid use [20 (74%) vs 6 (22%), P < 0.001], sputum as the source specimen [13 (48%) vs 3 (11%), P = 0.003], younger age (median age: 58 vs 66 years, P = 0.006), and male sex [22 (81%) vs 13 (48%), P = 0.01]. Haematological cancers other than acute myeloid leukaemia (AML)/myelodysplastic syndromes (MDS) were less common in MMPIs than in IPA patients [AML/MDS: 6 (22%) vs 14 (52%), P = 0.04]. Only significant corticosteroid use [95% CI (2.7-42.7), P < 0.001], and sputum as the source specimen [95% (1.6-41.6), P = 0.012] were statistically significant as independently associated with increased risk of MMPIs diagnosis in multivariate analysis. Total mortality rate at day 42 postdiagnosis was comparable in both groups. PMID- 30015365 TI - Impact of venous leg ulceration on health-related quality of life: A synthesis of data from randomized controlled trials compared to population norms. AB - Venous insufficiency is the most common cause of leg ulceration, but the impact of venous leg ulceration on health-related quality of life has not been adequately assessed. This study compared data from randomized controlled trials to population norms obtained from a large national population survey. We combined the baseline Short Form-36 (SF-36) version 1 data from two New Zealand randomized controlled trials that recruited participants with VLU and compared the pooled data to the population scores obtained from the New Zealand Health Survey using general linear regression to adjust for age, sex, and ethnicity differences between the cohorts. Baseline SF-36 scores obtained from 618 trial participants were compared to the SF-36 scores obtained from the 12,529 participants in the New Zealand Health Survey. Participants with VLU had significantly lower crude SF 36 scores across all eight SF-36 domains, but there was interaction between age and group. Adjusted mean differences for participants aged 65 years or younger were -25.8, -32.1, -21.2, -9.6, -7.6, -23.9, -21.5, and -9.3, respectively, for Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health whereas the adjusted mean differences for older participants were -15.7, -23.8, -13.8, -0.3 (nonsignificant), -4.6, -15.3, -21.2, and -6.6. This study is the first to compare a VLU population to norms from a general population survey and the first to show VLU interacts with age creating stronger impact in younger patients compared their age cohort. Younger patients may have need of more pastoral care as a consequence. PMID- 30015366 TI - Letter to 'Ring compression suture for controlling post-partum hemorrhage during cesarean section': Some additions. PMID- 30015367 TI - Conductivity Maximum in 3D Graphene Foams. AB - In conventional foams, electrical properties often play a secondary role. However, this scenario becomes different for 3D graphene foams (GrFs). In fact, one of the motivations for synthesizing 3D GrFs is to inherit the remarkable electrical properties of individual graphene sheets. Despite immense experimental efforts to study and improve the electrical properties of 3D GrFs, lack of theoretical studies and understanding limits further progress. The causes to this embarrassing situation are identified as the multiple freedoms introduced by graphene sheets and multiscale nature of this problem. In this article, combined with transport modeling and coarse-grained molecular dynamic (MD) simulations, a theoretical framework is established to systematically study the electrical conducting properties of 3D GrFs with or without deformation. In particular, through large-scale and massive calculations, a general relation between contact area and conductance for two van der Waals bonded graphene sheets is demonstrated, in terms of which the conductivity maximum phenomenon in GrFs is first theoretically proposed and its competition mechanism is explained. Moreover, the theoretical prediction is consistent with previous experimental observations. PMID- 30015369 TI - Antibiotics and lactation: An overview of relative infant doses and a systematic assessment of clinical studies. AB - Breastfeeding is important for the development of the child. Many antibiotics are considered safe during breastfeeding. The aim of the study was to assess the quality of lactation studies with antibiotics using the FDA and International Lactation Consultant Association quality guidelines for lactation studies. The secondary goal was to determine the exposure of the breastfed infant to antibiotics in relation to bacterial resistance and the developing microbiome. A literature search was performed and the included studies were scored on methodology, parameters concerning maternal exposure to antibiotics, maternal plasma and milk sampling. The infant exposure has been calculated and expressed as a percentage of a normal infant therapeutic dose. Sixty-six studies were included in five antibiotic groups (broad-spectrum penicillin, cephalosporins, macrolides and lincosamides, quinolones and sulphonamides). Cephalosporins were the most studied group of antibiotics (n = 21). Fifteen studies met all the criteria of "mother exposure to antibiotic". Six studies met every criterion related to "plasma sampling". Only one case report met all listed criteria for lactation studies. The correct calculation of infant exposure to antibiotics via the milk:plasma ratio (AUC) varies between 13% for macrolides and 38% for broad spectrum penicillin. The highest assessed exposure as a percentage of infant therapeutic dose was for metronidazole (11%). The studies meet to a limited extent with the quality standards for lactation research. The breastfed infants are exposed to a subtherapeutic concentration of antibiotics. PMID- 30015368 TI - Measuring the Relative Reactivity of the Carbon-Hydrogen Bonds of Alkanes as Nucleophiles. AB - We report quantitative measurements of the relative reactivities of a series of C H bonds of gaseous or liquid Cn H2n+2 alkanes (n=1-8, 29 different C-H bonds) towards in situ generated electrophiles (copper, silver, and rhodium carbenes), with methane as the reference. This strategy surpasses the drawback of previous model reactions of alkanes with strong electrophiles suffering from C-C cleavage processes, which precluded direct comparison of the relative reactivities of alkane C-H bonds. PMID- 30015370 TI - The level of vitamin D using the LC-MS/MS method and related factors in healthy Korean postmenopausal women. AB - AIM: The main purposes of the study were (i) to evaluate serum vitamin D concentration in the forms of 25(OH)D2 , 25(OH)D3 and total 25(OH)D in Korean postmenopausal women using the LC-MS/MS method, which offers increased sensitivity and selectivity; (ii) to determine the relationship between the bone turnover marker, parathyroid hormone (PTH) and 25(OH)D3 , total 25(OH)D separately; and (iii) to determine the factors that may be associated with vitamin D deficiency using body composition analysis and laboratory blood tests. METHOD: A total of 200 postmenopausal women were recruited from November 2012 to March 2014. To control for seasonal ultraviolet exposure time differences in serum 25(OH)D, laboratory tests were performed only from November to March when vitamin D is not synthesized. Independent relationships between 25(OH)D3 , total 25(OH)D and other variables were assessed by multiple regression analysis. RESULTS: The mean serum 25(OH)D2 , 25(OH)D3 and total 25(OH)D levels were 0.51 (+/-0.44) ng/mL, 14.23 (+/-7.05) ng/mL and 14.69 (+/-7.13) ng/mL, respectively. Both 25(OH)D3 and total 25(OH)D were positively correlated with erythrocyte sedimentation rate (ESR), Apo A-I and C-terminal cross-linked telopeptides of type I collagen in Korean postmenopausal women. Both serum 25(OH)D3 and total 25(OH)D were negatively correlated with alkaline phosphatase , PTH and percent body fat. However, osteocalcin showed a negative correlation (r = -0.451; P = 0.041) with only 25(OH)D3 and not with total 25(OH)D (r = -0.417; P = 0.064). CONCLUSION: Both 25(OH)D3 and total 25(OH)D were negatively correlated with PTH, a bone formation marker (alkaline phosphatase) and percent body fat. Both 25(OH)D3 and total 25(OH)D were positively correlated with a bone resorption marker (C-terminal cross-linked telopeptides of type I collagen), ESR and Apo A-I after multiple regression analysis. PMID- 30015371 TI - A survey of mobile technology usage and desires by caregivers of children with cancer. AB - BACKGROUND: The use of mobile health (mHealth) has grown exponentially, even by caregivers of vulnerable populations. The study objective was to understand mobile technology usage, barriers, and desires by caregivers of children with cancer. PROCEDURE: Paper surveys were mailed to caregivers of children diagnosed with cancer at Riley Hospital for Children between June 2015 and June 2017. The survey contained 13 questions, both fixed and open-ended, and was sent in both English and Spanish up to three times. RESULTS: Respondents (n = 121) were primarily parents (93.2%), median age was 40.7 years (range 23-63), and most were white, non-Hispanic (74.4%). The majority made under $100,000 annual household income (72.9%) and had an education of at least some college or greater (74.5%). Nearly all owned a smart phone (99.2%) and most (61.2%) owned a tablet. Among operating systems, the majority used iOS (62.8%), while 49.6% used Android. About a third (37.1%) reported no barriers to mobile technology use, but 22.4% experienced "data limitations." Overall, 86.2% wanted at least one medical management website/app: medical knowledge (61.2%), symptom tracking/management (49.1%), and medication reminders (44.8%). Further, 62.1% wanted access to child's medical record and 58.6% wanted communication with medical providers. Lower education was significantly associated with experiencing phone/plan barriers (P = 0.008). CONCLUSION: The majority of caregivers of children with cancer use mobile technology with minimal barriers; future research should focus on designing an mHealth tool to address the medical management needs by caregivers of children with cancer. PMID- 30015373 TI - Four! Drivers of melanoma differentiation-When to use iron. PMID- 30015372 TI - Pre-intensive care unit intubation and subsequent delayed intensive care unit admission is independently associated with increased occurrence of ventilator associated pneumonia. AB - INTRODUCTION: Critically ill intubated patients are at risk for ventilator associated pneumonia. However, intubation may not occur in intensive care unit (ICU) and subsequent ICU admission may be delayed. OBJECTIVES: To evaluate whether intubation >24 h prior ICU admission and delay in ICU admission is associated with ventilator-associated pneumonia (VAP) in non-trauma critically ill patients. MATERIALS AND METHODS: Prospective observational study conducted in a medical-surgical ICU of a tertiary hospital. Consecutive patients with >48 h of invasive mechanical ventilation and >72 h hospitalization, were recruited in the study. Pre-ICU intubation and delay in ICU admission, demographical, clinical, microbiological data and ICU interventions were assessed as risk factors for VAP and ICU mortality. RESULTS: 100 patients were included in the study. Pre-ICU intubation and delayed (>24 h) ICU admission (PDA patients) (P = 0.014, OR = 3.294, confidence interval 1.268-8.557) and SOFA score on ICU admission (P = 0.045, OR = 1.154, confidence interval 1.003-1.328) were independent risk factors for VAP in ICU care setting. Yet, PDA patients, presented significantly increased incidence of VAP due to MDR bacteria, mainly from Acinetobacter baumannii. Acinetobacter baumannii infection was the only independent risk factor for ICU mortality (P = 0.049, OR = 3.253, confidence interval 1.006-10.521). SOFA score on ICU admission, presented a fair prognostic accuracy of overall ICU mortality (SOFA >= 8.5, AUC = 0.850, P < 0.001). CONCLUSIONS: Pre-ICU intubation and delayed ICU admission was independent risk factor for VAP Acinetobacter baumannii infection and a high SOFA score on ICU admission were predictors of increased ICU mortality. PMID- 30015374 TI - Malignancy in the tracheal bronchus: A case series and review of the literature. AB - BACKGROUND/AIMS: The tracheal bronchus is a rare congenital abnormality with incidence reported in a range of 0.1%-2%. Infrequently, malignancy has been reported as occurring in the tracheal bronchus. In order to ascertain a relationship between malignancy and the tracheal bronchus, we performed a literature review and present a case series. METHODS: We reviewed 21 case reports of malignancy occurring in the tracheal bronchus. CONCLUSION: Although the number of cases is limited, it appears that bronchoscopy is the most frequently utilized diagnostic tool. Surgery portends the best clinical results even in higher stages of malignancy. Squamous cell carcinoma is the most common type of malignancy to occur in the tracheal bronchus. PMID- 30015375 TI - Extraversion and happiness: The mediating role of social support and hope. AB - Studies have found that extraversion enhances happiness indirectly through social support. However, it is unclear how social support may be connected to happiness. On the basis of a literature review, we hypothesize that individual hope may play an important role in the relationship between social support and happiness. Using a serial mediation model, the present study attempted to investigate the hypothetical mediating role of hope in the relationship between extraversion and happiness and between social support and happiness. Analysis of responses of 360 undergraduate students showed that extraversion, social support, and hope were significantly linked with happiness. Moreover, hope was found to mediate the linkage of extraversion and happiness and of social support and happiness. The results also supported the view that extraversion enhances happiness through social support and then hope (serial mediating effect). Lastly, the serial mediating effect was found to be significantly lower than the other two indirect effects. The findings offer insights into the effect of social support on happiness and extend the understanding of the relationship between extraversion and happiness. PMID- 30015376 TI - Primary Biliary Cholangitis in Medicare Population: The Impact on Mortality and Resource Utilization. AB - BACKGROUND: Primary biliary cholangitis (PBC) is a disease of small bile-ducts, which can lead to morbidity and mortality. Our aim was to assess recent trends in mortality and healthcare utilization of PBC patients in Medicare program. METHODS: Data from Medicare beneficiaries between 2005 and 2015 (5% random samples) were used. The diagnosis of PBC was established with ICD-9 code 571.6 used for both primary and secondary diagnoses. Mortality was assessed by Medicare linked death registry. Healthcare utilization included episodes of care, length of stay, total charges/payments. Independent predictors of outcomes were evaluated in multiple generalized linear or logistic regression models. RESULTS: The study cohort included a total of 6,375 inpatient/outpatient Medicare beneficiaries (mean age 69.8 years, 17% male, 88% white and 18% with disability). Over the study period, 1-year mortality remained stable (9.1% to 14.3%, p=0.11). Independent predictors of 1-year mortality were older age, male gender, black race, the presence of ascites, encephalopathy, hepatocellular carcinoma, and higher Charlson score. Outpatient total yearly charges and payments per beneficiary with PBC increased from $3065 and $777 (2005) to $5773 and $967 (2014), respectively. Similarly, inpatient total yearly charges and payments per beneficiary with PBC increased from $59,765 and $19,406 (2007), to $98,941and $27,948 (2013), respectively (p<0.05). The presence of ascites, portal hypertension, and higher Charlson score were independent predictors of higher payments for both inpatient and outpatient resource utilization, and the presence of hepatic encephalopathy was an additional predictor of higher inpatient resource utilization (all p<0.02). CONCLUSION: The prevalence of PBC among the Medicare beneficiaries has increased. Despite stable mortality rates, resource utilization for Medicare patients with PBC continues to rise. This article is protected by copyright. All rights reserved. PMID- 30015377 TI - Enhanced Crystallinity of Low-Temperature Solution-Processed SnO2 for Highly Reproducible Planar Perovskite Solar Cells. AB - Low-temperature solution-processed SnO2 as a promising electron-transport material for planar perovskite solar cells (PSCs) has attracted particular attention because of its outstanding properties such as high optical transparency or high electron mobility. However, low-temperature sol-gel processes used in the synthesis are inevitably affected by the humidity of the atmosphere, which results in a wide distribution in the performance of the prepared PSCs owing to the inability to control crystallinity and defects. Herein, a highly crystalline SnO2 film is synthesized using a simple water bath post-treatment, which can remove the surface residuals of SnCl4 on the SnO2 films, which is beneficial for the interface charge transport from the perovskite to the SnO2 electron-transport layer. An improved performance of the PSCs can be easily obtained applying this treatment, giving rise to a high power conversion efficiency (PCE) of 19.17 %, much higher than that of the pristine SnO2 -based device (17.59 %). Most importantly, the reproducibility of the devices has been greatly improved, independent of the environmental humidity. Therefore, the enhanced crystallinity of SnO2 has shown promise for future commercial PSC applications: 5 cm*5 cm PSC modules have achieved a PCE of 16.16 %. PMID- 30015378 TI - Laparoscopic resection of retroperitoneal paraganglioma behind the Spiegel lobe in a kyphotic patient: A rare case report. AB - Extra-adrenal paraganglioma is a rare form of neuroendocrine neoplasm capable of catecholamine secretion. The surgical risks associated with the tumor location are compounded in this case of a kyphotic patient. This report presents the successful application of laparoscopy on extra-adrenal paraganglioma located behind the Spiegel lobe in a kyphotic patient. The operation was performed after 1 week of alpha-blocker administration. The laparoscopic approach, with the patient in the left hemilateral decubitus position on a rotating table, provided optimal access for safe tumor resection after complete hepatic right lobe mobilization. The patient's postoperative course was uneventful. Based on the results, the laparoscopic approach can be a safe and effective method for resecting extra-adrenal paraganglioma in the challenging case of a kyphotic patient. PMID- 30015379 TI - Clonal immunoglobulin lambda light-chain gene rearrangements detected by next generation sequencing in POEMS syndrome. AB - Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, extravascular fluid overload, M protein, and a myriad of skin changes. The pathogenesis is poorly understood, but monoclonal plasma cells are lambda-restricted and these immunoglobulin lambda light chain variable (IGLV) region genes are derived from only two germlines, either IGLV1-44 or 1-40. Here we analyzed the clonal IGLV gene rearrangements of genomic DNA samples of bone marrow mononuclear cells using next-generation sequencing (NGS) to understand the clonal composition of IGLV genes in patients with POEMS syndrome (n = 30). The dominant IGLV gene rearrangement of POEMS syndrome specific germline sequences were significantly increased in 11 POEMS patients (36.7%; IGLV1-44: n = 9, IGLV1-40: n = 2). In some cases, IGLV gene rearrangement clone was not detected as significant increase but was detected using cDNA samples by heteroduplex (HD) analysis and Sanger sequencing, suggesting that the quite small number of monoclonal plasma cells may produce large quantity of mRNA of monoclonal proteins. However, significant increase of dominant clone sizes was not directly linked to the initial disease status. On the other hand, in cases with significantly increased dominant clones, they decreased and increased accompanying with disease remission and relapse. These data demonstrate that monoclonal plasma cells are related to the pathogenesis of POEMS syndrome. PMID- 30015380 TI - Functional cerebral asymmetry analyses reveal how the control system implements its flexibility. AB - The control system in human brain generally exerts the goal-directed regulation on a variety of mental processes. To deal with different control demands, these brain areas of the control system, especially the dorsolateral prefrontal cortex (DLPFC), may be flexibly recruited across different tasks. However, few studies have investigated how the flexibility of the control system is realized during cognitive control. Present study employed functional magnetic resonance imaging to examine the brain responses during two domain distinct conflict tasks (verbal color-word Stroop and visuospatial arrow flanker). The voxel-wise asymmetries in both functional activity and psychophysiological interaction (PPI) between these two tasks were compared. The results showed that the brain areas of control system were consistently activated in these two tasks. When considering functional cerebral asymmetries, the left DLPFC was dominantly activated during the Stroop task, while more symmetric DLPFC activation was found during the flanker task. The left DLPFC rather than the right DLPFC showed greater positive interaction with the visual areas V1 and V2 during the Stroop interference, but interactions of both the left and right DLPFC with the right visual area V5/MT were positively enhanced during the flanker interference. These results suggest that the flexible cognitive control is achieved by the control system's task specific activity and its top-down interaction with domain-specific brain areas, in implementing flexible representation and modulation of control demands. PMID- 30015381 TI - Hydrogen-Bonded Donor-Acceptor Arrays at the Solution-Graphite Interface. AB - Controlling the nanoscale morphology of organic thin films represents a critical challenge in the fabrication of organic (opto)electronic devices. The morphology of the (multicomponent) thin films in turn depends on the mutual orientation of the molecular components and their supramolecular packing on the surface. Here, it is shown how the surface co-assembly of electron-donating and -accepting building blocks can be controlled via (supra)molecular design. Hexa-peri hexabenzocoronene (HBC) derivatives with multiple hydrogen-bonding (H-bonding) sites were synthesized and their co-assembly with alkyl-substituted perylene tetracarboxy diimide (PDI) was studied using scanning tunneling microscopy (STM) at the solution-graphite interface. STM data shows that electron-rich HBCs co assemble laterally with electron deficient PDIs via preprogrammed H-bonding sites with high fidelity. The surface stoichiometry of the two components could be readily tuned by changing the number of H-bonding sites on the HBC derivatives via organic synthesis. This model study highlights the utility of (supra)molecular design in co-assembly of building blocks relevant for organic electronics. PMID- 30015382 TI - Biallelic tumour suppressor loss and DNA repair defects in de novo small-cell prostate carcinoma. AB - Small-cell prostate carcinoma (SCPC) is an aggressive malignancy that is managed similarly to small-cell lung cancer. SCPC can evolve from prostate adenocarcinoma in response to androgen deprivation therapy, but, in rare cases, is present at initial cancer diagnosis. The molecular aetiology of de novo SCPC is incompletely understood, owing to the scarcity of tumour tissue and the short life-expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology, and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. The median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumour tissue. We observed frequent biallelic deletion and/or mutation of the tumour suppressor genes TP53, RB1, and PTEN, similarly to what was found in treatment-related SCPC. Indeed, at the RNA level, pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes, including BRCA1, BRCA2, ATM, and MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harboured ETS gene rearrangements involving androgen-driven promoters, consistent with the evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathological variant, and suggest opportunities for targeted therapy strategies in a disease with few treatment options. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30015383 TI - Role of exosomal competing endogenous RNA in patients with hepatocellular carcinoma. AB - Recent research has tried to use exosomal RNAs (coding and noncoding) as potential diagnostic markers for hepatocellular carcinoma (HCC). Initially, by using bioinformatics, we selected an HCC-exosomal RNA-based biomarker panel. The choice of this panel depends on the integration of Ras-related in brain (RAB11A) gene expression and its competing endogenous network. This network includes long noncoding RNA RP11-513I15.6 (lncRNA-RP11-513I15.6) and microRNA-1262 (miR-1262). Secondly, we tried to validate the expression of this network in the sera of 60 patients with HCC in comparison with 42 chronic hepatitis C virus-infected patients and 18 healthy controls. Then we assessed the diagnostic efficiency of this panel using a receiver operating characteristic curve analysis. The panel of 3 exosomal RNA-based biomarkers (lncRNA-RP11-513I15.6, miR-1262, and RAB11A) showed excellent sensitivity and specificity in discriminating patients with HCC from patients with chronic hepatitis C virus and healthy controls. Among these 3 RNAs, serum RAB11A mRNA was the most independent prognostic factor. The selected circulatory exosomal RNA-based biomarker panel showed its ability to be used as a diagnostic and prognostic biomarker tool for HCC. Moreover, these biomarkers could be therapeutic targets. PMID- 30015384 TI - Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) and synovial sarcoma are rare tumors with dismal outcomes requiring new therapeutic strategies. Immunotherapies have shown promise in several cancer types, but have not been evaluated in DSRCT and synovial sarcoma. Because the immune microenvironment can provide indications of the inflammatory nature of tumors, immunohistochemical staining is able to assess the tumor immune infiltrates in both tumor types. PROCEDURE: Using tissue microarrays of DSRCT and synovial sarcoma tumor samples, we detected tumoral HLA-A/B/C, beta-2-microglobulin(B2M), and PD-L1 expression, and quantified tumor-infiltrating lymphocytes expressing CD4, CD8, CD56, CD45RO, or FOXP3 by immunohistochemistry. We used staining intensity on a scale of 0-3 and percentage of tumor stained to determine HLA, B2M, and PD-L1 scores. We calculated the cytotoxic T lymphocyte (CTL) target score as HLA score * B2M score/100. RESULTS: In diagnostic samples, we found high HLA and CTL target scores and low PD-L1 expression with decreased scores in recurrence for both tumor types. We found an increase in CD56+ natural killer cells in DSRCT samples from diagnosis to recurrence. CONCLUSIONS: We found similar immunostimulatory profiles in DSRCT and synovial sarcoma. Our findings suggest that DSRCT and synovial sarcoma may be amenable to immunotherapies, albeit there was significant heterogeneity. Interestingly, HLA and CTL target scores decreased at recurrence, possibly reflecting immunoevasion. Our findings suggest both tumor types may be amendable to CTL-based therapies at diagnosis but less so at relapse. Our results support further investigation into the prognostic and predictive value of these findings in a larger dataset. PMID- 30015385 TI - Metal-Free Synthetic Approach to 3-Monosubstituted Unsymmetrical 1,2,4,5 Tetrazines Useful for Bioorthogonal Reactions. AB - A facile, efficient and metal-free synthetic approach to 3-monosubstituted unsymmetrical 1,2,4,5-tetrazines is presented. Dichloromethane (DCM) is for the first time recognized as a novel reagent in the synthetic chemistry of tetrazines. Using this novel approach 11 3-aryl/alkyl 1,2,4,5-tetrazines were prepared in excellent yields (up to 75 %). The mechanism of this new reaction, including the role of DCM in the tetrazine ring formation, has been investigated by 13 C labeling of DCM, and is also presented and discussed as well as the photophysical and electrochemical properties. PMID- 30015386 TI - Quantum Effects Allow the Construction of Two-Dimensional Co3 O4 -Embedded Nitrogen-Doped Porous Carbon Nanosheet Arrays from Bimetallic MOFs as Bifunctional Oxygen Electrocatalysts. AB - In terms of promising candidates for high-performance fuel cells and water splitting electrocatalysts, two-dimensional (2D) materials refer to a class of materials with high electrical conductivity along 2D conducting channels and possessing abundant active sites in the form of surface atoms and edge sites. Herein, we report an ammonia-modulated method for the synthesis of nanosized bimetallic ZnCo-ZIF, and owing to quantum effects, the nanosized ZnCo-ZIF can be transformed into novel 2D nanosheet arrays, which can be used as a bifunctional electrocatalyst. The size of the ZnCo-ZIF crystals can be controlled to less than 10 nm by increasing the ammonia amount. The products from the nanosized particles through calcination have a distinct structure from the microsized nanoparticles owing to quantum effects and appear to be well-aligned 2D mono-crystalline Co3 O4 -embedded nitrogen-doped porous carbon nanosheet arrays (2D-MCo3 O4 -NCNAs). These novel 2D nanosheet arrays lead to large active surface areas, enhanced mass/charge transport capability, numerous active sites, and strong structure stability. When used as bifunctional catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), the 2D-MCo3 O4 -NCNAs exhibit superior ORR activity as well as efficient OER activity in alkaline electrolyte, in comparison to the state-of-the-art precious metal catalysts. PMID- 30015387 TI - Computational and biochemical studies of isothiocyanates as inhibitors of proteasomal cysteine deubiquitinases in human cancer cells. AB - Isothiocyanates (ITCs) are natural chemoprotective products found abundantly in cruciferous vegetables. However, the cancer-relevant targets and molecular mechanisms of ITCs remain unclear. We hypothesize that ITCs, as electrophiles, can interact with the catalytic triads (CYS, HIS, and ASP) of the proteasomal cysteine deubiquitinases USP14 and UCHL5, ultimately inhibiting their activities. In the current study, we exploited this possibility by performing both computational docking and biochemical validation assays using human breast and prostate cancer cell models. Docking results suggest that benzyl isothiocyanate, phenethyl isothiocyanate, and DL-sulforaphane are more potent inhibitors of UCHL5 than USP14, and these ITCs could interact with the catalytic triads of UCHL5 and USP14. Indeed, ubiquitin vinyl sulfone assay confirmed the inhibitory activity of each ITC on the ubiquitin-binding activity of UCHL5 and USP14. We also found that inhibition of USP-14 and UCHL5 activities by the ITCs caused increased levels of USP14 and UCHL5 proteins, but not the third 19S-deubiquitinating enzyme (DUB), POH1/RPN11, suggesting feedback loop activation and further supporting that ITCs are inhibitors of proteasomal cysteine DUBs. Associated with DUB inhibition by ITCs, ubiquitinated proteins were significantly increased, accompanied with induction of apoptosis, inhibition of proliferation and suppression of cell invasion. Our findings of ITCs as proteasomal cysteine DUB inhibitors should provide insightful information for designing, discovering and developing potent, specific 19S-DUB inhibitors for cancer therapies. PMID- 30015389 TI - The evolution of GRADE (part 2): Still searching for a theoretical and/or empirical basis for the GRADE framework. AB - RATIONALE, AIMS, AND OBJECTIVES: The GRADE framework has been widely adopted as the preferred method for developing clinical practice recommendations. In the first article of our three part series examining the evolution of GRADE, we showed an absence (in the first two versions of GRADE) of a theoretical basis and/or empirical data to support why the presented criteria for determining the quality of evidence regarding the effect estimate and the components under consideration for determining the strength of the recommendation were included and other criteria/components excluded. Furthermore, often, it was not clear how to operationalize the included criteria/components (and integrate them) when using the framework. In part 2 of this series, we examine if version 3 of GRADE offered improvements on previous versions with respect to a justification scheme and how to operationalize the framework's criteria/components. METHODS: Narrative review. RESULTS: Our examination suggests that version 3 has done little to improve on the justification scheme that sustains GRADE. Still absent is a justification (theoretical and/or empirical) for why the criteria/components were chosen. Likewise, version 3 is still lacking clarity regarding how to implement and integrate the criteria/considerations in the framework (ie, operationalize the framework) when determining the quality of evidence or strength of recommendation. Transparency is now emphasized as the merit of GRADE. However, we are offered no theoretical justification for how the use of GRADE should achieve transparency or empirical evidence to support that transparency is achieved. CONCLUSIONS: While version 3 reveals acknowledgement by the authors of GRADE that the framework is a work in progress, it still lacks a justification scheme (theoretical and/or empirical) to sustain it and clarity in its criteria/components to operationalize it. As was suggested in part 1, such issues limit one's ability to scientifically assess the appropriateness of GRADE for its stated purpose. PMID- 30015388 TI - Systemic inflammation in acute cardiorenal syndrome: an observational pilot study. AB - AIMS: Acute cardiorenal syndrome (CRS) with and without consideration of the volume state was assessed with regard to inflammatory parameters. METHODS AND RESULTS: Blood samples from patients with acute CRS (Ronco type 1 or 3, Group 1, n = 15), end-stage renal disease (Group 2, n = 12), hypertension (Group 3, n = 15), and, in a second cohort, with acute CRS and hypervolemia (Group 4, n = 9) and hypertension (Group 5, n = 10) were analysed with regard to lipopolysaccharide-binding protein (LBP), interleukins (ILs), and monocyte function (flow cytometry) both on admission (all groups) and on discharge (Groups 1 and 4). By discharge, one Group 1 patient died. LBP (ANOVA for Groups 1-3: P = 0.001) and IL-6 (Kruskal-Wallis for Groups 1-3: P < 0.0001) were higher in Group 1 (LBP: 11.7 +/- 2.0 MUg/mL; IL-6: 15.0 +/- 6.1 pg/mL) and in Group 2 (LBP: 10.4 +/- 1.4 MUg/mL; IL-6: 14.6 +/- 3.8 pg/mL) than in Group 3 (LBP: 5.8 +/- 0.4 MUg/mL; IL-6: 1.8 +/- 0.4 pg/mL). In a direct comparison, the proportion of activated monocytes (CD14 and CD16 positive) was higher in Group 1 (6.9% +/- 0.7%) vs. Group 3 (5.1% +/- 0.6%; P = 0.018). Group 4 patients had higher IL-6 plasma levels (34.2 +/- 10.1 pg/mL) than Group 1 patients (15.0 +/- 6.1 pg/mL; P = 0.03). All other findings obtained in CRS groups (Groups 1 and 4) were comparable. CONCLUSIONS: In acute CRS, a state of systemic inflammation was found, which is comparable with the end-stage renal disease situation. In comparison with hypertensive controls, a monocytic activation was found in acute CRS regardless of volume state. PMID- 30015390 TI - Molecular insight into multiple Wilms tumors arising in germline WT1 mutated/11p13-deleted patients. PMID- 30015391 TI - Rice Bran Oil Improves Insulin Resistance by Affecting the Expression of Antioxidants and Lipid-Regulatory Genes. AB - The present study investigated the molecular effects of rice bran oil (RBO) on lipid-regulatory genes (sterol regulatory element binding protein-1 [Srebf1] and peroxisome proliferator-activated receptors-alpha [Ppara]) and the expression of catalase (CAT) and superoxide dismutase (SOD1) genes in insulin-resistant rats. Rats were divided into five groups: animals that received standard diet (control); rats fed standard diet containing RBO as the sole source of fat (RBO); a high-fructose diet (HFD) group, which was further divided into two subgroups: rats fed HFD either for only 1 month (HFD1) or for 2 months (HFD2) and rats fed HFD containing RBO for 1 month; while rats in the last group fed HFD for 30 days then treated with RBO for another 30 days. The HFD induced a state of insulin resistance (IR) as indicated by the hyperinsulinemia and elevated homeostasis model assessment insulin resistance index. Hepatic lipid levels and radical scavenging enzymes were altered by the HFD. Lipid-regulatory genes, Srebf1 and Ppara, were upregulated while Sod1 and Cat were downregulated in insulin resistant rats. Addition of RBO to the two diet regimens alleviated the disorders of IR to some extent. RBO reduced the hepatic levels of triacylglycerol, malondialdehyde, SREBP, and PPAR-alpha mRNA. Hepatic SOD and CAT were elevated at gene and protein levels. The HFD induces de novo lipogenesis by upregulating the lipid-regulatory genes resulting in increased serum and hepatic triacylglycerol. Moreover, IR induced by the HFD caused a state of oxidative stress. Supplementation of RBO to fructose-fed rats not only improves insulin resistance but also downregulates lipogenic genes and improves the unbalanced oxidative status. PMID- 30015392 TI - Care trajectory management: A conceptual framework for formalizing emergent organisation in nursing practice. AB - AIM: To offer a new conceptual framework for formalizing nurses' work in managing emergent organisation in health and social care. BACKGROUND: Much health and social care requires continuous oversight and adjustments in response to contingencies. Nurses have an important role in managing these relationships. EVALUATION: A longstanding programme of research on the social organisation of health and social care work provided the foundations for the article. KEY ISSUE: Nurses' work in managing emergent organisation may be conceptualized as care trajectory management and factors contributing to trajectory complexity are explored. CONCLUSIONS: Care trajectory management is essential for the quality and safety of health and social care but poorly served by existing management frameworks. IMPLICATIONS FOR NURSING MANAGEMENT: Care trajectory management offers a conceptual framework for the development of new management structures to support an important but poorly supported element of nursing practice. PMID- 30015393 TI - Distinct developmental trajectories of endometriotic epithelium and stroma: implications for the origins of endometriosis. AB - Endometriosis is a common gynecological disease characterized by the ectopic growth of endometrium-like tissue. Despite the widespread prevalence of endometriosis, its pathogenesis remains poorly understood. A recent study by Noe et al provides evidence that the epithelium and stroma within the same endometriotic lesions follow distinct and independent developmental trajectories. They used droplet digital polymerase chain reaction analysis of laser-captured epithelium-enriched and stroma-enriched endometriosis tissue, and found that all 19 somatic passenger mutations analyzed were enriched exclusively in the epithelial compartment. These findings are consistent with the clonal expansion of epithelial cells, whereas stromal cells may be continuously regenerated or recruited over the course of disease. Further findings of differing allelic frequencies among passenger mutations within the epithelium of the same endometriotic lesions are suggestive of subclonality or the existence of multiple clones in some cases. Overall, the authors' observations of clonally dominant somatic passenger mutations in the epithelium and not the stroma of endometriosis add to the recent description of cancer-associated mutations in such lesions, and provide clues to the pathogenesis of endometriosis. Further studies to determine where and when these mutations occur and whether they can be used to develop the first biologically informed classification system for endometriosis are warranted. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30015394 TI - The serum KL-6 levels in untreated idiopathic pulmonary fibrosis can naturally decline in association with disease progression. AB - BACKGROUND: Serum KL-6 is known to be a useful biomarker for the diagnosis and assessment of the disease activity in idiopathic pulmonary fibrosis (IPF). However, some patients with untreated IPF present with a serial decline in their serum KL-6 levels, despite showing clinical progression. OBJECTIVES: The aim of the present study was to evaluate the association between the time course of the serum KL-6 levels and the clinical course of patients with untreated IPF. METHODS: We conducted a retrospective study of 59 patients who met the diagnostic criteria for IPF, who regularly underwent laboratory tests, including the measurement of KL-6 and pulmonary function tests, and who were untreated during the follow-up period. RESULTS: The rates of decline in comparison to the baseline FVC values were comparable between survivors (n = 30) and non-survivors (n = 29); however, the rates of change in comparison to the baseline KL-6 levels were heterogeneous in all subjects, and the KL-6 levels of the non-survivors were observed to decline significantly more frequently in comparison to the survivors (P = .001). Patients with a higher breathlessness scale, lower pulmonary functions and higher levels of baseline KL-6 were predisposed to demonstrate a decline in the serum KL-6 levels during the untreated period. CONCLUSIONS: A reduction in the serum KL-6 levels of patients with untreated IPF may not mean that the disease activity has subsided. Serum KL-6 levels can naturally decline in association with disease progression. PMID- 30015395 TI - Diagnosing and grading heart failure with tomographic perfusion lung scintigraphy: validation with right heart catheterization. AB - AIMS: Pulmonary congestion remains a diagnostic challenge in patients with heart failure (HF). The recommended method, chest X-ray (CXR), lacks in accuracy, whereas quantitative tomographic lung scintigraphy [ventilation/perfusion single photon emission computed tomography (V/P SPECT)] has shown promising results but needs independent validation. The aim of this study is to evaluate V/P SPECT as a non-invasive method to assess and quantify pulmonary congestion in HF patients, using right heart catheterization as reference method. The secondary objective was to investigate the performance of V/P SPECT in the clinical setting compared with CXR. METHODS AND RESULTS: Forty-six consecutive patients with HF that were under consideration for heart transplantation were studied prospectively. All participants were examined with V/P SPECT, CXR, and right heart catheterization. Pulmonary artery wedge pressure served as reference method. Quantitative perfusion gradients were derived from V/P SPECT images. Ventilation/perfusion single-photon emission computed tomography images were also assessed both by expert readers and clinical nuclear medicine physicians. Expert readers correctly identified 87% of all patients with an elevated pulmonary artery wedge pressure > 15 mmHg. The average sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for V/P SPECT assessed by the expert readers were 87%, 72%, 85%, and 75%, respectively. In the clinical nuclear medicine setting, V/P SPECT had 87% sensitivity, 63% specificity, 81% PPV, and 71% NPV. Clinically, V/P SPECT outperformed CXR, which had 27% sensitivity, 75% specificity, 67% PPV, and 35% NPV. CONCLUSIONS: Ventilation/perfusion single photon emission computed tomography can be used as a non-invasive method to diagnose and quantify pulmonary congestion in patients with HF and is more accurate than CXR in diagnosing pulmonary congestion in the clinical setting. PMID- 30015396 TI - Risk stratification of high-risk metastatic neuroblastoma: A report from the HR NBL-1/SIOPEN study. AB - BACKGROUND: Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged >=18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication. PROCEDURE: Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged >=18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi variable model and an additive scoring system developed based on estimated log cumulative hazard ratios. RESULTS: The cohort included 1053 patients with median follow-up 5.5 years and EFS 27 +/- 1%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi-variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250 U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 +/- 9% for score = 0 versus 6 +/- 3% for score = 5 (P < 0.0001). CONCLUSIONS: A simple score can identify an "ultra-high risk" (UHR) cohort (score = 5) comprising 8% of patients with 5-year EFS <10%. These patients appear not to benefit from induction therapy and could potentially be directed earlier to alternative experimental therapies in future trials. PMID- 30015397 TI - Older men with bipolar disorder: Clinical associations with early and late onset illness. AB - OBJECTIVES: Older adults living with bipolar disorder (BD) include people with early and late onset of symptoms. This study aimed to clarify the cross-sectional and longitudinal clinical associations of BD with early and late onset. METHODS: Cohort study of 38 173 men aged 65-85 years followed for up to 17.6 years. We used the Western Australian Data Linkage System to establish the presence of BD, as well as diabetes, cardiovascular and renal diseases, cancer, respiratory and gastrointestinal diseases, alcohol use disorder, dementia, and mortality. The causes of death were recorded according to the International Classification of Diseases. We defined late onset BD using 2 different cut-points: 50 and 60 years. RESULTS: The prevalence of medical morbidities was greater among participants with than without BD, and cardiovascular diseases were more frequent among those with onset before than after 50 years (odds ratio = 1.72, 95% confidence interval = 1.01, 2.94). Bipolar disorder was associated with increased hazard ratio of dementia and death, but there was no difference between early and late onset participants. Death by suicide or accidents occurred exclusively among BD participants with illness onset <60 years, whereas death associated with strokes and neurodegenerative diseases was more frequent among those with illness onset >=60 years than in the general population (HR = 2.28, 95% confidence interval = 1.34, 3.88). CONCLUSIONS: Our results indicate that the clinical associations and outcomes of older adults living with BD are not markedly influenced by age of onset. However, mortality data suggest that differences between older adults with BD onset before and after age 60 years should continue to be explored. PMID- 30015398 TI - Significance of gestational weight gain in spontaneous onset of labor at term. AB - AIM: To investigate the significance of gestational weight gain (GWG) in association with the spontaneous onset of labor at term. METHODS: A retrospective cohort study on 985 pregnant women (629 nullipara and 356 pluripara) who delivered singleton babies at term was conducted. We reviewed the maternal demographics (age, parity, prepregnancy body mass index [BMI]) and the perinatal outcomes (gestational age [GA] and the type [spontaneous or induced] of labor onset, and GWG). The subjects were categorized by prepregnancy BMI and GWG. The rates of spontaneous onset of labor were compared between the nullipara and pluripara groups. Kaplan-Meier survival analysis was applied to evaluate the time to spontaneous labor according to prepregnancy BMI and GWG. A Cox proportional hazards model was used to determine the independent predictive factor for spontaneous onset of labor. RESULTS: In both the nullipara and pluripara group, women with prepregnancy obesity were less likely to enter spontaneous labor. In nullipara, women with excessive weight gain were less likely to enter spontaneous labor. In pluripara, women with poor gain were more likely to enter spontaneous labor. In the multivariate model, GWG was independently associated with the spontaneous onset of labor in both nullipara (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75-0.98, P = 0.03) and pluripara (HR 0.82, 95% CI 0.64 0.93, P = 0.005). CONCLUSION: Greater maternal weight gain was significantly associated with longer gestation and a decreased likelihood of spontaneous onset of labor at term. PMID- 30015399 TI - Early gastric cancer successfully treated by endoscopic submucosal resection 1 year after laparoscopic sleeve gastrectomy with duodenal-jejunal bypass. AB - This case involved a 64-year-old female patient with a BMI of 35.3 kg/m2 and poorly controlled type 2 diabetes mellitus. Preoperative upper gastrointestinal endoscopy revealed chronic, atrophic gastritis. Helicobacter pylori antibody was negative. The patient underwent laparoscopic sleeve gastrectomy with duodenal jejunal bypass as a metabolic surgery to treat obesity and type 2 diabetes mellitus. At 1 year postoperatively, routine endoscopy detected a flat elevated lesion at the distal gastric sleeve, near the posterior wall of the antrum; biopsy revealed adenocarcinoma. Endoscopic submucosal resection was performed without complication. This case shows the advantage of laparoscopic sleeve gastrectomy with duodenal-jejunal bypass in screening the excluded stomach as compared to laparoscopic Roux-en-Y gastric bypass. Therefore, laparoscopic sleeve gastrectomy with duodenal-jejunal bypass can be a viable alternative to laparoscopic Roux-en-Y gastric bypass for regions where gastric cancer is endemic. PMID- 30015400 TI - HLA-DRB1 allele frequency and immunological response in obstructive sleep apnea syndrome in Turkish population. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a complex, polygenic and multifactorial disease. The relationship between Human Leukocyte Antigen (HLA) polymorphisms and sleep disturbances has been established, but the relationship with HLA alleles has not been fully clarified. In addition, sleep deprivation in OSAS patients can cause changes that affect the components and responses of the immune system. OBJECTIVE: The aim of this study has assessed the effect of HLA DRB1 alleles on OSAS disease and the changes occurring in immune response cells in Turkish population. METHOD: OSAS was diagnosed by polysomnography and severity was determined. PCR SSP and flow cytometry methods were used. RESULTS: We found that DRB1*07 and DRB1*11 were significantly increased in the control group and DRB1*03 and DRB1*08 alleles in the patient group in our study (P = 0.048, P = 0.005, P = 0.012 and P = 0.030, respectively). DRB1*08 was significantly increased in patients with severe OSAS (P = 0.002). When the immunological response was examined in OSAS patients, there was a decrease in CD4, an increase in HLA DR, CD8 and NK cells (P = 0.002, P = 0.00, P = 0.020, P = 0.040, respectively). We also found that CD19 was reduced in severe OSAS (P = 0.048). CONCLUSION: These results suggest that the DRB1*03 allele may play a predisposing role in OSAS disease and that the DRB1*08 allele may be related to the severity of the disease. In addition, the decrease in CD4, CD8, NK and HLA DR increase in this disease suggests that the disease causes impairment of the immunological system and may be associated with autoimmunity. PMID- 30015401 TI - Silybum marianum (milk thistle) and its main constituent, silymarin, as a potential therapeutic plant in metabolic syndrome: A review. AB - Metabolic syndrome describes a complex metabolic risk factors including obesity, hypertension, dyslipidemia, and diabetes. This syndrome is diagnosed by medical conditions such as weight gain, high blood pressure, high blood glucose, and disturbance in lipid profile. Metabolic syndrome has become as an important and increasing global health problem, so finding potentially novel solutions with less adverse effects is favorable for health problems. Herbal therapy plays an important role for treatment of different diseases. Silybum marianum is a plant that is used for centuries as a herbal treatment in liver and biliary tract diseases. Silymarin is the main component of S. marianum and derived from fruits and seeds of S. marianum (milk thistle). S. marianum has been found to exhibit antioxidant, lipid-lowering, antihypertensive, antidiabetic, antiatherosclerotic, anti-obesity, and hepatoprotective effects. Therefore, the aim of this review is to summarize different animal and human studies regarding the effect of S. marianum in metabolic syndrome and to identify the underlying mechanisms of action. PMID- 30015402 TI - Palladium/Rhodium Cooperative Catalysis for the Production of Aryl Aldehydes and Their Deuterated Analogues Using the Water-Gas Shift Reaction. AB - A novel Pd/Rh dual-metallic cooperative catalytic process has been developed to effect the reductive carbonylation of aryl halides in moderate to good yield. In this reaction, water is the hydride source, and CO serves both as the carbonyl source and the terminal reductant through the water-gas shift reaction. The catalytic generation of the Rh hydride allows for the selective formation of highly hindered aryl aldehydes that are inaccessible through previously reported reductive carbonylation protocols. Moreover, aldehydes with deuterated formyl groups can be efficiently and selectively synthesized using D2 O as a cost effective deuterium source without the need for presynthesizing the aldehyde. PMID- 30015403 TI - Mechanochemical Activation of Zinc and Application to Negishi Cross-Coupling. AB - A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross-coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp3 )-C(sp2 ) and C(sp2 )-C(sp2 ) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods. PMID- 30015404 TI - Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the Na+ -Ca2+ -Ca2+ /calmodulin-dependent protein kinase II-reactive oxygen species feedback. AB - Quantitative systems modeling aims to integrate knowledge in different research areas with models describing biological mechanisms and dynamics to gain a better understanding of complex clinical syndromes. Heart failure (HF) is a chronic complex cardiac disease that results from structural or functional disorders impairing the ability of the ventricle to fill with or eject blood. Highly interactive and dynamic changes in mechanical, structural, neurohumoral, metabolic, and electrophysiological properties collectively predispose the failing heart to cardiac arrhythmias, which are responsible for about a half of HF deaths. Multiscale cardiac modeling and simulation integrate structural and functional data from HF experimental models and patients to improve our mechanistic understanding of this complex arrhythmia syndrome. In particular, they allow investigating how disease-induced remodeling alters the coupling of electrophysiology, Ca2+ and Na+ handling, contraction, and energetics that lead to rhythm derangements. The Ca2+ /calmodulin-dependent protein kinase II, which expression and activity are enhanced in HF, emerges as a critical hub that modulates the feedbacks between these various subsystems and promotes arrhythmogenesis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models. PMID- 30015406 TI - Topical rapamycin (sirolimus) for the treatment of uncomplicated tufted angiomas in two children and review of the literature. AB - The mTOR inhibitor rapamycin is used systemically for the treatment of vascular lesions. We report the first use of topical rapamycin for the successful treatment of two cases of tufted angioma. The evidence for the use of topical rapamycin in other dermatologic conditions is summarized to aid in clinical decision making on preparations and anticipated side effects. PMID- 30015405 TI - Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment. AB - AIMS: Left atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments. METHODS AND RESULTS: Two-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 +/- 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034). CONCLUSIONS: In patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation. PMID- 30015408 TI - The Effect of Organic Additives on the Activity and Selectivity of CO2 Electroreduction: The Role of Functional Groups. AB - Electrochemical reduction of CO2 (ERC) to useful chemicals is an environmentally and technologically significant process. The process is confronted with significant challenges to simultaneously enhance the catalyst activity and product selectivity. In this paper, the effects of organic additives on the ERC process were systematically investigated by using DFT to screen additives with different functional groups for enhanced activity and selectivity. In particular, the additives with -NH3 + and -SO3 H groups had a remarkably positive effect on the ERC activity and hydrocarbon selectivity, which were predicted to impart a positive shift on onset potential of approximately 162 and 108 mV, respectively. Importantly, the additive can accelerate the electron transfer of the intermediate and tune the electronic structure of the catalyst surface, resulting in a clear deviation from transition-metal scaling lines. Combining bonding energy of crucial intermediates with partial atomic charge analysis, we rationalized the negative effect of high concentration additives and confirmed the proposed electron transfer model. Furthermore, additive molecules containing functional groups with positive charges and maximizing the deviation from transition-metal scaling lines are meaningful strategies to design and choose organic additives to enhance activity and selectivity of ERC. PMID- 30015407 TI - Translation, psychometric validation, and baseline results of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric measures to assess health-related quality of life of patients with pediatric lymphoma in Malawi. AB - INTRODUCTION: Internationally validated tools to measure patient-reported health related quality of life (HRQoL) are available, but efforts to translate and culturally validate such tools in sub-Saharan Africa (SSA) are scarce, particularly among children. METHODS: The Patient-Reported Outcomes Measurement Information System 25-item pediatric short form (PROMIS-25) assesses six HRQoL domains-mobility, anxiety, depression, fatigue, peer relationships, and pain interference-by asking four questions per domain. There is a single-item pain intensity item. The PROMIS-25 was translated into Chichewa and validated for use in Malawi using mixed qualitative and quantitative methods. The validity and reliability of the PROMIS-25 was assessed. RESULTS: Fifty-four pediatric patients with lymphoma completed the PROMIS-25. Structural validity was supported by interitem correlations and principal component analysis. Reliability of each scale was satisfactory (range alpha = 0.71-0.93). Known group validity testing showed that anemic children had worse fatigue (P = 0.016) and children with poor performance status had worse mobility (P < 0.001) and pain interference (P = 0.005). Compared to children with cancer in the United States, children from Malawi reported lower levels of mobility, higher anxiety, higher depressive symptoms, higher fatigue, better satisfaction with peer relationships, and higher pain interference. CONCLUSION: Translation and cultural validation of the PROMIS 25 into Chichewa for Malawi was successful. Baseline HRQoL for patients with pediatric lymphoma in Malawi is poor for all domains except peer relationships. This emphasizes an urgent need to address HRQoL among children undergoing cancer treatment in SSA using self-reported instruments validated within the local context. PMID- 30015409 TI - Chromophobe renal cell carcinoma with sarcomatoid differentiation containing various heterologous components. AB - Renal cell carcinoma (RCC) occasionally has sarcomatoid differentiation and rarely contains heterologous components. We report a case of chromophobe RCC with sarcomatoid differentiation that had various heterologous components including a unique lipomatous area. The patient was an 83-year-old woman with a palpable mass in the left lower abdomen. Grossly, the tumor was 14 cm in diameter and had yellowish-to-whitish color with focal necrosis and hemorrhage. Histologically, the tumor was composed of an eosinophilic subtype of chromophobe RCC with sarcomatoid differentiation including mainly chondrosarcoma, some osteosarcoma and a lipomatous area. The heterologous components of sarcomatoid RCC are usually osteosarcoma or chondrosarcoma, and sarcomatoid RCC with multiple heterologous components is extremely rare. PMID- 30015410 TI - Effects of adiponectin during in vitro maturation of goat oocytes: MEK 1/2 pathway and gene expression pattern. AB - Recent studies have shown that adiponectin, an adipokine predominantly produced by adipose tissue, regulates several reproductive processes. However, the mechanisms of action of adiponectin on the maturation of goat oocytes remain to be determined. The aim of this study was to investigate whether (a) adiponectin influences the meiotic maturation of goat oocytes; (b) MAPK MEK 1/2 mediates the effects of adiponectin; and 3) adiponectin differentially affects mRNA relative abundance of genes relevant for adiponectin signal transduction in goat oocytes. The addition of adiponectin (5 MUg/ml) during the maturation of goat oocytes resulted in a higher percentage of successful nuclear maturation compared to those of the group without adiponectin (p < 0.05). Adiponectin-stimulated nuclear oocyte maturation was significantly impaired by a mitogen-activated protein kinase MEK 1/2 inhibitor, U0126 (p < 0.05). There was no evidence of any adiponectin-induced difference in the relative transcript abundances of AdipoR1, AdipoR2, AMPKalpha1, AMPKalpha2, PPARalpha and PPARgamma genes. In conclusion, these results indicate that adiponectin has a positive effect on the meiotic maturation of goat oocytes through the MAPK MEK 1/2 pathway. Furthermore, the adiponectin does not affect the relative abundance of genes relevant for adiponectin signal transduction in goat oocytes. PMID- 30015411 TI - Determination of the softening point of rosin by a simple and automated headspace gas chromatographic technique. AB - We report a simple and automated headspace gas chromatographic technique for the determination of the softening point of rosin. A lumpy solid of rosin is added into a headspace vial, then an automated stepwise temperature ramping and headspace sampling was performed at each temperature stage and gas chromatography measurement. By plotting the gas chromatography signal for an impurity in rosin versus the temperature, a transition point (corresponding to the rosin softening point) was determined. The results show that the present method has a good precision (<0.76%), and good accuracy (the relative differences compared to the ring and ball method was <4.0%). The present method is simple, accurate, and automated. It is practical and suitable for testing the softening of rosin and derivatives in mills. PMID- 30015412 TI - High detection rates of Torque teno sus virus in co-infection with important viral pathogens in porcine kidneys on St. Kitts Island, Lesser Antilles. AB - We report here high rates of detection (50.8%, 31/61 pigs) of Torque teno sus virus (TTSuV) in kidneys of slaughter-age, apparently healthy pigs on St. Kitts island, Lesser Antilles. TTSuV1 and TTSuVk2a were detected in 23 (37.7%) and 13 (21.3%) pigs, respectively, including mixed infection in five animals. By nucleotide sequence identities and phylogenetic analysis, significant genetic diversity was observed among both TTSuV1 and TTSuVk2a on St. Kitts, with TTSuVk2a showing higher genetic diversity than TTSuV1. Fourteen (45.2%) and 10 (32.2%) of the TTSuV infected pigs tested positive for porcine circovirus type 2 (PCV2) and porcine parvovirus (PPV), respectively, revealing high rates of co-infection of TTSuV with PCV2 and PPV. This is the first report on detection and genetic diversity of TTSuV from the Lesser Antilles. Also, PCV2 and PPV were detected for the first time in the Lesser Antilles. Considering the impact of pig farming on the regional livestock economy, the increasing demand for local pork and lack of information on emerging and re-emerging porcine viruses in the Lesser Antilles, the present findings have important implications on swine health. PMID- 30015413 TI - Heat Shock Protein 90alpha-Dependent B-Cell-2-Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto-Oncogene c-MYC mRNA Stability. AB - : B-cell lymphoma 2 (Bcl-2)-associated transcription factor 1 (Bclaf1) is known to be involved in diverse biological processes, but, to date, there has been no evidence for any functional role of Bclaf1 in hepatocellular carcinoma (HCC) progression. Here, we demonstrate that Bclaf1 is frequently up-regulated in HCC and that Bclaf1 up-regulation is associated with Edmondson grade, lower overall survival rates, and poor prognosis. Overexpression of Bclaf1 in HCC cell lines HepG2 and Huh7 promoted proliferation considerably, whereas Bclaf1 knockdown had the opposite effect. Xenograft tumors grown from Bclaf1 knockdown Huh7 cells had smaller tumor volumes than tumors grown from control cells. Furthermore, our study describes MYC proto-oncogene (c-Myc) as a downstream target of Bclaf1, given that Bclaf1 regulates c-MYC expression posttranscriptionally by its RS domain. To exert this function, Bclaf1 must interact with the molecular chaperone, heat shock protein 90 alpha (Hsp90alpha). In HCC tissue samples, Hsp90alpha levels were also increased significantly and Hsp90alpha-Bclaf1 interaction was enhanced. Bclaf1 interacts with the C-terminal domain of Hsp90alpha, and this interaction is disrupted by the C-terminal domain inhibitor, novobiocin (NB), resulting in proteasome-dependent degradation of Bclaf1. Moreover, NB-induced disruption of Hsp90alpha-Bclaf1 interaction dampened the production of mature c-MYC mRNA and attenuated tumor cell growth in vitro and in vivo. CONCLUSION: Our findings suggest that Bclaf1 affects HCC progression by manipulating c-MYC mRNA stability and that the Hsp90alpha/Bclaf1/c-Myc axis might be a potential target for therapeutic intervention in HCC. PMID- 30015414 TI - Tropical heterothermy is "cool": The expression of daily torpor and hibernation in primates. AB - Living nonhuman primates generally inhabit tropical forests, and torpor is regarded as a strategy employed by cold-adapted organisms. Yet, some primates employ daily torpor or hibernation (heterothermy) under obligatory, temporary, or emergency circumstances. Though heterothermy is present in most mammalian lineages, there are only three extant heterothermic primate lineages: bushbabies from Africa, lorises from Asia, and dwarf and mouse lemurs from Madagascar. Here, we analyze their phenotypes in the general context of tropical mammalian heterothermy. We focus on Malagasy lemurs as they have been the most intensively studied and also show an unmatched range of flexibility in their heterothermic responses. We discuss the evidence for whether heterothermy should be considered an ancestral or derived condition in primates. This consideration is particularly intriguing given that an understanding of the underlying mechanisms for hibernation in lemurs opens the possibility for insight into genotype-phenotype interactions, including those with biomedical relevance for humans. PMID- 30015415 TI - Deficient primary cilia in obese adipose-derived mesenchymal stem cells: obesity, a secondary ciliopathy? AB - Obesity alters the composition, structure and function of adipose tissue, characterized by chronic inflammation, insulin resistance and metabolic dysfunction. Adipose-derived mesenchymal stem cells (ASCs) are responsible for cell renewal, spontaneous repair and immunomodulation in adipose tissue. Increasing evidence highlights that ASCs are deficient in obesity, and the underlying mechanisms are not well understood. We have recently shown that obese ASCs have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functions. This work suggests an intertwined connection of obesity, defective cilia and dysfunctional ASCs. We have here discussed the current data regarding defective cilia in various cell types in obesity. Based on these observations, we hypothesize that obesity, a systemic chronic metainflammation, could impair cilia in diverse ciliated cells, like pancreatic islet cells, stem cells and hypothalamic neurons, making these critical cells dysfunctional by shutting down their signal sensors and transducers. In this context, obesity may represent a secondary form of ciliopathy induced by obesity-related inflammation and metabolic dysfunction. Reactivation of ciliated cells might be an alternative strategy to combat obesity and its associated diseases. PMID- 30015416 TI - Molecular Tweezers with Additional Recognition Sites. AB - A new synthetic access to molecular tweezers with one or two aliphatic phosphate ester groups in the central benzene spacer-unit is presented. Alkynyl ester groups offer the prospect to attach additional functional units by click chemistry and greatly broaden the scope of these tools for chemical biology. We present two alternative strategies: the trichloroacetonitrile method involves activation of only one OH group of each phosphoric acid substituent by way of trichloroacetimidate intermediates and subsequent introduction of an aliphatic ester alcohol moiety. The method is versatile, robust and combines simple workup with high yields. Mono- and disubstituted novel host structures are thus accessible in a convenient way. Alternatively, the phosphoramidite strategy activates the hydroquinone precursor by way of phosphoramidite intermediates and couples the desired ester alcohols followed by mild oxidation to the desired phosphate esters. Each step of the synthesis is carried out at very mild conditions and allows to combine sensitive host candidates and recognition elements. After neutralization of the phosphoric acids to water-soluble tri- and tetra-anions the cavities of the new tweezer derivatives are open to bind lysine and arginine as well as peptidic guests. The concept of introducing clickable alkynyl phosphates to free OH groups may be transferred to other major macrocyclic host classes to introduce additional recognition elements, biomolecules or fluorescence labels. PMID- 30015417 TI - Detection of Aujeszky's disease virus DNA and antibody in swine oral fluid specimens. AB - Aujeszky's disease virus (ADV) continues to circulate in commercial swine populations in many regions and in feral swine populations in most parts of the world, that is, ADV continues to present a risk to pork producers everywhere. Current DIVA vaccines and assays are highly effective in the control and/or eradication of ADV, but detection of wild-type ADV infection relies on testing individual pig specimens, for example, serum or muscle exudate ("meat juice"). Oral fluid specimens have been shown to be highly effective for the surveillance of a variety of swine pathogens and could offer the means to improve the efficiency of ADV surveillance in the field. In this study, the temporal patterns of ADV DNA and antibody detection in oral fluid and serum specimens were established in ADV-inoculated pigs (n = 14) using gB and gE PCRs, virus neutralization (VN) and three commercial serum antibody ELISAs (gB bELISA, gI bELISA and ADV iELISA). ADV DNA was detected in oral fluid samples (20% to 100%) from 3 to 21 days postinoculation (DPI), but not in serum. ADV antibody was detected in oral fluid specimens at DPI >= 10 with the gB bELISA (36% to 79%) and ADV iELISA (29% to 100%), but not the gI bELISA. These results suggest that oral fluid could be used as an alternative to individual pig sampling for ADV surveillance using PCR- and/or antibody-based assays. PMID- 30015418 TI - Mandibular ridge reconstruction: A review of contemporary methods. AB - Reconstruction can be very problematic in the case of mandibular alveolar bone loss, which can also hinder the implant restorative treatment. The aim of the study was to present current views on reconstructing the alveolar part of mandibular bone, which allows the insertion of implants and then the placement of denture. Based on the available literature, the efficacy of various techniques of filling of mandibular bone losses was described and compared. Reconstruction with autogenous bone block graft had been used as a gold standard. Recently, other techniques have appeared that offer better functional and esthetics results. They include reconstruction with allogeneic bone block graft, osteotomy allowing immediate insertion of implants, bone distraction, guided bone regeneration using titanium mesh (Ti-mesh), new techniques using scaffolds (biphasic calcium phosphate, poly-lactide-co-glycolide/tricalcium phosphate, bioresorbable polycaprolactone), Sonic Weld Technique(r) (Tuttlingen, Germany) using resorbable membrane and pins with polymer lactide acid (PLA), and the tent technique. These abovementioned techniques allow solving the problem of insufficient amount of bone for prosthetic treatment. PMID- 30015419 TI - Detection of Acinetobacter spp. in Blood Cultures by an Improved Fluorescent in Situ Hybridization Assay. AB - Fluorescent in situ hybridization (FISH) allows rapid detection of microorganisms. We aimed (i) to evaluate the sensitivity and specificity of FISH for the detection of Acinetobacter spp. in blood culture specimens and (ii) to test the simultaneous application of two genus-specific probes labeled with the same fluorochrome to increase the fluorescent signal intensity and improve the detection of Acinetobacter spp. Three hundred and twenty blood culture specimens were tested via both the conventional laboratory methods and FISH to detect Acinetobacter spp. The specimens were examined separately with each genus specific probe Aci and ACA, and also using a mixture of the both probes Aci and ACA. In all examinations, probe EUB338 was used accompanied by Aci and ACA. The specificity of FISH was 100% (97.5% confidence interval [CI] = 98.7% - 100%). The sensitivity of FISH by the use of probe Aci was 96.4% (95% CI = 81.7% - 99.9%), whereas, the sensitivity of this technique by the use of probe ACA as well as by the combination of both probes Aci and ACA was 100% (97.5% CI = 87.7% - 100%). Moreover, simultaneous hybridization by probes Aci and ACA increased the fluorescent signal of Acinetobacter spp. cells to 3+ in 13 specimens. In conclusion, FISH, particularly using a combination of Aci and ACA, is a highly accurate method for the detection of Acinetobacter spp. in blood cultures. Furthermore, simultaneous hybridization by the both probes Aci and ACA can increase the fluorescent signal intensity of Acinetobacter spp. cells in some blood culture specimens and facilitate the detection of these microorganisms. PMID- 30015420 TI - Non-invasive Diagnostic of Helicobacter pylori in Stools by Nested-qPCR. AB - The aim of this study was to develop a non-invasive diagnostic test for the detection of Helicobacter pylori in stool samples from digestive symptomatic patients, using a new protocol of nested-qPCR. A total of 143 patients were invited to participate in the study. A gastric biopsy of each patient was collected for Rapid Urease Testing (RUT) and histology by Giemsa stain. A fecal sample for nested-qPCR analysis was also obtained. DNA was extracted from the fecal samples, and conventional PCR followed by qPCR of the ureC gene of H. pylori was carried out. We evaluated the presence of H. pylori, in 103 females and 40 males, mean (+/- SD) age of 56.5 +/- 14.18. The sensitivity of RUT to detect the infection was 67.0% (95% C.I.: 57.2 - 75.8) and specificity was 92.3% (95% C.I.: 76.5 - 99.1). Histology by Giemsa stain, commonly used as a reference for H. pylori detection, showed a sensitivity of 98.6% (95% C.I.: 92.5 - 100.0) and a specificity of 89.7% (95% C.I.: 72.7 - 97.8). In contrast, detection of H. pylori infection in stools by nested-qPCR showed a sensitivity of 100% (95% C.I.: 94.9 - 100.0) and a specificity of 83.9% (95% C.I.: 66.3 - 94.6). Our test, based in nested-qPCR is a better diagnostic alternative than conventional RUT, and is similar to histology by Giemsa stain in the detection of H. pylori, by which the test could be used for non-invasive diagnosis in clinical practice. PMID- 30015421 TI - Molecular Characterization of the cry Gene profile of Bacillus thuringiensis Isolated from a Caribbean Region of Colombia. AB - In order to characterize native strains of Bacillus thuringiensis of the Colombian Caribbean with toxic effect against insect vectors, 28 samples of bacteria identified as B. thuringiensis were isolated from different soils and muds around the city of Valledupar. Using a biological test, five isolates of B. thuringiensis showed toxic effect against larvae of Aedes aegypti. PCR methods were used to detect cry1, cry2, cry4B, cry10 and cyt1 genes. Cry1 and cry2 genes were detected in 35.7% and 32.1% of the 28 isolates analyzed, respectively. Surprisingly, reduced lengths of cry4B gene segments were detected in 28.6% of B. thuringiensis samples. The presence of cry10 or cyt1 was not detected in any of the 28 samples of B. thuringiensis, despite the high sensitivity of the assays used. The results show that B. thuringiensis samples from the Colombian Caribbean have atypical characteristics compared to those of Latin America and elsewhere in the world, which is consistent with the idea that the geographic origin of B. thuringiensis samples is associated with their biological and genetic characteristics. PMID- 30015422 TI - High-Throughput Sequencing Analysis of Endophytic Bacteria Diversity in Fruits of White and Red Pitayas from Three Different Origins. AB - Pitaya contains various types of polyphenols, flavonoid and vitamins which are beneficial for health and it is among the most important commercial tropical fruits worldwide. Endophytic bacteria might be beneficial for plant growth and yield. However, bacterial diversity in pitaya is poorly characterized. In this study, fruits of white and red pitayas from three different origins (Thailand, Vietnam and China) were chosen for endophytic bacteria diversity investigation by using Illumina HiSeq second-generation high-throughput sequencing technology. Large number of endophytic bacteria were detected and 22 phyla, 56 classes, 81 orders, 122 families and 159 genera were identified. Endophytic bacteria diversity was uneven among pitaya fruits from different origins and bacteria structure was different between white pitaya group and red pitaya group. Phylum Bacteroidetes, classes Bacteroidia and Coriobacteriia, orders Bacteroidales and Coriobacteriales, families Prevotellaceae, Bacteroidaceae, Ruminococcaceae, Paraprevotellaceae, Rikenellaceae, Alcaligenaceae and Coriobacteriaceae, genera Prevotella, Bacteroides, Roseburia, Faecalibacterium and Sutterella were statistically significant different species (P < 0.05) between white and red pitayas. These findings might be useful for growth improvement, fruit preservation and processing of different pitaya species from different origins. PMID- 30015423 TI - Natural Attenuation Potential of Polychlorinated Biphenyl-Polluted Marine Sediments. AB - The marine environment in Kuwait is polluted with various hazardous chemicals of industrial origin. These include petroleum hydrocarbons, halogenated compounds and heavy metals. Bioremediation with dedicated microorganisms can be effectively applied for reclamation of the polluted marine sediments. However, information on the autochthonous microbes and their ecophysiology is largely lacking. We analyzed sediments from Shuwaikh harbor to detect polychlorinated biphenyls (PCBs) and total petroleum hydrocarbons (TPHs). Then we adopted both culture dependent and culture-independent (PCR-DGGE) approaches to identify bacterial inhabitants of the polluted marine sediments from Shuwaikh harbor. The chemical analysis revealed spatial variation among the sampling stations in terms of total amount of PCBs, TPHs and the PCB congener fingerprints. Moreover, in all analyzed sediments, the medium-chlorine PCB congeners were more abundant than the low chlorine and high-chlorine counterparts. PCR-DGGE showed the presence of members of the Proteobacteria, Spirochaetes, Firmicutes and Bacteroidetes in the analyzed sediments. However, Chloroflexi-related bacteria dominated the detected bacterial community. We also enriched a biphenyl-utilizing mixed culture using the W2 station sediment as an inoculum in chemically defined medium using biphenyl as a sole carbon and energy source. The enriched mixed culture consisted mainly of the Firmicute Paenibacillus spp. Sequences of genes encoding putative aromatic ring hydroxylating dioxygenases were detected in sediments from most sampling stations and the enriched mixed culture. The results suggest the potential of bioremediation as a means for natural attenuation of Shuwaikh harbor sediments polluted with PCBs and TPHs. PMID- 30015424 TI - Isolation and Characteristics of Biotechnologically Important Antagonistic Thermophilic Bacteria from Rhizosphere of Haloxylon salicornicum. AB - Rhizobacteria are an active part of microbial population in the rhizosphere of plants. In this study, twenty rhizobacteria were isolated from the rhizosphere of a perennial grass, Haloxylon salicornicum, found in Cholistan desert, an arid landmass near Bahawalpur Pakistan, in one set of experimental conditions. Colony characteristics, biochemical and molecular analyses of these isolates were performed. All isolates were bacilli, gram positive with off-white colonies and exhibited typical bacilli colony morphology. None of the isolates was gelatinase, urease, indole, H2S and catalase producer. Eleven isolates were amylase producers and 8 isolates were acid producers. All isolates fermented glucose, 3 fermented lactose and 19 fermented fructose. Molecular data revealed that out of twenty isolates, 14 isolates showed 91-99% identity with Brevibacillus borstelensis, 4 with Bacillus subtilis (97-98%) and 2 with Bacillus licheniformis (94-99%) through BLAST analysis. All identified bacterial isolates cladded with their respective groups in the phylogenetic tree. Many (11-15 out of 20) of the isolates were more effective in inhibiting growth of the tested bacterial strains as compared to the positive control (Ampicillin 50 MUg/disc). We conclude that bacilli are the predominant form populating rhizosphere of this desert grass. Among the isolated bacteria Brevibacillus borstelensis, Bacillus subtilis and Bacillus licheniformis are the most predominant species. PMID- 30015425 TI - A Low-Tech Bioreactor System for the Enrichment and Production of Ureolytic Microbes. AB - Ureolysis-driven microbially induced carbonate precipitation (MICP) has recently received attention for its potential biotechnological applications. However, information on the enrichment and production of ureolytic microbes by using bioreactor systems is limited. Here, we report a low-tech down-flow hanging sponge (DHS) bioreactor system for the enrichment and production of ureolytic microbes. Using this bioreactor system and a yeast extract-based medium containing 0.17 M urea, ureolytic microbes with high potential urease activity (> 10 MUmol urea hydrolyzed per min per ml of enrichment culture) were repeatedly enriched under non-sterile conditions. In addition, the ureolytic enrichment obtained in this study showed in vitro calcium carbonate precipitation. Fluorescence in situ hybridization analysis showed the existence of bacteria of the phylum Firmicutes in the bioreactor system. Our data demonstrate that this DHS bioreactor system is a useful system for the enrichment and production of ureolytic microbes for MICP applications. PMID- 30015426 TI - MALDI-TOF MS Detection of Endophytic Bacteria Associated with Great Nettle (Urtica dioica L.), Grown in Algeria. AB - Any plant with a vascular system has a specific endophytic microflora. The identification of bacteria is essential in plant pathology. Although identification methods are effective, they are costly and time consuming. The purpose of this work is to isolate and to identify the different bacteria from the internal tissues of Urtica dioica L. and to study their diversity. This last is based on the different parts of the plant (stems, leaves and roots) and the harvest regions (Dellys and Tlamcen). The identification of bacteria is done by biochemical tests and confirmed by MALDI-TOF MS. Seven genus and eleven species were isolated from the Great Nettle. They belong to the genera Bacillus, Escherichia, Pantoea, Enterobacter, Staphylococcus, Enterococcus and Paenibacillus. The majority of these bacteria were isolated from Tlemcen which makes this region the richest in endophytic bacteria compared to that harvested from Dellys. The results show also that the leaves are the most diversified in endophytic bacteria. Bacillus pumilus-ME is the common species of the three parts of the plant harvested in both regions. From this work, it emerges that the Great Nettle can be settled by various endophytic bacteria which are differently distributed within the same plant harvested in different regions. PMID- 30015427 TI - The Very Low Frequency of Epstein-Barr JC and BK Viruses DNA in Colorectal Cancer Tissues in Shiraz, Southwest Iran. AB - Viruses including Epstein-Barr virus (EBV), JCV and BKV have been reported to be associated with some cancers. The association of these viruses with colorectal cancers remains controversial. Our objective was to investigate their infections association with adenocarcinoma and adenomatous polyps of the colon. Totally, 210 paraffin-embedded tissue specimens encompassing 70 colorectal adenocarcinoma, 70 colorectal adenomatous and 70 colorectal normal tissues were included. The total DNA was extracted, then qualified samples introduced to polymerase chain reaction (PCR). The EBV, JCV and BKV genome sequences were detected using specific primers by 3 different in-house PCR assays. Out of 210 subjects, 98 cases were female and the rest were male. The mean age of the participants was 52 +/- 1.64 years. EBV and JCV DNA was detected just in one (1.42%) out of seventy adenocarcinoma colorectal tissues. All adenomatous polyp and normal colorectal tissues were negative for EBV and JCV DNA sequences. Moreover, all the patients and healthy subjects were negative for BKV DNA sequences. The results suggested that EBV and JCV genomes were not detectable in the colorectal tissue of patients with colorectal cancer in our population. Hence, BKV might not be necessitated for the development of colorectal cancer. The findings merit more investigations. PMID- 30015428 TI - Comparison of Methods Used for the Diagnosis of Epstein-Barr Virus Infections in Children. AB - The accurate diagnosis of Epstein-Barr virus (EBV) infections is important, as many other infectious agents or diseases can cause similar symptoms. In this study, sera of pediatric patients who were suspected to have an EBV infection, were sent to Eskisehir Osmangazi University Faculty of Medicine, Department of Clinical Microbiology, and investigated by IFA, ELISA, immunoblotting and Real time PCR. The performances of these tests were compared with IFA. The rates of agreement between ELISA and IFA were found as 100% for seronegative, 100% for acute primary infection, 22.2% for late primary infection, 92.1% for past infection. The rates of agreement between immunoblotting and IFA were found as 80.8% for seronegative, 68.8% for acute primary infection, 55.6% for late primary infection, 86.6% for past infection. The sensitivity of immunoblotting for anti VCA IgM was identical with ELISA, and higher for anti-VCA IgG, anti-EBNA IgG, anti-EA antibodies, while the specificity of immunoblotting for these antibodies were found to be lower. The sensitivity and specificity of Real-time PCR for detection of viremia in acute primary infection were found as 56.25% (9/16) and 97.89% (139/142), respectively. The diagnostic methods should be chosen by evaluating the demographic characteristics of patients and laboratory conditions together. PMID- 30015429 TI - Isolation of Sabin-like Polioviruses from Sewage in Poland. AB - As a complement to the active search for cases of acute flaccid paralysis, environmental sampling was conducted from January to December 2011, to test for any putative polio revertants and recombinants in sewage. A total of 165 environmental samples were obtained and analyzed for the presence of polioviruses by use of cell culture (L20B, RD and Caco-2) followed by neutralization and reverse-transcription polymerase chain reaction. Out of the 31 CPE positive samples, 26 contained one and 5 two different serotypes, yielding a total of 36 PVs. The microneutralization test revealed the presence of 7, 10 and 19 strains belonging to poliovirus serotype 1, 2 and 3, respectively. The genomic variability of 36 poliovirus strains was examined by the restriction fragment length polymorphism assay (RFLP). By combined analyses of two distant, polymorphic segments of the viral genome, one situated in the capsid protein VP1 coding region and the other in the 3D-polymerase coding region, we screened for the putative poliovirus revertants and recombinants. All detected PVs were classified as vaccine strains on the basis of RFLP-VP1 test. None of wild-type PVs or vaccine derived polioviruses were detected. RFLP assay also revealed the presence of 11 recombinants in 3D-polymerase coding region. Nine isolates appeared to be S3/S2, one S3/S1 and S1/S2 recombinant in analyzed 3Dpol region. This study revealed, through environmental monitoring, the introduction of SL PVs into the population associated with the routine use of OPV in Poland before the April 2016. Our findings demonstrate the usefulness of environmental surveillance in the overall polio eradication program. PMID- 30015430 TI - Evaluation of the Carba NP Test for the Detection of Carbapenemase Activity in Bacteroides Species. AB - We evaluated the usefulness of the Carba NP test for rapid detection of carbapenemase activity in Bacteroides spp. The minimum inhibitory concentration (MIC) for imipenem was determined with gradient test strips, and cfiA gene was investigated by polymerase chain reaction for 27 clinical Bacteroides spp. isolates. Carba NP test was performed according to recommendations of the Clinical and Laboratory Standards Institute. Among three cfiA gene harboring clinical isolates, two imipenem resistant isolates were Carba NP test positive, while the imipenem intermediate isolate was negative. Our preliminary results suggest that the Carba NP test can be useful as a rapid test to detect carbapenemases in Bacteroides species. PMID- 30015431 TI - Rapid Detection of Bloodstream Pathogens in Oncologic Patients with a FilmArray Multiplex PCR Assay: a Comparison with Culture Methods. AB - The results of the FilmArray(r) Blood Culture Identification Panel (BCID) (BioFire Diagnostics) and the culture with susceptibility testing of 70 positive blood cultures from oncologic patients were compared. The multiplex PCR assay (BCID) identified 81 of the 83 isolates (97.6%), covered by the panel. The panel produced results in significantly shorter time than standard identification methods, when counted from receiving positive blood cultures bottles to the final results. It is an accurate method for the rapid identification of pathogens and resistance genes from blood culture in oncologic patients. PMID- 30015432 TI - Changes of Microbial Diversity During Swine Manure Treatment Process. AB - We investigated microbial diversity in a manure storage tank (MST) storing untreated manure and an aeration tank (AT) during swine manure treatment process using the next-generation sequencing in order to find the aeration effect on microbial diversity. Proteobacteria were more abundant in the AT group than in the MST group and may include denitrifying bacteria contributing to nitrous oxide (N2O) emission or aerobic bacteria stimulated by oxygen. The opposite held true for the phyla Bacteroidetes and Firmicutes that may include anaerobic bacteria inhibited under aerobic conditions in the AT group. PMID- 30015433 TI - Comparative Seroprevalence of Hepatitis A And E Viruses in Blood Donors from Wielkopolska Region, West-Central Poland. AB - The objective of the present study was to investigate the seroprevalence of HAV and HEV in Polish blood donors (BDs). One hundred and ten randomly selected healthy BDs, living in Wielkopolska Region were tested for anti-HAV IgG and anti HEV IgG with commercial assays. The seroprevalence of anti-HAV was 11.8%; anti HEV were detected in 60.9% of BDs (p < 0.0001). Consumption of risky food was more common in anti-HEV-positive BDs (59.1% vs. 33.3%; p = 0.01). Twelve out of 20 BDs (60%) with no history of travel abroad were exposed to HEV. Wielkopolska Region, Poland should be regarded as a new HEV infection-hyperendemic area in Europe. PMID- 30015434 TI - The Prevalence of Campylobacter spp. in Polish Poultry Meat. AB - The prevalence, count and molecular identification of Campylobacter spp. in Polish poultry meat were analysed. 181 samples of meat from chicken (70), turkey (47), duck (54) and goose (10) were studied. Campylobacter spp. was found in 64% of meat samples. The highest prevalence of this pathogen was detected for duck meat. On average 80% of duck samples were contaminated with Campylobacter spp. The counts of Campylobacter spp. in positive samples remained under ten colony forming units per gram of product in 59% of poultry meat. C. jejuni was more frequently detected in poultry meat than C. coli. PMID- 30015437 TI - Microbial Glycosylation of Flavonoids. AB - Flavonoids constitute a large group of polyphenolic compounds naturally found in plants, which have a wide range of biological activity. Although flavonoids are beneficial to human health, their application is limited by their low bioavailability and poor water-solubility. Therefore, recently there has been a particular interest in glycosylated forms of flavonoids, which usually are better soluble, more stable, and more functional compared to their aglycones. Microbial transformation of natural flavonoids may be an attractive way of receiving their glycosylated derivatives in amounts sufficient for the research on the effect of glycoside group on compound properties and for further application of these compounds as ingredients of dietary supplements and pharmaceuticals. PMID- 30015438 TI - Relationship between ureB Sequence Diversity, Urease Activity and Genotypic Variations of Different Helicobacter pylori Strains in Patients with Gastric Disorders. AB - Association of the severity of Helicobacter pylori induced diseases with virulence entity of the colonized strains was proven in some studies. Urease has been demonstrated as a potent virulence factor for H. pylori. The main aim of this study was investigation of the relationships of ureB sequence diversity, urease activity and virulence genotypes of different H. pylori strains with histopathological changes of gastric tissue in infected patients suffering from different gastric disorders. Analysis of the virulence genotypes in the isolated strains indicated significant associations between the presence of severe active gastritis and cagA+ (P = 0.039) or cagA/iceA1 genotypes (P = 0.026), and intestinal metaplasia and vacA m1 (P = 0.008) or vacA s1/m2 (P = 0.001) genotypes. Our results showed a 2.4-fold increased risk of peptic ulcer (95% CI: 0.483-11.93), compared with gastritis, in the infected patients who had dupA positive strains; however this association was not statistically significant. The results of urease activity showed a significant mean difference between the isolated strains from patients with PUD and NUD (P = 0.034). This activity was relatively higher among patients with intestinal metaplasia. Also a significant associa-tion was found between the lack of cagA and increased urease activity among the isolated strains (P = 0.036). While the greatest sequencevariation of ureB was detected in a strain from a patient with intestinal metaplasia, the sole determined amino acid change in UreB sequence (Ala201Thr, 30%), showed no influence on urease activity. In conclusion, the supposed role of H. pylori urease to form peptic ulcer and advancing of intestinal metaplasia was postulated in this study. Higher urease activity in the colonizing H. pylori strains that present specific virulence factors was indicated as a risk factor for promotion of histopathological changes of gastric tissue that advance gastric malignancy. PMID- 30015439 TI - Interaction of Gram-Positive and Gram-Negative Bacteria with Ceramic Nanomaterials Obtained by Combustion Synthesis - Adsorption and Cytotoxicity Studies. AB - This paper presents the interactions of Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas putida) bacteria with ceramic materials obtained by combustion synthesis. These studies were conducted based on an analysis of the adsorption of bacteria onto aggregates of ceramic materials in an aqueous suspension. The materials used in the studies were of a nanostructured nature and consisted mainly of carbides: silicon carbide (SiC) in the form of nanofibers (NFs) and nanorods (NRs), titanium carbide, and graphite, which can also be formed by combustion synthesis. Micrometric SiC was used as a reference material. Gram-positive bacteria adsorbed more strongly to these materials. It seems that both the point of zero charge value and the texture of the ceramic material affected the bacterial adsorption process. Additionally, the viability of bacteria adsorbed onto aggregates of the materials decreased. Generally, P. putida cells were more sensitive to the nanomaterials than S. aureus cells. The maximum loss of viability was noted in the case of bacteria adsorbed onto NRSiC and NFSiC aggregates. PMID- 30015440 TI - Biocontrol of Gray Mold Decay in Pear by Bacillus amyloliquefaciens Strain BA3 and its Effect on Postharvest Quality Parameters. AB - The economic losses caused by postharvest fruits diseases have attracted global attention. Traditional chemical fungicide could not meet the need of humans. In recent years, microbial agent which has begun to take the place of chemical fungicide comes into people's vision. The aim of this paper was to investigate the potential of Bacillus amyloliquefaciens strain BA3 for its biocontrol capability on gray mold decay of pears and its effect on postharvest quality of pears. Compared with other treatments, the inhibition effect on gray mold of washed cell suspension of B. amyloliquefaciens was the best. Consequently it was utilized in subsequent experiments. Spore germination and germ tube length of Botrytis cinerea was 18.72% and 12.85 MUm treated with BA3, while the control group was 62.88% and 30.44 MUm. We confirmed that increase of the concentration of B. amyloliquefaciens, improved the efficacy of BA3 in controlling gray mold decay of pears. Colonization variation of BA3 in wounds of pears was recorded. To begin with, the populations of B. amyloliquefaciens increased rapidly and remained stable. On the fourth day, there was a declining trend , after that the population increased to 4 * 105 CFU/wound and remained stable. BA3 had no significant effect on mass loss, titratable acidity, firmness and total soluble solids of pears that were stored at 25 degrees C for 7 days comparing with control group. However, the effect of B. amyloliquefaciens on ascorbic acid was significantly higher than that of the control group. Our study indicates that B. amyloliquefaciens has a potential as postharvest biocontrol agent on pears. PMID- 30015441 TI - Enzymes Involved in Naproxen Degradation by Planococcus sp. S5. AB - Naproxen is a one of the most popular non-steroidal anti-inflammatory drugs (NSAIDs) entering the environment as a result of high consumption. For this reason, there is an emerging need to recognize mechanisms of its degradation and enzymes engaged in this process. Planococcus sp. S5 is a gram positive strain able to degrade naproxen in monosubstrate culture (27%). However, naproxen is not a suf-ficient growth substrate for this strain. In the presence of benzoate, 4 hydroxybenzoic acid, 3,4-dihydroxybenzoic acid or vanillic acid as growth substrates, the degradation of 21.5%, 71.71%, 14.75% and 8.16% of naproxen was observed respectively. It was shown that the activity of monooxygenase, hydroxyquinol 1,2-dioxygenase, protocatechuate 3,4-dioxygenase and protocatechuate 4,5-dioxyegnase in strain S5 was induced after growth of the strain with naproxen and 4-hydroxybenzoate. Moreover, in the presence of naproxen activity of gentisate 1,2-dioxygenase, enzyme engaged in 4-hydroxybenzoate metabolism, was completely inhibited. The obtained results suggest that monooxygenase and hydroxyquinol 1,2-dioxygenase are the main enzymes in naproxen degradation by Planococcus sp. S5. PMID- 30015442 TI - Characterization of Bacteria Isolation of Bacteria from Pinyon Rhizosphere, Producing Biosurfactants from Agro-Industrial Waste. AB - Two hundred and fifty bacterial strains were isolated from pinyon rhizosphere and screened for biosurfactants production. Among them, six bacterial strains were selected for their potential to produce biosurfactants using two low cost wastes, crude glycerol and lactoserum, as raw material. Both wastes were useful for producing biosurfactants because of their high content in fat and carbohydrates. The six strains were identified by 16S rDNA with an identity percentage higher than 95%, three strains belonged to Enterobacter sp., Pseudomonas aeruginosa, Bacillus pumilus and Rhizobium sp. All strains assayed were able to grow and showed halos around the colonies as evidence of biosurfactants production on Cetyl Trimethyl Ammonium Bromide agar with crude glycerol and lactoserum as substrate. In a mineral salt liquid medium enriched with both wastes, the biosurfactants were produced and collected from free cell medium after 72 h incubation. The biosurfactants produced reduced the surface tension from 69 to 30 mN/m with an emulsification index of diesel at approximately 60%. The results suggest that biosurfactants produced by rhizosphere bacteria from pinyon have promising environmental applications. PMID- 30015443 TI - Levels of Organic Compounds, Number of Microorganisms and Cadmium Accumulation in Festuca ovina Hydroponic Culture. AB - Understanding the microbiological, biochemical and physiological aspects of phytoremediation of soil and water environments polluted to different degrees with heavy metals has very important theoretical and practical implications. In this study, a comparison was made between total cadmium concentration in root and shoot tissues as well as concentrations of particular fractions of Cd immobilized by roots of Festuca ovina (Sheep's fescue) hydroponically cultivated in nutrient solutions supplemented with 1 MUg Cd ml-1 and those cultivated at 10 MUg Cd ml-1. After three weeks of F. ovina cultivation, the number of bacterial CFU and the amounts of organic chelators, siderophores, proteins and reducing sugars in the growth medium and on the root surface were higher at 10 than at 1 MUg Cd ml-1. The grass also reacted to the high Cd concentration by a decrease in plant growth and dehydrogenase activity in root tissues. The concentration of Cd determined in fractions bound with different strength in roots was significantly dependent on Cd concentration in the growth medium. When the plants were grown at 1 MUg Cd ml 1, 9% of the immobilized cadmium was loosely bound to the root surface, 20% was exchangeable adsorbed, and 28% was bound by chelation; at 10 MUg Cd ml-1, the respective values were 12%, 25%, and 20%. About 43% of the immobilized cadmium remained in roots after sequential extraction, and bioaccumulation factors in shoots had the same values independently of Cd concentra-tion. At both Cd concentrations, the cadmium translocation index for F. ovina was low (< 1), which is why this grass can be recommended for phytostabilization of the metal under study. PMID- 30015444 TI - Prevalence of Parasitic Contamination in Salad Vegetables Collected from Supermarkets and Street Vendors in Amman and Baqa'a - Jordan. AB - One of the main ways in transmitting parasites to humans is through consuming contaminated raw vegetables. The aim of this study was to evaluate the prevalence of parasitological contamination (helminthes eggs, Giardia and Entamoeba histolytica cysts) of salad vegetables sold at supermarkets and street vendors in Amman and Baqa'a - Jordan. A total of 133 samples of salad vegetables were collected and examined for the prevalence of parasites. It was found that 29% of the samples were contaminated with different parasites. Of the 30 lettuce, 33 tomato, 42 parsley and 28 cucumber samples examined the prevalence of Ascaris spp. eggs was 43%, 15%, 21% and 4%; Toxocara spp. eggs was 30%, 0%, 0% and 4%; Giardia spp. cysts was 23%, 6%, 0% and 0%; Taenia/Echinococcus eggs was 20%, 0%, 5% and 0%; Fasciola hepatica eggs was 13%, 3%, 2% and 0%; and E. histolytica cysts was 10%, 6%, 0% and 0%, respectively. There was no significant difference in the prevalence of parasite in salad vegetables either between supermarkets and street vendors, or between Amman and Baqa'a, Ascaris spp. was found to be the highest prevalent parasite in salad vegetables from supermarkets and street vendors and from Amman and Baqa'a. Our results pointed out that, the parasitic contamination of salad vegetables found in our study might be caused by irrigating crops with faecal contaminated water. We concluded that salad vegetables sold in Amman and Baqa'a may cause a health risk to consumers. PMID- 30015445 TI - Identification and Localization of beta-D-Glucosidase from Two Typical Oenococcus oeni Strains. AB - beta-D-glucosidase (betaG) gene from Oenococcus oeni SD-2a and 31MBR was cloned, sequenced and analyzed, also intracellular betaG of the two strains was further localized. The results showed that betaG gene of the two strains was in high homology (> 99%) to reported betaG gene, con-firming both strains possess betaG activity at the molecular level. Intracellular betaG of SD-2a is a mainly soluble protein, existing mostly in the cytoplasm and to some extent in the periplasm. While for 31MBR, intracellular betaG is mainly insoluble protein existing in the cytoplasmic membrane. This study provides basic information for further study of the metabolic mechanism of betaG from O. oeni SD-2a and 31MBR. PMID- 30015446 TI - Characterization of Staphylococcal Cassette Chromosome mec (SCCmec) in Methicillin-Resistant Staphylococcus epidermidis Strains Isolated from Biomaterial-Associated Infections and their Antibiotic Resistance Patterns. AB - This work aims to provide an insight into staphylococcal cassette chromosome mec elements and antibiotic resistance in clinical isolates of Staphylococcus epidermidis. The dominating type was SCCmec - IV. Fifteen isolates were assigned to SCCmec type III, two isolates to SCCmec type II. Most isolates were resistant to at least three of the non-beta-lactam antibiotics tested. None of the strains exhibited resistance to new generation antibiotics, such as daptomycin and linezolid. Also, none of these strains showed resistance to tigecycline and only four strains were resistant to rifampin i.e. antibiotics which are very efficient in treating biofilm-associated infections. PMID- 30015447 TI - Qualitative and Quantitative Characteristics of Selected Bacterial Groups in Children with Inflammatory Bowel Diseases. AB - The aim of the study was evaluation of qualitative and quantitative changes in bacterial ecosystem in 109 children with inflammatory bowel diseases. Stools obtained from patients were analysed for selected bacteria and concentration of faecal inflammatory markers (calprotectin, lactoferrin, M2-PK). The number of selected microorganisms depends on the level of clinical activity of disease and is correlated with faecal concentration of inflammatory markers. Differences in microflora disturbance, observed in patients with Crohn's disease and ulcerative colitis, may suggest different causes of development of both pathologies. PMID- 30015448 TI - Cytotoxic and Bacteriostatic Activity of Nanostructured TiO2 Coatings. AB - Nanostructures are structures, mainly synthetic (nanosurfaces, cylindrical nanotubes, and nanospheres), which range between 1-100 nm in at least one dimension and can be engineered to a wide range of physical properties. This paper aims to explore the bacteriostatic and cytotoxic characteristics of nano TiO2 coated specimens of glass, stainless steel and ceramic with different thickness and roughness. The results show that stainless steel and glass specimens with a nano-TiO2 coating thickness of 200 nm have a bacteriostatic effect of 97% and 100%, respectively after 30 minutes of UV exposure. Glass specimens with a nano-TiO2 coating thickness of 750, 200 and 50 nm have a bacteriostatic effect of 86%, 93% and 100% after 60 minutes. Nano-TiO2 coatings show a great bacteriostatic but not a cytotoxic effect, thus representing a valuable alternative for biomedical applications. PMID- 30015449 TI - Enteroviruses Associated with Aseptic Meningitis in Poland, 2011-2014. AB - A 4-year study (2011-2014) of patients with meningitis was performed. Out of the 686 cerebrospinal fluid samples, 465 (67.8%) were posi-tive for eneteroviruses using RT-PCR and out of 334 clinical samples, 216 (64.7%) were positive for enteroviruses using cell culture methods. The highest detection rate was observed in the summer and autumn. In total, 185 enteroviruses were identified by using neutralization test. Echovirus 6 and 30 were the most common (41.7% and 37.5% respectively). The highest frequency of neurological infections (32.7%) occurred in children aged 5-9 years, mostly males (63.9%). PMID- 30015450 TI - Monitoring of Virulence Genes, Drug-Resistance in Campylobacter coli Isolated from Golden Retrievers. AB - The investigation was performed on 75 of Golden Retriever puppies. Faecal samples were collected on the 42 day of the puppies life (con-trol). Probiotic preparation was administered on 43 day of the puppies life and 10 days after the application of the probiotic, faecal samples were collected again (on 53 day of puppies life). All isolates of Campylobacter coli isolated prior to the administration of the probiotic were found to contain the cadF gene responsible for adhesion, as well as, the flaA gene influencing motility of the examined bacteria. Significant differences (P < 0.05) were recorded only in the case of enrofloxacin. PMID- 30015451 TI - Non-antibiotics, Efflux Pumps and Drug Resistance of Gram-negative Rods. AB - Non-antibiotic medicinal products consist of drugs with diverse activity against bacteria. Many non-antibiotics demonstrate direct anti-bacterial activity against Gram-positive cocci. The activity observed against Gram-negative rods is much lower and non-antibiotics primarily from the following groups: non-steroidal anti inflammatory drugs, cardiovascular and antidepressant medicinal products demonstrate this activity. It has been shown that the low activity of some non antibiotics or the absence of activity against Gram-negative rods is related, among other things, to the extrusion of these compounds from bacterial cells by multi-drug resistance efflux pumps. Substrates for the resistance-nodulation division efflux systems include the following non-antibiotics: salicylate, diclofenac, ibuprofen, mefenamic acid, naproxen, amitriptyline, alendronate sodium, nicergoline, and ticlopidine. In addition, interactions between non antibiotics and multi-drug resistance efflux pumps have been observed. It has also been revealed that depending on the concentration, salicylate induces expression of multi-drug resistance efflux pumps in Escherichia coli, Salmonella enterica subsp. enterica serotype Typhimurium, and Burkholderia cenocepacia. However, salicylate does not affect the expression of the resistance-nodulation division efflux systems in Stenotrophomonas maltophilia and Acinetobacter baumannii. Most importantly, there were no effects of medicinal products containing some non-antibiotic active substances, except salicylate, as substrates of multi-drug resistance efflux pumps, on the induction of Gram negative rod resistance to quinolones. PMID- 30015452 TI - Bacteriological, Clinical and Virulence Aspects of Aeromonas-associated Diseases in Humans. AB - Aeromonads have been isolated from varied environmental sources such as polluted and drinking water, as well as from tissues and body fluids of cold and warm blooded animals. A phenotypically and genotypically heterogenous bacteria, aeromonads can be successfully identified by ribotyping and/or by analysing gyrB gene sequence, apart from classical biochemical characterization. Aeromonads are known to cause scepticemia in aquatic organisms, gastroenteritis and extraintestinal diseases such as scepticemia, skin, eye, wound and respiratory tract infections in humans. Several virulence and antibiotic resistance genes have been identified and isolated from this group, which if present in their mobile genetic elements, may be horizontally transferred to other naive environmental bacteria posing threat to the society. The extensive and indiscriminate use of antibiotics has given rise to many resistant varieties of bacteria. Multidrug resistance genes, such as NDM1, have been identified in this group of bacteria which is of serious health concern. Therefore, it is important to understand how antibiotic resistance develops and spreads in order to undertake preventive measures. It is also necessary to search and map putative virulence genes of Aeromonas for fighting the diseases caused by them. This review encompasses current knowledge of bacteriological, environmental, clinical and virulence aspects of the Aeromonas group and related diseases in humans and other animals of human concern. PMID- 30015453 TI - Brucella - Virulence Factors, Pathogenesis and Treatment. AB - Brucellae are Gram-negative, small rods infecting mammals and capable of causing disease called brucellosis. The infection results in abortion and sterility in domestic animals (sheeps, pigs, rams etc). Especially dangerous for humans are: Brucella melitensis, Brucella suis, Brucella abortus, and Brucella canis that trigger unspecific symptoms (flu-like manifestation). Brucella rods are introduced via host cells, by inhalation, skin abrasions, ingestion or mucosal membranes. The most important feature of Brucella is the ability to survive and multiply within both phagocytic and non-phagocytic cells. Brucella does not produce classical virulence factors: exotoxin, cytolisins, exoenzymes, plasmids, fimbria, and drug resistant forms. Major virulence factors are: lipopolysaccharide (LPS), T4SS secretion system and BvrR/BvrS system, which allow interaction with host cell surface, formation of an early, late BCV (Brucella Containing Vacuole) and interaction with endoplasmic reticulum (ER) when the bacteria multiply. The treatment of brucellosis is based on two-drug therapy, the most common combinations of antibiotics are: doxycycline with rifampicin or fluoroquinolones with rifampicin. Currently, also other methods are used to disrupt Brucella intracellular replication (tauroursodeoxycholic acid or ginseng saponin fraction A). PMID- 30015454 TI - Isolation of Bacteriocin-producing Staphylococcus spp. Strains from Human Skin Wounds, Soft Tissue Infections and Bovine Mastitis. AB - A collection of 206 Staphylococcus spp. isolates was investigated for their ability to produce compounds exhibiting antistaphylococcal activity. This group included Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus xylosus strains recovered from bovine mastitis (n = 158) and human skin wounds and soft tissues infections (n = 48). Production of substances with antimicrobial activity was observed in six strains. Five of them were recovered from bovine mastitis, and one was isolated from the infected human skin wound. Three of the six antimicrobials produced by the different strains showed substantial loss of antimicrobial activity upon treatment with proteolytic enzymes, which suggests their peptidic structure. Additional studies have shown that one of the putative bacteriocins was efficiently secreted to the liquid medium, facilitating its large-scale production and isolation. The peptide produced by the M2B strain exhibited promising activity; however, against narrow spectrum of Staphylococcus spp. clinical and animal isolates. Growth inhibition was observed only in the case of 13 (including nine S. aureus, three S. xylosus and one S. epidermidis strains) out of 206 strains tested. Important advantage of the produced agent was its high thermal stability. Fifteen minutes of incubation at 90 degrees C did not affect its antimicrobial potential. The highest efficiency of production of the agent was demonstrated in TSB medium after 24 hours at 37 degrees C. The researches revealed that ability to production of bacteriocin among staphylococci is not very common. Only one (S. xylosus strain assigned as M2B) out of 206 strains tested produced satisfactory amounts of antistaphylococcal bacteriocin. In spite of that, we would encourage other researchers for investigation of their collections of Staphylococcus spp. isolates towards selection strains producing antimicrobial agents. PMID- 30015455 TI - Genetic Analysis Method for Staphylococcus chromogenes Associated with Goat Mastitis. AB - Mastitis in goats is mainly caused by coagulase-negative Staphylococcus (CNS). The identification methods for this group are based on evaluating the expression of phenotypic characteristics such as the ability to metabolize various substrates; however, this is disadvantageous as these methods are dependent on gene expression. In recent years, genotyping methods such as the Multiple Locus Variable-Number Tandem Repeat Analysis (MLVA) and gene identification have been useful for epidemiological study of several bacterial species. To develop a genotyping method, the genome sequence of Staphylococcus chromogenes MU970 was analysed. The analysis showed nine virulence genes described in Staphylococcus aureus. The MLVA was developed using four loci identified in the genome of S. chromogenes MU970. This genotyping method was examined in 23 strains of CNS isolated from goat mastitis. The rate of discrimination for MLVA was 0.8893, and the highest rates of discrimination per the index of Simpson and Hunter-Gaston were 0.926 and 0.968 for the locus 346_06, respectively. The virulence genes were present in all strains of S. chromogenes but not in other CNS. The genotyping method presented in this paper is a viable and easy method for typifying CNS isolates from mastitis cases in different regions and is an ideal mean of tracking this disease. PMID- 30015456 TI - Screening and Identification of Trichoderma Strains Isolated from Natural Habitats with Potential to Cellulose and Xylan Degrading Enzymes Production. AB - A total of 123 Trichoderma strains were isolated from different habitats and tested for their ability to degrade cellulose and xylan by simple plate screening method. Among strains, more than 34 and 45% respectively, exhibited higher cellulolytic and xylanolytic activity, compared to the reference strain T. reesei QM 9414. For strains efficiently degrading cellulose, a highest enzyme activity was confirmed using filter paper test, and it resulted in a range from 1.01 to 7.15 FPU/ml. Based on morphological and molecular analysis, the isolates were identified as Trichoderma. The most frequently identified strains belonged to Trichoderma harzianum species. Among all strains, the most effective in degradation of cellulose and xylose was T. harzianum and T. virens, especially those isolated from forest wood, forest soil or garden and mushroom compost. The results of this work confirmed that numerous strains from the Trichoderma species have high cellulose and xylan degradation potential and could be useful for lignocellulose biomass conversion e.g. for biofuel production. PMID- 30015457 TI - The Heavy-Metal Resistance Determinant of Newly Isolated Bacterium from a Nickel Contaminated Soil in Southwest Slovakia. AB - A bacterial isolate MR-CH-I2 [KC809939] isolated from soil contaminated mainly by high nickel concentrations in southwest Slovakia was previously found carrying nccA-like heavy-metal resistance determinant, marked as MR-CH-I2-HMR [KF218096]. According to phylogenetic analysis of short (696 bp) 16S rDNA (16S rRNA) sequences this bacterium was tentatively assigned to Uncultured beta proteobacterium clone GC0AA7ZA05PP1 [JQ913301]. nccA-like gene product was on the same base of its partial (581 bp) sequences tentatively assigned to CzcA family heavy metal efflux pump [YP_001899332] from Ralstonia picketii 12J with 99% similarity. In this study the bacterium MR-CH-I2 and its heavy-metal resistance determinant were more precisely identified. This bacterial isolate was on the base of phylogenetic analysis of almost the whole (1,500 bp) 16S rDNA (16S rRNA) sequence, MR-CH-I2 [MF102046], and sequence for gyrB gene and its product respectively, MR-CH-I2-gyrB [MF134666], assigned to R. picketii 12J [CP001068] with 99 and 100% similarities, respectively. In addition, the whole nccA-like heavy-metal resistance gene sequence (3,192 bp), marked as MR-CH-I2-nccA [KR476581], was obtained and on the base of phylogenetic analysis its assignment was confirmed to MULTISPECIES: cation efflux system protein CzcA [WP_004635342] from Burkholderiaceae with 98% similarity. Furthermore, although the bacterium carried one high molecular plasmid of about 50 kb in size, nccA-like gene was not located on this plasmid. Finally, the results from RT-PCR analysis showed that MR CH-I2-nccA gene was significantly induced only by the addition of nickel. PMID- 30015458 TI - Distribution of Cell Envelope Proteinases Genes among Polish Strains of Lactobacillus helveticus. AB - Most of the lactic acid bacteria (LAB) are able to grow in milk mainly due to the activity of a complex and well-developed proteolytic system. Cell envelope associated proteinases (CEPs) begin casein hydrolysis and allow for releasing the peptides, enclosed in the structure of native milk proteins that are essential for growth of Lactobacillus helveticus. The biodiversity of genes encoding CEPs among L. helveticus strains can have an effect on some technological parameters such as acid production, bacterial growth rate in milk as well as liberation of biologically active peptides. The study reveals significant differences in the presence of various variants of CEPs encoding genes among ten novel Polish strains and indicates the intraspecific diversity exhibited by L. helveticus. In terms of distribution of CEPs genes, four different genetic profiles were found among the microorganisms analyzed. Furthermore, the strains exhibited also various levels of proteolytic activity. Molecular analysis revealed that prtH3 is the most abundant CEPs-encoding gene among the strains investigated. The results indicate also that ecological niche and environmental conditions might affect proteolytic properties of L. helveticus strains. The greatest variety in terms of quantity of the detected CEP encoding genes was noticed in L. helveticus 141, T105 and T104 strains. In these strains, the combination of three nucleotide gene sequences (prtH/prtH2/prtH3) was identified. Interestingly, T104 and T105 exhibited the highest proteolytic activity and also the fastest dynamic of milk acidification among the tested strains of L. helveticus. PMID- 30015459 TI - The Usefulness of Chromogenic Media for Qualitative and Semi-Quantitative Diagnostic of Urinary Tract Infections. AB - The aim of this study was to evaluate the usefulness of chromogenic media for isolation of bacteria from urine and direct identification of UTI pathogens. A total of 100 urine specimens were inoculated on blood agar and MacConkey agar as a reference method and on the following media to be tested: chromID(r) CPS(r) Elite (CPSE, bioMerieux), CHROMagarTM Orientation (BioMaxima), BD CHROMagar Orientation Medium (ORI, Becton Dickinson), CHROMagarTM Orientation (ORIE, Graso) and Brillance UTI Clarity Agar (UTI C, Oxoid). After a 24-hour incubation period, 47 Gram-positive cocci and 62 Gram-negative rods were observed. The specificity and sensitivity of all chromogenic media was 97.3% and 93.5% respectively for qualitative diagnostic; and 81.9% and 81.3% respectively for semi-quantitative diagnostic. The mean PPV and NPV of the chromogenic media were 98.7% and 87.7% for qualitative UTI diagnostic, and 90.9% and 71.9% respectively for semi quantitative diagnostic. PMID- 30015460 TI - Identification of Pathogenicity of Yersinia enterocolitica in Pig Tonsils Using the Real-Time PCR. AB - The application of DNA-based methods enables to identify Yersinia enterocolitica carrying the ail-gene with a greater sensitivity compared to culture methods and biochemical tests used for detection of pathogenic Y. enterocolitica in animal and food samples. In this study, 100 samples of pig tonsils were examined, among which 17 were positive for the ail gene. Additionally, biochemical tests and RT PCR showed that nine Y. enterocolitica isolates carried the ail-gene. Two Y. enterocolitica isolates of 1A biotype had the ail gene. The results demonstrated the usefulness of RT-PCR method applied for detection of potentially pathogenic, possessing the ail gene Y. enterocolitica in the material examined. PMID- 30015461 TI - Global Transcriptome Changes of Biofilm-Forming Staphylococcus epidermidis Responding to Total Alkaloids of Sophorea alopecuroides. AB - Transcriptome changes of biofilm-forming Staphylococcus epidermidis response to total alkaloids of Sophorea alopecuroides was observed. Bioinformatic analyses were further used to compare the differential gene expression between control and the treated samples. It was found that 282 genes were differentially expressed, with 92 up-regulated and 190 down-regulated. These involved down-regulation of the sulfur metabolism pathway. It was suggested that inhibitory effects on Staphylococcus epidermidis and its biofilm formation of the total alkaloids of S. alopecuroides was mainly due to the regulation of the sulfur metabolism pathways of S. epidermidis. PMID- 30015462 TI - Sero-epidemiology and Risk Factor Analysis of Measles Among Children in Pakistan. AB - Comparative cross sectional study was conducted on blood samples (n = 231) collected from children of 1 to 10 years of age in Punjab Pakistan through convenient sampling method. Indirect haemagglutination assay (IHA) was standardized and used for serodiagnosis and evaluation of humoral immunity against measles. Associated risk factors including age, gender, locale, and vaccination status were analyzed. Geometric mean titre (GMT) of vaccinated individuals was significantly higher (p < 0.001) than that of non-vaccinated individuals showing that IHA titre of vaccinated individuals was a measure of humoral immune response; whereas, in case of non-vaccinated individuals an indicative of exposure to the measles infection. PMID- 30015464 TI - New Gene Responsible for Resistance of Clinical Corynebacteria to Macrolide, Lincosamide and Streptogramin B. AB - The subject of the study was phenotypic marking of the antibiotic susceptibility and MLSB resistance mechanism in Corynebacterium spp. isolated from human skin (18 isolates) and from clinical materials (19 isolates). The strains were tested for the presence of the erm(A), erm(B), erm(C), erm(X), lnu(A), msr(A), msr(B) and mph(C) genes. Clinical isolates showed wide resistance to antibiotics. In 89% clinical isolates and 72% skin microbiota a constitutive type of MLSB resistance was found. In 12 clinical isolates the erm(C) gene was detected-eight of which had erm(X) as well as erm(C), two harboured erm(X), erm(C) and erm(A) and two demonstrated only erm(C). PMID- 30015463 TI - Seroprevalence of Selected Zoonotic Agents among Hunters from Eastern Poland. AB - The aim of our study was the collection of seroprevalence data for Toxoplasma gondii, Coxiella burnetii, Trichinella spp., and Francisella tularensis from hunters in Lublin Province. The antibodies against T. gondii and C. burnetii were recorded in 38.5% and 16.2% of the sera, respectively. 4.05% of the sera were seropositive for both T. gondii and C. burnetii. None of the sera tested reacted positively with F. tulariensis or Trichinella spp. Seroprevalence of T. gondii and C. burnetii is common among the hunters from Lublin Province. It seems reasonable to undertake similar research among hunters from other regions of eastern Poland. PMID- 30015466 TI - Schedule for Rating Disabilities; Gynecological Conditions and Disorders of the Breast. Final rule. AB - This document amends the Department of Veterans Affairs (VA) Schedule for Rating Disabilities (VASRD) by revising the portion of the rating schedule that addresses gynecological conditions and disorders of the breast. The effect of this action is to ensure that this portion of the rating schedule uses current medical terminology and to provide detailed andupdated criteria for evaluation of gynecological conditions and disorders of the breast. PMID- 30015465 TI - Development and Evaluation of a Latex Agglutination Test for the Identification of Francisella tularensis Subspecies Pathogenic for Human. AB - Francisella tularensis are highly infectious bacteria causing a zoonotic disease called tularemia. Identification of this bacterium is based on antigen detection or PCR. The paper presents a latex agglutination test (LAT) for rapid identification of clinically relevant F. tularensis subspecies. The test can be performed within three minutes with live or inactivated bacteria. The possibility to test the inactivated samples reduces the risk of laboratory acquired infection and allows performing the test under BSL-2 conditions. PMID- 30015467 TI - Schedule for Rating Disabilities: the Organs of Special Sense and Schedule of Ratings--Eye. Final rule. AB - The Department of Veterans Affairs (VA) is revising the portion of the VA Schedule for Rating Disabilities (VASRD or rating schedule) that addresses the organs of special sense and schedule of ratings--eye. The final rule incorporates medical advances that have occurred since the last review, updates current medical terminology, and provides clearer evaluation criteria. PMID- 30015468 TI - Medicare Program; Contract Year 2019 Policy and Technical Changes to the Medicare Advantage, Medicare Cost Plan, Medicare Fee-for-Service, the Medicare Prescription Drug Benefit Programs, and the PACE Program. Final rule. AB - This final rule will revise the Medicare Advantage (MA) program (Part C) regulations and Prescription Drug Benefit program (Part D) regulations to implement certain provisions of the Comprehensive Addiction and Recovery Act (CARA) to further reduce the number of beneficiaries who may potentially misuse or overdose on opioids while still having access to important treatment options; implement certain provisions of the 21st Century Cures Act; support innovative approaches to improve program quality, accessibility, and affordability; offer beneficiaries more choices and better care; improve the CMS customer experience and maintain high beneficiary satisfaction; address program integrity policies related to payments based on prescriber, provider and supplier status in MA, Medicare cost plan, Medicare Part D and the PACE programs; provide an update to the official Medicare Part D electronic prescribing standards; and clarify program requirements and certain technical changes regarding treatment of Medicare Part A and Part B appeal rights related to premiums adjustments. PMID- 30015469 TI - Patient Protection and Affordable Care Act; HHS Notice of Benefit and Payment Parameters for 2019. Final rule. AB - This final rule sets forth payment parameters and provisions related to the risk adjustment and risk adjustment data validation programs; cost-sharing parameters; and user fees for Federally-facilitated Exchanges and State Exchanges on the Federal platform. It finalizes changes that provide additional flexibility to States to apply the definition of essential health benefits (EHB) to their markets, enhance the role of States regarding the certification of qualified health plans(QHPs); and provide States with additional flexibility in the operation and establishment of Exchanges, including the Small Business Health Options Program (SHOP) Exchanges. It includes changes to standards related to Exchanges; the required functions of the SHOPs; actuarial value for stand-alone dental plans; the rate review program; the medical loss ratio program; eligibility and enrollment; exemptions; and other related topics. PMID- 30015470 TI - Brain Targeting by Liposome-Biomolecular Corona Boosts Anticancer Efficacy of Temozolomide in Glioblastoma Cells. AB - Temozolomide (TMZ) is the current first-line chemotherapy for treatment of glioblastoma multiforme (GBM). However, similar to other brain therapeutic compounds, access of TMZ to brain tumors is impaired by the blood-brain barrier (BBB) leading to poor response for GBM patients. To overcome this major hurdle, we have synthesized a set of TMZ-encapsulating nanomedicines made of four cationic liposome (CL) formulations with systematic changes in lipid composition and physical-chemical properties. The targeting nature of this nanomedicine is provided by the recruitment of proteins, with natural targeting capacity, in the biomolecular corona (BC) layer that forms around CLs after exposure to human plasma (HP). TMZ-loaded CL-BC complexes were thoroughly characterized by dynamic light scattering (DLS), electrophoretic light scattering (ELS), and nanoliquid chromatography tandem mass spectrometry (nano-LC MS/MS). BCs were found to be enriched of typical BC fingerprints (BCFs) (e.g., Apolipoproteins, Vitronectin, and vitamin K-dependent protein), which have a substantial capacity in binding to receptors that are overexpressed at the BBB (e.g., scavenger receptor class B, type I and low-density lipoprotein receptor). We found that the CL formulation exhibiting the highest levels of targeting BCFs had larger uptake in human umbilical vein endothelial cells (HUVECs) that are commonly used as an in vitro model of the BBB. This formulation could also deliver TMZ to the human glioblastoma U-87 MG cell line and thus substantially enhance their antitumor efficacy compared to corona free CLs. Thus, we propose that the BC-based nanomedicines may pave a more effective way for efficient treatment of GBM. PMID- 30015471 TI - Photocured Materials with Self-Healing Function through Ionic Interactions for Flexible Electronics. AB - Photocured materials with self-healing function have the merit of long lifetime and environmentally benign preparation process and thus find potential applications in various fields. Herein, a novel imidazolium-containing photocurable monomer, (6-(3-(3(2-hydroxyethyl)-1 H-imidazol-3-ium bromide)propanoyloxy)hexyl acrylate, IM-A), was designed and synthesized. Self healing polymers were prepared by fast photocuring with IM-A, isobornyl acrylate, 2-(2-ethoxyethoxy)ethyl acrylate, and 2-hydroxyethyl acrylate as the monomers. The mechanical and self-healing properties of the polymers were tuned by varying the contents of IM-A and other monomers. The as-prepared self-healing polymer IB7 IM5 exhibited a tensile strength of 3.1 MPa, elongation at break of 205%, healing efficiency of 93%, and a wide healing temperature range from room temperature to 120 degrees C. The self-healing polymer was also employed as a flexible substrate to fabricate a flexible electronic device, which could be healed and completely restore its conductivity after the device was damaged. PMID- 30015473 TI - Mechanism of Methanol Inhibition of Photosynthetic Water Oxidation As Studied by Fourier Transform Infrared Difference and Time-Resolved Infrared Spectroscopies. AB - Photosynthetic water oxidation is performed at the Mn4CaO5 cluster in photosystem II. In this study, we investigated the effect of methanol, an analogue of water, on the water oxidation reaction and its interaction site using Fourier transform infrared (FTIR) difference and time-resolved infrared (TRIR) spectroscopies. Flash-induced FTIR difference measurement of the S-state cycle showed that methanol decreases mainly the efficiency of the S3 -> S0 transition. TRIR measurement further showed that methanol slowed the rates of the S2 -> S3 and S3 > S0 transitions. FTIR difference spectra upon the S1 -> S2 transition exhibited prominent methanol-induced changes in the amide I and II bands of the main chains, whereas little change was observed in the bands of carboxylate groups, histidine side chains, and a water network in the vicinity of the Mn4CaO5 cluster. Similar tendencies were also observed with ethanol and 2-propanol. The C O stretching vibration of methanol was further identified in the S2-minus-S1 spectrum using 18O-labeled methanol. These results indicate that methanol and small alcohols are bound near the Mn4CaO5 cluster but with no direct interaction. They probably replace a water molecule in a water channel around the Mn4CaO5 cluster, possibly interacting with a main chain amide. It is thus suggested that this replacement of water with methanol or a small alcohol inhibits water/proton transfer during the S2 -> S3 and S3 -> S0 transitions, which in turn provides experimental support for the view that these two transitions involve the water uptake and proton release processes. PMID- 30015472 TI - Mechanism of Radical Formation in the H-Bond Network of D1-Asn298 in Photosystem II. AB - In photosystem II (PSII), redox-active tyrosine Z (TyrZ) forms a low-barrier H bond with Nepsilon of D1-His190. The PSII crystal structures show that Ndelta of D1-His190 donates an H-bond to the carbonyl O of D1-Asn298. However, at a level of ~2 A resolution, a clear discrimination between the -NH2 and -C?O groups of the asparagine side chain may not be possible based on the electron density map. Using quantum mechanical/molecular mechanical calculations, we investigated the energetics of the D1-Asn298 conformations. In the D1-Asn298-rotated conformation, where the amide N group donates an H-bond to deprotonated Ndelta of D1-His190, oxidation of S2 resulted in formation of a neutral radical, either TyrZ* or D1 His190*. This suggests that in the D1-Asn298-rotated conformation, the redox potential ( Em) values of TyrZ/D1-His190 are lower than the Em of the Mn4CaO5 cluster due to deprotonated D1-His190. The large disorder of a water molecule (water 1117A) at D1-Asn298 in the crystal structure as well as the absence of water 1117A in the Sr2+-substituted crystal structure may be associated with coexistence of the two D1-Asn298 conformations in the crystals. PMID- 30015474 TI - Structural Basis for Binding of Fluorescent CMP-Neu5Ac Mimetics to Enzymes of the Human ST8Sia Family. AB - Polysialyltransferases synthesize polysialic acid on cell surface-expressed glycoconjugates, which is crucial for developing processes and signaling pathways in eukaryotes. Recent advances in cancer research have rendered polysialyltransferases important drug targets because polysialic acid contributes to cancer cell progression, metastasis, and treatment of resistant tumors. To aid the development of high-throughput screening assays for polysialyltransferase inhibitors, we demonstrate that a previously developed class of fluorescent CMP sialic acid mimetics for sialyltransferases has nanomolar affinities for oligo- and polysialyltransferases and can be used for the rapid screening of new polysialyltransferase inhibitors. We demonstrate that these CMP-Neu5Ac mimetics inhibit polysialylation in vitro and perform cell culture experiments, where we observe reduced polysialylation of NCAM. Furthermore, we describe the structural basis of CMP-Neu5Ac mimetics binding to the human oligosialyltransferase ST8SiaIII and extrapolate why their affinity is high for human polysialyltransferases. Our results show that this novel class of compounds is a promising tool for the development of potent and selective drugs against polysialyltransferase activity. PMID- 30015475 TI - Rational Engineering a Multichannel Upconversion Sensor for Multiplex Detection of Matrix Metalloproteinase Activities. AB - Optical sensing of cancer-relevant protease is of great value for cancer diagnostics, prognosis, and drug discovery. Multiplex sensing is known to improve predicative accuracy yet remains challenging because of severe fluorescence signal crosstalk in a single assay. Herein, we developed a multichannel optical sensor based on upconversion nanoparticles for multiplex ratiometric sensing of proteolytic activities of two matrix metalloproteinases (MMP-2 and MMP-7). To this end, we rationally designed a NaYF4:Gd3+/Yb3+@NaYF4:Yb3+/Tm3+/Er3+ core shell structure that favors multicolor narrow-band emission of both Tm3+ and Er3+ dopants and efficient luminescence resonance energy transfer (LRET) between the dopants in the shell and the fluorophores on the particle surface. The sensor was constructed via a facile phase transfer protocol using two polyhistidine containing peptides conjugated with different fluorophores (FITC and TAMRA) as coligands. The blue and green emission could be specifically activated by MMP-7 and MMP-2, respectively, upon peptide cleavage, and the red emission could serve as an internal reference for ratiometric sensing. The sensor exhibits high specificity and sensitivity toward both targets with little signal crosstalk and cross-reactivity. It could potentially serve as a general platform for multiplex detection of various types of proteases. PMID- 30015476 TI - Peptide-Based Acetylcholinesterase Inhibitor Crosses the Blood-Brain Barrier and Promotes Neuroprotection. AB - Design and development of acetylcholinesterase (AChE) inhibitor has tremendous implications in the treatment of Alzheimer's disease (AD). Here, we have adopted a computational approach for the design of a peptide based AChE inhibitor from its active site. We identified an octapeptide, which interacts with the catalytic anionic site (CAS) of AChE enzyme and inhibits its activity. Interestingly, this peptide also inhibits amyloid aggregation through its interaction at the 17-21 region of amyloid-beta (Abeta) and stabilizes microtubules by interacting with tubulin as well. Eventually, in the PC12 derived neurons, it shows noncytotoxicity, promotes neurite out-growth, stabilizes intracellular microtubules, and confers significant neuroprotection even upon withdrawal of nerve growth factor (NGF). Further, results reveal that this peptide possesses good serum stability, crosses the blood-brain barrier (BBB), and maintains the healthy architecture of the primary cortical neurons. This work shows discovery of an excellent peptide-based AChE inhibitor with additional potential as a microtubule stabilizer, which will pave the way for the development of potential anti-AD therapeutics in the near future. PMID- 30015478 TI - Discrimination of Isoleucine and Leucine by Dimethylation-Assisted MS3. AB - Protein sequencing by mass spectrometry has transformed the field of biopharmaceutical analysis, but a missing part in the analytical toolkit is the ability to distinguish between the isomeric residues isoleucine and leucine because it is a requisite for efficient analysis of the primary structure of proteins. To address this need, we have developed a novel mass spectrometric method that combines reductive dimethylation and MS3 fragmentation with LCMS peptide mapping. The dimethylation of peptide N-termini leads to intense a1-ions upon collision-induced fragmentation, and further fragmentation of the isoleucine/leucine a1-ion leads to informative spectra with fragments that can discriminate between the two isomers. The methodology of a1-directed MS3 was applied to two antibodies in combination with the proteases trypsin, thermolysin, chymotrypsin, and pepsin to generate peptides exposing N-terminal I/L residues. PMID- 30015477 TI - Self-Assembly of Ln(III)-Containing Tungstotellurates(VI): Correlation of Structure and Photoluminescence. AB - The generation of five types of Ln(III)-containing tungstotellurates(VI), dimeric (DMAH)12Na2[H10(WO2){Ln(H2O)5(TeW18O65)}2]. nH2O (abbreviated as {Ln2Te2W37}; Ln = Eu, Gd, or Tb; DMAH = dimethylammonium), tetrameric (DMAH)21Na7[H16{Ln(H2O)5(TeW18O64)}4]. nH2O (abbreviated as {Ln4Te4W72}, Ln = Eu or Gd), 2:2 dimeric (DMAH)12[H6{Tb(H2O)3(TeW17O61)}2].25H2O (abbreviated as {Tb2Te2W34}), 1:1 monosubstituted (DMAH)7Na2[H2Tb(H2O)4(TeW17O61)].21H2O (abbreviated as {TbTeW17}), and three-dimensional polymer (DMAH)2[HTb(H2O)4{TeW6O24}].14H2O (abbreviated as {TbTeW6} n), provides insight into the rich condensation chemistry of lacunary and other Dawson-type polyoxometalates. The pH and the type of Ln3+ source both dictate which of these new complexes form. To our knowledge, {Ln4Te4W72} is the highest-nuclearity tungstotellurate to date, and {Tb2Te2W34} and {TbTeW17} contain the first lacunary {TeW17O61}. Electrospray ionization mass spectra analyses indicate that the Dawson-like building blocks, {TeW18O65} and {TeW17O61}, found in solid structures are also present in solution. The intense photoluminescence (characteristic green emission) of {TbTeW6} n, 100* greater than those of {Tb2Te2W37}, {Tb2Te2W34}, and {TbTeW17}, is explained by analysis of all 4 X-ray structures and multiple structure-intensity correlations. PMID- 30015480 TI - Crystal Structure, Thermal Behavior, and Photocatalytic Activity of NaBiO3. nH2O. AB - The crystal structure of NaBiO3. nH2O was refined using synchrotron powder X-ray diffraction and was assigned to a trigonal unit cell (space group P3) consisting of layered structures formed by edge-sharing BiO6 octahedra and consisting of an interlayer composed of water molecules sandwiched between two layers of sodium atoms, perpendicular to the c axis. An intermediate phase was observed during the dehydration of the hydrated compound. Density of state calculations showed hybridization of the Bi 6s and O 2p orbitals at the bottom of the conduction bands for both the hydrated and the dehydrated phases, which narrows the band gap and promotes their photocatalytic activity in the visible region. PMID- 30015479 TI - Cu-Catalyzed Enantioselective Ring Opening of Cyclic Diaryliodoniums toward the Synthesis of Chiral Diarylmethanes. AB - A Cu-catalyzed enantioselective desymmetrizing ring-opening reaction of six membered cyclic diaryliodonium salts with carboxylic acids or thioacids is reported for the facile access to chiral diarylmethanes. A Cu/[cyclopropyl bis(oxazoline)] catalyst well discriminates two C-I bonds of prochiral cyclic diaryliodonium salts. A stereochemical model was proposed to rationalize the stereochemical outcome on the basis of the crystal structure of cyclic diaryliodonium salt. PMID- 30015481 TI - Catalytic Nitrene Homocoupling by an Iron(II) Bis(alkoxide) Complex: Bulking Up the Alkoxide Enables a Wider Range of Substrates and Provides Insight into the Reaction Mechanism. AB - The reaction of HOR' (OR' = di-t-butyl-(3,5-diphenylphenyl)methoxide) with an iron(II) amide precursor forms the iron(II) bis(alkoxide) complex Fe(OR')2(THF)2 (2). 2 (5-10 mol %) serves as a catalyst for the conversion of aryl azides into the corresponding azoarenes. The highest yields are observed for aryl azides featuring two ortho substituents; other substitution patterns in the aryl azide precursor lead to moderate or low yields. The reaction of 2 with stoichiometric amounts (2 equiv) of the corresponding aryl azide shows the formation of azoarenes as the only organic products for the bulkier aryl azides (Ar = mesityl, 2,6-diethylphenyl). In contrast, formation of tetrazene complexes Fe(OR')2(ArNNNNAr) (3-6) is observed for the less bulky aryl azides (Ar = phenyl, 4-methylphenyl, 4-methoxyphenyl, 3,5-dimethylphenyl). The electronic structure of selected tetrazene complexes was probed by spectroscopy (field-dependent 57Fe Mossbauer and high-frequency EPR) and density functional theory calculations. These studies revealed that Fe(OR')2(ArNNNNAr) complexes contain high-spin ( S = 5/2) iron(III) centers exchange-coupled to tetrazene radical anions. Tetrazene complexes Fe(OR')2(ArNNNNAr) produce the corresponding azoarenes (ArNNAr) upon heating. Treatment of a tetrazene complex Fe(OR')2(ArNNNNAr) with a different azide (N3Ar') produces all three possible products ArNNAr, ArNNAr', and Ar'NNAr'. These experiments and quantum mechanics/molecular mechanics calculations exploring the reaction mechanism suggest that the tetrazene functionality serves as a masked form of the reactive iron mono(imido) species. PMID- 30015483 TI - Visible Light and Hydroxynaphthylbenzimidazoline Promoted Transition-Metal Catalyst-Free Desulfonylation of N-Sulfonylamides and N-Sulfonylamines. AB - A visible light promoted process for desulfonylation of N-sulfonylamides and amines has been developed, in which 1,3-dimethyl-2-hydroxynaphthylbenzimidazoline (HONap-BIH) serves as a light absorbing, electron and hydrogen atom donor, and a household white light-emitting diode serves as a light source. The process transforms various N-sulfonylamide and -amine substrates to desulfonylated products in moderate to excellent yields. The observation that the fluorescence of 1-methyl-2-naphthoxy anion is efficiently quenched by the substrates suggests that the mechanism for the photoinduced desulfonylation reaction begins with photoexcitation of the naphthoxide chromophore in HONap-BIH, which generates an excited species via intramolecular proton transfer between the HONap and BIH moieties. This process triggers single electron transfer to the substrate, which promotes loss of the sulfonyl group to form the free amide or amine. The results of studies employing radical probe substrates as well as DFT calculations suggest that selective nitrogen-sulfur bond cleavage of the substrate radical anion generates either a pair of an amide or amine anion and a sulfonyl radical or that of an amidyl or aminyl radical and sulfinate anion, depending on the nature of the N-substituent on the substrate. An intermolecular version of this protocol, in which 1-methyl-2-naphthol and 1,3-dimethyl-2-phenylbenzimidazoline are used concomitantly, was also examined. PMID- 30015485 TI - Biosynthetic Baeyer-Villiger Chemistry Enables Access to Two Anthracene Scaffolds from a Single Gene Cluster in Deep-Sea-Derived Streptomyces olivaceus SCSIO T05. AB - Four known compounds, rishirilide B (1), rishirilide C (2), lupinacidin A (3), and galvaquinone B (4), representing two anthracene scaffolds typical of aromatic polyketides, were isolated from a culture of the deep-sea-derived Streptomyces olivaceus SCSIO T05. From the S. olivaceus producer was cloned and sequenced the rsd biosynthetic gene cluster (BGC) that drives rishirilide biosynthesis. The structural gene rsdK2 inactivation and heterologous expression of the rsd BGC confirmed the single rsd BGC encodes construction of 1-4 and, thus, accounts for two anthracene scaffolds. Precursor incubation experiments with 13C-labeled acetate revealed that a Baeyer-Villiger-type rearrangement plays a central role in construction of 1-4. Two luciferase monooxygenase components, along with a reductase component, are presumably involved in the Baeyer-Villiger-type rearrangement reaction enabling access to the two anthracene scaffold variants. Engineering of the rsd BGC unveiled three SARP family transcriptional regulators, enhancing anthracene production. Inactivation of rsdR4, a MarR family transcriptional regulator, failed to impact production of 1-4, although production of 3 was slightly improved; most importantly rsdR4 inactivation led to the new adduct 6 in high titer. Notably, inactivation of rsdH, a putative amidohydrolase, substantially improved the overall titers of 1-4 by more than 4 fold. PMID- 30015484 TI - Formal Synthesis of ent-Cephalotaxine Using a One-Pot Parham-Aldol Sequence. AB - A short formal synthesis of ent-Cephalotaxine is achieved. The approach features a new Lewis acid-mediated [2,3]-Stevens rearrangement of N-allylated prolineamide to generate a key quaternary stereogenic center. Additionally, a one-pot Parham aldol sequence was developed to rapidly assemble two of the four rings in the cephalotaxine core. PMID- 30015486 TI - Halo-Bridged Abnormal NHC Palladium(II) Dimer for Catalytic Dehydrogenative Cross Coupling Reactions of Heteroarenes. AB - This work describes the dehydrogenative coupling of heteroarenes using a dimeric halo-bridged palladium(II) catalyst bearing an abnormal NHC ( aNHC) backbone. The catalyst can successfully activate the C-H bond of a wide range of heteroarenes, which include benzothiazole, benzoxazole, thiophene, furan, and N methylbenzimidazole. Further, it exhibited good activity for heteroarenes bearing various functional groups such as CN, CHO, Me, OMe, OAc, and Cl. Additionally, we isolated the active catalyst by performing stoichiometric reaction and characterized it as the acetato-bridged dimer of ( aNHC)PdOAc by single-crystal X ray study. PMID- 30015487 TI - Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor. AB - We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with Ki values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development. PMID- 30015482 TI - Rapid Bioorthogonal Chemistry Enables in Situ Modulation of the Stem Cell Behavior in 3D without External Triggers. AB - Chemical modification of engineered microenvironments surrounding living cells represents a means for directing cellular behaviors through cell-matrix interactions. Presented here is a temporally controlled method for modulating the properties of biomimetic, synthetic extracellular matrices (ECM) during live cell culture employing the rapid, bioorthogonal tetrazine ligation with trans cyclooctene (TCO) dienophiles. This approach is diffusion-controlled, cytocompatible, and does not rely on light, catalysts, or other external triggers. Human bone-marrow-derived mesenchymal stem cells (hMSCs) were initially entrapped in a hydrogel prepared using hyaluronic acid carrying sulfhydryl groups (HA-SH) and a hydrophilic polymer bearing both acrylate and tetrazine groups (POM AT). Inclusion of a matrix metalloprotease (MMP)-degradable peptidic cross-linker enabled hMSC-mediated remodeling of the synthetic environment. The resultant network displayed dangling tetrazine groups for subsequent conjugation with TCO derivatives. Two days later, the stiffness of the matrix was increased by adding chemically modified HA carrying multiple copies of TCO (HA-TCO) to the hMSC growth media surrounding the cell-laden gel construct. In response, cells developed small processes radially around the cell body without a significant alteration of the overall shape. By contrast, modification of the 3D matrix with a TCO-tagged cell-adhesive motif caused the resident cells to undergo significant actin polymerization, changing from a rounded shape to spindle morphology with long cellular processes. After additional 7 days of culture in the growth media, quantitative analysis showed that, at the mRNA level, RGD tagging upregulated cellular expression of MMP1, but downregulated the expression of collagen I/III and tenascin C. RGD tagging, however, was not sufficient to induce the classic osteoblastic, chondrogenic, adipogenic, or fibroblastic/myofibroblastic differentiation. The modular approach allows facile manipulation of synthetic ECM to modulate cell behavior, thus potentially applicable to the engineering of functional tissues or tissue models. PMID- 30015488 TI - Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A-E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium. AB - Five novel modified linear peptides named brintonamides A-E (1-5) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of 1-5 in addition to two other structurally related analogues (6 and 7) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC50 near 20 MUM by both representative members 1 and 4, which differed in the presence or lack of the N terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds 1-7 to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (4) with an IC50 of 0.44 MUM. We performed in silico modeling to understand the structural basis underlying the differences in the antagonistic activity among brintonamides toward CCR10. Because of the significance of KLK7 and CCR10 in cancer progression and metastasis, we demonstrated the ability of brintonamide D (4) at 10 MUM to significantly target downstream cellular substrates of KLK7 (Dsg-2 and E-cad) in vitro and to inhibit CCL27-induced CCR10 mediated proliferation and the migration of highly invasive breast cancer cells. PMID- 30015489 TI - Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3 Kinase (PI3K) beta Inhibitor. AB - Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) beta inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kbeta inhibitor. PMID- 30015490 TI - Phosphine-Catalyzed Reaction between 2-Aminobenzaldehydes and Dialkyl Acetylenedicarboxylates: Synthesis of 1,2-Dihydroquinoline Derivatives and Toward the Development of an Olefination Reaction. AB - A series of 1,2-dihydroquinolines were synthesized in good to excellent yields by reacting 2-aminobenzaldehyde derivatives and dialkyl acetylenedicarboxylates with catalytic amounts of phosphine. This reaction was rendered catalytic by the selective in situ phosphine oxide reduction with the use of phenylsilane. Furthermore, with the same starting materials and with an additional role of the reducing agent, a new olefination reaction was discovered. Hydrogen/deuterium (H/D) exchange experiments revealed the possible mechanism of this reaction. PMID- 30015491 TI - Electrostatic-Driven Gelation of Colloidal Nanocrystals. AB - The assembly of colloidal nanocrystals (NCs) is a unique strategy to produce porous materials with high crystallinity and unmatched control over structural and chemical parameters. This strategy has been demonstrated mostly for single component nanomaterials. In the present work, we report the gelation of colloidal NC solutions driven by the electrostatic interaction of oppositely charged NCs. A key step for leading this strategy to success is to produce a stable colloidal solution of the positively charged component. We achieved this goal by functionalizing the NCs with inexpensive and nontoxic amino acids such as glutamine. We demonstrate the combination of positively and negatively charged NCs in proper concentrations to result in gels with a homogeneous distribution of the two compounds. In this way, porous nanocomposites with virtually any combination can be produced. We illustrate this approach by combining positively charged ceria NCs with negatively charged gold NCs to form Au-CeO2 gels. These gels were dried from supercritical CO2 to produce highly porous Au-CeO2 aerogels with specific surface areas of 120 m2 g-1. The formation of a proper interface is confirmed through the evaluation of nanocomposite catalytic activity toward CO oxidation. We further demonstrate the versatility of this strategy to produce porous metal chalcogenide-metal oxide and metal-metal chalcogenide nanocomposites by the examples of PbS-CeO2 and Au-PbS. PMID- 30015492 TI - Ervadivamines A and B, Two Unusual Trimeric Monoterpenoid Indole Alkaloids from Ervatamia divaricata. AB - Ervadivamines A (1) and B (2), two unprecedented trimeric monoterpenoid indole alkaloids, were isolated from Ervatamia divaricata. They are the first examples of vobasine-iboga-vobasine-type alkaloid with both C-C and C-N linkage patterns. Their structures including absolute configurations were fully accomplished by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electric circular dichroism methods. The plausible biogenetic pathways of these trimeric alkaloids were also proposed. In addition, compound 1 exhibited significant cytotoxicity against four cancer cells. PMID- 30015493 TI - Total Synthesis of Zwitterionic Tetrasaccharide Repeating Unit from Bacteroides fragilis ATCC 25285/NCTC 9343 Capsular Polysaccharide PS A1 with Alternating Charges on Adjacent Monosaccharides. AB - The tetrasaccharide repeating unit of zwitterionic polysaccharide A1 (PS A1) from Bacteroides fragilis ATCC 25285/NCTC 9343 has been synthesized using a linear glycosylation approach. One key step includes an alpha(1,4)-stereoselective [2 + 1] glycosylation of a 2,4,6-trideoxy-2-acetamido-4-amino-d-Gal p (AAT) donor with a poorly reactive axial C4-OH disaccharide acceptor. Mild acid-mediated deacetylation and a challenging [3 + 1] glycosylation are also highlighted. The strategy is inclusive of a single-pot, three-step deprotection affording PS A1 with alternating charges on adjacent monosaccharide units. PMID- 30015494 TI - Highly Regioselective and E/ Z-Selective Hydroalkylation of Ynone, Ynoate, and Ynamide via Photoredox Mediated Ni/Ir Dual Catalysis. AB - Exclusively alpha- and highly E/ Z-selective hydroalkylation of ynone, ynoate, and ynamide was achieved via photoredox mediated Ni/Ir dual catalysis with high atom and step economy, producing trisubstituted enones, which are versatile synthetic building blocks. The developed reaction selectively delivered the alpha/ Z isomer, which is complementary to the previously reported beta alkylation processes. The trisubstituted enones could be transformed to more valuable compounds via post-functionalization. PMID- 30015495 TI - Total Synthesis of Pestalotioprolide E and Structural Revision of Pestalotioprolide F. AB - A short and convergent strategy for the first asymmetric total synthesis of cytotoxic macrolides pestalotioprolides E and F has been developed. The key features of this synthesis include Takai olefination, Sonogashira coupling, Ni assisted partial hydrogenation of alkyne, modified Steglich reaction to generate the ester moiety, and intramolecular Horner-Wadsworth-Emmons (HWE) olefination to complete the macrocycle. This synthetic study revised the proposed structure of pesralotioprolide F. PMID- 30015497 TI - Stereoretentive Intramolecular Glycosyl Cross-Coupling: Development, Scope, and Kinetic Isotope Effect Study. AB - A series of cyclic C-glycosides were synthesized using the palladium-catalyzed stereoretentive intramolecular glycosylation of aryl iodides by employing a bulky phosphine ligand. A variety of functional groups are tolerated in the reaction, and enantioenriched anomeric nucleophiles could be coupled without erosion of optical purity. This study offers a unified method to access both cis- and trans fused rings by capitalizing on the stereoretentive nature of the Stille reaction. In addition, competition experiments for intermolecular and intramolecular cross couplings revealed secondary KIEs of 1.43 and 0.81, respectively, suggesting a profoundly different steric congestion at the transition state. PMID- 30015496 TI - Stereospecific Synthesis of the Saccharosamine-Rhamnose-Fucose Fragment Present in Saccharomicin B. AB - A synthetic route has been developed for constructing the d-saccharosamine-l rhamnose-d-fucose (Sac-Rha-Fuc) trisaccharide fragment present in the antibacterial natural product saccharomicin B. The Sac monosaccharide was synthesized through a modified nine step procedure starting from d-rhamnal in 23% overall yield. 1- O-TBS Sac donors were used to construct the beta-linked Sac-Rha disaccharide. This disaccharide was coupled to a Fuc acceptor under BSP/Tf2O conditions to afford a trisaccharide properly functionalized for elaboration to saccharomicin B. PMID- 30015499 TI - Comparison of the Short-term and Long-term Effects of Surgery and Nonsurgical Intervention in Treating Carpal Tunnel Syndrome: A Systematic Review and Meta analysis. AB - BACKGROUND: The objective of the study is to examine the short-term and long-term efficacy of surgical treatment of carpal tunnel syndrome (CTS) compared with conservative treatment (ie, splint, steroid injection, or physical therapy). METHODS: Two reviewers searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and PEDro up to September 2017. Quality appraisal and data extraction were performed in duplicate. Patient self-reported functional and symptom changes, as well as improvement of electrophysiological studies, were assessed as outcomes. Meta-analyses were performed in RevMan. RESULTS: From 1438 studies identified after searching, 10 remained for analysis after exclusion criteria were applied. Moderate-quality evidence indicated that surgical interventions were superior to splint or steroid injection at 6 months with a weighted mean difference of 0.25 (95% confidence interval [CI], 0.07-0.44) for functional status and 0.64 (95% CI, 0.07-1.21) for symptom severity. The surgical group had better nerve conduction outcomes at 6 months (0.57 [95% CI, 0.05-0.50] ms). No significant differences were observed at 3 or 12 months. CONCLUSIONS: Both surgical and conservative interventions provide treatment benefits in CTS. Further studies on long-term outcome are needed. PMID- 30015498 TI - Assessment of Different Methods for Pediatric Meningitis Dosing Clinical Decision Support: A Retrospective Study. AB - BACKGROUND: Indication-specific medication dosing support is needed to improve pediatric dosing support. OBJECTIVE: To compare the sensitivity and positive predictive value (PPV) of different meningitis dosing alert triggers and dosing error rates between antimicrobials with and without meningitis order sentences. METHODS: We retrospectively analyzed 4-months of pediatric orders for antimicrobials with meningitis-specific dosing. At the time of the order, it was determined if the antimicrobial was for meningitis management, if a cerebrospinal fluid (CSF) culture was ordered, and if a natural language processing (NLP) system could detect "meningitis" in clinical notes. RESULTS: Of 1383 orders, 243 were for the management of meningitis. A CSF culture or NLP combination trigger searching the electronic health record since admission yielded the greatest sensitivity for detecting meningitis management (67.5%, P < 0.01 vs others), but dosing error detection was similar if the trigger only searched 48 hours preceding the order (68.8% vs 62.5%, P = 0.125). Using a CSF culture alone and a 48-hour time frame had a higher PPV versus a combination with a 48-hour time frame (97.1% vs 80.9%, P < 0.001), and both triggers had a higher PPV than others ( P < 0.001). Antimicrobials with meningitis order sentences had fewer dosing errors (19.8% vs 43.2%, P < 0.01). Conclusion and Relevance: A meningitis dosing alert triggered by a combination of a CSF culture or NLP system and a 48-hour triggering time frame could provide reasonable sensitivity and PPV for meningitis dosing errors. Order sentences with indication-specific recommendations may provide additional dosing support, but additional studies are needed. PMID- 30015500 TI - Surface Replacement Arthroplasty Using a Volar Approach for Osteoarthritis of Proximal Interphalangeal Joint: Results After a Minimum 5-Year Follow-up. AB - BACKGROUND: Surface replacement arthroplasty (SRA) through a volar approach for the proximal interphalangeal (PIP) joint can preserve the integrity of the extensor tendon, which allows early range of motion (ROM) exercise postoperatively. However, a few reports have shown that the PIP ROM tends to decline with longer follow-up. The goal of this study is to assess the results of at least 5 years of follow-up of SRA through a volar approach and also to investigate the cause of deterioration of ROM with time after SRA through this approach. METHODS: Eleven fingers with degenerative osteoarthritis that underwent SRA through the volar approach were examined. ROM of the PIP joint preoperation, 1 year after the surgery, and at final follow-up was measured and statistically analyzed. Also, the relationship between PIP ROM and the osteophyte developed postoperatively was examined. RESULTS: The average follow-up period was 7.3 years. The average PIP ROM of the PIP joints was 52.3 degrees preoperatively, 54.1 degrees at 1 year postoperatively, and 31.1 degrees at the final follow up. PIP ROM at the final follow-up was significantly decreased compared with that preoperatively or at 1 year postoperatively. Also, the development of an osteophyte was negatively correlated with the ROM of the PIP joint at the final follow-up. CONCLUSIONS: PIP ROM after SRA through a volar approach has the tendency to deteriorate with a longer follow-up. Development of an osteophyte is considered to be a main risk factor of deterioration in the cases of SRA through a volar approach. PMID- 30015501 TI - Anterior Laxity at 2 Years After Anterior Cruciate Ligament Reconstruction Is Comparable When Using Adjustable-Loop Suspensory Fixation and Interference Screw Fixation. AB - BACKGROUND: Adjustable-loop suspensory fixation (ALSF) devices are commonly used in anterior cruciate ligament reconstruction (ACLR). However, concern exists regarding the potential for lengthening under cyclical loads. PURPOSE: To compare the residual anterior laxity of 2 methods of femoral fixation, ALSF versus interference screw fixation, in patients undergoing isolated ACLR in the absence of meniscal injuries. To determine the preoperative risk factors associated with residual postoperative anterior laxity. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective analysis was performed comparing 2 groups of patients that underwent primary ACLR using ALSF versus bioabsorbable interference screw fixation. Anterior knee laxity was assessed with Telos stress radiography, while functional outcomes were evaluated with the Knee injury and Osteoarthritis Outcome Score (KOOS) and Tegner activity level scale at a minimum of 2 years postoperatively. A multivariate analysis was performed to identify factors associated with residual postoperative laxity >3 mm. RESULTS: Of the 1136 patients who underwent ACLR during the study period, 363 met the inclusion criteria. A total of 272 patients (75%) (mean age, 31.7 +/- 10.7 years) with a mean follow-up of 25.7 +/- 4.6 months (range, 24-36 months) consented to participate (screw group: n = 121; ALSF group: n = 151). The 2 groups were statistically comparable in terms of age, sex ratio, time from injury to surgery, graft diameter, preoperative laxity, preoperative objective International Knee Documentation Committee (IKDC) grade, and preoperative Tegner score. The mean postoperative laxity as a continuous variable was significantly different comparing the ALSF and screw groups (1.49 +/- 1.98 mm and 2.32 +/- 1.97 mm, respectively; P < .001). In the screw group, 76 patients (62.8%) had normal (<3 mm), 40 (33.1%) had nearly normal (3-6 mm), and 5 (4.1%) had abnormal (>=6 mm) postoperative knee laxity according to the IKDC grade, while in the ALSF group, 112 patients (74.2%) had normal, 37 (24.5%) had nearly normal, and 2 (1.3%) had abnormal laxity ( P = .0833). No significant difference was found in KOOS or Tegner scores comparing the 2 femoral fixation methods: KOOS, 90.6 +/- 7.5 (ALSF group) and 90.6 +/- 7.4 (screw group) ( P = .7631), versus Tegner, 6.5 +/- 1.3 (ALSF group) and 6.3 +/- 1.4 (screw group) ( P = .2992). A negative correlation was found between postoperative laxity and final Tegner ( rs = -0.303, P < .001) and KOOS scores ( rs = -0.168, P = .005). The initial univariate analysis showed differences between groups of patients with residual knee laxity >=3 mm and <3 mm on preoperative pivot shift, preoperative laxity, age, fixation type, and preoperative objective IKDC grade. The multivariate analysis on these factors showed that the pivot shift remained the only significant predictor for residual laxity >=3 mm for pivot shift grade 2 compared with grade 1 (odds ratio, 4.689 [95% CI, 2.465-9.286]) and for pivot shift grade 3 compared with grade 1 (odds ratio, 58.025 [95% CI, 12.757-557.741]) ( P < .001). CONCLUSION: For primary ACLR, the use of an ALSF device for femoral fixation is associated with noninferior postoperative anterior knee laxity results compared with interference screw fixation at a minimum 2 years' follow-up. The preoperative pivot shift is the only significant risk factor for postoperative residual anterior knee laxity >3 mm. PMID- 30015502 TI - A Prospective Analysis of the Contralateral Hip Among Patients With Femoroacetabular Impingement: What Are the Risk Factors for Disease Progression? AB - BACKGROUND: The pathophysiology of femoroacetabular impingement (FAI) remains to be better understood, including factors affecting symptom development and disease progression. PURPOSE: (1) To determine rates of initial and subsequent symptom development in the contralateral hip of patients with symptomatic FAI and (2) to identify predictors of the development of symptomatic contralateral FAI. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This prospective study cohort included the contralateral hip of 179 consecutive patients undergoing primary surgical treatment of FAI. At presentation and follow-up time points, patients recorded the presence of symptoms in the contralateral hip. Patients with a minimum 1-year follow-up were included in the final cohort. Univariate analysis compared the patient characteristics and FAI imaging characteristics (cam and pincer) of initially asymptomatic patients who developed symptoms and those who remained asymptomatic. Kaplan-Meier survival curves were calculated to demonstrate symptom development over time. RESULTS: A total of 148 patients (83%) were followed for at least 1 year (mean, 2.9 years). Thirty-four (23%) patients had symptoms in the contralateral hip at the time of the initial presentation. An additional 27 hips (24% of the initially asymptomatic) developed symptoms during the follow-up period at a mean 2.0 years from presentation. Head-neck offset ratio on the anteroposterior pelvis radiograph was significantly lower among hips that developed symptoms (0.153 vs 0.163 asymptomatic group, P = .027). Maximum alpha angle ( P = .503), lateral center edge angle ( P = .975), and crossover sign ( P = .865) were not predictive of the development of symptoms. Patients developing contralateral hip symptoms were less likely to have a UCLA (University of California, Los Angeles) activity score of 9 or 10 at presentation (18.2% vs 43.8%, P = .032). The total arc of rotation in flexion (internal rotation in 90 degrees of flexion + external rotation in flexion) was significantly decreased in hips developing symptoms (39.4o vs 50.4o, P = .012). Kaplan-Meier survival analysis demonstrated that 72%, 67%, 56%, and 48% of all patients remained asymptomatic at 1, 2, 3, and 4 years, respectively. CONCLUSION: Approximately 1 in 4 patients with FAI presents with symptoms in the contralateral hip, and an additional 1 in 4 patients develops significant symptoms in the following 4 years. Several factors, including low activity level, less hip rotational motion, and decreased head-neck offset ratio, were significantly associated with the development of symptoms, while the alpha angle and crossover sign were not. PMID- 30015503 TI - Sex differences in response to emotion recognition training after traumatic brain injury. AB - OBJECTIVE: To examine sex differences in the effectiveness of a Stories intervention for teaching affect recognition in people with a traumatic brain injury (TBI). SETTING: Post-acute rehabilitation facilities. PARTICIPANTS: 203 participants (53 women and 150 men) with moderate to severe TBI were screened. 71 were eligible and randomized to one of three treatment conditions: two affect recognition conditions and an active control (cognition). This paper examines sex differences between the Stories intervention (n = 23, 5 women and 18 men) and the cognitive treatment control (n = 24, 8 women and 16 men). DESIGN: Randomized controlled trial with immediate, 3- and 6-month follow-up post-tests. Interventions were 9 hours of computer-based training with a therapist. MEASURES: Facial Affect Recognition (DANVA2-AF); Emotional Inference from Stories Test (EIST). RESULTS: A significant treatment effect was observed for the Stories intervention for women, who demonstrated and maintained improved facial affect recognition. In contrast, males in our sample did not benefit from the Stories intervention. CONCLUSION: This positive finding for the Stories intervention for females contrasts with our conclusions in a previous paper, where an analysis collapsed across sex did not reveal an overall effectiveness of the Stories intervention. This intervention warrants further research and development. PMID- 30015504 TI - Risk Factors and Outcomes of Revision Arthroscopic Posterior Shoulder Capsulolabral Repair. AB - BACKGROUND: Risk factors and outcomes of revision arthroscopic posterior capsulolabral repair of the shoulder are currently not well defined. HYPOTHESIS: Athletes who require revision arthroscopic posterior unidirectional capsulolabral repair will have poorer outcomes and return to play when compared with those undergoing primary procedures, with risk factors including younger age, injury size, bone loss, and anchor number. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 297 shoulders that underwent arthroscopic posterior capsulolabral repair at minimum 2-year follow-up were reviewed. In addition to surgical data, the American Shoulder and Elbow Surgeons scoring system with subjective stability, range of motion, strength, and pain scores as well as return to sport were compared pre- and postoperatively between those who did and did not require revision surgery. Magnetic resonance arthrogram measurements of glenoid labral, chondral, and bone version and labral and bone width were also compared. RESULTS: Nineteen shoulders required revision surgery (6.4%) at 8.9-year follow-up. Significant risk factors included female sex ( P = .001), dominant shoulder ( P = .005), and concomitant rotator cuff injury ( P = .029). Patients with <=3 anchors were more likely to require revision (odds ratio = 3.48). Smaller glenoid bone width was a risk factor for requiring future revision surgery ( P < .001), but glenoid labral, chondral, and bone version and labral width were not risk factors. All patients had significant improvements in American Shoulder and Elbow Surgeons, pain, range of motion, and strength scores after the original surgery; however, those who required revision surgery had less improvement ( P < .05). Stability improved significantly for nonrevisions ( P < .001) but did not for revisions ( P = .662). In the nonrevision group, 64.3% returned to sport at the same level, which was significantly higher than the 15.4% of the revision group ( P = .004). Overall, 78.6% of the nonrevision group and 61.6% of the revision group returned to sport at some level ( P = .280). CONCLUSION: Athletes underwent revision arthroscopic posterior capsulolabral repair at an incidence of 6.4%. Revision patients had significantly poorer outcome scores and return to play when compared with those who did not undergo revision surgery with risk factors being dominant shoulder surgery, female sex, concomitant rotator cuff injury, the use of 3 or fewer anchors, and smaller glenoid bone width. These data are essential for patient selection, optimal treatment techniques, and patient education as posterior shoulder instability failure requiring revision has not previously been evaluated. PMID- 30015505 TI - Outcomes Following Posterior and Posterolateral Plating of Distal Fibula Fractures. AB - : Ankle fractures are common orthopaedic injuries often requiring open reduction and internal fixation. A variety of positions for plate placement exist for surgical fixation of distal fibula fractures, including direct lateral, posterior, or posterolateral. Direct lateral is more common, despite evidence that posterior and posterolateral placement is mechanically superior. However, concern for peroneal tendon injury from posterior plating remains. Our study investigates clinical and functional outcomes of patients who underwent operative fixation of distal fibula fractures with posterior or posterolateral plating over a 3-year period. Analyses were performed on 59 patients with at least 2 years of follow-up. Questionnaires were used to obtain demographic data, in addition to information regarding the presence of ankle pain, subsequent hardware removal, and Foot and Ankle Outcome Scores (FAOS). In patients with at least 2 years of follow-up (average 39.6 +/- 10.6 months), 37.2% reported ongoing ankle pain; 11 patients underwent hardware removal (18.6%), with 8 patients undergoing removal because of hardware-related pain (13.6%). FAOS scores (n = 51) were as follows: pain (79.9 +/- 22.3), activities of daily living (84.2 +/- 22.6), symptoms (75.7 +/- 23.5), sports (69.4 +/- 31.6), and quality of life (58.3 +/- 30.5). Posterior and posterolateral plating achieved good clinical and high functional outcomes across our study population. The percentage of hardware removal in our study was either equivalent to, or less than, historical controls for any type of fibular fixation, and removal may be helpful for those patients whose postoperative ankle pain is subjectively related to the hardware. LEVELS OF EVIDENCE: Therapeutic, Level IV: Retrospective. PMID- 30015506 TI - Characteristics of High-Level Ciprofloxacin-Resistant Enterococcus faecalis and Enterococcus faecium from Retail Chicken Meat in Korea. AB - Genes encoding ciprofloxacin resistance in enterococci in animals may be transferred to bacteria in the animal gut and to zoonotic bacteria where they could pose a human health hazard. The objective of this study was to characterize antimicrobial resistance in high-level ciprofloxacin-resistant (HLCR) Enterococcus faecalis and Enterococcus faecium isolated from retail chicken meat. A total of 345 enterococci (335 E. faecalis and 10 E. faecium) were isolated from 200 chicken meat samples. Of these, 85 E. faecalis isolates and 1 E. faecium isolate were confirmed as HLCR enterococci. All 86 HLCR enterococci displayed gyrA- parC point mutations consisting of S83I-S80I (94.2%, 81 isolates), S83F S80I (2.3%, 2 isolates), S83Y-S80I (2.3%, 2 isolates), and S83Y-S80F (1.2%, 1 isolate). Sixty-one (72.9%) of the 86 HLCR enterococci showed multidrug resistance to three to six classes of antimicrobial agents. Multilocus sequence typing revealed that E. faecalis had 17 different sequence types (ST) and E. faecium had 1 different ST, with ST256 observed most often (44 isolates, 51.8%). Although these results cannot exclude the possibility that pathotypes of enterococci isolated from chicken might represent transmission to or from humans, the foodborne HLCR E. faecalis indicated that the food chain is a potential route of enterococcal infection in humans. PMID- 30015507 TI - Influence of Storage Temperature, Moisture Content, and Physical Impurities on the Distribution and Survival of Salmonella enterica in Poultry Fat Intended for Pet Food Use. AB - Contamination of rendered products with Salmonella is a concern for the rendering industry, particularly when those products are intended for use in other foodstuffs, such as pet food. This study was conducted to understand the influence of compositional variation on the location and survivability of Salmonella in a poultry fat matrix. Specifically, this study aimed to (i) assess the influence of postinoculation time and moisture content on the distribution of Salmonella in rendered poultry fat and (ii) evaluate the impact of postinoculation time and physical parameters (i.e., impurity level and moisture content) on survival of three Salmonella strains in rendered poultry fat stored at two different temperatures. Three studies, designated as study I(a), I(b), and II, respectively, were conducted to address these objectives. In study I(a), a green fluorescent protein-expressing strain of Salmonella Typhimurium was used to map the organism within warmed (45 degrees C) poultry fat containing various levels of moisture. In study I(b), the influence of storage temperature on the survivability of green fluorescent protein-expressing Salmonella was evaluated. In study II, the impacts of physical impurities, moisture content, and storage temperature on the survivability of three Salmonella strains (Enteritidis, Senftenberg, and Typhimurium) were assessed. The results of this study demonstrated that composition (i.e., moisture and impurity contents) influences the survivability of Salmonella in poultry fat; specifically, Salmonella is more persistent in poultry fat with a greater moisture content and water activity. Nonetheless, although composition impacts the distribution and survivability of Salmonella in poultry fat, Salmonella generally does not survive in poultry fat maintained at high temperatures (45 degrees C and above). PMID- 30015508 TI - Early Return to Play With Thumb Spica Gauntlet Casting for Ulnar Collateral Ligament Injuries Complicated by Adjacent Joint Dislocations in Collegiate Football Linemen. AB - BACKGROUND: Treatment of thumb ulnar collateral ligament (UCL) ruptures in elite athletes aims to restore thumb stability while minimizing lost playing time. Thus, surgical repair with early protected return to play in a thumb spica cast has been advocated. The purpose of this study was to document adjacent joint dislocations after primary surgical repair sustained during protected return to play with thumb spica casting in elite-level football players. METHODS: Three Division I collegiate starting linemen sustaining adjacent joint dislocations in thumb spica casts following acute surgical repair of ipsilateral thumb UCL ruptures were retrospectively reviewed. Demographic data were recorded as well as the timeline for injury, treatment, and subsequent return to sport. Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) scores were obtained at final follow-up. RESULTS: The mean time from thumb UCL injury to surgical repair was 8.7 days, and the mean return to sport was 13.3 days from surgery. There were 4 simple dislocations including 3 proximal interphalangeal (PIP) joints and 1 elbow. Each PIP dislocation was close reduced and treated with buddy straps with immediate return to play. The elbow dislocation was close reduced and splinted with return to play 22 days after injury. The mean QuickDASH score was 2.3 at 12 month follow-up. CONCLUSIONS: This report highlights that while thumb spica casting protects the surgically repaired thumb UCL and allows for earlier return to play, it risks placing additional stress upon adjacent joints and therefore adjacent injury. Appropriate counseling of the risks and benefits of this treatment strategy is essential. PMID- 30015509 TI - The Presence and Degree of Bone Marrow Edema Influence Midterm Clinical Outcomes After Microfracture for Osteochondral Lesions of the Talus. AB - BACKGROUND: Subchondral bone marrow edema (BME) has been associated with articular cartilage loss, with the potential to be a negative prognostic indicator for clinical outcomes after microfracture. However, no single study has investigated the association between BME and clinical outcomes after microfracture for osteochondral lesions of the talus (OLTs) at midterm follow-up. PURPOSE: To clarify the association between postoperative subchondral BME and clinical outcomes in patients treated with microfracture for OLTs at both short term and midterm follow-up using a grading system that classified the extent of BME of the talus. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients who underwent microfracture between 2008 and 2013 were assessed at 2- and 4-year postoperative follow-up. BME was evaluated using magnetic resonance imaging, and the presence of subchondral BME was determined with fat-suppressed T2-weighted sequences. Clinical outcomes were evaluated using the Foot and Ankle Outcome Score (FAOS). P < .05 was considered to be statistically significant. RESULTS: Forty-three (83%) of 52 eligible patients were included. No significant differences were found in the FAOS between the BME and no BME groups at 2-year follow-up (83.1 +/- 6.5 vs 88.6 +/- 8.0, respectively; P = .109), but there was a significant difference at 4-year follow-up (77.5 +/- 11.1 vs 84.7 +/- 8.4, respectively; P = .041). A significant difference was found among BME grades at 4 year follow-up (grade 0: 84.7 +/- 7.4, grade 1: 80.1 +/- 10.5, grade 2: 74.0 +/- 10.3, and grade 3: 67.5 +/- 7.1; P = .035). A post hoc analysis showed significant differences between grades 0 and 2, 0 and 3, and 1 and 3 ( P = .041, .037, and .048, respectively). In addition, at 4-year follow-up, a significant correlation was noted between the FAOS and BME grade ( r = -0.453, P = .003) but not at 2-year follow-up ( r = -0.212, P = .178). Seventy-four percent of patients still had subchondral BME at 4-year follow-up after microfracture for OLTs. CONCLUSION: Patients with subchondral BME at midterm follow-up after microfracture for OLTs had worse clinical outcomes than those without subchondral BME. In addition, the degree of subchondral BME at midterm follow-up was correlated with clinical outcomes. However, at short-term follow-up, there were no significant differences in clinical outcomes based on both the presence and degree of BME, and no correlation was found between clinical outcomes and the degree of BME. The current study suggests that BME at short-term follow-up is a normal physiological reaction. However, BME at midterm follow-up after microfracture for OLTs may be pathological and is associated with poorer clinical outcomes. PMID- 30015510 TI - Partial Controlled Early Postoperative Weightbearing Versus Nonweightbearing After Reconstruction of the Fibular (Lateral) Collateral Ligament: A Randomized Controlled Trial and Equivalence Analysis. AB - BACKGROUND: While early weightbearing protocols have been advocated after anterior cruciate ligament (ACL) reconstruction, early weightbearing after fibular (lateral) collateral ligament reconstruction has not been well defined. PURPOSE: (1) To determine if early partial controlled weightbearing after fibular collateral ligament (FCL) reconstruction resulted in an objective difference in laxity on varus stress radiographs at postoperative 6 months as compared with nonweightbearing, and (2) to determine if there was a difference in pain, edema, range of motion, and subjective patient-reported outcomes between these groups at 3 time points. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients were prospectively enrolled from January 2014 to April 2017. Patients who underwent isolated FCL reconstruction or combined ACL and FCL reconstructions were included in this study. Patients were randomly assigned to either a control group (nonweightbearing for 6 weeks) or a treatment group (partial controlled weightbearing at 40% body weight with crutches for 6 weeks). Patient-related data, including knee pain, edema, and range of motion, were collected for all patients at postoperative day 1, 6 weeks, and 6 months. Subjective outcomes were collected preoperatively and at 6 months postoperatively. The primary objective endpoint was varus stability, evaluated by bilateral varus stress radiographs obtained preoperatively and at 6 months postoperatively. RESULTS: Thirty-nine patients were enrolled in the study, with 6 month follow-up obtained for 36 (92%). There was a significant improvement between the preoperative side-to-side difference (SSD) (2.4 +/- 1.0) and postoperative SSD (0.2 +/- 1.0) for lateral compartment laxity on varus stress radiographs among all patients ( P < .001). Clinical and statistical equivalence was found between groups in terms of SSD on varus stress radiographs ( P < .001). The SSD in knee edema was significantly lower in the partial early weightbearing group (beta = -0.6 cm, P = .001), but there were no significant group differences in knee pain, flexion, or extension. All patients demonstrated significant improvements in subjective outcome scores between the preoperative and 6-month postoperative conditions ( P < .001 for every score measured). CONCLUSION: Clinical and statistical equivalence was found at postoperative 6 months between the early partial weightbearing and nonweightbearing groups among patients undergoing either an isolated FCL reconstruction or a combined ACL and FCL reconstruction. There were no significant differences observed between the groups regarding knee stability, pain, swelling, range of motion, or subjective outcomes. Given these findings, the authors recommend early partial weightbearing after isolated FCL reconstruction or combined ACL and FCL reconstruction. PMID- 30015511 TI - In their own words: developing the Parent Experiences Questionnaire following neonatal brain injury using participatory design. AB - PRIMARY OBJECTIVE: This study aimed to create a specific questionnaire (Parent Experiences Questionnaire) about early experiences, service involvement, and needs of children and parents following neonatal brain injury that could be used to inform clinical care and needed interventions. RESEARCH DESIGN AND METHODS: A mixed-method design was utilized, engaging in both qualitative and quantitative methods across three phases. Phase 1 employed participatory design involving 12 parent and clinician participants in semi-structured interviews to address main topics, item importance, and overall impressions of the questionnaire. In phase 2, the questionnaire was piloted by 32 parents. Post hoc revisions added four questions to address current parent and child therapeutic needs in phase 3. MAIN OUTCOMES AND RESULTS: The final questionnaire yielded 24 items addressing topics of early communication between parent and clinicians, early intervention services, efficacy, and barriers in optimizing the child's development and parents' experience. The questionnaire was reviewed positively by a group of parents in phase 2 and demonstrated good acceptance, online feasibility, stability, and association with current parental mental health and child development. CONCLUSIONS: This investigation offers a valuable new questionnaire to inform clinical care regarding discussions with parents about neonatal brain injury, evaluate the perceived efficacy of early intervention services, and guide relevant future intervention efforts. PMID- 30015512 TI - Influence of IL-6, IL-10, IFN-gamma and TNF-alpha genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients. AB - BACKGROUND: Data from previous studies on the role of inflammatory cytokines as biomarkers for diabetic kidney disease (DKD) are contradictory. The association of a particular inflammatory cytokine single nucleotide polymorphism (SNP) with susceptibility to DKD has not been consistently replicated. We aimed to investigate the utility of inflammatory cytokines as biomarkers for DKD in type 2 diabetes mellitus (T2DM) patients. Association of inflammatory cytokine gene SNPs with the development of DKD was also explored. SUBJECTS AND METHODS: One hundred and fifty-nine Kuwaiti subjects were recruited in this study, including 50 T2DM patients without DKD, 67 diabetic DKD patients and 42 healthy subjects. Plasma levels of interleukin-6 (IL-6), IL-10, interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assays. Nine SNPs, including 2 SNPs in IL-6, 3 SNPs in IL-10, 1 SNP in IFN-gamma and 3 SNPs in TNF-alpha, were genotyped using TaqMan SNP genotyping assays. RESULTS: Diabetic DKD patients showed higher IL-6, IL-10, IFN-gamma and TNF-alpha levels than those without DKD. Diabetic DKD patients had a significantly higher frequency of IL-10 - 1082 A allele than those without DKD (p = 0.001). No significant association of IL-6 - 174/-597 haplotypes with DKD risk was detected (p = 0.188). Distribution of IL-10 - 592/-819/-1082 haplotypes differ significantly between T2DM patients with/without DKD (p = 0.014). Diabetic DKD patients had a significantly lower frequency of IL-10 - 592C/-819C/-1082G haplotype than those without DKD (p = 0.002). CONCLUSIONS: Although inflammatory cytokine genotypes and, more importantly, haplotypes may have the potential to identify those patients at risk of DKD, hence, improving DKD predisposition prediction, further investigations regarding their real clinical significance is warranted in a large cohort of patients. PMID- 30015513 TI - A novel microRNA miR-1165-3p as a potential diagnostic biomarker for allergic asthma. AB - CONTEXT: A further examination of a novel potential miRNA asthma biomarker, miR 1165-3p, which was previously implicated in helper T cells (Th2) in a murine asthma model. OBJECTIVE: To determine whether serum miR-1165-3p can serve as a potential diagnostic biomarker for allergic asthma. METHODS: Serum miR-1165-3p was quantified via quantitative real-time PCR (qRT-PCR) in asthmatic and control samples. Serum miR-1165-3p levels were compared between groups and the clinical diagnostic abilities of miR-1165-3p were evaluated. The analyses utilized included a student's t test, one-way ANOVA, and the generation of receiver operating characteristic (ROC) curves. RESULTS: Serum miRNA-1165-3p levels were significantly elevated in asthmatics when compared to the healthy controls. Furthermore, the sensitivity and specificity of serum miR-1165-3p were found to be 83% and 68.2%. Additionally, serum miR-1165-3p levels were also found to be significantly elevated in patients with allergic rhinitis (AR) or allergic bronchopulmonary aspergillosis (ABPA). CONCLUSIONS: This study showed that serum miR-1165-3p can potentially be utilized as a noninvasive biomarker that is able to aid in the diagnosis and characterization of allergic asthma. PMID- 30015514 TI - Obesity is an independent determinant of elevated C-reactive protein in healthy women but not men. AB - BACKGROUND AND AIMS: High-sensitivity C-reactive protein (hs CRP) has emerged as an inflammatory biomarker to predict metabolic syndrome. Here, we investigate the association of hs CRP with metabolic variables and determine the risks for elevated hs CRP levels in healthy Singaporean adults. METHODS: We conducted a cross-sectional study of 225 participants (104 men). The levels of hs CRP and fasting lipid parameters were analyzed by COBAS. Body composition was determined with dual-energy X-ray absorptiometry. RESULTS: Twenty-one (9 %) participants had elevated hs CRP levels (>3 mg/mL). The levels of hs CRP had significant correlations (p <0.05) with obesity and metabolic variables among women. Stepwise multivariate regression analysis identified FM (%) (accounted for 22.5% of the variability in hs CRP levels) as a major determinant of hs CRP levels. On multivariate regression, FM (%) was the independent determinant of intermediate and elevated hs CRP in women after adjustment for the potential confounders. CONCLUSIONS: Obesity may play a direct role in the elevated hs CRP levels in women, but not men living in Singapore. This is probably due to different body composition or different effects of sex hormones on adipose tissue between men and women. PMID- 30015515 TI - Proposal of a New Dynamic Distraction Device to Treat Complex Periarticular Fractures of the Metacarpophalangeal Joint of Long Finger. AB - BACKGROUND: Complex periarticular fractures of the metacarpophalangeal joint (MCPJ) are often challenging to treat. Conservative and operative treatments are often burdened with stiffness, loss of function, and poor clinical outcome. These phenomena could be a direct consequence of long period of immobilization. To promote a short time of immobilization and a quick return to daily activities, it is mandatory to stabilize the fracture maintaining the active range of motion (AROM) of the ray. A simple solution is to reduce the fragments by means of dynamic ligamentotaxis. The authors propose a new dynamic distraction device (DDD) for the MCPJ. METHODS: The DDD for the MCPJ was made of Kirschner wires bent and connected to counteract dislocation forces and to allow mobilization of the joint. The DDD was tested on a cadaver model under a simulated load in physiological conditions, and also in metacarpal and proximal phalanx (P1) fracture patterns. The effectiveness of the device was evaluated under fluoroscopy. RESULTS: The data showed that DDD is able to achieve fracture reduction through ligamentotaxis and primary fragments stability and to avoid secondary dislocation during AROM of complex periarticular fractures of the MCPJ. CONCLUSIONS: The frame could be an alternative option to treat periarticular fractures of the MCPJ. The DDD implant has several advantages: It is time efficient because assembly and application take only few minutes. Furthermore, it is very versatile; indeed, it can be used in all metacarpal and phalanx bones, even in the central rays. PMID- 30015517 TI - Proceedings of the 2018 British Neurosurgical Research Group Meeting. PMID- 30015518 TI - Surgeons and the Model Calibration method of trial interpretation. PMID- 30015516 TI - The association between plasma miR-122-5p release pattern at admission and all cause mortality or shock after out-of-hospital cardiac arrest. AB - BACKGROUND: Data suggests that the plasma levels of the liver-specific miR-122-5p might both be a marker of cardiogenic shock and a prognostic marker of out-of hospital cardiac arrest (OHCA). Our aim was to characterize plasma miR-122-5p at admission after OHCA and to assess the association between miR-122-5p and relevant clinical factors such all-cause mortality and shock at admission after OHCA. METHODS: In the pilot trial, 10 survivors after OHCA were compared to 10 age- and sex-matched controls. In the main trial, 167 unconscious survivors of OHCA from the Targeted Temperature Management (TTM) trial were included. RESULTS: In the pilot trial, plasma miR-122-5p at admission after OHCA was 400-fold elevated compared to controls. In the main trial, plasma miR-122-5p at admission was independently associated with lactate and bystander cardiopulmonary resuscitation. miR-122-5p at admission was not associated with shock at admission (p = 0.14) or all-cause mortality (p = 0.35). Target temperature (33 degrees C vs 36 degrees C) was not associated with miR-122-5p levels at any time point. CONCLUSIONS: After OHCA, miR-122-5p demonstrated a marked acute increase in plasma and was independently associated with lactate and bystander resuscitation. However, miR-122-5p at admission was not associated with all-cause mortality or shock at admission. PMID- 30015519 TI - New opportunities with quantification of protein therapeutics by LC-MS. PMID- 30015520 TI - Role of Nitric Oxide in the Development of Cataract Formation in CdCl2-induced Hypertensive Animals. AB - PURPOSE: Previously we established a strong association of systemic hypertension with cataract formation. In the present study, we investigated the role of nitric oxide (NO) in the development of cataract formation in CdCl2-induced hypertensive animals. MATERIALS AND METHODS: Hypertension was induced in male albino rats by intraperitoneal administration of CdCl2 (0.5 mg/kg/day) for eight weeks. The NO modulators, 10 uM S-nitrosoglutathione (NO donor) and 1% w/v Nomega-nitro-L arginine methyl ester (L-NAME, NOS inhibitor) were applied topically once a day on the eye cornea during the experimental period. Amlodipine (3mg/kg/day) was used as a standard antihypertensive drug and administered orally. RESULTS: In the CdCl2 control group, mean arterial pressure was significantly increased along with augmentation of lens nitrite, opacity, and oxidative stress. The control of hypertension by amlodipine substantially restored lens nitrite and cataractogenic events. Moreover, topical application of L-NAME significantly alleviated the lens nitrite, opacity, antioxidants (GSH, CAT, SOD, and GPx), MDA, proteins, and ionic (Na+ and Ca2+) contents. Whereas, S-nitrosoglutathione topical application exacerbated these cataractogenic events without affecting hypertension as compared to CdCl2 control group. The findings demonstrated that NO donor exacerbates and NOS inhibitor alleviates the cataract formation in hypertensive condition. The control of hypertension also reduces the cataract formation with reduction of lens nitrite level. CONCLUSION: The overall findings suggested the strong correlation between NO and hypertension associated cataract formation. The elevation of lens nitrite (NO metabolite) is one of the key factors of augmentation of lenticular oxidative stress and cataract formation in the hypertensive condition. PMID- 30015521 TI - Relationship Between Post-Exercise Changes in the Lens and Schlemm's Canal: A Swept-Source Optical Coherence Tomography Study. AB - AIM: To observe post-exercise changes in the lens and Schlemm's canal (SC) in healthy individuals using swept-source optical coherence tomography (SS-OCT). METHODS: Thirty-five healthy, young individuals were recruited and performed aerobic exercise by jogging for 20 minutes. The SC area, SC perimeter, trabecular meshwork (TM) length, TM thickness, lens vault (LV), and lens thickness (LT) were assessed by SS-OCT before and after exercise. RESULTS: Following aerobic exercise, SC area (4260.85 +/- 1476.02 vs. 5158.24 +/- 1527.42 MUm2, p < 0.001), SC perimeter (349.21 +/- 62.22 vs. 391.24 +/- 71.77 MUm, p < 0.001), TM length (781.16 +/- 114.83 vs. 816.46 +/- 121.26 MUm, p < 0.001), and TM thickness (111.52 +/- 19.30 vs. 116.96 +/- 17.57 MUm, p = 0.004) increased significantly, while LV (-0.134 +/- 0.198 vs. -0.195 +/- 0.198 mm, p < 0.001) decreased significantly and LT showed no significant post-exercise changes (3.86 +/- 0.32 vs. 3.85 +/- 0.32 mm, p = 0.801). Moreover, post-exercise changes in SC area were significantly associated with post-exercise changes in LV (beta = -6487.83; p = 0.040). CONCLUSIONS: Aerobic exercise induces both backward axial displacement of the lens and SC expansion. This backward axial displacement of the lens could be an important causative factor of the post-exercise SC expansion via the lens zonular-ciliotrabecular vector and the connecting fibrils between ciliary body and SC. PMID- 30015522 TI - A Positive Feedback Loop Between Th17 Cells and Dendritic Cells in Patients with Endplate Inflammation. AB - BACKGROUND: Endplate inflammation remains a difficult disease to treat, in part due to its unclear pathology. Previous experiments showed that patients with idiopathic inflammation presented a systemic upregulation of Th17 cells. Here, we investigated how this change might affect the inflammatory environment in endplate inflammation. METHODS: Peripheral blood was obtained from patients and healthy controls, and Th17 cells were examined. RESULTS: Th17 cells significantly increased the differentiation of CD11c+ and DC-SIGN+ dendritic cells (DCs) from circulating monocytes in the absence of exogenous stimulation as well as in the presence of LPS stimulation. Th17 cells also increased CD80 and CD86 expression by DCs. Importantly, although Th17 cells from both healthy controls and patients with endplate inflammation could induce CD11c, DC-SIGN, CD80, and CD86 expression, Th17 cells from patients with endplate inflammation showed significantly more potent capacity. Both contact-dependent and IL-17-dependent mechanisms were employed by Th17 cells, since blocking cell-to-cell contact significantly inhibited Th17-mediated differentiation of CD11c+ DCs, and neutralization of IL-17 reduced the expression of CD80 and CD86. Strikingly, DCs following incubation with Th17 cells, but not the DCs derived directly from monocytes without Th17 cells, could significantly promote the expression of IL-17 from naive CD4+ T cells. CONCLUSIONS: These results demonstrated that Th17 cells from patients with endplate inflammation could potently induce the differentiation and activation of DCs that preferentially promoted IL-17 response in a positive feedback loop. PMID- 30015523 TI - The Effect of Prostaglandin Analogues on the Ciliary Zonular Fibers of the Rabbit Crystalline Lens. AB - PURPOSE: To evaluate the influence of prostaglandin (PG) analogues on the ciliary zonular fibers of the crystalline lens using scanning electron microscopy (SEM) of rabbit eyes, and to measure the matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) levels of the aqueous humor and crystalline lens treated with topical PG analogues Methods: Fifty eyes from 25 New Zealand white rabbits were divided into five groups of five rabbits each. In the control group, balanced salt solution was administered via the topical route once a day to the eyes. The benzalkonium chloride (BAC) group was treated with 0.02% BAC, the Latanoprost group with 0.005% latanoprost, the Travoprost group with 0.004% Travoprost, and the Bimatoprost group with 0.03% Bimatoprost for 10 months. We examined the ciliary zonular fibers using SEM. We also measured the MMP and TIMP levels of the aqueous humor and crystalline lens. RESULTS: SEM revealed some splitting of zonular fibers in eyes treated with topical PG analogues when compared with the control and BAC groups. The MMP-1 and TIMP-1 levels after treatment with the PG analogues did not differ significantly from the control and BAC groups (P > 0.05). There was no significant difference in MMP-1, MMP-3, TIMP 1, and MMP-1/TIMP-1 levels in the lens among all five groups. CONCLUSIONS: PG analogues may induce zonular change in rabbits microscopically. There was no association between zonular changes and the levels of certain types of MMP or TIMP in the aqueous humor or crystalline lens after topical treatment with PG analogues. PMID- 30015524 TI - The relationship of serum VEGF and sVEGFR-1 levels with vascular involvement in patients with Behcet's disease. AB - Behcet's disease (BD) is a rare, chronic, inflammatory disorder characterized by multisystemic vasculitis including mucocutaneous, neurologic, and ophthalmic involvement. Our aim is to compare vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) levels in BD, among the patients having or not having organ involvement, disease activation and especially vascular involvement. Fifty-five patients with BD, 25 of which were accompanied by vascular involvement, and 31 control subjects were included in the study. Disease activity was assessed with the Turkish version of Behcet Disease Current Activity Form (BDCAF) and active vasculitis lesions at the time of study were recorded. Age at diagnosis was 32.2 +/- 4.6, while the mean duration of BD was 96.3 (72.3) months. The median for BDCAF score was 2.0 (range 0, 3.0), and 29 (52%) of patients had active BD. The serum VEGF and sVEGFR-1 levels in patients with BD were significantly higher than that in controls [(298 (338.5) pg/mL; 93 (93.5) pg/mL in patients and 136.2 (73) pg/mL; 56.5 (48.5) pg/mL in controls, respectively, p < .001 for both values] while difference in VEGF/sVEGFR-1 ratio was obtained close to borderline of significance (p = .03). Our study is the first report indicating elevated serum VEGF, sVEGFR-1, and more importantly VEGF/sVEGFR-1 ratio could play an important role in the development of trombosis in BD. VEGF and/or sVEGFR-1 should not be evaluated independently in the same patient group and the ratio of these two parameters is a more important indicator, especially in the evaluation of BD especially with vascular involvement together with the duration of disease. PMID- 30015525 TI - Erratum. PMID- 30015526 TI - Amyloid Beta Deposition Could Cause Corneal Epithelial Cell Degeneration Associated with Increasing Apoptosis in APPswePS1 Transgenic Mice. AB - OBJECTIVE: To investigate the expression of amyloid precursor protein (APP) and amyloid beta (Abeta) in cornea and further explore the pathological and ultrastructural changes in corneal epithelium in APPswePS1 transgenic mice. METHODS: Twelve wild type mice were grouped into control group and twelve TgAPPswePS1 mice at least 8 months old were grouped into the young experiment group (Tg-8M group), and another twelve transgenic mice at least 15 months old were selected into the aged experiment group (Tg-15M group). The pathological degeneration, ultrastructural changes, and the expression of APP, Abeta deposition, and the TUNEL reaction in corneal epithelial cells were observed. Western blot analysis was performed to determine expression levels of APP and Abeta with scraped epithelial debridement. All the results were quantified and analyzed. RESULTS: In transgenic mice, the H&E-stained cornea sections demonstrated histopathological changes in corneal epithelial cells with irregular arrangement and the number of cell layers decreased, while normal structure observed in controls. In Tg-15M group, the corneal epithelial cell displaced a significant number of intracellular vacuoles with 1-2 cell layers left. Transmission electron microscopy (TEM) further confirmed the dramatic degeneration in corneal epithelium, the microvilli suffered degenerative changes and found with typical fingerpoint-like morphology in controls; however, microspike-like in Tg-15M group, and the number of microvilli decreased considerabely. An APP-positive immunoreaction was detected with a diffuse pattern in the corneal epithelial cells layer, about 3.122 +/- 0.596 and 7.372 +/- 0.936 fold changes in Tg-8M and Tg-15M groups, respectively, as compared with controls. On corneal flatmount, Abeta deposition found a diffuse pattern in the cytoplasm by fluorescence staining in TgAPPswePS1 with significantly increasing as compared with the controls, but no plaque was found. The apoptosis of TUNEL cells were observed in TgAPPswePS1 mice and increased 16.329 +/- 3.542 fold changes in Tg 15M group as compared with controls. CONCLUSION: The APP expression and Abeta deposition might cause cornea epithelial cells degeneration in TgAPPswePS1 mice, associated with apoptosis in basal lamina cells. PMID- 30015527 TI - Scanning laser ophthalmoscopy in an elderly Indian population. AB - PURPOSE: To study optic nerve head (ONH) characteristics using scanning laser ophthalmoscopy, Heidelberg retina tomograph (HRT), in an elderly population. METHODS: A population-based, cross-sectional study included 1460 eyes of 1460 consecutive, subjects >60 years, in North India. All subjects underwent a detailed ophthalmic evaluation and imaged on HRT. Stereometric parameters, Moorfields regression analysis (MRA) and discriminant function analysis were analyzed. Correlation between ONH parameters and disc area, age, sex, and intraocular pressure was analyzed. RESULTS: Disc size had a normal Gaussian distribution (2.22 +/- 0.48 mm2), but all other stereometric parameters showed a wide variation. MRA found 1320 (90.4%) eyes within normal limits, 71 (4.86%), borderline limits, and 69 (4.73%) outside normal limits. Comparison of eyes meeting International Society of Geographical and Epidemiological Ophthalmology criteria for a glaucoma suspect, C:D > 0.7, with those that did not show a statistically significant difference in the cup area, rim area, rim disc ratio, and cup volume (p = 0.02, 0.02, 0.02, 0.03, respectively). An Intraocular pressure (IOP) >=21 mmHg was seen in 3.01%, and only 12 eyes out of 1460, 0.82%, had an IOP >=21 mmHg and a cup:disc ratio of more than 0.7. A van Herick estimation of < Grade 3 was seen in 19.4% Conclusions: Stereometric parameter data, MRA, and clinical examination in this population at high risk for glaucoma found that about 10% of individuals over 60 years of age could be classified as glaucoma suspects and would need further evaluation. PMID- 30015528 TI - Adalimumab in Active and Inactive, Non-Infectious Uveitis: Global Results from the VISUAL I and VISUAL II Trials. AB - PURPOSE: Report global adalimumab safety and efficacy outcomes in patients with non-infectious uveitis. METHODS: Adults with non-infectious intermediate, posterior, or panuveitis were randomized 1:1 to receive placebo or adalimumab in the VISUAL I (active uveitis) or VISUAL II (inactive uveitis) trials. Integrated global and Japan substudy results are reported. The primary endpoint was time to treatment failure (TF). RESULTS: In the integrated studies, TF risk was significantly reduced (hazard ratio [95% CI]) with adalimumab versus placebo (VISUAL I: HR = 0.56 [0.40-0.76], p < 0.001; VISUAL II: HR = 0.52 [0.37-0.74], p < 0.001). In Japan substudies, no consistent trends were observed between groups (VISUAL I: HR = 1.20 [0.41-3.54]; VISUAL II: HR = 0.45 [0.20-1.03]). Adverse event rates were similar between treatment groups in both studies (854 to 1063 events/100 participant-years). CONCLUSIONS: Adalimumab lowered time to TF versus placebo in the integrated population; no consistent trends were observed in Japan substudies. Safety results were consistent between studies. PMID- 30015529 TI - Related Variables of Behavioral and Emotional Problems and Personal Growth of Hospitalized Children's Siblings: Mothers' and Other Main Caregivers' Perspectives. AB - The psychological well-being of the siblings of hospitalized children is at risk. This study examined the variables related to siblings' internalizing problems and personal growth during hospitalization from the perspectives of mothers and other main caregivers who temporarily assumed the main caregiver role to the siblings of hospitalized children in place of mothers in the period of children's hospitalization. A cross-sectional, exploratory survey conducted in Japan examined 113 mothers' and 90 other main caregivers' perspectives regarding the psychological state of 2- to 18-year-old siblings of hospitalized children. Mothers and/or other main caregivers of siblings during their brothers' or sisters' hospitalization completed the Child Behavior Checklist and the Siblings' Personal Growth Scale. Multiple linear regression analysis was performed with Child Behavior Checklist internalizing problems and total Siblings' Personal Growth Scale scores as dependent variables for mothers' and caregivers' perspectives. From mothers' perspectives, environmental factors that change with hospitalization affected siblings. From the perspectives of the other main caregivers, children's and families' demographic factors affected siblings' psychological state. Frequency of e-mail contact between mothers and siblings, explanation of the hospitalized child's condition, and hospital visitation rules ( F = 5.88, P = .001) explained 12.3% of variance in mothers' Siblings' Personal Growth Scale scores. Among other main caregivers, 11.6% of variance in the Child Behavior Checklist scores was explained by hospitalized children's birth order and main caregiver's prehospitalization residence ( F = 5.51, P = .006). Results suggest that the perceived variables related to siblings' psychological changes differ between mothers and other main caregivers. PMID- 30015530 TI - Corneal Manifestations of Systemic Sclerosis. AB - PURPOSE: Corneal involvement in systemic sclerosis (SSc) is rare, but due to rich collagen composition cornea is especially vulnerable to connective tissue diseases. Therefore, our aim was to evaluate corneal parameters of SSc patients. METHODS: The study included 32 SSc patients and 39 control subjects with no ocular symptoms or ocular surface disorders. All study participants underwent Pentacam evaluation and objective signs of dry eye disease (DED), and clinical parameters were evaluated. RESULTS: All pachymetric values, most of the corneal front surface, corneal volume, as well as anterior chamber depth measurements were significantly lower in the SSc group than in the control group (p < 0.05). Significant negative correlation was found between corneal parameters and age on the one hand, and disease duration on the other. CONCLUSIONS: Early recognition of corneal impairment, a possible extraintestinal manifestation of SSc, should be included in the check-up of the disease in order to reduce sight-threatening complications. PMID- 30015531 TI - Combining pharmacy expertise with asthma educator certification: assessing the impact on inner-city asthma patients. AB - OBJECTIVE: Asthma is one of the major causes of hospital readmissions in the South Bronx. The goal of this study was to assess the impact of asthma education provided by registered pharmacists with asthma educator certification (AE-C), on medication adherence and hospitalizations/Emergency Department (ED) visits. METHODS: This was a retrospective chart review of patients seen in the pulmonary clinic from October 2014 to August 2015 for asthma education by AE-C pharmacists. Medical records were reviewed over an 18-month period - 9 months before and after the initial asthma education session. Data obtained included adherence to asthma controller inhalers based on pharmacy refill claims, asthma control using asthma control test (ACT) scores and asthma-related hospitalizations or ED visits within 30 days of asthma education. Pre-education data served as the pre-intervention group data and post-education data served as the post-intervention group data, allowing each patient to serve as their own control. RESULTS: We found a statistically significant improvement in average medication adherence, i.e. asthma controller inhaler fills at pharmacy (46.3% vs 67.9%, p-value <0.001) and asthma control (15.71% vs 56.38%, p-value <0.001) between the pre-intervention and the post-intervention groups. Additionally, a lower hospitalization/ED utilization rate (31.2% vs 6.38%, p-value <0.001) was observed in the post intervention group within 30 days of education. CONCLUSIONS: Asthma education provided by AE-C pharmacists had a positive impact on asthma care in our inner city community. Improving medication adherence and asthma control as well as decreasing hospital utilization could potentially decrease health care costs in addition to improving quality of life. PMID- 30015532 TI - Culture Change in Nursing Homes: What Is the Role of Nursing Home Resources? AB - Quality of care has been a long-standing issue in US nursing homes. The culture change movement attempts to transition nursing homes from health care institutions to person-centered homes. While the adoption of culture change has been spreading across nursing homes, barriers to adoption persist. Nursing homes that disproportionately serve minority residents may have additional challenges implementing culture change compared with other facilities due to limited financial and staffing resources. The objective of this study was to examine how nursing home characteristics are associated with culture change adoption in Central Florida nursing homes. This cross-sectional study included 81 directors of nursing (DONs) who completed the Artifacts of Culture Change survey. In addition, nursing home organizational data were obtained from the Certification and Survey Provider Enhanced Reports (CASPER). A logistic regression was conducted to examine the relationship between high culture change adoption and nursing home characteristics. The overall adoption of culture change scores in Central Florida nursing homes was low. Nevertheless, there was variability across nursing homes in the adoption of culture change. High culture change adoption was associated with nursing homes having lower proportions of Medicaid residents. PMID- 30015534 TI - Impact of a culturally adapted behavioural family psychoeducational programme in patients with schizophrenia in Egypt. AB - OBJECTIVE: To study the effect of a culturally adapted, structured family intervention on symptom severity, medication attitudes and knowledge, social functioning and quality of life in patients with schizophrenia. METHODS: Thirty subjects with schizophrenia were selected to receive 14 sessions of a culturally adapted behavioural family psychoeducational programme (BFPEP). Another 30 subjects received standard treatment as usual (STU) for 6 months. Pre- and post intervention outcomes were assessed using the Positive and Negative Syndrome Scale (PANSS), Drug Attitude Inventory 10-item scale (DAI-10), Quality of Life Scale (QLS) and Social Functioning Questionnaire (SFQ). RESULTS: There was a no significant difference between BFPEP and STU at baseline on all measures. There was a significant difference (p < .05) between pre- and post-treatment scores for BFPEP on all measures, a significant difference (p < .05) between pre- and post treatment scores for STU on all measures (favouring pre-treatment scores) and a significant difference (p < .05) favouring BFPEP over STU on all measures post treatment. CONCLUSIONS: These results demonstrate the feasibility and effectiveness of implementing family therapy psychoeducational interventions in different cultural settings, with relatively minor modifications. This may have implications for mental health policy makers to make available such programmes for patients and mental health professionals. PMID- 30015535 TI - Potential neuroprotective role of astroglial exosomes against smoking-induced oxidative stress and HIV-1 replication in the central nervous system. AB - INTRODUCTION: HIV-1-infected smokers are at risk of oxidative damage to neuronal cells in the central nervous system by both HIV-1 and cigarette smoke. Since neurons have a weak antioxidant defense system, they mostly depend on glial cells, particularly astrocytes, for protection against oxidative damage and neurotoxicity. Astrocytes augment the neuronal antioxidant system by supplying cysteine-containing products for glutathione synthesis, antioxidant enzymes such as SOD and catalase, glucose for antioxidant regeneration via the pentose phosphate pathway, and by recycling of ascorbic acid. Areas covered: The transport of antioxidants and energy substrates from astrocytes to neurons could possibly occur via extracellular nanovesicles called exosomes. This review highlights the neuroprotective potential of exosomes derived from astrocytes against smoking-induced oxidative stress, HIV-1 replication, and subsequent neurotoxicity observed in HIV-1-positive smokers. Expert opinion: During stress conditions, the antioxidants released from astrocytes either via extracellular fluid or exosomes to neurons may not be sufficient to provide neuroprotection. Therefore, we put forward a novel strategy to combat oxidative stress in the central nervous system, using synthetically developed exosomes loaded with antioxidants such as glutathione and the anti-aging protein Klotho. PMID- 30015536 TI - Central Corneal Edema with Scleral-Lens Wear. AB - PURPOSE: To evaluate the safety of scleral-lens designs, we model and clinically assess central corneal edema induced by scleral-lens wear for healthy subjects. MATERIALS AND METHODS: Central corneal swelling during scleral-lens wear is measured using optical coherence tomography (OCT). Transport resistances are modeled for oxygen diffusion through the scleral lens and post-lens tear-film (PoLTF), and into the cornea. Oxygen deficiency in the cornea activates anaerobic metabolic reactions that induce corneal edema. Oxygen permeability, carbon dioxide permeability, settled-lens PoLTF thickness, and scleral-lens thickness are varied in the calculations to mimic different lens fits. RESULTS: Transport modeling predicts that for open eyes, increasing PoLTF thickness from 50 to 400 um increases central corneal swelling by approximately 1-1.5% when oxygen transmissibility (Dk/L) is greater than 10 hBarrer/cm (i.e., hectoBarrer/cm). Although swelling is larger for oxygen Dk/L < 10 hBarrer/cm, PoLTF thickness has minimal impact in this range. For open eye, oxygen transmissibility of the lens plays a significant role in corneal edema, but is negligible when oxygen Dk/L is > 40 hBarrer/cm. For closed eye, central corneal swelling is greater than 5% for an oxygen Dk/L range of 0-100 hBarrer/cm with typical lens-fitting parameters. For carbon-dioxide transmissibilities increasing from 50 to 250 hBarrer/cm and with a fixed oxygen Dk/L of 25 hBarrer/cm, calculated swelling diminishes by an additional 0.5%. Comparison of model calculations to clinical-swelling data is within the error range of the clinical measurements. CONCLUSIONS: Oxygen/metabolite transport calculations for open-eye scleral-lens wear show that typical PoLTF thicknesses fitted by clinicians (i.e., PoLTF thicknesses < 400 um) with modern scleral lenses (i.e., oxygen Dk/L > 25 hBarrer/cm) produce corneal swelling of less than 2% in agreement with experiment. Therefore, scleral lenses prescribed today evoke less than physiological hypoxic swelling (i.e., less than 4%) for healthy corneas during open-eye. Closed-eye wear, however, appears clinically unsafe. PMID- 30015533 TI - Examination of the New Short-Stay Nursing Home Quality Measures: Rehospitalizations, Emergency Department Visits, and Successful Returns to the Community. AB - In 2016, the Centers for Medicare & Medicaid Services (CMS) introduced 3 new quality measures (QMs) to its report card, Nursing Home Compare (NHC). These measures-rehospitalizations, emergency department visits, and successful discharges to the community-focus on short-stay residents. We offer a first analysis of nursing homes' performance in terms of these new measures. We examined their properties and distribution across nursing homes using descriptive statistics and regression models. We found that, similar to other QMs, performance varies across the country, and that there is very minimal correlation between these 3 new QMs as well as between these QMs and other NHC QMs. Regression models reveal that better performance on these QMs tends to be associated with fewer deficiencies, higher staffing and more skilled staffing, nonprofit ownership, and lower proportion of Medicaid residents. Other characteristics are associated with better performance for some but not all 3 QMs. We also found improvement in all 3 QMs in the second year of publication. This study contributes to the validity of these measures by demonstrating their relationship to these structural QMs. It also suggests that these QMs are important by demonstrating their large variation across the country, suggesting substantial room for improvement, and finding that nursing homes are already responding to the incentives created by publication of these QMs. PMID- 30015537 TI - An exploratory study of networks constructed using access data from an electronic health record. AB - Network analysis may be a powerful tool for studying interprofessional practice. Using electronic health record data and social network analysis, the network of healthcare professionals involved in colorectal cancer care at a large, urban academic medical center were mapped and studied. A total of 100 surgical colorectal cancer patients receiving treatment in 2013 and 2014 were selected at random. We used detailed access logs for the EHR to map the network of all healthcare professionals for each patient, including inpatient and outpatient settings. Approximately 2.45 million records of access logs from more than 6,800 unique users, representing over 150 roles or occupations were analyzed. Across all networks, professionals were connected to an average of 5.8 other professionals, but some were rarely connected with others while over 20 were very highly connected (> 100 other professionals). Housestaff, attending physicians, and nurses played central roles in the global network with a high number of inter and intra-professional connections. Clusters of professionals with frequent interaction were demonstrated but, based on the size and complexity of the network, serendipitous interactions were unlikely. Settings for care seemed to influence these clusters. Patient-centric care networks were similar to the global network with some potentially important differences. Access-log information from electronic health records can be an important source of information about relationships between healthcare professionals. Findings from analyses such as this one may help define the state of current networks and potential targets for interventions to improve the quality of care. PMID- 30015538 TI - Delivery of alpha-tocopherol through soluble dietary fibre-based nanofibres for improving the life span of Caenorhabditis elegans. AB - The effect of alpha-tocopherol (alpha-TOC) delivered by soluble dietary fibre based nanofibres (alpha-TOC-SDNF) on the life span of nematode Caenorhabditis elegans N2 (wild type) and TK22 (mev-1 mutants) with and without heat shock was investigated. Without heat shock, the wild-type and mev-1 mutants maintained in the 100 ug/mL of alpha-TOC-SDNF had longer life spans than their respective blank control groups. With heat shock, the wild-type N2 in the 200 ug/mL of alpha-TOC SDNF had a survival rate of 5% at day 49, while no nematodes survived in the blank control group. An increased pharyngeal pumping rate was observed in the alpha-TOC-SDNF treated mev-1 mutants worms compared to the blank control group. Encapsulating alpha-TOC in SDNF yielded protective effects and the life span and pumping rate of C. elegans was increased with alpha-TOC delivered by SDNF. PMID- 30015539 TI - Defending the art of physical therapy: Expanding inquiry and crafting culture in support of therapeutic alliance. AB - The successful practice of physical therapy requires a professional culture that places value on the interpersonal relationships that foster healing, and the face time required to build those relationships. Pressures on current practice are not facilitating this approach. The drive for increased productivity, cost effectiveness and ultimately, profit, are changing the landscape in which we practice. This phenomenon is fueled by an overemphasis on quantitative research in evidence-based medicine and an underappreciation of clinical expertise and patient values. This imbalance undermines the holistic, patient-centered approach that has been the basis for physical therapy since its inception. Authors suggest that in order to preserve defining characteristics of the profession, there is an urgent need to redirect our research agenda and PT education with a focus on the study of contextual and psychosocial factors that influence treatment outcomes. Recent research findings indicate that the effect of therapeutic alliance may be as important to outcomes as the chosen intervention. The authors suggest that excellence in Doctor of Physical Therapy (DPT) education must incorporate education addressing the vital importance of therapeutic alliance and also include training in the skills for developing such unique intentional relationships. PMID- 30015540 TI - Alpha-amylase inhibitors from mycelium of an oyster mushroom. AB - The alpha-Amylase and alpha-glucosidase are two main enzymes involved in carbohydrate metabolism. This study was aimed at detecting alpha-amylase inhibitory activity from edible mushroom mycelia. Oyster mushroom was collected from a natural source, from Indian Institute of Technology (Banaras Hindu University) campus and was maintained in vitro in mycelial form. Chloroform, acetone, methanol, and water were used separately for extraction of an active constituent from mycelial cells grown, for 7 days, in potato dextrose broth. The extracts were tested for alpha-amylase inhibitory activity. Chloroform, acetone, and methanol extracts were found to have alpha-amylase inhibitory activity, with IC50 values of 1.71, 224, and 383 MUg/mL, respectively. Aqueous extract had no enzyme inhibitory activity. The acetone extract inhibited alpha-amylase non competitively whereas chloroform extract showed competitive inhibition. Acetone extraction yielded highest total phenolic content (TPC) of 0.524 mM of gallic acid equivalent, whereas chloroform extraction resulted in lowest TPC of 0.006 mM. The HPLC and absorbance maxima of acetone and chloroform extracts suggest that the bioactive component responsible for enzyme inhibition could be glycoproteins in chloroform extract and catechins (flavonoids) in acetone extract. Thus, the mushroom mycelia under study may be exploited for production and purification of a lead compound for the development of the alpha-amylase inhibitory drug. PMID- 30015541 TI - Conceptualizing patient-reported outcome measures for use within two Danish psychiatric clinical registries: description of an iterative co-creation process between patients and healthcare professionals. AB - BACKGROUND: Denmark has national clinical indicator programs for adult patients diagnosed with depression and schizophrenia, respectively. Within each program, the responsible steering group (SG) decided to add some indicators based upon patient-reported outcome measures (PROMs). AIMS: The primary aim was to describe the process of selecting PROMs and defining a national measurement concept for use in clinical practice and for indicator monitoring and the secondary aim s to collect patient recommendations for implementation. METHODS: An interdisciplinary SG of healthcare professionals and a Patient Peer Board (PPB) representing both patient groups co-created the output in an iterative process. The work included literature search, PPB workshops, SG meetings, ratings of PROM topics and items, and a pilot. The PPB discussed the following: item relevance, mode of data collection, graphical format of the online PROMs, and display of results. Finally, requirements for PROM patient information were identified. Based upon input from the PPB, the SG selected the items and specified the measurement concept. RESULTS: The PPB prioritized 20 of 53 suitable items and suggested alternative wording and answer categories. A pilot was performed and 19 items covering well-being, lack of well-being, impairment of functioning, and overall health were selected for clinical testing. The patients recommended concrete, unambiguous, easily understandable information and procedures for data collection and display of results. CONCLUSIONS: The iterative co-creation process based upon a high degree of patient involvement resulted in a set of PROMs, a national measurement concept, and patient recommendations for implementation. The cooperation between patients and professionals was successful. PMID- 30015542 TI - Hippotherapy in adults with acquired brain injury: A systematic review. AB - BACKGROUND: Hippotherapy is used to supplement conventional therapy in neurological conditions with evidence supporting its use in pediatric patients. However, evaluation of its merit in adults with acquired brain injury (ABI) is lacking. The aim of this study was to determine if hippotherapy can improve motor function in adults with ABI. METHODS: A systematic review of all available controlled studies investigating the use of hippotherapy, in adults with ABI, was conducted. The primary outcome of interest was movement related function and secondary outcomes included impairment, quality of life, and adverse events. RESULTS: Nine studies with 256 participants were included, of which six studies with 204 participants were included for meta-analysis. When the data were pooled, hippotherapy did not produce statistically significant improvements in balance (SMD = 0.24, 95% CI -0.05, 0.54, p = 0.1) or gait parameters (SMD = -0.04, 95% CI -0.79, 0.72 p = 0.92) when compared to control and measured immediately after the intervention. Long-term effects remain unknown due to lack of follow-up evaluation. CONCLUSIONS: This review suggests that hippotherapy is safe and well tolerated by adults with ABI. Short-term functional benefits were not associated with the use of hippotherapy. Further high-quality research is required before hippotherapy can be endorsed as a modality in adult neurological rehabilitation. PMID- 30015543 TI - Short-term perspectives of parents and teachers on school reintegration of childhood brain tumour survivors. AB - OBJECTIVE: To discover short-term changes in perspectives of parents and teachers of childhood brain tumour survivors on school reintegration, in order to reveal similarities and differences between them over time. METHODS: Semi-structured interviews were conducted with parents and teachers of five children at the start and the end of a 1-year period following the child's school re-entry. RESULTS: Thematic analysis of data resulted in three main themes: 'the child's performance and wellbeing', 'the school's attitude and approach' and 'communication and working together'. Parental concerns about child-specific changes and the school's approach to the child could either decrease or increase over time. Teachers remained focused on assessing their pupil's learning potential and finding ways of appropriate support. Their different perspectives on communication and working together became more pronounced. CONCLUSIONS: This study emphasizes the importance of clear communication and collaboration, coordinated follow-up and availability of healthcare professionals during the child's school reintegration. PMID- 30015544 TI - Feasibility and Efficacy of Bright Light Therapy in Depressed Adolescent Inpatients. AB - OBJECTIVE: Bright light therapy (BLT) has recently come into increasing focus in the treatment of adolescent depression, whereby light glasses today appear to be more feasible than light therapy boxes. This study investigated the feasibility and efficacy of 4 weeks of BLT with light glasses. It also analyzed whether a treatment duration of 4 weeks of BLT yields larger effects than the 2 weeks of BLT investigated in previous studies. METHODS: This first open-label, single-arm, prospective clinical trial pursued a naturalistic approach: 39 inpatients aged 12 18 years with moderate or severe depression received 4 weeks of morning BLT with light glasses in addition to usual treatment. Depressive symptoms, sleep problems, circadian phase, and the clinical global impression were assessed at several timepoints. In a second analysis, the data of the present study were compared to those from a previous pilot trial. RESULTS: Depressive symptoms, sleep problems, and the global clinical impression improved significantly after BLT with light glasses, whereas the circadian phase did not change over time. Light glasses showed similarly positive effects on sleep parameters and depressive symptoms as light boxes. Contrary to expectation, prolonging BLT to 4 weeks did not yield larger effects on depressive symptoms and sleep complaints compared to 2 weeks of intervention. CONCLUSIONS: Light glasses seem to be a feasible and highly acceptable method for the treatment of adolescent depression. Further randomized controlled trials are needed to obtain sufficient evidence regarding the efficacy of BLT as an add-on intervention to psychological and pharmacological approaches for adolescent depression. PMID- 30015545 TI - Promoting well-being in psychosis. AB - BACKGROUND: Traditionally, treatment of psychosis has focused on the amelioration of psychopathology and return to adequate functioning: clinical recovery although there is growing recognition of the importance of subjective experiences associated with recovery: personal recovery. Positive psychiatry extends the focus of psychiatric treatment to go beyond the reduction of psychiatric symptoms and and improvement of functional disability to promote the attainment of well being. AIM: This article examined the conceptualization of well-being from the context of treatment for psychosis, its relationship with clinical recovery and highlighted some of challenges and implications for mental health services in promoting well-being. DISCUSSION: Recovery from psychosis is a complex and individual process, where well-being is more than just the absence of mental illness. Clinical and personal recovery processes may contribute to well-being although further longitudinal studies are required. A recent framework for understanding well-being in psychosis helps address the lack of consensus in this field. There is a considerable overlap between the indicators of well-being in this model and the CHIME framework for personal recovery. Thus, interventions targeting personal recovery processes may be a potential way to promote well being. Current mental health services face a considerable challenge if they are to fulfill the dual role of reducing psychopathology and/or disability whilst concurrently addressing personal recovery to promote well-being. The attainment of well-being may not only be a desirable treatment goal in recovery-orientated mental health services but also a potential protective factor against serious mental illness. PMID- 30015546 TI - The immediate and 1-week effects of mid-thoracic thrust manipulation on lower extremity passive range of motion. AB - BACKGROUND: Research suggests that spinal manipulation may effect motion. Less clear is whether this effect is limited to localized responses or may involve generalizable changes. OBJECTIVE: To determine whether Mid-thoracic manipulation (MTM) would result in a significant change in the lower extremity passive straight leg raise (PSLR) range of motion immediately and after 1 week. METHODS: Twenty-three healthy subjects were randomly assigned in a double-blinded study. An experimental group received MTM and a control group received a sham intervention. PSLR measurements were taken prior to, immediately after, and one week after the intervention. RESULTS: Mixed model repeated measure analysis of variance was used to determine that there was a significant interaction between MTM and time (F(2, 21) = 3.84, p < 0.05). Post hoc tests revealed a significant difference between the pretest to immediate posttest values (p < 0.05, SE = 1.47). PSLR in the MTM group increased 10.3 degrees while the sham group increased 1.9 degrees . Difference was non-significant between pretest and 1-week follow-up (p = 0.129, SE = 2.46). CONCLUSIONS: MTM may immediately increase lower extremity passive range of motion, but the effect was lost by the 1-week follow up. This supports evolving research suggesting that spinal manipulation may have a generalized but transient physiological effect. PMID- 30015547 TI - Lung management protocols increase the incidence of lung procurement and organ transplantation: A meta-analysis. AB - BACKGROUND: Improved donor management, including respiratory physiotherapy, may optimize donor suitability and increase successful lung procurement. This review aimed to determine the efficacy of lung management protocols on the incidence of successful lung procurement and transplantation. METHODS: Searches were completed in MEDLINE, CINAHL, EMBASE, PubMed, PEDRO, and Cochrane Registry of Controlled Clinical Trials, from database inception to March 2018. Randomized controlled trials and observational studies, with a control or comparison group, of humans, published in English, in peer-reviewed journals were included. Any respiratory management was eligible. Two investigators assessed eligibility and study quality. Meta-analysis and narrative analysis were completed. RESULTS: Ten of 430 articles identified were eligible for inclusion. Implementation of protocols in potential donors increased the incidence of lung procurement, odds ratio (OR), 95% CI: 3.42 (2.48, 4.71) and transplantation procedures OR 2.56 (1.41, 4.62) compared to control groups. Recipient survival was significantly higher, in favor of lung management protocols compared to control groups at 30 days (OR 2.37 (1.14, 4.95)) and 1 year (OR 1.82 (1.02, 3.27)). Pooling of randomized controlled trials was not possible due to heterogeneity between interventions. No studies reported adverse events associated with lung management protocols or the incidence of ventilator-associated pneumonia. Despite differences in intervention design and study quality, observational studies reported consistent direction and magnitude of effects in favor of protocolized interventions. CONCLUSIONS: Lung management protocols appear to increase transplantation success. High-quality randomized trials are warranted to test observed effects and ascertain the effects of specific protocol components on transplantation outcomes. PMID- 30015548 TI - The value of remembered pre-operative quick disabilities of the arm, shoulder and hand (QuickDASH) scores. AB - It would be useful if it were possible for the patients to recreate their pre operative QuickDASH scores in audits where this score had not been recorded before surgery. We assessed the accuracy of remembered pre-operative QuickDASH scores among 229 consecutive patients and the value of a previously developed algorithm for correcting these scores. Real pre-operative scores and remembered pre-operative scores were compared after a mean of 21 months. Furthermore, the scores of a subgroup of 79 patients with carpal tunnel syndrome, subacromial impingement, thumb basal joint arthrosis or Dupuytren's contracture were corrected using an algorithm. The mean difference between remembered and real pre operative scores for all patients showed heteroscedacity in the Bland-Altman plot. The scores of the 79 sub-analysis patients were homoscedastic. The mean difference between remembered and real pre-operative scores was 9 (SD 16, SEM 1.85). Correcting the scores of the sub-group patients using our algorithm decreased the variation only moderately. The remembered pre-operative score is too inaccurate to be useful in individual patients, also when using our algorithm. However, subtracting nine from the mean remembered pre-operative score in a group of patients with any of the above diagnoses gives the real pre operative score within the 95% confidence interval of four above and four below the real score. PMID- 30015550 TI - A prospective randomized controlled study of Li quick repositioning maneuver for geotropic horizontal canal BPPV. AB - BACKGROUND: Li quick repositioning maneuver for treatment of geotropic horizontal canal benign paroxysmal positional vertigo (HC-BPPV) was reported in the literature. OBJECTIVE: The aim of this study is to observe the clinical efficacy of the Li quick repositioning maneuver for the treatment of geotropic HC-BPPV. METHODS: The single-blind method was used to conduct a prospective controlled study on 120 patients with geotropic HC-BPPV from May 2014 to May 2017. Patients were randomly assigned to the Li quick repositioning maneuver (Li maneuver) group or the barbecue repositioning maneuver (barbecue maneuver) group. RESULTS: The successful repositioning rates were 53.3%, 70.4%, 90.7% and 92.3%, respectively, in barbecue maneuver group and 61.7%, 80.7%, 93.0% and 96.3%, respectively, in Li maneuver group at 1-day, 3-day, 1-week and 1-month follow-up. Differences in success rates of repositioning between Li and barbecue maneuver groups at 1 day, 3 days, 1 week and 1 month after initial treatment were not statistically significant using the Kaplan-Meier survival curve with a log-rank test (p = .270) . CONCLUSION: The Li maneuver is a rapid, simple and efficacious repositioning method for geotropic HC-BPPV and can be widely applied in clinical practice as an alternative method. PMID- 30015551 TI - Is Man the Measure of All Things? A Social Cognitive Account of Androcentrism. AB - Androcentrism refers to the propensity to center society around men and men's needs, priorities, and values and to relegate women to the periphery. Androcentrism also positions men as the gender-neutral standard while marking women as gender-specific. Examples of androcentrism include the use of male terms (e.g., he), images, and research participants to represent everyone. Androcentrism has been shown to have serious consequences. For example, women's health has been adversely affected by over-generalized medical research based solely on male participants. Nonetheless, relatively little is known about androcentrism's proximate psychological causes. In the present review, we propose a social cognitive perspective arguing that both social power and categorization processes are integral to understanding androcentrism. We present and evaluate three possible pathways to androcentrism deriving from (a) men being more frequently instantiated than women, (b) masculinity being more "ideal" than femininity, and/or PMID- 30015549 TI - Clinical characteristics of sepsis-induced acute kidney injury in patients undergoing continuous renal replacement therapy. AB - OBJECTIVE: The aim of this study was to investigate the clinical characteristics of sepsis-induced acute kidney injury (AKI) in patients undergoing continuous renal replacement therapy (CRRT). METHODS: From 2011 to 2015, we enrolled 340 patients who were treated with CRRT for sepsis at the Presbyterian Medical Center. In all patients, CRRT was performed using the PRISMA platform. We divided these patients into two groups (survivors and non-survivors) according to the 28 day all-cause mortality. We compared clinical characteristics and analyzed the predictors of mortality. RESULTS: The 28-day all-cause mortality was 62%. Survivors were younger than non-survivors and had higher platelet counts (178 +/- 101 * 103/mL vs. 134 +/- 84 * 103/mL, p < .01) and serum creatinine levels (4.2 +/- 2.8 vs. 3.3 +/- 2.7, p < .01). However, survivors had lower red blood cell distribution width (RDW) scores (14.9 +/- 2.1 vs. 16.1 +/- 3.3, p < .01) and APACHE II scores (24.5 +/- 5.8 vs. 26.9 +/- 5.7, p < .01) than non-survivors. Furthermore, survivors were more likely than non-survivors to have a urine output of >0.05 mL/kg/h (66% vs. 86%, p = .001) in the first day. In a multivariate logistic regression analysis, age, platelet count, RDW score, APACHE II score, serum creatinine level, and a urine output of <0.05 mL/kg/h the first day were prognostic factors for the 28-day all-cause mortality. CONCLUSION: Age, platelet count, APACHE II score, RDW score, serum creatinine level, and urine output the first day are useful predictors for the 28-day all-cause mortality in sepsis patients requiring CRRT. PMID- 30015553 TI - Postoperative infections following cochlear implant surgery. AB - INTRODUCTION: The aim of this study was to report the frequency and management of postoperative wound infections and to investigate bacteriology and biofilm formation following 653 consecutive cochlear implantations in adults. METHODS: A retrospective file review of 653 consecutive adult cochlear implantations between 1994 and 2015 at the Department of Otorhinolaryngology at Odense University Hospital. A reporting consensus was used to classify infections. RESULTS: The major and minor infection rates were 2% and 8%, respectively. The explantation rate due to infection was 1%. The most common pathogen found was Staphylococcus aureus and biofilm formation was found in 73% of the explantations. CONCLUSION: Postoperative infection occurred in 10% of the implantations. However, few of these were severe. Staphylococcus aureus was the most common pathogen and the presence of biofilm seemed to be associated with a higher risk of explantation. PMID- 30015552 TI - Assessing the validity of proxy caregiver reporting for potential palliative care outcome measures in Parkinson's disease. AB - BACKGROUND: There is increasing interest in applying palliative care approaches for patients with Parkinson's disease. Methodological studies are needed to validate palliative care outcome measures for Parkinson's disease to build this evidence base. As many patients with Parkinson's disease have cognitive and/or communication issues, proxy outcome measures may improve the inclusivity and relevance of research. AIM: To assess the validity of proxy caregiver reports for several potential palliative care outcome measures. DESIGN: A cross-sectional study of Parkinson's disease patients and caregivers completed a battery of outcome measures relevant to palliative care including the Memorial Symptom Assessment Scale, Hospital Anxiety and Depression Scale, Prolonged Grief Questionnaire 12, Parkinson Disease Questionnaire 39, Functional Assessment of Chronic Illness Therapy-Spiritual Wellbeing, and Schwab and England. Intraclass correlation coefficients were used to assess agreement. SETTING/PARTICIPANTS: A total of 50 Parkinson's disease patient and caregiver dyads recruited at an academic medical center, Veterans Affairs Medical Center, and community support groups. RESULTS: There was moderate to good agreement for Schwab and England, Parkinson Disease Questionnaire 39 total, and majority of Parkinson Disease Questionnaire 39 subscales; moderate to good agreement for the Hospital Anxiety and Depression Scale, Functional Assessment of Chronic Illness Therapy-Spiritual Wellbeing, Prolonged Grief Questionnaire 12, and Memorial Symptom Assessment Scale; and poor to moderate agreement for the Parkinson Disease Questionnaire 39 stigma, social support, and bodily pain subscales. Caregivers tended to attribute higher symptom severity than patients. We did not detect differences in intraclass correlation coefficient based on cognitive status but patients with advanced illness had significantly lower intraclass correlation coefficients for several outcomes. CONCLUSIONS: Caution is indicated when considering caregiver proxy reporting for most outcomes assessed, particularly in Parkinson's disease patients with advanced disease. PMID- 30015554 TI - Bilateral upper limb rehabilitation with videogame-based feedback in corticobasal degeneration: a case reports study. AB - Corticobasal degeneration (CBD) is a neurodegenerative disorder characterized by a combination of cortical and basal ganglia signs. We reported two cases treated with a bilateral upper limb rehabilitation tool with videogame based feedback for 3 time per week for 8 weeks. Both patients showed an improvement of pinch and grasp forces and motor function. However, both of them reported an increased upper limb pain. Bilateral upper limb mechanical device with exergame feedback was effective also in the two patients suffering of CBD for limiting the effects of apraxia by performing intensive purposeful task training. PMID- 30015556 TI - Investigation of hallmarks of carbonyl stress and formation of end products in feline chronic kidney disease as markers of uraemic toxins. AB - Objectives Cats are commonly affected by chronic kidney disease (CKD). Many reactive carbonyl intermediates and end products originating from the oxidative stress pathways are recognised as uraemic toxins and may play a role in CKD progression. The aim of the present study is to confirm whether carbonyl end product formation is higher in cats affected by CKD and to assess whether an angiotensin-converting enzyme inhibitor (ACEi) might affect these hallmarks. Methods Twenty-two cats were divided into three groups: a control group (CG), cats with chronic kidney disease (CKD) and cats with chronic kidney disease treated with an ACEi. Serum levels of pentosidine, carboxymethyllysine, advanced oxidation protein products, malondialdehyde, methylglyoxal and hexanoyl-lysine were measured. In addition, biochemical parameters and systolic blood pressure were evaluated. After checking for normality, comparisons between groups were performed followed by multiple comparison tests. P values ?0.05 were considered significant. Correlations between concentrations of the considered biomarkers and of the other metabolic parameters were investigated. Results Advanced oxidation protein products, malondialdehyde and hexanoyl-lysine concentrations were significantly higher in CKD and ACEi-treated groups compared with the CG ( P <0.05). Carboxymethyllysine increased in the ACEi-treated group when compared with the CG, whereas intermediate values of these biomarkers were found in the CKD group ( P <0.05). The ACEi-treated group showed the highest values of carboxymethyllysine, advanced oxidation protein products and hexanoyl-lysine. By contrast, the CKD group had the highest concentration of malondialdehyde. No statistically significant difference was found in the levels of pentosidine or methylglyoxal. End products correlated with creatinine and urea and with each other. Conclusions and relevance Significantly high concentrations of both intermediate and end products of carbonyl/oxidative stress were detected in CKD cats. This is the first study to have concurrently taken into account several uraemic toxins and biochemical parameters in cats affected by CKD. PMID- 30015557 TI - Metabolic engineering of Escherichia coli W3110 strain by incorporating genome level modifications and synthetic plasmid modules to enhance L-Dopa production from glycerol. AB - L-Tyrosine which is one of the terminal metabolites of highly regulated aromatic amino-acid biosynthesis pathway in Escherichia coli is a precursor for synthesis of L-Dopa. In this study, we report over production of L-Dopa by enhancing expression of rate limiting isoenzyme of shikimate kinase (aroL), chorismate synthase (aroC), aromatic-amino-acid aminotransferase (tyrB) and 3 phosphoshikimate 1-carboxyvinyltransferase (aroA) form a plasmid module harboring five enzymes under two inducible promoters converting shikimate to tyrosine. 4 hydroxyphenylacetate-3-hydrolase (hpaBC) which converts L-Tyrosine to L-Dopa was expressed constitutively from a separate plasmid module. Feedback deregulated expression of 3-Deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) synthase (aroG*) replacing wild type aroG under its natural promoter led to enhancement of L-Dopa production. Deletion of transcriptional repressor tyrR and links to other competing pathways improved titers of L-Dopa. We focused on having a balanced flux by constitutive expression of pathway enzymes from plasmid constructs rather than achieving higher amounts of catalytic protein by induction. We observed glycerol when used as a carbon source for the final strain led to low acid production. The best performing strain led to decoupling of acid production and product formation in bioreactor. Fed batch analysis of the final strain led to 12.5 g/L of L-Dopa produced in bioreactor. PMID- 30015558 TI - Absence of measurement is not evidence of absence. PMID- 30015560 TI - Role of glycosylation in hypoxia-driven cell migration and invasion. AB - Hypoxia, a common condition of the tumor microenvironment, induces changes in the proteome of cancer cells, mainly via HIF-1, a transcription factor conformed by a constitutively expressed beta-subunit and an oxygen-regulated alpha-subunit. In hypoxia, HIF-1alpha stabilizes, forms the heterodimeric complex with HIF-1beta, and binds to Hypoxia Response Elements (HRE), activating gene expression to promote metabolic adaptation, cell invasion and metastasis. Furthermore, the focal adhesion kinase, FAK, is activated in hypoxia, promoting cell migration by mechanisms that remain unclear. In this context, integrins, which are glycoproteins required for cell migration, are possibly involved in hypoxia induced FAK activation. Evidence suggests that cancer cells have an altered glycosylation metabolism, mostly by the expression of glycosyltransferases, however the relevance of glycosylation is poorly explored in the context of hypoxia. Here, we discuss the role of hypoxia in cancer, and its effects on protein glycosylation, with emphasis on integrins and cell migration. PMID- 30015555 TI - bantam microRNA is a negative regulator of the Drosophila decapentaplegic pathway. AB - Decapentaplegic (Dpp), the Drosophila homolog of the vertebrate bone morphogenetic protein (BMP2/4), is crucial for patterning and growth in many developmental contexts. The Dpp pathway is regulated at many different levels to exquisitely control its activity. We show that bantam (ban), a microRNA, modulates Dpp signaling activity. Over expression of ban decreases phosphorylated Mothers against decapentaplegic (Mad) levels and negatively affects Dpp pathway transcriptional target genes, while null mutant clones of ban upregulate the pathway. We provide evidence that dpp upregulates ban in the wing imaginal disc, and attenuation of Dpp signaling results in a reduction of ban expression, showing that they function in a feedback loop. Furthermore, we show that this feedback loop is important for maintaining anterior-posterior compartment boundary stability in the wing disc through regulation of optomotor blind (omb), a known target of the pathway. Our results support a model that ban functions with dpp in a negative feedback loop. PMID- 30015561 TI - Purification and kinetics of a protease-resistant, neutral, and thermostable phytase from Bacillus subtilis subsp. subtilis JJBS250 ameliorating food nutrition. AB - A novel protease-resistant and thermostable phytase from Bacillus subtilis subsp. subtilis JJBS250 was purified 36-fold to homogeneity with a combination of ammonium sulfate precipitation followed by Q-Sepharose and Sephadex G-50 chromatographic techniques. The estimated molecular mass of the purified phytase was 46 kDa by electrophoresis with optimal activity at pH 7.0 and 70 degrees C. About 19% of original activity was maintained at 80 degrees C for 10 min. Phytase activity was stimulated in presence of surfactants like Tween-20, Tween 80, and Triton X-100 and metal ions like Ca+2, K+, and Co+2 and it was inhibited by SDS and Mg+2, Al+2, and Fe+2. Purified enzyme showed specificity to different salts of phytic acid and values of Km and Vmax were 0.293 mM and 11.49 nmoles s 1, respectively for sodium phytate. The purified enzyme was resistant to proteases (trypsin and pepsin) that resulted in amelioration of food nutrition with simultaneous release of inorganic phosphate, reducing sugars, and soluble protein. PMID- 30015563 TI - Passive stretching-induced changes detected during voluntary muscle contractions. AB - Stretching exercises are known for reduction of musculoskeletal stiffness and elongation of electromechanical delay (EMD). However, computing a change in stiffness by means of time delays, detected between onset of electromyographic (EMG), mechanomyographic (MMG) and force signals, can reveal changes in subcomponents (Deltat EMG-MMG and Deltat MMG-FORCE) of EMD after stretching. In our study, the effect of stretching was investigated while quadriceps femoris (QF) muscle performed isometric contractions. The EMG, MMG, and Force signals were recorded from rectus femoris (RF) and vastus medialis (VM) during five voluntarily isometric contractions at 15 degrees , 30 degrees , and 45 degrees of knee flexion angle, while the leg was positioned on a custom-made device. Subjects in both intervention and control groups underwent same recording procedure before and after stretching. No difference between the baseline repeated contractions (before stretching) was ensured by ANOVA for repeated measures while a difference between PRE and POST was analyzed and concluded based on the effect size results. The EMD did not change; however, subcomponents (Deltat EMG-MMG and Deltat MMG-FORCE) showed differences within RF and VM muscles after stretching. The 30 degrees knee flexion angle appears to be a position where isometric contraction intensity needs to be carefully monitored during rehabilitation period. PMID- 30015564 TI - Chitin and chitosan biopolymer production from the Iranian medicinal fungus Ganoderma lucidum: Optimization and characterization. AB - Chitin and chitosan with unique properties and numerous applications can be produced from fungus. The production of chitin and chitosan from the mycelia of an Iranian Ganoderma lucidum was studied to improve cell growth and chitin productivity. Inoculum size and initial pH as two effective variables on the growth of G. lucidum and chitin production were optimized using response surface method (RSM) by central composite design (CCD). The results verified the significant effect of these two variables on the cell growth and chitin production. In optimum conditions, including pH = 5.7 and inoculum size of 7.4%, the cell dry weight was 5.91 g/L and the amount of chitin production was 1.08 g/L with the productivity of 0.083 g/(L day). The produced chitin and chitosan were characterized using XRD and FTIR. Moreover, the antibacterial activity of the produced chitosan was investigated and compared with the commercial chitosan. The results showed that the produced chitin and chitosan had suitable quality and the Iranian G. lucidum would be a great source for safe and high-quality chitin and chitosan production. PMID- 30015565 TI - Characterization of cotton fabric nanocomposites with in situ generated copper nanoparticles for antimicrobial applications. AB - In the present study, cotton fabric nanocomposites with in situ generated copper nanoparticles (CuNPs) were prepared using Cassia alata leaf extract as reducing agent. The prepared cotton fabric nanocomposites were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscoy (SEM) techniques. The cotton fabric nanocomposites exhibited significant antibacterial activity against Escherichia coli bacteria. These nanocomposites retained the antibacterial activity even after 15 washes indicating the generation of permanent CuNPs in them. The antibacterial activity of the nanocomposites prepared even in sewerage water was also studied. The obtained results suggest that the cotton fabric nanocomposites with in situ generated CuNPs can be considered for medical and water treatment applications. PMID- 30015562 TI - T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response. AB - The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, speed and capacity have been achieved but vaccine effectiveness remains a significant challenge. Here, we describe a novel vaccine design strategy called immune engineering in the context of H7N9 influenza vaccine development. The approach combines immunoinformatic and structure modeling methods to promote protective antibody responses against H7N9 hemagglutinin (HA) by engineering whole antigens to carry seasonal influenza HA memory CD4+ T cell epitopes - without perturbing native antigen structure - by galvanizing HA-specific memory helper T cells that support sustained antibody development against the native target HA. The premise for this vaccine concept rests on (i) the significance of CD4+ T cell memory to influenza immunity, (ii) the essential role CD4+ T cells play in development of neutralizing antibodies, (iii) linked specificity of HA-derived CD4+ T cell epitopes to antibody responses, (iv) the structural plasticity of HA and (v) an illustration of improved antibody response to a prototype engineered recombinant H7-HA vaccine. Immune engineering can be applied to development of vaccines against pandemic concerns, including avian influenza, as well as other difficult targets. PMID- 30015566 TI - Magnetic molecularly imprinted polymer prepared by microwave heating for confirmatory determination of chloramphenicol in chicken feed using high performance liquid chromatography-tandem mass spectrometry. AB - A magnetic molecularly imprinted polymer (MMIP) for chloramphenicol was prepared using a surface-imprinted and microwave-heating-induced polymerization method. The surfaces of the magnetic particles were first double-bond functionalized with 3-(trimethoxysilyl)propyl methacrylate (gamma-MPS), followed by the copolymerization of 4-vinyl pyridine (4-VP) and trimethylolpropane trimethacrylate (TRIM) in the presence of chloramphenicol as a template and 1,1 azobis(cyclohexane-carbonitrile) (ABCN) as an initiator in a mixture of dimethyl sulfoxide and water with microwave heating at 80 degrees C. The magnetic polymer possesses supraparamagnetic properties and was used to concentrate and cleanup chicken feed extract, followed by chromatographic separation using a Lichrospher(r)100 RP C8 column and detection with two multi-reaction monitoring transitions at m/z 321-> 152 and m/z 321-> 257. The mean recoveries obtained at two spiking levels were in the range of 94.6-100% The relative intra- and inter day standard deviations were in the range of 1.4-2.6% and 5.1-5.7%, respectively. The detection limit of the method was 0.12 ug kg-1. This confirmatory method was successfully applied to determine chloramphenicol in chicken feed samples. PMID- 30015567 TI - Where the Mind Cannot Dare: A Case of Addictive Use of Online Pornography and Its Relationship With Childhood Trauma. AB - Dysfunctional use of cybersex has often been conceptualized as a "behavioral addiction" sharing common traits with substance addiction. We describe the case of a treatment-seeking man, who displayed addictive use of pornography. The case is presented from two perspectives: (1) a symptom-based approach inspired by the addiction model of excessive sexual behaviors and (2) a process-based approach aimed to identify the psychological processes and risk factors that may foster the development of addiction-like symptoms. This article shows how case conceptualization according to a process-based approach is likely to result in psychological intervention that targets the specific processes and risk factors involved in addictive cybersex use. PMID- 30015568 TI - Further validation of the Traumatic Grief Inventory-Self Report (TGI-SR): A measure of persistent complex bereavement disorder and prolonged grief disorder. AB - The Traumatic Grief Inventory Self-Report version (TGI-SR) is an 18-item self report measure. It was designed to assess symptoms of Persistent Complex Bereavement Disorder (PCBD) included in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and Prolonged Grief Disorder (PGD) proposed by an international group of experts in grief. The research in this article used data from a bereaved patient sample and people who lost loved ones in the Ukrainian airplane crash in July 2014. Findings indicated that the TGI-SR is a reliable and valid tool to assess disturbed grief in research and to identify people needing a more comprehensive assessment of their grief in clinical settings. PMID- 30015569 TI - Performance evaluation of treating oil-containing restaurant wastewater in microbial fuel cell using in situ graphene/polyaniline modified titanium oxide anode. AB - Most studies conducted nowadays to boost electrode performance in microbial fuel cell (MFC) have focused on carbonaceous materials. The titanium suboxides (Ti4O7, TS) are able to provide a new alternative for achieving better performance in MFC and have been tested and demonstrated in this study. The Ti4O7 electrode with high electrochemical activity was modified by graphene/polyaniline by the constant potential method. Electrogenic microorganisms were more conducive to adhere to the anode electrode due to the presence of graphene/polyaniline. The MFC reactor with polyaniline /graphene modified TS (TSGP) anode achieves the highest voltage with 980 mV, and produces a peak power density of 2073 mW/m2, which is 2.9 and 12.7 times of those with the carbon cloth anode, respectively, at the 1000 Omega external resistance. In addition, this study evaluates the effects of anolyte conductivity, pH, and COD on the treatment of oil-containing restaurant wastewater (OCRW) in MFC using TSGP anode. The OCRW amended with 120 mS/cm obtains the lowest internal resistance (160.3 Omega). Increasing the anodic pH, gradually from acidic (pH 5.5) to alkaline conditions (pH 8.0), resulted in a gradual increase in maximum power density to 576.4 mW/m2 and a decrease in internal cell resistance to 203.7 Omega. The MFC at the COD 1500 mg/L could obtain steady-state output voltage during 103 h while removing up to 65.2% of the COD of the OCRW. PMID- 30015570 TI - Pro-poor governance in water and sanitation service delivery: evidence from Global Analysis and Assessment of Sanitation and Drinking Water surveys. AB - AIMS: The Sustainable Development Goal (SDG) for water and sanitation seeks to achieve universal and equitable access to safe and affordable drinking water and access to adequate and equitable sanitation and hygiene. This article examines what governments are doing to achieve this, paying particular attention to actions that governments report taking to better serve the poor and other vulnerable populations (i.e. pro-poor governance). This article also assesses the extent to which, and how, UN-Water's Global Analysis and Assessment of Sanitation and Drinking Water (GLAAS) has tracked governments' efforts to reach the poor since the inception of this global monitoring effort. METHOD: This article employs qualitative document analysis and iterative coding to identify pro-poor governance themes examined in GLAAS reports from 2008 to 2016 and provides a quantitative summary of findings related to pro-poor governance from the most recent GLAAS surveys. RESULTS: The dimensions of pro-poor governance and number of questions related to pro-poor governance in GLAAS surveys have increased from 2008 to 2016. While the majority of countries report taking actions to promote equity, many countries did not provide information about specific actions they were taking to provide better services to the poor. Moreover, several actions countries reported taking (e.g. implementing an increasing block tariff) are likely to be ineffective. CONCLUSION: The findings of this study raise concerns about the extent to which governments are taking - or are positioned to take - effective action to meet the SDG aspiration of safe and affordable water and sanitation services for all. Without information on what countries are doing to promote equity, policy makers and researchers are unable to discern which policies are effective in different contexts. PMID- 30015571 TI - Metabolite identification of ibuprofen biodegradation by Patulibacter medicamentivorans under aerobic conditions. AB - Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug that is becoming increasingly recognized as an important micropollutant to be monitored in wastewater treatment plants (WWTP), since it has been detected in effluents at the ug L-1 level. The IBU metabolites from biological degradation are not completely understood and can represent a threat to natural aquatic systems. P. medicamentivorans was previously isolated from WWTP sludge and found to be capable of IBU degradation. The aerobic biodegradation of ibuprofen by this organism was investigated in a batch lab-scale reactor for the identification of the metabolites formed. The metabolites were analysed and putatively identified by HPLC-DAD-MS/MS and GC-MS and biodegradation pathways were proposed. The toxicity and the biodegradability potential of the metabolites were also investigated. The results showed that IBU biotransformation was achieved by hydroxylation followed by the formation of a carboxylic acid in the IBU molecule and by the formation of a catechol, allowing the aromatic ring cleavage. Two biodegradation pathways were proposed: in one, the metabolites generated from the enzymatic action correspond to a less biodegradable chemical structure of the intermediate products (isobutylbenzene and 3-isobutylphenol), with comparatively higher toxicity; in the other mechanism, more oxidable chemical structures were formed with less toxicity and higher biodegradability. This suggests that the biodegradation of IBU by P. medicamentivorans can take place by more than one mechanism regarding the enzymes formed by this Gram-positive bacterium, with subsequent oxidation of the parent compound to overall more soluble and less toxic compounds to fish, daphnia and green algae. PMID- 30015572 TI - Immunology and efficacy of MF59-adjuvanted vaccines. AB - Adjuvants are included in vaccine formulations to enhance the immunogenicity and efficacy of vaccines. MF59(r) is an oil-in-water emulsion adjuvant and licensed for use in pandemic and seasonal influenza vaccines in many countries. MF59 is safe and well tolerated in humans. MF59-adjuvanted vaccination spares vaccine dose and enhances hemagglutination inhibiting antibodies against homologous and heterologous influenza virus strains. The mechanisms of MF59 involve rapid induction of chemokines, inflammatory cytokines, recruiting multiple immune cells, uric acid and benign apoptosis of certain innate immune cells. The adjuvant effects of MF59 on generating vaccine-specific isotype-switched IgG antibodies, effector CD8 T cells, and protective immunity were retained even in a CD4-deficient condition by inducing effective immune-competent microenvironment with various innate and antigen presenting cells in a mouse model. CD4 independent adjuvant effects of MF59 might contribute to improving the vaccine efficacy in children, the elderly, and immunocompromised patients as well as in healthy adults. Further studies will be needed to broaden the use of MF59 in various vaccine antigens and populations as well as lead to better understanding of the action mechanisms of MF59 adjuvant. PMID- 30015573 TI - Social support, negative social exchange, and response to case formulation-based cognitive behavior therapy. AB - We investigated associations between pretreatment social support, negative social exchange, and slope of weekly symptom change for depression, anxiety, and stress over the course of ideographic, case formulation-based, cognitive behavior therapy. Participants were 74 adults treated in a private practice setting. We used self-report measures to assess social support and negative social exchange at intake and to assess symptoms on a weekly basis. At pretreatment, a higher level of social support was associated with lower levels of depression, and a higher level of negative social exchanges was associated with higher levels of depression and stress. Pretreatment social support was not significantly associated with slope of symptom change. However, a higher level of pretreatment negative social exchanges was associated with steeper slope of change in symptoms of depression and stress during treatment. These findings suggest that the association between pretreatment negative social exchanges and subsequent symptoms may be stronger than that of social support and subsequent symptoms. Additionally, we discuss the possibility that having data on negative social exchanges at the start of treatment may benefit the outcome of ideographic, case formulation-based, cognitive behavior therapy. PMID- 30015574 TI - Perceived challenges in pediatric palliative care among doctors and nurses in Hong Kong. AB - This study aims to examine perceived challenges, including knowledge, skills, self, and work environment, of professionals in providing pediatric palliative care (PPC) in Hong Kong and the differences in perceived challenges between groups. A total of 680 pediatric doctors and nurses participated in the survey. They tended to perceive the provision of PPC as difficult and considered "advanced skills" (those dealing with death-related issues) challenging. Findings indicate that nurses, professionals who are less experienced, do not have children, and have not received palliative care training perceived a higher level of challenges in providing PPC. Implications for training and support are discussed. PMID- 30015576 TI - 'Despite Circumstance': The Principles of Medical Ethics and the Role of Hope. AB - In this paper, I will examine how the role of hope can inform our interpretation of the classical principles of medical ethics. Defining hope as a future-oriented expectation for the good, I will look at how it can shape our understanding of justice, beneficence, respect for autonomy and non-maleficence. I will suggest that ethically engaging with these principles in medical practice requires placing value on the patient-practitioner relation as a mode of hope. Engaging the writings of Emmanuel Levinas and Soren Kierkegaard, I will show how hope reveals itself through responsible and expectant relationship, even in the midst of suffering. PMID- 30015575 TI - Feasibility for the Use of a Standardized Fitness Testing Protocol Among Australian Fitness Industry Professionals. AB - PURPOSE: There is currently no standardized testing protocol for assessing clients' fitness/health within the Australian fitness industry. This study examined the perceptions of the feasibility of using a standardized testing protocol among Australian fitness industry professionals. METHOD: In 2014, 1,206 registered fitness industry professionals (aged 17-69 years) completed an online survey. Perceived feasibility for using a standardized testing protocol was assessed based on responses to 6 items. Respondents were classified as having a high level of perceived feasibility if they reported all 6 items to be "definitely feasible." A multivariate logistic regression analysis, adjusting for demographic and fitness industry-related factors (e.g., qualification/years of experience), assessed the likelihood of having a high level of perceived feasibility. RESULTS: Overall, 25.5% (95% CI [23.1%, 28.0%]) of the sample perceived the use of a standardized testing protocol as highly feasible. Items ranked most often as "definitely feasible" were "undertaking training to use the protocol" (55%) and "conducting follow-up testing every 6 to 12 weeks" (52%). After adjustment for the effect of confounding factors, casually employed professionals (OR = 0.63; 95% CI [0.45, 0.90]) and group instructors (OR = 0.58; 95% CI [0.41, 0.82]) were less likely to perceive standardized testing protocols as highly feasible. CONCLUSIONS: Among a large sample of Australian fitness industry professionals, slightly more than a quarter perceived using a standardized testing protocol to be highly feasible. Group instructors and casual employees perceived lower feasibility. Further research should determine the barriers to implementing a standardized testing protocol across the fitness industry. PMID- 30015577 TI - Highly acidic pH values of carbonated sweet drinks, fruit juices, mineral waters and unregulated fluoride levels in oral care products and drinks in India: a public health concern. AB - PURPOSE: The objective of this study was to quantify and assess the concentrations of fluoride in commonly used oral care products, fruit juices, bottled waters, soft drinks, favoured bottled milk and milkshakes and to determine the pH of carbonated sweet drinks and drinks marketed in India. MATERIALS AND METHODS: Various commercial brands of dentifrices, toothpowders, mouthwashes, bottled waters, sweet carbonated drinks and fruit juices were collected randomly from different outlets in Mangalore city, Karnataka, India. A fluoride ion-selective electrode was employed to estimate the fluoride concentrations. A standardised pH meter was used to detect pH in the drinks. RESULTS: The fluoride level in toothpastes ranged between 96 and 1397 mg/l, whereas in toothpowder the fluoride content ranged from 35 to 1380 mg/l and mouthwash fluoride concentrations varied from 6 to 228 mg/l. The fluoride level in bottled waters ranged between 0.10 and 0.12 mg/l, and that in fruit juices between 0.09 and 0.21 mg/l. Most of the carbonated sweet drinks and fruit juices had highly acidic pH values which ranged between 2.62 and 4.26. CONCLUSION: Of the wide variety of dentifrices and toothpowders available in India, most brands do not indicate the fluoride levels on their packaging or inserts. Similarly, the unregulated acidic pH values of carbonated sweet drinks are not only potentially contributing to non-carious tooth loss (enamel erosion and dentine erosion), but are also a contributing factor to the weight gain observed in Indian adolescents. PMID- 30015578 TI - Association of circulating blood HMGB1 levels with ischemic stroke: a systematic review and meta-analysis. AB - OBJECTIVES: Inflammation plays a key role in the pathogenesis and progression of ischemic stroke (IS). The high mobility group box 1 (HMGB1) nucleoprotein is involved in the amplification of inflammatory responses during acute ischemic injury. HMGB1 levels in patients with active disease are higher than those in healthy controls. We performed a meta-analysis to assess currently published data pertaining to circulating blood HMGB1 levels in IS and the relationship with stroke severity. METHODS: We systematically searched for studies investigating the circulating blood HMGB1 levels in patients with IS in PubMed/Medline, Embase, the Cochrane Library, Web of science and China National Knowledge Infrastructure (CNKI). Two independent researchers used the Cochrane Collaboration tools for data extraction and quality assessment. Extracted data were analyzed by Review Manager version 5.3. RESULTS: A total of 28 studies were included with a total of 4497 participants, including 2671 IS patients and 1826 matched controls. The meta analysis revealed that compared with control, IS patients had higher circulating blood HMGB1 levels (n = 4497, standardized mean difference (SMD) = 5.70, 95%confidence interval (CI) = 4.79 to 6.62, Z = 12.23, P < 0.00001), and the HMGB1 level was positively correlated with severity (n = 507, SMD = -2.12, 95%CI = -3.41 to -0.82, Z = 3.20, P < 0.00001) and infarct volume (n = 582, 95%CI = 4.06 to -1.70, Z = 4.79, P < 0.00001). CONCLUSIONS: This meta-analysis demonstrates that circulating blood HMGB1 levels elevate in IS and higher HMGB1 levels may indicate a more serious condition. PMID- 30015579 TI - Dead wives club. PMID- 30015581 TI - Radiation Dose in CT-guided Interventional Procedures: Establishing a Benchmark. PMID- 30015580 TI - Effect of Dehydration on Passing Decision Making in Soccer Athletes. AB - : It seems that dehydration may impair decision-making performance in athletes. PURPOSE: This study aimed to investigate the influence of dehydration on passing decision-making performance in soccer players. METHOD: Participants were 40 male soccer players (Mage = 22.3 +/- 2.3 years) who agreed to participate in the study and were randomly assigned to the following conditions: control (CON), dehydration (DEH), and euhydration (EUH). The players played in 2 games of 90 min in duration (2 45-min halves) followed by 2 15-min halves (overtime) with and without proper hydration. The Game Performance Assessment Instrument (GPAI) was considered for the analysis of passing decision making. RESULTS: The GPAI analysis indicated effective reduction in the decision-making index in the DEH condition compared with the EUH and CON conditions, F(2, 38) = 31.4, p < .05, ES = 0.8. CONCLUSIONS: In conclusion, dehydration may be considered a mediating factor in the passing decision-making performance of male soccer athletes. PMID- 30015582 TI - Cardiac MRI for Detection of Cardiac Sarcoidosis. PMID- 30015583 TI - Procedure-specific CT Dose and Utilization Factors for CT-guided Interventional Procedures. AB - Purpose To present procedure-specific radiation dose metric distributions and define quantitative CT utilization factors for CT-guided interventional procedures. Materials and Methods This single-center, retrospective study collected dictation reports and radiation dose data from 9143 consecutive CT guided interventional procedures in adult patients from 2012 to 2017. Procedures were sorted into four major interventional categories: ablation, aspiration, biopsy, and drainage, each of which was further divided into subcategories. After exclusion, a total of 8213 procedures (4391 in men and 3822 in women) were divided into 21 subcategories. The mean patient age at examination for men was 62 years +/- 15 (standard deviation; age range, 19-114 years), and for women it was 61 years +/- 15 (age range, 19-113 years). Distributions of dose metrics and CT usage-related parameters were analyzed by category with descriptive statistic outcomes. Quantitative CT utilization factors (which measure average CT usage) for each interventional subcategory were derived by using total scan length, acquisition count, and number of images. Results Interventional CT scans have distinctly different dose metric characteristics from diagnostic CT scans. Wide variations of dose metrics were observed among subcategories, even within the same major category. For the most frequently performed CT-guided interventional procedures within each major category, liver ablation, chest aspiration, liver biopsy, and single abdominal drainage, the median dose-length product was 2351, 657, 1175, and 1125 mGy ? cm, respectively. Procedure-specific CT utilization factors ranged between 0.6 and 3.6. Conclusion This study provides procedure specific CT dose metric distributions and quantitative CT utilization factors on the basis of a large number of procedures and categorization of CT-guided interventional procedures. (c) RSNA, 2018. PMID- 30015584 TI - US-based Particle Imaging Velocimetry: A Potential Method for Rapid and Inexpensive Assessment of Flow in the Abdominal Aorta. PMID- 30015585 TI - Mapping Deep Gray Matter Iron in Multiple Sclerosis by Using Quantitative Magnetic Susceptibility. PMID- 30015586 TI - High-Frame-Rate Contrast-enhanced US Particle Image Velocimetry in the Abdominal Aorta: First Human Results. AB - Purpose To study the feasibility of high-frame-rate (HFR) contrast material enhanced (CE) ultrasound particle image velocimetry (PIV), or echo PIV, in the abdominal aorta. Materials and Methods Fifteen healthy participants (six men; median age, 23 years [age range, 18-34 years]; median body mass index, 20.3 kg/m2 [range, 17.3-24.9 kg/m2]) underwent HFR CE US. US microbubbles were injected at incremental doses (0.25, 0.5, 0.75, and 1.5 mL), with each dose followed by US measurement to determine the optimal dosage. Different US mechanical index values were evaluated (0.09, 0.06, 0.03, and 0.01) in a diverging wave acquisition scheme. PIV analysis was performed via pairwise cross-correlation of all captured images. Participants also underwent phase-contrast MRI. The echo PIV and phase contrast MRI velocity profiles were compared via calculation of similarity index and relative difference in peak velocity. Results Visualization of the aortic bifurcation with HFR CE US was successful in all participants. Optimal echo PIV results were achieved with the lowest contrast agent dose of 0.25 mL in combination with the lowest mechanical indexes (0.01 or 0.03). Substantial bubble destruction occurred at higher mechanical indexes (>=0.06). Flow patterns were qualitatively similar in the echo PIV and MR images. The echo PIV and MRI velocity profiles showed good agreement (similarity index, 0.98 and 0.99; difference in peak velocity, 8.5% and 17.0% in temporal and spatial profiles, respectively). Conclusion Quantification of blood flow in the human abdominal aorta with US particle image velocimetry (echo PIV) is feasible. Use of echo PIV has potential in the clinical evaluation of aortic disease. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30015587 TI - Diagnostic Performance of Three-dimensional MRI for Depicting Cartilage Defects in the Knee: A Meta-Analysis. AB - Purpose To determine the diagnostic performance of three-dimensional (3D) MRI for the depiction and characterization of cartilage defects within the knee joint by using arthroscopy and/or open surgery as the standard of reference. Materials and Methods A systematic literature search was performed to extract diagnostic studies published between January 1985 and October 2017. Two independent investigators assessed the methodologic quality of each study by using Quality Assessment of Diagnostic Accuracy Studies 2. Bivariate random-effects model was used to compare the diagnostic odds ratio (DOR) of 3D and two-dimensional (2D) MRI for helping to detect knee cartilage defects and to assess the effect of relevant covariates on diagnostic performance of 3D MRI. Meta-regression analysis was performed to assess DOR of 3D MRI during the last 3 decades. Results Twenty seven studies (composed of 1710 MRI examinations) were included. Of those, 16 (59%) studies compared the diagnostic performance of 3D and 2D MRI. The diagnostic performance of 3D MRI statistically significantly improved over the last 3 decades (P = .003). Three-dimensional MRI obtained by using 3.0-T field strength had higher DOR relative to 1.5-T or lower field strength (relative DOR, 4.05; P = .01). Three-dimensional multiplanar reformation was associated with higher specificity (P = .001) compared with conventional axial, sagittal, and coronal 2D MRI planes. Three-dimensional fast-spin-echo sequences provided higher sensitivity and specificity (P < .05) than did 2D MRI. Conclusion Three dimensional MRI currently provides comparable diagnostic performance to two dimensional MRI, with improvement in diagnostic performance achieved by using 3.0 T field strength, three-dimensional fast-spin-echo sequences, and multiplanar reformation. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30015588 TI - Non-Small Cell Lung Cancer with Resistance to EGFR-TKI Therapy: CT Characteristics of T790M Mutation-positive Cancer. AB - Purpose To evaluate the clinical and CT characteristics of T790M mutation positive non-small cell lung cancer (NSCLC) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy failure. Materials and Methods A retrospective study of 304 patients with NSCLC who underwent rebiopsy after first-line EGFR-TKI therapy was conducted. Rebiopsy methods included CT- or fluoroscopy-guided lung biopsies (n = 105), endobronchial US- or bronchofibroscopy-guided biopsies (n = 66), pleural fluid analysis (n = 47), other solid organ biopsies (n = 43), US-guided axillary or supraclavicular lymph node biopsies (n = 31), and cerebrospinal fluid analysis (n = 12). CT findings at the initial diagnosis and rebiopsy were analyzed. Progression-free survival, the duration from the start of TKI therapy to rebiopsy, and survival were calculated. Results At rebiopsy, 144 (47.4%) patients were T790M mutation positive. The percentages of T790M mutation-positive NSCLCs were similar in 106 patients with rebiopsy of the lungs (53 [50%] of 106) and in 77 patients with rebiopsy of the primary lung lesions (36 [47%] of 77). T790M mutation positivity was associated with peripheral tumors (odds ratio [OR], 2.6; P = .01), pleural tag (OR, 5.0; P < .001), and air bronchogram (OR, 4.0; P = .006) at CT after TKI failure. The duration from the start of TKI therapy to rebiopsy was longer in T790M mutation positive than in T790M mutation-negative patients (20.5 vs 13.6 months; P < .001). Cumulative survival from the time of rebiopsy to the last follow-up was significantly longer in patients with T790M mutation-positive lung cancers (P = .014). However, median survival time after rebiopsy was not statistically different between patients with and those without T790M mutation. Conclusion Peripheral tumor location with vascular convergence, the presence of a pleural tag, and air bronchogram of lung lesions at CT at the time of rebiopsy were significantly associated with T790M mutation in patients with non-small cell lung cancer after first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy failure. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30015590 TI - Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy: The PRISMA-DTA Statement. PMID- 30015589 TI - Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis. AB - Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (beta = -0.42; P = .002), higher degree of disability (beta = -0.64; P = .03), and secondary progressive course (beta = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (beta = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30015591 TI - CT Detectability of Small Low-Contrast Hypoattenuating Focal Lesions: Iterative Reconstructions versus Filtered Back Projection. AB - Purpose To investigate performance in detectability of small (<=1 cm) low contrast hypoattenuating focal lesions by using filtered back projection (FBP) and iterative reconstruction (IR) algorithms from two major CT vendors across a range of 11 radiation exposures. Materials and Methods A low-contrast detectability phantom consisting of 21 low-contrast hypoattenuating focal objects (seven sizes between 2.4 and 10.0 mm, three contrast levels) embedded into a liver-equivalent background was scanned at 11 radiation exposures (volume CT dose index range, 0.5-18.0 mGy; size-specific dose estimate [SSDE] range, 0.8-30.6 mGy) with four high-end CT platforms. Data sets were reconstructed by using FBP and varied strengths of image-based, model-based, and hybrid IRs. Sixteen observers evaluated all data sets for lesion detectability by using a two alternative-forced-choice (2AFC) paradigm. Diagnostic performances were evaluated by calculating area under the receiver operating characteristic curve (AUC) and by performing noninferiority analyses. Results At benchmark exposure, FBP yielded a mean AUC of 0.79 +/- 0.09 (standard deviation) across all platforms which, on average, was approximately 2% lower than that observed with the different IR algorithms, which showed an average AUC of 0.81 +/- 0.09 (P = .12). Radiation decreases of 30%, 50%, and 80% resulted in similar declines of observer detectability with FBP (mean AUC decrease, -0.02 +/- 0.05, -0.03 +/- 0.05, and 0.05 +/- 0.05, respectively) and all IR methods investigated (mean AUC decrease, 0.00 +/- 0.05, -0.04 +/- 0.05, and -0.04 +/- 0.05, respectively). For each radiation level and CT platform, variance in performance across observers was greater than that across reconstruction algorithms (P = .03). Conclusion Iterative reconstruction algorithms have limited radiation optimization potential in detectability of small low-contrast hypoattenuating focal lesions. This task may be further complicated by a high degree of variation in radiologists' performances, seemingly exceeding real performance differences among reconstruction algorithms. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30015592 TI - The influence of T-shirt graphics on perceptions and behavioral intentions. AB - Do graphics on clothing drive perceptions? We used a between group design to test if athletic, academic, or suggestive graphics on clothing differentially influence perceptions and behavioral intentions. In study 1, participants (N = 199) rated five female t-shirt models, and in study 2 and 3, participants rated five male t-shirt models (N = 120) or university students (N = 50). Analyses of variance controlling for sex (ANCOVA) showed participants were least likely to want to interact with models/students wearing sexually suggestive graphics: Study 1, F(3,165) = 30.263, p < .001, etap2 = .30, power = 1.00; Study 2, F (3,119) = 11.630, p < .000, etap2 = .234, and Study 3, F(1, 42) = 12.578, p < .000. Participants did not rate models in the academic and athletic graphic shirts differently from models with plain white shirts. Results support the concept that people form different perceptions based upon the clothing a person wears, changing behavioral intentions. Neither sex role ideation (Study 1) or sexism (Study 2) were significant covariates of perceptions and intentions. PMID- 30015593 TI - Preliminary Study of Chronic Liver Classification on Ultrasound Images Using an Ensemble Model. AB - Chronic liver diseases are fifth leading cause of fatality in developing countries. Their early diagnosis is extremely important for timely treatment and salvage life. To examine abnormalities of liver, ultrasound imaging is the most frequently used modality. However, the visual differentiation between chronic liver and cirrhosis, and presence of heptocellular carcinomas (HCC) evolved over cirrhotic liver is difficult, as they appear almost similar in ultrasound images. In this paper, to deal with this difficult visualization problem, a method has been developed for classifying four liver stages, that is, normal, chronic, cirrhosis, and HCC evolved over cirrhosis. The method is formulated with selected set of "handcrafted" texture features obtained after hierarchal feature fusion. These multiresolution and higher order features, which are able to characterize echotexture and roughness of liver surface, are extracted by using ranklet, gray level difference matrix and gray-level co-occurrence matrix methods. Thereafter, these features are applied on proposed ensemble classifier that is designed with voting algorithm in conjunction with three classifiers, namely, k-nearest neighbor (k-NN), support vector machine (SVM), and rotation forest. The experiments are conducted to evaluate the (a) effectiveness of "handcrafted" texture features, (b) performance of proposed ensemble model, (c) effectiveness of proposed ensemble strategy, (d) performance of different classifiers, and (e) performance of proposed ensemble model based on Convolutional Neural Networks (CNN) features to differentiate four liver stages. These experiments are carried out on database of 754 segmented regions of interest formed by clinically acquired ultrasound images. The results show that classification accuracy of 96.6% is obtained by use of proposed classifier model. PMID- 30015594 TI - The obesogen tributyltin induces features of polycystic ovary syndrome (PCOS): a review. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterized by abnormal reproductive cycles, irregular ovulation, and hyperandrogenism. This complex disorder has its origins both within and outside the hypothalamic pituitary-ovarian axis. Cardio-metabolic factors, such as obesity and insulin resistance, contribute to the manifestation of the PCOS phenotype. Polycystic ovary syndrome is one of the most common endocrine disorders among women of reproductive age. Growing evidence suggested an association between reproductive and metabolic features of PCOS and exposure to endocrine-disrupting chemicals (EDC), such as bisphenol A. Further, the environmental obesogen tributyltin (TBT) was shown to induce reproductive, metabolic and cardiovascular abnormalities resembling those found in women and animal models of PCOS. However, the causal link between TBT exposure and PCOS development remains unclear. The objective of this review was to summarize the most recent research findings on the potential association between TBT exposure and development of PCOS-like features in animal models and humans. PMID- 30015595 TI - Suicidality Risk and (Repeat) Disaster Exposure: Findings From a Nationally Representative Population Survey. AB - OBJECTIVE: Despite growing awareness of adverse mental health consequences, the scarce existing evidence on the link of disaster exposure and suicidality has remained inconclusive, and the differential suicidality risk associated with distinct levels of natural and man-made disaster exposure is unknown. We therefore investigated the lifetime prevalence and risk of suicidal behavior associated with natural and man-made disaster exposure in Australia. METHOD: We utilized data from a nationally representative mental health survey (n = 8,841). Univariate and multivariate logistic regression analyses examined the lifetime risk of suicidal thoughts, plans, and attempts associated with varied types and levels of disaster exposure. We focused explicitly on natural and man-made disasters while controlling for other types of trauma exposure, including established risk factors for suicidality. RESULTS: Multivariate analyses indicated that those exposed to multiple natural (adjusted odds ratio [AOR] = 2.21, 95% confidence interval [CI] = [1.04, 4.71], p < .05) or man-made disasters (AOR 3.4, 95% CI = [1.20, 9.58] p < .05) were at significantly greater risk of making suicide attempts, whereas single natural or man-made disaster exposure was not associated with an increased risk of suicidal behavior. CONCLUSIONS: Our study findings establish the differential suicidality risk associated with natural and man-made disaster exposure in Australia and highlight the critical role of repeat disaster exposure across distinct disaster types. Suicidal behavior may warrant increasing attention in psychosocial recovery schemes, particularly in the context of disaster-prone areas and for population groups at elevated risk of repeat disaster exposure. PMID- 30015596 TI - Work-related musculoskeletal problems and associated factors among office workers. AB - PURPOSE: The aim of this study was to investigate musculoskeletal disorders (MSDs) and associated factors among Iranian office personnel. MATERIALS AND METHODS: In this cross-sectional study, 359 Iranian office workers were included. Data were gathered using a demographic questionnaire, the Nordic musculoskeletal questionnaire, the numeric rating scale, rapid office strain assessment (ROSA) and the NASA task load index (NASA-TLX). RESULTS: Our findings showed that the highest prevalence rate of MSDs within the last 12 months and the highest pain/discomfort severity were related to the participants' necks. The mean performance, mental demand and effort subscale scores of the NASA-TLX were higher than other subscales (physical demand, temporal demand and frustration level). ROSA scores showed that 53.8% of the participants were in action level 1 (low MSD risk) and the rest (46.2%) were in action level 2 (high MSD risk). The pain/discomfort severity in the shoulders, elbows, wrists/hands, thighs and ankles/feet was correlated to the final ROSA score. Age, gender, body mass index and some NASA-TLX subscales (effort, mental demand and performance) were associated with symptoms of MSDs in different body regions. CONCLUSIONS: Improving workplace conditions (both mentally and physically) is suggested for reducing and eliminating musculoskeletal problems among office workers. PMID- 30015597 TI - Suicide: An Unrecognized Epidemic Among Farmers. AB - Stress and depression are prevalent among farmers, and suicide has reached epidemic status. Occupational health nurses are in key positions to recognize these mental health issues and use strategies to control this epidemic. PMID- 30015598 TI - Relative Age Effect, Biological Maturation, and Coaches' Efficacy Expectations in Young Male Soccer Players. AB - PURPOSE: The talent identification and selection process in young male soccer players is mainly focused on anthropometrics and physical performance, but social factors are also considered in this process. The purpose of this study was to test the existence of the relative age effect and its possible influence on anthropometrics and physical performance and to analyze coaches' efficacy expectations. METHOD: Data for 564 young male soccer players (Mage = 13.7 +/- 1.5 years; Mweight = 53.7 +/- 11.6 kg; Mheight = 160.2 +/- 11.6 cm) included their birth quartile, maturity status, anthropometrics, a physical test battery, and coaches' efficacy expectations. RESULTS: Early-born players were overrepresented (p < .05). Early-born players were not statistically taller, heavier, or better at physical performance (p > .05) when maturation and chronological age were controlled as confounding factors. However, coaches expected more from early-born players (p < .05), and the inferential analysis showed likely to very likely worthwhile differences between the coaches' expectations for players born in the first quartile of the year and those born in the fourth quartile of the year. CONCLUSIONS: Anthropometrical and physical performance variables were not affected by birth quartile, and coaches' efficacy expectations were related to the relative age effect. PMID- 30015600 TI - Inner ear involvement in multiple sclerosis: An underestimated condition? PMID- 30015599 TI - Short-term air pollution exposure is associated with hospital length of stay and hospitalization costs among inpatients with type 2 diabetes: a hospital-based study. AB - Air pollution is a risk factor for type 2 diabetes (T2D), exerting heavy economic burden on both individuals and societies. However, there is no apparent report regarding the influence of air pollutants such as particulate matter (PM2.5 and PM10), sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide (NO2), and ozone (O3) on financial burden to individuals and societies suffering from T2D. This study aimed to determine whether short-term (no more than 16 d) air pollution exposure was associated with T2D-related length of stay (LOS) and hospitalization expenses incurred by patients. This investigation examined 2840 T2D patients hospitalized from December 17, 2013 to May 31, 2016 in China. Multiple linear regression analysis was applied to determine the association between short-term (no more than 16 d) ambient air pollution, LOS, and hospitalization expenses, controlling for age, gender, ethnicity, marital status, and weather conditions. Sulfur dioxide (SO2) and carbon monoxide (CO) were significantly positively while nitrogen dioxide (NO2) was negatively associated with presence of T2D, LOS, and expenses. A 10-MUg/m3 rise in 16-d (lag 0-15) average concentrations of SO2 and CO prior to hospitalization was correlated with a significant elevation in LOS and elevation in expenses in T2D patients. However, a 10-MUg/m3 rise in 16-d average NO2 was associated with marked negative alterations in LOS and hospital costs in T2D patients. Taken together, data demonstrate that exposure to air pollutants impacts differently on LOS and hospitalization costs for T2D patients. This is the first apparent report regarding the correlation between air pollution exposure and clinical costs of T2D in China. It is of interest that air pollutants affected T2D patients differently as evidenced by LOS and clinical expenses where SO2 and CO exhibited a positive adverse relationship in contrast to NO2. PMID- 30015601 TI - Depression and Coleman Care Transitions Intervention. AB - The Coleman Care Transitions Intervention (CTI) is a "Patient Activation Model." Depression can be a barrier to activation and may challenge CTI. This study addressed whether CTI coaches modified the intervention for older adults who screened positive for depression. Over 4,500 clients in a Centers for Medicare and Medicaid Services demonstration completed screening for depression with the PHQ-9; one in five screened positive (score = 9+). Our findings suggest that coaches modified CTI and played a more directive role for clients who screened positive for depression, resulting in similar 30-day readmission rates among patients who screened positive for depression risk and those who did not. That finding stands in contrast to the widely reported higher readmission rates among people screening positive for depression. PMID- 30015602 TI - The Unique Roles of Emotional Numbing and Arousal Symptoms in Relation to Social Connectedness Among Military Veterans in Residential Treatment for PTSD. AB - OBJECTIVE: While poor social connectedness is often a consequence of living with posttraumatic stress disorder (PTSD) symptoms, little is known about whether PTSD symptom clusters may be uniquely related to different aspects of social connectedness. This information can inform case conceptualization and treatment planning to potentially facilitate sustained recovery for individuals with PTSD. METHOD: We examined associations among a five-factor model of PTSD and two aspects of social connectedness-distress related to problems getting along with others and days of contact with supportive loved ones in the past 30 days-in a sample of 2,600 U.S. military veterans seeking residential treatment for PTSD. RESULTS: A large proportion of veterans reported experiencing distress related to problems getting along with others (66.2%) and few days of contact with supportive people (43.5%). Ordinal regression models controlling for intercorrelations among PTSD symptom clusters revealed that emotional numbing symptoms were independently associated with greater distress (beta = 0.130, p < 0.001) and fewer days of contact (beta = -0.159, p < 0.001); dysphoric arousal symptoms were associated with more distress (beta = 0.236, p < 0.001), while anxious arousal was associated with more days of contact (beta = 0.058, p < 0.05). CONCLUSIONS: Findings reveal high rates of difficulties in social connectedness and distinct associations among these difficulties with emotional numbing, dysphoric arousal, and anxious arousal symptoms in veterans receiving residential treatment for PTSD. Future studies should examine whether targeting poor social connectedness during treatment improves interpersonal functioning and supports sustained trauma recovery, which may be particularly beneficial to veterans with more severe emotional numbing and dysphoric arousal symptoms. PMID- 30015603 TI - Comparison of nutrient profiling models for assessing the nutritional quality of foods: a validation study. AB - Nutrient profiling (NP) is a method for evaluating the healthfulness of foods. Although many NP models exist, most have not been validated. This study aimed to examine the content and construct/convergent validity of five models from different regions: Australia/New Zealand (FSANZ), France (Nutri-Score), Canada (HCST), Europe (EURO) and Americas (PAHO). Using data from the 2013 UofT Food Label Information Program (n15342 foods/beverages), construct/convergent validity was assessed by comparing the classifications of foods determined by each model to a previously validated model, which served as the reference (Ofcom). The parameters assessed included associations (Cochran-Armitage trend test), agreement (kappa statistic) and discordant classifications (McNemar's test). Analyses were conducted across all foods and by food category. On the basis of the nutrients/components considered by each model, all models exhibited moderate content validity. Although positive associations were observed between each model and Ofcom (all P trend<0.001), agreement with Ofcom was 'near perfect' for FSANZ (kappa=0.89) and Nutri-Score (kappa=0.83), 'moderate' for EURO (kappa=0.54) and 'fair' for PAHO (kappa=0.28) and HCST (kappa=0.26). There were discordant classifications with Ofcom for 5.3 % (FSANZ), 8.3 % (Nutri-Score), 22.0 % (EURO), 33.4 % (PAHO) and 37.0 % (HCST) of foods (all P<0.001). Construct/convergent validity was confirmed between FSANZ and Nutri-Score v. Ofcom, and to a lesser extent between EURO v. Ofcom. Numerous incongruencies with Ofcom were identified for HCST and PAHO, which highlights the importance of examining classifications across food categories, the level at which differences between models become apparent. These results may be informative for regulators seeking to adapt and validate existing models for use in country-specific applications. PMID- 30015604 TI - Identifying usual food choices at meals in overweight and obese study volunteers: implications for dietary advice. AB - Understanding food choices made for meals in overweight and obese individuals may aid strategies for weight loss tailored to their eating habits. However, limited studies have explored food choices at meal occasions. The aim of this study was to identify the usual food choices for meals of overweight and obese volunteers for a weight-loss trial. A cross-sectional analysis was performed using screening diet history data from a 12-month weight-loss trial (the HealthTrack study). A descriptive data mining tool, the Apriori algorithm of association rules, was applied to identify food choices at meal occasions using a nested hierarchical food group classification system. Overall, 432 breakfasts, 428 lunches, 432 dinners and 433 others (meals) were identified from the intake data (n 433 participants). A total of 142 items of closely related food clusters were identified at three food group levels. At the first sub-food group level, bread emerged as central to food combinations at lunch, but unprocessed meat appeared for this at dinner. The dinner meal was characterised by more varieties of vegetables and of foods in general. The definitions of food groups played a pivotal role in identifying food choice patterns at main meals. Given the large number of foods available, having an understanding of eating patterns in which key foods drive overall meal content can help translate and develop novel dietary strategies for weight loss at the individual level. PMID- 30015605 TI - THIS (METHOD) IS (NOT) FINE. AB - SummaryIn their response to my criticism of their recent article in Journal of Biosocial Science (te Nijenhuis et al., 2017), te Nijenhuis and van den Hoek (2018) raise four points none of which concerns my main point that the method of correlated vectors (MCV) applied to item-level data represents a flawed method. Here, I discuss te Nijenhuis and van den Hoek's four points. First, I argue that my previous application of MCV to item-level data showed that the method can yield nonsensical results. Second, I note that meta-analytic corrections for sampling error, imperfect measures, restriction of range and unreliability of the vectors are futile and cannot help fix the method. Third, I note that even with perfect data, the method can yield negative correlations. Fourth, I highlight the irrelevance of te Nijenhuis and van den Hoek (2018)'s point that my comment had not been published in a peerreviewed journal by referring to my articles in 2009 and 2017 on MCV in peer-reviewed journals. PMID- 30015606 TI - IGNORING PSYCHOMETRIC PROBLEMS IN THE STUDY OF GROUP DIFFERENCES IN COGNITIVE TEST PERFORMANCE. AB - SummaryIn a recent study, te Nijenhuis et al. (2017) used a version of Jensen's method of correlated vectors to study the nature of ethnic group differences on Raven's Progressive Matrices test. In this comment, the author points out that this method has been shown to be psychometrically inappropriate in studying group differences in performance on dichotomous (correctly or incorrectly scored) items. Specifically, the method uses item statistics like the item-total correlation that necessarily differ across groups differing in ability and employs a linear model to test inherent non-linear relations. Wicherts (2017) showed that this method can provide correlations far exceeding r=0.44 in cases where the group differences cannot possibly be on g because the items measure different traits across the groups. The psychometric problems with their method cast serious doubts on te Nijenhuis et al.'s conclusions concerning the role of g in the studied group difference in cognitive test performance. PMID- 30015607 TI - ANALYSING GROUP DIFFERENCES IN INTELLIGENCE USING THE PSYCHOMETRIC META-ANALYTIC METHOD OF CORRELATED VECTORS HYBRID MODEL: A REPLY TO WICHERTS (2018) ATTACKING A STRAWMAN. AB - SummaryWicherts (2018) criticizes the use of the method of correlated vectors when testing Spearman's hypothesis. It is argued that Wicherts ignores the psychometric meta-analytic method of correlated vectors hybrid model and so is attacking a strawman. PMID- 30015608 TI - Fatal Nongroupable Neisseria meningitidis Disease in Vaccinated Patient Receiving Eculizumab. AB - Patients receiving eculizumab have an increased risk for meningococcal disease, but most reported cases are attributable to encapsulated meningococcal strains. We describe a case in which a nongroupable meningococcal strain, which rarely causes disease in healthy persons, caused fatal disease in an eculizumab recipient despite meningococcal vaccination. PMID- 30015609 TI - Outbreak of Trichinella T9 Infections Associated with Consumption of Bear Meat, Japan. AB - An outbreak of trichinellosis occurred in Japan in December 2016. All case patients had eaten undercooked bear meat, from which Trichinella larvae were subsequently isolated. DNA sequencing analysis of the mitochondrial genes cytochrome c-oxidase subunit 1 and internal transcribed spacer 2 confirmed that Trichinella T9 had caused the outbreak. PMID- 30015610 TI - Detection of Dengue Virus among Children with Suspected Malaria, Accra, Ghana. AB - We report new molecular evidence of locally acquired dengue virus infections in Ghana. We detected dengue viral RNA among children with suspected malaria by using a multipathogen real-time PCR. Subsequent sequence analysis revealed a close relationship with dengue virus serotype 2, which was implicated in a 2016 outbreak in Burkina Faso. PMID- 30015611 TI - Variation in Influenza B Virus Epidemiology by Lineage, China. AB - We used national sentinel surveillance data in China for 2005-2016 to examine the lineage-specific epidemiology of influenza B. Influenza B viruses circulated every year with relatively lower activity than influenza A. B/Yamagata was more frequently detected in adults than in children. PMID- 30015612 TI - Invasive Colonic Entamoebiasis in Wild Cane Toads, Australia. AB - We detected a disease syndrome in free-ranging Australian cane toads involving atypical behavior and emaciation that is associated with a previously undescribed Entamoeba sp. that infiltrates the colonic lining, causing it to slough. The organism may become seasonally pathogenic when toads are under hydric and nutritional stress. PMID- 30015614 TI - Setting the bar. AB - Analyzing the genomes of rock pigeons demonstrates that genetic variation comes in many forms and can have unexpected origins. PMID- 30015613 TI - A protein secreted by the Salmonella type III secretion system controls needle filament assembly. AB - Type III protein secretion systems (T3SS) are encoded by several pathogenic or symbiotic bacteria. The central component of this nanomachine is the needle complex. Here we show in a Salmonella Typhimurium T3SS that assembly of the needle filament of this structure requires OrgC, a protein encoded within the T3SS gene cluster. Absence of OrgC results in significantly reduced number of needle substructures but does not affect needle length. We show that OrgC is secreted by the T3SS and that exogenous addition of OrgC can complement a ?orgC mutation. We also show that OrgC interacts with the needle filament subunit PrgI and accelerates its polymerization into filaments in vitro. The structure of OrgC shows a novel fold with a shared topology with a domain from flagellar capping proteins. These findings identify a novel component of T3SS and provide new insight into the assembly of the type III secretion machine. PMID- 30015615 TI - Dual roles for ATP in the regulation of phase separated protein aggregates in Xenopus oocyte nucleoli. AB - For many proteins, aggregation is one part of a structural equilibrium that can occur. Balancing productive aggregation versus pathogenic aggregation that leads to toxicity is critical and known to involve adenosine triphosphate (ATP) dependent action of chaperones and disaggregases. Recently a second activity of ATP was identified, that of a hydrotrope which, independent of hydrolysis, was sufficient to solubilize aggregated proteins in vitro. This novel function of ATP was postulated to help regulate proteostasis in vivo. We tested this hypothesis on aggregates found in Xenopus oocyte nucleoli. Our results indicate that ATP has dual roles in the maintenance of protein solubility. We provide evidence of endogenous hydrotropic action of ATP but show that hydrotropic solubilization of nucleolar aggregates is preceded by a destabilizing event. Destabilization is accomplished through an energy dependent process, reliant upon ATP and one or more soluble nuclear factors, or by disruption of a co-aggregate like RNA. PMID- 30015616 TI - Radially patterned cell behaviours during tube budding from an epithelium. AB - The budding of tubular organs from flat epithelial sheets is a vital morphogenetic process. Cell behaviours that drive such processes are only starting to be unraveled. Using live-imaging and novel morphometric methods, we show that in addition to apical constriction, radially oriented directional intercalation of cells plays a major contribution to early stages of invagination of the salivary gland tube in the Drosophila embryo. Extending analyses in 3D, we find that near the pit of invagination, isotropic apical constriction leads to strong cell-wedging. Further from the pit cells interleave circumferentially, suggesting apically driven behaviours. Supporting this, junctional myosin is enriched in, and neighbour exchanges are biased towards the circumferential orientation. In a mutant failing pit specification, neither are biased due to an inactive pit. Thus, tube budding involves radially patterned pools of apical myosin, medial as well as junctional, and radially patterned 3D-cell behaviours, with a close mechanical interplay between invagination and intercalation. PMID- 30015617 TI - Insights into the ubiquitin transfer cascade catalyzed by the Legionella effector SidC. AB - The causative agent of Legionnaires' disease, Legionella pneumophila, delivers more than 330 virulent effectors to its host to establish an intracellular membrane-bound organelle called the Legionella containing vacuole. Among the army of Legionella effectors, SidC and its paralog SdcA have been identified as novel bacterial ubiquitin (Ub) E3 ligases. To gain insight into the molecular mechanism of SidC/SdcA as Ub ligases, we determined the crystal structures of a binary complex of the N-terminal catalytic SNL domain of SdcA with its cognate E2 UbcH5C and a ternary complex consisting of the SNL domain of SidC with the Ub-linked E2 UbcH7. These two structures reveal the molecular determinants governing the Ub transfer cascade catalyzed by SidC. Together, our data support a common mechanism in the Ub transfer cascade in which the donor Ub is immobilized with its C terminal tail locked in an extended conformation, priming the donor Ub for catalysis. PMID- 30015620 TI - Effect of Telehealth System on Glycemic Control in Children and Adolescents with Type 1 Diabetes. AB - OBJECTIVE: A close diabetes team-patient relationship is required for establishing a well metabolic control. The purpose of this study is to research the effect of telehealth system developed by the diabetes team on the diabetes control. METHODS: The study was carried out between June 2015 and January 2016 at the Gazi University Pediatric Endocrinology Department. The Telehealth system was developed by the diabetes team and the demographic characteristics, frequency of use and HbA1c changes of diabetic patients (type 1) using this communication network were noted. RESULTS: Eighty-two of the patients used The Telehealth system, 43(52.4%) female and 39 (47.6%) male with a mean age of 10,89+/-4 years. 14(17.1%) of the cases were pump therapy and 59(72.0%) were carbohydrate counts. The individuals with diabetes or their families prefer Whatsapp which is an instant messaging application at most (57.3%), contact with diabetes education nurse at most (32.9%) and consult with the diabetes team about insulin doses and blood glucose regulation at most (42.7%). At the beginning of the study, HbA1c level was rarely used cases (n = 34) in the teleheath system 9.1%, and frequently used cases were 8.3%. HbA1c values after 6 months were lower in those individuals calling frequently (p<.000). CONCLUSIONS: Increase in frequency of counselling to the diabetes team caused the blood glucose control of individuals with diabetes. Telehealth system is a useful system in early detection of the changes and intervention in the status of individual with diabetes, enhancing the patient's self care. Key words: Type 1 diabetes, telehealth, diabetes team, HbA1c. PMID- 30015618 TI - Adaptation to constant light requires Fic-mediated AMPylation of BiP to protect against reversible photoreceptor degeneration. AB - In response to environmental, developmental, and pathological stressors, cells engage homeostatic pathways to maintain their function. Among these pathways, the Unfolded Protein Response protects cells from the accumulation of misfolded proteins in the ER. Depending on ER stress levels, the ER-resident Fic protein catalyzes AMPylation or de-AMPylation of BiP, the major ER chaperone and regulator of the Unfolded Protein Response. This work elucidates the importance of the reversible AMPylation of BiP in maintaining the Drosophila visual system in response to stress. After 72 hr of constant light, photoreceptors of fic-null and AMPylation-resistant BiPT366A mutants, but not wild-type flies, display loss of synaptic function, disintegration of rhabdomeres, and excessive activation of ER stress reporters. Strikingly, this phenotype is reversible: photoreceptors regain their structure and function within 72 hr once returned to a standard light:dark cycle. These findings show that Fic-mediated AMPylation of BiP is required for neurons to adapt to transient stress demands. PMID- 30015621 TI - Hyperphosphatemic Familial Tumoral Calcinosis in Two Siblings with a Novel Mutation in GALNT3 gene: Experience from Southern Turkey. AB - Inactivating autosomal recessive mutations in both FGF23, KL and GALNT3 genes lead to a rare disorder, hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC constantly present hyperphosphatemia and tumor like soft tissue calcifications. Although 78% of patients develop their first symptoms between 2-13 years of age, diagnosis is usually delayed until adulthood. Some individuals with the same genetic defect overlap a condition named Hyperphosphatemic hyperostosis syndrome (HHS). Herein we report two siblings suffering from periarticular warm, hard and tender subcutaneous masses. Subcutaneous calcifications were present on X-ray and biopsy results were consistent with calcinosis in both patients. Laboratory results showed marked hyperphosphatemia and elevated renal tubular phosphate reabsorption, normal renal function tests and serum 25 hydroxyvitamin D levels. Thus, we suspected HFTC and performed next generation sequencing for GALNT3 gene, mostly causative in the literature. A novel homozygote P85Rfs*6 (c.254_255delCT) mutation in GALNT3 gene was identified in both siblings. Our report introduces two new patients to the knowledge about a rare genetic disease and suggests that small deletions in GALNT3 gene may be related with HFTC phenotype. Increased knowledge of physicians about this disease and studying phenotypegenotype correlation with more patients are needed to confirm our suggestion. PMID- 30015619 TI - Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization. AB - Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in Matrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3's zinc finger domains partially modulated toxicity, but elimination of its RNA recognition motifs had no effect on survival, instead facilitating its self-assembly into liquid-like droplets. In contrast to other RNA-binding proteins associated with ALS, cytoplasmic MATR3 redistribution mitigated neurodegeneration, suggesting that nuclear MATR3 mediates toxicity. Our findings offer a foundation for understanding MATR3 related neurodegeneration and how nucleic acid binding functions, localization, and pathogenic mutations drive sporadic and familial disease. PMID- 30015622 TI - Efficacy and Safety of Continuous Subcutaneous Insulin Infusion vs. Multiple Daily Injections on Type 1 Diabetes Children: A Meta-Analysis of Randomized Control Trials AB - Objective: This meta-analysis was performed to evaluate the efficacy and safety of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) in children with type 1 diabetes. Methods: A literature search was conducted on databases including PubMed and Embase up to June 2017. The pooled weighted mean difference or risk ratio as well as 95% confidence intervals were calculated using RevMan 5.3 software. Results: Eight studies involving 310 children with type 1 diabetes were included. Results showed that HbA1c (%) was significantly lower (p=0.007) after CSII compared with MDI in children with type 1 diabetes. In addition, there was no significant difference between groups in HbA1c (%) change, total daily insulin doses, change of total daily insulin doses and incidence of ketoacidosis and severe hypoglycemia. However, subgroup analyses indicated that age, treatment duration and study design were influenced the efficacy of CSII and MDI in children with type 1 diabetes. Conclusion: CSII is associated with lower HbA1c levels in children with type 1 diabetes but appears to have no effect on insulin requirement or incidence of ketoacidosis and severe hypoglycemia. PMID- 30015623 TI - Enhanced photocatalytic oxygen evolution activity by formation of Ir@IrOx(OH)y core-shell heterostructure. AB - Developing efficient catalysts to accelerate the rate of oxygen evolution reaction (OER) is critical for photocatalytic water-splitting. In this work, metallic Ir, IrOx(OH)y, and core-shell Ir@IrOx(OH)y were synthesized and employed as OER catalysts for photocatalytic water oxidation. It was found that the Ir@IrOx(OH)y core-shell heterostructure catalyst showed the best photocatalytic performance among these three catalysts, with the oxygen evolution rate as high as 59.63 mmol g-1 h-1. Detailed investigations revealed that the excellent photocatalytic activity of Ir@IrOx(OH)y could be attributed to both the outstanding intrinsic activity of IrOx(OH)y shell and the efficient electron transfer between the photosensitizer and catalyst. PMID- 30015624 TI - Three-dimensional microporous graphene decorated with lithium. AB - Three-dimensional (3D) graphene-based architectures can combine the two dimensional properties of graphene with the high surface-to-volume ratio required for a large variety of technological applications. We present a spectro microscopy study of stable microporous 3D few-layer graphene structures with a very low density of defects/edges and of unsaturated bonds, as deduced by Raman and core level photoemission spectroscopy. These qualities make these interconnected graphene networks ideal candidates to accommodate lithium adatoms, with a high density of Li per unit volume and a Li uptake per C atom higher than the value observed for graphite, as confirmed by core level photoemission spectroscopy. PMID- 30015625 TI - Phase diagram of the incommensurate off-diagonal Aubry-Andre model with p-wave pairing. AB - Using exact numerical methods, we study the interplay between p-wave superconductivity and off-diagonal modulation in the incommensurate off-diagonal Aubry-Andre model with p-wave pairing. When chemical potential is zero, the modulation not only leads to an Anderson-like localization with all bulk states changing into critical ones, but also induces a topological phase transition accompanying the disappearing of exponentially localized zero-energy edge Majorana fermions. These two transitions happen at different places and true Anderson localization is absent. With a finite chemical potential, the quasi periodicity of the modulation causes band splitting and drives the system into a band insulator phase. It has a fixed incommensurate particle density which is determined by the modulation frequency. Phase diagrams are identified, and can be tested with existing proposals for experimental realizations of the effective off diagonal disorder and the p-wave pairing. PMID- 30015626 TI - Continuous behavioral tracing-based online functional brain mapping with intracranial electroencephalography. AB - : Intracranial electroencephalography (iEEG) has proven to be a reliable tool in clinical functional brain mapping. While iEEG signals are believed to be highly informative, making online or real-time functional mapping possible, the utilization of corresponding behavioral information in traditional trial-based paradigms is typically low. This imbalance has limited the efficiency and effectiveness in current iEEG-based functional mapping approaches. OBJECTIVE: In the current study, we were to investigate whether using more dedicate behavioral information can improve iEEG-based functional mapping. APPROACH: We continuously monitored behavioral outputs of patients during iEEG recording, transformed them into regressors, and assessed their correlations with iEEG signals. MAIN RESULTS: Functional cortical sites identified in preliminary test using the proposed method showed considerable consistency with the results from electrical cortical stimulation (ECS) as well as a trial-based method. Continuous behavioral tracing yielded more dependency to neural signals than sole event markers-derived regressor. Based on this, we successfully performed online functional brain mapping during five neurosurgery operations, which yielded satisfactory results. SIGNIFICANCE: In the present study, we showed the utilization of continuous behavioral tracing can improve the efficiency of iEEG-based functional brain mapping. We then demonstrated this approach is adequate for multi-session intraoperative functional assessment within short time span, which is of considerable clinical value. PMID- 30015627 TI - Suppression of transport spin-polarization of surface states with emergence of ferromagnetism in Mn-doped Bi2Se3. AB - The surface states of topological insulators (TI) are protected by time reversal symmetry and they display intrinsic spin helicity where the momentum of the charge carriers decides their spin states. As a consequence, a current injected through the surface states becomes spin polarized and this transport spin polarization leads to a proportionate suppression of Andreev reflection in superconductor/TI junctions. Here we show that upon doping Bi2Se3 with Mn, the transport spin-polarization is seen to be monotonically suppressed. The parent compound Bi2Se3 is found to exhibit a transport spin-polarization of about 63% whereas crystals with 10% Mn doping show transport spin-polarization of about 48%. This suppression is accompanied by an increasing ferromagnetic order of the crystals with Mn doping. Scanning tunneling spectroscopy shows that the topological protection of the surface states reduces due to Mn doping. The net measured transport spin-polarization is due to a competition of this effect with the increased magnetization on Mn doping. The present results provide important insights for the choice of magnetic topological insulators for spintronic applications. PMID- 30015628 TI - Self-powered wearable sensing-textiles for real-time detecting environmental atmosphere and body motion based on surface-triboelectric coupling effect. AB - Self-powered wearable sensing-textiles for real-time detecting environmental atmosphere and body motion have been presented. The textile is based on highly stretchable conductive ecoflex fiber modified with multiwall carbon nanotube and polyaniline (PANI) derivatives (acting as one electrode). The surface of the fiber is twined with varnished wire (acting as the other electrode). Upon applied deformation of stretching or bending, the sensing-textile can harvest the mechanical energy and output electric signals through the triboelectrification effect between PANI and varnished wire. After being attached on the human body, the triboelectric output of the sensing-textile can be used to monitor body motion, including finger bending and body stretching. Interestingly, the triboelectric output of the sensing-textile is significantly dependent on the atmosphere, which can actively distinguish different gas species in the environment. The sensitivity, stability and selectivity against ethanol, ammonia, acetone and formaldehyde are high. The response against 400 ppm ethanol vapor at room temperature is up to 54.73%. The current density is 2.1 * 10-4 A m-2, and the power density is 4.2 * 10-5 W m-2. During both the motion detecting and gas sensing processes, no external electricity power is needed. The triboelectric signal can be treated as not only the sensing signal but also the power source for driving the device. The working mechanism is based on surface-triboelectric coupling effect. The present results can promote the development of self-powered wearable electronics. PMID- 30015629 TI - The effect of L-rhamnose on intestinal transit time, short chain fatty acids and appetite regulation: a pilot human study using combined 13CO2/H2 breath tests. AB - BACKGROUND: The appetite-regulating effects of non-digestible carbohydrates (NDC) have in part previously been attributed to their effects on intestinal transit rates as well as microbial production of short chain fatty acids (SCFA). Increased colonic production of the SCFA propionate has been shown to reduce energy intake and stimulate gut hormone secretion acutely in humans. OBJECTIVE: We investigated the effect of the propiogenic NDC, L-rhamnose, on gastrointestinal transit times using a combined 13CO2/H2 breath test. We hypothesised that L-rhamnose would increase plasma propionate leading to a reduction in appetite, independent of changes in gastrointestinal transit times. DESIGN: We used a dual 13C-octanoic acid/lactose 13C-ureide breath test combined with breath H2 to measure intestinal transit times following the consumption of 25 g d-1 L-rhamnose, compared with inulin and cellulose, in 10 healthy humans in a randomised cross-over design pilot study. Gastric emptying (GE) and oro-caecal transit times (OCTTs) were derived from the breath 13C data and compared with breath H2. Plasma SCFA and peptide YY (PYY) were also measured alongside subjective measures of appetite. RESULTS: L-rhamnose significantly slowed GE rates (by 19.5 min) but there was no difference in OCTT between treatments. However, breath H2 indicated fermentation of L-rhamnose before it reached the caecum. OCTT was highly correlated with breath H2 for inulin but not for L rhamnose or cellulose. L-rhamnose consumption significantly increased plasma propionate and PYY but did not significantly reduce subjective appetite measures. CONCLUSIONS: The NDCs tested had a minimal effect on intestinal transit time. Our data suggest that L-rhamnose is partially fermented in the small intestine and that breath H2 reflects the site of gastrointestinal fermentation and is only a reliable marker of OCTT for certain NDCs (e.g. inulin). Future studies should focus on investigating the appetite-suppressing potential of L-rhamnose and verifying the findings in a larger cohort. PMID- 30015630 TI - Mechanical relaxation and freezing in the room temperature strain glass alloy Ti50(Pd40Cr10). AB - The alloy Ti50(Pd40Cr10) undergoes a strain glass transition around room temperature evidenced by frequency dispersion of dynamic mechanical properties and lack of average structure change from that of the high symmetry austenite phase. However, since the strain glass transition is not a thermodynamic phase transition but a dynamic freezing process governed by the kinetics, a quantitative characterization of the slowing down of dynamics during the strain glass transition is still lacking. In the present study, the probability distribution function (PDF) of the relaxation time of the strain glass alloy is investigated spanning the whole transition temperature range (253 K-313 K). The slowing down of dynamics of the strain glass is indicated by the rapid increase of the characteristic relaxation time ([Formula: see text]) upon cooling. The [Formula: see text], as a function of temperature, shows a transition from Vogel Fulcher relationship to an Arrhenius relationship. Such a change suggests two fundamentally different states: unfrozen strain glass state and frozen strain glass state. Furthermore, the spread of the PDF is connected to the fraction of quasi-static nanodomains, which helps the understanding of the dynamic freezing process in the strain glass. PMID- 30015631 TI - Nonlocal statistical field theory of dipolar particles in electrolyte solutions. AB - We present a nonlocal statistical field theory of a dilute electrolyte solution with a small additive of dipolar particles. We postulate that every dipolar particle is associated with an arbitrary probability distribution function (PDF) of distance between its charge centers. Using the standard Hubbard-Stratonovich transformation, we represent the configuration integral of the system in the functional integral form. We show that in the limit of a small permanent dipole moment, the functional in integrand exponent takes the well known form of the Poisson-Boltzmann-Langevin (PBL) functional. In the mean-field approximation we obtain a non-linear integro-differential equation with respect to the mean-field electrostatic potential, generalizing the PBL equation for the point-like dipoles obtained first by Abrashkin et al. We apply the obtained equation in its linearized form to derivation of the expressions for the mean-field electrostatic potential of the point-like test ion and its solvation free energy in salt-free solution, as well as in solution with salt ions. For the 'Yukawa'-type PDF we obtain analytic relations for both the electrostatic potential and the solvation free energy of the point-like test ion. We obtain a general expression for the bulk electrostatic free energy of the solution within the Random phase approximation (RPA). For the salt-free solution of the dipolar particles for the Yukawa-type PDF we obtain an analytic relation for the electrostatic free energy, resulting in two limiting regimes. Finally, we analyze the limiting laws, following from the general relation for the electrostatic free energy of solution in presence of both the ions and the dipolar particles for the case of Yukawa type PDF. PMID- 30015633 TI - Foreword: Depression in the Pregnant Patient. PMID- 30015635 TI - Prevention of hospital-acquired pneumonia. AB - PURPOSE OF REVIEW: Hospital-acquired pneumonia (HAP) is the leading cause of death from hospital-acquired infection. Little work has been done on strategies for prevention of HAP. This review aims to describe potential HAP prevention strategies and the evidence supporting them. Oral care and aspiration precautions may attenuate some risk for HAP. Oral and digestive decontamination with antibiotics may be effective but could increase risk for resistant organisms. Other preventive measures, including isolation practices, remain theoretical or experimental. RECENT FINDINGS: Hospital-acquired pneumonia occurs because of pharyngeal colonization with pathogenic organisms and subsequent aspiration of these pathogens. SUMMARY: Most potential HAP prevention strategies remain unproven. PMID- 30015634 TI - Ethical issues in HIV remission trials. AB - PURPOSE OF REVIEW: Several promising experimental pathways exist for long-term control of HIV in the absence of antiretroviral therapy (HIV 'remission') and are now being tested in early clinical studies. These studies can be invasive and pose a host of distinctive risks to participants, as well as to nonparticipants, especially to participants' fetuses, and sexual partners. RECENT FINDINGS: Ethical analyses of these studies have mainly focused on the risks to study participants. They recommend, and some investigators implement, procedures to mitigate risks for participants or to offset them with direct, indirect, and nonmedical benefits. They also suggest ways to keep participants' consent highly voluntary and informed. Rarely do ethicists propose keeping the social value of studies high. Of these recommended responses, only the latter, rarer proposals help address the risk to nonparticipants, as would some novel ways to address that risk. SUMMARY: HIV remission studies pose a number of ethical dilemmas. Many current investigative approaches put the participant at significant risk, but well established guidelines exist for mitigating this risk. Ethical issues that are not being fully addressed include risk to nonparticipants and the need to consider the societal value of studies, for example, their prospective impact on the global HIV burden. VIDEO ABSTRACT. PMID- 30015636 TI - A Case Series and Literature Review: Isolated Traumatic First Rib Fracture in Athletes. AB - OBJECTIVE: To present a case series of 14 isolated traumatic first rib fractures sustained in sport and review the literature on clinical presentation, mechanism of injury, diagnosis, and management of sport-related traumatic first rib fractures. DESIGN: We compiled a series of isolated traumatic first rib fractures seen in 2 Division 1-associated sports medicine clinics. We also performed a literature search for additional publications of isolated traumatic first rib fractures in sport. SETTING: Patients in our case series were all evaluated and treated at 2 tertiary care center sports medicine clinics. PATIENTS: Patients were those who sustained isolated traumatic first rib fracture during sport. INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: None. CONCLUSIONS: Traumatic fracture of the first rib in sport is certainly not a common diagnosis, but it is likely more widespread than sports medicine providers realize. Considering the diagnosis of first rib fracture for athletes with shoulder pain after trauma is essential for identifying this injury. Although more study is likely needed to make definitive recommendations on treatment and return to play protocols, the case series and literature review presented suggests that rehabilitation and return to play when the patient is asymptomatic may be appropriate care. PMID- 30015632 TI - Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates. AB - Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules. PMID- 30015637 TI - Effects of Exercise on Sport Concussion Assessment Tool-Third Edition Performance in Women. AB - OBJECTIVE: The purpose of this study was to examine the influence of a brief exercise protocol on Sport Concussion Assessment Tool-Third Edition (SCAT3) performance in amateur women athletes. DESIGN: Cross-over repeated-measures design. SETTING: Off-season, uninjured community amateur athletes. PARTICIPANTS: We examined 87 amateur women athlete volunteers (age = 29.9, SD = 6.9 years). INDEPENDENT VARIABLES: Participants were assessed using the SCAT3 under 2 conditions: at rest and after a 5-minute physical exertion protocol, completed in a counterbalanced order. MAIN OUTCOME MEASURES: Participants' performance on the various components of the SCAT3 under the 2 conditions: at rest and after a 5 minute physical exertion protocol. RESULTS: No significant differences were detected between at-rest and postexercise conditions for the balance, orientation, or cognitive components of the SCAT3. There were no significant differences in the proportion of participants who endorsed specific symptoms at rest compared with the postexercise condition (P > 0.05). However, women athletes who rated their exertion after exercise as "hard" or greater (Borg scale rating 13-20) reported significantly greater blurred vision (M = 0.25, SD = 0.62 vs M = 0.00, SD = 0.00; P = 0.006) and fatigue/low energy (M = 1.38, SD = 1.17 vs M = 0.66, SD = 0.91; P = 0.002) symptoms after exercise than those who rated their exertion as "light" or lower (Borg scale rating 6-12). CONCLUSIONS: In this study of women athletes, a brief bout of exercise did not seem to adversely affect SCAT3 performance and had only small effects on self-reported symptoms. There were differences in symptom reporting, however, in the subgroup of women who rated their exertion levels as "hard" or greater; they reported more blurred vision and fatigue/low energy. PMID- 30015638 TI - Fluid management concepts for severe neurological illness: an overview. AB - PURPOSE OF REVIEW: The acute care of a patient with severe neurological injury is organized around one relatively straightforward goal: avoid brain ischemia. A coherent strategy for fluid management in these patients has been particularly elusive, and a well considered fluid management strategy is essential for patients with critical neurological illness. RECENT FINDINGS: In this review, several gaps in our collective knowledge are summarized, including a rigorous definition of volume status that can be practically measured; an understanding of how electrolyte derangements interact with therapy; a measurable endpoint against which we can titrate our patients' fluid balance; and agreement on the composition of fluid we should give in various clinical contexts. SUMMARY: As the possibility grows closer that we can monitor the physiological parameters with direct relevance for neurological outcomes and the various complications associated with neurocritical illness, we may finally move away from static therapy recommendations, and toward individualized, precise therapy. Although we believe therapy should ultimately be individualized rather than standardized, it is clear that the monitoring tools and analytical methods used ought to be standardized to facilitate appropriately powered, prospective clinical outcome trials. PMID- 30015639 TI - New biologics in the treatment of urticaria. AB - PURPOSE OF REVIEW: Symptomatic management of chronic spontaneous urticaria (CSU) basically depends on second-generation H1 antihistamines and omalizumab. Omalizumab is a game changer in the management, but still there is a need for new targets and new biologics targeting new pathways in the treatment which will provide long-lasting remission, which will be given orally and which will be cheaper. This review will focus on new biologics that are underway of production or are already under use for different disorders but could be beneficial for the treatment of Chronic urticaria. RECENT FINDINGS: In this review, the treatment targets are classified according to the cells which are involved in the pathogenesis of CSU. Those are mast cells/basophils, B cells, T cells and eosinophils. The treatments that are under clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules targeting intracellular signaling pathways such as spleen tyrosine kinase inhibitors, surface inhibitory molecules such as siglec-8, anti-IL-1s such as canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such as benralizumab and mepolizumab. SUMMARY: The ongoing clinical trials on new targets of treatment hold new hopes not only for a better care of the disease but also a better understanding of the pathomechanisms lying underneath. PMID- 30015640 TI - Ocular allergy as a risk factor for dry eye in adults and children. AB - PURPOSE OF REVIEW: To provide an overview of the pathogenic mechanisms underlying the correlation between ocular allergy and dry eye disease (DED), highlighting how the first condition may be a risk factor for the second one. RECENT FINDINGS: Recent advances in our comprehension of the pathogenesis of ocular allergy and DED allow identifying several pathways of interaction between these two conditions. A growing body of evidence supports the role of ocular allergy as a risk factor for DED. Ocular allergy, particularly the severe forms of keratoconjunctivitis, can impact on different key mechanisms of the DED vicious cycle, including tear film instability, ocular surface inflammation and damage, and neurosensory abnormalities. SUMMARY: Ocular allergy and DED are two common, relevant, symptomatic, not mutually exclusive conditions affecting the ocular surface. They share some clinical and biochemical features. To better understand the complex interactions between these two conditions, it's essential to consider the very wide spectrum of clinical conditions included in the term ocular allergy and the still largely unexplored peculiarities of the pediatric ocular surface physio-pathology and DED. PMID- 30015641 TI - Precision medicine in food allergy. AB - PURPOSE OF REVIEW: To familiarize the reader with the concept of precision medicine in food allergy through the most recent insights in the diagnosis, prognosis, and management of the disease. RECENT FINDINGS: With the advent of omics sciences, a new era is commencing. Food protein allergens characterization and quantification together with the immunoglobulin E epitope mapping will contribute to the diagnosis/prognosis of food allergy and will lead to a better safety assessment of foods. The characterization of biomarkers able to identify specific phenotypes and endotypes will improve the diagnostic accuracy. This together with a better understanding of mechanisms of action of the different therapeutic options will allow the accurate selection of the appropriate patient. SUMMARY: In the near future, advances in technologies and data interpretation will allow a better understanding of the pathogenesis of food allergy and the development of a personalized treatment tailored on the specific patient' profile. PMID- 30015642 TI - Pathophysiology of immune thrombocytopenia. AB - PURPOSE OF REVIEW: Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder with as of yet, no established clinical prognostic or diagnostic biomarkers. Patients frequently experience a markedly decreased quality of life and may be at risk for severe/fatal haemorrhage. Here, we address discoveries in the pathogenesis of ITP, and novel therapeutic strategies in mouse models and human patients. Consolidation of these findings should be important in providing insight to establish future prognostic protocols as well as cutting-edge therapeutics to target refractory ITP. RECENT FINDINGS: It is unknown why a significant portion of ITP patients are refractory to standard treatments. Recent findings suggest distinct heterogeneity in ITP including antibody-mediated platelet activation, Fc-independent desialylated platelet clearance, attenuation of platelet-mediated hepatic thrombopoietin generation, and decreased CD8 T suppressor generation. These mechanisms may partially explain clinical observations of increased refractoriness to standard therapies targeting classical Fc-dependent pathways. Moreover, these have initiated investigations into platelet desialylation as a diagnostic/prognostic marker and therapeutic target. SUMMARY: Recent evidence of distinct ITP pathophysiology has opened new exploratory avenues for disease management. We will discuss the utility of investigations into these mechanisms of ITP and its potential impact in our understanding of pathogenesis and future treatment strategies. PMID- 30015644 TI - Evaluation of a Barcode Medication Administration Information System. AB - When a medication administration error occurs, patient safety is endangered. Barcode medication administration system usage has been implemented to reduce medication errors. The purpose of this study was to evaluate barcode medication administration system usage outcomes. A survey based on DeLone and McLean's model of information systems success was utilized. The questionnaire, composed of 27 items, explored system quality, information quality, service quality, user satisfaction, and usage benefits. It was completed by 232 nurses. User satisfaction received the highest average score, and quality of information was the most critical factor related to this result (r = 0.83, P < .01). Medication errors occurring before and after barcode medication administration use were collected, and the reasons for errors related to work process were explored. Medication errors decreased from 405 at preimplementation to 314 at postimplementation (t = 77.62, P < .001). The main reason for medication errors related to work process was "not following the standard procedure," followed by "other factors." While technology is deployed to support individual practice, organizational elements also remain important to technology adoption. PMID- 30015643 TI - Emerging applications of aptamers for anticoagulation and hemostasis. AB - PURPOSE OF REVIEW: Since the selection of the first thrombin-binding aptamer in 1992, the use of nucleic acid aptamers to target specific coagulation factors has emerged as a valuable approach for generating novel anticoagulant and procoagulant therapeutics. Herein, we highlight the most recent discoveries involving application of aptamers for those purposes. RECENT FINDINGS: Learning from the successes and pitfalls of the FIXa-targeting aptamer pegnivacogin in preclinical and clinical studies, the latest efforts to develop antidote controllable anticoagulation strategies for cardiopulmonary bypass that avoid unfractionated heparin involve potentiation of the exosite-binding factor X (FX)a aptamer 11F7t by combination with either a small molecule FXa catalytic site inhibitor or a thrombin aptamer. Recent work has also focused on identifying aptamer inhibitors of contact pathway factors such as FXIa and kallikrein, which may prove to be well tolerated and effective antithrombotic agents in certain clinical settings. Finally, new approaches to develop procoagulant aptamers to control bleeding associated with hemophilia and other coagulopathies involve targeting activated protein C and tissue plasminogen activator. SUMMARY: Overall, these recent findings exemplify the versatility of aptamers to modulate a variety of procoagulant and anticoagulant factors, along with their capacity to be used complementarily with other aptamers or drugs for wide-ranging applications. PMID- 30015645 TI - Exploring Patient and Caregiver Perceptions of Primary Healthcare Sector Home Care for Simple Acute Wounds. AB - GENERAL PURPOSE: To provide information about a study exploring patient and caregiver perceptions of home wound care for patients with simple acute wounds in Singapore. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After completing this continuing education activity, you should be able to:1. Assess benefits and barriers to home wound care management.2. Analyze the methodology, results, and implications of the study. ABSTRACT: To control healthcare expenditure, patients with simple, acute, low-risk wounds are encouraged to perform self-wound care at home. However, patient perception of this care is not known. OBJECTIVE: To explore patient and caregiver perceptions of home wound care for patients with simple acute wounds in the primary healthcare sector in Singapore. METHODS: This study used the constructivist grounded theory approach. Nine participants from 2 polyclinics were interviewed. In vivo codes were extracted, and the constant comparative technique was applied throughout the analytical process. RESULTS: Fear, lack of knowledge, and the difficulty in performing care resulted in many patients avoiding self-wound care. Age, educational level, and cost did not have much impact. Participants with some first aid knowledge and those who appreciated the flexibility of self-wound care were more likely to embrace this concept. Participants also suggested that telecommunications and mobile nurses could assist in this concept. CONCLUSIONS: Generally, patients are willing to accept this self-wound care concept. To ensure successful implementation, nurses should encourage eligible patients to attend educational programs to prepare them to perform wound care at home. PMID- 30015647 TI - An introduction to left ventricular strain. AB - PURPOSE OF REVIEW: The assessment of left ventricular function by two-dimensional (2D) transthoracic echocardiography (TTE) is conventionally performed by measuring the ejection fraction, which has been shown to have important prognostic implications. However, left ventricular ejection fraction (LVEF) has notable shortcomings, including limited reproducibility, suboptimal inter/intraobserver variability and dependence on load/volume. Furthermore, subclinical left ventricular dysfunction cannot be measured with LVEF. With the advent of left ventricular deformation (strain) analysis, a new and robust means for assessing left ventricular function has emerged. RECENT FINDINGS: Contemporary research and guidelines have attempted to standardize the definition, acquisition and measurement of left ventricular strain. In addition, multiple studies have sought to establish normal values for left ventricular strain in addition to evaluating the benefits and prognostic value of strain assessment. SUMMARY: This article reviews the definition of left ventricular strain, outlines the types of strain and reviews how strain is acquired and measured. In addition, the advantages of strain analysis over LVEF as well as the incremental prognostic value of strain are examined. We further review the challenges associated with strain imaging as well as outline the future of strain imaging. PMID- 30015646 TI - Comparison of a new criteria for sepsis-induced coagulopathy and International Society on Thrombosis and Haemostasis disseminated intravascular coagulation score in critically ill patients with sepsis 3.0: a retrospective study. AB - : Recently, new criteria for sepsis-induced coagulopathy (SIC) were developed, including the sequential organ failure assessment (SOFA) criteria. The objective of this study was to evaluate the new SIC criteria in patients diagnosed with sepsis 3.0. Data from patients diagnosed with sepsis 3.0 after ICU admission were retrospectively obtained from July 2013 to June 2014. Relevant demographic, clinical, and laboratory parameters were noted. This study included 252 patients. The International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC), modified ISTH-DIC, and SIC scores were higher among nonsurvivors (P < 0.0001). The Acute Physiology and Chronic Health Evaluation II (P < 0.001), ISTH (P = 0.001), modified ISTH (P = 0.001), and SIC scores (P = 0.007) were independent predictors of ICU mortality. Using the receiver operating characteristic curve, SOFA had the greatest power for predicting ICU mortality; ISTH or modified ISTH score had greater predictive power than the SIC score. There were strong correlations between SIC score and ISTH (P < 0.0001), modified ISTH (P < 0.0001), the Acute Physiology and Chronic Health Evaluation II (P = 0.012), and SOFA (P < 0.0001) scores. More nonsurvivors were diagnosed with DIC using the ISTH and modified ISTH criteria (P < 0.001). In contrast, there was no significant difference in the proportion of patients with SIC between both groups (P = 0.055). ISTH score, modified ISTH score, and SIC score were independent risk factors for ICU mortality. Compared with the ISTH and modified ISTH scores, SIC score showed no advantage in diagnosing sepsis associated coagulopathy or DIC. The application of these three criteria in patients with sepsis 3.0 needs further evaluation. PMID- 30015648 TI - Amyloidosis cardiomyopathy: update in the diagnosis and treatment of the most common types. AB - PURPOSE OF REVIEW: The present article provides an update about the recent advances in the diagnosis and management of the most common types of cardiac amyloidosis, including light chain, wild-type transthyretin (ATTRwt), and mutant transthyretin (ATTRm). RECENT FINDINGS: The document reviews the utility of diagnostic tools including innovative echocardiographic indices, magnetic resonance T1 mapping and measurement of extracellular volume, and the role and validation of bone scintigraphy for the noninvasive assessment of ATTR amyloidosis. It summarizes the data about therapies for light chain amyloidosis including bortezomib regimens and also novel disease modifying therapies for ATTR amyloidosis such as gene silencers, transthyretin stabilizers, and degraders of amyloid fibrils. SUMMARY: The present review provides the readers with the necessary tools in order to recognize and diagnose cardiac amyloidosis early and introduces the recent advances in management that are improving the outcomes of a condition that was considered to be untreatable. PMID- 30015649 TI - In sickness and in health: relationship quality and cardiovascular risk and management. AB - PURPOSE OF REVIEW: To review the link between couple relationships and cardiovascular health, the plausible mechanisms by which relationship quality affects heart health, and to provide an overview of couple-based interventions aimed at improving cardiovascular health. RECENT FINDINGS: Marriage and the quality of the couple relationship bond are robust predictors of long-term health outcomes. Chronic relationship conflict and disconnection can be deadly. There are direct and indirect pathways by which couple relationship quality affect cardiovascular health. Direct pathways include effects of relationship quality on cardiovascular, neuroendocrine, and immune functioning. Indirect pathways include effects of emotional, cognitive and behavioural factors that impact lifestyle choices and adherence to treatment regimens. Effects of couple-based interventions addressing traditional cardiovascular risk factors have been null to modest and there is only one couple-based intervention that addressed relationship quality and heart health. On the basis of the literature, this is major oversight. We propose attachment-based interventions, such as our Healing Hearts Together program, for patients with heart disease and their partners. SUMMARY: Previous research indicates that couple-based interventions are promising. Large randomized controlled trials that aim to improve relationship quality among patients with CVD and their partners, as well as study mechanistic, surrogate, and clinical outcomes, are required to appropriately assess their impact. PMID- 30015650 TI - Influence of a Preoperative Conference on Surgeons' Decision-making for Adult Spinal Disorders: A Prospective Clinical Study From a Spine Hospital. AB - STUDY DESIGN: This was a prospective clinical study. OBJECTIVE: The aim of this study was to evaluate the influence of a preoperative conference on spine surgeons' decision-making in the treatment of adult spinal disorders. SUMMARY AND BACKGROUND DATA: There are several factors that spine surgeons have to consider when determining a surgical plan for the treatment of spinal disorders, which include surgical approach, application of fusion or nonfusion surgery, levels to be treated, treatment of accompanying spinal conditions, the need for further preoperative imaging, and the implant type to be used. MATERIALS AND METHODS: A consecutive series of patients with a variety of adult spinal disorders at a single spine hospital were analyzed. The imaging modalities and clinical examination history of these patients were presented at a daily preoperative conference attended by staff spine surgeons and spine surgery fellows at this spine hospital. The specific surgical plan before the preoperative conference and before the surgery were compared for each patient. RESULTS: A total of 506 consecutive patients were reviewed over a 4-month period. Changes in the surgical plan following the preoperative conference occurred in 29 cases (5.7%). Seventeen of these changes were minor modifications in the same surgical level, or inclusion/exclusion of adjacent or other levels in the surgical plan, without changing the planned surgical approach. The surgical approach changed in a total of 12 cases (2.3%). Statistical analysis showed that the surgeons with experience of <10 years and orthopedic surgeons changed their surgical plan more often after the preoperative conference (P<0.05). CONCLUSIONS: Preoperative conference for the surgical treatment of adult spinal disorders influenced the surgical plan in 5.7% of surgeries. This type of daily preoperative conference seems to have only a minor impact on spine surgeons' decision-making, but, instead, it could be used to provide training and insight to better a fellow or resident's education at the spine institution. LEVEL OF EVIDENCE: Level IV. PMID- 30015651 TI - Real-World Effectiveness of Physical Therapy for Common Neck Pain Diagnoses: A Multivariate Analysis of 1554 Patients. AB - STUDY DESIGN: Retrospective cohort study (Level of evidence-3). OBJECTIVE: The objective of this study was to investigate the real-life effectiveness of physical therapy (PT) for patients initially presenting with common neck pain diagnoses. SUMMARY OF BACKGROUND DATA: Neck pain is a common cause of morbidity and a leading cause of disability in the United States. PT is prescribed as a first-line treatment for the vast majority of patients with neck pain; however, there is limited literature supporting the effectiveness of these treatments. METHODS: A total of 1554 patients enrolled in PT for the nonoperative treatment of neck pain were included in the study. Three primary patient-reported outcome (PRO) measures [neck disability index (NDI), resting numeric pain rating scale (NPRS), and activity NPRS] were recorded before and at conclusion of therapy. Improvement was noted if patients met a threshold value for a minimal clinically important difference (MCID). Bivariate analysis using a chi test and multiple logistic regression analysis were performed to determine risk factors predictive of treatment failure. RESULTS: About 40.5% of patients achieved MCID for NDI with an average change of -6.31 points. For resting NPRS and activity NPRS scores, 50.6% and 52.1% of patients achieved MCID with an average change of -1.93 and 2.36, respectively. After multiple logistic regression analysis, worker's compensation status was found to be an independent predictor for treatment failure in all groups; whereas, Medicare status was found predictive of achieving MCID in the activity NPRS group. CONCLUSIONS: We observed that up to half of the patients analyzed met the minimum criteria for improvement in neck pain with respect to the PRO measures, suggesting that real-life effectiveness of PT for common neck pain diagnoses may approach 50%. PMID- 30015652 TI - Simultaneous Determination of Cefalexin, Cefazolin, Flucloxacillin, and Probenecid by Liquid Chromatography-Tandem Mass Spectrometry for Total and Unbound Concentrations in Human Plasma. AB - BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used beta-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories. METHODS: Unbound drug was separated from bound drug by ultrafiltration. A simple 1-step protein precipitation was used for sample preparation. Cefalexin, cefazolin, flucloxacillin, probenecid, and their corresponding isotopically labeled internal standards were then resolved on a C18 (2) column. All the compounds were detected using electrospray ionization in the positive mode. RESULTS: Standard curves were linear for all compounds over the concentration range of 0.2-100 mg/L (r > 0.99) for total drug in plasma and 0.01-10 mg/L (r > 0.99) for unbound drug in plasma ultrafiltrate. For both total and unbound drugs, bias was <+/-10%, and intra- and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 0.2 mg/L for total plasma concentrations and 0.01 mg/L for plasma ultrafiltrate concentrations of all drugs. CONCLUSIONS: The method has proven to be simple, rapid, robust, and reliable and is currently being used in clinical pharmacokinetic studies and in the routine clinical service to enhance the effective use of the beta-lactam antibiotics. PMID- 30015653 TI - Survival Analysis and Interpretation of Time-to-Event Data: The Tortoise and the Hare. AB - Survival analysis, or more generally, time-to-event analysis, refers to a set of methods for analyzing the length of time until the occurrence of a well-defined end point of interest. A unique feature of survival data is that typically not all patients experience the event (eg, death) by the end of the observation period, so the actual survival times for some patients are unknown. This phenomenon, referred to as censoring, must be accounted for in the analysis to allow for valid inferences. Moreover, survival times are usually skewed, limiting the usefulness of analysis methods that assume a normal data distribution. As part of the ongoing series in Anesthesia & Analgesia, this tutorial reviews statistical methods for the appropriate analysis of time-to-event data, including nonparametric and semiparametric methods-specifically the Kaplan-Meier estimator, log-rank test, and Cox proportional hazards model. These methods are by far the most commonly used techniques for such data in medical literature. Illustrative examples from studies published in Anesthesia & Analgesia demonstrate how these techniques are used in practice. Full parametric models and models to deal with special circumstances, such as recurrent events models, competing risks models, and frailty models, are briefly discussed. PMID- 30015655 TI - Special Cardiac Arrest Situations in the Perioperative Period. PMID- 30015654 TI - In Response. PMID- 30015656 TI - Unfavorable Structural and Functional Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis. AB - BACKGROUND: Recurrent optic neuritis (rON) associated with myelin oligodendrocyte glycoprotein (MOG)-specific antibodies has been initially reported to show a better clinical outcome than aquaporin-4 (AQP4)-seropositive ON in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterize clinical and neuroimaging findings in severe cases of MOG antibody-positive and AQP4 antibody-negative bilateral rON. METHODS: Three male adults with rON (ages 18, 44, and 63 years) were evaluated with optical coherence tomography (OCT), MRI, cerebrospinal fluid (CSF), and serological studies. RESULTS: All patients experienced >7 relapses of ON with severe reduction of visual acuity and partial response to steroid treatment. Optic nerves were affected bilaterally, although unilateral relapses were more frequent than simultaneous bilateral recurrences. Patients were MOG seropositive but repeatedly tested negative for AQP4 antibodies. OCT showed severe thinning of the peripapillary retinal nerve fiber layer. On MRI, contrast enhancing lesions extended over more than half the length of the optic nerve. CSF analyses during ON episodes were normal. Severe visual deficits accumulated over time in 2 of 3 patients, despite immunosuppressive therapy. CONCLUSIONS: MOG seropositive and AQP4-seronegative rON may be associated with an aggressive disease course and poor functional and structural outcomes. In contrast to previous reports, the severity and pattern of retinal and optic nerve damage closely resembled phenotypes commonly observed in AQP4-seropositive rON without fulfilling current diagnostic criteria for NMOSD. PMID- 30015657 TI - The 44th Annual Meeting of the North American Neuro-Ophthalmology Society in Waikola Village on the Big Island, Hawaii 2018. PMID- 30015658 TI - Prospective Serial FDG PET/CT During Treatment of Extrapulmonary Tuberculosis in HIV-Infected Patients: An Exploratory Study. AB - PURPOSE: The aim of this study was to prospectively describe evolution of F-FDG uptake of extrapulmonary tuberculosis (TB) throughout the course of TB treatment in HIV patients to evaluate F-FDG PET/CT as a monitoring tool of treatment response. METHODS: We performed baseline FDG PET/CT, PET-2 after 2 months, and PET-3 at the end of TB treatment in 18 HIV/TB patients. We correlated evolution of FDG uptake with clinical outcome of patients. RESULTS: After 2 months of treatment, 78% of the patients had a significant metabolic response. Lymph node (LN) metabolic response was heterogeneous, with 57% of LN sites showing decreased SUVmax and 41% showing unchanged FDG uptake. Organs other than LNs showed more homogeneous response. The FDG PET/CT performed at the end of TB treatment showed a complete response of all infected organs and a drastic response in terms of active LNs in 95% of the patients (SUVmax mean decrease = 85%, median = 100%). A complete metabolic response after TB treatment was seen in only 47% of patients. CONCLUSIONS: In difficult-to-treat entities such as extrapulmonary TB in HIV patients, FDG PET/CT is a potential tool in monitoring TB treatment response and should be explored in larger studies. PMID- 30015660 TI - FDG PET-CT in Adrenal Multiple Myeloma. AB - Extramedullary involvement in multiple myeloma is rare, but carries poor prognosis. We describe the FDG PET-CT findings of rare adrenal involvement in a case of multiple myeloma. PMID- 30015659 TI - Prognostic Value of FDG-PET/CT Metabolic Parameters in Metastatic Radioiodine Refractory Differentiated Thyroid Cancer. AB - PURPOSE: There are no standardized prognostication algorithms for metastatic radioiodine-refractory (RAI-R) differentiated thyroid cancer (DTC). We hypothesize that [F]-FDG PET/CT may predict progression versus stability of disease based on quantitative analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG). METHODS: Retrospective study of 62 patients with metastatic RAI-R DTC to determine clinical outcomes with median follow-up from initial diagnosis of 11.1 years (8.38, 14.1) (range, 1.2-20 years). Baseline [F] FDG PET/CT scans were evaluated qualitatively for regional and distant metastases and quantitatively for tumor burden based on MTV and TLG obtained using gradient segmentation method. RESULTS: After diagnosis of metastatic RAI-R disease was established, the 5-year overall survival (OS) probability was 34%, and median OS was 3.56 years (2.87, infinity). The 5-year progression-free survival (PFS) probability was 19%, and median PFS was 1.31 years (1.03, 2.38). TSH-suppressed thyroglobulin (Tg) levels greater than 100 ng/mL and Tg doubling time (Tg-DT) less than 6 months were significantly associated with worse OS and PFS. Higher than median values of MTV and TLG were associated with worse OS (P = 0.06) and PFS (P = 0.007). Higher hazard of death was noted for higher values of log-MTV and log-TLG (HR, 1.17 [95% confidence interval, 0.99-1.39], P = 0.05, and HR, 1.14 [95% confidence interval, 1.00-1.31], P = 0.05, respectively). CONCLUSIONS: [F]-FDG PET/CT metabolic parameters can help define the volume and biologic variations of metastatic tumor burden. Metabolic tumor volume and TLG can be used for dynamic risk stratification of patients with metastatic RAI-R DTC regarding PFS and complement Tg-DT for prognosis of clinical disease course. PMID- 30015661 TI - Unusual and Diffuse Hypermetabolism in Routine 18F-FDG PET/CT of the Supra-aortic Vessels in Biopsy-Positive Giant Cell Arteritis. AB - F-FDG PET-CT used to lack of resolution to detect vasculitis in the superficial cranial and cervical arteries. Very few cases, for which some of these arteries were visualized, are published, and the images were acquired using a dedicated PET protocol. We present a case, acquired using a routine whole-body protocol, with increased tracer uptake detected in vertebral arteries, internal and external carotid arteries, superficial temporal arteries, occipital arteries, maxillary arteries, facial arteries, and lingual arteries. It underlines the potential for newer-generation PET-CT system to assess vasculitis. F-FDG PET-CT may have an important role to detect and follow vasculitis in the future. PMID- 30015662 TI - 99mTc Sodium Pertechnetate Uptake in Ectopic Mediastinal Thyroid Tissue on Hybrid Thyroid Scintigraphy. AB - Ectopic thyroid is a rare/incidental imaging finding. When discovered, 90% of ectopic thyroid is found typically along the pathway of embryologic migration of thyroid tissue, whereas around 10% have been discovered in other anatomical locations including the mediastinum and the heart. Thyroid scintigraphy with Tc sodium pertechnetate (TcO4) is peculiar for thyroid tissue uptake. The current case, clinically euthyroid, had heterogeneous uptake in multinodular goiter with uptake in the ectopic thyroid tissue in right paratracheal location on functional imaging with TcO4. Subsequent single photon emission computed tomography/computed tomography (SPECT/CT) imaging confirmed the ectopic thyroid tissue. PMID- 30015663 TI - Biochemical Recurrence of Prostate Cancer Presenting as Solitary Testicular Metastasis on 68Ga-Labeled Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography/Computed Tomography. AB - Prostate adenocarcinoma (PCa) is the most frequently diagnosed malignancy in the male population, with the most common sites for secondary lesions being the lymph nodes, bones, and lungs. Testicular metastases from PCa are very rare and mostly identified incidentally after therapeutic orchiectomy for advanced PCa or during autopsy. Here we present a case involving a 64-year-old man with biochemical recurrence of castrated oligometastatic PCa that presented as solitary testicular metastasis on Ga-PSMA ligand positron emission tomography/computed tomography. PMID- 30015664 TI - Recurrent/Residual Intracranial Phosphaturic Mesenchymal Tumor Revealed on 68Ga DOTATATE PET/CT. AB - Phosphaturic mesenchymal tumors are benign tumors causing majority of tumor induced osteomalacia. These tumors are most commonly located in the lower extremities followed by craniofacial regions. However, intracranial lesion is very rare. Here we describe Ga-DOTATATE PET/CT findings of a recurrent intracranial phosphaturic mesenchymal tumor in a 68 year old woman. PMID- 30015665 TI - Maxillofacial Spindle Cell Sarcoma With Lung Metastases on FDG PET/CT Imaging. AB - A 45-year-old man presented with episodes of cough and chest discomfort. CT examination showed multiple nodules of bilateral lungs. The pathology of CT guided biopsy was consistent with spindle cell sarcoma. FDG PET/CT scan was performed to detect the primary lesion, which showed that in addition to multiple hypermetabolic pulmonary nodules, a mass in the right maxillofacial region with high FDG uptake was also found. A biopsy confirmed spindle cell sarcoma. PMID- 30015666 TI - Extreme Trachea Dilatation after Prolonged Ventilation at High Tracheal Cuff Pressure. PMID- 30015668 TI - Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: A Randomized, Double-Blind, Placebo-Controlled Study. AB - OBJECTIVE: To obtain preliminary evidence for the efficacy of lactoferrin as a preventative measure for nosocomial infections and inform the conduct of a definitive study. DESIGN: Phase 2, multicenter, randomized, double-blind, placebo controlled study. SETTING: Medical-surgical ICUs. PATIENTS: Adult, critically ill patients receiving invasive mechanical ventilation. INTERVENTIONS: Randomized, eligible, consenting patients expected to require invasive mechanical ventilation more than 48 hours received lactoferrin both enterally and via an oral swab or a placebo of sterile water for up to 28 days. MEASUREMENTS AND MAIN RESULTS: Of the 214 patients who were randomized, 212 received at least one dose of the intervention and were analyzed (107 lactoferrin and 105 placebo). Protocol adherence was 87.5%. Patients receiving lactoferrin were older (mean [SD], 66.3 [13.5] vs 62.5 [16.2] yr), had a higher Acute Physiology and Chronic Health Evaluation II score (26.8 [7.8] vs 23.5 [7.9]), and need for vasopressors (79% vs 70%). Antibiotic-free days (17.3 [9.0] vs 18.5 [7.1]; p = 0.91) and nosocomial infections (0.3 [0.7] vs 0.4 [0.6] per patient; p = 0.48) did not differ between lactoferrin and placebo groups, respectively. Clinical outcomes for lactoferrin versus placebo were as follows: ICU length of stay (14.5 [18.0] vs 15.0 [37.3] d; p = 0.82), hospital length of stay (25.0 [25.9] vs 28.1 [44.6] d; p = 0.57), hospital mortality (41.1% vs 30.5%; p = 0.11), and 90-day mortality (44.9% vs 32.4%; p = 0.06). Biomarker levels did not differ between the groups. CONCLUSIONS: Lactoferrin did not improve the primary outcome of antibiotic-free days, nor any of the secondary outcomes. Our data do not support the conduct of a larger phase 3 trial. PMID- 30015667 TI - Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study. AB - OBJECTIVES: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services' SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the "all-or-nothing" measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented. DESIGN: Retrospective cohort study. SETTING: Seven U.S. hospitals. PATIENTS: Adult patients included in SEP-1 reporting between October 2015 and September 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19-2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85-2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04-3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70-1.72; p = 0.674). CONCLUSIONS: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality. PMID- 30015669 TI - A Case for Change in Adult Critical Care Training for Physicians in the United States: A White Paper Developed by the Critical Care as a Specialty Task Force of the Society of Critical Care Medicine. AB - OBJECTIVES: In the United States, physician training in Critical Care Medicine has developed as a subspecialty of different primary boards, despite significant commonality in knowledge and skills. The Society of Critical Care Medicine appointed a multidisciplinary Task Force to examine alternative approaches for future training. DESIGN: The Task Force reviewed the literature and conducted informal discussions with key stakeholders. Specific topics reviewed included the history of critical care training, commonalities among subspecialties, developments since a similar review in 2004, international experience, quality patient care, and financial and workforce issues. MAIN RESULTS: The Task Force believes that options for future training include establishment of a 1) primary specialty of critical care; 2) unified fellowship and certification process; or 3) unified certification process with separate fellowship programs within the current specialties versus 4) maintaining multiple specialty-based fellowship programs and certification processes. CONCLUSIONS: 1) Changing the current Critical Care Medicine training paradigms may benefit trainees and patient care. 2) Multiple pathways into critical care training for all interested trainees are desirable for meeting future intensivist workforce demands. 3) The current subspecialties within separate boards are not "distinct and well-defined field[s] of medical practice" per the American Board of Medical Specialties. Recommendations for first steps are as follows: 1) as the society representing multidisciplinary critical care, the Society of Critical Care Medicine has an opportunity to organize a meeting of all stakeholders to discuss the issues regarding Critical Care Medicine training and consider cooperative approaches for the future. 2) A common Critical Care Medicine examination, possibly with a small percentage of base-specialty-specific questions, should be considered. 3) Institutions with multiple Critical Care Medicine fellowship programs should consider developing joint, multidisciplinary training curricula. 4) The boards that offer Critical Care Medicine examinations, along with national critical care societies, should consider ways to shorten training time. PMID- 30015670 TI - Postgraduate training in psychiatry in Asia. AB - PURPOSE OF REVIEW: To understand the current situation, needs and challenges in the area of postgraduate training in psychiatry in Asia and identify implementable solutions.Leaders in psychiatric education from nine Asia Pacific countries prepared country reports, based on a suggested list of items and met for a day to discuss and identify implementable solutions to improve the current unsatisfactory status of postgraduate training in psychiatry. RECENT FINDINGS: Except Japan, all the other countries have a very low number of psychiatrists per 100 000 population - far lower than the global target of 10 psychiatrist per 100 000 population. The undergraduate teaching in psychiatry in majority of the countries is restricted to 20 h of lectures given during the 4-6 semester and 2-3 weeks of clinical ward placements. The duration as well as the overall quality of postgraduate training and methods of assessment and accreditation varies widely across and within countries. SUMMARY: Numerous gaps that need to be addressed to enhance the quality of psychiatrists trained in Asia were identified. There is a need to have uniform minimum standards of training and mechanisms of mutual support, for not only training but also academics and research activities in Asia. PMID- 30015671 TI - An update on dementia training programmes in home and community care. AB - PURPOSE OF REVIEW: Many people living with dementia (PLWD) wish to continue living at home. The quality of home care services directly influences their ability to stay at home, their quality of life, and can promote independence for PLWD, and reduce burden for the family carer. For high-quality, effective, person centred community-based dementia care, a knowledgeable and empathetic workforce is crucial. This article presents an up-to-date review and summary of the literature investigating dementia training programmes for community home care professionals and care workers, referred to collectively as home care workers (HCWs). RECENT FINDINGS: We reviewed the literature between October 2016 and April 2018 on dementia training for HCWs. We found a significant lack of evidence based, codesigned specialist dementia training programmes for HCWs that address the needs of all stakeholders in home care, and which formally measure outcomes. SUMMARY: In order to enable PLWD to maintain living at home in the community, dementia-friendly and knowledgeable HCWs are needed. This review highlights the need for more research into the design and evaluation of evidence-based dementia specialist training programmes for community care. PMID- 30015672 TI - Malignant hyperthermia: still an issue for neuromuscular diseases? AB - PURPOSE OF REVIEW: We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate approach to interpret the risks. RECENT FINDINGS: An increasing number of neuromuscular phenotypes have been linked to malignant hyperthermia susceptibility (MHS). This is for an important part due to the highly variable phenotype associated with mutations in the ryanodine receptor 1 gene (RYR1), the gene most frequently associated with MHS. A RYR1-mutation or a clinical RYR1-phenotype does not automatically translate in MHS, but precautions should be taken nonetheless. In addition, several other genes and phenotypes are now considered to be associated with MHS. In contrast, several neuromuscular diseases that were long thought to be linked to MHS are now known to cause malignant hyperthermia-like reactions instead of malignant hyperthermia. This is highly relevant as not only the given preoperative advice differs, but also acute treatment. SUMMARY: This review provides a summary of current evidence linking certain neuromuscular diseases to malignant hyperthermia or malignant hyperthermia-like reactions. We provide a guide for the clinician, to determine which patients are at risk of malignant hyperthermia or malignant hyperthermia like reactions perioperatively, and to ensure adequate treatment in case such a severe acute complication occurs. PMID- 30015673 TI - Diagnostics and treatment of neuromusuclar disorders - a role model for rare diseases? PMID- 30015674 TI - Gastric Residual Volumes Versus Abdominal Girth Measurement in Assessment of Feed Tolerance in Preterm Neonates: A Randomized Controlled Trial. AB - BACKGROUND: Preterm neonates often have feed intolerance that needs to be differentiated from necrotizing enterocolitis. Gastric residual volumes (GRV) are used to assess feed tolerance but with little scientific basis. PURPOSE: To compare prefeed aspiration for GRV and prefeed measurement of abdominal girth (AG) in the time taken to reach full feeds in preterm infants. METHODS: This was a randomized controlled trial. Infants with a gestational age of 27 to 37 weeks and birth weight of 750 to 2000 g, who required gavage feeds for at least 48 hours, were included. Infants were randomized into 2 groups: infants in the AG group had only prefeed AG measured. Those in the GRV group had prefeed gastric aspiration obtained for the assessment of GRV. The primary outcome was time to reach full enteral feeds at 150 mL/kg/d, tolerated for at least 24 hours. Secondary outcomes were duration of hospital stay, need for parenteral nutrition, episodes of feed intolerance, number of feeds withheld, and sepsis. RESULTS: Infants in the AG group reached full feeds earlier than infants in the GRV group (6 vs 9.5 days; P = .04). No significant differences were found between the 2 groups with regard to secondary outcomes. IMPLICATIONS FOR PRACTICE: Our research suggests that measurement of AG without assessment of GRV enables preterm neonates to reach full feeds faster than checking for GRV. IMPLICATIONS FOR RESEARCH: Abdominal girth measurement as a marker for feed tolerance needs to be studied in infants less than 750 g and less than 26 weeks of gestation. PMID- 30015675 TI - Non-parenchymal hepatic cell lipotoxicity and the coordinated progression of non alcoholic fatty liver disease and atherosclerosis. AB - PURPOSE OF REVIEW: Non-alcoholic fatty liver disease (NAFLD) appears to be independently associated with the development of atherosclerosis. The biological mechanisms underlying this association are complex, and likely involve liver resident cell types other than hepatocytes. Thus, we review recent evidence that non-parenchymal hepatic cell responses to lipid excess contribute to the pathogenesis of both NAFLD and atherosclerosis. RECENT FINDINGS: Significant independent associations between NAFLD and atherosclerosis have been identified through cross-sectional studies and meta-analyses. Mechanistic studies in cell cultures and in rodent models suggest that liver-resident macrophages, activated hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) mount lipotoxic responses under NAFLD conditions which can contribute to the progression of both NAFLD and atherosclerosis. SUMMARY: Non-parenchymal hepatic cell types exhibit some similarity in their responses to lipid excess, and in their pathogenic mechanisms, which likely contribute to the coordinated progression of NAFLD and atherosclerosis. In response to lipotoxic conditions, macrophages, Kupffer cells and HSC initiate robust inflammatory responses, whereas LSEC generate excess reactive oxygen species (ROS). The extent to which inflammatory cytokines and ROS produced by non-parenchymal cells contribute to the progression of both NAFLD and atherosclerosis warrants further investigation. PMID- 30015676 TI - Pharmacokinetic Evaluation of a 1-Day Treatment Initiation Option for Starting Long-Acting Aripiprazole Lauroxil for Schizophrenia. AB - BACKGROUND: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation. We report findings from a phase 1 study investigating a nanocrystalline milled dispersion of AL (ALNCD) as a potential 1 day initiation regimen. The 1-day initiation regimen is designed to enable rapid achievement of plasma aripiprazole concentrations that are comparable with the 21 day oral initiation regimen. Here, a 6-month pharmacokinetic study compared 2 different initiation regimens for starting AL. METHODS: Patients were randomized 1:1:1:1 to receive 1 of 4 treatments consisting of the 1-day (single ALNCD injection + one 30-mg dose of oral aripiprazole on day 1 only) or the 21-day (15 mg daily dose of oral aripiprazole for 21 days) initiation regimen, each combined with a starting AL dose of either 441 mg or 882 mg. RESULTS: In total, 133/161 patients completed the study. The pharmacokinetic profile of the 1-day initiation regimen was comparable to the 21-day initiation regimen; both achieved aripiprazole concentrations in the therapeutic range within 4 days and remained in a comparable concentration range during treatment initiation. Common adverse events (>=5.0%) were injection-site pain, headache, increased weight, insomnia, dyspepsia, and anxiety. Nine akathisia events occurred (4 events in 4 patients and 5 events in 2 patients in the 1-day and 21-day initiation regimen groups, respectively). CONCLUSIONS: The 1-day initiation regimen resulted in plasma aripiprazole concentrations consistent with the 21-day initiation regimen. Therefore, a single dose of ALNCD with a single 30-mg oral dose of aripiprazole provides an alternative initiation regimen for starting AL. PMID- 30015677 TI - Metal Artifact Reduction Computed Tomography of Arthroplasty Implants: Effects of Combined Modeled Iterative Reconstruction and Dual-Energy Virtual Monoenergetic Extrapolation at Higher Photon Energies. AB - OBJECTIVE: The aim of this study was to compare the effects of combined virtual monoenergetic extrapolation (VME) of dual-energy computed tomography data and iterative metal artifact reduction (iMAR) at higher photon energies on low- and high-density metal artifacts and overall image quality of the ankle arthroplasty implants with iMAR, weighted filtered back projection (WFBP), and WFBP-based VME. MATERIALS AND METHODS: Total ankle arthroplasty implants in 6 human cadaver ankles served as surrogates for arthroplasty implants. All specimens underwent computed tomography with a 2 * 192-slice dual-source computed tomography scanner at tube voltages of 80 and tin-filtered 150 kVp to produce mixed 120 kVp equivalent polychromatic and virtual monoenergetic extrapolated images at 150 and 190 keV (VME 150 and VME 190, respectively). By implementing the WFBP and iMAR reconstruction algorithms on polychromatic, VME 150 and VME 190 data, 6 image datasets were created: WFBP-Polychromatic, iMAR-Polychromatic, WFBP-VME 150, WFBP VME 190, iMAR-VME 150, and iMAR-VME 190. High-density and low-density artifacts were separately quantified with a threshold-based computer algorithm. After anonymization and randomization, 2 observers independently ranked the datasets for overall image quality. Repeated measures analysis of variance, Friedman, and Cohen weighted kappa tests were applied for statistical analysis. A conservative P value of less than 0.001 was considered statistically significant. RESULTS: iMAR-VME 190 keV and iMAR-VME 150 keV created the least amount of high-density artifacts (all P < 0.001), whereas iMAR-Polychromatic was the most effective method to mitigate low-density streaks (P < 0.001). For low- and high-density artifacts, polychromatic iMAR acquisition was superior to WFBP-VME 150 keV and WFBP-VME 190 keV (all P < 0.001). On sharp kernel reconstructions, readers ranked the overall image quality of iMAR-Polychromatic images highest (all P < 0.001). Similarly, on soft tissue kernel reconstructions, readers ranked iMAR Polychromatic images highest with a statistically significant difference over other techniques (all P < 0.001), except for iMAR-VME 150 keV (P = 0.356). CONCLUSIONS: In computed tomography imaging of ankle arthroplasty implants, iMAR reconstruction results in fewer metal artifacts and better image quality than WFBP reconstruction for both polychromatic and virtual monoenergetic data. The combination of iMAR and VME at higher photon energies results in mixed effects on implant-induced metal artifacts, including decreased high-density and increased low-density artifacts, which in combination does not improve image quality over iMAR reconstruction of the polychromatic data. Our results suggest that, for ankle arthroplasty implants, the highest image quality is obtained by iMAR reconstruction of the polychromatic data without the need to implement VME at high-energy levels. PMID- 30015678 TI - Adherence to the Barcelona Clinic Liver Cancer recommendations in clinical practice. PMID- 30015679 TI - Imaging biomarkers and staging in IPF. AB - PURPOSE OF REVIEW: The application of computer-based imaging analysis in patients with idiopathic pulmonary fibrosis is a rapidly developing field. The purpose of this review is to provide insights into the problems associated with visual interpretation of HRCT patterns and describe some of the current technologies used to provide objective quantification of disease on HRCT. Future directions are also discussed. RECENT FINDINGS: Although there is strong evidence that visual quantification of disease on HRCT in idiopathic pulmonary fibrosis provides prognostic information, this approach is hampered by its subjective nature and interobserver variability. In contrast, computer-based quantification of disease on HRCT provides objective and reproducible data, which may help to predict mortality and time to decline in patients with idiopathic pulmonary fibrosis. The use of these technologies may also help to stratify clinical risk in patients enrolled in drug trials. SUMMARY: The future of imaging-based biomarker research in idiopathic pulmonary fibrosis is undoubtedly computer-based HRCT evaluation. However, if this field is to continue to innovate, large, well annotated imaging datasets for developing and testing. new computer-based tools are needed as well as prospective trials for biomarker validation. PMID- 30015680 TI - Flipping the Classroom in Health Care Higher Education: A Systematic Review. AB - BACKGROUND: The flipped classroom is an approach to teaching with independent and asynchronous study of content by students and active learning during scheduled class times. PURPOSE: The purpose of this review was to systematically examine research on the use of the flipped classroom approach in health professions education. METHODS: Eleven electronic databases were searched for peer-reviewed literature from 2005 through September 2017. Inclusion criteria for studies addressed health professions students and quantitative outcomes (quizzes, examinations, course grades). RESULTS: Of the 49 articles identified, 24 met the inclusion criteria. The majority of studies (n = 17) noted a significant improvement in at least 1 student academic outcome using the flipped classroom compared with the traditional lecture. CONCLUSIONS: This systematic review of the effects of the flipped classroom approach for the education of health professions students did not reveal compelling evidence for the effectiveness of the method in improving academic outcomes above that of traditional classroom approaches. PMID- 30015681 TI - Adaptive Quizzing Improves End-of-Program Exit Examination Scores. AB - BACKGROUND: A third of nursing schools use a standardized, end-of-program exit examination requiring minimum passing scores for student progression. Student failures on high-stakes tests have negative implications for students and schools of nursing. Adaptive quizzing has increased grades, graduation rates, and NCLEX RN passing rates and reduced test anxiety in nursing students. PURPOSE: To diminish the negative effects of high-stakes testing and increase standardized exit examination scores, an undergraduate nursing program incorporated customized adaptive quizzing for nursing students in their final nursing course before graduation. METHODS: End-of-program exit examination scores were compared in a preintervention cohort of students and postintervention cohort assigned individualized adaptive quizzing. RESULTS: Statistically significant increases in end-of-program exit examination scores were evident in groups of students completing the customized adaptive quizzing assignments. CONCLUSION: The use of tailored adaptive quizzing increased exit examination scores, supporting the implementation of customized assignments for remediation. PMID- 30015682 TI - Systems Thinking Education in RN-BSN Programs: A Regional Study. AB - BACKGROUND: Nurses need to take a lead in reducing medical errors. Formal education of systems thinking (ST) can be a catalyst for error prevention. PROBLEM: Integration of ST in RN-BSN education has not been studied. APPROACH: A descriptive, cross-sectional design using survey methods was used. OUTCOMES: Deans of accredited RN-BSN programs across the Midwest reported on ST integration across their RN-BSN programs. Gaps in ST integration were identified as (1) a lack of evaluation tools to determine mastery of systems theory, thinking and awareness, and the application of quality and safety competencies for systems level synthesis and (2) program outcomes emphasizing autonomy of systems-level decisions. CONCLUSIONS: Systems thinking was integrated across curricula among most accredited RN-BSN programs in the Midwest. Recommendations are to integrate systems theory into program outcomes and to develop evaluation tools that validate ST mastery. PMID- 30015683 TI - Effectiveness of Video-Assisted Debriefing in Simulation-Based Health Professions Education: A Systematic Review of Quantitative Evidence. AB - BACKGROUND: Debriefing helps learners to gain knowledge through guided reflection and discussion. Video-assisted debriefing (VAD) refers to adding video review during the debriefing process. PURPOSE: This review evaluated the effectiveness of VAD on learners' reactions, learning, and behavior compared with verbal debriefing (if possible) and identified its effective elements. METHODS: A structured search was conducted in PubMed, MEDLINE, CINAHL, ScienceDirect, Scopus, Web of Science, and PsycINFO. The quality of the included studies was evaluated using the Medical Education Research Study Quality Instrument. RESULTS: Twenty-three studies published between 2002 and 2017 were selected. Results showed that VAD improved learners' experience, attitude, and performance, but it did not show its advantage over verbal debriefing on knowledge acquisition. Effective elements included using experienced debriefers, curriculum-embedded simulation, a structured debriefing, and the time between 10 and 90 minutes. CONCLUSIONS: VAD improved learning outcomes and offered comparable benefits as verbal debriefing. PMID- 30015684 TI - Combining Cognitive Rehearsal, Simulation, and Evidence-Based Scripting to Address Incivility. AB - BACKGROUND: Nurses have a professional and ethical obligation to foster civility and healthy work environments to protect patient safety. Evidence-based teaching strategies are needed to prepare nursing students to address acts of incivility that threaten patient safety. PROBLEM: Incivility in health care must be effectively addressed because the delivery of safe patient care may depend on these vital skills. APPROACH: Cognitive rehearsal (CR) is an evidence-based technique where learners practice addressing workplace incivility in a nonthreatening environment with a skilled facilitator. The author describes the unique combination of CR, simulation, evidence-based scripting, deliberate practice, and debriefing to prepare nursing students to address uncivil encounters. OUTCOMES: Learners who participated in CR identified benefits using this approach. CONCLUSIONS: Combining CR with simulation, evidence-based scripting, repeated dosing through deliberate practice, and skillful debriefing is an effective method to provide nursing students with the skills needed to address incivility, thereby increasing the likelihood of protecting patient safety. PMID- 30015685 TI - Community Health Workers as an Extension of Care Coordination in Primary Care: A Community-Based Cosupervisory Model. AB - Community health workers (CHWs) bring their unique capacity as liaisons for patients, communities, and health care systems to health care teams. We describe the collaborative development of a community-based CHW program to address the social determinants of health that affect patients. This cosupervisory, generalist CHW model provides an innovative template for cocreation of patient centered infrastructure and resourcing within an evolving and replicable holistic care continuum across patient ages, diagnoses, health care payers, and communities to promote health equity. The program has been effective in decreasing health care utilization and cost. PMID- 30015686 TI - Genetic predisposition in pancreatitis. AB - PURPOSE OF REVIEW: Genetic mutations are the primary cause for acute recurrent (ARP) and chronic pancreatitis in children. Further, our medical approach for many diseases is changing from a one-drug therapy to more individualized therapeutic strategies. In respect to the therapeutic management of ARP/chronic pancreatitis, this entails an understanding of the individual, mainly genetic, risk factors that led to pancreatitis disease. RECENT FINDINGS: New pancreatitis associated genes are continuously emerging from increasingly large genetic cohort studies. Furthermore, newer research findings demonstrate that multiple genetic and nongenetic factors are required to increase the individual risk for developing ARP/chronic pancreatitis. Last, there is new exciting development towards targeted pancreatitis therapy in the future. SUMMARY: This review introduces the current concept of ARP/chronic pancreatitis as a complex disease caused by multiple genetic and nongenetic factors. This warrants careful evaluation of these patients and ideally consultation of a pancreas expert to help understand individual genetic risk profiles and to provide more effective patient consultation. PMID- 30015687 TI - Eosinophilic esophagitis: short and long-term considerations. AB - PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is a relatively new disease but its understanding is evolving over a period of time. This review highlights recent advances in the understanding of pathophysiology, diagnostic modalities, short and long-term goals of therapy and novel therapeutic agents. RECENT FINDINGS: The prevalence of EoE is increasing. Upper endoscopy and biopsy remains the gold standard for diagnosing EoE but less invasive and more cost-effective testing has been under investigation. Scoring systems to assess symptoms, histology and endoscopic findings can distinguish between active and inactive disease. Step up therapy with 2-4-6 food elimination can result in early identification of triggering foods and reduce frequency of endoscopies. The term proton pump inhibitor (PPI) responsive eosinophilia should be avoided and PPI should be considered a therapeutic modality. Oral viscous budesonide has been more effective than fluticasone in achieving remission. Adrenal suppression should be looked for patients on swallowed steroids. IL-13 antagonists can be a promising therapy for EoE and dilation is a safe and effective treatment modality in patients with EoE but as is expected, does not decrease inflammation. SUMMARY: EoE has been increasingly recognized as a cause of food impactions and dysphagia. Less invasive methods for diagnosis and to monitor treatment response have been studied but need validation in children. Short-term treatment goals include symptomatic and histological improvement, with prevention of fibrostenotic disease the primary long-term goal. Elemental diet and empiric elimination diet appear to be successful in inducing remission. PPI and swallowed steroids cause symptomatic improvement and histological remission but relapse is common after discontinuation of therapy. PMID- 30015688 TI - Cardiovascular disease in Down syndrome. AB - PURPOSE OF REVIEW: In the last 40 years, with a better understanding of cardiac defects, and with the improved results of cardiac surgery, the life expectancy of persons with Down syndrome has significantly increased. This review article reports on advances in knowledge of cardiac defects and cardiovascular system of persons with trisomy 21. RECENT FINDINGS: New insights into the genetics of this syndrome have improved our understanding of the pathogenetic mechanisms of cardiac defects. Recent changes in neonatal prevalence of Down syndrome suggest a growing number of children with cardiac malformations, in particular with simple types of defects. Ethnic and sex differences of the prevalence of specific types of congenital heart disease (CHD) have also been underlined. A recent study confirmed that subclinical morphologic anomalies are present in children with trisomy 21, also in the absence of cardiac defects, representing an internal stigma of Down syndrome. The results of cardiac surgery are significantly improved in terms of immediate and long-term outcomes, but specific treatments are indicated in relation to pulmonary hypertension. Particular aspects of the cardiovascular system have been described, clarifying a reduced sympathetic response to stress but also a 'protection' from atherosclerosis and arterial hypertension in these patients. SUMMARY: Continuing dedication to clinical and basic research studies is essential to further improve survival and the quality of life from childhood to adulthood of patients with trisomy 21. PMID- 30015689 TI - A contemporary review about the management of radiation-induced hemorrhagic cystitis. AB - PURPOSE OF REVIEW: There are various specific therapeutic intervention available to treat hemorrhagic cystitis, once emergency treatment has been carried out. The lack of prospective studies, because of the relative rarity of this condition, makes it difficult to hierarchize the therapeutic sequence. The present review presents and summarizes the literature published on radiation-induced hemorrhagic cystitis from April 2015, date of a precedent exhaustive review, to March 2018. RECENT FINDINGS: During our period of interest, 13 clinical studies and two new clinical trials protocols were published. Most of the clinical studies were retrospective and presented data about hyperbaric oxygen (HBO) therapy, comforting its place as a well tolerated and effective first-line treatment. Other studies reported the outcomes of treatments with alum, formalin, silver nitrate, fulguration with laser or definitive surgery. SUMMARY: Although authors seem to agree that formalin and surgery have their role as effective but potentially morbid last-line treatments, there is no consensus on primary approach to management of radiation-induced hemorrhagic cystitis beyond symptomatic measures. Several treatments have proven excellent response rates and few side effects. The results of on-going prospective studies on mesenchymal stromal cells or tacrolimus instillations are awaited, but the main discriminating factor to choose between treatments remains local availability. PMID- 30015690 TI - Management of nonmetastatic castration-resistant prostate cancer. AB - PURPOSE OF REVIEW: The widespread use of prostate-specific antigen (PSA) resulted in stage migration of prostate cancer where androgen deprivation therapy (ADT) is administered for biochemical recurrence in patients following primary treatment. A proportion of these patients progress to a disease state termed nonmetastatic castration-resistant prostate cancer (nmCRPC), with a rising PSA despite ADT and without evidence of metastases on conventional imaging. We will review the treatment options in nmCRPC, especially in light of recent trials showing significant improvement in metastasis-free survival with newer agents. RECENT FINDINGS: Historically, nmCRPC patients were followed-up if PSA doubling-time (PSADT) exceeded 10 months. Treatment options for patients with shorter PSADT included hormonal manipulations that often resulted in transient PSA decline. Denosumab was found to delay the onset of bone metastasis but did not impact survival. Recently, phase 3 trials showed that second-generation antiandrogens resulted in a significant delay in metastasis and a trend toward survival improvement in a select group of nmCRPC patients. SUMMARY: The importance of reducing mortality and morbidity associated with metastasis has led to the acceptance of new primary endpoints in the design of trials for nmCRPC and might result in widespread approval of new agents for this disease state. PMID- 30015691 TI - Treatment of hormone-naive metastatic prostate cancer. AB - PURPOSE OF REVIEW: Until 2015, androgen deprivation therapy (ADT) alone was the standard-of-care for metastatic hormone-naive prostate cancer (mHNPC). In the last decade, important landmark therapeutic advances occurred in the management of these patients permitting improvement of their survival. RECENT FINDINGS: At least two prospective randomized trials proved upfront docetaxel (DOC) + ADT benefit consequently providing strong evidence for guidelines modifications. Second, similar benefit results were demonstrated when using upfront abiraterone acetate + ADT in mHNPC. SUMMARY: Both DOC-based chemotherapy and abiraterone acetate provide survival improvement when added to ADT in mHNPC. In the current article, we review the evidence behind this progress and discuss ongoing clinical controversies. PMID- 30015692 TI - Myofascial pain: so common, and yet not understood. PMID- 30015694 TI - Which Protocol for Milrinone to Treat Cerebral Vasospasm Associated With Subarachnoid Hemorrhage? AB - BACKGROUND: Milrinone has emerged as an option to treat delayed cerebral ischemia after subarachnoid hemorrhage. However, substantial variation exists in the administration of this drug. We retrospectively assessed the effectiveness of 2 protocols in patients with angiographically proven cerebral vasospasm. METHODS: During 2 successive periods, milrinone was administered using either a combination of intra-arterial milrinone infusion followed by intravenous administration until day 14 after initial bleeding (IA+IV protocol), or a continuous intravenous milrinone infusion for at least 7 days (IV protocol). The primary endpoint was the reversion rate of vasospastic arterial segments following the first IA infusion of milrinone (IA+IV protocol) compared with the reversion rate during the first week of IV infusion (IV protocol). RESULTS: There were 24 and 77 consecutive patients in IA+IV and IV protocols, respectively. The reversion rate was comparable between the 2 protocols: 71% (95% confidence interval [CI], 59%-83%) in the IA+IV protocol versus 64% (95% CI, 58%-71%) in the IV protocol (P=0.36). Rescue procedures for persistence or recurrence of vasospasm, that is, mechanical angioplasty and/or IA milrinone infusion, were similar between the 2 protocols. Patients with a good neurological outcome at 1 year, that is, modified Rankin Scale scores 0-2, were comparable between the 2 protocols. Side effects of milrinone were uncommon and equally distributed within the 2 protocols. CONCLUSIONS: These findings indicate that a continuous IV infusion of milrinone was as efficient as combined IA+IV infusion and suggest that this modality could be considered as a first easy-to-use option to treat patients with CVS. PMID- 30015696 TI - The Effect of Fluid Loading and Hypertonic Saline Solution on Cortical Cerebral Microcirculation and Glycocalyx Integrity. AB - BACKGROUND: Fluid loading and hyperosmolar solutions can modify the cortical brain microcirculation and the endothelial glycocalyx (EG). This study compared the short-term effects of liberal fluid loading with a restrictive fluid intake followed by osmotherapy with hypertonic saline (HTS) on cerebral cortical microcirculation and EG integrity in a rabbit craniotomy model. METHODS: The experimental rabbits were allocated randomly to receive either <2 mL/kg/h (group R, n=14) or 30 mL/kg/h (group L, n=14) of balanced isotonic fluids for 1 hour. Then, the animals were randomized to receive 5 mL/kg intravenous infusion of either 3.2% saline (group HTS, n=14) or 0.9% saline (group normal saline, n=13) in a 20-minute infusion. Microcirculation in the cerebral cortex based on sidestream dark-field imaging, a morphologic index of glycocalyx damage to sublingual and cortical brain microcirculation (the perfused boundary region), and serum syndecan-1 levels were evaluated. RESULTS: Lower cortical brain perfused small vessel density (P=0.0178), perfused vessel density (P=0.0286), and total vessel density (P=0.0447) were observed in group L, compared with group R. No differences were observed between the HTS and normal saline groups after osmotherapy. Cerebral perfused boundary region values (P=0.0692) and hematocrit corrected serum syndecan-1 levels (P=0.0324) tended to be higher in group L than in group R animals. CONCLUSIONS: Liberal fluid loading was associated with altered cortical cerebral microcirculation and EG integrity parameters. The 3.2% saline treatment did not affect cortical cerebral microcirculation or EG integrity markers. PMID- 30015697 TI - Impact of CPAP on Forehead Near-infrared Spectroscopy Measurements in Patients With Acute Respiratory Failure: Truth or Illusion. AB - BACKGROUND: Critically ill patients with acute respiratory failure admitted to an intensive care unit are at high risk for cerebral hypoxia. We investigated the impact of continuous positive airway pressure (CPAP) therapy on regional cerebral tissue oxygenation (rSO2). MATERIALS AND METHODS: In total, 40 extubated surgical intensive care unit patients requiring classic oxygen therapy (COT) for acute respiratory failure were examined. Near-infrared spectroscopy (INVOS 5100C, Covidien) was used for 30 minutes to detect bilateral rSO2 during COT via facemask (6 L/min) and CPAP therapy (40% fraction of inspired oxygen, 8 cm H2O CPAP) using a randomized crossover study design. Patients served as their own control. Continuous hemodynamic routine monitoring and blood gas analysis were performed. The effect of CPAP therapy on rSO2 and influence of assessed covariables were investigated using a mixed linear model. RESULTS: Median rSO2 increased from 57.9% (95% confidence interval [CI], 54.2-61.5) during COT to 62.8% (95% CI, 59.2-66.5) during CPAP therapy (P<0.0001). The estimated difference from the mixed model between COT and CPAP is -5.0 (95% CI, -6.3 to 3.7). Median arterial partial pressure of carbon dioxide decreased from 47.8+/ 5.1 mm Hg during COT to 43.1+/-5 mm Hg during CPAP (P<0.001), whereas arterial partial pressure of oxygen remained unchanged (P=0.329). In total, 23% of patients had SO2 levels <50%, with a higher prevalence under COT. CONCLUSIONS: Our results reveal that CPAP therapy compared with COT may influence rSO2 in patients with acute respiratory failure. However, the cause of the rSO2 increase following CPAP application remains to be elucidated, and the accuracy of cerebral oximetry during CPAP therapy in patients with acute respiratory failure remains questionable. PMID- 30015698 TI - Poor cardiorespiratory fitness is a risk factor for sepsis in patients awaiting liver transplantation. AB - BACKGROUND: Patients with advanced liver disease are at increased risk of infection and other complications. A significant proportion of patients also have poor fitness and low muscle mass. The primary aim of this study was to investigate if cardiorespiratory fitness and body composition are risk factors for sepsis and other complications of advanced liver disease. METHODS: Patients being listed for liver transplantation underwent cardiopulmonary exercise testing to determine ventilatory threshold (VT). Computed tomography was used to measure skeletal muscle and subcutaneous and visceral adipose tissue indexes. All unplanned hospital admissions, deaths or delistings prior to transplantation were recorded. RESULTS: Eighty-two patients [aged 55.1 (50.6-59.4) years, median (interquartile range); male 87%] achieved a median VT of 11.7 (9.7-13.4) mL[BULLET OPERATOR]kg[BULLET OPERATOR]min. Their median MELD-Na score was 18 (14 22); and 37 had hepatocellular carcinoma. There were 50 admissions in 31 patients; with 16 admissions for sepsis in 13 patients. Patients with sepsis had a significantly lower VT [sepsis 9.5 (7.8-11.9), no sepsis 11.8 (10.5-13.8) mL[BULLET OPERATOR]kg[BULLET OPERATOR]min; P=0.003]. No body composition variables correlated with sepsis, nor were there any significant associations between VT and unplanned admissions for other indications. Multivariate logistic regression demonstrated that VT was independently associated with a diagnosis of sepsis (P=0.03). Poisson regression revealed that VT was a significant predictor for the number of septic episodes (P=0.02); independent of age, MELD-Na score, hepatocellular carcinoma diagnosis, presence of ascites, and beta-blocker use. CONCLUSION: Poor cardiorespiratory fitness is an independent risk factor for the development of sepsis in advanced liver disease. PMID- 30015699 TI - Extended-criteria allografts a strategy to reduce waiting list mortality in selected hepatocellular carcinoma recipients. PMID- 30015700 TI - No evidence for cross-reactivity of virus-specific antibodies with HLA allo antigens. AB - BACKGROUND: Antibodies directed against human leucocyte antigens (HLA) can develop through pregnancy, blood transfusions or organ transplants. Anecdotal evidence suggests that virus-specific antibodies may have the capacity to cross react with HLA, a phenomenon called heterologous immunity, which is well described for T cell alloreactivity. METHODS: To determine whether antibody cross reactivity between viral antigens and HLA is common, we tested 51 virus-specific human monoclonal antibodies (mAbs) specific for human immunodeficiency virus (HIV), varicella zoster virus (VZV), cytomegalovirus (CMV), and parvovirus, for reactivity against HLA class I and class II in single antigen bead assays. In addition, we tested the reactivity of 41 HLA-specific human mAbs against common viral antigens of CMV, VZV, HIV, Epstein-Barr virus, and BK polyomavirus. RESULTS: No cross-reactivity of any of the virus-specific mAbs with either HLA class I or class II molecules, as well as no cross-reactivity of any of the HLA specific mAbs with any of the viral antigens was observed. CONCLUSIONS: These findings indicate that the frequency of cross-reactivity on the antibody level between viral antigens and HLA, if present at all, is low. The emergence of HLA antibodies upon viral infection or vaccination is therefore probably due to bystander activation of dormant HLA-specific memory B cells. PMID- 30015701 TI - Prospective Validation of Prediction Model for Kidney Discard. AB - BACKGROUND: Many kidneys are discarded every year, with 3631 kidneys discarded in 2016 alone. Identifying kidneys at high risk of discard could facilitate 'rescue' allocation to centers more likely to transplant them. The Probability of Delay or Discard (PODD) model was developed to identify marginal kidneys at risk of discard or delayed allocation beyond 36 hours of cold ischemia time. However, PODD has not been prospectively validated, and patterns of discard may have changed following policy changes such as the introduction of Kidney Donor Profile Index and implementation of the Kidney Allocation System (KAS). METHODS: We prospectively validated the PODD model using SRTR data in the KAS era (1/1/15 3/1/18). C statistic was calculated to assess accuracy in predicting kidney discard. We assessed clustering in center's utilization of kidneys with PODD>0.6 ('high-PODD') using Gini coefficients. Using match run data 1/1/15-12/31/16, we examined distribution of these high-PODD kidneys offered to centers that never accepted a high-PODD kidney. RESULTS: PODD predicted discard accurately under KAS (C-statistic=0.87). Compared to utilization of low-PODD kidneys (Gini coefficient = 0.41), utilization of high-PODD kidneys was clustered more tightly among a few centers (Gini coefficient = 0.84 with >60% of centers never transplanted a high PODD kidneys). In total 11,684 offers (35.0% of all high-PODD offers) were made to centers that never accepted a high-PODD kidney. CONCLUSIONS: Prioritizing allocation of high-PODD kidneys to centers that are more likely to transplant them might help reduce kidney discard. PMID- 30015702 TI - Every Liver Graft Should Be Evaluated for Transplantation. PMID- 30015703 TI - Chikungunya on kidney transplant recipients: Is it the same? AB - BACKGROUND: Chikungunya virus (CHIKV) infection is an acute febrile illness with polyarthralgia and arthritis. There are few data about CHIKV infection in kidney transplant recipients (KTR). We report the largest case series of CHIKV infection in this population. METHODS: We retrospectively analyzed 32 cases of CHIKV infection in KTR between January 2016 and December 2017 at Hospital Universitario Walter Cantidio of Federal University of Ceara. RESULTS: All patients had been in endemic area before the beginning of the symptoms. All cases presented arthralgia, fifteen (46.9%) with joint inflammatory symptoms and 14 (43.8%) evolved to chronic arthralgia. Seven (21.9%) showed acute kidney injury (AKI) by KDIGO criteria during the acute phase. AKI was not related to prednisone use (OR 0.3, 95% CI 0.04 - 2.61, p=0.3) nor chronic arthralgia (OR 1.2, 95% CI 0.2 - 8.4, p=0.8) as well as male sex, chronic kidney disease and age above 60 years (OR 1.7, 95% CI 0.3 - 10.3, p=0.58; OR 0.4, 95% CI 0.1 - 2.7, p=0.4 and OR 2.1, 95% CI 0.3 - 14.9, p=0.45, respectively). Hospitalization was associated to AKI (OR 44.0, 95% CI 3.8 - 503.1, p=0.002), probably due to diarrhea or dehydration. One patient died during the study period, possibly not related to CHIKV infection. CONCLUSION: The chance of CHIKV infection becoming chronic arthralgia in KTR was not different from data in literature. Seven patients presented AKI in the acute phase of infection, although that did not persist. Previous costicosteroids use did not relate with AKI or chronic arthralgia. PMID- 30015704 TI - Hepatic Dysfunction in Deceased Donors in the Age of the Opioid Epidemic. PMID- 30015705 TI - Long-term pain relief in canine osteoarthritis by a single intra-articular injection of resiniferatoxin, a potent TRPV1 agonist. AB - The translational potential of analgesic approaches emerging from basic research can be augmented by client-owned dog trials. We report on a peripheral interventional approach that uses intra-articular injection of the ultrapotent TRPV1 agonist resiniferatoxin (RTX) to produce a selective long-term chemoinactivation of nociceptive primary afferent nerve endings for pain control in naturally occurring canine osteoarthritis. A single injection of 10 ug of RTX, produced suppression of pain, improvement in gait, weight bearing, and improvement in the dog's activities of daily living lasting 4 months or longer. Two to 3 years after the injection, there are no alterations to suggest that removal of inflammatory pain caused accelerated joint degeneration (Charcot joint) in any of the dogs. To amplify the effective use of canine subjects in translational analgesia research, we report a high-quality canine dorsal root ganglion transcriptome. Some targets for analgesia are highly conserved both in protein sequence and level of expression within a target tissue while others diverge substantially from the human. This knowledge is especially important for development of analgesics aimed at peripheral molecular targets and provides a template for informed translational research. The peripheral site of action, long duration of analgesia, apparent safety, and retention of coordination, all resulting from a single dose suggest that intra-articular RTX may be an effective intervention for osteoarthritis pain with few or no side effects and lead to an improved quality of life. PMID- 30015706 TI - Inflammation induces Epac-protein kinase C alpha and epsilon signaling in TRPV1 mediated hyperalgesia. AB - The exchange proteins activated by cAMP (Epacs) have been shown to play important roles in producing inflammation-induced nociception. Transient receptor potential vanilloid type 1 (TRPV1) is a major receptor processing thermal and chemosensitive nociceptive information. The role of Epacs in modulating the activity of TRPV1 has yet to be determined. Studying the effect of complete Freund adjuvant (CFA)-induced inflammation on capsaicin-activated TRPV1 nociceptive responses in dorsal root ganglia (DRG), we found that CFA produced a large increase in capsaicin-induced responses. The increase was inhibited by Epac1 and Epac2 antagonists. Thus, activation of Epacs is critical in producing enhancement in TRPV1-mediated responses under inflammatory conditions. In addition, the inflammation-induced enhancement of TRPV1 responses was blocked by PKCalpha and PKCepsilon inhibitors, suggesting the essential roles of these PKCs in enhancing TRPV1 responses. To determine the mechanism underlying the Epac actions on TRPV1, we studied the effects of the Epac activator, 8-(4 chlorophenylthio)-2-O-methyl-cAMP (CPT), on capsaicin-induced nociceptive behavioral responses, capsaicin-activated currents, expression and membrane trafficking of PKC and TRPV1 in DRG. CPT was found to enhance capsaicin-induced nociception and ionic currents. The enhancement was inhibited by PKCalpha and PKCepsilon inhibitors. In addition, CPT increased the expression of phosphorylated PKCalpha (pPKCalpha) and membrane TRPV1 expression in DRG. Studying the colocalization of TRPV1 and pPKCalpha or pPKCepsilon in DRG slices prepared from CFA-treated rats, we found that pPKCalpha or pPKCepsilon expressed with TRPV1 in different-sized neurons to exert differential influences on TRPV1 activity. Thus, Epac-PKC signaling is critically important in producing inflammation-induced potentiation of TRPV1 functions. PMID- 30015707 TI - Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy. AB - Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here, we analyze time dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction, correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes, and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses. PMID- 30015708 TI - Quantifying visual allodynia across migraine subtypes: the Leiden Visual Sensitivity Scale. AB - Enhanced sensitivity to light (photophobia) and patterns is common in migraine and can be regarded as visual allodynia. We aimed to develop and validate a questionnaire to easily quantify sensitivity to light and patterns in large populations, and to assess and compare visual allodynia across different migraine subtypes and states. We developed the Leiden Visual Sensitivity Scale (L-VISS), a 9-item scale (score range 0-36 points), based on literature and patient interviews, and examined its construct validity. Furthermore, we assessed ictal and interictal visual sensitivity in episodic migraine with (n = 67) and without (n = 66) aura and chronic migraine with (n = 20) and without (n = 19) aura, and in healthy controls (n = 86). Differences between migraine subtypes and states were tested using a linear mixed model with 3 fixed factors (episodic/chronic, with/without aura, and ictal/interictal). Test-retest reliability and construct validity of L-VISS were good. Leiden Visual Sensitivity Scale scores correlated in the expected direction with light discomfort (Kendall's tau = -0.25) and pattern glare tests (tau = 0.35). Known-group comparisons confirmed its construct validity. Within migraine subtypes, L-VISS scores were higher in migraine with aura versus without aura and in chronic versus episodic migraine. The linear mixed model showed all factors affected the outcome (P < 0.001). The L-VISS is an easy-to-use scale to quantify and monitor the burden of bothersome visual sensitivity to light and patterns in large populations. There are remarkable ictal and interictal differences in visual allodynia across migraine subtypes, possibly reflecting dynamic differences in cortical excitability. PMID- 30015709 TI - Contextual influences in decoding pain expressions: effects of patient age, informational priming, and observer characteristics. AB - We aimed to examine the effects of contextual factors (ie, observers' training background and priming texts) on decoding facial pain expressions of younger and older adults. A total of 165 participants (82 nursing students and 83 nonhealth professionals) were randomly assigned to one of 3 priming conditions: (1) information about the possibility of secondary gain (misuse); (2) information about the frequency and undertreatment of pain in the older adult (undertreatment); or (3) neutral information (control). Subsequently, participants viewed 8 videos of older adults and 8 videos of younger adults undergoing a discomforting physical therapy examination. Participants rated their perception of each patient's pain intensity, unpleasantness, and condition severity. They also rated their willingness to help, sympathy level, patient deservingness of financial compensation, and how negatively/positively they feel towards the patient (ie, valence). Results demonstrated that observers ascribed greater levels of pain and other indicators (eg, sympathy and help) to older compared with younger patients. An interaction between observer type and patient age demonstrated that nursing students endorsed higher ratings of younger adults' pain compared with other students. In addition, observers in the undertreatment priming condition reported more positive valence towards older patients. By contrast, priming observers with the misuse text attenuated their valence ratings towards younger patients. Finally, the undertreatment prime influenced observers' pain estimates indirectly through observers' valence towards patients. In summary, results add specificity to the theoretical formulations of pain by demonstrating the influence of patient and observer characteristics, as well as informational primes, on decoding pain expressions. PMID- 30015710 TI - Catastrophizing, pain, and functional outcomes for children with chronic pain: a meta-analytic review. AB - Pediatric chronic pain is associated with numerous negative outcomes including increased physical disability, increased rates of depression and anxiety, and decreased quality of life (QOL). Pain catastrophizing-broadly conceptualized as including rumination, magnification, and helplessness cognitions surrounding one's pain-has been linked with poor functional outcomes in children with chronic pain. Pain catastrophizing in pediatric chronic pain is often considered a key factor on which to focus treatment efforts. However, absent a systematic review that integrates the relevant literature, this call for routine assessment and targeted treatment may be premature. This study aimed to: (1) meta-analytically quantify the relationship between catastrophizing and pain and functional/psychosocial outcomes (functional disability/physical functioning, anxiety, depression, and QOL) in children with chronic pain, and (2) examine potential moderators of these relationships. Using a random-effects model, a total of 111 effect sizes from 38 studies were analyzed. Effect sizes ranged from medium to large, with anxiety, depression, and QOL demonstrating a strong association with catastrophizing. Pain intensity and physical disability had a moderate association with catastrophizing. These relationships were robust, minimizing potential publication bias. None of the examined moderators were significant. The strong relationships found between catastrophizing and anxiety, depression, and QOL suggest that successfully intervening on catastrophizing could have far reaching implications in improving pain outcomes in pediatric chronic pain. PMID- 30015711 TI - Neural mechanisms supporting the relationship between dispositional mindfulness and pain. AB - Interindividual differences in pain sensitivity vary as a function of interactions between sensory, cognitive-affective, and dispositional factors. Trait mindfulness, characterized as the innate capacity to nonreactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo analgesia, we sought to determine whether dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six meditation-naive and healthy volunteers completed the Freiburg Mindfulness Inventory and were administered innocuous (35 degrees C) and noxious stimulation (49 degrees C) during perfusion-based functional magnetic resonance imaging. Higher Freiburg Mindfulness Inventory ratings were associated with lower pain intensity (P = 0.005) and pain unpleasantness ratings (P = 0.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive, and affective appraisals. We propose that mindfulness and the posterior cingulate cortex should be considered as important mechanistic targets for pain therapies. PMID- 30015713 TI - Risk Factors for Positive Cultures in Presumed Aseptic Revision Spine Surgery. AB - STUDY DESIGN: Retrospective case-control study. OBJECTIVE: To report culturing patterns and results in the setting of presumed aseptic revision spinal surgery. SUMMARY OF BACKGROUND DATA: The indications for obtaining cultures in revision spinal surgery remain unclear in the absence of a definitive diagnosis of infection. Culture results and risk factors for having positive cultures in this setting have not been previously studied. METHODS: We retrospectively reviewed 595 consecutive revision spine surgeries performed by four senior spine surgeons between 2008 and 2013. Preoperative workup revealed the diagnosis of infection in 17 cases which were excluded from review. The remaining 578 presumed aseptic cases were included. Univariate and multivariate analyses were performed to identify variables associated with obtaining cultures and risk factors for positive cultures. RESULTS: Cultures were obtained in 112 (19.4%) cases and were positive in 40.2%. Pseudarthrosis was the most common revision diagnosis when cultures were obtained (49.1%) and propionibacterium acnes was the most common organism isolated from positive cultures (48.8%). Regarding culture results, multivariate analysis demonstrated that male sex (OR = 3.4) and pseudarthrosis (OR = 4.1) were significantly associated with having positive cultures while fusion procedures (OR = 0.3) were negatively correlated, with AUC 0.71. CONCLUSIONS: Unexpected positive cultures occurred commonly and propionibacterium acnes was the predominant isolated organism. Male sex, pseudarthrosis, and non fusion cases predicted positive cultures. Considering these results, we recommend cultures be obtained in revision cases for pseudarthrosis, even in the setting of negative infectious work-up preoperatively. LEVEL OF EVIDENCE: 4. PMID- 30015714 TI - Can C2-6 Cobb Angle Replace C2-7 Cobb Angle? An Analysis of Cervical kMRIs and X rays. AB - STUDY DESIGN: Retrospective study of consecutive 113 cervical kinetic magnetic resonance images (kMRIs) and 57 radiographs. OBJECTIVE: To elucidate the relationship between C2-6 or C2-7 Cobb angle and cervical sagittal alignment parameters using kMRI, and evaluate the visibility of C6 and C7 inferior endplates on cervical radiographs. SUMMARY OF BACKGROUND DATA: Several studies have used C2-6 Cobb angle instead of C2-7 Cobb angle since C7 inferior endplate is not always visible due to overlying shadows. However, the relationship between C2-6 or C2-7 Cobb angle and cervical sagittal alignment parameters remains unclear. Moreover, visibility of C6 inferior endplate remains unknown. METHODS: C2-6 Cobb angle, C2-7 Cobb angle, occiput-C2 angle, Atlas-dens interval (ADI), narrowest oropharyngeal airway space (nPAS), cervical sagittal vertical axis (cSVA), cervical tilt, cranial tilt, neck tilt, thoracic inlet angle (TIA) and T1 slope were measured using kMRI, and analyzed for their relationship with C2-6 or C2-7 Cobb angle. Visibility rates of C6 or C7 inferior endplates were evaluated using cervical radiographs. RESULTS: Linear regression analysis showed high association between C2-6 and C2-7 Cobb angle (R = 0.696, p < 0.01). C2-6 Cobb angle was significantly correlated with occiput-C2 angle, TIA, T1 slope, neck tilt, cSVA and cervical tilt; but not with nPAS, ADI, and cranial tilt. C2-7 Cobb angle resembled C2-6 Cobb angle regarding the relationships with other parameters. 94.7% C6 and 50.9% C7 inferior endplate were clearly visible. 1.8% C6 and 24.6% C7 inferior endplate were invisible. Chi square test and residual analysis showed significant difference between the two groups (p < 0.01). CONCLUSIONS: C2-6 Cobb angle highly resembled C2-7 Cobb angle regarding its relationships with parameters of craniovertebral, cervical and thoracic inlet alignment. C2-6 Cobb angle could be an alternative to C2-7 Cobb angle due to its significantly higher visibility rate. LEVEL OF EVIDENCE: 3. PMID- 30015712 TI - Isolated nociceptors reveal multiple specializations for generating irregular ongoing activity associated with ongoing pain. AB - Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors, but rodent models of pain-related OA have concentrated on allodynia rather than ongoing pain, and on OA generated in non-nociceptive Abeta fibers rather than C-fiber nociceptors. Little is known about how ongoing pain or nociceptor OA is generated. To define neurophysiological alterations underlying nociceptor OA, we have used isolated dorsal root ganglion neurons that continue to generate OA after removal from animals displaying ongoing pain. We subclassify OA as either spontaneous activity generated solely by alterations intrinsic to the active neuron or as extrinsically driven OA. Both types of OA were implicated previously in nociceptors in vivo and after isolation following spinal cord injury, which produces chronic ongoing pain. Using novel automated algorithms to analyze irregular changes in membrane potential, we have found, in a distinctive, nonaccommodating type of probable nociceptor, induction by spinal cord injury of 3 alterations that promote OA: (1) prolonged depolarization of resting membrane potential, (2) a hyperpolarizing shift in the voltage threshold for action potential generation, and (3) an increase in the incidence of large depolarizing spontaneous fluctuations (DSFs). Can DSFs also be enhanced acutely to promote OA in neurons from uninjured animals? A low dose of serotonin failed to change resting membrane potential but lowered action potential threshold. When combined with artificial depolarization to model inflammation, serotonin also strongly potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA that may promote ongoing pain in chronic and acute conditions. PMID- 30015715 TI - Unplanned immediate return to Operating Room after Spine Surgery: Significance of Immediate Postoperative Radiographs. AB - STUDY DESIGN: Retrospective analysis; Single center data. OBJECTIVE: The purpose of this study is to look at the utility and relevance of immediate post-operative radiographs in providing vital information leading to immediate revision after spine surgery. SUMMARY OF BACKGROUND DATA: Immediate postoperative radiographs are routinely obtained in the recovery room after spine surgery to verify the level, alignment of the spine, implant position, and the adequacy of the procedure. However with the ability to utilize intraoperative fluoroscopy imaging for the same purpose, the requirement for immediate post-operative radiographs needs to be validated. The purpose of this study is to look at the utility and relevance of these post-operative radiographs in providing critical information that may warrant immediate intervention. METHODS: Retrospective analysis of all spine surgeries (elective and emergent), performed at a single center from 2011 to 2016, was done and cases returning to operating room within 48 hours were identified. Indication of immediate revision was reviewed and utility of immediate post-operative radiographs in guiding immediate revision was analyzed. RESULTS: A total of 1804 elective and urgent spinal surgeries were performed by 7 surgeons. 22 patients returned to operating room within 48 hours of their index procedures. Of these 22 cases, only 2 patients were noted to have positive findings on recovery room radiographs. The findings of suboptimal spinal alignment or failed instrumentation led to the immediate revision in both cases. Both cases involved instrumentation at cervicothoracic region and intraoperative imaging provided only limited visualization. CONCLUSION: Routine recovery room radiographs played a role in the decision to emergently return to the Operating room in 0.10% (2/1804) cases at our institution. The potential benefit of immediate recovery room radiographs following spine surgery should be weighed against the added healthcare cost and patient discomfort associated with obtaining these radiographs routinely. Imaging may be delayed to a more elective time without any significant risk in majority of spine cases. LEVEL OF EVIDENCE: 3. PMID- 30015716 TI - Comparison of Patient Reported Outcome Measurement Information System (PROMIS) with Neck Disability Index (NDI) and Visual Analog Scale (VAS) in Patients with Neck Pain. AB - STUDY DESIGN: A retrospective analysis of a patient-reported outcomes database from a single institution from December 2016 to April 2017. OBJECTIVE: To validate the association of PROMIS with NDI in patients with neck pain and examine each instruments ability to capture concomitant arm pain and concomitant back pain. SUMMARY OF BACKGROUND DATA: PROMIS has been increasingly utilized and its computer adapted testing methodology improves assessment of pain and disability. However literature is lacking regarding how these instruments perform in neck pain patients with concomitant arm pain or back pain. METHODS: Inclusion criteria were age>18years and a primary complaint of neck pain. The NDI, VAS Back, Neck, Arm and Leg, and PROMIS Physical Function, Pain Intensity, and Pain Interference questionnaires were administered. Propensity score matching was performed to compare patients with high and low back and arm pain while controlling for neck pain. Bivariate correlations and independent samples t-tests were performed to assess linear relationships and compare back and arm pain groups with PROMIS. RESULTS: 130 patients were included. NDI correlated strongly to PROMIS Physical Function (r = -0.771, p < 0.001), Pain Intensity (r = 0.605, p < 0.001), and Pain Interference (r = 0.786, p < 0.001). VAS Neck and Arm Pain also correlated to the PROMIS Pain Intensity instrument (VAS Neck: r = 0.642, p < 0.001; VAS Arm: r = 0.376, p < 0.001).Following matching for neck pain, the high and low back pain groups each included 32 patients. There were significant differences in PROMIS Physical Function when high and low back pain groups were compared (39.07 vs 43.68, p = 0.031). No significant difference was found for any outcome metric for high and low arm pain groups. CONCLUSIONS: PROMIS instruments are capable of characterizing pain and disability in patients with neck pain and are sensitive to disability in regions adjacent to the neck. LEVEL OF EVIDENCE: 3. PMID- 30015717 TI - Opioid Dependence and Health Care Utilization Following Decompression and Fusion in Patients with Adult Degenerative Scoliosis. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To identify factors associated with opioid dependence following surgery for Adult Degenerative Scoliosis (ADSc). SUMMARY OF BACKGROUND DATA: Opioid epidemic is of prodigious concern throughout the United States. METHODS: Data was extracted using national MarketScan database (2000-2016). Opioid dependence was defined as continued opioid use or >10 opioid prescriptions for one year either prior to or 3-15 months following the procedure. Patients were segregated into four groups based on opioid dependence prior and post-surgery: NDND (prior nondependent who remain non-dependent), NDD (prior nondependent who become dependent), DND (prior dependent who become non dependent) and DD (prior dependent who remain dependent). Outcomes were discharge disposition, length of stay, complications and health care resource utilization. RESULTS: 35.82% (n = 268) of patients were identified to have opioid dependence before surgery and 28.34% (n = 212) were identified to have opioid dependence after surgery for ADSc. Following surgical fusion for ADSc, patients were twice likely to become opioid independent than they were to become dependent (13.77% vs. 6.28%, OR: 2.191, 95% CI: 21.552-3.094; p < 0.0001). Prior opioid dependence (RR: 14.841; 95% CI: 9.867, 22.323; p < 0.0001) was identified as a significant predictor of opioid dependence following surgery for ADSc. 57.9%, 6.28%, 13.77% and 22.06% of patients were in groups NDND, NDD, DND and DD respectively. DD and NDD were likely to incur 3.03 and 2.28 times respectively the overall costs compared to patients' in-group NDND (p < 0.0001), at 3-15 months post-surgery (Median $21648 for NDD; $40,975 for DD; $ 13571 for NDND groups). CONCLUSION: Surgery for ADSc was not associated with increased likelihood of opioid dependence, especially in opioid naive patients. Patients on regular opiate treatment prior to surgery were likely to remain on opiates after surgery. Patients who continued to be opioid dependent or become dependent following surgery incur significantly higher health care utilization at 3 and 3-15 months. LEVEL OF EVIDENCE: 4. PMID- 30015718 TI - Reoperation Rate After Microsurgical Uni- or Bilateral Laminotomy for Lumbar Spinal Stenosis with and Without Low-Grade Spondylolisthesis: What do Preoperative Radiographic Parameters Tell Us? AB - STUDY DESIGN: Retrospective single-center cohort study. OBJECTIVE: The aim of this study was to analyze the influence of preoperative radiographic parameters on reoperation rates after microsurgical laminotomy for lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: Decompression for symptomatic LSS has shown to be effective. However, the optimal surgical strategy remains a matter of debate, especially with underlying spondylolisthesis. METHODS: Adult patients with LSS who underwent primary laminotomy without fusion between January 2012 and September 2013 at our institution were included for analysis. Disc height (in mm), facet joint orientation (degrees) and grade of spondylolisthesis of all surgical index levels (SILs) were analyzed from preoperative magnetic resonance imaging. Patients were contacted in January 2017 by follow-up phone call (mean follow-up 49 months) regarding lumbar reoperation. RESULTS: A total of 161 patients (mean age 68.5 years, +/-11.3) and 236 SILs were analyzed. Fifty-six patients (34.8%) had low-grade spondylolisthesis involving 60 SILs (25.4%). Twenty-four patients (14.9%) underwent reoperation involving 32 levels. Of latter, 23 SILs (9.7%) had recurrent stenosis and 9 (3.8%) had adjacent level stenosis. Five patients in total (3.1%) required secondary fusion; all had preexisting spondylolisthesis. SILs with spondylolisthesis had a significantly higher rate of recurrent stenosis requiring reoperation compared to SILs without spondylolisthesis (18.3% (11/60) vs. 6.8% (12/176), p = 0.013). Disc height and facet joint orientation showed no significant difference between patients with and without reoperation, or with and without spondylolisthesis. CONCLUSIONS: Decompression alone is reasonable for most patients with LSS and stable low-grade spondylolisthesis. The overall reoperation rate and need for secondary fusion were low in our series. However, patients with spondylolisthesis had a higher rate of reoperation for recurrent stenosis after laminotomy without fusion. This must be taken into account for preoperative risk-benefit analysis, tailored surgical decision-making and patient counseling. LEVEL OF EVIDENCE: 4. PMID- 30015719 TI - Effect of Cetuximab on the Development of Epidural Fibrosis based on CD105 and Osteopontin Immunohistochemical Staining. AB - STUDY DESIGN: The effect of cetuximab on the development of epidural fibrosis (EF) was assessed using immunohistochemical methods as well as antibodies for CD105 and osteopontin (OPN). OBJECTIVES: The goal of this study was to assess of EGFR inhibition for the postoperative treatment of fibrosis. SUMMARY OF BACKGROUND DATA: EF is one of most common causes of failed back surgery syndrome, which occurs after laminectomy. Numerous causes and mechanisms have been proposed to explain its development after laminectomy. Many agents have been tested to prevent the development of EF. EGFR, a multi-functional transmembrane glycoprotein, causes cell growth, proliferation, and EF by interacting with EGF and TGF-beta1. The inhibition of postoperative fibrosis using cetuximab, an EGFR blocker, is theoretically possible. However, this has not been tested to date. METHODS: Sixteen Wistar-Albino rats were divided into two groups, namely, control and sorafenib groups. L1-2 laminectomy alone was performed in both groups, and topical cetuximab was applied to the treatment group. After six weeks, rats were sacrificed and examined histopathologically and immunohistochemically; EF tissue was also graded. Statistical significance was accepted at p < 0.05. RESULTS: Fibroblast counts and fibrosis density, determined by histopathologic examination, as well as EF, according to immunohistochemical assessment based on CD105, were found to be higher in the treatment group than in the control group, and this was statistically significant (p < 0.001). Based on OPN staining, the results were consistent with classical methods, and no significant difference was detected among the groups (p = 0.358). CONCLUSIONS: Our study revealed that cetuximab inhibits the development of EF and that CD105, and not OPN, is a reliable marker for grading EF. In addition, cetuximab did not result in toxic, systemic side effects in surrounding tissues. LEVEL OF EVIDENCE: N/A. PMID- 30015720 TI - ALK Is a Specific Diagnostic Marker for Inflammatory Myofibroblastic Tumor of the Uterus. AB - Inflammatory myofibroblastic tumor (IMT) is a myofibroblastic/fibroblastic neoplasm of intermediate malignant potential. It is frequently characterized by genetic fusion of ALK with a variety of partner genes, which results in the activated ALK signaling pathway that can be targeted with kinase inhibitors. IMTs can occur in the gynecologic tract, with the uterus (corpus and cervix) being the most frequent site. Recent studies suggest that IMTs in the gynecologic tract are underrecognized, and a low-threshold for performing ALK immunohistochemistry has been proposed. The aim of this study was to evaluate the specificity of ALK immunohistochemistry for IMTs among uterine mesenchymal and mixed epithelial/mesenchymal tumors. We performed ALK immunohistochemistry on 14 molecularly confirmed uterine IMTs and 260 other uterine pure mesenchymal and mixed epithelial/mesenchymal tumors. Cases showing any positive cytoplasmic and/or membranous staining of the tumor cells were considered to be ALK positive. All 14 IMTs were confirmed to harbor ALK genetic fusion by RNA sequencing, and ALK immunostaining in the form of granular cytoplasmic positivity with paranuclear accentuation was observed in all 14 cases. ALK was negative (complete absence of staining) in all the other pure mesenchymal tumors and in all mixed epithelial/mesenchymal tumors examined. Our findings show that ALK is a highly specific diagnostic immunohistochemical marker for ALK fusion in uterine mesenchymal tumors. In the work-up of uterine mesenchymal tumors, particularly smooth muscle tumors showing myxoid stromal changes, a diagnosis of IMT should be strongly considered if ALK positivity is observed. PMID- 30015721 TI - Using the Relational Coordination Instrument With a Diverse Patient Sample. AB - BACKGROUND: The Relational Coordination (RC) instrument has been used extensively in the context of health care interprofessional coordination. However, the instrument's applicability to patient experiences of their interactions with professionals is largely untested. OBJECTIVES: This study's objectives were to determine: (1) whether the RC instrument could be modified for phone administration to yield internally consistent results when used with a diverse group of patients with complex health needs; and (2) whether the RC factor was invariant across patients of differing education, levels of emotional problems, race, and ethnicity, thereby showing similar interpretation of items across these groups. RESEARCH DESIGN: The RC instrument was administered through a phone survey to patients in Texas (n=346) who reported receiving care coordination. Data collection occurred between 2014 and 2016. Cronbach alpha coefficients and confirmatory factor analysis were used to determine whether the original set of RC items could be used for phone surveys with patients. Factorial invariance testing was used to assess how consistently the instrument was interpreted across patient subgroups. RESULTS: The RC scale generally met acceptable alpha statistic and confirmatory factor analysis thresholds for internal consistency. Factorial invariance results indicated that the scale also generally performed consistently across patient subgroups. CONCLUSIONS: This study provides preliminary evidence that the RC instrument can be used for surveying diverse patient populations. Future use of this instrument with patients can better reflect their experiences as partners with professionals in improving their health. PMID- 30015722 TI - Does the Patient-centered Medical Home Model Change Staffing and Utilization in the Community Health Centers? AB - BACKGROUND: Few studies have looked under the hood of practice redesign to understand whether and, if so, how staffing changed with the adoption of patient centered medical home (PCMH), and whether these staffing changes impacted utilization. OBJECTIVES: To examine the workforce transformation occurring in community health centers that have achieved PCMH status, and to assess the relationship of those changes to utilization, as measured by the number of visits. RESEARCH DESIGN, SUBJECTS, MEASURES: Using a difference-in-differences approach, we compared staffing and utilization outcomes in 450 community health centers that had adopted a PCMH model between 2007 and 2013 to a matched sample of 243 nonadopters located in the 50 states and the District of Columbia. RESULTS: We found that adopting a PCMH model was significantly associated with a growth in use of advanced practice staff (nurse practitioners and physician assistants) [0.53 full-time equivalent (FTE), 8.77%; P<0.001], other medical staff (medical assistants, nurse aides, and quality assurance staff) (1.23 FTE, 7.46%; P=0.001), mental health/substance abuse staff (0.73 FTE, 17.63%; P=0.005), and enabling service staff (case managers and health educators) (0.36 FTE, 6.14%; P=0.079), but not primary care physicians or nurses. We did not observe a significant increase in utilization, as measured in total number of visits per year. However, the visits marginally attributed to advanced practice staff (539 FTE, 0.89%; P=0.037) and mental health/substance abuse staff (353 FTE, 0.59%; P=0.051) significantly increased. CONCLUSIONS: Our findings suggest that the implementation of PCMH actively reengineers staff composition and this, in turn, results in changes in marginal utilization by each staff type. PMID- 30015723 TI - Does Providing Positive Airway Pressure for Sleep Apnea Change Health Care Utilization? AB - BACKGROUND: Sleep apnea is underdiagnosed and thus undertreated. If therapy for sleep apnea results in reduced health care utilization in an entire treated population, then decision-makers will have key information for allocating limited health care resources. OBJECTIVES: To determine whether positive airway pressure (PAP) for sleep apnea was associated with reduced health care utilization in an entire treated population. RESEARCH DESIGN: This was a retrospective cohort; propensity score-matched cases and noncases; pre-post analyses of individual subject utilization. SUBJECTS: Electronic health records were used to identify adult subjects diagnosed with sleep apnea and dispensed PAP therapy (cases) and those without either diagnosed sleep apnea or dispensed PAP therapy (noncases). MEASURES: Acute care hospital days and dispensed medication days supply were compared in cases and noncases. Negative binomial regression was used to model utilization for up to 5 years before and 7 years after PAP dispensation (cases) or a random date (noncases). The association of PAP with changing annual utilization was estimated. RESULTS: There were 13,271 cases and 13,271 matched noncases from 2008 to 2012 for analyses. Trends in the annual rate of acute care utilization were no different between cases and noncases (rate ratio, 0.98, P=0.543). Trends in the annual rate of medication utilization were no different between cases and noncases (rate ratio, 1.008, P=0.112). CONCLUSIONS: PAP dispensation for sleep apnea did not appear to reduce the rate of acute care and medication utilization over several years of follow-up in a large integrated health care system. PMID- 30015724 TI - Nurse Practitioner Practice Environments in Primary Care and Quality of Care for Chronic Diseases. AB - BACKGROUND: The chronic disease burden in the United States represents a significant challenge for the primary care system. The nurse practitioner (NP) workforce can help meet the demand for care; however, organizational barriers such as poor practice environments prevent NPs from delivering high quality care. OBJECTIVES: We investigated the relationship between NP practice environments and quality of care for chronic diseases. RESEARCH DESIGN: We fit regression models to assess cross-sectional associations between claims-based quality measure performance and survey data on NP practice environments in Massachusetts. SUBJECTS: We used survey data from 221 primary care NPs from 118 practices. We obtained quality of care data for patients with asthma, diabetes, and cardiovascular disease. MEASURES: The Nurse Practitioner Primary Care Organizational Climate Questionnaire was used to measure practice environments with its following 4 subscales: NP-Physician Relations, Independent Practice and Support, Professional Visibility, and NP-Administration Relations. Three Healthcare Effectiveness Data and Information Set measures were used to evaluate the quality of care. RESULTS: A 1-SD increase in the organizational-level NP Administration Relations subscale score was associated with a near doubling of the odds of receiving medication management for asthma. A 1-SD increase in the organizational-level Independent Practice and Support subscale score was associated with a 60% increase in the odds of receiving recommended screening for cardiovascular disease. There was no impact on diabetes care measure. CONCLUSIONS: NP practice environment affected the quality of care for 2 chronic conditions. Efforts should be implemented to improve NP practice environment to potentially improve care quality. PMID- 30015725 TI - Effective Engagement Requires Trust and Being Trustworthy. PMID- 30015726 TI - Ethnoracial Disparities in Medicare Annual Wellness Visit Utilization: Evidence From a Nationally Representative Database. AB - INTRODUCTION: In 2011, Medicare began offering annual preventive care visits (annual wellness visit; AWV) to beneficiaries at no charge. Providing free preventive care supports primary and secondary prevention of chronic disease and may reduce ethnoracial disparities in health outcomes. OBJECTIVES: To estimate AWV utilization trends by ethnoracial group in a nationally representative sample of the Medicare population. RESEARCH DESIGN: We estimated the probability of AWV utilization using probit regression models with beneficiary-reported ethnoracial group as the primary predictor and demographics, socioeconomic indicators, and factors related to access and utilization of health care as covariates. SUBJECTS: In total, 14,687 fee-for-service Medicare beneficiaries aged 66 years or older who participated in the Medicare Current Beneficiary Survey 2011-2013. MEASURES: AWV utilization was identified using procedure codes. RESULTS: Overall AWV utilization increased from 8.1% (2011) to 13.4% (2013). In 2011, utilization was highest in non-Hispanic white (8.5%) and lowest in non-Hispanic black (4.5%) beneficiaries. Utilization increased the most in non-Hispanic black beneficiaries, to 15.4% in 2013. Significant differences in AWV utilization by non-Hispanic black and Hispanic/Latino beneficiaries were found in unadjusted models, but did not persist after controlling for income and education. Having a usual (nonemergent) place of care and a nonrural residence were strong predictors of utilization. CONCLUSIONS: Utilization of the AWV has increased modestly since its introduction, but remains low. Utilization varies by ethnoracial group, with disparities largely explained by differences in income and education. Further efforts are needed to evaluate AWV utilization and effectiveness, especially among low socioeconomic status ethnoracial minorities. PMID- 30015727 TI - Oral Myiasis in a Patient With HIV Manifestations and Neurologic Toxoplasmosis Treated by Ivermectin. AB - Myiasis has been defined as a pathologic condition where dipterous larvae are lodged in mammalian hosts causing an infestation, which feeds on living or dead tissue for at least a certain period inside the host and develops itself as parasites. In humans, the most commonly affected sites are the nose, eyes, skin wounds, sinuses, lungs, ears, gut, gall bladder, vagina, nasal cavities, and rarely the mouth because the oral tissues are rarely exposed to the external environment. The etiology of oral myiasis is usually related to local factors such as poor oral hygiene, periodontal disease and labial incompetence, and systemic factors such as neurologic deficits. PMID- 30015728 TI - An Easy Applicable Flap Tecnique for External Auditory Canal Defects. PMID- 30015729 TI - Causes of the Removal of High-Density Polyethylene Sheets (Medpor) in Revision Rhinoplasty. AB - The aim of this study was to identify the causes of complications in rhinoplasties using Medpor. The medical records of 71 patients who had undergoing a reoperation after a rhinoplasty using Medpor were reviewed. From each patient's history, examination records, and operative records, the method of the previous rhinoplasty using Medpor was extracted. The previously inserted Medpor and the septal mucosa covering it were removed during the reoperation and observed in 3 cases. A turned-up or short nose (43.8%) and tip stiffness (25.3%) were significantly more common than other complaints (P < 0.05). The strut type (49.2%) and the septal extension type (43.8%) were significantly more common than the spreader type (P < 0.001). In the reoperation, extension grafts (47.1%) and by tip grafts (39.7%) were significantly more common than other procedures (P < 0.001). Grossly, the specimens were covered with septal mucosa and multiple ball like granulation tissues (cobblestone appearance) at the "pores" of the Medpor. Microscopically, Medpor was covered with fibrous collagenous tissue, partially bridging through the pores. Inflammatory cells had infiltrated around the polyethylene. The authors classify the patients in the present series as: those with a long columella strut to the anterior nasal spine, those with Medpor inserted onto the membranous septum (septal extension graft or too large), and those with Medpor used as spreader graft covered with nasal mucosa (causing weakness of the nasal septum and thinning or necrosis of the mucosa). Using Medpor as a strut graft seems to be relatively safe if the floating type is used. PMID- 30015730 TI - Analysis of Intramaxillary and Mid-Face Skeletal Asymmetry in a Three-Dimensional Model With Complete Unilateral Cleft Lip and Palate. AB - Cleft lip and palate is the commonest congenital craniofacial anomaly and also affects the facial bones. In a unilateral cleft lip and palate (UCLP), there is asymmetry in the mid-face and also within the maxilla between the cleft and non cleft sides. The aim of this study is to develop a 3-dimensional model of an UCLP skull from a patient's cone-beam computed tomography and measure the asymmetry. The model is constructed with manual segmentation of all regions using MIMICS v14.0 and measurements were done by 3-matic software. Measurements in the mid face and maxilla were carried out in all planes of interest. Asymmetry was present not only in the maxilla but extends to the orbital, zygomatic, and frontal bones. Through this methodology and model, asymmetric variations <0.5 mm could be assessed precisely thus having potential applications in treatment planning of craniofacial deformities. PMID- 30015731 TI - Recurrence of Biphenotypic Sinonasal Sarcoma With Cerebral Hemorrhaging. AB - Biphenotypic sinonasal sarcoma (BSNS) is a newly classified tumor that is characterized by neural and myogenic differentiation. The authors herein report a rare patient of the recurrence of BSNS with intracranial hemorrhaging and a review of the literature. A 70-year-old man presented with disturbance of consciousness and vomiting blood. He had undergone resection of a sinonasal tumor 11 years earlier and shown no recurrence at his last follow-up 4 years ago. Computed tomography showed cerebral hemorrhaging around a low-density mass that occupied the left frontal base and left ethmoid sinus. Total resection was performed. A histological examination of tumor specimens obtained from the first and the second resections revealed almost the same characteristic morphological features and the patient was diagnosed with BSNS. The lesion was negative for any fusion genes, as previously reported. The long-term progression of BSNS is not clear. This case appears to be the first reported recurrence of BSNS with cerebral hemorrhaging. Biphenotypic sinonasal sarcoma should be considered to need long-term follow-up. PMID- 30015732 TI - Nerve Switch for Reducing Synkinesis After Gracilis Muscle Transfer Innervated Via the Masseter Nerve. AB - BACKGROUND: In surgical treatment for longstanding facial paralysis, muscle transplantation is considered a useful and important method. To obtain a spontaneous smile, the use of the facial nerve of the healthy side as a motor source is better, but use of the masseter nerve allows prompt reinnervation and powerful movement. However, in some patients in whom the masseter nerve is used, separating masticatory movement and commissure contraction is difficult. Solutions for such patients have not been determined. CASE HISTORY AND DISCUSSION: A 46-year-old female patient presented with longstanding complete facial paralysis after resection of a right acoustic neurinoma. As initial surgery, free gracilis transfer was performed on the cheek, but the patient experienced commissure movement during meals postsurgery. Secondary corrective surgery was performed to detach the motor nerve of the gracilis from the masseter nerve and suture it to the facial nerve of the healthy side via cross-face nerve graft. The symptom improved but partially recurred. Improvement in synkinetic movement can be obtained by performing cross-face nerve grafting and subsequent nerve switch. PMID- 30015733 TI - A Plastic Surgeon Striving for Anatomical Knowledge. PMID- 30015734 TI - The Outcome of Sling Retraction Technique in Microvascular Decompression for Hemifacial Spasm. AB - OBJECTIVE: This study explored the technical characteristics and effectiveness of sling retraction technique in microvascular decompression for hemifacial spasm. METHODS: Between January 2008 and May 2016, 158 patients affected by hemifacial spasm underwent microvascular decompression. Among them, the traditional technique was performed in 86 patients (A Group) and the sling retraction technique was used in 72 patients (B Group). The authors conducted a retrospective study and compared the surgical outcome of the 2 groups. The authors measured cure rate at 3 months and 5 years after microvascular decompression. RESULTS: In the traditional technique group, the cure rate of microvascular decompression was 94.2% and 83.3%. While in the sling retraction technique group, the cure rate of microvascular decompression was 95.8% and 94.4%. Facial nerve palsy, hearing loss, meningitis, and ataxia were frequent complications in both 2 groups. CONCLUSIONS: The sling technique using biomedical glue is an effective and safe option for patients of hemifacial spasm. During the long-term follow-up, the sling retraction technique of microvascular decompression was more effective than the traditional technique, while there were no significant differences in the incidences of complications. PMID- 30015735 TI - Three-Dimensional Analysis of Perioperative Condylar Displacement After Mandibular Setback Surgery With Intended Manual Condylar Positioning. AB - PURPOSE: The purpose of this study is to investigate the effect of orthognathic surgery with intended manual condylar positioning on condyle by examining a change in its position. METHOD: About 18 patients with mandibular prognathism who underwent orthognathic surgery with intentional manual condyle positioning were included. Condyle displacement was analyzed through 3D cone-beam computed tomography before and after operation. The patients were categorized into 2 experimental groups: group A (1-jaw) and group B (2-jaw). The experimental groups were examined before surgery (T0), 3 days (T1), and 6 months (T2) after surgery. Condylar displacement direction was investigated in terms of bodily shift and rotational movement. RESULTS: Downward bodily shift of condyle after surgery was significantly apparent from all of the patients. Condylar bodily shift in other directions was statistically insignificant. Gross bodily shift of condyle right after surgery was anterolateral-inferior direction. In perspective of rotational movement, condyle rotated in infero-medial direction right after operation, but no significant change was presented afterwards. In addition, no significant difference in the amounts of condylar shift and pattern existed between groups A and B. CONCLUSION: Intended manual condylar positioning may minimize postoperative displacement of condyle while accomplishing skeletal stability. PMID- 30015736 TI - Clinical Efficacy and Patient Perceptions of Pyogenic Granuloma Excision Using Diode Laser Versus Conventional Surgical Techniques. AB - The use of laser in oral surgery and periodontology is a matter of debate, mainly because of the lack of consensual therapeutic protocols. The aim of this study was to evaluate the surgical advantages of diode laser versus traditional surgery with a cold blade for the surgical excision of pyogenic granuloma (PG). Twenty one patients (10 males, 11 females, aged 19-66 years; mean age: 46.5 years), requiring PG excision, were enrolled in the study. Through a randomized clinical trial design, all patients were randomly subjected to PG surgical excision with either diode laser or cold blade. Parameters analyzed were the speed of incision, time of intervention, intraoperative bleeding, number of stitches, and patient compliance. Histologic examination was performed before and after surgical excision of the lesions. Patients compiled a subjective evaluation questionnaire. Both treatments were successful in surgical excision of PG. However, the mean speed of incision was significantly reduced in diode laser group (0.61 +/- 0.29 mm/s) compared with cold blade group (1.47 +/- 1.23 mm/s) (P < 0.05). The mean lengths of time for the whole surgical intervention were significantly lower in diode laser group (221.15 +/- 220.89 s) compared with cold blade group (316.10 +/ 248.69 s) (P < 0.05). Moreover, diode laser induced a reduced intrasurgical bleeding, and a better gingival healing compared with cold blade surgical treatment. This study demonstrated that the use of diode laser showed additional advantages compared with cold blade in terms of less postoperative discomfort and pain for surgical removal of PG. PMID- 30015737 TI - Retracted or Withdrawn Publications in Plastic Surgery Journals. PMID- 30015738 TI - Upper Airway Obstruction in a Panfacial Fracture. AB - Panfacial fractures are considered the most aggressive and complex facial fracture, and most of them are the results of a high energy trauma. Therefore, a clinical report of a male patient with a panfacial fracture and Richards type 3 fracture resulting in an airway obstruction is presented. This type of fracture can promote an upper airway obstruction, which needs a correct and fast diagnosis to the life support of the patient. PMID- 30015739 TI - Frontal Sinus Osteoplastic Flap Surgery Using a Surgical Navigation System. AB - OBJECTIVE: To report the case of a 38-year-old woman who underwent osteoplastic flap surgery for recurrent frontal sinus mucocele. During surgery, the exact shape of the frontal sinus was duplicated using a surgical navigation system. METHODS: In this case report, the authors suggest intraoperative surgical navigation systems are useful for accurately determining the dimensions of the frontal sinus for osteoplastic flap surgery. RESULTS: The patient underwent successful and safe osteoplastic flap surgery using a surgical navigation system. CONCLUSION: Surgical navigation is useful and safe for frontal sinus osteoplastic flap surgery. PMID- 30015740 TI - Bilateral Cleft Lip and Palate, With Facial Dysplasia: Interdisciplinary Treatment and Long-Term Follow-Up. AB - Bilateral complete clefts represent the result of an incomplete fusion with all the morphologic components present. It is well known that patients with bilateral cleft lip and palate have typical characteristics such as insufficient medial face development with an orthodontic class III tendency, flat nose and short columella with abnormal nasolabial angle, bilateral oronasal fistulas, alterations in the number and position of the lateral incisors, and agenesis or supernumerary teeth. Successfully solving these cases, results in a difficult challenge and studies showing extended follow-up are not frequent. Bilateral complete clefts, including medial facial dysplasia, are a rare condition, not only difficult to be included in any classification but also of complex solution. These patients require multiple surgical procedures throughout life, and long term results are often still far from ideal. Due to surgical intervention and diminished intrinsic growth potential, surgical results may change from initially good into a progressively disappointing outcome. However, if the ideal timing and type of surgery are known, in combination with the intrinsic growth potential, these results could be ameliorated. A patient with complete bilateral cleft, presenting hypoplasia of philtrum and premaxilla, flat nose with rudimentary columella and septum, is reported. A description of her interdisciplinary treatment and long-term outcome with an adequate and stable result was observed. Being the intrinsic growth restriction mainly localized in the central mid-face, a protocol oriented to stimulate facial development during growth period could be essential to reduce the number of surgical procedures and prevent sequels. Early referral to a specialized center is mandatory to achieve a correct treatment and result. PMID- 30015741 TI - Treatment Strategy of a Large Dentigerous Cyst in a Young Patient. PMID- 30015742 TI - Two Methods of Cleft Palate Repair in Patients With Complete Unilateral Cleft Lip and Palate. AB - OBJECTIVE: The objective of this study was to compare the surgical outcome between 2 patient groups with complete unilateral cleft lip and palate who underwent different types of palatoplasty. METHODS: This is a cohort study between 2 groups of patients with complete unilateral cleft lip and palate who were operated using different surgical techniques from 2008 to 2011. About 28 patients were operated using a primary lip nose repair with vomer flap for hard palate single-layer closure and delayed soft palate repair (modified Oslo protocol) and 32 patients were operated using our protocol in Lima. Data collection was accomplished by evaluation of symptomatic oronasal fistulas, presence of velopharyngeal insufficiency and evaluation of dental arch relationships (scored using the 5-year-olds' index). RESULTS: Our comparative study observed statistically significant differences between the 2 groups regarding the presence of oronasal fistulas and velopharyngeal insufficiency in favor of our palatoplasty technique. A statistically significant difference was not found in functional vestibular oronasal fistula development between the studied techniques for unilateral cleft palate repair. This comparative study did not observe significant differences in dental arch relationships between the studied techniques. CONCLUSION: In this study, better surgical outcome than modified Oslo protocol regarding oronasal fistulas and velopharyngeal insufficiency on patients with complete unilateral cleft lip and palate was observed. The results arising from this study do not provide evidence that one technique is enough to obtain better functional closure of the alveolar cleft and dental arch relationship at 5 years. PMID- 30015743 TI - Normal Patterns of Nasometric Values in Adult Jordanian Speakers of Arabic. AB - PURPOSE: The study sought to establish normative nasometric values for adult Jordanian speakers of Arabic. Gender-related differences and intraspeaker variability of nasalance scores were investigated. METHODS: A total of 113 adult speakers of Jordanian Arabic (56 men and 57 women) without speech-language and hearing impairments or craniofacial anomalies ranging in age between 18 and 55 participated in the study. Nasometer II, Model 6400 was used to obtain nasalance scores as speakers produced 3 recitations for each of the 3 standardized passages consisting of an oral passage, an oronasal passage, and nasal sentences. Descriptive statistics of nasalance scores for each passage were obtained and gender-related differences were determined by ANOVA. Standard deviation for the 3 repetitions for each passage was considered an index for intraspeaker variability. RESULTS: Average nasalance for each passage was (11.23%) for the oral passage, (25.48%) for the oronasal passage, and (51.92%) for the nasal sentence. There was no gender effect on nasalance on the oral passage, however women exhibited higher nasalance scores than men on the both oronasal passage (P = 0.002) and nasal sentences (P = 0.017). Intraspeaker variability for all speakers fell below 4.5% with repeated readings. CONCLUSION: The study provides normative nasometric data for Arabic speaking Jordanian adults to serve as references for the assessment of velopharyngeal dysfunction in craniofacial clinics. Arabic speakers demonstrated different nasalance scores than speakers of other languages. Gender differences can be attributed to variations in anatomical structure and velopharyngeal function between men and women. PMID- 30015744 TI - Facial Growth Changes Induced by Orthodontic Treatment in Patients With Unilateral Cleft Lip and Palate. AB - The aim of this study was to investigate the effect of orthodontic treatment on the maxillofacial growth of patients with unilateral cleft lip and palate. The Great Ormond Street, London and Oslo (GOSLON) yardstick was used for a longitudinal evaluation of 24 patients with cleft lip and palate treated at the Cleft Center of the Lauro Wanderley University Hospital, Paraiba State, northeastern Brazil. Dental casts were evaluated by 3 orthodontists and classified according to the GOSLON yardstick. The evaluation was performed at 2 different stages: T1 (before orthodontic treatment) and T2 (follow-up evaluation) after a 6-year mean follow-up interval. The Kappa test was used to evaluate intra and interexaminer agreement, and paired t-test was used to compare the differences between T1 and T2, with a 99% confidence interval. The average intraexaminer Kappa was 0.979, ranging from 0.971 to 0.990. The interexaminer Kappa value was 0.926 at T1, ranging from 0.885 to 0.964, and 0.896 at T2, ranging from 0.696 to 1.0. The mean GOSLON yardstick found at T1 was 2.5 +/- 1.18 with 50% in G1 + G2, 29.18% in G3, and 20.82% in G4 + G5. At T2, the GOSLON average was 1.71 +/- 1.12, with 79.18% in G1 + G2, 12.5% in G3, and 8.32% in G4 + G5. A statistically significant difference was found between T1 and T2. The results suggest that orthodontic treatment improves facial growth in patients with unilateral cleft lip and palate. PMID- 30015745 TI - Hypertelorism Secondary to Mucocele in the Paranasal Sinuses. AB - Ocular hypertelorism was introduced by Greig as an increased interpupillary distance. The paranasal sinus mucoceles are acquired lesions for various reasons; however, their behavior is progressive, capable of eroding the bone and extending to the orbital and intracranial regions. The objective is to present a clinical case of orbital hypertelorism secondary to mucocele in the paranasal sinuses. This is a 72-year-old male patient who came presenting an increase in volume in the right nasoorbitoethmoidal region. The isodense lesion occupying the maxillary and right ethmoidal sinuses was confirmed by an intimate relationship with the ipsilateral frontal and sphenoidal sinus, with osteolytic involvement of the orbit and nasal region. After incisional biopsy with mucocele results, a wide resection plus facial reconstruction was performed with autologous grafts and osteosynthesis material. Currently, the patient has 1 year of evolution, without significant functional commitment. It is important to consider giant mucoceles as part of the differential diagnoses in patients with deformities in the middle and upper third of the face. PMID- 30015746 TI - Anatomical Reconstruction in Bilateral Cleft Lip With Mendoza Technique. AB - : : The bilateral cleft lip (BCL) is the most severe manifestation of orofacial clefts. Multiple techniques have been described to reconstruct BCL to obtain good aesthetic and functional results with minimal complications. OBJECTIVE: Description of surgical technique for BCL reconstruction and present the postoperative results obtained. METHODS: Patients with BCL of the cleft lip and palate at ABC Medical Center from June 2013 to June 2017 operated with Mendoza bilateral cheiloplasty were included. The procedure includes an anatomical reconstruction of the lip with minimal resection of tissue, alignment of the orbicularis muscle, vestibule creation, and complete use of the prolabium. The evaluation was carried out by photographs analyzing parameters of quality, symmetry, and alignment of lip and nose structures. RESULTS: The authors included 36 patients, 15 women and 16 men. The average procedure time was 57 minutes. Photographs were evaluated 1 year postoperatively, symmetry in lip was observed in 91.6% of the patients, muscle continuity in 100%, deep gingivolabial sulcus in 94.5% of cases, closed nasal floor in 100% with no presence of nasovestibular fistulas. CONCLUSIONS: This technique allows an anatomical BCL reconstruction with good aesthetic and functional results. PMID- 30015747 TI - Craniofacial Microsomia: Orthodontic Surgical Treatment of Growing Patients. AB - Craniofacial microsomia covers a set of morphogenetic anomalies that affect structures arising from the first and second brachial arches. Due to the vast phenotypic variation and complexity of the malformation, a global treatment that is coordinated by a multidisciplinary team is imperative. Herein, the authors describe 3 clinical patients and discuss the different therapies used according to the type of microsomia present. It was concluded that early and integrated treatment, which considers all the affected and potentially affected soft and hard tissue, is needed, and that patients must be monitored until they have finished growing. PMID- 30015748 TI - Unilateral and Bilateral Audiological Benefit With an Adhesively Attached, Noninvasive Bone Conduction Hearing System. AB - OBJECTIVE: To assess the audiological benefit of a noninvasive, adhesively attached bone conduction device (BCD1) in subjects with induced bilateral conductive hearing loss. Secondary objectives were to evaluate the additional benefit of bilateral fitting compared with unilateral fitting and to compare the outcomes with bone conduction devices attached to a softband (BCD2). STUDY DESIGN: Prospective nonrandomized crossover study. SETTING: Tertiary referral center. PATIENTS: Fifteen subjects with induced bilateral conductive hearing loss. MAIN OUTCOME MEASURES: Sound field thresholds, speech understanding in quiet and in multinoise were assessed in unaided, unilateral, and bilateral treatment conditions. In addition, sound localization was evaluated in uni- and bilateral treatment conditions. RESULTS: The outcomes of BCD1 and BCD2 were comparable. Sound field thresholds improved by 24.6 dB (BCD1) and 24.8 dB (BCD2) in the unilateral and 26.8 dB (BCD1) and 25.1 dB (BCD2) in the bilateral treatment condition. Speech reception thresholds (SRTs) in quiet improved by 20.0 dB (BCD1) and 21.7 dB (BCD2) in the unilateral and by 22.7 dB (BCD1) and 21.5 dB (BCD2) in the bilateral condition. If speech was presented from the front, SRTs in noise were improved by 3.6 dB and 4.2 dB (unilateral) and by 4.5 dB and 4.4 dB (bilateral) for BCD1 and BCD2, respectively. With speech presented from the unilateral side, SRTs were improved by 4.0 dB and 4.7 dB (unilateral) and 3.8 dB and 4.8 dB (bilateral) compared with the unaided situation. If noise was presented from the contralateral side, small differences (-0.6 dB and -0.1 dB) were observed. Bilateral fitting brought additional benefits for speech understanding in noise and sound localization. CONCLUSIONS: Both bone conduction devices seem to be a valid treatment for patients with conductive hearing loss and minor sensorineural hearing loss component. PMID- 30015749 TI - Analysis of Different Approaches for Clinical Cochlear Coverage Evaluation After Cochlear Implantation. AB - HYPOTHESIS: Methods for cochlear coverage determination vary in their accuracy and are hence not equally reliable. BACKGROUND: The audiological outcome after cochlear implantation is known to depend on several factors. One factor shown to positively correlate with speech perception is the insertion angle. This parameter is one of the ways to describe the fraction of the cochlea spiral exposed to electric stimulation after implantation, also known as cochlear coverage, which itself is dependent on the length and type of electrode array as well as the size and shape of the implanted cochlea. While the assessment of cochlear coverage as the insertion angle is quick and uncomplicated, the accuracy of representing the relative fraction of the cochlea exposed to electric stimulation by this single measurement value remains unknown. METHODS: Both the cochlea spiral and implanted electrode array of N = 10 cochlear implant patients were traced within clinical imaging data and processed to derive the respective cochlear coverage values. These values were compared to ones derived with alternative measures like the insertion angle as well as other methods to yield the accuracy and reliability of these approaches. RESULTS: The insertion angle as well as two novel approaches were found to be superior to all other analyzed assessment options and well suited for clinical cochlear coverage evaluations. CONCLUSION: Insertion angle measurements are well suited for cochlear coverage determination, especially regarding retrospective analyses. Prospective studies independent of anatomical irregularities should be performed with the newly proposed approaches. PMID- 30015750 TI - MRI IDENTIFICATION OF THE SACCULE? DO IT YOURSELF! PMID- 30015751 TI - Development of an Automatic Diagnostic Algorithm for Pediatric Otitis Media. AB - HYPOTHESIS: The artificial intelligence and image processing technology can develop automatic diagnostic algorithm for pediatric otitis media (OM) with accuracy comparable to that from well-trained otologists. BACKGROUND: OM is a public health issue that occurs commonly in pediatric population. Caring for OM may incur significant indirect cost that stems mainly from loss of school or working days seeking for medical consultation. It makes great sense for the homecare of OM. In this study, we aim to develop an automatic diagnostic algorithm for pediatric OM. METHODS: A total of 1,230 otoscopic images were collected. Among them, 214 images diagnosed of acute otitis media (AOM) and otitis media with effusion (OME) are used as the database for image classification in this study. For the OM image classification system, the image database is randomly partitioned into the test and train subsets. Of each image in the train and test sets, the desired eardrum image region is first segmented, then multiple image features such as color, and shape are extracted. The multitask joint sparse representation-based classification to combine different features of the OM image is used for classification. RESULTS: The multitask joint sparse representation algorithm was applied for the classification of the AOM and OME images. The approach is able to differentiate the OME from AOM images and achieves the classification accuracy as high as 91.41%. CONCLUSION: Our results demonstrated that this automatic diagnosis algorithm has acceptable accuracy to diagnose pediatric OM. The cost-effective algorithm can assist parents for early detection and continuous monitoring at home to decrease consequence of the disease. PMID- 30015752 TI - The Novel Peptide Vaccine GV1001 Protects Hearing in a Kanamycin-induced Ototoxicity Mouse Model. AB - HYPOTHESIS: We tested whether GV1001 has any ototoxic side effects at different doses and whether it protects hearing in an aminoglycoside-induced ototoxicity mouse model. BACKGROUND: GV1001, a novel peptide vaccine currently being examined in a Phase 3 clinical trial to treat pancreatic cancer, also has anti inflammatory and antioxidant effects. METHODS: In the first experiment, C57/BL6 mice were injected with GV1001 preparations at concentrations of 0.1 to 100 mg/kg for 7 days to evaluate the toxicity of GV1001 on the inner ear and kidneys. In the second experiment, the protective effect of GV1001 was tested in an ototoxicity mouse model that was generated by injecting 800 mg/kg kanamycin (KM) for 2 weeks. The hearing threshold and hair cell loss were compared between the KM + GV1001 group (treated with 10 mg/kg GV1001 for 2 wk) and the KM + saline group. The hearing threshold was measured before, and 7, 14, and 21 days after the initial treatment. The blood urea nitrogen level was measured. RESULTS: No ototoxicity or renal toxicity was found following treatment with different doses of GV1001 (0.1-100 mg/kg). The KM + saline group showed impaired auditory function and markedly disoriented and missing cochlear hair cells, while the KM + GV1001 group showed significant hearing and hair cell preservation in comparison (p < 0.05). CONCLUSION: GV1001 itself did not have any detrimental effects on the inner ear or kidney. In the KM induced ototoxicity model, concomitant administration of GV1001 protected against cochlear hair cell damage and preserve hearing. PMID- 30015753 TI - Salvage Radiosurgery After Subtotal Resection for Catecholamine-secreting Jugular Paragangliomas: Report of Two Cases and Review of the Literature. AB - OBJECTIVES: Catecholamine-secreting jugular paragangliomas (JPs) represent a rare subset of head and neck paragangliomas that may present with hypertension, arrhythmia, or syncopal episodes. Subtotal resection to protect critical neurovascular structures may result in persistent catecholamine excess from residual tumor. Herein, we report our experience with stereotactic radiosurgery (SRS) for salvage treatment of catecholamine-secreting JP following subtotal microsurgical resection. PATIENTS: Adult patients treated with SRS after subtotal microsurgical resection of catecholamine-secreting JP. INTERVENTIONS: SRS. MAIN OUTCOME MEASURES: Post-treatment catecholamine and metanephrine levels, clinical outcomes, and tumor control. RESULTS: Of 85 patients with JPs treated with primary or salvage radiosurgery between 1990 and 2017, 2 (2%) harbored nonmalignant secreting tumors. Patient 1 developed catecholamine excess with elevated norepinephrine (NE) at 475 mcg/24 hours (normal < 80 mcg/24 h). Following subtotal resection, she developed catecholamine excess with radiographic evidence of tumor growth and therefore underwent SRS. Three years post-SRS and beyond, catecholamine levels remained normalized (NE 62 mcg/24 h at 10 yr) and tumor volume remained stable on serial MRI studies over the 17-year follow-up period.Patient 2 developed symptomatic arrhythmia and was found to have a JP. Urine norepinephrine (NE) was elevated at 213 mcg/24 hours. She underwent nerve-sparing subtotal resection and upfront SRS was used to treat residual tumor. Twenty months following SRS, the area of residual JP had not enlarged in size and catecholamine levels remained normal (NE 46 mcg/24 h). CONCLUSIONS: Radiosurgery can be used in salvage treatment of catecholamine-secreting JP, providing durable tumor control and resolution of catecholamine excess. For patients with large catecholamine-secreting JP and normal lower cranial nerve function, aggressive nerve-sparing subtotal resection with adjuvant radiosurgery may offer a low-morbidity alternative to gross total resection. Further study of this subset of patients is warranted to substantiate these promising, yet preliminary findings. PMID- 30015754 TI - Blood pressure level associated with lowest cardiovascular event in hypertensive diabetic patients. AB - BACKGROUND: The ACCORD BP trial failed to show the benefit of strict blood pressure (BP) control on cardiovascular events in diabetics with high cardiovascular risk. However, this result cannot be generalized to all diabetics. We investigated whether lower mean BP in diabetic people with hypertension is associated with better prognosis. METHODS: Participants from the Korea National Health Insurance Service Health Examinee Cohort who were diagnosed with diabetes and hypertension between 2003 and 2006 were included in the analysis (N = 7926). Mortality and cardiovascular events were compared among three groups according to mean SBP (<130, 130-<140, >=140 mmHg) and mean DBP (<80, 80-<90, >= 90 mmHg) recorded during follow-up health examinations for up to 11 years. RESULTS: Significant reductions in the risk of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and end-stage renal disease were observed in patients with a mean SBP of 130 mmHg to less than 140 mmHg, as compared with patients with a mean SBP of at least 140 mmHg. The additional clinical benefit of a mean SBP of less than 130 mmHg was unclear. Lower risk of all-cause death, cardiovascular mortality, and nonfatal strokes was observed in patients with a mean DBP of 80 mmHg to less than 90 mmHg. A mean DBP of less than 80 mmHg was associated with further reduction in all-cause mortality, cardiovascular mortality, ischaemic stroke, and total stroke. CONCLUSION: A mean BP of less than 140/80 mmHg was associated with further reduction in the risk of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events in diabetic hypertensive patients. PMID- 30015755 TI - Increased excitatory regulation of the hypothalamic paraventricular nucleus and circulating vasopressin results in the hypertension observed in polycystic kidney disease. AB - BACKGROUND: Hypertension and baroreflex dysfunction confer poorer outcomes in patients with polycystic kidney disease (PKD). METHOD: We examined whether hypothalamic paraventricular nucleus (PVN) activation or circulating vasopressin contribute to hypertension and baroreflex dysfunction in the Lewis polycystic kidney (LPK) rat. RESULTS: Bilateral PVN inhibition with muscimol reduced SBP further in urethane-anaesthetized adult LPK rats than in control Lewis rats (-43 +/- 4 vs. -18 +/- 3 mmHg; P < 0.0001, n = 14), but was not associated with a greater reduction in sympathetic nerve activity (SNA) or improvement in HR or SNA baroreflex function. Blockade of ionotropic glutamatergic input to the PVN with kynurenic acid also reduced SBP (P < 0.001), but not SNA, further in both adult and juvenile LPK rats. No differences in AMPA or NMDA receptor mRNA expression were noted. Systemic V1A receptor antagonism using OPC-21268 reduced SBP in adult LPK rats only (P < 0.001) and had no effect on the depressor response to PVN inhibition (P = 0.39). Combined peripheral V1A receptor antagonism and PVN inhibition, however, normalized SBP in adult LPK rats (122 +/- 11 vs. 115 +/- 6 mmHg; LPK vs. Lewis, P > 0.05, n = 10). CONCLUSION: Our data show that in the LPK rat model of PKD, hypertension is contributed to by increased PVN neuronal activity and, through an independent mechanism, systemic V1A receptor activation. Treatments that reduce PVN neuronal activity and/or inhibit peripheral V1A receptors may provide novel treatment strategies to ameliorate hypertension in individuals with PKD and limit overall disease progression. PMID- 30015756 TI - Nocturnal hypertension in high-risk mid-pregnancies predict the development of preeclampsia/eclampsia. AB - OBJECTIVE: The aim of this study was to test if hypertension detected by ambulatory blood pressure monitoring (ABPM) performed at mid-pregnancy, is a useful predictor for preeclampsia/eclampsia (PEEC). METHODS: The study was performed in women coursing high-risk mid-pregnancies. Office blood pressure (BP) was estimated as the mean of three values, taken by a specialized nurse after a 15-min interview, and office hypertension defined as at least 140/90 mmHg. Immediately after, an ABPM was started. Diurnal hypertension was defined as ABPM at least 135/85 mmHg during daily activities, nocturnal hypertension as ABPM at least 120/70 mmHg during night rest. The adjusted risk of PEEC was estimated using logistic regression. RESULTS: Eighty-seven women (mean age 31 +/- 7 years) with 23 +/- 2 weeks of pregnancy were included. The prevalence of office and ABPM hypertension was 13.8 and 40.2%, respectively. The concordance between both hypertension diagnosis was low (kappa = 0.170, P = 0.044). Nocturnal hypertension (35.6%) was more frequent than diurnal hypertension (26.4%). Nocturnal hypertension markedly increased the relative risk of PEEC (OR 5.32, 95% CI 1.48 19.10). The risk of PEEC attributed to diurnal hypertension did not reach statistical significance; and when both, diurnal and nocturnal hypertension were included in the same model, only the second one was a significant predictor (P = 0.012). The relative risk associated with nocturnal hypertension increased for women not taking acetylsalicylic acid (ASA); (OR 11.40, 95% CI 2.35-55.25). CONCLUSION: Nocturnal hypertension at high-risk mid-pregnancy is a frequent condition and a strong predictor for PEEC; the risk doubled for women not taking ASA. PMID- 30015757 TI - Excessive umbilical cord coiling confers risk of elevated nocturnal blood pressure and severe/early-onset preeclampsia. AB - BACKGROUND: The associations between umbilical cord coiling, feto-placental vascular resistance and maternal blood pressure (BP) are not well understood. METHOD: We retrospectively analyzed 502 pregnant women suspected of hypertensive disorders in the third trimester from a hospital-based cohort, who underwent ambulatory BP monitoring and umbilical artery Doppler velocimetry examinations within 14 days before delivery. By applying quantile regression, a significant quantile-dependent positive association between umbilical cord coiling index and umbilical artery pulsatility index (UAPIMOM; converted to multiples of median) was observed from above 0.75th quantiles for each parameter. RESULTS: Using the cutoffs both at the 0.75th quantile to define high umbilical cord coiling (>=0.28 coils/cm) and high UAPIMOM (>=1.30), respectively, a graded increase in BP level was observed from patients with both low, either high and both high categories. Multivariate linear and quantile regression revealed that the high umbilical cord coiling/high UAPIMOM interaction was significantly correlated with night-time mean DBP level. Moreover, umbilical cord hypercoiling (>=0.3 coils/cm) was significantly correlated with night-time DBP with an average increase of ~5 mmHg from the 0.05th to 0.70th quantiles and independently predicted the occurrence of severe (odds ratio 2.32, 95% confidence interval: 1.22-4.41) and early-onset (odds ratio 2.43, 95% confidence interval: 1.18-4.97) preeclampsia after adjusting for covariates. Further mediation analysis showed that elevated high UAPIMOM (>=1.30) could explain 11.4% of the umbilical cord hypercoiling -> high night-time DBP association. CONCLUSION: Therefore, this retrospective study identifies excessive umbilical cord coiling, and its interaction with increased feto-placental vascular resistance, as novel risk factors for nocturnal BP elevation and preeclampsia. PMID- 30015758 TI - Blood pressure changes during twin pregnancies: the Japan Environment and Children's Study. AB - OBJECTIVES: Although a twin pregnancy is a risk factor for hypertensive disorders of pregnancy, studies investigating longitudinal blood pressure changes during twin pregnancies are uncommon. The aims of this study were to evaluate the longitudinal blood pressure changes during twin pregnancies and to compare blood pressure levels between twin and singleton pregnancies. METHODS: Five hundred dichorionic diamniotic twin, 240 monochorionic diamniotic twin, and 80 775 singleton pregnancies were included in this Japanese prospective birth cohort study. A marginal model was applied to evaluate the SBP, DBP, and mean arterial pressure levels during early gestation, mid-gestation, and late gestation. RESULTS: The blood pressure levels fell from early-to-mid-gestation and rose after mid-gestation in the dichorionic and monochorionic diamniotic twin pregnancies. The SBP and mean arterial pressure levels during early gestation and the DBP and mean arterial pressure levels during late gestation were higher in the dichorionic diamniotic twin pregnancies than those in the singleton pregnancies. The blood pressure levels in the monochorionic diamniotic twin pregnancies were higher than those in the singleton pregnancies at each gestational stage, except for the SBP during late gestation. CONCLUSION: Although the longitudinal blood pressure changes during twin pregnancies were similar to those during singleton pregnancies, the blood pressure levels during twin pregnancies were higher. Further studies that examine the associations between the longitudinal blood pressure changes during pregnancy and the perinatal outcomes in twin pregnancies are necessary. PMID- 30015759 TI - European Society of Hypertension position paper on renal denervation 2018. AB - : This ESH update was deemed necessary with the publication of new results of sham-controlled randomized blinded prospective trials with renal denervation (RDN). Proof of concept studies and first randomized trials (some were sham controlled) displayed discrepant results about the efficacy of RDN. Three sham controlled randomized trials of the 2.0 generation yielded now similarity in the average blood pressure decrease following RDN. Reduction of ambulatory blood pressure was approximately 5 to 7 mmHg and of office blood pressure 10 mmHg. Such a decrease in blood pressure by pharmacologic therapy has been found to be associated with lower incidence of cardiovascular events in particular with respect to heart failure and stroke by roughly 25%. Nevertheless, some questions about renal denervation are unanswered. The heterogeneity of the blood pressure lowering response point to the clinical need to identify predictors for efficacy, and questions on long-term safety could not have been answered due to the short duration of the sham-controlled randomized clinical trials. PMID- 30015760 TI - PEDIATRIC RETINAL DETACHMENT IN AN ASIAN POPULATION WITH HIGH PREVALENCE OF MYOPIA: Clinical Characteristics, Surgical Outcomes, and Prognostic Factors. AB - PURPOSE: To evaluate the clinical characteristics and surgical outcomes of pediatric retinal detachments (RDs) in an Asian population. METHODS: Retrospective review of 171 eyes of 152 pediatric patients with rhegmatogenous RD over a 20-year period. RESULTS: Myopia was the most common risk factor in our population. At 6 months, primary anatomical success was 60.7%, and overall anatomical success was 86.7%. A total of 46.8% had best-corrected visual acuity of 20/40 or better, and 81.6% had best-corrected visual acuity of 20/200 or better. In primary RDs, high myopia (<=-6D) patients had a lower primary anatomical success compared to patients with moderate myopia (<=-2D) (59.3 vs. 100% P = 0.03). Increasing age and absence of proliferative vitreoretinopathy were associated with anatomical and visual success. Pars plana vitrectomy as the primary procedure was associated with decreased odds of anatomical success. A longer duration of symptoms, cataract, and a larger RD extent were associated with poorer functional outcome. CONCLUSION: Myopia was the commonest risk factor for pediatric RD in our population. Good anatomical and functional outcome can be achieved with surgery. Increasing age at presentation and absence of proliferative vitreoretinopathy was associated with anatomical and functional success. High myopia was associated with poorer anatomical and functional outcome. PMID- 30015761 TI - FIXATION STATUS AFTER RESOLUTION OF MACULAR EDEMA ASSOCIATED WITH BRANCH RETINAL VEIN OCCLUSION. AB - PURPOSE: To evaluate fixation status of eyes with branch retinal vein occlusion (BRVO) and to investigate its association with other clinical parameters. METHODS: This study included 57 consecutive eyes with BRVO after resolution of macular edema. Fixation status was determined by microperimetry. Defect length of the foveal ellipsoid zone band was measured by optical coherence tomography, and retinal perfusion status was assessed by optical coherence tomography angiography. RESULTS: In microperimetry, the mean fixation rate around the gravitational center of all fixation points (defined as the fixation center) was found to be 79.8 +/- 18.9%, which was significantly associated with defect length of the foveal ellipsoid zone band (P < 0.001) and distance between the foveal and fixation centers (P = 0.012). The integrity of the ellipsoid zone band at the fixation center was intact in 55 eyes (96.5%). Fixation centers were located within and outside the foveal avascular zone in 33 (57.9%) and 24 (42.1%) eyes, respectively; among the latter eyes, all fixation centers were perfused. Downward deviation of fixation points was rare, despite variations in the occluded area; there was a significant difference in distribution of deviation between eyes with superotemporal and inferotemporal BRVO (P < 0.001). CONCLUSION: In eyes with BRVO, fixation status was strongly associated with visual acuity, morphologic damage, and retinal perfusion status both in the foveal area and at the fixation center after resolution of macular edema. This information regarding fixation status could facilitate vision management in patients with BRVO. PMID- 30015762 TI - VITRECTOMY WITH INTERNAL LIMITING MEMBRANE PEELING AND AIR TAMPONADE FOR MYOPIC FOVEOSCHISIS. AB - PURPOSE: To evaluate the functional and anatomical outcomes of 23-gauge or 25 gauge pars plana vitrectomy with internal limiting membrane peeling and air tamponade for the treatment of myopic foveoschisis. METHODS: Retrospective, noncomparative, interventional case series. The records of 29 patients (32 eyes), with myopic foveoschisis who were treated by 23-gauge or 25-gauge 3-port pars plana vitrectomy with internal limiting membrane peeling and air tamponade, were reviewed. At each visit, a complete ophthalmic examination, intraocular pressure, best-corrected visual acuity, and central foveal thickness measured using optical coherence tomography were assessed. RESULTS: Twenty-five eyes of 23 patients (M:F = 4:19) matched the inclusion criteria, whereas 7 eyes of 6 patients were excluded. The mean logarithm of the minimum angle of resolution best-corrected visual acuity (Snellen equivalent) was 0.62 (20/80) (SE: 0.061), and the mean preoperative central foveal thickness was 619.5 um (SE: 16.38) at baseline. Visual acuity significantly improved of 5 Early Treatment Diabetic Retinopathy Study letters (45 letters) at the 1-month follow-up (P < 0.001), 2 lines (50 Early Treatment Diabetic Retinopathy Study letters) at the 6-month follow-up (P < 0.001), and it reached 55 Early Treatment Diabetic Retinopathy Study letters at the 1-year follow-up visit (P < 0.001). Central foveal thickness decreased to 292.4 um (SE: 15.93), to 227.3 um (SE: 14.05), and to 208.8 um (SE: 12.86), respectively, at the 1-, 6-, and 12-month follow-ups (for each P < 0.001). There were no differences in best-corrected visual acuity or central foveal thickness changes between the foveal detachment group and the nonfoveal detachment group (P > 0.05). CONCLUSION: Small-gauge vitrectomy with internal limiting membrane peeling and air tamponade results in favorable anatomical and functional outcomes for patients affected by myopic macular foveoschisis. PMID- 30015763 TI - VISUAL FUNCTION AND RETINAL CHANGES IN PATIENTS WITH BIPOLAR DISORDER. AB - PURPOSE: To evaluate visual and retinal changes in patients with bipolar disorder. To analyze the correlation between structural changes and visual function parameters. METHODS: Thirty patients with bipolar disorder and 80 healthy controls underwent visual function evaluation with Early Treatment Diabetic Retinopathy Study charts at 100%, 2.50%, and 1.25% contrast, Pelli Robson chart, and color vision Farnsworth and Lanthony tests. Analysis of the different retinal layers was performed using Spectralis optical coherence tomography with automated segmentation software. Correlation analysis between structural and functional parameters was conducted. RESULTS: Patients with bipolar disorder presented worse color vision compared with controls (Lanthony's index, P = 0.002). Full macular thickness, the retinal nerve fiber layer (RNFL), ganglion cell layer, and inner plexiform layer were reduced in patients compared with healthy individuals (P < 0.005). The inner nuclear layer was significantly thickened in patients (P < 0.005). Peripapillary RNFL thickness was reduced in all temporal sectors (P < 0.005). Significant correlations were found between visual acuity and the RNFL thickness, the Pelli-Robson score and the inner plexiform layer, and between the Lanthony's color index and the ganglion cell layer thickness. CONCLUSION: Patients with bipolar disorder present quantifiable thinning of the macular RNFL, ganglion cell layer, and inner plexiform layer, as well as in the peripapillary RNFL thickness, and increasing thinning in the inner nuclear layer. PMID- 30015764 TI - ANATOMICAL AND FUNCTIONAL TESTING IN DIABETIC PATIENTS WITHOUT RETINOPATHY: Results of Optical Coherence Tomography Angiography and Visual Acuity Under Varying Contrast and Luminance Conditions. AB - PURPOSE: To assess early retinal microvascular and functional changes in diabetic patients without clinical evidence of diabetic retinopathy with optical coherence tomography angiography and central visual analyzer. METHODS: This was an observational case-control study of diabetic patients without diabetic retinopathy and nondiabetic controls. Patients underwent optical coherence tomography angiography imaging and visual acuity testing using the central visual analyzer. The foveal avascular zone area and the capillary density in the superficial and deep capillary plexuses were measured manually by a masked grader. RESULTS: Sixty eyes from 35 diabetic patients were included in the study group, and 45 eyes from 31 nondiabetic patients were included in the control group. The foveal avascular zone area was not significantly different between the diabetic group and controls (both P > 0.05). The mean capillary density in the deep capillary plexus was significantly lower in diabetic eyes compared with control eyes (P = 0.04). The mean visual acuity in all central visual analyzer modules was significantly decreased in diabetic patients compared with controls (all P < 0.05). CONCLUSION: Optical coherence tomography angiography was able to detect retinal microvascular changes in the deep capillary plexus, and the central visual analyzer showed signs of decreased visual acuity under conditions simulating suboptimal contrast and glare in diabetic patients without diabetic retinopathy. PMID- 30015765 TI - SENSITIVITY OF 840-nm SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN DETECTING TYPE 1 NEOVASCULARIZATION ACCORDING TO THE HEIGHT OF THE ASSOCIATED PIGMENT EPITHELIAL DETACHMENT. AB - PURPOSE: To evaluate the ability of optical coherence tomography angiography (OCTA) to detect abnormal vascular blood flow in Type 1 neovascularization (NV) with or without significant pigment epithelial detachment (PED). METHODS: Consecutive age-related macular degeneration patients with either treatment-naive or anti-vascular endothelial growth factor-treated Type 1 NV were divided into 2 groups based on the PED height on structural OCT: greater than 250 MUm (Group 1) versus less than 250 MUm (Group 2). Two independent senior retina specialists analyzed the OCTA images (Zeiss Angioplex OCT, Carl Zeiss AG, Jena, Germany) using the automatic slabs alone (first reader) versus automatic and manual segmentation slabs (second reader). RESULTS: In Group 1, 15 men and 42 women, aged from 51 years to 97 years (mean: 87.5), were included. Optical coherence tomography angiography was able to show an abnormal blood flow suggestive of Type 1 NV in 23 (40.3%) of 57 eyes for the first reader and in 32 (56.1%) of 57 eyes for the second reader. In Group 2, 7 men and 30 women, aged from 60 years to 96 years (mean: 80.2), were included. The first and second readers were able to observe an image suggestive of Type 1 NV in 33/37 (89.2%) and 37/37 (100%) of eyes, respectively. CONCLUSION: The ability of OCTA to detect an abnormal blood flow in Type 1 NV was found to highly depend on the height of the associated PED and the use of manual segmentation slabs. Our results suggest that automatic slabs of OCTA should be interpreted with caution for the diagnosis of vascularized PED. The diagnosis of Type 1 NV using OCTA requires the use of manual segmentation and a multimodal imaging approach, especially when the height of the associated PED is >250 MUm. PMID- 30015766 TI - INTRAOPERATIVE OCULAR MANOMETRY IN SILICONE OIL-FILLED EYES WITH A BOSTON TYPE 1 KERATOPROSTHESIS. AB - PURPOSE: To demonstrate a novel technique to measure the intraocular pressure in silicone oil (SO)-filled eyes with Boston Type 1 keratoprosthesis (KPro) during intraocular surgery. METHODS: In this retrospective case series, an ocular manometer that is predicated on a continuous fluid column between a pressure sensor and interior of the eye was designed and used to directly measure intraocular pressure during intraocular surgery in SO-filled eyes with KPro. RESULTS: Six eyes of six patients were included in the study. The indications for SO injection with ocular manometry were hypotony in five patients, and endophthalmitis and complex retinal detachment with proliferative vitreoretinopathy in one patient. All patients had a successful reinflation of their globes without any evidence of SO underfill, without evidence of SO overfill, and without progression of glaucomatous optic neuropathy. Visual acuity increased in five eyes and was maintained in one eye. CONCLUSION: Intraoperative ocular manometry is a safe and effective technique in determining intraocular pressure in SO-filled eyes with KPro. PMID- 30015767 TI - AFLIBERCEPT FOR PERSISTENT DIABETIC MACULAR EDEMA: Forty-Eight-Week Outcomes. AB - PURPOSE: To evaluate functional and anatomical outcomes after a switch from intravitreal bevacizumab to aflibercept in patients with persistent diabetic macular edema. METHODS: Prospective, single-arm, open-label clinical trial of patients with persistent diabetic macular edema, despite previous treatment with bevacizumab. Five loading doses of intravitreal aflibercept were administered every 4 weeks with subsequent injections administered every 8 weeks. Patients were reviewed every 4 weeks, and best-corrected visual acuity and central macular thickness were recorded. Primary outcome measures included change in central macular thickness and best-corrected visual acuity at week 48 compared with baseline. Paired t-tests were used to assess change between baseline and follow up visits. RESULTS: At baseline, 43 eyes from 43 patients were recruited with a median (interquartile range) of 12 (7-24) previous intravitreal anti-vascular endothelial growth factor injections over a period of 18 (8-34) months. Mean +/- SD central macular thickness reduced by 59 +/- 114 MUm (P = 0.002), and best corrected visual acuity improved by 3.9 +/- 7.0 letters (P = 0.001) after 48 weeks in the 41 patients who completed the trial. Best-corrected visual acuity improvements were more marked in patients who gained >=5 letters after the first injection (8.9 +/- 5.7 vs. 1.8 +/- 6.5 letter gain at 48 weeks, P = 0.002), a difference which remained significant after regression analysis with baseline best-corrected visual acuity . Vision gains and central macular thickness reduction were similar in 9 fellow eyes eligible for inclusion being concurrently treated for diabetic macular edema with bevacizumab. CONCLUSION: Intravitreal aflibercept was effective in improving anatomical and visual outcomes among patients with an incomplete response to intravitreal bevacizumab with 48 weeks of follow-up. Patients with a good early response subsequent to switching had a better improvement in vision at 48 weeks. PMID- 30015768 TI - Use of Tipless Kidney Stone Basket for Removal of Intraocular Foreign Bodies or Dislocated Cataract in Eyes With Posterior Staphyloma. PMID- 30015769 TI - CONGENITAL TOXOPLASMOSIS ASSOCIATED WITH TRACTIONAL RETINAL DETACHMENT. AB - PURPOSE: We report a case of congenital toxoplasmosis associated with retinal detachment. METHODS: A 9-month-old white boy presented a unilateral tractional retina detachment associated with congenital toxoplasmosis retinochoroiditis. RESULTS: The diagnosis is supported by positive IgG (>400) for toxoplasmosis and intracranial calcification on magnetic resonance imaging, along with positive family history of Toxoplasma infection in the mother. CONCLUSION: Tractional retinal detachment is an infrequent and unconventional presentation of congenital Toxoplasma infection. Inflammatory interference with normal sequence of vitreous development may explain pathogenesis of tractional retinal detachments in the setting of congenital ocular toxoplasmosis. PMID- 30015770 TI - BILATERAL INTRAVITREAL 0.19-MG FLUOCINOLONE ACETONIDE IMPLANT FOR PERSISTENT NONDIABETIC CYSTOID MACULAR EDEMA AFTER VITRECTOMY. AB - BACKGROUND/PURPOSE: Iluvien (Alimera Science, Alpharetta, GA) is an injectable, nonbiodegradable, sustained-release 0.19-mg fluocinolone acetonide intravitreal implant. Although currently approved by the Food and Drug Administration only for diabetic macular edema previously treated with a course of corticosteroids without a clinically significant intraocular pressure response, the 0.19-mg fluocinolone acetonide implant could theoretically be used to treat other noninfectious inflammatory conditions including persistent cystoid macular edema because of nondiabetic etiologies. METHODS: Interventional case report. A 79-year old man had persistent cystoid macular edema after pars plana vitrectomy in both eyes that was refractory to topical treatments and intravitreal anti-vascular endothelial growth factor. His cystoid macular edema was responsive to preservative-free intravitreal triamcinolone acetonide after which he developed noninfectious endophthalmitis or pseudoendophthalmitis in both eyes precluding further intravitreal triamcinolone acetonide injections. He was subsequently treated with bilateral intravitreal 0.19-mg fluocinolone acetonide implants. RESULTS: At the most recent post-treatment follow-up (11 months for the right eye and 13 months for the left eye), the patient demonstrated an improvement in visual acuity, 20/126 to 20/50 in the right eye and 20/80 to 20/40 in the left eye, and in central subfield thickness, 592 MUm to 288 MUm in the right eye and 565 MUm to 287 MUm in the left eye, without intraocular pressure elevation. CONCLUSION: The intravitreal 0.19-mg fluocinolone acetonide implant is an effective and potentially safe off-label therapeutic option for persistent nondiabetic cystoid macular edema after vitrectomy. PMID- 30015771 TI - REVERSIBLE RETINAL TOXICITY IN A PATIENT TAKING AXITINIB. AB - PURPOSE: Axitinib (Inlyta, New York, NY) is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one previous systemic therapy. A case of bilateral retinal hemorrhages and cotton wool spots associated with axitinib is reported. METHODS: A 62-year-old woman with a 4-year history of renal cell carcinoma with metastases was treated with axitinib at a maximum oral daily dose of 8 mg. Soon after beginning higher dose therapy, she developed blurred vision, floaters, and photopsias. RESULTS: Funduscopic examination of both eyes revealed cotton wool spots and retinal hemorrhages that improved with cessation of therapy. CONCLUSION: Axitinib may be associated with microangiopathic retinal toxicity. PMID- 30015772 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY AFTER ENDOVASCULAR COIL EMBOLIZATION. AB - PURPOSE: To describe two cases of paracentral acute middle maculopathy (PAMM) that occurred unilaterally after endovascular coil embolization. METHODS: Medical records including ophthalmic examinations of two PAMM cases were retrospectively reviewed. RESULTS: The first case was a 64-year-old woman with hyperlipidemia and chronic sinusitis. The second case was a 49-year-old man with hypertension, hyperlipidemia, tension headache, and vertigo. Both cases exhibited paracentral scotomas just after endovascular coil embolization. Ophthalmoscopy showed multiple faint white-yellow lesions in each affected eye. Optical coherence tomography showed hyper-reflective bands that were mainly observed in the inner nuclear layer and corresponded to the PAMM lesions. Optical coherence tomography angiography revealed variable degrees of abnormal vasculature from slight dilation, decreased visualization, to nonvisualization in the superficial capillary plexuses and similar capillary changes in deep capillary plexuses. CONCLUSION: We described two cases with PAMM that occurred after endovascular coil embolization, which was a new precursor cause of PAMM. Our results demonstrate that optical coherence tomography angiography is especially useful for not only diagnosis, but also for follow-up evaluations in patients with PAMM. PMID- 30015773 TI - TRANSCORNEAL SUTURELESS SILICONE OIL REMOVAL USING 23-GAUGE TROCAR SYSTEM IN APHAKIA. AB - PURPOSE: To describe transcorneal sutureless silicone oil removal using 23-gauge trocars as an alternative surgical technique in an aphakic eye. METHODS: We retrospectively evaluated the management of a 50-year-old male patient who had a history of bilateral congenital cataract removal at the age of 5 and developed rhegmatogenous retinal detachment. A 3-port 23-gauge pars plana vitrectomy, removal of the vitreous up to the vitreous base, 60 degrees temporal retinotomy, and anterior flap retinectomy were performed. Silicone oil (1,000 cSt) was selected as a tamponading agent. The patients underwent active silicone oil removal at subsequent surgery 2 months after the initial vitrectomy. RESULTS: The silicone oil was successfully extracted from the aphakic eye by using transcorneal 23-gauge trocars. No suture was needed at the corneal wound sites. There were no intraoperative or postoperative complications. CONCLUSION: Transcorneal silicone oil removal using 23-gauge trocars can be performed easily with today's modern vitreoretinal surgery systems as an alternative treatment modality. PMID- 30015774 TI - MULTIMODAL IMAGING IN DIDANOSINE RETINOPATHY. AB - PURPOSE: To present the multimodal retinal imaging findings in didanosine retinopathy in a patient who presented 6.5 years after stopping the use of didanosine and to highlight the absence of progression during a 1.5-year follow up. METHODS: Case report involving clinical examination, fundus photography, fundus autofluorescence, fluorescein angiography, optical coherence tomography, Goldmann kinetic perimetry, and full-field electroretinography. RESULTS: A 52 year-old patient presented with bilateral retinopathy 6.5 years after stopping didanosine having used the medication for 8.5 years. Fundus examination showed a ring-shaped zone of atrophy of the retinal pigment epithelium involving the midperiphery. On autofluorescence imaging, there was diffuse hypoautofluorescence involving the midperipheral retina in both eyes. On fluorescein angiography, there was a granular mottled pattern of diffuse hyperfluorescence in the midperiphery in both eyes, with baring of the large choroidal vessels in some areas. On Goldmann kinetic perimetry, both eyes showed marked constriction of the isopter to the I4e stimulus, and there was a temporal scotoma to the III4e target in both eyes. Full-field electroretinography showed generalized rod and cone photoreceptor dysfunction in both eyes. During a follow-up for 1.5 years, there was no evidence of progression. CONCLUSION: Patients who have used didanosine should be evaluated for the presence of retinopathy, which involves the midperipheral retina. PMID- 30015775 TI - CHORIORETINAL CHANGES IN A GENETICALLY CONFIRMED CASE OF BOUCHER-NEUHAUSER SYNDROME. AB - PURPOSE: To describe the retinal findings in a 25-year-old white woman in whom a diagnosis of Boucher-Neuhauser Syndrome (BNS) was supported by genetic testing, which identified a missense and novel nonsense mutation in the PNPLA6 gene. METHODS: Observational case report of a 25-year-old woman who presented with primary amenorrhea, cerebellar ataxia, and mild retinal pigmentary abnormalities. Neurologic, endocrine, and genetic evaluations established a diagnosis of BNS. RESULTS: Clinical examination and multimodal imaging documented focal outer retinal and retinal pigment epithelium changes including bilateral foveal stippling and a circular area of hypopigmentation in the superior macula of the left eye. Optical coherence tomography showed a linear area of outer retinal attenuation superonasal to the fovea and multiple foci of pinpoint outer retinal defects in the temporal macula of the left eye. Humphrey visual field 24-2 testing showed nonspecific defects in both eyes. Full-field electroretinography showed no evidence of a generalized retinal dysfunction. CONCLUSION: Recognition that the chorioretinal abnormalities occurring in BNS can be rather subtle is essential because the diagnosis of BNS may depend on their detection. To the best of our knowledge, this is the first report in the ophthalmic literature of mild chorioretinal changes in a patient with BNS testing positive for a mutation in the PNPLA6 gene. PMID- 30015776 TI - ATYPICAL HEALING IN A CASE WITH RETINAL PIGMENT EPITHELIUM APERTURES. AB - PURPOSE: To analyze the multimodal imaging features in a case showing resolution of retinal pigment epithelium (RPE) apertures in association with an avascular pigment epithelium detachment secondary to nonneovascular age-related macular degeneration. METHODS: Report of a case diagnosed with aperture of the RPE with multimodal imaging long-term follow-up. Color fundus photography, fundus autofluorescence, eye-tracked spectral domain optical coherence tomography (OCT), and OCT angiography findings are discussed. RESULTS: A 71-year-old man diagnosed with nonneovascular age-related macular degeneration presented with three different areas of RPE aperture in his right eye. At baseline, best-corrected visual acuity was 20/100 in his right eye. Dilated fundus examination showed three round areas of RPE atrophy, and fundus autofluorescence demonstrated marked hypoautofluorescence in the corresponding areas. The OCT scans showed discontinuities of the RPE band with no evidence of RPE tear. The OCT angiography showed no evidence of abnormal blood flow within the sub-RPE space. Over time, fundus autofluorescence and eye-tracked spectral domain OCT scans demonstrated spontaneous resolution of two of the RPE defects and reduction of the size of the third one, with complete flattening of the pigment epithelium detachment. CONCLUSION: Distinction between RPE tears and apertures is important due to their different etiopathogenic mechanism and prognosis. To the best of our knowledge, this is the first report of a case of complete closure of an RPE aperture. The mechanism of the observed RPE closure remains unknown, and further studies are warranted to better understand the mechanisms of RPE restoration and remodeling. PMID- 30015777 TI - MULTIMODAL IMAGING OF MACULAR CHOROIDAL MACROVESSEL: A REPORT OF TWO CASES. AB - PURPOSE: To report two cases of macular choroidal macrovessel with description of multimodal imaging and review of published cases. METHODS: Medical and imaging records were retrospectively reviewed. A literature review was performed to identify other cases of macular choroidal macrovessel published between 1990 and 2018. RESULTS: There were 2 patients referred for evaluation of a potential choroidal tumor, including a 55-year-old white woman with no visual symptoms and a 68-year-old white woman with blurred vision. Funduscopic examination in each case revealed a focal area of choroidal elevation in the temporal foveal area with a single, dilated, slightly tortuous choroidal vessel, estimated to measure 250 MUm and 300 MUm, respectively, at widest girth, and extending temporally toward the equator with a tapering width. Optical coherence tomography showed an optically hollow choroidal lesion elevating the retinal pigment epithelium with overlying ellipsoid zone mottling. Both cases demonstrate shallow subretinal fluid, sparing the foveola. Fluorescein angiography showed faint staining along the course of the vessel in both cases. Indocyanine green angiography demonstrated clear visualization of the ectatic vessel with early filling and late staining without leakage. Both patients retained visual acuity of 20/25 in the affected eye and did not require treatment. CONCLUSION: Macular choroidal macrovessel is a rare vascular anomaly presenting as a single, dilated, tortuous choroidal vessel, originating in the temporal foveal region and extending temporally to the equator. This finding can simulate a choroidal neoplasm or parasitic track. Optical coherence tomography and indocyanine green angiography have diagnostic value demonstrating the vascular nature of this lesion and delineating the vascular course. PMID- 30015778 TI - CYSTOID MACULAR EDEMA IN THE SETTING OF PRIMARY VITREORETINAL LYMPHOMA. AB - PURPOSE: To present a rare case of primary vitreoretinal lymphoma presenting with cystoid macular edema without previous surgical intervention or radiotherapy. METHODS: Retrospective chart review of one patient. RESULTS: A 74-year-old patient was seen with a history of cataract surgery in 1 eye and presumed ocular inflammation with recurrent cystoid macular edema in both eyes. On examination, subretinal pigment epithelial and intraretinal infiltrates raised the suspicion of primary vitreoretinal lymphoma despite the unusual presentation with cystoid macular edema. A magnetic resonance imaging and brain biopsy confirmed the diagnosis of vitreoretinal lymphoma in the setting of central nervous system lymphoma. CONCLUSION: Primary vitreoretinal lymphoma can present with cystoid macular edema in rare cases. PMID- 30015779 TI - Percutaneous treatment of aneurysmatic right coronary fistula in an infant, pediatric cardiology. PMID- 30015780 TI - Platelet miRNA-26b down-regulates multidrug resistance protein 4 in patients on chronic aspirin treatment. AB - BACKGROUND: Multidrug resistance protein-4 (MRP4) is an ATP binding cassette membrane transporter, actively involved in the efflux of important pharmacological and physiological molecules. Recently, its over-expression has been associated with reduced aspirin (ASA) efficacy after by-pass surgery. MicroRNAs (miRNAs) are small molecules of non-coding RNA involved in the regulation of many physiological and pathophysiological pathways, are abundant in platelets, and can be modulated by several drugs. In the present study, we assessed the role of platelet miRNAs in modulating MRP4 function in response to ASA. METHODS: MRP4 mRNA expression has been analyzed by RealTime PCR in platelets from patients on chronic ASA treatment versus a control group. A panel of miRNAs was run on the pool of each cohort. MiRNAs validation was performed by RealTime PCR. To verify whether MRP4 is the target of miR-26b also in platelets, miR-26b was transfected in platelet and DAMI cells with miRNA mimic technology. MRP4 expression was evaluated by flow cytometry and western blotting. RESULTS: We observed a higher MRP4 mRNA expression in platelets of patients under ASA treatment compared to the control group (p<0.005). MiR-26b was found significantly down-regulated in patients on ASA treatment as compared to control group (P < 0.005) and this was validated by RealTime PCR. MiR-26b transfection in platelets was associated to a significant down-regulation of MRP4 expression (p<0.005). MiR-26b transfection in DAMI cells was associated to a significant reduction of MRP4 mRNA and protein level (P < 0.05). CONCLUSION: We found that miR-26b is down-regulated in platelets in patients on chronic ASA treatment. Importantly, miR-26b can specifically downregulate MRP4. Thus, miR-26b seems to be involved in MRP4 modulation and may contribute to ASA resistance. PMID- 30015781 TI - Sex-specific echocardiographic reference values: the women's point of view. AB - : Clinical presentation, diagnosis and outcomes of cardiac diseases are influenced by the activity of sex steroid hormones. These hormonal differences explain the later development of heart diseases in women in comparison with men and the different clinical picture, management and prognosis. Echocardiography is a noninvasive and easily available technique for the analysis of cardiac structure and function. The aim of the present review is to underline the most important echocardiographic differences between sexes. Several echocardiographic studies have found differences in healthy populations between women and men. Sex specific difference of some of these parameters, such as left ventricular (LV) linear dimensions and left atrial volume, can be explained on the grounds of smaller body size of women, but other parameters (LV volumes, stroke volume and ejection fraction, right ventricular size and systolic function) are specifically lower in women, even after adjusting for body size and age. Sex-specific differences of standard Doppler and Tissue Doppler diastolic indices remain controversial, but it is likely for aging to affect LV diastolic function more in women than in men. Global longitudinal strain appears to be higher in women during the childbearing age - a finding that also highlights a possible hormonal influence in women. All these findings have practical implications, and sex specific reference values are necessary for the majority of echocardiographic parameters in order to distinguish normalcy from disease. Careful attention on specific cut-off points in women could avoid misinterpretation, inappropriate management and delayed treatment of cardiac diseases such as valvular disease and heart failure. PMID- 30015782 TI - The role of computed tomography in the planning of transcatheter aortic valve implantation: a retrospective analysis in 200 procedures. AB - AIM: The aim of our study is to show the importance of multislice computed tomography (CT) assessment in the overall management and diagnostic framework of transcatheter aortic valve replacement (TAVI) procedure candidates. METHODS: Between June 2015 and April 2017, 200 patients with severe aortic stenosis, not eligible for surgery, were enrolled, as defined by EuroSCORE; they were submitted to TAVI at the interventional cardiology department of the Tor Vergata Polyclinic. CT studies were performed using a 64-slice scanner. RESULTS: The reports and datasets produced during the pre-TAVI CT evaluation were retrospectively evaluated. DISCUSSION: In TAVI candidates, accurate aortic valve shape and dimensions evaluation is crucial for the proper deployment of the prosthetic valve and in order to reduce postprocedural complications. ECG retrospective gated cardiac CT gives the clinician three-dimensional images of the heart, with high spatial resolution and multiplanar reconstructions allowing accurate visualization of the aortic annulus and coronary ostia to be obtained, and the evaluation of arterial calcifications. Furthermore, CT can provide data on the suitability of peripheral vascular accesses. Moreover, this technique can point out the presence of clinically relevant extracardiac findings. Therefore, CT evaluation assures a safe, reliable and prognostically relevant method for TAVI preprocedural planning. CONCLUSION: Our study remarks the importance of CT assessment in the overall management and diagnostic framework of TAVI candidates; the information provided is essential in order to minimize possible complications and to improve the quality of the therapeutic planning. PMID- 30015783 TI - Multiples. PMID- 30015784 TI - Characteristics of Successful Transitions From Inpatient to Outpatient Electroconvulsive Therapy. AB - OBJECTIVES: The purpose of this study was to identify clinical and psychosocial factors involved in transitioning hospitalized patients receiving electroconvulsive therapy (ECT) from the inpatient to the outpatient setting and to propose an algorithm to guide clinicians with this process. METHODS: A retrospective chart review was completed for adult patients discharged from a psychiatric hospital from 2002 to 2012 who had an acute course of ECT that was initiated in the hospital and completed as an outpatient. We reviewed demographic and clinical information and outcomes, including ECT treatments. RESULTS: Among the 277 patients who were identified, the mean age was 52.2 years, 60% were women, and 66% were married. The mean length of hospital stay was 12.9 days, and the mean number of ECT treatments was 4.9 as an inpatient and 3.1 as an outpatient. The most frequent primary diagnosis was depression. Most patients (81%) had a responsible adult at home. Patients had good cognitive functioning at both baseline and discharge, and showed improved functional status at discharge (P<0.001 for change in scores on the Global Assessment of Functioning from admission to discharge). CONCLUSIONS: Factors such as improved cognitive and functional status from admission to discharge, a medically uncomplicated course, and a responsible adult at home were observed among patients transitioned from inpatient to outpatient ECT. On the basis of these study results, a review of the literature, and clinical experience, an algorithm to assist clinical decisions for ECT transitioning was developed. PMID- 30015786 TI - Perinatal Mental Health Treatment Needs, Preferences, and Barriers in Parents of Multiples. AB - PURPOSE: Many parents of multiples experience elevated mental health symptoms in the perinatal period. This population often presents with unique treatment needs and barriers to care; however, no tailored interventions have been developed for pregnant or postpartum mothers of multiples and/or their partners. This study involved an initial exploration of the perceived mental health treatment needs, preferences, and barriers to care in this population, as a first step toward developing such an intervention. METHODS: Participants were 241 parents of multiples who were recruited in-person and online. They completed self-report measures assessing treatment history/preferences, barriers to care, and symptoms during the perinatal period. RESULTS: Participants identified postpartum months 0 to 3 as the most difficult time. Few participants received any form of mental health treatment, although a significant percentage (approximately half) expressed interest in such treatment. Treatment interest was high for a range of clinical concerns. Participants were interested in both traditional treatment paradigms and eHealth approaches. Barriers to care were common, with the most common barrier being lack of time. CONCLUSIONS: There is a large, unmet need for mental health treatment in parents of multiples in the perinatal period, especially the early postpartum months. eHealth strategies seem particularly feasible and acceptable in this population and may help circumvent common barriers to care. Clinical recommendations and considerations in treatment development are discussed. PMID- 30015785 TI - Symptom Dimensions and Trajectories of Functioning Among Bipolar Youth: A Cluster Analysis. AB - BACKGROUND: Accurate assessment of pediatric bipolar disorder (BD) is important for allocating appropriate treatment, but it is complicated by significant heterogeneity in symptom presentation and high rates of comorbidity. Investigating clinical subtypes of the disorder may help to clarify diagnostic boundaries and inform targeted treatment. This study used a full diagnostic instrument to examine symptom patterns among youth with BD. METHOD: Trained interviewers completed the Washington University Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) with 71 children (7 to 13 y of age) and families as part of the baseline assessment for a randomized clinical trial of Child- and Family-focused Cognitive-Behavioral Therapy (CFF-CBT) compared with treatment as usual (TAU) for pediatric BD. All participants met DSM-IV-TR criteria for a bipolar spectrum disorder. Hierarchical and K-means cluster analyses were performed. Resultant clusters were compared on symptom severity and psychosocial functioning at baseline and across treatment. RESULTS: Two distinct symptom profiles emerged: "dysregulated/defiant" and "classic presentation." The dysregulated/defiant cluster was characterized by more externalizing and disruptive behaviors, whereas the classic cluster presented with more severe depression, hallmark manic symptoms, anxiety, and inattention. CFF-CBT consistently promoted psychosocial coping skills, such as problem solving and self-control, for the dysregulated/defiant cluster. TAU also promoted these skills among the individuals in the classic presentation group but not those with symptoms in the dysregulated/defiant cluster. DISCUSSION: Pediatric BD may be characterized by distinct phenotypes with unique etiologies and pathways to impairment. The use of a parametric approach to classify the diverse symptom presentations helped yield valuable insights into how to promote the best prognosis for improved functional outcomes in CFF-CBT versus TAU for youth with pediatric BD. PMID- 30015787 TI - Predictors of Lifetime Suicide Attempts in Individuals With Attenuated Psychosis Syndrome. AB - BACKGROUND: A strong association has been shown to exist between schizophrenia and suicide; however, research examining suicidality in the prodromal phase of psychotic disorders is limited. This study aimed to meet this need by examining potential risk factors for lifetime suicide attempts in a population of individuals with attenuated psychosis syndrome (APS), as defined in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders as a condition for further study. METHODS: A retrospective chart review was conducted to identify individuals with APS during a 5-year period across a large medical university's inpatient and outpatient settings. Sociodemographic and clinical factors were examined in relation to suicide attempts to identify risk factors for suicide attempts. chi analyses were used to analyze dichotomous variables, and t test analyses were used to compare means of continuous predictors among those with versus without suicide attempts. Final analyses consisted of fitting multivariate logistic regression models to control for sociodemographic factors. RESULTS: In total, 26.3% of the APS population had at least 1 lifetime suicide attempt. Six covariates were found to be statistically significant predictors of suicide attempts: Axis II disorders (P=0.006); history of trauma as a whole (P=0.022); the subcategory of sexual trauma (P=0.005); tobacco use (P=0.039); family history of nonpsychotic Axis I disorders (P=0.042); and number of hospitalizations (P=0.001). CONCLUSIONS: Suicidality is a prominent feature of APS, and a number of risk factors increase the likelihood of suicide attempts in this population. PMID- 30015788 TI - Clinical Necessity Guidelines for Psychotherapy, Insurance Medical Necessity and Utilization Review Protocols, and Mental Health Parity. AB - The founding members of the Coalition for Psychotherapy Parity present Clinical Necessity Guidelines for Psychotherapy, Insurance Medical Necessity and Utilization Review Protocols, and Mental Health Parity. These guidelines support access to psychotherapy as prescribed by the clinician without arbitrary limitations on duration or frequency. The authors of the guidelines first review the evidence that psychotherapy is effective, cost-effective, and often provides a cost-offset in decreased overall medical expenses, morbidity, mortality, and disability. They highlight the disparity between clinicians' knowledge of generally accepted standards of care for mental health and substance use disorders and the much more limited "crisis stabilization" focus of many insurance companies. The clinical trials that health insurers cite as justification for authorizing only brief treatment for all patients involve highly selected, atypical populations that are not representative of the general population of patients in need of mental health care, who typically have complex conditions and chronic, recurring symptoms requiring ongoing availability of treatment. The standard for other medical conditions reimbursed by insurance is continuation of effective treatment until meaningful recovery, which is therefore the standard required by the Mental Health Parity and Addiction Equity Act for mental health care. However, insurance companies frequently evade the legal requirement to cover treatment of mental illness at parity with other medical conditions. They do this by applying inaccurate proprietary definitions of medical necessity and imposing utilization review procedures much more restrictively for mental health treatment than for other medical care to block access to ongoing care, thus containing insurance company costs in the short term without consideration of the adverse sequelae of undertreated illness (eg, increased costs of other medical services and increased morbidity, mortality, and costs to society in increased disability). The authors of the guidelines conclude that, given appropriate medical necessity guidelines at parity with other medical care, consistent with provider expertise and a broad range of psychotherapy research, there would be no need or place for utilization review protocols. Individuals and psychotherapy organizations are invited to visit the website psychotherapyparity.org to sign on to the guidelines to indicate agreement and support. PMID- 30015789 TI - Poststroke Psychosis Reduction: A Case Report. AB - Strokes have been shown to result in psychiatric phenomena that can range from mood disorders to psychosis. Ablative neurosurgeries have been performed with the goal of reducing the burden of psychiatric symptoms following such cerebrovascular accidents. In this report, we review poststroke psychiatric manifestations, and then present the case of a woman with schizophrenia whose thought disorder improved following a hemorrhagic stroke. Not only did she require less medication, but her remaining symptoms were significantly less impairing than they had previously been. We then compare and contrast the effects of this stroke with ablative neurosurgery. PMID- 30015790 TI - Differentiating Symptoms of Bipolar Disorder From Those of Temporal Lobe Epilepsy: A Case Report. AB - Bipolar I disorder and interictal personality syndrome have many overlapping characteristics that are difficult to distinguish. There is scant literature focused on interictal personality syndrome and no case reports to date detailing patients with comorbid bipolar pathology. We describe an individual with a history of bipolar I disorder who developed right temporal lobe epilepsy after several head injuries. He subsequently exhibited symptoms consistent with interictal personality syndrome that were independent of his bipolar symptomatology. Better understanding of these disorders can lead to improved diagnosis and symptom management. The similarities may also point to a partially shared neuropathology. PMID- 30015791 TI - Brain and Behavior: Commentary on Two Cases Involving the Effect of Structural Brain Lesions on Psychiatric Disorders. AB - In this issue of the journal, 2 case reports are presented that illustrate explicit influences of structural brain lesions on psychiatric symptoms. In both cases, the patients had preexisting, classically diagnosed psychiatric disorders schizophrenia in the first case and bipolar I disorder in the second case. In the first case, a 61-year-old woman with chronic paranoid schizophrenia experienced a marked reduction in psychotic symptoms after bilateral frontal strokes. In the second case, a 60-year-old man who had experienced manic and depressive episodes since his 20s developed partial complex seizures after having repeated head trauma in his 40s, with subsequent onset of chronic personality changes associated with temporal lobe epilepsy that made his psychiatric treatment a greater challenge. The presentations in these 2 cases raise intriguing neuropsychiatric questions concerning the effects on regional brain activity of a variety of nonpharmacological psychiatric interventions (eg, stereotactic neurosurgical techniques, deep brain stimulation, electroconvulsive therapy, certain types of psychotherapy), and concerning possible physiological pathways shared by seizure kindling in epilepsy and recurrent episodes of bipolar disorder. PMID- 30015792 TI - Does Involuntary Admission With Bipolar Disorder Differ From Involuntary Admission With Schizophrenia and Related Disorders? A Report From the Dublin Involuntary Admission Study (DIAS). AB - BACKGROUND: While involuntary psychiatric admission and treatment are common, little is known about what impact different diagnoses have on specific features of involuntary admission and on how involuntary status is terminated (eg, by psychiatrists or tribunals, which are independent, court-like bodies reviewing involuntary admissions). METHODS: We studied 2940 admissions, 423 (14.4%) of which were involuntary, at 3 psychiatry units covering a population of 552,019 individuals in Dublin, Ireland. RESULTS: Involuntary patients were more likely than voluntary patients to be male and unmarried. The median length of stay for involuntary patients was 27 days compared with 10 days for voluntary patients (P<0.001). Schizophrenia (and related disorders, including schizoaffective disorder) and bipolar disorder accounted for 58.6% and 17.3% of involuntary admissions, respectively, compared with 20.1% and 12.4% of voluntary admissions (P<0.001). Psychiatrists revoked the majority of involuntary orders for both patients with bipolar disorder (85.3%) and those with schizophrenia (and related disorders) (86.6%); in contrast, tribunals did not revoke any involuntary admission orders for patients with bipolar disorder and revoked orders for 3.8% of patients with schizophrenia (and related disorders) (P=0.034). On the basis of multivariable testing, increased age among patients with bipolar disorder was the only characteristic among those studied (sex, age, marital status, occupation, involuntary admission criteria, length of stay, method of involuntary order revocation, location) that independently distinguished involuntary patients with bipolar disorder from those with schizophrenia (and related disorders) (P=0.028). CONCLUSIONS: Involuntary admission of patients with bipolar disorder is similar in most respects to that of patients with schizophrenia (and related disorders). Consequently, it is important that measures aimed at reducing the need for involuntary admission (eg, patient advance statements/advance directives) are implemented equally across all diagnostic groups associated with involuntary care. PMID- 30015793 TI - Pediatric Neurodevelopmental Functioning After In Utero Exposure to Triple-NRTI vs. Dual-NRTI + PI ART in a Randomized Trial, Botswana. AB - BACKGROUND: In utero exposure to nucleoside reverse transcriptase inhibitor (NRTI)-containing antiretroviral treatment (ART) regimens may be associated with poor neurodevelopmental functioning in children of HIV-infected mothers. We investigated neurodevelopmental outcomes of HIV-exposed uninfected (HEU) children of HIV-infected women enrolled in a randomized trial of abacavir/zidovudine/lamivudine (triple-NRTI regimen) vs. lopinavir/ritonavir/zidovudine/lamivudine [dual-NRTI + protease inhibitor (PI) regimen]. SETTING: The Mma Bana randomized trial was conducted in urban and rural sites in Botswana. METHODS: The Mma Bana study randomized HIV-infected pregnant women with CD4 >=200 cells per mm to a triple-NRTI vs. dual-NRTI + PI regimen from 26- to 34-week gestation through planned weaning at 6-month postpartum. Partway through the study, neurodevelopmental assessments were added at 24 months of age, including the Developmental Milestones Checklist, the Bayley Scales of Infant and Toddler Development third edition, Ten Questions Questionnaire, and Profile of Social Emotional Development. We evaluated differences in mean scores between the 2 arms using unadjusted and adjusted linear regression. RESULTS: A total of 197 HEU infants (48% male) completed a neurodevelopmental assessment (101 in triple-NRTI arm and 96 in dual-NRTI + PI-exposed arm). Mean values for all neurodevelopmental outcomes were similar for children of mothers randomized to either ART regimen, with no significant differences in either unadjusted or adjusted models (estimated effect sizes ranging from -0.12 to 0.14). CONCLUSIONS: Neurodevelopmental outcomes in 24-month-old HEU children of HIV-infected mothers with baseline CD4 >=200 were similar in those randomized to a dual-NRTI + PI based vs. a triple-NRTI-based ART regimen, suggestive of lack of short-term toxicity. Monitoring of long-term toxicity and newer regimens is warranted. PMID- 30015794 TI - Brief Report: The Amsterdam Symptom and Risk-Based Score Predicts for Acute HIV Infection in Men Who Have Sex With Men in San Diego. AB - OBJECTIVE: Dijkstra et al recently described a risk- and symptom-based score moderately predictive for HIV seroconversion in the preceding 6-12 months in men who have sex with men (MSM) in Amsterdam. Our objective was to determine whether this "Amsterdam Score" could also predict for acute HIV infection (AHI) in MSM. DESIGN AND SETTING: This study is a case-control analysis of a prospectively enrolled cohort of MSM who voluntarily presented for HIV testing in San Diego. The study sample was composed of MSM who screened HIV antibody-negative and then either tested positive with AHI [HIV nucleic acid test (NAT)-positive] or tested HIV NAT-negative. METHODS: The Amsterdam Score was calculated for each participant in the study sample. Score performance was assessed using receiver operating characteristic curves and their area under the curve (AUC). An optimal cutoff was determined using the Youden index. RESULTS: Seven hundred fifty-seven MSM (110 AHI and 647 HIV NAT-negative) were included in the analysis. AHI and HIV negative cases were similar in age [median 32 years (interquartile range 26-42) vs 33 (27-45), respectively, P = 0.082]. The Amsterdam Score yielded a receiver operating characteristic curve with an AUC of 0.88 (95% confidence interval: 0.84 to 0.91). An optimal cutoff of >=1.6 was 78.2% sensitive and 81.0% specific. CONCLUSIONS: The risk- and symptom-based Amsterdam Score was highly predictive (AUC of 0.88) of AHI in MSM in San Diego. The Amsterdam Score could be used to target NAT utilization in resource-poor settings among MSM who test HIV antibody negative, although the potential cost-savings must be balanced with the risk of missing AHI diagnoses. PMID- 30015795 TI - End-tidal carbon dioxide monitoring improves patient safety during propofol-based sedation for breast lumpectomy: A randomised controlled trial. AB - BACKGROUND: The use of sedation is becoming more commonplace. Although pulse oximetry is a standard monitoring procedure during sedation, it cannot accurately detect early hypoventilation. End-tidal carbon dioxide (EtCO2) monitoring can be an earlier indicator of airway compromise; however, the existing literature is limited to a few studies with varying outcomes. OBJECTIVES: To evaluate whether EtCO2 monitoring decreases the incidences of CO2 retention and apnoeic events in propofol-based sedation. DESIGN: Randomised controlled study. SETTING: A tertiary hospital. PATIENTS: Two hundred women (aged 18 to 65 years, ASA physical status 1 or 2) who were scheduled for breast lumpectomy between June 2017 and August 2017. INTERVENTIONS: Patients were allocated randomly to receive either standard monitoring or standard monitoring and EtCO2 monitoring. MAIN OUTCOME MEASURES: The primary outcome was the incidence of CO2 retention. The secondary outcomes were the number of actions taken to restore ventilation, variations in PaCO2 and pH, the frequency of apnoea and the recovery time. RESULTS: CO2 retention occurred significantly less often in the EtCO2 monitoring group (10 vs. 87%; P < 0.0001). In the standard monitoring group, the mean PaCO2 was more than 6 kPa (45 mmHg) and the pH was less than 7.35 at 5, 10, 20 and 30 min after induction of anaesthesia and at the end of the procedure. Both values were within the normal range in the EtCO2 monitoring group. The number of airway interventions performed was significantly higher in the EtCO2 monitoring group (9.8 +/- 1.8 vs. 1.9 +/- 1.0; P < 0.0001). Apnoea occurred significantly less often in the EtCO2 monitoring group (0 vs. 10%; P < 0.0001) and recovery time was shorter (9.9 +/- 1.4 vs. 11.4 +/- 2.1 min; P = 0.048). CONCLUSION: The addition of EtCO2 monitoring to standard monitoring during propofol-based sedation can improve patient safety by decreasing the incidence of CO2 retention, and therefore the risk of hypoxaemia through early recognition of apnoea, and can also shorten recovery time. TRIAL REGISTRATION: This trial is registered with http://www.chictr.org.cn (ChiCTR-INR-17011537). PMID- 30015796 TI - Evaluation of Clinical Plus Imaging Features and Multidetector Computed Tomography Texture Analysis in Preoperative Risk Grade Prediction of Small Bowel Gastrointestinal Stromal Tumors. AB - OBJECTIVE: This study aimed to evaluate the prediction roles of clinical plus imaging features and multidetector computed tomography (MDCT) texture analysis in preoperative risk grade classification of small bowel (SB) gastrointestinal stromal tumors (GISTs). METHODS: This study included 213 SB GIST patients. Clinical features and MDCT imaging findings were reviewed. Tumor risk stratifications were determined according to modified National Institutes of Health criteria. Random forest models were performed to evaluate the correlation of risk stratification. RESULTS: The model of clinical plus imaging findings showed an area under receiver operating characteristic curve (AUC) of 92.0%. The AUC of texture analysis based on MDCT portal phase was 93.3%, without statistical difference from that of clinical plus imaging model (P = 0.378). The AUC of the model combined clinical plus imaging features and MDCT texture analysis was 94.3%, which was significantly higher than the AUC of clinical imaging model (P = 0.042). CONCLUSION: Texture analysis may become an important comprehensive tool for preoperative risk stratification of SB GISTs. PMID- 30015797 TI - Magnetic Resonance Arthrographic Demonstration of Association of Superior Labrum Anterior and Posterior Lesions With Extended Anterior Labral Tears. AB - OBJECTIVE: The objective of this study was to evaluate retrospectively the full extent of anterior labral tear and associated other labral tears on magnetic resonance arthrographic images in patients with anterior shoulder instability. MATERIALS AND METHODS: One hundred ten magnetic resonance arthrography images with anterior labral tear were retrieved from the database of the Radiology Department. Two skeletal radiologists, one with 15 years of experience and the other with 5 years of experience analyzed the images in random order. Approval for the study was granted by the Ethics Committee. Statistical analyses were performed using SPSS software. RESULTS: The most common localization of the labral lesions was at the anterior-inferior part of the glenoid labrum (22.7%). The anterior labral tears were commonly associate with superior labrum anterior and posterior (SLAP) lesions (45%). The most common type of SLAP lesion was type V (23.6%). Superior Labrum Anterior and Posterior type V lesion was more often detected in patients with Bankart lesion (27.7%, P = 0.043). CONCLUSIONS: Isolated anterior labral tears are less than expected. In majority of the cases, a distinct tear at a different site of the labrum accompanies the anterior labral tear. Massive anterior labral tears are mostly seen together with SLAP lesions. PMID- 30015799 TI - Whole-Body Magnetic Resonance Imaging in the Oncology Setting: An Overview and Update on Recent Advances. AB - Whole-body magnetic resonance imaging is becoming an important tool in oncology as a nonirradiating imaging technique since recent technological advances allowed the incorporation of high-quality imaging in an adequate time. Moreover, the noninjection of radioisotope/intravenous contrast, low cost compared with traditional nuclear medicine techniques, and fast acquisition times are another distinct feature. Thus, the purpose of this article is to review the whole-body magnetic resonance imaging protocol and its main applications in the oncology setting. PMID- 30015798 TI - The Accuracy of Left Ventricular and Left Atrial Volumetry Using 64-Slice Computed Tomography: In Vitro Validation Study With Human Cardiac Cadaveric Casts. AB - OBJECTIVE: We aimed to validate the accuracy of imaging of left atrial and ventricular volumes using cardiac cadaveric silicone casts. METHODS: Left atrial (n = 14) and ventricular (n = 15) casts were imaged using 64-slice computed tomography (CT). Water displacement (WD) of cardiac casts was used as the gold standard for volume measurements. RESULTS: Compared with WD, CT resulted in slightly higher left atrial and ventricular volumes (54 +/- 25 vs 56 +/- 26 mL [P = 0.003] and 57 +/- 47 vs 66 +/- 47 mL [P = 0.0001]). Variability between left atrial and ventricular volumes by CT and WD was low (coefficients of variation [CVs], 4% [intraclass correlation coefficient {ICC}, 0.99] and 12% [ICC, 0.97]). Intraobserver variability of CT was low for both the left atrium and the left ventricle (CVs, 1% [ICC, 1.00] and 4% [ICC, 1.00]). CONCLUSIONS: Cardiac CT is both accurate and reproducible in assessment of left ventricular and atrial chamber volumes. PMID- 30015800 TI - Automated Early Identification of an Excessive Air-in-Oil X-ray Tube Artifact That Mimics Acute Cerebral Infarct. AB - PURPOSE: This study aimed to develop an automated, quantitative method to increase the likelihood of identifying and preventing such air-in-oil (AIO) artifact. METHODS: A 1-dimensional radial representation of the 2-dimensional noise power spectrum (NPS) was calculated from AIO artifact images and compared with artifact-free images. A quality control (QC) software program was modified to include measurements of NPS average frequency within the water section of daily phantom scans. Threshold values for each CT system were incorporated into daily QC. RESULTS: Noise power spectrum for AIO artifact images included a large low-frequency peak compared with artifact-free images; NPS average frequencies were 0.197 and 0.319 line pairs per millimeter for AIO artifact and artifact-free images, respectively. Automated QC successfully identified 3 AIO artifacts before detrimental clinical effect occurred. CONCLUSIONS: Serious clinical problems associated with AIO artifact can be detected and avoided by incorporating NPS average frequency measurements of daily phantom images into an automated QC program. PMID- 30015801 TI - Differentiation of Glioblastoma and Solitary Brain Metastasis by Gradient of Relative Cerebral Blood Volume in the Peritumoral Brain Zone Derived from Dynamic Susceptibility Contrast Perfusion Magnetic Resonance Imaging. AB - OBJECTIVE: The purpose of our study was to evaluate the efficacy of the relative cerebral blood volume (rCBV) gradient in the peritumoral brain zone (PBZ)-the difference in the rCBV values from the area closest to the enhancing lesion to the area closest to the healthy white matter-in differentiating glioblastoma (GB) from solitary brain metastasis (MET). METHODS: A 3.0-T magnetic resonance imaging (MRI) machine was used to perform dynamic susceptibility contrast perfusion MRI (DSC-MRI) on 43 patients with a solitary brain tumor (24 GB, 19 MET). The rCBV ratios were acquired by DSC-MRI data in 3 regions of the PBZ (near the enhancing tumor, G1; intermediate distance from the enhancing tumor, G2; far from the enhancing tumor, G3). The maximum rCBV ratios in the PBZ (rCBVp) and the enhancing tumor were also calculated, respectively. The perfusion parameters were evaluated using the nonparametric Mann-Whitney test. The sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve were identified. RESULTS: The rCBVp ratios and rCBV gradient in the PBZ were significantly higher in GB compared with MET (P < 0.05 for both rCBVp ratios and rCBV gradient). The threshold values of 0.50 or greater for rCBVp ratios provide sensitivity and specificity of 57.69% and 79.17%, respectively, for differentiation of GB from MET. Compared with rCBVp ratios, rCBV gradient had higher sensitivity (94.44%) and specificity (91.67%) using the threshold value of greater than 0.06. CONCLUSIONS: The parameter of rCBV gradient derived from DSC MRI in the PBZ seems to be the most efficient parameter to differentiate GB from METs. PMID- 30015802 TI - Measurement of Vascular Diameter in Computed Tomography Angiography With Reduced Iodine Load: Comparison of Virtual Monochromatic Imaging in Dual-Energy Computed Tomography and Conventional Polychromatic Scan In Vitro. AB - OBJECTIVES: The aim of this study was to compare accuracy of measurement between virtual monochromatic imaging (VMI) in dual-energy computed tomography and conventional polychromatic 120-kVp computed tomographic scan in vascular models containing various densities of contrast material. METHODS: We evaluated measured diameters of 12 models of vessels of 4 inner diameters containing high, intermediate, and low densities of contrast material using software automation. RESULTS: Measurement errors with 70-keV VMI were significantly larger than or comparable to errors with 120-kVp scan for all models, and those with 50-keV VMI were significantly smaller than errors with 120-kVp scan for low-density models and larger for high-density models. CONCLUSIONS: Acquisition of images by VMI at low energy facilitates accurate measurement of diameters of poorly enhanced vessels with reduced iodine load but can increase measurement errors in other situations by decreasing spatial resolution, so VMI should be applied carefully to evaluate vessel diameter. PMID- 30015803 TI - Standardizing Magnetic Resonance Imaging Protocols, Requisitions, and Reports in Multiple Sclerosis: An Update for Radiologist Based on 2017 Magnetic Resonance Imaging in Multiple Sclerosis and 2018 Consortium of Multiple Sclerosis Centers Consensus Guidelines. AB - The advent of magnetic resonance imaging has improved our understanding of the pathophysiology and natural course of multiple sclerosis (MS). The ability of magnetic resonance imaging to show the evolution of MS lesions on sequential scans has brought it to be one of the endpoints in clinical trials for disease modifying therapies. Based on the most updated consensus guidelines from the American (Consortium of MS Centers) and European (Magnetic Resonance Imaging in MS) boards of experts in MS, this document shows the most relevant landmarks related to imaging findings, diagnostic criteria, indications to obtain a magnetic resonance, scan protocols and sequence options for patients with MS. Although incorporating the knowledge derived from the research arena into the daily clinical practice is always challenging, in this article, the authors provide useful recommendations to improve the information contained in the magnetic resonance report oriented to facilitate communication between radiologists and specialized medical teams involved in MS patients' multidisciplinary care. PMID- 30015804 TI - Systematic, continental scale temporal monitoring of marine pelagic microbiota by the Australian Marine Microbial Biodiversity Initiative. AB - Sustained observations of microbial dynamics are rare, especially in southern hemisphere waters. The Australian Marine Microbial Biodiversity Initiative (AMMBI) provides methodologically standardized, continental scale, temporal phylogenetic amplicon sequencing data describing Bacteria, Archaea and microbial Eukarya assemblages. Sequence data is linked to extensive physical, biological and chemical oceanographic contextual information. Samples are collected monthly to seasonally from multiple depths at seven sites: Darwin Harbour (Northern Territory), Yongala (Queensland), North Stradbroke Island (Queensland), Port Hacking (New South Wales), Maria Island (Tasmania), Kangaroo Island (South Australia), Rottnest Island (Western Australia). These sites span ~30 degrees of latitude and ~38 degrees longitude, range from tropical to cold temperate zones, and are influenced by both local and globally significant oceanographic and climatic features. All sequence datasets are provided in both raw and processed fashion. Currently 952 samples are publically available for bacteria and archaea which include 88,951,761 bacterial (72,435 unique) and 70,463,079 archaeal (24,205 unique) 16 S rRNA v1-3 gene sequences, and 388 samples are available for eukaryotes which include 39,801,050 (78,463 unique) 18 S rRNA v4 gene sequences. PMID- 30015805 TI - Mass spectrometry quantitation of proteins from small pools of developing auditory and vestibular cells. AB - Hair cells of the inner ear undergo postnatal development that leads to formation of their sensory organelles, synaptic machinery, and in the case of cochlear outer hair cells, their electromotile mechanism. To examine how the proteome changes over development from postnatal days 0 through 7, we isolated pools of 5000 Pou4f3-Gfp positive or negative cells from the cochlea or utricles; these cell pools were analysed by data-dependent and data-independent acquisition (DDA and DIA) mass spectrometry. DDA data were used to generate spectral libraries, which enabled identification and accurate quantitation of specific proteins using the DIA datasets. DIA measurements were extremely sensitive; we were able to detect proteins present at less than one part in 100,000 from only 312 hair cells. The DDA and DIA datasets will be valuable for accurately quantifying proteins in hair cells and non-hair cells over this developmental window. PMID- 30015806 TI - Leukocyte Tracking Database, a collection of immune cell tracks from intravital 2 photon microscopy videos. AB - Recent advances in intravital video microscopy have allowed the visualization of leukocyte behavior in vivo, revealing unprecedented spatiotemporal dynamics of immune cell interaction. However, state-of-the-art software and methods for automatically measuring cell migration exhibit limitations in tracking the position of leukocytes over time. Challenges arise both from the complex migration patterns of these cells and from the experimental artifacts introduced during image acquisition. Additionally, the development of novel tracking tools is hampered by the lack of a sound ground truth for algorithm validation and benchmarking. Therefore, the objective of this work was to create a database, namely LTDB, with a significant number of manually tracked leukocytes. Broad experimental conditions, sites of imaging, types of immune cells and challenging case studies were included to foster the development of robust computer vision techniques for imaging-based immunological research. Lastly, LTDB represents a step towards the unravelling of biological mechanisms by video data mining in systems biology. PMID- 30015808 TI - 39 years of directional wave recorded data and relative problems, climatological implications and use. AB - The dataset consists of 39 years of directional wave time series recorded since 1979 at the CNR-ISMAR "Acqua Alta" oceanographic research tower, located in the Northern Adriatic Sea. The extent of the time series allows us to describe the wave climate in the North Adriatic region and to identify trends and links with large scale climate patterns obtained from a single and permanent observational source. The northern part of the Adriatic Sea is characterized by two main wind and correspondingly wave regimes, strongly forced by the regional orography. The high sensitivity of this particular area to even small variations of large scale meteorological patterns allows to explore possible links of the local wave, hence wind, activity with large-scale north hemisphere circulation or weather regimes. Different wave gauges have been used since the start of the measurements, progressively upgraded and repositioned during maintenance operations. The recorded wave data have been thoroughly verified and corrected where necessary. PMID- 30015807 TI - Structural and functional brain scans from the cross-sectional Southwest University adult lifespan dataset. AB - Recently, the field of developmental neuroscience has aimed to uncover the developmental trajectory of the human brain and to understand the changes that occur as a function of ageing. Here, we present a dataset of functional magnetic resonance imaging (fMRI) data covering the adult lifespan that includes structural MRI and resting-state functional MRI. Four hundred ninety-four healthy adults (age range: 19-80 years; Males=187) were recruited and completed two multi modal MRI scan sessions at the Brain Imaging Center of Southwest University, Chongqing, China. The goals of the dataset are to give researchers the opportunity to map the developmental trajectories of structural and functional changes in the human brain and to replicate previous findings. PMID- 30015809 TI - A comprehensive database of thermal developmental plasticity in reptiles. AB - How temperature influences development has direct relevance to ascertaining the impact of climate change on natural populations. Reptiles have served as empirical models for understanding how the environment experienced by embryos can influence phenotypic variation, including sex ratio, phenology and survival. Such an understanding has important implications for basic eco-evolutionary theory and conservation efforts worldwide. While there is a burgeoning empirical literature of experimental manipulations of embryonic thermal environments, addressing widespread patterns at a comparative level has been hampered by the lack of accessible data in a format that is amendable to updates as new studies emerge. Here, we describe a database with nearly 10, 000 phenotypic estimates from 155 species of reptile, collected from 300 studies manipulating incubation temperature (published between 1974-2016). The data encompass various morphological, physiological, behavioural and performance traits along with growth rates, developmental timing, sex ratio and survival (e.g., hatching success). This resource will serve as an important data repository for addressing overarching questions about thermal plasticity of reptile embryos. PMID- 30015810 TI - [Series: Caries prevention in historical perspective. Early treatment of carious lesions]. AB - In the Dutch Journal of Dentistry the opinion is often expressed that treatment of carious deciduous teeth is necessary to reduce the risk of dental caries in the permanent teeth. It is clear that early restorative treatment of caries lesions can contribute to the preservation of teeth. The question is whether such a treatment also has a primary preventive impact on other not yet affected teeth. Results of epidemiological research carried out in the period 1960-1980 do not support the view that it does. To combat the 'disease' caries in children restoration of carious teeth alone will not suffice. Professional oral care in young children should be focused primarily on removing the causes of dental caries by insisting on improvements in hygiene and diet. PMID- 30015811 TI - [Myasthenia gravis in dentistry]. AB - In a patient with myasthenia gravis, a life-threatening myasthenic crisis can occur, a complication of myasthenia gravis. The crisis can be triggered by, among other things, emotional stress, pain, infections and a reaction to medication. The policy for invasive dental treatment in a patient with myasthenia gravis must be aimed at preventing a crisis. Prior to the intervention, consultation with the neurologist in charge is necessary because sometimes optimisation of the medication or preventive measures are required. Treatment of a myasthenia gravis patient with amide local analgesic is possible; narcosis is also possible. Local anaesthesia (using amide local analgesic in minimal dosage) is preferred to narcosis. After the dental treatment, optimal pain management is crucial to limit the chance of a crisis. PMID- 30015812 TI - [Complications due to an oral injury caused by diving]. AB - A 42-year-old man presented himself with a complaint of recurrent swelling of the chin. After clinical and radiographic examination, it was shown to be an injury caused by the use of an insufficiently disinfected mouthpiece when diving at an exotic destination. Oral injuries caused by diving mouthpieces are widely known. It is less well known that an untreated injury can ultimately lead to tooth loss. PMID- 30015813 TI - [A lung abscess caused by bad teeth]. AB - An odontogenic cause of a lung abscess is often overlooked. A 61-year-old man presented at an emergency department with a productive cough and dyspnoea. He was admitted to the pulmonary ward with a suspected odontogenic lung abscess. A thorax CT scan confirmed the diagnosis 'lung abscess', following which an oral maxillofacial surgeon confirmed that the lung abscess probably had an odontogenic cause. The patient made a full recovery following a 6-week course of antibiotics, and his teeth were remediated by means of full extraction and the fabrication of immediate dentures. Poor oral hygiene can be a cause of a lung abscess. A patient with a lung abscess can be treated successfully with antibiotics. If, however, the odontogenic cause is not recognised the abscess can recur. PMID- 30015814 TI - [The pink and white aesthetics of a new zirconia implant]. AB - Zirconia implants can offer a good alternative to titanium implants. Due to their specific material properties, they have the potential for a more appealing aesthetic result, which can be particularly important in the anterior zone. In the present study, the pink and white aesthetics of immediately placed zirconia implants in the anterior maxillary zone in 20 patients were assessed on the basis of Pink and White Esthetic Scores (PES and WES). To this end, two clinical photographs were compared: one taken immediately after placement of the permanent crown (mean PES = 12.8; mean WES = 8.5) and the other one taken at a later time (mean PES = 12.8; mean WES = 8.6). No statistically significant difference was found between the two moments. Volunteers found it difficult to correctly identify the implant among the other front teeth. Patients completed a questionnaire regarding the aesthetics of the pink and white implant and they graded the final result with an 8.5 score on a point scale of 0 to 10. The aesthetic appearance of a zirconia implant is excellent and stable over time. Patients are generally satisfied with the result. PMID- 30015815 TI - [Medicaments and oral healthcare. Proliferation of the gingiva]. AB - Adverse effects of medications and self care products on the gingiva can be divided into inflammation, intrinsic discolouration, irritation, trauma, cytotoxicity, lichenoid reaction, and proliferation. This article deals with the last-mentioned type of adverse effects; the other 6 have been discussed in a previous article. Proliferation of the gingiva as an adverse effect of medications has been reported for anticonvulsants, calcineurin inhibitors, calcium channel blockers and isotretinoin. With regard to the anticonvulsants that have been registered in the Netherlands, proliferation of the gingiva is predominantly induced by phenytoin, but also by carbamazepine, ethosuximide, phenobarbital, gabapentin, levetiracetam, primidone and valproic acid. All calcineurin inhibitors registered in the Netherlands may induce the adverse effect. This is also the case for nearly all calcium channel blockers, but particularly for dihydropyridines. Presumably, proliferation of the gingiva may be prevented or reduced in a number of ways. The most important one is good oral hygiene. Furthermore, proteins and cells that play an important role [in the process of gingival proliferation] have been discovered and there are medications that have the potential to eliminate these proteins and cells. PMID- 30015816 TI - [A PhD completed. Innovations in restorative dentistry: necessary or superfluous?] AB - Restorative dentists are faced with a dilemma: they needs to be aware of the most recent developments in order to be able to offer state-of-the-art care but they also have to be able to identify which of the many innovations are superfluous. In this doctoral dissertation the focus was on the role of digital production and procedures in restorative dentistry, and in oral implantology in particular. The variety of studies performed revealed that patients prefer to have impressions taken digitally rather than with dental impression putty and that digital impressions can be taken more quickly. Modern restorative materials are often made of ceramics, such as the white and aesthetically appealing zirconium dioxide (3Y-TZP). It was revealed that zirconia when used as abutment material for implant-born restorations showed no signs of degradation after 1 year of clinical use and was more or less as strong as it had been in the beginning. Milled composite resin crowns, however, that were cemented to them did not adhere well to the ceramic. PMID- 30015817 TI - Nuclearity effects in supported, single-site Fe(ii) hydrogenation pre-catalysts. AB - Dimeric and monomeric supported single-site Fe(ii) pre-catalysts on SiO2 have been prepared via organometallic grafting and characterized with advanced spectroscopic techniques. Manipulation of the surface hydroxyl concentration on the support influences monomer/dimer formation. While both pre-catalysts are highly active in liquid-phase hydrogenation, the dimeric pre-catalyst is ~3* faster than the monomer. Preliminary XAS experiments on the H2-activated samples suggest the active species are isolated Fe(ii) sites. PMID- 30015818 TI - Direct growth of CuCo2S4 nanosheets on carbon fiber textile with enhanced electrochemical pseudocapacitive properties and electrocatalytic properties towards glucose oxidation. AB - Flexible and wearable electronic devices with excellent performance have been desired for making the next generation of electronic products. Herein, the synthesis of CuCo2S4 nanosheets on flexible carbon fiber textile (CFT) by a facile one-step and scalable hydrothermal procedure is reported, which is free from the sulphurization process used in the conventional synthesis of mixed metal sulphospinels. The as-prepared CuCo2S4 nanostructures on CFT can provide rich reaction sites and short ion diffusion paths. The CuCo2S4 nanosheets are employed as the free-standing electrodes for two different applications: high-performance supercapacitors and non-enzymatic glucose sensors. When employed as a flexible electrode material for supercapacitors, the electrode presents ultrahigh performance in energy storage with a specific capacitance of 3321.6 F g-1 at 5 A g-1, which is attributed to the suitable mass loading and special morphology of the as-prepared nanosheets. Remarkably, a specific capacitance of 2931.4 F g-1 is still retained at the high current density of 30 A g-1, suggesting its excellent rate capability. The specific capacitance retains 87.1% after 3000 cycles, reflecting excellent cycling performance. For real applications, a flexible symmetric supercapacitor is assembled based on CuCo2S4 nanosheets, which achieves a high energy density of 64.6 W h kg-1 at 499.7 W kg-1 and a maximum power density of 2081.5 W kg-1 at 45.1 W h kg-1. Besides serving as a free-standing electrode for non-enzymatic glucose sensors, CuCo2S4 nanosheets have remarkable electrocatalytic activity towards glucose oxidation with a high sensitivity of 3852.7 MUA mM-1 cm-2 and an extraordinary linear range up to 3.67 mM. The experimental results suggest that CuCo2S4 nanosheets are more suitable for non enzymatic glucose sensors than the related single/binary transition metal oxides/sulfides. Such a superior performance demonstrates that CuCo2S4 nanosheets hold great potential for use as flexible multifunctional electronic devices including supercapacitors and non-enzymatic glucose sensors. PMID- 30015819 TI - A new diphosphine-carbonyl complex of ruthenium: an efficient precursor for C-C and C-N bond coupling catalysis. AB - Reaction of 1,2-bis(diphenylphosphino)benzene (dppbz) with [{Ru(CO)2Cl2}n] affords [Ru(dppbz)(CO)2Cl2], where the two carbonyls are mutually cis and the two chlorides are trans. The molecular structure of [Ru(dppbz)(CO)2Cl2], has been determined by X-ray crystallography, and the stability of the different available stereoisomers has been computationally evaluated. [Ru(dppbz)(CO)2Cl2] has been found to serve as an excellent pre-catalyst for catalytic Suzuki-type C-C coupling and Buchwald-type C-N coupling reactions. PMID- 30015820 TI - Stimuli-responsive metal-organic supercontainers as synthetic proton receptors. AB - We demonstrate a proof-of-concept design of a new platform for proton recognition and modulation. The new proton receptors are derived from a unique class of synthetic supercontainers that exhibit exceptional proton binding capacity (over 50 equiv.) and intriguing proton-dependent fluorescent switching behavior. Experimental and computational studies suggest that the proton-responsive event involves a two-step mechanism pertaining to proton binding by both amino and pyrenyl moieties of the supercontainer constructs. The high proton binding capacity of the supercontainers can be further modulated via small-molecule "regulators" that compete for the proton-binding sites, opening exiting new opportunities for proton manipulation in both chemistry and biology. PMID- 30015821 TI - Synthesis and thermoelastic properties of Zr(CN2)2 and Hf(CN2)2. AB - Two binary transition metal cyanamides, Zr(CN2)2 and Hf(CN2)2, were prepared by solid-state metathesis (SSM) reactions and separately controlled by differential thermoanalysis (DTA). The crystal structure of Hf(CN2)2 was solved and refined from a single-phase crystal powder by X-ray diffraction (XRD) in the space group Pbcn. Zr(CN2)2 was characterized by isotypic indexing. The crystal structure of M(CN2)2 compounds with M = Zr, Hf is closely related to that of LiY(CN2)2, but reveals large cavities due to the absence of lithium ions. Hf(CN2)2 exhibits thermoelastic properties characteristic of a flexible framework material. The calculated phonon energies, elastic tensor, and thermal expansion tensor are presented; the volumetric coefficient of thermal expansion is predicted to be near-zero under ambient conditions (alphaV = -3.5 * 10-6 K-1). PMID- 30015822 TI - Role of lincRNA-p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation-induced apoptosis in mesenchymal stem cells. AB - Stem cell transplantation is a promising clinical strategy for curing ischemic cardiomyopathy. However, its efficacy is impaired by low cell survival following transplantation, partly caused by insufficient resistance of the transplanted stem cells to severe oxidative stress at the injury site. In the current study, it was demonstrated that the small-molecule macrophage migration inhibitory factor (MIF) enhanced the defense of bone marrow-derived mesenchymal stem cells (MSCs) against hypoxia/serum deprivation (SD)-induced apoptosis in vitro. MIF significantly suppressed apoptosis and caspase family activities through inhibition of long intergenic noncoding (linc) RNA-p21 to maintain activation of the Wnt/beta-catenin signaling pathway. The regulatory loop between MIF and the lincRNA-p21-Wnt/beta-catenin signaling pathway was identified to be associated with the inhibition of oxidative stress. The involvement of the lincRNA-p21 Wnt/beta-catenin signaling pathway in the effects of MIF in MSCs by overexpression of lincRNA-p21and silencing beta-catenin using small interfering RNA was also demonstrated, both of which abolished the anti-apoptotic and anti oxidative effects of MIF in MSCs under hypoxia/SD conditions. In conclusion, MIF protected MSCs from hypoxia/SD-induced apoptosis by interacting with lincRNA-p21, leading to activation of the downstream Wnt/beta-catenin signaling pathway and decreased oxidative stress. Thus, treatment with MIF may have important therapeutic implications in improving MSC survival and therapeutic efficiency. PMID- 30015823 TI - Effects of FSS on the expression and localization of the core proteins in two Wnt signaling pathways, and their association with ciliogenesis. AB - Fluid shear stress (FSS) may alter ciliary structures and ciliogenesis, and it has been reported that the Wnt signaling pathway may regulate cilia assembly and disassembly. The present study aimed to investigate the effects of FSS on primary cilia, the Wnt/beta-catenin and Wnt/PCP signaling pathways, and the association among them. In the present study, human umbilical vein endothelial cells were subjected to FSS of differing velocities for various periods of time using a shear stress device. Subsequently, immunofluorescence and quantitative polymerase chain reaction were used to detect the expression and localization of the following core proteins: beta-catenin in the Wnt/beta-catenin signaling pathway; and dishevelled segment polarity protein 2 (Dvl2), fuzzy planar cell polarity protein (Fuz) and VANGL planar cell polarity protein 2 (Vangl2) in the Wnt/planar cell polarity (PCP) signaling pathway. Furthermore, the colocalization of Dvl2 with the basal body was analyzed under low FSS and laminar FSS. The results demonstrated that low FSS promoted the expression of Dvl2 and its colocalization with the basal body. Although Fuz expression was decreased with increasing duration of FSS, no visible alterations were detected in its localization, it was ubiquitously localized in the ciliated region. Conversely, the expression of Vangl2 was increased by laminar FSS, and beta-catenin was translocated into the nucleus at the early stage of low FSS. These findings suggested that Dvl2 may participate in low FSS-induced ciliogenesis and beta-catenin may participate at the early stage, whereas Vangl2 may be associated with laminar FSS-induced cilia disassembly. PMID- 30015824 TI - Promoted delivery of salinomycin sodium to lung cancer cells by dual targeting PLGA hybrid nanoparticles. AB - As the leading cause of cancer-associated mortality worldwide, lung cancer is often associated with therapy failure and decreases in survival; these factors are often attributed to lung cancer-initiating cells (CICs). In addition, sufficient evidence has suggested that simultaneous targeting of CICs, together with cancer cells, is critical for the achievement of preferable therapeutic efficacy, due to the spontaneous conversion between CICs and cancer cells. Salinomycin sodium (SS) is an antibacterial therapeutic agent that exerts potent activity against CICs in various types of cancer, including lung cancer. The present study generated SS lipid-polymer hybrid nanoparticles (NPs) with cluster of differentiation (CD)133 and epidermal growth factor receptor (EGFR) antibodies (CD133/EGFR SS NPs) for the simultaneous treatment of lung CICs and cancer cells. The activity of CD133/EGFR SS NPs was analyzed using cytotoxicity and tumorsphere formation assays, flow cytometry, and an in vivo anticancer assay in mice bearing lung cancer xenografts. The results revealed that CD133/EGFR SS NPs effectively promoted SS delivery to lung CICs and cancer cells, achieving superior therapeutic effects compared with non-targeted NPs or NPs with a single antibody. Furthermore, CD133/EGFR SS NPs exhibited the best efficacy in inhibiting tumor growth compared with the control agents in lung cancer-bearing mice. In conclusion, CD133/EGFR SS NPs may be capable of efficiently targeting and treating lung CICs together with cancer cells, and may represent an effective treatment for lung cancer. PMID- 30015825 TI - MicroRNA-488 inhibits proliferation, invasion and EMT in osteosarcoma cell lines by targeting aquaporin 3. AB - It has been reported that aquaporin 3 (AQP3) expression is associated with the progression of numerous types of cancer and microRNA (miRNA/miR) processing. However, the effects and precise mechanisms of AQP3 in osteosarcoma (OS) have not been fully elucidated. The present study aimed to investigate the interaction between AQP3 and miR-488 in OS. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay was performed to detect the levels of AQP3 and miR 488 in OS tissues and cell lines, respectively. Cell proliferation, invasion and epithelial-mesenchymal transition (EMT) were detected to analyze the biological functions of miR-488 and AQP3 in OS cells. Furthermore, mRNA and protein levels of AQP3 was measured by RT-qPCR and western blot analysis. Furthermore, AQP3 was validated as an miR-488 target using luciferase assays in OS cells. The present study revealed that the miR-488 level was significantly downregulated in OS tissues and cell lines, and that the expression of AQP3 was markedly increased. Notable, the low miR-488 expression level was associated with upregulated AQP3 expression in OS tissues. Furthermore, introduction of miR-488 markedly suppressed the proliferation, invasion and EMT of OS cells. However, miR-488 knockdown increased the proliferation, invasion and EMT of OS cells. The present study demonstrated that miR-488 could directly target AQP3 using bioinformatics analysis and luciferase reporter assays. In addition, AQP3-silencing had similar effects to miR-488 overexpression on OS cells. Overexpression of AQP3 in OS cells partially reversed the inhibitory effects of miR-488 mimic. miR-488 inhibited the proliferation, invasion and EMT of OS cells by directly downregulating AQP3 expression, and miR-488 targeting AQP3 was responsible for inhibition of the proliferation, invasion and EMT of OS cells. PMID- 30015826 TI - Efficient increase of the novel recombinant human plasminogen activator expression level and stability through the use of homozygote transgenic rabbits. AB - Expression efficacy of recombinant protein in current expression systems is generally low. Therefore, the expression levels of recombinant proteins in the breast milk of transgenic animals are typically low. In view of this, the present study aimed to construct homozygous transgenic rabbits with a high expression level of recombinant human plasminogen activator (rhPA) during the entire lactation period. Homozygous transgenic rabbits were obtained using an effective rhPA mammary-specific expression vector PCL25/rhPA. The expression level and thrombolytic ability of rhPA in the milk of both homozygous and hemizygous rabbits were detected by enzyme-linked immunosorbent and fibrin agarose plate assays. It was observed that the expression of rhPA was constant during the entire lactation period in homozygous rabbits, while the expression of rhPA declined slowly in hemizygote rhPA transgenic rabbits during the lactation period. In addition, the expression of rhPA in homozygous transgenic rabbit was ~950 ug/ml, which was markedly higher in comparison with that in hemizygote rabbits. Furthermore, increased gene copy number was observed to increase the expression level of rhPA at the same integration vector. PMID- 30015827 TI - BMS-345541 inhibits airway inflammation and epithelial-mesenchymal transition in airway remodeling of asthmatic mice. AB - The present study aimed to investigate the possible effects and regulatory mechanism of the inhibitor of nuclear factor-kappaB kinase complex beta subunit (IKKbeta) inhibitor BMS-345541 on airway inflammation, airway remodeling and epithelial-mesenchymal transition (EMT) in an ovalbumin (OVA) exposure asthma model in mice. The asthma mouse model was generated by sensitization and challenge with OVA. BMS-345541/dimethyl sulfoxide (DMSO) was administered perorally dairy in two therapeutic groups throughout the entire OVA challenge process. At 24 h following the last challenge, airway hyperresponsiveness (AHR) and airway inflammation were examined, and serum, bronchoalveolar lavage fluid (BALF) and lung samples were collected. Lung tissue was stained and assessed for pathological changes. The total number and classification of inflammatory cells in the BALF were examined. Levels of transforming growth factor beta1 (TGFbeta1) in the serum and BALF were measured using an enzyme-linked immunosorbent assay. The differential expression of EMT regulators E-cadherin and vimentin was detected by immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis. The results showed that OVA successfully induced allergic asthma. The asthmatic mice had AHR, airway inflammation, airway remodeling, a high expression of TGFbeta1, and evidence of EMT. Following BMS-345541 treatment, there was significant inhibition of pathophysiological signs, including increased pulmonary eosinophilia infiltration, mucus hypersecretion and AHR. Treatment with BMS-345541 significantly reduced levels of TGFbeta1. In addition, BMS-345541 notably downregulated the expression of vimentin and increased the expression of E cadherin. These data suggested that the increased secretion of TGFbeta1 induced by asthmatic inflammation can lead to EMT, and the IKKbeta inhibitor BMS-345541 may alter airway remodeling by preventing EMT in an OVA asthma model. Therefore, IKKbeta inhibitors require investigation as potential asthma therapies. PMID- 30015828 TI - Alantolactone induces apoptosis and suppresses migration in MCF-7 human breast cancer cells via the p38 MAPK, NF-kappaB and Nrf2 signaling pathways. AB - Human breast cancer is a malignant type of cancer with high prevalence. In the present study, the anticancer effects of alantolactone, a sesquiterpene lactone, on the human breast cancer cell line MCF-7 were investigated in vitro. The MCF-7 cell morphology changed from diamond to round subsequent to treatment with alantolactone, and the cell viability reduced significantly compared with that of the control cells. Alantolactone induced apoptosis of MCF-7 cells by regulating the protein expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, p53, caspase-3 and caspase-12, which are associated with the apoptotic pathway, and suppressed colony formation and migration by regulating the protein expression of matrix metalloproteinase (MMP)-2, MMP-7 and MMP-9. Cell signaling pathway analysis confirmed that alantolactone increased the phosphorylation of p38, and decreased the nuclear expression levels of p65 and nuclear factor erythroid 2-related factor 2 (Nrf2), suggesting that the apoptosis-promoting and migration-suppressing effect of alantolactone may partially depend on regulating the p38 MAPK, NF-kappaB and Nrf2 pathways. These results also suggested that alantolactone may become a potential therapeutic strategy for treating breast cancer. PMID- 30015829 TI - Obtusifolin inhibits high glucose-induced mitochondrial apoptosis in human umbilical vein endothelial cells. AB - DM is often accompanied by macrovascular complications. Obtusifolin, which is an anthraquinone-based compound with antioxidant activity, is obtained from the seeds of Cassia obtusifolia. In this study, the potential effect of obtusifolin was investigated in human umbilical vein endothelial cells. The results from flow cytometry analysis revealed that pretreatment with obtusifolin depressed the production of cellular reactive oxygen species that was induced by high glucose content. Moreover, the results showed that pretreatment with obtusifolin reduced the level of malondialdehyde, as well as recovered the activities of mitochondrial complex I/III, catalase and superoxide dismutase. Furthermore, flow cytometry analysis also revealed that mitochondrial membrane potential and cell apoptosis were recovered, and inhibited by obtusifolin, respectively. The expression of X chromosome-linked IAP was upregulated, whereas the expressions of poly ADP-ribose polymerase and cysteinyl aspartate specific proteinase-3/9 were downregulated by the pretreatment with obtusifolin. Notably, the western blot analyses showed that the release of Omi/HtrA2 into the cytosol was prevented by the pretreatment with obtusifolin. Conclusively, it was suggested that obtusifolin may provide protection against mitochondrial apoptosis largely through inhibition of the release of Omi/HtrA2 from mitochondria into cytosol. PMID- 30015830 TI - Identification of a novel idiopathic congenital nystagmus-causing missense mutation, p.G296C, in the FRMD7 gene. AB - Exploring the genetic basis for idiopathic congenital nystagmus is critical for improving our understanding of its molecular pathogenesis. In the present study, direct sequencing using gene specific primers was performed in order to identify the causative mutations in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. A comprehensive ophthalmological examination, including eye movement recordings, fundus examination, and retinal optical coherence tomography imaging was also conducted, to characterize the disease phenotype. The results revealed that the two brothers exhibited clear signs of nystagmus without any other ocular anomalies. Direct sequencing revealed a G to T transition (c.886G>T) in exon 9 of the four-point-one, ezrin, radixin, moesin domain-containing 7 (FRMD7) gene, which resulted in a conservative substitution of glycine to cysteine at codon 296 (p.G296C), leading to idiopathic congenital nystagmus in the two affected brothers. c.886G>T is a novel idiopathic congenital nystagmus-inducing mutation in the FRMD7 gene. This finding expands the spectrum of known gene mutations in idiopathic congenital nystagmus, and may be useful for faster gene diagnosis, prenatal testing, the development of potential gene therapies, and for improving the understanding of the molecular pathogenesis of idiopathic congenital nystagmus. PMID- 30015831 TI - Scopoletin downregulates MMP-1 expression in human fibroblasts via inhibition of p38 phosphorylation. AB - Irradiation of keratinocytes by ultraviolet B induces cytokine production, which in turn activates fibroblasts to produce cytokines and increase matrix metallopeptidase (MMP)-1 protein expression. The present study investigated the effect and potential mechanisms of scopoletin on the regulation of MMP-1 expression in fibroblasts. Scopoletin was isolated from Artemisia capillaris crude extract. Treatment of fibroblasts with scopoletin resulted in a decrease in the protein expression of MMP-1 following stimulation with human keratinocyte (HaCaT) conditioned medium. To further explore the mechanism underlying this effect, the expression levels of proteins in the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways were evaluated via western blot analysis. The mRNA expression levels of interleukin (IL)-1alpha and tumor necrosis factor (TNF) alpha were evaluated via reverse transcription quantitative polymerase chain reaction. The effect of scopoletin on cell viability was assessed with the MTT assay. The results demonstrated that scopoletin treatment markedly decreased MMP-1, IL-1alpha and TNFalpha mRNA expression in fibroblasts stimulated with HaCaT conditioned medium (40 mJ/cm2), without any apparent cell cytotoxicity, and in a dose-dependent manner. In addition, western blot analysis demonstrated that scopoletin reduced the phosphorylation of p38 MAPK in fibroblasts. In summary, the present study demonstrated that scopoletin inhibited MMP-1 and proinflammatory cytokine expression by inhibiting p38 MAPK phosphorylation. These findings suggest that scopoletin may have potential as a therapeutic agent to prevent and treat photoaging of the skin. PMID- 30015832 TI - Identification of genes and signaling pathways associated with arthrogryposis renal dysfunction-cholestasis syndrome using weighted correlation network analysis. AB - The present study aimed to identify the molecular basis of the arthrogryposis renal dysfunction-cholestasis (ARC) syndrome, which is caused by mutations in the vacuolar protein sorting 33 homolog B (VPS33B) gene. The microarray dataset GSE83192, which contained six liver tissue samples from VPS33B knockout mice and four liver tissue samples from control mice, was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were screened by the Limma package in R software. The DEGs most relevant to ARC were selected via weighted gene co-expression network analysis to construct a protein protein interaction (PPI) network. In addition, module analysis was performed for the PPI network using the Molecular Complex Detection function. Functional and pathway enrichment analyses were also performed for DEGs in the PPI network. Potential drugs for ARC treatment were predicted using the Connectivity Map database. In total, 768 upregulated and 379 downregulated DEGs were detected in the VPS33B knockout mice, while three modules were identified from the PPI network constructed. The DEGs in module 1 (CD83, IL1B and TLR2) were mainly involved in the positive regulation of cytokine production and the Toll-like receptor (TLR) signaling pathway. The DEGs in module 2 (COL1A1 and COL1A2) were significantly enriched with respect to cellular component organization, extracellular matrix-receptor interactions and focal adhesion. The DEGs in module 3 (ABCG8 and ABCG3) were clearly associated with sterol absorption and transport. Furthermore, mercaptopurine was identified to be a potential drug (connectivity score=-0.939) for ARC treatment. In conclusion, the results of the current study may help to further understand the pathology of ARC, and the DEGs identified in these modules may serve as therapeutic targets. PMID- 30015833 TI - Regenerative potential of human nucleus pulposus resident stem/progenitor cells declines with ageing and intervertebral disc degeneration. AB - Numerous studies have demonstrated the presence of resident nucleus pulposus stem/progenitor cells (NPSCs) in the tissue of the intervertebral disc (IVD). However, the cellular identity of NPSCs during IVD degeneration and ageing are poorly defined at present, despite significant progress in the understanding of NPSC biology. In the present study, NPSCs were isolated from human degenerated IVD and were characterized by flow cytometry, gene expression assays and proliferation and multipotency analysis. The results of the present study demonstrated that NPSCs isolated from human degenerated IVD may be divided into two groups according to the expression of mesenchymal stem cell (MSC) surface markers: The high expression of MSC surface markers group (H-NPSCs) was highly positive for CD29, CD44, CD73, CD90 and CD105 at rates >95%, and the low expression of MSC markers surface markers group (L-NPSCs), with the expression of CD29 and CD105 exhibiting individual variability, however, all at rates <95%. The donors for H-NPSCs were aged <20 years, while the majority of donors for L-NPSCs were aged >25 years, with one exception aged <20 years. The results highlighted that the low expression of MSC surface markers in NPSCs from aged and degenerated NP tissues were associated with a low rate of proliferation and reduced differentiation potential, as well as downregulation of the NP progenitor marker Tie2 and higher expression of NP cell-specific markers. These findings demonstrated that the regenerative potential of human NPSCs declines with ageing and degeneration of the IVD. PMID- 30015834 TI - Potential repositioning of GV1001 as a therapeutic agent for testosterone-induced benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is one of the leading causes of male reproductive disorders. Therapeutic agents currently in use have severe side effects; therefore, alternative drugs that exhibit improved therapeutic activity without side effects are required. The present study investigated the protective effect of GV1001 against testosterone-induced BPH in rats. BPH in castrated rats was established via daily subcutaneous (s.c.) injections of testosterone propionate (TP, 3 mg/kg) dissolved in corn oil for 4 weeks. GV1001 (0.01, 0.1 and 1 mg/kg, s.c.) was administered 3 times per week for 4 weeks, together with TP (3 mg/kg) injection. The rats were sacrificed on the last day of treatment, and their prostates were excised and weighed for biochemical and histological studies. Serum levels of testosterone and dihydrotestosterone (DHT) were also measured. In rats with TP-induced BPH, a significant increase in prostate weight (PW) and prostatic index (PI), accompanied by a decrease in antioxidant enzyme activity, was observed. Histological studies revealed clearly enlarged glandular cavities in rats with BPH. GV1001 (0.01 and 0.1 mg/kg) treatment significantly decreased PW and PI in rats with TP-induced BPH. In addition, GV1001 demonstrated a potent inhibitory effect on 5alpha-reductase in prostate. The present data suggest that the protective role of GV1001 against testosterone-induced BPH is closely associated with its antioxidant potential. Additional studies are required to identify the mechanisms by which GV1001 protects against BPH to determine its clinical application. PMID- 30015836 TI - Long non-coding RNA SNHG12promotes the proliferation and migration of glioma cells by binding to HuR. AB - Long non-coding RNAs (lncRNAs) play important roles in biological processes and provide a novel approach with which to understand the molecular mechanisms responsible for glioma. Previous studies have demonstrated that lncRNA small nucleolar RNA host gene 12 (SNHG12) is involved in cell growth and migration. However, the accurate expression pattern of SNHG12 in glioma and the possible associations between this pattern and the clinicopathological characteristics of glioma cohorts are not yet known. The present study investigated the role of lncRNA SNHG12 in the development and progression of glioma, as well as the potential diagnostic value of SNHG12 in patients with glioma. The levels of SNHG12 were detected in resected specimens from patients and in glioma cell lines using reverse transcription-quantitative polymerase chain reaction. The potential effects of SNHG12 on the viability, mobility and apoptosis of glioma cells were evaluated using in vitro assays. The association between SNHG12 and Hu antigen R (HuR) was also determined using RNA immunoprecipitation (RIP) and RNA pull-down assays. The results revealed that SNHG12 was significantly upregulated in glioma tissues and cell lines. High levels of SNHG12 were associated with the deterioration of patients with glioma. Patients with high levels of SNHG12 exhibited a reduced 5-year overall survival rate (compared to those with lower levels), particularly in cohorts with high-grade carcinoma (III-IV). The silencing of SNHG12 expression by RNA interference led to a reduced viability and mobility, and in an increased apoptosis of human glioma cells. Furthermore, RIP and RNA pull-down assays demonstrated that SNHG12 was associated with and was stabilized by HuR. The findings of the present study thus identify a novel therapeutic target in glioma. PMID- 30015835 TI - Fordin: A novel type I ribosome inactivating protein from Vernicia fordii modulates multiple signaling cascades leading to anti-invasive and pro-apoptotic effects in cancer cells in vitro. AB - Fordin, which is derived from Vernicia fordii, is a novel type I ribosome inactivating protein (RIP) with RNA N-glycosidase activity. In the present study, fordin was expressed by Escherichia coli and purified using nickel affinity chromatography. Previous studies have demonstrated RIP toxicity in a variety of cancer cell lines. To understand the therapeutic potential of fordin on tumors, the present study investigated the effects of fordin on the viability of several tumor and normal cell lines. The results demonstrated that fordin induced significant cytotoxicity in four cancer cell lines, compared with the normal cell line. Specifically, profound apoptosis and inhibition of cell invasion were observed following fordin exposure in U-2 OS and HepG2 cells; however, the molecular mechanism underlying the action of RIP remains to be fully elucidated. In the present study, it was found that the anticancer effects of fordin were associated with suppression of the nuclear factor (NF)-kappaB signaling pathway. In U-2 OS and HepG2 cells, fordin inhibited the expression of inhibitor of NF kappaB (IkappaB) kinase, leading to downregulation of the phosphorylation level of IkappaB, which quelled the nuclear translocation of NF-kappaB. Fordin also reduced the mRNA and protein levels of NF-kappaB downstream targets associated with cell apoptosis and metastasis, particularly B-cell lymphoma-2-related protein A1 (Blf-1) and matrix metalloproteinase (MMP)-9. The inactivation of NF kappaB and the reduction in the expression levels of Blf-1 and MMP-9 mediated by fordin were also confirmed by co-treatment with lipopolysaccharide or p65 small interfering RNA. These findings suggested a possible mechanism for the fordin induced effect on tumor cell death and metastasis. The results of the present study demonstrated the multiple anticancer effects of fordin in U-2 OS and HepG2 cells, in part by inhibiting activation of the NF-kappaB signaling pathway. PMID- 30015837 TI - Exosome-mediated transfer of lncRNA-SNHG14 promotes trastuzumab chemoresistance in breast cancer. AB - Currently, resistance to trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor, has become an important obstacle to improving the clinical outcome of patients with advanced HER2+ breast cancer. While cell behavior may be modulated by long non-coding RNAs (lncRNAs), the contributions of lncRNAs within extracellular vesicles (exosomes) are largely unknown. To this end, the involvement and regulatory functions of potential lncRNAs contained within exosomes during the formation of chemoresistance in human breast cancer were investigated. Trastuzumab-resistant cell lines were established by continuously grafting HER2+ SKBR-3 and BT474 cells into trastuzumab-containing culture medium. An lncRNA microarray assay followed by reverse transcription-quantitative polymerase chain reaction analysis identified that lncRNA-small nucleolar RNA host gene 14 (SNHG14) was upregulated in trastuzumab-resistant cells when compared with parental breast cancer cells. Functional experimentation demonstrated that knockdown of lncRNA-SNHG14 potently promoted trastuzumab induced cytotoxicity. Furthermore, extracellular lncRNA-SNHG14 was able to be incorporated into exosomes and transmitted to sensitive cells, thus disseminating trastuzumab resistance. Treatment of sensitive cells with exosomes highly expressing lncRNA-SNHG14 induced trastuzumab resistance, while knockdown of lncRNA-SNHG14 abrogated this effect. The Signal Transduction Reporter Array indicated that lncRNA-SNHG14 may promote the effect of trastuzumab by targeting the apoptosis regulator Bcl-2 (Bcl-2)/apoptosis regulator BAX (Bax) signaling pathway. Furthermore, the expression level of serum exosomal lncRNA-SNHG14 was upregulated in patients who exhibited resistance to trastuzumab, compared with patients exhibiting a response. Therefore, lncRNA-SNHG14 may be a promising therapeutic target for patients with HER2+ breast cancer. PMID- 30015839 TI - MicroRNA-130a inhibits the proliferation, migration and invasive ability of hepatocellular carcinoma cells by downregulating Rho-kinase 2. AB - MicroRNA-130a (miR-130a) has been reported to be downregulated in hepatocellular carcinoma (HCC). However, the roles and underlying tumor-suppressive mechanisms of miR-130a in the pathogenesis of HCC remain unclear. In the current study, reduced expression of miR-130a was observed in tumor tissues of patients with HCC in addition to in four HCC cell lines, BEL-7402, MHCC97H, HepG2 and Huh7. Results of methyl thiazolyl tetrazolium (MTT) assays identified decreased growth rates of MHCC97H and HepG2 cells transfected with miR-130a mimics. The in vitro colony formation assays demonstrated that the number of colonies formed by cells transfected with miR-130a mimics and cells transfected with miR-130a inhibitors was lower and higher, respectively, than that formed by the cells transfected with miR-negative control. In addition, it was identified that overexpression of miR-130a reduced the migration and invasiveness of MHCC97H and HepG2 cells. Luciferase reporter assays demonstrated that miR-130a directly targeted the 3' untranslated region of Rho-kinase 2 (ROCK2) mRNA. Northern and western blot analyses indicated that miR-130a could modulate the mRNA and protein expression of ROCK2. Additionally, small-interfering RNA-mediated knockdown of ROCK2 decreased the proliferation, migration and invasiveness of MHCC97H and HepG2 cells. Overall, these observation suggest that miR-130a is a regulator of ROCK2 and can inhibit proliferation, migration and invasive ability of HCC cells, at least in part, by suppressing the expression of ROCK2. The current study provides further insight into the molecular mechanisms of HCC pathogenesis and suggests a new potential biotarget for HCC treatment. PMID- 30015840 TI - MicroRNA-655 suppresses cell proliferation and invasion in oral squamous cell carcinoma by directly targeting metadherin and regulating the PTEN/AKT pathway. AB - MicroRNAs (miRNAs) are important regulators of a variety of biological processes and their dysregulation is closely related to cancer formation and progression. Therefore, examination of aberrantly expressed miRNAs in oral squamous cell carcinoma (OSCC) may provide important clues for the diagnosis and treatment of patients with OSCC. The aim of the present study was to determine miRNA (miR)-655 3p expression in OSCC tissues and cell lines, and to investigate the biological roles and mechanisms of miR-655-3p associated with OSCC. Data from the present study indicated that miR-655 expression was significantly downregulated in human OSCC tissues and cell lines. Overexpression of miR-655 attenuated cell proliferation and invasion in OSCC in vitro. Metadherin (MTDH) mRNA was predicted as a potential target of miR-655 by bioinformatics analysis, and this was confirmed by luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis. In OSCC tissues, MTDH was highly expressed and inversely correlated with miR-655 expression levels. MTDH overexpression reversed the inhibitory effects of miR-655 mimics in OSCC cells. Notably, the upregulation of miR-655 expression inhibited the activation of the phosphatase and tensin homolog (PTEN)/RAC-alpha serine/threonine-protein kinase (AKT) pathway in OSCC cells. Therefore, these results may provide the first evidence that miR-655 targets MTDH to inhibit proliferation and invasion of OSCC by inhibiting PTEN/AKT signaling. Thus, the restoration of miR-655 expression may be a novel therapeutic strategy for patients with OSCC. PMID- 30015838 TI - The enhanced antitumour response of pimozide combined with the IDO inhibitor L-MT in melanoma. AB - Melanoma is one of the most fatal and therapy-resistant types of cancer; therefore, identifying novel therapeutic candidates to improve patient survival is an ongoing effort. Previous studies have revealed that pimozide is not sufficient to treat melanoma; therefore, enhancing the treatment is necessary. Indoleamine 2, 3-dioxygenase (IDO) is an immunosuppressive, intracellular rate limiting enzyme, which contributes to immune tolerance in various tumours, including melanoma, and inhibition of IDO may be considered a novel therapeutic strategy when combined with pimozide. The present study aimed to assess the antitumour activities of pimozide in vitro, and to investigate the effects of pimozide combined with L-methyl-tryptophan (L-MT) in vivo. For in vitro analyses, the B16 melanoma cell line was used. Cell cytotoxicity assay, cell viability assay, wound-healing assay and western blotting were conducted to analyse the effects of pimozide on B16 cells. Furthermore, B16 cell-bearing mice were established as the animal model. Haematoxylin and eosin staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labelling staining, western blotting and flow cytometry were performed to determine the effects of monotherapy and pimozide and L-MT cotreatment on melanoma. The results demonstrated that pimozide exhibited potent antitumour activity via the regulation of proliferation, apoptosis and migration. Furthermore, the antitumour effects of pimozide were enhanced when combined with L-MT, not only via regulation of proliferation, apoptosis and migration, but also via immune modulation. Notably, pimozide may regulate tumour immunity through inhibiting the activities of signal transducer and activator of transcription (Stat)3 and Stat5. In conclusion, the present study proposed the use of pimozide in combination with the IDO inhibitor, L-MT, as a potential novel therapeutic strategy for the treatment of melanoma. PMID- 30015841 TI - The tumorigenic role of DSPP and its potential regulation of the unfolded protein response and ER stress in oral cancer cells. AB - Dentin sialophosphoprotein (DSPP) is upregulated in various human cancers, including head and neck squamous cell carcinoma. Cancer cells are commonly found under constant endoplasmic reticulum (ER) stress and exhibit increased levels of misfolded proteins, due to gene mutations and a stressful microenvironment. The present study examined the effects of DSPP silencing on the regulation of ER stress and the unfolded protein response (UPR) in oral cancer cells. A recently established stable DSPP short hairpin (sh)RNA-silenced OSC2 oral cancer cell line was used. The mRNA expression levels of ER stress-associated proteins, including 78 kDa glucose-regulated protein (GRP78), sarcoplasmic/endoplasmic reticulum calcium ATPase 2b (SERCA2b), inositol 1,4,5-trisphosphate receptor (IP3r), protein kinase R-like endoplasmic reticulum kinase (PERK), serine/threonine protein kinase/endoribonuclease IRE1 (IRE1), activating transcription factor 6 (ATF6) and matrix metalloproteinase 20 (MMP20), were assessed by reverse transcription-quantitative polymerase chain reaction. The expression levels of apoptosis-related [B-cell lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax) and cytochrome c] and cell proliferation-related [proliferating cell nuclear antigen (PCNA)] proteins were analyzed by western blotting. Cell viability, apoptosis and migration were monitored by MTT assay, Annexin V-fluorescein isothiocyanate flow cytometry and wound-healing assay, respectively. In transiently transfected puromycin-free OSC2 cells, DSPP silencing markedly downregulated the mRNA expression levels of major ER stress regulators, including GRP78, SERCA2b, PERK, IRE1 and ATF6, as well as MMP20. DSPP silencing also resulted in decreased cell viability and migration, and enhanced apoptosis. Furthermore, PCNA and Bcl2 levels were decreased, whereas Bax and cytochrome c protein levels were increased in DSPP-silenced OSC2 cells. Sustained puromycin treatment partially counteracted the effects of DSPP silencing on the mRNA expression levels of ER stress-related proteins and MMP20, and on the migratory capacity of OSC2 cells. However, following puromycin treatment of DSPP-silenced cells, cell viability was further reduced and apoptosis was enhanced. In conclusion, these data provide evidence to suggest that DSPP may be involved in ER stress mechanisms in oral squamous cell carcinoma, since its downregulation in OSC2 cells led to significant alterations in the levels of major ER stress-associated proteins, and subsequent collapse of the UPR system. PMID- 30015842 TI - Loss of profilin 2 contributes to enhanced epithelial-mesenchymal transition and metastasis of colorectal cancer. AB - Profilin 2 (PFN2) functions as an actin cytoskeleton regulator and serves an important role in cell motility. However, a role for PFN2 in the progression of colorectal cancer (CRC), particularly in metastasis, has yet to be clarified. The aim of the present study was to investigate whether PFN2 served specific roles in the progression of human CRC. The results demonstrated that PFN2 was differentially expressed in CRC tissues and cell lines by reverse transcription quantitative polymerase chain reaction and western blotting. PFN2 expression was also negatively associated with the degree of tumor metastasis. Low PFN2 expression in CRC cells was related with enhanced epithelial-mesenchymal transition (EMT) and, in turn, may increase migratory capabilities. Overexpression of PFN2 in CRC cell lines with a low level of endogenous PFN2 inhibited the EMT process, as well as the associated migration; in addition, myosin light chain (MLC) phosphorylation was upregulated. Inhibition of MLC phosphorylation attenuated the inhibition of EMT and cell migratory abilities induced by PFN2 overexpression in CRC cell lines, the results suggested that PFN2 may suppress cancer EMT and the subsequent metastasis by regulating cytoskeletal reorganization. These results demonstrated that PFN2 may serve a suppressive role in the metastasis of CRC and therefore may provide a new potential target for cancer therapeutics. PMID- 30015843 TI - Shear stress promotes differentiation of stem cells from human exfoliated deciduous teeth into endothelial cells via the downstream pathway of VEGF-Notch signaling. AB - Effects of shear stress on endotheliaxl differentiation of stem cells from human exfoliated deciduous teeth (SHEDs) were investigated. SHEDs were treated with shear stress, then reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to analyse the mRNA expression of arterial markers and western blot analysis was performed to analyse protein expression of angiogenic markers. Additionally, in vitro matrigel angiogenesis assay was performed to evaluate vascular-like structure formation. The secreted protein expression levels of the vascular endothelial growth factor (VEGF) of SHEDs after shear stress was also quantified using corresponding ELISA kits. Untreated SHEDs seeded on Matrigel cannot form vessel-like structures at any time points, whereas groups treated with shear stress formed a few vessel-like structures at 4, 8 and 12 h. When SHEDs were treated with EphrinB2-siRNA for 24, the capability of vessel-like structure formation was suppressed. After being treated with shear stress, the expression of VEGF, VEGFR2, DLL4, Notch1, EphrinB2, Hey1 and Hey2 (arterial markers) gene expression was significantly upregulated, moreover, the protein levels of VEGFR2, EphrinB2, CD31, Notch1, DLL4, Hey1, and Hey2 were also significantly up-regulated. Both the mRNA and protein expression levels of EphB4 (venous marker) were downregulated. The average VEGF protein concentration in supernatants secreted by shear stress treated SHEDs groups increased significantly. In conclusion, shear stress was able to induce arterial endothelial differentiation of stem cells from human exfoliated deciduous teeth, and VEGF-DLL4/Notch-EphrinB2 signaling was involved in this process. PMID- 30015844 TI - Downregulation of microRNA-21 expression inhibits proliferation, and induces G1 arrest and apoptosis via the PTEN/AKT pathway in SKM-1 cells. AB - Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and may progress to acute myeloid leukemia (AML). MicroRNAs (miRNA/miRs) as oncogenes or tumor suppressors regulate a number of biological processes including cell proliferation, cell cycle and apoptosis in different types of cancer cells. Recently, it has been reported that miR-21 as an oncogene is overexpressed and directly targets SMAD-7 in MDS. However, little is known about the mechanism of miR-21 in the progression of MDS. In the present study, the role of miR-21 in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line established in the AML/MDS leukemic phase was investigated. The present results demonstrated that downregulation of miR-21 inhibited proliferation, induced apoptosis and caused G1 phase cell cycle arrest of SKM-1 cells. In addition, the expression levels of apoptosis regulator Bcl-2 (bcl2), cyclinD1 and phosphorylated-protein kinase B (AKT) were significantly decreased in SKM-1 cells transfected with the miR-21 inhibitor, whilst the expression levels of phosphatase and tensin homolog (PTEN), bcl-associated protein X (bax) and cleaved caspase 3 were significantly elevated. Furthermore, knockdown of Akt by small interfering (si)RNA significantly increased the expression of bax, cleaved caspase 3 and reduced the expression of bcl2 and cyclinD1 in SKM-1 cells. Taken together, these data indicate that miR-21 targets the PTEN/AKT pathway in the pathogenesis of MDS and could be a potential target for MDS therapy. PMID- 30015845 TI - Downregulation of miR-486-5p in papillary thyroid carcinoma tissue: A study based on microarray and miRNA sequencing. AB - Abnormal expression of microRNA (miR) is associated with the occurrence and progression of various types of cancers, including papillary thyroid carcinoma (PTC). In the present study, the aim was to explore miR-486-5p expression and its role in PTC, as well as to investigate the biological function of its potential target genes. The expression levels of miR-486-5p and its clinicopathological significance were examined in 507 PTC and 59 normal thyroid samples via The Cancer Genome Atlas (TCGA). Subsequently, the results were validated using data from Gene Expression Omnibus (GEO) and ArrayExpress. Receiver operating characteristic and summary receiver operating characteristic curves were used to assess the ability of miR-486-5p in distinguishing PTC from normal tissue. Furthermore, potential miR-486-5p mRNA targets were identified using 12 prediction tools and enrichment analysis was performed on the encoding genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of miR-486-5p were consistently downregulated in PTC compared with in normal tissue across datasets from TCGA, GEO (GSE40807, GSE62054 and GSE73182) and ArrayExpress (E-MTAB-736). The results also demonstrated that miR-486-5p expression was associated with cancer stage (P=0.003), pathologic lymph node (P=0.047), metastasis (P=0.042), neoplasm (P=0.012) and recurrence (P=0.016) in patients with PTC. In addition, low expression of miR-486-5p in patients with PTC was associated with a worse overall survival. A total of 80 miR-486-5p-related genes were observed from at least 9 of 12 prediction platforms, and these were involved in 'hsa05200: Pathways in cancer' and 'hsa05206: MicroRNAs in cancer'. Finally, three hub genes, CRK like proto-oncogene, phosphatase and tensin homolog and tropomyosin 3, were identified as important candidates in tumorigenesis and progression of PTC. In conclusion, it may be hypothesized that miR-486-5p contributes towards PTC onset and progression, and may act as a clinical target. However, in vitro and in vivo experiments are required to validate the findings of the present study. PMID- 30015846 TI - Corosolic acid reduces 5-FU chemoresistance in human gastric cancer cells by activating AMPK. AB - 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents for gastric cancer. Resistance to 5-FU-based chemotherapy remains the major obstacle in the treatment of gastric cancer. A growing body of evidence has suggested that adenosine monophosphate-activated protein kinase (AMPK) is pivotal for chemoresistance. However, the mechanism by which AMPK regulates the chemosensitivity of gastric cancer remains unclear. In the present study, how corosolic acid enhanced the chemosensitivity of gastric cancer cells to 5-FU via AMPK activation was investigated. A 5-FU-resistant gastric cancer cell line (SNU 620/5-FUR) was established, which had a marked increase in thymidine synthase (TS) expression but reduced AMPK phosphorylation when compared with the parental cell line, SNU-620. AMPK regulation by 5-aminoimidazole-4-carboxamide ribonucleotide or compound c was revealed to be markedly associated with TS expression and 5-FU-resistant cell viability. In addition, corosolic acid activated AMPK, and decreased TS expression and the phosphorylation of mammalian target of rapamycin/4E-binding protein 1 in a dose-dependent manner. Corosolic acid treatment significantly reduced cell viability while compound c reversed corosolic acid-induced cell growth inhibition. The 5-FU-resistance sensitization effect of corosolic acid was determined by the synergistic reduction of TS expression and inhibition of cell viability in the presence of 5-FU. The corosolic acid-induced AMPK activation was markedly increased by additional 5-FU treatment, while compound c reversed AMPK phosphorylation. In addition, compound c treatment reversed corosolic acid-induced apoptotic markers such as capase-3 and PARP cleavage, and cytochrome c translocation to cytosol, in the presence of 5-FU. Corosolic acid treatment in the presence of 5-FU induced an increase in the apoptotic cell population based on flow cytometry analysis. This increase was abolished by compound c. In conclusion, these results implied that corosolic acid may have therapeutic potential to sensitize the resistance of gastric cancer to 5 FU by activating AMPK. PMID- 30015847 TI - LRIG2 promotes the proliferation and cell cycle progression of glioblastoma cells in vitro and in vivo through enhancing PDGFRbeta signaling. AB - The leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family, comprising LRIG1, 2 and 3, encodes integral membrane proteins. It has been well established that LRIG1 negatively regulates multiple growth factor signaling pathways and is considered to be a tumor suppressor; however, the biological functions of LRIG2 remain largely unexplored. It was previously demonstrated that LRIG2 positively regulates epidermal growth factor receptor (EGFR) signaling, the most common aberrant receptor tyrosine kinase (RTK) signaling in glioblastoma multiforme (GBM), which promotes GBM growth. In the present study, the effect of LRIG2 on the proliferation of GBM cells was further addressed, as well as the possible mechanisms underlying the regulatory effect of LRIG2 on platelet-derived growth factor receptor beta (PDGFRbeta) signaling, another common oncogenic RTK signaling pathway in GBM. First, the expression levels of endogenous LRIG2 and PDGFRbeta were found to vary notably in human GBM, and the LRIG2 expression level was positively correlated with the expression level of PDGFRbeta. Furthermore, to the best of our knowledge, this is the first study to demonstrate that LRIG2 promoted the PDGF-BB-induced proliferation of GBM cells in vitro and in vivo through regulating the PDGFRbeta signaling-mediated cell cycle progression. Mechanistically, LRIG2 has the ability to physically interact with PDGFRbeta, promoting the total expression and the activation of PDGFRbeta, and enhancing its downstream signaling pathways of Akt and signal transducer and activator of transcription 3 and the effectors of key regulators of cell cycle progression, resulting in increased GBM cell proliferation. Collectively, these data indicated that LRIG2 may serve as a tumor promoter gene in gliomagenesis by positively regulating PDGFRbeta signaling, another important oncogenic RTK signaling pathway, in addition to the previously reported EGFR signaling in GBM modulated by LRIG2, and validated LRIG2 as a promising therapeutic target for the treatment of GBM characterized by multiple aberrant RTK signaling. PMID- 30015848 TI - Aryl hydrocarbon receptor, a tumor grade-associated marker of oral cancer, is directly downregulated by polydatin: A pilot study. AB - Oral squamous cell carcinoma (OSCC) is one of the most aggressive and deadliest tumors worldwide. The aryl hydrocarbon receptor (AHR) is a nuclear transcription factor known as a dioxin receptor and mediates the toxic effects of industrial contaminants. In addition, AHR has been implicated in multiple cellular processes and its expression has been shown to play a critical role in tumorigenesis, including human oral cancer cell lines. In the present study, we evaluated the expression of AHR/HSP-90 in 25 formalin-fixed, paraffin-embedded human oral cancer specimens by IHC analysis. CYP1A1 expression was regarded as an AHR reporter gene. The data indicated a complete correlation between AHR expression and cancer grade enabling us to propose AHR as a prognostic marker of oral cancer. Moreover, in OSCC cell line CAL27, we observed the modulatory effect of polydatin, a widespread natural substance and direct precursor of resveratrol, on AHR expression. A computational approach was performed to predict the site of interaction of polydatin on the AHR surface. Our studies confirm the involvement of AHR signaling in the clinicopathological specimens of oral cancer and suggest the use of polydatin for oral cancer prevention. PMID- 30015849 TI - Evaluation of intestinal injury, inflammatory response and oxidative stress following intracerebral hemorrhage in mice. AB - Intestinal injury is a common complication following intracerebral hemorrhage (ICH), which leads to malnutrition, impaired immunity and unsatisfactory prognosis. Previous studies have revealed the pathogenesis of intestinal injury following traumatic brain injury using ischemic stroke models. However, the effects of ICH on intestinal injury remain unknown. The present study aimed to investigate the pathological alterations and molecular mechanism, as well as the time course of intestinal injury following ICH in mice. Male C57BL/6 mice were randomly divided into the following seven groups (n=6 mice/group): Control group, which underwent a sham operation, and six ICH groups (2, 6, 12 and 24 h, and days 3 and 7). The ICH model was induced by stereotactically injecting autologous blood in two stages into the brain. Subsequently, intestinal tissue was stained with hematoxylin and eosin for histopathological examination. Small intestinal motility was measured by charcoal meal test, and gut barrier dysfunction was evaluated by detecting the plasma levels of endotoxin. Quantitative polymerase chain reaction (qPCR), immunohistochemistry and ELISA analysis were performed to evaluate the mRNA and protein expression levels of inflammatory cytokines [interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, intercellular adhesion molecule 1, monocyte chemotactic protein 1 and chemokine (C-C motif) ligand-5] in intestinal tissue and serum. Furthermore, intestinal leukocyte infiltration was detected by measuring myeloperoxidase activity. Oxidative stress was indirectly detected by measuring reactive oxygen species-associated markers (malondialdehyde content and superoxide dismutase activity assays) and the mRNA and protein expression levels of antioxidant genes [nuclear factor (erythroid derived 2)-like 2, manganese superoxide dismutase and heme oxygenase 1] by qPCR and western blot analysis. The results demonstrated that significant destruction of the gut mucosa, delayed small intestinal motility, intestinal barrier dysfunction, and increased inflammatory responses and oxidative stress occurred rapidly in response to ICH. These symptoms occurred as early as 2 h after ICH and persisted for 7 days. These findings suggested that ICH may induce immediate and persistent damage to gut structure and barrier function, which may be associated with upregulation of inflammation and oxidative stress markers. PMID- 30015850 TI - Effects of a small, volatile bacterial molecule on Pseudomonas aeruginosa bacteria using whole cell high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and genomics. AB - In the present study, high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy was applied to live Pseudomonas aeruginosa (PA) bacterial cells to determine the metabolome of this opportunistic Gram negative human pathogen, and in particular, its response to the volatile aromatic low molecular weight signaling molecule, 2-aminoacetophenone (2-AA). Multi dimensional HRMAS NMR is a promising method which may be used to determine the in vivo metabolome of live intact bacterial cells; 2-AA is produced by PA and triggers the emergence of phenotypes that promote chronic infection phenotypes in in vitro and in vivo (animal) models. In the present study, we applied one dimensional and two-dimensional proton (1H) HRMAS NMR to PA cells which were grown with or without 2-AA in order to examine the associations between metabolites and cellular processes in response to 2-AA. We also compared whole genome transcriptome profiles of PA cells grown with or without 2-AA and found that 2-AA promoted profound metabolic changes in the PA cells. By comparing the whole-genome transcriptome profiles and metabolomic analysis, we demonstrated that 2-AA profoundly reprogramed the gene expression and metabolic profiles of the cells. Our in vivo 1H HRMAS NMR spectroscopy may prove to be a helpful tool in the validation of gene functions, the study of pathogenic mechanisms, the classification of microbial strains into functional/clinical groups and the testing of anti-bacterial agents. PMID- 30015851 TI - miR-199a-3p/Sp1/LDHA axis controls aerobic glycolysis in testicular tumor cells. AB - Aerobic glycolysis is one of the characteristics of tumor metabolism and contributes to the development of tumors. Studies have identified that microRNA (miRNA/miR) serves an important role in glucose metabolism of tumors. miR-199a-3p is a member of the miR-199a family that controls the outcomes of cell survival and death processes, and previous studies have indicated that the expression of miR-199a-3p is low and may be an inhibitor in several cancer types, including testicular tumors. The present study discussed the role and underlying mechanism of miR-199a-3p in aerobic glycolysis of Ntera-2 cells and identified its downstream factors. Firstly, miR-199a-3p exhibited an inhibitory effect on lactic acid production, glucose intake, and reactive oxygen species (ROS) and adenosine 5'-triphosphate (ATP) levels in Ntera-2 cells. Then, using bioinformatics, recombinant construction and a dual luciferase reporter gene system, transcription factor Specificity protein 1 (Sp1) was determined as the direct target of miR-199a-3p. Also, downregulation of Sp1 by RNA interference decreased lactic acid production, glucose intake, and ROS and ATP levels in Ntera-2 cells. Subsequently, through a functional rescue experiment, it was identified that the overexpression of Sp1 may abate the inhibition of miR-199a-3p on glucose metabolism, with the exception of ATP level, suggesting a reciprocal association between Sp1 and miR-199a-3p. Finally, it was determined that miR-199a-3p overexpression and Sp1 knockdown decreased lactate dehydrogenase A (LDHA) protein expression, which indicated that LDHA is a downstream target of the miR-199a 3p/Sp1 signaling pathway. To additionally verify the regulation of LDHA expression by 199a-3p/Sp1, a LDHA promoter reporter plasmid was generated and the high activity of the promoter, which contained 3 potential Sp1 binding elements, was confirmed. In addition, the overexpression of Sp1 led to the increased activity of the LDHA promoter, whereas knockdown of Sp1 exhibited the opposite effect. Therefore, the results of the present study demonstrated that miR-199a-3p can inhibit LDHA expression by downregulating Sp1, and provided mechanistic evidence supporting the existence of a novel miR-199a-3p/Sp1/LDHA axis and its critical contribution to aerobic glycolysis in testicular cancer cells. PMID- 30015852 TI - Luteolin inhibits angiogenesis of the M2-like TAMs via the downregulation of hypoxia inducible factor-1alpha and the STAT3 signalling pathway under hypoxia. AB - The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour-associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2-like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia-inducible factor 1alpha (HIF-1alpha), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase-9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF-1 and phosphorylated-signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2-like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF-1alpha and STAT3 signalling pathways. PMID- 30015853 TI - A comprehensive analysis of prognosis prediction models based on pathway-level, gene-level and clinical information for glioblastoma. AB - The present study aimed to develop a pathway-based prognosis prediction model for glioblastoma (GBM). Univariate and multivariate Cox regression analysis were used to identify prognosis-related genes and clinical factors using mRNA-seq data of GBM samples from The Cancer Genome Atlas (TCGA) database. The expression matrix of prognosis-related genes was transformed into pathway deregulation score (PDS) based on the Gene Set Enrichment Analysis (GSEA) repository using Pathifier software. With PDS scores as input, L1-penalized estimation-based Cox proportional hazards (PH) model was used to identify prognostic pathways. Consequently, a prognosis prediction model based on these prognostic pathways was constructed for classifying patients in the TCGA set or each of the three validation sets into two risk groups. The survival difference between these risk groups was then analyzed using Kaplan-Meier survival analysis and log-rank test. In addition, a gene-based prognostic model was constructed using the Cox-PH model. The model of prognostic pathway combined with clinical factors was also evaluated. In total, 148 genes were discovered to be associated with prognosis. The Cox-PH model identified 13 prognostic pathways. Subsequently, a prognostic model based on the 13 pathways was constructed, and was demonstrated to successfully differentiate overall survival in the TCGA set and in three independent sets. However, the gene-based prognosis model was validated in only two of the three independent sets. Furthermore, the pathway+clinic factor-based model exhibited better predictive results compared with the pathway-based model. In conclusion, the present study suggests a promising prognosis prediction model of 13 pathways for GBM, which may be superior to the gene-level information-based prognostic model. PMID- 30015854 TI - Targeted next-generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment. AB - Stickler syndrome is a group of inherited connective tissue disorders characterized by distinctive facial and ocular abnormalities, hearing loss and early-onset arthritis. The aim of the present study was to investigate the genetic changes in two Chinese patients with Stickler syndrome, manifested as bilateral retinal detachment and peripheral retinal degeneration. Complete ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination and fundus examination, were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the patients, their unaffected family members and 200 unrelated control subjects from the same population. Next-generation sequencing of established genes associated with ocular disease was performed. A heterozygous collagen type II alpha1 chain (COL2A1) mutation c.1310G>C (p.R437P) in exon 21 was identified in Family 1 and a heterozygous COL2A1 mutation c.2302-1G>A in intron 34 was identified in Family 2. The functional effects of the mutations were assessed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT) analysis. The c.1310G>C mutation was predicted to damage protein structure and function, and the c.2302 1G>A mutation was predicted to result in a splicing defect. The findings of the current study expand the established mutation spectrum of COL2A1, and may facilitate genetic counseling and development of therapeutic strategies for patients with Stickler syndrome. PMID- 30015856 TI - Notch signalling induces epithelial-mesenchymal transition to promote metastasis in oral squamous cell carcinoma. AB - The activation of Notch signalling induces epithelial-mesenchymal transition (EMT), but this signalling pathway and its association with EMT in the context of cell motility in oral squamous cell carcinoma (OSCC) remains unclear. The present study aimed to investigate the role of the Notch signalling pathway and EMT in the metastatic potential of OSCC using 2 cell lines, Tca8113 and CAL27. The data demonstrated that zinc finger domain SNAI1 (Snail) knockdown by small interfering RNA decreased the expression of vimentin and increased the expression of epithelial cadherin (E-cadherin). In addition, silencing Snail also significantly inhibited cell migration in the 2 OSCC cell lines. It was also identified that blocking Notch signalling with the g-secretase inhibitor DAPT decreased the expression of the EMT markers Snail and vimentin and increased E-cadherin expression, accompanied by a significant inhibition of cell migration in the 2 OSCC cell lines. These data clearly indicate that Notch signalling mediates EMT to promote metastasis in OSCC cells. Therefore, targeting Notch signalling and its association with EMT may provide novel insights into the mechanism of invasion and metastasis in OSCC and potential therapeutic interventions. PMID- 30015857 TI - Downregulation of hepatic lipase is associated with decreased CD133 expression and clone formation in HepG2 cells. AB - The drug resistance of cancer remains a major obstacle to successful chemotherapy. New strategies for improving chemotherapeutic efficacy are urgently required. Recent studies have indicated that LIPC plays a role in promoting the liver metastasis of colorectal cancer. In the present study, we aimed to investigate the effects of LIPC on theproliferation and clone formation of colorectal cancer-derived cells, and chemoresistance in hepatoblastoma-derived HepG2 cells. The activity and expression of LIPC were determined in the cell lines by RT-qPCR and western blot analysis. HepG2 cells in which LIPC was knocked down by LIPC short hairpin RNA (shRNA) and control cells [shRNA control (shCON)] were established and analyzed for cell proliferation and colony formation rates. FACS analysis was used to explore the association between LIPC and the tumor derived cell biomarker, CD133, and the percentages of CD133-positive cells were assessed by FACS. Additionally, shLIPC- and shCON-transfected cells were treated with various concentrations of doxorubicin and 5-floxuridine (5-FU), and cell viability was determined by MTT assay. mRNA levels in the shLIPC- and shCON transfected cells were compared by cDNA microarray and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The results revealed that the HepG2 cells exhibited a relatively higher LIPC activity and expression levels compared to the other colon cancer cell lines. The downregulation of LIPC in the HepG2 cells was associated with the decreased expression of CD133, decreased cell proliferation and colony formation, as well as increased resistance to chemotherapy. KEGG analysis of the cDNA microarray data revealed increased levels in the cell adhesion molecule (CAM) pathway, including CLDN10 and CLDN1, indicating that CAMs may play a role in LIPC-mediated tumor progression. The present findings indicate a potential role of LIPC as a promising therapeutic target in cancer. PMID- 30015855 TI - Functions of EpCAM in physiological processes and diseases (Review). AB - EpCAM (epithelial cell adhesion molecule) is a type I transmembrane glycoprotein, which was originally identified as a tumor-associated antigen due to its high expression level in rapidly growing epithelial tumors. Germ line mutations of the human EpCAM gene have been indicated as the cause of congenital tufting enteropathy. Previous studies based on cell models have revealed that EpCAM contributes to various biological processes including cell adhesion, signaling, migration and proliferation. Due to the previous lack of genetic animal models, the in vivo functions of EpCAM remain largely unknown. However, EpCAM genetic animal models have recently been generated, and are useful for understanding the functions of EpCAM. The authors here briefly review the functions and mechanisms of EpCAM in physiological processes and different diseases. PMID- 30015859 TI - Effect of celastrol on toll-like receptor 4-mediated inflammatory response in free fatty acid-induced HepG2 cells. AB - Toll-like receptor 4 (TLR4)-mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappaB (NF-kappaB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phospho-NF-kappaBp65, as well as of the downstream inflammatory cytokines interleukin-1beta and tumor necrosis factor alpha. Knockdown of TLR4 also alleviated FFA-induced inflammatory response. In addition, co-treatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4-mediated immune and inflammatory response in steatotic HepG2 cells. PMID- 30015858 TI - Effect of autophagy on allodynia, hyperalgesia and astrocyte activation in a rat model of neuropathic pain. AB - Primary damage or dysfunction of the nervous system may cause or initiate neuropathic pain. However, it has been difficult to establish an effective treatment for neuropathic pain, as the mechanisms responsible for its pathology remain largely unknown. Autophagy is closely associated with the pathological process of neurodegenerative diseases, neuropathic injury and cancer, among others. The aim of the present study was to examine the changes in the autophagy lysosomal pathway and discuss the effects of autophagy on allodynia, hyperalgesia and astrocyte activation in neuropathic pain. A neuropathic pain model was induced by chronic constriction injury (CCI) in rats. Inducers and inhibitors of autophagy and lysosomes were used to assess autophagy, allodynia, hyperalgesia and astrocyte activity. Neuropathic pain was found to induce an increase in the levels of the autophagy-related proteins, LC3II and Beclin 1 and, and in those of the lysosomal proteins, lysosomal-associated membrane protein type 2 (LAMP2) and Ras-related protein Rab-7a (RAB7), whereas p62 levels were found to decrease from day 1 to 14 following CCI. The autophagy inducer, rapamycin, further increased the LC3II, Beclin 1, lysosomal-associated membrane protein 2 (LAMP2) and Ras related protein Rab-7a (RAB7) expression levels, and decreased the p62 expression levels, which were accompanied by alleviation of allodynia, hyperalgesia and astrocyte activation in the rats subjected to CCI; the autophagy inhibitor, 3 methyladenine, reversed these effects. The use of the lysosomal inhibitors, bafilomycin and chloroquine, resulted in the accumulation of LC3II and Beclin 1, a decrease in the levels of LAMP2 and RAB7, and the exacerbation of allodynia, hyperalgesia and astrocyte activation in rats with neuropathic pain. On the whole, the findings of this study indicate that neuropathic pain activates autophagy, which alleviates mechanical and thermal hyperalgesia and suppresses astrocyte activity. Therefore, neuropathic pain induced by CCI in rats appears to be mediated via the autophagy-lysosomal pathway. PMID- 30015860 TI - Oncostatin M promotes the osteogenic differentiation of mouse MC3T3-E1osteoblasts through the regulation of monocyte chemotactic protein-1. AB - The present study investigated the function of oncostatin M (OSM), which may be associated with monocyte chemotactic protein-1 (MCP-1), on mouse MC3T3-E1 osteoblast development and bone remodeling. Levels of MCP-1, macrophage inflammatory protein 1alpha (MIP1alpha) and regulated upon activation normal T cell expressed and secreted (RANTES) were measured by ELISA. Cell viability, migration and invasion abilities were detected by MTT, wound healing and Transwell assays, respectively. Western blotting was performed to detect levels of phosphorylated protein kinase B (Akt). Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the levels of matrix metalloproteinases (MMP)-1, -2 and -3. The results demonstrated that OSM treatment significantly increased MCP-1 levels in a dose-dependent manner. Interleukin (IL)-1, also significantly increased MCP-1 levels; however, treatment with other cytokines, including IL-6, IL-11 and leukemia inhibitory factor did not affect MCP-1 levels to the same extent. In addition, OSM did not affect levels of the chemokines MIP1alpha and RANTES; indeed, only IL-1 significantly increased levels of MIP1alpha and RANTES. OSM treatment promoted the proliferation, migration and invasion in a dose-dependent manner, which were inhibited by MCP-1 silencing. The expression of phosphorylated-Akt, MMP-1, -2 and -3 were increased by OSM treatment; however, these increases were reversed following MCP-1 silencing. Collectively these data suggest that OSM promotes the differentiation of mouse MC3T3-E1 osteoblasts via regulation of MCP-1 expression. These results may therefore provide novel insights into bone repair and remodeling. PMID- 30015861 TI - LAMA4 expression is activated by zinc finger E-box-binding homeobox 1 and independently predicts poor overall survival in gastric cancer. AB - The present study aimed to investigate the association between the expression of ZEB1 and LAMA4 in gastric cancer and the possible underlying mechanisms of this. In addition, the present study also investigated the prognostic value of LAMA4 in gastric cancer. LAMA4, MMP2, MMP9 and ZEB1 expression and their associations were analyzed by data mining in The Cancer Genome Atlas-stomach adenocarcinoma (TCGA STAD). Overall survival (OS) curves of patients with gastric cancer were generated using data from TCGA and Kaplan-Meier plotting. Gastric cancer HGC-27 and SGC-7901 cell lines were used as in vitro cell models to assess the effect of LAMA4 on cell migration and invasion and to study the regulatory effect of ZEB1 on LAMA4 expression. The results of the present study indicated that LAMA4 upregulation was associated with higher grade tumors. LAMA4-knockdown significantly reduced MMP2 expression in gastric cancer cells and impaired the speed of wound healing and the invasive capability of the cancer cells. ZEB1 was strongly co-expressed with LAMA4 in TCGA-STAD (Pearson's r=0.85). Induced ZEB1 expression significantly increased LAMA4 expression at the mRNA and protein level in HGC-27 and SGC-7901 cells. A dual-luciferase assay confirmed that ZEB1 directly binded to the promoter of LAMA4. High LAMA4 expression independently predicted a poor OS (HR, 1.614; 95% CI, 1.155-2.256; P=0.005) in patients with primary gastric cancer. These results indicated that ZEB1 was able to epigenetically activate LAMA4 expression via binding to its promoter in gastric cancer cells. High LAMA4 expression was an independent indicator of a poor OS in patients with gastric cancer. PMID- 30015862 TI - Effect of phlorotannins on myofibroblast differentiation and ECM protein expression in transforming growth factor beta1-induced nasal polyp-derived fibroblasts. AB - Phlorotannins (PTNs), a group of phenolic compounds from seaweeds, have diverse bioactivities. However, there has been no report on their antifibrotic effects during nasal polyp (NP) formation. In the present study, the effect of PTNs on transforming growth factor (TGF)-beta1-induced profibrotic responses in nasal polyp-derived fibroblasts (NPDFs) were determined and the relevant signaling pathways were investigated. The expression levels of collagen type-1 (Col-1) and fibronectin in NP tissues were measured by western blot analysis and immunohistochemistry. The NPDFs were treated with TGF-beta1 (1 ng/ml) in the presence or absence of PTNs (5-30 ug/ml). The expression levels of alpha-smooth muscle actin (alpha-SMA), Col-1, fibronectin, and phosphorylated-small mothers against decapentaplegic (Smad)2/3 in NPDFs were measured by western blot analysis. The contractile activity of the NPDFs was determined by a collagen gel contraction assay. Col-1 and fibronectin proteins were found to be expressed in NP tissues. PTNs had no significant cytotoxic effect on TGF-beta1-induced NPDFs. TGF-beta1 induced the expression alpha-SMA, Col-1 and fibronectin, and stimulated fibroblast-mediated contraction of collagen gel. However, pre-treatment with PTNs inhibited the expression of these proteins. The inhibitory effects were mediated through the suppression of Smad2/3 signaling pathways in TGF-beta1-induced NPDFs. These resulted suggested that PTNs may be important in inhibiting myofibroblast differentiation and extracellular matrix protein accumulation in NP formation through the Smad2/3 signaling pathway. PMID- 30015863 TI - Loss of conserved ubiquitylation sites in conserved proteins during human evolution. AB - Ubiquitylation of lysine residues in proteins serves a pivotal role in the efficient removal of misfolded or unused proteins and in the control of various regulatory pathways by monitoring protein activity that may lead to protein degradation. The loss of ubiquitylated lysines may affect the ubiquitin-mediated regulatory network and result in the emergence of novel phenotypes. The present study analyzed mouse ubiquitylation data and orthologous proteins from 62 mammals to identify 193 conserved ubiquitylation sites from 169 proteins that were lost in the Euarchonta lineage leading to humans. A total of 8 proteins, including betaine homocysteine S-methyltransferase, clin and CBS domain divalent metal cation transport mediator 3, ribosome-binding protein 1 and solute carrier family 37 member 4, lost 1 conserved lysine residue, which was ubiquitylated in the mouse ortholog, following the human-chimpanzee divergence. A total of 17 of the lost ubiquitylated lysines are also known to be modified by acetylation and/or succinylation in mice. In 8 cases, a novel lysine evolved at positions flanking the lost conserved lysine residues, potentially as a method of compensation. We hypothesize that the loss of ubiquitylation sites during evolution may lead to the development of advantageous phenotypes, which are then fixed by selection. The ancestral ubiquitylation sites identified in the present study may be a useful resource for investigating the association between loss of ubiquitylation sites and the emergence of novel phenotypes during evolution towards modern humans. PMID- 30015865 TI - MicroRNA-665 suppresses the growth and migration of ovarian cancer cells by targeting HOXA10. AB - Ovarian cancer is the most lethal gynecological cancer and its metastasis leads to a poor prognosis. The present study was designed to elucidate how microRNA (miR)-665 regulates the proliferation and migration of ovarian tumor cells. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that miR 665 expression was decreased in ovarian cancer tissues. Increased expression of miR-665 suppressed the growth and migration of ovarian cancer cells, whereas the downregulated expression of miR-665 led to the opposite results. Bioinformatics tools identified homeobox A10 (HOXA10) as a target of miR-665. Following miR-665 overexpression, HOXA10 protein expression was significantly reduced. A dual luciferase assay revealed that miR-665 bound to the 3'-untranslated region of HOXA10. Immunohistochemistry and RT-PCR revealed that the expression of HOXA10 was negatively correlated with the expression of miR-665. It was concluded that miR-665 targets HOXA10 and may act as a tumor-suppressing gene in ovarian cancer. This pathway may be involved in the development and metastasis of ovarian cancer. PMID- 30015864 TI - Oxidative stress in electrohypersensitivity self-reporting patients: Results of a prospective in vivo investigation with comprehensive molecular analysis. AB - A total of 32 electrohypersensitivity (EHS) self-reporting patients were serially included in the present prospective study for oxidative stress and antioxidative stress response assessment. All thiobarbituric acid-reactive substances (TBARs) were measured in the plasma, particularly malondialdehyde (MDA) for lipid peroxidation; additional measurements included total thiol group molecules, reduced glutathione (GSH), oxidized glutathione (GSSG) for oxidative stress assessment and nitrotyrosine, a marker of peroxynitrite-induced oxidative/nitrosative stress. In addition, the activity of Cu-Zn superoxide dismutase (SOD1) was measured in red blood cells (RBCs) and glutathione reductase (GR) and glutathione peroxidase (GPx) in RBCs and plasma. Depending of the biomarker considered, 30-50% of EHS self-reporting patients presented statistically significantly increased TBARs, MDA, GSSG and NTT mean plasmatic level values in comparison with normal values obtained in healthy controls (P<0.0001). By contrast, there were no plasmatic level values above the upper normal limits for GSH, GSH/GSSG ratio, total glutathione (GluT) and GSH/GluT ratio, and values for these GSH-associated biomarkers were statistically significantly decreased in 20-40% of the patients (P<0.0001). Furthermore, in RBCs, mean SOD1 and GPx activities were observed to be statistically significantly increased in ~60% and 19% (P<0.0001) of the patients, respectively, while increased GR activity in RBCs was observed in only 6% of the patients. The present study reports for the first time, to the best of our knowledge, that overall ~80% of EHS self-reporting patients present with one, two or three detectable oxidative stress biomarkers in their peripheral blood, meaning that these patients-as is the case for cancer, Alzheimer's disease or other pathological conditions-present with a true objective new pathological disorder. PMID- 30015866 TI - Silencing GOLPH3 gene expression reverses resistance to cisplatin in HT29 colon cancer cells via multiple signaling pathways. AB - Golgi phosphorylated protein (GOLPH)3 is overexpressed in colorectal cancer tissues and promotes the proliferation of colon cancer cells. A previous study by the authors demonstrated that GOLPH3 was associated with poor prognosis in colorectal cancer. However, the association between GOLPH3 gene overexpression and resistance to platinum-based drugs in colon cancer remains unknown. In the present study, the association between GOLPH3 overexpression and resistance of HT29 colon cancer cells to cisplatin and the mechanism underlying the development of chemoresistance were investigated. HT29 cells were divided into five groups. The expression of GOLPH3 mRNA was measured in the control and siRNA transfection groups. Reverse transcription-quantitative polymerase chain reaction analysis, cell proliferation, colony formation assay, tumor sphere formation and apoptosis (Annexin V) assays, western blotting and a nude mouse tumorigenicity assay were performed. HT29 cells were resistant to 10 uM cisplatin treatment, whereas the expression of GOLPH3, P-glycoprotein, phosphorylated extracellular signal regulated kinase (pERK)1/2 and beta-catenin protein was significantly upregulated compared with the control group. With cisplatin treatment, silencing GOLPH3 gene expression downregulated the expression of these proteins, reduced cell proliferation and tumorigenicity, induced apoptosis and reversed the resistance of HT29 cells to cisplatin. In addition, the change in pERK1/2 and beta-catenin expression demonstrated that the mechanism of GOLPH3 overexpression involved in cisplatin resistance was associated with activation of the mitogen-activated protein kinase/ERK and Wnt/beta-catenin signaling pathways in HT29 cells. The tumorigenicity experiment in nude mice also demonstrated that silencing GOLPH3 expression increased the sensitivity of HT29 cells to cisplatin in vivo. Therefore, overexpression of GOLPH3 may be involved in the resistance of HT29 colon cancer cells to cisplatin chemotherapy by activating multiple cell signaling pathways. PMID- 30015867 TI - Long noncoding RNA UCA1 promotes anaplastic thyroid cancer cell proliferation via miR-135a-mediated c-myc activation. AB - The long non-coding RNA (lncRNA), urothelial carcinoma-associated 1 (UCA1), has been demonstrated to be dysregulated and serves a role in the progression of several cancer types. However, the exact effects and underlying molecular mechanisms of UCA1 in anaplastic thyroid cancer (ATC) remain unknown. The aim of the present study was to investigate the detailed function and the mechanism of UCA1 in the regulation of ATC cell progression. The present study identified that the expression levels of UCA1, in ATC cell lines and tissues, were significantly upregulated compared with normal human thyroid cell line and adjacent non cancerous tissues, respectively. UCA1 knockdown significantly inhibited ATC cell viability, proliferation, migration and invasion and the expression level of c myc proto-oncogene (c-myc) in vitro, and suppressed ATC tumor growth in vivo. In addition, using luciferase assays, it was confirmed that miR-135a directly bound to UCA1 and the 3' untranslated region of c-myc, and UCA1 competed with c-myc for miR-135a binding. miR-135a inhibition may upregulate c-myc expression, however, the upregulation of c-myc may be partially reduced by short hairpin UCA1. The present results illustrated that UCA1 promoted ATC cell proliferation through acting as a competing endogenous RNA by binding miR-135a. In conclusion, in the present study, UCA1 served as an oncogenic long non-coding RNA promoting ATC cell proliferation and may be a potential target for human ATC treatment. PMID- 30015868 TI - NT21MP negatively regulates paclitaxel-resistant cells by targeting miR-155-3p and miR-155-5p via the CXCR4 pathway in breast cancer. AB - Evidence has shown that microRNAs (miRNAs) are vital in cell growth, migration, and invasion by inhibiting their target genes. A previous study demonstrated that miRNA (miR)-155-3p and miR-155-5p exerted opposite effects on cell proliferation, apoptosis, migration and invasion in breast cancer cell lines. An miRNA microarray was used to show that miR-155-3p was downregulated whereas miR-155-5p was upregulated in paclitaxel-resistant (PR) cells compared with parental breast cancer cells. However, the role of miR-155 in breast cancer cell invasion and metastasis remains to be elucidated. A 21-residue peptide derived from the viral macrophage inflammatory protein II (NT21MP), competes with the ligand of CXC chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1alpha, inducing cell apoptosis in breast cancer. The present study aimed to identify the underlying mechanism of action of miR-155-3p/5p and NT21MP in PR breast cancer cells. Quantitative polymerase chain reaction, western blotting, wound-healing, cell cycle and apoptosis assays, and Cell Counting kit-8 assay were used to achieve this goal. The combined overexpression of miR-155-3p with NT21MP decreased the migration and invasion ability and increased the number of apoptotic and arrested cells in the G0/G1 phase transition in vitro. The knockdown of miR-155-5p combined with NT21MP had a similar effect on PR breast cancer cells. Furthermore, the ectopic expression of their target gene myeloid differentiation primary response gene 88 (MYD88) or tumor protein 53-induced nuclear protein 1 (TP53INP1) combined with NT21MP enhanced the sensitivity of the breast cancer cells to paclitaxel. Taken together, these findings suggested that miR-155-3p/5p and their target genes MYD88 and TP53INP1 may serve as novel biomarkers for NT21MP therapy through the CXCR4 pathway for improving sensitivity to paclitaxel in breast cancer. PMID- 30015870 TI - Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review). AB - High lactate production in cells during growth under oxygen-rich conditions (aerobic glycolysis) is a hallmark of tumor cells, indicating the role of mitochondrial function in tumorigenesis. In fact, enhanced mitochondrial biogenesis and impaired quality control are frequently observed in cancer cells. Mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS), is present in thousands of copies per cell, and has a very high mutation rate. Mutations in mtDNA and nuclear DNA (nDNA) genes encoding proteins that are important players in mitochondrial biogenesis and function are involved in oncogenic processes. A wide range of germline mtDNA polymorphisms, as well as tumor mtDNA somatic mutations have been identified in diverse cancer types. Approximately 72% of supposed tumor-specific somatic mtDNA mutations reported, have also been found as polymorphisms in the general population. The ATPase 6 and NADH dehydrogenase subunit genes of mtDNA are the most commonly mutated genes in breast cancer (BC). Furthermore, nuclear genes playing a role in mitochondrial biogenesis and function, such as peroxisome proliferators-activated receptor gamma coactivator-1 (PGC-1), fumarate hydratase (FH) and succinate dehydrogenase (SDH) are frequently mutated in cancer. In this review, we provide an overview of the mitochondrial germline variants and mutations in cancer, with particular focus on those found in BC. PMID- 30015869 TI - miR-577 suppresses cell proliferation and epithelial-mesenchymal transition by regulating the WNT2B mediated Wnt/beta-catenin pathway in non-small cell lung cancer. AB - MicroRNAs (miRNAs/miRs) serve important roles in regulating malignant phenotype in numerous cancers, such as non-small cell lung cancer (NSCLC); however, the role and function of miR-577 in NSCLC remains unknown. In the present study, miR 577 expression levels were observed to be downregulated in NSCLC via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay, and inhibited cell proliferation, cell migration and invasion and epithelial mesenchymal transition progress in NSCLC cells. The predicted target genes of miR 577 were determined by enhanced green fluorescent protein reporter assay, RT-qPCR and western blot analyses. miR-577 was demonstrated to suppress the expression of WNT2B by targeting the 3'-untranslated region of WNT2B mRNA in H522 and A549 cells. WNT2B was upregulated in NSCLC cells as observed via RT-qPCR analysis, and the malignant phenotype of H522 and A549 cells were promoted by WNT2B overexpression. In addition, miR-577 inactivated the Wnt/beta-catenin pathway by targeting WNT2B in NSCLC cells. Collectively, miR-577 may function as a suppressor gene by directly downregulatingWNT2B mRNA and protein expression levels in H522 and A549 cells, and may serve important roles in the malignancy of NSCLC. PMID- 30015871 TI - BECN1-knockout impairs tumor growth, migration and invasion by suppressing the cell cycle and partially suppressing the epithelial-mesenchymal transition of human triple-negative breast cancer cells. AB - Beclin1 (BECN1), which directly interacts with B-cell lymphoma 2, serves an important role in autophagy and is involved in the tumorigenesis of various types of cancer. However, the definite role of BECN1 in breast cancer remains controversial. Bi-allelic knockout of Becn1 in a mouse model leads to an embryonic lethal phenotype, which hampers further investigation. To generate cell lines with knockout of BECN1, the CRISPR/Cas9 technique was used to disrupt BECN1 in human triple-negative breast cancer (TNBC) MDA-MB-231 cells. To the best of our knowledge, the present study was the first to successfully disrupt BECN1 in MDA-MB-231 cells and to screen three stable monoclonal BECN1-knockout cell lines, suggesting that BECN1-knockout is not lethal in TNBC cells. Functional analysis revealed that complete loss of BECN1 suppressed MDA-MB-231 proliferation and colony formation via inducing G0/G1 cell cycle arrest, not apoptosis, in vitro. On the other hand, BECN1-knockout inhibited the migratory and invasive ability of MDA-MB-231 cells by partially reversing signals of epithelial-mesenchymal transition. Finally, analysis of publicly available gene expression datasets revealed increased expression of BECN1 in TNBC samples. Taken together, the results of the present study identified BECN1 as an oncogene, providing a novel potential target for the treatment of TNBC. PMID- 30015872 TI - Rottlerin promotes autophagy and apoptosis in gastric cancer cell lines. AB - It is widely accepted that apoptosis is closely associated with cancer cell death. However, whether autophagy induces tumor cell death has not been fully elucidated. Various studies have discussed the antitumor properties of rottlerin in human malignancies. The current study aimed to investigate the effects of rottlerin, a natural product isolated from the kamala tree (Mallotus philipensis), on growth inhibition and autophagy in gastric cancer (GC) cell lines in vitro. The results of the present study demonstrated that rottlerin suppressed cell growth, induced autophagy and apoptosis, and reduced migration and invasion in the SGC-7901 and MGC-803 GC cell lines. Furthermore, rottlerin led to microtubule-associated protein 1 light chain 3beta-II augmentation and the enrichment of autophagosomes. In addition, the protein expression levels of mechanistic target of rapamycin kinase and S-phase kinase-associated protein 2 were downregulated in GC cells following rottlerin treatment, which is associated with autophagy. The protein levels of caspase-3, cleaved-caspase-3, total poly (ADP-ribose) polymerase (PARP) and cleaved-PARP exhibited no marked alterations in the GC cells following rottlerin treatment, indicating that caspases were likely not involved in rottlerin-induced GC apoptosis. In summary, the results of the present study indicate that rottlerin may inhibit invasion and promote apoptosis in GC cells, which may be mediated by the activation of autophagy. Therefore, rottlerin may be of value in the treatment of GC. PMID- 30015874 TI - P2X7 receptor regulates EMMPRIN and MMP-9 expression through AMPK/MAPK signaling in PMA-induced macrophages. AB - The rupture of atherosclerotic plaques may result in the formation of thrombi, which may induce subsequent cardiac events such as acute myocardial infarction. Overproduction of matrix metalloproteinases (MMPs) and extracellular matrix metalloproteinase inducers (EMMPRINs) by monocytes and macrophages may lead to rupture of atherosclerotic plaques as a result of the degradation of the extracellular matrix. The purinergic 2X7 receptor (P2X7R) is expressed in macrophages that are assembled in atherosclerotic lesions of human carotid arteries. P2X7R may serve a crucial role in the development of atherosclerosis; therefore, the present study aimed to determine whether P2X7R regulated the expression of EMMPRIN and MMP-9 in phorbol 12-myristate 13-acetate (PMA)-induced macrophages. In addition, the potential molecular mechanisms involved in this process were investigated. THP-1 human monocytic cells were pretreated with A 438079 (a specific inhibitor of P2X7R) for 1 h and subsequently incubated with or without PMA for 48 h. Exposure to A-438079 significantly decreased the expression of MMP-9 and EMMPRIN in the PMA-induced macrophages and attenuated the activation (phosphorylation) of mitogen-activated protein kinase (MAPK) signaling, including c-Jun N-terminal kinase, p38 and extracellular signal-regulated kinase. The present study also demonstrated that 5'-AMP-activated protein kinase (AMPK) was activated by PMA exposure during differentiation from monocytes to macrophages. This activation was reversed by A-438079 treatment through the inhibition of P2X7R expression. These results suggested that the inhibition of P2X7R may be able to suppress the AMPK/MAPK signaling pathway and consequently downregulate both EMMPRIN and MMP-9 expression in PMA-induced macrophages. PMID- 30015873 TI - Effects of a checkpoint kinase inhibitor, AZD7762, on tumor suppression and bone remodeling. AB - Chemotherapy for suppressing tumor growth and metastasis tends to induce various effects on other organs. Using AZD7762, an inhibitor of checkpoint kinase (Chk) 1 and 2, the present study examined its effect on mammary tumor cells in addition to bone cells (osteoclasts, osteoblasts and osteocytes), using monolayer cell cultures and three-dimensional (3D) cell spheroids. The results revealed that AZD7762 blocked the proliferation of 4T1.2 mammary tumor cells and suppressed the development of RAW264.7 pre-osteoclast cells by downregulating nuclear factor of activated T cells cytoplasmic 1. AZD7762 also promoted the mineralization of MC3T3 osteoblast-like cells and 3D bio-printed bone constructs of MLO-A5 osteocyte spheroids. While a Chk1 inhibitor, PD407824, suppressed the proliferation of tumor cells and the differentiation of pre-osteoclasts, its effect on gene expression in osteoblasts was markedly different compared with AZD7762. Western blotting indicated that the stimulating effect of AZD7762 on osteoblast development was associated with the inhibition of Chk2 and the downregulation of cellular tumor antigen p53. The results of the present study indicated that in addition to acting as a tumor suppressor, AZD7762 may prevent bone loss by inhibiting osteoclastogenesis and stimulating osteoblast mineralization. PMID- 30015875 TI - ABT737 reverses cisplatin resistance by targeting glucose metabolism of human ovarian cancer cells. AB - The poor prognosis and high mortality of patients with ovarian cancer result in part from their poor response to platinum-based chemotherapy. However, the precise mechanism behind cisplatin resistance is still not fully understood. In the present study, the authors explored the mechanism of resistance to cisplatin from the perspective of glucose metabolism in human ovarian cancer. The experiments using genetically matched ovarian cancer cell lines SKOV3 (cisplatin sensitive) and SKOV3/DDP (cisplatin-resistant) in the present study provided some important findings. First, in comparison to SKOV3 cells, SKOV3/DDP cells exhibited decreased dependence on aerobic glycolysis and an increased demand for glucose. Secondly, the stable overexpression of Bcl-2 and ability to shift metabolism towards oxidative phosphorylation (OXPHOS) in SKOV3/DDP cells were associated with increased oxygen consumption. Furthermore, the metabolic characteristic of elevated OXPHOS primarily comprised most mitochondrial-derived reactive oxygen species (ROS) and, at least in part, contributed to the slight pro-oxidant state of SKOV3/DDP cells in turn. Thirdly, SKOV3/DDP cells reset the redox balance by overexpressing the key enzyme glucose 6-phosphate dehydrogenase (G6PD) of the pentose phosphate pathway to eliminate the cytotoxicity of highly elevated ROS. Furthermore, the inhibition of Bcl-2 reduced the OXPHOS and sensitivity of SKOV3/DDP cells to cisplatin in a selective manner. Furthermore, when combined with 2-deoxyglucose (2-DG), the anticancer effect of the Bcl-2 inhibitor ABT737 was greatly potentiated and hypoxia-inducible factor 1alpha (HIF 1alpha) appeared to be closely associated with Bcl-2 family members in the regulation of glucose metabolism. These results suggested that the special glucose metabolism in SKOV3/DDP cells might be selectively targeted by disrupting Bcl-2-dependent OXPHOS. PMID- 30015876 TI - miR-200b-3p inhibits proliferation and induces apoptosis in colorectal cancer by targeting Wnt1. AB - MicroRNA (miR)-200b-3p is downregulated in multiple human cancer types. Wnt signaling serves a role in human colorectal cancer (CRC). The present study aimed to examine the effect of miR-200b-3p on human CRC and its potential association with Wnt signaling. The Cell Counting Kit-8 (CCK-8) was employed to assess cell viability. A flow cytometric assay was conducted to examine cell proliferation and apoptosis. The regulation model of miR-200b-3p and Wnt1 was assessed by a luciferase reporter assay. A commercial kit was used to evaluate the activity of caspase-3 following treatment of the cells by miR-200b-3p or Wnt1. The expression of target factors was determined by a quantitative real-time polymerase chain reaction and western blot analysis. The expression of miR-200b-3p was decreased in human CRC tissues and in cell lines. The bioinformatics analysis and the luciferase reporter assay revealed that Wnt1 may be a direct target of miR-200b 3p. Moreover, the viability and proliferation of CRC cells was suppressed by miR 200b-3p. miR-200b-3p additionally induced apoptosis in CRC cells. Furthermore, the caspase-3 activity was enhanced in the miR-200b-3p mimics group. The expression of antigen Ki-67 (additionally termed KI-67) and beta-catenin was decreased, while the expression of cleaved caspase-3 was increased by miR-200b 3p. In conclusion, miR-200b-3p inhibited proliferation and induced apoptosis in CRC cells by inactivating Wnt/beta-catenin signaling. The present study provided potential biomarkers and candidate modalities for the management of CRC. PMID- 30015878 TI - Network-based gene function inference method to predict optimal gene functions associated with fetal growth restriction. AB - The guilt by association (GBA) principle has been widely used to predict gene functions, and a network-based approach may enhance the confidence and stability of the analysis compared with focusing on individual genes. Fetal growth restriction (FGR), is the second primary cause of perinatal mortality. Therefore, the present study aimed to predict the optimal gene functions for FGR using a network-based GBA method. The method was comprised of four parts: Identification of differentially-expressed genes (DEGs) between patients with FGR and normal controls based on gene expression data; construction of a co-expression network (CEN) dependent on DEGs, using the Spearman correlation coefficient algorithm; collection of gene ontology (GO) data on the basis of a known confirmed database and DEGs; and prediction of optimal gene functions using the GBA algorithm, for which the area under the receiver operating characteristic curve (AUC) was obtained for each GO term. A total of 115 DEGs and 109 GO terms were obtained for subsequent analysis. All DEGs were mapped to the CEN and formed 6,555 edges. The results of GBA algorithm demonstrated that 78 GO terms had a good classification performance with AUC >0.5. In particular, the AUC for 5 of the GO terms was >0.7, and these were defined as optimal gene functions, including defense response, immune system process, response to stress, cellular response to chemical stimulus and positive regulation of biological process. In conclusion, the results of the present study provided insights into the pathological mechanism underlying FGR, and provided potential biomarkers for early detection and targeted treatment of this disease. However, the interactions between the 5 GO terms remain unclear, and further studies are required. PMID- 30015877 TI - Rhaponticin decreases the metastatic and angiogenic abilities of cancer cells via suppression of the HIF-1alpha pathway. AB - Rhaponticin (RA; 3'5-dihydroxy-4'-methoxystilbene 3-O-beta-D-glucopyranoside) is a component isolated from various medicinal herbs including Rheum undulatum L. RA has been reported to be an effective treatment for allergy, diabetes, thrombosis, liver steatosis, lung fibrosis and colitis. In addition, RA effectively inhibits tumor growth and induces apoptosis; however, the effects of RA, at non-cytotoxic doses, on the metastasis and angiogenesis of malignant cancer cells have, to be the best of our knowledge, not been identified. In the present study, it was identified that RA suppressed the metastatic potential of MDA-MB231 breast cancer cells, including colony formation, migration and invasion. Human umbilical vein endothelial cells (HUVECs) treated with RA exhibited a decreased ability to form tube-like networks and to migrate across a Transwell membrane, when compared with RA-untreated HUVECs. Using the chick chorioallantoic membrane assay, RA treatment significantly suppressed spontaneous and vascular endothelial growth factor (VEGF)-induced angiogenesis. Furthermore, RA inhibited the production of pro angiogenic factors, including matrix metalloproteinase (MMP)-9, pentraxin-3, interleukin-8, VEGF and placental growth factor under normoxic and hypoxic conditions, and suppressed the phorbol 12-myristate 13-acetate-induced increase in the gelatinolytic MMP-9 activity and MMP-9 expression in HT1080 cells. RA also significantly inhibited the hypoxia-inducible factor (HIF)-1alpha pathway, leading to decreased HIF-1alpha accumulation and HIF-1alpha nuclear expression under hypoxia. These results indicated that RA exhibits potent anti-metastatic and anti-angiogenic activities with no cytotoxicity via suppression of the HIF 1alpha signaling pathway. Thus, RA may control malignant cancer cells by inhibiting the spread from primary tumors and expansion to distant organs. PMID- 30015879 TI - MiR-500a-5p promotes glioblastoma cell proliferation, migration and invasion by targeting chromodomain helicase DNA binding protein 5. AB - Glioblastoma is one of the most common malignant primary tumors and develops in brain. The molecular mechanism that regulates glioblastoma occurrence still remains unknown. MicroRNA (miR)-500a-5p has been reported to be involved in hepatocellular carcinoma and breast cancer. Whether miR-500a-5p regulates glioblastoma progression requires further investigation. In the present study, miR-500a-5p was highly expressed in malignant glioblastoma tissues and cell lines. Overexpression of miR-500a-5p promoted glioblastoma cell proliferation, migration and invasion in vitro. In addition, knockdown of miR-500a-5p accelerated cell apoptosis. Furthermore, miR-500a-5p inhibition significantly impaired tumor growth in vivo. The present study further explored the downstream mechanism. The luciferase reporter assay revealed that miR-500a-5p directly binds the 3'-untranslated region of chromodomain helicase DNA binding protein 5 (CHD5) mRNA. MiR-500a-5p markedly inhibited CHD5 expression in glioblastoma cells. Furthermore, CHD5 was downregulated in glioblastoma tissues, and the expression levels of miR-500a-5p and CHD5 were inversely correlated. In addition, knockdown of CHD5 restored the inhibition of cell proliferation and migration triggered by miR-500a-5p silence. Finally, it was demonstrated that miR-500a-5p can serve as a novel biomarker for the diagnosis and prognosis of glioblastoma patients. Taken together, the results of the present study indicated that miR-500a-5p may have promoted glioblastoma development and progression by targeting CHD5. PMID- 30015883 TI - Circular RNA-MTO1 suppresses breast cancer cell viability and reverses monastrol resistance through regulating the TRAF4/Eg5 axis. AB - Circular RNAs (circRNAs), a class of endogenous RNAs, have emerged as an enigmatic class of genes. However, little is known about their value in the progression and chemoresistance of cancers. The present study sought to determine the expression profiles and potential modulatory role of circRNAs on breast cancer cell viability and monastrol resistance. Monastrol-resistant cell lines were established by exposing breast cancer cells to increasing concentrations of monastrol. A human circRNA microarray was used to search for dysregulated circRNAs in monastrol-resistant cells, then circRNA-MTO1 (hsa-circRNA-007874) was validated as a circRNA that exhibited elevated expression levels in monastrol resistant cells. Mechanistic investigations suggested that upregulation of circRNA-MTO1 suppressed cell viability, promoted monastrol-induced cell cytotoxicity and reversed monastrol resistance. Subsequently, Eg5 was identified as the functional target of circRNA-MTO1, and MTO1 inhibited Eg5 protein level but not mRNA level. By treating with protein synthesis inhibitor cycloheximide (CHX), it was revealed that MTO1 did not affect the protein stability of Eg5. RNA pull down experiments followed by mass spectrometry revealed that MTO1 interacted with tumor necrosis factor receptor associated factor 4 (TRAF4), and sequester TRAF4 from activating Eg5 translation, thereby inhibiting the Eg5 protein level. Taken together, the data reveal a regulatory mechanism by circRNA-MTO1 to control cell viability and monastrol resistance in breast cancer cells. PMID- 30015882 TI - Protection of mouse pancreatic islet function by co-culture with hypoxia pre treated mesenchymal stromal cells. AB - Ectogenic pancreatic islet transplantation has long been discussed as having the potential to reverse diabetes. The aim of the present study was to evaluate the therapeutic efficacy of co-transplantation with hypoxia pretreated mesenchymal stem cells (MSCs) and islets in a diabetic mouse model. MSCs were isolated from femoral and tibial bone marrow aspirates from female BALB/c donor mice. MSC proliferation rates and the expression levels of vascular endothelial growth factor A (VEGFA), interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9 were measured in hypoxic conditions. Subsequently, a streptozotocin-induced diabetic model was established in BALB/c mice. Glucose tolerance and diabetes reversal rate following co-transplantation of hypoxia pre-cultured MSCs and islets were demonstrated at different conditions during transplantation. The present study results demonstrated that MSCs increased their proliferation rate and the secretion of growth-related cytokines, including VEGFA, IL-6, MCP-1 and MMP-9 in a hypoxic environment. In the diabetes animal model, fewer islets (~250) were required to reverse the impaired glucose tolerance condition in Islets + Hypoxia cultured MSCs transplant group compared with the Islets-only group (~400 islets) and the Islets + Normal cultured MSCs group (~300 islets). Hypoxia-cultured MSC co-transplantation accelerated glycemic utilization following glucose intake. In subjects with hyperglycemia control for islet only transplantation group, MSCs pre-cultured in hypoxic condition prior to co-transplantation may potentially improve islet tissue regeneration. PMID- 30015880 TI - NLRP3 in human glioma is correlated with increased WHO grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway. AB - Glioma is the most prevalent and fatal primary tumor of the central nervous system in adults, while the development of effective therapeutic strategies in clinical practice remain a challenge. Nucleotide-binding domain leucine-rich family pyrin-containing 3 (NLRP3) has been reported to be associated with tumorigenesis and progression; however, its expression and function in human glioma remain unclear. The present study was designed to explore the biological role and potential mechanism of NLRP3 in human glioma. The results demonstrated that overexpression of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1 and interleukin (IL)-1beta protein in human glioma tissues were significantly correlated with higher World Health Organization grades. The in vitro biological experiments demonstrated that NLRP3 downregulation significantly inhibited the proliferation, migration and invasion, and promoted the apoptosis of SHG44 and A172 glioma cell lines. Furthermore, western blot assays revealed that the downregulation of NLRP3 significantly reduced the expression of ASC, caspase-1 and IL-1beta protein. Furthermore, NLRP3 knockdown caused the inhibition of epithelial-mesenchymal transition (EMT), and inhibited the phosphorylation of AKT serine/threonine kinase (AKT) and phosphorylation of phosphatase and tensin homolog (PTEN). Consistently, the upregulation of NLRP3 significantly increased the expression of ASC, caspase-1, IL-1beta and phosphorylated-PTEN, promoted proliferation, migration, invasion and EMT, inhibited apoptosis, and activated the AKT signaling pathway. The data of the present study indicate that NLRP3 affects human glioma progression and metastasis through multiple pathways, including EMT and PTEN/AKT signaling pathway regulation, enhanced inflammasome activation, and undefined inflammasome independent mechanisms. Understanding the biological effects of NLRP3 in human glioma and the underlying mechanisms may offer novel insights for the development of glioma clinical therapeutic strategies. PMID- 30015881 TI - MicroRNA-155 promotes ox-LDL-induced autophagy in human umbilical vein endothelial cells by targeting the PI3K/Akt/mTOR pathway. AB - Endothelial cell autophagy has a protective role in inhibiting inflammation and preventing the development of atherosclerosis, which may be regulated by microRNA (miR)-155. The present study aimed to investigate the mechanisms of autophagy in the development of atherosclerosis. Human umbilical vein endothelial cells model in vitro and using oxidized low-density lipoprotein (ox-LDL) stimulated cells to simulate the atherosclerosis. MiR-155 mimics, miR-155 inhibitors, and a negative control were respectively transfected in human umbilical vein endothelial cells to analyzed alterations in the expression of miR-155. It was demonstrated that overexpression of miR-155 promoted autophagic activity in oxidized low-density lipoprotein-stimulated human umbilical vein endothelial cells, whereas inhibition of the expression of miR-155 reduced autophagic activity. Overexpression of miR 155 revealed that it regulated autophagy via the phosphatidylinositol-3 kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (Akt)/mechanistic target of rapamycin pathway (mTOR) signaling pathway. A luciferase reporter assay demonstrated that miR-155 directly bound to the PI3K catalytic subunit a and Ras homolog enriched in brain 3'-untranslated region and inhibited its luciferase activity. Therefore, the results of the present study suggested that miR-155 promoted autophagy in vascular endothelial cells and that this may have occurred via targeting of the PI3K/Akt/mTOR pathway. Thus, miR-155 may be considered as a potential therapeutic target for the treatment of atherosclerosis. PMID- 30015884 TI - Investigation of the role of cullin 4A overexpression in human liver cancer. AB - Cullin 4A (CUL4A) is the major component of cullin-RING-based E3 ubiquitin protein ligase complexes, which regulate the ubiquitination of target proteins. The overexpression of CUL4A has been associated with the development and progression of various cancer types. However, a detailed understanding of the role of CUL4A in human liver cancer has not been determined by previous studies. In the present study, the association between human liver cancer and CUL4A expression was investigated. The expression of CUL4A in liver cancer tissues and paracancerous tissues of patients was investigated by reverse transcription quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Overexpression and knockdown of CUL4A were induced with an overexpression vector and small interfering RNA transfection, respectively, in human liver cancer cell lines, and the effects on cell proliferation were analyzed by a Cell Counting Kit-8 assay to investigate the role of CUL4A in human liver cancer. Cell migration, invasion, apoptosis and the cell cycle were also analyzed following transfection. The results of the present study revealed that the mRNA and protein expression of CUL4A was increased in the liver cancer tissues compared with the paracancerous tissues of 3 patients. Additionally, the results demonstrated that downregulation of CUL4A expression inhibited cell proliferation, migration and invasion, and increased the percentage of cell apoptosis, in HEPG2 and MHCC97-H cells, while CUL4A overexpression led to the opposite effects. Therefore, the results of the current study indicated that CUL4A may serve an important role in the development and progression of human liver cancer, and highlights the potential of CUL4A as a novel target in the diagnosis and treatment of human liver cancer and potentially other cancer types. PMID- 30015885 TI - Candidate genes and microRNAs for glioma pathogenesis and prognosis based on gene expression profiles. AB - Glioma is the most common malignant brain tumor, and the incidence of glioma demonstrates an upward trend. It is vital to elucidate the pathogenesis of glioma and seek effective therapies. The aim of the present study was to identify the potential gene markers associated with glioma based on GSE31262 gene expression profiles, and to explore the underlying mechanism of glioma progression by analyzing the gene markers. The microarray dataset GSE31262 was downloaded and neural stem cell samples (control group) and glioma samples (glioma group) were analyzed to identify the differentially expressed genes (DEGs) between the two groups. Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using DAVID software. Subsequently, a protein-protein interaction (PPI) network was constructed and important modules were extracted from this network. Additionally, the miRNA-target regulatory network was established. In total, 1377 DEGs with P<0.01 and |log2 fold change| >=2 were identified between the control and glioma groups. The DEGs that were upregulated in glioma samples compared with controls were primarily associated with functions such as the M phase and cell cycle pathway, while the downregulated genes were associated with functions such as nerve impulse and the axon guidance pathway. The results also indicated that certain DEGs, including cyclin-dependent kinase 1 (CDK1) and cadherin 1 (CDH1), had important roles in the PPI network. The MCODE tool in Cytoscape software was used to identify upregulated and downregulated modules in the PPI network, and 5 upregulated and 2 downregulated modules were extracted. Furthermore, the WebGestal online tool was used to identify potential interactions of the upregulated and downregulated genes with microRNAs (miRNA/miR), and miR-135A/B and its two targets, discs large MAGUK scaffold protein 2 and forkhead box O1 (FOXO1), had the highest number of connections in the miRNA-target regulatory network. In addition, cell division cycle 20 and FOXO1 were confirmed to be upregulated in U87 glioma cells compared with normal human astrocytes (HA1800) by reverse transcription-quantitative polymerase chain reaction. In conclusion, M phase function and the axon guidance pathway may be vital for glioma progression. In addition, CDK1 and CDH1 may be associated with the process of glioma. Furthermore, miR-135A/B, and the target FOXO1, may be potential therapy targets for glioma treatment. PMID- 30015886 TI - Candidate gene and mechanism investigations in congenital obstructive nephropathy based on bioinformatics analysis. AB - The aim of the present study was to explore the candidate genes, chemicals and mechanisms of congenital obstructive nephropathy (CON). The gene expression profiles of GSE48041, including 24 kidney tissue samples from megabladder (mgb-/ ) mouse were downloaded from the Gene Expression Omnibus database. Samples were divided into 4 groups: Control, mild, moderate and severe. Differentially expressed genes (DEGs), protein-protein interaction network, Kyoto Encyclopedia of Genes and Genomes pathways and transcription factor (TF)-target gene analyses were performed on Set 1 (mild, moderate and severe groups), while Gene Ontology (GO) function enrichment analysis and chemical investigation were performed on Set 2 (severe group). A total of 187 and 139 DEGs were obtained in Set 1 and Set 2, respectively. Chemical carcinogenesis [enriched by genes such as Carbonyl reductase 1 (CBR1)] was one of the most prominent pathways in Set 1. GO analysis for Set 2 revealed that DEGs were mainly assembled in functions such as cellular response to interleukin-1 and cellular response to tumor necrosis. Furthermore, genes such as Fos Proto-Oncogene (FOS) were co-regulated by TFs including RNA polymerase II subunit A (Polr2a) and serum response factor (Srf). Chemical cyclosporine served the most important role in Set 2 by targeting several DEGs in Set 2. DEGs such as CBR1 and FOS, TFs including Polr2a and Srf, and pathways such as chemical carcinogenesis may serve important roles in the process of CON. Interleukin-1 and tumor necrosis function may be novel targets for CON gene therapy. Furthermore, cyclosporine may be a promising option for future CON therapy. PMID- 30015888 TI - Altered susceptibility to apoptosis and N-glycan profiles of hematopoietic KG1a cells following co-culture with bone marrow-derived stromal cells under hypoxic conditions. AB - Mesenchymal stromal cells are an important component of the bone marrow microenvironment (niche), where they support hematopoiesis via direct cell-cell interactions with hematopoietic stem and progenitor cells, and by releasing soluble factors. Glycans, including N-glycans, are involved in numerous biological processes, including inflammation, cell-cell interactions, as well as cancer development and progression. Lectin-based microarray analysis has provided a powerful new tool in recent years, for the investigation of aberrantly expressed N-glycans and their functions in the bone marrow microenvironment. In the present study, we used an in vitro stromal/hematopoietic cell co-culture system to examine the effects of stromal-derived signals on apoptosis susceptibility of co-cultured KG1a hematopoietic cells under hypoxic (1% O2) conditions. MALDI-TOF/TOF-MS analysis was used for the comparative global profiling of N-glycans in KG1a cells and co-cultured KG1a cells under hypoxia. KG1a cells became more susceptible to p53-dependent apoptosis when co-cultured with HS27A human stromal cells (derived from normal bone marrow) under hypoxia. We observed enhanced levels of core-fucosylated N-glycans (catalyzed by FUT8), bisecting GlcNAc (catalyzed by MGAT3), and their corresponding genes in co cultured cells. In addition we observed that overexpressing MGAT3 or FUT8 facilitated cell apoptosis in KG1a cells. Collectively, our data revealed the profiling of N-glycans in KG1a cells before and after stroma contact. Our findings and future functional studies of core-fucosylated N-glycans and bisecting GlcNAc, will improve our understanding of the bone marrow microenvironment. PMID- 30015887 TI - Quercetin-3-O-beta-D-glucoside decreases the bioavailability of cyclosporin A through regulation of drug metabolizing enzymes, transporters and nuclear receptors in rats. AB - Quercetin is a flavonoid compound that is widely present in food and drink. Quercetin-3-O-beta-D-glucoside (Q3GA) is a major metabolite of quercetin. The aim of the present study was to investigate the effect of Q3GA on the pharmacokinetics of orally and intravenously administered cyclosporin A (CsA) in rats, and to assess the effect of Q3GA on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs). The pharmacokinetic parameters of CsA were measured following oral (10 mg/kg) and intravenous (2.5 mg/kg) administration of CsA in the presence or absence of Q3GA. The mRNA and protein expression levels of DMEs, DTs and NRs in the liver and small intestine were detected by quantitative polymerase chain reaction and western blot analysis. The results indicated that the intravenous administration of Q3GA (2.5, 5 or 10 mg/kg) for 7 consecutive days reduced the bioavailability of oral CsA. By contrast, the pharmacokinetics of the intravenous administration of CsA were not affected by Q3GA. However, the mRNA and protein expression levels of DMEs and DTs were inhibited by Q3GA. The activation of DMEs and DTs by NRs, and the interplay between DMEs and DTs, may explain these results. The present study identified a novel flavonoid-drug interaction, which may have implications for patients taking CsA and quercetin supplements or on a quercetin-containing diet. PMID- 30015889 TI - Astragalin and dihydromyricetin as adjuncts to histidine-tryptophan-ketoglutarate cardioplegia enhances protection during cardioplegic arrest. AB - The present study used an in vitro model of cold cardioplegia in isolated working rat hearts to evaluate the possible effects of two flavonoids, astragalin and dihydromyricetin, as adjuncts to histidine-tryptophan-ketoglutarate (HTK) cardioplegia. The following three groups of male Sprague Dawley rats were evaluated: The HTK group, treated with HTK alone; the HTK-A group, treated with 10 umol/l astragalin; and the HTK-D group, treated with 10 umol/l dihydromyricetin. Isolated rat hearts were perfused with Krebs-Henseleit buffer for 30 min and incubated with the respective cardioplegic solution for 6 h at 4C. Subsequently, astragalin or dihydromyricetin was added to the cardioplegic solutions. Following 30 min of reperfusion, the left ventricular developed pressure (LVDP), maximum up/down rate of left ventricular pressure (+/-dp/dtmax) and heart rate were documented as indices of myocardial function using a physiological recorder. Myocardial infarct size (IS) was estimated using 2,3,5 triphenyltetrazolium chloride staining. Lactate dehydrogenase (LDH) and creatine kinase (CK) levels were also determined to assess the degree of cardiac injury. Cardiomyocyte apoptosis analysis was performed using an in situ cell death detection kit. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP) levels, as well as the glutathione/glutathione disulfide (GSH/GSSG) ratio were determined and analyzed using ELISA kits. The protein levels of caspase-9 and B-cell lymphoma-2 (Bcl-2) were determined using western blot analysis. The results demonstrated that exposure to astragalin or dihydromyricetin significantly improved the recovery of LVDP (P<0.05 and P<0.01, respectively), the +dP/dtmax (P<0.05 for dihydromyricetin only) and the -dP/dtmax (P<0.05 and P<0.01, respectively), increased SOD levels (P<0.05 and P<0.01, respectively) and GSH/GSSG ratios (P<0.05), reduced myocardial IS (P<0.05 and P<0.01, respectively), decreased CK, LDH, IL-6 (all P<0.05 and P<0.01, respectively), MDA (P<0.05), CRP (P<0.05) and TNF-alpha levels (P<0.05 and P<0.01, respectively), increased Bcl-2 levels (P<0.01) and decreased caspase-9 levels (P<0.01). The results indicated that the addition of either flavonoid (particularly dihydromyricetin) to HTK enhances protection during ischemia, decreases myocardial dysfunction by enhancing anti-inflammatory activities, attenuates myocardial oxidative injury and prevents apoptosis during ischemia/reperfusion. PMID- 30015890 TI - Homeobox containing 1 inhibits liver cancer progression by promoting autophagy as well as inhibiting stemness and immune escape. AB - Homeobox containing 1 (HMBOX1) is a novel transcription repressor that is significantly downregulated in human liver cancer tissues and cell lines, but the exact biological function of HMBOX1 in liver cancer is still unknown. We observed a negative association between HMBOX1 expression level and the clinical stages of liver cancer. HMBOX1 also increased the LC3 II/LC3 I ratio, the endogenous autophagy marker, and inhibited the p38/AKT/mTOR pathway. Furthermore, cancer stem cell specific genes, including CD133, KLF4, ESG1 and SOX2, were significantly downregulated upon HMBOX1 overexpression. Finally, the susceptibility of HepG2 cells to NK cell-mediated cytolysis was increased by HMBOX1 overexpression and weakened by siRNA-mediated inhibition of HMBOX1. All these findings indicated that HMBOX1 expression in hepatocytes could protect against the progression of liver cancer, and the underlying mechanisms may include promoting autophagy, inhibiting CSC phenotype and increasing the sensitivity of tumor cells to NK cell cytolysis. Therefore, HMBOX1 may be useful for developing new treatments for liver cancer. PMID- 30015891 TI - Differential responses of GC-1 spermatogonia cells to high and low doses of bisphenol A. AB - Bisphenol A (BPA) is an environmental endocrine disruptor. The exact effect of BPA on spermatogenesis and the specific epigenetic effects on mouse spermatogonia remain to be elucidated. The present study exposed the GC-1 spermatogonial cell line to a series of differing BPA concentrations and examined the subsequent effects on cell proliferation, mitogen activated protein kinase (MAPK) signaling, DNA and histone methylation. A Cell Counting Kit-8 assay revealed that BPA significantly inhibited cell growth at the concentration of 10 ug/ml, however no significant alterations were detected at lower BPA doses. The global DNA methylation levels were reduced at the dose of 10 ug/ml of BPA, via detection of 5-methylcytosine using a dot blot. The protein and mRNA expression levels of DNA methyltransferase (DNMT) 1 were decreased at 10 and 1 ug/ml of BPA, detected via western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. The global levels of H3K27me3 was decreased at 10 ug/ml BPA, detected via western blotting. Increased phosphorylation of p38 and decreased phosphorylation of extracellular signal-regulated kinases 1/2 were observed at 10 and 1 ug/ml BPA. The results demonstrated that high and low doses of BPA exposure exhibit differential effects on cell growth, global DNA methylation, histone H3K9Me3 and H3K27Me3 levels and additionally affect the MAPK signaling pathways. PMID- 30015892 TI - 'Psoriasis 1' reduces psoriasis-like skin inflammation by inhibiting the VDR mediated nuclear NF-kappaB and STAT signaling pathways. AB - 'Psoriasis 1', a Chinese herbal medicine (CHM) formulation, is extensively used to treat psoriasis in China. Although this CHM formulation yields good therapeutic effect, the underlying mechanism of how this works remains unknown. The present study aimed to test the hypothesis that the CHM formulation 'psoriasis 1' inhibits vitamin D receptor (VDR)-mediated inflammation in psoriasis. To test this, a model of psoriasis was established by stimulating keratinocytes (HaCaT cells) with tumor necrosis factor (TNF)-alpha; these cells were subsequently transfected with a lentiviral VDR RNA interference expression vector. The expression levels of 25-hydroxyvitamin D3 (25HVD3), TNF-alpha, interleukin (IL)-4, IL-1, IL-17C, IL-23 and IL-6 were measured using ELISA, and the expression levels of VDR, inhibitor of nuclear factor (NF)-kappaB (IKK), NF kappaB, signal transducer and activator of transcription (STAT) 3 and STAT4 were measured using reverse transcription-quantitative polymerase chain reaction analysis and western blotting. It was observed that 'psoriasis 1' downregulated the concentrations of TNF-alpha, IFN-gamma, IL-22, IL-17C, IL-1beta and IL-4, and upregulated the concentration of 25HVD3; furthermore, 'psoriasis 1' downregulated the expression levels of NF-kappaB, phosphorylated (p)-NF-kappaB, IKK, p-IKK, STAT3, p-STAT3, STAT4 and p-STAT4, and upregulated the expression level of VDR in TNF-alpha-induced HaCaT cells. These results suggested that 'psoriasis 1' suppressed the inflammatory response and the activation of the NF-kappaB and STAT signaling pathways. In addition, it was identified that silencing VDR expression decreased the levels of TNF-alpha, IFN-gamma, IL-22, IL-17C, IL-1beta and IL-4, and increased the level of 25HVD3; silencing VDR expression additionally downregulated the expression levels of NF-kB, p-NF-kB, IKK, p-IKK, STAT3, p STAT3, STAT4 and p-STAT4, and upregulated the level of VDR in TNF-alpha-induced HaCaT cells. It was concluded that 'psoriasis 1' exerts inflammation-suppressive effects in psoriasis by suppressing the NF-kB and STAT signaling pathways. PMID- 30015893 TI - Comprehensive analysis of gene expression profiles provides insight into the pathogenesis of Crohn's disease. AB - Crohn's disease (CD) is a type of inflammatory bowel disease that cannot be fully cured by medication or surgery. In the present study, the aim was to understand the underlying mechanisms of CD. Two CD microarray datasets were downloaded from The Gene Expression Omnibus database: GSE36807 (13 CD and 7 normal samples) and GSE59071 (8 CD and 11 normal samples). A series of bioinformatics analyses were conducted, including weighted gene co-expression network analysis to identify stable modules, and analysis of differentially expressed genes (DEGs) between CD and normal samples. The common DEGs in the GSE36807 and GSE59071 datasets were screened. Subsequently, overlapping genes in the stable modules and the DEGs were selected to construct a protein-protein interaction (PPI) network using Cytoscape software. Enrichment analysis of genes in the network was performed to explore their biological functions. A total of 10 stable modules and 927 DEGs were identified, of which 234 genes were shared in the stable modules and the DEGs. After removal of 32 uncharacterized genes, 202 genes were selected to build the PPI network. Low density lipoprotein receptor (LDLR), toll-like receptor 2 (TLR2), lipoprotein lipase (LPL), forkhead box protein M1 (FOXM1) and neuropeptide Y (NPY) were revealed as key nodes with high degree. Pathway enrichment analysis demonstrated that LPL was enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In conclusion, LDLR, TLR2, FOXM1 and NPY, as well as LPL in the PPAR signaling pathway may serve critical roles in the pathogenesis of CD. PMID- 30015895 TI - Downregulation of hypoxia-inducible factor-1alpha inhibits growth, invasion, and angiogenesis of human salivary adenoid cystic carcinoma cells under hypoxia. AB - Surgical and medical treatments usually fail to completely remove the primary lesions of salivary adenoid cystic carcinoma (SACC), resulting in local recurrence due to its strong infiltration, hematogenous metastasis and other unique biological behaviors. Targeted gene therapy, including hypoxia-inducible factor-1alpha (HIF-1alpha) therapy, sheds new light on the treatment of salivary gland tumors. However, the mechanisms underlying the downregulation of HIF-1alpha expression in SACC have not been well studied. The present study aimed to determine the effects of HIF-1alpha downregulation on the proliferation, invasion, apoptosis, cell cycle and angiogenesis of hypoxic SACC-83 cells, and to elucidate the molecular mechanisms underlying these effects. Western blot analysis was used to evaluate the protein expression levels of HIF-1alpha and matrix metalloproteinase-2 (MMP-2). Angiogenesis and the protein expression of vascular endothelial growth factor (VEGF) were detected by tube formation assay of human umbilical vein endothelial cells and ELISA, respectively. It was revealed that short hairpin RNA was considerably downregulated following overexpression of HIF-1alpha. In addition, downregulation of HIF-1alpha inhibited the expression of VEGF and MMP-2, as well as the proliferation, invasion, migration, and tube formation of hypoxic SACC-83 cells, while inducing apoptosis in these cells. These results suggest that the downregulation of HIF-1alpha may be a novel targeted therapy for SACC. PMID- 30015894 TI - Rapid diagnosis of human adenovirus B, C and E in the respiratory tract using multiplex quantitative polymerase chain reaction. AB - Human adenovirus (HAdV) is increasingly recognized as a major cause of human respiratory tract viral infections. Its outbreaks and epidemics in various populations resulted in considerable morbidity and mortality. Therefore, a rapid and specific assay for HAdV in clinical samples is of crucial importance to diagnosing HAdV infections. The present study aimed to develop and evaluate a multiplex quantitative polymerase chain reaction (qPCR) assay for the rapid detection and accurate quantification of HAdV B, C and E. The lower limit of detection for this assay was two genomic copies per reaction, and quantitative linearity ranged from 2 to 2x106 copies per reaction of the input viral DNA. Furthermore, 3,160 throat swab samples that tested HAdV negative by the immunofluorescence assay were collected and retested using the multiplex qPCR assay. The results showed that 2,906 samples were HAdV negative and the other 254 samples were HAdV positive. The HAdV species identified included B (184 samples), C (51 samples), and E (39 samples). Among the three HAdV species, HAdV B and E were detected from 8 samples, and HAdV C and E were detected from other 12 samples. The overall results demonstrated that the sensitivity and specificity of the proposed assay were 100% (254/254) and 99.6% (2894/2906), respectively. From the perspective of routine clinical diagnosis, this assay represented a rapid (<=1.5 h) and economic strategy, and had the potential to be used for the rapid and accurate diagnosis of human respiratory infections caused by HAdV B, C and E. PMID- 30015896 TI - SH2B1 protects against OGD/R-induced apoptosis in PC12 cells via activation of the JAK2/STAT3 signaling pathway. AB - Apoptosis acts as the primary pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Prior studies have revealed the effects of src homology 2 (SH2)B adaptor protein 1 (SH2B1) in myocardial infarction; however, involvement of SH2B1 in cerebral I/R injury and the underlying mechanisms remain to be investigated. In the present study, neural-like PC12 cells underwent 6 h of oxygen-glucose deprivation (OGD) followed by 24 h of reoxygenation (OGD/R). PC12 cells were pre transfected with an adenovirus encoding for SH2B1 or GFP prior to exposure to OGD/R. Cell viability, LDH release and the apoptotic cascade were investigated. Reverse transcription-quantitative polymerase chain reaction and western blotting were employed to analyze mRNA and protein expression levels, respectively. The results of the present study revealed that OGD/R reduced SH2B1 expression in PC12 cells, accompanied by suppressed cell viability and enhanced cell death. Adenovirus-mediated SH2B1 overexpression, however, resulted in increased viability, reduced LDH release and a reduction in the expression levels of proteins associated with the apoptotic cascade in PC12 cells under the OGD/R condition. A mechanistic explanation may be that the positive effects of SH2B1 on neurons were in part derived from the activation of the JAK2/STAT3 signaling pathway. Furthermore, abolishment of JAK2/STAT3 signaling using a pharmacological inhibitor suppressed the inhibitory effects of SH2B1 under the OGD/R condition. The results of the present study suggested that SH2B1 may protect PC12 cells from OGD/R injury partially by the JAK2/STAT3-dependent inhibition of apoptosis and may provide a novel therapeutic target for the treatment of cerebral I/R injury. PMID- 30015897 TI - PTEN enhances nasal epithelial cell resistance to TNFalpha-induced inflammatory injury by limiting mitophagy via repression of the TLR4-JNK-Bnip3 pathway. AB - Nasal epithelial cell inflammatory injury is associated with chronic obstructive pulmonary disease development. However, the mechanism by which inflammation triggers nasal epithelial cell damage remains unclear. In the present study, tumor necrosis factor (TNF)alpha was used to induce an inflammatory injury and explore the underlying pathogenesis for nasal epithelial cell apoptosis in vitro, with a focus on mitochondrial homeostasis. Then, cellular apoptosis was detected via a terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay and western blotting. Mitochondrial function was evaluated via JC-1 staining, mPTP opening measurement and western blotting. The results demonstrated that TNFalpha treatment induced nasal epithelial cell apoptosis, proliferation arrest and migration inhibition via downregulating phosphatase and tensin homolog (PTEN) levels. Increased PTEN expression was associated with reduce Toll-like receptor (TLR)4-c-Jun kinase (JNK)-Bcl2-interacting protein 3 (Bnip3) pathway signaling, leading to reductions in mitophagy activity. Excessive mitophagy resulted in ATP deficiencies, mitochondrial dysfunction, caspase-9 activation and cellular apoptosis. By contrast, PTEN overexpression in nasal epithelial cells alleviated the mitochondrial damage and cellular apoptosis via inhibiting the TLR4-JNK-Bnip3 pathway, favoring the survival of nasal epithelial cells under inflammatory injury. Therefore, this data uncovered a potential molecular basis for nasal epithelial cell apoptosis in response to inflammatory injury, and PTEN was identified as the endogenous defender of nasal epithelial cell survival via controlling lethal mitophagy by inhibiting the TLR4-JNK-Bnip3 pathway, suggesting that this pathway may be a potential target for clinically treating chronic nasal and sinus inflammatory injury. PMID- 30015898 TI - TMEM165, a Golgi transmembrane protein, is a novel marker for hepatocellular carcinoma and its depletion impairs invasion activity. AB - Transmembrane protein 165 (TMEM165), a Golgi protein, functions in ion homeostasis and vesicular trafficking in the Golgi apparatus. While mutations in TMEM165 are known to cause human 'congenital disorders of glycosylation', a recessive autosomal metabolic disease, the potential association of this protein with human cancer development has not been explored to date. In the present study, we revealed that TMEM165 is overexpressed in HCC and its depletion weakens the invasive activity of cancer cells through suppression of matrix metalloproteinase-2 (MMP-2) expression. Levels of TMEM165 mRNA and protein were clearly increased in HCC patient tissues and cell cultures. Quantitative real time RT-PCR analysis of fresh HCC tissues (n=88) revealed association of TMEM165 overexpression with more frequent macroscopic vascular invasion, microscopic serosal invasion and higher alpha-fetoprotein levels. Notably, depletion of TMEM165 led to a marked decrease in the invasive activity of two different HCC cell types, Huh7 and SNU475, accompanied by downregulation of MMP-2. Our collective findings clearly indicated that TMEM165 contributed to the progression of HCC by promoting invasive activity, supporting its utility as a novel biomarker and therapeutic target for cancer. PMID- 30015900 TI - Suppression of Elk1 inhibits thyroid cancer progression by mediating PTEN expression. AB - ETS-domain containing protein (Elk1) is reported to be a member of the ETS oncogene family, and promotes tumorigenesis in cancer such as bladder, prostate and ovarian. Nevertheless, the role of Elk1 in thyroid cancer progression remains unclear. In the present study, we aimed to investigate the role and underlying molecular mechanism of Elk1 in thyroid cancer. The results indicated that Elk1 was significantly upregulated in thyroid cancer tissues and cells. We found that loss of Elk1 function obviously induced the expression of early growth response-1 (Egr-1) and PTEN, promoted apoptosis and constrained the proliferation of thyroid cancer cells. Furthermore, Egr-1 inhibition obviously abrogated the induction of PTEN induced by Elk1 reduction. Moreover, Egr-1 suppression prevented the promotion of apoptosis and the inhibition of cell proliferation caused by Elk1 reduction. In conclusion, Elk1 inhibition induced thyroid cancer cell apoptosis and restrained their proliferation by regulating Egr-1/PTEN, indicating a potential role for Elk1 in thyroid cancer treatment. PMID- 30015899 TI - TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma. AB - In the past decades, chemotherapy has resulted in improved outcomes for patients with osteosarcoma. However, resistance to chemotherapy often leads to poor prognoses. Cisplatin is a standard drug for osteosarcoma therapy, and chemoresistance to cisplatin in osteosarcoma limits the effectiveness of chemotherapy drugs. Transglutaminase 2 (TGM2) is a member of the transglutaminase family, and it is reported to be associated with chemoresistance in various types of cancer. The present study aimed to investigate the function of TGM2 in regulating chemosensitivity of osteosarcoma cells to cisplatin. For in vitro experiments, a cisplatin-resistant osteosarcoma cell line (Saos2-CIS-R) was established, and TGM2 was demonstrated to be upregulated in the resistant Saos2 CIS-R cells compared with the normal Saos2 cells. The present study also revealed that TGM2 was associated with chemoresistance to cisplatin in osteosarcoma cells, and knockdown of TGM2 enhanced their chemosensitivity. In addition, TGM2 was demonstrated to affect the chemosensitivity of osteosarcoma cells via regulation of the activation of mitogen-activated protein kinase and AKT serine/threonine kinase pathways. Expression of BCL2 apoptosis regulator, BCL2 associated X and caspase-3 was also involved in chemoresistance development in osteosarcoma. For in vivo experiments, a mouse model was used to detect that the cisplatin sensitivity of Saos2-CIS-R cells was reversed following TGM2 knockdown. Taken together, the present data suggested a potentially important role for TGM2 in the regulation of osteosarcoma chemosensitivity. TGM2 might therefore serve as a therapeutic target for osteosarcoma. PMID- 30015902 TI - Spilanthol inhibits TNF-alpha-induced ICAM-1 expression and pro-inflammatory responses by inducing heme oxygenase-1 expression and suppressing pJNK in HaCaT keratinocytes. AB - Spilanthol has been reported to possess antioxidant, anti-inflammatory, antimicrobial and antinociceptive properties. At present, the literature has reported the beneficial role of spilanthol on tumor necrosis factor-alpha (TNF alpha)-stimulated HaCaT cells. The present study investigated the effects of spilanthol on the expression of TNF-alpha-induced intercellular adhesion molecule 1 (ICAM-1) and cyclooxygenase (COX)-2 in the human keratinocyte cell line HaCaT. Cells were pretreated with various concentrations of spilanthol (10-150 uM) followed by TNF-alpha to induce inflammation. Pretreatment with spilanthol decreased TNF-alpha-induced COX-2 expression by western blotting and suppressed the expression of pro-inflammatory mediators, including interleukin (IL)-6, IL-8 and monocyte chemotactic protein 1 using ELISA. Spilanthol also decreased the expression of TNF-alpha-induced ICAM-1 protein and mRNA assay by western blotting and RT-qPCR, respectively, in addition to the monocyte adhesiveness of HaCaT cells. Furthermore, spilanthol significantly suppressed the phosphorylation of c Jun N-terminal kinase (JNK), while pretreatment with spilanthol enhanced heme oxygenase (HO)-1 protein expression by western blotting. These results demonstrated that spilanthol may exert its anti-inflammatory activity by suppressing the TNF-alpha-induced expression of ICAM-1, COX-2 and pro inflammatory mediators by enhancing that of HO-1, and inhibiting the activation of the phosphorylated JNK signaling pathway. It is hypothesized that spilanthol may be a natural anti-inflammatory drug to attenuate skin inflammatory disease. PMID- 30015901 TI - ROS-mediated autophagy through the AMPK signaling pathway protects INS-1 cells from human islet amyloid polypeptide-induced cytotoxicity. AB - Oligomerization of human islet amyloid polypeptide (hIAPP) is toxic and contributes to progressive reduction of beta cell mass in patients with type 2 diabetes mellitus. Autophagy is a highly conserved homeostatic mechanism in eukaryotes. Previous studies have confirmed that hIAPP can promote autophagy in beta cells, but the underlying molecular mechanism and cellular regulatory pathway of hIAPP-induced autophagy remains not fully elucidated. Accumulation of reactive oxygen species (ROS) causes hIAPP induced-beta cell death. At present, little is known about the association between hIAPP-induced oxidative stress and autophagy in beta cells. Therefore, the present study investigated the underlying molecular mechanism and regulatory pathway of hIAPP-induced autophagy. Transmission electron microscopy was used to observe the number of autophagosome in cells. Cell viability was determined by an MTT test. A 2',7' dichlorofluorescin diacetate assay was used to measure the relative levels of reactive ROS. Western blotting was used to detect expression of adenosine monophosphate-activated protein kinase (AMPK) and autophagic markers p62 and microtubule associated protein 1 light chain 3. The results demonstrated that hIAPP induces autophagy through ROS-mediated AMPK signaling pathway in INS-1 cells. Upregulation of autophagy by AMPK activator 5-aminoimidazole-4 carboxamide1-beta-D-ribofuranoside decreased ROS and malondialdehyde generation, whereas inhibition of autophagy by 3-methyladenine and AMPK inhibitor compound C aggravated hIAPP-induced oxidative stress and toxicity in INS-1 cells. Taken together, the present study suggested that hIAPP induces autophagy via a ROS mediated AMPK signaling pathway. Furthermore, autophagy serves as a cell protective mechanism against hIAPP-induced toxicity and chemical promotion of autophagy through AMPK signaling pathway attenuates hIAPP induced cytotoxicity and oxidative stress in INS-1 cells. PMID- 30015903 TI - MicroRNA-29a contributes to intracranial aneurysm by regulating the mitochondrial apoptotic pathway. AB - Intracranial aneurysm (IA) is an abnormal expansion in the intracranial arteries that weakens the arterial wall by consistently pushing the vascular wall outwards, which leads to a higher risk of aneurysm rupture. A number of reports have demonstrated that apoptosis is associated with the growth and rupture of IA. MicroRNAs (miRNAs/miRs) perform vital roles in the regulation of the mitochondrial apoptotic pathway and signaling proteins. Increasing evidence has already revealed the role of miR-29a in injury, including liver injury, cardiovascular injury and ischaemia-reperfusion injury. However, the role of miR 29a in IA remains unclear at present. The present study investigated the role of miR-29a in IA pathogenesis and the underlying mechanisms. By using reverse transcription-quantitative polymerase chain reaction and western blot analysis, the present study demonstrated that genes, including caspase-3, -8 and -9, and proteins, including cytochrome c and myeloid cell leukemia 1 (Mcl-1), involved in mitochondrial apoptosis pathways were upregulated in IA groups compared with controls. In addition, microarray analysis demonstrated that miR-29a, one of the most altered miRs in IA mice, was overexpressed in IA mice compared with controls. In vitro experiments revealed that miR-29a downregulation attenuated human brain vascular smooth muscle cell (HBVSMC) apoptosis, while miR-29a overexpression increased the apoptosis of HBVSMCs. Furthermore, luciferase reporter analysis revealed that Mcl-1 is a direct target gene of miR-29a. An in vivo IA model confirmed that miR-29a overexpression may promote apoptosis through mitochondrial pathways. It was therefore concluded that miR-29a may contribute to the progression of IA by regulating mitochondrial apoptotic pathways. Thus, miR 29a is a potential therapeutic target for IA. PMID- 30015904 TI - miR-140-5p regulates cell migration and invasion of non-small cell lung cancer cells through targeting VEGFA. AB - Lung cancer is the most common type of cancer worldwide, the most prevalent form of which is non-small cell lung cancer (NSCLC). MicroRNAs (miRs) are involved in the progression of NSCLC; however, the specific function of miR-140-5p in NSCLC remains unclear. The present study demonstrated that miR-140-5p was downregulated in the tumor tissues of patients with NSCLC, and it was associated with a poor prognosis. Furthermore, miR-140-5p significantly suppressed cell migration and invasion of the NSCLC cell line A549. In addition, the direct regulatory effect of miR-140-5p on vascular endothelial growth factor-A (VEGFA) was predicted by TargetScan and verified using a luciferase reporter gene assay. The present study also hypothesized that miR-140-5p may inhibit the expression of phosphorylated protein kinase B by targeting VEGFA. In conclusion, miR-140-5p may be a potential target for the development of anti-neoplastic therapies in lung cancer. PMID- 30015905 TI - Analysis of non-alcoholic fatty liver disease microRNA expression spectra in rat liver tissues. AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing in recent years. Previous studies have suggested that micro (mi)RNAs may be involved in the pathogenesis of NAFLD. To investigate the role of miRNAs in rat NAFLD, a total of 16 male Sprague Dawley rats were randomly divided into a control group and a model group. Rats in the control group were fed a normal diet for 12 weeks, whereas the rats in the model group were fed a high-fat and high sugar diet for 12 weeks. Following this, the animals were sacrificed and liver tissues were rapidly removed to investigate the severity of NAFLD. Blood samples were collected to investigate liver function, in addition to total cholesterol, total triglyceride and fasting plasma glucose levels. Total RNA from three fresh liver samples per experimental group was extracted for subsequent miRNA gene chip analysis using GeneChip miRNA 4.0 to investigate differentially expressed miRNAs, and miRNA expression was further verified via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Compared with the control group, the results revealed that there were 10 differentially expressed miRNAs in the model group, five of which were overexpressed and five of which were underexpressed compared with the control group. The results of the RT-qPCR analysis revealed that miR 182, miR-29b-3p and miR-741-3p were significantly overexpressed in the model group compared with the control group, which was largely consistent with the results of the microarray analysis. The results suggested that the differentially expressed microRNAs demonstrated in the present study may be involved in the pathogenesis of NAFLD; however, the mechanism underlying the differential expression of miRNAs in NAFLD requires further investigation. PMID- 30015906 TI - Establishment of a novel non-alcoholic fatty liver disease model using cholesterol-fed rabbits with reference to the potential role of endoplasmic reticulum stress. AB - The aim of the present study was to establish a non-alcoholic fatty liver disease (NAFLD) model using cholesterol-fed rabbits and to investigate whether endoplasmic reticulum stress (ERS) serves a role in the pathogenesis of NAFLD. A total of 20 male rabbits were randomly divided into 3 groups: Those fed a normal chow diet, a high cholesterol diet (HCD) or a high fat and high cholesterol diet (HFCD) for 12 weeks. Total cholesterol, triglycerides and free fatty acids of plasma and the liver were measured. At 12 weeks, a glucose tolerance test was performed. The steatosis of the liver was evaluated using hematoxylin and eosin and Oil Red O staining. Expression levels of glucose regulation protein 78, CCAAT/enhancer-binding protein homologous protein, c-Jun N-terminal kinase (JNK) and caspase-12 mRNA was analyzed by reverse transcription-quantitative polymerase chain reaction. Plasma levels of total cholesterol, triglycerides and free fatty acids in the HCD and HFCD groups were significantly higher when compared with those in the control group (P<0.05 or P<0.01). Histological analysis revealed that HCD and HFCD groups demonstrated marked differences in the fatty liver compared with the control group, while there was no significant difference between the HCD and HFCD groups. JNK and caspase-12 expression were significantly increased in the HCD and HFCD groups when compared with the control. The HCD and HFCD groups exhibited prominent fatty livers, a typical pathological feature of NAFLD. However, the addition of high fat levels in the cholesterol diet did not increase the severity of hepatic steatosis in HFCD when compared with the HCD group. Thus, the ERS pathway may participate in the pathogenesis of NAFLD, and cholesterol-fed rabbits may become a novel model for the study of NAFLD. PMID- 30015907 TI - miR-330-5p inhibits H2O2-induced adipogenic differentiation of MSCs by regulating RXRgamma. AB - The elucidation of the underlying molecular mechanism of H2O2-induced adipocyte differentiation in mesenchymal stem cells (MSCs) is important for the development of treatments for metabolic diseases. The aim of the present study was to identify microRNA (miR)-330-5p, which targets retinoid X receptor gamma (RXRgamma) and to determine the function of H2O2-induced adipogenic differentiation of MSCs. During differentiation of MSCs into adipocytes induced by H2O2, miR-330-5p expression was decreased with a concomitant increase in RXRgamma expression. A luciferase assay with RXRgamma 3'-untranslated region (UTR) reporter plasmid, including the miR-330-5p-binding sequences, identified that the introduction of miR-330-5p decreases luciferase activity. However, it did not affect the activity of mutated RXRgamma 3'-UTR reporter. Enforced expression of miR-330-5p significantly inhibited adipocyte differentiation by decreasing RXRgamma mRNA and protein levels. In contrast, inhibition of the endogenous miR-330-5p promoted the formation of lipid droplets by rescuing RXRgamma expression. Furthermore, the effects of inhibition of RXRgamma were similar to those of overexpression of miR-330-5p on H2O2-induced adipogenic differentiation from MSCs. miR-330-5p inhibits H2O2-induced adipogenic differentiation of MSCs, and this is dependent on RXRgamma. Taken together, the results of the present study revealed that miR-330-5p acts as a critical regulator of RXRgamma, and is able to determinate the fate of MSCs to differentiate into adipocytes. This suggests that miR-330-5p and RXRgamma may be target molecules for controlling metabolic diseases. PMID- 30015908 TI - Triptolide exhibits antitumor effects by reversing hypermethylation of WIF-1 in lung cancer cells. AB - Triptolide (TP) exhibits numerous biological activities, including immunosuppressive, anti-inflammatory and antitumor effects. The aim of the present study was to investigate the role of TP as a potent therapeutic drug for the treatment of lung cancer and to investigate the underlying therapeutic mechanisms. Western blot analyses and reverse transcription-quantitative polymerase chain reaction (PCR) were performed to investigate the expression of genes at transcriptional and translational levels, respectively. Methylation specific PCR assays were conducted to investigate whether TP affects the Wnt inhibitory factor-1 (WIF-1) methylation status and subsequently affects apoptosis, migration or the invasion of lung cancer cells. The results of the present study revealed that the methylation status of WIF-1 in lung cancer cell lines A549 and H460 was significantly enhanced compared with the human normal bronchial epithelial cell line HBE, whereas treatment with TP was revealed to induce the demethylation of WIF-1. The present study aimed to investigate whether the biological activities of TP are regulated by inhibiting the Wnt signaling pathway via an increase in WIF-1 expression levels. The results of the present study revealed that Wnt signaling was suppressed in cells following treatment with TP, which was concluded by the downregulation of Axin 2 and beta-catenin expression. Further investigation demonstrated that the silencing of WIF-1 expression with small interfering RNA reversed the TP-induced upregulation of WIF 1 expression, upregulated Axin 2 and beta-catenin expression and enhanced the activation of Wnt signaling. Notably, an upregulation of cellular tumor antigen p53 expression, and downregulation of matrix metalloproteinase-9 (MMP-9) and phosphorylated-nuclear factor-kappaB (NF-kappaB) P65 (p-P65) levels was observed following TP treatment. These results suggest that the Wnt, p53 and NF-kappaB signaling pathways mediate the potent antitumor effects of TP. Notably, the silencing of WIF-1 did not completely recover the levels of p53, MMP-9 and p-P65 in cells treated with TP compared with the control cells, thus suggesting that TP exhibits further functions in addition to the targeting of WIF-1. PMID- 30015909 TI - Overexpression of HES6 has prognostic value and promotes metastasis via the Wnt/beta-catenin signaling pathway in colorectal cancer. AB - HES6 is a member of the hairy-enhancer of the split homolog family, which has been implicated in oncogenesis and cancer progression in a variety of human cancers, including prostate and breast cancer. However, its clinical significance and biological role in colorectal cancer (CRC) remain unclear. In the present study, the expression of HES6 was significantly upregulated in CRC cell lines and CRC tissues at both the mRNA and protein levels. The present study also reported high expression of HES6 in 138/213 (64.8%) paraffin-embedded archived CRC specimens. HES6 expression was significantly correlated with T classification (P<0.001), N classification (P=0.020), and distant metastasis (P<0.001). Patients with higher HES6 expression levels exhibited a reduced overall survival (P<0.001). In addition, a multivariate analysis revealed that the expression of HES6 may be a novel prognostic marker for the survival of patients with CRC. Furthermore, the present study demonstrated that ectopic expression of HES6 enhanced the migration and invasive abilities of CRC cells. These abilities were significantly inhibited upon knockdown of endogenous HES6 expression by specific short hairpin RNAs. Additionally, the present study reported that the effects of HES6 on metastasis may be associated with the activation of the Wnt/beta-catenin signaling pathway. Collectively, the findings of the present study revealed that overexpression of HES6 played a key role in the progression of CRC, leading to a poor prognosis and clinical outcome. PMID- 30015910 TI - Nicotine enhances store-operated calcium entry by upregulating HIF-1alpha and SOCC components in non-small cell lung cancer cells. AB - Store-operated calcium entry (SOCE) is critical for regulating the proliferation and metastasis of various cancer types. The present study aimed to investigate the role of SOCE on nicotine-promoted proliferation of non-small cell lung cancer (NSCLC) A549 cells. Cell proliferation was evaluated by BrdU incorporation assay. The SOCE and basal [Ca2+]i in NSCLC A549 cells were determined using Fura-2 fluorescence microscopy. The mRNA and protein expression levels were determined by real-time quantitative PCR and western blotting, respectively. The results demonstrated that, in A549 cells, the detectable store-operated calcium channel (SOCC) components were TRPC proteins 1, 3, 4 and 6 and Orail, among which TRPC1, TRPC6 and Orai1 are expressed at relatively high levels with TRPC3 and TRPC4 at relatively low levels. Nicotine upregulated the mRNA and protein expression of TRPC1, TRPC6 and Orai1, increased basal [Ca2+]i and enhanced SOCE. Promotion of cell proliferation but not migration was observed in the nicotine-treated cells, which was inhibited by SOCE inhibitor SKF-96365. Furthermore, nicotine upregulated HIF-1alpha expression in the A549 and NCI-H292 cells. Silencing of HIF-1alpha abrogated the increases in TRPCs and Orail and reversed the increases in basal [Ca2+]i and SOCE. Meanwhile, suppression of proliferation was observed in cells following HIF-1alpha silencing. In conclusion, the results indicate that nicotine promotes lung cancer cell proliferation likely by upregulating HIF 1alpha and SOCC components and therefore enhancing SOCE and increasing basal [Ca2+]i. PMID- 30015911 TI - Titanium particle-mediated osteoclastogenesis may be attenuated via bidirectional ephrin-B2/eph-B4 signaling in vitro. AB - The present study investigated the role of bidirectional ephrin-B2/erythropoietin producing human hepatocellular receptor 4 (ephB4) signaling in the regulation of wear particle-mediated osteoclastogenesis in vitro. Mouse bone marrow macrophages (BMMs) were induced into osteoclasts by receptor activator of nuclear factor kappaB ligand (RANKL, 50 ng/ml). EphB4-Fc, an osteoblast membrane surface receptor (4 ug/ml), was used to stimulate the ephrin-B2 ligand of osteoclasts in the presence and absence of titanium (Ti). Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the number of osteoclasts, and phalloidin staining was used to examine the cytoskeletons of the osteoclasts. A bone pit absorption experiment was used to measure osteoclast function. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to examine osteoclastogenesis. ELISAs were used to detect the production of inflammatory factors. The data demonstrated that Ti significantly promoted the differentiation of BMMs into mature osteoclasts in the presence of RANKL and significantly promoted expression of the ephrin-B2, nuclear factor of activated T-cells 1 (NFATc1), TRAP, Fos proto-oncogene, AP-1 transcription factor subunit (C-FOS), and matrix metalloproteinase 9 (MMP9) genes. Phalloidin and TRAP staining revealed that following the addition of ephB4-Fc, the number, size and cytoskeletal elements of osteoclasts were significantly decreased compared with those in the titanium particle group without ephB4-Fc. Compared with the titanium particle group, the bone pit absorption experiment revealed significantly decreased absorption pit areas in the titanium particle+ephB4-Fc group. The expression of the NFATc1, TRAP, C-FOS and MMP9 genes was markedly decreased in the ephB4-Fc group; however, the expression of the ephrin-B2 gene was increased compared with the Ti particle group without ephB4-Fc after 5 days. Production of inflammatory cytokines was inhibited by Ti particles through bidirectional signals. Addition of ephB4-Fc inhibited the osteoclast-mediated formation of Ti particles via bidirectional ephrin-B2/ephB4 signaling. Activation of this bidirectional signaling pathway may be a potential clinical treatment for osteolysis surrounding prostheses. PMID- 30015912 TI - miR-185-5p inhibits F-actin polymerization and reverses epithelial mesenchymal transition of human breast cancer cells by modulating RAGE. AB - In our previous study, advanced glycosylation end-product specific receptor (RAGE) was observed to bind to S100A8/A9 and cause epithelial mesenchymal transition (EMT). The results from target gene prediction revealed that microRNA (miR)-185-5p had a RAGE binding site. However, the function of miR-185-5p in the invasion and migration of breast cancer remains ambiguous. In the present study, the expression of miR-185-5p was examined in breast cancer tissues and cells. Clinical features revealed a negative correlation between miR-185-5p and tumor size, as well as in tumor differentiation and lymph node metastasis in breast cancer. In addition, miR-185-5p was negatively associated with RAGE, and this miRNA reversed the EMT of breast cancer by modulating RAGE in vitro. In addition, miR-185-5p inhibited the S100A8/A9-induced EMT of breast cancer cells by the nuclear factor-kappaB/Snail signaling pathway. Notably, miR-185-5p upregulation inhibited the F-actin polymerization induced by S100A8/A9 in breast cancer. Furthermore, overexpression of miR-185-5p and reduction of RAGE inhibited lung metastasis node in vivo. Thus, miR-185-5p represents a potential therapeutic target in breast cancer by modulating RAGE. PMID- 30015913 TI - Active fraction of clove induces apoptosis via PI3K/Akt/mTOR-mediated autophagy in human colorectal cancer HCT-116 cells. AB - Previous studies by our group have demonstrated that extract of clove exhibits potent anticancer effects in vitro and in vivo. In the present study, the effect of an extracted and isolated active fraction of clove (AFC) on induction of cellular apoptosis in human colorectal cancer HCT-116 cells was investigated by morphological observation, flow cytometry, and western blotting analysis. The results revealed that AFC induced apoptosis of HCT-116 cells. AFC also induced autophagy, demonstrated by increased punctuate microtubule-associated protein 1A/1B-light chain 3 (LC3) staining, and LC3-II and Beclin-1 protein expression levels. Furthermore, the autophagy inhibitors 3-MA and baflomycin A1 potentiated the pro-apoptotic activity of AFC in HCT-116 cells. AFC also inhibited the phosphorylation of the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin signaling pathway. The present study may improve the existing understanding of the anticancer mechanisms of clove and provide a scientific rationale for AFC to be further developed as a promising novel anticancer agent for the treatment of colorectal cancer. PMID- 30015915 TI - MicroRNA-634 alters nerve apoptosis via the PI3K/Akt pathway in cerebral infarction. AB - In the present study, the role and mechanism of microRNA-634 (miRNA-634) in the adjustment of nerve inflammation and apoptosis in cerebral infarction were investigated. In a cerebral infarction rat model, the expression of miRNA-634 was increased, compared with that in the normal control group. The upregulated expression of miRNA-634 in an in vitro model of cerebral infarction increased cell apoptosis and the protein expression of capsase-3/B-cell lymphoma 2 associated X protein (Bax) via inactivation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. The downregulation of miRNA-634 enhanced cell growth and inhibited cell apoptosis in the in vitro model of cerebral infarction through induction of the PI3K/Akt pathway. Subsequently, a PI3K inhibitor was used to inhibit the expression of PI3K in the in vitro model of cerebral infarction via the downregulation of miRNA-634, which showed that cell apoptosis and the protein expression of capsase-3/Bax were also increased. A PI3K agonist reduced the effects of the upregulation of miRNA-634 in the in vitro model of cerebral infarction. In conclusion, the data obtained demonstrated the possible future use of miRNA-634 as a therapeutic target in cerebral infarction through the PI3K/Akt pathway. PMID- 30015914 TI - High expression of leucine-rich repeat-containing 8A is indicative of a worse outcome of colon cancer patients by enhancing cancer cell growth and metastasis. AB - To survive, cells need to avoid excessive volume change that jeopardizes structural integrity and stability of the intracellular milieu. Searching for the molecular identity of volume-regulated anion channel (VRAC) has yielded multiple potential candidates, but none has been confirmed. Recently, it is reported that leucine-rich repeat-containing 8A (LRRC8A) is a main molecular determinant of VRAC current. The biological functions of LRRC8 family proteins are poorly understood, particularly in cancer. In the present study, we investigated LRRC8A in the most common cancers of the digestive system. LRRC8A proteins were found to be abundantly expressed in the esophagus, stomach, duodenum, colon, rectum, liver and pancreas. LRRC8A was elevated in 60% of colorectal cancer patient tissues, which was higher than that in patients with cancer of the esophagus, stomach, duodenum, liver and pancreas. Colon cancer patients with high- expressed LRRC8A had a survival time of 54.9+/-5.5 months, shorter than that of patients with low expressed LRRC8A (77.1+/-3.7). Moreover, survival time (52.6+/-7.3 months) of patients with metastases in the lymph nodes was shorter than that of patients without positive lymph nodes (72.2+/-3.6); patients with positive lymph nodes and an elevated LRRC8A expression had the highest mortality rate (~80%). These rates were not observed in rectal cancer. After LRRC8A protein was knocked down in colon cancer HCT116 cells, VRAC currents, migration and tumorigenesis in nude mice were significantly inhibited. In conclusion, we propose that LRRC8A could be a novel prognostic biomarker for colon cancer patient survival, and that the elevated expression of LRRC8A may enhance cancer cell growth and metastasis, and worsen the outcome of patients. PMID- 30015916 TI - Aucubin suppresses Titanium particles-mediated apoptosis of MC3T3-E1 cells and facilitates osteogenesis by affecting the BMP2/Smads/RunX2 signaling pathway. AB - Aucubin represents an iridoid glucoside separated from multiple Chinese herbs, which has been demonstrated to possess numerous pharmacological activities. In the present study, the aim was to investigate the roles and mechanisms of aucubin in the suppression of mouse MC3T3-E1 osteoblast apoptosis induced by Titanium particles and the promotion of bone formation. MTT assay and flow cytometry were performed to analyze cell viability and apoptosis, respectively. ELISA and para nitrophenyl phosphate colorimetry were carried out to evaluate the oxidative stress markers and alkaline phosphatase (ALP). Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to evaluate the associated mRNA and protein expression. The results revealed that aucubin enhanced the cell activity of MC3T3-E1 cells treated with Ti particles. Aucubin suppressed the apoptosis of Ti particles-induced MC3T3-E1 cells and facilitated osteogenesis by affecting the B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein, ALP and associated osteogenic factors expression. Aucubin reduced the oxidative stress in Ti particles-induced MC3T3-E1 cells. In addition, aucubin upregulated the bone morphogenetic protein 2 (BMP2)/Smads/runt related transcription factor 2 (RunX2) pathway in Ti particles-induced MC3T3-E1 cells. In conclusion, the present study confirmed that aucubin suppressed the Ti particles mediated apoptosis of MC3T3-E1 cells and facilitated osteogenesis by affecting the BMP2/Smads/RunX2 signaling pathway. PMID- 30015917 TI - Wogonin suppresses the LPS-enhanced invasiveness of MDA-MB-231 breast cancer cells by inhibiting the 5-LO/BLT2 cascade. AB - Wogonin, a naturally occurring bioactive monoflavonoid isolated from Scutellariae radix (roots of Scutellariae baicalensis Georgi), has known anticancer effects. However, the molecular signaling mechanism by which wogonin inhibits invasiveness in breast cancer cells remains unclear. In the present study, it was observed that wogonin exerted an inhibitory effect on the lipopolysaccharide (LPS) enhanced invasiveness of MDA-MB-231 cells. In addition, wogonin inhibited the synthesis of interleukin-8 (IL-8) and matrix metallopeptidase-9 (MMP-9), which are critical for promoting invasiveness in MDA-MB-231 cells. Wogonin also suppressed the expression of leukotriene B4 receptor 2 (BLT2) and the synthesis of its ligand, by inhibiting 5-lipoxygenase (5-LO) in LPS-stimulated MDA-MB-231 cells. Notably, wogonin attenuated the production of IL-8 and MMP-9 by inhibiting the BLT2/extracellular signal-regulated kinase (ERK)-linked cascade. Finally, in vivo, LPS-driven MDA-MB-231 cell metastasis was markedly suppressed by wogonin administration. Overall, the present results suggested that wogonin inhibited the 5-LO/BLT2/ERK/IL-8/MMP-9 signaling cascade and demonstrated that this cascade may be an important target through which wogonin exerts its anticancer effects in breast cancer. PMID- 30015918 TI - Activation of the KEAP1-NRF2-ARE signaling pathway reduces oxidative stress in Hep2 cells. AB - At present there are no studies investigating the effects of the kelch-like ECH associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant response element (ARE) signaling pathway on Hep2 cell line. The present study aimed to investigate this topic through knockdown of the KEAP1 gene. A stable Hep2 cell line specifically silencing the human KEAP1 gene was initially constructed. Hydrogen peroxide (H2O2) was added to the culture medium at various concentrations for various durations to interact with the short hairpin (sh)KEAP1-transfected Hep2 cells. Subsequently, the gene and protein expression levels of KEAP1, NRF2, NAD(P)H quinone oxidoreductase1 (NQO1) and heme oxygenase 1 (HO1) in experimental and control cells were measured by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Furthermore, the viability and apoptotic rate of the shKEAP1 transfected Hep2 cells were detected by a Cell Counting-Kit 8 assay and flow cytometry, respectively. In the shKEAP1 Hep2 cell line, the mRNA and protein expression levels of NRF2, NQO1 and HO1 were markedly higher compared with the scramble control-transfected Hep2 and parent Hep2 cell lines. Immunofluorescence staining indicated that NRF2 was primarily located in the cytoplasm of scHep2 and parent Hep2 cell lines, but was present in the nuclei and cytoplasm of the shKEAP1 Hep2 cell line, where it translocates into the nuclei in response to H2O2. Following knockdown of the KEAP1 gene Hep2 cells, the apoptosis rates were 31.8 and 45.3% in scHep2 cells at 0.1 and 0.25 mmol/l H2O2 respectively and 14.1 and 27.9% in shKEAP1 cells. The present study indicated that the KEAP1-NRF2-ARE signaling pathway may exhibit an antioxidative effect within Hep2 cells and may be used for clinical treatment of cancer. PMID- 30015919 TI - Tanshinone IIA attenuates paraquat-induced acute lung injury by modulating angiotensin-converting enzyme 2/angiotensin-(1-7) in rats. AB - Tanshinone IIA (TIIA) is an active compound that can be isolated from the Chinese herb, Salvia miltiorrhizae Bunge, also known as danshen. Previous studies have demonstrated that TIIA can effectively attenuate bleomycin-induced pulmonary fibrosis in rats. However, it has not been determined whether TIIA can attenuate paraquat (PQ)-induced acute lung injury (ALI). In the present study, the protective effects exhibited by TIIA on PQ-induced ALI, as well as its underlying mechanisms, were investigated using Sprague-Dawley (SD) rats. ALI animal models using rats were established via administration of PQ. Adult male SD rats were randomly divided into three groups: A control group, a PQ group and a PQ + TIIA group. Total cell count, total protein levels and lactic dehydrogenase (LDH) levels in bronchoalveolar lavage fluid (BALF), as well as myeloperoxidase (MPO) activity in lung tissues were determined. Lung histological alterations were also investigated. Angiotensin converting enzyme 2 (ACE2) and Angiotensin 1-7 [Ang-(1 7)] expression levels in the lung were also analyzed. The results demonstrated that administration of PQ induced marked histological alterations, and markedly increased neutrophil infiltration, lung wet/dry weight ratio, total cell count, protein content and LDH levels in BALF. In addition, PQ was revealed to significantly decrease ACE2 and Ang-(1-7) expression levels in lung tissues. However, it was demonstrated that TIIA attenuated these effects. Therefore, the results of the present study suggest that that TIIA may exhibit a therapeutic effect regarding PQ-induced ALI in rats, and that ACE2 and Ang-(1-7) may be involved in the underlying mechanisms of this effect. PMID- 30015920 TI - Long non-coding RNA urothelial cancer associated 1 regulates radioresistance via the hexokinase 2/glycolytic pathway in cervical cancer. AB - Cervical cancer is one of the most common types of female malignant tumor. It is well established that radiotherapy (RT) is the first-line treatment of cervical cancer; however, radioresistance is a substantial obstacle to cervical cancer RT. At present, the mechanism underlying radioresistance remains unclear. Emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) function as crucial regulators of diverse cancers. Aerobic glycolysis, which is a common phenomenon in cancer cells, is associated with various biological functions, including radioresistance. To the best of our knowledge, the present study is the first to explore the role of the lncRNA urothelial cancer associated 1 (UCA1) in cervical cancer radioresistance. In the present study, irradiation was used to establish irradiation-resistant (IRR) cells, after which a clonogenic survival assay was used to validate radioresistance, reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression levels of UCA1 and western blotting was conducted to detect the expression levels of glycolysis-related proteins. In addition, a glucose/lactate assay kit was used to evaluate glucose/lactate concentrations and cells were transfected with small interfering RNA/pcDNA to regulate the expression of UCA1. Following the establishment of IRR cell lines (SiHa-IRR and HeLa-IRR), it was demonstrated that SiHa-IRR and HeLa IRR cells exhibited increased expression levels of UCA1 and enhanced glycolysis. Dysregulation of UCA1 and inhibition of glycolysis affected radioresistance of cervical cancer cells. In addition, the results indicated that UCA1 promoted radioresistance-associated glycolysis in SiHa-IRR and HeLa-IRR cells, with the enzyme hexokinase 2 (HK2) acting as a significant regulator in this process. Inhibiting glycolysis by 2-DG reversed the effects of UCA1 overexpression on HK2 protein expression and radioresistance in SiHa and HeLa cells. Taken together, these findings suggested that UCA1 may have an important role in regulating radioresistance through the HK2/glycolytic pathway, providing novel potential targets to improve cervical cancer RT. PMID- 30015921 TI - Ulipristal acetate induces cell cycle delay and remodeling of extracellular matrix. AB - Uterine leiomyoma is a benign tumor that grows within the muscle tissue of the uterus. Ulipristal acetate (UPA) is a pre-operative drug used to reduce the size of leiomyoma. The aim of the present study was to examine the in vitro mechanistic details of action of UPA on uterine leiomyomas. Primary cultures of leiomyoma cells were isolated from patient myomectomy specimens and incubated in the presence or absence of UPA at various concentrations. The proliferation, cell viability and doubling time properties of the treated cells were analyzed. In addition, the mRNA and protein expression levels of p21, p27, cyclin E, cyclin dependent kinase 2 (CDK2), matrix metalloproteinase (MMP)-2 and MMP-9 were examined, as well as the structure of F-actin in the primary-cultured leiomyoma cells. The results demonstrated that UPA exerted inhibitory effects on proliferation of primary-cultured leiomyoma cells. Expression of p21 and p27 was upregulated, while cyclin E and CDK2 were downregulated in UPA-treated primary cultured leiomyoma cells. An increased expression of MMP-2 was observed in primary-cultured leiomyoma cells and a leiomyoma tissue sample of a patient with previous history of UPA treatment. Furthermore, a pronounced formation of F-actin stress fibers was observed in leiomyoma cells of the UPA-treated patient. These data suggest that UPA treatment attenuated the proliferation of uterine fibroid cells via upregulation of p21 and p27, resulting in cell cycle delay. The findings in the current study also suggest that UPA may cause extracellular matrix constriction, leading to the shrinkage in size of the leiomyoma possibly via stimulation of MMP-2 expression and induction of actin stress fibers. PMID- 30015922 TI - HOXA5 is a tumor suppressor gene that is decreased in gastric cancer. AB - The abnormal expression of homeobox A5 (HOXA5) has been observed in breast and colon cancer; however, the clinical significance of HOXA5 in gastric cancer (GC) is not yet clear. In this study, we found that HOXA5 expression was decreased in GC tissues at the mRNA and protein level compared with paracancerous tissues using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis, respectively. Immunohistochemistry and Kaplan-Meier survival analysis confirmed that the underexpression of HOXA5 was associated with GC progression and indicated a poor prognosis of patients with GC. Given that proliferation-related genes may be potential target genes of HOXA5, we performed a series of experiments in vitro to examine the effects of HOXA5 on the proliferation of GC cells. A CCK-8 assay, colony formation assay and flow cytometry revealed that HOXA5 inhibited the abnormal proliferation of GC cells, and this finding was further supported by a 5-ethynyl-2'-deoxyuridine (EdU) assay. Further mechanistic investigation clarified that HOXA5 promoted the protein expression of p21 and inhibited the protein expression of c-Myc and Ki67. Additionally, the use of nude mouse models also verified that HOXA5 suppressed the proliferation of GC cells in vivo. Collectively, the findings of this study demonstrate that HOXA5 acts as a tumor suppressor gene during the development and progresion of GC, possibly functioning by inhibiting the abnormal proliferation of cancer cells. PMID- 30015924 TI - MicroRNA-758 inhibits malignant progression of retinoblastoma by directly targeting PAX6. AB - Accumulated studies have highlighted that the dysregulation of microRNAs (miRNAs) in retinoblastoma (RB) is a leading cause for tumourigenesis and tumour development. Therefore, the elucidation of the expression, functional roles and underlying mechanisms of miRNAs in RB will help the development of promising therapeutic methods to improve the prognosis of RB patients. The aim of this study was to detect miRNA-758 (miR-758) expression in RB tissues and cell lines, and to determine the effects and underlying mechanisms of miR-758 on RB progression. The results demonstrated that miR-758 was downregulated in both RB tissues and cell lines. In vitro functional experiments revealed that upregulation of miR-758 inhibited cell proliferation, migration and invasion, and induced apoptosis in RB. In addition, paired box protein 6 (PAX6) was a direct target gene of miR-758 in RB. Furthermore, PAX6 was upregulated in RB tissues, and this upregulation was inversely associated with the expression level of miR 758. In addition, PAX6 reintroduction abrogated the tumour-suppressive effects of miR-758 overexpression on RB cell proliferation, migration, invasion and apoptosis. Furthermore, miR-758 overexpression inactivated the PI3K/Akt pathway in RB cells by inhibiting PAX6. In conclusion, our current study provided sufficient evidence to demonstrate that miR-758 inhibits the progression of RB by directly targeting PAX6 and regulating the PI3K/Akt pathway, thereby suggesting that this miRNA may be developed as a therapeutic target for treating patients with RB. PMID- 30015923 TI - Kaempferol inhibits interleukin-1beta stimulated matrix metalloproteinases by suppressing the MAPK-associated ERK and P38 signaling pathways. AB - Osteoarthritis (OA) is a common degenerative joint disease in older adults. A number of previous studies have demonstrated that natural flavonoids can serve as promising therapeutic drugs for OA. Kaempferol, a phytochemical ingredient mainly present in various fruits, has exhibited its prominent anti-inflammatory and antioxidant effects in numerous diseases. However, whether Kaempferol ameliorates the deterioration of arthritis remains to be elucidated. The aim of the present study was to investigate the therapeutic role of Kaempferol on OA in rat chondrocytes. The results revealed that Kaempferol significantly inhibited the interleukin (IL)-1beta-induced protein expression of inflammatory mediators such as inducible nitric oxide synthase and cyclo-oxygenase-2. In addition, the common matrix degrading enzymes [matrix metalloproteinase (MMP)-1, MMP-3, MMP-13 and a disintegrin and metalloproteinase with thrombospondin motif-5] induced by IL 1beta were also suppressed by Kaempferol, and consequently abolished the degradation of collagen II. Furthermore, the anti-inflammatory effect of Kaempferol was mediated by the inhibition of the mitogen activated protein kinase associated extracellular signal-regulated kinase and P38 signaling pathways. These results collectively indicated that Kaempferol can potentially prevent OA development and serve as a novel pharmacological target in the treatment of OA. PMID- 30015925 TI - Tumor suppressor LKB1 inhibits the progression of gallbladder carcinoma and predicts the prognosis of patients with this malignancy. AB - Gallbladder carcinoma (GBC) represents the most common fatal tumors of the biliary tract. The 3-year or 5-year survival rate for patients with this disease are 30 and 5%, respectively. Liver kinase B1 (LKB1), a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK) necessary for maintaining cell metabolism and energy homeostasis, has been found to be an important tumor suppressor gene in recent years, and its inactivation has also found to be closely associated with tumor growth, metastasis and cancer stem cell (CSC) proliferation. Nevertheless, the function of LKB1 in GBC remains unclear. In this study, we found that the expression of LKB1 in GBC tissues was decreased compared with that in non-cancerous tissues. LKB1 overexpression suppressed the proliferation, metastasis and expansion of GBC CSCs. Mechanically, LKB1 suppressed GBC cell progression via the JAK/signal transducer and activator of transcription 3 (STAT3) pathway. The use of the JAK2 inhibitor, AZD-1480, attenuated the suppressive effects of LKB1 overexpression on the growth, metastasis and self-renewal ability of the GBC cells, which further demonstrated that JAK/STAT3 was involved in the LKB1-induced suppression of GBC cell growth, metastasis and self-renewal ability. More importantly, the decreased expression of LKB1 was a predictor of a poor prognosis of patients with GBC. On the whole, our data indicate that LKB1 inhibits GBC cell growth, metastasis and self-renewal ability by disrupting JAK/STAT3 signaling, and may thus prove to be a novel prognostic biomarker for patients with GBC. PMID- 30015926 TI - Integrative analysis of promising molecular biomarkers and pathways for coronary artery disease using WGCNA and MetaDE methods. AB - The present study aimed to examine the molecular mechanisms of coronary artery disease (CAD). A total of four microarray datasets (training dataset no. GSE12288; validation dataset nos. GSE20680, GSE20681 and GSE42148) were downloaded from the Gene Expression Omnibus database, which included CAD and healthy samples. Weighted gene co-expression network analysis was applied to identify highly preserved modules across the four datasets. Differentially expressed genes (DEGs) with significant consistency in the four datasets were selected using the MetaDE method. The overlapping genes amongst the DEGs with significant consistency and in the preserved modules were used to construct a protein-protein interaction (PPI) network, followed by functional enrichment analysis. A total of 11 modules were established in the training dataset, and five of them were highly preserved across all four datasets, including 873 genes. There was a total of 836 DEGs with significant consistency in the four datasets. A total of 177 overlapping genes were selected, with which a PPI network was constructed. The top five genes of the PPI network were identified based on their degrees: LCK proto-oncogene, Src family tyrosine kinase (LCK), euchromatic histone lysine methyltransferase 2 (EHMT2), inosine monophosphate dehydrogenase 2 (IMPDH2), protein phosphatase 4 catalytic subunit (PPP4C) and zeta-chain of T cell receptor associated protein kinase 70 (ZAP70). Genes in the PPI network were significantly involved in a number of Kyoto Encyclopedia Genes and Genomes pathways, including the 'natural killer cell mediated cytotoxicity', 'primary immunodeficiency' and 'Fc gamma R-mediated phagocytosis' pathways. LCK, EHMT2, IMPDH2, PPP4C and ZAP70 are suggested as promising molecular biomarkers for CAD. The 'natural killer cell mediated cytotoxicity', 'primary immunodeficiency' and 'Fc gamma R-mediated phagocytosis' pathways may serve important roles in CAD. PMID- 30015928 TI - Biological effects of BMP7 on small-cell lung cancer cells and its bone metastasis. AB - Small-cell lung cancer (SCLC) is typically fatal if untreated. It is characterized by early and widespread metastases, and has the ability to rapidly develop resistance to chemotherapy. Bone morphogenetic protein 7 (BMP7), a member of the BMP family of signaling molecules, has been implicated in various types of cancer, particularly prostate cancer and breast cancer. However, there is little knowledge of the function of BMP7 in SCLC. The aim of the present study was to investigate the biological function of recombinant human (rh)BMP7 on SCLC cells and the underlying molecular basis for this regulatory mechanism. The effect of rhBMP7 on SCLC cell lines and associated signaling pathways was investigated. Results suggested that rhBMP7 significantly inhibited the proliferation, motility and invasion of SBC-3 and SBC-5 cells. However, rhBMP7 exhibited no effect on the apoptosis of SBC-5 cells, but promoted apoptosis of SBC-3 cells. Furthermore, cell cycle analysis revealed that rhBMP7 was able to increase the proportion of cells in G1 phase and decrease the S phase proportion. Total and membrane BMP receptor (BMPR)IA and BMPRIB were highly expressed in SBC-5 cells, whereas cytoplasmic BMPRIA and BMPRIB expression was higher in SBC-3 cells. However, activin A receptor type I expression was higher in SBC-3 cells in total and cytoplasmic proteins. Furthermore, following stimulation with rhBMP7, Smad2, Smad4 and p21 were downregulated. We hypothesized that rhBMP7 inhibited the progressiveness of SCLC cells by inducing G1 phase arrest and inhibiting S phase entry. The results of the present study indicated that BMP7 serves a key function in regulating the progression of SCLC. PMID- 30015927 TI - Protective effects of compound ammonium glycyrrhizin, L-arginine, silymarin and glucurolactone against liver damage induced by ochratoxin A in primary chicken hepatocytes. AB - Ochratoxin A (OTA) is a mycotoxin that is produced by fungi in improperly stored food and animal feed. It exhibits nephrotoxic, hepatotoxic, embryotoxic, teratogenic, neurotoxic, immunotoxic and carcinogenic effects in laboratory and farm animals. In the present study, the hepatotoxicity of OPA was investigated in chicken primary hepatocytes. On this basis, the cytoprotective effects of compound ammonium glycyrrhizin (CAG), L-arginine (L-Arg), silymarin (Sil) and glucurolactone (GA) were investigated in vitro. Hepatocytes were treated with OTA, which resulted in a significant decrease in cell viability and increases in serum aspartate transaminase and alanine transaminase activities, as determined by an MTT assay and commercial kits, respectively. Furthermore, following OTA treatment, the levels of hepatic antioxidants, such as superoxide dismutase and glutathione, were decreased, and the lipid peroxidation product malondialdehyde was increased, compared with the control group. However, pretreatment with CAG, L Arg, Sil and GA significantly ameliorated these alterations and Sil exerted the optimum hepatoprotective effect. The apoptotic rates were measured by flow cytometry and the results revealed that OTA increased cell apoptosis. The four types of hepatoprotective compounds employed in the present study decreased the apoptosis rate and significantly reversed OTA-induced increases in the mRNA expression levels of caspase-3, which was determined by reverse transcription quantitative polymerase chain reaction. Furthermore, B-cell lymphoma-2 (Bcl-2) mRNA expression was increased in OTA-treated cells when pretreated with CAG, L Arg, Sil and GA. However, no alterations in the mRNA expression of Bcl-2 associated X were observed in the L-Arg and GA groups, compared with the OTA-only group. These results indicate that OTA may exhibit hepatotoxicity in chickens and that CAG, L-Arg, Sil and GA may protect the liver against this via anti-oxidative and antiapoptosis mechanisms. In addition, CAG and GA are likely to mediate their effects through the mitochondrion-dependent apoptosis pathway; however, the exact hepatoprotective mechanism of L-Arg and GA require further investigation. Therefore, CAG, L-Arg, Sil and GA are potential candidates for the prevention and treatment of chicken liver injury. PMID- 30015929 TI - Growth inhibition of KRAS- and EGFR-mutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis. AB - The need for effective treatment of KRAS-mutant lung cancer is an emerging issue. Rho GTPase-activating protein 35 (ARHGAP35) is reported to be a possible molecular target for lung adenocarcinoma. We investigated the effect of long-term ARHGAP35 suppression on the proliferation, migration and molecular dynamics of lung adenocarcinomas harboring KRAS and EGFR gene mutations. Lung adenocarcinoma cell lines A549 (KRAS-mutant) and PC9 and H1975 (EGFR-mutants) were used, and ARHGAP35 knockdown was carried out using puromycin. Cell viability, migration and molecular dynamics were assayed 1 month after introducing small hairpin RNA. The compensatory upregulated mechanism was screened by western blotting and confirmed by a specific inhibitor. Finally, we tested the effects of cosuppression of the SRC/ARHGAP35 axis and the identified pathway in vitro. ARHGAP35 suppression was attenuated by long-term knockdown of the target genes. Compensatory mechanisms by SRC and STAT3 caused attenuation in A549 cells. After long-term ARHGAP35 knockdown, both A549 and PC9 cells were more sensitive to treatment with a STAT3 inhibitor. The suppressive effect of ARHGAP35 knockdown on migration was sustained, but only modest, in all cell lines. Synergistic and strong growth inhibition was observed with concomitant use of an SRC inhibitor and a STAT3 inhibitor in A549 cells. STAT3 activation compensated for ARHGAP35 knockdown in lung adenocarcinoma with the KRAS mutation. Moreover, cosuppression of the STAT3 pathway and SRC/ARHGAP35 axis may be an effective strategy for treating lung adenocarcinoma, especially in the presence of a KRAS mutation. PMID- 30015930 TI - Comprehensive analysis of a novel lncRNA profile reveals potential prognostic biomarkers in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is the main subtype of malignant kidney cancer. Long non-coding RNA (lncRNA) serves a key role in predicting survival in patients with cancer. The present study aimed to develop an lncRNA-related signature of prognostic values for patients with ccRCC. RNA sequencing data of 454 patients were analyzed from The Cancer Genome Atlas (TCGA). To identify the differentially expressed lncRNAs, the patients from four groups classified by tumor stages were compared. The association between survival outcome and lncRNA expression profile was assessed by the univariate and multivariate Cox proportional hazards model. Survival was analyzed using the log-rank test, and functions of target lncRNAs were investigated through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Finally, 19 lncRNAs were identified as significantly associated with overall survival (OS) time. These lncRNAs were gathered as a signal prognostic signature, which may be a potential biomarker for the prognosis of ccRCC. The risk score was built to evaluate the predictive value of the lncRNA signature. There was a significant positive correlation between ccRCC patients with the low-risk score and OS time (P<0.001). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to verify the result in 17 pairs of ccRCC and adjacent non-tumor tissues. Functional enrichment analysis revealed that these lncRNAs were associated with several molecular pathways of the tumor. The RT-qPCR validation was consistent with the TCGA bioinformatics results. In conclusion, a tumor-specific lncRNA signature of 19 lncRNAs was identified and the joint prognostic power was evaluated in the present study, and this signature was determined to be a potential biomarker for the prognosis of ccRCC. PMID- 30015931 TI - Elevated HTRA1 and HTRA4 in severe preeclampsia and their roles in trophoblast functions. AB - Aberrant gene expression during placental development may affect fetal growth and contribute to preeclampsia. The high-temperature requirement A (HTRA) family of proteins are serine proteases that may serve in the quality control of misfolded or mislocalized proteins. Recently, the potential involvement of HTRA1 and HTRA4 in the normal development of the placenta and in the pathogenesis of preeclampsia has been reported. The present study collected placental tissues from patients with severe preeclampsia and gestational age-matched control samples. The expression of HTRA1 and HTRA4 was analyzed using reverse transcription quantitative polymerase chain reaction, western blotting and immunohistochemistry. The human trophoblast line HTR-8 was transfected with HTRA1 or HTRA4, and cell function was assessed. The present study also detected the expression of HTRA1 and HTRA4 in HTR-8/SVneo transfected cells under hypoxia (1% O2) and further studied the effects of hypoxia on HTR-8 cell migration. HTRA1 and HTRA4 were mainly localized to the cytoplasm of syncytiotrophoblasts. The expression levels of the two genes were elevated in the placental tissues of patients with severe preeclampsia. Finally, it was determined in vitro that ectopic expression of HTRA1 and HTRA4 significantly attenuated HTR-8 cell migration, and elevated HTRA1 limited HTR-8 cell growth. Under hypoxic conditions, the expression levels of HTRA1 and HTRA4 improved significantly. It was hypothesized that the aberrant expression of HTRA1 or HTRA4 may be involved in the onset of preeclampsia, and increased HTRA1 or HTRA4 expression may affect trophoblast functions. PMID- 30015932 TI - MicroRNA-874 prohibits the proliferation and invasion of retinoblastoma cells by directly targeting metadherin. AB - MicroRNAs (miRNAs/miRs) serve important roles in regulating gene expression by directly binding to the 3'-untranslated regions of target genes. Multiple miRNAs are dysregulated in retinoblastoma (RB) and their dysregulation is closely related to RB malignancy. Therefore, exploring the detailed roles of miRNAs in RB is valuable to facilitate the development of effective therapeutic targets for patients with this disease. miRNA-874-3p (miR-874) has been recently reported to be downregulated in several types of human cancer and serves an essential role in cancer progression. However, the expression pattern and detailed roles of miR-874 in RB, as well as the underlying molecular mechanisms in RB, have not been clearly elucidated. Therefore, this study detected miR-874 expression in RB tissues and cell lines. The biological roles of miR-874 in RB were determined and the underlying mechanisms of its actions in RB cells were also examined. This study revealed that miR-874 expression was aberrantly underexpressed in RB tissues and cell lines. However, returning miR-874 expression restricted the proliferative and invasive abilities of RB cells. In terms of the underlying mechanism, metadherin (MTDH) was validated as a direct target gene of miR-874 in RB cells. MTDH inhibition could imitate the inhibitory roles of miR-874 overexpression in RB cells. Furthermore, forced MTDH expression partially reversed the suppressive effects of miR-874 on RB cells. In conclusion, this study revealed that miR-874 may inhibit RB progression by directly targeting MTDH. Restoration of miR-874 expression may be a novel strategy for preventing the rapid growth and metastasis of RB cells. PMID- 30015933 TI - [Corrigendum] Neurotoxin beta-N-methylamino-L-alanine induces endoplasmic reticulum stress-mediated neuronal apoptosis. AB - Following the publication of the article, the authors noted an error associated with the presentation of Fig. 4A. Fig 4 showed that overexpression of HSP70 suppresses ER stress-mediated neuronal death induced by beta-N-methylamino-L alanine (BMAA). An error was made in the compilation of this Figure, and the band images shown in the HA panel for Fig. 1A were selected incorrectly. A corrected version of Fig. 4 is shown below. This change affects neither the interpretation of the data nor conclusions of this work. We regret that this error occurred, and thank the Editor for allowing us the opportunity to publish this Corrigendum. [the original article was published in the Molecular Medicine Reports 14: 4873 4880, 2016; DOI: 10.3892/mmr.2016.5802]. PMID- 30015934 TI - Prevalence of hyperuricemia among the Chinese population of the southeast coastal region and association with single nucleotide polymorphisms in urate-anion exchanger genes: SLC22A12, ABCG2 and SLC2A9. AB - Genome-wide association studies identified that a series of genes, including solute carrier family (SLC) 2 member 9 (SLC2A9), SLC 22 member 12 (SLC22A12) and ATP-binding cassette sub-family G member 2 (ABCG2) polymorphisms were associated with serum uric acid (SUA) levels in the present study. High incidence rates of hyperuricemia were reported in the Chinese population of the southeast coastal region; however, no evidence has confirmed the genetic association with SUA levels in this region. The present study aimed to investigate the association between uric acid levels and hyperuricemia, and genotypes of the Chinese population of the southeast coastal region. In the present study, a total of 1,056 healthy patients attending routine checkups were employed to investigate the incidence of hyperuricemia; 300 subjects were then randomly selected from the 1,056 patients for the identification of genetic polymorphisms of SLC2A9rs11722228, SLC22A12rs893006 and ABCG2rs2231142 via high-resolution melting. The present study reported that the incidence rate of hyperuricemia was 32.6% (42.5% in males and 22.7% in females, respectively). The prevalence of ABCG2rs2231142 polymorphisms (CC, CA and AA) was 44.4, 44.8 and 11.8%, respectively; SLC2A9rs11722228 polymorphisms (CC, CT and TT) were reported to be 49.3, 40.3 and 10.3%, respectively. Additionally, SLC22A12rs893006 polymorphisms (CC, CT and TT) were determined to be 57.2, 38.7 and 4.1%, respectively. The SUA levels were observed to be statistically different among each investigated genotype of ABCG2rs2231142 (P=0.047). The A allele was significantly associated with an increased risk of hyperuricemia (odds ratio=2.405 and 1.133 for CA and AA, respectively). The present study reported that high incidence rates of hyperuricemia in the Chinese population of the southeast coastal region may be closely associated with the variants of ABCG2rs2231142. Whether polymorphisms of SLC2A9rs11722228 and SLC22A12rs893006 are involved in hyperuricemia require further investigation. PMID- 30015935 TI - Dysregulation of CD69 by overexpression of microRNA-367-3p associated with post myocardial infarction cardiac fibrosis. AB - Cardiac fibrosis is characterized as net accumulation of ECM (extracellular matrix) proteins in the cardiac interstitium, which contributes to dysfunction of both systolic and diastolic. The present study aimed to identify the association between microRNA (miR)-367-3p and cluster of differentiation 69 (CD69), and their roles in regulating the development of cardiac fibrosis. Participants (n=34) were enrolled and diagnosed with cardiac fibrosis [fibrosis (+); n=16] or non-fibrosis control [fibrosis (-); n=18]. In-silicon analysis and luciferase assay were used to identify CD69 as a target of miR-367-3p. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to determine the expression level of miR-367-3p and CD69 mRNA and protein, in patient groups or cells transfected with miR-367-3p mimics or inhibitors. Cytokine assays were used to detect the level of interleukin (IL)-17, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte macrophage colony-stimulating factor. Flow cytometry was used to detect the T helper (Th)-17 fraction of cells in different treatment groups. Analysis by RT-qPCR indicated that the expression of miR-367-3p was decreased in the cardiac fibrosis (+) group compared with the fibrosis (-) control group. In contrast, the level of CD69 mRNA was increased in the cardiac fibrosis group compared with the control group. The CD69 3'-untranslated region (UTR) contained two potential seed regions for miR 367-3p and was therefore predicted as a target. A dual-luciferase reporter assay demonstrated a reduced luciferase activity of cells transfected with wild-type CD69 3'-UTR and the mutant2 CD69 3'-UTR, however, the mutant1 CD69 3'-UTR completely abolished the interaction with miR-367-3p. Furthermore, the CD69 mRNA and protein expression levels in cells transfected with miR-367-3p mimics and CD69 siRNA were downregulated compared with the scramble control. Cytokine analysis demonstrated increased levels of IL-17 and TNF-alpha in cells transfected with miR-367-3p mimics or CD69 siRNA, compared with the scramble control. The IFN-gamma and GM-CSF levels of cells transfected with pcDNA3-CD69, miR-367-3p mimics or miR-367-3p + pcDNA3-CD69 were comparable with the scramble control. Notably, the Th17 fraction of cells was upregulated following the introduction of miR-367-3p mimics or CD69 siRNA. In conclusion, these results provide evidence that a decrease in miR-367-3p levels may be associated with cardiac fibrosis. PMID- 30015936 TI - High expression of microRNA-31 and its host gene LOC554202 predict favorable outcomes in patients with colorectal cancer treated with oxaliplatin. AB - The expression levels of microRNA-31 (miR-31) and LOC554202 have been previously investigated in colorectal cancer (CRC) and their oncogenic and/or tumor suppressive roles have been described. The aim of the present study was to examine the role of miR-31 and its host gene LOC554202 in the prognosis of patients with CRC. Patients with CRC treated with oxaliplatin-based chemotherapy between June 2005 and March 2010 were recruited to the First Affiliated Hospital of China Medical University. Tumor and adjacent mucosal tissues were collected. The detection of miR-31 and/or LOC554202 was performed with probe hybridization targeting. Correlation analysis was performed among the expression levels of miR 31, LOC554202, and their association with clinicopathological parameters and/or survival rates. miR-31 and LOC554202 were expressed at high levels in CRC (P<0.01) compared with adjacent intestinal mucosa. A linear correlation was noted for the two markers in CRC tissues (P<0.01). The expression of miR-31 was significantly higher in adenocarcinoma than in the adjacent intestinal mucosa (P<0.01), whereas the expression of LOC554202 was significantly higher in the adenocarcinoma and the rectal cancer tissue regions (P<0.01). The high expression levels of miR-31 and LOC554202 were associated with high disease-free survival (DFS) and overall survival (OS) rates (P<0.05). Associations between the increase in DFS and OS and the elevated expression levels of miR-31 and LOC554202 were present in patients with colon cancer but not in patients with rectal cancer (P<0.05). These data indicated that miR-31 and LOC554202 may be potential markers for evaluation of the prognosis of patients treated with oxaliplatin-based chemotherapy. PMID- 30015937 TI - Expression of transmembrane protein 41A is associated with metastasis via the modulation of E-cadherin in radically resected gastric cancer. AB - Gastric cancer (GC) is one of the most commonly occurring malignancies worldwide, and metastasis is one of the key processes affecting the prognosis of GC. TMEM41A, which belongs to a group of transmembrane proteins that participate in signaling pathways and tumor development, is a 264-amino acid protein encoded by a gene mapped to human chromosome The exact role of TMEM41A in GC has not been determined to date. In the present study, the expression of TMEM41A in 147 cases of GC was analyzed with immunohistohemistry and the prognoses of these patients were analyzed. It was revealed that TMEM41A was highly expressed in GC tissues, and may be associated with the progression of GC and poor prognosis. The expression of TMEM41A was observed to be correlated with lymph node metastasis, distant metastasis and advanced tumor, node and metastasis stages. Knockdown of TMEM41A in vitro and in vivo decreased the GC cell migration ability by regulating epithelial-to-mesenchymal transition and cell autophagy, via the upregulation of E-cadherin and downregulating N-cadherin expression in GC cells by reverse transcription-quantitative polymerase chain reaction (PCR), semi-PCR and western blotting. Furthermore, TMEM41A upregulation was associated with the upregulation of p62 and altered the conversion of light chain (LC)3-1 into LC3-2 by western blotting. Knockdown of TMEM41A was also observed to affect tumor metastasis in nude mice. Therefore, TMEM41A may be considered as a novel therapeutic target for the treatment of GC-associated metastasis. PMID- 30015938 TI - Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib. AB - Sorafenib resistance is one of the major factors affecting the prognosis of patients with hepatocellular carcinoma (HCC). Increasing evidence has indicated that certain traditional medicines can enhance the sensitivity of cancer cells to sorafenib. Berberine, an isoquinoline alkaloid, has been demonstrated to possess antitumor properties against various malignancies. However, the synergistic effect of the combination of berberine and sorafenib in HCC remains unknown. The aim of the present study was to determine the effects of berberine and sorafenib combination on the growth of liver cancer cells. Initially, it was observed that the combination of sorafenib and berberine exerted a synergistic inhibitory effect on the proliferation of SMMC-7721 and HepG2 cells in a dose- and time dependent manner by an MTS assay. Edu staining and colony formation assays also revealed that the combination of 100 uM berberine and 4 uM sorafenib exhibited a significant anti-proliferation effect on SMMC-7721 and HepG2 cells. Furthermore, western blotting assay indicated that the expressions levels of cleaved poly(ADP ribose) polymerase and cleaved caspase-3 increased, while those of the anti apoptotic protein B-cell lymphoma 2 and vascular endothelial growth factor decreased. To the best of our knowledge, this is the first study to demonstrate that berberine sensitized liver cancer cells to sorafenib treatment. These results suggest that berberine combined with sorafenib is able to inhibit the proliferation of liver cancer cells and induce apoptosis, which provides evidence for further clinical investigation in HCC patients with sorafenib resistance. PMID- 30015939 TI - Combined antitumor effects of 1,25-dihydroxy vitamin D3 and Notch inhibitor in liver cancer. AB - The combined antitumor effects of 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] and the Notch inhibitor N-[N--(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, a synthetic gamma secretase inhibitor) in liver cancer cells remain to be fully elucidated. In the present study, HepG2 cells were divided into six groups and different treatments were applied: Control, 10-10 M 1,25(OH)2D3, 10-8 M 1,25(OH)2D3, 10-6 M 1,25(OH)2D3, 1 uM DAPT, 5 uM DAPT, 10 uM DAPT, and 10-6 M 1,25(OH)2D3 + 10 uM DAPT. The proliferation, cell cycle, apoptosis, migration and invasion of the cells were then examined. The expression levels of Notch and its ligand Jagged were detected by reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results revealed that 1,25(OH)2D3 inhibited cell proliferation, migration and invasion; arrested cell cycle at the G1 phase, and promoted apoptosis in a concentration-dependent manner between 10 10 and 10-6 M. DAPT inhibited cell proliferation, migration and invasion, arrested cell cycle at the G1 phase, and promoted apoptosis in a concentration dependent manner between 1 and 10 uM. Additionally, 1,25(OH)2D3 and/or DAPT reduced the expression of Notch1, Notch2, Jagged1 and Jagged2. The co-application of 10 uM DAPT further increased the anticancer effect of 10-6 M 1,25(OH)2D3. Collectively, these results indicated that the treatment of HepG2 cells with 1,25(OH)2D3 inactivated Notch signaling, prevented proliferation, migration and invasion, and promoted apoptosis. The combined application of 1,25(OH)2D3 with DAPT may be a useful treatment for preventing the onset or progression of liver cancer. PMID- 30015940 TI - Short-term use of atorvastatin affects glucose homeostasis and suppresses the expression of LDL receptors in the pancreas of mice. AB - Low-density lipoprotein receptors (LDLRs) may serve a role in the diabetogenic effect of statins; however, the effects of statins on LDLR expression and its regulation in the pancreas and islets have yet to be determined. To exclude the long-term effects of treatment with atorvastatin, which allows mice to adapt, male C57BL/j and apolipoprotein E-deficient mice were acutely treated with oral atorvastatin for 6 weeks, and glucose homeostasis and LDLR expression in the pancreas and islets were examined. In the present study, it was observed that the short-term use of atorvastatin affected insulin sensitivity in normal mice and glucose tolerance in hyperlipidemic mice. Furthermore, it was identified that 6 weeks of treatment with atorvastatin suppressed LDLR expression in the pancreas and pancreatic islets in C57BL/j mice, and an increase in proprotein convertase subtilisin/kexin type 9 expression was additionally observed in the pancreas. However, 6 weeks of treatment with atorvastatin did not affect LDLR expression in the pancreas of hyperlipidemic mice. It may be concluded that the short-term use of atorvastatin disturbs glucose homeostasis and suppresses LDLR expression in the pancreas and pancreatic islets in C57BL/j mice, suggesting that the role of LDLR in the diabetogenic effect of statins requires further investigation. PMID- 30015941 TI - Overexpression of IQGAP1 promotes the angiogenesis of esophageal squamous cell carcinoma through the AKT and ERK-mediated VEGF-VEGFR2 signaling pathway. AB - Angiogenesis is crucial for the progression of esophageal squamous cell carcinoma (ESCC). Anti-angiogenesis by targeting important molecules has been considered as one of the most promising and efficient strategy for cancer therapy. Recent studies have demonstrated that the IQ-domain GTPase activating protein 1 (IQGAP1) plays critical roles in tumorigenesis and cancer progression. We previously reported that IQGAP1 is overexpressed in ESCC, and IQGAP1 knockdown can decrease cell proliferation and metastasis ability in vitro and in vivo. However, the effects of IQGAP1 on the angiogenesis of ESCC and its underlying mechanisms remain unknown. In the present study, we found that IQGAP1 overexpression promoted tumor angiogenesis confirmed by human umbilical vascular endothelial cell (HUVEC) tube formation in vitro and chicken embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, IQGAP1 overexpression in ESCC cells increased expression of vascular endothelial growth factor (VEGF) and phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). Meanwhile, we found that levels of AKT and ERK phosphorylation were upregulated in IQGAP1-overexpressing cells. Importantly, IQGAP1-knockdown cells showed the opposing results. Furthermore, AKT and ERK inhibitors not only significantly decreased VEGF expression and VEGFR2 phosphorylation in IQGAP1-overexpressing cells, but also abolished the pro-angiogenic effect of IQGAP1 overexpression on angiogenesis in the HUVEC tube formation and chicken embryo CAM assay. Taken together, this evidence confirms that IQGAP1 overexpression promotes tumor angiogenesis via the AKT and ERK-mediated VEGF-VEGFR2 signaling pathway in ESCC, and IQGAP1 may be an attractive therapeutic target for cancer anti-angiogenesis treatment. PMID- 30015942 TI - Apoptotic effect of pyrroloquinoline quinone on chondrosarcoma cells through activation of the mitochondrial caspase-dependent and caspase-independent pathways. AB - Chondrosarcomas are malignant tumors of the bone that exhibit resistance to chemotherapy and radiation. Pyrroloquinoline quinone (PQQ) is a bacterial redox co-factor and antioxidant that has been found to induce apoptosis in various cancer cells. This study investigated the role of PQQ in cell apoptosis of chondrosarcoma cells and the underlying pathways involved. We confirmed that PQQ was cytotoxic to chondrosarcoma SW1353 cells by a cell cytotoxicity assay. Furthermore, flow cytometry showed that the number of apoptotic cells increased in a concentration-dependent and time-dependent manner following PQQ treatment, but this effect was not significant in normal cells. Co-immunoprecipitation assays showed that the binding of Smac to X-linked inhibitor-of-apoptosis protein (XIAP) was significantly increased and the binding of XIAP with caspase-3 was significantly decreased following PQQ treatment. This was accompanied by a decrease in the levels of caspase-1 and procaspase-3, as demonstrated by western blot analysis. Western blotting also showed that the level of cytochrome c in the mitochondria was decreased and its level in the cytoplasm was increased. These findings indicate the role of caspase-dependent apoptotic pathways in the effect of PQQ. Furthermore, the cytoplasmic and nuclear levels of apoptosis-inducing factor (AIF) were increased and its mitochondrial levels were decreased, and similar results were obtained for endonuclease G. Thus, the role of caspase independent pathways was also demonstrated. Finally, in vivo tumor implantation experiments showed that PQQ was able to inhibit tumor growth in mice with chondrosarcoma. These findings demonstrated that PQQ induced apoptosis in human chondrosarcoma cells by activating mitochondrial caspase-dependent and caspase independent pathways. Thus, the proteins involved in these pathways may have potential as antitumor treatment targets for chondrosarcoma. PMID- 30015943 TI - ESE-1 suppresses the growth, invasion and migration of human NSCLC cells and tumor formation in vivo. AB - Lung cancer is the first leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a poor patient prognosis. Identification of promising molecular targets is required for the effective prevention and therapy of NSCLC. Epithelial-specific ETS-1 (ESE-1) belongs to the superfamily of ETS transcription factors. The effect of ESE-1 on tumorigenesis is controversial in several types of cancer while its role in lung cancer remains unknown. The present study was designed to investigate whether ESE-1 expression affects tumorigenic activity using human NSCLC cells and a mouse xenograft model. ESE-1 expression suppressed anchorage-independent growth in soft agar assay and led to an increase in G1 arrest and apoptosis in human NSCLC cells. ESE-1 expression suppressed the invasion and migration of human NSCLC cells. Western blot analysis, RT-PCR and promoter assay indicated that ESE-1 expression was transcriptionally downregulated by treatment of transforming growth factor (TGF)-beta, an EMT (epithelial-mesenchymal transition) stimulator. The xenograft study indicated that ESE-1 expression inhibited tumor formation and development. Our data demonstrated that ESE-1 plays a key role as a tumor suppressor in human NSCLC. PMID- 30015944 TI - MicroRNA-449a is a potential predictor of colitis-associated colorectal cancer progression. AB - An early diagnosis of colitis-associated colorectal cancer (CAC) is important for its clinical management. However, it is currently difficult to distinguish the different stages of CAC development. MicroRNA dysregulation is common in human colorectal disorders, however little is known regarding whether miRNA affects tumor progression by regulating inflammation. In the present study, we identified a novel miRNA (miR-449a), the expression of which was significantly reduced in CAC tissues than in paired adjacent non-cancerous tissues (ANTs). Notably, the level of miR-449a was in a markedly decreased pattern during the neoplastic transformation of ulcerative colitis (UC)-to-CAC, as demonstrated by both clinical investigations and the experimental mouse model induced by AOM/DSS treatment. In addition, we observed that decreased miR-449a expression was associated with advanced T or N status, later clinical stage and poor histological differentiation of CAC. Mechanistic studies revealed that miR-449a inhibited the growth and metastasis of human colon cancer cells by directly binding to the 3'-UTR of Notch-1 and thereby, suppressed the activation of the Notch signaling pathway. Therefore, these findings provide strong evidence for the translational potential of miR-449a in the discrimination of patients with UC that is likely to progress into CAC, from those unlikely to progress, as well as in the prognosis and diagnosis of CAC. PMID- 30015945 TI - Long non-coding RNA UCA1 promotes papillary thyroid cancer cell proliferation via miR-204-mediated BRD4 activation. AB - Long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been used in tumor development and progression in many types of cancer. However, the function and mechanism underlying the action of UCA1 in papillary thyroid cancer (PTC) remains unclear. Therefore, these topics were investigated in the present study by in vitro and in vivo experiments. It was demonstrated that the expression level of UCA1 was more significantly upregulated in PTC cell lines and tissues when compared with the immortal human thyroid follicular cell line and adjacent normal tissues, respectively. UCA1 knockdown significantly inhibited PTC cell viability, colony formation and the bromodomain containing 4 (BRD4) expression level in vitro, and retarded PTC tumor growth in vivo. In the previous study, microRNA (miR)-204 inhibited thyroid cancer progression and was regulated by UCA1 in other types of cancer. In addition, by conducting dual luciferase reporter assays, it was confirmed that miR-204 directly binds to UCA1 and the 3' untranslated region of BRD4. Furthermore, UCA1 competed with BRD4 for miR-204 binding. miR-204 knockdown enhanced BRD4 expression, which can be partially restored by short hairpin-UCA1. The results of the present study illustrated that UCA1 promotes PTC progression by acting as a competing endogenous RNA by sponging miR-204. In conclusion, UCA1 may be regarded as an oncogenic lncRNA, promoting PTC cell proliferation, and be a potential target for human PTC treatment. PMID- 30015946 TI - A novel regulatory circuit of miR-152 and DNMT1 in human bladder cancer. AB - Downregulation of microRNA-152 (miR-152) has been observed in various types of human malignancies, including Bladder cancer (BC). However, the role of miR-152 in the development and progression of BC is still unclear. In our previous study, we identified a functional crosstalk between miR-152 and DNA methyltransferase 1 (DNMT1) involved in Nis-induced malignant transformation. In the present study, we found that the expression of miR-152 was specifically downregulated in BC cells and tissues via the DNA hypermethylation of the miR-152 promoter. The overexpression of miR-152 in BC cells resulted in a reduction of DNMT1, whereas the inhibition of the expression of miR-152 induced an elevated level of DNMT1. Further studies revealed that miR-152 directly downregulated the expression of DNMT1 by targeting the 3'-UTR of its transcript in BC cells. In addition, ectopic expression of miR-152 in BC cells significantly inhibited cell proliferation, whereas the inhibition of miR-152 expression led to increased cell proliferation. These findings indicated a novel regulatory circuit of miR-152/DNMT1 in BC, and more importantly, the combination of miR-152 and DNMT1 may function as promising therapeutic modalities and early biomarkers for BC. PMID- 30015947 TI - Associations of miR-146aC>G, miR-149C>T, miR-196a2C>T and miR-499A>G polymorphisms with brain tumors. AB - MicroRNAs (miRNAs/miRs) are short, non-coding RNAs that are implicated in tumorigenesis, functioning as tumor suppressors and oncogenes. However, the clinical significance of miRNA expression profiles for brain tumors remains unclear. Therefore, the present study was designed to investigate the associations between miRNA genetic variants and brain tumor risk. A total 362 participants were recruited, including 179 who were healthy subjects and 183 who were patients with brain tumors confirmed as gliomas, meningiomas or schwannomas. This study investigated the single nucleotide polymorphisms miR-146aC>G, miR 149T>C, miR-196a2T>C and miR-499A>G by polymerase chain reaction-restriction fragment length polymorphism. It was found that the dominant miR-149 and CC genotypes were significantly more frequent in patients with glioma. The odds ratios for the C-C-C-G, C-T-C-G and G-C-T-G haplotypes (miR-146aC>G-miR-149T>C miR-196a2T>C-miR-499A>G) were significantly increased in glioma, as were the odds ratios for the GCT haplotype of miR-146aC>G, miR-149T>C and miR-196a2T>C, and for the C-C-G haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G. In meningioma, the odds ratios were increased in the G-T-C-G haplotype of miR-146aC>G, miR 149T>C, miR-196a2T>C and miR-499A>G. The odds ratios were also increased in the G C-G haplotype of miR-146aC>G, miR-196a2T>C and miR-499A>G, and in the C-C-G haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G. The odds ratios for schwannoma were increased in the G-C-T-G haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C and miR-499A>G, and in the C-C-G haplotype of miR-149T>C, miR 196a2T>C and miR-499A>G. In conclusion, these results suggested that the miR-149 polymorphism may be involved in the development of gliomas, and the C-C-G haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G showed increased odds ratios for all types of brain tumors. PMID- 30015948 TI - Eotaxin-1 and MCP-1 serve as circulating indicators in response to power frequency electromagnetic field exposure in mice. AB - The increasing public concern regarding the potential health risks of exposure to electromagnetic fields (EMFs) has led to intensive research in this area. However, it remains unclear whether potential pro-oncogenic effects may be caused by power frequency EMF (PFEMF) exposure. To address the associated risk factors, the present study exposed 4-week old Balb/c mice to 0, 0.1, 0.5 and 2.5 mT of constant 50 Hz Helmholtz coil-type PFEMF for 90 days to explore the circulating chemokine indicators that may be associated with inflammation or cancer. No measurable weight difference existed between the control and PFEMF-exposure groups; however, the Luminex assay clearly demonstrated differentially responsive profiles of circulating chemokines upon PFEMF treatment. Monocyte chemoattractant protein (MCP)-3, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and MIP 2 levels in serum were not significantly altered by PFEMF during the 3-month exposure period; however, the circulating levels of other chemokines including IP 10, GROalpha, RANTES, EOTAXIN-1 and MCP-1 exhibited significant changes upon treatment. Among the responsive chemokines, EOTAXIN-1 and MCP-1 were significantly increased by 0.5 mT of PFEMF treatment, which may support their use as indicators of PFEMF exposure. This novel finding highlights the potential pro inflammatory nature of power frequency, which may shed light on the mechanisms underlying PFEMF-induced diseases, including cancer. PMID- 30015949 TI - RBP4 regulates trophoblastic cell proliferation and invasion via the PI3K/AKT signaling pathway. AB - Insufficient trophoblast invasion is associated with preeclampsia (PE) development. Retinol-binding protein 4 (RBP4) is important for regulating cell differentiation, migration and invasion. The aim of the present study was to determine RBP4 expression and function in the human placenta and to examine the underlying mechanisms. In the present study, RBP4 expression was determined in serum samples from 35 pregnant women with PE and 30 healthy pregnant women using enzyme-linked immunosorbent assays. Cell proliferation was assessed by Cell Counting Kit-8 assays, and cell invasion was examined with transwell assays. RBP4 concentrations were significantly lower in the PE group when compared with the control group. RBP4 overexpression enhanced HTR8/SVneo cell proliferation and invasion, and the levels of phosphorylated (p-) phosphoinositide 3-kinase (PI3K) and p-protein kinase B (AKT) in HTR8/SVneo cells. RBP4 knockdown significantly inhibited HTR8/SVneo cell proliferation and invasion, and repressed the expression of matrix metalloproteinases. In addition, RBP4 knockdown significantly reduced the levels of p-PI3K and p-AKT in HTR8/SVneo cells. Taken together, the results of the present study demonstrated that RBP4 overexpression increased HTR8/SVneo cell proliferation and invasion by suppressing PI3K/AKT signaling and RBP4 knockdown induced the opposite effects. PMID- 30015950 TI - BMP9 inhibits the growth of breast cancer cells by downregulation of the PI3K/Akt signaling pathway. AB - Bone morphogenetic protein 9 (BMP9) is a member of the BMP family, which is involved in the regulation of tumor biogenesis, development and metastasis. The present study aimed to investigate whether BMP9 inhibits the growth of MDA-MB-231 breast cancer cells via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. It was shown that the expression level of BMP9 was significantly decreased, while that of phosphorylated Akt (p-Akt) was markedly increased in breast cancer tissues compared with these levels in the normal adjacent tissues. An adenovirus overexpressing BMP9 was used to infect the MDA-MB-231 cells. The expression level of p-Akt in the MDA-MB-231/BMP9 group was shown to be significantly lower than that in the MDA-MB-231/green fluorescent protein (GFP) and MDA-MB-231 control groups. The expression levels of cyclins D1, B1 and E1, c Myc and matrix metalloproteinase 9 (MMP9) in the MDA-MB-231/BMP9 group were also reduced. The generation of a nude mouse xenograft tumor model revealed that the tumor volumes of the MDA-MB-231/BMP9 group (0.32+/-0.05 cm3) was significantly lower compared with that of the MDA-MB-231/GFP (1.10+/-0.05 cm3) and MDA-MB-231 (1.12+/-0.12 cm3) groups, and the expression level of p-Akt protein in the MDA-MB 231/BMP9 group was significantly lower compared with that of the MDA-MB-231/GFP and MDA-MB-231 groups in the nude mouse xenograft model. Taken together, these results indicate that BMP9 inhibits the growth of MDA-MB-231 breast cancer cells by inhibiting the PI3K/Akt signaling pathway both in vivo and in vitro. PMID- 30015951 TI - Sevoflurane attenuates ventilator-induced lung injury by regulating c-PLA2 expression. AB - The aim of the present study was to investigate the potential role of club cell secretory protein (CCSP), an endogenous modulator, in reducing pulmonary inflammation induced by sevoflurane following one-lung ventilation (OLV). Healthy Japanese white rabbits were randomly assigned to six groups: Sham-operated group (group S); respiratory management of OLV group (group O); OLV + sevoflurane treated group (group OF), club cells exfoliated + sham-operated group (group NA), club cells exfoliated + OLV group (group NAO); and club cells exfoliated + OLV + sevoflurane treated group (group NAOF). At the end of the experimental observation, all animals in the different groups were sacrificed and lung injury was evaluated according to the lung wet/dry weight ratio and histological scoring system. Lung homogenates were harvested to detect the mRNA and protein expression of cytosolic phospholipase A2 (c-PLA2) and CCSP. The content of arachidonic acid was measured using an ELISA. Following OLV treatment, c-PLA2 expression was increased, CCSP expression was decreased and lung injury scores were significantly increased. Sevoflurane inhalation in the OLV-treated group induced an upregulation of CCSP and a downregulation of c-PLA2 expression. In the group NAO, in which the club cells were simultaneously exfoliated, OLV caused more severe lung damage and induced higher expression of c-PLA2 compared with that in group O. However, sevoflurane inhalation reduced the extent of lung injury and the expression of c-PLA2, even when the endogenous modulator of lung inflammation, CCSP, was exfoliated (group NAOF). These results indicated that OLV promoted lung inflammation through the CCSP and c-PLA2 pathway. However, the results from the club cells exfoliated group indicated that the CCSP may not be involved in the protective effect exerted by sevoflurane inhalation. PMID- 30015952 TI - Synergistic effects of tetrandrine combined with ionizing radiation on a murine colorectal carcinoma-bearing mouse model. AB - Tetrandrine (TET), a traditional Chinese clinical agent, has been used for the treatment of many diseases, including cancers. The purpose of the present study was to investigate the combined effects of TET and ionizing radiation (IR) on murine CT26 colorectal adenocarcinoma cells in vitro and in vivo. A CT26 cell line transfected with dual HSV-1 thymidine kinase and firefly luciferase (luc) reporter genes was used. The half-maximal inhibitory concentration (IC50) of TET in CT26/tk-luc cells was ~10 uM. An additive effect was observed after combination of both agents based on a colony formation assay. Apoptosis and cleaved caspase-3 levels were increased significantly in cells after combination treatment, as shown by flow cytometric analysis, DNA fragmentation and western blotting. However, tumor growth inhibition and therapeutic efficacy of TET combined with IR in vivo were identified to be synergistic, as monitored by tumor growth delay time, measured with a digital caliper. A significant inhibition of tumor growth was identified in the combination group compared with the radiation only group. Furthermore, non-invasive bioluminescent imaging (BLI) and gamma scintigraphy were also used to evaluate therapeutic efficacy. Both modalities revealed that the best tumor growth control was under combination treatment among all groups. The present study demonstrated that TET is not only beneficial for chemotherapy, but also has potential as a radiosensitizer for the treatment of cancer. PMID- 30015953 TI - Bioinformatic analysis of microRNA expression in Huntington's disease. AB - Huntington's disease (HD) is an inherited, progressive neurodegenerative disease caused by a CAG expansion in the Huntingtin (HTT) gene and various dysfunctions of biological processes in HD have been proposed. Although monogenic, the exact pathogenesis of HD currently remains unclear. To identify the synergistic microRNA (miRNA) pattern in HD, the miRNA expression profile dataset GSE64977 and the gene expression profile dataset GSE64810 were downloaded. Programming software R was used to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs). Target genes of DEMs were predicted using the TargetScan database. Gene ontology (GO) function of DEGs was generated using the FunRich and a miRNA-mRNA interaction network was constructed using Cytoscape software. In total, 1,612 DEGs and 10 DEMs were identified. GO terms mainly included inflammatory response and immune response in DEGs. A total of 745 target genes were predicted from the DEMs and 33 overlaps were identified between these target genes and DEGs. The miRNA network demonstrated that hsa-miR-4488, hsa-miR 196a-5p, and hsa-miR-549a had a high degree and may be involved with the pathogenesis and potential therapeutic targets of HD. PMID- 30015954 TI - miR-448 targets Rab2B and is pivotal in the suppression of pancreatic cancer. AB - Improvements in survival rates for pancreatic cancer have been slow and the morality rate continues to increase in patients. MicroRNA (miR)-448 is reported to be significantly downregulated in several types of cancer. In this study, Rab2B is target of miR-488 was confirmed by bioinformatics analysis and validated using a luciferase reporter assay. A total of 72 cases of pancreatic cancer in patients diagnosed at The First Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou, China) were enrolled, and cancer specimens and their adjacent normal tissues were collected for analysis. The expression levels of miR 448 and Rab2B in these tissues and in pancreatic cancer cell lines were quantified using reverse transcription-polymerase chain reaction analysis. miR 448 overexpression was achieved by cell transfection. Protein expression was assessed using western blot analysis. Cell viability, cell cycle and apoptosis were analyzed using CCK-8 assay and flow cytometry, respectively. The results revealed a negative correlation between miR-448 and Rab2B in the pancreatic tissues and cell lines. The results of bioinformatics analysis indicated that miR 448 directly targeted Rab2B. Aberrant miR-448 levels in PANC-1 cells downregulated the expression of Rab2B, and significantly decreased cell proliferation and promoted apoptosis of cancer cells. It was also found that miR 448 mimics resulted in G0/G1 cell cycle arrest and affected the expression of cell cycle regulators, including cyclin D1, p21 and p27. In addition, the miR-448 mimics led to inactivation of the Akt/Mammalian target of rapamycin signaling pathway. The miR-448 mimics induced apoptosis and activated the expression of caspase-3, caspase-9 and poly(ADP-ribose) polymerase. The results suggested that miR-448 was a negative regulator of Rab2B and promoted cell cycle arrest and apoptosis in pancreatic cancer. PMID- 30015955 TI - Low-frequency ultrasound and microbubbles combined with simvastatin promote the apoptosis of MCF-7 cells by affecting the LATS1/YAP/RHAMM pathway. AB - Ultrasound scanning has widespread used in clinical practice and also has therapeutic applications. Simvastatin is a statins that is able to competitively inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The aim of the present study was to investigate the roles and mechanisms of low-frequency ultrasound (LFU) and microbubbles combined with simvastatin on MCF-7 cell growth and apoptosis. Cell viability, apoptosis and cell cycle were evaluated using an MTT assay and flow cytometry, respectively. The expression of related proteins was measured by western blot assay. The results revealed that simvastatin and LFU with microbubbles reduces the viability of MCF-7 cells. The combination of LFU and microbubbles with simvastatin promoted the apoptosis of MCF-7 cells. Furthermore, it was confirmed that LFU and microbubbles combined with simvastatin affected the large tumor suppressor 1 (LATS1)/yes-associated protein (YAP)/receptor of the hyaluronan-mediated motility (RHAMM) pathway in MCF-7 cells. It was determined that LATS1 acts as a negative regulator in the LATS1/YAP/RHAMM pathway in MCF-7 cells. In conclusion, the results of the present study indicate that LFU and microbubbles combined with simvastatin promotes the apoptosis of MCF-7 cells via the LATS1/YAP/RHAMM pathway. The present study suggested a possible strategy for the treatment of breast cancer. PMID- 30015957 TI - Association between the HMGB1/TLR4 signaling pathway and the clinicopathological features of ovarian cancer. AB - In the present study, the expression levels of high-mobility group protein B1 (HMGB1), Toll-like receptor 4 (TLR4), nuclear factor (NF)-kappaB and tumor necrosis factor (TNF)-alpha in malignant epithelial ovarian cancer (MEOC) were investigated in regards to several clinicopathological characteristics. A total of 20 patients with MEOC who underwent surgery were recruited in the present study. The mRNA and protein expression of HMGB1, TLR4, NF-kappaB and TNF-alpha was determined in patients with MEOC and compared with expression levels in 20 patients diagnosed with benign ovarian cysts (BOC). It was demonstrated that the mRNA and protein expression of HMGB1, TLR4, NF-kappaB and TNF-alpha in MEOC was significantly increased, compared with the BOC group (P<0.01). The gene and protein expression of HMGB1, TLR4, NF-kappaB and TNF-alpha was significantly increased in the advanced tumor stage and poorly differentiated group (P<0.01). The present study suggested that the HMGB1/TLR4 signaling pathway was overactive in MEOC, and was associated with MEOC tumor cell proliferation, invasion and metastasis. Furthermore, this may have been mediated via NF-kappaB signaling. PMID- 30015956 TI - Moxidectin inhibits glioma cell viability by inducing G0/G1 cell cycle arrest and apoptosis. AB - Moxidectin (MOX), a broad-spectrum antiparasitic agent, belongs to the milbemycin family and is similar to avermectins in terms of its chemical structure. Previous research has revealed that milbemycins, including MOX, may potentially function as effective multidrug resistance agents. In the present study, the impact of MOX on the viability of glioma cells was examined by MTT and colony formation assay, and the molecular mechanisms underlying MOX-mediated glioma cell apoptosis were explored by using flow cytometry and apoptosis rates. The results demonstrated that MOX exerts an inhibitory effect on glioma cell viability and colony formations in vitro and xenograft growth in vivo and is not active against normal cells. Additionally, as shown by western blot assay, it was demonstrated that MOX arrests the cell cycle at the G0/G1 phase by downregulating the expression levels of cyclin-dependent kinase (CDK)2, CDK4, CDK6, cyclin D1 and cyclin E. Furthermore, it was revealed that MOX is able to induce cell apoptosis by increasing the Bcl-2-associated X protein/B-cell lymphoma 2 ratio and activating the caspase-3/-9 cascade. In conclusion, these results suggest that MOX may inhibit the viability of glioma cells by inducing cell apoptosis and cell cycle arrest, and may be able to function as a potent and promising agent in the treatment of glioma. PMID- 30015958 TI - Inhibitory effect of timolol on topical glucocorticoid-induced skin telangiectasia. AB - The aim of the present study wasto investigate the potential inhibitory effect of timolol on topical glucocorticoid-induced skin telangiectasia. In rabbits, flumethasone ointment was used to induce skin telangiectasia in the inner ear. Subsequently, timolol maleate (0.5%) eye drops (TMEDs) were administered twice daily for 4 weeks. Expression of the antibacterial peptides 37-amino acid peptide (LL-37) and kallikrein-5 (KLK5) was detected using quantitative polymerase chain reaction (PCR) and semi-quantitative reverse transcription-PCR. In patients with facial skin telangiectasia, one cheek of each patient was assigned to a treatment group and the other to a control group. For the treatment group cheeks, topical application of TMEDs was combined with 0.1% tacrolimus ointment once or twice daily for 8 weeks. The control group cheeks were administered with 0.1% tacrolimus ointment alone. Alterations in lesions were recorded by dermoscopy, and the L, a and b values of lesions were measured, based on the Commission Internationale de l'Eclairage system, with a chromameter prior to and at 1, 2, 4 and 8 weeks following treatment. The results indicated that erythema, papules and telangiectasia were significantly diminished following 4 weeks of treatment with TMEDs in rabbits. Notably, the expression of LL-37 and KLK5 mRNA was increased in the negative control group; however, it was decreased in the trial and blank groups. Clinical and dermoscopy images demonstrated that erythema was reduced in the 2 groups for 1 week, and that telangiectasia in the treatment group was markedly reduced compared with the control group at 4 weeks. The difference of the L and a values of lesions between the treatment and control group was significant (P<0.05). Overall, the present results suggested that the abnormal expression of LL-37 may be one of the mechanisms underlying the pathogenesis of facial corticosteroid addiction dermatitis (FCAD) and TMEDs may inhibit the mRNA expression of LL-37 by downregulating KLK5; in this regard, TMEDs may serve a role in attenuating telangiectasia, which may be beneficial in improving the telangiectasia symptoms of FCAD. PMID- 30015959 TI - Developing a radiosensitivity gene signature for Caucasian patients with breast cancer. AB - Adjuvant radiotherapy is an important clinical treatment option for patients with breast cancer. However, for Caucasian patients, the clinical benefit of adjuvant radiotherapy can differ from African-American patients with respect to the overall survival. The goal of the current study was to develop a gene signature and to pre-identify patients likely to benefit from radiotherapy. Using publicly available breast cancer data from The Cancer Genome Atlas, a new cross-validation procedure was proposed for developing a gene signature and predicting radiosensitive patients. The results demonstrated that the predicted radiosensitive patients who received radiotherapy exhibited a significantly better survival, while the effect of radiotherapy was not significant for predicted non-radiosensitive patients. Further hierarchical cluster analysis revealed that the predicted sensitivity for each patient corresponded closely to the results of the cluster analysis. Collectively, the findings of the current study demonstrated that a radiosensitive molecular signature can be used to identify radiosensitive Caucasian patients with breast cancer. PMID- 30015960 TI - Lycium barbarum polysaccharides protect human trophoblast HTR8/SVneo cells from hydrogen peroxide-induced oxidative stress and apoptosis. AB - Pregnancy complications are associated with abnormal cytotrophoblast differentiation and invasion. Hydrogen peroxide (H2O2) is an important mediator of oxidative ischemia/reperfusion stress in the placenta. Lycium barbarum polysaccharides (LBP) have been demonstrated to counteract oxidative free radicals. The effects of LBP in trophoblast HTR8/SVneo cells injured with H2O2 were examined. A cell counting kit-8 assay was performed to detect the effect of LBP at different concentrations on the proliferative ability of H2O2 injured trophoblast cells. Flow cytometry was used to determine the levels of reactive oxygen species (ROS), mitochondria membrane potential (MMP) disruption and apoptosis. Superoxide dismutase (SOD) activity and lactate dehydrogenase (LDH) leakage into the supernatant was detected by ultraviolet spectrophotometry. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to detect the expression of apoptosis-associated factors, including survivin, hypoxia inducible factor 1-alpha (HIF1-alpha), Bcl-2 apoptosis regulator (Bcl-2), Bcl-2 associated X apoptosis regulator (Bax). The results revealed that LBP protected the proliferative ability of trophoblast cells injured with H2O2 in a dose-dependent manner. LBP inhibited the oxidative stress induced by H2O2, by reducing ROS and LDH levels and increasing SOD activity. Additionally, LBP decreased MMP disruption and cell apoptosis induced by H2O2, by increasing the mRNA and protein expression of survivin, HIF1-alpha and Bcl-2 and decreasing Bax expression. Therefore, it was concluded that LBP protected human trophoblast cells from H2O2-induced oxidative stress and cell apoptosis via regulation of apoptosis-associated factor expression. It will provide a novel strategy for the treatment of pregnancy complications. PMID- 30015961 TI - Long non-coding RNA HR1 participates in the expression of SREBP-1c through phosphorylation of the PDK1/AKT/FoxO1 pathway. AB - Sterol regulatory element binding protein-1c (SREBP-1c), which serves an essential role in the process of fat synthesis, is a key adjustment factor that regulates the dynamic balance of lipid metabolism. SREBP-1c activates the transcription of multiple genes encoding for enzymes involved in the synthesis of triglycerides (TG) and fatty acids (FA) and accelerates lipid synthesis. Previous analysis indicated that long non-coding RNA HCV regulated 1 (lncHR1) participates in lipid metabolism in vivo and regulates the level of SREBP-1c protein. However, the mechanism of lncHR1 in regulating SREBP-1c levels has not been revealed. In the present study, a fatty degeneration cell model was used to study how lncHR1 regulates the SREBP-1c protein at the cellular level. Furthermore TG accumulation was assessed according to morphological analysis. Reverse transcription quantitative polymerase chain reaction and western blotting were used to detected the expression of SREBP-1c. An activator and an inhibitor of phosphoinositide 3 kinase/AKT phosphorylation (IGF-1 and LY294002, respectively) were used to study the effect of lncHR1 on this pathway. It was verified that lncHR1 regulated SREBP 1c levels and the phosphorylation of AKT in the steatosis cell model. Detailed molecular mechanisms mediated by lncHR1 were associated with the phosphorylation AKT/FoxO1 in Huh7 cell lines. Simultaneously, lncHR1 affected the location of FoxO1 inside and outside of the nucleus. Furthermore, the phosphorylation of PDK1 upstream of AKT was regulated through overexpression or knockdown lncHR1, as determined by western blotting. Taken together, these data show that lncHR1 inhibits SREBP-1c levels through the phosphorylation of the PDK1/AKT/FoxO1 axis. PMID- 30015962 TI - Knockdown of metadherin inhibits cell proliferation and migration in colorectal cancer. AB - Metadherin (MTDH) is a multifunctional oncogene involved in tumor cell migration and metastasis through regulating a number of oncogenic signaling pathways in various human malignancies. Previous studies have demonstrated that MTDH is overexpressed in human colorectal cancer (CRC) and associated with cancer progression and a poor prognosis. However, the underlying mechanisms remain largely unknown. The present study investigated the expression and role of MTDH in CRC cells as well as the underlying mechanism of this. Western blot analysis and quantitative polymerase chain reaction were conducted to determine protein and mRNA expression of MTDH in three human CRC cell lines. A short hairpin RNA (shRNA) targeting MTDH was introduced into CRC HCT116 cells to stably inhibit MTDH expression. A Cell Counting Kit-8 assay, colony formation assay, Transwell assay and flow cytometry were used to investigate the effect of MTDH-knockdown on cell proliferation, migration, apoptosis and cell cycle arrest. Western blotting was performed to examine the protein expression levels of cell growth- and apoptosis-associated genes. The results demonstrated that MTDH was commonly expressed in CRC cell lines. MTDH silencing significantly suppressed cell growth, colony forming ability and migration while inducing the apoptosis of HCT116 cells. In addition, MTDH depletion induced S phase cell cycle arrest in HCT116 cells. Mechanistically, knockdown of MTDH markedly downregulated the expression of phosphorylated protein kinase B, c-Myc, proliferating cell nuclear antigen and B-cell lymphoma 2 (Bcl-2) protein in HCT116 cells, and the expression of p53 and Bcl-2-associated X protein was significantly increased compared with the negative control shRNA group (P<0.05), suggesting that MTDH may function through the expression of numerous types of apoptosis-associated and signaling channel proteins in CRC cells. Taken together, these data indicated that MTDH may serve as a biomarker and candidate therapeutic target for CRC. PMID- 30015963 TI - Associations of CXCL16, miR-146a and miR-146b in atherosclerotic apolipoprotein E knockout mice. AB - Atherosclerosis is the primary cause of cardiovascular and cerebrovascular diseases. Recent studies have revealed that C-X-C motif chemokine ligand 16 (CXCL16), microRNA (miR)-146a and miR-146b may have important roles in atherosclerotic diseases. However, the associations of CXCL16, miR-146a and miR 146b in atherosclerotic diseases in vivo remain unclear. Previous studies have demonstrated that miR-146a and miR-146b may negatively regulate the toll like receptor (TLR4)/nuclear factor (NF)-kappaB signaling pathway to repress the inflammatory response. The present study investigated the associations of CXCL16, miR-146a and miR-146b in atherosclerotic apolipoprotein E (ApoE)-/- mice in vivo. The expression levels of CXCL16, TLR4/NF-kappaB signaling pathway, miR-146a and miR-146b in the control and atherosclerotic ApoE-/- mice were investigated via reverse transcription-quantitative polymerase chain reaction and western blot analysis. The present study demonstrated that the expression of CXCL16 was significantly upregulated in atherosclerotic ApoE-/- mice compared with control ApoE-/- mice. The expression levels of TRL4, interleukin-1 receptor-associated kinase 1, tumor necrosis factor receptor associated factor 6, NF-kappaB, tumor necrosis factor-alpha and interleukin-1beta were also significantly upregulated in atherosclerotic ApoE-/- mice compared with control mice. However, the present study revealed that the expression levels of miR-146a and miR-146b were significantly downregulated in atherosclerotic ApoE-/- mice compared with control ApoE-/- mice. Overall, the results of the present study suggested that CXCL16 may regulate the TRL4/NF-kappaB/CXCL16 signaling pathway, and that miR-146a and miR 146b may negatively regulate CXCL16 via this pathway in atherosclerosis in vivo. PMID- 30015964 TI - Alterations in necroptosis during ALDH2-mediated protection against high glucose induced H9c2 cardiac cell injury. AB - The aim of the present study was to investigate whether necroptosis occurs in high glucose (HG)-induced H9c2 cardiac cell injury and whether the activation of aldehyde dehydrogenase 2 (ALDH2) can inhibit necroptosis. H9c2 cardiac cells were treated with 35 mM glucose to establish a HG-induced cell injury model. Alda-1 (20 uM), a specific activator of ALDH2 and necrostatin-1 (Nec-1, 100 uM), an inhibitor of necroptosis were used to treat H9c2 cardiac cells under HG conditions. Cell viability was measured using a Cell Counting Kit-8 assay and reactive oxygen species (ROS) generation was measured by the dihydroethidium staining method. ALDH2 activity was measured at 450 nm. The mRNA and protein expression of ALDH2, necroptosis-associated genes, receptor-interacting protein (RIP)1, RIP3 and mixed lineage kinase domain like pseudokinase (MLKL), were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. The expression of cleaved caspase-3 protein was also examined by western blotting. The results demonstrated that under HG conditions, cell viability, ALDH2 activity, mRNA and protein expression were decreased. Furthermore, ROS generation, mRNA and protein expression of RIP1, RIP3, MLKL and the protein expression of cleaved caspase-3 were increased. Treatment with Alda-1 or Nec-1 attenuated HG-induced downregulation of ALDH2 activity, mRNA and protein expression. In addition, RIP1, RIP3, MLKL mRNA, and protein expression were downregulated. Furthermore, Alda-1 but not Nec-1 decreased cleaved caspase-3 protein expression. Collectively these data indicated that activation of ALDH2 protected H9c2 cardiac cells against HG-induced injury, partly by inhibiting the occurrence of necroptosis. PMID- 30015965 TI - Effect of cellular mass on chondrogenic differentiation during embryoid body formation. AB - One approach to cell differentiation is to use the natural capacity of pluripotent stem cells to form three germ layers via embryoid bodies (EB). However, unification of this process during in vitro culture remains challenging and many microenvironmental factors including the number of cells in the culture can influence differentiation patterns. The number of cells serves a crucial role as it determines access to nutrients, the distribution of oxygen concentration and cellular interactions, all of which influence the fate of the differentiated cells. The influence of EBs derived from human pluripotent cells on the chondrogenic potential of such cells is not well understood. For this reason, the present study sought to determine the effect of varying amounts of cells on the properties of EBs derived from human embryonic stem cells (BG01V cell line). In the present study, 500-2,000 cells per well were cultivated from 5 to 15 days in suspension cell culture. Expression of pluripotency genes and germ layer markers were evaluated in order to determine the EBs with the greatest and least mesodermal properties. Genes associated with pluripotency and chondrogenesis were also evaluated to assess the influence of suspension culture duration and EB size on chondrogenic differentiation. Immunofluorescence staining for pluripotent and chondrocyte-associated proteins confirmed successful differentiation into chondrocyte-like cells. Alcian blue staining confirmed deposition of proteoglycans. These results suggested that EBs formed in 500-cell wells possess the highest mesodermal and prochondrogenic properties. Differentiation of EBs into chondrocytes on day 5 in 500-cell wells was more efficient than in that observed in larger and older EBs. PMID- 30015966 TI - DMBA promotes ErbB2-mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability. AB - Environmental factors, including 7,12-dimethylbenz[a]anthracene (DMBA) exposure, and genetic predisposition, including ErbB2 overexpression/amplification, have been demonstrated to increase breast cancer susceptibility. Although DMBA- and ErbB2-mediated breast cancers are well-studied in their respective models, key interactions between environmental and genetic factors on breast cancer risk remain unclear. Therefore, the present study aimed to investigate the effect of DMBA exposure on ErbB2-mediated mammary tumorigenesis. MMTV-ErbB2 transgenic mice exposed to DMBA (1 mg) via weekly oral gavage for 6 weeks exhibited significantly enhanced mammary tumor development, as indicated by reduced tumor latency and increased tumor multiplicity compared with control mice. Whole mount analysis of premalignant mammary tissues from 15-week-old mice revealed increased ductal elongation and proliferative index in DMBA-exposed mice. Molecular analyses of premalignant mammary tissues further indicated that DMBA exposure enhanced epidermal growth factor receptor (EGFR)/ErbB2 and estrogen receptor (ER) signaling, which was associated with increased mRNA levels of EGFR/ErbB2 family members and ER-targeted genes. Furthermore, analysis of tumor karyotypes revealed that DMBA-exposed tumors displayed more chromosomal alterations compared with control tumors, implicating DMBA-induced chromosomal instability in tumor promotion in this model. Together, the data suggested that DMBA-induced deregulation of EGFR/ErbB2-ER pathways plays a critical role in the enhanced chromosomal instability and promotion of ErbB2-mediated mammary tumorigenesis. The study highlighted gene-environment interactions that may increase risk of breast cancer, which is a critical clinical issue. PMID- 30015967 TI - Bioinformatics approach reveals the key role of C-X-C motif chemokine receptor 2 in endometriosis development. AB - Endometriosis is a common gynecological disease, affecting 6-10% of women of reproductive age. The precise mechanisms underlying the development of endometriosis remain unclear. In the present study, a bioinformatics approach was applied to systematically identify the pathways and genes involved in the development of endometriosis and to discover potential biomarkers. The gene expression profiles of GSE6364, a microarray dataset of endometrial biopsies obtained from women with or without endometriosis, was downloaded from the Gene Expression Omnibus DataSets database that stores original submitter-supplied records (series, samples and platforms), as well as curated datasets. Differentially expressed gene (DEG) analysis was performed with GEO2R. DAVID was used to analyze the gene ontology enrichment of the DEGs. Gene Set Enrichment Analysis (GSEA) was conducted using the GSEA v3.0 software. Protein-protein interactions (PPI) were evaluated with the Search Tool for the Retrieval of Interacting Genes, and PPI network visualization was performed with Cytoscape. In addition, Cell Counting kit-8 and Transwell assays were performed on human endometrial stromal cells (HESCs). A total of 172 DEGs were extracted. Inflammatory response genes were significantly upregulated in the endometriosis tissues and C-X-C motif chemokine receptor 2 (CXCR2), was one of the most up regulated genes according to DEG analysis. Cell-based experiments confirmed that CXCR2 promoted the proliferation, migration and invasion of HESCs. In conclusion, a bioinformatics approach combined with in vitro experiments in the present study revealed that CXCR2 may be associated with the development of endometriosis and has potential as a biomarker for the diagnosis of endometriosis. PMID- 30015968 TI - MET-RON dual inhibitor, BMS-777607, suppresses cholangiocarcinoma cell growth, and MET-RON upregulation indicates worse prognosis for intra-hepatic cholangiocarcinoma patients. AB - Intra-hepatic cholangiocarcinoma (CCA) is an aggressive cancer with few effective therapeutic options. MET and RON have been found to be increased in a variety of tumors and to be associated with tumor progression and acquired resistance to therapy. The present study evaluated the efficacy of a MET-RON dual inhibitor (BMS-777607) for treating CCA and analyzed the prognostic significance of MET-RON upregulation. We treated CCA cell lines and rats with CCA with BMS-777607 to determine its effects on tumor growth and measured the MET-RON protein expression in samples obtained from 96 patients with CCA who previously underwent hepatectomies. A clonogenic assay revealed that BMS-777607 inhibited the growth of HuCCT1 and KKU-100 human CCA cells. It also decreased tumor growth in CCA rats. MET-RON upregulation independently predicted poor survival for CCA patients who previously underwent hepatectomies. In conclusion, MET-RON upregulation is a poor prognostic factor in CCA patients receiving hepatectomies and may be targeted using BMS-77760. PMID- 30015969 TI - miR-495 enhances the efficacy of radiotherapy by targeting GRP78 to regulate EMT in nasopharyngeal carcinoma cells. AB - Glucose-regulated protein 78 (GRP78) was revealed to be associated with the radioresistance of nasopharyngeal carcinoma (NPC) in our previous study. GRP78 is a highly expressed cell surface protein, and holds great promise as a cancer specific target. Its expression may be impacted by the regulation of miRNAs, which may be involved in the radioresistance of NPC. A better understanding of the mechanisms of radioresistance may generate new targets of therapy for NPC patients. The present study was designed to investigate the effect of microRNA targeting GRP78 on the radiosensitivity of NPC. First, we used miRWalk software to predict miRNAs that may interact with GRP78. Subsequently, analysis of miR-495 and GRP78 expression was performed in the primary tissues of 92 NPC tissues and cell lines by immunohistochemistry and real-time PCR and the results revealed that miR-495 expression was lower in radioresistant NPC tissues in comparison to chronic rhinitis tissues, and also lower in radioresistant 5-8F cells (5-8F-IR) in comparison to its parental 5-8F cells. Notably, we observed an inverse association between the expression miR-495 and GRP78. Our bioinformatics analysis led to the identification of miR-495 as the optimal miRNA interacting with GRP78 mRNA. Furthermore, miR-495 targeting the 3'untranslated region (UTR) of GRP78 was detected by a Dual-Glo Luciferase Assay system. Finally, we observed that miR-495 inhibition led to a significant increase in the radioresistance of 5-8F cells and higher GRP78 expression, which may be involved in epithelial-mesenchymal transition (EMT) phenotype. miR-495 targeted the 3'UTR of GRP78 and contributed to the efficacy of radiation therapy in NPC. PMID- 30015971 TI - Suppression of the SDF-1/CXCR4/beta-catenin axis contributes to bladder cancer cell growth inhibition in vitro and in vivo. AB - Previous studies have found that the activation of stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4)/beta-catenin signaling is associated with biological malignant potential in cancers. However, its function has been rarely reported in the progression of bladder cancer (BCa). The aim of the present study was to investigate the association of SDF-1/CXCR4 signaling and beta-catenin in regards to BCa cell proliferation, colony formation, migration and invasion. The methods used were MTS, colony formation, and Transwell migration and invasion assays which were performed in SW780 cells following treatment with the CXCR4 antagonist AMD3465, SDF-1, the beta-catenin antagonist FH535, AMD3465+SDF-1 or FH535+SDF-1. The mRNA and protein levels were assayed by RT-qPCR and western blotting, respectively. The effect of AMD3465 on SW780 cell xenograft growth in vivo was evaluated using a nude mouse model. According to our results, human BCa SW780 cells were identified as having high expression of CXCR4 and beta-catenin. Subsequently, we found that both CXCR4 and beta-catenin antagonists could significantly inhibit the proliferation, colony formation, migration and invasion of SW780 cells. Notably, SDF-1 could reverse the inhibitory effects of AMD3465 and FH535 on proliferation, colony formation, migration and invasion in SW780 cells. In AMD3465-treated SW780 cells, the expression of c-myc was significantly upregulated, and E-cadherin was downregulated in the presence of SDF-1. Furthermore, the tumor volume and average weight in the AMD3465-treated group were evidently less than these parameters in the control group, indicating that AMD3465 can inhibit SW780 cell growth in vivo. In conclusion, targeting the SDF-1/CXCR4/beta-catenin axis may be a potential therapeutic target for suppressing BCa progression. PMID- 30015970 TI - Caveolin-1 enhances RANKL-induced gastric cancer cell migration. AB - The classical pathway involving receptor activator of nuclear factor-kappaB (RANK) and its ligand (RANKL) induces the activation of osteoclasts and the migration of a variety of tumor cells, including breast and lung cancer. In our previous study, the expression of RANK was identified on the surface of gastric cancer cells, however, whether the RANKL/RANK pathway is involved in the regulation of gastric cancer cell migration remains to be fully elucidated. Lipid rafts represent a major platform for the regulation of cancer signaling; however, their involvement in RANKL-induced migration remains to be elucidated. To investigate the potential roles and mechanism of RANKL/RANK in gastric cancer migration and metastasis, the present study examined the expression of RANK by western blot analysis and the expression of caveolin-1 (Cav-1) in gastric cancer tissues by immunohistochemistry, in addition to cell migration which is measured by Transwell migration assay. The aggregation of lipid reft was observed by fluorescence microscopy and western blotting was used to measure signaling changes in associated pathways. The results showed that RANKL induced gastric cancer cell migration, accompanied by the activation of Cav-1 and aggregation of lipid rafts. Nystatin, a lipid raft inhibitor, inhibited the activation of Cav-1 and markedly reversed RANKL-induced gastric cancer cell migration. The RANKL induced activation of Cav-1 has been shown to occur with the activation of proto oncogene tyrosine-protein kinase Src (c-Src). The c-Src inhibitor, PP2, inhibited the activation of Cav-1 and lipid raft aggregation, and reversed RANKL-induced gastric cancer cell migration. Furthermore, it was demonstrated that Cav-1 was involved in RANKL-induced cell migration in lung, renal and breast cancer cells. These results suggested that RANKL induced gastric cancer cell migration, likely through mechanisms involving the c-Src/Cav-1 pathway and lipid raft aggregation. PMID- 30015972 TI - Combined assessment of low PGRMC1/positive ATP1A1 levels has enhanced prognostic value for renal cell carcinoma. AB - Progesterone receptor membrane component 1 (PGRMC1) and Na+/K+-ATPase alpha1 subunit (ATP1A1) are two proteins associated with the clinical prognosis of renal cell carcinoma (RCC) and RCC cell proliferation. However, the two proteins have been previously studied independently, and their combined influence on the clinical outcome of RCC remains unclear. The present study suggests that the combined expression levels of PGRMC1 and ATP1A1 (PGRMC1/ATP1A1) are associated with the clinical prognosis of RCC patients. RCC patients with low PGRMC1/positive ATP1A1 levels exhibited the best overall survival (OS) outcomes (103.08+/-1.85 months). The high PGRMC1/negative ATP1A1 group demonstrated the worst prognosis (73.1+/-8.87 months). The low PGRMC1/positive ATP1A1 group had the highest 7-year OS rate (92.3%). The high PGRMC1/negative ATP1A1 group had the lowest 7-year OS rate (46.7%). Although PGRMC1 and ATP1A1 both act on AKT phosphorylation in RCC cells, their expression levels are independent of each other. Moreover, the synergistic suppressive roles of PGRMC1 downregulation combined with ATP1A1 upregulation exhibit more efficient tumor inhibition potentials on RCC cells. Therefore, combined assessment of the two biomarkers (PGRMC1/ATP1A1) shows enhanced prognostic ability for RCC. PMID- 30015973 TI - Structure activity relationships of chrysoeriol and analogs as dual c-Met and VEGFR2 tyrosine kinase inhibitors. AB - Vascular endothelial growth factor receptor 2 (VEGFR2) and c-Met are tyrosine kinases, which are involved in the tumorigenesis of various types of cancer. Previous studies have demonstrated that the elevated activation of c-Met is associated with the drug resistance of VEGFR2 inhibitors. Therefore, dual c-Met and VEGFR2 kinase inhibitors are expected to overcome VEGFR2 inhibitor resistance and subsequently lead to a superior therapeutic outcome to regular VEGFR2 inhibitors. In the present study, it was found that chrysoeriol, which can be extracted from several natural plants, was a potential dual c-Met and VEGFR2 kinase inhibitor. The results of docking experiments revealed that chrysoeriol was able to efficiently bind in the active site cavity of c-Met and VEGFR2. The results of enzymatic assays showed relatively high binding affinities of chrysoeriol to c-Met (Kd=12 uM) and VEGFR2 (Kd=11 uM). The structure activity relationships (SARs) of chrysoeriol and its analogs were investigated using pharmacological and molecular docking experiments. To the best of our best knowledge, the present study is the first to report a natural product with both c Met and VEGFR2 inhibitory profiles, and provides insights into future dual c-Met and VEGFR2 kinase inhibitor development. PMID- 30015974 TI - Knockdown of NUPR1 inhibits the growth of U266 and RPMI8226 multiple myeloma cell lines via activating PTEN and caspase activation-dependent apoptosis. AB - Nuclear protein-1 (NUPR1) is a stress response factor that is important in the development of several human malignant tumor cells. However, the role of NUPR1 in multiple myeloma (MM) remains to be fully elucidated. In the present study, it was found that the mRNA levels of NUPR1 were significantly higher in specimens from patients with MM and MM cell lines (U266 and RPMI8226) than in cells of normal human bone marrow. The present study was undertaken to investigate the function of NUPR1 in the growth and apoptosis of MM cell lines. A lentivirus mediated short hairpin RNA was used to specifically inhibit the mRNA and protein expression of NUPR1 in the U266 and RPMI8226 MM cell lines. Flow cytometry and Cell Counting Kit-8 assays were applied to examine the apoptosis and proliferation of U266 and RPMI8226 cell lines. The results revealed the inhibitory effect of NUPR1 silencing on the proliferation of U266 and RPMI8226 cells through inducing apoptosis, and arrest of cell cycle at the G0/G1 phase. Furthermore, NUPR1 silencing caused activation of caspase-3, -8 and -9 and influenced specific gene expression, including an increase of phosphatase and tensin homolog (PTEN) and decrease of B-cell lymphoma 2 and proliferating cell nuclear antigen. These findings showed that NUPR1 may be involved in the proliferation and apoptosis of MM cells by adjusting caspase proteins and PTEN, suggesting that NUPR1 may be a novel therapeutic target for MM. PMID- 30015975 TI - Casticin suppresses the carcinogenesis of small cell lung cancer H446 cells through activation of AMPK/FoxO3a signaling. AB - Casticin, a natural polymethoxyflavone isolated from A. annua, V. trifolia, and V. agnus-castus induces apoptosis in cancer cells by activating FoxO3a. However, whether casticin inhibits in vitro carcinogenesis and cancer stem cell (CSC) characteristics, and whether casticin activates FoxO3a in small cell lung cancer (SCLC) cells remain unclear. We here demonstrated that casticin decreased sphere- and colony-formation capabilities, and downregulated uPAR and CD133 in second generation spheres, which were considered as lung cancer stem-like cells (LCSLCs), from SCLC H446 cells, in a concentration-dependent manner. In addition, casticin dose-dependently elevated the phosphorylation levels of AMPK and ACC, and reduced p-FoxO3a expression. The above effects were attenuated by AMPK knockdown with small interfering RNAs (siRNAs). FoxO3a silencing resulted in decreased protein expression of FoxO3a, increased in vitro carcinogenesis and CSC characteristics, with no appreciable effects on AMPK and ACC phosphorylation, and displayed similar activities to those neutralizing the effects of casticin on in vitro carcinogenesis and CSC characteristics. These findings reveal a novel mechanism for regulating AMPK/FoxO3a signaling in response to casticin, suggesting a new strategy for SCLC therapy by targeting cancer stem-like cells. PMID- 30015976 TI - Let-7i-5p inhibits the proliferation and metastasis of colon cancer cells by targeting kallikrein-related peptidase 6. AB - Colorectal cancer is one of the most common types of malignancies worldwide, and as it is often diagnosed at an advanced stage, it is a serious threat to human health. MicroRNAs are important regulators of the growth and metastasis of colon cancer (CC). In the present study, the results demonstrated that kallikrein related peptidase 6 (KLK6) plays a critical role in suppressing colon carcinoma progression. To further investigate whether microRNAs affect the impact of KLK6, a bioinformatics approach was employed, which indicated that let-7i-5p may directly target KLK6. Furthermore, the expression level of let-7i-5p was significantly negatively correlated with the expression of KLK6 at the mRNA and protein levels in CC. Functionally, overexpression of let-7i-5p inhibited the proliferation and invasion of CC cells, and suppressed the growth of CC in vitro. The luciferase reporter assays revealed that let-7i-5p targeted the KLK6 3' untranslated region. Collectively, these results indicated that let-7i-5p inhibited the proliferation and metastasis of CC cells by targeting KLK6, thereby blocking the cell cycle and promoting apoptosis in colon cells. Therefore, the present study revealed that the let-7i-5p/KLK6 axis may be a potential target for new therapeutic strategies to treat colon tumors. PMID- 30015977 TI - Overexpression of miR-221 and miR-222 in the cancer stroma is associated with malignant potential in colorectal cancer. AB - The cancer stroma is important in cancer development, however, whether the aberrant expression of microRNAs (miRNAs) in the cancer stroma is associated with cancer progression remains to be fully elucidated. The aim of the present study was to identify the miRNAs associated with liver metastasis in the cancer stroma of human colorectal cancer (CRC). Using laser capture microdissection, cancer stroma was obtained from the primary lesion of six patients with CRC with liver metastasis (CRCwLM) and six patients with CRC without liver metastasis (CRCwoLM), and miRNA microarray analysis was performed. Candidate miRNA expression status in the stroma was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis in 40 CRC cases (wLM, n=20; woLM, n=20), and the association between miRNA expression and clinicopathological factors was assessed in 101 advanced CRC samples. The localization of candidate miRNAs in CRCs was analyzed using in situ hybridization analysis (ISH). The microarray analysis identified six miRNAs with expression differing between the CRCwLM and CRCwoLM cancer stroma. Validation using RT-qPCR analysis of the stroma showed that the expression levels of miR-221 and miR-222 in the cancer stroma were significantly higher in CRCwLM than in CRCwoLM. The RT-qPCR analysis of 101 CRC samples showed that a high expression level of miR-221 or miR-222 in the cancer stroma was associated with liver metastasis, distant metastasis, and shorter overall survival rate of patients with CRC (P<0.05). Increased levels of miR-221 and miR 222 were observed in cancer cells and in fibroblasts in the stromal tissue in the ISH analysis. The results suggested that the overexpression of miR-221 and miR 222 in the cancer stroma is associated with the metastatic activity and malignant potential in patients with CRC. PMID- 30015978 TI - Pin2/TRF1-binding protein X1 inhibits colorectal cancer cell migration and invasion in vitro and metastasis in vivo via the nuclear factor-kappaB signaling pathway. AB - Pin2/TRF1-binding protein X1 (PinX1) functioned as a potent inhibitor of telomerase, which was also widely considered to be a sufficient tumor suppressor. Previous studies have demonstrated that PinX1 expression was reduced in several types of cancer and was associated with poor overall survival. However, little is known regarding the role of PinX1 in colorectal cancer (CRC). The present study investigated PinX1 expression via immunostaining of CRC tissue microarrays consisting of tumor and adjacent non-cancerous tissues (ANCT) from 568 patients. PinX1 expression was significantly lower in CRC tissues than in ANCT. Decreased PinX1 expression was revealed to be associated with lymph node metastasis, distant metastasis and advanced Tumor-Node-Metastasis stage, as well as a poorer overall and disease-free survival. Furthermore, Cox regression analysis determined that a decreased PinX1 expression was an independent prognostic marker for patients with CRC. In an in vitro assay, PinX1 markedly restricted CRC cell migration and invasion. Additionally, the present study revealed that PinX1 could hinder the activity of matrix metalloproteinase 2 (MMP2) through nuclear factor (NF)-kappaB-dependent transcription to further suppress the migration and invasion ability of CRC cells through western blot analysis and a gelatin zymography assay. In vivo studies verified that PinX1 could suppress CRC metastasis, as well as the expression of MMP2 and NF-kappaB p65. These results suggested that PinX1 can serve as an independent prognostic factor for patients with CRC and that it may function as a tumor metastasis suppressor in the progression of CRC though negatively regulating the NF-kappaB/MMP2 signaling pathway. PMID- 30015979 TI - Analysis of the causes of the misdiagnosis of hereditary spherocytosis. AB - Hereditary spherocytosis (HS) is an inherited hemolytic disease with clinical diversities. The aim of the present study was to examine the reasons for prolonged misdiagnosis and mistherapy of HS in a Chinese patient, and to summarize the laboratory screening and treatment methods for this disease in increasing the knowledge towards HS. Clinical data of the proband was reviewed. The proband was first screened by detection of eosin-5'-maleimide (EMA)-labeled red blood cells (RBCs) using flow cytometry. The type of protein defect in the extracted RBC membrane proteins was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Mutant fragments were verified using direct DNA sequencing and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy. The proband showed a significant hemolytic tendency and significant reduction in the number of EMA-labeled RBCs. DNA sequencing indicated three site mutations in the SPTA1 gene, including His54Pro, Leu1858Val and 6531-12C>T. Additional DNA analysis of the three mutations in the parents of the proband showed that both the Leu1858Val and 6531 12C>T mutations were carried by the father and the His54Pro mutation was carried by the mother. Moreover, the mutated peptides were identified by MALDI-TOF mass spectroscopy. HS has diverse clinical manifestations and is easily missed, misdiagnosed and mistreated. Therefore, a comprehensive analysis involving a routine blood test, blood smear, EMA labeling (flow cytometry) and SDS-PAGE can effectively distinguish HS from thalassemia, glucose-6-phosphate deficiency, iron deficiency anemia and autoimmune hemolytic anemia. PMID- 30015980 TI - TIPE2 inhibits GC via regulation of cell proliferation, apoptosis and inflammation. AB - Gastric cancer (GC), a type of gastric mucosal epithelium disease caused by common malignant tumors, has become a major threat to human health and survival. Tumor necrosis factor-alpha-induced protein-8 like-2 (TIPE2) is a negative immune regulatory factor that is selectively expressed in immune organs, immune cells and various epithelial cells and serves an important role in the maintenance of human physiological immune homeostasis. In our preliminary study, we found that the expression of TIPE2 was downregulated or absent in GC tissues compared with normal gastric mucosa tissues, indicating that TIPE2 may play a significant role in the development of GC. To clarify the role of TIPE2 in the progression of human GC and to elucidate the underlying mechanism, the association between TIPE2 and phosphatidylinositol 3-kinase (PI3K)/AKT, the cell cycle, the caspase-related apoptosis pathway and the NF-kappaB signaling pathway were investigated through western blot and flow cytometric analysis. It was determined that TIPE2 inhibited GC cell proliferation mainly by reducing the expression of phosphorylated AKT and ERK, which caused subsequent inhibition of the PI3K-AKT and Ras-Raf-MEK-ERK1/2 signaling pathways. Additionally, we investigated the relationship between TIPE2 and GC and discovered that TIPE2 inhibited tumor progression via growth, apoptosis and inflammatory pathways. The results of the present study provided a theoretical basis for the development and application of TIPE2 as an antitumor agent. PMID- 30015981 TI - NFIB promotes cell growth, aggressiveness, metastasis and EMT of gastric cancer through the Akt/Stat3 signaling pathway. AB - Nuclear factor I/B (NFIB) plays a crucial role in the progression of several types of cancers. However, its role in gastric cancer (GC) remains unclear. The present study revealed that NFIB was highly expressed in GC tissues and was positively associated with the clinicopathological features of GC patients. Downregulation of NFIB inhibited the tumor growth, migration and aggression of MKN45 and HGC27 cells in vitro. In addition, NFIB expression promoted epithelial mesenchymal transition (EMT), which was accompanied with decreased E-cadherin and increased vimentin expression. Since AKT and Stat3 play an important role in EMT and tumor progression, we examined whether there is a correlation between NFIB and AKT/Stat3 signaling pathways in GC. Our results revealed that NFIB exhibits its oncogenic functions in GC development by regulating the phosphorylation of both AKT and Stat3 molecules. Knocking down the NFIB expression may enhance the phosphorylation of AKT while inhibiting the Stat3 phosphorylation, suggesting that the AKT/Stat3 signaling pathway may be the downstream target of NFIB with which it exerts its roles on GC development. These results revealed that NFIB promotes tumor growth and aggressiveness of GC. In addition, downregulation of NFIB alters the protein kinase B/signal transducers and activators of transcription 3 (AKT/Stat3) axis, which could be a potential molecular mechanism for precise target treatment of GC. PMID- 30015984 TI - Replacement of foot-and-mouth disease virus cattle tongue titration by in vitro titration AB - Titration of foot-and-mouth disease cattle challenge virus in cattle tongue has been the standard for many years in many countries, although titration in animals has been replaced by in vitro methods for all other applications. The objective of the analysis was the replacement of in vivo titration of cattle challenge virus by in vitro titration. Using data from 32 in vivo titration experiments together with the in vitro titration results of the same samples obtained by plaque count on primary lamb or pig kidney cells, as well as data from the virus isolation control chart used in the laboratory, we show that the reproducibility of the in vitro titration is much higher than that of the in vivo titration. The titer on primary kidney cells was on average 1.4 log10 higher than the titer determined by titration in cattle tongue (PFU/ml compared to bovine ID50/ml), but the difference varied among different strains. The study also shows that the probability of infection in cattle tongue is high even when a lower challenge dose is used, which makes the variability between strains less important. Based on these results, we propose to change the standard dose for cattle challenge from 104 bovine ID50 to 105.4 PFU, and to replace the in vivo cattle tongue titration method with the in vitro titration method. PMID- 30015983 TI - Downregulation of long non-coding RNA UCA1 enhances the radiosensitivity and inhibits migration via suppression of epithelial-mesenchymal transition in colorectal cancer cells. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer and common cause of cancer-related deaths. Radiotherapy has become a routine treatment for CRC. However, radioresistance affects therapeutic efficacy. Long non-coding RNA urothelial carcinoma associated 1 (UCA1) has been demonstrated to be overexpressed in several tumors and predicts a poor prognosis. In the present study, we revealed that lncRNA-UCA1 was overexpressed in colorectal cancer tissue and colon cancer cells when compared to normal tissue and cells. Quantitative real-time PCR revealed that the expression of UCA1 was significantly higher in CRC tissues after chemoradiotherapy. Downregulation of UCA1 enhanced the radiosensitivity of CCL244 cells via inhibition of the colony formation, proliferation and promotion of radiation-induced apoptosis and G2/M arrest. Moreover, downregulation of UCA1 suppressed the epithelial-mesenchymal transition (EMT) in CCL244 cells. PMID- 30015982 TI - Silencing of CDCA5 inhibits cancer progression and serves as a prognostic biomarker for hepatocellular carcinoma. AB - Cell division cycle associated 5 (CDCA5) has been associated with the progression of several types of cancers. However, its possible role and mechanism in hepatocellular carcinoma (HCC) remain unknown. In the present study, immunohistochemical staining and real-time PCR were used to assess CDCA5 protein and mRNA levels in clinical samples. Statistical analysis was performed to explore the clinical correlation between CDCA5 protein expression and clinicopathological features and overall survival in HCC patients. Cell counting and colony formation assays were employed to analyse the effect of CDCA5 on cell proliferation, and flow cytometry was used to study the role of CDCA5 in cell cycle progression and apoptosis. Moreover, subcutaneous xenograft tumour models were implemented to predict the efficacy of targeting CDCA5 in HCC in vivo. We found that CDCA5 expression was significantly higher in HCC tumour tissues, was associated with clinicopathological characteristics, and predicted poor overall survival in HCC patients. Silencing of CDCA5 with small interfering RNA (siRNA) inhibited cell proliferation and induced G2/M cell cycle arrest in vitro. The xenograft growth assay revealed that CDCA5 downregulation impeded HCC growth in vivo. Further study indicated that CDCA5 depletion decreased the levels of ERK1/2 and AKT phosphorylation in vitro and in vivo. Taken together, these results indicate that CDCA5 may act as a novel prognostic biomarker and therapeutic target for HCC. PMID- 30015985 TI - Investigating cell type specific mechanisms contributing to acute oral toxicity. AB - The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 98 were identified with target organ specific effects, of which 93% were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% as non-toxic. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA. PMID- 30015986 TI - "Impact of comprehendible learning modes on oral health among visually impaired adults". AB - AIM: To assess changes in oral hygiene status, oral health knowledge and behavior among visually impaired individuals using dental health education material transcribed in Braille and Compressed speech. METHODOLOGY: A nonrandomized before and after comparison study was conducted among 4 purposively selected institutes for visually impaired in Indore region, Central India. A stratified random sampling was employed to select 144 visually impaired individuals aged 15-35 years. Oral health education (OHE) material was developed in Braille and compressed speech. Participants were intervened using OHE material. A self administered Braille transcribed proforma was used to record participants responses on oral health knowledge and behavior at baseline, 1-week, 1-month, and 3-months followed by clinical examination. Descriptive statistics was used for frequencies, mean, and standard deviation of variables. Bivariate regression analysis was performed to assess the effect of independent variables on self reported oral health, knowledge score and oral hygiene status. RESULTS: The mean knowledge score of participants in Braille group at 3-month was significantly higher (11.86 +/- 2.41) than in compressed speech group (8.59 +/- 2.74). Compressed speech showed significant reduction in mean gingival score (1.02 +/- 0.73) at 3-month (P <= 0.001). Bivariate regression indicated Braille education was significantly effective in improving knowledge (OR: 6.02) and oral hygiene status (OR: 8.24) (P <= 0.001). CONCLUSION: Braille method of intervention was more effective in improving knowledge scores and oral hygiene status among visually impaired participants. PMID- 30015987 TI - Integrated Circuits Comprising Patterned Functional Liquids. AB - Solid-state heterostructures are the cornerstone of modern electronics. To enhance the functionality and performance of integrated circuits, the spectrum of materials used in the heterostructures is being expanded by an increasing number of compounds and elements of the periodic table. While the integration of liquids and solid-liquid interfaces into such systems would allow unique and advanced functional properties and would enable integrated nanoionic circuits, solid-state heterostructures that incorporate liquids have not been considered thus far. Here solid-state heterostructures with integrated liquids are proposed, realized, and characterized, thereby opening a vast, new phase space of materials and interfaces for integrated circuits. Devices containing tens of microscopic capacitors and field-effect transistors are fabricated by using integrated patterned NaCl aqueous solutions. This work paves the way to integrated electronic circuits that include highly integrated liquids, thus yielding a wide array of novel research and application opportunities based on microscopic solid/liquid systems. PMID- 30015988 TI - Synaptic Barristor Based on Phase-Engineered 2D Heterostructures. AB - The development of energy-efficient artificial synapses capable of manifoldly tuning synaptic activities can provide a significant breakthrough toward novel neuromorphic computing technology. Here, a new class of artificial synaptic architecture, a three-terminal device consisting of a vertically integrated monolithic tungsten oxide memristor, and a variable-barrier tungsten selenide/graphene Schottky diode, termed as a 'synaptic barrister,' are reported. The device can implement essential synaptic characteristics, such as short-term plasticity, long-term plasticity, and paired-pulse facilitation. Owing to the electrostatically controlled barrier height in the ultrathin van der Waals heterostructure, the device exhibits gate-controlled memristive switching characteristics with tunable programming voltages of 0.2-0.5 V. Notably, by electrostatic tuning with a gate terminal, it can additionally regulate the degree and tuning rate of the synaptic weight independent of the programming impulses from source and drain terminals. Such gate tunability cannot be accomplished by previously reported synaptic devices such as memristors and synaptic transistors only mimicking the two-neuronal-based synapse. These capabilities eventually enable the accelerated consolidation and conversion of synaptic plasticity, functionally analogous to the synapse with an additional neuromodulator in biological neural networks. PMID- 30015989 TI - Families Created by Egg Donation: Parent-Child Relationship Quality in Infancy. AB - Increasing numbers of children are being born through egg donation and thus do not share a genetic relationship with their mother. Parent-infant relationship quality was examined in 85 egg donation families and a comparison group of 65 in vitro fertilization families (infant M = 11 months). Standardized interview and observational measures were used to assess mother-infant and father-infant relationship quality at the representational and behavioral levels. Few differences were found between family types in parents' representations of the parent-infant relationship. Differences were found between family types in the observational assessment of mother-infant relationship quality, indicating less optimal interactions in egg donation families. Findings suggest that egg donation families function well in infancy overall, but there may be subtle yet meaningful differences in mother-infant interaction quality. PMID- 30015990 TI - Low-Temperature Heteroepitaxy of 2D PbI2 /Graphene for Large-Area Flexible Photodetectors. AB - Heterostructures based on graphene and other 2D atomic crystals exhibit fascinating properties and intriguing potential in flexible optoelectronics, where graphene films function as transparent electrodes and other building blocks are used as photoactive materials. However, large-scale production of such heterostructures with superior performance is still in early stages. Herein, for the first time, the preparation of a submeter-sized, vertically stacked heterojunction of lead iodide (PbI2 )/graphene on a flexible polyethylene terephthalate (PET) film by vapor deposition of PbI2 on graphene/PET substrate at a temperature lower than 200 degrees C is demonstrated. This film is subsequently used to fabricate bendable graphene/PbI2 /graphene sandwiched photodetectors, which exhibit high responsivity (45 A W-1 cm-2 ), fast response (35 us rise, 20 us decay), and high-resolution imaging capability (1 um). This study may pave a facile pathway for scalable production of high-performance flexible devices. PMID- 30015992 TI - A Liquid-Metal-Based Magnetoactive Slurry for Stimuli-Responsive Mechanically Adaptive Electrodes. AB - Electrical communication between a biological system and outside equipment allows one to monitor and influence the state of the tissue and nervous networks. As the bridge, bioelectrodes should possess both electrical conductivity and adaptive mechanical properties matching the target soft biosystem, but this is still a big challenge. A family of liquid-metal-based magnetoactive slurries (LMMSs) formed by dispersing magnetic iron particles in a Ga-based liquid metal (LM) matrix is reported here. The mechanical properties, viscosity, and stiffness of such materials rapidly respond to the stimulus of an applied magnetic field. By varying the intensity of the magnetic field, regulation within a factor of 1000 of the Young's modulus from ~kPa to ~MPa, and the ability to reach GPa with more dense iron particles inside the LMMS are demonstrated. With the advantage of high conductivity of the LM matrix, the functions of the LMMS are not only limited to the soft implanted electrodes or penetrating electrodes in biosystems: the electrical response based on the LMMS electrodes can also be precisely tuned by simply regulating the applied magnetic field. PMID- 30015991 TI - Inhibition effects of pesticides on glutathione-S-transferase enzyme activity of Van Lake fish liver. AB - Glutathione-S-transferases (GSTs) have a function in xenobiotic metabolism. They are a significant multifunctional family with a wide variety of catalytic activities. In the current study, we determined in vitro inhibition effects of 2,4-dichlorophenoxyacetic acid dimethylamine salt (2,4-D DMA), haloxyfop-P methyl, glyphosate isopropylamine, dichlorvos, and lambda-cyhalothrin on purified GST. For this purpose, GST were purified from Van Lake fish (Chalcalburnus tarichii Pallas) liver with 29.25 EU mg-1 specific activity and 10.76% yield using GSH-agarose affinity chromatographic method. The pesticides were tested at various concentrations on in vitro GST activity. Ki constants were calculated as 0.17 +/- 0.01, 0.25 +/- 0.05, 3.72 +/- 0.32, 0.42 +/- 0.06, and 0.025 +/- 0.004 mM, for 2,4-D DMA, haloxyfop-P-methyl, glyphosate isopropylamine, dichlorvos, and lambda-cyhalothrin, respectively. lambda-Cyhalothrin showed a better inhibitory effect compared to the other pesticides. The inhibition mechanisms of lambda cyhalothrin were competitive, while the other pesticides were noncompetitive. PMID- 30015993 TI - Implantable cardioverter-defibrillator therapy in device recipients who survived a cardiac arrest associated with a reversible cause. AB - BACKGROUND: Guideline recommendations for implantable cardioverter-defibrillators (ICD) for secondary prevention of sudden cardiac arrest (SCA) have excluded patients with reversible causes. We previously demonstrated mortality benefit with the ICD in survivors of SCA associated with reversible causes other than myocardial infarction (MI) or ischemia treated with coronary revascularization. In the current study, we examined the incidence of ICD therapy in patients with SCA related to reversible causes. METHODS: Data were collected for all patients over the age of 18 years who had survived to hospital discharge after SCA between 2002 and 2012. ICD recipients with reversible causes were divided into 2 groups based on their reversible etiology of SCA: MI + ICD (n = 132) and non-MI + ICD (n = 75). Delivered ICD therapy was examined. RESULTS: Over a follow-up period of 3.8 +/- 3.1 years, more patients without MI/ischemia who received an ICD experienced appropriate (adjusted HR, 3.96; 95% CI, 1.32-11.84) but not inappropriate (adjusted HR, 0.65; 95% CI, 0.14-2.97) ICD therapy compared with patients without MI/ischemia. The proportion of patients receiving appropriate (P = 0.012) but not inappropriate (P = 0.80) ICD therapy was also higher in the non MI + ICD compared with the MI + ICD group. CONCLUSION: We show higher rates of appropriate ICD therapy in survivors of SCA associated with reversible causes other than MI/ischemia. This finding, in conjunction with the previously demonstrated lower all-cause mortality noted in the presence of an ICD in SCA survivors with reversible etiology other than MI/ischemia, further supports consideration of ICD implantation in this population. PMID- 30015994 TI - Horizons for Li-Ion Batteries Relevant to Electro-Mobility: High-Specific-Energy Cathodes and Chemically Active Separators. AB - Li-ion batteries (LIBs) today face the challenge of application in electrified vehicles (xEVs) which require increased energy density, improved abuse tolerance, prolonged life, and low cost. LIB technology can significantly advance through more realistic approaches such as: i) stable high-specific-energy cathodes based on Li1+ x Niy Coz Mnw O2 (NCM) compounds with either Ni-rich (x = 0, y -> 1), or Li- and Mn-rich (0.1 < x < 0.2, w > 0.5) compositions, and ii) chemically active separators and binders that mitigate battery performance degradation. While the stability of such cathode materials during cell operation tends to decrease with increasing specific capacity, active material doping and coatings, together with carefully designed cell-formation protocols, can enable both high specific capacities and good long-term stability. It has also been shown that major LIB capacity fading mechanisms can be reduced by multifunctional separators and binders that trap transition metal ions and/or scavenge acid species. Here, recent progress on improving Ni-rich and Mn-rich NCM cathode materials is reviewed, as well as in the search for inexpensive, multifunctional, chemically active separators. A realistic overview regarding some of the most promising approaches to improving the performance of rechargeable batteries for xEV applications is also presented. PMID- 30015995 TI - Relationships between supportive care needs and perceived burden in breast cancer survivor-caregiver dyads. AB - While burden in cancer caregivers is high and associated with poor outcomes, little is known about significance of specific supportive care needs' domains in determining survivors' or caregivers' perceived caregiver burden. This cross sectional study explored which domains of survivor- and caregiver-reported supportive care needs were most associated with survivor- and caregiver-reported caregiver burden, in breast cancer survivor-caregiver dyads. Cancer survivors (N = 55) and their caregivers (N = 44) completed measures of supportive care needs, anxiety, depression, functional well-being and perceived caregiver burden. Correlation and linear regression analyses were used to determine relative significance of survivor and caregiver supportive care needs in accounting for variance in survivor and caregiver perceptions of burden. Higher survivor perceived caregiver burden and higher caregiver-perceived difficulty of caregiving were associated with higher levels of survivor and caregiver supportive care needs. Survivors' psychological needs uniquely contributed to survivors' self-perceived burden, and survivors' sexual needs and caregivers' work and social needs uniquely contributed to caregivers' perceived difficulty of caregiving. Caregiver's perceived time spent caregiving was associated with access to services needs but not other needs. Survivor and caregiver supportive care needs and burden appear interdependent. Longitudinal research with larger samples is warranted to examine these relationships. PMID- 30015996 TI - Caring for patients with oral cancer in Taiwan: The challenges faced by family caregivers. AB - Family caregivers face multiple challenges when caring for patients with oral cancer at home. Understanding the difficulties they face may assist health professionals to better organise and provide support for family caregivers of oral cancer patients. The aim of this study was to describe the caregivers' primary tasks and the difficulties they encounter when caring for a family member with oral cancer. This qualitative study included a purposeful sample of 22 primary family caregivers ranging in age from 25 to 71 years old. The researchers used face-to-face, semi-structured and tape-recorded interviews to collect data and employed qualitative content analysis to elicit caregiving-related themes. Six task-related themes and associated challenges were identified. These included managing the patient's nutritional issues, investigating and making decisions about patient care, managing sudden and unpredictable changes in the patient's condition, managing emotional distress, adjusting their attitudes towards patient care, and seeking resources. Family caregivers handle such essential tasks when they care for patients in home settings and they face specific challenges related to them. This study identified several challenges related to each task. From the outset, healthcare providers should actively offer caregiving information and strategies. Health professionals can incorporate strategies for supporting caregivers' ability to carry out these tasks into their treatment model and can help caregivers manage difficulties that can impede them from doing so. PMID- 30015997 TI - Aggressive Man-Made Red Blood Cells for Hypoxia-Resistant Photodynamic Therapy. AB - Extreme hypoxia of tumors represents the most notable barrier against the advance of tumor treatments. Inspired by the biological nature of red blood cells (RBCs) as the primary oxygen supplier in mammals, an aggressive man-made RBC (AmmRBC) is created to combat the hypoxia-mediated resistance of tumors to photodynamic therapy (PDT). Specifically, the complex formed between hemoglobin and enzyme mimicking polydopamine, and polydopamine-carried photosensitizer is encapsulated inside the biovesicle that is engineered from the recombined RBC membranes. The mean corpuscular hemoglobin of AmmRBCs reaches about tenfold as high as that of natural RBCs. Owing to the same origin of outer membranes, AmmRBCs share excellent biocompatibility with parent RBCs. The introduced polydopamine plays the role of the antioxidative enzymes existing inside RBCs to effectively prevent the oxygen-carrying hemoglobin from the oxidation damage during the circulation. This biomimetic engineering can accumulate in tumors, permit in situ efficient oxygen supply, and impose strong PDT efficacy toward the extremely hypoxic tumor with complete tumor elimination. The man-made pseudo-RBC shows potentials as a universal oxygen-self-supplied platform to sensitize hypoxia-limited tumor treatment means, including but not limited to PDT. Meanwhile, this study offers ideas to the production of artificial substitutes of packed RBCs for clinical blood transfusion. PMID- 30015998 TI - Optimising eHealth tools for older patients: Collaborative redesign of a hospital website. AB - Most hospital websites have not been developed in collaboration with patients and, therefore, rarely take into account the preferences and abilities of older patients. This study describes the systematic redesign of an existing hospital website in a co-design process with patients and professional stakeholders (e.g. researchers, physicians, nurses, department heads, policymakers, website designers), with the aim to make it more user-friendly for older patients with colorectal cancer (CRC). The redesign process consisted of three phases, where (I) both existing content and design were evaluated among CRC patients; (II) a prototype website was developed based on these insights; which (III) was evaluated again before making final adjustments. Mixed research methods were used for the redesign process. Specifically, insights from existing literature, outcomes from qualitative and quantitative empirical studies conducted by our team, and expert knowledge from relevant stakeholders, were collected and discussed in multidisciplinary consensus meetings, and served as input for the redesigned website. While the existing website was evaluated poorly, the qualitative evaluation of the prototype website in phase 3 showed that the newly redesigned website was usable for older CRC patients. A practical roadmap on how to collaboratively redesign and optimise existing eHealth tools to make them suitable for and operational in clinical settings is provided. PMID- 30015999 TI - Spectrally Selective Nanocomposite Textile for Outdoor Personal Cooling. AB - Outdoor heat stress poses a serious public health threat and curtails industrial labor supply and productivity, thus adversely impacting the wellness and economy of the entire society. With climate change, there will be more intense and frequent heat waves that further present a grand challenge for sustainability. However, an efficient and economical method that can provide localized outdoor cooling of the human body without intensive energy input is lacking. Here, a novel spectrally selective nanocomposite textile for radiative outdoor cooling using zinc oxide nanoparticle-embedded polyethylene is demonstrated. By reflecting more than 90% solar irradiance and selectively transmitting out human body thermal radiation, this textile can enable simulated skin to avoid overheating by 5-13 degrees C compared to normal textile like cotton under peak daylight condition. Owing to its superior passive cooling capability and compatibility with large-scale production, this radiative outdoor cooling textile is promising to widely benefit the sustainability of society in many aspects spanning from health to economy. PMID- 30016000 TI - Valsartan reduced the vulnerability to atrial fibrillation by preventing action potential prolongation and conduction slowing in castrated male mice. AB - INTRODUCTION: Deficiency of testosterone was associated with the susceptibility of atrial fibrillation (AF). Angiotensin-II (AngII) receptor antagonists were shown to reduce AF by improving atrial electrical remodeling. This study investigated the effects and mechanism of valsartan, an AngII receptor antagonist, on the susceptibility to AF with testosterone deficiency. METHODS AND RESULTS: Five-week-old male ICR mice were castrated and valsartan was administered orally (50 mg/kg/d). High-frequency electrical stimulation method was used to induce atrial arrhythmia. Patch-clamp technique was used for recording action potential duration (APD), transient outward potassium current ( I to ), sustained outward potassium current ( I ksus ), and late sodium current ( I Na-L ). Optical mapping technique was used to examine atrial conduction velocity (CV). The expression of connexin40 (Cx40) and Cx43 were detected by Western blot analysis. The occurrence rate of AF was significantly increased in castrated mice and APDs measured at 50% and 90% repolarization were markedly prolonged in castrated mice than controls, which were alleviated by the administration of valsartan. Valsartan suppressed the increase of INa-L and rescued the reduction of Ito and Iksus in castrated mice. The left atrial CV in castrated mice was decreased and the expression of Cx43 reduced than controls, which were restored after valsartan treatment. CONCLUSIONS: Valsartan reduced the susceptibility of AF in castrated mice, which may be related to the inhibition of action potential prolongation and improvement of atrial conduction impairment. This study indicates that valsartan may represent a useful agent for the prevention of AF pathogenesis in elderly male patients. PMID- 30016001 TI - Microwave-Assisted Rapid Synthesis of Graphene-Supported Single Atomic Metals. AB - Graphene-supported single atomic metals (G-SAMs) have recently attracted considerable research interest for their intriguing catalytic, electronic, and magnetic properties. The development of effective synthetic methodologies toward G-SAMs with monodispersed metal atoms is vital for exploring their fundamental properties and potential applications. A convenient, rapid, and general strategy to synthesize a series of monodispersed atomic transition metals (for example, Co, Ni, Cu) embedded in nitrogen-doped graphene by two-second microwave (MW) heating the mixture of amine-functionalized graphene oxide and metal salts is reported here. The MW heating is able to simultaneously induce the reduction of graphene oxide, the doping of nitrogen, and the incorporation of metal atoms into the graphene lattices in one simple step. The rapid MW process minimizes metal diffusion and aggregation to ensure exclusive single metal atom dispersion in graphene lattices. Electrochemical studies demonstrate that graphene-supported Co atoms can function as highly active electrocatalysts toward the hydrogen evolution reaction. This MW-assisted method provides a rapid and efficient avenue to supported metal atoms for wide ranges of applications. PMID- 30016002 TI - Pediatric cancer families' participation in whole-genome sequencing research in Denmark: Parent perspectives. AB - With an impending introduction of genome sequencing into paediatric oncology to facilitate personalised medicine, this study examines parent perspectives on participating in whole genome sequencing (WGS) research in the difficult weeks following diagnosis. As an embedded part of Sequencing Tumor and Germline DNA Implications and National Guidelines (STAGING), a project aiming to implement WGS of all newly diagnosed paediatric cancer patients in Denmark, a parent perspective study was conducted by a clinical geneticist and anthropologist to document pragmatic, social and ethical dilemmas. Following genetic counselling, systematic debriefings were held and the anthropologist carried out in-depth parent interviews (N = 30 parents to 15 patients). Parents were approached about STAGING 2-28 days after diagnosis. The majority of interviewed parents reported that an early approach had been feasible for them, a few found it too early. Participation was explained in terms of altruism and a desire to learn more about why their child had developed cancer. A number of parents openly disagreed about the amount of information they wanted reported back. Enrolment in WGS research around the time of diagnosis is feasible, however, flexibility from researchers is essential. Notwithstanding high participation rates and a tendency to choose full disclosure, caution as regards the consequences of participating in WGS research is warranted. PMID- 30016003 TI - Simple and novel technique to confirm complete mitral isthmus block. AB - BACKGROUND: Differential pacing technique to confirm mitral isthmus (MI) block is sometimes challenging due to destroyed tissues after extensive ablation. The purpose of this study is to set an endpoint of MI ablation using conduction time around the mitral annulus (MA). METHODS: Forty-five consecutive patients with persistent atrial fibrillation who received MI linear ablation were included. The geometry and activation times of the left atrium around the MA were collected using a multipolar catheter before ablation. During coronary sinus (CS) pacing, the time between the stimulus and the wave-front collision at the opposite side of the MA (defined as T/2) was calculated, and the doubled value was defined as the estimated perimitral conduction time (E-PMCT). The endpoint for complete MI block was when the stimulus (at distal CS) minus the maximal delayed potential (St-MDP) on the MI interval reached the E-PMCT. RESULTS: St-MDP reached E-PMCT during MI ablation in 44/45 patients. Among these 44 patients, differential pacing revealed bidirectional block in 39/44 (88.6%), whereas in 5/44 (11.4%), the differential pacing was not possible because of the loss of capture of local potentials due to extensive applications around the linear line. In one patient, the St-MDP did not reach E-PMCT (E-PMCT: 148 ms, St-MDP :130 ms) and differential pacing revealed no MI block. E-PMCT values (median 176 ms) correlated strongly with St-MDP (median 185 ms, P < 0.0001, R = 0.98). CONCLUSIONS: Although E-PMCT differs between individuals, the value is significantly correlated with the St MDP. This technique may be useful in providing an individual endpoint of MI ablation as an alternative to differential pacing. PMID- 30016004 TI - Clinical anxiety disorders in the context of cancer: A scoping review of impact on resource use and healthcare costs. AB - Prevalence of clinical anxiety among patients with cancer is higher than the general population. Clinical anxiety in people with other medical conditions is associated with greater healthcare resource use and costs. This scoping review describes the evidence relating to costs associated with clinical anxiety in cancer populations. We conducted searches of online databases Medline, Embase, Cinahl, National Health Service Economic Evaluation Database (NHS-EED) and Cochrane Library of systematic reviews to identify studies published between 2006 and 2017 that included healthcare cost in terms of monetary or health service utilisation variables. Of 411 records screened, six studies met inclusion criteria. Only one study used formal diagnostic criteria to identify clinical anxiety. The healthcare system perspective was most common, with direct costs such as medications, hospital visits, type of therapy and use of mental health services reported. All studies found anxiety was related to increased costs/resource use; however, methodological differences mean specific costs and potential impact of interventions on resource use remain relatively unquantified. Despite the prevalence of clinical anxiety, there is little data on the economic impact on health service costs and utilisation. Future studies quantifying the true cost are urgently needed to inform healthcare service planning and delivery, and quality improvement initiatives. PMID- 30016005 TI - Frequency of in-hospital adverse outcomes and cost utilization associated with cardiac resynchronization therapy defibrillator implantation in the United States. AB - BACKGROUND: The utilization of cardiac resynchronization therapy defibrillator (CRT-D) has increased significantly, since its initial approval for use in selected patients with heart failure. Limited data exist as for current trends in implant-related in-hospital complications and cost utilization. The aim of our study was to examine in-hospital complication rates associated with CRT-D and their trends over the last decade. METHODS AND RESULTS: Using the Nationwide Inpatient Sample, we estimated 378 248 CRT-D procedures from 2003 to 2012. We investigated common complications, including mechanical, cardiovascular, pericardial complications (hemopericardium, cardiac tamponade, or pericardiocentesis), pneumothorax, stroke, vascular complications (consisting of hemorrhage/hematoma, incidents requiring surgical repair, and accidental arterial puncture), and in-hospital deaths described with CRT-D, defining them by the validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code. Mechanical complications (5.9%) were the commonest, followed by cardiovascular (3.6%), respiratory failure (2.4%), and pneumothorax (1.5%). Age (>=65 years), female gender (OR, 95% CI; P value) (1.08, 1.03-1.13; 0.001), and the Charlson score >=3 (1.52, 1.45-1.60; <0.001) were significantly associated with increased mortality/complications. CONCLUSIONS: The overall complication rate in patients undergoing CRT-D has been increasing in the last decade. Age (>=65), female sex, and the Charlson score >=3 were associated with higher complications. In patients who underwent CRT-D implantation, postoperative complications were associated with significant increases in cost. PMID- 30016006 TI - Behavioral Impact of Long-Term Chronic Implantation of Neural Recording Devices in the Rhesus Macaque. AB - BACKGROUND: Ensemble recording methods are pervasive in basic and clinical neuroscience research. Invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or Parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. Studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflammatory response as well as a chronic foreign body response. Despite use of invasive recording methods with animal models and humans, little is known of their effect on behavior in healthy populations. OBJECTIVE: To quantify the effect of chronic electrode implantation targeting the hippocampus on recognition memory performance. METHODS: Four healthy female rhesus macaques were tested in a delayed nonmatching-to-sample (DNMS) recognition memory task before and after hippocampal implantation with a tetrode array device. RESULTS: Trials to criterion and recognition memory performance were not significantly different before vs. after chronic electrode implantation. CONCLUSION: Our results suggest that chronic implants did not produce significant impairments on DNMS performance. PMID- 30016007 TI - Surface ECG and intracardiac spectral measures predict atrial fibrillation recurrence after catheter ablation. AB - INTRODUCTION: Outcome of patients undergoing catheter ablation of atrial fibrillation (AF) varies widely. We sought to investigate whether parameters derived from the spectral analysis of surface ECG and intracardiac AF electrograms can predict outcome in patients referred for pulmonary vein isolation (PVI). METHODS: We performed spectral analysis on the surface ECG and intracardiac electrograms from patients referred for AF ablation. After filtering and QRST subtraction, we measured the dominant frequency (DF), regularity index (RI) and the organizational index (OI) of fibrillatory electrograms and determined their value for predicting AF recurrence after ablation. A subjective, blinded prediction based on the surface ECG was also performed. RESULTS: We analyzed data from 153 PVI procedures in 140 patients (67.1% with persistent or longstanding AF). In a multivariable model, DF in the right atrium (RA) and distal coronary sinus (CSd)-to-RA DF gradient predicted AF recurrence (OR, 3.52, P = 0.023 and OR, 0.2, P = 0.034, respectively). DF in RA and CSd to RA DF gradient had a good predictive value for PVI outcome (area under the curve [AUC] of 0.73, P = 0.007 and 0.74, P = 0.007, respectively). These performed better than the subjective predictions of experienced electrophysiologists ( P = 0.2). CONCLUSIONS: Higher RA DF, lower CSd to RA DF gradient predicted recurrence after AF ablation. These spectral measures suggest a more remodeled atrial substrate and may provide simple tools for risk stratification or predict the need for additional substrate modification in patients referred for AF ablation. PMID- 30016008 TI - Laser balloon ablation for AF: A systematic review and meta-analysis. AB - INTRODUCTION: The HeartLight laser balloon ablation system was US Food and Drug Administration approved in 2016 for the treatment of paroxysmal atrial fibrillation (AF), but there have been numerous single-center and multicenter studies published reporting its outcomes, in addition to a few randomized trials. We aimed to systematically review and synthesize currently published outcome data on AF ablation using the laser balloon ablation system. METHODS AND RESULTS: We performed a systematic review and meta-analysis of published studies of AF ablation performed using the laser balloon ablation system. Human studies reporting acute procedural results with a minimum of 6 months follow-up were included. Outcomes of interest included acute and 12-month procedural efficacy, safety, and procedure duration. Aggregated data were analyzed with random effects models, using a Bayesian hierarchical approach. We identified 17 published manuscripts comprising a sample of 1188 patients (mean age 61 years, 80% paroxysmal). At procedure end, 98.8% of targeted pulmonary veins were successfully isolated. The pooled estimate for 12-month freedom from atrial arrhythmia without use of antiarrhythmic drugs for patients with paroxysmal AF was 74.3% (95% confidence interval [CI], 59.9% to 86.4%), and for all AF types combined was 72.9% (65.3% to 79.9%). The most commonly reported procedural complication was phrenic nerve injury (pooled incidence 2.6%; 95% CI, 1.4% to 3.9%), which resolved during follow-up in most cases. CONCLUSION: Laser balloon ablation is highly effective at achieving pulmonary vein isolation. Although comparisons are mainly indirect, safety and 12-month efficacy compare favorably with those observed using other currently used AF ablation technologies. PMID- 30016009 TI - Electrochemical Behavior of Single CuO Nanoparticles: Implications for the Assessment of their Environmental Fate. AB - The electrochemical behavior of copper oxide nanoparticles is investigated at both the single particle and at the ensemble level in neutral aqueous solutions through the electrode-particle collision method and cyclic voltammetry, respectively. The influence of Cl- and NO3- anions on the electrochemical processes occurring at the nanoparticles is further evaluated. The electroactivity of CuO nanoparticles is found to differ between the two types of experiments. At the single-particle scale, the reduction of the CuO nanoparticles proceeds to a higher extent in the presence of chloride ion than of nitrate ion containing solutions. However, at the multiparticle scale the CuO reduction proceeds to the same extent regardless of the type of anions present in solution. The implications for assessing realistically the environmental fate and therefore the toxicity of metal-based nanoparticles in general, and copper-based nanoparticles in particular, are discussed. PMID- 30016010 TI - The role of ultrasonography in the diagnostic criteria for rheumatoid arthritis and monitoring its therapeutic efficacy. AB - Rheumatoid arthritis (RA) is a chronic systemic disease of connective tissue. It is characterized by symmetrical multiple joint involvement and extra-articular symptoms. Modern RA treatment methods place a particular emphasis on the earliest possible diagnosis and initiation of appropriate treatment. Currently, ultrasonography (US) is the key imaging test performed in RA patients. However, despite the general acknowledgement of its role in the assessment of disease activity, US was not included in the applicable ACR/EULAR criteria. This is due to the lack of strictly defined criteria for US evaluation and the interpretation of test results. In addition, the absence of a correlation between the common DAS/DAS28 disease activity score and ultrasound assessment of joints makes developing new diagnostic criteria difficult. The objective of this article is to review recent scientific reports on the use of ultrasonography in the diagnosis and monitoring of RA and to indicate current problems associated with the interpretation of test results and the comparison with applicable scores of disease activity. PMID- 30016011 TI - Effect of metformin in the prognosis of patients with smallcell lung cancer combined with diabetes mellitus. AB - BACKGROUND: The prognosis for small-cell lung cancer (SCLC) is very poor, so a new therapeutic strategy and new drugs are imperative. OBJECTIVES: The aim of this study was to examine the effect of metformin on the prognosis of patients with SCLC combined with diabetes mellitus (DM). MATERIAL AND METHODS: From 2005 to 2013, 32 patients (4 female and 28 male) with SCLC combined with DM were included in this retrospective study at the Zhejiang Cancer Hospital, China. All patients were diagnosed with SCLC by pathological analysis and had received more than 4 cycles of chemotherapy. Metformin was used in 12 patients. Seventeen patients had limited-stage disease (LD) and 15 patients had extensive-stage disease (ED). Patients with LD SCLC were administered thoracic radiotherapy. The follow-up deadline was January 27, 2016. At that point, 4 patients were alive, 21 patients had died, and 7 patients did not participate in follow-up examinations. RESULTS: In patients with SCLC combined with DM using metformin, a complete response (CR) was observed in 4 patients, a partial response (PR) in 6 patients, a stable disease (SD) in 1 patient, and a progressive disease (PD) in 1 patient, whereas in patients who did not use metformin, CR was observed in 2 patients, PR in 15 patients, SD in 2 patients, and PD in 1 patient (p = 0.384). There was no difference in the median survival time (MST) between patients using metformin and those who did not (12 vs 13 months; p = 0.784). There was a trend toward prolonged MST in patients with LD SCLC using metformin compared with those who did not use metformin (58 vs 29 months; p = 0.084). There was no difference due to the use of metformin observed in MST of patients with ED SCLC (12 vs 13 months; p = 0.396). CONCLUSIONS: Metformin use may have a prognostic benefit in patients with SCLC combined with DM. This combination is promising and further clinical trials are required. PMID- 30016012 TI - Schedules of Controlled Substances: Placement of Butyryl Fentanyl and U-47700 Into Schedule I. Final order. AB - With the issuance of this final order, the Administrator of the Drug Enforcement Administration maintains the placement of the substances butyryl fentanyl (N-(1 phenethylpiperidin-4-yl)-N-phenylbutanamide) and U-47700 (3,4-dichloro-N-[2 (dimethylamino)cyclohexyl]-Nmethylbenzamide), including their isomers, esters, ethers, salts, and salts of isomers, esters and ethers, in schedule I of the Controlled Substances Act. This scheduling action discharges the United States obligations under the Single Convention on Narcotic Drugs (1961). This action continues to impose the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, butyryl fentanyl and U- 47700. PMID- 30016013 TI - Eligibility for Supplemental Service-Disabled Veterans' Insurance. Final rule. AB - The Department of Veterans Affairs (VA), in this final rule, amends its regulations governing the Service-Disabled Veterans' Insurance (S-DVI) program in order to explain that a person who was granted S-DVI as of the date of death is not eligible for supplemental S-DVI because the insured's total disability did not begin after the date of the insured'sapplication for insurance and while the insurance was in force under premium-paying conditions. PMID- 30016015 TI - Colostrum and breast milk in the neonatal period: The benefits keep adding up. PMID- 30016016 TI - The essentials of medical consultation. PMID- 30016017 TI - Neonatal mortality in the framework of the Millennium Development Goals and new post-2015 goals. PMID- 30016018 TI - Predatory journals. PMID- 30016019 TI - Language development delay in 24-month-old children at a health care center of the City of Buenos Aires. AB - INTRODUCTION: Language development delay is a frequent challenge for pediatricians and other health care providers. The main objective of this study was to establish its prevalence among children attending a health care center. POPULATION AND METHODS: The expressive vocabulary of 24-month-old children attending a health care center was assessed using the Spanish language MacArthur Bates Communicative Development Inventories, short form (Argentine version). The association between language delay and demographic, socioeconomic, behavioral/emotional, and parental stress characteristics was analyzed. In children with expressive language delay, receptive vocabulary was assessed and possible underlying causes were studied (non-verbal cognitive delay, autistic spectrum disorders, middle ear pathology, and hearing impairment). RESULTS: Language development delay was observed in 16 out of 138 participants (11.6%; 95% confidence interval: 6.2-17%), significantly associated with a family history of language delay, parental stress, and problem behavior. Receptive vocabulary compromise was identified in 13 out of 16 children with language development delay, and 7 were suspected of autistic spectrum disorder, overall developmental delay, or both. A middle ear pathology was observed in 5 out of 9 studied children. The 9 participants who had an audiometry did not have pathological results based on this study's criteria. CONCLUSIONS: Language development delay is a prevalent condition in our population and has been mainly associated with behavioral problems and a family history of language delay. PMID- 30016020 TI - Effects of age of diagnosis and dietary compliance on growth parameters of patients with celiac disease. AB - INTRODUCTION: The objective of this study was to evaluate the relation between age at diagnosis and compliance to gluten free diet (GFD) on growth in children with celiac disease and the factors that influenced compliance to GFD. POPULATION AND METHODS: Celiac disease (CD) patients with villous atrophy followed in our hospital between January 2015 and January 2017, were included. They were classified according to diagnosis age and GFD compliance. Patients' anthropometric characteristics at diagnosis and follow-up were compared. RESULTS: There were 73 patients with 10.4 +/- 4.5 years of average age, 35 (47.9%) patients had a short stature at diagnosis, the ages of patients who had short stature (7.8 +/- 4.2 years) were higher than those who did not (5.1 +/- 4.3 years) (p= 0.005). At diagnosis, 33 (45.2%) patients were aged <=6 years, 40 (54.8%) were aged >6 years. The height and weight z-scores of patients who were diagnosed at >6 years of age were significantly lower than those who were diagnosed <=6 years of age both at diagnosis (p= 0.01 and 0.04) and at last control (p= 0.001 and 0.001), respectively. Forty-five (61.6%) patients were fully compliant with GFD. In comparison of anthropometric data in terms of GFD compliance, the increase in BMI and weight z-score in the fully compliant group was found to be significantly higher when compared with the other group. CONCLUSIONS: Delay in CD diagnosis negatively affected both the height and weight and other growth parameters. GFD compliance positively affected the patients' all growth parameters, especially weight and BMI z-score. PMID- 30016021 TI - Caracteristicas y resultados de la ingestion de cuerpos extranos en ninos. AB - INTRODUCTION: Foreign body (FB) ingestion is a common home accident during childhood; a timely management by the specialists may help prevent complications in the short and long term. OBJECTIVE: To describe the characteristics and complications of FB ingestion located in the gastrointestinal tract in the pediatric population. MATERIAL AND METHODS: Two phases, retrospective, and prospective study. Patients diagnosed with FB ingestion between January 1971 and December 2016 were included. The general characteristics of patients, FB type, removal method, and complications were registered. A descriptive analysis was performed. RESULTS: Over 45 years, 2637 FBs were removed from the pharynx (n= 118), the esophagus (n= 2410), the stomach (n= 103), and the intestines (n= 6). Male patients predominated (50.9%); 74% were younger than 5 years. Besides, 57% arrived within the first 24 hours; ptyalism, dysphagia, and vomiting were the main symptoms; 16% of patients had no symptoms. It was possible to locate the FB using an X-ray in 93% of cases; the most common FBs were coins (78%); the most frequent location was the upper third of the esophagus (79%); 86% of FBs were removed using a rigid endoscope, and complications were observed in 7.8% of patients. CONCLUSIONS: FB ingestion predominated among children younger than 5 years; metal objects were the most common ones. A plain X-ray is the test of choice for diagnosis; removal is usually done with a rigid or flexible endoscope, depending on the endoscopist's experience. PMID- 30016022 TI - Measures stated by parents and caregivers of infants, toddlers, and preschoolers to prevent environmental tobacco smoke exposure. AB - INTRODUCTION: The exposure to environmental tobacco smoke is a public health problem because of its potential risks for children. Objective. To determine the preventive actions taken by parents and/or caregivers of infants, toddlers, and preschoolers regarding environmental tobacco smoke exposure. Methods. Cross sectional, analytical study in parents and caregivers of infants, toddlers, and preschoolers from Valdivia, Chile. A questionnaire on preventive measures regarding environmental tobacco smoke was administered. The questionnaire was analyzed with descriptive and association statistics using Fisher's exact test and logistic regression to calculate the odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) as an estimation of the risk for not taking preventive measures at home. RESULTS: A total of 469 parents and caregivers participated. The prevalence of households with one member who smoked was 51.8%. Most of them smoked outside the house (92.2%). The most common measure taken outside the household was to avoid places where people smoked. In this setting, a significant difference was observed between men and women in relation to avoiding exposure (7.6% versus 2.2%; p= 0.040). A higher risk for not avoiding tobacco use inside or outside the housewas confirmed when a household member smoked (OR: 3.55; 95% CI: 2.05-6.14). Also, a lower risk was observed when there were two or more children in the household (OR: 0.46; 95% CI: 0.26-0.83). CONCLUSIONS: Most parents and caregivers ask others to smoke outside and avoid places where people smoke; however, the level of prevention is lower among households with smokers. PMID- 30016023 TI - Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome. AB - INTRODUCTION: Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the chi2 and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. RESULTS: 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (+/- 8%) versus 73% (+/- 1%) (p= 0.006) and the EFI was 54% (+/- 9%) versus 75% (+/- 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6 9 years: 39% (+/- 19%) (p= 0.7885). CONCLUSIONS: A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality. PMID- 30016024 TI - Physical growth in young Chilean football players: Proposal of percentiles based on chronological and biological age. AB - OBJECTIVES: a) To compare physical growth to the 2012 American standard from the Centers for Disease Control and Prevention (CDC); b) to analyze physical growth by chronological and biological age; c) to propose physical growth charts based on chronological and biological age. Methodology. A descriptive (cross-sectional) study was conducted in young Chilean football players based on weight, standing height, and sitting height. These were compared to the CDC- 2012 standard. Percentiles were developed using the LMS method. RESULTS: A total of 642 young Chilean football players aged 13.0-18.9 years were studied. Their body weight was lower than that of the CDC standard from 13.0 to 18.9 years old (p < 0.05), whereas their height showed no significant differences in the initial age categories (13.0- 13.9 and 14.0-14.9 years). Differences started to be observed as of 15.0 years old up to 18.9 years old (p < 0.05). In relation to chronological age, weight explained 31%; standing height, 16%; and sitting height, 0.09%, whereas in relation to biological age, weight explained 51%; standing height, 40%; and sitting height, 54%. Percentiles were developed based on chronological and biological age. CONCLUSION: These youth showed different physical growth patterns compared to the CDC-2012 standard. Their assessment reflects better explanatory percentages for biological age than for chronological age. The proposed percentiles may be an alternative to keep track of the physical growth patterns of young football players in sports settings in the short, medium, and long term. PMID- 30016025 TI - Results of the implementation of a nutritional support protocol for major burn pediatric patients hospitalized in the Intensive Care Unit. AB - INTRODUCTION: "Major burn" is used to describe a person who suffers thermal damage affecting more than 30% of his/her total body surface area (TBSA). The secondary hypercatabolism causes lean body mass loss and delayed wound healing. OBJECTIVE: To describe and analyze the results of implementing a nutritional support protocol for pediatric burn patients hospitalized in the intensive care unit in the first 6 weeks. POPULATION AND METHODS: Analytical, prospective, observational, and longitudinal design. Weight, height, %TBSA, length of stay in the intensive care unit, and mortality were measured. The basal metabolic rate was measured by indirect calorimetry and the Schofield equation, and protein and energy intake, prealbumin, C-reactive protein, vitamins A, D, E, copper, and zinc levels were analyzed every week. RESULTS: Eighteen patients were included (mean: 3.9 years old, 49%TBSA). The mean energy target was achieved by week 2 and protein requirements were met by week 6. Twelve patients required complementary parenteral nutrition and there were no complications. Hypermetabolism parameters were observed, which returned to normal 4-6 weeks after hospitalization, except for C-reactive protein. Vitamins A and E and trace elements (zinc and copper) were reduced at the time of admission and showed a subsequent improvement. Vitamin D remained low. One patient died. CONCLUSIONS: Implementing the protocol was useful to cover the total energy requirement; the coverage of protein requirements was delayed until week 6. It is necessary to focus on solving limitations to achieve the latter. PMID- 30016026 TI - Ischemia-modified albumin levels in children with asthma: a pilot study. AB - INTRODUCTION: Hypoxia may occur in the severe exacerbations of asthma. Ischemia modified albumin (IMA) may increase in ischemia, in addition to oxidative stress and inflammation. The aim was to evaluate IMA levels in children during the asthma exacerbation and the asymptomatic period. POPULATION AND METHODS: Children with asthma who were followed up in our clinic were included and healthy children were selected as the control group. The severity of exacerbation was evaluated with Global Initiative for Asthma and Modified Pulmonary Index Score. Serum IMA levels were measured at the time of exacerbation and 4 weeks after treatment during asymptomatic period. Skin prick test and C reactive protein (CRP) levels were measured. RESULTS: A total of 26 patients and 26 controls were included. Mean IMA level was 0.45+/-0.12 absorbance units -ABSU- during asthma exacerbation and 0.32+/-0.08 ABSU in the control group (p=0.001). Mean IMA levels (0.41+/-0.14 ABSU) during the stable period were higher than the control group (p=0.005). There was no difference in terms of IMA levels when patients were grouped according to anti-inflammatory treatment, upper respiratory tract infection before exacerbation, CRP levels or sensitivity of skin prick tests. However, IMA levels were higher in patients with severe asthma exacerbation (p=0.009) in comparison with mild/moderate exacerbation. Positive correlation was observed between IMA levels and severity of exacerbation (r: 0.498, p=0.010). CONCLUSIONS: Asthmatic children had higher IMA levels than the control group, both in stable and exacerbated asthma. There was a positive relationship between IMA levels and severity of asthma exacerbation. PMID- 30016027 TI - Impact of a health care quality improvement intervention to prevent pressure ulcers in a Pediatric Intensive Care Unit. AB - INTRODUCTION: Among children hospitalized in the intensive care unit who have pressure ulcers (PUs), more than 50% are related to the sustained pressure from a device or equipment. PUs are an indirect indicator of the quality of health care. Objective. To assess the impact of a health care quality improvement intervention on the development of PUs at the pediatric intensive care unit. Materials and methods. Uncontrolled, before and after study. Pre-intervention: measurement of PUs; post-intervention: implementation of a bundle of measures (staff training, identification of patients at risk, and pressure relief by using antibedsore mattresses and polymer gel positioners) and the same measurements. RESULTS: A total of 152 patients were included: 74 before the intervention and 78 after the intervention. A significant reduction was observed in the incidence of PUs (preintervention: 50.60%; post-intervention: 23.08%; p= 0.001). A higher risk score was seen in the post-intervention group (pre-intervention: 12.4 +/- 1.9; post-intervention: 13.7 +/- 2.1; p= 0.001). No differences were observed in the risk score on the day of PU onset and the number of PUs. The risk-stratified analysis maintained the significant difference in the incidence of PUs (PIM2 < 5: 47.37%; 19.23%; p= 0.004; and PIM2 >= 5: 55.56%; 30.77%; p= 0.053). CONCLUSION: A lower incidence of PUs was observed after the implementation of the health care quality improvement intervention. No changes were detected in the number of PUs or the severity staging. PMID- 30016028 TI - Association of vesicoureteral reflux and renal scarring in urinary tract infections. AB - INTRODUCTION: The aim was to investigate the relationship between vesicoureteral reflux (VUR) and renal damage in non-febrile, febrile for the first time and recurrent urinary tract infection (UTI) patients. The secondary aim was to determine whether C-reactive protein (CRP) in febrile UTIs could be a predictor of renal scarring. POPULATION AND METHODS: This prospective study included non febrile, febrile for the first time and recurrent pediatric UTI cases. The routine lab analyses comprised a complete blood count, urea, creatinine, fully automated urinalysis, urine culture and CRP analyses. All the participants were examined using urine ultrasonography subsequent to their UTI diagnosis, voiding cystourethrography (VCUG) after six weeks and Tc-99m dimercaptosuccinic acid (DMSA) static renal scintigraphy after six months. RESULTS: There were included 47 children with non-febrile UTIs, 48 with first febrile UTIs and 61 with recurrent UTIs. A statistically significant difference was found among the groups in terms of VUR and renal scarring (p= 0.001 and p= 0.011, respectively). A statistically significant difference was also found in terms of renal scarring between patients with and without VUR (p= 0.001). Moreover, a statistically significant difference was also present in relation to renal scarring (p <0.05) in patients with five-fold lower or higher CRP values than the accepted cut-off value (5mg/dl). CONCLUSION: The ratio of renal scars detected was found to be parallel to the VUR frequency. The higher the VUR grade, the more renal damage was found. A positive correlation between elevated CRP and renal scarring was determined, indicating the presence of scarring during the diagnosis of pyelonephritis. PMID- 30016029 TI - Acute phase markers in obese children and adolescents with metabolic disorders. AB - INTRODUCTION: Obesity is a worldwide public health problem and the most common non-communicable chronic disease. It is associated with an increase in inflammatory acute phase proteins and proinflammatory cytokines. OBJECTIVE: To assess the levels of acute phase proteins in obese children and adolescents with hepatic steatosis and metabolic syndrome. Methodology. Forty-five children with a body mass index >= 95th percentile aged 5.0-15.5 years were included. The following acute phase reactants were determined: C-reactive protein, haptoglobin, alpha-2-macroglobulin, and apolipoprotein A-1; besides, an ultrasound was done to assess hepatic steatosis. RESULTS: C-reactive protein levels increased in all patients. Patients with metabolic syndrome also had high levels of apolipoprotein A-1 and haptoglobin. Patients with hepatic steatosis had a significant increase in alpha-2-macroglobulin in addition to high C-reactive protein. PMID- 30016030 TI - Characterization of drug poisoning among adolescents seen at the municipal hospital of Bahia Blanca, Province of Buenos Aires, Argentina. AB - INTRODUCTION: Drug poisoning among children is a frequent reason for visits to the emergency department; among adolescents, it is intentional. OBJECTIVE: To describe the characteristics of drug poisoning among adolescents admitted to the municipal hospital of Bahia Blanca. Material and method. Descriptive study based on the review of medical records of patients aged 10-19 years seen for drug poisoning between 2012 and 2016. The following outcome measures were analyzed: age, sex, drug used, cause, clinical manifestations, and length of stay in days. RESULTS: Data from 72 patients were collected. Their mean age was 16 years, and the female:male ratio was 2.5:1. Anxiolytic poisoning (30%) predominated, followed by polydrug use (25%). Ninety-five percent of patients showed a suicidal intention; of these, 55% had a history of suicide attempt. CONCLUSION: Drug poisoning was observed predominantly among girls; it is worth noting the high percentage of youth who had a history of suicide attempt. PMID- 30016031 TI - Medical-dental considerations in the care of children with facial cellulitis of odontogenic origin. A disease of interest for pediatricians and pediatric dentists. AB - An odontogenic infection is a polymicrobial, mixed infection (aerobic and anaerobic bacteria). It comprises various clinical conditions, whose importance varies depending on their frequency and potential severity. It is the most common type of oral infection and its treatment involves up to 10% of all antibiotic prescriptions. Facial cellulitis is a diffuse inflammation of soft tissue that is not confined or limited to a specific region and tends to spread. The objective of this review is to update the aspects considered in the care of children with facial cellulitis of odontogenic origin and the multidisciplinary management between dentists and pediatricians. PMID- 30016032 TI - Technology-mediated communication with patients: WhatsApp Messenger, e-mail, patient portals. A challenge for pediatricians in the digital era. AB - The digital revolution will have a profound impact on how physicians and health care delivery organizations interact with patients and the community. Primary pediatric care has been historically known in our setting because pediatricians are widely available for consultations. The rapid development of information and communication technologies and their impact on people's life pose a new challenge for pediatricians in relation to the way they communicate with the families of the patients they see. The objective of this article is to analyze the available channels for communication mediated by information and communication technologies with patients, and to propose recommendations for their adequate use. PMID- 30016033 TI - Clinical, radiological, and auxological characteristics of patients with cleidocranial dysplasia followed in a pediatric referral hospital in Argentina. AB - : Cleidocranial dysplasia is an autosomal dominant skeletal dysplasia caused by mutations in the RUNX2 gene; its prevalence has been estimated at 1/1 000 000 newborn infants. This study presents 37 patients (22 girls) assessed between 1992 and 2016 at the Skeletal Dysplasias Multidisciplinary Clinics of Hospital Garrahan, Argentina. FINDINGS: 35% of positive family history; median age at the time of diagnosis: 2.61 years old; positive radiological findings in the skull and pubis: 95%; in the clavicles: 100%. Dental and hearing complications were common. Auxology: boys had a median height of -1.81 SD (-3.26 to 0.2) and girls had a median height of -1.36 SD (-4.28 to 1.36). Five out of 13 patients were short for parental height. Adult height (median): 162.8 cm in boys and 149.2 cm in girls. No evident alterations were observed in the sitting height/height ratio. One patient had true macrocephaly; 12 (32%), relative macrocephaly. Intrafamily variability was described in terms of height. PMID- 30016034 TI - Evolution of fetal mortality in the setting of Argentine socioeconomic inequalities. Period 2007-2014. AB - INTRODUCTION: Few studies have established a relationship between adverse social conditions by geographic area (GA) and fetal mortality (FM). Objective. To assess health inequalities in relation to FM by GA. POPULATION AND METHODS: Descriptive, ecological study. The principal components of 525 GAs were analyzed. A socioeconomic status indicator and indices of inequality were developed and estimated, and the FM ratio was calculated. RESULTS: The Kunst and Mackenbach relative index of inequality ranged from 1.8 to 1.4 in the 2007/2008 and 2013/2014 biennia, and a higher FM ratio was estimated for the highly unfavorable socioeconomic level stratum. CONCLUSION: The FM ratio is higher in this stratum. The gap between the ends of the socioeconomic spectrum narrowed towards the latest biennium. Regardless of this, in the GAs with a very unfavorable socioeconomic status, the FM ratio reduced in the latest biennium and increased in those with a very favorable socioeconomic status. PMID- 30016035 TI - Preterm premature rupture of membranes. AB - Preterm premature rupture of membranes occurs in around 3% of pregnancies, and several aspects related to its management are still controversial. The objective of this update is to provide a detailed review of strategies aimed at reducing morbidity and mortality associated with this maternal condition. We will discuss the available evidence regarding the maternal use of antibiotics, the use of corticosteroids according to gestational age, the use of magnesium sulphate for fetal neuroprotection, the use of tocolytic agents, and the best moment for and route of delivery. This review also covers the effects of prolonged preterm premature rupture of membranes, infant morbidity and mortality in the short and long term, the harmful effects of antibiotics after delivery, including the effects on neurodevelopment and the presence of longterm chronic diseases. PMID- 30016036 TI - Effects of corrective, therapeutic exercise techniques on adolescent idiopathic scoliosis. A systematic review. AB - The objective of this study was to determine the effects of corrective, therapeutic exercise techniques on subjects with adolescent idiopathic scoliosis. A systematic review was conducted by searching the Cochrane Library Plus, Pubmed, PEDro, and SCOPUS databases. Studies in patients diagnosed with adolescent idiopathic scoliosis that considered corrective, therapeutic exercise as an independent outcome measure and symptoms, functional capacity, Cobb's angle and/or other angles or body asymmetries as dependent outcome measures were included. A total of 9 controlled clinical trials that carried out corrective, therapeutic exercise were included. Corrective, therapeutic exercise appears to have positive effects by reducing symptoms and improving function, as well as various angles and body asymmetries. However, further studies with better methodological quality are required to confirm these outcomes and determine the best therapeutic exercise intervention. PMID- 30016037 TI - [Mycoplasma pneumoniae: neurologic manifestations and diagnostic controversies. A case report]. AB - Mycoplasma pneumoniae (Mp) is responsible for 30% of the respiratory manifestations of the general population. Pneumonia occupies the first place within this group. Among the extra-respiratory forms (40%), the neurological ones are the most frequent. Meningoencephalitis and aseptic meningitis are the most common. The presentation of more than one clinical variant in the same patient associated with primoinfection by Mp is possible. In relation to the serological diagnosis, controversies in interpretation sometimes occur. This is a 7-year-old girl with conjunctival injection, cervical adenopathy, photophobia with bilateral papilla pseudoedema, and scaly rash that develops peripheral facial paralysis and aseptic meningitis. We will discuss diagnostic controversies. PMID- 30016038 TI - [Invasive acute sinusitis by Exserohilum rostratum in a patient with medullary relapse of acute lymphoblastic leukemia]. AB - Invasive fungal infection has increased in frequency over the last decade, with fungal sinusitis becoming more frequent. The fungi of the genus Exserohilum (family Pleosporaceae, order Pleosporales) are filamentous and dematiaceous of ubiquitous location. It is an emerging pathogen, which in most cases produces a systemic infection that mainly affects the paranasal sinuses and lungs. It is more common in immunosuppressed patients, although it may occur in immunocompetent patients. The treatment is based on three pillars: antifungal treatment, surgical debridement and restitution of immunity. We present the case of a patient with medullary relapse of acute lymphoblastic leukemia with invasive fungal sinusitis by Exserohilum rostratum. PMID- 30016039 TI - Ulcerative colitis in an infant aged 20 months. A case report. AB - Bloody diarrhea is a common problem in early childhood, typically caused by anal fissures, infectious enteritis, allergic proctocolitis, swallowed maternal blood and intussusception. More rarely, it can also be caused by volvulus, coagulopathies, necrotizing enterocolitis, polyps, Meckel diverticulitis and inflammatory bowel disease (IBD). The incidence of IBD is on the rise in children, even affecting infants. The most common subtypes are Crohn's disease (CD) and ulcerative colitis (UC). While IBD occurrence peaks in the second to third decades of life, paediatric IBD accounts for 7-20% of all cases. Within this age group, the highest rates are seen in the teenage years; however, very early onset IBD can be seen before six years of age. The classic symptoms of CD include abdominal pain, diarrhea and weight loss, while UC is typically associated with bloody diarrhea. The report describes the case of a 20-month-old boy with bloody diarrhea who was ultimately diagnosed with UC. PMID- 30016040 TI - Monosomy 9p24 in two non-related patients as result of a translocation (2;9). AB - In patients with malformations and delayed psychomotor development it is important to discard chromosomopathies. Balanced reciprocal translocations are the most frequent chromosomopathies present in 1:500 live newborns. In general, carriers have normal phenotype, but they may have infertility, abortions or children with congenital malformations. The reciprocal translocation between chromosomes 2 and 9 can lead to offspring with monosomies and trisomies of these chromosomes. Short arm monosomy of chromosome 9 may present delayed psychomotor development, trigonocephaly, facial dysmorphia and genital abnormalities. We reviewed GTG karyotype records from our Institution to identify cases with chromosomes 2 and/or 9 alterations from 2005 to 2014. We describe two cases with monosomy 9p secondary to a translocation between chromosomes 2 and 9. The patients share features of monosomy 9p24-pter, however the genotypephenotype correlation is complex due to the extension of the involved segments. We emphasize the importance of chromosomal diagnosis to offer genetic assessment. PMID- 30016041 TI - Netherton syndrome: A neonatal case with respiratory insufficiency. AB - Netherton syndrome (NS) is a rare, autosomal recessive disease characterized with congenital ichthyosiform erythroderma, hair abnormality and atopic manifestations. This syndrome is caused by recessive mutation in the SPINK5 gene. Disease manifestations vary considerably among NS individuals. We report a newborn presented with severe respiratory insufficiency, hypothermia and erythroderma, was diagnosed as having NS and confirmed with molecular genetic testing. PMID- 30016042 TI - [Methemoglobinemia due to Dapsone: a pediatric case report]. AB - Methemoglobinemia is a condition characterized by a high blood concentration of methemoglobin. Methemoglobinemia is a disorder that occurs when hemoglobin in the blood is oxidized to form methemoglobin, rendering it unable to transport oxygen. Although it can be congenital in cyanotic newborn, it is more often an adverse medication effect. The aim is to report a pediatric methemoglobinemia case, assisted in Magdalena V. de Martinez Hospital, with cyanosis in face and limb, in poor condition, that consumed dapsone accidentally. Her methemoglobin concentration was 35%. Intravenous methylene blue was administered with favorable outcome. PMID- 30016043 TI - Acute arterial embolism as the clinical presentation of a disseminated hydatidosis: case report. AB - Hydatidosis is a parasitic infection caused by the Echinococcus granulosus larvae, transmitted by the ingestion of infected food, characterized by the formation of cysts in vital organs. In Argentina, the disease is spread throughout the territory, constituting an important public health issue. The disease usually affects the liver and lungs. The affection of other organs is rare, and even more uncommon the affection of the heart. We present the case of a disseminated hydatidosis in a pediatric patient, whose initial clinical manifestation was an acute arterial embolism of the right limb caused by the rupture of a hydatidic cardiac cyst. PMID- 30016044 TI - [Fetal ascites as clinical presentation of inferior vena cava agenesis]. AB - Inferior Vena Cava (IVC) is composed of three segments from different embryological origin. Its lack of fusion originates a wide spectrum of anomalies of the IVC. These malformations are present in 0.07-8.7% of the population. It is generally diagnosed as an incidental finding in adult life. It represents between 5 and 9.5% of idiopathic deep vein thrombosis in patients younger than 30 years old without associated risk factors. We present a case of a term newborn with prenatal diagnosis of ascites during the 20th week of gestation. IVC Agenesis was diagnosed with the use of abdominal angiotomography. The treatment of patients with IVC Agenesis is based on the management of its complications. Due to the increased thrombotic risk of these patients, we should consider lifelong anticoagulation. We suggest initiating it during puberty. PMID- 30016045 TI - [Severe poisoning with naphazoline: update from a therapeutic error]. AB - Naphazoline is a drug commonly used as a decongestant in adult patients. Its indication in Pediatrics is not frequent, being approved its use from the age of 12 for the toxic effects it possesses. Intoxication in children generates a potentially serious clinical picture. It is characterized by the immediate appearance of hypotonia, deterioration of the sensory, hypothermia and bradycardia of variable degree of clinical compromise. Although it is an infrequent intoxication, the anamnesis and the initial management of the patient are the key in the evolution. We present a 4-year-old boy who, as a therapeutic error, receives this drug, emphasizing the rapid and potentially severe establishment of the clinical picture. PMID- 30016046 TI - [Isolated irreducible anterior radial head dislocation in a child: a rare case report]. AB - Anterior radial head dislocation in pediatric population is related to Monteggia fracture-dislocations. Isolated radial head dislocation is uncommon. Sometimes, radial head dislocation becomes irreducible. This entity can develop into chronic conditions such as nerve injuries, early osteoarthritis, limited range of motion and cubitus valgus. We describe a case of a 9-year-old patient who suffered elbow trauma. He was admitted to our institution 40 days after, where radial head dislocation was diagnosed. This condition was misdiagnosed at first stage. It was irreducible due to a tear in the annular ligament. He underwent open reduction. Radial head dislocation must be suspected even if there are no fractures or plastic deformity. Pure irreducible radial head dislocation is rare. Physical examination, together with plain bilateral radiographs and full acknowledgement of this rare condition are the basis to reach early diagnosis, which leads to proper non-delayed treatment. PMID- 30016047 TI - [Vitamin D in pediatrics, pregnancy and lactation]. AB - The main source of vitamin D is produced by the exposure of sunlight on the skin. It has been proven that the deficit is frequent and also occurs in pregnant women. Possible consequences may be preeclampsia and others. The level of vitamin D in breast milk depends on the level of the mother, so that deficient mothers produce milk with low concentration. Possible consequences for the baby are rickets and seizures, but also lower respiratory tract infections or risk of type 1 diabetes. Various suggestions have been published. For pregnancy and lactation the Institute of Medicine (IOM) suggests 600 international units (IU)/day for the mother, whereas the Endocrine Society considers 1500- 2000 IU/day. The Federacion Argentina de Sociedades de Endocrinologia suggests 800-1200 IU/day. The new suggestion of the IOM and the American Academy of Pediatrics for children between birth and one year is 400 IU/day, while it is 600 IU/day between 1 and 18 years. PMID- 30016048 TI - [Evaluation Exercise Vaccination status inquiry and hierarchy of prevention and health education opportunities. Experience in a Pediatric Residency using the Mini-Clinical Evaluation Exercise]. AB - INTRODUCTION: The Mini-Clinical Evaluation Exercise (Mini-CEX) is a formative tool with two descriptors assessing the inquiry of vaccination status and the hierarchy of prevention opportunities. Objectives. Determine the prevalence of both items in pediatric controls and spontaneous demands. Compare the performance between first and third year of their training. MATERIAL AND METHODS: Retrospective analysis based on trainees Mini-CEX charts. RESULTS: There were 119 residents evaluated during their first year. The prevalence of vaccination status screening in controls was 94.9% (confidence interval -CI-: 91.09-98.91); in demands 73.1% (CI: 65.2-81; OR 5.33; CI: 2.23- 12.75; p 0.00004). The prevalence of prevention opportunities in controls was 69.8% (CI: 61.6- 78); in demands 62.2% (CI: 53.5-70.9; OR 1.034; CI: 0.4638-2.306; p= 0.4673). There were 32 trainees compared between their first and third year performance in demands, without significant difference. CONCLUSIONS: We found high prevalence of vaccination inquiry and lower prevalence of hierarchization of prevention opportunities in controls, with less inquiry in demands. PMID- 30016049 TI - [Pediatric emergency medicine specialty: Welcome!] AB - Pediatric Emergency Medicine has developed around the world as a subspecialty of pediatrics. There is plenty of data reflecting a growing need for its services. The subspecialty was initiated in the United States and Argentina, together with other Latin American countries, followed the same path. Nevertheless, there is yet much to be done. It is necessary to strengthen its promotion and to stimulate research and teaching activities in order to continue improving the quality of care delivered to the pediatric population, their families and society as a whole. PMID- 30016050 TI - Clarification of Final Rules for Grandfathered Plans, Preexisting Condition Exclusions, Lifetime and Annual Limits, Rescissions,Dependent Coverage, Appeals, and Patient Protections Under the Affordable Care Act. Final rule; clarification. AB - On November 18, 2015, the Departments of Labor, Health and Human Services, and the Treasury (the Departments) published a final rule in the Federal Register titled "Final Rules for Grandfathered Plans, Preexisting Condition Exclusions, Lifetime and Annual Limits, Rescissions, Dependent Coverage, Appeals, and Patient Protections Under the Affordable Care Act" (the November 2015 final rule), regarding, in part, the coverage of emergency services by non- grandfathered group health plans and health insurance issuers offering non-grandfathered group or individual health insurance coverage, including the requirement that non grandfathered group health plans and health insurance issuers offering non grandfathered group or individual health insurance coverage limit cost-sharing for out-of-network emergency services and, as part of that rule, pay at least a minimum amount for out-of-network emergency services. The American College of Emergency Physicians (ACEP) filed a complaint in the United States District Court for the District of Columbia,which on August 31, 2017 granted in part and denied in part without prejudice ACEP's motion for summary judgment and remanded the case to the Departments to respond to the public comments from ACEP and others. In response, the Departments are issuing this notice of clarification to provide a more thorough explanation of the Departments' decision not to adopt recommendations made by ACEP and certain other commenters in the November 2015 final rule. PMID- 30016051 TI - General Hospital and Personal Use Devices; Reclassification of Sharps Needle Destruction Device. Final order. AB - The Food and Drug Administration (FDA or the Agency) is issuing a final order to reclassify the needle destruction device, renaming the device to "sharps needle destruction device, a postamendments class III device (regulated under product code MTV), into class II (special controls), subject to premarket notification. FDA is also identifying the special controls that the Agency believes are necessary to provide a reasonable assurance of safety and effectiveness of the device. FDA is finalizing this reclassification on its own initiative based on new information. The Agency is classifyingthe device into class II (special controls) to provide a reasonable assurance of safety and effectiveness of the device.This order reclassifies these types of devices from class III to class II and will reduce regulatory burdens on industrybecause these types of devices will no longer be required to submit a premarket approval application (PMA), but can instead submit a less burdensome premarket notification (510(k)) before marketing their device. PMID- 30016059 TI - Geometrical Confinement of Gadolinium Oxide Nanoparticles in Poly(ethylene glycol)/Arginylglycylaspartic Acid-Modified Mesoporous Carbon Nanospheres as an Enhanced T1 Magnetic Resonance Imaging Contrast Agent. AB - A new strategy for designing contrast agents (CAs) based on geometrical confinement will become a competent way to improve the relaxivity of CAs. Herein, a magnetic resonance imaging (MRI) nanoconstruct is fabricated through loading Gd2O3 nanoparticles into mesoporous carbon nanospheres, followed by conjugation of poly(ethylene glycol) (PEG) and the c(RGDyK) peptide (Gd2O3@OMCN-PEG-RGD), which could prolong the blood circulation half-life as well as improve the tumor targeting ability. As a result, the Gd2O3@OMCN-PEG-RGD exhibits an outstandingly high relaxivity ( r1 = 68.02 mM-1 s-1), which is ~5.3 times higher than that of Gd2O3 nanoparticles ( r1 = 12.74 mM-1 s-1). Afterward, both the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test and H&E staining show that the Gd2O3@OMCN-PEG-RGD has wonderful biocompatibility in vitro and in vivo. Moreover, the in vivo MR images indicate that the Gd2O3@OMCN-PEG-RGD could accumulate in the tumor region more rapidly than Gd2O3@OMCN-PEG. This study presents a facile method to fabricate an MRI CA with excellent T1 contrast ability based on geometrical confinement and excellent biocompatibility, which could act as an optimal contender for sensitive in vivo tumor imaging with outstanding targeting ability. PMID- 30016060 TI - Facile Approach to Graft Ionic Liquid into MOF for Improving the Efficiency of CO2 Chemical Fixation. AB - This work describes a facile approach to modify metal-organic frameworks (MOFs) with ionic liquids (ILs), rendering them as useful heterogeneous catalysts for CO2 chemical fixation. An amino-functionalized imidazolium-based ionic liquid is firmly grafted into the porous MOF, MIL-101-SO3H by the acid-base attraction between positively charged ammonium groups on the IL and negatively charged sulfonate groups from the MOF. Analyses by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, 1H NMR, and N2 sorption experiments reveal the MOF-supported ionic liquid (denoted as IL@MOF) material remains intact while functioning as a recyclable heterogeneous catalyst that can efficiently convert CO2 and epichlorohydrin into chloropropene carbonate without the addition of a cocatalyst. PMID- 30016061 TI - Detailed Investigation of Evaporated Perovskite Absorbers with High Crystal Quality on Different Substrates. AB - Dual-source vapor-phase deposition enables low-temperature fabrication of high performance planar structure perovskite (CH3NH3PbI3) solar cells (PSCs), applicable in tandem devices or for industrial production with high homogeneity. Herein, we report low-temperature fabrication of high-efficiency PSCs by dual source vapor-phase deposition and significance of TiO2 surface modification with [6,6]-phenyl C61 butyric acid methyl ester (PCBM) on cell performance. Co evaporation of PbI2 and CH3NH3I, as confirmed by X-ray diffraction and high resolution transmission electron microscopy analyses, results in CH3NH3PbI3 layers with a well-crystallized tetragonal phase formed on both TiO2 and TiO2/PCBM electron-transport layers (ETLs). The devices with PCBM interlayer between TiO2 and CH3NH3PbI3 showed remarkably higher performance than those with TiO2 only, which was attributed to enhance charge extraction and reduced recombination at the TiO2/PCBM/CH3NH3PbI3 interface. The devices composed of evaporated CH3NH3PbI3 on top of the TiO2/PCBM and [2,2',7,7'-tetrakis( N, N-di- p methoxyphenyl-amine)-9,9'-spirobifluorene] (Spiro-OMeTAD) as hole-transport material demonstrated power conversion efficiencies of 17.1% (reverse scan) and 13.4% (forward scan) with stabilized efficiency of over 16%, which is, to the best of our knowledge, the highest efficiency reported for evaporated perovskite solar cells using low-temperature fabrication method involving compact TiO2 layer as ETL. Furthermore, we show that this process can be used to deposit a CH3NH3PbI3 layer on top of a textured silicon substrate, which is the first step for preparing perovskite-silicon tandem devices with enhanced antireflection and light-trapping properties. PMID- 30016062 TI - The Fate of the Peroxyl Radical in Autoxidation: How Does Polymer Degradation Really Occur? AB - Bolland and Gee's basic autoxidation scheme (BAS) for lipids and rubbers has long been accepted as a general scheme for the autoxidation of all polymers. This scheme describes a chain process of initiation, propagation, and termination to describe the degradation of polymers in the presence of O2. Central to this scheme is the conjecture that propagation of damage to the next polymer chain occurs via hydrogen atom transfer with a peroxyl radical. However, this reaction is strongly thermodynamically disfavored for all but unsaturated polymers, where the product allylic radical is resonance-stabilized. Paradoxically, there is no denying that the autocatalytic degradation and oxidation of saturated polymers still occurs. Critical analysis of the literature, described herein, has begun to unravel this mystery. One possibility is that the BAS still holds for saturated polymers but only at unsaturated defect sites, where H transfer is thermodynamically favorable. Another is that peroxyl termination rather than H transfer is dominant. If this were the case, tertiary peroxyl radicals (formed at quaternary centers or quaternary branching defects) may terminate to form alkoxy radicals, which can much more readily undergo chain transfer. This process would lead to the creation of hydroxy groups on the degraded polymer. On the other hand, primary and secondary peroxyl radicals would terminate to form nonradical products and halt further degradation. As a result, under this scenario the degree of branching and substitution would have a major effect on polymer stability. Herein we survey studies of polymer degradation products and of the effect of polymer structure on stability and show that indeed peroxyl termination is competitive with peroxyl transfer and possibly dominant under some conditions. It is also feasible that oxygen may not be the only reactive atmospheric species involved in catalyzing polymer degradation. Herein we outline plausible mechanisms involving ozone, hydroperoxyl radical, and hydroxyl radical that have all been suggested in the literature and can account for the experimentally observed formation of hydroperoxides without invoking peroxyl transfer. We also show that oxygen itself has even been reported to slow the degradation of poly(methyl methacrylate)s, which might be expected if peroxyl radicals are unreactive toward hydrogen transfer. Discrepancies between the rate of oxidation and the rate of degradation have been observed for polyolefins and also support the counterintuitive notion that oxygen stabilizes these polymers against degradation. We show that together these studies support alternative mechanisms for polymer degradation. A thorough assessment of kinetic studies reported in the literature indicates that they are limited by their propensity to use models based on the BAS, disregarding the chemical differences intrinsic to each class of polymer. Thus, we propose that further work must be done to fully grasp the complex mechanism of polymer degradation under ambient conditions. Nonetheless, our analysis of the literature points to measures that can be used to enhance or prevent polymer degradation and indicates that we should focus beyond just the role of oxygen toward the specific chemical nature and environment of the polymer at hand. PMID- 30016063 TI - Implementing Lateral MoSe2 P-N Homojunction by Efficient Carrier-Type Modulation. AB - High-performance p-n junctions based on atomically thin two-dimensional (2D) materials are the fundamental building blocks for many nanoscale functional devices that are ideal for future electronic and optoelectronic applications. The lateral p-n homojunctions with conveniently tunable band offset outperform vertically stacked ones, however, the realization of lateral p-n homojunctions usually require efficient carrier-type modulation in a single 2D material flake, which remains a tech challenge. In this work, we have realized effective carrier type modulation in a single MoSe2 flake, and thus, a lateral MoSe2 p-n homojunction is achieved by sequential treatment of air rapid thermal annealing and triphenylphosphine (PPh3) solution coating. The rapid thermal annealing modulates MoSe2 flakes from naturally n-type doping to degenerated p-type doping and improves the hole mobility of the MoSe2 field effect transistors from 0.2 to 71.5 cm2.V-1.s-1. Meanwhile, the n-doping of MoSe2 is increased by drop-coating PPh3 solution on the MoSe2 surface with increased electron mobility from 78.6 to 412.8 cm2.V-1.s-1. The as-fabricated lateral MoSe2 p-n homojunction presents a high rectification ratio of 104, an ideality factor of 1.2, and enhanced photoresponse of 1.3 A.W-1 to visible light. This efficient carrier-type modulation within a single MoSe2 flake has potential for use in various functional devices. PMID- 30016064 TI - Hybrid Mesoporous Nanocarriers Act by Processing Logic Tasks: Toward the Design of Nanobots Capable of Reading Information from the Environment. AB - Here, we present the design of smart nanodevices capable of reading molecular information from the environment and acting accordingly by processing Boolean logic tasks. As proof of concept, we prepared Au-mesoporous silica (MS) nanoparticles functionalized with the enzyme glucose dehydrogenase (GDH) on the Au surface and with supramolecular nanovalves as caps on the MS surface, which is loaded with a cargo (dye or drug). The nanodevice acts as an AND logic gate and reads information from the solution (presence of glucose and nicotinamide adenine dinucleotide (NAD+)), which results in cargo release. We show the possibility of coimmobilizing GDH and the enzyme urease on nanoparticles to mimic an INHIBIT logic gate, in which the AND gate is switched off by the presence of urea. We also show that such nanodevices can deliver cytotoxic drugs in cancer cells by recognizing intracellular NAD+ and the presence of glucose. PMID- 30016065 TI - Polynuclear Complexes as Precursor Templates for Hierarchical Microporous Graphitic Carbon: An Unusual Approach. AB - A highly porous carbon was synthesized using a coordination complex as an unusual precursor. During controlled pyrolysis, a trinuclear copper complex, [CuII3Cl4(H2L)2].CH3OH, undergoes phase changes with melt and expulsion of different gases to produce a unique morphology of copper-doped carbon which, upon acid treatment, produces highly porous graphitic carbon with a surface area of 857 m2 g-1 and a gravimetric hydrogen uptake of 1.1 wt % at 0.5 bar pressure at 77 K. PMID- 30016066 TI - Electrochemistry on Stretchable Nanocomposite Electrodes: Dependence on Strain. AB - Stretchable nanocomposite conductors are essential for engineering of bio inspired deformable electronics, human-machine interfaces, and energy storage devices. While the effect of strain on conductivity for stretchable conductors has been thoroughly investigated, the strain dependence of multiple other electrical-transport processes and parameters that determine the functionalities and biocompatibility of deformable electrodes has received virtually no attention. The constancy of electrochemical parameters at electrode-fluid interfaces such as redox potentials, impedances, and charge-transfer rate constants on strain is often tacitly assumed. However, it remains unknown whether these foundational assumptions actually hold true for deformable electrodes. Furthermore, it is also unknown whether the previously used charge-transport circuits describing electrochemical processes on rigid electrodes are applicable to deformable electrodes. Here, we investigate the validity of the strain invariability assumptions for an elastic composite electrode based on gold nanoparticles (AuNPs). A comprehensive model of electrode reactions that accurately describes electrochemical processes taking place on nanocomposite electrodes for ferro-/ferricyanide electrochemicals pair at different strains is developed. Unlike rigid gold electrodes, the model circuit for stretchable electrodes is comprised of two parallel impedance segments describing (a) diffusion and redox processes taking place on the open surface of the composite electrode and (b) redox processes that occur in nanopores. AuNPs forming the open surface circuit support the redox process, whereas those forming the nanopores only increase the double-layer capacitance. The redox potential was found to be strain-independent for tensile deformations as high as 40%. Other parameters, however, display strong strain dependence, exemplified by the 2-2.5 and 27 times increases of active area of the open and nanopore surface area, respectively, after application of 40% strain. Gaining better understanding of the strain dependent and -independent electrochemical parameters enables both fundamental and practical advances in technologies based on deformable electrodes. PMID- 30016067 TI - Stretchable Seal. AB - Many stretchable electronic devices require stretchable hermetic seals. However, stretchability and permeability are inextricably linked at the molecular level: stretchable, low-permeability materials do not exist. We collect data for the permeation of water and oxygen in many materials and describe the scaling relations for both flat and wrinkled seals. Whereas flat seals struggle to fulfill the simultaneous requirements of stretchability, low stiffness, and low transmissibility, wrinkled seals can fulfill them readily. We further explore the behavior of wrinkled seals under cyclic stretch using aluminum, polyethylene, and silica films on elastomer substrates. The wrinkled aluminum develops fatigue cracks after a small number of cycles, but the wrinkled polyethylene and silica maintain low transmissibility after 10 000 cycles of tensile strain. PMID- 30016068 TI - Quantum Dots-Based Multifunctional Nano-Prodrug Fabricated by Ingenious Self Assembly Strategies for Tumor Theranostic. AB - The rapid developments of quantum dots (QDs)-based nanoagents for imaging tumor and tracking drug delivery have been proven to be reliable nanodiagnostic techniques. Although abundant types of QD nanoagents have been developed for fighting against cancer, it still is a challenge to control their quality and achieve prefect repetition due to the complicated synthetic steps. The precise intermolecular self-assembly (SA) may afford a facile and low-cost strategy for this challenge. Herein, a pH and H2O2 dual-sensitive Sb-cyclodextrin (CD) doxorubicin (DOX) molecule was designed to construct a QD-based theranostic prodrug (named as Sb-CD-DOX-ZAISe/ZnS) via host-guest strategy (1st SA strategy), in which QDs water-transfer and drug-uploading were integrated well. That is, the nano-prodrug (NPD) inherited highly luminescent properties from "host" QDs for bioimaging, as well as environment sensitivities from "guest" Sb-CD-DOX for drug release. Experimental results indicate that the Sb-CD-DOX-ZAISe/ZnS exhibited effectively passive tumor-targeting and could provide clear imaging for malignant tumors in metaphase or advanced stages; meanwhile, after coating with folic acid (FA) through electric attraction (2nd SA strategy), the final Sb-CD-DOX ZAISe/ZnS@FA NPD showed expected pH-controlled negative-to-positive charge reversal ability and a better curative effect compared with free DOX. Hence, fabricating nanocomposites by highly efficient self-assembly strategies is favorable toward inorganic nanoparticles-based prodrug delivery system for tumor targeting theranostic. PMID- 30016069 TI - IrCo Nanodendrite as an Efficient Bifunctional Electrocatalyst for Overall Water Splitting under Acidic Conditions. AB - Investigation of high-efficiency electrocatalysts for acidic overall water splitting is of great significance toward fulfillment of proton exchange membrane (PEM) electrolyzers but still remains challenging. Herein, we report the colloidally synthesis of IrCo alloy nanodendrites with petal-like architecture (NDs). Benefiting from unique hierarchical architecture and strong electronic interaction arising from synergistic alloying effect of IrCo at the atomic level, the resultant IrCo0.65 NDs display remarkable hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances with overpotentials of 17 and 281 mV to achieve 10 mA cm-2 in 0.1 M HClO4, respectively. Moreover, when further used as bifunctional electrocatalyst toward acidic overall splitting, a low cell voltage of 1.593 V is achieved at 10 mA cm-2. PMID- 30016070 TI - Atomic-Scale Deformations at the Interface of a Mixed-Dimensional van der Waals Heterostructure. AB - Molecular self-assembly due to chemical interactions is the basis of bottom-up nanofabrication, whereas weaker intermolecular forces dominate on the scale of macromolecules. Recent advances in synthesis and characterization have brought increasing attention to two- and mixed-dimensional heterostructures, and it has been recognized that van der Waals (vdW) forces within the structure may have a significant impact on their morphology. Here, we suspend single-walled carbon nanotubes (SWCNTs) on graphene to create a model system for the study of a 1D-2D molecular interface through atomic-resolution scanning transmission electron microscopy observations. When brought into contact, the radial deformation of SWCNTs and the emergence of long-range linear grooves in graphene revealed by the three-dimensional reconstruction of the heterostructure are observed. These topographic features are strain-correlated but show no sensitivity to carbon nanotube helicity, electronic structure, or stacking order. Finally, despite the random deposition of the nanotubes, we show that the competition between strain and vdW forces results in aligned carbon-carbon interfaces spanning hundreds of nanometers. PMID- 30016072 TI - Direct Formation of C-C Double-Bonded Structural Motifs by On-Surface Dehalogenative Homocoupling of gem-Dibromomethyl Molecules. AB - Conductive polymers are of great importance in a variety of chemistry-related disciplines and applications. The recently developed bottom-up on-surface synthesis strategy provides us with opportunities for the fabrication of various nanostructures in a flexible and facile manner, which could be investigated by high-resolution microscopic techniques in real space. Herein, we designed and synthesized molecular precursors functionalized with benzal gem-dibromomethyl groups. A combination of scanning tunneling microscopy, noncontact atomic force microscopy, high-resolution synchrotron radiation photoemission spectroscopy, and density functional theory calculations demonstrated that it is feasible to achieve the direct formation of C-C double-bonded structural motifs via on surface dehalogenative homocoupling reactions on the Au(111) surface. Correspondingly, we convert the sp3-hybridized state to an sp2-hybridized state of carbon atoms, i. e., from an alkyl group to an alkenyl one. Moreover, by such a bottom-up strategy, we have successfully fabricated poly(phenylenevinylene) chains on the surface, which is anticipated to inspire further studies toward understanding the nature of conductive polymers at the atomic scale. PMID- 30016073 TI - Quantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid Tumors. AB - Coating the nanoparticle surface with cancer cell recognizing ligands is expected to facilitate specific delivery of nanoparticles to diseased cells in vivo. While this targeting strategy is appealing, no nanoparticle-based active targeting formulation for solid tumor treatment had made it past phase III clinical trials. Here, we quantified the cancer cell-targeting efficiencies of Trastuzumab (Herceptin) and folic acid coated gold and silica nanoparticles in multiple mouse tumor models. Surprisingly, we showed that less than 14 out of 1 million (0.0014% injected dose) intravenously administrated nanoparticles were delivered to targeted cancer cells, and that only 2 out of 100 cancer cells interacted with the nanoparticles. The majority of the intratumoral nanoparticles were either trapped in the extracellular matrix or taken up by perivascular tumor associated macrophages. The low cancer cell targeting efficiency and significant uptake by noncancer cells suggest the need to re-evaluate the active targeting process and therapeutic mechanisms using quantitative methods. This will be important for developing strategies to deliver emerging therapeutics such as genome editing, nucleic acid therapy, and immunotherapy for cancer treatment using nanocarriers. PMID- 30016071 TI - Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma. AB - In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing desmoplastic melanoma. PMID- 30016074 TI - Origin of Chemically Ordered Atomic Laminates ( i-MAX): Expanding the Elemental Space by a Theoretical/Experimental Approach. AB - With increased chemical diversity and structural complexity comes the opportunities for innovative materials possessing advantageous properties. Herein, we combine predictive first-principles calculations with experimental synthesis, to explore the origin of formation of the atomically laminated i-MAX phases. By probing (Mo2/3 M1/32)2 AC (where M2 = Sc, Y and A = Al, Ga, In, Si, Ge, In), we predict seven stable i-MAX phases, five of which should have a retained stability at high temperatures. (Mo2/3Sc1/3)2GaC and (Mo2/3Y1/3)2GaC were experimentally verified, displaying the characteristic in-plane chemical order of Mo and Sc/Y and Kagome-like ordering of the A-element. We suggest that the formation of i-MAX phases requires a significantly different size of the two metals, and a preferable smaller size of the A-element. Furthermore, the population of antibonding orbitals should be minimized, which for the metals herein (Mo and Sc/Y) means that A-elements from Group 13 (Al, Ga, In) are favored over Group 14 (Si, Ge, Sn). Using these guidelines, we foresee a widening of elemental space for the family of i-MAX phases and expect more phases to be synthesized, which will realize useful properties. Furthermore, based on i-MAX phases as parent materials for 2D MXenes, we also expect that the range of MXene compositions will be expanded. PMID- 30016075 TI - Solid-State Nanopore Single-Molecule Sensing of DNAzyme Cleavage Reaction Assisted with Nucleic Acid Nanostructure. AB - The detection and investigation of biomolecules at a single-molecule level is important for improving diagnosis in biomedicine. Solid-state nanopores are a unique tool that have the potential to accomplish this task because they are label-free and require only low sample consumption. However, the event-readouts of current small polymer molecules are still limited because of its relatively large size and low signal-to-noise ratios. Here, we present a rapid sensing approach for the detection of GR-5 DNAzyme cleaving specific substrate reactions using relatively larger size silicon nitride nanopores by introducing a type of nucleic acid nanostructure (DNA tetrahedron) as a carrier. The proposed method is convenient and sensitive enough to detect the cleavage reactions by identifying translocation events before and after reactions with nanomolar concentrations of the target sample. Furthermore, this assay was also carried out by using larger size nanopores (60 nm diameter) to achieve the DNAzyme cleavage sensing with the same sample concentration. This approach can improve event detectability of other smaller molecules' translocation, which opens up a wide range of applications for analytes detection by incorporating solid-state nanopores. Nucleic acid nanostructure-assisted nanopore sensing can promote the development of single molecule studies. PMID- 30016078 TI - Targeted Treatment of Ischemic and Fibrotic Complications of Myocardial Infarction Using a Dual-Delivery Microgel Therapeutic. AB - Myocardial infarction (MI), commonly known as a heart attack, affects millions of people worldwide and results in significant death and disabilities. A major cause of MI is fibrin-rich thrombus formation that occludes the coronary arteries, blocking blood flow to the heart and causing fibrin deposition. In treating MI, re-establishing blood flow is critical. However, ischemia reperfusion (I/R) injury itself can also occur and contributes to cardiac fibrosis. Fibrin-specific poly( N-isopropylacrylamide) nanogels (FSNs) comprised of a core-shell colloidal hydrogel architecture are utilized in this study to design a dual-delivery system that simultaneously addresses the need to (1) re-establish blood flow and (2) inhibit cardiac fibrosis following I/R injury. These therapeutic needs are met by controlling the release of a fibrinolytic protein, tissue plasminogen activator (tPA), and a small molecule cell contractility inhibitor (Y-27632). In vitro, tPA and Y-27632-loaded FSNs rapidly degrade fibrin and decrease cardiac cell stress fiber formation and connective tissue growth factor expression, which are both upregulated in cardiac fibrosis. In vivo, FSNs localize to fibrin in injured heart tissue and, when loaded with tPA and Y-27632, showed significant improvement in left ventricular ejection fraction 2 and 4 weeks post-I/R as well as significantly decreased infarct size, alpha-smooth muscle actin expression, and connective tissue growth factor expression 4 weeks post-I/R. Together, these data demonstrate the feasibility of this targeted therapeutic strategy to improve cardiac function following MI. PMID- 30016077 TI - Living with Oxygen. AB - Work on the electronic structures of metal-oxo complexes began in Copenhagen over 50 years ago. This work led to the prediction that tetragonal multiply bonded transition metal-oxos would not be stable beyond the iron-ruthenium-osmium oxo wall in the periodic table and that triply bonded metal-oxos could not be protonated, even in the strongest Bronsted acids. In this theory, only double bonded metal-oxos could attract protons, with basicities being a function of the electron donating ability of ancillary ligands. Such correlations of electronic structure with reactivity have gained importance in recent years, most notably owing to the widespread recognition that high-valent iron-oxos are intermediates in biological reactions critical to life on Earth. In this Account, we focus attention on the oxygenations of inert organic substrates by cytochromes P450, as these reactions involve multiply bonded iron-oxos. We emphasize that P450 iron oxos are strong oxidants, so strong that they would destroy nearby amino acids if substrates are not oxygenated rapidly; it is our view that these high-valent iron oxos are such dangerous reactive oxygen species that Nature surely found ways to disable them. Looking more deeply into this matter, mainly by examining many thousands of structures in the Protein Data Bank, we have found that P450s and other enzymes that require oxygen for function have chains of tyrosines and tryptophans that extend from active-site regions to protein surfaces. Tyrosines are near the heme active sites in bacterial P450s, whereas tryptophan is closest in most human enzymes. High-valent iron-oxo survival times taken from hole hopping maps range from a few nanoseconds to milliseconds, depending on the distance of the closest Trp or Tyr residue to the heme. In our proposed mechanism, multistep hole tunneling (hopping) through Tyr/Trp chains guides the damaging oxidizing hole to the protein surface, where it can be quenched by soluble protein or small molecule reductants. As the Earth's oxygenic atmosphere is believed to have developed about 2.5 billion years ago, the increase in occurrence frequency of tyrosine and tryptophan since the last universal evolutionary ancestor may be in part a consequence of enzyme protective functions that developed to cope with the environmental toxin, O2. PMID- 30016076 TI - Analyzing 2000 in Vivo Drug Delivery Data Points Reveals Cholesterol Structure Impacts Nanoparticle Delivery. AB - Lipid nanoparticles (LNPs) are formulated using unmodified cholesterol. However, cholesterol is naturally esterified and oxidized in vivo, and these cholesterol variants are differentially trafficked in vivo via lipoproteins including LDL and VLDL. We hypothesized that incorporating the same cholesterol variants into LNPs which can be structurally similar to LDL and VLDL-would alter nanoparticle targeting in vivo. To test this hypothesis, we quantified how >100 LNPs made with six cholesterol variants delivered DNA barcodes to 18 cell types in wild-type, LDLR-/-, and VLDLR-/- mice that were both age-matched and female. By analyzing ~2000 in vivo drug delivery data points, we found that LNPs formulated with esterified cholesterol delivered nucleic acids more efficiently than LNPs formulated with regular or oxidized cholesterol when compared across all tested cell types in the mouse. We also identified an LNP containing cholesteryl oleate that efficiently delivered siRNA and sgRNA to liver endothelial cells in vivo. Delivery was as-or more-efficient as the same LNP made with unmodified cholesterol. Moreover, delivery to liver endothelial cells was 3 times more efficient than delivery to hepatocytes, distinguishing this oleate LNP from hepatocyte-targeting LNPs. RNA delivery can be improved by rationally selecting cholesterol variants, allowing optimization of nanoparticle targeting. PMID- 30016079 TI - Paper-Based System for Ion Transfer Across the Liquid-Liquid Interface. AB - While ion transfer studies were shown to be a promising method for fundamental electrochemistry, pharmacokinetic studies, and sensing, they suffer from inherent instability of the interface formed between the organic and aqueous phases. This limits to some extent the range of solvents which can be used and confines these studies to the laboratory. We propose here the use of paper, which has revolutionized the way we think of miniaturized analytical devices during the past decade, as a perfect substrate for ion transfer studies across the liquid liquid interface. We describe the design of a simple three-phase electrode paper based setup for redox-driven transfer of anions from an aqueous to an organic phase. Electrochemical measurements of seven different anions and concentration dependence studies are in good agreement with the results obtained with traditional setups. Additionally, we show the applicability and limitations of such setups to the analysis of anion mixtures. PMID- 30016080 TI - Critical Review: DNA Aptasensors, Are They Ready for Monitoring Organic Pollutants in Natural and Treated Water Sources? AB - There is a growing need to monitor anthropogenic organic contaminants detected in water sources. DNA aptamers are synthetic single-stranded oligonucleotides, selected to bind to target contaminants with favorable selectivity and sensitivity. These aptamers can be functionalized and are used with a variety of sensing platforms to develop sensors, or aptasensors. In this critical review, we (1) identify the state-of-the-art in DNA aptamer selection, (2) evaluate target and aptamer properties that make for sensitive and selective binding and sensing, (3) determine strengths and weaknesses of alternative sensing platforms, and (4) assess the potential for aptasensors to quantify environmentally relevant concentrations of organic contaminants in water. Among a suite of target and aptamer properties, binding affinity is either directly (e.g., organic carbon partition coefficient) or inversely (e.g., polar surface area) correlated to properties that indicate greater target hydrophobicity results in the strongest binding aptamers, and binding affinity is correlated to aptasensor limits of detection. Electrochemical-based aptasensors show the greatest sensitivity, which is similar to ELISA-based methods. Only a handful of aptasensors can detect organic pollutants at environmentally relevant concentrations, and interference from structurally similar analogs commonly present in natural waters is a yet-to be overcome challenge. These findings lead to recommendations to improve aptasensor performance. PMID- 30016081 TI - Extended Multiplicative Signal Correction Based Model Transfer for Raman Spectroscopy in Biological Applications. AB - The chemometric analysis of Raman spectra of biological materials is hampered by spectral variations due to the instrumental setup that overlay the subtle biological changes of interest. Thus, an established statistical model may fail when applied to Raman spectra of samples acquired with a different device. Therefore, model transfer strategies are essential. Herein we report a model transfer approach based on extended multiplicative signal correction (EMSC). As opposed to existing model transfer methods, the EMSC based approach does not require group information on the secondary data sets, thus no extra measurements are required. The proposed model-transfer approach is a preprocessing procedure and can be combined with any method for regression and classification. The performance of EMSC as a model transfer method was demonstrated with a data set of Raman spectra of three Bacillus bacteria spore species ( B. mycoides, B. subtilis, and B. thuringiensis), which were acquired on four Raman spectrometers. A three-group classification by partial least-squares discriminant analysis (PLS DA) with leave-one-device-out external cross-validation (LODCV) was performed. The mean sensitivities of the prediction on the independent device were considerably improved by the EMSC method. Besides the mean sensitivity, the model transferability was additionally benchmarked by the newly defined numeric markers: (1) relative Pearson's correlation coefficient and (2) relative Fisher's discriminant ratio. We show that these markers have led to consistent conclusions compared to the mean sensitivity of the classification. The advantage of our defined markers is that the evaluation is more effective and objective, because it is independent of the classification models. PMID- 30016082 TI - Resonant Sensors for Low-Cost, Contact-Free Measurement of Hydrolytic Enzyme Activity in Closed Systems. AB - A passive, resonant sensor was developed that can be embedded in closed systems for wireless monitoring of hydrolytic enzyme activity. The resonators are rapidly prototyped from copper coated polyimide substrates that are masked using an indelible marker with an XY plotter and subsequently etched. The resonator's frequency response window is designed by the Archimedean coil length and pitch and is tuned for the 1-100 MHz range for better penetration through soil, water, and tissue. The resonant frequency is measured up to 5 cm stand-off distance by a coplanar, two-loop coil reader antenna attached to a vector network analyzer monitoring the S21 scattering parameter. The resonant frequency is modulated (up to 50 MHz redshift) by changing the relative permittivity of the medium in contact with the resonator (e.g., air to water). The resonant sensors are coated by an enzyme substrate, which, when degraded, causes a change in dielectric and a shift in resonant frequency (up to 7 MHz redshift). The activity (turnover rate, or kcat) of the enzyme is calculated by fitting the measured data via a custom transport and reaction model which simulates the radial digestion profile. This is used to test purified Subtilisin A and unpurified bacterial protease samples at concentrations of 30 mg/mL to 200 mg/mL with kcat ranges of 0.003-0.002 and 0.008-0.004 gsubstrate/ genzyme per second. The sensor response rate can be tuned by substrate composition (e.g., gelatin and glycerol plasticizer weight percentage). Finally, the utility of these sensors is demonstrated by wirelessly measuring the proteolytic activity of farm soil with a measured kcat of 0.00152 gsubstrate/( gsoil.s). PMID- 30016083 TI - Self-Reporting Chemically Induced Protein Proximity System Based on a Malachite Green Derivative and the L5** Fluorogen Activating Protein. AB - A unique chemically induced proximity method is engineered based on mutant antibody VL domain using a fluorogenic malachite green derivative as the inducer, which gives fluorescent signals upon VL domain dimerization while simultaneously inducing downstream biological effects. PMID- 30016084 TI - Retention of a Paramagnetic Ground State at Low Temperatures in a Family of Structurally Related UIV Phosphates. AB - A new uranium fluoride phosphate, UFPO4, was synthesized via a mild hydrothermal route and characterized optically, thermally, and magnetically. Two thermal transformation products, U2O(PO4)2 and UIVUVIO2(PO4)2, were discovered to be structurally related, and were subsequently synthesized for bulk property measurements. All three materials failed to follow Curie-Weiss behavior at low temperatures, attributed to the nearly ubiquitous singlet ground state of U(IV), transitioning into a Curie-Weiss paramagnetic regime at high temperatures. Neutron diffraction experiments were performed on UFPO4 and UIVUVIO2(PO4)2 in order to characterize this unusual magnetic behavior. PMID- 30016085 TI - Development of a Decision Tree for Mitochondrial Dysfunction: Uncoupling of Oxidative Phosphorylation. AB - Mitochondrial dysfunction is the result of a number of processes including the uncoupling of oxidative phosphorylation. This study outlines the development of a decision tree-based profiling scheme capable of assigning chemicals to one of six confidence-based categories. The decision tree is based on a set of structural alerts and physicochemical boundaries identified from a detailed study of the literature. The physicochemical boundaries define a chemical relationship with both log P and p Ka. The study also outlines how the decision tree can be used to profile databases through an analysis of the publically available databases in the OECD QSAR Toolbox. This analysis enabled a set of additional structural alerts to be identified that are of concern for protonophoric ability. The decision tree will be incorporated in the OECD QSAR Toolbox V4.3. The intended usage is to group the chemicals into categories of chronic human health and environmental toxicological end points. PMID- 30016086 TI - Enantioselective Separation over a Chiral Biphenol-Based Metal-Organic Framework. AB - A chiral porous 3D metal-organic framework (MOF) is constructed from an enantiopure carboxylate ligand of 1,1'-biphenol, which can be utilized as adsorbent for the separation of aromatic alcohols and sulfoxides with enantioselectivity of up to 99.4%. Single-crystal X-ray diffraction analysis reveals the binding sites and host-guest interactions clearly, providing microscopic insight into the origin of the enantiosorption in the framework. PMID- 30016087 TI - Carbonate Disequilibrium in the External Boundary Layer of Freshwater Chrysophytes: Implications for Contaminant Uptake. AB - The interplay between biological and chemical reactions in the freshwater phytoplankton phycosphere and the resulting modulations of contaminant speciation and uptake is poorly characterized. Here we modeled the effect of algal C and N uptake on carbonate cycling and speciation of selected contaminants in the phycosphere (external boundary layer) of chrysophytes, a key phytoplankton group in oligotrophic systems. We calculated an enrichment in H+ concentration relative to that in the bulk solution (pH 7.0) of approximately 40% or a depletion of approximately 30% for NH4+ or NO3--grown cells, respectively, at the algal membrane surface of a 5-MUm radius cell. Such changes are mainly due to direct H+ uptake or release at the plasmalemma if NO3- or NH4+ is the N source, respectively. Due to these pH changes in the external boundary layer, competition between H+ and metals for uptake is enhanced, for NH4+-grown cells which contributes to a decrease in potential metal uptake. Our model suggests that the uptake of protonated weakly acidic organic acids (HA) is greater in NH4+-grown cells compared to that in NO3--grown cells. The account of chemical reactions in the algal external boundary layer could improve ecological risk assessments for a wide range of contaminants. PMID- 30016088 TI - Disorder-Induced Breaking of the Local Inversion Symmetry in Rhombohedral Pyrochlores M2La3Sb3O14 (M = Mg or Ca): A Structural and Spectroscopic Investigation. AB - A detailed investigation of the overall crystal structure, and in particular of the local structure around the cations in M2La3Sb3O14 (M = Mg, Ca) was accomplished using X-ray diffraction, steady state luminescence spectroscopy and decay kinetics, and state of the art density functional calculations. The computational tool was also used to investigate the structure of Mn2La3Sb3O14. The Eu3+ dopant ion was employed as an optical probe of the local symmetry at the cationic sites. The use of these complementary techniques shows that the antimonates under investigation belong to the rhombohedral pyrochlore family with space group R3 m (No. 166), but while Mg2La3Sb3O14 and Mn2La3Sb3O14 show an ordered cationic configuration, the Ca2+ and La3+ of Ca2La3Sb3O14 are disordered because of their similar ionic radii. In both the Mg- and the Ca-based compounds, the Eu3+ ions formally occupy centrosymmetric sites, but in the case of Ca2La3Sb3O14 the presence of disorder in the outer coordination spheres removes the local inversion symmetry in these sites. This has a strong influence on the Eu3+ luminescence spectrum and on the radiative decay rate of the 5D0 emitting level. PMID- 30016089 TI - Mechanism of Selective Enzyme Inhibition through Uncompetitive Regulation of an Allosteric Agonist. AB - Classical uncompetitive inhibitors are potent pharmacological modulators of enzyme function. Since they selectively target enzyme-substrate complexes (E:S), their inhibitory potency is amplified by increasing substrate concentrations. Recently, an unconventional uncompetitive inhibitor, called CE3F4R, was discovered for the exchange protein activated by cAMP isoform 1 (EPAC1). Unlike conventional uncompetitive inhibitors, CE3F4R is uncompetitive with respect to an allosteric effector, cAMP, as opposed to the substrate (i.e., CE3F4R targets the E:cAMP rather than the E:S complex). However, the mechanism of CE3F4R as an uncompetitive inhibitor is currently unknown. Here, we elucidate the mechanism of CE3F4R's action using NMR spectroscopy. Due to limited solubility and line broadening, which pose major challenges for traditional structural determination approaches, we resorted to a combination of protein- and ligand-based NMR experiments to comparatively analyze EPAC mutations, inhibitor analogs, and cyclic nucleotide derivatives that trap EPAC at different stages of activation. We discovered that CE3F4R binds within the EPAC cAMP-binding domain (CBD) at a subdomain interface distinct from the cAMP binding site, acting as a wedge that stabilizes a cAMP-bound mixed-intermediate. The mixed-intermediate includes attributes of both the apo/inactive and cAMP-bound/active states. In particular, the intermediate targeted by CE3F4R traps a CBD's hinge helix in its inactive conformation, locking EPAC into a closed domain topology that restricts substrate access to the catalytic domain. The proposed mechanism of action also explains the isoform selectivity of CE3F4R in terms of a single EPAC1 versus EPAC2 amino acid difference that destabilizes the active conformation of the hinge helix. PMID- 30016091 TI - Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors. AB - Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma. PMID- 30016092 TI - Phycobiliproteins Production Enhancement and Lipidomic Alteration by Titanium Dioxide Nanoparticles in Synechocystis sp. PCC 6803 Culture. AB - This study aimed to improve the production of phycobiliproteins using TiO2 nanoparticles (NPs) in Synechocystis sp. PCC 6803. The growth characteristics of Synechocystis cells were not affected by TiO2 NPs treatment, but this treatment increased the chlorophyll content significantly by 62.2% (14.6 mg/L) compared to that of control (9.0 mg/L) on day 16. Phycocyanin production was increased by 33.8% (29.3 g/L) compared to that of control (21.9 g/L) on day 8. Allophycocyanin production was increased by 55.0% (6.2 g/L) compared to that of control (4.0 g/L) on day 8, and by 22.4% (16.4 g/L) compared to that of control (13.4 g/L) on day 16. Direct infusion mass spectrometry revealed that TiO2 NPs treatment significantly increased the levels of major thylakoid membranes of monogalactosyldiacylglycerols (18:2/18:3, 18:2/18:2, 18:1/18:2), phosphatidylglycerol (16:0/16:1), and sulfoquinovosyldiacylglycerols (16:0/16:1, 16:0:18:4) on day 8. These findings indicate that TiO2 NPs have potential for commercial applications in Synechocystis species or other microalgal strains. PMID- 30016093 TI - Preparation and Characterization of Size-Controlled Nanoparticles for High Loading lambda-Cyhalothrin Delivery through Flash Nanoprecipitation. AB - Environmental concerns and low efficacy pose a challenge for the application of traditional insecticide formulations. In this study, a series of lambda cyhalothrin (LC)-loaded nanoparticles (NPs) were produced by flash nanoprecipitation (FNP), and the parameters that influence nanoparticle size were systematically studied. The narrowly distributed and size-controllable NPs formed stable suspensions in aqueous solution without organic solvents. The amphiphilic block polymer PEG-PDLLA played an important role as a drug carrier, and the encapsulation content was as high as 99%. The obtained NPs with high loading of LC exhibited toxicity comparable to those of two commercial formulations at low doses. This confirms that FNP technology is a promising and scalable method for agrochemical delivery. PMID- 30016094 TI - Polyethylenimine-Capped CdS Quantum Dots for Sensitive and Selective Detection of Nitrite in Vegetables and Water. AB - In the present work, polyethylenimine-capped CdS quantum dots (PEI-CdS QDs) with bright green fluorescence were synthesized and applied for sensitively and selectively detecting the nitrite in vegetable and water samples. Highly fluorescent and environment-friendly PEI-CdS QDs (quantum yield about 8%) with diameters of ca. 5 nm were easily synthesized by using hyperbranched PEI as functional polymer. Formation of the PEI-CdS QDs was verified by transmission electron microscopy and UV-vis spectroscopy. The fluorescence intensity of the as synthesized PEI-CdS QDs was enhanced pronouncedly by the increasing amount of PEI and was stable when the pH ranged from 5.0 to 9.0. Our results demonstrated that the fluorescence of the PEI-CdS QDs was effectively quenched by the nitrite in a rather wide linear range of 1.0 * 10-7-1.0 * 10-4 M while efficiently avoiding the interferences from nitrate ions and other commonly coexisting anions of nitrite in the vegetable samples. The detection limit of the present method was lower than the maximum limit of nitrite in drinking water (6.5 * 10-5 M) ruled by the World Health Organization, which is significant to the application of the method. PMID- 30016095 TI - Yeast Chemogenomic Profiling Reveals Iron Chelation To Be the Principle Cell Inhibitory Mode of Action of Gossypol. AB - Gossypol is an inhibitor of eukaryotic cells with an undetermined mode of action. Here we show that the chemogenomic profile of gossypol is strikingly similar to that of the iron chelators deferasirox and desferricoprogen. Iron import channels Fet1 and Fet3 are prominent in all three profiles. Furthermore, yeast inhibited by gossypol and deferasirox is rescued by the addition of Fe2+. We propose that Fe2+ chelation is in fact the principle mode of action of gossypol. PMID- 30016096 TI - Generation of a Diligand Complex of Bovine Serum Albumin with Quercetin and Carbon Nanotubes for the Protection of Bioactive Quercetin and Reduction of Cytotoxicity. AB - The interactions between proteins and bioactive ligands (such as flavonoids and nanomaterials) are vital to the design of effective protein carriers for the protection of bioactive molecules and reduction of the cytotoxicity of nanotubes. Bovine serum albumin (BSA) can bind various bioactive components and subsequently form protein-ligand complexes. Herein, the binding of BSA to quercetin and single walled carbon nanotubes (SWCNTs) was investigated by using experimental and molecular-docking methods. The fluorescence intensity of BSA was decreased by both quercetin and SWCNTs in static quenching mode (i.e., compound formation), which was authenticated by Stern-Volmer calculations. Although quercetin showed a higher affinity for BSA than SWCNTs, the binding of both components to BSA was located in site I (subdomain IIA). BSA-diligand complexes were successfully generated when SWCNTs and quercetin, in that sequence, were added. The cytotoxicity of SWCNTs and the formation of reactive oxygen species in endothelial cells were decreased with the BSA-diligand complexes relative to those of SWCNTs or BSA-SWCNT corona, whereas the stability problems of quercetin were ameliorated in the BSA-diligand complex relative to in the free flavonoid. The BSA-diligand complex showed a better inhibitive effect on the cytotoxicity of SWCNTs than the BSA-SWCNT complex, and thus the coexistence of quercetin played a crucial role. These data demonstrate the advantages and possibility of designing BSA carriers for the protection of bioactive ligands and reduction of the cytotoxicity of nanotubes in functional-food and biomedical applications. PMID- 30016097 TI - Asperversiamides, Linearly Fused Prenylated Indole Alkaloids from the Marine Derived Fungus Aspergillus versicolor. AB - Asperversiamides A-H (1-8), eight linearly fused prenylated indole alkaloids featuring an unusual pyrano[3,2- f]indole unit, were isolated from the marine derived fungus Aspergillus versicolor. The structures and absolute configurations of these compounds were elucidated by extensive spectroscopic analyses, single crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, and optical rotation (OR) calculations. The relative configuration of C-21 of iso notoamide B was herein revised, and a new methodology for preliminarily determining if the relative configuration of the bicyclo[2.2.2]diazaoctane moiety of a spiro-bicyclo[2.2.2]diazaoctane-type indole alkaloid is syn or anti was developed. The anti-inflammatory activities of the isolated compounds were all tested, and of these compounds, 7 exhibited a potent inhibitory effect against iNOS with an IC50 value of 5.39 MUM. PMID- 30016098 TI - Fabrication and Characterization of Quinoa Protein Nanoparticle-Stabilized Food Grade Pickering Emulsions with Ultrasound Treatment: Effect of Ionic Strength on the Freeze-Thaw Stability. AB - The development of multilayered interfacial engineering on the emulsion freeze thaw properties has recently attracted widespread attention, because of the essential freeze-thaw storage process in some emulsion-matrix food products. In this research, we studied the role of salt concentration on the freeze-thaw properties of quinoa protein (QPI) nanoparticles-stabilized Pickering emulsions. The QPI nanoparticles (particle concentration c = 2%, w/v) with increasing particle size and surface hydrophobicity ( H0) were fabricated by ultrasound treatment at 100 W for 20 min, by varying the NaCl addition (salt concentrations, 0-500 mM). The sonicated QPI nanoparticles with increasing salt concentrations showed higher beta-sheet structure contents and stronger hydrophobic interactions, which were attributed to the decreasing charged groups and particle aggregation by electrostatic interactions. As compared to the sonicated QPI nanoparticles-stabilized Pickering emulsions ( c = 2%, oil fraction phi = 0.5) without salt accretion, the emulsions with salt accretion exhibited better freeze thaw properties after three freeze-thaw circulations, which might be mainly caused by the generation of gel-like three-dimensional structure and multilayered network at the droplets' interface with smaller droplet sizes. Increasing the salt concentration progressively enhanced the freeze-thaw properties of sonicated QPI nanoparticles-stabilized Pickering emulsions probably due to the inhibit formation of ice crystal by the "salting-out" effects. The results of this study would provide great significance to investigate the role of salt concentration in the freeze-thaw properties of protein-stabilized Pickering emulsions. PMID- 30016100 TI - Theoretical Study of the Reactions of H Atoms with CH3I and CH2I2. AB - High level ab initio methods have been used to provide reliable kinetic data for the H + CH3I and H + CH2I2 gas-phase reactions. The (H, I)-abstraction and I substitution reaction pathways were identified. The structures were determined on the potential energy surface at the MP2/aug-cc-pVTZ level of theory. The energetics was then refined using the coupled cluster theory. For the iodinated species, the spin-orbit coupling was calculated using the MRCI approach. The core valence and the scalar relativistic corrections were considered. Thermal rate constants were reported using the canonical transition-state theory (TST) and compared to computed values with the canonical variational transition-state theory (CVT) using the zero curvature tunneling (ZCT) and the small curvature tunneling (SCT) corrections over a wide temperature range (250-2500 K) to show the importance of quantum tunneling effects at low temperatures. They are given by the following expressions for the overall reactions using the CVT/SCT method: kH+CH3I( T) = 1.07 * 10-17 * T2.13 exp(2.68 (kJ mol-1)/ RT) and kH+CH2I2( T) = 5.73 * 10-21 * T2.97 exp(3.15 (kJ mol-1)/ RT). The I-abstraction is predicted to be the major pathway for both H + CH3I and H + CH2I2 reactions. The obtained kinetic parameters for the H + CH3I reaction are in excellent agreement with their experimental counterparts over the temperature range 300-750 K. On the basis of our calculated reaction enthalpies, a new evaluation of the standard enthalpy of formation at 298 K of CH2I and CHI2 has been provided. Obtained values are Deltaf H degrees 298K (CH2I) = 219.5 kJ mol-1 and Deltaf H degrees 298K(CHI2) = 296.3 kJ mol-1. PMID- 30016099 TI - Synthesis of Amphiphilic Copolymers Containing Ciprofloxacin and Amine Groups and Their Antimicrobial Performances As Revealed by Confocal Laser-Scanning Microscopy and Atomic-Force Microscopy. AB - Two series of amphiphilic antimicrobial copolymers containing ciprofloxacin (CPF) and amine functional groups have been synthesized via free-radical copolymerization. The chemical structures of the different amine groups and the copolymer compositions have been systematically varied to study how the structure of the copolymer exerts an influence on the antibacterial activity. The viability of Escherichia coli in the presence of antimicrobial copolymers was observed by confocal laser-scanning microscopy (CLSM). CLSM as well as atomic-force microscopy (AFM) were applied to visualize changes in morphology of bacteria treated with antimicrobial copolymers and elucidate the antimicrobial mechanism of the antimicrobial copolymers. Morphological changes of bacteria observed via AFM and CLSM demonstrated that the antibacterial mechanism was due to the disruption of the bacterial membrane. The destruction of the cell membrane was also confirmed by the leakage of intracellular components, which had a strong absorbance at 260 nm. The inhibitory process was monitored by UV absorption dynamically. PMID- 30016101 TI - Cobalt-Rhodium Heterobimetallic Nanoparticle-Catalyzed N-Alkylation of Amines with Alcohols to Secondary and Tertiary Amines. AB - Without the requirement for base or other additives, Co2Rh2/C can selectively catalyze both mono- and bis-N-alkylation through the coupling of simple alcohols with amines, yielding a range of secondary and tertiary amines in good to excellent isolated yields. The reaction can be applied to benzyl alcohol with optically active 1-phenylethan-1-amines, and secondary amines were isolated in quantitative yields with an excellent enantiomeric excess (ee > 94%). Selectivity is achieved by varying the reaction temperature and amount of catalyst used. This catalytic system has several advantages including eco-friendliness and a simple workup procedure. The catalyst can be successfully recovered and reused ten times without any significant loss of activity. PMID- 30016102 TI - Linker-Dependent Singlet Fission in Tetracene Dimers. AB - Separation of triplet excitons produced by singlet fission is crucial for efficient application of singlet fission materials. While earlier works explored the first step of singlet fission, the formation of the correlated triplet pair state, the focus of recent studies has been on understanding the second step of singlet fission, the formation of independent triplets from the correlated pair state. We present the synthesis and excited-state dynamics of meta- and para bis(ethynyltetracenyl)benzene dimers that are analogues to the ortho bis(ethynyltetracenyl)benzene dimer reported by our groups previously. A comparison of the excited-state properties of these dimers allows us to investigate the effects of electronic conjugation and coupling on singlet fission between the ethynyltetracene units within a dimer. In the para isomer, in which the two chromophores are conjugated, the singlet exciton yields the correlated triplet pair state, from which the triplet excitons can decouple via molecular rotations. In contrast, the meta isomer in which the two chromophores are cross coupled predominantly relaxes via radiative decay. We also report the synthesis and excited-state dynamics of two para dimers with different bridging units joining the ethynyltetracenes. The rate of singlet fission is found to be faster in the dimer with the bridging unit that has orbitals closer in energy to that of the ethynyltetracene chromophores. PMID- 30016103 TI - Effects of Non-native Interactions on Frustrated Proteins Folding under Confinement. AB - In vitro, kinetically significant non-native interactions have been identified experimentally during the folding of proteins Im7, Im9, and A39V/N53P/V55L Fyn SH3 domain. To understand the role of non-native interactions on the folding of some frustrated proteins in chaperone, we employed native-centric models with and without additional transferable, sequence-dependent non-native hydrophobic interactions to comparatively study the folding behaviors of the three proteins confined in spherical cages. Under purely repulsive confinement, as a decrease of cavity size, the non-native interactions increase, especially in the unfolded state, enhancing the roughness of the folding energy landscape. As a result, the increase in native stability for the three proteins by the model incorporated non native interactions (db + MJ hphi model) is much smaller than that by the purely native-centric model (desolvation-barrier (db) model); the acceleration of folding simulated by the db + MJ hphi model is much slower than that via the db model; in particular, the folding rate of Im7 decreases when reducing the cavity size under zero-denaturant condition. The repulsive confinement can also promote formation of specific non-native contacts in the transition state and favor more folding pathways passing through the misfolded state, leading to a higher population of the misfolded intermediate. In an attractive cage, the attractive interactions could inhibit the formation of intrachain non-native contacts and provide alternate folding pathways to the native state so that the population of the misfolded intermediate decreases when increasing the strength of attractive interaction between the substrate protein and cavity wall. This study should be helpful in general to understand how the chaperonins reshape the folding energy landscape of some frustrated proteins. PMID- 30016104 TI - Nonradiative Decay and Stability of N-Heterocyclic Carbene Iridium(III) Complexes. AB - Devices based on deep-blue emitting iridium(III) complexes with N-heterocyclic carbene (NHC) ligands have recently been shown to give excellent performance as phosphorescent organic light-emitting diodes (PHOLEDs). To facilitate the design of even better deep-blue phosphorescent emitters, we carried out density functional theory (DFT) calculations of the lowest triplet (T1) potential-energy surfaces upon lengthening the iridium-ligand (Ir-C) bonds. Relativistic time dependent DFT calculations demonstrate that this changes the nature of T1 from a highly emissive metal-to-ligand charge transfer (3MLCT) state to a metal centered (3MC) state where the radiative decay rate is orders of magnitude slower than that of the 3MLCT state. We identify the elongation of an Ir-C bond on the NHC group as the pathway with the lowest energy barrier between the 3MLCT and 3MC states for all complexes studied and show that the barrier height is correlated with the experimentally measured nonradiative decay rate. This suggests that the thermal population of 3MC states is the dominant nonradiative decay mechanism at room temperature. We show that the 3MLCT -> 3MC transition is reversible, in marked contrast to deep-blue phosphors containing coordinating nitrogen atoms, where the population of 3MC states breaks Ir-N bonds. This suggests that, as well as improved efficiency, blue PHOLEDs containing phosphors where the metal is only coordinated by carbon atoms will have improved device lifetimes. PMID- 30016105 TI - Phase Diagrams of TIP4P/2005, SPC/E, and TIP5P Water at High Pressure. AB - We investigate high-pressure ice phases using molecular dynamics simulations. Spontaneous nucleation of a new crystalline solid, named ice T2, is observed in a simulation of TIP4P/2005 water at 260 K and 3.3 GPa. The phase diagram of ices VI, VII, T2, and recently reported two other hypothetical ices, ice R and ice T, is determined using the direct coexistence method and the Clausius-Clapeyron equation for TIP4P/2005, SPC/E, and TIP5P water. It is found that there exists at least one pressure region in which a hypothetical ice phase is the most stable at ambient temperature with those models. Although the hypothetical ices may be metastable in reality, these ices could be of great importance toward a comprehensive understanding of the phase behaviors of water including many metastable ice polymorphs settled in the hidden area of T- P space. The unit cell of ice T2 is tetragonal with a space group of I41/ acd and it contains 152 water molecules. This is probably the most entangled structure among crystals which have been found in nucleation simulations without bias. PMID- 30016106 TI - Three-Dimensional FRET Multiplexing for DNA Quantification with Attomolar Detection Limits. AB - Photoluminescence (PL) multiplexing usually relies on spectral or temporal separation. A combination into higher-order multiplexing for biosensing is extremely challenging because the PL intensity is required for target quantification at very low concentrations and the interplay of color, lifetime, and intensity must be carefully adapted. Here, we demonstrate time-gated Forster resonance energy transfer (TG-FRET) from a long-lifetime Tb complex to Cy3.5 and Cy5.5 dyes for spectrotemporal multiplexing of four different DNA targets in the same sample by single-color excitation and two-color detection. We used rolling circle amplification (RCA) for high specificity and sensitivity and for placing Tb donors and dye acceptors at controlled distances within the amplified DNA concatemers. This precise distance tuning led to target-specific PL decays of the FRET pairs and simple, separation-free, and higher-order multiplexed quantification of DNA. The RCA-FRET DNA assay could distinguish very homologous target sequences and provided limits of detection down to 40 zeptomoles (300 aM). PMID- 30016107 TI - Thermodynamic and Kinetic Limitations for Peroxide and Superoxide Formation in Na O2 Batteries. AB - The Na-O2 system holds great potential as a low-cost, high-energy-density battery, but under normal operating conditions, the discharge is limited to sodium superoxide (NaO2), whereas the high-capacity peroxide state (Na2O2) remains elusive. Here, we apply density functional theory calculations with an improved error-correction scheme to determine equilibrium potentials and free energies as a function of temperature for the different phases of NaO2 and Na2O2, identifying NaO2 as the thermodynamically preferred discharge product up to ~120 K, after which Na2O2 is thermodynamically preferred. We also investigate the reaction mechanisms and resulting electrochemical overpotentials on stepped surfaces of the NaO2 and Na2O2 systems, showing low overpotentials for NaO2 formation (etadis = 0.14 V) and depletion (etacha = 0.19 V), whereas the overpotentials for Na2O2 formation (etadis = 0.69 V) and depletion (etacha = 0.68 V) are found to be prohibitively high. These findings are in good agreement with experimental data on the thermodynamic properties of the Na xO2 species and provide a kinetic explanation for why NaO2 is the main discharge product in Na-O2 batteries under normal operating conditions. PMID- 30016108 TI - Dearomatization of Indole via Intramolecular [3 + 2] Cycloaddition: Access to the Pentacyclic Skeleton of Strychons Alkaloids. AB - An efficient method to build various multisubstituted polycyclic indoline annulated normal to medium-size rings through dearomatization of indole via a tandem 1,2-acyloxy migration/intramolecular [3 + 2] cycloaddition process is described. The pentacyclic skeleton of strychnine could be synthesized via this tandem cycloaddition and a further Mannich reaction. This approach would provide a novel strategy to the synthesis of strychons alkaloids. PMID- 30016109 TI - Multiexciton Lifetimes Reveal Triexciton Emission Pathway in CdSe Nanocrystals. AB - Multiexcitons in emerging semiconducting nanomaterials play a critical role in potential optoelectronic and quantum computational devices. We describe photon resolved single molecule methods to directly probe the dynamics of biexcitons and triexcitons in colloidal CdSe quantum dots. We confirm that biexcitons emit from a spin-correlated state, consistent with statistical scaling. Contrary to current understanding, we find that triexciton emission is dominated by band-edge 1Se1S3/2 recombination rather than the higher energy 1Pe1P3/2 recombination. PMID- 30016110 TI - Two-Photon Microscopy with a Double-Wavelength Metasurface Objective Lens. AB - Two-photon microscopy is a key imaging technique in life sciences due to its superior deep-tissue imaging capabilities. Light-weight and compact two-photon microscopes are of great interest because of their applications for in vivo deep brain imaging. Recently, dielectric metasurfaces have enabled a new category of small and lightweight optical elements, including objective lenses. Here we experimentally demonstrate two-photon microscopy using a double-wavelength metasurface lens. It is specifically designed to focus 820 and 605 nm light, corresponding to the excitation and emission wavelengths of the measured fluorophors, to the same focal distance. The captured two-photon images are qualitatively comparable to the ones taken by a conventional objective lens. Our metasurface lens can enable ultracompact two-photon microscopes with similar performance compared to current systems that are usually based on graded-index lenses. In addition, further development of tunable metasurface lenses will enable fast axial scanning for volumetric imaging. PMID- 30016111 TI - N6-(2-Deoxy-d- erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5- N-(2 hydroxy-3-buten-1-yl)-formamidopyrimidine Adducts of 1,3-Butadiene: Synthesis, Structural Identification, and Detection in Human Cells. AB - 1,3-Butadiene (BD) is an environmental and occupational toxicant classified as a human carcinogen. BD is metabolically activated by cytochrome P450 monooxygenases to 3,4-epoxy-1-butene (EB), which alkylates DNA to form a range of nucleobase adducts. Among these, the most abundant are the hydrolytically labile N7-guanine adducts such as N7-(2-hydroxy-3-buten-1-yl)-guanine (N7-EB-dG). We now report that N7-EB-dG can be converted to the corresponding ring open N6-(2-deoxy-d- erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5- N-(2-hydroxy-3-buten-1 yl)-formamidopyrimidine (EB-Fapy-dG) adducts. EB-Fapy-dG lesions were detected in EB-treated calf thymus DNA and in EB-treated mammalian cells using quantitative isotope dilution nanoLC-ESI+-MS/MS. EB-Fapy-dG adduct formation in EB-treated calf thymus DNA was concentration dependent and was greatly accelerated at an increased pH. EB-FAPy-dG adduct amounts were 2-fold higher in base excision repair-deficient NEIL1-/- mouse embryonic fibroblasts (MEF) as compared to isogenic controls (NEIL1+/+), suggesting that this lesion may be a substrate for NEIL1. Furthermore, NEIL1-/- cells were sensitized to EB treatment as compared to NEIL1+/+ fibroblasts. Overall, our results indicate that ring-opened EB-FAPy-dG adducts form under physiological conditions, prompting future studies to determine their contributions to genotoxicity and mutagenicity of BD. PMID- 30016112 TI - Quantifying Disproportionation in Pharmaceutical Formulations with 35Cl Solid State NMR. AB - Reliable methods for the characterization of drug substances are critical for evaluating stability and bioavailability, especially in dosage formulations under varying storage conditions and usage. Such methods must also give information on the molecular identities and structures of drug substances and any potential byproducts of the formulation process, as well as providing a means of quantifying the relative amounts of these substances. For example, active pharmaceutical ingredients (APIs) are often formulated as ionic salts to improve the pharmaceutical properties of dosage forms; however, exposure of such formulations to elevated temperature and/or humidity can trigger the conversion of an ionic salt of an API to a neutral form with different properties, through a process known as disproportionation. It is particularly challenging to identify changes of pharmaceutical components in solid dosage formulations, which are complex heterogeneous mixtures of the API and excipient components (e.g., binders, disintegrants, and lubricants). In this study, we illustrate that ultra wideline (UW) 35Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate excipients. 35Cl SSNMR can quantitatively detect the amount of PiogHCl in mixed samples within +/-1 wt % and measure the degree of PiogHCl disproportionation in formulation samples stressed at high relative humidity and temperature. Unlike other methods used for characterizing disproportionation, our experiments directly probe the Cl- anions in both the intact salt and disproportionation products, revealing all of the chlorine-containing products in the solid-state chemical reaction without interfering signals from the formulation excipients. PMID- 30016113 TI - Synthetic Access to Functionalized Dipolarophiles of Lewis Basic Complexant Scaffolds through Sonogashira Cross-Coupling. AB - Soft Lewis basic complexants that facilitate selective removal of discrete ions resident in spent nuclear fuel can decrease repository volume and radiotoxicity and are of significant interest. Optimization of chelation efficacy is predicated on modular access to synthons to rapidly evaluate structure-activity relationships. The following work highlights efficient access to functionalized synthons for use as potential dipolarophiles in subsequent cycloaddition processes via Sonogashira coupling of 3-(6-bromo-pyridin-2-yl)-[1,2,4]triazine scaffolds. The 41 examples explored during method development evaluated electrophile and nucleophile diversity affording the desired coupled products in 31-96% isolated yield. Method optimization, substrate scope, a scale-up reaction, and downstream product functionalization are reported herein. PMID- 30016114 TI - Structural Signature of beta-Relaxation in La-Based Metallic Glasses. AB - The secondary beta-relaxation is an intrinsic feature in glassy materials. However, its structural origin is still not well understood. Here we report that the beta-relaxations in La50Al15Ni35 and La50Al15Cu35 metallic glasses (MGs) mainly depend on the vibration of small Ni and Cu atoms in local cages. By using advanced synchrotron X-ray techniques and theoretical calculations, we elucidate that the tricapped-trigonal-prism-like polyhedra with more large La atoms in shells favor the local vibration of center Ni atoms, leading to the pronounced beta-relaxation event. In contrast, the in-cage vibration of Cu atoms is somehow suppressed by the appearance of more shell Cu atoms. Nevertheless, they could easily diffuse out of the cages compared with Ni, thus triggering the onset of alpha-relaxation. This work provides a pathway to understand the different structural relaxation behaviors in MGs and other disordered materials from their local atomic packing and dynamics points of view. PMID- 30016115 TI - Near-Field Thermophotonic Systems for Low-Grade Waste-Heat Recovery. AB - Low-grade waste heat contains an enormous amount of exergy that can be recovered for renewable-energy generation. Current solid-state techniques for recovering low-grade waste heat, such as thermoelectric generators and thermophotovoltaics, however, are limited by low conversion efficiencies or power densities. In this work, we propose a solid-state near-field thermophotonic system. The system consists of a light-emitting diode (LED) on the hot side and a photovoltaic (PV) cell on the cold side. Part of the generated power by the PV cell is used to positively bias the LED. When operating in the near-field regime, the system can have power density and conversion efficiency significantly exceeding the performance of current solid-state approaches for low-grade waste-heat recovery. For example, when the gap spacing is 10 nm and the hot side and cold side are, respectively, 600 and 300 K, we show that the generated electric power density and thermal-to-electrical conversion efficiency can reach 9.6 W/cm2 and 9.8%, respectively, significantly outperforming the current record-setting thermoelectric generators. We identify the alignment of the band gaps of the LED and the PV cell, the appropriate choice of thickness of the LED and PV cell to mitigate the effect of non-radiative recombination, and the use of highly reflective back mirrors as key factors that affect the performance of the system. Our work points to the significant potential of photonic systems for the recovery of low-grade waste heat. PMID- 30016116 TI - Epigenome Editing Enters the Arena. A New Tool to Reveal (and Reverse?) Pathologic Gene Regulation. PMID- 30016117 TI - A model comparison algorithm for increased forecast accuracy of dengue fever incidence in Singapore and the auxiliary role of total precipitation information. AB - Many time-series models for disease counts utilise information from environmental variables. We focus on weekly dengue fever (DF) incidence rates in Singapore and demonstrate the strong negative correlation between an appropriately time-lagged total weekly rainfall and DF incidence. A Bayesian neural network time-series model for predicting DF incidence which utilizes rainfall data is introduced. A comparison is made between this neural network model and a time-series model which does not use any covariate information. An easily implementable method for choosing between the models which optimizes future prediction accuracy is suggested as well. We note that our proposed comparison method is applicable to any competing time-series models. This algorithm is demonstrated through examples of comparisons between pairs of different time-series models. PMID- 30016118 TI - Chiropractic Integration into Private Sector Medical Facilities: A Multisite Qualitative Case Study. AB - OBJECTIVES: Chiropractic care may have value in improving patient outcomes and decreasing opioid use, but little is known about the impetus for or process of incorporating these services into conventional medical settings. The purpose of this qualitative study was to describe organizational structures, care processes, and perceived value of chiropractic integration within U.S. private sector medical facilities. DESIGN: Multisite, comparative organizational case study. SETTINGS: Nine U.S. private sector medical facilities with on-site chiropractic care, including five hospitals and four clinics. PARTICIPANTS: One hundred and thirty-five key facility stakeholders including doctors of chiropractic (DCs), non-DC clinicians, support staff, administrators, and patients. METHODS: Researchers conducted 2-day site visits to all settings. Qualitative data were collected from audio-recorded, semi-structured, role-specified, individual interviews; standardized organizational data tables; and archival document review. A three-member, interdisciplinary team conducted thematic content analysis of verbatim transcripts using an existing conceptual framework and emergent codes. RESULTS: These nine medical facilities had unique organizational structures and reasons for initiating chiropractic care in their settings. Across sites, DCs were sought to take an evidence-based approach to patient care, work collaboratively within a multidisciplinary team, engage in interprofessional case management, and adopt organizational mission and values. Chiropractic clinics were implemented within existing human resources, physical plant, information technology, and administrative support systems, and often expanded over time to address patient demand. DCs usually were co-located with medical providers and integrated into the collaborative management of patients with musculoskeletal and co-morbid conditions. Delivery of chiropractic services was perceived to have high value among patients, medical providers, and administration. Patient clinical outcomes, patient satisfaction, provider productivity, and cost offset were identified as markers of clinic success. CONCLUSION: A diverse group of U.S. private sector medical facilities have implemented chiropractic clinics, and a wide variety of facility stakeholders report high satisfaction with the care provided. PMID- 30016119 TI - Management and treatment of deep vein thrombosis in special populations. AB - INTRODUCTION: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most frequent cardiovascular disease besides myocardial infarction and stroke. Because DVT may cause life-threatening conditions, treatment should be started as soon as possible. This comprises certain challenges in special populations. Areas covered: In cancer-associated VTE, current treatment is different from non-cancer VTE due to disease-related interventions and higher bleeding risks. In the treatment of patients with extensive DVT, the role of catheter-directed thrombolysis has been investigated in two randomized trials, but results do not yield a recommendation for standard thrombolysis. The diagnosis of suspected recurrent DVT is especially challenging in case of ipsilateral DVT. Treatment strategies in recurrent DVT are dependent on the case and on particular risk factors. Also discussed is the therapy for DVT in pregnant women, which is more complex as a result of anticoagulants crossing the placenta. Expert commentary: DVT treatment in special populations poses special challenges due to high thrombotic and bleeding risk. This will be discussed in more detail in this review. PMID- 30016120 TI - Validation of a Driving Simulator Study on Driver Behavior at Passive Rail Level Crossings. AB - OBJECTIVE: The behavioral validation of an advanced driving simulator for its use in evaluating passive level crossing countermeasures was performed for stopping compliance and speed profile. BACKGROUND: Despite the fact that most research on emerging interventions for improving level crossing safety is conducted in a driving simulator, no study has validated the use of a simulator for this type of research. METHOD: We monitored driver behavior at a selected passive level crossing in the Brisbane region in Australia for 3 months ( N = 916). The level crossing was then replicated in an advanced driving simulator, and we familiarized participant drivers ( N = 54) with traversing this crossing, characterized by low road and rail traffic. RESULTS: We established relative validity for the stopping compliance and the approach speed. CONCLUSION: This validation study suggests that driving simulators are an appropriate tool to study the effects of interventions at passive level crossing with low road and rail traffic, which are prone to reduced compliance due to familiarity. APPLICATION: This study also provides support for the findings of previous driving simulator studies conducted to evaluate compliance and approach speeds of passive level crossings. PMID- 30016121 TI - The association of non-alcoholic fatty liver disease with thyroid peroxidase and thyroglobulin antibody: A new insight from SPECT-China study. AB - Non-alcoholic fatty liver disease (NAFLD) has been studied with inflammation and immune, but the link with thyroid autoimmunity is unreported. This study aimed to explore the direct association of NAFLD with thyroid autoimmune disease (AITD) among participants with normal thyroid stimulating hormone (TSH) levels. The data were obtained from a cross-sectional study (SPECT-China). A total of 7982 participants were enrolled. Participants underwent several checkups including peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), thyroid, and liver ultrasonography (US). The prevalence of NAFLD was higher in TPOAb and/or TgAb positive [TPO/TgAb (+)] group and TPOAb and/or TgAb together with US positive [TPO/TgAb (+) and US (+)] group for both genders. After full adjustment, binary logistic analysis showed the presence of NAFLD was positively associated with the serum level of TPOAb in men (p < .001) and TgAb in women (p = .001). Both TPO/TgAb (+) and TPO/TgAb (+) and US (+) were associated with an increased risk of NAFLD in both genders [TPO/TgAb (+): odds ratio (OR) 1.474, 95% confidence interval (CI) 1.102, 1.970 in men and OR 1.308, 95%CI 1.061, 1.612 in women; TPO/TgAb (+) and US (+): OR 1.796, 95%CI 1.143, 2.820 in men and OR 1.380, 95%CI 1.058, 1.801 in women]. Thus, we got a conclusion that the prevalence of NAFLD was positively associated with the level and the positivity of TPOAb and TgAb among participants with normal TSH levels. This is the first report suggesting that there might exist common pathways in the pathogenesis of NAFLD and thyroid autoimmunity. PMID- 30016122 TI - Levels of combatant control and the patterns of non-incumbent/insurgent violence experienced by civilians living in Sunni-Arab communities in Iraq (2004-2009). AB - This study explores how one social-structural variable, control over Sunni-Arab communities during the Iraq civil war, affected the types of violence used by insurgent/non-government actors that killed and injured civilians in these communities from January 2004 to December 2009. The study classifies three levels of control: (1) incumbent (government-supported) control, (2) insurgent control and (3) actively contested control. It uses Iraq Body Count (IBC) fatality data to characterize two general types of violence (selective and indiscriminate) evident during the Iraq conflict. It demonstrates that the type of violence committed by non-government actors was significantly (P > .01) different as related to the level of control insurgents had over territory. Primarily, insurgents/non-governmental actors used more selective forms of violence when insurgents controlled territory and more indiscriminate violence when incumbent (government-supported) forces controlled territory. Also, acts of indiscriminate violence cause considerably more injuries and death per act as compared to selective violence. Importantly, if control over territory has broadly generalizable effects on the types of violence that civilian's experience during civil war, than understanding this relationship could be useful when determining the types of medical assistance, medical supplies and training most needed in combat zones. PMID- 30016123 TI - End-of-Life Care Preference: Examination of Chinese Adults with Children and Those Who Lost Their Only Child. AB - BACKGROUND: Little is known about the end-of-life (EOL) care preference and its associated factors among community-dwelling adults in Mainland China. This study investigated the EOL care preference and its associated factors among community dwelling Chinese adults in Shanghai, China. METHODS: A cross-sectional survey was conducted in Shanghai, China, from April to June in 2013. A total of 1200 older adults aged 60 years and older and another 200 middle-aged and older adults aged 45 years and older who lost their only child were included in the current study. In the current study, the EOL care preference included three categories: preferred family care, preferred care provided by visiting healthcare professionals, and preferred care in a specialized EOL care institute. Childlessness was coded as lost the only child, had children but not coresiding, and had coresiding children. Mor and Hiris's model of choices of setting at the EOL was used to explore the EOL care preference and its associated factors, including sociodemographic characteristics, support networks, functional characteristics, and healthcare system. Multinomial logistic regressions were used to estimate the factors associated with their EOL care preference. RESULTS: In terms of EOL care preference, adults who lost their only child preferred care provided by a specialized EOL care institute (58.43%), while adults who had children preferred family care at home (46.72% for adults who did not coreside with children and 49.04% for those who did). Results from multinomial logistic regressions showed that adults with higher income, having properties, and having children tended to opt for family care at home. Participants with friends' support preferred EOL care provided by visiting healthcare professionals or specialized EOL care institutions over family care at home. CONCLUSIONS: Income, wealth, having children, and having friends' support were significant factors that were associated with the EOL care preference among Chinese adults. Home based EOL care, professional and individualized hospice, or palliative care provided by institutions need to be developed in China. PMID- 30016124 TI - The Western Diet: A Smoking Gun for Chronic Obstructive Pulmonary Disease and Asthma? PMID- 30016125 TI - Misery Loves Company: Presenting Symptom Clusters to Urgent Care by Patients Receiving Antineoplastic Therapy. AB - PURPOSE: The Centers for Medicare & Medicaid Services (CMS) identifies suboptimal management of treatment toxicities as a care gap and proposes the measurement of hospital performance on the basis of emergency department visits for 10 common symptoms. Current management strategies do not address symptom co-occurrence. METHODS: We evaluated symptom co-occurrence in three patient cohorts that presented to a cancer hospital urgent care center in 2016. We examined both the CMS-identified symptoms and an expanded clinician-identified set defined as symptoms that could be safely managed in the outpatient setting if identified early and managed proactively. The cohorts included patients who presented with a CMS-defined symptom within 30 days of treatment, patients who presented within 30 days of treatment with a symptom from the expanded set, and patients who presented with a symptom from the expanded set within 30 days of treatment start. Symptom co-occurrence was measured by Jaccard index. A community detection algorithm was used to identify symptom clusters on the basis of a random walk process, and network visualizations were used to illustrate symptom dynamics. RESULTS: There were 6,429 presentations in the CMS symptom-defined cohort. The network analysis identified two distinct symptom clusters centered around pain and fever. In the expanded symptom cohort, there were 5,731 visits and six symptom clusters centered around fever, emesis/nausea, fatigue, deep vein thrombosis, pain, and ascites. For patients who newly initiated treatment, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis. CONCLUSION: Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co occurrence can drive improved management strategies. PMID- 30016127 TI - Unconscious Repetition of a Patient's Dynamics on an Inpatient Unit: Treatment Challenges. AB - This article focuses on the unconscious repetition of a patient's dynamics among a multidisciplinary inpatient treatment team. The patient was diagnosed as having bipolar affective illness and borderline personality traits. The prominent borderline traits displayed by the patient during hypomanic episodes evoked a parallel process of the patient's internal conflicts, rendering the team temporarily divided regarding treatment plans. This divide was resolved by holding dedicated multidisciplinary team meetings in which the patient's projections onto the team were explained and understood. The article highlights some of the therapeutic complexities of and challenges in treating a patient with bipolar illness and borderline traits on an inpatient unit. PMID- 30016126 TI - Prematuration Culture with Phosphodiesterase Inhibitors After Vitrification May Induce Recovery of Mitochondrial Activity in Vitrified Mouse Immature Oocytes. AB - This study investigates the possible causes for low development of blastocysts in vitrified immature oocytes by evaluating the changes of mitochondrial membrane potential and reactive oxygen species (ROS) production and finds a recovery mechanism for these conditions in vitrified immature oocytes. To recover from the cryoinjury, we cultured vitrified immature oocytes in milrinone containing medium for 1, 3, and 5 hours and then extended the culture for oocyte maturation. There was no difference in in vitro maturation and fertilization rate between fresh and vitrified/warmed oocytes. However, the development rate of blastocysts in vitrified/warmed oocytes was significantly lower than that in fresh oocytes (p < 0.05). The development rate of blastocysts was recovered if these oocytes were cultured for 3 hours in milrinone. Vitrified/warmed oocytes incubated in milrinone for 0 and 1 hour showed a significantly higher level of ROS (p < 0.05) and a significantly lower mitochondrial membrane potential (p < 0.05) than fresh oocytes. However, there was no significant difference (p > 0.05) between vitrified oocytes incubated in milrinone for 3 hours and fresh oocytes in terms of ROS level and mitochondrial membrane potential. In conclusion, alteration of highly polarized mitochondria distribution in vitrified oocytes may have an effect on mitochondrial activity, including ROS production during fertilization and further development. Preincubation in milrinone before in vitro maturation of immature vitrified/warmed oocytes may help the redistribution of highly polarized mitochondrial inner membrane potential and in reducing ROS and enhance the further embryonic development after fertilization. PMID- 30016128 TI - Beyond Informed Consent: Talking to Patients About Therapeutic Action. AB - Psychodynamically oriented psychotherapists are faced with the question of what to say to new patients about the therapy they are beginning. This article reviews historical attitudes about early treatment discussions with patients in psychoanalysis with an emphasis on how these discussions have evolved as informed consent became a standard of care. Approaches to talking to patients about therapeutic action in psychodynamic psychotherapy are discussed, including the development and application of a psychoeducational document that is being used to facilitate these discussions in the outpatient residents' clinic of a large urban academic medical center. Finally, qualitative data are presented to describe residents' experiences with this document. The overwhelmingly positive responses suggest that this intervention is helpful for patients and residents and can serve to deepen the treatment relationship through mutual trust and understanding. PMID- 30016129 TI - Asthma and Chronic Obstructive Pulmonary Disease Overlap in Women. Incidence and Risk Factors. AB - RATIONALE: Women with asthma are at a high risk of developing chronic obstructive pulmonary disease (COPD) or asthma and COPD overlap syndrome (ACOS) as they age, which is a condition associated with a high mortality rate, low quality of life, and high healthcare costs. However, factors influencing the development of ACOS remain unclear. OBJECTIVES: To quantify the risk of developing COPD in women in Ontario with asthma and identify factors that are associated with increased risk. METHODS: Data for women in Ontario with asthma who participated in the Canadian National Breast Screening Study from 1980 to 1985 were linked to health administrative databases, and participants were followed from 1992 to 2015. A competing risks survival model was used to measure the associations between sociodemographic, lifestyle, and environmental risk factors and time to COPD incidence, accounting for death as a competing risk. RESULTS: A total of 4,051 women with asthma were included in the study, of whom 1,701 (42.0%) developed COPD. The mean age at the study end date was 79 years. Low education, high body mass index, rurality, and high levels of cigarette smoking were associated with ACOS incidence, whereas exposure to fine particulate matter, a major air pollutant, was not. CONCLUSIONS: Individual risk factors appear to play a more significant role in the development of ACOS in women than environmental factors, such as air pollution. Prevention strategies targeting health promotion and education may have the potential to reduce ACOS incidence in this population. PMID- 30016130 TI - Challenges for the Sustainability of University-Run Biobanks. AB - Most university biobanks begin like other university research projects, that is, with an idea conceived by an individual researcher in pursuit of his/her own research interests, publications, funding, and career. Some biobanks, however, come to have scientific value that goes beyond the projects that were initially responsible for the collection of the samples and data they contain. Such value may derive from among other things the uniqueness of the samples in terms of their sheer volume, the quality of the samples, the ability to link the samples with information retrieved in disease registries, or the fact that the samples represent very rare diseases. This article focuses on biobanks of this kind, and the special obligations that publicly funded universities have to ensure the sustainability of biobanks with continued scientific value. We argue that universities should adopt policies to deal with the various, diverse issues which may arise during the lifecycle of a biobank. The policies should be flexible, accommodate the freedoms of individual researchers, and reflect the multifaceted nature of biobanks. Yet they should be specific enough to provide guidance and robust enough to safeguard legal norms and ethical values. The article sets out concrete recommendations which universities should consider and act upon. PMID- 30016131 TI - End-to-End Sample Tracking in the Laboratory Using a Custom Internet of Things Device. AB - We describe a custom Internet of Things (IoT) device used for tracking barcoded containers end to end in a high-throughput analysis and purification laboratory. Our IoT device fills an important gap that previously prevented us from fully tracking barcoded sample containers through manual steps in a multistep workflow, such as when samples are "parked" for temporary storage, or when using instrumentation not otherwise equipped with barcode scanners, a common occurrence found with specific centrifugal evaporation instruments. The custom device reads container barcodes and sends a small amount of data to our back-end data systems. Once data have been received and processed, users are alerted to any system responses via aural and visual feedback. Components of the IoT system include a low-cost headless IoT computer, a barcode reader, and a multicolor LED strip. We believe that the model for our device will facilitate simple and rapid deployment of IoT to the broader laboratory community. All source code and device configurations will be released into the public domain and made freely available. PMID- 30016132 TI - Corticosteroids and pneumonia - targeting the ideal candidate. PMID- 30016133 TI - Frailty syndrome and functional disability among older adults with and without diabetes and foot ulcers. AB - OBJECTIVE: To assess frailty and disability among older adults with and without diabetes or foot ulcers. METHOD: A descriptive, comparative, controlled, multicentre study. Equal numbers of participants were allocated to three groups: (I) no diabetes/no foot ulcers (control), (II) diabetes but no foot ulcers or (III) diabetes and foot ulcers. Individuals with arterial, venous, pressure or mixed ulcers were not included. We collected data using three methods: a sociodemographic questionnaire and the validated Brazilian versions of the Edmonton Frail Scale and Stanford Health Assessment Questionnaire 20-item Disability Scale (HAQ-20). RESULTS: A total of 150 older people took part in the study. The majority of participants were female (n=84, 56%), married (n=86, 57%) and did not exercise (n=94, 63%). Their age ranged from 67.7-71.5 years. In group I, 32 (64%) patients showed no evidence of frailty. In group II, 18 (36%) patients and 12 (24%) patients were 'apparently vulnerable' and 'mildly frail', respectively and in group III 21 (42%) patients and 15 (22%) patients had 'moderate' and 'severe frailty', respectively. The mean total HAQ-20 scores were 0.24, 0.52, and 2.44 for groups I, II, and III, respectively. Patients in group III reported significantly higher scores on all HAQ-20 categories compared with patients in groups I and II. CONCLUSION: Older patients with DFUs showed frailty and physical disability in activities of daily living. PMID- 30016135 TI - Global collaborations create consensus. PMID- 30016134 TI - A simple and fast dressing for skin grafts: comparison with traditional techniques. AB - OBJECTIVE: The split-thickness skin graft (STSG) is commonly used for reconstruction of skin and soft tissue defects. For a successful graft, the thin skin must be in close contact with the recipient bed until the graft stabilises. This study introduces a simple and fast dressing technique, and compares it with the traditional tie-over dressing. METHOD: All patients who received STSGs between January 2013 and March 2015 were identified. From these patients, those who were treated with skin graft only were included in the study. For comparison of the dressing techniques, operation times from skin incision to the end of procedure were analysed, together with the outcomes of the grafts. For the simple and fast method, the dressing was fixed with a skin stapler, and for tie-over dressings, the graft was fixed with sutures. RESULTS: A total of 67 patients (38 females, 29 males), mean age 58.4 years (range: 24-86 years) were included in the study. Average operation times were 22.9 minutes (range: 10-40 minutes) using the simple and fast dressings and 45.3 minutes (range: 20-120 minutes) using the tie over dressings, demonstrating a significant difference in operation times. Partial graft loss was reported in three cases with the tie-over dressings and in four cases with the simple and fast dressings, without significant difference. CONCLUSION: The simple and fast dressing is easy to apply, is able to be shaped according to the wound surface, and provides a secure dressing over the skin graft. PMID- 30016136 TI - Topical oxygen therapy stimulates healing in difficult, chronic wounds: a tertiary centre experience. AB - OBJECTIVE: Oxygen plays a central role in wound healing. Recent technological advances have miniaturised oxygen delivery systems, with novel topical oxygen therapy allowing patients to receive oxygen therapy 24 hours a day while remaining completely mobile. Here we aim to examine the efficacy and safety of continuous topical oxygen diffusion in a 'real-world' setting. METHODS: Topical oxygen therapy (TOT) was evaluated in patients with chronic, non-healing wounds in a tertiary referral specialist clinic. RESULTS: The mean wound duration before TOT was 15 months. Regardless of treatment duration, in this previously non healing group complete wound closure was observed in 32% of the total patients treated with the TOT device. However, optimal wound healing occurred when the device was used for >25 days, with an 83% wound area reduction and 47% wound closure rate seen in venous leg ulcers (VLUs) and a 74% reduction and a 57% wound closure rate in arterial foot ulcers. CONCLUSION: Use of TOT in chronic wounds stimulates a healing state. In our study, almost half of the previously non healing wounds closed. PMID- 30016137 TI - Using AutoCAD software to measure venous leg ulcers: a reproducibility assessment study. AB - OBJECTIVE: To assess the reproducibility of using AutoCAD software to measure the area of venous leg ulcers (VLUs). METHOD: Data from patients with VLUs were collected between March and July 2015, using data collection forms and photographing the different ulcers. A researcher and five nurses collected the data. The wounds were measured using AutoCAD software. Data were analysed using intraclass correlation coefficient (ICC), concordance correlation coefficient (CCC) and Bland-Altman analysis. RESULTS: A total of 21 patients with 36 VLUs were included in the study. A statistically significant difference (p<0.05) was observed between the areas of VLUs measured by the researcher and the evaluators. There was an excellent agreement when analysing the ICC [p=0.98; 95% CI (0.97 0.99); p <0.05] and the CCC [CCC=CI 0.97; 95% (0.95-0.98)]. There was no difference between the measurements of VLUs <=10 cm2 (p=0.49) and those with an area >10cm2 (p=0.22). CONCLUSION: The use of AutoCAD software is appropriate for measuring VLUs and appears to be more accurate when used to measure VLUs with an area >10cm2. PMID- 30016138 TI - Use of a gelling fibre dressing in complex surgical or chronic wounds: a case series. AB - OBJECTIVE: To evaluate the safety and performance of a gelling fibre dressing, with respect to wound exudate management, maceration and periwound skin conditions. METHOD: Complex (non-healing) surgical or chronic wounds healing by secondary intention were treated with a gelling fibre dressing (Biosorb, Acelity) as part of a prospective, two-centre case series product evaluation study. Dressing performance was evaluated at each change, and weekly for up to four weeks or until the wound healed, if this was in less than four weeks. The main outcome measure was dressing performance, wound bed and periwound skin condition. RESULTS: A total of 15 patients, aged 26-87 years, were enrolled; 10 patients (66.7%) presented with chronic wounds including venous leg ulcers (VLUs), arterial leg ulcer, one mixed leg ulcer, pressure ulcer (PU), and diabetic foot ulcers (DFUs). The remaining wounds (33.3%) were postsurgical complex wounds healing by secondary intention, located in the upper leg, foot, abdomen, and sacrum. Mean wound area was 22.6+/-36.6cm2 (range: 1.3-144.0cm2). Treated wounds showed complete granulation in eight (53.0%) wounds, 75% granulation coverage in two (13.3%) wounds, 50% coverage in three (20.3%), and 25% coverage in two (13.3%) wounds. Patients evaluated the dressing effectiveness as 'excellent' or 'very good' in 45% of cases, 'moderate' in 45%, and 'poor' in 10% of cases. Results of Visual Analogue Scale (VAS) showed 70% of patients rated their pain as 'low' and 30% as 'moderate' at dressing removal. Clinicians' evaluation of dressing ability to absorb and retain wound exudate was rated 'excellent' or 'very good' in 80% of cases, and moderate in 20% and poor in 10% of cases. Overall, clinicians' impression of the dressing performance was reported as 'excellent' or 'very good' in 80% of cases and 'moderate' in 20% of cases. No patient had to be removed from the study due to adverse events directly related to the dressing or its performance. CONCLUSION: These clinical findings suggest the new gelling fibre dressing to be safe and effective in wound treatment of complex (non-healing) surgical or chronic wounds, to manage exudate effectively, and to optimise the conditions of wounds healing by secondary intention. PMID- 30016139 TI - Classification, microbiology and treatment of diabetic foot infections. AB - Diabetic foot ulcers (DFUs) are a common complication of type-1 and type-2 diabetes. About 10-15% of patients with diabetes develop foot ulcers. A validated foot ulcer classification system that will support the development of treatment strategis is necessary for clinicians managing DFUs. More than 10 classification systems have been described by researchers. Another important aspect of the management of DFUs is the proper identification of causative pathogens that trigger infections. While conventional diagnostic methods, such as swabs, cultures and biopsies are more widely used, novel molecular techniques have been exploring bacterial identification and quantification. Knowledge of the microbial aetiologies in diabetic foot infections, and understanding of antibiotic resistance, is critical for the effective management and treatment of these infected wounds. Initial antibiotic regimens are usually selected empirically. A set of common principles may help avoid selecting either an unnecessarily broad or inappropriately narrow antibiotic treatment regimen. In this review we provide a comprehensive summary and description of classification systems of diabetic foot infections, and a comprehensive discussion of microbiology. PMID- 30016140 TI - Strategies for improving outcomes in venous leg ulcer care. AB - In May 2018, BSN Medical hosted a symposium, 'The management of venous leg ulcers: the value of high-quality care', at the European Wound Management Association (EWMA) conference in Poland. It focused on the impact of excessive exudate on venous leg ulcer outcomes, how to address it, and concluded with a stepwise strategy for improving the quality of care. PMID- 30016141 TI - A purpose-designed monofilament-fibre pad for debridement of hard-to-reach wounds: experience in clinical practice. AB - OBJECTIVE: Effective and comfortable debridement is an important part of managing complex wounds. This user test evaluated a monofilament-fibre pad (with handle) (Debrisoft Lolly, Lohmann & Rauscher GmbH & Co. KG) in the debridement of various hard-to-reach wounds. METHOD: The multicentre, international user test was performed by experienced physicians and nurses in Germany and the UK, who used the monofilament-fibre pad in their clinical practice. After debridement, using the monofilament-fibre pad, the clinicians completed an evaluation questionnaire. The assessment comprised of performance, usability, tolerability, safety and suitability of the device for debridement, comparing it with standard methods used in the clinicians' centres. RESULTS: A total of 23 clinicians in 20 centres each treated between six and 10 patients with the monofilament-fibre pad (a total of 155 wounds of different aetiologies). Most participating patients had deep wounds (n=63 (41%)) or cavity (n=31 (20%)) wounds. When compared with the standard debridement method used at the centres, the tested device was scored as 'easier' or 'equally easy' to use in all cases. When comparing the standard debridement procedure with the monofilament-fibre pad, debridement duration was reported as equal to or shorter than the standard method in 90% of cases when using the monofilament-fibre pad. Debridement efficacy was scored by the clinician as 'better' or 'equal' for the monofilament-fibre pad in 67% of cases. Overall, patients reported that the study device was comfortable. CONCLUSION: The monofilament-fibre pad effectively, easily and safely removed slough and debris from wounds of various aetiologies and was effective in wounds of different shapes, such as in cavity wounds and those in hard-to-reach locations. PMID- 30016142 TI - Quantification of Liver Fat Content With Unenhanced MDCT: Phantom and Clinical Correlation With MRI Proton Density Fat Fraction. AB - OBJECTIVE: The purpose of this study was to evaluate the relation between unenhanced CT liver attenuation values and MRI-derived proton density fat fraction (PDFF) for estimation of liver fat content at CT. MATERIALS AND METHODS: A CT-MRI phantom was constructed and imaged containing 12 vials with lipid fractions ranging from 0% to 100%. For the retrospective clinical arm, 221 patients (120 men, 101 women; mean age, 54 years) underwent both unenhanced CT and chemical shift-encoded MRI of the liver between 2007 and 2017. Among these patients, 92 had more than one 120-kV CT scan for comparison. CT attenuation and MRI PDFF were derived with coregistered ROI measurements in the right hepatic lobe. The 120-kV subgroup of CT examinations performed within 1 month of MRI PDFF examinations (n = 72) served as the primary cohort for linear correlation. The effects of different tube voltage settings, time intervals between CT and MRI, and iron overload were assessed. Linear least squares regression analysis was performed. RESULTS: Phantom results showed excellent linear fit between CT attenuation and MRI PDFF (r2 = 0.986). In patients, 120-kV CT performed within 1 month of MRI PDFF exhibited strong linear correlation (r2 = 0.828) that closely matched the phantom data, yielding the following clinical CT-MRI conversion formula: MRI PDFF (%) = -0.58 * CT attenuation (HU) + 38.2. Correlation worsened for CT-to-MRI intervals longer than 1 month (r2 = 0.565), and this specific relationship did not apply as well to non-120-kV settings (r2 = 0.554). For patients with multiple scans, correlation progressively worsened over time. CT based liver fat content was underestimated in several patients with iron overload. CONCLUSION: The linear correlation between unenhanced CT attenuation and MRI PDFF allows quantification of liver fat content by means of unenhanced CT in clinical practice. As expected, correlation worsened with increasing CT-MRI time interval, variable tube voltage settings, and iron overload. PMID- 30016143 TI - County-Level Factors Predicting Low Uptake of Screening Mammography. AB - OBJECTIVE: The purpose of this study was to investigate county-level geographic patterns of mammographic screening uptake throughout the United States and to determine the impact of rural versus urban settings on breast cancer screening uptake. MATERIALS AND METHODS: This descriptive study used County Health Rankings data to identify the percentage of Medicare enrollees 67-69 years old per county who had at least one mammogram in 2013 or 2012 (uptake). Uptake was matched with U.S. Department of Agriculture Atlas of Rural and Small Town America categorizations along a rural-urban continuum scale from 1 to 9 based on county population size (large urban, population >= 20,000 people; small urban, < 20,000 people) and proximity to a metropolitan area. Univariable and multivariable analyses were performed. RESULTS: In all, 2,243,294 Medicare beneficiaries were eligible for mammograms. National mean uptake per county was 60.5% (range, 26.0 86.0%). Uptake was significantly higher in metropolitan and large urban counties in 25 states and lower in only one. County-level mammographic uptake was moderately positively correlated with percentage of residents with some college education (r = 0.40, p < 0.001) and moderately negatively correlated with age adjusted mortality (r = -0.41, p < 0.001). Multivariable analysis showed that percentage of white and black residents and age-adjusted mortality rate were the strongest significant independent predictors of uptake. CONCLUSION: Uptake of mammographic screening services in a Medicare population varies widely at the county level and is generally lowest in rural counties and urban counties with fewer than 20,000 people. PMID- 30016144 TI - In-Hospital Mortality Benefit of Inferior Vena Cava Filters in Patients With Pulmonary Embolism and Congestive Heart Failure. AB - OBJECTIVE: Pulmonary embolism (PE) is associated with a higher mortality rate in patients with congestive heart failure (CHF) than in those without heart failure. The purpose of this study was to evaluate if inferior vena cava (IVC) filter placement provides any mortality benefit in patients admitted with CHF and PE. MATERIALS AND METHODS: The 2005-2014 Nationwide Inpatient Sample (NIS) was used for this study. Adults (>= 18 years old) with PE were identified using International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) diagnosis codes. Patients with CHF were identified using the Elixhauser comorbidity variable (CM_CHF) in the NIS database. IVC filter placement was identified using the ICD-9-CM procedure code 38.7 (interruption of the vena cava). A multivariate logistic regression model was used to determine the association of IVC filter placement with in-hospital mortality. The model was adjusted for demographics, hospital characteristics, comorbidities, and PE severity indexes (pressor dependence, mechanical ventilation, nonseptic shock, and use of thrombolytic therapy). RESULTS: During the study years, 425,877 patients with a comorbidity of CHF were hospitalized with PE (44% male; mean age, 71.5 years old). Of them, 67,237 patients (15.8%) received an IVC filter during the admission, and 50,338 (11.8%) died during the hospital stay. The all-cause in hospital mortality rate among patients who received an IVC filter was 9.7% (6541 of 67,237 patients) compared with 12.2% (43,796 of 358,638 patients) among those without an IVC filter (p < 0.001), with an absolute risk reduction of 2.5%. The multivariate adjusted hazard ratio of in-hospital mortality associated with IVC filter placement was 0.535 (95% CI, 0.518-0.551; p < 0.001). CONCLUSION: A lower all-cause mortality rate was observed in patients with CHF and PE who received an IVC filter while hospitalized. In the absence of data from randomized controlled trials, this study suggests that IVC filters could help prevent in-hospital death among patients admitted with PE and CHF. PMID- 30016145 TI - Patient Selection for Ductal Carcinoma In Situ Observation Trials: Are the Lesions Truly Low Risk? AB - OBJECTIVE: The purpose of this article is to report on a study conducted to determine whether the lesions in patients with what is deemed to be low-risk ductal carcinoma in situ (DCIS) selected for two large clinical trials are in fact low-risk lesions. CONCLUSION: A retrospective review was conducted to determine whether the eligibility criteria of the two trials are predictive that DCIS is low risk. More than 20% of lesions are upgraded to invasive carcinoma in patients with low-risk DCIS as defined in two large clinical trials. More accurate methods are needed to determine whether patients with a diagnosis of low grade DCIS can be treated less aggressively. PMID- 30016146 TI - Yield of Learning Opportunities From a Radiology Random Peer Review Program. AB - OBJECTIVE: The purpose of this study is to assess the yield and usage of a radiology random peer review program in identifying potentially meaningful discrepancies in radiology reports that could serve as learning opportunities. MATERIALS AND METHODS: This retrospective study was performed at a 776-bed tertiary academic hospital that renders more than 620,000 radiology reports annually. A workstation-embedded peer review system was implemented on January 1, 2014, followed by radiologist training over the next 12 weeks. From April 1, 2014, through September 30, 2017 (14 quarters), randomly selected radiologic studies were peer reviewed and scored as follows: 1, agree with original interpretation; 2, minor discrepancy, not likely clinically significant; 3, moderate discrepancy, may be clinically significant; or 4, major discrepancy, likely clinically significant. Reports scored as 3 or 4 were defined as having potentially meaningful discrepancies, and the discrepancy type was characterized. The primary outcome was the quarterly rate of potentially meaningful discrepancies. The secondary outcome was program usage rate (number of reports peer reviewed / total reports generated). Chi-square trend test assessed changes in outcomes over time. RESULTS: Of a total of 42,891 peer reviews performed, the overall potentially meaningful discrepancy rate (or yield) was 0.5% (233/42,891). The quarterly potentially meaningful discrepancy rate decreased significantly over the study period (p < 0.0001). The quarter 14 potentially meaningful discrepancy rate (0.003) was 70% lower than the quarter 1 rate (0.011). Quarterly program usage also decreased significantly over the study period (p < 0.0001). Quarter 14 usage (0.015) was 56% lower than quarter 1 usage (0.034). Among 184 potentially meaningful discrepancy reports that could be categorized, the most common discrepancy type was error of perception (87/184). CONCLUSION: A workstation-embedded random radiology peer review program had a very low yield in identifying learning opportunities and declining usage over time. PMID- 30016147 TI - Atherosclerosis on CT Angiogram Predicts Acute Kidney Injury After Transcatheter Aortic Valve Replacement. AB - OBJECTIVE: The purpose of this study is to determine the association of vascular calcification and renal artery stenosis on CT angiogram (CTA) obtained before transcatheter aortic valve replacement (TAVR) with postprocedure acute kidney injury (AKI). MATERIALS AND METHODS: In this single-center retrospective cohort study, 106 pre-TAVR CTAs were evaluated by two independent blinded readers. Renal artery stenosis was visually graded as less than 50% or greater than or equal to 50% luminal narrowing. Calcification of the aorta and iliac arteries was scored from 0 (no calcification) to 3 (severe calcification) and was summed to develop a calcification score. Univariate comparisons between patients who did and did not develop AKI were made for radiologic measurements. Multivariable logistic regression was used to assess association of renal artery stenosis and atherosclerotic calcification with post-TAVR AKI. RESULTS: Post-TAVR AKI occurred in 20 of 106 patients. Subjects with bilateral main renal artery stenosis greater than or equal to 50% had significantly greater odds (odds ratio, 4.84; 95% CI, 1.41-16.54; p = 0.01) of developing post-TAVR AKI than did subjects with unilateral or no stenosis greater than or equal to 50% in the main renal arteries. Subjects who developed post-TAVR AKI had significantly higher aortic and iliac arterial calcification scores compared with subjects who did not develop post-TAVR AKI (mean +/- SD, 21.4 +/- 5.6 vs 17.9 +/- 6.7; p = 0.04). CONCLUSION: AKI as a complication of TAVR is more likely to develop in patients with bilateral renal artery stenosis greater than or equal to 50% or severe atherosclerotic calcification of the aorta and iliac arteries. PMID- 30016148 TI - Combined Analysis of Biparametric MRI and Prostate-Specific Antigen Density: Role in the Prebiopsy Diagnosis of Gleason Score 7 or Greater Prostate Cancer. AB - OBJECTIVE: The objective of our study was to investigate the diagnostic performance of prebiopsy biparametric MRI (bpMRI) and prostate-specific antigen density (PSAD) for Gleason score (GS) 7 or greater prostate cancer (PCa). MATERIALS AND METHODS: Sixty-eight consecutive patients who underwent prebiopsy bpMRI and biopsy were included. Pathologic results of systemic and targeted biopsies were the reference standard. Qualitative analyses comprised Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and modified PI-RADSv2 (mPI-RADSv2). Quantitative analyses comprised mean apparent diffusion coefficient (ADC) of tumor, 10th percentile ADC of tumor, mean ADC ratio (ADCR) between benign tissues and PCa, and 10th percentile ADCR between benign tissues and PCa. The AUCs of the following combined models for GS 7 or greater PCa were investigated: model 1, PSAD and PI-RADSv2; model 2, PSAD and mPI-RADSv2; model 3, PSAD and mean ADC; model 4, PSAD and 10th percentile ADC; model 5, PSAD and mean ADCR; and model 6, PSAD and 10th percentile ADCR. RESULTS: The rate of GS 7 or greater PCa was 45.6% (31/68). AUCs of bpMRI parameters were 0.816 for PI-RADSv2, 0.838 for mPI-RADSv2, 0.820 for mean ADC, 0.823 for 10th percentile ADC, 0.780 for mean ADCR, and 0.763 for 10th percentile ADCR (p > 0.05 in all comparisons), whereas AUCs of prostate-specific antigen (PSA)-based parameters were 0.650 for PSA and 0.745 for PSAD (PSA vs PSAD, p = 0.017). AUCs of the combined models from 1 to 6 were 0.860, 0.880, 0.837, 0.844, 0.811, and 0.806, respectively, for biopsy GS 7 or greater PCa (p > 0.05 in all comparisons). CONCLUSION: Combined analysis of prebiopsy bpMRI and PSAD is useful for identifying GS 7 or greater PCa. PMID- 30016149 TI - Diabetes-Associated Alterations in the Cecal Microbiome and Metabolome are Independent of Diet or Environment in the UC Davis Type 2-Diabetes Mellitus Rat Model. AB - The composition of the gut microbiome is altered in obesity and type 2 diabetes; however, it is not known whether these alterations are mediated by dietary factors or related to declines in metabolic health. To address this, cecal contents were collected from age-matched, chow-fed male UCD-T2DM rats before the onset of diabetes (pre-diabetic PD, n=15); 2 wk recently-diabetic (RD, n=10); 3 mo (D3M, n=11); and 6 mo (D6M, n=8) post-onset of diabetes. Bacterial species and functional gene counts were assessed by shotgun metagenomic sequencing of bacterial DNA in cecal contents, while metabolites were identified by GC-QTOF-MS. Metagenomic analysis showed a shift from Firmicutes species in early stages of diabetes (PD+RD) towards an enrichment of Bacteroidetes species in later stages of diabetes (D3M+D6M). In total, 45 bacterial species discriminated early and late stages of diabetes with 25 of these belonging to either Bacteroides or Prevotella genera. Furthermore, 61 bacterial gene clusters discriminated early and later stages of diabetes with elevations of enzymes related to stress response (e.g., glutathione and glutaredoxin), and amino acid, carbohydrate, and bacterial cell wall metabolism. Twenty-five metabolites discriminated early vs late stages of diabetes, with the largest differences observed in abundances of dehydroabietic acid and phosphate. Alterations in the gut microbiota and cecal metabolome track diabetes progression in UCD-T2DM rats when controlling for diet, age, and housing environment. Results suggest that diabetes-specific host signals impact the ecology and end-product metabolites of the gut microbiome when diet is held constant. PMID- 30016150 TI - Is palmitate truly pro-inflammatory? Experimental confounders and context specificity. AB - Based primarily on cell culture results, saturated fatty acids (SFAs) are proposed to promote inflammation and contribute to metabolic dysfunction through toll-like receptor activation. Studies are often complicated by a requirement for carriers (e.g. BSA) or solvents (e.g. ethanol) to increase SFA solubility. To ascertain if these factors influence interpretations of SFA-associated inflammation activity, we measured responses of RAW264.7 monocyte/macrophages and C2C12 myotubes to various BSA, ethanol and cyclodextrin (alternative FA carrier) conditions. Fatty acid free low-endotoxin BSA preparations (0.33% to 2% wt/vol) activated, whereas 0.5-1.0% ethanol inhibited, RAW264.7 TNF- release. Ethanol modestly increased IL-6 secretion in C2C12 myotubes. Cyclodextrins (0.3 - 6.0 mM) were tested as alternative carriers of palmitate, but their usefulness was limited due to toxicity and solubility issues. Using a lower-inflammation BSA source and no ethanol, ~24 hr sodium palmitate treatment (up to 600 uM) failed to trigger RAW264.7 TNF- release, and in fact significantly dampened BSA-induced inflammation by >50%. In C2C12 myotubes, only high palmitate concentrations (500 600 uM) elicited IL-6 secretion (> 2.5-fold increase). Acute palmitate (200 or 500 uM) treatment did not activate MAP-kinase pathways above that of fresh BSA containing media alone in either cell type. These results highlight the importance of experimental conditions in studies exploring SFA inflammation effects. The limited (or even anti-inflammatory) effects of palmitate that we observed indicate that immunomodulatory effects of SFAs are context-specific. Thus, caution is needed when interpreting the literature related to putative pro inflammatory effects of SFA. PMID- 30016151 TI - High-intensity interval, but not endurance training induces muscle fiber type specific subsarcolemmal lipid droplet size reduction in type 2 diabetic patients. AB - This study compared the effects of moderate-intensity endurance training and high intensity interval training on fiber type-specific subcellular volumetric content and morphology of lipid droplets and mitochondria in skeletal muscles of type 2 diabetic patients. Sixteen sedentary type 2 diabetic patients (57+/-7 years old) were randomized to complete 11 weeks of either 40-min cycling at 50% peak workload (Endurance, n = 8) or 10 1-min cycling intervals at 95% peak workload separated by 1 min of recovery (High-intensity Interval, n = 8), 3 times per week. Assessments for cardiorespiratory fitness, body composition, glycemic control, together with muscle biopsies were performed before and after the intervention. Morphometric analyses of lipid droplets and mitochondria were conducted in the subcellular fractions of biopsied muscle fibers using quantitative electron microscopy. The training intervention increased cardiorespiratory fitness, lowered fat mass and improved non-fasting glycemic control (P < 0.05), with no difference between training modalities. In the subsarcolemmal space, training decreased lipid droplet volume (P = 0.003), and high-intensity interval, but not endurance training, reduced the size of lipid droplets, specifically in type 2 fibers (P < 0.001). No training-induced change in intermyofibrillar lipid droplets was observed in both fiber types. Subsarcolemmal mitochondrial volume was increased by high-intensity interval (P = 0.02), but not endurance training (P = 0.79). Along with improvement in glycemic control, low volume high-intensity interval training is an alternative time saving training modality that affects subcellular morphology and volumetric content of lipid droplets in skeletal muscle of type 2 diabetic patients. PMID- 30016152 TI - Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse. AB - Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long co-morbidities. Insulin-like growth factor-II (IGF2) deficiency in humans as well as in mice leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type (Igf2+/+) littermates, brain size was preserved in Igf2 knockout (Igf2-/-), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2-/- mice are born with hepatic steatosis. Gene expression analysis in Igf2-/- newborn livers, showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most up regulated gene - serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also up-regulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2-/ newborns are related to lipid metabolism, with the top upstream regulator predicted to be the perixosome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn. PMID- 30016153 TI - Dynein 1 supports spermatid transport and spermiation during spermatogenesis in the rat testis. AB - In the mammalian testis, spermatogenesis is dependent on the microtubule (MT) specific motor proteins such as dynein 1 that serve as the engine to support germ cell transport. Yet the underlying molecular mechanism(s) remain unknown. Herein, we used RNAi to knockdown dynein 1 heavy chain (Dync1h1) and an inhibitor ciliobrevin D to inactivate dynein in Sertoli cells in vitro and the testis in vivo, thereby probing the role of dynein 1 in spermatogenesis. Both treatments were shown to induce extensively disruption of MT organization across Sertoli cells in vitro and the testis in vivo. These changes also perturbed the transport of spermatids and other organelles (such as phagosomes) across the epithelium. These changes thus led to disruption of spermatogenesis. Interestingly, the knockdown of dynein 1 or its inactivation by ciliobrevin D also perturbed gross disruption of F-actin across the Sertoli cells in vitro and the seminiferous epithelium in vivo, illustrating there are cross-talks between the two cytoskeletons. In summary, these findings confirm the role of dynein 1 to support the transport of spermatids and organelles across the seminiferous epithelium during spermatogenesis. PMID- 30016155 TI - NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction. AB - Inflammasomes are multi-protein inflammatory platforms that induce caspase-1 activation and subsequently interleukin (IL)-1beta and IL-18 processing. The NLRP3 inflammasome is activated by different forms of oxidative stress, and based on the central role of IL-1beta in the destruction of pancreatic islets, it could be related to the development of diabetes. We therefore investigated responses in wild-type C57Bl/6 (WT), NLRP3-/- and ASC-/- mice after exposing islets to short term hypoxia or alloxan induced islet damage. NLRP3 deficient islets compared to WT islets had preserved function ex vivo and were protected against hypoxia induced cell death. Further, NLRP3 and ASC deficient mice were protected against oxidative stress-induced diabetes caused by repetitive low dose alloxan administration, and this was associated with reduced beta-cell death and reduced macrophage infiltration. This suggests that the beneficial effect of NLRP3 inflammasome deficiency on oxidative stress-mediated beta-cell damage could involve reduced macrophage infiltration and activation. To support the role of macrophage activation in alloxan-induced diabetes, we injected WT mice with liposomal clodronate which causes macrophage depletion prior to induction of a diabetic phenotype by alloxan treatment resulting in improved glucose homeostasis in WT mice. We show here that the NLRP3 inflammasome acts as a mediator of hypoxia and oxidative stress in insulin producing cells, suggesting that inhibition of the NLRP3 inflammasome could have beneficial effects on beta-cell preservation. PMID- 30016156 TI - The Role of Phenotypic Plasticity in Moderating Evolutionary Conflict. AB - Evolutionary conflicts arise when the fitness interests of interacting individuals differ. Well-known examples include sexual conflict between males and females and antagonistic coevolution between hosts and parasites. A common feature of such conflicts is that compensating evolutionary change in each of the parties can lead to little overt change in the interaction itself. As a result, evolutionary conflict is expected to persist even if the evolutionary dynamic between the parties reaches an equilibrium. In these cases, it is of interest to know whether certain kinds of interactions are expected to lead to greater or lesser evolutionary conflict at such evolutionary stalemates. Here we present a theoretical analysis showing that when one of the interacting parties can respond to the other through adaptive phenotypic plasticity, evolutionary conflict is reduced. Paradoxically, however, it is the party that does not express adaptive plasticity that experiences less conflict. Conflict for the party displaying adaptive plasticity can increase or decrease, depending on the situation. PMID- 30016154 TI - Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine. AB - High concentrations of propionate and its metabolites are found in several diseases that are often associated with the development of cardiac dysfunction, such as obesity, diabetes, propionic acidemia, and methylmalonic acidemia. In the present work, we employed a stable isotope-based metabolic flux approach to understand propionate-mediated perturbation of cardiac energy metabolism. Propionate led to accumulation of propionyl-CoA (increased by ~101-fold) and methylmalonyl-CoA (increased by 36-fold). This accumulation caused significant mitochondrial CoA trapping and inhibited fatty acid oxidation. The reduced energy contribution from fatty acid oxidation was associated with increased glucose oxidation. The enhanced anaplerosis of propionate and CoA trapping altered the pool sizes of tricarboxylic acid cycle (TCA) metabolites. In addition to being an anaplerotic substrate, the accumulation of proprionate-derived malate increased the recycling of malate to pyruvate and acetyl-CoA, which can enter the TCA for energy production. Supplementation of 3 mM l-carnitine did not relieve CoA trapping and did not reverse the propionate-mediated fuel switch. This is due to new findings that the heart appears to lack the specific enzyme catalyzing the conversion of short-chain (C3 and C4) dicarboxylyl-CoAs to dicarboxylylcarnitines. The discovery of this work warrants further investigation on the relevance of dicarboxylylcarnitines, especially C3 and C4 dicarboxylylcarnitines, in cardiac conditions such as heart failure. PMID- 30016157 TI - Mechanistic Models of Conflict between Ant Colonies and Their Consequences for Territory Scaling. AB - Territory size in social insects depends on the rules by which border conflicts are resolved. We present three mechanistic mathematical models of conflict, inspired by the behavior of the pavement ant Tetramorium immigrans, to predict the advantage of larger colonies in pairwise contests and the resulting scaling of territory size with worker force. The models track the number of ants in the nest traveling to and from the boundary or engaged at the boundary. Ants at the boundary base their recruitment response on the relative numbers of ants from the two colonies. With two colonies, our central result is that the larger colony gains a territory disproportionately larger than the ratio of worker forces would indicate. This disproportionate territory control determines the scaling relation of territory size with worker force in a population. In two dimensions, if territory size were proportional to worker force, the slope of the scaling relation between log territory size and log worker force would be 1.0. With disproportionate territories, this slope is larger and can be explicitly approximated in terms of model parameters, and it is steepest when colonies are packed close to each other, when ants run quickly, or when colonies are small. A steeper slope exaggerates the advantage of larger colonies, creating a positive feedback that could amplify the inequality of the worker force distribution. PMID- 30016158 TI - The Genomics of Sexual Conflict. AB - Sexual dimorphism is a substantial contributor to the diversity observed in nature, extending from elaborate traits to the expression level of individual genes. Sexual conflict and sexually antagonistic coevolution are thought to be central forces driving the dimorphism of the sexes and its diversity. We have substantial data to support this at the phenotypic level but much less at the genetic level, where distinguishing the role of conflict from other forms of sex biased selection and from other processes is challenging. Here we discuss the powerful effects sexual conflict may have on genome evolution and critically evaluate the supporting evidence. Although there is much potential for sexual conflict to affect genome evolution, we have relatively little compelling evidence of a genomic signature of sexual conflict. A central obstacle is the mismatch between taxa in which we understand sexually antagonistic selection and those in which we understand genetics. PMID- 30016159 TI - Adaptive Foraging of Pollinators Can Promote Pollination of a Rare Plant Species. AB - Most pollinators have the foraging flexibility to visit a wide variety of plant species. Yet few studies of pollinator-mediated processes in plants have considered the effects of variation in individual foraging patterns on plant reproductive success. In this study, we use an individual-based model of pollinator foraging economics to predict how visitation rates and pollination success of two coflowering plant species change with their frequency (relative abundance). Whereas previous studies suggested that adaptive foraging of pollinators always favors pollination of abundant plant species (positive frequency dependence), here we show that under certain conditions the per capita pollination success of a rare plant species can exceed that of a more abundant species. Specifically, when the overall flower density is sufficiently high and pollinators' perception ranges are sufficiently large, animals with limited memory of previously encountered rewards forage in a way that favors pollination of the rarer plant species. Moreover, even with perfectly informed foragers, a rare plant species benefits more from offering a higher floral reward than a more abundant species. Our results show that adaptive foraging of individual pollinators can have important implications for plant community dynamics and the persistence of rare plant species. PMID- 30016160 TI - The Evolutionary Consequences of Selection at the Haploid Gametic Stage. AB - As an immediate consequence of sexual reproduction, biphasic life cycles with alternating diploid and haploid phases are a common characteristic of sexually reproducing eukaryotes. Much of our focus in evolutionary biology has been directed toward dynamics in diploid or haploid populations, but we rarely consider selection occurring during both phases when studying evolutionary processes. One of the reasons for this apparent omission is the fact that many flowering plants and metazoans are predominantly diploid with a very short haploid gametic phase. While this gametic phase may be short, it can play a crucial role in fundamental processes including the rate of adaptation, the load of mutation, and the evolution of features such as recombination. In addition, if selection acts in different directions between the two phases, a genetic conflict will occur, impacting the maintenance of genetic variation. Here we provide an overview of theoretical and empirical studies investigating the importance of selection at the haploid gametic phase in predominantly diploid organisms and discuss future directions to improve our understanding of the underlying dynamics and the general implications of haploid selection. PMID- 30016161 TI - Geographic Range Dynamics Drove Ancient Hybridization in a Lineage of Angiosperms. AB - Elucidating the dynamic distribution of organismal lineages has been central to biology since the nineteenth century, yet the difficulty of combining biogeographic methods with shifts in habitat suitability remains a limitation. This integration, however, is critical to understanding geographic distributions, present and past, as well as the time-extended trajectories of lineages. Here, we link previous advances in phyloclimatic modeling to develop a framework that overcomes existing methodological gaps by predicting potential ecological and geographic overlap directly from estimated ancestral trait distributions. We show the utility of this framework by focusing on a clade in the montane angiosperm genus Heuchera, which is noteworthy in that it experienced ancient introgression from circumboreally distributed species of Mitella, lineages now ~1,300 km disjunct. Using this system, we demonstrate an application of ancestral state reconstruction to assess geographic range dynamics in a lineage lacking a fossil record. We test hypotheses regarding inferred past geographic distributions and examine the potential for ancient geographic contact. Application of this multifaceted approach suggests potential past contact between species of Heuchera and Mitella in western North America during cooler periods of the Pleistocene. Integration of niche models and phylogenetic estimates suggests that climatic cooling may have promoted range contact and gene flow between currently highly disjunct species. Our approach has wide applicability for testing hypotheses concerning organismal co-occurrences in deep time. PMID- 30016162 TI - Integrating Genetic and Demographic Effects of Connectivity on Population Stability: The Case of Hatchery Trucking in Salmon. AB - Connectivity among populations can have counteracting effects on population stability. Demographically, connectivity can rescue local populations but increase the synchrony across populations. Genetically, connectivity can counteract drift locally but homogenize genotypes across populations. Population independence and diversity underlies system-level buffering against environmental variability, termed the portfolio effect. The portfolio effect has declined in California fall-run Chinook salmon, possibly in part because of the trucking of juvenile hatchery-reared fish for downstream release, which reduces juvenile mortality but increases the connectivity between rivers. We use a dynamical population model to test whether this increased connectivity can explain the loss of the portfolio effect and quantify the relative demographic and genetic contributions to portfolio effect erosion. In the model, populations experience different within-population environmental conditions and the same time-variable ocean conditions, the response to which can depend on a quantitative genetic trait. We find that increased trucking for one population's hatchery can lead to a loss of the portfolio effect, with a system-level trade-off between increased average abundance and increased variability in abundance. This trade-off is much stronger when we include the effects of genetic homogenization than when we consider demographic synchronization alone. Therefore, genetic homogenization can outweigh demographic synchrony in determining the system-level effect of connectivity. PMID- 30016163 TI - Toward Understanding the Repeated Occurrence of Associations between Melanin Based Coloration and Multiple Phenotypes. AB - Melanin is the most widespread pigment in organisms. Melanin-based coloration has been repeatedly observed to be associated with the same traits and in the same direction in different vertebrate and insect species. However, whether any factors that are common to different taxa account for the repeated evolution of melanin-phenotype associations remains unclear. We propose to approach this question from the perspective of convergent and parallel evolution to clarify to what extent different species have evolved the same associations owing to a shared genetic basis and being subjected to similar selective pressures. Our current understanding of the genetic basis of melanin-phenotype associations allows for both convergent and parallel evolution, but this understanding is still limited. Further research is needed to clarify the generality and interdependencies of the different proposed mechanisms (supergenes, pleiotropy based on hormones, or neural crest cells). The general ecological scenarios whereby melanin-based coloration is under selection-protection from ultraviolet radiation, thermoregulation in cold environments, or as a signal of social status offer a good opportunity to study how melanin-phenotype associations evolve. Reviewing these scenarios shows that some traits associated with melanin-based coloration might be selected together with coloration by also favoring adaptation but that other associated traits might impede adaptation, which may be indicative of genetic constraints. We therefore encourage further research on the relative roles that selection and genetic constraints play in shaping multiple melanin phenotype associations. Placed into a phylogenetic context, this will help clarify to what extent these associations result from convergent or parallel evolutionary processes and why melanin-phenotype associations are so common across the tree of life. PMID- 30016164 TI - Evolutionary Conflict between Mobile DNA and Host Genomes. AB - The proportion of eukaryotic genomes composed of active or formerly active mobile elements (MEs) is known to vary widely across lineages, but the explanations for why remain largely unknown. Given that ME activity, like other forms of mutation, is thought to be (on average) slightly deleterious in terms of phenotypic effects, understanding the widespread proliferation of MEs in host genomes requires an evolutionary framework. To better develop such a framework, we review the spectrum of resolutions to the genetic conflict between MEs and their hosts: inactivation of MEs due to mutation accumulation, negative selection (or lack thereof) against hosts with high ME loads, silencing of MEs (by hosts or MEs), ME domestication by their hosts, and the horizontal transfer of MEs to new hosts. We also highlight ecological and evolutionary theory from which ME researchers might borrow in order to explain large-scale patterns of ME dynamics across systems. We hope that a synthesis of the surprisingly significant role played by MEs in the genome, as well as the spectrum of resolutions, applicable theory, and recent discoveries, will have two outcomes for future researchers: better parsing of known variation in ME proliferation patterns across genomes and the development of testable models and predictions regarding the evolutionary trajectory of MEs based on a combination of theory, the comparative method, experimental evolution, and empirical observations. PMID- 30016165 TI - Sex Allocation Theory for Facultatively Sexual Organisms Inhabiting Seasonal Environments: The Importance of Bet Hedging. AB - Adaptive explanations for dormancy often invoke bet hedging, where reduced mean fitness can be adaptive if it associates with reduced fitness variance. Sex allocation theory typically ignores variance effects and focuses on mean fitness. For many cyclical parthenogens, these themes become linked, as only sexually produced eggs undergo the dormancy needed to survive harsh conditions. We ask how sex allocation and the timing of sex evolve when this constraint exists in the form of a trade-off between asexual reproduction and sexual production of dormant eggs-the former being crucial for within-season success and the latter for survival across seasons. We show that male production can be temporally separated from or co-occur with sex, depending on whether direct (time) or indirect (population density) cues of the season's end are available and whether population growth is density dependent. Sex generally occurs late in the season but is induced earlier in unpredictable environments. When only indirect cues are available, the temporal spread of sex, and with it the production of dormant stages, is even larger and, given sufficient mortality, leads to endogenous population cycles in which frequent sex coincides with high densities. In all scenarios, algorithms maximizing geometric mean fitness have reduced fitness variance compared with a hypothetical non-bet hedger, confirming that the timing of male production and sex in facultative seasonal settings can be bet-hedging traits. PMID- 30016166 TI - A Framework for Simultaneous Tests of Abiotic, Biotic, and Historical Drivers of Species Distributions: Empirical Tests for North American Wood Warblers Based on Climate and Pollen. AB - Understanding how abiotic, biotic, and historical factors shape species distributions remains a central question in ecology, but studies linking biotic factors to continental-scale patterns remain scarce. Here, we present a novel framework for simultaneously testing patterns expected when abiotic, biotic, or historical factors drive species range limits. We use ecological niche models to produce empirical estimates of the "biotic, abiotic, and movement" paradigm (BAM diagrams), which previously has been used only theoretically. On the basis of climatic and pollen data as well as explicit consideration of dispersal limitations, we implement the framework for a group of North American birds (Oreothlypis warblers) with clear habitat associations. Because the pollen-based predictor variables characterize vegetation, they represent biotic factors needed by each bird species. Although continental-scale patterns of distribution are traditionally attributed to abiotic factors, only one species matched the hypothesis of solely abiotic drivers. In contrast, pollen-based models indicate biotic drivers for two species, correctly predicting their absence in climatically suitable areas. These results highlight the feasibility of considering and quantifying the potential effects of biotic interactions on species ranges, especially when interactions can be decoupled from abiotic factors. Furthermore, the availability of pollen data now and in the Holocene highlights the potential of these data to be used to predict range shifts of other organisms tightly dependent on particular vegetation types. PMID- 30016167 TI - Sexual Conflict: Mechanisms and Emerging Themes in Resistance Biology. AB - Sexual conflict is acknowledged as pervasive, with the potential to generate and maintain genetic variation. Mechanistic studies of conflict have been important in providing direct evidence for the existence of sexual conflict. They have also led to the growing realization that there is a striking phenotypic diversity of adaptations whose evolution can be shaped by sexually antagonistic selection. The mechanisms involved range from the use of genital spines, claspers, songs, and smells to ejaculate molecules. In one well-studied example, sexual conflict can occur over the sexually antagonistic effects of seminal fluid proteins in Drosophila melanogaster. However, an important puzzle remains, namely, why seminal fluid proteins are so numerous and complex, hence whether all or some are involved in mediating sexual conflict. I hypothesize that this rich diversity and the complexity of traits subject to sexually antagonistic selection in general may arise, at least in part, due to the deployment of sexually antagonistic adaptations in males in a way that lessens the probability of broadscale, strong resistance evolution in females. In elaborating this hypothesis, I explore how research into the evolution of resistance to insecticides, antimicrobials, and vaccines might be used to provide insights into the evolution of female resistance to the effects of sexually antagonistic manipulative traits of males. In this manner, the manipulative traits of males can be resistance-proofed. PMID- 30016168 TI - High Gut Microbiota Diversity Provides Lower Resistance against Infection by an Intestinal Parasite in Bumblebees. AB - The microbiome, especially the gut flora, is known to affect the interaction between parasites and their hosts. In this context, a parasitic infection can be viewed as an invasion into the preexisting microbial ecological community. Hence, in addition to the intrinsic defense mechanisms of the host itself, infection success depends on the colonization resistance of the microbiota. In the bumblebee Bombus terrestris, the microbiota provides resistance to the intestinal parasite Crithidia bombi, yet which properties actually provide protection remains largely unknown. Here, we show that the community structure of the gut microbiota-in terms of bacterial operational taxonomic units (OTUs) of 16S ribosomal RNA gene sequences-before parasite exposure can be informative of the eventual infection outcome. Specifically, higher microbiota OTU diversity is associated with less resistance. However, the microbial community structure does not differ between infected and noninfected individuals or between infected individuals of varying susceptibility. This suggests that parasite infection success depends on the microbiota composition but that subsequent changes occur, although the exact alteration that occurs remains elusive. In fact, the bumblebee microbiota is surprisingly unaffected by parasite exposure and infection. Rather, the microbiota-host interaction before parasite exposure seems to be a key mechanism regulating resistance to infection. PMID- 30016169 TI - Matrix Models of Hierarchical Demography: Linking Group- and Population-Level Dynamics in Cooperative Breeders. AB - For highly social species, population dynamics depend on hierarchical demography that links local processes, group dynamics, and population growth. Here, we describe a stage-structured matrix model of hierarchical demography, which provides a framework for understanding social influences on population change. Our approach accounts for dispersal and affords insight into population dynamics at multiple scales. The method has close parallels to integral projection models but focuses on a discrete characteristic (group size). Using detailed long-term records for meerkats (Suricata suricatta), we apply our model to explore patterns of local density dependence and implications of group size for group and population growth. Taking into account dispersers, the model predicts a per capita growth rate for social groups that declines with group size. It predicts that larger social groups should produce a greater number of new breeding groups; thus, dominant breeding females (responsible for most reproduction) are likely to be more productive in larger groups. Considering the potential for future population growth, larger groups have the highest reproductive value, but per capita reproductive value is maximized for individuals in smaller groups. Across a plausible range of dispersal conditions, meerkats' long-run population growth rate is maximized when individuals form groups of intermediate size. PMID- 30016170 TI - Metabolic Scope as a Proximate Constraint on Individual Behavioral Variation: Effects on Personality, Plasticity, and Predictability. AB - Behavioral ecologists have hypothesized that among-individual differences in resting metabolic rate (RMR) may predict consistent individual differences in mean values for costly behaviors or for behaviors that affect energy intake rate. This hypothesis has empirical support and presently attracts considerable attention, but, notably, it does not provide predictions for individual differences in (a) behavioral plasticity or (b) unexplained variation (residual variation from mean individual behavior, here termed predictability). We outline how consideration of aerobic maximum metabolic rate (MMR) and particularly aerobic scope (= MMR - RMR) can be used to simultaneously make predictions about mean and among- and within-individual variation in behavior. We predict that while RMR should be proportional to an individual's mean level of sustained behavioral activity (one aspect of its personality), individuals with greater aerobic scope will also have greater scope to express behavioral plasticity and/or greater unpredictability in behavior (=greater residual variation). As a first step toward testing these predictions, we analyze existing activity data from selectively bred lines of mice that differ in both daily activity and aerobic scope. We find that replicate high-scope mice are more active on average and show greater among-individual variation in activity, greater among-individual variation in plasticity, and greater unpredictability. These data provide some tentative first support for our hypothesis, suggesting that further research on this topic would be valuable. PMID- 30016171 TI - Socio-reproductive Conflicts and the Father's Curse Dilemma. AB - Evolutionary conflicts between males and females can manifest over sexually antagonistic interactions at loci or over sexually antagonistic interests within a locus. The latter form of conflict, intralocus sexual conflict, arises from sexually antagonistic selection and constrains the fitness of individuals through a phenotypic compromise. These conflicts, and socio-reproductive interactions in general, are commonly mediated by hormones, and thus predictive insights can be gained from studying their mediating effects. Here, we integrate several lines of evidence to describe a novel, hormonally mediated reproductive dilemma that we call the father's curse, which results from an intralocus conflict between mating and parental efforts. Essentially, a genetic locus exerts pleiotropic and antagonistic effects on the mating effort of one individual and the parental effort of a related individual who is the primary provider of parental care. We outline the criteria for operation of the father's curse dilemma, provide evidence of the phenomenon, and discuss the predictions and outcomes arising from its dynamics. By integrating the effects of hormones into socio-reproductive conflicts and socio-reproductive effort, clearer links between genotypes, phenotypes, and fitness can be established. PMID- 30016172 TI - Reply: The Western Diet: A Smoking Gun for Chronic Obstructive Pulmonary Disease and Asthma? PMID- 30016173 TI - ABM Clinical Protocol #29: Iron, Zinc, and Vitamin D Supplementation During Breastfeeding. AB - A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols, free from commercial interest or influence, for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 30016174 TI - Does the Post-Feeding Position Affect Gastric Residue in Preterm Infants? AB - BACKGROUND: Body position affects the gastric emptying rate and hence the amount of gastric residue. OBJECTIVE: This study aims to analyze the effect of the post feeding position of preterm infants on gastric residue. MATERIALS AND METHODS: This experimental study was conducted in the neonatal intensive care unit (NICU) of a university hospital (Inonu University Turgut Ozal Medical Center) in Eastern Turkey. The study included 40 preterm infants weighing less than 2,000 g, who were fed orogastrically. The preterm infants were sequentially placed in four positions and were fed before each change of position. The infants were sequentially placed in the right lateral, left lateral, supine, and prone positions; their gastric residues were measured with a nasogastric tube. The gastric residue was recorded in percentages at 30, 60, 120, and 180 minutes. Ethical principles were applied in all phases of the study. RESULTS: The lowest mean gastric residue level was observed in the right lateral position at 30 minutes (58.16 +/- 12.71%) and 60 minutes (33.97 +/- 15.00%). The prone position showed the lowest mean gastric residue level (1.74 +/- 1.08%), followed by the right lateral (3.06 +/- 1.97%), supine (3.53 +/- 2.18%), and left lateral position (5.14 +/- 1.85%) at 120 minutes. The final measurements were taken at 180 minutes with the right lateral position showing the lowest mean gastric residue level (0.38 +/- 0.34%). CONCLUSION: The premature infants had similar lower levels of gastric residue in the right lateral and prone positions and higher levels of gastric residue in left lateral and supine positions. The gastric emptying rate was found to be highest in the right lateral position at 30, 60, and 180 minutes and in the prone position at 120 minutes. PMID- 30016175 TI - Recent progress in bio-inspired biofilm-resistant polymeric surfaces. AB - Any surface of human interest can serve as a substrate for biofilm growth, sometimes with detrimental effects. The social and economic consequences of biofilm-mediated damage to surfaces are significant, the financial impact being estimated to be billions of dollars every year. After describing traditional biocide-based approaches for the remediation of biofilm-affected surfaces, this review deals with more recent developments in material science, focusing on non toxic, eco-sustainable nature-inspired biomaterials with anti-biofilm properties superior to the conventional biocide-based approaches in terms of addressing the biofilm problem. PMID- 30016176 TI - Complaints About Hospice Care in the United States, 2005-2015. AB - BACKGROUND: Complaints are an opportunity for patients and family members to report allegations of substandard care. No prior studies have examined complaints in hospice care and what might be learned from them. OBJECTIVES: To describe hospice complaint trends, characterize state investigation practices, and assess the relationship between complaints and hospice agency traits of interest. METHODS: Retrospective analyses merged hospice complaints from 2005 to 2015 with agency characteristics from Medicare Cost Reports and Provider of Service files. MEASUREMENTS: Annual rates of complaint allegations and deficiencies on a per agency and per 10,000 patient days basis, nationally and by state. Likelihood of having any complaint allegations and deficiencies. Mean days to investigation and substantiation rates, by state. Hospice traits of interest were accreditation and profit status. RESULTS: Between 2005 and 2015, a total of 12,931 complaint allegations were received about hospice care, resulting in 6710 complaint deficiencies. Allegations centered on concerns about quality of care (45%), patients' rights (20%), and administrative/personnel concerns (14%). Complaint rates varied across states but were generally quite low-in a given year, 88% of agencies nationally did not have any complaints. Complaint investigation practices varied considerably across states, with 34% of complaints substantiated. For-profit agencies were 1.33 and 1.52 times more likely relative to not-for-profits to have a complaint allegation and deficiency, respectively. CONCLUSIONS: Although the number of complaints was low overall, these data have the potential to convey insights about the care that hospice agencies provide. Greater attention to the perspectives of patients and their families, even when focused on shortcomings in care, can help ensure transparency and accountability and promote higher quality hospice care. PMID- 30016177 TI - Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results. AB - Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory. PMID- 30016180 TI - Cochlear Changes Caused by Peginterferon alpha-2b. AB - To evaluate the effect of peginterferon alpha-2b on guinea pigs' hearing and its cochlea, and to determine whether these effects are permanent or reversible. This study is an experimental animal study done on the organs of Corti of 30 guinea pigs after a peginterferon alpha-2b injection course. The cochleae of guinea pigs were extracted and examined by scanning electron microscopy for the right side and immunohistochemistry for the left side. All guinea pigs were subjected to pinna reflex, otological examination, and distortion product otoacoustic emission (DPOAE) both before and after the receiving of interferon (IFN). Electron microscopic scanning and immunohistochemistry of the cochleae revealed that peginterferon alpha-2b has a harmful effect on guinea pigs' cochleae, in the form of structural changes in the hair cells and supporting cells with apoptotic changes in the organ of Corti and the stria vascularis. These changes were reversible. DPOAE showed a significant reduction in distortion product mean amplitude and signal-to-noise ratio in all frequencies after 3 days from the last dose of IFN injection except at 1,006 Hz. After 14 days, there was a significant improvement in most of the frequencies, but are still below the normal values. PMID- 30016179 TI - Recombinant Duck Interferon Gamma Inhibits H5N1 Influenza Virus Replication In Vitro and In Vivo. AB - The highly pathogenic H5N1 avian influenza virus (AIV) is widespread in waterfowl, causing enormous economic losses and posing a significant threat to public health. An increasing number of reagents have been identified to prevent the spread of influenza; however, there have been no reports on the anti-H5N1 effects of duck interferons, which exhibit antiviral activity against other viruses. Our aim was to investigate the antiviral effects of purified duck interferons. In this study, we successfully cloned and expressed duck interferon gamma (IFN-gamma) in Escherichia coli. The antiviral effects of this recombinant duck IFN-gamma (rDuIFN-gamma) was assessed in vitro and in vivo. rDuIFN-gamma displayed antiviral activity against vesicular stomatitis virus and AIV in duck embryo fibroblasts. Pretreating ducks with 3.4 * 104 U rDuIFN-gamma also partially decreased mortality from 70% to 30% and delayed onset in 2-day-old Peking ducks. Virus titers in tissues and viral shedding decreased, and the expression of interferon-stimulated genes increased in brain and spleen in rDuIFN gamma-treated ducks. These results indicate that duck IFN-gamma has the potential to inhibit viral replication in ducks. PMID- 30016178 TI - Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial. AB - Purpose Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. Patients and Methods The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. Results Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). Conclusion Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy. PMID- 30016181 TI - Unfractionated Heparin Modulates Lipopolysaccharide-Induced Cytokine Production by Different Signaling Pathways in THP-1 Cells. AB - Sepsis is a complex syndrome resulting from the innate host response to infection. Apart from the well-known anticoagulant effects of heparin, it also possesses various immunomodulatory properties. Thus heparin seems to be a therapeutic drug in sepsis. We have demonstrated that unfractionated heparin (UFH) can inhibit lipopolysaccharide (LPS)-induced inflammatory responses in endothelial cells. The monocyte/macrophage system is a major contributor to host immunity and immune surveillance against infection. The aim of the study is to determine the inhibitory effect of UFH on cytokine production in THP-1 monocytes induced by LPS and to define the possible signaling pathways. The THP-1 cells were treated with UFH (0.1-10 U/mL) for 15 min before exposure to LPS (100 ng/mL). After 1 h, nuclear factor-kappaB (NF-kappaB) and phosphorylated inhibitor kappaB-alpha (IkappaB-alpha), c-Jun, c-fos, ERK1/2, JNK, and p38 mitogen activated protein kinase (MAPK) expression levels were evaluated by Western blot. After 6 h, interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-8, and IL-18 protein concentrations were measured by enzyme-linked immunosorbent assay. Cell viability was determined by methyl thiazoyltetrazolium (MTT) assay. UFH inhibited LPS-induced phosphorylation of IkappaB-alpha, c-Jun, ERK1/2, JNK, and p38 MAPK but not c-fos. UFH also suppressed LPS-induced nuclear translocation of NF-kappaB. As expected, UFH decreased LPS-induced IL-1beta, TNF alpha, IL-6, IL-8, and IL-18 protein levels, suggesting that UFH has an anti inflammatory effect on THP-1 cells by interrupting the MAPK, NF-kappaB, and c-Jun signaling pathways. UFH could potentially contribute to treatments for sepsis. PMID- 30016182 TI - Differential Expression of Immune Inhibitory Checkpoint Signatures on Antiviral and Inflammatory T Cell Populations in Chronic Hepatitis B. AB - Virus-specific T cells are critical in mediating the pathogenesis of hepatitis B virus (HBV) infection. Interferon gamma (IFNgamma)-producing T cells are associated with resolution; in contrast, interleukin-17 (IL-17)-producing T cells are linked to exacerbation of liver inflammation and injury. Checkpoint receptors stringently regulate T cell functions, with their expression profiles varying on different T cell subsets. Blockade of checkpoint receptors may be an effective therapeutic strategy for chronic hepatitis B (CHB); however, blockade may also inadvertently exacerbate proinflammatory responses. In this study, we sought to determine the balance of inflammatory and antiviral T cells and determine their inhibitory receptor profile. The frequency of total and HBV antigen-specific Th17 and Tc17 cells was higher in CHB patients compared with healthy controls (HCs). Th17 and Tc17 cells in CHB patients had significantly lower expression of T cell immunoglobulin and mucin domain protein-3 (TIM-3) compared with HCs, with no difference in programmed death-1 (PD-1) or CD244 expression. Conversely, Th1 and Tc1 cells in CHB patients hyperexpressed PD-1 and CD244, while TIM-3 expression was comparable in both cohorts. During CHB, antiviral IFNgamma T cells hyperexpress multiple immune inhibitory receptors driving their functional impairment. In contrast, inflammatory Th17/Tc17 cells hypoexpress TIM-3, but not PD-1 or CD244. Checkpoint inhibitors for CHB should target PD-1 or CD244 to allow restoration of IFNgamma responses without affecting inflammatory IL-17 production. PMID- 30016183 TI - Azithromycin Resistance in Clinical Isolates of Salmonella enterica Serovars Typhi and Paratyphi in Bangladesh. AB - OBJECTIVE: Salmonella enterica serovars Typhi and Paratyphi, the causative agents of typhoid and paratyphoid, are major threats in developing countries. The present study aimed to investigate the resistance pattern of 40 clinically isolated Salmonella enterica serovars Typhi (n = 33) and Paratyphi (n = 7) to commonly used antibiotics, particularly azithromycin. MATERIALS AND METHODS: The disc diffusion method was used to investigate the resistance pattern of the clinical isolates against selected antibiotics. Minimum inhibitory concentration (MIC) was determined by the broth dilution method. Plate-based assays were used for the detection of efflux pumps. RESULTS: It was observed that 95% of the test isolates were resistant to azithromycin and 100% were resistant to clindamycin. MIC values of azithromycin ranged between 32 and 128 MUg mL-1. Although 90% of isolates contained efflux pump, none of the isolates was found to have the mef(A) gene, indicating that some other efflux pump(s) might be present. Macrolide resistance gene, erm(B), was present in 25 isolates (62.5%). Other resistance genes were absent. Plasmids were absent, but class 1 integrons were present in 80% of the isolates. CONCLUSIONS: The occurrence of macrolide resistance in clinical Salmonella enterica serovars Typhi and Paratyphi is of particular significance in Bangladesh where azithromycin is a commonly used drug against most diseases. PMID- 30016184 TI - A Single Surgeon Laparoscopic Duodenoduodenostomy Case Series for Congenital Duodenal Obstruction in an Academic Setting. AB - INTRODUCTION: Laparoscopic duodenoduodenostomy can be performed to repair congenital duodenal obstructions from atresia or duodenal web. There are only a few published case series in the literature. We are reporting on a single surgeon's experience with the operation and discuss the technical aspects of the operation. MATERIAL AND METHODS: A retrospective chart review was performed using the electronic medical record identifying all patients who underwent laparoscopic duodenoduodenostomy or duodenojejunostomy at two institutions by a singular surgeon. RESULTS: Fifteen patients were identified as having undergone laparoscopic duodenoduodenostomy from 2010 until 2017. The weight at the time of the operation ranged from 1.5 to 8.7 kg (median 2.5 kg). The age ranged from 0 days to 15 months (median 3 days). Operative time (including other procedures) ranged from 2 hours 10 minutes to 3 hours 45 minutes with a median of 2 hours 55 minutes. One case was converted to open due to poor visualization. One patient developed a stricture that required open anastomotic revision 4 weeks after the initial surgery. In 1 patient, an enterotomy in the first portion of the duodenum was created from a retraction stitch-this was immediately recognized and repaired by primary laparoscopic closure. One patient had a small anastomotic leak that was treated with antibiotics. There were no mortalities and no intraoperative blood loss requiring transfusion. CONCLUSION: Laparoscopic duodenoduodenostomy is an operation that can be performed with excellent outcomes following simple steps that are easily taught in a teaching setting. PMID- 30016185 TI - Effects of movement velocity and training frequency of resistance exercise on functional performance in older adults: a randomised controlled trial. AB - OBJECTIVES: To investigate the effects that high-velocity, low-load (HVLL) and low-velocity, high-load (LVHL) resistance exercise, performed once or twice weekly, have on indices of functional performance (primary outcome), maximal strength, and body composition (secondary outcomes) in older adults. METHODS: In a randomised, controlled, multi-armed, parallel design, 54 moderately-highly active, but resistance exercise naive older adults (aged 60-79 years), attended baseline and post-10-week intervention assessment sessions. Physical and functional assessments were completed, and predicted one-repetition maximums (1 RM) were obtained for eight exercises. Participants were then randomised into one of five conditions: HVLL once-weekly (HVLL1: n = 11) or twice-weekly (HVLL2: n = 11), LVHL once-weekly (LVHL1: n = 10) or twice-weekly (LVHL2: n = 11), no exercise control condition (CON: n = 11). The HVLL conditions completed 3 sets of 14 repetitions at 40% 1-RM and the LVHL conditions, 3 sets of 7 repetitions at 80% 1-RM. In total, 50 participants completed all testing and were included in analyses. RESULTS: Only LVHL2 improved 30-sec chair stand performance (p = .035; g = 0.89), arm curls (p = .011; g = 1.65) and grip-strength (p = .015; g = 0.34) compared to CON. LVHL2 improved maximal strength compared to CON for 7/8 exercises (p < .05). Whereas, LVHL1 and HVLL2 only improved seated row and chest press compared to CON (p < .05). CONCLUSION: Possibly due to the lower intensity nature of the HVLL conditions, LVHL, twice-weekly was most beneficial for improving functional performance and strength in moderately-highly active older adults. Therefore, we recommend that exercise professionals ensure resistance exercise sessions have sufficient intensity of effort and volume, in order to maximise functional performance and strength gains in older adults. PMID- 30016186 TI - Multi-hydrolytic enzyme accumulation and microbial community structure of anaerobic co-digestion of food waste and waste-activated sludge. AB - The accumulation of multi-hydrolytic enzyme through anaerobic co-digestion of waste-activated sludge (WAS) and food waste (FW) was studied by regulating temperature, pH and the mass ratio of FW to WAS (F/W). Experimental results showed that temperature had a profound effect on the activity of the enzyme and the most suitable temperatures for the accumulation of amylase and protease were 37 degrees C and 50 degrees C, respectively. The highest activity of amylase and protease accumulated reached 10.29 and 19.23 U/mL at an F/W ratio of 2:1. The addition of anaerobic co-digestion solution enriching protease and amylase had positive effects on the hydrolysis of WAS. In addition, the Illumina high throughput sequencing demonstrated that the bacterial diversity decreased, but the bacterial abundance increased during the co-digestion process of WAS and FW. The predominant strains for secreting amylase were Lactobacillus and Clostridium sensu-strito-1, and Aeromonas was the dominant strain for secreting protease. PMID- 30016187 TI - Nutritional intake and body composition changes in a UCI World Tour cycling team during the Tour of Spain. AB - The aim of this study was to quantify the food intake of an International Cyclist Union (UCI) World Tour professional cyclist team and to analyse changes in body composition during the Tour of Spain. Nine male professional road cyclists (31.3 +/- 3.0 years) volunteered to participate in the study. Nutritional data were collected each day throughout the 3-week Tour by two trained investigators who weighed the food ingested by the cyclists. Mean nutritional intake of the cyclists was as follows: carbohydrate, 12.5 +/- 1.8 g/kg/day of body weight (BW) (65.0 +/- 5.9%); fat, 1.5 +/- 0.5 g/kg/day BW (17.9 +/- 5.6%); and protein, 3.3 +/- 0.3 g/kg/day BW (17.1 +/- 1.6%). Intake of all micronutrients, except for folate, vitamin D and potassium (which were 78.7%, 46% and 84% of Recommended Dietary Allowances (RDA), respectively), exceeded the RDA. Height, weight, skinfolds, circumferences and diameters were taken following the guidelines outlined by the International Society for the Advancement of Kinanthropometry. Body density, body fat percentage, muscle mass, total muscle mass and fat mass of the arms and thighs were calculated. Percentage body fat, fat mass and upper arm fat mass significantly decreased (p < .05) after the Tour independent of the equation method used in the calculations. Total muscle mass remained unchanged. Generally, this sample of cyclists consumed more protein and less fat than the recommended amount and had low weight, BMI and fat mass. It is suggested that sports nutritionists design personalised diets in order to maintain a correct proportion of nutrients as well as controlling possible anthropometrical changes that could affect performance. PMID- 30016188 TI - Awake vs Sedated Tracheostomies: A Review and Comparison at a Single Institution. AB - OBJECTIVE: The literature surrounding awake tracheostomies is sparse, particularly comparing awake tracheostomy patients to that of the sedated tracheostomy population. This study sought to compare tracheostomy patient demographics, indications, and outcomes of the 2 populations. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. MATERIALS AND METHODS: All tracheostomies performed at our tertiary academic medical institution between January 2013 through November 2015 were reviewed. The data collected included demographics, comorbidity, anticoagulation, and outcomes. RESULTS: A total of 978 tracheostomies performed during this period met inclusion criteria, with 78 (8.0%) on awake patients. Most awake procedures were performed by otolaryngology (97.4%). Male sex predominated (73.1% awake vs 57.8% sedated). Forty-four patients (56.4%) were smokers in the awake group vs 326 of 900 (36.2%) in the sedated group. Malignancy was the primary indication for awake tracheostomy (68/78, 87.1%). One patient (1.3%) had significant postoperative bleeding compared to 26 of 900 (2.9%) of the sedated tracheostomy patients ( P = .406). Only 9 (11.4%) were ever decannulated. Thirty-one (39.2%) patients ultimately underwent total laryngectomy, 3 could not be decannulated secondary to anatomical causes (stenosis or vocal fold paralysis), and 19 were lost to follow-up after discharge. There were 12 of 78 (15.4%) overall deaths in the awake cohort, with 215 of 900 (23.9%) in the sedated cohort ( P = .088). CONCLUSION: Despite all the differences between the 2 patient populations, the urgent awake tracheostomy appears to be safe and its complications do not appear significantly different from the sedated population. PMID- 30016189 TI - Larger strength losses and muscle activation deficits in plantar flexors induced by backward downhill in reference to distance-matched forward uphill treadmill walk. AB - We tested the hypothesis that backward downhill walking (eccentric component) impairs both voluntary activation and muscle contractile properties in the plantar flexors and delays recovery as compared to a gradient and distance matched uphill walk. Fourteen males performed two 30-min walking exercises (velocity: 1 m/ s; grade: 25%; load: 12% of body weight), one downhill (DW) and one uphill (UP), in a counterbalanced order, separated by 6 weeks. Neuromuscular test sessions were performed before, after, 24-, 48- and 72-h post-exercise, including motor nerve stimulations during brief (5 s) and sustained (1 min) maximal isometric voluntary contractions of the plantar flexors. DW (-18.1 +/- 11.1%, P < .001), but not UP (-6.0 +/- 7.7%, P =.15), decreased torque production during brief contractions for at least three days post-exercise (P < .05). Voluntary activation during brief contractions decreased after DW (P < .05), but not UP, and recovered by 24 h. Both UP (-9.3 +/- 9.0%, P = .024) and DW (-25.6 +/ 10.3%, P < .001) decreased torque production during sustained contractions but voluntary activation (P = .001) was lower in DW than UP. Peak twitch torque and maximum rates of torque development and relaxation were equally reduced after UP and DW (P < .05), and recovered by 24 h. DW induced an increase in muscle soreness with peak values observed 48 h post-walking (P < .001), whereas post-UP exercise changes were non-significant (all P > .05). Using a direct comparison, the capacity to drive the plantar flexors during sustained contractions remains sub-optimal during the three-day recovery period in response to non-exhaustive, downhill backward walking in reference to an uphill exercise matched for distance covered. PMID- 30016190 TI - Evaluation of short chain chlorinated paraffins in human milk and their intake by infants in Hebei Province, China. AB - Short-chain chlorinated paraffins (SCCPs) have drawn increasing interest worldwide since they were included in the list of controlled persistent organic pollutants in Annex A of the Stockholm Convention in 2017, and the potential health risk they pose to humans must be evaluated. In this study, 86 human milk samples were collected from 55 healthy Chinese mothers living in the Shijiazhuang region of Northern China in 2014-2015. Advanced online gel permeation chromatography-gas-chromatography-coupled mass spectrometry with negative-ion chemical ionisation was used to quantify the SCCPs in the samples. The estimated mean level of SCCPs was 2.51 MUg g-1 lipid weight (range 0.21-16.12). The SCCP concentration correlated positively with the mother's bodyweight at the end of pregnancy (P < 0.05). The mean SCCP intake by infants via breast milk was 13.0 MUg kg-1 day-1 at 1 month, 7.1 MUg kg-1 day-1 at 3 months, and 2.5 MUg kg-1 day-1 at 6 months after birth. This study provides initial data on the levels of SCCPs in human milk in a chlorinated-paraffin-manufacturing area in China, and indicates a high health risk for infants. PMID- 30016191 TI - Life Cycle of the Parasite Profilicollis chasmagnathi (Acanthocephala) On the Patagonian Coast of Argentina Based On Morphological and Molecular Data. AB - This study verifies the identity of adult specimens of the parasite Profilicollis chasmagnathi (Acanthocephala, Polymorphidae) recovered from kelp gulls Larus dominicanus (Aves, Laridae), and cystacanths found in crabs Cyrtograpsus altimanus (Crustacea, Decapoda) from the southwestern Atlantic coast. The life cycle of this parasite is elucidated in the intertidal zone of Patagonia, Argentina, based on morphological and molecular data. Preferences by size and sex of the intermediate host and seasonal variation of this parasite are provided, contributing to the knowledge of this host-parasite association. PMID- 30016192 TI - Effect of resistance training with different frequencies and subsequent detraining on muscle mass and appendicular lean soft tissue, IGF-1, and testosterone in older women. AB - OBJECTIVE: To analyse the effect of resistance training (RT) frequency on muscle mass, appendicular lean soft tissue, insulin-like growth factor 1 (IGF-1), testosterone, and their changes with detraining in older women. METHODS: Forty five physically independent older women (>= 60 years) were randomly assigned to perform RT either two (G2X, n = 21) or three times/week (G3X, n = 24), during 12 weeks (8 exercises, 1 set of 10-15 repetition maximum). Muscle mass and appendicular lean soft tissue, IGF-1, testosterone, and dietary intake were measured at pre-training, post-training, and after detraining (12 weeks). RESULTS: Muscle mass and appendicular lean soft tissue significantly increased post-training (G2X = +5.5% and G3X = +5.8%, P < .0001) with no differences between groups, and gains were retained after detraining (G2X = 100% and G3X = 99%, P < .0001). IGF-1 and dietary intake did not change for the groups during the study. Testosterone did not change post-training but significantly decreased after detraining (G2X = -21% and G3X = -50%, P < .0001). CONCLUSION: We conclude that lower RT frequency is as effective as higher frequency to improve muscle mass and appendicular lean soft tissue, and to maintain testosterone and IGF-1. Additionally, detraining may reduce testosterone regardless of RT frequency. These results are specifically for community-dwelling older women and may not be generalized to other populations. PMID- 30016193 TI - Long-Term Effect of Pulsed Nd:YAG Laser in the Treatment of Children with Juvenile Rheumatoid Arthritis: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to evaluate the long-term impact of a pulsed neodymium-doped yttrium aluminum garnet (Nd:YAG) laser [high-intensity laser therapy (HILT)] in the treatment of juvenile rheumatoid arthritis (JRA). MATERIALS AND METHODS: A sample of 30 children participated in this study (15 in the laser group and 15 in the placebo group), with a mean age of 10.53 +/- 1.25 years. Children who were randomly assigned to the laser group received HILT thrice per week for 4 weeks, plus the exercise program. HILT scanned each knee with 600 J in two phases and 15 J to 10 points for a total of 750 J for each knee. The placebo laser group received placebo HILT plus the same exercise program. The outcomes measured in this study were the pain level by the visual analog scale (VAS) and gait parameters by the GAITRite(r) system. Statistical analysis was performed by ANOVA with repeated measures to compare the differences between the baseline, post-treatment, and 12-week follow-up measurements for both groups. The level of significance was set at p < 0.05. RESULTS: The VAS results significantly decreased post-treatment in the laser group relative to the placebo group and were still improved at the 12-week follow-up. Gait parameters significantly increased in the laser group after 4 weeks of treatment and after 12 weeks compared to the placebo group. CONCLUSIONS: HILT, when combined with an exercise program, appears to be more effective in children with JRA than a placebo laser procedure with exercises. PMID- 30016194 TI - Outcomes of Women Delivering at Very Advanced Maternal Age. AB - BACKGROUND: The purpose of this study was to evaluate the maternal outcome in women with very advanced maternal age (VAMA) at childbirth (>45 years) compared to advanced maternal age (35-39 and 40-44 years). METHODS: Retrospective cohort study using the Texas Public Use Data File, years 2013-2014. Maternal age was a three-level variable: 35-39 (referent), 40-44, and 45-59 years (VAMA). Adjusted risk ratios (aRRs) for the two older age groups for various obstetrical and nonobstetrical complications were calculated from log-binomial regression models. RESULTS: The sample consisted of 96,879 deliveries. In univariate analyses, a higher frequency (p < 0.05) of gestational diabetes, pregestational diabetes, chronic hypertension, pregnancy related hypertensive disorders, multiple gestation, oligohydramnios, polyhydramnios, placenta previa, postpartum hemorrhage, small for gestational age, intrauterine fetal death, and length of stay were noted in the two older maternal age groups compared to the youngest maternal age group. Multiple gestations were noted to be more frequent in the two older groups: the VAMA group had a 336% increase in their risk (aRR = 4.36, 95% CI: 3.68-5.17), while women 40-44 years of age experienced a 17% increase in their risk (aRR = 1.17, 95% CI: 1.07-1.29) compared to women in the 35-39 year group. The risk of the following outcomes was approximately doubled in VAMA women compared to the referent (all statistically significant): small for gestational age (aRR = 1.92), stillbirth (aRR = 2.12), and intrauterine fetal death (aRR = 1.96). CONCLUSIONS: This population-based study detected a dose-response association between maternal age and the risk of multiple maternal and fetal complications. PMID- 30016195 TI - Antifungal effect of organic acids from lactic acid bacteria on Penicillium nordicum. AB - The control of fungal contamination is particularly important to avoid both spoilage of food and feed products and the occurrence of toxic compounds, known as mycotoxins. Some lactic acid bacteria (LAB) strains have shown the capacity to inhibit fungal growth and the production of mycotoxins. In this work, cell-free supernatants (CFS) of Lactobacillus plantarum UM55 and Lactobacillus buchneri UTAD104 were tested against Penicillium nordicum radial growth and OTA production. When CFS of these strains were used, the radial growth of the fungus was inhibited by less than 20%, but the production of OTA was reduced by approx. 60%. These antifungal effects resulted from organic acids produced by LAB. The CFS of L. plantarum UM55 contained lactic acid, phenyllactic acid (PLA), hydroxyphenyllactic acid (OH-PLA) and indole lactic acid (ILA), while L. buchneri UTAD104 CFS contained acetic acid, lactic acid and PLA. These organic acids were further tested individually for their inhibitory capacity. Calculation of the inhibitory concentrations (ICs) showed that acetic acid, ILA and PLA were the most effective in inhibiting P. nordicum growth and OTA production. When the inhibitory activity of LAB cells incorporated into the culture medium was tested, L. buchneri UTAD104 inhibited the production of OTA entirely in all conditions tested, but fungal growth was only inhibited completely by the highest concentrations of cells. Acetic acid production was primarily responsible for this effect. In conclusion, the ability of LAB to inhibit mycotoxigenic fungi depends on strain capability to produce specific organic acids, and those acids may differ from strain to strain. Also, the use of LAB cells, especially from L. buchneri, in food products prone to contamination with P. nordicum (e.g. dry cured meats and cheeses) may be an alternative solution to control fungal growth and OTA production. PMID- 30016196 TI - Staged Thoracoscopic Repair of Long-Gap Esophageal Atresia Without Temporary Gastrostomy. AB - INTRODUCTION: Primary repair of long-gap esophageal atresia (LGEA) continues to present a surgical challenge. The number of treatment options, including the use of native esophagus or esophageal replacement, shows the difficulty in the treatment and lack of one superior option. Until recently all children with LGEA required temporary gastrostomy before esophageal reconstruction. OBJECTIVE: The aim of the study is to present new therapeutic management in patients with LGEA, involving staged thoracoscopic procedure with internal traction without gastrostomy. MATERIALS AND METHODS: Four neonates with LGEA were treated in two academic Departments of Pediatric Surgery in Poland from 2015 to 2018. The intervention was staged thoracoscopic approach, consisting in internal traction, followed by delayed esophageal anastomosis in neonatal period. The outcome measures were successful anastomosis, short time anastomosis complications, and timing of gastric/oral feeding. RESULTS: Internal traction was placed between 2 and 6 days of life. A successful repair of native esophagus by the second approach in neonatal period without gastrostomy was achieved in 3 out of 4 neonates, 5-8 days after internal traction placement. No anastomotic leakage was observed, two anastomoses developed stricture managed with three and four sessions of repeated dilatation. Nasogastric tube feeding started between 5 and 7 days with full oral feeding achieved between 10 and 35 days after anastomosis. Follow-up was after 1-34 months. CONCLUSIONS: Our technique should be considered an alternative first-line strategy for the repair of LGEA without the use of a gastrostomy. PMID- 30016197 TI - Tachyphylaxis and Dependence in Pharmacotherapy for Unexplained Chronic Cough. AB - Objective Unexplained chronic cough (UCC) is a perplexing condition treated with neuromodulators. Although previous literature describes the effectiveness of neuromodulators, there is little on the development of tachyphylaxis or dependence to neuromodulators over time. Our objective is to capture the experience of a large cohort of patients with UCC over an extended period, looking for these 2 phenomena. Study Design Case series with chart review. Setting Tertiary care hospital. Subjects and Methods We performed a retrospective review of patients diagnosed with UCC from 2010 to 2014. Patient outcomes were measured through percentage improvement scores. Treatment failures were attributed to no benefit, intolerable side effects, or tachyphylaxis. Tachyphylaxis was defined as the need for higher doses of medication following diminishing therapeutic benefit, while dependence was defined as a failure to stop therapy following attempted de-escalation or resurgence following drug cessation. Results Sixty-eight patients were included in the study. Tachyphylaxis was observed among 35% of patients while dependence was observed among 27% of successfully treated patients, together effecting >50% of the cohort. Sixty-eight percent of patients ultimately experienced successful treatment with neuromodulators, demonstrating strikingly distinct responses to different neuromodulator drug classes. Conclusion Tachyphylaxis and dependence occur frequently during UCC treatment and have a major impact on treatment outcomes. Patients sometimes demonstrate distinct responses to different neuromodulator classes. The majority of patients will experience successful treatment for their cough, although several trials may be required. PMID- 30016198 TI - Implementation of Targeted Temperature Management in a Patient with Cerebral Arterial Gas Embolism. AB - Cerebral arterial gas embolism (CAGE) shows various manifestations according to the quantity of gas and the brain areas affected. The symptoms range from minor motor weakness, headache, and confusion to disorientation, convulsions, hemiparesis, unconsciousness, and coma. A 46-year-old man was transferred to our emergency department due to altered sensorium. Immediately after a controlled ascent from 33 m of seawater, he complained of shortness of breath and rigid extremities, lapsing into unconsciousness. He was intubated at another medical center, where a brain computerized axial tomography scan showed no definitive abnormal findings. Pneumothorax and obstructing lesions were apparent in the left thorax of the computed tomography scan. Following closed thoracostomy, we provided hyperbaric oxygen therapy (HBOT) using U.S. Navy Treatment Table (USN TT) 6A. A brain magnetic resonance imaging diffusion image taken after HBOT showed acute infarction in both middle and posterior cerebral arteries. We implemented targeted temperature management (TTM) to prevent worsening of cerebral function in the intensive care unit. After completing TTM, we repeated HBOT using USN TT5 and started rehabilitation therapy. He fully recovered from the neurological deficits. This is the first case of CAGE treated with TTM and consecutive HBOTs suggesting that TTM might facilitate salvage of the penumbra in severe CAGE. PMID- 30016199 TI - INTRODUCTION OF THE 2018 RECIPIENT OF THE AMERICAN SOCIETY OF PARASITOLOGISTS' CLARK P. READ MENTOR AWARD, DR. JANINE N. CAIRA. AB - There is no abstract. PMID- 30016200 TI - Evaluation of the Efficacy of Tea Tree Oil On the Density of Demodex Mites (Acari: Demodicidae) and Ocular Symptoms In Patients With Demodectic Blepharitis. AB - The objective of this study was to examine the efficacy of 7.5% tea tree oil (TTO) eyelash shampoo on the density of Demodex (Acari: Demodicidae) and ocular symptoms in patients with demodectic blepharitis. A total of 135 patients diagnosed with demodectic blepharitis, following clinical inspection and parasitological examinations, were included in the study. Patients were treated with eyelash shampoo, with or without TTO. Full Demodex reduction was attained in 36% of the patients who used eyelash shampoo with TTO, and the average Demodex count was reduced from 6.33/eyelash to zero ( P < 0.001). In contrast, the average Demodex count in patients who did not achieve full reduction (64%) was reduced from 12.46/eyelash to 4.15/eyelash ( P < 0.001). Full reduction was observed in 11.7% of patients who used TTO-free eyelash shampoo, and average Demodex count reduced from 2.00/eyelash to zero ( P = 0.017). The average Demodex count was reduced from 11.98/eyelash to 7.91/eyelash in patients (88.3%) who did not achieve full reduction ( P = 0.024). Additionally, ocular symptom scores (which are generated based on subjective experiences of itching, burning, the feeling of a foreign body in the eye, eye redness, and cylindrical dandruff) were reduced significantly ( P < 0.001) in patients who used the eyelash shampoo with TTO. The symptom scores remained almost the same in patients who used TTO-free eyelash shampoo ( P > 0.05). In conclusion, it was determined that eyelash shampoo with TTO is 3 times more effective at achieving full Demodex reduction, significantly reducing the Demodex count, and relieving ocular symptoms in patients where full reduction cannot be attained, without adverse side effects. PMID- 30016201 TI - Mitigation of soil loss from turfgrass cultivation by utilizing poultry abattoir sludge compost and biochar on low-organic matter soil. AB - Commercial turfgrass cultivation is one of the main ornamental industries world wide; however, successive turfgrass sod cutting from the same site removes surface soil, leading to a decline in soil organic matter, impairment of soil fertility and degradation of environment. The present study was aimed to investigate the applicability of poultry abattoir sludge compost (PASC) and biochar (BC) on the establishment of turfgrass by evaluating plant growth performance and mitigation of soil loss by organic waste amendments. The experimental study was designed on the soil which had originally low-organic matter content and previously used as a turfgrass sod harvested site in a sandy loam soil. Incorporation of PASC to soil improved the physicochemical properties in terms of bulk density (BD), water holding capacity (WHC), cation exchange capacity (CEC), pH, total nitrogen, total organic carbon (TOC), and organic matter (OM) by 37 (+/-2)%, 45 (+/-3)%, 55 (+/-3)%, 21 (+/-2)%, 48 (+/-2)%, 90 (+/ 10)%, and 96 (+/-4)%, respectively. PASC-amended treatments enhanced the turfgrass growth rate more than the BC due to its increased nutrient availability. Incorporation of 100 Mg ha-1 (mega gram per hectare) PASC in surface soil with or without BC decreased the mineral soil removal rate by half of the respective soil (control) treatments. The results of the present study confirmed the utilization of PASC and BC as promising agro-industrial-based fertilizers in turfgrass sod production for sustainable soil and nutrient management. PMID- 30016202 TI - The Effect of Primary Care Team Realignment on Point-of-Care Screening. AB - Reporting primary care quality measures is an essential component of value-based care delivery and is part of the strategy to bend the health care cost curve. As primary care physicians are increasingly pressed for time, incorporating ancillary staff screening into pre-visit workflows can increase screening rates, but can pose a challenge in large practice settings. The objective was to improve screening rates for depression and falls risk at a large, urban primary care practice. Jefferson Family Medicine Associates is a practice in downtown Philadelphia that serves 35,000 patients and provides approximately 80,000 visits annually. The majority of patients are African American. Screening responsibilities were realigned within medical assistant workflows, and a training program was designed and implemented to ensure its success and sustainability. Monthly Group Practice Reporting Option data on depression screening and falls risk screening was collected from January 1, 2015, to October 31, 2016. The primary outcome measures were the rate of depression screening and falls risk screening performed for patients who had a visit during the study period. The average monthly depression screening rate changed from 1.41% pre intervention to 49.77% post intervention (z = -100.65; P < .001). The average monthly falls screening rate changed from 19.23% pre intervention to 61.33% post intervention (z = -77.97, P < .001). This workflow redesign, training model, and implementation was successful at increasing screening rates for depression and falls risk, and may benefit other practices that hope to accomplish similar quality measure improvements. PMID- 30016203 TI - Corticospinal changes induced by fatiguing eccentric versus concentric exercise. AB - The present study assessed neuromuscular and corticospinal changes during and after a fatiguing submaximal exercise of the knee extensors in different modes of muscle contraction. Twelve subjects performed two knee extensors exercises in a concentric or eccentric mode, at the same torque and with a similar total impulse. Exercises consisted of 10 sets of 10 repetitions at an intensity of 80% of the maximal voluntary isometric contraction torque (MVIC). MVIC, maximal voluntary activation level (VAL) and responses of electrically evoked contractions of the knee extensors were assessed before and after exercise. Motor evoked potential amplitude (MEP) and cortical silent period (CSP) of the vastus medialis (VM) and rectus femoris (RF) muscles were assessed before, during and after exercise. Similar reductions of the MVIC (-13%), VAL (-12%) and a decrease in the peak twitch (-12%) were observed after both exercises. For both VM and RF muscles, MEP amplitude remained unchanged during either concentric or eccentric exercises. No change of the MEP amplitude input-output curves was observed post exercise. For the RF muscle, CSP increased during the concentric exercise and remained lengthened after this exercise. For the VM muscle, CSP was reduced after the eccentric exercise only. For a similar amount of total impulse, concentric and eccentric knee extensor contractions led to similar exercise-induced neuromuscular response changes. For the two muscles investigated, no modulation of corticospinal excitability was observed during or after either concentric or eccentric exercises. However, intracortical inhibition showed significant modulations during and after exercise. PMID- 30016204 TI - Mild Therapeutic Hypothermia Increases Glutathione Levels in Postcardiac Arrest Patients. AB - Ischemia-reperfusion (I/R)-induced oxidative stress is one of the main mechanisms of tissue injury after cardiac arrest (CA). A decrease in antioxidant defenses may contribute to I/R injury. The present study aims to investigate the influence of mild therapeutic hypothermia (MTH) on levels of nonenzymatic antioxidants after CA. We investigated antioxidant levels at 6, 12, 36, and 72 hours after CA in central venous blood samples of patients admitted to intensive care. The sample consisted of 31 patients under controlled normothermia (36 degrees C) and 11 patients treated with 24 hours of MTH (33 degrees C). Erythrocyte glutathione (GSH) levels were elevated by MTH, increasing at 6, 12, 36, and 72 hours after CA in hypothermic patients (mean GSH levels in normothermic patients: 6 hours = 73.89, 12 hours = 56.45, 36 hours = 56.46, 72 hours = 61.80 vs. hypothermic patients: 6 hours = 176.89, 12 hours = 198.78, 36 hours = 186.96, and 72 hours = 173.68 MUmol/g of protein). Vitamin C levels decreased significantly at 6 and 12 hours after CA in hypothermic patients (median vitamin C levels in normothermic patients: 6 hours = 7.53, 12 hours = 9.40, 36 hours = 8.56, and 72 hours = 8.51 vs. hypothermic patients: 6 hours = 5.46, 12 hours = 5.44, 36 hours = 6.10, and 72 hours = 5.89 mmol/L), coinciding with the period of therapeutic hypothermia. Vitamin E and nitric oxide levels were not altered by hypothermic treatment. These findings suggest that MTH alters nonenzymatic antioxidants differently, decreasing circulating vitamin C levels during treatment; however, MTH elevates GSH levels, possibly protecting tissues from I/R injury after CA. PMID- 30016205 TI - In vitro model to assess the adsorption of oral veterinary drugs to mycotoxin binders in a feed- and aflatoxin B1-containing buffered matrix. AB - Mycotoxin binders are feed additives which are mixed in the feed to adsorb mycotoxins and thereby reducing their toxic effects on animals. Interactions with orally administered veterinary medicinal products, such as antimicrobials or coccidiostats, have been reported previously. This paper describes an in vitro model to screen the interaction between mycotoxin binders and veterinary drugs with respect to the non-specific binding of drugs. It is designed as a static setup using a single concentration of drug and binder in a feed-containing or a feed-plus-mycotoxin-containing matrix, buffered at different pH values. The model was applied to two frequently used antimicrobials in veterinary medicine, doxycycline (DOX) and tylosin (TYL), one major mycotoxin, aflatoxin B1 (AFB1), and four mycotoxin binders. Proportions of feed, DOX or TYL, AFB1, and binder are equivalent to the in vivo situation for broiler chickens, while pH and volume of the buffer are representative of the gastrointestinal tract of chickens. A substantial binding of DOX (~ 88%) and TYL (~ 66%) to the feed-matrix was observed. For the mycotoxin binders, similar results were obtained for DOX and TYL; more specifically up to an inclusion rate of 20 g binder/kg feed, no significant binding was demonstrated, determined as the free concentration of DOX and TYL. A single exception was noticed for TYL and one specific bentonite-based mycotoxin binder, for which no significant interaction could be demonstrated up to 10 g binder/kg but there was an effect at 20 g/kg. In all cases, there was no competition between the tested drugs DOX or TYL and the mycotoxin AFB1 for binding to the bentonite-based mycotoxin binder. PMID- 30016206 TI - Frequent Exposure to Many Hunting Dogs Significantly Increases Tick Exposure. AB - Certain professionals have more exposure to animals and therefore an increased risk of zoonoses. Professional hunting dog caretakers work with upwards of 50 dogs and are exposed to zoonoses through exposure to multiple potentially infectious canine secretions or excretions, as well as to the ticks that dogs carry. Dog caretakers reported having found embedded ticks on their bodies 5.83 times more than environment-only controls. Zoonotic Lyme disease, first in the United States for morbidity due to a vector-borne infection, has dramatically expanded its geographic range over the last two decades. This finding emphasizes the increased risk of tick-borne diseases, including Lyme disease, based on dog exposure and in areas of disease emergence. PMID- 30016207 TI - Using Teleneurology to Deliver Chronic Neurologic Care to Rural Veterans: Analysis of the First 1,100 Patient Visits. AB - BACKGROUND: A challenge confronting the United States is delivery of quality specialty healthcare to citizens living in rural areas. INTRODUCTION: The Veterans Administration (VA) developed a large national telehealth network to address 5.2 million rural veterans. New Mexico's Albuquerque VA Neurology Service developed a teleneurology program for their rural veterans. This article analyzes our first 1,100 teleneurology patient visits. MATERIALS AND METHODS: Veterans living in remote areas of New Mexico, southern Colorado, eastern Arizona, and western Texas were offered follow-up teleneurology care at 16 rural VA community based outpatient clinics (CBOCs) following an initial evaluation at the Albuquerque VA neurology outpatient clinic. Surveys were sent after all teleneurology visits focused on quality of care, ease of communication, satisfaction, and staff's ability to deliver same quality care as in person. Problems encountered, differences between face-to-face clinics and teleneurology, and cost savings were examined. RESULTS: Regarding the 701 (64%) returned surveys, we found 90% perceived they received good care, 91% felt there was good communication, 88% liked the convenience, and 87% reported they desired to continue teleneurology care. Ninety-six percent reported saving time, money, or both through CBOC visits instead of driving to Albuquerque. DISCUSSION: All providers felt that they could deliver excellent care through teleneurology. We found emergency room visits for neurologic problems was similar for both groups. CONCLUSIONS: Our rural veteran patients and neurology staff overwhelmingly found high quality patient care can be delivered via teleneurology for a variety of chronic neurologic problems and was comparable to care delivered in neurology face-to-face clinics. PMID- 30016208 TI - Validating the Association of Japanese Encephalitis Vector Abundance with Paddy Growth, Using MODIS Data. AB - Japanese encephalitis (JE) is one of the leading causes of viral encephalitis in Southeast Asia, particularly India. The major vector transmitting the disease, Culex tritaeniorhynchus, breeds in paddy field and its associated water bodies. The incidence of human infection usually occurs after the peak in vector abundance. Earlier, an association between JE vector abundance and paddy growth was demonstrated in Bellary district of Karnataka state, India, using radar satellite (RISAT 1) data. In this study, an attempt has been made to validate this phenomenon with the data collected from Uttar Pradesh state, using moderate resolution imaging spectroradiometer data. PMID- 30016210 TI - Evaluation of Chemical Immobilization in Captive Black Bears ( Ursus americanus) Receiving a Combination of Nalbuphine, Medetomidine, and Azaperone. AB - To assess potential seasonal differences in responses to immobilization, we sedated eight orphaned yearling black bears being held for rehabilitation at a wildlife facility in Colorado, US, using a premixed combination of nalbuphine (40 mg/mL), azaperone (10 mg/mL), and medetomidine (10 mg/mL; NalMed-A) in October (autumn) prior to hibernation and again after emergence in May (spring) prior to their release. We dosed all bears at 1 mL NalMed-A per estimated 45 kg body mass (1 mL NalMed-A/45 kg), delivered by intramuscular injection using a pole syringe, to facilitate routine examination and ear tagging. Arterial blood gases were measured to assess oxygenation and acid-base status of bears both pre and post oxygen supplementation. The mean (SE) dose calculated post hoc was 0.9 (0.04) mg nalbuphine/kg, 0.2 (0.01) mg azaperone/kg, and 0.2 (0.01) mg medetomidine/kg. The mean induction time was 8 (1) min for six of the bears in October and 6 (1) min for eight bears in May. The NalMed-A combination provided good sedation in captive yearling black bears in autumn and spring and was effectively antagonized with a combination of naltrexone and atipamezole. Mild hypoxemia (PaO2: 53.5-54.4 mmHg) was the most significant side effect and was corrected (PaO2: 68.4-150.1 mmHg) with supplemental oxygen administered at 2-5 L/min for 5 min (point of sampling). PMID- 30016209 TI - First Report of Natural Infection with Trypanosoma cruzi in Rhodnius montenegrensis (Hemiptera, Reduviidae, Triatominae) in Western Amazon, Brazil. AB - Rhodnius montenegrensis was described in 2012. Since then, reports of the occurrence of this species associated with palm trees near households in Rondonia have been published. This study aimed to analyze the natural infection of R. montenegrensis with trypanosomatids in the municipality of Monte Negro, Rondonia, Brazilian western Amazon. Capture of triatomines occurred in Attalea speciosa (babassu) specimens around households. Twelve of the 72 captured triatomines were identified by morphological and morphometric characters, by molecular analysis made using the PCR, DNA sequencing, and phylogenetic analyses. The intestinal content was collected from 60 of these 72 specimens. The positivity for trypanosomatids was confirmed by examining the intestinal content followed by PCR amplification of the cathepsin L-like gene specific for Trypanosoma cruzi (PCR DTcrCatL) and Trypanosoma rangeli (PCR-DTraCatL). Of the 60 specimens analyzed by microscopy, 22 (36.7%) were positive for trypanosomatids in the intestinal content analysis. Of these 22 specimens of R. montenegrensis, 16 (72.7%) were infected with T. cruzi, 2 (9.1%) were infected with T. rangeli, 2 (9.1%) had mixed infection with T. cruzi and T. rangeli, and 2 were negative (9.1%). These data suggest the need for attention of the health surveillance system of Chagas disease in the State of Rondonia, as this study points out to another potential vector of the disease. PMID- 30016211 TI - Potential Bacillus anthracis Risk Zones for Male Plains Bison ( Bison bison bison) in Southwestern Montana. AB - A re-emergence of anthrax, a zoonosis caused by the long-lived, spore-forming Bacillus anthracis, occurred with a multispecies outbreak in southwestern Montana in 2008. It substantially impacted a managed herd of about 3,500 free-ranging plains bison ( Bison bison bison) on a large, private ranch southwest of Bozeman, with about 8% mortality and a disproportionate 28% mortality of mature males; a similar high rate occurred in male Rocky Mountain elk ( Cervus canadensis nelson). Grazing herbivores are particularly at risk for anthrax from ingesting spore-contaminated soil and grasses in persistent environmental reservoirs. We predicted areas of mature male bison habitat preference on the landscape by using GPS collar data and a resource selection function model using environmental covariates. We overlaid preferred areas with ecologic niche, model-based predictions of B. anthracis environmental reservoirs to identify areas of high anthrax risk. Overlapping areas were distributed across the ranch and were not confined to pastures associated with the previous outbreak, suggesting that ongoing pasture exclusion alone will not prevent future outbreaks. The data suggested vaccination campaigns should continue for bison, and the results can be used to prioritize carcass surveillance in areas of greatest overlap. PMID- 30016212 TI - Treatment of Sarcoptic Mange in an American Black Bear ( Ursus americanus) with a Single Oral Dose of Fluralaner. AB - Sarcoptic mange in American black bears ( Ursus americanus) is a recent topic of concern in the mid-Atlantic US as accounts of affected bears have increased in recent years. We describe a black bear with sarcoptic mange that was successfully treated with one oral dose of fluralaner. The outcome of this case has positive implications for the treatment options available for free-ranging black bears. PMID- 30016213 TI - Pituitary Abscesses in Four Free-Ranging White-Tailed Deer ( Odocoileus virginianus). AB - Although intracranial abscesses are a well-recognized cause of morbidity and mortality in free-ranging white-tailed deer ( Odocoileus virginianus), reports of pituitary abscesses in this species are scarce. Pituitary abscesses were the cause of neurologic disease in four adult white-tailed deer from the southeastern United States in 2013-15. PMID- 30016214 TI - Reconsidering Oral Rabies Vaccine Bait Uptake Evaluation at Population Level: A Simple, Noninvasive, and Ethical Method by Fecal Survey Using a Physical Biomarker. AB - Tetracycline and rhodamine are bait uptake biomarkers commonly used for decades in oral rabies vaccination campaigns. They require tooth collection and the capture or death of animals. Here, we considered the use of marked baits with plastic beads, a physical biomarker allowing noninvasive scat survey by direct observation in the field. Such methodology would be in compliance with animal welfare concerns. The development of a relative bait uptake estimation on the basis of observation marked scat could indeed be beneficial for the monitoring of oral vaccination programs, especially in programs dedicated to dogs ( Canis familiaris) or protected species. PMID- 30016215 TI - History of schistosomiasis (bilharziasis) in humans: from Egyptian medical papyri to molecular biology on mummies. AB - Schistosomiasis is a parasitic infection that has evolved together with the humankind. Evidence in ancient Egyptian medical papyri or Assyrian medical texts reported signs and symptoms that could resemble schistosomiasis; similarly, some biblical passages describe an epidemic (depicted as a 'curse') that has been hypothesized to be associated with schistosomiasis' spread in Mesopotamia. In the modern era, Theodor Maximilian Bilharz and Patrick Manson (the 'father of tropical medicine') gave an impetus to the knowledge about the parasite and its spread until the present time, when immunoassays and molecular biology on mummies allowed retracing important milestones regarding schistosomiasis' evolution. Schistosomiasis affects more than 200 millions of people worldwide and it is an emblem of how hard it is to prevent, control and treat neglected tropical diseases. Our work reviews the history of schistosomiasis with regard to human infections. PMID- 30016216 TI - Using Video Telehealth to Facilitate Inhaler Training in Rural Patients with Obstructive Lung Disease. AB - BACKGROUND: Proper inhaler technique is important for effective drug delivery and symptom control in chronic obstructive pulmonary disease (COPD) and asthma, yet not all patients receive inhaler instructions. INTRODUCTION: Using a retrospective chart review of participants in a video telehealth inhaler training program, the study compared inhaler technique within and between monthly telehealth visits and reports associated with patient satisfaction. MATERIALS AND METHODS: Seventy-four (N = 74) rural patients prescribed >=1 inhaler participated in three to four pharmacist telehealth inhaler training sessions using teach-to goal (TTG) methodology. Within and between visit inhaler technique scores are compared, with descriptive statistics of pre- and postprogram survey results including program satisfaction and computer technical issues. Healthcare utilization is compared between pre- and post-training periods. RESULTS: Sixty nine (93%) patients completed all three to four video telehealth inhaler training sessions. During the initial visit, patients demonstrated improvement in inhaler technique for metered dose inhalers (albuterol, budesonide/formoterol), dry powder inhalers (formoterol, mometasone, tiotropium), and soft mist inhalers (ipratropium/albuterol) (p < 0.01 for all). Improved inhaler technique was sustained at 2 months (p < 0.01). Ninety-four percent of participants were satisfied with the program. Although technical issues were common, occurring among 63% of attempted visits, most of these visits (87%) could be completed. There was no significant difference in emergency department visits and hospitalizations pre- and post-training. DISCUSSION: This study demonstrated high patient acceptance of video telehealth training and objective improvement in inhaler technique. CONCLUSIONS: Video telehealth inhaler training using the TTG methodology is a promising program that improved inhaler technique and access to inhaler teaching for rural patients with COPD or asthma. PMID- 30016217 TI - Dosimetry as a Catch in Radiobiology Experiments. AB - Experimental radiobiological studies in which the effects of ionizing radiation on a biological model are examined often highlight the biological aspects while missing detailed descriptions of the geometry, sample and dosimetric methods used. Such omissions can hinder the reproducibility and comparability of the experimental data. An application based on the Geant4 simulation toolkit was developed to design experiments using a biological solution placed in a microtube. The application was used to demonstrate the influence of the type of microtube, sample volume and energy of a proton source on the dose distribution across the sample, and on the mean dose in the whole sample. The results shown here are for samples represented by liquid water in the 0.4-, 1.5- and 2.0-ml microtubes irradiated with 20, 30 and 100 MeV proton beams. The results of this work demonstrate that the mean dose and homogeneity of the dose distribution within the sample strongly depend on all three parameters. Furthermore, this work shows how the dose uncertainty propagates into the scored primary DNA damages in plasmid DNA studies using agarose gel electrophoresis. This application is provided freely to assist users in verifying their experimental setup prior to the experiment. PMID- 30016218 TI - Blocking Endogenous H2S Signaling Attenuated Radiation-Induced Long-Term Metastasis of Residual HepG2 Cells through Inhibition of EMT. AB - Recurrence and metastasis of hepatocellular carcinoma (HCC) after radiotherapy are frequently observed in clinical practice. To date, the involved mechanism, endogenous hydrogen sulfide (H2S), has not been well understood and warrants investigation. Here we demonstrated that both single-dose and fractionated irradiation enhanced metastasis of HCC cells both in vitro and in vivo at 20-60 days postirradiation. In particular, a gain in epithelial-mesenchymal transition (EMT) and mesenchymal features was observed. Further experiments revealed that endogenous H2S signaling was constitutively activated after irradiation. Knockdown of cystathionine-gamma-lyase (CSE) or cystathionine-beta-synthase (CBS), two main H2S-producing proteins, significantly diminished the increased expressions of EMT-related proteins induced by radiation through the p38MAPK pathway, leading to impaired invasion and metastasis of the residual HepG2 cells and their xenograft tumors. Moreover, blocking of the H2S pathway increased the radiosensitivity of the HepG2 xenograft tumor. Collectively, our results strongly suggest that endogenous H2S/CSE contributes to the long-term cell invasion and tumor metastasis induced by fractionated exposures and therefore, could become an attractive therapeutic target of HCC to eliminate radiotherapy-induced adverse effects. PMID- 30016220 TI - Antifibrotic Agent Pirfenidone Protects against Development of Radiation-Induced Pulmonary Fibrosis in a Murine Model. AB - Radiation-induced complications of the respiratory system are a common side effect of thoracic radiotherapy with no viable treatment option. Here, we investigated the potential therapeutic effect of the orphan drug pirfenidone for treating radiation-induced pulmonary fibrosis. C57BL/6 mice received a single fraction of 16 Gy to the thorax and were subsequently treated with 300 mg/kg/day pirfenidone for four weeks. Survival and body weight of the mice were quantified. Micro-CT in vivo lung imaging was performed to dynamically observe the developmental process of pulmonary fibrosis. The lungs were excised at the end of the experiment and evaluated for histological changes. Compared to the irradiated mice that received no pirfenidone, mice treated with pirfenidone after irradiation had an extended median survival time (>140 days vs. 73 days, P < 0.01). The accumulation of collagen and fibrosis in lung tissues after irradiation was decreased with pirfenidone treatment. Pirfenidone also reduced the expression of TGF-beta1 and phosphorylation of Smad3 in lung tissues. The dose level of Pirfenidone used in this study attenuated pulmonary fibrosis and prolonged the life span of irradiated mice. It may offer a promising approach to treat or minimize radiation-induced pulmonary fibrosis. PMID- 30016221 TI - Prevalence, pattern and correlates of work-related musculoskeletal disorders among school teachers in Enugu, Nigeria. AB - INTRODUCTION: There is insufficient literature on the prevalence of and risk factors for work-related musculoskeletal disorders (MSDs) among teachers in Nigeria. This study aimed to investigate the prevalence of work-related MSDs and their associations with occupational and socio-demographic factors of Nigerian based school teachers. MATERIALS AND METHODS: Socio-demographic and occupational characteristics, prevalence and pattern of work-related MSDs of 352 school teachers (age 24-60 years) were investigated using a standard Nordic questionnaire. Data were summarized with descriptive statistics. Univariate and multivariate analyses were used to assess predictors of work-related MSDs. RESULTS: The results showed that 70.2% of the teachers had work-related MSDs predominantly in the shoulder (62.3%) and neck (57.9%) regions. Most of the studied socio-demographic features and anthropometric and occupational characteristics were significantly associated (p < 0.05) with MSDs in at least one body region. CONCLUSIONS: There was a prevalence of work-related MSDs among the teachers. Advanced educational qualification, elevated teaching boards, teaching experience over 10 years and age range of 35-50 years were the major predictors of MSDs. PMID- 30016219 TI - Fibronectin Produced by Cerebral Endothelial and Vascular Smooth Muscle Cells Contributes to Perivascular Extracellular Matrix in Late-Delayed Radiation Induced Brain Injury. AB - Late-delayed radiation-induced brain injury (RIBI) is a major adverse effect of fractionated whole-brain irradiation (fWBI). Characterized by progressive cognitive dysfunction, and associated cerebrovascular and white matter injury, RIBI deleteriously affects quality of life for cancer patients. Despite extensive morphological characterization of the injury, the pathogenesis is unclear, thus limiting the development of effective therapeutics. We previously reported that RIBI is associated with increased gene expression of the extracellular matrix (ECM) protein fibronectin (FN1). We hypothesized that fibronectin contributes to perivascular ECM, which may impair diffusion to the dependent parenchyma, thus contributing to the observed cognitive decline. The goal of this study was to determine the localization of fibronectin in RIBI and further characterize the composition of perivascular ECM, as well as identify the cell of origin for FN1 by in situ hybridization. Briefly, fibronectin localized to the vascular basement membrane of morphologically normal blood vessels from control comparators and animals receiving fWBI, and to the perivascular space of edematous and fibrotic vascular phenotypes of animals receiving fWBI. Additional mild diffuse parenchymal staining in areas of vascular injury suggested blood-brain-barrier disruption and plasma fibronectin extravasation. Perivascular ECM lacked amyloid and contained lesser amounts of collagens I and IV, which localized to the basement membrane. These changes occurred in the absence of alterations in microvascular area fraction or microvessel density. Fibronectin transcripts were rarely expressed in control comparators, and were most strongly induced within cerebrovascular endothelial and vascular smooth muscle cells after fWBI. Our results demonstrate that fibronectin is produced by cerebrovascular endothelial and smooth muscle cells in late-delayed RIBI and contributes to perivascular ECM, which we postulate may contribute to diffusion barrier formation. We propose that pathways that antagonize fibronectin deposition and matrix assembly or enhance degradation may serve as potential therapeutic targets in RIBI. PMID- 30016222 TI - Occurrence of Orientia tsutsugamushi, the Etiological Agent of Scrub Typhus in Animal Hosts and Mite Vectors in Areas Reporting Human Cases of Acute Encephalitis Syndrome in the Gorakhpur Region of Uttar Pradesh, India. AB - Outbreaks of acute encephalitis syndrome (AES) with high fatality and disability, are reported every year in the Gorakhpur region of Uttar Pradesh, India, with the etiology of >60% of the cases being attributed to scrub typhus. In the present study, the prevalence of Orientia tsutsugamushi, the etiological agent of scrub typhus, was investigated among animal hosts and their ectoparasitic trombiculid mites prevalent in AES-reported areas of Gorakhpur. A total of 154 rodents/shrews were collected using 777 Sherman traps set in 12 study villages, and the overall trap rate was 19.8%. In total, 2726 trombiculid mites belonging to 12 species were collected from 154 rodents/shrews trapped. The shrew mouse Suncus murinus was the predominant animal species (78.6%) collected. The principal vector mite Leptotrombidium deliense was the predominant species (82.7%), and its index was 14.6 per animal. Of 114 rodent/shrew sera samples screened through the Weil-Felix test, 57% were positive for antibodies against O. tsutsugamushi. Of 128 blood samples tested by polymerase chain reaction (PCR), one rodent sample was positive for the gene encoding 56 kDa protein and 25 for 60 kDa. Among 2726 mite samples tested as 315 pools through nested PCR, seven pools were positive for 56 kDa gene. Phylogenetic analysis confirmed circulation of Gilliam, Karp, and TA678 serotypes of O. tsutsugamushi in Gorakhpur. The study clearly demonstrated natural infection of O. tsutsugamushi in both small-animal hosts and vector mites in the AES-reporting villages of Gorakhpur, which confirms transmission of the scrub typhus pathogen in this region. The high infestation rate of L. deliense with O. tsutsugamushi infection indicates that the people living in the rural villages of Gorakhpur are at risk of infection with scrub typhus, which might lead to AES. PMID- 30016223 TI - Fleas and Ticks of Red Foxes as Vectors of Canine Bacterial and Parasitic Pathogens, in Slovakia, Central Europe. AB - The present survey aimed to investigate flea and tick fauna parasitizing Slovak red fox populations with special emphasis on canine pathogens they transmit. A total of 407 fleas and 105 ticks were collected from 90 red foxes from two geographically distant regions. Seven flea species (Chaetopsylla globiceps, Pulex irritans, Archaeopsylla erinacei, Chaetopsylla rothschildi, Chaetopsylla trichosa, Ctenocephalides canis, and Ctenopthalmus assimilis) and three species of hard ticks (Ixodes ricinus, Ixodes hexagonus, Haemaphysalis concinna) were recorded on sampled animals. Consequently, the DNA of five different pathogen taxa was confirmed in collected arthropod vectors: Bartonella spp. (in P. irritans, Ch. globiceps, and Ct. assimilis), Rickettsia spp. (in A. erinacei, I. ricinus, I. hexagonus, and H. concinna), Anaplasma phagocytophilum (in I. ricinus), Theileria sp. (in Ch. globiceps and H. concinna), and Hepatozoon canis (in I. ricinus and I. hexagonus). Mycoplasma spp., Dipylidium caninum, and Acanthocheilonema reconditum were not found in fleas or ticks in this study. PMID- 30016224 TI - Phreatobacter cathodiphilus sp. nov., isolated from a cathode of a microbial fuel cell. AB - A novel bacterial strain, S-12T, of a member of the genus Phreatobacterwas isolated from a cathode of a microbial fuel cell from Suwon City, South Korea. Cells were Gram-staining-negative, aerobic, non-sporulating rods, motile by means of a polar flagellum, and formed white round colonies. The strain grew at the range of 10-40 degrees C (optimum, 28-30 degrees C), pH 6.0-10.0 (optimum 7.0 8.0) and 0-1 % NaCl. The 16S rRNA gene sequence analysis showed the relatedness of S-12T to Phreatobacter stygiusYC6-17T (98.2 %) and Phreatobacter oligotrophusPI_21T (98.1 %). The major respiratory quinone was ubiquinone Q-10. Polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and an unidentified lipid. The major fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The DNA G+C content was 69.3 mol%. On the basis of its differences from species of the genus Phreatobacter with validly published names, strain S-12T is identified as representing a novel species, for which the proposed name is Phreatobactercathodiphilus sp. nov., with S-12T as the type strain (=KACC 18497T=JCM 31612T). PMID- 30016225 TI - Evaluation of the genomic diversity of viruses infecting bacteria, archaea and eukaryotes using a common bioinformatic platform: steps towards a unified taxonomy. AB - Genome Relationship Applied to Virus Taxonomy (GRAViTy) is a genetics-based tool that computes sequence relatedness between viruses. Composite generalized Jaccard (CGJ) distances combine measures of homology between encoded viral genes and similarities in genome organizational features (gene orders and orientations). This scoring framework effectively recapitulates the current, largely morphology and phenotypic-based, family-level classification of eukaryotic viruses. Eukaryotic virus families typically formed monophyletic groups with consistent CGJ distance cut-off dividing between and within family divergence ranges. In the current study, a parallel analysis of prokaryotic virus families revealed quite different sequence relationships, particularly those of tailed phage families (Siphoviridae, Myoviridae and Podoviridae), where members of the same family were generally far more divergent and often not detectably homologous to each other. Analysis of the 20 currently classified prokaryotic virus families indeed split them into 70 separate clusters of tailed phages genetically equivalent to family level assignments of eukaryotic viruses. It further divided several bacterial (Sphaerolipoviridae, Tectiviridae) and archaeal (Lipothrixviridae) families. We also found that the subfamily-level groupings of tailed phages were generally more consistent with the family assignments of eukaryotic viruses, and this supports ongoing reclassifications, including Spounavirinae and Vi1virus taxa as new virus families. The current study applied a common benchmark with which to compare taxonomies of eukaryotic and prokaryotic viruses. The findings support the planned shift away from traditional morphology-based classifications of prokaryotic viruses towards a genome-based taxonomy. They demonstrate the feasibility of a unified taxonomy of viruses into which the vast body of metagenomic viral sequences may be consistently assigned. PMID- 30016226 TI - The potential of different molecular biology methods in tracking clones of Acinetobacter baumannii in an ICU setting. AB - PURPOSE: This study aimed to characterize A. baumannii strains isolated from patients in an intensive care unit (ICU) setting. Molecular techniques were used to study clonal relatedness and determine a fast, efficient and cost-effective way of detecting persistent clones. METHODOLOGY: A. baumannii (n=17) were obtained in June and November 2015 from a single ICU setting in South India. DNA typing methods such as multilocus sequence typing (MLST), single-locus sequence based typing (SBT) and DNA fingerprinting PCRs (M13, DAF4 and ERIC2) were employed to understand the association of clones. PCRs were performed for the antimicrobial resistance genes ISAba1-blaOXA-51-like, ISAba1-blaOXA-23-like, blaNDM-1, blaPER-7 and blaTEM-1, and the virulence genes cpa 1, cpa2 and pkf. RESULTS: The MLST showed some degree of corroboration with the other DNA typing methods. The M13 PCR was found to give better results than the other fingerprinting methods. ST848 (CC92) was the dominant strain isolated in both June and November. All isolates were blaOXA-51-like-positive, with 16 having ISAba1 upstream of the blaOXA-51-like and blaOXA-23-like genes. Genes such as blaNDM-1 (23 %, n=4), blaPER-7 (58.8 %, n=10), pkf (82 %, n=14), blaTEM-1 (5.8 %, n=1), cpa1 (5.8 %, n=1) and cpa2 (5.8 %, n=1) were also detected. CONCLUSION: M13 PCR can be used in routine environmental surveillance for the detection of persistent antibiotic resistant clones in an ICU setting because of its reliability and simplicity. Further studies based on greater sample size, conducted at the multi-centre level, can give us a better understanding of the reliability of the molecular methods that can be used for the detection of persistent clones in the hospital setting. PMID- 30016227 TI - Amylibacter kogurei sp. nov., a novel marine alphaproteobacterium isolated from the coastal sea surface microlayer of a marine inlet. AB - A novel Gram-negative bacterium, designated 4G11T, was isolated from the sea surface microlayer of a marine inlet. On the basis of 16S rRNA gene sequence analysis, the strain showed the closest similarity to Amylibacter ulvae KCTC 32465T (99.0 %). However, DNA-DNA hybridization values showed low DNA relatedness between strain 4G11T and its close phylogenetic neighbours, Amylibacter marinus NBRC 110140T (8.0+/-0.4 %) and Amylibacter ulvae KCTC 32465T (52.9+/-0.9 %). Strain 4G11T had C18 : 1, C16 : 0 and C18 : 2 as the major fatty acids. The only isoprenoid quinone detected for strain 4G11T was ubiquinone-10. The major polar lipids were phosphatidylglycerol, phosphatidylcholine, one unidentified polar lipid, one unidentified phospholipid and one unidentified aminolipid. The DNA G+C content of strain 4G11T was 50.0 mol%. Based on phenotypic and chemotaxonomic characteristics and analysis of the 16S rRNA gene sequence, the novel strain should be assigned to a novel species, for which the name Amylibacter kogurei sp. nov. is proposed. The type strain of Amylibacter kogurei is 4G11T (KY463497=KCTC 52506T=NBRC 112428T). PMID- 30016228 TI - Cohnella kolymensis sp. nov., a novel bacillus isolated from Siberian permafrost. AB - A facultative anaerobic, rod-shaped, endospore-forming and non-motile bacterium was isolated from permafrost sediment cores in the Kolyma lowland, Siberia, Russia. The permafrost isolate clustered with members of the genus Cohnella on the basis of 16S rRNA gene sequence analysis and showed the highest sequence similarity to Cohnella saccharovorans CJ22T (96.3 %), followed by Cohnella cellulosilytica FCN3-3T (96.0 %) and Cohnella panacarvi KCTC 13060T (96.0 %). The chemotaxonomic characteristics (quinone system, cellular fatty acids and polar lipid profile) of strain 20.16T were consistent with members of the genus Cohnella. The peptidoglycan diaminoacids included meso-diaminopimelic acid and a small amount of ll-diaminopimelic acid. The molar ratio and composition of major amino acids (meso-diaminopimelic acid, alanine, and glutamic acid) correspond to the peptydoglycan type A1gamma. The estimated genome size of strain 20.16T is 4.34 Mb (lower than those in other Cohnella species). The genome has a G+C content of 50.5 mol% and encodes 4843 predicted genes, of these 4740 are protein coding ones. The results of chemotaxonomic, physiological and biochemical characterization allowed clear differentiation of strain 20.16T from the closest Cohnella species. Based on data provided, a new species Cohnella kolymensis sp. nov. is proposed, with 20.16T (=VKM B-2846T=DSM 104983T) as the type strain. PMID- 30016229 TI - Emcibacter congregatus sp. nov., isolated from sediment cultured in situ. AB - A Gram-negative, aerobic, motile, rod-shaped, pale-yellow bacterial strain, designated as ZYLT, isolated from a cultured in situ sediment sample collected from the East China Sea coast, was studied using a polyphasic taxonomic approach. Strain ZYLT grew at 4-30 degrees C (optimum, 25 degrees C), at pH 6.0-8.5 (pH 7.0) and with 0-7.0 % (w/v) NaCl (2.0 %). Results of phylogenetic analysis based on 16S rRNA gene sequences clearly showed that strain ZYLT and Emcibacter nanhaiensis HTCJW17T, which was most closely related to strain ZYLT with 93.6 % sequence similarity, clustered together. The genomic DNA G+C content was 51.5 % (genome sequence). The quinone system was composed only of ubiquinone-10. Strain ZYLT possessed C18 : 1omega7c and/or C18 : 1omega6c (summed feature 8), iso-C15 : 0 2-OH and/or C16 : 1omega7c (summed feature 3), C14 : 0 2-OH and C14 : 0 as the major fatty acids. The content of summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1omega7c) in strain ZYLT was far greater than that in E. nanhaiensis. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, three unidentified aminophospholipids, three unidentified phospholipids, one unidentified aminolipid and four unidentified lipids. One unidentified aminophospholipid and two unidentified lipids present in strain ZYLT were not found in E. nanhaiensis in this research. On the basis of phenotypic, phylogenetic and chemotaxonomic data, strain ZYLT (=KCTC 62328T=JCM 32378T=MCCC 1K03526T) represents a novel species of the genus Emcibacter for which the name Emcibacter congregatus sp. nov. is proposed. PMID- 30016230 TI - Solitalea longa sp. nov., isolated from freshwater and emended description of the genus Solitalea. AB - A Gram-negative, strictly aerobic, oxidase-positive, catalase-negative and yellow pigmented bacterium, designated strain HR-AVT, was isolated from a water sample of the Han River. Cells were elongated rods with gliding motility without flagellum. Growth was observed at 5-30 degrees C (optimum, 20 degrees C), pH 7 8 and 0-0.5 % NaCl. The major respiratory quinone was menaquinone-7. The major fatty acids were iso-C15 : 0, summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and anteiso-C15 : 0. The polar lipids comprised phosphatidylethanolamine, an unidentified amino lipid and five unidentified lipids. The DNA G+C content of strain HR-AVT was 38.4 mol%. Results of phylogenetic analysis based on 16S rRNA gene sequences revealed that strain HR AVTbelonged to the family Sphingobacteriaceae in the phylum Bacteroidetes and formed a phylogenic lineage with Solitalea canadensis DSM 3403T and Solitalea koreensis R2A36-4T. Strain HR-AVT was most closely related to S. canadensis DSM 3403T and S. koreensis R2A36-4T with 97.3 and 94.0 % 16S rRNA gene sequence similarities, respectively, and then had low similarities (below 90.9 %) with other bacteria with validly published names. Average nucleotide identity and in silico DNA-DNA hybridization values between strain HR-AVT and S. canadensis were 74.0 and 19.7 %, respectively. Based on these results, strain HR-AVT represents a novel species of the genus Solitalea, for which the name Solitalea longa sp. nov. is proposed. The type strain is HR-AVT (=KACC 19411T=JCM 32259T). An emended description of the genus Solitalea is also proposed. PMID- 30016231 TI - In vitro activity of beta-lactams in combination with avibactam against multidrug resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Achromobacter xylosoxidans isolates from patients with cystic fibrosis. AB - The in vitro activity of anti-pseudomonal beta-lactams in combination with avibactam was evaluated against 54 multidrug-resistant non-fermenting Gram negative bacilli isolated from cystic fibrosis patients. Avibactam increased and/or restored the antibacterial activities of ceftazidime and aztreonam against Pseudomonas aeruginosa and Stenotrophomonas maltophilia, respectively. No beta lactam-avibactam combination was active against Achromobacter xylosoxidans. PMID- 30016232 TI - Pasteurella multocida inactivated with ferric chloride and adjuvanted with bacterial DNA is a potent and efficacious vaccine in Balb/c mice. AB - PURPOSE: Pasteurella multocida (P. multocida) is a principal pathogen of domestic animals and an opportunistic pathogen of humans. It is the causative agent of pneumonia and haemorrhagic septicaemia in cattle, sheep and goats, fowl cholera in chickens and progressive atrophic rhinitis in swine. In this study, we investigated the humoral and cellular immune responses and protective immunity conferred by an iron-inactivated vaccine with bacterial DNA (IIV+bDNA) as an adjuvant in mice. METHODOLOGY: P. multocida was grown in BHI broth, inactivated with formalin and FeCl3 and adjuvanted with alum and bDNA. Mice were immunized with two whole-cell inactivated vaccine doses 2 weeks apart. The animals were challenged 4 weeks after booster immunization. Immunogens (vaccines and bDNA) posed no safety problems when mice were injected subcutaneously (s/c) with these preparations. The serum antibody titres were tested by ELISA. At 28 days post immunization, cell-mediated immunity responses were determined. The responses were measured by assay of IL-6 and IL-12 in lymphocyte spleen culture supernatants. RESULTS: ELISA results showed that the levels of antibodies in iron inactivated with bDNA adjuvant groups were higher than in the formalin inactivated with alum adjuvant vaccine group. The protection rate of IIV+bDNA adjuvant vaccine was superior to that of the other vaccines and it protected 100 % of the challenge group mice. Following immunization, bDNA promoted increased production of interleukins compared to the control groups. CONCLUSION: These studies indicate that bDNA is effective as an immune adjuvant, and along with stimulatory bDNA represent promising new humoral and cellular immune enhancers for vaccination applications. In addition, this vaccine is able to provide long term protection against infection. PMID- 30016233 TI - Solimonas fluminis sp. nov., isolated from a freshwater river. AB - A strictly aerobic, catalase-negative and oxidase-positive bacterium (HR-BBT), isolated from a water sample of the Han River, was taxonomically studied using a polyphasic approach. Cells were Gram-stain-negative motile rods with a polar flagellum. The strain grew at 20-35 degrees C and pH 7-8 and in the absence of NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain HR-BBT belonged to the family Nevskiaceae in the phylum Proteobacteria and formed a phylogenic lineage with members of the genus Solimonas. A comparison of the 16S rRNA gene sequences of strain HR-BBT and the type strains of closely related species of the genus Solimonas showed that it shared highest sequence similarity with Solimonas terrae KIS83-12T (94.9 %), Solimonas soli DCY12T (94.8 %), Solimonas variicoloris MN28T (94.4 %) and Solimonas flava CW-KD 4T (94.2 %). The fatty acids of the strain consisted of summed features 8 (comprising C18 : 1omega6c and/or C18 : 1omega7c) and 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c), C16 : 0 and C12 : 0 as major components. The polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, three unidentified phospholipids and an unidentified lipid. Ubiquinone-8 was detected as the sole respiratory quinone. The DNA G+C content of strain HR-BBT was 68.5 mol%. Based on the genotypic, chemotaxonomic and phenotypic analyses, strain HR BBT represents a novel species of the genus Solimonas, for which the name Solimonas fluminis sp. nov. is proposed. The type strain is HR-BBT (=KACC 19410T=JCM 32268T). PMID- 30016234 TI - Arcobacter haliotis Tanaka et al. 2017 is a later heterotypic synonym of Arcobacter lekithochrous Dieguez et al. 2017. AB - The draft whole-genome sequence of Arcobacter haliotis strain LMG 28652T was obtained and compared against the type strain of Arcobacter lekithochrous LFT 1.7T. High similarity was found between the two strains, showing average nucleotide identity and in silico DNA-DNA hybridization values of 98.40 and 86.10 %, respectively. These values indicated that both genomes belonged to the same species, confirming the evidences derived from the phylogenetic analysis performed with the 16S rRNA gene and the concatenated sequences of five housekeeping genes. In addition, the metabolic, physiological and chemotaxonomic features of A. haliotis LMG 28652T were shown to be congruent with those of A. lekithochrous. We conclude that Arcobacter haliotis Tanaka et al. 2017 is a later heterotypic synonym of Arcobacter lekithochrousDieguez et al. 2017. PMID- 30016235 TI - Saccharospirillum mangrovi sp. nov., a bacterium isolated from mangrove sediment. AB - A Gram-negative, spirilla, non-spore-forming, motile and strictly aerobic bacterium, designated HK-33T, was isolated from a mangrove sediment sample in Haikou city, Hainan Province, China. Strain HK-33T was able to grow at 10-45 degrees C (optimum 37 degrees C), 0.5-12.0 % (w/v) NaCl (2.0 %, w/v) and pH 5.5 8.5 (pH 7.0). The major cellular fatty acids were C16 : 0 and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). Ubiquinone-8 was the predominant respiratory quinone, and Q-9 was present in trace amounts. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified phospholipids, two unidentified glycolipids, an unidentified aminophosphoglycolipid and two unidentified lipids. The DNA G+C content was 57.3 mol%. According to 16S rRNA gene sequences similarity, strain HK-33T shared 98.6 %, 96.4%, 95.7 and 94.9 % sequence similarities to the species Saccharospirillum correiae CPA1T, Saccharospirillum impatiens EL-105T, Saccharospirillum salsuginis YIM-Y25T and Saccharospirillum aestuarii IMCC 4453T, respectively. Phylogenetic analysis showed that strain HK 33T was clustered with S. correiae CPA1T, S. impatiens EL-105T, S. salsuginis YIM Y25T and S. aestuarii IMCC 4453T. Results of DNA-DNA hybridization analysis revealed that strain HK-33T shared 36.3+/-1.7 % DNA relatedness with S. correiae CPA1T. On the basis of its phenotypic, chemotaxonomic and genotypic characteristics, strain HK-33T is considered to represent a novel species in the genus Saccharospirillum, for which the name Saccharospirillummangrovi sp. nov. is proposed. The type strain is HK-33T (=KCTC 62178T=MCCC 1K03440T). PMID- 30016236 TI - Direct Detection of penA Gene Associated with Ceftriaxone-Resistant Neisseria gonorrhoeae FC428 Strain by Using PCR. AB - The ceftriaxone-resistant Neisseria gonorrhoeae FC428 clone was first observed in Japan in 2015, and in 2017, it was documented in Denmark, Canada, and Australia. Here, we describe a PCR for direct detection of the penA gene associated with this strain that can be used to enhance surveillance activities. PMID- 30016237 TI - Plasmodium ovale wallikeri in Western Lowland Gorillas and Humans, Central African Republic. AB - Human malaria parasites have rarely been reported from free-ranging great apes. Our study confirms the presence of the human malaria parasite Plasmodium ovale wallikeri in western lowland gorillas and humans in Dzanga Sangha Protected Areas, Central African Republic, and discusses implications for malaria epidemiology. PMID- 30016238 TI - Leptospirosis as Cause of Febrile Icteric Illness, Burkina Faso. AB - Patients in Burkina Faso who sought medical attention for febrile jaundice were tested for leptospirosis. We confirmed leptospirosis in 27 (3.46%) of 781 patients: 23 (2.94%) tested positive using serologic assays and 4 (0.51%) using LipL32 PCR. We further presumed leptospirosis in 16 (2.82%) IgM-positive specimens. PMID- 30016239 TI - Identification of Peste des Petits Ruminants Virus, Georgia, 2016. AB - A phylogenetic analysis of samples taken from reported outbreaks of peste des petits ruminants virus (PPRV) in Georgia revealed a closer relationship to viruses from northern and eastern Africa than to viruses from countries closer to Georgia. This finding has crucial implications for the control of PPRV in the region. PMID- 30016240 TI - Isolation of Complete Equine Encephalitis Virus Genome from Human Swab Specimen, Peru. AB - While studying respiratory infections in Peru, we identified Venezuelan equine encephalitis virus (VEEV) in a nasopharyngeal swab, indicating that this alphavirus can be present in human respiratory secretions. Because VEEV may be infectious when aerosolized, our finding is relevant for the management of VEEV infected patients and for VEEV transmission studies. PMID- 30016241 TI - Death from Transfusion-Transmitted Anaplasmosis, New York, USA, 2017. AB - We report a death from transfusion-transmitted anaplasmosis in a 78-year-old man. The patient died of septic shock 2 weeks after a perioperative transfusion with erythrocytes harboring Anaplasma phagocytophilum. The patient's blood specimens were positive for A. phagocytophilum DNA beginning 7 days after transfusion; serologic testing remained negative until death. PMID- 30016242 TI - Distinguishing Zika and Dengue Viruses through Simple Clinical Assessment, Singapore. AB - Dengue virus and Zika virus coexist in tropical regions in Asia where healthcare resources are limited; differentiating the 2 viruses is challenging. We showed in a case-control discovery cohort, and replicated in a validation cohort, that the diagnostic indices of conjunctivitis, platelet count, and monocyte count reliably distinguished between these viruses. PMID- 30016243 TI - Isolation of Candida auris from Ear of Otherwise Healthy Patient, Austria, 2018. AB - The emerging pathogen Candida auris is isolated mostly from hospitalized patients and often shows multidrug resistance. We report on the isolation of this yeast in Austria from an outpatient's auditory canal. The isolate showed good susceptibility against antifungals except for echinocandins; the patient was treated successfully with topical administration of nystatin. PMID- 30016244 TI - Paenibacillus assamensis in Joint Fluid of Man with Suspected Tularemia, China. AB - Paenibacillus assamensis is a bacterium usually found in warm springs. We detected P. assamensis in a man with suspected tularemia. The strain isolated from the man's knee joint fluid was identified as P. assamensis after analysis of a homologous sequence of the 16S rRNA gene. PMID- 30016245 TI - Capillaria Ova and Diagnosis of Trichuris trichiura Infection in Humans by Kato Katz Smear, Liberia. AB - We examined human stool samples from Liberia for soil-transmitted helminth ova by Kato-Katz smear and by quantitative PCR. Twenty-five samples were positive for Trichuris trichiura by smear but negative by quantitative PCR. Reexamination of samples showed that they contained Capillaria eggs that resemble T. trichiura in Kato-Katz smears. PMID- 30016246 TI - Epidemiology of Diphyllobothrium nihonkaiense Diphyllobothriasis, Japan, 2001 2016. AB - We report 958 cases of cestodiasis occurring in Japan during 2001-2016. The predominant pathogen was Diphyllobothrium nihonkaiense tapeworm (n = 825), which caused 86.1% of all cases. The other cestode species involved were Taenia spp. (10.3%), Diplogonoporus balaenopterae (3.3%), and Spirometra spp. (0.2%). We estimated D. nihonkaiense diphyllobothriasis incidence as 52 cases/year. We observed a predominance of cases during March-July, coinciding with the cherry salmon and immature chum salmon fishing season, but cases were present year round, suggesting that other fish could be involved in transmission to humans. Because of increased salmon trade, increased tourism in Japan, and lack of awareness of the risks associated with eating raw fish, cases of D. nihonkaiense diphyllobothriasis are expected to rise. Therefore, information regarding these concerning parasitic infections and warnings of the potential risks associated with these infections must be disseminated to consumers, food producers, restaurant owners, physicians, and travelers. PMID- 30016247 TI - Misdiagnosis of Babesiosis as Malaria, Equatorial Guinea, 2014. AB - We report a case of babesiosis, caused by Babesia microti, in a missionary who worked in Equatorial Guinea but also visited rural Spain. The initial diagnosis, based on clinical features and microscopy, was malaria. The patient's recovery was delayed until she received appropriate treatment for babesiosis. PMID- 30016248 TI - Unilateral Phrenic Nerve Palsy in Infants with Congenital Zika Syndrome. AB - Since the first identification of neonatal microcephaly cases associated with congenital Zika virus infection in Brazil in 2015, a distinctive constellation of clinical features of congenital Zika syndrome has been described. Fetal brain disruption sequence is hypothesized to underlie the devastating effects of the virus on the central nervous system. However, little is known about the effects of congenital Zika virus infection on the peripheral nervous system. We describe a series of 4 cases of right unilateral diaphragmatic paralysis in infants with congenital Zika syndrome suggesting peripheral nervous system involvement and Zika virus as a unique congenital infectious cause of this finding. All the patients described also had arthrogryposis (including talipes equinovarus) and died from complications related to progressive respiratory failure. PMID- 30016249 TI - Autochthonous Hepatitis E during Pregnancy, France. AB - Acute hepatitis E virus infections occurred during the third trimester in 2 pregnant women in France who sought treatment with nonspecific symptoms or asymptomatic elevation of liver enzymes. Infection cleared quickly in both women. We detected no hepatitis E RNA in 1 newborn's feces at 3 weeks of age. PMID- 30016250 TI - Visceral Leishmaniasis in Traveler to Guyana Caused by Leishmania siamensis, London, UK. PMID- 30016251 TI - Progressive Multifocal Leukoencephalopathy after Treatment with Nivolumab. AB - Progressive multifocal leukoencephalopathy (PML) is increasingly being reported in patients undergoing immunotherapy. We report a case of progressive multifocal leukoencephalopathy after treatment with nivolumab, a PD-1 blocker that is used to restore impaired T-cell responses in patients with cancer and infections. Data for 4 other cases were obtained from pharmacovigilance databases. PMID- 30016252 TI - Coxiella burnetii Endocarditis and Meningitis, California, USA, 2017. AB - The epidemiology of Coxiella burnetii infection in the United States is not well characterized. We report a case-patient with C. burnetii endocarditis and meningitis. Infection was diagnosed by detecting high serologic titers for C. burnetii and confirmed by sequencing of C. burnetii 16S rRNA isolated from resected valvular tissue and PCR of cerebrospinal fluid. PMID- 30016253 TI - Visceral Leishmaniasis in Traveler to Guyana Caused by Leishmania siamensis, London, UK. PMID- 30016254 TI - Probable Locally Acquired Babesia divergens-Like Infection in Woman, Michigan, USA. AB - We report an asplenic patient who was infected with Babesia divergens-like/MO-1. The clinical course was complicated by multiorgan failure that required intubation and dialysis. The patient recovered after an exchange transfusion and antimicrobial drug therapy. Physicians should be alert for additional cases, particularly in asplenic persons. PMID- 30016255 TI - Dapsone Resistance in Leprosy Patients Originally from American Samoa, United States, 2010-2012. AB - Skin biopsies from US leprosy patients were tested for mutations associated with drug resistance. Dapsone resistance was found in 4 of 6 biopsies from American Samoa patients. No resistance was observed in patients from other origins. The high rate of dapsone resistance in patients from American Samoa warrants further investigation. PMID- 30016257 TI - Seroprevalence of Toxoplasma gondii in commensal rodents sampled across Senegal, West Africa. AB - Risks related to Toxoplasma gondii infection in humans remain poorly known in Senegal. Although rodent surveys could help to assess the circulation of T. gondii, they have seldom been set up in sub-Saharan Africa. The aim of this study was to examine Toxoplasma seroprevalence in rodents from villages and towns across Senegal. Rodents were sampled in 40 localities using a standardised trapping protocol. Detection of T. gondii antibodies was performed on 1205 rodents, using a modified agglutination test (MAT) technique. Seroprevalence data were analysed depending on geography, the local rodent community, and individual characteristics of the rodent hosts. We found 44 seropositive rodents from four different species (Mastomys erythroleucus, Mastomys natalensis, Mus musculus domesticus, Rattus rattus). Toxoplasma seroprevalence was low, averaging 4% in the localities. Higher Toxoplasma seroprevalence (up to 24%) was found in northern Senegal, a region known to be the heart of pastoral herding in the country. PMID- 30016256 TI - Case Definition of Chronic Pulmonary Aspergillosis in Resource-Constrained Settings. AB - Chronic pulmonary aspergillosis (CPA) is a recognized complication of pulmonary tuberculosis (TB). In 2015, the World Health Organization reported 2.2 million new cases of nonbacteriologically confirmed pulmonary TB; some of these patients probably had undiagnosed CPA. In October 2016, the Global Action Fund for Fungal Infections convened an international expert panel to develop a case definition of CPA for resource-constrained settings. This panel defined CPA as illness for >3 months and all of the following: 1) weight loss, persistent cough, and/or hemoptysis; 2) chest images showing progressive cavitary infiltrates and/or a fungal ball and/or pericavitary fibrosis or infiltrates or pleural thickening; and 3) a positive Aspergillus IgG assay result or other evidence of Aspergillus infection. The proposed definition will facilitate advancements in research, practice, and policy in lower- and middle-income countries as well as in resource constrained settings. PMID- 30016258 TI - High-dose ivermectin in malaria and other parasitic diseases: a new step in the development of a neglected drug. AB - We highlight the absence of high-level evidence from dose-ranging studies regarding the use of oral ivermectin in susceptible parasitic diseases. We provide published data supporting the use of a higher dosage regimen of ivermectin in malaria and difficult-to-treat head lice, and announce an ongoing randomized clinical trial in severe scabies. PMID- 30016259 TI - A novel approach for electroanalytical determinations employing discharge of pseudocapacitor by electroactive species. AB - In this paper, we introduce a novel approach for the detection of electroactive analytes by using oxidant species accumulated in pseudocapacitors surface. We demonstrated that pseudocapacitors can be quickly discharged when in contact with electroactive species. Thus, the variation of potential can be monitored during the discharging process and correlated with the analyte concentration. Based on this, two electroanalytical methods were proposed: continuous discharging detection and pulsed discharging detection. As a proof of concept, these methods were employed for glucose, fructose and sucrose detection using an ion chromatograph containing an electrochemical detector. Copper|cupric oxide in alkaline medium was used as the pseudocapacitive system. The obtained results proved to be very promising and the analytical curves showed good linearity in both methods. In addition, this novel approach for the detection of saccharides based on potential variation as a result of the discharging of the pseudocapacitor in contact with the analyte is very attractive because it does not require current reading. Therefore, our approach can be applied to other pseudocapacitive systems, opening new possibilities for several electroanalytical applications. PMID- 30016260 TI - Combinations of NIR, Raman spectroscopy and physicochemical measurements for improved monitoring of solvent extraction processes using hierarchical multivariate analysis models. AB - The reliability of chemical processes can be greatly improved by implementing inline monitoring systems. Combining multivariate analysis with non-destructive sensors can enhance the process without interfering with the operation. We present here hierarchical models using both principal component analysis and partial least square analysis developed for different chemical components representative of solvent extraction process streams. A training set of 380 samples and an external validation set of 95 samples were prepared and Near infrared and Raman spectral data as well as conductivity under variable temperature conditions were collected. The results from the models indicate that careful selection of the spectral range is important. By compressing the data through Principal Component Analysis (PCA), we lower the rank of the data set to its most dominant features while maintaining the key principal components to be used in the regression analysis. Within the studied data set, concentration of five chemical components were modeled; total nitrate (NO3-), total acid (H+), neodymium (Nd3+), sodium (Na+), and ionic strength (I.S.). The best overall model prediction for each of the species studied used a combined data set comprised of complementary techniques including NIR, Raman, and conductivity. Our study shows that chemometric models are powerful but requires significant amount of carefully analyzed data to capture variations in the chemistry. PMID- 30016261 TI - Entrapment of bimetallic CoFeSe2 nanosphere on functionalized carbon nanofiber for selective and sensitive electrochemical detection of caffeic acid in wine samples. AB - The ever-increasing requirement of an electrochemical sensor in various paramedical and industrial applications, the recent research is motivated to fabricate a new type of electrode material with unique electrochemical properties for quantitative detection of various target analytes. Recently, the metal diselenides have been interested in a broad range of electrochemical applications due to their interesting electrocatalytic performances. Despite the metal diselenides have been widely focused on hydrogen evolution reaction (HER) and oxygen reduction reaction (ORR), it is not much focused on electrochemical sensor. For the first time, the bimetallic cobalt-iron diselenide nanosphere entrapped functionalized carbon nanofiber (CoFeSe2/f-CNF) composite have been synthesized by using simple hydrothermal synthesis and used as an electrode material for efficient electrochemical detection of caffeic acid (CA). The functionalization of CNF and the formation of CoFeSe2/f-CNF nanocomposite have been successfully scrutinized by using Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray powder diffraction, transmission electron microscopy and scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. In addition, the electrochemical properties of CoFeSe2/f-CNF modified glassy carbon electrode (GCE) towards CA sensing were investigated by using cyclic voltammetry, differential pulse voltammetry and electrochemical impedance spectroscopy. As the result of the electrochemical studies, the developed CoFeSe2/f-CNF/GCE sensor exhibits very low detection limit (0.002 MUM) and better sensitivity (2.04 MUA MUM-1 cm-2) of CA. And also, CoFeSe2/f-CNF/GCE sensor shows the feasible detection of CA in red wine samples, it reveals the excellent practicability of CoFeSe2/f-CNF/GCE. PMID- 30016262 TI - A fully automated analytical platform integrating water sampling-miniscale-liquid liquid extraction-full evaporation dynamic headspace concentration-gas chromatography-mass spectrometry for the analysis of ultraviolet filters. AB - A fully automated analytical platform that seamlessly integrates online water sampling-sample preparation-gas chromatography-mass spectrometry (GC-MS) was developed for ultraviolet (UV) filters in this work. The online water sampling system consisted of a conventional sample vial (slightly modified to have both inlet and outlet ports), two tubings and a peristaltic pump, which controlled the water flow into and out of the vial. The sample preparation segment consists of miniscale liquid-liquid extraction (msLLE), coupled to full evaporation dynamic headspace concentration (FEDHS) on a commercial dual-arm autosampler. The extract from the msLLE step was subjected to a derivatization step, before being passed through a Tenax TA sorbent tube at the FEDHS stage. UV filters were used as model compounds in this work due to their potential endocrine and developmental toxicities, including benzhydrol, 2-ethylhexyl salicylate, homosalate, 2-hydroxy 4-methoxybenzophenone, 3-(4'-methylbenzylidene) camphor and benzophenone. The analytes (of which the first four underwent derivatization, by virtue of them possessing hydroxyl groups, but not the last two) were concentrated on the sorbent, and were thermally desorbed before being introduced to the GC-MS system for analysis. An orthogonal array design (OAD) strategy was employed to facilitate the optimization of the msLLE and derivatization factors while univariate optimization was performed for FEDHS. The optimized settings achieved low limits of detection (0.6-9.7 ng L-1) with good linearity (r2 >= 0.9926), and satisfactory absolute extraction recoveries (62.0%-80.7%) were obtained. The fully automated online water sampling-extraction/concentration-detection approach was demonstrated by applying it to the analysis of swimming pool water. Relative recoveries of the analytes in the pool water ranged from 85.4% to 118.2%. The described procedure has the potential to be a fully automated online water sampling-msLLE-FEDHS-GC-MS platform for the purpose of conducting routine onsite water analysis. PMID- 30016263 TI - Low-cost and convenient ballpoint tip-protected liquid-phase microextraction for sensitive analysis of organic molecules in water samples. AB - Simplification and miniaturization in analytical procedures are highly preferred by analysts and other researchers. In this study, a low-cost, convenient and efficient liquid-phase microextraction method, termed ballpoint tip-protected liquid-phase microextraction (BT-LPME), was established. The bullet-shaped BT possessed a hollow cavity of several microliters for solvent storage and an opening tail for solute extraction. Magnetic field-induced BT spinning significantly accelerated the extraction process. By virtue of the adhesion between a stainless steel sheath and an organic solvent, along with cave protection, finely stable storage of extractant was achieved even under high spinning speeds (>1000 rpm). The BT-LPME performance was evaluated by extracting five polycyclic aromatic hydrocarbons (PAHs) from aqueous solution, followed by gas chromatography-mass spectrometry (GCMS) analysis. Compared to static single drop microextraction (SDME), the BT-LPME method provided higher enrichments (128 173-fold) for the five PAHs. Good linearities (from 0.01~0.05 MUg L-1 to 50 MUg L 1) with a regression coefficient (r2) >=0.9993, as well as low limits of detection (LODs, 0.002-0.011 MUg L-1) and limits of quantification (LOQs, 0.007 0.023 MUg L-1), were obtained. Relative recoveries varied from 92.3% to 103.4% at three spiked levels of 0.1, 1 and 10 MUg L-1. The BT-LPME technique was also successfully applied to the enrichment of other organic compounds, such as organophosphorus compounds, organochlorines and triazines. PMID- 30016265 TI - Synthetic cannabinoids in hair - Pragmatic approach for method updates, compound prevalences and concentration ranges in authentic hair samples. AB - Since the first detection of synthetic cannabinoids (SCs) in so-called 'legal high' products (e.g. 'Spice') sold as legal alternatives to marihuana, the rapid development of this class of designer drugs poses a great challenge for analytical laboratories. The aim of this study was the comprehensive validation of an up-to-date LC-MS/MS method for detection of SCs in human hair for the purpose of drug abstinence testing and evaluation of a pragmatic re-validation approach for frequent method adaption. The validation demonstrated low quantification limits (0.5-5.0 pg mg-1) and acceptable selectivity, linearity, accuracy, and precision for 72 SCs. High matrix effects have been taken into consideration as a major limitation of the method. The partial re-validation approach proved to be an appropriate compromise between reduced validation effort and sufficient control of the method performance enabling analysts to keep pace with the dynamics of the drug market. The analysis of 294 authentic samples resulted in 163 positive samples and showed a broad concentration range (<1.0 5,700 pg mg-1) for 52 SCs in hair with up to 17 different compounds detected in a single hair sample. Periods of detection between one and 58 months were observed for single compounds in hair. Regarding the interpretation of analytical findings semi-quantitative concentrations were considered sufficient for a rough classification of the intensity of drug exposure in (i) passive exposure or exposure in the distant past (lower pg mg-1 range), (ii) more intense exposure (elevated concentration range, >20 pg mg-1 (upper 25th-percentile)), and (iii) heavy/recent exposure (>150 pg mg-1). PMID- 30016266 TI - Facile fabrication of silver nanoparticle decorated alpha-Fe2O3 nanoflakes as ultrasensitive surface-enhanced Raman spectroscopy substrates. AB - Although great progress has been made on designing noble metal nanoparticle aggregates/assemblies as surface-enhanced Raman spectroscopy (SERS) substrates, an ever increasing research interest has focused on fabrication of hierarchical nanostructures for superior SERS performance. Here, we report effective decoration of silver nanoparticles (AgNPs) onto vertically and densely grown alpha-Fe2O3 nanoflakes (NFs) as SERS active substrates. The SERS substrate was prepared by thermally annealing Fe foil at 450 degrees C to grow alpha-Fe2O3 NFs and electroless deposition of AgNPs onto alpha-Fe2O3 NFs, with excellent ability to control the particle size and density. The AgNP-decorated alpha-Fe2O3 NFs offer high density hot spots and exhibited high SERS performance with enhancement factor of 8.1 * 106. Integration of alpha-Fe2O3 nanostructure functions as intrinsic internal standard and selective binder for specific analytes like the toxic arsenic. The substrate was successfully used for quantitative detection of arsenic with spatial uniformity (relative standard deviation, RSD, 8.8%) and good reproducibility (RSD, 9.7%). The Raman signal of alpha-Fe2O3 integrated to the SERS substrate was utilized as internal standard which significantly improves reproducibility. The substrate exhibited a high sensitivity for arsenic detection with a limit of detection down to 1.5 MUg L-1, which is much lower than permissible limit (10 MUg L-1) set by the WHO. Moreover, the SERS substrates showed excellent practicability and selectivity for determination of arsenic in environmental waters which is valuable for environmental and human health protection. PMID- 30016264 TI - Effect of temperature control on the metabolite content in exhaled breath condensate. AB - The non-invasive, quick, and safe collection of exhaled breath condensate makes it a candidate as a diagnostic matrix in personalized health monitoring devices. The lack of standardization in collection methods and sample analysis is a persistent limitation preventing its practical use. The collection method and hardware design are recognized to significantly affect the metabolomic content of EBC samples, but this has not been systematically studied. Here, we completed a series of experiments to determine the sole effect of collection temperature on the metabolomic content of EBC. Temperature is a likely parameter that can be controlled to standardize among different devices. The study considered six temperature levels covering two physical phases of the sample; liquid and solid. The use of a single device in our study allowed keeping saliva filtering and collector surface effects as constant parameters and the temperature as a controlled variable; the physiological differences were minimized by averaging samples from a group of volunteers and a period of time. After EBC collection, we used an organic solvent rinse to collect the non-water-soluble compounds from the condenser surface. This additional matrix enhanced metabolites recovery, was less dependent on temperature changes, and may possibly serve as an additional pointer to standardize EBC sampling methodologies. The collected EBC samples were analyzed with a set of mass spectrometry methods to provide an overview of the compounds and their concentrations present at each temperature level. The total number of volatile and polar non-volatile compounds slightly increased in each physical phase as the collection temperature was lowered to minimum, 0 degrees C for liquid and -30, -56 degrees C for solid. The low-polarity non-volatile compounds showed a weak dependence on the collection temperature. The metabolomic content of EBC samples may not be solely dependent on temperature but may be influenced by other phenomena such as greater sample dilution due to condensation from the ambient air at colder temperatures, or due to adhesion properties of the collector surface and occurring chemical reactions. The relative importance of other design parameters such as condenser coating versus temperature requires further investigation. PMID- 30016267 TI - L-tyrosine methyl ester-stabilized carbon dots as fluorescent probes for the assays of biothiols. AB - Over the past few decades, assays of biothiols had attracted much attention due to the essential role they played in human physiology, especially using the fluorescent analysis. In most cases, competitive mechanism was often employed, where the metal ions were often introduced as the quenchers and thiols competed with metal ions due to the high binding affinity and strong thiophilicity for 'signal-on' assays. To develop a metal ions-free approach for the assays of thiols, here, L-tyrosine methyl ester capped carbon dots (Tyr-CDs) were employed and prepared as the fluorescent probes. The as-prepared Tyr-CDs displayed narrow size distribution and distinct blue fluorescence with high quantum yield (12.9%) compared with the unmodified CDs. Moreover, Tyr-CDs exhibited higher quenching efficiency due to the efficient energy transfer between Tyr-CDs and the quinone products in the presence of tyrosinase. When the targeted biothiols was present, the catalytic reaction of the tyrosinase to the formation of quinone was inhibited and the fluorescence signal was recovered in a biothiols-concentration dependent manner, which provided the basis for the analysis of biothiols. The practical application of the present system was demonstrated by testing the biothiols in human plasma samples and good recovery was obtained, indicating that the sensing platform we proposed hold great promise in the accurate detection of biothiols in complex biosystems. PMID- 30016268 TI - Tyrosinase immobilization on aminated magnetic nanoparticles by physical adsorption combined with covalent crosslinking with improved catalytic activity, reusability and storage stability. AB - In the present study, the immobilization method of physical adsorption combined with covalent crosslinking was developed to avoid the shortcomings of both the noncovalent and covalent coupling methods. For the first time, tyrosinase (TYR) was immobilized on the surface of aminated magnetic nanoparticles (Fe3O4-NH2) by the developed method. TYR was firstly adsorbed on the surface of Fe3O4-NH2 by electrostatic interaction, and then by covalent crosslinking with glutaraldehyde (GA), TYR was firmly immobilized on the supports. The immobilized TYR showed enhanced pH and temperature endurances at the optimum pH of 7.0 and temperature of 35 degrees C. TYR reusability was significantly improved after immobilization and it retained 61.4 +/- 2.3% of its initial activity after 5 repeated cycles. Immobilized TYR also showed improved storage stability (73.2 +/- 1.1% after 30 days of storage at 4 degrees C). In addition, the immobilized TYR showed a higher biological affinity to substrate owing to the stabilization of TYR in its active conformation by electrostatic interaction prior to covalent crosslinking. Finally, the immobilized TYR was used to screen of enzyme inhibitors from 11 traditional Chinese medicines (TCMs) to validate whether this method can be used for enzyme inhibitor screening or not. PMID- 30016269 TI - Urinary measurement of circulating tumor DNA for treatment monitoring and prognosis of metastatic colorectal cancer patients. AB - Background Solid tumor tissue testing is the gold standard for molecular-based assays for metastatic colorectal cancer (mCRC). This poses challenges during treatment monitoring. Total DNA derived from urine specimens offers clear advantages to track the disease dynamics. Our study aims to evaluate the sensitivity for total DNA recovered from urine and its clinical relevance to mCRC. Methods KRAS mutations in urine specimens were examined in 150 mCRC patients. Baseline concordance was established to determined clinical relevance. The total DNA quantities were also prospectively examined in serial samplings during treatment. Results Analysis of the genetic mutations showed good agreement for baseline samples. Matched tumor and urine specimens' molecular profiles were observed to have 90% concordance. Comparing with healthy volunteers, we established a cutoff of 8.15 ng that demonstrated elevated total DNA levels was associated with mCRC patients (sensitivity: 90.7%; specificity: 82.0%). For patients treated with chemotherapy or anti-epidermal growth factor receptor inhibitors, DNA quantity mirrored early treatment response. Survival analysis showed that patients with sustained elevated quantities of KRAS mutations had poorer outcome. Conclusions Total urine DNA offers a viable complement for mutation profiling in mCRC patients, given the good agreement with matched tumor samples. Our study also established that this is specific based on the results from healthy individuals. Serial monitoring of total DNA levels allowed early prediction to treatment response and was effective to identify high risk patients. This is potentially useful to complement current disease management. PMID- 30016270 TI - The correlation between glucose fluctuation from self-monitored blood glucose and the major adverse cardiac events in diabetic patients with acute coronary syndrome during a 6-month follow-up by WeChat application. AB - Background This study aimed to investigate the correlation between glucose fluctuation from self-monitored blood glucose (SMBG) and the major adverse cardiac events (MACE) in diabetic patients with acute coronary syndrome (ACS) during a 6-month follow-up period using the WeChat application. Methods From November 2016 to June 2017, 262 patients with ACS were discharged in a stable condition and completed a 6-month follow-up period. SMBG was recorded using the WeChat application. The patients were divided to a high glucose fluctuation group (H group; n=92) and a low glucose fluctuation group (L group; n=170). The 6-month incidence of MACE, lost-to-follow-up rate and satisfaction rate were measured through the WeChat follow-up. Results MACE occurred in 17.4% of patients in the H group and in 8.2% of patients in the L group (p=0.04). Multivariable analysis suggested that high glucose fluctuation conferred an 87% risk increment of MACE in the 6-month follow-up period (odds ratio: 2.1, 95% confidence interval 1.95 4.85; p=0.03). The lost-to-follow-up rate was lower and the satisfaction rate was higher in the patients using the WeChat application during follow-up than those of the regular outpatient follow-up during the same period (p<0.05). Conclusions The trial demonstrates that higher glucose fluctuation from SMBG after discharge was correlated with a higher incidence of MACE in diabetic patients with ACS. WeChat follow-up might have the potential to promote a good physician-patient relationship. PMID- 30016271 TI - Genetic polymorphisms and variants in the LDL receptor associated with familial hypercholesterolemia: cascade screening and identification of the variants 666C>A, 862G>A, 901G>A, and 919G>A of a Brazilian family. PMID- 30016272 TI - National surveys on 15 quality indicators for the total testing process in clinical laboratories of China from 2015 to 2017. AB - Background As effective quality management tools, quality indicators (QIs) are widely used in laboratory medicine. This study aimed to analyze the results of QIs, identify errors and provide quality specifications (QSs) based on the state of-the-art. Methods Clinical laboratories all over China participated in the QIs survey organized by the National Health Commission of People' Republic of China from 2015 to 2017. Most of these QIs were selected from a common model of QIs (MQI) established by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All participants were asked to submit general information and original QIs data through a medical quality control data collection system. The results of QIs were reported in percentages and sigma, except turnaround time (TAT) which was measured in minutes. The 25th, 50th and 75th percentiles were, respectively, calculated as three levels of QSs, which were defined starting from the model proposed during the 1st Strategic Conference of the EFLM on "Defining analytical performance 15 years after the Stockholm Conference on Quality Specification in Laboratory Medicine". Results A total of 76 clinical laboratories from 25 provinces in China continuously participated in this survey and submitted complete data for all QIs from 2015 to 2017. In general, the performance of all reported QIs have improved or at least kept stable over time. Defect percentages of blood culture contamination were the largest in the pre-analytical phase. Intra-laboratory TAT was always larger than pre-examination TAT. Percentage of tests covered by inter-laboratory comparison was relatively low than others in the intra-analytical phase. The performances of critical values notification and timely critical values notification were the best with 6.0sigma. The median sigma level of incorrect laboratory reports varied from 5.5sigma to 5.7sigma. Conclusions QSs of QIs provide useful guidance for laboratories to improve testing quality. Laboratories should take continuous quality improvement measures in all phases of total testing process to ensure safe and effective tests. PMID- 30016273 TI - Evidence for the positive impact of ISO 9001 and ISO 15189 quality systems on laboratory performance - evaluation of immunohaematology external quality assessment results during 19 years in Austria. AB - Background ISO 9001 and ISO 15189 have been established as continuative models for quality systems beyond national laws, mandatory standards and guidelines of expert associations regarding analytical and organisational performance of medical laboratories and transfusion services. Although widely used, their impact on laboratory performance has not been investigated. Methods We retrospectively analysed the results of 167 laboratories in 59 distributions of the Austrian red cell immunohaematology external quality assessment (EQA) scheme in the years 1999 2017. The performance for each parameter and trends of individual participants were compared with respect to certification or accreditation status of participants' quality systems and to laboratory type. Results Considering more than 52,000 EQA results, the absence or presence of a laboratory quality management system showed different error rates. Laboratories with ISO 9001 or ISO 15189 certification/accreditation had 0.7% incorrect results, while this rate was doubled without such quality systems (1.4%, p=0.0002). Statistically significant error reductions were seen upon ISO 9001/ISO 15189 implementation (1.3% before vs. 0.7% after; p=0.0468). Transfusion services had fewer errors (0.9%) compared to hospital and independent laboratories (both 1.2%). Conclusions Implementation and maintenance of quality systems according to ISO 9001 or ISO 15189 as well as laboratory specialisation result in better analytical performance as can be seen in immunohaematology EQA results. The conclusion is that these results apply to other laboratory tests and perhaps to other areas of health care. PMID- 30016274 TI - New biomarkers and traditional cardiovascular risk scores: any crystal ball for current effective advice and future exact prediction? PMID- 30016275 TI - BCL2L12 improves risk stratification and prediction of BFM-chemotherapy response in childhood acute lymphoblastic leukemia. AB - Background Risk-adjusted treatment has led to outstanding improvements of the remission and survival rates of childhood acute lymphoblastic leukemia (ALL). Nevertheless, overtreatment-related toxicity and resistance to therapy have not been fully prevented. In the present study, we evaluated for the first time the clinical impact of the apoptosis-related BCL2L12 gene in prognosis and risk stratification of BFM-treated childhood ALL. Methods Bone marrow specimens were obtained from childhood ALL patients upon disease diagnosis and the end-of induction (EoI; day 33) of the BFM protocol, as well as from control children. Following total RNA extraction and reverse transcription, BCL2L12 expression levels were determined by qPCR. Patients' cytogenetics, immunophenotyping and minimal residual disease (MRD) evaluation were performed according to the international guidelines. Results BCL2L12 expression was significantly increased in childhood ALL and correlated with higher BCL2/BAX expression ratio and favorable disease markers. More importantly, BCL2L12 expression was associated with disease remission, while the reduced BCL2L12 expression was able to predict patients' poor response to BFM therapy, in terms of M2-M3 response and MRD>=0.1% on day 15. The survival analysis confirmed the significantly higher risk of the BFM-treated patients underexpressing BCL2L12 at disease diagnosis for early relapse and worse survival. Lastly, evaluation of BCL2L12 expression clearly strengthened the prognostic value of the established disease prognostic markers, leading to superior prediction of patients' outcome and improved specificity of BFM risk stratification. Conclusions The expression levels of the apoptosis related BCL2L12 predict response to treatment and survival outcome of childhood ALL patients receiving BFM chemotherapy. PMID- 30016276 TI - A multicenter study for the evaluation of the reference interval for TSH in Italy (ELAS TSH Italian Study). AB - Background The aims of this study were: (1) to calculate reliable thyroid stimulating hormone (TSH) reference intervals using laboratory databases; (2) to evaluate the relationship between TSH, sex and age values in different large Italian populations. Methods The TSH values stored in the laboratory information system of clinical laboratories of four Italian city hospitals, including 146,801 TSH measurements (with the respective age and sex data of individuals) were taken in consideration. Assuming a log-normal distribution, to log-transformed TSH values were applied the Dixon's iterative principle in order to exclude the outliers. At the end of this iterative process 142,821 log-transformed TSH results remained. The four clinical laboratories measured serum TSH concentrations using the same TSH immunoassay method (Access TSH 3rd IS, using UniCel DxI platform). Results The TSH reference interval calculated in the present study (0.362-5.280 mIU/L) is similar to that suggested by the manufacturer for the Access TSH 3rd IS assay (0.45-5.33 mIU/L). TSH values in females were significantly higher than in males (females: mean=2.06 mIU/L; standard deviation [SD]=1.26 mIU/L; n=101,243; males: mean=1.92 mIU/L; SD=1.19 mIU/L; n=41,578; p<0.0001). Moreover, a negative linear relationship was observed between TSH throughout all interval age values (from 0 to 105 years). Conclusions The results of the present multicenter study confirm that data mining techniques can be used to calculate clinically useful reference intervals for TSH. From a pathophysiological point of view, our results suggest that some Northern populations of Italy might still suffer some harmful effects on the thyroid gland due to mild to moderate iodine intake deficiency. Specific clinical trials are needed to confirm these results. PMID- 30016277 TI - Cognitive error in an academic emergency department. PMID- 30016278 TI - To diet or not to diet in neonatal diabetes responding to sulfonylurea treatment. AB - Background Neonatal diabetes mellitus (NDM) is defined as a monogenic form of diabetes that occurs in the first 6 months of life. As information on diet in NDM patients successfully treated with sulfonylurea is not yet available, we aimed to investigate the hypothesis that a carb-restricted diet is not needed in such cases. Case presentation In this case report, we present a successful implementation of a completely liberalized diet in a young patient with NDM, developmental delay and epilepsy (DEND syndrome), who was also switched to sulfonylurea treatment. The excellent metabolic control during follow-up despite completely ignoring any diet suggests that at least in some patients this approach might work. Conclusions If our proposed hypothesis is also confirmed by other reports, it might add significantly to the quality of life of these patients and broaden the knowledge in this medical field. PMID- 30016279 TI - Impact of the economic crisis on pain research: a bibliometric analysis of pain research publications from Ireland, Greece, and Portugal between 1997 and 2017. AB - Background and aims The recent economic crisis started in the USA in 2008 but quickly had worldwide impact. Ireland, Greece, and Portugal were in economic distress in 2009 and received rescue monetary packages from the European Union (EU) and the International Monetary Fund (IMF) in the following years. Meanwhile, the economic recovery has begun for those countries, but at different paces. The aim of the present study was to evaluate if the economic crisis influenced pain research outcomes, by performing a bibliometric analysis based on the ISI Web of Science to evaluate the evolution of the scientific production and performance in the field of pain research between 1997 and 2017. Methods Articles search was conducted using the ISI Web of Science, search keywords "pain or nocicep*", between 1997 and 2017, and one author affiliated in an Irish, Greek or Portuguese institution. The total number of published articles per country, total citations, h-index, document types and authors' institution were tabulated to determine the quantity and quality of the publications in this field. Results The search retrieved 2,368 publications over the 20 years' period, increasing from 26 in 1997 to 230 in 2017. The number of Irish publications per year increased steadily along the studied period, while the number of Greek publications stabilized from 2008 onward and Portuguese publications started to increase only in 2007 but declined slightly after 2014. In total, Irish authors published 1,143 articles, Greek authors 624 and Portuguese authors 618. There were nine articles with more than 100 citations, and Irish publications had a higher h-index (52) than Greek's (45) or Portuguese's (36) publications. Ireland had the highest number of pain publications per capita, but in 2016 Portugal had the lowest cost per publication, as measured by the GDP per capita per publication (in 1997 Portugal had the highest cost). The three major research fields of the publications were neurosciences/neurology (19%), general internal medicine (16%) and anaesthesiology (13%), and the affiliation institutions were mostly universities or universities hospitals. Conclusions The number of Irish, Greek, and Portuguese pain publications increased between 1997 and 2017, but at different paces. It appears that the economic crisis had no impact on the rate of pain publications in Ireland, had a delayed impact in Portugal, and affected mostly Greek pain scientific research. This may be related to the fact that Greece was the country that received more rescue packages and where the economic crisis was deepest and lasted longer. Implications Economics and scientific production have a mutual influence: usually research investment decreases in recession times (reducing grants and scientific employment), but health scientific production can improve health and quality of life and also benefit the economy. So in crisis periods, governments should create means to protect and foster scientific work. PMID- 30016280 TI - Preparation and application of modified zeolites as adsorbents in wastewater treatment. AB - Natural zeolite has been recognized as a useful adsorbent for wastewater treatment for removing cations. Natural zeolite is a kind of porous material with large specific surface area but limited adsorption capacity. In recent years, emphasis has been given to prepare the surface modified zeolite using various procedures to enhance the potential of zeolite for pollutants. Modification treatment for zeolite can greatly change surface chemistry and pore structure. The article describes various modification methods of zeolite, and introduces the removal mechanisms of common pollutants such as ammonium, phosphorus and heavy metals. In addition, this review paper intends to present feasibility of applying modified zeolite to constructed wetlands which will be beneficial to achieve higher removal effect. PMID- 30016281 TI - Removal of atenolol from aqueous solutions by multiwalled carbon nanotubes modified with ozone: kinetic and equilibrium study. AB - The aim of study is removal of atenolol from aqueous solutions by multiwalled carbon nanotubes modified with ozone. The design of the experiment was adopted across four levels with the L16 matrix arrangement. The factors influencing atenolol adsorption include changes in the pH value, contact time, the dose of the modified multiwall carbon nanotube, and the initial concentration of atenolol in the solution; these factors were evaluated along with the extent of their influence on removal efficiency. Data analyses were performed by the Design Expert 6 software. The results indicated that the pH, contact time, adsorbent dose, and the initial concentration were 7, 20 min, 0.15 g/L and 1 mg/L, respectively. In this state, the removal efficiency was calculated to be 75.79%. The maximum adsorption capacity was obtained as 5.05 mg/g under optimal conditions. The data were analyzed using adsorption models obtained from the isotherm fitting tool software. The results suggested that the data had a greater congruence with the Freundlich model (corrected Akaike information criterion = 2.58). Furthermore, the kinetics of the reactions followed pseudo second order kinetics (R2 = 0.95). Based on this study, it can be concluded that modified multiwall carbon nanotubes enjoy high potential and efficiency as adsorbents for the removal of atenolol from aqueous solutions. PMID- 30016283 TI - Catalytic wet oxidation of high concentration pharmaceutical wastewater with Fe3+ as catalyst. AB - Catalytic wet oxidation of high concentration pharmaceutical wastewater with Fe3+ as catalyst was carried out in a batch reactor. Results showed that the degradation of pharmaceutical wastewater was enhanced significantly by Fe3+. The effects of reaction parameters, such as the catalyst dose, reaction temperature, time, and initial oxygen pressure, were discussed. The chemical oxygen demand (COD) removal increased with the increases of catalyst dose, temperature, time and oxygen supply. With the initial COD 34,000-35,000 mg/L, approximately 70% COD removal can be achieved under the conditions of catalyst 1.0 g and oxygen pressure 1.0 MPa at 250 degrees C after 60 min. The results of kinetic studies showed that two reaction steps existed in this oxidation process, which followed an apparent first-order rate law. This process provides an effective approach for the pretreatment of high concentration pharmaceutical wastewater. PMID- 30016282 TI - Cyanide degradation kinetics during anaerobic co-digestion of cassava pulp with pig manure. AB - Anaerobic co-digestion of cassava pulp (CP) and pig manure (PM) under cyanide inhibition conditions was investigated and modeled. Batch experiments were performed with initial cyanide concentrations ranging from 1.5 to 10 mg/L. Cyanide acclimatized sludge from an anaerobic co-digester treating cyanide containing CP and PM was used as the seed sludge (inoculum). Cyanide degradation during anaerobic digestion consisted of an initial lag phase, followed by a cyanide degradation phase. After a short sludge acclimatization period of less than 3 days, the anaerobic sludge was able to degrade cyanide, indicating that the sludge inhibition due to cyanide was reversible. Cyanide degradation during anaerobic co-digestion of CP and PM followed the first-order kinetics with a rate constant of 0.094 d-1. Gas evolution during batch anaerobic degradation was modeled using the modified Monod-type kinetics to incorporate cyanide inhibition. The model predicted results yielded a satisfactory fit with the experimental data. PMID- 30016284 TI - Low cost sustainable materials for grey water reclamation. AB - Grey water reclamation is a sustainable solution for managing water shortages. However, grey water contains high levels of detergents, particularly surfactants, which alongside other chemical constituents can pose a serious risk to human health and the environment. Biological treatments are not effective in the treatment of grey water since the detergents inhibit the activities of microorganisms. Chemical treatment options have an impact on public perception and could be cost prohibitive for domestic and small scale reuse applications. In this paper, we review the characterization of the constituents of grey water and the application of various low cost sustainable materials such as zeolite, activated carbon, mussel shells, tyre granules, fly ash, ground granulated blast furnace slag and silica gel for the treatment and removal of detergent characteristics. PMID- 30016285 TI - The influence of energy input on the particle size of disintegrated excess sludge in the ultrasonic disintegration process. AB - The objective of this research was to examine the influence of energy input on the particle size distribution of disintegrated sludge. The change of particle size distribution indicates the deagglomeration of flocs and disruption of micro colonies. As the digestibility of sludge increases with dispersion, particle size analysis is an important factor in evaluating the disintegration process. Four different levels of energy input were used in the research: 10-100 kWh.m-3. All samples showed significant changes as far as dispersion (kdCST = 22.98-74.67, kdFCOD = 3.23-18.46), lysis (kdSCOD = 4.22-12.09), acidification (kdVFAs = 1.78 12.61), nitrogen release (kdTN = 4.02-21.61) indicators were concerned. Results indicate the gradual decrease of measured particle size with increasing energy input. The energy supplied to the disintegration process primarily promotes deagglomeration and with the rise of energy input, the destruction of cells. For EV = 50 and 100 kWh.m-3 an increased occurrence of lysis effects and increase in particle fraction <99.9 MUm was noted. The highest efficiency evaluated by increase of filtered chemical oxygen demand (FCOD) and soluble COD (SCOD) per unit of volumetric energy - DeltaCOD and DeltaSCOD (mgO2.Wh-1) was obtained for Ev = 10 WhL-1, which corresponds to the most significant change in particle size distribution. The volume of particles <99.9 MUm rose from 1.92% for non disintegrated sludge to 26.62% for volumetric energy 100 kWh.m-3. PMID- 30016286 TI - Efficient adsorption of benzoic acid from aqueous solution by nitrogen-containing activated carbon. AB - Adsorption is an efficient treatment process to remove benzoic acid from aqueous solution. In this study, nitrogen-containing surface groups were introduced onto activated carbon (AC) surface by modification with ammonium hydroxide, ammonium carbonate, melamine or urea. The nitrogen-containing AC samples were characterized using N2 adsorption-desorption, Boehm titration, determination of the pH of the point of zero charge (pHpzc) and X-ray photoelectron spectroscopy. The adsorption of benzoic acid from aqueous solution by nitrogen-containing AC has been studied. The Langmuir model fitted the experimental data of equilibrium isotherms better than the Freundlich model. At initial solution pH 2.1, the adsorption capacity was closely related with the amount of pyridinic and pyrrolic N on the AC surface, which indicated these two nitrogen-containing groups played an important part in the adsorption process. The enhancement of adsorption capacity was due to the strengthened pi-pi dispersion force between benzoic acid and the AC basal plane. Since the surface charge of AC as well as the existence form of benzoic acid varied with solution pH value, the adsorption capacity was found to be highest at pH 3.8 and dropped sharply at higher or lower pH values. PMID- 30016287 TI - Performance and microbial community in a combined VF-HF system for the advanced treatment of secondary effluent. AB - In this study, a laboratory-scale system combined a vertical flow constructed wetland (VF) with a horizontal flow constructed wetland (HF), which was used to treat the secondary effluent of a wastewater treatment plant. Removal efficiencies of 67.02%, 89.80%, 90.31% and 75.38% were achieved by the system for chemical oxygen demand (COD), ammonium nitrogen (NH4+-N), total nitrogen (TN) and total phosphorus (TP), respectively. The VF showed much higher average loading rates of COD, TP, NH4+-N and TN (7.96 g/m2/d, 0.076 g/m2/d, 0.31 g/m2/d and 0.99 g/m2/d) than in HF (0.65 g/m2/d, 0.016 g/m2/d, 0.25 g/m2/d and 0.50 g/m2/d), during the stable operation period. Biodegradation played a major role in pollutant removal, especially for COD and TN. The results of bacterial community analysis indicated that heterotrophic denitrifying bacteria (Hydrogenophaga and Flavobacterium) were the dominant contributors for nitrogen removal in the VF, while heterotrophic denitrifying bacteria (Rhodobacter, Flavobacterium and Dechloromonas) and the autotrophic denitrifying bacteria Sulfurimonas played the principal roles for nitrogen removal in the HF. Redundancy analyses showed that COD and NH4+-N were the important factors affecting the distribution of nitrogen removal bacteria in the VF, while pH, dissolved oxygen and oxidation-reduction potential were the key factors influencing the distribution of nitrogen removal bacteria in the HF. PMID- 30016288 TI - Pretreatment of printing and dyeing wastewater by Fe/C micro-electrolysis combined with H2O2 process. AB - A novel iron-carbon (Fe/C) micro-electrolysis combined with H2O2 (ICMH) process was proposed to pretreat the printing and dyeing wastewater (PDW), using a micro electrolysis filling. The effects of H2O2 concentration, reaction time, initial pH, and Fe/C dosage on chemical oxygen demand (COD) removal rate of PDW were optimized by response surface methodology (RSM). The maximum COD removal rate was approximately 77.65% after 186 min treatment, when the concentration of H2O2, initial pH and the dosage of Fe/C were 8.88 g/L, 1.5 and 837 g/L, respectively. Analysis of variance (ANOVA) showed a high coefficient of determination value (R2 = 0.9780). And H2O2 concentration and initial pH were the key factors to improve the treatment effect. UV-Vis spectra indicated that a significant blue shift at 220 nm, attributing that fused aromatic hydrocarbons were degraded effectively. 3D-EEM spectra analysis showed that the water samples of PDW mainly contained three kinds of organic matter: refractory fulvic acid, soluble microbial metabolites and aromatic proteins, and the degradation rate of these was 81.76%, 53.78% and 70.83%, respectively. PMID- 30016289 TI - Impact of meteorological conditions on the water quality of wastewater treatment systems: a comparative study of phytoremediation and membrane bioreactor system. AB - Two demonstration wastewater treatment systems, i.e. a phytoremediation system and a membrane bioreactor (MBR) system, were studied for a six-month period from August 2016 to January 2017. The phytoremediation system consists of wetland cells implanted with diverse phytoremediation macrophyte species at NUST H-12 sector Islamabad, Pakistan, while the MBR system comprises primary clarifiers, membrane tanks and bio tanks that treat domestic wastewater through hybridization of biological and biomechanical techniques. The phytoremediation system receives domestic wastewater at the rate of 283 m3/d, and greater hydraulic efficiencies were achieved because of compartmentalization and higher aspect ratios, whereas the MBR system receives 50 m3/d. The present study was conducted to analyze and compare the correlation between water quality parameters of wastewater treatment systems and meteorological conditions. Statistically significant correlation was exhibited between eight water quality parameters (pH, EC, turbidity, dissolved oxygen, total suspended solids (TSS), chemical oxygen demand (COD), biological oxygen demand (BOD) and total coliforms (TC)) and meteorological factors (ambient temperature and relative humidity). Predominant species isolated and identified through polymerase chain reaction and 16S rRNA sequencing from wastewater of the phytoremediation system and sludge of the MBR system belong to the phylum Proteobacteria with relatively higher abundance of Enterobacter, Shigella, Escherichia and Salmonella genera. PMID- 30016290 TI - Note on sediment removal efficiency in oil-grit separators. AB - Oil-grit separators (OGSs) are one type of best management practice, designed to remove oil and grit from stormwater runoff (e.g., from parking lots and paved roads). This note examines scaling parameters for OGS removal efficiency. Three dimensionless parameters are chosen as scaling parameters: Hazen number (Ha), Reynolds number (Re) and Froude number (Fr). The Hazen number is a ratio of hydraulic residence time to particle settling time. The Reynolds number measures the surrounding turbulence effects on sediment removal efficiency. The Froude number represents the ratio of inertial and gravitational forces, which indicates the influence of gravity on fluid motion. The collected data from the literature on sediment removal in OGSs can be represented by a single curve when the Hazen, Reynolds, and Froude numbers are combined into a new scaling parameter (HRF = Ha(Re/Fr)). A general form is proposed to correlate the sediment removal efficiency with this new parameter. This generalized prediction method can be used as a preliminary performance indicator for OGS units. The obtained curve can also be used to adjust raw laboratory and field measurement data to improve the evaluation of the performance of various OGSs. PMID- 30016291 TI - Identification of odorant characters using GC-MS/O in biosolids emissions from aerobic and anaerobic stabilisation. AB - Malodorous emissions from biosolids limit potential re-use opportunities. Emissions from anaerobically stabilised biosolids have been widely studied. In contrast, emissions from aerobically stabilised biosolids have not been well documented. Individual odorants in complex emissions can be detected using sensorial analysis methods, such as gas chromatography mass spectroscopy coupled with an odour detection port (GC-MS/O) where assessors sniff the GC effluent to identify odorants present. In this study, GC-MS/O was used to study and compare emissions from biosolids produced from aerobically and anaerobically stabilised biosolids from different wastewater treatment plants (WWTPs). The WWTPs varied in size, catchments and dewatering technology. Three GC-MS/O assessors were used for the sensorial analysis. The identified odorants varied significantly between the two sites using aerobic stabilisation, in number of odour characters detected, as well as their intensity. Different odour characters were noted from biosolids generated at the aerobic digestion sites compared to characters from biosolids generated at the anaerobic digestion site. Biosolids from the aerobic digestion sites had medicinal, acrid or putrid type odours not noted from the anaerobic site. However, descriptors of biosolids emissions were commonly noted as: rotten vegetables, seaweed, garbage, garlic, or bad-breath. Many of the descriptors were associated with the presence of sulfur-type compounds. The importance of assessor variability was also highlighted in the paper where certain characters were not detected or were described differently by assessors. PMID- 30016292 TI - Emerging plant-based flocculation treatment of phosphate clay: case study from Metlaoui-Gafsa (southwest Tunisia). AB - The objective of this study was to investigate the ability of cactus Opuntia ficus-indica, used as a natural flocculant in the treatment of phosphate clay as an industrial wastewater. It is a new process that has proven very promising in the removal of high turbidity from industrial effluents. The volume of clear water recovered (supernatant) is one of the characteristic features which allow us to judge the effectiveness of this bioflocculant. The following of the settling velocity on the one hand and the analysis of supernatant and sludge on the other hand allow us to compare the cactus-based flocculant effectiveness with that of a chemical flocculant (CF) of anionic polyacrylamide nature. The optimum pH required for maximum settling velocity was found to be 12. Obtained results indicated that after 900 seconds of settling, the highest volume of clear supernatant was obtained with the natural flocculant (740 mL/L), against 666 mL/L obtained with CF. Several analyses on recovered clear water (pH, turbidity, Cu, Zn, Fe, Cd and Cr) and on dry sludge (P2O5, CaO, MgO, organic C, SiO2 and Cd) are highlighted. PMID- 30016293 TI - Novel ZnFe2O4/TiO2/flake graphite composite as particle electrodes for efficient photoelectrocatalytic degradation of rhodamine B in water. AB - A novel ZnFe2O4/TiO2/flake graphite composite material was synthesized and used as particle electrodes in a photoelectrocatalytic (PEC) system to investigate the degradation of rhodamine B as a model dye pollutant in water. Results showed that a PEC process with the new composite evidently led to enhanced degradation of rhodamine B due to a synergistic effect of photocatalysis and electrocatalysis. Operating variables including electrolyte concentration, applied cell voltage, air flow, composite dosage, solution pH, and dye concentration were also found to play important roles in rhodamine B removal. A 99.0% removal efficiency was observed within 30 min of treatment under optimum conditions of 0.01 mol/L Na2SO4, applied cell voltage of 15 V, air flow of 20 mL/min, composite dosage of 10 g/L, solution pH of 2, and rhodamine B concentration of 20 mg/L, with a pseudo first-order rate constant of 0.278 min-1. These findings could provide new insights into the development of efficient PEC technologies on degradation of residual dyes in water. PMID- 30016294 TI - Characterization and prediction of odours from municipal sewage treatment plant. AB - One of the causes of public discomfort and complaint about odour in China is the nuisance odour, generated from the municipal sewage treatment plants. With the ability to be dispersed over a long distance, the odours can affect a large number of people. With the aim of identifying the compounds contributing the most to the overall odour emanating from municipal sewage treatment plant, and developing a prediction model for sensory odour concentration based on the compound odour activity value (OAV), odour samples from 2 days were collected at a municipal sewage treatment plant in Tianjin in the months of October and November 2013. Odour concentrations (OCs) were measured by the triangular odour bag method. Chemical components were quantified by gas chromatography-mass spectrometry. According to the analysis of odour emission characteristics, it was found that hydrogen sulfide and methyl mercaptan were the key odorants responsible for the overall odour. To understand the interrelationship of these two odorants, 10 groups of a binary mixture of hydrogen sulfide and methyl mercaptan, representing different levels of odour concentration and intensity, were prepared in the laboratory. OCs were regressed against OAV using multivariate linear regression. A statistically significant positive correlation was found between single-compound OAV and odour concentration (by both SPSS and Minitab software). Furthermore, the models were validated by field monitoring data, which showed the odour prediction concentration had a good fit to the measured concentration by using Minitab software. Lastly, the Austal 2000 model system was used for the simulation of the odour emission dispersion into the surrounding area. This study provides an effective way to predict the odour emission condition in municipal sewage treatment plant. PMID- 30016295 TI - Synthesis of a magnetic polystyrene-based cation-exchange resin and its utilization for the efficient removal of cadmium (II). AB - A magnetic cation-exchange resin (MCER) was prepared by copolymerization of oleic acid-grafted magnetite with styrene, divinylbenzene (DVB), and triallylisocyanurate (TAIC) for removing Cd(II) from wastewater. A non-magnetic cation-exchange polystyrene resin (CEPR) was also prepared as a reference. Structural and morphological analyses revealed that the MCER and CEPR were mesoporous microspheres; the MCER contained about 25% Fe3O4. The influence of temperature, pH, contact time, and the initial concentration of Cd(II) on the adsorption of Cd(II) was investigated. The maximum adsorption capacity of the MCER reached 88.56 mg/g, which was achieved at 343 K using a Cd(II) initial concentration of 200 mg/L. The adsorption processes attained equilibrium within 120 min for the MCER and 300 min for the CEPR, and were well described by a pseudo-second-order kinetic model. Furthermore, the equilibrium adsorption data fitted the Freundlich isotherm model better than the Langmuir model. The superior magnetic response and regeneration of the MCER make it a good candidate as an adsorbent for removing Cd(II) from wastewater. PMID- 30016297 TI - Enhanced photocatalytic degradation of doxycycline using a magnetic polymer-ZnO composite. AB - A novel magnetic polymer-ZnO composite was prepared by incorporating Fe3O4 and ZnO nano-particles in the structure of an adsorbent polymer. Precipitation polymerization was used for synthesizing the adsorbent polymer and its efficiency for extracting doxycycline from aqueous solution was optimized according to several parameters including time, pH and amount of polymer. Results showed the highest extraction efficiency at neutral pH of the doxycycline solution in 20 min, and the capacity of the polymer was about 20 mg/g. The magnetic property of a material is important for fast and facile separation of composite particles after each use. Magnetic polymer-ZnO composite was synthesized by adding Fe3O4 and ZnO nano-particles to the polymerization mixture in order to take advantage of both sorption and photocatalytic degradation mechanisms. The obtained composite was characterized using X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy equipped with wavelength dispersive X ray spectroscopy and used for enhanced photocatalytic degradation of doxycycline in aqueous solution. Results showed 76.5% degradation of doxycycline in 6 hours which was significantly higher than the degradation observed by an equivalent amount of ZnO nano-particles. Photocatalytic degradation of doxycycline fitted the pseudo first order kinetic model with a rate constant of 4 * 10-3 MUg mL-1 min-1. PMID- 30016296 TI - Mercury behaviour in flue gas from sewage sludge incinerators and melting furnace. AB - Thermal conversion of sewage sludge can be a clean source of renewable energy if the emission of air pollutants from the source is controlled. In 2013, the Minamata Convention on Mercury was adopted, placing greater emphasis on the control of mercury emissions, including mercury emissions from sewage sludge incinerators. To characterise the behaviour of mercury in flue gas, particulate and gaseous mercury concentrations in two incinerators and a melting furnace were measured by manual sampling. In a third facility, continuous emission monitoring was used to characterise temporal trends in gaseous mercury concentrations. Wet scrubbers were determined to be effective air pollution control devices suitable for mercury removal. Stack mercury concentrations were found to be <10 MUg/Nm3, which meets the mercury emission standard for existing plants (50 MUg/Nm3). PMID- 30016298 TI - Effect of using different proportions of inoculum during bioleaching on sludge dewaterability. AB - Bioleaching, the addition of bacteria to geological materials, has been applied to sludge to remove metals and improve upon sludge dewaterability. This paper investigates the effect of using different quantities of inoculum (bacteria) during bioleaching on sludge dewaterability. The analysis was based on bioleaching experiments conducted in a 20 L bio-reactor using different quantities of inoculum (20%, 10%, 5%, 2%, 0%). Changes in pH, oxidation reduction potential (ORP), capillary suction time (CST), specific resistance to filtration (SRF) and extracellular polymeric substances (EPS) were determined to gauge sludge dewatering. Results indicate that sludge dewaterability during the 2%, 10%, and 20% inoculum experiments declined through time. Decreased dewaterability is attributed to increases in the quantity of proteins and polysaccharides in slime EPS. Dewaterability improved during the 5% inoculum experiment, and reached a maximum when pH was 2.3. During this latter experiment, CST and SRF were reduced by 74% and 62%, respectively, in comparison to control conditions, while total EPS content decreased by 71%. The decrease in total EPS was primarily due to a decrease in proteins associated with tightly bound EPS (TB-EPS). Thus, changes in the amount of proteins in TB-EPS and sludge pH played a crucial role in sludge dewaterability. PMID- 30016299 TI - Degradation of textile dyes Remazol Yellow Gold and reactive Turquoise: optimization, toxicity and modeling by artificial neural networks. AB - In this work, the degradation of Remazol Yellow Gold RNL-150% and Reactive Turquoise Q-G125 were investigated using AOP: photolysis, UV/H2O2, Fenton and photo-Fenton. It was found that the photo-Fenton process employing sunlight radiation was the most efficient, obtaining percentages of degradation above 87%. The ideal conditions for the degradation of the dyes were determined from a factorial design 23 and study of the [H2O2] ([H2O2] equal to 100 mg.L-1); [Fe] equal to 1 mg.L-1 and pH between 3 and 4. In the kinetic study, a degradation of more than 97% was obtained after 150 min for the chromophoric groups and 91% for the aromatic compounds. The experimental data obtained presented a good fit to the nonlinear kinetic model. The model of artificial neural networks multilayer perceptron (MLP) (4-11-5) using the software Statistica 8.0 enabled the modeling of the degradation process and showed a better prediction of the data. The toxicity to the seeds of Lactuca sativa and the bacteria Escherichia coli and Salmonella enteritidis allowed to evaluate the effectiveness of the process. The results of this study suggest that the use of photo-Fenton process with sunlight radiation is an effective way to degrade the dyes under study. PMID- 30016300 TI - Performance of biochar derived from rice straw for removal of Ni(II) in batch experiments. AB - Biochar, as a cost-efficient adsorbent, is of major interest in the removal of heavy metals from wastewater. Herein, batch experiments were conducted to investigate the performance of biochar derived from rice straw for the removal of Ni(II) as a function of various environmental conditions. The results showed that Ni(II) sorption was strongly dependent on pH but independent of ionic strength and the effects of electrolyte ions could be negligible over the whole pH range. Ionic exchange and inner-sphere surface complexation dominated the sorption of Ni(II). Humic/fulvic acids clearly enhanced the Ni(II) sorption at pH <7.2 but inhibited the sorption at pH >7.2. The sorption reached equilibrium within 10 hours, and the kinetics followed a pseudo-second-order rate model. Any of the Langmuir, Freundlich, or Dubinin-Radushkevich isotherm models could describe the sorption well, but the Langmuir model described it best. The maximum sorption capacity calculated from the Langmuir model was 0.257 m.mol/g. The thermodynamic parameters suggested that Ni(II) sorption was a spontaneous and endothermic process and was enhanced at high temperature. The results of this work indicate that biochar derived from rice straw may be a valuable bio-sorbent for Ni(II) in aqueous solutions, but it still requires further modification. PMID- 30016301 TI - Assessment of ecotoxicological effects of ciprofloxacin in Daphnia magna: life history traits, biochemical and genotoxic effects. AB - Antibiotics (e.g. ciprofloxacin) have been detected in surface water and groundwater for several decades. In order to understand the potential impact of the continuous exposure of aquatic organisms to ciprofloxacin, a chronic assay was carried out with Daphnia magna. This approach allowed evaluation of the effects of ciprofloxacin on life-history and sub-individual parameters (antioxidant status and metabolic response: activities of catalase and glutathione S-transferases - GSTs; peroxidative damage; thiobarbituric acid reactive substances and genotoxic effects (genetic damage index, measured by the comet assay). Life-history parameters of D. magna showed no significant effects after ciprofloxacin exposure. Concerning oxidative stress and metabolism parameters, no significant alterations were reported for catalase and GSTs activities. However, a dual response was observed, with a significant decrease in lipid peroxidation levels at low ciprofloxacin concentrations (<0.013 mg/L), while a significant increase was verified at high ciprofloxacin concentrations (0.078 mg/L). The genotoxicity assay detected a significant increase in genetic damage index up to 0.013 mg/L of ciprofloxacin. The here-tested ciprofloxacin concentrations, which are ecologically relevant, did not cause significant impacts concerning the life-history parameters of D. magna; however, at the same levels of ciprofloxacin an oxidative stress and genotoxic damage scenarios were recorded. PMID- 30016302 TI - Variations in activities of sewer biofilms due to ferrous and ferric iron dosing. AB - Addition of ferrous and ferric iron salts to wastewater is a commonly used practice for sulfide abatement in sewer force mains. When iron is added to wastewater where sulfate respiration takes place, it produces ferrous sulfide precipitates with the formed sulfide. The effect of iron addition has traditionally been focused on solely from the perspective of reaction stoichiometry. Possible influences on the microbial communities in biofilms growing in force mains have largely been neglected. In this study the activity and microbiome was examined in three pilot scale force mains conveying real wastewater, two subjected to iron treatment and one operated as an untreated control. Activity was measured on suspended biofilm samples extracted from the experimental setup. The microbiome of the biofilm was analyzed by V3 + V4 16S rDNA sequencing. Correlation analysis of chemical composition of the biofilms and activity measurements for operational taxonomic units of relevance to sulfide and methane production were performed. In conclusion, it was found that both ferrous and ferric treatment reduced sulfate reduction and methane production, and that both iron salts induced significant changes to force main biofilm microbiomes. PMID- 30016303 TI - Removal of molybdenum(VI) from aqueous solutions using nano zero-valent iron supported on biochar enhanced by cetyl-trimethyl ammonium bromide: adsorption kinetic, isotherm and mechanism studies. AB - A new carbonized pomelo peel biosorbent (MCPP) modified with nanoscale zero valent iron (NZVI) and cetyl-trimethyl ammonium bromide was prepared and employed for the adsorption of molybdate (Mo(VI)) from aqueous solution. We investigated the effects of various conditions on Mo(VI) adsorption and evaluated the results based on adsorption kinetics models and isotherm equations. The kinetic data fitted to the pseudo-second-order model. The Langmuir model best described the adsorption of Mo(VI) on MCPP. The values of changes in Gibbs free energy, standard enthalpy, and standard entropy revealed that the adsorption process was feasible, spontaneous and endothermal. X-ray diffraction, Fourier transform infrared and X-ray photoelectron spectroscopy measurements suggested that Mo(VI) adsorption occurred via both the reduction and surface adsorption. Thus, biochar, prepared from fruit residue, can be applied to remove Mo(VI) from aqueous solutions. More importantly, our results provide a sustainable approach for Mo(VI) removal from wastewater by means of functional modification. PMID- 30016304 TI - Chemical coagulation of greywater: modelling using artificial neural networks. AB - In the present study, chemical coagulation with alum and polyaluminium chloride (PACl) was utilized for greywater treatment. More than 140 jar tests on greywater with varying characteristics were conducted in order to determine the optimum coagulant dosage and treated greywater characteristics. The average removal efficiencies of turbidity, chemical oxygen demand (COD) and total suspended solids were obtained as 91, 73 and 83% using alum and 93, 74 and 89% using PACl, respectively. For similar initial turbidity levels, optimum PACl dosages required were significantly less compared to optimum alum dosages. Further, PACl produced treated greywater with lower levels of turbidity compared to alum. Results of the coagulation tests were used to design artificial neural network (ANN) models for the prediction of the optimum coagulant dosage and treated greywater quality parameters. ANN models with initial turbidity, pH, conductivity and alkalinity as the input parameters could predict the optimum coagulant dose and treated greywater quality. The performance of the models was found to be good, with correlation coefficient values greater than 0.80. Empirical formulas for the prediction of alum and PACl dosages were also derived using the algorithm weights and bias values from the networks eliminating the need for running the ANN software. PMID- 30016305 TI - Removal of synthetic and industrial effluent color by photocatalytic process. AB - The present work aimed at evaluating the photocatalytic process as an alternative for color removal from a synthetic solution (methylene blue dye) and of a sample of textile effluent, obtained from the various stages of the process, mainly dyeing. The parameters were evaluated using titanium dioxide (anatase, rutile, commercial and synthetized by the sol-gel method) in order to determine their structural influence in the discoloration of the samples. A synthetic methylene blue dye solution and a real effluent (Brazilian textile industry) were treated. The photocatalytic degradation was carried out over three hours in a batch reactor, under constant agitation, aeration, radiation and temperature. It was observed that the characteristics of each catalyst directly influence the photocatalytic activity. As a result, for the variables used in this work, the photocatalyst TiO2 anatase phase with a concentration of 1 kg/m3 was the most efficient condition, presenting full color removal for the methylene blue and 71% for the sifted textile effluent. PMID- 30016306 TI - Development of platinum supported on single-walled carbon nanotubes by deposition precipitation for microbial fuel cells. AB - Microbial fuel cells (MFCs) are an ecologically friendly technology that can recover electricity and simultaneously treat wastewater. Among all the influential factors, cathode material and catalyst play a crucial role in electricity production and oxygen reduction. In this study, Pt nanocatalysts deposited on single-walled carbon nanotubes (Pt/SWCNTs) were synthesized by the deposition-precipitation (DP) method under optimal conditions. The results show that DP might be a promising method for the preparation of Pt/SWCNTs due to its simple, cost-effective and time-saving procedure, in addition to being highly efficient at creating small Pt particles (0.9 nm) that were very uniformly distributed. The synthesized Pt/SWCNTs suspension was spray-coated on to carbon cloth and then used as a cathode for MFCs. The electricity generation of MFCs equipped with a Pt/SWCNTs cathode was evaluated in terms of open circuit voltage (0.6954 V), internal resistance (63.3 Omega*m2) and maximum power density (2,022 mW/m2). The chemical oxygen demand removal, biological oxygen demand removal, total dissolved solids removal, total suspended solids removal and silver recovery was satisfactory at 84.5%, 74.0%, 45.7%, 60.0% and 99.0%, respectively. Therefore, Pt/SWCNTs from the DP method was identified as a potential candidate to replace commercial Pt-carbon cloth for MFC cathodes. PMID- 30016307 TI - A green method based on electro-assisted and photo-assisted regeneration for removal of chromium(VI) from aqueous solution. AB - In general, spent adsorbent is regenerated using high-concentration chemicals. Although chemical regeneration is efficient, it often leads to adsorbent damage and secondary waste. To overcome these problems, electro-assisted and photo assisted regeneration were proposed in this study for the remediation of hexavalent chromium (Cr(VI)). Filter paper was decorated with polyethylene glycol (PEG) and polypyrrole (PPy) to fabricate a FP/PEG/PPy nanocomposite, which could be used as an adsorbent for Cr(VI) with a high adsorption capacity. Moreover, it could be regenerated by electro-assisted or photo-assisted regeneration to reduce eluent use. As a result, secondary waste could be greatly reduced. PMID- 30016308 TI - Sensitivity analysis of the WATER9 model: emissions of odorous compounds from passive liquid surfaces present in wastewater treatment plants. AB - Empirical mathematical models have been frequently used to estimate emissions and to act in the prevention of possible impacts from odorous compounds. Based on the regulatory WATER9 model, the present study had the aim to evaluate the deviations originating from the simplification of using the effective diameter (in contrast to the conceptually appropriate use of the linear physical fetch) as fetch parameter in the calculation of the global mass transfer coefficient at passive liquid surfaces at wastewater treatment plants (WWTPs). The present analysis incorporated the influence of different values of wind velocity, molecular diffusivity and Henry's Law constant. The analyses for the calculation of the mass transfer coefficients were developed for 1,000 wind speeds, chosen using the Monte Carlo method, three WWTPs and three compounds of environmental relevance, spanning different behaviour regarding their volatilisation. The wind speed had a direct influence on the deviations for all types of compounds analysed. However, this parameter was found to be more representative for the compounds whose volatilisation is limited by conditions in the liquid phase. Furthermore, the deviations for the calculation of the mass transfer coefficient arising from the use of the effective diameter as fetch parameter were significantly larger for liquid phase-dominated compounds, compared to gas phase-dominated compounds. Comparison against available experimental data confirm that the use of the effective diameter as the fetch parameter makes the model predictions further depart from the experimental values. The present analysis shows that, for a varied range of wind speed and WWTP configurations, the use of the actual physical fetch shall be preferred over the use of the effective diameter in emission models for WWTPs, so as to avoid the introduction of potentially large systematic deviations. PMID- 30016309 TI - Evaluation of phosphate ion adsorption from aqueous solution by nickel-aluminum complex hydroxides. AB - We prepared a variety of nickel-aluminum complex hydroxides, investigated their physicochemical properties, and evaluated their ability to adsorb phosphate ions (the molar ratios of nickel to aluminum, 1:2, 1:1, 2:1, 3:1, and 4:1, are referred to as NA12, NA11, NA21, NA31, and NA41). NA12 and NA11 have amorphous structures; their specific surface areas and the concentration of associated hydroxyl groups were greater than those of other adsorbents. The number of phosphate ions adsorbed onto NA12 and NA11 was greater than that onto other adsorbents. These results indicated that the phosphate ion adsorption is related to the specific surface area and the amount of hydroxyl groups. The adsorption isotherm data, and the effects of contact time and pH on the adsorption were investigated; our results implied that both the Freundlich equation model and the pseudo-second-order kinetic model describe the adsorption of phosphate ions by NA11. We showed that phosphate ions adsorbed onto NA11 can be desorbed by sodium hydroxide solution at different concentrations and that NA11 could be reused for at least three repeated cycles of phosphate ion adsorption and desorption. This study illustrates that NA11 has the potential for practical application as an adsorbent for phosphate ions from wastewater. PMID- 30016310 TI - Corrigendum: Water Science and Technology 2017 (1), 36-47: Taguchi optimization approach for metronidazole removal from aqueous solutions by using graphene oxide functionalized beta-cyclodextrin/Ag nanocomposite. PMID- 30016311 TI - Renal tubular solute transport and oxygen consumption: insights from computational models. AB - PURPOSE OF REVIEW: To maintain electrolyte homeostasis, the kidneys reabsorb more than 99% of the filtered Na under physiological conditions, resulting in less than 1% of the filtered Na excreted in urine. In contrast, due to distal tubular secretion, urinary K output may exceed filtered load. This review focuses on a relatively new methodology for investigating renal epithelial transport, computational modelling and highlights recent insights regarding renal Na and K transport and O2 consumption under pathophysiological conditions, with a focus on nephrectomy. RECENT FINDINGS: Recent modelling studies investigated the extent to which the adaptive response to nephrectomy, which includes elevation in single nephron glomerular filtration rate and tubular transport capacity, may achieve balance but increases O2 consumption per nephron. Simulation results pointed to potential mechanisms in a hemi-nephrectomized rat that may attenuate the natriuresis response under K load, or that may augment the natriuretic, diuretic and kaliuretic effects of sodium glucose cotransporter 2 inhibition. SUMMARY: Computational models provide a systemic approach for investigating system perturbations, such as those induced by drug administration or genetic alterations. Thus, computational models can be a great asset in data interpretation concerning (but not limited to) renal tubular transport and metabolism. PMID- 30016312 TI - Analysis of Diagnostic Methods for Focal Lesions in Breast Glands with Use of Open Surgical Biopsies and Core-Needle Biopsies in Poland. AB - BACKGROUND Numerous studies confirm the benefits of using core-needle biopsy (CNB) for diagnosing patients with suspected breast cancer, thus reducing the costs and the stress, and allowing optimum treatment planning. The present study examined the number of patients in Poland who had been diagnosed with breast cancer through inpatient open surgical biopsy (OSB) and CNB by province. MATERIAL AND METHODS This retrospective study used a health needs map to identify patients in 2014 and partially in 2015 who had had OSB or CNB of the breast performed on an inpatient basis due to benign breast lesions and whose diagnosis had been changed from benign to malignant. RESULTS Among the total number of hospitalizations (13 718 cases with OSB) due to benign lesions of the breast, 1506 patients had their diagnosis changed to malignant, constituting 8.59% of new breast cancer diagnoses across the country. The resulting diagnosis change from benign to malignant varied significantly across provinces, from 5.3% to 23.4%. Among the total of 7205 hospitalizations in 2014 with CNB performed using different methods, there were 1574 malignancies, amounting to 8.9% of new diagnoses in Poland. The use of inpatient CNB to diagnose breast cancer differed significantly across provinces, from 0.6% to 34.4%. CONCLUSIONS OSBs are too often used to diagnose focal lesions in breast glands in Poland. In some regions, CNBs are too frequently performed on an inpatient rather than outpatient basis, thereby requiring an analysis of the quality of and access to modern diagnostic methods. PMID- 30016314 TI - Carbon pricing, co-pollutants, and climate policy: Evidence from California. AB - In a Perspective, James Boyce and Michael Ash discuss Lara Cushing and colleagues' research study on the implications of California's policy on carbon trading. PMID- 30016313 TI - Proper conditional analysis in the presence of missing data: Application to large scale meta-analysis of tobacco use phenotypes. AB - Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values. Existing methods for imputing missing summary association statistics and using imputed values in meta-analysis, approximate conditional analysis, or simple strategies such as complete case analysis all have theoretical limitations. Applying these approaches can bias genetic effect estimates and lead to seriously inflated type-I or type-II errors in conditional analysis, which is a critical tool for identifying independently associated variants. To address this challenge and complement imputation methods, we developed a method to combine summary statistics across participating studies and consistently estimate joint effects, even when the contributed summary statistics contain large amounts of missing values. Based on this estimator, we proposed a score statistic called PCBS (partial correlation based score statistic) for conditional analysis of single-variant and gene-level associations. Through extensive analysis of simulated and real data, we showed that the new method produces well-calibrated type-I errors and is substantially more powerful than existing approaches. We applied the proposed approach to one of the largest meta-analyses to date for the cigarettes-per-day phenotype. Using the new method, we identified multiple novel independently associated variants at known loci for tobacco use, which were otherwise missed by alternative methods. Together, the phenotypic variance explained by these variants was 1.1%, improving that of previously reported associations by 71%. These findings illustrate the extent of locus allelic heterogeneity and can help pinpoint causal variants. PMID- 30016315 TI - A quantitative physical model of the TMS-induced discharge artifacts in EEG. AB - The combination of Transcranial Magnetic Stimulation (TMS) with Electroencephalography (EEG) exposes the brain's global response to localized and abrupt stimulations. However, large electric artifacts are induced in the EEG by the TMS, obscuring crucial stages of the brain's response. Artifact removal is commonly performed by data processing techniques. However, an experimentally verified physical model for the origin and structure of the TMS-induced discharge artifacts, by which these methods can be justified or evaluated, is still lacking. We re-examine the known contribution of the skin in creating the artifacts, and outline a detailed model for the relaxation of the charge accumulated at the electrode-gel-skin interface due to the TMS pulse. We then experimentally validate implications set forth by the model. We find that the artifacts decay like a power law in time rather than the commonly assumed exponential. In fact, the skin creates a power-law decay of order 1 at each electrode, which is turned into a power law of order 2 by the reference electrode. We suggest an artifact removal method based on the model which can be applied from times after the pulse as short as 2 milliseconds onwards to expose the full EEG from the brain. The method can separate the capacitive discharge artifacts from those resulting from cranial muscle activation, demonstrating that the capacitive effect dominates at short times. Overall, our insight into the physical process allows us to accurately access TMS-evoked EEG responses that directly follow the TMS pulse, possibly opening new opportunities in TMS-EEG research. PMID- 30016316 TI - Improving rational use of ACTs through diagnosis-dependent subsidies: Evidence from a cluster-randomized controlled trial in western Kenya. AB - BACKGROUND: More than half of artemisinin combination therapies (ACTs) consumed globally are dispensed in the retail sector, where diagnostic testing is uncommon, leading to overconsumption and poor targeting. In many malaria-endemic countries, ACTs sold over the counter are available at heavily subsidized prices, further contributing to their misuse. Inappropriate use of ACTs can have serious implications for the spread of drug resistance and leads to poor outcomes for nonmalaria patients treated with incorrect drugs. We evaluated the public health impact of an innovative strategy that targets ACT subsidies to confirmed malaria cases by coupling free diagnostic testing with a diagnosis-dependent ACT subsidy. METHODS AND FINDINGS: We conducted a cluster-randomized controlled trial in 32 community clusters in western Kenya (population approximately 160,000). Eligible clusters had retail outlets selling ACTs and existing community health worker (CHW) programs and were randomly assigned 1:1 to control and intervention arms. In intervention areas, CHWs were available in their villages to perform malaria rapid diagnostic tests (RDTs) on demand for any individual >1 year of age experiencing a malaria-like illness. Malaria RDT-positive individuals received a voucher for a discount on a quality-assured ACT, redeemable at a participating retail medicine outlet. In control areas, CHWs offered a standard package of health education, prevention, and referral services. We conducted 4 population based surveys-at baseline, 6 months, 12 months, and 18 months-of a random sample of households with fever in the last 4 weeks to evaluate predefined, individual level outcomes. The primary outcome was uptake of malaria diagnostic testing at 12 months. The main secondary outcome was rational ACT use, defined as the proportion of ACTs used by test-positive individuals. Analyses followed the intention-to-treat principle using generalized estimating equations (GEEs) to account for clustering with prespecified adjustment for gender, age, education, and wealth. All descriptive statistics and regressions were weighted to account for sampling design. Between July 2015 and May 2017, 32,404 participants were tested for malaria, and 10,870 vouchers were issued. A total of 7,416 randomly selected participants with recent fever from all 32 clusters were surveyed. The majority of recent fevers were in children under 18 years (62.9%, n = 4,653). The gender of enrolled participants was balanced in children (49.8%, n = 2,318 boys versus 50.2%, n = 2,335 girls), but more adult women were enrolled than men (78.0%, n = 2,139 versus 22.0%, n = 604). At baseline, 67.6% (n = 1,362) of participants took an ACT for their illness, and 40.3% (n = 810) of all participants took an ACT purchased from a retail outlet. At 12 months, 50.5% (n = 454) in the intervention arm and 43.4% (n = 389) in the control arm had a malaria diagnostic test for their recent fever (adjusted risk difference [RD] = 9 percentage points [pp]; 95% CI 2-15 pp; p = 0.015; adjusted risk ratio [RR] = 1.20; 95% CI 1.05-1.38; p = 0.015). By 18 months, the ARR had increased to 1.25 (95% CI 1.09-1.44; p = 0.005). Rational use of ACTs in the intervention area increased from 41.7% (n = 279) at baseline to 59.6% (n = 403) and was 40% higher in the intervention arm at 18 months (ARR 1.40; 95% CI 1.19-1.64; p < 0.001). While intervention effects increased between 12 and 18 months, we were not able to estimate longer-term impact of the intervention and could not independently evaluate the effects of the free testing and the voucher on uptake of testing. CONCLUSIONS: Diagnosis-dependent ACT subsidies and community-based interventions that include the private sector can have an important impact on diagnostic testing and population-wide rational use of ACTs. Targeting of the ACT subsidy itself to those with a positive malaria diagnostic test may also improve sustainability and reduce the cost of retail-sector ACT subsidies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02461628. PMID- 30016317 TI - Multidrug resistance among Escherichia coli and Klebsiella pneumoniae carried in the gut of out-patients from pastoralist communities of Kasese district, Uganda. AB - BACKGROUND: Antimicrobial resistance is a worldwide public health emergency that requires urgent attention. Most of the effort to prevent this coming catastrophe is occurring in high income countries and we do not know the extent of the problem in low and middle-income countries, largely because of low laboratory capacity coupled with lack of effective surveillance systems. We aimed at establishing the magnitude of antimicrobial resistance among Escherichia coli and Klebsiella pneumoniae carried in the gut of out-patients from pastoralist communities of rural Western Uganda. METHODS: A cross-sectional study was carried out among pastoralists living in and around the Queen Elizabeth Protected Area (QEPA). Stool samples were collected from individuals from pastoralist communities who presented to the health facilities with fever and/or diarrhea without malaria and delivered to the microbiology laboratory of College of Health Sciences-Makerere University for processing, culture and drug susceptibility testing. RESULTS: A total of 300 participants fulfilling the inclusion criteria were recruited into the study. Three hundred stool samples were collected, with 209 yielding organisms of interest. Out of 209 stool samples that were positive, 181 (89%) grew E. coli, 23 (11%) grew K. pneumoniae and five grew Shigella. Generally, high antibiotic resistance patterns were detected among E. coli and K. pneumoniae isolated. High resistance against cotrimoxazole 74%, ampicillin 67%, amoxicillin/clavulanate 37%, and ciprofloxacin 31% was observed among the E. coli. In K. pneumoniae, cotrimoxazole 68% and amoxicillin/clavulanate 46%, were the most resisted antimicrobials. Additionally, 57% and 82% of the E. coli and K. pneumoniae respectively were resistant to at least three classes of the antimicrobials tested. Resistance to carbapenems was not detected among K. pneumoniae and only 0.6% of the E. coli were resistant to carbapenems. Isolates producing ESBLs comprised 12% and 23% of E. coli and K. pneumoniae respectively. CONCLUSION: We demonstrated high antimicrobial resistance, including multidrug resistance, among E. coli and K. pneumoniae isolates from pastoralist out patients. We recommend a One Health approach to establish the sources and drivers of this problem to inform public health. PMID- 30016318 TI - Short-term association between ambient temperature and acute myocardial infarction hospitalizations for diabetes mellitus patients: A time series study. AB - BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death among people with diabetes mellitus (DM) and has been found to occur more frequently with extreme temperatures. With the increasing prevalence of DM and the rising global mean temperature, the number of heat-related AMI cases among DM patients may increase. This study compares excess risk of AMI during periods of extreme temperatures between patients with DM and without DM. METHODS: Distributed lag nonlinear models (DLNMs) were used to estimate the short-term association between daily mean temperature and AMI admissions (International Classification of Diseases 9th revision [ICD-9] code: 410.00-410.99), stratified by DM status (ICD 9: 250.00-250.99), to all public hospitals in Hong Kong from 2002 to 2011, adjusting for other meteorological variables and air pollutants. Analyses were also stratified by season, age group, gender, and admission type (first admissions and readmissions). The admissions data and meteorological data were obtained from the Hong Kong Hospital Authority (HA) and the Hong Kong Observatory (HKO). FINDINGS: A total of 53,769 AMI admissions were included in the study. AMI admissions among DM patients were linearly and negatively associated with temperature in the cold season (cumulative relative risk [cumRR] [95% confidence interval] in lag 0-22 days (12 degrees C versus 24 degrees C) = 2.10 [1.62 2.72]), while those among patients without DM only started increasing when temperatures dropped below 22 degrees C with a weaker association (cumRR = 1.43 [1.21-1.69]). In the hot season, AMI hospitalizations among DM patients started increasing when the temperature dropped below or rose above 28.8 degrees C (cumRR in lag 0-4 days [30.4 versus 28.8 degrees C] = 1.14 [1.00-1.31]), while those among patients without DM showed no association with temperature. The differences in sensitivity to temperature between patients with DM and without DM were most apparent in the group <75 years old and among first-admission cases in the cold season. The main limitation of this study was the unavailability of data on individual exposure to ambient temperature. CONCLUSIONS: DM patients had a higher increased risk of AMI admissions than non-DM patients during extreme temperatures. AMI admissions risks among DM patients rise sharply in both high and low temperatures, with a stronger effect in low temperatures, while AMI risk among non-DM patients only increased mildly in low temperatures. Targeted health protection guidelines should be provided to warn DM patients and physicians about the dangers of extreme temperatures. Further studies to project the impacts of AMI risks on DM patients by climate change are warranted. PMID- 30016319 TI - Nonlinear and delayed impacts of climate on dengue risk in Barbados: A modelling study. AB - BACKGROUND: Over the last 5 years (2013-2017), the Caribbean region has faced an unprecedented crisis of co-occurring epidemics of febrile illness due to arboviruses transmitted by the Aedes sp. mosquito (dengue, chikungunya, and Zika). Since 2013, the Caribbean island of Barbados has experienced 3 dengue outbreaks, 1 chikungunya outbreak, and 1 Zika fever outbreak. Prior studies have demonstrated that climate variability influences arbovirus transmission and vector population dynamics in the region, indicating the potential to develop public health interventions using climate information. The aim of this study is to quantify the nonlinear and delayed effects of climate indicators, such as drought and extreme rainfall, on dengue risk in Barbados from 1999 to 2016. METHODS AND FINDINGS: Distributed lag nonlinear models (DLNMs) coupled with a hierarchal mixed-model framework were used to understand the exposure-lag response association between dengue relative risk and key climate indicators, including the standardised precipitation index (SPI) and minimum temperature (Tmin). The model parameters were estimated in a Bayesian framework to produce probabilistic predictions of exceeding an island-specific outbreak threshold. The ability of the model to successfully detect outbreaks was assessed and compared to a baseline model, representative of standard dengue surveillance practice. Drought conditions were found to positively influence dengue relative risk at long lead times of up to 5 months, while excess rainfall increased the risk at shorter lead times between 1 and 2 months. The SPI averaged over a 6-month period (SPI-6), designed to monitor drought and extreme rainfall, better explained variations in dengue risk than monthly precipitation data measured in millimetres. Tmin was found to be a better predictor than mean and maximum temperature. Furthermore, including bidimensional exposure-lag-response functions of these indicators-rather than linear effects for individual lags-more appropriately described the climate-disease associations than traditional modelling approaches. In prediction mode, the model was successfully able to distinguish outbreaks from nonoutbreaks for most years, with an overall proportion of correct predictions (hits and correct rejections) of 86% (81%:91%) compared with 64% (58%:71%) for the baseline model. The ability of the model to predict dengue outbreaks in recent years was complicated by the lack of data on the emergence of new arboviruses, including chikungunya and Zika. CONCLUSION: We present a modelling approach to infer the risk of dengue outbreaks given the cumulative effect of climate variations in the months leading up to an outbreak. By combining the dengue prediction model with climate indicators, which are routinely monitored and forecasted by the Regional Climate Centre (RCC) at the Caribbean Institute for Meteorology and Hydrology (CIMH), probabilistic dengue outlooks could be included in the Caribbean Health-Climatic Bulletin, issued on a quarterly basis to provide climate-smart decision-making guidance for Caribbean health practitioners. This flexible modelling approach could be extended to model the risk of dengue and other arboviruses in the Caribbean region. PMID- 30016320 TI - EPG combined with micro-CT and video recording reveals new insights on the feeding behavior of Philaenus spumarius. AB - The meadow spittlebug Philaenus spumarius plays a key role in the transmission of the bacterium Xylella fastidiosa to olive in Apulia (South Italy). Currently, available data on P. spumarius feeding behavior is limited, and a real-time observation of the different steps involved in stylet insertion, exploratory probes, and ingestion, has never been carried out. Therefore, we performed an EPG assisted characterization of P. spumarius female feeding behavior on olive, in order to detect and analyze the main EPG waveforms describing their amplitude, frequency, voltage level, and electrical origin of the traces during stylet penetration in plant tissues. Thereafter, each of the main waveforms was correlated with specific biological activities, through video recording and analysis of excretion by adults and excretion/secretion by nymphs. Furthermore, the specific stylet tips position within the plant tissues during each of the waveforms observed was assessed by microcomputer tomography (micro-CT). Additional EPG-recordings were carried out with males of P. spumarius on olive, in order to assess possible sex-related differences. P. spumarius feeding behavior can be described by five main distinct waveforms: C (pathway), Xc (xylem contact/pre-ingestion), Xi (xylem sap ingestion), R (resting), N (interruption within xylem phase). Compared to males, females require shorter time to begin the first probe, and their Xi phase is significantly longer. Furthermore, considering the single waveform events, males on olive exhibit longer np and R compared to females. PMID- 30016321 TI - Correction: Prevalence and risk factors of chlamydia infection in Hong Kong: A population-based geospatial household survey and testing. AB - [This corrects the article DOI: 10.1371/journal.pone.0172561.]. PMID- 30016322 TI - Qualitative study for betel quid cessation among oral cancer patients. AB - The psychoactive effects of using areca nut and its potential for dependence have been observed. However, the factors that create barriers to or promote chewing cessation are not well understood. This study aims to explore the behavioral changes of betel quid chewers who have been diagnosed with oral cancer within a transtheoretical model framework. Thirty oral cancer patients with betel quid chewing history were chosen for in-depth interviews. Qualitative content analysis was used to analyze the data and identify themes that described the behavioral changes of betel quid cessation. Our research showed that betel quid chewers with oral cancer typically experience four significant stages of behavior: pre contemplation, contemplation, action, and maintenance. Each stage change was marked by specific characteristics. At first, chewers showed positive attitudes toward the psychoactive or social effects of betel quid. They then realized the negative effects of betel quid, such as dental or other physical problems. Some also realized that they were addicted to betel quid. When they decided to quit, most chewers reported going "cold turkey." Some chewers successfully quit betel quid and attributed it to willpower. Those quitting because of the loss of oral functions were unable to chew anymore, though some chewers had experienced a relapse. In the maintenance stage, ex-chewers reported overcoming their addiction; however, relapse was possible. In this study, those who quit betel quid because of oral cancer usually quit tobacco and alcohol as well, with a lesser chance of recurrence. As the maintenance of chewing betel quid is multifactorial, this study provides information for betel quid cessation and oral cancer prevention. PMID- 30016323 TI - Improving forecasting accuracy for stock market data using EMD-HW bagging. AB - Many researchers documented that the stock market data are nonstationary and nonlinear time series data. In this study, we use EMD-HW bagging method for nonstationary and nonlinear time series forecasting. The EMD-HW bagging method is based on the empirical mode decomposition (EMD), the moving block bootstrap and the Holt-Winter. The stock market time series of six countries are used to compare EMD-HW bagging method. This comparison is based on five forecasting error measurements. The comparison shows that the forecasting results of EMD-HW bagging are more accurate than the forecasting results of the fourteen selected methods. PMID- 30016324 TI - HIV-1 infection among crack cocaine users in a region far from the epicenter of the HIV epidemic in Brazil: Prevalence and molecular characteristics. AB - Brazil has the largest cocaine market in South America, and crack cocaine use is closely associated with HIV-1 infection. This study investigated the prevalence, risk factors, and HIV-1 subtypes, including recombinant forms and mutations associated with drug resistance, among crack cocaine users in Central-West Brazil. We recruited 600 crack cocaine users admitted to a referral hospital in Goiania for psychiatric disorders. The participants were interviewed; blood samples were collected for anti-HIV-1/2 serological screening. HIV-1 pol gene sequences (entire protease [PR] and partial reverse transcriptase [RT]) were obtained from plasma RNA. HIV-1 subtypes, recombinant viruses, transmitted drug resistance (TDR), and secondary drug resistance mutations were investigated. The median participant age was 30 years (range, 18-68 years); most were male, single, unemployed, and of mixed races. Among them, 2.8% (17/600) were HIV-1 positive: 2.2% of men (11/507) and 6.5% of women (6/93). The main predictors of HIV-1 seropositivity were a sexual partner with HIV infection, irregular condom use, and previous homelessness. HIV-1 pol sequences (12/17) indicated the predominance of subtype B (n = 7), followed by recombinant forms FPR/BRT (n = 1) and BPR/FRT (n = 2) and subtypes F1 (n = 1) and C (n = 1). TDR prevalence was 58.3% (7/12). Isolates from two participants showed mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI) only (M41L, T125C, T125F, M184V), while an isolate from one patient who had received antiretroviral therapy (ART) since 2008 had a mutation associated with resistance to non-NRTI (G190S). Five isolates had secondary mutations to protease inhibitors (K20M, L10V, L33I, A71T, A71V). In conclusion, the findings of HIV-1 circulation, TDR to NRTI, and secondary mutations to protease inhibitors in ART-naive crack cocaine users support the importance of monitoring this population in regions far from the epicenter of the HIV epidemic. PMID- 30016325 TI - Development of a prediction model for late urinary incontinence, hematuria, pain and voiding frequency among irradiated prostate cancer patients. AB - BACKGROUND AND PURPOSE: Incontinence, hematuria, voiding frequency and pain during voiding are possible side effects of radiotherapy among patients treated for prostate cancer. The objective of this study was to develop multivariable NTCP models for these side effects. MATERIAL AND METHODS: This prospective cohort study was composed of 243 patients with localized or locally advanced prostate cancer (stage T1-3). Genito-urinary (GU) toxicity was assessed using a standardized follow-up program. The GU toxicity endpoints were scored using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 3.0) scoring system. The full bladder and different anatomical subregions within the bladder were delineated. A least absolute shrinkage and selection operator (LASSO) logistic regression analysis was used to analyze dose volume effects on the four individual endpoints. RESULTS: In the univariable analysis, urinary incontinence was significantly associated with dose distributions in the trigone (V55-V75, mean). Hematuria was significantly associated with the bladder wall dose (V40 V75, mean), bladder dose (V70-V75), cardiovascular disease and anticoagulants use. Pain during urinating was associated with the dose to the trigone (V50-V75, mean) and with trans transurethral resection of the prostate (TURP). In the final multivariable model urinary incontinence was associated with the mean dose of the trigone. Hematuria was associated with bladder wall dose (V75) and cardiovascular disease, while pain during urinating was associated with trigone dose (V75) and TURP. No significant associations were found for increase in voiding frequency. CONCLUSIONS: Radiation-induced urinary side effects are associated with dose distributions to different organs as risk. Given the dose effect relationships found, decreasing the dose to the trigone and bladder wall may reduce the incidence of incontinence, pain during voiding and hematuria, respectively. PMID- 30016326 TI - Establishing a mucosal gut microbial community in vitro using an artificial simulator. AB - The Twin Simulator of the Human Intestinal Microbial Ecosystem (TWINSHIME(r)) was initially developed to study the luminal gut microbiota of the ascending (AC), transverse (TC), and descending (DC) colon regions. Given the unique composition and potential importance of the mucosal microbiota for human health, the TWINSHIME was recently adapted to simulate the mucosal microbiota as well as the luminal community. It has been previously demonstrated that the luminal community in the TWINSHIME reaches a steady state within two weeks post inoculation, and is able to differentiate into region specific communities. However, less is known regarding the mucosal community structure and dynamics. During the current study, the luminal and mucosal communities in each region of the TWINSHIME were evaluated over the course of six weeks. Based on 16S rRNA gene sequencing and short chain fatty acid analysis, it was determined that both the luminal and mucosal communities reached stability 10-20 days after inoculation, and remained stable until the end of the experiment. Bioinformatics analysis revealed the formation of unique community structures between the mucosal and luminal phases in all three colon regions, yet these communities were similar to the inoculum. Specific colonizers of the mucus mainly belonged to the Firmicutes phylum and included Lachnospiraceae (AC/TC/DC), Ruminococcaceae and Eubacteriaceae (AC), Lactobacillaceae (AC/TC), Clostridiaceae and Erysipelotrichaceae (TC/DC). In contrast, Bacteroidaceae were enriched in the gut lumen of all three colon regions. The unique profile of short chain fatty acid (SCFA) production further demonstrated system stability, but also proved to be an area of marked differences between the in vitro system and in vivo reports. Results of this study demonstrate that it is possible to replicate the community structure and composition of the gut microbiota in vitro. Through implementation of this system, the human gut microbiota can be studied in a dynamic and continuous fashion. PMID- 30016327 TI - Unscheduled DNA synthesis leads to elevated uracil residues at highly transcribed genomic loci in Saccharomyces cerevisiae. AB - Recombination and mutagenesis are elevated by active transcription. The correlation between transcription and genome instability is largely explained by the topological and structural changes in DNA and the associated physical obstacles generated by the transcription machinery. However, such explanation does not directly account for the unique types of mutations originating from the non-canonical residues, uracil or ribonucleotide, which are also elevated at highly transcribed regions. Based on the previous findings that abasic (AP) lesions derived from the uracil residues incorporated into DNA in place of thymine constitute a major component of the transcription-associated mutations in yeast, we formed the hypothesis that DNA synthesis ensuing from the repair of the transcription-induced DNA damage provide the opportunity for uracil incorporation. In support of this hypothesis, we show here the positive correlation between the level of transcription and the density of uracil residues in the yeast genome indirectly through the mutations generated by the glycosylase that excise undamaged cytosine as well as uracil. The higher uracil-density at actively transcribed regions is confirmed by the long-amplicon PCR analysis. We also show that the uracil-associated mutations at a highly transcribed region are elevated by the induced DNA damage and reduced by the overexpression of a dUTP catalyzing enzyme Dut1 in G1- or G2-phases of the cell cycle. Overall, our results show that the DNA composition can be modified to include higher uracil content through the non-replicative, repair-associated DNA synthesis. PMID- 30016329 TI - Exploring an alternative explanation for the second phase of viral decay: Infection of short-lived cells in a drug-limited compartment during HAART. AB - Most HIV-infected patients who initiate combination antiretroviral therapy experience a viral load decline in several phases. These phases are characterized by different rates of viral load decay that decrease when transitioning from one phase to the next. There is no consensus as to the origin of these phases. One hypothesis put forward is that short- and long-lived infected cells are responsible for the first and second phases of decay, respectively. However, significant differences in drug concentrations are observed in monocytes from various tissues, suggesting the first two phases of decay in viral loads could instead be attributed to short-lived cells being differently exposed to drugs. Compared to a well-exposed compartment, new cell infection can be expected in a compartment with limited drug exposure, thus leading to a slower viral load decay with potential virologic failure and drug resistance. In the current study, the latter hypothesis was investigated using a model of viral kinetics. Empirical datasets were involved in model elaboration and parameter estimation. In particular, susceptibility assay data was used for an in vitro to in vivo extrapolation based on the expected drug concentrations inside physiological compartments. Results from numerical experiments of the short-term evolution of viral loads can reproduce the first two phases of viral decay when allowing new short-lived cell infections in an unidentified drug-limited compartment. Model long-term predictions are however less consistent with clinical observations. For the hypothesis to hold, efavirenz, tenofovir and emtricitabine drug exposure in the drug-limited compartment would have to be very low compared to exposure in peripheral blood. This would lead to significant long-term viral growth and the frequent development of resistant strains, a prediction not supported by clinical observations. This suggests that the existence of a drug-limited anatomical compartment is unlikely, by itself, to explain the second phase of viral load decay. PMID- 30016330 TI - Detection of cooperatively bound transcription factor pairs using ChIP-seq peak intensities and expectation maximization. AB - Transcription factors (TFs) often work cooperatively, where the binding of one TF to DNA enhances the binding affinity of a second TF to a nearby location. Such cooperative binding is important for activating gene expression from promoters and enhancers in both prokaryotic and eukaryotic cells. Existing methods to detect cooperative binding of a TF pair rely on analyzing the sequence that is bound. We propose a method that uses, instead, only ChIP-seq peak intensities and an expectation maximization (CPI-EM) algorithm. We validate our method using ChIP seq data from cells where one of a pair of TFs under consideration has been genetically knocked out. Our algorithm relies on our observation that cooperative TF-TF binding is correlated with weak binding of one of the TFs, which we demonstrate in a variety of cell types, including E. coli, S. cerevisiae and M. musculus cells. We show that this method performs significantly better than a predictor based only on the ChIP-seq peak distance of the TFs under consideration. This suggests that peak intensities contain information that can help detect the cooperative binding of a TF pair. CPI-EM also outperforms an existing sequence-based algorithm in detecting cooperative binding. The CPI-EM algorithm is available at https://github.com/vishakad/cpi-em. PMID- 30016331 TI - Effects of olanzapine on resting heart rate in Japanese patients with schizophrenia. AB - It has long been known that antipsychotic drugs (ATP) causes tachycardia, however details such as the differences between ATP are not well known. In recent years, the relationship between the rise in resting heart rate (RHR) and the increased risk of death in the general population has been garnering attention. In this study, we examined the difference in action on RHR between olanzapine (OLZ) and aripiprazole (ARP). The changes in the RHR on switching from OLZ to ARP and on increasing from the starting OLZ dose to the final one were evaluated in 19 outpatients (Study 1) and in 29 outpatients with schizophrenia (Study 2), respectively. To analyze the RHR, electrocardiographic measurements were obtained. At the same day, the Brief Psychiatric Rating Scale (BPRS) was evaluated, and fasting blood samples were drawn after an overnight fast of at least 8 h to examine electrolytes. Both Study 1 and 2 were conducted with the approval of the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences, and the patients were treated at the outpatient psychiatric clinic at Niigata University Medical and Dental Hospital. All patients had been diagnosed with schizophrenia based on the DSM-IV-TR. In the Study 1, OLZ of 14.6 +/- 9.2mg (mean +/- standard deviation) was switched to ARP of 20.8 +/- 8.1mg. Significant decreases were observed in the mean RHR after the switch to ARP (73.7 +/- 9.7 vs 65.8 +/- 10.9 beats/min, p = 0.008). In the Study 2, the starting OLZ dose was 7.2 +/- 3.2mg and the increasing OLZ dose was 18.3 +/- 7.4mg. Significant increases were observed in the mean RHR after increasing OLZ (69.7 +/- 14.0 vs 75.6 +/- 14.3 beats/min, p = 0.004). In this study, it was shown that OLZ has a stronger RHR enhancing effect compared to ARP and its effects are dose-dependent. If the increase in RHR increases the mortality rate of patients with schizophrenia, it may be necessary to further investigate the differences between ATP in terms of the effect on RHR of second-generation antipsychotics with a strong anticholinergic action or phenothiazine antipsychotics. PMID- 30016328 TI - Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. AB - BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP. METHODS AND FINDINGS: We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68 3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87 10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy. CONCLUSIONS: Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02163447. PMID- 30016332 TI - Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development. AB - Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9, Il6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, Il6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkb1 (produced in most immune cells) as key regulators of ANoA development in HgIA. PMID- 30016333 TI - Long-term outcome of low-energy extracorporeal shockwave therapy on gluteal tendinopathy documented by magnetic resonance imaging. AB - BACKGROUND: Previous outcome studies for extracorporeal shock wave therapy (ESWT) have included clinically diagnosed greater trochanteric pain syndrome (GTPS). The purpose of this study is to investigate outcome of ESWT on GTPS with gluteal tendinopathy documented by magnetic resonance imaging (MRI). METHODS: Medical records of 38 consecutive patients were retrospectively reviewed, who underwent ESWT for GTPS with MRI-documented gluteal tendinopathy (> 6 months). ESWT was conducted (1/week) when the Roles-Maudsley score (RMS) showed "Poor" or "Fair" grade after conservative treatment until RMS had reached "Good" or "Excellent" grade (treatment success) or until 12 treatments had been applied. Numeric rating scale (NRS) and RMS were evaluated before, 1 week after (immediate follow-up) and mean 27 months after ESWT program (long-term follow-up). Success rate was calculated at each follow-up point. RESULTS: Initial NRS (5.9 +/- 1.6) significantly decreased at immediate (2.5 +/- 1.5, p< 0.01) and long-term follow up (3.3 +/- 3.0, p< 0.01), respectively. Success rates were 83.3% (immediate) and 55.6% (long-term), respectively. There was no correlation among age, symptom duration and NRS. CONCLUSION: Low-energy ESWT can be an effective treatment for pain relief in chronic GTPS with MRI-documented gluteal tendinopathy. However, its long-term effect appears to decrease with time. PMID- 30016334 TI - Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis. AB - Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data. PMID- 30016336 TI - Effect of site of placentation on pregnancy outcomes in patients with placenta previa. AB - INTRODUCTION: We aimed to evaluate the site of placentation on the pregnancy outcomes of patients with placenta previa. METHODS: This retrospective study included 678 cases of placenta previa. Basic information and pregnancy outcome data were collected. Differences between the different placenta previa positions and pregnancy outcomes were compared using the chi-square and independent t tests. Logistic and multiple regression analyses were used to calculate the odds ratios (ORs) to determine the risk factors for PAS disorders and postpartum hemorrhage and evaluate the effect of placental attachment site on pregnancy outcomes. RESULTS: There was no significant difference between the PAS disorders rate and the incidence of complete placenta previa depending on the type of placentation; however, placental attachment site influenced the pregnancy outcome. Placental attachment to the anterior wall was associated with shorter gestational age, low birth weight, lower Apgar score, higher prenatal bleeding rate, increased postpartum hemorrhage, longer duration of hospitalization, and higher blood transfusion and hysterectomy rates compared to cases with lateral/posterior wall placenta. Placental attachment at the incision site of a previous cesarean section significantly increased the incidence of complete placenta previa and PAS disorders compared with placental attachment at a site without incision, but did not significantly influence pregnancy outcomes. Placental attachment to the anterior wall was an independent risk factor for postpartum hemorrhage in patients with placenta previa. Placental attachment to a previous incision site was an independent risk factor for PAS disorders. CONCLUSION: The site of placental attachment in patients with placenta previa has an important influence on the pregnancy outcome. When the placenta is located on the anterior wall, clinicians should pay attention to the adverse pregnancy outcomes and the possibility of massive postpartum hemorrhage. In cases of placental attachment to the uterine incision site, physicians should be highly vigilant regarding the occurrence of PAS disorders. PMID- 30016335 TI - No association between IFNL3 (IL28B) genotype and response to peginterferon alfa 2a in HBeAg-positive or -negative chronic hepatitis B. AB - BACKGROUND & AIMS: It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. METHODS: Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. RESULTS: The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. CONCLUSIONS: This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg negative patients. PMID- 30016337 TI - Assessment of northern bobwhite survival and fitness in the West Gulf Coastal Plain ecoregion. AB - In the West Gulf Coastal Plains (WGCP) northern bobwhite (Colinus virginianus) are declining faster than range-wide averages and such declines have been linked to the consequences of land management. Management for the endangered red cockaded woodpecker (Picoides borealis) has benefitted northern bobwhite by restoring mature pine-grassland ecosystems in some areas of the region. However, at Felsenthal National Wildlife Refuge, Crossett, Arkansas, USA, the bobwhite population was not increasing despite the availability of seemingly suitable habitat from management for the endangered species. To understand factors that may be affecting bobwhite survival on Felsenthal National Wildlife Refuge we conducted a telemetry study and assessed summer survival, brood survival, and nest success from 1 April- 11 August in 2013 and 1 April- 15 August in 2014. We also calculated home-range sizes and measured microhabitat characteristics around nests. Summer survival rates were 71% (SE = 0.17) and 47% (SE = 0.14); while nest success was 47% (SE = 0.02) and 100% for 2013 and 2014, respectively. Between years, both 95% and 50% kernel home-ranges were not different (pooled, 63.92+/ 6.07 ha and 14.94+/-1.75 ha); however minimum convex polygon home-range sizes were (113.8 +/- 20.1 ha in 2013; and 393.1 +/- 49.0 ha in 2014, P < 0.001). Only numerical differences in microhabitat vegetation characteristics of nest sites and non- nest sites were observed. We suggest management for red-cockaded woodpeckers supports bobwhite populations but only as a buffer against more severe declines. Since bobwhites are declining range-wide, we believe areas federally managed for red-cockaded woodpeckers will become increasingly more important for sustaining regional bobwhite population levels. PMID- 30016338 TI - A regulator of early flowering in barley (Hordeum vulgare L.). AB - Heading date (HD) of cereals is an important trait for adaptation to diverse environments and is critical for determining yield and quality and the number of genes and gene combinations that confer earliness in barley under short days is limited. In our study, a QTL for early flowering was identified from the cross between an Australian malting barley cultivar and a Chinese landrace. Four sets of near isogenic lines (NILs) were developed with a QTL located on chromosome 5H at the interval of 122.0-129.0 cM. Further experiments were conducted to investigate how this gene was regulated by photoperiod using the NILs with three sowing dates from autumn to summer. The NILs carrying the earliness allele were significantly earlier than the late genotype at all sowing dates. This gene was different from previously reported vernalisation genes that are located at a similar position as no vernalisation was required for all the NILs. The difference between this gene and Eam5 (HvPHYC) locus which also located between two co-segregated markers (3398516S5, 122.5 cM, and 4014046D5, 126.1 cM), is that with the existence of Ppd-H1 (Eam1), Eam5 has no effect on ear emergence under long days while the gene from TX9425 still reduced the time to ear emergency. The locus showed no pleiotropic effects on grain pasting properties and agronomic traits except for spike length and number of spikelets per spike, and thus can be effectively used in breeding programs. The array of early heading dates caused by interactions of Eam5 gene with other maturity genes provides an opportunity to better fine tune heading dates with production environments, which can be critical factor in barley breeding. PMID- 30016339 TI - First description of extrafloral nectaries in Opuntia robusta (Cactaceae): Anatomy and ultrastructure. AB - To our knowledge, there are no studies about the structure and ecological function of extrafloral nectaries (EFNs) in Opuntia robusta. This is the first description of EFNs in O. robusta, where young spines have an interesting structure and a secreting function, which are different from EFNs described in other Cactaceae species. We used light, scanning-electron, and transmission electron microscopy to examine morphology, anatomy, and ultrastructure of the secretory spines in areoles in female and hermaphrodite individuals of O. robusta. Young cladodes develop areoles with modified and secretory spines as EFNs only active during the early growth phase. EFNs are non-vascularized structures, with no stomata, that consist of a basal meristematic tissue, a middle elongation region, and an apical secretory cone formed by large globular epidermal cells, containing nectar and medullar elongated cells. We observed the presence of Golgi apparatus, vesicles and plastids in the medullar and sup epidermal cells of the spine. We propose that the nectar is stored in the globular cells at the apex of the spine and secreted by breaking through the globular cells or by pores. We recorded a more frequent presence of ants on younger cladode sprouts producing young secreting spines: this result is parallel with the predictions of Optimal Defense Hypothesis, which states that younger plant organs should be better defended than older ones because their loss produces a higher fitness impairment. Although Diaz-Castelazo's hypothesis states that a more complex structure of EFNs correlates with their lower among-organs dispersion, comparing to less complex EFNs, non-vascularized structure of EFNs in O. robusta is not associated with their higher among-organs dispersion likened to O. stricta, which produces vascularized EFNs. We provide evidence that this characteristic is not a good taxonomic feature of Opuntia genus. Moreover, the comparison of EFNs of O. robusta and O. stricta suggests that the hypothesis of Diaz-Castelazo should be revised: it is rather a rule but not a law. PMID- 30016340 TI - Macrobenthic communities in a shallow normoxia to hypoxia gradient in the Humboldt upwelling ecosystem. AB - Hypoxia is one of the most important stressors affecting the health conditions of coastal ecosystems. In highly productive ecosystems such as the Humboldt Current ecosystem, the oxygen minimum zone is an important abiotic factor modulating the structure of benthic communities over the continental shelf. Herein, we study soft-bottom macrobenthic communities along a depth gradient-at 10, 20, 30 and 50 m-for two years to understand how hypoxia affects the structure of shallow communities at two sites in Mejillones Bay (23 degrees S) in northern Chile. We test the hypothesis that, during months with shallow hypoxic zones, community structure will be much more dissimilar, thereby depicting a clear structural gradient with depth and correlated abiotic variables (e.g. organic matter, temperature and salinity). Likewise, during conditions of deeper hypoxic zones, communities will be similar among habitats as they could develop structure via succession in conditions with less stress. Throughout the sampling period (October 2015 to October 2017), the water column was hypoxic (from 2 to 0.5ml/l O2) most of the time, reaching shallow depths of 20 to 10 m. Only one episode of oxygenation was detected in June 2016, where normoxia (>2ml/l O2) reached down to 50 m. The structure of the communities depicted a clear pattern of increasing dissimilarity from shallow normoxic and deep hypoxic habitat. This pattern was persistent throughout time despite the occurrence of an oxygenation episode. Contrasting species abundance and biomass distribution explained the gradient in structure, arguably reflecting variable levels of hypoxia adaptation, i.e. few polychaetes such as Magelona physilia and Paraprionospio pinnata were only located in low oxygen habitats. The multivariable dispersion of community composition as a proxy of beta diversity decreased significantly with depth, suggesting loss of community structure and variability when transitioning from normoxic to hypoxic conditions. Our results show the presence of semi-permanent shallow hypoxia at Mejillones Bay, constraining diverse and more variable communities at a very shallow depth (10-20 m). These results must be considered in the context of the current decline of dissolved oxygen in most oceans and coastal regions and their impact on seabed biota. PMID- 30016341 TI - The association between outpatient follow-up visits and all-cause non-elective 30 day readmissions: A retrospective observational cohort study. AB - BACKGROUND: As an effort to reduce hospital readmissions, early follow-up visits were recommended by the Society of Hospital Medicine. However, published literature on the effect of follow-up visits is limited with mixed conclusions. Our goal here is to fully explore the relationship between follow-up visits and the all-cause non-elective 30-day readmission rate (RR) after adjusting for confounders. METHODS AND RESULTS: To conduct this retrospective observational study, we extracted data for 55,378 adult inpatients from Advocate Health Care, a large, multi-hospital system serving a diverse population in a major metropolitan area. These patients were discharged to Home or Home with Home Health services between June 1, 2013 and April 30, 2015. Our findings from time-dependent Cox proportional hazard models showed that follow-up visits were significantly associated with a reduced RR (adjusted hazard ratio: 0.86; 95% CI: 0.82-0.91), but in a complicated way because the interaction between follow-up visits and a readmission risk score was significant with p-value < 0.001. Our analysis using logistic models on an adjusted data set confirmed the above findings with the following additional results. First, time matter. Follow-up visits within 2 days were associated with the greatest reduction in RR (adjusted odds ratio: 0.72; 95% CI: 0.63-0.83). Visits beyond 2 days were also associated with a reduction in RR, but the strength of the effect decreased as the time between discharge and follow up visit increased. Second, the strength of such association varied for patients with different readmission risk scores. Patients with a risk score of 0.113, high but not extremely high risk, had the greatest reduction in RR from follow-up visits. Patients with an extremely high risk score (> 0.334) saw no RR reduction from follow-up visits. Third, a patient was much more likely to have a 2-day follow-up visit if that visit was scheduled before the patient was discharged from the hospital (30% versus < 5%). CONCLUSIONS: Follow-up visits are associated with a reduction in readmission risk. The timing of follow-up visits can be important: beyond two days, the earlier, the better. The effect of follow-up visits is more significant for patients with a high but not extremely high risk of readmission. PMID- 30016342 TI - Identification and characterization of circRNAs in Pyrus betulifolia Bunge under drought stress. AB - Circular RNAs (circRNAs) play important roles in miRNA function and transcriptional control. However, little is known regarding circRNAs in the pear. In this study, we identified circRNAs using deep sequencing and analyzed their expression under drought stress. We identified 899 circRNAs in total, among which 33 (23 upregulated, 10 downregulated) were shown to be dehydration-responsive. We performed GO and KEGG enrichment analysis to predict the functions of differentially expressed circRNAs. 309 circRNAs were predicted to act as sponges for 180 miRNAs. A circRNA-miRNA co-expression network was constructed based on correlation analysis between the differentially expressed circRNAs and their miRNA binding sites. Our study will provide a rich genetic resource for the discovery of genes related to drought stress, and can readily be applied to other fruit trees. PMID- 30016343 TI - Developmental milestones of the autonomic nervous system revealed via longitudinal monitoring of fetal heart rate variability. AB - BACKGROUND: Fetal heart rate variability (fHRV) of normal-to-normal (NN) beat intervals provides high-temporal resolution access to assess the functioning of the autonomic nervous system (ANS). AIM: To determine critical periods of fetal autonomic maturation. The developmental pace is hypothesized to change with gestational age (GA). STUDY DESIGN: Prospective longitudinal observational study. SUBJECTS: 60 healthy singleton fetuses were followed up by fetal magnetocardiographic heart rate monitoring 4-11 times (median 6) during the second half of gestation. OUTCOME MEASURE: FHRV parameters, accounting for differential aspects of the ANS, were studied applying linear mixed models over four predefined pregnancy segments of interest (SoI: <27; 27+0-31+0; 31+1-35+0; >35+1 weeks GA). Periods of fetal active sleep and quiescence were accounted for separately. RESULTS: Skewness of the NN interval distribution VLF/LF band power ratio and complexity describe a saturation function throughout the period of interest. A decreasing LF/HF ratio and an increase in pNN5 indicate a concurrent shift in sympathovagal balance. Fluctuation amplitude and parameters of short term variability (RMSSD, HF band) mark a second acceleration towards term. In contrast, fetal quiescence is characterized by sequential, but low-margin transformations; ascending overall variability followed by an increase of complexity and superseded by fluctuation amplitude. CONCLUSIONS: An increase in sympathetic activation, connected with by a higher ability of parasympathetic modulation and baseline stabilization, is reached during the transition from the late 2nd into the early 3rd trimester. Pattern characteristics indicating fetal well-being saturate at 35 weeks GA. Pronounced fetal breathing efforts near-term mirror in fHRV as respiratory sinus arrhythmia. PMID- 30016344 TI - Associations between perfluorinated chemicals and serum biochemical markers and performance status in uremic patients under hemodialysis. AB - Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) are commonly used perfluorinated chemicals (PFCs). PFCs are mainly excreted by urine. Uremic patients tend to accumulate toxins in their body and have poor functional status. We investigated the associations between PFCs and the clinical profile of uremic patients under hemodialysis (HD). Liquid chromatography tandem mass spectrometry coupled with isotope dilution was used to quantify PFOA and PFOS. We enrolled 126 patients under regular HD. Compared with previous research, the concentration of PFOA was lower, but that of PFOS was higher in uremic patients than in the general population. The levels of PFOA and PFOS in uremic patients before dialysis were 0.52 (ng/ml) and 21.84 (ng/ml) respectively. The PFOA level remained unchanged but that of PFOS decreased to1.85 ng/mL after dialysis. PFOS can be removed by HD. Patients using hypertensive medication had a lower PFOS then those who did not. The PFOS level was negatively correlated with the duration of the HD session and patient performance status, but positively correlated with levels of cholesterol, chloride (an indicator of acidemia), ferritin, and total protein. (p<0.05). The association with serum protein may explain the long half-life of PFCs in humans. This is the first study which investigated PFCs in uremic patients and showed PFCs are associated with adverse effects in this population. PMID- 30016345 TI - Is gender inequity a risk factor for men reporting poorer self-rated health in the United States? AB - Theoretical approaches suggest that gender inequity increases men's health risks. Previous findings from the United States support this contention, however only a small number of health outcomes have been explored. This study extends the range of health outcomes examined by using a cross-sectional, multilevel analysis to investigate whether measures of state-level gender inequity are predictors of men's self-rated health. Data were derived primarily from the Behavioral Risk Factor Surveillance System and the full-case data set included 116,594 individuals nested within 50 states. Gender inequity was measured with nine variables: higher education, women's reproductive rights, abortion provider access, elected office, management, business ownership, labour force participation, earnings and relative poverty. Covariates at the individual level were age, income, education, race/ethnicity, marital status and employment status. Covariates at the state level were income inequality and gross domestic product per capita. In fully adjusted models for all-age men the reproductive rights (OR 1.06 95% CI 1.01-1.11), abortion provider access (OR 1.11 95% CI 1.05 1.16) and earnings (OR 1.06 95% CI 1.02-1.12) measures all predicted an increased risk of men reporting poorer self-rated health for each 1 standard deviation increase in the gender inequity z-score. The most consistent effect was seen for the 65+ age group where the reproductive rights (OR 1.09 95% CI 1.03-1.16), abortion provider access (OR 1.15 95% CI 1.09-1.21), elected office (OR 1.06 95% CI 1.01-1.11) and earnings (OR 1.10 95% CI 1.04-1.16) measures all showed a significant effect. These findings provide evidence that some aspects of gender inequity increase the risk of poorer self-rated health in men. The study contributes to a growing body of literature implicating gender inequity in men's health patterns. PMID- 30016346 TI - QTL mapping of male sterility and transmission pattern in progeny of Satsuma mandarin. AB - Seedlessness is one of the important traits in citrus breeding. Male sterility derived from Satsuma mandarin (Citrus unshiu) has been used in Japanese citrus breeding programs to obtain seedless cultivars. The efficiency of seedless cultivar breeding would be improved by developing a selection marker linked to seedlessness. In this study, we performed QTL mapping in 'Okitsu No. 46' * 'Okitsu No. 56' (O46-O56) crosses for the number of pollen grains per anther (NPG) and apparent pollen fertility (APF), two traits used as an index of male sterility, and detected a candidate QTL for NPG (MS-P1) on linkage group 8 with a significant LOD score (7.31) and 47% of variance explained. The QTL for APF (MS F1) was detected on linkage group 6 with a significant LOD score (5.71) and 63.6% of variance explained. The role of both MS-P1 in reducing NPG and MS-F1 in decreasing APF were confirmed with the 'Okitsu No.46' * 'Kara' (O46-K) cross. Pedigree analysis inferred that both MS-P1 and MS-F1 in 'Okitsu No. 46' were derived from kunenbo (Citrus nobilis) through hassaku (C. hassaku) and 'Sweet Spring'. Cytoplasm analysis revealed that both male-sterile 'Sweet Spring' and 'Okitsu No. 46' have cytoplasm derived from Kishu (C. kinokuni hort. ex Tanaka), but the cytoplasm of male-sterile kunenbo and hassaku were derived from other varieties rather than Kishu. These results suggest that MS-P1 and MS-F1 primarily reduce the NPG and decrease APF, but their expression requires a cytoplasm derived from Kishu. These findings will improve our understanding of the molecular mechanism of male sterility in citrus and help to develop a DNA marker for seedless breeding in citrus. PMID- 30016347 TI - Invasive rat eradication strongly impacts plant recruitment on a tropical atoll. AB - Rat eradication has become a common conservation intervention in island ecosystems and its effectiveness in protecting native vertebrates is increasingly well documented. Yet, the impacts of rat eradication on plant communities remain poorly understood. Here we compare native and non-native tree and palm seedling abundance before and after eradication of invasive rats (Rattus rattus) from Palmyra Atoll, Line Islands, Central Pacific Ocean. Overall, seedling recruitment increased for five of the six native trees species examined. While pre eradication monitoring found no seedlings of Pisonia grandis, a dominant tree species that is important throughout the Pacific region, post-eradication monitoring documented a notable recruitment event immediately following eradication, with up to 688 individual P. grandis seedlings per 100m2 recorded one month post-eradication. Two other locally rare native trees with no observed recruitment in pre-eradication surveys had recruitment post-rat eradication. However, we also found, by five years post-eradication, a 13-fold increase in recruitment of the naturalized and range-expanding coconut palm Cocos nucifera. Our results emphasize the strong effects that a rat eradication can have on tree recruitment with expected long-term effects on canopy composition. Rat eradication released non-native C. nucifera, likely with long-term implications for community composition, potentially necessitating future management interventions. Eradication, nevertheless, greatly benefitted recruitment of native tree species. If this pattern persists over time, we expect long-term benefits for flora and fauna dependent on these native species. PMID- 30016348 TI - Associations between pneumonia and residential distance to livestock farms over a five-year period in a large population-based study. AB - In a recent study of electronic health records (EHR) of general practitioners in a livestock-dense area in The Netherlands in 2009, associations were found between residential distance to poultry farms and the occurrence of community acquired pneumonia (CAP). In addition, in a recent cross-sectional study in 2494 adults in 2014/2015 an association between CAP and proximity to goat farms was observed. Here, we extended the 2009 EHR analyses across a wider period of time (2009-2013), a wider set of health effects, and a wider set of farm types as potential risk sources. A spatial (transmission) kernel model was used to investigate associations between proximity to farms and CAP diagnosis for the period from 2009 to 2013, obtained from EHR of in total 140,059 GP patients. Also, associations between proximity to farms and upper respiratory infections, inflammatory bowel disease, and (as a control disease) lower back pain were analysed. Farm types included as potential risk sources in these analyses were cattle, (dairy) goats, mink, poultry, sheep, and swine. The previously found association between CAP occurrence and proximity to poultry farms was confirmed across the full 5-year study period. In addition, we found an association between increased risk for pneumonia and proximity to (dairy) goat farms, again consistently across all years from 2009 to 2013. No consistent associations were found for any of the other farm types (cattle, mink, sheep and swine), nor for the other health effects considered. On average, the proximity to poultry farms corresponds to approximately 119 extra patients with CAP each year per 100,000 people in the research area, which accounts for approximately 7.2% extra cases. The population attributable risk percentage of CAP cases in the research area attributable to proximity to goat farms is approximately 5.4% over the years 2009 2013. The most probable explanation for the association of CAP with proximity to poultry farms is thought to be that particulate matter and its components are making people more susceptible to respiratory infections. The causes of the association with proximity to goat farms is still unclear. Although the 2007-2010 Q-fever epidemic in the area probably contributed Q-fever related pneumonia cases to the observed additional cases in 2009 and 2010, it cannot explain the association found in later years 2011-2013. PMID- 30016349 TI - NMR-based metabolic profiling of urine, serum, fecal, and pancreatic tissue samples from the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer. AB - Pancreatic cancer is the third leading cause of cancer deaths in the United States with more than 53,000 expected to be diagnosed with the disease in 2018. The median survival time after diagnosis is four to six months. The poor survival statistics are due in part to the fact that pancreatic cancer is typically asymptomatic until it reaches advanced stages of the disease. Although surgical resection provides the best chance of survival, pancreatic cancer is rarely detected when surgery is still possible due, in part, to lack of effective biomarkers for early detection. The goal of the research reported here was to determine if it was possible to identify metabolic biomarkers for detection of pre-cancerous pancreatic intraepithelial neoplasia (PanIN) that precede pancreatic adenocarcinoma. The transgenic Ptf1a-Cre; LSL-KrasG12D mouse strain was used as a model of pancreatic cancer progression. Nuclear magnetic resonance (NMR) spectroscopy was employed to compare metabolic profiles of urine, sera, fecal extracts, and pancreatic tissue extracts collected from control and study mice aged 5, 11, and 15 months, including 47 mice with tumors. We were able to identify the following potential biomarkers: decreased 3-indoxylsulfate, benzoate and citrate in urine, decreased glucose, choline, and lactate in blood, and decreased phenylalanine and benzoate and increased acetoin in fecal extracts. Potential biomarkers were validated by p-values, PLS-DA VIP scores, and accuracies based on area under ROC curve analyses. Essentially, all of the metabolic profiling changes could be explained as being associated with the consequences of bicarbonate wasting caused by a complete substitution of the normal pancreatic acinar tissue by tissue entirely composed of PanIN. Given the nature of the mouse model used here, our results indicate that it may be possible to use NMR-based metabolic profiling to identify biomarkers for detection of precancerous PanIN that immediately precede pancreatic cancer. PMID- 30016350 TI - Cardiac vagal dysfunction moderates patterns of craving across the day in moderate to heavy consumers of alcohol. AB - BACKGROUND: Alcohol craving, a known correlate of vulnerability to Alcohol Use Disorder (AUD), has been found to be inversely related to cardiac vagal tone (CVT). Here we examine how resting CVT, CVT reactivity to a postural challenge, and their interaction influence craving during imposed alcohol abstinence and their usual drinking among moderate to heavy drinkers. METHODS: Participants were recruited from the local community (final n = 29) and assessed for CVT functioning via respiratory sinus arrhythmia (RSA) at rest (RSA-rest) and during a postural challenge (RSA-react). Craving intensity was assessed throughout the day during 3-day periods of imposed alcohol abstinence (abstained days) and drinking as usual (normal days) via Ecological Momentary Assessment (EMA). Multilevel statistical modeling assessed relationships between patterns of CVT and diurnal craving. The primary hypothesis of interest was that the interaction of RSA-rest with RSA-react would be significantly associated with increased craving across the day. RESULTS: Overall, craving increased throughout the day and significantly decreased after drinking (p < 0.001). There was a significant interaction between RSA-rest and RSA-react with plots revealing that this effect was driven by an aberrant craving pattern among participants with higher RSA-rest and a sluggish vagal brake in response to a postural shift-atypical RSA-react. CONCLUSION: Although additional research is needed to corroborate these findings, our results suggest that moderate-heavy drinkers characterized by higher RSA-rest and atypical RSA-react exhibit aberrant patterns of craving across the day that may represent a risk factor for AUD. PMID- 30016351 TI - Adverse pregnancy outcomes and imbalance in angiogenic growth mediators and oxidative stress biomarkers is associated with advanced maternal age births: A prospective cohort study in Ghana. AB - BACKGROUND: Advanced maternal age (AMA) has been associated with negative pregnancy outcomes. Oxidative stress (OS) and defective placental dysfunction are contributing factors. This study determined the association between AMA and adverse pregnancy outcomes, OS biomarkers and angiogenic growth mediators (AGMs) in normal pregnancies. METHODS: This prospective cohort study conducted at the Obstetrics and Gynaecology (O&G) Department of the Komfo Anokye Teaching Hospital (KATH) finally included 175 normal pregnant women comprising, 58 AMA (35-45 years), 55 (30-34 years) and 62 optimal childbearing age (20-29 years). Venous blood samples were collected at 28-32 weeks for soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PIGF), 8-epiprostaglandinF2-alpha (8-epi PGF2alpha) and total antioxidant capacity (TAC) assays. RESULTS: Pregnancies of AMA had a significantly higher levels of sFlt-1, 8-epi-PGF2alpha and 8-epi PGF2alpha: PIGF ratio but a reduced level of PIGF, TAC and PIGF: sFlt-1 ratio compared to 20-29 years (p<0.0001). A significant negative correlation between AMA and PIGF (r = -0.294; p = 0.038); TAC (r = -0.215; p = 0.001) and PIGF: sFlt 1 ratio (r = -0.457; p<0.0001) and a positive correlation with sFlt-1 (r = 0.269; p = 0.017), 8-epiPGF2alpha (r = 0.277; p = 0.029) and 8-epi-PGF2: PIGF ratio (r = 0.461; p<0.0001) levels were observed. The adjusted odds ratio (aOR), and 95% confidence interval, and p value for the significant independent adverse outcomes associated with AMA were emergency caesarean section [21.7 (5.9-121.3), p<00001], elective caesarean section [2.7(0.9-5.8), p = 0.0105], stillbirth [12.6(1.4 82.1), p<0.0001], post-partum haemorrhage [4.3(1.1-18.5), p = 0.0094], preterm delivery [8.2(3.5-28.4), p<0.0001], low birth weight babies [9.7(2.8-29.3), p<0.0001], birth asphyxia [3.8(1.6-12.7), p = 0.0054], Apgar score <= 7 after 5 min for babies [10.1(4.7-23.2), p<0.0001], placental abruption [3.5(1.3-8.4), p = 0.0117] and intrauterine growth restriction (IUGR) [4.6(2.3-12.9), p = 0.0001]. CONCLUSION: AMA pregnancies correlate with adverse pregnancy outcomes and imbalance in OS biomarkers and AGMs. It is incumbent on health care givers to provide effective antenatal care among AMA mothers as early identification of these imbalance and treatment can prevent adverse pregnancy outcomes. PMID- 30016352 TI - In vitro activity of fosfomycin against Campylobacter isolates from poultry and wild birds. AB - Fosfomycin is a broad-spectrum antibiotic with the activity against both Gram positive and Gram-negative pathogens by inhibiting the bacterial cell wall synthesis. Given the potential therapeutic efficacy of fosfomycin against Campylobacter spp., the aim of the present study was to determine the in vitro fosfomycin susceptibility of Campylobacter isolates from avian sources including poultry and wild birds. A total of eight (1.8%) strains of Campylobacter including five C. jejuni strains isolated from ducks and three C. coli strains isolated from chickens and duck showed resistance to fosfomycin, with MICs ranging from 64 to >= 256 MUg/mL. The extent of fosfomycin resistance was 0%, 0.9% and 3.9% in wild birds, chicken and ducks respectively. The MIC50, MIC90, and MIC100 values were 8, 32, and 32 MUg/mL respectively in wild bird, 32, 32, and 64 MUg/mL respectively in chicken, and 32, 32, and >= 256 MUg/mL respectively in ducks. All eight fosfomycin-resistant Campylobacter strains were multidrug resistant; six were also resistant to fluoroquinolones, ampicillin, and tetracycline, and two were also resistant to fluoroquinolones, ampicillin, tetracycline, and macrolides. However, the fosfomycin resistance gene fosXCC was not detected in the eight fosfomycin-resistant strains. Because food animals can harbor fosfomycin-resistant Campylobacter and transmit them to humans, greater efforts are needed to monitor the prevalence of fosfomycin resistance in Campylobacter strains isolated from such animals. PMID- 30016353 TI - Significance of distance between tumor and thyroid capsule as an indicator for central lymph node metastasis in clinically node negative papillary thyroid carcinoma patients. AB - The aim of this study was to evaluate preoperatively identifiable clinical and ultrasonographic characteristics associated with central lymph node metastasis (CLNM) in clinically node negative papillary thyroid carcinoma (PTC) patients. Records of the patients who underwent thyroidectomy with prophylactic central lymph node dissection due to clinically node negative PTC (size, 1.0-3.0 cm) were reviewed. Of a total of 174 patients, 71 (40.8%) had CLNMs. CLNM was more associated with capsule invasion than capsule non-invasion on ultrasonography (68.4% vs. 37.4%, p = 0.009). In the 155 patients without capsule invasion, a distance from the capsule < 1.9 mm was associated with CLNM in univariable (p = 0.002) and multivariable analysis (p < 0.001). Any PTC patient with a distance from the capsule >= 1.9 mm did not have CLNM whereas 40.8% (58/142) of PTC patients with a distance from the capsule < 1.9 mm had CLNM. CLNM was not associated with age, gender, or tumor size on ultrasonography. Distance from capsule >= 1.9 mm on preoperative ultrasonography was a significant indicator for not having CLNM in clinically node negative PTC patients. Measuring distance from the capsule on preoperative ultrasonography images could help select patients with PTC who could benefit from prophylactic central lymph node dissection. PMID- 30016354 TI - Effects of infection by Turnip mosaic virus on the population growth of generalist and specialist aphid vectors on turnip plants. AB - Recent studies have revealed that relationships between plant pathogens and their vectors differ depending on species, strains and associated host plants. Turnip mosaic virus (TuMV) is one of the most important plant viruses worldwide and is transmitted by at least 89 aphid species in a non-persistent manner. TuMV is fundamentally divided into six phylogenetic groups; among which Asian-BR, basal BR and world-B groups are known to occur in Japan. In Kyushu Japan, basal-BR has invaded approximately 2000 and immediately replaced the predominant world-B virus group. To clarify the relationships between TuMV and vector aphids, we examined the effects of the TuMV phylogenetic group on the population growth of aphid vectors in turnip plants. The population growth of a generalist aphid, Myzus persicae, was not significantly different between non-infected and TuMV-infected treatments. The population growth of a specialist aphid, Lipaphis erysimi, was higher in TuMV-infected plants than non-infected ones. Similar results were obtained in experiments using world-B and basal-BR groups of TuMV. Therefore, we conclude that L. erysimi is more mutualistic with TuMV than M. persicae, and differences in TuMV phylogenetic groups do not affect the growth of aphid vectors on turnip plants. PMID- 30016355 TI - Neuroprotective effects of leonurine against oxygen-glucose deprivation by targeting Cx36/CaMKII in PC12 cells. AB - Leonurine has been reported to play an important role in ameliorating cognitive dysfunction, inhibiting ischemic stroke, and attenuating perihematomal edema and neuroinflammation in intracerebral hemorrhage. However, the exact mechanism and potential molecular targets of this effect remain unclear. Thus, in this study we investigated the neuroprotective effects of leonurine on hypoxia ischemia injury and explored the underlying mechanisms. An in vitro model of oxygen-glucose deprivation (OGD)-induced PC12 cells was established to mimic ischemic-like conditions. Cell viability, apoptosis, Cx36 and pCaMKII/CaMKII expression levels were evaluated after treatment with leonurine. The Cx36-selective antagonist mefloquine and CaMKII Inhibitor KN-93 were used to investigate the neuroprotective effect of leonurine on and the involvement of Cx36/CaMKII in this process. The results revealed that cell viability decreased and cell apoptosis and the protein expression of Cx36 and pCaMKII/CaMKII increased in the OGD induced PC12 cells. Leonurine significantly increased cell viability and decreased cell apoptosis and the protein expression of Cx36 and pCaMKII/CaMKII in the OGD-induced PC12 cells. The specific inhibitor of Cx36 and CaMKII displayed similar protective effects. Moreover, the inhibition of Cx36 reduced pCaMKII levels and the ratio of pCaMKII/CaMKII in the OGD-induced PC12 cells, and vice versa. Taken together, these results suggest that leonurine might have a protective effect on OGD-induced PC12 cells through targeting the Cx36/CaMKII pathway. Thus, leonurine appears to have potential as a preventive or therapeutic drug against ischemic-induced neuronal injury. PMID- 30016356 TI - The fast contribution of visual-proprioceptive discrepancy to reach aftereffects and proprioceptive recalibration. AB - Adapting reaches to altered visual feedback not only leads to motor changes, but also to shifts in perceived hand location; "proprioceptive recalibration". These changes are robust to many task variations and can occur quite rapidly. For instance, our previous study found both motor and sensory shifts arise in as few as 6 rotated-cursor training trials. The aim of this study is to investigate one of the training signals that contribute to these rapid sensory and motor changes. We do this by removing the visuomotor error signals associated with classic visuomotor rotation training; and provide only experience with a visual proprioceptive discrepancy for training. While a force channel constrains reach direction 30o away from the target, the cursor representing the hand unerringly moves straight to the target. The resulting visual-proprioceptive discrepancy drives significant and rapid changes in no-cursor reaches and felt hand position, again within only 6 training trials. The extent of the sensory change is unexpectedly larger following the visual-proprioceptive discrepancy training. Not surprisingly the size of the reach aftereffects is substantially smaller than following classic visuomotor rotation training. However, the time course by which both changes emerge is similar in the two training types. These results suggest that even the mere exposure to a discrepancy between felt and seen hand location is a sufficient training signal to drive robust motor and sensory plasticity. PMID- 30016357 TI - Reinforcement learning for solution updating in Artificial Bee Colony. AB - In the Artificial Bee Colony (ABC) algorithm, the employed bee and the onlooker bee phase involve updating the candidate solutions by changing a value in one dimension, dubbed one-dimension update process. For some problems which the number of dimensions is very high, the one-dimension update process can cause the solution quality and convergence speed drop. This paper proposes a new algorithm, using reinforcement learning for solution updating in ABC algorithm, called R ABC. After updating a solution by an employed bee, the new solution results in positive or negative reinforcement applied to the solution dimensions in the onlooker bee phase. Positive reinforcement is given when the candidate solution from the employed bee phase provides a better fitness value. The more often a dimension provides a better fitness value when changed, the higher the value of update becomes in the onlooker bee phase. Conversely, negative reinforcement is given when the candidate solution does not provide a better fitness value. The performance of the proposed algorithm is assessed on eight basic numerical benchmark functions in four categories with 100, 500, 700, and 900 dimensions, seven CEC2005's shifted functions with 100, 500, 700, and 900 dimensions, and six CEC2014's hybrid functions with 100 dimensions. The results show that the proposed algorithm provides solutions which are significantly better than all other algorithms for all tested dimensions on basic benchmark functions. The number of solutions provided by the R-ABC algorithm which are significantly better than those of other algorithms increases when the number of dimensions increases on the CEC2005's shifted functions. The R-ABC algorithm is at least comparable to the state-of-the-art ABC variants on the CEC2014's hybrid functions. PMID- 30016359 TI - Retraction: The cryoprotectant trehalose could inhibit ERS-induced apoptosis by activating autophagy in cryoprotected rat valves. PMID- 30016358 TI - Aetiology of neonatal sepsis in Nigeria, and relevance of Group b streptococcus: A systematic review. AB - BACKGROUND: Group B Streptococcus (GBS) causes invasive infections in neonates and has been implicated as a cause of prelabour rupture of membranes, preterm delivery and stillbirths. The success of phase II trials of polyvalent polysaccharide GBS vaccines indicates that these infections are potentially preventable. Nigeria is the most populous country in Africa with one of the highest birth rates, one of the highest neonatal sepsis incidence rates and one of the highest mortality rates in the world. Therefore, before the possible introduction of preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine into Nigeria, it is vital that there is accurate data on the aetiology of neonatal sepsis and on the incidence of GBS neonatal sepsis in particular. The objective of this study was to determine the incidence and aetiology of neonatal sepsis in Nigeria with a focus on GBS sepsis and also to assess the potential impact of a GBS vaccine. METHODS: A literature search was conducted on the databases of African journals online, PubMed and Google Scholar for works conducted between 1987 to 2017. Case reports, reviews, and studies not stating specific culture methods or specific bacteria isolated were excluded. Data extracted included; incidence of neonatal sepsis, method of blood culture, blood volume, sample size, bacterial agents isolated and history of antibiotic use. PRISMA guidelines were followed and modified Down's and Black criteria used to evaluate the quality of studies. RESULTS: A total of 5,114 studies were reviewed for neonatal sepsis out of which 24 consisting of a total of 2,280 cases were selected for final review. Nine studies met criteria for assessment of hospital based incidence of neonatal sepsis representing 31,305 hospital births. The incidence of neonatal sepsis was 18.2/1000 livebirths with range from 7 55/1000 livebirths while the GBS incidence was 0.06/1000 livebirths with range from 0-2/1000 live births. We discovered various limitations such as identification techniques that could result in underestimation of the true incidence of GBS sepsis. Pathogens such as Klebsiella pneumoniae and Staphylococcus aureus were more commonly isolated than GBS. IMPLICATIONS OF KEY FINDINGS: The hospital based incidence of neonatal sepsis was high at 18.2/1000 live births while that due to GBS was 0.06/1000 live births. The burden of neonatal sepsis, including that attributable to GBS is substantial and could be reduced by preventive strategies such as intrapartum antibiotic prophylaxis or GBS vaccine. There is however very sparse meaningful data currently. Well planned prospective studies with larger sample sizes, more advanced isolation and identification techniques and those following up invasive disease cases for possible short and long term sequelae are needed-not only prior to possible introduction of the vaccine to determine the baseline epidemiology, but also thereafter to monitor its impact on the population. Strategies need to be developed to also reduce the morbidity and mortality attributable to other bacteria that have an incidence even greater than that of GBS. PMID- 30016360 TI - Correction: Infant CPAP for low-income countries: An experimental comparison of standard bubble CPAP and the Pumani system. AB - [This corrects the article DOI: 10.1371/journal.pone.0196683.]. PMID- 30016361 TI - Correction: Association of nefopam use with postoperative nausea and vomiting in gynecological patients receiving prophylactic ramosetron: A retrospective study. AB - [This corrects the article DOI: 10.1371/journal.pone.0199930.]. PMID- 30016362 TI - Correction: Chronic Maternal Low-Protein Diet in Mice Affects Anxiety, Night-Time Energy Expenditure and Sleep Patterns, but Not Circadian Rhythm in Male Offspring. AB - [This corrects the article DOI: 10.1371/journal.pone.0170127.]. PMID- 30016364 TI - A pilot study into reaching performance after severe to moderate stroke using upper arm support. AB - Stroke effects millions of people each year and can have a significant impact on the ability to use the impaired arm and hand. One of the results of stroke is the development of an abnormal shoulder-elbow flexion synergy, where lifting the arm can cause the elbow, wrist, and finger flexors to involuntarily contract, reducing the ability to reach with the arm and hand opening. This study explored the effect of using support at the upper arm to improve hand and arm reaching performance. Nine participants were studied while performing a virtual reaching task under three conditions: while the weight of their impaired arm was supported by a robot arm, while unsupported, and while using their non-impaired arm. Most subjects exhibited faster and more accurate reaching while supported compared to unsupported. For the subjects who could voluntarily open their hand, most were able to more swiftly open their hand when using upper arm support. In many cases, performance with support was not statistically different than the unaffected arm and hand. Muscle activity of the impaired limb with upper arm support showed decreased effort to lift the arm and reduced biceps activity in most subjects, pointing to a reduction in the abnormal flexion synergy while using upper arm support. While arm support can help to reduce the activation of abnormal synergies, weakness resulting from hemiparesis remains an issue impacting performance. Future systems will need to address both of these causes of disability to more fully restore function after stroke. PMID- 30016363 TI - Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein. AB - CCCH-type zinc-finger antiviral protein (ZAP) is a host factor that restricts the infection of many viruses mainly through RNA degradation, translation inhibition and innate immune responses. So far, only one flavivirus, yellow fever virus, has been reported to be ZAP-resistant. Here, we investigated the antiviral potential of human ZAP (isoform ZAP-L and ZAP-S) against three flaviviruses, Japanese encephalitis virus (JEV), dengue virus (DENV) and Zika virus (ZIKV). Infection of JEV but not DENV or ZIKV was blocked by ZAP overexpression, and depletion of endogenous ZAP enhanced JEV replication. ZAP hampered JEV translation and targeted viral RNA for 3'-5' RNA exosome-mediated degradation. The zinc-finger motifs of ZAP were essential for RNA targeting and anti-JEV activity. JEV 3'-UTR, especially in the region with dumbbell structures and high content of CG dinucleotide, was mapped to bind ZAP and confer sensitivity to ZAP. In summary, we identified JEV as the first ZAP-sensitive flavivirus. ZAP may act as an intrinsic antiviral factor through specific RNA binding to fight against JEV infection. PMID- 30016365 TI - Glucosamine prevents polarization of cytotoxic granules in NK-92 cells by disturbing FOXO1/ERK/paxillin phosphorylation. AB - Glucosamine (GlcN) is a naturally occurring derivative of glucose and an over-the counter food additive. However, the mechanism underlying GlcN action on cells is unknown. In this study, we investigated the effect of GlcN on natural killer (NK) cells. We demonstrate that GlcN affects NK-92 cell cytotoxicity by altering the distribution of cathepsin C, a cysteine protease required for granzyme processing in cytotoxic granules. The relocation of cathepsin C due to GlcN was shown to be accompanied by a decrease in the intracellular enzyme activity and its extracellular secretion. Similarly, the relocation of endosomal aspartic cathepsin E was observed. Furthermore, we elucidated that repositioning of cathepsin C is a consequence of altered signaling pathways of cytotoxic granule movement. The inhibition of phosphorylation upstream and downstream of ERK by GlcN disturbed the polarized release of cytotoxic vesicles. Considerable changes in the ERK phosphorylation dynamics, but not in those of p38 kinase or JNK, were observed in the IL2-activated NK-92 cells. We found decreased phosphorylation of the transcription factor FOXO1 and simultaneous prolonged phosphorylation of ERK as well as its nuclear translocation. Additionally, a protein downstream of the ERK phosphorylation cascade, paxillin, was less phosphorylated, resulting in a diffuse distribution of cytotoxic granules. Taken together, our results suggest that dietary GlcN affects signaling pathway activation of NK-92 immune cells. PMID- 30016366 TI - Microfluidic viscometry using magnetically actuated micropost arrays. AB - Here we describe development of a microfluidic viscometer based on arrays of magnetically actuated micro-posts. Quantitative viscosities over a range of three orders of magnitude were determined for samples of less than 20 MUL. This represents the first demonstration of quantitative viscometry using driven flexible micropost arrays. Critical to the success of our system is a comprehensive analytical model that includes the mechanical and magnetic properties of the actuating posts, the optical readout, and fluid-structure interactions. We found that alterations of the actuator beat shape as parameterized by the dimensionless "sperm number" must be taken into account to determine the fluid properties from the measured actuator dynamics. Beyond our particular system, the model described here can provide dynamics predictions for a broad class of flexible microactuator designs. We also show how the model can guide the design of new arrays that expand the accessible range of measurements. PMID- 30016367 TI - Head-eye movement of collegiate baseball batters during fastball hitting. AB - Successful baseball hitting involves a combination of highly trained perceptual skills and forceful bat swing motions. The purpose of the present study was to quantify the horizontal movement of the head and eyes while baseball batters hit a fastball to clarify a visual strategy for this highly trained interceptive task. Six collegiate baseball players hit a fastball that was launched from a pitching machine. The ball speed was 31.9 m.s-1 for the Slow Ball Task and 40.3 m.s-1 for the Fast Ball Task. Horizontal head movements were analysed using images that were captured by two high-speed video cameras. The Horizontal eye movement was recorded with electrooculography. The angular speed of the horizontal head and eye movements during hitting were divided into four time periods (I-40 = 21-40% of total ball-flight, I-60 = 41-60% of total ball-flight, I-80 = 61-80% of total ball-flight, I-100 = 81-100% of total ball-flight) and analysed using analysis of variance and a Tukey post-hoc multiple-comparison. In the Slow Ball Task, the horizontal angular velocity of the head during I-80 was significantly faster than that during I-40 (p < 0.05). In the Fast Ball Task, the horizontal angular velocity of the head during I-80 was significantly faster than that during I-40 and I-60 (p < 0.05). These results indicated that the tracking motion of the head became faster as the launched ball came close to the batters, but there was no change in the angular tracking motion of the eyes. Therefore, rapid eye movement may not be suitable to accurately estimate the ball's future location during fastball hitting based on the eye-centered coordinates. Our findings suggest that conventional vision training with a wide range of saccadic or smooth-pursuit eye movements does not reflect the characteristics of tracking strategies during baseball hitting. PMID- 30016368 TI - Wishes and needs of community-dwelling older persons concerning general practice: A qualitative study. AB - INTRODUCTION: Community-dwelling older persons often experience hindering health complaints that disturb daily activities. If general practitioners (GPs) are unaware of such complaints, this could lead to a mismatch in provided care and needed or expected care. In this qualitative study with community-dwelling older persons we investigated how older persons experience hindering health complaints, how they deal with them, and what they expect from their GP. METHODS: Participants (aged >=80 years) with pain and/or problems with walking/standing were invited to participate in a (group)interview about hindering health problems and expectations from general practice. Data were analysed using the framework method and results were discussed with a client panel. RESULTS: Participants experienced various hindering health complaints in addition to pain and/or problems with walking/standing. Complaints affecting social activities were experienced as the most hindering. Participants actively tried to remain independent and, to achieve this, GPs were expected to be involved and be easily accessible. However, they did not expect specific help from their GP for pain or problems with walking/standing. Suggestions for improvement of care from GPs included optimisation of accessibility (continuous availability by telephone), a yearly check including medication review, open communication, and empathy and support during major life events. CONCLUSIONS: According to older persons with hindering health complaints, GPs could improve their accessibility/relationship with patients by: 1) continuous telephonic availability, 2) initiating regular contact with medication reviews, and 3) initiating support during major life events. This might lower the reported barriers to contact the GP for hindering health complaints. PMID- 30016369 TI - The association between obesity and dengue virus (DENV) infection in hospitalised patients. AB - Both obesity and DENV infections are growing public health concerns that have far ranging socioeconomic effects, especially in developing countries. Despite the increasing prevalence of these conditions, there is a scarcity of data investigating the potential relationships between these two entities. Our study aims to examine the influence of obesity on various clinical and laboratory parameters amongst patients with DENV infections. A total of 335 hospitalized patients aged >12 years who were DENV non-structural protein 1 (NS1) antigen positive were enrolled in this study. Clinical and laboratory variables were compared between patients with and without obesity. Multivariate analysis showed that the following admission clinical findings and laboratory results were independently associated with obesity; chills and rigors (AOR:2.653, 95% CI: 1.286-5.474), higher temperature (AOR:1.485, 95% CI: 1.080-2.042), higher systolic BP (AOR:1.057, 95% CI:1.037-1.078), raised haematocrit (AOR: 1.953, 95% CI: 1.010-3.778), elevated creatinine (AOR:3.504, 95% CI:1.351-9.008) and elevated ALT (AOR: 4.146, 95% CI:1.878-9.154). Obesity was found to be significantly associated with hospitalization >3 days (AOR: 1.990, 95% CI: 1.134 3.494) and the presence of increasing haematocrit with decreasing platelets (AOR: 2.134, 95% CI = 1.235-3.688). Serial assessment of laboratory data revealed that peak haematocrit was significantly higher and nadir platelets levels were significantly lower in obese patients. Both peak and admission levels of leukocyte counts, AST, ALT and creatinine were significantly higher in the obese group. Conversely, both admission and nadir albumin levels were lower for the obese group, although only nadir albumin levels achieved statistical significance. These findings support closer clinical monitoring of obese patients who present with DENV infections, as this patient cohort may possess an increased tendency towards developing more severe clinical manifestations of DENV infections as compared to non-obese patients. PMID- 30016371 TI - Exchange of functional domains between a bacterial conjugative relaxase and the integrase of the human adeno-associated virus. AB - Endonucleases of the HUH family are specialized in processing single-stranded DNA in a variety of evolutionarily highly conserved biological processes related to mobile genetic elements. They share a structurally defined catalytic domain for site-specific nicking and strand-transfer reactions, which is often linked to the activities of additional functional domains, contributing to their overall versatility. To assess if these HUH domains could be interchanged, we created a chimeric protein from two distantly related HUH endonucleases, containing the N terminal HUH domain of the bacterial conjugative relaxase TrwC and the C-terminal DNA helicase domain of the human adeno-associated virus (AAV) replicase and site specific integrase. The purified chimeric protein retained oligomerization properties and DNA helicase activities similar to Rep68, while its DNA binding specificity and cleaving-joining activity at oriT was similar to TrwC. Interestingly, the chimeric protein could catalyse site-specific integration in bacteria with an efficiency comparable to that of TrwC, while the HUH domain of TrwC alone was unable to catalyze this reaction, implying that the Rep68 C terminal helicase domain is complementing the TrwC HUH domain to achieve site specific integration into TrwC targets in bacteria. Our results illustrate how HUH domains could have acquired through evolution other domains in order to attain new roles, contributing to the functional flexibility observed in this protein superfamily. PMID- 30016373 TI - Anemia, a moderate public health concern among adolescents in South Ethiopia. AB - BACKGROUND: Adolescence is characterized by rapid growth and development and iron requirements increase during this time. Adolescents with poor diet in early childhood and/or females with an early onset of menarche may be at greater risk for developing anemia due to the rapid depletion of iron stores in their bodies. OBJECTIVE: The objective of this study was to assess the prevalence and severity of anemia among school adolescents in Wonago district, Gedeo Zone, South Ethiopia. METHODS: A school based cross-sectional study was conducted among 443 randomly selected school adolescents across 15 schools (2 secondary schools and 13 primary schools) in the district. Hemoglobin concentration from a capillary blood sample was determined by portable hemoglobin meter (HemoCue). Descriptive statistics were computed for prevalence of anemia, anthropometric measurements, socio-economic and socio-demographic variables. A hierarchical multivariable logistic regression analysis was done to identify determinants of anemia among adolescents. RESULTS: The prevalence of anemia among adolescents in the study area was 22%. Anemia was higher among those in early adolescence period (10-13 years) (AOR: 4.75, CI: 1.69-13.35) compared to late adolescence (17-19 years) and among those with height for age z-score less than -2 (AOR: 6.23, CI: 1.98-19.62). Similarly, anemia was higher among those in households with a family size greater than five members (AOR: 9.82, CI: 2.42-39.88), adolescents from rural areas (AOR: 4.37, CI: 1.54-12.46) and families who purchase food needed for daily consumption (AOR: 3.25, CI: 1.42-7.45). On the other hand, adolescents from middle wealth quintiles (AOR: 0.26 (CI: 0.07-0.98)) and female adolescents (AOR: 0.34 (CI: 0.15 0.79) were less likely to be anemic in this study. CONCLUSIONS: The prevalence of anemia in this population is of moderate public health concern, adolescents of both sexes are among groups at risk for the development of anemia. The need for further assessment of the etiology of anemia should be considered to design pragmatic intervention programs. PMID- 30016372 TI - Zika virus outbreak in the Pacific: Vector competence of regional vectors. AB - BACKGROUND: In 2013, Zika virus (ZIKV) emerged in French Polynesia and spread through the Pacific region between 2013 and 2017. Several potential Aedes mosquitoes may have contributed to the ZIKV transmission including Aedes aegypti, the main arbovirus vector in the region, and Aedes polynesiensis, vector of lymphatic filariasis and secondary vector of dengue virus. The aim of this study was to analyze the ability of these two Pacific vectors to transmit ZIKV at a regional scale, through the evaluation and comparison of the vector competence of wild Ae. aegypti and Ae. polynesiensis populations from different Pacific islands for a ZIKV strain which circulated in this region during the 2013-2017 outbreak. METHODOLOGY/PRINCIPAL FINDINGS: Field Ae. aegypti (three populations) and Ae. polynesiensis (two populations) from the Pacific region were collected for this study. Female mosquitoes were orally exposed to ZIKV (107 TCID50/mL) isolated in the region in 2014. At 6, 9, 14 and 21 days post-infection, mosquito bodies (thorax and abdomen), heads and saliva were analyzed to measure infection, dissemination, transmission rates and transmission efficiency, respectively. According to our results, ZIKV infection rates were heterogeneous between the Ae. aegypti populations, but the dissemination rates were moderate and more homogenous between these populations. For Ae. polynesiensis, infection rates were less heterogeneous between the two populations tested. The transmission rate and efficiency results revealed a low vector competence for ZIKV of the different Aedes vector populations under study. CONCLUSION/SIGNIFICANCE: Our results indicated a low ZIKV transmission by Ae. aegypti and Ae. polynesiensis tested from the Pacific region. These results were unexpected and suggest the importance of other factors especially the vector density, the mosquito lifespan or the large immunologically naive fraction of the population that may have contributed to the rapid spread of the ZIKV in the Pacific region during the 2013-2017 outbreak. PMID- 30016374 TI - Monitoring indexes of concrete dam based on correlation and discreteness of multi point displacements. AB - Monitoring indexes are significant for real-time monitoring of dam performance in ensuring safe and normal operation. Traditional methods for establishing monitoring indexes are mostly focused on single point displacements, and rational monitoring indexes based on multi-point displacements are rare. This study establishes monitoring indexes based on correlation and discreteness of multi point displacements. The proposed method is applicable when several monitoring points show strong correlation. In this study, principal component analysis (PCA) was introduced for preprocessing the observations of multi-point displacements. Correlation and discreteness of multi-point displacements were extracted and constructed. The correlation and discreteness parts described the integral and local variance of the displacement field. On this basis, the annual maximum values of the correlation and discreteness parts were selected and their probability density functions (PDF) could be generated by employing the principle of maximum entropy. PDF was constructed using maximum entropy method and was least subjective because it barely provided the moment information of the observations. The multi-point monitoring indexes were then determined by the typical low probability method based on the obtained PDFs. Finally, the proposed method was analyzed using a practical engineering and was verified in terms of its feasibility. PMID- 30016370 TI - Neutrophils use superoxide to control bacterial infection at a distance. AB - Understanding the roles of neutrophils and macrophages in fighting bacterial infections is a critical issue in human pathologies. Although phagocytic killing has been extensively studied, little is known about how bacteria are eliminated extracellularly in live vertebrates. We have recently developed an infection model in the zebrafish embryo in which leukocytes cannot reach the injected bacteria. When Escherichia coli bacteria are injected within the notochord, both neutrophils and macrophages are massively recruited during several days, but do not infiltrate the infected tissue presumably because of its tough collagen sheath. Nevertheless, the bacteria are killed during the first 24 hours, and we report here that neutrophils, but not macrophages are involved in the control of the infection. Using genetic and chemical approaches, we show that even in absence of phagocytosis, the bactericidal action relies on NADPH oxidase dependent production of superoxide in neutrophils. We thus reveal a host effector mechanism mediated by neutrophils that eliminates bacteria that cannot be reached by phagocytes and that is independent of macrophages, NO synthase or myeloperoxidase. PMID- 30016375 TI - Mild hydrostatic pressure triggers oxidative responses in Escherichia coli. AB - Hydrostatic pressure is an important physical stimulus which can cause various responses in bacterial cells. The survival and cellular processes of Escherichia coli under hydrostatic pressures between 10 MPa and 110 MPa have been studied. However, understanding bacterial responses to moderately elevated pressure of up to 10 MPa is useful for a range of different applications including for example in smart and responsive materials. In this study, the genetic responses of E. coli K-12 MG1655 to 1 MPa pressure was examined using transcriptomic analysis by RNA-Seq. The results show that 101 genes were differentially expressed under 1 MPa pressure in E. coli cells, with 85 of them up-regulated. The analysis suggested that some genes were over expressed to adapt the increase of oxygen levels in our system, and several functional categories are involved including oxidative stress responses, Fe-S cluster assembly and iron acquisition. Two differentially expressed genes azuC and entC were further investigated using RT qPCR, and GFP reported strains of those two genes were created, AG1319 (PazuC azuC-msfgfp) and AG1321 (PentC entC-msfgfp). A linear response of azuC expression was observed between 0 MPa to 1 MPa by monitoring the fluorescence signal of strain AG1319 (PazuC azuC-msfgfp). This study is the first report to demonstrate the genetic response of bacterial cells under 1 MPa hydrostatic pressure, and provides preliminary data for creating pressure sensing bacterial strains for a wide range of applications. PMID- 30016377 TI - Glioblastoma and Survival Prediction. AB - Glioblastoma is a stage IV highly invasive astrocytoma tumor. Its heterogeneous appearance in MRI poses critical challenge in diagnosis, prognosis and survival prediction. This work extracts a total of 1207 different types of texture and other features, tests their significance and prognostic values, and then utilizes the most significant features with Random Forest regression model to perform survival prediction. We use 163 cases from BraTS17 training dataset for evaluation of the proposed model. A 10-fold cross validation offers normalized root mean square error of 30% for the training dataset and the cross validated accuracy of 63%, respectively. PMID- 30016378 TI - Inhibitory effect of selenomethionine on carcinogenesis in the model of human colorectal cancer in vitro and its link to the Wnt/beta-catenin pathway. AB - Selenium compounds have been implicated as anticancer agents; however, the mechanism of their inhibitory action against cancer development has not been extensively investigated. A constitutive activation of the Wnt/beta-catenin pathway is a central event in colorectal carcinogenesis. In this pathway, excessive cell proliferation is initiated by generation of beta-catenin followed by overexpression of proto-oncogenes, such as c-Myc. It is believed that under physiological conditions the level of c-Myc is efficiently controlled by accessibility of the beta-catenin protein through the process of phosphorylation by glycogen synthase kinase 3beta (GSK-3beta). Here, we determined whether selenomethionine (SeMet) can inhibit cell growth and affect the Wnt/beta-catenin pathway in the HT-29 human colorectal cancer cells in vitro. The effective cytotoxic doses of SeMet have been selected after 48 h of incubation of this compound with colorectal cancer HT-29 cell line. MTT assay was used to assess cell viability and the protein and mRNA levels of beta-catenin and c-Myc were determined by Western blotting and qPCR, respectively. SeMet potently inhibited growth of HT-29 cells, significantly decreased level of the beta-catenin protein and mRNA concentration, down-regulated the c-Myc gene expression and up-regulated the pro-apoptotic Bax protein level. Moreover, SeMet increased the level of GSK 3beta phosphorylated at serine 9 (S9) and significantly increased the level of beta-catenin phosphorylated at S33 and S37. We conclude that SeMet suppresses growth of HT-29 colorectal cancer cells by a mechanism linked to the Wnt/beta catenin pathway, however, degradation of beta-catenin may occur independently of GSK-3beta catalytic activity and its phosphorylation status. PMID- 30016376 TI - N-acetylcysteine: A potential treatment for substance use disorders. PMID- 30016386 TI - Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment. AB - Background: In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anticancer agents or proapoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA). Methods: We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated S. typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models. Results: INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl 2 and Bcl-xL expressions. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). Salmonella typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage. Conclusion: Our results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option. PMID- 30016379 TI - Highlights of Skin Disease Education Foundations 42nd Annual Hawaii Dermatology Seminar. AB - Updates on managing some of the most common dermatologic conditions for which patients seek care illuminated presentations at the Skin Disease Education Foundation's 42nd Annual Hawaii Dermatology Seminar(r). This educational supplement summarizes the highlights of clinical sessions presented during this CME/CE conference. Treatment of psoriasis has continued to advance, with three interleukin (IL)-17 antagonists approved by the US Food and Drug Administration (FDA) and a fourth in phase 3 trials. An authority on the use of biologics in psoriasis presents current data on the safety and efficacy of these therapies. Tumor necrosis factor (TNF) inhibitors also retain a place in the management of psoriasis, with records of long-term safety. A fourth TNF inhibitor awaits FDA approval for use in psoriasis, offering data on transmission during pregnancy and lactation. An expert on the use of this drug class presents the evidence. Topical therapies remain the cornerstone of care for many patients with psoriasis as well as those with rosacea. Our faculty update readers about new and investigational topical therapies for moderate or severe psoriasis, as well as for acne and rosacea. The current literature on monitoring patients receiving isotretinoin also is summarized. Aesthetic and cosmetic dermatology services form a sizable portion of some practices. Our faculty review data on safety of topical and procedural therapies for cellulite as well as safe injection of facial fillers. PMID- 30016385 TI - Identifying and Characterizing Subpopulations of Heavy Alcohol Drinkers Via a Sucrose Preference Test: A Sweet Road to a Better Phenotypic Characterization? AB - Aims: Sweet preference in individuals with alcohol use disorder (AUD) has been associated with family history of AUD and personality traits. Therefore, testing sweet preference may help identify subpopulations of AUD individuals. Short summary: Sweet preference has been associated with family history of AUD and personality traits. We compared heavy drinkers based on their sweet liker status and using two cutoffs. Our findings support the role of sweet preference in heavy drinkers and point to the importance of how sweet likers are defined. Methods: This study aimed at describing and comparing heavy drinkers based on their sweet liker status, through demographic, neuroendocrine, inflammatory, behavioral and drinking characteristics. Participants rated the pleasantness and intensity of sucrose solutions (0.05, 0.10, 0.21, 0.42 and 0.83 M). Two cutoffs were used to identify likers versus dislikers: Grouping A likers preferred 0.83 M and Grouping B likers preferred 0.83 or 0.42 M; the rest were dislikers. Results: Sweet likers were 36% (n = 20) using Grouping A and 58.2% (n = 32) using Grouping B. Grouping B, but not Grouping A, sweet likers had higher BMI (P = 0.01). In Grouping B, sweet likers had higher plasma leptin and insulin concentrations and higher insulin resistance (P's < 0.05). C-reactive protein concentrations were higher in sweet likers in Grouping A (P = 0.0015) and at a trend level in Grouping B (P = 0.07). Grouping A sweet likers had higher alcohol craving (P = 0.0004). Sweet likers preferred spirits compared to nonspirits (wine and beer) across both grouping (P's < 0.05). Conclusions: These results provide further support for the role of sweet liking phenotype in identifying subpopulations of AUD individuals. These findings also point to the importance of how sweet likers are defined, therefore highlighting the need for further research. PMID- 30016387 TI - Respiratory Health Outcomes, Rhinitis, and Eczema in Workers from Grain Storage Facilities in Costa Rica. AB - Objectives: To examine the associations of inhalable grain dust exposure with respiratory health outcomes, rhinitis, and eczema reported by workers from rice, wheat, and maize storage facilities. Methods: A cross-sectional study of 136 workers (73 operators and 63 administrative staff and other workers) from eight Costa Rican grain storage facilities was conducted in 2014-2015. Full-shift personal inhalable dust samples from all workers were collected. Study participants were administered a short version of the European Community Respiratory Health Survey questionnaire to identify symptoms of asthma, chronic bronchitis, rhinitis, and eczema. Associations between grain dust exposure and health outcomes were assessed using multivariable logistic and negative binomial regression models adjusted for age, smoking history, grain type, and presence of pets or farm animals in the home. Results: The median inhalable grain dust concentration was 2.0 (25th to 75th percentile: 0.3-7.0) mg m-3. Higher concentrations of inhalable dust were associated with increased odds of (i) asthma symptoms or medication use [adjusted Odds ratio (ORa) per 10-fold increase in dust concentration 2.7; 95% confidence interval (CI): 1.3-6.7]; (ii) a score of at least two out of five symptoms suggestive of asthma (ORa 1.2; 95% CI: 1.0 1.3); and (iii) eczema (ORa 3.6; 95% CI: 1.7-9.6). No associations of inhalable grain dust exposure with chronic bronchitis and rhinitis were observed. Conclusions: High exposure to inhalable dust in Costa Rican grain storage facilities was associated to asthma symptoms and eczema in workers. PMID- 30016388 TI - Retrospective Assessment of Respirable Quartz Exposure for a Silicosis Study of the Industrial Sand Industry. AB - Background: In 2016, the OSHA PEL for crystalline silica was reduced, renewing interest in evaluating risk of silicosis from occupational exposures. The industrial sand industry, which deals with high-purity quartz sands, is the setting for a current epidemiologic investigation of silicosis risk and progression. In support of that investigation, respirable quartz (RQ) exposures were retrospectively estimated for 67 workers with silicosis and 167 matched control workers from 21 industrial sand plants, in which some started work as early as 1929. Methods: A job exposure matrix (JEM) was constructed by integrating a modern (post-1970) RQ exposure database containing more than 40000 measurements with archival particle count exposure data from a 1947 survey. A simulation algorithm was used to develop a conversion factor to convert the archival particle count data into modern measures of RQ by randomly generating 100000 virtual dust particles of varying diameters corresponding to the size distributions of 14 archival particle size distribution samples. The equivalent respirable mass and particle counts of the virtual particles were calculated, totalled, and ratioed to derive the conversion factor. The JEM was integrated with individual job histories to calculate average and cumulative exposure for each case and control. Multiple exposure estimates were derived for unprotected exposures as well as for exposures adjusted for estimated respiratory protective equipment use and efficiency. Results: The mean of the count to respirable mass conversion factors derived from 14 archival particle size samples was 157 ug m-3 per mppcf (SD: 42; range: 96-263) with no statistical difference across process areas (drying, screening, vibrating, binning, bulk loading, bagging), P = 0.29. The JEM demonstrated an industry-wide decrease in prevailing exposures to RQ of up to about 2 orders of magnitude from the distant (1929) to the recent (2012) past. Unadjusted cumulative exposures for cases and controls were statistically different (P < 0.001) with respective medians (range) of 3764 ug m-3 year (221 25121) and 1595 ug m-3 year (0-16446). Adjustment of exposure for use of respiratory protection showed modest reductions in estimated exposure: median adjusted cumulative exposures assuming a protection factor of 5 were 86% and 77% of the unadjusted values for cases and controls, respectively. Conclusions: The industrial sand industry offers a unique setting for examination of silicosis risk because of the high silica content of industrial sand and a long history of radiographic silicosis surveillance of industry workers. However, the great majority of silicosis cases in this industry are found among former workers and are associated with exposures occurring in the distant past, which necessitates extensive retrospective exposure assessment and increases the likelihood of exposure misclassification. Nonetheless, the estimated cumulative exposures for silicosis cases and controls in this work were significantly different, with the median cumulative exposure for cases being more than twice that of their matched controls. PMID- 30016389 TI - Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. PMID- 30016390 TI - Examining Risk of Workplace Violence in Canada: A Sex/Gender-Based Analysis. AB - Objectives: Workplace violence (WPV) is a serious issue, resulting in significant negative health outcomes. Understanding sex/gender differences in risk of WPV has important implications for primary prevention activities. Methods: Utilizing two waves of the Canadian General Social Survey on Victimization (N = 27,643), we examined the likelihood of WPV, and sub-categories of WPV, for women relative to men. Using a sex/gender analytical approach, a series of logistic regression models examined how the associations between being a woman and each of the outcomes changed upon adjustment for work and socio-demographic characteristics. Results: After adjustment for work hours, women were at more than twice the risk of WPV compared to men (odds ratio = 2.12, 95% confidence interval 1.52-2.95). Adjustment for work characteristics attenuated, but did not eliminate this risk. Differences in associations were observed across sub-categories of violence, with adjustment for work characteristics attenuating sex/gender differences in physical WPV, but having minimal impact on sex/gender differences in sexual WPV. Conclusions: Work characteristics explain a substantial proportion of the sex/gender differences in risk of physical WPV. However, even after adjustment for work characteristics, women still showed an elevated risk relative to men for almost all types of violence (as defined by nature of the violence, sex of the perpetrator, and relationship to the perpetrator) examined in this study. Future investigations should examine why these differences between women and men remain, even within similar occupational contexts. PMID- 30016391 TI - Final results of a randomized phase III trial of induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with stage IVA and IVB nasopharyngeal carcinoma-Taiwan Cooperative Oncology Group (TCOG) 1303 Study. AB - Background: Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. Patients and methods: This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30 mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8-2.2 Gy per fraction with five daily fractions per week, to a total dose of 70 Gy or greater to the primary tumor and 66-70 Gy to the involved neck. The primary end point was disease-free survival (DFS). Results: In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0 months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm [5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565-0.965; P = 0.0264], after stratified for N3b and LDH, and adjusted for T stage. Conclusion: Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. Clinical trial information: NCT00201396. PMID- 30016393 TI - A Randomized Controlled Trial of a Truck Seat Intervention: Part 2-Associations Between Whole-Body Vibration Exposures and Health Outcomes. AB - This randomized controlled trial study was conducted to determine whether two different seating interventions would reduce exposure to whole-body vibration (WBV) and improve associated health outcomes. Forty professional truck drivers were randomly assigned to two groups: (i) a control group of 20 drivers who received a new, industry-standard air-suspension seat, and (ii) an intervention group of 20 drivers who received an active-suspension seat. This study collected regional body pain (10-point scale), low back disability [Oswestry Disability Index (ODI)], physical and mental health [the Short Form 12-item Health Survey (SF-12)], and work limitations [Work Limitation Questionnaire (WLQ)] before and 3, 6, and 12 months after the seating intervention. WBV exposures were also collected during the same time periods. Due to dropouts at the 12-month time period, only data up to 6 months post-intervention were included in the analyses. The post-intervention A(8) WBV exposures were lower in both groups with a more substantial WBV exposure reduction (~50%) in the intervention group compared to the control group (~26%). There was little to no change in the impulsive exposures [VDV(8) and Sed(8)] post-intervention and no differences between the two groups. The self-reported musculoskeletal health outcomes showed that intervention group experienced a greater reduction in the low back pain (LBP) and other musculoskeletal outcomes than the control group. The LBP reduction in the intervention group was clinically meaningful (>25%); however, none of the changes in pain reached statistical significance (P's > 0.22). The SF-12 health scores demonstrated that the intervention group's physical health improved after the intervention (P's < 0.06) while the control group experience little to no improvement (P's > 0.11). The WLQ scores showed that the intervention group generally experienced reduced (improved) work limitation over time whereas the control group showed inconsistent changes in work limitation scores. These study findings indicate that reducing truck drivers' exposure to WBV through seating intervention can lead to improvements in LBP and other health outcomes. PMID- 30016394 TI - AJCC eighth edition for soft tissue sarcoma of the extremities and trunk. PMID- 30016392 TI - Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer. AB - Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633. PMID- 30016395 TI - Novel therapies in urothelial carcinoma: a biomarker-driven approach. AB - Urothelial malignancies, including carcinomas of the bladder, ureters, and renal pelvis comprised approximately 8% of new cancer cases in the United States in 2016. In the metastatic setting, 15% of patients exhibit long-term survival following cisplatin-based chemotherapy and in patients with recurrent disease, response rates to second-line chemotherapy are generally 15-20% with a 3-month progression-free survival. However, recent advances in immunotherapy represent an opportunity to significantly improve patient outcomes. Moreover, the advent of next-generation sequencing (NGS) has resulted in both an improved understanding of the fundamental genetic changes that characterize urothelial carcinoma (UC) and identification of several candidate biomarkers of response to various therapies. Incorporation of prospective genotyping into clinical trials will allow for the identification and enrichment of patients most likely to respond to specific targeted therapies and chemotherapy. Combining different therapeutic classes to enhance outcomes is also an area of active research in UC. PMID- 30016396 TI - Remote Monitoring and Clinical Outcomes: Details on Information Flow and Workflow in the IN-TIME Study. AB - Aims: Randomized clinical trials investigating a possible outcome effect of remote monitoring in patients with implantable defibrillators have shown conflicting results. This study analyses information flow and workflow details from IN-TIME and discusses whether differences of message content, information speed and completeness, and workflow may contribute to the heterogeneous results. Methods and results: IN-TIME randomized 664 patients with an implantable cardioverter/defibrillator indication to daily remote monitoring vs. control. After 12 months, a composite clinical score and all-cause mortality were improved in the remote monitoring arm. Messages were received on 83.1% of out-of-hospital days. Daily transmissions were interrupted 2.3 times per patient-year for more than 3 days. During one year, absolute transmission success declined by 3.3%. Information on medical events was available after 1 day (3 days) in 83.1% (94.3%) of the cases. On all working days, a Central Monitoring Unit informed investigators of protocol defined events. Investigators contacted patients with a median delay of 1 day and arranged follow-ups, the majority of which took place within one week of the event being available. Discussion: Only limited data on information flow and workflow have been published from other studies which failed to improve outcome. However, a comparison of those data to IN-TIME suggest that the ability to see a patient early after clinical events may be inferior to the set-up in IN-TIME. These differences may be responsible for the heterogeneity found in clinical effectiveness of remote monitoring concepts. PMID- 30016398 TI - Economic evaluation of the use of non-vitamin K oral anticoagulants in patients with atrial fibrillation on anti-platelet therapy: A modelling analysis using the healthcare system in the Netherlands. AB - Aims: Non-vitamin K oral anticoagulants (NOACs) have consistently demonstrated superior efficacy in terms of stroke prevention and safety in terms of bleeding over vitamin K antagonist (VKA) in patients with non-valvular atrial fibrillation (AF). The potential use of NOACs in AF patients requiring anti-platelet therapy has only been assessed in small meta-analyses reporting consistent benefits of NOACs over VKAs. However, the prescription costs of NOACs are higher than those of VKAs. The aim of his study was to estimate the cost-effectiveness of NOACs compared to VKAs in patients with non-valvular AF also requiring anti-platelet therapy with the Dutch healthcare system used as a surrogate of many European healthcare systems. Methods and Results: A decision tree was constructed to analyse the cost-effectiveness of NOACs compared to VKAs in patients with non valvular AF with an indication for anti-platelet therapy over a horizon of 1 year. Beside the base case analysis, univariate probabilistic sensitivity and two sensitivity analyses were performed: first, we assessed the impact of VKA home monitoring; second, we varied the NOACs price assuming patent expiration. Use of NOACs instead of VKA is associated with a health gain of 0.0171 QALYs and with an incremental cost of ?357, resulting in an ICER of ?20.919, which is almost equal to the generally accepted cost-effectiveness threshold of ?20.000 used in the Netherlands. The probability that NOACs are cost-effective at a conservative willingness-to pay threshold of ?20,000 per QALY was 50%. Introducing home monitoring increased VKAs costs so much that NOACs became the dominant option (less costly and more effective). Price drops associated to patent expiration of NOACs increased its cost-effectiveness. Conclusion: This analysis suggests that the use of NOACs is a cost-effective alternative of VKAs in patients with AF needing anti-platelet therapy. Our findings in the Netherlands healthcare system are probably consistent with other European populations. PMID- 30016397 TI - dbCID: a manually curated resource for exploring the driver indels in human cancer. AB - While recent advances in next-generation sequencing technologies have enabled the creation of a multitude of databases in cancer genomic research, there is no comprehensive database focusing on the annotation of driver indels (insertions and deletions) yet. Therefore, we have developed the database of Cancer driver InDels (dbCID), which is a collection of known coding indels that likely to be engaged in cancer development, progression or therapy. dbCID contains experimentally supported and putative driver indels derived from manual curation of literature and is freely available online at http://bioinfo.ahu.edu.cn: 8080/dbCID. Using the data deposited in dbCID, we summarized features of driver indels in four levels (gene, DNA, transcript and protein) through comparing with putative neutral indels. We found that most of the genes containing driver indels in dbCID are known cancer genes playing a role in tumorigenesis. Contrary to the expectation, the sequences affected by driver frameshift indels are not larger than those by neutral ones. In addition, the frameshift and inframe driver indels prefer to disrupt high-conservative regions both in DNA sequences and protein domains. Finally, we developed a computational method for discriminating cancer driver from neutral frameshift indels based on the deposited data in dbCID. The proposed method outperformed other widely used non-cancer-specific predictors on an external test set, which demonstrated the usefulness of the data deposited in dbCID. We hope dbCID will be a benchmark for improving and evaluating prediction algorithms, and the characteristics summarized here may assist with investigating the mechanism of indel-cancer association. PMID- 30016399 TI - Making complex pathology simple: added value of 3D transthoracic echocardiography in an adult patient with congenitally corrected transposition of great arteries and severe tricuspid regurgitation. PMID- 30016400 TI - Exchange-protein activated by cyclic-AMP (EPAC) regulates atrial fibroblast function and controls cardiac remodeling. AB - Aims: Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodeling via a variety of signaling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1 signaling on LA-fibroblast (FB) function and its potential role in HF-related atrial remodeling. Methods and Results: HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP). Epac1-expression decreased in LA-FBs within 12 h (-3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 uM) reduced, whereas the Epac blocker ESI-09 (1 uM) enhanced, collagen-expression in LA-FBs. Norepinephrine (1 uM) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The beta-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (beta2-AR blocker), but not by CGP (beta1-AR-blocker). beta-AR-activation with isoproterenol decreased collagen-expression, an effect mimicked by the beta2-AR agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-beta1, known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3-inhibitor SIS3. To evaluate effects on atrial fibrosis in vivo, mice subjected to myocardial infarction (MI) received the Epac activator Sp-8-pCPT or vehicle for 2 weeks post-MI; Sp-8-pCPT diminished LA fibrosis and attenuated cardiac dysfunction. Conclusions: HF reduces LA-FB Epac1 expression. Adrenergic activation has complex effects on FBs, with alpha-AR activation suppressing Epac1-expression and increasing collagen expression, and beta2-AR-activation having opposite effects. Epac1-activation reduces cardiac dysfunction and LA-fibrosis post-MI. Thus, Epac1 signaling may be a novel target for the prevention of profibrillatory cardiac remodeling. PMID- 30016402 TI - The effect of blood pressure on left atrial size and function assessed by 3 dimensional echocardiography. PMID- 30016401 TI - Sex-specific regulation of collagen I and III expression by 17beta-Estradiol in cardiac fibroblasts: role of estrogen receptors. AB - Aims: Sex differences in cardiac fibrosis point to the regulatory role of 17beta Estradiol (E2) in cardiac fibroblasts (CF). We therefore asked whether male and female CF in rodent and human models are differentially susceptible to E2, and whether this is related to sex-specific activation of estrogen receptor alpha (ERalpha) and beta (ERbeta). Methods and Results: In female rat CF (rCF), 24 h E2 treatment (10-8 M) led to a significant down-regulation of collagen I and III expression, whereas both collagens were up-regulated in male rCF. E2-induced sex specific collagen regulation was also detected in human CF, indicating that this regulation is conserved across species. Using specific ERalpha- and ERbeta agonists (10-7 M) for 24 h, we identified ERalpha as repressive and ERbeta as inducing factor in female and male rCF, respectively. In addition, E2-induced ERalpha phosphorylation at Ser118 only in female rCF, whereas Ser105 phosphorylation of ERbeta was exclusively found in male rCF. Further, in female rCF we found both ER bound to the collagen I and III promoters using chromatin immunoprecipitation assays. In contrast, in male rCF only ERbeta bound to both promoters. In engineered connective tissues (ECT) from rCF, collagen I and III mRNA were downregulated in female ECT and up-regulated in male ECT by E2. This was accompanied by an impaired condensation of female ECT, whereas male ECT showed an increased condensation and stiffness upon E2-treatment, analyzed by rheological measurements. Finally, we confirmed the E2-effect on both collagens in an in vivo mouse model with ovariectomy for E2 depletion, E2 substitution, and pressure overload by transverse aortic constriction. Conclusions: The mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERalpha and ERbeta signaling in CFs. PMID- 30016403 TI - Acetylation of PGC1alpha by histone deacetylase 1 downregulation is implicated in radiation-induced senescence of brain endothelial cells. AB - Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1alpha) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1alpha also promotes brain cell proliferation and memory. However, how PGC1alpha is involved in aging is not well known. In brain endothelial cells, we found that PGC1alpha knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated gamma-galactosidase-positive cells and a decrease in cell proliferation and ATP production. PGC1alpha knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by gamma-H2AX foci staining assay. Overexpression of PGC1alpha reduced senescence-associated gamma-galactosidase positive cells and increased the proliferation of senescent cells. Although PGC1alpha protein levels were not decreased, PGC1 acetylation was increased by ionizing radiation treatment and aging. Histone deacetylase 1 (HDAC1) expression was decreased by ionizing radiation treatment and aging, and downregulation of HDAC1 induced acetylation of PGC1alpha. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1alpha. In the mouse brain cortex, acetylation of PGC1alpha was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1alpha is induced by DNA damage agents such as ionizing radiation, which deregulates mitochondrial mechanisms and metabolism, resulting in acceleration of radiation-induced senescence. Therefore, acetylation of PGC1alpha may be a cause of brain disorders and has the potential to serve as a therapeutic target for radiation-induced senescence after radiation cancer therapy. PMID- 30016404 TI - Comparison of Energy-Based Tissue Dissection Techniques in Abdominoplasty: A Randomized, Open-Label Study Including Economic Aspects. AB - Background: Abdominoplasty is one of the most common procedures in plastic surgery, and energy-based tissue dissection techniques have become the gold standard. Despite its frequency, abdominoplasty is still associated with high complication rates. Objectives: We compare clinical and economic data of four methods of energy-based tissue dissection in a randomized, open-label study. Methods: A total of 57 patients were preoperatively randomized into four groups: Electrocautery, Ultracision Harmonic Scalpel, Argon Plasma Coagulation, and PEAK Plasmablade. Demographic and operational data, as well as information on the postoperative course and complications were collected. For economic analysis, quotes were obtained from the device companies or official suppliers. Results: We found no significant difference in the duration of surgery, the drainage quantity, or wound healing complications between treatment groups. The Ultracision method caused significantly greater blood loss compared to all other techniques (p<0.01). When comparing surgical costs, we found PEAK and Ultracision devices more expensive compared to APC and Electrocautery. Conclusions: All methods evaluated can be applied safely and effectively in abdominoplasty procedures. However, our data demonstrate a significantly higher blood loss for the Ultracision Harmonic Scalpel. Considering our clinical data, we are unable to find justification for the higher costs of PEAK and Ultracision methods. PMID- 30016406 TI - ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R. AB - Summary: After more than fifteen years of existence, the R package ape has continuously grown its contents, and has been used by a growing community of users. The release of version 5.0 has marked a leap towards a modern software for evolutionary analyses. Efforts have been put to improve efficiency, flexibility, support for 'big data' (R's long vectors), ease of use, and quality check before a new release. These changes will hopefully make ape a useful software for the study of biodiversity and evolution in a context of increasing data quantity. Availability: ape is distributed through the Comprehensive R Archive Network: http://cran.r-project.org/package=apeFurther information may be found athttp://ape-package.ird.fr/. PMID- 30016407 TI - Automatic Recognition of Ligands in Electron Density by Machine Learning. AB - Motivation: The correct identification of ligands in crystal structures of protein complexes is the cornerstone of structure-guided drug design. However, cognitive bias can sometimes mislead investigators into modeling fictitious compounds without solid support from the electron density maps. Ligand identification can be aided by automatic methods, but existing approaches are based on time-consuming iterative fitting. Results: Here we report a new machine learning algorithm called CheckMyBlob that identifies ligands from experimental electron density maps. In benchmark tests on portfolios of up to 219,931 ligand binding sites containing the 200 most popular ligands found in the Protein Data Bank, CheckMyBlob markedly outperforms the existing automatic methods for ligand identification, in some cases doubling the recognition rates, while requiring significantly less time. Our work shows that machine learning can improve the automation of structure modeling and significantly accelerate the drug screening process of macromolecule-ligand complexes. Availability: Code and data are available on GitHub at https://github.com/dabrze/CheckMyBlob. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30016408 TI - Plasma Nuclear Magnetic Resonance Metabolomics Discriminates Between High and Low Endoscopic Activity and Predicts Progression in a Prospective Cohort of Patients With Ulcerative Colitis. AB - Background and Aims: Endoscopic assessment of ulcerative colitis [UC] is one of the most accurate measures of disease activity, but frequent endoscopic investigations are disliked by patients and expensive for the healthcare system. A minimally invasive test that provides a surrogate measure of endoscopic activity is required. Methods: Plasma nuclear magnetic resonance [NMR] spectra from 40 patients with UC followed prospectively over 6 months were analysed with multivariate statistics. NMR metabolite profiles were compared with endoscopic [Ulcerative Colitis Endoscopic Index of Severity: UCEIS], histological [Nancy Index] and clinical [Simple Clinical Colitis Activity Index: SCCAI] severity indices, along with routine blood measurements. Results: A blinded principal component analysis spontaneously separated metabolite profiles of patients with low [<=3] and high [>3] UCEIS. Orthogonal partial least squares discrimination analysis identified low and high UCEIS metabolite profiles with an accuracy of 77 +/- 5%. Plasma metabolites driving discrimination included decreases in lipoproteins and increases in isoleucine, valine, glucose and myo-inositol in high compared to low UCEIS. This same metabolite profile distinguished between low [Nancy 0-1] and high histological activity [Nancy 3-4] with a modest although significant accuracy [65 +/- 6%] but was independent of SCCAI and all blood parameters measured. A different metabolite profile, dominated by changes in lysine, histidine, phenylalanine and tyrosine, distinguished between improvement in UCEIS [decrease >=1] and worsening [increase >=1] over 6 months with an accuracy of 74 +/- 4%. Conclusion: Plasma NMR metabolite analysis has the potential to provide a low-cost, minimally invasive technique that may be a surrogate for endoscopic assessment, with predictive capacity. PMID- 30016409 TI - Reproducible and replicable comparisons using SummarizedBenchmark. AB - Summary: Benchmark studies are widely used to compare and evaluate tools developed for answering various biological questions. Despite the popularity of these comparisons, the implementation is often ad hoc, with little consistency across studies. To address this problem, we developed SummarizedBenchmark, an R package and framework for organizing and structuring benchmark comparisons. SummarizedBenchmark defines a general grammar for benchmarking and allows for easier setup and execution of benchmark comparisons, while improving the reproducibility and replicability of such comparisons. We demonstrate the wide applicability of our framework using four examples from different applications. Availability and Implementation: SummarizedBenchmark is an R package available through Bioconductor (http://bioconductor.org/packages/SummarizedBenchmark). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30016405 TI - Future directions for therapeutic strategies in post-ischaemic vascularization: a position paper from European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology. AB - Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro- and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population. Nevertheless, there is a large body of evidence that validate the importance of angiogenesis as a therapeutic concept. The overall aim of this Position Paper of the ESC Working Group of Atherosclerosis and Vascular biology is to provide guidance for the next steps to be taken from pre-clinical studies on vascularization towards clinical application. To this end, the current state of knowledge in terms of therapeutic strategies for targeting vascularization in post-ischaemic disease is reviewed and discussed. A consensus statement is provided on how to optimize vascularization studies for the identification of suitable targets, the use of animal models of disease, and the analysis of novel delivery methods. PMID- 30016412 TI - Simulating Illumina Metagenomic Data with InSilicoSeq. AB - Motivation: The accurate in-silico simulation of metagenomic datasets is of great importance for benchmarking bioinformatics tools as well as for experimental design. Users are dependant on large-scale simulation to not only design experiments and new projects but also for accurate estimation of computational needs within a project. Unfortunately, most current read simulators are either not suited for metagenomics, out of date or relatively poorly documented. In this article, we describe InSilicoSeq, a software package to simulate metagenomic Illumina sequencing data. InsilicoSeq has a simple command-line interface and extensive documentation. Results: InSilicoSeq is implemented in Python and capable of simulating realistic Illumina (meta) genomic data in a parallel fashion with sensible default parameters. Availability: Source code and documentation are available under the MIT license at https://github.com/HadrienG/InSilicoSeq and https://insilicoseq.readthedocs.io/. PMID- 30016413 TI - Microbiota-Host Crosstalk: A Bridge Between Cardiovascular Risk Factors, Diet, and Cardiovascular Disease. AB - Cardiovascular disease is the leading cause of death and is also a major cause of disability worldwide. Indeed, even in well-treated patients for hypertension or dyslipidemia, there is still a high cardiovascular risk called residual risk. It is of utmost importance to identify the pathway leading from risk factors to cardiovascular disease to further improve stroke and myocardial infarction prevention. In this review, we presented some of experimental and epidemiological evidences suggesting that microbiota-host crosstalk is involved in this pathway and bridges the gap between cardiovascular risk factors, diet, and cardiovascular residual risk. We considered the 3 participants in this dialogue: the gut microbiota, the intestinal barrier, and bacterial translocation. We analyzed their relations with cardiovascular risk factors and cardiovascular diseases. Also, we presented some of therapeutic strategies aiming to control microbiota to further prevent cardiovascular disease and the take home messages that can be drawn for clinical practice. PMID- 30016410 TI - Deficits in mesolimbic reward pathway underlie social interaction impairments in children with autism. AB - Lack of interest in social interaction is a hallmark of autism spectrum disorder. Animal studies have implicated the mesolimbic reward pathway in driving and reinforcing social behaviour, but little is known about the integrity of this pathway and its behavioural consequences in children with autism spectrum disorder. Here we test the hypothesis that the structural and functional integrity of the mesolimbic reward pathway is aberrant in children with autism spectrum disorder, and these aberrancies contribute to the social interaction impairments. We examine structural and functional connectivity of the mesolimbic reward pathway in two independent cohorts totalling 82 children aged 7-13 years with autism spectrum disorder and age-, gender-, and intelligence quotient matched typically developing children (primary cohort: children with autism spectrum disorder n = 24, typically developing children n = 24; replication cohort: children with autism spectrum disorder n = 17, typically developing children n = 17), using high angular resolution diffusion-weighted imaging and functional MRI data. We reliably identify white matter tracts linking-the nucleus accumbens and the ventral tegmental area-key subcortical nodes of the mesolimbic reward pathway, and provide reproducible evidence for structural aberrations in these tracts in children with autism spectrum disorder. Further, we show that structural aberrations are accompanied by aberrant functional interactions between nucleus accumbens and ventral tegmental area in response to social stimuli. Crucially, we demonstrate that both structural and functional circuit aberrations in the mesolimbic reward pathway are related to parent-report measures of social interaction impairments in affected children. Our findings, replicated across two independent cohorts, reveal that deficits in the mesolimbic reward pathway contribute to impaired social skills in childhood autism, and provide fundamental insights into neurobiological mechanisms underlying reduced social interest in humans. PMID- 30016414 TI - Apheresis to Mitigate Atherosclerotic Vascular Disease. AB - BACKGROUND: Therapeutic apheresis is a term used to describe a group of treatments where blood components are separated in real time, and one component is removed, exchanged, and/or treated to remove pathogenic substances from the circulation. Plasma exchange, which removed all plasma components, and lipid apheresis which selectively removes lipoproteins from circulation, have both been used to treat atherosclerotic vascular diseases. METHODS: To review the literature regarding the application of therapeutic apheresis for atherosclerotic vascular diseases. RESULTS: Primarily lipid apheresis is used to treat atherosclerotic vascular diseases, particularly familial hypercholesterolemia, lipoprotein (a) hyperlipoproteinemia and peripheral vascular diseases. Lipid apheresis can be used as first line or second line treatment with a strong evidenced-based recommendation. Its use has decreased atherosclerotic events. CONCLUSION: Lipid apheresis is an important therapy for the treatment of familial hypercholesterolemia, lipoprotein (a) hyperlipoproteinemia and peripheral vascular diseases. Lipid apheresis does more than remove low-density lipoproteins and other lipoproteins but also decreases inflammatory markers and improves blood flow. PMID- 30016415 TI - Interest of Combined Blood Pressure Measurements in Very Old Frail Subjects: The PARTAGE Study. AB - BACKGROUND: Several clinical studies have shown that blood pressure (BP) measurements in very old frail individuals are of limited interest due to the fact that several age-related alterations and geriatric syndromes may modify BP. We studied in persons over 80-year old living in nursing homes the combined effects of 3 BP patterns on total mortality and major cardiovascular (CV) events: (i) low pulse pressure amplification (L-PPA) between carotid and brachial artery, (ii) systolic BP (SBP) <130 mm Hg (L-SBP), under >1 antihypertensive drugs, and (iii) changes in SBP between supine and upright position of >20 mm Hg in both directions (hypotension/hypertension, orthostatic SBP [O-SBP]). METHODS: This analysis was performed in subjects of the PARTAGE study presenting all these 3 measurements (n = 883). The combined effects of L-PPA, L-SBP, and O-SBP were studied during the 2 years followed-up period. RESULTS: After adjusting for age, sex, and history of CV events, all 3 BP patterns were independent determinants of major CV events (L-PPA, (P = 0.023); L-SBP, (P = 0.050); O-SBP, (P = 0.015)), whereas L-PPA (P = 0.012) and L-SBP (P = 0.006) were also independent determinants of total mortality. Compared with the subjects without any BP pattern, the presence of 2 or 3 BP patterns was associated with an increase in total mortality and major CV events greater than 2 and 2.5 times, respectively. CONCLUSIONS: In very old frail subjects, there is a particular interest for using different BP measurement approaches, than in younger populations, in order to evaluate the risks related to the BP levels. CLINICAL TRIALS REGISTRATION: Trial Number: NCT00901355 (Clinical Trials.gov). PMID- 30016416 TI - Structure and Function of Systemic Arteries: Reflections on the Arterial Pulse. AB - "Structure and Function of Arteries"-is a topic of great importance to those who deal with arterial hypertension, since it links the source of flow, the left ventricle of the heart (whose output is pulsatile) to the peripheral tissues (whose flow is near continuous). The arterial tree acts passively as a conduit and cushion, and the interaction of heart, arterial tree, and organs is conventionally gauged on the basis of blood pressure measured by cuff in a conveniently located place (the brachial artery). For any precision and perspective to be gained, measurements of brachial systolic and diastolic pressure need be supplemented by other information. When such information is gained, one can understand how beautifully the arterial tree is tuned to the beat of the heart in animals of different size and shape and in humans at age 30 through the first third of a 3 billion beat lifetime. After age 30, the beats themselves progressively destroy the human arteries and their tuning to the heart, with emergence of clinical syndromes. In this review, the subject is tackled quantitatively on the basis of published numerical, physical, physiological, and pathophysiological basis, with principal focus on the beat of the heart, the pulse of the arteries, and their interaction. PMID- 30016417 TI - A Randomized Controlled Trial of a Truck Seat Intervention: Part 1-Assessment of Whole Body Vibration Exposures. AB - Full-time vehicle and heavy equipment operators often have a high prevalence of musculoskeletal disorders, especially low back pain (LBP). In occupations requiring vehicles or heavy equipment operation, exposure to whole body vibration (WBV) has been consistently associated with LBP. LBP is the most common cause of work-related disability and continues to be the leading cause of morbidity and lost productivity in the US workforce. Using a parallel randomized controlled trial design, over a 12-month period, this study evaluated two different seating interventions designed to reduce WBV exposures. Forty professional truck drivers were initially recruited and randomly assigned to one of two groups: (i) a passive suspension/control group-20 drivers who received a new, industry-standard air-suspension seat, and (ii) an intervention group-20 drivers who received an active-suspension seat, which has been shown to reduce vertical WBV exposures by up to 50% compared to passive seats. WBV exposures from the truck seat and floor were collected during driver's full shifts (6-18 h) before (pre-intervention) and after the intervention (0, 3, 6, and 12 months post-intervention) per International Standards Organization (ISO) 2631-1 and 2631-5 WBV standards. After subject dropout and turnover, 16 truck drivers remained in each group. The pre intervention WBV data showed that there were no differences in the daily equivalent time-weighted average WBV exposures [A(8)], vibration dose values [VDV(8)], and static spinal compression doses [Sed(8)] between the two groups (P's > 0.36). After the new seats were installed, the A(8) values showed that the active suspension/intervention group experienced much greater reduction in the vertical (z) axis [~50%; P = <0.0001; Cohen's d effect size (95% CI) = 1.80 (1.12, 2.48)] exposures when compared to in the passive suspension/control group [~20%; P = 0.23; 0.33 (-0.36, 1.02)]. The post-intervention z-axis VDV(8) and Sed(8) WBV exposure measures were not different between the two seat groups [VDV(8), P = 0.33; 0.35 (-0.32, 1.03); Sed(8), P = 0.61; 0.08 (-0.59, 0.76)]. These study findings indicate that, relative to the current industry-standard, passive air-suspension seats which are ubiquitous in all semi-trucks today, the active suspension seat dramatically reduced average continuous [A(8)] WBV exposures but not periodic, cumulative impulsive exposures [VDV(8) and Sed(8)]. PMID- 30016411 TI - Molecular properties underlying regional vulnerability to Alzheimer's disease pathology. AB - Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology specific treatment targets that warrant further exploration in independent studies. PMID- 30016418 TI - Prediction of premature ventricular complex origin in left vs. right ventricular outflow tract: a novel anatomical imaging approach. AB - Aims: Left ventricular (LV) outflow tract ventricular arrhythmias (OTVA) are associated with hypertension (HT), older age, and LV dysfunction, suggesting that LV overload plays a role in the aetiopathogenesis. We hypothesized that anatomical modifications of the LV outflow tract (LVOT) could predict left vs. right OTVA site of origin (SOO). Methods and results: Fifty-six (32 men, 53 +/- 18 years old) consecutive patients referred for OTVA ablation were included. Cardiac multidetector computed tomography was performed before ablation and then imported to the CARTO system to aid the mapping and ablation procedure. Anatomical characteristics of the aortic root as well as aortopulmonary valvular planar angulation (APVPA) were analysed. The LV was the OTVA SOO (LVOT-VA) in 32 (57%) patients. These patients were more frequently male (78% vs. 22%, P = 0.001), older (57 +/- 18 vs. 47 +/- 18 years, P = 0.055), and more likely to have HT (59% vs. 21%, P = 0.004), compared to right OTVA patients. Aortopulmonary valvular planar angulation was higher in LVOT-VA patients (68 +/- 5 degrees vs. 55 +/- 6 degrees , respectively; P < 0.001). Absolute size of all aortic root diameters was associated with LVOT origin. However, after indexing by body surface area, only sinotubular junction diameter maintained a significant association (P = 0.049). Multivariable analysis showed that APVPA was an independent predictor of LVOT origin. Aortopulmonary valvular planar angulation >=62 degrees reached 94% sensitivity and 83% specificity (area under the curve 0.95) for predicting LVOT origin. Conclusions: The measurement of APVPA as a marker of chronic LV overload is useful for the prediction of left vs. right ventricular OTVA origin. PMID- 30016419 TI - Evidence That Dynorphin Acts Upon KNDy and GnRH Neurons During GnRH Pulse Termination in the Ewe. AB - A subpopulation of neurons located within the arcuate nucleus, colocalizing kisspeptin, neurokinin B, and dynorphin (Dyn; termed KNDy neurons), represents key mediators of pulsatile GnRH secretion. The KNDy model of GnRH pulse generation proposes that Dyn terminates each pulse. However, it is unknown where and when during a pulse that Dyn is released to inhibit GnRH secretion. Dyn acts via the kappa opioid receptor (KOR), and KOR is present in KNDy and GnRH neurons in sheep. KOR, similar to other G protein-coupled receptors, are internalized after exposure to ligand, and thus internalization can be used as a marker of endogenous Dyn release. Thus, we hypothesized that KOR will be internalized at pulse termination in both KNDy and GnRH neurons. To test this hypothesis, GnRH pulses were induced in gonad-intact anestrous ewes by injection of neurokinin B (NKB) into the third ventricle and animals were euthanized at times of either pulse onset or termination. NKB injections produced increased internalization of KOR within KNDy neurons during both pulse onset and termination. In contrast, KOR internalization into GnRH neurons was seen only during pulse termination, and only in GnRH neurons within the mediobasal hypothalamus (MBH). Overall, our results indicate that Dyn is released onto KNDy cells at the time of pulse onset, and continues to be released during the duration of the pulse. In contrast, Dyn is released onto MBH GnRH neurons only at pulse termination and thus actions of Dyn upon KNDy and GnRH cell bodies may be critical for pulse termination. PMID- 30016420 TI - Utilization of urea and cyanate in waters overlying and within the eastern tropical north Pacific oxygen deficient zone. AB - In marine oxygen deficient zones (ODZs), which contribute up to half of marine N loss, microbes use nitrogen (N) for assimilatory and dissimilatory processes. Here, we examine N utilization above and within the ODZ of the Eastern Tropical North Pacific Ocean, focusing on distribution, uptake and genes for the utilization of two simple organic N compounds, urea and cyanate. Ammonium, urea and cyanate concentrations generally peaked in the oxycline while uptake rates were highest in the surface. Within the ODZ, concentrations were lower, but urea N and C and cyanate C were taken up. All identified autotrophs had an N assimilation pathway that did not require external ammonium: ODZ Prochlorococcus possessed genes to assimilate nitrate, nitrite and urea; nitrite oxidizers (Nitrospina) possessed genes to assimilate nitrite, urea and cyanate; anammox bacteria (Scalindua) possessed genes to utilize cyanate; and ammonia-oxidizing Thaumarchaeota possessed genes to utilize urea. Urease genes were present in 20% of microbes, including SAR11, suggesting the urea utilization capacity was widespread. In the ODZ core, cyanate genes were largely (~95%) associated with Scalindua, suggesting that, within this ODZ, cyanate N is primarily used for N loss via anammox (cyanammox), and that anammox does not require ammonium for N loss. PMID- 30016422 TI - Which English is English? PMID- 30016421 TI - Reply to 'Bromocriptine for the treatment of peripartum cardiomyopathy: comparison of outcome with a nationwide Danish cohort'. PMID- 30016423 TI - Diversity of yeast species from Dutch garden soil and the description of six novel Ascomycetes. AB - A Citizen Science initiative by the Westerdijk Fungal Biodiversity Institute and the Utrecht University Museum gave rise to a project where fungal and yeast isolates were obtained and identified from Dutch soil samples. During the current study, 386 yeast strains were isolated from 157 different locations in the Netherlands. These strains were identified using sequence data of the large subunit rRNA gene (D1/D2 region) and the internal transcribed spacer 1 and 2 regions. A total of 53 different yeast species were found as well as 15 potentially novel species. Six novel ascomycetous species are described during this study that include Hanseniaspora mollemarum sp. nov., Ogataea degrootiae sp. nov., Pichia gijzeniarum sp. nov., Saccharomycopsis oosterbeekiorum sp. nov., Trichomonascus vanleenenius sp. nov. and Zygoascus flipseniorum sp. nov. This study made it possible to incorporate numerous yeast isolates into the CBS collection without any restrictions, which make these isolates readily available for use by others. Many of the isolates represented species of which only a few isolates or even only a single ex-type strain were available. Therefore, it is a clear indication that such biodiversity-orientated Citizen Science projects can enrich the pool of available yeasts for future research projects. PMID- 30016425 TI - Bromocriptine for the treatment of peripartum cardiomyopathy: comparison of outcome with a Danish cohort. PMID- 30016424 TI - Evidence for Adipocyte-Derived Extracellular Vesicles in the Human Circulation. AB - Adipocyte-derived extracellular vesicles (EVs) may serve as novel endocrine mediators of adipose tissue and impact upon vascular health. However, it is unclear whether adipocyte-derived EVs are present in the human circulation. Therefore, the purpose of this study was to seek evidence for the presence of adipocyte-derived EVs in circulating plasma. Size-exclusion chromatography of platelet-free plasma identified fractions 5 to 10 as containing EVs by a peak in particle concentration, which corresponded with the presence of EV and adipocyte proteins. Pooling fractions 5 to 10 and subjecting to ultracentrifugation yielded a plasma EV sample, as verified by transmission electron microscopy (TEM) showing EV structures and Western blotting for EV (e.g., CD9 and Alix) and adipocyte markers. Magnetic beads and a solid-phase assay were used to deplete the EV sample of the four major families of circulating EVs: platelet-derived, leukocyte derived, endothelial-derived, and erythrocyte-derived EVs. Postdepletion samples from both techniques contained EV structures as visualized by TEM, as well as CD9, Alix, and classic adipocyte proteins. Postdepletion samples also contained a range of other adipocyte proteins from an adipokine array. Adipocyte proteins and adipokines are expressed in optimally processed plasma EV samples, suggesting that adipocyte-derived EVs are secreted into the human circulation. PMID- 30016426 TI - Selective prevention of cardiometabolic diseases: activities and attitudes of general practitioners across Europe. AB - Background: Cardiometabolic diseases (CMDs) are the number one cause of death. Selective prevention of CMDs by general practitioners (GPs) could help reduce the burden of CMDs. This measure would entail the identification of individuals at high risk of CMDs-but currently asymptomatic-followed by interventions to reduce their risk. No data were available on the attitude and the extent to which European GPs have incorporated selective CMD prevention into daily practice. Methods: A survey among 575 GPs from the Czech Republic, Denmark, Greece, the Netherlands and Sweden was conducted between September 2016 and January 2017, within the framework of the SPIMEU-project. Results: On average, 71% of GPs invited their patients to attend for CMD risk assessment. Some used an active approach (47%) while others used an opportunistic approach (53%), but these values differed between countries. Most GPs considered selective CMD prevention as useful (82%) and saw it as part of their normal duties (84%). GPs who did find selective prevention useful were more likely to actively invite individuals compared with their counterparts who did not find prevention useful. Most GPs had a disease management programme for individuals with risk factor(s) for cardiovascular disease (71%) or diabetes (86%). Conclusions: Although most GPs considered selective CMD prevention as useful, it was not universally implemented. The biggest challenge was the process of inviting individuals for risk assessment. It is important to tailor the implementation of selective CMD prevention in primary care to the national context, involving stakeholders at different levels. PMID- 30016427 TI - Double semilunar valve replacement in complex congenital heart disease using decellularized homografts. AB - OBJECTIVES: Patients with complex congenital heart disease often require multiple reoperations, resulting in increased rates of operative morbidity and mortality. Decellularized heart valves (DHVs) have led to reduced reoperation rates compared with current other valve substitutes when used for pulmonary valve replacement and have also shown very auspicious early results in aortic valve replacement. The aim of the work was to analyse the outcome of a single-stage decellularized valve implantation in the aortic and pulmonary position. METHODS: A prospective follow-up of all patients who received a single-stage double semilunar valve replacement using DHV at our institution. RESULTS: Since 2011, 5 patients underwent combined semilunar valve replacement with DHV at our institution: two following a Ross procedure (31-year-old man and 38-year-old woman) and 3 after repair of the truncus arteriosus communis (2-year-old boy and 11-year-old and 16 year-old girls). All patients had undergone previous surgery. The Ross patients had preceding valve procedures, and the patients with truncus arteriosus communis had undergone 1 repair and subsequent operative procedures. Despite challenging operations (median bypass time 346 min, range 275-477 min; median cross-clamp time 229 min, range 140-307 min), there was no perioperative mortality or reoperations. Four of the patients were extubated within 24 h, and the other patient was extubated on postoperative day 2. During follow-up, a good semilunar valve and biventricular heart function was present in all 5 patients, and the New York Heart Association functional class was I for all the patients at the time of their latest follow-up (median 31 months, range 8-82 months). The mean echocardiographic gradient of decellularized aortic homografts was 5.4 +/- 3.2 mmHg and 11.6 +/- 4.2 mmHg for the decellularized pulmonary homografts. Valvular regurgitation was 0 or 0-I for all DHVs. CONCLUSIONS: A single-stage double semilunar valve replacement with DHV has shown promising early results in these 5 very complex cases, providing an additional surgical option after multiple preceding valve procedures in young patients. PMID- 30016428 TI - Cohort Profile: The New South Wales Child Development Study (NSW-CDS)-Wave 2 (child age 13 years). PMID- 30016430 TI - Corrigendum to Postoperative Outcomes in Vedolizumab-Treated Patients Undergoing Major Abdominal Operations for Inflammatory Bowel Disease: Retrospective Multicenter Cohort Study. PMID- 30016431 TI - Ovarian response is associated with anogenital distance in patients undergoing controlled ovarian stimulation for IVF. AB - STUDY QUESTION: Is the length of the anogenital distance (AGD) a biomarker of ovarian reserve and response to controlled ovarian stimulation (COS)? SUMMARY ANSWER: Shorter AGD is associated with presence of poor ovarian response. WHAT IS KNOWN ALREADY: Organ development during prenatal life is influenced by the prevailing intrauterine environment, and it has been suggested that nutritional, environmental and toxic factors could affect ovarian reserve set prenatally. AGD is a biomarker of prenatal-hormonal environment and observational studies have shown an association between its length and reproductive parameters in both sexes. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study of 437 women treated with IVF/ICSI conducted in a tertiary-care university hospital between January and December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women underwent their first COS for IVF/ICSI and reached criteria for oocyte retrieval. Based on the number of oocytes obtained, patients were divided into three groups: poor responders (<=3 oocytes) (n = 50), normoresponders (4-15 oocytes) (n = 332) and high responders (>15 oocytes) (n = 55). Before retrieval, the following patient data were recorded: age, body mass index (BMI), ovarian reserve markers (anti-Mullerian hormone [AMH], antral follicle count [AFC] and follicular stimulation hormone [FSH]), cause of infertility, total doses of gonadotropins used and ovarian sensitivity index (OSI). Patients with previous pregnancies, polycystic ovary syndrome (PCOS), endometriosis and previous ovarian or genital surgery were excluded. Anthropometric biomarkers of AGDAC (anus clitoris) and AGDAF (anus-fourchette) were measured in all patients under sedation on the day of retrieval and before proceeding to oocyte pick-up. Multiple linear regression analyses were used to examine the association between both AGD and ovarian reserve markers, the total units of gonadotropins used, the number of oocytes obtained and the OSI. Logistic regression was used to predict poor response in COS for IVF/ICSI, while accounting for confounders such as age and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline FSH, AMH, AFC and age were significantly different among the three groups of ovarian response, as were the units of gonadotropin used, and the ovarian sensitivity index (OSI) (P < 0.001). Both AGDAC and AGDAF measurements were positively correlated with AMH levels (r = 0.38 and r = 0.21; P < 0.05), AFC (r = 0.41 and r = 0.20; P < 0.05), the OSI (r = 0.24 and r = 0.19; P < 0.05) and the number of oocytes retrieved (r = 0.29 and r = 0.28, respectively; P < 0.05). Conversely, there was a negative correlation between both AGD measurements and the doses of gonadotropins used (r= -0.19 and r= -0.15; P < 0.05). The area under the curve (AUC) for prediction of poor response of AGDAC was 0.70 (95% CI 0.66, 0.75), which was comparable to the classic ovarian reserve markers, such as AFC and AMH. AGDAF showed a significantly worse predictive capacity for poor ovarian response (AUC 0.60 [95% CI 0.55, 0.60]) than AMH and AFC. LIMITATIONS, REASONS FOR CAUTION: The population used for the study was a highly selected group of infertile women who underwent COS for IVF, so the findings of this research may not be applicable for general population. Besides, measurement or selection biases might have been possible and must be considered. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study suggest that in utero exposure to certain hormonal environments could affect the ovarian reserve set prenatally. STUDY FUNDING/COMPETING INTEREST(S): None. The authors have no competing interests to declare. PMID- 30016429 TI - Presence-Absence Polymorphisms of Highly Expressed FP Sequences Contribute to Fluorescent Polymorphisms in Acropora digitifera. AB - Despite many hypotheses regarding the roles of fluorescent proteins (FPs), their biological roles and the genetic basis of FP-mediated color polymorphisms in Acropora remain unclear. In this study, we determined the genetic mechanism underlying fluorescent polymorphisms in A. digitifera. Using a high-throughput sequencing approach, we found that FP gene sequences in FP multigene family exhibit presence-absence polymorphism among individuals. A few particular sequences in short-to-middle wavelength emission and middle-to-long wavelength emission clades were highly expressed in adults, and different sequences were highly expressed in larvae. These highly expressed sequences were absent in the genomes of individuals with low total FP gene expression. In adults, presence absence differences of the highly expressed FP sequences were consistent with measurements of emission spectra of corals, suggesting that presence-absence polymorphisms of these FP sequences contributed to the fluorescent polymorphisms. The functions of recombinant FPs encoded by highly expressed sequences in adult and larval stages were different, suggesting that expression of FP sequences with different functions may depend on the life-stage of A. digitifera. Highly expressed FP sequences exhibited presence-absence polymorphisms in subpopulations of A. digitifera, suggesting that presence-absence status is maintained during the evolution of A. digitifera subpopulations. The difference in FPs between adults and larvae and the polymorphisms of highly expressed FP genes may provide key insight into the biological roles of FPs in corals. PMID- 30016432 TI - Sports interest mediating exercise and compulsive internet use among undergraduates. AB - With the massive growth in Internet technologies, people have become wary of excessive Internet usage, known as compulsive Internet usage or Internet addiction. This study looks into how exercise is related to compulsive Internet usage. Previous research showed varying results regarding the relationship between sports habit and Internet usage; this project clarifies the relationship by investigating mediating variables in terms of interest in different aspects of sports, such as physical education, mastering sport skills, sports participation, and watching sports. Two survey studies were conducted. The participants were 232 male and 107 female Taiwanese undergraduate students in the first survey, totaling 339 students. The second survey had 233 males, 98 female students, and 2 who did not disclose their gender, with a final total of 333. The results reveal that interest in physical education (IPE) mediates sports habit and compulsive Internet usage. As long as the student had a habit of doing sports that increased IPE, this would in turn decrease compulsive Internet use. The importance of igniting students' IPE is discussed. PMID- 30016433 TI - T-box genes and retinoic acid signaling regulate the segregation of arterial and venous pole progenitor cells in the murine second heart field. AB - The arterial and venous poles of the mammalian heart are hotspots of congenital heart defects (CHD) such as those observed in 22q11.2 deletion (or DiGeorge) and Holt-Oram syndromes. These regions of the heart are derived from late differentiating cardiac progenitor cells of the Second Heart Field (SHF) located in pharyngeal mesoderm contiguous with the elongating heart tube. The T-box transcription factor Tbx1, encoded by the major 22q11.2 deletion syndrome gene, regulates SHF addition to both cardiac poles from a common progenitor population. Despite the significance of this cellular addition the mechanisms regulating the deployment of common progenitor cells to alternate cardiac poles remain poorly understood. Here we demonstrate that Tbx5, mutated in Holt-Oram syndrome and essential for venous pole development, is activated in Tbx1 expressing cells in the posterior region of the SHF at early stages of heart tube elongation. A subset of the SHF transcriptional program, including Tbx1 expression, is subsequently downregulated in Tbx5 expressing cells, generating a transcriptional boundary between Tbx1-positive arterial pole and Tbx5-positive venous pole progenitor cell populations. We show that normal downregulation of the definitive arterial pole progenitor cell program in the posterior SHF is dependent on both Tbx1 and Tbx5. Furthermore, retinoic acid (RA) signaling is required for Tbx5 activation in Tbx1-positive cells and blocking RA signaling at the time of Tbx5 activation results in atrioventricular septal defects at fetal stages. Our results reveal sequential steps of cardiac progenitor cell patterning and provide mechanistic insights into the origin of common forms of CHD. PMID- 30016434 TI - Defining Failure of Medical Therapy for Inflammatory Bowel Disease. AB - Over the past 2 decades, advances in biologic and small molecule therapeutics have resulted in a rapid increase in our armamentarium of therapies for inflammatory bowel disease. Despite these advancements, Crohn's disease and ulcerative colitis remain chronic and progressive diseases. One of the primary reasons for persistent inflammation and bowel damage is failure of medical therapy. With growing therapeutic options, there is an increased temptation to quickly move to the next therapy and label the prior therapy as a failure; however, this can lead to inadequate optimization of medications and poor control of disease. On the other hand, failure to recognize ongoing mucosal inflammation despite optimized treatment and moving to the next agent can lead to progression of disease and long-term complications. As our options for medical therapy continue to increase, it has become more important to recognize failure of therapy in order to promptly move to the next therapeutic agent without abandoning therapies prematurely. In this review, we aim to define failure of medical therapy for inflammatory bowel disease with the goal of offering guidance on when it is appropriate to attempt optimization of current medical treatment as opposed to moving on to the next agent or treatment approach. PMID- 30016436 TI - Knockout of myomaker results in defective myoblast fusion, reduced muscle growth and increased adipocyte infiltration in zebrafish skeletal muscle. AB - The fusion of myoblasts into multinucleated muscle fibers is vital to skeletal muscle development, maintenance and regeneration. Genetic mutations in the Myomaker (mymk) gene cause Carey-Fineman-Ziter syndrome (CFZS) in human populations. To study the regulation of mymk gene expression and function, we generated three mymk mutant alleles in zebrafish using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology and analyzed the effects of mymk knockout on muscle development and growth. Our studies demonstrated that knockout of mymk resulted in defective myoblast fusion in zebrafish embryos and increased mortality at larval stage around 35-45 days post fertilization. The viable homozygous mutants were smaller in size and weighed approximately one-third the weight of the wild type (WT) sibling at 3 months old. The homozygous mutants showed craniofacial deformities, resembling the facial defect observed in human populations with CFZS. Histological analysis revealed that skeletal muscles of mymk mutants contained mainly small-size fibers and substantial intramuscular adipocyte infiltration. Single fiber analysis revealed that myofibers in mymk mutant were predominantly single-nucleated fibers. However, myofibers with multiple myonuclei were observed, although the number of nuclei per fiber was much less compared with that in WT fibers. Overexpression of sonic Hedgehog inhibited mymk expression in zebrafish embryos and blocked myoblast fusion. Collectively, these studies demonstrated that mymk is essential for myoblast fusion during muscle development and growth. PMID- 30016435 TI - What Is Successful Aging? A Psychometric Validation Study of Different Construct Definitions. AB - Background and Objectives: We examined the validity of 5 successful aging (SA) operationalizations that assessed different facets of the SA construct (cognitive and physical health and disability; well-being; social engagement). Research Design and Methods: A total of 2,478 participants (mean age = 82.5 years, standard deviation [SD] = 3.47) were studied. We used confirmatory factor analysis to investigate the relationships between facets and to determine the convergent validity as well as short-term (1.5 years) and long-term (4.5 years) predictive validity of the 5 SA operationalizations for measures of quality of life (QoL) and objective health outcomes. Results: A general SA operationalization that included all SA facets but also allowed differences between them showed the best model fit and construct validity. A biomedical operationalization of SA that excluded either the well-being or the social engagement facet showed lower convergent and predictive validity for subjective measures (e.g., QoL) but higher associations with objective measures (e.g., health). A purely psychosocial SA operationalization that excluded the physiological facet did not allow good prediction of objective health outcomes. Discussion and Implications: Our results suggest that a well-balanced SA operationalization should include measures assessing health, disability, well being, and social engagement. PMID- 30016437 TI - Towards a Holistic Approach to Studying Human-Robot Interaction in Later Life. AB - Background and Objectives: Implementation of robotics technology in eldercare depends on successful human-robot interaction (HRI). Relying on a systematic literature review, this article proposes a holistic approach to the study of such interaction. Research Design and Methods: A literature search was carried out in five databases. A Boolean phrase search included the term robot and at least one term referencing older age, leading to an initial corpus of 543 articles. Articles were included in this review if they described older adults' interaction with robots. Exclusion of articles that did not meet this criterion, as well as duplicate material, led to a total of 80 articles, that were then subjected to quantitative and qualitative analyses. Results: Studies tended to focus on older users, typically community-dwelling adults, without sufficient consideration of the users' characteristics and the physical, social, and cultural context of the HRI. Using a variety of methods, many studies were snapshot inquiries. The chief topics explored were use patterns, the resulting outcomes thereof and factors that constrain use. Commonly, however, these topics were examined separately. In addition, most studies lacked any theoretical framework. Discussion and Implications: Additional studies are needed to more fully understand what makes HRI successful. The model presented here suggests scholars to conduct theory driven research, and distinguish among various segments of older users, different types of robots, and group and individual HRI. It also proposes paying greater attention to the users' cultural, physical and social environment, and application of longitudinal and simultaneous examination of uses, outcomes, and constraints. PMID- 30016440 TI - We need to monitor mortality to improve public health programs: here's why and how to do it. PMID- 30016438 TI - Video-assisted thoracoscopic surgery versus open surgery for Stage I thymic epithelial tumours: a propensity score-matched study. AB - OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) has been increasingly used in the management of thymic epithelial tumours. However, its oncological efficacy remains to be proved. The purpose of this study is to compare the oncological outcomes following thoracoscopic versus open surgery in the case matched groups of patients with early-stage thymic tumours from the Chinese Alliance for Research in Thymomas (ChART) retrospective database. METHODS: Between 1994 and 2012, a total of 1087 patients who underwent surgery for UICC (Union for International Cancer Control) pathological Stage I tumours from the ChART retrospective database were recruited for this study. A propensity score matched analysis was used to compare the long-term outcomes in patients who received VATS or open surgery. RESULTS: VATS resection was performed in 271 patients (24.9%) and open surgery in 816 patients (75.1%). Before propensity score matching, the VATS group had a smaller tumour size (P = 0.002), lower grade histology (P = 0.034), lower T stage (P < 0.001) and less adjuvant therapy (P < 0.001). Propensity score matching by gender, myasthenia gravis, tumour size, histological classification, pathological T stage, extent of thymectomy, adjuvant radiotherapy and adjuvant chemotherapy identified 110 patients in each group. After matching, there was no significant difference in patient demographics, tumour characteristics or adjuvant therapy. All matched patients had R0 resection. Overall survival, disease-free survival and cumulative incidence of recurrence were only predicted by WHO histology, but not by surgical approach, in both univariable and multivariable analyses. There was no significant difference in the overall survival (85.7% vs 93.1%, P = 0.539), disease-free survival (92.5% vs 91.9%, P = 0.773), cumulative incidence of recurrence (7.1% vs 5.8%, P = 0.522) and improvement rate of myasthenia gravis (83.3% vs 88.2%, P = 0.589) between the 2 groups. CONCLUSIONS: This propensity score-matched study suggests that VATS and open surgeries are associated with similar oncological outcomes for Stage I thymic epithelial tumours. Minimally invasive surgery might be an acceptable surgical approach for early-stage thymic malignancies. PMID- 30016441 TI - Plasma contact activation by a fucosylated chondroitin sulfate and its structure activity relationship study. AB - Plasma contact system is the initial part of both the intrinsic coagulation pathway and kallikrein-kinin pathway, which mainly involves three proteins: coagulation factor XII (FXII), prekallikrein (PK) and high-molecular weight kininogen. Fucosylated chondroitin sulfate (FCS) is a unique sulfated glycosaminoglycan (GAG) composed of a chondroitin sulfate-like backbone and sulfated fucose branches. The native FCS was preliminary found to cause undesired activation of the plasma contact system. How this unusual GAG functions in this process remains to be clarified. Herein, the relationship between its structure, plasma contact activation and its effects on the PK-FXII reciprocal activation loop were studied. The recalcification time assay indicated that the FCS at high concentration could be procoagulant which may be attributed to its contact activation activity. The structure-activity relationship study indicated that its high molecular weight and distinct fucose side chains are required for contact activation by FCS, although the sulfate substitution types of its side chains have less impact. In human plasma, the native FCSs potently induced FXII dependent contact activation. However, in purified systems FCS did not significantly activate FXII per se or induce its autoactivation, whereas FCS significantly promoted the activation of PK by factor XIIa. Polysaccharide protein interaction assays showed that FCS bound to PK with higher affinity than other contact system proteins. These data suggested that potent contact activation by FCS requires the positive feedback loop between PK and FXII. These findings contribute to better understanding of contact activation by complex GAG. PMID- 30016439 TI - Early life abuse and risk of endometriosis. AB - STUDY QUESTION: Is there an association between physical and sexual abuse occurring in childhood or adolescence and risk of laparoscopically-confirmed endometriosis? SUMMARY ANSWER: Early life sexual and physical abuse was associated with an increased risk of endometriosis. WHAT IS KNOWN ALREADY: Previous studies have reported that physical and sexual abuse are associated with chronic pelvic pain (CPP). However, only one study has examined the association between childhood physical abuse and laparoscopically-confirmed endometriosis, and did not observe an association with endometriosis risk. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 60 595 premenopausal women from 1989 to 2013 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants completed an exposure to violence victimization questionnaire in 2001. Cases were restricted to laparoscopically-confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% confidence intervals (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Three thousand three hundred and ninety-four cases of laparoscopically-confirmed endometriosis were diagnosed during 24 years of follow-up. Compared to those reporting no physical or sexual abuse, the risk of endometriosis was greater among those who experienced severe physical abuse (RR = 1.20; 95% CI = 1.06, 1.37) or severe sexual abuse (RR = 1.49; 95% CI = 1.24, 1.79). There was a 79% increased risk of laparoscopically-confirmed endometriosis for women reporting severe-chronic abuse of multiple types (95% CI = 1.44, 2.22). The associations between abuse and endometriosis were stronger among women presenting without infertility, a group that was more likely to have been symptomatic with respect to pain. LIMITATIONS, REASONS FOR CAUTION: The violence exposure was recalled by the study participants and thus is subject to misclassification as well as recall bias for the cases who were diagnosed prior to 2001. However, our results were similar in a sensitivity analysis including only endometriosis cases incident after their violence history report. In addition, residual or unmeasured confounding is a possibility; however, we were able to adjust for a variety of potential early life confounders. Finally, selection bias is also a possibility if those who chose to return the violence questionnaire did so based jointly on abuse history and endometriosis risk. WIDER IMPLICATIONS OF THE FINDINGS: Early life sexual and physical abuse was associated with an increased risk of endometriosis. Severity, chronicity and accumulation of types of abuse were associated with greater risk. Understanding the mechanisms underlying these relations may better define the biologic impacts of abuse and the related pathophysiology of endometriosis. STUDY FUNDING/COMPETING INTEREST(s): This work was supported by National Institute of Child Health and Human Development [Grant numbers HD48544, HD52473, HD57210 and CA50385] and the Atlanta Clinical and Translational Science Institute [Grant number ULRR025008]. The Nurses' Health Study II is supported by the National Institutes of Health grant UM1 CA176726 from the National Cancer Institute. H.R.H. is supported by the National Cancer Institute, National Institutes of Health [Grant number K22 CA193860]. Authors report no conflict of interest. PMID- 30016442 TI - Social Interactions and Social Activities After Burn Injury: A Life Impact Burn Recovery Evaluation (LIBRE) Study. AB - Social interactions and activities are key components of social recovery following burn injuries. The objective of this study is to determine the predictors of these areas of social recovery. This study provides a secondary analysis of a cross-sectional survey of adult burn survivors. The Life Impact Burn Recovery Evaluation-192 was administered to 601 burn survivors for the field testing of the Life Impact Burn Recovery Evaluation Profile. Survivors aged 18 years and older with injuries >=5% total BSA or burns to critical areas (hands, feet, face, or genitals) were eligible to participate. Multivariate linear regression analyses were used to determine predictors of the Social Activities and Social Interactions scale scores. A total of 599 people completed the Social Interactions and Social Activities scales. Of these, 77% identified as White Non Hispanic, 55% were female, 55% were unmarried, and 80% had burns to critical areas. Participants had a mean age of 45 years, a mean time since burn injury of 15 years, and a mean burn size of 41% total BSA. Younger age (P < .01) and being married/living with a significant other (P <= .01) were associated with higher Social Activities and Social Interactions scale scores. Individual item responses reveal that survivors had lower scores on items related to participating in outdoor activities (30.4%) or feeling uncomfortable with their appearance (32.4% report dressing to avoid stares). Social interactions and activities are long term challenges for burn survivors. It is important for clinicians to identify patients who may struggle with social recovery in order to focus on future community-based interventions. PMID- 30016443 TI - Regional differences in vision health: findings from Mwanza, Tanzania. AB - Background: Visual impairment in developing countries has both social and economic impact on individuals and communities. Understanding the subjective visual functioning of populations will allow for local policymakers to identify the need for optometric or ophthalmic services in their communities. Methods: The authors surveyed 644 adult patients in Mwanza, Tanzania at three clinics (Buzuruga, Mwananchi and Kisesa) using a modified Visual Functioning Questionnaire 25. Responses were categorized into General health, General vision, Ocular pain, Near activities, Distance activities, Social function, Mental health, Role difficulties, Color vision, Peripheral vision and Dependency. Results: Patients at Buzuruga reported the lowest scores on most subscales. Of 100 employed patients, 37% claimed to have at least some difficulty in performing job duties due to their eyesight. At Kisesa, 146 (246/221) patients (66.1%) had never had an eye exam, compared with 134/227 (59.0%) at Buzuruga and 69/173 (39.9%) at Mwananchi (p<0.01). Common reasons for not seeing an eye doctor were the perceived expense and lack of vision problems. Conclusions: Due to regional differences in visual functioning in Mwanza, a national effort for vision health cannot be entirely successful without addressing the individualized needs of local communities. Reducing the cost of vision care appointments may expand vision health care utilization in Mwanza. PMID- 30016444 TI - In Vitro and In Vivo Activity of Amiodarone Against Ebola Virus. AB - At the onset of the 2013-2016 epidemic of Ebola virus disease (EVD), no vaccine or antiviral medication was approved for treatment. Therefore, considerable efforts were directed towards the concept of drug repurposing or repositioning. Amiodarone, an approved multi-ion channel blocker for the treatment of cardiac arrhythmia, was reported to inhibit filovirus entry in vitro. Compassionate use of amiodarone in EVD patients indicated a possible survival benefit. In support of further clinical testing, we confirmed anti-Ebola virus activity of amiodarone in different cell types. Despite promising in vitro results, amiodarone failed to protect guinea pigs from a lethal dose of Ebola virus. PMID- 30016445 TI - Diagnosis of Human Echinococcosis via Exhaled Breath Analysis: A Promise for Rapid Diagnosis of Infectious Diseases Caused by Helminths. AB - Background: Human echinococcosis is a neglected infectious disease affecting more than one million people globally. Its diagnosis is expensive and difficult because of lack of adequate resources in low-resource locations, where most cases occur. Methods: A group of volunteers diagnosed with the two main types of echinococcosis and corresponding control groups were recruited in hospitals from Tunisia (32 patients with cystic echinococcosis and 43 controls) and Poland (16 patients with alveolar echinococcosis and 8 controls). Breath samples were collected from all patients and analyzed by means of gas chromatography coupled to mass spectrometry and a specifically developed electronic nose system. Results: The chemical analysis revealed two statistically different compounds in the breath of patients with cystic echinococcosis as compared to controls, and seven statistically different compounds in the breath of patients with alveolar echinococcosis as compared to controls. The discrimination accuracy achieved by the electronic nose system was 100% for cystic echinococcosis and 92.9% for alveolar echinococcosis, while the discrimination accuracy between these patient groups was 92.1%. Conclusion: Here we advocate a non-invasive, fast, easy-to operate and non-expensive diagnostic tool for the diagnosis of human echinococcosis disease through exhaled breath analysis, suitable for early diagnosis and population screening. PMID- 30016446 TI - Atrial fibrillation: is there enough evidence to recommend opportunistic or systematic screening? PMID- 30016447 TI - First Trimester Urinary Bisphenol and Phthalate Concentrations and Time to Pregnancy: A Population-Based Cohort Analysis. AB - Background: Increasing evidence suggests that exposure to synthetic chemicals such as bisphenols and phthalates can influence fecundability. The current study describes associations of first trimester urinary concentrations of bisphenol A (BPA), BPA analogs, and phthalate metabolites with time to pregnancy (TTP). Methods: Among 877 participants in the population-based Generation R pregnancy cohort, we measured first trimester urinary concentrations of bisphenols and phthalates [median gestational age, 12.9 weeks (interquartile range, 12.1, 14.4)]. We used fitted covariate-adjusted Cox proportional hazard models to examine associations of bisphenol and phthalate concentrations with TTP. Participants who conceived using infertility treatment were censored at 12 months. Biologically plausible effect measure modification by folic acid supplement use was tested. Results: In the main models, bisphenol and phthalate compounds were not associated with fecundability. In stratified models, total bisphenols and phthalic acid were associated with longer TTP among women who did not use folic acid supplements preconceptionally [respective fecundability ratios per each natural log increase were 0.90 (95% CI, 0.81 to 1.00) and 0.88 (95% CI, 0.79 to 0.99)]. Using an interaction term for the exposure and folic acid supplement use showed additional effect measure modification by folic acid supplement use for high-molecular-weight phthalate metabolites. Conclusions: We found no associations of bisphenols and phthalates with fecundability. Preconception folic acid supplementation seems to modify effects of bisphenols and phthalates on fecundability. Folic acid supplements may protect against reduced fecundability among women exposed to these chemicals. Further studies are needed to replicate these findings and investigate potential mechanisms. PMID- 30016448 TI - Anaplastic Large Cell Lymphoma Manifesting as Pleural Effusion in a Patient with Long-Standing Eosinophilia. AB - Anaplastic large cell lymphoma (ALCL) is a lymphoma of T-cell origin, characterized by the presence of large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei (hallmark cells), as well as strong and uniform expression of cluster of differentiation (CD)30. Two distinct clinicopathologic categories of ALCL include primary cutaneous ALCL and systemic ALCL. Systemic ALCL is further classified into anaplastic lymphoma kinase (ALK) positive, ALK-negative, and breast implant-associated ALCL. Most ALCLs occurring in adults are ALK negative and present in lymph nodes rather than extranodal sites.Primary diagnosis of ALCL in the pleural fluid is extremely rare, with no convincing recent reports available that are based in current understanding of this entity. Herein, we describe a well-characterized case of ALK-negative ALCL with no rearrangement but amplification of DUSP22/IRF4, diagnosed by cytologic examination of the pleural effusion in a 68-year-old white man with a 3-year history of unexplained eosinophilia and pulmonary infiltrates. Also, we present a review of the literature and discuss the current understanding of ALCL based on the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. PMID- 30016449 TI - Online peer support groups for family caregivers: are they reaching the caregivers with the greatest needs? AB - Background: Online peer support groups are an increasingly common venue for caregivers supporting disabled family members to exchange informational, emotional, and instrumental support. We know very little, however, about who uses these groups and whether they are reaching those with the greatest needs. Objective: To examine whether caregiving factors (ie, caregiving demands and strain, competing demands, access to support and services, and other caregiving characteristics) are related to online community support use and intensity of use. Method: This study used data from a new survey of family caregivers who provide care to disabled military veterans. We used logistic regression models to examine the likelihood of online community support group usage and intensity of use as a function of a variety of caregiving factors. Results: Those with greater caregiving demands were more likely to use online peer support. Specifically, helping the care recipient with more activities was associated with a statistically significantly greater likelihood of visiting an online community support group. Caring for a veteran with a neurological or psychological condition, which, in prior work, suggests more complex care needs, was also positively and significantly related to visiting an online community support group. Hours of care and several other caregiving factors were related to intensity of use. Conclusions: We show that family caregivers with the most caregiving demands are most engaged with online support communities. This suggests that online communities could be used to support the most vulnerable family caregivers. The implications of this work for online support systems are discussed. PMID- 30016450 TI - Comparative effects of three methods of promoting breastfeeding among human immunodeficiency virus-infected women in Uganda: a parallel randomized clinical trial. AB - Background: The objective of this study was to evaluate the comparative effects of three breastfeeding promotion interventions on the duration of exclusive breastfeeding (EBF) and any breastfeeding (BF) among human immunodeficiency virus (HIV)-infected women in Uganda. Methods: Between February 2012 and February 2013, 218 HIV-infected pregnant mothers were randomly assigned to (A) standard care (n=73), (B) enhanced family/peer support (n=72) or (C) enhanced nutrition education (n=73). Results: The prevalence (%) of EBF/BF did not differ between intervention arms at the sixth (A, 85/92; B, 84/91; C, 87/89) and ninth (A, 17/91; B, 18/89; C, 16/87) postpartum month assessments (p>0.05). However, the risk of early BF cessation differed between intervention arms depending on the mother's level of formal education (p=0.04). Among women with no formal education, the risk of early BF cessation was 88% (adjusted hazard ratio [aHR] 0.12 [95% confidence interval {CI} 0.05-0.30]) and 93% (aHR 0.07 [95% CI 0.03 0.18]) lower in arms B and C, respectively, than in arm A (p<0.01). HIV status disclosure to a partner was associated with a higher risk of early EBF (p=0.03) and BF (p=0.04) cessation. Conclusions: In resource-limited settings, enhanced (vs standard care) EBF promotion interventions may not differentially influence EBF but reduce the risk of early BF cessation among women with no formal education. Targeted enhanced interventions among women with no formal education and a mother's partner may be critical to reducing the risk of early EBF/BF cessation. PMID- 30016451 TI - Kingella kingae Septic Arthritis in an Older-Than-Expected Child. AB - Kingella kingae typically causes musculoskeletal infection in young children between the ages of 6 months and 4 years who may be in close contact with other similarly aged children who are colonized with the organism in their oropharynx. Kingella infections have rarely been described in older individuals with chronic medical conditions or immune compromise. This is a case report of a healthy, older child who developed an invasive infection due to Kingella kingae. Clinical and laboratory details are provided of an otherwise healthy 11-year-old female who developed an acute onset of septic arthritis of her shoulder. The organism was identified by culture and 16S polymerase chain reaction. Her clinical course necessitated an antibiotic change after the organism was correctly identified. The affected child had close contact with a 2-year-old sibling who recently had a viral upper respiratory infection. This case illustrates the potential for Kingella kingae to rarely cause invasive infection in older, healthy children. Supplemental laboratory techniques may be helpful to identify this organism. Although it is reasonable to limit the antibiotic spectrum for older children, clinicians should be aware of this possibility, particularly if there is a history of close contact with young children. PMID- 30016452 TI - A Conservation Hatchery Population of Delta Smelt Shows Evidence of Genetic Adaptation to Captivity After 9 Generations. AB - Genetic adaptation to captivity is a concern for threatened and endangered species held in conservation hatcheries. Here, we present evidence of genetic adaptation to captivity in a conservation hatchery for the endangered delta smelt (Fish Conservation and Culture Laboratory, University of California Davis; FCCL). The FCCL population is genetically managed with parentage analysis and the addition of wild fish each year. Molecular monitoring indicates little loss of genetic variation and low differentiation between the wild and conservation populations. Yet, we found an increase in offspring survival to reproductive maturity during the subsequent spawning season (recovery rate) in crosses that included one or both cultured parents. Crosses with higher levels of hatchery ancestry tend to produce a greater number of offspring that are recovered the following year. The recovery rate of a cross decreases when offspring are raised in a tank with fish of high levels of hatchery ancestry. We suggest changes in fish rearing practices at the FCCL to reduce genetic adaptation to captivity, as delta smelt numbers in the wild continue to decline and the use of FCCL fish for reintroduction becomes more likely. PMID- 30016453 TI - LRIF1 interacts with HP1alpha to coordinate accurate chromosome segregation during mitosis. AB - Heterochromatin protein 1alpha (HP1alpha) regulates chromatin specification and plasticity during cell fate decision. Different structural determinants account for HP1alpha localization and function during cell division cycle. Our earlier study showed that centromeric localization of HP1alpha depends on the epigenetic mark H3K9me3 in interphase, while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors. Here, we identified a PXVXL-containing protein, ligand-dependent nuclear receptor-interacting factor 1 (LRIF1), which recruits HP1alpha to the centromere of mitotic chromosomes and its interaction with HP1alpha is essential for accurate chromosome segregation during mitosis. LRIF1 interacts directly with HP1alpha chromoshadow domain via an evolutionarily conserved PXVXL motif within its C-terminal. Importantly, the LRIF1-HP1alpha interaction is critical for Aurora B activity in the inner centromere. Mutation of PXVXL motif of LRIF1 leads to defects in HP1alpha centromere targeting and aberrant chromosome segregation. These findings reveal a previously unrecognized direct link between LRIF1 and HP1alpha in centromere plasticity control and illustrate the critical role of LRIF1-HP1alpha interaction in orchestrating accurate cell division. PMID- 30016454 TI - Circulating 27-Hydroxycholesterol and Breast Cancer Risk: Results From the EPIC Heidelberg Cohort. AB - Background: 27-hydroxycholesterol (27HC) was the first identified endogenous selective estrogen receptor modulator (SERM); 27HC promoted growth and metastasis in experimental models of estrogen receptor-positive mammary cancer. There are no data on prediagnosis circulating 27HC and breast cancer risk in women. Methods: We conducted a nested case-control study in the well-characterized Heidelberg, Germany, cohort of the European Investigation into Cancer and Nutrition (EPIC) including 530 incident invasive breast cancer cases, each matched to up to two control participants (n = 1036). Serum 27HC was analyzed by liquid chromatography mass spectrometry (LC-MS) in blood samples collected at study recruitment. Multivariable conditional logistic regression models were used to quantify the association between circulating 27HC and breast cancer risk overall, by tumor hormone receptor status (ie estrogen and progesterone receptors), and by menopausal status at blood collection. All statistical tests were two-sided. Results: 27HC was not associated with breast cancer risk overall (relative risk [RR]Quartile4vsQuartile1 [Q4vsQ1] = 0.90, 95% confidence interval [CI] = 0.66 to 1.22). The association between 27HC and breast cancer risk differed by menopausal status at blood collection (Phet = .02), but not by age at diagnosis (Phet = .78). Among women who were postmenopausal at blood collection, higher serum 27HC levels were associated with lower breast cancer risk (RRQ4vsQ1 = 0.56, 95% CI = 0.36 to 0.87). We observed no association between 27HC and breast cancer risk (RRQ4vsQ1 = 1.33, 95% CI = 0.75 to 2.38) among women who were premenopausal at blood collection. Conclusions: In this first prospective study, higher circulating 27HC was associated with lower risk of breast cancer in postmenopausal women. Identification of the first endogenous SERM associated with reduced risk of invasive breast cancer in postmenopausal women may offer novel avenues for breast cancer prevention strategies. PMID- 30016455 TI - The Cipro conundrum: updated guidelines not completely translated to practice. PMID- 30016456 TI - Interleukin-6 secretion is limited by self-signaling in endosomes. AB - Cells producing cytokines often express the receptor for the same cytokine, which makes them prone to autocrine signaling. How cytokine release and signaling are regulated in the same cell is not understood. In this study, we demonstrate that signaling by exogenous and self-synthesized inflammatory cytokine interleukin-6 (IL-6) within endosomal compartments acts as a cellular brake that limits synthesis of IL-6. Our data show that IL-6 is internalized by dendritic cells and signals from endosomal compartments containing the IL-6 receptor. Newly synthesized IL-6 also traffics via these endosomal compartments and signals in transit to the plasma membrane. This allows activation of STAT3 which in turn limits Toll-like receptor 4 stimulant lipopolysaccharide (LPS) triggered transcription of IL-6. Long-term exposure to LPS removes this brake via inhibition of STAT3 by increased expression of suppressor of cytokine signaling 3 (SOCS3) and results in fully-fledged IL-6 production. This transient regulation could prevent excessive IL-6 production during early infections. PMID- 30016457 TI - Serostatus-dependent performance of the first licensed dengue vaccine: implications for travellers. PMID- 30016458 TI - beta-Amyloid Induces Pathology-Related Patterns of Tau Hyperphosphorylation at Synaptic Terminals. AB - A synergy between beta-amyloid (Abeta) and tau appears to occur in Alzheimer disease (AD), but the mechanisms of interaction, and potential locations, are little understood. This study investigates the possibility of such interactions within the cortical synaptic compartments of APP/PS1 mice. We used label-free quantitative mass spectrometry to study the phosphoproteome of synaptosomes, covering 2400 phosphopeptides and providing an unbiased survey of phosphorylation changes associated with amyloid pathology. Hyperphosphorylation was detected on 36 synaptic proteins, many of which are associated with the cytoskeleton. Importantly, tau is one of the most hyperphosphorylated proteins at the synapse, upregulated at both proline-directed kinase (PDK) sites (S199/S202, S396/S404) and nonPDK sites (S400). These PDK sites correspond to well-known pathological tau epitopes in AD patients, recognized by AT8 and PHF-1 antibodies, respectively. Hyperphosphorylation at S199/S202, a rarely examined combination, was further validated in patient-derived human synaptosomes by immunoblotting. Global surveys of upregulated phosphosites revealed 2 potential kinase motifs, which resemble those of cyclin-dependent kinase 5 (CDK5, a PDK) and casein kinase II (CK2, a nonPDK). Our data demonstrate that, within synaptic compartments, amyloid pathology is associated with tau hyperphosphorylation at disease-relevant epitopes. This provides a plausible mechanism by which Abeta promotes the spreading of tauopathy. PMID- 30016459 TI - Histological Features of Cerebellar Neuropathology in Patients With Alcoholic and Nonalcoholic Steatohepatitis. AB - Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) affect 29 million people in the European Union. Patients with ASH and NASH may exhibit cognitive impairment, reducing their quality of life. Steatohepatitis induces cerebral alterations. It is not known if histological analysis could allow distinguishing ASH, NASH, and/or cirrhosis neuropathology and other entities. The aim of this work was to analyze a set of histopathological features characterizing the brain lesions due to ASH, NASH, and cirrhosis. We performed a histological study using hematoxylin and eosin staining and immunohistochemical techniques in cerebellum of 31 subjects who died with healthy liver (n = 6), NASH (n = 14), ASH (n = 3), nonalcoholic cirrhosis (n = 4), and alcoholic cirrhosis (n = 4). We analyzed in cerebellum, as an early marker for brain injury: 1) vascular damage; 2) cerebellar atrophy and neurodegeneration in Purkinje layer; and 3) microglia and astrocytes activation in white matter and molecular layer. Patients with steatohepatitis have increased number of microtrombi in cerebellar parenchyma, neuronal loss in Purkinje layer and microglial and astrocyte activation in white matter and molecular layer. These alterations are stronger in patients with ASH than in those with NASH. These results provide a set of histopathological features in brain that may allow differentiation of steatohepatitis from other conditions. PMID- 30016460 TI - Fenton reactions drive nucleotide and ATP syntheses in cancer. AB - We present a computational study of tissue transcriptomic data of 14 cancer types to address: what may drive cancer cell division? Our analyses point to that persistent disruption of the intracellular pH by Fenton reactions may be at the root of cancer development. Specifically, we have statistically demonstrated that Fenton reactions take place in cancer cytosol and mitochondria across all the 14 cancer types, based on cancer tissue gene-expression data integrated via the Michaelis-Menten equation. In addition, we have shown that (i) Fenton reactions in cytosol of the disease cells will continuously increase their pH, to which the cells respond by generating net protons to keep the pH stable through a combination of synthesizing glycolytic ATPs and consuming them by nucleotide syntheses, which may drive cell division to rid of the continuously synthesized nucleotides; and (ii) Fenton reactions in mitochondria give rise to novel ways for ATP synthesis with electrons ultimately coming from H2O2, largely originated from immune cells. A model is developed to link these to cancer development, where some mutations may be selected to facilitate cell division at rates dictated by Fenton reactions. PMID- 30016461 TI - Comparison of Phosphatidylserine-Exposing Red Blood Cells, Fragmented Red Blood Cells and Red Blood Cell-Derived Microparticles in beta-Thalassemia/HbE Patients. AB - Objective: To determine the number and intensity of phosphatidylserine (PS) expression of the red blood cells (RBCs), fragmented RBCs, and RBC-derived microparticles (RMPs) in patients with beta-thalassemia/hemoglobin (Hb)E. Methods: We used flow cytometry to determine the number and levels of PS expression. Results: The number of PS-exposing RBCs was statistically significantly higher (P <.001) than that of PS-exposing fragmented RBCs or RMPs. In contrast, the intensity of PS expression was significantly higher (P <.001) in RMPs than in RBCs or fragmented RBCs. Our study showed a trend of association between RBC distribution width (RDW) and both the number of fragmented RBCs and RMPs and their intensity of PS expression. Conclusion: In beta-thalassemia/HbE, PS-exposing RBCs, fragmented RBCs, and RMPs all differed in their numbers and their intensity of PS expression. The effects of these differences among PS exposing populations on the pathophysiology of the disease require further investigation. PMID- 30016462 TI - Modern Surgical Management of Early Onset and Adolescent Idiopathic Scoliosis. AB - The early principles of spinal fusion in the adolescent population focused on preventing progression while simultaneously correcting the spinal deformity. These principles have remained relatively unchanged since their introduction more than a century ago, but recent improvements in imaging, instrumentation, and corrective techniques have provided new insight on the diagnosis, management, and postoperative care of this condition. Treatment options for the management of patients with early onset scoliosis have also evolved dramatically over the last 2 decades. Further knowledge on the physiology of lung development and the detrimental effects of early fusion in the early onset scoliosis population has led to the development of growth friendly implants and other surgical techniques that allow correction of the deformity while maintaining spine, lung, and chest wall development. The following is an overview of current techniques on the management of adolescent idiopathic and early onset scoliosis to help provide guidance on the available surgical alternatives to address these conditions. PMID- 30016463 TI - Bidirectionality of Pain Interference and PTSD Symptoms in Military Veterans: Does Injury Status Moderate Effects? AB - Objective: Pain and post-traumatic stress disorder (PTSD) symptoms are strongly correlated in veteran populations. Arguments for which one condition predicts or worsens the other condition have gone in both directions. However, research addressing this issue has been primarily limited to cross-sectional studies rather than examinations of a potential bidirectional relationship between pain interference and PTSD symptoms over time. In addition, no studies have examined deployment injury status as potentially moderating this bidirectional effect in veterans. To address these gaps in the literature, the present longitudinal study examined whether there is a bidirectional relationship between pain interference and PTSD symptoms in a sample of male and female veterans returning from Operation Iraqi Freedom, Operation Enduring Freedom, or Operation New Dawn (N = 729) and whether deployment injury status moderates this relationship. Methods: Participants completed phone interviews regarding pain interference and PTSD symptoms at three time points, each three months apart. Results: Pain interference at Time 1 predicted worse PTSD symptoms at Time 2 for the subset of veterans who sustained injuries during deployment (n = 381) but not for veterans with pain interference who did not sustain injuries (n = 338). From Time 1 to Time 3, elevations in PTSD symptoms were mediated by pain interference for injured veterans; in contrast, PTSD symptoms did not appear to drive changes in pain interference in either group. Conclusions: These results indicate that physical symptom management should be a crucial target of psychological intervention for returning veterans with PTSD symptoms and deployment-related injuries. PMID- 30016464 TI - Risk factors and attack rates of seasonal influenza infection: results of the SHIVERS seroepidemiologic cohort study. AB - Background: Understanding the attack rate of influenza infection and the proportion who become ill by risk group is key to implementing prevention measures. While population-based studies of anti-haemagglutinin antibody responses have been described previously, studies examining both anti haemagglutinin and anti-neuraminidase antibodies are lacking. Methods: In 2015, we conducted a sero-epidemiologic cohort study of individuals randomly selected from a population in New Zealand. We tested paired sera for haemagglutinin inhibition (HAI) or neuraminidase-inhibition (NAI) titres for seroconversion . We followed participants weekly and performed influenza PCR for those reporting influenza-like illness (ILI). Results: Influenza infection (either HAI or NAI seroconversion) was found in 321 (35%; 95%CI:32-38%) of 911 unvaccinated participants, of which 100 (31%) seroconverted to NAI alone. Young children and Pacific peoples experienced the highest influenza infection attack rates, but overall only a quarter of all infected reported influenza-PCR-confirmed ILI and one-quarter of these sought medical attention. Seroconversion to NAI alone was higher among children aged <5 years vs. those aged >=5 years (14% vs 4%; p<0.001) and among those with influenza B vs A(H3N2) virus infections (7% vs 0.3%; p<0.001). Conclusions: Measurement of anti-neuraminidase antibodies in addition to anti- hemagglutinin antibodies may be important in capturing the true influenza infection rates. PMID- 30016468 TI - Travel vaccine preventable diseases-updated logarithmic scale with monthly incidence rates. PMID- 30016465 TI - Characterization of the accessible genome in the human malaria parasite Plasmodium falciparum. AB - Human malaria is a devastating disease and a major cause of poverty in resource limited countries. To develop and adapt within hosts Plasmodium falciparum undergoes drastic switches in gene expression. To identify regulatory regions in the parasite genome, we performed genome-wide profiling of chromatin accessibility in two culture-adapted isogenic subclones at four developmental stages during the intraerythrocytic cycle by using the Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq). Tn5 transposase hypersensitivity sites (THSSs) localize preferentially at transcriptional start sites (TSSs). Chromatin accessibility by ATAC-seq is predictive of active transcription and of the levels of histone marks H3K9ac and H3K4me3. Our assay allows the identification of novel regulatory regions including TSS and enhancer-like elements. We show that the dynamics in the accessible chromatin profile matches temporal transcription during development. Motif analysis of stage-specific ATAC seq sites predicts the in vivo binding sites and function of multiple ApiAP2 transcription factors. At last, the alternative expression states of some clonally variant genes (CVGs), including eba, phist, var and clag genes, associate with a differential ATAC-seq signal at their promoters. Altogether, this study identifies genome-wide regulatory regions likely to play an essential function in the developmental transitions and in CVG expression in P. falciparum. PMID- 30016466 TI - Kinetics of Cytokine Levels during Antipsychotic Treatment in Schizophrenia: A Meta-Analysis. AB - Background: Immune system dysfunction is a hypothesis in the psychopathology of schizophrenia, but the impact of antipsychotic treatment within this system is not clear. The aim of this meta-analysis was to investigate the impact of antipsychotic treatment on cytokine levels in in vivo studies on schizophrenia. Methods: After a systematic database search, original data were extracted with the help of certain authors. Means and SDs were extracted to calculate standardized mean differences. Cytokine levels were compared in vivo in schizophrenia patients, before and after antipsychotic treatment. Meta regressions were performed to explore the influence of demographic and clinical variables on cytokine level standardized mean differences. Stratifications by treatment and diagnosis were also performed. Results: Forty-seven studies were included in this meta-analysis. Proinflammatory cytokine level decreases were found for interleukin-1 beta levels (P<.0001) and interferon-gamma (P=.01) and a statistical trend towards a decrease in interleukin-6 (P=.08) and tumor necrosis factor-alpha (P=.07) levels. An antiinflammatory cytokine level increase was found for soluble tumor necrosis factor-R2 (P<.001) and soluble interleukin 2-R (P=.03) levels. A meta-regression analysis found a correlation between interleukin-6 level standardized mean differences and positive schizophrenia symptom score standardized mean differences before and after treatment (P=.01). Stratification by diagnosis or treatment found a possible impact of the kinetics of cytokine levels. Conclusions: The present meta-analysis provides evidence that antipsychotic treatment has an antiinflammatory effect and could normalize immune balance dysfunction in schizophrenia. Interleukin-6 level normalization could be a marker of illness equilibration and thus used in clinical practice. PMID- 30016469 TI - Zika in travellers 1947-2017: a systematic review. AB - Introduction: Travellers contributed substantially to the rapid spread of Zika virus (ZIKV). They act as sentinel and may unmask ongoing ZIKV transmission in countries where outbreaks have not yet been reported. Our objectives were to (i) describe the burden of ZIKV infections in international travellers over time; (ii) estimate the proportion of birth defects as a result of maternal ZIKV infection in travellers; (iii) track the extent of sexual transmission; (iv) summarize ZIKV infections in returning travellers as reported by the GeoSentinel network; and (v) identify countries without reports on local ZIKV transmission where travellers served as sentinel. Methods: We performed a systematic review from 1947 to April 2017 on travel-associated ZIKV infections. We also compared published reports on autochthonous ZIKV transmission in Asia with published reports on exportations from travellers in Asia. Results: Of 314 papers that fit the inclusion criteria, 61 were eligible for final analysis. There was an exponential increase in the number of reported ZIKV infected travellers from the years 2013 to 2016, which declined in 2017. Amongst pregnant women with ZIKV infection, (5%) resulted in a fetus or infant with ZIKV-associated birth defects. An estimated 1% of the total number of ZIKV cases reported in the USA and Europe were acquired through sexual transmission. Through the GeoSentinel network, five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon) were identified as sentinel markers where ZIKV was exported despite the absence of reported local transmission. Conclusions: Mobility patterns and travel volumes can help to identify the most likely origin of importation, and also in predicting further propagation. Studies on pregnant returning travellers have contributed to a better understanding of the risk estimates of congenital Zika syndrome/microcephaly as a result of maternal ZIKV infection, and the relative contribution of sexual transmisison. PMID- 30016467 TI - Catecholaminergic Modulation of Conflict Control Depends on the Source of Conflicts. AB - Background: To display goal-directed behavior, we must be able to resolve response conflicts that arise from processing various distractors. Such conflicts may be triggered by different kinds of distractor stimuli (e.g., priming and flanker stimuli), but it has remained largely unclear whether the functional and neurobiological underpinnings of both conflict types differ. We therefore investigated the functional relevance of the catecholamines dopamine and norepinephrine, which have been shown to increase the signal-to-noise ratio in neuronal processing and should therefore modulate response conflicts. Methods: In a double-blind, randomized, placebo-controlled study design, we examined the effect of methylphenidate (0.5 mg/kg) on both flanker-induced and priming-induced response conflicts in a group of n=25 healthy young adults. We used EEG recordings to examine event-related potentials in combination with source localization analyses to identify the cognitive-neurophysiological subprocesses and functional neuroanatomical structures modulated by methylphenidate. Results: Compared with placebo, methylphenidate decreased flanker conflicts. This was matched by increased congruency effects in the fronto-central N2/P3 event-related potential complex and associated with modulations in the right inferior frontal gyrus. In contrast to this, methylphenidate did not modulate the size of prime evoked conflicts. Conclusions: Our results suggest that catecholamine-driven increases in signal-to-noise ratio and neural gain control do not equally benefit differently evoked conflicts. This supports the hypothesis of an at least partly different neurobiological basis for flanker- and prime-evoked response conflicts. As the right inferior frontal gyrus plays an important role in inhibition, the catecholaminergic system may reduce flanker conflicts by supporting the inhibition of distracting information. PMID- 30016470 TI - Is a Shigella vaccine needed for travellers and the military? PMID- 30016471 TI - Morning blisters: cantharidin-related Meloidae burns. AB - We report several cases of Meloidae-related blisters in French soldiers deployed to Mali. Blister beetles of the Meloidae family produce cantharidin, a blistering agent, for defensive purposes. These virtually cosmopolitan Coleoptera can cause significant nuisance to travellers and deployed soldiers especially during the rainy season in the Sahel region. PMID- 30016472 TI - Patterns of multimorbid health conditions: a systematic review of analytical methods and comparison analysis. AB - Background: The latest review of studies on multimorbidity patterns showed high heterogeneity in the methodology for identifying groups of multimorbid conditions. However, it is unclear how analytical methods used influence the identified multimorbidity patterns. Methods: We undertook a systematic review of analytical methods used to identify multimorbidity patterns in PubMed and EMBASE from their inception to January 2017. We conducted a comparison analysis to assess the effect the analytical methods had on the multimorbidity patterns identified, using the Australian National Health Survey (NHS) 2007-08 data. Results: We identified 13 194 studies and excluded 13 091 based on titles/abstracts. From the full-text reviews of the 103 remaining publications, we identified 41 studies that used five different analytical methods to identify multimorbid conditions in the studies. Thirty-seven studies (90%) adopted either the factor-analysis or hierarchical-clustering methods, but heterogeneity arises for the use of different proximity measures within each method to form clusters. Our comparison analysis showed the variation in identified groups of multimorbid conditions when applying the methods to the same NHS data. We extracted main similarities among the groupings obtained by the five methods: (i) cardiovascular and metabolic diseases, (ii) mental health problems and (iii) allergic diseases. Conclusion: We showed the extent of effects for heterogeneous analytical methods on identification of multimorbidity patterns. However, more work is needed to guide investigators for choosing the best analytical method to improve the validity and generalizability of findings. Investigators should also attempt to compare results obtained by various methods for a consensus grouping of multimorbid conditions. PMID- 30016474 TI - Evaluation of Complications and Costs During Overlapping Transsphenoidal Surgery in the Treatment of Pituitary Adenoma. PMID- 30016473 TI - Reducing Health Risk Behaviors and Improving Depression in Adolescents: A Randomized Controlled Trial in Primary Care Clinics. AB - Objective: Primary care (PC) is a major service delivery setting that can provide preventive behavioral health care to youths. To explore the hypothesis that reducing health risk behaviors (HRBs) would lower depressive symptoms, and that health risk and depression can be efficiently targeted together in PC, this study (1) evaluates an intervention designed to reduce HRBs among adolescent PC patients with depressive symptoms and (2) examines prospective links between HRBs and depressive symptoms. Method: A Randomized controlled trial was conducted comparing a behavioral health intervention with enhanced Usual PC (UC+). Participants were 187 adolescents (ages 13-18 years) with past-year depression, assessed at baseline, 6 months, and 12 months. Primary outcome was the Health Risk Behavior Index (HRBI), a composite score indexing smoking, substance use, unsafe sex, and obesity risk. Secondary/exploratory outcomes were an index of the first three most correlated behaviors (HRBI-S), each HRB, depressive symptoms, and satisfaction with mental health care. Results: Outcomes were similar at 6 and 12 months, with no significant between-group differences. HRBI, HRBI-S, and depressive symptoms decreased, and satisfaction with mental health care increased across time in both groups. HRBI, HRBI-S, and smoking predicted later severe depression. Conversely, severe depression predicted later HRBI-S and substance use. Conclusions: UC+ and the behavioral health intervention yielded similar benefits in reducing HRBs and depressive symptoms. Findings underscore the bidirectional links between depression and HRBs, supporting the importance of monitoring for HRBs and depression in PC to allow for effective intervention in both areas. PMID- 30016475 TI - Pseudomonas aeruginosa PcrV and Psl, the Molecular Targets of Bispecific Antibody MEDI3902, Are Conserved Among Diverse Global Clinical Isolates. AB - Background: Bispecific antibody MEDI3902, targeting the Pseudomonas aeruginosa type 3 secretion system (PcrV) and Psl exopolysaccharide, is currently in phase 2b development for prevention of nosocomial pneumonia in patients undergoing mechanical ventilation. We surveyed a diverse collection of isolates to study MEDI3902 epitope conservation and protective activity. Methods: P. aeruginosa clinical isolates (n = 913) were collected from diverse patients and geographic locations during 2003-2014. We conducted whole-genome sequencing; performed PcrV and Psl expression analyses via immunoblotting and enzyme-linked immunosorbent assay, respectively; performed crystallography to determine the MEDI3902 PcrV epitope, using anti-PcrV Fab and PcrV components (resolved at 2.8 A); and evaluated MEDI3902 protective activity against select isolates in vitro and in vivo. Results: Intact psl operon and pcrV genes were present in 94% and 99% of isolates, respectively, and 99.9% of isolates contained at least one of the genetic elements. Anti-Psl binding was confirmed in tested isolates harboring a complete Psl operon or lacking nonessential psl genes. We identified 46 PcrV variant sequences, and MEDI3902-PcrV contact residues were preserved. MEDI3902 maintained potent in vivo activity against various strains, including strains expressing only a single target. Conclusions: Psl and PcrV are highly prevalent in global clinical isolates, suggesting MEDI3902 can mediate broad coverage against P. aeruginosa. PMID- 30016477 TI - SPEEK: effect evaluation of a Ghanaian school-based and peer-led sexual education programme. AB - In sub-Saharan Africa, theory and evidenced-based interventions that are systematically designed and using sound evaluation methods to report on effectiveness are limited. A sex education programme called SPEEK was developed, implemented and evaluated in Ghana using the Intervention Mapping approach. SPEEK aimed at delaying sexual initiation, reducing sexually transmitted infections (STIs) and preventing pregnancy, targeting junior high school students in a West African rural setting. The final programme included 11 (interactive) lessons using a diverse range of theory-based methods. In this article, we report on the effect evaluation of the programme. Participating schools were randomized to the intervention (N = 10 schools) and a waiting-list control group (N = 11 schools). The students completed survey questionnaires at baseline (N = 1822), at direct post-test (N = 1805) and at six months follow-up (N = 1959), measuring cognitive and affective psychosocial determinants of sexual delay, condom use and STI testing. Mixed regression models showed that at direct post-test, students having received the SPEEK programme scored significantly more positively on knowledge on condom use, pregnancy and STIs testing; attitude toward exercising sexual rights, condom availability and condom use; perceived behavioural control toward sexual delay, condom use and sexual intercourse; and perceived risk toward STIs (P's < 0.002). The results suggest that the programme may improve adolescent sexual health in Ghana or in similar cultures, but would need further study that include behavioural measures and a longer follow-up to make this assertion with more confidence. PMID- 30016476 TI - Hierarchical groove discrimination by Class I and II aminoacyl-tRNA synthetases reveals a palimpsest of the operational RNA code in the tRNA acceptor-stem bases. AB - Class I and II aaRS recognition of opposite grooves was likely among the earliest determinants fixed in the tRNA acceptor stem bases. A new regression model identifies those determinants in bacterial tRNAs. Integral coefficients relate digital dependent to independent variables with perfect agreement between observed and calculated grooves for all twenty isoaccepting tRNAs. Recognition is mediated by the Discriminator base 73, the first base pair, and base 2 of the acceptor stem. Subsets of these coefficients also identically compute grooves recognized by smaller numbers of aaRS. Thus, the model is hierarchical, suggesting that new rules were added to pre-existing ones as new amino acids joined the coding alphabet. A thermodynamic rationale for the simplest model implies that Class-dependent aaRS secondary structures exploited differential tendencies of the acceptor stem to form the hairpin observed in Class I aaRS*tRNA complexes, enabling the earliest groove discrimination. Curiously, groove recognition also depends explicitly on the identity of base 2 in a manner consistent with the middle bases of the codon table, confirming a hidden ancestry of codon-anticodon pairing in the acceptor stem. That, and the lack of correlation with anticodon bases support prior productive coding interaction of tRNA minihelices with proto-mRNA. PMID- 30016478 TI - Erratum to "Characterization of strain of fowl adenoviruses circulating in Morocco". PMID- 30016479 TI - Lateral Transpsoas Approach for Lumbar Indirect Lateral Recess Decompression: 2 Dimensional Operative Video. AB - Neurogenic claudication is a common symptom of lumbar spinal stenosis; its pathophysiology is thought to be ischemia of the nerve roots secondary to compression from surrounding structures. The stenosis of the lateral recesses and neuroforamen can cause these symptoms and its surgical treatment is decompression. The placement of interbody cages that restore the disc space height may indirectly decompress the neuroforamen and alleviate the nerve impingement symptoms. In case of concomitant low-grade spondylolisthesis, interbody devices might also reduce the slippage. We present a technical surgical video of a minimally invasive lateral transpsoas fusion, relying on indirect decompression to treat a patient with neurogenic claudication secondary to grade 1 spondylolisthesis. The patient signed a written consent to publish a video, recording, photograph, image, illustration, and/or information about him. PMID- 30016480 TI - Deficiency of HIF-1alpha in myeloid cells protects Escherichia coli or LPS induced acute lung injury. AB - Background: Deficiency of hypoxia-induced factor-1alpha (HIF-1alpha) in macrophages reduced lipopolysaccharide (LPS)-induced mortality; however, whether HIF-1alpha expression in myeloid cells would contribute to the development of Escherichia coli (E. coli) or LPS-induced acute lung injury (ALI) is less investigated. Aim: To test whether deletion of Hif1alpha in myeloid cells affects E. coli or LPS-induced ALI and to elicit the underlying mechanisms. Design: Laboratory study. Methods: We intratracheally challenged Hif1alphafl/fl and Hif1alphafl/flLysMCre mice with E. coli or LPS to analyze lung and spleen inflammatory responses. Flow cytometry was used to analyze the changes of alpha7 nAChR+CD11b+ cells in the lung and spleen. Double knockout of Chrna7 and Itgam mice were used to examine expression of HIF-1alpha during E. coli lung infection. Vagotomy was performed to demonstrate the role of vagus nerve in mediating protective effects of deletion of Hif1alpha in myeloid cells on LPS-induced ALI. Results: Deletion of Hif1alpha in myeloid cells could reduce lung edema, inflammatory cell infiltration, and lung and BAL inflammatory cytokines in E. coli-induced ALI. Flow cytometric analysis revealed that alpha7 nAChR+CD11b+ cells in the lung and spleen were markedly increased in E. coli-challenged Hif1alphafl/flLysMCre mice compared with E. coli-challenged Hif1alphafl/fl mice. Double knockout of Chrna7 and Itgam increased HIF-1alpha expression in lung and spleen cells during lung E. coli infection. Vagotomy abolished the protective effect of deletion of Hif1alpha in myeloid cells on LPS-induced ALI. Conclusion: Deletion of Hif1alpha in myeloid cells could protect mice from lung injury depending on alpha7 nAChR+CD11b+ cells and innervation of vagal circuits. PMID- 30016482 TI - Analyses of prevalence and molecular typing reveal the spread of antimicrobial resistant Salmonella infection across 2 breeder chicken farms1. AB - In this study, Salmonella prevalence and antimicrobial resistance were evaluated at various production stages in 2 geographically separated breeder farms (referred to as G and F). Day-old chicks for the breeder flock at farm F were purchased from farm G. A total of 219 Salmonella isolates, all identified as Salmonella enterica subsp. enterica serovar Enteritidis, were recovered from 1,430 samples (sick chicken carcasses and/or dead embryos). The isolation rates at breeder farms G and F were 10.53% (56/532) and 18.15% (163/898), respectively. Resistance to 4-6 antimicrobial agents was the most frequent phenotype during the laying stage at both farms, suggesting that chicks are exposed to higher risk of antimicrobial-resistant Salmonella infection during this stage of the breeding process. Using clustered regularly interspaced short palindromic repeat (CRISPR) typing, 5 CRISPR patterns were identified, out of which one pattern was shared by the 2 farms. In addition, pulsed-field gel electrophoresis (PFGE) typing result indicated that 2 clusters (PF-1 and PF-2) were shared among the 2 breeder farms, suggesting that strains were transmitted from breeder farm G to farm F via the trade of day-old chicks. Our findings suggested that the trade of day-old breeder chicks could be one of the potential Salmonella transmission routes, and antibiotics should be administered with caution during the laying stage. PMID- 30016481 TI - Neural sensitivity to personal and vicarious reward differentially relates to prosociality and well-being. AB - Individuals stably vary in their responses to rewards, but researchers have not yet determined whether sensitivity to rewarding outcomes translates across social and non-social contexts or whether different forms of reward sensitivity relate to distinct behavioral tendencies. We tested for responsiveness to different types of rewards by assessing individuals' neural sensitivity to personal vs. vicarious monetary reward outcomes and explored how responses to each related to prosociality and well-being. Forty-six participants underwent functional magnetic resonance imaging (fMRI) scanning while winning money for themselves and observing a friend and stranger win money. All types of reward outcomes engaged the ventral striatum, but neural sensitivity to rewards for the self and for others were uncorrelated across individuals. Further, while sensitivity to rewards for the self or a close friend correlated with individuals' psychological well-being, only sensitivity to a friend's rewards correlated with individuals' prosociality. These findings highlight the value of independently assessing responsiveness to different types of reward and illuminate affective mechanisms that may promote prosocial behavior and well-being. PMID- 30016483 TI - The Impact of Early Corticosteroid Pretreatment Before Initiation of Chemotherapy in Patients With Primary Central Nervous System Lymphoma. AB - BACKGROUND: The optimal timing of corticosteroid (CS) treatment in patients with primary central nervous system (CNS) lymphoma (PCNSL) remains controversial. While poor clinical presentation may justify early treatment with CS, this may ultimately result in reduced concentrations of chemotherapeutic agents via perturbations in the permeability of the blood-brain barrier. OBJECTIVE: To investigate whether early CS exposure is associated with beneficial outcomes and/or reduced occurrence of adverse events as opposed to delayed/concomitant administration. METHODS: Herein we performed a retrospective observational analysis using patients that were prospectively entered into a database. All patients whom were admitted to the University Hospital between 2009 and 2015 with newly diagnosed PCNSL were included within our study. RESULTS: Our cohort included 50 consecutive patients diagnosed with PCNSL; of these, in 30 patients CS administration was initiated prior to chemotherapy (early), whilst in the remaining 20 patients CS administration was initiated concomitantly with their chemotherapeutic regimen (concomitant). Within the early vs concomitant CS administration groups, no significant differences were observed with regard to progression-free survival (PFS) (P = .81), overall survival (OS) (P = .75), or remission (P = .68; odds ratio 0.76 and confidence interval [95%] 0.22-2.71). Critically, the timing of CS initiation was not associated with either PFS (P = .81) or PFS (P = .75). CONCLUSION: Early CS administration was not associated with a deterioration in response to chemotherapy, PFS, or OS. As such, administration of CS prior to initiation of chemotherapy is both reasonable and safe for patients with newly diagnosed PCNSL. PMID- 30016484 TI - Vein of Galen Aneurysmal Malformation: Advances in Management and Endovascular treatment. PMID- 30016485 TI - Effect of elevated dietary inorganic zinc on live performance, carcass yield, and quality of male and female broilers. AB - This study evaluated the effects of elevated dietary inorganic zinc (Zn) on live performance, carcass and parts yield, and carcass and meat quality of broilers. A total of 288 d-old Ross 344 * 708 broilers were distributed among 3 dietary treatments with 12 replicate cages per treatment and raised sex-separate with 8 birds per cage. Birds were fed practical diets supplemented with either 0, 120, or 240 mg Zn/kg diet. Feed intake and body weight (BW) were measured and feed conversion ratio (FCR) was calculated. At 42 d, 3 birds per cage were processed to assess carcass and meat quality. Male BW at 42 d was increased (P <= 0.05) by 120 mg Zn/kg. The FCR to 42 d was also improved (P <= 0.05) for males supplemented with 120 mg Zn/kg as compared to 240 mg Zn/kg with the 0 mg Zn/kg diet intermediate. Dietary Zn had no effect on BW or FCR of females. Dietary Zn had no effect on carcass weight and parts yield but absolute weights of male, but not female, total breast and tenders were increased by 240 mg Zn/kg relative to 0 mg Zn/kg with 120 mg Zn/kg intermediate. Breast fillets cook yield and tenderness as well as color were not influenced by Zn in either sex. Supplementing 120 mg Zn/kg resulted in increased Zn in male breast muscle (P <= 0.01) whereas 240 mg Zn/kg reduced Zn in breast muscle of females. The 240 mg Zn/kg diet increased Zn in femurs (P <= 0.05) of males relative to the other diets. For females, Zn concentration in femurs was increased (P <= 0.05) by 240 mg Zn/kg relative to 120 mg Zn/kg with the non-supplemented birds intermediate. PMID- 30016486 TI - The Association Between Daily Physical Activity and Pain Among Patients with Knee Osteoarthritis: The Moderating Role of Pain Catastrophizing. AB - Objective: The primary objective of this study was to examine the day-to-day association between physical activity and pain intensity among a sample of patients with knee osteoarthritis (KOA) and the potential moderation of this association by negative cognitive processes. Methods: In this micro-longitudinal daily diary study, KOA patients (N = 121) completed questionnaires assessing pain (Brief Pain Inventory) and psychosocial functioning (pain catrophizing scale, WOMAC McMaster Universities Osteoarthritis Index function, Patient-Reported Outcomes Measurement Information System [PROMIS; anxiety and depression], the Godin-Shephard Leisure-Time Physical Activity questionnaire, the six-minute walking test) and were then asked to report their levels of physical activity and pain intensity once per day for a period of seven days using an electronic diary. Results: Multilevel modeling analyses indicated that day-to-day increases in physical activity were associated with heightened levels of pain intensity (B = 0.13 SE = 0.03, P < 0.001). In addition, it was revealed that the association between physical activity and pain intensity was moderated by catastrophizing (B = -0.01 SE = 0.002, P < 0.05), with patients scoring higher in catastrophizing showing a relatively stronger link between day-to-day physical activity and increased knee pain. This effect was specific to catastrophizing, as depression and anxiety did not moderate the activity-pain relationship (P > 0.05). Conclusions: Our findings suggest that increases in daily physical activity are associated with concurrent increases in KOA patients' levels of knee pain, particularly among patients reporting higher levels of pain catastrophizing. These results may have clinical implications for the design and testing of interventions targeted at reducing catastrophizing and increasing physical activity among patients with chronic osteoarthritis pain. PMID- 30016487 TI - Nodular skin lesion secondary to Mycobacterium abscessus tenosynovitis. PMID- 30016488 TI - Atherosclerosis and renal disease involvement in patients with systemic lupus erythematosus: a cross-sectional cohort study. AB - Objective: To investigate the association between LN, renal function and atherosclerosis measured by coronary artery calcium (CAC) and carotid plaque in a cross-sectional study of patients with SLE. Methods: Presence of CAC and carotid plaque was measured in 147 SLE patients with and without LN. The patients were divided into four groups according to LN and renal function [by first quartile of estimated glomerular filtration rate (eGFR): 70 ml/min/1.73 m2]. Impaired renal function was defined by an eGFR <70 ml/min/1.73 m2. We used multivariate logistic regression models to explore the association between LN, renal function, CAC and carotid plaque. Results: Of the 147 SLE patients, 74 had LN. Median age of the study cohort was 46 years, 89% were women and median eGFR was 89 ml/min/1.73 m2. CAC score >0 was present in 57 (39%) and carotid plaque in 29 (20%) of the SLE patients. The presence of CAC and/or carotid plaque was highest in SLE patients with impaired renal function. Regression analyses showed that compared with SLE patients without LN and eGFR ?70 ml/min/1.73 m2 (reference group), only the combination of LN and impaired renal function was associated with the presence of CAC (odds ratio: 6.82, 95% CI: 1.59, 29; P = 0.01) and carotid plaque (odds ratio: 5.60, 95% CI: 1.19, 26; P = 0.03). Conclusion: Our findings indicate that LN in combination with impaired renal function defined by an eGFR <70 ml/min/1.73 m2 is strongly associated with the presence of atherosclerosis in SLE. PMID- 30016489 TI - Corrigendum to "Characteristics of the antimicrobial resistance of Staphylococcus aureus isolated from chicken mean produced by different integrated broiler operations in Korea". PMID- 30016490 TI - Ankylosing spondylitis and bamboo spine. PMID- 30016491 TI - Implementing a dengue vaccination programme-who, where and how? AB - The complex interaction between dengue viruses and the human immune system means that development of a safe, effective dengue vaccine was never going to be simple. The only currently licenced dengue vaccine (Dengvaxia(r)) does, indeed, have a complex immune profile depending on recipients' immune status, meaning that use of this vaccine is not straightforward. This commentary reviews the recommendations for vaccine use to date, and discusses issues and opportunities related to the implementation of vaccination programmes in light of these recommendations. Future dengue vaccines may also have similar profiles, so it is vital that these issues are addressed now to ensure optimal use of vaccination in the fight against dengue globally. PMID- 30016492 TI - Features distinguishing clinically amyopathic juvenile dermatomyositis from juvenile dermatomyositis. AB - Objective: We examined features of clinically amyopathic JDM (CAJDM), in which patients have characteristic rashes with little to no evidence of muscle involvement, to determine whether this is a distinct phenotype from JDM. Methods: Demographic, clinical, laboratory and treatment data from 12 (9 hypomyopathic, 3 amyopathic) patients meeting modified Sontheimer criteria for CAJDM and from 60 matched JDM patients meeting Bohan and Peter criteria were examined. Differences were evaluated by Fisher's exact and Mann-Whitney tests, random forests and logistic regression analysis. Results: Nine (75%) CAJDM patients had anti p155/140 (transcriptional intermediary factor 1), one (8.3%) anti-melanoma differentiation-associated gene 5 autoantibodies and two (16.7%) were myositis autoantibody negative. CAJDM patients were younger at diagnosis and frequently had mild disease at onset. CAJDM patients had less frequent myalgias, arthritis, contractures, calcinosis, dysphagia, abdominal pain and fatigue. The muscle, skeletal and overall clinical scores were lower in CAJDM. Serum muscle enzymes were less frequently increased in CAJDM, and peak values were lower. CAJDM patients received fewer medications compared with JDM patients. Only 50% of CAJDM patients received oral prednisone, but the maximum dose and treatment duration did not differ from JDM. At a median follow-up of 2.9 years, CAJDM patients had no documented functional disability, and none developed weakness, calcinosis, interstitial lung disease or lipodystrophy. Multivariable modelling revealed a lower skeletal score and less frequent myalgias as the most important factors in distinguishing CAJDM from JDM. Conclusion: CAJDM may be distinguished from JDM, in that they often have p155/140 (transcriptional intermediary factor 1) autoantibodies, have fewer systemic manifestations and receive less therapy. PMID- 30016493 TI - Oral squamous carcinoma cells promote macrophage polarization in an MIF-dependent manner. AB - Background: Tumor-associated macrophages (TAMs) are important determinants of intratumoral immune evasion, neoangiogenesis, extracellular matrix remodeling and dysregulated tumor cell proliferation. Our prior studies revealed that macrophage derived, but not tumor cell-derived, macrophage migration inhibitory factor (MIF), is an important determinant of TAM alternative activation and M2 polarization. Aim: Because MIF is historically thought to initiate signaling via a receptor-dependent, outside-in mode of action, we wished to investigate the specific contributions of tumor-derived vs. macrophage-derived MIF to M2 marker expression during macrophage polarization. Design: Murine oral squamous cell carcinoma cells (SCCVII) were co-cultured with either the RAW 264.7 mouse macrophage cell line or mouse primary bone marrow-derived macrophages in the context of MIF genetic loss/inhibition individually or in combination each cell type. Methods: Twelve well Transwell plates were used to co-culture SCCVII cells and RAW 264.7, MIF+/+ or MIF-/- macrophages treated with/without the small molecule MIF inhibitor, 4-iodo-6-phenylpyrimidine and incubated in the presence or absence of interleukin (IL-4) for 48 h. Macrophages were analyzed by quantitative real-time polymerase chain reaction and/or immunoblotting for relative macrophage polarization marker expression. Results: IL-4 treatment synergizes with SCCVII co-culture in inducing the expression of macrophage M2 markers and loss or inhibition of macrophage-derived MIF significantly reduces both IL-4 alone and IL-4/SCCVII co-culture-induced macrophage M2 marker expression. Conclusion: These studies identify an important and dominant requirement for macrophage MIF in maximal Th2-cytokine and oral squamous carcinoma cell-induced macrophage polarization and M2 marker expression. PMID- 30016494 TI - Narcissism and risky decisions: a neurophysiological approach. AB - Narcissists are prone to risky decision-making, but why? This study tested-via behavioral and event-related potential (ERP) measures-two accounts: deficiencies in error monitoring and deficiencies in action updating. High and low narcissists were engaged in a monetary gambling task by choosing between a high-risk and a low-risk option while the electroencephalogram (EEG) was being recorded. Two ERP components relevant to outcome evaluation-feedback-related negativity (FRN) and P3-were analyzed, with the FRN serving as an index of error monitoring and the P3 as an index of action updating. Generally, high and low narcissists differed in the high-risk condition but not in the low-risk condition. At the behavioral level, high (vs low) narcissists made riskier decisions following high-risk decision outcomes, which was in line with past findings; at the neurophysiological level, while no FRN difference emerged between high and low narcissists, the outcome valence effect (positive vs negative) on the P3 was stronger among low narcissists than high narcissists following high-risk decision outcomes. One possible interpretation of the results is that narcissism is associated with reduced action updating. The findings contribute to the understanding of narcissistic decision-making and self-regulation. PMID- 30016495 TI - Effect of Dietary Fructooligosaccharide (FOS) Supplementation on Ileal Microbiota in Broiler Chickens. AB - The dietary effect of fructooligosaccharide (FOS) supplementation as an alternative to antibiotics on ileal mucosa and digesta microbiota was investigated in broiler chickens (n = 180). The study included three dietary treatments from d1 to 21: 1) positive control (PC), a wheat-corn-soybean meal based diet containing antibiotics (virginiamycin and monensin); 2) negative control (NC), as wheat-corn-soybean meal based diet without antibiotics; and 3) NC + FOS, as NC diet supplemented 0.5% of FOS. Ileal mucosa and digesta were collected and subjected to 16S rRNA-based next generation sequencing. No significant difference on alpha-, beta-diversity and bacterial phyla was observed between ileal mucosa and digesta or between the three dietary treatments. Partial least square discriminant analysis and Venn analysis showed that different bacterial genera were associated with different ileal sites or diets. A distinct distance on ileal mucosa bacteria communities were observed between PC and NC + FOS dietary treatments. FOS supplementation increased the number of unique genera and resulted in a more diverse microbiota in the ileal mucosa when compared with PC and NC groups. Furthermore, microorganisms that have pathogenic properties such as Helicobacter and Desulfovibrio were found significantly reduced when compared between NC and NC + FOS groups in the ileal mucosa. Lachnospiraceae (f) was greater in the ileal mucosa than that in the digesta, particularly among the NC + FOS dietary group. Overall, supplementing FOS in broiler chicken diets may be able to modulate gut microbiota in favor of chicken health, which in turn, can be used as an alternative method to replace antibiotic growth promoters (AGPs). Future investigation on the mechanism of FOS and other prebiotic products as dietary supplements is warranted. PMID- 30016496 TI - Asymmetric neural tracking of gain and loss magnitude during adolescence. AB - Adolescence has been characterized as a developmental period of heightened reward seeking and attenuated aversive processing. However, it remains unclear how the neural bases of distinct outcome valuation processes shift during this stage of the lifespan. A total of 74 participants ranging in age from 13 to 20 years completed a value-modulated functional magnetic resonance imaging (fMRI) task in which participants earn low and high magnitude monetary outcomes to test whether gain and loss magnitude tracking-the neural representation of relative value in context-change differentially over this age span. Results revealed that gain and loss magnitude tracking follow asymmetric developmental trajectories. Gain magnitude tracking is elevated in the striatum during early adolescence and then decreases with age. By contrast, loss magnitude tracking in the anterior insula follows a quadratic pattern, undergoing a temporary attenuation during mid-late adolescence. A typical comparison of gain vs loss outcomes (collapsing over magnitude effects) showed robust activity across a suite of brain regions sensitive to value based on prior work including the ventral striatum, but they exhibited no changes with age. These findings suggest that value coding subprocesses follow divergent developmental paths across adolescence, which may contribute to normative shifts in adolescent motivated behavior. PMID- 30016497 TI - Cis-regulatory determinants of MyoD function. AB - Muscle-specific transcription factor MyoD orchestrates the myogenic gene expression program by binding to short DNA motifs called E-boxes within myogenic cis-regulatory elements (CREs). Genome-wide analyses of MyoD cistrome by chromatin immnunoprecipitation sequencing shows that MyoD-bound CREs contain multiple E-boxes of various sequences. However, how E-box numbers, sequences and their spatial arrangement within CREs collectively regulate the binding affinity and transcriptional activity of MyoD remain largely unknown. Here, by an integrative analysis of MyoD cistrome combined with genome-wide analysis of key regulatory histones and gene expression data we show that the affinity landscape of MyoD is driven by multiple E-boxes, and that the overall binding affinity-and associated nucleosome positioning and epigenetic features of the CREs-crucially depend on the variant sequences and positioning of the E-boxes within the CREs. By comparative genomic analysis of single nucleotide polymorphism (SNPs) across publicly available data from 17 strains of laboratory mice, we show that variant sequences within the MyoD-bound motifs, but not their genome-wide counterparts, are under selection. At last, we show that the quantitative regulatory effect of MyoD binding on the nearby genes can, in part, be predicted by the motif composition of the CREs to which it binds. Taken together, our data suggest that motif numbers, sequences and their spatial arrangement within the myogenic CREs are important determinants of the cis-regulatory code of myogenic CREs. PMID- 30016498 TI - LAT1-like transporters regulate dopaminergic transmission and sleep in Drosophila. AB - Amino acid transporters are involved in functions reportedly linked to the sleep/wake cycle: neurotransmitter synthesis and recycling, the regulation of synaptic strength, protein synthesis, and energy metabolism. In addition, the existence of bidirectional relationships among extracellular content, transport systems, and sleep/wake states is receiving emerging support. Nevertheless, the connection between amino acid transport and sleep/wake regulation remains elusive. To address this question, we used Drosophila melanogaster and investigated the role of LAT1 (large neutral amino acid transporter 1) transporters. We show that the two Drosophila LAT1-like transporters: Juvenile hormone Inducible-21 and minidiscs (Mnd) are required in dopaminergic neurons for sleep/wake regulation. Down-regulating either gene in dopaminergic neurons resulted in higher daily sleep and longer sleep bout duration during the night, suggesting a defect in dopaminergic transmission. Since LAT1 transporters can mediate in mammals the uptake of L-DOPA, a precursor of dopamine, we assessed amino acid transport efficiency by L-DOPA feeding. We find that downregulation of JhI-21, but not Mnd, reduced the sensitivity to L-DOPA as measured by sleep loss. JhI-21 downregulation also attenuated the sleep loss induced by continuous activation of dopaminergic neurons. Since LAT1 transporters are known to regulate target of rapamycin (TOR) signaling, we investigated the role of this amino acid sensing pathway in dopaminergic neurons. Consistently, we report that TOR activity in dopaminergic neurons modulates sleep/wake states. Altogether, this study provides evidence that LAT1-mediated amino acid transport in dopaminergic neurons is playing a significant role in sleep/wake regulation and is providing several entry points to elucidate the role of nutrients such as amino acids in sleep/wake regulation. PMID- 30016499 TI - Brain networks of happiness: dynamic functional connectivity among the default, cognitive and salience networks relates to subjective well-being. AB - Subjective well-being (SWB) reflects the cognitive and emotional evaluations of an individual's life and plays an important role in individual's success in health, work and social relationships. Although previous studies have revealed the spontaneous brain activity underlying SWB, little is known about the relationship between brain network interactions and SWB. The present study investigated the static and dynamic functional connectivity among large-scale brain networks during resting state functional magnetic resonance imaging (fMRI) in relation to SWB in two large independent datasets. The results showed that SWB is negatively correlated with static functional connectivity between the salience network (SN) and the anterior default mode network (DMN). Dynamic functional network connectivity (dFNC) analysis found that SWB is negatively correlated with the fraction of time that participants spent in a brain state characterized by weak cross-network connectivity (between the DMN, SN and frontal-parietal network [FPN]) and strong within-network connectivity (within the DMN and within the FPN). This connectivity profile may account for the good mental adaptability and flexible information communication of people with high levels of SWB. The dFNC results were well replicated with different analysis parameters and further validated in an independent sample. Taken together, these findings reveal that the dynamic interaction between networks involved in self-reflection, emotional regulation and cognitive control underlies SWB. PMID- 30016500 TI - Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR. AB - The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation. PMID- 30016502 TI - A novel transcriptional network for the androgen receptor in human epididymis epithelial cells. AB - STUDY QUESTION: What is the transcriptional network governed by the androgen receptor (AR) in human epididymis epithelial (HEE) cells from the caput region and if the network is tissue-specific, how is this achieved? SUMMARY ANSWER: About 200 genes are differentially expressed in the caput HEE cells after AR activation; the AR transcriptional network is tissue-specific and may be mediated in part by distinct AR co-factors including CAAT-enhancer binding protein beta (CEBPB) and runt-related transcription factor 1 (RUNX1). WHAT IS KNOWN ALREADY: Little is known about the AR transcriptional program genome wide in HEE cells, nor its co-factors in those cells. AR has been best studied in the prostate gland epithelium and prostate cancer cell lines, due to the important role of this factor in prostate cancer. However AR-associated differentially expressed genes (DEGs) and AR co-factors have not yet been compared between human epididymis and prostate epithelial cells. STUDY DESIGN, SIZE, DURATION: Caput HEE cells from two donors were exposed to the synthetic androgen R1881 at 1 nM for 12-16 h after 72 h of hormone starvation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Chromatin was prepared from R1881-treated and vehicle control HEE cells. AR-associated chromatin was purified by chromatin immunoprecipitation (ChIP) and AR occupancy genome wide was revealed by deep sequencing (ChIP-seq). Two independent biological replicates were performed. Total RNA was prepared from R1881 and control-treated HEE cells and gene expression profiles were documented by RNA seq. The interaction of the potential novel AR co-factors CEBPB and RUNX1, identified through in-silico motif analysis of AR ChIP-seq data, was examined by ChIP-qPCR after siRNA-mediated depletion of each co-factor individually or simultaneously. MAIN RESULTS AND THE ROLE OF CHANCE: The results identify about 200 genes that are differentially expressed (DEGs) in HEE cells after AR activation. Some of these DEGs show occupancy of AR at their promoters or cis regulatory elements suggesting direct regulation. However, there is little overlap in AR-associated DEGs between HEE and prostate epithelial cells. Inspection of over-represented motifs in AR ChIP-seq peaks identified CEBPB and RUNX1 as potential co-factors, with no evidence for FOXA1, which is an important co-factor in the prostate epithelium. CEBPB and RUNX1 ChIP-seq in HEE cells showed that both these factors often occupied AR-binding sites, though rarely simultaneously. Further analysis at a single AR-regulated locus (FK506-binding protein 5, FKPB5) suggests that CEBPB may be a co-activator. These data suggest a novel AR transcriptional network governs differentiated functions of the human epididymis epithelium. LARGE SCALE DATA: AR ChIP-seq and RNA-seq data are deposited at GEO: GSE109063. LIMITATIONS, REASONS FOR CAUTION: There is substantial donor-to-donor variation in primary HEE cells cultures. We applied stringent statistical tests with a false discovery rate (FDR) of 0.1% for ChIP seq and standard pipelines for RNA-seq so it is possible that we have missed some AR-regulated genes that are important in caput epididymis function. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that a novel AR transcriptional network governs differentiated functions of the human epididymis epithelium. Since this cell layer has a critical role in normal sperm maturation, the results are of broader significance in understanding the mechanisms underlying the maintenance of fertility in men. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Development: R01 HD068901 (PI: Harris). The authors have no competing interests to declare. PMID- 30016504 TI - Neuroimmune regulation of lung infection and inflammation. AB - The distal airway of the lung is innervated by vagus nerve. Upon stimulation, vagus nerve endings release acetylcholine or neuropeptides via C-fiber afferents to regulate lung infection and immunity. Vagal sensory nerve endings, brain integration center, acetylcholine, and alpha7 nicotinic acetylcholine receptor (nAChR) expressing cells are key components of pulmonary parasympathetic inflammatory reflex. Meanwhile, this local machinery synergizes with spleen (as a functional hub of cholinergic anti-inflammatory pathway) to finely tune recruitment of the splenic alpha7 nAChR+CD11b+ cells into the inflamed lungs during lung infection. Recent studies have showed that lung group 2 innate lymphoid cells (ILC2) express both alpha7 nAChR and neuropeptide receptors. Acetylcholine and neuropeptides can regulate ILC2 and reshape pulmonary infection and immunity. Among the airway epithelial cells, pulmonary neuroendocrine cells (PNECs) are rare cell population; however, these cells are innervated by sensory nerve endings and they could secrete neuropeptides that influence lung infection and immunity. PMID- 30016503 TI - The cecal microbiome of commercial broiler chickens varies significantly by season. AB - Next-generation DNA sequencing is rapidly becoming a powerful tool for food animal management. One valuable use of this technology is to re-examine long standing observations of performance differences associated with animal husbandry practices to better understand how these differences may be modulated by the gastrointestinal (GI) microbiome. The influences of environmental parameters such as air temperature and relative humidity on broiler chicken performance have commonly been observed, but how the GI microbiome may respond to seasonal environmental changes remains largely unknown. The purposes of this study were therefore to: (1) characterize the cecal microflora of commercial broilers (N = 87) collected at harvest across all 4 seasons, and (2) identify any significant changes of the GI microbiome and specific taxa according to season and Campylobacter status. Finding taxa with significant positive or negative correlations with Campylobacter could be useful by identifying indicator or antagonistic taxa and could also inform inferences regarding the ecological niche of Campylobacter. Whole GI tracts were removed from commercial broilers representing 87 independent flocks between April 2013 and May 2014 in the U.S. state of Georgia. Intact ceca were separated, cultured for Campylobacter and cecal contents were frozen. The cecal microbiome was characterized using barcoded sequencing of 16S rRNA genes on the Illumina MiSeq platform. The composition of the microbiome measured at processing was generally not affected by Campylobacter status but was most significantly affected by season of grow-out. Significantly fewer bacterial genera were found in winter than spring or summer. Bacterial genera with prior evidence for both positive or negative influences on gut health outcomes were significantly less abundant in the fall. Identifying specific members of the GI microbiota that vary according to season may help develop novel interventions to improve husbandry practices and growth performance. PMID- 30016501 TI - Arrhythmogenic mechanisms of obstructive sleep apnea in heart failure patients. AB - Heart failure (HF) affects 23 million people worldwide and results in 300000 annual deaths. It is associated with many comorbidities, such as obstructive sleep apnea (OSA), and risk factors for both conditions overlap. Eleven percent of HF patients have OSA and 7.7% of OSA patients have left ventricular ejection fraction <50% with arrhythmias being a significant comorbidity in HF and OSA patients. Forty percent of HF patients develop atrial fibrillation (AF) and 30% 50% of deaths from cardiac causes in HF patients are from sudden cardiac death. OSA is prevalent in 32%-49% of patients with AF and there is a dose-dependent relationship between OSA severity and resistance to anti-arrhythmic therapies. HF and OSA lead to various downstream arrhythmogenic mechanisms, including metabolic derangement, remodeling, inflammation, and autonomic imbalance. (1) Metabolic derangement and production of reactive oxidative species increase late Na+ currents, decrease outward K+ currents and downregulate connexin-43 and cell-cell coupling. (2) remodeling also features downregulated K+ currents in addition to decreased Na+/K+ ATPase currents, altered Ca2+ homeostasis, and increased density of If current. (3) Chronic inflammation leads to downregulation of both Nav1.5 channels and K+ channels, altered Ca2+ homeostasis and reduced cellular coupling from alterations of connexin expression. (4) Autonomic imbalance causes arrhythmias by evoking triggered activity through increased Ca2+ transients and reduction of excitation wavefront wavelength. Thus, consideration of these multiple pathophysiological pathways (1-4) will enable the development of novel therapeutic strategies that can be targeted against arrhythmias in the context of complex disease, such as the comorbidities of HF and OSA. PMID- 30016506 TI - Corrigendum. PMID- 30016505 TI - Maternal Communication in Childhood Cancer: Factor Analysis and Relation to Maternal Distress. AB - Objective: This study aimed to characterize mothers' communication with their children in a sample of families with a new or newly relapsed pediatric cancer diagnosis, first using factor analysis and second using structural equation modeling to examine relations between self-reported maternal distress (anxiety, depression, and posttraumatic stress) and maternal communication in prospective analyses. A hierarchical model of communication was proposed, based on a theoretical framework of warmth and control. Methods: The sample included 115 children (age 5-17 years) with new or newly relapsed cancer (41% leukemia, 18% lymphoma, 6% brain tumor, and 35% other) and their mothers. Mothers reported distress (Beck Anxiety Inventory, Beck Depression Inventory-II, and Impact of Events Scale-Revised) 2 months after diagnosis (Time 1). Three months later (Time 2), mother-child dyads were video-recorded discussing cancer. Maternal communication was coded with the Iowa Family Interaction Ratings Scales. Results: Confirmatory factor analysis demonstrated poor fit. Exploratory factor analysis suggested a six-factor model (root mean square error of approximation = .04) with one factor reflecting Positive Communication, four factors reflecting Negative Communication (Hostile/Intrusive, Lecturing, Withdrawn, and Inconsistent), and one factor reflecting Expression of Negative Affect. Maternal distress symptoms at Time 1 were all significantly, negatively related to Positive Communication and differentially related to Negative Communication factors at Time 2. Maternal posttraumatic stress and depressive symptoms each predicted Expression of Negative Affect. Conclusions: Findings provide a nuanced understanding of maternal communication in pediatric cancer and identify prospective pathways of risk between maternal distress and communication that can be targeted in intervention. PMID- 30016508 TI - Confusional arousals during non-rapid eye movement sleep: evidence from intracerebral recordings. AB - Study Objectives: Confusional arousals (CA) are characterized by the association of behavioral awakening with persistent slow-wave electroencephalographic (EEG) activity during non-rapid eye movement (NREM) sleep-suggesting that sensorimotor areas are "awake" while non-sensorimotor areas are still "asleep." In the present work, we aimed to study the precise temporo-spatial dynamics of EEG changes in cortical areas during CA using intracerebral recordings. Methods: Nineteen episodes of CA were selected in five drug-resistant epileptic patients suffering incidentally from arousal disorders. Spectral power of EEG signal recorded in 30 non-lesioned, non-epileptogenic cortical areas and thalamus was compared between CA and baseline slow-wave sleep. Results: Clear sequential modifications in EEG activity were observed in almost all studied areas. In the last few seconds before behavior onset, an increase in delta activity occurred predominantly in frontal regions. Behavioral arousal was associated with an increase of signal power in the whole studied frequency band in the frontal lobes, cingulate cortex, insular cortex, and precuneus. Afterwards, a diffuse cessation of very low frequencies (<1 Hz) occurred. Simultaneously, a hypersynchronous delta activity (HSDA) (1-1.5 Hz) arose in a broad network involving medial and lateral frontoparietal cortices, whereas higher frequency activities increased in sensorimotor, orbitofrontal, and temporal lateral cortices. This HSDA was predominantly observed in the inferior frontal gyrus. Conclusions: During CA, the level of activity changed in almost all the studied areas. The embedding of a broad frontoparietal network, especially the inferior frontal gyrus, in an HSDA might explain the participants' altered state of consciousness. PMID- 30016507 TI - Neighborhood disadvantage is associated with actigraphy-assessed sleep continuity and short sleep duration. AB - Study Objectives: Neighborhood disadvantage has been linked to poor sleep. However, the extant research has primarily focused on self-reported assessments of sleep and neighborhood characteristics. The current study examines the association between objective and perceived neighborhood characteristics and actigraphy-assessed sleep duration, efficiency, and wakefulness after sleep onset (WASO) in an urban sample of African American adults. Methods: We examined data from predominantly African American adults (n = 788, mean age 55 years; 77% female) living in two low-income neighborhoods. Perceived neighborhood characteristics included safety, social cohesion, and satisfaction with one's neighborhood as a place to live. Objective neighborhood conditions included walkability, disorder, street lighting, and crime levels. Sleep duration, efficiency, and WASO were measured via 7 days of wrist-worn actigraphy. Analyses estimated each of the sleep outcomes as a function of perceived and objective neighborhood characteristics. Individual-level sociodemographics, body mass index, and psychological distress were included as covariates. Results: Greater perceived safety was associated with higher sleep efficiency and shorter WASO. Greater neighborhood disorder and street lighting were associated with poorer sleep efficiency and longer WASO and greater likelihood of short sleep duration (<7 versus 7-9 hr as referent). Higher levels of crime were associated with poorer sleep efficiency and longer WASO, but these associations were only evident in one of the neighborhoods. Conclusions: Both how residents perceive their neighborhood and their exposure to objectively measured neighborhood disorder, lighting, and crime have implications for sleep continuity. These findings suggest that neighborhood conditions may contribute to disparities in sleep health. PMID- 30016509 TI - MAVIS: Merging, Annotation, Validation, and Illustration of Structural variants. AB - Summary: Reliably identifying genomic rearrangements and interpreting their impact is a key step in understanding their role in human cancers and inherited genetic diseases. Many short read algorithmic approaches exist but all have appreciable false negative rates. A common approach is to evaluate the union of multiple tools increasing sensitivity, followed by filtering to retain specificity. Here we describe an application framework for the rapid generation of structural variant consensus, unique in its ability to visualize the genetic impact and context as well as process both genome and transcriptome data. Availability and Implementation: http://mavis.bcgsc.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30016511 TI - Pharmacoinvasive strategy as rescue treatment for acute right ventricular failure from chronic thromboembolic pulmonary hypertension. PMID- 30016510 TI - From random to regular: neural constraints on the emergence of isochronous rhythm during cultural transmission. AB - A core design feature of human communication systems and expressive behaviours is their temporal organization. The cultural evolutionary origins of this feature remain unclear. Here, we test the hypothesis that regularities in the temporal organization of signalling sequences arise in the course of cultural transmission as adaptations to aspects of cortical function. We conducted two experiments on the transmission of rhythms associated with affective meanings, focusing on one of the most widespread forms of regularity in language and music: isochronicity. In the first experiment, we investigated how isochronous rhythmic regularities emerge and change in multigenerational signalling games, where the receiver (learner) in a game becomes the sender (transmitter) in the next game. We show that signalling sequences tend to become rhythmically more isochronous as they are transmitted across generations. In the second experiment, we combined electroencephalography (EEG) and two-player signalling games over 2 successive days. We show that rhythmic regularization of sequences can be predicted based on the latencies of the mismatch negativity response in a temporal oddball paradigm. These results suggest that forms of isochronicity in communication systems originate in neural constraints on information processing, which may be expressed and amplified in the course of cultural transmission. PMID- 30016512 TI - Skipping breakfast and the risk of coronary artery disease. AB - Background/Introduction: Nutritional studies have indicated a critical role of dietary habits in development of cardiovascular diseases (CVD). Aim: We aimed to compare the risk of coronary artery disease (CAD) in habitual 'breakfast skippers' with those of 'habitual breakfast eaters' in Western part of India. We also planned to compare the cardiometabolic profiles of both the groups. Design: In this prospective, case-control study of 1607 individuals; 980 were patients of CAD (cases) undergoing various cardiac interventions for revascularisation and other 627 were healthy individuals (controls) who were free from CAD. Methods: Details of demographics and classical risk factors were collected for all the participants. Subjects were categorized as 'breakfast eater' or 'breakfast skippers' according to their response to the questionnaire. Logistic regression and correlation analysis were performed to assess the independent risk of all the factors and their inter-variable association. Results: Significantly (P < 0.05) high prevalence of classical risk factors and breakfast skipping habit was found in cases when compared with controls. Diabetes showed the highest odds ratio (7.296; 95% confidence interval (CI) 4.825-11.030; P < 0.0001) for CAD, followed by hypertension (3.756; 95% CI 2.891-4.881; P < 0.0001) and habits of smoking/tobacco/alcohol consumption (1.914; 95% CI 1.528-2.398; P < 0.0001) and breakfast skipping 1.348 (95% CI 1.076-1.689; P < 0.0001). Breakfast skipping emerged as stronger risk factor than obesity and sedentary life style in Indians and showed close association with presence of hypertension. Discussion/Conclusion: Habitual breakfast skippers are at increased risk for development of CAD and hypertension in Western India. PMID- 30016513 TI - Kinome-wide identification of phosphorylation networks in Eukaryotic proteomes. AB - Motivation: Signaling and metabolic pathways are finely regulated by a network of protein phosphorylation events. Unraveling the nature of this intricate network, composed of kinases, target proteins and their interactions, is therefore of crucial importance. Although thousands of kinase-specific phosphorylations have been annotated in model organisms their kinase-target network is far from being complete, with less studied organisms lagging behind. Results: In this work we achieved an automated and accurate identification of kinase domains, inferring the residues that most likely contribute to peptide specificity. We integrated this information with the target peptides of known human kinase-specific phosphorylations to predict kinase-specific interactions in other Eukaryotes through a deep neural network, outperforming similar methods. We analyzed the differential conservation of kinase specificity among Eukaryotes revealing the high conservation of the specificity of Tyrosine kinases. With this approach we discovered 1590 novel kinase-specific phosphorylations of potential clinical relevance in the human proteome. Availability: http://akid.bio.uniroma2.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30016514 TI - Determinants of health behavior inequalities: a cross-sectional study from Israel. AB - Health behaviors are shaped by the opportunities people have; and the choices they make according to these opportunities. Inequality in economic, cultural and social resources causes disparities in health and health behaviors. Jerusalem has a multiethnic structure, mainly made up of Jews and Arabs. Arabs and Ultra Orthodox Jews are disadvantaged in terms of socio-economic and health indicators. The purpose of this study is to determine the factors associated with three health behaviors: physical activity (PA), fruit and vegetable consumption, and smoking. This cross-sectional study was conducted among 1682 adults from a stratified sample by age, sex and neighborhood from 2011 to 2015, in accordance with the Healthy Cities project. Univariate analyses were conducted by Chi-square test of independence; and multivariate analyses by logistic regression models. Of the total population, 12% do adequate amounts of PA; 17.6% consume adequate amounts of fruits/vegetables; and 19.4% are current smokers. Multivariate analyses indicates for both genders: ethnicity/religion and education level is associated with doing PA; ethnicity/religion, education and income level is associated with fruit/vegetable consumption; and ethnicity/religion, and age is associated with smoking. However, gender significantly modifies the effect of ethnicity/religion for all the three health behaviors. Gender disparities regarding health behaviors are higher among Arabs and Ultra-Orthodox Jews. In similar economic, cultural and social circumstances, men and women have similar health behaviors; and unequal opportunity to education and income creates a vicious gender inequality cycle. Therefore, to reduce health behavior inequalities, besides economic and cultural inequalities, social and gender inequalities should also be reduced. PMID- 30016515 TI - Prognostic role of the sialyltransferase ST6GAL1 in ovarian cancer. AB - Aberrant sialylation of glycoproteins has been detected in many tumors, and upregulation of the beta-galactosamide alpha-2,6-sialyltransferase 1 (ST6GAL1) has been implicated with tumor aggressiveness and chemoresistance in experimental models. In our present study, we aimed to study the prognostic or predictive role of ST6GAL1 in ovarian carcinoma, using two independent ovarian cancer cohorts. ST6GAL1 mRNA levels were retrieved from a publicly available database (n = 517), and ST6GAL1 protein levels were analyzed by western blot analysis in a cohort of 204 ovarian tumor samples. The results were correlated with clinical and histological tumor parameters and follow-up information. High ST6GAL1 mRNA levels significantly correlated with lymphovascular invasion and shorter survival, whereas high ST6GAL1 protein expression was associated with advanced stage, distant metastasis and shorter recurrence-free intervals. In both cohorts the prognostic role was most pronounced in tumors without macroscopically visible residual tumor after surgery. In these cases, ST6GAL1 expression levels might help to identify cases with a higher risk of chemoresistance and metastatic relapse that might require an adapted therapeutic regime. PMID- 30016516 TI - Cognitive Performance in Indian School-Going Adolescents Is Positively Affected by Consumption of Iron-Biofortified Pearl Millet: A 6-Month Randomized Controlled Efficacy Trial. AB - BACKGROUND: Iron deficiency remains the most prevalent micronutrient deficiency globally, but few studies have examined how iron status relates to cognition in adolescents. Iron biofortification of staple food crops is being scaled up, yet it is unknown whether consuming biofortified crops can benefit cognition. Objective: Our objective was to determine the efficacy of iron-biofortified pearl millet in improving attention and memory in Indian school-going adolescents. Methods: A double-blind, randomized, intervention study was conducted in 140 Indian boys and girls, aged 12-16 y, who were assigned to consume iron biofortified [Fe = 86 parts per million (ppm)] or conventional (Fe = 21-52 ppm) pearl millet. Hemoglobin, ferritin, and transferrin receptor (TfR) were measured and body iron (BI) was calculated at baseline and after 4 and 6 mo. Five measures of cognitive function were obtained at baseline and 6 mo: simple reaction time (SRT), Go/No-Go (GNG) task, Attentional Network Task (ANT), Composite Face Effect (CFE) task, and Cued Recognition Task (CRT). Intention-to-treat analysis was used. Results: Daily iron intake from pearl millet was higher in those consuming biofortified compared with conventional pearl millet (19.6 compared with 4.8 mg/d). Effects on ferritin, TfR, and BI at 4 mo, and on TfR at 6 mo (all P < 0.05), indicated efficacy of biofortified pearl millet over conventional pearl millet in improving iron status. Compared with conventional pearl millet, the consumption of biofortified pearl millet resulted in greater improvement in attention (SRT, GNG, and ANT) and memory (CFE and CRT). Reaction time decreased twice as much from 0 to 6 mo in those consuming biofortified compared with conventional pearl millet on attention tasks (SRT: -123 compared with -63 ms; GNG: -67 compared with -30 ms; ANT double cue: -74 compared with -32 ms; all P < 0.01). Conclusion: Consuming iron-biofortified pearl millet improves iron status and some measures of cognitive performance in Indian adolescents. This trial was registered at http://www.clinicaltrials.gov as NCT02152150. PMID- 30016517 TI - Engaging Latina breast cancer survivors in research: building a social network research registry. AB - Disparities persist in breast cancer outcomes between Latina survivors and non Hispanic Whites. Identifying methods to ensure that Latinas participate in and benefit from translational behavioral medicine research is important to reduce disparities. We developed a "Social Network Research Registry" to enhance Latina survivors' engagement in research and explored the social networks and research/cancer organization participation in this population. We initially recruited 30 Latina breast cancer survivors ("seeds") from community organizations and identified other survivors through snowball sampling. Guided by Social Network Analysis, we assessed the structural (e.g., size) and functional (e.g., social support) characteristics of the network, willingness to join the registry, prior research participation, involvement in cancer organizations, and interest in different types of research and roles in research. The resulting network size was 98, including 53 women who enrolled in the study and 45 who were listed in the network but did not enroll. All enrolled participants (N = 53) agreed to be part of the registry. We identified 15 participants who occupied strategic positions as hubs and/or bridges. Women who were currently involved in cancer organizations were more likely to have participated in research (70.3% vs. 18.8%); chi2 (1, 53) = 11.97, p = .001. Most were interested in surveys/interviews (98%), behavioral interventions (96%), and becoming health promoters (79%). The Social Network Research Registry is an acceptable and feasible strategy to engage underrepresented Latina survivors in research. Social network analysis can be useful to identify members who occupy key positions to enhance recruitment and translational efforts. PMID- 30016518 TI - Networks for prevention in 19 communities at the start of a large-scale community based obesity prevention initiative. AB - Community-based obesity prevention efforts are dependent on the strength and function of collaborative networks across multiple community members and organizations. There is little empirical work on understanding how community network structure influences obesity prevention capacity. We describe network structures within 19 local government communities prior to a large-scale community-based obesity prevention intervention, Healthy Together Victoria, Australia (2012-2015). Participants were from a large, multi-site, cluster randomized trial (cRCT) of a whole-of-systems chronic disease prevention initiative. Community leaders from 12 intervention and seven comparison (non intervention) regions identified and described their professional networks in relation to dietary, physical activity, and weight status among young children (<5 years of age). Social network measures of density, modularity, clustering, and centrality were calculated for each community. Comparison of means and tests of association were conducted for each network relationship. One-hundred and seven respondents (78 intervention; 29 comparison) reported on 996 professional network relationships (respondent average per region: 10 intervention; 8 comparison). Networks were typically sparse and highly modular. Networks were heterogeneous in size and relationship composition. Frequency of interaction, close and influential relationships were inversely associated with network density. At baseline in this cRCT there were no significant differences between community network structures of key actors with influence over environments affecting children's diet and physical activity. Tracking heterogeneity in both networks and measured outcomes over time may help explain the interaction between professional networks and intervention effectiveness of community-based obesity prevention. PMID- 30016519 TI - Egocentric social networks and smoking among adults with serious mental illness. AB - Evidence-based smoking cessation treatment is safe and effective for smokers with serious mental illness (SMI); however, quit rates remain low in this population. We explored how social networks influence smoking outcomes among people with SMI who participated in smoking cessation treatment at community mental health centers. We conducted egocentric social network interviews with 41 individuals with SMI who participated in a statewide Medicaid demonstration project of smoking cessation treatment. We estimated the proportions of current smokers, former smokers, and never smokers in participants' (i.e., egos') networks and examined support for quitting from alters, defined as family, friends, peers, or significant others. We used logistic regression and mixed-effect logistic regression to explore the relationship between social network variables and ego's smoking status following cessation treatment. Egos reported an average of 5.9 +/- 2.2 alters; 52% of alters were current smokers; 18% were former smokers; and 30% never smoked. The majority (57%) of alters helped an ego quit smoking. The presence of former smokers in the network was associated with decreased odds that the ego was smoking post-treatment. Egos whose friends were highly interconnected were less likely to smoke after treatment. Former smokers in the network may be a valuable resource for quitting particularly for vulnerable groups where there is a high prevalence and acceptability of smoking. Our initial findings suggest that a highly interconnected friendship network structure may be beneficial for people with SMI who are trying to quit smoking. PMID- 30016522 TI - The nature and scope of patient-sharing network research: a novel, important area for network science. AB - A robust literature exists that draws on social network approaches to understand connections among individuals, and healthcare and behavior-related implications. This article offers commentary on the scoping review conducted by Dugoff et al. that examines "patient-sharing" networks, their characteristics, and various methodological approaches. The scoping review conducted by Dugoff et al. examines the characteristics and methods employed in patient-sharing network studies. It identified the most common measures used in patient-sharing network research, as well as theories used in patient-sharing network studies. Dugoff et al. also identified many studies that examined healthcare utilization considerations for patient sharing. Understanding the connections between providers and the flow of patients between providers could lend insight into barriers and enablers to efficient healthcare systems. PMID- 30016521 TI - A scoping review of patient-sharing network studies using administrative data. AB - There is a robust literature examining social networks and health, which draws on the network traditions in sociology and statistics. However, the application of social network approaches to understand the organization of health care is less well understood. The objective of this work was to examine approaches to conceptualizing, measuring, and analyzing provider patient-sharing networks. These networks are constructed using administrative data in which pairs of physicians are considered connected if they both deliver care to the same patient. A scoping review of English language peer-reviewed articles in PubMed and Embase was conducted from inception to June 2017. Two reviewers evaluated article eligibility based upon inclusion criteria and abstracted relevant data into a database. The literature search identified 10,855 titles, of which 63 full text articles were examined. Nine additional papers identified by reviewing article references and authors were examined. Of the 49 papers that met criteria for study inclusion, 39 used a cross-sectional study design, 6 used a cohort design, and 4 were longitudinal. We found that studies most commonly theorized that networks reflected aspects of collaboration or coordination. Less commonly, studies drew on the strength of weak ties or diffusion of innovation frameworks. A total of 180 social network measures were used to describe the networks of individual providers, provider pairs and triads, the network as a whole, and patients. The literature on patient-sharing relationships between providers is marked by a diversity of measures and approaches. We highlight key considerations in network identification including the definition of network ties, setting geographic boundaries, and identifying clusters of providers, and discuss gaps for future study. PMID- 30016523 TI - Organizational network strengthening effects on antiretroviral therapy initiation and adherence. AB - The WHO recommends antiretroviral therapy (ART) initiation immediately after HIV diagnosis. When HIV services are fragmented and poorly coordinated, initiation of ART can be delayed. MEASURE Evaluation conducted an organizational network intervention in Addis Ababa, Ethiopia, which increased referral network density and client satisfaction in the intervention versus control networks. The objective of our study was to extend the parent study by assessing effects of network density on the speed of ART initiation and adherence to ART. Measures of client-time since HIV diagnosis, use of ART, satisfaction with HIV-related services, and adherence were obtained from cross-sectional interviews with female service recipients with HIV/AIDS at baseline (T1, 402) and at 18-month follow-up (T2, 524) and compared between network sites. We used weighted least squares estimation with probit regression techniques in a structural equation modeling framework for analyses. On average at follow-up, clients in the intervention network were more likely to have quicker ART initiation, and were initiated on ART 15 days faster than clients in the control network. Moreover, quicker ART initiation was associated with higher adherence. A unit increase in speed of ART initiation was associated with 0.5 points increase in latent adherence score in the intervention group (p < .05). Satisfaction with care positively predicted adherence to ART. Network density had no direct effect on ART adherence. This quasi-experiment demonstrated that increased referral network density, through improved HIV client referrals, can enhance speed of ART initiation, resulting in improved adherence. PMID- 30016520 TI - A conceptual model of social networks and mechanisms of cancer mortality, and potential strategies to improve survival. AB - Women with larger personal social networks have better breast cancer survival and a lower risk of mortality. However, little work has examined the mechanisms through which social networks influence breast cancer outcomes and cancer outcomes more generally, potentially limiting the development of feasible, clinically effective interventions. In fact, much of the emphasis in cancer research regarding the influence of social relationships on cancer outcomes has focused on the benefits of the provision of social support to patients, especially through peer support groups, and only more recently through patient navigation. Though critically important, there are other ways through which social relationships might influence outcomes, around which interventions might be developed. In addition to social support, these include social resources, social norms, social contagion, social roles, and social burdens and obligations. This narrative review addresses how social networks may influence cancer outcomes and discusses potential strategies for improving outcomes given these relationships. The paper (a) describes background and limitations of previous research, (b) outlines terms and provides a conceptual model that describes interrelationships between social networks and relevant variables and their hypothesized influence on cancer outcomes, (c) clarifies social and psychosocial mechanisms through which social networks affect downstream factors, (d) describes downstream behavioral, treatment, and physiological factors through which these subsequently influence recurrence and mortality, and (e) describes needed research and potential opportunities to enhance translation. Though most literature in this area pertains to breast cancer, this review has substantial relevance for cancer outcomes generally. Further clarification and research regarding potential mechanisms are needed to translate epidemiological findings on social networks into clinical and community strategies to improve cancer outcomes. PMID- 30016526 TI - Enhancing cultural considerations in networks and health: a commentary on racial differences in family health history knowledge and interpersonal mechanisms. AB - In this commentary, I commend and expand upon the article of Lin et al., "Racial differences in family health history knowledge of type 2 diabetes: exploring the role of interpersonal mechanisms." In particular, the commentary discusses the role and importance of culture in family health history communication, as this topic is very relevant to Lin and colleagues' primary finding that in comparison to their White counterparts, African American families had uneven distributions of family health history knowledge due to them having fewer reciprocal health communication ties. I offer insights and suggestions regarding cultural influences on family health communication and the importance of incorporating cultural considerations in family networks studies. I also provide perspective on the translation of family networks and health study findings into the types of culturally appropriate interventions needed to activate family health history communication in racial and ethnic minority families. Information discussed has implications for future efforts seeking to reduce racial and ethnic disparities in family health history communication and knowledge. PMID- 30016524 TI - Team Red, White & Blue: a community-based model for harnessing positive social networks to enhance enrichment outcomes in military veterans reintegrating to civilian life. AB - Military service assimilates individuals into a socially cohesive force to address dangerous and traumatic situations that have no counterpart in civilian life. Upon leaving active duty, many veterans experience a "reverse culture shock" when trying to reintegrate into civilian institutions and cultivate supportive social networks. Poor social reintegration is associated with greater morbidity and premature mortality in part due to adoption of risky health behaviors, social isolation, and inadequate engagement in health care services. Although institutions like the Veterans Health Administration (VA) do much to address the complex psychosocial and health care needs of veterans and their families with evidence-based care, only 61% of Operations Enduring and Iraqi Freedom (OEF/OIF) Veterans are enrolled in VA care and there are numerous perceived barriers to care for enrollees. To address this gap, a community-based nonprofit organization, Team Red, White & Blue (RWB), was created to help veterans establish health-enriching social connections with communities through the consistent provision of inclusive and locally tailored physical, social, and service activities. This article provides an overview of the development and refinement of a theory-based framework for veteran health called the Enrichment Equation, comprised of three core constructs: health, people, and purpose. By operationalizing programming activities and roles, we describe how theoretical components were translated into a social networking implementation package that enabled rapid national spread of Team RWB. We conclude with future opportunities to partner with researchers and other organizations to understand program impact, and to identify effective intervention components that could be adapted for similar vulnerable groups. PMID- 30016527 TI - Introduction to the Special Section: Networks and Health Care Outcomes. PMID- 30016525 TI - A conceptual model of social networks and mechanisms of cancer mortality, and potential strategies to improve survival: an invited commentary. AB - In this article, the importance of social factors for cancer survivorship has been theoretically considered and empirically studied. This commentary and Kroenke's narrative review highlight how social network theory and methods may innovatively expand this substantive body of work. First, we add to a new understanding of cancer survivorship through: (a) discussing the delineation and differences between multiple social factors of interest across existing conceptual models; (b) characterizing their relationships to each other and to cancer survivorship through a social network lens; and (c) overall, sharing terminology and strengthening connections within this diverse body of literature. Second, we note opportunities for future research in terms of (a) simultaneous measurement of multiple social factors at different levels and (b) adaptation of designs to leverage and measure the theorized mechanisms. This commentary describes how incorporation of social network research can optimize research, practice, and policy contributions regarding cancer survival and survivorship. PMID- 30016528 TI - Epidemiology of adolescent substance use in Norfolk schools. AB - Background: The pattern of alcohol and substance use is changing, with the introduction of novel psychoactive substances, the internet as a means of acquisition and variations in drug purity and price. Alcohol and substance use among adolescents is associated with behavioural, mental health, health and social difficulties; arising at a vulnerable period in their development. Little is known about adolescent substance use in the UK, especially in rural areas. Aim: To investigate the prevalence of substance use amongst young people, aged 16 21 years, in Norfolk schools. Design: Cross sectional questionnaire survey. Method: Pupils from two, sixth form colleges in Norfolk answered a self-report questionnaire designed to measure prevalence, age of onset and frequency of use for alcohol, tobacco, illicit substances including new psychoactive substances as well as demographic data. Results: A total of 482 students completed the survey (68% participation rate). Life-time use of alcohol was reported by 442 (91.7%) students and over half the pupils had tried tobacco (52.5%, n=253). About 40.7% reported cannabis use and nearly one-fifth (18.9%, n=91) reported using 3,4 methylenedioxymethamphetamine (MDMA); 41.1% (n=198) students reported using 'any drug' and 23.2% (n=112) 'using an illicit drug other than cannabis' and 8.7% (n=42) reported the use of a novel psychoactive substance. Conclusion: The most widely used substances were alcohol, tobaccos and cannabis; in keeping with European trends. Over the past decade a decline in alcohol and drug use by adolescents has been seen in the UK. However, since 2010 this decline has slowed with an increase in substance use noted in the past 2 years. This study provides evidence to support this trend. The findings demonstrate differences between the use of substances by pupils in this Norfolk sample compared to national surveys and more urbanized areas. These regional differences can be used to assist the development of local interventions targeting substance use among adolescents. PMID- 30016529 TI - Higher Whole-Grain Intake Is Associated with Lower Risk of Type 2 Diabetes among Middle-Aged Men and Women: The Danish Diet, Cancer, and Health Cohort. AB - BACKGROUND: Type 2 diabetes is a major health concern worldwide. Whole grains and cereal fiber may offer protective effects on type 2 diabetes risk. However, few studies have been conducted in cohorts with detailed information on whole-grain cereal intakes and product types and with wide ranges of intake. Objective: We investigated the associations between whole-grain intake, including intakes of different cereal types and products, and the risk of type 2 diabetes in a population with wide and diverse whole-grain intake. Methods: We used data from the Danish Diet, Cancer, and Health cohort including 55,465 participants aged 50 65 y at baseline. Of these, 7417 participants were diagnosed with type 2 diabetes during follow-up (median: 15 y). Detailed information on the intake of whole grain products was available from a food-frequency questionnaire, and total whole grain intake and whole-grain cereal types (wheat, rye, oats) were calculated in grams per day. Associations were examined by using Cox proportional hazards models with adjustment for potential confounders. Results: Whole-grain intake was associated with an 11% and 7% lower risk of type 2 diabetes per whole-grain serving (16 g) per day for men and women, respectively [HR (95% CI)-men: 0.89 (0.87, 0.91); women: 0.93 (0.91, 0.96)]. For men, the intake of all whole-grain cereal types investigated (wheat, rye, oats) was significantly associated with a lower risk of type 2 diabetes, but only wheat and oats intake was significantly associated for women. Among the different whole-grain products, rye bread, whole grain bread, and oatmeal/muesli were significantly associated with a lower risk of type 2 diabetes for both men and women. Conclusions: In this cohort study, we found consistent associations between high whole-grain intake and lower risk of type 2 diabetes. Overall, an association was found for all different cereals and whole-grain products tested. PMID- 30016530 TI - Widespread white matter changes in post-H1N1 patients with narcolepsy type 1 and first-degree relatives. AB - Study Objectives: To assess white matter involvement in H1N1-vaccinated hypocretin deficient patients with narcolepsy type 1 (NT1) compared with first degree relatives (a potential risk group) and healthy controls. Methods: We compared four diffusion tensor imaging-based microstructural indices (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) in 57 patients with NT1 (39 females, mean age 21.8 years, 51/57 H1N1-vaccinated, 57/57 HLA-DQB1*06:02-positive, 54/54 hypocretin-deficient), 54 first-degree relatives (29 females, mean age 19.1 years, 37/54 H1N1-vaccinated, 32/54 HLA-DQB1*06:02-positive), and 55 healthy controls (38 females, mean age 22.3 years). We tested for differences between these groups, for parametric effects (controls > first-degree relatives > patients) and associations in patients (cerebrospinal fluid [CSF] hypocretin-1 and disease duration) and first degree relatives (HLA-DQB1*06:02 and H1N1-vaccination). We employed tract-based spatial statistics and used permutation testing and threshold-free cluster enhancement for inference. Results: Patients with NT1 had a widespread, bilateral pattern of significantly lower FA compared with first-degree relatives and healthy controls. Additionally, patients with NT1 also exhibited significantly higher RD and lower AD in several focal white matter clusters. The parametric model showed that first-degree relatives had intermediate values. Full sample of patients with NT1 showed no significant associations with disease duration or CSF hypocretin-1. Conclusions: Our study suggests widespread abnormal white matter involvement far beyond the already known focal hypothalamic pathology in NT1, possibly reflecting the combined effects of the loss of the widely projecting hypothalamic hypocretin neurons, and/or secondary effects of wake/sleep dysregulation. These findings demonstrate the importance of white matter pathology in NT1. PMID- 30016531 TI - Effects of Age on Emotion Regulation, Emotional Empathy, and Prosocial Behavior. AB - Objectives: The degree to which older adults experience emotional empathy and show subsequent prosocial behavior versus experience personal distress in response to another's distress remains unclear. Method: Young (n = 40; 17-29 years) and older (n = 39; 61-82 years) adults watched videos of individuals expressing pain or no pain. Pain mimicry was recorded using facial electromyography. Participants were then asked if they would spend the remaining time helping the experimenter. Self-reported tendency to suppress or reappraise emotion was assessed, as well as trait and state emotional empathy and personal distress. Results: Pain mimicry was associated with reduced trait suppression in older adults. In both age groups, greater emotional empathy, averaged across video condition, was associated with increased helping. In addition, relative to young adults, older adults reported more personal distress and emotional reactivity in response to the videos, but were just as willing to help. They also put more effort into helping. Discussion: These findings contribute to clarification of mixed previous evidence regarding the experience of emotional empathy in young versus older adulthood. We discuss the importance of considering additional subcomponents of empathy such as emotion regulation, while also accounting for the relevance of the empathy induction to each age group. PMID- 30016532 TI - [Hospital-acquired pneumonia in the light of current recommendations - is there a space for improving patient care?] AB - Hospital-acquired pneumonia (HAP) is an infection of the lung parenchyma. It is the second most frequent nosocomial infection and the leading cause of death from infection in critically ill patients. Hospital-acquired and, particularly, ventilator-associated pneumonia prolong the hospital stay and increase treatment costs. The clinical signs of pneumonia are rather non-specific, with limited possibilities to distinguish the lung condition from other nosological entities. The yield, effectiveness and cost of new rapid diagnostic procedures as well as early biochemical markers specific for pneumonia have not been sufficiently verified and clinical translation of technological innovations is slow. In bedside clinical practice, the diagnosis continues to be based on clinical examination together with imaging methods, most frequently X-ray. The spectrum of etiologic agents changes, with an increase in the prevalence of multidrug resistant (MDR) bacterial pathogens. Initial antibiotic therapy, particularly in critically ill ventilated patients, needs to include broad-spectrum agents due to the risk of the presence of MDR bacteria. The likelihood of successful treatment may be increased by regular updates of recommendations for adequate initial antibiotherapy with regard to the epidemiological situation and knowledge of bacterial resistance to antimicrobials in a particular hospital and region. As part of the current valid guidelines, recommendation were newly translated; however, their level of evidence is often very low and the strength of recommendation is mostly weak or moderate. Their benefit to everyday practice is questionable. The article points to changes brought about by the recent European guidelines published in fall 2017 and summarizes current issues concerning HAP pathogens in intensive care units in the Czech Republic. PMID- 30016533 TI - [A Case of a patient with AIDS and pneumocystis pneumonia complicated by cytomegalovirus pneumonitis]. AB - We report a case of a 39-year-old male admitted for respiratory failure. On admission, the patient was diagnosed with advanced HIV infection and Pneumocystis jirovecii pneumonia (PJP). The patient's condition improved following specific PJP therapy but then deteriorated. The patient was subsequently diagnosed with cytomegalovirus pneumonitis and treated with ganciclovir. The severe course of both opportunistic infections required long-term care at an intensive care unit. Despite complications, the patient was discharged after 108 inpatient days in a stable clinical condition. The case demonstrates a rare coincidence of PJP and cytomegalovirus pneumonitis while also emphasizing the importance of correct diagnosis, treatment and interdisciplinary care which, despite poor prognosis, may lead to successful cure of serious simultaneous opportunistic infections in AIDS. PMID- 30016534 TI - [Lethal course of complicated vascular prosthesis infections]. AB - Presented are two cases of vascular prosthesis infections complicated by peritonitis with a lethal course. The authors describe complicated antibiotic therapy with findings, exhausted options for surgical therapy and subsequent decision that the condition was untreatable and palliative care was initiated. PMID- 30016535 TI - [Anti-NMDAR encephalitis as a serious adverse event probably related to yellow fever vaccination]. AB - We present a case of a 17-year-old female with anti-NMDAR encephalitis probably associated with vaccination against yellow fever. Her symptoms occurred 27 days after vaccination against yellow fever. Anti-NMDAR encephalitis manifested as acute psychosis, memory loss and catatonia following fever with complex partial epileptic seizures. Interictal electroencephalogram showed slow-wave delta background activity with "delta brushes". The diagnosis was confirmed by NMDAR antibody positivity in serum and cerebrospinal fluid. Since ovarian teratoma, as the most common cause of anti-NMDAR encephalitis, did not develop within five years from its onset, the association with vaccination against yellow fever seems to be highly probable. PMID- 30016536 TI - [Diagnosis, treatment and prophylaxis of malaria in the Czech Republic]. AB - Malaria represents the most important parasitic infection imported from the tropics causing death in 1-2 % of travelers with this diagnosis. Around 30 cases of malaria are diagnosed in the Czech Republic every year. Fever is the most common clinical presentation. The most severe forms of malaria are caused by Plasmodium falciparum. The diagnosis of malaria is based on examination of stained thick and thin blood smears. This method enables determination of Plasmodium species and parasite count. The treatment of ma-laria has to be initiated immediately after the laboratory confirmation. In the Czech Republic, uncomplicated falciparum malaria is treated by oral administration of artemether/lumefantrine or atovaquone/proguanil. Complicated falciparum malaria is treated by parenteral administration of quinine in combination with clindamycin. For the chemoprophylaxis of malaria in travelers to the highly endemic regions, atovaquone/proguanil, doxycycline or mefloquine are recommended. PMID- 30016537 TI - Superior protein titers in half the fermentation time: Promoter and process engineering for the glucose-regulated GTH1 promoter of Pichia pastoris. AB - Protein production in Pichia pastoris is often based on the methanol-inducible P AOX1 promoter which drives the expression of the target gene. The use of methanol has major drawbacks, so there is a demand for alternative promoters with good induction properties such as the glucose-regulated P GTH1 promoter which we reported recently. To further increase its potential, we investigated its regulation in more details by the screening of promoter variants harboring deletions and mutations. Thereby we could identify the main regulatory region and important putative transcription factor binding sites of P GTH1 . Concluding from that, yeast metabolic regulators, monomeric Gal4-class motifs, carbon source responsive elements, and yeast GC-box proteins likely contribute to the regulation of the promoter. We engineered a P GTH1 variant with greatly enhanced induction properties compared with that of the wild-type promoter. Based on that, a model-based bioprocess design for high volumetric productivity in a limited time was developed for the P GTH1 variant, to employ a glucose fed-batch strategy that clearly outperformed a classical methanol fed-batch of a P AOX1 strain in terms of titer and process performance. PMID- 30016538 TI - A novel homozygous frame-shift variant in the LHCGR gene is associated with primary ovarian insufficiency in a Pakistani family. PMID- 30016539 TI - Head circumference at birth and neurodevelopmental disorders: Where do we go from here? PMID- 30016540 TI - Vaginal preparation with antiseptic solution before cesarean section for preventing postoperative infections. AB - BACKGROUND: Cesarean delivery is one of the most common surgical procedures performed by obstetricians. Infectious morbidity after cesarean delivery can have a tremendous impact on the postpartum woman's return to normal function and her ability to care for her baby. Despite the widespread use of prophylactic antibiotics, postoperative infectious morbidity still complicates cesarean deliveries. This is an update of a Cochrane review first published in 2010 and subsequently updated in 2012, and twice in 2014. OBJECTIVES: To determine if cleansing the vagina with an antiseptic solution before a cesarean delivery decreases the risk of maternal infectious morbidities, including endometritis and wound complications. We also assessed the side effects of vaginal cleansing solutions to determine adverse events associated with the intervention. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 July 2017), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomized trials and one quasi-randomized trial assessing the impact of vaginal cleansing immediately before cesarean delivery with any type of antiseptic solution versus a placebo solution/standard of care on post cesarean infectious morbidity. Cluster-randomized trials were eligible for inclusion but none were identified. We excluded trials that utilized vaginal preparation during labor or that did not use antibiotic surgical prophylaxis. We also excluded any trials using a cross-over design. DATA COLLECTION AND ANALYSIS: At least three of the review authors independently assessed eligibility of the studies. Two review authors were assigned to extract study characteristics, quality assessments, and data from eligible studies. MAIN RESULTS: We included 11 trials reporting results for 3403 women evaluating the effects of vaginal cleansing (eight using povidone-iodine, two chlorhexidine, one benzalkonium chloride) on post-cesarean infectious morbidity. Additionally, some trials used vaginal preparations using sponge sticks, douches, or soaked gauze wipes. The control groups were typically no vaginal preparation (eight trials) or the use of a saline vaginal preparation (three trials). The risk of bias in the studies reduced our confidence in the results for endometritis outcomes.Vaginal preparation with antiseptic solution immediately before cesarean delivery probably reduces the incidence of post-cesarean endometritis from 8.7% in control groups to 3.8% in vaginal cleansing groups (average risk ratio (RR) 0.36, 95% confidence interval (CI) 0.20 to 0.63, 10 trials, 3283 women, moderate quality of evidence). Subgroup analysis could not rule out larger reductions in endometritis with antiseptics in women who were in labor or in women whose membranes had ruptured when antiseptics were used. Risks of postoperative fever and postoperative wound infection may be slightly lowered by antiseptic preparation, but the confidence intervals around the effects for both outcomes are consistent with a large reduction in risk and no difference between groups (fever: RR 0.87 (0.72 to 1.05; wound infection: RR 0.74 (95% CI 0.49 to 1.11), both moderate quality evidence). Two trials reported a lower risk of a composite outcome of wound complication or endometritis in women receiving preoperative vaginal preparation (RR 0.46, 95% CI 0.26 to 0.82, two trials, 499 women, moderate quality evidence). No adverse effects were reported with either the povidone iodine or chlorhexidine vaginal cleansing. AUTHORS' CONCLUSIONS: Vaginal preparation with povidone-iodine or chlorhexidine solution compared to saline or not cleansing immediately before cesarean delivery probably reduces the risk of post-cesarean endometritis. Subgroup analysis could not rule out larger reductions in endometritis with antiseptics in women who were in labor or in women whose membranes had ruptured when antiseptics were used.The quality of the evidence using GRADE was moderate for all reported outcomes. We downgraded the outcome of post-cesarean endometritis and composite of wound complications or endometritis for risk of bias and postoperative fever and postoperative wound infections for wide CIs.As a simple, generally inexpensive intervention, providers may consider implementing preoperative vaginal cleansing with povidone iodine or chlorhexidine before performing cesarean deliveries. PMID- 30016541 TI - Intravaginal practices and genital human papillomavirus infection among female sex workers in Cambodia. AB - OBJECTIVES: Intravaginal practices (IVPs) include washing, wiping, or inserting something inside the vagina. This study investigates the associations between IVPs and genital human papillomavirus (HPV) infection. METHODS: We conducted a cross-sectional study of 200 female sex workers aged 18 to 35 years in Phnom Penh, Cambodia. From August to September 2014. Data on sociodemographic characteristics, IVPs, and other behaviors were collected through face-to-face interviews. Self-collected cervicovaginal specimens were tested for 37 HPV genotypes. RESULTS: Multivariable Poisson regression models showed that a lower number of infecting HPV genotypes were associated with intravaginal washing in the past 3 months (incident rate ratios [IRR] = 0.65, 95% confidence interval [CI]: 0.46-0.94) and often performing intravaginal washing shortly after sex (IRR = 0.89, 95% CI: 0.81-0.99). Intravaginal washing before vaginal sex, intravaginal wiping, and intravaginal insertion were not associated with HPV infection. CONCLUSION: These findings challenge the existing view that all types of vaginal cleansing are harmful. Specifically, intravaginal washing shortly after sex (mainly with water) may help prevent HPV infection in female sex workers, who have several partners and thus frequently expose to sources of HPV infection with different genotypes. PMID- 30016542 TI - Age-related changes in hepatic expression and activity of drug metabolizing enzymes in male wild-type and breast cancer resistance protein knockout mice. AB - This study aimed to reveal age-related changes in the expression and activity of seven hepatic drug metabolizing enzymes (DMEs) in male wild-type and breast cancer resistance protein knockout (Bcrp1-/- ) FVB mice. The protein expression of four cytochrome P450 (Cyps) (Cyp3a11, 2d22, 2e1, and 1a2), and three UDP glucuronosyltransferases (Ugts) (Ugt1a1, 1a6a, and 1a9) in liver microsomes of wild-type and Bcrp1-/- FVB mice at different ages were determined using a validated ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method. The activities and mRNA levels of these DMEs were measured using the probe substrates method and real-time PCR, respectively. In the liver of wild-type FVB mice, Cyp3a11, 2d22, 2e1, 1a2, Ugt1a1, and 1a6a displayed maximum protein levels at 6-9 weeks of age. Cyp1a2, Ugt1a1, 1a6a, and 1a9 showed maximum activities at 6-9 weeks of age, whereas Cyp3a11, 2d22, and 2e1 showed maximum activities in 1-3-week-old mice. Additionally, most of the DMEs showed maximum mRNA levels in 17-week-old mice liver. Compared with wild-type FVB mice, the protein levels of these DMEs showed no significant changes in Bcrp1-/- FVB mice liver. However, the activity of Cyp2e1 was increased and that of Cyp2d22 was decreased. In conclusion, the seven hepatic DMEs in FVB mice liver showed significant alterations in an isoform-specific manner with increased age. Although the protein levels of these DMEs showed no significant changes, the activities of Cyp2e1 and 2d22 were changed in Bcrp1-/- mice. PMID- 30016543 TI - Proficiency testing for the detection of Middle East respiratory syndrome coronavirus demonstrates global capacity to detect Middle East respiratory syndrome coronavirus. AB - The first reported case of Middle East respiratory syndrome coronavirus (MERS CoV) infection was identified in Saudi Arabia in September 2012, since which time there have been over 2000 laboratory-confirmed cases, including 750 deaths in 27 countries. Nucleic acid testing (NAT) is the preferred method for the detection of MERS-CoV. A single round of a Proficiency Testing Program (PTP) was used to assess the capability of laboratories globally to accurately detect the presence of MERS-CoV using NAT. A panel of eleven lyophilized specimens containing different viral loads of MERS-CoV, common coronaviruses, and in vitro RNA transcripts was distributed to laboratories in all six World Health Organization regions. A total of 96 laboratories from 79 countries participating in the PTP, with 76 of 96 (79.2%) reporting correct MERS-CoV results for all nine scored specimens. A further 10 laboratories (10.4%) scored correctly in eight of nine specimens of the PTP. The majority of laboratories demonstrated satisfactory performance in detecting the presence of MERS-CoV using NAT. However, some laboratories require improved assay sensitivity, reduced cross contamination of samples, and improved speciation of coronavirus subtypes for potentially complex clinical specimens. Further PTP and enhanced links with expert laboratories globally may improve the laboratory performance. PMID- 30016545 TI - Foetal ultrasound measurement imputations based on growth curves versus multiple imputation chained equation (MICE). AB - BACKGROUND: Ultrasound measures are valuable for epidemiologic studies of risk factors for growth restriction. Longitudinal measurements enable investigation of rates of change and identification of windows where growth is impacted more acutely. However, missing data can be problematic in these studies, limiting sample size, ability to characterise windows of vulnerability, and in some instances creating bias. We sought to compare a parametric linear mixed model (LMM) approach to multiple imputation in this setting with multiple imputation by chained equation (MICE) methodology. METHODS: Ultrasound scans performed for clinical purposes were abstracted from women in the LIFECODES birth cohort (n = 1003) if they were close in time to three study visits (median 18, 26, and 35 weeks' gestation). We created imputed datasets using LMM and MICE and calculated associations between demographic factors and ultrasound parameters cross sectionally and longitudinally. Results were compared with a complete-case analysis. RESULTS: Most participants had ultrasounds at 18 weeks' gestation, and ~50% had measurements at 26 and 35 weeks; 100% had birthweight. Associations between demographic factors and ultrasound measures were similar in magnitude, but more precise, when either imputed datasets were used, compared with a complete-case analysis, in both the cross-sectional or longitudinal analyses. CONCLUSIONS: MICE, though ignoring the non-linear features of the trajectory and within subject correlation, is able to provide reasonable imputation of foetal growth data when compared to LMM. Because it simultaneously imputes missing covariate data and does not require specification of variance structure as in LMM, MICE may be preferable for imputation in this setting. PMID- 30016544 TI - Synthesis, Structure and Application of Intramolecularly-Coordinated Gallium Chalcogenides: Suitable Single-Source precursors for Gax Sey Materials. AB - Studies have been focused on the synthesis of N->Ga-coordinated organogallium selenides and tellurides [L1 Ga(MU-Se)]2 (1), [L2 Ga(MU-Se)]2 (2) and [L1 Ga(MU Te)]2 (3), respectively, containing either N,C,N- or C,N-chelating ligands L1, 2 (L1 is {2,6-(Me2 NCH2 )2 C6 H3 }- and L2 is {2-(Et2 NCH2 )-4,6-tBu2 -C6 H2 }- ) having Ga/E (E=Se or Te) atoms in 1/1 ratio. To change the Ga/E ratio, an unusual N->Ga-coordinated organogallium tetraselenide L1 Ga(kappa2 -Se4 ) (4) was prepared. An unprecedented complex (L1 Ga)2 (MU-Te2 )(MU-Te) (5), as the result of the non-stability of 3, was also isolated. Compound 2 is a suitable single source precursor for the preparation of amorphous GaSe thin films by the spin coating. Moreover, simple heating of an octadecylamine solution of 2 provided, after work up, monoclinic Ga2 Se3 crystals with different crystallinity according to conditions used. Therefore, compound 2 may be also used as a source of Ga2 Se3 in the low-temperature doping process of Bi2 Se3 . PMID- 30016546 TI - Bridging the micro- and macroevolutionary levels in phylogenomics: Hyb-Seq solves relationships from populations to species and above. AB - Reconstructing phylogenetic relationships at the micro- and macroevoutionary levels within the same tree is problematic because of the need to use different data types and analytical frameworks. We test the power of target enrichment to provide phylogenetic resolution based on DNA sequences from above species to within populations, using a large herbarium sampling and Euphorbia balsamifera (Euphorbiaceae) as a case study. Target enrichment with custom probes was combined with genome skimming (Hyb-Seq) to sequence 431 low-copy nuclear genes and partial plastome DNA. We used supermatrix, multispecies-coalescent approaches, and Bayesian dating to estimate phylogenetic relationships and divergence times. Euphorbia balsamifera, with a disjunct Rand Flora-type distribution at opposite sides of Africa, comprises three well-supported subspecies: western Sahelian sepium is sister to eastern African-southern Arabian adenensis and Macaronesian-southwest Moroccan balsamifera. Lineage divergence times support Late Miocene to Pleistocene diversification and climate-driven vicariance to explain the Rand Flora pattern. We show that probes designed using genomic resources from taxa not directly related to the focal group are effective in providing phylogenetic resolution at deep and shallow evolutionary levels. Low capture efficiency in herbarium samples increased the proportion of missing data but did not bias estimation of phylogenetic relationships or branch lengths. PMID- 30016548 TI - Granulocyte colony-stimulating factors and aortitis: A rare adverse event. PMID- 30016547 TI - Serum ALT elevations in survivors of childhood cancer. A report from the St. Jude Lifetime Cohort Study. AB - : Background and Rationale for Study: To define the prevalence of and risk factors for elevated serum alanine aminotransferase (ALT) level among adult childhood cancer survivors (CCS). PATIENTS AND METHODS: 2751 CCS from the St. Jude Lifetime Cohort Study (>10 years post-diagnosis, age >=18 years). Serum ALT level graded using the Common Terminology Criteria for Adverse Events v 4.03. Modified Poisson regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association between demographic and clinical factors and grades 1 - 4 ALT on the selected models. MAIN RESULTS: 1339 (48.7%) of CCS were female; 2271 (82.6%) were non-Hispanic white. Median age at evaluation was 31.4 years (Interquartile Range (IQR) = 25.8 - 37.8); median elapsed time from diagnosis to evaluation was 23.2 years (IQR = 17.6 - 29.7). 1137 (41.3%) had ALT > Upper Limit of Normal [Common Terminology Criteria for Adverse Events v 4.03 - Grade 1 - 1058 (38.5%); Grade 2 - 56 (2.0%); Grade 3 - 23 (0.8%); Grade 4 - none]. Multivariable models demonstrated non-Hispanic white race/ethnicity, age at evaluation in years, being overweight or obese, presence of the metabolic syndrome, current treatment with atorvastatin or rosuvastatin or simvastatin, hepatitis C virus infection, prior treatment with busulfan or thioguanine, history of hepatic surgery, and the percentage of liver treated with >= 10 Gray, >= 15 Gray, or >= 20 Gray were associated with elevated ALT. CONCLUSION: Grade 3 or 4 hepatic injury is infrequent in CCS. Mild hepatic injury in this group may be amenable to lifestyle modifications. This article is protected by copyright. All rights reserved. PMID- 30016549 TI - Serum free light chain measurements to reduce 24-h urine monitoring in patients with multiple myeloma with measurable urine monoclonal protein. AB - Detection of myeloma progression (PD) relies on serial 24-h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24-h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55 312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase >= 25%, 94% had absolute increase in dFLC > 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC (n = 118), 89% had increase in dFLC >= 25%, 97% had dFLC increase of > 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24-h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of >10 mg/dL from the nadir, a 24-h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria. PMID- 30016550 TI - Survival following right lobe split graft, living- and deceased-donor liver transplantation in adult patients: a systematic review and network meta-analysis. AB - Graft and patient survival outcomes following split liver transplantation (SLT), living-donor liver transplantation (LDLT) and deceased-donor liver transplantation (DDLT) were estimated using Bayesian network meta-analysis. Databases were searched for relevant articles over the previous 20 years (MEDLINE, Embase, Cochrane Library and Google Scholar). Systematic review, pairwise meta-analysis and Bayesian network meta-analysis were performed. Pairwise meta-analysis demonstrated that there were no significant differences in graft and patient survival outcomes. Consequently, Bayesian network meta-analysis demonstrated no significant differences in 1-, 3- and 5-year graft and patient survival between the three alternative liver transplantations. No discrepancies were demonstrated after comparisons of direct and indirect evidence of 1-, 3- and 5-year patient and graft survival of the three node-split models namely SLT, LDLT and DDLT. The 1-, 3- and 5-year graft and patient survival of the SLT and LDLT cohorts compared to the DDLT cohort demonstrated no significant differences. The direct and indirect evidence of this study can serve as comparator for future studies. PMID- 30016551 TI - ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice. AB - KEY POINTS: ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy. ABSTRACT: The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy. PMID- 30016553 TI - Lenalidomide combined with mismatched microtransplantation for acute myeloid leukemia. PMID- 30016552 TI - Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. AB - CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28 day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged >=75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure. PMID- 30016554 TI - A response by Strauss et al. to "a comment on the comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia". PMID- 30016555 TI - Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C. AB - BACKGROUND: Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. METHODS: Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. RESULTS: The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for >=3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV treated patients. CONCLUSION: Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy. PMID- 30016556 TI - Cycloaddition versus Cleavage of the C=S Bond of Isothiocyanates Promoted by Digallane Compounds with Noninnocent alpha-Diimine Ligands. AB - Whereas the chemistry of single-bond activation by compounds of the main group elements has undergone some development in recent years, the cleavage of multiple bonds remains underexplored. Herein, the reactions of two digallanes bearing alpha-diimine ligands, namely, [L1 Ga-GaL1 ] (1, L1 =dpp-dad=[(2,6-iPr2 C6 H3 )NC(CH3 )]2 ) and [L2 Ga-GaL2 ] (2, L2 =dpp-bian=1,2-[(2,6-iPr2 C6 H3 )NC]2 C10 H6 ), with isothiocyanates are reported. Reactions of 1 or 2 with isothiocyanates in 1:2 molar ratio proceeded with [2+4] cycloaddition of the C=S bond across the C2 N2 Ga metallacycle with formation of C-C and S-Ga single bonds to afford [L1 (RN=C-S)Ga-Ga(S-C=NR)L1 ] (3, R=Me; 4, R=Ph) and [L2 (RN=C-S)Ga-Ga(S-C=NR)L2 ] (8, R=allyl; 9, R=Ph). In the cases of 8 and 9, this cycloaddition is reversible. The digallanes reacted with 2 equiv of PhNCS in the presence of Na metal or at high temperatures through a unique reductive cleavage of the C=S bond to yield the disulfide-bridged digallium species [Na(THF)3 ]2 [L1 Ga(MU-S)2 GaL1 ] (5), [L2 Ga(MU-S)2 GaL2 ] (10), and [Na(DME)3 ][L2 Ga(MU-S)2 GaL2 ] (11). Moreover, products 4 and 5 can further react with an excess of isothiocyanate, through cleavage of the C=S bond or cycloaddition, to give the bis- or mono-S-bridged complexes [Na(THF)2 ]2 [L1 (PhN=C-S)Ga(MU-S)2 Ga(S-C=NPh)L1 ] (6) and [L1 (PhN=C S)Ga(MU-S)Ga(S-C=NPh)L1 ] (7). All the newly prepared compounds were characterized by elemental analysis, single-crystal X-ray diffraction, IR spectroscopy, NMR (3-9) or ESR spectroscopy (11), and DFT calculations. PMID- 30016557 TI - Programmed cell death-1 3'-untranslated region polymorphism is associated with spontaneous clearance of hepatitis B virus infection. AB - Hepatitis B virus (HBV)-specific CD8+ T cells play an important role in the clearance of HBV infection. Programmed cell death-1 (PD-1), an immunosuppressive molecule that regulates T-cell activation and peripheral immune tolerance, is increasingly shown to influence the outcome of HBV infection. rs10204525, a single-nucleotide polymorphism in the 3'-untranslated region (3'-UTR) of PD-1, has been associated with susceptibility and disease progression of chronic HBV infection in far-eastern patients. The aim of our study was to assess the impact of rs10204525 variation on HBV infection in Moroccan patients. A total of 236 patients with chronic HBV infection and 134 individuals with spontaneous HBV resolution were genotyped using a Taqman assay. In addition, PD-1 mRNA expression in peripheral blood nuclear cells was determined by quantitative reverse transcription polymerase chain reaction. We found that the AA genotype is protective (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.97; P = 0.038) against HBV infection. Interestingly, PD-1 messenger RNA (mRNA) expression analysis has revealed that chronic HBV carriers with GG and GA displayed higher levels of PD-1 mRNA compared with corresponding genotypes in resolved subjects (P = 0.031 and 0.014, respectively). Our data suggest that Mediterranean HBV infected patients carrying PD-1 GG and GA genotypes at rs10204525 have high PD-1 mRNA expression and may be more prone to installation of chronicity. PMID- 30016558 TI - Alkylating Reagents Employed in Catellani-Type Reactions. AB - The Catellani reaction is a powerful strategy that allows the expeditious synthesis of highly substituted arenes, which are not easily accessible through traditional transition-metal-catalyzed cross-coupling reactions. This reaction utilizes the synergistic interplay of palladium and norbornene catalysis to facilitate sequential ortho-C-H functionalization and ipso termination of aryl iodides in a single operation. Since pioneering work by the group of Catellani in 1997, and later by the group of Lautens, this chemistry has attracted considerable attention from the synthetic chemistry community. Dramatic progress has been made by a number of groups in the past two decades. In this Minireview, the alkylating reagents employed in this intriguing reaction and the corresponding applications in organic synthesis are summarized; thus complementing existing reviews to inspire future developments. PMID- 30016559 TI - Thermodynamic Programming of Erbium(III) Coordination Complexes for Dual Visible/Near-Infrared Luminescence. AB - Intrigued by the unexpected room-temperature dual visible/near-infrared (NIR) luminescence observed for fast-relaxing erbium complexes embedded in triple stranded helicates, in this contribution, we explore a series of six tridentate N donor receptors L4-L9 with variable aromaticities and alkyl substituents to extricate the stereoelectronic features responsible for such scarce optical signatures. Detailed solid-state (X-ray diffraction, differential scanning calorimetry, optical spectroscopy) and solution (speciations and thermodynamic stabilities, spectrophotometry, NMR and optical spectroscopy) studies of mononuclear unsaturated [Er(Lk)2 ]3+ and saturated triple-helical [Er(Lk)3 ]3+ model complexes reveal that the stereoelectronic changes induced by the organic ligands affect inter- and intramolecular interactions to such an extent that 1) melting temperatures in solids, 2) the affinity for trivalent erbium in solution, and 3) optical properties in luminescent complexes can be rationally varied and controlled. With this toolkit in hand, mononuclear erbium complexes with low stabilities displaying only NIR emission can be transformed into molecular-based dual Er-centered visible/NIR emitters operating at room temperature in both solid and solution states. PMID- 30016560 TI - HULC and 7SL RNA expression levels in patients with Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the Crimean-Congo hemorrhagic fever virus. Long non-coding RNAs (lncRNAs) are generally classified as transcripts longer than 200 nucleotides (nt). The various lncRNAs expressed in infected cells are responsible for regulating the expression of viral and host genes. This is the first study to investigate hepatocellular carcinoma upregulated long non-coding RNA (HULC) and 7SL RNA expression levels in patients with CCHF. Blood samples were taken from 100 individuals (60 patients and 40 controls), and total RNA isolation was performed. Quantitative polymerase chain reaction (qPCR) was performed using the SYBR Green method to determine HULC and 7SL RNA expression levels in the study population. Compared the patient and control groups, HULC was upregulated statistically significantly (P = 0.04) and 7SL RNA was downregulated (P = 0.93) in patients. Also, there was a statistically significant difference between fatal cases and surviving patients for HULC and 7SL RNA (P < 0.01 and P = 0.03, respectively). In addition, HULC expression was increased statistically significantly in fatal cases compared with surviving patients in terms of clinical parameters such as aspartate aminotransferase (P < 0.01), alanine aminotransferase (P < 0.01), international normalized ratio (P = 0.05), prothrombin time (P = 0.01), active partial thromboplastin time (P < 0.01), and lactate dehydrogenase (P < 0.01). These findings highlighted that HULC and 7SL RNA could be important mediators for studying the pathogenesis of CCHF and significant therapeutic targets of the disease. PMID- 30016561 TI - Three Silver Nests Capped by Thiolate/Phenylphosphonate. AB - Introducing phenylphosphonic acid (H2 PPA) into the Ag/tBuSH assembly system has produced a family of nanoscale-sized, high-atom number, silver thiolate/PPA nests (SD/Ag45 a, SD/Ag66 a, and SD/Ag73 a) with impressive core-shell features. SD/Ag45 a is a 45-atom ellipsoid comprised of an Ag36 shell trapping an Ag9 S2 three-bladed rotor inside. SD/Ag66 a comprises an inner rod-like Ag20 core and an outer Ag44 shell, giving a 64-atom nest. These Ag64 nests are further extended by Ag(CN)2 linkers to form a one-dimensional chain structure. SD/Ag73 a is a three shell 73-nucleus silver nest with a central silver atom enclosed in a rhombicuboctahedron of 24 silver atoms, which is itself enclosed in the outermost shell of a rectified version of a 48-Ag octahedral Goldberg 2,0 cage. The solution behaviors and optical absorption properties of the three nests are described in detail. Of note, SD/Ag45 a and SD/Ag73 a emit in the near-infrared region and show different luminescent thermochromic behavior. This work demonstrates that the participation of H2 PPA strongly influences the structures of silver thiolate nests, thus providing a new route to fabricate and modify them in a more rational way. PMID- 30016562 TI - Heterocyclization and Spirocyclization Processes Based on Domino Reactions of N Tosylhydrazones and Boronic Acids Involving Intramolecular Allylborylations of Nitriles. AB - Polycyclic molecules featuring all-carbon quaternary bridgehead centers were synthesized through domino cyclizations between N-tosylhydrazones and boronic acids. Variations of the general cascade have been applied for the preparation of 3-quinuclidinones and related alkaloid-like scaffolds through transannular heterocyclizations. Moreover, the employment of 3-cyanopropyl and 4 cyanobutylboronic acids and alpha,beta-unsaturated N-tosylhydrazones led to spirocycles through unprecedented formal [n+1] cyclizations, including the stereoselective spirocyclization of the Hajos-Parrish ketone. The common feature of all the new reactions described is the creation of an all-carbon quaternary center by formation of two Csp3 -C bonds on the hydrazonic carbon atom. DFT-based calculations suggested the occurrence of cascade processes, which involve a diazo compound carboborylation followed by a 1,3-borotropic rearrangement on an intermediate allylboronic acid and a novel bora-aza-ene cyclization. PMID- 30016563 TI - Pressure-Induced Spin-Crossover Features at Variable Temperature Revealed by In Situ Synchrotron Powder X-ray Diffraction. AB - An accurate high-pressure X-ray diffraction investigation, at various temperatures, on a powder of a spin-crossover (SCO) complex has allowed the rare deconvolution of the structural features of the high-spin and low-spin phases. As a result, the pressure dependence of the structural parameters of the high-spin and low-spin phases can be discussed independently in the pressure domain where both phases co-exist within the powder. Consequently, crucial unprecedented information is given, such as the variation of bulk moduli with temperature, similar here in amplitude for both spin phases, the temperature-dependence of the pressure-induced SCO abruptness, the temperature dependence of the pressure at which SCO occurs, and arguments for a possible piezo-hysteresis. Performed on the molecular complex [Fe(PM-PeA)2 (NCSe)2 ] (PM-PeA=N-(2'-pyridylmethylene)-4 (phenylethynyl) aniline), this study reveals a pressure-induced SCO at 0.16 GPa and demonstrates that, when increasing temperature, the pressure of transition increases linearly, the abruptness of the pressure-induced SCO strongly increases, and the bulk moduli decrease. PMID- 30016564 TI - NHC-Catalyzed Electrophilic Trifluoromethylation: Efficient Synthesis of gamma Trifluoromethyl alpha,beta-Unsaturated Esters. AB - Described herein is a highly regioselective and efficient N-heterocyclic-carbene catalyzed gamma-trifluoromethylation of vinylogous enolates. Control experiments and DFT calculations provided important insight into the reaction mechanism. PMID- 30016565 TI - Improving the handover and transport of critically ill pediatric patients. AB - AIMS AND OBJECTIVES: The aims of this project were to (a) determine barriers to current handover and transport process, (b) develop a new protocol and process for team-to-team handover, and (c) evaluate staff satisfaction with the new process. BACKGROUND: The handover and transport of critically ill patients from the paediatric emergency department to the paediatric intensive care unit is a period of vulnerability associated with adverse events. DESIGN: A mixed-methods study using a quasi-experimental design and qualitative approach. METHODS: Focus groups were conducted to determine the barriers and facilitators of the current handover and transport process. Using these themes, a multidisciplinary team developed and implemented a new process including establishment of eight patient criteria for specialised transport and a standardised, interdisciplinary handover tool for team-to-team handover. Staff satisfaction was examined pre- and postintervention. RESULTS: Content analysis of focus groups revealed five categories: need for improved communication, cultural dissonance among units, defects in system and processes, need for standardisation and ambiguity between providers regarding acuity. Staff members reported improvements in their perceptions of satisfaction, safety, communication and role understanding associated with the new process. CONCLUSIONS: Standardisation through the establishment of severity of illness criteria and communication tools creates shared mental models and decreases risks to safety. A paradigm shift of team-to team handover and transport is recommended. RELEVANCE TO CLINICAL PRACTICE: This paper suggests the importance of improving communication during the handover and transport process through establishing standardised patient severity of illness criteria, use of standardised tools and team-to-team handover processes. PMID- 30016566 TI - Metal-Organic Layers Catalyze Photoreactions without Pore Size and Diffusion Limitations. AB - Metal-organic frameworks (MOFs) have emerged as promising single-site solid catalysts for organic reactions. However, MOF catalysts suffer from pore size limitation and slow diffusion, which are detrimental for photoreactions. Metal organic layers (MOLs) have unique ultrathin 2D monolayer structures and overcome pore size and diffusion limitations. Here, the synthesis of photoactive Zr-RuBPY MOL based on Zr-oxo clusters and [Ru(bpy)3 ]2+ -containing linkers is reported as well as its application in photocatalytic [2+2] cyclizations of enones and Meerwein addition reactions between aryl diazonium salts, styrenes, and nitriles. PMID- 30016567 TI - Genetic Manipulation of Cryptococcus neoformans. AB - Cryptococcus neoformans is an opportunistic fungal pathogen, which causes life threatening meningoencephalitis in immunocompromised individuals and is responsible for more than 1,000,000 infections and 600,000 deaths annually worldwide. Nevertheless, anti-cryptococcal therapeutic options are limited, mainly because of the similarity between fungal and human cellular structures. Owing to advances in genetic and molecular techniques and bioinformatics in the past decade, C. neoformans, belonging to the phylum basidiomycota, is now a major pathogenic fungal model system. In particular, genetic manipulation is the first step in the identification and characterization of the function of genes for understanding the mechanisms underlying the pathogenicity of C. neoformans. This unit describes protocols for constructing target gene deletion mutants using double-joint (DJ) PCR, constitutive overexpression strains using the histone H3 gene promoter, and epitope/fluorescence protein-tagged strains in C. neoformans. (c) 2018 by John Wiley & Sons, Inc. PMID- 30016568 TI - Wilson cell origin for kupffer's vesicle in the zebrafish. AB - BACKGROUND: Bilaterally symmetric animals have evolved highly reproducible asymmetries between left and right. In teleosts, Kupffer's vesicle, the structure necessary for the determination of left-right asymmetry, is derived from a group of cells in the gastrula termed the dorsal forerunners. RESULTS: Wilson cells are a ring of marginal enveloping layer cells that are cytoplasmically connected to the yolk cell and thus the last blastomeres to inherit yolk cell cytoplasm. Afterward, they collapse into the yolk to form the yolk syncytial layer. Without exception, forerunner cells are the progeny of dorsal Wilson cells. At the beginning of gastrulation, these Wilson cell progeny ingress beneath the enveloping layer, transform into Kupffer's vesicle, and eventually become tail notochord and muscle. Before ingressing, the forerunner precursor cells express endodermal promoting genes and require high-levels of Nodal signaling. CONCLUSIONS: Despite a derived function of the enveloping layer as an epithelium covering the entire embryo, its dorsal margin retains many behaviors of what might be expected of the dorsal superficial layers of the ancestral fish embryo, including an early program of endodermal development, cell ingression, and an eventual contribution of cells to caudal notochord and muscle, as well as the control of laterality. Developmental Dynamics 247:1057-1069, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30016569 TI - Conceptions of professional work in contemporary health care-Perspectives from registered nurses in somatic care: A phenomenographic study. AB - AIMS AND OBJECTIVES: To explore the variation of registered nurses' conceptions of the professional work in contemporary somatic health care. BACKGROUND: The turnover of registered nurses has consistently been high in recent years. This implies that competence is at risk of disappearing from patient care, which might lead to an increase in organisational costs and a decreased quality of care. Therefore, management at all levels within healthcare organisations is trying to find ways to make use of available nursing resources more efficiently. This could imply new views on nurses' professional work in future. DESIGN: Qualitative design with a phenomenographic approach. METHODS: Semistructured interviews with registered nurses in somatic care. RESULT: Four descriptive categories emerged: registered nurse as an expert in nursing, registered nurse as a close collaborator to the patients, registered nurse as a coordinator and leader and registered nurse as an administrator. CONCLUSIONS: The registered nurses' conception of their work is being experts in nursing and having a key role in leading the care forward. They perceive that they are important in coordinating the care to guarantee that the patient receives the right competence. Registered nurses perceive their work to be most important when working in close interaction with the patients, whereas the organisation is perceived as an obstacle to achieve this. RELEVANCE TO CLINICAL PRACTICE: This result may be a contribution to understand what registered nurses conceive is their work. The result can also help identifying factors influencing registered nurses intent to stay. Thus, it is of importance for managers to involve the professionals in the development of clinical care, as well as allowing professionals to influence higher-level organisational changes to ensure quality in care and patient safety. PMID- 30016571 TI - Nanoparticle-Mediated Immunogenic Cell Death Enables and Potentiates Cancer Immunotherapy. AB - Cancer immunotherapies that train or stimulate the inherent immunological systems to recognize, attack, and eradicate tumor cells with minimal damage to healthy cells have demonstrated promising clinical responses in recent years. However, most of these immunotherapeutic strategies only benefit a small subset of patients and cause systemic autoimmune side effects in some patients. Immunogenic cell death (ICD)-inducing modalities not only directly kill cancer cells but also induce antitumor immune responses against a broad spectrum of solid tumors. Such strategies for generating vaccine-like functions could be used to stimulate a "cold" tumor microenvironment to become an immunogenic, "hot" tumor microenvironment, working in synergy with immunotherapies to increase patient response rates and lead to successful treatment outcomes. This Minireview will focus on nanoparticle-based treatment modalities that can induce and enhance ICD to potentiate cancer immunotherapy. PMID- 30016570 TI - The ambulance nurse experiences of non-conveying patients. AB - AIMS AND OBJECTIVES: To explore ambulance nurses' (ANs) experiences of non conveying patients to alternate levels of care. BACKGROUND: Increases in ambulance utilisation and in the number of patients seeking ambulance care who do not require medical supervision or treatment during transport have led to increased nonconveyance (NC) and referral to other levels of care. DESIGN: A qualitative interview study was conducted using an inductive research approach. METHODS: The study was conducted in a region in the middle of Sweden during 2016 2017. Twenty nurses were recruited from the ambulance departments in the region. A conventional content analysis was used to analyse the interviews. The study followed the COREQ checklist. RESULTS: The ANs experienced NC as a complex and difficult task that carried a large amount of responsibility. They wanted to be professional, spend time with the patient and find the best solution for him or her. These needs conflicted with the ANs' desire to be available for assignments with a higher priority. The ANs could feel frustrated when they perceived that ambulance resources were being misused and when it was difficult to follow the NC guidelines. CONCLUSION: If ANs are expected to nonconvey patients seeking ambulance care, they need a formal mandate, knowledge and access to primary health care. RELEVANCE TO CLINICAL PRACTICE: This study provides new knowledge regarding the work situation of ANs in relation to NC. These findings can guide future research and can be used by policymakers and ambulance organisations to highlight areas that need to evolve to improve patient care. PMID- 30016572 TI - The Hydrazine-O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline-Catalyzed Oxidation of Alkyl Halides to Aldehydes. AB - An organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis. PMID- 30016573 TI - Simultaneous high-performance liquid chromatography with diode array detection and time-of-flight mass spectrometric confirmation of the ten bioactive compounds in Semen Sojae Preparatum. AB - Semen Sojae Preparatum is one of the most widely used traditional Chinese medicines. A reliable and accurate high-performance liquid chromatography with diode array detection method has been developed and validated for the quantitative determination of the ten bioactive compounds contained in Semen Sojae Preparatum. The samples were first extracted by pressurized liquid extraction using 80% ethanol at 100 degrees C for 15 min and three static extraction cycles. Chromatographic separation was conducted on a C18 column using a mobile phase consisting of water and acetonitrile under gradient elution, and the detection wavelength was set at 210 nm. The samples were further analyzed on a high-performance liquid chromatography with time-of-flight mass spectrometry system to confirm the determination results. All the ten analytes were well separated, and the calibration curves showed good linearity. The intra- and interday precisions were evaluated in terms of relative standard deviation values within the ranges of 0.20-1.43% and 0.40-4.78%, respectively. The recoveries for the ten analytes were all in the ranges of 96.2-104.3%, with relative standard deviation values < 3.85%. The established high-performance liquid chromatography method could serve as a reliable and accurate method for the quality evaluation of Semen Sojae Preparatum from different origins. PMID- 30016574 TI - Late-life living and care arrangements of older Filipino New Zealanders. AB - AIMS AND OBJECTIVES: To explore the living and care arrangement plans of older Filipino immigrants in New Zealand. BACKGROUND: New Zealand is rapidly becoming the host to an increasing number of ageing Filipino immigrants. Despite this sizeable population growth of ageing Filipinos in New Zealand, still very little is known about this ethnic group's care needs and living arrangement preferences in later life within the New Zealand context. DESIGN: Qualitative descriptive approach. METHODS: Data were collected from 15 older Filipinos who participated in face-to-face interviews. Data were analysed using a thematic analytical framework. RESULTS: Two major themes were identified from the data analysis. The first theme "preferred living and care arrangements" is about older Filipinos' preferred plans for future residence and in receiving care when no longer able to function independently in their own homes. The second theme "negotiating readiness and acceptance" is about hypothetical situations that older Filipinos described and anticipated that will greatly facilitate their readiness and acceptance to living in aged care facilities. CONCLUSION: The study results have implications for service delivery within the New Zealand residential aged care sector. Due to an increasing number of older Filipino immigrants requiring care, residential aged care facilities must ensure their care models meet the needs of this growing group of older people. RELEVANCE TO CLINICAL PRACTICE: Nursing staff skill sets in the aged care sector require sensitivity to older immigrants' health needs without compromising cultural beliefs and practices while living in residential aged care facilities. PMID- 30016575 TI - Two-Dimensional Materials for Antimicrobial Applications: Graphene Materials and Beyond. AB - Since the "birth" of graphene in 2004, two-dimensional (2D) materials have attracted unprecedented research interest from scientists and have stimulated numerous applications in various fields, such as electronic/optical devices, energy storage, catalysis, sensors, and biomedicine. In this review, we summarize recent advances in the antimicrobial applications of 2D materials, such as graphene materials (GMs), layered double hydroxides (LDHs), transition-metal dichalcogenides (TMDs), graphitic carbon nitride (g-C3 N4 ), MXenes, black phosphorus (BP), and their derivatives. This review also correlates the unique physicochemical properties of 2D materials with their antimicrobial activities. Finally, some current challenges and future perspectives in this field are also presented. PMID- 30016576 TI - Iron(II)-Catalyzed Site-Selective Functionalization of Unactivated C(sp3 )-H Bonds Guided by Alkoxyl Radicals. AB - An alkoxyl radical guided strategy for site-selective functionalization of unactivated methylene and methine C-H bonds enabled by an FeII -catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional-group tolerance. The application for one-pot 1,4-hydroxyl functionalization of non-oxygenated alkane substrates initiated by aerobic C-H oxygenation is also demonstrated. PMID- 30016578 TI - Independent validation of machine performance check for the Halcyon and TrueBeam linacs for daily quality assurance. AB - PURPOSE: To evaluate the ability of the machine performance check (MPC) on the Halcyon to detect errors, with comparison with the TrueBeam. METHODS: MPC is an automated set of quality assurance (QA) tests that use a phantom placed on the couch and the linac's imaging system(s) to verify the beam constancy and mechanical performance of the Halcyon and TrueBeam linacs. In order to evaluate the beam constancy tests, we inserted solid water slabs between the beam source and the megavoltage imager to simulate changes in beam output, flatness, and symmetry. The MPC results were compared with measurements, using two-dimensional array under the same conditions. We then studied the accuracy of MPC geometric tests. The accuracies of the relative gantry offset and couch shift tests were evaluated by intentionally inserting phantom shifts, using a rotating or linear motion stage. The MLC offset and absolute gantry offset tests were assessed by miscalibrating these motions on a Halcyon linac. RESULTS: For the Halcyon system, the average difference in the measured beam output between the IC Profiler and MPC, after intentional changes, was 1.3 +/- 0.5% (for changes <=5%). For Halcyon, the MPC test failed (i.e., prevented treatment) when the beam symmetry change was over 1.9%. The accuracy of the MLC offset test was within 0.05 mm. The absolute gantry offset test was able to detect an offset as small as 0.02 degrees . The accuracy of the absolute couch shift test was 0.03 mm. The accuracy of relative couch shift test of Halcyon was measured as 0.16 mm. CONCLUSION: We intentionally inserted errors to evaluate the ability of the MPC to identify errors in dosimetric and geometric parameters. These results showed that the MPC is sufficiently accurate to be effectively used for daily QA of the Halcyon and TrueBeam treatment devices. PMID- 30016577 TI - Heparin-protamine balance after neonatal cardiopulmonary bypass surgery. AB - : Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative bleeding occurred in 36% and heparin rebound in 73%. Thrombin initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB. SUMMARY: Background Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin. Objectives To evaluate heparin-protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding. Patients/Methods Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin-protamine balance was assessed with calibrated automated thrombography, thrombin-initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti-FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade. Results and Conclusions Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti-FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long-established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population. PMID- 30016579 TI - Highly Selective Mitochondrial Targeting by a Ruthenium(II) Peptide Conjugate: Imaging and Photoinduced Damage of Mitochondrial DNA. AB - Mitochondrial DNA (mtDNA) plays a crucial but incompletely understood role in cellular biochemistry and etiology of numerous disease states. Thus, there is an urgent need for targeted probes that can dynamically respond to changes to mtDNA such as copy number in live cells, but it is difficult to permeate the mitochondrial membrane of the living cell. Now, a ruthenium(II) light-switching probe targeted by peptide vectorization selectively to mitochondrial nucleoids is presented. Evidence for DNA binding by the probe in live cells is derived from confocal fluorescence microscopy, resonance Raman, and luminescence lifetime imaging. While viable under imaging conditions, specific staining of mitochondrial DNA permitted efficient and selective photoinduced toxicity on a cell-by-cell basis under higher excitation intensities. This powerful combination of imaging and photocytotoxicity is an important step towards realizing phototheranostic application of such RuII probes. PMID- 30016580 TI - Nck2 is essential for limb trajectory selection by spinal motor axons. AB - BACKGROUND: The development of a functioning nervous system requires precise assembly of neuronal connections, which can be achieved by the guidance of axonal growth cones to their proper targets. How axons are guided by signals transmitted to the cytoskeleton through cell surface-expressed guidance receptors remains unclear. We investigated the function of Nck2 adaptor protein as an essential guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory into the limb. RESULTS: Nck2 mRNA and protein are preferentially expressed in the medial subgroups of chick LMC neurons during axon trajectory into the limb. Nck2 loss- and gain-of-function in LMC neurons using in ovo electroporation perturb LMC axon trajectory selection demonstrating an essential role of Nck2 in motor axon guidance. We also showed that Nck2 knockdown and overexpression perturb the growth preference of LMC neurites against ephrins in vitro and Eph-mediated redirection of LMC axons in vivo. Finally, the significant changes of LMC neurite growth preference against ephrins in the context of Nck2 and alpha2-chimaerin loss- and gain-of-function implicated Nck2 function to modulate alpha2-chimaerin activity. CONCLUSIONS: Here, we showed that Nck2 is required for Eph-mediated axon trajectory selection from spinal motor neurons through possible interaction with alpha2-chimaerin. Developmental Dynamics 247:1043-1056, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30016581 TI - Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1) in a patient with concomitant simplex and junctional epidermolysis bullosa. AB - Epidermolysis bullosa (EB) is a heterogeneous group of heritable blistering diseases. We developed a next generation sequencing (NGS) panel covering 21 genes associated with skin fragility disorders, and it was applied to DNA from 91 probands with the diagnosis of EB. In one patient, novel homozygous mutations were disclosed in two different, unlinked EB-associated genes: EXPH5, chr11 g.108510085G > A; p.Arg1808Ter and COL17A1, chr10 g.104077423delT; p.Thr68LeufsTer106. Consequences of the COL17A1 mutation were examined by RNAseq which revealed a complex splicing pattern predicting synthesis of a truncated polypeptide (85%) or in-frame deletion of exon 4 (15% of transcripts). Transmission electron microscopy (TEM) and immunostaining revealed findings consistent with EB simplex (EBS) and junctional EB (JEB), and clinical examination revealed a complex phenotype with features of both subtypes. This case illustrates the power of next generation sequencing in identifying mutations in patients with complex EB phenotype, with implications for genotype-phenotype correlations, prenatal testing, and genetic counseling of families at risk for recurrence. PMID- 30016582 TI - T7 Expression Systems for Inducible Production of Proteins from Cloned Genes in E. coli. AB - Inducible T7 expression systems are capable of producing a wide range of proteins in E. coli. Improvements over common practice include: (1) preventing unintended induction by establishing and maintaining expression strains in non-inducing growth media composed entirely of purified components instead of complex growth media that may variably induce target proteins on approach to saturation; and (2) expressing many target proteins in parallel by convenient and productive auto induction in BL21(DE3) and other suitable hosts, instead of IPTG induction. From the earliest days, basal expression prevented establishment of inducible strains for producing proteins that are stressful to the host. Newly developed pAL vectors now reduce basal expression to levels where coding sequences for even the most stressful proteins can be maintained and induced. Asymmetric ligation allows simple and efficient cloning of individual coding sequences or simultaneous cloning of two or three coding sequences for co-expression from a single pAL vector. (c) 2018 by John Wiley & Sons, Inc. PMID- 30016583 TI - Low-Weight 3D Al2 O3 Network as an Artificial Layer to Stabilize Lithium Deposition. AB - Lithium metal has been regarded as an ideal anode for high-energy-density batteries. However, safety and efficiency concerns still linger due to dendrite formation, reactions between the liquid electrolyte and lithium, high resistance with lithium metal, and the weight of interface layer. A new nanometer-thick, hollow, Al2 O3 fiber network with an elastic and porous 3D structure has been prepared through an atomic-layer deposition process by using cotton sacrificial templates. Through a comparison study of the lithium deposition behavior by employing artificial layers with different structures, the low-weight 3D layer with lithiophilic properties overcomes the issues resulting from the 2D rigid Al2 O3 layer and provides a low overpotential and dendrite-free growth of lithium metal. Moreover, stable lithium deposition enables Li-Li symmetric cells with a 3D artificial layer to be stably cycled 300 times in carbonate-based electrolyte, with superior rate capability, and with a LiNi1/3 Co1/3 Mn1/3 O2 cathode. PMID- 30016584 TI - Concepts toward directing human astroplasticity to promote neuroregeneration. AB - Astrocytes exhibit dynamic and complex reactions to various insults. Recently, investigations into the transitions that occur during cellular specification, differentiation, maturation, and disease responses have provided insights into understanding the mechanisms that underlie these altered states of reactivity and function. Here we summarize current concepts in how astrocyte state transitions, termed astroplasticity, are regulated, as well as how this affects neural circuit function through extracellular signaling. We postulate that a promising future approach toward enhancing functional repair after injury and disease would be to steer astrocytes away from an inhibitory response and toward one that is beneficial to neuroplasticity and neuroregeneration. Toward this goal, we discuss emerging biotechnological advancements, with a focus on human pluripotent stem cell bioengineering, which has high potential for effective manipulation and control of astroplasticity. Highlights include innovations in cellular transdifferentiation techniques, nanomedicine, organoid and three-dimensional (3D) spheroid microcircuit development, and the use of biomaterials to influence the extracellular environment. Current barriers and future applications are also summarized in order to augment the design of future preclinical trials aimed toward astrocyte-targeted neuroregeneration with a concept termed astrocellular therapeutics. PMID- 30016585 TI - Site-Specific Protein Labeling with N-Hydroxysuccinimide-Esters and the Analysis of Ubiquitin Ligase Mechanisms. AB - N-Hydroxysuccinimide (NHS)-esters are widely used to label proteins nonselectively on free amino groups. Such broad labeling can be disadvantageous because it can interfere with protein structure or function and because stoichiometry is poorly controlled. Here we describe a simple method to transform NHS-esters into site-specific protein labeling on N-terminal Cys residues. MESNA addition converts NHS-esters to chemoselective thioesters for N-Cys modification. This labeling strategy was applied to clarify mechanistic features of the ubiquitin E3 ligase WWP2 including its interaction with one of its substrates, the tumor suppressor PTEN, as well as its autoubiquitination molecularity. We propose that this convenient protein labeling strategy will allow for an expanded application of NHS-esters in biochemical investigation. PMID- 30016586 TI - Isolation and Identification of Tyrosinase-Inhibitory and Copper-Chelating Peptides from Hydrolyzed Rice-Bran-Derived Albumin. AB - Rice-bran albumin (RBAlb), which shows higher tyrosinase-inhibitory activity than other protein fractions, was hydrolyzed with papain to improve the bioactivity. The obtained RBAlb hydrolysate (RBAlbH) was separated into 11 peptide fractions by RP-HPLC. Tyrosinase inhibition and copper chelation activities decreased with increasing retention times of the peptide fractions. RBAlbH fraction 1, which exhibited the greatest activity, contained 13 peptides whose sequences were determined by using LC-MS/MS. Most of the peptide sequences contained features of previously reported tyrosinase-inhibitory and metal-chelating peptides, especially peptide SSEYYGGEGSSSEQGYYGEG. RBAlbH fraction 1 showed more effective tyrosinase inhibition (IC50 = 1.31 mg/mL) than citric acid (IC50 = 9.38 mg/mL), but it was less effective than ascorbic acid (IC50 = 0.03 mg/mL, P <= 0.05). It showed copper-chelating activity (IC50 = 0.62 mg/mL) stronger than that of EDTA (IC50 = 1.06 mg/mL, P <= 0.05). These results suggest that RBAlbH has potential as a natural tyrosinase inhibitor and copper chelator for application in the food and cosmetic industries. PMID- 30016587 TI - Conditional Molecular Design with Deep Generative Models. AB - Although machine learning has been successfully used to propose novel molecules that satisfy desired properties, it is still challenging to explore a large chemical space efficiently. In this paper, we present a conditional molecular design method that facilitates generating new molecules with desired properties. The proposed model, which simultaneously performs both property prediction and molecule generation, is built as a semisupervised variational autoencoder trained on a set of existing molecules with only a partial annotation. We generate new molecules with desired properties by sampling from the generative distribution estimated by the model. We demonstrate the effectiveness of the proposed model by evaluating it on drug-like molecules. The model improves the performance of property prediction by exploiting unlabeled molecules and efficiently generates novel molecules fulfilling various target conditions. PMID- 30016588 TI - Protein-RNA Docking Using ICM. AB - Protein-RNA interactions play an important role in many biological processes. Computational methods such as docking have been developed to complement existing biophysical and structural biology techniques. Computational prediction of protein-RNA complex structures includes two steps: generating candidate structures from the individual protein and RNA parts and scoring the generated poses to pick out the correct one. In this work, we considered three recently developed data sets of protein-RNA complexes to evaluate and improve the performance of the FFT-based rigid-body docking algorithm implemented in the ICM package. An electrostatic term describing interactions between negatively charged phosphate groups and positively charged protein residues was added to the energy function used during the docking step to take into account the greater role that electrostatic interactions play in protein-RNA complexes. Next, the docking results were used to optimize a scoring function including van der Waals, electrostatic, and solvation terms. This optimization yielded a much smaller weight for the solvation term indicating that solvation energy may be less important for the scoring of protein-RNA structures. Rescoring of the generated poses with the new scoring function led to much higher success rates, while pose clustering by contact fingerprints produced further improvements, achieving a success rate of 0.66 for the top 100 structures. PMID- 30016589 TI - Antibody Fucosylation Lowers the FcgammaRIIIa/CD16a Affinity by Limiting the Conformations Sampled by the N162-Glycan. AB - Therapeutic monoclonal antibodies (mAbs) are largely based on the immunoglobulin G1 (IgG1) scaffold, and many elicit a cytotoxic cell-mediated response by binding Fc gamma receptors. Core fucosylation, a prevalent modification to the asparagine (N)-linked carbohydrate on the IgG1 crystallizable fragment (Fc), decreases the Fc gamma receptor IIIa (CD16a) binding affinity and mAb efficacy. We determined IgG1 Fc fucosylation reduced the CD16a affinity by 1.7 +/- 0.1 kcal/mol when compared to that of afucosylated IgG1 Fc; however, CD16a N-glycan truncation decreased this penalty by 1.2 +/- 0.1 kcal/mol or 70%. Fc fucosylation restricted the manifold of conformations sampled by displacing the CD16a Asn162-glycan that impinges upon the linkage between the alpha-mannose(1-6)beta-mannose residues and promoted contacts with the IgG Tyr296 residue. Fucosylation also impacted the IgG1 Fc structure as indicated by changes in resonance frequencies and nuclear spin relaxation observed by solution nuclear magnetic resonance spectroscopy. The effects of fucosylation on IgG1 Fc may account for the remaining 0.5 +/- 0.1 kcal/mol penalty of fucosylated IgG1 Fc binding CD16a when compared to that of afucosylated IgG1 Fc. Our results indicated the CD16a Asn162-glycan modulates the antibody affinity indirectly by reducing the volume sampled, as opposed to a direct mechanism with intermolecular glycan-glycan contacts previously proposed to stabilize this system. Thus, antibody engineering to enhance intermolecular glycan-glycan contacts will likely provide limited improvement, and future designs should maximize the affinity by maintaining the CD16a Asn162-glycan conformational heterogeneity. PMID- 30016590 TI - Multistage Ultraviolet Photodissociation Mass Spectrometry To Characterize Single Amino Acid Variants of Human Mitochondrial BCAT2. AB - Unraveling disease mechanisms requires a comprehensive understanding of how the interplay between higher-order structure and protein-ligand interactions impacts the function of a given protein. Recent advances in native mass spectrometry (MS) involving multimodal or higher-energy activation methods have allowed direct interrogation of intact protein complexes in the gas phase, allowing analysis of both composition and subunit connectivity. We report a multistage approach combining collisional activation and 193 nm ultraviolet photodissociation (UVPD) to characterize single amino acid variants of the human mitochondrial enzyme branched-chain amino acid transferase 2 (BCAT2), a protein implicated in chemotherapeutic resistance in glioblastoma tumors. Native electrospray ionization confirms that both proteins exist as homodimers. Front-end collisional activation disassembles the dimers into monomeric subunits that are further interrogated using UVPD to yield high sequence coverage of the mutated region. Additionally, holo (ligand-bound) fragment ions resulting from photodissociation reveal that the mutation causes destabilization of the interactions with a bound cofactor. This study demonstrates the unique advantages of implementing UVPD in a multistage MS approach for analyzing intact protein assemblies. PMID- 30016591 TI - Improving the Stability and Efficiency of CuO Photocathodes for Solar Hydrogen Production through Modification with Iron. AB - Cupric oxide (CuO) is considered as a promising photocathode material for photo(electro)chemical water splitting because of its suitable band gap, low cost related to copper earth abundancy, and straightforward fabrication. The main challenge for the development of practical CuO-based photocathodes for solar hydrogen evolution is to enhance its stability against photocorrosion. In this work, stable and efficient CuO photocathodes have been developed by using a simple and cost-effective methodology. CuO films, composed of nanowires and prepared by chemical oxidation of electrodeposited Cu, develop relatively high photocurrents in 1 M NaOH. However, this photocurrent appears to be partly associated with photocorrosion of CuO. It is significant though that, even unprotected, a faradaic efficiency for hydrogen evolution of ~45% is attained. The incorporation of iron through an impregnation method, followed by a high temperature thermal treatment for promoting the external phase transition of the nanowires from CuO to ternary copper iron oxide, was found to provide an improved stability at the expense of photocurrent, which decreases to about one-third of its initial value. In contrast, a faradaic efficiency for hydrogen evolution of ~100% is achieved even in the absence of co-catalysts, which is ascribable to the favorable band positions of CuO and the iron copper ternary oxide in the core shell structure of the nanowires. PMID- 30016592 TI - Hazy Weather-Induced Variation in Environmental Behavior of PCDD/Fs and PBDEs in Winter Atmosphere of A North China Megacity. AB - Haze is a serious pollution problem during the wintertime in North China. In this study, we investigated how the periodic cycle of winter haze events affect the environmental behaviors of two typical persistent organic pollutants, namely, polychlorinated dibenzo- p-dioxins and dibenzofurans (PCDD/Fs) and polybrominated diphenyl ethers (PBDEs), in the atmosphere of a typical megacity, Beijing. The average atmospheric concentrations of the total di- to octa-CDD/Fs (?PCDD/Fs: 378.0 pg/m3) and the total mono- to nona-BDEs (?9hPBDEs: 166.5 pg/m3) during haze episodes increased by 3.6-fold and 1.9-fold compared with those during the nonhaze periods, respectively; and their concentrations both linearly increased with PM2.5 levels and decreased as a power function of the atmospheric boundary layer height. The elevated concentrations could be clearly attributed to the vertically sinking motion of airflow in the midlower troposphere. When a haze event occurred, the partitioning rate of PCDD/Fs and PBDEs into particles was reduced; the largest fraction of the particle-bound ?PCDD/Fs was shifted from ultrafine particles to accumulation mode particles; and a steady-state model (Li Ma-Yang model) satisfactorily described the gas-particle partitioning of the PCDD/F and PBDE homologues. The inhalation exposure risk evaluation indicated that special attention should be paid to the increased cancer risk induced by the elevated inhalation intake of PCDD/Fs during haze episodes. PMID- 30016593 TI - Surface Characterization of TiO2 Polymorphic Nanocrystals through 1H-TD-NMR. AB - Nanocrystals (NCs) surface characterization is a fundamental step for understanding the physical and chemical phenomena involved at the nanoscale. Surface energy and chemistry depend on particle size and composition, and, in turn, determine the interaction of NCs with the surrounding environment, their properties and stability, and the feasibility of nanocomposites. This work aims at extracting more information on the surface of different titanium dioxide polymorphs using 1H-TD-NMR of water. Taking advantage of the interaction between water molecules and titanium dioxide NCs, it is possible to correlate the proton transverse relaxation times ( T2) as the function of the concentration and the specific surface area (deltap. Cm) and use it as an indicator of the crystal phase. Examples of three different crystals phase, rutile, anatase, and brookite, have been finely characterized and their behavior in water solution have been studied with TD-NMR. The results show a linear correlation between relaxivity ( R2) and their concentration Cm. The resulting slopes, after normalization for the specific surface, represent the surface/water interaction and range from 1.28 g m 2 s-1 of 50 nm rutile nanocrystals to 0.52 for similar sized brookite. Even higher slopes (1.85) characterize smaller rutile NCs, in qualitative accordance with the trends of surface energy. Thanks to proton relaxation phenomena that occur at the NCs surface, it is possible to differentiate the crystal phase and the specific surface area of titanium dioxide polymorphs in water solution. PMID- 30016594 TI - Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5). AB - INTRODUCTION: Transporters in the plasma membrane have been exploited successfully for the delivery of drugs in the form of prodrugs and nanoparticles. Organic cation/carnitine transporter 2 (OCTN2, SLC22A5) has emerged as a viable target for drug delivery. OCTN2 is a Na+-dependent high-affinity transporter for L-carnitine and a Na+-independent transporter for organic cations. OCTN2 is expressed in the blood-brain barrier, heart, liver, kidney, intestinal tract and placenta and plays an essential role in L-carnitine homeostasis in the body. Areas covered: In recent years, several studies have been reported in the literature describing the utility of OCTN2 to enhance the delivery of drugs, prodrugs and nanoparticles. Here we summarize the salient features of OCTN2 in terms of its role in the cellular uptake of its physiological substrate L carnitine in physiological and pathological context; the structural requirements for recognition and the recent advances in OCTN2-targeted drug delivery systems, including prodrugs and nanoparticles, are discussed. Expert opinion: This transporter has great potential to be utilized as a target for drug delivery to improve oral absorption of drugs in the intestinal tract. It also has potential to facilitate the transfer of drugs across the biological barriers such as the blood-brain barrier, blood-retinal barrier, and maternal-fetal barrier. PMID- 30016595 TI - Is end-of-life care a priority for policymakers? Qualitative documentary analysis of health care strategies. AB - BACKGROUND: Prioritisation of end-of-life care by policymakers has been the subject of extensive rhetoric, but little scrutiny. In England, responsibility for improving health and care lies with 152 regional Health and Wellbeing Boards. AIM: To understand the extent to which Health and Wellbeing Boards have identified and prioritised end-of-life care needs and their plans for improvement. DESIGN: Qualitative documentary analysis of Health and Wellbeing Strategies. Summative content analysis to quantify key concepts and identify themes. DATA SOURCES: Strategies were identified from Local Authority web pages and systematically searched to identify relevant content. RESULTS: In total, 150 strategies were identified. End-of-life care was mentioned in 78 (52.0%) and prioritised in 6 (4.0%). Four themes emerged: (1) clinical context - in 43/78 strategies end-of-life care was mentioned within a specific clinical context, most often ageing and dementia; (2) aims and aspirations - 31 strategies identified local needs and/or quantifiable aims, most related to the place of death; (3) narrative thread - the connection between need, aim and planned intervention was disjointed, just six strategies included all three components; and (4) focus of evidence - where cited, evidence related to evidence of need, not evidence for effective interventions. CONCLUSION: Half of Health and Wellbeing Strategies mention end-of-life care, few prioritise it and none cite evidence for effective interventions. The absence of connection between need, aim and intervention is concerning. Future research should explore whether and how strategies have impacted on local populations. PMID- 30016597 TI - Devices for penile traction: the long and winding road to treating Peyronie's disease. AB - INTRODUCTION: Penile traction therapy (PTT) is increasingly being recognized as a viable nonsurgical approach to Peyronie's disease (PD). The goal of this article is to review the current literature on PTT with attention to traction protocols, devices, and outcomes. Areas covered: Literature on the pathophysiology of PD, PTT as primary and adjunctive treatment for PD, perioperative use of PTT, and vacuum erection devices are all reviewed. Pertinent literature was obtained from the PubMed database. The key words 'penile traction,' 'mechanotransduction,' and 'Peyronie's disease' were searched and results were narrowed down based on relevance to the review. Expert commentary: PTT appears beneficial but the true magnitude of effect is difficult to discern. Most studies are not randomized, have small sample sizes, lack control arms, or have varying traction protocols. Patient compliance is critical and new devices and traction protocols are needed to maximize the benefit of PTT. PMID- 30016596 TI - Hemolysis-mediated Toxicity during Cardiopulmonary Bypass Ameliorated by Inhaled Nitric Oxide Gas. PMID- 30016598 TI - Lung Function through the PRISm. Spreading Light or Creating Confusion? PMID- 30016599 TI - Fictional First Memories. AB - In a large-scale survey, 6,641 respondents provided descriptions of their first memory and their age when they encoded that memory, and they completed various memory judgments and ratings. In good agreement with many other studies, where mean age at encoding of earliest memories is usually found to fall somewhere in the first half of the 3rd year of life, the mean age at encoding here was 3.2 years. The established view is that the distribution around mean age at encoding is truncated, with very few or no memories dating to the preverbal period, that is, below about 2 years of age. However, we found that 2,487 first memories (nearly 40% of the entire sample) dated to an age at encoding of 2 years and younger, with 893 dating to 1 year and younger. We discuss how such improbable, fictional first memories could have arisen and contrast them with more probable first memories, those with an age at encoding of 3 years and older. PMID- 30016600 TI - Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5. AB - Osteoarthritis is a common disease in joint cartilages. Because the molecular pathogenesis of osteoarthritis remains elusive, early diagnostic markers and effective therapeutic agents have not been developed. To understand the molecular mechanisms, we attempted to identify transcription factors involved in the onset of osteoarthritis. Microarray analysis of mouse articular cartilage cells indicated that retinoic acid, a destructive stimulus in articular cartilage, up regulated expression of sex-determining region Y-box (Sox)4, a SoxC family transcription factor, together with increases in Adamts4 and Adamts5, both of which are aggrecanases of articular cartilages. Overexpression of Sox4 induced a disintegrin-like and metallopeptidase with thrombospondin type 4 and 5 motif (ADAMTS4 and ADAMTS5, respectively) expression in chondrogenic cell lines C3H10T1/2 and SW1353. In addition, luciferase reporter and chromatin immunoprecipitation assays showed that Sox4 up-regulated ADAMTS4 and Adamts5 gene promoter activities by binding to their gene promoters. Another SoxC family member, Sox11, evoked similar effects. To evaluate the roles of Sox4 and Sox11 in articular cartilage destruction, we performed organ culture experiments using mouse femoral head cartilages. Sox4 and Sox11 adenovirus infections caused destruction of articular cartilage associated with increased Adamts5 expression. Finally, SOX4 and SOX11 mRNA expression was increased in cartilage of patients with osteoarthritis compared with nonosteoarthritic subjects. Thus, Sox4, and presumably Sox11, are involved in osteoarthritis onset by up-regulating ADAMTS4 and ADAMTS5.-Takahata, Y., Nakamura, E., Hata, K., Wakabayashi, M., Murakami, T., Wakamori, K., Yoshikawa, H., Matsuda, A., Fukui, N., Nishimura, R. Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5. PMID- 30016603 TI - Should degenerative horizontal tear of the medial meniscus be treated with surgery? PMID- 30016601 TI - Aging Reduces Intermittent Hypoxia-induced Lung Carcinoma Growth in a Mouse Model of Sleep Apnea. PMID- 30016604 TI - Evaluation of clinical outcomes of cemented vs uncemented knee prostheses covered with titanium plasma spray and hydroxyapatite: A minimum two years follow-up. AB - OBJECTIVES: In this study, we introduce the SanatSwing cementless total knee prosthesis coated with a combination of titanium plasma spray and hydroxyapatite porous coating and compared its early results to the SanatSwing cemented knee prosthesis. PATIENTS AND METHODS: We compared 278 patients, who underwent total knee replacement between September 2012 and February 2017. A total of 142 patients (Group A; 78 male, 64 female, mean age 69+/-14) were implanted a cemented SanatSwing and 136 patients (Group B; 83 male, 53 female, mean age 59+/ 10), a cementless SanatSwing knee prosthesis was implanted. Implant position and periprosthetic bone conditions were investigated over time on radiographs after a mean follow-up period of two years. Range of motion, pain level, distance of painless walk, and the ability to climb stairs were evaluated. RESULTS: Significant improvement was observed in both the cemented and uncemented groups when the preoperative scores were compared to the scores of their final visit, but we did not find any difference in measured scores between the cemented and uncemented group. Complication rates were low and almost similar in both groups without any significant difference. CONCLUSION: We used the combination of titanium plasma spray and the hydroxyapatite porous coating technique in cementless prostheses. Our results showed us that the novel SanatSwing cementless total knee prosthesis could be a great alternative to cemented total knee arthroplasty. PMID- 30016605 TI - Antibiotic release and antibacterial efficacy in cement spacers and cement beads impregnated with different techniques: In vitro study. AB - OBJECTIVES: This study aims to compare the antibiotic release and biological effectiveness of bead type and articulating spacers of different cement types with antibiotics added at alternative phases of cement preparation. MATERIALS AND METHODS: Four gram vancomycin was added into two types of antibiotic-free cement (Simplex(r), Biomet(r)) with similar viscosity and also gentamycin-containing cement (Refobacin(r)). Prepared specimens were used to create cement beads and articulating hip spacers, making a total of six different groups. Two alternative groups were formed by adding the Vancomycin while the cement was in dough phase. Antibiotic release and biological activity were evaluated with immunoassay techniques and agar-disk diffusion methods. RESULTS: All groups showed initial antibiotics surge in the first week, which was 2 to 4 times more evident in the beads group. Antibiotic release and change in release rate were significantly different between Simplex-alternative and Simplex, Biomet, Refobacin-beads, and between Biomet-spacer and Refobacin-beads groups (p<0.05). Elution of antibiotics was not different between mobile spacers prepared with conventional or alternative methods (p>0.05). Biomet cement showed larger diffusion inhibition zone in agar. There was no difference between biological activity of the bead and mobile designs of the Biomet brand (p>0.05). Inhibition zone analyses of agar and disk diffusion tests revealed significant differences between several groups (p<0.05). CONCLUSION: Cement beads provide superior antibiotic release regardless of cement type or preparation method. Simplex P(r) cement has lower anti bacterial efficiency than Biomet(r). Different methods for cement and antibiotics mixing and addition of extra vancomycin into the commercially drug loaded cement do not have any effect on the results. PMID- 30016606 TI - How is hip prosthesis and proximal femoral nail stability affected by lesser trochanter fractures: A comparative finite element analysis. AB - OBJECTIVES: This study aims to evaluate the effects of lesser trochanter (LT) and iliopsoas tendon on implant stability by using finite element analysis (FEA). MATERIALS AND METHODS: Effects of iliacus and psoas major muscles on hip joint was evaluated with inverse dynamics methods to calculate joint reaction and muscle forces. Intertrochanteric femur fracture was simulated according to AO (Arbeitsgemeinschaft fur Osteosynthesefragen) 31A1 and 31A2 classifications in three-dimensional modelling software. Uncemented three-dimensional model of modular nail prosthesis combination was used in FEA. All analyses were performed with Ti6Al4V's 114 GPa elastic modulus value. Effects of LT on implant stability were evaluated with two different implant designs using the same femoral stems and four different femoral models, two of which with intact LT and two of which with fractured LT. RESULTS: Reaction forces of the hip joint decreased by 10% in the 0-40 degrees hip flexion range. Maximum stress distribution for proximal femoral nail (PFN) model with fractured LT was 204.68 MPa at the distal locking screw on the interconnection point of PFN, while it was 335.35 MPa for the hip prosthesis with fractured LT. The direction of stress distribution for PFN model with fractured LT varied from medial to lateral and anterior to posterior. Maximum stress distribution for the hip prosthesis model with intact LT was 357.42 MPa, with direction of stress distribution from lateral to medial and posterior to anterior. CONCLUSION: Hip prosthesis models with intact or fractured LT were similar in terms of stress distribution and deformation values, while there were differences between PFN models with intact or fractured LT. Thus, intact LT was significant in PFN implant stability. Further clinical and experimental analyses are necessary on this topic. PMID- 30016607 TI - Effect of intramedullary nail compression amount on the union process of tibial shaft fracture and the evaluation of this effect with a different parameter. AB - OBJECTIVES: This study aims to investigate the effects of different amounts of compression used in intramedullary nailing on the stress values of the fracture surface and time of the union process in tibia diaphysis fractures treated with intramedullary nails. PATIENTS AND METHODS: Seventy patients (50 males, 20 females; mean age 34.0+/-10.7 years; range, 20 to 56 years) who had suffered from tibial shaft fractures between January 2007 and December 2015 were included in the study. Patients who had A2, A3, and B2 type fractures according to AO (Arbeitsgemeinschaft fur Osteosynthesefragen) classification and those with closed fractures were included. The patients were divided into three groups. No compression was applied to Group A, dynamic compressive fixation intramedullary nailing was applied to Groups B and C. Amount of applied compression was 1 mm for Group B and 1.5 mm for Group C. Postoperative and follow-up radiographs of patients were evaluated according to Rust criteria, and functional results were evaluated according to Johner-Wrush criteria. Additionally, finite element analyses were performed separately for 1 mm and 1.5 mm compressions that were applied in Group B and C, respectively. The data were analyzed using a statistical software package. RESULTS: Clinical and radiological union was achieved in all patients. The average time of radiological union was 15.05+/-2.06 weeks in Group A, 12.48+/-1.42 weeks in Group B, and 11.64+/-1.63 weeks in Group C. The time of union for the group in which no compression was applied (Group A) was significantly longer than the other groups in which compression was applied (Group B and C) (p<0.001). Functional outcomes were 17 patients (85%) with excellent and three patients (15%) with good-moderate results in Group A, 23 (92%) excellent and two (8%) good-moderate in Group B, and 23 (92%) excellent and two patients (8%) with good-moderate results in Group C. In total, seven patients had knee pain. No infection was seen in any patient. CONCLUSION: Interlocking compression intramedullary nailing is a very effective treatment method for tibial shaft fractures. As the compression applied by the nail increases, the time of union shortens significantly. PMID- 30016608 TI - Association between patellofemoral congruence and patellofemoral chondropathy in patients with anterior knee pain: A T2 mapping knee MRI study. AB - OBJECTIVES: In this study, the T2 mapping magnetic resonance imaging technique was used to evaluate early cartilage changes associated with patellofemoral alignment and morphology. PATIENTS AND METHODS: Fifty four patients (Study group: 38 females, 16 males) with anterior knee pain and a randomly selected and age matched 50 controls (Control group; 37 females, 13 males) were compared by two blinded authors in terms of T2 values of the patella medial, lateral facet, and trochlea, Insall-Salvatti index, lateral trochlear inclination angle, patellar tilt angle, sulcus angle, and patella medial and lateral facet lengths. The inter and intra-observer reliability tests were assessed. RESULTS: The T2 medial patellar facet value, T2 lateral patellar facet value, T2 trochlea value, Visual Analog Scale, tibial tubercle - greater trochanter distance, and patellar tilt angle measure were statistically significantly higher in the study group. CONCLUSION: Based on our study findings, the T2 mapping magnetic resonance imaging (MRI) technique was found to be reliable test that can be used to diagnose early cartilage damage in patients with anterior knee pain. In patients with anterior knee pain, especially with decreased Insall Salvatti index, low lateral trochlear inclination angle, and higher patellar tilt angle, adding a T2 mapping sequence to the standard knee MRI protocol is recommended to help detect early cartilage damage. PMID- 30016609 TI - Can distal radius or vertebra fractures due to low-energy trauma be a harbinger of a hip fracture? AB - OBJECTIVES: This study aims to investigate whether or not low-energy distal radius or vertebra fractures are harbingers of hip fracture. PATIENTS AND METHODS: A total of 142 patients had surgical treatment due to hip fracture in our clinic between February 2013 and January 2017. The patients had low-energy fractures before hip fracture, and they received either medical treatment for osteoporosis or not before hip fracture developed. RESULTS: Of 142 patients, 32 had distal radius, humeral neck, ankle, vertebra fractures and 15 had a second hip fracture. The patients were determined to have most frequently a distal radius and vertebra fracture before hip fracture. The treatment of osteoporosis was determined to be neglected in 58% of 47 patients in total who had a fracture previously. CONCLUSION: Distal radius and vertebra fractures are the harbingers of a potential hip fracture. Physicians, especially orthopedists, who face with these fractures should be careful in terms of osteoporosis. PMID- 30016610 TI - A comparative study of three commonly used fixation techniques for isolated medial malleolus fracture. AB - OBJECTIVES: This study aims to compare the three most commonly used fixation techniques: tension-band wire fixation, partially threaded cannulated screws, and fully threaded cannulated headless compression screws. PATIENTS AND METHODS: Ninety patients with medial malleolus fractures were included in the study. Patients were divided into three groups. Group A included patients who underwent tension-band wire fixation (n=26), Group B partially threaded cannulated compression screws (n=32), and Group C fully threaded cannulated headless compression screws (n=32). The type of medial malleolus fracture, healing rates, implant-related complications, rate of infection, hardware removal, weight bearing restrictions, mean interval time from the injury to the surgery, and Body Mass Indexes (BMIs) were investigated. The patients' radiographs (standard anteroposterior, lateral, and mortise) were reviewed. The American Orthopedic Foot and Ankle Society (AOFAS) scoring system was used for clinical evaluation. RESULTS: No significant difference was observed between the three groups in terms of age, gender, BMI, follow-up period, and fracture type. Union rate for group C was significantly shorter than groups A and B. There was no implant failure or irritation in group C and this was statistically significant comparing to group A and B (p=0.037). However, there was no significant difference between group A and B (p=0.41). There were no significant differences in the three groups according to AOFAS. Patients with low BMI in groups A and B had a high rate of implant related complications. There was a significant correlation between low BMI and implant-related complication (p<0.001). CONCLUSION: Union rate in the group who were operated with fully threaded cannulated headless compression screws was significantly shorter than the other groups. This study has shown that tension band wiring and partially threaded cannulated compression screws can cause irritation of soft tissues and pain over the hardware implantation site. Patients with low BMI are vulnerable for implant-related complications. PMID- 30016611 TI - Are orthobiologics the next chapter in clinical orthopedics? A literature review. AB - Orthobiologics are biologically derived materials which aim to promote healing and regeneration of tissues that are the focus of orthopedic surgery. Since bones, ligaments, tendons, and cartilage have different healing and regeneration characteristics, treatment strategies and clinical problems related to these tissues greatly differ. Although orthobiolgics are an old concept, most of the advancements in this field have been accomplished within the last two decades. A large number of promising laboratory studies show that orthobiolics hold a great potential in launching the next chapter of orthopedics. In this article, the use, research on this subject, future potential of orthobiologics, and the tissues in focus have been briefly reviewed. PMID- 30016612 TI - Reconstruction of the Achilles tendon using quadriceps tendon graft in bilateral xanthomas secondary to familial hypercholesterolemia: A case report. AB - Achilles tendon xanthomas are rarely seen masses that are highly associated with hyperlipidemia. They are manifested in two types: Xanthomas developed secondary to familial hypercholesterolemia and cerebrotendinous xanthomatoses. In this report, we present a case of bilateral Achilles tendon xanthoma secondary to familial hypercholesterolemia and resection along with a portion of the Achilles tendon. The patient was a 49-year-old male who presented to our clinic with complaints of difficulty walking and swelling in both heels. The swellings had started insidiously without a trauma history. The xanthomas were operated at different time points, albeit with the same surgical technique. Quadriceps tendon graft and flexor hallucis longus transfer was used for autografting. Xanthoma should be considered in cases with swellings in the Achilles tendon. Total resection is necessary to avoid recurrence of the xanthomas. Large gaps formed after resection can be filled and reconstruction of the Achilles tendon can be realized using quadriceps tendon autografts (containing bony fragments) and the flexor hallucis longus tendon. We believe a functional ankle and an Achilles tendon can be achieved with the employment of this technique. PMID- 30016613 TI - Bilateral congenital dislocation of the patella associated with synostosis of proximal tibiofibular and proximal radioulnar joints: A case report. AB - Congenital dislocation of the patella is a rare and difficult pathology to treat. We present a case of bilateral congenital dislocation of the patella with synostosis of proximal tibiofibular and proximal radioulnar joints without genu valgum deformity of both knees in a 30-year-old man. To our knowledge, congenital dislocation of the patella associated with synostosis of proximal tibiofibular and proximal radioulnar joints has not been reported in the literature yet. PMID- 30016614 TI - Cellular Dynamics Driving Elongation of the Gut. AB - During embryonic development, the midgut needs to undergo extensive elongation to form the small intestine. In this issue of Development Cell, Wang et. al. (2018) explore the cell dynamics of this tissue and find that regulated re-integration of cells into the epithelial layer is important for elongation. PMID- 30016615 TI - The Domino Effect in EGFR-ERK Signaling. AB - A gradient of EGFR-ERK signaling has been classically implicated in various developmental processes. In this issue of Developmental Cell, Ogura et al. (2018) show that in the Drosophila tracheal placode, EGFR-ERK signaling propagates via a cell-by-cell relay mechanism rather than a gradient, and this sequential ERK activation controls proper placode invagination. PMID- 30016616 TI - InterSEPTIN' Kinesins in Dendrites. AB - Cargo transport to axons and dendrites is essential for maintaining neuronal polarity and function. In this issue of Developmental Cell, Karasmanis et al. (2018) identify a septin-SEPT9-in differentially regulating the motility of two kinesin motors, thereby controlling cargo entry into dendrites. PMID- 30016617 TI - A lncRNA-like Role for LINE1s in Development. AB - Transposable elements (TEs) have profoundly affected the evolution of transcriptional and chromatin profiles in mammalian genomes. In a recent paper, Percharde et al. (2018) identify a lncRNA-like function for LINE1 transposable elements in regulating gene expression to facilitate embryonic stem cell self renewal and preimplantation development. PMID- 30016619 TI - Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome. AB - Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor. PMID- 30016618 TI - A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration. AB - Skeletal muscle has an extraordinary regenerative capacity due to the activity of tissue-specific muscle stem cells. Consequently, these cells have received the most attention in studies investigating the cellular processes of skeletal muscle regeneration. However, efficient capacity to rebuild this tissue also depends on additional cells in the local milieu, as disrupting their normal contributions often leads to incomplete regeneration. Here, we review these additional cells that contribute to the regenerative process. Understanding the complex interactions between and among these cell populations has the potential to lead to therapies that will help promote normal skeletal muscle regeneration under conditions in which this process is suboptimal. PMID- 30016620 TI - Radial WNT5A-Guided Post-mitotic Filopodial Pathfinding Is Critical for Midgut Tube Elongation. AB - The early midgut undergoes intensive elongation, but the underlying cellular and molecular mechanisms are unknown. The early midgut epithelium is pseudostratified, and its nuclei travel between apical and basal surfaces in concert with cell cycle. Using 3D confocal imaging and 2D live imaging, we profiled behaviors of individual dividing cells. As nuclei migrate apically for mitosis, cells maintain a basal process (BP), which splits but is inherited by only one daughter. After mitosis, some daughters directly use the inherited BP as a "conduit" to transport the nucleus basally, while >50% of daughters generate a new basal filopodium and use it as a path to return the nucleus. Post-mitotic filopodial "pathfinding" is guided by mesenchymal WNT5A. Without WNT5A, some cells fail to tether basally and undergo apoptosis, leading to a shortened midgut. Thus, these studies reveal previously unrecognized strategies for efficient post-mitotic nuclear trafficking, which is critical for early midgut elongation. PMID- 30016621 TI - Selective Filopodia Adhesion Ensures Robust Cell Matching in the Drosophila Heart. AB - The ability to form specific cell-cell connections within complex cellular environments is critical for multicellular organisms. However, the underlying mechanisms of cell matching that instruct these connections remain elusive. Here, we quantitatively explored the dynamics and regulation of cell matching processes utilizing Drosophila cardiogenesis. We found that cell matching is highly robust at boundaries between cardioblast (CB) subtypes, and filopodia of different CB subtypes have distinct binding affinities. Cdc42 is involved in regulating this selective filopodia binding adhesion and influences CB matching. Further, we identified adhesion molecules Fasciclin III (Fas3) and Ten-m, both of which also regulate synaptic targeting, as having complementary differential expression in CBs. Altering Fas3 expression changes differential filopodia adhesion and leads to CB mismatch. Furthermore, only when both Fas3 and Ten-m are lost is CB alignment severely impaired. Our results show that differential adhesion mediated by selective filopodia binding efficiently regulates precise and robust cell matching. PMID- 30016622 TI - Polarity of Neuronal Membrane Traffic Requires Sorting of Kinesin Motor Cargo during Entry into Dendrites by a Microtubule-Associated Septin. AB - Neuronal function requires axon-dendrite membrane polarity, which depends on sorting of membrane traffic during entry into axons. Due to a microtubule network of mixed polarity, dendrites receive vesicles from the cell body without apparent capacity for directional sorting. We found that, during entry into dendrites, axonally destined cargos move with a retrograde bias toward the cell body, while dendritically destined cargos are biased in the anterograde direction. A microtubule-associated septin (SEPT9), which localizes specifically in dendrites, impedes axonal cargo of kinesin-1/KIF5 and boosts kinesin-3/KIF1 motor cargo further into dendrites. In neurons and in vitro single-molecule motility assays, SEPT9 suppresses kinesin-1/KIF5 and enhances kinesin-3/KIF1 in a manner that depends on a lysine-rich loop of the kinesin motor domain. This differential regulation impacts partitioning of neuronal membrane proteins into axons dendrites. Thus, polarized membrane traffic requires sorting during entry into dendrites by a septin-mediated mechanism that bestows directional bias on microtubules of mixed orientation. PMID- 30016624 TI - A Quick HYL1-Dependent Reactivation of MicroRNA Production Is Required for a Proper Developmental Response after Extended Periods of Light Deprivation. AB - Light is the most influential environmental stimulus for plant growth. In response to deficient light, plants reprogram their development to adjust their growth in search for a light source. A fine reprogramming of gene expression orchestrates this adaptive trait. Here we show that plants alter microRNA (miRNA) biogenesis in response to light transition. When plants suffer an unusual extended period of light deprivation, the miRNA biogenesis factor HYPONASTIC LEAVES 1 (HYL1) is degraded but an inactive pool of phosphorylated protein remains stable inside the nucleus. Degradation of HYL1 leads to the release of gene silencing, triggering a proper response to dark and shade. Upon light restoration, a quick dephosphorylation of HYL1 leads to the reactivation of miRNA biogenesis and a switch toward a developmental program that maximizes the light uptake. Our findings define a unique and fast regulatory mechanism controlling the plant silencing machinery during plant light response. PMID- 30016626 TI - A rapid ultra-performance LC-MS/MS assay for determination of serum unbound fraction of voriconazole in cancer patients. AB - BACKGROUND: Voriconazole (VOR), an antifungal agent, is clinically monitored to guide therapeutic dosing and avoid toxicity. It is believed that measurement of serum unbound VOR provides more accurate information, especially in hypoalbuminemia patients. We developed and validated an accurate, simple and fast test with ultrafiltration and ultra-performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) to measure unbound VOR in human serum. METHODS: The Agilent UPLC system coupled with a SCIEX QTRAP4000 MS with a positive ionization mode was developed and validated for VOR analysis. RESULTS: A good linearity was demonstrated from 0.02 to 2.5 MUg/ml for unbound VOR (r2 = 0.9969). The within-run and between-run accuracy and precision was <5% and < 6%. The levels of total VOR were well correlated with reference laboratory results. Serum unbound VOR levels were correlated with the total VOR levels (r = 0.78, p < 0.0001). There was a reverse correlation between unbound VOR fractions and plasma albumin levels (p < 0.05). In hypoalbuminemia patients, the unbound VOR levels were increased to a higher degree than total VOR. CONCLUSION: This assay is suitable for monitoring both unbound and bound VOR in cancer patients especially in those with hypoalbuminemia in clinical laboratories. Measurement of unbound VOR offers a better approach in prediction of VOR toxicity. PMID- 30016625 TI - Design of DNA rolling-circle templates with controlled fork topology to study mechanisms of DNA replication. AB - Rolling-circle DNA amplification is a powerful tool employed in biotechnology to produce large from small amounts of DNA. This mode of DNA replication proceeds via a DNA topology that resembles a replication fork, thus also providing experimental access to the molecular mechanisms of DNA replication. However, conventional templates do not allow controlled access to multiple fork topologies, which is an important factor in mechanistic studies. Here we present the design and production of a rolling-circle substrate with a tunable length of both the gap and the overhang, and we show its application to the bacterial DNA replication reaction. PMID- 30016623 TI - Global Proteome Remodeling during ER Stress Involves Hac1-Driven Expression of Long Undecoded Transcript Isoforms. AB - Cellular stress responses often require transcription-based activation of gene expression to promote cellular adaptation. Whether general mechanisms exist for stress-responsive gene downregulation is less clear. A recently defined mechanism enables both up- and downregulation of protein levels for distinct gene sets by the same transcription factor via coordinated induction of canonical mRNAs and long undecoded transcript isoforms (LUTIs). We analyzed parallel gene expression datasets to determine whether this mechanism contributes to the conserved Hac1 driven branch of the unfolded protein response (UPRER), indeed observing Hac1 dependent protein downregulation accompanying the upregulation of ER-related proteins that typifies UPRER activation. Proteins downregulated by Hac1-driven LUTIs include those with electron transport chain (ETC) function. Abrogated ETC function improves the fitness of UPRER-activated cells, suggesting functional importance to this regulation. We conclude that the UPRER drives large-scale proteome remodeling, including coordinated up- and downregulation of distinct protein classes, which is partly mediated by Hac1-induced LUTIs. PMID- 30016627 TI - Dexamethasone and insulin stimulate ghrelin secretion of broilers in a different way. AB - Ghrelin is one of the most important appetite regulating peptides, involved in the regulation of energy homeostasis. The role of ghrelin on the appetite and fat metabolism in chickens is different from that of ghrelin in mammals. Glucocorticoids and insulin are important hormones and work differently in energy regulation of body. In this study, the effects of dexamethasone (DEX, 2.0 mg/kg BW), subcutaneous insulin injection (40 ug/kg BW), and glucose load on ghrelin secretion and expression were determined in broilers. DEX treatment increased circulating ghrelin concentration in broiler fed with either a low-energy diet (11.05 MJ/kg of metabolizable energy) or a high-energy diet (14.44 MJ/kg of metabolizable energy). The expression levels of ghrelin were increased while both ghrelin and its receptor GHS-R1a expression levels were stimulated by DEX. A single subcutaneous insulin injection (40 ug/kg BW) or oral glucose infusion (2 g/kg BW) rise circulating ghrelin level. Ghrelin expression in the proventriculus was increased by insulin treatment but unchanged by glucose load. DEX had no detectable influence on ghrelin and GHS-R1a expression in the hypohtalamus, whereas insulin suppressed their expression. In conclusion, both insulin and glucocorticoid stimulate ghrelin secretion in chickens, in contrast to mammals. Glucocorticoids evoke peripheral ghrelin/GHS-R1a system while insulin increases peripheral ghrelin expression and suppress the activation of central ghrelin/GHS R1a system. The result suggests that ghrelin involved in the modulating network of energy homeostasis in concert with glucocorticoids and insulin. PMID- 30016628 TI - Survival and reproductive costs of repeated acute glucocorticoid elevations in a captive, wild animal. AB - Organisms are continuously encountering both predictable and unpredictable ecological stressors within their environment. The activation of the hypothalamic pituitaryadrenal (stress) axis is a fundamental process allowing animals to cope with and respond to such encounters. A main consequence of HPA axis activation is the release of glucocorticoid hormones. Although short-term glucocorticoid elevations lead to changes in physiological and behavioral processes that are often adaptive, our understanding of fitness consequences of repeated acute elevations in glucocorticoid hormones over a longer time period is largely lacking. This is of particular current importance as animals are facing a significant increase in exposure to stressors including those associated with human-induced rapid environmental change. Here, we test fitness-relevant consequences of repeated exposure to glucocorticoids in the absence of natural challenges, by treating wild-caught gravid female eastern fence lizards (Sceloporus undulatus) with a daily transdermal dose of a glucocorticoid hormone until laying. This treatment causes an increase in plasma glucocorticoids that mimics the natural response lizards have when they encounter a stressor in the wild, without confounding effects associated with the encounter itself. This treatment reduced females' reproductive success (hatching success) and survival. Further, glucocorticoid-induced reductions in reproductive success were greater when females had experienced higher temperatures the previous winter. This demonstrates the potential significant consequences of repeated exposure to acute elevations in glucocorticoid hormones. Additionally, the costs of repeated glucocorticoid elevation may be further exaggerated by an individual's previous experience, such as the potential compounding effects of winter warming increasing animals' vulnerability to increased glucocorticoid levels during spring breeding. PMID- 30016629 TI - The assessment of multipotent cell transplantation in acute-on-chronic liver failure: a systematic review and meta-analysis. AB - Acute-on-chronic liver failure (ACLF) is a serious life-threatening disease with high prevalence. Liver transplantation is the only efficient clinical treatment for ACLF. Because of the rapid progression and lack of liver donors, it is urgent to find an effective and safe therapeutic approach to ACLF. Recent studies showed that multipotent cell transplantation could improve the patients' liver function and enhance their preoperative condition. Cells such as mesenchymal stem cells, bone marrow mononuclear cells and autologous peripheral blood stem cells, which addressed in this study have all been used in multipotent cell transplantation for liver diseases. However, its clinical efficiency is still debatable. This systematic review and meta-analysis explored the clinical efficiency of multipotent cell transplantation as a therapeutic approach for patients with ACLF. A detailed search of the Cochrane Library, MEDLINE, and Embase databases was conducted from inception to November 2017. The outcome measures were serum albumin, prothrombin time, alanine aminotransferase, total bilirubin, platelets, hemoglobin, white blood cells, and survival time. The quality of evidence was assessed using GRADEpro and Jaded scores. A literature search resulted in 537 citations. Of these, 9 articles met the inclusion criteria. It was found that multipotent cell transplantation was able to alleviate liver damage and improve liver function. Multipotent cell transplantation can also enhance the short-term and medium-term survival rates of ACLF. All 9 research articles included in this analysis reported no statistically significant adverse events, side effects, or complications. In conclusions, this study suggested that multipotent cell transplantation could be recommended as a potential therapeutic supplementary tool in clinical practice. However, clinical trials in large-volume centers still needed. PMID- 30016631 TI - Timing of mirror system activation when inferring the intentions of others. AB - Neuroimaging studies have shown mirror system (MS) activation when participants infer internal states e.g. emotions, intentions or beliefs (known as 'mentalizing') from others' actions. However, the exact role of the MS in mentalizing tasks is unknown. Dysfunctional MS activation may underlie mentalizing deficits experienced by adults with autism spectrum disorder (ASD). This study investigated the timing of MS activity when inferring intentions in order to delineate between existing models of MS involvement. Single-pulse transcranial magnetic stimulation (TMS) was applied to the primary motor cortex at different time points during the observation of hand actions whilst participants inferred intentions (mentalizing task) and performed a non mentalizing task. Electromyographic activity in the contralateral hand was used as an indirect measure of MS activity. Greater corticospinal activity was found during the mentalizing task than the non-mentalizing task, but only at the end of observed actions, suggesting late MS involvement in processing intentions. Enhanced corticospinal activity was not related to autistic traits or behavioural performance suggesting the MS has a more automatic role in processing others' intentions, irrespective of mentalizing ability. Our results extend current knowledge of MS activation when mentalizing, allowing initial delineation between different models of MS involvement in mentalizing. PMID- 30016630 TI - Lack of Galectin-3 attenuates neuroinflammation and protects the retina and optic nerve of diabetic mice. AB - Diabetic retinopathy is the leading cause of acquired blindness in working-age individuals. Recent work has revealed that neurodegeneration occurs earlier than vascular insult and that distal optic nerve damage precedes retinal degeneration and vascular insult. Since we have shown that optic nerve degeneration is reduced after optic nerve crush in Galectin-3 knockout (Gal-3 -/-) mice, we decided to investigate whether Gal-3 -/- could relieve inflammation and preserve both neurons and the structure of the retina and optic nerve following 8 weeks of diabetes. Diabetes was induced in 2-month-old male C57/bl6 WT or Gal-3 -/- mice by a single injection of streptozotocin (160 mg/kg). Histomorphometric retinal analyses showed no gross difference, except for a reduced number of retinal ganglion cells in WT diabetic mice, correlated to increased apoptosis. In the optic nerve, Gal-3 -/- mice showed reduced neuroinflammation, suggested by the smaller number of Iba1+ cells, particularly the amoeboid profiles in the distal end. Furthermore, iNOS staining was reduced in the optic nerves of Gal-3 -/- mice, as well as GFAP in the distal segment of the optic nerve. Finally, optic nerve histomorphometric analyses revealed that the number of myelinated fibers was higher in the Gal-3 -/- mice and myelin was more rectilinear compared to WT diabetic mice. Therefore, the present study provided evidence that Gal-3 is a central target that stimulates neuroinflammation and impairs neurological outcomes in visual complications of diabetes. Our findings provide support for the clinical use of Gal-3 inhibitors against diabetic visual complications in the near future. PMID- 30016633 TI - Fluoro-urodynamic Image Interpretation Is Not Altered by Using Dilute Intravesical Contrast. AB - OBJECTIVE: To determine if using one 250 mL bottle of intravesical contrast followed by sterile saline alters interpretation of fluoroscopic images during fluoro-urodynamics. MATERIALS AND METHODS: Subjects were randomized to receive 250 mL of intravesical contrast followed by sterile saline until maximal cystometric capacity vs non-dilute intravesical contrast alone during fluoro urodynamics. Interpreters, blinded to study group, graded images on an ordinal rank scale rating confidence in image interpretation. Primary endpoint was differences in image interpretation between the two groups using visual grading characteristics curves and contrast-to-noise ratios (CNR). Secondary endpoints were obtaining anthropometric data such as body mass index and waist circumference to determine predictors of CNR in a multivariate multiple regression analysis. RESULTS: 26 subjects were randomized to receive dilute intravesical contrast and 22 non-dilute contrast; two subjects were unable to complete the study. There was no difference in baseline characteristics between the two groups. Visual grading characteristics demonstrated no difference in readability of the fluoroscopic images between groups and CNR was not statistically different between the two groups. No correlation was identified between CNR and waist circumference or body mass index. CONCLUSION: Interpretation of fluoro-urodynamic images and image quality was not altered with using of 250 mL of contrast followed by saline. Expert reviewers did not perceive a difference in their confidence to distinguish between the two groups. Fluoro urodynamics can be reliably performed using only 250 mL of contrast without compromising the ability to read the fluoroscopic images. PMID- 30016632 TI - Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-kappaB signaling in A549 cells. AB - Nickel exposure promotes the invasive potential of human lung cancer cells. Polyphenols such as quercetin, curcumin, chrysin, apigenin, and luteolin, present in many plant foods may suppress the development of cancers. However, whether these compounds inhibit the promoting effects of Nickel on cancer cell invasion and migration as well as the possible mechanisms are unclear. In the present study, we first showed that quercetin, curcumin, chrysin, apigenin, and luteolin at 5 MUM, significantly suppressed the promoting effects of NiCl2 (Ni) on migration and invasion in H1975 and A549 human lung cancer cells. The five phytochemicals also significantly suppressed the secretion of cytokines, IL 1beta, IL-6, TNF-alpha and IL-10, induced by Ni in A549 cells. The overall efficiency of quercetin was the best, followed by chrysin and the other compounds. Furthermore, we found that quercetin and chrysin suppressed the mRNA and protein expression of TLR4 and Myd88. Consistently, quercetin and chrysin also decreased the phosphorylation of IKKbeta and IkappaB, the nuclear level of p65 (NF-kappaB) as well as the expression of MMP-9 in A549 cells exposed to Ni. In conclusion, these results suggest the potential preventive effects of the five phytochemicals on the promoting effect of Ni on human lung cancer cell invasion. In addition, the preventive effects are associated with downregulation of the TLR4/NF-kappaB signaling pathway, especially for quercetin and chrysin. PMID- 30016634 TI - Myeloperoxidase promotes tube formation, triggers ERK1/2 and Akt pathways and is expressed endogenously in endothelial cells. AB - Myeloperoxidase is a member of the mammalian peroxidase family, mainly expressed in the myeloblastic cell lineage. It is considered a major bactericidal agent as it is released in the phagosome where it catalyzes the formation of reactive oxygen species. It is also released in the extracellular spaces including blood where it is absorbed on (lipo)proteins and endothelial cell surface, interfering with endothelial function. We performed RNA sequencing on MPO-treated endothelial cells, analyzed their transcriptome and validated the profile of gene expression by individual qRT-PCR. Some of the induced genes could be grouped in several functional networks, including tubulogenesis, angiogenesis, and blood vessel morphogenesis and development as well as signal transduction pathways associated to these mechanisms. MPO treatment mimicked the effects of VEGF on several signal transduction pathways, such as Akt, ERK or FAK involved in angiogenesis. Accordingly MPO, independently of its enzymatic activity, stimulated tube formation by endothelial cells. RNA interference also pointed at a role of endogenous MPO in tubulogenesis and endothelium wound repair in vitro. These data suggest that MPO, whether from endogenous or exogenous sources, could play a role in angiogenesis and vascular repair in vivo. PMID- 30016635 TI - Medical Tourists: Incoming and Outgoing. PMID- 30016637 TI - Cellular alignment and fusion: Quantifying the effect of macrophages and fibroblasts on myoblast terminal differentiation. AB - Successful skeletal muscle wound repair requires the alignment and fusion of myoblasts to generate multinucleated myofibers. In vitro, the accurate quantification of cellular alignment remains a challenge. Here we present the application of ImageJ and ct-FIRE to quantify muscle cell orientation by means of an alignment index (AI). Our optimised method, which does not require programming skills, allows the alignment of myoblasts in vitro to be determined independently of a predefined reference point. Using this method, we demonstrate that co culture of myoblasts with macrophages, but not fibroblasts, promotes myoblast alignment in a cell density-dependent manner. Interestingly, myoblast fusion was significantly decreased in response to co-culture with macrophages, while the effect of fibroblasts on fusion was density-dependent. At lower numbers, fibroblasts significantly increased myoblast fusion, whereas at higher numbers a significant decrease was observed. Finally, triple co-culture revealed that the effect of macrophages on myoblast alignment and fusion is unaltered by the additional presence of fibroblasts. Application of our optimised method has therefore revealed quantitative differences in the roles of macrophages versus fibroblasts during alignment and fusion: while successful myoblast alignment is promoted by increasing macrophage numbers, regenerative fusion coincides with a decreasing macrophage population and initial rise in fibroblast numbers. PMID- 30016638 TI - An extracellular matrix (ECM) model at high malignant colorectal tumor increases chondroitin sulfate chains to promote epithelial-mesenchymal transition and chemoresistance acquisition. AB - Chemoresistance is one of the major barriers for tumor chemotherapy. It is clinically known that chemoresistance increases during tumor progression. Additionally, the extracellular matrix (ECM) is also remodeled during tumor progression. However, it remains unclear how ECM remodeling contributes to chemoresistance acquisition. Recently, it has been reported that epithelial mesenchymal transition (EMT) contributes to chemoresistance acquisition. Here, how ECM remodeling contributes to 5-fluorouracil (5-FU) resistance acquisition was investigated from the viewpoints of EMT using in vitro ECM models mimicking native ECM in colorectal tumor tissue at three different malignant levels. 5-FU partially induced EMT and increased ABCB1 in colorectal HT-29 cells via TGF-beta signaling (an invasive tumor cell model). When HT-29 cells were cultured on an ECM model (high malignant matrices) mimicking native ECM in highly malignant tumor tissues, the cells facilitated TGF-beta-induced EMT and increased ABCB1 upregulation compared with that of other ECM models mimicking the low malignant level and normal tissues. High malignant matrices contained more chondroitin sulfate (CS) chains than those of other ECM models. Finally, CS chain-reduced high malignant matrices could not facilitate ABCB1 upregulation and TGF-beta induced EMT. These results demonstrated that ECM remodeling during tumor progression increased CS chains to facilitate EMT and ABCB1 upregulation, contributing to chemoresistance acquisition. PMID- 30016636 TI - Trends in 30-Day Readmission Rates for Medicare and Non-Medicare Patients in the Era of the Affordable Care Act. AB - BACKGROUND: Temporal changes in the readmission rates for patient groups and conditions that were not directly under the purview of the Hospital Readmissions Reduction Program (HRRP) can help assess whether efforts to lower readmissions extended beyond targeted patients and conditions. METHODS: Using the Nationwide Readmissions Database (2010-2015), we assessed trends in all-cause readmission rates for 1 of the 3 HRRP conditions (acute myocardial infarction, heart failure, pneumonia) or conditions not targeted by the HRRP in age-insurance groups defined by age group (>=65 years or <65 years) and payer (Medicare, Medicaid, or private insurance). RESULTS: In the group aged >=65 years, readmission rates for those covered by Medicare, Medicaid, and private insurance decreased annually for acute myocardial infarction (risk-adjusted odds ratio [OR; 95% confidence interval] among Medicare patients, 0.94 [0.94-0.95], among Medicaid patients, 0.93 [0.90 0.97], and among patients with private-insurance, 0.95 [0.93-0.97]); heart failure (ORs, 0.96 [0.96-0.97], 0.96 [0.94-0.98], and 0.97 [0.96-0.99], for the 3 payers, respectively), and pneumonia (ORs, 0.96 [0.96-0.97), 0.94 [0.92-0.96], and 0.96 [0.95-0.97], respectively). Readmission rates also decreased in the group aged <65 years for acute myocardial infarction (ORs: Medicare 0.97 [0.96 0.98], Medicaid 0.94 [0.92-0.95], and private insurance 0.93 [0.92-0.94]), heart failure (ORs, 0.98 [0.97-0.98]: 0.96 [0.96-0.97], and 0.97 [0.95-0.98], for the 3 payers, respectively), and pneumonia (ORs, 0.98 [0.97-0.99], 0.98 [0.97-0.99], and 0.98 [0.97-1.00], respectively). Further, readmission rates decreased significantly for non-target conditions. CONCLUSIONS: There appears to be a systematic improvement in readmission rates for patient groups beyond the population of fee-for-service, older, Medicare beneficiaries included in the HRRP. PMID- 30016641 TI - Design and semisynthesis of new herbicide as 1,2,3-triazole derivatives of the natural maslinic acid. AB - Interesting biological activities (anti-inflammatory, anticancer, antiviral, antioxidant, antidiabetic...) have been reported for maslinic acid (MA) and MA based compounds. In continuation of our previous work on MA, herbicide potential of Tunisian plant extracts and 1,4-triazolyl derivatives of MA, we now wish to report semisynthesis of new MA-based triazole hybrid compounds with herbicide potential. These compounds were synthesized through Cu-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave irradiation conditions between propargylated MA and a series of phthalimide azides. Here, the first partner of CuAAC reaction (propargylated MA) resulted from propargylation of C-28 carboxylic acid group of isolated MA from the well-known Mediterranean plant Olea europaea L. (Oleaceae). So far, phthalimide azide derivatives were achieved by trapping of N-acyliminium ion, in-situ generated under catalytic condition of Bi(OTf)3, by aromatic nucleophiles. The cycloaddition reaction afforded regiospecifically 1,4 disubstituted triazoles in good yields. The latter hybrid compounds were shown to exhibit a high inhibition potential of seed germination. This constitutes the first step in development of potent herbicides since one of the final semisynthesized structures can serve as a promising lead candidate for further studies. PMID- 30016639 TI - The phenotypic and functional properties of mouse yolk-sac-derived embryonic macrophages. AB - Macrophages are well characterized as immune cells. However, in recent years, a multitude of non-immune functions have emerged many of which play essential roles in a variety of developmental processes (Wynn et al., 2013; DeFalco et al., 2014). In adult animals, macrophages are derived from circulating monocytes originating in the bone marrow, but much of the tissue-resident population arise from erythro-myeloid progenitors (EMPs) in the extra-embryonic yolk sac, appearing around the same time as primitive erythroblasts (Schulz et al., 2012; Kierdorf et al., 2013; McGrath et al., 2015; Gomez Perdiguero et al., 2015; Mass et al., 2016). Of particular interest to our group, macrophages have been shown to act as pro-angiogenic regulators during development (Wynn et al., 2013; DeFalco et al., 2014; Hsu et al., 2015), but there is still much to learn about these early cells. The goal of the present study was to isolate and expand progenitors of yolk-sac-derived Embryonic Macrophages (EMs) in vitro to generate a new platform for mechanistic studies of EM differentiation. To accomplish this goal, we isolated pure (>98%) EGFP+ populations by flow cytometry from embryonic day 9.5 (E9.5) Csf1r-EGFP+/tg mice, then evaluated the angiogenic potential of EMs relative to Bone Marrow-Derived Macrophages (BMDMs). We found that EMs expressed more pro-angiogenic and less pro-inflammatory macrophage markers than BMDMs. EMs also promoted more endothelial cell (EC) cord formation in vitro, as compared to BMDMs in a manner that required direct cell-to-cell contact. Importantly, EMs preferentially matured into microglia when co-cultured with mouse Neural Stem/Progenitor Cells (NSPCs). In conclusion, we have established a protocol to isolate and propagate EMs in vitro, have further defined specialized properties of yolk-sac-derived macrophages, and have identified EM-EC and EM-NSPC interactions as key inducers of EC tube formation and microglial cell maturation, respectively. PMID- 30016642 TI - Near complete interocular transfer of the attentional repulsion effect. AB - During a brief period following attention capture by an abrupt-onset cue, a briefly presented item in the vicinity appears to be displaced away from the focus of attention. This effect, termed the attentional repulsion effect (ARE), can be induced with various ways of focusing attention (e.g., color pop-out, an auditory cue, voluntary focusing), and can be measured in various ways (e.g., as a vernier offset, shape deformation, action error). While most prior results on ARE have confirmed its close relationship with attention mechanisms, DiGiacomo and Pratt Vision Research 64 (2012) 35-41 reported no interocular transfer of ARE, placing ARE's operational locus at the level of monocular processing in V1 and/or LGN. DiGiacomo's and Pratt's result is surprising because even local pattern adaptation effects thought to be mediated by V1 show 50%-80% of interocular transfer. How could it be that a strongly attention-dependent effect is exclusively mediated by monocular processes? It was thus important to replicate DiGiacomo's and Pratt's surprising results using a transient-free mirror-based stereoscope and a broader method where ARE was measured with both vertical and horizontal vernier offsets. Our results demonstrate a nearly complete interocular transfer of ARE, with stronger ARE obtained with horizontal than with vertical verniers, implying that ARE may be hemifield dependent. We speculate that the null ARE result reported by DiGiacomo and Pratt in their dichoptic condition may be due to a statistical anomaly or to a potential visual artifact generated by the eye shutters that were used to present dichoptic stimuli. PMID- 30016643 TI - Two morbidity indices developed in a nationwide population permitted performant outcome-specific severity adjustment. AB - OBJECTIVE: The objective of the study was to develop and validate two outcome specific morbidity indices in a population-based setting: the Mortality-Related Morbidity Index (MRMI) predictive of all-cause mortality and the Expenditure Related Morbidity Index (ERMI) predictive of health care expenditure. STUDY DESIGN AND SETTING: A cohort including all beneficiaries of the main French health insurance scheme aged 65 years or older on December 31, 2013 (N = 7,672,111), was randomly split into a development population for index elaboration and a validation population for predictive performance assessment. Age, gender, and selected lists of conditions identified through standard algorithms available in the French health insurance database (SNDS) were used as predictors for 2-year mortality and 2-year health care expenditure in separate models. Overall performance and calibration of the MRMI and ERMI were measured and compared to various versions of the Charlson Comorbidity Index (CCI). RESULTS: The MRMI included 16 conditions, was more discriminant than the age adjusted CCI (c-statistic: 0.825 [95% confidence interval: 0.824-0.826] vs. 0.800 [0.799-0.801]), and better calibrated. The ERMI included 19 conditions, explained more variance than the cost-adapted CCI (21.8% vs. 13.0%), and was better calibrated. CONCLUSION: The proposed MRMI and ERMI indices are performant tools to account for health-state severity according to outcomes of interest. PMID- 30016644 TI - Activities, bioavailability, and metabolism of lipids from structural membranes and oils: Promising research on mild cognitive impairment. AB - Concomitant with increased lifespan, large segments of the population are experiencing cognitive decline, which might progress to Alzheimer's disease (AD). Currently, there is no cure for AD and, once the neurodegenerative disorders are established, patients use pharmacologic therapy to slow the progression of the symptoms and require appropriate care to manage their condition. The preclinical stage of neural degeneration that progress through mild cognitive impairment (MCI) before the onset of AD is when it might be possible to introduce behavioral changes and pharma-nutritional interventions that modify the risk factors of MCI conversion to AD. Some food components accumulate in brain tissues, where they play essential roles. Among them, polar lipids, omega 3 fatty acids, and carotenoids appear to work additively or synergistically. Therefore, there is an opportunity to formulate nutraceuticals/functional foods to slow the progression of MCI. In this paper, we review the biochemical bases and recent interventions with bioactive lipids-rich formulations. Based on accumulated evidence, we propose that appropriate large-scale trials are warranted. PMID- 30016640 TI - The b-HLH transcription factor Hes3 participates in neural plate border formation by interfering with Wnt/beta-catenin signaling. AB - Hes3 belongs to the Hes basic helix-loop-helix family of transcriptional repressors that play central roles in maintaining progenitor cells and regulating binary cell fate decisions in the embryo. During Xenopus laevis development, hes3 is expressed in the embryonic ectoderm in a horseshoe shape domain at the edge of the developing neural pate. Hes3 mis-expression at early neurula stage blocks neural crest (snai2, sox8, sox9 and sox10) and cranial placode (six1 and dmrta1) gene expression, and promotes neural plate (sox2 and sox3) fate. At tailbud stage, these embryos exhibited a massive up-regulation of both sox8 and sox10 expression, associated with an increase in genes important for melanocytes differentiation (mitf and dct). Using a hormone inducible construct we show that Hes3 does not induce a pigment cell differentiation program de novo, rather it maintains progenitor cells in an undifferentiated state, and as Hes3 expression subsides overtime these cells adopt a pigment cell fate. We demonstrate that mechanistically Hes3 mediates its activity through inhibition of Wnt/beta-catenin signaling, a molecular pathway critical for neural crest specification and pigment cell lineage differentiation. We propose that Hes3 at the edge of the neural plate spatially restricts the response to mesoderm-derived Wnt ligands, thereby contributing to the establishment of sharp boundaries of gene expression at the neural plate border. PMID- 30016645 TI - Modulation of calcium oxalate dihydrate growth by phosphorylated osteopontin peptides. AB - Osteopontin (OPN) is a significant component of kidney stone matrix and a key modulator of stone formation. Here, we investigated the effects of different phosphorylated states of a synthesized peptide of OPN (the ASARM peptide; acidic, serine- and aspartate-rich motif) on calcium oxalate dihydrate (COD) crystals, a major mineral phase of kidney stones. In vitro, phosphorylated OPN-ASARM peptides strongly inhibited COD crystal growth in solution as compared to the nonphosphorylated state, with increasing inhibitory potency correlating with the degree of peptide phosphorylation. Scanning electron microscopy revealed that the inhibition from the phosphopeptides resulted in distinctive, rosette-like crystal aggregates called spherulites. The OPN-ASARM peptides preferentially bound and specifically inhibited the {1 1 0} crystallographic faces of COD, as identified by combining atomic force microscopy and computational simulation approaches. These {1 1 0} surfaces of COD have high lattice calcium occupancy (exposure), providing preferential binding sites for the highly acidic peptides; binding and inhibition by OPN-ASARM peptides at the {1 1 0} faces led to crystal aggregation and intergrowth. The crystal spherulite formations obtained in vitro when using the most phosphorylated form of OPN-ASARM peptide at a high concentration, resembled crystal morphologies observed in vivo in a rat model of urolithiasis, in which crystal deposits in the kidney contain abundant OPN as revealed by immunogold labeling. A mechanistic model for spherulite formation is proposed based on the symmetry and crystallographic structure of COD, where the phosphate groups of OPN-ASARM bind to calcium atoms at [1 1 1] step risers on the COD {1 1 0} surface, inducing the periodic emergence of new COD crystals to form spherulites. PMID- 30016646 TI - Ric-8A, a GEF for heterotrimeric G-proteins, controls cranial neural crest cell polarity during migration. AB - The neural crest (NC) is a transient embryonic cell population that migrates extensively during development. Ric-8A, a guanine nucleotide exchange factor (GEF) for different Galpha subunits regulates cranial NC (CNC) cell migration in Xenopus through a mechanism that still remains to be elucidated. To properly migrate, CNC cells establish an axis of polarization and undergo morphological changes to generate protrusions at the leading edge and retraction of the cell rear. Here, we aim to study the role of Ric-8A in cell polarity during CNC cell migration by examining whether its signaling affects the localization of GTPase activity in Xenopus CNC using GTPase-based probes in live cells and aPKC and Par3 as polarity markers. We show that the levels of Ric-8A are critical during migration and affect the localization of polarity markers and the subcellular localization of GTPase activity, suggesting that Ric-8A, probably through heterotrimeric G-protein signaling, regulates cell polarity during CNC migration. PMID- 30016647 TI - Novel dry powder inhaler formulation containing antibiotic using combined technology to improve aerodynamic properties. AB - Dry Powder Inhaler (DPI) could offer a propellant-free, easy-to-use powder form ensuring better stability than liquid dosage forms. Therefore the development of traditional carrier-based and carrier-free new generation systems is a determinative factor in the field of DPI formulation. The purpose of our research work was to combine these two systems, utilizing their beneficial properties to produce a novel pulmonary drug delivery system containing ciprofloxacin hydrochloride (CIP). Co-spray drying, surface smoothing and the preparation of an interactive physical mixture were applied as the technological procedures of sample preparation. The carrier-based and carrier-free formulations, as well as the developed novel product were compared to each other. Structural investigations were made by X-ray powder diffraction and micrometric properties (habit, bulk density) were determined. Particle interactions were also evaluated to investigate surface free energy, cohesive-adhesive forces, and spreading coefficient. In vitro aerodynamic properties (mass median aerodynamic diameter), fine particle fraction (FPF) and emitted dose of DPIs were measured using Andersen Cascade Impactor. A novel in silico Stochastic Lung Model was also used to quantify the amount of particles deposited at the target area. The novel formulated composition presented amorphous spherical particles with an average size of about 2 MUm. The in vitro aerodynamic investigations showed a variance in FPF as a function of formulation method (carrier-based: 24%, carrier-free: 54% and applying the novel combination method: 63%). The in silico deposition results were in line with the in vitro measurements and yielded increased lung doses for the sample prepared by the combined technology. This novel DPI formulation provides an opportunity for a more effective therapy with deeper deposition of CIP. PMID- 30016648 TI - Reversal of epigenetic aberrations associated with the acquisition of doxorubicin resistance restores drug sensitivity in breast cancer cells. AB - Acquired resistance against doxorubicin is a major limitation in clinical treatment of breast cancer. The molecular mechanism behind the aberrant expression of genes leading to doxorubicin resistance is not clear. Epigenetic changes play an important role in the regulation of gene expression. Therefore, the objective of this study was to identify the epigenetic mechanism underlying acquired doxorubicin resistance in breast cancer cells. Doxorubicin-resistant cells were selected by repeated exposure of MCF-7 and MDA-MB-231 breast cancer cell lines to clinically relevant doses of doxorubicin for 18 months. MTT assay, cell cycle analysis, colony formation, qRT-PCR, and Western blot analyses were used to characterize the epigenetic and molecular mechanism. Pyrosequencing was used to detect MSH2 promoter hypermethylation. Aberrant expression of epigenetic regulatory genes, a significant increase in H3 acetylation and methylation, as well as promoter hypermethylation-mediated inactivation of MSH2 gene were associated with the acquired resistant phenotype. Demethylating agent 5-Aza deoxycytidine and HDAC inhibitor Trichostatin A significantly re-sensitized resistant cells to doxorubicin. Findings of this study revealed that epigenetic aberrations including promoter hypermethylation-mediated inactivation MSH2 contribute to the acquisition of doxorubicin resistance in breast cancer cells. Additionally, our data suggest that some of these epigenetic aberrations are progressive during resistance development and therefore can potentially be used as biomarkers for early detection of resistance. These epigenetic aberrations, being reversible, can also serve as targets for epigenetic therapy to re sensitize doxorubicin-resistant breast cancer cells. Epigenetic inactivation of mismatch repair gene MSH2 further suggests that loss of MMR-dependent apoptotic potential could be a novel mechanistic basis for the acquisition of doxorubicin resistance in breast cancer cells. PMID- 30016649 TI - Outbreak of West Nile Virus disease in Israel (2015): A retrospective analysis of notified cases. AB - BACKGROUND: West Nile Virus (WNV) is mosquito-borne virus that is endemic in Israel. In 2015, national disease surveillance demonstrated a sharp increase in disease cases, with 149 cases diagnosed. METHODS: Clinical data was extracted from the patients' medical files and laboratory analysis on blood, cerebrospinal fluid or urine was carried out. Data on climate was extracted from the Israel Meteorological Service. RESULTS: Neuroinvasive disease was reported in 70% of cases and case-fatality rate was 16%. Simultaneously with the outbreak, an intense heat wave and an upsurge in summer temperatures occurred. CONCLUSIONS: Clinical data shows substantial morbidity and mortality of WNV disease in Israel. Climatic measures are consistent with previous reports and point to the importance of temperature monitoring and rapid implementation of preventive environmental measures during the summer to reduce potential mosquito breeding sites. WNV disease should be suspected as a cause of fever or neurologic disease in travelers returning from endemic countries. PMID- 30016650 TI - Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors. AB - Fibrillin microfibrils are extensible polymers that endow connective tissues with long-range elasticity and have widespread distributions in both elastic and non elastic tissues. They act as a template for elastin deposition during elastic fibre formation and are essential for maintaining the integrity of tissues such as blood vessels, lung, skin and ocular ligaments. A reduction in fibrillin is seen in tissues in vascular ageing, chronic obstructive pulmonary disease, skin ageing and UV induced skin damage, and age-related vision deterioration. Most mutations in fibrillin cause Marfan syndrome, a genetic disease characterised by overgrowth of the long bones and other skeletal abnormalities with cardiovascular and eye defects. However, mutations in fibrillin and fibrillin-binding proteins can also cause short-stature pathologies. All of these diseases have been linked to dysregulated growth factor signalling which forms a major functional role for fibrillin. PMID- 30016651 TI - Multilocus phylogeny of the zebra mussel family Dreissenidae (Mollusca: Bivalvia) reveals a fourth Neotropical genus sister to all other genera. AB - Dreissenidae is one of the most economically and ecologically important families of freshwater and estuarine mollusks. Fourteen extant species and three genera are currently recognized: Congeria contains three species from karst caves along the eastern Adriatic coast and one from the Orinoco River of Venezuela, Dreissena contains six species native to Eastern European rivers and estuaries, and Mytilopsis contains three species from the Gulf of Mexico, Caribbean, and northwestern coast of South America and one from the Tocantins River of Brazil. Previous molecular phylogenetic studies have examined all species except those from South American rivers, and found each genus to be monophyletic with Congeria and Mytilopsis forming a clade sister to Dreissena. We present the first multilocus phylogeny of Dreissenidae inclusive of South American riverine species. Bayesian and maximum likelihood analyses of a 3085 bp alignment consisting of mitochondrial (COI and 16S) and nuclear (18S and 28S) gene regions found Neotropical species to be consistently and strongly supported as sister to all other dreissenids, although incomplete sequencing of the single Orinoco specimen obscured Neotropical monophyly. Our intergeneric relationships are inconsistent with an extensive fossil record suggesting that dreissenids originated in Europe approximately 30 My before dispersing to the Western Hemisphere. Fossil-calibrated analyses indicated that Neotropical dreissenids diverged from European lineages in the mid to late Eocene (~39.3 Ma), and Brazilian and Guiana shield populations diversified during the Oligocene to Miocene. We erect the new genus Rheodreissena for all Neotropical freshwater dreissenids and present haplotype data indicative of at least three species. Widespread anthropogenic alteration of the middle Xingu River and lower Amazon threatens the persistence of these endemic, poorly studied mussels and may facilitate introduction beyond their native range. PMID- 30016652 TI - Para-tertiary butyl catechol induces eryptosis in vitro via oxidative stress and hemoglobin leakage in human erythrocytes. AB - Exposure of human population to industrial chemicals is believed as a significant contributing factor to the outgrowth of occupational diseases especially in developing countries due to improper safety measures and sanitary conditions. Para-tertiary butylcatechol (PTBC) widely employed in petrochemical, thermofax and phototypesetting industries, induces melanocytotoxicity and contact dermatitis leading to occupational leukoderma/vitiligo. Few vitiligo patients were reported for oxidative stress-induced hemolytic anemia and thrombocytopenia, however its impact on blood components is still not clear. Erythrocytes are the major cell population in circulation and play a prominent role in various diseases. In this work, the effect of PTBC on human erythrocytes is evaluated in vitro. PTBC induces oxidative stress-mediated eryptosis (erythrocyte death) causing detrimental changes such as depleted antioxidant levels, altered surface morphology, hemoglobin denaturation and heinz body formation. These findings validate that PTBC could induce toxic effects on human erythrocytes. Exposure of humans to toxic chemicals constitutes an important issue in various industries; one such issue is the exposure of PTBC at work place resulting in a spectrum of dermal complications. Therefore, it is imperative to appraise the long-term toxicities in order to further delineate the mechanisms of resultant disorders associated with PTBC and to establish the therapeutic interventions. PMID- 30016654 TI - Co-expression of squalene epoxidases with triterpene cyclases boosts production of triterpenoids in plants and yeast. AB - Triterpene cyclases catalyze the first committed step in triterpene biosynthesis, by forming mono- to pentacyclic backbone structures from oxygenated C30 isoprenoid precursors. Squalene epoxidase precedes this cyclization by providing the oxygenated and activated substrate for triterpene biosynthesis. Three squalene epoxidases from Cucurbita pepo (CpSEs) were isolated and shown to have evolved under purifying selection with signs of sites under positive selection in their N- and C-termini. They all localize to the Endoplasmic Reticulum (ER) and produce 2,3-oxidosqualene and 2,3:22,23-dioxidosqualene when expressed in a yeast erg1 (squalene epoxidase) erg7 (lanosterol synthase) double mutant. Co-expression of the CpSEs with four different triterpene cyclases, either transiently in Nicotiana benthamiana or constitutively in yeast, showed that CpSEs boost triterpene production. CpSE2 was the best performing in this regard, which could reflect either increased substrate production or superior channeling of the substrate to the triterpene cyclases. Fluorescence Lifetime Imaging Microscopy (FLIM) analysis with C. pepo cucurbitadienol synthase (CpCPQ) revealed a specific interaction with CpSE2 but not with the other CpSEs. When CpSE2 was transformed into C. pepo hairy root lines, cucurbitacin E production was increased two folds compared to empty vector control lines. This study provides new insight into the importance of SEs in triterpene biosynthesis, suggesting that they may facilitate substrate channeling, and demonstrates that SE overexpression is a new tool for increasing triterpene production in plants and yeast. PMID- 30016655 TI - Multifaceted Burden of Chronic Graft-versus-Host Disease. PMID- 30016653 TI - In vitro potency determination of botulinum neurotoxin serotype A based on its receptor-binding and proteolytic characteristics. AB - Botulinum neurotoxins (BoNTs) inhibit the release of the neurotransmitter acetylcholine from motor neurons, resulting in highly effective muscle relaxation. In clinical and aesthetic medicine, serotype BoNT/A, which is most potent for humans, is widely used to treat a continuously increasing spectrum of disorders associated with muscle overactivity. Because of the high toxicity associated with BoNTs, it is mandatory to precisely determine the potency of every batch produced for pharmaceutical purposes. Here we report a new quantitative functional in vitro assay for BoNT/A. In this binding and cleavage (BINACLE) assay, the toxin is first bound to specific receptor molecules. Then a chemical reduction is performed, thereby releasing the light chain of BoNT/A and activating its proteolytic domain. The activated light chain is finally exposed to its substrate protein SNAP-25, and the fragment resulting from the proteolytic cleavage of this protein is quantified in an antibody-mediated reaction. The BoNT/A BINACLE assay offers high specificity and sensitivity with a detection limit below 0.5 mouse lethal dose (LD50)/ml. In conclusion, this new in vitro assay for determining BoNT/A toxicity represents an alternative to the LD50 test in mice, which is the "gold standard" method for the potency testing of BoNT/A products. PMID- 30016656 TI - Impact of Induction Therapy on the Outcome of Immunoglobulin Light Chain Amyloidosis after Autologous Hematopoietic Stem Cell Transplantation. AB - With the availability of immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy before autologous hematopoietic stem cell transplantation (auto-HCT). In this study we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. We identified 128 patients with AL who underwent high-dose chemotherapy and auto-HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: no induction, conventional chemotherapy (CC)-based induction (melphalan, steroids), and IMiD/PI-based induction (thalidomide, lenalidomide, or bortezomib). The hematologic response (HR) and organ response were defined according to the established criteria. Median age at auto-HCT was 58 years (range, 35 to 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC, and 83 (65%) received IMiDs/PIs. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), and 18 (14%) patients, respectively. After auto-HCT 12 of 20 (60%), 15 of 24 (62%), and 72 of 83 (87%) assessable patients achieved HR at 100 days in no induction, CC, and IMiD/PI groups, respectively (P = .001). Organ response at 1 year after auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%), and 37 of 79 (47%) assessable patients in no induction, CC, and IMiD/PI groups, respectively (P = .3). Achieving a hematologic complete response was associated with a significantly higher probability of achieving an organ response (P = .02). After a median follow-up of 26 months, rates of 2-year progression-free survival were 67%, 56%, and 73% in no induction, CC, and IMiD/PI groups, respectively (P = .07; hazard ratio, .5; 95% confidence interval [CI], .3 to 1.1). Rates of 2-year overall survival were 73%, 76%, and 87% in no induction, CC, and IMiD/PI groups, respectively (P = .05; hazard ratio, .4; 95% CI, .2 to .9). On multivariate analysis a low beta2-microglobulin (P = .01; hazard ratio, .3; 95% CI, .1 to .7) and induction therapy with IMiD/PI (P = .01; hazard ratio, .3; 95% CI, .1 to .7) were associated with a better overall survival. Induction therapy with either CC or IMiDs/PIs is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer overall survival compared with patients who received no induction or CC before auto-HCT. PMID- 30016657 TI - Spirulina maxima peptides suppress mast cell degranulation via inactivating Akt and MAPKs phosphorylation in RBL-2H3 cells. AB - In this study, the suppressive effects of peptides P1 (LDAVNR) and P2 (MMLDF) from enzymatic hydrolysate of Spirulina maxima on mast cell degranulation was elucidated. It was revealed that P1 and P2 exhibited significant inhibition on cell degranulation via decreasing beta-hexosaminidase release at concentration of 200 MUM. Moreover, the inhibitory effects of P1 and P2 on expression and production of interleukin (IL)-13 were evidenced. Furthermore, peptide treatment caused a remarkable inhibition on the phosphorylation of Akt and mitogen activated protein kinases (MAPKs) including ERK, p38, and JNK. Notably, the inhibitory activity of P1 on cell degranulation was found due to blockade of FcepsilonRI receptor. Meanwhile, the inhibitory activity of P2 was involved in alleviation of intracellular reactive oxygen species (ROS) production. Collectively, peptides P1 and P2 from S. maxima were suggested to be promising inhibitors of mast cell degranulation, contributing to the development of bioactive ingredients for amelioration of allergic diseases. PMID- 30016658 TI - Structural basis for the substrate recognition of peptidoglycan pentapeptides by Enterococcus faecalis VanYB. AB - Vancomycin resistance in Enterococci and its transfer to methicillin-resistant Staphylococcus aureus are challenging problems in health care institutions worldwide. High-level vancomycin resistance is conferred by acquiring either transposable elements of the VanA or VanB type. Enterococcus faecalis VanYB in the VanB-type operon is a d,d-carboxypeptidase that recognizes the peptidyl-d Ala4-d-Ala5 extremity of peptidoglycan and hydrolyses the terminal d-Ala on the extracellular side of the cell wall, thereby increasing the level of glycopeptide antibiotics resistance. However, at the molecular level, it remains unclear how VanYB manipulates peptidoglycan peptides for vancomycin resistance. In this study, we have determined the crystal structures of E. faecalis VanYB in the d Ala-d-Ala-bound, d-Ala-bound, and -unbound states. The interactions between VanYB and d-Ala-d-Ala observed in the crystal provide the molecular basis for the recognition of peptidoglycan substrates by VanYB. Moreover, comparisons with the related VanX and VanXY enzymes reveal distinct structural features of E. faecalis VanYB around the active-site cleft, thus shedding light on its unique substrate specificity. Our results could serve as the foundation for unravelling the molecular mechanism of vancomycin resistance and for developing novel antibiotics against the vancomycin-resistant Enterococcus species. PMID- 30016659 TI - Effect of hydrothermal modifications on properties and digestibility of grass pea starch. AB - This study aimed to investigate functional and thermal properties and digestibility of grass pea starch, and provide information on the effect of hydrothermal modifications - annealing (ANN) and heat-moisture treatment (HMT) on the physico-chemical characteristics of the starch and digestibility, especially after processing (cooking, storage after cooking and freezing). After heat treatment, especially after cooking and storage at a temperature of -18 degrees C, the total content of slowly digestible starch and resistant starch in grass pea starch was high, which may indicate its great tendency for retrogradation. The HMT and ANN modifications of grass pea starch caused changes in its crystalline structure and increased integrity of its granules, which in turn resulted in a lower swelling power and amylose leaching, however this effect was more pronounced upon HMT which contributed to starch polymorphic type transformation from C to A. Despite greater resistance of granules of modified starches to swelling during cooking their suspensions, after cooking these starches were characterized by a higher predicted glycemic index than the non modified ones. A similar content of resistant starch determined in modified and non-modified gelatinized starches stored at lowered temperatures indicates that starch modifications, HMT in particular, cause no changes in its susceptibility to retrogradation. PMID- 30016660 TI - Effect of plasticizers on microstructure, compatibility and mechanical property of hydroxypropyl methylcellulose/hydroxypropyl starch blends. AB - Polymer film blends of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl starch (HPS) were produced with an incorporation of three different plasticizers, including polyethylene glycol (PEG), glycerol and 1, 2-propylene glycol (PG) respectively, and the influence of these plasticizers were compared and studied by X-ray Diffraction (XRD), small angel X-ray Scattering (SAXS), optical microscope and dynamic mechanical analysis (DMA). Results showed that multi-scale structure of the blends were greatly affected by the plasticizers and therefore caused significant changes in mechanical properties. In the course, blends with glycerol presented lamellar structure rather than self-similar structure. Moreover, crystalline degree was increased with an order of glycerol > PEG > PG, whereas the compactness of amorphous region of all samples was decreased by PEG and PG. PMID- 30016661 TI - A novel porcine model of thrombotic myocardial infarction with cardiac dysfunction sensitive to dual antiplatelet therapy. AB - Few effective porcine models of myocardial infarction (MI) related to platelet thrombus formation are available. In this study, we established a novel porcine MI model and examined the effect of dual antiplatelet therapy (DAPT) with aspirin and prasugrel, a P2Y12 antagonist, using this MI model. Thrombotic MI was photochemically induced using rose bengal. Male miniature pigs were divided into 3 treatment groups: Sham, MI, and DAPT. In the DAPT group, aspirin (10 mg/kg, p.o.) and prasugrel (1 mg/kg, p.o.) were administered 4 h before photo irradiation. Platelet aggregation, MI volume, and cardiac function were evaluated 24 h after photo-irradiation. Inhibition of ADP-induced platelet aggregation in the DAPT group was about 45%, similar to the effects of DAPT in a clinical setting. No MI was observed in the Sham group, and MI volume was 12.9 +/- 2.9% in the left ventricle (P = 0.0016) in the MI group. Additionally, an increase in end systolic volume (P = 0.0006), and a decrease in stroke volume (P = 0.0001) and ejection fraction (P < 0.0001) were observed in the MI group compared to the Sham group without any changes in end-diastolic volume. DAPT significantly decreased MI volume (P = 0.0006) and ameliorated cardiac dysfunction compared to the MI group. In conclusion, a novel porcine model of thrombotic MI with cardiac dysfunction was established. In this model, DAPT decreased MI volume and ameliorated of cardiac dysfunction, suggesting that this porcine MI model could be useful for future research on MI and antithrombotic agents. PMID- 30016662 TI - Gasotransmitters and the immune system: Mode of action and novel therapeutic targets. AB - Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H2S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H2S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions. PMID- 30016663 TI - Sumatriptan effects on morphine-induced antinociceptive tolerance and physical dependence: The role of nitric oxide. AB - Sumatriptan, a 5HT (5-hydroxytryptamine)1B/1D receptor agonist, showed neuroprotection in different studies. The aim of the present study was to investigate the effect of sumatriptan on morphine-induced antinociceptive tolerance and physical dependence. We also investigated the possible role of nitric oxide (NO) on sumatriptan effects. Tolerance was induced by morphine injection (50, 50, 75 mg/kg) three times daily for five days. Antinociceptive latency after acute and chronic treatment with sumatriptan (0.001, 0.01, 0.1 and 1 mg/kg) was measured by hot plate test in morphine-dependent animals. To investigate the possible involvement of NO, different isoforms of nitric oxide synthase (NOS) inhibitors including L-NAME, aminoguanidine and 7-nitroindazole were co-administered with sumatriptan. Nitrite level in mice hippocampus was quantified by Griess method. To examine the role of sumatriptan on physical dependence, three parameters of withdrawal signs were recorded after injection of naloxone (4 mg/kg). Acute treatment with sumatriptan (0.01, 0.1 and 1 mg/kg) attenuated the antinociceptive tolerance (P < 0.001). Chronic injection of sumatriptan (0.001, 0.01 and 0.1 mg/kg), as well, decreased the antinociceptive tolerance (P < 0.001). Moreover, co-administration of NOS inhibitors prevented the effects of sumatriptan. Sumatriptan significantly increased the level of nitrite only after chronic administration. Sumatriptan administration showed no alteration in naloxone-precipitated withdrawal signs. Acute and chronic administration of sumatriptan attenuated morphine antinociceptive tolerance; at least in chronic phase via nitrergic pathway. Our data did not support beneficial effects of sumatriptan on morphine-induced physical dependence in mice. PMID- 30016664 TI - Characterization and molecular basis for the block of Kv1.3 channels induced by carvedilol in HEK293 cells. AB - Carvedilol is a non-selective beta-adrenoreceptor antagonist and exhibits a wide range of biological activities. The voltage-gated K+ (Kv) channel is one of the target ion channels of this compound. The rapidly activating Kv1.3 channel is expressed in several different tissues and plays an important role in the regulation of physiological functions, including cell proliferation and apoptosis. However, little is known about the possible action of carvedilol on Kv1.3 currents. Using the whole-cell configuration of the patch-clamp technique, we have revealed that exposure to carvedilol produced a concentration-dependent blocking of Kv1.3 channels heterologously expressed in HEK293 cells, with an IC50 value of 9.7 MUM. This chemical decelerated the deactivation tail current of Kv1.3 currents, resulting in a tail crossover phenomenon. In addition, carvedilol generated a markedly hyperpolarizing shift (20 mV) of the inactivation curve, but failed to affect the activation curve. Mutagenesis experiments of Kv1.3 channels identified G427 and H451, two related sites of TEA block, as important residues for carvedilol-mediated blocking. The present results suggest that carvedilol acts directly on Kv1.3 currents by inducing closed- and open-channel block and helps to elucidate the mechanisms of action of this compound on Kv channels. PMID- 30016666 TI - Prenatal stress leads to chromatin and synaptic remodeling and excessive alcohol intake comorbid with anxiety-like behaviors in adult offspring. AB - Epidemiologic evidence suggests that individuals during their prenatal development may be especially vulnerable to the effects of environmental factors such as stress that predisposes them to psychiatric disorders including alcohol use disorder (AUD) later in life. Currently, the epigenetic mechanisms of anxiety comorbid with AUD induced by prenatal stress (PRS) remain to be elucidated. Here, we examined anxiety-like and alcohol drinking behaviors in adult offspring of prenatally stressed dam (PRS-mice) using elevated plus maze, light/dark box and two-bottle free-choice paradigm. It was found that PRS-mice exhibit heightened anxiety-like behaviors and increased alcohol intake in adulthood and these behavioral deficits were associated with a significant decrease in dendritic spine density (DSD) in medial prefrontal cortex (mPFC) relative to non-stressed mice (NS mice). To determine the mechanisms by which PRS reduces DSD, we examined the expressions of key genes associated with synaptic plasticity, including activity regulated cytoskeleton associated protein (Arc), spinophilin (Spn), postsynaptic density 95 (Psd95), tropomyosin receptor kinase B (TrkB), protein kinase B (Akt), mammalian target of rapamycin (mTOR) and period 2 (Per2) in mPFC of PRS and NS mice. The mRNA levels of these genes were significantly decreased in PRS mice. Methylated DNA and chromatin immunoprecipitation studies revealed hyper DNA methylation or reduced histone H3K14 acetylation on promoters of above genes suggesting that epigenetic dysregulation may be responsible for the deficits in their expression. Findings from this study suggest that prenatal stress induced abnormal epigenetic mechanisms and synaptic plasticity-related events may be associated with anxiety-like and alcohol drinking behaviors in adulthood. PMID- 30016665 TI - The alpha6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation. AB - Novel treatments against migraine are an urgent medical requirement. The alpha6 subunit-containing GABAA receptors (alpha6GABAARs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of alpha6GABAARs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified alpha6GABAAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two alpha6GABAAR-active PAMs (Ro15-4513 and loreclezole), an alpha6GABAAR-inactive benzodiazepine (diazepam), an alpha6GABAAR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the alpha6GABAAR in TG is a novel drug target for TGVS activation and that alpha6GABAAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine. PMID- 30016667 TI - The NMDA receptor antagonist Radiprodil reverses the synaptotoxic effects of different amyloid-beta (Abeta) species on long-term potentiation (LTP). AB - Abeta1-42 is well accepted to be a primary early pathogenic agent in Alzheimer's disease (AD). However, other amyloid peptides are now gaining considerable attention as potential key participants in AD due to their proposed higher neuronal toxicity. Impairment of the glutamatergic system is also widely accepted to be associated with pathomechanisms underlying AD. There is ample evidence that Abeta1-42 affects GLUN2B subunit containing N-methyl-D-aspartate receptor function and abolishes the induction of long term potentiation (LTP). In this study we show that different beta-amyloid species, 1-42 Abeta1-42 and 1-40 (Abeta1-40) as well as post-translationally modified forms such as pyroglutamate modified amyloid-(AbetapE3) and nitrated Abeta (3NTyr10-Abeta), when applied for 90 min to murine hippocampal slices, concentration-dependently prevented the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with IC50s of 2, 9, 2 and 35 nM, respectively whilst having no effect on baseline AMPA receptor mediated fEPSPs. Abeta1-43 had no effect. Interestingly, the combination of all Abeta species did not result in any synergistic or additive inhibitory effect on LTP - the calculated pooled Abeta species IC50 was 20 nM. A low concentration (10 nM) of the GLUN2B receptor antagonist Radiprodil restored LTP in the presence of Abeta1-42, 3NTyr10-Abeta, Abeta1-40, but not AbetapE3. In contrast to AMPA receptor mediated fEPSPs, all different beta-amyloid species tested at 50 nM supressed baseline NMDA-EPSC amplitudes. Similarly, all different Abeta species tested decreased spine density. As with LTP, Radiprodil (10 nM) reversed the synaptic toxicity of Abeta species but not that of AbetapE3. These data do not support the enhanced toxic actions reported for some Abeta species such as AbetapE3, nor synergistic toxicity of the combination of different Abeta species. However, whilst in our hands AbetapE3-42 was actually less toxic than Abeta1-42, its effects were not reversed by Radiprodil indicating that the target receptors/subunits mediating such synaptotoxicity may differ between the different Abeta species tested. PMID- 30016668 TI - Decreased circular RNA hsa_circ_0001649 predicts unfavorable prognosis in glioma and exerts oncogenic properties in vitro and in vivo. AB - Glioma is a devastating disease with increasing incidence worldwide. Circular RNAs (circRNAs) was demonstrated to be involved in a wide range of pathophysiological processes, including tumorigenesis and development. Recently, the abnormally expressed hsa_circ_0001649 was found in several malignancies. In the current study, the expression levels of hsa_circ_0001649 in glioma and its clinical significance were explored. The biological functions including cell growth, colony-forming ability and apoptosis altered by hsa_circ_0001649 were further investigated in vitro. Tumor formation assay was also carried out to elucidate the oncogenic properties of hsa_circ_0001649. The data documented a decrease of hsa_circ_0001649 expression in glioma specimens and cell lines. In addition, down-regulated hsa_circ_0001649 is linked to larger tumor size (p = 0.002) and advanced WHO grade (p = 0.023). Additionally, hsa_circ_0001649 may be an independent prognostic marker for glioma patients after surgery (p = 0.046). Moreover, up-regulated hsa_circ_0001649 inhibits glioma cell growth in vitro and in vivo. Importantly, increased expression of hsa_circ_0001649 facilitates apoptosis by regulating Bcl-2/caspase-3 pathway. Ultimately, this study suggests that hsa_circ_0001649 may be a potential glioma-related prognostic/therapeutic target. PMID- 30016669 TI - Genome-wide DNA methylation analysis of the regenerative and non-regenerative tissues in sika deer (Cervus nippon). AB - Deer antlers, the secondary organs of deer, are a unique model to study regeneration of organ/tissue in mammals. Pedicle periosteum (PP) is the key tissue type for antler regeneration. Based on our previous study, the DNA methylation was found to be the basic molecular mechanism underlying the antler regeneration. In this study, we compare the genome-wide DNA methylation level in regenerative tissues (the potentiated PP of antler, muscle, heart and liver) and non-regenerative tissue (the dormant PP) of deer by the fluorescence-labeled methylation-sensitive amplified polymorphism (F-MSAP) method. Our results showed that DNA methylation level was significantly lower in the regenerative tissues compared to the non-regenerative tissue (P < 0.05). Furthermore, 26 T-DMRs which displayed different methylated status in regenerative and non-regenerative tissues were identified by the MSAP method, and were further confirmed by Southern blot analysis. Taken together, our data suggest that DNA methylation, an important epigenetic regulation mechanism, may play an important role in the mammalian tissue/organ regeneration. PMID- 30016670 TI - Identification of microRNAs involved in cold adaptation of Litopenaeus vannamei by high-throughput sequencing. AB - The Litopenaeus vannamei (L. vannamei) is one of the most widely cultured shrimp species in the world, with low temperature being one of the most serious threats to its growth and survival. To examine the potential regulatory mechanism of cold adaptation, we conducted a microRNAs (miRNAs) analysis on the hepatopancreas of L. vannamei under normal temperature 28 degrees C (M28), cold acclimation 16 degrees C for 6 days (M16), and recovered under normal temperature (MR). In total 14,754,823, 14,945,246 and 15,880,093 raw reads representing 10,690,259, 8,587,144, and 11,512,941 unique sequences of 18-32 nt length were obtained from the M28, M16 and MR libraries, respectively. After comparing the miRNA sequences with the miRBase database, 68 known mature miRNAs and 47 novel miRNAs were identified. Expression analysis showed that 34 miRNAs were significantly differential expressed in response to cold adaptation. Compared to the M28 library, 21 miRNAs were upregulated and 13 miRNAs were downregulated significantly in the M16 library. After recovery to normal temperature, there are 16 miRNAs upregulated and 15 miRNAs downregulated significantly compared to M28 library. Then, five significantly differential expressed miRNAs under cold acclimation including three known miRNAs (mja-miR-6491, mja-miR-6494, and Bta-miR 2478) and two newly-identified miRNAs (novel_68 and novel_5) were selected for validation by RT-qPCR in the hepatopancreas and muscle tissues of cold treated shrimps. The expression trend of most the miRNAs from RT-qPCR were consistent with the next-generation sequencing data. Further, the Gene Ontology (GO) annotation showed that the metabolic process GO term was significantly enriched with target genes of the differentially expressed miRNAs. Additionally, KEGG pathway analysis suggested that the fatty acid degradation and glycerolipid metabolism pathways etc. are significantly enriched with the target genes. These findings may contribute to a better understanding of the molecular mechanisms governing the responses to low temperature in L. vannamei. PMID- 30016671 TI - Multi-drug delivery system based on lipid membrane mimetic coated nano hydroxyapatite formulations. AB - Local delivery systems from an osteoconductive biomaterial are suggested as a promising strategy to avoid simultaneously peri-implant traumas and to induce tissue regeneration. In this work, it is detailed the design and construction of a multi-drug delivery formulation based on lipid membrane mimetic coated nano hydroxyapatite, LMm/nano-HA, as a bone-specific drug delivery approach. The optimal LMm/nano-HA formulation was selected after analysing the lipid/nano-HA interaction by dynamic light scattering (DLS), zeta-potential, transmission electron microscopy (TEM), polarized optical microscopy (POM), differential scanning calorimetry (DSC) and UV-vis spectroscopy. After the initial screening, Ciprofloxacin and Ibuprofen simultaneous -load and -release efficiency from selected LMm/nano-HA was assessed. pH-responsive kinetic profiles of local drug distribution were characterized and compared with currently applied systemic doses. Finally, the systems' biocompatibility and drug released activity were positively validated. The obtained results demonstrated that LMm/nano-HA formulations can represent a valuable multi-modal platform in bone tissue therapies. PMID- 30016672 TI - Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system. AB - Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state 13C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) - an estrogenic steroid molecule also containing an ethynyl functional group - to an addition cure silicone elastomer. By preparing silicone elastomer samples containing 13C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications. PMID- 30016673 TI - Gel formation of puerarin and mechanistic study during its cooling process. AB - Recently, low molecular weight gelators are getting increasing interests in pharmaceutical field. In the current study, puerarin (PUE), a natural and bioactive flavonoid from the plant Pueraria lobata, was found to be able to gelate water to form hydrogel during cooling down process of its hot solution. In order to explore its gelation mechanism, the crystallization process, characterization, interaction force, morphology, rheological properties of PUE hydrogel were investigated by polarized light microscopy (PLM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Karl Fischer (KF), Raman spectrum, 1H NMR, environmental scanning electron microscope (ESEM) and rheometer. The results indicated that at a high supersaturation condition, the gelation process of PUE was initiated by nucleation, and then fibers emanated rapidly from the nucleation center. The types of fiber growth changed from "fiber-like" growth to "less linear" growth as the increase of supersaturation, leading to a denser structure with higher fractal dimension and stronger mechanical properties. Notably, the CO?pi interaction facilitated the gelation assembly process, and the crystallographic mismatch branching played a vital role in constructing the network of PUE hydrogel. PMID- 30016674 TI - Applications of mesoporous silica in biosensing and controlled release of insulin. AB - The development of new oral insulin delivery systems could bring significant benefits to insulin-dependent patients due to the simplicity of the method, avoidance of pain caused by parenteral administration and maintenance of optimal therapeutic levels for a longer period. However, administration of such therapeutic proteins orally remains a challenge because insulin (Ins) is a very sensitive molecule and can be easily degraded under the existing pH conditions in the stomach and intestines. Moreover, due to the large size of insulin, intestinal epithelium permeability is very low. This could be improved by immobilizing insulin in the mesoporous silica pores (MSN), acting as a shield to protect the molecule integrity from the proteolytic degradation existing in the stomach and upper part of the small intestine. Due to the high adsorption capacity of insulin, biocompatibility, ease of functionalization with various organic and/or inorganic groups, high mechanical and chemical resistance, adjustable pore size and volume, MSN is considered an ideal candidate for the development of controlled release systems that are sensitive to various stimuli (pH, temperature) as well as to glucose. Modifying MSN surfaces by coating with various mucoadhesive polymers (chitosan, alginate, etc.) will also facilitate interaction with the intestinal mucus and improve intestinal retention time. Moreover, the development of glucose-responsive systems for achieving MSN-based self-regulated insulin delivery, decorated with various components serving as sensors - glucose oxidase (GODx) and phenylboronic acid (PBA) that can control the insulin dosage, avoiding overdose leading to serious hypoglycemia. MSN have also been tested for application as biosensors for glucose monitoring. PMID- 30016675 TI - Investigation of miscibility estimation methods between indomethacin and poly(vinylpyrrolidone-co-vinyl acetate). AB - The investigation of the miscibility between active pharmaceutical ingredients (API's) and polymeric excipients is of great interest for the formulation and development of amorphous solid dispersions, especially in the context of the prediction of the stability of these systems. Two different methods were applied to determine the miscibility between model compounds poly(vinylpyrrolidone-co vinyl acetate) (PVPVA) and indomethacin (IND), viz. the measurement of the glass transition temperature (Tg) and the melting point depression method framed on the Flory-Huggins theory. Measurement of the glass transition temperatures of the binary blends showed the formation of an amorphous single phase system between the PVPVA and the IND regardless of the composition. Variation of Tg with the composition was well described by the Gordon-Taylor equation leading to the error of concluding lack of intermolecular interactions between the materials. Application of the Brostow-Chiu-Kalogeras-Vassilikou-Dova (BCKV) model shows a negative interaction parameter (a0) suggesting the presence of drug-drug intermolecular interactions. Application of the melting point depression method within the framework of the Flory-Huggins theory proved the miscibility of the system at temperatures close to the melting point of IND. PMID- 30016676 TI - Changes in neonatal regional brain volume associated with preterm birth and perinatal factors. AB - BACKGROUND: Preterm birth is associated with altered brain development, with younger gestational age (GA) at birth often associated with greater brain volume reduction. Such volume alterations at term equivalent age (TEA) have been found with differing magnitude across different brain regions, although this has mostly been investigated with regards to whole tissue volumes and large-scale subdivisions. In addition to degree of prematurity, many other perinatal factors have been found to influence brain structure and development in infants born preterm. We aimed to clarify the relationships between degree of prematurity and regional brain volumes at TEA, and between perinatal factors and regional brain volumes at TEA, in finer spatial detail. METHODS: 285 preterm and term-born infants (GA at birth 24.6-42.1 weeks; 145 female; 59 born at term) were scanned at TEA. Data on perinatal factors were obtained by chart review, including sex, multiple birth, birthweight standard deviation (SD) score, postnatal growth and social risk. The Melbourne Children's Regional Infant Brain (M-CRIB) atlas was registered to the current sample, then 100 brain regions were labelled for volumetric analyses. Linear regressions with generalised estimating equations and likelihood ratio tests were performed to investigate whether GA at birth or perinatal factors were associated with regional volumes at TEA. RESULTS: Younger GA at birth was associated with smaller volumes at TEA in some regions including bilateral cerebral white matter, middle temporal gyri, amygdalae, pallidum and brainstem. In other regions, younger GA at birth was associated with larger volumes, including in primary visual, motor and somatosensory cortices. Positive associations between perinatal factors and regional volumes at TEA were found in many brain regions for birthweight SD score, and male sex, independent of GA at birth. These associations were seen on both univariable analyses, and multivariable analyses controlling for other perinatal factors. Social risk and multiple birth were generally not associated with regional brain volumes, and postnatal growth was associated with volume in many regions only after adjusting for other perinatal factors. CONCLUSIONS: These results elucidate regional brain volume differences associated with preterm birth and perinatal factors at a more detailed parcellated level than previously reported, and contribute to understanding of the complex array of correlates of preterm birth. PMID- 30016677 TI - Delta activity encodes taste information in the human brain. AB - The categorization of food via sensing nutrients or toxins is crucial to the survival of any organism. On ingestion, rapid responses within the gustatory system are required to identify the oral stimulus to guide immediate behavior (swallowing or expulsion). The way in which the human brain accomplishes this task has so far remained unclear. Using multivariate analysis of 64-channel scalp EEG recordings obtained from 16 volunteers during tasting salty, sweet, sour, or bitter solutions, we found that activity in the delta-frequency range (1-4 Hz; delta power and phase) has information about taste identity in the human brain, with discriminable response patterns at the single-trial level within 130 ms of tasting. Importantly, the latencies of these response patterns predicted the point in time at which participants indicated detection of a taste by pressing a button. Furthermore, taste pattern discrimination was independent of motor related activation and encoded taste identity rather than other taste features such as intensity and valence. On comparison with our previous findings from a delayed taste-discrimination task (Crouzet et al., 2015), taste-specific neural representations emerged earlier during this speeded taste-detection task, suggesting a goal-dependent flexibility in gustatory response coding. Together, these findings provide the first evidence of a role of delta activity in taste information coding in humans. Crucially, these neuronal response patterns can be linked to the speed of simple gustatory perceptual decisions - a vital performance index of nutrient sensing. PMID- 30016679 TI - Bacterial endotoxins and microorganisms in the oral cavities of patients on cancer therapy. AB - OBJECTIVES: This study investigated the presence of Streptococci, Staphylococci, aerobic gram negative bacteria (AGNB), Candida and bacterial endotoxins in the oral cavities of patients receiving chemo- and/or radiotherapy for cancer. METHODS: Samples of oral cavity rinse were collected from 100 patients on cancer treatment and 70 healthy individuals. Demographic and clinical data were recorded. Samples were cultured onto various agar plates for qualitative and quantitative analysis and tested for the presence of endotoxin. Results were analysed using the Mann-Whitney and chi-square tests. RESULTS: In cancer patients, S. aureus counts were high and 66.7% of patients on chemo- and radiotherapy carried these bacteria (p=<0.05). The Candida carrier rate was significantly (p < 0.01) high in cancer patients (54%). No significant difference was found in the carrier rate of Streptococci and AGNB between the healthy and cancer group as well as between the cancer patients with chemo and radio- and chemotherapy alone. No significant difference was found in the level of endotoxin between the cancer patients and healthy individuals, and cancer patients with and without AGNB. CONCLUSIONS: No differences in the prevalence of bacteria and bacterial endotoxins were found between the cancer patients and healthy individuals. Oral cavity endotoxins did not correlate with the carriage of AGNB. However, due to the high prevalence in cancer patients, the role of Candida species and S. aureus in the pathology may not be excluded. PMID- 30016680 TI - Molecular survey and characterization of Trypanosoma evansi in naturally infected camels with suspicion of a Trypanozoon infection in horses by molecular detection in Egypt. AB - In Egypt, although the Trypanosoma evansi has been reported frequently among domestic animals, there is no published data on T. evansi in horses. Therefore, this study aimed to assess the prevalence and characterization of T. evansi in three governorates by examining blood samples from 40 local camels, 35 imported camels, 25 horses and 10 donkeys by PCR targeting the sequences of TBR and RoTat 1.2VSG. The overall prevalence of T. evansi was 54.5% and 21.8% by TBR PCR and RoTat 1.2VSG PCR, respectively. The TBR PCR detected T. evansi in 60% and 71.4%, respectively, of local and imported camels and in 10% and 40% of donkeys and horses, respectively. For RoTat 1.2VSG PCR, T. evansi was detected in 32.5% and 31.4 of local and imported camels, respectively. All horses and donkeys were negative by RoTat 1.2VSG PCR. TBR PCR was superior to RoTat 1.2VSG PCR in T. evansi infection detection. Statistically significant differences in the prevalence of the infection were observed on the basis of body condition and location. Sequencing and phylogenetic analysis, based on RoTat 1.2VSG, confirmed the presence of T. evansi, which was closely related to Egyptian and Indian isolates. In conclusion, TBR PCR is the best assay to monitor T. evansi infections in camels, horses, and donkeys. The presence of T. evansi in horses and donkeys possibly play a role in the transport of the infection to camels. This is the first report of T. evansi infection in horses in Egypt using TBR PCR. PMID- 30016678 TI - Cognitive neuroscience using wearable magnetometer arrays: Non-invasive assessment of language function. AB - Recent work has demonstrated that Optically Pumped Magnetometers (OPMs) can be utilised to create a wearable Magnetoencephalography (MEG) system that is motion robust. In this study, we use this system to map eloquent cortex using a clinically validated language lateralisation paradigm (covert verb generation: 120 trials, ~10 min total duration) in healthy adults (n = 3). We show that it is possible to lateralise and localise language function on a case by case basis using this system. Specifically, we show that at a sensor and source level we can reliably detect a lateralising beta band (15-30 Hz) desynchronization in all subjects. This is the first study of human cognition using OPMs and not only highlights this technology's utility as tool for (developmental) cognitive neuroscience but also its potential to contribute to surgical planning via mapping of eloquent cortex, especially in young children. PMID- 30016681 TI - Diet-induced obesity precipitates kidney dysfunction and alters inflammatory mediators in mice treated with Shiga Toxin 2. AB - Shiga Toxin (Stx)-producing E. coli (STEC) continue to be a prominent cause of foodborne outbreaks of hemorrhagic colitis worldwide, and can result in life threatening diseases, including hemolytic uremic syndrome (HUS), in susceptible individuals. Obesity-associated immune dysfunction has been shown to be a risk factor for infectious diseases, although few studies have addressed the role of obesity in foodborne diseases. We hypothesized that obesity may affect the development of HUS through an alteration of immune responses and kidney function. We combined diet-induced obese (DIO) and HUS mouse models to look for differences in disease outcome between DIO and wild-type (WT) male and female C57 B l/6 mice. Following multiple intraperitoneal injections with endotoxin-free saline or sublethal doses of purified Stx2, we examined DIO and WT mice for signs of HUS development. DIO mice receiving Stx2 injections lost more body weight, and had significantly higher (p < 0.001) BUN, serum creatinine, and neutrophil counts compared to WT mice or DIO mice receiving saline injections. Lymphocyte counts were significantly (p < 0.05) lower in Stx2-treated obese mice compared to WT mice or saline-treated DIO mice. In addition to increased Stx2-induced kidney dysfunction, DIO mouse kidneys also had significantly increased expression of IL 1alpha, IL-1beta, IL-6, TNF-alpha, MCP-1, and KC RNA compared to saline controls (p < 0.05). Serum cytokine levels of IL-6 and KC were also significantly higher in Stx2-treated mice compared to saline controls, but there were no significant differences between the WT and DIO mice. WT and DIO mice treated with Stx2 exhibited significantly higher degrees of kidney tubular dilation and necrosis as well as some signs of tissue repair/regeneration, but did not appear to progress to the full pathology typically associated with human HUS. Although the combined obesity/HUS mouse model did not manifest into HUS symptoms and pathogenesis, these data demonstrate that obesity alters kidney function, inflammatory cells and cytokine production in response to Stx2, and may play a role in HUS severity in a susceptible model of infection. PMID- 30016682 TI - O-deGlcNAcylation is required for Entamoeba histolytica-induced HepG2 cell death. AB - Entamoeba histolytica is an enteric tissue-invading protozoan parasite that causes amoebic colitis and occasionally liver abscess in humans. E. histolytica can induce host-cell apoptosis by initiating various intracellular signaling mechanisms closely associated with tissue pathogenesis and parasitic immune evasion. O-GlcNAcylation, similar to phosphorylation, is involved in various cell signaling processes, including apoptosis and proliferation, with O-GlcNAc addition and removal regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. However, whether O-GlcNAc alterations in host cells affect E. histolytica-induced cell death and which signal molecules participate in E. histolytica-induced deglycosylation remain unknown. In this study, co-incubation of HepG2 cells with E. histolytica increased DNA fragmentation and LDH release as compared with control cells. Additionally, Gal-lectin-mediated amoebic adherence of live trophozoites to HepG2 cells decreased O-GlcNAcylated protein levels within 5 min. We also observed a rapid decrease in cellular OGT protein level, but not OGA, in HepG2 cells in a contact-dependent manner. Furthermore, HepG2 pretreatment with OGA inhibitors or OGA siRNA prevented E. histolytica-induced O deGlcNAcylation, DNA fragmentation, and LDH release. Our results suggested that E. histolytica-induced O-deGlcNAcylation in HepG2 cells was an important process required for hepatocyte cell death induced by E. histolytica adherence. PMID- 30016683 TI - Understanding microRNAs regulation in heat shock response in the sea cucumber Apostichopus japonicus. AB - The sea cucumber Apostichopus japonicus is a valuable species in China. The extreme high temperature in the summer often results in high mortality. MicroRNAs (miRNAs) play important post-transcriptional regulatory roles in gene expression and can influence heat shock response (HSR) greatly. In this study, we determined the expression profiles of miRNAs under heat stress (HS) in A. japonicus by using high-throughput sequencing technique. Among the differential expression miRNAs, we highlighted 41 differentially expressed miRNAs, many of which were involved in immunity process and disease regulation. Gene ontology and pathway analyses of putative target genes were also carried out. Cell-substrate adherens junction and cell-substrate junction were significantly enriched in GO analysis. Moreover, we made a correlation analysis between remarkable miRNAs and the differentially expressed genes (DEGs) in sea cucumbers under HS. We identified 17 key miRNA target pairs potentially regulated HSR of sea cucumbers. These results will provide new insights about miRNAs regulation and molecular adaptive mechanisms in sea cucumbers under HS. PMID- 30016684 TI - Carbon: Nitrogen (C:N) ratio level variation influences microbial community of the system and growth as well as immunity of shrimp (Litopenaeus vannamei) in biofloc based culture system. AB - Biofloc technology (BFT) is a novel modern aquaculture farming technique used to reduce toxic nitrogen concentration, act as in situ food source and eradicate pollutants using carbon and therefore to control C:N ratio in an aquaculture system. In this study, effect of different C:N ratios of a biofloc based system on water quality such as the level of Total ammonia nitrogen (TAN) nitrite nitrogen (NO2--N) and nitrate nitrogen (NO3--N) were explored. Further, the growth and immunity status of shrimp L. vannamei under the influence of different C:N ratios were evaluated. Two of the C:N ratios (15 and 20) could significantly (P < 0.05) reduce TAN, NO2-N and NO3-N levels (0.456 +/- 0.01, 0.145 +/- 0.09, and 0.102 +/- 0.02 ppm) compared to control (1.45 +/- 0.1, 0.749 +/- 0.14 and 0.675 +/- 0.16 ppm). Large variations in the frequency distribution of operational taxonomic units (OTUs) for the bacterial community in water with different C:N ration (BFT) and control were observed. Vibrios often considered as opportunistic pathogens, where the most dominant bacterial flora of water in control (79%) and C:N5 (37%) group. In C:N10, Thauera (62%) was most represented genus. Similarly, Attheyaceae (56%), followed by Peridiniaceae (30%) were the most dominant groups in C:N15 treatment. The diversity of bacterial flora was more spread in C:N20 treatments with Psychrobacter (26%), Proteobacteria (25%) and Peridiniaceae (20%) as the major groups. The trend of Vibrio dominance decreased with the increase in C:N ratios and thus confirming the dominance of heterotrophic bacteria in high C:N ratio groups. Upon challenge with pathogens, shrimps from C:N10, C:N15 and C:N20 groups showed significantly higher survival (P < 0.05) compared to the C:N5 and control group. Similarly, better growth rate was also observed in BFT tanks compared to control both during the culture and at harvest. Comparatively higher expression of four immune-related genes (ras related nuclear gene (RAN), serine proteinase gene (SP), prophenoloxidase activating enzyme (PPAE), and crustin were observed in different C:N ratio ponds than control and these were in increasing trend with the C:N ratio. Gene expression analysis showed that the transcripts of those immune genes were significantly increased among all C:N treatments than that of control. Overall, these findings demonstrated that with optimum C:N ratio, BFT can be used to optimize the bacterial community composition for both optimal water quality and optimal shrimp health. This study thus indicates the possibility of obtaining better performance of L. vannamei culture with proper adjustment of C:N ratio in a biofloc based system. PMID- 30016685 TI - Characterization of MyD88 in Japanese eel, Anguilla japonica. AB - Myeloid differentiation factor 88 (MyD88) is a key adaptor protein required for the signaling of all Toll-like receptors except TLR3, which results to the interaction of activated TLR complexes via C-terminal TIR domain and the binding of downstream kinase via N-terminal death domain. In this study, the MyD88 gene from the Japanese eel (Anguilla japonica) was identified. The open reading frame of AjMyD88 was 918 bp in length, encoding a protein composed of conserved N terminal death domain and C-terminal TIR domain, respectively. Multiple alignment revealed highly conserved sites across all examined vertebrate lineages in death and TIR domains. Site-directed mutagenesis and luciferase analysis revealed that the W78A, L91A and L95A mutations in death domain had modest impairment of their ability in activating NF-kappaB promoter. The expression level of AjMyD88 was investigated by real-time PCR in response to poly I:C stimulation and Edwardsiella tarda infection. Significantly increased MyD88 expression was observed at early phase in all tested tissues/organs in response to E. tarda infection and slight increase was detected in intestine and gill at 16 hpi and in head kidney, spleen and liver at 24 hpi after poly I:C stimulation. Immunofluorescence staining revealed that AjMyD88 is present as condensed forms in the cytoplasm. Taken together, sequence characterization, gene expression and cellular distribution data obtained in this study suggest that AjMyD88, similar to its mammalian ortholog, plays an important role in eel immune response against bacteria. PMID- 30016686 TI - Pichia pastoris yeast as a vehicle for oral vaccination of larval and adult teleosts. AB - Oral vaccination is of major interest because it can be used for mass vaccination of fish of various size and age. Given that their administration is relatively easy and stress-free, oral vaccines have both economic and animal welfare benefits. Yet, mostly due to their limited efficacy, only very few oral vaccines are available to aquaculture industry. Here we present a method for oral vaccine delivery based on the yeast Pichia pastoris. We could express a model antigen, green fluorescent protein (GFP), in this yeast and subsequently show delivery of the GFP protein to the intestine of juvenile flounder or adult carp and trout. We tested this approach in several commercially-relevant fish species, from juvenile to adult stage. To test the oral delivery of antigen to larval fish, the GFP expressing Pichia pastoris was first fed to planktonic crustacean Daphnia or rotifers that served as 'bioencapsulation vehicles' and afterwards, fed to flounder larvae. Again, we could show delivery of intact GFP protein to the intestine. In rainbow trout, the orally-administered GFP-expressing yeast elicited a rapid local innate immune response in the intestine and a subsequent systemic response in the spleen. Our results show that Pichia pastoris is a good vehicle for oral antigen delivery and that it can be used in non-encapsulated form for older fish or in bioencapsulated form for larval fish. We discuss the immunomodulatory properties of the yeast itself, and its potential to enhance local immune responses and act as an adjuvant. PMID- 30016687 TI - Recent advances in the mechanisms of neuroinflammation and their roles in neurodegeneration. AB - Neuroinflammation is associated with the pathogenesis of many neurological disorders including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis and Huntington disease. Current studies in this area have advanced the mechanism of neuroinflammation and its role in neurodegeneration. Studies from epidemiologic, clinical and animal models also contributed in the various new mechanisms of neuroinflammation. In this line, activation of monocytes is an important emerging mechanism that has a, profound role in neuroinflammation and neurodegeneration. Ion channels, matrix metalloproteases and microRNAs are also found to be the key players in the pathogenesis of neuroinflammation. In particular, microRNA-32 regulates microglia-mediated neuroinflammation and thus neurodegeneration. Notably, some important studies describe the role of Th17 cells in neuroinflammation, but, very little knowledge is available about their mechanism of action. Particularly, the role of autophagy gets emphasized, which plays a very critical role in protein aggregation and neurodegeneration. In this review, we highlight and discuss the mechanisms of these mediators of inflammation by which they contribute to the disease progression. In conclusion, we focus on the various newer molecular mechanisms that are associated with the basic understanding of neuroinflammation in neurodegeneration. PMID- 30016688 TI - Activation of membrane-bound and soluble Toll-like Receptors 5 in Salmo salar depends on the MyD88 signalling pathway. PMID- 30016689 TI - Prominent synovial plicae in radiocapitellar joints as a potential cause of lateral elbow pain: clinico-radiologic correlation. AB - BACKGROUND: Thickened synovial plicae in the radiocapitellar joint have been reported as a cause of lateral elbow pain. However, few reports regarding diagnosis based on detailed physical examination and magnetic resonance imaging (MRI) findings are available. The aims of this study were to characterize the clinical manifestations of this syndrome and to investigate the clinical outcomes of arthroscopic surgery. METHODS: We analyzed 20 patients who received a diagnosis of plica syndrome and underwent arthroscopic debridement between 2006 and 2011. The diagnosis was based on physical examination and MRI findings. Elbow symptoms were assessed using a visual analog scale for pain; the Mayo Elbow Performance Index; and the Disabilities of the Arm, Shoulder and Hand score at a minimum of 2 years after surgery. The thickness of plicae on MRI was compared with the normal data in the literature. RESULTS: Plicae were located on the anterior side in 1 patient, on the posterior side in 15, and on both sides in 4. Radiocapitellar joint tenderness and pain with terminal extension were observed in 65% of patients. MRI showed enlarged plicae consistent with intraoperative findings. The mean plica thickness on MRI was 3.7 +/- 1.0 mm, which was significantly thicker than the normal value. The mean lengths (mediolateral length, 9.4 +/- 1.6 mm; anteroposterior length, 8.2 +/- 1.7 mm) were also greater than the normal values. The visual analog scale score for pain decreased from 6.3 to 1.0 after surgery. The Mayo Elbow Performance Index and Disabilities of the Arm, Shoulder and Hand scores improved from 66 to 89 and from 26 to 14, respectively. CONCLUSIONS: Specific findings of the physical examination and MRI provide clues for the diagnosis of plica syndrome. Painful symptoms were successfully relieved after arthroscopic debridement. PMID- 30016690 TI - Long-term results after simple rotational osteotomy of the radius shaft for congenital radioulnar synostosis. AB - BACKGROUND: The present study was conducted to clarify the long-term (>=10 years) results of simple rotational osteotomy for congenital radioulnar synostosis (CRUS). METHODS: Twelve forearms in 9 Asian patients with CRUS who underwent simple rotational osteotomy of the radius shaft were monitored for an average of 13.6 years (range, 10-19 years) postoperatively. Before surgery, the forearm fixation averaged 51.3 degrees of pronation (range, 30 degrees -90 degrees ). The true position of the forearm in ankylosis was measured by a line through the styloid processes of the radius and the ulna. Palm pronation and supination angles were also measured. The osteotomy was performed at the insertion of the pronator teres to the shaft of the radius. The pronation position was then corrected manually to allow 90 degrees of palm supination with compensatory rotation around the wrist, and a cast was applied. We evaluated activities of daily living items at a mean of 5.2 years after surgery. At the final follow-up, the 11-item version of the Disability of the Arm, Shoulder and Hand score was recorded. RESULTS: After surgery, the forearm was fixed at an average of 4.2 degrees of supination. At the final follow-up, the palm was able to achieve an average motion arc ranging from 26 degrees of pronation to 62 degrees of supination. There were no neurologic or circulatory complications after surgery. Ability to perform daily activities was markedly improved, and all patients were satisfied with the results of surgery. The average score on the 11-item version of the Disability of the Arm, Shoulder, and Hand was 3.79 points at the final follow-up. CONCLUSION: Our procedure for forearm rotation in patients with CRUS is simple, reliable, satisfactory, and safe. PMID- 30016691 TI - Macroscopic investigation of failed Kudo type 5 total elbow arthroplasty. AB - BACKGROUND: On the basis of the intra-articular findings during Kudo type 5 elbow prosthesis revision surgery, we infer the mechanisms leading to implant failure. MATERIALS AND METHODS: We performed primary Kudo type 5 total elbow arthroplasty on 60 rheumatoid elbows in 45 patients between 1994 and 2003. Revision surgery was performed in 8 patients (9 elbows) because of implant failure. We radiographically assessed their status before this surgical procedure and then assessed the surgical intra-articular findings based on surgery records and photographs. RESULTS: In all cases, revision surgery was necessitated by failure of the ulnar component. There were 2 types of implant failure: fracture of the ulnar component neck (n = 3) and loosening of the ulnar component (n = 6). In the latter group, 2 elbows exhibited valgus deformity of the retrieved ulnar component. There were no cases of metallosis or wear of the articular surface. CONCLUSION: This study describes the types of implant failure in unlinked Kudo type 5 total elbow arthroplasties with all-polyethylene ulnar components based on the intra-articular findings. Failure of the all-polyethylene ulnar component could have been caused by ulnar neck distortion that occurred prior to polyethylene wear on the joint surface. In addition, valgus stress on the elbow joint may have contributed to these implant failures. PMID- 30016694 TI - Glenohumeral cerclage for salvage of recalcitrant instability after reverse total shoulder arthroplasty. PMID- 30016692 TI - Predictors of pain and functional outcomes after operative treatment for rotator cuff tears. AB - BACKGROUND: Optimal patient selection is key to success of operative treatment for cuff tears. We assessed predictors of pain and functional outcomes in a longitudinal cohort of patients undergoing operative treatment. METHODS: From March 2011 to January 2015, a cohort of patients with rotator cuff tears undergoing rotator cuff surgery was recruited. Patients completed a detailed health and demographic questionnaire, standardized shoulder questionnaires, including the Shoulder Pain and Disability Index (SPADI), and underwent a magnetic resonance imaging scan. Patients received follow-up questionnaires at 3, 6, 12, and 18 months. We assessed longitudinal predictors of SPADI using longitudinal mixed models. Interactions with follow-up duration after surgery were also assessed. RESULTS: In our analysis (n = 50), a lower Fear-Avoidance Beliefs Questionnaire physical activity score (P = .001) predicted a lower SPADI score (better shoulder pain and function). Those consuming alcohol 1 to 2 times per week or more had lower SPADI scores than those consuming alcohol 2 to 3 times per month or less (P = .017). Both of these variables had a significant interaction with duration of follow-up. Variables that were not significant predictors of SPADI included sociodemographic characteristics, magnetic resonance imaging characteristics, such as tear size and muscle quality, shoulder strength, and variations in surgical techniques/performance of adjuvant surgical procedures. CONCLUSIONS: Those with higher fear avoidance behavior and alcohol use of 1 to 2 times per week had worse shoulder pain and function at 18 months of follow-up. These data can be used to select optimal candidates for operative treatment of rotator cuff tears and assist with patient education and expectations before treatment. PMID- 30016693 TI - Culture positivity in primary total shoulder arthroplasty. AB - BACKGROUND: The clinical significance of positive cultures in shoulder surgery remains unclear. This study determined the rate and characteristics of positive intraoperative cultures in a cohort of patients undergoing primary shoulder arthroplasty. METHODS: From February 2015 to March 2016, 94 patients, without prior surgery, underwent primary shoulder arthroplasty. Before surgery, all shoulders were prospectively enrolled and consented to obtain standardized intraoperative cultures. All patients received standard preoperative antibiotic prophylaxis. Standardized fluid and tissue locations were sampled and sent for aerobic and anaerobic cultures and held for 13 days. Patients and surgeon were blinded to the culture results. RESULTS: Average age at surgery was 70.5 years (range, 50-91 years), and 41 patients (47%) were male. At least 1 positive culture was found in 33 shoulders (38%), with 17 patients (19%) having >=2 positive cultures. Cutibacterium (formerly Propionibacterium) acnes was the most common organism (67%), followed by coagulase-negative Staphylococcus (21%), Staphylococcus aureus (3%), and other organisms (18%). The rate of positive culture was higher in men (51%) than in women (26%, P = .016). Cutibacterium acnes was more common in men with positive cultures (95% vs. 17%, P < .001) and coagulase-negative Staphylococcus and Staphylococcus epidermidis were more common in women with positive cultures (42% vs. 10%, P = .071). CONCLUSION: Positive deep tissue cultures develop in a high percentage of patients undergoing primary shoulder arthroplasty despite antibiotic prophylaxis. The long-term clinical implication of this finding requires further study, especially with regard to the risk of late failures of shoulder arthroplasty. PMID- 30016695 TI - Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux. AB - Homozygous and/or heterozygous loss of function mutations in the natriuretic peptide receptor B (NPR2) have been reported in causing acromesomelic dysplasia, type Maroteaux with variable clinical features and idiopathic short stature with nonspecific skeletal deformities. On the other hand, gain of function mutations in the same gene result in overgrowth disorder suggesting that NPR2 and its ligand, natriuretic peptide precursor C (CNP), are the key players of endochondral bone growth. However, the precise mechanism behind phenotypic variability of the NPR2 mutations is not fully understood so far. In the present study, three consanguineous families of Pakistani origin (A, B, C) with variable phenotypes of acromesomelic dysplasia, type Maroteaux were evaluated at clinical and molecular levels. Linkage analysis followed by Sanger sequencing of the NPR2 gene revealed three homozygous mutations including p.(Leu314 Arg), p.(Arg371*), and p.(Arg1032*) in family A, B and C, respectively. In silico structural and functional analyses substantiated that a novel missense mutation [p.(Leu314 Arg)] in family A allosterically affects binding of NPR2 homodimer to its ligand (CNP) which ultimately results in defective guanylate cyclase activity. A nonsense mutation [p.(Arg371*)] in family B entirely removed the transmembrane domain, protein kinase domain and guanylate cyclase domains of the NPR2 resulting in abolishing its guanylate cyclase activity. Another novel mutation [p.(Arg1032*)], found in family C, deteriorated the guanylate cyclase domain of the protein and probably plundered its guanylate cyclase activity. These results suggest that guanylate cyclase activity is the most critical function of the NPR2 and phenotypic severity of the NPR2 mutations is proportional to the reduction in its guanylate cyclase activity. PMID- 30016696 TI - Characterization of a novel endogenous cysteine proteinase inhibitor, trichocystatin-3 (TC-3), localized on the surface of Trichomonas vaginalis. AB - Trichomonas vaginalis is a flagellated protist responsible for human trichomoniasis. T. vaginalis has three genes encoding for endogenous cysteine proteinase (CP) inhibitors, known as trichocystatin-1 through trichocystatin-3 (TC-1, TC-2, and TC-3). These inhibitors belong to the cystatin family. In this study, we characterized trichocystatin-3 (TC-3), an endogenous cysteine proteinase (CP) inhibitor of T. vaginalis. TC-3 possesses a signal peptide in the N-terminus and two putative glycosylation sites (typical of family 2, cystatins) but lacks the PW motif and cysteine residues (typical of family 1, stefins). Native TC-3 was recognized as an ~18 kDa protein band in a T. vaginalis protein extract. By confocal microscopy, endogenous TC-3 was found in the Golgi complex, cytoplasm, large vesicles, and the plasma membrane. These localizations are consistent with an in silico prediction. In addition, the purified recombinant protein (TC-3r) functions as an inhibitor of cathepsin L CPs, such as human liver cathepsin L and trichomonad CPs, present in a proteinase-resistant extract (PRE). Via a pull-down assay using TC-3r as bait and PRE, we identified several trichomonad CPs targeted by TC-3, primarily TvCP3. These CP-TC-3 interactions occur in vesicles, in the cytoplasm, and on the parasite surface. In addition, TC 3r showed a protective effect on HeLa cell monolayers by inhibiting trichomonad surface CPs involved in cellular damage. Our results show that the endogenous inhibitor TC-3 plays a key role in the regulation of endogenous CP proteolytic activity. PMID- 30016698 TI - Trypanosoma cruzi epimastigotes store cholesteryl esters in lipid droplets after cholesterol endocytosis. AB - The Chagas disease agent Trypanosoma cruzi proliferates in the insect vector as highly endocytic epimastigotes that store nutrients, including lipids in reservosomes (lysosome related compartments). Although nutrient storage is important for epimastigote transformation into infective metacyclics, the epimastigote lipid droplets (LDs) remain uncharacterized. Here, we characterized the epimastigote LDs and examined their relationship with the endocytic pathway. Fluorescence microscopy using BODIPY showed that LDs have high neutral lipid content and harbor Rab18, differently from other lipid-rich organelles (such as reservosomes). Using transmission electron microscopy (TEM), we observed a close relationship between LDs and the endoplasmic reticulum, mitochondria and glycosomes. We developed a reproducible protocol to isolate LDs, and showed (by HTPLC and GC/MS analyses) that they have 89% neutral lipids and 11% phospholipids, which are likely to form the LD monolayer seen by TEM. The LD neutral lipids were mostly sterols, although triacylglycerol, diacylglycerol, monoacylglycerol and free fatty acids (FFA) were also found. Endocytosis of 3H labeled cholesterol-BSA showed that internalized cholesterol is stored in LDs mostly in the cholesteryl ester form. Together, these results suggest that exogenous cholesterol internalized by endocytosis reaches the reservosomes and is then stored into LDs after esterification. PMID- 30016697 TI - Risk assessment for potentially toxic metal(loid)s in potatoes in the indigenous zinc smelting area of northwestern Guizhou Province, China. AB - We investigated potentially toxic metal (loid)s (arsenic, As; cadmium, Cd; chromium, Cr; copper, Cu; mercury, Hg; lead, Pb; selenium, Se; and zinc, Zn) in agricultural samples (i.e., Solanum tuberosum L. tubers (potatoes) and their planting media) in the indigenous zinc smelting area of northwestern Guizhou Province, China. Based on the pollution index values for As, Cd, Pb and Zn, the order of the samples was as follow: slag > planting soil with slag > planting soil without slag, and the order of the samples in terms of the bioconcentration factor was the opposite. Cr, Cu and Hg were present in the planting soil with and without slag at slight pollution levels, and the other potentially toxic metal (loid)s had different degrees of contamination. Additionally, the potentially toxic metal (loid) contents in potato were under their limit values except for Cd (all samples) and Pb and Se (some samples). All bioconcentration factors for potatoes were below 0.5, and no health risk index value for potatoes was higher than 0.1. Therefore, although no significant health risk associated with potentially toxic metal (loid)s via consuming potato exists for either adult men or women in the research area, the Cd concentration in this crop should be monitored. PMID- 30016699 TI - TbRRM1 knockdown produces abnormal cell morphology and apoptotic-like death in the bloodstream form of T. brucei. AB - TbRRM1, an SR-related protein, is involved in transcriptional and post transcriptional gene expression regulation in procyclic T. brucei. In previous work, we found that TbRRM1 is essential and its depletion leads to cell cycle impairment, aberrant phenotypes and cell loss by apoptotic-like death. Here, we report the findings obtained after TbRRM1 knockdown in bloodstream parasites. Depletion of TbRRM1 in this cell stage led also to growth arrest and cell loss by apoptosis-like death. However, microscopic analysis showed aberrant cell morphology with parasites displaying flagellum detachment and cytokinesis impairment after RNAi induction, suggesting that TbRRM1 could play different roles depending on parasite stage. PMID- 30016700 TI - Endomorphin-1 analogs with oligoarginine-conjugation at C-terminus produce potent antinociception with reduced opioid tolerance in paw withdrawal test. AB - For clinical use, it is essential to develop potent endomorphin (EM) analogs with reduced antinociceptive tolerance. In the present study, the antinociceptive activities and tolerance development of four potent EM-1 analogs with C-terminal oligoarginine-conjugation was evaluated and compared in the radiant heat paw withdrawal test. Following intracerebroventricular (i.c.v.) administration, all analogs 1-4 produced potent and prolonged antinociceptive effects. Notably, analogs 2 and 4 with the introduction of D-Ala in position 2 exhibited relatively higher analgesic potencies than those of analogs 1 and 3 with beta-Pro substitution, consistent with their MU-opioid binding characteristic. In addition, at a dose of 50 MUmol/kg, endomorphin-1 (EM-1) failed to produce any significant antinociceptive activity after peripheral administration, whereas analogs 1-4 induced potent antinociceptive effects with an increased duration of action. Herein, our results indicated the development of antinociceptive tolerance to EM-1 and morphine at the supraspinal level on day 7. By contrast, analogs 1-4 decreased the antinociceptive tolerance. Furthermore, subcutaneous (s.c.) administration of morphine at 50 MUmol/kg also developed the antinociceptive tolerance, whereas the extent of tolerance developed to analogs 1 4 was largely reduced. Especially, analog 4 exhibited non-tolerance-forming antinociception after peripheral administration. The present investigation gave the evidence that C-terminal conjugation of EM-1 with oligoarginine vector will facilitate the development of novel opioid analgesics with reduced opioid tolerance. PMID- 30016701 TI - Unequal distribution of the mating type (MAT) locus idiomorphs in dermatophyte species. AB - The mating type (MAT) locus is the key regulator of sexual reproduction in fungi. In the dermatophytes and other Ascomycetes this genomic region exists in two distinct forms (idiomorphs) and their balanced presence is a precondition for successful mating in heterothallic fungi. But the MAT locus not only drives sexual reproduction, it has also been shown to influence pathogenicity, virulence, and/or morphological changes in pathogenic fungi of the genera Candida, Histoplasma, and Cryptococcus. In order to find out whether there are similar trends in dermatophytes, we investigated the MAT locus of 19 anthropophilic and zoophilic species via Sanger sequencing and primer walking. We identified for the first time the MAT locus idiomorphs of the dermatophyte species Microsporum audouinii (MAT1-2), M. ferrugineum (MAT1-2), Trichophyton schoenleinii (MAT1-2), T. bullosum (MAT1-1), T. quinckeanum (MAT1-1), T. concentricum (MAT1-1), T. eriotrephon (MAT1-1), and T. erinacei (MAT1-2). In addition, we determined the MAT locus sequence for dermatophyte species whose mating type idiomorphs had been described on the basis of results of classical confrontation experiments (e.g. M. canis, MAT1-2) and we confirmed recently published molecular data (e.g. T. rubrum, MAT1-2). Our results corroborate that MAT locus idiomorphs are unequally distributed in the majority of the analyzed species and the ability to mate with a partner of the opposite sex is limited to a few zoophilic species. Clonal spreads are identified that are connected to one of the idiomorphs and a higher virulence and/or a higher transmission rate to humans (T. benhamiae and T. mentagrophytes). For the imbalanced idiomorph distribution pattern we hypothesize that either: (I) one of the mating type idiomorphs may be extinct due to clonal reproduction (e.g., T. rubrum and M. canis), (II) mating partners of one species adapted to different hosts followed by speciation in the new niche (e.g., T. equinum and T. tonsurans) or (III) unisexual reproduction is the next evolutionary stage of propagation in dermatophytes which involves the extinction of one mating idiomorph. PMID- 30016702 TI - Development of an indirect ELISA assay for detecting antibodies against mammalian reovirus in pigs. AB - Mammalian reovirus (MRV) infects many species. Over the past decades, MRV infections in pigs have been reported, and several highly pathogenic MRV strains have recently been isolated in the United States. In this study, an indirect enzyme-linked immunosorbent assay (ELISA) against the sigma1 protein from a serotype 3 reovirus strain (MPC/04) was established to detect antibodies in pigs. The assay did not react with antisera against other pig pathogens and was consistent with the indirect immunofluorescence assay (IFA) and virus neutralization test (VNT). In conclusion, the assay is specific and highly sensitive, providing a method for large-scale monitoring of the serotype 3 MRV infection epidemiology in pigs. PMID- 30016704 TI - 3D double inversion recovery MR imaging: Clinical applications and usefulness in a wide spectrum of central nervous system diseases. AB - Double inversion recovery (DIR) imaging provides two inversion pulses that attenuate signals from cerebrospinal fluid and normal white matter. This review was undertaken to describe the principle of the DIR sequence, the clinical applications of 3D DIR in various central nervous system diseases and the clinical benefits of the 3D DIR compared with those of other MR sequences. 3D DIR imaging provides better lesion conspicuity and topography than other MR techniques. It is particularly useful for diagnosing the following disease entities: cortical and subcortical abnormalities such as multiple sclerosis, cortical microinfarcts and cortical development anomalies; sulcal abnormalities such as meningitis and subacute/chronic subarachnoid hemorrhage; and optic neuritis caused by multiple sclerosis or neuromyelitis optica. PMID- 30016703 TI - Cerebellar injury and impaired function in a rabbit model of maternal inflammation induced neonatal brain injury. AB - Cerebellum is involved in higher cognitive functions and plays important roles in neurological disorders. Cerebellar injury has been detected frequently in patients with preterm birth resulting in cognitive dysfunction later in life. Maternal infection and inflammation is associated with preterm birth and in neonatal brain injury. We have previously shown that intrauterine lipopolysaccharide (LPS) exposure induces white matter injury and microglial activation in the cerebral white matter tracts of neonatal rabbits, resulting in motor deficits consistent with the clinical findings of cerebral palsy (CP). Here we investigated whether intrauterine LPS exposure induced cerebellar inflammation and functional impairment. Timed-pregnant New Zealand white rabbits underwent a laparotomy on gestational day 28 (G28) and LPS (3200 EU, endotoxin group) was injected along the wall of the uterus as previously described. Controls did not receive surgical intervention. Kits born to control and endotoxin treated dams were euthanized on postnatal day (PND)1 (3 days post-injury) or PND5 (7 days post injury) and cerebellum evaluated for presence of inflammation. The microglial morphology in cerebellar white matter areas was analyzed using Neurolucida and Neurolucida Explorer. mRNA expression of inflammatory cytokines was quantified by real-time-PCR. We found that intrauterine exposure to LPS induced intensive microglial activation in cerebellar white matter areas, as evidenced by increased numbers of activated microglia and morphological changes (amoeboid soma and retracted processes) that was accompanied by significant increases in pro inflammatory cytokines. The Purkinje cell layer was less developed in endotoxin exposed kits than healthy controls. In kits that survived to PND 60, soma size and cell density of Purkinje cells were significantly decreased in endotoxin exposed kits compared to controls. The findings of altered Purkinje cell morphology were consistent with impaired cerebellar function as tested by eye blink conditioning at 1 month of age. The results indicate that the cerebellum is vulnerable to perinatal insults and that therapies targeting cerebellar inflammation and injury may help in improving outcomes and function. PMID- 30016705 TI - Arterial spin labeling: Clinical applications. AB - Arterial spin labeling (ASL) is a magnetic resonance imaging perfusion technique that enables quantification of cerebral blood flow (CBF) without the use of intravenous gadolinium contrast. An understanding of the technical basis of ASL and physiologic variations in perfusion are important for recognizing normal variants and artifacts. Pathologic variations in perfusion can be seen in a number of disorders including acute and chronic ischemia, vasculopathy, vascular malformations, tumors, trauma, infection/inflammation, epilepsy and dementia. PMID- 30016706 TI - The influence of liming on cadmium accumulation in rice grains via iron-reducing bacteria. AB - Cadmium (Cd) in soil is attracting worldwide attention, and many valuable measures and suggestions of minimizing the rice grain Cd are available. Among these methods, liming can increase the soil pH and decrease the rice grain Cd content. Here, we report that soil pH was negatively and significantly correlated with the concentration of soil extractable Fe and Cd. In addition, the iron concentration on root surface was significantly and positively associated with the available metals in soil and the rice grain Cd. However, the return of contaminated rice straw significantly increased the Cd accumulation in the rice grain, although the returned straw did not significantly influence the concentration of extracted soil Cd. Furthermore, an analysis of the functional microbe community was performed, and the response of iron-reducing bacteria (IRB) under the six treatments provides valuable insights for reducing the available Cd concentration in soil. A LEfSe (LDA coupled with effect size measurement for significant differences) analysis showed that the application of liming reduced the abundance of IRB. The results of a redundancy analysis (RDA) indicated that soil pH was significantly and negatively associated with the abundance of Proteobacteria and Geobacter and the concentration of bioavailable Fe and Cd in the soil, which could explain the reduced accumulation of bioavailable Cd in rice grain. Collectively, our results demonstrated that liming in Cd-polluted paddy soil is a reasonable strategy for minimizing rice grain Cd by increasing the soil pH, which reduces the soil available iron and Cd concentration by shifting the diversity and composition of IRB, thus ultimately resulting in decreased Cd in rice. PMID- 30016707 TI - At the core of the socio-ecological transition: Agroecosystem energy fluxes in Austria 1830-2010. AB - Analyses of energy efficiency in biomass production offer important insights in the context of sustainable land management and biomass production. However, much of the previous research on the topic has focused on the energy efficiency of either food or energy provision. Only recently, comprehensive analyses at the total agroecosystem level have been operationalized, studying long-term change in agroecosystem energetics in the course of the socio-ecological transition. We contribute to this line of research by offering an empirical assessment of agroecosystem energetics for the case of Austria, covering the period 1830-2010 at an annual resolution. We present a quantitative assessment of energy inputs, outputs and internal energy fluxes of Austria's agroecosystem, including crop production, livestock production and forestry, as well as energy return on investment indicators. We identify three major periods: (1) "pre-industrial land use intensification" (1830-1914) is characterized by moderate agricultural growth based on increased biomass recirculation, declining wood harvest, and, probably, slightly declining energy returns on investments. (2) From 1918 to 1985, "industrialization of land use and the green revolution" exhibits a substitution of labor by modern energy inputs, while livestock continued to rely greatly on domestic biomass. (3) "Industrialized extensification and environmental awareness" (1986-2010) features increasing energy efficiency due to declines in livestock numbers, a shift towards forestry, and a rising amount of final products from croplands at stable energy inputs. We discuss these periods in the context of changes in both ecological impacts and social metabolism, and identify trade-offs among food and bioenergy provision. PMID- 30016708 TI - Stevensite-based geofilter for the retention of tetracycline from water. AB - The antibiotic tetracycline, is considered a contaminant of emerging concern due to its presence in wastewater effluents, surface waters and groundwaters. Adsorption of tetracycline on soils and clays has been extensively studied to remove the contaminant from the water. A decreasing adsorption as the pH increases is normally reported in the pH range 3-9. However, adsorption isotherms performed on a commercial stevensite presented increasing adsorption with the increasing pH, in the pH range 2-8. This is very interesting since the pH in natural and wasterwaters are normally in the range 6-8. A laboratory design of a geofilter using a mixture of sand and stevensite was tested against an inflow solution of tetracycline 1 g/L, NaNO3 0.1 M and pH = 7 in an advective transport cell experiment. The number of tetracycline molecules exceed by >3 times the number exchangeable positions in the stevensite geofilter. Under these conditions, the TC adsorption on the geofilter reaches 590 mg/g, surpassing the retention capacity of most adsorbents found in literature. Besides, the tetracycline is completely desorbed by the inflow of a saline solution (Mg(NO3)2 0.5 M, at pH = 2) with capacity to replace the exchangeable positions, thus, recovering the geofilter and the tetracycline. PMID- 30016709 TI - Design and development of a hybrid macrophyte assisted vermifilter for the treatment of dairy wastewater: A statistical and kinetic modelling approach. AB - Global urbanization, exponential increase in population and sophisticated life style of the present generation are the major causes leading to a rapid increase in water demand in recent years. In order to nullify this rising water demand, it's high time to reuse domestic as well as industrial effluent after providing suitable chemical/biological treatment. Macrophyte filter incorporated with earthworm is identified as one of the most economic system for the treatment purpose in developing countries. However, very few literatures and technical information are available to scale up the design and its easy operation. This paper aims to develop a hybrid system and assess its performance for the purification of dairy wastewater. In the present study, two stage macrophyte assisted vermifilters (MAVFs) have been designed. The 1st stage encompassed a vertical flow (VF) unit, and the 2nd stage contained a horizontal flow (HF) unit. Both the units were inoculated with earthworm Eisenia fetida and were planted with Canna indica. Box-Behnken model was applied to design the system and study the effect of various parameters. It was observed that hybrid MAVF system removed a maximum of 83.2% COD and 57.3% TN at HLR 0.6 m/d and an active layer depth of 30 cm. Ammonification and nitrification typically occurred in the active layer (earthworm inoculated zone) of VF unit due to high activity of earthworms and its associated gut microbes, whereas HF unit facilitate denitrification process. Earthworm growth characteristics in the system were monitored, which is an imperative factor for the design of MAVF reactor. Kinetic modelling of 1st order, grau 2nd order and Stover-Kincannon model were performed and the Stover-Kincannon model showed high regression coefficient (COD, R2 0.9961 and TN, R2 0.9353) supporting its applicability as compared to the other models. PMID- 30016710 TI - Interferon regulatory factor 3 from sea perch (Lateolabrax japonicus) exerts antiviral function against nervous necrosis virus infection. AB - Interferon (IFN) regulatory factor 3 (IRF3) is a major regulator contributing to the host away from viral infection. Here, an IRF3 gene from sea perch (LjIRF3) was identified and its role in regulating early apoptosis signaling and IFN response was investigated during red spotted grouper nervous necrosis virus (RGNNV) infection. The cDNA of LjIRF3 encoded a putative 465 amino acids protein, containing a DNA binding domain, an IRF association domain and a serine-rich domain. Phylogenetic analysis suggested that LjIRF3 shared the closest genetic relationship with Epinephelus coioides IRF3. LjIRF3 was constitutively expressed in all examined tissues with the highest expression level in the liver. Upon RGNNV infection, mRNA transcript level of LjIRF3 was significantly up-regulated in vivo and in vitro, indicating the involvement of LjIRF3 in immune response to RGNNV infection. Furthermore, overexpression of LjIRF3 significantly suppressed RGNNV replication in vitro, meanwhile significantly up-regulating the expression of IFNI and IFN stimulated genes and resulting in the activation of caspase 3 and 9 proteases in the early stage of RGNNV infection. In short, these results demonstrated that LjIRF3 exerted antiviral function against RGNNV infection via triggering early apoptotic cell death and inducing IRF3-dependent IFN immune response. PMID- 30016712 TI - Cognitive rehabilitation in multiple sclerosis: An overview of clinical tools. PMID- 30016711 TI - Early-life socioeconomic disadvantage, not current, predicts accelerated epigenetic aging of monocytes. AB - Low socioeconomic status (SES) in early-life and adulthood independently contribute to increased risk for aging-related chronic diseases. One mechanistic hypothesis for these associations involves faster cellular aging of immune cells, which could plausibly contribute to chronic disease pathogenesis by compromising host resistance and/or up-regulating inflammation. However, little is known about the association between life-course SES and cellular aging. The present study examines the association of early-life and current SES with a novel biomarker of cellular aging termed the "epigenetic clock," in monocytes. Additionally, we examine health behaviors and depressive symptoms as potential explanatory pathways. The study involved 335 participants between the ages of 15 and 55 from Vancouver, Canada and surrounding areas. Enrolled participants had to fit into four life-course SES trajectories, corresponding to low-low, low-high, high-low and high-high combinations of early-life (ages 0 to 5) and current SES respectively. Cellular aging of monocytes was measured using Horvath's DNA methylation derived measure of epigenetic age acceleration. Results indicated that socioeconomic disadvantage during early-life, but not later in life, was associated with accelerated epigenetic aging of monocytes. No early-life SES by current SES interaction was detected, suggesting that socioeconomic mobility is unrelated to epigenetic age acceleration. In path analyses, neither current health behaviors nor current depressive symptoms emerged as mediators of the early-life SES effect. These findings suggest socioeconomic disadvantage in early life is independently predictive of cellular aging of immune cells, with potential implications for aging-related diseases later in life. PMID- 30016713 TI - Variation in intronic microsatellites and exon 2 of the Plasmodium falciparum chloroquine resistance transporter gene during modification of artemisinin combination therapy in Thailand. AB - The amino acid substitution at residue 76 of the food vacuolar transmembrane protein encoded by the chloroquine resistance transporter gene of Plasmodium falciparum (Pfcrt) is an important, albeit imperfect, determinant of chloroquine susceptibility status of the parasite. Other mutations in Pfcrt can modulate susceptibility of P. falciparum to other antimalarials capable of interfering with heme detoxification process, and may exert compensatory effect on parasite growth rate. To address whether nationwide implementation of artemisinin combination therapy (ACT) in Thailand could affect sequence variation in exon 2 and introns of Pfcrt, we analyzed 136 P. falciparum isolates collected during 1997 and 2016 from endemic areas bordering Myanmar, Cambodia and Malaysia. Results revealed 6 haplotypes in exon 2 of Pfcrt with 2 novel substitutions at c.243A > G (p.R81) and c.251A > T (p.N84I). Positive selection was observed at amino acid residues 75, 76 and 97. Four, 3, and 2 alleles of microsatellite (AT/TA) repeats occurred in introns 1, 2 and 4, respectively, resulting in 7 different 3-locus haplotypes. The number of haplotypes and haplotype diversity of exon 2, and introns 1, 2 and 4 were significantly greater among isolates collected during 2009 and 2016 than those collected during 1997 and 2008 when 3 day ACT and 2-day ACT regimens were implemented nationwide, respectively (p < 0.05). By contrast, the number of haplotypes and haplotype diversity of the merozoite surface proteins 1 and 2 of these parasite populations did not differ significantly between these periods. Therefore, the Pfcrt locus of P. falciparum in Thailand continues to evolve and could have been affected by selective pressure from modification of ACT regimen. PMID- 30016715 TI - Reactive oxygen species in seminal plasma as a cause of male infertility. AB - Male factor is responsible for 40-50% of infertility cases, contributing equally as a female factor. Oxidative stress has now emerged as one of the major causes of unexplained male infertility, as it leads to increased risk of deoxyribonucleic acid (DNA) fragmentation, decreased sperm motility, concentration and abnormal morphology. Though a certain amount of reactive oxygen species (ROS) activity is essential for normal functioning of sperms, an excess lead to pathological effects on semen parameters, ultimately resulting in male sub-fertility or infertility. Furthermore, oxidative stress affected sperm cells with damaged DNA result in increased risk of birth defects, neuropsychiatric problems and cancers in off-springs of such fathers due to increased risk of de novo mutations in the germline and post-fertilization. Hence, present review helps in highlighting the facts about ROS, their production, physiological functions and pathological effects on sperm dysfunction and DNA damage, leading to male infertility. The literature regarding male infertility and role of ROS was searched from various peer-reviewed printed and online articles indexed in PubMed, MEDLINE, SCOPUS, EMBASE, etc. and from various governmental organizations till Jan 2018. PMID- 30016716 TI - Detection of carbapenem-resistant bacteria in the public area of a hospital. PMID- 30016714 TI - Analysis of genetic polymorphisms and tropism in East African Leishmania donovani by Amplified Fragment Length Polymorphism and kDNA minicircle sequencing. AB - Visceral leishmaniasis (VL), the most severe form of leishmaniasis, is caused by Leishmania donovani. In addition to fatal VL, these parasites also cause skin diseases in immune-competent and -suppressed people, post-kala azar dermal leishmaniasis (PKDL) and HIV/VL co-infections, respectively. Genetic polymorphism in 36 Ethiopian and Sudanese L. donovani strains from VL, PKDL and HIV/VL patients was examined using Amplified Fragment Length Polymorphism (AFLP), kDNA minicircle sequencing and Southern blotting. Strains were isolated from different patient tissues: in VL from lymph node, spleen or bone marrow; and in HIV/VL from skin, spleen or bone marrow. When VL and PKDL strains from the same region in Sudan were examined by Southern blotting using a DNA probe to the L. donovani 28S rRNA gene only minor differences were observed. kDNA sequence analysis distributed the strains in no particular order among four clusters (A - D), while AFLP analysis grouped the strains according to geographical origin into two major clades, Southern Ethiopia (SE) and Sudan/Northern Ethiopia (SD/NE). Strains in the latter clade were further divided into subpopulations by zymodeme, geography and year of isolation, but not by clinical symptoms. However, skin isolates showed significantly (p < 0.0001) fewer polymorphic AFLP fragments (average 10 strains = 348.6 +/- 8.1) than VL strains (average 26 strains = 383.5 +/- 3.8). PMID- 30016717 TI - O-GlcNAcylation site mapping by (azide-alkyne) click chemistry and mass spectrometry following intensive fractionation of skeletal muscle cells proteins. AB - : The O-linked-N-acetyl-d-glucosaminylation (O-GlcNAcylation) modulates numerous aspects of cellular processes. Akin to phosphorylation, O-GlcNAcylation is highly dynamic, reversible, and responds rapidly to extracellular demand. Despite the absolute necessity to determine post-translational sites to fully understand the role of O-GlcNAcylation, it remains a high challenge for the major reason that unmodified proteins are in excess comparing to the O-GlcNAcylated ones. Based on a click chemistry approach, O-GlcNAcylated proteins were labelled with azido GalNAc and coupled to agarose beads. The proteome extracted from C2C12 myotubes was submitted to an intensive fractionation prior to azide-alkyne click chemistry. This combination of fractionation and click chemistry is a powerful methodology to map O-GlcNAc sites; indeed, 342 proteins were identified through the identification of 620 peptides containing one or more O-GlcNAc sites. We localized O-GlcNAc sites on proteins involved in signalling pathways or in protein modification, as well as structural proteins. Considering the recent role of O-GlcNAcylation in the modulation of sarcomere morphometry and interaction between key structural protein, we focused on proteins involved in the cytoarchitecture of skeletal muscle cells. In particular, several O-GlcNAc sites were located into protein-protein interaction domains, suggesting that O GlcNAcylation could be strongly involved in the organization and reorganization of sarcomere and myofibrils. SIGNIFICANCE: O-GlcNAcylation is an atypical glycosylation involved in the regulation of almost all if not all cellular processes, but its precise role remains sometimes obscure because of the ignorance of the O-GlcNAc site localization; thus, it remains indispensable to precisely map the O-GlcNAcylated sites to fully understand the role of O GlcNAcylation on a given protein. For this purpose, we combined extensive fractionation of skeletal muscle cells proteome with click chemistry to map O GlcNAc sites without an a priori consideration. A total of 620 peptides containing one or more O-GlcNAc sites were identified; interestingly, several of them belong to low expressed proteins, in particular proteins involved in signalling pathways. We also focused on structural proteins in view of recent data supporting the role of O-GlcNAcylation in the modulation of sarcomere cytoarchitecture; importantly, some of the O-GlcNAc sites were mapped into protein-protein interaction domains, reinforcing the involvement of O GlcNAcylation in the organization and reorganization of sarcomere, and in larger extent, of myofibrils. PMID- 30016718 TI - Conformal coating by multilayer nano-encapsulation for the protection of human pancreatic islets: In-vitro and in-vivo studies. AB - To improve the efficiency of pancreatic islet transplantation, we performed in vitro and in-vivo experiments with isolated human pancreatic islets coated by multi-layer nano-encapsulation using differently charged polymers [chitosan and poly(sodium styrene sulfonate)] to obtain up to 9 layers. The islet coating (thickness: 104.2 +/- 4.2 nm) was uniform, with >= 90% cell viability and well preserved beta- and alpha-cell ultrastructure. Nano-encapsulated islets maintained physiological glucose-stimulated insulin secretion by both static incubation and perifusion studies. Notably, palmitate- or cytokine-induced toxicity was significantly reduced in nano-coated islets. Xenotransplantation of nano-encapsulated islets under the kidney capsule of streptozotocin-induced C57Bl/6J diabetic mice allowed long term normal or near normal glycemia, associated with minimal infiltration of immune cell into the grafts, well preserved islet morphology and signs of re-vascularization. In summary, the multi layer nano-encapsulation approach described in the present study provides a promising tool to effectively protect human islets both in-vitro andin-vivo conditions. PMID- 30016719 TI - Chemerin in human cardiovascular disease. AB - Adipose tissue, initially known only for storing excess fat, produces a number of active cytokine-like hormones, collectively known as adipokines or adipocytokines. These molecules are further known to elicit auto-, para- and endocrine functions in the body. In healthy bodies, the cardiovascular endothelium maintains vascular health by critically controlling the interplay between various factors. However, in diseased states such as obesity, owing to numerous metabolic malfunctions, this vascular homeostasis is disrupted. The dysregulated metabolic stimuli perturb vascular homeostasis via initiating or exacerbating the pre-existing inflammatory processes. These inflammatory processes further recruit immune cells to the site of injury, alter cell adhesion molecule expression, and reduce Nitric Oxide levels. These altered mechanisms result in increased blood pressure, endothelial cell migration, proliferation, and apoptosis. In this review article, we aim to evaluate the current literature in understanding the role of Chemerin in vascular health and furthermore, its role in maintaining vascular homeostasis with respect to inflammation, obesity and associated Metabolic Syndrome (MetS) risk factors. For over fifteen years, a growing body of research has been published studying Chemerin in the disease states associated with obesity, MetS and cardiovascular disease. Chemerin appears to form an integral link between obesity and related dysfunctional cardiometabolic states as well as in inflammation and immune-system related complications. These combine to suggest a significant Chemerin role in human vascular health and disease. PMID- 30016720 TI - Dexamethasone in pEdiatric Cardiac Surgery (DECiSion): Rationale and design of a randomized controlled trial. PMID- 30016722 TI - An unsupervised machine learning method for discovering patient clusters based on genetic signatures. AB - INTRODUCTION: Many chronic disorders have genomic etiology, disease progression, clinical presentation, and response to treatment that vary on a patient-to patient basis. Such variability creates a need to identify characteristics within patient populations that have clinically relevant predictive value in order to advance personalized medicine. Unsupervised machine learning methods are suitable to address this type of problem, in which no a priori class label information is available to guide this search. However, it is challenging for existing methods to identify cluster memberships that are not just a result of natural sampling variation. Moreover, most of the current methods require researchers to provide specific input parameters a priori. METHOD: This work presents an unsupervised machine learning method to cluster patients based on their genomic makeup without providing input parameters a priori. The method implements internal validity metrics to algorithmically identify the number of clusters, as well as statistical analyses to test for the significance of the results. Furthermore, the method takes advantage of the high degree of linkage disequilibrium between single nucleotide polymorphisms. Finally, a gene pathway analysis is performed to identify potential relationships between the clusters in the context of known biological knowledge. DATASETS AND RESULTS: The method is tested with a cluster validation and a genomic dataset previously used in the literature. Benchmark results indicate that the proposed method provides the greatest performance out of the methods tested. Furthermore, the method is implemented on a sample genome wide study dataset of 191 multiple sclerosis patients. The results indicate that the method was able to identify genetically distinct patient clusters without the need to select parameters a priori. Additionally, variants identified as significantly different between clusters are shown to be enriched for protein protein interactions, especially in immune processes and cell adhesion pathways, via Gene Ontology term analysis. CONCLUSION: Once links are drawn between clusters and clinically relevant outcomes, Immunochip data can be used to classify high-risk and newly diagnosed chronic disease patients into known clusters for predictive value. Further investigation can extend beyond pathway analysis to evaluate these clusters for clinical significance of genetically related characteristics such as age of onset, disease course, heritability, and response to treatment. PMID- 30016721 TI - A data-driven method to detect adverse drug events from prescription data. AB - Drug safety issues such as Adverse Drug Events (ADEs) can cause serious consequences for the public. The clinical trials that are undertaken to assess medicine efficacy and safety prior to marketing, generally, may provide sufficient samples for discovering common ADEs. However, more samples are needed to detect infrequent and rare events. Additionally, clinical trials may not include all subgroups of patients. For these reasons, post-marketing surveillance of medicines is necessary for identifying drug safety issues. Most regulatory agencies use the Spontaneous Reporting Systems to identify associations between medicines and suspected ADEs. Data mining with effective analytical frameworks and large-scale medical data is potentially an alternative method to discover and monitor ADEs. In the present paper, we aim to detect potential ADEs from prescription data by discovering ADE associated prescription sequences. In an ADE associated prescription sequence Ds>, the prior medicine Dp leads to an ADE for which the succeeding medicine Ds is dispensed to treat. We propose a data driven method which integrates (1) a constrained sequential pattern mining to uncover prescription sequences as potential signals of ADEs, (2) domain constraints to eliminate interference signals and (3) an adapted Self-Controlled Case Series model to evaluate the potential signals of ADEs. Despite ample prior works using Electronic Health Records (EHRs), our method utilises pure prescription data which does not contain additional information, e.g. symptoms or diagnoses as included in EHRs. To assess the performance of the proposed method, we apply it to a real-world dataset from the Pharmaceutical Benefits Scheme of Australia. The dataset contains over 50 million records covering approximately 2 million patients. The results demonstrate the effectiveness of our method in identifying both known ADEs and unknown yet suspicious ADEs with limited detection of false positive signals. Comparing to a recognised gold standard, our method successfully detects 67.4% of the positive adverse events while only 8.78% false positives exist. PMID- 30016723 TI - Electrophysiological responses of the ventrolateral periaqueductal gray matter neurons towards peripheral bladder stimulation. AB - INTRODUCTION: Many of the currently available therapies for urinary incontinence target the peripheral autonomic system, despite many etiologies residing in the central nervous system. Following previous experiments that determined the ventrolateral column of the periaqueductal gray matter (vlPAG), to be the main afferent station of bladder sensory signals, we aimed for electrophysiological characterization of vlPAG neurons using single unit recording. METHODS: 15 rats were anesthetized and underwent implantation with electrodes at the dome and the neck of the bladder, to electrically stimulate the detrusor. After craniotomy, a glass micropipette was inserted in vlPAG to record neuronal action potentials. The detrusor was stimulated by a series of 20 Hz pulses, for a total duration of 50 s at an intensity of 2 mA, for each vlPAG neuron selected. Single unit recordings were performed on a total of 26 neurons. Confirmation of electrode position was made by iontophoretic ejection of Pontamine sky blue. RESULTS: The firing rate of vlPAG neurons decreased significantly during the stimulation period. Peristimulus time histogram (PSTH) analysis showed 24 out of 26 neurons to be unresponsive to stimulation. All recorded vlPAG neurons showed irregular firing patterns. CONCLUSIONS: The change in firing rate may point to an overall inhibitory influence of bladder stimulation on vlPAG neurons. These data suggest an inhibitory relay station at the vlPAG, before sensory bladder signals would affect pontine micturition center. The lack of the inhibitory effect on PSTH may be due to a longer interval between neuronal response and the stimulation. PMID- 30016724 TI - Neuroprotective effects of hydrogen inhalation in an experimental rat intracerebral hemorrhage model. AB - OBJECTIVE: Hydrogen inhalation has been found to be neuroprotective and anti oxidative in several brain injury models. Building on these studies, we investigated potential neuroprotective effects of hydrogen inhalation in a rat model of intracerebral hemorrhage (ICH), focusing on apoptosis and inflammation. METHODS: Forty-five 8-week-old male Sprague-Dawley rats were randomly divided into three groups (n = 15 per each group): a sham group, ICH group, and ICH + hydrogen group. Induction of ICH was performed via injection of 0.23 U of bacterial collagenase type IV into the left striatum. Hydrogen was administered via spontaneous inhalation. Mortality and neurologic deficits were investigated at 6, 24, and 48 h after ICH. To investigate the antioxidative activity of hydrogen gas, the expression of malondialdehyde was measured. Real-time polymerase chain reaction analyses of TNF-a, IL-1b, BDNF, and caspase-3 expression were used to detect anti-inflammatory and anti-apoptotic effects. Neuroprotective effect was evaluated by immunohistochemical and TUNEL staining. RESULT: At 6, 24 and 48 h post-intracerebral hemorrhage, animals showed brain edema and neurologic deficits, accompanied by up-regulation of TNF-a, IL-b, BDNF, and caspase-3, which is indicative of neuroinflammation, neuroprotection, and apoptosis. Hydrogen treatment significantly reduced the level of oxidative stress, neuroinflammation, neuronal damage, and apoptosis-related genes. This was accompanied by increased neurogenesis and expression of growth factor-related genes at <24 h, but not 48 h, after ICH. CONCLUSION: H2 gas administration exerted a neuroprotective effect against early brain injury after ICH through anti-inflammatory, neuroprotective, anti-apoptotic, and antioxidative activity. PMID- 30016725 TI - Caudate nucleus neurons participate in methylphenidate function: Behavioral and neuronal recordings from freely behaving adolescent rats. AB - Methylphenidate (MPD) is the most commonly prescribed psychostimulant for the treatment of attention-deficit hyperactivity disorder (ADHD). MPD acts on brain structures of the reward/motivation system, including the caudate nucleus (CN). The objective of this study was to investigate the acute and chronic dose response effects of MPD on CN neurons in freely behaving adolescent rats. Semi microelectrodes were implanted into the CN of one hundred and sixty-three adolescent male Sprague-Dawley rats. On experimental day one (ED1), each rat was injected with 0.8 ml saline followed by an injection of MPD (0.6, 2.5, or 10.0 mg/kg). Behavioral and neuronal recordings of 60 min followed each injection. Throughout ED2-6, each rat remained in its home cage and received daily injections of a specific dose of MPD. ED7-9 consisted of a three-day washout period during which no injections were given. On the last day (ED10), each rat was returned to the testing chamber in its home cage and an identical protocol was performed as on ED1. The same repetitive (i.e. chronic) dose of MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. After chronic MPD exposure, CN units recorded from rats expressing behavioral sensitization responded mainly with increased neuronal firing rates. Conversely, rats expressing behavioral tolerance responded mainly with decreased neuronal firing rates. These findings suggest a direct correlation between the behavioral and CN neurophysiological response to chronic MPD in adolescent animals. PMID- 30016726 TI - Sleep and brain infections. AB - Sleep is frequently altered in systemic infections as a component of sickness behavior in response to inflammation. Sleepiness in sickness behavior has been extensively investigated. Much less attention has instead been devoted to sleep and wake alterations in brain infections. Most of these, as other neuroinfections, are prevalent in sub-Saharan Africa. The present overview highlights the importance of this topic from both the clinical and pathogenetic points of view. Vigilance states and their regulation are first summarized, emphasizing that key nodes in this distributed brain system can be targeted by neuroinflammatory signaling. Sleep-wake changes in the parasitic disease human African trypanosomiasis (HAT) and its animal models are then reviewed and discussed. Experimental data have revealed that the suprachiasmatic nucleus, the master circadian pacemaker, and peptidergic cell populations of the lateral hypothalamus (the wake-promoting orexin neurons and the sleep-promoting melanin concentrating hormone neurons) are targeted by African trypanosome infection. It is then discussed how prominent and disturbing are sleep changes in HIV/AIDS, also when the infection is cured with antiretroviral therapy. This recalls attention on the bidirectional interactions between sleep and immune system, including the specialized brain immune response of which microglial cells are protagonists. Sleep changes in an ancient viral disease, rabies, and in the emerging infection due to Zika virus which causes a congenital syndrome, are also dealt with. Altogether the findings indicate that sleep-wake regulation is targeted by brain infections caused by different pathogens and, although the relevant pathogenetic mechanisms largely remain to be clarified, these alterations differ from hypersomnia occurring in sickness behavior. Thus, brain infections point to the vulnerability of the neural network of sleep-wake regulation as a highly relevant clinical and basic science challenge. PMID- 30016727 TI - cPKCgamma alleviates ischemic injury through modulating synapsin Ia/b phosphorylation in neurons of mice. AB - Conventional protein kinase C (cPKC)gamma and synapsin Ia/b have been implicated in the development of ischemic stroke, but their relationships and functions are unclear. In the present study, the oxygen-glucose deprivation (OGD)-induced ischemic insult in primary cultured cortical neurons in vitro and middle cerebral artery occlusion (MCAO)-induced ischemic stroke model in vivo were used to elucidate the function of cPKCgamma and its modulation on synapsin Ia/b phosphorylation in ischemic stroke. We found that cPKCgamma knockout significantly increased the infarct volume of mice after 1 h MCAO/72 h reperfusion by using triphenyltetrazolium chloride (TTC) staining. In the primarily cultured cortical neurons, cPKCgamma knockout also aggravated the OGD induced cell death and morphological damage of neurites, while cPKCgamma restoration could alleviate the ischemic injury. Among the five phosphorylation sites of synapsin Ia/b, only the phosphorylation levels of Ser549 and 553 could be modulated by cPKCgamma in neurons following 0.5 h OGD/24 h reoxygenation. In addition, we found that cPKCgamma and synapsin Ia/b could be reciprocally co immunoprecipitated in the cerebral cortex of MCAO mice. Taken together, we proposed that cPKCgamma alleviates ischemic injury through modulating Ser549/553- synapsin Ia/b phosphorylation in neurons of mice. PMID- 30016728 TI - Aspirin resistance predicts unfavorable functional outcome in acute ischemic stroke patients. AB - OBJECTIVE: To investigate the prognostic value of aspirin reaction units (ARU) in a 3-month follow-up study in a cohort of Chinese patients with first-ever ischemic stroke. METHODS: Prospective single-center survey of acute ischemic stroke patients receiving aspirin therapy. Two hundred and seventy-five Chinese patients with first-ever ischemic stroke who previously received aspirin therapy were enrolled. ARU was measured using the VerifyNow system. A cutoff of 550 ARU was used to determine the presence of aspirin resistance (AR). RESULTS: Median age at study entry was 67 years (IQR: 59-75) and 142(51.6%) were male. A total of 52 of 275 enrolled patients (18.9%) were AR. Median regression estimated a statistically significant increase in NIHSS score of 0.033 point for every 1 point increase in ARU (95% CI, 0.024 to 0.068; P < 0.001). The unfavorable outcomes distribution across the ARU quartiles ranged between 11.8% (first quartile) to 64.8% (fourth quartile). After adjusting for other established risk factors, in multivariate models comparing the third and fourth quartiles against the first quartile of the ARU, levels of ARU were associated with unfavorable outcome, and the adjusted risk of unfavorable outcome increased by 145% (OR = 2.45 [95% CI 1.46-3.87], P = 0.011) and 317% (4.17[2.76-6.15], P < 0.001), respectively. Similarly, the adjusted risk of mortality increased by 215% (OR = 3.15 [95% CI 1.98-4.73], P = 0.008) and 429% (5.29[4.02-8.17], P < 0.001), respectively. CONCLUSIONS: The results suggest that AR is a meaningful and independent marker to predict short-term functional outcome in patients with ischemic stroke. PMID- 30016729 TI - Catestatin is involved in neuropathic pain mediated by purinergic receptor P2X4 in the spinal microglia of rats. AB - Neuropathic pain is defined as a type of chronic pathological pain that often results from nerve damage or disease. The purinergic receptor P2X4 is mainly expressed on the cell surface of spinal dorsal horn microglia and is known to be involved in neuropathic pain. Catestatin (CST) is an endogenous peptide derived from chromogranin A. Here, we attempted to identify how CST function in neuropathic pain. Rat model of chronic constriction injury (CCI) was used and experimental results indicated that mechanical and thermal pain sensitivities were significantly increased in CCI rats. The group of CCI rats that received intrathecal CST injection (CCI + CST) exhibited higher P2X4 mRNA and protein levels compared with the CCI group. Moreover, the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) in the CCI + CST group was higher than in the CCI group. This suggested that CST might aggravate neuropathic pain by enhancing P2X4 receptor expression in spinal microglia, and that the ERK1/2 pathway might be key in the development of neuropathic pain. PMID- 30016730 TI - alpha- (phenylselanyl) acetophenone mitigates reserpine-induced pain-depression dyad: Behavioral, biochemical and molecular docking evidences. AB - Chronic pain and depressive disorders have been estimated to co-occur in up to 80% of patients and traditional antidepressants and analgesics have shown limited clinical efficacy. alpha- (phenylselanyl) acetophenone (PSAP) is an organic selenium compound which has already demonstrated antioxidant, antidepressant and antinociceptive activities in animal models, without showing acute toxicity. In view of develop more effective treatments to comorbid pain and depression, the purpose of this study was to evaluate the behavioral and biochemical effects of PSAP on reserpine induced pain-depression dyad model in mice as well to analyze the interaction of PSAP with specific targets by molecular docking analysis. Reserpine (0.5 mg/kg daily, for 3 days, i.p.) decreased the latency for the first episode of immobility and the swimming time, as well as increased the immobility time of mice in the modified forced swimming test (mFST). Reserpine also led to a significant decrease in nociceptive threshold in thermal hyperalgesia in the hot plate test. PSAP or imipramine (10 mg/kg daily, for 2 days, i.g.) reversed these alterations in both mFST and hot plate test. Additionaly, PSAP reduced nitrite and malondialdehyde (MDA) levels and catalase (CAT) activity in the cerebral cortex and hippocampus of reserpinised mice. PSAP also normalized monoamine oxidase (MAO-A and MAO-T) activity increased in reserpinised mice. According to the molecular docking analysis, PSAP has affinity to MAO-A, suggesting an inhibition of this enzyme. The data presented here show that PSAP had reversed effects in the pain-depression dyad induced by reserpine, possibly by its antioxidant property and MAO-A inhibition. PMID- 30016731 TI - Copper-CX-5461: A novel liposomal formulation for a small molecule rRNA synthesis inhibitor. AB - CX-5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA-deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX-5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX-5461 and copper. Copper binds CX-5461 through the nitrogens of the pyrazine ring. Here, we describe synthesizing this copper complexed CX-5461 (Cu(CX-5461)) within liposomes. CX-5461 was added to copper containing liposomes and incubated at 60 degrees C for 30 min. The pharmacokinetics of CX-5461 was assessed in mice following a single i.v. injection at 30 mg/kg. Efficacy studies were completed in multiple subcutaneous mouse xenografts as well as in a bone marrow engraftment model of acute myeloid leukemia (AML). The novel Cu(CX-5461) formulation was stable at pH 7.4 and exhibited increased plasma circulation longevity, increasing the total exposure to CX5461 by an order of magnitude. Cu(CX-5461) was more active than CX-5461 in AML models in vivo. In HCT116-B46 and Capan-1 solid tumour models that are BRCA deficient, the Cu(CX-5461) formulation engendered activity that was comparable to that of the low pH CX-5461 formulation. We have generated the first Cu(CX-5461) formulation suitable for i.v. administration that is more efficacious than the existing low-pH formulation in pre-clinical models of AML. The Cu(CX-5461) formulation may serve as an alternative formulation for CX-5461 in BRCA-deficient cancers. PMID- 30016733 TI - Connecting the in vitro and in vivo experiments in electrochemotherapy - a feasibility study modeling cisplatin transport in mouse melanoma using the dual porosity model. AB - In electrochemotherapy two conditions have to be met to be successful - the electric field of sufficient amplitude and sufficient uptake of chemotherapeutics in the tumor. Current treatment plans only take into account critical electric field to achieve cell membrane permeabilization. However, permeabilization alone does not guarantee uptake of chemotherapeutics and consequently successful treatment. We performed a feasibility study to determine whether the transport of cisplatin in vivo could be calculated based on experiments performed in vitro. In vitro, a spectrum of parameters can be explored without ethical issues. Mouse melanoma B16-F1 cell suspension and inoculated B16-F10 tumors were exposed to electric pulses in the presence of chemotherapeutic cisplatin. The uptake of cisplatin was measured by inductively coupled plasma mass spectrometry. We modeled the transport of cisplatin with the dual-porosity model, which is based on the diffusion equation, connects pore formation with membrane permeability, and includes transport between several compartments. In our case, there were three compartments - tumor cells, interstitial fraction and peritumoral region. Our hypothesis was that in vitro permeability coefficient could be introduced in vivo, as long as tumor physiology was taken into account. Our hypothesis was confirmed as the connection of in vitro and in vivo experiments was possible by introducing a transformation coefficient which took into account the in vivo characteristics, i.e., smaller available area of the plasma membrane for transport due to cell density, presence of cell-matrix in vivo, and reduced drug mobility. We thus show that it is possible to connect in vitro and in vivo experiments of electrochemotherapy. However, more experimental work is required for model validation. PMID- 30016734 TI - The potential for clinical translation of antibody-targeted nanoparticles in the treatment of acute myeloid leukaemia. AB - Acute myeloid leukaemia (AML) is a heterogeneous haematopoietic malignancy. Currently, treatment options offer a 5 year survival of <60%. In elderly patients, where the incidence is highest, the survival is much lower. Current standard treatments have significant toxicity and are least well tolerated in older adults, where the need is greatest. Therefore, alternatives are required. Monoclonal antibodies (mAbs), due to the specific targeting to cell surface proteins (i.e. antigens), represent a promising strategy for drug delivery to malignant cells. This concept favours the therapeutic ratio simultaneously by reducing toxicity and increasing efficacy. Although delivery of chemotherapeutics, genes and imaging agents using multifunctional nanoparticles has been substantially explored in treating solid cancers, less information on this approach is available in the case of AML. This review describes the development of antibody-targeted nanoparticulate drug delivery systems, and discusses the barriers to clinical translation in the treatment of AML. PMID- 30016732 TI - Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system. AB - The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions. PMID- 30016735 TI - Cellular recycling-driven in vivo half-life extension using recombinant albumin fusions tuned for neonatal Fc receptor (FcRn) engagement. AB - Recombinant albumin-drug genetic fusions are an effective technology to prolong the serum half-life of therapeutics that has resulted in marketed products. Indirect evidence suggests albumin fusions' long circulation is controlled by engagement with the cellular recycling neonatal Fc receptor (FcRn) in addition to reduced kidney filtration. In this work, we have used a panel of recombinant fusions, engineered with different human FcRn (hFcRn) affinity, including a novel high binding albumin variant (HBII), to directly define and importantly, control the intracellular mechanism as a half-life extension tuning method. mNeonGreen or mCherry fusion to the N-terminal of the recombinant human albumin (rHA) variants null-binder (rHA NB), wild-type (rHA WT), high-binder I (rHA HBI), and high binder II (rHA HBII) did not generally interfere with hFcRn interaction determined by Biolayer Interferometry. Co-localisation of the albumins with endosomal, but not lysosomal, markers was shown by confocal microscopy for high, but not low, hFcRn binders in a human microvascular endothelial hFcRn overexpressing cell line (HMEC-1 FcRn) suggestive of endosomal compartmentalisation. Furthermore, a cellular recycling assay revealed increased recycling of albumin fusions for the high binding variants (mNeonGreen WT; ~1, mNeonGreen HBI; 5.26-fold higher, and mNeonGreen HBII; 5.77-fold higher) in the hFcRn overexpressing cell line. In vivo experiments demonstrated a direct in vitro recycling/in vivo half-life correlation with a longer circulation for the mCherry fusions engineered with high hFcRn affinity that was highest with the HBII variant of 30.1 h compared to 18.2 h for the mCherry WT. This work gives the first direct evidence for an FcRn-driven endosomal cellular recycling pathway for recombinant albumin fusions that correlates with half-life extension controlled by the affinity to hFcRn; promoting a versatile method to tune the pharmacokinetics of albumin fusion-based therapeutics not met by current technologies. PMID- 30016737 TI - Integrating genome-wide association study, chromosomal enhancer maps and element gene interaction networks detected brain regions related associations between elements and ADHD/IQ. AB - OBJECTIVE: To explore the associations between chemical elements and attention deficit hyperactivity disorder (ADHD)/intelligence quotient (IQ). METHODS: We applied elements related gene set enrichment analysis (ERGSEA) to explore the relationships between elements and ADHD/IQ. The GWAS dataset of ADHD was derived from the Psychiatric Genomics Consortium, involving 55,374 individuals. The GWAS dataset of IQ was derived from UK Biobank web-based measure (n = 17,862), UK Biobank touchscreen measure (n = 36,257), CHIC consortium (n = 12,441) and five additional cohorts (n = 11,748). Enhancer-gene datasets of eight brain tissues consist of 935 individuals. Utilizing the published GWAS summary and eight brain region-related chromosomal enhancer maps to obtain the SNP association testing signals. The element-gene interaction datasets of 21 elements were downloaded from the comparative toxicogenomics database (CTD). RESULTS: ERGSEA observed significant associations between 4 elements and ADHD, such as Al at Hippocampus Middle (P value = 0.040), As at Angular Gyrus (P value = 0.007) and Na at Hippocampus Middle (P value = 0.026). Additionally, ERGSEA identified that 5 elements were associated with IQ, mainly including Al at Dorsolateral Prefrontal Cortex (P value = 0.017), As at Dorsolateral Prefrontal Cortex (P value = 0.004) and Pb at Germinal Matrix (P value = 0.045). CONCLUSION: Our study results provide novel clues for understanding the associations between elements and ADHD/IQ. This study also illustrated the good performance of ERGSEA approach for complex diseases. PMID- 30016736 TI - The moderating effect of perceived social support on the relation between heaviness of smoking and quit attempts among adult homeless smokers. AB - BACKGROUND: Over 70% of homeless adults smoke cigarettes. Despite the desire to quit, this group rarely receives the external support to make or maintain a successful quit attempt (SQA; intentional quit attempt lasting >24 h). The Heaviness of Smoking Index (HSI) is a cigarette dependence measure that independently predicts SQAs among domiciled adults. For homeless adults, social support may be a way to buffer the impact of cigarette dependence on SQAs. METHODS: The association of the HSI and past-year SQAs, and the potential moderating role of social support, was examined among 445 homeless smokers (Mage = 43.2 + 11.8, 65% male, 57.5% white). Support was measured by the International Support Evaluation List (ISEL-12) and its 3 subscales: tangible, belonging, & appraisal support. RESULTS: The HSI was negatively correlated with SQAs (r=-.283, p < .01) and in a regression model controlling for age, sex, and race/ethnicity, appraisal support significantly moderated this relationship (p < .05). The HSI was significantly related to SQAs across low, moderate, and high levels of appraisal support [mean, +1 SD; low (beta=-.657, p < .001), medium (beta=-.457, p < .001), and high (beta=-.258, p < .05)]. Neither the ISEL-12 total nor the other subscales were moderators. CONCLUSION: The perceived availability of someone to talk to about one's problems appeared to attenuate the strength of the inverse relationship between the heaviness of smoking and SQAs. Fostering appraisal support for homeless smokers through group treatment may reduce the impact of cigarette dependence on making quit attempts. Social support coupled with the increased availability of empirically-supported cessation aids may improve dismal quit rates among homeless adults. PMID- 30016738 TI - Observational threat conditioning is induced by circa-strike activity burst but not freezing and requires visual attention. AB - Social transmission refers to a process in which an observer (OB) acquires new information about the environment including threat situations, through the action of familiar conspecifics. Recently, a number of studies employing observational threat conditioning (OTC) in which OB mice expressed defensive responses following indirect exposure to pair-housed partner mice (demonstrator: DE) which were receiving repeated footshocks, have produced interesting insights into the social mechanisms of emotional transfer. However, the nature of the transmitted information or the critical cognitive processes involved in OTC is not clear. In a series of experiments, we investigated the key elements involves in triggering socially-induced defensive responses. In Exp.1, we compared the effectiveness in conveying a threat of two different types of defensive reactions of DEs: the circa-strike activity burst (CSAB) vs. freezing. The results show that the CSAB is more effective than freezing in inducing defensive freezing in an OB. In Exp. 2, we investigated different types of the OBs' defensive responses by measuring their change in head orientation or their "gazing" at the DEs, and their temporal synchrony with the DEs' defensive reactions in the form of their CSAB. The results show that OBs' gazing was significantly correlated with the DEs' CSAB, especially the DEs' jumping behavior, but not with the freezing of the DEs, indicating that jumping is a more effective trigger stimulus in inducing attentional capture in conspecific partner animals. In Exp. 3, the role of visual information was tested. The result shows that the OBs' level of freezing was significantly reduced when visual information was blocked by an opaque partition. In Exp. 4, to confirm the critical role of visual attention, we introduced distracting flashing lights, which were switched on and off at random intervals during the conditioning process. With all other conditions being maintained unaltered, the OBs in the distractor condition displayed a significantly decreased level of freezing, indicating that the visual attention paid to the DEs by the OBs during the conditioning process was critical for the social transmission of threat. Taken together, the results of the current study strongly suggest that socially transmitted defensive behavior is dependent on the specific behavioral elements of a DE's defensive behavior, and moreover, that a visual attentional process is required during the OTC. PMID- 30016739 TI - Intracellular transformation rates of fatty acids are influenced by expression of the fatty acid transporter FadL in Escherichia coli cell membrane. AB - Fatty acids have a low permeability through the cell membrane. Therefore, the intracellular biotransformation of fatty acids can be slow due to supply limitations. The effects of expression level of the fatty acid transporter FadL in Escherichia coli on the biotransformations were investigated. The enhanced expression of FadL led to 5.5-fold increase of the maximum reaction rate Vmax (i.e., 200 MUmol/min per g dry cells (200 U/g dry cells)) of the recombinant E. coli expressing a hydratase of Stenotrophomonas maltophilia in the periplasm with respect to hydration of oleic acid. The FadL expression level was also critical for oxidation of 12- and 10- hydroxyoctadecanoic acid by the recombinant E. coli expressing an alcohol dehydrogenase (ADH) of Micrococcus luteus. In addition, the multistep biotransformation of ricinoleic acid into the ester (i.e., (Z)-11 (heptanoyloxy)undec-9-enoic acid) by the recombinant E. coli expressing the ADH of M. luteus and a Baeyer-Villiger monooxygenase of Pseudomonas putida KT2440 was 2-fold increased to 40 U/g dry cells with expression of FadL to an appropriate level. The FadL expression level is one of the critical factors to determine whole-cell biotransformation rates of not only long chain fatty acids but also hydroxy fatty acids. This study may contribute to whole-cell biocatalyst engineering for biotransformation of hydrophobic substances. PMID- 30016740 TI - Biosynthesis of 4-vinylguaiacol from crude ferulic acid by Bacillus licheniformis DLF-17056. AB - 4-vinylguaiacol, a kind of volatile phenolic compound with tobacco flavor, is widely used as a component of edible flavor and intermediate of medicine. Ferulic acid is usually used as substrate for the biosynthesis of 4-vinylguaiacol. However, the price of ferulic acid is high, leading to high production cost. In this study, a feasible low-cost process for the production of 4-vinylguaiacol was developed. The ultrasonic assisted weak alkali was used to extract protein from rice bran, and waste liquid and residue were then mixed to extract crude ferulic acid by alkaline hydrolysis. Subsequently crude ferulic acid without further purification was directly converted into 4-vinylguaiacol via alginate-immo cells of the strain Bacillus licheniformis DLF-17056, which was newly isolated and highly active with ferulic acid conversion to 4-vinylguaiacol. 4-Vinylguaiacol could be produced up to 0.76 g/L from 1.0 g/L ferulic acid within 24 h biotransformation. Furthermore, the immobilized biocatalysts retained above 60% initial activity even after 8 times biotransformations. Thereby, it was assumed that our study would contribute to the industrial production of 4-vinylguaiacol from ferulic acid. PMID- 30016741 TI - Potato snakin-1 gene enhances tolerance to Rhizoctonia solani and Sclerotinia sclerotiorum in transgenic lettuce plants. AB - Snakin-1 is a cysteine-rich antimicrobial peptide (AMP) isolated from potato tubers, with broad-spectrum activity. It belongs to the Snakin/GASA family, whose members have been studied because of their diverse roles in important plant processes, including defense. To analyze if this defensive function may lead to disease tolerance in lettuce, one of the most worldwide consumed leafy vegetable, we characterized three homozygous transgenic lines overexpressing Snakin-1. They were biologically assessed by the inoculation with the fungal pathogens Rhizoctonia solani and Sclerotinia sclerotiorum both in vitro and in planta at the greenhouse. When in vitro assays were performed with R. solani on Petri dishes containing crude plant extracts it was confirmed that the expressed Snakin 1 protein has antimicrobial activity. Furthermore, transgenic lines showed a better response than wild type in in vivo challenges against R. solani both in chamber and in greenhouse. In addition, two of these lines showed significant in vivo protection against the pathogen S. sclerotiorum in challenge assays on adult plants. Our results show that Snakin-1 is an interesting candidate gene for the selection/breeding of lettuce plants with increased fungal tolerance. PMID- 30016742 TI - Associating disabilities, school environments, and child victimization. AB - Inclusive education has become one of the key policy objectives for the education for children with disabilities in recent decades. However, its effectiveness in promoting happy school life among those children has been questioned. In this study, we aimed to provide a detailed profile of the associations between disabilities and child victimization, and to examine the effects of school environments on those associations. We conducted a cross-sectional survey with a sample of 4114 school-aged children (6-18 years), who were receiving primary or secondary education in Hong Kong in 2016-2017. Children's experiences of 7 types of victimization in the past year, status of disabilities, type of school attending, and other demographic factors were captured with questionnaire completed by the children or their parents. Apart from descriptive statistics, we conducted logistic regression analyses to examine the associations between disabilities, types of school, and child victimization. Children with ADHD, internalizing disorder, autistic spectrum disorder, and restrictions in body movement were at higher risks of victimization while other types of disabilities were not. Children attending special schools were at lower risks of victimization, while children with disabilities who had been placed in ordinary schools for inclusive education were at higher risks of most types of victimization when compared to children without disabilities. Our findings suggested an important role of the school environments on the associations between disabilities and victimization. When placed in a protective environment, children with disabilities could even be less vulnerable to victimization than those without disabilities. PMID- 30016743 TI - The impact of SafeCare(r) Dads to Kids program on father maltreatment risk and involvement: Outcomes and lessons learned from an efficacy trial. AB - Child Maltreatment (CM) is a public health problem, and experts recommend parent training programs as a prevention method. Few programs target fathers, even though male caregivers are involved as perpetrators in approximately 45% of substantiated CM cases. This study examines the efficacy of an adapted version of SafeCare (Dad2K) with marginalized fathers. Participants include a convenience sample of fathers with children ages 2-5 years. Fathers (n=99) were randomized to an 1) intervention group (SafeCare Dad2K) or to a 2) comparison group (receiving parenting information in the mail). Quantitative data were collected at baseline, post-intervention (7-weeks post-baseline), and 3-months post-intervention. Qualitative data (semi-structured interviews) were collected from 11 intervention father completers following the second quantitative data collection timepoint. Multi-level modeling results indicated no statistically significant time-by treatment findings for father involvement (b=0.03, 95% confidence interval [CI]: 0.03, 0.08, p=0.38), total corporal punishment (b=-0.03, 95% CI: -0.47, 0.41, p=0.89), or neglect (b=-0.13, 95% CI: -1.93, 1.68, p=0.89). Qualitative findings indicated that Dad2K completers exhibited positive knowledge and behavioral change related to parenting. Study limitations, lessons learned from this formative work, and recommendations for future research are discussed. PMID- 30016744 TI - Intergenerational transmission of out-of-home care in Sweden: A population-based cohort study. AB - The objective of this study is to examine the intergenerational transmission of out-of-home care. This population-based study used data from the Swedish National Registers and included all children born in Sweden between 1990 and 2012 (followed for up to 13 years), whose parents were both born in Sweden between 1973 and 1980 (278 327 children; 145 935 mothers; 146 896 fathers). Cox regression models are used to obtain crude and adjusted hazard ratios (HR) of OHC placement among children based on parents' history of OHC. Compared with children whose parents both did not have a history of OHC, the risk of being placed in OHC was greater when both parents spent time in OHC (crude HR = 48.70, 95% CI 41.46 57.21; adjusted HR = 3.04, 95% CI = 2.54-3.64), however, children who had only one parent who spent time in care were also at higher risk (mothers only adjusted HR = 2.37, 95% CI = 2.08-2.70; fathers only adjusted HR = 1.33, 95% CI = 1.13 1.55). The crude rate of placement in OHC was highest for children whose parents were placed in care during adolescence, but after adjusting for social and behavioral covariates, children whose parents were in care in early childhood were at greater risk of OHC than children whose parents were in care in adolescence. To reduce this intergenerational transmission of OHC, more supports should be provided to parents who spent time in OHC to ensure a successful transition to parenthood. PMID- 30016745 TI - Efficient computation of image moments for robust cough detection using smartphones. AB - Health Monitoring apps for smartphones have the potential to improve quality of life and decrease the cost of health services. However, they have failed to live up to expectation in the context of respiratory disease. This is in part due to poor objective measurements of symptoms such as cough. Real-time cough detection using smartphones faces two main challenges namely, the necessity of dealing with noisy input signals, and the need of the algorithms to be computationally efficient, since a high battery consumption would prevent patients from using them. This paper proposes a robust and efficient smartphone-based cough detection system able to keep the phone battery consumption below 25% (16% if only the detector is considered) during 24 h use. The proposed system efficiently calculates local image moments over audio spectrograms to feed an optimized classifier for final cough detection. Our system achieves 88.94% sensitivity and 98.64% specificity in noisy environments with a 5500* speed-up and 4* battery saving compared to the baseline implementation. Power consumption is also reduced by a minimum factor of 6 compared to existing optimized systems in the literature. PMID- 30016746 TI - Tubulin genes and malformations of cortical development. AB - A large number of genes encoding for tubulin proteins are expressed in the developing brain. Each is subject to specific spatial and temporal expression patterns. However, most are highly expressed in post-mitotic neurons during stages of neuronal migration and differentiation. The major tubulin subclasses (alpha- and beta-tubulin) share high sequence and structural homology. These globular proteins form heterodimers and subsequently co-assemble into microtubules. Microtubules are dynamic, cytoskeletal polymers which play key roles in cellular processes crucial for cortical development, including neuronal proliferation, migration and cortical laminar organisation. Mutations in seven genes encoding alpha-tubulin (TUBA1A), beta-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB) and gamma-tubulin (TUBG1) isoforms have been associated with a wide and overlapping range of brain malformations or "Tubulinopathies". The majority of cortical phenotypes include lissencephaly, polymicrogyria, microlissencephaly and simplified gyration. Well-known hallmarks of the tubulinopathies include dysmorphism of the basal ganglia (fusion of the caudate nucleus and putamen with absence of the anterior limb of the internal capsule), midline commissural structures hypoplasia and/or agenesis (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, cerebellar hypoplasia or dysplasia and dysmorphism of the hind-brain structures. The cortical and extra cortical brain phenotypes observed are largely dependent on the specific tubulin gene affected. In the present review, all the published data on tubulin family gene mutations and the associated cortical phenotypes are summarized. In addition, the most typical neuroimaging patterns of malformations of cortical development associated with tubulin gene mutations detected on the basis of our own experience are described. PMID- 30016747 TI - Altruism in preventive health behavior: At-scale evidence from the HIV/AIDS pandemic. AB - Preventive behavior with regards to disease transmission offers a promising context in which to provide empirical evidence on altruism in human populations. I examine the association between HIV status, own knowledge about status, and preventive health behavior using household survey data from over 200,000 individuals in 25 sub-Saharan African countries. I find that individuals who are HIV positive and have taken a standard HIV test are much more likely to engage in efforts to prevent HIV transmission than are individuals who are HIV negative and have taken a standard HIV test. Moreover, this difference is greater than the difference between HIV positives and HIV negatives for individuals who have not taken a standard HIV test. Consistent with an altruistic motivation, this double difference is larger for individuals who are married than for individuals who are not married. These results appear to be the first evidence on the change in risky sexual behavior associated with HIV testing at scale and are consistent with altruism dominating any self-interested response to HIV testing. PMID- 30016748 TI - Parental human capital and child health at birth in India. AB - Health at birth shapes an individual's well-being over her life cycle. We categorize the Indian states into high and low infant mortality regions to capture the diverse disease environment and analyze the nature of the association between parental human capital and child survival and nutrition measures at birth. We restrict our analysis only to firstborns to avoid confounding from a number of factors including sex-selective abortions in the higher birth orders. We broadly find that parental human capital, especially maternal health, is a strong and significant predictor of a child's birth outcomes under adverse disease environment. In the rural areas of the high infant mortality states, a 10 centimeter increase in maternal height is associated with 1.7% lower probability of a child dying as a neonate and 5% increase in birth weight around the mean. These estimates suggest that an investment in human capital of the mothers from this region could accompany large gains in survival and nutrition outcomes of their children. PMID- 30016749 TI - Development of functionalized gold nanoparticles as nanoflare probes for rapid detection of classical swine fever virus. AB - Classical swine fever (CSF) is a devastating viral disease affecting pigs that causes major economic losses worldwide. Conventional assays to identify classical swine fever virus (CSFV) face challenges, such as the required molecular amplification of the target molecules via polymerase chain reaction (PCR). We designed a gold nanoflare probe to directly detect CSFV. Gold nanoparticles (AuNPs) were conjugated with a pair of complementary DNA sequences that specifically recognized and captured CSFV RNA, resulting in a fluorescence signal to indicate the existence of CSFV. The constructed nanocomposite was then utilized in a quantitative analysis to recognize the virus sequence present at amounts as low as 50 pg/MUL. The CSFV-AuNP probe enabled real-time, quantitative detection of native CSFV in response to doses of the specific RNA sequence (CSFV NS2) that indicated active viral replication of CSFV Shimen in macrophages after 12, 24, and 48 h. The potential diagnostic applications of the probe were demonstrated by measuring CSFV without nucleic acid amplification in samples from seven types of tissue samples, specifically heart, spleen, kidney, liver, lymph, intestine, and muscle samples obtained from one pig confirmed to suffer CSF. The speed, sensitivity, and versatility of this CSFV-AuNP biosensor make it an ideal candidate for further application in the prevention and control of animal epidemic diseases. PMID- 30016750 TI - Analysis of Reported Adverse Events with Uterine Artery Embolization for Leiomyomas. AB - STUDY OBJECTIVE: To analyze and investigate reports associated with uterine artery embolization used for treatment of myomas using this database. DESIGN: A retrospective review of the Manufacturer and User Facility Device Experience (MAUDE) database for events related to uterine artery embolization (Canadian Task Force Classification III). SETTING: The MAUDE database was accessed online. PATIENTS: Patients with myomas undergoing uterine artery embolization. INTERVENTIONS: The MAUDE database was accessed online and searched for events related to uterine artery embolization reported between 1998 and 2018. These reports were reviewed and analyzed, reported events were categorized, and other relevant information was collected and tabulated. MEASUREMENTS AND MAIN RESULTS: A total of 193 reports published during the study period were identified. Pain was the most frequently reported event (68 events; 35.2%), followed by vaginal discharge (45 events; 23.3%), operational misfire (37 events; 19.2%), and fever or infectious complications (36 events; 18.7%). A surgical procedure was required in 27 events (14.0%), with hysterectomy reported in 7.8% of the events. Death following this procedure was mentioned in 5 events (2.6%). CONCLUSION: The MAUDE database may be useful for clinicians using a Food and Drug Administration approved medical device to identify the occurrence of adverse events and complications. A variety of adverse events associated with the use of uterine artery embolization were reported to the MAUDE database related to its use in the treatment of uterine myomas. We encourage physicians to review the MAUDE database when using medical devices, because this is an important tool to assess uncommon but major problems that could be associated with a medical device. PMID- 30016751 TI - Modelling public bus/minibus transport accident severity in Ghana. AB - The current safety concerns with buses/minibuses (public transport) in both developed and developing countries have warranted a renewed interest in bus/minibus safety research. Prior to this, there was a paucity of research in this domain especially in developed countries where the safety associated with buses was deemed adequate. In this study, we examined the factors that influence bus/minibus accident severity in Ghana using bus/minibus accident data from 2011 2015. We estimated the severity of bus/minibus accidents by fitting generalised ordered logit models. Our findings revealed that weekends, the absence of road median, night-time conditions, bad road terrain (curved, wet and rough roads), hit-pedestrian collisions, and drunk driving are associated with more severe bus/minibus accident outcomes. Conversely, minibuses, the absence of road shoulder, accidents in intersections, the presence of traffic control and collision types (except hit-pedestrian) are associated with less severe bus/minibus accidents. PMID- 30016752 TI - The influence of 5-aminolevulinic photodynamic therapy on colon cancer cell interleukin secretion in hypoxia-like condition in vitro. AB - Photodynamic therapy (PDT) becomes a method of personalized cancer treatment, based on the individual determination of cancer biomarkers. The aim of the study was to evaluate the influence of PDT with delta-aminolevulinic acid (ALA-PDT) used in sub-lethal dose on the interleukins secretion (IL-6, IL-8 and IL-10) by the residual colon cancer cells (CCC) under hypoxia-like conditions (addition of cobalt chloride- CoCl2). CCC: SW480 and SW620 cells were incubated with ALA, CoCl2 and irradiated with red light. The cells viability was detected using MTT assay, LDH and apoptosis tests. Determination of interleukins was carried out using the Bio- Plex Assay ProTM kit on the Bio- Plex Suspension Array System. After ALA-PDT we found no change in the IL-6 level secreted by SW480 cells, but decrease of IL-6, IL-10 secretion by SW620 cells, an increase in the IL-8 secreted by both cells lines. The levels of IL-6, IL-8 and IL-10 secreted by more aggressive SW620 cells were higher than released by SW480 cells. We concluded, that PDT not only effectively destroy malignant tissue, but also used in sub lethal dose can develops its anticancer activity through the reduction of IL-6 and IL-10 secretion. On the other hand, we reveal an unfavorable PDT effect, connected with increase of IL-8 secretion by both treated colon cancer cell lines, which implicates the use of adjuvant immunotherapy against IL-8, as a part of individualized colon cancer therapy. PMID- 30016753 TI - A novel nano-superparamagnetic agent for photodynamic and photothermal therapies: An in-vitro study. AB - BACKGROUND: In this study, iron oxide nanoparticles (SPIONs) were synthesized and coated by GA (SG) and then SG was encapsulated by ICG (SGI). After identifying specifications and cytotoxicity of the agents, the potential of SGI for photodynamic therapy (PDT) and photothermal therapy (PTT) was studied. METHODS: An SGI size of 12-13 nm was determined by TEM images and its zeta potential was measured at -23.8 +/- 5.8 mV. MCF-7 and HT-29 cells were exposed to a non coherent light source at a wavelength of 730 nm and a range of 3.9-124.8 J/cm2 under two different concentrations of agents. The viability of treated cells was determined via MTT assay. To analyze the effects of different irradiation conditions, some indices such as Coefficient of Light Effect, Synergism Index, Addition Ratio, Treatment Efficacy and ED50 were defined. RESULTS: Cell survival at the highest power of irradiation in the absence of any agent was decreased to 93% and 73% for HT-29 and MCF-7, respectively. In both cell lines, the cellular survival dropped by increasing the light source intensity. The maximum cell death recorded for SG, ICG and SGI was 63 +/- 2%, 63 +/- 2% and 21 +/- 2% for MCF-7 cells and 67 +/- 2%, 78 +/- 1% and 53 +/- 1% for HT-29 cells, respectively. CONCLUSION: SGI had a significant photodynamic and photothermal effect on cells. This is a promising outcome, which can help enhance the effectiveness of a minimally invasive treatment. Moreover, SPIONs can be used to apply magnetic hyperthermia or act as a contrast agent in MRI images. PMID- 30016754 TI - CSF cystatin C and diffusion tensor imaging parameters as biomarkers of upper motor neuron degeneration in amyotrophic lateral sclerosis. AB - OBJECTIVES: The establishment of biomarkers for amyotrophic lateral sclerosis (ALS) will be useful for early diagnosis and may provide evidence about pathogenesis. To elucidate whether high-field magnetic resonance (MR) findings and multimodal analysis of cerebrospinal fluid (CSF) levels of cystatin C could be indicators of upper motor neuron (UMN) involvement in ALS. PATIENTS AND METHODS: Patients with ALS (n = 20), multiple sclerosis (n = 15), immune mediated chronic polyneuropathy (n = 17), and acute polyneuropathy (n = 12) were included in this retrospective study. Clinical indices including UMN signs were assessed, and 3.0-Tesla diffusion tensor imaging and MR spectroscopy were performed in patients with ALS. CSF levels of cystatin C were measured using enzyme-linked immunosorbent assay. RESULTS: MR findings indicated that decreased anisotropy, increased diffusion, and increased myo-inositol/creatine ratio were also significantly correlated with UMN involvement in patients with ALS. The CSF cystatin C levels were significantly lower in patients with ALS than in the other three groups. The reduction of CSF cystatin C levels was significantly correlated with clinical UMN involvement (r = -0.505, p = 0.023). CONCLUSIONS: Reduced cystatin C in CSF can reflect UMN involvement as shown in high-field MR of ALS, potentially providing a new biomarker for UMN degeneration in ALS. PMID- 30016755 TI - Causes of ATtrition in CHIldren's NursinG (CATCHING): An exploratory mixed method study. AB - Professional, financial and ethical reasons necessitate nursing improves its understanding of student attrition. Previous studies identify causes of attrition as multifactorial. However, few studies focus on children's nursing. This study aimed to explore causes of pre-registration children's nursing attrition. Exploring the causes of attrition was achieved through quantitative and qualitative approaches. Three years of quantitative data relating to attrition rates and causes was obtained. These data informed semi-structured interviews of children's nursing students, from four London universities. These students had faced challenges and either 'left' (n = 5) or 'stayed on' (n = 13) their pre registration programme. Most attrition occurred in the first year of programmes and was primarily due to academic failure or personal circumstances; clinical placements also played a role. Emergent themes were 'expectations of pre registration children's nursing'; 'realities of a pre-registration children's nursing course', and 'factors that influence students leaving or staying on the course'. Many participants reported a reluctance to disclose issues while on their course. Support to continue on the programme was frequently obtained away from university and students described relying on self-determination to complete programmes. Findings indicated several areas of potential improvement for student support including targeted interventions focusing on a student's first year and reducing variation in support services provided. PMID- 30016756 TI - Will daytime occupational noise exposures induce nighttime sleep disturbance? AB - BACKGROUND: Nighttime environmental noise affects sleep quality. However, the effects of daytime occupational noise remain unclear. METHODS: A quasi-experiment of 48 participants who had been employed for at least six months in two hospital cafeterias. The participants were randomly designated to be assessed on high- and low-noise workdays for 8 h or low- and high-noise workdays, separated by a washout period of 14 days. Subsequently, pure tone audiometry, autonomic nervous system (ANS) function tests, serum cortisol tests, and polysomnography were conducted. RESULTS: For the 40 participants in the study, the 8-h time-weighted average of personal noise exposed on high- and low-noise workdays was 76.8 dBA (standard deviation, SD: 6.2) and 61.0 dBA (SD: 7.1), respectively. Participants with higher personal noise exposure during the day were found to have a lower percentage of slow wave sleep (percent change of mean value: -1.287%; 95% CI: 2.602%, -0.037%) and lower sleep efficiency (-0.267%; 95% CI: -0.525%, -0.008%). In addition, after work, personal noise exposure was revealed to be related to increased serum cortisol levels (1.698%; 95% CI: 0.887%, 2.528%), and sympathetic activity as measured by low frequency/high frequency (3.000%; 95% CI: 1.294%, 4.706%) and blood pressures by cold pressor test (systolic: 5.163%; 95% CI: 2.780%, 7.537%) (diastolic: 3.109%; 95% CI: 1.604%, 4.614%). CONCLUSIONS: Daytime occupational noise exposure had sustained effects on nighttime sleep quality, specifically on slow wave sleep and sleep efficiency. These disturbances could be partially explained by post-shift elevated cortisol and ANS activity. The psychosocial and metabolic consequences of poorer sleep quality induced by occupational noise exposure warrant further investigation. PMID- 30016757 TI - Attention capture, processing speed, and inattentional blindness. AB - Previous theories of inattentional blindness (IB; a phenomenon of observers failing to notice a salient but unexpected event when attention is already occupied) have suggested that an unexpected object reaches conscious awareness when: 1) the location of the unexpected object and attention align, and 2) the unexpected object undergoes sufficient processing. Moreover, it is expected that the same factors that influence the allocation of observers' attention in attention capture studies influence what reaches conscious awareness in IB studies. We explored the degree to which individual differences in susceptibility to attention capture and processing speed are important predictors of IB. One hundred forty-six participants (from Study 1 of Roque, Wright, & Boot, 2016) completed four classic attention (implicit) capture tasks designed to assess stimulus-driven and contingent capture. Following the completion of these capture tasks, participants completed a sustained IB (multiple object tracking) task where an unexpected event appeared during the final critical trial. Indices of stimulus-driven and contingent capture were derived from the capture tasks, and a measure of processing speed was derived from aggregating reaction times from the three speed-based capture tasks. Surprisingly, results of logistic regression analyses revealed no relationship between measures of implicit and explicit capture (noticing the unexpected event). However, consistent with the a priori hypothesis, processing speed did predict IB. Findings suggest that attention capture is unrelated to the noticing of an unexpected stimulus, but efficient encoding and recognition of a stimulus is an important factor. PMID- 30016758 TI - Response to fatigue stress of biomedical grade polyethylene joints welded by a diode laser. AB - Biomedical grade UHMWPE double lap joint, welded by a diode laser, has been mechanically characterized by static and dynamic tests. A nanocomposite sheet (UHMWPE filled with low carbon nanoparticles amount) was interposed between two polymeric sheets in order to absorb the laser light, sealing the sheets by means of a melting process. Fatigue test has been performed in the joint with 0.016 wt% of carbon nanofiller for its best mechanical static resistance among those studied. Its fatigue limits resulted to be equal to 22000 cycles. Breaks occurred at the 2nd welded interface, where a poor melting process weakens the entire joint. PMID- 30016759 TI - The acquisition of different classes of words in Spanish children with Down syndrome. AB - PURPOSE: The primary aim of this study was to analyze the acquisition of different classes of words in Spanish-speaking children with Down syndrome (DS), with special emphasis on nouns and verbs. A second objective was to compare the results obtained with those reported by Checa et al. (2016), who used a different measure to study vocabulary composition. METHOD: We studied 108 children with DS and 108 children with typical development (TD), with mental ages between 9 and 29 months (DS M = 21;26 months;days, TD M = 20;23) and chronological ages between 8;24 and 68;19 months;days (mean = 41;11 and 20;19 for DS and TD, respectively). Children were matched individually for size of productive vocabulary and gender. Data were gathered using the MacArthur-Bates CDIs, adapted to the profile of children with DS (the CDI-Down). Relative proportions were used as the measure of vocabulary. RESULTS: The results differed from those obtained by Checa et al. (2016) when using absolute proportions to examine vocabulary composition. The most significant difference was the trend among children with DS to produce fewer verbs and closed-class words (articles, prepositions, pronouns, conjunctions, and auxiliaries). There were no differences in the production of nouns and social words. CONCLUSIONS: The tendency of children with DS to produce fewer verbs and closed-class words could be due to difficulties with morphology and syntax. This underlines the importance of morphosyntactic skills for learning these classes of words. The methodological and clinical implications of the results are discussed. PMID- 30016760 TI - Assessing off-target cytotoxicity of the field lampricide 3-trifluoromethyl-4 nitrophenol using novel lake sturgeon cell lines. AB - Lampricides are currently being applied to streams and rivers to control the population of sea lamprey, an invasive species, in the Great Lakes. The most commonly used lampricide agent used in the field is 3-trifluoromethyl-4 nitrophenol (TFM), which targets larval sea lamprey in lamprey-infested rivers and streams. The specificity of TFM is due to the relative inability of sea lamprey to detoxify the agent relative to non-target fishes. There is increasing concern, however, about non-target effects on fishes, particularly threatened populations of juvenile lake sturgeon (LS; Acipenser fulvescens). There is therefore a need to develop models to better define lake sturgeon's response to TFM. Here we report the establishment of five LS cell lines derived from the liver, gill, skin and intestinal tract of juvenile LS and some of their cellular characteristics. All LS cell lines grew well at 25 degrees C in Leibovitz's (L)- 15 medium supplemented with 10% FBS. All cell lines demonstrated high senescence associated beta-galactosidase activity and varying levels of Periodic acid Schiff positive polysaccharides, indicating substantial production of glycoproteins and mucosubstances by the cells. Comparative toxicity of TFM in the five LS cell lines was assessed by two fluorescent cell viability dyes, Alamar Blue and CFDA AM, in conditions with and without serum and at 24 or 72 h exposure. Deduced EC50 values were compared between the cell lines and to the reported in vivo LC50s. Tissues sensitive to the effects of TFM in vivo correlated with cell lines from the same tissues being most sensitive to TFM in vitro. EC50 values for the LSliver-e cells was significantly lower than the EC50 for the rainbow trout (RBT) liver cells RTL-W1, reaffirming the in vivo observation that LS was generally more TFM-sensitive than rainbow trout. Our data suggests that whole-fish sensitivity of LS to TFM is likely attributable to sensitivity at the cellular level. Thus, LS cell lines, as well as those of RBT, can be used to screen and evaluate the toxicity of the next generation of lampricides on non-target fish such as lake sturgeon. PMID- 30016761 TI - Enhanced degradation of trichloroethylene in oxidative environment by nZVI/PDA functionalized rGO catalyst. AB - Nano zero-valent iron (nZVI) particles with higher reactivity have been recognized as more efficient catalysts than Fe(II) for the groundwater remediation. The rapid emergence of novel catalyst supports efficiently prevent the rapid aggregation of nZVI and further improve catalytic reactivity. However, the lack of ability to avoid the potential oxidation of bare nZVI-support structure in air environment hinders its wider application in the actual contaminated sites. In this study, nZVI on reduced graphene oxide (rGO) functionalized by polydopamine (PDA) (nZVI-PDA@rGO) was synthesized successfully and applied into sodium persulfate (SPS), potassium monopersulfate (PMS) and H2O2 oxidative environments to remove trichloroethylene (TCE). For comparison, nZVI supported on solely rGO was prepared. The XRD test displayed the stronger stability of alpha-Fe(0) in nZVI-PDA@rGO catalyst against oxidation exposed to air. Compared with nZVI-rGO, a core shell structure of nZVI-PDA@rGO was observed in TEM image obviously. The dosage tests showed nZVI-PDA@rGO had a better catalytic reactivity than nZVI-rGO for TCE removal at lower catalyst and oxidant dosages, i.e. PMS dosage: 0.3 mM, catalyst dosage: 50 mg L-1, TCE removal: 45.0% (nZVI-rGO) up to 99.6% (nZVI-PDA@rGO). TCE removal mechanisms were revealed through radical scavenger tests, demonstrating sulfate radicals played more important role in nZVI-PDA@rGO catalyzed-oxidant systems. PMID- 30016762 TI - Hookah use as a predictor of other tobacco product use: A longitudinal analysis of Texas college students. AB - INTRODUCTION: Hookah use is particularly prevalent among U.S. college students; however, few studies have investigated whether hookah use is a risk factor for the initiation of other tobacco products. This study examined whether hookah use predicted subsequent initiation of other combustible tobacco products (conventional cigarettes and cigar products) and Electronic Nicotine Delivery Systems (ENDS) among Texas college students during a 2.5-year study period. METHODS: This study involved a longitudinal analysis of data from Waves 1-6, with 6 months between each wave, of the Marketing and Promotions Across Colleges in Texas Project (Project M-PACT). Two separate multilevel discrete-time survival analyses were used to model the associations between past 30-day hookah use and subsequent initiation of 1) other combustible tobacco products, and 2) ENDS during the 2.5 year study period, after controlling for demographic, other tobacco use, and risk-taking personality characteristics (i.e. sensation seeking and impulsivity). RESULTS: After controlling for covariates, past 30-day hookah use was associated with significantly higher odds of subsequent initiation of other combustible tobacco products. Past 30-day hookah use also predicted subsequent initiation of ENDS after controlling for covariates. CONCLUSIONS: This study is one of the first to demonstrate that hookah use is a predictor of subsequent initiation of other combustible tobacco products and ENDS among college students. These findings suggest that hookah may prime individuals to use other tobacco products, which has important implications for prevention programs and future research. PMID- 30016764 TI - Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia Reperfusion Injury by Increasing High Mobility Group Box 1 Release. AB - BACKGROUND/AIMS: Interferon regulatory factor 1(IRF-1) and high mobility group box 1(HMGB1) have been independently identified as being key players in hepatic ischemia-reperfusion injury (IRI). We attempted to determine whether IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release. METHODS: The hepatic IRI model was generated in C57BL/6 mice, euthanized at 2, 6, 12 or 24 h after reperfusion. To examine the effects of HMGB1 release inhibition, Glycyrrhiza acid (GA) was administered to the mice and at six hours after injectiont. AML12 cells were immersed in mineral oil for 90 min and then cultured in complete Dulbecco's Modified Eagle's Medium (DMEM)/F12 to simulate IRI. AML12 cells were treated with IRF-1 siRNA, Ad-IRF-1 or GA. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Next, autophagic vacuoles were detected by transmission electron microscopy (TEM) or LC3 dots. The expression of IRF-1 and HMGB1 mRNA were measured by real-time polymerase chain reaction. The expression of IRF-1, microtubule-associated protein 1 light chain 3 (LC3), Bcl-2, Beclin 1, HMGB1 were detected by western blotting or immunohistochemistry. RESULTS: The levels of hepatic IRF-1, mRNA and protein were significantly increased in livers after exposure to IRI, together with, IRI-induced increase of HMGB1 mRNA and release of HMGB1 in liver tissue. Knockout of IRF-1 decreased expression and release of HMGB1 in liver, and inhibiting the release of HMGB1 could alleviate hepatic IRI. In addition, knockout of IRF-1 downregulated LC3II and Beclin1, while number of autophagosomes or LC3 dots were increased. Up-regulating IRF-1 expression could increase the levels of LC3II expression in AML12 cells after exposure to IRI. The levels of HMGB1 in Ad-IRF-1 transfected AML12 cell supernatants increased, together with number of LC3 dots increasing. However, GA could inhibit both Ad-IRF-1 induced HMGB1 release and the increase in the number of LC3 dots. CONCLUSIONS: IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release. PMID- 30016763 TI - Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway. AB - BACKGROUND/AIMS: Narrowing of the lumbar spinal canal is a condition called lumbar spinal stenosis (LSS) and is a high-morbidity problem in the elderly. LSS is commonly caused by hypertrophy of the ligamentum flavum (HLF). Previous studies showed that fibrosis of the ligamentum flavum (LF) largely contributed to HLF. However, the underlying pathomechanism remains unclear. Insulin-like growth factor-1 (IGF-1) is known to have an intimate relationship with fibrosis in various tissues. Nevertheless, currently, there are few studies regarding IGF-1 in HLF. In this study, we investigated the role of IGF-1 in HLF and its potential molecular mechanism of action. METHODS: First, the IGF-1, phosphorylation of IGF 1 receptor (pIGF-1R), phosphorylation of AKT (pAKT), phosphorylation of S6(pS6), collagen I and collagen III expression levels were examined via immunohistochemistry and Western blotting in LF tissues from patients with LSS or Non-LSS. Second, primary LF cells were isolated from adults with a normal LF thickness and were cultured with different concentrations of IGF-1 with or without NVP-AEW541/rapamycin. RESULTS: The results showed that IGF-1, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression in the LSS group was significantly higher than that in the Non-LSS group. Meanwhile, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression was significantly enhanced in LF cells after IGF-1 exposure, which can be notably blocked by NVP-AEW541. In addition, pS6, collagen I and collagen III protein expression was blocked by rapamycin. CONCLUSIONS: Enhanced IGF-1 promotes the synthesis of collagen I and collagen III via the mTORC1 signaling pathway, which eventually contributes to hypertrophy of the ligamentum flavum. PMID- 30016765 TI - Preoperative Alfa-Fetoprotein and Fibrinogen Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation Regardless of the Milan Criteria: Model Development with External Validation. AB - BACKGROUND/AIMS: Patient selection is critically important in improving the outcomes of liver transplantation for hepatocellular carcinoma. The aim of the current study was to identify biochemical measures that could affect patient prognosis after liver transplantation. METHODS: A total of 119 patients receiving liver transplantation for hepatocellular carcinoma were used to construct a model for predicting recurrence. The results were validated using an independent sample of 109 patients from independent hospitals. All subjects in both cohorts met the Hangzhou criteria. RESULTS: Analysis of the discovery cohort revealed an association of recurrence with preoperative fibrinogen and AFP levels. A mathematical model was developed for predicting probability of recurrence within 5 years: Y = logit(P) = -4.595 + 0.824 *fibrinogen concentration (g/L) + 0.641 * AFP score (1 for AFP<=20ng/ml, 2 for 20 400ng/ml). At a cutoff score of -0.85, the area under the curve (AUC) was 0.819 in predicting recurrence (vs. 0.655 when using the Milan criteria). In the validation cohort, this model had reasonable performance in predicting 5-year overall survival (68.8% vs. 28.1% in using the 0.85 cutoff, p< 0.001) and disease-free survival (65.7% vs. 25.9%, p< 0.001). The sensitivity and specificity were 77.0% and 62.5%, respectively. The AUC of this newly developed model was similar to that with the Milan criteria (0.698 vs. 0.678). Surprisingly, the DFS in patients with score <= -0.85 under this model but not meeting the Milan criteria was similar to that in patients meeting the Milan criteria (53.8% vs. 60.0%, p=0.380). CONCLUSIONS: Preoperative AFP and fibrinogen are useful in predicting recurrence of hepatocellular carcinoma after liver transplantation. PMID- 30016766 TI - LncRNA TP73-AS1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Clear Cell Renal Cell Carcinoma Through Repressing KISS1 Expression and Inactivation of PI3K/Akt/mTOR Signaling Pathway. AB - BACKGROUND/AIMS: Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a vital regulatory role in the pathogenesis and progression of renal cell carcinoma (RCC). We aim to determine lncRNA profiles in clear cell RCC (ccRCC) and investigate key lncRNAs involved in ccRCC tumorigenesis and progression. METHODS: RNA sequencing technique and qPCR were used to determine the candidate lncRNAs in ccRCC tissues. The correlations between lncRNA P73 antisense RNA 1T (TP73-AS1) levels and survival outcomes were analyzed to elucidate its clinical significance. The underlying mechanisms of TP73-AS1 in ccRCC were analyzed through in vitro functional assays. RESULTS: We found TP73-AS1 was upregulated in 40 ccRCC tissues compared with adjacent normal renal tissues and increased TP73 AS1 was correlated to aggressive clinicopathologic features and unfavorable prognosis. Knockdown of TP73-AS1 suppressed cell proliferation, invasion and induced cell apoptosis. We also identified KISS-1 metastasis-suppressor (KISS1) was significantly upregulated in TP73-AS1 knockdown cells. Further, we revealed that TP73-AS1 suppressed KISS1 expression through the interaction with Enhancer of zeste homolog 2 (EZH2) and the specific binding to KISS1 gene promoter region. Knockdown of KISS1 partly reversed TP73-AS1 knockdown-induced inhibition of cell proliferation and promotion of apoptosis. We further determined that TP73-AS1 knockdown activated PI3K/Akt/mTOR signaling pathway, while overexpression of TP73 AS1 induced inhibition of PI3K/Akt/mTOR pathway and these effects could be partly abolished by overexpression of KISS1. CONCLUSION: In conclusion, we identified that TP73-AS1 as an oncogenic lncRNA in the development of ccRCC and a potential target for human renal carcinoma treatment. PMID- 30016767 TI - Clinical Management of Chronic Kidney Disease Patients in Italy: Results from the IRIDE Study. AB - BACKGROUND: Lack of adequate management of chronic kidney disease (CKD) often results in delayed diagnosis and inadequate treatment. This study assessed the clinical management and outcome of stages 1-5 CKD patients. METHODS: Patients were prospectively followed for 3 years in 25 nephrology centers across Italy. Clinical characteristics were measured at baseline and every 6 months. Outcome measures included CKD staging, presence of comorbidities, treatment, mineral bone disorder (MBD) parameters, and patient outcomes. RESULTS: Of 884 enrolled patients (59.7% males, aged 66.2 +/- 14.6 years), 587 (66.4%) completed the study. The majority of patients were referred by a general practitioner (44.7%) and had stage 3 or 4 CKD (40.9 and 23.8% respectively). Data reveal that 91.3% of patients had at least 1 concomitant disease, most frequently hypertension (80.1%) and dyslipidemia (42.5%); 94.6% of patients were receiving cardiovascular medication and 52.6% were receiving lipid-lowering medication. Approximately 40% of patients had proteinuria and intact parathyroid hormone levels outside the normal range. As expected, stages 4 and 5 CKD patients had a higher prevalence of proteinuria (68 and 74%), MBD (59 and 88%) and anemia (28 and 73%), as well as a higher risk of hospitalization (34.3 and 51.9%) and need for dialysis (69.5 and 70%). The overall probability of survival over 36 months was 90.6%. CONCLUSIONS: This is the first Italian prospective study performed with a large cohort of CKD patients over a 3-year period. Considering the multifactorial burden of diseases associated with CKD patients, the need for greater attention to CKD and related disorders is paramount. PMID- 30016768 TI - Angelman Syndrome-Affected Individual with a Numerically Normal Karyotype and Isodisomic Paternal Uniparental Disomy of Chromosome 15 due to Maternal Robertsonian Translocation (14;15) by Monosomy Rescue. AB - Angelman syndrome (AS) is a neurodevelopmental disorder caused by deletion of the maternally inherited 15q11q13 region, paternal uniparental disomy 15 [upd(15)pat], an imprinting defect of the maternal chromosome region 15q11q13, or a pathogenic mutation of the maternal UBE3A allele. Predisposing factors for upd(15)pat, such as nonhomologous robertsonian translocation involving chromosome 15, have been discussed, but no evidence for this predisposition has been published. In the present study, chromosomal analysis was performed in a child with AS, both parents, and the maternal grandparents. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was employed on DNA of the index individual, and microsatellite analysis was carried out on DNA of the index individual and his parents. The cytogenetic analysis showed that the mother and maternal grandfather are carriers of a rob(14;15). The index individual has a numerically normal karyotype, but MS-MLPA and microsatellite analyses confirmed the clinical diagnosis of AS and revealed a pattern highly suggestive of isodisomic upd(15)pat. This is the first report of an AS-affected individual with isodisomic upd(15)pat and a numerically normal karyotype that most likely results from a rob(14;15)-associated meiotic error in the maternal germline followed by monosomy 15 rescue in the early embryo. PMID- 30016769 TI - Transoral Robotic Surgery for Oropharyngeal Cancer. AB - Transoral robotic surgery has shown significant promise in the management of oropharyngeal cancer since its description in 2007. The oncological efficacy of this procedure has been proven in several single-centre studies, multicentre collaborative publications and systematic reviews. The rapid take-up of transoral robotic surgery shows greater acceptance by professionals and is associated with a relatively short learning curve. This overview discusses the rationale and principles underlying the use of transoral robotic surgery in primary and recurrent oropharyngeal cancer and the emerging role for this technique in diagnosing the unknown primary site, and summarizes ongoing research in this field. PMID- 30016771 TI - Erratum. PMID- 30016770 TI - Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. SUMMARY: L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6-9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA's ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required. PMID- 30016772 TI - Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review. AB - BACKGROUND: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation. METHODS: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: "duloxetine" OR "venlafaxine" OR "desvenlafaxine" OR "milnacipran" OR "levomilnacipran" OR "SNRI" OR "second generation antidepressant" OR "serotonin norepinephrine reuptake inhibitor" AND "discontinuation" OR "withdrawal" OR "rebound." Only published trials in the English language were included. RESULTS: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well. CONCLUSIONS: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders. PMID- 30016773 TI - MicroRNA-141 Inhibits the Proliferation of Penile Cavernous Smooth Muscle Cells Associated with Down-Regulation of the Rhoa/Rho Kinase Signaling Pathway. AB - BACKGROUND/AIMS: The role of the RhoA/Rho kinase signaling pathway in diabetes mellitus-induced erectile dysfunction has been partially understood. METHODS: In the present study, we explored the changes of the RhoA/Rho associated kinase (ROCK) signaling pathway in diabetic erectile dysfunction in vivo and the effects of microRNA-141 on the RhoA/ROCK signaling pathway in vitro. RESULTS: The mRNA and protein expressions of RhoA and ROCK2 were significantly increased while the expression of microRNA-141 was decreased in the penile cavernous smooth muscle cells of rats with diabetic erectile dysfunction. Moreover, increased expression of microRNA-141, decreased expressions of RhoA and ROCK2 (mRNA and protein), accelerated cell proliferation rate and reduced cell apoptosis were found in the microRNA-141 mimics group and the siRNA-Rho group. The microRNA-141 expression in the microRNA-141 inhibitors + siRNA-Rho group was significantly decreased. microRNA-141 specifically bound to Rho-3'-UTR and down-regulated the expression of Rho gene at the post transcriptional level. CONCLUSION: Decreased expression of miR-141 is associated with up-regulation of RhoA and ROCK2 in the RhoA/ROCK signaling pathway in rats with diabetic erectile dysfunction. miR-141 inhibits the growth of penile cavernous smooth muscle cells associated with down regulation of the RhoA/ROCK signaling pathway in vitro. PMID- 30016774 TI - MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-kappaB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1. AB - BACKGROUND/AIMS: Postmenopausal osteoporosis is a common disease associated with estrogen deficiency leading to bone loss and bone tissue changes. The resultant bone fragility and increased risk of fracture has serious adverse effects on health and quality of life of the elderly, making it an important health issue. MicroRNA-218 (miR-218) is closely related to the development of osteoporosis. In this study, we investigated the regulatory mechanisms of miR-218 in osteoclastogenesis. METHODS: We investigated miR-218 levels on differentiation of RAW 264.7 cells into osteoclasts compared with normal cells. Next, RAW 264.7 cells were transfected with miR-218 mimics or inhibitors to study the role of miR 218 in osteoclastogenic differentiation. Tartrate-resistant acid phosphatase (TRAP) staining was performed to determine osteoclastogenic differentiation. Bioinformatics analysis and luciferase reporter assay were used to identify and validate miR-218 target genes. RESULTS: miR-218 was downregulated following RAW 264.7 cell differentiation into osteoclasts. miR-218 overexpression attenuated osteoclast differentiation, whereas low miR-218 expression promoted it as demonstrated by increased expression of osteoclast-specific genes and TRAP staining. Bioinformatics analysis and the luciferase reporter assay showed that tumor necrosis factor receptor 1 (TNFR1), a cell membrane receptor of TNF (TNF is an activator of nuclear factor-kappaB [NF-kappaB]), is a direct target of miR 218. CONCLUSIONS: Our findings indicate that miR-218 regulates osteoclastogenic differentiation negatively by repressing NF-kappaB signaling by targeting TNFR1, suggesting that targeting miR-218 may be a therapeutic approach in postmenopausal osteoporosis. PMID- 30016776 TI - G1359A Variant of the Cannabinoid Receptor Gene (rs1049353) and Obesity-Related Traits and Related Endophenotypes: A Meta-Analysis. AB - BACKGROUND: This study aimed to investigate the comparison of G1359A variant of cannabinoid receptor gene (rs1049353) with obesity-related traits including body mass index (BMI), fat mass (FM), fat-free mass (FFM), food-related traits, and leptin among healthy and non-healthy adults. METHODS: We searched PubMed, Cochrane, Scopus, Web of Science, and EMBASE until December 2016 for observational studies assessing each of the anthropometric measurements, food related traits, and leptin of 1359 G/A polymorphism of CNR1 gene. A total of 22 studies were included in the meta-analysis comparing mean and SD differences of the anthropometric measurements, leptin, and dietary intake between GA/AA and GG genotypes. RESULTS: The results showed that subjects with GA/AA genotype had significantly lower BMI (weighted mean difference = -0.59 kg/m2, p < 0.001) compared to those with the GG genotype. Dietary intake of fat, carbohydrate, and protein as well as serum levels of leptin was not significantly different between GA/AA and GG genotypes. CONCLUSION: It was revealed that subjects with mutant polymorphism (GA/AA) of CNR1, compared to the wild-type group (GG), had lower BMI (although there was unexplained heterogeneity). PMID- 30016775 TI - Clinicopathological Characteristics, Role of Immunosuppressive Therapy and Progression in IgA Nephropathy with Hyperuricemia. AB - BACKGROUND/AIMS: The aim of the study was to investigate clinicopathological characteristics, the role of immunosuppressive therapy and renal outcome in IgA nephropathy (IgAN) patients with hyperuricemia. METHODS: 206 biopsy-proven primary IgAN patients were included between January 2010 and December 2015, and divided into two groups: patients without hyperuricemia (n=122), and patients with hyperuricemia (n=84). The clinicopathological features, response, renal outcome and safety were recorded. In univariate and multivariate models, hyperuricemia-associated pathological factors were analyzed. RESULTS: The patients with hyperuricemia presented higher systolic blood pressure, worse kidney function and more severe time-averaged proteinuria. Proportions of glomerulosclerosis, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, lymphocytes and monocytes infiltration were higher, while the proportion of segmental adhesion was lower in patients with hyperuricemia. By multivariate logistic regression analysis, only tubular atrophy/interstitial fibrosis (T1~2) (HR=3.969, 95% CI=1.439-10.945, P=0.008) was significantly associated with hyperuricemia. For hyperuricemic patients, the response rate to therapy and renal survival rate were significantly higher in patients that received RAS blockade in combination with immunosuppressive therapy. After RAS blockade treatment, renal survival in the patients with hyperuricemia was worse compared with the patients without hyperuricemia. CONCLUSION: Hyperuricemic IgAN patients presented more severe clinical features. Tubulointerstitial injury could be a pathological feature closely related to hyperuricemia in IgAN. Immunosuppressive therapy and RAS blockade could reduce proteinuria and improve renal outcome in IgAN patients with hyperuricemia. PMID- 30016778 TI - The Effects of Pitch, Gender, and Prosodic Context on the Identification of Creaky Voice. AB - BACKGROUND/AIMS: Creaky voice in American English plays both a prosodic role, as a phrase-final marker, and a sociolinguistic one, but it is unclear how accurately naive listeners can identify creak, and what factors facilitate or hinder ist identification. METHODS: In this study, American listeners are presented with 2 experiments containing stimuli from both high- and low-pitched male and female speakers. Other manipulations include whether the auditory stimulus is a full sentence or a sentence fragment, and whether it is completely modally voiced, completely creaky, or partially creaky (final 40-50% of the utterance). RESULTS: Accuracy is lowest on partial creak, suggesting that creaky voice is least salient when it serves as an utterance-final marker. There are no strong gender effects aside from a weak tendency to identify creak more often in females than males in the whole creak condition in one experiment. In contrast, when no creak is present, listeners false alarm on the low-pitched males. CONCLUSION: Rates of identifying creak in male and female speakers are similar, suggesting that listeners have a comparable ability to hear creaky voice in all speakers. PMID- 30016777 TI - Relationships between Clinical Presentation, Serology, Histology, and Duodenal Deposits of Tissue Transglutaminase Antibodies in Pediatric Celiac Disease. AB - BACKGROUND: The clinical, histological, and serological spectrum of celiac disease (CD) vary widely. We aimed to examine relationships between symptoms, serum anti-tissue transglutaminase antibodies (tTG) levels, mucosal damage, and mucosal anti-tTG deposits in pediatric CD. METHODS: A retrospective single center, cohort study of children referred for endoscopy with suspected CD during 2011-2014. We retrieved the clinical data, blindly reviewed duodenal biopsies, and performed immunohistochemical staining for anti-tTG deposits. Patients were classified as monosymptomatic or polysymptomatic. Mucosal anti-tTG deposits were classified according to the location of deposits, dominant intensity, maximal intensity, and percentage of stained area. RESULTS: Of 252 patients with confirmed CD, complete data were available for 100: 37 males in the age range 1.3 16.7 with median 4.0 years. Monosymptomatic patients (n = 54) presented at an older age than polysymptomatic patients (1.3-15.5, median 8.1 vs. 1.3-16.7, median 6.3 years, p = 0.026). Marsh 2-3c was more prevalent in polysymptomatic patients (93 vs. 78%, p = 0.028). The intensity of mucosal anti-tTG deposits correlated with serum anti-tTG levels but not with the clinical presentation. CONCLUSIONS: Multiple symptoms and high serum anti-tTG antibody levels correlated with mucosal damage in children with CD. The role of immunohistochemical staining for intestinal anti-tTG mucosal deposits in the diagnosis of borderline CD is not yet established. PMID- 30016780 TI - IL-8 Enhances Therapeutic Effects of BMSCs on Bone Regeneration via CXCR2 Mediated PI3k/Akt Signaling Pathway. AB - BACKGROUND/AIMS: Tissue engineering bone transplantation with bone marrow mesenchymal stem cells (BMSCs) is an effective technology to treat massive bone loss, while molecular regulation of the bone regeneration processes remains poorly understood. Here, we aimed to assess the role of interleukin-8 (IL-8) in the recruitment of host cells by seeded BMSCs and in the bone regeneration. METHODS: A transwell assay was performed to examine the role of IL 8/CXCR1/CXCR2/PI3k/Akt on the migration potential of hBMSCs. The in vitro chondrogenic differentiation of hBMSCs was assessed by examination of 2 chondrogenic markers, Sox9 and type 2 collagen (COL2). mBMSCs were used in tissue engineered bone (TEB) with/without IL-8 implanted into bone defect area with CXCR2 or Akt inhibitors. Density and Masson staining of the regenerated bone were assessed. The chondrogenesis was assessed by expression levels of associated proteins, Sox9 and COL2, by RT-qPCR and by immunohistochemistry. RESULTS: IL-8 may trigger in vitro migration of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway. IL-8 enhances osteogenesis in the TEB-implanted bone defect in mice. IL 8 induces chondrogenic differentiation of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway in vitro and in vivo. CONCLUSIONS: IL-8 enhances therapeutic effects of MSCs on bone regeneration via CXCR2-mediated PI3k/Akt signaling pathway. PMID- 30016781 TI - Quercetin Shows the Pharmacological Activity to Simultaneously Downregulate the Inflammatory and Fibrotic Responses to Tissue Injury in Association with its Ability to Target Multi-Kinases. AB - AIM: Previous studies have suggested that quercetin is effective for treating diverse chronic disorders including organ fibrosis and airway and cardiovascular disorders. To access the pharmacological background for its broad efficacy, we examined the ability of quercetin to modulate the inflammatory and fibrotic responses associated with organ injury that commonly underlie the pathogenesis of those disorders. METHODS: A cutaneous wound model on rabbit ear was used for in vivo study. Quercetin was topically applied to the wounds, and the number of macrophages and myofibroblasts and the size of the hypertrophic scar formed were estimated. An in vitro study examined the ability of quercetin to inhibit cell signaling pathways that activate RAW264.7 macrophages and primary dermal fibroblasts and the tyrosine kinase activity of discoidin domain receptor 2. RESULTS: Quercetin reduced the population of macrophages and myofibroblasts and the scar formation in cutaneous wound healing. Quercetin suppressed the signaling pathways activating RAW264.7 macrophages and dermal fibroblasts, which is associated with its inhibition of multiple tyrosine kinases to regulate the pathways. This pharmacological activity of quercetin to simultaneously inhibit the inflammatory and fibrotic responses upon tissue damage by targeting multi kinases could be the action mechanism to support its broad efficacy for various chronic disorders. PMID- 30016782 TI - Regulation of Apoptosis and Radiation Sensitization in Lung Cancer Cells via the Sirt1/NF-kappaB/Smac Pathway. AB - BACKGROUND/AIMS: SirT1, a conserved NAD+-dependent deacetylase, has been implicated in modulating cell survival and stress responses, and it appears to play an important role in tumorigenesis and cancer resistance to chemoradiotherapy. The mechanism of SirT1 in cancer chemoradiotherapy remains to be further elucidated, which could provide potential targets for cancer therapy. METHODS: We performed colony formation, immunofluorescence microscopy, flow cytometry, RNA interference, and western blotting assays to determine whether SirT1 regulates radiation sensitization and which mechanisms and/or pathways it takes in lung cancer cell lines A549 and H460. RESULTS: Initially, the expression of SirT1 was found to be negatively correlated with radiosensitivity in lung cancer cell lines A549 and H460. RNA interference with siSirT1 against SirT1 specifically reduced SirT1 expression and induced radiosensitivity both in A549 and H460 cell lines. In contrast, the radiosensitivity was significantly reduced once SirT1 was activated by resveratrol. Immunofluorescence assay and apoptosis analysis indicated that the effect of SirT1 on the radiosensitivity observed in the A549 and H460 cell lines was mainly achieved by regulating DNA damage repair and apoptosis processes. Furthermore, the expression of SirT1 negatively modulated the expression of apoptosis-related protein NF-kappaB and its downstream regulator of Smac. CONCLUSION: Our results indicate that SirT1 regulates apoptosis and radiation sensitization in lung cancer cell lines A549 and H460 via the SirT1/NF-kappaB/Smac pathway. PMID- 30016784 TI - Pembrolizumab in Recurrent Squamous Cell Carcinoma of the Vulva: Case Report and Review of the Literature. AB - Advanced vulvar cancer is associated with a very poor prognosis. Surgical resection is the mainstay of treatment, with radiation indicated for areas at high risk for recurrence. When surgical and radiation options have been exhausted, the effectiveness of systemic chemotherapy is poor. No biologic or targeted agents have been approved for the management of advanced or recurrent vulvar cancer. Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been successfully used as a target of tumor immune therapy in small cell lung cancer and melanoma. We present the first case in the literature of a patient with recurrent vulvar cancer who was treated successfully with pembrolizumab. Caris next-generation testing revealed a PD-L1 and PD-1 mutation (PD-L1 positive, 2+, 100%). She attained a complete clinical remission after 2 cycles, and a CT scan after 6 cycles revealed a significant response by RECIST criteria. After completing 10 cycles, treatment was stopped due to complications of severe malnutrition related to narcotic abuse. A CT scan 10 weeks after the final treatment revealed no adenopathy. Pembrolizumab is a safe and effective chemotherapeutic agent to treat recurrent vulvar carcinoma. PMID- 30016783 TI - Distinguishable Prognostic Signatures of Left- and Right-Sided Colon Cancer: a Study Based on Sequencing Data. AB - BACKGROUND/AIMS: Left- and right-sided colon cancers are considered to be two different diseases and have altered outcomes. However, specific molecules to predict the prognosis of left- and right-sided colon cancers are currently lacking. METHODS: Expression profiling of colon cancer were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) of left- and right-sided colon cancers were compared by DESeq analysis. The prognostic values of DEGs were assessed by univariate and multivariate Cox regression. Prognostic index models of two side colon cancers were conducted with prognostic values genes, respectively. Interaction of DEGs was then analyzed by the protein-protein interaction (PPI). Different biology function of two sides of colon cancer was assessed by Gene Set Enrichment Analysis (GSEA). RESULTS: A total of 167 DEGs were identified between left- and right-sided colon cancers based on TCGA data. Using univariate COX regression analysis, five genes (PHACTR3, CKMT2, CYP2W1, ERFE, HOXC4) were related to overall survival in left-sided, and eight distinguishable genes (EREG, ERFE, HOXC6, SLC22A31, TFF1, GFI1, ZG16, RASL10B) in right-sided. Further, left-sided prognostic model was established with PHACTR3 and CKMT2 (HR=2.040; 95%CI=1.004-4.145; P=0.049). Distinguishable prognostic signature for right-sided colon cancer was established based on EREG, ERFE, GFI1, and RASL10B (HR=3.530; 95%CI: 1.934-6.444; P< 0.001) in multivariate analysis. PPI analysis of 167 DEGs showed that CCL5, GNG4, GNLY, GZMH, DRD2, and FASLG genes were at the core of interaction network. In GSEA function analysis, four pathways, including antigen processing and presentation, natural killer cell mediated cytotoxicity, intestinal immune network for Iga production, and type I diabetes mellitus, were significantly enriched in the DEGs of the right-sided colon cancer. CONCLUSIONS: This study constructs a panel of potential prognostic model of left- and right-sided colon cancers, respectively. We also provide molecular biological alterations between left- and right-sided colon cancers. PMID- 30016785 TI - MicroRNA-29a-3p Downregulation Causes Gab1 Upregulation to Promote Glioma Cell Proliferation. AB - BACKGROUND/AIMS: Glioma causes significant human mortalities annually. Molecularly-targeted therapy is a focus of glioma research. METHODS: Grb2 associated binding 1 (Gab1) expression and microRNA-29a-3p ("miR-29a-3p") expression in human glioma cells and tissues were tested by Western blotting assay and qRT-PCR assay. shRNA/siRNA strategy was applied to silence Gab1 in human glioma cells. miR-29a or anti-sense miR-29a construct was transfected to human glioma cells. Cell proliferation was tested by BrdU ELISA assay and cell counting assay. RESULTS: We show that expression of Gab1 was significantly elevated in human glioma tissues and cells, which correlated with downregulation of its putative microRNA: miR-29a-3p. In A172 glioma cells and primary human glioma cells, Gab1 shRNA/siRNA inhibited Akt-Erk activation and cell proliferation. Forced-expression of miR-29a-3p downregulated Gab1, inhibiting glioma cell proliferation, whereas miR-29a-3p was in-effective on cell proliferation in Gab1-silenced A172 cells. Furthermore, introduction of a 3' untranslated region (3'-UTR) mutant Gab1 (UTR-G160A) blocked miR-29a-3p-induced inhibition on Akt signaling and A172 cell proliferation. CONCLUSIONS: miR-29a-3p downregulation leads to Gab1 upregulation to promote glioma cell proliferation. PMID- 30016786 TI - Association Between Thyroid-Stimulating Hormone and Renal Function: a Mendelian Randomization Study. AB - BACKGROUND/AIMS: Increasing evidence suggests an association between thyroid stimulating hormone (TSH) and estimated glomerular filtration rate (eGFR). We conducted a Mendelian randomization (MR) analysis to examine the causality of the association between TSH and eGFR. METHODS: 10,603 participants were recruited from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China), which was performed in 23 sites in East China during 2014 2016. We constructed weighted genetic risk scores (GRS) for TSH based on three TSH-related single nucleotide polymorphisms. eGFR was calculated using the CKD Epidemiology Collaboration formula. The instrumental variable (IV) was used to explore the causal relationship between TSH and eGFR. RESULTS: Higher measured TSH levels were associated with lower eGFR (B -0.717, 95%CI -0.958, -0.476) after multivariable adjustment. However, by MR analysis, per SD increase in the TSH_GRS was significantly associated with TSH (B 0.155, 95%CI 0.076, 0.235, P< 0.001) but not with eGFR (B -0.127, 95%CI -0.364, 0.110). Using IV estimator, no causal associations were observed for genetically instrumented TSH with eGFR. CONCLUSION: By a genetic approach that limits residual confounding and reverse causation in observational conventional epidemiological studies, TSH and eGFR are not causally associated, which suggests genetically elevated TSH concentrations may not affect the renal function. PMID- 30016787 TI - F0 Timing and Tone Contrasts in Luganda. AB - Scholars of Luganda (Bantu, Uganda) have described a contrast between falling and high tone, which is limited to syllables with a long vowel or a coda. The contrast has been represented with H on the first mora of a falling-tone syllable and on both moras in a high-tone syllable. This article explores this contrast through an instrumental study of the timing of f0 events in Luganda. It was found that the 2-tone classes differed in the timing of both the f0 rise and the subsequent f0 fall, supporting a reanalysis of the contrast as one between an early high tone and a late high tone. It was also found that for the speakers in this study, the contrast was limited to syllables with long vowels. The timing of f0 events was sensitive to the duration of segments in the CVC interval centered on the high-toned syllable, including non-moraic elements and consonants outside the syllable. The association of a tone to a syllable identifies the segments relevant for the timing of the f0 contour, but that timing is not directly sensitive to the interval of the syllable. PMID- 30016788 TI - The Unexpected Effects of L-Carnitine Supplementation on Lipid Metabolism in Hemodialysis Patients. AB - BACKGROUND/AIMS: There is a growing body of evidence that the long-term hemodialysis (HD) treatment leads to disturbances of carnitine homeostasis but the results of L-carnitine supplementation in HD patients have been conflicting. In the present prospective study, we investigated the effectiveness of intravenous L-carnitine in mitigating dialysis-related protein-energy wasting (PEW) based on pre-treatment albumin levels. METHODS: Fifty patients (46% male, mean age 63+/-18.28 years, HD vintage 37.5 (7-288) months) received 1 g L carnitine intravenously at the end of every HD session for 12 months. Clinical data were obtained from the medical records and charts. Intradialytic hypotension periods (defined as a decrease of systolic blood pressure by >= 20 mmHg) were recorded. Dietary habits were evaluated using a self-administered questionnaire prior to L-carnitine supplementation. Laboratory parameters were measured prior to the supplementation and controlled in 6-months intervals. Anthropometric measurements were performed prior to HD session, including "dry" body weight and height, body mass index (BMI), and body composition analysis using bioimpedance spectroscopy. Malnutrition-inflammation score (MIS) was used as a scoring system representing the severity of PEW and an indicator of general functional capacity. RESULTS: A significant increase in total cholesterol, predominantly on the account of LDL was found (p=0.005). Simultaneously, HDL decreased (p=0.001) while triglyceride levels remained unchanged. Although the rise in serum prealbumin could be observed, lean tissue index (LTI) decreased and fat tissue index (FTI) increased which resulted in reduction of the LTI/FTI ratio (p=0.002). When divided into two groups according to the pre-treatment albumin values (< 35 g/L or >=35 g/L), patients from the higher albumin group showed significant increase in prealbumin (p=0.005), and improved MIS (p=0.03). Multivariate regression analysis showed that higher FTI after introduction of L-carnitine led to greater hemodynamic stability (OR 1.709, 95% CI 1.006-2.905, p=0.048). As there was no differences in HD treatment characteristics, primery kidney disease or residual diuresis we could conclude that positive energy balance (with an increase in prealbumin and FTI) eventually led to better hemodynamic stability. CONCLUSION: Our results show significant effects of L-carnitine supplementation on lipid metabolism. Further clinical trials, as well as experimental research are needed to define the role of lipid metabolism in CKD population. Significant benefits of L-carnitine supplementation in patients with better initial serum albumin levels suggest that this therapy should not be restricted to patients with the worst nutritional and overall status. PMID- 30016790 TI - PLA1A Participates in the Antiviral Innate Immune Response by Facilitating the Recruitment of TANK-Binding Kinase 1 to Mitochondria. AB - As a key molecule in the antiviral innate immune response, the activation of TANK binding kinase 1 (TBK1) is under tight regulation. In this report, we identified phosphatidylserine-specific phospholipase PLA1A as a host factor that modulates the TBK1 activation. Knockdown of PLA1A expression suppressed the innate immune signaling induced by RNA viruses, while PLA1A overexpression enhanced the signaling. PLA1A functioned at the TBK1 level of the signaling pathway, as PLA1A silencing blocked TBK1, but not interferon regulatory factor 3 (IRF3) induced interferon-beta (IFN-beta) promoter activity. The phosphorylation and kinase activity of TBK1 was reduced in PLA1A knockdown cells. Mechanistically, PLA1A was required in TBK1-mitochondrial antiviral signaling protein (MAVS) interactions but not the interactions of TBK1 with other adaptor proteins. Furthermore, PLA1A knockdown reduced the recruitment of TBK1 and IRF3 to mitochondria, concomitant with altered mitochondria morphology. PMID- 30016791 TI - Role of 1alpha,25-Dihydroxyvitamin D3 in Adipogenesis of SGBS Cells: New Insights into Human Preadipocyte Proliferation. AB - BACKGROUND/AIMS: Compared with non-obese individuals, obese individuals commonly store more vitamin D in adipose tissue. VDR expression in adipose tissue can influence adipogenesis and is therefore a target pathway deserving further study. This study aims to assess the role of 1,25(OH)2D3 in human preadipocyte proliferation and differentiation. METHODS: RTCA, MTT, and trypan blue assays were used to assess the effects of 1,25(OH)2D3 on the viability, proliferation, and adipogenic differentiation of SGBS cells. Cell cycle and apoptosis analyses were performed with flow cytometry, triglycerides were quantified, and RT-qPCR was used to assess gene expression. RESULTS: We confirmed that the SGBS cell model is suitable for studying adipogenesis and demonstrated that the differentiation protocol induces cell maturation, thereby increasing the lipid content of cells independently of treatment. 1,25(OH)2D3 treatment had different effects according to the cell stage, indicating different modes of action driving proliferation and differentiation. In preadipocytes, 1,25(OH)2D3 induced G1 growth arrest at both tested concentrations without altering CDKN1A gene expression. Treatment with 100 nM 1,25(OH)2D3 also decreased MTT absorbance and the lipid concentration. Moreover, increased normalized cell index values and decreased metabolic activity were not induced by proliferation or apoptosis. Exposure to 100 nM 1,25(OH)2D3 induced VDR, CEBPA, and CEBPB expression, even in the preadipocyte stage. During adipogenesis, 1,25(OH)2D3 had limited effects on processes such as VDR and PPARG gene expression, but it upregulated CEBPA expression. CONCLUSIONS: We demonstrated for the first time that 1,25(OH)2D3 induces changes in preadipocytes, including VDR expression and growth arrest, and increases the lipid content in adipocytes treated for 16 days. Preadipocytes are important cells in adipose tissue homeostasis, and understanding the role of 1,25(OH)2D3 in adipogenesis is a crucial step in ensuring adequate vitamin D supplementation, especially for obese individuals. PMID- 30016794 TI - Intravenous Sotalol: An Under Used Treatment Strategy. AB - The pharmacologic treatment of arrhythmias has seen little advance over the past few years. Physicians treating life threatening or hemodynamically destabilizing arrhythmias depend almost entirely on intravenous (IV) amiodarone. This is regrettable due to the multiple toxicities of amiodarone and its long half-life. Once administered, it is a therapeutic commitment to long-term therapy. Given the very long terminal elimination half-life, treatment with amiodarone may interfere with baseline electrophysiologic studies and ablation procedures. Additionally, the side effect profile can be consequential, even with brief periods of treatment. Currently, sotalol, like amiodarone, is available in both IV and oral formulations, facilitating their use in emergency situations. IV sotalol has a rapid onset of action with linear pharmacokinetics. While sotalol's efficacy has mostly been evaluated in small clinical trials, 2 recent meta-analysis have been informative as to the utility of sotalol. Sotalol has similar efficacy as amiodarone, but has much more favorable adverse event profile. IV sotalol has been underutilized and could offer advantage in the treatment of AF for rate and rhythm control, as well in the pediatrics for treatment of supraventricular arrhythmias often resistant to other therapies. PMID- 30016789 TI - VEGF-A and VEGF-B Coordinate the Arteriogenesis to Repair the Infarcted Heart with Vagus Nerve Stimulation. AB - BACKGROUND/AIMS: Vagus nerve stimulation (VNS) suppresses arrhythmic activity and minimizes cardiomyocyte injury. However, how VNS affects angiogenesis/arteriogenesis in infarcted hearts, is poorly understood. METHODS: Myocardial infarction (MI) was achieved by ligation of the left anterior descending coronary artery (LAD) in rats. 7 days after LAD, stainless-steel wires were looped around the left and right vagal nerve in the neck for vagus nerve stimulation (VNS). The vagal nerve was stimulated with regular pulses of 0.2ms duration at 20 Hz for 10 seconds every minute for 4 hours, and then ACh levels by ELISA in cardiac tissue and serum were evaluated for its release after VNS. Three and 14 days after VNS, Real-time PCR, immunostaining and western blot were respectively used to determine VEGF-A/B expressions and alpha-SMA- and CD31 postive vessels in VNS-hearts with pretreatment of alpha7-nAChR blocker mecamylamine (10 mg/kg, ip) or mACh-R blocker atropine (10 mg/kg, ip) for 1 hour. The coronary function and left ventricular performance were analyzed by Langendorff system and hemodynamic parameters in VNS-hearts with pretreatment of VEGF-A/B-knockdown or VEGFR blocker AMG706. Coronary arterial endothelial cells proliferation, migration and tube formation were evaluated for angiogenesis following the stimulation of VNS in coronary arterial smooth muscle cells (VSMCs). RESULTS: VNS has been shown to stimulate VEGF-A and VEGF-B expressions in coronary arterial smooth muscle cells (VSMCs) and endothelial cells (ECs) with an increase of alpha-SMA- and CD31-postive vessel number in infarcted hearts. The VNS-induced VEGF-A/B expressions and angiogenesis were abolished by m-AChR inhibitor atropine and alpha7-nAChR blocker mecamylamine in vivo. Interestingly, knockdown of VEGF-A by shRNA mainly reduced VNS-mediated formation of CD31+ microvessels. In contrast, knockdown of VEGF-B powerfully abrogated VNS-induced formation of alpha-SMA+ vessels. Consistently, VNS-induced VEGF-A showed a greater effect on EC tube formation as compared to VNS-induced VEGF-B. Moreover, VEGF-A promoted EC proliferation and VSMC migration while VEGF-B induced VSMC proliferation and EC migration in vitro. Mechanistically, vagal neurotransmitter acetylcholine stimulated VEGF-A/B expressions through m/nACh-R/PI3K/Akt/Sp1 pathway in EC. Functionally, VNS improved the coronary function and left ventricular performance. However, blockade of VEGF receptor by antagonist AMG706 or knockdown of VEGF-A or VEGF-B by shRNA significantly diminished the beneficial effects of VNS on ventricular performance. CONCLUSION: VNS promoted angiogenesis/arteriogenesis to repair the infracted heart through the synergistic effects of VEGF-A and VEGF-B. PMID- 30016793 TI - Development of a Genetic and Clinical Data-Based (GC) Risk Score for Predicting Survival of Hepatocellular Carcinoma Patients After Tumor Resection. AB - BACKGROUND/AIMS: Carnitine palmitoyltransferase 1A (CPT1A) is a rate-limiting enzyme in the transport of long-chain fatty acids for beta-oxidation. Increasing evidence has indicated that CPT1A plays an important role in carcinogenesis. However, the expression and prognostic value of CPT1A in hepatocellular carcinoma (HCC) have not been extensively studied. METHODS: Here, we collected 66 post operative liver cancer tissue samples. Gene profile expression was tested by RT PCR. Receiver operating characteristic (ROC) analysis was performed and multivariate analysis with Cox's Proportional Hazard Model was used for confirming the selected markers' predictive efficiency for HCC patients' survival. A simple risk scoring system was created based on Cox's regression modeling and bootstrap internal validation. RESULTS: Cox multivariate regression analysis demonstrated that CPT1A, tumor size, intrahepatic metastasis, TNM stage and histological grade were independent risk factors for the prognosis of HCC patients after surgery. Our genetic and clinical data-based (GC) risk scoring system revealed that HCC patients whose total score>=3 are more likely to relapse and die than patients whose total score < 3. Finally, the good discriminatory power of our risk scoring model was validated by bootstrap internal validation. CONCLUSIONS: The genetic and clinical data-based risk scoring model can be a promising predictive tool for liver cancer patients' prognosis after operation. PMID- 30016792 TI - Sarcopenic Obesity: Time to Meet the Challenge. AB - The prevalence of overweight and obesity has reached epidemic proportions worldwide due to increasingly pervasive obesogenic lifestyle changes. Obesity poses unprecedented individual, social, and multidisciplinary medical challenges by increasing the risk for metabolic diseases, chronic organ failures, and cancer as well as complication rates in the presence of acute disease conditions. Whereas reducing excess adiposity remains the fundamental pathogenic treatment for obese individuals, complex metabolic and lifestyle abnormalities as well as weight reduction therapies per se may also compromise the ability to preserve muscle function and mass, especially when chronic disease co-exists with obesity. Emerging evidence indicates that low muscle mass and quality have a strong negative prognostic impact in obese individuals and may lead to frailty, disability, and increased morbidity and mortality. Awareness of the importance of skeletal muscle maintenance in obesity is however low among clinicians and scientists. The term 'sarcopenic obesity' has been proposed to identify obesity with low skeletal muscle function and mass, but its utilization is largely limited to the aging patient population, and consensus on its definition and diagnostic criteria remains insufficient. Knowledge on prevalence of sarcopenic obesity in various clinical conditions and patient subgroups, on its clinical impacts in patient risk stratification, and on effective prevention and treatment strategies remain therefore dramatically inadequate. In particular, optimal dietary options and medical nutritional support strategies to preserve muscle mass in obese individuals remain largely undefined. The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recognize and indicate obesity with altered body composition due to low skeletal muscle function and mass (sarcopenic obesity) as a scientific and clinical priority for researchers and clinicians. ESPEN and EASO therefore call for coordinated action aimed at reaching consensus on its definition, diagnostic criteria, and optimal treatment with particular regard to nutritional therapy. We are convinced that achievement of these goals has a strong potential to reduce the burden of morbidity and mortality in the rapidly increasing obese patient population. PMID- 30016795 TI - A Feasibility Study Utilizing the Thulium and Holmium Laser in Patients for the Treatment of Recurrent Benign Prostatic Hyperplasia after Previous Prostatic Surgery. AB - BACKGROUND: Transurethral resection of the prostate (TURP) is considered to be the standard treatment for patients with benign prostatic obstruction (BPO) <=80 mL. However, up to 14.7% of the patients require secondary TURP due to recurrent BPO. The aim of our study was to describe specific features of holmium laser enucleation of the prostate (HoLEP) and thulium laser enucleation of the prostate (ThuLEP) in patients with recurrent BPO after previous prostate surgery. MATERIALS AND METHODS: A total of 768 consecutive patients from our prospective collected database were retrospectively reviewed and divided into 4 groups: group A (489 patients) and group C (253 patients) underwent primary HoLEP and ThuLEP treatment, while group B (17 patients) and D (9 patients) included patients with recurrent BPO who were treated with HoLEP and ThuLEP, respectively. RESULTS: There were no significant differences in preoperative parameters between the groups at primary (A and C) and secondary (B and D) treatment except their age. At 6-month follow-up, voiding parameters and symptom scores showed statistically significant improvements compared to baseline without differences between the groups. The mean operative time was comparable between the groups and did not differ significantly (p > 0.05). CONCLUSIONS: Laser enucleation for the treatment of recurrent BPO is feasible and seems to be a safe and effective procedure. PMID- 30016797 TI - Sensitivity of Initial Thoracentesis for Malignant Pleural Effusion Stratified by Tumor Type in Patients with Strong Evidence of Metastatic Disease. AB - BACKGROUND: Thoracentesis with cytological examination of pleural fluid is the initial test of choice for evaluation of pleural effusions in patients with suspected malignant pleural effusion (MPE). There is limited data on the sensitivity of thoracentesis stratified by tumor type. A better understanding of stratified sensitivities is of clinical interest, and may guide early and appropriate referral for pleural biopsy. OBJECTIVE: The primary objective was sensitivity of thoracentesis with pleural fluid cytology stratified by tumor type. METHODS: This is a retrospective cohort study of consecutive patients with a solid tumor malignancy with proven or strong suspicion for metastatic disease with new pleural effusions that underwent an initial thoracentesis. Only patients with metastatic disease were included. RESULTS: Of the 725 patients examined, 63% had pleural fluid cytology positive for malignancy. Sensitivity of thoracentesis varied from a low of 0.38 (95% CI 0.13-0.68) in head and neck malignancy, 0.38 (95% CI 0.15-0.65) in sarcoma, and 0.53 (95% CI 0.34-0.72) in renal cancer to a high of 93 (95% CI 88-97) in breast cancer, and 100 (95% CI 0.82-100) in pancreatic cancer. Factors associated with an increased risk of MPE included larger amount of fluid drained (p = 0.014) and higher pleural fluid protein (p = 0.002). The only factor associated with decreased risk of MPE if first cytology was negative for malignancy was the presence of contralateral effusion (p = 0.005). CONCLUSIONS: Sensitivity of thoracentesis for solid tumors varies significantly depending on the type of tumor and is lowest in those with sarcomas, head and neck malignancies, and renal cell cancers. PMID- 30016796 TI - The Clinical Efficacy of Mindfulness-Based Treatments for Alcohol and Drugs Use Disorders: A Meta-Analytic Review of Randomized and Nonrandomized Controlled Trials. AB - INTRODUCTION: The current study aims to evaluate if and to what extent mindfulness-based interventions (MBIs) could promote an incremental effectiveness compared to interventions usually provided in clinical practice to treat Alcohol and Drugs Use Disorders. In line with this aim, we accomplished a meta-analytic review of randomized and nonrandomized controlled trials, considering primary and secondary outcomes that comprehensively operationalize treatment efficacy. METHODS: We conducted the online research up to August 31st 2017. Adequate procedures for Cohen's d computation were applied. Heterogeneity indexes, moderators, bias of publication, and Orwin's fail-safe number were also estimated. RESULTS: Thirty-seven studies were included (n = 3,531 patients). We observed null effect sizes for attrition rate and overall mental health. Small effect sizes were detected in abstinence, levels of perceived stress, and avoidance coping strategies. Moderate effect sizes were revealed in anxiety and depressive symptoms. Large effect sizes were associated to levels of perceived craving, negative affectivity, and post-traumatic symptoms. CONCLUSION: MBIs seemed to show clinically significant advantages compared to other clinical approaches in relation to specific primary and secondary outcomes. Conversely, treatment retention was independent of the therapeutic approach. PMID- 30016798 TI - Developing an Arabic Screening Test for Adult-Onset Chronic Aphasia. AB - AIM: To develop a time-efficient Arabic test battery for adult-onset chronic aphasia that provides information about the type and the severity of the disorder. PATIENT AND METHODS: A total of 90 participants were recruited and divided into 3 groups. The groups consisted of 30 adult-onset post-stroke chronic aphasic patients, 30 adult non-aphasic adults with central neurological disorders, and a group of 30 non-brain-damaged healthy adults. All participants were assessed using the Mansoura Arabic Screening Aphasia Test (MASAT), which consists of 4 main sections: (1) language expression abilities including repetition and naming items, (2) language comprehension questions, (3) fluency, and (4) reading, writing and calculation items. The content validity, internal consistency, clinical validity, and convergent validity of the MASAT were evaluated. RESULTS: The MASAT demonstrated statistically high reliability and validity. The high alpha-values in all subtotal scores among the 3 groups were judged to denote excellent intercorrelation among the screening test items. CONCLUSION: The MASAT is a valid and a reliable brief assessment tool that can be completed on the first clinic appointment that detects the type and severity of Arabic-speaking aphasic patients. PMID- 30016799 TI - The Pattern of Elevated Liver Function Tests in Nonalcoholic Fatty Liver Disease Predicts Fibrosis Stage and Metabolic-Associated Comorbidities. AB - BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) and with abnormal liver function tests (LFTs) most commonly present with elevated hepatocellular enzymes (H pattern), but a subset of patients is found to have elevated cholestatic enzymes (C pattern) or a mixed (M) pattern. AIMS AND METHODS: To determine whether the epidemiologic background and comorbidities, as well as the degree of liver fibrosis, differ between NAFLD patients with different patterns of elevated LFTs by retrospectively analyzing data of 106 patients with a biopsy-proven diagnosis of NAFLD. The pattern of elevated LFTs was determined by adopting the "R-Ratio" formula commonly used for drug-induced liver injury. RESULTS: Advanced fibrosis (F > 2) was found in 15 out of 48 (31.3%) patients with a C pattern of elevated LFTs as compared to 2 out of 44 (4.5%) in M patients and 2 out of 11 (18.2%) in H patients (p = 0.004). Group C patients are older and also had a higher prevalence of diabetes, a higher mean hemoglobin A1c, and a higher prevalence of hypertension, as well as a trend for a higher prevalence of hypertriglyceridemia. CONCLUSIONS: Using a simple formula incorporating routine LFTs can help to categorize NAFLD patients as low or high risk for advanced fibrosis stage and metabolic-associated comorbidities. PMID- 30016800 TI - MiR-410 Acts as a Tumor Suppressor in Estrogen Receptor-Positive Breast Cancer Cells by Directly Targeting ERLIN2 via the ERS Pathway. AB - BACKGROUND/AIMS: Endoplasmic reticulum lipid raft-associated 2 (ERLIN2) is reported to be overexpressed in human breast cancer cells and plays an important role in cell proliferation. MicroRNAs (miRNAs) act as post-transcriptional regulators of gene expression and are involved in the development of multiple malignancies, including breast cancer. However, the molecular mechanism of the aberrant ERLIN2 expression in human breast cancer remains poorly understood. METHODS: MiR-410 expression level was analyzed using Real-time PCR, and ERLIN2 expression was analyzed using Western blot, Real-time PCR and immunohistochemical staining. The effect of miR-410 on ERLIN2 3'UTR intensity was performed using a luciferase assay. Cell proliferation was analyzed using CCK-8 and colony formation assay, together with an Annexin V-PE/7-AAD kit for cell apoptosis assay. Cell migration and invasion was detected using a Transwell migration and invasion assay. Methylation specific PCR was used to examine whether miR-410 promoter was demethylated. RESULTS: In this study, we validated that ERLIN2 was a direct target of miR-410 and miR-410 suppressed ERLIN2 expression at the post transcriptional level. Importantly, the regulation of ERLIN2 by miR-410 was estrogen receptor (ER) dependent. Functional studies demonstrated that miR-410 inhibited breast cancer cell proliferation, migration and invasion, but promoted cell apoptosis. However, inhibition of miR-410 resulted in opposite effects. A xenograft nude mouse model further confirmed that miR-410 suppressed breast tumor growth. In addition, miR-410 modulated the expression levels of epithelial mesenchymal transition (EMT)-related genes. ERLIN2 knockdown suppressed cell proliferation, migration and invasion, as well as EMT. ERLIN2 overexpression can restore the cell proliferation, migration and invasion that were inhibited by miR 410. Furthermore, our data demonstrated that miR-410 inhibition suppressed the expression of endoplasmic reticulum-stress (ERS)-related genes, while ERLIN2 knockdown abrogated the effects of miR-410 inhibitor. Finally, we showed that miR 410 was downregulated in human ER-positive breast cancer tissues, inversely correlated with ERLIN2. We further demonstrated the downregulation of miR-410 in breast cancer might be due to the hypermethylation of its promoter. CONCLUSIONS: Our study indicates that miR-410 suppresses cell growth, migration and invasion by directly downregulating ERLIN2 in ER positive breast cancer, acting as a tumor suppressor. Our study also suggests that miR-410 may serve as a potential therapeutic target for patients with ER positive breast cancer. PMID- 30016801 TI - Comparison of the Effects of Ticagrelor and Clopidogrel on Inflammatory Factors, Vascular Endothelium Functions and Short-Term Prognosis in Patients with Acute ST Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention: a Pilot Study. AB - BACKGROUND/AIMS: Acute ST-segment elevation of myocardial infarction (STEMI) is the most severe type of acute coronary syndrome (ACS). Particular attention has been focused on studying the pathogenesis of STEMI, and how to prevent thrombosis, reduce inflammatory reaction, stabilize plaques and improve vascular endothelial functions to preserve the survived myocardium. This study aimed to compare the anti-inflammatory endothelium-protective effects, clinical prognosis, and relevant bleeding risks of ticagrelor versus clopidogrel in patients with STEMI who underwent urgent percutaneous coronary intervention (PCI) and provide certain experimental evidence and a theoretical basis for the selection of safe and effective drugs and their proper dosage, thereby further guiding clinical medication. METHODS: We sequentially enrolled 193 patients (104 males and 89 females) admitted to hospital due to acute STEMI. These patients underwent urgent PCI between December 2013 and May 2015 and met the inclusion criteria. They were assigned (1: 1) into two groups according to different treatments, 97 patients in the ticagrelor group (treatment group), and 96 patients in the clopidogrel group (control group). Levels of hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and endothelial cell-specific molecule 1 (ESM-1) taken at admission and 24 h, 4 days, and 7 days after administration, as well as the correlation between the levels of IL-6, hs-CRP, and ESM-1, were determined in the two groups. At the same time, the effects of treatment with ticagrelor and clopidogrel on the efficacy endpoint events (ischemic and safety) were explored. RESULTS: No statistically significant difference was found in the levels of hs CRP, IL-6, or ESM-1 at admission between the two groups (P> 0.05); Their levels were significantly elevated 24 h after administration, with statistical differences between two groups (P< 0.05). Furthermore, a downward trend with statistically significant differences was found on Day 4 and Day 7 (P< 0.05); ESM 1 levels increased along with increases of hs-CRP and IL-6 levels, indicating ESM 1 was positively correlated with hs-CRP (r=0.523, P< 0.001) and IL-6 (r=0.431, P< 0.001); and the occurrence rates of ischemic endpoint events at 30 days were lower in the treatment group than in the control group. The occurrence of safety endpoint events was higher than in the control group; however, no statistically significant difference was found (P> 0.05). CONCLUSIONS: Compared with clopidogrel, ticagrelor appears to rapidly reduce the prevalence of inflammatory reactions and stabilize the functions of vascular endothelium to improve the stability of atherosclerotic plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome events without any obvious increase in the risk of bleeding in patients with acute STEMI receiving urgent PCI. This renders it a potential drug for clinical practice. At the same time, measurement of ESM 1, a new biological marker for vascular endothelial function disorder, could possibly become a simple, effective, and practical new method for clinical evaluation of risk stratification of patients with acute STEMI at admission. PMID- 30016802 TI - Creation of a Balloon-Expandable Bifurcated Covered Stent to Treat a Complex Left Anastomotic Stricture in a Lung Transplant Recipient. AB - Airway complications after lung transplant occur in approximately 10-15% of the recipients and often occur at the anastomosis, largely due to ischemia. To decrease anastomotic ischemia, surgeons minimize the length of the donor bronchus. However, a shortened donor bronchus creates technical challenges if a stent is required to treat an airway complication. We present a case of a lung transplant recipient with the combination of left main stem bronchial malacia and a triad of severe strictures at the left anastomosis, entrance to the left upper lobe, and left lower lobe. After failing several attempts using other modalities, success was achieved with in situ creation of a bifurcated fully covered balloon expandable metallic stent. We describe a novel technique of punching a side branch hole through the wall of the stent to allow a left upper lobe stent to be placed through a stent directed into the left lower lobe in a Y configuration with a good clinical outcome. PMID- 30016804 TI - Recurrent Urinary Tract Infections in Women: What Is the Evidence for Investigating with Flexible Cystoscopy, Imaging and Urodynamics? AB - : Background/Aims/Objectives: Women with recurrent urinary tract infections (UTIs) are commonly referred to urology outpatient clinics. However, there is no clear consensus in existing guidelines as to if, or how, these should be investigated. The primary outcome was to evaluate all available literature to determine the percentage of abnormal findings in non-pregnant women with recurrent simple UTIs. Secondary outcomes were to determine the percentage that were serious, consequential or incidental findings. METHODS: A full literature search was performed of the following databases: MEDLINE; Pubmed; Cochrane Central Register of Controlled Trials-CENTRAL; and ClinicalTrials.gov. Two assessors reviewed the articles independently. Any discrepancy was discussed and an agreement reached. RESULTS: The literature search yielded 662 titles; 652 were excluded on initial review. A further 13 studies were gathered from references of yielded papers. After full review, 12 were included for analysis. These showed that < 1.5% of women investigated for recurrent simple UTIs with imaging or flexible cystoscopy had life-threatening pathology, but up to 67% had abnormal urodynamics. CONCLUSIONS: Women presenting with simple recurrent UTIs should have a flow rate and post-void residual measured. Cystoscopy is not warranted and imaging is unlikely to be of value in the absence of symptoms of upper tract disease or gynaecological problems. PMID- 30016803 TI - Gender Differences in Anxiety and Depression before and after Alcohol Detoxification: Anxiety and Depression as Gender-Related Predictors of Relapse. AB - BACKGROUND/AIMS: The aim of this prospective study was to estimate gender differences in anxiety, depression, and alcohol use severity among patients with alcohol use disorder (AUD) before and after detoxification program and within 12 months after discharge. METHODS: AUD severity, state and trait anxiety, and depression were assessed in 187 patients entering an inpatient alcohol detoxification program. Follow-up assessments were performed at 6 and 12 months after discharge. A between- and within-subjects analyses explored gender differences. The predictive value of anxiety and depression for alcohol relapse was analyzed by logistic and linear regression in both genders. RESULTS: Females had higher levels of anxiety and depression than males both at admission and after discharge. Trait anxiety and depression significantly increased 6 months after discharge in males and females respectively. Both state and trait anxiety levels at the 6-month follow-up predicted alcohol relapse at the 12-month follow up in males. Conversely, in females, depression level at the 6-month follow-up was a predictor of relapse at the 12-month follow-up. CONCLUSIONS: In both genders, the psychopathological dimension that showed the most significant worsening at 6-month follow-up (i.e., anxiety in males and depression in females) was found to be a significant predictor of relapse at the 12-month follow-up. PMID- 30016805 TI - Frequency of Complete Atrioventricular Block Complicating ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention. AB - OBJECTIVES: ST-segment elevation myocardial infarction (STEMI) can be associated with many conduction disturbances including complete atrioventricular block (CAVB). CAVB complicating STEMI resulted in an increased mortality before the modern era of primary percutaneous coronary intervention (PCI). The aim of this study was to ascertain the rate and risk factors for CAVB in STEMI patients undergoing rapid reperfusion with PCI. METHODS: We analyzed 223 patients presenting with STEMI. Patient characteristics, procedural characteristics, and in-hospital data were compared between patients with and without CAVB. RESULTS: Out of 223 patients, 174 underwent PCI; the majority (87%) was African-American. CAVB was present in 8 patients (4.6%), and 6 of them had RCA occlusion. Independent predictors of CAVB included diabetes mellitus, female gender, lower systolic and diastolic blood pressure, and inferior-lateral/lateral STEMI. Ten patients (5.7%) required temporary pacing at presentation; only 1 patient required permanent pacing before discharge. No patient with anterior STEMI developed CAVB. CONCLUSIONS: The incidence and in-hospital mortality rate of CAVB in patients with STEMI who underwent primary PCI was reduced when compared to data from the thrombolytic era. This may be due to faster flow recovery in the infarct-related artery achieved with PCI. PMID- 30016806 TI - Long-Term Opioid Agonist Treatment Participation after First Treatment Entry is Similar across 4 European Regions but Lower in Non-Nationals. AB - Heroin users in opioid agonist treatment (OAT) show markedly reduced heroin consumption, less crime and a lower mortality rate. However, the extent of long term OAT participation over subsequent treatment episodes remains unclear. We analysed the annual proportion of patients in treatment (at least 1 day) since the start of first OAT in 4 European regions: Barcelona (BA) 1996-2012: 8,602 patients; Czech -Republic (CZ) 2000-2014: 4,377 patients; Netherlands (NL) 1994 2014: 33,235 patients, Zurich (ZU) 1992-2015: 11,795. We estimated the long-term decline of treatment need due to mortality or abstinence and also a "nuisance" short-term decline until the equilibrium level of cycling in and out of OAT is reached to obtain the adjusted treatment participation value. The adjusted treatment participation was around 50% (BA: 47.4-51.4%; CZ: 49.8-53.9%; NL: 52.3 54.0%; ZU: 46.4-49.3%), and the annual decline of treatment need was close to 4%. Non-nationals (NL patients with a migrant background) showed substantial lower adjusted treatment participation (rate ratio BA: 0.059-0.343; NL: 0.710-0.751; ZU: 0.681-0.797; CZ: n.a.). Our method may provide a policy-relevant indicator of long-term provision, quality and access to OAT following first treatment. PMID- 30016807 TI - [Parkinson Disease and Pain - diagnostic and therapeutic approaches to a challenging non-motor symptom]. PMID- 30016808 TI - [Parkinson's disease and neuroinflammation - Cellular pathology, mechanisms and therapeutic options]. PMID- 30016810 TI - Assessment of Needs for Counseling After Prenatal Diagnosis of Congenital Heart Disease - A Multidisciplinary Approach. AB - BACKGROUND: Congenital heart disease is the most common cause of major congenital anomalies. After prenatal diagnosis effective counseling is crucial. However, little research has been undertaken in determining the most effective techniques. OBJECTIVES: To develop a questionnaire suitable to assess parental needs for counseling. MATERIAL AND METHODS: A questionnaire was developed by pediatric cardiologists, maternal-fetal-medicine specialists and sociologists. Likert scaled and open-ended questions are combined with socio-demographical data. The questionnaire was prospectively pilot-tested on 17 parents. We present first analyses of n=41 parents. RESULTS: Response rate was 89.5%. The dependent variable "effective counseling" was measured in 5 dimensions (transfer of medical information, trust in medical staff, transparency of treatment process, coping resources and perceived situational control). The questionnaire's internal consistency is high (Cronbach's alpha>0.7). First analyses show that 44.7% perceived counseling as successful. Transfer of medical information seems difficult (36.6% success rate). Trust in medical staff was high with 75%. CONCLUSIONS: This newly developed tool measures counseling success in five dimensions. A multidisciplinary approach is recommended as methodological expertise is essential for constructing adequate tests. Preliminary data indicate that transfer of medical information is not easily achieved. Further analyses are needed to identify factors that determine counseling success. PMID- 30016809 TI - Perineal Trauma in a Low-risk Maternity with High Prevalence of Upright Position during the Second Stage of Labor. AB - OBJECTIVE: Perineal trauma is a negative outcome during labor, and until now it is unclear if the maternal position during the second stage of labor may influence the risk of acquiring severe perineal trauma. We have aimed to determine the prevalence of perineal trauma and its risk factors in a low-risk maternity with a high incidence of upright position during the second stage of labor. METHODS: A retrospective cohort study of 264 singleton pregnancies during labor was performed at a low-risk pregnancy maternity during a 6-month period. Perineal trauma was classified according to the Royal College of Obstetricians and Gynecologists (RCOG), and perineal integrity was divided into three categories: no tears; first/second-degree tears + episiotomy; and third and fourth-degree tears. A multinomial analysis was performed to search for associated factors of perineal trauma. RESULTS: From a total of 264 women, there were 2 cases (0.75%) of severe perineal trauma, which occurred in nulliparous women younger than 25 years old. Approximately 46% (121) of the women had no tears, and 7.95% (21) performed mediolateral episiotomies. Perineal trauma was not associated with maternal position (p = 0.285), health professional (obstetricians or midwives; p = 0.231), newborns with 4 kilos or more (p = 0.672), and labor analgesia (p = 0.319). The multinomial analysis showed that white and nulliparous presented, respectively, 3.90 and 2.90 times more risk of presenting perineal tears. CONCLUSION: The incidence of severe perineal trauma was low. The prevalence of upright position during the second stage of labor was 42%. White and nulliparous women were more prone to develop perineal tears. PMID- 30016811 TI - [Classification of Acute Diverticulitis for Stage-directed Therapy]. AB - BACKGROUND: In recent years, there has been a significant change in the treatment recommendations for acute diverticulitis. In order to provide the right treatment to the individual patient, it is therefore important to classify the stage of the disease accurately, after taking various aspects into consideration. METHODS: Patients treated for acute diverticulitis in Wurzburg University Hospital during 2010 to 2014 were included. Inclusion criteria were the presence of a computer tomography for disease classification. RESULTS: More than half of the patients examined (n = 135, 52.9%) had acute uncomplicated diverticulitis on admission; 112 (43.2%) had a covered perforation (small paracolic abscess n = 63, 24,3%; large abscess n = 49, 18,9%) and 12 (4.6%) a free perforation. In a total of 150 (57.9%) patients, this was the first episode of diverticulitis, with a covered (66.1%) or a free perforation (75.0%) occurring at a higher than average rate as the first manifestation. Nearly two-thirds (66.4%, n = 168) of patients underwent sigmoid resection during follow-up. DISCUSSION AND CONCLUSION: Despite current trends towards more conservative therapy of acute diverticulitis, sigmoid resection remains a corner stone of successful therapy throughout all types of acute diverticulitis. The indication of sigmoid resection nowadays requires profound knowledge of the individual prognosis for recurrent diverticulitis and quality of life. PMID- 30016812 TI - Data Integration for Future Medicine (DIFUTURE). AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. Future medicine will be predictive, preventive, personalized, participatory and digital. Data and knowledge at comprehensive depth and breadth need to be available for research and at the point of care as a basis for targeted diagnosis and therapy. Data integration and data sharing will be essential to achieve these goals. For this purpose, the consortium Data Integration for Future Medicine (DIFUTURE) will establish Data Integration Centers (DICs) at university medical centers. OBJECTIVES: The infrastructure envisioned by DIFUTURE will provide researchers with cross-site access to data and support physicians by innovative views on integrated data as well as by decision support components for personalized treatments. The aim of our use cases is to show that this accelerates innovation, improves health care processes and results in tangible benefits for our patients. To realize our vision, numerous challenges have to be addressed. The objective of this article is to describe our concepts and solutions on the technical and the organizational level with a specific focus on data integration and sharing. GOVERNANCE AND POLICIES: Data sharing implies significant security and privacy challenges. Therefore, state-of-the-art data protection, modern IT security concepts and patient trust play a central role in our approach. We have established governance structures and policies safeguarding data use and sharing by technical and organizational measures providing highest levels of data protection. One of our central policies is that adequate methods of data sharing for each use case and project will be selected based on rigorous risk and threat analyses. Interdisciplinary groups have been installed in order to manage change. ARCHITECTURAL FRAMEWORK AND METHODOLOGY: The DIFUTURE Data Integration Centers will implement a three-step approach to integrating, harmonizing and sharing structured, unstructured and omics data as well as images from clinical and research environments. First, data is imported and technically harmonized using common data and interface standards (including various IHE profiles, DICOM and HL7 FHIR). Second, data is preprocessed, transformed, harmonized and enriched within a staging and working environment. Third, data is imported into common analytics platforms and data models (including i2b2 and tranSMART) and made accessible in a form compliant with the interoperability requirements defined on the national level. Secure data access and sharing will be implemented with innovative combinations of privacy-enhancing technologies (safe data, safe settings, safe outputs) and methods of distributed computing. USE CASES: From the perspective of health care and medical research, our approach is disease-oriented and use-case driven, i.e. following the needs of physicians and researchers and aiming at measurable benefits for our patients. We will work on early diagnosis, tailored therapies and therapy decision tools with focuses on neurology, oncology and further disease entities. Our early uses cases will serve as blueprints for the following ones, verifying that the infrastructure developed by DIFUTURE is able to support a variety of application scenarios. DISCUSSION: Own previous work, the use of internationally successful open source systems and a state-of the-art software architecture are cornerstones of our approach. In the conceptual phase of the initiative, we have already prototypically implemented and tested the most important components of our architecture. PMID- 30016813 TI - HiGHmed - An Open Platform Approach to Enhance Care and Research across Institutional Boundaries. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. HiGHmed brings together 24 partners from academia and industry, aiming at improvements in care provision, biomedical research and epidemiology. By establishing a shared information governance framework, data integration centers and an open platform architecture in cooperation with independent healthcare providers, the meaningful reuse of data will be facilitated. Complementary, HiGHmed integrates a total of seven Medical Informatics curricula to develop collaborative structures and processes to train medical informatics professionals, physicians and researchers in new forms of data analytics. GOVERNANCE AND POLICIES: We describe governance structures and policies that have proven effective during the conceptual phase. These were further adapted to take into account the specific needs of the development and networking phase, such as roll-out, carerelated aspects and our focus on curricula development in Medical Inform atics. ARCHITECTURAL FRAMEWORK AND METHODOLOGY: To address the challenges of organizational, technical and semantic interoperability, a concept for a scalable platform architecture, the HiGHmed Platform, was developed. We outline the basic principles and design goals of the open platform approach as well as the roles of standards and specifications such as IHE XDS, openEHR, SNOMED CT and HL7 FHIR. A shared governance framework provides the semantic artifacts which are needed to establish semantic interoperability. USE CASES: Three use cases in the fields of oncology, cardiology and infection control will demonstrate the capabilities of the HiGHmed approach. Each of the use cases entails diverse challenges in terms of data protection, privacy and security, including clinical use of genome sequencing data (oncology), continuous longitudinal monitoring of physical activity (cardiology) and cross-site analysis of patient movement data (infection control). DISCUSSION: Besides the need for a shared governance framework and a technical infrastructure, backing from clinical leaders is a crucial factor. Moreover, firm and sustainable commitment by participating organizations to collaborate in further development of their information system architectures is needed. Other challenges including topics such as data quality, privacy regulations, and patient consent will be addressed throughout the project. PMID- 30016814 TI - MIRACUM: Medical Informatics in Research and Care in University Medicine. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. Similar to other large international data sharing networks (e.g. OHDSI, PCORnet, eMerge, RD-Connect) MIRACUM is a consortium of academic and hospital partners as well as one industrial partner in eight German cities which have joined forces to create interoperable data integration centres (DIC) and make data within those DIC available for innovative new IT solutions in patient care and medical research. OBJECTIVES: Sharing data shall be supported by common interoperable tools and services, in order to leverage the power of such data for biomedical discovery and moving towards a learning health system. This paper aims at illustrating the major building blocks and concepts which MIRACUM will apply to achieve this goal. GOVERNANCE AND POLICIES: Besides establishing an efficient governance structure within the MIRACUM consortium (based on the steering board, a central administrative office, the general MIRACUM assembly, six working groups and the international scientific advisory board), defining DIC governance rules and data sharing policies, as well as establishing (at each MIRACUM DIC site, but also for MIRACUM in total) use and access committees are major building blocks for the success of such an endeavor. ARCHITECTURAL FRAMEWORK AND METHODOLOGY: The MIRACUM DIC architecture builds on a comprehensive ecosystem of reusable open source tools (MIRACOLIX), which are linkable and interoperable amongst each other, but also with the existing software environment of the MIRACUM hospitals. Efficient data protection measures, considering patient consent, data harmonization and a MIRACUM metadata repository as well as a common data model are major pillars of this framework. The methodological approach for shared data usage relies on a federated querying and analysis concept. USE CASES: MIRACUM aims at proving the value of their DIC with three use cases: IT support for patient recruitment into clinical trials, the development and routine care implementation of a clinico molecular predictive knowledge tool, and molecular-guided therapy recommendations in molecular tumor boards. RESULTS: Based on the MIRACUM DIC release in the nine months conceptual phase first large scale analysis for stroke and colorectal cancer cohorts have been pursued. DISCUSSION: Beyond all technological challenges successfully applying the MIRACUM tools for the enrichment of our knowledge about diagnostic and therapeutic concepts, thus supporting the concept of a Learning Health System will be crucial for the acceptance and sustainability in the medical community and the MIRACUM university hospitals. PMID- 30016817 TI - German Medical Informatics Initiative: Unlocking Data for Research and Health Care. AB - This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. The Medical Informatics Initiative of the German Federal Ministry of Education and Research will make use of the potential of digitalization in the field of medicine in Germany. The aim is to improve the possibilities for medical research and patient care through innovative IT solutions. In an initial step, data integration centres will be set up at university hospitals to ensure the technical and organizational conditions necessary for multi-site exchange of data between health care and clinical and biomedical research. The Federal Ministry of Education and Research will provide a total of around EUR 150 million for this initiative over the next four years. PMID- 30016815 TI - Smart Medical Information Technology for Healthcare (SMITH). AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. "Smart Medical Information Technology for Healthcare (SMITH)" is one of four consortia funded by the German Medical Informatics Initiative (MI-I) to create an alliance of universities, university hospitals, research institutions and IT companies. SMITH's goals are to establish Data Integration Centers (DICs) at each SMITH partner hospital and to implement use cases which demonstrate the usefulness of the approach. OBJECTIVES: To give insight into architectural design issues underlying SMITH data integration and to introduce the use cases to be implemented. GOVERNANCE AND POLICIES: SMITH implements a federated approach as well for its governance structure as for its information system architecture. SMITH has designed a generic concept for its data integration centers. They share identical services and functionalities to take best advantage of the interoperability architectures and of the data use and access process planned. The DICs provide access to the local hospitals' Electronic Medical Records (EMR). This is based on data trustee and privacy management services. DIC staff will curate and amend EMR data in the Health Data Storage. METHODOLOGY AND ARCHITECTURAL FRAMEWORK: To share medical and research data, SMITH's information system is based on communication and storage standards. We use the Reference Model of the Open Archival Information System and will consistently implement profiles of Integrating the Health Care Enterprise (IHE) and Health Level Seven (HL7) standards. Standard terminologies will be applied. The SMITH Market Place will be used for devising agreements on data access and distribution. 3LGM2 for enterprise architecture modeling supports a consistent development process.The DIC reference architecture determines the services, applications and the standardsbased communication links needed for efficiently supporting the ingesting, data nourishing, trustee, privacy management and data transfer tasks of the SMITH DICs. The reference architecture is adopted at the local sites. Data sharing services and the market place enable interoperability. USE CASES: The methodological use case "Phenotype Pipeline" (PheP) constructs algorithms for annotations and analyses of patient-related phenotypes according to classification rules or statistical models based on structured data. Unstructured textual data will be subject to natural language processing to permit integration into the phenotyping algorithms. The clinical use case "Algorithmic Surveillance of ICU Patients" (ASIC) focusses on patients in Intensive Care Units (ICU) with the acute respiratory distress syndrome (ARDS). A model-based decision-support system will give advice for mechanical ventilation. The clinical use case HELP develops a "hospital-wide electronic medical record-based computerized decision support system to improve outcomes of patients with blood-stream infections" (HELP). ASIC and HELP use the PheP. The clinical benefit of the use cases ASIC and HELP will be demonstrated in a change of care clinical trial based on a step wedge design. DISCUSSION: SMITH's strength is the modular, reusable IT architecture based on interoperability standards, the integration of the hospitals' information management departments and the public-private partnership. The project aims at sustainability beyond the first 4-year funding period. PMID- 30016818 TI - German Medical Informatics Initiative. AB - This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. The Medical Informatics Initiative (MII) was launched within the scope of the German Federal Ministry of Education and Research's (BMBF) Medical Informatics Funding Scheme, with the goal of developing infrastructure for the integration of clinical data from patient care and medical research in Germany. Its work is to be performed over the course of a decade (2016-2025) across three funding phases, with the first two concentrating on university hospitals. During the conceptual phase (now concluded), a central supporting project ensured coordination - and laid the ground for standardised solutions for all the initiative's sites and scientific consortia that will enable effective data use and exchange, both for health care as well as research. The conceptual phase focused on the following: a) interoperability, through the consistent use of international standards (from an early stage, i.e. primary IT systems in patient care); b) standardised templates for patient consent and harmonised data protection; and c) standard rules for data use and access (monitoring and safeguarding access to data). On this basis, the initiative aims in the long term to improve medical research (particularly health care research, using data from treatments), to accelerate the transfer of knowledge from research to patient care - and to provide important impetus for the digitalization of medicine in Germany. PMID- 30016816 TI - Health Information Systems - from Present to Future? AB - This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. Funded by the German Federal Ministry of Education and Research with about 150 million Euro in its currently starting development and networking phase this initiative has already a significant impact on the development of health information systems in Germany. In this Focus Theme two editorials introduce this initiative, one from the viewpoint of its funding institution and one from the initiative's accompanying institutions. Then the initiative's four consortia DIFUTURE (Data Integration for Future Medicine), HiGHmed (Heidelberg-Gottingen-Hannover Medical Informatics), MIRACUM (Medical Informatics in Research and Care in University Medicine), and SMITH (Smart Medical Information Technology for Healthcare) present their concepts and plans. For better readability their manuscripts all contain three major sections on governance and policies, on architectural framework and methodology, and on use cases. As the German Medical Informatics Initiative is a large national experiment, we are convinced that communicating on this initiative already at this early stage to an international audience is of importance. PMID- 30016819 TI - Practice Variation in Antenatal Steroid Administration for Anticipated Late Preterm Birth: A Physician Survey. AB - OBJECTIVE: The objective of this study was to measure knowledge and practice variation in late preterm steroid use. STUDY DESIGN: Electronic survey of American College of Obstetricians and Gynecologists (ACOG) members about data supporting the ACOG/Society for Maternal-Fetal Medicine (SMFM) recommendations and practice when caring for women with anticipated late preterm birth (PTB), 340/7 to 366/7 weeks. RESULTS: Of 352 administered surveys, we obtained 193 completed responses (55%); 82.5% were generalist obstetrician-gynecologists (OB/GYNs), and 42% cared for women with anticipated late PTB at least weekly. Most believed that late preterm steroids provided benefit by reducing respiratory distress syndrome (93%), transient tachypnea of the newborn (83%), and neonatal intensive care unit admission (82%). More than half administered late preterm steroids to women with multiple gestations (73%), and pregestational diabetes (55 80%) depending on glycemic control. OB/GYNs administered steroids to insulin dependent and poorly controlled diabetics more often than MFMs (75 vs. 46% and 59 vs. 37% respectively, p < 0.05 for both). While providers believed there was increased maternal hyperglycemia (88%) and neonatal hypoglycemia (59%), 88% believed neonatal respiratory benefits outweighed these risks. Respondents agreed research is needed to determine who are appropriate candidates (77%) and how to minimize adverse outcomes (82%). CONCLUSION: Most providers are administering late preterm steroids to all women, even those populations who have been excluded from previous trials. Despite widespread use, providers believe more research is needed to optimize management. PMID- 30016820 TI - Outcomes after Neonatal Seizures in Infants Less Than 29 Weeks' Gestation: A Population-Based Cohort Study. AB - OBJECTIVE: The aim of this study was to evaluate the association between neonatal seizure and neurodevelopmental impairment (NDI) at 18 to 24 months in extremely preterm neonates. The association between anticonvulsants use and NDI was also assessed. STUDY DESIGN: In this retrospective cohort study of infants born at <29 weeks' gestation from the Canadian Neonatal Network and Canadian Neonatal Follow Up Network databases, we compared mortality and neurodevelopmental outcomes in infants who had neonatal seizures with those without seizures after adjusting for confounders. RESULTS: Of the 2,762 eligible neonates, 133 (4.8%) had seizures. Infants who had seizures were of lower gestation (25.2 vs. 26.2 weeks) and birth weight (819 vs. 920 g) and had higher rates of adverse outcomes. Neonatal seizure was associated with higher odds of composite outcome of death or significant NDI (74 vs. 27%; adjusted odds ratio [OR]: 3.4; 95% confidence interval [CI]: 2.2 5.4). Death or significant NDI was higher in infants with seizures treated with anticonvulsants than those without treatment (89 vs. 70%); however, when adjusted for confounders, it was not significantly different (adjusted OR: 3.5; 95% CI: 0.83-14.6). CONCLUSION: Neonatal seizures were independently associated with higher odds of death or significant NDI at 18 to 24 months of age. Relationship of anticonvulsant and neurodevelopmental outcomes needs further studies. PMID- 30016822 TI - Interdelivery Interval and Medically Indicated Preterm Delivery. AB - OBJECTIVE: The objective of this study was to examine whether a medically indicated preterm delivery is relatively more likely following longer interdelivery intervals. STUDY DESIGN: This is a case-control study of women with two consecutive deliveries of a live singleton at the same institution between 2005 and 2015, with the subsequent delivery occurring preterm. Preterm deliveries were classified as spontaneous if women delivered following preterm labor, preterm premature rupture of membranes, or placental abruption. Preterm deliveries were classified as medically indicated if women underwent delivery for fetal or maternal medical indications. Interdelivery interval was categorized as < 18, 18 to 59, and 60 months or more. Characteristics of women who had a medically indicated versus spontaneous preterm delivery were compared. RESULTS: Of the 1,276 women, 25.6% had a medically indicated preterm delivery and 74.4% had a spontaneous preterm delivery. Compared with women with an interdelivery interval of 18 to 59 months (of whom 25.7% had a preterm delivery for medical indications), women with a shorter interdelivery interval were less likely (19.3%), while women with a longer interdelivery interval were more likely (37.4%; p = 0.003) to have a medically indicated preterm delivery. This relationship persisted even when accounting for other factors. CONCLUSION: Preterm deliveries are more likely to be medically indicated as the interdelivery interval lengthens. PMID- 30016821 TI - Maternal and Fetal Death on Weekends. AB - BACKGROUND: Higher mortality rates have been reported in patients admitted to the hospital on weekends. This study aimed to compare maternal mortality ratio (MMR), fetal mortality ratio, and other maternal and neonatal outcomes by day of death or delivery in the United States. METHODS: Our database consisted of a population-level analysis of live births and maternal and fetal deaths between 2004 and 2014 in the United States from the Centers for Disease Control and Prevention's National Center for Health Statistics. We also examined the relationship between these deaths and various documented maternal and fetal clinical conditions. RESULTS: A total of 2,061 maternal deaths occurred on weekends and 5,510 deaths on weekdays. During the same period of time, 65,063 and 210,851 cases of fetal demise were delivered on weekends and on weekdays, respectively. Maternal mortality was significantly higher on weekends than weekdays (22.9 vs. 15.3/100,000 live births, p < 0.001) as was fetal mortality (7.21 vs. 5.85/100,000, p < 0.001), despite a lower frequency of serious comorbidities among women delivering on weekends. CONCLUSION: Our data demonstrate a significant increase in the U.S. MMR and stillbirth delivery on weekends. Relative representation of antepartum, intrapartum, and postpartum deaths cannot be ascertained from these data. PMID- 30016823 TI - Number of Risk Factors in Down Syndrome Pregnancies. AB - OBJECTIVE: The objective of this study was to evaluate risk factor prevalence in pregnancies with fetal Down syndrome, in an effort to characterize efficacy of population-based screening. STUDY DESIGN: Retrospective review of singleton pregnancies with delivery of live born or stillborn infant with Down syndrome from 2009 through 2015. Risk factor categories included maternal age >=35 years, abnormal serum screening, identification of >=1 ultrasound marker at 16 to 22 weeks (nuchal thickness >=6 mm, echogenic intracardiac focus, echogenic bowel, renal pelvis dilatation, femur length =1 ultrasound marker in 66 (53%), and >=1 anomaly in 41 (34%). The calculated risk was at least 1:270 in 93% of Down syndrome pregnancies. More pregnancies had multiple risk factors than had a single risk factor, 90 (72%) versus 30 (24%), p < 0.001. An abnormal ultrasound marker or anomaly was identified in >50% of fetuses in women <35 years and in >75% of those 35 years and older. CONCLUSION: In a population-based cohort, sensitivity of second-trimester Down syndrome screening was 93%, with multiple risk factors present in nearly three-fourths of cases. PMID- 30016824 TI - [Correction: Cost and Revenue Relationship in Orthopaedic and Trauma Surgery Patients in Relation to Body Mass Index]. PMID- 30016825 TI - Perioperative Care of the TKA Patient. PMID- 30016826 TI - Differential Modulation of Gene Expression Encoding Hepatic and Renal Xenobiotic Metabolizing Enzymes by an Aspalathin-Enriched Rooibos Extract and Aspalathin. AB - Modulation of the expression of hepatic and renal genes encoding xenobiotic metabolizing enzymes by an aspalathin-enriched green rooibos (Aspalathus linearis) extract (GRE) was investigated in the liver and kidneys of F344 rats following dietary exposure of 28 d, as well as selected xenobiotic metabolizing genes in rat primary hepatocytes. In the liver, GRE upregulated genes (p < 0.05) encoding aldehyde dehydrogenase, glucose phosphate isomerase, and cytochrome P450 while 17beta-hydroxysteroid dehydrogenase 2 (Hsd17beta2) was downregulated. In primary hepatocytes, GRE lacked any effect, while aspalathin downregulated Hsd17beta2, mimicking the effect of GRE in vivo, and upregulated catechol-O methyl transferase and marginally (p < 0.1) cytochrome P450 2e1. In the kidneys, GRE upregulated (p < 0.05) genes encoding the phase II xenobiotic metabolism enzymes, glutathione-S-transferase mu and microsomal glutathione-S-transferase, while downregulating genes encoding the ATP binding cassette transporter, cytochrome P450, gamma glutamyltransferase 1, and N-acetyltransferase 1. Differential modulation of the expression of xenobiotic metabolizing genes in vivo and in vitro by GRE is dose-related, duration of exposure, the tissue type, and interactions between specific polyphenol and/or combinations thereof. Aspalathin is likely to be responsible for the downregulation of estradiol and testosterone catabolism by GRE in the liver. The differential gene expression by GRE in the liver and kidneys could, depending on the duration exposure and dose utilized, determine the safe use of such an extract in humans for specific health and/or disease outcomes. PMID- 30016827 TI - Delitpyrones: alpha-Pyrone Derivatives from a Freshwater Delitschia sp. AB - In research focused on the discovery of new chemical diversity from freshwater fungi, a peak library was built and evaluated against a prostate cancer cell line, E006AA-hT, which was derived from an African American, as this population is disproportionately affected by prostate cancer. The chemical study of the bioactive sample accessioned as G858 (Delitschia sp.) led to the isolation of eight new alpha-pyrone derivatives (1: - 7: , and 11: ), as well as the new 3S*,4S*-7-ethyl-4,8-dihydroxy-3,6-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (15: ). In addition, the known compounds 5-(3-S-hydroxybutyl)-4-methoxy-6-methyl-2H pyran-2-one (8: ), 5-(3-oxobutyl)-4-methoxy-6-methyl-2H-pyran-2-one (9: ), pyrenocine I (10: ), 5-butyl-6-(hydroxymethyl)-4-methoxy-2H-pyran-2-one (12: ), sporidesmin A (13: ), 6-ethyl-2,7-dimethoxyjuglone (14: ), artrichitin (16: ), and lipopeptide 15G256epsilon (17: ) were also obtained. The structures of the new compounds were elucidated using a set of spectroscopic (NMR) and spectrometric (HRMS) methods. The absolute configuration of the most abundant member of each subclass of compounds was assigned through a modified Mosher's ester method. For 15: , the relative configuration was assigned based on analysis of 3J values. Compounds 1, 2, 5: - 14, 16: , and 17: were evaluated against the cancer cell line E006AA-hT under hypoxic conditions, where compound 13: inhibited cell proliferation at a concentration of 2.5 uM. PMID- 30016828 TI - Traditional Uses, Phytochemistry, and Antimicrobial Activities of Eugenia Species - A Review. AB - Antimicrobial resistance is a critical health problem, and pathogens responsible for common infections have developed resistance to antimicrobials, posing a threat to global health and placing a huge burden on health services. During the past two decades, the search for new bioactive agents in nature has become extremely important for promoting health and in the development of more efficient antimicrobials. The genus Eugenia is one of the largest in the Myrtaceae family, comprising approximately 1000 species from Mexico to Argentina, with a few species distributed in Australia and Africa. Eugenia species are used in folk medicine, with antidiabetic, antirheumatic, antipyretic, anti-inflammatory, antidiarrheal, antifungal, and antibacterial properties. This study systematically reviews the Eugenia species to compile the phytochemical composition and antimicrobial effects. In addition, we provide information regarding the traditional uses and cytotoxic activity of Eugenia species. We conducted a systematic literature search of specialized databases (Web of Science, Scielo, Lilacs, Pubmed, Science Direct, Scopus) and selected articles published between 1973 and 2015 using Eugenia and antimicrobial activity, Eugenia and toxicity, and Eugenia and chemical composition as key words. Ninety-three studies were included, and the phytochemical analyses from these studies show that Eugenia species are a rich source of flavonoids, tannins, triterpenes, and sesquiterpenes. Chemical constituents play an apparent role in the antimicrobial effects and reinforce the known antimicrobial potential of the Eugenia genus. It is worth mentioning that some Eugenia species cause significant cytotoxicity. PMID- 30016829 TI - Chemotherapy for metastatic testicular cancer: The first nationwide multi institutional study by the Cancer Registration Committee of the Japanese Urological Association. AB - OBJECTIVES: To assess clinicopathological data and oncological outcomes focused on metastatic testicular cancer patients, who received chemotherapy as the initial treatment, in the nationwide multi-institutional study by the Cancer Registration Committee of the Japanese Urological Association. METHODS: A testicular cancer survey was carried out by the Japanese Urological Association in 2011 to register newly diagnosed testicular cancers in 2005 and 2008. Among 1121 registered patients, 278 patients with metastases who received chemotherapy as the initial treatment and could be categorized by the Japanese Urological Association classification were eligible for the analysis. RESULTS: As first-line chemotherapy, bleomycin, etoposide and cisplatin, and etoposide and cisplatin therapies were chosen for 260 patients (93.5%). As second-line therapy, vinblastine, ifosfamide and cisplatin/etoposide, ifosfamide and cisplatin; and paclitaxel, ifosfamide and cisplatin/paclitaxel, ifosfamide and nedaplatin therapies were carried out in 23 out of 63 (36.5%) and 29 out of 63 (46.0%) patients, respectively. The response rate and serum tumor marker normalization rate were 93.4% and 81.3% at first line, 75.4% and 60.7% at second line, and 41.7% and 16.7% at third line, respectively. The Japanese Urological Association classification (>=IIIB2 vs <=IIIB1) and choriocarcinoma component in primary histology were independent prognostic factors of overall survival before starting chemotherapy. Furthermore, in patients with non-seminomatous germ cell tumors, serum tumor marker normalization was an independent factor that was associated with better outcome of overall survival after completion of the initial series of chemotherapies. CONCLUSIONS: The initial accurate diagnosis and risk stratification is an important prognostic factor to achieve better oncological outcomes. In patients with non-seminomatous germ cell tumors, aiming for serum tumor marker normalization with continuous sequential chemotherapy could improve overall survival. PMID- 30016831 TI - Special Monthly Compensation for Veterans With Traumatic Brain Injury. Final rule. AB - The Department of Veterans Affairs (VA) amends its adjudication regulations to add an additional compensation benefit for veterans with residuals of traumatic brain injury (TBI). This final rule incorporates in regulations a benefit authorized by the enactment of the Veterans' Benefits Act of 2010. The Veterans' Benefits Act authorizes special monthly compensation (SMC) for veterans with TBI who are in need of aid and attendance, and in the absence of suchaid and attendance, would require hospitalization, nursing home care, or other residential institutional care. PMID- 30016832 TI - Expanded Access to Non-VA Care Through the Veterans Choice Program. Final rule. AB - The Department of Veterans Affairs (VA) adopts as final, with no change, an interim final rule revising its medical regulations that implement section 101 of the Veterans Access, Choice, and Accountability Act of 2014, as amended, (hereafter referred to as "the Choice Act), which requires VA to establish a program (hereafter referred to as the Veterans Choice Program" or the "Program") to furnish hospital care and medical services through eligible non- VA health care providers to eligible veterans who either cannot be seen within the wait time goals of the Veterans Health Administration (VHA) or who qualify based on their place of residence or face an unusual or excessive burden in traveling to a VA medical facility. Those revisions contained in the interim final rule, which is now adopted as final, were required by amendments to the Choice Act made by the Construction Authorization and Choice Improvement Act of 2014, and by the Surface Transportation and Veterans Health Care Choice Improvement Act of 2015. VA published an interim final rule on December 1, 2015, implementing those regulatory revisions, and we received seven public comments. This final rule responds to those public comments and does not make any further regulatory revisions. PMID- 30016833 TI - Authority of Health Care Providers To Practice Telehealth. Final rule. AB - The Department of Veterans Affairs (VA) is amending its medical regulations by standardizing the delivery of care by VA health care providers through telehealth. This rule ensures that VA health care providers can offer the same level of care to all beneficiaries, irrespective of the State or location in a State of the VA health care provider or the beneficiary. This final rule achieves important Federal interests by increasing the availability of mental health, specialty, and general clinical care for all beneficiaries. PMID- 30016830 TI - Effect of mistimed eating patterns on breast and prostate cancer risk (MCC-Spain Study). AB - Modern life involves mistimed sleeping and eating patterns that in experimental studies are associated with adverse health effects. We assessed whether timing of meals is associated with breast and prostate cancer risk taking into account lifestyle and chronotype, a characteristic correlating with preference for morning or evening activity. We conducted a population-based case-control study in Spain, 2008-2013. In this analysis we included 621 cases of prostate and 1,205 of breast cancer and 872 male and 1,321 female population controls who had never worked night shift. Subjects were interviewed on timing of meals, sleep and chronotype and completed a Food Frequency Questionaire. Adherence to the World Cancer Research Fund/American Institute of Cancer Research recommendations for cancer prevention was examined. Compared with subjects sleeping immediately after supper, those sleeping two or more hours after supper had a 20% reduction in cancer risk for breast and prostate cancer combined (adjusted Odds Ratio [OR] = 0.80, 95%CI 0.67-0.96) and in each cancer individually (prostate cancer OR = 0.74, 0.55-0.99; breast cancer OR = 0.84, 0.67-1.06). A similar protection was observed in subjects having supper before 9 pm compared with supper after 10 pm. The effect of longer supper-sleep interval was more pronounced among subjects adhering to cancer prevention recommendations (OR both cancers= 0.65, 0.44-0.97) and in morning types (OR both cancers = 0.66, 0.49-0.90). Adherence to diurnal eating patterns and specifically a long interval between last meal and sleep are associated with a lower cancer risk, stressing the importance of evaluating timing in studies on diet and cancer. PMID- 30016834 TI - Medicare Program; Durable Medical Equipment Fee Schedule Adjustments To Resume the Transitional 50/50 Blended Rates To Provide Relief in Rural Areas and Non Contiguous Areas. Interim final rule with comment period. AB - This interim final rule with comment period makes technical amendments to the regulation to reflect the extension of the transition period from June 30, 2016 to December 31, 2016 that was mandated by the 21st Century Cures Act for phasing in fee schedule adjustments for certain durable medical equipment (DME) and enteral nutrition paid in areas not subject to the Durable Medical Equipment, Prosthetics, Orthotics, and Supplies (DMEPOS) Competitive Bidding Program (CBP). In addition, this interim final rule with comment period amends the regulation to resume the transition period's blended fee schedule rates for items furnished in rural areas and non-contiguous areas (Alaska, Hawaii, and United States territories) not subject to the CBP from June 1, 2018 through December 31, 2018. This interim final rule with comment period also makes technical amendments to existing regulations for DMEPOS items and services to reflect the exclusion of infusion drugs used with DME from the DMEPOS CBP. PMID- 30016835 TI - Medical Devices; Exemption From Premarket Notification: Class II Devices; Surgical Apparel. Final order. AB - The Food and Drug Administration (FDA or Agency) is publishing this final order to exempt certain surgical apparel from premarket notification requirements, subject to conditions and limitations. FDA is limiting the exemption to single use, disposable respiratory protective devices (RPD) used in a healthcare setting and worn by healthcare personnel during procedures to protect both the patient and the healthcare personnel from the transfer of microorganisms, body fluids, and particulate material. These devices, commonly referred to as N95 filtering facepiece respirators (FFRs) and surgical N95 respirators (herein collectively referred to as N95s) are currently regulated by FDA under product code MSH. This exemption will decrease regulatory burden on the medical device industry and will eliminate private costs and expenditures required to comply with certain Federal regulations. All other class II devices classified under FDA's surgical apparel classification regulation continue to be subject to premarket notification requirements. FDA is also amending the codified language for the surgical apparel devices classification regulation to reflect this final determination. PMID- 30016836 TI - Dr. Lighthall Responds. PMID- 30016837 TI - Making it Easier to Get it Right: Successful Prevention of Air-Oxygen Misconnections in Hospitals. PMID- 30016838 TI - Department of Error. PMID- 30016840 TI - Department of Error. PMID- 30016839 TI - Department of Error. PMID- 30016841 TI - Department of Error. PMID- 30016842 TI - Ultrastructure of the colon of Locusta migratoria. AB - The ultrastructure of the colon of Locusta migratoria is described. The colon is lined by a thick cuticle that, for the most part, adheres to the underlying epithelium. The cuboid epithelial cells are characterized by moderate invaginations of the apical and, to a lesser extent, basal plasma membranes; the lateral plasma membranes are relatively flat. The bulk of the mitochondria are located in the apical region of the cell and are not particularly associated with any of the plasma membranes. The basal region of the cells contains much rough endoplasmic reticulum, glycogenlike granules, and a predominance of spherical, electron-dense bodies of various sizes. Where muscle fibers make contact with the epithelium, the cells are much reduced; the cytoplasm is usually less electron dense, and, typically, the nucleus has a thick layer of granular material associated with the inner nuclear membrane. The apical and basal plasma membranes of the reduced epithelial cells contain numerous hemidesmosomes. The apical hemidesmosomes occur in pairs around an extracellular space that contains electron-opaque material. The latter forms tonofibrillae that extend into the endocuticle. Bundles of microtubules are associated with the hemidesmosomes. The tubules traverse the cell from the apical to the basal region. The possible significance of these findings is discussed. PMID- 30016843 TI - Antennal receptors in the blowfly Calliphora erythrocephala: II. Fine structure of the large pedicellar campaniform sensillum. AB - A large mechanosensory campaniform sensillum (LCS) is found close to the flagellum/pedicellus joint in the antennae of the blowfly Calliphora erythrocephala. The LCS possesses a single sensory cell, enveloping cells and a cuticular stimulus-conducting structure. The distal part of the sensory process is developed as a tubular body and is connected to the two parts of the stimulusconducting apparatus. The sensory cell is characterized by the complete absence of ciliary structures in the transition zone between dendrite and sensory process. PMID- 30016844 TI - Cellular and ultrastructural features of the regenerating adult eye in the marine gastropod llyanassa obsoleta. AB - Light and electron microscopic techniques were used to study the cellular and ultrastructural components of the regenerating adult eye of the marine prosobranch gastropod Ilyanassa obsoleta. Behavioral tests were used to determine return of vision in animals with generated eyes. As early as 3 days after removal of the adult eye, the regenerating eye primordium appeared as a pigmented mass of cells that invaginated from the surface epithelium in the area of the wound. Twelve days after eye removal, the regenerating eye was very similar to the postmetamorphic juvenile eye and to the adult eye: It contained a retinal layer, as well as an extracellular lens, cornea, connective tissue capsule, and forming optic nerve; vision had returned. Growth of the eye and its components was linear; size ratios established among forming eye components were maintained during growth. The events of eye regeneration appear to recapitulate embryonic eye formation. The sequence of invagination, pigmentation, and lens, optic nerve, and retinal pattern formation are similar. PMID- 30016845 TI - Allogeneic recognition in sponges: Development, structure, and nature of the nonmerging front in Ephydatia fluviatilis. AB - Whenever individuals of the freshwater sponge Ephydatia fluviatilis belonging to different strains come into contact, they reject each other by building a nonmerging front. The present work describes the development, the structure, and the nature of the barrier secreted between two individuals. The observations reported give unequivocal data about the collagen nature of the incompatibility barrier. First, ultrastructural investigations reveal the presence of fibrils and microfibrils which are, respectively, typical of collagen and spongin. Second, incorporation of tritiated proline, a characteristic precursor of collagen and related products, is particularly intense in the front. The involvement of several cell types in the barrier formation is discussed. The allogeneic incompatibility reaction between E. fluviatilis individuals appears very close to the process of allograft chronic rejection that we formerly described for some marine sponges. Both phenomena are basically analogous to the process which fixes to and isolates the sponges from their substrate. PMID- 30016846 TI - Antennal receptors in the blowfly Calliphora erythrocephala. I. The gigantic central projection of the pedicellar campaniform sensillum. AB - In the pedicellar segment of the fly antenna there is a large campaniform sensillum. The central projection of the sensory cell (LCC) of this large campaniform sensillum is described from labeling with horseradish peroxidase (HRP) and cobalt. The LCC projects bilaterally to several regions of the brain and subesophageal and thoracic ganglia. The LCC processes in these termination areas were analyzed in relation to other neural processes, including the remaining antennal sensory and motor projection. This analysis was aided by combining HRP labeling with Golgi silver impregnation. Based on earlier findings and the present data we suggest that the LCC, with its various outputs in, e.g., antennal and leg motor centers, serves as a multifunctional sensory path involved in control functions necessary in flight. PMID- 30016847 TI - Variation of lymphoid activity in the spleen of a migratory bird, the pied flycatcher (Ficedula hypoleuca; Aves, passeriformes). AB - The size and microscopic structure of the spleen of the migratory pied flycatcher (Ficedula hypoleuca) show marked changes during the reproductive cycle. Upon the spring return to their northern breeding sites, the birds have a small spleen with little lymphoid activity and a poorly developed red pulp. During the breeding period the volume of red and white pulp increases, the number and distinctness of lymphoid follicles (germinal centres) in the white pulp increase, and groups of cells with intensely basophilic cytoplasm, probably B cells (plasma cells), appear. The findings suggest that the immune system of the adult pied flycatcher is activated during periods when it is bound to the nest. Young flycatchers beginning their autumn migration also show a marked increase of lymphoid activity in the spleen. PMID- 30016848 TI - A Golgi study of anterior dorsal ventricular ridge in the alligator, Alligator mississippiensis. AB - The anterior dorsal ventricular ridge was examined in the American alligator, Alligator mississippiensis, with cresyl violet and Golgi-Kopsch preparations. Four cytoarchitectonic areas (lateral dorsolateral, medial dorsolateral, intermediolateral, and lateral) can be distinguished by variations in the density of neurons and their tendency to form clusters of neurons with apposed somata. Three distinct types of neurons are distributed throughout these areas. Juxtaependymal neurons lie near the ventricular surface and have dendritic fields paralleling the ependymal layer. Their dendrites bear a moderate density of spines. Spiny neurons all have stellate shaped dendritic fields and dendrites that bear dendritic spines, but they vary greatly in the density of spines and the thickness of their dendrites. A very spiny variety has a high spine density and relatively thick dendrites. A moderately spiny variety has a moderate spine density and thin dendrites. A sparsely spiny variety has a low spine density and thick dendrites. Aspiny neurons have a relatively large number of dendrites that form a gnarled dendritic field and lack spines. PMID- 30016849 TI - Ultrastructure of the spermatozoon and spermiogenesis in the interstitial annelid Potamodrilus fluviatilis. AB - The ultrastructure of spermatozoa and its genesis (spermiogenesis) have been investigated in the interstitial annelid Potamodrilus fluviatilis. The mature spermatozoa are threadlike cells which are bent at the base of the flagellum, giving the cell a hairpinlike appearance. The acrosome consists of an unusual, long, flasklike vesicle with a granum in its basal part. The cylindrical nuclear region is characterized by a monolayer of vesicles enwrapping the posterior half of the nucleus. This region is endowed with a number of altered rodlike mitochondria. No middlepiece is present. The basal body of the flagellum is obliquely arranged with respect to the long axis, giving rise to a curved flagellum, which, along most of its length, exhibits a thick layer of vacuolized cytoplasm around the axoneme. During spermiogenesis, which occurs in the body fluid, spermatids develop at the surface of syncytial masses which have been formed during meiotic divisions. The acrosome protrudes in the distal part of the cell, while the basal body of the flagellum is shifted toward the proximal region, which connects the cell with the cytophore. These are unusual features in annelid spermiogenesis. As indicated in Discussion, the phylogenetic implications of these findings include the assumption that Potamodrilus is not related to any oligochaete or even any other clitellate group or species and, hence, has to be excluded from these taxa. PMID- 30016850 TI - Cellular and ultrastructural features of the adult and the embryonic eye in the marine gastropod, Ilyanassa obsoleta. AB - Light and electron microscopic techniques show that the eye of the marine prosobranch gastropod, Ilyanassa obsoleta, is composed of an optic cavity, lens, cornea, retina, and neuropile, and is surrounded by a connective tissue capsule. The adult retina is a columnar epithelium containing three morphologically distinct cell types: photoreceptor, pigmented, and ciliated cells. The retina is continuous anteriorly with a cuboidal corneal epithelium. The neuropile, located immediately behind the retina, is composed of photoreceptor cell axons, accessory neurons, and their neurites. The embryonic eye is formed from surface ectoderm, which sinks inward as a pigmented cellular mass. At this time, the eye primordium already contains presumptive photoreceptor cells, pigmented retinal cells, and corneal cells. Several days later, just before hatching, the embryonic eye remains in intimate contact with the cerebral ganglion. It has no ciliated retinal cells, neuropile, optic nerve, or connective tissue capsule and its photoreceptor cells lack the electron-lucent vesicles and multivesicular bodies of adult photoreceptor cells. As the eye and the cerebral ganglion grow apart, the optic nerve, neuropile, and connective tissue capsule develop. PMID- 30016851 TI - Adrenergic innervation of the gills of brown and rainbow trout, Salmo trutta and S. gairdneri. AB - The adrenergic innervation of structures in the gills of brown and rainbow trout was studied with catecholamine fluorescence histochemistry. In the arterio arterial vascular pathway, there was an innervation of the afferent and efferent lamellar arterioles, but the afferent and efferent filamental arteries and the secondary lamellae were devoid of any fluorescent nerve fibres. In S. trutta only, there was an additional innervation of the afferent and efferent branchial arteries and the base of the efferent filamental artery. The innervation of the arterio-venous vascular pathway was similar in both trout species. Many fluorescent nerve fibres were found on nutritive arterioles in the gill arch and interbranchial septum, and in the core of each filament between the surface epithelium and the wall of the filament venous sinus. No fluorescent nerve fibres were observed at the origins of the capillaries arising from the efferent filamental artery. The sympathetic nerve supply is provided to the gills mainly through the posttrematic nerve, with an occasional small contribution through the pretrematic nerve. The presence of adrenergic nerves in the gills is discussed in relation to the regulation of blood flow through the arterio-arterial and arterio venous pathways. PMID- 30016852 TI - Skeletal muscle-gut axis: emerging mechanisms of sarcopenia for intestinal and extra intestinal diseases. AB - In recent years, there has been an increasing interest on muscle wasting, considering the reduction of quality of life and the increase of morbidity and mortality associated. Sarcopenia and cachexia represent two conditions of reduction of muscle mass, sharing several elements involved in their pathogenesis, such as systemic inflammation, impaired muscle protein synthesis, increased muscle apoptosis, mitochondrial dysfunction in skeletal muscle tissue and insulin resistance. These features often characterize cancer, inactivity or denervation, but also inflammatory diseases, such as chronic obstructive pulmonary disease, renal failure, cardiac failure, rheumatoid arthritis, inflammatory bowel disease and aging in general. The gastrointestinal tract and gut microbiota are thought to be deeply associated with muscle function and metabolism, although the exact mechanisms that link gut with skeletal muscle are still not well known. This review summarized the potential pathways linking gut with muscle, in particular in conditions as sarcopenia and cachexia. The main emerging pathways implicated in the skeletal muscle-gut axis are: the myostatin/activin signaling pathway, the IGF1/PI3K/AKT/mTOR signaling pathway, which results suppressed, the NF-kB signaling pathway and the FOXO signaling pathway. Further researches in this field are necessary to better explain the linkage between gut microbiota and muscle wasting and the possible emerging therapies associated. PMID- 30016853 TI - Improving the value of ultrasound in children with suspected appendicitis: a prospective study integrating secondary sonographic signs. AB - Purpose: The purpose of this study was to determine whether the awareness and inclusion of secondary sonographic signs of appendicitis, in combination with a structured evaluation as part of engagement and training for sonographers, improved appendix visualization rates and reduced equivocal findings in children with suspected acute appendicitis. Methods: This was a prospective study of 230 children at a tertiary children's hospital in Australia referred for an ultrasound examination of suspected appendicitis. The ultrasound findings, radiology reports, histology, clinical results, and follow-up were collated. Secondary signs were used as an additional assessment of the likelihood of disease where possible, even in the absence of an identified appendix. Results: The implementation of a structured evaluation as part of sonographer engagement and training resulted in a 28% improvement in appendix visualization (68.7%) compared with a prior retrospective study in a similar population (40.7%). The diagnostic accuracy was 91.7%, with likelihood ratios suggesting a meaningful influence of the pre-test probability of appendicitis in children studied (positive likelihood ratio, 11.22; negative likelihood ratio, 0.09.). Only 7.8% of the findings were equivocal. A binary 6-mm diameter cut-off did not account for equivocal cases, particularly lymphoid hyperplasia. Conclusion: Engagement of sonographers performing pediatric appendiceal ultrasound through training in the scanning technique and awareness of secondary signs significantly improved the visualization rate and provided more meaningful findings to referrers. PMID- 30016854 TI - Examiner seniority and experience are associated with bias when scoring communication, but not examination, skills in objective structured clinical examinations in Australia. AB - PURPOSE: The biases that may influence objective structured clinical examination (OSCE) scoring are well understood, and recent research has attempted to establish the magnitude of their impact. However, the influence of examiner experience, clinical seniority, and occupation on communication and physical examination scores in OSCEs has not yet been clearly established. METHODS: We compared the mean scores awarded for generic and clinical communication and physical examination skills in 2 undergraduate medicine OSCEs in relation to examiner characteristics (gender, examining experience, occupation, seniority, and speciality). The statistical significance of the differences was calculated using the 2-tailed independent t-test and analysis of variance. RESULTS: Five hundred and seventeen students were examined by 237 examiners at the University of New South Wales in 2014 and 2016. Examiner gender, occupation (academic, clinician, or clinical tutor), and job type (specialist or generalist) did not significantly impact scores. Junior doctors gave consistently higher scores than senior doctors in all domains, and this difference was statistically significant for generic and clinical communication scores. Examiner experience was significantly inversely correlated with generic communication scores. CONCLUSION: We suggest that the assessment of examination skills may be less susceptible to bias because this process is fairly prescriptive, affording greater scoring objectivity. We recommend training to define the marking criteria, teaching curriculum, and expected level of performance in communication skills to reduce bias in OSCE assessment. PMID- 30016855 TI - Comparison of the Minimum Plateau Width by Plateau and a New Method in People with Conductive Hearing Loss. AB - BACKGROUND AND OBJECTIVES: In clinical masking, the plateau is a state in which the non-test ear (NTE) is completely masked by the noise and tone is heard only by the test ear (TE). At least 15 to 20 dB of plateau width is needed to obtain valid threshold. In the study, a part of plateau after initial masking level known as the minimum plateau width (mPW) was determined and compared by a new formula and the plateau searching method. Subjects and. METHODS: Minimum plateau widths of air conduction were obtained in 29 participants with unilateral and 30 participants with bilateral conductive hearing loss (CHL) aged 20 to 45 years old by using step by step plateau method and mPW estimation by the formula between two points of masking diagram [mPW=(N2-N1)-(T2-T1)] and then the mPW of two methods was compared for each frequency. RESULTS: There was no significant difference between the minimum plateau width obtained by the plateau and formula methods for two given point of masking diagram in people with unilateral and bilateral CHL at octave frequencies from 500 Hz to 4,000 Hz. CONCLUSIONS: Threshold obtaining of TE by two tones for two noise levels delivered to the NTE is enough to estimate the mPW between these two noise points and it is not necessary that for clinicians to know the actual values of masking diagram components. PMID- 30016857 TI - Unusual Tumors Obstructing the External Auditory Canal: Report of Two Cases. AB - Primary tumors arising from the external auditory canal (EAC) are rare. We describe two cases of mass lesions within the EAC causing slowly progressive hearing loss without otorrhea or otalgia. Otoendoscopic examination demonstrated total obstruction of the EAC, and pure tone audiometry revealed conductive hearing loss. Based on the findings of the histopathologic examination, one patient was diagnosed with venous hemangioma that was treated using surgical resection, and the other patient was diagnosed with diffuse large B-cell lymphoma (DLBCL) that was treated using external-beam radiation therapy. Although primary tumors in the EAC are rare, both benign tumors such as venous hemangiomas and malignant lesions such as DLBCL should be considered as possible differential diagnoses of mass lesions in the EAC. PMID- 30016856 TI - The Effects of the Vestibular Rehabilitation on the Benign Paroxysmal Positional Vertigo Recurrence Rate in Patients with Otolith Dysfunction. AB - BACKGROUND AND OBJECTIVES: Although repositioning maneuvers have shown remarkable success rate in treatments of benign paroxysmal positional vertigo (BPPV), the high recurrence rate of BPPV has been an important issue. The aims of present study were to examine the effects of otolith dysfunction on BPPV recurrence rate and to describe the effect of vestibular rehabilitation exercises on BPPV recurrence in BPPV patients with concomitant otolith dysfunction. Subjects and. METHODS: Forty-five BPPV patients included in this study (three groups). Patients in group 1 had no otolith dysfunction and patients in groups 2 and 3 had concomitant otolith dysfunction. Otolith dysfunction was determined with ocular/cervical vestibular evoked myogenic potential (oVEMP and cVEMP) abnormalities. Epley's maneuver was performed for the patients in all groups but patients in group 3 also received a 2-month vestibular rehabilitation program (habituation and otolith exercises). RESULTS: This study showed that BPPV recurrent rate was significantly higher in patients with otolith dysfunction in comparison to the group 1 (p<0.05). Vestibular rehabilitation resulted in BPPV recurrence rate reduction. Utricular dysfunction showed significant correlation with BPPV recurrence rate. CONCLUSIONS: Otolith dysfunction can increase BPPV recurrence rate. Utricular dysfunction in comparison to saccular dysfunction leads to more BPPV recurrence rate. Vestibular rehabilitation program including habituation and otolith exercises may reduce the chance of BPPV recurrence. PMID- 30016859 TI - Activity, Selectivity, and Durability of Ruthenium Nanoparticle Catalysts for Ammonia Synthesis by Reactive Molecular Dynamics Simulation: The Size Effect. AB - We report a molecular dynamics (MD) simulation employing the reactive force field (ReaxFF), developed from various first-principles calculations in this study, on ammonia (NH3) synthesis from nitrogen (N2) and hydrogen (H2) gases over Ru nanoparticle (NP) catalysts. Using ReaxFF-MD simulations, we predict not only the activities and selectivities but also the durabilities of the nanocatalysts and discuss the size effect and process conditions (temperature and pressure). Among the NPs (diameter = 3, 4, 5, and 10 nm) considered in this study, the 4 nm NPs show the highest activity, in contrast to our intuition that the smallest NP should provide the highest activity, as it has the highest surface area. In addition, the best selectivity is observed with the 10 nm NPs. The activity and selectivity are mainly determined by the hcp, fcc, and top sites on the Ru NP surface, which depend on the NP size. Moreover, the selectivity can be improved more significantly by increasing the H2 pressure than by increasing the N2 pressure. The durability of the NPs can be determined by the mean stress and the stress concentration, and these two factors have a trade-off relationship with the NP size. In other words, as the NP size increases, its mean stress decreases, whereas the stress concentration simultaneously increases. Because of these two effects, the best durability is found with the 5 nm NPs, which is also in contrast to our intuition that larger NPs should show better durability. We expect that ReaxFF-MD simulations, along with first-principles calculations, could be a useful tool in developing novel catalysts and understanding catalytic reactions. PMID- 30016858 TI - Prognostic Significance of EPHB2 Expression in Colorectal Cancer Progression. AB - BACKGROUND: A receptor tyrosine kinase for ephrin ligands, EPHB2, is expressed in normal colorectal tissues and colorectal cancers (CRCs). The aim of this study was to investigate EPHB2 expression over CRC progression and determine its prognostic significance in CRC. METHODS: To measure EPHB2 mRNA and protein expression, real-time polymerase chain reaction and immunohistochemistry were performed in 32 fresh-frozen and 567 formalin-fixed paraffin-embedded CRC samples, respectively. We further investigated clinicopathological features and overall and recurrence-free survival according to EPHB2 protein expression. RESULTS: The EPHB2 level was upregulated in CRC samples compared to non-cancerous tissue in most samples and showed a strong positive correlation with AXIN2. Notably, CD44 had a positive association with both mRNA and protein levels of EPHB2. Immunohistochemical analysis revealed no difference in EPHB2 expression between adenoma and carcinoma areas. Although EPHB2 expression was slightly lower in invasive fronts compared to surface area (p < .05), there was no difference between superficial and metastatic areas. EPHB2 positivity was associated with lymphatic (p < .001) and venous (p = .001) invasion, TNM stage (p < .001), and microsatellite instability (p = .036). Kaplan-Meier analysis demonstrated that CRC patients with EPHB2 positivity showed better clinical outcomes in both overall (p = .049) and recurrence-free survival (p = .015). However, multivariate analysis failed to show that EPHB2 is an independent prognostic marker in CRCs (hazard ratio, 0.692; p = .692). CONCLUSIONS: Our results suggest that EPHB2 is overexpressed in a subset of CRCs and is a significant prognostic marker. PMID- 30016860 TI - Development of Novel Monoamine Oxidase-B (MAO-B) Inhibitors with Reduced Blood Brain Barrier Permeability for the Potential Management of Noncentral Nervous System (CNS) Diseases. AB - Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that do not permeate the blood brain barrier (BBB) the MAO-B-selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a CO2H function, and incorporating a para OCH2Ar motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CH2CN. In vitro, 10c, 10j, 10k, and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal, and hepatocyte stability assays. In vivo, they demonstrated greater plasma bioavailability. Assessment of in vitro BBB permeability showed that compound 10k is a P-glycoprotein (P-gp) substrate and 10j displayed mild interaction. Importantly, compounds 10c, 10j, 10k, and 32 displayed significantly reduced BBB permeability after intravenous, subcutaneous, and oral administration. These polar MAO-B inhibitors are pertinent leads for evaluation of efficacy in noncentral nervous system (CNS) inflammatory disease models. PMID- 30016861 TI - Carboxylesterase-2-Selective Two-Photon Ratiometric Probe Reveals Decreased Carboxylesterase-2 Activity in Breast Cancer Cells. AB - Human carboxylesterase-2 (CE2) is a carboxylesterase that catalyzes the hydrolysis of endogenous and exogenous substrates. Abnormal CE2 levels are associated with various cancers, and CE2 is a key mediator of anticancer prodrugs, including irinotecan. Here, we developed a two-photon ratiometric probe for detecting CE2 activity using succinate ester as a recognition site for CE2. The probe showed high selectivity to CE2, a clear emission color change, high photostability, and bright two-photon microscopy (TPM) imaging capability, allowing the quantitative detection of CE2 activity in live cells. Using TPM ratio analysis, we show for the first time that CE2 activity was much lower in breast cancer cells than in normal cells. In CE2 overexpression studies, cancer cells had a markedly enhanced sensitivity to the cytotoxic effect of irinotecan, corresponding well with the TPM ratio of the probe. These results may provide useful information for quantitatively measuring CE2 activity in situ and predicting the responsiveness to anticancer drugs. PMID- 30016863 TI - Multiorder Stimulated Raman Scattering in Colliding Droplets. AB - Nonlinear Raman spectroscopy is a versatile method to enhance the intensities of Raman scattering. It requires an intense light field that can be provided by a liquid droplet acting as a high-quality optical cavity. Here, colliding droplets were used as a novel optical cavity to enhance the intensity of Raman scattering. Specifically, multiorder stimulated Raman-scattered light was generated with significant intensity from colliding droplets of carbon tetrachloride (CCl4). The intensities of the Raman bands were analyzed with a simple theory that roughly reproduced the experimental spectrum. Overall, the method facilitates Raman spectroscopy of molecules in liquids because of its high sensitivity and resolution. PMID- 30016862 TI - Insights into Interfacial Synergistic Catalysis over Ni@TiO2- x Catalyst toward Water-Gas Shift Reaction. AB - The mechanism on interfacial synergistic catalysis for supported metal catalysts has long been explored and investigated in several important heterogeneous catalytic processes (e.g., water-gas shift (WGS) reaction). The modulation of metal-support interactions imposes a substantial influence on activity and selectivity of catalytic reaction, as a result of the geometric/electronic structure of interfacial sites. Although great efforts have validated the key role of interfacial sites in WGS over metal catalysts supported on reducible oxides, direct evidence at the atomic level is lacking and the mechanism of interfacial synergistic catalysis is still ambiguous. Herein, Ni nanoparticles supported on TiO2- x (denoted as Ni@TiO2- x) were fabricated via a structure topotactic transformation of NiTi-layered double hydroxide (NiTi-LDHs) precursor, which showed excellent catalytic performance for WGS reaction. In situ microscopy was carried out to reveal the partially encapsulated structure of Ni@TiO2- x catalyst. A combination study including in situ and operando EXAFS, in situ DRIFTS spectra combined with TPSR measurements substantiates a new redox mechanism based on interfacial synergistic catalysis. Notably, interfacial Ni species (electron-enriched Nidelta- site) participates in the dissociation of H2O molecule to generate H2, accompanied by the oxidation of Nidelta--O v-Ti3+ (O v: oxygen vacancy) to Nidelta+-O-Ti4+ structure. Density functional theory calculations further verify that the interfacial sites of Ni@TiO2- x catalyst serve as the optimal active site with the lowest activation energy barrier (~0.35 eV) for water dissociation. This work provides a fundamental understanding on interfacial synergistic catalysis toward WGS reaction, which is constructive for the rational design and fabrication of high activity heterogeneous catalysts. PMID- 30016864 TI - Inherent Acidity of Perfluorosulfonic Acid Ionomer Dispersions and Implications for Ink Aggregation. AB - Perfluorosulfonic acid (PFSA) dispersions are used as components in a variety of electrochemical technologies, particularly in fuel-cell catalyst-layer inks. In this study, we characterize dispersions of a common PFSA, Nafion, as well as inks of Nafion and carbon. It is shown that solvent choice affects a dispersion's measured pH, which is found to scale linearly with Nafion loading. Dispersions in water-rich solvents are more acidic than those in propanol-rich solvents: a 90% water versus 30% water dispersion can have up to a 55% measured proton deviation. Furthermore, because electrostatic interactions are a function of pH, these differences affect how particles aggregate in solution. Despite having different water contents, all inks studied demonstrate the same particle size and surface charge trends as a function of pH, thus providing insights into the relative influence of solvent and pH effects on these properties. PMID- 30016865 TI - Going beyond Structure: Nickel-Substituted Rubredoxin as a Mechanistic Model for the [NiFe] Hydrogenases. AB - Well-defined molecular systems for catalytic hydrogen production that are robust, easily generated, and active under mild aqueous conditions remain underdeveloped. Nickel-substituted rubredoxin (NiRd) is one such system, featuring a tetrathiolate coordination environment around the nickel center that is identical to the native [NiFe] hydrogenases and demonstrating hydrogenase-like proton reduction activity. However, until now, the catalytic mechanism has remained elusive. In this work, we have combined quantitative protein film electrochemistry with optical and vibrational spectroscopy, density functional theory calculations, and molecular dynamics simulations to interrogate the mechanism of H2 evolution by NiRd. Proton-coupled electron transfer is found to be essential for catalysis. The coordinating thiolate ligands serve as the sites of protonation, a role that remains debated in the native [NiFe] hydrogenases, with reduction occurring at the nickel center following protonation. The rate determining step is suggested to be intramolecular proton transfer via thiol inversion to generate a NiIII-hydride species. NiRd catalysis is found to be completely insensitive to the presence of oxygen, another advantage over the native [NiFe] hydrogenase enzymes, with potential implications for membrane-less fuel cells and aerobic hydrogen evolution. Targeted mutations around the metal center are seen to increase the activity and perturb the rate-determining process, highlighting the importance of the outer coordination sphere. Collectively, these results indicate that NiRd evolves H2 through a mechanism similar to that of the [NiFe] hydrogenases, suggesting a role for thiolate protonation in the native enzyme and guiding rational optimization of the NiRd system. PMID- 30016866 TI - Structure Based Modulation of Electron Dynamics in meso-(4-Pyridyl)-BODIPYs: A Computational and Synthetic Approach. AB - The effects of structural modification on the electronic structure and electron dynamics of cationic meso-(4-pyridyl)-BODIPYs were investigated. A library of 2,6 difunctionalized meso-(4-pyridyl)-BODIPYs bearing various electron-withdrawing substituents was designed, and DFT calculations were used to model the redox properties, while TDDFT was used to determine the effects of functionalization on the excited states. Structural modification was able to restructure the low-lying molecular orbitals to effectively inhibit d-PeT. A new meso-(4-pyridyl)-BODIPY bearing 2,6-dichloro groups was synthesized and shown to exhibit enhanced charge recombination fluorescence. The fluorescence enhancement was determined to be the result of functionalization modulating the kinetics of the excited state dynamics. PMID- 30016867 TI - Self-Assembling Hydrophilic Magnetic Covalent Organic Framework Nanospheres as a Novel Matrix for Phthalate Ester Recognition. AB - The development of covalent organic framework (COF)-derived materials with additional functions and applications is highly desired. In this work, a unique COF-functionalized hydrophilic magnetic nanosphere (Fe3O4@PDA@TbBd) with Fe3O4 as a magnetic core, polydopamine (PDA) as a hydrophilic middle layer, and TbBd as an outer COF shell was facilely prepared as a novel hydrophilic platform for efficient detection of phthalic acid esters (PAEs). The resultant Fe3O4@PDA@TbBd nanosphere displayed strong magnetic response, high surface area, and good hydrophilicity. Accordingly, the newly synthesized COF exhibited great potential in phthalate analysis with a wide linearity (50-8000 ng/mL), good recovery (92.3 98.9%), a low limit of detection (0.0025-0.01 ng/mL), and a small relative standard deviation (for intraday less than 4.6% and for interday less than 6.8%). More excitingly, the new COF was applied to analyze nine PAEs in the human plasma sample. This work opens up new avenues for the development and application of functionalized COF-derived materials. PMID- 30016868 TI - Mechanisms of Physical Stabilization of Concentrated Water-In-Oil Emulsions Probed by Pulse Field Gradient Nuclear Magnetic Resonance and Rheology through a Multiscale Approach. AB - The long-term physical stability of surfactant-stabilized (Span 80 and Tween 20) concentrated water-in-mineral oil (W/O) emulsions in the presence of an electrolyte (NaCl) was studied. Pulse field gradient NMR and rheology (bulk and interfacial) were used to probe the response at the macroscopic, microscopic, and molecular levels, rendering a multiscale approach. The results show that: (1) Emulsions prepared with NaCl exhibit higher values of the elastic shear modulus ( Gwith NaCl' > Gwithout NaCl') even after ~20 days. (2) The stabilization effect of salt against the coarsening of droplets is not due to the differences in droplet size (and thus G') or the energy incorporated through emulsification. (3) NaCl relaxes the liquid-liquid interface via a salting-in effect, which results in a lower interfacial shear elasticity ( Gwith NaCls' < Gwithout NaCls') and a higher resistance to coarsening events because of the changes in the adsorption density of the layer. PMID- 30016869 TI - Amplified Tandem Spinach-Based Aptamer Transcription Enables Low Background miRNA Detection. AB - MicroRNAs (miRNAs) play key roles in regulating gene expression and cell functions, which are recognized as potential biomarkers for many human diseases. Sensitive, specific, and reliable detection of miRNA is highly demanded for clinical diagnosis and therapy. Herein, we describe a label-free and low background fluorescent assay, termed amplified tandem Spinach-based aptamer transcription assay (AmptSpi assay) for highly sensitive miRNA detection by polymeric rolling circle amplicon mediated multiple transcription. Target miRNA is recognized by padlock probe to form polymeric rolling circle amplicon. Then the following transcription process rapidly produces large amounts of repeats of RNA Spinach aptamers, lightened up by the addition of fluorescent dye DFHBI for miRNA quantitative analysis, achieving label-free and nearly zero-background. Besides, the assay could also confer high selectivity to distinguish miRNA among the miRNA family members with 1- or 2-nucleotide (nt) difference. This method was capable of completing detection in human serum sample or cell extracts in hours, indicating great potential in the early diagnosis of diseases. PMID- 30016870 TI - Fe-T1 Sensor Based on Coordination Chemistry for Sensitive and Versatile Bioanalysis. AB - The main challenge of paramagnetic ions-mediated magnetic sensors is their relatively low sensitivity. In this study, we observe the amplification of longitudinal relaxation time (T1) signal when Fe2+ transforms into Fe3+ followed by the coordination of potassium thiocyanate (KSCN) and develop a sensitive Fe-T1 sensor based on the coordination chemistry between KSCN and Fe3+ to amplify the T1 signal for detecting a series of targets, such as hydrogen peroxide, glucose, and antigen/antibody. We justify the practicability of our assay by successfully detecting tetracycline in milk samples and hepatitis C virus in clinical samples with satisfactory accuracy. This KSCN-mediated Fe-T1 sensor not only realizes biochemical analysis and immunoassay with higher sensitivity but also retains many advantages of paramagnetic ions-mediated magnetic sensors (good stability and straightforward operation), which holds great promise for the detection of a range of targets of interest in complex samples. PMID- 30016871 TI - How Implementation of Entropy in Driving Structural Ordering of Nanoparticles Relates to Assembly Kinetics: Insight into Reaction-Induced Interfacial Assembly of Janus Nanoparticles. AB - The ability to understand and exploit entropic contributions to ordering transition is of essential importance in the design of self-assembling systems with well-controlled structures. However, much less is known about the role of assembly kinetics in entropy-driven phase behaviors. Here, by combining computer simulations and theoretical analysis, we report that the implementation of entropy in driving phase transition significantly depends on the kinetic process in the reaction-induced self-assembly of newly designed nanoparticle systems. In particular, such systems comprise binary Janus nanoparticles at the fluid-fluid interface and undergo phase transition driven by entropy and controlled by the polymerization reaction initiated from the surfaces of just one component of nanoparticles. Our simulations demonstrate that the competition between the reaction rate and the diffusive dynamics of nanoparticles governs the implementation of entropy in driving the phase transition from randomly mixed phase to intercalated phase in these interfacial nanoparticle mixtures, which thereby results in diverse kinetic pathways. At low reaction rates, the transition exhibits abrupt jump in the mixing parameter, in a similar way to first-order, equilibrium phase transition. Increasing the reaction rate diminishes the jumps until the transitions become continuous, behaving as a second-order-like phase transition, where a critical exponent, characterizing the transition, can be identified. We finally develop an analytical model of the blob theory of polymer chains to complement the simulation results and reveal essential scaling laws of the entropy-driven phase behaviors. In effect, our results allow for further opportunities to amplify the entropic contributions to the materials design via kinetic control. PMID- 30016872 TI - Measurement of Cell-Matrix Adhesion at Single-Cell Resolution for Revealing the Functions of Biomaterials for Adherent Cell Culture. AB - Cell adhesion is essential for a cell to maintain its functions, and biomaterials acting as the extracellular matrix (ECM) play a vital role. However, conventional methods for evaluating the functions of biomaterials become insufficient and sometimes incorrect when we give a deeper insight into single-cell research. In this work, we reported a novel methodology for the measurement of cell-matrix adhesion at single-cell resolution that could precisely evaluate the functions of biomaterials for adherent cell culture. A microfludic device, a live single-cell extractor (LSCE), was used for cell extraction. We applied this method to evaluate various modified biomaterials. The results indicated that poly(l polylysine) (PLL)-coated glass and fibronection (FN)-coated glass slides showed the best biocompatibility for adherent cell culture following by the (3 aminopropyl)triethoxysilane (APTES)-coated glass, while piranha solution treated glass slide and octadecyltrichlorosilane (OTS)-coated glass showed weak biocompatibilities. Furthermore, APTES, PLL, and FN modifications enhanced the cell heterogeneity, while the OTS modification weakened the cell heterogeneity compare to the initial piranha solution treated glass. The method not only clarified the cell-matrix adhesion strength at single-cell resolution but also revealed the influences of biomaterials on cell-matrix adhesion and heterogeneity of cell-matrix adhesion for adherent cell culture. It might be a general strategy for precise evaluation of biomaterials. PMID- 30016874 TI - 2018: A New Impact Factor and an Expanded Cast of Associate Editors. PMID- 30016873 TI - In This Issue, Volume 9, Issue 7. PMID- 30016875 TI - New 2017 Data and Statistics for Pharmaceutical Products. PMID- 30016878 TI - Corrigendum. AB - Galabov AS, Mukova L, Abashev YP, Wassilewa L, Tzvetkov P, Minkov V, Barinskiy IF, Ouzounov S, Sidzhakova D. Cycluridine: A novel antiviral effective against flaviviruses. Antivir. Chem. Chemother 2017; 25: 58-67. DOI: 10.1177/2040206617723442 The authors acknowledge that Charles M Rice did not co author or contribute to this article and was erroneously listed as co-author. The correct authorship is indicated above. The article has been corrected. PMID- 30016879 TI - Allogeneic Mesenchymal Stromal Cells (MSCs) are of Comparable Efficacy to Syngeneic MSCs for Therapeutic Revascularization in C57BKSdb/db Mice Despite the Induction of Alloantibody. AB - Intramuscular administration of mesenchymal stromal cells (MSCs) represents a therapeutic option for diabetic critical limb ischemia. Autologous or allogeneic approaches may be used but disease-induced cell dysfunction may limit therapeutic efficacy in the former. Our aim was to compare the efficacy of allogeneic and autologous MSC transplantation in a model of hindlimb ischemia in diabetes mellitus and to determine whether allogeneic transplantation would result in the activation of an immune response. MSCs were isolated from C57BL/6 (B6) and diabetic obese C57BKSdb/db mice. Phosphate-buffered saline (control group), and MSCs (1 * 106) from B6 (allogeneic group) or C57BKSdb/db (syngeneic group) were administered intramuscularly into the ischemic thigh of C57BKSdb/db mice following the induction of hindlimb ischemia. MSCs derived from both mouse strains secrete several angiogenic factors, suggesting that the potential therapeutic effect is due to paracrine signaling. Administration of allogeneic MSCs significantly improved blood perfusion as compared with the control group on week 2 and 3, post-operatively. In comparison with the control group, syngeneic MSCs significantly improved blood perfusion at week 2 only. There was no statistical difference in blood perfusion between allogeneic and syngeneic MSC groups at any stages. There was no statistical difference in ambulatory and necrosis score among the three groups. Amputation of toes was only observed in the control group (one out of seven animals). Alloantibody was detected in three out of the eight mice that received allogeneic MSCs but was not observed in the other groups. In summary, we demonstrated comparable efficacy after transplantation of autologous and allogeneic MSCs in a diabetic animal model despite generation of an immune response. PMID- 30016877 TI - Continuous Inhalation Exposure to Fungal Allergen Particulates Induces Lung Inflammation While Reducing Innate Immune Molecule Expression in the Brainstem. AB - Continuous exposure to aerosolized fine (particle size <=2.5 um) and ultrafine (particle size <=0.1 um) particulates can trigger innate inflammatory responses in the lung and brain depending on particle composition. Most studies of manmade toxicants use inhalation exposure routes, whereas most studies of allergens use soluble solutions administered via intranasal or injection routes. Here, we tested whether continuous inhalation exposure to aerosolized Alternaria alternata particulates (a common fungal allergen associated with asthma) would induce innate inflammatory responses in the lung and brain. By designing a new environmental chamber able to control particle size distribution and mass concentration, we continuously exposed adult mice to aerosolized ultrafine Alternaria particulates for 96 hr. Despite induction of innate immune responses in the lung, induction of innate immune responses in whole brain samples was not detected by quantitative polymerase chain reaction or flow cytometry. However, exposure did trigger decreases in Arginase 1, inducible nitric oxide synthase, and tumor necrosis factor alpha mRNA in the brainstem samples containing the central nervous system respiratory circuit (the dorsal respiratory group, ventral respiratory group, and the pre-Botzinger and Botzinger complexes). In addition, a significant decrease in the percentage of Toll-like receptor 2-expressing brainstem microglia was detected by flow cytometry. Histologic analysis revealed a significant decrease in Iba1 but not glial fibrillary acidic protein immunoreactivity in both the brainstem and the hippocampus. Together these data indicate that inhalation exposure to a natural fungal allergen under conditions sufficient to induce lung inflammation surprisingly causes reductions in baseline expression of select innate immune molecules (similar to that observed during endotoxin tolerance) in the region of the central nervous system controlling respiration. PMID- 30016880 TI - Inhaler usability of a pressurized metered dose inhaler and a soft mist inhaler in patients with COPD: A simulated-use study. AB - The objective of this study was to evaluate task performance and handling errors with soft mist inhalers (SMIs) or pressurized metered-dose inhalers (pMDIs) among patients with chronic obstructive pulmonary disease (COPD) experienced with, but not recently trained in, using these devices. This exploratory, noninterventional, simulated-use study (D5970R00004) assessed handling/usability of SMIs and pMDIs in inhaler-experienced patients with COPD (40-78 years; diagnosis >=6 months). Patients received a device and instruction-for-use leaflet but no training and were recorded while performing tasks required for checking the device, priming, and dosing. Errors that could substantially affect the lung delivered dose were considered critical. Sixteen of 61 patients (52% male) had used SMIs and 55 had used pMDIs. Thirty-one patients received an SMI and 30 a pMDI. Overall, 79% made >=5 performance errors (SMI 94%; pMDI 63%) and 49% made >=5 critical errors (SMI 68%; pMDI 30%). All patients made >=1 error; three (all pMDI) made no critical errors. Regardless of the device used and previous inhaler experience, patient-centered training, education, and continuous retraining on correct inhaler use should be key aspects of routine patient care in COPD. PMID- 30016881 TI - Mean Platelet Volume and Platelet Distribution Width in Patients With Obstructive Sleep Apnea Syndrome and Concurrent Chronic Obstructive Pulmonary Disease. AB - Evidence suggests that there is platelet activation in obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD). Our objective is to evaluate mean platelet volume (MPV) and platelet distribution width (PDW) in patients with overlap syndrome (OS), that is, concurrent COPD with OSAS. Mean platelet volume and PDW were assessed in consecutive patients who had undergone polysomnography and pulmonary function testing. They were divided into the following groups: controls (apnea-hypopnea index [AHI] <5/hour, and forced expiratory volume in 1st second [FEV1]/forced vital capacity [FVC] >70%), OSAS group (AHI >=5/hour and FEV1/FVC >70%), and OS group (AHI >=5/hour and FEV1/FVC <70%). A total of 485 patients (360 males and 125 females) were included. Mean platelet volume in controls was lower compared with the other groups: 10 +/- 0.9 fL for controls versus 10.3 +/- 1.2 fL for OSAS ( P = .006), versus 10.7 +/- 1 fL for OS ( P < .001). Additionally, MPV was higher in OS group than OSAS: 10.7 +/- 1 fL versus 10.3 +/- 1.2 fL, respectively ( P = .002). Platelet distribution width was lower in controls compared with the other groups: 12.9 +/- 2 fL for controls versus 13.6 +/- 1.9 fL for OSAS ( P = .007), versus 13.8 +/- 2.3 fL for OS ( P = .008), while there was no difference between OS and OSAS groups. Mean platelet volume and PDW are increased in patients with OS compared with healthy controls, with respiratory function being the major contributor in platelet activation in this series. PMID- 30016882 TI - Mental Health Service Utilization in Depressed Canadian Armed Forces Personnel. AB - BACKGROUND: Major depression is prevalent, impactful, and treatable in military populations, but not all depressed personnel seek professional care in a given year. Care-seeking patterns (including the use of primary vs. specialty care) and factors associated with the likelihood of mental health service utilization in depressed military personnel are poorly understood. METHODS: Our sample included 520 Regular Force respondents to the 2013 Canadian Forces Mental Health Survey. All study participants had past-year major depression. Subjects reported whether they had spoken about their mental health with at least one health professional in the past 12 months. We used multivariate Poisson regression to explore factors associated with past-year mental health service use. RESULTS: Three-quarters of Canadian military personnel with past-year depression had sought mental health care in the previous 12 months. Among care-seeking personnel, 70% had seen a psychologist or psychiatrist, while 5% had exclusively received care from a primary care physician. Belief in the effectiveness of mental health care was the factor most strongly associated with care seeking. Female gender, functional impairments, and psychiatric comorbidities were also associated with care seeking. Surprisingly, stigma perceptions had no independent association with care seeking. CONCLUSIONS: The proportion of depressed Canadian Armed Forces personnel who seek professional care and who access specialty mental health care is higher than in most other populations. However, an important minority of patients are not accessing health services. Efforts to further increase mental health service utilization in the Canadian military should continue to target beliefs about the effectiveness of mental health care. PMID- 30016883 TI - Case Report: Allergic Contact Dermatitis to Topical Brimonidine Demonstrated With Patch Testing: Insights on Evaluation of Brimonidine Sensitization. PMID- 30016884 TI - Positive Practice Toward Voluntary Unpaid Blood Donation Among College Students in Shandong, China, 2013-2017. AB - The chronic worldwide shortage of blood for transfusions has become an important public health problem, especially in developing countries. The aim of the current study was to assess the practice of voluntary unpaid blood donation (VUBD) among college students in the past 5 years (2013-2017). The blood donation data of college students from 41 universities were collected. Change trends in the rate of blood donation among college students from 2013 to 2017 were examined. A continuous increasing trend in the rate of VUBD was observed over the past 5 years, from 3.36% in 2013 to 6.56% in 2017 ( p < .01). In conclusion, a positive practice toward VUBD was observed among college students in Shandong, China. It is necessary to improve the recruitment strategies, establishing a long-term mechanism and promoting the sustainable development of VUBD. PMID- 30016885 TI - Exploring national trends of patient- and family-centered care among US children. AB - We explored national trends in the receipt of high-quality patient-physician communication and patient empowerment through behavioral health counseling among children in the United States. We used data from the Medical Expenditure Panel Survey from 2010 to 2014. We employed two measures of patient- and family centered care (PFCC): (1) a composite measure of high-quality patient-physician communication ( n = 34,629) and (2) patient empowerment through behavioral health counseling about healthy eating ( n = 36,527) and exercise ( n = 38,318). We used multivariate logistic regression models to estimate the variation of receiving PFCC by social determinants of health over time. Rates of receiving behavioral health counseling about healthy eating (53-60%) and exercise (37-42%) were lower than the rate of receiving high-quality physician-patient communication (92-93%). Parents were significantly more likely to report receiving high-quality physician patient communication in 2014 than in 2010 (odds ratio 1.37, confidence interval 1.08-1.67); however, no association was found for empowerment through behavioral health counseling. Low income and parental educational attainment, and lack of insurance were associated with lower odds of receiving behavioral health counseling. Results showed significant variation of physician-patient communication and empowerment by social and demographic factors. The results suggest more providers need to empower parents and their children to self-care through behavioral health counseling. PMID- 30016888 TI - ACMQ President's Report. PMID- 30016886 TI - Clinical and Dermoscopic Features of Lichenoid Keratosis: A Retrospective Case Study. AB - BACKGROUND: Lichenoid keratosis is a benign cutaneous lesion exhibiting many clinical faces and different dermoscopic features. OBJECTIVE: This study aims to determine the pattern of different clinical subtypes of lichenoid keratosis and to establish whether there is any correlation between the clinical variants of lichenoid keratosis and their dermoscopic appearance. METHODS: We retrospectively analyzed the medical records and clinical database of patients who had received a histological diagnosis of lichenoid keratosis. Based on the literature review and the clinical-dermoscopic features of lichenoid keratosis, we divided the lesions into 6 clinical subtypes to evaluate potential correlations between clinical and dermoscopic features in all subtypes. RESULTS: Fifty-one lesions were included in this clinical study. Preoperatively, only 1.9% of cases were clinically diagnosed as lichenoid keratosis, and the most common misdiagnosis was basal cell carcinoma (52.9%). We identified 6 subtypes of lichenoid keratosis and their corresponding dermoscopic features and clues. CONCLUSION: Since lichenoid keratosis has no pathognomonic dermoscopic clues and it is commonly misdiagnosed as malignant skin neoplasms, such as basal cell carcinoma and melanoma, improving the knowledge of both clinical and dermoscopic variability of lichenoid keratosis may help dermatologists to reduce unnecessary surgery and to reduce health care spending. PMID- 30016889 TI - An evaluation of the diagnostic methods in head and neck cancer of unknown primary site. AB - BACKGROUND: Various detection methods to identify the primary in head and neck cancer of unknown primary (HN-CUP) require evaluation to improve and standardize management. OBJECTIVES: To evaluate the use of different diagnostic methods, which aim at decreasing the incidence of HN-CUP. MATERIAL AND METHODS: We conducted a retrospective analysis of patients with HN-CUP at the Helsinki University Hospital during 1995-2011. We evaluated clinical assessment, definitive treatment, histopathology, and follow up. We analyzed the success in identifying the primary site to show any changes in diagnostic methods over time. RESULTS: Frequency of HN-CUP and success in identifying the primary site have remained constant despite the addition of PET-CT and determination of human papilloma virus (HPV) status in diagnostics. Among 133 patients, the diagnostic work up identified the primary site in 53% and the oropharynx predominated (69%). This left 85 patients with HN-CUP and 5-year overall and disease-free survival rates were 71 and 69%, respectively. CONCLUSIONS: Panendoscopy including tonsillectomy should not be omitted in the work up. SIGNIFICANCE: We demonstrate a steady frequency of HN-CUP and constant success in identifying the primary site. Detection of a primary later in the follow up did not impact the survival. PMID- 30016890 TI - Hand embolization due to thrombosed arteriovenous fistulae. PMID- 30016891 TI - The role of prostate cancer antigen 3 (PCA3) in prostate cancer detection. AB - INTRODUCTION: The prostate cancer antigen 3 (PCA3) score has been the first urine assay to obtain the Food and Drug Administration approval for guiding decisions regarding additional biopsies. Different aspects of this urinary assay (diagnostic performance, prognostic value, cost/benefit balance, integration with other molecular and imaging modalities) have now been well evaluated. Areas covered: This expert review will summarize current achievements and future perspectives provided by this urine biomarker. Expert commentary: The clinical benefit of the PCA3 score, in addition to the other established factors has been demonstrated before regarding biopsy decision making in men with persistent risk of prostate cancer. Its potential prognostic value also suggests its usefulness in selecting low risk patients for active surveillance protocols, however future daily-practice changing studies are needed. Economics assessment and additional value compared with other biomolecular and imaging modalities are still under investigation. PMID- 30016892 TI - Cytochrome C suppresses renal accumulation and nephrotoxicity of polymyxin B. AB - The receptor megalin plays an important role in the accumulation of polymyxin B (PMB) in renal cells in vitro. This study aimed to examine the effects of cytochrome c (cyto c), a typical megalin ligand, on renal accumulation and nephrotoxicity of PMB in vivo. Thirty Sprague-Dawley rats were randomly divided into the vehicle control group, PMB group, PMB + cyto c 50, 100, or 200 mg/kg group, respectively, and were treated with intravenous cyto c 30 min before the administration of PMB 4.0 mg/kg once a day for consecutive 5 days. On the 4th day after administration, 24 h urine was collected to determine N-acetyl-beta-D glucosaminidase excretion. Six hours after the last injection on the 5th day, kidneys were harvested to assay PMB concentration and observe pathological alterations, and blood samples were collected to assay serum creatinine (SCr), blood urea nitrogen (BUN), and blood beta2-microglobulin (beta2-MG) levels. Cyto c 50, 100, and 200 mg/kg decreased the accumulation of PMB in the kidney by 18.5%, 39.1% ( p < 0.01), and 36.8% ( p < 0.01), respectively, and reduced 24 h N acetyl-beta-D- glucosaminidase excretion by 22.5% ( p < 0.05), 40.4% ( p < 0.01), and 40.4% ( p < 0.01), respectively. Kidney pathological damage induced by PMB was markedly reduced by cyto c 100 mg/kg and 200 mg/kg. However, there were no significant differences in SCr, BUN, and blood beta2-MG levels among the groups. These results indicated that cyto c may inhibit the renal accumulation and nephrotoxicity of PMB in a rat model, further proving the role of megalin in the accumulation of PMB. PMID- 30016893 TI - Diagnostic lymph node extirpation in CUP syndrome - useful or damaging? AB - OBJECTIVE: In a proportion of patients with cervical lymph node metastasis no primary can be found even with modern imaging and careful clinical examination (cancer of unknown primary syndrome = CUP syndrome). The ideal diagnostic approach is still debated on. METHODS: The clinical data of 75 patients (median age: 61.8 years; 16 females and 59 males), which have been treated for cervical squamous cell carcinoma of unknown primary syndrome in our hospital were retrospectively analyzed. RESULTS: In 12% of patients (n = 9) the primary demarcated in a time period of up to 5.3 years after diagnosis. In the patients who did not receive adjuvant radiotherapy (n = 13), primary became apparent in 38%. Diagnostic lymph node extirpation delayed time until therapeutic neck dissection on average for 3 weeks. In 62% of patients with previous lymph node extirpation (pN2a-N2c), a modified radical neck dissection was required compared to 41% when the surgical site was not operated on. CONCLUSIONS: In 12% of patients' primary demarcated in the course of the disease. A diagnostic lymph node extirpation was compared to direct therapeutic neck dissection after frozen section analysis associated with a three weeks delayed therapy and higher rate of modified radical neck dissection. PMID- 30016894 TI - Patient, disease, and outcome characteristics of benign paroxysmal positional vertigo with and without Meniere's disease. AB - BACKGROUND: Meniere's disease (MD)-associated benign paroxysmal positional vertigo (BPPV) is complex and difficult to diagnose, and reports of its prevalence, pathologic features and outcomes are sparse and conflicting. OBJECTIVE: Report disease characteristics and outcomes associated with the presence of MD in patients with BPPV. MATERIALS/METHODS: A retrospective study of patients with BPPV between 2007 and 2017 at a single, high-volume institution. RESULTS: Of 1581 patients with BPPV identified, 7.1% had MD and 71.9% of those patients had BPPV in the same ear(s) as MD. Patients with MD were more likely to have lateral semicircular canalithiasis (11.6% vs. 5.5%, p = .009) and multiple canalithiasis (7.1% vs. 2.5%, p = .005). MD was associated with an increased rate of resolution of BPPV (p = .008) but also increased time to resolution (p = .007). There was no association between MD and recurrence of BPPV. CONCLUSIONS: MD is associated with lateral canalithiasis. Contrary to prior reports, BPPV in MD can affect either ear and was not associated with poorer outcomes than idiopathic BPPV. SIGNIFICANCE: The largest series to date investigating disease and outcome characteristics for BPPV in MD is presented. These data inform diagnosis and expectations in the management of these complex patients. PMID- 30016895 TI - Using telemonitoring to support personal care planning for adults with learning disabilities. AB - Introduction We report on an evaluation of the Just Right approach for planning care for adults with learning disabilities and how it can support culture change. Just Right combines installing a telemonitoring system with training for care managers in person-centred care planning and the interpretation of charts that summarise activity data for their setting. By providing insights into the needs of individuals Just Right allows existing care provision to be reviewed to ensure it is 'just right'. The Just Right approach can also potentially identify over care and resources that can released. Methods A mixed-methods approach was used, triangulating qualitative and quantitative baseline and follow-up data. Qualitative data were collected before and after implementation from focus groups on barriers, enablers, success outcomes and impacts. A theory of change was developed. Detailed data on individual adults with learning disabilities were collected before and after installation of equipment using a linked online survey completed by their care managers. Results Nine commissioning local authorities were recruited with 33 care providers serving 417 adults with learning disabilities. Issues relating to implementation included staff acceptance, culture, consent, safeguarding, local authority engagement, interpretation of data and residential setting. Changes to care were identified for 20.3% of individuals, with 66% of providers not identifying any changes because Just Right confirmed that they were providing the right level of support. Discussion By combining telemonitoring and person-centred care planning, Just Right provides a holistic approach and necessary information for conversations amongst stakeholders about the care needs of adults with learning disabilities. Depending on how it is introduced, and the nature of conversations held, the Just Right approach can potentially change culture, leading to improved outcomes. PMID- 30016896 TI - Prescription of Antidementia Drugs and Antipsychotics for Elderly Patients in Japan: A Descriptive Study Using Pharmacy Prescription Data. AB - BACKGROUND: Antipsychotics are commonly used for managing behavioral and psychological symptoms of dementia among elderly patients with dementia receiving antidementia drugs (ADDs). However, the use of antipsychotics among these patients has not been investigated since 3 ADDs were approved in 2011 in Japan. METHOD: We conducted a descriptive study using pharmacy prescription data and identified patients aged >=65 years who were newly prescribed donepezil, memantine, rivastigmine, and galantamine between January 1, 2012, and September 30, 2014. We determined the proportion of antipsychotic prescription and the factors affecting antipsychotic prescription using multivariable Cox proportional hazard models. RESULT: Of 13 876 patients, 1705 were memantine users, and the proportion of antipsychotic prescription among them was the highest (11.1%). Adjusted hazard ratios for donepezil, rivastigmine, and galantamine were 0.66, 0.56, and 0.66, respectively, relative to that for memantine. CONCLUSION: Compared to other ADD users, new memantine users were most likely to be prescribed antipsychotics. PMID- 30016897 TI - Nasal plasmacytoma: a rare cause of persistent epistaxis. AB - Extramedullary plasmacytoma (EP) is a rare neoplasm characterized by monoclonal proliferation of plasma cells without features of multiple myeloma. EP constitutes 3% of all plasma cell tumors. Most of the cases of EP occur in the head and neck regions, especially in the aerodigestive tract. We present a case of recurrent epistaxis for 6 months and extensive workup revealed EP of the right nasal cavity. Primary care physicians and otolaryngologists should be aware of this very rare but a plausible cause of epistaxis and keep EP in the differential diagnosis of recurrent epistaxis. PMID- 30016898 TI - Validation of Quantitative Light-Induced Fluorescence for Quantifying Calculus on Dogs' Teeth. AB - Periodontal disease is a common disease of dogs and is initiated by the buildup of plaque on the tooth surface. As plaque matures, it becomes mineralized to form calculus, which although not directly involved in the etiology of periodontal disease, provides an irregular surface to which plaque can adhere. Evaluation of the quantity of plaque and calculus on dogs' teeth is therefore essential to enable the efficacy of products, designed to prevent or retard plaque and calculus accumulation, to be evaluated. The objective of this study was to determine whether quantitative light-induced fluorescence (QLFTM) is a suitable tool to quantify the amount of calculus on the buccal surface of dogs' teeth following the removal of disclosed plaque by tooth brushing. The amount of calculus on the teeth of 26 miniature schnauzers was measured, using QLF and a calculus index method (Warrick-Gorrel), during a 28-day phase crossover study comparing feeding a daily dental chew versus providing no daily chew. Quantification of calculus using the Warrick-Gorrel method showed a 43.8% reduction in calculus buildup, with 95% confidence interval of 27.3 to 60.3 ( P < .001). With QLF, the percentage reduction in calculus accumulation was 65.8% (58.1-73.4, P < .001). A retrospective sample size analysis showed that fewer dogs were required for QLF analysis compared to the Warrick-Gorrel method. This study demonstrated that QLF is a sensitive and precise method for quantification of calculus on dogs' teeth. It removes the subjective element of human examiners and has greater accuracy and reduced variability through the continuous nature of the data. PMID- 30016899 TI - Changes of video head impulse test results in lateral semicircular canal plane by different peak head velocities in patients with vestibular neuritis. AB - BACKGROUND: The peak head velocity influences on the video head impulse test (vHIT) results, but it has been not known how much the difference is. AIMS: To evaluate the clinical evidence for the superiority of high-velocity compared to low-velocity vHIT. MATERIAL AND METHODS: vHIT was performed in 30 patients with vestibular neuritis using two peak head velocities (mean 80 vs. 240 degrees /s). vHIT gains and parameters of corrective saccades (CSs) were compared. A vHIT gain of <=0.8 or a peak CS velocity of >=100 degrees /s was considered pathologic. RESULTS: The vHIT gains were significantly lower (mean 0.5 vs. 0.6), and GA was larger (35 vs. 25%) at high-velocity vHIT, compared to low-velocity vHIT. CSs were significantly more frequent (100 vs. 80%) and peak CS velocities were larger (252 vs. 112 degrees /s) at high-velocity vHIT. The abnormal rates based on vHIT gains were higher (90% vs. 73%) and CSs occurred more frequently (100% vs. 80%) at high-velocity vHIT. The abnormal rates based on the peak CS velocity were significantly higher at high-velocity vHIT (100% vs. 57%). CONCLUSION: High velocity vHIT is superior to low-velocity vHIT with a difference of 17-20% based on pathologic vHIT gains and presence of CSs. PMID- 30016900 TI - Association between an insertion/deletion polymorphism in the interleukin-1alpha gene and the risk of colorectal cancer in a Chinese population. AB - BACKGROUND: Previous studies have reported that polymorphisms in the interleukin 1 gene may be involved in tumorigenesis and tumor progression. AIM: The purpose of the present study was to evaluate whether an insertion/deletion polymorphism, rs3783553, located in the miR-122 target gene interleukin-1alpha, was associated with the risk of colorectal cancer. METHODS: Genomic DNA was extracted from peripheral venous blood of 382 patients with colorectal cancer and 433 controls, and the polymorphism was genotyped using a polymerase chain reaction assay. RESULTS: Significantly decreased colorectal cancer risk was observed to be associated with the interleukin-1alpha rs3783553 insertion/insertion genotype ( P=0.0001; OR=0.41; 95% CI 0.26, 0.65) and the insertion allele ( P<0.001; OR=0.68; 95% CI 0.55, 0.83). Stratification analysis based on clinical and pathological features also revealed that the "TTCA" insertion allele of rs3783553 contributes to slow the progression of colorectal cancer. CONCLUSION: These results suggest that the rs3783553 polymorphism could be a useful genetic marker to predict the size/extent of colorectal cancer. PMID- 30016901 TI - Developing consensus among movement disorder specialists on clinical indicators for identification and management of advanced Parkinson's disease: a multi country Delphi-panel approach. AB - BACKGROUND: Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care. OBJECTIVES: To reach consensus among movement disorder specialists regarding key patient characteristics indicating transition to APD and guiding appropriate use of device-aided therapies in the management of PD symptoms. METHODS: A Delphi-panel approach was utilized to synthesize opinions of movement disorder specialists and build consensus. RESULTS: A panel was comprised of movement disorder specialists from 10 European countries with extensive experience of treating PD patients (mean =24.8 +/- 7.2 years). Consensus on indicators of suspected APD and eligibility for device-aided therapies were based on motor symptoms, non-motor symptoms, and functional impairments. Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, >=1 h of troublesome dyskinesia/day, >=2 h "off" symptoms/day, and >=5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living. Patients with good levodopa response, good cognition, and <70 years of age were deemed as good candidates for all three device-aided therapies. Patients with troublesome dyskinesia were considered good candidates for both levodopa-carbidopa intestinal gel and Deep Brain Stimulation (DBS). PD patients with levodopa-resistant tremor were considered good candidates for DBS. CONCLUSION: Identifying patients progressing to APD and suitable for device-aided therapies will enable general neurologists to assess the need for referral to movement disorder specialists and improve the quality of care and patient outcomes. PMID- 30016902 TI - Low-dose dexamethasone with fosaprepitant and palonosetron to prevent cisplatin induced nausea and vomiting in head and neck cancer patients. AB - OBJECTIVE: To determine if a lower dose of dexamethasone can be used in combination with fosaprepitant and palonosetron for cisplatin-induced nausea and vomiting in head and neck cancer patients, we conducted a single-center, two-arm, cross-over comparison study. METHODS: Patients were randomly assigned to either standard dose dexamethasone group: intravenous 9.9 mg on day 1 and 6.6 mg on days 2-4 or low-dose dexamethasone group: intravenous 3.3 mg on days 1-4 for the first course and crossed over to the other treatment for the second course. The primary endpoint was complete response (CR) in the overall period. RESULTS: Twenty-five patients were screened for the study and 22 were evaluable. Eleven patients were randomly assigned to the standard dose dexamethasone group and 12 patients to the low-dose dexamethasone group. The CR rate in the overall period was 86% in the standard dose group and 73% in the low-dose group, showing no significant difference (p = .61). CONCLUSION: The efficacy of low-dose dexamethasone with fosaprepitant and palonosetron was not inferior to that of the standard dose dexamethasone in the highly emetogenic cisplatin-based treatment for head and neck cancer patients. PMID- 30016903 TI - Outcomes of cementless joint prosthesis versus tendon interposition for trapeziometacarpal osteoarthritis: a prospective study. AB - : We compared 84 patients with the Ivory trapeziometacarpal prosthesis versus 62 with ligament reconstruction and tendon interposition arthroplasty performed for osteoarthritis. There were 134 women and 12 men with a mean age of 60 years. Prospective clinical assessment was made using the Quick Disability of the Arm, Shoulder and Hand (DASH) questionnaire, visual analogue scale for pain, range of motion, and grip and pinch strength. The mean follow-up was 4 years (range 2-5). Prosthetic replacement provided significantly better thumb abduction, adduction, pinch strength, QuickDASH, pain relief, satisfaction and a faster return to daily activities and previous work. Revision surgery was required for two patients in the prosthesis group, two for dislocation and one cup loosening, while in the ligament reconstruction group there were no revisions. We conclude that trapeziometacarpal prosthesis provides better mid-term results in terms of function compared with ligament reconstruction and tendon interposition for patients with Stages 2 and 3 osteoarthritis of the trapeziometacarpal joint. LEVEL OF EVIDENCE: II. PMID- 30016904 TI - Epidemiology of distal radius fractures in a geographically defined adult population. AB - Distal radial fractures are the most common adult orthopaedic fracture. We sought to determine whether the incidence of this injury is changing and identify trends in its occurrence. We analysed data for all adult patients presenting to University Hospitals of Leicester with a distal radial fracture from 2007-2016. Incidence rates were calculated using United Kingdom population data. Poisson regression techniques were used to analyse weekly, seasonal and annual variation in fracture incidence. There was no significant change in average age or incidence of fracture. Increased incidence was associated with inclement weather conditions. Younger patients more commonly sustain fractures on weekends. We predict a 23% rise in the number of fractures in the United Kingdom in the next 20 years. The incidence of fracture does not appear to be changing, although the number of fractures is growing. Weekly and seasonal trends are apparent. Level of evidence: III. PMID- 30016905 TI - Incidence of re-deviated nasal septum after septoplasty in adolescent and adult patients. AB - BACKGROUND: Re-deviation of the nasal septum may occur after septoplasty. Because the cartilaginous septum grows until the age of 16-17 years, septoplasty is usually recommended thereafter. However, severely deviated septum may necessitate septoplasty in younger adolescents. OBJECTIVES: To compare the incidence of re deviated nasal septum in patients who underwent septoplasty at <=18 versus >=19 years of age. MATERIALS AND METHODS: The medical records and endoscopic photographs of patients who underwent septoplasty between 2005 and 2015 were retrospectively reviewed. Re-deviation of the nasal septum was defined as >50% narrowing of one side of the nasal cavity compared to immediately after septoplasty. RESULTS: The inclusion criteria were met by 52 adolescent patients and 549 adult patients. Re-deviation of the septum occurred in 11 (21.2%) and 39 (7.1%) patients, respectively; the difference was significant. Most patients had caudal and upper cartilaginous deviations. Four adolescent and 14 adult patients underwent revisional septoplasty. CONCLUSIONS AND SIGNIFICANCE: Adolescent patients who underwent septoplasty had a significantly higher incidence of re deviation of the nasal septum than adult patients. Therefore, when septoplasty is deemed necessary in adolescent patients, they and their parents should be informed about the possibility of re-deviation and the need for revisional septoplasty. PMID- 30016906 TI - The lateralized brain: the neuroscience and evolution of hemispheric asymmetries. PMID- 30016907 TI - Disappearance of Biased Visual Attention in Infants: Remediated Tonic Neck Reflex or Maturating Visual Asymmetry? AB - Typically, infants younger than four months fail to attend to the left side of their spatial field, most likely due to an innate asymmetrical tonic neck reflex (ATNR). In a critical transition, by four months of age, infants begin to reach and develop depth perception; and, by five months, they tend to monitor the entire spatial field. However, this developmental transition can be delayed. Moreover, there is always a residual right-sided spatial bias under cognitive load, a phenomenon that may also occur among adult stroke patients. While causative factors of biased visual attention in both infants and brain-injured adults may vary, mechanisms of remediation may be similar. This literature review addresses whether the infant's emergence of attention toward a full visual spatial field and the associated shift from monocular to binocular vision occurs because of (a) increased left side reaching, loosening the rarely mentioned high muscle tension ATNR or (b) maturational resolution of visual asymmetry in motion perception. More research is needed to investigate the origins of the infants' visual control system and factors involved in its development, especially because Alzheimer and dementia patients may also show primitive two-dimensional vision and deficits in perceiving objects-in-motion that seem to mirror infant visual perception. PMID- 30016908 TI - Saddle Height and Cadence Effects on the Physiological, Perceptual, and Affective Responses of Recreational Cyclists. AB - Saddle height influences cycling performance and would be expected to influence cyclists physically, perceptually, and emotionally. We investigated how different saddle positions and cadences might affect cyclists' torque, heart rate, rate of perceived exertion (RPE), and affective responses (Feeling scale). Nine male recreational cyclists underwent cycling sessions on different days under different conditions with a constant load. On Day 1, the saddle was at the reference position (109% of the distance from the pubic symphysis to the ground), and on Days 2 and 3, the saddle was in the "upward position" (reference + 2.5%) and "downward position" (reference - 2.5%) in random order. Each session lasted 30 minutes and was divided into three cadence-varied 10-minute stages without interruption: (a) freely chosen cadence (FCC), (b) FCC - 20%, and (c) FCC + 20%. We assessed all dependent measures at the end of each 10 minute stage. While there was no significant interaction (Saddle * Cadence) for any of the analyzed variables, torque values were higher at lower cadences in all saddle configurations, and the FCC + 20% cadence was associated with faster heart rate, higher RPE, and lower affect compared with FCC and FCC - 20% in all saddle positions. At all cadences, the saddle at "downward position" generated a higher RPE compared with "reference position" and "upward position." The affective response was lower in the "downward position" compared with the "reference position." Thus, while cyclists perceived the downward (versus reference) saddle position as greater exercise effort, they also associated it with unpleasant affect. PMID- 30016909 TI - Advance Care Planning and End-of-Life Issues in Head and Neck Cancer. AB - Advance Care Planning and End of Life discussions are critical in all cancers but are often overlooked or delayed. Head and Neck Cancer patients have the added stigma of visible morbidity and negative quality of life issues. We present a case example and discussion of these issues in the Head and Neck cancer clinic. PMID- 30016911 TI - Journal of Correctional Health Care. PMID- 30016910 TI - Endolymphatic duct blockage for refractory Meniere's disease: assessment of intraoperative CSF leak on short-term surgical outcomes. AB - BACKGROUND: Endolymphatic sac decompression has shown limited success for the treatment of Meniere's disease (MD). We have published a novel technique with very promising results for the treatment of refractory MD: the Endolymphatic Duct Blockage (EDB) with two titanium clips. One of the challenges of this technique was an increased incidence of intraoperative Cerebrospinal Fluid (CSF) Leak. OBJECTIVE: To assess the effect of intraoperative CSF Leak on short-term surgical outcomes. METHODS: Retrospective comparative study in a tertiary care center (61 patients). MD patients who underwent EDB were included. Intraoperative CSF Leaks were documented. Surgical outcomes assessed were the presence of postoperative Benign Paroxysmal Positional Vertigo (BPPV), aural fullness, tinnitus, vertigo spells and pure tone average (PTA), speech discrimination scores (SDS) and bone conduction thresholds (BCT). Data were collected for these visits: preoperative, 1 week, 1 and 6 months postoperatively. RESULTS: Outcomes for the CSF Leak group (CSF +) (n = 22) were compared to remaining patient (CSF-) (n = 39). There was no significant difference in the occurrence of postoperative BPPV, aural fullness, tinnitus and vertigo spells. There was no significant difference in PTA, BCT or SDS between our groups at any visit. CONCLUSIONS: Intraoperative CSF Leak may cause a temporary non-significant worsening of hearing in the first-month postoperatively without any difference at 6 months. PMID- 30016913 TI - Editor's Letter. PMID- 30016912 TI - Effectiveness of a Prison-Based Healthy Pregnancy Curriculum Delivered to Pregnant Inmates: A Pilot Study. AB - Incarcerated women experience stress related to their prison sentence, and this can be aggravated by pregnancy-related changes, with pregnant women at higher risks of adverse maternal and fetal health outcomes related to mental health problems and infant low birth weight. In a Midwestern correctional facility, 25 pregnant women were enrolled in a 4-week health and mental health education workshop comprised of seven sessions that taught women about self and infant care. Each 90-minute session included education and guided discussions using handouts that each participant could take with them. Pre and post-test surveys to measure change in knowledge were completed after each session. Findings indicate that an educational intervention for incarcerated pregnant women can lead to change in knowledge about self and infant care. PMID- 30016914 TI - Language and transient emotional states affect implicit cultural bias. AB - Bilinguals react to cultural information in a language-dependent fashion, but it is unknown whether this is influenced by the individual's emotional state. Here, we show that induced mood states increase cultural bias-measured using the Implicit Association Test (IAT)-but this effect occurs asymmetrically across languages. In the native language, bilinguals show a strong cultural bias, which is not influenced by mood. But in the non-native language, a relatively low cultural bias significantly increases as a function of a positive or negative mood. Our findings suggest that the native language promotes an inherent cultural bias, which is impervious to fluctuations in the bilingual's mood state. In the second language, however, bilinguals are culturally impartial, unless they are in a heightened mood state. PMID- 30016915 TI - Editor's Note. PMID- 30016916 TI - How Did I Ever Get Here? The 2018 Mildred S. Christian Award Winner. PMID- 30016918 TI - Using Lean tools to reduce patient waiting time. AB - Purpose This paper aims to address problems in patient flow and identify the reasons behind extensive wait time at a public liver transplant outpatient clinic in an education and research hospital through the use of Lean health-care theories. Design/methodology/approach This paper opted for the application of Lean thinking and action research strategy. Data were collected through personal observations, interviews with users and team brainstorming. A value stream map was developed, improvement possibilities were identified and non-value-added activities were attempted to be eliminated. Findings Significant problems were identified and improvements were implemented and measured. The major remedial measures were: change the scheduling pattern, create a flow chart and a Kanban visual guide for medical students. In addition, an institutional change in the medical appointment scheduling software collaborated in the reduction of time and in the patient's displacement. The waiting time was reduced by 4.5 h, and the per cent complete and accurate increased by 50 per cent. Practical implications The flow was redesigned, and a culture of continuous improvement was introduced. Visiting the place where work was being done, leaders identified and created more value to the process without significant costs. The Gemba Walk was a powerful tool, interacting with people and processes in a Kaizen spirit. Originality/value Public health services in developing countries are one of the most deprived social needs of good practice. It will be useful for those who need examples about how to apply Lean tools in health care. PMID- 30016919 TI - Leveraging supply chain infrastructure to advance patient safety in community health-care settings. AB - Purpose The purpose of this paper is to examine the opportunity for supply chain processes and infrastructure to reduce the risk of medical error and create traceability of adverse events in community care settings. Patient safety has become an important area of focus over the past few decades, with medical error now accounting for the third most common cause of death in Canada and the USA. The majority of patient safety studies to date have focused specifically on safety in hospital settings; however, deaths and harm experienced by patients in the community (home care, long-term care, complex care and rehabilitation settings) are not well understood. Design/methodology/approach This paper discusses the evidence that adverse events occur at similar, if not more, frequent rates in community care settings. Findings The authors propose that above and beyond current efforts to increase awareness and promote a "safety culture" in health-care settings, system infrastructure should be designed in a way that enables clinicians to provide the safest care possible. There is currently no line of sight across the health-care continuum. The authors suggest that improving system infrastructure would reduce the occurrence of adverse events. Originality/value Such visibility across the continuum of care holds the potential to transform health-care in Canada from a fragmented system, where information is inadequately captured and transferred from provider to provider, to a system that provides complete, accurate and up-to-date information regarding patient care, procedures, medications and outcomes so as to provide the best and safest care possible. System visibility achieves quality and safe care, which is transparent and accountable and achieves value for patients. PMID- 30016917 TI - Genotype scores predict drug efficacy in subtypes of female sexual interest/arousal disorder: A double-blind, randomized, placebo-controlled cross over trial. AB - Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of 'one size fits all', and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects' genetic profile was assessed using a microarray chip that measures 300,000 single nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach. PMID- 30016920 TI - Medical commitment to Lean: an inductive model development. AB - Purpose The purpose of this paper is to study the factors influencing doctors' involvement in Lean change initiatives in public healthcare organizations in Canada. Design/methodology/approach An inductive research was conducted over a three-year span studying Lean implementation across three healthcare organizations in Canada. Various interviews were conducted with healthcare actors. Through analytical induction, analysis of the data allowed for multiple factors to be triangulated from which a conceptual model was developed. Findings Fifty-four interviews with 18 Lean healthcare actors allowed for the identification of ten factors possibly influencing the commitment of doctors towards Lean change. These factors are categorized into pre-change antecedents and change antecedents. Also, the level of transformational leadership demonstrated by a project manager was shown to potentially moderate the effect of medical behavioral support for change on change outcomes. These findings allowed us to develop a conceptual model of medical commitment and its impact of Lean change outcomes. Originality/value The paper investigates the role doctors play in Lean implementation, currently an important issue discussed among healthcare actors and researchers. Yet, very little academic research has been published on this subject. PMID- 30016921 TI - Improving patient flow through applying lean concepts to emergency department. AB - Purpose This paper aims to propose lean-based interventions that address the main causes of emergency department overcrowding. Emergency department overcrowding (EDOC) and increased length of stay (LOS) have been key global issues for more than 20 years, as they have serious repercussions. No measurements have been done to assess the situation nationally. Expanding emergency departments (EDs) and adding more beds have never succeeded in eliminating wastes and targeting the root causes of the problem. Design/methodology/approach This paper is a quantitative analytical applied research. The paper used direct observation for seven days to collect patient flow data on ED patients at a secondary care hospital in Kuwait. It calculated wait times and services to identify the major causes of EDOC and increased LOS. Findings Around one-third of the ED design capacity was used by 12 per cent of the patients who stayed >6 h each. The wasted waiting time represents 56.2 per cent of the aggregated LOS, which puts lean management (LM) on the top of the process reengineering approaches suitable for improving overcrowding by reducing waste. Guided by the LM concepts, the paper proposes solutions that fall into three themes. The selected solutions address the vital few causes of the EDOC and prolonged EDLOS. Originality/value This paper is the first study of its kind in Kuwait, and one of the most outstanding studies in the Gulf region, in terms of the number of the daily ED visits and the comprehensive multi-level proposed interventions. PMID- 30016922 TI - Strengthening quality culture in private sector and health care. AB - Purpose The purpose of this study is to present a comprehensive approach to studying organizational culture using "soft measures" to facilitate sustainable quality development in organizations. The purpose is also to present, discuss and compare the results from a survey designed to measure a company's value base. Design/methodology/approach A number of different methods were used to collect soft data to study and measure organizational culture and at the same time influence the culture and the leadership within three organizations. One method, the survey, was used on two different occasions to obtain an overview of the culture within an organization and to investigate if the activities had influenced the culture and the leadership. Findings The application of soft measures used by leaders to study and develop organizational culture resulted in statistically significant positive changes in organizational work culture, according to a pre-post survey after a short period of one year. Practical implications The approach can be used by leaders in different types of organizations as the challenge of changing the organizational culture through the leadership seems to be a common challenge regardless of line of business. Originality/value The study shows the benefits of using a comprehensive approach to assess an organization's culture based on qualitative measures and analysis. PMID- 30016924 TI - Guest editorial. PMID- 30016923 TI - A model for measuring effectiveness of quality management practices in health care. AB - Purpose Health care is an example of an organization where the needs of potential clients are much greater than the capabilities of the service delivery system. The implementation of any medical procedure, as well as the provision of any service, just like the manufacturing of any product, can be decomposed into a series of tasks. The purpose of this paper is to propose a model for measuring the effectiveness of quality assurance tasks in health-care delivery processes. Design/methodology/approach The authors analyze a system of factors that affect the implementation of tasks in a process. In their considerations, they have focused on four areas of science that describe conditions that are related to the implementation of tasks: Scheduling as a methodology for allocating resources to perform tasks; Capacity planning as a methodology for assigning values to given resources expressed by the number of tasks that can be executed with the resources; Queueing theory, used as a methodology for describing phenomena in which not all planned tasks are performed within the prescribed specification limits; and Quality management, as a methodology to ensure appropriate conditions for completing tasks (CCTs), where CCT is a representation of parameters of casual relationship between variables. Findings The authors show that the effectiveness of executing any scheduled tasks in the process is determined by the difference between the capacity of resources allocated (at a given time interval) and the number of tasks planned to be carried out at that time. The CCT conditions determine the level of capacity of the fixed amount of resources. It is shown that their deviation from the reference CCT specification may cause the nominally correct amount of resources be either too small (causing queue formation and longer wait time in hospitals) or too large to contribute to the waste in the system by creating idle capacity. Practical implications The scope of application of the model is wide. It covers tasks performed with different degrees of uncertainties regarding the capacity of resources. It applies in all areas of health care where unlike manufacturing, the services delivered and the tasks performed in the health-care delivery system are seldom identical. Every patient is treated differently than the one waiting next in line. The workloads are pre-arranged in the order they are needed and completed in accordance with the FI-FO (first in-first out) principle. The model presented in this paper makes it possible to better understand the mechanism of effectiveness and efficiency improvement and the role of humans as a specific carrier of capacity. Originality/value As most of the health-care organizations are still stuck in the soft side of quality assurance, there has been little research conducted to test the applicability of well-known productions/operation management methodologies and theories benefitting health-care systems. The formulation of a reference point of CCT in this study is to serve as a stabilizing control point with the same connotation as that of a central reference line in the statistical process control chart. The correct capacity planning is needed to determine with a high degree of probability of success in implementation of all tasks to assure quality all the time. PMID- 30016926 TI - Constructions of Decision Making for Risk-Reducing Mastectomy. AB - This research article explores constructions of the decision-making process for risk-reducing mastectomy and considers the consequent role and responsibility of clinical psychologists. Using a Foucauldian discourse analysis approach, three online newspaper articles, five online forums, and four semi-structured interviews were analyzed. Seven discursive constructions are identified and discussed within three broader discourses of mental illness, risk, and embodied selves. Primary conclusions highlight the role for clinical psychologists and health professionals to incorporate the multiple social and political factors involved in discourses that shape decision making. The role of power is critically considered and there is a need for further analysis of "talk" among health professionals. PMID- 30016927 TI - Corrigendum. AB - Boychuk, C., Lysaght, R., Stuart, H., Career Decision-Making Processes of Young Adults With First-Episode Psychosis. Qualitative Health Research, 28, 1016-1031. doi: https://doi.org/10.1177/1049732318761864 The (Smith & Milson 2011) reference has inadvertently been removed from the following sentence: "Career development theories provide foundations that conceptualize career development processes and contextual influences that affect career progress." The correct citation of the reference is as follows: "Career development theories provide foundations that conceptualize career development processes and contextual influences that affect career progress (Smith & Milson 2011)." PMID- 30016928 TI - SLE mortality remains disproportionately high, despite improvements over the last decade. AB - Despite a marked improvement in 10-year survival for systemic lupus erythematosus (SLE) patients over the past five decades, mortality rates from SLE remain high compared to those in the general population. SLE was also among the leading causes of death in young women in the United States during 2000-2015. However, it is encouraging that SLE mortality rates and the ratios of SLE mortality rates to non-SLE mortality rates have decreased every year since the late 1990s. Despite this improvement, disparities in SLE mortality persist according to sex, race, age, and place of residence. Furthermore, demographic and geographic variables seem to modify the effect of each other in influencing SLE mortality, leading to interactions between sex/race/ethnicity-associated factors and geographic differences. In other words, individuals of the same sex/race/ethnicity had differences in SLE mortality depending on where they lived. These observations highlight SLE as an important public health issue. The recognition of SLE as a leading cause of death in the general population might spur targeted public health programs and research funding to address the high lupus mortality. PMID- 30016931 TI - Hydroxychloroquine: an update. PMID- 30016930 TI - Impaired Callosal Motor Fiber Integrity and Upper Extremity Motor Impairment Are Associated With Stroke Lesion Location. AB - BACKGROUND: Damage to the callosal motor fibers (CMFs) may affect motor recovery in patients with stroke. However, whether the severity of CMF impairment varies with lesion locations remains unclear. OBJECTIVE: To investigate (1) whether CMF impairment occurs after stroke and whether the impairment varies with lesion locations and (2) the associations of CMF impairment and upper extremity (UE) motor impairment. METHODS: Twenty-nine patients with lesions involving the corticospinal tract (CST) were categorized into 2 groups: lesions involving the CMFs (CMF group, n = 15), and lesions not involving the CMFs (non-CMF group, n = 14). Thirteen healthy adults served as the control group. Tract integrity, assessed by the mean generalized fractional anisotropy (mGFA) using diffusion spectrum imaging, of the CMFs and the CST above the internal capsule (CSTABOVE) of the ipsilesional hemisphere were compared. RESULTS: After accounting for the effect of lesion load on the CST, the CMF group exhibited a significantly lower mGFA of the CMFs than did the control and non-CMF groups (post hoc P = .005 and .001, respectively). No significant difference was observed between the non-CMF and control groups (post hoc P = .999). The CST and CMF impairment accounted for 56% of the variance of UE motor impairment in the CMF group ( P = .007), whereas no significant association was observed in the non-CMF group ( P = .570). CONCLUSIONS: CMF impairment after stroke depends on lesion locations and CMF integrity has an incremental contribution to the severity of UE motor impairment in the CMF group. PMID- 30016929 TI - Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome. AB - Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068. PMID- 30016932 TI - Correction to: In vitro mineral nutrition of Curcuma longa L. affects production of volatile compounds in rhizomes after transfer to the greenhouse. AB - Following publication of the original article [1], the author reported a formatting error and an error in the figure caption. The original article has been corrected. The details of the errors are as follows. PMID- 30016933 TI - HGT-ID: an efficient and sensitive workflow to detect human-viral insertion sites using next-generation sequencing data. AB - BACKGROUND: Transfer of genetic material from microbes or viruses into the host genome is known as horizontal gene transfer (HGT). The integration of viruses into the human genome is associated with multiple cancers, and these can now be detected using next-generation sequencing methods such as whole genome sequencing and RNA-sequencing. RESULTS: We designed a novel computational workflow, HGT-ID, to identify the integration of viruses into the human genome using the sequencing data. The HGT-ID workflow primarily follows a four-step procedure: i) pre processing of unaligned reads, ii) virus detection using subtraction approach, iii) identification of virus integration site using discordant and soft-clipped reads and iv) HGT candidates prioritization through a scoring function. Annotation and visualization of the events, as well as primer design for experimental validation, are also provided in the final report. We evaluated the tool performance with the well-understood cervical cancer samples. The HGT-ID workflow accurately detected known human papillomavirus (HPV) integration sites with high sensitivity and specificity compared to previous HGT methods. We applied HGT-ID to The Cancer Genome Atlas (TCGA) whole-genome sequencing data (WGS) from liver tumor-normal pairs. Multiple hepatitis B virus (HBV) integration sites were identified in TCGA liver samples and confirmed by HGT-ID using the RNA Seq data from the matched liver pairs. This shows the applicability of the method in both the data types and cross-validation of the HGT events in liver samples. We also processed 220 breast tumor WGS data through the workflow; however, there were no HGT events detected in those samples. CONCLUSIONS: HGT-ID is a novel computational workflow to detect the integration of viruses in the human genome using the sequencing data. It is fast and accurate with functions such as prioritization, annotation, visualization and primer design for future validation of HGTs. The HGT-ID workflow is released under the MIT License and available at http://kalarikrlab.org/Software/HGT-ID.html . PMID- 30016934 TI - Prevalence of human anelloviruses in Romanian healthy subjects and patients with common pathologies. AB - BACKGROUND: Human anelloviruses (TTV, TTMDV and TTMV) are at high prevalence all across the globe, having also a controversial disease-inducing potential. This study aimed to estimate the prevalence of anelloviral DNA in the Romanian human population and to investigate the association of infections with common pathologies in Romanian population. METHODS: After informed consent, blood samples were collected from 2000 subjects represented by: clinically healthy individuals (n = 701) and a group of patients with pathologies linked to low grade inflammation or alteration of carbohydrate metabolism (n = 1299). All samples were analysed for the presence of TTV, TTMDV and TTMV DNA by hemi-nested PCR. RESULTS: The prevalence of TTV, TTMDV and TTMV in the studied population was 68.2, 54.4%, respectively 40.1%, lower than the recent reports from other geographic regions. The three viral species were significantly more frequent in the group of patients compared to the healthy subjects and were associated with type 2 diabetes mellitus. The presence of anelloviral DNA was also associated with medical procedures (e.g. haemodialysis/transfusions, surgical procedures) and previous hepatitis A virus infection. Lifestyle choices related to alcohol consumption, smoking, physical activity and living environment were not associated with differences in distribution of the three viruses. CONCLUSION: Further evidence is needed to establish a correlation between infection with human anelloviruses and a pathology or group of pathologies. PMID- 30016936 TI - Metabolic syndrome among type 2 diabetic patients in Ethiopia: a cross-sectional study. AB - BACKGROUND: Metabolic syndrome (MetS) increases risk of cardiovascular diseases (CVD), premature death as well as cost related to health care.This study was aimed at investigating the prevalence of MetS and its determinant factors among type2 diabetes mellitus (T2DM) patients attending a specialized hospital. METHODS: A cross-sectional study was conducted on a total of 256 T2DM patients from the first march to 30th May 2017 at university of gondar comprehensive specialized hospital (UGCSH). Data was collected based on STROBE (strengthening the reporting of observational studies in epidemiology) statement. Bivariable and multivariable logistic regression analysis were run to identify predictors of MetS from the independent variables and significance test was set at P < 0.05. RESULTS: The prevalence of MetS in this study was 70.3, 57 & 45.3% and it is more common in females (66.1, 83.3 & 70.7%) by using national cholesterol education program adult treatment panel III (NCEP-ATP III), International diabetic federation (IDF) and world health organization (WHO) criteria respectively. The most prevalent components of MetS were low level of high density lipoprotein (HDL) and triglyceride(TG). By usingIDF criteria, female gender was significantly associated with MetS (AOR = 0.2 at 95%CI: 0.1, 0.6 P = 0.00). Where as by NCEP ATP IIIcriteria, age between 51 and 64 years old (AOR = 2.4 95% CI: 1.0,5.8, P = 0.04), self employment (AOR = 2.7 95% CI:1.1, 6.5, P = 0.03), and completetion of secondary school and above (AOR = 3.2, 95% CI:1.6,6.7, P = 0.001) were predictors for the development of MetS. In the WHO criteria, being single in marital status was significantly associated with MetS (AOR = 17 at 95%CI: 1.8, 166, P = 0.000). CONCLUSIONS: This study demonstrates that Metabolic syndrome is a major health concern for diabetic patients in Ethiopia and they are at increased risk of developing complications such as cardiovascular diseases and premature mortality. The predictors female gender, age between 51 and 64 years old, urban area residence, and being single are modifiable.Thus,health authorities shall provide targeted interventions such as life style modifications to these most at risk sub populations of diabetic patients. PMID- 30016935 TI - The effectiveness of 6 versus 12-months of dialectical behaviour therapy for borderline personality disorder: the feasibility of a shorter treatment and evaluating responses (FASTER) trial protocol. AB - BACKGROUND: Although Dialectical Behaviour Therapy (DBT) is an evidence-based psychosocial treatment for borderline personality disorder (BPD), the demand for it exceeds available resources. The commonly researched 12-month version of DBT is lengthy; this can pose a barrier to its adoption in many health care settings. Further, there are no data on the optimal length of psychotherapy for BPD. The aim of this study is to examine the clinical and cost-effectiveness of 6 versus 12 months of DBT for chronically suicidal individuals with BPD. A second aim of this study is to determine which patients are as likely to benefit from shorter treatment as from longer treatment. METHODS/DESIGN: Powered for non-inferiority testing, this two-site single-blind trial involves the random assignment of 240 patients diagnosed with BPD to 6 or 12 months of standard DBT. The primary outcome is the frequency of suicidal or non-suicidal self-injurious episodes. Secondary outcomes include healthcare utilization, psychiatric and emotional symptoms, general and social functioning, and health status. Cost-effectiveness outcomes will include the cost of providing each treatment as well as health care and societal costs (e.g., missed work days and lost productivity). Assessments are scheduled at pretreatment and at 3-month intervals until 24 months. DISCUSSION: This is the first study to directly examine the dose-effect of psychotherapy for chronically suicidal individuals diagnosed with BPD. Examining both clinical and cost effectiveness in 6 versus 12 months of DBT will produce answers to the question of how much treatment is good enough. Information from this study will help to guide decisions about the allocation of scarce treatment resources and recommendations about the benefits of briefer treatment. TRIAL REGISTRATION: NCT02387736 . Registered February 20, 2015. PMID- 30016937 TI - Immunoglobulin-induced aseptic meningitis: a case report. AB - BACKGROUND: Immunoglobulin associated meningitis is a rare disease that mimics infectious meningitis. This is, to our knowledge, the first case of Immunoglobulin-associated meningitis described in a patient with Systemic Lupus Erythematosus and hypogammaglobulinemia secondary to Rituximab. CASE PRESENTATION: A 46-year-old female with a past medical history of Systemic Lupus Erythematosus, presented with meningismus 36 h after first infusion of intravenous immunoglobulin. The cerebrospinal fluid analysis showed neutrophilic pleocytosis and hyperproteinorrachia. All microbiological tests were negative. The patient recovered remarkably fast without sequela after just five days of antibiotic therapy. CONCLUSION: Systemic Lupus Erythematosus is a well-documented risk factor for aseptic meningitis associated with other drugs. Possibly, it is also a risk factor for Immunoglobulin associated meningitis. This diagnosis, although rare, should be considered in patients receiving Immunoglobulin since it is a self-limited condition and treatment is supportive. PMID- 30016938 TI - Gastroesophageal reflux symptoms among Italian university students: epidemiology and dietary correlates using automatically recorded transactions. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders worldwide, with relevant impact on the quality of life and health care costs.The aim of our study is to assess the prevalence of GERD based on self-reported symptoms among university students in central Italy. The secondary aim is to evaluate lifestyle correlates, particularly eating habits, in GERD students using automatically recorded transactions through cashiers at university canteen. METHODS: A web-survey was created and launched through an app, ad-hoc developed for an interactive exchange of information with students, including anthropometric data and lifestyle habits. Moreover, the web-survey allowed users a self-diagnosis of GERD through a simple questionnaire. As regard eating habits, detailed collection of meals consumed, including number and type of dishes, were automatically recorded through cashiers at the university canteen equipped with an automatic registration system. RESULTS: We collected 3012 questionnaires. A total of 792 students (26.2% of the respondents) reported typical GERD symptoms occurring at least weekly. Female sex was more prevalent than male sex. In the set of students with GERD, the percentage of smokers was higher, and our results showed that when BMI tends to higher values the percentage of students with GERD tends to increase. When evaluating correlates with diet, we found, among all users, a lower frequency of legumes choice in GERD students and, among frequent users, a lower frequency of choice of pasta and rice in GERD students. DISCUSSION: The results of our study are in line with the values reported in the literature. Nowadays, GERD is a common problem in our communities, and can potentially lead to serious medical complications; the economic burden involved in the diagnostic and therapeutic management of the disease has a relevant impact on healthcare costs. CONCLUSIONS: To our knowledge, this is the first study evaluating the prevalence of typical GERD-related symptoms in a young population of University students in Italy. Considering the young age of enrolled subjects, our prevalence rate, relatively high compared to the usual estimates, could represent a further negative factor for the future economic sustainability of the healthcare system. PMID- 30016939 TI - Epidemiological characterization of respiratory tract infections caused by Mycoplasma pneumoniae during epidemic and post-epidemic periods in North China, from 2011 to 2016. AB - BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is a commonly causative pathogen for respiratory tract infections (RTIs) in humans. The epidemiological features of M. pneumoniae infections during post-epidemic, including age distribution and the seasonality of the patients, are not well investigated. METHODS: We retrospectively analyzed the clinical data of 7835 consecutive RTIs patients (3852 adults and 3983 children) who visited a teaching hospital, and defined an epidemic (2011-2013) and a post-epidemic period (2014-2016). M. pneumoniae was detected by fluorescence-quantatitive PCR in respiratory samples. Informed consent was obtained by all adults and the legal representatives of patients aged < 18 years, and the study was approved by Institutional Review Board of Beijing Chao-Yang Hospital (project approval number 10-KE-49). RESULTS: The median (IQR) age was 16 (53) years (range < 0-105 years). The M. pneumoniae positive rate was 14.4% (21.2%, epidemic; 6.7%, post-epidemic), with seasonal peaks from late summer to autumn during epidemic, and from fall to winter during post-epidemic period, which was highest in children aged 7-17 years. In epidemic, no statistical difference was found in the positive rates between children and adults among most months (except February, July and August), neither for the positive rates among age groups (P = 0.801). However, in post-epidemic period, significant differences were observed in the positive rates between children and adults in nearly every month (P< 0.05 or P< 0.001, except May), as well as in the positive rates among age groups (P< 0.001). Most of the older patient admissions and all of ICU admissions occurred during the epidemic. CONCLUSIONS: Different patterns of age distribution and seasonality of M. pneumoniae RTIs between epidemic and post-epidemic periods were reported. Our results suggest that M. pneumoniae should be considered as a possible pathogen in pneumonia patients admitted to the ICU in the setting of an epidemic. PMID- 30016940 TI - Persistent presence of outer membrane epitopes during short- and long-term starvation of five Legionella pneumophila strains. AB - BACKGROUND: Legionella pneumophila, the causative agent of Legionnaire's disease, may enter a viable but non-culturable (VBNC) state triggered by environmental stress conditions. Specific outer-membrane epitopes of L. pneumophila are used in many diagnostic applications and some of them are linked to important virulence related factors or endotoxins. However, it is not clear how the presence and status of these epitopes are influenced by environmental stress conditions. In this study, changes of outer membrane epitopes for monoclonal antibodies (mAb) from the Dresden panel and the major outer membrane protein MOMP were analysed for five L. pneumophila strains during short- and long-term starvation in ultrapure water. RESULTS: With ELISA and single cell immuno-fluorescence analysis, we could show that for most of the investigated mAb-strain combinations the total number of mAb-stained Legionella cells stayed constant for up to 400 days. Especially the epitopes of mAb 3/1, 8/5, 26/1 and 20/1, which are specific for L. pneumophila serogroup 1 subtypes, and the mAb 9/1, specific for serogroup 6, showed long-term persistence. For most mAb- stained cells, a high percentage of viable cells was observed at least until 118 days of starvation. At the same time, we observed a reduction of the fluorescence intensity of the stained cells during starvation indicating a loss of epitopes from the cell surface. However, most of the epitopes, including the virulence-associated mAb 3/1 epitope were still present with high fluorescence intensity after 400 days of starvation in up to 50% of the starved L. pneumophila population. CONCLUSIONS: The results demonstrate the continuous presence of outer membrane epitopes of L. pneumophila during short-term and long-term starvation. Thus, culture-independent mAb-based diagnostic and detection tools, such as immuno-magnetic separation and microarray techniques are applicable for both L. pneumophila in the culturable and the VBNC state even after long-term starvation but nevertheless require careful testing before application. However, the mere presence of those epitopes is not necessarily an indication of viability or infectivity. PMID- 30016942 TI - Combined transepithelial phototherapeutic keratectomy and corneal collagen cross linking for corneal ectasia after small-incision lenticule extraction preoperative and 3-year postoperative results: a case report. AB - BACKGROUND: Corneal ectasia after small-incision lenticule extraction (SMILE) is uncommon. To our knowledge, this is the first report of 3-year results of combined phototherapeutic keratectomy (PTK) and corneal collagen cross-linking (CXL) for corneal ectasia after SMILE. CASE PRESENTATION: Herein, we describe a case of prominent corneal ectasia after SMILE treated with PTK combined with CXL 3 years ago. After surgery, maximum corneal keratometry, mean corneal keratometry, spherical equivalent and uncorrected distance visual acuity were significantly improved at follow-up intervals. CONCLUSIONS: Transepithelial PTK combined with CXL for corneal ectasia after SMILE may be an effective and safe treatment in the long term. PMID- 30016941 TI - Male sex and history of ischemic heart disease are major risk factors for anastomotic leakage after laparoscopic anterior resection in patients with rectal cancer. AB - BACKGROUND: Anastomotic leakage (AL) is the most serious and common complication of surgery for rectal cancer, and associated risk factors remain unknown despite developments in laparoscopic surgery. The present study aimed to determine risk factors for AL after laparoscopic anterior resection (AR) of rectal cancer. METHODS: This retrospective cohort study extracted information from a prospective database of all consecutive colorectal resections that proceeded at Nippon Medical School Hospital between January 2011 and December 2015 (n = 865). We identified 154 patients with rectal cancer treated by elective laparoscopic AR with anastomosis using primary double-stapling. Clinical variables and comorbidity, habits, and surgery-related variables were assessed by univariate and multivariate analyses to determine preoperative risk factors for clinical AL. RESULTS: The overall rate of clinical AL was 11.7% (18 of 154 patients), and 5 (27.8%) of 18 patients required revised laparotomy. Data from males were analyzed because AL occurred only in males. Univariate analysis of male patients (n = 100) significantly associated preoperative creatinine values (p = 0.03) and a history of ischemic heart disease (IHD) (p = 0.012) with AL. The frequency of AL tended to increase (p = 0.06) when patients had low AR (p = 0.06) and transanal drainage. Having AL significantly prolonged hospital stays compared with patients without leakage (36.2 vs. 11.1 days; p < 0.01). Multivariate analysis identified a history of IHD (odds ratio [OR], 4.73; 95% confidence interval [CI], 1.27-17.5; p = 0.025] as an independent risk factor for AL. CONCLUSIONS: Male sex and a history of IHD are possible risk factors for AL after elective laparoscopic rectal cancer surgery. PMID- 30016943 TI - A model for predicting utilization of mHealth interventions in low-resource settings: case of maternal and newborn care in Kenya. AB - BACKGROUND: In low-resource settings, there are numerous socioeconomic challenges such as poverty, inadequate facilities, shortage of skilled health workers, illiteracy and cultural barriers that contribute to high maternal and newborn deaths. To address these challenges, there are several mHealth projects particularly in Sub-Sahara Africa seeking to exploit opportunities provided by over 90% rate of mobile penetration. However, most of these interventions have failed to justify their value proposition to inspire utilization in low-resource settings. METHODS: This study proposes a theoretical model named Technology, Individual, Process-Fit (TIPFit) suitable for user-centred evaluation of intervention designs to predict utilization of mHealth products in low-resource settings. To investigate the predictive power of TIPFit model, we operationalized its latent constructs into variables used to predict utilization of an mHealth prototype called mamacare. The study employed single-group repeated measures quasi-experiment in which a random sample of 79 antenatal and postnatal patients were recruited from a rural hospital. During the study conducted between May and October 2014, the treatment involved sending and receiving SMS alerts on vital signs, appointments, safe delivery, danger signs, nutrition, preventive care and adherence to medication. RESULTS: Measurements taken during the study were cleaned and coded for analysis using statistical models like Partial Least Squares (PLS), Repeated Measures Analysis of Variance (RM-ANOVA), and Bonferroni tests. After analyzing 73 pretest responses, the model predicted 80.2% fit, and 63.9% likelihood of utilization. However, results obtained from initial post-test taken after three months demonstrated 69.1% fit, and utilization of 50.5%. The variation between prediction and the actual outcome necessitated improvement of mamacare based on feedback obtained from users. Three months later, we conducted the second post-test that recorded further drop in fit from 69.1 to 60.3% but utilization marginally improved from 50.5 to 53.7%. CONCLUSIONS: Despite variations between the pretest and post-test outcomes, the study demonstrates that predictive approach to user-centred design offers greater flexibility in aligning design attributes of an mHealth intervention to fulfill user needs and expectations. These findings provide a unique contribution for decision makers because it is possible to prioritize investments among competing digital health projects. PMID- 30016944 TI - Protocol for regional implementation of collaborative self-management services to promote physical activity. AB - BACKGROUND: Chronic diseases are generating a major health and societal burden worldwide. Healthy lifestyles, including physical activity (PA), have proven efficacy in the prevention and treatment of many chronic conditions. But, so far, national PA surveillance systems, as well as strategies for promotion of PA, have shown low impact. We hypothesize that personalized modular PA services, aligned with healthcare, addressing the needs of a broad spectrum of individual profiles may show cost-effectiveness and sustainability. METHODS: The current manuscript describes the protocol for regional implementation of collaborative self management services to promote PA in Catalonia (7.5 M habitants) during the period 2017-2019. The protocols of three implementation studies encompassing a broad spectrum of individual needs are reported. They have a quasi-experimental design. That is, a non-randomized intervention group is compared to a control group (usual care) using propensity score methods wherein age, gender and population-based health risk assessment are main matching variables. The principal innovations of the PA program are: i) Implementation of well-structured modular interventions promoting PA; ii) Information and communication technologies (ICT) to facilitate patient accessibility, support collaborative management of individual care plans and reduce costs; and iii) Assessment strategies based on the Triple Aim approach during and beyond the program deployment. DISCUSSION: The manuscript reports a precise roadmap for large scale deployment of community-based ICT-supported integrated care services to promote healthy lifestyles with high potential for comparability and transferability to other sites. TRIAL REGISTRATION: This study protocol has been registered at ClinicalTrials.org ( NCT02976064 ). Registered November 24th, 2016. PMID- 30016945 TI - Academic dishonesty among academics in Malaysia: a comparison between healthcare and non-healthcare academics. AB - BACKGROUND: This study was carried out to gauge the prevalence of academic dishonesty among academics in Malaysian universities. A direct comparison was made between academics of healthcare and non-healthcare courses to note the difference in the level of academic integrity between the two groups. In addition, the predisposing factors and implications of academic dishonesty, as well as the different measures perceived to be effective at curbing this problem were also investigated. METHODS: A cross-sectional study design with mixed qualitative and quantitative approaches was employed and data collection was carried out primarily using self-administered questionnaire. RESULTS: Approximately half (52.5%, n = 74) of all respondents (n = 141) reported having personally encountered at least one case of academic dishonesty involving their peers. The results also revealed the significantly higher prevalence of various forms of academic misconduct among healthcare academics compared to their non healthcare counterparts. Although respondents were generally conscious of the negative implications associated with academic dishonesty, more than half of all cases of misconduct were not reported due to the indifferent attitude among academics. Low levels of self-discipline and integrity were found to be the major factors leading to academic misdeeds and respondents opined that university managements should be more proactive in addressing this issue. CONCLUSIONS: The outcome of this study should serve as a clarion call for all relevant stakeholders to start making immediate amends in order to improve the current state of affairs in academia. PMID- 30016946 TI - Risk of heart failure hospitalization among users of dipeptidyl peptidase-4 inhibitors compared to glucagon-like peptide-1 receptor agonists. AB - BACKGROUND: Incretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) receptor agonists are novel medications for type 2 diabetes management. Several studies have found cardioprotective effects of incretin-based therapies; however, it remains unclear whether there is any difference in heart failure (HF) risk between the two incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists). We aimed to assess the risk of hospitalization due to HF with the use of DPP-4 inhibitors compared to GLP-1 receptor agonists. METHODS: Using Truven Health Marketscan data, we conducted a retrospective cohort study of patients with type 2 diabetes, who were newly initiated on DPP-4 inhibitors or GLP-1 agonists. Follow-up continued from drug initiation until the first occurrence of: HF hospitalization (primary outcome), discontinuation of therapy (i.e. no fill for 7 days), switch to the comparator, end of enrollment, or end of study (December 2013). Cox proportional hazards models with propensity-score-matching were used to compare the risk of HF hospitalization between DPP-4 inhibitors and GLP-1 agonists. RESULTS: A total of 321,606 propensity score-matched patients were included in the analysis (n = 160,803 for DPP-4 inhibitors; n = 160,803 for GLP-1 agonists). After adjusting for baseline characteristics and disease risk factors, the use of DPP-4 inhibitors was associated with a 14% decreased risk of HF hospitalization compared to GLP-1 agonists use [hazard ratio (HR), 0.86; 95% confidence interval (CI) 0.83, 0.90]. The results were consistent in patients without baseline HF (HR, 0.85; 95% CI 0.82, 0.89), but the association was not statistically significant for patients with baseline HF (HR, 0.90; 95% CI 0.74, 1.07). CONCLUSION: In this retrospective matched cohort of patients with type 2 diabetes, the use of DPP-4 inhibitors was associated with a reduced risk of HF hospitalization compared to GLP-1 agonists. However, the association was not statistically significant in patients who had HF prior to the use of DPP-4 inhibitors. PMID- 30016947 TI - Comparative analysis reveals unexpected genome features of newly isolated Thraustochytrids strains: on ecological function and PUFAs biosynthesis. AB - BACKGROUND: Thraustochytrids are unicellular fungal-like marine protists with ubiquitous existence in marine environments. They are well-known for their ability to produce high-valued omega-3 polyunsaturated fatty acids (omega-3 PUFAs) (e.g., docosahexaenoic acid (DHA)) and hydrolytic enzymes. Thraustochytrid biomass has been estimated to surpass that of bacterioplankton in both coastal and oceanic waters indicating they have an important role in microbial food-web. Nevertheless, the molecular pathway and regulatory network for PUFAs production and the molecular mechanisms underlying ecological functions of thraustochytrids remain largely unknown. RESULTS: The genomes of two thraustochytrids strains (Mn4 and SW8) with ability to produce DHA were sequenced and assembled with a hybrid sequencing approach utilizing Illumina short paired-end reads and Pacific Biosciences long reads to generate a highly accurate genome assembly. Phylogenomic and comparative genomic analyses found that DHA-producing thraustochytrid strains were highly similar and possessed similar gene content. Analysis of the conventional fatty acid synthesis (FAS) and the polyketide synthase (PKS) systems for PUFAs production only detected incomplete and fragmentary pathways in the genome of these two strains. Surprisingly, secreted carbohydrate active enzymes (CAZymes) were found to be significantly depleted in the genomes of these 2 strains as compared to other sequenced relatives. Furthermore, these two strains possess an expanded gene repertoire for signal transduction and self-propelled movement, which could be important for their adaptations to dynamic marine environments. CONCLUSIONS: Our results demonstrate the possibility of a third PUFAs synthesis pathway besides previously described FAS and PKS pathways encoded in the genome of these two thraustochytrid strains. Moreover, lack of a complete set of hydrolytic enzymatic machinery for degrading plant-derived organic materials suggests that these two DHA-producing strains play an important role as a nutritional source rather than a nutrient-producer in marine microbial-food web. Results of this study suggest the existence of two types of saprobic thraustochytrids in the world's ocean. The first group, which does not produce cellulosic enzymes and live as 'left-over' scavenger of bacterioplankton, serves as a dietary source for the plankton of higher trophic levels and the other possesses capacity to live on detrital organic matters in the marine ecosystems. PMID- 30016948 TI - The effectiveness of functional task exercise and physical therapy as prevention of functional decline in community dwelling older people with complex health problems. AB - BACKGROUND: A physically active lifestyle in older people contributes to the preservation of good health. We assessed the influence of physiotherapy on daily functioning among community dwelling older people (75+) with complex health problems identified with screening, versus usual care. We also compared functional task exercise (FTE), with problems prioritized by older people, trained in the home environment, versus usual preventive physical therapy (PPT). METHODS: Design: FTE and PPT were compared in a randomized controlled trial (RCT). Both interventions were compared with daily functioning in an observational study: control group. SETTING/PARTICIPANTS: Community-dwelling persons aged >=75 years with daily activity limitations enlisted in 83 general practices (n = 155). INTERVENTIONS: Both intervention groups (FTE, n = 76 and PPT, n = 79) received individual, 30 min treatments. The control group (n = 228) did not get any experimental intervention offered. MEASUREMENTS: Groningen Activities of Daily Living Restriction Scale (GARS). STATISTICAL ANALYSES: Linear Mixed Model analysis, correcting for age, sex, baseline scores and clustering by physiotherapist were used to compare the different groups. RESULTS: At baseline, 74% percent of the intervention trial group was female vs 79% in the control group. Median ages were 83.9 and 84.7 respectively. The median baseline GARS score for the control group was 41.0 (25 and 75 percentile): 35.0; 48.0) and 40.0 (25 and 75 percentile: 32.3; 46.0) for the intervention group (FTE + PPT). The mean change over time was 3.3 (2.5; 4.1) for the control group. Mean difference in change over time between the intervention (FTE + PPT) and the control group was - 2.5 (- 4.3; - 0.6) (p = .009). Between FTE and PPT the difference in change was - 0.4 (95% CI: -2.3; 3.0, p = 0.795). CONCLUSION: An exercise intervention led by physiotherapists may slow down decline in self-reported daily functioning in older persons with daily activity limitations, identified by pro-active case finding. TRIAL REGISTRATION: Netherlands trial register ( NTR2407 ). Registered 6th of July 2010. PMID- 30016950 TI - Random forest versus logistic regression: a large-scale benchmark experiment. AB - BACKGROUND AND GOAL: The Random Forest (RF) algorithm for regression and classification has considerably gained popularity since its introduction in 2001. Meanwhile, it has grown to a standard classification approach competing with logistic regression in many innovation-friendly scientific fields. RESULTS: In this context, we present a large scale benchmarking experiment based on 243 real datasets comparing the prediction performance of the original version of RF with default parameters and LR as binary classification tools. Most importantly, the design of our benchmark experiment is inspired from clinical trial methodology, thus avoiding common pitfalls and major sources of biases. CONCLUSION: RF performed better than LR according to the considered accuracy measured in approximately 69% of the datasets. The mean difference between RF and LR was 0.029 (95%-CI =[0.022,0.038]) for the accuracy, 0.041 (95%-CI =[0.031,0.053]) for the Area Under the Curve, and - 0.027 (95%-CI =[-0.034,-0.021]) for the Brier score, all measures thus suggesting a significantly better performance of RF. As a side-result of our benchmarking experiment, we observed that the results were noticeably dependent on the inclusion criteria used to select the example datasets, thus emphasizing the importance of clear statements regarding this dataset selection process. We also stress that neutral studies similar to ours, based on a high number of datasets and carefully designed, will be necessary in the future to evaluate further variants, implementations or parameters of random forests which may yield improved accuracy compared to the original version with default values. PMID- 30016949 TI - Diagnosis of acute canine leptospirosis using multiple laboratory tests and characterization of the isolated strains. AB - BACKGROUND: Dogs presenting with acute leptospirosis may present non-specific clinical and laboratory findings, and the definitive diagnosis may require additional confirmatory tests, including bacterial culture, for the direct or indirect identification of the pathogen. The present study describes the diagnosis of leptospirosis in suspected dogs based on the use of multiple diagnostic tests, including serological, molecular and bacteriological tests, along with the characterization of the recovered leptospiral strains. RESULTS: Urine, serum and blood samples were collected from 33 dogs with suspected clinical leptospirosis treated at the University of Sao Paulo Veterinary Hospital Service (Hovet FMVZ-USP) between 2013 and 2016. Only dogs with high blood urea nitrogen and creatinine levels in association with multiple clinical manifestations of the disease were included. Leptospiral culture, PCR and serology (Microscopic agglutination test - MAT) were performed in blood and urine samples taken from all suspected dogs at clinical presentation, and an additional prospective MAT titration was performed in seven dogs. Infection could be identified exclusively by PCR in 10 dogs (30.3%), exclusively by MAT in four dogs (12.1%) and by both tests in four dogs, totaling 18 dogs (54.5-95%CI: 37.6-71.5). Six out of eight MAT-confirmed cases presented with the highest titers against the Icterohaemorrhagiae serogroup. Leptospires were recovered from urine samples from two PCR-positive dogs, and both strains could be characterized by Multilocus Sequence Analysis and serogrouping as L. interrogans serogroup Icterohaemorrhagiae. Both isolates were shown to be pathogenic in the hamster model. CONCLUSIONS: The simultaneous use of MAT and PCR was able to increase the diagnosis of leptospirosis in clinically suspected cases. Despite the increasing incidence of new serovars affecting dogs being reported in different locations, our results suggest that leptospiral strains belonging to the Icterohaemorrhagiae serogroup are still a major causative agent of canine leptospirosis in Sao Paulo, Brazil. PMID- 30016951 TI - A quantitative systems pharmacology (QSP) model for Pneumocystis treatment in mice. AB - BACKGROUND: The yeast-like fungi Pneumocystis, resides in lung alveoli and can cause a lethal infection known as Pneumocystis pneumonia (PCP) in hosts with impaired immune systems. Current therapies for PCP, such as trimethoprim sulfamethoxazole (TMP-SMX), suffer from significant treatment failures and a multitude of serious side effects. Novel therapeutic approaches (i.e. newly developed drugs or novel combinations of available drugs) are needed to treat this potentially lethal opportunistic infection. Quantitative Systems Pharmacological (QSP) models promise to aid in the development of novel therapies by integrating available pharmacokinetic (PK) and pharmacodynamic (PD) knowledge to predict the effects of new treatment regimens. RESULTS: In this work, we constructed and independently validated PK modules of a number of drugs with available pharmacokinetic data. Characterized by simple structures and well constrained parameters, these PK modules could serve as a convenient tool to summarize and predict pharmacokinetic profiles. With the currently accepted hypotheses on the life stages of Pneumocystis, we also constructed a PD module to describe the proliferation, transformation, and death of Pneumocystis. By integrating the PK module and the PD module, the QSP model was constrained with observed levels of asci and trophic forms following treatments with multiple drugs. Furthermore, the temporal dynamics of the QSP model were validated with corresponding data. CONCLUSIONS: We developed and validated a QSP model that integrates available data and promises to facilitate the design of future therapies against PCP. PMID- 30016952 TI - Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia. AB - BACKGROUND: There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia. METHODS: In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method. RESULTS: For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier-rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier-rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503 rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642-rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582). CONCLUSION: We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction. PMID- 30016953 TI - Analysis of codon usage patterns in Hirudinaria manillensis reveals a preference for GC-ending codons caused by dominant selection constraints. AB - BACKGROUND: Hirudinaria manillensis is an ephemeral, blood-sucking ectoparasite, possessing anticoagulant capacities with potential medical applications. Analysis of codon usage patterns would contribute to our understanding of the evolutionary mechanisms and genetic architecture of H. manillensis, which in turn would provide insight into the characteristics of other leeches. We analysed codon usage and related indices using 18,000 coding sequences (CDSs) retrieved from H. manillensis RNA-Seq data. RESULTS: We identified four highly preferred codons in H. manillensis that have G/C-endings. Points generated in an effective number of codons (ENC) plot distributed below the standard curve and the slope of a neutrality plot was less than 1. Highly expressed CDSs had lower ENC content and higher GC content than weakly expressed CDSs. Principal component analysis conducted on relative synonymous codon usage (RSCU) values divided CDSs according to GC content and divided codons according to ending bases. Moreover, by determining codon usage, we found that the majority of blood-diet related genes have undergone less adaptive evolution in H. manillensis, except for those with homologous sequences in the host species. CONCLUSIONS: Codon usage in H. manillensis had an overall preference toward C-endings and indicated that codon usage patterns are mediated by differential expression, GC content, and biological function. Although mutation pressure effects were also notable, the majority of genetic evolution in H. manillensis was driven by natural selection. PMID- 30016954 TI - Quality of care for children with acute malnutrition at health center level in Uganda: a cross sectional study in West Nile region during the refugee crisis. AB - BACKGROUND: Arua district, in Uganda, hosts some of the largest refugee camps in the country. The estimated prevalence of moderate and severe acute malnutrition in children is higher than the national estimates (10.4 and 5.6% respectively, compared to 3.6 and 1.3%). This study aimed at assessing the quality of care provided to children with acute malnutrition at out-patient level in such a setting. METHODS: Six facilities with the highest number of children with malnutrition were selected. The main tool used was the National Nutrition Service Delivery Assessment Tool, assessing 10 key areas of service delivery and assigned a score as either poor, fair, good or excellent. Health outcomes, quality of case management and data quality were assessed from the health management information system and from the official nutrition registers. RESULTS: All facilities except two scored either poor or fair under all the 10 assessment areas. Overall, 33/60 (55%) areas scored as poor, 25/60 (41%) as fair, 2/60 (3.3%) as good, and none as excellent. Main gaps identified included: lack of trained staff; disorganised patient flow; poor case management; stock out of essential supplies including ready-to-use therapeutic foods; weak community linkage. A sample coverage of 45.4% (1020/2248) of total children admitted in the district during the 2016 financial year were included. The overall mean cure rate was 52.9% while the default rate was 38.3%. There was great heterogeneity across health facilities in health outcomes, quality of case management, and data quality. CONCLUSION: This study suggests that quality of care provided to children with malnutrition at health center level is substandard with unacceptable low cure rates. It is essential to identify effective approaches to enhance adherence to national guidelines, provision of essential nutritional commodities, regular monitoring of services and better linkage with the community through village health teams. PMID- 30016955 TI - Evolution of contact and alarm calls in the Kenyan endemic Hinde's babbler (Aves: Passeriformes). AB - BACKGROUND: Spatial isolation, diverging environmental conditions and social structures may lead to the differentiation of various traits, e.g. molecules, morphology and behaviour. Bird calls may provide important information on effects of geographic isolation and may reflect diverging ecological conditions related to altitude. Furthermore, bird calls are strongly shaped by the social behaviour of species. The Kenyan endemic bird Hinde's Babbler, Turdoides hindei, is a cooperative breeder existing in distinct family groups. The species occurs in five isolated population groups at different altitudes across its distribution range in south-eastern Kenya. With this model species we test for potential effects of geographic isolation, diverging altitudes, and social structures. We recorded and analysed contact and alarm calls of T. hindei, including its entire distribution range and all existing population groups. RESULTS: Our data show significant differentiation of call characteristics among population groups across the species' distribution range. This differentiation is correlated with geographical distance, but also with altitude. We also found strong call differentiation among neighbouring family groups. Call differentiation of contact calls was comparatively high in comparison to alarm calls, which showed a lower degree of divergence. CONCLUSION: Our data show that call differentiation is governed by geographic isolation as well as altitude. Diverging degrees of call differentiation in contact and alarm calls suggests that both call types are under different selective pressures. Alarm calls are required to be understood by all members of the species across the entire distribution range and thus call differentiation is lower. In contrast, contact calls are more specific and differ even among neighbouring families supporting the maintenance of distinct bird families and groups. PMID- 30016956 TI - The use of the DTOTM hybrid dynamic device: a clinical outcome- and radiological based prospective clinical trial. AB - BACKGROUND: The purpose of this study was to assess the radiological and clinical outcome parameters following lumbar hybrid dynamic instrumentation with the focus on the adjacent segment degeneration (ASD) and adjacent segment disease (ASDi). METHODS: In this prospective trial all patients presenting with degenerative changes to the lumbar spine have been included. Precondition was a stable adjacent level with/without degenerative alteration. The elected patients underwent a standardised fusion procedure with hybrid instrumentation (DTOTM, Zimmer Spine Inc., Denver, USA). Patients' demographics have been documented and the follow-up visits were conducted after 6 weeks, and then stepwise after 6 up to 48 months. Each follow-up visit included assessment of quality of life and pain using specific questionnaires (COMI, SF-36, ODI) and the radiological evaluation with focus on the adjacent level alterations. RESULTS: At a mean follow up of 24 months an incidence of ASD with 10.91% and for ASDi with 18.18% has been observed. In 9% a conversion to standardised fusion was needed. There was a high rate of mechanical complication: (1) screw loosening (52.73%), (2) pedicle screw breakage (10.91%), and (3) rod breakage (3.64%) after a follow up of a maximum of 60 months. There were no significant difference of COMI, ODI and SF-36(v2) in comparison to all groups but all 55 patients showed a clinical improvement over the time. CONCLUSION: The dynamic hybrid DTOTM device is comparable to the long-term results after standardised fusion procedure, while a high rate of mechanical complication decreased the initial benefit. TRIAL REGISTRATION: This trial was registered at the ClinicalTrials Register ( #NCT03404232 , 2018/01/18, registered retrospectively). PMID- 30016957 TI - Efficacy, effectiveness and safety of vaccination against human papillomavirus in males: a systematic review. AB - BACKGROUND: Human papillomavirus (HPV) vaccination is safe and effective in preventing cervical cancer in females. As HPV infections can also induce cancers of the anus, penis and oral cavity, male vaccination is also advocated, but systematic reviews on efficacy and safety in males are lacking. METHODS: We performed a systematic review on the efficacy, effectiveness and safety of HPV vaccination in males of any age. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from inception to April 2017. RESULTS: We identified 5196 articles and seven studies (four randomized controlled trials (RCTs), three non-randomized studies) were included, comprising a total of 5294 participants. Vaccine efficacy against at least 6-month persisting anogenital HPV 16 infections was 46.9% (95% confidence interval (CI) 28.6-60.8%), whereas efficacy against persisting oral infections was 88% (2-98%). A vaccine efficacy of 61.9% (21.4-82.8%) and 46.8% (- 20 to -77.9%) was observed against anal intraepithelial neoplasia grade 2 and grade 3 lesions, respectively. No meaningful estimates were available on vaccine efficacy or effectiveness against penile intraepithelial neoplasia grade 2 or 3, and no data were identified for anal, penile or head and neck squamous cell cancer. In participants who were HPV-seronegative and PCR-negative at enrolment, efficacy against all outcomes was higher as compared to seropositive and/or PCR-positive individuals. Risk of bias was low in three RCTs and high in one, while the three non-randomized studies were at serious to critical risk of bias. Grading of Recommendations Assessment, Development and Evaluation evidence quality was moderate to low for most outcomes. CONCLUSIONS: HPV vaccination in males is moderately effective against persistent anogenital HPV infection and high-grade anal intraepithelial lesions in studies where the population consists mainly of HPV-infected males. Vaccine effectiveness was high in study groups comprising HPV naive males. This supports a recommendation for vaccination of boys before the onset of sexual activity with the goal of establishing optimal vaccine-induced protection. Mathematical modelling studies will still be needed to assess the effects of adding males to existing HPV vaccination programs in females. TRIAL REGISTRATION: Prospective Register for Systematic Reviews (PROSPERO) registration CRD42016038965 . PMID- 30016958 TI - High-resolution epidemic simulation using within-host infection and contact data. AB - BACKGROUND: Recent epidemics have entailed global discussions on revamping epidemic control and prevention approaches. A general consensus is that all sources of data should be embraced to improve epidemic preparedness. As a disease transmission is inherently governed by individual-level responses, pathogen dynamics within infected hosts posit high potentials to inform population-level phenomena. We propose a multiscale approach showing that individual dynamics were able to reproduce population-level observations. METHODS: Using experimental data, we formulated mathematical models of pathogen infection dynamics from which we simulated mechanistically its transmission parameters. The models were then embedded in our implementation of an age-specific contact network that allows to express individual differences relevant to the transmission processes. This approach is illustrated with an example of Ebola virus (EBOV). RESULTS: The results showed that a within-host infection model can reproduce EBOV's transmission parameters obtained from population data. At the same time, population age-structure, contact distribution and patterns can be expressed using network generating algorithm. This framework opens a vast opportunity to investigate individual roles of factors involved in the epidemic processes. Estimating EBOV's reproduction number revealed a heterogeneous pattern among age groups, prompting cautions on estimates unadjusted for contact pattern. Assessments of mass vaccination strategies showed that vaccination conducted in a time window from five months before to one week after the start of an epidemic appeared to strongly reduce epidemic size. Noticeably, compared to a non intervention scenario, a low critical vaccination coverage of 33% cannot ensure epidemic extinction but could reduce the number of cases by ten to hundred times as well as lessen the case-fatality rate. CONCLUSIONS: Experimental data on the within-host infection have been able to capture upfront key transmission parameters of a pathogen; the applications of this approach will give us more time to prepare for potential epidemics. The population of interest in epidemic assessments could be modelled with an age-specific contact network without exhaustive amount of data. Further assessments and adaptations for different pathogens and scenarios to explore multilevel aspects in infectious diseases epidemics are underway. PMID- 30016960 TI - Prevalence and correlates of gender inequitable norms among young, church-going women and men in Kinshasa, Democratic Republic of Congo. AB - BACKGROUND: Prolonged political instability may have exacerbated gender inequitable beliefs in the Democratic Republic of Congo (DRC). The aim of this study was to assess attitudes related to gender-equitable norms and its determinants among young, church-going women and men in Kinshasa, DRC. METHOD: Data were collected through a cross-sectional survey with 291 church-going women and 289 men aged 18-24 years old, residing in three disadvantaged communes of Kinshasa. Variables included sociodemographic characteristics, attitudes towards gender equality, and responses to issues related to the gender-equitable men (GEM) scale. The GEM scale is a 24 item-questionnaire developed to measure attitudes towards gender equitable norms. Logistic regression was applied to discover the associations between the independent variables and the GEM outcome. RESULTS: Our study reflected the existence of attitudes hampering gender equality that were endorsed by both women and men. For example, 91.4% of women and 83% of men agreed with the statement "a woman's most important role is to take care of her home and cook for her family". Similarly, 88.3% of women and 82.9% of men concurred with the idea that men need more sex than women. These findings coexisted with a few equitable norms, because 93.7% of women and 92.3% of men agreed that a man and a woman should decide together if they want to have children. A positive association was found in both women and men between being educated, being single and separated and having supportive attitudes towards gender equality and a higher GEM scale score. Residency in Camp Luka and Masina was also a significant social determinant associated with equitable gender norms among men whilst job status was only significant among women. CONCLUSION: While both women and men had high levels of gender inequitable norms, those with more education, single, and with supportive attitudes to gender equality had high GEM scale scores. The results highlight an urgent need for the church to challenge and change gender norms among church youths. PMID- 30016959 TI - Targeted genome editing in acute lymphoblastic leukemia: a review. AB - BACKGROUND: Genome editing technologies offers new opportunities for tackling diseases such as acute lymphoblastic leukemia (ALL) that have been beyond the reach of previous therapies. RESULTS: We show how the recent availability of genome-editing tools such as CRISPR-Cas9 are an important means of advancing functional studies of ALL through the incorporation, elimination and modification of somatic mutations and fusion genes in cell lines and mouse models. These tools not only broaden the understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. CONCLUSIONS: New approaches including CRISPR Cas9 are crucial for functional studies of genetic aberrations driving cancer progression, and that may be responsible for treatment resistance and relapses. By using this approach, diseases can be more faithfully reproduced and new therapeutic targets and approaches found. PMID- 30016961 TI - Quality of life of female and male vegetarian and vegan endurance runners compared to omnivores - results from the NURMI study (step 2). AB - BACKGROUND: Health-related effects of a vegetarian or vegan diet are known to support parameters positively affecting exercise performance in athletes, whereas knowledge about psyche and wellbeing is sparse. Therefore, the aim of the Nutrition and Running High Mileage (NURMI) Study (Step 2) was to compare Quality of Life (QOL) scores among endurance runners following a vegetarian or vegan diet against those who adhere to an omnivorous diet. METHODS: The study was conducted following a cross-sectional design. A total of 281 recreational runners (159 women, 122 men) completed the WHOQOL-BREF questionnaire consisting of the domains physical health, psychological wellbeing, social relationships and environment, which generates scores on a scale from 4 to 20. Data analysis was performed using ANOVA. RESULTS: It was found that 123 subjects followed an omnivorous diet and 158 adhered to a vegetarian/vegan diet. There were 173 runners who met the inclusion criteria ('NURMI-Runners'), among them 103 half-marathoners and 70 marathoners and ultramarathoners, as well as 108 10 km runners as control group. Overall QOL scores were high (~ 16.62 +/- 1.91). Men had higher scores than women due to high scores in the physical health and psychological well-being dimensions. Adhering to an omnivorous diet affected environment scores for women and social relationships scores for men. A minor effect concerning race distance was observed in women, where half-marathoners had a higher environmental score than 10-km runners. A moderate diet*race distance interaction on environment scores was shown for men. CONCLUSIONS: The results revealed that endurance runners had a high QOL regardless of the race distance or diet choice. These findings support the notion that adhering to a vegetarian or vegan diet can be an appropriate and equal alternative to an omnivorous diet. TRIAL REGISTRATION: ISRCTN73074080 . Registered 12th June 2015, retrospectively registered. PMID- 30016962 TI - beta Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice. AB - BACKGROUND: The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and beta-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of beta-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in beta-cells. METHODS: Mice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in beta-cells (beta GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. beta-cell size and number were measured by immunofluorescence-based islet morphometry. RESULTS: In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from beta GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in beta GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in beta-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and beta-cell morphology were similar in beta GC-A KO mice and control littermates. However, HFD-fed beta GC-A KO animals had accelerated glucose intolerance and diminished adaptative beta-cell proliferation. CONCLUSIONS: Our studies of beta GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate beta-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of beta-cells to HFD induced obesity. Impaired beta-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes. PMID- 30016963 TI - Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens. AB - BACKGROUNDS: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver. METHODS: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated. RESULTS: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 * 10-4) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms. CONCLUSION: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C. PMID- 30016964 TI - RNA-sequencing in non-small cell lung cancer shows gene downregulation of therapeutic targets in tumor tissue compared to non-malignant lung tissue. AB - BACKGROUND: Gene expression of specific therapeutic targets in non-malignant lung tissue might play an important role in optimizing targeted therapies. This study aims to identify different expression patterns of fifteen genes important for targeted therapy in non-small cell lung cancer (NSCLC). METHODS: We prospectively collected tissue of NSCLC and non-malignant lung tissue from 25 primary resected patients. RNA-sequencing and 450 K methylation array profiling was applied to both NSCLC and non-malignant lung tissue and data were analyzed for 14 target genes. We analyzed differential expression and methylation as well as expression according to patient characteristics like smoking status, histology, age, chronic obstructive pulmonary disease, C-reactive protein (CRP) and gender. TCGA data served as a validation set. RESULTS: Nineteen men and 6 women were included. Important targets like PD-L2 (p = 0.035), VEGFR2 (p < 0.001) and VEGFR3 (p < 0.001) were downregulated (respective fold changes = 1.8, 3.1, 2.7, 3.5) in tumor compared to non-malignant lung tissue. The TCGA set confirmed these findings almost universally. PD-L1 (p < 0.001) became also significantly downregulated in the TCGA set. In NSCLC, MUC1 (p = 0.003) showed a higher expression in patients with a CRP < 5 mg/L compared to > 5 mg/L. In the TCGA data but not in our primary data, PD-L1 & 2 were both borderline more expressed in tumors of active smokers vs. tumors of ex-smokers (p = 0.044 and 0.052). CONCLUSIONS: Our results suggest a lower PD-L1 & 2 and VEGFR expression in NSCLC vs. non-malignant lung tissue. Specific patient characteristics did not seem to change the overall expression differences as they were in line with the overall results. This information may contribute to the optimization of targeted treatments. PMID- 30016965 TI - Lycorine inhibits glioblastoma multiforme growth through EGFR suppression. AB - BACKGROUND: Lycorine has been revealed to inhibit the development of many kinds of malignant tumors, including glioblastoma multiforme (GBM). Although compelling evidences demonstrated Lycorine's inhibition on cancers through some peripheral mechanism, in-depth mechanism studies of Lycotine's anti-GBM effects still call for further exploration. Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in GBM. Targeting EGFR by small molecular inhibitors is a rational strategy for GBM treatment. METHODS: The molecular docking modeling and in vitro EGFR kinase activity system were employed to identify the potential inhibitory effects of Lycorine on EGFR. And the Biacore assay was used to confirm the direct binding status between Lycorine and the intracellular EGFR (696-1022) domain. In vitro assays were conducted to test the suppression of Lycorine on the biological behavior of GBM cells. By RNA interference, EGFR expression was reduced then cells underwent proliferation assay to investigate whether Lycorine's inhibition on GBM cells was EGFR-dependent or not. RT-PCR and western blotting analysis were carried out to investigate the underlined molecular mechanism that Lycorine exerted on EGFR itself and EGFR signaling pathway. Three different xenograft models (an U251-luc intracranially orthotopic transplantation model, an EGFR stably knockdown U251 subcutaneous xenograft model and a patient-derived xenograft model) were performed to verify Lycorine's therapeutic potential on GBM in vivo. RESULTS: We identified a novel small natural molecule Lycorine binding to the intracellular EGFR (696-1022) domain as an inhibitor of EGFR. Lycorine decreased GBM cell proliferation, migration and colony formation by inducing cell apoptosis in an EGFR-mediated manner. Furthermore, Lycorine inhibited the xenograft tumor growths in three animal models in vivo. Besides, Lycorine impaired the phosphorylation of EGFR, AKT, which were mechanistically associated with expression alteration of a series of cell survival and death regulators and metastasis-related MMP9 protein. CONCLUSIONS: Our findings identify Lycorine directly interacts with EGFR and inhibits EGFR activation. The most significant result is that Lycorine displays satisfactory therapeutic effect in our patient derived GBM tumor xenograft, thus supporting the conclusion that Lycorine may be considered as a promising candidate in clinical therapy for GBM. PMID- 30016967 TI - Incidence of tuberous sclerosis and age at first diagnosis: new data and emerging trends from a national, prospective surveillance study. AB - BACKGROUND: Tuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited. METHODS: Prospective, national surveillance study in Germany over a 2-year-period (03/2015-02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data. RESULTS: In total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth - 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760-1:13.520 live births in Germany. CONCLUSIONS: This is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage. PMID- 30016968 TI - Ube2v1-mediated ubiquitination and degradation of Sirt1 promotes metastasis of colorectal cancer by epigenetically suppressing autophagy. AB - BACKGROUND: Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. METHODS: Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. RESULTS: Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. CONCLUSIONS: Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients. PMID- 30016970 TI - The Improving Global Health fellowship: a qualitative analysis of innovative leadership development for NHS healthcare professionals. AB - BACKGROUND: The importance of leadership development in the early stages of careers in the NHS has been highlighted in recent years and many programmes have been implemented which seek to develop leadership skills in healthcare professionals. The Improving Global Health (IGH) Fellowship scheme is one such programme, it provides a unique leadership development opportunity through an overseas placement with a focus on quality improvement work. This evaluation examines the impact of completing an IGH Fellowship on the career and leadership development of participants, who are referred to as Fellows. METHODS: Fellows who had returned from overseas placement between August 2008 and February 2015 were invited to complete an anonymised online questionnaire, which collected information on: demographic details, motivations for applying to the programme, leadership development and the impact of the IGH Fellowship on their career. Fifteen semi-structured interviews were conducted to further explore the impact of the programme on Fellows' leadership development and career progression. Interview transcripts were manually coded and underwent thematic content analysis. RESULTS: The questionnaire had a 67% (74/111) response rate. The number of fellows who self-identified as a leader more than doubled on completion of the IGH Fellowship (24/74 pre-fellowship versus 58/74 post-fellowship). 74% (55/74) reported that the IGH Fellowship had an impact upon their career, 35 of which reported that the impact was "substantial". The themes that emerged from the interviews revealed a personal development cycle that consolidated the fellows' interests and values whilst enhancing their self-efficacy and subsequently impacted positively upon their career choices. Three interviewees expressed frustration at the lack of opportunity to utilise their new skills on returning to the United Kingdom (UK). CONCLUSIONS: The IGH Fellowship successfully empowered healthcare professionals to self-identify as leaders. Of the 45/74 respondents who commented on the impact of the IGH Fellowship on their career, 41/45 comments were positive. The fellows described a process of experiential learning, reflection and evolving cultural intelligence, which consolidated their interests and values. The resultant increase in self-efficacy empowered these returned fellows in their choice of career. PMID- 30016966 TI - Advances in pediatrics in 2017: current practices and challenges in allergy, endocrinology, gastroenterology, genetics, immunology, infectious diseases, neonatology, nephrology, neurology, pulmonology from the perspective of Italian Journal of Pediatrics. AB - This review provides an overview of a remarkable number of significant studies in pediatrics that have been published over the past year in the Italian Journal of Pediatrics. We have selected information from papers presented in the Journal that deal with allergy, endocrinology, gastroenterology, genetics, immunology, infectious diseases, neonatology, nephrology, neurology, pulmonology. The relevant epidemiologic findings, and developments in prevention, diagnosis and treatment of the last year have been discussed and placed in context. We think that advances achieved in 2017 will help readers to make the future of patients better. PMID- 30016969 TI - Calcium-dependent cyto- and genotoxicity of nickel metal and nickel oxide nanoparticles in human lung cells. AB - BACKGROUND: Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. Therefore, an increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The aim of this study was to perform an in-depth investigation regarding the genotoxicity of well-characterized Ni and NiO NPs in human bronchial epithelial BEAS-2B cells and to discern possible mechanisms. Comparisons were made with NiCl2 in order to elucidate effects of ionic Ni. METHODS: BEAS-2B cells were exposed to Ni and NiO NPs, as well as NiCl2, and uptake and cellular dose were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS). The NPs were characterized in terms of surface composition (X-ray photoelectron spectroscopy), agglomeration (photon cross correlation spectroscopy) and nickel release in cell medium (ICP-MS). Cell death (necrosis/apoptosis) was investigated by Annexin V FITC/PI staining and genotoxicity by cytokinesis-block micronucleus (cytome) assay (OECD 487), chromosomal aberration (OECD 473) and comet assay. The involvement of intracellular reactive oxygen species (ROS) and calcium was explored using the fluorescent probes, DCFH-DA and Fluo-4. RESULTS: NPs were efficiently taken up by the BEAS-2B cells. In contrast, no or minor uptake was observed for ionic Ni from NiCl2. Despite differences in uptake, all exposures (NiO, Ni NPs and NiCl2) caused chromosomal damage. Furthermore, NiO NPs were most potent in causing DNA strand breaks and generating intracellular ROS. An increase in intracellular calcium was observed and modulation of intracellular calcium by using inhibitors and chelators clearly prevented the chromosomal damage. Chelation of iron also protected against induced damage, particularly for NiO and NiCl2. CONCLUSIONS: This study has revealed chromosomal damage by Ni and NiO NPs as well as Ni ionic species and provides novel evidence for a calcium-dependent mechanism of cyto- and genotoxicity. PMID- 30016971 TI - A multi-layered poroelastic slab model under cyclic loading for a single osteon. AB - BACKGROUND: An osteon consists of a multi-layered bone matrix and interstitial fluid flow in the lacunar-canalicular system. Loading-induced interstitial fluid flow in the lacunar-canalicular system is critical for osteocyte mechanotransduction and bone remodelling. METHODS: To investigate the effects of the lamellar structure and heterogeneous material properties of the osteon on the distributions of interstitial fluid flow and seepage velocity, an osteon is idealized as a hollow two-dimensional poroelastic multi-layered slab model subjected to cyclic loading. Based on poroelastic theory, the analytical solutions of interstitial fluid pressure and seepage velocity in lacunar canalicular pores were obtained. RESULTS: The results show that strain magnitude has a greater influence on interstitial fluid pressure than loading frequency. Interestingly, the heterogeneous distribution of permeability produces remarkable variations in interstitial fluid pressure and seepage velocity in the cross section of cortical bone. In addition, interstitial fluid flow stimuli to osteocytes are mostly controlled by the value of permeability at the surface of the osteon rather than at the inner wall of the osteon. CONCLUSION: Interstitial fluid flow induced by cycling loading stimuli to an osteocyte housed in a lacunar canalicular pore is not only correlated with strain amplitude and loading frequency, but also closely correlated with the spatial gradient distribution of permeability. This model can help us better understand the fluid flow stimuli to osteocytes during bone remodelling. PMID- 30016972 TI - Challenge in direct Spoligotyping of Mycobacterium tuberculosis: a problematic issue in the region with high prevalence of polyclonal infections. AB - OBJECTIVE: Based on our recent studies the prevalence of polyclonal infection in tuberculosis clinical specimens is more than 50% in Tehran, Iran. With this background, Spoligotyping was performed on clinical specimens and their respective cultures, and we examined whether mixed infections interfere with the results or not. RESULTS: Based on the Spoligotyping pattern, among the fourteen patients, 57.1% had different genotypes in clinical samples and their respective cultures. These discrepant patterns were suggestive of polyclonal infections in clinical samples with possible overlapping Spoligotype patterns. We propose that in societies with high mixed infections (e.g. Iran), direct Spoligotyping on clinical samples can be controversial. PMID- 30016973 TI - Autologous transplantation of adipose-derived stem cells improves functional recovery of skeletal muscle without direct participation in new myofiber formation. AB - BACKGROUND: Skeletal muscle has a remarkable regenerative capacity. However, extensive damage that exceeds the self-regenerative ability of the muscle can lead to irreversible fibrosis, scarring, and significant loss of function. Adipose-derived stem cells (ADSC) are a highly abundant source of progenitor cells that have been previously reported to support the regeneration of various muscle tissues, including striated muscles. The aim of this study was to evaluate the effect of ADSC transplantation on functional skeletal muscle regeneration in an acute injury model. METHODS: Mouse ADSC were isolated from subcutaneous fat tissue and transplanted with a collagen hydrogel into the crushed tibialis anterior muscle of mice. Recovering muscles were analyzed for gene and protein expression by real-time quantitative polymerase chain reaction and immunohistochemistry. The muscle contractility was assessed by myography in an organ bath system. RESULTS: Intramuscular transplantation of ADSC into crushed tibialis anterior muscle leads to an improved muscle regeneration with ADSC residing in the damaged area. We did not observe ADSC differentiation into new muscle fibers or endothelial cells. However, the ADSC-injected muscles had improved contractility in comparison with the collagen-injected controls 28 days post-transplantation. Additionally, an increase in fiber cross-sectional size and in the number of mature fibers with centralized nuclei was observed. CONCLUSIONS: ADSC transplantation into acute damaged skeletal muscle significantly improves functional muscle tissue regeneration without direct participation in muscle fiber formation. Cellular therapy with ADSC represents a novel approach to promote skeletal muscle regeneration. PMID- 30016974 TI - PBX3/MEK/ERK1/2/LIN28/let-7b positive feedback loop enhances mesenchymal phenotype to promote glioblastoma migration and invasion. AB - BACKGROUND: Brain invasion by glioblastoma (GBM) determines recurrence and prognosis in patients, which is, in part, attributed to increased mesenchymal transition. Here, we report evidence favoring such a role for the Pre-B-cell leukemia homebox (PBX) family member PBX3. METHODS: Western blot, immunohistochemistry, qRT-PCR and datasets mining were used to determined proteins or genes expression levels. Wound-healing and transwell assays were used to examine the invasive abilities of GBM cells. Dual-luciferase reporter assays were used to determine how let-7b regulates PBX3. Chromatin-immunoprecipitation (ChIP) and rescue experiments were performed to investigate the involved molecular mechanisms. Orthotopic mouse models were used to assess the role of PBX3 in vivo. RESULTS: We found that PBX3 expression levels positively correlated with glioma mesenchymal markers. Ectopic expression of PBX3 promoted invasive phenotypes and triggered the expression of mesenchymal markers, whereas depletion of PBX3 reduced GBM cell invasive abilities and decreased the expression of mesenchymal markers. In addition, inhibition of PBX3 attenuated transforming growth factor-beta (TGFbeta)-induced GBM mesenchymal transition. Mechanistic studies revealed that PBX3 mediated GBM mesenchymal transition through activation of MEK/ERK1/2, leading to increased expression of LIN28 by c-myc. Increased LIN28 inhibited let-7b biogenesis, which then promoted the pro-invasive genes, such as HMGA2 and IL-6. Furthermore, let-7b suppressed PBX3 by directly targeting 3'-UTR of PBX3. Thus, repressed let-7b by PBX3 amplifies PBX3 signaling and forms a positive feedback loop to promote GBM mesenchymal transition. CONCLUSIONS: These data highlight the importance of PBX3 as a key driver of mesenchymal transition and potential therapeutic target. PMID- 30016976 TI - Pulmonary nocardiosis masquerading renascence of tuberculosis in an immunocompetent host: a case report from Nepal. AB - BACKGROUND: Pulmonary nocardiosis is an opportunistic infection in an immunocompromised patient; however, often neglected in the immunocompetent patient from the diagnosis considerations. CASE PRESENTATIONS: We describe a case of pulmonary nocardiosis masquerading renascence of tuberculosis, in a 51-years Nepali farmer. After a 6 month of presumed successful antitubercular therapy; the patient develops the clinical presentations and radiological features showing similarities with that of tuberculosis and malignancy. MTB complex was not detected with Xpert MTB/RIF assay and cytological examinations were negative for the malignant cells, however. The Ziehl-Neelsen staining of the broncho-alveolar lavage revealed acid-fast, thin branching filamentous organisms suggestive Nocardia spp. Further, identifications and susceptibility pattern against recommended antibiotics were assessed as per the CLSI guidelines. The case was then, subsequently, diagnosed as pulmonary nocardiosis. Trimethoprim sulfamethoxazole was prescribed for 12 months. The patient underwent progressive changes and no relapse was noted in a periodic follow-up. CONCLUSIONS: This case underscores that pulmonary nocardiosis requires diagnostic considerations, regardless of a patient's immunologic status and other mimicking infections. PMID- 30016975 TI - GIVE: portable genome browsers for personal websites. AB - Growing popularity and diversity of genomic data demand portable and versatile genome browsers. Here, we present an open source programming library called GIVE that facilitates the creation of personalized genome browsers without requiring a system administrator. By inserting HTML tags, one can add to a personal webpage interactive visualization of multiple types of genomics data, including genome annotation, "linear" quantitative data, and genome interaction data. GIVE includes a graphical interface called HUG (HTML Universal Generator) that automatically generates HTML code for displaying user chosen data, which can be copy-pasted into user's personal website or saved and shared with collaborators. GIVE is available at: https://www.givengine.org/ . PMID- 30016977 TI - PBMC fixation and processing for Chromium single-cell RNA sequencing. AB - BACKGROUND: Interest in single-cell transcriptomic analysis is growing rapidly, especially for profiling rare or heterogeneous populations of cells. In almost all reported works investigators have used live cells, which introduces cell stress during preparation and hinders complex study designs. Recent studies have indicated that cells fixed by denaturing fixative can be used in single-cell sequencing, however they did not usually work with most types of primary cells including immune cells. METHODS: The methanol-fixation and new processing method was introduced to preserve human peripheral blood mononuclear cells (PBMCs) for single-cell RNA sequencing (scRNA-Seq) analysis on 10* Chromium platform. RESULTS: When methanol fixation protocol was broken up into three steps: fixation, storage and rehydration, we found that PBMC RNA was degraded during rehydration with PBS, not at cell fixation and up to 3-month storage steps. Resuspension but not rehydration in 3* saline sodium citrate (SSC) buffer instead of PBS preserved PBMC RNA integrity and prevented RNA leakage. Diluted SSC buffer did not interfere with full-length cDNA synthesis. The methanol-fixed PBMCs resuspended in 3* SSC were successfully implemented into 10* Chromium standard scRNA-seq workflows with no elevated low quality cells and cell doublets. The fixation process did not alter the single-cell transcriptional profiles and gene expression levels. Major subpopulations classified by marker genes could be identified in fixed PBMCs at a similar proportion as in live PBMCs. This new fixation processing protocol also worked in several other fixed primary cell types and cell lines as in live ones. CONCLUSIONS: We expect that the methanol based cell fixation procedure presented here will allow better and more effective batching schemes for a complex single cell experimental design with primary cells or tissues. PMID- 30016979 TI - Comparing the order of the London Measure of Unplanned Pregnancy and the Demographic and Health Survey question on pregnancy intention in a single group of postnatal women in Malawi - the effect of question order on assessment of pregnancy intention. AB - OBJECTIVE: To investigate the effect of question order on women's responses to the London Measure of Unplanned Pregnancy (LMUP) or the pregnancy intention question of the Demographic and Health Survey (DHS) when both are asked in the same survey. We collected data on pregnancy intention from a cohort of 4244 pregnant women in Malawi who were re-interviewed at 1, 6 and 12 months postnatally. Women in Zone 1 were asked the LMUP, then antenatal questions, then the DHS pregnancy intention question, women in Zone 2 were asked the DHS pregnancy intention question, then antenatal questions, then the LMUP; women in Zone 3 were only asked the DHS pregnancy intention question. We used linear regression to compare the LMUP score and ordinal regression to compare DHS categorisations of pregnancy intention across Zones, adjusting for baseline socioeconomic differences between the Zones. RESULTS: We found no effect of question order on the assessment of pregnancy intention by the LMUP. There were differences in the assessment of pregnancy intention when the pregnancy intention question in the DHS was used, however this seemed to be due to baseline sociodemographic differences between the groups of pregnant women being compared, and not due to question order. PMID- 30016978 TI - An esophagus-sparing technique to limit radiation esophagitis in locally advanced non-small cell lung cancer treated by simultaneous integrated boost intensity modulated radiotherapy and concurrent chemotherapy. AB - BACKGROUND: To investigate the incidence of radiation esophagitis (RE) and tumor local control using esophagus sparing technique in locally advanced non-small cell lung cancer (LANSCLC) treated by simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) and concurrent chemotherapy. METHODS: Eighty-seven patients with stage IIIA/B NSCLC who received definitive SIB-IMRT and concurrent chemotherapy had been divided into two groups: 1.with esophagus sparing technique; 2.without esophagus sparing technique. Chi-square test was performed to compare sex, clinical stage, histology, concurrent chemotherapy, RE and nutrition status between two groups. T-test was used to compare the dosimetric parameters. Overall survival (OS) and loco-regional failure free survival (LRFS) were calculated by the Kaplan-Meier method and compared by a log rank test. RESULTS: There were 44 patients in the esophagus sparing group and 43 in the non-sparing group. The incidence of severe RE (Grade 3) was significantly lower in patients with esophagus sparing technique (p = 0.002). Patients in esophagus sparing group had better nutrition status (p = 0.045). With a median follow-up of 18 months (range 1-51 months), the 1-year, 2-year and 3-year OS of all the patients was 86.6, 65.4 and 43.7%. The 1-year, 2-year LRFS was 78.4, 65.9%. OS time (p = 0.301) and LRFS (p = 0.871) was comparable between two groups. CONCLUSIONS: Esophagus-sparing technique is an effective and essential method to limit RE in LANSCLC treated by SIB-IMRT and concurrent chemotherapy without compromising local control. PMID- 30016980 TI - Traditional knowledge of wild edible plants with special emphasis on medicinal uses in Southern Shan State, Myanmar. AB - BACKGROUND: Myanmar is one of the hotspots of biodiversity and is a rapidly developing country. Performing floristic research in Myanmar is an urgent issue, and ethnobotanical studies of wild edible plants (WEPs) will provide new information on natural plant resources. METHOD: Ethnobotanical data were collected in three villages with different historical backgrounds in Southern Shan State, Myanmar. A total of 19 key informants were interviewed, and specimens were collected in the fields with the participation of key informants in June July 2015. Group discussions were organized during 2016 and 2017 to reinforce the information on use of WEPs. DNA barcoding was used to facilitate species identification. RESULTS: A total of 83 species from 44 families of angiosperms were recorded as WEPs. Most of the species were used as wild vegetables (47 species), followed by fruits and nuts (31 species). Eighteen WEPs were consumed as medicinal foods. Differences in use of WEPs between the communities of the villages were observed. The age class of 30-39 years was more familiar with the environments where they could collect WEPs and had more knowledge of WEPs than did the older groups. The use of Elaeocarpus floribundus as an edible oil is a very interesting tradition. CONCLUSION: WEPs play an important role in the livelihood of local communities. The indigenous society has maintained traditional knowledge of the WEPs. Historical background, land use system and surrounding vegetation could have effects on the variation in the traditional uses of WEPs. Increasing awareness of the importance of WEPs will encourage the conservation of traditional knowledge of indigenous populations. PMID- 30016981 TI - Blunt trauma to the antecubital fossa causing brachial artery injury and minor fractures around the elbow joint, an easily missed diagnosis with potential devastating consequences: a case report. AB - BACKGROUND: Blunt trauma causing brachial artery injury in a young patient is very rare. Cases of brachial artery injury may be associated with closed elbow dislocation or instability. Elbow dislocation may not be evident clinically and radiologically on initial presentation. CASE PRESENTATION: This is a case of a 37 year-old, right-hand dominant, Malay man who fell approximately 6 meters from a rambutan tree and his left arm hit the tree trunk on his way down. He was an active tobacco smoker with a 20 pack year smoking history. On clinical examination, Doppler signals over his radial and ulnar arteries were poor. He proceeded with emergency computed tomography angiogram of his left upper limb which showed non-opacification of contrast at the distal left brachial artery just before the bifurcation of the left brachial artery at his left elbow joint. Radiographs and computed tomography scan also showed undisplaced fracture of left lateral epicondyle and radial head with no evidence of elbow dislocation. He subsequently underwent left brachial to brachial artery bypass which was done using reversed saphenous vein graft and recovered well. His fractures were treated using 90 degree long posterior splint for 2 weeks and he was then allowed early range of motion of the left elbow. This patient developed left elbow dislocation 6 weeks postoperatively. Closed manipulative reduction of his left elbow resulted in incomplete reduction. The functional outcome of his left elbow was limited with a range of motion of left elbow of 0-45 degrees. However, he was not keen for surgery to stabilize his elbow joint during his last follow-up 6 months post injury. CONCLUSIONS: This is an uncommon case of brachial artery injury in a civilian caused by blunt trauma associated with occult elbow instability/dislocation and minor fractures around the elbow joint. The treatment of brachial artery injury with clinical evidence of distal ischemia is surgical revascularization. The possibility of elbow instability and dislocation need to be considered in all cases of brachial artery injury because early radiographs and computed tomography scans may be normal. Short-term posterior splint immobilization is not sufficient to prevent recurrent dislocations. PMID- 30016982 TI - Air pollution and airway resistance at age 8 years - the PIAMA birth cohort study. AB - BACKGROUND: Air pollution has been found to adversely affect children's lung function. Forced expiratory volume in 1 s and forced vital capacity from spirometry have been studied most frequently, but measurements of airway resistance may provide additional information. We assessed associations of long term air pollution exposure with airway resistance. METHODS: We measured airway resistance at age 8 with the interrupter resistance technique (Rint) in participants of the Dutch PIAMA birth cohort study. We linked Rint with estimated annual average air pollution concentrations [nitrogen oxides (NO2, NOx), PM2.5 absorbance ("soot"), and particulate matter < 2.5 MUm (PM2.5), < 10 MUm (PM10) and 2.5-10 MUm (PMcoarse)] at the birth address and current home address (n = 983). Associations between air pollution exposure and interrupter resistance (Rint) were assessed using multiple linear regression adjusting for potential confounders. RESULTS: We found that higher levels of NO2 at the current address were associated with higher Rint [adj. mean difference (95% confidence interval) per interquartile range increase in NO2: 0.018 (0.001, 0.035) kPa.s.L- 1]. Similar trends were observed for the other pollutants, except, PM10. No association was found between Rint and exposure at the birth address. CONCLUSIONS: Our results support the hypothesis that air pollution exposure is associated with a lower lung function in schoolchildren. PMID- 30016984 TI - Methicillin-resistant Staphylococcus aureus contamination and distribution in patient's care environment at Muhimbili National Hospital, Dar es Salaam Tanzania. AB - OBJECTIVE: Environmental contamination with methicillin-resistant Staphylococcus aureus in routine medical care settings poses an increased risk of health care associated infections through cross-transmission. This study aimed at determining the magnitude and distribution of methicillin-resistant S. aureus contamination among various items in patients' care surroundings at Muhimbili National Hospital, Tanzania's largest tertiary hospital. RESULTS: A total of 200 environmental samples from high touch items were processed and out of these methicillin-resistant S. aureus was 19.5% with significantly higher contamination in general wards. Patients' beds surfaces were the most contaminated among studied items (43.7%), whilst the surgical trolleys were least contaminated (7.7%). Presence of 10 or more patients in a room was an important significant correlate for methicillin-resistant S. aureus contamination by bivariate logistic regression model (odds ratio: 4.75, 95% confidence interval 1.624-13.895, p = 0.004). These findings warrant further study of decontamination practices and improved infection control mechanisms, especially in light of the drug resistant isolates identified. PMID- 30016983 TI - Effects of traditional Chinese herbal medicine in patients with diabetic kidney disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and the primary cause of end-stage renal disease. Existing therapies for DKD are not sufficiently effective. We report the protocol of a pragmatic randomized controlled trial of the use of traditional Chinese herbal medicine to treat patients with DKD. METHODS/DESIGN: This will be a multicenter randomized controlled trial. A total of 266 patients with DKD (106 with early stage, 80 with middle-stage, and 80 with advanced-stage disease) with an estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73m2will be included. Participants with DKD of each stage will be randomly allocated at a 1:1 ratio to either the experimental group, which will receive Xiaozhen formula and basic treatment, or the control group, which will receive basic treatment only. The study duration will be 24 weeks. The primary outcome will be urinary microalbumin excretion rate for early stage DKD, 24-h urinary protein for middle-stage DKD, and eGFR for advanced-stage DKD. Adverse events will also be evaluated. Data for all outcome indicators will be collected at baseline and weeks 4, 12, and 24. DISCUSSION: This study will provide evidence of the effectiveness and safety of traditional Chinese herbal medicine in treating patients with DKD. TRIAL REGISTRATION: Chinese Clinical Trials Registry: ChiCTR-IOR-16010072 . Registered on 2 December 2016. PMID- 30016985 TI - Correcting the literature: Improvement trends seen in contents of retraction notices. AB - OBJECTIVE: To analyse retraction notices from 2016 and compare their quality to the 2008 notices. RESULTS: From 146 retractions retrieved, only 123 were included, of which, a clear reason for retraction was available for 122 (99.2%) and no reason was given for one (0.8%). The main reasons for retraction were mistakes 26.0% (n = 32), fraud 26.0% (n = 32), plagiarism 20.3% (n = 25), and overlap 8.1% (n = 10). In 100 (81.3%) cases, a mention of retraction was available on the original paper, in 15 (12.2%) there was no mention of retraction, and 8 (6.5%) papers were deleted. Compared to the previous cohorts, management of retraction has improved because 99.2% provided a clear reason, and 81.3% of original articles were available with a mention of the retraction. PMID- 30016986 TI - Making genome browsers portable and personal. AB - GIVE is a framework and library for creating portable and personalized genome browsers. It makes visualizing genomic data as easy as building a laboratory homepage. PMID- 30016987 TI - Self-assembling functional programmable protein array for studying protein protein interactions in malaria parasites. AB - BACKGROUND: Plasmodium vivax is the most widespread malarial species, causing significant morbidity worldwide. Knowledge is limited regarding the molecular mechanism of invasion due to the lack of a continuous in vitro culture system for these species. Since protein-protein and host-cell interactions play an essential role in the microorganism's invasion and replication, elucidating protein function during invasion is critical when developing more effective control methods. Nucleic acid programmable protein array (NAPPA) has thus become a suitable technology for studying protein-protein and host-protein interactions since producing proteins through the in vitro transcription/translation (IVTT) method overcomes most of the drawbacks encountered to date, such as heterologous protein production, stability and purification. RESULTS: Twenty P. vivax proteins on merozoite surface or in secretory organelles were selected and successfully cloned using gateway technology. Most constructs were displayed in the array expressed in situ, using the IVTT method. The Pv12 protein was used as bait for evaluating array functionality and co-expressed with P. vivax cDNA display in the array. It was found that Pv12 interacted with Pv41 (as previously described), as well as PvMSP142kDa, PvRBP1a, PvMSP8 and PvRAP1. CONCLUSIONS: NAPPA is a high performance technique enabling co-expression of bait and query in situ, thereby enabling interactions to be analysed rapidly and reproducibly. It offers a fresh alternative for studying protein-protein and ligand-receptor interactions regarding a parasite which is difficult to cultivate (i.e. P. vivax). PMID- 30016989 TI - Randomized Embolization Trial for NeuroEndocrine Tumor Metastases to the Liver (RETNET): study protocol for a randomized controlled trial. AB - BACKGROUND: Neuroendocrine tumors (NETs) are the second most common gastrointestinal malignancy after colon cancer. Up to 90% of patients with NETs develop liver metastases, which are a major determinant of symptoms and survival. Current guidelines recommend embolotherapy for progressive or symptomatic NET liver metastases, but the optimal technique among bland embolization, lipiodol chemoembolization, and drug-eluting bead chemoembolization remains unknown and controversial. METHODS/DESIGN: A prospective, open-label, multicenter randomized controlled trial will be conducted in patients with progressive or symptomatic unresectable NET liver metastases. Patients will be randomized to treatment with bland embolization, lipiodol chemoembolization, or drug-eluting microsphere chemoembolization, with 60 enrollees per arm. The primary endpoint will be hepatic progression-free survival (HPFS) following initial embolotherapy by RECIST criteria. The sample size is powered to detect an HR of 1.78 for HPFS following chemoembolization compared with bland embolization, which was estimated on the basis of existing retrospective studies. Secondary endpoints include overall progression-free survival, duration of symptom control, quality of life, rate of adverse events, and interval between embolotherapy cycles. Interim safety analyses will be performed at 10 and 30 patients per arm. DISCUSSION: The RETNET trial is a prospective, multicenter randomized controlled trial designed to determine the optimal embolotherapy technique for NET liver metastases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02724540 . Registered on March 31, 2016. PMID- 30016988 TI - Long-chain fatty acid activates hepatocytes through CD36 mediated oxidative stress. AB - BACKGROUND: Accumulating evidence suggests that activated hepatocytes are involved in the deposition of the excess extracellular matrix during liver fibrosis via the epithelial to mesenchymal transition. Lipid accumulation in hepatocytes are implicated in the pathogenesis of chronic liver injury. CD36 is known to mediate long-chain fatty acid (LCFA) uptake and lipid metabolism. However, it is unclear whether LCFA directly promotes hepatocyte activation and the involved mechanisms have not been fully clarified. METHODS: Mice were fed with a high fat diet (HFD) and normal hepatocyte cells (Chang liver cells) were treated with palmitic acid (PA) in vivo and in vitro. Real-time polymerase chain reaction (RT-PCR) and western blotting were used to examine the gene and protein expression of molecules involved in hepatic fibrogenesis and hepatocyte activation. CD36 was knocked down by transfecting CD36 siRNA into hepatocyte cells. Hydrogen peroxide (H2O2) and reactive oxygen species (ROS) levels were detected using commercial kits. RESULTS: HFD induced a profibrogenic response and up-regulated CD36 expression in vivo. Analogously, PA increased lipid accumulation and induced human hepatocyte activation in vitro, which was also accompanied by increased CD36 expression. Interestingly, knockdown of CD36 resulted in a reduction of hepatocyte lipid deposition and decreased expression of Acta2 (34% decrease), Vimentin (29% decrease), Desmin (60% decrease), and TGF beta signaling pathway related genes. In addition, HFD and PA increased the production of H2O2 in vivo (48% increase) and in vitro (385% increase), and the antioxidant, NAC, ameliorated PA-induced hepatocyte activation. Furthermore, silencing of CD36 in vitro markedly attenuated PA-induced oxidative stress (H2O2: 41% decrease; ROS: 39% decrease), and the anti-activation effects of CD36 knockdown could be abolished by pretreatment with H2O2. CONCLUSIONS: Our study demonstrated that LCFA facilitates hepatocyte activation by up-regulating oxidative stress through CD36, which could be an important mechanism in the development of hepatic fibrosis. PMID- 30016990 TI - High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology. AB - BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates. METHOD: Here we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments. RESULTS: Consistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression. CONCLUSION: These results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods. PMID- 30016991 TI - Thrombopoietin knock-in augments platelet generation from human embryonic stem cells. AB - BACKGROUND: Refinement of therapeutic-scale platelet production in vitro will provide a new source for transfusion in patients undergoing chemotherapy or radiotherapy. However, procedures for cost-effective and scalable platelet generation remain to be established. METHODS: In this study, we established human embryonic stem cell (hESC) lines containing knock-in of thrombopoietin (TPO) via CRISPR/Cas9-mediated genome editing. The expression and secretion of TPO was detected by western blotting and enzyme-linked immunosorbent assay. Then, we tested the potency for hematopoietic differentiation by coculturing the cells with mAGM-S3 cells and measured the generation of CD43+ and CD45+ hematopoietic progenitor cells (HPCs). The potency for megakaryocytic differentiation and platelet generation of TPO knock-in hESCs were further detected by measuring the expression of CD41a and CD42b. The morphology and function of platelets were analyzed with electronic microscopy and aggregation assay. RESULTS: The TPO gene was successfully inserted into the AAVS1 locus of the hESC genome and two cell lines with stable TPO expression and secretion were established. TPO knock-in exerts minimal effects on pluripotency but enhances early hematopoiesis and generation of more HPCs. More importantly, upon its knock-in, TPO augments megakaryocytic differentiation and platelet generation. In addition, the platelets derived from hESCs in vitro are functionally and morphologically comparable to those found in peripheral blood. Furthermore, TPO knock-in can partially replace the large quantities of extrinsic TPO necessary for megakaryocytic differentiation and platelet generation. CONCLUSIONS: Our results demonstrate that autonomous production of cytokines in hESCs may become a powerful approach for cost-effective and large-scale platelet generation in translational medicine. PMID- 30016992 TI - Transcriptional network analysis on brains reveals a potential regulatory role of PPP1R3F in autism spectrum disorders. AB - OBJECTIVE: This study aims at identifying master regulators of transcriptional networks in autism spectrum disorders (ASDs). RESULTS: With two sets of independent RNA-Seq data generated on cerebellum from patients with ASDs and control subjects (N = 39 and 45 for set 1, N = 24 and 38 for set 2, respectively), we carried out a network deconvolution of transcriptomic data, followed by virtual protein activity analysis. We identified PPP1R3F (Protein Phosphatase 1 Regulatory Subunit 3F) as a candidate master regulator affecting a large body of downstream genes that are associated with the disease phenotype. Pathway analysis on the identified targets of PPP1R3F in both datasets indicated alteration of endocytosis pathway. Despite a limited sample size, our study represents one of the first applications of network deconvolution approach to brain transcriptomic data to generate hypotheses that may be further validated by large-scale studies. PMID- 30016994 TI - Utilizing compassion and collaboration to reduce violence in healthcare settings. AB - Violence in healthcare settings is a global problem and violent acts are more likely to occur in emergency departments (EDs). Significant barriers to reporting workplace violence persist among healthcare workers. This, and lack of shared definitions and metrics, increase the difficulty of assessing its prevalence, understanding its causes, and comparing the impact of interventions to reduce its frequency. While risk factors for violence in EDs have been articulated, less is known about how the perspectives of patients and accompanying persons, and their interactions with ED staff may contribute to violence.We discuss the nature and social context of ED violence and some approaches used to address this problem in the U.S. We argue that perpetrators of violence as well as healthcare staff who experience ED violence suffer when it occurs. While securing safety is paramount, compassionate practices to address this suffering and the social context from which it emerges should be developed and provided for all involved. Collaboration among stakeholders, including patients and family members, may lead to effective approaches to address this problem. PMID- 30016993 TI - Carry-over effects of urban larval environments on the transmission potential of dengue-2 virus. AB - BACKGROUND: Mosquitoes are strongly influenced by environmental temperatures, both directly and indirectly via carry-over effects, a phenomenon by which adult phenotypes are shaped indirectly by the environmental conditions experienced in previous life stages. In landscapes with spatially varying microclimates, such as a city, the effects of environmental temperature can therefore lead to spatial patterns in disease dynamics. To explore the contribution of carry-over effects on the transmission of dengue-2 virus (DENV-2), we conducted a semi-field experiment comparing the demographic and transmission rates of Aedes albopictus reared on different urban land classes in the summer and autumn season. We parameterized a model of vectorial capacity using field- and literature-derived measurements to estimate the bias introduced into predictions of vectorial capacity not accounting for carry-over effects. RESULTS: The larval environment of different land classes and seasons significantly impacted mosquito life history traits. Larval development and survival rates were higher in the summer than the autumn, with no difference across land class. The effect of land class on adult body size differed across season, with suburban mosquitoes having the smallest wing length in the summer and the largest wing length in the autumn, when compared to other land classes. Infection and dissemination rates were higher in the autumn and on suburban and rural land classes compared to urban. Infectiousness did not differ across land class or season. We estimate that not accounting for carry-over effects can underestimate disease transmission potential in suburban and urban sites in the summer by up to 25%. CONCLUSIONS: Our findings demonstrate the potential of the larval environment to differentially impact stages of DENV-2 infection in Ae. albopictus mosquitoes via carry-over effects. Failure to account for carry-over effects of the larval environment in mechanistic models can lead to biased estimates of disease transmission potential at fine-scales in urban environments. PMID- 30016995 TI - Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients. AB - BACKGROUND: Gallbladder carcinoma is highly aggressive and resistant to chemotherapy, with no consistent strategy to guide first line chemotherapy. However, patient-derived xenograft (PDX) model has been increasingly used as an effective model for in preclinical study of chemosensitivity. METHODS: Mini-PDX model was established using freshly resected primary lesions from 12 patients with gallbladder to examine the sensitivity with five of the most commonly used chemotherapeutic agents, namely gemcitabine, oxaliplatin, 5-fluorouracil, nanoparticle albumin-bound (nab)-paclitaxel, and irinotecan. The results were used to guide the selection of chemotherapeutic agents for adjunctive treatment after the surgery. Kaplan-Meier method was used to compare overall survival (OS) and disease free survival (DFS) with 45 patients who received conventional chemotherapy with gemcitabine and oxaliplatin. RESULTS: Cell viability assays based on mini-PDX model revealed significant heterogeneities in drug responsiveness. Kaplan-Meier analysis showed that patients in the PDX-guided chemotherapy group had significantly longer median OS (18.6 months; 95% CI 15.9 21.3 months) than patients in the conventional chemotherapy group (13.9 months; 95% CI 11.7-16.2 months) (P = 0.030; HR 3.18; 95% CI 1.47-6.91). Patients in the PDX-guided chemotherapy group also had significantly longer median DFS (17.6 months; 95% CI 14.5-20.6 months) than patients in the conventional chemotherapy group (12.0 months; 95% CI 9.7-14.4 months) (P = 0.014; HR 3.37; 95% CI 1.67 6.79). CONCLUSION: The use of mini-PDX model to guide selection of chemotherapeutic regimens could improve the outcome in patients with gallbladder carcinoma. PMID- 30016996 TI - Pain rewarded: hyperalgesic and allodynic effect of operant conditioning in healthy humans-protocol for a systematic review and meta-analysis. AB - BACKGROUND: 'Pain rewarded' is a hypothesis wherein acute pain sufferers are exposed to reinforcers and punishers from their environment that shape their behaviour, i.e. pain responses. Such a point of view has been taken for granted by many clinicians and researchers although existing evidence has not yet been systematically summarized. This planned systematic review and meta-analysis is aiming to summarize the research findings on pain modulation (hyperalgesic effect) and pain elicitation (allodynic effect) resulting from operant conditioning procedures in healthy humans. METHODS: The systematic review will be performed by searching for articles indexed in PubMed database, Cochrane Register of Controlled Trials (CENTRAL), Web of ScienceTM, ScienceDirect, EBSCO database, PsycINFO, MEDLINE, PsycARTICLES and CINAHL. Studies will be included if they investigate healthy humans, exposed to modulation or elicitation of a pain experience induced by operant conditioning. Studies will be screened for eligibility and risk of bias by two independent assessors. Narrative and meta analytical syntheses are planned. DISCUSSION: Data will be pooled and analyzed qualitatively and quantitatively (if possible) in order to advance the understanding of pain mechanisms, especially the development of chronic pain. This systematic review will guide the planning of future experiments and research by summarizing important technical details of conditioning procedures in healthy humans. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017051763. PMID- 30016997 TI - Social support in the general population: standardization of the Oslo social support scale (OSSS-3). AB - BACKGROUND: The objectives of the study were to generate normative data for the Oslo Social Support Scale (OSSS-3) for different age groups for men and women and to further investigate the factor structure in the general population. METHODS: Nationally representative face-to face household surveys were conducted in Germany in 2008 (n = 2524). RESULTS: Normative data for the Oslo Social Support Scale were generated for men and women (52.3% female) and different age levels (mean age (SD) of 48.9 (18.3) years). Men had mean scores comparable to women (10.1 [SD = 2.3] vs. 10.2 [SD = 2.2]). The EFA resulted in a clear one-factor solution for the OSSS-3. CONCLUSIONS: The normative data provide a framework for the interpretation and comparisons of social support with other populations. PMID- 30017000 TI - Goat pasteurellosis: serological analysis of circulating Pasteurella serotypes in Tanqua Aberegelle and Kola Tembien Districts, Northern Ethiopia. AB - OBJECTIVES: A cross-sectional study was employed with the aim to explore the serological status of goats; we evaluated the presence of serum antibodies of the circulating serotypes of the genus Pasteurella. A total of 124 serum samples were collected from randomly selected goats and subsequently serotyped using indirect haemagglutination test. RESULTS: In the current study, the overall prevalence of pasteurellosis in goats was 31.4%. Additionally, a total of eight serotypes of Pasteurella were serotyped. It is evident that 25% out of 124 sampled animals were found infected by four or more circulating serotypes and 6.4% animals were also found positive for all serotypes. Accordingly, the prevalence of Pasteurella multocida serotype A were 16.9%, Mannheimia haemolytica serotype A1 26.6%, M. haemolytica serotype A2 18.5%, M. haemolytica serotype A7 16.1%, Bibersteinia trehalosi serotype T3 20.9%, B. trehalosi serotype T4 21.7%, B. trehalosi serotype T10 27.4%, and B. trehalosi serotype T15 was 25.8%. Therefore, although there has been vaccination campaign with monovalent vaccine P. multocida type A, the diseases still exerts negative impacts through death of goats to smallholder farmers. Therefore, to control the disease the government should provide multivalent vaccine of the above serotypes. PMID- 30017001 TI - Resolving the taxonomic status of biocontrol agents belonging to the Aphidius eadyi species group (Hymenoptera: Braconidae: Aphidiinae): an integrative approach. AB - Species that belong to the Aphidius eadyi group have been used as biocontrol agents against Acyrthosiphon pisum worldwide. However, despite their extensive use, there are still gaps in our knowledge about their taxonomy and distribution. In this study, we employed an integrative taxonomic approach by combining genetic analyses (mtDNA COI barcoding) with standard morphological analyses and geometric morphometrics of forewing shape. We identified three species within the A. eadyi species group, viz., A. smithi, A. eadyi and A. banksae. Genetic separation of all three species was confirmed, with mean genetic distances between species ranging from 5 to 7.4%. The following morphological characters were determined as the most important for separating species of the A. eadyi group: number and shape of costulae on the anterolateral part of the petiole, shape of the central areola on the propodeum, and shape and venation of the forewings. The differences in wing shape of all three species were statistically significant, but with some overlapping. We identified A. banksae as a widely distributed pea aphid parasitoid, whose known range covers most of the western Palaearctic (from the UK to Israel). Aphidius banksae is diagnosed and redescribed. PMID- 30016998 TI - Sex gap in aging and longevity: can sex chromosomes play a role? AB - It is well known that women live longer than men. This gap is observed in most human populations and can even reach 10-15 years. In addition, most of the known super centenarians (i.e., humans who lived for > 110 years) are women. The differences in life expectancy between men and women are often attributed to cultural differences in common thinking. However, sex hormones seem to influence differences in the prevalence of diseases, in the magnitude of aging, and in the longevity between men and women. Moreover, far from being human specific, the sex gap in longevity is extremely common in non-human animals, especially in mammals. Biological factors clearly contribute to such a sex gap in aging and longevity. Different hypotheses have been proposed to explain why males and females age and die differently. The cost of sexual selection and sexual dimorphism has long been considered the best explanation for the observed sex gap in aging/longevity. However, the way mitochondria are transmitted (i.e., through females in most species) could have an effect, called the mother's curse. Recent data suggest that sex chromosomes may also contribute to the sex gap in aging/longevity through several potential mechanisms, including the unguarded X/Z, the toxic Y/W and the loss of Y/W. We discuss future research directions to test these ideas. PMID- 30017002 TI - Exploring the association between optimism and quality of life among informal caregivers of persons with dementia. AB - : ABSTRACTObjective:We aimed to analyze the relationship between optimism and quality of life (QoL) among informal caregivers of patients with dementia (PWD). DESIGN: In this cross-sectional study, a hierarchical multiple linear regression analysis was used to determine the association between optimism and caregiver's QoL after controlling the effect of different covariates, including burden. PARTICIPANTS: A sample of 130 PWD and their informal caregivers underwent a comprehensive protocol of assessment. MEASUREMENTS: Caregivers completed the Battery of Generalized Expectancies of Control Scales, the Zarit Burden Interview, and the World Health Organization Quality of Life-Brief as measure of QoL. Optimism was estimated based on the combination of three expectancies of control, namely, self-efficacy, contingency, and success. RESULTS: QoL correlated positively with optimism and negatively with burden. Optimism predicted each dimension of QoL, even after controlling for the effect of sociodemographic, care recipients' clinical covariates, and burden in all models. CONCLUSION: Optimism consistently predicted well-being and QoL in informal caregivers of PWD. PMID- 30016999 TI - Cognitive Behavioural Therapy for schizophrenia - outcomes for functioning, distress and quality of life: a meta-analysis. AB - BACKGROUND: The effect of cognitive behavioural therapy for psychosis (CBTp) on the core symptoms of schizophrenia has proven contentious, with current meta analyses finding at most only small effects. However, it has been suggested that the effects of CBTp in areas other than psychotic symptoms are at least as important and potentially benefit from the intervention. METHOD: We meta-analysed RCTs investigating the effectiveness of CBTp for functioning, distress and quality of life in individuals diagnosed with schizophrenia and related disorders. Data from 36 randomised controlled trials (RCTs) met our inclusion criteria- 27 assessing functioning (1579 participants); 8 for distress (465 participants); and 10 for quality of life (592 participants). RESULTS: The pooled effect size for functioning was small but significant for the end-of-trial (0.25: 95% CI: 0.14 to 0.33); however, this became non-significant at follow-up (0.10 [95%CI -0.07 to 0.26]). Although a small benefit of CBT was evident for reducing distress (0.37: 95%CI 0.05 to 0.69), this became nonsignificant when adjusted for possible publication bias (0.18: 95%CI -0.12 to 0.48). Finally, CBTp showed no benefit for improving quality of life (0.04: 95% CI: -0.12 to 0.19). CONCLUSIONS: CBTp has a small therapeutic effect on functioning at end-of-trial, although this benefit is not evident at follow-up. Although CBTp produced a small benefit on distress, this was subject to possible publication bias and became nonsignificant when adjusted. We found no evidence that CBTp increases quality of life post intervention. PMID- 30017003 TI - Differences in priority by age group and perspective: implications for public health education and campaigning in relation to dementia. AB - : ABSTRACTObjectives:A shift toward public health responses to dementia, raises questions about the most appropriate approaches to specific population groups. We examined perspective and age as elements in effective campaigning. Implications from the standpoint of the recipient are drawn for public health education and practice. DESIGN: In-depth semi-structured face-to-face and telephone interview with self-selected participants recruited via adverts, contact with provider organizations and cards placed in retail and service settings. Questions focused on attitudes to dementia and expectations of public campaigning and education. SETTING: Community-dwelling adults were interviewed across five Australian states. PARTICIPANTS: A total of 111 people from 5 target groups: people with dementia (n = 19), carers (n = 28), care work and service professionals from healthcare (n = 21), social work (n = 23) and commercial service professions (n = 20) involving people in younger adulthood (n = 13), early midlife (n = 23), later midlife (n = 54), and older age (n = 21). MEASUREMENTS: All interviews were transcribed and analyzed thematically by three researchers, reaching consensus before coding and further analysis in NVivo. Narrative analysis of transcripts included 330 topics relating to 6 main areas of focus. RESULTS: Attitudes and views on effective future campaigning reflected a desire for greater social inclusion, but did not focus on prevention and health services. Professionals focused on increasing interpersonal skills, people with dementia on normalization, and carers on awareness-raising. CONCLUSIONS: Public health campaigning and education in relation to dementia, could benefit from closer consideration of perspective and age of recipient in intervention design. Interpersonal skills and social inclusion were identified as key issues. PMID- 30017004 TI - Mapping modified Mini-Mental State Examination (MMSE) scores to dementia stages in a multi-ethnic Asian population. AB - ABSTRACTThe MMSE is used to screen for cognitive impairment and estimate dementia severity. In clinical settings, conventional cut-off scores have been used to distinguish between dementia stages. However, these scores have not been validated for different populations. This study maps scores from the modified version of the MMSE to dementia stages delineated by the Diagnostic and Statistical Manual of Mental Disorders-3rd revised edition (DSM-III-R), the Clinical Dementia Rating (CDR) and Functional Assessment Staging Test (FAST). We used cross-sectional data from a tertiary hospital memory clinic. Subjects were stratified into "primary education and below" (PE) or "secondary education and above" (SE). Receiving operating characteristic (ROC) analyses and Cohen's kappa were performed to determine MMSE cut-off scores for dementia stages. Our derived cut-off scores were lower compared to the conventional scores. Scores also differed between subjects of different education levels. MMSE cut-off scores were 19, 15, and 9 for CDR stages 1, 2, and 3 respectively in PE subjects, and 23, 17, and 10 for SE subjects. Cut-off scores were comparable for staging by DSM-III-R Criteria and FAST. There is a need for locally derived stage-specific MMSE cut off scores for the Asian population adjusted for education. PMID- 30017005 TI - Life story books for people with dementia: a systematic review. AB - : ABSTRACTObjectives:There is an increasing evidence that reminiscence therapy is effective in improving cognitive functions and reducing depressive symptoms in people with dementia. Life story books (LSBs) are frequently used as a reminiscence tool to support recollecting autobiographical memories. As little is known about how LSBs are used and what type of studies have been employed to evaluate LSB interventions, we conducted a systematic review. METHODS: The electronic databases Scopus, PubMed, and PsychINFO as well as reference lists of existing studies were searched to select eligible articles. Out of the 55 studies found, 14 met the inclusion criterion of an original empirical study on LSBs in people with dementia. RESULTS: The majority of the LSBs were tangible books, although some digital applications were also found. The LSBs were created mostly in individual sessions in nursing homes with a median of six sessions. Some studies only focused on the person with dementia, while others also examined (in)formal caregivers. Most studies used qualitative interviews, case studies, and/or (pilot) randomized controlled trial (RCTs) with small sample sizes. Qualitative findings showed the value of LSBs in triggering memories and in improving the relation with the person with dementia. Quantitative effects were found on, e.g. autobiographical memory and depression of persons with dementia, quality of relationship with informal caregivers, burden of informal caregivers, and on attitudes and knowledge of formal caregivers. CONCLUSIONS: This systematic review confirms that the use of LSBs to support reminiscence and person-centered care is promising, but larger RCTs or implementation studies are needed to establish the effects of LSBs on people with dementia. PMID- 30017006 TI - The effectiveness and cost-effectiveness of the Incredible Years(r) Teacher Classroom Management programme in primary school children: results of the STARS cluster randomised controlled trial. AB - BACKGROUND: We evaluated the effectiveness and cost-effectiveness of the Incredible Years(r) Teacher Classroom Management (TCM) programme as a universal intervention, given schools' important influence on child mental health. METHODS: A two-arm, pragmatic, parallel group, superiority, cluster randomised controlled trial recruited three cohorts of schools (clusters) between 2012 and 2014, randomising them to TCM (intervention) or Teaching As Usual (TAU-control). TCM was delivered to teachers in six whole-day sessions, spread over 6 months. Schools and teachers were not masked to allocation. The primary outcome was teacher-reported Strengths and Difficulties Questionnaire (SDQ) Total Difficulties score. Random effects linear regression and marginal logistic regression models using Generalised Estimating Equations were used to analyse the outcomes. TRIAL REGISTRATION: ISRCTN84130388. RESULTS: Eighty schools (2075 children) were enrolled; 40 (1037 children) to TCM and 40 (1038 children) to TAU. Outcome data were collected at 9, 18, and 30-months for 96, 89, and 85% of children, respectively. The intervention reduced the SDQ-Total Difficulties score at 9 months (mean (s.d.):5.5 (5.4) in TCM v. 6.2 (6.2) in TAU; adjusted mean difference = -1.0; 95% CI-1.9 to -0.1; p = 0.03) but this did not persist at 18 or 30 months. Cost-effectiveness analysis suggested that TCM may be cost effective compared with TAU at 30-months, but this result was associated with uncertainty so no firm conclusions can be drawn. A priori subgroup analyses suggested TCM is more effective for children with poor mental health. CONCLUSIONS: TCM provided a small, short-term improvement to children's mental health particularly for children who are already struggling. PMID- 30017007 TI - Symptoms of persistent complex bereavement disorder, depression, and PTSD in a conjugally bereaved sample: a network analysis. AB - BACKGROUND: Complicated and persistent grief reactions afflict approximately 10% of bereaved individuals and are associated with severe disruptions of functioning. These maladaptive patterns were defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as persistent complex bereavement disorder (PCBD), but its criteria remain debated. The condition has been studied using network analysis, showing potential for an improved understanding of PCBD. However, previous studies were limited to self report and primarily originated from a single archival dataset. To overcome these limitations, we collected structured clinical interview data from a community sample of newly conjugally bereaved individuals (N = 305). METHODS: Gaussian graphical models (GGM) were estimated from PCBD symptoms diagnosed at 3, 14, and 25 months after the loss. A directed acyclic graph (DAG) was generated from initial PCBD symptoms, and comorbidity networks with DSM-5 symptoms of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) were analyzed 1 year post-loss. RESULTS: In the GGM, symptoms from the social/identity PCBD symptoms cluster (i.e. role confusion, meaninglessness, and loneliness) tended to be central in the network at all assessments. In the DAG, yearning activated a cascade of PCBD symptoms, suggesting how symptoms lead into psychopathological configurations. In the comorbidity networks, PCBD and depressive symptoms formed separate communities, while PTSD symptoms divided in heterogeneous clusters. CONCLUSIONS: The network approach offered insights regarding the core symptoms of PCBD and the role of persistent yearnings. Findings are discussed regarding both clinical and theoretical implications that will serve as a step toward a more integrated understanding of PCBD. PMID- 30017008 TI - Which interventions work for dementia family carers?: an updated systematic review of randomized controlled trials of carer interventions. AB - : ABSTRACTObjective:The aim of this study was to update the literature on interventions for carers of people with dementia published between 2006 and 2016 and evaluate the efficacy of psychoeducational programs and psychotherapeutic interventions on key mental health outcomes (depression, anxiety, burden, and quality of life). METHODS: A meta-analysis was carried out of randomized controlled trials of carer interventions using MEDLINE, PsycINFO, Scopus, and Cochrane Central Register of Controlled Trials. RESULTS: The majority of studies were conducted in Western and Southern Europe or the United States and recruited carers of people with Alzheimer's disease or dementia grouped as a whole. The most commonly used outcome measures were depression and burden across studies. The updated evidence suggested that psychoeducation-skill building interventions delivered face-to-face can better impact on burden. Psychotherapeutic interventions underpinned by Cognitive Behavior Therapy (CBT) models demonstrated strong empirical support for treating anxiety and depression and these effects were not affected by the mode of delivery (i.e. face-to-face vs. technology). A modern CBT approach, Acceptance and Commitment Therapy (ACT), seemed to be particularly beneficial for carers experiencing high levels of anxiety. CONCLUSIONS: Future research needs to explore the efficacy of interventions on multiple clinical outcomes and which combination of interventions (components) would have the most significant effects when using CBT. The generalization of treatment effects in different countries and carers of different types of dementia also need to be addressed. More research is needed to test the efficacy of modern forms of CBT, such as ACT. PMID- 30017009 TI - The effect of social network on the physical activity-cognitive function nexus in late life. AB - : ABSTRACTBackground:To examine the contribution of vigorous physical activity to subsequent cognitive functioning, taking into account the effect of social network. METHODS: The sample included respondents aged 65 years and older who participated in both the fourth and sixth waves of Survey of Health, Ageing and Retirement in Europe (n = 17,104). Cognitive functioning in Wave 6, measured as the average of standardized scores for recall, fluency, and numeracy, was regressed on the extent of vigorous physical activity, social network size, and several confounders in Wave 4 (including the corresponding cognition score at baseline). Interaction terms for physical activity and network size were also considered. RESULTS: Moderate and high levels of vigorous physical activity, as well as social network size, were related to the cognition outcome after controlling for the confounders. Introduction of the interaction terms showed a direct and positive association of both moderate and high physical activity with the cognition outcome scores as social network size increased. However, among respondents in small- (0-1 members) and moderate-sized networks (2-3 members), greater physical activity was unrelated to the cognition score at follow-up. Only the interaction of high social connectedness (4-7 network members) and vigorous physical activity was significant. CONCLUSIONS: Vigorous physical activity is, indeed, related to subsequent cognitive functioning. However, the relationship is tempered by social network size. Therefore, interventions that increase both social connectedness and physical activity, especially among older people who are isolated and sedentary, are warranted. PMID- 30017010 TI - Validation of the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural sample across five Western European countries: diagnostic accuracy and normative data. AB - : ABSTRACTBackground:With increasing cultural diversity and growing elderly immigrant populations in Western European countries, the availability of brief cognitive screening instruments adequate for assessment of dementia in people from diverse backgrounds becomes increasingly important. The aim of the present study was to investigate diagnostic accuracy of the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural sample and to calculate normative data as a basis for demographic adjustment of RUDAS scores. METHODS: The study was a prospective international cross-sectional multi-center study. Receiver operating characteristic curve analysis was used to examine diagnostic accuracy. Regression analysis was used to assess the impact of demographic variables. RESULTS: Data was collected from 341 cognitively intact participants and 80 people with dementia with a wide age- and educational range. Of the 421 included participants, 239 (57%) had immigrant background. The RUDAS had high diagnostic accuracy with an area under the curve (AUC) of 0.93. The optimal cut-off score was <25 (sensitivity 0.80, specificity 0.90). Regression analysis revealed that RUDAS scores were mainly affected by education and were unrelated to data collection site and immigrant status. Education-adjusted normative data was calculated as a basis for education adjustment of RUDAS scores. Applying education-adjusted RUDAS scores slightly but significantly improved diagnostic accuracy with an AUC of 0.95. CONCLUSION: We found the RUDAS to have excellent diagnostic properties in our multicultural sample. However, we suggest that RUDAS scores should be adjusted for education to increase diagnostic accuracy and that the choice of cut-off score should be considered based on the clinical context and expected base rate of dementia. PMID- 30017011 TI - Can front-of-pack labels influence portion size judgements for unhealthy foods? AB - OBJECTIVE: By clearly conveying the healthiness of a food, front-of-pack (FOP) labels have the potential to influence the portion size considered appropriate for consumption. The present study examined the how the Daily Intake Guide (DIG), Multiple Traffic Lights (MTL) and Health Star Rating (HSR) FOP labels affect judgements of appropriate portion sizes of unhealthy foods compared with when no FOP label is present. DESIGN: Respondents viewed mock packages of unhealthy variations of pizzas, cookies, yoghurts and cornflakes featuring the DIG, MTL, HSR or no FOP label, and indicated the portion size they believed should be eaten of each food on a single occasion. SETTING: The survey was completed on the respondent's personal computer. SUBJECTS: A total of 1505 Australian adults provided 4166 ratings across 192 mock packages relating to four product categories: pizza, yoghurt, cornflakes and cookies. RESULTS: Compared with no FOP label, the HSR resulted in a small but significant reduction in the portion size selected as appropriate for consumption of pizzas and cornflakes (P<0.05). The MTL resulted in smaller portions of cornflakes being selected compared with no FOP label (P<0.05). CONCLUSIONS: Respondents perceived smaller portion sizes as appropriate for some, but not all, of the foods tested when FOP labels with more interpretative formats (HSR, MTL) appeared on-pack compared with no FOP label. No effect was found for the less interpretive FOP label (the DIG). Interpretive FOP labels may have the potential to influence portion size judgements, albeit at modest levels. PMID- 30017012 TI - Occurrence of Contracaecum bancrofti larvae in fish in the Murray-Darling Basin. AB - There is a paucity of information on the diversity and occurrence of freshwater fish parasites in Australia. This study investigates the distribution and occurrence of a parasitic nematode of the genus Contracaecum in freshwater fish from south-eastern Australia. Fish (n = 508) belonging to nine species and eight families were collected from eight wetlands associated with the Murrumbidgee River floodplain in the southern Murray-Darling Basin and subjected to laboratory examination. Third-stage nematode larvae were found in eight of the nine fish species. The exception was the fly-specked hardeyhead (Craterocephalus stercusmuscarum), although only one specimen of this species was examined. Nematode larvae were identified as Contracaecum bancrofti using a combined morphological and molecular approach. The parasite was most prevalent in weather loach (Misgurnus anguillicaudatus; 34.8%) and Australian smelt (Retropinna semoni; 21.4%), followed by carp (Cyprinus carpio; 9.5%), of which the former and latter are non-native species. Contracaecum prevalence differed between locations, with Two Bridges having the highest number of infected fish. This may be due to the higher number of suitable host species collected at these localities. Contracaecum spp. are parasites with low host specificity that have also been reported in Australian marine fish, humans and piscivorous birds. The high parasite prevalence in the two abundant non-native fish species in the region suggests that they act as a suitable host for this endemic parasite, resulting in the increase in the parasite population. It would be interesting to study host-parasite interactions in this area, especially if introduced fish populations declined dramatically in the attempt to eradicate them or control their population. PMID- 30017013 TI - Implementation and impact of unforgettable: an interactive art program for people with dementia and their caregivers. AB - : ABSTRACTBackground:Previous research shows that museum programs can be beneficial for the quality of life of people with dementia. This study evaluated the implementation of "Unforgettable," an interactive museum program for people with dementia and their caregivers in the Netherlands, and investigated the impact of the program's implementation on the museums as an organization and on the attitudes toward dementia of the museum staff. METHOD: Semi-structured interviews were held with 23 stakeholders to identify facilitators and barriers to the implementation of the Unforgettable program in 12 Dutch museums. Based on the model of Meiland et al. (2004), an overview is made of factors influencing the different levels and phases of the implementation process. The impact of Unforgettable on the attitudes of the museum staff was assessed using the Approaches to Dementia Questionnaire (n = 176). RESULTS: The training in the Unforgettable method, regular evaluation with the program guides and hosts, and cooperation with other organizations appeared essential for successful implementation of Unforgettable. A lack of promotional activities was an impeding factor. Compared to before the implementation, the museum employees' attitudes toward people with dementia became more positive. CONCLUSION: Both successful dissemination of the Unforgettable program and the more positive attitudes toward dementia of employees in museums implementing this program can contribute to the social participation of people with dementia and thereby to their quality of life. PMID- 30017014 TI - The Genetic Relationship Between Psychological Distress, Somatic Distress, Affective Disorders, and Substance Use in Young Australian Adults: A Multivariate Twin Study. AB - Psychological distress (PSYCH), somatic distress (SOMA), affective disorders (AD), and substance use (SU) frequently co-occur. The genetic relationship between PSYCH and SOMA, however, remains understudied. We examined the genetic and environmental influences on these two disorders and their comorbid AD and SU using structural equation modeling. Self-reported PSYCH and SOMA were measured in 1,548 twins using the two subscales of a 12-item questionnaire, the Somatic and Psychological Health Report. Its reliability and psychometric properties were examined. Six ADs, involvement of licit and illicit substance, and two SU disorders were obtained from 1,663-2,132 twins using the World Mental Health Composite International Diagnostic Interview and/or from an online adaption of the same. SU phenotypes (heritability: 49-79%) were found to be more heritable than the affective disorder phenotypes (heritability: 32-42%), SOMA (heritability: 25%), and PSYCH (heritability: 23%). We fit separate non parametric item response theory models for PSYCH, SOMA, AD, and SU. The IRT scores were used as the refined phenotypes for fitting multivariate genetic models. The best-fitting model showed the similar amount of genetic overlap between PSYCH-AD (genetic correlation rG = 0.49) and SOMA-AD (rG =0.53), as well as between PSYCH-SU (rG = 0.23) and SOMA-SU (rG = 0.25). Unique environmental factors explained 53% to 76% of the variance in each of these four phenotypes, whereas additive genetic factors explained 17% to 46% of the variance. The covariance between the four phenotypes was largely explained by unique environmental factors. Common genetic factor had a significant influence on all the four phenotypes, but they explained a moderate portion of the covariance. PMID- 30017016 TI - An association analysis of sow parity, live-weight and back-fat depth as indicators of sow productivity. AB - Understanding how critical sow live-weight and back-fat depth during gestation are in ensuring optimum sow productivity is important. The objective of this study was to quantify the association between sow parity, live-weight and back fat depth during gestation with subsequent sow reproductive performance. Records of 1058 sows and 13 827 piglets from 10 trials on two research farms between the years 2005 and 2015 were analysed. Sows ranged from parity 1 to 6 with the number of sows per parity distributed as follows: 232, 277, 180, 131, 132 and 106, respectively. Variables that were analysed included total born (TB), born alive (BA), piglet birth weight (BtWT), pre-weaning mortality (PWM), piglet wean weight (WnWT), number of piglets weaned (Wn), wean to service interval (WSI), piglets born alive in subsequent farrowing and sow lactation feed intake. Calculated variables included the within-litter CV in birth weight (LtV), pre-weaning growth rate per litter (PWG), total litter gain (TLG), lactation efficiency and litter size reared after cross-fostering. Data were analysed using linear mixed models accounting for covariance among records. Third and fourth parity sows had more (P0.05). Heavier sow live-weight throughout gestation was associated with an increase in PWM (P0.05). In conclusion, this study showed that sow parity, live weight and back-fat depth can be used as indicators of reproductive performance. In addition, this study also provides validation for future development of a benchmarking tool to monitor and improve the productivity of modern sow herd. PMID- 30017015 TI - Reducing micronutrient deficiencies in Pakistani children: are subsidies on fortified complementary foods cost-effective? AB - OBJECTIVE: To estimate the cost-effectiveness of price subsidies on fortified packaged complementary foods (FPCF) in reducing iodine deficiency, iron deficiency anaemia and vitamin A deficiency in Pakistani children. DESIGN: The study proceeded in three steps: (i) we determined the current lifetime costs of the three micronutrient deficiencies with a health economic model; (ii) we assessed the price sensitivity of demand for FPCF with a market survey in two Pakistani districts; (iii) we combined the findings of the first two steps with the results of a systematic review on the effectiveness of FPCF in reducing micronutrient deficiencies. The cost-effectiveness was estimated by comparing the net social cost of price subsidies with the disability-adjusted life years (DALY) averted. SETTING: Districts of Faisalabad and Hyderabad in Pakistan. SUBJECTS: Households with 6-23-month-old children stratified by socio-economic strata. RESULTS: The lifetime social costs of iodine deficiency, iron-deficiency anaemia and vitamin A deficiency in 6-23-month-old children amounted to production losses of $US 209 million and 175 000 DALY. Poor households incurred the highest costs, yet even wealthier households suffered substantial losses. Wealthier households were more likely to buy FPCF. The net cost per DALY of the interventions ranged from a return per DALY averted of $US 783 to $US 65. Interventions targeted at poorer households were most cost-effective. CONCLUSIONS: Price subsidies on FPCF might be a cost-effective way to reduce the societal costs of micronutrient deficiencies in 6-23-month-old children in Pakistan. Interventions targeting poorer households are especially cost-effective. PMID- 30017017 TI - Assessing mild behavioral impairment with the mild behavioral impairment checklist in people with subjective cognitive decline. AB - : ABSTRACTObjectives:To estimate the prevalence of Mild Behavioral Impairment (MBI) in people with Subjective Cognitive Decline (SCD), and validate the Mild Behavioral Impairment Checklist (MBI-C) with respect to score distribution, sensitivity, specificity, and utility for MBI diagnosis, as well as correlation with other neuropsychological tests. DESIGN: Correlational study with a convenience sampling. Descriptive, logistic regression, ROC curve, and bivariate correlations analyses were performed. SETTING: Primary care health centers. PARTICIPANTS: 127 patients with SCD. MEASUREMENTS: An extensive evaluation, including Questionnaire for Subjective Memory Complaints, Mini-Mental State Examination, Cambridge Cognitive Assessment-Revised, Neuropsychiatric Inventory Questionnaire (NPI-Q), the Geriatric Depression Scale-15 items (GDS-15), the Lawton and Brody Index and the MBI-C, which was administered by phone to participants' informants. RESULTS: MBI prevalence was 5.8% in those with SCD. The total MBI-C scoring was low and differentiated people with MBI at a cut-off point of 8.5 (optimizing sensitivity and specificity). MBI-C total scoring correlated positively with NPI-Q, Questionnaire for Subjective Cognitive Complaints (QSCC) from the informant and GDS-15. CONCLUSIONS: The phone administration of the MBI-C is useful for detecting MBI in people with SCD. The prevalence of MBI in SCD was low. The MBI-C detected subtle Neuropsychiatric symptoms (NPS) that were correlated with scores on the NPI-Q, depressive symptomatology (GDS-15), and memory performance perceived by their relatives (QSCC). Next steps are to determine the predictive utility of MBI in SCD, and its relation to incident cognitive decline over time. PMID- 30017018 TI - Livestock production evolving to contribute to sustainable societies. PMID- 30017019 TI - Staphylococcus xylosus Cystitis and Struvite Urolithiasis in Nude Mice Implanted with Sustained-release Estrogen Pellets. AB - Female nude mice (J:NU-Foxn1nu; age, 6 wk) were injected with 1 million MCF7 human breast cancer cells in the fourth mammary fat pads and received a 21-d sustained-release estrogen pellet (0.25 mg) subcutaneously in the dorsum of the neck. All mice were maintained in sterile housing and provided sterile water and irradiated rodent chow. Approximately 6 wk after implantation, 4 of the 30 mice showed clinical signs of depression and dehydration. The 2 animals most severely affected were euthanized and presented for necropsy. The urinary bladders of these animals were distended with variable sized white, opaque uroliths. Urinalysis revealed coccal bacteria, erythrocytes, neutrophils and struvite crystals. Urine cultures from both necropsied animals grew heavy, pure growths of Staphylococcus xylosus. The organism was sensitive to all antibiotics tested except erythromycin (intermediate). Analysis of the uroliths revealed 100% struvite composition. Remaining mice in the study were evaluated clinically for hydration status, the ability to urinate, and the presence of palpable stones in the urinary bladder; one additional mouse had a firm, nonpainful bladder (urolithiasis suspected). Given the sensitivity of the organisms cultured from urine samples, the remaining mice were placed on enrofloxacin in the drinking water (0.5 mg/mL). All remaining mice completed the study without further morbidity or mortality. Previous studies have reported the association of estrogen supplementation with urinary bladder pathology, including infection and urolithiasis. Here we present a case of urolithiasis and cystitis in nude mice receiving estrogen supplementation that was associated with Staphylococcus xylosus, which previously was unreported in this context. When assessing these nude mice for urolithiasis, we found that visualizing the stones through the body wall, bladder palpation, and bladder expression were helpful in identifying affected mice. PMID- 30017020 TI - Refinement and Successful Implementation of a Scoring System for Myxomatosis in a Susceptible Rabbit (Oryctolagus cuniculus) Model. AB - Myxoma virus is a member of Leporipoxviridae whose tropism is tightly restricted to lagomorphs. In susceptible Oryctolagus rabbits, the virus causes a highly lethal disease known as myxomatosis, which begins as a localized infection but rapidly disseminates throughout the animal, leading to immune compromise, mucosal infections, multiorgan failure, and death. In a research setting, myxoma infection of susceptible Oryctolagus cuniculus rabbits is used as a model of poxviral disease progression and represents one of only a few means to study the pathogenesis of this viral family in a native host species. However, the rapid progression of myxomatosis makes accurate prediction of humane endpoints critical to limiting animal pain and distress and preventing death as an endpoint. Here we present case studies of myxomatosis at 2 institutions and offer a refined scoring system to reliably track the course of disease in susceptible rabbits infected with myxoma virus. PMID- 30017021 TI - Need for additional capacity and improved capability for molecular detection of yellow fever virus in European Expert Laboratories: External Quality Assessment, March 2018. AB - An external quality assessment of yellow fever virus (YFV) molecular detection in European laboratories was organised in rapid response to an increase in human cases in Brazil in 2018 with risk of import to Europe. Detection of YFV was assessed among 32 laboratories in 23/31 European Union (EU) and European Economic Area (EEA) countries and two laboratories in one non-EU/EEA country. Adequate capabilities were lacking in 10/23 countries; five did not participate as they lacked implemented assays. PMID- 30017022 TI - Community outbreak of serogroup B invasive meningococcal disease in Beaujolais, France, February to June 2016: from alert to targeted vaccination. AB - In February and March 2016, four cases of serogroup B invasive meningococcal disease (IMD) occurred over 3 weeks in a small area north of Lyon in the Auvergne Rhone-Alpes region, France. There were no deaths but two cases had sequelae. This community outbreak was caused by a rare meningococcal strain of the clonal complex ST-32, covered by the 4CMenB/Bexsero vaccine. The incidence rate for serogroup B IMD in this area was 22.5 per 100,000 inhabitants, which is above the epidemic threshold (10/100,000). The number of cases observed was significantly higher than expected in the age group of 0-24 year-olds (standardised incidence ratio: 96). These results suggested the potential emergence of this invasive strain in this sub-population. In accordance with French recommendations, it was decided to vaccinate the population aged between 2 months and 24 years, living, working or studying in the epidemic area. The vaccination campaign took place from April to September 2016. Vaccination coverage was estimated at 47% for one dose and 40% for two doses. The lowest coverage estimations were observed for the age groups younger than 3 and 15-19 years. Enhanced epidemiological and microbiological surveillance reported a fifth case in June 2016, outside the epidemic area. PMID- 30017023 TI - Screening for infectious diseases in newly arrived migrants in Europe: the context matters. PMID- 30017024 TI - Challenging measles case definition: three measles outbreaks in three Health Regions of Portugal, February to April 2018. AB - We report three simultaneous measles outbreaks with 112 confirmed cases in three Health Regions of Portugal, from February to April 2018. The mean age of cases was 30 years, 79% worked in a healthcare setting and 87% were vaccinated. Genotype B3 was identified in 84 cases from the three outbreaks. Primary cases in each outbreak were imported. Several cases presented with modified measles, highlighting the importance of rethinking the measles case definition for vaccinated cases. PMID- 30017025 TI - Single-cell RNA sequencing reveals distinct gene expression patterns in glucose metabolism of human preimplantation embryos. AB - Precise regulation of glucose metabolism-related genes is essential for early embryonic development. Although previous research has yielded detailed information on the biochemical processes, little is yet known of the dynamic gene expression profiles in glucose metabolism of preimplantation embryos at a single cell resolution. In the present study, we performed integrated analysis of single cell RNA sequencing (scRNA-seq) data of human preimplantation embryos that had been cultured in sequential medium. Different cells in the same embryo have similar gene expression patterns in glucose metabolism. During the switch from the cleavage to morula stage, the expression of glycolysis-related genes, such as glucose transporter genes (solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) and solute carrier family 2 (facilitated glucose transporter), member 3 (SLC2A3) and genes encoding hexokinase, phosphofructokinase, pyruvate kinase and lactate dehydrogenase, is increased. The genes involved in the pentose phosphate pathway are highly expressed at the cleavage stage, generating the reducing power to balance oxidative stress derived from biosynthesis. Expression of the genes involved in the biosynthesis of glycerophospholipids is increased after the morula stage. Nevertheless, the expression of tricarboxylic acid-related genes remains relatively unchanged during the preimplantation stages. In conclusion, we discovered that the gene expression profiles are dynamic according to glucose utilisation in the embryos at different stages, which contributes to our understanding of regulatory mechanisms of glucose metabolism-related genes in human preimplantation embryos. PMID- 30017026 TI - Video Versus Direct Laryngoscopy for Inpatient Emergency Intubation in Adults. AB - BACKGROUND: Emergency intubation carries a higher risk of complications than elective airway management. Video laryngoscopy (VL) could potentially improve patient safety. The goal of this study was to determine whether VL is superior to direct laryngoscopy for the emergency intubation of adults in the inpatient setting. METHODS: Pertinent studies were retrieved by a systematic literature search in the MEDLINE, Embase, and CENTRAL databases. The selection of studies, data extraction, and assessment of the potential for bias were carried out independently by two of the authors. Effect sizes were reported as odds ratios (OR) or mean differences (MD). The primary endpoint was successful intubation at the first attempt. Further variables were considered as secondary endpoints. RESULTS: 1098 titles and abstracts were retrieved, and the full texts of 43 articles were examined. Eight randomized and controlled trials, with a total of 1796 patients, were analyzed. VL was not found to confer any statistically significant advantage with respect to successful intubation at the first attempt (OR 0.72, 95% confidence interval [0.47; 1.12]) or with respect to the time to successful intubation (MD -8.99 seconds [-24.00; 6.01]). On the other hand, the use of VL was significantly associated with a lower number of intubation attempts (MD -0.17 [-0.31; -0.03]) and with a lower frequency of esophageal intubation (OR 0.27 [0.10; 0.75]). CONCLUSION: The routine use of VL for airway management in emergency medicine might improve patient safety, as VL is associated with a lower number of intubation attempts and with a lower frequency of esophageal intubation. Further randomized controlled trials are needed before any definitive conclusions can be drawn about the advantages of video laryngoscopy. PMID- 30017028 TI - Penile Mondor's Disease Triggered by May-Thurner Syndrome. PMID- 30017027 TI - The Diagnosis and Treatment of Pacemaker-Associated Infection. AB - BACKGROUND: Approximately 105 000 cardiac electronic devices are newly implanted in Germany each year. Germany has the highest implantation rate with respect to population of any European country. Infections in cardiac implants are serious complications, with an associated in-hospital mortality of 5-15%. It is thus very important to optimize the diagnostic and therapeutic strategies by which such infections can be detected early and treated effectively. METHODS: This review is based on pertinent publications retrieved by a search in PubMed, with special attention to the current recommendations of international medical specialty societies. RESULTS: According to the international literature, the incidence of device-associated infection is 1.7% (in six months) for implanted defibrillators and 9.5% (in two years) for resynchronization devices. No absolute figures on infection rates are available for Germany. Infection can involve either the site where the impulse generator is implanted or the intravascular portion of the electrodes. The most important elements of the diagnostic evaluation are: assessment of the local findings; pathogen identification by culture of peripheral blood, swabs of the infected site, or material recovered at surgery; and transesophageal echocardiography to detect endocarditic deposits on the electrodes or cardiac valves. The treatment consists of appropriate antibiotic administration and the complete removal of all foreign material. These special extractions are generally performed via the transvenous route. With the aid of various sheath systems, the procedure can be carried out safely and effectively, with a success rate above 95% and a complication rate below 3%. The indications for the implantation of a new device after eradication of the infection should be critically reassessed. CONCLUSION: Untreated infection carries a high mortality. Evaluation and treatment according to a standardized clinical algorithm facilitate correct and timely diagnosis and the choice of an appropriate therapeutic strategy. PMID- 30017029 TI - Benefits of Breastfeeding. PMID- 30017030 TI - Migration Background Should Be Considered. PMID- 30017031 TI - In Reply. PMID- 30017032 TI - Arthralgia and an Unusual Radiological Finding. PMID- 30017033 TI - The American Board of Ophthalmology, the American Journal of Ophthalmology, and Edward Jackson. PMID- 30017034 TI - Long-term Effect of Scleral Encircling on Axial Elongation. PMID- 30017035 TI - Suicide behaviour in Colombia. PMID- 30017036 TI - Therapeutic Communities In Latin America: An International Descriptive Study In Different Countries Across Latin America. AB - OBJECTIVE: In Latin America is not known for certain the quantity or quality of therapeutic communities (TCs) available in the region. The objective of this study is to describe and quantify the quantity and quality of the existing TCs in 5 different countries. DESIGN: A multicenter quantitative description of the TCs was conducted in Argentina, Brazil, Colombia, Mexico and Peru. METHODS: A survey was realized through the TCs regulatory entities of each country that accepted to participate in the study. RESULTS: Of the 285 TCs identified in the 5 countries, 176 (62%) accepted to participate in this study. The TCs quality vas evaluated according to the scoring system stablished by De Leon, finding that 70% of the facilities have scores of 11/12 or 12/12 using these criteria. We also found that the majority of the De Leon criteria are known by more than 90% of the institutions, however, the dimensions of "separation of the community" and "encounter groups between residents" were the least known with 63 and 85% respectively. The main reasons for abandonment of TCs were "not accepting the rules of the institution", "lack of money" and "not feeling comfortable with the facilities". 98% of the TCs provided services to other substance abuse problems, 94% for alcohol and 40% for other types of substances. CONCLUSIONS: The majority of the TCs identified in our sample meet the quality criteria stablished by De Leon, mostly providing services for substance abuse. However, they should put in place additional policies to improve the unfulfilled conditions and investigate the reasons for the dissatisfaction and abandonment of these institutions. PMID- 30017037 TI - Risk Factors and Hospital Mortality in Surgical and Non-surgical Patients with Delirium. AB - INTRODUCTION: Delirium is a common neuropsychiatric syndrome with severe consequences, especially for elderly patients with pre-existing cognitive impairment. METHODOLOGY: Descriptive study of one retrospective cohort, with the aim of comparing risk factors and mortality between surgical treatment and non surgical treatment in a group of hospitalised patients with delirium. RESULTS: Of the 184 hospitalised patients with delirium analysed, 29.3% were for surgical causes and 70.7% for non-surgical causes. Just over half (50.5%) were women, and 50% of the patients were 74 years or less (interquartile range, 27 years), with statistical differences (P=.002). Prior cognitive impairment was observed in 42.9% of patients, with a greater proportion of non-surgical (50.8% vs 24.1%) with significant differences (P=.001). Anticholinergic medications were received by 89.7% of patients, and almost all of them (99.5%) received three or more medicines, with no significant differences. Half (50%) of the patients remained in hospital for 16.3 days or less (interquartile range, 23 days). Hospitalisation was significantly longer in the surgical group (P<.001). The hospital mortality was 14.7%, with no statistical differences between groups (P=.073). DISCUSSION: Although there were no significant differences in mortality between the groups, it was higher in the non-surgical (17.7% vs. 7.4%). Increased mortality was found in the older group (non-surgical) that also had significantly greater cognitive impairment, which coincides with that in the scientific literature. PMID- 30017038 TI - The Visible and Less Visible in the Suffering of a Conversion Disorder in Children and Adolescents. A Qualitative Study of Illness Explanatory Models Presented to Caregivers of Children and Adolescents with Conversion Disorder. AB - BACKGROUND: Conversion disorder is a challenge for clinicians due to the conceptual gaps as regards its pathogenesis, the way in which it converges with other psychiatric disorders, and the lack of approaches to the experiences of both patients and family members with the disease. OBJECTIVE: To describe Explanatory Models (EM) offered to caregivers of paediatric patients with conversion disorder who attended the Hospital de la Misericordia. METHODS: A qualitative study was conducted with a convenience sample of 10 patients who attended the Hospital de La Misericordia, ?Bogota? between May 2014 and April 2015. The tool used was an in-depth interview applied to parents and/or caregivers. RESULTS: Caregivers have different beliefs about the origin of the symptoms, especially considering sickness, magical-mystical factors, and psychosocial factors. The symptoms are explained in each case in various ways and there is no direct relationship between these beliefs, the pattern of symptoms, and help-seeking behaviours. Symptomatic presentation is polymorphous and mainly interferes in the patient's school activities. The medical care is perceived as relevant, and psychiatric care as insufficient. Among the therapeutic routes, consultations with various agents are described, including medical care, alternative medicine, and magical-religious approaches. CONCLUSIONS: EMs in conversion disorder are varied, but often include magical-religious elements and psychosocial factors. The underlying beliefs are not directly related to help seeking behaviours or other variables. PMID- 30017039 TI - Knowledge About ADHD in Primary Teachers of Public Schools of Sabaneta, Antioquia. AB - OBJECTIVES: The present research aims to describe the knowledge of elementary school teachers about attention deficit hyperactivity disorder (ADHD) through interviews about general information, symptoms/diagnosis and treatment, in addition to perceived self-efficacy. METHODS: A descriptive cross-sectional population study was carried out, involving 62 teachers from public schools in the municipality of Sabaneta. The teachers were evaluated by the Spanish adaptation of the Knowledge of Attention Deficit Hyperactivity Disorder (KADDS), an estimation scale composed of 36 items of three alternative answers (true, false and I do not know). RESULTS: Teachers correctly answered a little less than half of the items in the total questionnaire (48.52%). Specifically, it was in the subscale of dymptoms/diagnosis in which they presented more hits with 69.35%, followed by the treatment subscale (45.30%), and finally the general information (38.60%). CONCLUSIONS: According to the data obtained, the need for interventions on the subject is confirmed, so that this is reflected in new teaching techniques that facilitate the learning and development of children with the disorder. PMID- 30017040 TI - Social Cognition in Schizophrenia: Cognitive and Neurobiological Aspects. AB - Social cognition in schizophrenia is currently one of the major fields of interest in studies of this disorder. It is commonly conceptualised as a set of mental operations underlying social interactions, and therefore related to the ability to interpret and predict the behaviour of others in different social contexts. The research community has defined the functional areas that constitute the domain of social cognition, including, at least, the theory of mind, sensory perception, social perception, and attributional bias. Different bodies of evidence have shown that alterations in these functions in patients with schizophrenia are linked to some of their main psychopathological dysfunctions, such as defects in sensory perception, insight and attributional origin, and authorship of human acts. These behavioural alterations have been linked to structural and functional disturbances in the constituents of the so-called social brain. This includes a set of medial parietal, temporal, and pre-frontal areas that have been associated with some anomalies in the theory of mind, the perception of emotions, and the ability to consider the perspective of others, phenomena commonly found in schizophrenia. Future research in the domain of social cognition should be aimed at clarifying its relationship with the social brain and neurocognition. PMID- 30017041 TI - Pro-inflammatory Cytokines, Biomarkers, Genetics and the Immune System: A Mechanistic Approach of Depression and Psoriasis. AB - OBJECTIVE: To highlight the inflammatory and immunological mechanisms involved in depression and psoriasis. METHODS: A comprehensive literature search was performed in various databases, in total 145 studies were selected. RESULTS: Depression and psoriasis have an association. Immune mechanisms -the actions of tumor necrosis factor-alpha, interleukin 1 (IL-1), IL-2, IL-10, IL-22, IL-17, interferon-gamma, IL-1beta, prostaglandin E2, C-reactive protein, IL-6, and IL-8 etc.-, and some genetic changes are involved. CONCLUSIONS: A possible bidirectional relationship of psoriasis and major depression exists; i.e. the depression leads to psoriasis, and psoriasis leads to depression. We recommend more studies in the future to get a deeper and better understanding about this relationship. PMID- 30017042 TI - Adolescence With Freud and Flaubert. AB - The text approaches two fundamental aspects of the adolescent crisis from the works of Sigmund Freud and Gustave Flaubert: their encounter with their object in desire, pleasure, sexual act, and the causes the detachment from parental authority and their effects. A study was made on the work of Flaubert on the causes of the enigma, which the author suggests in his Memoirs of a Madman: Am I another or myself? That feeling of strangeness the adolescent experiences on waking up in a dream, with a new feeling and desire of the love object. The ardent desire of being like a grown-up, and the motions toward their parents, influence decisions for which the young are not prepared, given their cradled education and the unsatisfactory answers to their infant sexual investigation. Lacan notes that the sexual relationship does not exist. Freud rates love as being narcissistic and childish. The first amorous manifestations, given the fantasy that cloaks them always remain the same, as explained by Flaubert and Lacan's comment to Wedekind, in The Spring Awakening. In childhood the enjoyment of body is not involved. For this reason, it is so simple, the adolescent would be a representation of the division of the subject, the cut made by their unconscious, which their body, in certain cases, will carry the marks. They will be surprised, puzzled by this new desire that produces their unconscious to step toward the sexual act. PMID- 30017043 TI - The Research Question in Clinical Practice: A Guideline for Its Formulation. AB - The systematic formulation of the research question allows the researcher to focus the study, guide the method decisions, and to put forward possible solutions. In practice, there are difficulties in the formulation of research problems. Diversity of clinical scenarios can lead to a mismatch between the structure of the research question and the classical PICO (population, intervention, control, and outcomes) format. The aim of this article is to provide guidelines that help in the proper formulation of clinical practice research questions for general practitioners, specialists, and healthcare personnel in training. PMID- 30017044 TI - Arthropods life cycle and temperature: Beyond isomorphy hypothesis. AB - In poikilotherms, developmental time and adult lifespan are biological traits driven by temperature although their underlying physiological mechanisms differ. The developmental theory of ageing predicts a positive correlation between these two traits without confirming a genetic or causal relationship. The developmental rate isomorphy hypothesis established that the proportionality in the duration of each pre-imaginal stage with respect to total developmental time does not vary with temperature. This may have important evolutionary implications. We conducted an analysis with arthropods of agronomic interest to study if the hypothesis could be extended to the total lifespan of poikilotherms, including adult lifespan. We showed that isomorphy could be acceptable for a global description of this relationship. However a general model of power law type is more appropriate for characterizing the relationship between developmental time and adult lifespan. In this model, the shape of the curve is a constant characteristic, but the parameters that control it depend on the functional type of the arthropod (phytophagous, predator or parasitoid). Presumably this power law could be extended to all arthropods of agricultural interest, and more generally to all arthropod. PMID- 30017045 TI - Dietary mannan oligosaccharide improves growth performance, muscle oxidative status, and meat quality in broilers under cyclic heat stress. AB - This study investigated the effects of dietary mannan oligosaccharide (MOS) supplementation on growth performance, serum corticosterone level, and antioxidant ability, meat quality as well as chemical composition of breast muscle in broilers exposed to cyclic heat stress (HS). 144 one-day-old male broiler chicks (Arbor Acres plus) were randomly allocated to 3 treatments with 6 replicates each. Broilers in the control and HS groups were fed a basal diet, and in the MOS group were given the basal diet supplemented with 1 g/kg MOS for 42 days, respectively. The temperature was maintained 32-33 degrees C for the first 3 days for all broilers, and it was gradually reduced by 3 degrees C per week to a final temperature of 20 degrees C in the control group, whereas it remained unchanged for 8 h and reduced to the same level to the control group for the remaining 16 h daily in the both HS and MOS groups. Compared with the control group, cyclic HS resulted in retarded growth performance and increased serum corticosterone level (P < 0.05). The supplementation of MOS promoted growth performance and reduced serum corticosterone concentration in broilers subjected to cyclic HS (P < 0.05). Cyclic HS increased drip loss48 h, cooking loss, malondialdehyde accumulation, and moisture content, whereas decreased pH24 h value, glutathione peroxidase (GSH-Px) activity, and crude protein content in the breast muscle (P < 0.05). In contrast, dietary MOS supplementation reduced drip loss48 h and malondialdehyde concentration, and increased GSH-Px activity in breast muscle compared with the HS group (P < 0.05). The results indicated that dietary MOS supplementation could improve growth performance, and oxidative status and meat quality of breast muscle in broilers under cyclic HS. PMID- 30017046 TI - The influence of body composition on exercise-associated skin temperature changes after resistance training. AB - Resistance exercise leads to an increase in skin temperature (Tskin) in the area of the exercised muscle. Infrared thermography seems to be applicable to identify these primary used functional muscles with measuring Tskin changes. The aim of the current study was to investigate the influence of body composition on Tskin patterns after resistance exercise. 38 male subjects (19-32 years, BMI 20.4-55.2 kg/m2) participated. Body fat percentage and biceps skinfold thickness were calculated. The subjects were divided into two groups: lean group (LG) with body fat percentage < 25%, obese group (OG) with body fat percentage >= 25%. All participants completed three sets with ten repetitions of unilateral biceps curl at 50% of the one repetition maximum. To represent exercise-induced changes of Tskin to rest (Trest), the algebraic difference of each time point to Trest was calculated. The resulting delta values (?) are as follows: immediately after the first, second, and third set (?Tset1,?Tset2,?Tset3), and at 1,2,3,4,5,6,7,8,9,10,15,20,25,30 min after the third set (?T1-?T30). The maximum positive difference to Trest was defined as ?Tmax, and the time to reach ?Tmax was defined as Time to ?Tmax. LG and OG differed significantly at Trest (32.8 +/- 0.9 vs. 31.1 +/- 1.4 degrees C), ?Tmax (1.9 +/- 0.4 vs. 0.9 +/- 0.8 degrees C), Time to ?Tmax (4.5 +/- 2.0 vs. 17.6 +/- 10.2 min) and at ?Tset2 to ?T15 (p < 0.005). Correlations between body composition (BMI, body fat percentage, biceps skinfold thickness) and Trest, ?Tset2, ?Tset3, ?Tmax (-0.47 1 month) (n = 16). At our institution, the minimally invasive surgical approach is considered for clinically stable CDH patients, who are likely to have type A or B defects. 21 patients had a sac-type defect. Forty seven patients with type A defect had primary closure, buttressed in 6 cases. In 21 patients, the type B defect was repaired with a patch, buttressed in 11 patients. Median follow-up was 36 months (IQR 9-45). Recurrence occurred in 13 patients (overall 19% recurrence rate); all had a neonatally presented defect (25% vs. 0%, p = 0.03). Patients with a sac-type defect had a lower recurrence rate than patients with no hernia sac (5% vs. 26%, p = 0.05). Recurrence complicated 7 of 47 (15%) patients after primary closure and 6 of 21 (29%) patients with patch repair; none of the 17 cases with buttressed repairs had a recurrence. CONCLUSIONS: Due to a higher rate of recurrence following thoracoscopic CDH repair compared to the standard open approach, we suggest a sandwich-type buttress repair with underlay and overlay components for both primary and patch repairs. LEVEL OF EVIDENCE: Level III cohort study. PMID- 30017068 TI - Letter to the editor. PMID- 30017069 TI - Delayed access to care and unmet burden of pediatric surgical disease in resource constrained African countries. AB - BACKGROUND: The purpose of this study was to estimate the unmet burden of surgically correctable congenital anomalies in African low- and middle-income countries (LMICs). METHODS: We conducted a chart review of children operated for cryptorchidism, isolated cleft lip, hypospadias, bladder exstrophy and anorectal malformation at an Ethiopian referral hospital between January 2012 and July 2016 and a scoping review of the literature describing the management of congenital anomalies in African LMICs. Procedure numbers and age at surgery were collected to estimate mean surgical delays by country and extrapolate surgical backlog. The unmet surgical need was derived from incidence-based disease estimates, established disability weights, and actual surgical volumes. RESULTS: The chart review yielded 210 procedures in 207 patients from Ethiopia. The scoping review generated 42 data sets, extracted from 36 publications, encompassing: Benin, Egypt, Ghana, Ivory Coast, Kenya, Nigeria, Madagascar, Malawi, Togo, Uganda, Zambia, and Zimbabwe. The largest national surgical backlog was noted in Nigeria for cryptorchidism (209,260 cases) and cleft lip (4154 cases), and Ethiopia for hypospadias (20,188 cases), bladder exstrophy (575 cases) and anorectal malformation (1349 cases). CONCLUSION: These data support the need for upscaling pediatric surgical capacity in LMICs to address the significant surgical delay, surgical backlog, and unmet prevalent need. TYPE OF STUDY: Retrospective study and review article LEVEL OF EVIDENCE: III. PMID- 30017070 TI - What pediatric surgeons read: Utilization of APSA email blast literature reviews. AB - PURPOSE: American Pediatric Surgical Association (APSA) committees send monthly email blasts to members with links to peer-reviewed publications. This study assesses the utilization of this service. METHODS: Email-opening and click through rates were analyzed from 5/2012 to 4/2017 and compared to APSA and industry standards. Access was analyzed based on subject, disease type, journal, impact factor, and committee. CME questions were added in 10/2014 and emails consolidated in 1/2016. Effects of these changes were analyzed. RESULTS: Over 60 months, 281 articles were distributed from 58 journals. Access increased significantly with impact factor (P = 0.0039). Overall email opening rate (53% +/ 3%) and click-through rate (37% +/- 10%) were significantly higher than all APSA emails (43%,18%, P < 0.0001) and 2017 industry standard (26%,12%,P < 0.0001). Access rates differed significantly between the twenty-five topics covered (P < 0.0001), with the highest access for appendicitis (240 +/- 79, P < 0.0001). Common condition articles (157 +/- 93) were accessed more than rare (55 +/- 60, P < 0.0001). With email consolidation, opening rates increased (53 +/- 3 to 55 +/- 2, P = 0.003) and click-through rates decreased (40 +/- 9 to 30 +/- 8, P = 0.0002). By adding CME questions, opening rates increased nonsignificantly (52 +/ 3 to 54 +/- 2, P = 0.066) and click-through rate decreased significantly(41 +/- 10 to 33 +/- 9, P = 0.001). CONCLUSIONS: APSA email blasts are valued by members based on high access rates. Click-through rates have declined, potentially indicating user fatigue. APSA members prefer common conditions and high impact factor journals. These data will help refine this service. LEVEL-OF-EVIDENCE: Level III. PMID- 30017072 TI - Cellular apoptosis and nitric oxide production in PBMC and spleen from dogs with visceral leishmaniasis. AB - Nitric oxide (NO) is involved in the death of the Leishmania parasite and regulation of apoptosis. We quantified the frequency of cells producing NO and its levels in the peripheral blood mononuclear cells (PBMC), leukocytes from spleen in Visceral Leishmaniasis (VL) symptomatic dogs and correlated NO levels with apoptosis and parasite load in the spleen. The percentage of NO+ cells and CD14+/NO+ was higher in PBMC and spleen cells in infected dogs than in controls. The levels of NO+ and CD14+/NO+ cells was higher in PBMC, but lower spleen of dogs infected than compared to control. Late apoptosis rates increased in PBMC and spleen of infected dogs compared to controls, and the NO levels and apoptosis not showed correlation. There was a positive correlation between the percentage of cells producing NO in the spleen and parasite load. The NO participates in the immune response in the canine VL, but it is not apoptosis inducer. PMID- 30017071 TI - Lipoprotein Particle Formation by Proapoptotic tBid. AB - The interactions of Bcl-2 family proteins with intracellular lipids are essential for the regulation of apoptosis, a mechanism of programmed cell death that is central to the health and development of multicellular organisms. Bid and its caspase-8 cleavage product, tBid, promote the permeabilization of the mitochondrial outer membrane and sequester antiapoptotic Bcl-2 proteins to counter their cytoprotective activity. Bid and tBid also promote lipid exchange, a characteristic trait of apoptosis. Here, we show that tBid is capable of associating with phospholipids to form soluble, nanometer-sized lipoprotein particles that retain binding affinity for the antiapoptotic protein Bcl-xL. The tBid lipoprotein particles form with a lipid/protein stoichiometry in the range of 20/1 and have a diameter of ~11.5 nm. Lipoparticle-bound tBid retains an alpha helical structure and binds Bcl-xL through its third Bcl-2 homology motif, forming a soluble, lipid-associated heteroprotein complex. The results shed light on the role of lipids in mediating Bcl-2 protein mobility and interactions. PMID- 30017073 TI - Serological and molecular evidence of coxiellosis and risk factors in sheep flocks in central-eastern Tunisia. AB - In this study, we conducted an investigation to determine the true prevalence of coxiellosis in sheep in central-eastern Tunisia. A total of 492 veterinary samples taken from 110 flocks were screened for coxiellosis using IS1111-based real-time PCR assay. Sheep sera were tested using an indirect enzyme-linked immunosorbent assay. Based on molecular and serological results, the true adjusted animal and herd-level prevalence of coxiellosis were 11.8% and 20.21%, respectively. Bacterial excretion was observed in 17 flocks, and 19 females showed evidence of Coxiella burnetii shedding (100%). In addition, a statistically significant association was found between vaginal and milk shedding for sheep. Multivariable logistic regression analysis at the animal-population level indicated that strata and vaccination variables were found to be associated with coxiellosis. Besides, it was shown that this infection increased when the intensive farm was exposed to carnivores and when the cleaning practices were not respected, while it decreased when a suitable quarantine was introduced for any introduction of a new animal. Good hygiene and sanitation practices on-farm should be handled as strategies to deal with this zoonotic pathogen in herds. PMID- 30017074 TI - In vitro e in silico evaluation of the inhibition of Staphylococcus aureus efflux pumps by caffeic and gallic acid. AB - Staphylococcus aureus has been reported as one of the most difficult to treat. In the search for new treatment alternatives, isolated plant substances such as phenolic compounds, have demonstrated the ability to reverse bacterial resistance. The present study aims to evaluate the inhibitory action of caffeic acid and gallic acid on efflux pumps from S. aureus resistant strains. The broth microdilution assay was carried out to obtain the MICs of caffeic acid and gallic acid while the efflux pump inhibition test was assessed through the reduction of the minimum inhibitory concentration of the antibiotic and ethidium bromide. In addition, in silico theoretical parameters were analyzed to determine the theoretical efficacy of the compound and its free energy of interaction. In the results, the inhibition concentration of the two compounds did not certify clinical relevance with 1024 MUg/mL for all strains. In the efflux pump inhibition effect, caffeic acid inhibited the MrsA pumps of the strain RN-4220 and NorA of the strain 1199B. Caffeic acid showed greater efficacy in the docking model, in agreement with the demonstrated experimental efficacy. Isolated compounds can be indicated as efficient options in the inhibition of resistance mechanisms. PMID- 30017075 TI - Pathogenic and endosymbiont apicomplexans in Ctenocephalides felis (Siphonaptera: Pulicidae) from cats in Jerusalem, Israel. AB - This study was conducted to determine the prevalence of pathogenic and endosymbiont apicomplexans in the cat flea, Ctenocephalides felis (Bouche) infesting 185 stray cats in Jerusalem, Israel using PCR assay and sequencing approach. Two pathogens, Hepatozoon felis and Babesia vogeli and an endosymbiont Steinina ctenocephali were detected in 1.9%, 0.2% and 5.8% of 685 C. felis evaluated respectively. There was a significant association (p < 0.05) between the prevalence of H. felis and the sex of cats hosting the fleas as well as the season of sampling but not for age or health status of the cats or sex of the fleas tested. Prevalence of S. ctenocephali was significantly (p < 0.001) associated with season, being higher in the warm season. This report represents the first molecular detection of S. ctenocephali in C. felis. Further studies to determine the potential role of C. felis in the epidemiology of H. felis and B. vogeli are warranted. PMID- 30017076 TI - In vitro antimicrobial activity of monensin against common clinical isolates associated with canine otitis externa. AB - Antimicrobial resistance and antimicrobial stewardship are of ever-increasing importance in veterinary medicine. Multidrug-resistant infections of the canine skin and ear continue to emerge, but the use of antibiotic classes of critical importance to human medicine may not represent good antimicrobial stewardship. Repurposing of old drugs that are not used in human medicine is one approach that addresses both these issues. In this study, the minimal inhibitory concentration (MIC) of monensin for 111 bacterial and yeast canine otitis isolates was determined using microdilution methodology according to Clinical Laboratory Standards Institute (CLSI) guidelines. Monensin was effective against all Gram positive bacteria including the multidrug-resistant staphylococcal strains with MICs ranging from 1 to 4 MUg/ml, but lacked antimicrobial activity against Gram negative bacteria and yeast isolates. Monensin has potential to be incorporated as one of the main components in an otic formulation. PMID- 30017077 TI - MALDI-TOF MS identification of ticks of domestic and wild animals in Algeria and molecular detection of associated microorganisms. AB - Recent studies have reported the reliability of MALDI-TOF MS for arthropod identification, including fresh or alcohol-preserved ticks based on leg-derived mass spectra. The aim of this study was to evaluate the performance of MALDI-TOF MS for the identification of alcohol-preserved Algerian ticks collected from different domestic and wild hosts. Secondly, we conducted a molecular survey to detect the presence of bacterial DNA in all ticks that were previously subjected to MALDI-TOF MS. A total of 2635 ixodid and 1401 argasid ticks belonging to 9 distinct species were collected in nine different regions of northeastern Algeria. The legs of 230 specimens were subjected to MALDI-TOF MS assays. Spectral analysis revealed intra-species similarity and inter-species specificity for the MS spectra, which was consistent with the morphological identification. Blind tests against the in-lab database revealed that 93.48% of the tested specimens were correctly identified. The accuracy of the morphological and MALDI TOF MS identifications was validated by sequencing the 12S ribosomal RNA gene (rRNA) for 33 specimens and all the ticks were correctly identified. The quantitative PCR screening showed that for 219 tested ticks, 15 were positive for Rickettsia spp., 8 for Borrelia spp. and 17 for Anaplasmataceae. The PCR tests were negative for Coxiella burnetii and Bartonella spp. This study supports MALDI TOF MS being a reliable tool for the identification of arthropods and brings new data that sheds light on tick species diversity and tick-borne diseases in Algeria. PMID- 30017078 TI - Genotyping of Coxiella burnetii detected in placental tissues from aborted dairy cattle in the north of Algeria. AB - Coxiella burnetii, is an obligate intracellular bacterium which is present throughout the world. In humans, C. burnetii is the causative agent of Q fever. In cattle, the infection is suspected to cause stillbirths, retained fetal membranes, metritis and infertility. The birth products of ruminants shed huge amounts of bacteria, and are considered a major source for human infection. The present study was designed to search for the presence of C. burnetii in placental tissues collected from aborted and normal calving dairy cows in Algeria, using molecular tools. A total of 77 placental tissue fragments were collected from dairy cows. 73 samples were collected from aborted cows and four samples were collected from natural calving cows over a period of two years from January 2013 to March 2015. The presence of C. burnetii in these samples was screened by quantitative real-time polymerase chain reaction (qPCR) targeting two different genes, IS1111 and IS30 A. The positive PCR amplicons were subsequently sequenced for Multispacer Sequence Typing determination (MST) using seven pairs of sequences (Cox2, Cox5, Cox18, Cox37, Cox56, Cox57, and Cox61). Fourteen placental tissues (19.1%) were found to be positive for C. burnetii by qPCR; 9 (12.3%) from the city of Blida and 5 (6.84%) from the city of Medea. Genotyping of the corresponding amplicons displayed 100% identity with C. burnetii MST20 genotype, confirming the circulation of this clone in dairy farms from Algeria. PMID- 30017079 TI - Comparative immunosecretome analysis of prevalent Streptococcus suis serotypes. AB - Streptococcus suis is a major Gram-positive swine pathogen associated with a wide variety of diseases in pigs. The efforts made to develop vaccines against this pathogen have failed because of lack of common cross-reactive antigens against different serotypes. Nowadays the interest has moved to surface and secreted proteins, as they have the highest chances to raise an effective immune response because they are in direct contact with host cells and are really exposed and accessible to antibodies. In this work, we have performed a comparative immunosecretomic approach to identify a set of immunoreactive secreted proteins common to the most prevalent serotypes of S. suis. Among the 67 proteins identified, three (SSU0020, SSU0934, and SSU0215) were those predicted extracellular proteins most widely found within the studied serotypes. These immunoreactive proteins may be interesting targets for future vaccine development as they could provide possible cross-reactivity among different serotypes of this pathogen. PMID- 30017080 TI - Mycobacterium avium complex infection in pigs: A review. AB - Mycobacterial infections in pigs are caused particularly by the Mycobacterium avium complex (MAC) and these infections lead to great economic losses mainly within the countries with high pork meat production. The importance of the MAC infections in humans is rising because of its higher prevalence and also higher mortality rates particularly in advanced countries. In addition, treatment of the MAC infections in humans tends to be complicated because of its increasing resistance to antimicrobial agents. Several studies across Europe have documented the MAC occurrence in the slaughtered pigs - not only in their lymph nodes and tonsils, which are the most frequent, but also in the diaphragmas, other organs and not least in meat. This is why we need both more specific and more sensitive methods for the MAC infection detection. Different PCR assays were established as well as advanced intravital testing by the gamma interferon release test. On the other hand, tuberculin skin test is still one of the cheapest methods of mycobacterial infections detection. PMID- 30017081 TI - Molecular assessment of Neospora caninum and Toxoplasma gondii in hooded crows (Corvus cornix) in Tehran, Iran. AB - Neospora caninum and Toxoplasma gondii are two closely related protozoan parasites that have been detected from various species of bird hosts. However, little is known about the prevalence of N. caninum and T. gondii in crows. Hence, we examined the molecular frequency of N. caninum and T. gondii in the brain samples of hooded crows (Corvus cornix) that collected from different public parks of Tehran, Iran by nested-PCR method. We used the primers targeting the Nc5 and GRA6 genes for detection of N. caninum and T. gondii, respectively. From a total of 55 brain samples, 5 (9.9%) and 9 (16.36%) samples were positive for N. caninum and T. gondii, respectively. Sequencing of a N. caninum isolate revealed 95%-100% identity with the deposited N. caninum in GenBank. Genotyping of T. gondii isolates by PCR-RFLP analysis of the GRA6 gene revealed type III genotype in 8 isolates. The results of this study indicate that hooded crows may have a putative role in transmission of N. caninum and T. gondii to canines and felines definitive hosts, respectively. PMID- 30017082 TI - Corrigendum to "Development of an improved ESAT-6 and CFP-10 peptide-based cytokine flow cytometric assay for bovine tuberculosis" [Comp. Immunol. Microbiol. Infect. Dis. 42 (2015) 1-7]. PMID- 30017083 TI - Bovine herpesvirus type 5 replication and induction of apoptosis in vitro and in the trigeminal ganglion of experimentally-infected cattle. AB - Bovine herpesvirus (BoHV) types 1 and 5 are neuroinvasive. Cases of BoHV-1 induced encephalitis are not as frequent as those caused by BoHV-5. In this study, the capability of BoHV-5 to induce apoptosis in cell cultures and in the trigeminal ganglion during acute infection of experimentally-infected cattle was analyzed. Apoptotic changes in cell cultures agree with the ability of the viral strains to replicate in each cell line. Marked differences were observed between the in vitro induction of apoptosis by BoHV-1Cooper and BoHV-5 97/613 strains. Apoptotic neurons were clearly evident in the trigeminal ganglion of BoHV-1 infected calves. For BoHV-5 a fewer number of positive neurons was observed. There is an association between the magnitude of bovine herpesviruses replication and the induction of apoptosis in trigeminal ganglion. These findings suggest that the induction of apoptosis and the innate immune response orchestrate the final outcome of alpha herpesviruses infection of the bovine nervous system. PMID- 30017084 TI - Nurse Practitioner residents' perceptions of competency development during a year long immersion in Veterans Affairs primary care. AB - BACKGROUND: Nurse Practitioner (NP) Postgraduate Residency programs are rapidly expanding. Currently, little is known about trainees' self-perceptions during these experiences. PURPOSE: Describe NP residents' perceptions of their strengths, areas for improvement, and goals while participating in the Veterans Affairs Centers of Excellence in Primary Care Education NP Residency program. METHODS: NP residents responded to open-ended questions at three time points across their training year. Responses were analyzed using inductive and deductive approaches. FINDINGS: NP residents self-reported strengths in patient-centered care and interprofessional teamwork. They identified clinical skill acquisition as the major area for improvement. Their short- and long-term goals focused on personal and professional growth. DISCUSSION: These results suggest NPs prioritize clinical skill acquisition during a primary care residency. In contrast, leadership and performance improvement skills did not capture their attention. When aggregated at the programmatic level, assessments identified opportunities to improve the NP Residency program curriculum. PMID- 30017085 TI - Autocrine GABA signaling distinctively regulates phenotypic activation of mouse pulmonary macrophages. AB - In response to micro-environmental cues such as microbial infections or T-helper 1 and 2 (TH1 and TH2) cytokines, macrophages (Mphis) develop into M1- or M2-like phenotypes. Phenotypic polarization/activation of Mphis are also essentially regulated by autocrine signals. Type-A gamma-aminobutyric acid receptor (GABAAR) mediated autocrine signaling is critical for phenotypic differentiation and transformation of various cell types. The present study explored whether GABAAR signaling regulates lung Mphi (LMphi) phenotypic activation under M1/TH1 and M2/TH2 environments. Results showed that GABAAR subunits were expressed by primary LMphi of mice and the mouse Mphi cell line RAW264.7. The expression levels of GABAAR subunits in mouse LMphis and RAW264.7 cells decreased or increased concurrently with classical (M1) or alternative (M2) activation, respectively. Moreover, activation or blockade of GABAARs distinctively influenced the phenotypic characteristics of Mphi. These results suggested that microenvironments leading to LMphi phenotypic polarization concurrently modulates autocrine GABA signaling and its role in Mphi activation. PMID- 30017086 TI - IL10 restrains autoreactive B cells in transgenic mice expressing inactive RAG1. AB - IL10 plays a dual role in supporting humoral immunity and inhibiting inflammatory conditions. B cells producing IL10 are thought to play a key regulatory role in maintaining self-tolerance and suppressing excessive inflammation during autoimmune and infectious diseases, primarily by inhibiting associated T cell responses. The extent to which B cells, through the provision of IL10, might function to sustain or inhibit autoantibody production is less clear. We previously described transgenic mice expressing catalytically inactive RAG1 (dnRAG1 mice), which show expansion of an IL10-compentent CD5+ B cell subset that phenotypically resembles B10 B cells, hypogammaglobulinemia, and a restricted B cell receptor repertoire with features indicative of impaired B cell receptor editing. We show here that B10-like B cells in dnRAG1 mice bind the membrane associated autoantigen phosphatidylcholine (PtC), and that in vitro lipopolysaccharide (LPS) stimulation of dnRAG1 splenocytes induces a robust IgM response enriched in reactivity toward lupus-associated autoantigens. This outcome was correlated with detection of sIgMhi B cell populations that were distinct from, but in addition to, sIgMint populations observed after similar treatment of wild-type splenocytes. Loss of IL10 expression in dnRAG1 mice had no significant effect on B10-like B cell expansion or the frequency of PtC+ B cells. Compared to IL10+/+ dnRAG1 mice, levels of serum IgM, but not serum IgG, were highly elevated in some naive IL10-/- dnRAG1 mice, and was correlated with a significant increase in serum BAFF levels. Differentiation of sIgMint B cells from LPS-stimulated dnRAG1 splenocytes was enhanced by loss of IL10 expression and IL10 blockade, but was suppressed by treatment with recombinant IL10. In vitro LPS-induced differentiation and antibody production was inhibited by treatment with JAK/STAT inhibitors or a synthetic corticosteroid, independent of IL10 expression and genotype. Taken together, these data suggest that IL10 expression in dnRAG1 mice maintains suppression of IgM levels in part by inhibiting BAFF production, and that regulatory B10-like B cells, through the provision of IL10, constrains B cell differentiation in response to mitogenic stimuli. Furthermore, autoantibody profiling raises a possible link between CD5+ B cell expansion, mitogenic stimulation, and autoantibodies associated with autoimmune complications observed in lupus and lupus-related disorders. PMID- 30017087 TI - Magnetic dispersive micro solid-phase extraction and gas chromatography determination of organophosphorus pesticides in strawberries. AB - Magnetic nanoparticles (MNPs) with different sizes and characteristics were synthesized to be used as a QuEChERS sorbents for the determination of seven organophosphorus pesticides (OPPs) in strawberries by gas chromatography analysis with flame photometric and mass spectrometry detection. To achieve the optimum conditions of modified QuEChERS procedure several parameters affecting the cleanup efficiency including the amount of the sorbents and cleanup time were investigated. The results were compared with classical QuEChERS methodologies and the modified QuEChERS procedure using MNPs showed the better performance. Under the optimum conditions of the new methodology, three spiking levels (25, 50 and 100 MUg kg-1) were evaluated in a strawberry sample. The results showed that the average recovery was 93% and the relative standard deviation was less than 12%. The enrichment factor ranged from 111 to 145%. The good linearity with coefficients of determination of 0.9904-0.9991 was obtained over the range of 25 250 MUg kg-1 for 7 OPPs. It was determined that the MNPs have an excellent function as sorbent when purified even using less amount of sorbents and the magnetic properties allowed non-use of the centrifugation in cleanup step. The new methodology was applied in strawberry samples from conventional and organic farming. The new sorbents were successfully applied for extraction and determination of OPPs in strawberries. PMID- 30017088 TI - Ionic liquid-coated alumina-pretreated micro gas chromatography columns for high efficient separations. AB - These studies demonstrate the influence of an intermediate layer of aluminum oxide on the separation performance of a room temperature ionic liquid (RTIL) coated gas chromatography silicon microcolumn. A 1 m long semipacked column having 190 MUm wide and 240 MUm deep rectangular cross-sectional channels with embedded arrays of micro pillars was microfabricated. A thin layer of alumina was then deposited on the surface of the channels via atomic layer deposition. Following the alumina deposition, the channels were coated with an RTIL. The separation performance of the RTIL-coated columns with and without the alumina layer was evaluated by measuring the separation efficiency and peak capacity. A substantial increase in separation efficiency was observed in the presence of the alumina layer. The alumina-pretreated columns, at optimum flow rate, exhibited as high as 8000 plates per meter, which is a 2.1-fold increase as compared to the column with no alumina layer. It is inferred that alumina coating promotes the formation of a more uniform RTIL film, thereby enhancing the separation efficiency. The peak production rates of alumina-RTIL columns for temperature programmed separation were found to be 0.80-1.1 peaks per second, which is an improvement compared to silicon-RTIL columns. The separation performance of these columns were further evaluated by separating a standard 21-component mixture of hazardous organic compounds, a sample of kerosene, diesel, and B20 biodiesel. These studies open up new possibilities of enhancing the separation efficiency of microcolumns by coating silicon surface with a suitable material prior to depositing an ionic liquid. PMID- 30017089 TI - Prediction tool for loading, isocratic elution, gradient elution and scaling up of ion exchange chromatography of proteins. AB - An efficient mathematical tool for the design and scaling up of protein chromatography is suggested, in which the model parameters can be determined quickly over a wide operating space without large material investments. The design method is based on mathematical modelling of column dynamics and moment analysis. The accuracy of the dynamic models that are most frequently used for simulations of chromatographic processes is analyzed, and possible errors that can be generated using the moment analysis are indicated. The so-called transport dispersive model was eventually employed for the process simulations. The model was modified to account for the protein dispersion in void volumes of chromatographic systems. The manner of the model calibration was suggested, which was based on a few chromatographic runs and verified over a wide space of the operating parameters, including composition and flow rate of the mobile phase, column dimensions, residence time, and mass loading. The model system for the study was ion-exchange chromatography. The analysis was performed based on the elution profiles of basic fibroblast growth factor 2 and lysozyme, on two different IEX media. PMID- 30017090 TI - The Eye's mind - Visual imagination, neuroscience and the humanities. PMID- 30017091 TI - Honored papers 2017. AB - The following editorial provides information concerning papers published in Computers in Biology and Medicine journal during 2017. Specifically, those papers on which have been bestowed honored status are listed. PMID- 30017092 TI - The Human Genome Editing Race: Loosening Regulatory Standards for Commercial Advantage? AB - Medicinal products based on genome editing must undergo rigorous preclinical testing and are subject to regulatory oversight for proper risk assessment prior to first evaluation in humans. We give a European perspective on the regulatory expectations to translate genome editing to the clinic to ensure their timely progress to market. PMID- 30017093 TI - Chemoproteomics and Chemical Probes for Target Discovery. AB - Chemical probes represent versatile tools to validate disease-modifying targets. However, evaluating the selectivity of chemical probes in complex cellular systems is a major challenge that needs to be addressed to better understand the mode of action of small molecules and the interpretation of their pharmacological effects. Chemoproteomics has emerged as a key technology to characterize the mode of action of pharmacological modulators such as chemical probes and drugs, and these studies have unraveled the cellular targets of many bioactive compounds. Here we review the role of chemical probes for the validation of new therapeutic targets and their characterization by proteome wide affinity- and activity-based chemical proteomics and recently developed label-free technologies. PMID- 30017094 TI - Surgical Management of Nasal Valve Collapse. AB - Nasal valve collapse has multiple causes, including congenital, traumatic, and, unfortunately, iatrogenic. Recognition of the causes of nasal valve collapse and the methodology for treatment is paramount not only for the otolaryngologist but also for any physician managing the nasal airway. This article focuses on the cause and surgical management of internal and external nasal valve collapse. PMID- 30017095 TI - Office-Based Procedures for Nasal Airway Obstruction. AB - Treatment of common rhinologic problems with in-office surgical procedures has increased dramatically in response to patient preference, evolving insurance patterns, and changes in coding and reimbursement. Because this is an emerging practice, there is not a lot of evidence published about how to best perform these techniques. This article provides practical advice from experienced surgeons related to logistics and anesthetic techniques for conducting in-office surgical treatment of nasal airway obstruction; an overview of office set-up and necessary equipment; and specific procedural considerations. Attention also is paid to pharmacologic issues. Logistics and clinical considerations for common office-based procedures for obstructive pathology are reviewed. PMID- 30017096 TI - Nasal Obstruction Considerations in Cosmetic Rhinoplasty. AB - Cosmetic rhinoplasty is an increasingly popular procedure in the United States. There are critical aspects of preoperative planning and intraoperative execution that facilitate successful rhinoplasty. Thorough preoperative assessment of the structures comprising the internal and external nasal valves and identification of potential at-risk areas for static or dynamic compromise must be done before surgery. Thoughtful maneuvers and meticulous surgical technique must be used. Postoperative counseling ranges from simple reassurance to medical therapy to procedural efforts to alleviate a patient's concerns. It is important to establish rapport with the patient and dutifully address all cosmetic and functional concerns. PMID- 30017097 TI - Unipedal balance test for older adults: a systematic review and meta-analysis of studies providing normative data. AB - BACKGROUND: The unipedal balance test (UBT) is widely used with older adults, but interpreting performance on the test requires the availability of normative values. OBJECTIVE: To use meta-analysis to provide normative values for the UBT for adults >=60years. DATA SOURCES: Electronic searches of PubMed, CINAHL, and Scopus as well as hand searches. STUDY SELECTION: Inclusion required that articles provided means and standard deviations for UBT time for strata including at least 30 participants without pathology. STUDY APPRAISAL AND SYNTHESIS: The two authors independently abstracted information on UBT procedures and performance. The Comprehensive Meta Analysis (3.0) program (random effects model) was used to consolidate UBT data from 23 articles. A custom six component (14 point) checklist was used to rate article quality. RESULTS: Meta-analysis showed the mean UBT time for 13,454 tested individuals to be 26.9 seconds. Times were longer for individuals who were younger, male, and allowed longer test durations (e.g. >=120seconds vs 30seconds). LIMITATIONS: Although the UBT norms presented herein provide a better estimate of normal performance than individual studies, differences between studies in age and gender strata and test durations limit the generalizability of some of the normative values generated using meta-analysis. PMID- 30017098 TI - 'If you can't help me, so help me God I will cut it off myself...' The experience of living with knee pain: a qualitative meta-synthesis. AB - OBJECTIVE: To identify and explore the feelings and experiences of people living with knee pain as a precursor to exploring how this might contribute to improved care in the future. DESIGN: The qualitative meta-synthesis was undertaken in three parts (1) a systematic search of the literature, (2) a critical appraisal of the relevant studies and (3) meta-aggregation of the findings from the selected studies. A qualitative meta-synthesis is a process that enables researchers to answer a specific research question by combining and summarising a variety of qualitative sources. This was undertaken using a contextualist approach which acknowledges different realities exist but tries to determine an underlying 'truth'. SETTING: The participants from the selected studies were from a range of settings and ethnic groups, and cultural backgrounds. PARTICIPANTS: There were nine articles included in the meta-synthesis. Articles focused on the experiences of surgery, return to sport, or other aspects of care were excluded. RESULTS: No articles were excluded following critical appraisal. Eleven categories were identified from 55 findings which resulted in two synthesised findings being identified: knee pain affects every aspect of life and Searching for the best way forward. LIMITATIONS: Articles were largely limited to older adults living with osteoarthritis. Many of the findings did not report demographic data. Only English language studies were included. CONCLUSION: Many people living with knee pain struggle to adapt to living with knee pain and this is often exacerbated by a lack of knowledge and available information to help them plan for the future. PROSPERO NO: CRD42017070227. PMID- 30017099 TI - To what extent do current total hip and knee replacement patient information resources adhere to enhanced recovery after surgery principles? AB - OBJECTIVES: Total hip replacement (THR) and total knee replacement (TKR) are two of the most common orthopaedic surgeries that occur in the United Kingdom (UK) annually. Enhanced recovery after surgery (ERAS) programmes aim to decrease convalescence across procedures. It has been highlighted that post operative physiotherapy routines may not contain the correct ingredients for promoting acceleration of return to function. This research aims to analyse if current THR and TKR patient information resources adhere to ERAS principles, thus optimising post operative recovery. DATA SOURCES: Twenty hip and knee replacement patient information booklets were sourced using a UK Google search. A flowchart of exercise prescription components was formulated from a review of 5 trial booklets. A content analysis was utilised to assess the information included within the patient information booklets. RESULTS: Forty percent of patient information booklets identified their pathways to be ERAS. Fifty five percent of the hospitals stated their patients would be mobilised on the day of surgery. Ninety percent of THR and 100% of TKR guidelines suggested the use of bed exercises for rehabilitation. Fifteen percent of THR and 35% of TKR booklets suggested functional exercise as a method of rehabilitation. Strength or resistance based exercises were proposed in 40% of THR and 55% of TKR booklets. CONCLUSION: Many patient information booklets do not follow ERAS principles for fast-track rehabilitation and the exercise prescription procedure is non specific. This must be considered within post operative rehabilitation in order to enhance recovery and reduce length of stay following THR or TKR surgery. PMID- 30017100 TI - Peri-ictal transient MRI signal abnormalities with crossed cerebellar diaschisis due to status epilepticus. PMID- 30017101 TI - Myasthenia gravis exacerbation after red yeast rice use. PMID- 30017102 TI - Hereditary neuropathy with liability to pressure palsies mimicking chronic inflammatory demyelinating polyneuropathy. PMID- 30017103 TI - A geochemical perspective on the natural abundance and predominant sources of trace elements in cranberries (Vaccinium oxycoccus) from remote bogs in the Boreal region of northern Alberta, Canada. AB - Trace elements in native cranberry (Vaccinium oxycoccus) were compared with the underlying Sphagnum moss on which it grows, from two remote ombrotrophic (rain fed) peat bogs in northern Alberta, Canada. The purpose of the comparison was to distinguish between dust inputs to the berries versus plant uptake from the substrate, and to determine the natural abundance of trace elements in native berries. Using Al as an indicator of the abundance of soil-derived mineral particles, the abundance of dust on the surface of the berries is 20 to 29* lower than that of the substrate (moss). Other lithophile elements (V, Cr, Co, Ga, Li and Y) show similar differences between moss and berry. The concentrations of Rb and Ba in berries were similar to moss and Sr within a factor of 3 to 4*, probably reflecting passive uptake of these lithophile elements by the plants, even though they have no known physiological function. Of the micronutrients examined (Mn, Fe, Ni, Cu, Zn and Mo), Cu and Mn were more abundant in berries than moss, Ni and Zn yielded similar concentrations in both whereas Fe followed by Mo showed the greatest concentration difference. For these micronutrients, uptake by the plants through their roots via the substrate (moss and peat) outweighs contributions from atmospheric dusts. In respect to potentially toxic "heavy metals", Pb concentrations in the moss (BMW, 89 +/- 7.3 MUg/kg; CMW, 93 +/ 27 MUg/kg) are below the natural, "background" values reported for ancient layers of Swiss peat from the mid-Holocene (>6000 years old). The Pb concentrations in the berries, however, are 19 to 47* lower than in the underlying moss indicating that Pb in the berries, like Al, is exclusively supplied by dust. Cadmium in the berries is at or above the level found in moss due to active uptake by the plants from the substrate, most likely because of the chemical similarity of this element to Zn. Silver, Sb and Tl in the berries were =grade 4 acute toxicity from re-irradiation. LR failure was a component of cancer-related death in 60% vs. 40% of the unirradiated and re-irradiated group (p = 0.02). CONCLUSION: Salvage re-irradiation appears tolerable with acceptable morbidity and may reduce the risk of subsequent LR as a component of death in patients with LR RMS. PMID- 30017105 TI - Inhomogeneous tumor dose distribution provides better local control than homogeneous distribution in stereotactic radiotherapy for brain metastases. AB - INTRODUCTION: The aim of this study was to analyze the impact of inhomogeneous versus homogeneous dose distribution on local control (LC) and radionecrosis (RN) in patients treated with fractionated stereotactic radiotherapy (SRT) for newly diagnosed brain metastases (BM). PATIENTS AND METHODS: From 2014 to 2017, 134 patients (median age 61 years) underwent SRT for BM (n = 114 with <=2, n = 20 with 3-6 BM) at our institution. Treatment was delivered using volumetric modulated arc therapy on a linear accelerator. Ninety-one consecutive patients (BM = 136) were irradiated at a dose of 21-23.1 Gy in 3 fractions delivered homogeneously (99% of the dose had to cover 99% of the planning target volume (PTV)) (group 1) whereas the following 43 patients (BM = 72) received an inhomogeneous dose of 10 or 11 Gy prescribed to the isocenter with the 70% isodose line covering the PTV (group 2). Variables analyzed included dose distribution, age, gender, histology, diagnosis-specific Graded Prognostic Assessment score, number of brain metastases, presence of extracranial metastases, and tumor volumes. RESULTS: After a median follow-up of 12.4 months (range, 1.4-33.1), the 1-year LC and RN rate were 78% and 7.5% in group 1 and 93% and 0% in group 2, respectively (p = 0.005). In multivariate analysis, improved LC was significantly correlated with SRT dose distribution (p = 0.009) and tumor volume (p = 0.03). The number of metastases (p = 0.03) and SRT dose distribution (p = 0.04) were both associated with increased risk of RN. CONCLUSION: SRT delivered with inhomogeneous dose distribution resulted in better LC and a lower risk of RN compared to homogeneous distribution. PMID- 30017106 TI - Socioeconomic inequalities in health among Indigenous peoples living off-reserve in Canada: Trends and determinants. AB - Using three nationally representative Aboriginal Peoples Surveys (2001, 2006 and 2012, n = 68,040), we examined income-related inequalities in self-perceived poor/fair general health status among Indigenous adults (18+) living off-reserve in Canada. We used the relative and absolute concentration indices (RC and AC, respectively) to quantify income-related inequalities in health for men and women, within the three Indigenous populations (First Nations, Metis, and Inuit), and in different geographic regions. Moreover, we performed decomposition analysis to determine factors that explain income-related inequality in health within the Indigenous peoples living off-reserve in Canada. The prevalence of poor/fair health status among the Indigenous population living off-reserve increased from 18% in 2001 to 22% in 2012. The extent of pro-rich relative (absolute) income-related inequalities in health increased by 23% (42%) from 2001 to 2012. Income-related inequalities in health increased statistically significantly within First Nations and Metis populations as well as in Atlantic provinces, Ontario, Alberta, British Columbia and Territories. Decomposition analyses indicated that, besides income itself, occupational status and educational attainment were the most important factors contributing to the pro rich distribution of health among Indigenous peoples living off-reserve. Growing socioeconomic inequalities in health among Indigenous peoples should warrant more attention. Policies designed to address the broader array of social determinants of health may mitigate the continuing inequalities in health among Indigenous peoples living off-reserve in Canada. PMID- 30017107 TI - "Not an afterthought": Power imbalances in systemic partnerships between health service providers and consumers in a hospital setting. AB - Contemporary health policies require consumers be involved at all stages of health service planning, implementation, delivery, and evaluation. The extent to which this policy is met, however, varies widely across the sector. One barrier to meeting policy requirements is power imbalances within systemic partnerships between consumers and other health professionals. Between September 2016 and February 2017, interviews were conducted with health care managers, clinicians, and consumers working on partnerships across various health service departments in one hospital. An exploratory, qualitative approach was used. Data were analysed using principles of discursive psychology, which focuses on the way power is constructed through participants' accounts of partnerships. The findings suggest providers have significant power over consumers in partnerships at the systematic level of health services. Managers were responsible for setting the parameters for partnerships, and consumers were seen more as a resource to be used by health services rather than as equal partners to work with. The findings suggest that although contemporary health policies require partnership with consumers, better guidelines are needed to specifically address and challenge power imbalances within these partnerships. PMID- 30017108 TI - Mass spectrometry-based methods to study macromolecular higher order structure and interactions. PMID- 30017109 TI - Improvement of taste and shelf life of yeasted low-salt bread containing functional sourdoughs using Lactobacillus amylovorus DSM 19280 and Weisella cibaria MG1. AB - The challenge remains for the baking industry to reduce salt levels in yeasted bread as directed by governments, retailers and consumers around the world. The two main problems associated with the reduction of salt are a lack of salty taste and the reduction in shelf-life. Both of these issues are addressed in the presented work. A range of breads containing different levels of salt (0.0%, 0.3% and 1.2% of NaCl) in combination with various levels of sourdough (0%, 6%, 12%, 18%, 24%) was produced. The different doughs were analysed for their rheological behaviour. The bread quality characteristics such as loaf volume, crumb structure, staling rate and microbial shelf life were also determined. The sourdoughs were analysed for their different metabolites: organic acids, sugars, exopolysaccharides (EPS), and antifungal compounds. A trained sensory panel was used to perform descriptive analysis of the bread samples. The object of this paper is to use functional sourdoughs, containing Lactobacillus amylovorus DSM 19280 and Weisella cibaria MG1 to compensate for the quality problems that occur when salt is reduced in yeasted bread. The application of functional sourdoughs containing exopolysaccharides and/or antifungal substances in salt reduced breads significantly improved the quality. The application of functional sourdoughs allows the reduction of salt to a level of 0.3%. PMID- 30017110 TI - Do people care about pine invasions? Visitor perceptions and willingness to pay for pine control in a protected area. AB - Tree invasions are increasing globally, causing major problems for biodiversity, ecosystem services and human well-being. In South America, conifer invasions occur across many ecosystems and while numerous studies address the ecological consequences of these invasions, little is known about social perceptions and people's attitudes toward their control. The social perceptions on the effect of invasive conifers can include recreational, cultural and conservation dimensions. This study, conducted in the Malalcahuello National Reserve, aims to assess visitor's perception about invasive pines (Pinus spp.) and their effects on the endangered Araucaria araucana forests and determine their willingness to pay for pine control. We used a questionnaire to survey visitors to the reserve in both winter and summer (n = 138 for each season). When confronted with six images of araucaria and pine forests with and without snow, visitors consistently preferred landscapes without pines and disliked those completely dominated by pines the most. Almost half, 46.5%, of the visitors expressed their willingness to pay (WTP) for pine control and after given a brief explanation about pine impacts, this number rose to 79%. Visitors who said they were unwilling to pay argue ethical, aesthetic and pragmatic considerations relating closely to a number of social value systems and beliefs. Our study shows that there is a high variation in how people assess the threat of invasive pine species in natural areas, but education even in a very brief format can help to increase awareness of the problem and build social and financial support for its control. PMID- 30017111 TI - Multiple Endocrine Neoplasia in Children and the Importance of Screening: Part 2. PMID- 30017112 TI - Developing hybrid molecule therapeutics for diverse enzyme inhibitory action: Active role of coumarin-based structural leads in drug discovery. AB - Hybrid drugs featuring two or more potentially bioactive pharmacophores have been recognized as advanced and superior chemical entities to simultaneously modulate multiple drug targets of multifactorial diseases, thus overcoming the severe side effects associated with a single drug molecule. The selection of these chemical moieties to produce hybrid structures with druggable properties is generally facilitated by the observed and/or anticipated synergistic pharmacological activities of the individual molecules. In this perspective, coumarin template has extensively been studied in pursuit of structurally diverse leads for drug development due to high affinity and specificity to different molecular targets. This review highlights the most commonly exploited approaches conceptualizing the design and construction of hybrid molecules by coupling two or more individual fragments with or without an appropriate linker. In addition to the design strategies, this review also summarizes and reflects on the therapeutic potential of these hybrid molecules for diverse enzyme inhibitory action as well as their observed structure-activity relationship (SAR). Several key features of the synthesized hybrid structures that assert a profound impact on the inhibitory function have also been discussed alongside computational investigations, inhibitor molecular diversity and selectivity toward multiple drug targets. Finally, these drug discovery and development efforts should serve as a handy reference aiming to provide a useful platform for the exploration of new coumarin based compounds with enhanced enzyme inhibitory profile. PMID- 30017113 TI - Synthesis of 1,5-Anhydro-d-fructose derivatives and evaluation of their inflammasome inhibitors. AB - Synthesis of several 1,5-Anhydro-d-fructose (1,5-AF) derivatives to evaluate inhibitory activities of the inflammasome was carried out. Recently, 1,5-AF reported to suppress the inflammasome, although with only low activity. We focused on the hydration of 2-keto form of 1,5-AF and speculated that this hydration was the cause of low activity. Therefore, we synthesized some 1,5-AF derivatives that would not be able to form the dimer conformation and can be expected to have high activity against inflammasome, and then evaluated their inhibitory activities with respect to the NLRP3 inflammasome by using mouse bone marrow-derived macrophages and human THP-1 cells. As a result, some synthesized 2 keto form compounds had much higher inhibitory activities with respect to the NLRP3 inflammasome than did 1,5-AF. PMID- 30017114 TI - New somatostatin-drug conjugates for effective targeting pancreatic cancer. AB - Pancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5. Three major drugs were conjugated to our best SSTps that served as delivery vehicles, including Camptothecin (CPT), Combretastatin-4A (COMB) and Azatoxin (AZA). All designed drug conjugates demonstrated penetration to pancreatic cancer cell lines, and significant toxicity towards them. Furthermore, the drug conjugates specifically accumulated in tumors in the animal xenograft model, though some accumulation was also seen in kidney. Overall these findings lay the basis for development of novel drug series that could target the fatal pancreatic cancer. PMID- 30017115 TI - How Montgomery is reconfiguring consent in the UK. PMID- 30017117 TI - Offline: The UK's child health emergency. PMID- 30017116 TI - Denicotinised cigarettes. PMID- 30017118 TI - Prospects for health in Mexico after the presidential election. PMID- 30017119 TI - Proposed regulation of oxytocin in India causes concern. PMID- 30017120 TI - African Union launches a pan-African anti-malaria campaign. PMID- 30017121 TI - Devastation in Yemen ongoing. PMID- 30017122 TI - A fellowship of error. PMID- 30017123 TI - Trepanned cranium. PMID- 30017124 TI - Ahmed Salim Saif Al-Mandhari: bridge-builder from Oman. PMID- 30017125 TI - Defiant gardens: from Helmand to Headley Court. PMID- 30017127 TI - Should hydroxyethyl starch be banned? PMID- 30017128 TI - Should hydroxyethyl starch be banned? PMID- 30017129 TI - Should hydroxyethyl starch be banned? PMID- 30017130 TI - Should hydroxyethyl starch be banned? - Authors' reply. PMID- 30017131 TI - Women in Global Health-Germany network. PMID- 30017132 TI - Metformin as first-line treatment for type 2 diabetes. PMID- 30017133 TI - Canadian Women in Global Health #CWIGH: call for nominations. PMID- 30017134 TI - Continuous positive airway pressure device detects atrial fibrillation induced central sleep apnoea. PMID- 30017135 TI - Is digital medicine different? PMID- 30017136 TI - Food security in the Middle East and north Africa. PMID- 30017137 TI - Indonesia disavows "unity in diversity". PMID- 30017138 TI - A woman revolts. PMID- 30017139 TI - Equity in the gender equality movement in global health. PMID- 30017140 TI - [Perioperative lumbar plexus block and cardiac ischemia in patients with hip fracture: randomized clinical trial]. AB - BACKGROUND: Perioperative myocardial ischemia is common among patients undergoing hip fracture surgery. Our aim is to evaluate the efficacy of perioperative continuous lumbar plexus block in reducing the risk of cardiac ischemic events of elderly patients undergoing surgery for hip fractures, expressed as a reduction of ischemic events per subject. METHODS: Patients older than 60 years, ASA II III, with risk factors for or known coronary artery disease were enrolled in this randomized controlled study. Patients were randomized to conventional analgesia using opioid intravenous patient-controlled analgesia or continuous lumbar plexus block analgesia, both started preoperatively and maintained until postoperative day three. Continuous electrocardiogram monitoring with ST segment analysis was recorded. Serial cardiac enzymes and pain scores were registered during the entire period. We measured the incidence of ischemic events per subject registered by a continuous ST-segment Holter monitoring. RESULTS: Thirty-one patients (intravenous patient-controlled analgesia 14, lumbar plexus 17) were enrolled. There were no major cardiac events during the observation period. The number of ischemic events recorded by subject during the observation period was 6 in the lumbar plexus group and 3 in the intravenous patient-controlled analgesia group. This difference was not statistically significant (p=0.618). There were no statistically significant differences in the number of cases with increased perioperative troponin values (3 cases in the lumbar plexus group and 1 case in the intravenous patient-controlled analgesia group) or in terms of pain scores. CONCLUSIONS: Using continuous perineural analgesia, compared with conventional systemic analgesia, does not modify the incidence of perioperative cardiac ischemic events of elderly patients with hip fracture. PMID- 30017141 TI - [Awake axillary giant lipoma excision under serratus plane block]. PMID- 30017142 TI - Chitosan/alginate microparticles for the oral delivery of fowl typhoid vaccine: Innate and acquired immunity. AB - Oral fowl typhoid (FT) vaccine is necessary for improved flock vaccinations and economic growth. This study was undertaken to evaluate the immune responses of birds given oral fowl typhoid vaccine coated with chitosan/alginate microparticles and comparing it with the conventional subcutaneous route of administration. Preliminary studies were done to evaluate the particle size, encapsulation efficiency and agglutination. Sixty day-old chicks were divided into three groups of twenty birds each. This comprised a negative control group NEG 451 (non-vaccinated and non-challenged used as control for cytokine quantification), SC 634 (live 9R vaccine by the injection route) and OCV 567 (live 9R vaccine coated with chitosan/alginate microparticles). Vaccination was done at 10 weeks and 14 weeks of age followed by challenge at 16 weeks of age. IgG was measured using ELISA. mRNA fold expression of IFN-gamma in spleen was calculated using qRT-PCR. Particle sizes ranged between 0.55 um and 10 um. Encapsulation efficiency was above 60%. ELISA showed E-values of 0.10 +/- 0.14, 0.07 +/- 0.01 and 0.02 +/- 0.01 for OCV 567, SC 634 and NEG 451 respectively after primary vaccination. Also E-values were 0.25 +/- 0.16, 0.19 +/- 0.04 and 0.0008 +/- 0.005 for SC 634, OCV 567 and NEG451 respectively after boost vaccination. The expression of IFN-gammain spleen using 2-DeltaDelta CT calculation was upregulated with values of 1.97 and 0.75 for OCV 567 and SC 634 respectively. After challenge with the 85-kb virulence plasmid SG9, there was 100% protection of the birds in both OCV 567 and SC 634 groups with no mortality. In conclusion, there was no significant difference at p < 0.05 of the means +/- SD in immune responses between the oral fowl typhoid vaccine coated with chitosan/alginate microparticles and the subcutaneous route of administration. However, it is noteworthy to mention that the protective efficacy of the oral route is due to the chitosan/alginate biopolymers which coated the vaccine preventing destruction in the gastrointestinal tract. PMID- 30017143 TI - Regulated delayed attenuation enhances the immunogenicity and protection provided by recombinant Salmonellaenterica serovar Typhimurium vaccines expressing serovar Choleraesuis O-polysaccharides. AB - Regulated delayed attenuation is a well-studied strategy for retaining the immunogenicity of Salmonella-vectored vaccines. In this study, this strategy was used to optimize two previously constructed recombinant Salmonella enterica serovar Typhimurium vaccines expressing S. Choleraesuis O-polysaccharides (OPS). The novel vaccine strains SLT31 (Deltaasd DeltarmlB-rfbP DeltaPcrp::T araC PBAD) and SLT33 (Deltaasd DeltarfbP DeltapagL::T araC PBADrfbP DeltaPcrp::T araC PBAD) were constructed by replacement of the native crp promoter with the arabinose dependent araC PBAD promoter. As controls, two vaccine strains with direct crp mutations were also constructed, namely, SLT30 (Deltaasd DeltarmlB-rfbP Deltacrp) and SLT32 (Deltaasd DeltarfbP DeltapagL::T araC PBADrfbP Deltacrp). Then, the ability to deliver the heterologous S. Choleraesuis OPS on the Asd+ plasmid pCZ1 to the mouse immune system was evaluated in the strains with or without regulated delayed attenuation. The SLT30 (pCZ1) and SLT31 (pCZ1) strains expressed only the heterologous OPS, while the SLT32 (pCZ1) and SLT33 (pCZ1) strains co-expressed the homologous and heterologous OPS. The strain SLT31 (pCZ1) or SLT33 (pCZ1), which exhibited regulated delayed attenuation, colonized mouse tissues significantly better and stimulated stronger antibody responses against S. Choleraesuis LPS post immunization than the SLT30 (pCZ1) or SLT32 (pCZ1) strain. Immunization with SLT31 (pCZ1) or SLT33 (pCZ1) resulted in a significant reduction in bacterial loads in mouse tissues and a greater degree of protection against a lethal S. Choleraesuis dose compared with the effects observed after SLT30 (pCZ1) or SLT32 (pCZ1) immunization (100% vs. 80% or 70% vs. 50%, respectively). In addition, all four vaccines conferred complete protection against S. Typhimurium challenge. Overall, our study demonstrates that regulated delayed attenuation via an araC PBAD-regulated crp gene can enhance the cross protection by Salmonella-vectored vaccines expressing heterologous OPS, and strain SLT31 (pCZ1) is a good candidate vaccine for preventing both S. Typhimurium and S. Choleraesuis infections. PMID- 30017144 TI - The 2015-2016 influenza epidemic in Beijing, China: Unlike elsewhere, circulation of influenza A(H3N2) with moderate vaccine effectiveness. AB - BACKGROUND: While the 2015-2016 influenza season in the northern hemisphere was dominated by A(H1N1)pdm09 and B/Victoria viruses, in Beijing, China, there was also significant circulation of influenza A(H3N2) virus. In this report we estimate vaccine effectiveness (VE) against influenza A(H3N2) and other circulating viruses, and describe further characteristics of the 2015-2016 influenza season in Beijing. METHODS: We estimated VE of the 2015-2016 trivalent inactivated vaccine (TIV) against laboratory-confirmed influenza virus infection using the test-negative study design. The effect of prior vaccination on current VE was also examined. RESULTS: Of 11,000 eligible patients included in the study, 2969 (27.0%) were influenza positive. Vaccination coverage was 4.2% in both cases and controls. Adjusted VE against all influenza was 8% (95% CI: -16% to 27%): 18% (95% CI: -38% to 52%) for influenza A(H1N1)pdm09, 54% (95% CI: 16% to 74%) for influenza A(H3N2), and -8% (95% CI: -40% to 18%) for influenza B/Victoria. The overall VE for receipt of 2015-2016 vaccination only, 2014-2015 vaccination only, and vaccinations in both seasons was -15% (95% CI: -63% to 19%), -25% (95% CI: 78% to 13%), and 18% (95% CI: -11% to 40%), respectively. CONCLUSIONS: Overall the 2015-2016 TIV was protective against influenza infection in Beijing, with higher VE against the A(H3N2) viruses compared to A(H1N1)pdm09 and B viruses. PMID- 30017145 TI - Cost-effectiveness of an Adjuvanted Recombinant Zoster Vaccine in older adults in the United States. AB - In the United States, herpes zoster (HZ) and related complications are estimated to result in approximately $1.3 billion in medical care costs and $1.7 billion in indirect costs annually. In this study, we compared the cost-effectiveness of a new Adjuvanted Recombinant Zoster Vaccine (RZV), containing recombinant varicella zoster virus glycoprotein E and the AS01B Adjuvant System, versus No Vaccine, as well as versus the live attenuated HZ vaccine (Zoster Vaccine Live (ZVL)) in subjects aged 60+ years of age (YOA) and other age cohorts aged 50+ YOA. A multi cohort Markov model was developed which follows 1 million individuals over their remaining lifetimes from the year of vaccination with annual cycle lengths. Second dose compliance for RZV was assumed to be 69%. Efficacy and waning parameters were derived from clinical trials for both vaccines. Epidemiological parameters, costs and utility model inputs were derived from US-specific population-based data. Costs and outcomes were discounted at 3% per year. Deterministic and probabilistic sensitivity analysis, along with scenario and threshold analysis were carried out to explore the overall uncertainty in the model. The model estimated that, compared to No Vaccine against HZ, RZV would prevent 103,603 HZ cases, 11,197 postherpetic neuralgia (PHN) cases, and 14,455 other complications, at an incremental cost of $11,863 per quality-adjusted life year saved from a societal perspective. Compared to ZVL, the model estimated that, RZV would prevent 71,638 additional HZ cases, 6403 PHN cases, and over 10,582 other complications, resulting in net total societal cost savings of over $96 million. The results were robust to a wide range of sensitivity analyses. Vaccination against HZ with RZV is cost-effective compared to No Vaccine and cost saving compared to ZVL, in the US population aged 60+ YOA. Clinicaltrial.gov. registered#: NA. PMID- 30017146 TI - Cost-effectiveness of sex-neutral HPV-vaccination in Sweden, accounting for herd immunity and sexual behaviour. AB - INTRODUCTION: The aim was to assess cost-effectiveness of expanding the Swedish HPV-vaccination program to include preadolescent boys, by comparing health effects and costs of HPV-related disease, with a sex-neutral vaccination program versus only vaccinating girls. METHODS: We used a dynamic compartmental model to simulate the burden of HPV16/18-related disease in Sweden, accounting for indirect effects of vaccination through herd-immunity. The model accounted for sexual behaviour, such as age preferences and men who have sex with men. The main outcome was number of individuals with HPV-related cancers (cervical, genital, anal and oropharyngeal cancer) and cervical intraepithelial neoplasia (CIN). Costs included in the analysis were those incurred when treating HPV-related cancer and CIN, production losses during sick-leave, and acquisition and administration of vaccine. Health effects were measured as quality-adjusted life years (QALY). The time horizon was set to 100 years, and both effects and costs were discounted by 3% annually. Health effects and costs were accumulated over the time horizon and used to create an incremental cost-effectiveness ratio. RESULTS: A sex-neutral vaccination program would reduce HPV-related cancer and CIN, both due to direct effects among vaccinated as well as through herd immunity, further decreasing HPV-related cancer burden annually by around 60 cases among men and women respectively in steady-state. The cost per gained QALY was estimated to 40,000 euro. Applying the procurement price of 2017, sex-neutral vaccination was dominant. CONCLUSION: Introducing a sex-neutral HPV-vaccination program would be good value for money also in Sweden where there this 80% coverage in the current HPV-vaccination program for preadolescent girls. The cost effectiveness of a sex-neutral program is highly dependent on the price of the vaccine, the lower the price the more favourable it is to also vaccinate boys. PMID- 30017147 TI - Immunization regimen in Asian sea bass (Lates calcarifer) broodfish: A practical strategy to control vertical transmission of nervous necrosis virus during seed production. AB - Outbreaks of viral nervous necrosis (VNN) in Asian sea bass (Lates calcarifer) at the larval stages via vertical transmission of nervous necrosis virus (NNV) from asymptomatic broodfish remain as a major deterrent during seed production. A five year study was conducted to produce NNV-specific-free sea bass broodfish reared in land-based tanks through an annual immunization regimen with the formalin inactivated NNV. We primarily immunized (intraperitoneal injection) sea bass juveniles (5 g) and monitored the neutralizing antibody (Nab) titers in the sera of these fish at scheduled intervals post-immunization. Nab titers in the sera of immunized fish peaked at Month 2 (titer: 1:4480 +/- 1185) but thereafter gradually declined and significantly dropped (1:260 +/- 83) at Month 12 post primary immunization. Booster immunization of these fish at Month 12 post immunization led to abrupt increases in Nab titers in booster immunized (B-Im) fish at Month 1 (1:12800 +/- 6704) but thereafter declined and dropped at Month 12 (1:480 +/- 165) post-booster immunization. The annual booster injections with the inactivated vaccine or L-15 (Unimmunized [U-Im]) were consecutively conducted for 4 years until the fish became sexually mature. Mature fish from both groups were successively induced to spawn twice (1-month interval) via intramuscular injection with luteinizing hormone-releasing hormone analogue (LHRH-a; 100 ug/kg BW). NNV was not detected by RT-PCR in oocytes and milts, and spawned eggs of B Im fish. In contrast, oocytes and milts, and spawned eggs of U-Im fish were NNV positive. Spawned eggs of B-Im broodfish exhibited Nab titers ranging from 1:192 +/- 34 to 1:240 while such was not detected (<1:40) in eggs of U-Im fish. Taken together, current data clearly demonstrate that annual immunization regimen with inactivated NNV vaccine is a pragmatic approach for sustaining immunocompetent sea bass broodfish reared in land-based tanks and circumvent the risk of vertical transmission of NNV from asymptomatic broodfish to their offspring under stress of repetitive spawning. PMID- 30017148 TI - Dual route vaccination for plague with emergency use applications. AB - Here, we report a dual-route vaccination approach for plague, able to induce a rapid response involving systemic and mucosal immunity, whilst also providing ease of use in those resource-poor settings most vulnerable to disease outbreaks. This novel vaccine (VypVaxDuo) comprises the recombinant F1 and V proteins in free association. VypVaxDuo has been designed for administration via a sub cutaneous priming dose followed by a single oral booster dose and has been demonstrated to induce early onset immunity 14 days after the primary immunisation; full protective efficacy against live organism challenge was achieved in Balb/c mice exposed to 2 * 104 median lethal doses of Yersinia pestis Co92, by the sub-cutaneous route at 25 days after the oral booster immunisation. This dual-route vaccination effectively induced serum IgG and serum and faecal IgA, specific for F1 and V, which constitute two key virulence factors in Y. pestis, and is therefore suitable for further development to prevent bubonic plague and for evaluation in models of pneumonic plague. This is an essential requirement for control of disease outbreaks in areas of the world endemic for plague and is supported further by the observed exceptional stability of the primary vaccine formulation in vialled form under thermostressed conditions (40 degrees C for 29 weeks, and 40 degrees C with 75% relative humidity for 6 weeks), meaning no cold chain for storage or distribution is needed. In clinical use, the injected priming dose would be administered on simple rehydration of the dry powder by means of a dual barrel syringe, with the subsequent single booster dose being provided in an enteric-coated capsule suitable for oral self administration. PMID- 30017149 TI - Anterior composite resin crown in an adverse situation: A dental technique with a 3-year follow-up. AB - Endodontically treated teeth often exhibit severe coronal structure loss. Given the reversibility and tissue conservation of adhesive procedures, a conservative approach using an indirect resin crown with an adhesively cemented custom fiber reinforced composite resin post provided a predictable and esthetic solution. The 24-hour and 3-year follow-ups of this technique showed good function, marginal adaptation, and esthetics. PMID- 30017150 TI - An accessory technique for the intraoral removal of a fractured implant abutment screw. AB - As the use of dental implants becomes more prevalent, mechanical complications become more common. When an implant abutment screw fractures, it can be difficult to retrieve the retained fragment. The purpose of this article is to describe a technique to remove the abutment screw fragments without damaging the implant body or its screw threads. PMID- 30017151 TI - Staged extractions and implant placement in a periodontally compromised patient: A clinical report. AB - Staging the extraction of selected teeth in a periodontally compromised patient during complete mouth rehabilitation has advantages, including avoiding a transitional complete denture, keeping the patient with a fixed prosthesis throughout the treatment without the need to immediately load the implants, maintaining the interdental papillae, and providing comfort for the patient. The need for a multistep extended treatment and additional cost are the main disadvantage of this approach. This clinical report describes the clinical steps and follow-up of a staging approach and implant placement in a periodontally compromised patient with excessive gingival display to achieve a good functional and esthetic result. PMID- 30017152 TI - Randomized controlled clinical trial of digital and conventional workflows for the fabrication of zirconia-ceramic fixed partial dentures. Part I: Time efficiency of complete-arch digital scans versus conventional impressions. AB - STATEMENT OF PROBLEM: Clinical trials are needed to evaluate digital and conventional technologies for providing fixed partial dentures. PURPOSE: The purpose of the first part of this clinical study was to test whether complete arch digital scans were similar to or better than complete-arch conventional impressions regarding time efficiency and participant and clinician perceptions. MATERIAL AND METHODS: Ten participants in need of a posterior tooth-supported 3 unit fixed partial denture were included. Three intraoral digital scanners and subsequent workflows (Lava C.O.S.; 3M [Lava], iTero; Align Technology Inc [iTero], Cerec Bluecam; Dentsply Sirona [Cerec]) were compared with the conventional impression method using polyether (Permadyne; 3M) and the conventional workflow. A computer-generated randomization list was used to determine the sequence of the tested impression procedures for each participant. The time needed for the impression procedures, including the occlusal registration, was assessed. In addition, the participant and clinician perceptions of the comfort and difficulty of the impression were rated by means of visual analog scales. Data were analyzed with the nonparametric paired Wilcoxon test together with an appropriate Bonferroni correction to detect differences among the impression systems (alpha=.05). RESULTS: The total time for the complete-arch impressions, including the preparation (powdering) and the occlusal registration, was shorter for the conventional impression than for the digital scans (Lava 1091 +/-523 seconds, iTero 1313 +/-418 seconds, Cerec 1702 +/ 558 seconds, conventional 658 +/-181 seconds). The difference was statistically significant for 2 of the 3 digital scanners (iTero P=.001, Cerec P<.001). The clinicians preferred the conventional impression to the digital scans. Of the scanning systems, the system without the need for powdering was preferred to the systems with powdering. No impression method was clearly preferred over others by the participants. CONCLUSIONS: For complete-arch impressions, the conventional impression procedures were objectively less time consuming and subjectively preferred by both clinicians and participants over digital scan procedures. PMID- 30017153 TI - Effect of manufacturing techniques on the marginal and internal fit of cobalt chromium implant-supported multiunit frameworks. AB - STATEMENT OF PROBLEM: Subtractive and additive computer-aided design and computer aided manufacturing (CAD-CAM) systems have been used in the fabrication of cobalt chromium (Co-Cr) long-span restorations. However, the accuracy of fit of multiunit frameworks is unclear. PURPOSE: The purpose of this in vitro study was to compare the marginal and internal fit of implant-supported, cement-retained 3 unit, 4-unit, and 5-unit Co-Cr metal frameworks fabricated by the lost wax (LW), CAD-CAM milling, and selective laser melting (SLM) techniques. MATERIAL AND METHODS: A total of 90 Co-Cr metal frameworks were fabricated for 3-unit, 4-unit, or 5-unit implant-supported cement-retained restorations on stock abutments with 3 different manufacturing technique subgroups (LW, CAD-CAM milling, and SLM). The silicone replica technique was used to evaluate the marginal and internal discrepancy values. By using a light microscope at *45 magnification and a digital measurement program, the thickness of the silicone layer was measured at 16 reference points on each abutment for a total of 3360 measurements. The effect of manufacturing techniques and number of units (groups) on discrepancy values was evaluated using a full factorial ANOVA model. Group and manufacturing technique effects were analyzed separately by 1-way ANOVA in case of significant interactions. Pairwise comparisons were evaluated using the Tukey post hoc test (alpha=.05). RESULTS: The mean marginal discrepancy of 3-unit frameworks showed no statistically significant differences in the LW (35 MUm) and SLM (25 MUm) techniques; however, the frameworks manufactured by CAD-CAM milling (68 MUm) had the highest marginal discrepancy values (P<.001). The mean marginal discrepancy values were 40 MUm (LW), 33 MUm (CAD-CAM milling), and 25 MUm (SLM) for 4-unit frameworks, and no significant differences were found among the manufacturing techniques. For 5-unit frameworks, CAD-CAM milling techniques had the widest mean marginal discrepancy values (85 MUm), and copings manufactured by the LW technique had the lowest mean marginal discrepancy values (36 MUm). For all manufacturing techniques, axial discrepancy values were not affected with respect to the unit number (P=.526). The highest internal discrepancy values were measured at the occlusal area in all groups. CONCLUSIONS: CAD-CAM milling had the poorest marginal fit values for 5-unit frameworks, whereas the LW technique demonstrated the best results. Unit number had no significant influence on the marginal and internal fit of the LW manufactured frameworks. PMID- 30017154 TI - Bonding properties of universal adhesives to root canals prepared with different rotary instruments. AB - STATEMENT OF PROBLEM: Preparation of coronal dentin by using a diamond rotary instrument usually results in higher bond strength values than preparation with tungsten carbide burs, but information is lacking about the influence of rotary instruments on root canals before the bonding of fiber posts. PURPOSE: The purpose of this in vitro study was to evaluate the influence of the rotary instrument used to prepare the root canal and bonding strategies on the adhesion of fiber posts to root dentin with universal adhesive systems. MATERIAL AND METHODS: Human premolars were used and divided into 8 groups according to the combination of the following factors: rotary instrument (tungsten carbide bur versus diamond rotary instrument), cementation system (single-bond versus prime and bond), and bonding method (etch-and-rinse versus self-etch). Eight teeth per group were evaluated by push-out bond strength, 4 teeth were evaluated for nanoleakage by using scanning electron microscopy (SEM), and 2 teeth were evaluated for shape by SEM. Data for bond strength and nanoleakage for each cementation system were subjected to 2-way ANOVA and Tukey honest significant differences tests (alpha=.05). RESULTS: The highest bond strength values were observed for preparation using a diamond rotary instrument for both cementation systems. For prime and bond, the highest bond strength values were observed with the self-etch adhesion strategy, and the self-etch strategy was better for the single-bond; and the self-etch strategy was better than etch-and-rinse just after the use of a diamond instrument. In relation to nanoleakage for the cementation system, the prime and bond had the lowest values for groups using a diamond instrument and self-etch strategy. For the single bond, the adhesion strategy did not influence nanoleakage, but the rotary instrument did, with diamond rotary instruments resulting in lower values. SEM analyses showed a greater number of unobliterated tubules in the self-etch mode and a more regular surface when prepared with a diamond rotary. CONCLUSIONS: To improve the adhesion of fiber posts to root canal, a diamond rotary instrument should be used, and generally, universal adhesive systems must be used in self-etch mode. PMID- 30017155 TI - Optimizing accuracy in computer-guided implant surgery with a superimposition anchor microscrew system: A clinical report. AB - The accuracy of computer-guided implant placement decreases when the remaining teeth are poorly distributed. This clinical report demonstrates a protocol for using a superimposition-anchor microscrew (SAM) system to improve the accuracy of computer-guided implant surgery in a posterior unilateral edentulous area. The SAM functioned as a fiducial marker for image superimposition and as an anchor for guide positioning. Applying the SAM system to computer-guided implant surgery enhances the accuracy of implant placement by minimizing possible errors occurring during image registration and guide positioning. PMID- 30017156 TI - Accuracy of digital technologies for the scanning of facial, skeletal, and intraoral tissues: A systematic review. AB - STATEMENT OF PROBLEM: The accuracy of the virtual images used in digital dentistry is essential to the success of oral rehabilitation. PURPOSE: The purpose of this systematic review was to estimate the mean accuracy of digital technologies used to scan facial, skeletal, and intraoral tissues. MATERIAL AND METHODS: A search strategy was applied in 4 databases and in the non-peer reviewed literature from April through June 2017 and was updated in July 2017. Studies evaluating the dimensional accuracy of 3-dimensional images acquired by the scanning of hard and soft tissues were included. RESULTS: A total of 2093 studies were identified by the search strategy, of which 183 were initially screened for full-text reading and 34 were considered eligible for this review. The scanning of facial tissues showed deviation values ranging between 140 and 1330 MUm, whereas the 3D reconstruction of the jaw bone ranged between 106 and 760 MUm. The scanning of a dentate arch by intraoral and laboratorial scanners varied from 17 MUm to 378 MUm. For edentulous arches, the scanners showed a trueness ranging between 44.1 and 591 MUm and between 19.32 and 112 MUm for dental implant digital scanning. CONCLUSIONS: The current digital technologies are reported to be accurate for specific applications. However, the scanning of edentulous arches still represents a challenge. PMID- 30017157 TI - Prediction of the learning curves of 2 dental CAD software programs. AB - STATEMENT OF PROBLEM: Dental clinical procedures are being replaced by digital workflows. Therefore, the time necessary to learn dental computer-aided design (CAD) software to achieve a change in the digital workflow should be evaluated. PURPOSE: The purpose of this study was to predict the learning curve according to the type of dental CAD software with the Wright model and to determine the rate of improvement in the learner's working time with iterative learning. MATERIAL AND METHODS: A total of 40 participants with various degrees of experience with dental computer-aided design and computer-aided manufacturing (CAD-CAM) systems were recruited. The 4 specified steps of a custom abutment design were performed with 3DSystem CAD software (Daesung) and exocad DentalCAD (Exocad GmbH) software and were repeated 3 times in stages. The times were analyzed with repeated measures 1-factor and 2-factor analyses. The learning time for 300 design iterations was estimated by applying the Wright model formula, and the 300 repetition times were analyzed with the Mann-Whitney U test (alpha=.05). RESULTS: EXOCAD had a longer mean learning time than the 3DSystem. The overall change with repeated learning was significantly different (P<.001), and all differences were found in the first to third iterations. Software-dependent differences were also observed (P=.005). The Mann-Whitney U test also revealed a significant difference between the 2 software programs (P=.015), but no significant difference was found after the 56th iteration (57th iteration: P=.051). CONCLUSIONS: As the time reduction patterns for iterative learning differ depending on the type of CAD software, the learning curves may differ according to the type of software. As the operator's skill increased through iterative learning, the differences in learning times between the software programs gradually disappeared. PMID- 30017158 TI - Use of a surgical template for minimally invasive second-stage surgery: A dental technique. AB - The introduction of new techniques and new technology has been directly related to successful outcomes in implant dentistry. Merging information from high quality cone beam computed tomography images and detailed prosthetically driven digital planning translates into computer-guided surgery. A surgical template is a guide used to assist in the proper surgical placement and angulation of dental implants. However, a surgical guide not only facilitates implant placement but can also be used for other purposes, including diagnosis, treatment planning, and even second-stage surgery. In situations where multiple implants have been placed through computer-guided implant surgery, the preexisting surgical template can be used to perform the second-stage surgery with a flapless approach if the patient's soft tissue condition permits. PMID- 30017159 TI - Use of an esthetic overdenture as an alternative treatment in a patient with bilateral cleft lip and palate. AB - Stable occlusion and a pleasing esthetic appearance are often difficult to achieve in patients with congenital defects and severe midfacial deficiencies. Conventional therapy, such as orthodontic treatment followed by orthognathic surgery, is often not sufficient to fully correct the dental and esthetic problems. An interdisciplinary approach for these patients should include prosthodontic treatment that will assist in establishing a harmonious occlusion and improve facial appearance. This clinical report describes the interdisciplinary approach for a young patient with a history of bilateral cleft lip and palate, spina bifida, hydrocephalus, and ventriculoperitoneal shunt. The patient was treated with conventional orthodontic treatment and orthognathic surgery that failed to fully correct the malocclusion. A removable overlay prosthesis made of crystallized acetyl resin was used to reestablish esthetics and create a stable occlusion. PMID- 30017160 TI - Esthetic management of fused incisors with ceramic veneers. AB - This clinical report describes a patient for whom single veneers with pink staining were used on fused maxillary incisors to camouflage and improve dental appearance. PMID- 30017161 TI - Measuring the space required for symmetrical prosthetic restorations in the esthetic zone for an orthodontic patient: A dental technique. AB - This article describes a technique for measuring the length of the edentulous space to be restored and transferring the same size of the dentate space on the contralateral side to plan for symmetrical definitive restorations for the restorative dentist and orthodontist. The technique involves incorporating 2 archwire locks with hooks on a stainless steel wire that can be easily moved and adjusted to assess the curved space being measured. PMID- 30017162 TI - Energy dissipation capacities of CAD-CAM restorative materials: A comparative evaluation of resilience and toughness. AB - STATEMENT OF PROBLEM: Well-balanced physical properties of computer-aided design and computer-aided manufacturing (CAD-CAM) materials are important to ensure the clinical success and longevity of restorations. Therefore, the capacity of a material to dissipate destructive fracture energy by means of elastic and plastic material deformation is of interest. However, little information is available on how to quantify the resilience and toughness of CAD-CAM materials. PURPOSE: The purpose of this in vitro study was to investigate and compare the resilience and toughness of CAD-CAM restorative materials and assess their capability to dissipate destructive fracture energy in comparison with a high-gold-content alloy. MATERIAL AND METHODS: Restorative materials for 3-unit fixed partial dentures (Alphador No. 1, IPS e.max CAD, Lava Plus, PEEK Optima), crowns and onlays (CERASMART, CEREC Blocs, Lava Ultimate, VITA ENAMIC), and interim prostheses (M-PM Disc, Telio CAD) were investigated. The strain energy density was determined with a 3-point bend test to calculate the modulus of toughness, the modulus of resilience, and the elastic recovery and thus characterize the material properties of resilience and toughness. Data were statistically analyzed with a generalized linear mixed model by using the Huber-White sandwich estimator (alpha=.05). RESULTS: Significant differences were found among the materials concerning the modulus of toughness, the modulus of resilience, the elastic recovery, and the difference between the elastic recovery and the modulus of resilience (P<.001). Alphador produced the highest mean regarding the modulus of toughness followed by Telio CAD, Lava Plus, M-PM Disc, CERASMART, and Lava Ultimate; all showed significantly higher capacities to dissipate energy by elastic and plastic deformation when compared with the ceramic materials (IPS e.max CAD, VITA ENAMIC, CEREC Blocs). For the modulus of resilience and elastic recovery, Lava Plus and Alphador showed the highest mean values and therefore better able to only elastically absorb destructive fracture energy; the least able materials were VITA ENAMIC and CEREC Blocs. As PEEK Optima, M-PM Disc, and Lava Ultimate showed higher mean values for the modulus of resilience than IPS e.max CAD, they were better able to elastically dissipate energy. CONCLUSIONS: Alphador had the highest values for the modulus of toughness, the elastic recovery, and the difference between the elastic recovery and the modulus of resilience; this was equivalent to pronounced energy dissipation capacities. In comparison, Lava Plus showed the highest modulus of resilience but significantly lower results for all other parameters and therefore fewer energy-consuming capabilities. The new polymer-based CAD-CAM restorative materials in general had a higher modulus of toughness and elastic recovery than ceramics and thereby partially resemble Lava Plus, all with similar capacities to dissipate destructive energy. PMID- 30017163 TI - A modified technique for single-step border molding. AB - The sectional and the single-step are techniques for border molding. Even though the sectional technique is routinely taught in dental schools in the United States, and is followed by a large number of general dental practitioners, it is not without disadvantages. Common problems associated with the sectional technique include its time-consuming nature and the difficulty in mastering it because of the short manipulation time of the impression compound modeling plastic. Single-step border molding, however, presents advantages; for example, fewer insertions of the tray for border molding are necessary, and development of all borders simultaneously avoids the propagation of error. This article presents a simplified technique for performing single-step border molding using visible light-polymerizing tray material. PMID- 30017164 TI - Chemical hygiene protocols for complete dentures: A crossover randomized clinical trial. AB - STATEMENT OF PROBLEM: Clinical evidence on the best chemical protocol for the disinfection and removal of biofilm from complete dentures is lacking. PURPOSE: The purpose of this crossover randomized clinical trial was to assess the effectiveness of various chemical hygiene clinical protocols in reducing the microbial viability of biofilm formed on complete dentures. MATERIAL AND METHODS: In this triple-blind (participants, dentist, and outcome evaluator) study, complete denture wearers without candidiasis were randomly divided into 4 groups (n=40) according to the chemical hygiene protocol: water (placebo), 0.5% sodium hypochlorite solution, 0.12% chlorhexidine gluconate solution, and 5% sodium bicarbonate solution. The biofilm formed on the palate intaglio and denture teeth was collected and assessed in each experimental phase for quantitative microbial viability at the seventh and 14th day after using the chemical protocol. RESULTS: Two participants were lost. Data were analyzed by MANOVA and Tukey HSD tests. Soaking dentures was not effective in decreasing Candida albicans, C. non albicans, and lactobacillus counts. The use of sodium hypochlorite and chlorhexidine decreased total microorganisms and Streptococcus mutans counts for both palate and teeth compared with water and sodium bicarbonate. The intaglio of the dentures always presented higher microbial counts than did the denture teeth. CONCLUSIONS: The use of sodium hypochlorite and chlorhexidine and mechanical cleansing with a toothbrush decreased microbial viability in healthy complete denture wearers. PMID- 30017165 TI - How does the piston material affect the in vitro mechanical behavior of dental ceramics? AB - STATEMENT OF PROBLEM: Variables involving the indication, manufacturing, and clinical use of ceramic restorations make the standardization of in vitro studies a challenge and raise questions as to the clinical validity of the resulting data. PURPOSE: The purpose of this in vitro study was to assess the effect of piston material on the fracture behavior of ceramics tested under compressive load. MATERIAL AND METHODS: Two ceramics were evaluated: a lithium disilicate based glass-ceramic (D) and a feldspathic porcelain (P). Plate-shaped ceramic specimens (1.5-mm thick) were adhesively cemented onto a dentin analog substrate. The specimens from each ceramic were divided into 4 groups according to the piston material (n=20): metal (M) (stainless steel), composite resin (R) (NEMA G10, fiber-reinforced epoxy resin), ceramic (C) (lithium disilicate-based glass ceramic), and human tooth (T) (canine). A gradual compressive load (0.5 mm/min) was applied to the center of the specimen with a universal testing machine. The test was performed in 37 degrees C distilled water, and the initial crack was detected by using an acoustic system. The fracture load values (N) were statistically analyzed with the Kruskal-Wallis and Dunn tests (alpha=.05). A finite element analysis (FEA) was also performed. RESULTS: Piston material had no influence on fracture load and failure mode of ceramic D. Ceramic P showed higher fracture load values when loaded with the composite resin piston. Ceramic P showed more combined failures (cone crack and radial crack) than D. The FEA showed a distinct stress distribution for R piston on P. Pistons C and T resulted in similar stress distribution, fracture load, and failure mode for both ceramics. CONCLUSIONS: The effect of piston material on the ceramic fracture behavior depends on the ceramic being evaluated. PMID- 30017166 TI - Midline diastema closure using a vacuum-formed retainer. PMID- 30017167 TI - Trueness analysis of zirconia crowns fabricated with 3-dimensional printing. AB - STATEMENT OF PROBLEM: The primary manufacturing method of zirconia ceramic crowns is computer-aided design and computer-aided manufacture (CAD-CAM), but a disadvantage of this technique is material waste. Three-dimensional (3D) printing, which has been recently introduced into dentistry, has improved the processing of polymers and metals, but not yet of ceramic crowns. PURPOSE: The purpose of this in vitro study was to evaluate the 3D trueness of zirconia crowns fabricated by 3D printing to investigate the potential application of this technology in dental ceramic restorations. MATERIAL AND METHODS: A typodont tooth was prepared for a ceramic crown, and a digital crown was designed using the CAD software. The digital crown was processed either with a 3D-printing system or with a dental milling system. The crowns were scanned using a dental laboratory scanner, and the data collected for each crown were divided into 4 parts (the external surface, intaglio surface, marginal area, and intaglio occlusal surface). Finally, the trueness of each part was determined using the 3D inspection software. The 3D trueness of the crowns fabricated by either 3D printing or milling was compared by a 1-sided test (alpha=.05). RESULTS: The trueness of the external surface, intaglio surface, marginal area, and intaglio occlusal surface of the 3D-printed crowns was no worse than the corresponding trueness of the CAD-CAM crowns (P<.05). CONCLUSIONS: Zirconia crowns produced by 3D printing meet the trueness requirements, and 3D printing may be suitable for fabricating zirconia crowns. PMID- 30017168 TI - Antihypertensive Drugs in Croatia: What Changes the Drug Usage Patterns? AB - PURPOSE: Possible factors that could influence changes in patterns of prescribing antihypertensives could be identified by monitoring national trends in hypertension treatment. The choice of pharmacologic treatment in people with hypertension has important therapeutic and financial implications, due to the fact that the financial costs associated with hypertension continue to increase. The aims of our study were to identify and analyze changes in the usage of antihypertensive drugs in Croatia from 2000 to 2016 and to identify the changes in prescribing patterns as well as mean prices per defined daily dose (DDD). METHODS: Data on consumption in Croatia were obtained from the International Medical Statistics database. According to the World Health Organization's Collaborating Center for Drugs Statistics Methodology, per-annum volumes of drugs are presented in DDD per 1000 population per day (DDD/1000), while data on financial expenditure are presented in euros. FINDINGS: The consumption of drugs for cardiovascular disease in Croatia during the period from 2000 to 2016 increased 150.81%, while financial expenditure in the same period increased 47.32%. The most frequently prescribed subgroup was agents acting on the renin angiotensin system (RAS). Their share among antihypertensives increased from 39.13% (2000) to 53.39% (2016). The share of diuretics in the same period decreased from 20.16% in 2000 to 12.73% in 2016. IMPLICATIONS: The prescribing patterns of antihypertensive drugs in Croatia have changed, which could be a result of a combination of different factors, such as changes in laws, pharmaceutical marketing, and guidelines on hypertension therapy. The most prescribed subgroup in all of the investigated years was agents acting on the RAS, mainly because of the increased prescribing of combinations of RAS agents plus diuretics. The financial implications of legal changes and the introduction of new generic drugs led to decreased cost per DDD of antihypertensives during the investigated period, but the total expenditure on antihypertensives in Croatia increased due to increased consumption. PMID- 30017169 TI - Effects of CYP2C19 Genetic Polymorphisms on the Pharmacokinetic and Pharmacodynamic Properties of Clopidogrel and Its Active Metabolite in Healthy Chinese Subjects. AB - PURPOSE: Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. METHODS: Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate-induced platelet aggregation was measured by light-transmittance aggregometry. FINDINGS: There were no significant differences in Cmax and AUC0-t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P = 0.003] and 19.55 [2.19] ng/mL [P = 0.004], respectively). The mean CAM AUC0-t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng . h/mL [P = 0.007] and 27.08 [2.72] ng . h/mL [P = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P = 0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0-t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01). IMPLICATION: In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382. PMID- 30017170 TI - Evolution of Business Models in Regenerative Medicine: Effects of a Disruptive Innovation on the Innovation Ecosystem. AB - PURPOSE: This article focuses on 10 case studies of companies/organizations that are part of the current innovation ecosystem of regenerative medicine (RM) in the United Kingdom. It analyzes the actors, linkages, and influences that will determine the future shape of the RM industry sector and its capacity to live up to its initial expectations. METHODS: Using the case study approach, purposive sampling was used to get 18 interview respondents from 10 RM companies/organizations in the United Kingdom. We used semistructured interviews for data gathering and thematic analysis for identifying gaps in the RM value chain (ie, the range of activities required for bringing a product from conception to market and end-use) and the influences of the innovation ecosystem on the evolving RM business models. FINDINGS: RM promises to address currently unmet health care needs by restoring the normal form and function of cells, tissues, and organs. The innovations emerging to support the progress of RM to satisfy these important health care markets will disrupt the business models of incumbent industry sectors, particularly pharmaceuticals. Companies involved in this area must develop innovative business models and value chains and negotiate the complex influences of the innovation ecosystem, including regulatory systems and standards, financial support systems, and new market dynamics. IMPLICATIONS: This article highlights the needs for more systemic analyses of the needs of potentially disruptive innovations, in RM and more widely, and for policymakers to give greater attention to these insights in planning regulatory and other supporting initiatives, with the promotion of innovation in mind. PMID- 30017171 TI - Effect of Fluconazole on the Pharmacokinetic Properties of Imrecoxib, a Novel NSAID: A Single-center, Open-label, Self-controlled Study in Healthy Chinese Male Volunteers. AB - PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters. METHODS: In this single center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study. FINDINGS: All subjects completed the study. There was 1 adverse event; drug induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments. IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxib + fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors. PMID- 30017172 TI - Effect of Resveratrol Supplementation on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - PURPOSE: The evidence has suggested that resveratrol has anti-inflammatory effect; however, the results are inconsistent and inconclusive. The aim of this study was to assess the effect of resveratrol supplementation on the levels of inflammatory markers through a systematic review and meta-analysis of available randomized controlled trials (RCTs). METHODS: A search strategy was completed using Medline, ISI Web of Science, Directory of Open Access Journal, SID, ProQuest, Cochrane Library, Scopus, and EMBASE up to May 2017, to identify placebo-controlled RCTs that assessed resveratrol effects on circulating (serum and plasma) inflammatory markers (interleukin [IL]-6, tumor necrosis factor-alpha [TNF-alpha], and high-sensitivity C-reactive protein [hs-CRP]) among adult participants aged 17 years and older in 17 RCTs with a total of 736 subjects. The evaluation of study quality was performed using the Jadad scale. Weighted mean difference (WMD) was calculated for evaluating the changes in the inflammatory markers using fixed-effects or random-effects models. We performed subgroup and sensitivity analyses to evaluate the heterogeneity of the studies. FINDINGS: Seventeen RCTs, including 736 subjects, fulfilled the eligibility criteria and were selected for analyses. The results of meta-analysis found significant reductions in the level of TNF-alpha (WMD, -0.44; 95% CI, -0.71 to -0.164; P = 0.002; Q statistic = 21.60; I2 = 49.1%; P = 0.02) and hs-CRP (WMD, -0.27; 95% CI, -0.5 to -0.02; P = 0.033; Q statistic = 26.95; I2 = 51.8%; P = 0.013) after supplementation with resveratrol. Resveratrol supplementation had no significant effect on the level of IL-6 (WMD, -0.16; 95% CI, -0.53 to 0.20; P = 0.38; Q statistic = 36.0; I2 = 72.3%; P = 0.001). Statistically significant heterogeneity was observed for the type of sample in IL-6 and study duration in inflammatory markers IL-6, TNF-alpha, and hs-CRP. IMPLICATIONS: Available evidence from RCTs suggests that resveratrol supplementation significantly reduced TNF-alpha and hs CRP levels. Significant improvement in inflammatory markers support resveratrol as an adjunct to pharmacologic management of metabolic diseases. PMID- 30017173 TI - Automatic detection System for Degenerative Disk and simulation for artificial disc replacement surgery in the spine. AB - This paper presents an automatic detection system for the degenerative disc and simulates the artificial disc replacement surgery in the spine. It starts by visualizing the Digital Imaging and Communications in Medicine (DICOM) in three views and then identifies regions for the lumber or sacral, followed by applying an adaptive threshold and modified region growing techniques to separate the spine from the surrounding tissues, organs, and bones. Then, segment each vertebral in the spine using K-means clustering algorithm. Then, the distance of intervertebral space was computed to detect the degenerative disk automatically in the lumbar region. Finally, the replacement surgery simulation occurred to design the disc with exact dimensions and identifies the appropriate place that will be implanted in the spine. The proposed system was tested on ten 3D computed tomography (CT) images downloaded from the Cancer Imaging Archive (TCIA). It was accessible to implant the artificial disk instead of the degenerative disk in the space that was specified automatically by the proposed system. The experimental outcomes positively demonstrate that the intended system is efficacious in the detection of degenerative disc and replacement of artificial disc simulation. PMID- 30017174 TI - Distal pancreatectomy in the community setting: Application of the Donabedian principles. PMID- 30017175 TI - A partial Homo pelvis from the Early Pleistocene of Eritrea. AB - Here we analyze 1.07-0.99 million-year-old pelvic remains UA 173/405 from Buia, Eritrea. Based on size metrics, UA 173/405 is likely associated with an already described pubic symphysis (UA 466) found nearby. The morphology of UA 173/405 was quantitatively characterized using three-dimensional landmark-based morphometrics and linear data. The Buia specimen falls within the range of variation of modern humans for all metrics investigated, making it unlikely that the shared last common ancestor of Late Pleistocene Homo species would have had an australopith like pelvis. The discovery of UA 173/405 adds to the increasing number of fossils suggesting that the postcranial morphology of Homo erectus s.l. was variable and, in some cases, nearly indistinguishable from modern human morphology. This Eritrean fossil demonstrates that modern human-like pelvic morphology may have had origins in the Early Pleistocene, potentially within later African H. erectus. PMID- 30017176 TI - Use of the cardiovascular polypill 40mg in secondary cardiovascular prevention. AB - Controlling cardiovascular risk factors (CV) is essential for patients with cardiovascular disease. The CV polypill contains aspirin 100mg, atorvastatin 20mg or 40mg, and ramipril 2.5mg, 5mg or 10mg in a fixed combination pill. The objective was to review the evidence on the secondary prevention of cardiovascular disease, to establish the eventual patient profiles suitables to consider the use of CV polypill with atorvastatin 40mg in secondary CV prevention (P40PS), and to define the priority situations most adequate for the use of P40PS. A bibliographic review was carried out, which was complemented with the clinical opinion of 19 specialists. During hospitalization and discharge, P40PS is an option for patients admitted because of an atherothrombotic event, peripheral arterial disease, or other causes, and with the indication of the monocomponents. Its priority use is proposed in: prior intolerance to the highest dose of atorvastatin (80mg), age>75 years, low weight, stage 3 of chronic renal failure, hypothyroidism, drug interactions and Asian origin. Outside the hospital setting, the P40PS is a therapeutic alternative in patients with a need for secondary CV prevention and with indication to receive the monocomponents. The priority situations to receive the P40PS are: to be taking the three components separately, to require polypharmacy, lack of adherence or understanding of the treatment, and lack of control of CV risk factors. This work is the first with proposals for the use of P40PS and can facilitate the treatment of patients with cardiovascular disease in secondary prevention. PMID- 30017177 TI - High-density lipoprotein function is associated with atherosclerotic burden and cardiovascular outcomes in type 2 diabetes. AB - BACKGROUND AND AIMS: Measures of HDL function are emerging tools for assessing cardiovascular disease (CVD) event risk. HDL-apoA-I exchange (HAE) reflects HDL capacity for reverse cholesterol transport. METHODS: HAE was measured in 93 participants with type 2 diabetes (T2D) and at least one additional CVD risk factor in the Asker and Baerum Cardiovascular Diabetes study. At baseline and after seven years, the atherosclerotic burden was assessed by invasive coronary angiography. Major CVD events were registered throughout the study. RESULTS: Linear regression analysis demonstrated a significant inverse association between HAE and atherosclerotic burden. Cox proportional hazard regression analysis showed a significant association between HAE and a composite of major CVD events when controlling for waist-hip ratio, HR = 0.89, 95% CI = 0.80-1.00 and p=0.040. CONCLUSIONS: Despite the relatively small size of the study population and the limited number of CVD events, these findings suggest that HAE provides valuable information in determining CVD risk. PMID- 30017178 TI - Unwarranted clinical variation in the care of children and young people hospitalised for injury: a population-based cohort study. AB - INTRODUCTION: Injury is a leading cause of death and disability among children and young people. Recovery may be negatively affected by unwarranted clinical variation such as representation to an emergency department (ED), readmission to a hospital, and mortality. The aim of this study was to examine unwarranted clinical variation across providers of care of children and young people who were hospitalised for injury in New South Wales (NSW). MATERIALS AND METHODS: Retrospective population-based cohort study using linked ED, hospital, and mortality data of all children and young people aged <=25 years who were injured and hospitalised during 1 January 2010-30 June 2014 in NSW. Unwarranted clinical variation across providers was examined using three indicators. That is, for each hospital that treated >=100 cases per year, risk standardised ratios were calculated with 95% and 99.8% confidence limits using the number of observed and expected events of (1) representations to ED within 72 h, (2) unplanned readmissions to hospital within 28 days, and (3) all-cause mortality within 30 days. RESULTS: There were 189,990 injury-related hospitalisations of children and young people. Of these, 4.4% represented to an ED, 8.7% were readmitted to hospital, and 0.2% died. Of the 45 public hospitals that treated >=100 cases per year, higher than expected rates of ED representations, hospital readmissions, and mortality were observed in eleven, six, and two hospitals, respectively. CONCLUSION: The rates of ED representations, hospital readmissions, and mortality among children and young people hospitalised for injury in NSW were similar to the rates reported in other countries. However, unwarranted clinical variation across public hospitals was observed for all three indicators. These findings suggest that by improving routine follow-up support services post-discharge for children and young people and their families, it may be possible to reduce unwarranted clinical variation and improve health outcomes. PMID- 30017179 TI - Volar plating in distal radius fractures: A prospective clinical study on efficacy of dorsal tangential views to avoid screw penetration. AB - PURPOSE: The purpose of this prospective cohort study of patients treated with volar plating for distal radius fractures is to evaluate the efficacy (defined as detection rate, or the ability to detect dorsally protruding screws) of additional dorsal tangential views (DTV) after obtaining standard anteroposterior (AP) and elevated lateral views by evaluating the change in intraoperative strategy in 100 patients. MATERIALS AND METHODS: 100 patients aged 18 years and older undergoing volar plating for acute extra- or intra- articular distal radius fractures were prospectively enrolled. Intraoperative fluoroscopy views, including AP, elevated lateral and DTV were obtained. Intraoperative -screw- revision frequency for dorsal screw protrusion, screw position relative to volar plate and to dorsal compartment, and screw lengths were evaluated. RESULTS: Additional DTV led to a change of intraoperative management in 31 of 100 (31%) of patients. A total of 35 out of 504 screws (6.9%) were changed. Screws in the two most radial screws in the plate were at the highest risk of being revised; 16 (46%) screws in most radial position and nine (26%) screws in the 2nd from radial position were revised. Furthermore, five (14%) screws in both the 2nd from ulnar and most ulnar screw holes were revised after DTV. No screws were revised in the central hole. The median length of revised protruding screws was 22 mm (range, 12 26 mm), and these were changed to a mean length of 20 mm (range, 10-22 mm). CONCLUSION: In this prospective series of 100 patients, obtaining additional DTV is found to be efficacious as it led to change in intraoperative strategy in one third of patients. We concur with previous pilot studies that DTV, after obtaining conventional AP and elevated lateral views, is advised to avoid dorsally protruding screws, which could minimise the potential for iatrogenic extensor tendon rupture after volar plating for distal radius fractures. Diagnostic accuracy of DTV is subject of a subsequent prospective cohort study with post-operative CT to serve as the reference standard. LEVEL OF EVIDENCE: .Prognostic I. PMID- 30017180 TI - Intra-operative fluoroscopy time and radiation dose during suprapatellar tibial nailing versus infrapatellar tibial nailing. AB - BACKGROUND: Fractures of the tibial shaft are routinely managed with intramedullary nailing. An increasingly accepted technique is the suprapatellar extended leg method. The aim of this study was to investigate whether the suprapatellar tibial nailing technique offers shorter intraoperative fluoroscopy times and lower radiation doses when compared to the traditional infrapatellar technique. STUDY DESIGN AND METHODS: Data from 200 consecutive intramedullary tibial nailing operations in our level 1 Major Trauma Centre were retrospectively collected from a prospective database (January 2014-December 2017). Only acute diaphyseal nailing procedures were included. The operations were performed by seven senior trauma consultants experienced in both suprapatellar and infrapatellar tibial nailing. The operations were divided into two groups: infrapatellar and suprapatellar. Intraoperative radiation time and dose data were collected. RESULTS: A total of 90 cases were included and analysed. The majority of the patients were male (82%). 37 operations were infrapatellar and 53 were suprapatellar. Independent samples t-test revealed lower radiation time and dose for the suprapatellar group. The infrapatellar group had a mean radiation time of 129.7 +/- 56.6 s versus 94.4 +/- 47.9 s for the suprapatellar group. The infrapatellar group had a mean radiation dose (Dose Area Product) 53.6 +/- 34.2 cGY cm2 versus 38.2 +/- 26.7 cGY cm2 for the suprapatellar group. The difference in mean radiation time and mean radiation dose were both significant (p = 0.002 and p = 0.02 respectively). CONCLUSIONS: Suprapatellar tibial nailing is an increasingly accepted technique in the management of tibial fractures. It is shown here that amongst surgeons experienced in both suprapatellar and infrapatellar nailing techniques, the suprapatellar approach trends towards lower use of intra-operative fluoroscopy as measured by time and dose and thus potentially lower radiation exposure to the operating surgeon, assistants and patient. PMID- 30017181 TI - Use of an intravascular temperature control catheter for rewarming of hypothermic trauma patients with ongoing hemorrhagic shock after combined damage control thoracotomy and laparotomy: A case series. AB - BACKGROUND: Correction of hypothermia is a key component of the resuscitation of critically injured patients with hemorrhagic shock who require damage control surgery. External rewarming methods may not be sufficient in this population, while extracorporeal techniques lack widespread feasibility. Intravascular catheter-based temperature modulation is increasingly being employed in different critically ill patient populations but has not been described as part of a damage control resuscitation strategy in trauma patients. METHODS: We retrospectively reviewed the medical records of all patients admitted to our multi-trauma intensive care unit from July 1, 2015 - December 31, 2017 in whom an intravascular temperature control catheter (IVTCC) was employed for rewarming from hypothermia during the immediate postoperative resuscitation of continued hemorrhage after undergoing combined damage control thoracotomy and laparotomy for trauma. All patients received baseline treatment with active external rewarming modalities and inline fluid/blood warmers. Core temperature values over the first 24 h of hospital admission were analyzed. Efficacy (rewarming rate) and safety (associated adverse events) of the IVTCC system were determined. RESULTS: Three patients (age 22 +/- 4.6, 100% male, 100% torso gunshot wounds with prehospital cardiac arrest) meeting the inclusion criteria were treated with the IVTCC system during the study period. Temperature at the start of rewarming using the IVTCC ranged from 30.1 to 35.5 degrees C. Despite ongoing severe hemorrhagic shock (24-hour ICU blood product requirement: 104 +/- 44 units), a mean rewarming rate of 1.04 +/- 0.63 degrees C/hour was achieved. One patient suffered an uncomplicated catheter-associated deep vein thrombosis. Two of the 3 patients survived to hospital discharge with intact cognitive function. CONCLUSIONS: Use of an IVTCC may be a minimally-invasive, practical, and effective method for rewarming critically ill trauma patients with ongoing hemorrhagic shock after multi-cavitary damage control surgery. Further studies are needed to compare this technology with currently available rewarming methods. PMID- 30017182 TI - Immediate weight bearing after plate fixation of fractures of the tibial plateau. AB - BACKGROUND: Proximal articular fractures of the tibia are commonly stabilised with internal fixation using plates and screws. There is a lack of evidence and conflicting guidelines as to the most suitable post-operative rehabilitation regime including weight bearing status. There are numerous physiological and socioeconomic benefits of early weight bearing after orthopaedic surgery, but concerns remain around loss of fracture reduction. Therefore, the aim of this study is to investigate whether the weight bearing status after tibial plateau plate fixation is associated with any loss of reduction or articular collapse. METHODS: We retrospectively analysed data from our prospectively collected major trauma centre database. All tibial plateau fractures that required open reduction and internal fixation with plate and screws were included. The immediate post operative weight bearing status of these patients was recorded. Group I consisted of those patients that were either non-weight bearing or touch weight bearing for the first six post-operative weeks. Group II consisted of patients who were instructed to weight bear fully (as tolerated) immediately after the operation. Radiographs were taken on day one post-operation, at six weeks and at three months and analysed for fracture displacement and joint depression or loss of fixation. RESULTS: A total of 90 patients were included in the study. Group I (non-weight bearing or touch weight bearing) consisted of 60 patients (67%). Group II (full weight bearing as tolerated) consisted of 30 patients (33%). The follow up radiographs demonstrated no failure of fixation in either study group. One patient from the weight bearing group had >1 mm joint depression (4 mm) identified at the first follow up, which did not progress. CONCLUSIONS: This study shows immediate post-operative full weight bearing does not affect the fixation or cause articular collapse up to three months after surgery and thus we propose that patients should be allowed to weight bear immediately after surgical stabilisation of tibial plateau fractures. This will enable patients to benefit from the positive effects on fracture healing of early weight bearing post surgery and avoid the complications of non-weight bearing without loss of fixation or articular collapse. PMID- 30017183 TI - Straight proximal humeral nailing: Risk of iatrogenic tendon injuries with respect to different entry points in anatomical specimens. AB - BACKGROUND: The purpose of the study was to evaluate the relationship of implant related injuries to the adjacent anatomical structures in a newer generation straight proximal humeral nail (PHN) regarding different entry points. The proximity of the proximal lateral locking-screws of the MultiLoc proximal humeral nail (ML PHN) may cause iatrogenic tendon injuries to the lateral edge of the bicipital humeral groove (BG) as reference point for the tendon of the long head of biceps brachii (LBT) as well as the lateral insertion of the infraspinatus tendon (IST). MATERIALS AND METHODS: The study comprised n = 40 upper extremities. Nail application was performed through a deltoid approach and supraspinatus tendon (SSP) split with a ML PHN. All tests were performed in three different entry points. First nail (N1) - standard position in line with the humeral shaft axis; second nail (N2) - a more lateral entry point; third alternative (N3) - medial position, centre of the humeral head. After nail placement, each specimen was screened for potential implant-related injuries or worded differently hit rates (HR) to the BG and the IST. The distances to the anatomical structures were measured and statistically interpreted. RESULTS: The observed iatrogenic IST injury rate was 17.5% (n = 7/40) for N1, 5% (n = 2/40) for N2 and 62.5% (n = 25/40) for N3, which was statistically significantly higher (p < 0.001). Regarding the BG, the evaluated HR was 7.5% (n = 3/40) for both N1 and N2. Only the nail placed in the head centre (N3) showed an iatrogenic injury rate of 20% (n = 8/40) (p < 0.062). No statistically significant association between humeral head size and the HR could be observed (head diameter: IST: p = 0.323, BG: p = 0.621; head circumference: IST: p = 0.167; BG: p = 0.940). For the IST and BG, all distances in nail positions N1 and N2 as well as N2 and N3 differ statistically significant (p < 0.001). CONCLUSIONS: An entry point for nail placement in line or slightly laterally to the humeral shaft axis - but still at the cartilage - should be advocated. PMID- 30017184 TI - Integrating extended focused assessment with sonography for trauma (eFAST) in the initial assessment of severe trauma: Impact on the management of 756 patients. AB - BACKGROUND: Before total body computed tomography scan, an initial rapid imaging assessment should be conducted in the trauma bay. It generally includes a chest x ray, pelvic x-ray, and an extended focused ultrasonography assessment for trauma. This initial imaging assessment has been poorly described since the increase in the use of ultrasound. Therefore, our study aimed to evaluate the diagnostic accuracy and therapeutic impact of this initial imaging work-up in severe trauma patients. A secondary aim was to assess the therapeutic impact of a chest x-ray according to the lung ultrasonography findings. METHODS: Patients with severe trauma who were admitted directly to our level 1 trauma center were consecutively included in this retrospective single center study. The diagnostic accuracy, therapeutic impact, and appropriate decision rate were calculated according to the initial assessment results of the whole body computed tomography scan and surgery reports. RESULTS: Among the 1315 trauma patients admitted, 756 were included in this research. Lung ultrasound showed a higher diagnostic accuracy for haemothorax and pneumothorax cases than the chest x-ray. Sensitivity and specificity of the abdominal ultrasound to detect intraperitoneal effusion were 70% and 96%, respectively. The initial assessment had a therapeutic impact in 76 (10%) of the patients, including 16 (2%) immediate laparotomies and 58 (7%) chest tube insertions. The pelvic x-ray had no therapeutic impact, and when the lung ultrasound was normal, the chest x-ray had a therapeutic impact of only 0.13%. Combining the chest x-ray and lung ultrasound allowed adequate management of all the pneumothorax and haemothorax cases. Only one of the 756 patients had initial management that was judged as inappropriate. This patient had a missed pelvic disjunction with active retroperitoneal bleeding, and underwent an inappropriate immediate laparotomy. CONCLUSIONS: In our cohort, the initial imaging assessment allowed appropriate decisions in 755 of 756 patients, with a global therapeutic impact of 10%. The pelvic x-ray had a minimal therapeutic impact, and in the patients with normal lung ultrasounds, the chest x-ray marginally affected the management of our patients. The potential consequences of abandoning systematic chest and pelvic x-rays should be investigated in future randomized prospective studies. PMID- 30017185 TI - Dialogue on the nomenclature and classification of prokaryotes. AB - The application of next generation sequencing and molecular ecology to the systematics and taxonomy of prokaryotes offers enormous insights into prokaryotic biology. This discussion explores some major disagreements but also considers the opportunities associated with the nomenclature of the uncultured taxa, the use of genome sequences as type material, the plurality of the nomenclatural code, and the roles of an official or computer-assisted taxonomy. PMID- 30017186 TI - TUG1 is involved in liver fibrosis and activation of HSCs by regulating miR-29b. AB - TUG1 has been shown to be involved in diverse human diseases by regulating gene expression at transcriptional and post-transcriptional levels via interaction with miRNA or proteins. However, the role of TUG1 in liver fibrosis remains unclear. Here, we found that Tug1 is dysregulated in liver fibrosis according to the microarray analysis. Moreover, we investigated the expression files of Tug1 by using CCl4-and BDL-induced liver fibrosis model mice as well as in the primary cells isolated from the mice. We demonstrated that Tug1 is over-expressed in the fibrotic livers and activated HSCs, but not injured hepatocytes. In addition, we assessed the function of Tug1 in HSCs and found that Tug1 promotes the expression of alpha-SMA, Col1alpha1, Mmp2/9/10 and Timp1. Mechanically, Tug1 promotes the expression of these pro-fibrogenic genes by down-regulating miR-29b, thus accelerating the progression of liver fibrosis. Further study revealed that TUG1was up-regulated in liver tissues of patients with cirrhosis. All together, our data indicate that TUG1 might be a potential therapy target of liver fibrosis. PMID- 30017187 TI - Effect of the interaction of metformin and bone morphogenetic proteins on ovarian steroidogenesis by human granulosa cells. AB - In the present study, we studied the effects of metformin and its interactions with the actions of bone morphogenetic proteins (BMPs) on ovarian steroidogenesis. It was revealed that metformin treatment enhanced progesterone production by human granulosa KGN cells and rat primary granulosa cells induced by forskolin and FSH, respectively. In human granulosa cells, it was found that metformin treatment suppressed phosphorylation of Smad1/5/9 activated by BMP-15 compared with that induced by other BMP ligands. Moreover, metformin treatment increased the expression of inhibitory Smad6, but not of that Smad7, in human granulosa cells, while metformin had no significant impact on the expression levels of BMP type-I and -II receptors. Thus, the mechanism by which metformin suppresses BMP-15-induced Smad1/5/9 phosphorylation is likely, at least in part, to be upregulation of inhibitory Smad6 expression in granulosa cells. The results suggest the existence of functional interaction between metformin and BMP signaling, in which metformin enhances progesterone production by downregulating endogenous BMP-15 activity in granulosa cells. PMID- 30017188 TI - YAP1 inhibits circRNA-000425 expression and thus promotes oncogenic activities of miR-17 and miR-106. AB - YAP1, a vital effector of Hippo pathway, promotes cancer development via transcriptionally regulating a batch of target genes involved in various signaling pathways, including proliferation, apoptosis, and cell drug sensitivity. Recently, circular RNAs (circRNAs) have been shown to control gene expression post-transcriptionally and become a new layer of gene regulation. However, whether circRNAs play roles in YAP1-induced tumorigenesis is still largely elusive. Here, we identify circRNA-000425 as a new inhibitory target of YAP1, and also find that it binds to miR-17/miR-106b, and thus suppresses cancer cell growth induced by these miRNAs. circRNA-000425 is revealed as a YAP1 target through circRNA microarray analysis of RNAs extracted from cells treated with or without YAP1 siRNAs, and further confirmed by RT-q-PCR and ChIP assays. Interestingly, bioinformatics analysis, luciferase assay, and RT-q-PCR results showed that circRNA-000425 binds to miR-17 and miR-106b, but not let-7a, and rescues the inhibitory effect of miR-17/miR-106 on the expressions of both p21 and BIM. In addition, colony formation and MTT assay showed that circRNA-000425 inhibits cancer cell growth induced by miR-17. These findings reveal a mechanism by which YAP1 promotes oncogenic activities of miR-17 and miR-106b through transcriptionally inhibiting circRNA-000425 expression. PMID- 30017189 TI - Nanopore occlusion: A biophysical mechanism for bipolar cancellation in cell membranes. AB - Extraordinarily large but short electric field pulses are reported by many experiments to cause bipolar cancellation (BPC). This unusual cell response occurs if a first pulse is followed by a second pulse with opposite polarity. Possibly universal, BPC presently lacks a mechanistic explanation. Multiple versions of the "standard model" of cell electroporation (EP) fail to account for BPC. Here we show, for the first time, how an extension of the standard model can account for a key experimental observation that essentially defines BPC: the amount of a tracer that enters a cell, and how tracer influx can be decreased by the second part of a bipolar pulse. The extended model can also account for the recovery of BPC wherein the extent of BPC is diminished if the spacing between the first and second pulses is increased. Our approach is reverse engineering, meaning that we identify and introduce an additional biophysical mechanism that allows pore transport to change. We hypothesize that occluding molecules from outside the membrane enter or relocate within a pore. Significantly, the additional mechanism is fundamental and general, involving a combination of partitioning and hindrance. Molecules near the membrane can enter pores to block transport of tracer molecules while still passing small ions (charge number +/-1) that govern electrical behavior. Our extension of the standard model accounts for key BPC behavior. PMID- 30017190 TI - Alpha-lipoic acid reduces retinal cell death in diabetic mice. AB - Oxidative stress plays an important role in the development of diabetic retinopathy. Here, we examined whether alpha-lipoic acid (alpha-LA), a natural antioxidant, attenuated retinal injury in diabetic mice. The alpha-LA was orally administered to control mice or mice with streptozotocin-induced diabetes. We found that alpha-LA reduced oxidative stress, decreased and increased retinal 4 hydroxy-2-nonenal and glutathione peroxidase, respectively, and inhibited retinal cell death. Concomitantly, alpha-LA reversed the decreased activation of AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase, and increased the levels of peroxisome proliferator-activated receptor delta and sirtuin3 in diabetic mouse retinas, similar to results shown after metformin treatment of retinal pigment epithelial cells (RPE) exposed to high glucose. Moreover, alpha LA lowered the levels of O-linked beta-N-acetylglucosamine transferase (OGT) and thioredoxin-interacting protein (TXNIP) in diabetic retinas that were more pronounced after metformin treatment of RPE cells. Importantly, alpha-LA lowered interactions between AMPK and OGT as shown by co-immunoprecipitation analyses, and this was accompanied by less cell death as measured by double immunofluorescence staining by terminal deoxynucleotide transferase-mediated dUTP nick-end labelling and OGT or TXNIP in retinal ganglion cells. Consistently, alpha-LA lowered the levels of cleaved poly(ADP-ribose) polymerase and pro apoptotic marker cleaved caspase-3 in diabetic retinas. Our results indicated that alpha-LA reduced retinal cell death partly through AMPK activation or OGT inhibition in diabetic mice. PMID- 30017191 TI - Novel selenylated imidazo[1,2-a]pyridines for breast cancer chemotherapy: Inhibition of cell proliferation by Akt-mediated regulation, DNA cleavage and apoptosis. AB - A novel series of selenylated imidazo[1,2-a]pyridines were designed and synthesized with a view to a promising activity against breast cancer cell. The compounds, 7-methyl-3-(naphthalene-1-ylselanyl)-2-phenylimidazo[1,2-a]pyridine, named IP-Se-05, and 3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazo[1,2 a]pyridine, named IP-Se-06, showed high cytotoxicity for MCF-7 cells (IC50 = 26.0 MUM and 12.5 MUM, respectively). Both the compounds inhibited the cell proliferation and caused decrease in the number of cells in the G2/M phase of cell cycle. IP-Se-05 and IP-Se-06 were also evaluated for effects on CT-DNA and DNA of MCF-7 cells. The compounds intercalated into CT-DNA and both treatments caused cleavage of DNA in cells. In addition, the compounds induced cell death by apoptosis. However, the presence of (2-methoxyphenyl) selenyl moiety at the imidazo[1,2-a]pyridine (IP-Se-06) appears to have a better antitumor effect with higher cytotoxicity at a lower concentration and caused less necrosis. Overall, the current study established IP-Se-06 more than IP-Se-05 as a potential prototype compound to be employed as an antiproliferative agent for the treatment of breast cancer. PMID- 30017192 TI - Protein kinase C alpha-mediated phosphorylation of PIM-1L promotes the survival and proliferation of acute myeloid leukemia cells. AB - FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) is a constitutively active mutant of FLT3 and causes 20%-30% of acute myeloid leukemia (AML) cases. FLT3-ITD upregulates the proviral integration site for Moloney murine leukemia virus 1 (PIM-1) expression and promotes the proliferation of AML cells. In this study, we investigated the role of protein kinase C (PKC)-mediated phosphorylation on the expression and function of PIM-1L. Drug screening in leukemia cell lines revealed that sotrastaurin (a PKC inhibitor) suppressed the proliferation of the FLT3-ITD-positive AML cell line MV4-11 but not of K562, HL60, or KG-1a cells, similar to SGI-1776 (a PIM-1/FLT3 inhibitor) and quizartinib (an FLT3 inhibitor). Sotrastaurin decreased the expression of pro survival protein myeloid cell leukemia (MCL-1) and the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are downstream effectors of PIM-1. PKCalpha directly phosphorylated Ser65 of PIM-1L, which is a long isoform of PIM-1. The PKCalpha-mediated phosphorylation stabilized PIM-1L. The phosphorylation-mimicked mutant, PIM-1L-S65D, was more stable and showed higher kinase activity than PIM-1L-S65A. Expression of PIM-1L wildtype or -S65D reduced sotrastaurin-mediated apoptosis and growth inhibition in MV4-11 transfectants. These results suggest that PKCalpha directly upregulates PIM-1L, resulting in promotion of the survival and proliferation of AML cells. PMID- 30017193 TI - Distinct non-invasive evaluation values of tumor-derived cell-free microRNAs, circulating microvesicles and exosomal microRNAs after renal carcinoma cryoablation. AB - The detection of peripheral circulating tumor-derived components, such as cell free microRNAs, circulating microvesicles, and exosomal microRNAs, has been shown as a promising noninvasive strategy. However, the different roles of these components in tumor therapy evaluations have remained largely undefined. In this paper, we employed an in vivo model of the human clear cell renal cell carcinoma line Caki-1-bearing mice to evaluate the therapeutic effects of cryoablation, which is a new minimally invasive treatment for renal cell carcinoma. At different times after cryoablation, we found that the levels of the cell-free microRNAs miR-122, miR-155 and miR-210 were first increased and then decreased. Additionally, the number of large-sized microvesicles was increased after cryoablation, but the number of small-sized circulating microvesicles did not change. Furthermore, the exosomal microRNAs miR-126-3p, miR-17-5p, and miR-21-3p rapidly decreased one day after cryoablation, an effect that was well correlated with the treatment degree. Therefore, we suggest that these circulating components may have different levels of importance in the evaluation of the efficacy of renal cell cryoablation, furthermore, exosomal microRNAs may be more suitable for the early postoperative judgment of tumor elimination effects, which are worth further exploration in clinical practice. PMID- 30017194 TI - Protein hypoacylation induced by Sirt5 overexpression has minimal metabolic effect in mice. AB - Sirtuins are a family of evolutionary conserved enzymes that dynamically regulate cellular physiology. Mammals have 7 sirtuins, which are located in different cellular compartments. Sirt5, a sirtuin isoform located in multiple subcellular sites, is involved in regulating a diverse range of cellular and metabolic processes through the removal of a range of acyl-lysine modifications on target proteins. Loss of Sirt5 leads to hyper-malonylation and hyper-succinylation of both mitochondrial and extra-mitochondrial proteins, influencing oxidative phosphorylation, the TCA cycle and glycolysis. However despite these findings, the effect of Sirt5 overexpression on metabolism remains poorly investigated. Here we report that overexpression of Sirt5 has minimal effect on mitochondrial metabolism and overall physiology in mice, despite inducing widespread decreases in protein acylation. Our data confirms the role of Sirt5 as an important demalonylase and desuccinylase enzyme in vivo, but questions the relevance of physiological changes in protein acylation levels in the regulation of cellular metabolism. PMID- 30017195 TI - Salusin-beta mediate neuroprotective effects for Parkinson's disease. AB - Neuropeptides, small peptides found in many mammalian brain, play key roles in communicating with each other to modulate neuronal activity. Here, we reported that endogenous neuropeptide salusin-beta has neuroprotective effects on the midbrain dopamine neurons and can be used as an effective therapeutic treatment for Parkinson's disease (PD). We found that the MrgprA1 receptor mediates the neuroprotective effects of salusin-beta on the midbrain dopamine neurons. Importantly, intranasal administration of salusin-beta in a PD mouse model show the neuroprotection of dopaminergic neurons and increased the survival of midbrain dopamine neurons. Furthermore, inhibition of the salusin-beta receptor, MrgprA1, abolished the neuroprotective effects induced by salusin-beta. Taken together, these results demonstrate the novel role of salusin-beta in the central nervous system and salusin-beta can be used as a novel therapeutic to effectively treat PD. PMID- 30017196 TI - Lung tissue destruction by proteinase 3 and cathepsin G mediated elastin degradation is elevated in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by high levels of protease activity leading to degradation of elastin followed by loss of elasticity of the lung and the development of emphysema. Elastin is an essential structural component of the lung parenchyma to support the expansion and recoil of the alveoli during breathing. The lung extracellular matrix is vulnerable to pathological structural changes upon upregulation of serine proteases, including cathepsin G (CG) and proteinase 3 (PR3). In this study, we explored the diagnostic features of elastin neo-epitopes generated by CG and PR3. Two novel competitive enzyme-linked immunosorbent assays (ELISA) measuring CG and PR3 generated elastin fragments (EL-CG and ELP-3 respectively) were developed for assessment in serum. Both assays were technically robust and biologically validated in serum from patients with COPD. Serological levels of both elastin fragments were significantly elevated in patients with COPD compared to healthy controls. These data suggest that EL-CG and ELP-3 may serve as plausible biologic markers of destructive changes in COPD. PMID- 30017197 TI - Metagenomic analysis revealed the effects of goat milk feeding and breast feeding on the gut microbiome of Amur tiger cubs. AB - BACKGROUND: Ingredients in breast milk can help establish a healthy community of microorganisms in the infant gut, but no research exists regarding the effects of goat milk feeding and breast feeding on the gut microbiome of the Amur tiger, which is one of the most endangered species in the world. METHODS: In this study, we used whole-metagenome shotgun sequencing to analyze the effects of two different feeding patterns, goat milk feeding and breast feeding, on the composition and functional structures of gut microbiota in Amur tiger cubs. RESULTS: Goat milk-fed cubs have fewer beneficial bacteria and more pathogenic bacteria and a higher microbial diversity in their gut than breastfed cubs. A total of 15 genera showed statistically significant differences; the relative abundances of Streptomyces scabiei, Streptomyces avermitilis and Streptomyces davawensis were significantly decreased, whereas those of Niabella soli, Aeromonas media and Brochothrix thermosphacta were significantly increased in the goat milk-fed group compared with those in the breastfed group. At the functional level, carbohydrate metabolism, translation and replication and repair decreased, and amino acid metabolism, membrane transport and metabolism of cofactors and vitamins increased in the gut microbiota of goat milk-fed cubs compared with breastfed cubs. CONCLUSION: Our results indicate for the first time that the different milk feeding patterns of goat milk feeding and breast feeding can change the composition and functional structures of gut microbiota in Amur tiger cubs and that breastfed tiger cubs and goat milk-fed tiger cubs have distinct microbiotas in their guts. PMID- 30017198 TI - Proteomic profile changes associated with diminished expression of T-cell intracellular antigens reveal a hormesis response. AB - T-cell intracellular antigen (TIA) proteins function as regulators of cell homeostasis by controlling global gene expression in response to dynamic regulatory changes and environmental stress. Here, we used two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry (MALDI TOF/TOF) to identify protein changes associated with the down-regulated expression of TIA proteins. We detected 30 differentially expressed proteins (DEPs), 24 of which were identified, and some of these DEPs were validated by western blotting. In silico analysis showed that DEPs were associated with metabolic processes, detoxification and proteostasis. We mapped the DEPs to the available biological pathways and networks, which included the metabolism of small molecules such as sugars, lipids, amino acids, and nucleotides. Our findings support previous studies and suggest that low expression of TIA proteins might act as a potential adaptive switch to link gene expression reprogramming to a proliferative phenotype mediated by a hormesis phenomenon. PMID- 30017199 TI - ABT-199-mediated inhibition of Bcl-2 as a potential therapeutic strategy for nasopharyngeal carcinoma. AB - BACKGROUND: Aberrant overexpression of Bcl-2 protein has been detected in 80% of nasopharyngeal carcinoma (NPC), and Bcl-2 family proteins are implicated in both NPC oncogenesis and chemotherapy resistance. Previous studies have shown that while treatment of NPC cells with Bcl-2 family inhibitors alone is rarely effective, concomitant treatment with a cytotoxic reagent such as cisplatin can increase efficacy through a synergistic effect. The aim of the current work was to determine how we might increase the efficacy of Bcl-2 family inhibitors in the absence of cytotoxic reagents, which are associated with negative side effect profiles. METHODS: We assessed cell proliferation in Bcl-2 high-expressing NPC cells by CCK-8 assay after treatment with the Bcl-2 inhibitor ABT-199 and/or the Mcl-1 inhibitor S63845. Apoptotic induction by ABT-199 was evaluated by Annexin V FITC and PI double staining. We also evaluated Bcl-2 family protein expression (Bim, Mcl-1, Bcl-xL, Noxa) after treatment with ABT-199 by western blotting. Finally, xenografted Balb/c nude mice were used to test ABT-199 efficacy in vivo, H&E and immunohistochemistry assay were used to analyze tumor samples. RESULTS: ABT-199 effectively induced NPC cell apoptosis in vitro and in the xenograft model. Following ABT-199 treatment in NPC cells, upregulation of Mcl-1 and Bcl-xL can lead to drug resistance, while concomitant Noxa overexpression partially neutralized the Mcl-1-caused resistance. Given that ABT-199 induces apoptosis in NPC cells through the Bcl-2/Noxa/Mcl-1 axis, treatment avenues further targeting this pathway should be promising. Indeed, the newly developed Mcl-1 inhibitor S63845 in combination with ABT-199 had a synergistic effect on NPC cell apoptosis. CONCLUSION: Bcl-2 inhibition in NPC cells with ABT-199 triggers apoptosis through the Bcl-2/Noxa/Mcl-1 axis, and dual inhibition of the anti apoptotic Bcl-2 family proteins Bcl-2 and Mcl-1 provided a strong synergistic effect without the need for adjunctive cytotoxic agent treatment with cisplatin. PMID- 30017200 TI - Prototype foamy virus integrase is promiscuous for target choice. AB - Retroviruses have two essential activities: reverse transcription and integration. The viral protein integrase (IN) covalently joins the viral cDNA genome to the host DNA. Prototype foamy virus (PFV) IN has become a model of retroviral intasome structure. However, this retroviral IN has not been well characterized biochemically. Here we compare PFV IN to previously reported HIV-1 IN activities and discover significant differences. PFV IN is able to utilize the divalent cation calcium during strand transfer while HIV-1 IN is not. HIV-1 IN was shown to completely commit to a target DNA within 1 min, while PFV IN is not fully committed after 60 min. These results suggest that PFV IN is more promiscuous compared to HIV-1 IN in terms of divalent cation and target commitment. PMID- 30017201 TI - Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. AB - Genetic amplification, overexpression, and increased signaling from the epidermal growth factor receptor (EGFR) are often found in oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed effects of cetuximab in control of EGF-driven malignant traits of OSCC cells. EGF stimulation promoted progression level of mesenchymal traits in OSCC cells, which were attenuated by cetuximab but incompletely. We pursued a potential mechanism underlying such incomplete attenuation of OSCC malignant traits. Cetuximab promoted secretion of EGFR-EVs by OSCC cells and failed to inhibit EGF-driven secretion of EGFR-EVs. Cetuximab was also found to be robustly secreted with the EGFR-EVs by the OSCC cells. Thus, EGF promotes the level of mesenchymal traits of OSCC cells and secretion of EGFR-EVs, which involve cetuximab resistance. PMID- 30017202 TI - Ecological feedback mechanisms and variable disturbance regimes: the uncertain future of Mediterranean macroalgal forests. AB - Loss of algal canopies can result in a shift towards a turf-dominated state, where variability in species life-history traits can determine new mechanisms of feedback, and influence the degraded system under variable regimes of disturbance. By focusing on rockpools dominated by Cystoseira brachycarpa, we tested the hypothesis that the alga Dictyopteris polypodioides could take advantage of extreme regimes of disturbance related to storms, and outcompete other turfs through a distinctive combination of life traits. Replacement of the canopy was initially driven by a mix of taxon-specific life-traits and resulting assemblages were susceptible to intense events of disturbance. Subsequently, D. polypodioides dominated removal quadrats, favored by density-dependent abilities to intercept more light and reach larger size than the rest of turf. These new positive feedbacks may contribute to maintain the modified state of the system and influence its ability to withstand extreme abiotic conditions. PMID- 30017203 TI - Noninvasive predictors of cardiac arrhythmias in bodybuilders. AB - INTRODUCTION AND OBJECTIVE: Arrhythmias are often recorded in strength training athletes without cardiovascular abnormalities but may also be a sign of an underlying cardiovascular disease which carries a risk of sudden cardiac death (SCD). Nowadays, bodybuilding is a popular sport among adolescents and young adults. There have been few studies of arrhythmias comparing bodybuilders with healthy controls and excluding anabolic steroid use. We aimed to assess the structural, functional and electrical characteristics of bodybuilders' hearts compared with control subjects. METHODS: In this study, we assessed 35 male competitive bodybuilders and 35 healthy control subjects matched for age, gender, and body mass index. A detailed cardiovascular and systemic examination was performed at the beginning of the study to collect demographic data and anthropometric measures. Biochemical and hematologic, echocardiographic, 24-h Holter, and ECG measurements were obtained from all participants. RESULTS: Ventricular arrhythmias were encountered significantly more frequently in bodybuilders than in the control group. QT and QTc were not significantly different between groups. Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were significantly greater in bodybuilders than in the control group (p<0.001 for all). There was a positive correlation between Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio and right ventricular (RV) diameter and arrhythmias. CONCLUSION: Prolonged repolarization is common in athletes, although its predictive value is unclear. In this study, alterations in ventricular repolarization were positively correlated with RV dimensions. Therefore, we postulate that arrhythmias in strength athletes may be predicted by assessing the right ventricle echocardiographically and dispersions of repolarization on the ECG, and that SCD could be avoided in strength athletes by careful application of this information. PMID- 30017204 TI - Trends in Albuminuria and GFR Among Adolescents in the United States, 1988-2014. AB - RATIONALE & OBJECTIVE: Albuminuria and low estimated glomerular filtration rate (eGFR) define chronic kidney disease in adults and youth. Different from adults, the burden of abnormal kidney markers among youth in the general United States population is largely unknown. STUDY DESIGN: Serial cross-sectional national surveys. SETTING & PARTICIPANTS: Adolescents aged 12 to 18 years participating in the National Health and Nutrition Examination Surveys 1988 to 2014. Surveys were grouped into three 6-year periods. PREDICTORS: Demographic and clinical determinants of kidney markers. OUTCOME: Prevalence and trends in persistent albuminuria, low (< 60mL/min/1.73m2) and reduced (< 90mL/min/1.73m2) eGFRs. ANALYTICAL APPROACH: Outcomes defined as persistent albumin-creatinine ratio >= 30mg/g (persistent albuminuria), eGFR < 90mL/min/1.73m2 (reduced kidney function), and eGFR < 60mL/min/1.73m2 (low kidney function). Multiple imputation analysis was used to estimate missing follow-up values of albuminuria. RESULTS: Prevalences of persistent albuminuria were 3.64% (95% CI, 1.82%-5.46%) in 1988 1994 and 3.29% (95% CI, 1.94%-4.63%) in 2009-2014 (adjusted prevalence ratio, 0.93; 95% CI, 0.53-1.62; P=0.8 for trend). Prevalences of reduced eGFR were 31.46% (95% CI, 28.42%-34.67%) and 34.58% (95% CI, 32.07%-37.18%), respectively (adjusted prevalence ratio, 1.21; 95% CI, 1.00-1.46; P < 0.001 for trend). Prevalences of low eGFR were 0.32% (95% CI, 0.12%-0.84%) in 1988-1994 and 0.91% (95% CI, 0.58%-1.42%) in 2009-2014 (adjusted prevalence ratio, 3.10; 95% CI, 1.10 9.01; P = 0.09 for trend). Prevalences of albuminuria and/or low eGFR remained at 4.0% in 1988-1994 and 2009-2014 (adjusted prevalence ratio, 1.06; 95% CI, 0.64 1.77; P = 0.8 for trend). LIMITATIONS: Persistent albuminuria data were based on imputed values (for second assessment of albuminuria) in 91% of participants; lack of second eGFR assessment to confirm sustained reduction in kidney function. CONCLUSIONS: Albuminuria prevalence has not changed significantly in the US adolescent population between 1988 and 2014. Prevalences of both reduced and low eGFRs were higher in the most recent study period; however, < 1% of adolescents had low eGFRs. PMID- 30017205 TI - Sepsis early warning scoring systems: The ideal tool remains elusive! PMID- 30017207 TI - Austerity, bad-governance, innovation and the future of the Spanish National Health Service. PMID- 30017206 TI - Patterns of Failure Following Dose-escalated Chemoradiotherapy for Fluorodeoxyglucose Positron Emission Tomography Staged Squamous Cell Carcinoma of the Oesophagus. AB - AIMS: To analyse outcomes and patterns of failure following dose-escalated definitive chemoradiotherapy (CRT) for oesophageal squamous cell carcinoma using fluorodeoxyglucose positron emission tomography for staging and treatment planning. MATERIALS AND METHODS: A retrospective review of patients with oesophageal squamous cell carcinoma receiving definitive CRT to a dose of >=56 Gy was conducted. Patient and tumour characteristics, treatment received and first sites of relapse were analysed. RESULTS: Between 2003 and 2014, 72 patients were treated with CRT to a median dose of 60 Gy (range 56-66 Gy). The median age was 63 years; most (61%) were stage III/IVa. The median follow-up was 57 months. Three year in-field control, relapse-free survival and overall survival was 64% (95% confidence interval 50-75%), 38% (95% confidence interval 27-50%) and 42% (95% confidence interval 30-53%), respectively. Of the 41 failures prior to death or at last follow-up date, isolated locoregional relapse occurred in 16 patients (22%) with isolated in-field recurrence in 11 patients (15%). Distant failure as first site of relapse was present in 25 patients (35%). No in-field failures occurred in the 11 patients with cT1-2, N0-1 tumours. The median survival for cT4 tumours was 8 months, with five of eight patients developing local progression within the first 6 months. CONCLUSIONS: Dose-escalated radiotherapy was associated with promising rates of in-field local control, with the exception of cT4 tumours. Distant failure remains a significant competing risk. Our data supports the need for current trials re-examining the role of dose escalation in the modern era. PMID- 30017208 TI - Euglycemic diabetic ketoacidosis. PMID- 30017209 TI - Quality of life and chronic health conditions in childhood acute leukaemia survivors. AB - BACKGROUND: Survival of childhood acute lymphoblastic leukaemia involves an increasing risk of long-term morbidities. Due to the impact of cancer treatment and comorbidities, AL survivors may experience a decrease in their health-related quality of life. OBJECTIVE: We aimed to describe the long-term comorbidities, related quality of life and their development predictors in these survivors. METHODS: cross-sectional study of 54 survivors aged >=18 and who have a survival rate of more than 10 years. Quality of life was assessed by personal interview using SF-36 questionnaire. RESULTS: 53.7% of AL survivors developed more than one comorbidity (24.7% hypothyroidism; 20.3% obesity; 14.8% metabolic syndrome; 18.5% subclinical cardiac dysfunction); 20.3% of them were severe. 73.3% of high-risk leukaemias and 66.6% of patients treated with radiotherapy or stem cells transplantation reported long-term comorbidity, P<.05. Global quality of live score was: 86.3 (14) (classified as very good). Patients with high-risk acute leukaemia (83.2 vs. 89.5), severe long-term comorbidities (80.4 vs. 89.7) and females (81.8 vs. 89.9), reported worse quality of life, P<.05. Physical summary score was worse in: obese (80 vs. 92) and hypothyroid (84.9 vs. 92.4) and radiotherapy-treated survivors (82.3 vs. 87.5); mental summary was worse in survivors with hypogonadism (68.2 vs. 86.3) and trasplanted patients (77.2 vs. 83.1), P<.05. CONCLUSIONS: Acute leukaemia survivors reported an increase prevalence of chronic comorbidities, related to cancer-treatment. Despite a decrease in scores for certain physical or mental items, global quality of life was very good in all acute leukaemia survivors, even better than compared with the general population. PMID- 30017210 TI - Corrigendum to: "Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment" [Exp. Cell. Res. 2014 15 323(1) 155-64]. PMID- 30017211 TI - Severe upper gastrointestinal bleeding due to eosinophilic gastritis. PMID- 30017212 TI - Autoimmune hepatitis - primary biliary cholangitis overlap syndrome. Long-term outcomes of a retrospective cohort in a university hospital. AB - BACKGROUND: Autoimmune hepatitis (AIH) with characteristics of primary biliary cholangitis (PBC) is known as overlap syndrome. Its prevalence and prognosis have not yet been determined comparatively with AIH. METHODS: A retrospective cohort study was conducted comparing patients diagnosed with AIH and AIH-PBC overlap syndrome, followed-up for seven years in a university hospital in Colombia, until 31 December 2016. RESULTS: A total of 210 patients were included (195 women, mean age 48.5years). Of these, 32 (15.2%) had AIH-PBC overlap syndrome. At diagnosis, no significant differences were found by demographic profile, positive autoantibodies (ANA, ASMA), except AMA (81.2% vs 3.9%, P<.001), and histological grade of fibrosis. The most frequent clinical presentations were nonspecific symptoms in AIH-PBC and acute hepatitis in AIH. Although there were no significant differences, AIH showed a greater biochemical response to immunosuppressive management (87.3% vs 74.2%, P=.061) and a greater number of relapses in those who achieved partial or complete remission during treatment (12.4% vs 7.63%; P=.727). Patients with AIH-PBC had greater progression to cirrhosis (22.2% vs 13.1%, P=.038), even in those who achieved partial or complete biochemical remission without relapse, with greater indication of orthotopic liver transplantation (P=.009), but not retransplantation (P=.183); there were no differences in mortality. CONCLUSIONS: AIH-PBC overlap syndrome accounts for a significant proportion of patients with AIH, with greater progression to cirrhosis, indication of liver transplantation and possibly retransplantation. This higher risk of adverse outcomes suggests closer monitoring, probably with follow-up until confirmed histopathological remission. PMID- 30017213 TI - Retrospective definition of reaction risk in Italian children with peanut, hazelnut and walnut allergy through component-resolved diagnosis. AB - BACKGROUND: Serum IgE evaluation of peanut, hazelnut and walnut allergens through the use of component-resolved diagnosis (CRD) can be more accurate than IgE against whole food to associate with severe or mild reactions. OBJECTIVES: The aim of the study was to retrospectively define the level of reaction risk in children with peanut, hazelnut and walnut sensitization through the use of CRD. METHODS: 34 patients [n=22 males, 65%; median age eight years, interquartile range (IQR) 5.0-11.0 years] with a reported history of reactions to peanut and/or hazelnut and/or walnut had their serum analyzed for specific IgE (s-IgE) by ImmunoCAP(r) and ISAC(r) microarray technique. RESULTS: In children with previous reactions to peanut, the positivity of Arah1 and Arah2 s-IgE was associated with a history of anaphylaxis to such food, while the positivity of Arah8 s-IgE were associated with mild reactions. Regarding hazelnut, the presence of positive Cora9 and, particularly, Cora14 s-IgE was associated with a history of anaphylaxis, while positive Cora1.0401 s-IgE were associated with mild reactions. Concerning walnut, the presence of positive Jug r 1, Jug r 2, Jug r 3 s-IgE was associated with a history of anaphylaxis to such food. ImmmunoCAP(r) proved to be more useful in retrospectively defining the risk of hazelnut anaphylaxis, because of the possibility of measuring Cor a14 s-IgE. CONCLUSIONS: Our data show that the use of CRD in patients with allergy to peanut, hazelnut and walnut could allow for greater accuracy in retrospectively defining the risk of anaphylactic reaction to such foods. PMID- 30017214 TI - How molecular diagnosis may modify immunotherapy prescription in multi-sensitized pollen-allergic children. AB - INTRODUCTION: Specific immunotherapy (SIT) is used to treat asthma and allergic rhinitis, and a dose-response relationship has been found for SIT efficacy, creating a need to accurately select the allergen used in therapy. This need is especially pronounced in poly-sensitized children living in areas where different pollen allergen sources coexist in the same season, as this circumstance complicates diagnostic efforts. In such cases, component-resolved diagnosis (CRD) can increase diagnostic accuracy and aid in SIT prescription. MATERIALS AND METHODS: We hypothesized that CRD results would lead to modifications in classical immunotherapy prescription based on sources such as medical history, season of symptom presentation, and skin testing. We studied a sample of children indicated for immunotherapy in whom classical methods had not pointed out the most relevant allergen due to sensitization to more than two pollens. We used a small panel of recombinant allergens, analyzing the percentage of changes to prescription considering the findings of molecular studies. RESULTS: Of the 70 children included, CRD led to modified immunotherapy prescription in 54.3%. Indications of single-allergen therapy increased from 18% to 51% when CRD was included. The decision to prescribe immunotherapy was reversed following CRD in 9.3% of cases. DISCUSSION: CRD use alters the choice of specific immunotherapy in poly-sensitized children. A wide panel of recombinant allergens may not be necessary to improve immunotherapy indication using molecular techniques; rather, a smaller panel adapted to include those allergens prevalent in the geographical area in question appears to be sufficient for more effective immunotherapy, also leading to an improved cost-benefit ratio. PMID- 30017215 TI - The relationship between nurses assessment of early pressure ulcer damage and sub epidermal moisture measurement: A prospective explorative study. AB - AIM: To explore the relationship between nurses' visual assessment of early pressure ulceration and assessment using sub epidermal moisture measurement (a measure of skin and tissue water). MATERIALS AND METHODS: A descriptive prospective observational study design was employed. Following ethical approval and written informed consent, data were collected daily, for four weeks, from at risk patients within an acute care facility in Ireland. Data included nurses documented assessment of the patient's skin condition and researcher led sub epidermal moisture measurement, over the sacrum and both heels. RESULTS: A total of 47 patients were included, 38.3% (n = 18) were male and 61.5% (n = 29) were female, with a mean age of 74.7 years. Nineteen patients (40%) developed 21 Stage 1 pressure ulcers and all of these had sustained elevated sub epidermal moisture (SEM) levels before visual signs of damage became evident indicating 100% sensitivity of SEM readings in predicting pressure ulceration. Specificity was 83% with the majority of false positives having insufficient follow-up time. Furthermore a medium correlation between nurses' visual skin assessment (the current gold standard in pressure ulcer detection) and SEM findings (r = .47; p = 0.001) was identified. The mean number of days for nurses to detect this damage was 5.5 (+/-2,5; max 11, min 2), whereas the mean number of days that it took SEM measurement to detect damage was 1.5 (+/-1.4; max 7, min 1). SEM measurement identified early damage, on average, 4 days sooner than nurses' assessment. CONCLUSION: Given that pressure ulcers develop from within the deeper tissues, knowing that early pressure ulcer damage is present can facilitate heightening of prevention strategies to avoid extension. This is of importance in clinical practice as the earlier that pressure ulcers can be detected; the earlier interventions can be implemented to prevent further extension, avoiding their associated morbidity and mortality. PMID- 30017216 TI - The Impact of Diabetes on Patient Outcomes After Total Knee Arthroplasty in an Asian Population. AB - BACKGROUND: Diabetes is implicated with poorer outcomes and more complications after total knee arthroplasty (TKA). We aim to determine whether diabetes affects infection risk, functional outcomes, patient-reported outcome measures, and patient satisfaction in Asian patients after TKA. METHODS: Prospectively collected data for 905 patients who underwent unilateral TKA by a single surgeon from February 2004 to July 2014 were reviewed, of which 123 (13.6%) patients suffered from diabetes. At 2-year follow-up, the change in range of motion of the operated knee, body mass index, Knee Society Score, Oxford Knee Score (OKS), and Short Form-36 from baseline was compared between diabetic and nondiabetic patients. We also analyzed the length of hospitalization stay, infection risk, and patient satisfaction between the 2 groups. RESULTS: Compared with nondiabetic patients, diabetic patients had significantly poorer preoperative OKS (37.6 on 8.3 to 35.8 .38.0, P = .02) and Short Form-36 Mental Component Score (48.3 Me11.2 to 51.7 1.10.7, P = .01). At 2-year follow-up, diabetes continued to be associated with poorer OKS of 21.2 018.4 and Knee Society Score Function score of 64.7 Fu20.9 compared to 19.1 0.6.2 (P = .02) and 71.8 0220.1 (P = .01) respectively in nondiabetic patients. Interestingly, the difference in mental well-being was no longer significant after TKA. A significantly larger proportion of diabetic patients (50%) had a reduction in body mass index after TKA compared to 36% in nondiabetic patients (P < .01). There was no difference in range of motion, length of hospitalization stay, infection risk, and patient satisfaction. CONCLUSION: Despite poorer physical scores throughout, diabetic patients are no less satisfied and had significantly greater improvement in mental well-being and weight reduction after surgery. PMID- 30017217 TI - Feedback From Activity Trackers Improves Daily Step Count After Knee and Hip Arthroplasty: A Randomized Controlled Trial. AB - BACKGROUND: Commercial wrist-worn activity monitors have the potential to accurately assess activity levels and are being increasingly adopted in the general population. The aim of this study was to determine if feedback from a commercial activity monitor improves activity levels over the first 6 weeks after total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: One hundred sixty-three consecutive subjects undergoing primary TKA or THA were randomized into 2 groups. Subjects received an activity tracker with the step display obscured 2 weeks before surgery and completed patient-reported outcome measures (PROMs). On day 1 after surgery, participants were randomized to either the "feedback (FB) group" or the "no feedback (NFB) group." The FB group was able to view their daily step count and was given a daily step goal. Participants in the NFB group wore the device with the display obscured for 2 weeks after surgery, after which time they were also able to see their daily step count but did not receive a formal step goal. The mean daily steps at 1, 2, 6 weeks, and 6 months were monitored. At 6 months after surgery, subjects repeated PROMs and daily step count collection. RESULTS: Of the 163 subjects, 95 underwent THA and 68 underwent TKA. FB subjects had a significantly higher (P < .03) mean daily step count by 43% in week 1, 33% in week 2, 21% in week 6, and 17% at 6 months, compared with NFB. The FB subjects were 1.7 times more likely to achieve a mean 7000 steps per day than the NFB subjects at 6 weeks after surgery (P = .02). There was no significant difference between the groups in PROMs at 6 months. Ninety percent of FB and 83% of NFB participants reported that they were satisfied with the results of the surgery (P = .08). At 6 months after surgery, 70% of subjects had a greater mean daily step count compared with their preoperative level. CONCLUSION: Subjects who received feedback from a commercial activity tracker with a daily step goal had significantly higher activity levels after hip and knee arthroplasty over 6 weeks and 6 months, compared with subjects who did not receive feedback in a randomized controlled trial. Commercial activity trackers may be a useful and effective adjunct after arthroplasty. PMID- 30017218 TI - Synovial Fluid Alpha-Defensin Is an Adjunctive Tool in the Equivocal Diagnosis of Periprosthetic Joint Infection. AB - BACKGROUND: Synovial fluid alpha-defensin has shown to be a reliable diagnostic test for the diagnosis of periprosthetic joint infection (PJI), but its use in equivocal cases has yet to be established. The purpose of this study was to determine the reliability of alpha-defensin testing in patients, where the diagnosis of PJI was unclear. METHODS: A consecutive series of 41 synovial aspirations by a single surgeon that were sent for alpha-defensin testing in equivocal cases of PJI were retrospectively reviewed. Indications for alpha defensin testing included recent antibiotic use, borderline synovial fluid cell count, and differential, suspected culture-negative infection, and suspected false-positive culture. PJI was diagnosed using the Musculoskeletal Infection Society (MSIS) criteria. RESULTS: Of the 39 aspirations in 32 patients included in the study, there were 33 (85%) knee and 6 (15%) hip samples. Eleven (28%) samples met MSIS criteria for PJI. Of the 23 samples that had recent antibiotic use (6 MSIS positive, 17 negative), alpha-defensin results confirmed the correct MSIS diagnosis in 19 (83%) samples. Of the 11 samples in which alpha-defensin testing was performed for a borderline cell count (3 MSIS positive, 8 negative), alpha-defensin confirmed the MSIS diagnosis in 10 of 11 (91%) samples. Finally, among the 5 samples with suspected false-positive or false-negative cultures (2 MSIS positive, 3 negative), alpha-defensin confirmed the correct diagnosis in 3 (60%) samples. The overall sensitivity, specificity, negative predictive value, and positive predictive value of synovial alpha-defensin were 82%, 82%, 92%, and 64%, respectively. CONCLUSION: In patients for whom the diagnosis of PJI is unclear because of recent antibiotic use, equivocal laboratory findings, or suspected false-negative or false-positive cultures, synovial fluid alpha defensin can provide an additional data point to assist the clinician in determining whether PJI is present but is prone to false-positive results in this challenging population. PMID- 30017219 TI - Evaluation of Native Femoral Neck Version and Final Stem Version Variability in Patients With Osteoarthritis Undergoing Robotically Implanted Total Hip Arthroplasty. AB - BACKGROUND: Combined anteversion in total hip arthroplasty influences both dislocation risk and range of motion. One of its components, stem version (SV), could be dictated by many factors, from native femoral anatomy to stem geometry and surgeon's choice. In the present multicenter study, robotic technology was used to assess the influence of native femoral version on final SV and combined anteversion using a straight, uncemented stem. METHODS: Three hundred sixty-two patients undergoing total hip arthroplasty were enrolled from 3 different orthopedic centers from 2012 and 2016. All patients underwent computed tomography planning with measurement of femoral neck version (FNV) and intraoperative measurement of stem version (SV), acetabular component version (AV), and combined version (CV) with robotic instrumentation. RESULTS: Mean FNV was 5.0 degrees +/- 9.6 degrees , and SV was 6.4 degrees +/- 9.7 degrees . The average difference between FNV and SV was 1.6 degrees +/- 9.8 degrees . A moderate correlation was found between FNV and SV (R = 0.48, P < .001). SV was between 5 degrees and 20 degrees in 174 patients (48%). Mean CV was 28.2 degrees +/- 7.9 degrees . A strong correlation was found between SV and CV (R = 0.89, P < .001). A significant difference in SV was found between the 3 centers (P < .001). CV was <25 degrees in 109 patients (30.1%). Relative risk of CV < 25 degrees was 8.6 times greater with SV < 5 degrees (P < .001). CONCLUSION: With the use of an uncemented, single-wedge, straight stem, SV is highly variable. Despite being moderately correlated with native FNV, SV can be partially influenced by the surgeon. A low SV could be hardly corrected, bringing high risk of low CV. PMID- 30017220 TI - Differences in Reported Outcomes in Industry-Funded vs Nonfunded Studies Assessing Thromboprophylaxis After Total Joint Arthroplasty. AB - BACKGROUND: There are numerous studies discussing thromboprophylaxis after total joint arthroplasty (TJA), with varying conclusions. Patient inclusion criteria may be different for each study, which may lead to selection bias and misrepresentation of data. This study aimed to investigate if industry funding impacted patient demographics and overall reported outcomes of studies analyzing venous thromboembolism (VTE) prevention after TJA. METHODS: Electronic searches were completed using Ovid, PubMed, and Embase databases. Studies were included if (1) they are published in the English language between 2000 and 2016; (2) they included patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA); and (3) they evaluated prevention and control of postoperative VTE with at least one of the following thromboprophylactic agents: aspirin, enoxaparin, dalteparin, dabigatran, apixaban, rivaroxaban, dabigatran, ximelagatran, fondaparinux, or coumadin. Data were extracted and analyzed via mixed-effect logistic regression. RESULTS: Fifty-seven studies were included; 29 were industry funded, and 28, nonfunded. There were no significant differences between patient's age, body mass index, or revision exclusions between funded and nonfunded studies. Funded studies reported less pulmonary embolisms, fewer events of major bleeding, and significantly less 90-day mortality compared with nonfunded studies. CONCLUSION: Industry-funded studies reported less pulmonary embolisms, major bleeding, and mortality compared with nonfunded studies. Detailed demographic data were missing from the literature, and we were unable to demonstrate the cause of different reported outcomes between industry-funded and nonfunded studies. Further investigations should be aimed toward understanding how funded studies report less adverse outcomes in analyzing VTE after TJA. PMID- 30017221 TI - Direct injection analysis of polar micropollutants in natural drinking water sources with biphenyl liquid chromatography coupled to high-resolution time-of flight mass spectrometry. AB - A method for the trace analysis of polar micropollutants (MPs) by direct injection of surface water and groundwater was validated with ultrahigh performance liquid chromatography using a core-shell biphenyl stationary phase coupled to time-of-flight high-resolution mass spectrometry. The validation was successfully conducted with 33 polar MPs representative for several classes of emerging contaminants. Identification and quantification were achieved by semi automated processing of full-scan and data-independent acquisition MS/MS spectra. In most cases good linearity (R2 >= 0.99), recovery (75% to 125%) and intra-day (RSD < 20%) and inter-day precision (RSD < 10%) values were observed. Detection limits of 9 to 83 ng/L and 9 to 93 ng/L could be achieved in riverbank filtrate and surface water, respectively. A solid-phase extraction was additionally validated to screen samples from full-scale reverse osmosis drinking water treatment at sub-ng/L levels and overall satisfactory analytical performance parameters were observed for RBF and reverse osmosis permeate. Applicability of the direct injection method is shown for surface water and riverbank filtrate samples from an actual drinking water source. Several targets linkable to incomplete removal in wastewater treatment and farming activities were detected and quantified in concentrations between 28 ng/L for saccharine in riverbank filtrate and up to 1 MUg/L for acesulfame in surface water. The solid phase extraction method applied to samples from full-scale reverse osmosis drinking water treatment plant led to quantification of 8 targets between 6 and 57 ng/L in the feed water, whereas only diglyme was detected and quantified in reverse osmosis permeate. Our study shows that combining the chromatographic resolution of biphenyl stationary phase with the performance of time-of-flight high resolution tandem mass spectrometry resulted in a fast, accurate and robust method to monitor polar MPs in source waters by direct injection with high efficiency. PMID- 30017222 TI - Development and validation of a method for direct, underivatized analysis of free amino acids in rice using liquid chromatography-tandem mass spectrometry. AB - Inspired by the apparent relationship of free amino acids (FAAs) which are present in minute quantities with the organoleptic characteristics of food, there is an increased demand for analytical methods sensitive in trace level detection. This study presents the validation results of a simple and rapid method developed for direct, underivatized analysis of FAAs in rice using liquid chromatography tandem mass spectrometry (LC-MS/MS) with electrospray ionization (ESI). The method demonstrated satisfactory selectivity for twenty FAAs with minimum matrix effect. The recoveries obtained for samples fortified at three concentration levels: low mid and high, covering the working range of the method were in the range 80%-110%. The precision measured in terms of repeatability and reproducibility of the method expressed as percentage relative standard deviation (% RSD) were below 10% for the amino acids analyzed. The detection limits (LODs) and quantification limits (LOQs) of the method were in the range 0.4-1.0 mg/kg and 0.6-1.2 mg/kg respectively. Method had a wide linear range between 1.25-100 mg/kg with regression coefficients greater than 0.999 obtained over seven calibration levels. The method was also found robust over other cereals including corn, wheat and finger millet with satisfactory recoveries and precision values. The percentage expanded uncertainties calculated with the coverage factor of 2 (k = 2), were below 14% for the analyzed amino acids. The developed, simple and rapid LC-MS/MS method is accurate and reproducible, allowing determination of underivatized FAAs in rice and comply with the international method validation guideline requirements. PMID- 30017223 TI - Qualitative and quantitative comparison of cyclic phosphatidic acid and its related lipid species in rat serum using hydrophilic interaction liquid chromatography with tandem-mass spectrometry. AB - Cyclic phosphatidic acid (cPA) is a simple lipid containing a fatty acid attached at the sn-1 position and a cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. The pharmacological effects of cPA have been demonstrated in several diseases such as cancer and neuropathic pain; however, the composition of the molecular species of cPA in relative to other lipid species in biological samples is still unclear. Recently, hydrophilic interaction liquid chromatography (HILIC) has demonstrated the ability to perform lipidomic analyses of biological samples. In the present study, we developed the quantitative measurement of cPA and its related lipid species, such as lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC), in rat serum using HILIC equipped with tandem-mass spectrometry (MS/MS). The lipid analysis using HILIC-MS/MS system demonstrated high linearity and reproducibility. The modified Bligh and Dyer method using citric acid was showed high efficiency on the extraction of cPA and LPA without contamination of artificial products. In rat serum, cPA and LPC contained more saturated fatty acids such as palmitic acid and stearic acid than unsaturated fatty acids, whereas LPA and phosphatidylcholine more contained unsaturated fatty acids than saturated fatty acids. The analytical methods for measuring cPA and its related lipid species in the present study will aid the analysis of their metabolism. PMID- 30017224 TI - Slow progress. How do we shift the paradigm of thinking in pediatric thrombosis and anticoagulation? AB - Since Maureen Andrew began systematically describing thrombosis in children in 1994, there has been surprisingly slow process in advancing our knowledge in terms of diagnosis, prevention and treatment of thrombosis in children. There are a variety of reasons for this slow progress. Overwhelmingly the low incidence of thrombosis in children has been a major barrier. Second, the developmental, age related, changes in haemostasis mean that the physiology of haemostasis in children, and the interaction of the haemostatic system with anticoagulant drugs is constantly changing. This presents further challenges in identifying the risk benefit ratio of therapies. In addition, the failure to adequately understand the subtleties of pathogenesis of the variety of thrombotic syndromes, and the failure to know the natural history of many types of thrombosis are also significant problems. We continue to try and solve these problems by extrapolation, not just of adult based data, but of methodologies for research founded in the adult paradigm. If we are truly going to improve our understanding of thrombosis in children and improve our ability to prevent and adequately treat thrombosis in this population, then we need multiple paradigm shifts; First, in the way we think about thrombosis and anticoagulation in children. Second in the way we design and conduct research studies to provide evidence on which to base the care of children suffering from thrombosis in the future. PMID- 30017225 TI - Direct oral anticoagulants: What will be their role in children? AB - Thrombotic events in children differ from those in adults in epidemiology, pathophysiology, and anatomical location. However, anticoagulation in children is mostly based on evidence from adults while scarce evidence exists from children. The classical anticoagulants currently used in children have several limitations, resulting in the need for regular monitoring. Several direct oral anticoagulants (DOACs) are now authorized for adults in whom they have established efficacy and safety without the need for monitoring. Given their pharmacological properties and the special characteristics of children requiring anticoagulation, the DOACs have the potential to be particularly suitable for children. All currently approved DOACs have paediatric development plans, targeting various indications for prevention and treatment of thrombosis. Paediatric formulations are being developed and systematic age-specific dosing information will be generated. Whether therapeutic drug monitoring will be necessary in certain situations in children remains to be elucidated. The results of ongoing clinical studies still need to demonstrate whether there is a positive benefit-risk balance in all targeted paediatric indications and age-groups, particularly in indications that have not been explored in adults, such as catheter-related thrombosis or congenital heart disease. If the advantages of DOACs bear out in the results of the current paediatric studies, they will likely be used widely in children. As of now, the DOACs should not be used routinely in children as there is still insufficient information on appropriate dosing, safety and efficacy. The paediatric community is encouraged to promote participation of children and adolescents into the multiple ongoing studies of DOACs. PMID- 30017226 TI - In utero exposure to tobacco smoke, subsequent cardiometabolic risks, and metabolic syndrome among U.S. adolescents. AB - PURPOSE: Maternal smoking during pregnancy increases risk of adverse pregnancy outcomes. However, little is known regarding in utero smoke exposure and offspring cardiometabolic risk. Thus, we examined the association between in utero smoke exposure and cardiometabolic risk factors and the metabolic syndrome (MetS) in adolescents. METHODS: Participants included 7464 adolescents aged 12-15 years identified from the National Health and Nutrition Examination Survey (1999 2014). Multiple logistic and linear regression analyses estimated sex-specific means and odds ratios (ORs) for the association between in utero smoke exposure and MetS and cardiometabolic risk factors. RESULTS: MetS prevalence was 9.0% in exposed versus 5.9% in unexposed adolescents. In utero smoke exposure was significantly associated with increased odds of MetS among males in models controlling for adolescent age, maternal age, and race/ethnicity (OR: 2.48, 95% confidence interval: 1.19, 5.20), with attenuation of this effect in subsequent models. In utero smoke exposure was associated with significantly elevated mean body mass index and waist circumference percentiles among female adolescents across most models in regression analyses. CONCLUSIONS: In utero smoke exposure appears to be associated with an increased likelihood of high waist circumference and body mass index percentiles, especially among female adolescents. Our study demonstrates the long-term cardiometabolic impact in offspring, highlighting the importance of prepregnancy smoking cessation. PMID- 30017227 TI - Complex interactions of age and sex on acute coronary syndromes. PMID- 30017228 TI - Another Notch for bicuspid aortic valve aortopathy? PMID- 30017229 TI - Portable ultrasound imaging system with super-resolution capabilities. AB - This paper discusses an ultrasound technique where the echo signals from the array of transducer elements are compressed to as few as two RF channels while still in analog domain, with a much simplified front-end electronics. The method can achieve resolutions well beyond the diffraction limit, which is set by the excitation signal wavelength and numerical aperture of the imaging system. The fundamental principle that underlies this model based imaging technique is the preservation of the spatial frequency information content of the recorded echo signals with the help of pseudo-random apodization function followed by summation. A Verasonics V1 ultrasonic scanner is used to conduct experiments using an anechoic cyst made from gel phantom, immersed in degassed water. The estimated images were compared to those obtained using traditional B-mode delay and-sum imaging available with the Verasonics V1 ultrasound machine. The estimated images using the proposed imaging technique showed a contrast ratio of 0.96 and Full-Width-Half-Maximum (FWHM) of about half the wavelength at a depth of 9.1 cm and at 1.875 MHz center frequency while the traditional delay and sum images had a contrast ratio of 0.62 and FWHM of about 5.5 wavelengths. PMID- 30017230 TI - Protein kinase C-mediated impairment of glutamine outward transport and SN1 transporter distribution by ammonia in mouse cortical astrocytes. AB - SN1, a system N amino acid transporter specific for astrocytes, is mainly responsible for export of newly synthesized L-glutamine from the cells. Astrocytic retention of L-glutamine which plays a critical role in ammonia induced astrocytic swelling resulting in brain edema, could be tentatively attributed to the impaired L-glutamine export from astrocytes. The present study demonstrates that treatment of cultured mouse cortical astrocytes for 24 h with 5 mM ammonium chloride ("ammonia") inhibits the system N-mediated L-glutamine transport out of the cell, and that this inhibition is related to the reduced presence of the SN1 transporter on the cell membrane. Ammonia decreased total protein kinase C (PKC) activity in the absence but not in the presence of PKC activator, phorbol 12-myristate 13-acetate (PMA), and activation of PKC by PMA reversed both the ammonia-induced decrease of system N-mediated L-glutamine release and ammonia-induced SN1 deficit in the membrane fraction. However, while ammonia did not change the protein level of PKCalpha isoform, it decreased the protein content of PKCdelta. Moreover, ammonia treatment increased the cell surface expression of SN1 in cells with silenced PKCalpha and PKCdelta. Silencing of PKCdelta abrogated the decrease of system N (SN1)-mediated L-glutamine release by ammonia. The results implicate the involvement of PKCdelta in the inhibition of SN1 membrane expression and activity by ammonia. PMID- 30017231 TI - Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson's disease mouse model. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is no recognised therapy to cure it. Recently, it has been shown that treatments to improve insulin resistance in type 2 diabetes (T2DM) may be useful for PD patients. In previous studies, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide showed good neuroprotective effects in animal models of PD. In addition, the GLP-1 mimetic exendin-4 has shown good protective effects in PD patients in a phase II clinical trial. Here, we report the protective effects of semaglutide (25 nmol/kg ip. once-daily for 7 days), a new long-acting GLP-1 analogue, in the MPTP mouse model of PD. Moreover, we compared the neuroprotective effect of semaglutide with liraglutide given at the same dose. Our work shows that both semaglutide and liraglutide improved 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced motor impairments. In addition, both GLP-1 analogues rescued the decrease of tyrosine hydroxylase (TH) levels, alleviated the inflammation response, reduced lipid peroxidation, inhibited the apoptosis pathway, and also increased autophagy- related protein expression, to protect dopaminergic neurons in the substantia nigra and striatum. Moreover, the long-acting GLP-1 analogue semaglutide was superior to liraglutide in most parameters measured in this study. Our results demonstrate that the new long- acting GLP-1 analogue semaglutide may be a promising treatment for PD. PMID- 30017232 TI - The outcome of surgical management of proximal humeral fractures using locking plates: comparison between locking plates with different geometry. AB - BACKGROUND: Locking plate fixation appears to be a standard treatment for proximal humeral fracture. Different locking plate designs might result in different radiographic and functional outcomes. The original version of the Proximal Humeral Internal Locking System (PHILOS; DePuy Synthes, Warsaw, IN, USA) occupied the largest volume of the humeral head by screw distribution, whereas the Zimmer Periarticular Locking Plate (ZPLP) system (Zimmer Biomet, Warsaw, IN, USA) occupied the smallest. METHODS: We enrolled 50 patients undergoing ZPLP treatment and 50 undergoing PHILOS treatment. RESULTS: The postoperative amount of impaction was significantly higher using the ZPLP System than using the PHILOS. Subgroup analysis showed that medial calcar support was another critical factor that affected surgical outcomes, especially when using the ZPLP System. CONCLUSION: The amount of postoperative impaction was significantly higher when the ZPLP was used compared with the PHILOS locking plate. Medial calcar support is another critical factor that affects surgical outcomes. However, no significant differences in functional outcomes (Constant-Murley score) between the ZPLP System and the PHILOS were noted at the 12-month follow-up. PMID- 30017233 TI - Human CATSPER1 Promoter Is Regulated by CREB1 and CREMtau Transcriptional Factors In Vitro. AB - BACKGROUND: The CATSPER1 gene encodes a CATSPER channel protein that selectively permeates Ca2+ ions, and CATSPER expression in sperm is essential for flagellum hyperactivation and, thus, male fertility. Little is known regarding the transcriptional regulation of CATSPER1, but previous studies have performed in silico analyses of transcription factor binding sites, including three CRE sites designated 0-2, in which CRE0 is located near the transcription start site. OBJETIVES: We investigate if overexpression of CREB-A and CREMtau transcription factors might regulate CATSPER1 expression. MATERIAL AND METHODS: In this study, the transcriptional regulation of the CATSPER1 gene by CREB-A and CREMtau transcriptions factors was determined by dual-luciferase assays in HEK293 and GC1 spg cells, and important CRE sites were mutated and analyzed for transcriptional regulation. RESULTS: The deletion of the CRE1 site dramatically increased the transcriptional activity of the CATSPER1 promoter in HEK293 and GC1-spg cells. In HEK293 cells, the CREB-A transcription factor positively regulated CATSPER1 gene expression, while the presence of CREB-A and CREMtau factors synergistically enhanced promoter activity in these cells. In contrast, deletion of CRE0 prevented any transcriptional activity of the CATSPER1 promoter in GC1-spg spermatogonial cells, but expression of either CREB-A or CREMtau restored such transcriptional activity. CONCLUSIONS: The human CATSPER1 promoter is positively regulated in vitro by CREB-A in HEK293 and GC1-spg cells. Both lines showed differential transcriptional regulation, which was defined by the factors and coactivators present in each cell line as well as the context in which the CRE sites were found in the promoter. PMID- 30017234 TI - Effect of Endoplasmic Reticulum Stress and Autophagy in the Regulation of Post infarct Cardiac Repair. AB - BACKGROUND: Acute myocardial infarction (AMI) is reported to be accompanied by endoplasmic reticulum (ER) stress and autophagy induction. Nevertheless, the roles of ER stress and autophagy in post-infarct reparative fibrosis remain to be elucidated. AIM: To investigate the effects of ER stress and autophagy on the regulation of post-infarct reparative fibrosis. METHODS: The expression of GRP78 and LC3 in cardiac fibroblasts in human heart tissues obtained from patients with or without AMI was assessed by immunofluorescence. In vitro, human cardiac fibroblasts (HCFs) were stimulated by various agents, the expression of GRP78, LC3 and fibronectin in these was evaluated by immunoblot and/or immunofluorescence. RESULTS: After AMI, HCFs expressed significantly higher levels of GRP78 and LC3. ER stress inducer, tunicamycin (200 ng/mL) significantly increased the level of autophagy and reduced expression of fibronectin in HCFs, both of which were reversed by 4 Phenylbutyric acid. Under the condition of ER stress, the expression of fibronectin in HCFs was regulated by different levels of autophagy. LC3 co-localized with fibronectin when stimulated HCFs with tunicamycin. CONCLUSION: AMI induces ER stress in cardiac fibroblasts, down regulating fibronectin via enhanced autophagy. These findings suggest that ER stress and autophagy may be a therapeutic target to improve prognosis of patients with AMI. PMID- 30017235 TI - Comparison of clinical outcomes between butterfly inlay cartilage tympanoplasty and conventional underlay cartilage tympanoplasty. AB - OBJECTIVE: To assess the efficacy of butterfly inlay cartilage tympanoplasty and compare it with conventional underlay cartilage tympanoplasty in terms of success rate and hearing outcomes. MATERIALS AND METHODS: The study included 35 patients (36 ears) who underwent butterfly inlay cartilage tympanoplasty (inlay group, 23 ears of 22 patients) or conventional underlay cartilage tympanoplasty (underlay group, 13 ears). The anatomical success rate and hearing outcomes were analysed. RESULTS: Re-perforation occurred in 2 cases (8.7%) in the inlay group and 3 (23.1%) in the underlay group. One patient in the inlay group developed a serious infection, and one in the underlay group developed massive granulation of the tympanic membrane. In the inlay group, the air-bone gap (ABG) decreased from 19.9 (+/-12.6) dB HL preoperatively to 13.8 (+/-11.3) dB HL postoperatively (p=0.047), in the underlay group, it decreased from 23.5 (+/-15.8) dB HL to 18.3 (+/-20.6) dB HL. Regarding improvement in ABG, the difference between the group was not statistically significant (p=0.968). CONCLUSION: Butterfly inlay cartilage tympanoplasty is comparable with conventional underlay cartilage tympanoplasty in both anatomic and audiological success rates. Owing to its simplicity, shorter operation time, and rapid patient recovery, butterfly inlay cartilage tympanoplasty could be considered a favourable surgical option. PMID- 30017236 TI - Management of retrosternal goiter: Retrospective study of 72 patients at two secondary care centers. AB - OBJECTIVE: Data pertaining to the outcomes of retrosternal goiter surgeries performed at secondary care centers, where thoracic surgery expertise is not readily available, is infrequently reported. Careful patient selection is crucial to avoid an unexpected need for a sternotomy during surgery. We sought to evaluate the surgical management of patients with retrosternal goiters treated at two secondary care centers. METHODS: Retrospective review of clinical records and computed tomographic (CT) scans of 557 patients who underwent thyroid surgery at the Departments of Otolaryngology, Head and Neck Surgery of Manukau Surgery Center and Whangarei Base Hospital. Inclusion criterion was extension of goiter below the plane of the thoracic inlet on CT scan. Clinicopathologic features and surgical outcomes were recorded. RESULTS: The prevalence of retrosternal goiter was 72 of 557 patients (12.9%). All patients in this series underwent thyroidectomy transcervically. Dyspnea was present in 48 patients (66.7%). On preoperative CT scans, the goiter was noted to extend beyond the aortic arch in seven patients (9.7%), tracheal bifurcation in five patients (6.9%) and posterior mediastinum in 15 patients (20.8%). Malignancy was diagnosed in eight patients (11.1%) histologically. Postoperatively, vocal cord paralysis was temporary in 5 patients (6.9%) and permanent in 1 patient (1.4%). Hypocalcaemia was transient in 10 patients (13.9%). No permanent hypocalcemia, tracheomalacia, postoperative hematoma or patient death was reported. During the study period, 4 patients were encountered in the outpatients setting whereby the evaluation of their CT imaging demonstrated features deemed to be at high risk of requiring a sternotomy: primary mediastinal goiter (n=2) and inferior extent of goiter to the level of right atrium (n=2). These patients were pre-emptively referred to a tertiary center where thoracic surgery service was available and their data was reported separately. CONCLUSION: With careful patient selection, the majority of retrosternal goiter can be resected transcervically with minimal morbidities. Preoperative CT scan yielded useful surgical information; in the presence of primary mediastinal goiter or inferior extent of goiter to the level of the right atrium, surgery should be planned in a tertiary center where thoracic surgeon is available. PMID- 30017237 TI - Refining Delirium: A Transtheoretical Model of Delirium Disorder with Preliminary Neurophysiologic Subtypes. AB - The development of delirium indicates neurophysiologic disruption and predicts unfavorable outcomes. This relationship between delirium and its outcomes has inspired a generation of studies aimed at identifying, predicting, and preventing both delirium and its associated sequelae. Despite this, evidence on delirium prevention and management remains limited. No medication is approved for the prevention or treatment of delirium or for its associated psychiatric symptoms. This unmet need for effective delirium treatment calls for a refined approach. First, we explain why a one-size-fits-all approach based on a unitary biological model of delirium has contributed to variance in delirium studies and prevents further advance in the field. Next, in parallel with the shift from dementia to "major neurocognitive disorder," we propose a transtheoretical model of "delirium disorder" composed of interactive elements-precipitant, neurophysiology, delirium phenotype, and associated psychiatric symptoms. We explore how these relate both to the biopsychosocial factors that promote healthy cognition ("procognitive factors") and to consequent neuropathologic sequelae. Finally, we outline a preliminary delirium typology of specific neurophysiologic disturbances. Our model of delirium disorder offers several avenues for novel insights and clinical advance: it univocally differentiates delirium disorder from the phenotype of delirium, highlights delirium neurophysiology as a treatment target, separates the core features of delirium from associated psychiatric symptoms, suggests how procognitive factors influence the core elements of delirium disorder, and makes intuitive predictions about how delirium disorder leads to neuropathologic sequelae and cognitive impairment. Ultimately, this model opens several avenues for modern neuroscience to unravel this disease of antiquity. PMID- 30017238 TI - Half of Home Care Recipients Are Depressed: How Do We Optimize Their Care? PMID- 30017240 TI - Reply-Letter to the Editor - Timing of PROTein INtake and clinical outcomes of adult critically ill patients on prolonged mechanical VENTilation: The PROTINVENT retrospective study. PMID- 30017239 TI - Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults. AB - OBJECTIVES: Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. METHODS: Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. RESULTS: Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. CONCLUSIONS: Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults. PMID- 30017241 TI - Clinical approach to the management of Intestinal Failure Associated Liver Disease (IFALD) in adults: A position paper from the Home Artificial Nutrition and Chronic Intestinal Failure Special Interest Group of ESPEN. AB - We recommend that intestinal failure associated liver disease (IFALD) should be diagnosed by the presence of abnormal liver function tests and/or evidence of radiological and/or histological liver abnormalities occurring in an individual with IF, in the absence of another primary parenchymal liver pathology (e.g. viral or autoimmune hepatitis), other hepatotoxic factors (e.g. alcohol/medication) or biliary obstruction. The presence or absence of sepsis should be noted, along with the duration of PN administration. Abnormal liver histology is not mandatory for a diagnosis of IFALD and the decision to perform a liver biopsy should be made on a case-by-case basis, but should be particularly considered in those with a persistent abnormal conjugated bilirubin in the absence of intra or extra-hepatic cholestasis on radiological imaging and/or persistent or worsening hyperbilirubinaemia despite resolution of any underlying sepsis and/or any clinical or radiological features of chronic liver disease. Nutritional approaches aimed at minimising PN overfeeding and optimising oral/enteral nutrition should be instituted to prevent and/or manage IFALD. We further recommend that the lipid administered is limited to less than 1 g/kg/day, and the prescribed omega-6/omega-3 PUFA ratio is reduced wherever possible. For patients with any evidence of progressive hepatic fibrosis or overt liver failure, combined intestinal and liver transplantation should be considered. PMID- 30017242 TI - Corrigendum to 'Nutritional status predicts preterm death in older people: A prospective cohort study' [Clin Nutr 33 (2) (2014) 354-359]. PMID- 30017243 TI - Maternal influences on the glucocorticoid concentrations of human milk: The STEPS study. AB - BACKGROUND & AIMS: Human milk (HM) contains a wide array of non-nutritive bioactive elements, including glucocorticoid hormones (glucocorticoid; cortisol and cortisone). The relationship between milk-borne glucocorticoids, measures of maternal health and patterns of breast-feeding is not yet established. This study was conducted to determine the influence of maternal and infant related biological and socio-demographic factors on the levels of glucocorticoids hormones in HM. METHODS: Samples were obtained from lactating mothers (n = 656) participating in the Finnish cohort the STEPS study (Steps to the Healthy Development and Well-being of Children) when the infants were 11.29 (+/-2.6) weeks of age. Glucocorticoids (both cortisol and cortisone) concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Maternal demographics, biological and social factors were obtained using hospital records and self-reported diaries and questionnaires. RESULTS: The majority of women reported that they were exclusively breastfeeding at the time of sample donation (51.2%). For all collected samples, cortisone (9.55 +/- 3.44 ng/ml) was the predominant hormone and cortisol (7.39 +/- 5.97 ng/ml) was present in all samples. Strong and positive correlation was found between cortisol and cortisone (r = 0.60, p=<0.0001). Cortisone was statistically different between overweight, normal and underweight women (p = 0.01) for cortisol no difference was seen (p = 0.96). Whilst, preterm birth (born before 37 week gestation) was positively associated with both cortisol (p = 0.04) and cortisone (p = 0.01). There was also a significant but weaker negative relationship between mothers educational status and cortisol (p = 0.05) and no effect was seen for cortisone (p = 0.82). Interestingly, no significant differences was found in glucocorticoid concentrations between exclusive and partial breastfeeding women. CONCLUSION: HM contains glucocorticoids hormones. The concentrations are influenced by the varying maternal factors including maternal weight, preterm birth and maternal educational status, suggesting the possible role of maternal biological and social influences on milk hormonal composition. Interestingly, there was no influence of feeding patterns on HM glucocorticoids. Further analysis is required to fully explore the relationship with measures of maternal stress, including mother's glucocorticoid status. PMID- 30017244 TI - Health-related quality of life, anxiety, depression and distress of mothers and fathers of children on Home parenteral nutrition. AB - BACKGROUND & AIMS: Parents of children with intestinal failure, dependent on Home Parenteral Nutrition (HPN), may experience psychosocial problems due to the illness and intensive treatment of their child. Literature concerning psychosocial problems is scarce. Therefore, we aimed to investigate Health Related Quality of Life (HRQOL), levels of anxiety, depression, distress and everyday problems of these mothers and fathers. METHODS: A multicenter study was conducted among 37 mothers and 25 fathers of 37 children on HPN (response-rate 37/49 = 76%, mean age children = 5.1 years, SD = 4.6). Parents completed three questionnaires to measure different outcomes on the KLIK website (www.hetklikt.nu): the TNO-AZL QOL Questionnaire (TAAQOL) to measure HRQOL, the Hospital Anxiety and Depression Scale (HADS) to measure anxiety and depression, and the Distress Thermometer for Parents (DT-P) to measure distress. Scores were compared to Dutch reference mothers and fathers using Mann-Whitney U-tests. RESULTS: No differences were found in HRQOL, measured by the TAAQOL, between HPN parents compared to the reference groups, except for the subscale 'depressive emotions' for mothers (p = .01) and 'daily activities' for fathers (p = .04). HPN mothers reported higher levels of depression compared to reference mothers (p = .001). In addition, HPN mothers and fathers reported higher levels of distress than reference mothers (p = .001) and fathers (p = .03). HPN mothers reported significantly more problems in the practical, emotional, cognitive and parenting domains, fathers in the social, emotional and parenting domains. CONCLUSIONS: On HRQOL, anxiety and depression, HPN parents generally did not show much differences compared to reference parents. However, when asked about parental distress and everyday problems, HPN treatment of their child seems highly stressful for some parents and influences daily functioning. Therefore, structural screening for parental psychosocial problems in clinical practice, e.g. using the DT-P, is necessary in order to improve the well-being of both these parents and their children dependent on HPN. PMID- 30017245 TI - Toward Minimal Residual Disease-Directed Therapy in Melanoma. AB - Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance. PMID- 30017247 TI - Accounting for Complexity in Resilience Comparisons: A Reply to Yeung and Richardson, and Further Considerations. PMID- 30017246 TI - Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production. AB - The ex vivo generation of platelets from human-induced pluripotent cells (hiPSCs) is expected to compensate donor-dependent transfusion systems. However, manufacturing the clinically required number of platelets remains unachieved due to the low platelet release from hiPSC-derived megakaryocytes (hiPSC-MKs). Here, we report turbulence as a physical regulator in thrombopoiesis in vivo and its application to turbulence-controllable bioreactors. The identification of turbulent energy as a determinant parameter allowed scale-up to 8 L for the generation of 100 billion-order platelets from hiPSC-MKs, which satisfies clinical requirements. Turbulent flow promoted the release from megakaryocytes of IGFBP2, MIF, and Nardilysin to facilitate platelet shedding. hiPSC-platelets showed properties of bona fide human platelets, including circulation and hemostasis capacities upon transfusion in two animal models. This study provides a concept in which a coordinated physico-chemical mechanism promotes platelet biogenesis and an innovative strategy for ex vivo platelet manufacturing. PMID- 30017248 TI - Impaired topographic organization in cognitively unimpaired drug-naive patients with rigidity-dominant Parkinson's disease. AB - BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) and graph theory approaches have been combined to investigate the topographic organization in Parkinson's disease (PD). METHOD: Twenty cognitively unimpaired drug-naive patients with rigidity-dominant PD (PDAR) and 20 age-, sex-, and education matched healthy controls were included. Small-world profile and topographic properties (clustering coefficient (Cp), characteristic path length (Lp), local efficiency (Eloc), global efficiency (Eglob), nodal efficiency (Enod), nodal degree (NDeg), and nodal betweenness (NBet)) were measured and compared between two groups, with age, gender and education as covariates. Correlation analyses between topographic features and the unified PD rating scale part-III (UPDRS-III) scores, cognitive scores were performed. RESULTS: PDAR patients presented the small-world property, and abnormalities at the nodal level (Enod, NDeg, and NBet) but not at the global level (Cp, Lp, Eloc, and Eglob). Our results revealed lower nodal centralities mainly in the occipital lobe and areas of the limbic system (including amygdala nucleus), and higher nodal centralities in distributed frontal and temporal regions. Notably, the decreased nodal efficiency of occipital regions (including the calcarine area, lingual area and superior occipital gyrus (SOG)) was negatively correlated with UPDRS-III scores. And the nodal efficiency of the calcarine area was positively correlated with visuospatial scores. CONCLUSION: Our results may provide insights into the underlying pathophysiology of PDAR and aid the development of potential biomarkers of the disease progression and cognitive decline in PDAR patients. PMID- 30017249 TI - New mode of burst spinal cord stimulation improved mental status as well as motor function in a patient with Parkinson's disease. AB - Traditional tonic spinal cord stimulation has been shown to improve locomotor behaviour of Parkinson's disease (PD), but may induce paresthesia. Recently developed new stimulation mode, called BurstDR, improved pain, gait and posture of later developed PD patients without inducing paresthesia, in addition to improve emotional symptoms. PMID- 30017250 TI - Neoadjuvant radiation for clinical T4 colon cancer: A potential improvement to overall survival. AB - BACKGROUND: Resection of T4 colon cancer remains challenging compared to lower T stages. Data on the effect of neoadjuvant radiation to improve resectability and survival are lacking. The purpose of this study is to describe the use and outcomes of neoadjuvant radiation therapy in clinical T4 colon cancer. METHODS: Adults with clinical evidence of T4 locally advanced colon cancer were included from the National Cancer Database (2004-2014). Bivariate and multivariable analyses were used to examine the association between neoadjuvant radiation therapy and R0 resection rate, multivisceral resection, and overall survival. RESULTS: Fifteen thousand two hundred and seven patients with clinical T4 disease who underwent resection were identified over the study period. One hundred ninety five (1.3%) underwent neoadjuvant radiation therapy. Factors associated with the use of neoadjuvant radiation therapy included younger age, male sex, private insurance, lower Charlson Comorbidity Index score, and treatment at an academic research program. Neoadjuvant radiation therapy was associated with superior R0 resection rates (87.2% neoadjuvant radiation therapy vs 79.8% no neoadjuvant radiation therapy; P = .009). Five-year overall survival was increased in the neoadjuvant radiation therapy group (62.0% neoadjuvant radiation therapy vs 45.7% no neoadjuvant radiation therapy; P < .001). The benefit of neoadjuvant radiation therapy persisted in a Cox proportional hazards multivariable model containing a number of confounding variables, including comorbidity and postoperative chemotherapy (odds ratio 1.37; 95% confidence interval 1.05-1.77; P = .01). In a subgroup analysis of T4b patients, there was an even greater size effect in adjusted overall survival (odds ratio 1.71; 95% confidence interval 1.07-2.72; P = .02). CONCLUSION: Although radiation is rarely used in locally advanced colon cancer, this National Cancer Database analysis suggests that the use of neoadjuvant radiation for clinical T4 disease may be associated with superior R0 resection rates and improved overall survival. Patients with clinical T4b disease may benefit the most from treatment. Neoadjuvant radiation therapy should be considered on a case-by-case basis in locally advanced colon cancer. PMID- 30017251 TI - Extrapolation of fistula grade from the pancreatectomy participant use file of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). PMID- 30017252 TI - Striatal Microstructure and Its Relevance for Cognitive Control. AB - The relevance of the striatum for cognitive control processes is increasingly appreciated. The striatum is not a homogenous structure but instead is compartmentalized into the 'matrix' and 'striosomes'. Here, we discuss experiments on a model disease of striosomal dysfunction and provide evidence for the importance of the striatal microstructure for cognitive control in humans. PMID- 30017253 TI - Combination Therapy in Patients with Acute Respiratory Failure: High-Flow Nasal Cannula and Non-Invasive Mechanical Ventilation. PMID- 30017254 TI - Biologics in the treatment of diffuse interstitial lung disease associated with connective tissue disease. PMID- 30017255 TI - Pseudoprogression in a Patient with Metastatic Lung Adenocarcinoma Treated with Nivolumab. PMID- 30017256 TI - Agenesis of the Left Pulmonary Vein and Artery. PMID- 30017257 TI - Is there any association between abdominal strength training before and during pregnancy and delivery outcome? The Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Abdominal strength training before and during pregnancy has been recommended to enhance normal vaginal birth by enabling increased force needed for active pushing. However, to date there is little research addressing this hypothesis. OBJECTIVE: To investigate whether nulliparous pregnant women reporting regular abdominal strength training prior to and at two time points during pregnancy have reduced risk of cesarean section, instrumental assisted vaginal delivery and third- and fourth-degree perineal tears. METHODS: Analysis of 36124 nulliparous pregnant women participating in the Norwegian Mother and Child Cohort Study during the period 1999-2009 who responded to questions regards the main exposure; regular abdominal strength training. Data on delivery outcomes were retrieved from the Medical Birth Registry of Norway. Logistic regression analyses were used to evaluate the association between exposure and outcome before pregnancy and at gestational weeks 17 and 30. RESULTS: Amongst participants, 66.9% reported doing abdominal strength training exercises before pregnancy, declining to 31.2% at gestational week 30. The adjusted odds ratios were 0.97 (95% CI 0.79-1.19) for acute cesarean section, among those training with the same frequency before and during pregnancy compared to those that never trained. The results were similar for instrumental assisted vaginal delivery and third- and fourth-degree perineal tear. CONCLUSION: There was no association between the report of regular abdominal strength training before and during pregnancy and delivery outcomes in this prospective population-based cohort. PMID- 30017259 TI - Young adults and HIV. Awareness and risk behaviour of a group living in Spain. AB - INTRODUCTION: Sexual intercourse is currently the main route of HIV infection in Spain. Despite decreases in new infections among women and drug users, the rate remains stable in men. The aim of this study was to assess risk behaviour and HIV awareness in a sample of young adults in Spain. METHODS: A cross-sectional, observational, descriptive study was performed on a non-HIV infected sample, using a questionnaire on sexual health and HIV awareness adapted from the Spanish National Institute of Statistics. A sexual risk variable was included (high and low), which was classified as high if subjects had had three or more sexual partners and did not always use a condom in all their sexual encounters. RESULTS: 243 subjects were included (65.6% women) aged between 16 and 36years (mean=25.7; SD=4.1) (16-24years: 134 subjects; 25-29years: 60 subjects; over 30years: 47 subjects). Approximately 40.9% said that they used a condom in all sexual relations and 61% did not perceive any risk of infection. There were no significant differences in awareness of infection routes between the high and low risk profiles. Washing after sex, having few partners, spermicide use and having undetectable viral load were protective measures significantly associated with differences in sexual risk (P<.05). CONCLUSIONS: The main finding of the study was the underestimation of risk of infection, analysed after differences found between self-assessment and sexual risk. Both positive and negative results were found concerning HIV awareness. PMID- 30017258 TI - Can demographic and anthropometric characteristics predict clinical improvement in patients with chronic non-specific low back pain? AB - OBJECTIVE: To identify potential prognostic factors that may predict clinical improvement of patients treated with different physical therapy interventions in the short-term. METHODS: This is a prospective cohort study. A total of 616 patients with chronic non-specific low back pain treated with interventions commonly used by physical therapists were included. These patients were selected from five randomized controlled trials. Multivariate linear regression models were used to verify if sociodemographic characteristics (age, gender, and marital status), anthropometric variables (height, body mass, and body mass index), or duration of low back pain, pain intensity at baseline, and disability at baseline could be associated with clinical outcomes of pain intensity and disability four weeks after baseline. RESULTS: The predictive variables for pain intensity were age (beta=0.01 points, 95% CI=0.00 to 0.03, p=0.03) and pain intensity at baseline (beta=0.23 points, 95% CI=0.13 to 0.33, p=0.00), with an explained variability of 4.6%. Similarly, the predictive variables for disability after four weeks were age (beta=0.03 points, 95% CI=0.00 to 0.06, p=0.01) and disability at baseline (beta=0.71 points, 95% CI=0.65 to 0.78, p=0.00), with an explained variability of 42.1%. CONCLUSION: Only age, pain at baseline and disability at baseline influenced the pain intensity and disability after four weeks of treatment. The beta coefficient for age was statistically significant, but the magnitude of this association was very small and not clinically important. PMID- 30017260 TI - Abnormal serum potassium levels and 6-month all-cause mortality in patients co treated with antipsychotic and diuretic drugs - A Danish register-based cohort study. AB - Psychiatric patients have excess mortality compared to the general population, and several potential mechanisms may explain this increased risk. This study examined the relationship between serum potassium levels and risk of all-cause mortality in patients co-treated with antipsychotic and diuretic drugs. Using a register-based cohort design, we identified patients between 1995 and 2012 who received a combination of an antipsychotic and a diuretic drug and who further had a serum potassium measurement within 90 days. During the study period, we included the most frequently redeemed antipsychotic drugs with regard to the propensity of corrected QT (QTc) prolongation: zuclopenthixol (unknown/mild), flupentixol (mild), levomepromazine (moderate), and quetiapine (moderate/severe). Patients co-treated with antidepressant drugs, lithium, and other antipsychotic drugs were excluded. Outcome was 6-month all-cause mortality, estimated with multivariable Cox regression. Patients were divided into seven serum potassium levels using restricted cubic splines (reference: 4.2-4.4 mmol/L) and stratified according to the included antipsychotic drugs. Of 6729 patients (median age: 74.0 years; women: 65.3%), 10.8% had hypokalemia and 4.9% had hyperkalemia. Hyperkalemia (>5.0 mmol/L, HR 2.82 [95% CI 2.25-3.54]), hypokalemia (<3.5 mmol/L, HR 1.59 [95% CI 1.29-1.95]), and high normal potassium levels (4.5-4.7 mmol/L, HR 1.44 [95% CI 1.19-1.75]; 4.8-5.0 mmol/L, HR 1.60 [95% CI 1.26-2.04]) were associated with an increased risk of 6-month all-cause mortality. This risk was independent of antipsychotic drugs (interaction: P = 0.06). Our findings imply that excess mortality in patients co-treated with antipsychotic and diuretic drugs is related to serum potassium levels and independent of antipsychotic drugs. PMID- 30017261 TI - Peripheral blood SIRT1 mRNA levels in depression and treatment with electroconvulsive therapy. AB - Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+) dependent enzymes that regulate cellular functions through deacetylation of protein targets. They have roles in both the periphery and central nervous system and have been implicated in depression biology. A recent genome-wide association study has identified a locus for major depression in the Sirtuin1 gene (SIRT1) and lower blood levels of SIRT1 mRNA in patients with depression have also been observed in two studies. To our knowledge, no studies have examined the effect of treatment on SIRT1 levels in patients with depression. We therefore examined SIRT1 mRNA levels in a well characterised group of patients with depression, compared to healthy controls, and characterised the effects of a course of electroconvulsive therapy (ECT) on peripheral blood SIRT1 mRNA. Depressed patients (n = 91) were matched to healthy controls (n = 85) on the basis of age and sex. In line with previous studies, blood SIRT1 mRNA levels were lower in depressed patients in comparison to controls (p = 0.005). However, ECT had no effect on SIRT1 levels (p = 0.67). There was no relationship between baseline pre ECT SIRT1 levels and depression severity, change in mood scores, suicidality, depression polarity, presence of psychosis, or response to treatment. There was a trend for a negative association between an increase in SIRT1 mRNA and a decrease in HAM-D24 scores in ECT responders and remitters. These results indicate that reduced peripheral blood SIRT1 mRNA could be a trait feature of depression. PMID- 30017262 TI - Interleukin 4 affects lipid metabolism and the expression of pro-inflammatory factors in mature rat adipocytes. AB - Chronic low-grade inflammation contributes to diseases associated with fat tissue metabolism such as obesity and diabetes by the disturbed production of adipose tissue proteins, both pro- and anti-inflammatory. Interleukin-4 (IL-4) is one of the main inflammatory cytokines that activates Th2-dependent immune response and its increased expression was observed in the course of diseases characterized by chronic low-grade systemic inflammation such as obesity and asthma. We aimed to investigate if IL-4 may influence lipid metabolism and inflammatory responses in primary mature rat adipocytes. Mature adipocytes were isolated from male Wistar rats in incubated with IL-4 at three concentrations. We measured lipogenesis and lipolysis as well as the expression of selected genes using ddCt method was used to calculate relative gene expression. Protein level in tissue was analyzed using Western blot. Protein concentration in cell medium was analyzed using ELISA. Statistical analysis was done using GraphPad Prism 5 software. In primary cell model, we found that IL-4 stimulated lipogenesis and inhibited lipolysis in mature rat adipocytes. It also stimulated the expression of pro-inflammatory cytokines produced by adipocytes and decreased the expression of anti inflammatory protein, adiponectin. Moreover, we found increased expression of inflammatory cytokines and transcription factors associated with Th2 response. Our observations suggest that low-grade inflammation enhances fat accumulation and significantly alters adipocyte metabolism. PMID- 30017263 TI - Effect of redox status of peripheral blood on immune signature of circulating regulatory and cytotoxic T cells in streptozotocin induced rodent model of type I diabetes. AB - Diabetes mellitus is an autoimmune chronic inflammatory disease manifested by hyperglycemia and associated with imbalance in redox status and inflammatory response. Oxidative stress has been reported to affect functions of T cell repertoire- regulatory T cells (Tregs) and cytotoxic lymphocytes (CTLs). Tregs are involved in prevention against autoreactive T cells and controlling inflammation while CTLs are major mediators of tissue injury. Hence the present study is novel as it contemplates to understand oxidative stress in diabetes vis a-vis T cells. Comparative analysis was carried out between two groups, i.e., healthy Sprague Dawley (SD) and Streptozotocin (STZ) induced SD rat model of type1 diabetes (T1D). Various hematological, biochemical and oxidative stress parameters were assessed in plasma samples in the study. Peripheral blood mononuclear cells (PBMCs), Tregs and CTLs were evaluated for intracellular oxidative stress using 2',7'-dichlorofluorescin diacetate (DCFDA), mitochondrial ROS using Mitosox-red, mitochondrial membrane potential using JC-1 in PBMCs. Treg populations expressing IL-4, IL-6 and IL-10 and CTLs expressing alphabeta-T cell receptor (alphabeta -TCR), interferon- gamma (IFN-gamma), perforin and granzyme were also considered. We found decreased activity of enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and reduced glutathione(GSH) and increased lipid peroxidation (LPO) in plasma indicated altered redox state in diabetic animals. Elevated intracellular reactive oxygen species (ROS) and mitochondrial superoxide was observed in T1D group confirming oxidative stress in cell specific manner. Cell population with hyperpolarized mitochondrial membrane potential was found to be elevated in T1D group. We found a decrease in Treg population in T1D group in comparison to healthy group. Treg population expressing IL-4, IL-6 were increased and those expressing IL-10 were found to be reduced in diabetic group. The CTL numbers were dropping whereas alphabeta-TCR, IFN-gamma, perforin and granzyme expressing CTLs were on the rise in diabetic group. Our finding suggested an increased oxidative stress in Tregs and CTLs which might be responsible for progressive inflammatory environment built up due to persistent hyperglycemia. This was fortified by the statistical analyses where strong correlation between LPO and CTLs expressing TCR, IFN-gamma, perforin and granzyme was noted. Lipid peroxidation was also found to be correlated to intracellular ROS in Tregs and CTLs along with other important revelations. The present study gives important insights into the significance of oxidative stress on immune system and its mediators in diabetes. PMID- 30017264 TI - The prognostic value of SUVmax measuring on primary lesion and ALN by 18F-FDG PET or PET/CT in patients with breast cancer. AB - PURPOSE: To evaluate the prognostic value of maximum standardized uptake values (SUVmax) measured in the primary lesion and axillary lymph nodes (ALN) by pretreatment fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) in patients with breast cancer. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library. The primary prognosis endpoint was event-free survival (EFS), and the secondary endpoint was overall survival (OS). The pooled hazard ratio (HR) was estimated by using random-effects model according to the results of heterogeneity. RESULTS: Fifteen eligible studies with 3574 breast cancer patients were included. For EFS, patients with higher primary SUVmax showed a poorer survival prognosis with pooled HR of 1.96 (95% confidence interval (CI) 1.40-2.73). The combined HR of high SUVmax in ALN and ALN-to-primary SUVmax ratio (N/T ratio) were 1.89 (95% CI 0.70-5.07) and 2.06 (95% CI 0.59-7.21), respectively. In analyzing invasive ductal carcinoma (IDC) patients, the pooled HR was 1.91 (95% CI 1.40-2.64). For OS, the pooled HR of SUVmax in primary lesion and ALN were 0.64 (95% CI 0.23-1.84) and 1.09 (95% CI 0.07-16.53), respectively. CONCLUSIONS: Our meta-analysis suggested that patients with high primary SUVmax may experience a higher risk for recurrence or a poor progression. Moreover, the SUVmax of 18F-FDG showed a significant prognostic value in IDC patients. PMID- 30017265 TI - Noninvasive method for measurement of cerebral blood flow using O-15 water PET/MRI with ASL correlation. AB - PURPOSE: A noninvasive image derived input function (IDIF) method was applied to estimate arterial input function from brain H215O-PET/MRI images for the measurement of cerebral blood flow (CBF) because of difficulty in arterial blood sampling during PET/MRI scans. To evaluate accuracy and reproducibility of radioactivity in the internal carotid arteries (ICA) for the IDIF method, a new phantom using a skull bone was applied in the cross-calibration process between the scanner and a gamma-well counter. METHODS: Eleven healthy volunteers (9 males, 43.9 +/- 10.9y) underwent PET/MRI studies with a 3-min H215O-PET and several MRI scans including arterial spin labeling (ASL) perfusion MRI. PET images were reconstructed as dynamic data using two sets of reconstruction parameters, which were determined by basic assessment of radioactivity concentration reproducibility in the tubes of the phantom. The IDIF method extracted the time-activity curves of the ICA from several image slices in the PET data. CBF images were calculated using the autoradiographic (ARG) method and a one-tissue compartment model (1-TCM). RESULTS: The global means of CBF from the ARG, 1-TCM, and ASL-MRI were 44.8 +/- 4.3, 47.9 +/- 5.9 and 57.9 +/- 8.6 (mL/min/100 g), respectively. CBF from ASL-MRI was significantly greater compared with CBF from H215O-PET (P < 0.001). However, these CBF values were significantly correlated with each other in the scatter plots (P < 0.05). CONCLUSIONS: Noninvasive measurement of CBF using H215O-PET/MRI and IDIF with the cross calibration method with a skull phantom experiment provided reasonable quantitative values. The IDIF method allowed reliable estimation of arterial radioactivity concentration, which is useful for clinical application. The ASL MRI perfusion image from the simultaneous acquisition tended to overestimate CBF. PMID- 30017266 TI - Dual-energy CT of the heart current and future status. AB - Several applications utilizing dual-energy cardiac CT (DECT) have recently transitioned from the realm of research into clinical workflows. DECT acquisition techniques and subsequent post-processing can provide improved qualitative analysis, allow quantitative imaging, and have the potential to decrease requisite radiation and contrast material doses. Additionally, several experimental DECT techniques are pending further investigation and may improve the diagnostic accuracy of cardiac CT and/or provide evaluation of emerging imaging biomarkers in the future. This review article will summarize the major applications utilizing DECT in diagnosis of cardiovascular disease, including both the clinically used and investigational techniques examined to date. PMID- 30017267 TI - Diagnostic accuracy of DW MR imaging in the differentiation of chordomas and chondrosarcomas of the skull base: A 3.0-T MRI study of 105 cases. AB - PURPOSE: To determine the diagnostic accuracy of DW MR imaging with apparent diffusion coefficient (ADC) mapping for the distinction of skull base chordoma from skull base chondrosarcoma. PATIENTS AND METHODS: From October 2009 to April 2014, 105 consecutive patients (chordomas (n = 70), and chondrosarcomas (n = 35) who were planned to receive proton or heavy-ion beam therapy underwent DW MR imaging on a 3.0 T. MR images were assessed by means of consensus of three experienced radiologists who were blinded to pathologic and clinical information. ADC values (mean, minimum, maximum, and normalized) of the solid tumor component were evaluated. Group means and cut-off points were established to separate skull base chordoma from skull base chondrosarcoma, and statistical significances were calculated by Student's t or Mann-Whitney-U tests, and receiver operating characteristic (ROC) curve analyses. The prospective study was approved by the institutional ethics committee. RESULTS: For solid tumor component, there were higher mean, minimum, maximum, and normalized ADC values in chondrosarcomas compared with those in chordomas (all p < 0.001). ROC analysis revealed areas under the curve for mean, minimum, maximum, and normalized ADC values between 0.79 and 0.93. The mean ADC value of the solid tumor components had the best AUC, with a cut-off point of 1585 * 10(-6) mm (2)/s and sensitivity and specificity of 94.3% and 98.6%, respectively. CONCLUSION: Skull base Chondrosarcomas generally have higher mean, minimum, maximum, and normalized ADC values than skull base chordomas, with the mean ADC value of the solid tumor component offering the highest accuracy for characterization. PMID- 30017268 TI - Pseudoenhancement effects on iodine quantification from dual-energy spectral CT systems: A multi-vendor phantom study regarding renal lesion characterization. AB - PURPOSE: To measure the effect of pseudoenhancement on spectral CT iodine quantification as a function of lesion size, lesion iodine level, background iodine level, helical versus axial scanning, and spectral CT scanner type in a phantom model. MATERIALS AND METHODS: A custom-built water-filled cylindrical phantom contained either six small vials (8 mm diameter) or six large vials (27 mm diameter) of aqueous iopamidol solutions (0, 0.5, 1.0, 2.0, 4.0 and 6.0 mg iodine/mL). The background iodine concentration was 0, 5, or 10 mg iodine/mL. Helical and axial scans were taken on three different dual-energy spectral CT scanners (two image-based and one projection-based) with the scan parameters consistent between the systems. ROIs were used to measure the average iodine concentration of the vials in the 36 individual scans. Linear fits of the true versus measured iodine values were used for pvalue statistical analysis. Having a y-intercept or slope p-value less than 0.05 implied statistically significant iodine quantification errors. RESULTS: Iodine quantification pseudoenhancement effects are inversely proportional to lesion size and lesion enhancement and are directly proportional to background attenuation level. No significant differences between helical and axial scans were observed. 100% and 88% of the slope and y intercept p-values were below 0.05 for the two image-based systems, while 13% of the slope and y-intercept p-values were below 0.05 for the projection-based system. CONCLUSIONS: Pseudoenhancement can artificially increase spectral CT iodine quantification levels most notably for small low-enhancing lesions (<5.0 mg iodine/mL) surrounded by a high attenuating background (10 mg iodine/mL). In this study we found iodine quantification to be more accurate on projection-based spectral CT systems than image-based systems. PMID- 30017269 TI - The interobserver agreement in the detection of recurrent HNSCC using MRI including diffusion weighted MRI. AB - INTRODUCTION: For the detection of local recurrences of head and neck squamous cell carcinomas (HNSCC) after (chemo)radiation, diagnostic imaging is generally performed. Diffusion weighted magnetic resonance imaging (DW-MRI) has been proven to be able to adequately diagnose the presence of cancer. However evaluation of DW-MR images for recurrences is difficult and could be subject to individual interpretation. AIM: To determine the interobserver agreement, intraobserver agreement and influence of experience of radiologists in the assessment of DW-MRI in patients clinically suspected of local recurrent HNSCC after (chemo)radiation. METHODS: Ten experienced head and neck radiologists assessed follow-up MRI including DW-MRI series of 10 patients for the existence of local recurrence on a two point decision scale (local recurrence or local control). Patients were clinically suspected for a recurrence of laryngeal (n = 3), hypopharyngeal (n = 3) or oropharyngeal (n = 4) cancer after (chemo)radiation with curative intent. Fleiss' and Cohen's Kappa were used to determine interobserver agreement and intraobserver agreement, respectively. RESULTS: Interobserver agreement was kappa = 0.55. Intraobserver agreement was kappa = 0.80. Prior experience within the field of radiology and with DW-MRI had no significant influence on the scoring. CONCLUSION: For the assessment of HNSCC recurrence after (chemo)radiation by DW MRI, moderate interobserver agreement and substantial intraobserver agreement was found. PMID- 30017270 TI - Cardiac magnetic resonance characteristics in young survivors of aborted sudden cardiac death. AB - PURPOSE: We aimed to identify and assess cardiac abnormalities by cardiovascular magnetic resonance (CMR) in a non-ischaemic aborted sudden cardiac death (SCD) population and to establish possible predictors of SCD. METHODS: Thirty-six consecutive SCD survivors [median age 37.6 years (IQR 24.1-43.2), 31% female] with no previous cardiac history or evidence of ischaemic heart disease underwent CMR on day 6 (IQR 4-10) after admission. Data on ventricular volumes and the extent of late gadolinium enhancement (LGE) were collected. Systolic strain analysis was performed using feature tracking software. RESULTS: Left ventricular (LV) and right ventricular (RV) indexed diastolic volumes were 92.9 +/- 28.4 ml/m2 and 94.1 +/- 29 ml/m2, respectively. LV ejection fraction (EF) and RV EF were 56.8 +/- 10.7% and 53.7 +/- 10.7%, respectively. Global peak endocardial longitudinal, circumferential, and radial strain were -17.9 +/- 4.28%, -23.2 +/- 5.8%, and 32.8 +/- 10.6%, respectively. Compared to normal range, global longitudinal endocardial strain, longitudinal epicardial strain, circumferential endocardial strain, radial strain, and circumferential endocardial strain rate were impaired. Median volume of LGE was 0.25% (IQR 0.12-1.12) of the LV myocardium with highest prevalence in the inferolateral wall. Patients with cardiomyopathy diagnosis (n = 16) had lower LV strain rate compared to patients without cardiomyopathy (n = 20). CONCLUSIONS: CMR findings in young patients with aborted SCD due to non-ischaemic heart disease seem to be minor. Although only present in small amounts, LGE appears to have a predilection towards the inferolateral wall in this population. PMID- 30017271 TI - Isolated impact of liver herniation on outcome in fetuses with congenital diaphragmatic hernia - A matched-pair analysis based on fetal MRI relative lung volume. AB - PURPOSE: To evaluate liver-herniation as individual parameter on outcome in children with congenital diaphragmatic hernia. MATERIALS AND METHODS: In a retrospective matched-pair analysis based on observed to expected fetal lung volume (o/e FLV), birth weight, gestational age at time-point of examination, status of tracheal occlusion therapy and side of the defect the individual impact of liver-herniation on survival, need for extracorporeal membrane oxygenation (ECMO) therapy and chronic lung disease (CLD) was investigated. In total 61 pairs (122 patients) were included. Fisher's exact test was used to evaluate influence of liver-herniation and a p-value of <0.05 was defined as statistically significant. The study was approved by the local review board. RESULTS: Children with liver-herniation have lower survival rates (78.7% vs. 95.1%; p = 0.0073), need ECMO-therapy more often (41.0% vs. 16.4%; p = 0.0027) and are more likely to develop CLD (71.7% vs. 37.9%; p = 0.0004) than their corresponding matched-pair without liver-herniation. CONCLUSION: Liver-herniation itself and not further lung-volume restriction due to liver-herniation is responsible for poor outcome in CDH. PMID- 30017272 TI - Dynamic change of carotid intraplaque hemorrhage volume in subjects with mild carotid stenosis. AB - BACKGROUND AND PURPOSE: Early detection of intraplaque hemorrhage (IPH) in the carotid artery is important as it is correlated with an increased risk of cerebral ischemic events. We examined changes in IPH with magnetic resonance imaging (MRI) over an extended follow-up period in patients with mild carotid stenosis. MATERIALS AND METHODS: From November 2013 to November 2015, we retrospectively reviewed cerebral MRI of 2036 patients, including magnetization prepared rapid acquisition with gradient-echo (MPRAGE) sequences obtained with a 3.0 T (T) MRI unit. An experienced neuroradiologist reviewed all studies and found 38 patients with carotid IPH and carotid stenosis that were categorized as mild (<30%), according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Twenty-five patients agreed to join this study and signed informed consent for (MPRAGE) sequence imaging. We used semi-automated software to measure IPH volume on both the initial and follow up scans. RESULTS: The median follow-up time of patients with mild carotid stenosis and IPH was 33.3 months. IPH volume increased in 10 of 27 carotid arteries (37.0%), with a mean volume increase of 42.6 +/- 44.0 mm3. IPH volume decreased in 17 of 27 carotid arteries (63%), with a mean volume decrease of 17.2 +/- 22.8 mm3. Two patients without IPH at baseline showed IPH development on follow-up imaging. There were no significant differences in patient demographics between the two groups. CONCLUSIONS: Carotid IPH volume in subjects with mild carotid stenosis can change over time and may not be correlated with any typical patient demographics. PMID- 30017273 TI - Pediatric dual-energy X-ray absorptiometry in clinical practice: What the clinicians need to know. AB - The importance of childhood and adolescence for bone development and mineral accrual is increasingly accepted, leading to a need of suitable methods for monitoring bone health even in pediatric setting. Among the several different imaging methods available for clinical measurement of bone mineral density (BMD) in children, dual-energy X-ray absorptiometry (DXA) is the most widely available and commonly used due to its reproducibility, negligible radiation dose and reliable pediatric reference data. Nevertheless, DXA in children has some technical specific features that should be known by those physicians who interpret and report this examination. We provide recommendations for optimal DXA scan reporting in pediatric setting, including indications, skeletal sites to be examined, parameters to be measured, timing of follow-up BMD measurements. Adequate report and analysis of DXA examinations are essential to prevent over- and underdiagnosis of bone mineral impairment in pediatric patients. In conclusion, a complete and exhaustive DXA report in children and adolescents is mandatory for an accurate diagnosis and a precise monitoring of pediatric bone status. PMID- 30017274 TI - Robotic Insertion of Various Ablation Needles Under Computed Tomography Guidance: Accuracy in Animal Experiments. AB - OBJECTIVE: To evaluate the accuracy of robotic insertion of various ablation needles at various locations under computed tomography (CT) guidance in swine. MATERIALS AND METHODS: The robot was used for CT-guided insertion of four ablation needles, namely a single internally cooled radiofrequency ablation (RFA) needle (Cool-tip), a multi-tined expandable RFA needle (LeVeen), a cryoablation needle (IceRod), and an internally cooled microwave ablation needle (Emprint). One author remotely operated the robot with the operation interface in order to orient and insert the needles under CT guidance. Five insertions of each type of ablation needle towards 1.0-mm targets in the liver, kidney, lung, and hip muscle were attempted on the plane of an axial CT image in six swine. Accuracy of needle insertion was evaluated as the three-dimensional length between the target centre and needle tip. The accuracy of needle insertion was compared according to the type of needle used and the location using one-way analysis of variance. RESULTS: The overall mean accuracy of all four needles in all four locations was 2.8 mm. The mean accuracy of insertion of the Cool-tip needle, LeVeen needle, IceRod needle, and Emprint needle was 2.8 mm, 3.1 mm, 2.5 mm, and 2.7 mm, respectively. The mean accuracy of insertion into the liver, kidney, lung, and hip muscle was 2.7 mm, 2.9 mm, 2.9 mm, and 2.5 mm, respectively. There was no significant difference in insertion accuracy among the needles (P = .38) or the locations (P = .53). CONCLUSION: Robotic insertion of various ablation needles under CT guidance was accurate regardless of type of needle or location in swine. PMID- 30017275 TI - Image based simulation of the low dose computed tomography images suggests 13 mAs 120 kV suitability for non-syndromic craniosynostosis diagnosis without iterative reconstruction algorithms. AB - OBJECTIVES: The aim of this study was to simulate low dose paediatric head CT images with different noise levels corresponding to various tube current time product values and assess simulated image suitability in non-syndromic craniosynostosis diagnostics. METHOD: 29 paediatric patients who underwent head CT examinations for cranial deformity were enrolled in the study. The low dose CT images, corresponding to 120 kV and 120 mAs, 100 mAs, 80 mAs, 50 mAs and 13 mAs settings, were synthesised by adding noise to original data. Three researchers evaluated suitability for diagnostics of original and simulated images by using questionnaire assessing image suitability. RESULT: 174 separate cases (containing 1 axial and 1 3D image) were evaluated. Percentage of images evaluated as suitable for diagnosis were 98.9% on original images, 100% on 120 mAs, 100% on 100 mAs, 97.1% on 80 mAs, 96.6% on 50 mAs and 96% on 13 mAs. CONCLUSIONS: Images registered with 120 kV 13 mAs can be used to diagnose non-syndromic craniosynostosis with statistically same accuracy as with standard protocol and correspond to decrease of effective dose from 4.98 mSv to 0.33 mSv (median values). PMID- 30017276 TI - Longitudinal changes in magnetic resonance imaging of malignant and borderline tumors associated with ovarian endometriotic cyst comparing with endometriotic cysts without arising malignancy. AB - PURPOSE: To investigate magnetic resonance (MR) findings and to detect malignant transformation of ovarian endometriotic cysts by comparing longitudinal changes in patients with ovarian malignant/borderline tumors associated with ovarian endometriotic cysts (tumor group) with those of patients with endometriotic cysts (control group). METHODS: Tumor group patients (n = 10) had ovarian malignant/borderline tumors with pathologically confirmed association with endometriosis and available prior MRI of endometriotic cysts. Control group patients (n = 40) had been diagnosed more than two times as having ovarian endometriotic cysts by MRI examination. The tumor and solid portion sizes were measured. Two radiologists independently evaluated signal intensity (SI) of the cystic portion on both T1-weighted and T2-weighted images (WI), presence of shading on T2WI, and T2 dark spot sign in both groups and evaluate longitudinal changes of those findings. RESULTS: Pathological diagnoses of the tumor group were clear cell carcinoma (n = 6), endometrioid carcinoma (n = 1), serous carcinoma (n = 1), mucinous borderline tumor (n = 1), and endometrioid borderline tumor (n = 1). Tumor size had increased significantly in the tumor group (p = .004), but not in controls. Solid portions were identified in all cases only when neoplasms were suspected. Disappearance of shading during the follow-up period was observed more in tumor group (n = 2) than in the controls (n = 0). No significant difference was found between groups in the SI on T1 and T2WI, and T2 dark spot sign for the two MR examinations. CONCLUSIONS: The MR findings suggesting malignant transformation were emergence of a solid portion and increase in cyst size. Disappearance of shading also facilitates the follow-up of endometriotic cysts. PMID- 30017277 TI - Value of time-intensity curve analysis of contrast-enhanced ultrasound in the differential diagnosis of thyroid nodules. AB - OBJECTIVE: To assess the feasibility of time-intensity curve (TIC) analysis of contrast-enhanced ultrasound (CEUS) in demonstrating features of benign and malignant thyroid nodules. METHODS: CEUS images of 98 patients with 103 thyroid nodules were retrospectively analyzed. The final diagnosis was confirmed by histology after surgical excision, or cytology after fine needle aspiration (FNA). Among the benign nodules, which were confirmed using cytology and not surgically removed, those with a >50% cystic component that showed no changes for 1 year on follow-up US, were diagnosed as clinically benign nodules. Similarly, nodules with a <50% cystic component that were aspirated twice and showed no changes for 1 year on follow-up US were also regarded as clinically benign nodules. TIC parameters, including perfusion parameters of relative values (RV) of peak intensity (PI) (?PI), RV of rise time (?RT), RV of time to peak (?TTP), RV of maximum slope coefficient (MSC) of wash-in (?MSCWI), RV of area under the rising curve (?AUCR), clearance parameters of RV of area under the falling curve (?AUCF), RV of MSC of washout (?MSCWO), comprehensive parameters of RV of mean transit time (?MTT), and area under the falling curve (?AUCF) were observed. RESULTS: Compared with benign thyroid nodules, malignant nodules on TIC analysis of CEUS showed a lower ?PI (119.73 (115.34, 129.7), -15.82 (-17.7, -4.31)), later ?RT (-0.27 (-0.51, -0.2), 0.58 (-0.26, 0.65)) and ?TTP (-0.52 (-0.55, -0.36), 0.69 (-0.04, 0.74)), gentler ?MSCWI (6.18 (5.29, 7.44), -6.1 (-7.6, 2.14)), and smaller ?AUCR (75.7 (56.95, 93.22), -88.43 (-108.89, -73.21)) in perfusion parameters; a smaller ?AUCF (112.92 (87.77, 137.58), -75.55 (-105.28, -59.32)) in clearance parameters; and a smaller ?AUC (181.7 (151.50, 219.06), -160.64 ( 200.08, -144.11)), and an earlier ?MTT (2.00 (1.85, 3.14), -2.09 (-2.48, -0.95)) in comprehensive parameters (P < 0.05). Multivariate analysis of RV of TIC parameters demonstrated that ?MSCWI (OR = 0.112; 95% confidence interval [CI], 0.025-0.507) and ?MTT (OR = 0.099; 95% CI, 0.028-0.346) were protective factors. CONCLUSIONS: TIC of CEUS is a very promising and valuable technique for differentiating benign and malignant thyroid nodules. PMID- 30017278 TI - Comparison of screening performance metrics and patient dose of two mammographic image acquisition modes in the Danish National Breast Cancer Screening Programme. AB - INTRODUCTION: In this study, screening performance metrics and radiation dose were compared for two image acquisition modes for breast cancer screening with MAMMOMAT Inspiration (Siemens Healthcare GmbH, Forchheim, Germany). This mammography system can operate without an anti-scatter grid in place but using software scatter correction instead. This grid-less acquisition mode (PRIME) requires less patient dose due to the increase in primary radiation reaching the detector. This study retrospectively analyses data from the Region of Southern Denmark where the grid-less mode has been installed in November 2013 and replaced grid-based screening. METHODS AND MATERIALS: A total of 72,188 screening cases from the same geographical region in Denmark were included in the study. They were subdivided into two study populations: cases acquired before and after installation of the grid-less acquisition mode. Sensitivity and specificity of breast cancer screening were calculated for the two populations; thus representing the performance of grid-less and grid-based screening. To measure the entrance surface air kerma (ESAK) additional phantom tests were carried out. Polymethylmethacrylate (PMMA) attenuation plates with different thicknesses (20 70 mm in steps of 10 mm) simulated the compressed breast (21 mm-90 mm) and a solid-state dosimeter was used. RESULTS: Statistical testing of the results showed that screening with grid-less acquisition provides equivalent performance with respect to sensitivity and specificity compared to grid-based screening. The specificity was 98.11% (95% confidence interval (CI) from 97.93% to 98.29%) and 97.96% (95% CI from 97.84% to 98.09%) for screening with grid-less acquisition and grid-based acquisition, respectively. The cancer detection rate as a measure for sensitivity was equal (0.55%) for grid-less screening and grid-based screening. An average glandular dose saving between 13.5% and 36.4% depending on breast thickness in grid-less acquisition was obtained compared to grid-based acquisition. CONCLUSION: Statistically significant equivalence was shown with an equivalence margin of 0.12% points for cancer detection rate and with an equivalence margin of 0.40% points for specificity. A marked patient dose savings in grid-less acquisition of up to 36% compared to grid-based acquisition was achieved. It can be concluded that grid-less acquisition with software scatter correction is an alternative to grid-based acquisition in mammography. PMID- 30017279 TI - Dual layer computed tomography: Reduction of metal artefacts from posterior spinal fusion using virtual monoenergetic imaging. AB - INTRODUCTION: To evaluate the clinical potential of dual layer computed tomography (DLCT) for posterior fusions of the thoracic and lumbar spine and determine the optimal keV-settings for an improved overall image quality and effective reduction of metal artefacts affecting the implant inheriting vertebral body, the spinal canal, the paravertebral muscle and aorta. METHODS AND MATERIALS: Twenty patients with posterior thoracic and lumbar spinal fusion, who underwent a 120kVp- DLCT scan were included in this study. Two independent readers evaluated axial 0.9 mm slides with soft tissue and bone window settings. Image quality of the conventional scan was compared to virtual monoenergetic images (VMI) at 40, 60, 80, 100,120, 140, 160, 180 and 200 keV. Diagnostic image quality was assessed on a four point Likert-scale overall, as well as specifically for the implant inheriting bone, paravertebral muscle, spinal canal or aorta. The Hounsfield Units (HU) of the area with the most pronounced streak artefact as well as HU of a reference area containing fat and muscle were documented for each keV-setting and compared to the conventional image. SNR and CNR were calculated for each of the four anatomic areas. Statistical analysis was conducted for the total collective and separately for the thoracic and lumbar spine level. RESULTS: Starting from 80 keV qualitative analysis revealed significant improvement of overall image quality and benefit for each tissue separately compared to the conventional images (CI) (p-values in the range from <0.001 to 0.005). 180 keV was considered the optimal monoenergetic setting regarding the overall image quality. For the assessment of the implant inheriting bone, the spinal canal, paravertebral muscle and aorta 200, 180, 160 and 180 keV were rated to be the most sufficient. Our results reveal high inter-reader agreement for qualitative evaluations (intra-class correlation coefficients >0.927; p < 0.05). HU values within the most pronounced streak artefact increased significantly with higher keV (p < 0.001), while there was no significant alteration of HU within the reference area. A decrease in SNR and CNR for higher VMI was revealed by our results. CONCLUSION: VMIs of higher energies provide significant reduction of metallic artefacts from posterior spinal fusions. Dedicated keV settings to evaluate either the implant inheriting bone, the spinal canal,adjacent muscle or aorta - structures, which are frequently of particular interest after posterior spinal fusion - are recommended. In addition, an optimal keV for an improved overall image quality is proposed. PMID- 30017280 TI - Iodine quantification to distinguish hepatic neuroendocrine tumor metastasis from hepatocellular carcinoma at dual-source dual-energy liver CT. AB - PURPOSE: To investigate the value of third-generation dual-source dual-energy computed tomography (DECT) iodine quantification to distinguish hepatic neuroendocrine tumor (NET) metastasis from hepatocellular carcinoma (HCC) in non cirrhotic liver parenchyma. MATERIAL AND METHODS: Forty-six patients (mean age, 64.9 +/- 10.1 years; 28 male and 18 female) with either hepatic NET metastasis or HCC, who had undergone liver DECT, were included in this retrospective study. For each lesion, arterial-phase attenuation values and DECT quantitative parameters, including iodine uptake, fat fraction, normalized iodine uptake (NIU), and lesion to-liver-parenchyma ratio (LPR) were evaluated. Available cumulative data from histopathology, MRI, PET/CT, or interval imaging follow-up served as the reference standard for all liver lesions. In addition, the diagnostic accuracy of contrast-enhanced and material decomposition analysis for the differentiation of hepatic NET metastasis and HCC was assessed using receiver operating characteristics (ROC) curve analysis. RESULTS: Hepatic NET metastasis and HCC showed significant differences in arterial attenuation (P = 0.003), iodine uptake (P < 0.001), NIU (P < 0.001), and LPR (P = 0.003). No significant differences were found for unenhanced attenuation and fat fraction values (P = 0.686 and P = 0.892, respectively). NIU showed superior sensitivity (100%; iodine uptake, 71%), while both iodine uptake and NIU revealed superior specificity (100% and 90%, respectively) compared to LPR (sensitivity, 96%; specificity, 80%) and arterial attenuation analysis (sensitivity, 79%; specificity, 80%) (P <= 0.016). CONCLUSION: Third-generation DECT with assessment of iodine uptake improves the differentiation of hepatic NET metastasis and HCC in non-cirrhotic liver, with NIU showing the strongest diagnostic performance. PMID- 30017281 TI - Weekly enhanced T1-weighted MRI with Gadobutrol injections in MS patients: Is there a signal intensity increase in the dentate nucleus and the globus pallidus? AB - BACKGROUND AND PURPOSE: Gadolinium-based contrast agents (GBCAs) administration have drastically improved the accuracy of Multiple Sclerosis (MS) diagnosis by highlighting any damage to the brain blood barrier, thereby differentiating between active and non-active lesions. Following multiple administrations of GBCAs, several MS studies have reported a signal intensity (SI) increase on unenhanced T1-weighted images in certain brain regions such as the dentate nucleus (DN) and the globus pallidus (GP). Our aim was therefore to determine the accumulation of macrocyclic GBCAs on enhanced T1-weighted images SI in the DN and the GP of MS patients injected eight times. MATERIALS AND METHODS: Five MS patients underwent eight weekly consecutive MRI scans. Enhanced 3D T1-weighted images with Gadobutrol as a macrocyclic GBCA, were acquired. A ROI-based approach was applied for the evaluation of SI in the DN to middle cerebellar peduncle (DN MCP) and GP to semi-oval white matter (GP-SOWM) ratios. An analysis of variance on repeated measures was used for the statistical analysis of each ratio. RESULTS: No DN-MCP and GP-SOWM SI ratio differences were observed over the eight weeks period using the macrocyclic GBCA. CONCLUSION: Iterative and weekly injections of macrocyclic GBCAs are not associated with T1 signal increase in the DN and GP of MS patients. These results would suggest a no gadolinium accumulation in the brain using macrocyclic GBCA even after several close injections and promote the use of a macrocylcic GBCA rather than linear agents for MS patients. PMID- 30017283 TI - Bone marrow edema in traumatic vertebral compression fractures: Diagnostic accuracy of dual-layer detector CT using calcium suppressed images. AB - PURPOSE: To evaluate calcium suppressed images (CaSupp) in dual-layer detector computed tomography (DLCT) for the detection of bone marrow edema (BME) in vertebral fractures. MATERIALS AND METHODS: The retrospective study was approved by the institutional review board. 34 patients with synchronous DLCT and MRI, who were diagnosed with one or more acute vertebral fractures, were included. MRI were systematically analyzed as reference standard. Two blinded and independent readers evaluated CaSupp for vertebral BME. Additionally, both readers determined the optimal calcium suppression indices (CaSupp-I) for visualization of BME in consensus and correlated the CaSupp-I with parallel measurement of trabecular density as surrogate parameter for bone mineral density. ROI-based measurements of the contrast-to-noise ratios (CNR) were also conducted. Interrater agreement was determined by kappa-statistics. CNR were analyzed using Wilcoxon signed rank test. RESULTS: Fifty-seven acute fractured vertebrae out of 383 vertebrae (14.9%) were found. CaSupp yielded an average sensitivity of 87% and specificity of 99%, a positive predictive value of 95%, a negative predictive value of 98% and an accuracy of 97% for the detection of fracture-associated edema. Interrater agreement was excellent (kappa 0.91). Increase in CNR of BME correlated with increasing CaSupp-I. Edema adjacent to the cortical endplates was better visualized using CaSupp-I of 70 and 80, while extensive edema was better visualized using a CaSupp-I of 90 and 100 (chi2 < 0.0001). No correlation between optimal CaSupp-I and trabecular density was found (p > 0.2). CONCLUSION: CaSupp reconstructed from DLCT enable visualization and detection of BME in traumatic fractured vertebrae with high diagnostic accuracy using CaSupp-I of 70-100. PMID- 30017282 TI - Inter- and intra-observer repeatability of aortic annulus measurements on screening CT for transcatheter aortic valve replacement (TAVR): Implications for appropriate device sizing. AB - OBJECTIVES: To investigate intra- and inter-observer repeatability of aortic annulus CT measurements for transcatheter aortic valve replacement (TAVR) by readers with different levels of experience and evaluate the impact of different multi-reader paradigms to improve prosthesis sizing. METHODS: 82 TAVR screening CTAs were evaluated twice by three raters with six (R1 = radiologist), three (R2 = 3D-laboratory technician) or zero (R3 = medical student) years of experience. Results were translated into hypothetical TAVR size recommendations. Intra- and inter-observer repeatability between single readers and three different multi reader paradigms ([A]: two readers, [B]: three readers, or [C]: two readers + an optional third reader) were evaluated. RESULTS: Intra-observer variability did not differ significantly (range: 50.1-67.8mm2). However, we found significant differences in mean inter-observer variance (p = 0.001). Multi-reader paradigms led to significantly increased precision (lower variability) for scenarios [B] and [C] (p = 0.03, p < 0.05). Compared to single readers, all multi-reader strategies clearly lowered the rate of discrepant device size categorization between repeated measurements (22-26% to 5-10%). CONCLUSIONS: Aortic annulus CT measurements for TAVR are highly reproducible. Multi-reader strategies provide higher precision than evaluations from single readers with different levels of experience and could effectively be implemented with two readers and an optional third reader (Paradigm C) in a clinical setting. PMID- 30017284 TI - Decreased functional connectivity within the default-mode network in acute brainstem ischemic stroke. AB - PURPOSE: Ischemic stroke within the brainstem is associated with an increased risk of cognitive dysfunction. This study aimed to explore the integrity of a default-mode network (DMN) and its relationship with clinical variables in patients with acute ischemic brainstem stroke using an independent component analysis (ICA) approach. MATERIALS AND METHODS: Twenty-one patients with acute ischemic brainstem stroke and 25 well-matched healthy subjects were enrolled in this study and underwent resting-state functional magnetic resonance imaging. The ICA was adopted to extract the DMN, including its anterior and posterior components. Pearson correlation analyses were performed to investigate the relationship between DMN connectivity and clinical variables. RESULTS: Compared with healthy controls, patients with acute ischemic stroke showed significantly decreased functional connectivity in the right medial prefrontal cortex (mPFC) and right precuneus within the anterior and posterior DMN, respectively. After correcting for age, sex, and education, hypoconnectivity in the right mPFC and right precuneus was negatively correlated with higher homocysteine in patients with stroke (r = -0.592, p = 0.010 and r = -0.491, p = 0.039, respectively). CONCLUSION: The finding of decreased functional connectivity within the DMN of patients with acute brainstem stroke provides novel insight into the neural mechanisms that underlie cognitive impairment following ischemic insult to this brain region. PMID- 30017285 TI - Articular and peri-articular hip lesions in soccer players. The importance of imaging in deciding which lesions will need surgery and which can be treated conservatively? AB - Soccer is one of the most popular sports worldwide engaging millions of participants each year. During play, injuries occur rather frequently and most of them involve the hip joint and the surrounding structure. In professional athletes, injuries are often complex scenarios and in the case of misdiagnosis, patients' return to play is delayed or it may progress to a more serious injury with consequent damage for their career and for the soccer team. The most frequent articular pathologies are Femoro-acetabular impingement and labral tears. Stress fracture, avulsion, ischiofemoral impingement, subspine impingement, athletic pubalgia, muscle injuries and Morel-Levallee lesion are the most frequent hip peri-articular pathologies whereas snapping hip may be both intra- or extra-articular pathology. With an increasing number of football players, the radiologist plays a crucial role in the detection and characterization of the extent of the injuries. This article reviews the current imaging concepts frequently seen in injuries around the hips of professional football players focusing in particular on the most suitable therapeutic approaches, whether surgical or conservative. PMID- 30017286 TI - Urologic tumor imaging. PMID- 30017287 TI - Quantitative volume-based morphometry in focal cortical dysplasia: A pilot study for lesion localization at the individual level. AB - PURPOSE: Surgical resection is the most effective treatment for focal cortical dysplasia (FCD). However, many patients with FCD have unremarkable or even negative findings on conventional magnetic resonance imaging (MRI). In this study, we explored the brain volume abnormalities of FCD patients at the individual level using an experimental volume-based morphometry algorithm and further estimated whether the volume abnormalities can help in the detection of FCD lesions. MATERIALS AND METHODS: Sixteen patients with histologically-proven FCD lesions were retrospectively studied. Among them, eight patients had no visible abnormalities on routine MRI, three had abnormalities which partly matched the location of the surgical resection regions, and two did not match. For each patient, cerebral high-resolution T1-weighted magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images were segmented into 45 structures, according to a brain anatomy template, and the volume of each structure was compared with an age- and gender-matched normal population at the individual level, based on a MorphoBox prototype. A Receiver Operating Characteristics (ROC) curve was used to evaluate the performance of the prototype in patients. To find the most appropriate threshold value for localizing the epileptogenic zones, deviations from the normative ranges of each resulting volume estimate were assessed by z-scores. RESULTS: Volume abnormalities including atrophic and hypertrophic volumes could be found in all the patients. Epileptogenic zones were found in brain structures with an abnormal volume in 87.5% (14/16) of patients. In 71.4% of patients (10/14), these zones were fully located in regions with an atrophic volume. This suggests that FCD lesions are more likely to be in regions with an atrophic volume than in those with a hypertrophic volume. When the best cut-off z-score value was -3.0, the sensitivity, specificity, and ROC area under the curve of the volume estimates were 93.9%, 79.6%, and 0.89, respectively. CONCLUSION: Volume abnormalities can assist in the diagnosis of epileptogenic zones at the individual level in FCD patients with negative or positive findings on conventional MR images. Atrophic regions are more likely than hypertrophic ones to represent epileptogenic zones. Volume-based morphometry based on a MorphoBox prototype has potential to assist a careful scrutiny by radiologists with target in atrophic regions in patients who are initially deemed to be MR-negative, further trying to increase the detection rate of FCD. PMID- 30017288 TI - The past, present and future role of artificial intelligence in imaging. AB - Artificial intelligence (AI) is already widely employed in various medical roles, and ongoing technological advances are encouraging more widespread use of AI in imaging. This is partly driven by the recognition of the significant frequency and clinical impact of human errors in radiology reporting, and the promise that AI can help improve the reliability as well the efficiency of imaging interpretation. AI in imaging was first envisioned in the 1960s, but initial attempts were limited by the technology of the day. It was the introduction of artificial neural networks and AI based computer aided detection (CAD) software in the 1980s that marked the advent of widespread integration of AI within radiology reporting. CAD is now routinely used in mammography, with consistent evidence of equivalent or improved lesion detection, with small increases in recall rates. Significant false positive rates remain a limitation for CAD, although these have markedly improved in the last decade. Other challenges include the difficulty clinicians encounter in trying to understand the reasoning of an AI system, which may limit their confidence in its advice, and a question mark hangs over who should be liable if CAD makes an error. The future integration of CAD with PACS promises the development of more comprehensively intelligent systems that can identify multiple, challenging diagnoses, and a move towards more individualised patient outcome predictions based upon AI analysis. PMID- 30017289 TI - Urolithiasis: Comparison of diagnostic performance of digital tomosynthesis and ultrasound. Which one to choose and when? AB - OBJECTIVE: To assess the diagnostic performance of digital tomosynthesis (DT) in detecting urolithiasis and compare it with ultrasonography (USG), keeping standard volumetric multi-detector computed tomography (MDCT) as the reference. MATERIALS AND METHODS: This prospective analytical study was approved by our institutional ethical committee. A total of 66 patients were enrolled who had either clinical suspicion of urolithiasis or history of recurrent urolithiasis. All patients underwent DT, USG and MDCT within 24 h. In all these three investigations, the calculi were categorised according to their location and size by two radiologists. Sensitivity, specificity, positive and negative predictive values of DT and USG were calculated with MDCT as a reference standard. RESULTS: Our study comprised of 66 patients (36 males and 30 females with age range of 19 73 years). A total of 121 calculi were assessed with 52 calculi <5 mm in size, 32 calculi measuring 5-10 mm and 37 calculi >10 mm. Kappa test of agreement was used to assess the interobserver agreement for all observations. The measurement of agreement kappa value was 1. The overall sensitivity of DT and USG in detecting urolithaisis was 50% (p value <0.001) and 50.4% (p value 0.005) respectively. No statistically significant difference was noted between USG and DT in detecting urolithiasis. The sensitivity of DT and USG in detecting renal calculi was 47.1% and 50.9% respectively and the sensitivity of DT and USG in detecting ureteric calculi was 74.9% and 39.2% respectively. We observed statistically significant difference between USG and DT in detecting ureteric calculi. CONCLUSION: In our study, there was no statistically significant difference noted between USG and DT in diagnosis of urolithiasis. DT performed significantly better than USG in detecting ureteric calculi with a higher sensitivity. Hence, we are tempted to opine that DT may be preferred over USG for initial evaluation of patients with suspected ureteric calculi. However considering the strength of ultrasound in demonstrating associated signs as hydroureteronephosis, we are still of the opinion, that both DT and USG should be used as complementary techniques in resolving these common clinical screnarios. PMID- 30017290 TI - Clinical validation of a pressure-standardized compression mammography system. AB - OBJECTIVES: Validation of a pressure-standardized compression mammography (PSCM) system, which aims to reduce discomfort and pain by applying the same pressure to every breast, independent of breast size. METHODS: We retrospectively studied mammograms of 39 patients acquired with a conventional force-standardized compression mammography (FSCM) technique and intra-individually compared them to mammograms acquired on a checkup visit with PSCM technique. Patients received one craniocaudal (CC) and one mediolateral oblique (MLO) compression for both breasts. All images were processed to obtain the contact area between the breast and the compression paddle. The pressure was calculated by dividing the compression force by the contact area. RESULTS: A total of 150 FSCM and 150 PSCM images were analyzed. The mean pressure decreased significantly from 17.1 to 12.8 kPa (p < 0.001), when using PSCM instead of FSCM. The applied pressure hardly depended on the breast contact area with the paddle (-0.014 kPa/cm2), while a clear dependency was observed using FSCM. Furthermore, the relative number of over-compressions reduced from 26% to 2%, benefitting patients with smaller breasts. CONCLUSIONS: Our study suggests that using PSCM can reduce patient discomfort and pain during mammographic compression compared to conventional FSCM as a result of lower average pressure. Moreover, standardized pressure may provide a more constant image quality, which could improve diagnostic performance. PMID- 30017291 TI - Dual-energy CT-based iodine quantification to differentiate abdominal malignant lymphoma from lymph node metastasis. AB - PURPOSE: To investigate the value of dual-energy computed tomography (DECT) derived iodine and fat quantification in differentiating malignant abdominal lymphoma from lymph node metastasis. MATERIALS AND METHODS: In this retrospective study, 59 patients (39 men; mean age, 62.7 years) with histopathologically confirmed diagnosis of either malignant lymphoma or lymph node metastasis were included. For each lesion, contrast-enhanced attenuation, as well as DECT-derived iodine density and fat fraction measurements were recorded. Mean attenuation and material density values were compared between malignant lymphomas and lymph node metastases. The receiver operating characteristic (ROC) curve analysis was adopted to estimate the optimal threshold for discriminating between both entities. A control group (n = 60) was analyzed for comparison of attenuation and material density values of normal abdominal lymph nodes. RESULTS: Assessment of DECT-derived iodine density and fat fraction values revealed significant differences between lymph node metastases (1.7 +/- 0.4 mg/ml and 15.5 +/- 7.3%) and malignant lymphomas (2.5 +/- 0.5 mg/ml and 26.7 +/- 12.2%) as well as normal lymph nodes (2.4 +/- 0.8 mg/ml and 24.1 +/- 10.8%) (P <= 0.013). An iodine concentration of 2.0 mg/ml represented the optimal threshold to discriminate between lymphoma and lymph node metastasis (sensitivity, 87%; specificity, 89%). Moreover, a significant correlation was found between iodine concentration and fat fraction for both lymphomas and lymph node metastases (P = 0.001). CONCLUSION: DECT enables characterization of abdominal masses as derived iodine and fat fraction values differ significantly between malignant abdominal lymphomas and lymph node metastases. PMID- 30017292 TI - Assessment of the degree of abdominal myosteatosis by magnetic resonance imaging in subjects with diabetes, prediabetes and healthy controls from the general population. AB - OBJECTIVES: Intra- and intermyocellular lipid deposition and adipose tissue are part of glucose homeostasis and insulin resistance; however, their role in type 2 diabetes mellitus (T2DM) remains unclear. We assessed differences in the degree of abdominal myosteatosis among subjects with T2DM and prediabetes. MATERIALS AND METHODS: Asymptomatic subjects from the general population were classified as subjects with T2DM, prediabetes or healthy controls and underwent multi-echo Dixon magnetic resonance imaging (MRI) (TR 8.90 ms, six echo times, flip-angle 4 degrees ). Abdominal myosteatosis was quantified as proton-density fat-fraction (PDFFmuscle) by a standardized segmentation-algorithm. Cardiometabolic risk factors were prospectively obtained in a comprehensive health assessment and visceral and subcutaneous adipose tissue (VAT and SAT) were quantified semi automatically. Uni- and multivariate quantile regression were used to examine associations. RESULTS: Among 349 included subjects (mean age: 56.0 +/- 8.0years, 56.7% males), 45 were classified as subjects with T2DM and 84 with prediabetes (12.9% and 24.1%; respectively). Median PDFFmuscle was significantly higher in subjects with T2DM and prediabetes compared to healthy controls (13.1% (IQR10.5 16.6%); 11.1% (IQR8.9-15.0%) and 10.1% (IQR7.5-13.3%); respectively, p < 0.001). The observed differences were independent of age and gender (all p < 0.002) but attenuated after adjustment for BMI (beta: -0.02, 95%CI: -1.49 to 1.44, p = 0.974; beta: 0.47, 95%CI: -0.91 to 1.86, p = 0.506; prediabetes and T2DM, respectively). This effect was attributable to VAT, which remained independently associated with PDFFmuscle after full adjustment (beta: 0.01, 95%CI: 0.01-0.02, p = 0.002). CONCLUSIONS: There are significant differences in the degree of abdominal myosteatosis between subjects with T2DM, prediabetes and healthy controls, that may be confounded by VAT. However, abdominal myosteatosis by MRI might serve as a cardiometabolic imaging-biomarker, specifically in the setting of impaired glucose metabolism. PMID- 30017293 TI - Kienbock's disease: Role of cross-sectional imaging in treatment choice and patient follow-up. AB - The management of Kienbock's disease is complex and constantly evolving in parallel with progress in the understanding of the pathophysiological mechanisms of this condition. Cross-sectional imaging techniques have an essential role in the diagnosis and prognostic assessment of this disease. CT allows the optimal study of the morpho-structure of lunate bone. MRI makes it possible to study bone marrow viability. As for CT arthrography, it allows to evaluate accurately articular cartilage of the different carpal joints. The evaluation of these different aspects of Kienbock's disease is essential for optimal treatment selection. Cross-sectional imaging also has an interest in post-treatment follow up, by having a prognostic value and allowing the identification of post operative complications. The purpose of this article is to review the contribution of cross-sectional imaging in the assessment of Kienbock's disease before and after treatment according to the most common surgical procedures. Pathophysiological mechanisms, predisposing factors, the different classifications and their interests will be discussed. PMID- 30017294 TI - Endometrial cancer after radiation therapy for cervical carcinoma: A radiological approach. AB - Clinical and pathological aspects of endometrial cancers that develop after radiation therapy for cervical carcinoma have been studied for years but their imaging features have not yet been described. To determine these features, we performed a retrospective study that included all patients of our institution that were diagnosed with an endometrial cancer after being submitted to radiation therapy for cervical cancer and that performed computed tomography (CT) or magnetic resonance (MR) imaging at the time of the diagnosis, in a period of 11 years. We found 13 patients meeting these inclusion criteria. A wide range of morphologies were observed: single solid tumors (46%); single mixed tumors (15%); large heterogeneous multifocal tumors (15%) and multifocal small polypoid tumors (15%). Large tumors were frequent at presentation, with 65% of the lesions measuring more than 5 cm (mean, 7.4 cm; range, 1.2-14.9 cm). Hematometra was a striking feature that was present in 85% of the cases, with a mean volume of 318 mL and was associated in 91% of the cases with cervical stenosis, a known complication of pelvic radiotherapy that could justify a delay in symptoms presentation. Post-radiotherapy changes and hematometra limited the utility of MR imaging in local staging. Distant metastases could be promptly diagnosed with CT or MR imaging and were observed in 42% of the patients. These rare heterogeneous tumors should be considered after radiotherapy for cervical carcinoma, especially when hematometra is observed. Aggressive histological presentations and delayed symptoms due to cervical stenosis are responsible for an unfavorable prognosis. PMID- 30017295 TI - 18F-FDG PET-MRI with T1 MOLLI mapping to detect systemic sclerosis bowel inflammation and fibrosis. AB - BACKGROUND: Systemic sclerosis-associated gastrointestinal tract involvement (SSc GIT) is an independent predictor of 2-year mortality in early SSc. Availability of non-invasive investigations will facilitate early diagnosis and monitoring. HYPOTHESIS: We investigate the role of 18F-FDG-PET-MRI in SSc-GIT, hypothesizing that i) higher bowel FDG-PET uptake, a surrogate biomarker for inflammation, distinguishes healthy bowel from inflamed SSc-GIT; ii) MRI T1-MOLLI mapping, a surrogate biomarker for cardiac fibrosis, distinguishes healthy bowel from fibrotic SSc-GIT. METHODS: In this prospective study, 16 SSc patients and 15 healthy controls were recruited. All SSc patients and 5 controls underwent PET MRI (with T1-MOLLI mapping) on a Siemens 3T mMR; 10 controls underwent MRI without PET. Manual segmentation of the large and small bowels was performed jointly by two trained analysts in order to report T1 and PET values. Control dataset was used to assess normal healthy range. Mean T1 values, mean Tissue-to Background (TBR) PET values, as well as amount of supposedly abnormal bowel (measured using the healthy ranges) was compared using Student's t-test and Cohen's d effect size. RESULTS: Mean T1 values in large (1113 +/- 182 ms vs 856 +/- 176 ms; p-value < 0.001) and small bowel (1331 +/- 239 ms vs 1169 +/- 118 ms; p = 0.02) were higher in SSc patients than controls. 87.5% of the SSc patients' bowel had at least a grade 3 segmental FDG-PET uptake, while no controls showed more than a grade 2 segmental uptake. Patients had higher large bowel mean PET TBR (1.12 +/- 0.22) than controls (0.82 +/- 0.20, p = 0.02). Using PET and T1 thresholds defined using the control PET-MR data, the percentage of supposedly healthy (non-fibrotic and non-inflamed) tissue was significantly lower in SSc patients (81.1 +/- 13.1%) than controls (95.7 +/- 3.1%, p = 0.03) for the large bowel. CONCLUSION: Our novel study of FDG-PET-MRI in SSc-GIT demonstrated promising results in non-invasively evaluating concurrently bowel inflammation and fibrosis. PMID- 30017296 TI - Indication of whole body computed tomography in pediatric polytrauma patients Diagnostic potential of the Glasgow Coma Scale, the mechanism of injury and clinical examination. AB - OBJECTIVE: To evaluate the diagnostic potential of the Glasgow Coma Scale (GCS), the mechanism of injury (MOI) and clinical examination (CE) for the indication of whole body computed tomography (WBCT) in pediatric polytrauma patients. MATERIALS & METHODS: 100 pediatric polytrauma patients with WBCT were analysed in terms of age, gender, (MOI), GCS, detected injury, FAST, CE and Injury Severity Score (ISS). Correlations between all clinical variables and patient groups with (p+) and without (p-) injury were assessed. RESULTS: Mean age was 9.13 +/- 4.4 years (28% female patients). Injury was detected in 71% of the patients, most commonly of the head (43%). There was no significant correlation between type or severity of MOI and ISS (p > 0.1). None of the clinical variables had a significant predictive effect on p+. The optimum discrimination threshold of GCS was at 12.5 relating to craniocerebral injuries. Severity of MOI and FAST showed best predictive effects on thoracic and abdominal pathologies, respectively, but with only low sensitivities (<20%). CONCLUSION: There is no clinical variable, which can be used as sole indication for WBCT in pediatric polytrauma patients. GCS had a significant predictive value for craniocerbral injuries and CCT is recommended at GCS <= 13. PMID- 30017297 TI - Contrast-enhanced ultrasound for characterizing renal masses. AB - On cross-sectional imaging studies performed for other indications, incidental discovery of renal lesions is not uncommon. In daily use, grey-scale ultrasonography (US) and conventional Doppler modes are often the modality of choice for the initial assessment. While simple cysts are fully characterized with US, other lesions require further characterization, which is traditionally obtained by multiphase imaging, such as contrast-enhanced CT and MRI. Contrast enhanced ultrasound (CEUS) has become a powerful additional tool for imaging renal lesions. With its lack of nephrotoxicity, the absence of ionizing radiation, and the ability to evaluate the enhancement pattern of renal lesions quickly and in real- time, CEUS has unique advantages over traditional modes. Established applications are differentiation between solid tumours, pseudolesions, and complex cysts; characterization of complex cysts with different malignant potential, and evaluation of tumor ablation. Microbubble contrast agents are safe. Adverse reactions are rare. This article provides an overview of the current clinical applications of CEUS in characterizing renal masses, discussing advantages and limitations. The aim is to provide the framework for sonologists to make informed decisions regarding this emerging imaging test in appropriate circumstances. PMID- 30017299 TI - The epidemiology of MRI-detected pelvic injuries in athletes in the Rio de Janeiro 2016 Summer Olympics. AB - OBJECTIVE: To describe the prevalence, severity and location of pelvic injuries, including hip, muscle and tendon pathologies, as assessed on MRI in athletes participating in the Rio de Janeiro 2016 Summer Olympic Games. METHODS: We analyzed all pelvic MRIs that were acquired for suspected injury as reported by the National Olympic Committee (NOC) medical teams and the Organizing Committee medical staff during the Rio 2016 Summer Olympics. Diagnostic imaging was performed through the Olympic Village Polyclinic, using 3 T and 1.5 T MR scanners. Images were interpreted retrospectively according to standardized criteria. RESULTS: A total of 11,274 athletes participated in the Games, of which 40 (0,4%) were referred for a pelvic MRI. Thirty-seven of the 40 (92%) had at least one abnormal finding, and some had as many as 17, for an average of 4.1 pathologies per examination. Almost half of all abnormal findings were assessed as pre-existing (46%). The majority of acute/subacute injuries were observed in track and field athletes (44%), whereas the highest number of pre-existing findings was seen in ball-sports athletes (39%). Forty-seven per cent of all acute/subacute injuries were muscle injuries with the gluteus maximus muscle the most commonly affected. In contrast, most pre-existing findings were detected at the symphysis (59%). CONCLUSION: Our study demonstrated a high prevalence of both acute/subacute injuries and chronic changes in Olympic athletes undergoing pelvic MRI. Muscle injuries were the most common acute injuries, found mainly in track and field athletes. Most chronic changes were identified at the symphysis region in ball-sports athletes. PMID- 30017298 TI - Tumor thrombus in the large veins draining primary pelvic osteosarcoma on cross sectional imaging. AB - PURPOSE: To evaluate the frequency of tumor thrombus in the large veins draining primary pelvic osteosarcoma on early cross-sectional imaging studies and its effect on patient survival. MATERIALS AND METHODS: Our retrospective study included all patients with primary pelvic osteosarcoma treated at our facility between January 2000 and May 2014, who were <= 45 years of age, and had adequate imaging studies and clinical follow up. Four radiologists evaluated for tumor in the large draining veins on initial CT, MRI and PET/CTs. A consensus evaluation by the four radiologists together with findings on operative reports, pathology reports or follow-up imaging was used as the reference standard. RESULTS: Thirty nine patients with primary pelvic osteosarcoma met final inclusion criteria. Tumor thrombus was identified in the large draining veins in 10 of the 22 (45%) patients who underwent tumor resection and 10 of the 17 (59%) who did not. In the 22 patients who underwent tumor resection, tumor thrombus was significantly associated with worse overall survival (p = 0.03). CONCLUSIONS: Tumor thrombus in the large draining veins is identified in a significant proportion of initial imaging studies in patients with pelvic osteosarcoma, and is associated with worse overall survival in patients who undergo tumor resection. PMID- 30017300 TI - Preoperative histogram analysis of intravoxel incoherent motion (IVIM) for predicting microvascular invasion in patients with single hepatocellular carcinoma. AB - PURPOSE: To evaluate the value of intravoxel incoherent motion (IVIM) histogram analysis based on whole tumor volume in predicting microvascular invasion (MVI) of single hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The study enrolled 41 patients with pathologically proven HCCs who underwent IVIM diffusion weighted imaging with nine b values and contrast-enhanced magnetic resonance imaging (MRI). Histogram parameters including mean; skewness; kurtosis; and percentiles (5th, 10th, 25th, 50th, 75th, 90th, 95th) were derived from apparent diffusion coefficient (ADC), perfusion fraction (f), true diffusion coefficient (D), and pseudo diffusion coefficient (D*). Quantitative histogram parameters and clinical data were compared between HCCs with and without MVI. For significant parameters, receiver operating characteristic (ROC) curves were further plotted to compare the diagnosis performance for identifying MVI. RESULTS: The mean, 5th, 10th, 25th, 50th, and 75th percentiles of D, and the 5th, 10th, and 25th percentiles of ADC between HCCs with and without MVI were statistically significant (all P<0.05). The histogram parameters of D* and f showed no statistically significant differences between HCCs with and without MVI (all P>0.05). The areas under the ROC curves (AUCs) were 0.707-0.874 for D and 0.668 0.720 for ADC. The largest AUC of D (5th percentile) showed significantly higher accuracy than that of ADC or tumor size (P = 0.009-0.046). With a cut-off of 0.403 * 10-3 mm2/s, the 5th percentile of D value provided a sensitivity of 81% and a specificity of 85% in the prediction of MVI. CONCLUSIONS: Histogram analysis of IVIM based on whole tumor volume can be useful for predicting MVI. The 5th percentile of D was most useful value to predict MVI of HCC. PMID- 30017301 TI - Pelvic MRI staging of endometriosis at 3 T without patient preparation or anti peristaltic: Diagnostic performance outcomes. AB - PURPOSE: Endometriosis is a disease of significant burden among pre-menopausal women characterised by the appearance of functional endometrial tissue in locations outside the uterus. Deep infiltrating endometriosis (DIE) is an invasion of the endometriotic lesion that exceeds 5 mm in depth into the peritoneum. In most cases, pelvic MRI is the imaging modality of choice for the pre-operative workup for DIE to guide surgery. The recommended standard for pelvic MRI images is at 1.5 T with patient preparations in the form of laxatives, anti-spasmodics and/or rectal contrast. However, there appears to be equally diagnostic quality imaging obtainable with a 3 T system using fast imaging acquisition without any patient preparation. This reduces imaging time, movement artefacts, is more comfortable for the patient and is easier for workflow coordination. This study aims to confirm that this approach reaches diagnostic performance outcomes comparable to reported international standards, particularly in the detection of endometriotic bowel lesions, in order to guide surgical pre operative planning. METHODS AND MATERIALS: Pre-operative diagnostic radiology reports were identified by a search of the Radiology Information System (RIS) for all pelvic MRI studies performed at a tertiary referral centre, King Edward Memorial Hospital for Women, between January 2015 to April 2017 that contained the keyword "endometriosis". Reported sites of endometriotic deposits at MRI findings were tallied based on anatomical location and correlated to laparoscopic surgical report findings and/or pathology report as a reference standard. Pooled sensitivities and specificities were then calculated and compared with established studies. RESULTS: Ninety-eight MRI studies were identified, of which 76 identified DIE and 22 were normal studies. Sixty-one patients did not have a surgical or pathology record. Of the remainder who underwent laparoscopy, operative and/or pathology reports were obtainable in 37 female patients, with a median age of 35 years (range: 24 to 49 years). The average time interval from MRI report to surgical operation was 195 days (range: 5 to 563 days). Middle compartment estimated sensitivity was 79.4% (95% CI = (69.4%, 89.4%)), specificity 95.1% (95% CI = (91.2%, 98.9%)). Posterior compartment estimated sensitivity was 76.5% (95% CI = (66.4%, 86.6%)), specificity 99.4% (95% CI = (98.1%, 100%)). Overall sensitivity 76.9% (95% CI = (69.7%, 84.0%)), specificity 98.5% (95% CI = (97.3%, 99.6%)). Sensitivity and specificity of detecting bowel endometriosis were estimated to be 94.4% (95% CI = (83.9%, 100%) and 94.7% (84.7%, 100%)) respectively. CONCLUSION: Using a 3 T MRI system without patient preparation is feasible and achieves benchmark diagnostic performance outcomes in the pre-operative assessment for DIE, especially in detecting posterior compartment lesions and bowel DIE to correctly guide surgical planning. PMID- 30017302 TI - Multiple solid pancreatic lesions: Prevalence and features of non-malignancies on dynamic enhanced CT. AB - OBJECTIVE: To determine the prevalence of multiple solid pancreatic lesions on dynamic enhanced CT performed for suspected pancreatic diseases, and to identify CT features of non-malignancies. METHODS: We investigated 8096 consecutive patients who underwent dynamic enhanced CT pancreas protocol at a tertiary center over 40 months. The final clinical /pathological diagnosis served as reference standard. The diagnostic accuracy of dynamic enhanced CT for non-malignancies was calculated. A univariate and multivariate analysis was conducted to identify features that predict non-malignancies. RESULTS: Multiple solid pancreatic lesions were identified in 121 patients. The prevalence of non-malignancies was 19.8% (24/121). The most common non-malignancy was autoimmune pancreatitis (n = 21; 17.4%). Common lesions with malignant potential included neuroendocrine neoplasia (n = 62; 51.2%), ductal adenocarcinoma (n = 15; 12.4%), metastasis (n = 9; 7.4%), and lymphoma (n = 7; 5.8%). Dynamic enhanced CT had a sensitivity of 79.2% and a specificity of 92.8% for diagnosing non-malignancies. Elevated serum IgG4 level (p < 0.001), hypo-enhancement in arterial phase (p = 0.001), hyper enhancement in equilibrium phase (p = 0.009) and location in both proximal and distal pancreas (p = 0.036) were predictors of non-malignancies, whereas pancreatic duct morphology and vascular invasion status were not. CONCLUSION: Multiple solid pancreatic lesions were rare, with a wide spectrum. Dynamic enhanced CT provides clues for identifying non-malignancies. PMID- 30017303 TI - Spinal cellular schwannoma: An analysis of imaging manifestation and clinicopathological findings. AB - OBJECTIVES: Cellular schwannoma that occurs in the spine is relatively rare. Herein, we retrospectively analyzed the clinical and imaging data from nine cases of spinal cellular schwannoma. MATERIALS AND METHODS: The clinical, imaging data and pathological manifestations were retrospectively analyzed from nine cases of pathologically confirmed spinal cellular schwannoma. RESULTS: All nine cases were treated with surgical excision; seven cases were solitary lesions characterized by a dumbbell-shaped soft tissue mass growing out across the intervertebral foramen and two cases were multiple nodular lesions in the spinal canal. Six cases had compressive bony destruction, one case displayed osteolytic and compressive bony destruction, and two cases were without apparent bony destruction. Computed Tomography (CT)scans showed three cases were isodense and two cases were miscellany density. Magnetic Resonance Imaging (MRI) scans showed that the solid part of the tumor was isointense on the T1-weighted imaging (T1WI); five cases were isointense and three cases were slightly hyperintense on T2-weighted imaging (T2WI). Five cases exhibited hyperintense cystic regions. MRI enhanced scanning showed that 3/7 cases showed moderately to markedly heterogeneous enhancement and the remaining 4/7 cases showed markedly homogeneous enhancement. Except for one recurrence, 8/9 cases had a good prognosis. CONCLUSION: Spinal cellular schwannoma should be diagnosed combining the imaging manifestation with clinical performance and pathological examination in order to distinguish it from other tumors, such as classical schwannoma and malignant peripheral nerve sheath tumors. PMID- 30017304 TI - Inter-reader agreement of CT features of acute mesenteric ischemia. AB - PURPOSE: To evaluate the inter-reader agreement of the CT features of acute mesenteric ischemia (AMI). METHODS: Between 2006 and 2014, 109 patients (57 men, 52%, mean age 50 years old [17-83]) admitted to our institution with a diagnosis of AMI were included. CT scans (42% were initially performed in our institution) were reviewed by two abdominal radiologists. Inter-observer agreement of the imaging features of vascular insufficiency and bowel ischemia was assessed by the percentage of agreement and the kappa value. RESULTS: The final population included, Inter-observer agreement varied according to the different features (kappa = 0.25-0.98). Inter-observer agreement for decreased/absent bowel wall enhancement was moderate (kappa = 0.52), but was almost perfect (kappa = 0.82) in the 47 patients (43%) with both unenhanced and arterial-phase images without positive oral contrast agent and excellent CT images quality. CONCLUSION: Inter reader agreement was moderate to substantial for most CT features of AMI. Multiphasic CT scan protocol, including unenhanced, arterial phase and venous phase images, without positive oral contrast agent, and excellent CT images quality improve inter-observer agreement of imaging features of AMI, especially for decreased/absent bowel wall enhancement, and should be performed in patients with suspected AMI. PMID- 30017306 TI - FRIEND or FOE: A prospective evaluation of risk factors for reintubation in surgical and trauma patients. AB - BACKGROUND: A Form for Re-Intubation Evaluation by Nurses and Doctors (FRIEND) was used to prospectively collect pre-extubation data, to determine failure of extubation (FOE) risk. METHODS: FRIENDs, including airway, breathing, and neurologic variables, were completed before extubation on trauma & surgical patients in one ICU from 1/1/16 to 5/31/17. Those with failed vs. successful extubation were compared. We excluded those with tracheostomy, comfort measures, or death before extubation. RESULTS: There were 464 eligible extubations in 436 patients. Thirty five reintubations (7.9% FOE rate) occurred in 32 patients within 96 h of extubation. FOE patients had higher ICU days (6 d vs. 2 d), ventilator days (6 d vs. 2 d), and mortality (15.6% vs. 2.7%) [all p < 0.001] compared to those without FOE. Odds of FOE (OR [CI]) increased with age (1.03, [1, 1.06]), delirium (3, [1.16, 7.76]), moderate/copious secretions (3.95, [1.46, 10.66]), and enteral opioid use (4.23, [1.28, 14.02]). CONCLUSIONS: Several characteristics present at the time of extubation were risk factors for FOE in trauma and surgical patients. Patients with FOE had higher mortality. PMID- 30017305 TI - Ablation treatment of primary and secondary liver tumors under contrast-enhanced ultrasound guidance in field practice of interventional ultrasound centers. A multicenter study. AB - The present retrospective study was aimed at characterizing the clinical impact of contrast-enhanced ultrasound (CEUS) as a guidance technique for ablation of primary and secondary liver tumors at six interventional ultrasound centers. 148 patients (103M/45F, median age 74 yrs.) with 151 liver target lesions (median size 15 mm, 86.7% Hepatocellular Carcinomas) in whom CEUS guidance was used for Percutaneous Ethanol Injection (35.2%), Radiofrequency (46.3%) and Microwave (18.5%) were selected during the period 2008-2016. CEUS-guided ablations represented 7.3% (range 2.5%-13.8%) of 2015 ablative sessions performed at the participating centers. Indications to CEUS-guided ablation were: improvement of conspicuity of the target (28.5%), a target lesion undetectable on B-mode ultrasound (29.8%), detection of viable areas in nodules with either incomplete ablation or local tumor progression (41.7%). Overall, complete radiological ablation was obtained in 113/151 tumors (74.8%), with heat-based techniques (RF and MW) achieving higher rate of successful ablation (86.7%) than PEI (51%). Neither deaths nor major complications occurred after ablations. CEUS guidance demonstrates improved visibility and effectiveness in aiding ablation procedures that are otherwise technically difficult using only B-Mode US guidance. PMID- 30017307 TI - The influence of payor status on outcomes associated with surgical repair of upper gastrointestinal perforations due to peptic ulcer disease in the United States. AB - BACKGROUND: An association between lack of insurance and inferior outcomes has been well described for a number of surgical emergencies, yet little is known about the relationship of payor status and outcomes of patients undergoing emergent surgical repair for upper gastrointestinal (UGI) perforations. We evaluated the association of payor status and in-hospital mortality for patients undergoing emergency surgery for UGI perforations in the United States. METHODS: Nationwide Inpatient Sample (NIS) was queried to identify patients between 18 and 64 years of age who underwent emergent (open or laparoscopic) repair for UGI perforations secondary to peptic ulcer disease (2010-2014). Primary outcome was in-hospital mortality. Secondary outcomes were major and minor postoperative complications. The main predictor outcome was insurance status (Private, Medicaid, Uninsured). Univariate and multivariable regression analyses were performed. Data were weighted to provide national estimates. RESULTS: 21,005 patients underwent surgical repair for UGI perforations. Patients with private insurance represented the largest payor group (47%). After adjustment of other factors, payor status was not a statistically significant predictor of in hospital mortality (Medicaid vs. Private: [OR] 1.1; 95% [CI] 0.67-1.81; Uninsured vs. Private: OR 0.9, 95% CI 0.52-1.61). However, payor status remained a statistically significant predictor of major postoperative complications (Medicaid vs. Private [OR] 1.4; 95% CI 1.1, 1.8; Uninsured vs. Private [OR]1.2, 95% CI 0.9, 1.5) and minor postoperative complications (Medicaid vs. Private [OR] 1.4; 95% CI 1.1, 1.9; Uninsured vs. Private [OR]1.2, 95% CI 0.9, 1.6). CONCLUSIONS: Emergency surgery for UGI perforations is associated with high mortality and morbidity across all payor classes; however, Medicaid is a predictor for both major and minor postoperative complications. Preventing perforation through preventative measures will be key to reducing the burden of peptic ulcer disease across all populations. PMID- 30017308 TI - Upper body position analysis of different experience level surgeons during laparoscopic suturing maneuvers using optical motion capture. AB - BACKGROUND: This study aimed to analyze the posture patterns of surgeons with two different skill levels during laparoscopic surgery using an optical motion capture system. METHODS: Twenty participants were divided into novice and expert groups. Their upper body motions during suturing tasks were captured, including average angle and angle variability (shoulder, elbow, wrist), joint fixation, head movement, and thoracolumbar flexion angle. RESULTS: Our analysis showed that (1) the arms of the expert surgeons were more loosely held at their sides by about 7 degrees ; (2) their elbows were more bent by about 10 degrees ; (3) they had a greater change in shoulder angle by about 1.4 times and a more fluid posture; (4) their heads were more stable, particularly in the longitudinal and vertical axes; and (5) their thoracolumbar flexion angle was smaller by about 10 degrees . CONCLUSIONS: The posture patterns of different technical level surgeons during laparoscopic suturing maneuvers revealed differences in limb positions. These results may provide new insights into the efficient acquisition of technical skills and reduced physical stress during laparoscopic surgery. PMID- 30017309 TI - Hospital readmission after pancreaticoduodenectomy: A systematic review and meta analysis. AB - BACKGROUND: Appropriate postoperative readmission rates and modifiable risk factors for readmission have yet to be defined for many operations. This systematic review and meta-analysis attempt to define these parameters for pancreaticoduodenectomy. MATERIALS AND METHODS: The main outcomes were readmission rate, risk factors, and reasons for readmission. Meta-analyses were performed when data was homogeneous, otherwise, a qualitative review was performed. RESULTS: The 30-day, 90-day, and overall readmission rates were 17.63%, 26.14%, and 27.18%, respectively. In the meta-analysis, chronic pancreatitis (OR, 1.44, p = 0.04), operative length (MD, 26.1; p < 0.01), wound infection (OR, 1.9, p < 0.01), intra-abdominal abscess (OR, 3.79, p < 0.01), VTE (OR, 2.27, p = 0.01), and LOS (MD, 1.66, p < 0.01) where associated with readmission. CONCLUSION: Hospital readmission will continue to be a quality metric and will influence reimbursement models. Thirty and 60-day readmission data underestimate the true readmission rate. Chronic pancreatitis, operative length, and several post-operative complications were associated with greater readmission. More uniform reporting is necessary to identify modifiable risk factors associated with readmission. PMID- 30017310 TI - A modified frailty index predicts adverse outcomes among patients with colon cancer undergoing surgical intervention. AB - INTRODUCTION: Assessing outcomes in patients with colon cancer (CC) undergoing surgical intervention is challenging. Frailty has been as established tool for assessing patient outcomes. The aim was of this study was to assess role of frailty in patients with CC. METHODS: National estimates for patients with CC were abstracted from the National Inpatient Sample (NIS) database (2011). Frailty was calculated using a 11 variable CCFI. Patient was stratified as frail (FL) (mFI>=0.25) and non-frail (Non-FL). Outcome measures were: in-hospital complications, hospital and intensive care unit (ICU) length of stay (LOS), discharge disposition, and mortality. Regression analysis was performed. RESULTS: A total of 53,652 patients with CC who underwent surgery were analyzed. The mean age was 69 +/- 19 years with 62% males and mean CCFI being 0.13. 34% of patients were frail. 22.3% patients had in-hospital complications and mortality rate was 3.2%. Frail patients were more likely to have in-hospital complications (p = 0.001), longer hospital LOS (p = 0.001), more likely to be discharged to a facility (p = 0.001). On regression analysis after controlling for age, gender, type of procedure, hospital status, insurance status, frail status was independently associated with in-hospital complications (OR[95% CI]: 1.8[1.1 2.9], p = 0.035) and adverse discharge disposition (OR[95% CI]: 1.3[1.08-3.5], p = 0.043). CONCLUSION: Frailty status is an independent predictor of adverse outcomes (complications, discharge disposition, and LOS) in CC patient undergoing surgical intervention. Age was not independently associated with outcome and had poor correlation with frailty status. Pre-operative assessment of frailty in CC patient may help early identifications and risk stratification to help improve outcomes and discharge planning. PMID- 30017311 TI - Disparities in hepatitis C virus infection screening among Baby Boomers in the United States. AB - BACKGROUND: The study objective was to identify potential sociodemographic disparities in hepatitis C virus (HCV) infection screening among Baby Boomers in the United States. METHODS: We analyzed cross-sectional data from the 2013-2016 National Health Interview Survey. The outcome was whether a person had an HCV infection screening (yes/no). Key independent variables were race/ethnicity, geographic region, poverty level, education level, and health insurance status. Multivariate logistic regression was performed to examine the factors associated with the receipt of HCV screening. RESULTS: The study sample included a total of 41,914 United States Baby Boomers, who represented a population size of 69,554,339. In 2016, the HCV screening rate among Baby Boomers was 13.9%. In the multivariate logistic regression, we found that Asians had 27% lower odds of receiving an HCV screening compared to Blacks (odds ratio [OR] = 0.74, P = .02). People who lived in the Northeast, South, and West had a higher likelihood of having an HCV screening than those who lived in the Midwest (OR = 1.33, 1.39, and 1.69, respectively; all P values <.001). Additionally, people with less education, lower income, and private health insurance were significantly less likely to have an HCV screening. CONCLUSION: Future studies or interventions are needed to target these disadvantaged populations to improve HCV screening in Baby Boomers. PMID- 30017312 TI - New and Prospective Roles for lncRNAs in Organelle Formation and Function. AB - The observation that long noncoding RNAs (lncRNAs) represent the majority of transcripts in humans has led to a rapid increase in interest and study. Most of this interest has focused on their roles in the nucleus. However, increasing evidence is beginning to reveal even more functions outside the nucleus, and even outside cells. Many of these roles are mediated by newly discovered properties, including the ability of lncRNAs to interact with lipids, membranes, and disordered protein domains, and to form differentially soluble RNA-protein sub organelles. This review explores the possibilities enabled by these new properties and abilities, such as likely roles in exosome formation and function. PMID- 30017313 TI - Strategies to Annotate and Characterize Long Noncoding RNAs: Advantages and Pitfalls. AB - The past decade has seen an explosion of interest in long noncoding RNAs (lncRNAs). However, despite the massive volume of scientific data implicating these transcripts in a plethora of molecular and cellular processes, a great deal of controversy surrounds these RNAs. One of the main reasons for this lies in the multiple unique features of lncRNAs which limit the available methods used to characterize them. Combined with their vast numbers and inadequate classification, comprehensive annotation of these transcripts becomes a daunting task. The solution to this complex challenge likely lies in deep understanding of the strengths and weaknesses of each computational and empirical approach, and integration of multiple strategies to reduce noise, authenticate the results, and classify lncRNAs. We review here both the advantages and caveats of strategies commonly used for functional characterization and annotation of lncRNAs in the context of emerging conceptual guidelines for their application. PMID- 30017314 TI - Liquid biopsy for infectious diseases: sequencing of cell-free plasma to detect pathogen DNA in patients with invasive fungal disease. AB - Diagnosis of life-threatening deep-seated infections currently requires invasive sampling of the infected tissue to provide a microbiologic diagnosis. These procedures can lead to high morbidity in patients and add to healthcare costs. Here we describe a novel next-generation sequencing assay that was used to detect pathogen-derived cell-free DNA in peripheral blood of patients with biopsy-proven invasive fungal infections. The noninvasive nature of this approach could provide rapid, actionable treatment information for invasive fungal infections when a biopsy is not possible. PMID- 30017316 TI - Synthesis and evaluation of thiomannosides, potent and orally active FimH inhibitors. AB - FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice. PMID- 30017317 TI - Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors. AB - A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7 nM) and BACE-1 inhibition (IC50 value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood brain barrier (BBB) in PAMPA-BBB assay were further studied. PMID- 30017315 TI - Critical analysis of a doxycycline treatment trial of rhesus macaques infected with Borrelia burgdorferi. AB - A critical analysis was conducted of a doxycycline treatment trial of Indian rhesus macaques. In this treatment trial, the investigators attempted to infect the primates with Borrelia burgdorferi sensu stricto by at least 10 tick bites from artificially infected ticks. None of the primates became ill; nevertheless, 5 primates were treated with a 28-day course of oral doxycycline. In contrast to the conclusions of the authors, the data did not convincingly document the existence of viable B. burgdorferi in antibiotic-treated primates. The investigators were unable to cultivate the spirochete from any animal after treatment using highly sensitive in vitro methods. Like many prior animal studies, the current study also did not document that the doxycycline exposure in these animals was similar to that expected in humans. Numerous additional methodologic problems are discussed. PMID- 30017318 TI - Design, characterization, and in vitro antiproliferative efficacy of gemcitabine conjugates based on carboxymethyl glucan. AB - Gemcitabine (GEM) is widely used in clinical practice in the treatment of cancer and several other solid tumors. Nevertheless, the antitumor effect of GEM is partially prevented by some limitations including short half life, and lack of tumor localizing. Carboxymethyl glucan (CMG), a carboxymethylated derivative of beta-(1-3)-glucan, shows biocompatibility and biodegradability as well as a potential anticarcinogenic effect. To enhance the antiproliferative activity of GEM, four water soluble conjugates of GEM bound to CMG via diverse amino acid linkers were designed and synthesized. 1H NMR, FT IR, elementary analysis and RP HPLC chromatography were employed to verify the correct achievement of the conjugates. In vitro release study indicated that conjugates presented slower release in physiological buffer (pH 7.4) than acidic buffer (pH 5.5) mimicking the acidic tumor microenvironment. Moreover, A549, HeLa and Caco-2 cancer cell lines were used to evaluate the in vitro cytotoxicity of conjugates and the results showed that binding GEM to CMG significantly enhanced antiproliferative activity of GEM on A549 cells. Therefore, these conjugates may be potentially useful as a delivery vehicle in cancer therapy and worthy of further study on structure-activity relationship and antiproliferative activity in vitro and in vivo, especially for lung tumor. PMID- 30017319 TI - Synthesis and antimicrobial studies of hydrazone derivatives of 4-[3-(2,4 difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid and 4-[3-(3,4 difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid. AB - Microbial resistance to antibiotics is an unresolved global concern, which needs urgent and coordinated action. One of the guidelines of the Centers for Disease Control and Preventions (CDC) to combat antibiotic resistance is the development of new antibiotics to treat drug-resistant bacteria. In our effort to find new antibiotics, we report the synthesis and antimicrobial studies of 30 new pyrazole derivatives. These novel molecules have been synthesized by using readily available starting materials and benign reaction conditions. Some of these molecules have shown activity with MIC values as low as 0.78 ug/mL against four bacterial strains; Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus subtilis, and Acinetobacter baumannii. Furthermore, active molecules are non-toxic to mammalian cell line. PMID- 30017320 TI - The synthetic chalcone derivative 2-hydroxy-3',5,5'-trimethoxychalcone induces unfolded protein response-mediated apoptosis in A549 lung cancer cells. AB - The synthetic chalcone derivative 2-hydroxy-3',5,5'-trimenthoxyochalcone (named DK-139) exhibits anti-inflammatory and anti-tumor invasion properties. However, effects of DK-139 on tumor cell growth remain unknown. In the present study, we evaluated the inhibitory activity of DK-139 against human lung cancer cells. Treatment with DK-139 inhibited clonogenicity in various lung cancers and stimulated the caspase cascade, leading to the apoptosis of A549 lung cancer cells. To investigate the mode of action of DK-139-induced apoptosis, we analyzed the effect of DK-139 on the endoplasmic reticulum (ER) stress response. DK-139 increased expression of ER stress sensors, including p-PERK, GRP78/BiP, and IRE1alpha. IRE1alpha-regulated XBP-1 mRNA splicing and PERK-induced ATF4 expression was also upregulated following DK-139 treatment. In addition, expression levels of the pro-apoptotic transcription factor CHOP and its downstream target Bim, which is involved in mitochondria-mediated apoptosis, were increased by DK-139 treatment. These results suggest that DK-139 triggers caspase mediated apoptosis via the ER stress-activated unfolded protein response (UPR) pathway. We propose that the synthetic chalcone derivative DK-139 may be used as a potential agent for the prevention and/or treatment of human lung cancer. PMID- 30017323 TI - Detection and molecular characterization of Chlamydia psittaci and Chlamydia abortus in psittacine pet birds in Buenos Aires province, Argentina. AB - In order to determine the presence and genetic diversity of Chlamydia spp. in the north-eastern area of Buenos Aires province, Argentina, conjunctival, oropharyngeal, cloacal swab and tissues were collected from a total of 90 psittacine pet birds of different age and clinical manifestations. Through molecular methods, Chlamydiaceae was detected in 30% (27/90) of the samples, out of which 70.3% (19/27) were positive for Chlamydia psittaci and 14.9% (4/27) for Chlamydia abortus. Nine C. psittaci positive samples were genotyped by ompA gene sequences, 8 clustered within genotype A and 1 within genotype B. A significant association was observed between the presence of Chlamydia spp. and the manifestation of clinical signs compatible with chlamydiosis, as well as with the age of the birds (younger than one year old). This report contributes to the improvement of our understanding of chlamydial agents in our country. PMID- 30017324 TI - Veil-like pellicle development by Azospirillum brasilense in semisolid NFb medium. PMID- 30017325 TI - Twin pregnancy in non-communicating rudimentary horn. PMID- 30017326 TI - Autosomal recessive polycystic kidney disease prenatally diagnosed in a fetus with unreported paternal inherited PKHD1 mutation. PMID- 30017327 TI - Impact of a program ensuring consistent response to acute drops in lung function in children with cystic fibrosis. AB - BACKGROUND: Variation in CF pulmonary outcomes is multifactorial, but a significant component appears to be dependent upon differences in CF Center care. Previous investigations suggest that high performing CF centers are more consistent and proactive in the treatment of pulmonary exacerbations. We incorporated this approach into a program that could be bundled and shared with other CF Centers. METHODS: The reorganization of CF pulmonary care at the Children's Hospital of Richmond included the development of a pulmonary algorithm to define a standard response to changes in lung function and run charts to track process and outcome measures. We calculated the rolling average of the best percent predicted FEV1 (ppFEV1) over the previous 12 months as our primary outcome measure. RESULTS: The mean of the best ppFEV1 in the previous 12 months rose from 87% predicted (65% predicted for those 13-18 years, 97% predicted for those 6-13 years) in January 2013 to 98% predicted (95% predicted for those 13-18 years, 110% predicted for those 6-13 years) in January 2018. The ppFEV1 difference between children 6-13 years and adolescents 13-18 years dropped from 34 to 14 during that time. CONCLUSIONS: Improvements in pulmonary outcomes can be accomplished rapidly using basic quality improvement principles, including interdisciplinary team goal setting, standardized and proactive approaches that ensure consistent recognition and treatment of pulmonary exacerbations, and the use of data to follow the effectiveness of the process. We believe that the steps involved would be easy for other CF Centers to adapt to their own settings. PMID- 30017328 TI - Patterns of complications following urinary tract reconstruction after multivisceral surgery in colorectal and anal cancer. AB - BACKGROUND: Multi-visceral resection, including parts of the urinary tract, is sometimes warranted to achieve cancer clear resection margins and optimize survival in patients with locally advanced colorectal and anal cancer. The aim of this study was to assess morbidity after urinary tract reconstruction dictated by colorectal and anal malignancy and to identify potential predictors of urological complications. METHODS: All patients undergoing surgery for colorectal or anal malignancy, including urinary tract resection and synchronous reconstruction, performed at the Karolinska University Hospital during 2004-2015 were included in this retrospective cohort study. Data was collected from medical records with follow-up until at least one year after the index surgery. Complications were graded according to the Clavien-Dindo classification system of surgical complications. RESULTS: The study included 189 patients; 121 underwent cystectomy and 68 partial ureter resection. The rate of high grade urological complications was 22%. The risk of major urological complications was significantly higher in patients subjected to ureter resection compared to after cystectomy (OR 2.60, 95% CI 1.23-5.49). Also, preoperative radiotherapy and intestinal anastomotic dehiscence significantly increased the risk of high grade urological complications. CONCLUSION: To achieve potentially curative resections with uninvolved margins in patients with locally advanced colorectal and anal cancer, multi-visceral resection including urinary tract reconstruction can be performed with reasonable morbidity. PMID- 30017330 TI - Adequate use of radioactive seed localization. Where are we? PMID- 30017329 TI - Electrochemotherapy of cholangiocellular carcinoma at hepatic hilum: A feasibility study. AB - AIM: We evaluated feasibility, safety and efficacy of Electrochemotherapy (ECT) in a prospective series of patients with unresectable Perihilar Cholangiocarcinoma (PHCCA). PATIENTS AND METHODS: Five patients with PHCCA underwent ECT. Three patients underwent percutaneous ECT of a single PHCCA nodule. One patient underwent resection of a nodule in the IV segment and intraoperative ECT of a large PHCCA in the VIII segment. Another patient underwent percutaneous ECT of a large PHCCA recurrence after left lobectomy and RF ablation of a synchronous metastasis in the VI segment. ECT was performed under US guidance. Efficacy was evaluated by contrast-enhanced multiple-detector computed-tomography (MDCT) 4 weeks after treatment. Follow-up entailed MDCT every 6 months thereafter. RESULTS: No major complication occurred. Follow-up ranges from 10 to 30 months. Four weeks post-treatment CT showed complete response in 3 cases. These patients are still alive, and follow-up CT controls demonstrated no local or distant intrahepatic recurrences and no biliary duct dilation in 2 cases and local recurrence at 18 months follow-up control in 1 patient. In the remaining 2 cases, 4-weeks-post-treatment CT showed incomplete response (>90%). In these patients follow-up CT demonstrated local progression of the disease at 6 months. One of them had bilateral external biliary drainages and died because of tumor progression at 16-months-follow-up. The other patient, died at 10 months follow-up for cardiovascular failure not related to the hepatobiliary disease. CONCLUSIONS: ECT is feasible, safe and effective therapy to improve prognosis and quality of life of patients with unresectable PHCCA. PMID- 30017332 TI - Diabetes mellitus and tobacco: The perfect storm. PMID- 30017331 TI - Single centre guidelines for radiological follow-up based on 775 patients treated by cytoreductive surgery and HIPEC for appendiceal pseudomyxoma peritonei. AB - AIM: Pseudomyxoma peritonei (PMP) is an uncommon malignancy, generally originating from a ruptured epithelial tumour of the appendix. Despite successful cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), some patients recur. Currently there are no guidelines on the methods, frequency and intensity of follow-up. METHODS: Between 1994 and 2016, 1070 patients underwent surgery for a perforated epithelial tumour of the appendix, predominantly with PMP. Overall (OS) and Disease Free Survival (DFS) were documented by annual CT scanning and evaluated according to the Kaplan-Meier method. The influence of histological differentiation was investigated. RESULTS: Overall, 775/1070 (72%) had complete cytoreductive surgery (CCRS) and HIPEC. Histological classification was low grade PMP in 615 (79.4%), high grade PMP in 134 (17.3%) and adenocarcinoma in 26 (3.4%). DFS and OS were significantly worse for high grade disease, with the steepest decline for both in the first three years. DFS curves, for low as well as high grade PMP, levelled off at year 6 at approximately 60% and 20% respectively. Thereafter there were few recurrences in either group. CONCLUSION: Annual CT of the abdomen and pelvis in the first six years appears to be adequate follow-up for low grade PMP. In high grade PMP, additional imaging of the chest and more frequent surveillance, during the first three years postoperatively, may detect recurrent disease earlier. From year 6 on, reduced frequency of follow-up is proposed, independent of the histology. This long-term follow-up in a large number of patients gives insight into tumour behavior after CCRS and HIPEC for PMP and guides intensity of surveillance. PMID- 30017333 TI - Biological function of UCA1 in hepatocellular carcinoma and its clinical significance: Investigation with in vitro and meta-analysis. AB - Urothelial cancer associated 1 (UCA1) was upregulated in hepatocellular carcinoma (HCC) tissues and cell lines, and the expression of UCA1 was associated with several clinical features and malignant behaviours in HCC. However, none of these findings completely interpreted the role of UCA1 in HCC. We conducted this investigation to validate the expression of UCA1 and its relationship with Tumor Node Metastasis (TNM) stage in 41 HCC tissues and their paired noncancerous adjacent tissues by real-time qPCR. Furthermore, we also explored the biological functions of UCA1 in vitro with HCC cell lines. Most importantly, we conducted a comprehensive meta-analysis and bioinformatics investigation based on peer reviewed literature and in silico approaches to further summarise the clinical value and functions of UCA1 in HCC. UCA1 expression was remarkably upregulated in HCC tissues, and its expression was profoundly higher in advanced stages than in early stages. Reducing the expression levels of UCA1 suppressed the proliferation and induced apoptosis of HCC cells. Furthermore, the present meta-analysis validated that up-regulated UCA1 was closely related to larger tumour size and advanced TNM stages, and the overexpression of UCA1 was significantly correlated with a shorter OS. Additionally, according to GO analysis, the target genes were found concentrated in the following biological processes: extracellular matrix organisation, cilium assembly and cilium morphogenesis. KEGG pathway analysis showed that the UCA1-related genes were significantly enriched in the following pathways: hippo signalling pathway, bile secretion and gastric acid secretion. This evidence hinted that UCA1 could play an indispensable proliferation-related key role in HCC via the hippo signalling pathway. However, the exact molecular mechanism needs to be verified with future functional experiments. PMID- 30017334 TI - Digital image analysis of pan-cytokeratin stained tumor slides for evaluation of tumor budding in pT1/pT2 colorectal cancer: Results of a feasibility study. AB - Tumor budding is an independent prognostic factor in colorectal cancer. However, varying degrees of interobserver agreement and reproducibility challenges the use of tumor budding in diagnostics. Immunohistochemical staining of tumor slides with pan-cytokeratin visualizes the budding tumor cells and has been suggested to improve reproducibility. Here we demonstrate the methodology of tumor budding assessment using digital image analysis based on tumor slides stained for pan cytokeratin, and investigate interobserver agreement, agreement between manual and digital assessment methods and digital reproducibility between users. Tumor slides from 126 patients with pT1/pT2 colorectal cancer were stained with pan cytokeratin and tumor budding at the invasive tumor front was assessed by conventional manual microscopy. A digital image analysis algorithm for identification and quantification of budding tumor cells was developed and tested on the pan-cytokeratin stained slides. Manual assessment of tumor budding using pan-cytokeratin stained tumor slides exhibited high correlations (Spearman Rank 0.84-0.89, p < 0.001),excellent agreement between observers (Intra-class correlation coefficient (ICC): 0.86 -0.87) and 2.20 higher odds for regional metastases with increasing budding counts (p = 0.017). Digital image analysis correlated well to manual assessment (Spearman Rank 0.71-0.88) and agreement between the two methods was good (ICC 0.62-0.82). However, only a trend towards increased odds for metastatic progression was found for the adjusted digital estimates (p = 0.076). Digital estimates were higher than manual estimates, demonstrated by a systematic median difference of 3-4.5 buds. Image analysis was highly reproducible between users of the algorithm (ICC 0.98). In conclusion, assessment of tumor budding using pan-cytokeratin stained tumor slides is a method with high correlation and agreement between observers. Digital image analysis quantifies budding tumor cells in high agreement with manual estimates, but approval of the digital slides by a pathologist is mandatory. The method qualifies for further investigation. PMID- 30017336 TI - Corrigendum to "Implicit aggressiveness self-concepts in patients with obsessive compulsive disorder as assessed by an implicit associations test" [Journal of Behavior Therapy and Experimental Psychiatry 55 (June 2017) 106-112]. PMID- 30017335 TI - Loss of LINC01939 expression predicts progression and poor survival in gastric cancer. AB - As highly tissue-specific genes, it is increasingly recognized that long non coding RNAs (lncRNAs) are considered as promising prognostic biomarkers for multiple human cancers. However, lack of tissue-specific lncRNAs in gastric cancer (GC) still exist. In this study, we identified a novel lncRNA LINC01939 which showed the largest fold change in GC than other human cancers from lnCAR database by bioinformatic analysis. Reverse transcription quantitative polymerase chain reaction (qPCR) assay confirmed that LINC01939 was significantly downregulated in GC tissues compared with matched normal tissues. Low expression of LINC01939 was positively associated with advanced TNM stage and lymphatic metastasis. Patients with low LINC01939 expression have remarkably shorter overall survival (OS) and progression-free survival (PFS) than those with high LINC01939 expression. Univariate and multivariate analysis showed that LINC01939 is an independent protective predictor of OS and PFS in GC patients. Therefore, our data suggest that the newly identified lncRNA LINC01939 might act as a potential prognostic biomarker for GC. PMID- 30017337 TI - Factors Associated with Cell Phone Use While Driving: A Survey of Parents and Caregivers of Children Ages 4-10 Years. AB - OBJECTIVES: To examine characteristics associated with cell phone use while driving by parents and caregivers of children ages 4-10 years. STUDY DESIGN: National cross-sectional online survey with a convenience sample (March 2017 April 2017). INCLUSION CRITERIA: Parent/caregiver of a child age 4-10 years in their home, age >=18 years, read and spoke English, and drove child >=6 times in previous 3 months. Adjusted logistic regression analyses were modeled for outcome measures of previous 3-month self-report cell phone use while driving with the child. RESULTS: The analytic sample was n = 760. In the previous 3 months, 47% of parent/caregivers talked on a hand-held phone, 52.2% talked on a hands-free phone, 33.7% read texts, 26.7% sent texts, and 13.7% used social media while driving with their child in the vehicle. Compared with those who always used their typical child restraint system, participants who did not always use were more likely to talk on a hands-free phone (aOR 1.97, 95% CI 1.26-3.09), read a text (aOR 1.74, 95% CI 1.11-2.73), send a text (aOR 1.65, 95% CI 1.04-2.62), and use social media (aOR 2.92, 95% CI 1.73-4.94) while driving. Higher income, not wearing a seat belt (driver) on every trip, and driving under influence of alcohol also were associated with various types of cell phone use while driving. CONCLUSIONS: Inconsistent child restraint system use, lack of seat belt use, and driving under the influence of alcohol are associated with parent/caregiver cell phone use while driving. Screening and education related to parental driving behaviors should include addressing multiple risk behaviors. PMID- 30017338 TI - Hamman's Sign in a Patient with Spontaneous Pneumomediastinum. PMID- 30017339 TI - On the Gendering of Plasma: What is Transfusion-Related Acute Lung Injury to Bronchopulmonary Dysplasia? PMID- 30017340 TI - Reply. PMID- 30017341 TI - Stop the planet of the apes, I want to get off. PMID- 30017342 TI - Etiology of increased cancer incidence after solid organ transplantation. AB - Over the past decades, there has been an encouraging increase in survival after solid organ transplantation. However, with longer life spans, more transplant recipients are at risk of dying with functioning grafts from illnesses such as cancer and cardiovascular conditions. Malignancy has emerged as an important cause of death in transplant recipients and is expected to become the leading cause of death in transplanted patients within the next decade. While it is known that solid organ transplant recipients have a three to five-fold increased risk of developing cancer compared with the general population, the mechanisms that lead to the observed excess risk in transplant recipients are less clear. This review explores the etiology of the increased cancer incidence in solid organ transplant including the effect of immunosuppressants on immunosurveillance and activation of oncogenic viruses, and carcinogenic effects of these medications; the role of chronic stimulation of the immune system on the development of cancer; and the impact of pre-existing cancer risk factors and factors related to end-stage organ disease on the cancer excess incidence in solid organ transplant recipients. PMID- 30017343 TI - Corrigendum to "Endocytosis of particulate matter induces cytokine production by neutrophil via toll-like receptor 4" [Int. Immunol. 57 (2018) 190-199]. PMID- 30017344 TI - Autoimmune associations in a Mexican cohort with primary biliary cholangitis. AB - INTRODUCTION: Several groups have reported associations of primary biliary cholangitis with other autoimmune entities, particularly Sjogren's syndrome and hypothyroidism. Its prevalence and characteristics in Mexican patients is unknown. AIM: To determine the frequency and characteristics of autoimmune diseases in a Mexican cohort of patients with primary biliary cholangitis. MATERIALS AND METHODS: The medical records of patients that presented with primary biliary cholangitis within the time frame of 2005 and 2012 were reviewed and assessed for other autoimmune diseases. RESULTS: Seventy-eight patients, 75 women and 3 men, were included. Their mean age was 55.8 years. Seventy-three cases had positive antimitochondrial antibodies (94.8%) and disease was confirmed in 5 through liver biopsy. Five patients (8%) had anti-smooth muscle antibodies and 55/78 (70.5%) had antinuclear antibodies by indirect immunofluorescence. Forty-nine patients (62.8%) were positive for an autoimmune disease other than primary biliary cholangitis. Among those, 20 patients had one associated disease, 14 had 2, and 15 patients had 3 concomitant diseases. They included: Sjogren's syndrome in 23/78 patients (29.5%), dysthyroidism in 21/78 cases (26.9%), Raynaud syndrome in 11/78 (14.1%), CREST syndrome in 9/78 patients (11.4%), rheumatoid arthritis in 6/78 patients (7.7%), vitiligo in 5/78 (6.4%), scleroderma in 4/78 patients (5.1%), and other diseases in 8 patients. In 12/78 patients (15.4%), there was a documented family background of autoimmune disease. CONCLUSIONS: The presence of autoimmune associations in our cohort was frequent, and similar in characteristics to the information reported by other groups. The clinical implications of those findings remain to be determined. PMID- 30017345 TI - The ABCs for Nutrition Poststroke: An Evidence-Based Practice Guide for Rehabilitation Professionals. PMID- 30017347 TI - Cervical HPV testing versus cytology. PMID- 30017346 TI - Relationship of Absolute Telomere Length With Quality of Life, Exacerbations, and Mortality in COPD. AB - BACKGROUND: COPD is an age-related disease. The role of cellular senescence in COPD has not been fully elucidated. This study examined the relationship between telomere length of peripheral blood leukocytes and clinical outcomes, including health status, rate of exacerbations, and risk of mortality in individuals with COPD. METHODS: Using quantitative polymerase chain reaction, we measured the absolute telomere length (aTL) of DNA extracted from blood samples of 576 participants with moderate-to-severe COPD treated with either azithromycin or placebo for 12 months in the Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO) study. All participants were followed for approximately 13 months, during which time health status and exacerbations were carefully ascertained, and an additional 29 months for mortality. The rates of exacerbation and mortality were determined by dividing the aTL into two groups using the median value as the cutoff. RESULTS: Participants with shorter telomere length had worse health status defined by higher St. George's Respiratory Questionnaire scores (beta = -0.09, P = .034). In the placebo arm of the study, the rate of exacerbation (rate ratio, 1.50; 95% CI, 1.16-1.95; P = .002) and the risk of mortality (hazard ratio, 9.45; 95% CI, 2.85-31.36; P = .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm (interaction P = .008 for exacerbation and interaction P = .017 for mortality) CONCLUSIONS: These data suggest that replicative senescence may help to predict poor outcomes in COPD. Shorter leukocyte telomere lengths may represent a clinically translatable biomarker for identifying individuals at increased risk of poor clinical outcomes in COPD. PMID- 30017349 TI - Systemic therapy after IFRT for follicular lymphoma. PMID- 30017348 TI - Growing pains for US proton therapy. PMID- 30017350 TI - Much ado about robotic versus open radical prostatectomy. PMID- 30017351 TI - Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: 24-month outcomes from a randomised controlled study. AB - BACKGROUND: Previous trials have found similar early outcomes after robot assisted laparoscopic prostatectomy and open radical retropubic prostatectomy. We report functional and oncological postoperative outcomes up to 24 months after surgery for these two surgical techniques. METHODS: In this randomised controlled phase 3 study, men who had newly diagnosed clinically localised prostate cancer and who had chosen surgery as their treatment approach, and were aged between 35 years and 70 years were eligible and recruited from the Royal Brisbane and Women's Hospital (Brisbane, QLD, Australia). Participants were randomly assigned (1:1) to have either robot-assisted laparoscopic prostatectomy or open radical retropubic prostatectomy. Randomisation was computer generated and occurred in blocks of ten. This was an open trial; however, study investigators involved in data analysis were masked to each patient's surgical treatment. Primary outcomes were urinary function (urinary domain of Expanded Prostate Cancer Index Composite [EPIC]) and sexual function (sexual domain of EPIC and International Index of Erectile Function Questionnaire [IIEF]) at 6 months, 12 months, and 24 months and oncological outcome (biochemical recurrence and imaging evidence of progression). The trial was powered to assess health-related and domain-specific quality-of life outcomes over 24 months. All analyses were done on a per-protocol basis. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000661976. FINDINGS: Between Aug 23, 2010, and Nov 25, 2014, 326 men were enrolled, of whom 163 were randomly assigned to robot-assisted laparoscopic prostatectomy and 163 to open radical retropubic prostatectomy. 18 withdrew (12 assigned to radical retropubic prostatectomy and six assigned to robot-assisted laparoscopic prostatectomy); thus, 151 in the radical retropubic prostatectomy group and 157 in the robot-assisted laparoscopic prostatectomy group proceeded to surgery. At the 24-month follow-up time point, 150 men remained in the robot-assisted laparoscopic prostatectomy group and 146 remained in the open radical retropubic prostatectomy group. Urinary function scores did not differ significantly between robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy at 6 months post-surgery (88.68 [95% CI 86.79-90.58] vs 88.45 [86.54-90.36]; p1<0.0001, p2<0.0001), 12 months post surgery (90.76 [88.89-92.62] vs 91.53 [90.07-92.98]; p1<0.0001, p2<0.0001), or 24 months post-surgery (91.33 [89.64-93.03] vs 90.86 [89.01-92.70]; p1<0.0001, p2<0.0001). Sexual function scores were not significantly different between robot assisted laparoscopic prostatectomy and open radical retropubic prostatectomy at 6 months post-surgery (EPIC: 37.40 [33.60-41.19] vs 38.63 [34.76-42.49], p1=0.0001, p2<0.0001; IIEF: 29.75 [26.66-32.84] vs 29.78 [26.41-33.16], p1<0.0001, p2<0.0001), 12 months post-surgery (EPIC: 42.28 [38.05-46.51] vs 42.51 [38.29-46.72], p1<0.0001, p2<0.0001; IIEF: 33.10 [29.59-36.61] vs 33.50 [29.87 37.13], p1=0.0002, p2<0.0001), or 24 months post-surgery (EPIC: 45.70 [41.17 50.23] vs 46.90 [42.20-51.60], p1=0.0003, p2<0.0001; IIEF: 33.95 [30.11-37.78] vs 33.89 [29.82-37.96], p1=0.0003, p2=0.0004). Equivalence testing on the difference between the proportion of biochemical recurrences between the two groups (13 [9%] in the open radical retropubic prostatectomy group vs four [3%] in the robot assisted laparoscopic prostatectomy group) showed that equality between the two techniques could not be established based on a 90% CI with a prespecified margin of 10%. However, a superiority test showed that the two proportions were significantly different (p=0.0199). Equivalence testing on the proportion of patients who had imaging evidence of progression revealed that the two groups were not significantly different (p=0.2956). INTERPRETATION: Robot-assisted laparoscopic prostatectomy and open radical retropubic prostatectomy yielded similar functional outcomes at 24 months. We advise caution in interpreting the oncological outcomes of our study because of the absence of standardisation in postoperative management between the two trial groups and the use of additional cancer treatments. Clinicians and patients should view the benefits of a robotic approach as being largely related to its minimally invasive nature. FUNDING: Cancer Council Queensland. PMID- 30017352 TI - Gut Microbiota-Stimulated Innate Lymphoid Cells Support beta-Defensin 14 Expression in Pancreatic Endocrine Cells, Preventing Autoimmune Diabetes. AB - The gut microbiota is essential for the normal function of the gut immune system, and microbiota alterations are associated with autoimmune disorders. However, how the gut microbiota prevents autoimmunity in distant organs remains poorly defined. Here we reveal that gut microbiota conditioned innate lymphoid cells (ILCs) induce the expression of mouse beta-defensin 14 (mBD14) by pancreatic endocrine cells, preventing autoimmune diabetes in the non-obese diabetic (NOD) mice. MBD14 stimulates, via Toll-like receptor 2, interleukin-4 (IL-4)-secreting B cells that induce regulatory macrophages, which in turn induce protective regulatory T cells. The gut microbiota-derived molecules, aryl hydrocarbon receptor (AHR) ligands and butyrate, promote IL-22 secretion by pancreatic ILCs, which induce expression of mBD14 by endocrine cells. Dysbiotic microbiota and low affinity AHR allele explain the defective pancreatic expression of mBD14 observed in NOD mice. Our study reveals a yet unidentified crosstalk between ILCs and endocrine cells in the pancreas that is essential for the prevention of autoimmune diabetes development. PMID- 30017353 TI - A2A Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21. AB - Adipocytes play important roles in regulating cardiovascular health and disease. However, the molecular mechanism underlying the endocrine role of brown adipose tissue (BAT) in pathological cardiac remodeling remains unknown. Herein we show that adenosine A2A receptor (A2AR) knockout (A2ARKO) causes interscapular BAT (iBAT) dysfunction, leading to accelerated cardiac remodeling in hypertension compared with wild-type (WT) mice. Surgical iBAT depletion induces dramatic cardiac remodeling in WT but not in A2ARKO hypertensive mice. AMPK/PGC1alpha signaling-induced fibroblast growth factor 21 (FGF21) in brown adipocytes is required for A2AR-mediated inhibition of hypertensive cardiac remodeling. Recombinant FGF21 administration improves cardiac remodeling in iBAT-depleted hypertensive mice. More importantly, brown adipocyte-specific A2ARKO inhibits FGF21 production and accelerates cardiac damage in hypertension. Consistently, brown adipocyte-specific FGF21 knockout abolishes the effects of A2AR agonism in attenuating hypertensive cardiac remodeling. Our findings reveal a distinctive endocrine role of BAT in hypertensive cardiac remodeling via activating A2AR/FGF21 pathway. PMID- 30017355 TI - Serine Synthesis via PHGDH Is Essential for Heme Production in Endothelial Cells. AB - The role of phosphoglycerate dehydrogenase (PHGDH), a key enzyme of the serine synthesis pathway (SSP), in endothelial cells (ECs) remains poorly characterized. We report that mouse neonates with EC-specific PHGDH deficiency suffer lethal vascular defects within days of gene inactivation, due to reduced EC proliferation and survival. In addition to nucleotide synthesis impairment, PHGDH knockdown (PHGDHKD) caused oxidative stress, due not only to decreased glutathione and NADPH synthesis but also to mitochondrial dysfunction. Electron transport chain (ETC) enzyme activities were compromised upon PHGDHKD because of insufficient heme production due to cellular serine depletion, not observed in other cell types. As a result of heme depletion, elevated reactive oxygen species levels caused EC demise. Supplementation of hemin in PHGDHKD ECs restored ETC function and rescued the apoptosis and angiogenesis defects. These data argue that ECs die upon PHGDH inhibition, even without external serine deprivation, illustrating an unusual importance of serine synthesis for ECs. PMID- 30017354 TI - Mitofusin 2 Regulates Axonal Transport of Calpastatin to Prevent Neuromuscular Synaptic Elimination in Skeletal Muscles. AB - Skeletal muscles undergo atrophy in response to diseases and aging. Here we report that mitofusin 2 (Mfn2) acts as a dominant suppressor of neuromuscular synaptic loss to preserve skeletal muscles. Mfn2 is reduced in spinal cords of transgenic SOD1G93A and aged mice. Through preserving neuromuscular synapses, increasing neuronal Mfn2 prevents skeletal muscle wasting in both SOD1G93A and aged mice, whereas deletion of neuronal Mfn2 produces neuromuscular synaptic dysfunction and skeletal muscle atrophy. Neuromuscular synaptic loss after sciatic nerve transection can also be alleviated by Mfn2. Mfn2 coexists with calpastatin largely in mitochondria-associated membranes (MAMs) to regulate its axonal transport. Genetic inactivation of calpastatin abolishes Mfn2-mediated protection of neuromuscular synapses. Our results suggest that, as a potential key component of a novel and heretofore unrecognized mechanism of cytoplasmic protein transport, Mfn2 may play a general role in preserving neuromuscular synapses and serve as a common therapeutic target for skeletal muscle atrophy. PMID- 30017356 TI - Dietary Fat, but Not Protein or Carbohydrate, Regulates Energy Intake and Causes Adiposity in Mice. AB - The impacts of different macronutrients on body weight regulation remain unresolved, with different studies suggesting increased dietary fat, increased carbohydrates (particularly sugars), or reduced protein may all stimulate overconsumption and drive obesity. We exposed C57BL/6 mice to 29 different diets varying from 8.3% to 80% fat, 10% to 80% carbohydrate, 5% to 30% protein, and 5% to 30% sucrose. Only increased dietary fat content was associated with elevated energy intake and adiposity. This response was associated with increased gene expression in the 5-HT receptors, and the dopamine and opioid signaling pathways in the hypothalamus. We replicated the core findings in four other mouse strains (DBA/2, BALB/c, FVB, and C3H). Mice regulate their food consumption primarily to meet an energy rather than a protein target, but this system can be over-ridden by hedonic factors linked to fat, but not sucrose, consumption. PMID- 30017359 TI - A new case expanding the mutation and phenotype spectrum of TMEM5-related alpha dystroglycanopathy. AB - Dystroglycanopathies are a diverse group of neuromuscular disorders caused by aberrant glycosylation of alpha-dystroglycan. TMEM5 is one of many glycosyltransferases recently described to be associated with alpha dystroglycanopathies. We report the case of a 15-year-old boy suffering from a congenital muscular dystrophy with elevated serum creatine kinase levels and an almost complete absence of alpha-dystroglycan in muscle biopsy. The clinical course was milder than any previously reported case and did not include brain or eye defects. Standard next-generation sequencing analysis revealed a homozygous mutation in the donor splice site region of exon 5 in TMEM5 (c.914+6 T>G). Available in-silico prediction tools anticipated a reduced efficiency of the splice site. Subsequent cDNA sequencing confirmed the expression of a truncated transcript of TMEM5 lacking exon 5, hence leading to an in-frame deletion in the exostosin domain of the protein. This report expands the clinical and mutation spectrum of alpha-dystroglycanopathies. PMID- 30017358 TI - CalR: A Web-Based Analysis Tool for Indirect Calorimetry Experiments. AB - We report a web-based tool for analysis of experiments using indirect calorimetry to measure physiological energy balance. CalR simplifies the process to import raw data files, generate plots, and determine the most appropriate statistical tests for interpretation. Analysis using the generalized linear model (which includes ANOVA and ANCOVA) allows for flexibility in interpreting diverse experimental designs, including those of obesity and thermogenesis. Users also may produce standardized output files for an experiment that can be shared and subsequently re-evaluated using CalR. This framework will provide the transparency necessary to enhance consistency, rigor, and reproducibility. The CalR analysis software will greatly increase the speed and efficiency with which metabolic experiments can be organized, analyzed per accepted norms, and reproduced and will likely become a standard tool for the field. CalR is accessible at https://CalRapp.org/. PMID- 30017357 TI - Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease. AB - It is unknown what occurs if both mitochondrial division and fusion are completely blocked. Here, we introduced mitochondrial stasis by deleting two dynamin-related GTPases for division (Drp1) and fusion (Opa1) in livers. Mitochondrial stasis rescues liver damage and hypotrophy caused by the single knockout (KO). At the cellular level, mitochondrial stasis re-establishes mitochondrial size and rescues mitophagy defects caused by division deficiency. Using Drp1KO livers, we found that the autophagy adaptor protein p62/sequestosome 1-which is thought to function downstream of ubiquitination-promotes mitochondrial ubiquitination. p62 recruits two subunits of a cullin-RING ubiquitin E3 ligase complex, Keap1 and Rbx1, to mitochondria. Resembling Drp1KO, diet-induced nonalcoholic fatty livers enlarge mitochondria and accumulate mitophagy intermediates. Resembling Drp1Opa1KO, Opa1KO rescues liver damage in this disease model. Our data provide a new concept that mitochondrial stasis leads the spatial dimension of mitochondria to a stationary equilibrium and a new mechanism for mitochondrial ubiquitination in mitophagy. PMID- 30017361 TI - TEMPORARY REMOVAL: Continuing Education and Meeting Calendar. AB - The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 30017360 TI - Authors' response to "An unnecessary pain: A commentary on Gao et al. (2018)". PMID- 30017362 TI - Repeated ethanol fermentation from membrane-concentrated sweet sorghum juice using the flocculating yeast Saccharomyces cerevisiae F118 strain. AB - The aim of this study was to construct a cost-effective method for repeated bioethanol production using membrane (ultrafiltration permeation and nanofiltration concentration)-concentrated sweet sorghum juice by using flocculent Saccharomyces cerevisiae F118 strain. With low initial dry cell concentrations at around 0.28-0.35 g L-1, the S. cerevisiae F118 strain provided an ethanol titer of 86.19 +/- 1.15 g L-1 (theoretical ethanol yield of 70.77%), which was higher than the non-flocculent S. cerevisiae BY4741 strain at 33.92 +/- 0.99 g L-1 after 24 h fermentation. This result was correlated with higher gene expressions of the sucrose-hydrolysing enzyme invertase, sugar phosphorylation, and pyruvate-to-ethanol pathways in the F118 strain compared with the BY4741 strain. Sequential fed-batch fermentation was conducted, and the F118 strain was easily separated from the fermentation broth via the formation of flocs and sediment. After the 5th cycle of fermentation with the F118 strain, the ethanol concentration reached 100.37 g L-1. PMID- 30017363 TI - Relationships between galvanic interaction, copper extraction and community dynamics during bioleaching of chalcopyrite by a moderately thermophilic culture. AB - A moderately thermophilic culture was enriched and adapted to bioleach chalcopyrite at high pulp density. In order to further improve copper extraction, effects of galvanic interaction on bioleaching performance and community dynamics were investigated by adding pyrite. Copper extractions were improved by 2.91 and 1.97 times in the initial and the final stages when pyrite was present, respectively. However, it did not benefit chalcopyrite dissolution in the middle stage. Community dynamics analysis showed that succession of the attached cells was significantly different from community dynamics of the planktonic cells. One of planktonic populations always dominated the communities in most cases, while no species had absolutely competitive advantages in the attached communities. In addition, the presence of pyrite had significant effects on planktonic and attached community structures, and could accelerate planktonic community succession. PMID- 30017364 TI - Approaches and processes for ammonia removal from side-streams of municipal effluent treatment plants. AB - The main objective of this review article is to provide a comprehensive view on various conventional and emerging side-stream ammonia removal treatment options for municipal wastewater treatment plants (WWTPs). Optimization of wastewater treatment facilities from an energy and emissions stand-point necessitates consideration of the impact of the various internal side-streams. Side-streams from anaerobic sludge digesters in particular have the potential to be a significant ammonium load to the mainstream treatment process. However, the literature suggests that managing side-streams through their treatment in the mainstream process is not the most energy efficient approach, nor does it allow for practical recovery of nutrients. Furthermore, as effluent criteria become more stringent in some jurisdictions and sludge hydrolysis pre-treatment for digesters more common, an understanding of treatment options for ammonia in digester supernatant becomes more important. Given these considerations, a variety of side-stream treatment processes described in the literature are reviewed. PMID- 30017365 TI - Impact of lignin content on alkaline-sulfite pretreatment of Hybrid Pennisetum. AB - This work focuses to investigate the impact of lignin content on chemical compositions, crystallinity, surface characterizations, cellulase adsorption profiles and hydrolysability of Hybrid Pennisetum (HP) after alkaline sulfite pretreatment (ASP). For the HP with lower lignin content, the increase of the cellulose content by ASP was more obvious than raw HP. ASP decreased total lignin content and surface lignin content of HP substrates. HP with lower lignin content (e.g., ~15%) is suitable for ASP, because a pretty perfect glucose yield (91%) was obtained using a low dosage of enzyme loadings (5 FPU of cellulases/g dry matter). The study provides a potential strategy to efficiently produce platform sugars from HP with reduced lignin content, indicating the importance of reduction HP lignin content properly by breeding or transgenesis programs. The work could also help elucidate the mechanism of alkaline sulfite pretreatment for efficient production of fermentable sugars from lignocelluloses. PMID- 30017366 TI - Performances study of UV/O3-aMBR recirculation system in treating polluted surface water. AB - This study used UV/O3-aMBR system for treating polluted surface water with CODMn around 10 mg/L, to improve the removal of non-biodegradable components. UV/O3 was used in the recirculation stream, partially treating the recalcitrant in aMBR permeate to improve its biodegradability, and then send back to aMBR for biodegradation. Removal performance of UV/O3-aMBR system with recirculation ratio 20, 40, 60 and 80% was tested and compared. The removal of CODMn, UV254 and NH3-N increased with the increment of recirculation ratio. UV/O3-aMBR system has higher recalcitrant removal performance and less membrane fouling. The fluorescent dissolved organic matter (FDOM) was largely reduced in UV/O3-aMBR system, and the system hydrophilicity was higher than aMBR system. The Modified Stover Kincanoon model was able to describe UV/O3-aMBR system; and has higher Umax than aMBR system. UV/O3-aMBR can be develop as an effective technology in improving recalcitrant removal in polluted surface water treatment. PMID- 30017367 TI - A critical review of one-stage anammox processes for treating industrial wastewater: Optimization strategies based on key functional microorganisms. AB - The one-stage nitritation/anammox (anaerobic ammonium oxidation) process is an energy-saving technology, which has been successfully developed and widely applied to treat industrial wastewaters. For the one-stage nitritation/anammox process, key functional microbes generally include anaerobic ammonia oxidation bacteria (AnAOB), ammonia-oxidizing bacteria (AOB), nitrite oxidizing bacteria (NOB), and heterotrophic bacteria (HB). Cooperation and competition among the key functional microbes are critical to the stability and performance of anammox process. Based upon key functional microorganisms, this review summarizes and discusses the optimized strategies that promote the operation of one-stage nitritation/anammox process. In particular, the review focuses on strategies related to: (1) the retention of anammox biomass through granular sludge or biofilm, (2) the balanced relationship between AOB and AnAOB, (3) the NOB suppression and (4) the HB management by controlling the influent organic matter. In addition, the review proposes further research to address the existing challenges. PMID- 30017368 TI - A real-world analysis of cancer drug wastage due to oversized vials. AB - OBJECTIVES: A recent theoretical economic model suggested that oversized vials of cancer drugs lead to $1.8 billion of drug wastage annually in the United States. It is currently unknown how precisely this theoretical model is consistent with the real world. We performed a real-world analysis to assess the economic impact of drug wastage. METHODS: We performed a systematic examination of the usage and wastage of all intravenous cancer drugs in the cancer center of a large tertiary care hospital in Israel. During a period of 1 month, we collected usage and wastage data from the hospital's pharmacy dispensing computerized logs. We calculated the local financial impact using Israeli drug prices list (June 2016) from the ministry of health. We performed an additional analysis using discounted U.S. prices, using the October 2016 Average Sales Prices from the Centers of Medicare and Medicaid Services. RESULTS: Seventy-four injectable anticancer drugs were used during March 2016, and 68 Israeli drug prices were available. The total amount spent on wasted drugs in 1 month was then extrapolated to calculate the annual spending, which was $141,196 per month (5.11% of the total cost) or $1,694,352 per year. Using U.S. prices, the total wastage would be $2,208,876 annually. The 5 drugs that led to the highest expenditure on wastage were bortezomib, trastuzumab, azacytidine, pemetrexed and carfilzomib. There was no wastage of 24 of the 74 drugs. CONCLUSION: This real-world study demonstrates the economic impact of wastage of anticancer drugs on health systems. To decrease wastage, particular attention should be paid to drugs with high usage rates, high cost, and oversized vials. PMID- 30017369 TI - Inpatient pharmacists' patient referrals to a transitions-of-care pharmacist: Evaluation of an automated referral process. AB - OBJECTIVES: To evaluate the impact of a pharmacist screening and automated referral process that identifies patients at risk for readmission due to medication-related problems (MRPs). SETTING: University of Wisconsin (UW) Hospital is 505-bed flagship hospital that is part of UW Health, an academic health system. PRACTICE DESCRIPTION: The integrated pharmacy practice model at UW Health has inpatient pharmacists who perform discharge medication reconciliation. Before enhancing the screening and referral process, a transitions-of-care (TOC) pharmacist identified patients with the use of a low yield report and performed a second postdischarge medication reconciliation on selected patients. PRACTICE INNOVATION: A screening process was developed to identify patients at risk for readmission due to MRPs and allow for direct referral from inpatient pharmacists to a TOC pharmacist for postdischarge follow-up. EVALUATION: Patient characteristics, readmission risk, and readmission rate were compared between inpatient only (before referral) and inpatient plus second medication reconciliation (after referral). MRPs identified during medication reconciliation were quantified and categorized as provider or patient-associated. RESULTS: Before process improvement, 9 patients (5%) received a second medication reconciliation out of 175 patients who received standard-of-care inpatient medication reconcilation. After implementation, 45 patients (24%) received a second medication reconcilation out of 188 referrals. Patients referred for postdischarge follow-up with the TOC pharmacist had an average of 3.2 more medications and 2.7 more chronic conditions than before process implementation (P < 0.01). Both inpatient and TOC pharmacists identified at least 1 MRP in about two-thirds of patients (P = 0.60). Provider-associated MRPs were more commonly identified in both inpatient and postdischarge settings. CONCLUSION: Inpatient pharmacist screening is an effective method for identifying patients for referral to a TOC pharmacist to receive postdischarge follow-up. Despite the robustness of the inpatient medication reconciliation process in identifying provider associated MRPs, patient-associated MRPs still emerged after discharge that warranted additional pharmacist intervention. PMID- 30017370 TI - The effect of a pharmacist-led multidisciplinary transitions-of-care pilot for patients at high risk of readmission. AB - OBJECTIVES: To evaluate the feasibility and effect of a pharmacist-led transitions-of-care (TOC) pilot targeted to patients at high risk of readmission on process measures, hospital readmissions, and emergency department (ED) visits. SETTING: Academic medical center in Colorado. PRACTICE DESCRIPTION: Pharmacists enrolled patients identified as high risk for readmission in a TOC pilot from July 2014 to July 2015. The pilot included medication reconciliation, medication counseling, case management or social work evaluation, a postdischarge telephone call, and an expedited primary care follow-up appointment. PRACTICE INNOVATION: Implementation and evaluation of the pharmacist-led TOC pilot program with risk score embedded into the electronic health record. EVALUATION: Comparison of TOC related process measures and clinical outcomes between pilot patients and randomly matched control patients included readmissions or ED visits at 30 and 90 days. RESULTS: We enrolled 34 pilot patients and randomly matched them to 34 control patients. The intervention took an average of 57.1 minutes for pharmacists to deliver. More pilot patients had a case management or social work note compared with control patients (88% vs. 59%; P = 0.006 [statistically significant]). Readmission rates in pilot versus nonpilot patients, respectively, were 18% versus 24% (P = 0.547) at 30 days and 27% versus 39% (P = 0.296) at 90 days. The composite outcome of a readmission or ED visit in pilot versus nonpilot patients was 24% versus 30% (P = 0.580) at 30 days and 36% versus 49% (P = 0.319) at 90 days. CONCLUSION: A pharmacist-led TOC pilot demonstrates potential for reducing hospital readmissions. The intervention was time intensive and led to creation of a TOC pharmacist role to implement medication-related transitional care. PMID- 30017371 TI - A review of suicide prevention programs and training policies for pharmacists. AB - OBJECTIVES: The availability of suicide prevention training programs for pharmacists is unknown and may depend on state training requirements. This study's objectives were to: 1) report state training requirements for pharmacist suicide education; and 2) describe educational resources that are available to prepare pharmacists for interactions with patients at risk of suicide. METHODS: Each state's board of pharmacy was contacted from July to November 2017 to determine whether that state required pharmacists to complete suicide prevention training. A scoping literature review completed in August 2017 identified suicide prevention resources for pharmacy professionals. A systematic search of 5 databases and Google yielded publications and online resources that were screened for full review. Two coders reviewed articles and resources that met inclusion criteria and extracted data on program format and length, intended audience (i.e., students, practicing pharmacists), learning methods, topics covered, and outcomes assessed. RESULTS: Only Washington State requires pharmacists to obtain suicide prevention training. Sixteen suicide education programs and resources targeted pharmacists, including 8 in-person courses, 6 online courses, and 2 written resources. Five resources exclusively targeted pharmacists and 2 exclusively targeted student pharmacists. Most programs included information on suicide statistics, how to identify individuals at risk of suicide, how to communicate with someone who is suicidal, and how to refer patients to treatment resources. The long-term effectiveness of the programs at improving outcomes was not reported. CONCLUSION: Although only 1 state requires pharmacists to obtain training on suicide prevention, there are several resources available to help prepare pharmacists to interact with individuals at risk of suicide. PMID- 30017372 TI - Sleep study indices and early post-tonsillectomy outcomes. AB - OBJECTIVES: To investigate the relationships between preoperative sleep study findings of children undergoing adenotonsillectomy anesthesia emergence time, recovery room time, and length of stay. STUDY DESIGN: Retrospective case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: All children aged 1-17 years who had undergone adenotonsillectomy between 2013 and 2016 were included. Apnea-hypopnea index (AHI), central apnea index (CAI), oxygen saturation nadir, and end-tidal carbon dioxide were compared with the in-operating room times, recovery room time, and length of stay. RESULTS: Three hundred and fourteen patients with a mean age of 6.67 (95% CI 6.25 7.09) years were included. Mean AHI was 9.14 (95% CI 7.33-10.95), mean CI was 0.88 (95% CI 0.50-1.26), mean oxygen saturation nadir was 82.9% (95% CI 81.41 84.32), mean end-tidal carbon dioxide was 50.3 (95% CI 49.39-51.15). Mean emergence time was 16 min (95% CI 15:11-17:13 min), recovery room time was 66 min (95% CI 1:00-1:11 h), and length of stay was 25.7 h (95% CI 21:43-30:00 h). When controlled for age, gender and BMI, linear regression showed that children with a higher AHI had a significantly longer operating room and operative times (p < 0.001), emergence time (p < 0.001) and length of stay (p = 0.01). CAI was related to shorter total operating room times (p = 0.03). AHI, oxygen saturation nadir, CAI and end-tidal carbon dioxide were not associated with recovery room time. CONCLUSION: Preoperative sleep study indices are associated with longer in operating room times and length of stay, and can be useful in planning operating room and hospital flow. PMID- 30017374 TI - Sublingual gland excision for the surgical management of plunging ranula. AB - OBJECTIVE: A plunging ranula is a pseudocystic collection of mucin extravasated from the sublingual gland into the floor of mouth and through the mylohyoid muscle into the neck. While the lining of a ranula is non-secreting and resection of the sublingual gland is adequate for simple sublingual mucoceles, many surgeons attempt to address plunging ranulas with extensive transoral and transcervical dissections. We review our experience managing plunging ranulas with intraoral sublingual gland excision and ranula drainage alone. METHODS: This is a case series of patients with plunging ranulas who underwent transoral sublingual gland excision and ranula drainage in the past 10 years at the Massachusetts Eye and Ear. All ranulas were confirmed by radiographic imaging. Data were gathered from the medical record and telephone surveys. RESULTS: Twenty one patients with 22 distinct ranulas underwent this surgical approach. Average ranula size on imaging was 4.3 cm (SD = 1.3). Thirteen patients with 14 ranulas were followed up for greater than 6 months while the remaining 7 patients were lost to follow-up. Median follow-up for the 13 patients was 30 months (range 6 to 80). One ranula recurred requiring excision of residual sublingual gland (7%). One patient developed a local infection that was treated with antibiotics (7%). No long term complications were reported. CONCLUSION: Simple transoral excision of the sublingual gland with ranula drainage is sufficient for treatment of plunging ranulas. It is essential to obtain a full resection of the gland to prevent relapse. This limited approach has low rates of complications and ranula recurrence. PMID- 30017373 TI - Total intravenous versus inhaled anesthesia in transsphenoidal tumor surgery. AB - PURPOSE: Visualization of the surgical field is essential for patient safety during endoscopic transsphenoidal tumor surgery. In this retrospective chart review and data analysis of patients undergoing endoscopic transsphenoidal resection of pituitary tumors under general anesthesia we sought to determine if total intravenous anesthesia with propofol and remifentanil leads to decreased bleeding, surgical duration, time to extubation and/or length of stay in the recovery room compared to inhaled anesthesia with sevoflurane or desflurane. METHODS: After IRB approval, chart reviews of 193 American Society of Anesthesiologists class 1 to 3 patients were conducted who had undergone transsphenoidal, endonasal resections of pituitary tumors under total intravenous or inhaled anesthesia at an academic teaching hospital in the United States over a seven-year time period. One hundred four patients fulfilled the inclusion criteria and were further reviewed. Primary outcome was intraoperative blood loss; secondary outcomes were surgical duration, time to extubation and length of stay in the recovery room. RESULTS: Gender, age, and Lund-Mackay-Scores were equally distributed between the two anesthetic groups. We found no significant effect of the anesthetic technique, age, gender, or Lund Mackay score on any of the primary or secondary outcomes. The only significant predictor for recovery room length of stay was intraoperative blood loss. CONCLUSION: Our study shows no evidence that total intravenous anesthesia is superior to inhaled anesthesia or vice versa during endoscopic transsphenoidal sinus surgery with regard to relevant clinical outcome parameters. PMID- 30017375 TI - Does long-term success from endoscopic DCR correlate with early post-operative reduction in tearing? AB - PURPOSE: The purpose of the study was to determine the association between early post-operative improvement in tearing and the long-term success rate of endoscopic dacryocystorhinostomy (eDCR). METHODS: A retrospective review of consecutive patients who underwent eDCR and were followed up for at least 6 months at our institution from January 2010 to December 2017 was performed. RESULTS: 47 cases(39 patients) of eDCR met the inclusion and exclusion criteria during this time period. Mean follow up after the surgery was 12.5 +/- 8 months. In 45 out of 47 (96%) cases post-operative improvement in epiphora within 2 weeks of surgery, or lack thereof, correlated with long-term success or failure of the procedure. There were only 2 cases in which the patients felt improvement in tearing at the initial post-operative visit and the tearing recurred in the late post-operative period (>6 months). CONCLUSIONS: There is a strong association between the early initial post-operative assessment of tearing resolution and the long-term result of eDCR. PMID- 30017376 TI - [Involvement of addictovigilance in emergency department for the detection of abuse and dependence cases: 3 years of experience]. AB - INTRODUCTION: Due to the increase of hospitalization at emergency department (ED) related to psychoactive substances use (PSU), the addictovigilance center of Montpellier has been integrated into the URGEIM program for the detection of iatrogenic events at the ED. The objective of the present work was to analyze spontaneous reports (SR) collected via the URGEIM program. METHODS: Analysis of spontaneous reports related to PSU at the ED of the Montpellier University Hospital, collected through the URGEIM program, between January 2014 and December 2016. RESULTS: During the study period, 160 SR were collected through the URGEIM program on 1118 SR collected by the Addictovigilance center over the period: 40SR/342 in 2014, 46 SR/303 in 2015 and 74 SR/473 in 2016. Most patients were male (70%) and the mean age at admission was 33 years old. A total of 240 psychoactive substances were identified with 160 illicit substances (66.6%) [cocaine 38.1%, cannabis 30.6%] and 80 medications (33.3%) [buprenorphine 22.5%, benzodiazepines 20% and methadone 18.8%]. Mental and behavioral disorders (20.0%), general health problems associated with substance use (17.5%), cardiovascular diseases (13.1%) and infectious diseases (12.5%) were the main reported effects. The duration of emergency stay was inferior to 12hours in 63.1% of cases and greater than 24hours in 12.5% of cases. In 69.4% of cases, the event was considered as serious. The outcome was unknown for 6.9% of patients. CONCLUSION: The number of SR from ED has increased over the study period, with the notification of serious and worrying cases, and the possibility of setting up actions. The deployment of addictovigilance within clinical services is a significant factor for notification and quality of care. PMID- 30017377 TI - Differences in the auxological characters of children with short stature - Differential diagnostic possibilities of hypothyreosis. AB - This study aimed to define the differences in growth characteristics in the three most frequent causes of growth retardation - growth hormone deficiency, hypothyreosis and constitutional delay of growth and development - in order to provide diagnostic means for distinguishing these disorders. The study included 166 children with growth disorders aged 4-18 years. The height for age, the bone age using the TW3 method, the predicted height as the target height and the current prediction using the TW3 method were studied. For bone age, the radius, ulna and short bones compartment (RUS) and carpal bones (CARP) were evaluated separately and the difference in their delay in relation to chronological age (DeltaBA_RUS_CARP) was determined. The relationship of the studied variables with sex and the underlying diagnosis was tested and the relationship of hypothyreosis and growth data was estimated. The model was tested on the growth data of 104 randomly selected patients with a growth disorder. The largest significant distinction was demonstrated by the difference DeltaBA_RUS_CARP in hypothyreosis. The created linear regression model was highly statistically significant (chi2 = 19.4, p < 0.0001) and showed high selectivity (0.609, 95% CI 0.409; 0.808) as well as high specificity (0.864, 95% CI 0.781; 0.946). The clinical validity of the model demonstrated a 61% predictive value for the detection and an 81% successful specification of hypothyreosis. The study demonstrated the possibility of distinguishing suspected hypothyreosis from other causes of growth retardation based on differences in severity of the ossification delay in skeletal compartments of the hand. PMID- 30017378 TI - Sinistrality is associated with (slightly) lower general intelligence: A data synthesis and consideration of the secular trend in handedness. AB - The relationship between the general factor of intelligence (g) and handedness is investigated using a combined sample of 23511 respondents from three large databases: the NLSY'79 (US), NLSY'97 (US) and NCDS (UK). Dextrals - those who use their right hands were found to be 1.22 IQ points higher than sinistrals (left handers) after controlling for sex and age and correcting for sources of measurement error. To see if the association between IQ and handedness was strongest on the abilities that were the best measures of g, the method of correlated vectors was used to test for moderation. Across the three studies, g was found to very weakly negatively moderate the association between ability measure and handedness (rho = -.023, K = 3, N = 23511), however in the NLSY'79, the coding speed subtest was an outlier in terms of the strength of its association with handedness. Its removal yielded indications of positive moderation in this dataset, which when aggregated boosted the overall vector correlation value to .539 (K = 3, N = 23511), suggesting that g might be an important moderator of this relationship. Secondary analysis of secular trend data on the changing percentage of sinistrals in Western populations indicates that overall, sinistrality has increased, entailing a g decline of .106 points over 150 years (.006 points per decade). The secular increase in sinistrality is consistent with other data indicating long-term declines in developmental stability and may stem from some combination of increasing mutation load and environmental stress in Western populations. PMID- 30017379 TI - Spatial diffusion of surnames by long transhumance routes between highland and lowland: A study in Sardinia. AB - RIASSUNTO. PMID- 30017380 TI - Fatal autoimmune myocarditis with anti-PD-L1 and tyrosine kinase inhibitor therapy for renal cell cancer. PMID- 30017381 TI - Monitoring potentially modifiable lifestyle factors in cancer survivors: A narrative review on currently available methodologies and innovations for large scale surveillance. AB - In most European countries, the prevalence of cancer has increased from 1-3% in the 1990's to 4-5% in the 2010's. This increase is largely due to earlier detection and improved treatment. The number of cancer patients who survive longer than 5 years after their primary diagnosis is increasing, emphasizing the need for research in cancer survivors focussing on improving quality of life and cancer prognosis. In this narrative review, we provide an overview of the current and novel methodologies for the ambulant assessment of potentially modifiable lifestyle factors in large-scale prospective studies and discuss future innovations for optimal surveillance of cancer survivors. Lifestyle factors described are potentially modifiable and include dietary intake, body composition, alcohol consumption, smoking behaviour and physical activity. To date, mostly questionnaires are used, but many monitoring tools are already available that allow ambulant measurements. However, technological improvements are still needed to longitudinally measure lifestyle factors on a large scale from diagnosis onwards. Measuring lifestyle factors non-invasively in a home setting could help to increase its feasibility and ultimately improve our understanding of the individual and synergistic effects of lifestyle factors on quality of life and long-term outcomes. In the process of developing such surveillance programmes, several aspects should be taken into account including, but not limited to, methodological considerations, study design optimisation, patient perspectives, privacy issues and information and communications technology solutions to capture, store and analyse big data. Future large-scale lifestyle surveillance studies in cancer survivors will, in addition to questionnaires, increasingly include ambulant monitoring using sensors and wireless tools as this lowers patient burden, provides objective information and facilitates longitudinal data collection. PMID- 30017382 TI - Towards the standard use of (neo)adjuvant chemotherapy in selected localised soft tissue sarcoma at high risk of relapse: are we finally getting there? PMID- 30017383 TI - Developments in the understanding of blood involvement and stage in mycosis fungoides/Sezary syndrome. PMID- 30017384 TI - Comment on B ratings for erythrodermic cutaneous T-cell lymphoma. PMID- 30017385 TI - Nocardiosis in a patient with anti-PD-1-associated colitis treated with infliximab. PMID- 30017386 TI - Autologous graft-versus-host disease with combined immune checkpoint blockade. PMID- 30017387 TI - Silencing of the interferon-inducible gene Ifi204/p204 induces resistance to interferon-gamma-mediated cell growth arrest of tumor cells. AB - Many tumor cells escape from cancer immunosurveillance and resist treatment with interferons (IFNs). Although the mechanism underlying IFN resistance is mostly attributed to a deficiency of components of the IFN-signaling pathway, some types of tumor cells resist IFN-mediated cell growth arrest despite the presence of an intact JAK/STAT signaling pathway. However, the molecular mechanisms underlying the unresponsiveness to IFNs independent of the defective JAK/STAT pathway remain to be clarified. To elucidate the mechanisms underlying IFNgamma resistance, we examined the anti-proliferative effect of IFNgamma on mouse tumor cell lines. Mouse squamous cell carcinoma (SCCVII) cells were resistant to IFNgamma-mediated cell growth arrest despite the presence of the IFNgamma-induced STAT1-dependent signaling pathway, whereas IFNgamma inhibited cell growth of B16/F1 cells, a well known IFNgamma-sensitive mouse melanoma cell line, at the G1 phase of the cell cycle. Treatment of SCCVII cells with IFNgamma neither downregulated the expression of cyclin D1, cyclin A2, and cyclin E1 nor induced a hypo phosphorylated, active form of retinoblastoma protein (pRb). Interestingly, the hyper-phosphorylated, inactive form of pRb was exclusively localized in the cytoplasm in SCCVII cells. The IFN-inducible 204 gene (Ifi204), whose gene product, p204, binds to pRb and exerts an anti-proliferative effect, was repressed in SCCVII cells. p204 overexpression in SCCVII significantly inhibited cell growth, and mutation of a pRb-binding LXCXE motif decreased the anti proliferative effect. These results suggest that silencing of Ifi204/p204 induces resistance to IFNgamma-mediated cell growth arrest in SCCVII cells. PMID- 30017388 TI - The impact of IL-10 dynamic modulation on host immune response against visceral leishmaniasis. AB - Leishmaniasis is a vector-borne disease caused by protozoan parasites from the genus Leishmania. The most severe form of disease is visceral leishmaniasis (VL), which is fatal if left untreated. It has been demonstrated that interleukin (IL) 10, is associated with disease progression and susceptibility. In this work, we took advantage of a transgenic mouse model that expresses high levels of IL-10 upon zinc sulfate administration (pMT-10). We addressed the role of IL-10 during the initial stages of L. donovani infection by analyzing the parasite burden in the spleen and liver of the infected pMT-10 and WT mice as well as the histopathological alterations upon IL-10 induction. Furthermore, the profile of cytokines expressed by T cells was assessed. Our results demonstrate that an increase in IL-10 production has an impact early but not later after infection. This specific temporal role for IL-10-mediated susceptibility to VL is of interest. PMID- 30017389 TI - Leprosy and its reactional episodes: Serum levels and possible roles of omega-3 and omega-6-derived lipid mediators. AB - The disease leprosy is caused by Mycobacterium leprae. The disease displays a spectrum of clinical manifestations relating to the stage of the infection and the pathogen-specific immune response. The most frequent M. leprae-specific hypersensitivity reactions are erythema nodosum leprosum (ENL) and type-1 (reversal) reaction (T1R). Omega-3 and omega-6 fatty acid-derived lipid mediators are involved in the regulation of these M. leprae-specific inflammatory and immune responses. Studies on lipid mediators showed their presence during different manifestations of leprosy-before and after multidrug therapy (MDT) and during T1R. This review aims to compare the lipid mediators at different stages of the disease. This review also presents new data on the significance of lipid mediators (cysteinyl leukotrienes and leukotriene B4, prostaglandin E2 and D2, lipoxin A4 and resolvin D1) on ENL. PMID- 30017390 TI - Methylation of RNA N6-methyladenosine in modulation of cytokine responses and tumorigenesis. AB - Among myriads of distinct chemical modification in RNAs, the dynamic, reversible and fine-tuned methylation of N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic mRNAs. This RNA mark is generated by proteins that act as m6A writers and can be reversed by proteins that act as m6A erasers. The RNA m6A modification is also mediated by another group of proteins capable of recognizing m6A that act as m6A readers. The m6A modification exerts direct control over the RNA metabolism including mRNA processing, mRNA exporting, translation initiation, mRNA stability and the biogenesis of long-non-coding RNA (LncRNA), thereby can influence various aspects of cell function. Evidently, m6A is intimately associated with cancer development and progression such as self renewal capacity of cancer stem cells, proliferation, apoptosis and therapeutic resistance, and immune response. In this review, we will discuss the regulation and function of m6A, the various functions ascribed to these proteins and the emerging concepts that impact our knowledge of these proteins and their roles in the epitranscriptome. Conceivably, m6A may play pivotal roles in cytokine and immune response and carcinogenesis. PMID- 30017391 TI - [Impact of the obstructive sleep hypopnea-apnea syndrom treated on employment for military employment]. AB - INTRODUCTION: The diurnal hypersomnia associated with obstructive sleep apnea (OSA) affects soldier employment and deployability. In this study, we examined the impact of OSA on the employment of soldiers on continuous positive airways pressure (CPAP) therapy by measuring several items: work absenteeism using the Work Productivity and Activity Impairment (WPAI) questionnaire, diurnal hypersomnia, and career advancement. METHODS: A questionnaire was sent by regular mail to 940 soldiers with OSA on CPAP therapy who are insured by the French Military Healthcare Fund (Caisse Nationale Militaire de Securite Sociale). RESULTS: Questionnaires were returned by 439 soldiers: mean age 47 years; mean body mass index 29.8kg/m2. Absenteeism reached 0.45%, and work productivity impairment 8.7%. Hypersomnia was reported by 15.4% and was severe for 9.7%. The average daily working time was 6.5hours. Quality of life was improved for 91.1%. The military practitioner had diagnosed OSA in 19.6% of these soldiers and had prescribed treatment in 14.9%. DISCUSSION: Residual OSA in these soldiers on CPAP therapy had little impact on work productivity impairment that was less than observed in populations with chronic diseases. In our study population, hypersomnia was less common than observed in the general population. An impact on career advancement could not be clearly demonstrated. Close medical follow-up is warranted in certain populations due to the persistence of severe somnolence in a significant number of patients. PMID- 30017394 TI - Sensorimotor Integration and Amplification of Reflexive Whisking by Well-Timed Spiking in the Cerebellar Corticonuclear Circuit. AB - To test how cerebellar crus I/II Purkinje cells and their targets in the lateral cerebellar nuclei (CbN) integrate sensory and motor-related inputs and contribute to reflexive movements, we recorded extracellularly in awake, head-fixed mice during non-contact whisking. Ipsilateral or contralateral air puffs elicited changes in population Purkinje simple spike rates that matched whisking kinematics (~1 Hz/1 degrees protraction). Responses remained relatively unaffected when ipsilateral sensory feedback was removed by lidocaine but were reduced by optogenetically inhibiting the reticular nuclei. Optogenetically silencing cerebellar output suppressed movements. During puff-evoked whisks, both Purkinje and CbN cells generated well-timed spikes in sequential 2- to 4-ms windows at response onset, such that they alternately elevated their firing rates just before protraction. With spontaneous whisks, which were smaller than puff evoked whisks, well-timed spikes were absent and CbN cells were inhibited. Thus, sensory input can facilitate millisecond-scale, well-timed spiking in Purkinje and CbN cells and amplify reflexive whisker movements. PMID- 30017392 TI - Entrainment of Circadian Rhythms Depends on Firing Rates and Neuropeptide Release of VIP SCN Neurons. AB - The mammalian suprachiasmatic nucleus (SCN) functions as a master circadian pacemaker, integrating environmental input to align physiological and behavioral rhythms to local time cues. Approximately 10% of SCN neurons express vasoactive intestinal polypeptide (VIP); however, it is unknown how firing activity of VIP neurons releases VIP to entrain circadian rhythms. To identify physiologically relevant firing patterns, we optically tagged VIP neurons and characterized spontaneous firing over 3 days. VIP neurons had circadian rhythms in firing rate and exhibited two classes of instantaneous firing activity. We next tested whether physiologically relevant firing affected circadian rhythms through VIP release. We found that VIP neuron stimulation with high, but not low, frequencies shifted gene expression rhythms in vitro through VIP signaling. In vivo, high frequency VIP neuron activation rapidly entrained circadian locomotor rhythms. Thus, increases in VIP neuronal firing frequency release VIP and entrain molecular and behavioral circadian rhythms. VIDEO ABSTRACT. PMID- 30017393 TI - Melanopsin Phototransduction Is Repurposed by ipRGC Subtypes to Shape the Function of Distinct Visual Circuits. AB - Melanopsin is expressed in distinct types of intrinsically photosensitive retinal ganglion cells (ipRGCs), which drive behaviors from circadian photoentrainment to contrast detection. A major unanswered question is how the same photopigment, melanopsin, influences such vastly different functions. Here we show that melanopsin's role in contrast detection begins in the retina, via direct effects on M4 ipRGC (ON alpha RGC) signaling. This influence persists across an unexpectedly wide range of environmental light levels ranging from starlight to sunlight, which considerably expands the functional reach of melanopsin on visual processing. Moreover, melanopsin increases the excitability of M4 ipRGCs via closure of potassium leak channels, a previously unidentified target of the melanopsin phototransduction cascade. Strikingly, this mechanism is selective for image-forming circuits, as M1 ipRGCs (involved in non-image forming behaviors), exhibit a melanopsin-mediated decrease in excitability. Thus, melanopsin signaling is repurposed by ipRGC subtypes to shape distinct visual behaviors. PMID- 30017395 TI - Functional Networks for Social Communication in the Macaque Monkey. AB - All primates communicate. To dissect the neural circuits of social communication, we used fMRI to map non-human primate brain regions for social perception, second person (interactive) social cognition, and orofacial movement generation. Face perception, second-person cognition, and face motor networks were largely non overlapping and acted as distinct functional units rather than an integrated feedforward-processing pipeline. Whereas second-person context selectively engaged a region of medial prefrontal cortex, production of orofacial movements recruited distributed subcortical and cortical areas in medial and lateral frontal and insular cortex. These areas exhibited some specialization, but not dissociation, of function along the medio-lateral axis. Production of lipsmack movements recruited areas including putative homologs of Broca's area. These findings provide a new view of the neural architecture for social communication and suggest expressive orofacial movements generated by lateral premotor cortex as a putative evolutionary precursor to human speech. PMID- 30017397 TI - Re: Gladell P. Paner, Walter M. Stadler, Donna E. Hansel, Rodolfo Montironi, Daniel W. Lin, Mahul B. Amin. Updates in the Eighth Edition of the Tumor-node metastasis Staging Classification for Urologic Cancers. Eur Urol 2018;73:560-9: Tumour, Node, and Metastasis Staging System for Urological Malignancies: Are We Ready for the Next Step? PMID- 30017398 TI - Re: Giorgio Gandaglia, Carlo Andrea Bravi, Paolo Dell'Oglio, et al. The Impact of Implementation of the European Association of Urology Guidelines Panel Recommendations on Reporting and Grading Complications on Perioperative Outcomes after Robot-assisted Radical Prostatectomy. Eur Urol 2018;74:4-7. PMID- 30017399 TI - Re: Brandon A. Mahal, David D. Yang, Natalie Q. Wang, et al. Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High-grade Prostate Cancer. Eur Urol 2018;74:146-54. PMID- 30017396 TI - Radial Glial Lineage Progression and Differential Intermediate Progenitor Amplification Underlie Striatal Compartments and Circuit Organization. AB - The circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of these organizations and their developmental relationships are unknown, leaving a conceptual gap in understanding the cortico-basal ganglia system. Through genetic fate mapping, we demonstrate that striosome-matrix compartmentalization arises from a lineage program embedded in lateral ganglionic eminence radial glial progenitors mediating neurogenesis through two distinct types of intermediate progenitors (IPs). The early phase of this program produces striosomal spiny projection neurons (SPNs) through fate-restricted apical IPs (aIPSs) with limited capacity; the late phase produces matrix SPNs through fate-restricted basal IPs (bIPMs) with expanded capacity. Notably, direct and indirect pathway SPNs arise within both aIPS and bIPM pools, suggesting that striosome-matrix architecture is the fundamental organizational plan of basal ganglia circuitry. PMID- 30017400 TI - The Probability of Aggressive Versus Indolent Histology Based on Renal Tumor Size: Implications for Surveillance and Treatment. AB - BACKGROUND: While the probability of malignant versus benign histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent malignant tumors can be managed with active surveillance. OBJECTIVE: To characterize the probability of aggressive versus indolent histology based on radiographic tumor size. DESIGN, SETTING, AND PARTICIPANTS: We evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990 and 2010. Pathology was reviewed by one genitourinary pathologist. High-grade clear-cell renal cell carcinoma (RCC), high-grade papillary RCC, collecting duct RCC, translocation-associated RCC, hereditary leiomyomatosis RCC, unclassified RCC, and malignant non-RCC tumors were all considered aggressive, as well as any tumors demonstrating coagulative necrosis (except low-grade papillary RCC) or sarcomatoid differentiation. The remaining benign and malignant tumors were considered indolent. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer specific survival (CSS) was estimated using the Kaplan-Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed. RESULTS AND LIMITATIONS: Of the 2650 patients included, there were 1860 patients with indolent tumors (300 benign; 1560 malignant) and 790 with aggressive tumors. The 10-yr CSS was 96% for indolent malignant tumors and 81% for aggressive malignant tumors. The predicted percentages of any malignant histology as well as aggressive histology increased with tumor size. Specifically, 2cm, 3cm, and 4cm tumors have an estimated 84%, 87%, and 88% likelihood of malignancy, respectively, and an 18%, 24%, and 29% likelihood of aggressive histology, respectively. For any given tumor size, men had a greater chance of aggressive histology than women. Potential limitations of this observational surgical cohort include selection bias. CONCLUSIONS: We present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for initial patient counseling and management. PATIENT SUMMARY: Active surveillance is an option for kidney masses, even if they are malignant. Beyond knowing whether the mass is benign or cancer, it is important to know whether or not it is an aggressive tumor. This study presents tumor size-specific and sex-specific estimates of the probability of cancer overall and aggressive cancer among patients with a kidney mass in order to aid with initial decision-making. PMID- 30017401 TI - Simultaneous Bilateral Endoscopic Surgery (SBES) for Patients with Bilateral Upper Tract Urolithiasis: Technique and Outcomes. AB - BACKGROUND: The incidence of bilateral and multiple renal stones is not negligible. To date, some sparse data on simultaneous bilateral stone surgery are available in literature showing good outcomes in terms of both effectiveness and safety. OBJECTIVE: To describe our series of patients with bilateral renal stones who underwent simultaneous bilateral endoscopic surgery (SBES), reporting its effectiveness and safety. DESIGN, SETTING, AND PARTICIPANTS: A prospective analysis of 27 consecutive patients who underwent simultaneous flexible ureteroscopy (fURS) in one side and percutaneous nephrolithotomy (PCNL) in the other side for bilateral renal stones was performed. SURGICAL PROCEDURE: SBES, performing fURS in one side and PCNL in the other side contemporaneously. MEASUREMENTS: Clinical data were collected in a dedicated database. Intra- and postoperative outcomes were assessed. Comparisons among pre- and postoperative serum creatinine levels and estimated glomerular filtration rate values during the study period were performed using the Kruskal-Wallis test with the Dunn multiple comparison test. RESULTS AND LIMITATIONS: All the procedures were carried out until the end in both sides without encountering any complications intraoperatively. The mean stone size was 27.1+/-8.1 and 11.1+/-3.6mm for the PCNL and fURS side respectively. The mean operative time was 79.4+/-25.2min. There were no differences in patients' creatinine and eGFR when comparing at baseline with 1-mo after SBES. No postoperative major complications were experienced (Clavien-Dindo grade I 3.7%; II 11.1%). Stone-free rate was 74% at 1 mo follow-up. The main limitation of the study is the small size of the group analyzed. CONCLUSIONS: SBES is safe and effective, with minimal morbidity. SBES has the potential advantages of shorter operative time, reduced anesthesia, and reduced hospital time, which can benefit patients, surgeons, and health care systems. PATIENT SUMMARY: Simultaneous bilateral endoscopic surgery is an effective treatment with low complication rates for bilateral urolithiasis. This innovative and complicated procedure should be performed in high-volume centers by experienced surgeons. PMID- 30017402 TI - Therapeutic Discovery for Castration Resistant Prostate Cancer: Patient-derived Xenograft Modelling Brings New Options to the Table. PMID- 30017403 TI - Prediction of Aggressive Histology: The Ongoing Dilemma of Renal Masses in the "Omics" Era. PMID- 30017404 TI - Active Surveillance Magnetic Resonance Imaging Study (ASIST): Results of a Randomized Multicenter Prospective Trial. AB - BACKGROUND AND OBJECTIVE: This study aimed to determine, in men recently diagnosed with grade group 1 (GG1) prostate cancer, if magnetic resonance imaging (MRI) with targeted biopsy could identify a greater proportion of men with GG >=2 cancer on their confirmatory biopsy compared with systematic biopsies. The study was registered with www.clinicaltrials.gov (NCT01354171). DESIGN, SETTING, AND PARTICIPANTS: This study is a prospective, randomized, multicenter, open-label trial. Eligible patients were men diagnosed with GG1 cancer within 1 yr prior to study entry in whom a confirmatory biopsy was indicated. Patients were randomized to 12-core systematic biopsy or MRI with systematic and targeted biopsy using the Artemis fusion targeting system. The primary end point was the proportion upgraded to GG >=2 in each arm. RESULTS AND LIMITATIONS: In total, 296 men were registered and 273 randomized. Of the MRI group, 64% had a region of interest. No difference was observed in the rate of GG >=2 upgrading (the intent-to-treat population, p=0.7, and per-protocol [PP] population, p=0.4), GG >=2 upgrading within each stratum separately, or GG >=3. After central pathology review, upgrading was observed in 36/132 (27%) men in the systematic biopsy arm and 42/127 (33%) men in the MRI arm (p=0.3). Upgrading was seen in 19/137 (14%) patients in the MRI arm on targeted biopsy alone (median, 2 cores) compared with 31/136 (23%) in the systematic biopsy arm (median, 12 cores; p=0.09). In the MRI arm, 8/127 (6.5%) patients had GG >=2 disease identified on targeted biopsy, but <=GG1 on the systematic biopsy, and 10/127 (7.9%) patients had GG >=2 disease identified by systematic biopsy but <=GG1 on targeted biopsy. Significant differences in upgrading on targeted biopsies were seen between sites, likely reflecting different levels of expertise with the targeted biopsy technique. CONCLUSIONS: The addition of MRI with targeted biopsies to systematic biopsies did not significantly increase the upgrading rate compared with systematic biopsy alone. Furthermore, 2-core targeted biopsies alone resulted in a nonsignificant trend to less upgrading than 12-core systematic biopsy (p=0.09). In men on active surveillance, targeted biopsies identify most, but not all, clinically significant cancers. PMID- 30017405 TI - Treatment Strategy for Newly Diagnosed T1 High-grade Bladder Urothelial Carcinoma: New Insights and Updated Recommendations. AB - CONTEXT: High-grade T1 (T1HG) bladder cancer (BCa) has a very high likelihood of disease recurrence and progression to muscle invasion. Radical cystectomy is considered the best chance at cure, albeit with a high risk of morbidity, and is overtreatment for some patients. Treatment with bacillus Calmette-Guerin (BCG) allows bladder preservation but may risk disease progression. OBJECTIVE: To systematically review the current literature on the management of T1HG BCa and provide updated treatment recommendations. EVIDENCE ACQUISITION: Medline, EMBASE, and Epub Ahead of Print databases were searched in November 2017 to identify observational cohort studies and controlled trials, between 1946 and 2017, associated with diagnosis, treatment, and prognosis of T1HG BCa. EVIDENCE SYNTHESIS: Clinical understaging and/or persistence of disease is not uncommon at initial transurethral resection (TUR); thus, a second re-TUR is recommended for cases with T1HG BCa. Patients electing a bladder preservation approach should undergo induction BCG therapy followed by a maintenance schedule, while patients with several high-risk features should consider immediate cystectomy and those with BCG-refractory or BCG-unresponsive disease should be considered for early cystectomy. Current phase I/II clinical trials for T1HG patients may offer future bladder preservation therapy approaches. CONCLUSIONS: T1HG tumours are heterogeneous in nature and challenging to treat. Bladder preservation with BCG induction and maintenance, or radical cystectomy is the current standard treatment modality of choice for these tumours. Promising therapies for BCG unresponsive disease are currently under investigation. PATIENT SUMMARY: Patients with high-grade T1 bladder cancer are at a high risk of tumour recurrence and progression, requiring more aggressive treatment such as bladder removal. Bladder preservation therapies are available (and new therapies are being tested in clinical trials); however, patients should be aware that currently bladder removal is considered the best opportunity for cancer cure. PMID- 30017406 TI - Re: Exercise and Cancer Treatment: Balancing Patient Needs. Lancet Oncol 2018;19:715: Cancer Prevention and Treatment: More than Exercising. PMID- 30017407 TI - Comparison of CA125, HE4, and ROMA index for ovarian cancer diagnosis. AB - OBJECTIVE: In view of the high rate of misdiagnosis of ovarian cancer, our study aimed to compare the performances of serum levels of human epididymis secretory protein 4 (HE4) and cancer antigen 125 (CA125), as well as ROMA index in the diagnosis of ovarian cancer. METHODS: Three hundred and seventy-three patients who suffered ovarian cancer were selected in Tianjin Medical University Cancer Institute and Hospital from July 2016 to July 2017. Patients were divided into premenopause group and postmenopause group. Based on the results of pathologic examinations, patients were divided into malignant, benign, and borderline groups, which were further divided into different pathologic type groups. HE4 and CA125 serum levels in each patient were detected and the ROMA index was analyzed. ROC curve analysis was conducted to compare the performances of serum CA125, serum HE4, and ROMA index in the diagnosis of ovarian cancer. RESULTS: Proportion of postmenopausal patients in malignant group (65.2%) was significantly higher than that in the benign group (34.3%). Serum levels of CA125 and HE4, and ROMA index were higher in patients with different types of malignant tumor than those in corresponding benign group. Serum HE4, serum CA125, and ROMA index had better performance in the diagnosis of postmenopausal ovarian cancer than that of premenopausal ovarian cancer. The overall performance of ROMA and HE4 was better than that of CA125, but it was affected by pathologic types. CONCLUSIONS: Serum HE4, serum CA125, and ROMA can be used to predict ovarian cancer. HE4 and ROMA have better performance than CA125 in most cases, but pathologic types can also affect them. PMID- 30017408 TI - Evaluation of written and video education tools after mallet finger injury. AB - STUDY DESIGN: Prospective cohort. INTRODUCTION: Successful nonoperative treatment of mallet finger injuries requires compliance to prolonged immobilization and understandable educational materials. PURPOSE OF THE STUDY: This study evaluated the use of written and online video education tools after mallet finger injury. METHODS: After ethics board approval and informed consent, adults with an acute mallet finger injury referred to hand therapy were included. Standard nonoperative treatment was instituted with orthotic immobilization and verbal instructions, in addition to an education pamphlet and an online video link. A questionnaire regarding the educational materials was administered at the follow up appointment. RESULTS: There were 61 patients (mean age, 42 +/- 14 years). The middle (n = 21) and ring (n = 22) fingers were most commonly injured. All patients were fluent in English. Written instructions (n = 57) were used by more patients than the videos (n = 30). Comparing patients who viewed the video with those who did not, there were no differences (P > .05) in demographics (sex, age, education, work status, and second language). Both written and video instructions were reported as helpful; mean helpful score for the video was significantly (P = .03) higher than written instructions. Most patients preferred having written and video instructions, and both were easy to understand and convenient. DISCUSSION: In our study of patients with acute mallet finger injuries, written and video instructions were utilized and both were reported as helpful. CONCLUSIONS: This study provides evidence of the usefulness of online videos as an educational aid and the opportunity for future investigations to improve patient access to education materials. PMID- 30017409 TI - Outcomes and indications for early hand therapy after multiple concomitant elective hand procedures. AB - STUDY DESIGN: Retrospective comparative study. INTRODUCTION: Trigger finger and carpal tunnel surgery are common, but not without complications including pain and edema, which are treated with hand therapy (HT). There are limited data for the outcomes of multiple trigger finger releases (MTFRs) or combined trigger finger and carpal tunnel surgery and the subsequent need for HT. PURPOSE OF THE STUDY: Based on our hypothesis that patients with more than 1 procedure may benefit from an early HT visit, we performed this study to compare the frequency of HT orders after single trigger finger releases (STFRs) and MTFRs and determine the reasoning for variation in the rate of HT orders after releases. METHODS: Subjects receiving either an STFR or an MTFR were identified. Patient-reported outcomes were recorded preoperatively and 2 weeks postoperatively. RESULTS: One hundred fifty-nine eligible subjects were identified; 33 MTFRs and 126 STFRs. MTFR subjects were prescribed postoperation HT at a higher rate compared with STFR subjects (66.7% vs 34.1%; P < .001). Of the HT subjects, MTFR subjects received prescriptions for edema management at a significantly higher rate compared with STFR subjects (P = .02). DISCUSSION: Patients with soft tissue dissection, edema, and stiffness would most likely benefit from HT services. It is important to identify these at-risk subpopulations to potentially alter their postoperative trajectories and improve outcomes. CONCLUSIONS: Higher rates of referral to HT occur when there are multiple concomitant hand procedures. This suggests surgeons triage HT services based on need. Policies that disallow postoperative therapy will have a greater impact on patients with these indications. PMID- 30017410 TI - The role of proprioception in the management of lateral elbow tendinopathy. PMID- 30017411 TI - Linking hand therapy outcome measures used after carpal tunnel release to the International Classification of Functioning, Disability and Health: A systematic review. AB - INTRODUCTION: The goal of hand therapy after carpal tunnel release (CTR) is restoration of function. Outcome assessment tools that cover the concepts contained in the International Classification of Functioning, Disability and Health (ICF), a framework for describing functioning and disability, are appropriate for hand therapy treatment of this diagnosis. PURPOSE OF THE STUDY: To identify and review outcome measures used in studies on rehabilitation after CTR and link these to the concepts contained in the ICF. METHODS: A comprehensive literature search was conducted. Outcome measures in the included studies were linked to the ICF. For data calculation purposes, outcome measures were linked to the specific ICF category, which matched the majority of assessment items if there were components that fit into more than 1 category. The quality of the studies was evaluated, and effect sizes for the treatment interventions were calculated for a comprehensive systematic review. RESULTS: Seven studies met the inclusion criteria. Eleven outcomes (68.75%) were linked to body function, 1 (6.25%) to body structure, 3 (18.75%) to activity and participation, and 1 (6.25%) to environmental factors. No outcomes were associated with environmental factors or personal factors. Structured Effectiveness for Quality Evaluation of Study scores of the included studies ranged from 23 to 43/48. DISCUSSION: The predominant outcome tools in the current research on rehabilitation after CTR are impairment measures and are linked to the category of body structures and body functions. CONCLUSIONS: Functional measures, associated with the activity and participation category, are only modestly represented, and there is a lack of representation of environmental and personal factors for outcome measures used following CTR. PMID- 30017412 TI - A novel staged wrist sensorimotor rehabilitation program for a patient with triangular fibrocartilage complex injury: A case report. AB - STUDY DESIGN: Case report. INTRODUCTION: Studies have highlighted the sensory innervations and stabilizing role of forearm muscles on wrist joint and implications to wrist sensorimotor rehabilitation. This case explored the novel incorporation of dart-throwing motion and proprioceptive neuromuscular facilitation in wrist sensorimotor rehabilitation. PURPOSE OF THE STUDY: To describe and evaluate a staged wrist sensorimotor rehabilitation program for a patient with triangular fibrocartilage complex (TFCC) injury. METHODS: The patient participated in the staged program for 9 sessions over a 3-month period. Treatment involved neuromuscular strengthening at the wrist and movement normalization of the upper extremity. Outcome measures were grip strength, visual analog scale, joint position sense, Quick Disabilities of the Arm, Shoulder and Hand, and patient-rated wrist evaluation. RESULTS: The patient showed improvement in all outcome measures. Most outcomes exceeded the established minimal clinically important difference values. DISCUSSION: The results suggest that dart throwing motion and proprioceptive neuromuscular facilitation are beneficial in rehabilitation of TFCC injury. CONCLUSIONS: This is the first study that incorporated dart-throwing motion and proprioceptive neuromuscular facilitation in the sensorimotor rehabilitation of TFCC injury and yielded promising results. There is a need to further evaluate the program in prospective randomized controlled trial recruiting a larger group of patients with TFCC injury. PMID- 30017413 TI - A systematic review of the benefits of occupation-based intervention for patients with upper extremity musculoskeletal disorders. AB - STUDY DESIGN: Systematic review of intervention studies (level 3a). INTRODUCTION: Occupation-based intervention (OBI) uses daily activities as a treatment modality. Its growing use with patients diagnosed with upper extremity musculoskeletal disorders (UE MSK) has driven interest in its supporting body of evidence. PURPOSE OF THE STUDY: The purpose of this study was to locate, appraise, and summarize current evidence of the effectiveness of OBI in treating patients with UE MSK. METHODS: Searches of PubMed, CINAHL, the Cochrane Register for Controlled Trials, and PEDro databases were conducted using predetermined keywords. Studies included in this systematic review described the use of OBI in UE MSK. Two examiners independently reviewed and assessed the quality of each study using the PEDro scale. RESULTS: Results of the database searches yielded 991 studies, 13 of which were deemed eligible to include in this review (6 randomized controlled trials, 4 pretreatment/post-treatment cohort or case series studies, and 3 single case reports). Quality of the studies varied, with 4 rated poor, 2 moderate, and 4 excellent. Overall, individuals receiving OBI showed superior benefits in patient-reported, performance, and physical measures assessing the upper extremity. DISCUSSION: Findings of this review provide preliminary evidence for the use of OBI with patients with UE MSK, however, generalizability of the evidence was compromised due to heterogeneity in study subjects as well as conceptualization, dosage, and delivery of OBI. CONCLUSIONS: The existing literature reflects promising trends in the use of OBI, underscoring its utility as a treatment option for UE MSK-related impairment, limitations, and restrictions. Nonetheless, scientific evidence concerning the effectiveness of OBI needs to be improved by conducting high-quality studies that clearly conceptualize this intervention and heighten understanding of its role in hand therapy practice. PMID- 30017414 TI - Effectiveness of virtual reality in the treatment of hand function in children with cerebral palsy: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Children with cerebral palsy (CP) may have limited use of their hands for functional activities and for fine motor skills. Virtual reality (VR) is a relatively new and innovative approach to facilitate hand function in children with CP. PURPOSE OF THE STUDY: The primary purpose of this study was to determine the effectiveness of VR as an intervention to improve hand function in children with CP compared to either conventional physiotherapy or other therapeutic interventions. The secondary purpose was to classify the outcomes evaluated according to the International Classification of Functioning, Disability and Health (ICF) dimensions. METHODS: A International prospective register of systematic reviews (PROSPERO)-registered literature search was carried out in August 2015 in MEDLINE, CINAHL, ERIC, HealthSTAR, AMED, BNI, Embase, PsycINFO, PEDro, Cochrane Central Register, DARE, OTSeeker, REHABDATA, HaPI, CIRRIE, and Scopus. PRISMA guidelines were followed. Only randomized controlled trials (RCTs) were included, and their methodological qualities were examined using the Cochrane collaboration's risk of bias (RoB) tool. A narrative synthesis was performed. RESULTS: The 6 RCTs published on this topic provide conflicting results. Four studies reported improved hand function (2 low RoB, 1 high RoB, and 1 unclear RoB), whereas 2 studies reported no improvement. All of the RCTs reported the activity element of ICF, but no study explicitly described the effect of VR intervention based on the ICF model. CONCLUSION: The role of VR ti imrpove hand fucntion in children with CP is unclear due to limited evidence; use as an adjunct has some support. PMID- 30017415 TI - Conservative therapeutic interventions for osteoarthritic finger joints: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Hand osteoarthritis (OA) is a chronic and disabling disease causing pain and functional limitations in approximately 54%-67% of the adult population aged 55 years and older. PURPOSE OF THE STUDY: The objective of the study is to evaluate the evidence supporting conservative therapeutic interventions for the treatment of OA finger joints. METHODS: Eighteen studies dated between 1979 and 2016 were identified meeting the inclusion criteria. They were analyzed based on Structured Effectiveness for Quality Evaluation of a Study, level of evidence, and effect size. RESULTS AND CONCLUSIONS: The current evidence varies in quality and effect sizes but generally supports the use of active range of motion and resistive exercises, joint protection, electromagnetic therapy, paraffin wax, and balneotherapy (combined and/or not combined with mud packs and magnetotherapy), and distal interphalangeal orthoses as effective treatment interventions for individuals with OA finger joints. PMID- 30017416 TI - Anatomical relationship of palmar carpal bone landmarks used in locating the lunate and capitate during palpation: A cadaveric investigation. AB - STUDY DESIGN: Descriptive in situ cadaveric study. INTRODUCTION: Performing accurately directed examination and treatment to the wrist requires clinicians to orient to carpal bone structures. PURPOSE OF THE STUDY: To examine the anatomical relationships that exist within the wrist-hand complex and identify the accuracy of surface anatomy mapping strategies for localizing anatomical landmarks using a palmar approach. METHODS: Twenty-three embalmed cadavers were dissected using standardized procedures. Metal markers were placed in the most prominent palmar landmark of key carpal structures. Relationships between the most prominent palpation landmarks and the carpal bones of interest were visualized using fluoroscopy. RESULTS: The most successful methods of palmar capitate localization included the midpoint of a line from trapezium tubercle to pisiform; the midpoint of a line from scaphoid tubercle to hamate hook; or the intersection (cross) of these 2 diagonal lines, with successful capitate identification 100% (23/23) of the time. The most successful method for locating the lunate included the midpoint of a line from the radial styloid process to the ulnar styloid process, which identified the lunate in 100% (23/23) of cases. DISCUSSION: The results of this cadaveric anatomical relationship study support the use of the midpoint of a line from pisiform to trapezium tubercle, the midpoint of a line from scaphoid tubercle to hamate hook, or a combination (cross) of these lines to locate the capitate from a palmar approach. In addition, the anatomical relationships examined in this study support the use of the midpoint of a line from the radial styloid process to ulnar styloid process to locate the lunate from a palmar approach. Knowledge of these anatomical relationships may improve the clinician's confidence in locating the capitate and lunate during intercarpal examination, special testing, and treatment. CONCLUSION: Results of this study provide information of the anatomical relationships of the carpal bones from a palmar approach, giving clinicians a foundation for proper orientation to the carpal bones during clinical examination and intervention. Further research is needed to evaluate the reliability and accuracy of these methods for surface palpation on live patients. PMID- 30017417 TI - Reliability and accuracy of the brachial plexus neurodynamic test. AB - STUDY DESIGN: Observational study. INTRODUCTION: The brachial plexus neurodynamic test (BPNT), based on previous neurodynamic tests, is considered a clinically meaningful tool to objectively assess brachial plexus extensibility. This novel test's psychometric properties have yet to be determined. PURPOSE OF THE STUDY: The primary study aim was to assess the inter- and intrarater reliability and accuracy of the BPNT, which biases the median nerve and brachial plexus, among clinicians of various professional experience levels and geographic US regions. The secondary study aim was to determine if professional experience or geographic region affects the accuracy levels of this test. METHODS: In phase 1, inter-rater reliability and accuracy was determined. About 307 participants attending neural mobilization conferences and courses were instructed in the BPNT and asked to score 7 different videos of 14 possible test levels. In phase 2, intrarater reliability was determined via scoring the same test videos twice. RESULTS: High inter-rater intraclass correlation coefficient (range, 0.98-0.99) and accuracy (range, 0.88-0.94) levels were determined for all clinical experience levels and geographic regions. Intrarater intraclass correlation coefficient values were high (range, 0.96-1.0) among all participants. One-way analysis of variance indicated no significant differences on test accuracy based on professional clinical experience (F = 0.104; P = .958) and geographic region (F = 0.416; P = .416) among all 307 participants. DISCUSSION: Excellent inter- and intrarater reliability and accuracy levels may allow clinicians to correctly identify BPNT positions regardless of their professional experience or geographic location. CONCLUSION: The BPNT can reliably and accurately quantify outcomes in neural mobility scoring. PMID- 30017418 TI - Self-measured wrist range of motion by wrist-injured and wrist-healthy study participants using a built-in iPhone feature as compared with a universal goniometer. AB - STUDY DESIGN: Cross-sectional cohort. INTRODUCTION: Smartphone gyroscope and goniometer applications have been shown to be a reliable way to measure wrist ROM when used by researchers or trained staff. If wrist-injured patients could reliably measure their own ROM, rehabilitation efforts could be more effectively tailored. PURPOSE OF THE STUDY: To assess agreement of self-measured ROM by wrist injured and wrist-healthy study participants using a built-in iPhone 5 level feature as compared to researcher-measured ROM using a universal goniometer (UG). METHODS: Thirty wrist-healthy and 30 wrist-injured subjects self-measured wrist flexion, extension, supination, and pronation ROM using the built-in preinstalled digital level feature on an iPhone 5. Simultaneously a researcher measured ROM with a UG. RESULTS: Average absolute deviation between the self-measured iPhone 5 level feature and researcher-measured UG ROM was less than 2 degrees for all 4 movements individually and combined was found to be 1.6 degrees for both populations. Intraclass correlation coefficient showed high correlation with values over 0.94 and Bland-Altman plots showed very strong agreement. There was no statistical difference in the ability of wrist-injured and healthy patients to self-measure wrist ROM. DISCUSSION: Both populations showed very high agreement between their self-measured ROM using the built-in level feature on an iPhone 5 and the researcher-measured ROM using the UG. Both populations were able to use the iPhone self-measurement equally well and the injury status of the subject did not affect the agreement results. CONCLUSION: Wrist-healthy and wrist-injured subjects were able to reliably and independently measure ROM using a smartphone level feature. PMID- 30017419 TI - Mycotic keratitis caused by Scedosporium apiospermum in an immunocompetent patient. AB - CLINICAL CASE: A 51 year-old immunocompetent male was referred due to presenting with a large corneal ulcer with hypopyon in the right eye. Topical amphotericin B, fluconazole and moxifloxacin, as well as oral itraconazole were initially indicated. Following the report of mycotic structures on staining, topical natamycin was started. The result of the culture was reported two weeks later as, Scedosporium apiospermum (S. apiospermum), and topical voriconazole was then added. The response to treatment was very slow, and took five weeks after receiving triple therapy (natamycin, voriconazole and fluconazole) and one dose of intrastromal voriconazole, for the hypopyon to disappear. The final outcome was successful, achieving healing of the ulcer. The patient is waiting for a corneal transplant. DISCUSSION: A microbiological study is essential in patients in whom fungal keratitis is suspected. The treatment of choice against S. apiospermum is with voriconazole, but the combination of various antifungal agents may be required. PMID- 30017420 TI - Renal cell cancer with duodenal invasion: Towards standard care? PMID- 30017421 TI - Comments on "Operative technique: Superficial temporal artery biopsy". PMID- 30017422 TI - Routine Follow-Up Radiographs for Ankle Fractures Seldom Add Value to Clinical Decision-Making: A Retrospective, Observational Study. AB - Currently, the routine use of radiographs for uncomplicated ankle fractures represents good clinical practice. However, radiographs are associated with waiting time, radiation exposure, and costs. Studies have suggested that radiographs seldom alter the treatment strategy if no clinical indication for the imaging study was present. The objective of the present study was to evaluate the effect of routine radiographs on the treatment strategy during the follow-up period of ankle fractures. All patients aged >=18 years, who had visited 1 of the participating clinics with an eligible ankle fracture in 2012 and with complete follow-up data were included. The data were retrospectively analyzed. The sociodemographic and clinical characteristics and the number of, and indications for, the radiographs taken were collected from the medical records of the participating clinics. We assessed the changes in treatment strategy according to the radiographic findings. In 528 patients with an ankle fracture, 1174 radiographs were performed during the follow-up period. Of these radiographs, 936 (79.7%) were considered routine. Of the routine radiographs taken during the follow-up period, only 11 (1.2 %) resulted in changes to the treatment strategy. Although it is common practice to take radiographs routinely during the follow-up period for ankle fractures, the results from the present study suggest that routine radiographs seldom alter the treatment strategy. This limited clinical relevance should be weighed against the health care costs and radiation exposure associated with the use of routine radiographs. For a definitive recommendation, however, the results of our study should be confirmed by a prospective trial, which we are currently conducting. PMID- 30017423 TI - Emergency Nurses' Department Design Recommendations for Improved End-of-Life Care. AB - INTRODUCTION: Although death is common in emergency departments, there is limited research regarding ED design as an obstacle to end-of-life care. This study identifies emergency nurses' recommendations regarding ways designs have negative or positive impact on care for dying patients and their families. METHODS: A 25 item questionnaire was sent to a national random sample of 500 emergency nurses. Inclusion criteria were nurses who could read English, worked in emergency departments, and had cared for at least 1 patient at the end of life (EOL). Responses were individually reviewed and coded. RESULTS: Major obstacles included (1) issues related to limited space, (2) poor department layout and design, and (3) lack of privacy. Despite emergency departments being a challenging place to provide EOL care, positive ED design characteristics had impact on EOL care. DISCUSSION: Emergency nurses understand the need for family presence during resuscitation, for secure body stowage areas, and for more resuscitation rooms so that families have time to grieve before being removed because of the immediate needs of a second trauma patient. Nurses can evaluate existing facilities to identify areas in which potential change and remodeling could improve care, increase patient privacy, or further utilize space. Understanding ED design's impact on EOL care is crucial. Modifications to ED layout and design may be challenging; however, improvements to space, layout, and privacy need to be considered when planning new emergency departments or remodeling existing departments. Further research is required to determine the impact of ED design on EOL care. PMID- 30017424 TI - Diffusion kurtosis imaging as a neuroimaging biomarker in patients with carbon monoxide intoxication. AB - Attempting suicide by burning charcoal can lead to carbon monoxide (CO) intoxication and cognitive deficits. Changes in white matter (WM) quantified by diffusion tensor imaging (DTI)-derived parameters have been validated to reflect cognitive test scores. As diffusion kurtosis imaging (DKI) measures biological microstructures using non-Gaussian diffusivity, we assessed the added-information of DKI with neuropsychological test scores as the major outcome measure. A total of 45 patients were enrolled and compared with 30 age-matched controls. The patients were stratified into acute or chronic phase according to the intervals of intoxication and assessments. WM status was assessed using tract-based spatial statistics for DKI and DTI topographies, and the sensitivity/specificity of either model was tested using area under the curve (AUC) analysis. To evaluate their clinical significance, values of DKI- and DTI-derived parameters were extracted from seven regions of interest (ROI) and correlated with neuropsychiatric scores. The kurtosis parameters were lower in the patients than in the controls but none of the parameters provided differentiations between the acute or chronic phase. Kurtosis fractional anisotropy (KFA) had a higher AUC than fractional anisotropy while the other 3 DTI parameters had higher AUC than the corresponding DKI ones. In clinical correlations, KFA value of right posterior WM correlated with visual memory (r = 0.326, p = 0.029), and KFA values of bilateral posterior WM correlated with the digit forward score (right: r = 0.302, p = 0.043; left: r = 0.314, p = 0.036). Although DTI was more sensitive in reflecting disease status, KFA may be more sensitive and specific than fractional anisotropy in cognitive test score predictions. PMID- 30017425 TI - Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: Impact on Sirt1/NRF2 signaling pathways. AB - Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (alpha-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that alpha-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2-related factor 2 (NRF2) and silencing information regulator 1 (Sirt1) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and alpha-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and alpha-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only. PMID- 30017426 TI - Response to: Low level evidence supporting the choice of optimal multimodality treatment approach in patients with stage IIIA NSCLC- ain't no mountain high enough.... to keep me getting to you by Jeremic Branislav. PMID- 30017427 TI - At last we can go ahead with low-dose CT screening for lung cancer in Europe. PMID- 30017428 TI - Corrigendum to "Validation of the 8th TNM classification for small-cell lung cancer in a retrospective material from Sweden" [Lung Cancer 120 (June) (2018) 75 81]. PMID- 30017429 TI - Assessment of Resonant Voice Therapy in the Treatment of Vocal Fold Nodules. AB - OBJECTIVE: This study aimed to evaluate objective and subjective changes in the voices of adults with vocal fold nodules who received resonant voice therapy. METHODS: Twenty-six female patients who had bilateral vocal fold nodules and 30 healthy women were included in the study. Patients were treated with vocal hygiene education and resonant voice therapy. Voice records were obtained for acoustic and aerodynamic analysis. Fundamental frequency, jitter, shimmer, and noise-to-harmonic ratio were analyzed for acoustic analysis. Maximum phonation time was used for aerodynamic evaluation. Voice Handicap Index 10 was completed by patients for subjective assessment. After 8 weeks of therapy analyses were repeated. RESULTS: Stroboscopic analysis revealed that 14 patients had total and 9 had partial regression. Fundamental frequency increased from 152.27 +/- 28.34 to 199.56 +/- 11.25 in study group and this was statistically significant. Jitter, shimmer, and noise-to-harmonic ratio improvements were also significant. Voice Handicap Index scores decreased from 22.25 +/- 3.82 to 8.92 +/- 5.48 and this was statistically significant. CONCLUSION: Our finding that resonant voice therapy improved objective and subjective parameters of vocal function in patients with vocal fold nodules indicates that it is an effective treatment for VFNs and should be considered a therapeutic option. PMID- 30017430 TI - Topical Anesthesia for Endoscopic Office-based Procedures of the Upper Aerodigestive Tract. AB - OBJECTIVE: Over the last two decades, an increase in office-based procedures under topical anesthesia in laryngology and head and neck oncology has occurred. Adequate anesthesia in the nasal cavity, pharynx, and larynx is essential for successful performance of these procedures. Our goal is to provide an objective summary on the available local anesthetics, methods of application, local secondary effects, efficacy, and complications. MATERIAL AND METHODS: A descriptive review of literature on topical anesthesia for office-based procedures in laryngology and head and neck oncology was performed. RESULTS: Lidocaine is the most applied and investigated topical anesthetic. Topical anesthesia results in decreased sensory function without impairing motor function of the pharynx and larynx. For the nasal cavity, cotton pledgets soaked in anesthetic spray and decongestant, or anesthetic gel, are effective. For the pharynx, anesthetic spray is the most frequently used and effective method. For the larynx, applying local anesthesia through a catheter through the working channel of the endoscope or anesthetic injection through the cricothyroid membrane is effective. Studies comparing the most effective application methods for each anatomical site are lacking. Complications of topical lidocaine administration are rare. CONCLUSIONS: By properly applying topical anesthesia to the upper aerodigestive tract, several surgical procedures in laryngology and head and neck oncology can be performed in the outpatient clinic under topical anesthesia instead of the operating room under general anesthesia. Lidocaine is the most investigated anesthetic, with adequate efficacy and few complications. Studies that determine the most effective application methods are still wanting. PMID- 30017431 TI - Botox Injection for Laryngeal Dysfunction in Alexander Disease. PMID- 30017432 TI - Comparative Anatomy of Pig Arytenoid Cartilage and Human Arytenoid Cartilage. AB - OBJECTIVE: This study aims to investigate the feasibility of pig arytenoid cartilage as an animal model for simulating arytenoidectomy under microlaryngoscope by comparing the similarities and differences between pig arytenoid cartilage and human arytenoid cartilage. STUDY DESIGN: This is a methodological study on the excised pig arytenoid cartilage and human arytenoid cartilage. METHODS: Five excised human adult cadaver larynges and five adult excised porcine larynges were dissected and all the soft tissue and mucous membrane attached to the arytenoid and cricoarytenoid joint were removed. The anatomical structure and morphology of the arytenoid cartilage were observed and measured with a vernier caliper. Measurements included cricoarytenoid articular facet major and minor diameter, cricoarytenoid articular facet center distance, cricoarytenoid facet major and minor diameter, length of vocal process and muscular process, and distance between tip of vocal process, muscular process, and junction/apex of arytenoid cartilage. Data were then compared across these major anatomic markers using student t test. RESULTS: The gross anatomy of the pig arytenoid cartilage was similar to the human. However, the size of the pig larynx arytenoid cartilage was obviously larger in total, and there was statistical significance for almost all measurements (P < 0.05), except the mean value of cricoarytenoid articular facet center distance, the cricoarytenoid facet minor diameter, and the length of vocal process of pig and human, without statistically significant difference (P > 0.05). Moreover, the biggest differences between the pig arytenoid cartilage and the human arytenoid cartilage were that the pig arytenoid cartilage apex had the angle winding structure toward the back, and that the posterior part of the bilateral arytenoid cartilages was partially connected. Whereas after the angle winding was removed from the junction, pig arytenoid cartilage and human arytenoid cartilage were shaped both like a triangular pyramid. CONCLUSION: The data of this metric comparative study indicate that pig arytenoid, after resecting the angle winding structure and incising the interarytenoid cartilage, is similar to the human's. Therefore, pig larynx is an appropriate experimental model for endoscopic arytenoidectomy. In addition, regarding the pig laryngeal angle winding structure, we still require further basic and clinical research to clarify its physiological function and significance. PMID- 30017434 TI - Gender-specific associations of body mass index and waist circumference with type 2 diabetes mellitus in Chinese rural adults: The Henan Rural Cohort Study. AB - AIM: To assess the relationship between various obesity categories according to body mass index (BMI) and waist circumference (WC) and risk of type 2 diabetes mellitus (T2DM) among Chinese rural adults. METHODS: A total of 38,466 eligible participants were derived from The Henan Rural Cohort Study. Structured questionnaires and anthropometric and laboratory measurements were undertaken. Logistic regression was performed by gender. RESULTS: The age-standardized prevalence of T2DM in current study was 3.94% in men and 5.14% in women. Compared with participants with both normal BMI and WC, participants with normal BMI but high WC, high BMI but normal WC, or both high BMI and WC showed elevated risk of T2DM, in addition to being women with high BMI but normal WC. Moreover, when BMI and WC were included in the same multivariate adjusted model, both BMI and WC were significantly associated with increased T2DM risk in men, however, WC but not BMI remained positively associated with T2DM risk in women. CONCLUSIONS: In summary, gender-specific differences between obesity measures and T2DM were found. WC was independently associated with increased risk of T2DM regardless of BMI status in women, whereas both BMI and WC showed positive association with T2DM risk in men. PMID- 30017435 TI - Fish consumption is associated with a decreased risk of death among adults with diabetes: 18-year follow-up of a national cohort. AB - BACKGROUND: There is a paucity of studies examining the beneficial effects of fish consumption on cardiovascular diseases (CVDs) among adults with diabetes, who experience a substantially high risk of CVDs. METHODS AND RESULTS: We analyzed the data of 1136 adults with diabetes mellitus aged 18 years and older who participated in the National Health and Nutrition Examination Survey, 1988 1994, and were followed up through December 31, 2010. We used Cox regression to estimate the adjusted hazard ratios (HRs) for the relative risk across the levels of fish consumption. A total of 698 deaths were recorded at the end of 11,465 person-years follow-up with a mortality rate of 60.88 per 1000 person-years. CVDs were listed as a contributing cause for 326 deaths, thus accounting for 46.4% of total deaths. Stroke-specific mortality rate among patients who ate fish less than once a week was more than twice as high as that among patients who ate fish more than twice a week, 6.23 vs. 2.36 per 1000 person-years, respectively. The corresponding CVD-specific rate was 34.38 vs. 22.99 per 1000 person-years, respectively. The adjusted HRs of death due to stroke were 1.00 (reference), 0.55 (95% confidence interval = 0.28-1.07), and 0.30 (0.11-0.80) among patients who ate fish <1, 1-2, and 2 + times a week, and the corresponding HRs of death due to CVDs were 1.00 (reference), 0.78 (0.60-1.02), and 0.69 (0.50-0.96), respectively. CONCLUSIONS: A high consumption of fish was associated with a low risk of death due to CVDs, especially stroke, among adults with diabetes. PMID- 30017433 TI - Association between physical activity and abnormal glucose metabolism-A population-based cross-sectional study in China. AB - BACKGROUND: Association between physical activity and abnormal glucose metabolism (AGM) remains unclear. METHODS: Data were collected from a random sample of the Chinese population aged 26-77 years. Participants were classified into an AGM group or a normal glucose tolerance (NGT) group. Total physical activity energy expenditure (PAEE), sedentary time, and ratios of PAEE in different domains to the total PAEE were calculated according to the International Physical Activity Questionnaire. Logistic regression was used to analyze the associations between total PAEE, ratios of PAEE under different domains to total PAEE, sedentary time, and AGM. RESULTS: Data from 3510 participants aged 50 +/- 12 years were analyzed; 1390 (39.6%) were diagnosed with AGM. In the multivariate logistic regression analysis, total PAEE (1000 MET-min/week) was significantly associated with AGM [OR (95% CI) 0.96 (0.94, 0.99)]. After stratification by sex and BMI, total PAEE was negatively associated with AGM in men and overweight people. The ratios of PAEE in different domains to total PAEE or sedentary time were not associated with AGM. CONCLUSIONS: Total PAEE was negatively associated with AGM. Ratios of PAEE in different domains to total PAEE and sedentary time were not associated with AGM in this Chinese population. PMID- 30017436 TI - Treatment with crocin improves cardiac dysfunction by normalizing autophagy and inhibiting apoptosis in STZ-induced diabetic cardiomyopathy. AB - BACKGROUND AND AIM: The association of diabetes mellitus (DM) and poor metabolic control with high incidence of cardiovascular diseases is well established. The aim of this study was to investigate the potential cardioprotective effect of crocin (Crocus sativus L. extract) on diabetic heart dysfunction and to elucidate the mediating molecular mechanisms. METHODS AND RESULTS: Streptozotocin (STZ) induced diabetic rats were treated with two different concentrations of crocin (10 or 20 mg/kg), while isolated cardiac myocytes exposed to 25 mM glucose, were treated with 1 or 10 MUM of crocin. Treatment of STZ-diabetic rats with crocin resulted in normalization of plasma glucose levels, inhibition of cardiac hypertrophy and fibrosis, and improvement of cardiac contractile function. Heat Shock Response was enhanced. Myocardial AMPK phosphorylation was increased after treatment with crocin, resulting in normalization of autophagy marker proteins (LC3BII/LC3BI ratio, SQSTM1/p62 and Beclin-1), while the diabetes-induced myocardial apoptosis was decreased. Similar results regarding the effect of crocin on autophagy and apoptosis pathways were obtained in isolated cardiac myocytes exposed to high concentration of glucose. CONCLUSION: The results suggest that crocin improves the deteriorated cardiac function in diabetic animals by enhancing the heat shock response, inhibiting apoptosis and normalizing autophagy in cardiac myocytes. Thus, treatment with crocin may represent a novel approach for treating diabetic cardiomyopathy. PMID- 30017437 TI - Association between bone metabolism regulators and arterial stiffness in type 2 diabetes patients. AB - BACKGROUND AND AIM: Osteopontin (OPN), osteonectin (ON) and osteocalcin (OC) play an important role in the development of vascular calcifications, but it is unclear whether these bone metabolism regulators contribute to the development of arterial stiffness in type 2 diabetes patients. We therefore aim to determine the relationship between plasma concentrations of OPN, ON, OC and arterial stiffness in type 2 diabetes patients. METHODS: Cross-sectional study of 1003 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART)-cohort. Generalized linear models were used to evaluate the relation between plasma levels of OPN, ON and OC and arterial stiffness as measured by pulse pressure (PP), ankle-brachial index (ABI) (>=0.9), carotid artery distension and an arterial stiffness summary score. Analyses were adjusted for age, sex, kidney function, diabetes duration and diastolic blood pressure. Higher OPN plasma levels were significantly related to a lower ABI (beta-0.013; 95%CI 0.024 to -0.002) and a higher arterial stiffness summary score (OR1.24; 95%CI 1.03-1.49). OPN levels were not related to PP (beta 0.59; 95%CI -0.63-1.81) or absolute carotid artery distention (beta -7.03; 95%CI -20.00-5.93). ON and OC plasma levels were not related to any of the arterial stiffness measures. CONCLUSION: Only elevated plasma levels of OPN are associated with increased arterial stiffness in patients with type 2 diabetes as measured by the ankle brachial index and arterial stiffness summary score. These findings indicate that OPN may be involved in the pathophysiology of arterial stiffness and call for further clinical investigation. PMID- 30017438 TI - Physical performance measures in screening for reduced lean body mass in adult females with obesity. AB - BACKGROUND & AIMS: Little is known about the reduction of lean body mass (LBM) in obesity, or how to identify it in standard clinical settings. We therefore aimed to assess the prevalence of low LBM in adult females with obesity, and to identify the reliability of simple tools for its screening in this population. METHODS AND RESULTS: Dual-energy X-ray absorptiometry (DXA) body composition assessment was used to categorise 147 female participants with obesity as with or without low LBM, according to the new definition that takes into account both appendicular lean mass (ALM) and body mass index (BMI)-ALM/BMI <0.512. Participants were also administered the six-minute walking test, handgrip strength test and 4-metre gait-speed test. Of the sample of 147 participants, 93 (63.3%) met the criteria for reduced LBM. Stepwise multivariate logistic regression analysis showed that the six-minute walking test was the only independent test associated with low LBM (OR = 0.992, 95%CI 0.987-0.998). Receiver operating characteristic (ROC) curve analysis found that the discriminating cut-off points of the tests considered were 470 m, 3.30 s (gait speed = 1.2 m/sec) and 23.5 kg respectively; the 4-metre gait-speed test seems to provide the best balance of sensitivity and specificity, and the greatest discriminatory power at 90% sensitivity. CONCLUSIONS: Treatment-seeking adult females with obesity display a great prevalence of reduced LBM. The six-minute walking test was the only independent test associated with low LBM, but the 4 metre gait-speed test seems to be the most accurate functional test for screening for this condition in that population. PMID- 30017439 TI - Assessment of coronary lesions by optical coherence tomography: An attempt to improve results of coronary artery bypass surgery. PMID- 30017440 TI - Preoperative renal dysfunction does not affect outcomes of left ventricular assist device implantation. AB - OBJECTIVE: Selection criteria for durable left ventricular assist device (LVAD) implantation remain unclear. One such criterion is renal function. In this study we evaluated outcomes of LVAD implantation in patients with preoperative renal dysfunction. METHODS: Patients with implanted LVADs as destination therapy (DT) or bridge to transplantation (BTT) at a single institution between 2006 and 2015 were included. Primary stratification was according to pre-implantation glomerular filtration rate (GFR): >60 mL/min versus <60 mL/min or dialysis dependence. The primary outcome was post-LVAD implantation overall survival. RESULTS: Two hundred thirty-eight patients underwent LVAD implantation during the study period as DT (60%; n = 142) or BTT (40%; n = 96). Reduced GFR was present in 56% (n = 132), with 8% (n = 18) being dialysis-dependent. Normal versus reduced GFR cohorts were well matched except for a higher incidence of coronary artery disease in the patients with reduced GFR (61% vs 48%; P = .04). Mean follow-up was 13.5 +/- 17.0 months. Unadjusted and risk-adjusted survival at 1, 3, 6, and 12 months after LVAD implantation were similar between the cohorts for DT and BTT. Rates of transplantation were comparable in BTT patients (61% normal vs 53% reduced GFR; P = .43). Recovery of renal function to a GFR >60 mL/min occurred in 43% (n = 17) and 57% (n = 42) of patients with reduced GFR in the BTT and DT cohorts, respectively, by 1 year post implantation. CONCLUSIONS: Well selected patients with preexisting renal dysfunction can undergo LVAD implantation with acceptable outcomes. Approximately half of LVAD recipients with preimplantation renal dysfunction will recover normal renal function within the first postoperative year. Renal dysfunction alone should not serve as an absolute contraindication to LVAD therapy. PMID- 30017441 TI - Treatment of aortic dissection involving the right coronary. PMID- 30017442 TI - Are you sure you can do a perfect Maze? PMID- 30017443 TI - Simulating the trajectory of off-pump surgery: The heroic defense of the homograft. PMID- 30017444 TI - Discussion. PMID- 30017446 TI - Left ventricular assist device therapy instead of conventional cardiac surgery in high-risk patients: To boldly go where no one has gone before? PMID- 30017445 TI - PACIFIC: Time for a surgical IIIA uprising. PMID- 30017447 TI - Evaluating outcomes after cardiac surgery: A complex challenge requiring flexibility. PMID- 30017448 TI - Value-driven cardiac surgery: Achieving "perfect care" after coronary artery bypass grafting. AB - OBJECTIVE: The objective of this study was to determine if the implementation of a value-driven outcomes tool comprising modifiable quality and utilization metrics lowers cost and improves value of coronary artery bypass grafting (CABG) postoperative care. METHODS: Ten metrics were defined for CABG patients in 2 temporally separated phases. Clinical care protocols were designed and implemented to increase compliance with these metrics. Clinical outcomes and cost data were harvested from the electronic medical record using a proprietary value driven outcomes tool and verified by a data management team. "Perfect care" was defined as achieving all 10 metrics per patient episode. RESULTS: Over a 45-month period, data of 467 consecutive patients who underwent isolated CABG were analyzed. "Perfect care" was successfully achieved in 304 patients (65.1%). There were no observed differences in mortality between patient groups. Linear regression analysis showed a negative correlation between percent compliance with "perfect care" and mean cost. When multivariate analysis was used to adjust for preoperative risk score, mean cost for patients with "perfect care" was 37.0% less than for those without "perfect care." CONCLUSIONS: In the context of focused institution-specific interventions to target quality and utilization metrics for CABG care, clinical care pathways and protocols informed by innovative tools that link automated tracking of these metrics to cost data might simultaneously promote quality and decrease costs, thereby enhancing value. This descriptive study provides preliminary support for a systematic approach to define, measure, and modulate the drivers of value for cardiothoracic surgery patients. PMID- 30017449 TI - Awakenings: From empiricism to an evidence-based management of malignant pleural effusions. PMID- 30017450 TI - Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species. AB - BACKGROUND AND OBJECTIVES: Candida infections are frequent in necrotising pancreatitis. Candidemia is associated with very high mortality and its risk due to infected pancreatic necrosis is unknown. So we aimed to assess potential risk factors and the risk of candidemia in necrotising pancreatitis. METHODS: We retrospectively searched our clinical database for the diagnosis necrotising pancreatitis from 2007 till March 2017 and entered relevant information in a database for statistical analysis. RESULTS: in total, 136 patients met the inclusion criteria. Candida infected pancreatic necrosis were found in 54 patients and 7 patients developed candidemia. Patients with Candida infected necrosis had a significantly higher in hospital mortality (35.2% versus 13.4%, p = 0.003). The highest mortality was observed in patients with candidemia (57.1% versus 20.2%, p = 0.042). Male gender (OR 0.32, CI 0.13-0.78, p = 0.013) and post ERCP pancreatitis (OR 4.32, CI 1.01-18.36, p = 0.048) had a significant impact on the risk of Candida infections of pancreatic necrosis. Candidemia was significantly more frequent in patients with Candida infected necrosis (11.1% versus 1.2%, p = 0.016). Candida albicans was the most common species followed by Candida glabrata. CONCLUSION: Candidemia is a relevant complication of necrotising pancreatitis and associated with high mortality. If patients do not respond to antibiotic therapy empiric antifungal therapy should be discussed. PMID- 30017451 TI - [On the quality and prestige of a scientific journal: advancing the principle of transparency]. PMID- 30017452 TI - [The role of emotional intelligence in cardiovascular disease]. AB - OBJECTIVE: To identify the classical risk factors and dimensions of emotional intelligence that are good predictors of cardiovascular disease according to sex. METHOD: The sample comprised 220 participants (110 with cardiovascular disease and 110 without cardiovascular disease). The demographic data and classic risk factors of each participant were recorded, and emotional intelligence evaluated through two questionnaires (TMMS-24 and PEC). RESULTS: Men with low emotional regulation had an increased risk of cardiovascular disease (Exp(B) = 0.813; p <0.05). Women with low intrapersonal comprehension (Exp(B) = 0.252, p <=0.05) or low emotional regulation (Exp(B) = 0.679; p <0.05) were more at risk. CONCLUSIONS: Emotional regulation predicts cardiovascular disease in both men and women and therefore can be considered as a risk factor in cardiovascular health, for both men and women. PMID- 30017453 TI - [Study on press coverage about the exodus of Spanish nurses to the United Kingdom]. AB - OBJECTIVE: To analyse the media representation of the exodus of Spanish nurses to the United Kingdom through general information newspapers. METHODS: Content analysis, quantitative and qualitative. Documents published in the newspapers ABC, El Pais, El Mundo and La Razon, about "emigrants," "nurses" and "migrant health workers," were located from January 1, 2007, to December 31, 2016, with Boolean operators. This selected period corresponds to the beginning of the economic crisis and concludes in the year of the Brexit referendum in the United Kingdom. After applying the descriptors, 9559 texts were obtained. Once the noise of the documents was eliminated, 484 textual units were found. To carry out a more exhaustive analysis, the specific documents on "migrant nurses", which were 77, were selected and analysed qualitatively. RESULTS: a) 2013 was the year in which the most stories about emigration in general were published, and also about nurses in particular; b) the ABC newspaper published the most stories about the exodus of nurses to the United Kingdom (31); c) El Pais published the most texts on Spanish emigration, with a total of 397 documents; d) 98% of the headlines analysed (n = 77) had a negative tone; and e) social discourse had greater relevance than political discourse. CONCLUSIONS: The press promoted the push factor for nurses to migrate to the United Kingdom. PMID- 30017454 TI - The effect of age-related risk factors and comorbidities on white matter injury and repair after ischemic stroke. AB - White matter injury is a crucial component of human stroke, but it has often been neglected in preclinical studies. Most human stroke is associated with one or more comorbidities, including aging, hypertension, diabetes and metabolic syndrome including hyperlipidemia. The purpose of this review is to examine how age and hypertension impact stroke-induced white matter injury as well as white matter repair in both human stroke and preclinical models. It is essential that comorbidities be examined in preclinical trials as they may impact translatability to the clinic. In addition, understanding how comorbidities impact white matter injury and repair may provide new therapeutic opportunities for patients with those conditions. PMID- 30017455 TI - Orthostatic hypotension: an often overlooked risk factor for falls. PMID- 30017456 TI - Truly comprehensive advanced care planning. PMID- 30017457 TI - New geriatrics legislation in Senate highlights bipartisan collaboration aimed at better present, future for us all. PMID- 30017458 TI - Sex differences in DEK expression in the anterior cingulate cortex and its association with dementia severity in schizophrenia. AB - DEK is a chromatin-remodeling phosphoprotein found in most human tissues, but its expression and function in the human brain is largely unknown. DEK depletion in vitro induces cellular and molecular anomalies associated with cognitive impairment, including down-regulation of the canonical Wnt/beta-catenin signaling pathway. ToppGene analyses link DEK loss to genes associated with various dementias and age-related cognitive decline. To examine the role of DEK in cognitive impairment in severe mental illness, DEK protein expression was assayed by immunoblot in the anterior cingulate cortex (ACC) of subjects with schizophrenia. Cognitive impairment is a core feature of schizophrenia and cognitive function in subjects was assessed antemortem using the clinical dementia rating (CDR) scale. DEK protein expression was not significantly altered in schizophrenia (n = 20) compared to control subjects (n = 20). Further analysis revealed significant reduction in DEK protein expression in women with schizophrenia, and a significant increase in expression in men with schizophrenia, relative to their same-sex controls. DEK protein expression levels were inversely correlated with dementia severity in women. Conversely, in men, DEK protein expression and dementia severity were positively correlated. Notably, there was no sex difference in DEK protein expression in the control group, suggesting that this sex difference is specific to schizophrenia and not due to inherent differences in DEK expression between males and females. These results suggest a novel, sex-specific role for DEK in cognitive performance and highlight a putative sex-specific link between central nervous system DEK protein expression and a neuropsychiatric disease that is commonly associated with cognitive impairment. PMID- 30017459 TI - Cognitive Behavioral Therapy for antipsychotic-free schizophrenia spectrum disorders: Does therapy dose influence outcome? AB - This study investigated the effect of "dose" and the components of Cognitive Behavioral Therapy (CBT) on treatment effects. It is a secondary analysis of the ACTION (Assessment of Cognitive Therapy Instead of Neuroleptics) trial which investigated CBT for people with schizophrenia spectrum disorders that chose not to take antipsychotic medication. Using instrumental variable methods, we found a "dose-response" such that each CBT session attended, reduced the primary outcome measure (the PANSS total score) by approximately 0.6 points (95% CI -1.20 to 0.06, p = 0.031). This suggests that length of therapy is important for those that receive CBT in the absence of antipsychotic medication. Secondly, using principal stratification we examined the process variables that modified treatment effects. Findings revealed that those who received a longitudinal formulation in the first 4 sessions of CBT had poorer treatment effects than those who did not, however this finding was not statistically significant (95% CI -37.244, 6.677, p = 0.173). However, it is important to note that these findings were evident in an exploratory analysis with a small sample. Future larger scale studies are needed to help understand components of effective treatment. PMID- 30017460 TI - Psychotic disorder symptom rating scales: Are dichotomous or multi-point scales more clinically useful?-An ICD-11 field study. AB - Classifications of psychotic disorders are moving towards utilizing dimensional symptom domains as the preferred mechanism for describing psychotic symptomatology. The ICD-11 has proposed six symptom domains (Positive symptoms, Negative symptoms, Depressive symptoms, Manic symptoms, Psychomotor symptoms, and Cognitive symptoms) that would be rated in addition to providing a psychotic disorder diagnosis. This study investigated clinicians' use of dichotomous versus multi-point scales for rating these six domains. Global mental health professionals (n = 273) rated case vignettes using both a 2-point and 4-point version of a rating scale for the six domains. Clinicians were more accurate using the 2-point scale in absolute terms, but after correcting for chance guessing and disagreements, the two versions of the scale were equally accurate. Clinicians believed the 2-point scale would be easier to use, although they also indicated that the 4-point scale would provide richer clinical information. Participants were able to detect the presence of psychotic symptom domains in the vignettes with good reliability with no special training using either scale. We recommend that clinicians and researchers use the version of the scale that best matches their purpose (i.e., to maximize accuracy or enhance case description). Future work should develop the implementation characteristics of the scale to improve its potential for global application. PMID- 30017461 TI - Abnormalities of eye movement are associated with work hours in schizophrenia. AB - Eye movement abnormalities have been reported in schizophrenia; however, their influences on everyday life remain unknown. From data on 69 subjects with schizophrenia and 246 healthy subjects, we found positive correlations between eye movement measures and work hours, which were only significant in subjects with schizophrenia. This relationship was also confirmed in a multi-site dataset including 118 subjects with schizophrenia and 280 healthy subjects. These findings further strengthen our understanding of eye movement abnormalities and their relevance in clinical recovery. PMID- 30017463 TI - Surprising conservation of schizophrenia risk genes in lower organisms reflects their essential function and the evolution of genetic liability. AB - Schizophrenia is a devastating psychiatric illness that affects approximately 1% of the population. Genetic variation in multiple genes causes elevated risk for the disorder, but the molecular basis is inadequately understood and it is not clear how risk genes have evolved and persisted in the genome. To address these issues, we have identified orthologs/homologs of 344 schizophrenia risk genes (from the Psychiatric Genomics Consortium dataset) in lower organisms, including C. elegans, Drosophila and zebrafish, along with phenotypes produced by genetic disruption in C. elegans. Schizophrenia risk genes were evolutionarily conserved at significantly higher rates in C. elegans (81%) and zebrafish (88%) than genes in general for these two species (40-70%). The risk-gene equivalents were highly (~3-fold) enriched for essential genes consistent with polygenic mutation threshold models, which propose that genetic susceptibility results from the inevitable expression of harmful combinations of risk variants in the population. Most notably, numerous examples of cross-species synteny revealed how blocks of risk genes geared toward a shared biological purpose coalesced into proximity during evolution. We obtained initial evidence that schizophrenia risk genes affected different stages of development, potentially allowing differential modulation by the environment. Taken together, studies of the conservation of schizophrenia risk genes in simple model organisms provided novel insights into the molecular basis for genetic susceptibility to a complex human psychiatric disorder. PMID- 30017462 TI - Social cognition and metacognition contribute to accuracy for self-evaluation of real-world functioning in patients with schizophrenia. PMID- 30017464 TI - Active versus local vibration warm-up effects on knee extensors stiffness and neuromuscular performance of healthy young males. AB - OBJECTIVES: To compare the effects of local-vibration and active warm-up on knee extensors muscle stiffness and neuromuscular performance. DESIGN: Experimental crossover study. METHODS: Thirteen participants performed three 15-min warm-up protocols of control (CON), active (ACT) and local-vibration (LV) in separate testing session. Passive stiffness of vastus lateralis (VL) and vastus medialis (VM) by shear wave elastography and neuromuscular performance were assessed before and 2-min after each condition. RESULTS: A decrease in muscle stiffness was reported after ACT for VL (-16.0+/-6.6%; p<0.001) and VM (-10.2+/-8.7%; p=0.03) while no changes were reported after CON (p=0.46 and p=0.34 for VL and VM, respectively) and LV (p=0.07 and p=0.46 for VL and VM, respectively). Maximal jump performances increased during squat (+8.5+/-6.6%; p<0.001) and countermovement jump (+5.2+/-5.8%; p<0.001) after ACT while no changes were reported after CON and LV during squat (p=0.16 and p=0.81, respectively) and countermovement jump (p=0.18 and p=0.31, respectively). We further report that each condition was ineffective to inducing changes in maximal voluntary isometric contraction force (p=0.18), rate of force development (p=0.92), twitch parameters (p>0.05) as well as central modulations as reported by the unchanged voluntary activation level (p=0.24) and maximal electromyography (EMG) recorded from the VL (p=0.44). CONCLUSIONS: The active warm-up acutely reduced muscle stiffness and increased muscle performance during maximal dynamic tasks. With regard to LV, further studies are required to determine optimal parameters (frequency, amplitude, duration) to significantly increase muscle performance. PMID- 30017465 TI - Does brain functional connectivity contribute to musculoskeletal injury? A preliminary prospective analysis of a neural biomarker of ACL injury risk. AB - OBJECTIVES: We aimed to present a unique prospective neurological dataset for participants who experienced an ACL injury. DESIGN: Prospective longitudinal case control. METHODS: High school female soccer athletes were evaluated using functional magnetic resonance imaging to capture resting-state brain connectivity prior to their competitive season. Two of these athletes later experienced an ACL injury (ACLI). We matched these ACLI participants with eight teammates who did not go on to sustain an ACL injury (uninjured controls, Con) based on age, grade, sex, height, and weight to examine differences in preseason connectivity. Knee motor regions of interest (ROIs) were created based on previously published data from which five specific areas were selected as seeds for analysis. Independent samples t-tests with a false discovery rate correction for multiple comparisons determined differences in connectivity between the ACLI and Con. RESULTS: There was significantly greater connectivity between the left primary sensory cortex (a brain region responsible for proprioception) and the right posterior lobe of the cerebellum (a brain region responsible for balance and coordination) for the Con relative to ACLI, t (8)=4.53, p=0.03 (false discovery rate corrected). CONCLUSIONS: These preliminary data indicate that those who do not later sustain an ACL injury exhibit a stronger functional connection between a cortical sensory motor region and a cerebellar region responsible for balance and coordination. These findings may help to guide development of brain-driven biofeedback training that optimizes and promotes adaptive neuroplasticity to reduce motor coordination errors and injury risk. PMID- 30017466 TI - [Evaluation of the characteristics of aortic dissection by computed angio tomography in the Mexican population]. AB - OBJECTIVE: To review aortic dissection (AD) in the Mexican population. METHOD: A retrospective study was conducted using 434 medical records of patients with aortic angio-tomography between November 2014 and October 2015. A sample was obtained of 32 patients with a first time diagnosis of AD. An analysis was performed of the dissections according to gender, age group, Stanford/De Bakey classification, and mortality rate 6 months after diagnosis. Statistical analysis was performed by obtaining the Chi squared index for the independent variables of gender, Marfan syndrome, systemic arterial hypertension, as well as calcified atheromatous disease in association with dissection subtypes, re-entry sites, and hypo-perfusion signs. RESULTS: The patients included 65.6% males with a mean age of 54.5 years, and 34.4% females with mean age of 42.5 years. The most common dissection subtype was B/3. Mortality rate at 6 months was 18.7%. There was a significant association, with a marginal P in patients with Marfan syndrome and Stanford subtypes of AD (P=.0506). There was a significant association in patients with abdominal aortic aneurysm, when compared with Stanford subtypes of AD (P=.047104). CONCLUSIONS: AD is an emergency in which diagnosis and timely management are essential to improve prognosis. In the sample presented here, a significant association was found in patients with a history of Marfan syndrome and abdominal aneurysms with dissections according to the Stanford classification. The rest of the independent variables did not show any significant association, probably related to the size of the sample. PMID- 30017467 TI - Should children with chronic diarrhea be referred to a lipid clinic? PMID- 30017468 TI - Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis. AB - BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeoxycholic acid (CDCA) production and high plasma cholestanol levels. OBJECTIVES: Our objective was to review the diagnosis and treatment results in 43 CTX cases. METHODS: We conducted a careful review of the diagnosis, laboratory values, treatment, and clinical course in 43 CTX cases. RESULTS: The mean age at diagnosis was 32 years; the average follow-up was 8 years. Cases had the following conditions: 53% chronic diarrhea, 74% cognitive impairment, 70% premature cataracts, 77% tendon xanthomas, 81% neurologic disease, and 7% premature cardiovascular disease. The mean serum cholesterol concentration was 190 mg/dL; the mean plasma cholestanol level was 32 mg/L (normal <5.0 mg/L), which decreased to 6.0 mg/L (-81%) with CDCA therapy generally given as 250 mg orally 3 times daily. Of those tested on treatment, 63% achieved cholestanol levels of <5.0 mg/L; 91% had normal liver enzyme levels; none had significant liver problems after dose adjustment. Treatment improved symptoms in 57% at follow-up, but 20% with advanced disease continued to deteriorate. In the United States, CDCA has been approved for gallstone dissolution, but not for CTX despite long-term efficacy and safety data. CONCLUSIONS: Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease. PMID- 30017474 TI - Editorial: Avoid being tripped up by statistics: Statistical guidance for a successful research paper. PMID- 30017475 TI - Mental Health Screening Results Associated with Women Veterans' Ratings of Provider Communication, Trust, and Care Quality. AB - BACKGROUND: Identifying factors influencing patient experience and communication with their providers is crucial for tailoring comprehensive primary care for women veterans within the Veterans Health Administration. In particular, the impact of mental health (MH) conditions that are highly prevalent among women veterans is unknown. METHODS: From January to March 2015, we conducted a cross sectional survey of women veterans with three or more primary care and/or women's health visits in the prior year at 12 Veterans Health Administration sites. Patient measures included ratings of provider communication, trust in provider, and care quality; demographics, health status, health care use; and brief screeners for symptoms of depression, anxiety, and posttraumatic stress disorder. We used multivariate models to analyze associations of patient ratings and characteristics. RESULTS: Among the 1,395 participants, overall communication ratings were high, but significant variations were observed among women screening positive for MH conditions. In multivariate models, high communication ratings were less likely among women screening positive for multiple MH conditions compared with patients screening negative (odds ratio, 0.43; p < .001). High trust in their provider and high care ratings were significantly less likely among women with positive MH screens. Controlling for communication, the effect of MH on trust and care ratings became less significant, whereas the effect of communication remained highly significant. CONCLUSIONS: Women veterans screening positive for MH conditions were less likely to give high ratings for provider communication, trust, and care quality. Given the high prevalence of MH comorbidity among women veterans, it is important to raise provider awareness about these differences, and to enhance communication with patients with MH symptoms in primary care. PMID- 30017477 TI - Contribution of brain imaging to the diagnosis of intracranial tuberculoma and other brain lesions in patients presenting with miliary tuberculosis. AB - BACKGROUND: Miliary tuberculosis (miliary TB) is characterized by a hematogenous spread of Mycobacterium tuberculosis. Cerebral lesions associated with miliary TB have been reported with diverse frequencies. METHODS: We retrospectively analyzed brain imaging in 34 patients presenting with proven miliary TB hospitalized in our teaching hospital between 2008 and 2014. RESULTS: Neurological symptoms were present at admission in 15 patients, emerged during treatment in six, and were never reported in 13. Twenty-one of 34 patients had cerebral involvement, of which five patients did not present with any neurological symptoms. The most common brain lesions on MRI were tuberculomas. Cerebrospinal fluid (CSF) analysis showed elevated cell count in eight patients who all had abnormal MRI results. Nine patients with normal CSF had abnormal MRI results. CSF cultures were positive in only eight patients. Paradoxical clinical worsening during TB and corticosteroid treatment was observed in six patients. CONCLUSION: Among patients presenting with miliary TB who underwent brain imaging, more than 60% demonstrated cerebral involvement. Abnormal imaging could occur without any clinical nor CSF impairment. Systematically performing brain imaging in miliary TB patients could therefore be informative. PMID- 30017478 TI - The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations. AB - The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with ~11 kb TDs feature loss of TP53 and BRCA1. TDPs with ~231 kb and ~1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them. Lastly, we show how TDs in TDP tumors disrupt heterogeneous combinations of tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers. PMID- 30017479 TI - Mutation -388 C>G of NR5A1 gene affects litter size and promoter activity in sheep. AB - The Nuclear receptor superfamily 5, group A, member 1 (NR5A1) gene encodes a nuclear receptor that regulates the transcription of genes involved in steroidogenesis, follicular development and female fertility. Little, however, is known about the relationship of this gene with reproductive performance in sheep. In this study, the transcription initiation site of Hu sheep NR5A1 gene was located 193 nucleotides (i.e., at -193 nt) before the translational start site (ATG). The core promoter region of the NR5A1 gene ranged from -696 nt to -298 nt, and a C>G mutation at -388 nt was detected in this region. Association analysis indicated ewes with the GG genotype had greater litter size at the second and third parity than those with the CC genotype (P < 0.05). The results from the luciferase assay provided evidence that the -388 G allele increased luciferase activity compared with that of the -388 C allele. Furthermore, the -388 C>G mutation lost a CpG site and gained a novel binding site for the transcription factor, SP1, and results from an overexpression experiment and methylation analysis indicated transcription factor SP1 and methylation of the -388 C>G mutation were both involved in alteration of NR5A1 transcription activity. Results of the present study revealed that the -388 C>G mutation lost a CpG site and promoted NR5A1 gene expression, which completely superimposed positive effects on NR5A1 gene transcription activity by transcription factor SP1, resulting in a fecundity increase in Hu sheep. PMID- 30017476 TI - The Neuroplastic and Therapeutic Potential of Spinal Interneurons in the Injured Spinal Cord. AB - The central nervous system is not a static, hard-wired organ. Examples of neuroplasticity, whether at the level of the synapse, the cell, or within and between circuits, can be found during development, throughout the progression of disease, or after injury. One essential component of the molecular, anatomical, and functional changes associated with neuroplasticity is the spinal interneuron (SpIN). Here, we draw on recent multidisciplinary studies to identify and interrogate subsets of SpINs and their roles in locomotor and respiratory circuits. We highlight some of the recent progress that elucidates the importance of SpINs in circuits affected by spinal cord injury (SCI), especially those within respiratory networks; we also discuss potential ways that spinal neuroplasticity can be therapeutically harnessed for recovery. PMID- 30017481 TI - Theta Rhythmic Neuronal Activity and Reaction Times Arising from Cortical Receptive Field Interactions during Distributed Attention. AB - Growing evidence suggests that distributed spatial attention may invoke theta (3 9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is, however, not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields (RFs) elicits rhythmic multi-unit activity (MUA) at 3-6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RTs) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at theta frequencies. These findings show that theta rhythmic neuronal activity can arise from competitive RF interactions and that this rhythm may result in rhythmic RTs potentially subserving attentional sampling. PMID- 30017483 TI - Cross-Contamination Explains "Inter and Intraspecific Horizontal Genetic Transfers" between Asexual Bdelloid Rotifers. AB - A few metazoan lineages are thought to have persisted for millions of years without sexual reproduction. If so, they would offer important clues to the evolutionary paradox of sex itself [1, 2]. Most "ancient asexuals" are subject to ongoing doubt because extant populations continue to invest in males [3-9]. However, males are famously unknown in bdelloid rotifers, a class of microscopic invertebrates comprising hundreds of species [10-12]. Bdelloid genomes have acquired an unusually high proportion of genes from non-metazoans via horizontal transfer [13-17]. This well-substantiated finding has invited speculation [13] that homologous horizontal transfer between bdelloid individuals also may occur, perhaps even "replacing" sex [14]. In 2016, Current Biology published an article claiming to supply evidence for this idea. Debortoli et al. [18] sampled rotifers from natural populations and sequenced one mitochondrial and four nuclear loci. Species assignments were incongruent among loci for several samples, which was interpreted as evidence of "interspecific horizontal genetic transfers." Here, we use sequencing chromatograms supplied by the authors to demonstrate that samples treated as individuals actually contained two or more highly divergent mitochondrial and ribosomal sequences, revealing cross-contamination with DNA from multiple animals of different species. Other chromatograms indicate contamination with DNA from conspecific animals, explaining genetic and genomic evidence for "intraspecific horizontal exchanges" reported in the same study. Given the clear evidence of contamination, the data and findings of Debortoli et al. [18] provide no reliable support for their conclusions that DNA is transferred horizontally between or within bdelloid species. PMID- 30017480 TI - The Iceman's Last Meal Consisted of Fat, Wild Meat, and Cereals. AB - The history of humankind is marked by the constant adoption of new dietary habits affecting human physiology, metabolism, and even the development of nutrition related disorders. Despite clear archaeological evidence for the shift from hunter-gatherer lifestyle to agriculture in Neolithic Europe [1], very little information exists on the daily dietary habits of our ancestors. By undertaking a complementary -omics approach combined with microscopy, we analyzed the stomach content of the Iceman, a 5,300-year-old European glacier mummy [2, 3]. He seems to have had a remarkably high proportion of fat in his diet, supplemented with fresh or dried wild meat, cereals, and traces of toxic bracken. Our multipronged approach provides unprecedented analytical depth, deciphering the nutritional habit, meal composition, and food-processing methods of this Copper Age individual. PMID- 30017482 TI - A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia. AB - Stress elicits a variety of autonomic responses, including hyperthermia (stress fever) in humans and animals. In this present study, we investigated the circuit basis for thermogenesis and heat conservation during this response. We first demonstrated the glutamatergic identity of the dorsal hypothalamic area (DHAVglut2) neurons that innervate the raphe pallidus nucleus (RPa) to regulate core temperature (Tc) and mediate stress-induced hyperthermia. Then, using chemogenetic and optogenetic methods to manipulate this hypothalamomedullary circuit, we found that activation of DHAVglut2 neurons potently drove an increase in Tc, but surprisingly, stress-induced hyperthermia was only reduced by about one-third when they were inhibited. Further investigation showed that DHAVglut2 neurons activate brown adipose tissue (BAT) but do not cause vasoconstriction, instead allowing reflex tail artery vasodilation as a response to BAT-induced hyperthermia. Retrograde rabies virus tracing revealed projections from DHAVglut2 neurons to RPaVglut3, but not to RPaGABA neurons, and identified a set of inputs to DHAVglut2 -> RPa neurons that are likely to mediate BAT activation. The dissociation of the DHAVglut2 thermogenic pathway from the thermoregulatory vasoconstriction (heat-conserving) pathway may explain stress flushing (skin vasodilation but a feeling of being too hot) during stressful times. PMID- 30017484 TI - Processive Kinesin-14 HSET Exhibits Directional Flexibility Depending on Motor Traffic. AB - A common mitotic defect observed in cancer cells that possess supernumerary (more than two) centrosomes is multipolar spindle formation [1, 2]. Such structures are resolved into a bipolar geometry by minus-end-directed motor proteins, such as cytoplasmic dynein and the kinesin-14 HSET [3-8]. HSET is also thought to antagonize plus-end-directed kinesin-5 Eg5 to balance spindle forces [4, 5, 7, 9]. However, the biomechanics of this force opposition are unclear, as HSET has previously been defined as a non-processive motor [10-16]. Here, we use optical trapping to elucidate the mechanism of force generation by HSET. We show that a single HSET motor has a processive nature with the ability to complete multiple steps while trapped along a microtubule and when unloaded can move in both directions for microns. Compared to other kinesins, HSET has a relatively weak stall force of 1.1 pN [17, 18]. Moreover, HSET's tail domain and its interaction with the E-hook of tubulin are necessary for long-range motility. In vitro polarity-marked bundle assays revealed that HSET selectively generates force in anti-parallel bundles on the order of its stall force. When combined with varied ratios of Eg5, HSET adopts Eg5's directionality while acting as an antagonizing force brake, requiring at least a 10-fold higher Eg5 concentration to surpass HSET's sliding force. These results reveal HSET's ability to change roles within the spindle from acting as an adjustable microtubule slider and force regulator to a processive motor that aids in minus end focusing. PMID- 30017487 TI - The Central Stalk Determines the Motility of Mitotic Kinesin-14 Homodimers. AB - Mitotic kinesin-14 homodimers that contain an N-terminal nonmotor microtubule binding tail contribute to spindle organization by preferentially crosslinking two different spindle microtubules rather than interacting with a single microtubule to generate processive motility. However, the mechanism underlying such selective motility behavior remains poorly understood. Here, we show that when a flexible polypeptide linker is inserted into the coiled-coil central stalk, two homodimeric mitotic kinesin-14s of distinct motility-the processive plus-end-directed KlpA from Aspergillus nidulans [1] and the nonprocessive minus end-directed Ncd from Drosophila melanogaster [2]-both switch to become processive minus-end-directed motors. Our results demonstrate that the polypeptide linker introduces greater conformational flexibility into the central stalk. Importantly, we find that the linker insertion significantly weakens the ability of Ncd to preferentially localize between and interact with two microtubules. Collectively, our results reveal that besides the canonical role of enabling dimerization, the central stalk also functions as a mechanical component to determine the motility of homodimeric mitotic kinesin-14 motors. We suggest that the central stalk is an evolutionary design that primes these kinesin-14 motors for nontransport roles within the mitotic spindle. PMID- 30017485 TI - A Neuronal Hub Binding Sleep Initiation and Body Cooling in Response to a Warm External Stimulus. AB - Mammals, including humans, prepare for sleep by nesting and/or curling up, creating microclimates of skin warmth. To address whether external warmth induces sleep through defined circuitry, we used c-Fos-dependent activity tagging, which captures populations of activated cells and allows them to be reactivated to test their physiological role. External warming tagged two principal groups of neurons in the median preoptic (MnPO)/medial preoptic (MPO) hypothalamic area. GABA neurons located mainly in MPO produced non-rapid eye movement (NREM) sleep but no body temperature decrease. Nitrergic-glutamatergic neurons in MnPO-MPO induced both body cooling and NREM sleep. This circuitry explains how skin warming induces sleep and why the maximal rate of core body cooling positively correlates with sleep onset. Thus, the pathways that promote NREM sleep, reduced energy expenditure, and body cooling are inextricably linked, commanded by the same neurons. This implies that one function of NREM sleep is to lower brain temperature and/or conserve energy. PMID- 30017486 TI - A Critical Role for Thermosensation in Host Seeking by Skin-Penetrating Nematodes. AB - Skin-penetrating parasitic nematodes infect approximately one billion people worldwide and are a major source of neglected tropical disease [1-6]. Their life cycle includes an infective third-larval (iL3) stage that searches for hosts to infect in a poorly understood process that involves both thermal and olfactory cues. Here, we investigate the temperature-driven behaviors of skin-penetrating iL3s, including the human-parasitic threadworm Strongyloides stercoralis and the human-parasitic hookworm Ancylostoma ceylanicum. We show that human-parasitic iL3s respond robustly to thermal gradients. Like the free-living nematode Caenorhabditis elegans, human-parasitic iL3s show both positive and negative thermotaxis, and the switch between them is regulated by recent cultivation temperature [7]. When engaging in positive thermotaxis, iL3s migrate toward temperatures approximating mammalian body temperature. Exposing iL3s to a new cultivation temperature alters the thermal switch point between positive and negative thermotaxis within hours, similar to the timescale of thermal plasticity in C. elegans [7]. Thermal plasticity in iL3s may enable them to optimize host finding on a diurnal temperature cycle. We show that temperature-driven responses can be dominant in multisensory contexts such that, when thermal drive is strong, iL3s preferentially engage in temperature-driven behaviors despite the presence of an attractive host odorant. Finally, targeted mutagenesis of the S. stercoralis tax-4 homolog abolishes heat seeking, providing the first evidence that parasitic host-seeking behaviors are generated through an adaptation of sensory cascades that drive environmental navigation in C. elegans [7-10]. Together, our results provide insight into the behavioral strategies and molecular mechanisms that allow skin-penetrating nematodes to target humans. PMID- 30017488 TI - Isotretinoin induced achilles tendinopathy: Histopathological and biomechanical evaluation on rats. AB - OBJECTIVE: The aim of the present study was to evaluate histopathological and biomechanical effects of isotretinoin on Achilles tendon. MATERIALS & METHODS: Sixteen rats were divided into two groups including the control group (n = 8) and isotretinoin group (n = 8). The control group received 1.42 ml/kg soy oil per day whereas the isotretinoin group received 15 mg/kg/day (gavage dose 1.42 ml/kg) isotretinoin dissolved in soy oil through gavage method for 6 weeks. Achilles tendons were excised at the end of week 6. The tendon samples were evaluated by hematoxylin-eosin under a light microscope. Quantitative evaluation was performed via Movin and Bonar scoring. A computer-monitored tensile testing machine was utilised for biomechanical testing. Biomechanical characteristics of the tendon samples (elastic modulus, yield force, ultimate tensile force) were measured. RESULTS: Histopathological evaluation revealed a significantly higher Movin and Bonar scores in histopathological evaluation. Movin score in isotretinoin group was 4.1 +/- 2.5 and it was 2.3 +/- 1.0 in control group (p = 0.032). Bonar score in isotretinoin group was 2.9 +/- 1.4 and it was 1.6 +/- 0.7 in control group (p = 0.022). In line with histopathological evaluation, biomechanical measurements in isotretinoin group (elastic modulus, yield force, ultimate tensile force) were significantly lower than the control group. Elastic modulus in isotretinoin group was 227 +/- 27.7 N/mm2 and in control group it was 281.7 +/- 38.7 N/mm2 (p = 0.006). In isotretinoin group; yield force was 33.7 +/- 4.3 Pa and in control group it was 40.8 +/- 5.9 Pa (p = 0.021). Ultimate tensile force in isotretinoin group was 35.7 +/- 4.2 Pa and in control group it was 44 +/- 7 Pa (p = 0.009). CONCLUSION: The present study detected histopathological and biomechanical negative effect of isotretinoin on Achilles tendon. Therefore, isotretinoin should be questioned in medical history of patients with tendinopathy. PMID- 30017489 TI - The patellar tendon wavy sign as a new secondary sign of ACL tear on MRI. AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic value of the patellar tendon wavy (PTW) sign for an anterior cruciate ligament (ACL) tear on MRI. METHODS: One hundred MRI scans were prospectively analyzed, with 50 patients with an ACL tear underwent an ACL reconstruction (group 1) and 50 patients with knee complaints other than ACL tear (group 2). The PTW sign was confirmed on the sagittal MRI. In addition, the patellar tendon length, tibial-femoral angle and tibial anterior translation (TAT) were compared between the groups. RESULTS: The PTW sign was present in 41/50 (82%) MRI scans in group 1 and 10/50 (20%) in group 2, with significant difference between two groups (p = 0.000). Significant differences were also found, in medial TAT (6.29 +/- 3.25 mm versus 3.12 +/- 2.85 mm) and in lateral TAT (7.62 +/- 3.85 mm versus 1.58 +/- 3.93 mm) between two groups (both p = 0.000). Comparison of MRI with and without PTW sign, ACL injury was found to be of significant difference with 41/51 (80.4%) versus 9/49 (18.4%) (p = 0.000), and both medial and lateral TAT were with significant differences, 5.39 +/- 3.90 mm versus 3.99 +/- 2.71 mm (p = 0.039) and 7.67 +/- 3.77 mm versus 1.40 +/- 3.81 mm (p = 0.000), respectively. The sensitivity and specificity of PTW sign were 82% and 80%. The positive and negative predictive value were 80.4% and 81.6%. The diagnosis accuracy was 81%. CONCLUSION: The PTW sign is a useful secondary MRI sign to establish the diagnosis of an ACL tear. It may be associated with the TAT secondary to an ACL tear. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 30017490 TI - Management of Infections in Solid Organ Transplant Recipients. PMID- 30017491 TI - Review of pelvic and perineal neuromuscular fatigue: Evaluation and impact on therapeutic strategies. AB - BACKGROUND: Pelvic floor fatigue is known by its clinical consequences (fecal incontinence, stress urinary incontinence, pelvic organ prolapse), but there are still few studies on the subject. OBJECTIVE: This article presents an overview of the current knowledge of pelvic and perineal fatigue, focusing on its assessment and consequences in terms of evaluation and therapeutic strategies, to propose an evaluation that could be routinely performed. METHODS: We performed a systematic review of the literature in MEDLINE via PubMed and Cochrane Library databases by using the keywords pelvic floor, muscular fatigue, physiopathology, stress urinary incontinence, pelvic organ prolapse, fecal incontinence, physical activity, and pelvic rehabilitation. We included reports of systematic reviews and retrospective and prospective studies on adult humans and animals in English or French published up to April 2018 with no restriction on start date. RESULTS: We selected 59 articles by keyword search, 18 by hand-search and 3 specific guidelines (including the 2009 International Continence Society recommendations); finally 45 articles were included; 14 are described in the Results section (2 reviews of 6 and 20 studies, and 12 prospective observational or cross-over studies of 5 to 317 patients including 1 of animals). Perineal fatigue can be assessed by direct assessment, electromyography and spectral analysis and during urodynamics. Because pelvic floor fatigue assessments are not evaluated routinely, this fatigability is not always identified and is often falsely considered an exclusive pelvic floor weakness, as suggested by some rehabilitation methods that also weaken the pelvic floor instead of enhancing it. CONCLUSION: Pelvic floor fatigue is not evaluated enough on a routine basis and the assessment is heterogeneous. A better knowledge of pelvic floor fatigue by standardized routine evaluation could lead to targeted therapeutic strategies. PMID- 30017492 TI - The impact of alcohol on breathing parameters during sleep: A systematic review and meta-analysis. AB - Alcohol, a muscle relaxant, can potentially worsen obstructive sleep apnea (OSA) but the literature on the effects of alcohol on OSA is conflicting. This systematic review and meta-analysis of randomized controlled trials examined the impact of alcohol on breathing parameters during sleep. Ovid Medline, Embase and PsycINFO databases were queried through November 1, 2017 for studies that reported objective measures of breathing during sleep, prior to and after alcohol administration. Weighted mean differences (WMD) and 95% confidence intervals (CI) were calculated for apnea-hypopnea index (AHI) and mean oxyhemoglobin saturation (SpO2). Secondary outcome measures were examined where available. The meta analysis of 14 eligible studies (n = 422; 71.9% male) found that AHI increased significantly after alcohol administration (WMD = 2.33; 95% CI = 1.41 to 3.25, I2 = 62%) and mean SpO2 was significantly reduced (WMD = -0.60; 95% CI = -0.72 to 0.49, I2 = 0%). The increase in AHI was greater in snorers (WMD = 4.20; 95% CI = 1.19 to 6.50, I2 = 0%) and those with a diagnosis of OSA (WMD = 7.10; 95% CI = 3.59 to 10.61, I2 = 0%). Additionally, a significant increase in respiratory event duration (WMD = 0.86; 95% CI = 0.18 to 1.55, I2 = 19%) and decrease in nadir SpO2 (WMD = -1.25; 95% CI = -2.00 to -0.50, I2 = 25%) were noted. Alcohol is a modifiable risk factor that can result in the development or worsening of OSA. PMID- 30017494 TI - Top-down effects in the brain. AB - The purpose of this investigation is to demonstrate that one is unable to understand the operation of the brain without taking top-down effects into account. This is demonstrated by looking in turn at evolutionary and developmental aspects, then at functional aspects related to sensory systems, learning processes, and motor processes that lead to action on the world. It is also clear in terms of the effects of a society on brains located in that society. The possibility of top down affects exists both because of multiple realisability of higher level processes at lower levels, and because lower level elements are adapted to perform their higher level functions. These top-down processes validate a non-reductionist approach to how the brain works. PMID- 30017493 TI - Towards a more explicit account of the transformation: Reply to comments on "An integrative review of the enjoyment of sadness associated with music". PMID- 30017495 TI - Enzyme activity of Schistosoma japonicum cercarial elastase SjCE-2b ascertained by in vitro refolded recombinant protein. AB - Cercarial elastase (CE) secreted from cercariae is evinced to play a pivotal role in initial skin penetration of mammalian host. SjCE-2b, a Schistosoma japonicum CE orthologous to SmCE-2b in S. mansoni, was previously found present in cercarial stage to aid skin invasion, but its enzyme activity has not been validated due to the insolubility and altered conformation when expressed recombinantly in bacteria as inclusion bodies. We report here for the first time a bioactive and soluble recombinant SjCE-2b recovered successfully from inclusion bodies by refolding approaches, enabling our biochemical and immunological investigation of this enzyme. Using a "two-step-denaturing and refolding" method, we recovered an 83% yield with 90% purity of refolded protein. Proteolytic activity of rSjCE-2b was demonstrated and characterized by enzymatic assay, showing a Km of 0.116 mM and a specific activity of 1900 nmol p nitroaniline/min/mg protein. A significant immunoprotective response was evidenced in mice immunized with refolded rSjCE-2b. The result of immunoprotection test is at apparent variance with previously reported findings using S. mansoni CE preparation, which was poorly immunogenic in immunized animals. This work extends the knowledge of schistosome cercarial protease, and presents a bioactive form of S. japonicum recombinant CE with high yield and good quality. This will allow further biochemical and biological investigations to explore schistosome CE activity and better understand the molecular mechanisms associated with cercarial skin invasion of the mammalian host. PMID- 30017496 TI - Mummy studies and the bioarchaeology of care. AB - The bioarchaeology of care is a framework through which researchers can begin to infer the level of care an individual may have required based on the presence of paleopathological evidence. To date, all of the research that has employed the framework has been based on evidence derived from skeletal material. This special issue was organized in order to highlight how the analysis of mummified soft tissue, as well as other sources of data commonly associated with mummified remains, such as coprolites and intestinal contents, has the potential to provide valuable insight into the reconstruction of care in the past. PMID- 30017498 TI - Roundtable Discussion. The future of midwifery education: a global perspective. PMID- 30017497 TI - Genome editing technologies for plant physiology. PMID- 30017499 TI - Midwifery matters. PMID- 30017500 TI - Low Dose Lung CT Screening in an Asian Population. PMID- 30017501 TI - Lightly Embalmed Cadavers as a Training Tool for Ultrasound-Guided Procedures Commonly Used in Interventional Radiology. AB - RATIONALE AND OBJECTIVES: Competency in ultrasound (US) imaging and US-guided procedures is often difficult for medical students and residents to master. The use of simulation training has been strongly encouraged but the quality of phantom models available for US-guided procedures is limited. As a feasible alternative, we describe the innovative use of a lightly embalmed cadaver for realistic practice of common interventional radiology (IR) procedures prior to direct patient care. MATERIALS AND METHODS: Lightly embalmed cadavers were positioned as patients would be in the IR suite: supine, prone, and erect seated position. Lidocaine was injected and visualized under standard percutaneous techniques and sonographic guidance was used to simulate common US-guided procedures performed in IR including liver biopsy, kidney biopsy, thoracentesis, and vascular access. RESULTS: The ability to position cadavers was a key factor that allowed entire procedures to be simulated. Medical students with very limited exposure to US imaging and diagnostic radiology residents with minimal exposure to US imaging successfully completed common US-guided procedures. Arterial and venous vascular access was obtained. Wires were passed and catheters easily placed via both access sites. The texture of the tissue layers provided realistic feedback for the trainees as they advanced the needle or dilated the tissues. Images from each simulated procedure resembled images expected in a living patient. CONCLUSION: Lightly embalmed cadavers are an innovative and feasible tool to simulate common IR US-guided procedures in a realistic fashion for deliberate practice in advance of first-attempt encounters with patients. PMID- 30017502 TI - Quantitative Analysis of Airway Tree in Low-dose Chest CT with a New Model-based Iterative Reconstruction Algorithm: Comparison to Adaptive Statistical Iterative Reconstruction in Routine-dose CT. AB - OBJECTIVE: We aimed to evaluate a new model-based iterative reconstruction (MBIRn) algorithm either with spatial resolution and noise reduction balance (MBIRSTND) or spatial resolution preference (MBIRRP20) for quantitative analysis of airway in low-dose chest computed tomography (CT) with a computer-aided detection (CAD) software, in comparison to adaptive statistical iterative reconstruction (ASIR) in routine-dose CT. METHODS: Thirty patients who underwent both the routine-dose (noise index [NI] = 14 HU) and low-dose (at 30% level with NI = 28 HU) CT examination for pulmonary disease were included. Image acquisition was performed with 120 kVp tube voltage and automatic tube current modulation. Routine-dose scans were reconstructed with ASIR, whereas low-dose scans were reconstructed with ASIR, MBIRSTND, and MBIRRP20. Airway dimensions of the right middle lobe bronchus from the four reconstructions were measured using CAD software. Two radiologists used a semiquantitative 5 scoring criteria (-2, inferior to; +2, superior to; -1 slightly inferior to; +1, slightly superior to; and 0, equal to ASIR in routine-dose CT) to rate the subjective image quality of MBIRSTND and MBIRRP20 of airway trees. The paired t test and Wilcoxon signed-rank test were used for statistical comparison. RESULTS: The low-dose CT provided 70.76% dose reduction compared to the routine-dose CT (0.88 +/- 0.83 mSv vs 3.01 +/- 1.89 mSv). MBIRSTND and MBIRRP20 with low-dose CT provided longer bronchial length measurements and were better in measurement variability and continuity and completeness of bronchial walls than ASIR in routine-dose CT (P < .05). MBIRSTND was better for subjective noise and MBIRRP20 for showing distal branches. CONCLUSIONS: MBIRSTND and MBIRRP20 algorithms provide better airway quantification at 30% of the radiation dose, compared to ASIR at routine-dose CT. PMID- 30017503 TI - Responses exhibited by various microbial groups relevant to uranium exposure. AB - There is a strong interest in knowing how various microbial systems respond to the presence of uranium (U), largely in the context of bioremediation. There is no known biological role for uranium so far. Uranium is naturally present in rocks and minerals. The insoluble nature of the U(IV) minerals keeps uranium firmly bound in the earth's crust minimizing its bioavailability. However, anthropogenic nuclear reaction processes over the last few decades have resulted in introduction of uranium into the environment in soluble and toxic forms. Microbes adsorb, accumulate, reduce, oxidize, possibly respire, mineralize and precipitate uranium. This review focuses on the microbial responses to uranium exposure which allows the alteration of the forms and concentrations of uranium within the cell and in the local environment. Detailed information on the three major bioprocesses namely, biosorption, bioprecipitation and bioreduction exhibited by the microbes belonging to various groups and subgroups of bacteria, fungi and algae is provided in this review elucidating their intrinsic and engineered abilities for uranium removal. The survey also highlights the instances of the field trials undertaken for in situ uranium bioremediation. Advances in genomics and proteomics approaches providing the information on the regulatory and physiologically important determinants in the microbes in response to uranium challenge have been catalogued here. Recent developments in metagenomics and metaproteomics indicating the ecologically relevant traits required for the adaptation and survival of environmental microbes residing in uranium contaminated sites are also included. A comprehensive understanding of the microbial responses to uranium can facilitate the development of in situ U bioremediation strategies. PMID- 30017504 TI - A comparison of the sensitivity and specificity of anthropometric measurements to predict unhealthy metabolic phenotype in overweight and obese women. AB - AIM: Metabolically Healthy Obese (MHO) is called to obese people that their insulin sensitivity, lipid profiles and inflammatory profiles are favorable, and there are no signs of hypertension and cardio-metabolic diseases. The metabolically unhealthy obese (MUHO) is the opposite. A Body Shape Index (ABSI) is a marker to identifying abdominal obesity that is derived from weight, height and waist circumference (WC). Several studies have reported ABSI is associated with diabetes, metabolic syndrome, hypertension and higher mortality rate. MATERIALS AND METHODS: A total of 305 overweight and obese women were included in the current comparative cross-sectional study. Body composition was measured using body composition analyzer. Blood samples were obtained. The usual food intake of evaluated through the use of a semi-quantitative food frequency questionnaire. RESULTS: The results of this study revealed that there is a significant relationship between ABSI and MHO and MUHO (p = 0.04) and area under the ROC curve was 0.60. Also there is a significant relationship between BMI, fat mass index (FMI), free fat mass index (FFMI), neck circumference (NC), WC, fat mass (FM) and metabolic healthy status (MHS). The largest area under the ROC curve belonged to NC, WC, FM and BMI (0.66). CONCLUSION: The findings of this study suggest that there is a significant relationship between ABSI, BMI, FMI, FFMI, NC, WC, FM and MHS. The largest area under the ROC curve was related to the NC, WC, FM and BMI not ABSI, that means NC, WC, FM and BMI have maximum sensitivity and specificity. PMID- 30017505 TI - Diabetes knowledge, attitude, and practice among type 2 diabetes mellitus patients in Kuala Muda District, Malaysia - A cross-sectional study. AB - Diabetes is among leading public health concerns in Malaysia due to premature and preventable mortality involving macro and microvascular complications. Diabetes knowledge, attitude, and practice (KAP) are vital in diabetes management. The present study assessed the level of diabetes KAP among type 2 diabetes patients with associated and correlated factors through a self-administered questionnaire based study on a convenience sample of 386 type 2 diabetes mellitus patients in Kuala Muda District, Kedah, Malaysia. Majority of the respondents possessed levels above the cut-off points for poor levels in knowledge (63.21%), attitude (62.69%), and practices (58.03%). Age, academic qualification, occupation, monthly income, current therapy type, comorbid diseases, and therapy preference were associated with KAP whereas the associations of disease duration, the best source of information about diabetes, and health status satisfaction were witnessed for attitude and practice. Academic qualification had strongest correlation for knowledge (r = 0.785), attitude (r = 0.725), and practice (r = 0.709). Knowledge level was significantly correlated with attitude level (r = 0.735), practice level (r = 0.786), income (r = 0.556), occupation (r = 0.358), age (r = 0.173), current therapy type (r = 0.133), and diabetes education exposure (r = 0.113). Attitude level had significant correlations with practice level (r = 0.679), income (r = 0.357), occupation (r = 0.348), health status satisfaction (r = 0.147), age (r = 0.145), and gender (r = 0.109). Practice level correlated significantly with income (r = 0.448), occupation (r = 0.317), age (r = 0.173), health status satisfaction (r = 0.167), and current therapy type (r = 0.118). All associations and correlations were significant at P < 0.005. Although overall having good levels of diabetes KAP, educational interventions are required to further improve diabetes KAP. PMID- 30017506 TI - Klippel-Trenaunay Syndrome: A Dramatic Presentation. PMID- 30017507 TI - When Surgeons Create Their Own Tools! PMID- 30017508 TI - Systematic Review and Meta-analysis of Clinical Trials Examining the Benefit of Exercise Programmes Using Nordic Walking in Patients With Peripheral Artery Disease. AB - OBJECTIVES: An exercise programme is part of the initial management of peripheral artery disease (PAD). Nordic walking uses poles and a core-focused walking technique to reduce the load on the legs, which may have advantages as an exercise programme for PAD. This systematic review examined the benefit of a Nordic walking programme for treating PAD compared with other programmes. METHODS: A systematic approach was used to identify clinical trials comparing Nordic walking and control programmes in PAD patients. For inclusion, studies had to report maximum walking distance (MWD) measured with a treadmill test or corridor walking test both at entry and follow up. Study quality was appraised using the Cochrane collaboration tool for assessing risk of bias. An inverse variance weighted meta-analysis was performed to compare improvements in MWD. RESULTS: Five independent trials involving 294 patients were identified. In three trials, supervised Nordic walking programmes were compared with supervised standard walking. One trial compared a home based Nordic walking programme with a similar standard walking programme. One trial compared a partly supervised Nordic walking programme with best medical management. Meta-analysis of all data suggested that MWD improvements were similar for patients treated by Nordic and standard walking programmes (standardised mean difference, SMD = 1.31, 95% CI 1.28 to 3.91; p = .322). Findings for completely supervised programmes were similar to the primary analysis (SMD = -0.79, 95% CI -2.81 to 1.24; p = .446) while those from partially supervised or home based programmes favoured Nordic walking (SMD = 4.46, 95% CI 3.39, 5.53; p < .001), mainly due to results from one home based trial. CONCLUSIONS: This systematic review suggests no benefit of Nordic over standard walking as supervised exercise for PAD. Favourable results were reported for one home based Nordic walking programme. A larger trial is needed to assess whether this finding can be replicated or not. PMID- 30017509 TI - Phenotypic and lipidomic characterization of primary human epidermal keratinocytes exposed to simulated solar UV radiation. AB - BACKGROUND: Ultraviolet (UV) radiation is known to be one of the most important environmental hazards acting on the skin. The most part of UV radiation is absorbed in the epidermis, where keratinocytes are the most abundant and exposed cell type. Lipids have an important role in skin biology, not only for their important contribution to the maintenance of the permeability barrier but also for the production and storage of energy, membrane organization and cell signalling functions. However, the effects on the lipid composition of keratinocytes under UV radiation are little explored. OBJECTIVE: The present work aims to explore the effects on the phenotype and lipid content of primary human keratinocytes exposed to simulated solar UV radiation. METHODS: Keratinocytes were exposed to a single (acute exposure) and repeated simulated solar UV irradiations for 4 weeks (chronic exposure). Cell viability and morphology were explored, as well as the production of reactive oxygen species. Then, lipid extracts were analysed through liquid chromatography coupled to mass spectrometry (LC-MS) and the data generated was processed using the ROIMCR chemometric methodology together with partial least squares discriminant analysis (PLS-DA), to finally reveal the most relevant lipid changes that occurred in keratinocytes upon UV irradiation. Also, the potential induction of keratinocyte differentiation was explored by measuring the increase of involucrin. RESULTS: Under acute irradiation, cell viability and morphology were not altered. However, a general increase of phosphatidylcholines (PC) phosphatidylethanolamines (PE) and phosphatidylglycerol (PG) together with a slight sphingomyelin (SM) decrease were found in UV irradiated cells, among other changes. In addition, keratinocyte cultures did not present any differentiation hallmark. Contrary to acute irradiated cells, in chronic exposures, cell viability was reduced and keratinocytes presented an altered morphology. Also, hallmarks of differentiation, such as the increase of involucrin protein and the autophagy induction were detected. Among the main lipid changes that accompanied this phenotype, the increase of long-chain ceramides, lysoPC and glycerolipid species were found. CONCLUSION: Important lipid changes were detected under acute and chronic UV irradiation. The lipid profile under chronic exposure may represent a lipid fingerprint of the keratinocyte differentiation phenotype. PMID- 30017510 TI - Acute effects of different orthotic interventions on knee loading parameters in knee osteoarthritis patients with varus malalignment. AB - BACKGROUND: Knee osteoarthritis (KOA) is the most common form of arthritis with an estimated lifetime prevalence of 45%. The use of orthotic devices is a generally accepted conservative therapy in KOA. A new conservative treatment is an ankle-foot orthosis (AFO); however, studies on the biomechanical effects are limited. The aim of this study was to examine the acute effects of different orthotic devices (AFO, knee brace and wedged shoes) on (un)loading parameters in subjects with KOA. METHODS: Fifty-two medial KOA patients (mean age 59 (standard deviation (SD) 10) years and mean body mass index 27.5 (SD 4.9) kg/m2) were recruited. Three-dimensional gait analysis was undertaken with different interventions in a randomized order: control (own shoes), new AFO, conventional unloader brace and laterally wedged shoes (six degrees). RESULTS: Significant decreases of 27% and nine percent in first peak knee adduction moment (KAM) were observed for the AFO and wedged shoes, respectively, in comparison with the control. Significant decreases of 21%, seven percent and 18% in the KAM impulse were observed for the AFO, brace and wedged shoes, respectively, compared to the control. The knee flexion moment (KFM) increased compared to the control for all conditions, but only significantly while using the AFO, showing an increase of 26% as compared to the control. CONCLUSIONS: The AFO and wedged shoes were more effective in unloading the medial compartment of the knee compared to the unloader brace. However, the effect of an increased KFM on KOA remains unclear and requires further investigation. PMID- 30017511 TI - Predicting patient reported outcome in total knee arthroplasty using body mass index and limb measurements. AB - BACKGROUND: Body mass index (BMI) has not been shown to correlate with Patient Reported Outcome Measures (PROMs) following total knee arthroplasty (TKA). We investigated the relationship between weight, BMI, limb morphology, and Oxford Knee Score (OKS). Furthermore, the utility of a novel radiological measurement, the Knee Mass Index (KMI), was investigated. METHODS: Data including weight, BMI, gender, preoperative and 12 month OKS were collected from an arthroplasty database that contained 268 patients who underwent TKA. Measurements of soft tissue and bone width were made from the preoperative radiograph and 'KMI' was calculated. Pearson correlation and multivariate regression analyses were used to assess the relationship between OKS and the above variables. RESULTS: The novel measurement, KMI, was not a predictor of the OKS. The BMI was predictive of initial OKS (Odds Ratio (OR) -0.26 p < 0.001), 12 month OKS (OR -0.39 p < 0.001) and change in OKS (OR -0.39 p < 0.001). The initial OKS was predictive of 12 month OKS (OR 0.32 p < 0.001) and change in OKS (OR -0.68 p < 0.001). CONCLUSIONS: The novel KMI metric was not useful in predicting function. Both the post-operative OKS and change in OKS are predicted by BMI and pre-operative OKS. This is one of the first studies to show a relationship between BMI and OKS. PMID- 30017512 TI - A review of statistical and machine learning methods for modeling cancer risk using structured clinical data. AB - Advancements are constantly being made in oncology, improving prevention and treatment of cancers. To help reduce the impact and deadliness of cancers, they must be detected early. Additionally, there is a risk of cancers recurring after potentially curative treatments are performed. Predictive models can be built using historical patient data to model the characteristics of patients that developed cancer or relapsed. These models can then be deployed into clinical settings to determine if new patients are at high risk for cancer development or recurrence. For large-scale predictive models to be built, structured data must be captured for a wide range of diverse patients. This paper explores current methods for building cancer risk models using structured clinical patient data. Trends in statistical and machine learning techniques are explored, and gaps are identified for future research. The field of cancer risk prediction is a high impact one, and research must continue for these models to be embraced for clinical decision support of both practitioners and patients. PMID- 30017513 TI - Prospective associations between socioeconomically disadvantaged groups and metabolic syndrome risk in European children. Results from the IDEFICS study. AB - OBJECTIVE: Socioeconomic disadvantages during childhood are hypothesised to have negative implications for health. We aimed to investigate the association between socioeconomic disadvantages and children's total metabolic syndrome (MetS) score at baseline and follow-up and the extent to which socioeconomic disadvantages over time and the accumulation of these socioeconomic disadvantages can affect children's MetS risk. METHODS: The two-year longitudinal IDEFICS study included 2401 European children (aged 2.0-9.9) with complete information of the 16,229 participating at baseline. Sociodemographic variables, psychosocial factors and lifestyle were proxy-reported via questionnaires. Socioeconomically disadvantaged groups included children from families with low income, low education, migrant origin, unemployed parents, parents who lacked a social network, and from non traditional families. MetS risk score was calculated as the sum of z-scores of waist circumference, blood pressure, lipids and insulin resistance. Linear mixed effects models were used to study the association between social disadvantages and MetS risk. Models were adjusted for sex, age, well-being and lifestyle (fruit and vegetables consumption, physical activity, screen time). RESULTS: At both time points, children from low-income families (0.20 [0.03-0.37]); (beta estimate and 99% confidence interval), children from non-traditional families (0.14 [0.02 0.26]), children whose parents were unemployed (0.31 [0.05-0.57]) and children who accumulated >3 disadvantages (0.21 [0.04-0.37]) showed a higher MetS score compared to non-socioeconomically disadvantaged groups. CONCLUSION: Children from socioeconomically disadvantaged families are at high metabolic risk independently of diet, physical activity, sedentary behaviours and well-being. Interventions focusing on these socioeconomically disadvantaged groups should be developed to tackle health disparities. PMID- 30017514 TI - The ACEF score in acute coronary syndrome: "Never was so much owed by so many to so few". PMID- 30017515 TI - Hybrid invasive coronary imaging with intravascular ultrasound and optical coherence tomography: Informing research and guiding practice. PMID- 30017516 TI - Acute heart failure: Diagnosis first and then treatment. PMID- 30017517 TI - Sequential treatment with sildenafil and riociguat in patients with persistent or inoperable chronic thromboembolic pulmonary hypertension improves functional class and pulmonary hemodynamics. AB - BACKGROUND: This study evaluated the incremental effect of riociguat on pulmonary hemodynamics in patients with inoperative or persistent chronic thromboembolic pulmonary hypertension (CTEPH) treated previously with sildenafil. METHODS: The retrospective study included 28 patients diagnosed with CTEPH who were ineligible for surgical treatment due to distal thrombi location or who suffered from persistent CTEPH after pulmonary endarterectomy and who were treated with sildenafil at a dose of 25 mg TID for a minimum of 3 months. Sildenafil was subsequently discontinued, and riociguat therapy was started with gradually increasing doses. Right heart catheterization was performed and WHO functional class (FC) was assessed in each patient at three time points: before starting sildenafil therapy (baseline), before the transition to riociguat, and after 3 to 6 months of therapy with riociguat. RESULTS: Compared to baseline, the use of sildenafil and riociguat significantly decreased pulmonary vascular resistance (PVR) (10.47 +/- 3.56 vs. 7.81 +/- 3.58 Wood units, p < 0.001) and mean pulmonary arterial pressure (PAP) (54.1 +/- 11.6 vs. 46.1 +/- 13.2 mm Hg; p < 0.001) while increasing cardiac output (CO) (4.31 +/- 0.88 vs. 4.85 +/- 0.87 L/min; p = 0.007). Switching from sildenafil to riociguat reduced PVR by 14% (p = 0.005) and the mean PAP by 6% (p = 0.03) while increasing CO by 11% (p = 0,002). The number of patients with WHO FC III and IV symptoms decreased from 71,4% to 57,1% (p = 0,02) after the change from sildenafil to riociguat. CONCLUSIONS: Replacing sildenafil with riociguat in patients with inoperable or persistent CTEPH may improve pulmonary hemodynamics and FC. PMID- 30017518 TI - Inflammation in aortic stenosis: Shaping the biomarkers network. PMID- 30017519 TI - Anti-TNF modulation reduces myocardial inflammation and improves cardiovascular function in systemic rheumatic diseases. AB - BACKGROUND: Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are common disorders associated with increased rates of cardiovascular disease (CVD), but the contribution of cytokine-induced inflammation to impaired cardiovascular function in these conditions remains poorly understood. OBJECTIVES: We assessed the effect of anti-TNF therapy on myocardial and vascular function, myocardial tissue characteristics and perfusion in inflammatory arthropathy and systemic rheumatic disease (IASRD) patients, using cardiovascular magnetic resonance (CMR). METHODS: 20 RA patients, 7 AS patients, 5 PsA patients without previously known CVD scheduled to commence anti TNF therapy and 8 RA patients on standard disease modifying antirheumatic drugs underwent CMR at 1.5 T, including cine, tagging, pulse wave velocity (PWV), T2 weighted, native and postcontrast T1 mapping, ECV quantification, rest and stress perfusion and late gadolinium enhancement (LGE) imaging. RESULTS: Following anti TNF therapy, there was significant reversal of baseline subclinical cardiovascular dysfunction, as evidenced by improvement in peak systolic circumferential strain (p < 0.001), peak diastolic circumferential strain rate (p < 0.001), and total aortic PWV, (p < 0.001). This was accompanied by a reduction in myocardial inflammation, as assessed by T2-weighted imaging (p = 0.005), native T1 mapping (p = 0.009) and ECV quantification (p = 0.001), as well as in serum inflammatory markers like CRP (p < 0.001) and ESR (p < 0.001), and clinical measures of disease activity (DAS28-CRP, p = 0.001; BASDAI, p < 0.001). A trend towards improvement in myocardial perfusion was observed (p = 0.07). Focal myocardial fibrosis, as detected by LGE CMR was not altered by anti-TNF therapy (p = 0.92). CONCLUSIONS: Anti-TNF therapy reduces subclinical myocardial inflammation and improves cardiovascular function in RA, AS and PsA. CMR may be used to track disease progression and response to therapy. Future CMR-based studies to demonstrate effect of anti-TNF therapy modulation of vascular structure and function on hard clinical events and outcomes would be useful. PMID- 30017520 TI - Software-automated multidetector computed tomography-based prosthesis-sizing in transcatheter aortic valve replacement: Inter-vendor comparison and relation to patient outcome. PMID- 30017521 TI - Long-term exposure to high altitude hypoxia during pregnancy increases fetal heart susceptibility to ischemia/reperfusion injury and cardiac dysfunction. AB - BACKGROUND: High altitude hypoxia (HAH) exposure affects fetal development. However, the fetal cardiovascular responses to the HAH are not well understood. We have tested the hypothesis that long-term HAH exposure alters the hypoxia/ischemia-sensitive gene expressions, leading to an increase in fetal heart susceptibility to ischemia/reperfusion (I/R) injury and cardiac dysfunction. METHODS: Time-dated pregnant sheep were exposed to high-altitude (3820 m) or were maintained at sea level (~300 m) for 110 days. Fetal hearts were isolated from the near-term ewes and subjected to I/R in a Langendorff preparation. RESULTS: HAH decreased the fetal body and heart weights in the female but not male fetuses. HAH had no effect on the left ventricle (LV) function at baseline, but increased the LV infarct size and attenuated the post ischemic recovery of LV function in both male and female fetuses, as compared with the normoxic groups. HAH increased the protein levels of hypoxia-inducible factor (HIF)-1alpha and DNA methyltransferases type 3b (DNMT3b), but attenuated protein kinase C epsilon (PKCepsilon) levels in the fetal hearts. AHA induced a 4.3 fold increase of miR-210 in the males and a 2.9 fold increase in female hearts. In addition, HAH had no effect on mTOR protein and phosphorylation levels but increased the autophagy biomarker, LC3B-II protein levels and LC3B-II/LC3B-I ratio in the fetal hearts. CONCLUSION: The results suggest that gestational HAH exposure induces in utero programming of the hypoxia/ischemia-sensitive gene expression pattern in the developing heart and increases cardiac susceptibility to I/R injury. PMID- 30017522 TI - Electro-mechanical (dys-)function in long QT syndrome type 1. AB - BACKGROUND: Prolonged repolarization is the hallmark of long QT syndrome (LQTS), which is associated with subclinical mechanical dysfunction. We aimed at elucidating mechanical cardiac function in LQTS type 1 (loss of IKs) and its modification upon further prolongation of the action potential (AP) by IKr blockade (E-4031). METHODS: Transgenic LQT1 and wild type (WT) rabbits (n = 12/10) were subjected to tissue phase mapping MRI, ECG, and epicardial AP recording. Protein and mRNA levels of ion channels and Ca2+ handling proteins (n = 4/4) were determined. In silico single cell AP and tension modeling was performed. RESULTS: At baseline, QT intervals were longer in LQT1 compared to WT rabbits, but baseline systolic and diastolic myocardial peak velocities were similar in LQT1 and WT. E-4031 prolonged QT more pronouncedly in LQT1. Additionally, E-4031 increased systolic and decreased diastolic peak velocities more markedly in LQT1 - unmasking systolic and diastolic LQT1-specific mechanical alterations. E-4031-induced alterations of diastolic peak velocities correlated with the extent of QT prolongation. CONCLUSION: While baseline mechanical function is normal in LQT1 despite a distinct QT prolongation, further prolongation of repolarization by IKr-blocker E-4031 unmasks mechanical differences between LQT1 and WT with enhanced systolic and impaired diastolic function only in LQT1. These data indicate an importance of the extent of QT prolongation and the contribution of different impaired ion currents for conveying mechanical dysfunction. PMID- 30017523 TI - Circadian rhythm of cardiac troponins. Does it really exist? PMID- 30017524 TI - Mitral annulus enlargement in mitral regurgitation: Look to the north. PMID- 30017525 TI - Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching. AB - BACKGROUND: Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. We aimed to investigate whether Homocysteine responsive endoplasmic reticulum protein (Herp) was involved in VSMC phenotypic switching and affected atheroprogression. METHODS: To assess the role of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp-/- and LDLR-/- double knockout mice were generated and fed with a high methionine diet (HMD) to induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of VSMCs were assessed in vivo. We used siRNAs to knockdown Herp in cultured VSMCs to further validate our findings in vitro. RESULTS: HMD significantly activated the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR-/- mice, and induced the phenotypic switch of VSMCs, with the loss of contractile proteins (SMA and calponin) and an increase of OPN protein. Herp-/-/LDLR-/- mice developed reduced atherosclerotic lesions in the aortic sinus and the whole aorta when compared with LDLR-/- mice. However, Herp deficiency had no effect on diet induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, decreased proliferation and collagen accumulation were observed in Herp-/-/LDLR-/ mice when compared with LDLR-/- mice. In vitro experiments demonstrated that Hcy caused VSMC phenotypic switching, promoted cell proliferation and migration; this was reversed by Herp depletion. We achieved similar results via inhibition of ER stress using 4-phenylbutyric-acid (4-PBA) in Hcy-treated VSMCs. CONCLUSION: Herp deficiency inhibits the phenotypic switch of VSMCs and the development of atherosclerosis, thus providing novel insights into the role of Herp in atherogenesis. PMID- 30017526 TI - Should we screen hereditary thrombophilia testing in patients with provoked/unprovoked venous thromboembolism? PMID- 30017527 TI - Extent and magnitude of low-voltage areas assessed by ultra-high-density electroanatomical mapping correlate with left atrial function. AB - INTRODUCTION: The extent of left atrial (LA) adverse remodeling as a cardiac disease marker has become increasingly important. In patients with atrial fibrillation (AF), atrial remodeling (AR) is accompanied by increased mortality. The relation between LA function and the extent of low-voltage areas (LVAs) has not yet been systematically investigated. METHODS: In patients with AF undergoing catheter-ablation, LA was studied using echocardiography and ultra-high-density mapping (Rhythmia(r)). Fibrosis (i.e. extent of LVAs) was estimated by quantifying areas with bipolar electrogram amplitudes of <=0.5, <=0.4, <=0.3, <=0.2 or <=0.1 mV. RESULTS: A total of 22 patients with a mean LVEF of 53 +/- 2% was studied. Mean LA volume index (LAVI) was significantly increased at 39 +/- 3 ml/m2 indicating AR. Size of LVAs was 57 +/- 7 cm2 representing 47 +/- 5% of the total LA area (low-voltage set to <=0.5 mV). With low-voltage set to <=0.4, <=0.3, <=0.2 and <=0.1, total area decreased to 34 +/- 6, 28 +/- 6, 22 +/- 5 and 12 +/- 3 cm2. LAVI positively correlated with the extent of LVAs at all cut-offs. Mean LA emptying fraction was 42 +/- 3% and showed a negative correlation with LVAs with low-voltage set to <=0.4 mV. Moreover, mean LA strain was 13 +/- 2% and correlated with LVAs with low-voltage at all cut-offs further supporting the notion that the extent of LVAs impacts LA function. Notably, with low-voltage set to <=0.2, <=0.3 and <=0.4 mV impaired LA strain was detected with an accuracy of >76% (p < 0.05). CONCLUSION: Structural (i.e. LAVI) and functional (i.e. LA emptying fraction and LA strain) parameters of the LA correlate with the extent of LVAs. PMID- 30017528 TI - Improved management of patients after acute coronary syndrome: using nonalcoholic fatty liver disease fibrosis score and ezetimibe? PMID- 30017529 TI - Consensus recommendations for echocardiography in adults with congenital heart defects from the International Society of Adult Congenital Heart Disease (ISACHD). AB - The population of adults with congenital heart disease (ACHD) is increasing constantly due to medical, surgical and interventional successes and the input from advanced cardiovascular imaging. ACHD patients are at continuing risk of residua and sequelae related to their CHD contributing to significant morbidity and mortality. Consequently, lifelong expert surveillance is recommended for most patients. Healthcare providers are still working out how best to achieve this objective, how to train enough experts to provide high quality care, and how to organize the delivery of care. Echocardiography is crucial to clinical surveillance providing a comprehensive assessment of cardiac morphology, physiology, pathophysiology, and function. Thus it contributes significantly to the overall clinical management of ACHD patients. The International Society for Adult Congenital Heart Disease (ISACHD; www.isachd.org) is the leading organization of professionals worldwide dedicated to the pursuit of excellence in the care of ACHD patients. Recognizing the critical role of imaging in the diagnosis and management of ACHD, ISACHD established a task force to provide guidance on echocardiographic studies and reporting. The rationale is that standardization of echocardiographic imaging and reporting carries the potential to improve the overall quality of these exams around the world and facilitate collaborative multicenter research. The standardized ACHD protocols provided by the ISACHD task force (found in the appendices) include specific recommendations for data acquisition and reporting for each of the major adult congenital heart lesions. These protocols give a comprehensive and structured approach in the evaluation of ACHD patients and help to ensure excellent patient care. PMID- 30017530 TI - Can angiography predict physiology? PMID- 30017531 TI - CRISPR: Stressed about p53? AB - Two recent reports show that, in some contexts, CRISPR-mediated genome editing can lead to a p53-mediated stress response and cell-cycle arrest. These findings may help to explain why CRISPR-mediated genetic manipulation in different cell types leads to dissimilar outcomes, and highlights the need for a better understanding of the factors that influence effective genome editing in vitro and in vivo. PMID- 30017532 TI - Corrigendum to "Autophagy- and MMP-2/9-mediated Reduction and Redistribution of ZO-1 Contribute to Hyperglycemia-increased Blood-Brain Barrier Permeability During Early Reperfusion in Stroke" [Neuroscience 377 (2018) 126-137]. PMID- 30017534 TI - The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center. AB - BACKGROUND/PURPOSE: 45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. PATIENTS AND METHODS: We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. RESULTS: Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4 +/- 1.1 to -1.4 +/- 0.9 in adulthood (P < 0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. CONCLUSIONS: The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy. PMID- 30017533 TI - 2018 Guidelines of the Taiwan Society of Cardiology, Taiwan Society of Emergency Medicine and Taiwan Society of Cardiovascular Interventions for the management of non ST-segment elevation acute coronary syndrome. AB - In Taiwan, the incidence of non-ST segment elevation acute coronary syndrome (NSTE-ACS) continues to increase in recent years. The purpose of this guideline is to help health care professionals in Taiwan to use adequate tests and treatments for management of NSTE-ACS. For rapid diagnosis, in addition to history and physical examination, 0/3 h rapid diagnosis protocol with high sensitivity cardiac troponin assay is recommended in this guideline. Dual antiplatelet and anticoagulation therapies are important parts in the initial treatment. Risk stratification should be performed to identify high risk patients for early coronary angiography. Through evaluation of the coronary anatomy and other clinical factors, the decision for coronary revascularization, either by percutaneous coronary intervention or coronary artery bypass grafting, should be decided by the heart team. The duration of dual antiplatelet therapy should be given for at least 12 months after discharge. Other secondary preventive medications are also recommended for long term use. PMID- 30017535 TI - Secular trends in liver cancer incidence from 1997 to 2014 in Taiwan and projection to 2035: An age-period-cohort analysis. AB - BACKGROUND/PURPOSE: Liver cancer is the second most common cancer in Taiwan. Research on projected cancer incident rates can facilitate appropriate public health planning, and incidence rate studies can offer insights and enable hypotheses about the etiology of particular cancers. METHODS: Age-period-cohort models are used to estimate incidence trends in liver cancer from 1997 to 2014 and project trends up to 2035. RESULTS: For men, the age-adjusted incidence rate showed an increasing trend from 1997, which peaked in 2004 (157.6 cases per 100,000 population), and a decreasing trend thereafter. The age-adjusted incidence rate is projected to decrease by 22.2% from 2014 to 2025 and by 37.3% from 2014 to 2035. For women, the age-adjusted incidence rate also showed an increasing trend from 1997, which peaked in 2004 (63.4 cases per 100,000 population), and a decreasing trend thereafter. The age-adjusted incidence rate is projected to decrease by 17.5% from 2014 to 2025 and by 27% from 2014 to 2035. CONCLUSION: This study revealed a reduction in the incidence rate of liver cancer for both sexes after 2004, and a further decrease until 2035 is projected. PMID- 30017536 TI - The evaluation of a brief motivational intervention to promote intention to participate in cardiac rehabilitation: A randomized controlled trial. AB - OBJECTIVES: Cardiac rehabilitation (CR) is an effective treatment for cardiovascular disease, yet many referred patients do not participate. Motivational interviewing could be beneficial in this context, but efficacy with prospective CR patients has not been examined. This study investigated the impact of motivational interviewing on intention to participate in CR. METHODS: Individuals recovering from acute coronary syndrome (n = 96) were randomized to motivational interviewing or usual care, following CR referral but before CR enrollment. The primary outcome was intention to attend CR. Secondary outcomes included CR beliefs, barriers, self-efficacy, illness perception, social support, intervention acceptability, and CR participation. RESULTS: Compared to those in usual care, patients who received the motivational intervention reported higher intention to attend CR (p = .001), viewed CR as more necessary (p = .036), had fewer concerns about exercise (p = .011), and attended more exercise sessions (p = .008). There was an indirect effect of the intervention on CR enrollment (b = 0.45, 95% CI 0.04-1.18) and CR adherence (b = 2.59, 95% CI 0.95-5.03) via higher levels of intention. Overall, patients reported high intention to attend CR (M = 6.20/7.00, SD = 1.67), most (85%) enrolled, and they attended an average of 65% of scheduled CR sessions. CONCLUSION: A single collaborative conversation about CR can increase both intention to attend CR and actual program adherence. PRACTICE IMPLICATIONS: The findings will inform future efforts to optimize behavioral interventions to enhance CR participation. PMID- 30017537 TI - HMGA2 and MED12 alterations frequently co-occur in uterine leiomyomas. AB - OBJECTIVE: Around 70% of uterine leiomyomas show MED12 mutations while overexpression of HMGA2 mRNA is also highly frequent in fibroids. However, previous studies suggested that alterations in both genes are mutually exclusive. In the present study, we searched for mutation in MED12 and analyzed the expression of HMGA2 in 20 uterine leiomyomas and their matched myometrium. METHODS: Normal and tumor tissue obtained from premenopausal women who underwent hysterectomy were collected after surgery and DNA, RNA and proteins were isolated and analyzed for MED12 mutations using Sanger sequencing, HMGA2 mRNA expression by quantitative PCR and HMGA2 protein detection by western blot and immunohistochemistry. RESULTS: 75% of the tumors displayed MED12 mutation while 65% of them showed overexpression of HMGA2 mRNA in leiomyomata compared to myometrial tissues (p = 0,0008). Interestingly, 50% of the tumors showed mutations in MED12 and overexpression of HMGA2 mRNA simultaneously, suggesting that alterations in both genes are relatively frequent in uterine leiomyomas. CONCLUSIONS: Contrary to the present findings, former studies showed that mutations in MED12 and overexpression of HMGA2 are mutually exclusive. Here, we observed that overexpression of HMGA2 mRNA in tumors measured by quantitative PCR and compared to myometrium is a common phenomenon in fibroids and is frequently associated with MED12 mutations. In addition, the common clonal origin of tumors overexpressing HMGA2 mRNA and its expression in few myometrial tissue points to HMGA2 up-regulation as an early event in leiomyoma tumorigenesis. PMID- 30017538 TI - The promise of image-guided brachytherapy of better clinical outcomes in treatment of cervical cancer: Does it deliver? An Indian scenario. AB - PURPOSE: The purpose of this series is to study the effectiveness of MRI based image-guided brachytherapy (IGBT) in Indian patients with cervical cancer who mostly present in later stages with bulky diseases. PATIENTS AND METHODS: 151 cervical cancer patients treated at our institution in last four years, with definitive chemoradiation followed by MRI-based brachytherapy were reviewed. With median follow up of 26 months, Kaplan Meier estimates at two years were calculated for local control (LC), pelvic control (PC), disease-free survival (DFS) and overall survival (OS). Also, severe late sequelae were reported. RESULTS: The patients predominantly presented with locally advanced cervical cancer in FIGO stages IIB (53.6%) and IIIB (23.2%). Tumour dimensions at diagnosis were >=5 cm in 56.3% and pelvic nodal involvement was found in 38.4% of the patients. 94% of the patients received curative chemoradiation. Mean HRCTV volume at the time of brachytherapy was 42.2 +/- 19 cm3 and mean cumulative dose to HRCTV was 78.9 +/- 5.6 Gy. Overall LC, PC, DFS and OS at 2 years were 88.7%, 88.1%, 82.2% and 94% respectively. The predictors for local failure were FIGO stage (p = 0.002) and tumour size at diagnosis (p = 0.009). Late grade 3-4 bladder and bowel toxicities were observed in 3.8% of the patients. CONCLUSION: Our review demonstrates that IGBT is an effective strategy to improve locoregional control with limited long-term sequelae in patients with locally advanced extensive cervical cancer in the setting of a developing country. PMID- 30017539 TI - Isolated para-aortic lymph node metastasis in FIGO stage IA2-IB2 carcinoma of the cervix: Revisiting the role of surgical assessment. AB - OBJECTIVES: To investigate the utility of para-aortic lymph node dissection among women undergoing radical hysterectomy and pelvic lymph adenectomy for FIGO Stage IA2-IB2 cervical cancer using the National Cancer Database (NCDB). METHODS: We identified patients with stage IA2-IB2 squamous cell, adenosquamous, or adenocarcinoma of the cervix diagnosed 2011-2014 in the NCDB. The primary outcome was the negative predictive value of histologically assessed pelvic lymph node status for para-aortic lymph node status among women undergoing pelvic and para aortic lymph node dissection. We calculated probability of para-aortic lymph node metastasis conditional on pelvic lymph node status. Finally, we compared overall survival between patients undergoing para-aortic lymph node dissection and those in whom this procedure was omitted. RESULTS: A total of 3212 patients met study inclusion criteria, of whom 994 (30.9%) underwent para-aortic lymph node dissection. In this group, the risk of isolated para-aortic metastasis was 0.11%. The negative predictive value of surgically assessed pelvic lymph nodes to predict para-aortic lymph node status was 99.9% (95% CI 99.9-99.9). Among 93 patients with pelvic lymph node metastasis, 18 (19.4%) had concurrent para-aortic lymph node metastasis. There was no difference in overall survival between women undergoing pelvic and para-aortic lymph node dissection compared with those undergoing pelvic lymphadenectomy only (p = 0.69). CONCLUSIONS: In patients undergoing radical hysterectomy and pelvic lymphadenectomy for stage IA2-IB2 cervical cancer, para-aortic lymph node dissection is not warranted based on the low risk of isolated metastatic disease, and lack of survival benefit associated with the procedure. PMID- 30017540 TI - Influence of sensorimotor adaptation and learning process for rehabilitation on the functional mobility of a patient with traumatic brain injury: A case report. AB - This case report reveals the implementation of sensorimotor adaptation and learning process for rehabilitation in a patient with traumatic brain injury to achieve optimum recovery which is permanent in nature in compliance to the disability rating scale. A twenty two year old gentleman who had a history of fall was diagnosed as having subarachnoid hemorrhage along with diffuse axonal injury of the brain and bilateral lung contusion with pneumothorax. He underwent a total of ten months of sensorimotor adaptation and learning process for rehabilitation, which achieved functional mobility with a walker. PMID- 30017541 TI - Misdiagnosed coronary artery disease-acute aortic syndrome: A case report. AB - It is estimated that 15% of traffic accidents cause trauma to large vessels. In about 70%-95% of cases, aortic rupture took place in the distal ligament of the left subclavian artery, whereas in the remaining cases rupture occurred in the ascending aorta above the aortic valve. Trauma to the aortic sinus and coronary arteries is rarely found in traffic accident victims. Therefore, coronary artery trauma is often misdiagnosed as coronary atherosclerotic heart disease. The present case is a 42 years old male who survived from a traffic accident. He presented with aortic sinus and left coronary artery trauma. He was misdiagnosed as having coronary atherosclerotic heart disease, and therefore wrongly given antiplatelet medicine, such as aspirin, in another hospital. Definite diagnosis was achieved in our hospital, and the patient underwent Bentall and mitral valve replacement, as well as tricuspid valvuloplasty. The aortic occlusion time during surgery was 47 min, and the total cardiopulmonary bypass time was 63 min. After surgery, transthoracic echocardiography confirmed that all the artificial valves worked sufficiently. The patient felt good and symptoms such as asthma and decreased exercise tolerance disappeared. This case taught us that acute aortic syndrome cannot be ignored when patients present with pectoralgia; antiplatelet medication should not be given before definite diagnosis. PMID- 30017542 TI - Early and mid-term results of transarticular external fixation in the treatment of supination-external rotation type IV equivalent ankle fractures. AB - PURPOSE: To investigate the early and mid-term results of open reduction and internal fixation (ORIF) with transarticular external fixation (TEF) but no deltoid ligament repair (DLR) in the treatment of supination-external rotation type IV equivalent (SER IV E) ankle fractures (AO/OTA classification 44-B 3.1) and provide evidence for clinical practice. METHODS: This study cohort consisted of 22 patients with SER IV E ankle fractures that underwent ORIF with TEF but no DLR between December 2011 and December 2014. There were 13 males and 9 females, mean age 38.9 years (range, 17-73 years). Eight cases involved the left side and 14 the right side. The causes of fractures included road traffic accidents (11 cases), falling from height (6 cases) and sports injuries (5 cases). The mean period of hospitalization was 9.8 days (range, 6-14 days). For all the patients, MRI and three-dimensional CT were done before surgery and X-rays done preoperatively and during follow-ups. The external frame was kept for 8-10 weeks. The preoperative American Orthopedic Foot and Ankle Society (AOFAS) ankle hindfoot score was 56.86 +/- 4.400, the Medical Outcomes Short Form 36-item (SF 36) questionnaire score was 57.41 +/- 4.102 and the visual analog score (VAS) was 5.50 +/- 1.058. Patients' main complaints about inconvenience of daily life were also recorded. RESULTS: All the 22 patients were followed up for 24-63 months (mean, 33.6 months). None of them developed nonunion during the follow-up; pin site infection was observed in one patient and posttraumatic osteoarthritis in another. At the final follow-up, the average AOFAS score, SF-36 score and VAS score were respectively 90.59 +/- 5.096, 79.59 +/- 5.394 and 1.82 +/- 1.181, which were significantly improved compared with the preoperative data (t = 26.221, p < 0.001; t = 11.910, p < 0.001; t = 11.571, p < 0.001). The therapeutic effect was excellent in 13 cases, good in 7 cases and fair in 2 cases, with a good-excellent rate of 90.9%. Patients' main complaints were inconvenience of clothing (17 cases) and extremity cleaning (5 cases). CONCLUSION: In the treatment of SER IV E ankle fractures, ORIF with TEF but no DLR can achieve satisfactory outcome, but long-term effect should be confirmed by large sample randomized controlled trials. PMID- 30017543 TI - Effects of estrogen receptor GPR30 agonist G1 on neuronal apoptosis and microglia polarization in traumatic brain injury rats. AB - PURPOSE: To investigate the effects of estrogen G protein-coupled receptor 30 (GPR30) agonist G1 on hippocampal neuronal apoptosis and microglial polarization in rat traumatic brain injury (TBI). METHODS: Male SD rats were randomly divided into sham group, TBI + vehicle group, TBI + G1 group. Experimental moderate TBI was induced using Feeney's weigh-drop method. G1 (100MUg/kg) or vehicle was intravenously injected from femoral vein at 30 min post-injury. Rats were sacrificed at 24 h after injury for detection of neuronal apoptosis and microglia polarization. Neuronal apoptosis was assayed by immunofluorescent staining of active caspase-3. M1 type microglia markers (iNOS and IL-1beta) and M2 type markers (Arg1 and IL-4) were examined by immunoblotting or ELISA. Total protein level of Akt and phosphorylated Akt were assayed by immunoblotting. RESULTS: G1 significantly reduced active caspase-3 positive neurons in hippocampus. Meanwhile G1 increased the ratio of Arg1/iNOS. IL-1beta production was decreased but IL-4 was increased after G1 treatment. G1 treatment also increased the active form of Akt. CONCLUSIONS: GPR30 agonist G1 inhibited neuronal apoptosis and favored microglia polarization to M2 type. PMID- 30017546 TI - Development of a dynamic index finger and thumb model to study impairment. AB - Modeling of the human hand provides insight for explaining deficits and planning treatment following injury. Creation of a dynamic model, however, is complicated by the actions of multi-articular tendons and their complex interactions with other soft tissues in the hand. This study explores the creation of a musculoskeletal model, including the thumb and index finger, to explore the effects of muscle activation deficits. The OpenSim model utilizes physiological axes of rotation at all joints, passive joint torques, and appropriate moment arms. The model was validated through comparison with kinematic and kinetic experimental data. Simulated fingertip forces resulting from modeled musculotendon loading largely fell within one standard deviation of experimental ranges for most index finger and thumb muscles, although agreement in the sagittal plane was generally better than for the coronal plane. Input of experimentally obtained electromyography data produced the expected simulated finger and thumb motion. Use of the model to predict the effects of activation deficits on pinch force production revealed that the intrinsic muscles, especially first dorsal interosseous (FDI) and adductor pollicis (ADP), had a substantial impact on the resulting fingertip force. Reducing FDI activation, such as might occur following stroke, altered fingertip force direction by up to 83 degrees for production of a dorsal fingertip force; reducing ADP activation reduced force production in the thumb by up to 62%. This validated model can provide a means for evaluating clinical interventions. PMID- 30017545 TI - Long-term quality of life after sepsis and predictors of quality of life in survivors with sepsis. AB - PURPOSE: To evaluate the quality of life among survivors after sepsis in 2 years, comparing with critical patients without sepsis and the general people, analyze the changes and the predictors of quality of life among septic survivors. METHODS: This prospective case-control study screened the intensive care unit (ICU) patients in Tianjin Third Central Hospital from January 2014 to October 2017, and the Chinese general population in the previous studies was also included. According to inclusion criteria and exclusion criteria, 306 patients with sepsis were enrolled as the observation group, and another 306 patients without sepsis in ICU during the same period, whose ages, gender and Charlson Comorbidity Index matched with observation group, were enrolled as the control group. At 3 mo, 12 mo, and 24 mo after discharge, the Mos 36-item Short Form Health Survey (SF-36), the Euroqol-5 dimension (EQ-5D), and the activities of daily living (ADL) were evaluated in face-to-face for the quality of life among survivors. RESULTS: There were 210 (68.6%) septic patients and 236 (77.1%) non septic critically ill patients surviving. At 3 months after discharge, the observation and control groups had the similar demographic characteristics (age: 58.8 +/- 18.1years vs. 57.5 +/- 17.6 years, p = 0.542; male: 52.0% vs. 51.4%, p = 0.926). However, the observation group had higher acute physiology and chronic health evaluation II (APACHEII) scores, higher sequential organ failure assessment (SOFA) scores, longer hospital stay, and longer ICU stay than the control group did (p < 0.05). There were no significant differences in the eight dimensions of the SF36 scale, the EQ-5D health utility scores, and the activities of daily life scores between septic survivors and non-septic survivors (p > 0.05). In addition, compared with the quality of life of the Chinese general population (aged 55-64 years), the quality of life of septic patients were significantly lower at 3 months after discharge (p < 0.05). Comparing the quality of life of the ill patients who had been discharged at 3 mo and 24 mo, the general health improved statistically (p = 0.000) and clinically (score improvement > 5 points). Older age (OR, 1.050; 95% CI, 1.022-1.078, p = 0.000), female (OR, 3.375; 95% CI, 1.434-7.941, p = 0.005) and longer mechanical ventilation time (OR, 3.412; 95% CI, 1.413, 8.244, p = 0.006) were the risk factors for the quality of life of septic survivors. CONCLUSION: The long-term quality of life of septic survivors was similar to that of non-sepsis critically ill survivors. After discharge, the general health of sepsis improved overtime. Age, female and mechanical ventilation time (>5 days) were the predictors of the quality of life after sepsis. PMID- 30017547 TI - End immigration detention: an open letter. PMID- 30017544 TI - The subsequent biological effects of simulated microgravity on endothelial cell growth in HUVECs. AB - PURPOSE: Microgravity is known to cause endothelium dysfunction in astronauts returning from spaceflight. We aimed to reveal the regulatory mechanism in alterations of human endothelial cells after simulated microgravity (SMG). METHODS: We utilized the rotary cell culture system (RCCS-1) to explore the subsequent effects of SMG on human umbilical vein endothelial cells (HUVECs). RESULTS: SMG-treated HUVECs appeared obvious growth inhibition after return to normal gravity, which might be attributed to a set of responses including alteration of cytoskeleton, decreased cell adhesion capacity and increased apoptosis. Expression levels of mTOR and its downstream Apaf-1 were increased during subsequent culturing after SMG. miR-22 was up-regulated and its target genes SRF and LAMC1 were down-regulated at mRNA levels. LAMC1 siRNAs reduced cell adhesion rate and inhibited stress fiber formation while SRF siRNAs caused apoptosis. CONCLUSION: SMG has the subsequent biological effects on HUVECs, resulting in growth inhibition through mTOR signaling and miR-22-mediated mechanism. PMID- 30017548 TI - Health, transatlantic trade, and President Trump's populism: what American Patients First has to do with Brexit and the NHS. PMID- 30017549 TI - Addressing the global challenge of snake envenoming. PMID- 30017550 TI - The need for transparency of clinical evidence for medical devices in Europe. AB - To use medical devices rationally, health-care professionals must base their choices of which devices to recommend for individual patients on an objective appraisal of their safety and clinical efficacy. The evidence submitted by manufacturers when seeking approval of their high-risk devices must be publicly available, including technical performance and premarket clinical studies. Giving physicians access to this information supplements the peer-reviewed scientific literature and might be essential for comparing alternative devices within any class. Interested patients should be encouraged to review the evidence for any device that has been recommended for them. The new EU law on medical devices states that the manufacturer is to prepare a summary of the evidence for any implantable or high-risk device. Defining its content, however, has been delegated to implementing legislation, which is now being considered. From a clinical perspective, it is imperative that all evidence reviewed by notified bodies and regulatory authorities is disclosed-with the exception, if justified, only of technical specifications that are considered confidential or manufacturing details that are protected as intellectual property-and public access to this evidence must be guaranteed by EU law. From ethical and other perspectives, there are no grounds for less clinical evidence being available to health-care professionals about the medical devices that they use than is already available for new pharmaceutical products. Full transparency is needed; without it, informed decisions relating to the use of new medical devices will remain impossible. PMID- 30017553 TI - Weight-adjusted aspirin for cardiovascular prevention. PMID- 30017551 TI - Vulnerability to snakebite envenoming: a global mapping of hotspots. AB - BACKGROUND: Snakebite envenoming is a frequently overlooked cause of mortality and morbidity. Data for snake ecology and existing snakebite interventions are scarce, limiting accurate burden estimation initiatives. Low global awareness stunts new interventions, adequate health resources, and available health care. Therefore, we aimed to synthesise currently available data to identify the most vulnerable populations at risk of snakebite, and where additional data to manage this global problem are needed. METHODS: We assembled a list of snake species using WHO guidelines. Where relevant, we obtained expert opinion range (EOR) maps from WHO or the Clinical Toxinology Resources. We also obtained occurrence data for each snake species from a variety of websites, such as VertNet and iNaturalist, using the spocc R package (version 0.7.0). We removed duplicate occurrence data and categorised snakes into three groups: group A (no available EOR map or species occurrence records), group B (EOR map but <5 species occurrence records), and group C (EOR map and >=5 species occurrence records). For group C species, we did a multivariate environmental similarity analysis using the 2008 WHO EOR maps and newly available evidence. Using these data and the EOR maps, we produced contemporary range maps for medically important venomous snake species at a 5 * 5 km resolution. We subsequently triangulated these data with three health system metrics (antivenom availability, accessibility to urban centres, and the Healthcare Access and Quality [HAQ] Index) to identify the populations most vulnerable to snakebite morbidity and mortality. FINDINGS: We provide a map showing the ranges of 278 snake species globally. Although about 6.85 billion people worldwide live within range of areas inhabited by snakes, about 146.70 million live within remote areas lacking quality health-care provisioning. Comparing opposite ends of the HAQ Index, 272.91 million individuals (65.25%) of the population within the lowest decile are at risk of exposure to any snake for which no effective therapy exists compared with 519.46 million individuals (27.79%) within the highest HAQ Index decile, showing a disproportionate coverage in reported antivenom availability. Antivenoms were available for 119 (43%) of 278 snake species evaluated by WHO, while globally 750.19 million (10.95%) of those living within snake ranges live more than 1 h from population centres. In total, we identify about 92.66 million people living within these vulnerable geographies, including many sub-Saharan countries, Indonesia, and other parts of southeast Asia. INTERPRETATION: Identifying exact populations vulnerable to the most severe outcomes of snakebite envenoming at a subnational level is important for prioritising new data collection and collation, reinforcing envenoming treatment, existing health-care systems, and deploying currently available and future interventions. These maps can guide future research efforts on snakebite envenoming from both ecological and public health perspectives and better target future estimates of the burden of this neglected tropical disease. FUNDING: Bill & Melinda Gates Foundation. PMID- 30017554 TI - COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. AB - BACKGROUND: Classical FcepsilonRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C4, prostaglandin [PG] D2, and thromboxane A2), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms. OBJECTIVES: We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity. METHODS: We used an ex vivo model of mouse bone marrow-derived mast cells and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease (AERD). RESULTS: IL-33 potently liberates AA and elicits LTC4, PGD2, and thromboxane A2 production by bone marrow-derived mast cells. Unexpectedly, the constitutive function of COX-1 is required for IL 33 to activate group IVa cytosolic phospholipase A2 with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX-1 was dispensable for FcepsilonRI-driven CysLT production. Inhibition of COX-1 prevented IL-33-induced phosphorylation of extracellular signal-related kinase, an upstream effector of cytosolic phospholipase A2, which was restored by exogenous PGH2, implying that the effects of COX-1 required its catalytic function. Administration of a COX-1-selective antagonist to mice completely prevented the generation of both PGD2 and LTC4 in a model of AERD in which MC activation is IL-33 driven. CONCLUSIONS: MC-intrinsic COX-1 amplifies IL-33 induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD. PMID- 30017555 TI - Muscle contractility of leg muscles in patients with mitochondrial myopathies. AB - BACKGROUND: The primary disease mechanism underlying mitochondrial myopathies (MM) is impaired energy generation to support muscle endurance. Little is known about muscle contractility before energy becomes deficient during muscle contractions. We investigated muscle contractility in MM to uncover potentially fixed weakness aspects of the disorders. METHODS: Contractility of calf and thigh muscles was investigated by comparing strength with contractile cross-sectional area (CCSA) of the used muscles, as measured by stationary dynamometry and MRI, respectively. RESULTS AND DISCUSSION: Our findings suggest reduced contractile properties in thigh and calf muscles of patients with MM. PMID- 30017552 TI - Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. AB - BACKGROUND: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes. METHODS: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (<=100 mg) and higher doses (300 325 mg or >=500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer. RESULTS: Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60.0 kg to 81.2 kg (p<0.0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0.0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0.75 [95% CI 0.65-0.85]) but not in those weighing 70 kg or more (0.95 [0.86-1.04]; 1.09 [0.93-1.29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1.33 [95% CI 1.08-1.64], p=0.0082). Higher doses of aspirin (>=325 mg) had the opposite interaction with bodyweight (difference pinteraction=0.0013), reducing cardiovascular events only at higher weight (pinteraction=0.017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0.0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0.038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0.0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1.52 [95% CI 1.04-2.21], p=0.031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1.20 [1.03-1.47], p=0.02), particularly in those weighing less than 70 kg (1.31 [1.07-1.61], p=0.009) and consequently in women (1.44 [1.11-1.87], p=0.0069). INTERPRETATION: Low doses of aspirin (75-100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required. FUNDING: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre. PMID- 30017556 TI - Successful slow tocilizumab desensitization in a patient with adult onset Still disease. PMID- 30017558 TI - A jelly belly: An unusual cause of ascites. PMID- 30017557 TI - Development of screening method for intranasal influenza vaccine and adjuvant safety in preclinical study. AB - Recently, many vaccine adjuvants have been developed; however, most of the newly developed adjuvants have been dropped out of preclinical and clinical trials owing to their unexpected toxicity. Thus, the development of highly quantitative and comparable screening methods for evaluating adjuvant safety is needed. In a previous study, we identified specific biomarkers for evaluating the safety of an intranasal influenza vaccine with CpG K3 adjuvant by comparing biomarker expression. We hypothesized that these biomarkers might be useful for screening newly developed adjuvant safety. We compared the expression of biomarkers in mouse lungs by the intranasal administration of 4 types of adjuvants: Alum, Pam3CSK4, NanoSiO2, and DMXAA with subvirion influenza vaccine. The control adjuvant alum did not show any significant increase in biomarker expression or preclinical parameters; however, NanoSiO2 and Pam3CSK4 increased the expression of biomarkers, such as Timp1 and Csf1. DMXAA at 300 MUg induced the expression of over 80% of biomarkers. Hierarchical clustering analysis showed that 300 MUg DMXAA was classified in the toxicity reference whole-particle influenza vaccine cluster. FACS analysis to confirm specific phenotypes that the number of T cells decreased in DMXAA-treated mouse lungs. Thus, our biomarkers are useful for initial adjuvant safety and toxicity screening. PMID- 30017559 TI - The added value of health indicators to mortality predictions in old age: A systematic review. AB - BACKGROUND: Numerous risk prediction models use indicators of health to predict mortality in old age. The added value to mortality predictions based on demographic variables is unknown. OBJECTIVE: To evaluate the accuracy of health indicators in predicting all-cause mortality among individuals aged 50+ using area under receiver operating characteristic curve (AUC). Specifically, to assess the added value of health indicators relative to demographic variables. METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. There were no restrictions on study designs, follow-up duration, language, or publication dates. We also examined the quality of studies using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies. RESULTS: Out of 804 studies investigating all-cause mortality in older persons, 16 studies were eligible. In community-dwelling populations, the accuracy of demographic variables and health indicators combined ranged from AUC 0.71 to 0.82, indicating modest ability to predict mortality. Age contributed the most to mortality prediction (AUC 0.65 to 0.78) and compared to age and sex, the added values of genetics, physiology, functioning, mood, cognition, nutritional status, subjective health, disease, frailty, and lifestyle ranged from AUC 0.01 to 0.10. The lack of validation samples made it difficult to assess their true added value. Findings were similar in institutionalized populations. Heterogeneity of the studies prevented us from performing a meta-analysis. CONCLUSION: Age and sex contributed the most to mortality predictions in old age while the added value of health indicators is likely to be limited. PMID- 30017560 TI - Funding is not enough. PMID- 30017561 TI - An overview of recent developments in FLUKA PET tools. AB - The new developments of the FLUKA Positron-Emission-Tomography (PET) tools are detailed. FLUKA is a fully integrated Monte Carlo (MC) particle transport code, used for an extended range of applications, including Medical Physics. Recently, it provided the medical community with dedicated simulation tools for clinical applications, including the PET simulation package. PET is a well-established imaging technique in nuclear medicine, and a promising method for clinical in vivo treatment verification in hadrontherapy. The application of clinically established PET scanners to new irradiation environments such as hadrontherapy requires further experimental and theoretical research to which MC simulations could be applied. The FLUKA PET tools, besides featuring PET scanner models in its library, allow the configuration of new PET prototypes via the FLUKA Graphical User Interface (GUI) Flair. Both the beam time structure and scan time can be specified by the user, reproducing PET acquisitions in time, in a particle therapy scenario. Furthermore, different scoring routines allow the analysis of single and coincident events, and identification of parent isotopes generating annihilation events. Two reconstruction codes are currently supported: the Filtered Back-Projection (FBP) and Maximum-Likelihood Expectation Maximization (MLEM), the latter embedded in the tools. Compatibility with other reconstruction frameworks is also possible. The FLUKA PET tools package has been successfully tested for different detectors and scenarios, including conventional functional PET applications and in beam PET, either using radioactive sources, or simulating hadron beam irradiations. The results obtained so far confirm the FLUKA PET tools suitability to perform PET simulations in R&D environment. PMID- 30017562 TI - Changes in epidemiology and antimicrobial susceptibility of nontyphoid Salmonella in children in southern Taiwan, 1997-2016. AB - BACKGROUND: This study aimed to investigate the changing trends in serogroup distribution and antimicrobial susceptibility of nontyphoid Salmonella (NTS) isolated from children in the past two decades in Taiwan. METHODS: This retrospective study enrolled patients aged younger than 18 years with culture proven NTS infection in a tertiary medical center from 1997 to 2016. Data on age, Salmonella serogroup, culture sample, and antimicrobial susceptibility were obtained from medical records. The rates of Salmonella serogroups and antimicrobial resistance were compared between period 1 (1997-2006) and period 2 (2007-2016). RESULTS: A total of 2075 NTS isolates were identified from 1997 to 2016 (1036 in period 1, 1039 in period 2). The major isolates were from feces (89.1%) and blood (10.4%). The most common serogroup was serogroup B (54.8%), followed by serogroup D (18.8%). There was a significant decline in the proportion of serogroup B with a concomitant rise in serogroup D in the past two decades. In period 2, resistance to cefotaxime and cefixime increased remarkably among serogroup B, whereas resistance to ampicillin increased notably among serogroup D. Furthermore, the incidence of multidrug-resistant (>=3 antibiotics) NTS significantly decreased in both serogroup B and serogroup D in period 2. CONCLUSION: This study revealed a significant rise in serogroup D with a concomitant decline in serogroup B NTS infection in Taiwanese children. Moreover, antimicrobial resistance to third-generation cephalosporins increased in serogroup B. Continuous surveillance of NTS serogroup distribution and antimicrobial susceptibility is mandatory to formulate therapeutic strategies for NTS infections. PMID- 30017564 TI - Structure of an RNA Aptamer that Can Inhibit HIV-1 by Blocking Rev-Cognate RNA (RRE) Binding and Rev-Rev Association. AB - HIV-1 Rev protein mediates nuclear export of unspliced and partially spliced viral RNAs for production of viral genomes and structural proteins. Rev assembles on a 351-nt Rev response element (RRE) within viral transcripts and recruits host export machinery. Small (<40-nt) RNA aptamers that compete with the RRE for Rev binding inhibit HIV-1 viral replication. We determined the X-ray crystal structure of a potential anti-HIV-1 aptamer that binds Rev with high affinity (Kd = 5.9 nM). The aptamer is structurally similar to the RRE high-affinity site but forms additional contacts with Rev unique to its sequence. Exposed bases of the aptamer interleave with the guanidinium groups of two arginines of Rev, forming stacking interactions and hydrogen bonds. The aptamer also obstructs an oligomerization interface of Rev, blocking Rev self-assembly. We propose that this aptamer can inhibit HIV-1 replication by interfering with Rev-RRE, Rev-Rev, and possibly Rev-host protein interactions. PMID- 30017563 TI - Crystal Structure of an Unusual Single-Stranded DNA-Binding Protein Encoded by Staphylococcal Cassette Chromosome Elements. AB - Methicillin-resistant Staphylococcus aureus is a global public health threat. Methicillin resistance is carried on mobile genetic elements belonging to the staphylococcal cassette chromosome (SCC) family. The molecular mechanisms that SCC elements exploit for stable maintenance and for horizontal transfer are poorly understood. Previously, we identified several conserved SCC genes with putative functions in DNA replication, including lp1413, which we found encodes a single-stranded DNA (ssDNA)-binding protein. We report here the 2.18 A crystal structure of LP1413, which shows that it adopts a winged helix-turn-helix fold rather than the OB-fold normally seen in replication-related ssDNA-binding proteins. However, conserved residues form a hydrophobic pocket not normally found in winged helix-turn-helix domains. LP1413 also has a conserved but disordered C-terminal tail. As deletion of the tail does not significantly affect cooperative binding to ssDNA, we propose that it mediates interactions with other proteins. LP1413 could play several different roles in vivo. PMID- 30017565 TI - Homologous Lympho-Epithelial Kazal-type Inhibitor Domains Delay Blood Coagulation by Inhibiting Factor X and XI with Differential Specificity. AB - Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXIa, whereas LEKTI domain 6 inhibits both FXIa and FXaB (bovine FXa). Nuclear magnetic resonance structural and dynamic experiments plus molecular dynamics simulation revealed that LEKTI domain 4 has enhanced backbone flexibility at the reactive-site loop. A model of the LEKTI-protease complex revealed that FXaB has a narrower S4 pocket compared with FXIa and hence prefers only small side-chain residues at the P4 position, such as Ala in LEKTI domain 6. Mutational studies combined with a molecular complex model suggest that both a more flexible reactive-site loop and a bulky residue at the P4 position make LEKTI domain 4 a weaker but highly selective inhibitor of FXIa. PMID- 30017566 TI - Crystal Structure of ATP-Bound Human ABCF1 Demonstrates a Unique Conformation of ABC Proteins. AB - Gene translation requires the correct selection of start codon AUG in mRNA. ATP binding cassette subfamily F member 1 (ABCF1) plays a key role in the accuracy of start codon selection. However, the function of human ABCF1 is not clearly understood. Here, we solve the crystal structure of an ATP-bound wild-type human ABCF1 at 2.3-A resolution. The comparative studies indicate that the structure is in a pre-activation intermediate conformation. This conformation is stabilized by the interaction between ATP and protein. Thus, we propose that this conformation is an important step in the activation of ABCF1. This study extends our understanding of ABC (ATP-binding cassette) protein activation at the molecular level. PMID- 30017567 TI - Should we use prophylactic tranexamic acid in orthognathic surgery to decrease blood loss? PMID- 30017568 TI - Aesthetic outcomes and morphological changes in chin parameters after mandibular distraction and subsequent advancement genioplasty in patients with mandibular micrognathia. AB - Despite the wide uses of mandibular distraction osteogenesis (MDO), no study appears to have evaluated the use of MDO and subsequent advancement genioplasty. This study addressed lower facial third aesthetics in a consecutive series of subjects with micrognathia who underwent MDO and subsequent advancement genioplasty. Standard cephalometric measurements were performed pre-MDO, at the end of consolidation, and at 1 week, 6 months, and 12 months after genioplasty. At the end of follow-up, questionnaires were given to measure patient satisfaction. Forty patients were included, 33 of whom underwent genioplasty. The mean patient age was 22.35+/-1.12years. Pre-genioplasty cephalometric measurements showed that all patients had a deficient chin position and projection; they were dissatisfied with their facial aesthetics. Post-genioplasty cephalometric measurements showed that the hard and soft tissue pogonion had moved significantly: 8.4+/-2.3mm and 11.0+/-2.11mm, respectively. According to the questionnaire, the patients were satisfied with the final results. The MDO reduced the amount of chin advancement and minimized relapses; the soft tissue response of the lower facial third was more sensitive to genioplasty than isolated MDO. MDO and genioplasty lead to a modest horizontal chin movement that achieves the preferred pogonion position and projection. PMID- 30017569 TI - Fixation methods in sagittal split ramus osteotomy: a systematic review on in vitro biomechanical assessments. AB - The aim of this systematic review was to assess the stability of rigid internal fixation (RIF) techniques in sagittal split ramus osteotomy (SSRO) based on in vitro biomechanical assessments, with particular interest in large mandibular advancements. In general, RIF methods can be divided into three groups: bicortical screws, miniplates, and a combination of the two. An electronic search of the PubMed, CINAHL, and Embase databases was performed, and studies published between January 2003 and March 2018 were screened for inclusion. Comparative studies with an in vitro experimental design, using biomechanical assessments to measure the stability of RIF methods in SSRO, were included. Of 104 unique studies identified in the initial search, 24 were included. Twenty-two of these 24 studies analyzed an advancement of the mandible of 7mm or less. The use of a single four-hole or six-hole miniplate was less stable than the use of bicortical screws, hybrid techniques, double miniplates, or grid plates. Two studies analyzed advancements of 10mm, for which two miniplates placed in parallel and a grid plate showed most stability. Although there was agreement between studies with regard to results, more biomechanical studies are required to quantify the stability of fixation methods in larger mandibular advancements. PMID- 30017570 TI - Psychogenic coma after dental surgery under general anaesthesia. AB - Delayed awakening after general anaesthesia due to psychogenic coma is a phenomenon that rarely presents to the oral and maxillofacial surgeon. A case of psychogenic coma following general anaesthesia for dental extractions is presented here. It is recommended that patients at risk of conversion disorder should be counselled about the risks of psychogenic coma. Early diagnosis of this condition could lead to better patient management. PMID- 30017571 TI - The effect of different dosage regimens of tranexamic acid on blood loss in bimaxillary osteotomy: a randomized, double-blind, placebo-controlled study. PMID- 30017572 TI - Coronectomy of mandibular third molars: a clinical and radiological study of 231 cases with a mean follow-up period of 5.7years. AB - Coronectomy is a widely accepted treatment for mandibular third molars that are in close relationship to the mandibular canal. However, long-term studies on morbidity following this procedure have not been presented. The aim of this study was to examine the long-term morbidity after coronectomy, with sensory disturbances of the inferior alveolar nerve (IAN) and root migration as the primary outcome variables. A total of 231 mandibular third molar coronectomies were performed in 191 patients with a mean follow-up period of 5.7years (range 1 12years). The prevalence of IAN injury was 1.3%, and 3.5% of the retained roots were removed. None of the reoperations to remove the retained roots caused IAN impairment. Infections occurred in 11.7% of the cases and all were treated with antibiotics. Overall, 97% of the retained roots showed signs of migration and 65% showed signs of rotation. Therefore, coronectomy of the mandibular third molars with an intimate relationship to the mandibular canal seems to be a safe treatment modality with a good long-term prognosis. PMID- 30017573 TI - 3D Analysis of Cortical and Trabecular Bone From Hip DXA: Precision and Trend Assessment Interval in PostmenopausalWomen. AB - The 3D distribution of the cortical and trabecular bone mass is a critical component in determining the resistance of a bone to fracture that is not assessed in standard dual-energy X-ray absorptiometry (DXA) exams. In this work, we assessed in vivo short-term precision of measurements provided by 3D modeling techniques from DXA scans and trend assessment intervals (TAIs) in postmenopausal women. Subjects included to study precision errors were scanned twice, with repositioning for duplicate hip scans, using either a Lunar iDXA scanner (GE Healthcare, Madison, WI) or a Discovery W scanner (Hologic, Inc., Waltham, MA). Postmenopausal women having baseline and 18-mo follow-up visit were scanned using a Lunar iDXA device to assess TAIs. TAIs indicate what time intervals are required to allow accurate assessment of response to treatment or progression of disease. The 3D-SHAPER software (Galgo Medical, Barcelona, Spain) was used to derive 3D measurements from hip DXA scans. Least significant changes were 10.39 and 8.72 mg/cm3 for integral volumetric bone mineral density (BMD), 9.64 and 9.59 mg/cm3 for trabecular volumetric BMD, and 6.25 and 5.99 mg/cm2 for cortical surface BMD, using the Lunar iDXA and Discovery W scanners, respectively. TAIs in postmenopausal women were 2.9 yr (integral volumetric BMD), 2.6 yr (trabecular volumetric BMD), and 3.5 yr (cortical surface BMD), using the Lunar iDXA scanner. As a comparison, TAIs for areal BMD were 2.8 yr at neck and 2.7 yr at total femur. Least significant changes of measurements provided by 3D modeling techniques from DXA were assessed. TAIs in postmenopausal women were similar to those measured for areal BMD measurements. DXA-derived 3D measurements could potentially provide additional indicators to improve patient monitoring in clinical practices. PMID- 30017574 TI - Three-layered technique to repair an oroantral fistula using a posterior-pedicled inferior turbinate, buccal fat pad, and buccal mucosal advancement flap. PMID- 30017575 TI - Re: Management of oral and maxillofacial infections in a regional unit: a seven day service? PMID- 30017576 TI - Publication of scientific research presented at scientific meetings of the British Association of Oral and Maxillofacial Surgeons: 10 years on - have we published or perished? AB - In 2009 we evaluated the publication of research presented at annual scientific meetings of the British Association of Oral and Maxillofacial Surgeons (BAOMS) 2002-2006, inclusive. Since then, the format of these meetings has changed, there has been a rapid increase in the number of online-only journals, and restraints on time during training and consultant practice have continued. We have therefore investigated the pattern of publication after presentation at these meetings between 2010 and 2014. All abstracts accepted for oral presentations or posters were included, and publication had to follow no more than four years later. We searched PubMed for papers in peer-reviewed journals and compared the data with those from 2002-2006. A total of 975 abstracts were accepted (2010-2014) of which 221 (23%) went on to be published. The median (IQR) delay to publication was 13 (4-25) months. Most were clinical papers from groups based in the UK (p<0.001) and most were published in BJOMS (p<0.001). The rate of publication has not changed significantly between the two periods (23% compared with 24%), and patterns in the type of papers, delays, journals, and research groups, were similar. Despite consistent rates of publication within the specialty, OMFS produces fewer publications after presentation than other surgical specialties. Further research is required to evaluate this more fully. PMID- 30017577 TI - Reconstruction of the oral commissure in patients with unilateral transverse facial cleft. AB - The normal commissure is not a simple joint of the upper and lower lip, but a triangular mucosal area. To reconstruct a symmetrical oral commissure in patients with a unilateral transverse facial cleft, we designed composite vermilion flaps, including triangular flaps. We retrospectively studied 17 patients with unilateral transverse facial clefts from 2013-2016. Three-dimensional images were obtained with a 3-dimensional photogrammetry system at the 1-year follow-up, and we used an anthropometric method to evaluate the postoperative symmetry of the commissure. No obvious deformity was found during the follow-up examination, and comparison of the cleft and non-cleft sides by the paired samples t test showed that in all cases both horizontally and vertically symmetrical commissures had been achieved. PMID- 30017579 TI - Revisions to the Code of Ethics for the Nutrition and Dietetics Profession. PMID- 30017578 TI - Biopsy of the sentinel lymph node in oral squamous cell carcinoma: analysis of error in 100 consecutive cases. AB - UK national guidelines in 2016 recommended that sentinel lymph node biopsy should be offered to patients with early oral cancer (T1-T2 N0) in which the primary site can be reconstructed directly. This study describes the pitfalls that can be avoided in the technique of biopsy to improve outcomes. We retrospectively analysed the data from 100 consecutive patients and recorded any adverse events. Lymphatic drainage of tracer failed in two patients as a result of procedural errors. Two patients with invaded nodes developed recurrence after total neck dissection, one after micrometastases had been diagnosed, and the other as a result of extranodal spread that had led to understaging and therefore undertreatment. Two results would not have been mistakenly classified as clear if all the harvested nodes had been analysed histologically according to the protocol. The disease-specific (96%) and disease-free (92%) survival were better than expected for a group of whom a third had stage 3 disease. If all harvested nodes had been analysed by the correct protocol then two of the three nodes wrongly designated clear would have been detected, two deaths potentially avoided, and the false-negative rate would have fallen from 8.3% to 2.7%. We conclude that minor deviations from protocol can result in a detrimental outcome for the patient. PMID- 30017580 TI - The Academy of Nutrition and Dietetics and Commission on Dietetic Registration Disciplinary and Ethics Complaints Process. PMID- 30017581 TI - Risk for and consequences of endometriosis: A critical epidemiologic review. AB - Endometriosis affects approximately 10% of women of reproductive age. Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk. Relationships with other potential characteristics including physical activity, dietary factors, and lactation have been less consistent, partially because of the need for rigorous data collection and a longitudinal study design. Critical methodologic complexities include the need for a clear case definition; valid selection of comparison/control groups; and consideration of diagnostic bias and reverse causation when exploring demographic characteristics, medical history, and lifestyle factors. Reviewers and editors must demand a detailed description of rigorous methods to facilitate comparison and replication to advance our understanding of endometriosis. PMID- 30017583 TI - N6-Methyladenine DNA Modification in the Human Genome. AB - DNA N6-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in the human genome, and we cataloged 881,240 6mA sites accounting for ~0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. DNA 6mA and N6-demethyladenine modification in the human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompanied by decreased N6AMT1 and increased ALKBH1 levels, and downregulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis. PMID- 30017582 TI - Systematic Study of Nucleosome-Displacing Factors in Budding Yeast. AB - Nucleosomes present a barrier for the binding of most transcription factors (TFs). However, special TFs known as nucleosome-displacing factors (NDFs) can access embedded sites and cause the depletion of the local nucleosomes as well as repositioning of the neighboring nucleosomes. Here, we developed a novel high throughput method in yeast to identify NDFs among 104 TFs and systematically characterized the impact of orientation, affinity, location, and copy number of their binding motifs on the nucleosome occupancy. Using this assay, we identified 29 NDF motifs and divided the nuclear TFs into three groups with strong, weak, and no nucleosome-displacing activities. Further studies revealed that tight DNA binding is the key property that underlies NDF activity, and the NDFs may partially rely on the DNA replication to compete with nucleosome. Overall, our study presents a framework to functionally characterize NDFs and elucidate the mechanism of nucleosome invasion. PMID- 30017585 TI - The Transcription Factor ThPOK Orchestrates Stochastic Interchromosomal Interactions Required for IFNB1 Virus-Inducible Gene Expression. AB - Virus infection induces stochastic activation of the interferon-beta gene. Three previously identified Alu-like DNA elements called NRCs (NF-kappaB reception centers) function by capturing and delivering NF-kappaB to the IFNB1 enhancer via stochastic interchromosomal interactions. We show that the transcription factor ThPOK binds cooperatively with NF-kappaB to NRCs and mediates their physical proximity with the IFNB1 gene via its ability to oligomerize when bound to DNA. ThPOK knockdown significantly decreased the frequency of interchromosomal interactions, NF-kappaB DNA binding to the IFNB1 enhancer, and virus-induced IFNB1 gene activation. We also demonstrate that cooperative DNA binding between ThPOK and NF-kappaB on the same face of the double DNA helix is required for interchromosomal interactions and distinguishes NRCs from various other Alu elements bearing kappaB sites. These studies show how DNA binding cooperativity of stereospecifically aligned transcription factors provides the necessary ultrasensitivity for the all-or-none stochastic cell responses to virus infection. PMID- 30017586 TI - Corrigendum to "Wastewater treatment for Amoxicillin removal using magnetic adsorbent synthesized by ultrasound process" [Ultrason. Sonochem. 45 (2018) 248 256]. PMID- 30017584 TI - MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining. AB - The modulator of retrovirus infection (MRI or CYREN) is a 30-kDa protein with a conserved N-terminal Ku-binding motif (KBM) and a C-terminal XLF-like motif (XLM). We show that MRI is intrinsically disordered and interacts with many DNA damage response (DDR) proteins, including the kinases ataxia telangiectasia mutated (ATM) and DNA-PKcs and the classical non-homologous end joining (cNHEJ) factors Ku70, Ku80, XRCC4, XLF, PAXX, and XRCC4. MRI forms large multimeric complexes that depend on its N and C termini and localizes to DNA double-strand breaks (DSBs), where it promotes the retention of DDR factors. Mice deficient in MRI and XLF exhibit embryonic lethality at a stage similar to those deficient in the core cNHEJ factors XRCC4 or DNA ligase IV. Moreover, MRI is required for cNHEJ-mediated DSB repair in XLF-deficient lymphocytes. We propose that MRI is an adaptor that, through multivalent interactions, increases the avidity of DDR factors to DSB-associated chromatin to promote cNHEJ. PMID- 30017587 TI - Assessment of surgeon performed caudal block for anorectal surgery. AB - BACKGROUND: The surgical anorectal diseases are common and distressful pathologies and their management mostly needs surgical intervention. Caudal anesthesia is effective in doing surgical procedures whenever the surgical area is mainly innervated by the sacral and lower lumbar nerve roots. It is used to give the local anesthesia by surgeons, in the present study the surgeon is the person who also gives the caudal anesthesia. METHODS: 202 patients (118 males vs. 84 females) were enrolled in this study with different surgical anorectal diseases. All of them were planned to be treated surgically under the effect of caudal anesthesia that was given by injection 10 ml of 2% lidocaine through sacral hiatus. All caudal anesthesia attempts were performed by the author surgeon. RESULTS: The total success rate of caudal anesthesia performed by the surgeon was 72.2% (divided into ?67.7% in the first year of the study, ?72 in the second and ?76.4% in the third year). The failed attempts were in 18.81% males vs. 8.91 females. The morbidity rate was 0.99% and the mortality rate was zero. CONCLUSIONS: The surgeon can perform the caudal anesthesia effectively and safely. This success improved with gaining more experience. This can help partly in solving the shortage in no. of anesthetists in some developing countries. PMID- 30017588 TI - Pregnancy outcome after first-trimester exposure to metformin: A prospective cohort study. AB - The aim of this study was to evaluate the risk of major birth defects and spontaneous abortion after metformin use during the first trimester of pregnancy. We conducted an observational cohort study comparing pregnancies with metformin treatment during the first trimester with non-exposed women matched for BMI and year of enrolment. Pregnancies were prospectively ascertained in the German Embryotox pharmacovigilance database between 2004 and 2014. The study sample included 336 pregnancies with metformin exposure for PCOS and fertility disorders (56.8%), diabetes (25.9%) and insulin resistance (14.9%) and 1011 matched controls. Independent of the treatment indication, neither the rate of major birth defects (OR adjusted 0.58, 95% CI 0.3-1.3) nor of spontaneous abortions (HR adjusted 0.95, 95% CI 0.6-1.5) was significantly increased among metformin exposed. Our study supports the evidence that metformin does not carry a developmental risk for the fetus when used during the first trimester. PMID- 30017589 TI - GRHL2-Dependent Enhancer Switching Maintains a Pluripotent Stem Cell Transcriptional Subnetwork after Exit from Naive Pluripotency. AB - The enhancer landscape of pluripotent stem cells undergoes extensive reorganization during early mammalian development. The functions and mechanisms behind such reorganization, however, are unclear. Here, we show that the transcription factor GRHL2 is necessary and sufficient to activate an epithelial subset of enhancers as naive embryonic stem cells (ESCs) transition into formative epiblast-like cells (EpiLCs). Surprisingly, many GRHL2 target genes do not change in expression during the ESC-EpiLC transition. Instead, enhancers regulating these genes in ESCs diminish in activity in EpiLCs while GRHL2 dependent alternative enhancers become activated to maintain transcription. GRHL2 therefore assumes control over a subset of the naive network via enhancer switching to maintain expression of epithelial genes upon exit from naive pluripotency. These data evoke a model where the naive pluripotency network becomes partitioned into smaller, independent networks regulated by EpiLC specific transcription factors, thereby priming cells for lineage specification. PMID- 30017592 TI - Situs Inversus Double Outlet Right Ventricle With Restrictive Interventricular Communication: Role of Transesophageal Echocardiography. PMID- 30017591 TI - PGC-1alpha Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ. AB - Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Here, we identify peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs. Loss of PGC-1alpha promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Deletion of PGC 1alpha in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Conversely, induction of PGC-1alpha attenuated osteoporotic bone loss and MAT accumulation. Mechanistically, PGC-1alpha maintains bone and fat balance by inducing TAZ. Our results suggest that PGC 1alpha is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging. PMID- 30017590 TI - Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming. AB - Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbing additional genes or pathways, during iPSC generation from mouse embryonic fibroblasts. Analysis of these cells uncovered transcription factors (e.g., Tfap2c and Bex2) that are important for reprogramming but dispensable for pluripotency maintenance. Additionally, we observed striking patterns of chromatin hyperaccessibility at pluripotency loci, which preceded gene expression in poised intermediates. Finally, inspection of these hyperaccessible regions revealed an early wave of DNA demethylation that is uncoupled from de novo methylation of somatic regions late in reprogramming. Our study underscores the importance of investigating rare intermediates poised to produce iPSCs, provides insights into reprogramming mechanisms, and offers a valuable resource for the dissection of transcriptional and epigenetic dynamics intrinsic to cell fate change. PMID- 30017593 TI - Moyamoya vasculopathy with anti-SCL-70 antibodies: A case report and review of the literature. AB - Moyamoya disease and syndrome constitute two distinct pathological entities with a primary finding of progressive distal internal carotid artery occlusion, which results in either an ischemic or hemorrhagic sequela. While the disease entity stands as a primary arterial vasculopathy, moyamoya syndrome represents a secondary vasculopathy associated with a systemic inflammatory process. We describe a patient with an ischemic stroke and angiographic findings of moyamoya in the setting of positive antinuclear antibodies and anti-Scl-70 antibodies with clinical features of scleroderma on exam. A review of current literature identified three similar cases where immunosuppression in addition to secondary stroke prevention led to reduced frequency of neurological sequelae. These cases plus our own demonstrate that patients with moyamoya vasculopathy in association with anti-Scl 70 antibodies exist on a spectrum with either predominant scleroderma features or neurological symptoms. There are a limited number of cases reported of moyamoya vasculopathy in association with anti-Scl 70 antibodies. This case report demonstrates that not only may the association be more common than we think, but that it exists on a dynamic spectrum with variable clinical presentation and course. PMID- 30017594 TI - Designing patient-specific 3D printed devices for posterior atlantoaxial transarticular fixation surgery. AB - Atlantoaxial transarticular screw fixation is an effective technique for arthrodesis. Surgical accuracy is critical due to the unique anatomy of the atlantoaxial region. Intraoperative aids such as computer-assisted navigation and drilling templates offer trajectory guidance but do not eliminate screw malposition. This study reports the operative and clinical performance of a novel process utilising biomodelling and 3D printing to develop patient specific solutions for posterior transarticular atlantoaxial fixation surgery. Software models and 3D printed 1:1 scale biomodels of the patient's bony atlantoaxial spine were developed from computed tomography data for surgical planning. The surgeon collaborated with a local medical device manufacturer using AnatomicsC3D to design patient specific titanium posterior atlantoaxial fixation implants using transarticular and posterior C1 arch screws. Software enabled the surgeon to specify screw trajectories, screw sizes, and simulate corrected atlantoaxial alignment allowing patient specific stereotactic drill guides and titanium posterior fixation implants to be manufactured using 3D printing. Three female patients with unilateral atlantoaxial osteoarthritis were treated using patient specific implants. Transarticular screws were placed using a percutaneous technique with fluoroscopy and neural monitoring. No screw malposition and no neural or vascular injuries were observed. Average operating and fluoroscopy times were 126.0 +/- 4.1 min and 36.7 +/- 11.5 s respectively. Blood loss was <50 ml per patient and length of stay was 4-6 days. Clinical and radiographic follow up data indicate satisfactory outcomes in all patients. This study demonstrates a safe, accurate, efficient, and relatively inexpensive process to stabilise the atlantoaxial spine using transarticular screws. PMID- 30017595 TI - Chronic Lymphocytic Leukemia: Clinical Stages Maintain Their Prognostic Significance Over the Course of the Disease and Are Surrogates for Response to Therapy. AB - BACKGROUND: To determine whether in patients with chronic lymphocytic leukemia (CLL), the clinical stage maintains prognostic significance over time and can be considered as a surrogate for the response to therapy. PATIENTS AND METHODS: The data from 229 CLL patients were retrospectively evaluated. The main aims of the study were to describe the changes in clinical stage during the course of CLL as a result of the response to treatment and to determine the time to next therapy (TTNT) and overall survival (OS) according to those changes, in particular, among the heterogeneous International Workshop on CLL (IWCLL) partial response (PR) category. RESULTS: Among the patients in the IWCLL PR category, differences were found in TTNT and OS according to the clinical stage at the response evaluation. With a median follow-up period of 91 months (range, 2-390 months), patients with a PR- Binet A at the response evaluation had significantly longer TTNT and OS compared with those with PR-Binet B/C (median TTNT, 26 vs. 11 months; P = .00; median OS, 63 vs. 43 months; P = .047). CONCLUSION: The results of the present study have shown that for patients with CLL, the Binet clinical stages are good outcome predictors throughout the disease course and also suggest that changes in Binet clinical stage could be useful as response surrogates and to divide the IWCLL PR category into different prognostic subgroups. PMID- 30017596 TI - Utility of PET-CT for Evaluation of Patients With Peripheral T-cell Lymphoma. AB - BACKGROUND: Fluorine-18 fluorodeoxyglucose (FDG) avidity varies in peripheral T cell lymphoma (PTCL). We evaluated FDG avidity of pretreatment positron emission tomography/computed tomography (P-PET/CT), to appraise the prognostic significance of interim PET/CT (I-PET/CT) and end of treatment PET/CT (E-PET/CT) in PTCL. PATIENTS AND METHODS: We performed a retrospective cohort study of patients with newly diagnosed or relapsed PTCL who had received any chemotherapy regimen from 2008 to 2015 in a tertiary center. P-PET/CT, I-PET/CT, and E-PET/CT studies were centrally reviewed. The primary outcomes were the prognostic role of I-PET/CT and E-PET/CT on progression-free survival (PFS) and overall survival (OS). The secondary outcomes were P-PET/CT avidity, the prognostic role of other baseline characteristics, and the correlation between the PET/CT and bone marrow biopsy findings. RESULTS: We included 40 patients in the present analysis. The median OS and PFS for the whole cohort was 39 and 16 months, respectively. Of the 40 patients, 36 had positive P-PET/CT findings. A total of 23 patients underwent I-PET/CT, with positive findings for 10. Of the 40 patients, 34 underwent E PET/CT, 26 of which had positive findings. The sensitivity, specificity, and negative predictive value of P-PET/CT for bone marrow involvement was 40%, 83%, and 89%, respectively. The factors significantly associated with PFS and OS on univariate analysis included elevated lactate dehydrogenase, and low lymphocyte, hemoglobin, and albumin levels. On multivariate analysis, only lymphopenia remained prognostic for PFS and OS. The E-PET/CT and I-PET/CT results were not prognostic for PFS or OS. CONCLUSION: Our study has shown that 90% of PTCL cases will be FDG avid. However, PET/CT was not predictive for PFS or OS at any point. The only predictive factor was the presence of lymphopenia. PMID- 30017597 TI - Sustained Remission of gammadelta T-Cell Lymphoma by Graft-Versus-Lymphoma Effect That Relapsed Early After Cord Blood Transplantation. PMID- 30017598 TI - Scandinavian Prostate Cancer Patients' Sexual Problems and Satisfaction With Their Sex Life Following Anti-Cancer Treatment. AB - INTRODUCTION: Active prostate cancer treatment is often associated with significant adverse physiological and psychological effects including significant sexual problems. Most studied among these sexual problems is erectile dysfunction while related sexual bothers such as overall sexual function and satisfaction with one's sex life are much less studied. AIM: To investigate problems related to erectile functioning, orgasmic ability, sexual function, and satisfaction with one's sex life among a cohort of Scandinavian prostate cancer patients age 40 years and older who were sexually active prior to their diagnosis of prostatic cancer. METHODS: The survey study used a cross-sectional design and a mixed recruitment procedure. Patients were recruited through the prostate cancer patient advocate organizations in Denmark, Norway, and Sweden (Scandinavia). The final sample included 1,707 prostate cancer patients. For analyses, participants were stratified into 4 groups according to their total treatment burden. OUTCOMES: Outcomes included subjective reporting of erectile functioning, orgasm, and sexual functioning, and satisfaction with one's sex life. RESULTS: The study found that the prevalence of erectile dysfunction and problems related to orgasm and overall sexual function ranged from 72-92% across prostatic cancer treatment groups. Conversely, this range was 61-69% among the respondents who had not undergone prostatic cancer treatment. Across treatment groups, a minority of patients (<15%) reported being satisfied with their sex lives. After socio demographic variables were controlled for, patients who did not receive prostatic cancer treatment were 3.75 times more likely than those in the reference group to not report sexual function problems. CONCLUSION: Among older prostate cancer patients, who at their time of diagnose were sexually active, sexual satisfaction is low and prevalence rates of sexual problems is high, thus underlining the strong clinical need to address sexual problems and satisfaction among this cohort of patients in order to promote sexual health and well-being following active cancer treatments. Martin Hald G, Dahl Pind M, Borre M, et al. Scandinavian Prostate Cancer Patients' Sexual Problems and Satisfaction With Their Sex Life Following Anti-Cancer Treatment. Sex Med 2018;6:210-216. PMID- 30017599 TI - Inflatable Penile Prostheses Implantation: Does Antibiotic Exposure Matter? AB - BACKGROUND: Inflatable penile prosthetic (IPP) infections are unusual but carry high patient morbidity and healthcare costs. AIM: To increase the bactericidal effect of IPP tubing material to prevent future bacterial infections and to determine whether this effect is time-dependent. METHODS: A modified disk diffusion assay was developed to measure the zones of inhibition against Escherichia coli, Proteus mirabilis, Staphylococcus aureus, and Staphylococcus epidermidis when tubing was immersed in gentamycin, ampicillin, tetracycline, kanamycin, erythromycin, or ciprofloxacin. To further assess the efficacy of this approach, IPP tubing was exposed to ampicillin or ciprofloxacin for 30 seconds, 2 minutes, 10 minutes, or 60 minutes. OUTCOMES: Bacterial zones of inhibition against IPP tubing material exposed to various treatments. RESULTS: IPP tubing was more effective against Gram-positive bacteria (S aureus and S epidermidis) then Gram-negative bacteria (E coli and P mirabilis). Immersing IPP tubing material in ampicillin or ciprofloxacin increased bactericidal effect of tubing material against Gram-positive and Gram-negative bacteria, respectively. The observed inhibitory effect was time dependent. CLINICAL TRANSLATION: Exposing IPP to a specific antimicrobial directly before implantation increases the bactericidal properties of the material, potentially decreasing the likelihood of infection. STRENGTHS & LIMITATIONS: This study is limited in that it is in vitro experimentation observing the effect of a single strain of each bacterium. Although the strains used were clinically relevant, further analysis is required to determine whether these results were strain specific. CONCLUSION: Immersing IPP material into an antibiotic solution, such as ampicillin or ciprofloxacin, increases the bactericidal properties and may aid in the prevention of infection. Chanyi RM, Alzubaidi R, Leung EJY, Wilcox HB, Brock GB, Burton JP. Inflatable Penile Prostheses Implantation: Does Antibiotic Exposure Matter? Sex Med 2018;6;248-254. PMID- 30017600 TI - Real-world prevalence of mild to moderate hypoglycemic episodes in type 2 diabetes in Portugal: Results from the HIPOS-PHARMA study. AB - AIMS: This study aimed to characterize and estimate prevalence and frequency of mild to moderate hypoglycemia and potentially associated factors in a population of type 2 diabetes mellitus (T2DM) patients treated at ambulatory care level. METHODS: HIPOS-PHARMA was a nationwide observational, cross-sectional, multicenter study conducted in community pharmacies, which surveyed T2DM patients treated for at least 3 months. RESULTS: Overall, 233 pharmacies recruited 1890 patients (males: 50.6%) with mean 67.1 years. On average, participants reported having diabetes for 11.8 years. A total of 86.9% had at least one chronic illness or complication of diabetes, and 76.8% were usually followed in the primary care setting. Fifty eight percent were treated without a secretagogue or insulin. Overall prevalence of mild to moderate hypoglycemic episodes in the 3 months prior to recruitment was 17.8%. A 3.13% prevalence of severe hypoglycemia was observed in the last 12 months. Results suggested that men and patients on antihyperglycemic therapies excluding secretagogues or insulin were less likely to have mild to moderate hypoglycemic episodes. CONCLUSIONS: Mild to moderate hypoglycemic episodes were commonly reported, and factors like type of antihyperglycemic therapy, duration of disease and due complications may contribute. Almost half of episodes were not reported. Such factors should be considered in T2DM management. PMID- 30017601 TI - Sports participation for young athletes with medical conditions: Seizure disorder, infections and single organs. AB - Organized and recreational sports have been shown to be an important part of growth and development in children, adolescents and young adults. In addition to the health benefits of increased physical activity, sports also provide social benefits. Pediatricians play an important role in determining if young athletescan participate in various sports and the proper equipment or precautions that are necessary. This review provides information on sports participation for athletes with specific health considerations, such as: febrile illnesses, solitary organs, seizures, and skin infections. PMID- 30017602 TI - Foreword: Clearance for sports participation: Concussions, cardiovascular and other medical concerns. PMID- 30017603 TI - Evaluation and Management of Concussion in Young Athletes. AB - Learning about concussion diagnosis and management is important for all individuals who will be taking care of young athletes. There are about 1.7million reported concussions per year, and, of these, about 20% are sports related. There are risks in all sports, but the highest rates of concussions are from football, rugby, and hockey, with soccer being the highest cause for girls. An on-field assessment includes evaluating airway, breathing, and circulation, followed by cervical spine assessment. Then, concussion evaluation tools can be used to aid in making the diagnosis. While concussion symptoms for the majority of youth resolve within a few weeks, some individuals may have persistence of symptoms for 3 months or more, referred to as postconcussive syndrome. Providers should consider ongoing symptoms in assessing when an athlete may safely return to sports and to learning. A major concern that has become more apparent in recent years is the possibility that concussions may have a longitudinal effect on health, such as in the development of chronic traumatic encephalopathy. Research has shown that there is an increase in the number of patients presenting to their primary care physician with concussions. Knowing how best to prevent, diagnose, and manage concussions will help to minimize risks to young athletes. PMID- 30017605 TI - Robot-assisted laparoscopic transplant-to-native ureteroureterostomy of an intraperitoneal renal allograft. AB - OBJECTIVE: The objective is to describe our experience with robot-assisted laparoscopic transplant-to-native ureteroureterostomy (UU) in a pediatric patient with an intraperitoneal renal allograft. We have previously demonstrated this technique for an extraperitoneal allograft. METHODS: The patient is a 17-year-old female who had undergone a deceased donor renal transplant at 5 years of age. She developed acute kidney injury and hydronephrosis because of a ureteral stricture that developed after a right ovarian cyst excision. A retrograde pyelogram of her native ureter showed normal morphology. Her options were discussed and she proceeded with a robotic transplant-to-native UU. RESULTS: Robot-assisted laparoscopic transplant-to-native UU was performed via an intraperitoneal approach. The procedure time was 217 min with an estimated blood loss of 10 mL. Her postoperative course was unremarkable. After ureteral stent removal, her serum creatinine remained stable and follow-up imaging showed an improvement in hydronephrosis. CONCLUSIONS: Pediatric robot-assisted laparoscopic transplant-to native UU for an intraperitoneal allograft is a technically feasible approach for the treatment of transplant ureteral strictures that combines the durability of open revision with the minimal invasiveness of endourologic management. PMID- 30017604 TI - Genetic linkage between altered tooth and eye development in lens-ablated Astyanax mexicanus. AB - The phenotype of lens-ablated Mexican tetra (Astyanax mexicanus) compared to wild type surface fish has been described and includes, among other effects, eye degeneration, changes in tooth number and cranial bone changes. Here, we investigate the spatiotemporal expression patterns of several key genes involved in the development of these structures. Specifically, we show that the expression of pitx2, bmp4 and shh is altered in the eye, oral jaw, nasal pit and forebrain in these lens-ablated fish. Furthermore, for the first time, we show altered pitx2 expression in the cavefish, which also has altered eye and tooth phenotypes. We thus provide evidence for a genetic linkage between the eye and tooth modules in this fish species. Furthermore, the altered pitx2 expression pattern, together with the described morphological features of the lens-ablated fish suggests that Astyanax mexicanus could be considered as an alternative teleost model organism in which to study Axenfeld-Rieger syndrome (ARS), a rare autosomal dominant developmental disorder that is associated with PITX2 and which has both ocular and non-ocular abnormalities. PMID- 30017606 TI - Clinical outcomes of children with Wilms tumor treated on a SIOP WT 2001 protocol in a tertiary care hospital in south India. AB - INTRODUCTION: Wilms tumor is the most common pediatric renal malignancy. While developed countries have had excellent survival, it remains poorer by comparison in developing countries. The aim was to analyze the clinical outcome of children with Wilms tumor managed in a developing country from 2004 to 2014 by the SIOP WT 2001 protocol. METHODS: Fifty-nine children with Wilms tumor managed by a SIOP WT 2001 regimen from 2004 to 2014 were analyzed. RESULTS: The median age at presentation was 36 months, and 59% were boys. The average size of the tumor at presentation was 523 mL. Inferior vena cava thrombus was present in 11, distant metastases in 18, and bilateral tumors in six. Preoperative chemotherapy was given to all children after a diagnostic core needle biopsy. Preoperative chemotherapy reduced the tumor size to a mean of 208 mL and resolved venacaval thrombus in eight. Fifty-five children underwent definitive surgery while two children died during preoperative chemotherapy and two remained inoperable. All surviving children received adjuvant chemotherapy with 17 receiving radiotherapy as well. The overall survival (OS) was 80% and the event-free survival (EFS) was 73% after a mean follow up of 42 months after completion of therapy. DISCUSSION: The tumor volumes at presentation and the incidence of venous tumor thrombosis in our cohort were much higher than those reported from developed countries. The incidence of metastatic disease at diagnosis (30.5%) was significantly higher than the 10-12% reported in Western data, but similar to that reported from various developing countries (14.1-31%). The OS in our cohort was 80% and the EFS was 73% with there being no events after 28 months. Although the survival rate for localized disease is similar to that in developed countries, the OS for metastatic disease was significantly less (50% vs. 75%). We also found that using an upfront posterior flank core biopsy was safe and beneficial for differentiating Wilms tumor from other pediatric renal tumors that are less chemosensitive. CONCLUSION: In a resource-restricted environment such as ours, the SIOP WT 2001 protocol has been found to show excellent results. PMID- 30017607 TI - Alvarado or RIPASA score for diagnosis of acute appendicitis? A meta-analysis of randomized trials. AB - BACKROUND: The electronic diagnostic tools of acute appendicitis present serious disadvantages, thus some clinical scores have been formed in order to reach the diagnosis easily and safely. Alvarado and RIPASA scores are the most commonly used and the purpose of this meta-analysis is to compare the diagnostic accuracy of these two scoring systems. METHOD: We searched MEDLINE (1966-2017), Scopus (2004-2017), ClinicalTrials.gov (2008-2017), Google Scholar (2004-2017) and Cochrane Central Register of Controlled Trials CENTRAL (1999-2017) databases. We selected all observational cohort studies that reported diagnostic parameters of Alvarado and RIPASA diagnostic scores on patients with clinical status of acute appendicitis. Statistical meta-analysis was performed with Meta Disc 1.4 software. RESULTS: Twelve studies were included in our meta-analysis which enrolled 2161 patients. The sensitivity of RIPASA score was 94% (95% CI, 92%-95%) and the specificity was 55% (95% CI, 51%-55%). In addition, the area under the Roc Curve (AUC) was 0.9431 and the diagnostic Odds Ratio was 24.66 (95% CI, 8.06 to 75.43). The sensitivity of Alvarado score was 69% (95% CI, 67%-71%) and the specificity was 77% (95% CI, 74%-80%). Moreover, the AUC was 0.7944 and the diagnostic Odds Ratio was 7.99 (95% CI, 4.75 to 13.43). CONCLUSION: RIPASA scoring system is more sensitive than Alvarado one, but the low specificity forms the need of a supplementary mean to provide the accurate diagnosis. Nevertheless, the wide and safe use of both tests is recommended in health systems that lack electronic diagnostic tests, such us developing countries or rural hospitals. PMID- 30017609 TI - Prevalence of rotavirus and rapid changes in circulating rotavirus strains among children with acute diarrhea in China, 2009-2015. AB - BACKGROUND: Rotavirus is a leading cause of morbidity and mortality in young children worldwide. In China, the universal immunization of children with the rotavirus vaccine has not been introduced, and the two globally distributed vaccines (RotaTeq and Rotarix) are not licensed in the country. We aim to determine the prevalence and strain diversity of rotavirus in children with diarrhea aged <= five years across China. MATERIALS AND METHODS: Sentinel-based surveillance of acute diarrhea was conducted at 213 participating hospitals in China from January 1, 2009, through December 31, 2015. Group A rotavirus (RVA) was tested by using enzyme-linked immunosorbent assays, and G- and P-genotype of RVA were tested by RT-PCR methods. RESULTS: Of 33,616 children with diarrhea, 10,089 (30%) were positive for RVA; RVA-associated diarrhea was identified in 2247 (39.5%, n = 2247/5685) inpatients and 7842 (28.1%, n = 7842/27931) outpatients. Children living in low-middle-income regions suffered from the highest burden of rotavirus, with 40.7% of diarrhea cases attributed to rotavirus infection, followed by 31.3% in upper-middle-income and 11.2% in high-income regions. The majority of children (88.9%, n = 8976/10089) who tested positive for RVA were children aged <= 2 years. The seasonal peak of RVA was in the winter. Among all 2533 RVA strains genotyped, five strain combinations, G9P[8], G3P[8], G1P[8], G2P[4] and G3P[4], contributed to 71.3% (1807/2533) of the RVA-associated diarrhea cases. The predominant strain of RVA has rapidly evolved from G3P[8] and G1P[8] to G9P[8] in the recent years, with the proportion of G9P[8] having increased remarkably from 3.4% in 2009 to 60.9% in 2015. CONCLUSIONS: The burden of diarrhea attributed to rotavirus is high in China, highlighting the potential value of vaccination. The rapid shift of RVA strains highlights the importance of conducting rotavirus surveillance to ensure that currently marketed vaccines provide protective efficacy against the circulating strains. PMID- 30017610 TI - Fluoroquinolones in the management of tuberculous meningitis: Systematic review and meta-analysis. AB - OBJECTIVES: Tuberculous meningitis carries a high rate of mortality and morbidity despite of an adequate treatment. Newer agents are being searched to improve outcome of these patients. Fluoroquinolones might be useful in the management of tuberculous meningitis in view of good cerebrospinal fluid penetration and good in-vitro activity against the mycobacterium. This review summarizes the effects of fluoroquinolone in first line regimens in tuberculous meningitis. METHODS: A systematic search of literature was performed using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and LILACS for articles published till march 2017. We also searched meta-register of controlled trials and bibliography of relevant studies. Randomized controlled trials (RCTs) where a fluoroquinolone was administered in addition or substitution of standard antituberculosis drugs formed the basis of selection criteria. Data was extracted on a pre-specified format. Risk ratio (RR) for dichotomous data was calculated and fixed effect model was used to combined the data if no heterogeneity was found. Death was taken as the primary outcome measure. RESULTS: Five trials including 1115 patients of tuberclous meningitis were included. Addition of a fluoroquinolone to a standard regimen was not found to significantly reduce mortality [RR = 0.68 (0.30-1.52)] (low-quality evidence). Addition of a fluoroquinolone to an intensified regimen (containing high dose rifampicin) was not found to significantly reduce mortality [RR = 0.97 (0.78-1.20)] (low-quality evidence). Substitution of fluoroquinolone for ethambutol [RR = 1.17 (0.67-2.07)] (moderate quality evidence, risk of harm cannot be ruled out) or for rifampicin [RR = 0.57 (0.32-1.01)] (low-quality evidence) in the standard regimen in terms of mortality did not show any benefit. There was no significant difference in the distribution of overall adverse events except for a higher incidence of vision loss and seizures in the fluoroquinolone arm. CONCLUSION: Routine addition or substitution of a fluroquinolone in the standard regimen can not be recommended at present. As most of the evidence driven in this review was of moderate- to low-quality, further research in this area is expected to make a significant impact in formulating a directive. PMID- 30017611 TI - Human infection with an avian-origin influenza A (H7N4) virus in Jiangsu: A potential threat to China. PMID- 30017612 TI - Disparities in Receipt of Preventive Dental Services in Children From Low-Income Families. AB - INTRODUCTION: Healthy People 2020 includes a goal of increasing use of preventive dental care among children from low-income families. The services used to define preventive care are evidence-based services (i.e., dental sealants and professionally applied topical fluoride) and professional dental cleaning, which lacks evidence of effectiveness in preventing caries. This study examined how increasing preventive dental care use and reducing disparities by race/ethnicity among children from low-income families varied by the services included in case definitions of preventive dental care use. METHODS: Three case definitions of past-year preventive dental care use were considered: (1) the Healthy People 2020 definition; (2) receipt of an evidence-based caries prevention service; and (3) dental cleaning only. Using pooled data from the 2001-2002 and 2013-2014 Medical Expenditure Panel Survey for each definition, this study conducted in 2017 used multivariate logistic regression to estimate changes in preventive dental care use among children from low-income families by race/ethnicity. RESULTS: Use increased for all racial/ethnic groups for all definitions. Use of preventive dental care (Healthy People 2020 definition), however, was at least two times higher than evidence-based preventive dental use for all racial/ethnic groups in both survey periods. After controlling for insurance status and parental education, the disparity between non-Hispanic black and non-Hispanic white children in use of preventive dental care that was present in 2001-2002 was not detected in 2013-2014 whereas the disparity for evidence-based preventive dental care use persisted. CONCLUSIONS: Case definitions of preventive dental care that include non-evidence-based services may overstate receipt of effective preventive dental care and reductions in certain racial/ethnic disparities. PMID- 30017608 TI - Coronary plaque characteristics in computed tomography and 2-year outcomes: The PREDICT study. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) not only provides information regarding luminal stenoses but also allows for visualization of mural atheromatous changes (coronary plaques). OBJECTIVE: We sought to elucidate whether plaques seen on CCTA enable prediction of 2-year outcomes in patients with suspected and known coronary artery disease (CAD). METHODS: Of 3015 patients who underwent CCTA, the images and 2-year clinical courses of 2802 patients were independently analyzed. The primary endpoint was the composite of all-cause death and acute coronary syndrome. RESULTS: During the 2-year observation period, 49 (1.7%) patients developed the primary outcome. The 2-year rates of the primary outcome in the normal (n = 515, no mural lesions), calcium (n = 654, calcified lesion alone), and plaque groups (n = 1633, presence of noncalcified or partially calcified plaques) were 0.2%, 2.0%, and 2.1%, respectively (P = 0.0028). Adverse plaque features such as low attenuation, positive remodeling, spotty calcification, and the napkin-ring sign (low-attenuation core with a higher attenuation rim) were assessed by an independent core laboratory. Stepwise multivariate Cox proportional hazard analysis showed that a plaque with two or more characteristics (adjusted hazard ratio, 1.98; 95% confidence interval, 1.09 3.60; P = 0.0254), age of >=67 years (mean), statin treatment after CCTA, and obstructive stenosis remained independent predictors of the primary outcome. CONCLUSIONS: Plaque imaging in CCTA has predictive value for the 2-year outcome and is a useful identifier for high-risk patients among those with known and suspected CAD. PMID- 30017613 TI - Editorial overview: Next generation therapeutics. PMID- 30017614 TI - Osteogenesis Imperfecta. Report of 15 Cases. AB - Osteogenesis imperfecta (OI) is an inherited connective tissue disease. The disease has been linked to mutations in one of the type I collagen genes. The diagnosis is based on clinical and radiologic findings. The management of OI in adults is not well-established and includes physical rehabilitation, surgical procedures, the use of antiresorptive therapy and anabolic agents. The aim of the present work was to analyze the clinical and analytical characteristics of these patients in adulthood, as well as to evaluate the different treatments administered. We reviewed the cases of OI diagnosed in our center over the last 12 years (2005-2017). We describe 15 adult patients with OI. PMID- 30017615 TI - Leiomyosarcomas affecting main vessels in the lower extremities. AB - OBJECTIVE: To evaluate the results of bloc resection and vascular reconstruction of leiomyosarcomas with involvement of main vessels in the lower extremities. MATERIAL AND METHODS: From January 1983 to December 2016, 42 patients with leiomyosarcomas were diagnosed. Six of these leiomyosarcomas affected main vessels of the lower extremities (called vascular). Epidemiological data, imaging studies, surgery performed, adjuvant treatments, complications, as well as recurrences and mortality were retrospectively recorded. RESULTS: All the patients were affected by high-grade leiomyosarcomas (ii-iii FNCLCC classification), with a larger tumour average diameter of 9.1cm(6-15) and a mean follow-up of 23 months (7-36). The average age was 64 years (29-84). The first symptom was a palpable tumour in 4 of them. The other 2 cases debuted with thromboembolic phenomena. In 5 cases the origin was the femoral vessels, while one case was at the popliteal level. Although all cases preserved the limb, in 3 cases (50%) they presented pulmonary dissemination,2 cases (33%) hepatic dissemination and one case had local recurrence. Two cases died at the end of the study and there was one case of loss to follow-up. DISCUSSION AND CONCLUSIONS: Vascular leiomyosarcomas are highly aggressive tumours with a low survival rate at 5 years. In our study, 50% of the patients remain in complete remission with a mean follow-up of 23 months. Their onset frequently associates the presence of tumour mass with thrombotic phenomena (33% of our cases). Tumour resection surgery usually compromises the main vascular structures, which implies resection and vascular reconstructive techniques to salvage the limb. PMID- 30017617 TI - Reference intervals for serum 1,5-anhydroglucitol in children, adolescents, adults, and pregnant women. AB - BACKGROUND: 1,5-anhydroglucitol (1,5-AG) is a validated marker of short-term glycemic control. We determined the reference intervals of 1,5-AG in different age groups and during pregnancy. METHODS: Blood samples were collected from 2303 Euro-Brazilian healthy subjects: 580 children, 496 adolescents, 922 adults matched by age and sex, and 305 pregnant women in four gestational periods. Serum 1,5-AG was measured using an enzymatic reagent in an automated system. RESULTS: The calculated reference intervals (nonparametric, 2.5th-97.5th) for males and females were, respectively: children, 96-302 and 89-277 MUmol/l; adolescents, 84 311 and 79-277 MUmol/l; and adults, 80-260 and 62-241 MUmol/l. Males consistently showed significantly higher concentrations than females. 1,5-AG reference intervals in pregnant women were 56-298 MUmol/l at <23 weeks gestation (n = 110), 37-166 MUmol/l at 24-28 weeks gestation (n = 106), 34-155 MUmol/l at 29-32 weeks gestation (n = 52), and 33-246 MUmol/l at >32 weeks gestation (n = 37). No significant differences in 1,5-AG concentration were observed between non pregnant and pregnant women at <23 weeks of gestation. A negative correlation (r = -0.287; p < .001) between 1,5-AG concentration and age was observed. CONCLUSIONS: The reference intervals for 1,5-AG were affected by sex and age. PMID- 30017616 TI - A preliminary investigation of metal element profiles in the serum of patients with bloodstream infections using inductively-coupled plasma mass spectrometry (ICP-MS). AB - BACKGROUND: We determined metal element profiles (MEPs) by inductively-coupled plasma mass spectrometry (ICP-MS) in the serum of patients with blood stream infection (BSI) and find out very important (VIP) metal elements in specific infections. METHODS: Sixty-eight metal elements were identified in both serum and the bacteria isolated from 14 BSI patients with Staphylococcus infection, 39 with Enterobacteriaceae infection, 5 with Enterococcus infection and 58 healthy subjects without infection by ICP-MS methods. Statistical analysis, Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) were performed to process data among different groups, select differential metal elements and operate correlation analysis. RESULTS: The MEPs in the serum of BSI patients with 4 types of bacteria (Staphylococcus aureus, Escherichia coli, Enterococcus faecium, and Klebsiella pneumonia), and the corresponding MEPs of the bacteria were established. VIP metal elements were screened out in different BSI patients. Correlation analysis showed that there were some correlations between serum concentrations of metal elements and bacterial infection. CONCLUSION: We found differential metal elements in the serum of BSI patients compared with controls, thus providing a basis for the diagnosis, prevention and treatment of BSI from the perspective of metallomics. PMID- 30017618 TI - Benefits of hippotherapy in children with cerebral palsy: A narrative review. AB - : Children with cerebral palsy display disorders in pelvic movement and require effective rehabilitation. There is evidence to support the hippotherapy due to improvements in balance. The aim of this narrative review was to summarise the grades of recommendation regarding the benefits of hippotherapy in children with cerebral palsy. DATA SOURCES AND EXTRACTION: We searched electronic databases, limiting the searches to studies published between 2004 and February 2017. The selected documents were classified according to the strength of recommendation provided by Duodecim (the Finnish medical society). The methodological quality of the selected studies was evaluated using the PEDro scale. RESULTS: 18 studies (four graded A, eight graded B and six graded C) showed clinical changes in the outcomes of gross motor function, sitting independently, speed of walking, length of stride and postural alignment of the head in children with cerebral palsy. Study quality was poor to good (mean PEDro Score of 6 out of 10). Benefits were identified in relation to psychological factors, as well as positive effects on quality of life and the performance of daily life activities. CONCLUSIONS: Gains were also observed in postural alignment and the balance of head and trunk. Moreover, there were improvements in quality of life and the activities of daily life, such as jumping, balance, strength and ascending and descending stairs. PMID- 30017619 TI - Multifocal epilepsy in children is associated with increased long-distance functional connectivity: An explorative EEG-fMRI study. AB - OBJECTIVE: Multifocal epileptic activity is an unfavourable feature of a number of epileptic syndromes (Lennox-Gastaut syndrome, West syndrome, severe focal epilepsies) which suggests an overall vulnerability of the brain to pathological synchronization. However, the mechanisms of multifocal activity are insufficiently understood. This explorative study investigates whether pathological connectivity within brain areas of the default mode network as well as thalamus, brainstem and retrosplenial cortex may predispose individuals to multifocal epileptic activity. METHODS: 33 children suffering from multifocal and monofocal (control group) epilepsies were investigated using EEG-fMRI recordings during sleep. The blood oxygenated level dependent (BOLD) signal of 15 regions of interest was extracted and temporally correlated (resting-state functional connectivity). RESULTS: Patients with monofocal epilepsies were characterized by strong correlations between the corresponding interhemispheric homotopic regions. This pattern of correlations with pronounced short-distance and weak long distance functional connectivity resembles the connectivity pattern described for healthy children. Patients with multifocal epileptic activity, however, demonstrated significantly stronger correlations between a large number of regions of the default mode network as well as thalamus and brainstem, with a significant increase in long-distance connectivity compared to children with monofocal epileptic activity. In the group of patients with multifocal epilepsies there were no differences in functional connectivity between patients with or without Lennox-Gastaut syndrome. CONCLUSION: This explorative study shows that multifocal activity is associated with generally increased long-distance functional connectivity in the brain. It can be suggested that this pronounced connectivity may represent either a risk to pathological over-synchronization or a consequence of the multifocal epileptic activity. PMID- 30017620 TI - Developing Quality Measures for Diagnostic Radiologists: Part 1. AB - The ACR convened a cross-specialty, multidisciplinary technical expert panel to identify and define new measures for quality improvement. These measures can be included in the ACR's National Radiology Data Registry and potentially used in the CMS quality reporting programs. The technical expert panel was tasked with developing measures that reflect the most rigorous clinical evidence and address areas most in need of performance improvement. The measures described in these articles represent a new phase in the ACR's efforts to develop meaningful measures for radiologists that promote population health through diagnostic accuracy, clinical effectiveness, and care coordination. PMID- 30017621 TI - 2018 Residency Match Update and the Most Competitive Specialty. PMID- 30017622 TI - Structured Radiation Oncology Clerkship Curricula: Evaluating the Effect on Residency Applicant Knowledge of Radiation Oncology. PMID- 30017623 TI - Impact of Performing Nonurgent Interventional Radiology Procedures on Weekends. AB - Most clinical services limit weekend care to urgent or emergent situations. However, providing access to nonemergent procedures on weekends may reduce length of hospital stay and unnecessary admissions. No data are available on the impact of providing nonemergent interventional radiology (IR) procedural services on weekends. A retrospective review of nonurgent IR inpatient services on weekends over a 12-month period was performed. Using intent-to-treat analysis, 453 procedures were performed on 447 patients on 100 weekend days. Procedures included venous access (116 of 453, 25.6%), dialysis interventions (83 of 453, 18.3%), enteral access (73 of 453, 16.1%), genitourinary interventions (37 of 453, 8.2%), venous interventions (35 of 453, 7.7%), biliary interventions (33 of 453, 7.3%), percutaneous drainage (32 of 453, 7.1%), biopsy (24 of 453, 5.3%), arterial interventions (14 of 453, 3.1%), and other (3 of 453, 0.7%). Routine weekend procedural services allowed 108 of 447 (24.2%) patients to be discharged earlier than anticipated if such services were not available, resulting in 174 hospital days gained. Procedures were performed earlier than anticipated in 268 of 447 (60.0%) patients resulting in 415 days of progression of care gained over the 12-month period. For dialysis interventions, 35% (29 of 83) of patients received hemodialysis within 24 hours of intervention, and 25 patients were discharged early with 33 hospital days saved. IR procedures were performed on patients from 97% of the hospital inpatient units (22 of 23 inpatient or observation units, and 10 of 10 intensive care units) over the 12-month period. In conclusion, increased availability of nonurgent IR services on weekends can directly reduce hospital length of stay as well as improve progression of inpatients toward an early discharge. PMID- 30017624 TI - A Role for Imaging in the Detection of Physical Elder Abuse. PMID- 30017625 TI - Ethics, Artificial Intelligence, and Radiology. PMID- 30017626 TI - Legal Outcome of a Failure to Communicate an Unexpected Finding. PMID- 30017627 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria: Ovarian Cancer Screening. PMID- 30017628 TI - Radiology Rounds in the Intensive Care Units Through a Telepresence Model. PMID- 30017629 TI - Volume and Coverage of Secondary Imaging Interpretation Under Medicare, 2003 to 2016. AB - PURPOSE: The aim of this study was to assess changing Medicare volumes of, and coverage for, secondary interpretations of diagnostic imaging examinations stratified by modality and body region service families. METHODS: Medicare Physician/Supplier Procedure Summary Master Files for 2003 to 2016 were obtained. Aggregate Part B fee-for-service claims frequency and payment data were isolated for noninvasive diagnostic imaging and stratified by service family. Using published Medicare payment rules, secondary interpretations were identified as studies billed using both modifiers 26 and 77. Billed and denied services volumes were calculated and compared across modality and body region service families. RESULTS: Seven service families showed a compound annual growth rate from 2003 to 2016 of >20% (an additional 12 service families, >10% growth). For select high volume service families (chest radiography and fluoroscopy [R&F], brain MRI, and abdominal and pelvic CT), relative growth in billed secondary interpretation services exceeded that for primary interpretations. In 2016, body region and modality service families with the most billed secondary interpretations were chest R&F (674,124), abdominal and pelvic R&F (65,566), brain CT (45,642), extremity R&F (34,560), abdominal and pelvic CT (14,269), and chest CT (10,914). All service families had secondary interpretation denial rates <25% in 2016 (15 service families, <10%). CONCLUSIONS: Among Medicare beneficiaries, the frequency of billed secondary interpretation services for diagnostic imaging services increased from 2003 to 2016 across a broad range of modalities and body regions, often dramatically. Payment denial rates were consistently low across service families. As CMS continues to seek input on appropriate coverage for these services, these findings suggest increasing clinical demand for and payer acceptance of these value-added radiologist services. PMID- 30017631 TI - Correction to Lancet Glob Health 2018; 6: e619-29. PMID- 30017630 TI - Does working memory training improve dietary self-care in type 2 diabetes mellitus? Results of a double blind randomised controlled trial. AB - AIMS: Controlling food intake despite adequate knowledge remains a struggle for many people with type 2 diabetes. The present study investigated whether working memory training can reduce food intake and improve glycaemic control. It also examined training effects on cognition, food cravings, and dietary self-efficacy and self-care. METHODS: In a double-blind multicentre parallel-group randomised controlled trial, adults with type 2 diabetes mellitus were randomly allocated to receive 25 sessions of either active (n = 45) or control (n = 36) working memory training. Assessments at baseline, post-training and 3-month follow-up measured cognition, food intake (primary outcomes), glycaemic control (HbA1c) and cholesterol (secondary outcomes). Semi-structured interviews assessed participants' experiences of the training. RESULTS: Intention-to-treat ANOVAs (N = 81) showed improved non-trained updating ability in active compared to control training from pre-test (active M = 34.37, control M = 32.79) to post-test (active M = 31.35, control M = 33.53) and follow-up (active M = 31.81, control M = 32.65; eta2 = 0.05). There were no overall effects of training on other measures of cognition, food intake, HbA1c, cholesterol, food cravings and dietary self efficacy and self-care. In post-hoc analyses, those high in dietary restraint in the active training group showed a greater reduction in fat intake pre to post test compared to controls. Interviews revealed issues around acceptability and performance of the training. CONCLUSIONS: Transfer of working memory training effects to non-trained behaviour were limited, but do suggest that training may reduce fat intake in those who are already motivated to do so. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22806944. PMID- 30017633 TI - Transcatheter Valve-in-Valve Therapy Using a Balloon Expanding Valve for Treatment of Aortic Paravalvular Leakage. AB - Aortic paravalvular leakage (PVL) is a recognised complication of surgically replaced valves which is often treated using vascular plugs. Whilst transcatheter valve-in-valve therapy has been increasingly used for failed surgical bioprostheses, it is not considered as a treatment option for aortic PVL. However, the newer design of transcatheter aortic valves has a fabric skirt to create a more effective seal around the annulus. To our best knowledge, for the first time, we report successful adoption of the valve-in-valve therapy for the treatment of PVL in surgical bioprsthetic aortic valves such that the fabric skirt is placed immediately below the regurgitant orifice resulting in significant reduction in the PVL. PMID- 30017632 TI - New insights into TGF-beta/Smad signaling in tissue fibrosis. AB - Transforming growth factor-beta1 (TGF-beta1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF beta signalings play different roles in fibrogenesis. TGF-beta1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-beta1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-beta1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-beta1/Smad pathway thereby protects against TGF-beta1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-beta/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-beta/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-beta/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis. PMID- 30017634 TI - The Prevalence of Pacing-Induced Cardiomyopathy (PICM) in Patients With Long Term Right Ventricular Pacing - Is it a Matter Of Definition? AB - BACKGROUND: Chronic right ventricular pacing may contribute to deterioration in left ventricular ejection fraction (LVEF). The aim of the study was to identify the prevalence of pacing-induced cardiomyopathy (PICM) in patients with chronic right ventricular pacing. METHODS: Patients attending a pacemaker clinic were retrospectively identified as having had transthoracic echocardiographic LVEF measurement during the 12 months prior to device implantation. Those with cardioverter-defibrillators or biventricular devices were excluded. The remaining patients were invited back for a repeat echocardiogram. Three different definitions of PICM were employed: 1) follow-up LVEF of <=40% if baseline LVEF was >=50%, or an absolute reduction in LVEF >=5% if baseline LVEF was <50%; 2) follow-up LVEF of <=40% if baseline LVEF was >=50%, or an absolute reduction in LVEF >=10% if baseline LVEF was <=50%; 3) absolute reduction in LVEF >=10% irrespective of baseline LVEF. Alternate causes of cardiomyopathy were excluded following a chart review. RESULTS: The study cohort of 118 included 67 males (mean age 77.8+/-10.5years) and 51 females (mean age 76.8+/-11.2years). The mean time between baseline and follow-up echocardiograms was 3.5+1.4years (range 1.5 6.4 years). The prevalence of PICM ranged from 5.9 to 39.0% depending on PICM definition. Multivariate analysis found that PICM was significantly associated with ventricular pacing burden (p=0.013). CONCLUSIONS: The prevalence of pacing induced cardiomyopathy is dependent on current accepted clinical definitions. A clear definition of PICM is required for a better understanding of the clinical implications of right ventricular pacing. PMID- 30017635 TI - Syndrome 'Z': A Predictor of Angiographic Severity of Coronary Artery Disease in Patients of Acute Coronary Syndrome. AB - BACKGROUND: Owing to the growing evidence that the pathophysiology of obstructive sleep apnoea (OSA) and metabolic syndrome (MS) overlap considerably and both adversely impact cardiovascular health, we hypothesised that the presence of OSA with MS additively and adversely affect the severity of coronary artery disease (CAD). Exploration and understanding of this may have direct implications for the development of targeted, preventive strategies for CAD. Thus, this prospective study was aimed to determine the prevalence of 'Syndrome Z' in patients of MS who present with an acute coronary event and to correlate it with the angiographic severity of CAD in these patients. METHODS: The present study was a single centre, cross sectional study conducted in a university teaching hospital. In a span of 6 months, 922 patients with acute coronary syndromes (ACS) were screened for the study. Among these, 861 patients had no evidence of MS. The remaining 61 patients who were diagnosed to have MS were then subjected to an overnight sleep study. Only 58 had good sleep data so were included for further analysis. Angiographic parameters in terms of number of vessels involved and culprit lesions were noted and correlated with presence and absence of OSA and also with its severity based on the Apnoea/Hypopnoea Index (AHI). RESULTS: The prevalence of OSA positivity in patients with MS who presented with ACS was 34.5% (n=20). Most of the patients in the OSA negative group (78.9%, n=30) had disease limited to only one vessel while in the OSA positive group only a minority (15%, n=3) of patients had their disease limited to a single vessel (p=0.001). The number of lesions in the culprit vessel was also significantly less in the OSA negative group compared to the OSA positive group. While in the OSA negative group 68.4% (n=26) patients had a solitary lesion, followed by two and three lesions in 15.8% (n=6) of the patients each, multiple lesions were more common in OSA positive patients, involving 80% of cases (45.0%, n=9 with two lesions; 35.0%, n=7 with three lesions; only 20%, n=4 had a solitary lesion). CONCLUSIONS: Prevalence of 'Syndrome Z' is high in patients having MS presenting with ACS and it correlates with the angiographic severity of CAD. PMID- 30017636 TI - Pressure-driven spontaneous ion concentration polarization using an ion-selective membrane. AB - In this study, the spontaneous ion concentration polarization phenomenon induced by pressure via a cation-selective membrane was theoretically and experimentally investigated. Unlike conventional electrokinetic ion concentration polarization, which uses electric current as a driving flux of cations through the membrane, advection caused by pressure is used as a transmembrane driving flux of cations to spontaneously and stably form an ion depletion zone in the present ion concentration polarization technique. The ion depletion zone produced in a simple experimental setup was used to filter electrolyte and preconcentrate ions and microparticles. Different from the general assumption of the negligible thickness of the electric double layer in microchannels, the low concentration in the ion depletion zone considerably increased the length of the electric double layer. This enhanced the formation of the ion depletion zone. The present results can improve the understanding on ion transport in the ion concentration polarization system and can be utilized to develop a portable water desalination device for rural/remote areas and for preconcentrating biomolecules. PMID- 30017637 TI - Explaining the dynamics of tumor aggressiveness: At the crossroads between biology, artificial intelligence and complex systems. AB - Facing metastasis is the most pressing challenge of cancer research. In this review, we discuss recent advances in understanding phenotypic plasticity of cancer cells, highlighting the kinetics of cancer stem cell and the role of the epithelial mesenchymal transition for metastasis. It appears that the tumor micro environment plays a crucial role in triggering phenotypic transitions, as we illustrate discussing the challenges posed by macrophages and cancer associated fibroblasts. To disentangle the complexity of environmentally induced phenotypic transitions, there is a growing need for novel advanced algorithms as those proposed in our recent work combining single cell data analysis and numerical simulations of gene regulatory networks. We conclude discussing recent developments in artificial intelligence and its applications to personalized cancer treatment. PMID- 30017638 TI - Involvement of estrogen receptor alpha in pro-pruritic and pro-inflammatory responses in a mouse model of allergic dermatitis. AB - It has been reported that endogenous or exogenous estrogens can affect the immune system, resulting in immune disorders; however, their direct involvement in such conditions remains to be demonstrated. The purpose of this study was to investigate whether estrogen receptors (ER) are directly implicated in pro pruritic and pro-inflammatory reactions in cutaneous allergy. Initially, enhancement of the pro-inflammatory response by several ER agonists [methoxychlor (MXC), beta-estradiol (E2), propylpyrazoletriol (PPT; an ERalpha agonist), and diarylpropionitrile (DPN; an ERbeta agonist)] was examined in vivo using a male BALB/c mouse model of allergic dermatitis induced by toluene-2,4-diisocyanate administration. The ear swelling response, itch response, and local cytokine secretion were measured. Subsequently, the mechanism underlying the development of such allergic reactions was analyzed in vitro using human epidermal keratinocytes, murine bone marrow-derived dendritic cells (mBMDCs), and the mixed leucocyte reaction assay. Activated cells were exposed to each ER agonist for 24 h, and cytokine secretion and cell proliferation were measured. Our in vivo experiments indicated significant upregulation of pro-inflammatory and pro pruritic responses in the E2-, MXC-, and PPT-treated groups compared to the control group; however, no change was observed in the DPN-treated group. Levels of cytokines expressed by keratinocytes, such as TSLP and IL-33, were particularly increased by exposure to E2, MXC, or PPT. These in vivo results were confirmed in vitro in keratinocytes, but not mBMDCs or T cells. Our findings imply that ERalpha is involved in pro-inflammatory and pro-pruritic responses in cutaneous allergy through activation of keratinocytes. PMID- 30017639 TI - Bisphenol A induced male germ cell apoptosis via IFNbeta-XAF1-XIAP pathway in adult mice. AB - Bisphenol A (BPA) impairs male fertility by acting as an endocrine disruptor. However, the mechanisms by which BPA cause reproductive toxicity are not fully elucidated. Here, we explored the role of XAF1, a novel pro-apoptosis molecule, in BPA-induced abnormal spermatogenesis and the transcriptional regulation mechanism of BPA-induced XAF1. BPA exposure detrimentally impacted spermatogenesis by inducing excessive germ cell apoptosis. XAF1 was upregulated in germ cells after BPA exposure, which was involved in the apoptosis pathway. In addition, the expression levels of XIAP and XAF1 were inversely correlated after BPA exposure. Knockdown of XAF1 expression partially inhibited the apoptosis of GC-2 cells, suppressed the activation of caspase 3 and improved the BPA-induced XIAP expression. Moreover, IFNbeta expression levels were significantly upregulated after BPA exposure both in vitro and in vivo, and these levels were positively related to the expression of XAF1. Furthermore, IFNbeta knockdown reduced the expression of XAF1 and increased the expression of XIAP in BPA treated GC-2 cells. Together, these data indicated that BPA triggers male germ cell apoptosis in mice via the IFNbeta-XAF1-XIAP pathway, which may contribute to BPA-induced testis toxicity. PMID- 30017640 TI - Naringenin protects against oxido-inflammatory aberrations and altered tryptophan metabolism in olfactory bulbectomized-mice model of depression. AB - Oxido-inflammatory aberrations play a substantial role in the pathophysiology of depression. Oxido-inflammatory stress increases catabolism of tryptophan into kynurenine which leads to imbalance in kynurenine and serotonin levels in the brain. Naringenin a flavonoid, has been reported to possess antidepressant property by restoring serotonin and noradrenaline levels in the brain. Its effects on oxido-inflammatory aberrations in depression has not been investigated. With this background, the present study was designed to investigate the antidepressant-like potential of naringenin in olfactory bulbectomy (OBX) induced neuroinflammation, oxidative stress, altered kynurenine pathway, and behavioural deficits in BALB/c mice. OBX-mice showed depression-like behavioural alterations characterized by hyperactivity in open field, increased immobility time in forced swim test and decreased sucrose preference. After 14 days, OBX mice were treated by gavage with naringenin (25, 50 and 100 mg/kg) and fluoxetine (5 mg/kg) for two weeks. Naringenin significantly ameliorated depression-like behavioural alterations. Naringenin significantly restored corticosterone levels in serum and antioxidant enzymes (Catalase, SOD GSH), nitrite and MDA in cerebral cortex and hippocampus showing its anti-stress and antioxidant property. Naringenin also significantly decreased elevated pro-inflammatory cytokines like IL-1beta, IL-6, TNF-alpha and NF-?beta levels. Naringenin also significantly increased neurotrophic growth factor like BDNF. Naringenin reversed altered levels of tryptophan, serotonin, 5-Hydroxyindole acetic acid and kynurenine in hippocampus and cortex. A positive correlation was found between KYN/TRP ratio and proinflammatory parameters while endogenous antioxidants were negatively correlated. In conclusion, naringenin showed potent neuroprotective effect in depression comparable to the fluoxetine by restoring alterations in kynurenine pathway via its antioxidant and anti-inflammatory potential. PMID- 30017641 TI - The motivation to behaviorally thermoregulate during passive heat exposure in humans is dependent on the magnitude of increases in skin temperature. AB - We tested the hypothesis that the motivation to behaviorally thermoregulate in humans is dependent on the magnitude of changes in mean skin temperature. Ten healthy subjects (22 +/- 3 y, 5 females) underwent 60 min of seated rest in a 32+/-1 degrees C or 42+/-1 degrees C environment (20% relative humidity). Trials were completed in a counterbalanced order. The motivation to behaviorally thermoregulate was measured using an operant behavior task on a fixed ratio schedule, in which subjects received thermal reinforcement after clicking a button 100 times. The reinforcer was 30 s of cooling on the dorsal aspect of the neck. The motivation to behave was defined as the cumulative number of button clicks over time and behavioral thermoregulation was defined as the change in neck skin temperature. Mean skin temperature was higher throughout the 42 degrees C versus the 32 degrees C trial (at 60 min: 36.3+/-0.5 degrees C vs. 34.5+/-0.5 degrees C, P < .01) and core temperature became higher in this trial 40 min into heat exposure (at 60 min: 37.2+/-0.2 degrees C vs. 37.1+/-0.1 degrees C, P <= .04), but did not differ from pre- heat exposure (P = .81). Neck skin temperature was lower in the 42 degrees C compared to the 32 degrees C trial starting at 30 min (33.7+/-0.8 degrees C vs. 35.3+/-0.5 degrees C, P < .01), which was maintained thereafter (P <= .04). Cumulative responding for thermal reinforcement was greater in the 42 degrees C trial compared to the 32 degrees C trial at 20 min (180+/-155 clicks vs. 0+/-0 clicks, P < .01), which persisted thereafter (P < .01). These data indicate that the motivation to behaviorally thermoregulate during passive heat exposure in humans is dependent on the magnitude of increases in skin temperature. PMID- 30017642 TI - Regulatory burden and salary for pharmacy technicians in the United States. AB - BACKGROUND: Education, training, and certification requirements for pharmacy technicians are determined by individual state boards of pharmacy resulting in heterogeneity in the entry-level requirements to practice in the United States (US). OBJECTIVE: To determine an association between state-level registration/licensure requirements and salary for pharmacy technicians. METHODS: All 50 states and the District of Columbia (DC) were categorized into two groups, high regulation (HR) or low regulation (LR). Salaries were compared using the 2016 hourly salary published by the Bureau of Labor Statistics (BLS). To adjust for cost of living, an index was created using median hourly salary and hourly wage needed to afford a two-bedroom rental for each state obtained from the National Low Income Housing Coalition (NLIHC) 2016 Out of Reach Report. Average median salary and the average salary-housing index (SHI) were compared using a student t-test. RESULTS: The sample included 23 H R states and 28 L R states. Salary differences were not significant despite regulatory requirements (LR: $14.74+/-$1.57; HR: $15.60+/-$1.80; p-value: 0.065). There was also no difference in SHI scores (LR: 0.83 +/- 0.15; HR: 0.88 +/- 0.19; p-value: 0.21). CONCLUSION: Despite increased regulatory burden in the HR states, income levels are not significantly higher. PMID- 30017643 TI - Combined spinal-epidural anesthesia with non-invasive ventilation during cesarean delivery of a woman with a recent diagnosis of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is the most common neurodegenerative upper and lower motor neuron disease in adults but is not common in women of child-bearing age. We present a case of a pregnant woman who was diagnosed with amyotrophic lateral sclerosis and developed respiratory distress at 32 weeks-of-gestation. She underwent a cesarean delivery under combined spinal-epidural anesthesia with non-invasive ventilation. This resulted in a successful outcome for both the mother and the baby. PMID- 30017644 TI - Epidermal Growth Factor Receptor Gene Amplification Predicts Worse Outcome in Patients With Surgically Resected Nonadenocarcinoma Lung Cancer. AB - PURPOSE: The aim of the present study was to examine the prognostic role of amplification and increased expression of the epidermal growth factor receptor (EGFR) gene in surgically resected non-adenocarcinoma of non-small cell lung cancer (NA-NSCLC). MATERIALS AND METHODS: The present retrospective study included 114 consecutive NA-NSCLC patients with available tumor tissue and survival data. EGFR gene copy number and protein expression were evaluated using fluorescent in situ hybridization (FISH) and immunohistochemistry in tissue microarray sections, respectively. RESULTS: Among 114 patients, 99 (86.8%) had squamous cell carcinoma histologic features. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 7.9% and 31.6% of cases, respectively. Patients with EGFR FISH+ had significantly shorter overall survival (P = .011). A multivariate model confirmed that patients with EGFR FISH+ had a significantly greater risk of death than EGFR FISH- patients after adjusting for pathologic stage, presence of pleural invasion, venous invasion, and surgical margins (hazard ratio, 1.36; 95% CI, 1.040 to 1.782; P = .025). EGFR protein expression by immunohistochemistry was not associated with overall survival in the same group. Neither EGFR gene amplification nor EGFR immunohistochemistry expression was associated with relapse-free survival. CONCLUSION: An increased EGFR gene copy number in surgically resected NA-NSCLC was associated with worse survival. PMID- 30017645 TI - Patient-Reported Outcomes in OAK: A Phase III Study of Atezolizumab Versus Docetaxel in Advanced Non-Small-cell Lung Cancer. AB - BACKGROUND: The randomized phase III OAK (a study of atezolizumab compared with docetaxel in participants with locally advanced or metastatic non-small-cell lung cancer [NSCLC] who have failed platinum-containing therapy) trial investigated the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab for advanced or metastatic, previously treated, NSCLC. Atezolizumab significantly improved overall survival (OS) compared with docetaxel (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.62-0.87; P = .0003; median OS, 13.8 vs. 9.6 months, respectively). Patient-reported outcomes (PROs) were collected to evaluate disease-related symptoms and health-related quality of life (HRQoL) to support the finding of a survival benefit. PATIENTS AND METHODS: The first 850 patients were randomized to receive atezolizumab (1200 mg every 3 weeks) or docetaxel (75 mg/m2 every 3 weeks). PROs were collected on day 1 of cycle 1, day 1 of every subsequent cycle, and at the end-of-treatment visit for patients who completed >= 1 baseline and 1 postbaseline PRO assessment. The European Organisation for the Research and Treatment of Cancer QoL questionnaire and lung cancer module were used to assess PROs. RESULTS: Atezolizumab delayed the time to deterioration (TTD) in physical function (HR, 0.75; 95% CI, 0.58-0.98) and role function (HR, 0.79; 95% CI, 0.62-1.00) and numerically improved patients' HRQoL from baseline compared with docetaxel. Atezolizumab also prolonged the TTD in chest pain (HR, 0.71; 95% CI, 0.49-1.05; P = .0823), although both arms showed an objective reduction relative to baseline. Overall, the patients had no clinically significant worsening in treatment-related symptoms, although the scores favored atezolizumab. CONCLUSION: These PRO data support the clinical benefit of atezolizumab in patients with previously treated advanced or metastatic NSCLC. Atezolizumab prolonged the TTD of patients' limitations in role and physical functions compared with docetaxel. PMID- 30017647 TI - Ensuring timely treatment of patients with primary biliary cholangitis. PMID- 30017648 TI - Hand Infections. AB - Infections are common in hand surgery and proper management is important to achieve optimal outcomes. Although most cases are not urgent, less common, severe infections such as flexor tenosynovitis and necrotizing fasciitis require urgent identification with both medical and surgical management. It is common for diagnoses to be missed or delayed because clinical and laboratory indicators are often variably present. Delayed identification and management can result in poor outcomes with permanent deficits. This article will provide a review of hand infections with a focus on identifying serious hand infections requiring urgent or emergent treatment, and distinguishing these from less urgent scenarios. PMID- 30017649 TI - Evaluation of Articular Surface Similarity of Hemi-Hamate Grafts and Proximal Middle Phalanx Morphology: A 3D Geometric Morphometric Approach. AB - PURPOSE: Hemi-hamate arthroplasty has been described as a viable treatment option for unstable proximal interphalangeal joint fracture-dislocations. The procedure uses a dorsal distal hamate osteochondral graft to recreate the injured volar middle phalanx (MP) proximal base. The purpose of this study was to evaluate the similarity in shape of these articular surfaces using quantitative 3-dimensional methods. METHODS: Three-dimensional virtual renderings were created from laser scans of the articular surfaces of the dorsal distal hamate and the volar MP bases of the index, middle, ring, and little fingers from cadaveric hands of 25 individuals. Three-dimensional landmarks were obtained from the articular surfaces of each bone and subjected to established geometric morphometric analytical approaches to quantify shape. For each individual, bone shapes were evaluated for covariation using 2-block partial least-squares and principal component analyses. RESULTS: No statistically significant covariation was found between the dorsal distal hamate and volar MP bases of the middle, ring, or little digits. Whereas the volar MP bases demonstrated relative morphologic uniformity among the 4 digits both within and between individuals, the dorsal distal hamates exhibited notable variation in articular surface morphology. CONCLUSIONS: Despite the early to midterm clinical success of hemi-hamate arthroplasty, there is no statistically significant, uniform similarity in shape between the articular surfaces of the dorsal distal hamate and the volar MP base. In addition, there is wide variation in the articular morphology of the hamate among individuals. CLINICAL SIGNIFICANCE: The lack of uniform similarity in shape between the dorsal distal hamate and the volar MP base may result in unpredictable outcomes in HHA. It is recommended that the variation in hamate morphology be considered while reconstructing the injured volar MP base in the procedure. PMID- 30017650 TI - Metacarpal Aneurysmal Bone Cyst En Bloc Resection Reconstructed With Osteoarticular Allograft. AB - Aneurysmal bone cysts are large lytic lesions that appear most often around metaphyseal bone. The lesions are locally aggressive with high recurrence rates. Therefore, wide resection is commonly necessary, leading to challenging reconstruction of the defect, especially when the articular surface is involved. We present a case of an aneurysmal bone cyst of the fourth metacarpal, treated with an en bloc resection and reconstruction with a metacarpal osteoarticular allograft. At 8 years after surgery, the patient has shown no signs of recurrence, but radiographic articular reabsorption was noted. However, the patient showed an excellent outcome with a satisfactory active range of motion and grip strength. Despite potential complications, osteoarticular allograft is a feasible alternative when autologous osteoarticular reconstruction is not an option. PMID- 30017651 TI - Complex Determination of the Gametocyte Conversion Rate. PMID- 30017652 TI - A better definition of the anti-DFS70 antibody screening by IIF methods. AB - BACKGROUND: Anti-DFS70 antibodies have been recently included in a new testing algorithm for patients with suspicion of connective tissue diseases (CTDs). This algorithm enables to assess the probability of having a CTD in patients with a positive antinuclear antibodies (ANA) result. The aim of the study was to analyze the the inter-method agreement between three different HEp-2 cell substrates for anti-DFS70 detection, focusing on two novel IIF methods that assess the presence of monospecific anti-DFS70 antibodies. METHODS: Immunological and clinical records of 29 patients who were double positive for anti-DFS70 autoantibodies using chemiluminescence assay (CIA) and Immunoblot (IB) were studied. The IIF on HEp-2 cells were determined using slides from Inova Diagnostics, Euroimmun and Immco. The capability to detect isolated anti-DFS70 antibodies was compared using immunoadsorption on NOVA Lite HEp-2 Select (Inova Diagnostics) and the HEp-2 ELITE/DFS70 knockout test (Immco). RESULTS: The three substrates had very good sensitivity for detecting patients with anti-DFS staining pattern (93.1%, 79.3% and 72.4% for Euroimmun, Immco and Inova respectively). Most of the patients had full inhibition of DFS pattern (65.5%) by immunoabsorption test. Also, the 55.2% of the subjects were positive for monospecific DFS pattern using HEp-2 ELITE/DFS70 knockout test. However, the correlation between the full inhibition by immunoadsorption and the monospecific DFS pattern in knockout cells was very low (kappa: 0.22). CONCLUSION: The evaluation of monospecific anti-DFS70 antibodies is clinically fundamental and challenging using traditional HEp-2 IIF. Results obtained in this study support the hypothesis that the lack of standardization across IIF kits along with the subjectivity of user interpretation among other factors contribute to the overall reduction in the agreement. PMID- 30017654 TI - The contributions of individual galactosyltransferases to protein specific N glycan processing in Chinese Hamster Ovary cells. AB - Galactosylation as part of N-glycan processing is conducted by a set of beta-1,4 galactosyltransferases (B4GALTs), with B4GALT1 as the dominant isoenzyme for this reaction. Nevertheless, the exact contributions of this key-player as well as of the other isoenzymes involved in N-glycosylation, B4GALT2, B4GALT3 and B4GALT4, have not been studied in-depth. To increase the understanding of the protein- and site-specific activities of individual galactosyltransferases in Chinese Hamster Ovary cells, a panel of triple deletion cell lines was generated that expressed only one isoform of B4GALT each. Two model proteins were selected for this study to cover a large spectrum of possible N-glycan structures: erythropoietin and deamine-oxidase. They were expressed as Fc-fusion constructs (EPO-Fc and Fc-DAO) and their N-glycan processing status was analyzed by site-specific mass spectrometry. The sole activity of B4GALT1 resulted in a decrease of 15-21 % of fully galactosylated structures for erythropoietin, emphasizing the involvement of other isoenzymes. Interestingly, the contributions of B4GALT2 and B4GALT3 differed for the two model proteins. Unexpectedly, removal of galactosyltransferases influenced the overall process of N-glycan maturation, with the result of a higher occurrence of poorly processed oligosaccharides. In the context of high productivity cell lines, which can push N-glycan maturation towards incomplete galactosylation, galactosyltransferases are potential targets to ensure stable product quality. In view of our results, specifically engineered "designer" cell lines may be required for different proteins. PMID- 30017653 TI - European expert consensus statement on therapeutic goals in Fabry disease. AB - BACKGROUND: Fabry disease, an inherited lysosomal storage disorder, causes multi organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation. METHODS: A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion. RESULTS: A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis. CONCLUSIONS: These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life. PMID- 30017655 TI - Outcome after liver transplantation in elderly recipients (>65 years) - A single center retrospective analysis. AB - BACKGROUND: Liver transplantation (LT) in elderly recipients is controversially discussed in the literature with only little data on long-term outcome available. We aimed to evaluate the safety and efficiency of LT in elderly recipients (>65 years). METHODS: Between 1989-2016, 139 patients >65 years-old were listed for liver transplantation, and 76 (55%) were transplanted. Patient outcome and characteristics were evaluated separately for the time period before (1989-2004) and after (2005-2016) MELD-implementation. Post-transplant outcome was compared between the elderly cohort and LT-recipients aged 18-65 years (n = 1395). RESULTS: Overall survival of patients >65 years was better in the MELD-era compared to the earlier period (1- and 5-year-survival: 73%, 60% vs. 69%, 37%, respectively; p = 0.055). The main differences between the two groups included higher recipient age (p = 0.001) and BMI (p = 0.001), higher donor age (p < 0.001), less need of intraoperative red blood cells (p = 0.008) and a lower number of postoperative rejections (p = 0.03) after 2004. Comparing the overall survival of patients transplanted in the MELD-era aged 18-65 years vs. >65 years displayed comparable 1- and 5 year-survival rates (81%, 68% vs. 73% and 60%, respectively, p = 0.558). CONCLUSION: In the modern era, outcome of patients receiving LT with >65 years is comparable to <65 year-old patients. After careful evaluation, patients >65 years old should be considered for LT. PMID- 30017656 TI - Hospital admission for digestive diseases: Gastroenterology units offer a more effective and efficient care. AB - BACKGROUND: Digestive diseases imply a substantial burden for health care systems. Effectiveness of specialized gastroenterology care has been demonstrated in a few real life surveys. AIMS: To perform an in-depth analysis of Hospital Discharge Records (HDRs) of patients admitted for digestive diseases (DDs) from all Italian regions over the years 2010-2014. METHODS: Data on National HDRs were provided by the Italian Health Ministry. RESULTS: During the years 2010-2014, a mean of 949,830 patients with DDs were admitted to hospital per year, representing 10.0% of all admissions in Italy. Only 7.4% of patients with DDs were admitted to Gastroenterology units due to the limited number of the specialty-focused beds (3.4/100,000 inhabitants). DDs urgent admissions in Gastroenterology units represented 33% of admissions. The mean length of stay was 8.1 days in Gastroenterology units, as opposed to 8.3 in other units. Mortality rate for DDs altogether, for urgent admissions, and for urgent admissions with bleeding were 2.2%, 1.7%, 2.2% in Gastroenterology units, and 3.1%, 3.9%, 3.5% in other units, respectively. DDs admissions were appropriate in 81.3% in Gastroenterology units as opposed to 66.6% in all other units. CONCLUSIONS: Gastroenterology units offer a better specific care in terms of length of hospital stay and mortality even for patients admitted for emergent conditions. PMID- 30017657 TI - Metformin promotes autophagy in Echinococcus granulosus larval stage. AB - Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation between autophagy and the activation of the unfolded protein response in E. granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible to metformin (Met), a drug that indirectly activates Eg AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway, Met could play a role in the death of the parasite contributing to the demonstrated anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents. PMID- 30017659 TI - Spontaneous bleeding in thrombocytopenia: Is it really spontaneous? AB - Spontaneous bleeding is a clinical hallmark of thrombocytopenia and can take multiple forms including petechiae, epistaxis, gum bleeding, or, in worst cases, intracranial hemorrhage. Those bleeding events are called " spontaneous " because they occur in the absence of overt trauma. Spontaneous bleeding manifestations have long been considered to be a direct consequence of low platelet counts. Nevertheless, although low platelet counts may lead to ultrastructural endothelial alterations, those alterations and the associated state of vascular fragility are unlikely sufficient to cause spontaneous rupture of the microvessel wall. Indeed, in addition to endothelial injury, factors capable of damaging the basement membrane are required to allow escape of red blood cells in the extravascular space. Therefore, despite their misleading name, spontaneous bleeding events in thrombocytopenia are most likely provoked and involve subclinical biological processes in which platelets normally intervene to ensure hemostasis. In this review, we discuss past and more recent studies on the possible triggers of spontaneous bleeding events in thrombocytopenia, with a particular focus on the role of inflammatory reactions. PMID- 30017658 TI - Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin. AB - BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT). CASE PRESENTATION: A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3A (c.2645G > A, p.R882H), and IDH1 (c.395G > A, p.R132H) genes. He achieved complete remission with intensive chemotherapy and was subsequently submitted to alloHSCT. Eleven years later, he was given chemotherapy and radiotherapy to treat a lung carcinoma. Three years later, t-AML was diagnosed; the disease had arisen from a pre-existing DNMT3A mutated patient-origin clone that had subsequently acquired a TP53 mutation and a complex karyotype. Although a second transplantation was intended, the disease was refractory to induction chemotherapy, and the patient eventually died from disease complications. We retrospectively demonstrated the persistence and post-transplantation latency of the R882H-DNMT3A mutation using a real-time PCR allele-specific analysis at different time-points during the observation period. DISCUSSION AND CONCLUSION: The present case highlights the potential clinical implications of a R882H-DNMT3A mutated clone that persisted after conventional AML treatment, including alloHSCT. It also reinforces the notion of the importance of cell non-intrinsic factors, such as the hematopoietic stress induced by chemotherapy and radiotherapy, as drivers of clonal expansion. PMID- 30017660 TI - Cut Costs at All Costs! AB - The UK Government decision to close its Forensic Science Service (FSS) in 2010 left the criminal justice system in England and Wales bereft of impartial, high level scientific support. The private sector was entrusted to fill the gap and to ensure that all results were accurate, timely, fit for purpose, easy to interpret, and above all gave value for money. In the event, however, a major provider has collapsed necessitating a rescue deal to minimise the impact of the fiasco. Moreover, there have been allegations of data manipulation in another private sector laboratory and possible falsification of evidence in a laboratory set up by a police force in an attempt to fill the gap left by the FSS. As to the future, appropriate laboratory regulation and inspection clearly has a part to play, but ironically 'quality management' adds an unnecessary and ever-increasing cost burden that may detract from quality. What is really needed are systems that combine public service and professional integrity with research and development. Involving investigators, coroners/medical examiners/judges, and prosecution and defence lawyers in educational fora would help build cross-professional co operation and understanding. PMID- 30017661 TI - Total tryptase or beta-tryptase in post mortem settings: Which is to be preferred? PMID- 30017662 TI - Forensic science in England & Wales, a commentary. PMID- 30017646 TI - Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score. AB - BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1.67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0.0001), higher total bilirubin concentration (p=0.0003), lower aminotransferase concentration (p=0.0012), younger age (p<0.0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0.0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0.0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0.83 (95% CI 0.79-0.87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0.556, p=0.0130) and intermediate hepatocytes (probability of response was 0.90 if intermediate hepatocytes were absent vs 0.51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. FUNDING: UK Medical Research Council and University of Milan-Bicocca. PMID- 30017663 TI - The use of stereological methods in the histomorphometric assessment of bone for age-at-death estimation. AB - Stereological examination of the anterior femur was done for the estimation of age-at-death. The aim of this study was to assess particular bone microstructures that change with advancing age and use these variables to create revised regression formulae applicable to the black population of South Africa. A sample of 99 bone sections (n=60 males and n=39 females) that had previously been analysed using 2D methods, were re-analysed using the optical fractionator and nucleator sampling methods. Single and multiple regression analyses were performed to assess the strength of the relationship between known age and all independent variables. For sex-pooled data, the average number of osteons per grid area (Avg_OPD) showed the highest correlation with age (r=0.528; r2=0.278), followed by average osteon volume (r=-0.383; r2=0.146). The remaining variables reflected a low correlation with age. Pooled, as well as sex-specific single regression formulae were constructed. Multiple regression formulae were constructed for pooled sexes only, as there were no significant difference between males and females overall. Although the employment of stereological methods ensured that the results are accurate and unbiased, the outcome was on par with previously reported SEE's and SD's for this population. PMID- 30017665 TI - Biomechanical characteristics of immediately loaded and osseointegration dental implants inserted into Sika deer antler. AB - This study aimed to compare biomechanical characteristics of immediately loaded (IL) and osseointegrated (OS) dental implants inserted into Sika deer antler and lay a foundation for developing an alternative animal model for dental implants studies. Two implants per antler were inserted. One implant was loaded immediately via a self-developed loading device; the other was submerged and unloaded as control. IL implants were harvested after different loading periods. The unloaded implants were collected after OS and the shedding of antler. Specimens were scanned by uCT scanner and finite element models were generated. A vertical force of 10 N was applied on the implant. The mean values of maximum displacements, stresses and strains were compared. The results showed that the density of antler tissue around the implants dramatically increased as the loading time increased. After shedding the antler, 3 pairs of antlers were collected and the density of antler tissue remained in a similar value in all specimens. The maximum values of displacement and stresses in implant and stresses and strains in antler tissue were significantly different among OS models. In one antler, all the biomechanical parameters of IL model were significantly higher than those of OS model of the same animal (P < 0.05) and wider distributions were obtained from IL model. It can be concluded that implants inserted into Sika deer antler might not disturb the growth and calcification process of antler and the use of Sika deer antler model is a promising alternative for implant studies that does not require animal sacrifice. PMID- 30017664 TI - Intentional heroin administration resulting in homicide in a 10-month old infant. AB - Homicide occurs in approximately one in five injury-related deaths among infants in the United States and studies suggest that male caretakers (fathers or mothers' intimate partners) are the perpetrators of the majority of infant homicides. Opioid abuse is common and it is estimated that between 26.4 million and 36 million people abuse opioids worldwide. In this case report, we add to the literature the first reported homicide by intentional heroin administration in a 10-month old infant. Toxicology revealed morphine 1092ng/L, codeine 74ng/mL, and 6-monoacetyl-morphine 359ng/L in cardiac blood. Morphine 803ng/g, codeine 54ng/g in liver tissue, and morphine 181ng/mL was found in vitreous humor. With the prevalence of opioid abuse on the rise accidental opioid ingestions in the pediatric population have increased. However, forensic personnel must recognize the possibility of intentional poisoning in this vulnerable population. PMID- 30017666 TI - Changing Nursing Practice: The Role of the Editorial Process. PMID- 30017667 TI - Shaping the Patient-Centered Medical Home to the Needs of HIV Safety Net Patients: The Impact of Stigma and the Need for Trust. AB - The patient-centered medical home (PCMH) is a promising model for increasing the efficiency and quality of HIV care. We evaluated the implementation of PCMH related demonstration projects in HIV care settings serving safety net populations. We conducted 113 qualitative interviews with key informants and patients to understand which PCMH components were perceived as best meeting patient medical and support service needs. Our results demonstrate the value and limitations of the PCMH, as currently conceived, for HIV care settings. Clinics focused on modifying workflows and improving care coordination. Patients welcomed such changes because they reinforced existing trust in the providers. Clinics dedicated less attention to promoting patient activation, such as building self management skills, because such changes were seen as duplicative or undermined existing practices to meet patient social support needs. Research should explore how components of the PCMH could be modified to more fully meet the needs of this patient population. PMID- 30017669 TI - Volume change in the rectus abdominis muscle after deep inferior epigastric perforator flap harvest. AB - Deep inferior epigastric perforator (DIEP) flap is associated with less donor site morbidity than transverse rectus abdominis myocutaneous flap. However, abdominal muscle atrophy and donor site complications caused by denervation during pedicle dissection cannot be avoided. This retrospective study investigated the change in the rectus abdominis muscle volume after DIEP flap harvest. Of 395 patients who underwent unilateral DIEP flap breast reconstruction between August 2007 and July 2017, 25 patients with >2-year postoperative abdominal computed tomography data were evaluated. Preoperative and postoperative images of the abdominal muscle after pedicle dissection and the nonoperated side were compared. The volume of the muscles from the lower margin to the umbilicus was determined by using OsiriX image analysis application. The muscle volumes on the side of pedicle dissection decreased from 72.63 +/- 23.29 cm3 preoperation to 53.09 +/- 16.93 cm3 postoperation (p < 0.001). The corresponding volumes on the side without dissection were 73.29 +/- 19.25 cm3 and 60.89 +/- 18.79 cm3 (p < 0.001). The percentage of postoperative retained volume relative to the preoperative retained volume was 75.65% +/- 19.18% on the pedicle dissection side and 84.65% +/- 19.00% on the contralateral side. The 9% difference was not statistically significant (p = 0.10). No major abdominal complications were observed. Despite nerve injury during DIEP flap surgery, the volume loss of the involved and contralateral muscles did not differ. More than 75% of the abdominal muscle volume was retained. Muscle integrity was well maintained without any postoperative complications. PMID- 30017668 TI - Asiatic acid protects differentiated PC12 cells from Abeta25-35-induced apoptosis and tau hyperphosphorylation via regulating PI3K/Akt/GSK-3beta signaling. AB - Amyloid beta (Abeta) peptide can cause neurotoxicity in Alzheimer's disease (AD). The main purpose of the present study is to investigate the protective role of asiatic acid (AA) against Abeta25-35-induced neurotoxicity in neuronally differentiated PC12 cells. Differentiated PC12 cells were pretreated with 5, 10 or 20 MUM AA before treatment with 20 MUM Abeta25-35. The viability and apoptosis of differentiated PC12 cells were determined by MTT assay and Annexin V-FITC/PI double staining, respectively. The mitochondrial membrane potential (MMP) of differentiated PC12 cells was analyzed by JC-1 staining. The expression levels of proteins were detected by western blot analysis. We found that AA significantly increased the viability of differentiated PC12 cells but attenuated the mitochondria-mediated apoptosis dose-dependently when challenging with Abeta25 35. Besides, the results of western blot analysis showed that AA prevented IkappaBalpha degradation and p65 nuclear translocation, and promoted the phosphorylation of Akt and GSK-3beta in Abeta25-35-treated differentiated PC12 cells. Moreover, LY294002, a specific PI3K inhibitor, was found to abolish the beneficial effects of AA on Abeta25-35-induced apoptosis and tau protein hyperphosphorylation. Our findings demonstrated that AA protects differentiated PC12 cells from Abeta25-35-induced apoptosis and tau protein hyperphosphorylation, which might be partially mediated by the activation of the PI3K/Akt/GSK-3beta signaling pathway. PMID- 30017670 TI - Preliminary analysis of pulsed radiofrequency therapy combined with carpal tunnel release for reducing the pain in postoperative Period: Early outcomes. PMID- 30017671 TI - Topical application of Photofrin(r) for photodynamic diagnosis of malignant cutaneous neoplasms. AB - OBJECTIVES: The prognosis of patients suffering from malignant cutaneous neoplasms can be improved by early diagnosis. Exact demarcation of tumor margins could contribute to optimum results in surgical excision and reconstruction. The purpose of our study is to evaluate Photofrin(r) with a new diagnostic procedure, photodynamic diagnosis (PDD), for the detection of Bowen's disease (squamous cell carcinoma (SCC) in situ), SCC, and basal cell carcinoma (BCC). MATERIALS AND METHODS: Sixty patients with cutaneous neoplasms received 2.5 mg/mL Photofrin(r) solution topically. After a period of 3 hours, the patients underwent fluorescence illumination (lambdaex = 370-450 nm). Guided by their visible fluorescence, lesions were biopsied at four suspicious sites in each patient. All specimens were analyzed and measured by a pathologist. A quantitative analysis of the fluorescence contrast between the neoplasms and healthy tissue was performed using the Red, Blue, and Green (RGB) Mode and Gray Scale (GS). Statistical analysis was performed by the analysis of variance (ANOVA) test for multiple comparisons. RESULTS: Of the 60 patients (20 Bowen's disease, 20 SCC, and 20 BCC), malignant neoplasms could be clearly distinguished from adjacent healthy tissue under fluorescence illumination (P < 0.0001). The sensitivity of the malignant neoplasms evaluated using the RGB and GS modes combined showed 92.74% in image results. The specificity of the malignant neoplasms evaluated using the RGB and GS modes combined showed 95.77%. CONCLUSION: Light-induced fluorescence detection using topical Photofrin(r) provides a sensitive, noninvasive technique for the early identification of malignant cutaneous neoplasms. PMID- 30017672 TI - Corrigendum to ''Patient-rated long-term results after complete denervation of the wrist'' [Journal of Plastic, Reconstructive & Aesthetic Surgery Volume 71 Issue 1 (2018) 57-61]. PMID- 30017673 TI - A comprehensive review of immune-mediated dermatopathology in systemic lupus erythematosus. AB - Lupus erythematosus (LE) is an autoimmune disease with a broad clinical spectrum ranging from cutaneous lesions to severe systemic manifestations. The pathogenesis of the disease and the immunological mechanisms for the heterogeneities in lupus remain unclear. The LE-specific cutaneous manifestations are generally divided into three categories: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Clinically, lupus patients with skin lesions can be divided into two subsets based on the organs involved: cutaneous LE, such as DLE and SCLE, which appears only as a skin manifestation, and systemic lupus erythematosus (SLE), e.g., ACLE, which involves other organs, such as kidneys, joints, and the hematopoietic system. However, lupus is an aggressive disease, and cutaneous lupus and systemic lupus partially overlap. Fewer than 5% of DLE patients and approximately 50% of SCLE patients might develop major organ damage and then develop SLE in subsequent years. Furthermore, there are no predictive biomarkers in clinical use. To the best of our knowledge, increasing evidence from clinical trials has revealed that early intervention can either reduce or delay the onset of severe manifestations. Therefore, identification of certain biomarkers in skin lesions or circulation from patients with skin lesions to predict future flares and advise treatment is an unmet need. In this review, we comprehensively describe the subtypes of LE with pathological criteria and clinical manifestations; summarize the up-to-date evidence on certain cell distributions, such as keratinocytes, neutrophils, dendritic cells, T cells and B cells, in skin and peripheral blood; and discuss their pathogenic roles and their potential roles in predictive diagnosis and as therapeutic targets. PMID- 30017674 TI - Trends in patient procurement of postoperative opioids and route of hysterectomy in the United States from 2004 through 2014. AB - BACKGROUND: The opioid epidemic in the United States is a public health emergency. Minimally invasive surgical technology has decreased length of hospital stay, improved postoperative recovery, and decreased postoperative pain. Hysterectomy is one of the most commonly performed surgeries in the United States. Increasing trends in minimally invasive gynecologic surgery are expected to reduce patients' postoperative pain. It is unclear whether this assumption has resulted in decreasing postoperative opioid prescriptions or patient need for these prescriptions, as prescribing patterns may be contributing to the current opioid public health emergency. OBJECTIVE: We sought to describe opioid prescribing and patient procurement practices for postoperative pain at time of discharge for benign hysterectomy from 2004 through 2014 using the Truven Health Analytics MarketScan Research Database. The trends of the route of hysterectomy over this time period were concomitantly described to reflect the movement toward more minimally invasive approaches. STUDY DESIGN: The Truven Health Analytics MarketScan Research Database including the Commercial Claims and Encounters Database, and the Medicare Supplemental and Coordination of Benefits Database were utilized. Current Procedural Terminology, 4th Edition, and International Classification of Diseases, Ninth Revision, codes identified all patients who underwent a hysterectomy for benign indications from 2004 through 2014. Hysterectomy routes were categorized into abdominal, laparoscopic, and vaginal. The MarketScan database captures prescriptions filled at a retail or mail-order pharmacy and does not capture prescriptions filled within the inpatient, hospital facility. The days of opioids procured by patients at the time of discharge were identified for each encounter. Descriptive statistics were used to summarize data within the entire study period. Although this article is purely descriptive, further analyses were conducted for exploratory purposes only. analysis of variance and chi2 analyses were used for continuous and categorical variables, respectively. Multiple linear regression models were used to describe associations between variables of interest and postoperative opioid prescriptions. RESULTS: We identified 793,016 patients who underwent a hysterectomy for benign indications from 2004 through 2014. Of these, 96% were identified from the Commercial Claims and Encounters Database. During the study period, the overall route of hysterectomy was categorized into 40.5% abdominal, 42.0% laparoscopic, and 17.5% vaginal hysterectomy. The route of hysterectomy changed from 60.2-25.6% (a decrease of Delta = 34.58; 95% confidence interval, 33.96-35.20) for abdominal, 17.0-61.9% (an increase of Delta = 44.83; 95% confidence interval, 44.21-45.44) for laparoscopic, and 22.8-12.6% (a decrease of Delta = 10.25; 95% confidence interval, 9.77-10.73) for vaginal. At discharge, the percentage of patients who were prescribed opioids and filled them increased from 25.6-82.1% (an increase of Delta = 56.50; 95% confidence interval, 55.88 57.13 with P < .001) from 2004 through 2014 for all hysterectomy routes. Additionally, the quantity of opioids prescribed also increased. CONCLUSION: Opioid prescriptions filled for postoperative pain after hysterectomy substantially increased from 2004 through 2014. Opioid prescription procurement has increased despite a concomitant increase in minimally invasive hysterectomy routes. In light of the current opioid epidemic, physicians must recognize that postoperative prescribing practices may contribute to chronic opioid use. Heightened awareness of opioid prescribing practices following surgery is critically important to decrease risk of development of chronic opioid dependence. PMID- 30017675 TI - Postpartum venous thromboembolism readmissions in the United States. AB - BACKGROUND: There are limited data on when postpartum readmissions for thromboembolism occur after delivery hospitalizations on a population basis in the United States. OBJECTIVE: We sought to characterize risk factors for and timing of postpartum venous thromboembolism readmission after delivery hospitalization discharge. STUDY DESIGN: The Healthcare Cost and Utilization Project Nationwide Readmissions Database for calendar years 2013 and 2014 was used to perform a retrospective cohort study evaluating risk for readmission for venous thromboembolism within 60 days of discharge from a delivery hospitalization. Risks for deep vein thrombosis and pulmonary embolism were individually assessed. Obstetric, medical, demographic, and hospital factors associated with postpartum readmission for venous thromboembolism were analyzed. Risk was characterized as odds ratios with 95% confidence intervals. Both unadjusted and adjusted analyses were performed. Adjusted analyses included relevant obstetric, medical, demographic, and hospital factors within logistic regression models. RESULTS: From Jan. 1 through Oct. 31 in 2013 and 2014, 6,269,641 delivery hospitalizations were included in the analysis. In all, 2975 cases of readmission for any venous thromboembolism were identified (4.7 per 10,000 delivery hospitalizations) including 1170 cases of deep vein thrombosis and 1805 cases of pulmonary embolism. In all, 69.6% of readmissions for any venous thromboembolism occurred within the first 20 days of discharge vs 22.3% and 8.0% at 21-40 and 41-60 days after discharge. Median times to readmission were 12.7, 14.0, and 11.7 days for venous thromboembolism, deep vein thrombosis, and pulmonary embolism, respectively. Women readmitted for any venous thromboembolism were more likely to have a history of venous thromboembolism (4.2% vs 0.3%, P < .01), to have had a cesarean delivery (54.4% vs 32.4%, P < .01), to have a thrombophilia (1.8% vs 0.4%, P < .01), to have had a longer delivery hospitalization of >3 days for vaginal delivery and >4 days for cesarean (18.0% vs 6.6%, P < .01), to have been diagnosed with gestational hypertension or preeclampsia (19.7% vs 8.2%, P < .01), and to have had postpartum hemorrhage with transfusion (2.6% vs 0.5%, P < .01). These factors retained significance in adjusted models. History of venous thromboembolism and hemorrhage with transfusion were associated with the largest odds of readmission (odds ratio, 9.5; 95% confidence interval, 6.6-13.6, and odds ratio, 3.6; 95% confidence interval, 2.4-5.5, respectively). Other factors associated with increased odds included thrombophilia (odds ratio, 2.0; 95% confidence interval, 1.2-3.5), cesarean delivery (odds ratio, 2.0; 95% confidence interval, 1.8-2.3), longer delivery hospitalization (odds ratio, 1.8; 95% confidence interval, 1.5-2.2), and preeclampsia or gestational hypertension (odds ratio, 2.0; 95% confidence interval, 1.6-2.4). CONCLUSION: While the majority of events occurred within 20 days of discharge, risk factors other than thrombophilia and prior venous thromboembolism were generally associated with modestly increased odds of events, and only a small proportion of readmissions occurred among women with thrombophilia and prior events. Our data demonstrate both the challenging nature and urgent need for further research to determine which clinical practices and interventions may reduce risk for venous thromboembolism readmissions on a population basis. PMID- 30017676 TI - Reply. PMID- 30017677 TI - Femur-sparing pattern of fetal growth after maternal Zika virus infection. PMID- 30017678 TI - Reply. PMID- 30017679 TI - Racial difference in postpartum hemorrhage outcome: pathophysiologic, clinical, and social significance? PMID- 30017680 TI - Sexism in obstetrics and gynecology: not just a "women's issue". AB - Women in medicine have made strides towards equality and yet the gender gap continues to exist. Despite being the specialty dedicated to the promotion of women's health, obstetrics and gynecology is also marred by gender disparity. Obstetrician-gynecologists who are women continue to face barriers to advancement to leadership positions and earn $36,000 per year less than men in obstetrics and gynecology according to a recent study. Similarly, men in obstetrics and gynecology may be negatively affected by unconscious bias and socially prescribed roles for men and women, resulting in patient preferences for providers who are women. Both men and women have a vested interest in promoting greater gender parity in obstetrics and gynecology, and participation of men is critical for realization of this goal. For the obstetrician-gynecologist, sexism is not just a "women's issue". PMID- 30017681 TI - Do Pregnant Inmates have a Constitutional Right to Opioid Replacement Therapy? AB - Changes in the national drug laws have resulted in a marked increase in the number of individuals who have been incarcerated in the United States over the past several decades; women have not been exempt from this trend. Incarcerated women who are pregnant and at risk of experiencing opioid withdrawal often lack access to opioid replacement therapy while in jails and prisons, although this treatment is necessary to prevent significant acute withdrawal that can be detrimental to maternal-fetal health. I contend that pregnant inmates who are at risk of experiencing opioid withdrawal possess a constitutional right to receive opioid replacement therapy while incarcerated and that failure to provide this treatment represents a violation of the Eighth Amendment's protection against cruel and unusual punishment. PMID- 30017682 TI - Vaginal delivery within 24 hours of labor induction as a primary outcome: what's the rush? PMID- 30017683 TI - Cervical cerclage for singleton pregnant patients on vaginal progesterone with progressive cervical shortening. AB - BACKGROUND: Premature cervical ripening plays a significant role in spontaneous preterm birth. Vaginal progesterone is the recommended treatment in singleton pregnancy with incidental short cervix. There is lack of evidence on whether it is beneficial to reinforce the cervix with cerclage when the cervical length becomes progressively shortened <10 mm while on vaginal progesterone. OBJECTIVE: Our aims are to determine whether cerclage with vaginal progesterone will: (1) reduce the overall spontaneous preterm birth rate, (2) prolong pregnancy latency, and (3) improve neonatal outcomes compared to vaginal progesterone alone. STUDY DESIGN: This was a retrospective cohort study at the University of Illinois at Chicago of all women with singleton pregnancy on vaginal progesterone for incidental short cervix, cervical length <20 mm. Only those with progressive cervical length shortening <10 mm who delivered at the University of Illinois at Chicago from January 2013 through December 2016 were included. The decision to perform cerclage was based on individual physician preference. Demographic data; information on serial cervical length status; medical, obstetric, and social history; cerclage vs no cerclage; and neonatal outcomes were compared. RESULTS: A total of 310 women with incidental short cervix on vaginal progesterone were identified, and of these, 75 had progressive shortening cervical length <10 mm and met inclusion criteria. Among the women with extremely shortened cervical length <10 mm, 36 women (48%) had cervical cerclage plus vaginal progesterone, and 39 women (52%) continued on vaginal progesterone alone. The baseline characteristics, mean cervical length (5.06 vs 5.52 mm), and mean gestational age at diagnosis of extreme short cervix (21.5 vs 21.3 weeks) were similar between women who received cerclage vs those who did not, respectively. The mean gestational age at delivery was significantly greater for those with cerclage (34 weeks and 3 days vs 27 weeks and 2 days; P < .001). The rate of spontaneous preterm birth at <37, 35, 32, 28, and 24 weeks were significantly lower in the cerclage group: 44.1% vs 84.2%, 38.2% vs 81.6%, 23.5% vs 78.9%, 14.7% vs 63.2%, and 11.8% vs 39.5%, respectively. The rate of spontaneous preterm birth <37 weeks remained significant after controlling for confounders (relative risk, 0.11; 95% confidence interval, 0.03-0.41; P < .001). The average pregnancy latency was 14 weeks in the cerclage combined with vaginal progesterone group compared to vaginal progesterone alone group. Neonatal intensive care unit admission and development of respiratory distress syndrome were significantly lower in the cerclage group compared to vaginal progesterone alone group: 13 (36.1%) vs 23 (65.7%) (relative risk, 0.55; 95% confidence interval, 0.34-0.90; P = .018) and 8 (22.2%) vs 17 (43.6%) (relative risk, 0.59; 95% confidence interval, 0.29-0.90; P = .027), respectively. Neonates of women with cerclage were also significantly less likely to develop necrotizing enterocolitis or experience neonatal death. CONCLUSION: Our study showed that cerclage plus vaginal progesterone in women with extremely shortened cervix significantly decreased overall spontaneous preterm birth rates, prolonged pregnancy latency by 2-fold, and decreased the overall neonatal morbidity and mortality. PMID- 30017684 TI - Sexual response in women with Mayer-Rokitansky-Kuster-Hauser syndrome with a nonsurgical neovagina. AB - BACKGROUND: Sexual dysfunction is prevalent in women with Mayer-Rokitansky-Kuster Hauser syndrome after the creation of a neovagina. Insight into the physiologic response of the neovagina during sexual arousal is lacking, although this would help in the understanding of sexual function of these patients. The physiologic sexual response of the vagina can be measured objectively by vaginal photoplethysmography to assess vaginal blood flow. OBJECTIVE: Testing whether the physiologic and subjective sexual response in women with Mayer-Rokitansky-Kuster Hauser syndrome with a neovagina differs from the response in women with a natal vagina. STUDY DESIGN: Vaginal blood flow (vaginal pulse amplitude) and subjective sexual responses during neutral and erotic film viewing were assessed in premenopausal women with Mayer-Rokitansky-Kuster-Hauser syndrome with a nonsurgically created neovagina (n=15) and were compared with responses of an age matched control group (n=21). RESULTS: All women with Mayer-Rokitansky-Kuster Hauser syndrome had created their neovagina themselves by dilation. Women with Mayer-Rokitansky-Kuster-Hauser syndrome showed a significantly smaller vaginal pulse amplitude compared with control subjects during neutral film viewing (P=.002). In both groups, vaginal pulse amplitude increased significantly during erotic film viewing, but this increase was significantly smaller in the Mayer Rokitansky-Kuster-Hauser syndrome group (P<.005). Levels of subjective sexual arousal did not significantly differ between the 2 groups (P>.2). CONCLUSION: Women with Mayer-Rokitansky-Kuster-Hauser syndrome with a nonsurgically created neovagina showed a weaker vaginal blood flow response during visual sexual stimulation and poorer basal blood flow compared with control subjects. The differences in vaginal blood flow may be related to less vascularization and innervation of the neovagina compared with the natal vagina. The weaker vaginal sexual response can play a role in sexual dysfunction; however, despite the weaker vaginal response, women with Mayer-Rokitansky-Kuster-Hauser syndrome did not differ in their level of subjective sexual arousal. Future studies may compare vaginal blood flow and subjective sexual response of women with Mayer Rokitansky-Kuster-Hauser syndrome with nonsurgically and surgically created vaginas. PMID- 30017685 TI - A systematic review of safety and adverse effects in the practice of therapeutic hypothermia. AB - OBJECTIVE: To carry out a systematic review to estimate the rate and magnitude of adverse effects following therapeutic hypothermia (TH) procedure in patients resuscitated from out-of-hospital cardiac arrest (OHCA) and highlight the specific complications seen after the procedure. METHODS: A systematic review of currently published studies was performed following standard guidelines. Online database searches were performed for controlled trials for the last twenty years. Papers were examined for methodological soundness before being included. Data were independently extracted by two blinded reviewers. Studies were also assessed for bias using the Cochrane criteria. The adverse effects attributed to TH in the literature were appraised critically. RESULTS: The initial data search yielded 78 potentially relevant studies; of these, 59 were excluded for some reason. The main reason for exclusion (n = 43, 55.8%) was that irrelevance to adverse effects of TH. Finally, 19 underwent full-text review. Studies were of high-to-moderate (n = 12, 63%) to low-to-very low (n = 7, 37%) quality. Five studies (27.7%) were found to have high risk of bias, while 8 (42.1%) had low risk of bias. INTERPRETATION: Although adverse effects related to the practice of TH have been studied extensively, there is substantial heterogeneity between study populations and methodologies. There is a considerable incidence of side effects attributed to the procedure, e.g., from life-threatening ventricular arrhythmias to self limited consequences. Most studies analyzed in this systematic review indicated that the procedure of TH has not caused severe adverse effects leading to significant alterations in the outcomes following resuscitation from OHCA. PROSPERO, registration number is: CRD42018075026. PMID- 30017686 TI - Bedside ultrasound as a predictive tool for acute chest syndrome in sickle cell patients. AB - BACKGROUND: Acute chest syndrome (ACS) is the leading cause of death for patients with sickle cell disease (SCD). Early recognition of ACS improves prognosis. OBJECTIVE: Investigate the use of bedside lung ultrasound (BLU) in identification of early pulmonary findings associated with ACS in SCD patients. METHODS: Prospective, observational study of a convenience sample of SCD patients presenting to the Emergency Department (ED) for a pain crisis. BLU interpretations were made by an emergency physician blinded to the diagnosis of ACS, and were validated by a second reviewer. The electronic medical record was reviewed at discharge and at 30 days. RESULTS: Twenty SCD patients were enrolled. Median age was 31 years, median hemoglobin was 7.7 g/dL. Six patients developed ACS. Five patients in the ACS group had lung consolidations on BLU (83%) compared to 3 patients in the non-ACS group (21%), p = 0.0181, (OR = 12.05, 95% CI 1.24 to 116.73). The ACS group was also more likely to have a pleural effusion and B lines on BLU than the non-ACS group, p = 0.0175; 0.1657, respectively. In the ACS group, peripheral and frank consolidations on BLU was 83% and 50% sensitive, 79% and 100% specific for ACS, respectively; whereas an infiltrate on initial chest X ray (CXR) was only 17% sensitive. BLU identified lung abnormalities sooner than CXR (median 3.6 vs. 31.8 h). CONCLUSIONS: Pulmonary abnormalities on BLU of an adult SCD patient presenting to the ED for a painful crisis appear before CXR, and highly suggest ACS. BLU is a promising predictive tool for ACS. PMID- 30017688 TI - Aggressive fluid therapy for pain control in pediatric acute pancreatitis: A topic for future research. PMID- 30017687 TI - QTc prolongation as a marker of 30-day serious outcomes in older patients with syncope presenting to the Emergency Department. AB - BACKGROUND: Syncope is a common chief complaint in the ED, and the electrocardiogram (ECG) is a routine diagnostic tool in the evaluation of syncope. We assessed whether increasingly prolonged QTc intervals are associated with composite 30-day serious outcomes in older adults presenting to the ED with syncope. METHODS: This is a secondary analysis of a prospective, observational study at 11 EDs in adults 60 years or older who presented with syncope or near syncope. We excluded patients presenting without an ECG, measurement of QTc, non sinus rhythm, bundle branch block or those without 30-day follow-up. We categorized QTc cutoffs into values of <451; 451-470; 471-500, and >500 ms. We determined the rate of composite 30-day serious outcomes including ED serious outcomes and 30-day arrhythmias not identified in ED. RESULTS: The study cohort included 2609 patients. There were 1678 patients (64.3%) that had QTc intervals <451 ms; 544 (20.8%) were 451-470 ms; 302 (11.6%) were 471-500 ms, and 85 (3.3%) had intervals >500 ms. Composite 30-day serious outcomes was associated with increasingly prolonged QTc intervals (13.0%, 15.3%, 18.2%, 22.4%, p = 0.01), but this association did not persist in multivariate analysis. CONCLUSIONS: In a cohort of older patients presenting with syncope, increased QTc interval was a marker of but was not independently predictive of composite 30-day serious outcomes. PMID- 30017689 TI - Subacute aortic prosthetic mechanical valve thrombosis complicated with acute coronary syndrome. AB - A prosthetic valve thrombosis (PVT), which is a potentially fatal complication, refers to the presence of non-infective thrombotic material on a prosthetic valve apparatus, interfering with its function. Possible complications of a PVT include transient neurologic embolic events, cardiac arrest due to a stuck valve prosthesis, and cardio-embolic myocardial infarction (MI). The choice of treatments, including a redo surgery, a percutaneous coronary intervention (PCI), and a fibrinolysis with PVT or MI dosages, depends on the patient's clinical and hemodynamic status and thrombotic burden involving the prosthetic valve and surrounding tissues. An early postoperative mechanical valve thrombosis is associated with increased risks due to the need for unforeseen early redo surgery complications and excessive bleeding risk in case of thrombolytic therapy usage. Here, we present a fifty-seven-year old female patient who was admitted to the emergency department with the complaint of acute chest pain seven days after an aortic prosthetic mechanical valve implantation. The clinical presentation was consistent with ST segment elevated MI and echocardiography revealed a large mass on the recently implanted prosthetic aortic valve. Valvular thrombotic complications after heart valve replacement operations are associated with high morbidity and mortality rates. Efficient and urgent treatment is necessary. Considering the clinical status of the patient, we preferred fibrinolytic therapy rather than PCI or surgery. The aim of this case report was to show the efficiency and safety of low-dose slow-infusion fibrinolytic therapy in PVT complicated with acute coronary syndrome. PMID- 30017690 TI - Pre-hospital invasive ventilation in patients with septic shock: Is hyperoxemia an unwanted company? PMID- 30017691 TI - Quantification of ventilation volumes produced by compressions during emergency department cardiopulmonary resuscitation. AB - BACKGROUND: Clinical investigations have shown improved outcomes with primary compression cardiopulmonary resuscitation strategies. It is unclear whether this is a result of passive ventilation via chest compressions, a low requirement for any ventilation during the early aspect of resuscitation or avoidance of inadvertent over-ventilation. OBJECTIVES: To quantify whether chest compressions with guideline-compliant depth (>2 in) produce measurable and substantial ventilation volumes during emergency department resuscitation of out-of-hospital cardiac arrest. METHODS: This was a prospective, convenience sampling of adult non-traumatic out-of-hospital cardiac arrest patients receiving on-going cardiopulmonary resuscitation in an academic emergency department from June 1, 2011 to July 30, 2013. Cardiopulmonary resuscitation quality files were analyzed using R-Series defibrillator/monitors (ZOLL Medical) and ventilation data were measured using a Non-Invasive Cardiac Output monitor (Philips/Respironics, Wallingford, CT). RESULTS: cardiopulmonary resuscitation quality data were analyzed from 21 patients (17 males, median age 59). The median compression depth was 2.2 in (IQR = 1.9, 2.5) and the median chest compression fraction was 88.4% (IQR = 82.2, 94.1). We were able to discern 580 ventilations that occurred during compressions. The median passive tidal volume recorded during compressions was 7.5 ml (IQR 3.5, 12.6). While the highest volume recorded was 45.8 ml, 81% of the measured tidal volumes were <20 ml. CONCLUSION: Ventilation volume measurements during emergency department cardiopulmonary resuscitation after out-of-hospital cardiac arrest suggest that chest compressions alone, even those meeting current guideline recommendations for depth, do not provide physiologically significant tidal volumes. PMID- 30017692 TI - The effect of peer influence on the use of computed tomography by emergency physicians for patients with headaches. AB - BACKGROUND: It is challenging for emergency physicians (EPs) to distinguish between patients with life-threatening and benign headaches. We examined the effect of peer influence on computed tomography use by EPs for patients with headache and evaluated the peer influence effect in EPs with different levels of risk tolerance. METHODS: We conducted a before- and after-retrospective case review, and administered the Risk-Taking subscale of the Jackson Personality Index to attending physicians. Each EP computed tomography (CT) use rate, patient number, and CT use, were e-mailed every two months to enhance EP team norm and establish a trend in behavior. RESULTS: Of the 665 (before intervention) and 669 (after intervention) patients with headache, 206 (31%) and 171 (25.6%) underwent brain CT scans, respectively. Decreased use of CT examination was found in the post-intervention group (OR = 0.758, 95% CI: 0.593-0.967), especially for most risk-tolerant physicians (OR = 0.530, 95% CI: 0.311-0.889). There was prolonged ED length of stay (LOS) in the pre-intervention group (OR = 51.52, 95% CI: 26.998 76.050). CONCLUSIONS: We observed that peer influence is an effective way to improve CT use rate and emergency department LOS for patients with isolated headache, especially for most risk-tolerant physicians. These findings could enhance the development of appropriate guidelines to assist ED physicians' CT use. PMID- 30017693 TI - Diagnostic performance of emergency physician-performed point-of-care ultrasonography for acute appendicitis: A meta-analysis. AB - OBJECTIVE: To assess the sensitivity and specificity of emergency physician performed point-of-care ultrasonography (EP-POCUS) for diagnosing acute appendicitis (AA). MATERIAL AND METHODS: The PubMed and EMBASE databases were searched, and the diagnostic performance of EP-POCUS was evaluated using bivariate modeling and hierarchical summary receiver operating characteristic curves. Subgroup analysis was performed for pediatric patients to compare EP POCUS and radiologist-performed ultrasonography (RADUS). Meta-regression analyses were performed according to patient and study characteristics. RESULTS: In 17 studies (2385 patients), EP-POCUS for diagnosing AA exhibited a pooled sensitivity of 84% (95% confidence interval [CI]: 72%-92%) and a pooled specificity of 91% (95% CI: 85%-95%), with even better diagnostic performance for pediatric AA (sensitivity: 95%, 95% CI: 75%-99%; specificity: 95%, 95% CI: 85% 98%). A direct comparison revealed no significant differences (p = 0.18-0.85) between the diagnostic performances of EP-POCUS (sensitivity: 81%, 95% CI: 61% 90%; specificity: 89%, 95% CI: 77%-95%) and RADUS (sensitivity: 74%, 95% CI: 65% 81%; specificity: 97%, 95% CI: 93%-98%). The meta-regression analyses revealed that study location, AA proportion, and mean age were sources of heterogeneity. Higher sensitivity and specificity tended to be associated with an appendix diameter cut-off value of 7 mm and the EP as the initial operator. CONCLUSION: The diagnostic performances of EP-POCUS and RADUS were excellent for AA, with EP POCUS having even better performance for pediatric AA. Accurate diagnoses may be achieved when the attending EP is the initial POCUS operator and uses a 7-mm cut off value. PMID- 30017694 TI - Inter-scanner variability in Hounsfield unit measured by computed tomography of the brain and effect on gray-to-white matter ratio. AB - PURPOSE: The density ratio of gray matter (GM) to white matter (WM) on brain computed tomography (CT) (gray-to-white matter ratio, GWR) helps predict the prognosis of comatose patients after cardiac arrest. However, Hounsfield units (HU) are not an absolute value and can change based on imaging parameters and CT scanners. We compared the density of brain GM and WM and the GWR by using images scanned with different types of CT machines. METHOD: 102 patients with normal readings who were scanned using three types of CT scanners were included in the study. HU were measured at the basal ganglia level by two observers with circular regions of interest. RESULT: The difference in GM was 0.98-10.30 HU and WM was 1.05-7.55 HU. The mean value of measured HU and GWR were different for each CT group. The ANOVA test showed significant difference all variables. The post hoc test for GWR, which was used to compare the differences between each scanner, was statistically significant. Interclass correlation coefficients of measured GM and WM between the two observers were very high (Cronbach's alpha=0.995 and 0.990, respectively) and GWR was showed good confidence level (0.798). CONCLUSION: In this study, the HU values of GM and WM in the normal adult brain differed up to 23% among scanners. Unfortunately, the GWR may not compensate for the HU difference between GM and WM occurring between scanners. Therefore, rather than applying consistent GWR cut-offs, the protocol or manufacturer differences between imaging scanners should be considered. PMID- 30017695 TI - [Frailty: Critical term for critical care]. PMID- 30017696 TI - [Memory units in Catalonia]. PMID- 30017697 TI - Corrigendum to "The molecular selectivity of UNC3866 inhibitor for Polycomb CBX7 protein from molecular dynamics simulation" [Comput. Biol. Chem. 74 (2018) 339 346]. PMID- 30017698 TI - Effects of an acute bout of physical exercise on reward functioning in healthy adults. AB - Exercise has been proposed as a treatment for several psychiatric disorders. Exercise may act in part through beneficial effects on reward functioning, as it alters neurotransmitter levels in reward-related circuits. However, there has been little investigation of the effect of exercise on reward functions in humans. We hypothesized an acute bout of exercise would increase motivation for and pleasurable responses to rewards in healthy humans. In addition, we examined possible moderators of exercise's effects, including demographics, fitness and previous exercise experience. Thirty-five participants completed exercise and sedentary control sessions in randomized, counterbalanced order on separate days. Immediately after each activity, participants completed measures of motivation for and pleasurable responses to rewards, consisting of willingness to exert effort for monetary rewards and subjective responses to emotional pictures. Exercise did not increase motivation or pleasurable responses on average. However, individuals who had been running for more years showed increases in motivation for rewards after exercise, while individuals with less years running showed decreases. Further, individuals with higher resting heart rate variability reported lower arousal in response to all emotional pictures after exercise, while individuals with low heart rate variability reported increased arousal in response to all emotional pictures after exercise. General fitness did not have similar moderating effects. In conclusion, acute exercise improved reward functioning only in individuals accustomed to that type of exercise. This suggests a possible conditioned effect of exercise on reward functioning. Previous experience with the exercise used should be examined as a possible moderator in exercise treatment trials. PMID- 30017699 TI - Multi-session anodal tDCS enhances the effects of postural training on balance and postural stability in older adults with high fall risk: Primary motor cortex versus cerebellar stimulation. AB - BACKGROUND: Postural control impairment is a key target for rehabilitation of older adults with high fall risk. OBJECTIVE: To investigate whether anodal transcranial direct current stimulation (a-tDCS) over primary motor cortex (M1) or cerebellum can enhance the positive effects of postural training on balance and postural stability in older adults with high fall risk. METHOD: In this randomised, double-blinded sham-controlled study, 65 participants were randomly assigned into five groups; M1 a-tDCS with postural training, bilateral cerebellar a-tDCS with postural training, sham a-tDCS with postural training, postural training alone and cerebellar a-tDCS alone. Participants in the first two a-tDCS groups received 2 mA stimulation for 20 min concurrently with postural training. Postural training was conducted for three sessions of 20 min per week for two weeks. The Berg Balance Score (BBS) and the stability indices at both static and dynamic levels of the Biodex Balance System were evaluated before and after intervention. A general linear model repeated measure ANOVA was used to assess the effects of variables among groups. RESULT: Simultaneous postural training with M1 or bilateral cerebellar a-tDCS significantly improved postural stability indices (p < 0.05) and BBS scores (p < 0.05). Besides, the effects of bilateral cerebellar a-tDCS were significantly higher than that of M1 stimulation on these indices (p < 0.05). Moreover, two weeks postural training alone or cerebellar a tDCS alone is not an adequate intervention to improve the postural stability indices (p > 0.05). CONCLUSION: Postural training with M1 or bilateral cerebellar a-tDCS, especially bilateral cerebellar a-tDCS, can significantly improve postural control or balance in older adults with high fall risk, while two weeks of postural training alone or two weeks cerebellar a-tDCS alone is not a sufficient intervention. PMID- 30017700 TI - Evaluation system and web infrastructure for the second cryo-EM model challenge. AB - An evaluation system and a web infrastructure were developed for the second cryo EM model challenge. The evaluation system includes tools to validate stereo chemical plausibility of submitted models, check their fit to the corresponding density maps, estimate their overall and per-residue accuracy, and assess their similarity to reference cryo-EM or X-ray structures as well as other models submitted in this challenge. The web infrastructure provides a convenient interface for analyzing models at different levels of detail. It includes interactively sortable tables of evaluation scores for different subsets of models and different sublevels of structure organization, and a suite of visualization tools facilitating model analysis. The results are publicly accessible at http://model-compare.emdatabank.org. PMID- 30017701 TI - A simple and robust procedure for preparing graphene-oxide cryo-EM grids. AB - Graphene oxide (GO) sheets have been used successfully as a supporting substrate film in several recent cryogenic electron-microscopy (cryo-EM) studies of challenging biological macromolecules. However, difficulties in preparing GO covered holey carbon EM grids have limited their widespread use. Here, we report a simple and robust method for covering holey carbon EM grids with GO sheets and demonstrate that these grids can be used for high-resolution single particle cryo EM. GO substrates adhere macromolecules, allowing cryo-EM grid preparation with lower specimen concentrations and provide partial protection from the air-water interface. Additionally, the signal of the GO lattice beneath the frozen-hydrated specimen can be discerned in many motion-corrected micrographs, providing a high resolution fiducial for evaluating beam-induced motion correction. PMID- 30017702 TI - Association Between Late-Life Blood Pressure and the Incidence of Cognitive Impairment: A Community-Based Prospective Cohort Study. AB - OBJECTIVES: To investigate the association between late-life blood pressure and the incidence of cognitive impairment in older adults. DESIGN: Prospective cohort study. SETTING: Community-living older adults from 22 provinces in China. PARTICIPANTS: We included 12,281 cognitively normal [Mini-Mental State Examination (MMSE) >= 24] older adults (median age: 81 years) from the Chinese Longitudinal Healthy Longevity Survey. Eligible participants must have baseline blood pressure data and have 1 or more follow-up cognitive assessments. MEASUREMENTS: Baseline systolic (SBP) and diastolic blood pressure (DBP) were measured by trained internists. Cognitive function was evaluated by MMSE. We considered mild/moderate/severe cognitive impairment (MMSE <24, and MMSE decline >=3) as the primary outcome. RESULTS: The participants with hypertension had a significantly higher risk of mild/moderate/severe cognitive impairment (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.10-1.24). Overall, the associations with cognitive impairment seem to be hockey stick-shaped for SBP and linear for DBP, though the estimated effects for low SBP/DBP were less precise. High SBP was associated with a gradual increase in the risk of mild/moderate/severe cognitive impairment (P trend < .001). Compared with SBP 120 to 129 mmHg, the adjusted HR was 1.17 (95% CI 1.07-1.29) for SBP 130 to 139 mmHg, increased to 1.54 (95% CI 1.35-1.75) for SBP >=180 mmHg. Analyses for high DBP showed the same increasing pattern, with an adjusted HR of 1.09 (95% CI 1.01 1.18) for DBP 90 to 99 mmHg and 1.19 (95% CI 1.02-1.38) for DBP >=110 mmHg, as compared with DBP 70 to 79 mmHg. CONCLUSION: Late-life high blood pressure was independently associated with cognitive impairment in cognitively normal Chinese older adults. Prevention and management of high blood pressure may have substantial benefits for cognition among older adults in view of the high prevalence of hypertension in this rapidly growing population. PMID- 30017703 TI - [Partial nephrectomy for renal masses >7cm: Morbidity, oncological and functional outcomes (UroCCR-7 study)]. AB - OBJECTIVES: To describe the morbidity, mortality, oncological and functional results of Partial nephrectomy (PN) for the treatment of renal tumors of more than 7cm. MATERIAL AND METHODS: Thirty-seven partial nephrectomies for tumors larger than 7cm operated in a single center between 1987 and 2016 were analyzed retrospectively. The pre, per and postoperative clinico-biological data were collected within the UroCCR database. The GFR was assessed at day 5, 1 month and last follow-up. Intraoperative and postoperative surgical complications, the recurrence rate and the overall and specific mortality were collected. RESULTS: The mean age of the patients was 57 years (44-68). The preoperative GFR and the median tumor size were 80mL/min and 8cm, respectively. The indication for surgery was elective in 21 cases (60%) and 19 tumors (54%) were malignant. Postoperative complications occurred in 24,3 cases (24.3%). The median post-operative GFR was respectively 77mL/min, 80mL/min and 77mL/min at day 5, 1month and at last follow up. With a median follow up of 31 months [1-168], 5 patients (26,3%) had metastatic progression of whom 1 (5.3%) had a concomitant local recurrence and 3 (15.8%) had died from cancer. CONCLUSION: This study confirms the feasibility of PN for large tumors with acceptable morbidity, limited risk of local recurrence and excellent functional results. LEVEL OF EVIDENCE: 4. PMID- 30017704 TI - Emptying cystometry: A feasibility and validation pilot study on female patients. AB - INTRODUCTION: To assess the feasibility and the accuracy of emptying cystometry in order to simplify the manometric follow-up of overactive detrusor in neurological patients under anticholinergic or botulinum toxin injections. MATERIAL: Female patients with a stable detrusor underwent both a conventional cystometry and sequential measurements of bladder pressure during emptying (emptying cystometry). At the end of the standard cystometry, a CH12 urinary catheter was introduced in the bladder and was connected to a three-way stopcock. The second way of the stopcock permitted the emptying. The third way of the stopcock was connected to a vertical graduated tube to measure the bladder pressure each 50mL during the bladder emptying. RESULTS: Eleven female patients were included (mean age: 59.4years). Nine patients (82%) had neurogenic bladder. Mean cystometric capacity was 439mL (SD: 35mL). During the emptying cystometry, 8 to 10 measures were taken (mean: 9.4). The mean detrusor pressure was 1.7cmH2O (SD 2.1) for the filling cystometry and 2.3cmH2O (SD: 2.7) for the emptying cystometry. The agreement between the detrusor pressure between the two cystometries was good with intra-class correlation coefficient at 0.66 [0.48 0.77] - and the correlation was high (r=0.7; P<0.000001). CONCLUSION: In a small, selected sample of patients, emptying cystometry provides similar results of detrusor pressure to filling cystometry. This technique could constitute a home monitoring of bladder pressures in a selected population of patients with intermittent catheterization in whom a manometric follow-up of detrusor overactivity is required. LEVEL OF EVIDENCE: 4. PMID- 30017705 TI - CME Part I Psoriasis: Which Therapy for Which Patient Psoriasis comorbidities and preferred systemic agents. AB - Psoriasis is a systemic inflammatory disease associated with increased risk of comorbidities such as psoriatic arthritis, Crohn disease, malignancy, obesity and cardiovascular diseases. All these factors have a significant impact on the decision to use one therapy over another. The past decade has seen a paradigm shift in our understanding of the pathogenesis of psoriasis which has led to identification of new therapeutic targets. Several new drugs have gained FDA approval, expanding the psoriasis armamentarium but still a large number of patients continue to be untreated or undertreated. Treatment regimens for psoriasis patients should be tailored to meet specific needs based on disease severity, impact on quality of life, response to previous therapies and presence of comorbidities. Part 1 of this CME article will focus on specific comorbidities and provide insights to choose appropriate systemic treatment in patients with moderate to severe psoriasis. PMID- 30017706 TI - CME Part II Psoriasis: Which Therapy for Which Patient Focus on special populations and chronic infections. AB - Despite the availability of several new systemic agents for psoriasis treatment, it can be challenging to choose the right therapy in certain patient populations. There are few up-to-date reviews on systemic drugs for moderate to severe psoriasis in pregnant and pediatric patients and in patients with concomitant chronic infections such as hepatitis, HIV and latent tuberculosis. These groups are usually excluded from clinical trials and much of the available evidence is based on anecdotal case reports and case series. Being a chronic disease, psoriasis requires long-term treatment and there are concerns of adverse maternal fetal outcomes, long term side-effects in children and reactivation of latent infections with use of systemic agents in these patients. Part 2 of this CME article will provide insights for choosing appropriate systemic agents for treating moderate-to-severe psoriasis in pregnant and pediatric patients and in the setting of chronic infections such as hepatitis, HIV and latent tuberculosis. PMID- 30017707 TI - Novel biobutanol fermentation at a large extractant volume ratio using immobilized Clostridium saccharoperbutylacetonicum N1-4. AB - Product inhibition by butanol and acetone is a known drawback in acetone-butanol ethanol (ABE) fermentation. Extractive fermentation improves butanol production by several ABE-producing Clostridium spp., but only low volume ratios (<4) of extractant to broth (Ve/Vb) have been studied. Here, a novel extractive fermentation process was developed using Clostridium saccharoperbutylacetonicum N1-4 and a large Ve/Vb ratio. A mixture of oleyl alcohol-tributyrin (1:1 (v/v)) yielded high distribution coefficients for both butanol (3.14) and acetone (0.660). Although a fed-batch culture using free cells and the oleyl alcohol tributyrin mixture at a Ve/Vb ratio of 5 had a lag phase of >24 h, it produced a higher concentration of total butanol (i.e., butanol produced in all the phases per broth volume used) of 24.2 g/L-broth after 96 h compared with 14.4 g/L-broth at a Ve/Vb ratio of 1, resulting in a low butanol concentration in the aqueous phase. The use of cells immobilized with calcium alginate beads shortened the lag phase to <12 h. Butanol production was achieved not only in a 3-phase mode (extractant, beads, and tryptone-yeast extract-acetate (TYA) medium) but also in a 2-phase mode (extractant and beads containing TYA medium, without an aqueous phase) at a Ve/Vb ratio of 5, resulting butanol concentrations of 30.9 g/L-broth and 27.7 g/L-broth, respectively. The 3-phases fed-batch extractive fermentation at a Ve/Vb ratio of 10 showed a better performance compared with published reports: a total butanol concentration of 64.6 g/L-broth and a butanol yield to consumed sugar of 0.378 C-mol/C-mol. PMID- 30017708 TI - Analysis of intracellular IgG secretion in Chinese hamster ovary cells to improve IgG production. AB - The production of biopharmaceutical immunoglobulin G (IgG) using cultured mammalian cells, especially Chinese hamster ovary (CHO) cells is well established and has been markedly improved through the modification of cells and cell culture engineering technologies. The establishment of high-production cell lines remains a challenge. The intracellular secretion of IgG has been investigated to identify and solve the rate-limiting steps in antibody production. However, strategies that regulate the expression of proteins that are related to antibody secretory pathway have not consistently improved their production. In this study, key features and limitations of the antibody secretion process in recombinant CHO cells were analyzed to develop more efficient approaches for establishing high production cells. By chase assay with protein translation inhibitors, IgG secretion reached a plateau when at least 20% of IgG remained in the cells. The secretion kinetics and retention ratio of IgG varied between IgG subclasses (two types of IgG1 and an IgG3 subclass). Immunofluorescent microscopy and size exclusion chromatography showed that the remaining intracellular IgG localized mainly within the endoplasmic reticulum (ER) and less with the cis-Golgi network, despite the formation of fully assembled IgG. These results show that remaining intracellular IgG is a target for enhancing antibody secretion, even in high production CHO cells. PMID- 30017709 TI - Effects of concurrent blockade of OX2 and CB1 receptors in the ventral tegmental area on nicotine-induced place preference in rats. AB - In this study, the role of orexin-2 (OX2) and cannabinoid-1 (CB1) receptors and their potential interaction within the ventral tegmental area (VTA) on nicotine induced place preference, was examined in male rats. A 5-day conditioned place preference (CPP) paradigm was used. Nicotine (0.5 mg/kg; s.c.) induced a significant CPP, without any effect on the locomotor activity during the testing phase. TCS-OX2-29 (0.4, 0.8 and 4 MUg/rat), as a selective OX2 receptor antagonist and AM251 (0.2, 1 and 2 MUg/rat), as a selective cannabinoid CB1 receptor antagonist, individually or simultaneously were microinjected bilaterally into the VTA. The results showed that administration of AM251 (1 and 2 MUg/rat) or TCS-OX2-29 (0.4, 0.8 and 4 MUg/rat) into the VTA, during the 3-day conditioning phase or testing day, could dose-dependently inhibit the development of nicotine-induced CPP, in the acquisition or expression, respectively. Concurrent administration of ineffective doses of TCS-OX2-29 and AM251 into the VTA could not affect conditioning scores. The findings of this study support the possible role of OX2 and CB1 receptors in the VTA, in the acquisition and the expression of nicotine-induced place preference. Furthermore, our data suggest that there is a possible interaction between the VTA orexinergic and cannabinoid systems in nicotine-induced place preference. PMID- 30017710 TI - Childhood trauma and emotion regulation: The moderator role of BDNF Val66Met. AB - Emotion regulation difficulties have been involved in multiple forms of psychopathology and may represent an important focus for current efforts to understand the biological mechanisms underlying transdiagnostic symptoms. The present study investigated a gene-environment interaction (G * E) in reappraisal, a form of emotion regulation that has been extensively linked to psychopathology. In light of recent meta-analytic evidence of its consistent role in depression and anxiety disorders, this study focused on the Val66Met (rs6265) single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and examined its moderator role in the relation between childhood trauma and reappraisal. A sample of N = 266 participants were genotyped for BDNF Val66Met, filled in a self-report measure of childhood trauma, and underwent a cognitive task designed to assess reappraisal ability. The results indicated that, as expected, BDNF Val66Met was a significant moderator in the relation between childhood trauma and reappraisal. There was a negative relation between the number of childhood traumatic events and reappraisal ability in BDNF Met carriers, but not Val homozygotes. This finding suggests that BDNF Val66Met contributes to susceptibility to childhood stress, with long term impact on emotion regulation. PMID- 30017711 TI - Radiographic characteristics of chronic diffuse sclerosing osteomyelitis/tendoperiostitis of the mandible: A comparison with chronic suppurative osteomyelitis and osteoradionecrosis. AB - Diffuse sclerosing osteomyelitis (DSO) of the mandible is a poorly understood chronic disease. It is assumed to be a form of chronic osteomyelitis. Other forms of chronic osteomyelitis are chronic suppurative osteomyelitis (CSO) and osteoradionecrosis (ORN). This study aimed to investigate radiographic characteristics of DSO and compare these findings with the radiographic characteristics of CSO and ORN in order to radiographically distinguish these three diseases. In this retrospective study, 33 patients were clinically diagnosed with DSO (13), CSO (6), or ORN (14). The panoramic radiographs, computed tomography images, and magnetic resonance images of these patients were evaluated. Osseous and soft tissue changes were analysed. Patients with DSO showed extensive cortical and medullary sclerosis combined with subperiosteal bone formation, condylar process deformation, and hypertrophy and oedema of the masseter muscle. DSO patients showed no pathological fractures or sequestra, which were observed in patients with CSO and ORN. The radiographic characteristics that differentiate DSO from CSO and ORN include subperiosteal bone formation, condylar process deformation, masticatory muscle changes, and the absence of sequestra and pathological fractures. PMID- 30017713 TI - Midterm outcomes after arthroscopic surgery for hypermobile lateral meniscus in adults: Restriction of paradoxical motion. AB - BACKGROUND: Hypermobile lateral meniscus (HLM) is one of the causes of knee pain and a locking sensation. It is thought that disruption of the popliteomeniscle fascicles lead to hypermobility of the lateral meniscus in adults. In cases of HLM, the posterior portion of the lateral meniscus shows forward abnormal translation with knee flexion and backward translation with knee extension. We refer to this phenomenon as paradoxical motion. The purpose of this study was to report an arthroscopic HLM stabilization and evaluate the midterm clinical outcomes. METHODS: Twenty consecutive HLM patients (21 knees) who underwent arthroscopic surgery were included. The mean age at the time of surgery was 37.7 (19-63) years. Mean duration from surgery to final follow-up was 37 (24-68) months. Meniscus movement according to the knee flexion and extension was observed by diagnostic arthroscopy. We performed arthroscopic inside-out vertical stacked suturing of disrupted popliteomeniscle fascicles. The number of suturing and details of meniscal movement were assessed. The Tegner activity level score and Lysholm knee scores were determined preoperatively and at 2 years postoperatively. Clinical outcomes included locking sensation, recurrences and complications reported at the final follow-up. RESULTS: Paradoxical motion of the lateral meniscus was observed in all patients. We performed an average of 5.0 (2 8) vertical stacked sutures of the disrupted popliteomeniscal fascicles. Physiological motion of the lateral meniscus was observed after meniscus repairs. The mean Tegner activity level scales before and after surgery were 4.6 (2-8) and 4.7 (2-8), respectively. The mean Lysholm knee scores significantly improved from 72.0 (48-85) preoperatively to 97.8 (78-100) at 2 years postoperatively. There were no complications or recurrences of locking symptoms at the final follow-up. CONCLUSIONS: Use of arthroscopic inside-out vertical sutures for disrupted popliteomeniscle fascicles improved the clinical outcomes for HLM patients without complications. PMID- 30017712 TI - Perioperative safety and complications in treatment of oral and maxillofacial surgery patients under general anesthesia with obstructive sleeping disorders. AB - Patients with sleeping disorders, such as obstructive sleep apnea, (OSA) have a higher risk for postoperative complications after maxillofacial surgery under general anesthesia. The aim of this study was to detect specific complications after oral and maxillofacial surgery. Sixty-nine cases of patients with middle or severe sleep apnea who underwent an operation under general anesthesia in the oral and maxillofacial region were retrospectively analyzed. This group was compared with an age and diagnosis matched group without sleep apnea receiving the same operative treatment. We found a significant difference between the two groups concerning body mass index, the ASA-Index, the Cormack-Mallampati Index, the number of pre-existing conditions, and home medication (p < 0.05). Concerning the length of stay, overrun of estimated mean length of stay, and number of surgical complications and hypertonic events, no difference could be detected. Almost 28% of the patients with OSA in our study suffered a substantial respiratory complication even under intensive care observation. The number of patients with oxygen desaturation was 9% in the control group, which differed significantly (p = 0.0093) from the number of such patients in the OSA group. In this study, we have shown that the presence of OSA in patients undergoing elective maxillofacial surgery is associated with a considerable number of comorbidities in the postoperative period. Through preoperative OSA screening and OSA evaluation, an improvement in management of surveillance resources could be achieved and the OSA-specific risk could be assessed more precisely and also reduced. PMID- 30017714 TI - Clinical significance of the tail-like pattern in soft-tissue sarcomas on magnetic resonance imaging. AB - BACKGROUND: An infiltrating abnormal signal around soft-tissue tumors along the fascial, neurovascular, or musculature plane on magnetic resonance imaging (T2 weighted, gadolinium-enhanced T1-weighted, or short-tau inversion recovery) is recognized as the "tail-like pattern". The tail-like pattern was intensively analyzed in myxofibrosarcoma, but not in other sarcomas. We aimed to answer some key questions about the tail-like pattern such as its incidence and effect on oncological outcomes. METHODS: The presence of the tail-like pattern in 114 soft tissue sarcomas was evaluated on T2-weighted images or gadolinium-enhanced T1 weighted images, or both. We analyzed the incidence of the tail-like pattern in all cases and in specific histological subtypes. We also assessed the clinical backgrounds of the presence of the tail-like pattern and its impact on achieving adequate surgical margins and oncological outcomes, including local recurrence and overall survival. RESULTS: The tail-like pattern was detected in 50% of cases. The tail-like pattern was most common in myxofibrosarcoma and undifferentiated pleomorphic sarcoma, and less common in low-grade sarcomas. Trans-compartmental invasion of the tumor and high-grade malignancy were common clinical backgrounds for the presence of the tail-like pattern. The presence of the tail-like pattern significantly inhibits the achievement of preoperatively planned surgical margins despite planning the margins outside the tail-like pattern area. The tail-like pattern was an independent risk factor for local recurrence. The pattern was not an independent risk factor for worse overall survival, although it was a risk factor in univariate analysis. CONCLUSION: The tail-like pattern is clinically significant in myxofibrosarcomas and other sarcomas with respect to the preoperative evaluation of malignancy by magnetic resonance imaging, and negatively affects successful resection and oncological outcomes. A more sophisticated modality for the evaluation and clinical management of the tail-like pattern is needed in the future. PMID- 30017715 TI - Innovations in improving lipid production: Algal chemical genetics. AB - Perturbation of a biological system with small molecules to achieve a desired phenotype or activity is commonly referred as chemical genetics. In pharmaceutical discovery, this approach is most often employed in target-based screening but in plants systems the focus is primarily on phenotypic selection for commercially relevant phenotype generation such as crop improvement or disease and pathogen resistance. Likewise, algae are considered feedstock organisms for viable and sustainable biofuels and other high value products with commercial applications. Algal triacylglycerol synthesis is therefore an important target for chemical genetics using high throughput technologies. In this review, efforts are directed towards summarizing our present understanding of the regulation of algal triacylglycerol biosynthesis, highlighting critical enzymes in lipid and carbon metabolism that may be manipulated to increase lipid metabolism in algae. These enzymes and pathways are targets for chemical genetics with the focus on selection of small molecules as tools to improve triacylglycerol storage. Using case studies, we summarize how chemical genetics is being used in plant and microalgal systems to address these critical problems. PMID- 30017716 TI - Electrophysiological reward signals predict episodic memory for immediate and delayed positive feedback events. AB - Previous research has shown that in reinforcement learning, the hippocampus is involved in the processing of feedback when it is delayed for several seconds. Also, better recognition memory has been reported for temporally delayed than for immediately presented feedback pictures. Event-related potential (ERP) studies have found that feedback delay affects the amplitude of the feedback-related negativity (FRN), and there is evidence suggesting that the FRN is modulated by declarative learning. In the present study, a subsequent memory paradigm was used to investigate the effects of feedback delay on the incidental encoding and subsequent retrieval of feedback events. Participants used immediate or delayed feedback to learn associations between Chinese characters and reactions. Unrelated pictures were presented simultaneously with positive or negative feedback, and recognition memory for the pictures was tested in a surprise memory test. Behaviorally, memory was better for positive than negative feedback pictures, but there was no effect of feedback delay on memory performance. Electrophysiological activity during the FRN time window was found to predict subsequent memory for positive, but not negative feedback pictures, suggesting that positive reward prediction errors as reflected in the FRN contribute to successful memory encoding. Consistent with previous studies, the FRN was reduced for delayed feedback, but only in a condition in which feedback was useful for learning. Behavioral and ERP estimates of familiarity and recollection support the view that positive feedback enhanced memory mainly by boosting familiarity based recognition. PMID- 30017717 TI - Sexual Health Knowledge of U.S. Medical Students: A National Survey. AB - BACKGROUND: Sexual health is a critical component of overall wellness; however, only half of U.S. medical schools currently require formal instruction in sexuality. AIM: This study sought to quantify the sexual health knowledge of undergraduate medical students using a novel survey tool evaluating 6 domains: sexual function and dysfunction; fertility and reproduction; sexuality across the lifespan; sexual minority health; society, culture, and behavior; as well as safety and prevention. METHODS: A novel 32-question survey tool was developed by subject matter experts from the University of Minnesota Program in Human Sexuality. Survey questions were derived from the 2012 and 2014 Summits on Medical School Education in Sexual Health as well as the Sexuality Information and Education Council of the United States Guidelines for Kindergarten through 12th Grade. The total knowledge score was calculated out of 30 points (excluding 2 terminology questions that were subjective). Medical students at 178 allopathic and osteopathic medical schools in the United States were invited to take the online survey. OUTCOMES: Students performed below a passing rate (70%) in 4 of the 6 knowledge categories and below a passing rate overall in the knowledge assessment. RESULTS: Survey respondents (n = 1,014) scored an average of 66% correct (approximately 20/30). Overall, students scored lowest on questions regarding safety and prevention (x- = 49%) and highest on questions regarding sexuality across the lifespan (x- = 75%). Higher knowledge scores were associated with the following variables (P < .05): medical school year, race/ethnicity, sexual orientation, religious affiliation, future medical specialty choice, program type (MD/DO), and taking a human sexuality course in medical school. CLINICAL IMPLICATIONS: Medical students may be under-prepared to address essential sexual health issues in future clinical practice. STRENGTHS & LIMITATIONS: To the knowledge of the authors this is the only contemporary study seeking to measure U.S. medical student sexual health knowledge. Limitations include sample population size and diversity as well as a non-validated survey tool. CONCLUSION: Significant advances must be made in undergraduate medical education in order to prepare future physicians to address critical issues such as sexually transmitted disease, family planning, and health disparities. Warner C, Carlson S, Crichlow R, et al. Sexual Health Knowledge of U.S. Medical Students: A National Survey. J Sex Med 2018;15:1093-1102. PMID- 30017718 TI - Predictors of Satisfaction in Men After Penile Implant Surgery. AB - INTRODUCTION: Despite the high satisfaction with penile implant (PI) surgery reported in the literature, a significant proportion of patients remain dissatisfied. AIM: To evaluate satisfaction after PI surgery, using a single question and a scoring system. Furthermore, we attempted to define factors that predicted high patient satisfaction. METHODS: The study population consisted of all patients undergoing PI surgery between 2009 and 2015. Comorbidity, demographic, and implant information were recorded. Complications recorded included: minor (requiring no re-operation) such as penile or scrotal hematoma, superficial wound breakdown; major (requiring hospitalization or re-operation) such as device infection, erosion, and mechanical malfunction. Patient satisfaction was defined using a single question posed to the patient 6 months after surgery using a 5-point Likert scale (5 being the most satisfied). Descriptive statistics were used to define complication rates and multivariable analysis (MVA) was performed to define predictors of high satisfaction (score >= 4), including presence and degree of complications, Peyronie's disease (PD), diabetes mellitus (DM), number of vascular comorbidities, body mass index (BMI) > 30, and patient age. MAIN OUTCOME MEASURE: Patients with a major complication, with or without an additional minor complication, had a higher likelihood of being dissatisfied (25%) compared to patients with no complication or only minor complication 1.9% (no complications) and 3.7% (only minor complications), P < .001. RESULTS: 902 patients were analysed. Mean age was 56.6 +/- 10.6 years. Mean BMI was 30 +/- 5. Comorbidity profile was diabetes 75%, dyslipidaemia 44%, hypertension 33%, cigarette smoking 32%, and PD 34%. 76% had a malleable implant (MPP) and 24% an inflatable implant (IPP). 31% had a minor complication and 9% a major complication. 93% had high satisfaction (score >=4). Patients with any complication had a reduced rate of high satisfaction (97.5% vs 87.7%; P < .001) and even more pronounced with a major complication (96.7% vs 64.2%; P < .001). On MVA, only the absence of a major complication was a significant predictor of high satisfaction (OR 20, 95% CI 9-50, P < .001). CONCLUSION: A high percentage of men are satisfied after penile implant surgery. Only the presence of a major complication is linked to a lower likelihood of achieving high satisfaction. Habous M, Tal R, Tealab A, et al. Predictors of Satisfaction in Men After Penile Implant Surgery. J Sex Med 2018;15:1180-1186. PMID- 30017719 TI - Novel Multi-Modal Analgesia Protocol Significantly Decreases Opioid Requirements in Inflatable Penile Prosthesis Patients. AB - BACKGROUND: Inflatable penile prosthesis (IPP) surgery is associated with significant perioperative pain that may reduce patient satisfaction. Though various pain management strategies have been proposed, most implanters manage postoperative patients with only prescription opioids. No protocol to date has been implemented and reported for pain management in IPP patients throughout the entire recovery process following surgery. AIM: Develop a multimodal analgesic (MMA) regimen consisting of perioperative administration of acetaminophen, meloxicam, and gabapentin with intraoperative local anesthetic injections, and compare post-operative pain control to a matched cohort of patients managed with an opioid-based (OB) regimen. METHODS: We retrospectively analyzed our prospectively maintained IPP database from November 2015-January 2018. The MMA protocol was instituted for all patients beginning June 2017, and these patients were matched in a 1:2 ratio to a cohort of eligible IPP patients managed through an OB protocol. Only patients receiving a 3-piece IPP were included; those with a history of narcotic dependence, neuropathy, or chronic non-steroidal anti inflammatory drug use were excluded. Postoperative pain scores (visual analog scale) and opioid usage (total morphine equivalents [TME] in milligrams) were compared temporally in the post-anesthesia care unit, postoperative day (POD) 0, POD 1, and following discharge. OUTCOMES: The primary outcomes of the study are postoperative pain scores and narcotic usage. RESULTS: 57 patients were eligible for analysis: 19 (33%) and 38 (66%) in the MMA and OB groups, respectively. Groups were similar in demographics. MMA patients had significantly lower visual analog scale scores in post-anesthesia care unit, POD 0, or POD 1 (mean 0.84 vs 2.97, P = .01; 2.62 vs 4.73, P = .003; and 2.26 vs 4.0, P = .01, respectively) and used fewer narcotics on POD 0 (mean 4.08 vs 13.8 mg TME, P < .001) and POD 1 (mean 5.05 vs 25.1 mg TME, P < .001). MMA patients were discharged home with fewer narcotics (mean 12.7 vs 51.3 tabs, P < .001), and despite this, the MMA group needed less narcotic medication refills (11% vs 49%, P = .007). Neither group experienced a medication-related postoperative adverse event. CLINICAL IMPLICATIONS: Multimodal pain management allows for effective pain control with minimal side effects, enhancing recovery. STRENGTHS & LIMITATIONS: This is the first report to assess use of a multi-modal pain regimen on IPP recipients with demonstration of tangible benefit throughout the recovery process. Limitations include a single-surgeon and retrospective study design. CONCLUSION: In our rigorous assessment of IPP patients, implementation of a novel MMA protocol achieved equivalent and effective pain control, while resulting in substantially fewer narcotics throughout the entire post-operative period following IPP implantation. Tong CMC, Lucas J, Shah A, et al. Novel Multi-Modal Analgesia Protocol Significantly Decreases Opioid Requirements in Inflatable Penile Prosthesis Patients. J Sex Med 2018;15:1187-1194. PMID- 30017720 TI - Neurochemistry evaluated by MR spectroscopy in a patient with xeroderma pigmentosum group A. AB - MRI of a female patient with xeroderma pigmentosum group A (XP-A) showed progressive cerebral atrophy, but no disease-specific lesion. MR spectroscopy with short TE sequences in the bilateral white matter revealed decreased N-acetyl aspartate (neuro-axonal marker) and increased myo-inositol (astroglial marker) with a normal concentration of choline (membrane marker), which are compatible with the neuropathology of XP-A, consisting of a reduced number of neurons, and fibrillary astrogliosis with preservation of myelinated fibers. MR spectroscopy reveals neurochemical derangement in XP-A, which cannot be observed on conventional MRI, and will be useful to monitor the neurochemical derangements of XP-A. PMID- 30017721 TI - Precisely albumin-hitchhiking tumor cell-activated reduction/oxidation-responsive docetaxel prodrugs for the hyperselective treatment of breast cancer. AB - The anticancer efficacy of chemotherapy is greatly limited by short blood circulation and poor tumor selectivity. Thus, anticancer prodrugs with prolonged systemic circulation, tumor-specific distribution and bioactivation, could significantly strengthen the chemotherapy efficacy. Herein, we design two novel tumor cell reduction/oxidation-responsive docetaxel (DTX) prodrugs, DTX-maleimide conjugates with disulfide bond (DSSM) or thioether bond (DSM) linkages, to evaluate the roles of different sensitive linkages in drug release, pharmacokinetics and therapeutic efficacy. An ester bond-linkage prodrug (DM) is utilized as a non-sensitive control. DSSM and DSM show reduction- or oxidation sensitive release behavior, respectively, and exhibit hyperselective bioactivation and cytotoxicities between cancerous and normal cells. They could instantly hitchhike blood circulating albumin after i.v. administration with albumin-binding half-lives as short as 1 min, resulting in prolonged systemic circulation, increased tumor accumulation. In response to the upregulated reduction/oxidation environment within tumor cells, DSSM and DSM exhibit selectively release capacity in tumor tissues, their TAITumor/Liver values are over 30-fold greater than DM. Combining the above delivery advantages into one, DSSM and DSM achieve enhanced antitumor efficacy of DTX. Such a uniquely developed strategy, integrating high albumin-binding capability and reduction/oxidation-sensitive drug superselective release in tumors, has great potential to be applied in clinical cancer therapy. PMID- 30017722 TI - Bilayer polymeric nanocapsules: A formulation approach for a thermostable and adjuvanted E. coli antigen vaccine. AB - One of the strategies used to improve the immunogenicity of purified protein antigens has relied on their association with synthetic nanocarriers, which, in general, have functioned as simple antigen containers. Here, we present a more advanced strategy based on the design of an antigen nanocarrier at the molecular level. The nanocarrier is composed of a vitamin E oily core, surrounded by two layers: a first layer of chitosan and a second of dextran sulphate. The selected antigen, IutA protein from Escherichia coli, was harboured between the two polymeric layers. The final bilayer nanocapsules had a nanometric size (~ 200 nm), a negative zeta potential (< -40 mV) and a good antigen association efficiency (~ 70%). The bilayer architecture led to an improvement on the formulation stability and the controlled release of the associated antigen. Remarkably, after being administered to mice, bilayer nanocapsules elicited higher IgG levels than those obtained with antigen precipitated with Alum. Moreover, freeze-dried nanocapsules were stable at room temperature for, at least, 3 months. These promising data, in addition to their contribution to the development of an uropathogenic E. coli vaccine, has allowed us to validate these novel bilayer nanocapsules as adequate platforms for the delivery of protein antigens. PMID- 30017723 TI - Therapeutic effect of vitamin D3-containing nanostructured lipid carriers on inflammatory bowel disease. AB - The active form of vitamin D3, 1,25(OH)2D3 has been found to exert multiple effects on the suppression of progression of inflammatory bowel disease (IBD). Vitamin D3 has been gathering attention as a therapy for IBD. However, the clinical trials conducted to date revealed that a relatively high dosage of vitamin D3 was required to see a significant therapeutic effect. Thus, effective formulation and delivery of vitamin D3 to colonic inflammatory lesions will be required. Herein we describe the preparation of a nanostructured lipid carrier (NLC) for the encapsulation of 1,25(OH)2D3 for colonic delivery via oral administration. The optimized fabrication procedure enabled the incorporation of 1,25(OH)2D3 in the NLC by minimizing the destruction of chemically unstable 1,25(OH)2D3. The obtained NLCs orally delivered 1,25(OH)2D3 to the colon in mice and maintained a high concentration of 1,25(OH)2D3 in the colonic tissue for at least 12 h. The NLC showed multiple effects on the suppression of symptoms of colitis induced by dextran sodium sulfate, namely maintaining crypt structure, reducing the tissue concentration of inflammatory cytokines, suppressing the infiltration of polymorphonuclear leukocytes, and augmenting anti-inflammatory CX3CR1high macrophages. Our NLCs containing 1,25(OH)2D3 may be an alternative treatment for IBD therapy. PMID- 30017724 TI - Molecular epidemiology of Babesia species, Theileria parva, and Anaplasma marginale infecting cattle and the tick control malpractices in Central and Eastern Uganda. AB - East Coast fever, babesiosis, and anaplasmosis are the major tick-borne diseases affecting cattle productivity in Uganda. The emergence of acaricide-resistant ticks is suspected to have caused a rise in hemoparasites. This study sought to detect and characterize hemoparasites among farms in acaricide-failure hotspots of central as compared to the acaricide-failure naive areas in Eastern Uganda. Nested PCR assays were performed to determine the prevalences of Babesia bovis, Babesia bigemina, Theileria parva, and Anaplasma marginale in cattle blood samples sourced from randomly selected farms. Randomly selected isolates were sequenced to determine the genetic diversity of the parasites using the following marker genes: B. bovis spherical body protein 4, B. bigemina rhoptry-associated protein 1a, T. parva 104 kDa microneme-rhoptry antigen, and A. marginale major surface protein 5. Furthermore, partially and fully engorged adult ticks were collected for taxonomy, and tick-control practices were assessed using a semi structured questionnaire. The prevalences of B. bigemina, T. parva, and A. marginale in cattle were 17.2, 65.1, and 22.0%, and 10.0, 26.5, and 3% in the central and eastern region, respectively. Whilst, B. bovis was not detected in the farms involved. The sequences for B. bigemina, T. parva, and A. marginale from the central region showed 99% identity with those from the eastern region. Of the 548 ticks collected, 319, 147, 76, and 6 were Rhipicephalus (Boophilus) decoloratus, Rhipicephalus appendiculatus, Amblyomma variegatum, and Rhipicephalus evertsi evertsi, respectively. The Rhipicephalus ticks were more abundant in the central region, whereas A. variegatum ticks were more abundant in the eastern region. Tick control malpractices were found in both Central and Eastern Uganda, and 42 of the 56 surveyed farms lacked appropriate restraining facilities and so they utilized either ropes or a 'boma' (enclosure). In summary, B. bigemina, T. parva, A. marginale and their co-infections were more prevalent in the central than eastern region; even though, tick control malpractices were observed in both regions. Therefore, an urgent tick and TBD control strategy is needed. PMID- 30017725 TI - Immunomics analysis of Babesia microti protein markers by high-throughput screening assay. AB - Babesia microti is a protozoan considered to be a major etiological agent of emerging human babesiosis. It imposes an increasing public-health threat and can be overlooked because of low parasitemia or mixed infection with other pathogens. More sensitive and specific antigens are needed to improve the diagnosis of babesiosis. To screen the immune diagnostic antigens of B. microti, 204 sequences from homologue proteins between B. microti and B. bovis genome sequences in PiroplasmaDB were selected. The high throughput cloned and expressed B. microti proteins were screened with the sera from the BALB/c mice infected by B. microti using protein arrays. Ten (5.9%, 10/169) highly immunoreactive proteins were identified, and most (80%, 8/10) of these highly immunoreactive proteins had not been characterized before, making them potentially useful as candidate antigens for the development of diagnostic tools for babesiosis. PMID- 30017726 TI - The relationship between two different measures of osteoarthritis bone pathology, bone marrow lesions and 3D bone shape: data from the Osteoarthritis Initiative. AB - OBJECTIVE: Bone shape and bone marrow lesions (BMLs) represent different features of Magnetic resonance imaging (MRI)-detected subchondral pathology in osteoarthritis (OA). The aim of this study was to determine how these features are related and how they change in OA progression. METHODS: 600 participants from the Osteoarthritis Initiative (OAI) FNIH Biomarkers Initiative were included, having Kellgren-Lawrence grade 1-3, at baseline and MRI data at baseline and 24 months. The associations between 3D quantitative bone shape vectors and presence of (MRI Osteoarthritis Knee Score) MOAKS semi-quantitative BMLs (total BML size >=1) were analysed for femurs and tibias using linear regression. Responsiveness over 24 months was calculated for both features in four pre-defined progression groups and reported as standardised response means (SRMs). Multilevel models investigated the longitudinal relationship between change in BML size and change in bone shape. RESULTS: Mean age was 61.5, 59% female and mean body mass index (BMI) 30.7. Correlation between baseline femur vector and BML was r = 0.28, P < 0.001. The presence of BMLs was associated with higher bone shape vector; coefficient (95% CI) 0.75 (0.54, 0.96) and 0.57 (0.38, 0.77) for femur and tibia respectively, both P < 0.001. After covariate adjustment, only the femur remained significant [coefficient 0.49, (95% CI 0.30, 0.68)]. Longitudinally bone vector demonstrated more responsiveness to change than BMLs (SRM 0.89 vs 0.13) while multilevel models revealed that increase in BML size was related to a more positive bone shape vector (representing worsening OA). CONCLUSION: There is a relationship between bone shape and BMLs, with prevalence of BMLs associated with increasing OA bone shape. Bone shape demonstrated greater responsiveness than semi-quantitative BMLs. PMID- 30017728 TI - Haptics and the heart: Force and tactile feedback system for cardiovascular interventions. AB - BACKGROUND/PURPOSE: Interventional cardiovascular procedures are performed while operators view multiple visual displays including fluoroscopic and ultrasonic images, intracardiac electrical signals, electroanatomic mapping data, and hemodynamic indices. Operators are unable to palpate physiologic and biophysical signals or feel intracardiac anatomy due to the attenuation and dampening properties of cardiac catheters. This poses a significant limitation when performing higher risk procedures such as complex coronary interventions, transeptal or epicardial puncture to gain access to the left atrium or pericardium for ablation of heart rhythm disorders, cardiac device delivery, and when attempting to maintain stable tissue contact force ("CF") during ablation of cardiac arrhythmia. METHODS/MATERIALS: We utilized signals acquired from a prototype sensorized cardiac guiding catheter, conventional transeptal puncture kit with end hole manometry, commercially available contact force sensing ablation catheter, and epicardial puncture needle, input these signals into a novel signal processing system and generated palpable sensations to blinded subjects using a proprietary tactile/force (haptic) feedback system. Qualitative and quantitative analysis of the system was performed. RESULTS/CONCLUSION: The proprietary haptic (tactile and force) feedback system provides sense of touch during cardiovascular interventions recreating palpable, real-time biophysical events and physiologic information and enables operators to react to critical cardiovascular signals with minimal delay relative to visual motor reaction time to simple display data. SUMMARY: We describe a proprietary haptic (tactile and force) feedback system that provides sense of touch during cardiovascular interventions recreating palpable, real-time biophysical events and physiologic information. PMID- 30017727 TI - Factors associated with the orthopaedic surgeon's decision to recommend total joint replacement in hip and knee osteoarthritis: an international cross sectional study of 1905 patients. AB - OBJECTIVE: To determine factors associated with orthopaedic surgeons' decision to recommend total joint replacement (TJR) in people with knee and hip osteoarthritis (OA). DESIGN: Cross-sectional study in eleven countries. For consecutive outpatients with definite hip or knee OA consulting an orthopaedic surgeon, the surgeon's indication of TJR was collected, as well as patients' characteristics including comorbidities and social situation, OA symptom duration, pain, stiffness and function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), joint-specific quality of life, Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) radiographic grade (0-4), and surgeons' characteristics. Univariable and multivariable logistic regressions were performed to identify factors associated with the indication of TJR, adjusted by country. RESULTS: In total, 1905 patients were included: mean age was 66.5 (standard deviation [SD], 10.8) years, 1082 (58.0%) were women, mean OA symptom duration was 5.0 (SD 7.0) years. TJR was recommended in 561/1127 (49.8%) knee OA and 542/778 (69.7%) hip OA patients. In multivariable analysis on 516 patients with complete data, the variables associated with TJR indication were radiographic grade (Odds Ratio, OR for one grade increase, for knee and hip OA, respectively: 2.90, 95% confidence interval [1.69-4.97] and 3.30 [2.17-5.03]) and WOMAC total score (OR for 10 points increase: 1.65 [1.32-2.06] and 1.38 [1.15-1.66], respectively). After excluding radiographic grade from the analyses, on 1265 patients, greater WOMAC total score was the main predictor for knee and hip OA; older age was also significant for knee OA. CONCLUSION: Radiographic severity and patient-reported pain and function play a major role in surgeons' recommendation for TJR. PMID- 30017729 TI - Complex disease management of pregnant young patient with familial hypercholesterolaemia complicated by coronary artery disease and cerebrovascular disease. AB - Inherited disorders of lipid metabolism may cause a heavy burden of cardiovascular disease early in life. Familial hypercholesterolaemia (FH) with abnormalities of LDL metabolism results in marked LDL elevations and accelerated, multivessel atherosclerosis presenting in teenage or young adulthood. We describe the case of a 33-year-old woman who presented with exertional angina in the setting of pregnancy who was found post-partum to have severe triple-vessel disease including left main disease on coronary angiography (Figs. 1 and 2). She was also noted to have a typical supravalvular "hourglass" [1] abnormality of the aortic root (Fig. 3), and heavy calcification of the proximal aorta precluding conventional aortic cross clamping and bypass surgery. After discussion with the multidisciplinary team, her disease was felt to be amenable to a beating-heart coronary bypass technique with an anaortic approach to minimise the possibility of cerebral embolism. Significant extracranial cerebrovascular disease, a major risk for cardiopulmonary bypass, reinforced the beating-heart technique. Her ongoing management has consisted of medical therapy with cessation of breast feeding, statins, ezetimibe, and introduction of PCSK9-inhibitor therapy. This case illustrates a number of the difficulties associated with management of widespread atherosclerotic disease associated with FH, in which an excellent outcome was achieved with the assistance of a multi-disciplinary team. PMID- 30017731 TI - First report of colistin resistance in an OXA-48- and a CTX-M-15 producing Klebsiella pneumoniae clinical isolate in Algeria due to PmrB protein modification and mgrB inactivation. PMID- 30017730 TI - Draft genome sequence of Bacillus sp. M13(2017), a multidrug-resistant subclass B1 blaNDM-producing, spore-forming bacterium isolated from China. AB - OBJECTIVES: Bacillus spp., which have relevance to pseudo-epidemics in clinics, may cause serious infections as well as high morbidity and mortality in hospitalised patients with haematological malignancies. Here we report the isolation of Bacillus sp. M13(2017) with a multidrug-resistant phenotype and spore-producing structures, a new strain isolated from radiation-polluted soil in Xinjiang Uyghur Autonomous Region, China. METHODS: The draft genome of Bacillus sp. M13(2017) was obtained using an Illumina HiSeqTM 2000 next-generation DNA sequencing platform. Subsequently, clean sequencing data were assembled using SOAPdenovo and were optimised using GapCloser. RESULTS: The draft genome sequence of Bacillus sp. M13(2017) includes 5873661bp, a GC content of 34.84% and is assembled into 6108 open reading frames, of which ca. 5.08% and 1.76% are related to spore formation and antimicrobial resistance, respectively. The blaNDM gene encoding a subclass B1 metallo-beta-lactamase was also discovered in this isolate. CONCLUSIONS: The genome sequence of Bacillus sp. M13(2017) reported here will be a reference for comparative analysis with genomic and clinically important multidrug resistance features of Bacillus sp. PMID- 30017732 TI - Utilization of hypofractionated radiation therapy in older glioblastoma patients. AB - BACKGROUND: Though the optimal treatment regimen in older patients with glioblastoma multiforme (GBM) remains to be established, multiple randomized studies have supported the use of hypofractionated (1-3 weeks) versus traditional regimens (6 weeks). Here we examine hypofractionated regimen practice patterns among older patients with GBM. METHODS: We used the National Cancer Database and included individuals aged >=65 years with GBM diagnosed from 2005 to 2014 undergoing biopsy/resection followed by chemotherapy and radiation initiated <=8 weeks of diagnosis. We defined traditional fractionation as <=200 cGy and hypofractionation as >200 cGy. We compared patient characteristics using a chi squared test and multivariable logistic regression. We compared 90-day mortality rates following initiation of radiation using the Wald statistic in propensity score matched cohorts. RESULTS: The final cohort included 14,931 individuals with 1524 undergoing hypofractionated treatment. From 2005 to 2014 hypofractionated utilization rates were 7%, 9%, 13%, and 18% among those 65-69, 70-74, 75-79, and >=80 years of age, respectively. Patients treated at an academic/research center had a >60% increased odds (OR, 1.61; 95% CI, 1.43-1.81) of undergoing hypofractionated regimens versus a community center. Ninety-day mortality rates were high in both groups (hypofractionated: 32%; traditional: 24%; p < .001). CONCLUSIONS: The majority of older GBM patients do not undergo hypofractionated radiation. High 90-day mortality in both groups suggests that hypofractionation may improve the survival-to-treatment time ratio and positively impact patient quality of life. Hypofractionated radiation regimens for GBM should be discussed with older patients and considered for inclusion in efforts to improve the quality and value of cancer care. PMID- 30017733 TI - Gait speed and survival of older surgical patient with cancer: Prediction after machine learning. AB - PURPOSE: Gait speed in older patients with cancer is associated with mortality risk. One approach to assess gait speed is with the 'Timed Up and Go' (TUG) test. We utilized machine learning algorithms to automatically predict the results of the TUG tests and its association with survival, using patient-generated responses. METHODS: A decision tree classifier was trained based on functional status data, obtained from preoperative geriatric assessment, and TUG test performance of older patients with cancer. The functional status data were used as input features to the decision tree, and the actual TUG data was used as ground truth labels. The decision tree was constructed to assign each patient to one of three categories: "TUG < 10 s", "TUG >= 10 s", and "uncertain." RESULTS: In total, 1901 patients (49% women) with a mean age of 80 years were assessed. The most commonly performed operations were urologic, colorectal, and head and neck. The machine learning algorithm identified three features (cane/walker use, ability to walk outside, and ability to perform housework), in predicting TUG results with the decision tree classifier. The overall accuracy, specificity, and sensitivity of the prediction were 78%, 90%, and 66%, respectively. Furthermore, survival rates in each predicted TUG category differed by approximately 1% from the survival rates obtained by categorizing the patients based on their actual TUG results. CONCLUSIONS: Machine learning algorithms can accurately predict the gait speed of older patients with cancer, based on their response to questions addressing other aspects of functional status. PMID- 30017734 TI - Clinical pharmacology of oncology agents in older adults: A comprehensive review of how chronologic and functional age can influence treatment-related effects. AB - Unique challenges exist when managing older adults with cancer. Associations between cancer and age-related physiologic changes have a direct impact on pharmacokinetics and pharmacodynamics of cancer therapies and can affect drug dosing, dose intensity, efficacy, safety and quality of life. The breadth and depth of these issues, however, have not been fully evaluated because the majority of clinical trials have focused on a younger and healthier population. As a consequence, little information is available to support clinicians in making evidence-based decisions regarding treatment with cancer therapies in older adults, especially those over age 75. Prior clinical pharmacology reviews summarized the literature on how age-related physiologic changes can influence and affect conventional and targeted anti-cancer treatments. Our article provides an updated review with expanded information that includes small molecule kinase inhibitors, monoclonal antibodies, immunotherapies, hormonal, conventional, and miscellaneous agents. Additionally, our article integrates how functional age, determined by the geriatric assessment (GA), can also influence treatment-related effects and health outcomes. Broadening cancer therapy trials to capture not only chronologic age but also functional age would allow clinicians to better identify subsets of older adults who benefit from treatment versus those most vulnerable to morbidity and/or mortality. PMID- 30017735 TI - Single-nucleotide polymorphisms of the adherent junction component cadherin gene are associated with leukoaraiosis. AB - BACKGROUND: Leukoaraiosis (LA) is one of the manifestations of cerebral small vessel disease. Blood-brain barrier (BBB) disruption plays a key role in LA. Cadherin is a component of adherent junctions (AJ), which play a crucial role in cell-cell adhesion, cell-cell recognition and homeostasis in BBB development. We hypothesized that alterations in cadherin genes might be a potential cause of BBB abnormalities that result in LA. METHODS: A total of 339 LA individuals (LA-PVWM, 183; LA-DWM 156) were enrolled, who underwent brain magnetic resonance imaging with obtainable vascular risk factors. Genotyping of cadherin single-nucleotide polymorphisms (SNPs) (rs5030625, rs1801026, and rs16260) was performed by real time polymerase chain reaction with LightSNiP reagents (coupled primer and probe) and FastStart DNAMaster HybProbe (Roche Diagnostic, GmBH, Mannheim, Germany) on a LightCycler 2.0 instrument. RESULTS: Two SNPs, rs1801026 and rs16260, were significantly different between the control and LA groups. The combinatorial effects of the three SNPs were also significant. The haplotypes G-T-C and GA-T-A increased the development of LA-PVWM (OR = 1.76 and OR = 40.7, respectively). The haplotypes G-T-A and GA-T-A increased the development of LA-DWM (OR = 2.56 and OR = 10.48, respectively), but G-C-C decreased the development of LA-DWM (OR = 17.57). CONCLUSION: This study provides evidence for genetic polymorphisms of the AJ component cadherin gene and the association of its haplotypes with LA. PMID- 30017736 TI - Upregulation of circular RNA hsa_circ_0007534 predicts unfavorable prognosis for NSCLC and exerts oncogenic properties in vitro and in vivo. AB - Emerging evidence documented the key functions of circular RNAs (circRNAs) in various malignancies. Nevertheless, the research relevant to the clinical value and functions of circRNAs in non-small cell lung cancer (NSCLC) is still very limited. In this study, we performed qRT-PCR to assess the levels of hsa_circ_0007534 in NSCLC tissues and cell lines and evaluated its clinical significance using Fisher's exact test, Kaplan-Meier analysis and Cox regression analysis. Additionally, loss-of-function and gain-of-function experiments were performed to detect whether hsa_circ_0007534 could affect cell proliferation, apoptosis, metastatic properties and epithelial-mesenchymal transition (EMT) in A549 and H1299 cells. Further xenograft study was carried out to validate the in vitro data. The results indicated that hsa_circ_0007534 was up-regulated in both NSCLC tissue samples and cell lines and this up-regulation is linked to lymph node invasion and advanced TNM stage. Hsa_circ_0007534 could also function as an unfavorable prognostic indicator for the patients with NSCLC. For the part of functional assays, down-regulation of hsa_circ_0007534 suppressed cell growth, migratory and invasive capacities; facilitating cell apoptosis in A549 and H1299 cells. Conversely, up-regulation of hsa_circ_0007534 caused the opposite biological behaviors. What's more, animal experiments validated the oncogenic role of hsa_circ_0007534. Ultimately, the present study indicates that hsa_circ_0007534 might be a potential NSCLC-associated prognostic/therapeutic target. PMID- 30017737 TI - Evaluation of TRIM5 and TRIM22 polymorphisms on treatment responses in Iranian patients with chronic hepatitis C virus infection. AB - The tripartite motif (TRIM)-5 and TRIM22 are involved in innate immune response and show anti-viral activities. The current study aimed at evaluating the association of TRIM5 and TRIM22 polymorphisms with treatment outcomes in patients with chronic hepatitis C virus (CHC). TRIM5 rs3824949 and TRIM22 polymorphisms (rs7113258, rs7935564, and rs1063303) were genotyped using TaqMan polymerase chain reaction (PCR) assay in 425 treatment-naive CHC patients. Rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR) were found in 54.1%, 74.8%, and 67.1% of the patients, respectively. RVR and SVR were associated with TRIM5 rs3824949 (GG), TRIM22 rs1063303 (GC), and TRIM22 rs7113258 (AA), while there was a relationship between TRIM5 rs3824949 (GG) and EVR. TRIM5 and TRIM22 single nucleotide polymorphisms (SNPs) were strongly associated with increased odds of RVR, EVR, and SVR after an interferon-based therapy in patients with CHC. PMID- 30017738 TI - Correlation study between ADA and IFN-gamma gene polymorphisms and the risk of developing tuberculous pericarditis. AB - OBJECTIVE: To study the correlation between adenosine deaminase (ADA) and IFN gamma gene polymorphism and the risk of tuberculous pericarditis (TBP). METHODS: Two-hundred and forty-five patients with TBP were enrolled as a study group, including 140 males and 105 females. According to the general information of TBP patients in the study group, 115 patients with non-tuberculous pericarditis were recruited as the control group. Four ADA single nucleotide polymorphisms (SNPs; rs121908715, rs79281338, rs121908723, and rs61737144) and the rs2069707 locus of the IFN-gamma polymorphism were detected using PCR and Sanger sequencing. RESULTS: Carriers with the T allele at the rs121908715 locus of ADA had a higher risk of TBP (adjusted OR = 3.986, 95% CI = 1.858-8.718, p < 0.001). There was a significantly higher risk of TBP in carriers with the G allele at the rs121908723 locus of ADA (adjusted OR = 2.334, 95% CI = 1.084-5.102, p = 0.018). The risk of TBP was higher in carriers with the G allele at the rs2069707 locus of IFN-gamma (adjusted OR = 2.844, 95% CI = 1.399-5.853, p = 0.002). TB patients who carry both the T allele at the rs121908715 locus of ADA and the G allele of the IFN gamma gene, or who both carry the G allele at the rs126908723 locus of ADA and the G allele at the rs2069707 locus of IFN-gamma have a higher risk of contracting TBP (adjusted OR = 11.034, 95% CI = 2.781-15.328, p < 0.001 and adjusted OR = 10.315, 95% CI = 4.522-13.854, p < 0.001). CONCLUSION: The ADA SNPs rs12190871 and rs121908723, and the rs2069707 locus SNPs of IFN-gamma are risk factors for contracting TBP. PMID- 30017739 TI - Integrating proteomic and transcriptomic analyses of loquat (Eriobotrya japonica Lindl.) in response to cold stress. AB - The expression levels of many genes and the related proteins change and regulate physiological and metabolic processes that help the plant survive harsh environmental conditions under cold stress. Damage due to cold and freezing conditions often causes dynamic loss of loquat fruits in cultivated parts of northern China. To illustrate the mechanism of cold tolerance in the loquat, we combined the transcriptomic analysis with isobaric tags for relative and absolute quantification (iTRAQ) and RNA sequencing (RNA-Seq) data from loquat leaves under 4 degrees C treatment. The results showed 122,081 genes and 1210 differentially expressed genes (DEGs), while only 4582 proteins and 300 differential proteins (DEPs) were identified. Functional annotation and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated that metabolic pathways and biosynthesis of secondary metabolites were the two most common pathways in transcriptional and translational processes in this study. Comparison analysis of the transcriptomic and proteomic profiles, only 27 of 3620 genes were found to be shared both in DEGs and DEPs. Further validation with Real-Time Quantitative RT PCR analysis showed that the genes expression of NADP-dependent D-sorbitol-6 phosphate dehydrogenase, anthocyanin synthase and phenylalanine ammonia-lyase were consistent with the pattern of transcriptome profile, which suggested that these three genes might play vital roles in cold tolerance in loquat. PMID- 30017740 TI - Pink Adipocytes. AB - Adipocytes are lipid-rich parenchymal cells contained in a very plastic organ, whose composition can undergo striking physiologic changes. In standard conditions the organ contains white and brown adipocytes which play opposite roles: lipid storage to meet metabolic requirements and lipid burning for thermogenesis, respectively. During chronic cold exposure, white adipocytes transdifferentiate to brown, to increase thermogenesis, whereas in conditions of chronic positive energy balance brown adipocytes transdifferentiate to white, to increase energy stores. During pregnancy, lactation, and post-lactation, subcutaneous white adipocytes convert to milk-producing glands formed by lipid rich elements that can be defined as pink adipocytes. Recent fate-mapping data support the conversion of pink to brown adipocytes and the reversible conversion of brown adipocytes to myoepithelial cells of alveoli. PMID- 30017742 TI - Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide induced liver toxicity? AB - Hepatotoxicity occurs as a result of adverse effects of some xenobiotics on the liver, which is often the target tissue of toxicity for environmental chemicals. Rotenone, used as a natural pesticide, is an environmental poison reported to cause organ toxicity. This study investigated the protective effect of three flavonoids, catechin, quercetin and taxifolin (2,3-Dihydroquercetin) in rotenone induced hepatotoxicity. Male Wistar rats were administered rotenone for 10 days followed by post treatment with catechin (5, 10 and 20 mg/kg), quercetin (5, 10 and 20 mg/kg) or taxifolin (0.25, 0.5 and 1 mg/kg), respectively, for 3 days. Bioindices of oxidative stress and hepatocellular injury were measured in serum and tissue homogenate of animals. Rotenone intoxication produced liver damage in rats as reflected in alterations to activities/levels of enzymic and non-enzymic oxidative stress markers and enzymes linked with inflammation, as well as the transaminases, gamma glutamyl transpeptidase, bilirubin, and lactate dehydrogenase. Catechin, quercetin and taxifolin post treatment significantly attenuated these (p < 0.0001) rotenone-induced imbalances. Comparatively, quercetin displayed the best apparent ameliorative activity. It clearly showed superior activity to catechin. However, taxifolin appeared to show comparable activity to quercetin and better activity than catechin in some of the assays despite being administered at considerably lower doses. The results provide insight on the relative efficacy and structure-activity relationships of the selected flavonoids in ameliorating liver damage and also indicate that additional structural and metabolic factors may be involved in the structure activity relationships of flavonoids. PMID- 30017743 TI - Resveratrol prevents high-fat diet-induced obesity and oxidative stress in rabbits. AB - The rapid epidemiological progression of obesity worldwide has been associated with increased consumption of diets, rich in fat and sugar. Mediterranean diets rich in resveratrol are associated with reduced risk of obesity and oxidative stress. The aim of the experiment was to investigate the protective effect of resveratrol on high fat diet (HFD) induced obesity and oxidative stress changes in rabbits. Thirty rabbits divided into six groups of five animals each were used for the experiment: Group 1 = control (C), Group 2 = high fat diet (HFD) only, Group 3 = resveratrol 200 mg/kg (R200), Group 4 = resveratrol 400 mg/kg (R400), Group 5 = HFD + R200 and group 6 = HFD + R400. After four weeks of treatment, the HFD group showed significant (P < 0.05) increase in body weight of the animals, when compared with the groups co- administered with resveratrol and high-fat diet, and resveratrol alone groups. Activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) decreased significantly (P < 0.05) in the HFD groups co-administered with resveratrol when compared with HFD group only. In conclusion, administration of HFD to rabbits increased body weight and decreased antioxidant enzyme activities which were mitigated by resveratrol administration. PMID- 30017744 TI - Comparative proteomic analysis of Pogostemon cablin leaves after continuous cropping. AB - A proteomic approach was used to understand the molecular mechanisms underlying obstacles to the continuous cropping of Pogostemon cablin. We examined differences in protein abundance between control (CK) and continuously cropped (TR) P. cablin leaves at different time points (90, 150, and 210 days after culture). Comparative analysis by two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) revealed 183 differentially expressed protein spots, of which 87 proteins or isoforms were identified using mass spectrometry. Among these differentially expressed proteins (DEPs), 50 proteins or isoforms showed increased abundance and 37 proteins or isoforms showed decreased abundance in the TR sample compared with the abundance in the CK sample. Bioinformatic tools were used to analyze the DEPs. These proteins were classified into 12 categories according to clusters of orthologous groups (COG) analysis, with the majority being involved in post-translational modification, protein turnover, and chaperones, followed by carbohydrate transport and metabolism, and finally, energy production and conversion. Protein-protein interactions revealed that 18 DEPs were involved in energy metabolism, 6 DEPs were involved in stress response, and 4 DEPs were involved in amino acid biosynthesis. Continuous cropping altered the expression of proteins related to energy metabolism, carbohydrate metabolism, and amino acid metabolism in P. cablin leaves. Among these processes, the most affected was energy metabolism, which may be pivotal for resistance to continuous cropping. PMID- 30017745 TI - [Diagnostic efficiency of renal ultrasound after the first urine infection in infants]. AB - INTRODUCTION: Several authors question the performance of systematic renal ultrasound after first urinary tract infection (UTI) in young children, given the high sensitivity of prenatal ultrasounds to detect major malformations and the low prevalence of clinical relevant findings. The aims of this study are to evaluate the yield of renal ultrasound performed after the first UTI in patients aged less than 2 years and to analyse potential risk factors (RF) of altered renal ultrasound. PATIENTS AND METHODS: Retrospective study, including patients aged less than 2 years diagnosed with UTI in the Emergency Department between July 2013 and December 2014. Patients with an underlying nephro-urological pathology, previous UTIs and those without prenatal or post-infection renal ultrasound were excluded. Altered renal ultrasound was defined as the presence of dilated urinary tract or structural abnormalities. Potential RF analysed were: male, age less than 3 months, presence of fever and microorganism other than Escherichia coli. Univariate and multivariate logistic regression were performed. RESULTS: A total of 306 patients were included. Altered renal ultrasound was found in 35 cases (11.4%; 95% CI 8.3-15.5): 24 (68.6%) urinary tract dilation, and 11 (31%) structural abnormalities. Among the cases with altered ultrasound, 68.6% were male, 51.4% were younger than 3 months, 74.3% were febrile, and 31.4% were caused by microorganisms other than E. coli, compared to 45% (P=.009), 31.7% (P=.021), 78.2% (P=.597) and 10% (P=.001) of cases with normal ultrasound. In the multivariate analysis, age less than 3 months (OR 2.1; 95% CI 1.0-4.3, P=.05) and microorganism other than E. coli (OR 3.8; 95% CI 1.7-8.7, P=.002) remained as RF. CONCLUSIONS: The yield of renal ultrasound after the first UTI is low. Its indication should be individualised according to the presence of RF: age less than 3 months and microorganism other than E. coli. PMID- 30017746 TI - [Response to pregnancy in adolescents in the last 11 years. Reasons for consulting and risk factors. Authors reply]. PMID- 30017741 TI - Obesogenic Endocrine Disrupting Chemicals: Identifying Knowledge Gaps. AB - Endocrine disrupting chemicals (EDCs) are compounds that are part of everyday consumer products and industrial manufacturing processes. EDCs can interfere with the endocrine system, including the adipose tissue. Accumulating evidence from epidemiological, animal, and in vitro studies demonstrates that EDCs can alter body weight, adipose tissue expansion, circulating lipid profile, and adipogenesis, with some resulting in transgenerational effects. These outcomes appear to be mediated through multiple mechanisms, from nuclear receptor binding to epigenetic modifications. A better understanding of the signaling pathways via which these EDCs contribute to an obesogenic phenotype, the interaction amongst complex mixtures of obesogenic EDCs, and the risks they pose relative to the obesity epidemic are still needed for risk assessment and development of prevention strategies. PMID- 30017748 TI - Modulation of the endocannabinoid system by sex hormones: Implications for posttraumatic stress disorder. AB - The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations. PMID- 30017747 TI - Safety of Recanalization Therapy in Patients with Acute Ischemic Stroke Under Anticoagulation: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Intravenous thrombolysis treatment (IVT) and endovascular therapy (EVT) have been proved as fist-line beneficial option for eligible patients who have acute ischemic stroke (AIS) with major safety concern of symptomatic intracranial hemorrhage (sICH). Unfortunately, the emergency management of patients with AIS taking vitamin K antagonists and with international normalized ratio higher than 1.7 or taking new oral anticoagulants (NOACs) represents a great challenge. We aim to comprehensively determine the safety of EVT in patients under prior-stroke anticoagulants and IVT in patients under NOAC use. METHODS: Clinical researches published in the Embase, PubMed, and Cochrane Library electronic databases up to December 2017 were identified for analysis. Subgroup and sensitivity analyses were also conducted to evaluate the robustness of the conclusions. RESULTS: Overall, 9 studies involving 3885 patients met the inclusion criteria. The rate of sICH (risk ratio [RR] = .94, 95% CI = .61-1.47, P = .799), mortality (P = .495), and recanalization (P = .655) after EVT did not differ between patients under and those who were not under anticoagulants, although patients under anticoagulants were less likely to achieve good functional outcome (P < .001) than those who were not. Moreover, prior NOAC therapy was not significantly associated with increasing sICH in patients with AIS after IVT (RR = .79, 95% CI = .41-1.53, P = .492). CONCLUSIONS: Patients under anticoagulation appear to be safe after EVT with relatively lower rate of good outcome; furthermore, prior NOAC therapy was not associated with an increasing sICH rate after IVT. This offered a practical information to select appropriate therapeutic strategies for patients under anticoagulation, although the level of evidence seems to be quite shaky. PMID- 30017749 TI - Environmental stressors and alcoholism development: Focus on molecular targets and their epigenetic regulation. AB - Alcohol exposure and stressful events in life can induce long-lasting changes in physiology, behavior and gene expression patterns, eventually facilitating the development of psychiatric diseases like alcohol use disorders (AUD). Epigenetic mechanisms have been recently proposed to play a role in the cellular actions of alcohol via chromatin remodeling. Here we discuss interactions between stress and the pharmacological effects of alcohol, including the possibility that early exposure to, or withdrawal of, alcohol might induce stressful effects of their own. A specific aim is to describe novel molecular mechanisms by which stress, alcohol or their combined presentation impact on the epigenome. A key question is why only a fraction of the population progresses from regular, non-problematic, alcohol use to AUD, despite suffering from similar alcohol exposure. It is important to analyze how environmental factors, most notably stress, interact with the epigenetic machinery to increase vulnerability for AUD. The knowledge derived from this endeavor will be critical for the development of preventive strategies and new, drug- or gene-based, therapies. PMID- 30017750 TI - [Awake bilateral video-assisted thoracoscopic surgery for recidivist malignant pleural effusion]. PMID- 30017751 TI - [Relevance of fluoroquinolones prescriptions in medical service]. AB - INTRODUCTION: Fluoroquinolones (FQ) are antibiotics which favour the emergence of resistance and remain widely prescribed in the French hospital environment. A focus of prescription recommendation was published by the French Infectious Diseases Society (SPILF) in 2015 in order to preserve their use. The pneumology oriented medical service of Salon de Provence's hospital had high FQ consumption for the year 2015; thus a relevant assessment of prescriptions was carried out. METHODS: This retrospective study was conducted between January 1 and December 31, 2015 and concerned patients who received at least one FQ administration during their hospitalization. RESULTS: Thirty-eight per cent of the prescriptions were justified, 37 % were inappropriate and 25 % unjustified. The majority of unjustified prescriptions were for lung infections. Only 35 % of the patients received bacteriological documentation and 53 % of the prescriptions were reassessed at 48-72hours. Twenty-two per cent of the justified prescriptions showed non-conformities concerning the duration of prescriptions, the dosage or an association with another antibiotic. CONCLUSION: The diffusion of these results, combined with the implementation of corrective actions, should make it possible to improve the relevance of the FQ prescription. PMID- 30017752 TI - [A case of malformation of aortic arches simulating asthma]. AB - INTRODUCTION: Abnomalies of the aortic arches are rare and account for 1% of congenital cardiovascular malformations. They constitute one of the causes of compression of the airways with attacks of dyspnea sometimes simulating an asthma. We report the case of an infant with an anomaly development of aortic arches with impact breathing. CASE REPORT: It was a 22-month-old infant who consulted for a dyspnea with a type of stridor associated with a fat cough. This clinical table started 45 days after its birth and led to many hospitalizations in the pediatric emergency. Clinical exam found polypnea, with a wheezing, bronchial groan and diffuse sibilants on the auscultation. The chest X-ray revealed a slightly retractile right lung. The angioscanner of the thoracic and abdominal aorta showed a double aortic arch with retro-oesophageal left ventricular artery. A thoracotomy was performed and the operative sequences were simple. CONCLUSION: The congenital anomalies of the aortic arch are rare and varied, sometimes asymptomatic. This case reminds us that, in front of any recurrent or digestive respiratory signs in the infant, malformation of the aortic arches should be considered. PMID- 30017753 TI - [What contribution for mediastinoscopy in non-tumor specific mediastinal lesions?] AB - INTRODUCTION: The aim of our study was to assess the interest of cervical mediastinoscopy in the management of benign mediastinal lymphadenopathy. METHOD: We performed a single-center retrospective descriptive study over a period of 5 years (2013-2017) in the department of thoracic surgery of university hospital Hassan II of Fez. RESULTS: During this period, a total of 137 cervical mediastinoscopies were performed among which 68 for a benign disease. This represents a frequency of 49.63 %. There were 22 men and 46 women with a mean age of 43.76 years+/-17.08. Chest CT showed isolated mediastinal lymphadenopathy in 52 %, associated with pulmonary images in 35 %. Cervical mediastinoscopy led to pathological diagnosis in 94 %. The pathological results showed a sarcoidosis in 51.5 %, tuberculosis in 41.2 % and a lymph node echinococcosis in 1 case. CONCLUSION: Cervical mediastinoscopy remains a low risk modality in expert hands, which allows pathological diagnosis with excellent sensitivity, acceptable morbidity and no mortality in our experience. PMID- 30017754 TI - Surgery for Giant Calcified Herniated Thoracic Discs: A Systematic Review. AB - OBJECTIVE: The giant calcified herniated thoracic disc (HTD), a rare disease, is a challenge for surgeons because of its complications. This review aimed to confirm the surgical treatment, including surgical approach, results, and complications of HTDs. METHODS: This systematic review of the literature complies with the PRISMA guidelines and involves a search of PubMed, Embase, and the Cochrane Library for all papers describing surgical treatment of giant calcified HTDs in >=3 patients. Data on the surgical approach, change in neurologic impairment, and complications were extracted from the search results. RESULTS: A total of 11 studies, including 164 patients with giant calcified HTDs that met the inclusion criteria, were included in this systematic review. Of the 164 patients, 145 had myelopathy in giant calcified HTDs, and 8 surgical approaches were included. After the surgical treatment, the neurologic grades were improved in 69% of patients, remained unchanged in 22% of patients, and worsened further in 3% of patients at the final follow-up. Also, of the total patients analyzed, 3% had permanent neurologic deterioration, 4% patients had subarachnoid-pleural cerebrospinal fluid fistula complications, 30% had other complications, 4% had reoperation via transthoracic approach, 13% had permanent neurologic deterioration via the posterolateral approach, and 25% had permanent neurologic deterioration via the thoracoscopy approach. CONCLUSIONS: Surgical treatment can improve or stabilize neurologic impairment for most patients with giant calcified HTDs. We thus recommend the anterior thoracotomy approach for giant calcified HTDs because of the theoretical advantages over other approaches and the low rate of neurologic deterioration, subarachnoid-pleural cerebrospinal fluid fistula, and reoperation. PMID- 30017755 TI - Probe Laminotomy: A Simple Technique for Precise Lateral Gutter Placement in Cervical Expansive Laminoplasty. AB - BACKGROUND: In cervical expansive laminoplasty, precise placement of lateral gutters is important. Placing them too medially results in suboptimal canal expansion, and placing them too laterally results in facet joint violation. However, precise placement is often difficult. METHODS: We have included a simple procedure called probe laminotomy in cervical expansive laminoplasty since 2013. This technique consisted of identifying the location of the pedicles through a small laminotomy with medial facetectomy before making lateral gutters. A case control study was performed to compare the achieved postoperative canal area and duration of surgery between the original technique and the added probe laminotomy. RESULTS: The postoperative canal area was 21% larger in the probe laminotomy group compared with the standard technique group (P = 0.0003). There was no significant difference in duration of surgery between the groups. CONCLUSIONS: This technique facilitated more precise placement of the lateral gutter in cervical expansive laminoplasty, which resulted in a larger postoperative canal. This technique should be considered as an option in cervical expansive laminoplasty. PMID- 30017756 TI - Marked Guidewire Technique Prevents Complications of Percutaneous Pedicle Screws and Precisely Controls Depth: Technical Note. AB - OBJECTIVE: We sought to describe a novel modified guidewire technique used in the placement of percutaneous pedicle screws (PPSs), which enables safe and precise control of the depth of screw placement and prevents excessive advancement of the guidewire with low radiation exposure. PPSs have been widely used and have many advantages. However, inadvertent advancement of the guidewire may damage peripheral tissue or viscera, and repeated confirmation of the depth of screw and guidewire leads to extensive radiation exposure. METHODS: A modified guidewire with markers was used intraoperatively. The reading of the mark on the guidewire increased as the PPS advanced into the pedicle. The depth of the screw in the pedicle was calculated as the mark reading after each screw was rotated into the pedicle minus the initial mark reading. After all pedicle screws were placed, the positions of the screws were checked by C-arm or G-arm fluoroscopy. RESULTS: The modified guidewire was applied in 41 thoracic-lumbar fracture patients. The depths of the percutaneous screws were precisely controlled as planned. There were no inadvertent breaches of the anterior cortices of the vertebrae. No patients reported neurologic symptoms, and there was no screw misplacement detected. Surgeons had no radiation exposure, and patients were only exposed once to the radiation. CONCLUSIONS: The modified guidewire with markers is an effective device to precisely control the depth of PPSs and prevent complications of the guidewire in the placement of pedicle screws. PMID- 30017757 TI - Hyperglycemic Nonketotic Signal Changes of the Striatum: An Unusual Complication in the Setting of Neurosurgical Procedures. AB - BACKGROUND: Hyperglycemic nonketotic chorea is an uncommon complication of poorly controlled diabetes mellitus. Patients typically develop abnormal signal changes in the striatum on imaging studies. Whereas the condition is well reported in the medical literature, reports on this topic in the surgical literature are lacking. CASE DESCRIPTION: We report the first case of striatal hyperglycemic nonketotic signal changes occurring in the setting of a frontotemporal craniotomy for resection of a sphenoid wing meningioma. Postoperative magnetic resonance imaging (MRI) of the patient demonstrated restricted diffusion within the bilateral caudate nuclei, globus pallidus, putamen, and thalami in response to intraoperative hyperglycemia. Normalization of the patient's serum glucose levels postoperatively was followed by improvement in the radiographic abnormalities and their associated clinical sequelae. At the patient's last follow-up appointment 5 months after surgery, MRI demonstrated complete resolution of the abnormal signal changes to the patient's neurologic baseline. CONCLUSIONS: Although uncommon, striatal signal changes associated with nonketotic hyperglycemia should be recognized as a potential complication of surgery. Knowledge of this rare entity is important so that tight control of perioperative serum glucose can be achieved in diabetic patients to prevent this rare entity. PMID- 30017758 TI - Subdural Hygroma Following Endoscopic Third Ventriculostomy: Understanding the Pathophysiology. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) has overtaken the use of a ventriculoperitoneal shunt for the treatment of congenital hydrocephalus. Although ETV is relatively safe, several postoperative complications have been reported. One of the least described and understood complications is subdural hygroma following third ventriculostomy. METHODS: In this series, we retrospectively analyzed patients who were managed for postventriculostomy subdural hygroma and analyzed the possible factors responsible for this condition. RESULTS: A total of 248 patients who underwent ETV between 2014 and 2016 were included in this study. Twelve patients (4.8%) had developed subdural hygroma, including 6 patients with bilateral hygroma, 2 with contralateral hygroma, and 4 with ipsilateral subdural hygroma. Only 4 patients (1.6%) were symptomatic, with complains of pseudomeningocele, persistent vomiting, or headache. Significant mass effect was present in 2 patients with unilateral subdural hygroma, which improved after placement of a subduroperitoneal shunt. In 1 patient, the subdural hygroma decreased with persistent ventriculomegaly and improved after ventriculoperitoneal shunt implantation. One patient with posttraumatic hydrocephalus who had a bilateral subdural hygroma following ETV improved with conservative management. At a 12-month follow-up, all patients remained asymptomatic. CONCLUSIONS: Post-ETV subdural hygroma may result from poor absorption of cerebrospinal fluid (CSF) in the subarachnoid space, dysfunction of the stoma with persistence of the ventriculosubdural fistula, or altered CSF cytology, such as hemorrhage. Most of these patients remain asymptomatic and improve with time. Symptomatic patients should be properly evaluated for the cause of the formation of subdural hygroma, which will guide the appropriate interventions. PMID- 30017759 TI - Hemodynamic Changes in the Treatment of Multiple Intracranial Aneurysms: A Computational Fluid Dynamics Study. AB - BACKGROUND: Intracranial aneurysm rupture is associated with a high mortality and disability despite modern medical care. Multiple aneurysms occur in nearly 16% of patients, and imaging studies of naturally occurring multiple aneurysms are valuable for computational fluid dynamics studies. In this study, we describe and analyze the hemodynamic changes produced in a distal aneurysm after the treatment of a proximal aneurysm. METHODS: Between January 2008 and December 2017, 24 cases of multiple intracranial aneurysms of the same vascular tree were treated in our center. Full carotid segmentations from digital subtraction angiography, computed tomography angiography, or magnetic resonance angiography were obtained, and transient pulsatile simulations were performed using computational fluid dynamics software. Output variables included maximum peak systole wall shear stress (WSS), minimum mid-diastolic WSS, maximum systolic pressure, low shear area, and high shear area both before and after treatment of the proximal aneurysm. RESULTS: The mean size of ruptured and unruptured aneurysms was 7.05 and 5.23 mm, respectively (P = 0.035), with respective aspect ratios of 1.22 and 2.04 (P = 0.001). Maximum peak systole WSS was lower and minimum mid-diastolic WSS was higher in unruptured aneurysms (P = 0.04 and 0.034, respectively). After treatment of the proximal aneurysm, low shear area in the distal aneurysm increased from 54.15% to 56.93% (P = 0.02). The opposite effect is noted in aneurysms with an interaneurysmal distance <10 mm. Posttreatment peak systole pressure was also increased significantly (P = 0.03). CONCLUSIONS: The hemodynamic changes in a distal aneurysm after treatment of a proximal aneurysm showed an unfavorable profile associated with an increased theoretical risk of bleeding. PMID- 30017760 TI - Primary Spinal Cord Small-Cell Glioblastoma: Case Report and Literature Review. AB - BACKGROUND: Approximately 2%-10% of all central nervous system tumors are primary spinal cord tumors (SCTs). Spinal cord glioblastoma is a rare tumor type accounting for 1%-3% of all SCTs and 7.5% of all spinal cord gliomas. Notably, the small-cell variant of spinal cord glioblastoma is even rarer with only 2 previously reported cases. CASE DESCRIPTION: We present herein a case report of a rare primary spinal cord glioblastoma in a 48-year-old patient with a 2-month history of numbness in the left arm and mild cervical pain radiating to the occipital zone. Clinical examination revealed hypoalgesia and thermal dissociation of the left arm and the ipsilateral superior part of the trunk treated through subtotal surgical resection followed by adjuvant chemotherapy and radiotherapy. Histologic examination of the surgical tumor specimen revealed features of the small-cell spinal cord glioblastoma. CONCLUSIONS: To the best of our knowledge, this is only the third reported case of small-cell spinal cord glioblastoma. The aggressive nature of this tumor variant reduces overall survival rate regardless of the treatment. PMID- 30017761 TI - Involved Small Arteries in Patients Who Underwent Microvascular Decompression for Hemifacial Spasm. AB - BACKGROUND: Microvascular decompression (MVD) has become widely accepted as first line therapy for hemifacial spasm. However, not all patients are candidates for the procedure, and some surgeons ignore arterioles that represent the actual underlying cause of the condition. The aim of this study was to address the role of involved arterioles in management of MVD in patients with hemifacial spasm. METHODS: Data were collected from 765 consecutive patients who underwent MVD from January 2009 to August 2010 in our hospital. Electromyographic abnormal muscle response and Z-L response were used to identify the involved arterioles. All patients were followed for 25-35 months. RESULTS: Compression by the involved arterioles was identified in 20 patients. The most commonly involved arteriole was a branch of the anterior inferior cerebellar artery, followed by the posterior inferior cerebellar artery. During follow-up, effective outcomes were achieved in 93.6% of patients with involved arterioles. There was no MVD-related mortality. CONCLUSIONS: The main reason for failed MVD is that the involved offending vessel is not correctly identified. Intraoperative abnormal muscle response and Z-L response are good supplementary measures to identify involved arterioles. In addition, not isolating or coagulating the involved arterioles increases the risk associated with the operation. PMID- 30017762 TI - Herniated Discs at the Cervicothoracic Junction. AB - BACKGROUND: Disc herniations at the cervicothoracic junction (C7-T1 level) are unusual, and there have only been a few studies of patients with herniated C7-T1 discs. In addition, previous studies did not focus on the mechanism and causes of solitary cervicothoracic junction disc herniation. The authors investigated the characteristics, symptom duration, clinical course, and biomechanics of cervicothoracic junction disc herniation by comparing patients with C7-T1 disc herniation (C7-T1 group) with control groups. METHODS: Thirty-six patients who underwent solitary C7-T1 single-level disc surgery between 2006 and 2015 were included. For radiographic comparison, patients in a herniated C5-C6 disc group and the healthy control group were cohort matched. RESULTS: In the C7-T1 group, the disc herniation mainly occurred in the foraminal space (P < 0.0001). The C7 T1 group was significantly associated with a history of trauma (P < 0.0001). In addition, the cervical vertebral body was more readily observed on plain lateral radiographs in the C7-T1 group (7.36 +/- 0.068). Patients in the C5-C6 group tended to have the sternal notch more frequently located above the T2-T3 disc space than other groups (P = 0.014). CONCLUSIONS: C7-T1 disc herniation demonstrates unique characteristics. Understanding the features of disc herniation at the cervicothoracic junction would be helpful for optimal care. PMID- 30017764 TI - Neuroendoscopic Management of Coexisting Congenital Agenesis of Bilateral Foramen of Monro with Aqueductal Stenosis and Chiari Malformation: Case Report and Review of the Literature. AB - BACKGROUND: Bilateral occlusion of the foramen of Monro with aqueductal stenosis is a rare entity. Only 1 previous case has been reported in the literature. CASE DESCRIPTION: We present a 25-year-old female who presented with chronic headache of 7 years duration. Neurologic examination revealed only papilledema. Imaging showed symmetrical dilation of both lateral ventricles with mild dilation of the third ventricle and a normal fourth ventricle, suggesting occlusion of both foramina of Monro with membranous web formation in the upper part of the aqueduct. There was tonsillar herniation without syrinx. She underwent neuroendoscopic foraminoplasty, septostomy, and third ventriculostomy. The patient experienced total relief of headache and showed reduced volume of both lateral ventricles at follow-up. CONCLUSIONS: Bilateral occlusion of foramen of Monro with aqueductal stenosis and tonsillar herniation is rare cause of obstructive hydrocephalus, and can be managed effectively with neuroendoscopic procedure. PMID- 30017765 TI - Optical Frequency Domain Imaging Evaluation of Progressive Carotid Plaque and In Stent Restenosis Lesion with Multiple Neovascularizations. AB - BACKGROUND: Neovascularization (NV) plays an important role in plaque progression and plaque vulnerability. However, visualization of NV is difficult using standard imaging tools. Recently, optical frequency domain imaging (OFDI) has provided images of intraplaque microstructure that could not be visualized by previous imaging modalities. Here we report a rare case of NV in the carotid plaque detected both before carotid artery stenting (CAS) and in an in-stent restenotic lesion using OFDI. CASE DESCRIPTION: A 71-year-old man with asymptomatic severe left carotid artery stenosis was scheduled for CAS. The degree of stenosis had progressed during short-term follow-up. Preoperative magnetic resonance imaging suggested vulnerable plaque. We performed OFDI to evaluate plaque morphology before and after the CAS procedure. Before CAS, OFDI revealed multiple NVs in the carotid plaque, localized around the most stenotic lesion. After CAS, OFDI showed good apposition of the stent to the vascular wall. At 5 months after CAS, in-stent restenosis was detected, which was treated by CAS. Before CAS of the restenotic lesion, OFDI revealed multiple NVs in the restenotic lesion inside the stent struts. After stenting, no ischemic lesions were detected, and restenosis did not occur again over the 1-year follow-up period. CONCLUSIONS: In carotid artery plaque, NV might correlate with plaque progression and in-stent restenosis. OFDI enables advanced evaluation of NVs in the carotid artery plaque. PMID- 30017763 TI - Effectiveness of Cadaveric Simulation in Neurosurgical Training: A Review of the Literature. AB - OBJECTIVE: Increased restrictions on working hours and the resultant decrease in theater time coupled with greater scrutiny to demonstrate proficiency at surgical tasks has resulted in the incorporation of simulators for surgical training. This literature review describes the use of cadaveric simulators in postgraduate neurosurgical training, with the aim to analyze their effectiveness in improving surgical performance. METHODS: An electronic literature search of the MEDLINE, Embase, and Cochrane Library databases was conducted to identify studies that look at the efficacy of cadaveric simulation in neurosurgical training. Studies that were eligible were those that assessed either objectively or subjectively the effectiveness of human cadaver models in cranial or spinal neurosurgical training. Studies that did not assess efficacy on training, looked at animal cadavers, or noncadaveric simulators were excluded. RESULTS: Twelve studies were deemed to meet the eligibility criteria. Only 4 of the studies used objective measures to assess the effectiveness of cadaveric simulators on training. Most studies reported a positive impact of cadaveric simulators on training. CONCLUSIONS: Most studies identified in this review failed to provide strong objective evidence for effectiveness in achieving competency and good outcomes in the theatres. Lack of use of validated skills assessment tools prevented studies from associating cadaveric training with improvement in operating skills. Future studies should aim to address these shortcomings and focus on validating cadaveric simulation, ensuring only those that improve performance of both technical and nontechnical skills are pursued. PMID- 30017766 TI - Deep Decompression of the Lateral Femoral Cutaneous Nerve Under Local Anesthesia. AB - OBJECTIVE: Meralgia paresthetica is a mononeuropathy of the lateral femoral cutaneous nerve (LFCN) caused by compression around the inguinal ligament. We report a surgical alternative for the treatment of meralgia paresthetica under local anesthesia and its outcomes. METHODS: We operated on 12 patients with unilateral meralgia paresthetica whose age at surgery ranged from 62 to 75 years. The mean postoperative follow-up period was 19 months. Microsurgical deep decompression of LFCN was performed with the patient under local anesthesia. Clinical outcomes of surgical treatment were assessed based on the patient's most recent follow-up visit and were classified into 3 categories: complete, partial, or no relief of symptoms. Symptoms of pain or numbness in the anterolateral part of the thigh were evaluated, using a visual analog scale, before surgery and after surgery, i.e., at the most recent follow-up visit. RESULTS: All patients reported symptom improvement: complete relief in 9 patients (75%) and partial relief in 3 patients (25%). In the 3 patients with partial relief, the remaining symptoms did not affect their daily living. Overall, the visual analog scale scores were significantly improved in all patients (P < 0.05), and no patient experienced postoperative recurrence of their symptoms at the time of the last follow-up visit. CONCLUSIONS: Symptoms of meralgia paresthetica can resemble those of a lumbosacral disorder. Microsurgical deep decompression under local anesthesia produces good surgical outcomes. The use of local anesthesia contributes not only to reduction of pain during surgery but also eliminates excessive surgical procedures and reduces the duration of hospital stay. PMID- 30017767 TI - Granular Cell Tumor of the Neurohypophysis: 3 Cases and a Systematic Literature Review of 98 Cases. AB - BACKGROUND: Granular cell tumors (GCTs) of the neurohypophysis are rare neoplastic diseases of the pituitary. Because of the rare nature of the disease, previous descriptions have been limited to single-case studies, small series, or simple reviews. METHODS: We reported 3 cases in our medical center and systematically reviewed 98 cases who met inclusion criteria. Data were gathered on different aspects of GCTs' characteristics, including demographics, clinical features, laboratory features, histological features, immunocytochemical features, radiologic features, and treatment to elucidate any associations useful in determining pathogenesis and appropriate treatment. RESULTS: Female sex was significantly associated with GCTs (P < 0.001). The most common presenting symptom and tentative diagnosis were ophthalmologic defects in 61.2% and pituitary adenoma preoperatively in 18.4%, respectively. Most neurohypophysial GCTs possess immunopositivity for S-100 protein (59.1%, 26/44) and negative staining for glial fibrillary acidic protein (69.8%, 30/43). CONCLUSIONS: These findings lend strong support to the suggestion that tumors probably remain in the transitional cell type. To our knowledge, our systematic review presents the largest number of symptomatic cases ever enumerated, with 98 cases meeting the inclusion criteria. PMID- 30017768 TI - Anterior Greater Auricular Point: Novel Anatomic Landmark to Facilitate Harvesting of the Greater Auricular Nerve. AB - BACKGROUND: The greater auricular nerve (GAN) may be used as a nerve graft during neurosurgical procedures to repair damaged nerves. There is extensive literature on localization of the GAN at the posterior triangle of the neck, but objective information on localization of the GAN at the anterior triangle of the neck close to cranial neurosurgical fields is lacking. The aim of this study was to introduce simple and reliable landmarks to localize the GAN at the anterior triangle of the neck to facilitate its harvest during neurosurgical procedures. METHODS: The GAN was exposed bilaterally in 11 cadaveric specimens at the point of crossing the anterior border of the sternocleidomastoid muscle (anterior greater auricular point [AGA]). Distances from the AGA point to the angle of the mandible and the tip of the mastoid process were measured. Additionally, the location of the crossing point between the GAN and an imaginary line passing through the mastoid tip and the angle of the mandible (M-A line) was found relative to these bony landmarks. RESULTS: Mean (+/-SD) distances from the AGA point to the mastoid tip and the angle of the mandible were 29.1 +/- 3.4 mm and 27.5 +/- 4.5 mm, respectively. The GAN was always found to cross the M-A line in its middle third (mean 48.2% +/- 6.9% from the mastoid tip). CONCLUSIONS: The AGA point and the M-A line are reliable landmarks for locating the GAN at the anterior triangle of the neck and for helping neurosurgeons expose and harvest the GAN efficiently. PMID- 30017770 TI - Temporomandibular joint arthritis: Clinical, orthodontic, orthopaedic and surgical approaches. AB - Rheumatic diseases (RD) of the temporomandibular joints (TMJs) are increasingly frequent affections and unfortunately often confused with "classic" manducatory dysfunctions (disk dislocation, myofascial pain syndroms). Their diagnosis is mandatory, given the major subsequent craniofacial disorders, which may occur (mandibular condylar hypoplasia, facial hyperdivergence, remodelling of the condylar unit, ankylosis), although the clinical implementation remains unspecific. The delayed diagnosis may be explained by the embryologic, anatomical and physiological characteristics of this joint. Magnetic resonance imaging (MRI), scans and more recently cone-beam computed tomography (CBCT) allow to diagnose its early signs (alteration of the disc-ligament complex, intra articular effusion, osteochondral lesions). The treatment of TMJ rheumatic diseases (RD) is not consensual, and often includes a non surgical phase (hygiene and dietary rules, non-steroid anti-inflammatory drugs (NSAI), occlusal splints, and/or a surgical phase for the advanced stages (joint washing, orthognathic surgery, or joint surgery), and non responding patients to the medical treatment of inflammatory rheumatism. Orthodontics will be useful to correct dento-alveolar compensations, while monitoring, however, the impact on joint function. PMID- 30017769 TI - Postarachnoiditis Anterior Spinal Arachnoid Cyst Formation with Compressive Myelopathy: Report of 2 Cases. AB - BACKGROUND: Spinal cystic arachnoiditis is a rare complication of a subarachnoid haemorrhage or infectious meningitis. The inflammatory process leads to fibrosis, adhesions, and in severe cases cyst formation. Large arachnoid cysts are an uncommon cause of compressive myelopathy. The majority are located posterior of the spinal cord at the thoracic level. Anterior cyst formation is exceptional, especially at the cervical region. CASE DESCRIPTION: We present 2 cases of progressive myelopathy secondary to anterior arachnoid cyst formation. In a 54 year-old female a large anterior symptomatic thoracic cyst arose 4 years after rupture of a posterior inferior cerebellar artery aneurysm. The other 59-year-old patient, however, developed an anterior cervical cyst only weeks after a varicella meningoencephalitis. Both female patients were treated with a decompressive laminectomy and wide fenestration of the cysts. Partial recovery was obtained in 1 patient, but there was no improvement in the other case. CONCLUSIONS: Spinal cystic arachnoiditis with anterior cyst formation is an extremely rare complication of subarachnoid haemorrhage and infectious meningitis but can cause severe neurologic deficits. Clinicians should be aware of this rare complication. Due to the risk of irreversible spinal cord injury, rapid surgical intervention is recommended in most cases. PMID- 30017771 TI - ? PMID- 30017772 TI - Middle phalanx maturation of the third finger (MPM) method in the evaluation of skeletal age in a growing orthodontic patient. AB - A 12-year-old boy consulted with a severe skeletal class II malocclusion, proclination of the upper incisors with diastemas in the upper arch, 11mm of overjet, a Bolton discrepancy, deep bite and a severe curve of Spee. Treatment included evaluation of the skeletal age using the middle phalanx maturation of the third finger (MPM) method in order to assess the pubertal growth spurt. When this period was reached, a Herbst was applied for 8 months; then fixed orthodontic treatment was delivered for 16 months. At the end of orthodontic treatment, restorative therapy was given to improve the shape of the upper incisors. Retention was provided with a Boston splint in the upper arch and a spring retainer in the lower arch. Precise evaluation of a patient's skeletal age can shorten orthodontic treatment and enhance compliance. PMID- 30017773 TI - A predictive model of advancement genioplasty in Class III bimaxillary surgical cases. AB - INTRODUCTION: The aim of our study was to try to standardize the surgeon's clinical sense in order to avoid revision surgery. MATERIALS AND METHODS: Twenty nine patients with skeletal Class III treated by bimaxillary surgery were selected according to inclusion and exclusion criteria. These patients were divided into two groups according to the type of surgery: Group 1 (G1): bimaxillary surgery alone, and Group 2 (G2): bimaxillary surgery with genioplasty. The study was conducted based on the presurgical (t0) and postchirurgical (t1) lateral cephalograms. The different changes were compared between the two groups using the Mann-Whitney Test. One way and multiple linear regression analyses were used to determine the variables influencing the amount of displacement of the chin fragment during the genioplasty procedure. The significance level was fixed at 0.05. RESULTS: The labiomental profile was significantly more improved in group G2 (bimaxillary surgery with genioplasty), the aesthetic changes included the thickness increase of the lower labial sulcus and soft tissue pogonion, and also the reduction of the labiomental angle (P<0.05). Only the presurgical value of the labiomental angle would influence the amount of chin displacement. Starting from the regression analysis, we suggested a predictive equation allowing to predict this amount of displacement, based on the presurgical value of the labiomental angle. CONCLUSION: The analysis of changes (specifically the aesthetic ones) between the two groups of patients, allowed the proposal of a model predicting the amount of chin displacement performed in genioplasty group, based on the presurgical parameters. This model could contribute to determine an indicative value for bimaxillary surgery with additional genioplasty. PMID- 30017774 TI - ? PMID- 30017775 TI - ? PMID- 30017776 TI - SGLT2 inhibition and glucagon secretion in humans. AB - With the increasing prevalence of type 2 diabetes (T2D), therapies aimed at delineating diabetes pathophysiology and understanding their mechanisms of action are of critical importance. As such, growing interest in the clinical pharmacology of sodium-glucose cotransporter 2 (SGLT2) and its inhibition by gliflozins in the treatment of T2D is becoming increasingly evident. SGLT2 inhibition results in urinary glucose excretion, thereby reducing blood glucose levels. The importance of this homoeostasis mechanism is evident from several clinical trials demonstrating that patients taking this class of compounds have reductions in glycaemia, body weight and blood pressure compared with other antidiabetic agents. Yet, while such outcomes are very encouraging, some studies have reported elevated plasma glucagon levels and endogenous glucose production (EGP), two traits that are already prevalent in T2D. However, these findings were later explained by the specific expression of SGLT2 by pancreatic alpha cells, where glucagon secretion is directly regulated. Although conflicting data are now emerging on SGLT2 regulation of glucagon secretion, as SGLT2 is not expressed in the intestines, circulating glucagon concentrations are most likely of pancreatic origin. Thus, the present review considers the mechanism of action of SGLT2 inhibitors in the regulation of glucagon secretion, and the discrepancies in data from mice compared with people. The pragmatic use of human islets to accurately decipher SGLT2 inhibition in the regulation of glucagon secretion is also discussed. PMID- 30017777 TI - Differential effects of citalopram on sleep-deprivation-induced depressive-like behavior and memory impairments in mice. AB - Recently there is increasing concern over the association between sleep deprivation (S-Dep) and depression. Mounting evidence suggests that S-Dep might be a risk factor for depression. However, underlying molecular mechanism remains elusive and currently there is no effective therapy to negate the effects of S Dep. In this study, we aimed to examine whether subchronic treatment of citalopram (CTM), an antidepressant, can attenuate the negative effects of S-Dep in mice. Three-month-old C57BL/6J mice were divided into control, S-Dep, CTM control and CTM + S-Dep groups. CTM and CTM + S-Dep group treated with citalopram for 5 consecutive days at a dose of 10 mg/kg per day before experimental procedure. S-Dep and CTM + S-Dep group mice were sleep deprived for 24 h using an automated treadmill method. Our results revealed that S-Dep animals displayed an increased depressive-like behavior in forced swim, tail suspension and sucrose preference test and anxiety-like behavior in the open field and elevated plus maze, as well as disrupted spatial memory in Morris water maze. Western blotting analysis revealed that S-Dep caused reductions in the levels of the plasticity- and memory-related signaling molecules i.e. pCaMKII and pCREB in the hippocampus. Moreover, S-Dep animals showed synaptic plasticity deficits in the Schaffer collateral pathway. Interestingly, subchronic CTM treatment prevented S-Dep induced decrease in pCaMKII and pCREB levels in the hippocampus. Furthermore, CTM treatment prevented S-Dep-induced deficits in synaptic plasticity, spatial memory, depressive-like behavior in sucrose preference test and anxiety-like behavior in open field test but not in force swim, tail suspension and elevated plus maze test. This data suggests differential effects of CTM on S-Dep associated behavioral alterations and cognitive impairments. PMID- 30017778 TI - Speech structure links the neural and socio-behavioural correlates of psychotic disorders. AB - BACKGROUND: A longstanding notion in the concept of psychosis is the prominence of loosened associative links in thought processes. Assessment of such subtle aspects of thought disorders has proved to be a challenging task in clinical practice and to date no surrogate markers exist that can reliably track the physiological effects of treatments that could reduce thought disorders. Recently, automated speech graph analysis has emerged as a promising means to reliably quantify structural speech disorganization. METHODS: Using structural and functional imaging, we investigated the neural basis and the functional relevance of the structural connectedness of speech samples obtained from 56 patients with psychosis (22 with bipolar disorder, 34 with schizophrenia). Speech structure was assessed by non-semantic graph analysis. RESULTS: We found a canonical correlation linking speech connectedness and i) functional as well as developmentally relevant structural brain markers (degree centrality from resting state functional imaging and cortical gyrification index) ii) psychometric evaluation of thought disorder iii) aspects of cognitive performance (processing speed deficits) and iv) functional outcome in patients. Of various clinical metrics, only speech connectedness was correlated with biological markers. Speech connectedness filled the dynamic range of responses better than psychometric measurements of thought disorder. CONCLUSIONS: The results provide novel evidence that speech dysconnectivity could emerge from neurodevelopmental deficits and associated dysconnectivity in psychosis. PMID- 30017779 TI - The prevalence of psychological distress in Parkinson's disease patients: The brief symptom inventory (BSI-18) versus the Hopkins symptom checklist (SCL-90-R). AB - The prevalence of psychological distress in Parkinson's disease (PD) patients has been evaluated by many different assessment instruments and with diverse control groups. The most frequently used distress symptom scale has been the Hopkins Symptom Checklist (SCL-90-R), although it contains many symptoms with problematic validity clinically. The 18-item subscale of the SCL-90-R, the Brief Symptom Inventory (BSI-18) has recently been shown to have a sufficient validity to screen for the prevalence of psychological distress (somatization) in PD patients. We have performed a clinimetric analysis by comparing the BSI-18 with SCL-90-R relevant subscales in PD patients. Our micro-analysis has focused on the Mokken model to test the scalability of the subscales. The macro-analysis has focused both on effect size statistics and the normative level of psychological distress with reference to the Italian general population data using T-score metric. The Mokken analysis indicated acceptable scalability for all the subscales of BSI-18. The effect size statistics identified somatization in both BSI-18 and SCL-90-R as the most prevalent and intense symptom of psychological distress. The T-score metric identified the phobic anxiety subscale of SCL-90-R to be clinically much more important than the BSI-18 anxiety subscale in the PD patients. We have found the SCL-90-R subscale of phobic anxiety and the BSI-18 somatization subscale most clinically valid when measuring psychological distress in PD patients. PMID- 30017780 TI - Carbamoylated erythropoietin induces a neurotrophic gene profile in neuronal cells. AB - Erythropoietin (EPO), a cytokine molecule, is best-known for its role in erythropoiesis. Preclinical studies have demonstrated that EPO has robust neuroprotective effects that appear to be independent of erythropoiesis. It is also being clinically tested for the treatment of neuropsychiatric illnesses due to its behavioral actions. A major limitation of EPO is that long-term administration results in excessive red blood cell production and increased blood viscosity. A chemical modification of EPO, carbamoylated erythropoietin (CEPO), reproduces the behavioral response of EPO in animal models but does not stimulate erythropoiesis. The molecular mechanisms involved in the behavioral effects of CEPO are not known. To obtain molecular insight we examined CEPO induced gene expression in neuronal cells. PC-12 cells were treated with CEPO followed by genome-wide microarray analysis. We investigated the functional significance of the gene profile by unbiased bioinformatics analysis. The Ingenuity pathway analysis (IPA) software was employed. The results revealed activation of functions such as neuronal number and long-term potentiation. Regulated signaling cascades included categories such as neurotrophin, CREB, NGF and synaptic long term potentiation signaling. Some of the regulated genes from these pathways are CAMKII, EGR1, FOS, GRIN1, KIF1B, NOTCH1. We also comparatively examined EPO and CEPO-induced gene expression for a subset of genes in the rat dentate gyrus. The CEPO gene profile shows the induction of genes and signaling cascades that have roles in neurogenesis and memory formation, mechanisms that can produce antidepressant and cognitive function enhancing activity. PMID- 30017781 TI - Serum level of brain-derived neurotrophic factor in Parkinson's disease: a meta analysis. AB - Brain-derived neurotrophic factor (BDNF), a critical modulator in the neurodevelopment and maintenance of both central and peripheral nervous systems, is regarded as a potential therapeutic target of Parkinson's disease (PD). However, its association with PD remains unclear and the data are inconsistent. To explore the correlation, studies reporting BDNF levels in PD patients and healthy controls are searched and a sample of 1496 participants are pooled in the meta-analysis, demonstrating significantly decreased serum levels of BDNF in PD patients when compared with the healthy controls (SMD = -1.03; 95% CI [-1.83, 0.23]; P = .012). Meta-regression analysis indicates gender is an important confounding factor (Adj R2 = 69.20%, p = .004, I2 res = 90.64%), whereas age (Adj R2 = 11.91%, P = .95, I2 res = 96.86%), H-Y stages of PD progression (Adj R2 = 30.18%, P = .612, I2 res = 96.62%) and MoCA score assessed cognitive impairment (Adj R2 = 2.18%, P = .517, I2 res = 64.41%) show few moderating effects. The research provides evidence of moderate quality that blood levels of BDNF are decreased in PD patients despite various influencing factors, supporting an association between decreased level of peripheral BDNF and PD. PMID- 30017783 TI - Alpha-fetoprotein response following transarterial chemoembolization indicates improved survival for intermediate-stage hepatocellular carcinoma. AB - BACKGROUND: To investigate the clinical value of the alpha-fetoprotein (AFP) response following transcatheter arterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma (HCC). METHODS: Data on patients with Barcelona Clinic Liver Cancer B staging system were analyzed. An AFP response was defined as a decrease in AFP of more than 20% after a TACE session. The association between AFP response and treatment outcome regarding imaging response and overall survival (OS) was explored. Cox proportional hazards models were applied to identify independent risk factors for OS after TACE. RESULTS: Of the enrolled 376 patients with elevated serum AFP >20 ng/mL, 214 (57%) with AFP responses were identified. AFP responders had improved median survival than non responders (20 vs. 12 months, P = 0.002). AFP response was significantly correlated with imaging response (P < 0.001). The Cox proportional hazards model revealed that AFP response was an independent factor for OS (hazard ratio, 0.59; 95% confidence interval, 0.45-0.78; P < 0.001). In stratified analyses, an AFP response achieved improved survival in patients with tumor diameters <=5 cm, diameters >5 cm, tumor number <=3 and without underlying cirrhosis. CONCLUSIONS: The AFP response indicates enhanced survival after TACE in patients with intermediate-stage BCLC. PMID- 30017784 TI - Recurrent pyogenic cholangitis - an independent poor prognostic indicator for resectable intrahepatic cholangiocarcinoma: A propensity score matched analysis. AB - BACKGROUND: Recurrent pyogenic cholangitis (RPC) is a known risk factor for intrahepatic cholangiocarcinoma (ICC), whether it represents a poor prognostic factor remains controversial. The aim of this study was to investigate the post hepatectomy oncological outcomes of patients with ICC and coexisting RPC. METHOD: A retrospective analysis with propensity score matching (PSM) was performed for comparison between ICC patient with and without RPC. RESULTS: There were 143 patients with ICC with a median follow-up of 21 months. RPC was diagnosed in 18% of patients. The time from RPC diagnosis to ICC diagnosis was 137(47-481) months. The 3-year disease-free (DFS) and overall survival for the whole population was 34% and 43% respectively. Preoperative child score, elevated carcinoembryonic antigen, presence of microvascular invasion, multiple tumours, presence of postoperative complications and RPC were independent factors for DFS and OS. After PSM, 60 ICC patients who did not have RPC were compared with 20 ICC patients with RPC. Patients with RPC had significantly worse median DFS (10 vs 23 months, P = 0.020) and OS (15 vs 45 months, P = 0.004) when compared to the patients without RPC. CONCLUSION: RPC represents a poor prognostic factor affecting outcomes after hepatectomy for patients with ICC. PMID- 30017785 TI - Collision risk mitigation of Varian TrueBeam linear accelerator with supplemental live-view cameras. AB - BACKGROUND: Noncoplanar radiation therapy techniques such as 4pi have potential dosimetric advantages but introduce complexities in treatment delivery that increase the risk for collision. Direct or remote visual confirmation of clearance is a safeguard against collisions of the gantry, couch, and patient. With our institution's Varian TrueBeam system, we identified configurations that cannot be visualized with the included closed-circuit television cameras. At our practice, electronic, portal imaging device (EPID) collision risk also exists because of the routine deployment to capture exit-dose images for treatment quality assurance. We propose a simple, cost-effective solution using network cameras to help eliminate blind spots that permits safe, noncoplanar arrangements with an EPID-acquired exit dose. METHODS AND MATERIALS: Two Panasonic cameras were installed overhead while a third Panasonic camera was mounted onto the pedestal to monitor the couch undersurface. Live views from each camera were accessed with a web-based client. The EPID and gantry were visually assessed at 52 couch and gantry rotational angle configurations at 6 couch translational positions. Visibility was compared for the standard and supplemental camera setups at each configuration (chi2 test). RESULTS: Of the 294 assessable couch gantry configurations, the standard camera setup had limited visibility of either gantry or EPID for 146 configurations compared with 72 configurations with additional cameras (51% blind-spot reduction; P < .01). An 87% blind-spot reduction was observed for our laterally centered, cranial-based, couch translational position (P < .01). CONCLUSIONS: The supplemental cameras were simple, effective additions for collision detection, especially for noncoplanar radiation therapy with EPID-acquired, exit-dose imaging. Over half of the assessable noncoplanar configurations had blind spots using standard cameras, which was reduced to <25% with additional cameras. In practice, there were almost no blind spots for patients with brain tumors who were treated with our templated beam arrangements. Using live-view camera feeds, vault re-entry to visually confirm clearance was reduced approximately 10-fold, which increased the treatment efficiency. In the most recent 12 months, no collision or near collision events have been reported. PMID- 30017782 TI - Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Gottingen minipigs. AB - OBJECTIVE: The worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet induced obesity (DIO) models in rodents have provided important insights into the pathophysiology of obesity and, in most instances, are the first in line for exploratory pharmacology studies. To deepen the relevance towards translation to human patients, we established a corresponding DIO model in Gottingen minipigs (GM). METHODS: Young adult female ovariectomized GM were fed a high-fat/high energy diet for a period of 70 weeks. The ration was calculated to meet the requirements and maintain body weight (BW) of lean adult minipigs (L-GM group) or increased stepwise to achieve an obese state (DIO-GM group). Body composition, blood parameters and intravenous glucose tolerance were determined at regular intervals. A pilot chronic treatment trial with a GLP1 receptor agonist was conducted in DIO-GM. At the end of the study, the animals were necropsied and a biobank of selected tissues was established. RESULTS: DIO-GM developed severe subcutaneous and visceral adiposity (body fat >50% of body mass vs. 22% in L-GM), increased plasma cholesterol, triglyceride, and free fatty acid levels, insulin resistance (HOMA-IR >5 vs. 2 in L-GM), impaired glucose tolerance and increased heart rate when resting and active. However, fasting glucose concentrations stayed within normal range throughout the study. Treatment with a long-acting GLP1 receptor agonist revealed substantial reduction of food intake and body weight within four weeks, with increased drug sensitivity relative to observations in other DIO animal models. Extensive adipose tissue inflammation and adipocyte necrosis was observed in visceral, but not subcutaneous, adipose tissue of DIO-GM. CONCLUSIONS: The Munich DIO-GM model resembles hallmarks of the human metabolic syndrome with extensive adipose tissue inflammation and adipocyte necrosis reported for the first time. DIO-GM may be used for evaluating novel treatments of obesity and associated comorbidities. They may help to identify triggers and mechanisms of fat tissue inflammation and mechanisms preventing complete metabolic decompensation despite morbid obesity. PMID- 30017787 TI - Mapping the asynchrony of cortical maturation in the infant brain: A MRI multi parametric clustering approach. AB - While the main neural networks are in place at term birth, intense changes in cortical microstructure occur during early infancy with the development of dendritic arborization, synaptogenesis and fiber myelination. These maturational processes are thought to relate to behavioral acquisitions and the development of cognitive abilities. Nevertheless, in vivo investigations of such relationships are still lacking in healthy infants. To bridge this gap, we aimed to study the cortical maturation using non-invasive Magnetic Resonance Imaging, over a largely unexplored period (1-5 post-natal months). In a first univariate step, we focused on different quantitative parameters: longitudinal relaxation time (T1), transverse relaxation time (T2), and axial diffusivity from diffusion tensor imaging (lambda//) These individual maps, acquired with echo-planar imaging to limit the acquisition time, showed spatial distortions that were first corrected to reliably match the thin cortical ribbon identified on high-resolution T2 weighted images. Averaged maps were also computed over the infants group to summarize the parameter characteristics during early infancy. In a second step, we considered a multi-parametric approach that leverages parameters complementarity, avoids reliance on pre-defined regions of interest, and does not require spatial constraints. Our clustering strategy allowed us to group cortical voxels over all infants in 5 clusters with distinct microstructural T1 and lambda// properties The cluster maps over individual cortical surfaces and over the group were in sound agreement with benchmark post mortem studies of sub cortical white matter myelination, showing a progressive maturation of 1) primary sensori-motor areas, 2) adjacent unimodal associative cortices, and 3) higher order associative regions. This study thus opens a consistent approach to study cortical maturation in vivo. PMID- 30017788 TI - Editorial overview: Cellular neuroscience. PMID- 30017786 TI - Integrative Bayesian analysis of brain functional networks incorporating anatomical knowledge. AB - Recently, there has been increased interest in fusing multimodal imaging to better understand brain organization by integrating information on both brain structure and function. In particular, incorporating anatomical knowledge leads to desirable outcomes such as increased accuracy in brain network estimates and greater reproducibility of topological features across scanning sessions. Despite the clear advantages, major challenges persist in integrative analyses including an incomplete understanding of the structure-function relationship and inaccuracies in mapping anatomical structures due to inherent deficiencies in existing imaging technology. This calls for the development of advanced network modeling tools that appropriately incorporate anatomical structure in constructing brain functional networks. We propose a hierarchical Bayesian Gaussian graphical modeling approach which models the brain functional networks via sparse precision matrices whose degree of edge specific shrinkage is a random variable that is modeled using both anatomical structure and an independent baseline component. The proposed approach adaptively shrinks functional connections and flexibly identifies functional connections supported by structural connectivity knowledge. This enables robust brain network estimation even in the presence of misspecified anatomical knowledge, while accommodating heterogeneity in the structure-function relationship. We implement the approach via an efficient optimization algorithm which yields maximum a posteriori estimates. Extensive numerical studies involving multiple functional network structures reveal the clear advantages of the proposed approach over competing methods in accurately estimating brain functional connectivity, even when the anatomical knowledge is misspecified up to a certain degree. An application of the approach to data from the Philadelphia Neurodevelopmental Cohort (PNC) study reveals gender based connectivity differences across multiple age groups, and higher reproducibility in the estimation of network metrics compared to alternative methods. PMID- 30017789 TI - Synaptic plasticity in human cortical circuits: cellular mechanisms of learning and memory in the human brain? AB - Synaptic plasticity is the cellular basis of learning and memory, but to what extent this holds for the adult human brain is not known. To study synaptic plasticity in human neuronal circuits poses a huge challenge, since live human neurons and synapses are not readily accessible. Despite this, various lines of research have provided insights in properties of adult human synapses and their plasticity both in vitro and in vivo, with some unexpected surprises. We first discuss the experimental approaches to study activity-dependent plasticity of adult human synapses, and then highlight rules and mechanisms of Hebbian spike timing-dependent plasticity (STDP) found in these synapses. Finally, we conclude with thoughts on how these synaptic principles can underlie human learning and memory. PMID- 30017790 TI - Development of an ELISA assay to determine neutralising capacity of horse serum following immunisation with Daboia siamensis venom in Myanmar. AB - Snakebite envenoming is a serious problem in Myanmar. The great majority of snakebite in this country is due to Russell's Viper (Daboia siamensis). For many years, the Burma Pharmaceutical Industry has produced a monovalent antivenom to Russell's Viper in horses. At present, the only way of determining the level of antibody against D. siamensis venom in hyperimmune horse serum is to perform venom neutralisation tests in mice. In this study, we describe the development of an in vitro ELISA assay to estimate neutralising capacity of horse serum. We found a strong correlation between the ELISA assay and the venom neutralisation test in mice (r = 0.982). The assay is robust and has sufficient sensitivity (92%) and specificity (96%) to replace the venom neutralisation test in mice during the immunisation phase in horses. PMID- 30017791 TI - VEGF-Grab Enhances the Efficacy of Radiation Therapy by Blocking VEGF-A and Treatment-Induced PlGF. AB - PURPOSE: Several clinical trials have combined antiangiogenic agents and radiation therapy (RT), but evidence of its clinical benefit is insufficient. In this study, we rationalized and investigated the combination of vascular endothelial growth factor-Grab (VEGF-Grab), an antiangiogenic drug that inhibits VEGF-A and placental growth factor (PlGF) and radiotherapy for anti-cancer therapy. METHODS AND MATERIALS: To observe for changes in PlGF after radiation, HCT116, HCT15, SW480, BxPC3, and RAW264.7 cells and Lewis lung carcinoma (LLC) and BxPC3 tumors were given 10 Gy of radiation, and changes in the expression of PlGF were analyzed. Patients scheduled for RT for solid tumor mass were recruited, and their plasma VEGF-A and PlGF were analyzed at baseline and 2 and 4 weeks after the start of radiotherapy. To assess the effects of combining VEGF Grab and radiotherapy, mice bearing LLC tumors were given 10 Gy of radiation once and 25 mg/kg of VEGF-Grab every 2 days for 5 rounds. To show that VEGF-Grab is effective in human tumors, mice bearing BxPC3 xenografts were given 2 doses of 15 mg/kg of VEGF-Grab or VEGF-Trap. To assess the efficacy of combination therapy in BxPC3 xenografts, the same experiment used in the LLC model was performed. RESULTS: We demonstrated that PlGF is increased as a direct consequence of irradiation in vitro and in vivo and in the plasma of patients being treated with radiation. Using a syngeneic tumor model, we showed that the combination of VEGF Grab and RT most effectively inhibited tumor growth through antiangiogenesis, tumor vessel normalization, and tumor-associated macrophage polarization from protumorigenic M2-type to antitumorigenic M1-type. Finally, we demonstrated similar enhanced antitumor effects using a human xenograft model. CONCLUSIONS: This study shows that PlGF is a potential target in patients being treated with RT and suggests VEGF-Grab as a viable therapeutic option in the context of inhibiting secondarily activated pathways responsible for tumor recurrence. PMID- 30017792 TI - Kinetics of Intratumoral Immune Cell Activation During Chemoradiation for Cervical Cancer. AB - PURPOSE: Radiation therapy has direct cytotoxic effects on tumor-infiltrating lymphocytes, but it also has immune stimulatory effects that increase immune cell infiltration. The dynamics of these competing effects on immune cells at the site of the tumor are poorly characterized during chemoradiation treatment (CRT) because of the difficulty of obtaining consecutive tumor biopsies. We used a minimally invasive cervical cytobrushing method to analyze the kinetics of intratumoral immune cell changes in patients with cervical cancer during CRT. METHODS AND MATERIALS: Cervical brushings were obtained from 20 patients with cervical cancer at baseline and during fractionated radiation therapy and cisplatin (weeks 1, 3, and 5). Matching peripheral blood mononuclear cells were obtained from 9 patients at the same time points. Cells were analyzed using multispectral flow cytometry to identify T cell and myeloid cell subsets and their activation status. Changes in immune cell subsets throughout treatment were calculated using matched-pair analysis with Wilcoxon rank sum test. RESULTS: We observed a significant decline in CD3+ total T cells, as well as CD8+ and CD4+ T cell subsets in the first week of treatment from baseline, followed by variable expansion at weeks 3 and 5. This coincided with higher levels of proliferating CD8+ T cells expressing Ki67 at week 3 of treatment. The percentages of activated CD8+ T cells expressing CD69 continuously increased over the course of treatment, whereas the percentage of activated CD11c+CD11b- dendritic cells was highest during the first week. Many of these changes were not observed in the blood. CONCLUSIONS: Our results identified immune dynamic changes during CRT, indicating that CRT may be immune activating at the site of the tumor. This study also suggests the importance of sequential analyses of the local tumor microenvironment in addition to peripheral blood. PMID- 30017793 TI - Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System. AB - PURPOSE: Recent in vivo investigations have shown that short pulses of electrons at very high dose rates (FLASH) are less harmful to healthy tissues but just as efficient as conventional dose-rate radiation to inhibit tumor growth. In view of the potential clinical value of FLASH and the availability of modern proton therapy infrastructures to achieve this goal, we herein describe a series of technological developments required to investigate the biology of FLASH irradiation using a commercially available clinical proton therapy system. METHODS AND MATERIALS: Numerical simulations and experimental dosimetric characterization of a modified clinical proton beamline, upstream from the isocenter, were performed with a Monte Carlo toolkit and different detectors. A single scattering system was optimized with a ridge filter and a high current monitoring system. In addition, a submillimetric set-up protocol based on image guidance using a digital camera and an animal positioning system was also developed. RESULTS: The dosimetric properties of the resulting beam and monitoring system were characterized; linearity with dose rate and homogeneity for a 12 * 12 mm2 field size were assessed. Dose rates exceeding 40 Gy/s at energies between 138 and 198 MeV were obtained, enabling uniform irradiation for radiobiology investigations of small animals in a modified clinical proton beam line. CONCLUSIONS: This approach will enable us to conduct FLASH proton therapy experiments on small animals, specifically for mouse lung irradiation. Dose rates exceeding 40 Gy/s were achieved, which was not possible with the conventional clinical mode of the existing beamline. PMID- 30017794 TI - Breast Cancer Risk Associated With Benign Intraductal Papillomas Initially Diagnosed on Core Needle Biopsy. AB - BACKGROUND: The long-term risk for patients with benign intraductal papillomas (IDPs) on core needle biopsy (CNB) who are not upgraded on excision is not well defined. The goal of this study was to determine the cumulative breast cancer (BC) incidence for patients with benign IDP on CNB. MATERIALS AND METHODS: There were 152 benign IDPs diagnosed on CNB between 2003 and 2008. Radiology and pathology data were reviewed by breast radiologists and pathologists. Clinical follow-up was obtained from the electronic medical record (Epic). RESULTS: Excision results were: 96 (63%) not upgraded, 9 (6%) with BC on excision (6 ductal carcinoma in situ, 3 invasive carcinoma), and 5 (3%) lacked correlation with the CNB site. Excision reports were unavailable for 42 (28%). Excluding cases with Breast Imaging Reporting and Data System (BI-RADS) 5 or discordant imaging, there were 6 (4%) true upgrades (all ductal carcinoma in situ). After the exclusion of patients with other major risk factors, follow-up was available for 55 of 58 patients with benign IDPs, and 8 (14%) developed BC after a median of 112 months (range, 11-159 months). None of the benign IDP patients without an excision report developed BC after a median of 97 months (range, 5-164 months). CONCLUSIONS: The upgrade rate for benign IDP diagnosed on CNB was 4%, similar to recent studies. The cumulative BC incidence for those who were not upgraded and who had no history of BC was 14% at a median of 9 years. When combined with patients without an excision pathology report, the overall BC incidence was 9%. The findings support continued breast cancer surveillance in this patient population. PMID- 30017795 TI - Use of Granulocyte-colony Stimulating Factor During Chemotherapy and Its Association With CA27.29 and Circulating Tumor Cells-Results From the SUCCESS A Trial. AB - BACKGROUND: Little is known about the effect of granulocyte colony-stimulating factor (G-CSF) treatment during adjuvant chemotherapy on prognostic markers. The present study explored the association between G-CSF and changes in cancer antigen (CA)27.29 and circulating tumor cell (CTC) levels during therapy. PATIENTS AND METHODS: A total of 3754 node-positive or high-risk node-negative early-stage breast cancer patients were treated within the SUCCESS-A trial (simultaneous study of gemcitabine-docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance-trial). CA27.29 and CTCs were determined before the start and within 6 weeks after the end of chemotherapy. RESULTS: Overall, 1324 of the 2646 patients (50.0%) available for analysis had >= 1 G-CSF applications during chemotherapy. G-CSF application was significantly associated with CA27.29 status before and after chemotherapy (chi2 = 30.6, df = 3; P < .001), because 238 patients (18.0%) with G-CSF treatment but only 146 (11.0%) without G-CSF treatment switched from a negative CA27.29 status before to a positive CA27.29 status after chemotherapy. In addition, patients with G-CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy compared with patients without any G-CSF application during chemotherapy (Mann-Whitney U test; Z = -7.81, P < .001). No significant association was found between G-CSF application and CTC status before or after chemotherapy (chi2 = 1.2, df = 3; P = .75). CONCLUSION: Cautious interpretation is needed regarding elevated levels of MUC-1-derived tumor markers such as CA27.29 shortly after adjuvant chemotherapy when G-CSF has been given, because G CSF treatment was associated with increased CA27.29 levels after chemotherapy. PMID- 30017796 TI - Seroprevalence of severe fever with thrombocytopenia syndrome (SFTS) virus antibodies in humans and animals in Ehime prefecture, Japan, an endemic region of SFTS. AB - Severe fever with thrombocytopenia syndrome (SFTS) was first identified as an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) in China and has also been found to be endemic to Japan and South Korea, indicating that SFTS is of great concern in East Asia. The aim of the present study was to determine the seroprevalence of SFTSV antibodies in humans and animals in SFTS endemic regions of Japan. One of 694 (0.14%) healthy persons over 50 years of age and 20 of 107 (18.7%) wild and domestic animals in Ehime prefecture of western Japan were determined to be seropositive for SFTSV antibodies by virus neutralization test and ELISA, respectively. The seropositive person, a healthy 74-year-old woman, was a resident of the southwest part of Ehime prefecture engaged in citriculture and field work. This woman's sample exhibited neutralizing activity against SFTSV although she had neither a clear experience with tick bites nor SFTS-like clinical illness. These findings indicate that most people living in the endemic regions are not infected with SFTSV and suggest that most of the SFTS patients reported so far do not reflect the tip of an iceberg of people infected with SFTSV, but at the same time, that SFTSV infection does not always induce severe SFTS-associated symptoms. These findings also suggested that SFTSV has been maintained in nature within animal species and ticks. PMID- 30017797 TI - Phototrophic production of heterologous diterpenoids and a hydroxy-functionalized derivative from Chlamydomonas reinhardtii. AB - Photosynthetic microalgae harbor enormous potential as light-driven green-cell factories for sustainable bio-production of a range of natural and heterologous products such as isoprenoids. Their capacity for photosynthesis and rapid low input growth with (sun)light and CO2 is coupled to a robust metabolic architecture structured toward the generation of isoprenoid pigments and compounds involved in light capture, electron transfer, and radical scavenging. Metabolic engineering approaches using eukaryotic green microalgae have previously been hampered mainly by low-levels of nuclear transgene expression. Here, we employed a strategy of optimized transgene design which couples codon optimization and synthetic intron spreading for the expression of heterologous plant enzymes from the algal nuclear genome. The diterpenoids casbene, taxadiene, and 13R(+) manoyl oxide were produced after expressing heterologous diterpene synthases and enzymes participating in the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway which were all targeted to the algal chloroplast. Additionally, a truncated and soluble plant microsomal cytochrome P450 monooxygenase was functionally expressed and able to hydroxylate 13R(+) manoyl oxide when directed into the chloroplasts. The heterologous diterpenoids were found to be excreted from the cells and accumulate in dodecane solvent-culture overlays. It was shown that the algal cell could tolerate significant metabolic pull towards diterpenoids without loss of native pigments. Using an algal strain producing 13R(+) manoyl oxide as a model, diterpenoid production was shown to be highest in photoautotrophic cultivations using CO2 as the sole carbon source and day:night illumination cycles. Up to 80 mg 13R(+) manoyl oxide per gram cell dry mass (CDM) could be produced from C. reinhardtii in a 7 day batch cultivation with a sustained maximal productivity of 22.5 mg gcdm-1 d-1 over 3 consecutive days. Collectively the results presented here suggest that green algal cells have remarkable potential for the heterologous production of non-native isoprenoids and support the use of these hosts for (sun)light driven bioproduction concepts. PMID- 30017798 TI - Frailty and the endocrine system. AB - Frailty is a condition characterised by loss of biological reserves, failure of homoeostatic mechanisms, and vulnerability to adverse outcomes. The endocrine system is considered particularly important in frailty, because of its complex inter-relationships with the brain, immune system, and skeletal muscle. This Review summarises evidence indicating a key role for the hypothalamic-pituitary axis in the pathogenesis of frailty through aberrant regulation of glucocorticoid secretion, insulin-like growth factor signalling, and androgen production. Evidence also indicates a potential role for vitamin D and insulin resistance in the pathogenesis of frailty. The role of thyroid hormones in the pathogenesis of frailty remains uncertain. Key convergent pathological effects of frailty include loss of muscle mass and strength, with consequent impact on mobility and activities of daily living. Future translational research should focus on the understanding of endocrine mechanisms, to identify potential biomarkers of the condition, modifiable targets for treatment, and novel pharmacological drugs targeted at the endocrine components of frailty. PMID- 30017801 TI - Clinical aspects of thyroid function during ageing. AB - Globally, populations are ageing at a rapid rate. The increase in the number of older citizens is accompanied by an increased prevalence of thyroid dysfunction, one of the most common disorders in older people. However, the diagnosis of thyroid dysfunction in older people is hindered by several factors, including the scarcity of thyroid dysfunction symptoms in older people. We describe the physiological changes in thyroid function that occur with increasing age, focusing on literature regarding changes in thyroid function test results in older populations. We also discuss treatment considerations for clinical and subclinical thyroid dysfunction according to international guidelines for older people. Finally, we discuss the relationship between variations in thyroid function and common diseases of old age including cardiovascular disease, osteoporosis, cognitive impairment, and frailty and suggest directions for future research. PMID- 30017800 TI - Testosterone treatment in older men: clinical implications and unresolved questions from the Testosterone Trials. AB - A decrease in the concentration of circulating testosterone in many older men is a biomarker and possibly a rectifiable contributing factor to ill health. Low circulating testosterone concentration has been associated with cardiovascular disease, reduced cognition, fracture risk, and anaemia. However, randomised placebo-controlled trials are essential to clarify the benefits and possible risks of testosterone treatment in men without hypothalamic, pituitary, or testicular disease. The Testosterone Trials (T-Trials) were a coordinated set of trials that, following a screening-to-enrolment ratio of 65:1, randomly assigned 790 men aged 65 years or older who had a baseline testosterone concentration of less than 9.54 nmol/L and symptoms consistent with hypogonadism, but no recognisable hypothalamic-pituitary-testicular axis pathology, to daily transdermal testosterone or placebo for 12 months. In the main trial, testosterone treatment resulted in a modest benefit for sexual function, whereas the other primary outcomes of vitality and physical function were not met. Data from concomitant substudies raised a possible concern over changes in coronary plaque volume, showed a neutral effect on memory and other cognitive functions, and revealed improvements in volumetric bone mineral density and anaemia. Although insufficient to alter the existing clinical equipoise, the T-Trials provided substantial new data on organ-specific outcomes for testosterone treatment in older men. Further clinical trials are necessary to determine whether testosterone treatment will translate into patient-valued health outcomes and to clarify effects on the cardiovascular system. PMID- 30017802 TI - The regulatory effects of metformin on the [SNAIL/miR-34]:[ZEB/miR-200] system in the epithelial-mesenchymal transition(EMT) for colorectal cancer(CRC). AB - The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, metastasis and drug resistance. The transcription factor(TF) and microRNA (miR) chimeric [SNAIL/miR-34]:[ZEB/miR-200] unit is the core regulatory system for the EMT process. Here, we proposed to assess the anti-EMT abilities and explore the inherent pharmacological mechanisms of the classic hypoglycaemic agent metformin for colorectal cancer(CRC). For the EMT model, the TGF-beta induced CRC cell lines SW480 and HCT116 were treated with metformin. The viability, migration and invasion abilities of the cells were evaluated with the Cell Counting Kit-8, wound-healing and trans-well assay. The alterations of the [SNAIL/miR-34]:[ZEB/miR-200] system and the EMT markers E-cadherin and vimentin were detected by western blot, qPCR and immunofluorescent staining. Metformin exhibited inhibitory effects on the proliferation, migration and invasion of the CRC SW480 cells. The up-regulation of E-cadherin and the down-regulation of vimentin for both SW480 and HCT116 cells revealed the anti-EMT abilities of metformin. For the [SNAIL/miR-34]:[ZEB/miR-200] system, metformin increased miR 200a, miR-200c and miR-429 levels and decreased miR-34a, SNAIL1 and ZEB1 levels in the TGF-beta-induced EMT. From immunofluorescence, we observed increased E cadherin and ZEB1 co-expression in metformin-treated cells. Metformin may perform bidirectional regulations of the [SNAIL/miR-34]:[ZEB/miR-200] system in the EMT process for colorectal cancer. Such regulation is expressed as the inhibition of EMT in general as well as an increased higher proportion of E/M hybrid cells in the total population. PMID- 30017799 TI - The physiology of endocrine systems with ageing. AB - During ageing, the secretory patterns of the hormones produced by the hypothalamic-pituitary axis change, as does the sensitivity of the axis to negative feedback by end hormones. Additionally, glucose homoeostasis tends towards disequilibrium with increasing age. Along with these endocrine alterations, a loss of bone and muscle mass and strength occurs, coupled with an increase in fat mass. In addition, ageing-induced effects are difficult to disentangle from the influence of other factors that are common in older people, such as chronic diseases, inflammation, and low nutritional status, all of which can also affect endocrine systems. Traditionally, the decrease in hormone activity during the ageing process has been considered to be detrimental because of the related decline in bodily functions. The concept of hormone replacement therapy was suggested as a therapeutic intervention to stop or reverse this decline. However, clearly some of these changes are a beneficial adaptation to ageing, whereas hormonal intervention often causes important adverse effects. In this paper, we discuss the effects of age on the different hypothalamic-pituitary hormonal organ axes, as well as age-related changes in calcium and bone metabolism and glucose homoeostasis. PMID- 30017803 TI - Impact of Estrogen on the Relationship Between Obesity and Renal Cell Carcinoma Risk in Women. AB - The relationship between obesity and renal cell carcinoma (RCC) has been widely investigated. However, the effect of estrogen on this relationship in female RCC patients has not been evaluated. We conducted a case-control study to investigate the role of estrogen as a potential modifier of the association between obesity and RCC risk in Chinese women. A total of 497 consecutive female patients with pathologically confirmed RCC, including 364 clear cell RCC (ccRCC), were enrolled. Age-matched controls were selected from cancer-free females seeking physical examination in our institution. Estrogen receptor-beta (ER-beta) and insulin-like growth factor (IGF)-1 receptor (IGF-1R) expression levels were detected in RCC tissues. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated by logistic regression models. We observed a positive association between overweight and RCC risk in pre-menopausal but not post-menopausal women. Similar association was also observed between overweight and ccRCC risk. Overweight pre-menopausal women had an increased risk of RCC (OR: 1.67, 95%CI: 1.01-2.76), as well as an increased risk of ccRCC (OR: 1.73, 95%CI: 1.02-2.99), after adjusting for potential confounders. IGF-1R expression levels were higher in pre-menopausal compared with post-menopausal cases (P = 0.015). These results suggest that estrogen plays an important role in RCC etiology and may modify the association between obesity and RCC risk in women. We hypothesize that estrogen may up-regulate IGF-1R and potentiate the deleterious effects of obesity-related elevations of insulin and IGFs. PMID- 30017804 TI - Genetic variants in the CNTNAP2 gene are associated with gender differences among dyslexic children in China. AB - BACKGROUND: It is well known that males have a higher prevalence of developmental dyslexia (DD) than females. Although the mechanism underlying this gender difference remains unknown, the contactin-associated protein-like 2 (CNTNAP2) gene, which shows sex-specific patterns in some neurodevelopmental disorders, has attracted extensive attention. This study aimed to explore whether CNTNAP2 shows a sex-specific association with DD in a Chinese population. METHODS: Using genomic DNA samples of 726 students [372 cases (282 male, 90 female), 354 controls (267 male, 87 female)], we genotyped five SNPs of CNTNAP2. Gender stratified logistic regression models were used to determine the relationships between the CNTNAP2 variants and DD. FINDINGS: After adjustment for the false discovery rate (FDR), two SNPs (rs3779031, rs987456) of CNTNAP2 were associated with DD risk in females but not in males. Female participants carrying the rs3779031 G allele had a lower risk of DD than those with the A genotype [GG vs AA: OR (95%CI) = 0.281 (0.097-0.814)]. The rs987456 CC genotype was associated with a decreased risk of DD in females [CC vs AA+CA: OR (95%CI) = 0.222 (0.078 0.628)]. Furthermore, the interaction between CNTNAP2 (rs987456) and environmental factors (scheduled reading time) played a protective role in females [OR (95%CI) = 0.431 (0.188-0.987)]. INTERPRETATION: We performed a genetic association study on CNTNAP2 variants and DD. The sex specificity of CNTNAP2 in DD, along with the gene-environment interaction may help us to understand gender differences in DD. PMID- 30017806 TI - Comment on: second-stage duodenal switch for the management of sleeve gastrectomy failure: a matched controlled trial. PMID- 30017805 TI - Factors associated with Chagas disease among blood donors in Brazilian Northeast region. AB - BACKGROUND: Despite the intensification of Chagas disease control in Brazil, around 1980s and 1990s, the transmission still occurs. The aim of this study was to identify the factors associated with Chagas disease among blood donors in Piaui State, Brazilian Northeast Region from 2004 to 2013. METHODOLOGY: Records of 597 blood donors from Management System in Hemotherapy Services and Laboratory Environment Manager System of Piaui were studied. Sociodemographic variables and serological tests results for Chagas disease's confirmation were analyzed using adjusted multiple logistic regression and odds ratio (OR) evaluation. RESULTS: The frequency of serological test confirming Chagas disease was 15.6%. Multivariate analysis showed that the most important associated factors were among blood donors who were born until 1960 (OR 5.1; 95%; CI 1.95-13.14), with low educational level (OR 2.8; 95%; CI 0.75-10.29), who lives in cities with <=50% of urbanization rate (OR 3.5; 95%; CI 1.42-8.72) and first-time blood donors (OR 3.0; 95%; CI 1.74-5.23). CONCLUSIONS: Unfortunately, the factors associated with Chagas disease are still the same pointed out in the scientific literature of decades ago. Our results are in line with the postulate of the 2nd Brazilian Consensus on Chagas disease, regarding the need to develop research that presents new scientific evidence, contributing not only to the Brazilian scenario but also to Latin America. PMID- 30017807 TI - Paired editorial: biphasic changes in angiopoietin-like 8 level after laparoscopic sleeve gastrectomy and type 2 diabetes remission during a 1-year follow-up. PMID- 30017808 TI - Composition of urinary tract stones formed by children in two populations in the Uyghur region of China. AB - BACKGROUND: To retrospectively compare the composition of urinary tract stones formed by Uyghur children from the southern (Kashgar) and northern (Urumchi) parts of the Xinjiang region. METHODS: The chemical composition of urinary tract calculi formed by 855 Uyghur children from the two regions in Xinjiang (366 Kashgar and 489 Urumchi) was compared retrospectively. Stone composition was determined by infrared spectroscopy. Factors that might have been of relevance for the findings such as age, gender, stone location and geographic region were also considered. RESULTS: Kashgar children were younger than Urumchi children (2.8 +/- 2.7 vs. 4.3 +/- 3.7 years, p < 0.001). Although ammonium urate was the dominant stone component in the whole population, calcium oxalate was most common in children from Urumchi. The mean occurrence of ammonium urate, calcium oxalate and uric acid differed significantly between stones formed by Kashgar and Urumchi children (52.5% vs. 29.2%, 18.9% vs. 29.4%, 12.3% vs. 20.9%; respectively, p < 0.001). Renal stones were less frequently recorded in Kashgar children than in Urumchi children (65.8% vs. 91.6%, p < 0.001). Interestingly, bladder stones were more common in children from Kashgar (28.4% vs. 3.7%; p < 0.001). CONCLUSION: Uyghur children from the southern part of Xinjiang apparently had a more serious form of stone disease than children from the northern part and the occurrence of stones dominated by ammonium urate stones was extremely high in children from the southern part of the region. PMID- 30017809 TI - Characterization and management of various renal cystic lesions by sonographic features. AB - Renal cysts are common incidental findings in clinical practice. Most renal cysts detected in medical imaging are benign simple cysts. However, some are complicated by hemorrhage or infection or are associated with calcification. In these instances, difficulties can be encountered distinguishing the complicated cysts from cystic renal tumors such as cystic renal cell carcinoma, multilocular cystic nephroma, and mixed epithelial and stromal tumors. The Bosniak classification is widely used to categorize cystic renal lesions but is used to classify those discovered via computed tomography. Ultrasonography (US) and color Doppler US are the most frequently used imaging techniques for abdominal surveys and long-term follow-up because of their noninvasiveness, relatively low cost, wide availability, and frequently, lack of contrast medium. Herein, we review the features of various cystic lesions of the kidney that can be found using US, discuss differential diagnoses using US, and propose a feature-oriented algorithmic approach to classifying renal cystic lesions using US. PMID- 30017810 TI - Use of prokinetic agents or antibiotics is associated with the occurrence of spontaneous bacterial peritonitis in cirrhotic patients. AB - BACKGROUND: Prokinetics have been shown to improve intestinal bacterial overgrowth and dysmotility in cirrhotic patients. Antibiotics are suggested for high risk patients for prophylaxis of spontaneous bacterial peritonitis (SBP). However, limited studies have investigated the association of SBP and these medications. We examined the association of prokinetics or antibiotics use and the first episode of SBP development in patients with cirrhosis. METHODS: We conducted a case-crossover study using the Taiwanese National Health Insurance Research Database from 2001 to 2010. A total of 129 cirrhotic patients with SBP were identified (defined as International Classification of Disease-Ninth Revision-CM codes: 571.xx for cirrhosis; 567.2, 567.8, and 567.9 for ascites; 789.5 for SBP). We investigated the short term (defined as 14-day period) effect of prokinetic agents or antibiotics use on SBP development using conditional logistic regressions with the adjustment of potential confounders. RESULTS: The results suggested that prokinetic agents or antibiotics use during the 14 days before SBP were associated with an increased risk of SBP [adjusted odds ratio (OR) = 3.2, 95% confidence interval (CI): 1.02-10.04 for prokinetic agents; and adjusted OR = 2.95, 95% CI: 1.05-5.23 for antibiotics]. In dose analysis, the use of prokinetic agents more than 0.5 defined daily dose was more commonly found in the case period without a statistical difference (adjusted OR = 3.637; 95% CI: 0.69-19.13). CONCLUSION: The results demonstrated an increased risk of primary SBP development among cirrhotic patients with prokinetic agents or antibiotics use. It is important to closely monitor those patients for the occurrence of SBP. PMID- 30017811 TI - Outcome of perioperative hemostatic management in patients with hemophilia without inhibitors undergoing 161 invasive or surgical procedures. AB - Perioperative management of persons with hemophilia (PWH) is a challenge for surgeons and hematologists. Reductions in mortality rate and complications have been achieved since the introduction of clotting factor concentrates (CFCs), which improve hemostatic control. However, there is no clear consensus on the optimal dosing of CFC administration. The aim of this study was to evaluate the outcome of PWH without inhibitors in patients undergoing invasive or surgical procedures. A total of 161 procedures, including 57 major and 104 minor ones were retrospectively reviewed. The characteristics of PWH, age at procedure, duration and total amount of CFC administration during the perioperative period, hemostatic adequacy, and complications were summarized. The study showed a low rate of bleeding (1.2%), infection (0%), thromboembolic event (0%), and inhibitor development (0%). The results revealed the doses and duration of CFC administration for several major and minor procedures which were capable of achieving excellent hemostatic control. PMID- 30017812 TI - The Shipai cohort for cardiovascular metabolic risk factors and outcome study - Design and preliminary results. AB - BACKGROUND: The aim of this study was to identify genotypic and phenotypic cardiovascular metabolic risk factors, and to establish risk models of diseases, including diabetes mellitus, cardiovascular disease, stroke, kidney dysfunction and psychiatric disorders, in Taiwanese adults. METHODS: In 2009, a community based cohort study was initiated in the Shipai area of the Shilin and Beitou districts in Taipei. Residents were randomly sampled by age (young adults: 35-44 years and middle-aged adults: 45-55 years) and urbanization (rural and urban). Residents who agreed to participate were scheduled to receive examinations (physical and blood) and answer questionnaires. A ten-year follow-up is anticipated. Metabolic syndrome (MetS) was defined based on the Adult Treatment Panel III guidelines, and individuals with only one or two of the five MetS components was identified for prevention target. RESULTS: The response rate of the 9000 invited residents was 10.1%. After screening, 906 participants were enrolled. While 31.0% (281) had no MetS components, 29.1% (264) had only one, and 22.0% (199) had two. MetS with at least three components was diagnosed in 17.9% (162) of the cohort. Concerning gender difference, 25.4% of men and 13.2% of women had MetS (p < 0.001). The percentage of MetS was higher in middle-aged participants than in young adults (20.5% versus 13.4%, p = 0.008). Forty-six percent of participants had central obesity. After adjusting for gender, age, and urbanization, the central obesity odds ratio for MetS was 23.7, with a 95% confidence internal of 13.1-42.7. CONCLUSION: Our preliminary results revealed a high MetS percentage among young and middle-aged adults in Taiwan, with central obesity being a particularly urgent prevention target. The research design and operational protocol of this cohort study may stimulate more research in the future. PMID- 30017813 TI - Generation of high quality of hepatocyte-like cells from induced pluripotent stem cells with Parp1 but lacking c-Myc. AB - BACKGROUND: Induced pluripotent stem cells (iPSCs) have a great potential for application in patient-specific therapy. The reprogramming method that does not involve c-Myc reduces tumorigenic risk, but also largely reduces the efficiency of generation of iPSCs, especially for those reprogrammed from damaged cells. Poly(ADP-ribose) polymerase 1 (Parp1) catalyzes a reaction of poly(ADP ribosylation) and has been reported to enhance cell reprogramming. METHODS: Using Oct-4/Sox2/Klf4/Parp1 (OSKP) reprogramming method, reprogramming factors plus Parp1 were capable of generation of iPSCs from adult fibroblasts and further toward to differentiate from iPSCs status into hepatocyte-like cells. RESULTS: Our results showed that Oct-4/Sox2/Klf4/Parp1 (OSKP)-derived iPSC exhibited regular pluripotent properties, long-term passages and more stable cellular divided period. These OSKP-derived iPSCs can effectively differentiate into hepatocyte-like cells (OSKP-iPSC-Heps), and present high mRNA levels of Sox17, HNF3b, and HNF4a in OSKP-iPSC-Heps. The mature hepatic functions, including CYP3A4, LDL uptake, glycogen synthesis and urea secretion were analyzed and well detected in OSKP-iPSC-Heps on day 14 post-differentiation. CONCLUSION: In conclusion, we demonstrated that Parp1 promoted reprogramming process to generate the high quality of iPSCs, which could be used as a high quality source of hepatocytes. PMID- 30017814 TI - Design and rationale of the "Sedation strategy and cognitive outcome after critical illness in early childhood" study. AB - There is increasing concern that sedatives commonly used during critical illness may be neurotoxic during the period of early brain development. The Sedation strategy and cognitive outcome after critical illness in early childhood (RESTORE cognition) study is a prospective cohort study designed to examine the relationships between sedative exposure during pediatric critical illness and long-term neurocognitive outcomes. We assess multiple domains of neurocognitive function 2.5-5 years post-hospital discharge, at a single time point and depending on participant and clinician availability, in up to 500 subjects who had normal baseline cognitive function, were aged 2 weeks to 8 years at pediatric intensive care unit admission, and were enrolled in a cluster randomized controlled trial of a sedation protocol (the RESTORE trial; U01 HL086622 and HL086649). In addition, to provide comparable data on an unexposed group with similar baseline biological characteristics and environment, we are studying matched, healthy siblings of RESTORE patients. Our goal is to increase understanding of the relationships between sedative exposure, critical illness, and long-term neurocognitive outcomes in infants and young children by studying these subjects 2.5 to 5 years after their index hospitalization. This paper highlights the design challenges in conducting comprehensive neurocognitive assessment procedures across a broad age span at multiple testing centers across the United States. Our approach, which includes building interprofessional teams and novel cohort retention strategies, may be of help in future longitudinal trials. PMID- 30017815 TI - Impact of atrial fibrillation on improvement of functional mitral regurgitation in cardiac resynchronization therapy. AB - BACKGROUND: Functional mitral regurgitation (FMR) and atrial fibrillation (AF) are frequent heart failure (HF) complications. Cardiac resynchronization therapy (CRT) can improve FMR; however, little is known about the influence of AF on FMR improvement. OBJECTIVE: The purpose of this study was to investigate the mechanisms and impact of baseline AF on FMR improvement after CRT. METHODS: CRT recipients with HF, AF, or sinus rhythm (SR) at baseline with moderate or severe FMR, were included from an ongoing registry. Left atrial (LA), mitral annular (MA), and left ventricular (LV) dimensions were evaluated echocardiographically. FMR improvement was defined as >=1 grade decrease from baseline to 6-month follow up. Clinical and echocardiographic measurements were performed at baseline and 6 month follow-up. RESULTS: A total of 419 patients (age 66 +/- 8 years; 73% male) were analyzed. At 6-month follow-up, FMR improved in 145 patients (45.6%) with SR vs 31 of AF patients (30.7%) (P = .011). Despite similar LV reverse remodeling at 6 months after CRT (LV end-systolic volume decreased by 32.1 +/- 43.2 mL in the SR group and by 27.7 +/- 6.3 mL in those with AF; P = .353), patients with SR exhibited smaller LA volumes (63.0 +/- 26.5 mL vs 103.1 +/- 41.0 mL; P <.001) and MA diameters (42.3 +/- 5.6 mm vs 46.1 +/- 5.8 mm; P <.001) compared to AF patients. CONCLUSION: FMR improvement is more common in CRT recipients in SR vs AF, despite a similar degree of LV remodeling. LA volume and MA diameter are greater in the AF group, causing the negative impact of AF on FMR improvement in CRT, as well as indicating a potential therapeutic target (ie, AF rhythm control). PMID- 30017816 TI - Silent cerebral events/lesions after second-generation cryoballoon ablation: How can we reduce the risk of silent strokes? AB - BACKGROUND: Atrial fibrillation (AF) ablation is associated with a substantial risk of silent cerebral events/lesions (SCEs/SCLs) detected on magnetic resonance imaging (MRI). OBJECTIVE: The purpose of this study was to investigate the factors associated with the incidence of SCEs/SCLs during second-generation cryoballoon ablation. METHODS: Two hundred fifty-six AF patients underwent brain MRI 1 day after pulmonary vein (PV) isolation using second-generation cryoballoons with a single 28-mm balloon and short freeze strategy. RESULTS: Overall, 991 of 1016 PVs (97.5%) were successfully isolated by 4.9 +/- 1.3 cryoballoon applications per patient, and 25 PVs required touch-up radiofrequency ablation. The total procedure time was 72.7 +/- 26.1 minutes. SCEs and SCLs were detected in 68 (26.5%) and 27 (10.5%) patients, respectively. None of the patients reported any neurologic symptoms. Reinsertion of once withdrawn cryoballoons and subsequent applications significantly increased the incidence of SCEs (odds ratio [OR] 2.057; 95% confidential interval [CI] 1.051-4.028; P = .035), and additional left atrial mapping with a multielectrode catheter significantly increased the incidence of SCLs (OR 3.317; 95% CI 1.365-8.056; P = .008). Transient coronary air embolisms were significantly associated with the incidence of SCLs (OR 3.447; 95% CI 1.015-11.702; P = 0.047). On the contrary, an uninterrupted anticoagulation regimen, use of radiofrequency deliveries for transseptal access, cryoballoon air removal with extracorporeal balloon inflations, strength of the MRI magnet, internal electrical cardioversion, and touch-up ablation were not associated with the incidence of SCEs/SCLs. CONCLUSION: A significant number of SCE/SCL occurrences was observed after second generation cryoballoon ablation procedures. These results suggest that air embolisms are the main mechanism of SCEs/SCLs, and the injected air volume might determine the lesion type. PMID- 30017817 TI - Cardiac impact of R-wave triggered irreversible electroporation therapy. AB - BACKGROUND: Irreversible electroporation (IRE) is a novel tumor ablative therapy technique, using electric fields to induce apoptosis in target tissues. Whether these electric pulses of high field strength can cause cardiac damage and/or ablation-induced arrhythmias is unclear. OBJECTIVE: The purpose of this study was to systematically evaluate the safety of electrocardiogram (ECG)-gated IRE with regard to cardiac side effects. METHODS: In all patients, 12-lead ECG and signal averaged ECG (SAECG) recordings were performed before and after IRE and 24-hour Holter recording on the day of the IRE procedure. Venous blood samples (N terminal pro-brain-type natriuretic peptide [NT-proBNP], high-sensitive troponin I [hsTnI]) were obtained before and 4 and 16 hours after the procedure. Patients with abnormal findings were reevaluated after 3 months. RESULTS: In total, 26 patients with an oncologic indication for IRE (11 females, mean age 62.9 years) were prospectively enrolled. Nine patients (34.6%) showed an increase in hsTnI and 21 patients (80.8%) an increase in NT-proBNP after ablation. Fifteen patients (57%) developed arrhythmias related to the procedure. One patient, in whom hsTnI and NT-proBNP had increased, developed multiple, nonsustained ventricular tachycardia events. In another patient, atrial fibrillation was triggered twice in 2 separate procedures. Twelve patients had clinically benign arrhythmias. SAECG was negative in all patients. CONCLUSION: Subclinical myocardial injury and nonfatal cardiac arrhythmias can occur in the context of IRE treatment. Although no sustained cardiac injuries could be found at 3-month follow-up, we propose implementation of a cardiac safety algorithm consisting of cardiac biomarkers and ECG monitoring when IRE is conducted. PMID- 30017819 TI - Optical diagnostics studies of air flow and powder fluidisation in Nexthaler(r). Part II: Use of fluorescent imaging to characterise transient release of fines from a dry powder inhaler. AB - The fine particle fraction is a key indicator of therapeutic effectiveness of inhaled pharmaceutical aerosols. This paper presents a fluorescence imaging technique to visualise and characterise the emission of active pharmaceutical ingredient (API) fines in model formulations containing coarse lactose carrier and 1.5-2 MUm diameter fluorescent microspheres (model API fines). A two-camera arrangement was used to acquire simultaneous images of spatial and temporal distribution of model API fines and fluidised powder formulation near the mouthpiece exit of a DPI. Digital image analysis showed that the model API fines were released along with the bulk of the powder dose. More rapidly accelerating airflows were found to cause earlier release of API fines. The fluorescence imaging technique analyses a substantial fraction of the aerosol plume and was found to provide effective time-resolved characterisation of the de-aggregation and release of API fines with consistent results across a wide range of model API concentrations. Future studies should demonstrate the usefulness of the fluorescence imaging technique across different formulations and DPI devices. PMID- 30017818 TI - Post-resection treatment of glioblastoma with an injectable nanomedicine-loaded photopolymerizable hydrogel induces long-term survival. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Despite available therapeutic options, the prognosis for patients with GBM remains very poor. We hypothesized that the intra-operative injection of a photopolymerizable hydrogel into the tumor resection cavity could sustain the release of the anti-cancer drug paclitaxel (PTX) encapsulated in poly (lactic-co glycolic acid) (PLGA) nanoparticles and prevent GBM recurrence. The tumor was resected 13 days after implantation and a pre-gel solution composed of polyethylene glycol dimethacrylate (PEG-DMA) polymer, a photoinitiator and PTX loaded PLGA nanoparticles (PTX PLGA-NPs) was injected into the tumor resection cavity. A solid gel filling the whole cavity was formed immediately by photopolymerization using a 400 nm light. PTX in vitro release study showed a burst release (11%) in the first 8 h and a sustained release of 29% over a week. In vitro, U87 MG cells were sensitive to PTX PLGA-NPs with IC50 level of approximately 0.010 MUg/mL. The hydrogel was well-tolerated when implanted in the brain of healthy mice for 2 and 4 months. Administration of PTX PLGA-NPs-loaded hydrogel into the resection cavity of GBM orthotopic model lead to more than 50% long-term survival mice (150 days) compared to the control groups (mean survival time 52 days). This significant delay of recurrence is very promising for the post-resection treatment of GBM. PMID- 30017820 TI - LincU Preserves Naive Pluripotency by Restricting ERK Activity in Embryonic Stem Cells. AB - Although the functional roles of long noncoding RNAs (lncRNAs) have been increasingly identified, few lncRNAs that control the naive state of embryonic stem cells (ESCs) are known. Here, we report a naive-state-associated lncRNA, LincU, which is intrinsically activated by Nanog in mESCs. LincU-deficient mESCs exhibit a primed-like pluripotent state and potentiate the transition from the naive state to the primed state, whereas ectopic LincU expression maintains mESCs in the naive state. Mechanistically, we demonstrate that LincU binds and stabilizes the DUSP9 protein, an ERK-specific phosphatase, and then constitutively inhibits the ERK1/2 signaling pathway, which critically contributes to maintenance of the naive state. Importantly, we reveal the functional role of LincU to be evolutionarily conserved in human. Therefore, our findings unveil LincU as a conserved lncRNA that intrinsically restricts MAPK/ERK activity and maintains the naive state of ESCs. PMID- 30017823 TI - Molecular systematics of swifts of the genus Chaetura (Aves: Apodiformes: Apodidae). AB - Phylogenetic relationships among swifts of the morphologically conservative genus Chaetura were studied using mitochondrial and nuclear DNA sequences. Taxon sampling included all species and 21 of 30 taxa (species and subspecies) within Chaetura. Our results indicate that Chaetura is monophyletic and support the division of the genus into the two subgenera previously identified using plumage characters. However, our genetic data, when considered in combination with phenotypic data, appear to be at odds with the current classification of some species of Chaetura. We recommend that C. viridipennis, currently generally treated as specifically distinct from C. chapmani, be returned to its former status as C. chapmani viridipennis, and that C. andrei, now generally regarded as synonymous with C. vauxi aphanes, again be recognized as a valid species. Widespread Neotropical species C. spinicaudus is paraphyletic with respect to more range-restricted species C. fumosa, C. egregia, and C. martinica. Geographically structured genetic variation within some other species of Chaetura, especially notable in C. cinereiventris, suggests that future study may lead to recognition of additional species in this genus. Biogeographic analysis indicated that Chaetura originated in South America and identified several dispersal events to Middle and North America following the formation of the Isthmus of Panama. PMID- 30017821 TI - The Zinc Finger Transcription Factor PLAGL2 Enhances Stem Cell Fate and Activates Expression of ASCL2 in Intestinal Epithelial Cells. AB - Intestinal epithelial stem cell (IESC) fate is promoted by two major transcriptional regulators, the TCF4/beta-catenin complex and ASCL2, which drive expression of IESC-specific factors, including Lgr5, Ephb2, and Rnf43. Canonical Wnt signaling via TCF4/beta-catenin directly transactivates Ascl2, which in turn auto-regulates its own expression. Conversely, Let-7 microRNAs antagonize the IESC lineage by repressing specific mRNA targets. Here, we identify the zinc finger transcription factor PLAGL2 as a Let-7 target that regulates IESC fate. PLAGL2 drives an IESC expression signature, activates Wnt gene expression, and enhances a TCF/LEF reporter in intestinal organoids. In parallel, via cell autonomous mechanisms, PLAGL2 is required for lineage clonal expansion and directly enhances expression of ASCL2. PLAGL2 also supports enteroid growth and survival in the context of Wnt ligand depletion. PLAGL2 expression is strongly associated with an IESC signature in colorectal cancer and may be responsible for contributing to the aberrant activation of an immature phenotype. PMID- 30017822 TI - Elevated Oxidative Stress Impairs Hematopoietic Progenitor Function in C57BL/6 Substrains. AB - C57BL/6N (N) and C57BL/6J (J) mice possess key genetic differences, including a deletion in the Nicotinamide nucleotide transhydrogenase (Nnt) gene that results in a non-functional protein in J mice. NNT regulates mitochondrial oxidative stress. Although elevated oxidative stress can compromise hematopoietic stem and progenitor cell (HSPC) function, it is unknown whether N- and J-HSPCs are functionally equivalent. Here, we report that J-HSPCs display compromised short term hematopoietic repopulating activity relative to N-HSPCs that is defined by a delay in lymphoid reconstitution and impaired function of specific multi-potent progenitor populations post transplant. J-HSPCs also displayed elevated reactive oxygen species (ROS) relative to N-HSPCs post transplant and upregulate ROS levels more in response to hematopoietic stress. Nnt knockdown in N-HSPCs recapitulated J-HSPCs' short-term repopulating defect, indicating that NNT loss contributes to this defect. In summary, C57BL/6N and C57BL/6J HSPCs are not functionally equivalent, which should be considered when determining the substrain most appropriate for investigations of HSPC biology. PMID- 30017824 TI - Evolutionary and ecological drivers of plant flavonoids across a large latitudinal gradient. AB - Flavonoids are important secondary metabolites that play an integral role in protecting plants against UV radiation and other forms of environmental stress. Given widespread impacts of environmental effects associated with latitude on a multitude of biological systems and a well-documented increase in solar radiation towards the equator, plant flavonoid production is expected to increase as a response to factors associated with decreasing latitude. Using data from a Neotropical genus (Ruellia) that spans an exceptionally broad latitudinal gradient, we tested a hypothesis of a positive latitudinal gradient in flavonoid concentration and assessed other factors that influence flavonoid production including habitat type (xeric vs. wet), altitude, phylogenetic relatedness, and pleiotropic effects. Two flavones with peak absorbance in ultraviolet wavelengths, apigenin and luteolin, were detected across all species. Transcriptome data confirm high expression of the gene required for flavone biosynthesis, flavone synthase (FNS). Contrary to our prediction, data revealed a positive correlation between flavone concentration and higher latitudes. Further, we recovered strong impacts of xeric habitat, pleiotropy, and phylogenetic relatedness on flavone concentrations. This study documents a complex interplay of ecological, historical, phylogenetic relatedness, and pleiotropic factors driving plant flavonoid production. PMID- 30017825 TI - Michel Jouvet: an explorer of dreams and a great storyteller. AB - In the late 50s Michel Jouvet discovered the presence of muscle atonia during REM sleep in cats and created the first model of REM sleep behavior disorder. He built and led in Lyon, France, the "Laboratory of Molecular Dream Science" (a merry oxymoron to silently protest against the research policy of favoring molecular biology over physiology), where in the late 80s, you could cross people who had worked on sleep in the python, tench fish, tortoise, iguana, hen, lamb, mouse, rat and cat. This brilliant physiologist was also a great storyteller with a very good sense of humor. He supported the theory that dreaming is equivalent to REM sleep (which he called "paradoxical sleep"), kept his own dream diary, and imagined that the ponto-geniculo-occipital waves during REM sleep could compose the song sheet of dreams. He wrote several books published in French on dreams and dreaming. PMID- 30017826 TI - Bronchoprotective effect of vilanterol against methacholine-induced bronchoconstriction in mild asthmatics: A randomized three-way crossover study. AB - BACKGROUND: Ultra-long-acting beta2 agonists (uLABA) are relatively new anti asthma medications of which there are three different formulations currently available: olodaterol, indacaterol, and vilanterol. The first 2 formulations have been shown to exert bronchoprotective effects; they are able to prevent airway smooth muscle contraction on exposure to constricting stimuli. However, studies have found that these 2 drugs produce different degrees and durations of bronchoprotection against methacholine. OBJECTIVE: The objective of this study was to investigate the degree of bronchoprotection provided by vilanterol against methacholine-induced bronchoconstriction. METHODS: Fourteen patients with mild-to moderate asthma (8 male; baseline percent predicted forced expiratory volume in 1 second [FEV1] > 65%; provocative concentration of methacholine causing a 20% reduction in FEV1 [PC20] <= 8 mg/mL) completed this randomized, double-blind, 3 way crossover study. Methacholine challenges were performed before treatment administration (placebo, 100 MUg fluticasone furoate, or 25 MUg vilanterol + 100 MUg fluticasone furoate) and at 0.5 and 24 hours posttreatment. Each treatment arm was separated by a minimum 7-day washout period. A combination therapy of vilanterol+fluticasone furoate was used, because vilanterol is not available as a monotherapy. RESULTS: Significant bronchoprotection was evident after the combination treatment at both 0.5 and 24 hours with doubling dose shifts in methacholine PC20 of 2.0 (P = .0004) and 1.6 (P = .0001), respectively. Clinically significant bronchodilation was only recorded at 24 hours after combination treatment (P < .05). CONCLUSION: These findings suggest that vilanterol (in combination with fluticasone furoate) provides significant bronchoprotection against methacholine-induced bronchoconstriction for at least 24 hours in patients with mild-to-moderate asthma. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT03315000). PMID- 30017827 TI - Bemisia tabaci-mediated facilitation in diversity of begomoviruses: Evidence from recent molecular studies. AB - Begomoviruses are considered as one of the most notorious plant viruses worldwide, which cause substantial economic losses to various field crops. Management of begomoviruses has become a challenge due to the continuous evolution and the emergence of new strains. Bemisia tabaci is globally known to be the key vector of begomoviruses, having relatively high reproductivity, fast dispersal ability, high survival rate due to its polyphagous nature and high resistance to various groups of insecticides. Continuous transmission of begomoviruses by the vector has led to the development and spread of epidemics of various diseases worldwide. In this review, we have critically analyzed the various dynamics which facilitate the diversity of begomoviruses through their vector. The interaction of begomovirus-whitefly leads to continuous research activities regarding management of both virus and its vector, thus opening exciting new horizons to formulate potential control strategies to ensure a disease-free cropping environment. PMID- 30017828 TI - Nivolumab-Induced Hemophilia A Presenting as Gastric Ulcer Bleeding in a Patient With NSCLC. PMID- 30017830 TI - Inflammation Flare and Radiation Necrosis Around a Stereotactic Radiotherapy Pretreated Brain Metastasis Site After Nivolumab Treatment. PMID- 30017829 TI - Proteogenomic Analysis of Surgically Resected Lung Adenocarcinoma. AB - INTRODUCTION: Despite apparently complete surgical resection, approximately half of resected early-stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse, and novel targets in this setting. METHODS: RNA sequencing and liquid chromatography/liquid chromatography-mass spectrometry proteomics data were generated from 51 surgically resected non-small cell lung tumors with known recurrence status. RESULTS: We present a rationale and framework for the incorporation of high-content RNA and protein measurements into integrative biomarkers and show the potential of this approach for predicting risk of recurrence in a group of lung adenocarcinomas. In addition, we characterize the relationship between mRNA and protein measurements in lung adenocarcinoma and show that it is outcome specific. CONCLUSIONS: Our results suggest that mRNA and protein data possess independent biological and clinical importance, which can be leveraged to create higher-powered expression biomarkers. PMID- 30017831 TI - Nedaplatin Plus Docetaxel Versus Cisplatin Plus Docetaxel as First-Line Chemotherapy for Advanced Squamous Cell Carcinoma of the Lung - A Multicenter, Open-label, Randomized, Phase III Trial. AB - INTRODUCTION: This study aimed to compare the efficacy of first-line nedaplatin (80 mg/m2) plus docetaxel (75 mg/m2) (ND) versus cisplatin (75 mg/m2) plus docetaxel (75 mg/m2) (CD) in patients with advanced squamous cell lung carcinoma. METHODS: This open-label randomized controlled phase III trial was performed at 12 hospitals in China. Patients with squamous cell lung carcinoma were randomized to four cycles of ND or CD. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to progression, best overall response, and adverse events. RESULTS: In the intent-to-treat analysis set (ND: n = 141; CD: n = 139), median PFS was 4.63 months (95% confidence interval: 4.43-5.10) for the ND and 4.23 months (95% confidence interval: 3.37-4.53) for CD groups (p = 0.056). No significant difference in time to progression was observed between the two groups. Best overall responses and disease control rate were better with ND 51.5%, than with CD 38.1% (p = 0.033 and p = 0.0004, respectively). Grade III or IV adverse events and grade 3-4 nausea and fatigue were more frequent in the CD group compared with the ND group (all p < 0.05). CONCLUSIONS: There is no improvement in PFS with the nedaplatin and docetaxel combination in the intent-to treat analysis. More hematologic toxicities were observed in the ND group (compared with CD), whereas more nonhematologic toxicities were observed in the CD group. ND could be a new treatment option for advanced or relapsed squamous cell lung cancer (NCT02088515 at ClinicalTrials.gov). PMID- 30017833 TI - Associated and predictive factors of quality of life in patients with temporal lobe epilepsy. AB - OBJECTIVE: Identifying the factors that are correlated with and predictive of reduced quality of life (QOL) is essential to optimize the treatment of epilepsy and the management of comorbidities. METHODS: We analyzed the independent associations between the Quality of Life in Epilepsy-31 (QOLIE-31) inventory and the demographic, clinical, psychiatric, and cognitive variables of 47 consecutive patients with temporal lobe epilepsy (TLE). Predictors of the correlated variables were analyzed by multiple linear regression analysis. RESULTS: The QOLIE-31 total score was positively correlated with occupational status and Mini Mental State Examination (MMSE) scores (r = 0.290 and 0.295, respectively; P < 0.05) and negatively correlated with the duration of seizures, adverse effects of antiepileptic drugs (AEDs), and the Pittsburgh Sleep Quality Inventory (PSQI), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) scores (r = -0.357, 0.321, 0.328, -0.672, and -0.565, respectively; P < 0.05; P < 0.01 for the SAS and SDS). In the final multivariate regression model, anxiety, long durations of seizures, adverse effects of AEDs, and depression explained approximately 60.6% (adjusted R2 = 0.606, R coefficient = 0.800) of the QOLIE-31 overall score variance. CONCLUSION: Anxiety, long durations of seizures, adverse effects of AEDs, and depression were significant predictors of QOL, and these variables had relatively high prediction capacities for the overall QOLIE-31 in the regression model. Comorbid anxiety is the most powerful negative determinant of the QOLIE-31. PMID- 30017834 TI - Frontal lobe cognitive functions and electroencephalographic features in juvenile myoclonic epilepsy. AB - PURPOSE: The study aimed to examine the relationship between frontal lobe functions and interictal electroencephalography (EEG) discharge characteristics of patients with juvenile myoclonic epilepsy (JME). METHOD: Thirty patients with JME who had EEG with asymmetrical generalized discharge (aEEG), 15 patients with JME who had EEG with symmetrical generalized discharge (sEEG), and 15 healthy controls were included in the study. To evaluate attention, the digit span and Corsi block tests were used; to evaluate memory, we applied verbal and visual memory tests; to evaluate frontal lobe functions, we used clock drawing, verbal fluency, the Stroop test, trail making, mental control, and antisaccadic eye movement tests as well as the continuous performance (CPT) tests. ETHICAL CONSIDERATIONS: The research was approved by the Research Ethics Committee of the Bakirkoy Research and Training Hospital for Psychiatry, Neurology, Neurosurgery, with protocol number: 41340010/4891-262, date: 05.02.2013. RESULTS: The mean age of the 45 patients with JME was 22.89 +/- 6.77 years, and 34 (75.6%) were female. The age at onset of seizures and disease duration of the patients with JME was 15.56 +/- 4.06 years (range, 9-26 years) and 7.20 +/- 5.59 years (range, 1-25 years), respectively. All patients were under valproate (VPA) treatment, and the mean VPA dosage was 783.33 +/- 379.14 mg/day. Patients with JME scored worse than the control group in attention, memory, and frontal lobe functions. In patients with aEEG, scores of attention, memory, and frontal lobe function tests were lower than in patients with sEEG; however, with the exception of CPT, they were not statistically significant. CONCLUSION: Cognitive functions in JME have been shown to be impaired. Furthermore, we concluded that the frontal lobe cognitive functions may be worse in patients with aEEG than in patients with sEEG. Further studies in patients with JME with aEEG abnormalities may lead to a better understanding of the pathophysiology of JME. PMID- 30017835 TI - Seeing the developments of epileptology from inside the stream. PMID- 30017832 TI - Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers. AB - INTRODUCTION: In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. METHODS: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. RESULTS: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (+/- everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months). CONCLUSIONS: Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed. PMID- 30017836 TI - Higher IQ in juvenile myoclonic epilepsy: Dodging cognitive obstacles and "masking" impairments. AB - Executive deficits and impulsiveness are extensively reported in juvenile myoclonic epilepsy (JME). Previous literature suggests that intelligence may mediate these deficits. In this study, we evaluated and compared the performance of adults with JME with high and low intelligence quotient (IQ) and controls on tasks for executive function (EF) and impulsive traits. We investigated the neuropsychological performance of 53 adults with JME and below average IQ (57% women; 26.9 [+/-7.88] years; mean IQ: 89.8 [+/-5.1]), 26 adults with JME and average or above average IQ (53.8% women; 28.2 [+/-9.33] years; mean IQ: 110.7 [+/-8.3]), 38 controls with below average IQ (55% women; 28.4 [+/-8.4] years; mean IQ: 90.1 [+/-5.8]), and 31 controls with average or above average IQ (61.3% women; 32.20 [+/-11.3] years; mean IQ: 111.6 [+/-10.5]) with a comprehensive battery of neuropsychological tests that measure executive/attentional function. Impulsive traits were assessed using the Cloninger et al.'s Temperament and Character Inventory (novelty seeking (NS) domain). The group with JME with higher IQ presented worse performance compared with controls with higher IQ on Controlled Oral Word Association (COWA) and Wisconsin Card Sorting Test (WCST) (errors). This group showed worse performance than controls with lower IQ on Stroop Color-Word Test (SCT) 1, Trail Making (TM) A, COWA, and WCST (errors). Patients with lower IQ showed worse performance than controls with higher IQ on Digit Span Forward (DSF), Digit Span Backward (DSB), SCT1, SCT2, SCT3, TM A, COWA, and WCST (errors and failure to maintain set). Patients with lower IQ showed worse performance than controls with lower IQ on DSF, DSB, SCT1, SCT2, SCT3, TM A, TM B, COWA, and WCST (errors and failure to maintain set). Patients from groups with low and high IQ showed higher scores than controls with higher and lower IQ on impulsivity for NS1 and NS2 (except for patients with higher IQ versus controls with lower IQ). Adults with JME and higher IQ show less evidence of EF deficits compared with those with JME and below average IQ, suggesting that a higher degree of intellectual efficiency may act as a compensatory mechanism. However, it does not minimize some aspects of impulsive traits. Patients with JME and higher cognitive reserve may create strategies to dodge their cognitive obstacles. In this context, intelligence may protect and, at the same time, "mask" impairments that could be detected earlier. PMID- 30017837 TI - Early-life hyperthermic seizures upregulate adenosine A2A receptors in the cortex and promote depressive-like behavior in adult rats. AB - Febrile seizures (FS) represent one of the most frequent convulsive disorders in children which can be classified into simple and prolonged depending on the duration. Although simple FS are generally considered as benign, there is controversy about the outcome of prolonged FS. Here, we have used an animal model of prolonged FS to investigate persistent neurochemical and behavioral alterations in adult rats. Hyperthermic seizures were induced in 12-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited arrest of heat induced hyperkinesis followed by body flexion and rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. After 48 days, the animals were assayed on dark-light box and forced swim tests in order to detect if rats will show signs of anxiety or depression. Finally, animals were sacrificed 56 days after hyperthermia-induced seizures (HIS), and their effects on adenosine A2A receptor signaling and 5' nucleotidase activity were studied in plasma membranes from the cerebral cortex by using radioligand-binding assay and by measuring the activities of adenylate cyclase and 5'-nucleotidase. Results obtained have shown that adult rats submitted to HIS during the neonatal period showed depressive-like behavior. Furthermore, animals exposed to hyperthermic insult showed an increase in A2A receptor level which was also accompanied by an increase in A2A receptor functionality. PMID- 30017838 TI - Incidence rate of sudden death in epilepsy: A systematic review and meta analysis. AB - OBJECTIVE: The aim of the study was to summarize the pooled incidence rate of sudden unexpected death in epilepsy (SUDEP) in patients. Meta-regression analysis was applied to identify factors influencing the incidence rate. DESIGN: The study was a systematic review and critical appraisal with a meta-analysis of cohort studies, both prospective and retrospective. MATERIAL AND METHOD: In a literature search, a total of 45 cohort studies were identified. A random effect model was used to synthesize the results. Heterogeneity between studies was examined by subgroup and meta-regression analysis. The small-study effect was evaluated and not corrected for by the "trim and fill" method because of great heterogeneity. RESULTS: A substantial heterogeneity was present. The pooled estimated incidence rate for SUDEP was 1.4/1000 patient years. A meta-regression pinpointed a negative association between the incidence rate of SUDEP and the mean follow-up time and a positive association with the mean age of the patient. The definition of epilepsy showed statistical significance, with a higher incidence rate of SUDEP in studies where the definition of epilepsy was described and clear (p = 0.019) compared with studies having an inadequate or failing epilepsy definition. CONCLUSION: Evidence from this study suggests a high incidence rate of sudden death in epilepsy. Its incidence rate was 23 times the incidence rate of sudden death in the total population of the same age. There was heterogeneity and variability of incidence rate depending on the quality of the study and on the definition of epilepsy and the mean age of the patients. PMID- 30017839 TI - Vagus nerve stimulation (VNS) therapy update. AB - Epilepsy affects millions of people worldwide. Approximately one-third have pharmacoresistant epilepsy, and of these, the majority are not candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy has been an option to treat pharmacoresistant seizures for 30 years. In this update, we will review the clinical data that support the device's efficacy in children, adolescents, and adults. We will also review its side-effect profile, quality of life and cost benefits, and the impact the device has on sudden unexpected death in epilepsy (SUDEP). We will then discuss candidate selection and provide guidance on dosing and future models. Vagus nerve stimulation therapy is an effective treatment for many seizure types and epilepsy syndromes with a predictable and benign side effect profile that supports its role as the most commonly prescribed device to treat pharmacoresistant epilepsy. This article is part of the Special Issue "Neurostimulation for Epilepsy". PMID- 30017840 TI - Public awareness and experiences associated with epilepsy in Japan, 2013-2017. AB - BACKGROUND: Public attitudes and stigma toward epilepsy may limit people with epilepsy (PWE) in seeking treatment and participating in social activities. The prevalence of epilepsy is approximately 0.8% in Japan, similar to rates reported in other countries. Although epilepsy is relatively common, few studies have investigated public awareness about epilepsy in Japan. Recently, several serious car accidents in Japan involving PWE resulted in pedestrian fatalities. Traffic accidents involving PWE have been reported extensively and repeatedly in the media since 2011. In 2013 and 2017, our research group conducted a large investigation of awareness about epilepsy targeting the general public. Previous studies have reported that knowledge is one of the factors involved in improving attitudes and reducing stigma. The aim of the current study was to compare survey results, especially regarding knowledge of epilepsy, and capture changes in public awareness between 2013 and 2017. METHODS: A total of 2160 people (1080 in each year) participated, with a total of 540 women in each year, aged 20-79 years. Participants lived in the greater Tokyo area as well as the Tohoku and Kansai regions of Japan. All participants answered survey questions online in January 2013 and April 2017. We analyzed five questions regarding the participants' demographic data, nine questions regarding knowledge about epilepsy, and five questions regarding experiences with epilepsy. For questions investigating the respondents' knowledge about epilepsy, we counted only the correct answers and scored these for each respondent. RESULTS: Knowledge scores decreased from 2013 to 2017, demonstrated by statistical analysis. However, the effect size was very small. Knowledge scores among the following groups were higher in both 2013 and 2017: people who had read or heard about epilepsy, those who had witnessed people having an epileptic seizure, people who had acquaintances who were PWE, those who had PWE in their family, and people who had studied medicine or worked in a medical profession. CONCLUSION: We revealed that participants who had some experience with epilepsy had higher knowledge levels in both 2013 and 2017. This suggests that such experiences could be important for motivating people to seek appropriate and accurate knowledge about epilepsy, and could result in a reduction of stigma. Greater awareness is needed among the general public in Japan about various aspects of epilepsy. PMID- 30017842 TI - Use of Virtual Surgical Planning as an Adjunct for Enucleation of Multiple Recurrent Odontogenic Keratocysts: Case Report. AB - This case report describes an interesting use of virtual surgical planning to fabricate tooth-borne cutting guides to assist in localization and enucleation of multiple recurrent odontogenic keratocysts close to the inferior alveolar nerve. The 3-dimensional models generated and cutting guides increased the accuracy and precision of the procedure and decreased surgical time and potential patient morbidity. PMID- 30017841 TI - Multicenter Evaluation of Prosthesis Oversizing of the SAPIEN 3 Transcatheter Heart Valve. Impact on Device Failure and New Pacemaker Implantations. AB - INTRODUCTION AND OBJECTIVES: A certain degree of prosthesis oversizing (OS) is recommended for the SAPIEN 3 to achieve device success. However, an increase in OS may increase permanent pacemaker implantation (PPI) rates. We therefore investigated the influence of OS on device failure and PPI. METHODS: A total of 804 patients were treated with SAPIEN 3 at 3 centers. Multislice computed tomography-derived OS was calculated and analyzed both as a continuous variable and categorized in 5% increments with -4% to 0% as reference. RESULTS: Device failure occurred in 8.8% of patients. Median OS was lower in patients with device failure vs those with device success (+4% vs +8%; P=.038). A nonlinear risk pattern was shown for OS with a significantly reduced device failure rate within 4% to +22% of OS. There was no case of paravalvular leakage II+ between +10% to +20% of OS. The overall PPI rate was 16.2% and the median OS was significantly larger in patients with PPI (PPI: +9% vs no PPI: +7%; P = .025), while implantation depth did not vary in patients with vs without PPI (6.9+/-1.7 mm vs 6.6+/-1.9 mm; P=.101). The risk of PPI increased with increasing OS and was highest in the 2 highest categories. CONCLUSIONS: An increase in OS reduces the risk for device failure but increases the risk for PPI. There was no ideal range of OS to minimize both device failure and PPI. PMID- 30017843 TI - Unique laser coding technology to fight falsified medicines. AB - Based on WHO statistics, counterfeit medicines represent 10% of the global drug trade. According to Directive 2011/62/EU as regards the prevention of falsified medicines from entering into the legal supply chain, a unique identification should be put on each box of drugs to be able to track and trace them. The objective of this study is to develop a technology to mark an individual traceability code directly on the surface of the tablet. By using this technique, anyone with a camera-enabled phone and a suitable application installed should be able to authenticate these drugs. By marking the medicine's surface, patients could be protected from fake drugs. The aim of the present work was to study how different types of lasers affect the film coating of the tablet during the laser marking intervention. To sum up, the present findings may contribute to efficient and reliable laser marking solutions in the unique identification procedure. Based on our measurement results, it can be stated that the excimer UV laser is clearly the most suitable marking instrument for anti-counterfeiting coding on solid coated tablet form as this caused the least amount of chemical degradation of the polymer film. PMID- 30017844 TI - Spectroscopic characterization of tablet properties in a continuous powder blending and tableting process. AB - By the advent of continuous pharmaceutical manufacturing, fast and accurate characterization of product quality has become of a major interest. Although it also promotes the real-time release testing approach, so far mainly content uniformity studies were performed by near-infrared (NIR) spectroscopy. This paper proposes the simultaneous application of NIR and Raman spectroscopy to nondestructively analyze the critical quality attributes of continuously produced tablets in a real-time release testing procedure. A face-centered composite design was applied to determine the impact of lubrication and compression force on the properties of a tablet formulation containing caffeine, glucose monohydrate and magnesium stearate and to provide a systematic comparison of the applicability of spectroscopic methods. Quantitative methods were developed to evaluate different lubrication approaches in a continuous blending and tableting line. The simultaneous application of NIR and Raman spectroscopy revealed that NIR spectroscopy is more suitable to follow the changes of compression force, while Raman spectroscopy could be successfully applied for the detection of overlubrication. The presented approach can be a part of a comprehensive real time release strategy, where NIR and Raman spectroscopy provide complementary information about multiple critical quality attributes, such as content uniformity, tablet hardness, friability and dissolution. PMID- 30017845 TI - Impact of PCL nanofiber mat structural properties on hydrophilic drug release and antibacterial activity on periodontal pathogens. AB - Electrospinning enables to design and manufacture novel drug delivery systems capable of advancing the local antibacterial therapy. In this study, two hydrophilic drugs - metronidazole and ciprofloxacin hydrochloride - were loaded both individually and in combination into hydrophobic poly(epsilon-caprolactone) (PCL) matrix using electrospinning. We aimed to develop prolonged release drug delivery systems suitable for the treatment of periodontal diseases and understand how different rarely studied structural features, such as nanofiber mat thickness, surface area, wettability, together with intrinsic properties, like solid state and localization of incorporated drugs in nanofibers, affect the drug release. Furthermore, the safety of nanofiber mats was assessed in vitro on fibroblasts, and their antibacterial activity was tested on selected strains of periodontopathogenic bacteria. The results showed that the structural properties of nanofiber mat are crucial in particular drug-polymer combinations, affecting the drug release and consequently the antibacterial activity. The hydrophobicity of a PCL nanofiber mat and its thickness are the key characteristics in prolonged hydrophilic drug release, but only when wetting is the rate-limiting step for the drug release. Combination of drugs showed beneficial effects by inhibiting the growth of all tested pathogenic bacterial strains important in periodontal diseases. PMID- 30017847 TI - Enterovirus B74 associated with hand, foot and mouth disease. AB - Enterovirus 74 (EV-B74) has been associated with cases of acute flaccid paralysis (AFP) but it is not a commonly found enterovirus. In this work, we present the characterization of an EV-B74 detected from the serum sample of a one-year-old boy presenting with signs and symptoms clinically compatible with hand, foot and mouth disease (HFMD). This is the first report of EV-B74 in Brazil. PMID- 30017846 TI - Development of novel gastroretentive salbutamol sulfate-loaded sodium alginate pectin bubble beads prepared by co-axial needle air-injection method and in vivo clinical evaluation by ultrasound studies. AB - In the present study, the salbutamol sulfate-loaded sodium alginate-pectin (SS loaded SA-PEC) bubble beads have been optimized and evaluated for drug loading, in vitro drug release, in vivo floating behavior in the stomach, etc. Nine batches (F1-F9) of bubble beads with different SA and PEC contents were prepared by novel co-axial needle air-injection method and related to their percent drug loading efficiency (%DLE) and percent drug release at 4 h (%R4h) as response factors. The multivariate analysis has shown the effect of SA/PEC ratio, total polymer content, as well as their interaction on %DLE and %R4h. In the quantitative modeling, the satisfactory adjustment of the linear models (along with interaction terms) with the experimental data for both %DLE and %R4h has confirmed the findings of the multivariate analysis. The optimized SS-loaded SA PEC bubble beads based on 2D (contours), 3D, desirability, and overlay plots has exhibited %DLE of 87.35 +/- 2.48% (n = 3 and error = 2.94%) and %R4h of 85.79 +/- 2.98% (n = 3 and error = 0.25%). The in vitro drug release studies have shown almost complete (>=85%) SS release from all the batches within 4-6 h in simulated gastric fluid (SGF) pH 1.2. The in vivo clinical findings by ultrasound studies have shown excellent floatation (>6 h) behavior of bubble beads in the upper gastrointestinal tract (GIT) and efficient stomach-specific gastroretention. PMID- 30017848 TI - Efficient transformation of Pleurotus eryngii with a safe selective marker mutated from the Pesdi1 gene. AB - We introduced a site-directed mutation in the sdi1 gene and used it as a selective marker for the polyethylene glycol-mediated transformation of Pleurotus eryngii monokaryon protoplasts. The transformants displayed obvious and stable resistance to the fungicide carboxin indicating that the mutant Pesdi1 gene is an efficient selective marker. PMID- 30017849 TI - Quantification of plasmid DNA standards for U.S. EPA fecal indicator bacteria qPCR methods by droplet digital PCR analysis. AB - An obstacle to establishing widely useful data acceptance criteria for U.S. Environmental Protection Agency (EPA) qPCR methods has been the unavailability of standardized reference materials. Earlier versions of EPA Methods 1609 and 1611 for enterococci used cellular reference materials for quantifying enterococci in unknown test samples, however, EPA updates to these fundamentally DNA-based analysis methods have shifted toward the use of DNA standards. This report describes the application of droplet digital PCR (ddPCR) analysis for the quantification of a set of synthetic plasmid DNA standards that have been made available for updated EPA Methods 1609.1 and 1611.1 as well as for EPA Draft Method C for Escherichia coli. To obtain the most accurate concentration estimates possible, part of this effort was to develop a data analysis model for determining the fluorescence thresholds that distinguish positive from negative droplets produced by the ddPCR reactions. Versions of this model are described for applications with individual reactions, multiple reactions within a ddPCR system run, and multiple reactions within and across different system runs. The latter version was applied toward determinations of error in the concentration estimates of the standards from replicate analyses of each standard in multiple ddPCR system runs. Mean concentration estimates for the five standards from the ddPCR analyses were 4.356, 3.381, 2.371, 1.641 and 1.071 log10 copies/5 MUL with associated standard deviations of 0.074, 0.082, 0.108, 0.131 and 0.188, respectively. These estimates contrasted with expected log10 concentrations of 4.6, 3.6, 2.6, 1.9 and 1.3 copies/5 MUL, respectively, based on the yield of the plasmid reported by the vendor and spectrophotometric analysis of the initial stock solution of this material. These results illustrate how the analyses of original stocks may lead to potential bias(es) in the concentration estimates of final DNA standards and subsequently in the estimates of unknown test samples determined from these standards in qPCR analyses. PMID- 30017850 TI - Development and characterization of a 3D oral mucosa model as a tool for host pathogen interactions. AB - The aim of this study was to (i) design, develop and validate a practical and physiologically relevant reconstituted in vitro oral mucosa tissue model and (ii) to assess its applicability in in vitro host-pathogen interactions with C. albicans and S. aureus. Co-culture organotypic constructions were created by incorporating specific numbers of keratinocytes (NOK-si) onto cellularised, collagen gel scaffolds containing human gingival fibroblasts incubated in KGM media and cultured for 14 days. The detection of the appropriate oral mucosa/epithelial structure was evaluated by histology (hematoxylin and eosin (HE), periodic acid-Schiff (P.A.S.) and Picrosirius red), and immunocytochemistry (cytokeratin 13, cytokeratin 14, Ki-67 and collagen IV) compared to a normal human gingiva. The morphology of the reconstituted tissue was analyzed by Transmission Electron Microscopy. To further quantitate tissue damage, lactate dehydrogenase (LDH) was measured in the tissue supernatant. NOK-si grown upon a gingival scaffold provided an organotypic model in an in vitro setting and exhibited structural characteristics typically associated with normal oral mucosa. Immunocytochemistry revealed the detection of epithelial cytokeratins 13 and 14, Col IV and Ki-67 in the reconstituted oral mucosa model. Infection was detected after 8 h and 16 h. This study presents an in vitro cellularised, organotypic model of reconstituted oral mucosa, which enables close control and characterization of its structure and differentiation over a mid-length period of time in culture. PMID- 30017851 TI - Filling the gaps in clinical proteomics: a do-it-yourself guide for the identification of the emerging pathogen Arcobacter by matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Arcobacters are considered emerging gastrointestinal pathogens. Rapid, reliable and species-specific identification of these bacteria is important. Biochemical tests commonly yield negative or variable results. Molecular methods prove more reliable but are time consuming and lack specificity. Matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) is a fast, cheap and robust technique that has revolutionized genus and species identification in clinical microbiology. The performance of an in vitro diagnostic (RUO) spectral database of MALDI-TOF MS for the identification of human clinically relevant Arcobacter isolates was validated and compared to an in house created Reference Spectral database (RS) containing a representative set of deposited Arcobacter strains of zoonotic interest. A challenge panel of clinical, human and veterinary, unique Campylobacteraceae strains was used to test accuracy. Using direct colony transfer, sensitivity with RS was significantly better than with RUO for A. butzleri and A. cryaerophilus identification (100% and 92% versus 74% and 16%). For A. skirrowii, sensitivity remained low (21% versus 0%). Reanalysis using formic acid overlay (on-target extraction) augmented sensitivity for the latter species to 64%. Specificity of RS database remained excellent without any misidentifications of human clinical strains including Campylobacter fetus and C. jejuni/coli. The use of an enriched database for MALDI TOF MS identification of Arcobacter spp. of human interest produced high confidence identifications to species level resulting in a significantly improved sensitivity with conservation of excellent specificity. Misidentifications, which can have therapeutic and public health consequences, were not encountered. PMID- 30017852 TI - Optimization of the synthesis of a key intermediate for the preparation of glucocorticoids. AB - A short and efficient synthesis, based on a one-step double elimination, of a key intermediate in the synthesis of various glucocorticosteroids has been developed. This method can be carried out on large scale for further industrial applications. The synthesis allowed us to identify a novel prednisolone derivative 10 and its anti-inflammatory activity was determined in an in vivo model of inflammation. In order to understand the regioselectivity of the double elimination under various conditions, mechanistic studies were undertaken and confirmed the experimental results. We also propose a mechanism for the formation of the new steroid 10 studied by molecular modeling. PMID- 30017853 TI - Murmur grading in humans and animals: past and present. AB - Cardiac murmurs were first described approximately 200 years ago. Subsequently, various clinicians, starting with Samuel Levine, have proposed grading schemes, depicting intensity, or other murmur characteristics, in an attempt to differentiate pathological and physiological murmurs or different degrees of pathology. In the 1960s, these schemes were adapted by veterinary cardiologists and have been used over the last 50 years. However, the clinical utility of these schemes has only recently been examined in veterinary medicine (and never examined in humans), and these studies suggest that the current, commonly used murmur grading scheme is unnecessarily complex and contains redundant information. A simpler, more intuitive grading scheme might achieve the same desired outcome as the more complex scheme, potentially with less confusion. This review examines the history of murmur grading and proposes a reconsideration of the current grading scheme to improve clinical communication. PMID- 30017854 TI - Schistosomal liver fibrosis and hepatocellular carcinoma - case series of patients submitted to liver transplantation. AB - Schistosomiasis affects approximately 207 million people in 76 countries. The association between hepatocellular carcinoma and Schistosoma mansoni infection has been investigated. Studies using animal models suggest that the parasite may accelerate the oncogenic process when combined with other factors, such as hepatitis C virus infection or exposure to a carcinogen. Herein, we report a case series of six hepatocellular carcinoma patients from Northeast Brazil, with negative serology for both hepatitis B and C virus, submitted to liver transplantation, whose explant showed evidence of schistosomal liver fibrosis. Since all patients enrolled in this study were submitted to liver transplantation, we were able to access the whole explanted liver and perform histopathological analysis, which is often not possible in other situations. Although 50% of them showed signs of liver failure, no cirrhosis or any liver disease other than schistosomal fibrosis had been detected. These uncommon findings suggest that Schistosoma mansoni infection might predispose to hepatocellular carcinoma development, regardless of the absence of other risk factors. PMID- 30017855 TI - Involvement of a short-type peptidoglycan recognition protein (PGRP) from Chinese giant salamanders Andrias davidianus in the immune response against bacterial infection. AB - PGRPs (Peptidoglycan recognition proteins) could recognize peptidoglycan and play vital roles in innate immunity among different animals. Till present, the functions of PGRP have been studied in various animals, but few reports have studied the amphibian PGRPs. In the current research, a short type PGRP was identified from Chinese giant salamander and its involvement in the innate immunity was studied. The ORF of AdPGRP-SC2 cDNA was 573 bp, which encoded 190 amino acids, and contained a PGRP and an amidase_2 domain. The qPCR analysis revealed that AdPGRP-SC2 mRNA transcripts expressed in different tissues, with the highest expression level in muscle, intestine and spleen. Results of immune challenges with peptidoglycan (PGN) demonstrated that expression patterns of AdPGRP-SC2 were significantly up-regulated in erythrocyte and spleen at the early injection stage. The recombinant AdPGRP-SC2 protein was successfully produced and purified, and it could show binding affinity to different bacteria. In the presence of Zn2+, the rAdPGRP-SC2 could exhibit a broad PAMPs binding activities, strongly agglutinate bacteria and exhibit amidase enzyme activity. Collectively, these data indicate AdPGRP-SC2 could act as PRR to recognize the invading microorganisms and as the antimicrobial effectors during the innate immune response of A. davidianus. PMID- 30017856 TI - Establishment of fin cell lines and their use to study the immune gene expression in cyprinid fishes with different ploidy in rhabdovirus infection. AB - Triploid hybrid (3n = 150) of red crucian carp (?, 2n = 100) and allotetraploid (?, 4n = 200) display improved disease resistance and stress resistance than their parents. In order to elucidate their innate immune mechanisms, three novel cell lines from the caudal fin of red crucian carp, triploid hybrid and allotetraploid (named 2nFC, 3nFC and 4nFC accordingly) were established and characterized respectively. 2nFC, 3nFC and 4nFC showed fibroblast-like morphology and characteristics. They have been subcultured for more than 100 passages since the initial primary culture. Viral infection experiments showed that 2nFC, 3nFC and 4nFC were susceptible to spring viraemia of carp virus (SVCV) infection. Intriguingly, 3nFC performed the stronger resistance ability against SVCV than 2nFC and 4nFC, which indicated that 2nFC, 3nFC and 4nFC might be used as the suitable in vitro models for exploring and analyzing the differences among these three cyprinid fishes in antiviral innate immune mechanisms. Based on this, we analyzed the transcriptome profile of 2nFC, 3nFC and 4nFC in the context of SVCV infection. The KEGG enrichment analysis showed that the differentially expressed genes (DEGs) were primarily enriched to immune-related signaling pathways. However, some signaling pathways against viral infection were activated remarkably in 2nFC and 3nFC but not in 4nFC. Overall, the establishment of 2nFC, 3nFC and 4nFC provided us a suitable platform to elucidate the innate immunity of fishes with different ploidy and clear genetic relationship. PMID- 30017857 TI - Comparative analysis of the immune system of an invasive bark beetle, Dendroctonus valens, infected by an entomopathogenic fungus. AB - Dendroctonus valens LeConte is one of the most economically important forest pest in China. Leptographium procerum, a mutualistic fungus can assist the host beetle in overcoming the pine's chemical defenses, and Beauveria bassiana, an entomopathogenic fungus has shown high beetle killing efficiency. Considering that the D. valens immune system remains unknown at the genomic level, a mutualistic and antagonistic fungus associated with the beetle provides an ideal model for studying immune interactions between the insect and associated fungi. Here, B. bassiana killed most tested larvae more effectively than L. procerum and Tween. The entomopathogenic fungus provoked stronger responses than the symbiotic fungus at the transcriptome level. We identified 185 immunity-related genes, including pattern recognition receptors, signal modulators, members of immune pathways (Toll, IMD, and JAK/STAT), and immune effectors. Quantitative real-time PCR analysis confirmed that several recognition receptors and effector genes were activated at 1 or 2 days post infection, while the effector genes were suppressed at 4 days post infection by B. bassiana, respectively. In contrast, effector genes were upregulated in response to L. procerum. Together, this study provides a comprehensive sequence resource and insight into the D. valens immune system and lays a basis for understanding the molecular aspects of the interaction between the host and associated fungi. PMID- 30017858 TI - Tetrabenazine, a vesicular monoamine transporter-2 inhibitor, attenuates morphine induced hyperlocomotion in mice through alteration of dopamine and 5 hydroxytryptamine turnover in the cerebral cortex. AB - A single administration with morphine (30 mg/kg, i.p.) induced long-lasting hyperlocomotion in male ICR mice. Pretreatment of mice with a benzoquinolizine derivative tetrabenazine (TBZ; a reversible vesicular monoamine transporter-2 inhibitor) (1 mg/kg, i.p.) for 30 min significantly attenuated the hyperlocomotion induced by morphine, as compared with vehicle (saline)-pretreated mice. No significant change in locomotion was observed in mice pretreated with TBZ (1 mg/kg) alone. Mice treated with TBZ (1 mg/kg) showed an increase in immobility time in a tail suspension test, as compared with saline-treated mice. Pretreatment with TBZ (1 mg/kg) had no effect on morphine (1-30 mg/kg)-induced antinociception. TBZ at a dose of 1 mg/kg inhibited dopamine turnover (the ratio of 3,4-dihydroxyphenylacetic acid/dopamine) and 5-hydroxytryptamine turnover (the ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the cerebral cortex of mice challenged with morphine, as compared with saline-pretreated mice challenged with morphine. No stereotypic behavior was observed in mice treated with morphine (30 mg/kg) in combination with TBZ (1 mg/kg), so the reduction in observed locomotion did not result from induction of stereotypical behavior. Moreover, TBZ (1 and 2 mg/kg) pretreatment had no effect on stereotyped behaviors observed in mice challenged with 10 mg/kg methamphetamine. These data support the potential antagonistic actions of TBZ on some opiate actions, and encourage further exploration of potential effects on morphine reinforcement. PMID- 30017859 TI - Have we made true progress in surgical indications and determining the limitations of spinal fusion in patients with idiopathic scoliosis? PMID- 30017860 TI - Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node. AB - Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 MUM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 MUM). A whole-cell patch clamp was used to record the late sodium current (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 MUM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 MUM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 MUM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 MUM (N = 6, P < 0.05). However, neither edoxaban (1 MUM) nor rivaroxaban (0.3 MUM) reduced PV spontaneous beating rates in the presence of 1 MUM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 MUM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 MUM) and rivaroxaban (0.1 and 0.3 MUM) respectively decreased the INa late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs. PMID- 30017861 TI - Hyper-insulinemia increases the glutamate-excitotoxicity in cortical neurons: A mechanistic study. AB - Insulin resistance in type-2 diabetic condition increases the risk of stroke and cognitive deficits in which involvement of glutamate has been postulated. It has been hypothesized that hyper-insulinemia in cortical neurons increases the vulnerability towards glutamate-induced excitotoxicity. To mimic insulin resistance, cortical neurons were incubated with high insulin (1 uM) and high glucose (50 mM final concentration) in in-vitro condition for 24 h. Pre-treatment of cortical neurons with high insulin blocked acute insulin-induced activation of Akt and GSK-3beta but not in the case of high glucose. Our results demonstrate that chronic high insulin exposure increases glutamate-induced excitotoxity, which was blocked by insulin receptor antagonist (S961) and GSK-3beta inhibitor (SB216763). These inhibitors also ameliorated pAkt (Ser473) and pGSK-3beta(Ser9) levels after chronic insulin exposure. Increase in glutamate-excitotoxicity in insulin-resistant cortical neurons was found to be associated with increased expression of PICK1. However, GluR2 did not get altered in hyper-insulinemia condition. This study demonstrates that hyper-insulinemia increases glutamate excitotoxicity which could be attributed to activation of GSK-3beta and increased expression of PICK1. PMID- 30017862 TI - Experiences and outcome from the implementation of a national Swedish automated external defibrillator registry. AB - BACKGROUND: Early cardiopulmonary resuscitation (CPR) and defibrillation with an Automated External Defibrillator (AED) increase survival from out-of-hospital cardiac arrest (OHCA). Although international guidelines recommend the use of AED registries to increase AED use, little is known about implementation. The aim of this paper is to describe the development of a national AED registry, to analyse the coverage and barriers to register AEDs. METHODS: The Swedish AED Registry (SAEDREG) was initiated in 2009 with the purpose of gathering the data of all public AEDs in Sweden. Data on all AEDs between 2013 and 2016 were included in the study. Additionally, data of non-registered AEDs was collected in one region using a survey to AED owners focusing on AED functionality. RESULTS: The number of AEDs doubled between 2013-2016. A total of 6703 AEDs (30%) were removed due to unavailability of validation. At the end of 2016, AEDs were most frequently registered in offices and workplaces, 45% (n = 7241) followed by shops, 7% (n = 1200). In the Gotland region, 218 AEDs, 57% (n = 124) were registered in the SAEDREG. Of n = 94 Non-registered AED functionality was high, the main reason not to register was unawareness of the SAEDREG, 74.5%. Of those aware of the register but not having registered, 25% stated "hard to register" as cause. CONCLUSIONS: A national AED registry may gather information of AEDs on a national level. Although numbers have doubled between 2013-2016 in Sweden, a large proportion is still non-registered. More awareness of the registry and easier registration process is needed. General AED functionality seems high regardless of registered or non-registered AEDs. A key area for future research may be to use AED registers to ascertain effectiveness of AED programs in terms of actual patient outcome. PMID- 30017864 TI - Long-term neurotoxic effects of domoic acid on primary dopaminergic neurons. AB - Domoic acid, an excitatory neurotoxin produced by certain algae, reaches the food chain through accumulation in some sea organisms. To investigate its long-term neurotoxicity on dopaminergic neurons, prepared primary mesencephalic cell cultures were exposed to different concentrations of domoic acid (0.1, 1, 10, 100 MUM) on the 8th day in vitro (DIV) for 4 days. On the 12th DIV, culture media were collected for measurement of lactate dehydrogenase and cultured cells were subjected to immunohistochemistry against tyrosine hydroxylase, neuronal nuclear antigen and glial fibrillary acidic protein, and fluorescence staining using H2DCFDA, JC-1 and Hoechst 33342 dyes. Moreover, roles of AMPA/KA and NMDA receptors in domoic acid neurotoxicity were also investigated. Domoic acid significantly decreased the number of dopaminergic neurons and adversely affected their morphology, and slightly reduced the expression of neuronal nuclear antigen and glial fibrillary acidic protein. Co-treatment of cultures with domoic acid and the AMPA/KA or NMDA receptor antagonists NBQX and MK-801 rescued significant number of dopaminergic neurons. Domoic acid significantly decreased red:green fluorescence ratio of JC-1 and did not affect production of reactive oxygen species and apoptotic cell death. In conclusions, the present study reveals that long-term treatment of primary mesencephalic cell culture with domoic acid significantly destroyed dopaminergic neurons. This effect appears to be attributed to activation of AMPA/KA and NMDA receptors and mitochondrial damage. PMID- 30017863 TI - Clip domain prophenoloxidase activating protease is required for Ostrinia furnacalis Guenee to defend against bacterial infection. AB - The prophenoloxidase (PPO) activating system in insects plays an important role in defense against microbial invasion. In this paper, we identified a PPO activating protease (designated OfPAP) containing a 1203 bp open reading frame encoding a 400-residue protein composed of two clip domains and a C-terminal serine protease domain from Ostrinia furnacalis. SignalP analysis revealed a putative signal peptide of 18 residues. The mature OfPAP was predicted to be 382 residues long with a calculated Mr of 44.8 kDa and pI of 6.66. Multiple sequence alignment and phylogenetic analysis indicated that OfPAP was orthologous to the PAPs in the other lepidopterans. A large increase of the transcript levels was observed in hemocytes at 4 h post injection (hpi) of killed Bacillus subtilis, whereas its level in integument increased continuously from 4 to 12 hpi in the challenged larvae and began to decline at 24 hpi. After OfPAP expression had been silenced, the median lethal time (LT50) of Escherichia coli-infected larvae (1.0 day) became significantly lower than that of E. coli-infected wild-type (3.0 days, p < 0.01). A 3.5-fold increase in E. coli colony forming units occurred in larval hemolymph of the OfPAP knockdown larvae, as compared with that of the control larvae not injected with dsRNA. There were notable decreases in PO and IEARase activities in hemolymph of the OfPAP knockdown larvae. In summary, we have demonstrated that OfPAP is a component of the PPO activation system, likely by functioning as a PPO activating protease in O. furnacalis larvae. PMID- 30017865 TI - LC-MS/MS based profiling and dynamic modelling of the steroidogenesis pathway in adrenocarcinoma H295R cells. AB - Endocrine disrupting chemicals have been reported to exert effects directly on enzymes involved in steroid biosynthesis. Here, we present a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for profiling the steroid metabolome of H295R human adrenocarcinoma cells. Our method can simultaneously analyse 19 precursors, intermediates and end-products, representing the adrenal steroid biosynthesis pathway. In order to obtain better insights into the processes of steroidogenesis, we investigated the dose-response relationship of forskolin, an activator of adenylate cyclase, on steroid production in H295R cells. We observed that 1.5 MUM forskolin stimulated steroid production at approximately 50% of the maximum rate for most steroids. Hence, we studied the time course for steroid synthesis over 72 h in H295R cells that were stimulated with forskolin. At 24 h, we observed a peak in steroid levels for the intermediate metabolites, such as progesterone and pregnenolone, while end products such as testosterone and cortisol continued to increase until 72 h. Finally, we show how global data provide a unique basis to develop a comprehensive, dynamic model for steroidogenesis using first order kinetics. The timeline data made it possible to estimate all reaction rate constants of the network. We propose this method as a unique and sensitive screening tool to identify effects on adrenal steroidogenesis by endocrine disrupting compounds. PMID- 30017867 TI - Customary practices in the monitoring of dry eye disease in Sjogren's syndrome. AB - PURPOSE: Diagnostic testing for dry eye disease (DED) in Sjogren's syndrome (SS) is well described. Little is published about monitoring this systemic autoimmune DED. We analyzed the SS related DED tests used in North American optometric practices and compared academic settings to private practice settings. METHODS: A retrospective chart review of 123 SS charts from 6 optometric practices in North America was conducted. Testing done during the first examination following a SS diagnosis was recorded on Research Electronic Data Capture (REDCap) database. The complete data file was reviewed and testing type and methodology were compared. RESULTS: Symptoms of DED (98.4% of charts),meibomian gland dysfunction (76.4% of charts), corneal staining with fluorescein (75.6% of charts) and anterior blepharitis (73.2% of charts) were the most frequently recorded variables. Clinicians used different methodologies to measure and grade these variables. Private practitioners were more likely to use symptom questionnaires and grading scales and to describe anterior blepharitis. Academic settings were more likely to record TBUT and tear meniscus height. CONCLUSIONS: The monitoring of DED in SS is not uniform in optometric offices across North America. Creating accepted standards of testing will improve the ability of clinicians and researchers to communicate and understand the course of DED in SS. PMID- 30017866 TI - The eyelash follicle features and anomalies: A review. AB - The primary role of eyelashes is to protect and maintain the health of the lid margin. However, the mechanisms to fulfill this role are not fully understood. Unraveling these mechanisms will stand to greatly improve the efficiency of eye care professionals' interventions in anomalies of the eyelashes. The aim of this article is to provide a review on eyelashes including highlights and new avenues for research; the biology of both the lash and its follicle; the pathophysiology and management of lash anomalies by eye care professionals; and the effect of iatrogenic factors on lashes. Using the database of Ovid MEDLINE, we reviewed studies specifically directed on human/mammalian eyelashes and key articles on current trends in scalp hair methodologies that can be applicable to lash research. The eyelash morphology, pigmentation and growth rate have been documented using techniques ranging from lash imaging to follicle immunohistochemistry. Furthermore, studies have demonstrated that the lash follicle is sensitive to many factors of the external environment, a variety of systemic/topical medications and cosmetics. Recently, aerodynamic studies using a mammalian eye model confirmed that an optimal lash length was needed so that eyelashes serve a protective role in reducing the number of particles that can reach the eye. Despite recent advances in lash research, studies are still scarce, due to the limited availability of the human lid for sampling. This review brings awareness that further research is needed with respect to eyelashes and will hopefully reduce the gap with scalp hair research. PMID- 30017868 TI - A neural network algorithm for detection of GI angiectasia during small-bowel capsule endoscopy. AB - BACKGROUND AND AIMS: GI angiectasia (GIA) is the most common small-bowel (SB) vascular lesion, with an inherent risk of bleeding. SB capsule endoscopy (SB-CE) is the currently accepted diagnostic procedure. The aim of this study was to develop a computer-assisted diagnosis tool for the detection of GIA. METHODS: Deidentified SB-CE still frames featuring annotated typical GIA and normal control still frames were selected from a database. A semantic segmentation images approach associated with a convolutional neural network (CNN) was used for deep-feature extractions and classification. Two datasets of still frames were created and used for machine learning and for algorithm testing. RESULTS: The GIA detection algorithm yielded a sensitivity of 100%, a specificity of 96%, a positive predictive value of 96%, and a negative predictive value of 100%. Reproducibility was optimal. The reading process for an entire SB-CE video would take 39 minutes. CONCLUSIONS: The developed CNN-based algorithm had high diagnostic performances, allowing detection of GIA in SB-CE still frames. This study paves the way for future automated CNN-based SB-CE reading softwares. PMID- 30017869 TI - Etiological spectrum and response to endoscopic balloon dilation in patients with benign gastric outlet obstruction. AB - BACKGROUND AND AIMS: Peptic ulcer disease (PUD)-related gastric outlet obstruction (GOO) is known to respond favorably to endoscopic balloon dilation (EBD). However, data on efficacy of EBD for other etiologies of benign GOO are sparse. We aimed to compare the response of EBD among different etiologies of GOO. METHODS: Records of all patients with benign GOO who underwent EBD at our tertiary-care center between January 1998 and December 2017 were analyzed. Dilation was done by using through-the-scope balloons. Procedural and clinical success of EBD was compared among different etiologies. RESULTS: A total of 306 patients were evaluated, of whom 264 (mean [+/- standard deviation] [SD] age 37.89 +/- 17.49 years; men 183, women 81) underwent dilation. Etiologically, caustic ingestion was the commonest cause of GOO (53.8%) followed by PUD (26.1%) and medication-induced (8.3%). Overall procedural and clinical success was achieved in 200 (75.7%) and 243 (92.04%) patients, respectively, requiring a mean (+/- SD) of 2.55 (2.8) and 5.37 (3.9) sessions, respectively. Caustic-induced GOO responded less favorably, requiring a higher number of dilation sessions and having more refractory strictures than other etiologies. Medication-induced GOO performed worse than PUD-related GOO. Of the 264 patients, 9 (3.4%) had perforations during EBD, 3 had contained leaks and were managed conservatively, and 6 underwent successful surgery. CONCLUSION: EBD is successful in a majority of patients with benign GOO, with caustic-induced GOO and medication-induced GOO being more difficult than PUD-related GOO. PMID- 30017870 TI - 18F-FDG PET/CT imaging of trichoblastoma of the knee. PMID- 30017871 TI - Does sexual conflict increase juvenile survival by reducing cannibalism? AB - To test the hypothesis that male harassment of females reduces adult female time spent on the water foraging (water use), and thus cannibalism by adult females on juveniles, we manipulated heterospecific prey availability, and social context in adult water striders and measured their effects on: 1) cannibalism of juveniles, 2) activity of adults and 3) habitat use of adults and juveniles. Cannibalism rarely occurred with alternative prey present, but was common without alternative prey. Without alternative prey, females cannibalized much more than males, but contrary to predictions, male presence did not reduce cannibalism rates. Male presence decreased female water use; however, this was counteracted by the fact that the lack of alternative prey increased female water use and activity while on the water. Furthermore, in groups of 4 males with 4 females, lack of alternative prey reduced male activity while on the water. Thus the predicted negative effect of sexual conflict on cannibalism was reduced by female and male responses to low food availability. Juveniles increased time off the water when more females or males were more on the water and active. Overall, cannibalism rates depended on alternative prey, male-female social dynamics, female foraging and juvenile refuge use. PMID- 30017872 TI - Prophylactic central neck dissection and local recurrence in papillary thyroid microcarcinoma: a meta-analysis. AB - INTRODUCTION: For papillary thyroid microcarcinoma patients, the reported incidence of lymph node metastasis is as high as 40%, and these occur mainly in the central compartment of the neck. Because these metastases are difficult to detect using ultrasonography preoperatively, some authors advocate routine central neck dissection in papillary thyroid microcarcinoma patients at the time of initial thyroidectomy. OBJECTIVE: To evaluate whether prophylactic central neck dissection can decrease the local recurrence rate of papillary thyroid microcarcinoma after thyroidectomy. METHODS: The publicly available literature published from January 1990 to December 2017 concerning thyroidectomy plus prophylactic central neck dissection versus thyroidectomy for papillary thyroid microcarcinoma was retrieved by searching the national and international online databases. A meta-analysis was performed after the data extraction process. RESULTS: Four studies were finally included with a total of 727 patients, of whom, 366 cases underwent thyroidectomy plus prophylactic central neck dissection and 361 cases received thyroidectomy only. As shown by the meta-analysis results, the recurrence rates in cases of thyroidectomy plus prophylactic central neck dissection were approximately 1.91% and were significantly lower than those with thyroidectomy only (OR=0.24, 95% CI [0.10, 0.56], p=0.0009). CONCLUSION: For patients with papillary thyroid microcarcinoma, thyroidectomy plus prophylactic central neck dissection is a safe and efficient procedure and it results in lower recurrence rate. Since the evidences are of low quality (non-randomized studies), further randomized trials are needed. PMID- 30017873 TI - The influence of standardized dry ivy leaf extract on the proportion of nasal secretion after post-septoplasty nasal packing removal. AB - INTRODUCTION: After post-septoplasty nasal packing removal, a certain proportion of nasal secretion occurs, leading to local and sometimes systemic infections. OBJECTIVE: The aim was to determine if standardized dry ivy leaf extract application after nasal packing removal influences the reduction of nasal secretion and diminish the occurrence of local infections. METHODS: The study included 70 post-septoplasty patients (divided into two equal groups) whose nasal packing was removed on the third day after the procedure. Group I was treated with standardized dry ivy leaf extract syrup along with regular nasal irrigation for the five days after the nasal packing removal whereas the Group II had only nasal lavage. On the sixth day after nasal packing removal, the quantity of nasal secretion was determined using a visual analog scale and nasal endoscopic examination. RESULTS: The group treated with standardized dry ivy leaf extract syrup had significantly lesser nasal secretion both by subjective patients' assessment (p<0.001) and by nasal endoscopic examination (p=0.003). The post surgical follow up examination on the sixth day after nasal packing removal showed no development of local infection in the Group I, while in the Group II a local infection was evident in five patients (14.29%) and antibiotic therapy was required. CONCLUSION: The use of the standardized dry ivy leaf extract after nasal packing removal significantly lowers the proportion of nasal secretion. PMID- 30017874 TI - Elaboration of an instrument to evaluate the recognition of Brazilian melodies in children. AB - INTRODUCTION: There is evidence pointing to the importance of the evaluation of musical perception through objective and subjective instruments. In Brazil, there is a shortage of instruments that evaluates musical perception. OBJECTIVE: To develop an instrument to evaluate the recognition of traditional Brazilian melodies and investigate the performance of children with typical hearing. METHODS: The study was carried out after approval of the research ethics committee (1.198.607). The instrument was developed in software format with website access, using the languages PHP 5.5.12, Javascript, Cascade style sheets and "HTML5"; database "MYSQL 5.6.17" on the "Apache 2.4.9" server. Fifteen melodies of Brazilian folk songs were recorded in piano synthesized timbre, with 12 seconds per melody reproduction and four second intervals between them. A total of 155 schooled children, aged eight to 11 years, of both sexes, with typical hearing participated in the study. The test was performed in a silent room with sound stimuli amplified by a sound box at 65dBNA, positioned at 0 azimuth, and at one meter from the participant, the notebook was used for children to play with on the screen on the title and illustration of the melody they recognized they were listening to. The responses were recorded on their own database. RESULTS: The instrument titled "Evaluation of recognition of traditional melodies in children" can be run on various devices (computers, notebooks, tablets, mobile phones) and operating systems (Windows, Macintosh, Android, Linux). Access: http://192.185.216.17/ivan/home/login.php by login and password. The most easily recognized melody was "Cai, cai balao" (89%) and the least recognized was "Capelinha de melao" (25.2%). The average time to perform the test was 3'15". CONCLUSION: The development and application of the software proved effective for the studied population. This instrument may contribute to the improvement of protocols for the evaluation of musical perception in children with hearing aid and/or cochlear implants users. PMID- 30017875 TI - Fine needle non-aspiration cytology for the diagnosis of cervical lymph node tuberculosis: a single center experience. AB - INTRODUCTION: The fine-needle cytology is being used as a first line of investigation in the diagnosis of head and neck swellings, as it is simple, cost effective and less invasive as compared to biopsy. OBJECTIVE: The aims of this study were to evaluate the results of the fine-needle non-aspiration cytology of cervical lymphadenopathy and to study the factors influencing the rate of non diagnosis results. METHODS: This retrospective study was conducted on selected patients with cervical lymphadenopathy that had undergone a fine-needle non aspiration cytology followed by a histological biopsy. The sensitivity, specificity, positive predictive value and negative predictive value of fine needle non-aspiration cytology for diagnosing tuberculosis were estimated. The risk factors of non-diagnosis results were evaluated. RESULTS: The sensitivity, specificity, positive predictive value rates of fine-needle non-aspiration cytology for tuberculosis were 83.3%, 83.3%, 78.9% and 86.9% respectively. In total, 47 out of the 131 samples (35.8%) were considered non-diagnosis. Of the non-diagnosis samples, 84.2% (38 out of 47) were benign mostly due to tuberculosis (30 cases). Among the studied factors, only tuberculosis (confirmed by histopathological examination) was significantly associated with non-diagnosis cytology (p=0.02, Odds-Ratio=2.35). CONCLUSION: Tuberculosis is currently the commonest cause of cervical lymphadenopathy in North Africa. Fine-needle non aspiration cytology is safe and accurate in the diagnosis of cervical tuberculous lymph node that is associated with the risk of non-diagnosis cytology. PMID- 30017876 TI - Ancestral Adeno-Associated Virus Vector Delivery of Opsins to Spiral Ganglion Neurons: Implications for Optogenetic Cochlear Implants. AB - Optogenetics is a transformative technology based on light-sensitive microbial proteins, known as opsins, that enable precise modulation of neuronal activity with pulsed radiant energy. Optogenetics has been proposed as a means to improve auditory implant outcomes by reducing channel interaction and increasing electrode density, but the introduction of opsins into cochlear spiral ganglion neurons (SGNs) in vivo has been challenging. Here we test opsin delivery using a synthetically developed ancestral adeno-associated virus (AAV) vector called Anc80L65. Wild-type C57BL/6 mouse pups were injected via the round window of cochlea with Anc80L65 carrying opsin Chronos under the control of a CAG promoter. Following an incubation of 6-22 weeks, pulsed blue light was delivered to cochlear SGNs via a cochleosotomy approach and flexible optical fiber. Optically evoked auditory brainstem responses (oABRs) and multiunit activity in inferior colliculus (IC) were observed. Post-experiment cochlear histology demonstrated opsin expression in SGNs (mean = 74%), with an even distribution of opsin along the cochlear basal/apical gradient. This study is the first to describe robust SGN transduction, opsin expression, and optically evoked auditory electrophysiology in neonatal mice. Ultimately, this work may provide the basis for a new generation of cochlear implant based on light. PMID- 30017879 TI - Oncolytic Virotherapy: Single Cycle Cures or Repeat Treatments? (Repeat Dosing Is Crucial!). PMID- 30017877 TI - Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy. AB - Lymphodepleting preconditioning with high-dose chemotherapy is commonly used to increase the clinical efficacy of adoptive T cell therapy (ACT) strategies, however, with severe toxicity for patients. Conversely, oncolytic adenoviruses are safe and, when engineered to express interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-alpha), they can achieve antitumor immunomodulatory effects similar to lymphodepletion. Therefore, we compare the safety and efficacy of such adenoviruses with a cyclophosphamide- and fludarabine-containing lymphodepleting regimen in the setting of ACT. Human adenovirus (Ad5/3-E2F-D24-hTNF-alpha-IRES hIL-2; TILT-123) replication was studied using a Syrian hamster pancreatic tumor model (HapT1) infused with tumor-infiltrating lymphocytes (TILs). Using the oncolytic virus instead of lymphodepletion resulted in superior efficacy and survival. Immune cells responsive to TNF-alpha IL-2 were studied using an immunocompetent mouse melanoma model (B16.OVA) infused with ovalbumin-specific T (OT-I) cells. Here, the adenovirus approach improved tumor control together with increased intratumoral Th1 cytokine levels and infiltration of CD8+ T cells and CD86+ dendritic cells. Similar to humans, lymphodepleting preconditioning caused severe cytopenias, systemic inflammation, and damage to vital organs. Toxicity was minimal in adenovirus- and OT-I-treated mice. These findings demonstrate that ACT can be effectively facilitated by cytokine-coding adenovirus without requiring lymphodepletion, a rationale being clinically investigated. PMID- 30017878 TI - Extracellular Vesicles Containing IL-4 Modulate Neuroinflammation in a Mouse Model of Multiple Sclerosis. AB - Extracellular vesicles (EVs) play a major role in cell-to-cell communication in physiological and pathological conditions, and their manipulation may represent a promising therapeutic strategy. Microglia, the parenchymal mononuclear phagocytes of the brain, modulate neighboring cells also through the release of EVs. The production of custom EVs filled with desired molecules, possibly targeted to make their uptake cell specific, and their administration in biological fluids may represent a valid approach for drug delivery. We engineered a murine microglia cell line, BV-2, to release EVs overexpressing the endogenous "eat me" signal Lactadherin (Mfg-e8) on the surface to target phagocytes and containing the anti inflammatory cytokine IL-4. A single injection of 107 IL-4+Mfg-e8+ EVs into the cisterna magna modulated established neuroinflammation and significantly reduced clinical signs in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Injected IL-4+Mfg-e8+ EVs target mainly phagocytes (i.e., macrophages and microglia) surrounding liquoral spaces, and their cargo promote the upregulation of anti-inflammatory markers chitinase 3-like 3 (ym1) and arginase-1 (arg1), significantly reducing tissue damage. Engineered EVs may represent a biological drug delivery tool able to deliver multiple functional molecules simultaneously to treat neuroinflammatory diseases. PMID- 30017881 TI - The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Nav 1.6. AB - Parkinson's disease (PD), the second most common age-related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an-anti-convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO-B). However, zonisamide has additional targets, including voltage-gated sodium channels (Nav), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Nav1.6 is highly expressed in microglia of post-mortem PD brain and of mice treated with the parkinsonism-inducing neurotoxin MPTP. Administration of zonisamide (20 mg/kg, i.p. every 4 h * 3) following a single injection of MPTP (12.5 mg/kg, s.c.) reduced microglial Nav 1.6 and microglial activation in the striatum, as indicated by Iba-1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro-inflammatory cytokine TNF-alpha and gp91phox, and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down regulation of microglial Nav 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO-B, zonisamide may have disease modifying potential through the inhibition of Nav 1.6 and neuroinflammation. PMID- 30017880 TI - Combination of Asiatic Acid and Naringenin Modulates NK Cell Anti-cancer Immunity by Rebalancing Smad3/Smad7 Signaling. AB - Transforming growth factor beta1 (TGF-beta1) plays a promoting role in tumor growth via a mechanism associated with hyperactive Smad3 and suppressed Smad7 signaling in the tumor microenvironment. We report that retrieving the balance between Smad3 and Smad7 signaling with asiatic acid (AA, a Smad7 inducer) and naringenin (NG, a Smad3 inhibitor) effectively inhibited tumor progression in mouse models of invasive melanoma (B16F10) and lung carcinoma (LLC) by promoting natural killer (NK) cell development and cytotoxicity against cancer. Mechanistically, we found that Smad3 physically bound Id2 and IRF2 to suppress NK cell production and NK cell-mediated cytotoxicity against cancer. Treatment with AA and NG greatly inhibited Smad3 translation and phosphorylation while it restored Smad7 expression, and, therefore, it largely promoted NK cell differentiation, maturation, and cytotoxicity against cancer via Id2/IRF2 associated mechanisms. In contrast, silencing Id2 or IRF2 blunted the protective effects of AA and NG on NK cell-dependent anti-cancer activities. Thus, treatment with AA and NG produced an additive effect on inactivating TGF-beta1/Smad3 signaling, and, therefore, it suppressed melanoma and lung carcinoma growth by promoting NK cell immunity against cancer via a mechanism associated with Id2 and IRF2. PMID- 30017882 TI - Criteria to define mild, moderate, and severe traumatic brain injury in the mouse controlled cortical impact model. AB - Traumatic brain injury (TBI) is a major health concern in the United States resulting in a substantial number of hospitalizations and in a broad spectrum of symptoms and disabilities. In the clinical setting, neurological responsiveness and structural imaging are used to classify mild, moderate and severe TBI. To evaluate the complex secondary and severity-specific injury response, investigators have relied on pre-clinical rodent models. The controlled cortical impact (CCI) model in mice is a widely used to study TBI. The CCI method has demonstrated consistent intra-laboratory outcomes due to precise control of cortical depth penetration, dwell time and speed of impact. While the CCI method results in control of injury severity, there is no consensus regarding the injury parameters or behavioral and histological endpoints that constitute a mild, moderate or severe TBI in this model. This discrepancy has resulted in considerable variability across laboratories in the outcomes of CCI-induced mild, moderate, and severe TBI. Inconsistent with clinical evaluation, injury severity in the CCI model has predominately relied on the extent of tissue damage. In the present review, we discuss variations in surgical parameters for injury induction as well as the criteria used to determine injury severity. Additionally, we propose guiding principles for the induction and defining of mild, moderate and severe TBI in the craniectomy-dependent experimental mouse CCI model. PMID- 30017883 TI - Circulating tumour DNA genomics in EGFR-mutant lung adenocarcinoma. PMID- 30017885 TI - Freeze-Drying From Organic Co-Solvent Systems, Part 2: Process Modifications to Reduce Residual Solvent Levels and Improve Product Quality Attributes. AB - The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various cosolvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low-melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation. PMID- 30017884 TI - Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial. AB - BACKGROUND: Detection of EGFR mutations in tumour tissue is the gold-standard approach to ascertain if a patient will benefit from treatment with an EGFR tyrosine kinase inhibitor. However, if tissue is scant, another strategy is to use circulating tumour DNA (ctDNA), but this method needs validation in clinical trials. We did a prospective clinical trial to assess ctDNA-based EGFR mutation detection as a selection criterion for patients with lung adenocarcinoma receiving gefitinib as first-line treatment. METHODS: BENEFIT is a multicentre, single-arm, phase 2 clinical trial at 15 centres in China. Patients aged 18-75 years with stage IV metastatic lung adenocarcinoma and EGFR mutations detected in ctDNA were given oral gefitinib 250 mg once daily as first-line treatment. The primary endpoint was the proportion achieving an objective response. Secondary endpoints included median progression-free survival and safety. Next-generation sequencing (NGS) of a 168-gene panel was used for genetic analysis of baseline blood samples. The primary efficacy analysis was done by intention to treat in patients who had at least one post-baseline tumour assessment. The safety analysis was done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02282267. FINDINGS: Between Dec 25, 2014, and Jan 16, 2016, 426 patients were screened for the trial, of whom 188 with EGFR mutations in ctDNA were enrolled and received gefitinib. 183 patients had one or more post-baseline tumour assessment and were included in the primary efficacy analysis. Median follow-up was 14.5 months (IQR 12.2-16.5). At the time of data cutoff (Jan 31, 2017), 152 patients had progressive disease or had died. The proportion achieving an objective response was 72.1% (95% CI 65.0-78.5). Median progression-free survival was 9.5 months (95% CI 9.07-11.04). Of 167 patients with available blood samples, 147 (88%) showed clearance of EGFR mutations in ctDNA at week 8, and median progression free survival was longer for these patients than for the 20 patients whose EGFR mutations persisted at week 8 (11.0 months [95% CI 9.43-12.85] vs 2.1 months [1.81-3.65]; hazard ratio [HR] 0.14, 95% CI 0.08-0.23; p<0.0001). From baseline NGS data in 179 patients, we identified three subgroups of patients: those with EGFR mutations only (n=58), those with mutations in EGFR and tumour-suppressor genes (n=97), and those with mutations in EGFR and oncogenes (n=24). Corresponding median progression-free survival in these subgroups was 13.2 months (95% CI 11.5-15.0), 9.3 months (7.6-11.0), and 4.7 months (1.9-9.3), respectively (EGFR mutations only vs mutations in EGFR and tumour-suppressor genes, HR 1.78, 95% CI 1.23-2.58; p=0.002; EGFR mutations only vs mutations in EGFR and oncogenes, 2.66, 1.58-4.49; p=0.0003). The most common grade 3 or 4 adverse events were hepatic function abnormalities (n=24). Serious adverse events were reported in 17 (9%) patients. No unexpected safety events for gefitinib were recorded. INTERPRETATION: Detection of EGFR mutations in ctDNA is an effective method to identify patients who might benefit from first-line gefitinib treatment. Further analyses of dynamic alterations of EGFR mutations and accompanying gene aberrances could predict resistance to gefitinib. FUNDING: Guangdong Association of Clinical Trials, AstraZeneca, National Natural Sciences Foundation Key Programme, and National Key Research and Development Programme of China. PMID- 30017886 TI - Long-Term Stability and Reversible Thermal Unfolding of Antibody Structure at Low pH: Case Study. AB - We have here observed that the differential scanning calorimetry profiles and melting temperatures of a humanized antibody were unchanged over a 10-year span when stored at 4 degrees C and at different pH values, even at pH 2.7. This is somewhat surprising, as this particular antibody undergoes conformational changes below pH 4.0. Differential scanning calorimetry analysis showed that melting of the antibody at pH 2.7 was highly reversible, suggesting a possibility that the observed reversibility is at least in part responsible for a 10-year stability at low pH. Conversely, it showed thermal unfolding followed by aggregation at higher pH. PMID- 30017887 TI - How Well Do Low- and High-Concentration Protein Interactions Predict Solution Viscosities of Monoclonal Antibodies? AB - Protein-protein interactions (PPI) and solution viscosities were measured at low and high protein concentrations under a range of formulation conditions for 4 different monoclonal antibodies. Static light scattering was used to quantify the osmotic second virial coefficient (B22) and the zero-q limit static structure factor (Sq=0), versus protein concentration (c2) from low to high c2. Dynamic light scattering was used to measure the collective diffusion coefficient as a function of c2 and to determine the protein interaction parameter (kD). Static light scattering and dynamic light scattering were combined to determine the hydrodynamic factor (Hq=0), which accounts for changes in hydrodynamic PPI as a function of c2. The net PPI ranged from strongly repulsive to attractive interactions, via changes in buffer pH, ionic strength, and choice of monoclonal antibodies. Multiple-particle tracking microrheology and capillary viscometery were used to measure monoclonal antibodies solution viscosities under the same solution conditions. In most cases, even large and qualitative changes in PPI did not result in significant changes in protein solution viscosity. This highlights the complex nature of PPI and how they influence protein solution viscosity and raises questions as to the validity of using experimental PPI metrics such as kD or B22 as predictors of high viscosity. PMID- 30017888 TI - Dietary-Induced Obesity and Changes in the Biodistribution and Metabolism of Amiodarone in the Rat. AB - The metabolism and biodistribution of the antiarrhythmic drug amiodarone (AM) was assessed in male Sprague-Dawley rats given either normal chow or high-fat and high-fructose diets for 14 weeks. After the feeding period, microsomes were prepared from liver and intestine, and the metabolism of AM to desethylamiodarone was determined. Intrinsic clearance (CL) was reduced by hepatic microsomes isolated from rats given high-calorie diets. In intestinal microsomes, there was no change or a small increase in metabolic rate in obese rats. A biodistribution study was also undertaken in a group of control and high-fat + high fructose-fed rats. Excess calories led to a significant increase in plasma AM compared to normal chow-fed control animals. A population pharmacokinetic analysis of AM confirmed that its oral CL was reduced. In plasma, there was a decrease in the metabolite to drug ratio. Some tissue:plasma ratios of AM in high calorie-fed rats were aligned with a decrease in plasma unbound fraction. It is concluded that the findings reinforced those of a recent report where we found decreases in expressions of enzymes involved in AM dealkylation, in showing greater exposure and lower oral CL, and generally decreases in liver microsomal metabolism of AM after high-calorie diets. PMID- 30017889 TI - Physical Characterization and Stabilization of a Lentiviral Vector Against Adsorption and Freeze-Thaw. AB - A replication-deficient lentiviral vector encoding the tumor antigen gene NY-ESO 1 was characterized in terms of vector morphology, particle size range, concentration, and zeta potential using a variety of physical methods. Environmentally stressed vector samples were then evaluated in terms of viral vector particle size and concentration by nanoparticle tracking analysis (NTA). These NTA stability results correlated reasonably well with a quantitative polymerase chain reaction assay for quantitation of viral genome copy number (r2 = 0.80). Approximately 40 pharmaceutical excipients were examined for their ability to stabilize the vector against exposure to an adsorptive container surface (glass) as well as freeze-thaw cycling using NTA as the screening method. Stabilizing additives that inhibited viral vector particle loss under these conditions included proline, lactose, and mannitol. Several candidate frozen liquid formulations that contained a combination of these lead excipients and various buffering agents were further evaluated for their ability to stabilize the viral vector. The additional benefit of lowering the Tris buffer concentration was observed. This study highlights the use of physical particle assays such as NTA for initial screening of stabilizing excipients to minimize vector loss due to container adsorption and freeze-thaw cycling to facilitate early formulation development of viral vector candidates in frozen liquid formulations. PMID- 30017890 TI - Improving Dissolution Properties by Polymers and Surfactants: A Case Study of Celastrol. AB - Two polymorphs of celastrol were discovered and fully characterized by X-ray powder diffraction, thermogravimetry analysis, and differential scanning calorimetry. The single-crystal structures of form I and the isostructural solvate of form II were disclosed by single-crystal X-ray diffraction. The apparent solubility and wettability of both the crystalline forms were determined. It was found that surfactant can significantly improve the solubility of celastrol up to more than 104 times. Tween 80 and sodium dodecyl sulfate largely improved the wettability of the 2 crystals. Form I shows better wettability than form II in all the buffer solutions with polymers and surfactants. Compared with form II, form I exhibits higher solubility in carboxymethylcellulose and polyvinylpyrrolidone media but much lower solubility in tween 80 and sodium dodecyl sulfate solutions. An investigation of wettability and solubility mechanisms was fully explored, and a hypothesis was proposed to understand the abnormal solubility differences. PMID- 30017891 TI - Quantification of Moisture-Induced Cohesion in Pharmaceutical Mixtures. AB - Moisture-induced flow variabilities in pharmaceutical blends lead to multiple impediments during manufacturing of solid dosage formulations. Processing and storage humidity conditions both govern the moisture contents of the pharmaceutical mixtures and bear significant impact on the final product quality. In this study, experimentally validated discrete element method-based computational models along with statistical formalism have been implemented to develop a predictive tool for moisture-induced cohesion in binary and tertiary mixtures. V-blending was applied to prepare the pharmaceutical blends, and mixing characterization was performed using a Raman PhAT probe. Optimum fill volume was established for the mixing conditions to minimize static charging due to blender wall interactions on the pharmaceutical powders. A simplex-centroid (augmented) design for 3-component system was implemented to predict and quantify the nonlinear behavior of moisture-induced cohesion between the pharmaceutical powders based on their systematic hopper discharge studies (experiments and simulations). A methodical implementation of these quantification tools was hence performed to validate a design space that enables an approach to the appropriate selection of blend concentrations that achieve minimum mixture flow variability across different humidity conditions. PMID- 30017892 TI - The experiences of breastfeeding mothers returning to work as hospital nurses in Pakistan: A qualitative study. AB - BACKGROUND: Pakistan has a higher infant mortality rate than countries with comparable economies, with around half of all under-5 deaths occurring in the first month of life. Breastfeeding is known to improve infant morbidity and mortality, but rates of formula feeding in Pakistan are increasing. Maternal employment is recognised globally as a major barrier to the continuation of breastfeeding. AIM: To describe the attitudes and experiences of breastfeeding mothers returning to full-time work as nurses in a tertiary hospital in Pakistan. METHODS: A qualitative study was conducted using semi-structured interviews with seven purposively sampled participants who were breastfeeding at the time of return to work. Interviews were audio recorded, transcribed and analysed thematically. RESULTS: Three major themes were identified: belief in a child's right to breastfeed, conflict with institutional power and the importance of family support in maintaining breastfeeding. Antenatally mothers described breastfeeding as the preferred infant feeding option and the child's right. When returning to work mothers encountered rigid hospital policies and practices, such as a short and non-negotiable period of maternity leave, inflexible shift patterns, and lack of childcare provision. Parents' strategies to continue breastfeeding included some mothers bringing babies to hospital wards while they worked, and babies' fathers bringing the baby to the hospital for feeds. CONCLUSION: This study highlighted the barriers to breastfeeding experienced by mothers working as hospital nurses in Pakistan. Babies can be put at risk due to the strategies parents adopt to reconcile continued breastfeeding with maternal employment. PMID- 30017893 TI - Hysteroscopic Endometrial Focal Resection followed by Levonorgestrel Intrauterine Device Insertion as a Fertility-Sparing Treatment of Atypical Endometrial Hyperplasia and Early Endometrial Cancer: A Retrospective Study. AB - STUDY OBJECTIVE: To evaluate safety and effectiveness of the combination of hysteroscopic endometrial focal resection with levonorgestrel-releasing intrauterine device (LNG-IUD) for International Federation of Gynecology and Obstetrics stage IA G1 early endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) in young women to preserve their fertility. DESIGN: Retrospective case series (Canadian Task Force classification II-3). SETTING: University Federico II, Naples, Italy. PATIENTS: The medical records of 69 consecutive patients treated from 2007 to 2017 with diagnosis of EEC (n = 14) or AEH (n = 55) meeting inclusion criteria were reviewed. INTERVENTIONS: Patients with focal EEC were treated by hysteroscopic resection of the lesion according to Mazzon's technique; patients with AEH were treated by superficial endometrial resection, preserving the basal layer of the endometrium. An LNG-IUD was inserted in all patients after surgery. Patients were followed for 24 months with serial hysteroscopic biopsies. MEASUREMENTS AND MAIN RESULTS: Rates of response, live birth, and recurrence were assessed. Of the 14 patients with EEC, 11 (78.6%) achieved a complete response, 2 (18.2%) of whom had subsequent relapse, 1 (7.1%) showed partial response, whereas 2 (14.3%) were nonresponders (1 stable disease and 1 progression). Of the 55 patients with AEH, 51 (92.7%) achieved a complete response, 2 (3.9%) of whom had subsequent relapse, 3 (5.5%) showed partial response, whereas only 1 (1.8%) was nonresponder with stable disease. Among 25 patients who had removed the LNG-IUD, 10 (40%) gave birth after natural conception in the last 12 months of follow-up. CONCLUSION: The combination of hysteroscopic resection with an LNG-IUD as fertility-sparing treatment of EEC and AEH showed similar response and live birth rates compared with those reported in literature for progestins alone, but with considerably lower relapse rate. We advocate the use of this combined approach as an alternative fertility-sparing option in patients with ECC and AEH. PMID- 30017894 TI - Regarding "Transvaginal Natural Orifice Transluminal Endoscopic Surgery for Tubal Pregnancy and a Device Innovation from Our Institution". PMID- 30017895 TI - Modeling epidemics: A primer and Numerus Model Builder implementation. AB - Epidemiological models are dominated by compartmental models, of which SIR formulations are the most commonly used. These formulations can be continuous or discrete (in either the state-variable values or time), deterministic or stochastic, or spatially homogeneous or heterogeneous, the latter often embracing a network formulation. Here we review the continuous and discrete deterministic and discrete stochastic formulations of the SIR dynamical systems models, and we outline how they can be easily and rapidly constructed using Numerus Model Builder, a graphically-driven coding platform. We also demonstrate how to extend these models to a metapopulation setting using NMB network and mapping tools. PMID- 30017897 TI - Trax: A versatile signaling protein plays key roles in synaptic plasticity and DNA repair. AB - Translin-associated protein X (TSNAX), also called trax, was first identified as a protein that interacts with translin. Subsequent studies demonstrated that these proteins form a heteromeric RNase complex that mediates degradation of microRNAs, a pivotal finding that has stimulated interest in understanding the role of translin and trax in cell signaling. Recent studies addressing this question have revealed that trax plays key roles in both synaptic plasticity and DNA repair signaling pathways. In the context of synaptic plasticity, trax works together with its partner protein, translin, to degrade a subset of microRNAs. Activation of the translin/trax RNase complex reverses microRNA-mediated translational silencing to trigger dendritic protein synthesis critical for synaptic plasticity. In the context of DNA repair, trax binds to and activates ATM, a central component of the double-stranded DNA repair process. Thus, these studies focus attention on trax as a critical signaling protein that interacts with multiple partners to impact diverse signaling pathways. To stimulate interest in deciphering the multifaceted role of trax in cell signaling, we summarize the current understanding of trax biology and highlight gaps in our knowledge about this protean protein. PMID- 30017896 TI - Intestinal persistence of a plasmid harbouring the OXA-48 carbapenemase gene after hospital discharge. AB - To study intestinal colonization by OXA-48-producing Klebsiella pneumoniae (KpO48) after hospital discharge, stool samples from 22 previously colonized subjects were collected. Time from discharge was 33-611 days, without readmissions. Eight subjects (36%) were identified as blaOXA-48 gene carriers. In all of them the hospital-acquired strain of KpO48 had been lost, and the gene was harboured by other strains of K. pneumoniae, Klebsiella oxytoca and/or Escherichia coli. Our findings show intestinal persistence for several months of a plasmid harbouring the OXA-48 carbapenemase gene in a significant proportion of individuals in the absence of antibiotic treatment. PMID- 30017898 TI - Fishing wild-type sparing inhibitors of proto-oncogene c-met variants in renal cell carcinoma from a curated tyrosine kinase inhibitor pool using analog sensitive kinase technology. AB - A variety of missense mutations in proto-oncogene protein tyrosine kinase c-Met have been clinically observed in the patients and families of papillary renal cell carcinoma (pRCC), imparting that the kinase mutations can be exploited as a new and potential therapeutic target for pRCC. Here, a systematic inhibitor response-to-kinase mutation profile for ATP-competitive tyrosine kinase inhibitors (TKIs) against pRCC-related c-Met mutations is created using a rigorous thermodynamic cycle scheme, from which we are able to identify a number of representative inhibitor/mutation pairs with passivation and sensitization. It is revealed that passivation is commonly caused by steric hindrance between the mutated residue and inhibitor ligand, while sensitization usually results from the formation of favorable nonbonded interactions upon the mutation. The type II inhibitor Nintedanib possesses a high selectivity (7.2-fold) for c-MetY1248H variant over wild type. Structural and energetic analysis revealed that the Y1248H mutation is located in kinase's activation loop which can directly contact the extended moiety of type II inhibitor. The titratable variant residue His1248 is protonated with stabilization by its vicinal negatively charged residue Asp1246, which can form a geometrically satisfactory hydrogen bond and a weak cation-pi interaction with the inhibitor ligand, thus conferring variant selectivity to the Nintedanib/Y1248H sensitization. PMID- 30017899 TI - Infection Prevention Strategies Prior to Penile Implant Surgery. AB - CONTEXT: Over the last 4 decades, penile implant surgery has advanced significantly. Penile implant infection prevention continues to be an active area of research due to the significant patient morbidity associated with infection. OBJECTIVE: To summarize current approaches and supporting data for infection prevention. EVIDENCE SYNTHESIS: Common approaches to infection prevention include careful patient selection and preoperative evaluation, broad-spectrum antimicrobial prophylaxis, and modifications to surgical technique that minimize skin contact and postoperative hematoma formation. CONCLUSION: Many of these measures have proven efficacious, but our knowledge regarding the pathophysiology of penile prosthesis infection continues to evolve and demands continued efforts towards infection prevention. PMID- 30017900 TI - Combination Intravesical Chemotherapy for Non-muscle-invasive Bladder Cancer. AB - Bacillus Calmette-Guerin (BCG) replaced early intravesical chemotherapeutic agents as the standard of care for non-muscle-invasive bladder cancer (NMIBC) with its US Food and Drug Administration approval in 1990. Multiple studies have proven the superiority of BCG to surgery alone, and to older single-agent intravesical chemotherapy regimens. However, new multiagent intravesical chemotherapy regimens have been developed and tested in recent years. Such regimens offer the possibility of better efficacy and/or tolerability compared to BCG. However, high-quality data comparing such regimens to BCG remain scant. We briefly review the literature regarding combination intravesical chemotherapy for NMIBC. PMID- 30017901 TI - Systematic Review of the Impact of Testosterone Replacement Therapy on Depression in Patients with Late-onset Testosterone Deficiency. AB - CONTEXT: Clinical guidelines recommend testosterone replacement therapy (TRT) for adult men with late-onset testosterone deficiency (TD), with the goal of improving symptoms and elevating testosterone levels into the normal reference range. OBJECTIVE: To investigate and critically analyze the current evidence regarding the impact of TRT on depression and depressive symptoms in adult men with late-onset TD compared with placebo. EVIDENCE ACQUISITION: A systematic search of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials databases, and clinicaltrials.gov was performed on April 1, 2018 using any combination of the terms Testosterone (EXP) OR Testosterone replacement therapy (EXP) AND Depression (EXP) OR Depressive symptoms (EXP). Studies were considered eligible if they included adult men with late-onset TD (total testosterone <350ng/ml and age >30yr.) treated with TRT, used placebo groups comparison arm, were randomized clinical trials (RCTs), included at least 10 individuals per treatment arm, and assessed the impact of TRT on depression compared with that of placebo. EVIDENCE SYNTHESIS: Fifteen studies encompassing 1586 individuals were included. Six RCTs investigated the impact of TRT on patients with late-onset TD compared with placebo in patients with clinically significant levels of depression, and nine RCTs investigated the impact of TRT on patients with late onset TD compared with placebo in patients with no clinically significant depression. CONCLUSIONS: TRT reduces depressive symptoms, according to data coming from small-sized, placebo-controlled RCTs of patients with pretreatment clinical mild depression. This impact was not noticed in men with major depressive disorders. In patients without pretreatment depression, TRT leads to a reduction of scores for depressive symptoms; however, clinical value of this is difficult to measure. PATIENT SUMMARY: We investigated the effect of testosterone replacement therapy (TRT) on depressive symptoms in patients with late-onset testosterone deficiency. TRT improves depressive symptoms in most trials, except in patients with major depressive disorder. PMID- 30017902 TI - Patient education and health literacy. AB - INTRODUCTION: Patient education is a relatively new science within the field of health care. In the past it consisted mainly of the transfer of knowledge and mostly biomedically based advice. Research has shown this to not be effective and sometimes counterproductive. As health care has moved away from applying a traditional paternalistic approach of 'doctor knows best' to a patient-centred care approach, patient education must be tailored to meet persons' individual needs. PURPOSE: The purpose of this master paper is to increase awareness of patients' health literacy levels. Health literacy is linked to literacy and entails people's knowledge, motivation and competences to access, understand, appraise and apply health information in order to make judgements and take decisions in everyday life concerning health care, disease prevention and health promotion to maintain or improve quality of life during the life course. Many patients have low health literacy skills, and have difficulty with reading, writing, numeracy, communication, and, increasingly, the use of electronic technology, which impede access to and understanding of health care information. IMPLICATIONS: Multiple professional organizations recommend using universal health literacy precautions to provide understandable and accessible information to all patients, regardless of their literacy or education levels. This includes avoiding medical jargon, breaking down information or instructions into small concrete steps, limiting the focus of a visit to three key points or tasks, and assessing for comprehension by using the teach back cycle. Printed information should be written at or below sixth-grade reading level. Visual aids can enhance patient understanding. PMID- 30017903 TI - Parental transfer of perfluorooctane sulfonate and ZnO nanoparticles chronic co exposure and inhibition of growth in F1 offspring. AB - Perfluorooctane sulfonate (PFOS) and ZnO nanoparticles (Nano-ZnO) are two kinds of environmental contaminants that have been frequently detected in natural waters. The potential joint toxicity of PFOS and nano-ZnO remains to be fully elucidated. The objective of this study was to evaluate co-exposure effects of PFOS and nano-ZnO on growth in initial generation (F0) zebrafish after chronic exposure and to examine possible parental transfer of PFOS and nano-ZnO transgenerational effects on the growth of first generation (F1) larvae. When zebrafish (2 h after incubation) were exposed to single- and co-exposure groups for 120 days, bioconcentration resulted in significantly less growth as measured by body length and body weight, higher mortality, and less spawning in the F0 generation. These effects were possibly due to the down-regulation of the expression of Vtg1 genes along with a sex hormone (T/E2) involved in the hypothalamus-pituitary-gonad (HPG) axis. Furthermore, after long-term exposure, less fertilization, less hatching, greater mortality and more malformation were found in the F1 generation. The down-regulation of genes and hormones might be responsible for transgenerational toxicity. This study suggested that chronic exposure to PFOS and nano-ZnO adversely impacts development, reproduction in the F0 generation, and offspring embryonic growth. PMID- 30017905 TI - Phase separated microenvironments inside the cell nucleus are linked to disease and regulate epigenetic state, transcription and RNA processing. AB - Proteins and RNAs inside the cell nucleus are organized into distinct phases, also known as liquid-liquid phase separated (LLPS) droplet organelles or nuclear bodies. These regions exist within the spaces between chromatin-rich regions but their function is tightly linked to gene activity. They include major microscopically-observable structures such as the nucleolus, paraspeckle and Cajal body. The biochemical and assembly factors enriched inside these microenvironments regulate chromatin structure, transcription, and RNA processing, and other important cellular functions. Here, we describe published evidence that suggests nuclear bodies are bona fide LLPS droplet organelles and major regulators of the processes listed above. We also outline an updated "Supply or Sequester" model to describe nuclear body function, in which proteins or RNAs are supplied to surrounding genomic regions or sequestered away from their sites of activity. Finally, we describe recent evidence that suggests these microenvironments are both reflective and drivers of diverse pathophysiological states. PMID- 30017904 TI - Obfuscating transparency? AB - Several recent and prominent articles in Science and Nature deliberately mischaracterized the nature of genuine scientific evidence. Those articles take issue with the United States Environmental Protection Agency's recent proposal to structure its policies and rules only from studies with transparently published raw data. The articles claim it is an effort to obfuscate with transparency, by eliminating a host of studies not offering raw data. A remarkable declaration by a Science editorial is that properly trained experts can verify the scientific evidence of studies without access to raw data, We assert the Agency's proposal must be sustained. Transparency in reporting is a fundamental ethical imperative of objective scientific research justifying massive official regulations and policies. Putative hazards bereft of independent scientific evidence will continue to stoke public anxieties, calling for precautionary regulations and policies. These should rely not on spurious science but on transparent tradeoffs between the smallest exposures compatible with utility and with social perceptions of affordable precaution. PMID- 30017906 TI - 3D genomic regulation of lncRNA and Xist in X chromosome. AB - Long noncoding RNAs (lncRNAs) act as important regulators in cardiovascular diseases, neural degenerative disease, or cancers, by localizing and spreading across chromatins. lncRNA can regulate the 3D architecture of the enhancer cluster at the target gene locus, relevant to analogous lncRNA-protein coding gene pairs. X inactive specific transcript (Xist) plays a critical role in the process and biological function of lncRNAs. The lncRNA Jpx, Xist activator, is a nonprotein-coding RNA transcribed from a gene within the X-inactivation center and acts as a numerator element to control X-chromosome number and activate Xist transcription by interacting with CCCTC-binding factor. Up-regulated lncRNA Xist initiates X chromosome inactivation process and attracts specific chromatin modifiers. A number of chromatin-modified factors interact with lncRNAs modify 3D genome architecture and mediate Xist function in embryo development. Thus, the regulation of lncRNAs in 3D genome progresses is the key mechanism of Xist, as a therapeutic potential for Xist associated diseases. PMID- 30017907 TI - The role of 3D genome organization in disease: From compartments to single nucleotides. AB - Since the advent of the chromosome conformation capture technology, our understanding of the human genome 3D organization has grown rapidly and we now know that human interphase chromosomes are folded into multiple layers of hierarchical structures and each layer can play a critical role in transcriptional regulation. Alterations in any one of these finely-tuned layers can lead to unwanted cascade of molecular events and ultimately drive the manifestation of diseases and phenotypes. Here we discuss, starting from chromosome level organization going down to single nucleotide changes, recent studies linking diseases or phenotypes to changes in the 3D genome architecture. PMID- 30017908 TI - Zebrafish as a model of mammalian cardiac function: Optically mapping the interplay of temperature and rate on voltage and calcium dynamics. AB - The zebrafish (Danio rerio) heart is a viable model of mammalian cardiovascular function due to similarities in heart rate, ultrastructure, and action potential morphology. Zebrafish are able to tolerate a wide range of naturally occurring temperatures through altering chronotropic and inotropic properties of the heart. Optical mapping of cannulated zebrafish hearts can be used to assess the effect of temperature on excitation-contraction (EC) coupling and to explore the mechanisms underlying voltage (Vm) and calcium (Ca2+) transients. Applicability of zebrafish as a model of mammalian cardiac physiology should be understood in the context of numerous subtle differences in structure, ion channel expression, and Ca2+ handling. In contrast to mammalian systems, Ca2+ release from the sarcoplasmic reticulum (SR) plays a relatively small role in activating the contractile apparatus in teleosts, which may contribute to differences in restitution. The contractile function of the zebrafish heart is closely tied to extracellular Ca2+ which enters cardiomyocytes through L-type Ca2+ channel (LTCC), T-type Ca2+ channel (TTCC), and the sodium-calcium exchanger (NCX). Novel data found that despite large temperature effects on heart rate, Vm, and Ca2+ durations, the relationship between Vm and Ca2+ signals was only minimally altered in the face of acute temperature change. This suggests that zebrafish Vm and Ca2+ kinetics are largely rate-independent. In comparison to mammalian systems, zebrafish Ca2+ cycling is inherently more dependent on transsarcolemmal Ca2+ transport and less reliant on SR Ca2+ release. However, the compensatory actions of various components of the Ca2+ cycling machinery of the zebrafish cardiomyocytes, allow for maintenance of EC coupling over a wide range of environmental temperatures. PMID- 30017909 TI - Thrombotic risk assessment and analytical performance of the chemiluminescent analyzer IDS-iSYS for the detection of anti-cardiolipin and anti-beta 2 glycoprotein I autoantibodies. AB - Patients with antiphospholipid antibodies (APLA) are predisposed to develop thrombosis, however the standardization of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein I (beta2-GPI) Ab assays are challenging. Therefore we decided to test the performance of a new chemiluminescent assay (CLIA), and assayed aCL and abeta2-GPI IgG/M in serum from 120 healthy individuals, 108 patients with idiopathic venous thrombosis, 78 patients with antiphospholipid syndrome (APS), and 64 non-thrombotic APLA-carriers using CLIA IDS-iSYS. Very good (aCL/abeta2 GPI IgG) to moderate (aCL/abeta2-GPI IgM) agreement with a commercial and an in house ELISA assay were observed and, in particular, CLIA demonstrated the highest sensitivity in abeta2-GPI IgG detection. Finally, aCL/abeta2-GPI Ab capacity to predict the thrombotic risk was tested showing for CLIA a significant odds ratio (OR) when considering double positivity for aCL/abeta2-GPI IgG, aCL IgG at high levels, and abeta2-GPI IgG at high levels. In conclusion, CLIA improves abeta2 GPI IgG detection and thrombotic risk assessment. PMID- 30017910 TI - Practical identifiability and uncertainty quantification of a pulsatile cardiovascular model. AB - Mathematical models are essential tools to study how the cardiovascular system maintains homeostasis. The utility of such models is limited by the accuracy of their predictions, which can be determined by uncertainty quantification (UQ). A challenge associated with the use of UQ is that many published methods assume that the underlying model is identifiable (e.g. that a one-to-one mapping exists from the parameter space to the model output). In this study we present a novel workflow to calibrate a lumped-parameter model to left ventricular pressure and volume time series data. Key steps include using (1) literature and available data to determine nominal parameter values; (2) sensitivity analysis and subset selection to determine a set of identifiable parameters; (3) optimization to find a point estimate for identifiable parameters; and (4) frequentist and Bayesian UQ calculations to assess the predictive capability of the model. Our results show that it is possible to determine 5 identifiable model parameters that can be estimated to our experimental data from three rats, and that computed UQ intervals capture the measurement and model error. PMID- 30017911 TI - Changes in glycogen concentration and gene expression levels of glycogen metabolizing enzymes in muscle and liver of developing masu salmon. AB - Glycogen, as an intracellular deposit of polysaccharide, takes important roles in energy balance of many animals. In fish, however, the role of glycogen during development is poorly understood. In the present study, we assessed changes in glycogen concentration and gene expression patterns of glycogen-metabolizing enzymes in developing masu salmon (Oncorhynchus masou masou), a salmonid species inhabiting west side of North Pacific Ocean. As we measured glycogen levels in the bodies and yolk sacs containing the liver separately, the glycogen concentration increased in both parts as the fish developed, whereas it transiently decreased in the yolk sac after hatching, implying glycogen synthesis and breakdown in these tissues. Immunofluorescence staining using anti-glycogen monoclonal antibody revealed localization of glycogen in the liver, muscle and yolk syncytial layer of the pre-hatching embryos and hatched larvae. In order to estimate glycogen metabolism in the fish, the genes encoding homologs of glycogen synthase (gys1 and gys2) and glycogen phosphorylase (pygma, pygmb and pygl) were cloned, and their expression patterns were assessed by quantitative PCR and in situ hybridization. In the fish, gys1 and gys2 were robustly expressed in the muscle and liver, respectively. Also, expression of pyg isoforms was found in muscle, liver and yolk syncytial layer during hatching. With changes in glycogen concentration and expression patterns of relevant genes, our results suggest, for the first time, possible involvement of glycogen in energy balance of fish embryos, especially during hatching. PMID- 30017912 TI - Selenoprotein S silencing triggers mouse hepatoma cells apoptosis and necrosis involving in intracellular calcium imbalance and ROS-mPTP-ATP. AB - Selenoprotein S (SelenoS) is one of the cellular endoplasmic reticulum (ER) and membrane located selenoproteins, and it has the main functions of anti-oxidation, anti-apoptosis and anti-ER stress. To investigate the effect of SelenoS silencing on mouse hepatoma cell death and the intracellular biological function of SelenoS, we knocked down SelenoS in Hepa1-6 cells, and detected ER stress, intracellular calcium homeostasis, mitochondrial dynamics, apoptosis and necrosis. To further explore whether reactive oxygen species (ROS) has an effect on apoptosis and necrosis under SelenoS silencing, we used NAC (2.5 mM) to pretreat cells, and detected DeltaPsim, ATP, and apoptosis and necrosis rates. SelenoS silencing broke the intracellular calcium homeostasis, induced mitochondrial dynamic disorder, ROS accumulation, loss of DeltaPsim and ATP, and triggered apoptosis and necrosis in mouse hepatoma cells. The clearance of ROS alleviated the loss of DeltaPsim and ATP caused by silencing of SelenoS, reduced cell necrosis and increased apoptosis. However, SelenoS silencing did not cause ER stress in Hepa1-6 cells. These results indicate that SelenoS silencing triggers mouse hepatoma cells apoptosis and necrosis through affecting intracellular calcium homeostasis and ROS-mPTP-ATP participates in cell death transformation from apoptosis to necrosis to rise damage. PMID- 30017914 TI - Sequencing Mirror-Image DNA Chemically. AB - The development of mirror-image biology systems faces a crucial barrier of lacking an L-DNA sequencing technique. Here, we developed a practical method for sequencing mirror-image DNA by adopting the Maxam-Gilbert sequencing approach, through which specific nucleobases in an end-labeled L-DNA are cleaved by achiral chemicals. This technique may facilitate the therapeutic application of nuclease resistant L-aptamer drugs, and bring the vision of building an alternative, mirror-image self-replicating system closer to reality. PMID- 30017915 TI - The Meisenheimer Complex as a Paradigm in Drug Discovery: Reversible Covalent Inhibition through C67 of the ATP Binding Site of PLK1. AB - The polo kinase family are important oncology targets that act in regulating entry into and progression through mitosis. Structure-guided discovery of a new class of inhibitors of Polo-like kinase 1 (PLK1) catalytic activity that interact with Cys67 of the ATP binding site is described. Compounds containing the benzothiazole N-oxide scaffold not only bind covalently to this residue, but are reversible inhibitors through the formation of Meisenheimer complexes. This mechanism of kinase inhibition results in compounds that can target PLK1 with high selectivity, while avoiding issues with irreversible covalent binding and interaction with other thiol-containing molecules in the cell. Due to renewed interest in covalent drugs and the plethora of potential drug targets, these represent prototypes for the design of kinase inhibitory compounds that achieve high specificity through covalent interaction and yet still bind reversibly to the ATP cleft, a strategy that could be applied to avoid issues with conventional covalent binders. PMID- 30017913 TI - The MALDI-TOF E2/E3 Ligase Assay as Universal Tool for Drug Discovery in the Ubiquitin Pathway. AB - Due to their role in many diseases, enzymes of the ubiquitin system have recently become interesting drug targets. Despite efforts, primary screenings of compound libraries targeting E2 enzymes and E3 ligases have been strongly limited by the lack of robust and fast high-throughput assays. Here we report a label-free high throughput screening assay for ubiquitin E2 conjugating enzymes and E3 ligases based on MALDI-TOF mass spectrometry. The MALDI-TOF E2/E3 assay allows testing E2 enzymes and E3 ligases for their ubiquitin transfer activity, identifying E2/E3 active pairs, inhibitor potency and specificity and screening compound libraries in vitro without chemical or fluorescent probes. We demonstrate that the MALDI TOF E2/E3 assay is a universal tool for drug discovery screening in the ubiquitin pathway as it is suitable for working with all E3 ligase families and requires a reduced amount of reagents, compared with standard biochemical assays. PMID- 30017916 TI - Linkage-Specific Detection and Metabolism of Human Milk Oligosaccharides in Escherichia coli. AB - Human milk oligosaccharides (HMOs) are important prebiotic complex carbohydrates with demonstrated beneficial effects on the microbiota of neonates. However, optimization of their biotechnological synthesis is limited by the relatively low throughput of monosaccharide and linkage analysis. To enable high-throughput screening of HMO structures, we constructed a whole-cell biosensor that uses heterologous expression of glycosidases to generate linkage-specific, quantitative fluorescent readout for a range of HMOs at detection limits down to 20 MUM in approximately 6 hr. We also demonstrate the use of this system for orthogonal control of growth rate or protein expression of particular strains in mixed populations. This work enables rapid non-chromatographic linkage analysis and lays the groundwork for the application of directed evolution to biosynthesis of complex carbohydrates as well as the prebiotic manipulation of population dynamics in natural and engineered microbial communities. PMID- 30017917 TI - Aggregation, Phase Separation and Spatial Morphologies of the Assemblies of FG Nucleoporins. AB - Nuclear pore complex (NPC) is a biomolecular "nanomachine" that controls nucleocytoplasmic transport in eukaryotic cells. The key component of the functional architecture of the NPC is the assembly of intrinsically disordered proteins that line its passageway and play a central role in the NPC transport mechanism. Due to paucity of experimental methods capable to directly probe the morphology of this assembly in intact NPCs, much of our knowledge about its properties derives from in vitro experiments augmented by theoretical and computational modeling. I review the major insights into the biophysics of the assemblies of the intrinsically disordered proteins of the NPC arising from the theoretical analysis of the recent in vitro experimental results, with the emphasis on the phase separation and aggregation phenomena. PMID- 30017918 TI - Methods for Physical Characterization of Phase-Separated Bodies and Membrane-less Organelles. AB - Membrane-less organelles are cellular structures which arise through the phenomenon of phase separation. This process enables compartmentalization of specific sets of macromolecules (e.g., proteins, nucleic acids), thereby regulating cellular processes by increasing local concentration, and modulating the structure and dynamics of their constituents. Understanding the connection between structure, material properties and function of membrane-less organelles requires inter-disciplinary approaches, which address length and timescales that span several orders of magnitude (e.g., Angstroms to micrometer, picoseconds to hours). In this review, we discuss the wide variety of methods that have been applied to characterize the morphology, rheology, structure and dynamics of membrane-less organelles and their components, in vitro and in live cells. PMID- 30017919 TI - Multilayer View of Pathogenic SNVs in Human Interactome through In Silico Edgetic Profiling. AB - Non-synonymous mutations linked to the complex diseases often have a global impact on a biological system, affecting large biomolecular networks and pathways. However, the magnitude of the mutation-driven effects on the macromolecular network is yet to be fully explored. In this work, we present a systematic multi-level characterization of human mutations associated with genetic disorders by determining their individual and combined interaction rewiring, "edgetic," effects on the human interactome. Our in silico analysis highlights the intrinsic differences and important similarities between the pathogenic single-nucleotide variants (SNVs) and frameshift mutations. We show that pathogenic SNVs are more likely to cause gene pleiotropy than pathogenic frameshift mutations and are enriched on the protein interaction interfaces. Functional profiling of SNVs indicates widespread disruption of the protein protein interactions and synergistic effects of SNVs. The coverage of our approach is several times greater than the recently published experimental study and has the minimal overlap with it, while the distributions of determined edgotypes between the two sets of profiled mutations are remarkably similar. Case studies reveal the central role of interaction-disrupting mutations in type 2 diabetes mellitus and suggest the importance of studying mutations that abnormally strengthen the protein interactions in cancer. With the advancement of next-generation sequencing technology that drives precision medicine, there is an increasing demand in understanding the changes in molecular mechanisms caused by the patient-specific genetic variation. The current and future in silico edgotyping tools present a cheap and fast solution to deal with the rapidly growing data sets of discovered mutations. PMID- 30017920 TI - Structural and Functional Characterization of the BcsG Subunit of the Cellulose Synthase in Salmonella typhimurium. AB - Many bacteria secrete cellulose, which forms the structural basis for bacterial multicellular aggregates, termed biofilms. The cellulose synthase complex of Salmonella typhimurium consists of the catalytic subunits BcsA and BcsB and several auxiliary subunits that are encoded by two divergently transcribed operons, bcsRQABZC and bcsEFG. Expression of the bcsEFG operon is required for full-scale cellulose production, but the functions of its products are not fully understood. This work aimed to characterize the BcsG subunit of the cellulose synthase, which consists of an N-terminal transmembrane fragment and a C-terminal domain in the periplasm. Deletion of the bcsG gene substantially decreased the total amount of BcsA and cellulose production. BcsA levels were partially restored by the expression of the transmembrane segment, whereas restoration of cellulose production required the presence of the C-terminal periplasmic domain and its characteristic metal-binding residues. The high-resolution crystal structure of the periplasmic domain characterized BcsG as a member of the alkaline phosphatase/sulfatase superfamily of metalloenzymes, containing a conserved Zn2+-binding site. Sequence and structural comparisons showed that BcsG belongs to a specific family within alkaline phosphatase-like enzymes, which includes bacterial Zn2+-dependent lipopolysaccharide phosphoethanolamine transferases such as MCR-1 (colistin resistance protein), EptA, and EptC and the Mn2+-dependent lipoteichoic acid synthase (phosphoglycerol transferase) LtaS. These enzymes use the phospholipids phosphatidylethanolamine and phosphatidylglycerol, respectively, as substrates. These data are consistent with the recently discovered phosphoethanolamine modification of cellulose by BcsG and show that its membrane-bound and periplasmic parts play distinct roles in the assembly of the functional cellulose synthase and cellulose production. PMID- 30017922 TI - New insights into the viscoelastic and failure mechanical properties of the elastic fiber network of the inter-lamellar matrix in the annulus fibrosus of the disc. AB - : The mechanical role of elastic fibers in the inter-lamellar matrix (ILM) is unknown; however, it has been suggested that they play a role in providing structural integrity to the annulus fibrosus (AF). Therefore, the aim of this study was to measure the viscoelastic and failure properties of the elastic fiber network in the ILM of ovine discs under both tension and shear directions of loading. Utilizing a technique, isolated elastic fibers within the ILM from ovine discs were stretched to 40% of their initial length at three strain rates of 0.1% s-1 (slow), 1% s-1 (medium) and 10% s-1 (fast), followed by a ramp test to failure at 10% s-1. A significant strain-rate dependent response was found, particularly at the fastest rate for phase angle and normalized stiffness (p < 0.001). The elastic fibers in the ILM demonstrated a significantly higher capability for energy absorption at slow compared to medium and fast strain rates (p < 0.001). These finding suggests that the elastic fiber network of the ILM exhibits nonlinear elastic behavior. When tested to failure, a significantly higher normalized failure force was found in tension compared to shear loading (p = 0.011), which is consistent with the orthotropic structure of elastic fibers in the ILM. The results of this study confirmed the mechanical contribution of the elastic fiber network to the ILM and the structural integrity of the AF. This research serves as a foundation for future studies to investigate the relationship between degeneration and ILM mechanical properties. STATEMENT OF SIGNIFICANCE: The mechanical role of elastic fibres in the inter-lamellar matrix (ILM) of the disc is unknown. The viscoelastic and failure properties of the elastic fibre network in the ILM in both tension and shear directions of loading was measured for the first time. We found a strain-rate dependent response for the elastic fibres in the ILM. The elastic fibres in the ILM demonstrated a significantly higher capability for energy absorption at slow compared to medium and fast strain rates. When tested to failure, a significantly higher normalized failure force was found in tension compared to shear loading, which is consistent with the orthotropic structure of elastic fibres in the ILM. PMID- 30017923 TI - Cell sheet composed of adipose-derived stem cells demonstrates enhanced skin wound healing with reduced scar formation. AB - : Scar formation remains a major clinical concern following tissue injuries such as skin wounds. Adipose-derived stem cell (ASC) sheets can be fabricated quickly through stimulation with l-ascorbate 2-phosphate and have valuable applications in tissue regeneration and wound healing. However, the antifibrotic capability of ASCs in cell sheet format has not been sufficiently investigated. We employed a murine model of healing-impaired cutaneous wounds and observed faster wound healing with ASC sheet treatment. Significantly more engrafted ASCs were observed in the wound tissue treated with ASC sheets at 14 days after wounding compared with dissociated cells. Moreover, no ASCs were found at day 28, which indicated a minimal risk of long-term side effects. The neoskin formed in the presence of ASC sheets exhibited a thickness comparable to normal skin and possessed a highly organized collagen structure. ASC sheets also suppressed macrophage infiltration and modulated TNF-alpha and TGF-beta1 expression in vivo. Examination of fibroblasts cultured in ASC-conditioned medium indicated an anti-scarring effect of the ASC sheets evidenced by the downregulation of TGF-beta1 and alpha-SMA in fibroblasts, which was likely mediated through the increased secretion of hepatocyte growth factor. Moreover, ASC sheets secreted significantly more C1q/TNF-related protein-3, which inhibited the C-C motif ligand 2 release by macrophages in vitro and subsequently reduced the chemotaxis of unstimulated macrophages. This mechanism may account for the observed decrease in recruitment of macrophages into the wound tissue. We conclude that ASC sheets possess the necessary paracrine factors to improve skin wound healing with a superior neoskin quality. STATEMENT OF SIGNIFICANCE: Adipose-derived stem cell (ASC) sheets exhibit great potential for tissue regeneration. In this study, we investigated whether ASC sheets can ameliorate skin wound healing with reduced scar formation, and faster wound healing was observed when applying ASC sheets in an impaired wound healing model of mice. The neoskin formed in the presence of ASC sheets exhibited a thickness comparable to normal skin with a more organized collagen structure. In vitro experiments suggested that the anti-scarring effect of the ASC sheets was partly mediated through increased secretion of hepatocyte growth factor. Moreover, ASC sheets secreted significantly more C1q/TNF-related protein 3, which may account for the decreased recruitment of macrophages into the wound tissue. Therefore, ASC sheets possess the necessary paracrine factors to improve skin wound healing with less scarring, thus representing a desirable method of topical wound treatment. PMID- 30017924 TI - Construction of vascularized tissue-engineered bone with a double-cell sheet complex. AB - : A double-cell sheet (DCS) complex composed of an osteogenic cell sheet and a vascular endothelial cell sheet with osteogenesis and blood vessel formation potential was developed in this study. The osteogenic and vascular endothelial cell sheets were obtained after induced culture of rabbit adipose-derived mesenchymal stem cells. The osteogenic cell sheet showed positive alizarin red, von Kossa, and alkaline phosphatase (ALP) staining. The vascular endothelial cell sheet exhibited visible W-P bodies in the cells, the expression of CD31 was positive, and a vascular mesh structure was spontaneously formed in a Matrigel matrix. The subcutaneous transplantation results for four groups of DCS and DCS coral hydroxyapatite (CHA) complexes, and the CHA scaffold group in nude mice revealed mineralization of collagen fibers and vascularization in each group at 12 weeks, but the degrees of mineralization and vascularization showed differences among groups. The pattern involving endothelial cell sheets covered with osteogenic cell sheets, group B, exhibited the best results. In addition, the degree of mineralization of the DCS-CHA complexes was more mature than those of the same group of DCS complexes and the CHA scaffold, and the capillary number was greater than those of the same group of DCS complexes and the CHA scaffold. Therefore, the CHA scaffold strengthened the osteogenesis and blood vessel formation potential of the DCS complexes. Meanwhile, the DCS complexes also promoted the osteogenesis and blood vessel formation potential of the CHA scaffold. This study will provide a basis for building vascularized tissue engineered bone for bone defect therapy. STATEMENT OF SIGNIFICANCE: This study developed a double-cell sheet (DCS) complex composed of an osteogenic cell sheet and a vascular endothelial cell sheet with osteogenesis and blood vessel formation potential. Osteogenic and vascular endothelial cell sheets were obtained after induced culture of rabbit adipose-derived mesenchymal stem cells. The DCS complex and DCS-CHA complex exhibited osteogenic and blood vessel formation potential in vivo. CHA enhanced the osteogenesis and blood vessel formation abilities of the DCS complexes in vivo. Meanwhile, the DCS complexes also promoted the osteogenesis and blood vessel formation potential of the CHA scaffold. Group B of the DCS complexes and DCS-CHA complexes exhibited the best osteogenesis and blood vessel formation abilities. PMID- 30017921 TI - Amyloid by Design: Intrinsic Regulation of Microbial Amyloid Assembly. AB - The term amyloid has historically been used to describe fibrillar aggregates formed as the result of protein misfolding and that are associated with a range of diseases broadly termed amyloidoses. The discovery of "functional amyloids" expanded the amyloid umbrella to encompass aggregates structurally similar to disease-associated amyloids but that engage in a variety of biologically useful tasks without incurring toxicity. The mechanisms by which functional amyloid systems ensure nontoxic assembly has provided insights into potential therapeutic strategies for treating amyloidoses. Some of the most-studied functional amyloids are ones produced by bacteria. Curli amyloids are extracellular fibers made by enteric bacteria that function to encase and protect bacterial communities during biofilm formation. Here we review recent studies highlighting microbial functional amyloid assembly systems that are tailored to enable the assembly of non-toxic amyloid aggregates. PMID- 30017925 TI - Regulation of IL-17 by lncRNA of IRF-2 in the pearl oyster. AB - Long noncoding RNAs (lncRNAs), once thought to be nonfunctional, have recently been shown to participate in the multilevel regulation of transcriptional, posttranscriptional and epigenetic modifications and to play important roles in various biological processes, including immune responses. However, the expression and roles of lncRNAs in invertebrates, especially nonmodel organisms, remain poorly understood. In this study, by comparing a transcriptome to the PfIRF-2 genomic structure, we identified lncIRF-2 in the PfIRF-2 genomic intron. The results of the RNA interference (RNAi) and the nucleus grafting experiments indicated that PfIRF-2 might have a negative regulatory effect on lncIRF-2, and PfIRF-2 and lncIRF-2 may have a positive regulatory effect on PfIL-17. Additionally, lncIRF-2, PfIRF-2 and PfIL-17 were involved in responses to the nucleus graft. These results will enhance the knowledge of lncIRF-2, IRF-2, and IL-17 functions in both pearl oysters and other invertebrates. PMID- 30017926 TI - Molecular cloning and characterization of TANK of black carp Mylopharyngodon piceus. AB - The TRAF family member-associated NF-kappaB activator (TANK) is linked to the regulation of the transcription of NF-kappaB in mammals; however, its role in interferon induction is unclear. To elucidate the roles of TANK in teleost, the TANK homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized in this paper. The open reading frame (ORF) of black carp TANK (bcTANK) comprises 1050 nucleotides and the predicted bcTANK protein contains 350 amino acids. The transcription of bcTANK in host cells increased in response to the stimulation of LPS, poly (I:C), SVCV and GCRV. bcTANK migrated around 50 KDa in immunoblot assay and was identified as a cytosolic protein by immunofluorescent staining in both EPC and HeLa cells. bcTANK could not induce the activity of IFN promoter in luciferase reporter assay in EPC cells; however, the IFN-activation ability of bcTANK was obviously enhanced when the cells were treated with LPS, poly (I:C) or virus. Both CPE ratio and virus titer in the media of EPC cells expressing bcTANK were obviously lower than those of the control cells, which were examined by violet crystal staining and plaque assay separately. Taken together, our data support the conclusion that bcTANK plays an important role in the antiviral innate immune activation of black carp. PMID- 30017927 TI - Dietary values of macroalgae Porphyra haitanensis in Litopenaeus vannamei under normal rearing and WSSV challenge conditions: Effect on growth, immune response and intestinal microbiota. AB - Two trials were conducted to determine the effects of dietary macroalgae Porphyra haitanensis on growth, immunity and intestinal microbiota of Litopenaeus vannamei. In trial 1, shrimp (mean initial wet weight about 0.64 g) were fed with seven diets (P0, P1, P2, P3, P4, P5 and P6) containing 0% (basal diet), 1%, 2%, 3%, 4%, 5% and 6% P. haitanensis in triplicate for 60 days. Growth performance (weight gain, WG; specific growth rate, SGR) of shrimp fed the P4 diet were significantly higher than that of shrimp fed P0, P5 and P6 diets (P < 0.05) but without significant differences with shrimp fed P1-P3 diets (P > 0.05). Hepatopancreas phenoloxidase (PO) activity of shrimp fed the P. haitanensis containing diets was significantly higher than that of shrimp fed the basal diet (P0) (P < 0.05). Total haemocyte count (THC) of shrimp fed basal diet (P0) was significantly lower than that of shrimp fed diets containing P. haitanensis. Our results declared that dietary P. haitanensis supplementation increases the abundance of beneficial bacterials such as Nitrosopumilus, Marinobacter or Bifidobacterium and reduces the abundance of harmful bacterias such as Vibrio, and especially pronounced in P4 diet treatment. In trial 2, a WSSV injection challenge test was conducted for 7-day after the rearing trial and shrimp survival was also compared among treatments. A sudden shrimp death was found from the 4th day, and values of survival of shrimp fed the P3-P4 diets were higher than that of shrimp fed other diets during 4-7 days challenge test. The immune response in trial 2 were characterized by higher superoxide dismutase activity (SOD) and PO activities, lower THC and higher HCT compared to levels found in trial 1. In conclusion, suitable dietary P. haitanensis could enhance the growth performance, antioxidant capacity and alter total bacterial numbers or microbial diversity of L. vannamei and furthermore reduce oxidative stress and immune depression challenged by WSSV injection stress, and the level of P. haitanensis supplemented in the diet should be between 2.51% and 3.14%. PMID- 30017928 TI - Identification and functional analysis of immune deficiency (IMD) from Scylla paramamosain: The first evidence of IMD signaling pathway involved in immune defense against bacterial infection in crab species. AB - Immune deficiency (IMD) pathway, one of the most essential pattern recognition receptor signaling pathways, plays vital roles in innate immune responses to eliminate pathogen infection in invertebrates. In the present study, an immune deficiency (IMD) gene and two NF-kappaB family members, Relish and Dorsal, were identified and characterized in mud crab Scylla paramamosain for the first time. The deduced SpIMD, SpRelish and SpDorsal protein contained conserved death domain and classical NF-kappaB domains, respectively. Phylogenetic analysis suggested that SpIMD was classified into the invertebrate IMD branch, and SpRelish could be classified into the type I NF-kappaB class while SpDorsal could be grouped into the type II NF-kappaB class. Tissue distribution results showed these three genes were ubiquitously expressed in all tested tissues. The expression patterns of IMD signaling pathway and NF-kappaB genes, including SpIMD, SpIKKbeta, SpIKKepsilon, SpRelish and SpDorsal, were distinct when crabs were stimulated with Vibro alginolyticus, indicating that they might be involved in responding to bacterial infection. When SpIMD was silenced by in vivo RNA interference assay, the expression levels of IMD pathway and antimicrobial peptides (AMPs) genes, including SpIKKbeta, SpRelish, SpALF1-6 and SpCrustin, were significantly down regulated (p < 0.05). Correspondingly, the bacteria clearance ability of hemolymph was extremely impaired in IMD silenced crabs. Overall, the IMD played vital roles in innate immune response by regulating the expressions of its down stream signaling genes and AMPs in S. paramamosain. These findings might pave the way for a better understanding of innate immune system and establish a fundamental network for the IMD signaling pathway in crustaceans. PMID- 30017930 TI - Streptococcus agalactiae infection kills red tilapia with chronic Francisella noatunensis infection more rapidly than the fish without the infection. AB - In this study we examined the effect that a Francisella noatunensis (Fno) infection had on hybrid red tilapia (Oreochromis niloticus * Oreochromis mossambicus) subsquently infected with Streptococcus agalactiae. A variety of hemato-immunological parameters (haematocrit, total red blood cell count, mean corpuscular volume, total white blood and differential cell counts, total plasma protein, plasma lysozyme and plasma peroxidase activities, and respiratory burst and phagocytic activities of head-kidney macrophages) were measured in hybrid red tilapia that had been previously exposed to an Fno outbreak in a tilapia grow-out farm. The head-kidneys of these apparently healthy survivors, when checked by PCR were found to be Fno-positive with hemato-immunological parameters that were similar to fish without an a priori infection. The only exception was the percentage lymphocyte count in the peripheral blood, which was slightly, but significantly, lower in the Fno-infected fish, compared to those without the infection. When experimentally infected with S. agalactiae, the Fno-infected fish died more rapidly and at a significantly higher rate than fish without the infection. During the challenge, the hemato-immunological parameters of both groups of fish were very similar, although the Fno-infected fish, challanged with S. agalactiae expressed significantly higher plasma lysozyme and peroxidase activities, and their head kidney macrophages had significantly higher respiratory burst activity compared to non-Fno-infected fish challanged with S. agalactiae. The only two parameters for which Fno-infected fish showed significantly lower expressions than that of their non-infected counterparts were haematocrit and total red blood cell count. The cause of the rapidity and higher rates of mortality observed in the Fno-infected fish when challenged with S. agalactiae is unknown; but it may be due to a reduced erythropoiesis capability within the head-kidney because of the presence of Fno. PMID- 30017929 TI - Physiological and immune response in the gills of Litopenaeus vannamei exposed to acute sulfide stress. AB - Sulfide is a harmful environmental pollutant that affects the survival and immunity of shrimps. The gill is important for shrimp respiratory and osmotic adjustment, the physiological and immune homeostasis of the organ can be influenced by sulfide. In this study, we investigated the acute toxicity of sulfide (5 mg/L) on the morphology, physiological and immune response in the gills of Litopenaeus vannamei. H&E stain showed that sulfide stress damaged the gills histological structure. Specifically, osmoregulation capacity including of Na+/K+-ATPase and Ca2+/Mg2+-ATPase activity was both increased at 6 h and 12 h, and decreased at 72 h; the contents of free amino acid including of Gly, Pro, Ser, Thr and Ala were decreased at 72 h. Respiratory metabolic enzymes, such as cytochrome c oxidase and succcinate dehydrogenase activity was decreased at 12 h 72 h, while fumarate reductase and lactate dehydrogenase activity kept a higher level at 12 h-72 h. Significant variations in the activities of immune enzymes (acid phosphatase, alkaline phosphatase, total antioxidant capacity and lysozyme). The expression of immune-related genes (heat shock protein 70, thioredoxin and caspase-3) was increased at first and then decreased, while hypoxia inducible factor 1alpha kept a higher level at 6 h-72 h. These results revealed that sulfide stress influenced the L. vannamei gills physiological and immune function by damaging histological structure, and confusing osmoregulation, respiratory metabolic and immune capacity. PMID- 30017931 TI - DNA vaccination for finfish aquaculture. AB - In fish, DNA vaccines have been shown to give very high protection in experimental facilities against a number of viral diseases, particularly diseases caused by rhabdoviruses. However, their efficacy in generating protection against other families of fish viral pathogens is less clear. One DNA vaccine is currently in use commercially in fish farms in Canada and the commercialisation of another was authorised in Europe in 2017. The mechanism of action of DNA vaccines, including the role of the innate immune responses induced shortly after DNA vaccination in the activation of the adaptive immunity providing longer term specific protection, is still not fully understood. In Europe the procedure for the commercialisation of a veterinary DNA vaccine requires the resolution of certain concerns particularly about safety for the host vaccinated fish, the consumer and the environment. Relating to consumer acceptance and particularly environmental safety, a key question is whether a DNA vaccinated fish is considered a Genetically Modified Organism (GMO). In the present opinion paper these key aspects relating to the mechanisms of action, and to the development and the use of DNA vaccines in farmed fish are reviewed and discussed. PMID- 30017932 TI - beta-actin gene expression is variable among individuals and not suitable for normalizing mRNA levels in Portunus trituberculatus. AB - The housekeeping gene encoding beta-actin appears to be the most widely-used internal reference for gene expression studies in experimental animals or their cell lines. However, the effectiveness of beta-actin to normalize mRNA levels expression in many crustacean species is still object of debate. To date, it is still unclear if beta-actin is suitable to be utilized as the internal reference in qualitative real-time gene expression study in crab species. To address this concern, we evaluated 5 candidate reference genes encoding beta-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cyclophilin A, elongation factor 1-alpha (EF1-alpha), and 18 S ribosomal RNA (18 S rRNA) in the swimming crabs (Portunus trituberculatus) models. Our data showed that the beta-actin gene expression varied significantly across individual swimming crab individuals in gills or hemocytes and the expression of 18 S rRNA, EF1-alpha, cyclophilin or GAPDH gene were relatively stable compared to that of beta-actin. Moreover, the expression stability of the reference genes among different tissues in normal crabs or after WSSV challenge was also tested by geNorm and NormFinder software. Among tissues, 18 S rRNA was most stably expressed in different tissues, followed by cyclophilin A and EF1-alpha, compared to beta-actin and GAPDH. Upon to viral simulation, GAPDH was found to be the most stable internal control gene in gills and cyclophilin A was ranked as the most stable gene in hemocytes. PMID- 30017933 TI - microRNA-212-induced protection of the heart against myocardial infarction occurs via the interplay between AQP9 and PI3K/Akt signaling pathway. AB - Myocardial infarction (MI) is defined as the irreversible death of heart muscle that occurs secondary to prolonged lack of oxygen supply, which has resulted in millions of death worldwide. This study was conducted with aims of investigating how microRNA-212 (miR-212) and the inhibition of aquaporin-9 (AQP9) through the activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway plays a role in the prevention of MI. The relationship between miR-212 and AQP9 was determined with the use of bioinformatics combined with the dual luciferase reporter gene assay. Next, the MI model was established and the cardiomyocytes were transfected with different mimic, inhibitor and siRNAs to investigate the specific activity of miR-212, AQP9 and the PI3K/Akt signaling pathway in MI. The expression of miR-212, AQP9, PI3K, Akt, VEGF, Bax, and B cell lymphoma 2 (Bcl-2), along with cell apoptosis were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot analysis and flow cytometry. Based on the results, AQP9 was verified as the direct target gene of miR-212. MI led to a decrease in miR-212 expression and an increase in AQP9 expression. It was also found that miR-212 activated the PI3K/Akt signaling pathway in MI through the inhibition of AQP9 expression. The overexpression of miR-212 or silencing AQP9 decreased cardiomyocytes apoptosis. These findings indicated that the overexpression of miR-212 inhibited AQP9 by activating the PI3K/Akt signaling pathway, thus decreasing cardiomyocytes apoptosis, promoting vascular regeneration and alleviating ventricular remodeling in rats with MI. PMID- 30017934 TI - HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1. AB - Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38- K562 or KU812 cells, we showed that CD34+/CD38- SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38- cells positively correlates with enhanced expression of HDACs 1-6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38- and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hsa-miR-196a expression. This hsa-miR-196a-mediated SC-limiting effect of SAHA is dose-dependent, low-dosed, cell cycle-modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti-SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD-SCID mice models. PMID- 30017935 TI - TRAF6 mediates high glucose-induced endothelial dysfunction. AB - To investigate the role of tumor necrosis factor-associated factor 6 (TRAF6) in high glucose-induced endothelial cell dysfunction. Human aortic endothelial cells (HAECs) were cultured in high glucose medium, and TRAF6 expression was assayed by quantitative real-time Polymerase Chain Reaction (PCR) and western blotting. The effect of TRAF6 on in vitro endothelial cell viability, apoptosis, migration, and endothelial-monocyte adhesion was investigated by gene knockdown. The expression of TRAF6 and related adhesion molecules was assayed in a mouse streptozotocin induced type I diabetes model. The signaling pathways associated with TRAF6 effects on endothelial cells were investigated in high glucose HAEC cultures. Culture of HAECs in high glucose medium significantly increased TRAF6 mRNA and protein expression in a time dependent manner. High glucose markedly reduced HAEC viability, apoptosis, and migration, and these effects was significantly reversed by TRAF6 knockdown. High glucose significantly increased intercellular adhesion of THP-1 monocytic cells and HAECs via upregulation of ICAM-1 and VCAM-1 expression, and TRAF6 knockdown attenuated the effect on THP-1 cell adhesion. TRAF6, ICAM-1, and VCAM-1 expression were increased in aorta tissue of mice with streptozotocin-induced diabetes. The free radical scavenger N-acetyl-L-cysteine attenuated TRAF6 expression in HAECs cultured in high glucose medium, and TRAF6 knockdown inhibited high glucose-induced IkappaB-alpha degradation and JNK phosphorylation. TRAF6 mediated high glucose-induced endothelial dysfunction via NF-kappaB- and AP-1-dependent signaling. Targeting TRAF6 may delay progression of vascular diseases during diabetes mellitus and atherosclerosis. PMID- 30017936 TI - Association between bruxism and symptomatic gastroesophageal reflux disease: A case-control study. AB - OBJECTIVES: To examine the relation between bruxism and gastroesophageal reflux disease (GERD) and the contribution of depression, anxiety and impaired sleep quality to that association. METHODS: A three-centre case-control study was conducted consisting of 887 consecutive clinically-diagnosed bruxism patients aged 18-75 years and 887 matched controls. Diagnosis of GERD was based on the Montreal definition: moderate/severe symptoms >= one day/week or mild symptoms >= two days/week. Logistic regression was used to evaluate the association between bruxism and GERD. Mediation analyses were used to test whether the association between bruxism and GERD was mediated by depression, anxiety or impaired sleep quality. RESULTS: Binary logistic regression identified that GERD was associated with bruxism (odds ratio, 6.87; 95% confidence interval (CI), 4.34-10.88). This association was stronger in females (odds ratio, 12.27; 95% CI, 5.81-25.91) than in males (odds ratio, 3.99; 95% CI, 2.17-7.32). Multinomial logistic regression identified that GERD was associated with all types of bruxism (sleep bruxism alone, odds ratio, 6.71, 95% CI, 4.22-10.68; awake bruxism alone, odds ratio, 13.06, 95% CI, 5.32-32.05; overlap of sleep bruxism and awake bruxism, odds ratio, 6.48, 95% CI, 3.05-13.77). Ordinal logistic regression identified that longer GERD duration (> 2 years vs <= 2 years) was associated with bruxism frequency (odds ratio, 1.50; 95% CI, 1.10-2.05). Mediation analyses found that the association between bruxism and GERD was partially-mediated through depression, anxiety and impaired sleep quality. CONCLUSIONS: Clinically-diagnosed bruxism is associated with symptomatic GERD and is partially-mediated through depression, anxiety and impaired sleep quality. CLINICAL SIGNIFICANCE: Because bruxism is strongly associated with symptomatic GERD and patients with frequent bruxism symptoms tend to suffer from GERD for extensive time-periods, dentists should consider evaluation of GERD status as an elemental part of the medical examination of bruxism, especially severe bruxism. PMID- 30017937 TI - Comparison of ART and conventional techniques on clinical performance of glass ionomer cement restorations in load bearing areas of permanent and primary dentitions: A systematic review. AB - OBJECTIVES: To review the clinical performance of GIC restorations using calculated annual failure rates (AFRs) and qualitative descriptions based on conventional and ART techniques from two aspects: occlusal and approximal cavities in permanent or deciduous posterior teeth. SOURCES: Search strategies were undertaken of the PubMed database from January 1983 to March 2018. Additional articles were collected by hand searching. STUDY SELECTION: The following basic search terms, "(glass ionomer cement) and (clinical performance or survival or ART or atraumatic restorative or high viscosity)" with inclusion and exclusion criteria according to PRISMA flow diagram were used. DATA: A total of 904 articles were initially identified. Finally, 67 articles were included for quantitative and qualitative analysis after applying the inclusion and exclusion criteria. Assessment of risk of bias was performed for all included studies using ROBINS-I. CONCLUSIONS: For single-surface occlusal or multi-surface GIC restorations, the conventional technique showed better survival than ART technique regardless of dentition type (primary or permanent). When comparing the same treatment technique, AFRs of approximal or multi-surface GIC restorations were greater than those of single-surface (occlusal) restorations, irrespective of dentition type. RMGIC-conventional technique seems to be promising for restoring approximal cavities of primary teeth compared to other restorative materials. CLINICAL SIGNIFICANCE: The GIC-ART technique is an alternative option for single-surface (occlusal) restorations in permanent and primary teeth. However, the application of the GIC-ART technique for load-bearing approximal restorations should be carefully considered before employing this option, especially in primary teeth. PMID- 30017938 TI - Experimental measurement of endocytosis in fungal hyphae. AB - The present study examines the notion that polarized exocytosis in the tips of growing hyphae creates an excess of plasma membrane and thus the need for its removal by endocytosis. To measure endocytosis experimentally, we developed a photobleaching (FRAP) procedure to count endocytic events in hyphae of Neurospora crassa carrying a fluorescent tag on the actin-binding protein fimbrin (FIM-1 GFP). Given 40 nm as the average diameter of endocytic vesicles, we calculated that about 12.5% of the plasma membrane discharged in the apex becomes endocytosed in the subapex. According to our calculations, the GFP-tagged hyphae of N. crassa, measured under the constrained conditions of confocal microscopic examination, needed about 8800 vesicles/min to extend their plasma membrane or about 9800/min, if we include predicted demands for cell wall growth and extracellular secretion. Our findings support the notion that exocytosis and endocytosis operate in tandem with the latter serving as a compensatory process to remove any excess of plasma membrane generated by the intense exocytosis in the hyphal tips. Presumably, this tandem arrangement evolved to support the hallmark features of fungi namely rapid cell extension and abundant secretion of hydrolytic enzymes. PMID- 30017939 TI - Comparison of neurotoxicity of dexmedetomidine as an adjuvant in brachial plexus block in rats of different age. AB - Dexmedetomidine is a local anesthetic adjuvant that exerts neuroprotective effects in addition to its sedative and analgesic properties. However, it is not clear whether dexmedetomidine causes any neurotoxicity in neonates. We injected dexmedetomidine alone or in combination with ropivacaine to induce brachial plexus block in rats of different age, corresponding to human neonate, childhood, adolescence and adulthood. We then examined pro-inflammatory cytokines and activated caspase 3 to determine the neurotoxicity effects. We found that high dose of dexmedetomidine significantly reduced IL-6 and TNF-alpha levels in all aged rat brachial plexus compared to saline treatment, and these levels are similar to that of control brachial plexus at postnatal day 14, 18 and adulthood. Caspase 3 level is not significantly different between dexmedetomidine and control group, except that it is higher in dexmedetomidine treated group at postnatal day 5. We found that this neurotoxicity effect of dexmedetomidine is only present at a high dose. Dexmedetomidine shows minimal neurotoxicity in neonate rats during brachial plexus block when moderate doses are administered. This observation warrants more detailed clinical studies to determine the safety of using dexmedetomidine for brachial plexus block in infant or early childhood patients. PMID- 30017940 TI - Acute liver failure and misdiagnosis: Do not forget viral hepatitis E. PMID- 30017941 TI - Gliotoxin destructs the pulmonary epithelium barrier function by reducing cofilin oligomer formation to promote the dissolution of actin stress fibers. AB - The destruction of pulmonary epithelium is a major feature of lung diseases caused by the fungal pathogen Aspergillus fumigatus (A. fumigatus). Gliotoxin, a major mycotoxin of A. fumigatus, is widely postulated to be associated with the tissue invasion. However, the mechanism is unclear. In this study, we first discovered that cofilin, a regulator of actin dynamics in the pulmonary epithelial cells, existed mainly in the form of oligomer, which kept it unable to depolymerize actin filaments. Gliotoxin could reduce the formation of cofilin oligomer and promote the release of active cofilin monomer by regulating cofilin phosphorylation balance. Then, the active cofilin induced the dissolution of actin stress fibers to result in the disruption of pulmonary epithelium barrier function. Collectively, our study revealed a novel mechanism of gliotoxin destructing lung epithelium barrier function and for the first time indicated the role of cofilin oligomer in this process. PMID- 30017942 TI - Nisin, a potent bacteriocin and anti-bacterial peptide, attenuates expression of metastatic genes in colorectal cancer cell lines. AB - Colorectal cancer is the third most common cause of cancer-related death in the world which genetic and environmental agents are responsible for cancer. When cells detach from the tumor and invade surrounding tissues, the tumor is malignant and may form secondary tumors at other locations in a process called metastasis. Probiotics are the largest group of inhabitation bacteria in the colon. Gut microbiota has a central role in prevented the risk colon cancer. Probiotics are beneficial microorganisms, like Lactic acid bacteria and Lactobacilli bacteria which are using in the dairy industry. Probiotics nisin are having the most important category of safe usage. In this study LS180, SW48, HT29 and Caco2 was cultured and treated with different dose of nisin. Cell proliferation was assayed with MTT. The expression of CEA, CEAM6 and MMP2F genes was analyzed with Real-time PCR. Protein expression of CEA was evacuated with ELISA. Our result was shown that the 40-50 IU/mL nisin could suppress proliferation of LS180. Cell proliferation of SW48, HT29, Caco2 cells was decreased in 250-350 IU/mL concentration of nisin. The gene expression of CEA, CEAM6, MMP2F was significantly down-regulated with nisin treatment (p < 0.001, p < 0.01). Also, after cells treated with nisin, CEA protein expression was down regulated (p < 0.01). In conclusion, nisin could suppressed metastatic process via down-regulation of CEA, CEAM6, MMP2F, MMP9F genes. We suggested the new treatment strategies beyond Probiotics, which play a role in the prevention local tumor invasion, metastasis and recurrence. PMID- 30017943 TI - Vaccination threshold size and backward bifurcation of SIR model with state dependent pulse control. AB - Depending on the potential susceptible human size, we consider the state dependent integrated infectious disease control strategies including vaccination, isolation and treatment. Correspondingly, we propose a state-dependent pulse SIR model, in which whether the control measures implemented or not depends on the threshold size of susceptible population. By defining the Poincare map, we first investigate the existence and global stability of the semi-trivial (or disease free) periodic solution, and the threshold condition is proposed. Further, by employing bifurcation theories of the one-parameter family of maps related to the Poincare map, we then focus on the bifurcation with respect to the key parameters. The main results reveal that backward bifurcation via transcritical bifurcation or pitchfork bifurcation can occur for all the interesting parameters including isolation rate, vaccination rate, threshold susceptible population size and birth rate. The complex relationships between the basic reproduction number of classical SIR model and the threshold condition of the model with state dependent pulse control depict that the control strategies related to the four parameters should be carefully designed, otherwise the paradoxical effects could occur and the gains cannot make up for losses. For example, too small vaccination rate will result in an increasing of threshold condition and the number of infected population. Therefore, our results suggest that when the state-dependent feedback control strategy is implemented for infectious disease control, the effective and optimal control program should take the population dynamics, the threshold susceptible population size, vaccination and isolation or treatment rate into consideration. PMID- 30017944 TI - The role of stochastic sequestration dynamics for intrinsic noise filtering in signaling network motifs. AB - The relation between design principles of signaling network motifs and their robustness against intrinsic noise still remains illusive. In this work we investigate the role of cascading for coping with intrinsic noise due to stochasticity in molecular reactions. We use stochastic approaches to quantify fluctuations in the terminal kinase of phosphorylation-dephosphorylation cascade motifs and demonstrate that cascading highly affects these fluctuations. We show that this purely stochastic effect can be explained by time-varying sequestration of upstream kinase molecules. In particular, we discuss conditions on time scales and parameter regimes which lead to a reduction of output fluctuations. Our results are put into biological context by adapting rate parameters of our modeling approach to biologically feasible ranges for general binding-unbinding and phosphorylation-dephosphorylation mechanisms. Overall, this study reveals a novel role of stochastic sequestration for dynamic noise filtering in signaling cascade motifs. PMID- 30017945 TI - Examining the effect of reoccurring disturbances on population persistence with application to marine mammals. AB - We develop a two-state Markov chain to describe the effect of reoccurring disturbances on a population that is modeled by discrete-time matrix model. The environment is described by three parameters that define the magnitude of impact of a disturbance, the average duration of impact of a disturbance, and the average time between disturbances. We derive an approximation for the stochastic growth rate in order to examine how these three parameters affect population growth. From this approximation, we calculate the sensitivity and elasticity of the growth rate with respect to the environmental parameters. We show that the average duration of impact of a disturbance and the average time between disturbances contribute equally to the stochastic growth rate. We also show that the elasticity of the stochastic growth rate is more sensitive to changes in the magnitude of impact than to changes in either the average duration of impact of a disturbance or the average time between disturbances. These conclusions hold irrespective of the population under consideration. We then provide an application of the model formulation to examine how disturbances, such as oil spills, may affect a sperm whale population. The model results suggest that, in oder to mitigate the impact of disturbances, management strategies should focus on reducing the magnitude of impact. Meanwhile, if it is more feasible to reduce either the duration of impact or the time between impacts, managers should focus on whichever is easier to obtain. In addition, when applied to a sperm whale population, our model shows that the probability of extinction can dramatically increase when disturbance frequency increases but is not greatly impacted by the assumption that all disturbances have the same magnitude. PMID- 30017946 TI - Leishmaniasis recidivans by Leishmania tropica in Central Rift Valley Region in Kenya. AB - OBJECTIVES: This study sought to determine the endemic Leishmania species, the clinical features of cutaneous leishmaniasis (CL) in the Central Rift Valley in Kenya and to give an account on unresponsiveness to treatment in the region. METHODS: Participants were clinically identified and grouped into untreated, classical and recidivate based on clinical manifestation and clinical data. Leishmaniasis recidivans lesions were scaly hyperemic papules that appeared before the classic lesion had healed or after healing. The demographics and socio economic data were recorded and lesion scraping samples screened through microscopy and Internal Transcribed Spacer 1-PCR. Leishmania species were identified using Restriction Fragment Length Polymorphism. RESULTS: A total of 52 participants were sampled, of which, 44.2% of the cases were recidivate and L. tropica the only species identified. All patients had been treated using sodium stibogluconate (SSG) which is the recommended first-line drug in Kenya. 60% of the patients experienced prolonged exposure to the drug (>30 days). CONCLUSION: L. tropica is the endemic Leishmania species for CL leading to classical and leishmaniasis recidivans. Treatment of CL in the area is not effective hence, alternative measures/therapy should be considered to cope with the unresponsiveness. PMID- 30017947 TI - Bi-directional associations between parental feeding practices and children's body mass in parent-child dyads. AB - OBJECTIVE: This study investigated whether parental feeding practices, such as pressure to eat, permitting unhealthy food, and restriction of unhealthy food predict children's body mass index (BMI) percentile or if children's BMI percentiles predict parental feeding practices. DESIGN: Longitudinal data were collected among 526 dyads of children (6-11 years old) and one of their parents. Parents reported parental feeding practices, restriction of unhealthy food, permission of unhealthy food, and pressure to eat. Children's weight and height were assessed objectively. All measurements were conducted twice with a time lag of 10 months. RESULTS: Cross-lagged panel analyses demonstrated that low levels of children's BMI percentiles (measured at the baseline) predicted parental feeding practices (measured at the follow-up) but not vice versa. Only one effect suggesting bi-directionality was found, with parental restriction of unhealthy food preceding higher levels of children's BMI percentiles at the follow-up. CONCLUSIONS: Parental feeding practices seem to be a reaction to the levels of children's BMI percentiles. PMID- 30017949 TI - 'Candidatus Aquirickettsiella gammari' (Gammaproteobacteria: Legionellales: Coxiellaceae): A bacterial pathogen of the freshwater crustacean Gammarus fossarum (Malacostraca: Amphipoda). AB - Invasive and non-native species can pose risks to vulnerable ecosystems by co introducing bacterial pathogens. Alternatively, co-introduced bacterial pathogens may regulate invasive population size and invasive traits. We describe a novel candidate genus and species of bacteria ('Candidatus Aquirickettsiella gammari') found to infect Gammarus fossarum, from its native range in Poland. The bacterium develops intracellularly within the haemocytes and cells of the musculature, hepatopancreas, connective tissues, nervous system and gonad of the host. The developmental cycle of 'Candidatus Aquirickettsiella gammari' includes an elementary body (496.73 nm +/- 37.56 nm in length, and 176.89 nm +/- 36.29 nm in width), an elliptical, condensed spherical stage (737.61 nm +/- 44.51 nm in length and 300.07 nm +/- 44.02 nm in width), a divisional stage, and a spherical initial body (1397.59 nm +/- 21.26 nm in diameter). We provide a partial genome for 'Candidatus Aquirickettsiella gammari', which clades phylogenetically alongside environmental 16S rRNA sequences from aquatic habitats, and bacterial symbionts from aquatic isopods (Asellus aquaticus), grouping separately from the Rickettsiella, a genus that includes bacterial pathogens of terrestrial insects and isopods. Increased understanding of the diversity of symbionts carried by G. fossarum identifies those that might regulate host population size, or those that could pose a risk to native species in the invasive range. Identification of 'Candidatus Aquirickettsiella gammari' and its potential for adaptation as a biological control agent is explored. PMID- 30017948 TI - Differential protein expression of hippocampal cells associated with heavy metals (Pb, As, and MeHg) neurotoxicity: Deepening into the molecular mechanism of neurodegenerative diseases. AB - : Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb < As < MeHg on hippocampal cells. The main objective of this study was combining in vitro label free proteomics and systems biology approach for elucidating patterns of biological response, discovering underlying mechanisms of Pb, As, and MeHg toxicity in hippocampal cells. The omics data was refined by using different filters and normalization and multilevel analysis tools were employed to explore the data visualization. The functional and pathway visualization was performed by using Gene ontology and PathVisio tools. Using these all integrated approaches, we identified significant proteins across treatments within the mitochondrial dysfunction, oxidative stress, ubiquitin proteome dysfunction, and mRNA splicing related to neurodegenerative diseases. The systems biology analysis revealed significant alterations in proteins implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). The current proteomics analysis of three metals support the insight into the proteins involved in neurodegeneration and the altered proteins can be useful for metal-specific biomarkers of exposure and its adverse effects. SIGNIFICANCE: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure. PMID- 30017950 TI - Prevalence of naturally-occurring strains of Beauveria bassiana in populations of coffee berry borer Hypothenemus hampei on Hawai'i Island, with observations on coffee plant-H. hampei-B. bassiana interactions. AB - Beauveria bassiana (Bb) strain GHA is a major component of an areawide pest management program for coffee berry borer (CBB) in Hawai'i. Recent studies have aimed to provide comprehensive assessments of the efficacy of the Bb-spray component of these programs for economic analyses; however, evaluations have been complicated by activity of naturally-occurring strains of this pathogen infecting CBB. Investigations were therefore undertaken to characterize these strains, assess their natural epizootic potential, and account for their contribution to CBB population suppression. A number of field sites were encountered with no history of significant use of commercial Bb-based biopesticides and where strain GHA was not detectable. Sampling of these sites was conducted early in the coffee season. Greatest activity of wild-type Bb strains was observed on high-elevation farms (>500 m), where 24-42% of foundress beetles in green coffee berries were infected. In contrast, infection rates did not exceed 4% on farms at low elevations (<300 m). Rates of 23-29% infection, comparable to those on high elevation farms, were recorded in a stand of feral coffee at 293 m elevation, but the coffee was completely shaded and ventilation restricted by a dense overstory of vegetation. Despite high activity of naturally-occurring Bb at some sites (primarily sites at high elevations with humid, moderate-temperature environments and dense pest populations), these fungi did not prevent CBB from exceeding the economic threshold for commercial spray applications. Nevertheless, the high natural epizootic potential of these fungal strains suggests strong potential for development as microbial biocontrol agents. PMID- 30017951 TI - Diversity and abundance of entomopathogenic fungi at ant colonies. AB - The purpose of this study was to identify whether entomopathogenic fungi in the genera Metarhizium and Beauveria were found at ant nests. These fungi have been used in studies of ant social immunity, however experimental conditions used may not normally be representative of that found within ant colonies. The presence of insect pathogenic fungi including Metarhizium and Beauveria was assessed in soils at 22 ant nests in Ontario, Canada. Soil samples were plated onto selective agar, fungi were isolated and DNA extracted and the fungi identified by amplifying the internal transcribed spacer region (ITS) and comparing sequences to those found in GenBank. We found that Metarhizium species were found in soils in and around most ant nests. Concentrations of Metarhizium in the soil were not influenced by the presence of ant nests suggesting co-existence rather than avoidance or seeking behaviour. Thus, Metarhizium appears to be a good pathogen to study ant fungal interactions. Beauveria on the other hand, was not found in any of the samples indicating a decreased likelihood that ants encounter this pathogen. Other fungi found at relatively high concentrations at ant nests include Pochonia and Purpureocillium species, both recognized as nematode pathogens. PMID- 30017952 TI - Possible source of the high UV-B and heat tolerance of Metarhizium acridum (isolate ARSEF 324). AB - The isolate ARSEF 324 of Metarhizium acridum is very tolerant to UV-B radiation and heat, but the intrinsic traits behind the extreme tolerance of this isolate to both stress conditions have not been elucidated. Because trehalose and mannitol are documented stress reducers in fungi, we investigated the accumulation of these compounds in conidia of ARSEF 324 compared with the accumulation of these two compounds in conidia of M. robertsii (ARSEF 23 and ARSEF 2575), which are considerably more susceptible to UV-B radiation and heat than ARSEF 324. Conidia of ARSEF 324 produced on potato dextrose agar plus yeast extract accumulated two-fold more trehalose and mannitol than conidia of ARSEF 23 and ARSEF 2575 produced on the same medium. The high accumulation of trehalose and mannitol in conidia of ARSEF 324 suggests one mechanism that it uses to attain its high tolerance to UV-B radiation and heat. PMID- 30017953 TI - Cry78Aa, a novel Bacillus thuringiensis insecticidal protein with activity against Laodelphax striatellus and Nilaparvata lugens. AB - Transgenic plants expressing insecticidal proteins originating from Bacillus thuringiensis (Bt) have successfully been used to control lepidopteran and coleopteran pests with chewing mouthparts. However, only a handful of Bt proteins have been identified that have bioactivity against sap sucking pests (Hemiptera), including aphids, whiteflies, plant bugs and planthoppers. A novel Bt insecticidal protein with significant toxicity against a hemipteran insect pest is described here. The gene encoding the 359 amino acid, 40.7 kDa protein was cloned from strain C9F1. After expression and purification of the toxin, its median lethal concentration (LC50) values against Laodelphax striatellus and Nilaparvata lugens were determined as 6.89 MUg/mL and 15.78 MUg/mL respectively. Analysis of the toxin sequence revealed the presence of both Toxin_10 and Ricin_B_Lectin domains. PMID- 30017954 TI - Optineurin Insufficiency Disbalances Proinflammatory and Anti-inflammatory Factors by Reducing Microglial IFN-beta Responses. AB - Mutations in a ubiquitin (Ub)-binding adaptor protein optineurin have been found in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a prominent neuroinflammatory component. Unlike more frequent ALS mutations which cause disease by gaining toxic properties such as aggregation, mutated optineurin is thought to cause disease by loss-of-function, highlighting its neuroprotective role. Optineurin regulates inflammatory signaling by acting as a scaffold for Tank-binding kinase 1 (TBK1) activation and interferon (IFN)-beta production in peripheral immune cells. The relevance of this pathway in the CNS is unclear. To investigate IFN-beta pathway as a potential mechanism of optineurin-mediated protection from neurodegeneration, we have generated a mouse model in which the Ub-binding region of optineurin was deleted (Optn470T), mimicking C-terminal truncations found in patients. Here we report reduced TBK1 activation and IFN beta production in primary microglia from Optn470T model upon Toll-like receptor (TLR) stimulation. Likewise, we found diminished expression and activation of several transcription factors that support the amplification loop for IFN-beta production including STAT1, IRF7 and IRF9. Notably, although optineurin was also reported to block proinflammatory transcription factor NF-kappaB, normal NF kappaB activation and TNF production were found in Optn470T microglia. However, expression of both proinflammatory and anti-inflammatory factors distal to IFN beta was diminished, and could be restored upon IFN-beta supplementation. Taken together with the recent discoveries of TBK1 mutations as an important genetic factor in ALS, our results open up the possibility that disruption of optineurin/TBK1-mediated IFN-beta axis leads to an immune failure in containing neuronal damage, which could predispose to neurodegeneration. PMID- 30017955 TI - Handedness and the Corpus Callosum: A Review and Further Analyses of Discordant Twins. AB - Handedness effects with respect to regional corpus callosum (CC) anatomy remain open to question. Midsagittal CC tracings were obtained from structural MRIs in 21 female monozygotic twin pairs with discordant handedness (MZHd). The CC was divided into 99 percentile widths which were grouped into seven regions based on Denenberg's (1989, 1991b) factor analysis. Results showed that left handed (LH) twins had significantly larger regional widths in CC region W22-39 compared to right handed (RH) twins, an effect present in 19/21 MZHd pairs. Cross-study analyses revealed CC W22-39 to have the highest variation across female singletons (Cowell et al., 1992, 1993). In the adjacent genu region (W3-18), CC size did not differ between RH and LH twins. However, when twins were reclassified according to handedness direction and consistency to form consistent RH, non-consistent RH, consistent LH and non-consistent LH groups, patterns of CC size in W3-18 closely matched those of singleton women (Cowell et al., 1993). Namely, CC W3-18 was larger in consistent compared to non-consistent RHs. Results support a claim that CC region W22-39, interconnecting premotor cortex in females, provides for environmentally influenced components of handedness, given the difference within MZHd twin pairs. By contrast, CC W3-18, connecting prefrontal cortex, was sensitive to direction and consistency of handedness, both in twins and singletons, a result consistent with combined genetic and environmental effects. Findings highlight the significance of MZHd twin studies in elucidating the developmental mechanisms underpinning structure-function asymmetry, cortical interconnectivity and neurodevelopmental bases of left hand preference. PMID- 30017956 TI - Potential Brain Age Reversal after Pregnancy: Younger Brains at 4-6 Weeks Postpartum. AB - Pregnancy is accompanied by complex biological adaptations, including extreme hormonal fluctuations. Moreover, changes on the endocrine level are accompanied by changes in cerebral anatomy, such as reductions in brain or gray matter volume. Since declining brain and tissue volumes are characteristic for normal aging, the question arises of whether such pregnancy-induced anatomical effects are permanent or transient. To answer this question, we acquired high-resolution brain image data of 14 healthy women in their mid-twenties to late thirties at two time points: within 1-2 days of childbirth (early postpartum) and at 4-6 weeks after childbirth (late postpartum). At both time points, we estimated the brain ages for each woman using a well-validated machine learning approach based on pattern recognition. Ultimately, this algorithm - designed to identify anatomical correlates of age across the entire brain - reveals a single score for each individual: the BrainAGE index. Comparing the BrainAGE indices between both time points, female brains at late postpartum were estimated to be considerably younger than at early postpartum. On average, that difference was about five years (mean +/- SD: 5.4 +/- 2.4 years). These findings suggest a substantial restoration/rejuvenation effect after giving birth, which is evident already within the first couple of months. PMID- 30017957 TI - Neurologic outcomes after extracorporeal membrane oxygenation assisted CPR for resuscitation of out-of-hospital cardiac arrest patients: A systematic review. AB - INTRODUCTION: Extracorporeal membrane oxygenation-assisted CPR (ECPR) is an evolving adjunct for resuscitation of OHCA patients. The primary objective of this systematic review was to assess survival-to-hospital discharge with good neurologic recovery after OHCA among patients treated with ECPR compared to conventional CPR (CCPR). METHODS: A systematic search of MEDLINE(r) and EMBASE(r) electronic databases was performed from inception until July 2016 to identify studies reporting ECPR use in adults with OHCA and survival outcomes. RESULTS: Of the 1512 citations identified, 75 studies met our inclusion criteria (63 case series and 12 cohort studies). Among case series, 0 to 71.4% of patients treated with ECPR survived to discharge with a good neurologic outcome. Subgroup analysis of the cohort studies demonstrated survival-to-hospital discharge with good neurologic recovery in the ECPR group ranging from 8.3 to 41.6% compared to 1.5 to 9.1% in the CCPR group. Five cohort studies adjusted for confounders, 3 of which demonstrated significantly increased adjusted odds ratios of survival among the ECPR-treated patients. Due to significant heterogeneity (I2 = 63%, p = 0.03), pooling of outcomes and a meta-analysis were not conducted. CONCLUSION: Although a trend towards improved survival with good neurologic outcome was reported in controlled, low-risk of bias cohort studies, a preponderance of low quality evidence may ascribe an optimistic effect size of ECPR on survival among OHCA patients. Our confidence in a clinically relevant difference in outcomes compared to current standards of care for OHCA remains weak. In this state of equipoise, high quality RCT data is urgently needed. PMID- 30017958 TI - HPV Vaccination Recommendation Practices among Adolescent Health Care Providers in 5 Countries. AB - STUDY OBJECTIVE: To assess adolescent health care providers' recommendations for, and attitudes towards human papillomavirus (HPV) vaccination in 5 countries. DESIGN: In-depth interviews of adolescent health care providers, 2013-2014. SETTING: Five countries where HPV vaccination is at various stages of implementation into national programs: Argentina, Malaysia, South Africa, South Korea, and Spain. PARTICIPANTS: Adolescent health care providers (N = 151) who had administered or overseen provision of adolescent vaccinations (N = Argentina: 30, Malaysia: 30, South Africa: 31, South Korea: 30, Spain: 30). MAIN OUTCOME MEASURES: Frequency of HPV vaccination recommendation, reasons providers do not always recommend the vaccine and facilitators to doing so, comfort level with recommending the vaccine, reasons for any discomfort, and positive and negative aspects of HPV vaccination. RESULTS: Over half of providers 82/151 (54%) recommend HPV vaccination always or most of the time (range: 20% in Malaysia to 90% in Argentina). Most providers 112/151 (74%) said they were comfortable recommending HPV vaccination, although South Korea was an outlier 10/30 (33%). Providers cited protection against cervical cancer 124/151 (83%) and genital warts 56/151 (37%) as benefits of HPV vaccination. When asked about the problems with HPV vaccination, providers mentioned high cost 75/151 (50% overall; range: 26% in South Africa to 77% in South Korea) and vaccination safety 28/151 (19%; range: 7% in South Africa to 33% in Spain). Free, low-cost, or publicly available vaccination 59/151 (39%), and additional data on vaccination safety 52/151 (34%) and efficacy 43/151 (28%) were the most commonly cited facilitators of health provider vaccination recommendation. CONCLUSION: Interventions to increase HPV vaccination should consider a country's specific provider concerns, such as reducing cost and providing information on vaccination safety and efficacy. PMID- 30017960 TI - Structural Consistency of the Pain Sensitivity Questionnaire in the Cooperative Health Research In South Tyrol (CHRIS) Population-Based Study. AB - The self-reported Pain Sensitivity Questionnaire (PSQ) is a valid supplement to experimental pain testing. However, the latent constructs determining the originally proposed 1 general score (PSQ-total) and 2 subscores (PSQ-moderate and PSQ-minor) have not been consistently investigated in population-based studies or between genders. Based on a single construct hypothesized by expert knowledge or alternative constructs upon empirical evidence, PSQ structures were explored and confirmed among 4,820 participants aged 18 to 93 years of the Cooperative Health Research In South Tyrol (CHRIS) study. By exploratory factor analysis, we identified 3 alternative sets of PSQ imagined painful situations comprising 14, 10, and 9 items, which displayed simple structures of the rotated factor loadings of direct interpretation. In confirmatory analysis (CFA) of 1 latent factor, the 10-item set yielded acceptable goodness-of-fit overall, better fit than the alternative sets and consistent structural properties between genders. Separate analyses based on 14- and 9-item sets returned considerable correlations between 2 latent constructs. In higher-order CFA with each set, 1 first-order general factor explained a large part of the variances of 2 second-order factors. One dominant construct consistently describes the factorial structure of the PSQ. Averaging across the 10-item set, the PSQ-short score represents a structurally robust, gender-consistent, and practical measure of general pain sensitivity. PERSPECTIVE: One dominant latent construct of general pain sensitivity consistently determines responses to the self-reported PSQ. The PSQ-short score maintains similar psychometric properties to the PSQ-total and between genders. This measure is attractive for large-scale research and clinical screening of pain sensitivity. PMID- 30017959 TI - Di (2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in quails (Coturnix japonica) via triggering nuclear xenobiotic receptors and modulating cytochrome P450 systems. AB - Di (2-ethylhexyl) phthalate (DEHP) is a widely distributed pollutant that is of great concern due to its negative health effects. However, whether DEHP exposure causes liver toxicity in birds remains unclear. To clarify the potential hepatotoxicity of DEHP, quails were exposed to 0, 250, 500 and 1000 mg/kg BW/day DEHP by gavage treatment for 45 days. The livers of DEHP-exposed quails showed histomorphological changes. DEHP exposure induced a significant increase in cytochrome P450 enzyme system (CYP450s) activity (including aniline-4-hydroxylase (AH), aminopyrine N-demethylase (APND), erythromycin N-demethylase (ERND) and NADPH-cytochrome C reductase (NCR)) and in the contents of total cytochrome P450 (CYP450) and cytochrome b5 (Cyt b5) in quail liver. DEHP exposure also influenced the expression of nuclear xenobiotic receptors (NXRs) and CYP450 isoforms in the liver. The results suggested that DEHP-induced hepatotoxicity in quail liver is associated with activation of the NXRs pathway responses and disruption of CYP450s homeostasis. This study will help to further elucidate DEHP exposure induced liver toxicity in quails. PMID- 30017961 TI - Disease-directed design of biodegradable polymers: Reactive oxygen species and pH responsive micellar nanoparticles for anticancer drug delivery. AB - Herein, we report reactive oxygen species (ROS)- and pH-responsive biodegradable polyethylene glycol (PEG)-block-polycarbonate by installing thioether groups onto the polycarbonate and its self-assembled core/shell structured micelles for anticancer drug delivery. Oxidation of thioethers to sulfoxide and subsequently sulfone induces an increase in hydrophilicity, resulting in more hydrophilic micellar core. This phase-change caused the micelles to swell and enhance cargo release. Carboxylic acid groups have also been installed onto thioether containing polycarbonate to promote loading of amine-containing anticancer doxorubicin through electrostatic interaction. Urea-functionalized thioether containing PEG-block-polycarbonates were synthesized to mix with the acid functionalized PEG-block-polycarbonate for stabilizing micelle structure through hydrogen-bonding interaction. The mixed micelles were 50 nm in diameter and had a 25 wt% loading capacity for doxorubicin. Enhanced drug release from the micelles was triggered by low pH and high content of ROS. Drug-encapsulated micelles accumulated in tumors through leaky tumor vasculature in PC-3 human prostate cancer xenograft mouse model. PMID- 30017963 TI - Painful Bladder Symptoms Related to Somatic Syndromes in a Convenience Sample of Community Women with Overactive Bladder Symptoms. AB - PURPOSE: We investigated the relationship of painful bladder filling and urinary urgency to somatic and chronic pain symptoms in women with overactive bladder without an interstitial cystitis/bladder pain syndrome diagnosis. MATERIALS AND METHODS: Women who met overactive bladder criteria based on symptoms were recruited, including 183 (83.9%) from the community and 35 (16.1%) from the urology clinic to complete validated questionnaires assessing urinary symptoms, somatic symptoms and pain syndromes. Participants were categorized into 1 of 3 groups, including 1) neither symptom, 2) either symptom or 3) both symptoms, based on their reports of painful urinary urgency and/or painful bladder filling. Multivariable regression analyses were performed to determine factors predictive of having painful urgency and/or painful filling. RESULTS: Of 218 women with overactive bladder 101 (46%) had neither painful bladder filling nor urinary urgency, 94 (43%) had either symptom and 23 (11%) had both symptoms. When controlling for age, women with either or both urological pain symptoms were more likely to have irritable bowel syndrome, chronic pelvic pain and temporomandibular disorder than women in the neither group. Additionally, these women had higher pain intensity and somatic symptoms scores than women with neither symptom. CONCLUSIONS: The majority of women with overactive bladder who had not been diagnosed with interstitial cystitis/bladder pain syndrome reported painful urgency and/or painful filling. Experiencing painful urgency and/or filling was associated with an increased somatic symptom burden and greater pain intensity. These findings support the hypothesis that overactive bladder and interstitial cystitis/bladder pain syndrome diagnoses may represent a continuum of bladder hypersensitivity. PMID- 30017962 TI - Visual targeted therapy of hepatic cancer using homing peptide modified calcium phosphate nanoparticles loading doxorubicin guided by T1 weighted MRI. AB - Effective treatment and real-time monitoring of hepatic cancer are essential. A multifunctional calcium phosphate nanoparticles loading chemotherapeutic agent doxorubicin and magnetic resonance imaging contrast agent diethylenetriaminepentaacetic acid gadolinium (A54-CaP/Gd-DTPA/DOX) was developed for visual targeted therapy of hepatic cancer via T1-weighted MRI in real-time. A54-CaP/Gd-DTPA/DOX exhibited a higher longitudinal relaxivity (6.02 mM-1 s-1) than commercial MR contrast agent Gd-DTPA (3.3765 mM-1 s-1). The DOX release from the nanoparticles exhibited a pH dependent behavior. The cellular uptake results showed that the internalization of A54-CaP/Gd-DTPA/DOX into BEL-7402 cells was1.9 fold faster than that of HepG2 cells via A54 binding. In vivo experiments presented that A54-CaP/Gd-DTPA/DOX had higher distribution and longer retention time in tumor tissue than CaP/Gd-DTPA/DOX and free DOX, and also displayed great antitumor efficacy (95.38% tumor inhibition rate) and lower toxicity. Furthermore, the Gd-DTPA entrapped in the nanoparticles could provide T1-weighted MRI for real-time monitoring the progress of tumor treatment. PMID- 30017964 TI - Accuracy of Transperineal Targeted Prostate Biopsies, Visual Estimation and Image Fusion in Men Needing Repeat Biopsy in the PICTURE Trial. AB - PURPOSE: We evaluated the detection of clinically significant prostate cancer using magnetic resonance imaging targeted biopsies and compared visual estimation to image fusion targeting in patients requiring repeat prostate biopsies. MATERIALS AND METHODS: The prospective, ethics committee approved PICTURE trial (ClinicalTrials.gov NCT01492270) enrolled 249 consecutive patients from January 11, 2012 to January 29, 2014. Men underwent multiparametric magnetic resonance imaging and were blinded to the results. All underwent transperineal template prostate mapping biopsies. In 200 men with a lesion this was preceded by visual estimation and image fusion targeted biopsies. As the primary study end point clinically significant prostate cancer was defined as Gleason 4 + 3 or greater and/or any grade of cancer with a length of 6 mm or greater. Other definitions of clinically significant prostate cancer were also evaluated. RESULTS: Mean +/- SD patient age was 62.6 +/- 7 years, median prostate specific antigen was 7.17 ng/ml (IQR 5.25-10.09), mean primary lesion size was 0.37 +/- 1.52 cc with a mean of 4.3 +/- 2.3 targeted cores per lesion on visual estimation and image fusion combined, and a mean of 48.7 +/- 12.3 transperineal template prostate mapping biopsy cores. Transperineal template prostate mapping biopsies detected 97 clinically significant prostate cancers (48.5%) and 85 insignificant cancers (42.5%). Overall multiparametric magnetic resonance imaging targeted biopsies detected 81 clinically significant prostate cancers (40.5%) and 63 insignificant cancers (31.5%). In the 18 cases (9%) of clinically significant prostate cancer on magnetic resonance imaging targeted biopsies were benign or clinically insignificant on transperineal template prostate mapping biopsy. Clinically significant prostate cancer was detected in 34 cases (17%) on transperineal template prostate mapping biopsy but not on magnetic resonance imaging targeted biopsies and approximately half was present in nontargeted areas. Clinically significant prostate cancer was found on visual estimation and image fusion in 53 (31.3%) and 48 (28.4%) of the 169 patients (McNemar test p = 0.5322). Visual estimation missed 23 clinically significant prostate cancers (13.6%) detected by image fusion. Image fusion missed 18 clinically significant prostate cancers (10.8%) detected by visual estimation. CONCLUSIONS: Magnetic resonance imaging targeted biopsies are accurate for detecting clinically significant prostate cancer and reducing the over diagnosis of insignificant cancers. To maximize detection visual estimation as well as image fusion targeted biopsies are required. PMID- 30017965 TI - Telomerase reverse transcriptase regulates DNMT3B expression/aberrant DNA methylation phenotype and AKT activation in hepatocellular carcinoma. AB - Telomerase reverse transcriptase (TERT)1 acts as a master regulator of cancer hallmarks, but underlying mechanisms remain incompletely understood. We show that TERT is required for the aberrant DNA methyltransferase 3 B (DNMT3B)2 expression and cancer-specific methylation in hepatocellular carcinoma (HCC)3, through which AKT is activated. TERT depletion inhibited, while its over-expression promoted DNMT3B expression in HCC cells, respectively. Mechanistically, TERT cooperates with the transcription factor Sp1 to stimulate DNMT3B transcription. The tumor suppressors PTEN and RASSF1A were de-repressed following DNMT3B inhibition in TERT-depleted HCC cells. The PTEN promoter analysis demonstrated significantly reduced methylation in these cells. TERT silencing also led to diminished global DNA methylation. The analysis of the Cancer Genome Atlas (TCGA)4 dataset showed that higher levels of TERT and DNMT3B expression predicted significantly shorter survival in HCC patients. Collectively, our findings establish TERT as an important contributor to cancer-specific DNA methylation and AKT hyperactivation in HCC cells. Given critical roles of both the aberrant DNA methylation and AKT activation in carcinogenesis, this TERT-regulated network or the TERT-DNMT3B-PTEN AKT axis provides a biological explanation for multi-oncogenic activities of TERT and may be exploited in HCC treatment. PMID- 30017966 TI - DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2 positive breast cancer through disruption of Hsp90-Cdc37 interaction. AB - Hsp90 regulates the stability of oncoproteins important in tumor development and progression, and represents a potential therapeutic target. However, all Hsp90 inhibitors currently in clinical trials target Hsp90 ATPase activity and exhibit low selectivity and high toxicity. In this study, we discovered a new Hsp90 inhibitor, DCZ3112, with a novel mechanism of action. DCZ3112 directly bound to the N-terminal domain of Hsp90 and inhibited Hsp90-Cdc37 interaction without inhibiting ATPase activity. DCZ3112 inhibited the proliferation predominantly in HER2-positive breast cancer cells, including those resistant to the classical Hsp90 inhibitor geldanamycin, which mainly targets ATPase. DCZ3112 produced synergistic in vitro activity in inhibiting cell proliferation, inducing G1-phase arrest and apoptosis, and reducing AKT and ERK phosphorylation. Consistent with this, DCZ3112 alone inhibited the growth of HER2-positive BT-474 xenografts, and exhibited enhanced antitumor activity when combined with the anti-HER2 antibody trastuzumab. Importantly, DCZ3112 also significantly inhibited the growth of trastuzumab-resistant BT-474 cells, and combined treatment retained synergistic antitumor activity. Thus, our findings show that disrupting Hsp90-Cdc37 interaction may represent a promising strategy against HER2-positive breast cancer, especially those with acquired resistance to trastuzumab. PMID- 30017967 TI - Community screening campaign for Strongyloides stercoralis among Latin American immigrants in Spain. PMID- 30017968 TI - Scoring systems for sepsis: which purposes can they serve? PMID- 30017969 TI - The 3-day rule for stool cultures: should all patients with haematological malignancies be excluded? AB - OBJECTIVES: The '3-day rule' for stool culture ordering suggests that only selected inpatients with nosocomial diarrhoea should have stool cultures for enteropathogenic bacteria (EPBs). Patients with haematological malignancies are not included in this group. We have analysed the ordering of stool cultures at Laikon Hospital to investigate whether all patients with haematological malignancies should be excluded from the 3-day rule. METHODS: We have retrospectively analysed all inpatient stool specimens sent to the microbiology laboratory for enteropathogenic bacteria culture at Laikon Hospital, Athens, Greece, between January 1, 2014 and December 31, 2014. We classified stool cultures sent after the third day as 'appropriate', 'excluded' with standard rule, 'excluded' with haematological malignancies, and 'inappropriate'. RESULTS: During the study period, 1101/1593 inpatient stool cultures (69.1%) had been ordered after the third day of hospitalization. The total yield for inpatient EPB stool cultures was 0.7% (11/1593). The yield for 'appropriate' cultures was significantly higher than the yield of all 'excluded' specimens (3.7% (3/81) versus 0.3% (2/585), p 0.018) and to 'inappropriate' orders (3.7% (3/81) versus 0.0% (0/485), p 0.0028). There was no difference in the yield between specimens 'excluded' with the standard rule and 'excluded' with haematological malignancies. CONCLUSIONS: In our hospital, the yield of stool cultures from patients with haematological malignancies is similar to that of patients 'excluded' from the standard 3-day rule. If patients with haematological malignancies were not excluded from the rule, we would reduce the inpatient stool cultures by 13.6% (217/1593) at the cost of missing one positive stool culture. PMID- 30017970 TI - Prevalence of hepatitis E virus infection in liver donors in Spain. PMID- 30017971 TI - The great influenza centennial-what have we learned about the epidemiology and prevention of transmission? PMID- 30017973 TI - Chemical-induced disease relation extraction with dependency information and prior knowledge. AB - Chemical-disease relation (CDR) extraction is significantly important to various areas of biomedical research and health care. Nowadays, many large-scale biomedical knowledge bases (KBs) containing triples about entity pairs and their relations have been built. KBs are important resources for biomedical relation extraction. However, previous research pays little attention to prior knowledge. In addition, the dependency tree contains important syntactic and semantic information, which helps to improve relation extraction. So how to effectively use it is also worth studying. In this paper, we propose a novel convolutional attention network (CAN) for CDR extraction. Firstly, we extract the shortest dependency path (SDP) between chemical and disease pairs in a sentence, which includes a sequence of words, dependency directions, and dependency relation tags. Then the convolution operations are performed on the SDP to produce deep semantic dependency features. After that, an attention mechanism is employed to learn the importance/weight of each semantic dependency vector related to knowledge representations learned from KBs. Finally, in order to combine dependency information and prior knowledge, the concatenation of weighted semantic dependency representations and knowledge representations is fed to the softmax layer for classification. Experiments on the BioCreative V CDR dataset show that our method achieves comparable performance with the state-of-the-art systems, and both dependency information and prior knowledge play important roles in CDR extraction task. PMID- 30017972 TI - Spinal interneuronal mechanisms underlying pudendal and tibial neuromodulation of bladder function in cats. AB - This study examined the mechanisms underlying pudendal and tibial neuromodulation of bladder function at the single neuron level in the spinal cord. A microelectrode was inserted into the S2 spinal cord of anesthetized cats to record single neuron activity induced by bladder distention over a range of constant intravesical pressures (10-40 cmH2O). Pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) was applied at 5 Hz frequency and 0.2 ms pulse width and at multiples of the threshold (T) intensities for inducing anal or toe twitches. A total of 14 spinal neurons from 11 cats were investigated. Both PNS and TNS at 2 T intensity significantly (p < .05) reduced by 40-50% the frequency of firing induced by bladder distention at 20-40 cmH2O in the same spinal neurons. This reduction was not changed by blocking opioid receptors with naloxone (1 mg/kg, i.v.). Activation of pudendal afferents by repeatedly stroking (3-5 times per second) the genital skin using a cotton swab also inhibited the neuron activity induced by bladder distention. Prolonged (30 min) TNS at 4 T intensity produced a short lasting (10-18 min) post-stimulation inhibition that reduced by 40-50% bladder-related neuron activity at different bladder pressures. These results indicate that PNS and TNS inhibition of reflex bladder activity may be mediated in part by convergence of inhibitory inputs onto the same population of bladder-related interneurons in laminae V-VII of the S2 spinal cord and that an opioid receptor mechanism is not involved in the inhibition. PMID- 30017974 TI - A beginner's guide to avoiding Protected Health Information (PHI) issues in clinical research - With how-to's in REDCap Data Management Software. AB - Protecting personally identifiable information is important in clinical research. The authors, two faculty members involved in developing and implementing research infrastructure for a medical school, observed challenges novice researchers encountered in recognizing, collecting, and managing Protected Health Information (PHI) for clinical research. However, we had difficulty finding resources that provide practical strategies for novice clinical researchers for this topic. Common issues for beginners were: 1. Recognition of PHI, e.g. lack of recognition of 'indirect' PHI, i.e., that the combination of two or more non-PHI data types or other specific information could result in identifiable data requiring protection; 2. Collection of PHI, e.g., proposed collection of data not necessary for fulfillment of the project's objectives or potential inadvertent collection of PHI in free text response items; and 3. Management of PHI, e.g., proposed use of coding systems that directly included PHI, or proposed data collection techniques, electronic data storage, or software with inadequate protections. From these observations, the authors provide the following in this paper: 1. A brief review of the elements of PHI, particularly 'indirect' PHI; 2. Sample data management plans for common project types relevant to novice clinical researchers to ensure planning for data security; 3. Basic techniques for avoiding issues related to the collection of PHI, securing and limiting access to collected PHI, and management of released PHI; and 4. Methods for implementing these techniques in the Research Electronic Data Capture (REDCap) system, a commonly used and readily available research data management software system. PMID- 30017975 TI - Data standards for interoperability of care team information to support care coordination of complex pediatric patients. AB - OBJECTIVE: Seamless access to information about the individuals and organizations involved in the care of a specific patient ("care teams") is crucial to effective and efficient care coordination. This is especially true for vulnerable and complex patient populations such as pediatric patients with special needs. Despite wide adoption of electronic health records (EHR), current EHR systems do not adequately support the visualization and management of care teams within and across health care organizations. Electronic health information exchange has the potential to address this issue. In the present study, we assessed the adequacy of available health information exchange data standards to support the information needs related to care coordination of complex pediatric patients. METHODS: We derived data elements from the information needs of clinicians and parents to support patient care teams; and mapped them to data elements in the Health Level Seven (HL7) Consolidated Clinical Document Architecture (C-CDA) standard and in the HL7 Fast Healthcare Interoperability Resources (FHIR) standard. We also identified additional C-CDA data elements and FHIR resources that include patients' care team members. RESULTS: Information about care team members involved in patient care is generally well-represented in the C-CDA and FHIR specifications. However, there are gaps related to patients' non-clinical events and care team actions. In addition, there is no single place to find information about care team members; rather, information about practitioners and organizations may be available in several different types of C-CDA data elements and FHIR resources. CONCLUSION: Through standards-based electronic health information exchange, it appears to be feasible to build patient care team representations irrespective of the location of patient care. In order to gather care team information across disparate systems, exchange of multiple C-CDA documents and/or execution of multiple FHIR queries will be necessary. This approach has the potential to enable comprehensive patient care team views that may help improve care coordination. PMID- 30017976 TI - Thai silk fibroin gelation process enhancing by monohydric and polyhydric alcohols. AB - Silk fibroin hydrogel is an interesting natural material in various biomedical applications. However, the self-assembled gelation takes a long time. In this work, different alcohol types are used as gelation enhancers for aqueous silk fibroin solution. Monohydric alcohols having carbon chain length from C1 to C4 and polyhydric alcohols with the number of mono- to tri- hydroxyl groups were used as the enhancers which are effective for rapid gelation. The addition of monohydric alcohol distinctively reduced the gelation time, comparing to the polyhydric alcohol. The gelation process is directly dependent on the polarity of alcohol and hydrophobicity. The alcohol mediated gelation imparts strong viscoelastic property and enhanced compressive modulus of resulting hydrogels. This is due to the effective formation of self-assembled beta sheet network of the silk fibroin chains facilitates the gelation process. PMID- 30017977 TI - Local structural motifs in proteins: Detection and characterization of fragments inserted in helices. AB - The global/local fold of protein structures is stabilized by a variety of specific interactions. A primary role in this context is played by hydrogen bonds. In order to identify novel motifs in proteins, we searched Protein Data Bank structures looking for backbone H-bonds formed by NH groups of two (or more) consecutive residues with consecutive CO groups of distant residues in the sequence. The present analysis unravels the occurrence of recurrent structural motifs that, to the best of our knowledge, had not been characterized in literature. Indeed, these H-bonding patterns are found (i) in a specific parallel beta-sheet capping, (ii) in linking of beta-hairpins to alpha-helices, and (iii) in alpha-helix insertions. Interestingly, structural analyses of these motifs indicate that Gly residues frequently occupy prominent positions. The formation of these motifs is likely favored by the limited propensity of Gly to be embodied in helices/sheets. Of particular interest is the motif corresponding to insertions in helices that was detected in 1% of analyzed structures. Inserted fragments may assume different structures and aminoacid compositions and usually display diversified evolutionary conservation. Since inserted regions are physically separated from the rest of the protein structure, they represent hot spots for ad-hoc protein functionalization. PMID- 30017978 TI - The inhibitory and binding studies of methyl-sulfone hydroxamate based inhibitors against LpxC from drug resistant Moraxella catarrhalis using biophysical, biochemical and in silico approaches. AB - Several reported potential compounds against UDP-3-O-(R-3-Hydroxymyristoyl)-N acetylglucosamine deacetylase (LpxC) have shown large variation in the potency and efficacy. The differential susceptibility and selective binding of these inhibitors against LpxC are still unexplored. In the present work, we have characterized LpxC from Moraxella catarrhalis (McLpxC) and investigated its binding with potent inhibitors LpxC-2 and LpxC-4 using biochemical, biophysical and in silico approaches. The circular dichroism studies have revealed the changes in the secondary and tertiary structure of McLpxC upon inhibitors binding. The fluorescence quenching mechanism was found to be static with kq > 1010 suggesting the ground state complex formation between the McLpxC and inhibitors. Altogether spectroscopic findings suggest that the interaction of LpxC-4 and LpxC-2 caused conformational changes marked by the loss of alpha helical content in McLpxC. In ITC based studies, both inhibitors have shown comparable binding affinities (KD = ~10.0 MUMU), and their interactions were exothermically driven by enthalpy change. The docking studies have shown the possibility of two binding sites in McLpxC for these inhibitors with similar binding energies (~10.0 kcal mol-1). Thus, the present study significantly suggests that further optimization and utilization of molecules based on this scaffold will be helpful in designing the new antimicrobial agents targeting LpxC. PMID- 30017979 TI - Characterization of a Kunitz trypsin inhibitor from Enterolobium timbouva with activity against Candida species. AB - Scientific advances have not been sufficient to accompany the growing resistance to antimicrobial medicines. High mortality rates due to opportunistic infections have threated human health. The development of new drugs, such as those obtained from plant sources, is a world priority. Herein, we report the purification of a trypsin inhibitor from Enterolobium timbouva seeds (EtTI) with regard to its homology, physico-chemical and inhibitory properties. Furthermore, we evaluated its activity against Candida strains, opportunistic pathogens regularly found in hospital infections. EtTI belongs to the Kunitz family and inhibits two trypsin molecules simultaneously; a feature shared among double-headed Kunitz inhibitors. A high inhibitory activity against trypsin was determined (Ki = 0.5 nM), and refractory to digestion by pepsin. EtTI was candidicidal against C. albicans, C. buinensis and C. tropicalis, triggering disturbances on integrity of the plasma membrane and morphological alterations, presumably mediated via apoptosis. The presence of two reactive sites is an unusual feature detected in EtTI. Numerous diseases and pathologies involve changes in peptidase activities, encouraging studies with multifunctional inhibitors. Accordingly, the further exploration of EtTI could provide new insights into the Kunitz inhibitors and their applications in disease control. PMID- 30017980 TI - Binding mechanism of kinase inhibitors to EGFR and T790M, L858R and L858R/T790M mutants through structural and energetic analysis. AB - Experimental studies have demonstrated that L858R mutation in the EGF receptor (EGFR) confers tumor sensitivity whereas T790M and L858R/T790M mutations cause resistance to tyrosine kinase inhibitors in patients with non-small cell lung cancer. Theoretical studies have been carried out to try to clarify the structural and energetic details linked to acquired resistance to Gefitinib, Erlotinib or Lapatinib, however, some of these studies are contradictory with each other and with experimental reports and did not mention whether the study was performed by considering the inactive or active EGFR states. In this study, we combined structural data and molecular dynamic simulations coupled to a molecular mechanics generalized Born surface area approach to provide insight into the binding mechanism between three FDA-approved drugs (Erlotinib, Gefitinib and Lapatinib) that target the wild-type and T790M, L858R and L858R/T790M mutants of EGFR. Structural analysis showed that the drugs impact differently the conformational space of active and inactive EGFR. Energetic analysis pointed out that some ligands have better affinity for the inactive EGFR than the active EGFR state. Comparative analysis of the molecular recognition of Gefitinib, Erlotinib and Lapatinib provided insight into the drug sensitivity or resistance observed for the three FDA-approved drugs evaluated. PMID- 30017981 TI - Cobalt oxide nanoparticles mediate tau denaturation and cytotoxicity against PC 12 cell line. AB - It has not been well explored how NPs may induce some adverse effects on the biological systems. In this research, the interaction of cobalt oxide NPs (Co3O4 NPs) with tau protein and PC-12 cell line, as nervous system models, was investigated with several approaches including fluorescence spectroscopy, CD spectroscopy, docking study, MTT, LDH, AO/EB dual staining, and flow cytometry assays. Fluorescence investigation displayed that Co3O4 NPs spontaneously mediate the formation of a static complex with tau protein through hydrogen bonds and van der Waals forces. Docking study also revealed that Ser and Gln residues play important roles in the formation of hydrogen bonds between tau and Co3O4 NPs. Far UV-CD measurement determined that Co3O4 NPs changed the unfolded structure of tau protein toward a more folded conformation. Moreover, Co3O4 NPs demonstrated to stimulate the reduction of PC-12 cell viability through membrane leakage, fragmentation of DNA, apoptosis, and necrosis. In conclusion, Co3O4 NPs may trigger marked alterations on the tertiary and secondary structure of tau protein. Also, the dose of Co3O4 NPs is the crucial factor which induces their adverse effects on the cells. Because, all side effects of NPs are not well explored, additional detailed experiments are more needed. PMID- 30017982 TI - Chitosan-grafted-poly(methacrylic acid)/graphene oxide nanocomposite as a pH responsive de novo cancer chemotherapy nanosystem. AB - The aim of this study was the design and development of a novel de novo drug delivery system for cancer chemotherapy. For this purpose, chitosan (CS) functionalized using phthalic anhydride followed by 4-cyano, 4 [(phenylcarbothioyl) sulfanyl] pentanoic acid as a chain transfer agent (CTA) to afford CS-CTA macroinitiator. The synthesized CS-CTA macroinitiator was then copolymerized with methacrylic acid (MAA) monomer using reversible addition fragmentation chain transfer (RAFT) polymerization technique to produce chitosan graft-poly(methacrylic acid) (CS-g-PMAA) graft copolymer. Afterward, graphene oxide (GO) nanosheets were incorporated into the synthesized copolymer through the physical interactions. The CS-g-PMAA/GO nanocomposite was loaded with doxorubicin hydrochloride (DOX) as a universal anticancer drug. The biocompatibility, DOX-loading capacity, and pH dependent drug release behavior of the developed nanocomposite were also investigated. As the experimental results, as well as superior biological and physicochemical features of CS and GO, we envision that the developed CS-g-PMAA/GO nanocomposite may be applied as de novo drug delivery nanosystem for cancer chemotherapy. PMID- 30017983 TI - Purification and biochemical characterization of photo-active membrane protein bacteriorhodopsin from Haloarcula marismortui, an extreme halophile from the Dead Sea. AB - Bacteriorhodopsin (BR) is an exciting photo-active retinal protein with many potential industrial applications. In this study, BR from the extremely halophilic archaeon Haloarcula marismortui (HmBR) was purified successfully using aqueous two phase extraction method. Absorption spectroscopy analysis showed maximum absorption peak of HmBR retinal protein (lambdamax) at 415 nm. The purified HmBR was visualized by SDS-PAGE, with a subunit molecular mass of 27 kDa, and its identity was confirmed by resonance Raman spectroscopy, Fourier transform infrared spectroscopy and atomic force microscopy. The effect of pH and salt concentration on the absorption spectrum of HmBR was evaluated. Red-shifted in lambdamax of HmBR was recorded at acidic condition (pH 5) and HmBR showed remarkable optical activity under high salinity condition. The photoelectric activity of HmBR was evaluated by measuring the DC-voltage generated from HmBR coated on indium tin oxide (ITO) glass when light illumination was applied. PMID- 30017984 TI - Chitosan hydrogels cross-linked with tris(2-(2-formylphenoxy)ethyl)amine: Swelling and drug delivery. AB - Tris(2-(2-formylphenoxy)ethyl)amine was designed and synthesized by reaction of salicylaldehyde with tris(2-chloroethyl)amine hydrochloride and evaluated as a new multi-functional cross-linker for preparation of new pH- and thermo responsive chitosan hydrogels through formation of covalent Schiff-base linkage. The structure and properties of the hydrogels were characterized by FT-IR, 1H NMR and scanning electron microscopy (SEM). The swelling behavior of prepared hydrogels at different pHs and temperatures was investigated. Also, in vitro controlled release behavior of the metronidazole model drug was studied with prepared hydrogels. The release profiles of metronidazole from the hydrogels were determined by UV-Vis absorption measurement. The results showed that the new hydrogels exhibit a pH and temperature-responsive swelling ratio. Also, the pH and temperature were found to strongly influence the drug release behavior of these swollen polymers. Due to the concurrent rapid and significant stimuli response, these smart hydrogels prepared from chitosan as a natural polymer may expand the scope of hydrogel applications in various fields of research such as targeted (cellular or tissue) delivery of drugs. In addition, these new hydrogels can be used to improve bioavailability, sustain release of drugs or solubilize drugs for systemic delivery. PMID- 30017985 TI - Enhanced antimicrobial activity and reduced water absorption of chitosan films graft copolymerized with poly(acryloyloxy)ethyltrimethylammonium chloride. AB - Chitosan shows selective antimicrobial activity as a bioactive polymer. In this work, a quaternary ammonium derivative of chitosan was synthesized by graft copolymerization of chitosan with poly[2-(acryloyloxy)ethyltrimethylammonium chloride] or pATC by the redox polymerization method to enhance chitosan's antimicrobial activity. The structural characterizations of the quaternized chitosan were confirmed by Fourier transform infrared spectroscopy, and also by 1H and 13C nuclear magnetic resonance spectroscopy. The produced chitosan was converted into films by solution casting. The physicomechanical properties of the modified chitosan were compared with the unmodified chitosan. Thermal stability of the films was characterized by thermogravimetric analysis. The pATC grafted chitosan films showed lower thermal stability, water absorption, swelling ratio, and tensile strength compared to the unmodified chitosan film. Antimicrobial activity of the quaternized chitosan was tested against three kinds of bacteria (Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and two fungi (Aspergillus brasiliensis and Aspergillus fumigatus). The unmodified chitosan showed good antibacterial activity but no resistance against any fungus. However, the pATC grafted chitosan showed enhanced antibacterial activity against all bacteria investigated. The fungicidal test shows that the pATC-grafted chitosan showed higher activity against the tested fungi (Aspergillus fumigatus and Aspergillus brasiliensis) compared to the unmodified chitosan, especially against Aspergillus fumigatus. PMID- 30017986 TI - Expression changes of the notch signaling pathway of PC12 cells after oxygen glucose deprivation. AB - Ischemic stroke is caused by obstructed blood supply to the brain. It is a common as well as a serious health problem worldwide, which is often linked to disability and mortality. Here we studied, under the conditions of oxygen glucose deprivation (OGD), the expression of Notch signaling pathway proteins in PC12 cells. PC12 cells were stimulated and converted into neuron-like cells by nerve growth factor. Exposure to OGD was used as an in vitro model of cerebral hypoxia ischemia. Our findings demonstrate that, after 3 h of OGD exposure, the expression of Notch1, Hes1 and Hes5 significantly increased, on both mRNA and protein levels. This effect gradually reduced with continuous OGD treatment, but the expression levels of these three genes remained higher, compared to untreated controls, even after 24 h of OGD exposure. Our results suggest that OGD exposure up-regulates the expression of Notch1, Hes1 and Hes5, which are important participants in Notch signaling pathway. Since their regulatory roles appear to change dynamically with the extension of OGD, the activation of the Notch pathway may play an important role in cerebral ischemic injury. PMID- 30017987 TI - Radiation fabrication of Xanthan-based wound dressing hydrogels embedded ZnO nanoparticles: In vitro evaluation. AB - Depending on the biocompatibility of Xanthan, polyvinyl alcohol and the antibacterial efficiency of zinc oxide nanoparticles (ZnO), a series of (Xanthan polyvinyl alcohol)/ZnO nanocomposite hydrogels were prepared as wound dressing using eco-friendliness 60Co gamma-ray irradiation facility. ZnO nanoparticles were characterized using X-ray diffraction, UV-vis spectroscopy, transmission electron microscopy and energy dispersive X-ray analysis. The size of ZnO nanoparticles was ranged between 15 and 25 nm. The presence of ZnO nanoparticles reconstructed the internal structure of the hydrogel network which aid in a homogenous porous structure as indicated by scanning electron micrographs. Such adequate porosity along with the presence of ZnO nanoparticles controls the fluid uptake ability, water retention and water vapor transmission rate. The fluid uptake ability in pseudo-extracellular fluid and water ranged between (554-664%) and (1281-1603%), respectively. After exposure to air for 6 h, ZnO dressings kept about 50-65% of their water content which makes them more suitable for moderate exudating wounds. Water vapor transmission rate ranged between 167 and 184 (g/(m2 h) which is sufficient to keep wound's surface moist. ZnO dressings show an efficient microbial barrier potency and profound antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans. In vitro cytotoxicity and haemolytic potency evaluation showed their biocompatibility. PMID- 30017988 TI - Physicochemical properties of scaffolds based on mixtures of chitosan, collagen and glycosaminoglycans with nano-hydroxyapatite addition. AB - Scaffolds based on chitosan (CTS), collagen (Coll), and glycosaminoglycans (GAGs) mixtures with nano-hydroxyapatite (HAp) were obtained with the use of the freeze drying method. They were characterized by different analyses, e.g. SEM images and mechanical testing. Moreover, swelling behavior and biocompatibility tests were carried out. The results showed that the scaffolds based on the blends of chitosan, collagen, and glycosaminoglycans with hydroxyapatite are stable in aqueous environment. SEM images allowed the observation of a porous scaffolds structure with the pores size ~250 MUm. The main purpose of the research was to detect the influence of hydroxyapatite addition on the glycosaminoglycans enriched scaffolds properties. The physicochemical properties as swelling and mechanical parameters were tested. The scaffolds structure was observed by SEM. Moreover, the preliminary assessment of scaffolds suitability for cell growth, human osteosarcoma cell line SaOS-2 was used. The obtained results indicate that the addition of hydroxyapatite improves the mechanical parameters and cells biological response of the studied materials. PMID- 30017989 TI - Protein biomarker for psoriasis: A systematic review on their role in the pathomechanism, diagnosis, potential targets and treatment of psoriasis. AB - Psoriasis is defined as a long-lasting multifactorial inflammatory autoimmune skin condition precisely characterized by delimited, erythematic papules with adherent shiny scales. The conditions are led by hyperproliferative responses of epidermis due to hyperactivation and immature keratinocytes production. The psoriatic skin consists of the thickened epidermal layer, in concurrence with inflammatory exudates in the dermis mainly of dendritic cells, neutrophils, T cells, and macrophages, contributing to the distinct manifestation of psoriatic lesions. It consents to multifaceted and discrete pathology due to the genetic and immunological alteration resulting from abnormal expression of various regulatory and structural proteins. These proteins are associated with various cellular and sub-cellular activities. Therefore, the presence of protein in a pathological cellular environment in the psoriatic lesions as well as in serum could be a great avenue for the insight of pathomechanism, anticipation and diagnosis of psoriasis. Research of protein biomarker in psoriasis is yet a developing realm to be explored by both fundamental and clinical researchers. This review is an attempt to assimilate the current discoveries and revelations of different proteins as a biomarker and their importance in pathogenesis, diagnosis, treatment, and anticipation of both the inflammatory and other dermatological aspects of psoriasis. PMID- 30017990 TI - Alginate-based nanocomposite films reinforced with halloysite nanotubes functionalized by alkali treatment and zinc oxide nanoparticles. AB - Functionalized halloysite nanotubes were prepared by surface activation of halloysite (Hal) with sodium hydroxide and deposition of zinc oxide nanoparticles (ZnONP). The surface charge of Hal was changed from 0.18 +/- 0.6 mV to -35.2 +/- 2.8 mV after alkali treatment. The functionalized Hal (AT-Hal/ZnONP) was incorporated into alginate biopolymer as a reinforcing filler with different concentration of AT-Hal/ZnONP (1, 3, 5, and 7 wt% of alginate). Alginate films with AT-Hal/ZnONP exhibited a significant increase in the mechanical, water vapor barrier, and UV light barrier properties. The thermal stability of composite films has not changed after AT-Hal/ZnONP incorporation. The AT-Hal/ZnONP incorporated alginate films demonstrated strong antibacterial activity against food-borne pathogenic bacteria, Escherichia coli and Listeria monocytogenes. The nanocomposite film with 7 wt% of AT-Hal/ZnONP exhibited complete sterilization of E. coli and L. monocytogenes after 3 and 9 h of treatment, respectively. PMID- 30017991 TI - The role of iron in hepatic inflammation and hepatocellular carcinoma. AB - Iron is an essential for organisms and the liver plays a major role in its storage. In pathologic conditions, where iron absorption from the intestine or iron uptake into the hepatocytes is increased, excess iron accumulates in the hepatocytes, leading to hepatocyte injury through the production of free radicals. Iron exerts its toxicity by catalyzing the generation of reactive oxygen species (ROS). ROS causes cell injury by inducing damage to the lysosomal, cytoplasmic, nuclear and mitochondrial membranes, apoptosis through activation of the caspase cascade, and hyperoxidation of fatty chains. In this manuscript, we reviewed the articles regarding role of iron in hepatic inflammation and hepatocellular carcinoma. PMID- 30017992 TI - Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14. AB - Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAs 1-3, 6-8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient. PMID- 30017993 TI - Head and trunk stability during gait before and after levodopa intake in Parkinson's disease subtypes. AB - INTRODUCTION: People with Parkinson's disease (PD) can be classified into tremor dominant (TD) and postural instability and gait difficulty (PIGD) subtypes; the latter group having more impaired gait and increased fall risk. While there is some evidence that anti-parkinsonian medication, levodopa, might not improve balance and gait control or reduce fall risk in the PIGD subtype, it is unclear whether the levodopa dosage intake affects gait stability. To address these issues, this study used accelerometry to compare gait stability: (i) during before and after levodopa intake between non-PIGD and PIGD subtypes; (ii) between individuals who took less or >750 mg of levodopa/day. METHODS: In 15 non-PIGD (Combination of 13 TD patients and 2 classified as indeterminate subtype) and 23 PIGD participants of similar mean (SD) age ((63.0 (7.6) versus 62.6 (10.0) years, respectively)) and disease-duration (8.9 (8.9) versus 11.3 (4.6) years, respectively), head and trunk stability during gait was examined using anteroposterior, vertical and mediolateral acceleration harmonic ratios (HRs). Participants were assessed before and after a levodopa dose, during typical "off" and "on" periods, respectively. RESULTS: Two-way analyses of variance (group * medication status) revealed that compared to the non-PIGD subgroup, the PIGD subgroup showed significantly worse head stability (lower anteroposterior HR) in the "off" state, and significantly worse pelvis stability (significantly lower mediolateral and vertical HRs) in the "on" state (p < 0.05 for both). Levodopa was effective in treating most of the disease-related impairments (not bradykinesia) in both groups, (p < 0.05) but improved gait stability (lowered pelvis mediolateral and vertical HRs) only in people with the non-PIGD subtype (p < 0.05) and those taking <750 mg of levodopa/day (p < 0.05). CONCLUSIONS: People with the PD PIGD subtype exhibit impaired gait stability that is not improved and frequently worsened by levodopa. New non-pharmaceutical approaches, technological (e.g. cueing) or exercise-based (e.g. balance training) are required to improve or compensate for mediolateral gait instability in this subtype and ultimately prevent falls. PMID- 30017994 TI - Response of the nuclear receptors PXR and CAR and their target gene mRNA expression in female piglets exposed to zearalenone. AB - A study was conducted to determine the effects of zearalenone (ZEN) on the mRNA expression of pregnane X receptor (PXR), constitutive and rostane receptor (CAR), and phase I and II enzymes as well as the toxicity in the liver of female weanling piglets. Thirty-two female weanling piglets (Duroc * Landrace * Large white, 12.27 +/- 0.30 kg)were divided into four groups (n = 8 piglets/group) that were supplemented with 0 (control), 0.5, 1 or 2 mg/kg ZEN. The trial period lasted for 28 d. The results showed that the ZEN supplementation in the diets (0.5-2 mg/kg) had no effect on growth performance but dose-dependently increased serum aspartate aminotransferase, alanineaminotransferase, alkaline phosphatase, and gamma-glutamyltransferase activities (P < 0.05). The ZEN residue in the liver (P < 0.01) was also linearly and dose-dependently increased. Furthermore, the mRNA expression of PXR, CAR, phase I enzymes (i.e., cyp2e1, cyp3a5, cyp2a6, cyp1a1, and cyp1a2), and phase II enzymes (i.e., gsta1, gsta2, ugt1a3) significantly increased linearly in a dose-dependent manner (P < 0.05). However, the spleen relative weight and the glutathione peroxidase activity in the liver (P < 0.05) linearly decreased as the dietary ZEN concentration increased; the mRNA expression of the nuclear receptors PXR and CAR is responsive to ZEN in female piglets, and ZEN increases the mRNA expression of their target genes. This finding shows that the nuclear receptor signaling system plays an important role in the defense against ZEN. PMID- 30017995 TI - Recombinant mutagenic 3ABC protein and monoclonal antibody for quality-control testing in foot-and-mouth disease vaccines. AB - To achieve the goal of performing quality control on vaccines for foot-and-mouth disease several steps were performed in this study. First, the gene that encodes the 3ABC region of the A24 Cruzeiro strain (which is used in vaccine production) was amplified. Second, to improve protein stability, the 3ABC protein was mutated at the 3Cpro catalytic site and cloned the amplification products in the pET-SUMO expression vector. In the third step, the resulting recombinant protein was tested, which the polyclonal antibody recognized, with the semi-purified viral 3ABC protein using an immunoassay test. Fourth, the muted recombinant protein was used to produce a monoclonal antibody. Of the 217 clones obtained, two of them that were particularly stable (mAb2D3 and mAb3D12) were selected to work with. One showed better results, as characterized by immunoassay (ELISA), Western blotting, spot synthesis, and sequencing methodologies; it also showed high reactivity against the 3ABC protein. This kind of monoclonal antibodies, which was considered as immunochemical inputs, have been used in industrial processes as part of quality-control procedures, to evaluate the elimination of the 3ABC protein so as to ensure regulatory approval of the vaccine. They have also been used in immunological tests to distinguish infected from vaccinated animals. PMID- 30017996 TI - Creation of a drug-sensitive reporter strain of Pseudomonas aeruginosa as a tool for the rapid screening of antimicrobial products. AB - Antibiotic resistance of bacteria is a considerable challenge to human health in the 21st century. With our discovery pipeline for new and effective antibiotics rapidly drying out, innovative approaches are needed to find new antimicrobials. Soil fungi are known to produce a variety of antimicrobials but rapid screening of fungi that produce such compounds remains a challenge. In this work, we used a hyper-susceptible strain of Pseudomonas aeruginosa to create a luminescent reporter strain to be used as a screening tool to select fungi producing antimicrobials. We show that use of such a strain can not only significantly expedite the initial screening but also allows us to detect antimicrobials that may be produced in low concentrations. We believe that our reporter strain can be a valuable tool in identifying fungi that produce novel antimicrobials. PMID- 30017997 TI - Phylodynamics of parapoxvirus genus in Mexico (2007-2011). AB - In this study we report for the first time the phylodynamics of the parapoxvirus (PPV) genus in Mexico. Based on the analysis by PCR of 124 epithelial samples collected between 2007 and 2011 from naturally infected goats, sheep and cows in Mexico, we found that different PPV were present in 21 out of the 24 states sampled during this study. Our phylogenetic analysis confirmed the presence of different PPV species in Mexico, and their phylogenetic relationship with other PPV circulating in the US and Canada. Furthermore, we describe the existence of two different ORFV phylogenetic groups that are clearly host associated (sheep or goat). Evidence of directional selection at five specific amino acid residues in the enveloped glycoprotein B2L might help to support this host predilection. Collectively, the results generated in this study highlight the importance of PPV genus in Mexico and open the possibility for future studies describing with more detail the importance of this genus in North America. PMID- 30017999 TI - Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: Opportunities, challenges and future directions for cerebral stroke management. AB - Cerebral stroke is a leading cause of early death and physical disability in adults throughout the world. Oxidative stress and inflammation plays an important role in the pathological process associated with the stroke. The available reperfusion therapy itself enhances the oxidative stress by overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from the neurons, as well as non-neuronal cells, thus further worsens the condition. Excessive ROS and RNS production contributes to the brain injury during or after the stroke by activating inflammatory processes. Glycogen synthase kinase-3 (Gsk 3) is an evolutionary conserved serine-threonine kinase that plays an important role in cellular growth, development, inflammation and apoptosis processes. Gsk-3 is activated during the brain stroke and suppresses the expression of nuclear factor-E2-related factor 2, an important regulator of endogenous antioxidant defence mechanism. It also modulates the expression of anti-inflammatory protein like, cAMP response element binding protein and activator protein 1. It has been found that the inhibition of Gsk-3 shows neuroprotection via reducing the oxidative stress and inflammation in cerebral ischemia/reperfusion. The present review describes in depth the role of oxidative stress, neuroinflammatory processes and endogenous defence systems involved in cerebral stroke pathogenesis, and their regulation by Gsk-3. Further the reports of all the potential agents modulating Gsk-3 activity via different signalling pathways have been summarized to substantiate its effectiveness in cerebral stroke management. PMID- 30017998 TI - Absence of renal adverse effects from beta-myrcene dietary administration in OECD guideline-compliant subchronic toxicity study. AB - beta-Myrcene is a flavoring substance that occurs naturally in a large variety of foods. At the request of the European Food Safety Authority (EFSA) for additional toxicological data on beta-myrcene, groups of Sprague Dawley rats (10/sex/group) were administered diets containing 0, 700, 2100, or 4200 ppm of beta-myrcene designed to provide nominal doses of 0, 50, 150, or 300 mg/kg bw/day in a 90-day GLP-compliant study. Based on body weights, feed consumption, and substance stability data, final estimated daily intakes of beta-myrcene were calculated to be 20.4, 58.8, and 115.2 mg/kg bw for males and 24.2, 70.0, and 135.9 mg/kg bw for females. No effects on clinical observations, hematology and clinical chemistry parameters, organ weights, or macroscopic and histopathological examinations were found attributable to ingestion of beta-myrcene. The oral no observed-adverse-effect level (NOAEL) for rats of both sexes was the highest dose tested. Based on feed consumption and test substance stability in the diet, the NOAEL was calculated to be 115 and 136 mg/kg bw/day for males and females, respectively. PMID- 30018000 TI - Local low dose curcumin treatment improves functional recovery and remyelination in a rat model of sciatic nerve crush through inhibition of oxidative stress. AB - Traumatic injuries to peripheral nerves are frequent, however, specific pharmacological treatments are currently lacking. Curcumin has antioxidant, anti inflammatory and neuroprotective properties but high oral doses are required for therapeutic use, particularly due to its low bioavailability. The aim of the present study was to investigate the effects of local and continuous treatment using low curcumin doses on functional recovery and nerve regeneration after rat sciatic nerve crush (SNC). Curcumin was administered by osmotic pumps with a catheter delivering the drug at the injury site (0.2 mg/day for 4 weeks). Functionally, early improvements in mechanical sensitivity, finger spacing of the injured paw, skilful walking and grip strength were observed in curcumin-treated animals. The curcumin treatment increased expression of compact myelin proteins (MPZ and PMP22), myelin sheath thickness and, correspondingly, increased motor and sensitive nerve conduction velocity. Microscopic analysis of gastrocnemius muscle indicated a curcumin-induced decrease in neurogenic lesions. Curcumin treatment reduced the production of reactive oxygen species (ROS) (which were notably produced by macrophages), lipid peroxidation and increased expression of transcription factor Nrf2. In silico analyses indicated that curcumin combines all the characteristics required to be an efficient lipid peroxidation inhibitor at the heart of biological membranes, hence protecting their degradation due to ROS. This antioxidant capacity is likely to contribute to the beneficial effects of curcumin after SNC injury. These results demonstrate that, when administrated locally, low doses of curcumin represent a promising therapy for peripheral nerve regeneration. PMID- 30018001 TI - Dynamics of HIV-1 coinfection in different susceptible target cell populations during cell-free infection. AB - HIV-1 mutations rapidly accumulate through genetic recombination events, which require the infection of a single cell by two virions (coinfection). Accumulation of mutations in the viral population may lead to immune escape and high-level drug resistance. The existence of cell subpopulations characterized by different susceptibility to HIV-1 infection has been proposed as an important parameter driving coinfection (Dang et al., 2004). While the mechanism and the quantification of HIV-1 coinfection have been recently investigated by mathematical models, the detailed dynamics of this process during cell-free infection remains elusive. In this study, we constructed ordinary differential equations considering the heterogeneity of target cell populations during cell free infection in cell culture, and reproduced the cell culture experimental data. Our mathematical analyses showed that the presence of two differently susceptible target cell subpopulations could explain our experimental datasets, while increasing the number of subpopulations did not improve the fitting. In addition, we quantitatively demonstrated that cells infected by multiple viruses mainly accumulated from one cell subpopulation under cell-free infection conditions. In particular, the frequency of infection events in the more susceptible subpopulation was 6.11-higher than that from the other subpopulation, and 98.3% of coinfected cells emerged from the more susceptible subpopulation. Our mathematical-experimental approach is able to extract such a quantitative information, and can be easily applied to other virus infections. PMID- 30018002 TI - Cytotoxic steroids from the Vietnamese gorgonian Verrucella corona. AB - Using various chromatographic separations, seventeen steroids including seven new compounds, verrucorosteroids A-F (1-6) and verrucorosterone (7), were isolated from the Vietnamese gorgonian Verrucella corona. Their structures were elucidated by spectroscopic analysis, including HR QTOF MS, 1D and 2D NMR. Among isolates, verrucorosterone (7), 5,6alpha-epoxy-3beta-hydroxy-(22E)-ergosta-8,22-dien-7-one (14), and 5,6alpha-epoxy-3beta-hydroxy-(22E)-ergosta-8(14),22-dien-7-one (15) showed significant cytotoxicity (IC50 values ranging from 12.32 +/- 1.47 to 33.77 +/- 1.28 MUM) against eight human cancer cell lines as LNCaP (prostate cancer), HepG2 (hepatoma cancer), KB (epidermoid carcinoma), MCF-7 (breast cancer), SK Mel2 (melanoma), HL-60 (acute leukemia), LU-1 (lung cancer), and SW480 (colon adenocarcinoma). PMID- 30018003 TI - Corticosterone biosynthesis in mouse clonal myoblastic C2C12 cells. AB - Corticosterone (CORT), the major glucocorticoid in rodents, is secreted from the adrenal gland, affects various organs in the body and regulates energy metabolism as a stress response. Although local steroidogenesis of androgens and estrogens in skeletal muscles has been previously reported, local CORT synthesis in skeletal muscle remains unconfirmed. In the present study, we investigated steroidogenic activities in a clonal myoblastic cell line, C2C12 cells. Three enzymes involved in CORT synthesis, 3beta-hydroxysteroid dehydrogenase (3beta HSD), cytochrome P450c21 and cytochrome P45011beta, were identified in C2C12 cells by detecting the enzymatic reaction products with LC-MS/MS analysis. Only one enzyme that mediates cholesterol cleavage was not detected in the cells. After the addition of pregnenolone-sulfate conjugates to the cell culture medium, pregnenolone was detected and increased according to the incubation time. In conclusion, CORT synthesis occurs in C2C12 cells, and it is suggested that the initial steroidogenesis substrate is the pregnenolone-sulfate conjugate. PMID- 30018004 TI - The expression of natriuretic peptide receptors in developing zebrafish embryos. AB - There are three isoforms of natriuretic peptide (NP) specific cell surface receptor: NP receptor-A (NPRA), receptor-B (NPRB), and receptor-C (NPRC). They are also known as NPR1, NPR2 and NPR3, respectively. NPs and their receptors were revealed to involve in diverse cellular and physiological processes including renal, cardiovascular, neuronal, and immunological aspects. However, the systematic analysis of the expression of these receptors in non-mammalian vertebrates is thus far lacking. In this study, two versions of the npr1 gene (npr1a and npr1b) in zebrafish was identified. Multiple sequences alignment analysis showed that zebrafish NPRs shared high homologies with NPRs of other species and possessed a typical signature domain of NPRs. The results of whole mount in situ hybridization and reverse transcription polymerase chain reaction analysis revealed that at embryonic stages, npr1a was mainly expressed in tectal ventricle, brian, heart and retina, whereas npr1b was broadly present in anterior pronephric duct. Unlike npr1, npr2 mainly expressed in branchial arches and neural tube during embryonic development. However, npr3 was expressed in pronephric ducts and corpuscle of stannius in zebrafish embryos at 72 hpf. In adults, we demonstrated that all the three NP receptors were highly existed in brain and kidney. Overall, these findings will provide an important basis for the functional analysis of NPs and its receptor during embryonic development. PMID- 30018005 TI - The impact of the vitamin D-modulated epigenome on VDR target gene regulation. AB - The micronutrient vitamin D significantly modulates the human epigenome via enhancing genome-wide the rate of accessible chromatin and vitamin D receptor (VDR) binding. This study focuses on histone marks of active chromatin at promoter and enhancer regions and investigates, whether these genomic loci are sensitive to vitamin D. The epigenome of THP-1 human monocytes contains nearly 23,000 sites with H3K4me3 histone modifications, 550 of which sites are significantly (p < 0.05) modulated by stimulation with the VDR ligand 1alpha,25 dihydroxyvitamin D3 (1,25(OH)2D3). H3K27ac histone modifications mark active chromatin and 2473 of 45,500 sites are vitamin D sensitive. The two types of ligand-dependent histone marks allow to distinguish promoter and enhancer regulation by vitamin D, respectively. Transcription start site overlap is the prime attribute of ligand-dependent H3K4me3 marks, while VDR co-location is the top ranking parameter describing 1,25(OH)2D3-sensitive H3K27ac marks at enhancers. A categorization of 1,25(OH)2D3-sensitive histone marks by machine learning algorithms - using the attributes overall peak strength and ligand inducibility - highlights 260 and 287 regions with H3K4me3 and H3K27ac modifications, respectively. These loci are found at the promoter regions of 59 vitamin D target genes and their associated enhancers. In this way, ligand dependent histone marks provide a link of the effects of 1,25(OH)2D3 on the epigenome with previously reported mRNA expression changes of vitamin D target genes. In conclusion, the human epigenome responds also on the level of histone modifications to 1,25(OH)2D3 stimulation. This allows a more detailed understanding of vitamin D target gene regulation. PMID- 30018007 TI - Seasonal-and dose-dependent effects of recombinant gonadotropins on sperm production and quality in the flatfish Solea senegalensis. AB - Consecutive treatments with recombinant follicle-stimulating and luteinizing hormones (rFsh and rLh, respectively) stimulate spermatogenesis and potentiate sperm production in pubescent specimens of the oligospermic Senegalese sole (Solea senegalensis). However, sperm production in response to the hormones is highly variable, and the steroidogenic potential of the testis may be diminished due to sustained hormone supply. Here, we compared the effectiveness of low (9 MUg/kg) and high (18 MUg/kg) doses of rFsh and rLh to improve sperm production in adult sole during late winter-early spring (onset of the natural spawning period), and in autumn under a controlled temperature of 12 degrees C (period of testicular recrudescence). Treatment with rFsh over six weeks during spring, followed by a single rLh injection, did not enhance sperm production, possibly because of an advanced stage of sexual maturation of the males, as reflected by high Lh plasma levels (~17 ng/ml) before rFsh treatment. In contrast, in autumn, when the Lh circulating levels were much lower (~3 ng/ml), the low doses of rFsh and rLh generated a four-times increase in sperm production, whereas the high doses of the hormones were ineffective. However, treatment with rLh, regardless of the effect of rFsh, improved the motility of spermatozoa during both spring and autumn. These data confirm that consecutive rFsh and rLh treatments increase sperm production and quality in adult sole males, although they seem to be highly sensitive to the rFsh dose. The efficiency of recombinant gonadotropins also appears to be season-dependent despite the asynchronous nature of the sole testis. PMID- 30018008 TI - Deguelin attenuates non-small cell lung cancer cell metastasis through inhibiting the CtsZ/FAK signaling pathway. AB - Lung cancer is the leading cause of cancer-related death among both men and women every year, mainly due to metastasis. Although natural compound deguelin has been reported to inhibited cell migration and invasion in various cancer cells, the details of this regulation progress remain to be fully elucidated. In this study, we investigated the underlying mechanism of deguelin-suppressed metastasis of non small cell lung cancer (NSCLC) cells. Our results demonstrate that deguelin inhibits NSCLC cell migration, invasion, and metastasis both in vitro and in vivo. These inhibitory effects of deguelin were mediated by suppressing of Cathepsin Z (CtsZ) expression and interrupting the interaction of CtsZ with integrin beta3. Moreover, deguelin inhibits the activation of CtsZ downstream FAK/Src/Paxillin signaling. Knockdown of CtsZ mimicked the effect of deguelin on NSCLC cells migration and invasion. Our study reveals that deguelin exerts its anti-metastatic effect both in vitro and in vivo is partly dependent on the suppression of CtsZ signaling. Deguelin would be a potential anti-metastasis agent against NSCLC. PMID- 30018006 TI - Transcription factor 21 regulates expression of ERbeta and SF-1 via upstream stimulatory factor-2 in endometriotic tissues. AB - Steroidogenic factor-1 (SF-1, encoded by NR5A1) and estrogen receptor beta (ERbeta, encoded by ESR2), which are highly expressed in endometriotic stromal cells (ESCs), contribute to the pathogenesis of endometriosis, but the regulation mechanism remains largely unknown. Transcription factor 21 (TCF21) belongs to the helix-loop-helix (bHLH) family characterized by regulating gene expression via binding to E-box element. Here, we attempted to determine the molecular mechanism of TCF21 on SF-1 and ERbeta expression in endometriosis. We found that TCF21 expression in ESCs was higher than that in endometrial stromal cells (EMs), and positively correlated with SF-1 and ERbeta expression in ESCs. Since the importance of E-box element for NR5A1 promoter activity has been previously reported, we performed site-mutation and luciferase assay, revealing that the E box sequence in the ESR2 promoter is also a critical element modulating ERbeta expression. Upstream stimulatory factor 2 (USF2) is another bHLH factor implicated in transcriptional regulation. Further analyses elucidated that it is not TCF21, but USF2 exhibited higher binding affinities in ESCs to NR5A1 and ESR2 promoters than in EMs. Additionally, TCF21 knockdown significantly decreased the binding activities of USF2 to NR5A1 and ESR2 promoters via disruption of the TCF21-USF2 complex. Meanwhile, manipulating TCF21 expression significantly affected MMP9 and cyclinD1 expression, as wells as proliferation and invasion of ESCs. Moreover, TCF21 depletion in endometriotic xenografts reduced SF-1 and ERbeta expression, abrogating ectopic lesion growth in mice. Cumulatively, a critical role of TCF21 in the pathogenesis of endometriosis is demonstrated, suggesting a potential druggable target for future therapy. PMID- 30018009 TI - Improvement of cutaneous delivery of methylene blue by liquid crystals. AB - The purpose of this study was to evaluate the effect of composition and characteristics of liquid crystalline phases (LCPs) on cutaneous delivery of methylene blue (MB). LCPs were obtained by mixing Brij97(r) with water at various ratios; Brij97(r):water at 8:2 (F8:2), 7:3 (F7:3), and 6:4 (F6:4) were selected, and MB was incorporated at 0.1%. F8:2 and F7:3 exhibited textures and small angle X-ray scattering (SAXS) patterns corresponding to lamellar phase, whereas F6:4 displayed characteristics of hexagonal phase. All three LCPs were stable for 9 months, and exhibited thixotropic pseudoplastic behaviour. Increasing water content increased viscosity. All three LCPs released less (3.2- to 6.6-fold) MB than control gel (3.0% hydroxyethylcellulose (HEC) + 0.1% MB), demonstrating their ability to sustain release. Despite the lower release, all LCPs improved skin retention of MB at 6 h post-application (1.3- to 2.1-fold) compared to the control gel. Among the LCPs, F8:2-mediated skin retention of MB was more pronounced, followed by F7:3. Consistent with the increased penetration, transepidermal water loss (TEWL) also increased after treatment with the LCPs (2.0-2.8 fold), which suggests their influence on skin barrier. Irritation studies by Hen's Egg Test - Chorioallantoic Membrane (HET-CAM) suggest that F7:3 and F6:4 may be better tolerated by the skin than F8:2. PMID- 30018010 TI - Competing for water: A new approach to understand disintegrant performance. AB - The understanding of tablet disintegration is still incomplete as not all involved factors and processes are known or accounted for. E.g., the negative influence of soluble fillers, on disintegration is usually attributed to increased viscosity due to dissolved filler. When the most common filler, lactose, dissolves, the viscosity increases only slightly. The impact of binders has hardly been studied systematically. In this study, water uptake and force development as well as water sorption experiments were performed of tablets containing either a soluble or an insoluble filler, one of four different binders, and one of four different disintegrants. For both fillers, one disintegrant performed distinctly worse than the others. For the insoluble filler, dibasic calcium phosphate (DCP), sodium starch glycolate resulted in the longest disintegration, for the soluble filler, lactose, croscarmellose sodium performed worst. Based on the experimental results, the authors introduce the competition-for-water hypothesis, which takes into consideration the amount of freely available water molecules and hydration kinetics of excipients. Soluble fillers bind a large number of water molecules in hydrate shells and prevent, therefore, proper disintegrant action. Previously inconsistent observations can be approached with this hypothesis and a better understanding of the underlying processes and explanations is possible. PMID- 30018011 TI - Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte complex based delivery systems. AB - Benznidazole (BZ), first-line drug for Chagas treatment, is available as immediate-release tablets. High frequency of administration, long-term therapy, and side effects of BZ conspire against treatment adherence, and negatively impact in therapeutic success. We have developed BZ-loaded interpolyelectrolyte complexes (IPECs) composed of polymethacrylates (EE-EL-BZ) or polysaccharides (Ch AA-BZ) for controlled BZ release. This work aimed to evaluate their preclinical pharmacokinetics compared to Abarax(r) (reference treatment) and to correlate them with the in vitro BZ release. A randomization schedule with a 3 * 2 cross over design was used. Each healthy dog received a single oral dose of 100 mg of BZ from EE-EL-BZ, Ch-AA-BZ or Abarax(r). BZ quantification was performed in plasma by a validated HPLC-UV method. Moreover, in silico simulations using the pharmacokinetic software PK Solutions 2.0TM were calculated for the multiple-dose administration at two dose regimens: 100 mg of BZ administered every 12 and 24 h. Also, the relationship between in vitro dissolution and in vivo plasma BZ concentration profiles in a single step was model for IVIVC analysis. BZ was rapidly absorbed from all formulations. The Cmax value for Ch-AA-BZ was 32% higher than reference (p < 0.05) and an earlier Tmax (4.2 h) was observed as compared to EE-EL-BZ (6.0 h). For both IPECs, the Tmax values were higher (p < 0.05) and the areas under the curve were 25% greater than those of Abarax(r) (p < 0.01). Despite these variations in pharmacokinetics parameters, simulations of once or twice daily dosing showed that all formulations reached a steady-state range concentration above of the minimum therapeutic dose while avoiding high BZ concentrations related to increased side effects. A linear level A IVIVC model was established using plasma concentration profiles and dissolved data obtained. Thus, BZ-loaded IPECs prolonged drug release and formulated as capsules showed improved in vivo performance, in terms of bioavailability and Tmax values, which were significantly higher compared to Abarax(r). These BZ carrier systems would be useful for oral administration in the treatment of Chagas disease. PMID- 30018012 TI - Point-of-care identification of organophosphates in gastric juice by ambient mass spectrometry in emergency settings. AB - BACKGROUND: For emergency management, it is important to promptly identify the organophosphate ingested by self-poisoning patients since different organophosphates cause intoxication through different mechanisms and require different therapeutic strategies. This study aimed at the development of a point of-care ambient mass spectrometric approach for rapid identification of organophosphate(s) in gastric juice for emergency management. METHODS: Six organophosphate insecticides that are commonly ingested by self-poisoning patients in Taiwan were examined. The sample solutions were prepared and diluted with human gastric juice. A direct metallic probe was dipped and removed immediately from the sample solution. The probe was then inserted into the thermal desorption-electrospray ionization/mass spectrometry (TD-ESI/MS) to detect the analyte on the probe. RESULTS: Since no pretreatment of the specimen was required, the sampling processes followed by thermal desorption-electrospray ionization and mass spectrometric analysis of the organophosphate in the gastric juice were completed within 30 s. The detection limit of the organophosphates is at the 10-100 parts per billion level. Good linearity was observed between the corresponding changes in mass spectrometric signal intensities and the changes of organophosphate concentrations within the range of 5-1000 parts per billion. The high efficiency of this ambient mass spectrometric platform was further confirmed when a real sample of the drained gastric lavage fluid of a patient who suffered from ingestion of chlorpyrifos was collected in the emergency room and tested with this cutting-edge technique. CONCLUSIONS: The results suggested that TD ESI/MS is promising in promptly providing toxicological information to assist succeeding medical management in an emergency room. PMID- 30018013 TI - Liquid chromatography-tandem mass spectrometry method for estimation of a panel of lysophosphatidylcholines in dried blood spots for screening of X-linked adrenoleukodystrophy. AB - BACKGROUND: Elevated C26:0-lysophosphatidylcholine (LPC) is used as a biomarker to screen newborns for X-linked adrenoleukodystrophy (X-ALD), an inherited peroxisomal disorder. Our aim was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assay for estimating a panel of LPCs (C20:0, C22:0, C24:0 and C26:0) from dried blood spots (DBS) and to evaluate its sensitivity and specificity for identification of X-ALD in clinically suspected cases. METHODS: LPCs (C20:0 - C26:0) were extracted from 3.2 mm DBS, spiked with an isotopically labelled internal standard (C26:0-d4-LPC) in a 96-well plate, and measured by LC MS/MS in electrospray ionization positive, multiple reaction monitoring mode. The sensitivity and specificity of the method was evaluated in 21 patients diagnosed with X-ALD and 375 healthy controls. RESULTS: Elevated C26:0 and C24:0-LPCs were 100% sensitive and specific for identification of X-ALD. The sensitivity and specificity of elevated C26:0/C20:0, C26/C22:0, C24:0/C20:0 and C24/C22:0-LPCs were > 80% and 70%, respectively. CONCLUSION: The LC-MS/MS method for estimating LPCs in DBS can be used to identify X-ALD in clinically suspected patients. Further large-scale studies to determine the pre-analytical variables and to define age- and gender-specific reference ranges in various ethnic groups are warranted before introducing this method for high-risk screening in India. PMID- 30018014 TI - Intimate estrogen receptor-alpha/ligand relationships signal biological activity. AB - How does estrogen receptor-alpha bind its natural ligands - estrogens? How can other molecules mimic estrogens and elicit different estrogenic responses? The answers lie in a complex and intimate chemical biology between ligands and receptor. This delicate interaction at the ligand binding cleft signals, via conformational change, exposure of a specific new charge topography at a second site (Activation Function-2). This, in turn, attracts a regulatory protein which modulates gene expression and controls biological activity. PMID- 30018015 TI - Rigid and non-rigid registration of polarized light imaging data for 3D reconstruction of the temporal lobe of the human brain at micrometer resolution. AB - To understand the spatial organization as well as long- and short-range connections of the human brain at microscopic resolution, 3D reconstruction of histological sections is important. We approach this challenge by reconstructing series of unstained histological sections of multi-scale (1.3MUm and 64MUm) and multi-modal 3D polarized light imaging (3D-PLI) data. Since spatial coherence is lost during the sectioning procedure, image registration is the major step in 3D reconstruction. We propose a non-rigid registration method which comprises of a novel multi-modal similarity metric and an improved regularization scheme to cope with deformations inevitably introduced during the sectioning procedure, as well as a rigid registration approach using a robust similarity metric for improved initial alignment. We also introduce a multi-scale feature-based localization and registration approach for mapping of 1.3MUm sections to 64MUm sections and a scale-adaptive method that can handle challenging sections with large semi-global deformations due to tissue splits. We have applied our registration method to 126 consecutive sections of the temporal lobe of the human brain with 64MUm and 1.3MUm resolution. Each step of the registration method was quantitatively evaluated using 10 different sections and manually determined ground truth, and a quantitative comparison with previous methods was performed. Visual assessment of the reconstructed volumes and comparison with reference volumes confirmed the high quality of the registration result. PMID- 30018016 TI - Effects of the Antidepressant Fluoxetine on the Somatostatin Interneurons in the Basolateral Amygdala. AB - Although the precise mechanism of action of antidepressant drugs remains elusive, the neuroplastic hypothesis has gained acceptance during the last two decades. Several studies have shown that treatment with antidepressants such as Fluoxetine is associated with enhanced plasticity in control animals, especially in regions such as the visual cortex, the hippocampus and the medial prefrontal cortex. More recently, the basolateral amygdala has been shown to be affected by Fluoxetine leading to a reopening of critical period-like plasticity in the fear and aggression circuits. One of the key elements triggering this type of brain plasticity are inhibitory networks, especially parvalbumin interneurons. However, recent work on fast-acting antidepressants has shown also an important role for somatostatin interneurons. Here we show that Fluoxetine reorganizes inhibitory circuits through increased expression of the plasticity-related molecule PSA-NCAM which regulates interneuronal structure and connectivity. In addition, we demonstrate that treatment with this antidepressant alters the structure of somatostatin interneurons both at the level of dendritic spines and of axonal en passant boutons. Our findings suggest that new strategies targeting somatostatin interneuron activity might help us to better understand depression and the action of antidepressants. PMID- 30018017 TI - Intrathecal Injection of miR-133b-3p or miR-143-3p Prevents the Development of Persistent Cold and Mechanical Allodynia Following a Peripheral Nerve Injury in Rats. AB - In DRG an increase in miR-133b-3p, miR-143-3p, and miR-1-3p correlates with the lack of development of neuropathic pain following a peripheral nerve injury. Using lentiviral (LV) vectors we found that a single injection of LV-miR-133b-3p or LV-miR-143-3p immediately after a peripheral nerve injury prevented the development of sustained mechanical and cold allodynia. Injection of LV-miR-133b 3p or LV-miR-143-3p by themselves or in combination, on day 3 post-injury produced a partial and transient reduction in mechanical allodynia and a sustained decrease in cold allodynia. Injection of LV-miR-1-3p has no effect. Co injection of LV-miR-1a with miR-133b-3p or miR-143-3p on day 3 post-injury produced a sustained decrease in mechanical and cold allodynia. In DRG cultures, miR-133b-3p and miR-143-3p but not miR-1-3p, enhanced the depolarization-evoked cytoplasmic calcium increase. Using 3'UTR target clones containing a Gaussian luciferase reporter gene we found that with the 3'UTR-Scn2b, miR-133-3p and miR 143-3p reduced the expression while miR-1-3p enhanced the expression of the reporter gene. With the 3'UTR-TRPM8, miR-133-3p and miR-143-3p reduced the expression and miR-1-3p had no effect. With the 3'UTR-Piezo2, miR-133-3p increased the expression while miR-143-3p and miR-1-3p had no effect. LV-miR133b 3p, LV-miR-143-3p and LV-miR1a-3p reduced Scn2b-mRNA and Piezo2-mRNA. LV-miR133b 3p and LV-miR-143-3p reduced TRPM8-mRNA. LV-miR-133b-3p and LV-miR-143-3p prevent the development of chronic pain when injected immediately after the injury, but are only partially effective when injected at later times. LV-miR-1a-3p had no effect on pain, but complemented the actions of LV-miR-133b-3p or LV-miR-143-3p resulting in a sustained reversal of pain when co-injected 3 days following nerve injury. PMID- 30018018 TI - Temporal Profile and Limb-specificity of Phasic Pain-Evoked Changes in Motor Excitability. AB - A fundamental function of nociception is to trigger defensive motor responses to threatening events. Here, we explored the effects of phasic pain on the motor excitability of ipsilateral and contralateral arms. We reasoned that the occurrence of a short-lasting nociceptive stimulus should result in a specific modulation of motor excitability for muscles involved in the withdrawal of the stimulated limb. This was assessed using transcranial magnetic stimulation (TMS) of the left and right primary motor cortex to elicit motor-evoked potentials (MEPs) in three flexor and two extensor muscles of both arms. To assess the time course of nociception-motor interactions, TMS pulses were triggered 50-2000 ms after delivering short-lasting nociceptive laser stimuli to the left or right hand. We made three main observations. First, nociceptive stimuli induced an early-latency (100 ms) enhancement of MEPs in flexor muscles of the stimulated hand. Considering its latency, this modulation is likely consequent to nociceptive-motor interactions at spinal level. This early and lateralized enhancement was followed by a later (150-400 ms) MEP reduction in extensor muscles of the stimulated hand and flexor muscles of both hands, predominant at the stimulated hand. Finally, we observed a long-lasting (600-2000 ms) MEP enhancement in muscles of the non-stimulated hand. These later effects of the nociceptive stimulus could reflect nociception-motor interactions occurring at cortical level. PMID- 30018019 TI - Substitutions of a buried glutamate residue hinder the conformational change in horse liver alcohol dehydrogenase and yield a surprising complex with endogenous 3'-Dephosphocoenzyme A. AB - Glu-267 is highly conserved in alcohol dehydrogenases and buried as a negatively charged residue in a loop of the NAD coenzyme binding domain. Glu-267 might have a structural role and contribute to a rate-promoting vibration that facilitates catalysis. Substitutions of Glu-267 with histidine or asparagine residues increase the dissociation constants for the coenzymes (NAD+ by ~40-fold, NADH by ~200-fold) and significantly decrease catalytic efficiencies by 16-1200-fold various substrates and substituted enzymes. The turnover numbers modestly change with the substitutions, but hydride transfer is at least partially rate-limiting for turnover for alcohol oxidation. X-ray structures of the E267H and E267 N enzymes are similar to the apoenzyme (open) conformation of the wild-type enzyme, and the substitutions are accommodated by local changes in the structure. Surprisingly, the E267H and E267 N enzymes have endogenous (from the expression in E. coli) 3'-dephosphocoenzyme A bound in the active site with the ADP moiety in the NAD binding site and the pantethiene sulfhydryl bound to the catalytic zinc. The kinetics and crystallography show that the substitutions of Glu-267 hinder the conformational change, which occurs when wild-type enzyme binds coenzymes, and affect productive binding of substrates. PMID- 30018020 TI - Psychopharmacology in transplantation medicine. AB - Organ transplantation has become a well-established treatment option in patients with end-stage organ diseases. Although quality of life has markedly improved, psychiatric disorders before and after transplantation are more frequent compared to the general population. Psychopharmacological treatment is recommended for almost all mental disorders according to current guidelines, but may pose particular problems in organ transplant patients. Changes in the metabolism and elimination of drugs during organ insufficiency, drug interactions, and overlapping side effects between psychopharmacological and immunosuppressive drugs are challenging problems in clinical management. Furthermore, questions frequently arise concerning the use of psychopharmacological treatment options for sleeping and anxiety disorders. This article reviews psychopharmacology in organ transplant patients, with particular attention to frequent psychiatric disorders observed in the disease course of end-stage organ diseases. PMID- 30018022 TI - Effect of acute restraint stress in a polytrauma rat model. AB - INTRODUCTION: A stressful environment may contribute to poor outcomes after TBI. The current study evaluates the impact of acute stress in a polytrauma rat model. METHODS: Rats were stressed by a 45-minute immobilization period before instrumentation under ketamine (t1). Polytrauma was produced by blast overpressure and controlled hemorrhage (t2). Rats were euthanized immediately after a 3 h simulated Medevac-transport time (t3) or after 72 h post-trauma (t4). Corticosterone, ACTH, and ACTH receptor gene expression were measured at these time points. Physiological parameters were monitored throughout the study. RESULTS: HR was higher in stressed compared to unstressed animals at t1. Corticosterone and ACTH levels were similar for all conditions at t1 and t2; ACTH and corticosterone became elevated in all groups at t3 and at t4, respectively. The ACTH receptor gene expression trended towards higher values at t4 for the stressed animals whether being injured or not. Survival after injury was 83% in both unstressed and stressed animals. CONCLUSION: Overall, corticosterone was not significantly affected following acute stress in ketamine-anesthetized rats. Early mortality was primarily due to polytrauma and change in the animal's biochemical parameters appeared at t4 post trauma. The findings indicate that ketamine-anesthesia and/or surgery may have overshadowed the effect of the initial stress. PMID- 30018021 TI - Optimal alpha-lipoic acid strengthen immunity of young grass carp (Ctenopharyngodon idella) by enhancing immune function of head kidney, spleen and skin. AB - This study was for the first time to investigate the effects of alpha-lipoic acid (LA) on growth and immune function of head kidney, spleen and skin in young grass carp (Ctenopharyngodon idella). A total of 540 healthy grass carp (with initial body weight at 216.59 +/- 0.33 g) were randomly divided into six groups and fed six separate diets with graded dietary levels of LA for 70 days. Un-supplemented group did not find LA and its concentrations in the other five diets were 203.25, 403.82, 591.42, 781.25 and 953.18 mg kg-1, respectively. After the growth trial, fish were challenged with A. hydrophila for 14 days. The results showed that, compared with the un-supplemented group, optimal LA improved lysozyme (LZ) and acid phosphatase (ACP) activities, enhanced complement 3 (C3), C4 and immunoglobulin (Ig) M contents and up-regulated hepcidin, liver expressed antimicrobial peptide (LEAP)-2A, LEAP-2B and beta-defensin-1 mRNA levels in the head kidney, spleen and skin of young grass carp; meanwhile, optimal LA up regulated anti-inflammatory cytokines transforming growth factor (TGF)-beta1, TGF beta2, interleukin (IL)-4/13A (not IL-4/13B), IL-10 and IL-11 mRNA levels partly related to target of rapamycin (TOR) signaling and down-regulated pro inflammatory cytokines tumor necrosis factor (TNF)-alpha, interferon (IFN) gamma2, IL-1beta, IL-6, IL-8, IL-12p40 (not IL-12p35), IL-15 (not in the skin) and IL-17D mRNA levels partially associated with nuclear factor-kappa B (NF kappaB) signaling in the head kidney, spleen and skin of young grass carp. Above results indicated that optimal LA enhanced the immune function of head kidney, spleen and skin in fish. Interestingly, excessive LA decreased the growth and impaired the immune function of head kidney, spleen and skin in fish. Finally, on the basis of the percent weight gain (PWG), the ability against skin hemorrhage and lesion, the IgM content in the head kidney and the LZ activity in the spleen, the optimal dietary LA levels were estimated to be 315.37, 382.33, 353.19 and 318.26 mg kg-1 diet, respectively. PMID- 30018023 TI - APECED in Turkey: A case report and insights on genetic and phenotypic variability. AB - APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies. PMID- 30018024 TI - YB-1 increases glomerular, but decreases interstitial fibrosis in CNI-induced nephropathy. AB - Calcineurin inhibitors (CNIs) are a cornerstone of the current treatment in solid organ transplantation and autoimmune disease. However, CNIs also bear deleterious effects as they cause glomerular and tubulointerstitial fibrosis in the kidney. We recently identified Y-box protein-1 (YB-1) as a novel downstream effector of CNI-signaling in the cytoplasm of glomerular cells. In the present study, we corroborate the pro-fibrotic role of YB-1 in glomeruli of patients under CNI treatment. Such effects in glomeruli are significantly mitigated in CNI-treated mice with half-normal YB-1 expression (Yb1+/-). Surprisingly, in the tubulointerstitium we observe an opposite role of the CNI-YB-1 axis. Here, YB-1 is predominantly located to the nuclei and represses transcription of several extracellular matrix genes. Consistently, CNI-treatment in Yb1+/- mice markedly increases pro-fibrotic changes in the tubulointerstitium. In summary, our data provide evidence that fibrotic CNI-induced YB-1 effects in glomerular cells need to be contrasted with beneficial anti-fibrotic effects in the tubulointerstitium. PMID- 30018025 TI - Embodied disruption: "Sorting out" gender and nonconformity in the doctor's office. AB - Among LGBTQ people, those who are gender nonconforming (GNC) may be at heightened risk of both discrimination and underutilization of healthcare-yet little is known about what happens during healthcare encounters to compel GNC individuals to continue or avoid seeking future care. This study qualitatively examines the healthcare experiences of a racially diverse sample of 34 adult LGBTQ cis women, transgender men, and nonbinary individuals in a metropolitan area of the United States who do not conform to dominant biomedical schemas of sex and gender. GNC individuals experience embodied disruption in medical settings when patients are mis/recognized; providers respond to disruption in ways that further distress patients. Broadly, participants report similar experiences across racial and gender identities, but patients manage disruption somewhat differently depending on their embodied positions to gender norms. This study contributes to literature of stress, stigma, and sex, gender, and sexuality within medicine by illuminating how stigmatizing healthcare interactions deter LGBTQ individuals from seeking healthcare. Findings point to the importance of considering both structural factors and embodied visibility in future research addressing how stigma and discrimination manifest within health settings to disadvantage LGBTQ groups. PMID- 30018026 TI - Resveratrol stimulation induces interleukin-8 gene transcription via NF-kappaB. AB - The polyphenol resveratrol activates stimulus-regulated transcription factors, including activator protein-1 (AP-1). As part of a search for resveratrol regulated target genes we analyzed the gene encoding the chemokine interleukin-8 (IL-8) which is regulated by AP-1. Here, we show that treatment of HEK293 cells with resveratrol induced the expression of IL-8 and activated transcription of a chromatin-embedded IL-8 promoter-controlled reporter gene. Mutational analysis of the IL-8 promoter revealed that it was not the AP-1 binding site, but rather the NF-kappaB site that was essential to connect resveratrol stimulation with the transcriptional activation of the IL-8 gene. Thus, the NF-kappaB site of the IL-8 gene functions as resveratrol-responsive element. The analysis of an NF-kappaB responsive reporter gene, controlled by the HIV-1 long terminal repeat (LTR), showed that resveratrol stimulation increased the transcriptional activity of NF kappaB. These data were corroborated by an experiment showing that incubation of the cells with the NF-kappaB inhibitor JSH-23 attenuated resveratrol-induced activation of the IL-8 promoter and reduced the cellular NF-kappaB activity following stimulation of the cells with resveratrol. The protein kinase extracellular signal-regulated protein kinase ERK1/2 was identified to function as signal transducer connecting resveratrol stimulation with the activation of NF kappaB and IL-8 promoter-controlled transcription. We conclude that resveratrol, proposed to exhibit anti-inflammatory activity, stimulates expression of the pro inflammatory chemokine IL-8 via NF-kappaB, which is known as an important mediator of inflammatory processes. PMID- 30018027 TI - Association between environmental exposure to pesticides and epilepsy. AB - There is increasing evidence of an association between long-term environmental exposure to pesticides and neurodegenerative disorders; however, the relationship with epilepsy has not been addressed thus far. This study was aimed at determining the prevalence and risk of developing epilepsy among people from South-East Spain living in areas of high vs. low exposure to pesticides based on agronomic data. The study population consisted of 4007 subjects with a diagnosis of epilepsy and 580,077 control subjects adjusted for age, sex and geographical area. Data were collected from hospital records of the Spanish health care system (basic minimum dataset) between the years 1998 and 2010. The prevalence of epilepsy was significantly higher in areas of greater pesticide use relative to areas of lesser use. Overall, an increased risk of epilepsy was observed in the population living in areas of high vs. low use of pesticides (OR: 1.65; p < 0.001). Although this study was exploratory in nature, the results suggest that environmental exposure to pesticides might increase the risk of having epilepsy. PMID- 30018028 TI - In vitro activity of eravacycline and comparator antimicrobials against 143 recent strains of Bacteroides and Parabacteroides species. AB - Eravacycline, a novel fluorocycline antibiotic, has been evaluated against complicated mixed aerobic/anaerobic intra-abdominal infections but scant supporting in vitro data against anaerobes has been published. We found that eravacycline had good anaerobic in vitro activity with MICs of 4 MUg/ml or less against all Bacteroides and Parabacteroides strains tested, except for two B. ovatus strains that had MICs of 8 MUg/ml and one strain that had an MIC of 16 MUg/ml. Eravacycline was four-to-eight fold more active than tigecycline. PMID- 30018029 TI - Differential infectivity of two Trypanosoma cruzi strains in placental cells and tissue. AB - Congenital Chagas disease, caused by Trypanosoma cruzi (T. cruzi), has become epidemiologically relevant. The probability of congenital transmission depends on the maternal and developing fetal/newborn immune responses, placental factors and importantly, the virulence of the parasite. It has been proposed, that different genotypes of T. cruzi and their associated pathogenicity, virulence and tissue tropism may play an important role in congenital infection. Since there is no laboratory or animal model that recapitulates the complexities of vertical transmission in humans, here we studied parasite infectivity in human placental explants (HPE) as well as in the human trophoblast-derived cell line BeWo of the Y(DTU II) and the VD (TcVI) T. cruzi strains; the latter was isolated from a human case of congenital infection. Our results show that the VD strain is more infective and pathogenic than the Y strain, as demonstrated by qPCR and cell counting as well as by histopathological analysis. The present study constitutes the first approach to study the relationship between parasite two parasite strains from different genotypes and the infection efficiency in human placenta. PMID- 30018031 TI - BRAF/MEK Combo Approved for Melanoma. AB - The FDA approved the BRAF/MEK inhibitor combination encorafenib/binimetinib for patients with metastatic or inoperable melanoma with a BRAF V600E or V600K mutation. The approval was based on results of a phase III trial in which patients treated with the combination had a median progression-free survival of 14.9 months, compared with 7.3 months in a control group that received vemurafenib alone. PMID- 30018030 TI - In vitro and in vivo evaluation of etoposide - silk wafers for neuroblastoma treatment. AB - High-risk neuroblastoma requires surgical resection and multi-drug chemotherapy. This study aimed to develop an extended release, implantable and degradable delivery system for etoposide, commonly used for neuroblastoma treatment. Different concentrations of silk, a biodegradable, non-toxic, non-immunogenic material were employed to prepare etoposide-loaded wafer formulations. Secondary structure of silk in the formulations was characterized using Fourier Transform Infrared (FTIR) spectroscopy and optimized based on the crystalline structure. Accelerated in vitro degradation studies under different conditions such as acidic, alkaline, oxidizing mediums and high temperature, were performed. The integrity of the silk wafer structure was maintained unless exposed to 0.1 N NaOH for 24 h. In vitro release of etoposide was performed in PBS (phosphate buffered saline) at 37 degrees C. Silk coated 6% wafers released the drug up to 45 days, while uncoated wafers released the drug for 30 days. Cytotoxicity study was performed on KELLY cells to evaluate the etoposide cytotoxicity (LC50) and the long-term efficacy of the etoposide wafer formulations. The results showed that etoposide killed 50% of the cells at 1 MUg/mL concentration and the wafer formulations demonstrated significant cytotoxicity up to 22 days when compared to untreated cells. Using an orthotopic neuroblastoma mouse model, intra-tumoral implantation of the coated 6%, uncoated 6%, or uncoated 3% silk wafers were all effective at decreasing tumor growth. Histological examination revealed tumor cell necrosis adjacent to the drug-loaded silk wafer. PMID- 30018032 TI - Protein Kinase D2 Modulates Cell Cycle By Stabilizing Aurora A Kinase at Centrosomes. AB - Aurora A kinase (AURKA) is a master cell-cycle regulator that is often dysregulated in human cancers. Its overexpression has been associated with genome instability and oncogenic transformation. The protein kinase D (PKD) family is an emerging therapeutic target of cancer. Aberrant PKD activation has been implicated in tumor growth and survival, yet the underlying mechanisms remain to be elucidated. This study identified, for the first time, a functional crosstalk between PKD2 and Aurora A kinase in cancer cells. The data demonstrate that PKD2 is catalytically active during the G2-M phases of the cell cycle, and inactivation or depletion of PKD2 causes delay in mitotic entry due to downregulation of Aurora A, an effect that can be rescued by overexpression of Aurora A. Moreover, PKD2 localizes in the centrosome with Aurora A by binding to gamma-tubulin. Knockdown of PKD2 caused defects in centrosome separation, elongated G2 phase, mitotic catastrophe, and eventually cell death via apoptosis. Mechanistically, PKD2 interferes with Fbxw7 function to protect Aurora A from ubiquitin- and proteasome-dependent degradation. Taken together, these results identify PKD as a cell-cycle checkpoint kinase that positively modulates G2-M transition through Aurora A kinase in mammalian cells.Implications: PKD2 is a novel cell-cycle regulator that promotes G2-M transition by modulating Aurora A kinase stability in cancer cells and suggests the PKD2/Aurora A kinase regulatory axis as new therapeutic targets for cancer treatment. Mol Cancer Res; 16(11); 1785-97. (c)2018 AACR. PMID- 30018033 TI - Acute hepatitis E infection as a cause of unexplained neurological symptoms. AB - Neurological disease is the most common extrahepatic manifestation of autochthonous infection with hepatitis E virus (HEV). The association between acute neurological symptoms and hepatitis E is not well known, and hence HEV testing is often omitted. This case describes aberrant neurology in a 35-year-old woman with a background of HEV infection, highlighting the need for increased awareness of acute hepatitis E infection as a cause of unexplained neurological illness. PMID- 30018034 TI - Spontaneous gall bladder perforation with ischaemic bowel disease: a rare cause of acute abdomen with pneumoperitoneum in elderly. AB - Perforation of the gall bladder can occur due to a complication of acute (in 3% 10%) or chronic cholecystitis, presenting with or without gallstones. Other causes include trauma, neoplasms, steroid therapy or vascular compromise. In 1934, Niemeier classified the condition into three types: type I, acute perforation into the free peritoneal cavity; type II, subacute perforation with abscess formation; and type III, chronic perforation with fistula formation between the gall bladder and another viscus with type I experiencing the highest mortality rate. In particular, there are very few cases of gall bladder perforation associated with ischaemic bowel disease. We present a case of type I gall bladder perforation in a 70-year-old woman, without any apparent comorbidities, presenting with acute abdomen consistent with perforated duodenal ulcer with pneumoperitoneum on a plain abdominal radiograph and contrast-enhanced CT with eventual discovery of fundal perforation and ischaemic small bowel at laparotomy. PMID- 30018036 TI - Are we doing enough to identify and prioritise occupational carcinogens? PMID- 30018035 TI - Carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis overlap in a Filipino with positive HLA-B75 serotype. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two related mucocutaneous disorders with different severities. Although the incidence is low, SJS and TEN are life-threatening and predominantly drug-induced conditions. There is a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in different Southeast Asian populations. Here, we report a case of Filipino with SJS/TEN overlap probably induced by carbamazepine. The condition was treated with hydrocortisone followed by prednisone. The HLA-B*1502 allele was not found in this case. The patient tested positive for the HLA-B75 serotype, suggesting that carbamazepine-induced SJS/TEN may be serotype specific. Establishing the genotype before initiation of the drug may be advantageous for some patients and will aid physicians in determining the optimal drug therapy. Prevention of adverse drug reactions (ADR) may be done if pharmacists and other healthcare professionals work as a multidisciplinary ADR team to ensure that safe medication practices are realised. PMID- 30018037 TI - Co-conspirator with the radiologist in impossible errors. PMID- 30018040 TI - Omega 3 supplements do not reduce risk of heart disease, stroke, or death, finds review. PMID- 30018038 TI - Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation coupled inactivation. AB - Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 uM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation coupled inactivation. PMID- 30018039 TI - Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites. AB - Voltage-gated sodium (NaV) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects on NaChBac function and nearly identical anesthetizing effects on tadpole mobility. Using quantitative analysis by 19F-NMR saturation transfer difference spectroscopy, we reveal strong intermolecular cross-relaxation rate constants between 4-fluoropropofol and four different regions of NaChBac, including the activation gate and selectivity filter in the pore, the voltage sensing domain, and the S4-S5 linker. Unlike volatile anesthetics, 4-fluoropropofol does not bind to the extracellular interface of the pore domain. Collectively, our results show that propofol inhibits NaChBac at multiple sites, likely with distinct modes of action. This study provides a molecular basis for understanding the net inhibitory action of propofol on NaV channels. PMID- 30018041 TI - Wnt3a/beta-Catenin Signaling Conditions Differentiation of Partially Exhausted T effector Cells in Human Cancers. AB - In this study, we investigated the role of the Wnt/beta-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or nontumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and beta catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4+ or CD8+ T cells. The majority of these T cells expressed a dysfunctional effector memory Eomes+T-bet-phenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-gamma and tumor necrosis factor-alpha production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/beta-catenin signaling in T naive cells in vitro recapitulated the T-cell setting in vivo Indeed, the differentiation of cultured T naive cells was arrested, producing cells that resembled the EomeshighT-betlowbeta cateninhigh T cells with moderate effector functions that infiltrated tumor and nontumor areas. Wnt3a blockade improved the capacity of T naive cells to differentiate into effector cells in vitro However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor infiltrating T cells ex vivo Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/beta-catenin signaling to inhibit the differentiation of T naive cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting. Cancer Immunol Res; 6(8); 941-52. (c)2018 AACR. PMID- 30018042 TI - Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth. AB - The Wnt/beta-catenin pathway regulates T-cell functions, including the repression of effector functions to the advantage of memory development via Tcf1. In a companion study, we demonstrate that, in human cancers, Wnt3a/beta-catenin signaling maintains tumor-infiltrating T cells in a partially exhausted status. Here, we have investigated the effects of Wnt3a neutralization in vivo in a mouse tumor model. Abundant Wnt3a was released, mostly by stromal cells, in the tumor microenvironment. We tested whether Wnt3a neutralization in vivo could rescue the effector capacity of tumor-infiltrating T cells, by administering an antibody to Wnt3a to tumor-bearing mice. This therapy restrained tumor growth and favored the expansion of tumor antigen-specific CD8+ effector memory T cells with increased expression of Tbet and IFNgamma and reduced expression of Tcf1. However, the effect was not attributable to the interruption of T-cell-intrinsic beta-catenin signaling, because Wnt3a/beta-catenin activation correlated with enhanced, not reduced, T-cell effector functions both ex vivo and in vitro Adoptively transferred CD8+ T cells, not directly exposed to the anti-Wnt3a antibody but infiltrating previously Wnt3a-neutralized tumors, also showed improved functions. The rescue of T-cell response was thus secondary to T-cell-extrinsic changes that likely involved dendritic cells. Indeed, tumor-derived Wnt3a strongly suppressed dendritic cell maturation in vitro, and anti-Wnt3a treatment rescued dendritic cell activities in vivo Our results clarify the function of the Wnt3a/beta catenin pathway in antitumor effector T cells and suggest that Wnt3a neutralization might be a promising immunotherapy for rescuing dendritic cell activities. Cancer Immunol Res; 6(8); 953-64. (c)2018 AACR. PMID- 30018043 TI - Expanded CD56superbrightCD16+ NK Cells from Ovarian Cancer Patients Are Cytotoxic against Autologous Tumor in a Patient-Derived Xenograft Murine Model. AB - Natural killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematologic malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although rearming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56superbrightCD16+ subset with activation state and antitumor functions that increase with CD56 brightness. We investigated whether these expanded NK cells may overcome the limitations of autologous NK cell therapy against solid tumors. Peripheral blood- and ascites-derived NK cells from ovarian cancer patients were expanded and then adoptively transferred into cell-line and autologous patient derived xenograft models of human ovarian cancer. Expanded ovarian cancer patient NK cells reduced the burden of established tumors and prolonged survival. These results suggest that CD56bright NK cells harbor superior antitumor function compared with CD56dim cells. Thus, NK cell expansion may overcome limitations on autologous NK cell therapy by converting the patient's NK cells to a cytotoxic subset that exerts a therapeutic effect against autologous tumor. These findings suggest that the value of expanded autologous NK cell therapy for ovarian cancer and other solid malignancies should be clinically assessed. Cancer Immunol Res; 6(10); 1174-85. (c)2018 AACR. PMID- 30018044 TI - Response to Immune Checkpoint Inhibition in Two Patients with Alveolar Soft-Part Sarcoma. AB - Alveolar soft-part sarcoma (ASPS) is a morphologically distinctive mesenchymal tumor characterized by a canonical ASPL-TFE3 fusion product. In the metastatic setting, standard cytotoxic chemotherapies are typically ineffective. Studies have suggested modest clinical response to multitargeted receptor tyrosine kinase inhibitors. Here, we report sustained partial responses in two patients with immune checkpoint inhibition treated with either durvalumab (anti-PD-L1) alone or in combination with tremelimumab (anti-CTLA-4), which appeared unrelated to tumor immune infiltrates or mutational burden. Genomic analysis of these patients, and other cases of ASPS, demonstrated molecular mismatch-repair deficiency signatures. These findings suggest that immune checkpoint blockade may be a useful therapeutic strategy for ASPS. Cancer Immunol Res; 6(9); 1001-7. (c)2018 AACR. PMID- 30018045 TI - Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3- Cell-Mediated Modulation of CD103+ Dendritic Cells. AB - Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4+Foxp3- cells activated by dual PD-1/CTLA-4 blockade modulated the myeloid compartment, including activation of conventional CD103+ dendritic cells (DC) and expansion of a myeloid subset that produces TNFalpha and iNOS (TIP-DCs). CD4+Foxp3- T cell-mediated activation of CD103+ DCs resulted in enhanced IL12 production by these cells and IL12 enhanced the therapeutic effect of dual PD-1/CTLA-4 blockade. Given the importance of these myeloid subsets in the antitumor immune response, our data point to a previously underappreciated role of CD4+Foxp3- cells in modulating this arm of the antitumor immune response. Cancer Immunol Res; 6(9); 1069-81. (c)2018 AACR. PMID- 30018046 TI - Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells. AB - Tumor cell-derived microparticles (T-MP) contain tumor antigen profiles as well as innate signals, endowing them with vaccine potential; however, the precise mechanism by which DCs present T-MP antigens to T cells remains unclear. Here, we show that T-MPs activate a lysosomal pathway that is required for DCs presenting tumor antigens of T-MPs. DCs endocytose T-MPs to lysosomes, where T-MPs increase lysosomal pH from 5.0 to a peak of 8.5 via NOX2-catalyzed reactive oxygen species (ROS) production. This increased pH, coupled with T-MP-driven lysosomal centripetal migration, promotes the formation of MHC class I-tumor antigen peptide complexes. Concurrently, endocytosis of T-MPs results in the upregulation of CD80 and CD86. T-MP-increased ROS activate lysosomal Ca2+ channel Mcoln2, leading to Ca2+ release. Released Ca2+ activates transcription factor EB (TFEB), a lysosomal master regulator that directly binds to CD80 and CD86 promoters, promoting gene expression. These findings elucidate a pathway through which DCs efficiently present tumor antigen from T-MPs to CD8+ T cells, potentiating T-MPs as a novel tumor cell-free vaccine with clinical applications. Cancer Immunol Res; 6(9); 1057-68. (c)2018 AACR. PMID- 30018047 TI - Challenges in modelling the Charcot-Marie-Tooth neuropathies for therapy development. AB - Much has been achieved in terms of understanding the complex clinical and genetic heterogeneity of Charcot-Marie-Tooth neuropathy (CMT). Since the identification of mutations in the first CMT associated gene, PMP22, the technological advancement in molecular genetics and gene technology has allowed scientists to generate diverse animal models expressing monogenetic mutations that closely resemble the CMT phenotype. Additionally, one can now culture patient-derived neurons in a dish using cellular reprogramming and differentiation techniques. Nevertheless, despite the fact that finding a disease-causing mutation offers a precise diagnosis, there is no cure for CMT at present. This review will shed light on the exciting advancement in CMT disease modelling, the breakthroughs, pitfalls, current challenges for scientists and key considerations to move the field forward towards successful therapies. PMID- 30018049 TI - Urgent Start Peritoneal Dialysis: Defining What It Is and Why It Matters. PMID- 30018050 TI - Organ Donation and the Principles of Gift Law. PMID- 30018052 TI - US drugs were granted breakthrough approval on weak evidence, study finds. PMID- 30018048 TI - Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition. AB - High-grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Phyllanthus poilanei Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines in vitro and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its cytotoxic effects by inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition may be required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly inhibited the growth of cancer cell lines in hollow fibers, as well as reduced tumor burden in a xenograft model. We demonstrate that PHY34 acts as a late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single agent against HGSOC in vivo This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating ovarian cancer. Mol Cancer Ther; 17(10); 2123-35. (c)2018 AACR. PMID- 30018051 TI - Rebuilding the Pipeline of Investigators in Nephrology Research in the United States. PMID- 30018053 TI - An interview with the preLights community manager, Mate Palfy. PMID- 30018055 TI - David Oliver: Outpatient clinics are ripe for reform. PMID- 30018054 TI - ModelHeart: a resident-led implementation of metrics to reduce 30-day heart failure readmissions. AB - Hospitals have been penalised for excessive 30-day readmissions via Medicare payment penalties. As such there has been keen interest in finding ways of reducing readmissions. The basis for the study was a retrospective review of heart failure (HF) admissions at Cleveland Clinic Florida from 1 January 2010 to 31 December 2010. The result of this was a set of metrics associated with >30 day span between admissions: N-terminal pro-brain natriuretic peptide by at least 23%, fluid balance of <=-1.3 L and sodium >=135 mEq/L on discharge. The ModelHeart trial was a prospective resident-led validation of these criteria that consisted of education about and implementation of these metrics. A total of 200 patients carrying a diagnosis of HF, admitted between 1 November 2012 and 14 January 2014 were included in the trial. Of the 200 enrolled patients, 94% of discharged patients met at least one criteria, 58% met at least two criteria and 20% met all three. There were forty-eight all-cause 30-day readmissions. 30-day readmission rates between themore than equal to two criteria cohort and the remaining patients were not significantly different (p=0.71). Overall readmission rates were higher in the 2011-2012 retrospective patient pool (19%) versus the ModelHeart cohort (11%), and proportional differences were significant, (p<0.001). This may suggest that education provided sufficient awareness to alter discharge practices outside of the measured metrics. However, the lack of significant differences between groups with respect to discharge metrics suggests that further study is needed to refine the metrics and that reducing HF readmissions involves a continuum of care that spans the inpatient and outpatient setting. PMID- 30018056 TI - Evaluation of Preanalytical Conditions and Implementation of Quality Control Steps for Reliable Gene Expression and DNA Methylation Analyses in Liquid Biopsies. AB - BACKGROUND: Liquid biopsy provides important information for the prognosis and treatment of cancer patients. In this study, we evaluated the effects of preanalytical conditions on gene expression and DNA methylation analyses in liquid biopsies. METHODS: We tested the stability of circulating tumor cell (CTC) messenger RNA by spiking MCF-7 cells in healthy donor peripheral blood (PB) drawn into 6 collection-tube types with various storage conditions. CTCs were enriched based on epithelial cell adhesion molecule positivity, and RNA was isolated followed by cDNA synthesis. Gene expression was quantified using RT-quantitative PCR for CK19 and B2M. We evaluated the stability of DNA methylation in plasma under different storage conditions by spiking DNA isolated from MCF-7 cells in healthy donor plasma. Two commercially available sodium bisulfite (SB)-conversion kits were compared, in combination with whole genome amplification (WGA), to evaluate the stability of SB-converted DNA. SB-converted DNA samples were analyzed by real-time methylation-specific PCR (MSP) for ACTB, SOX17, and BRMS1. Quality control was assessed using Levey-Jennings graphs. RESULTS: RNA-based analysis in CTCs is severely impeded by the preservatives used in many PB collection tubes (except for EDTA), as well as by time to analysis. Plasma and SB converted DNA samples are stable and can be used safely for MSP when kept at -80 degrees C. Downstream WGA of SB-converted DNA compensated for the limited amount of available sample in liquid biopsies. CONCLUSIONS: Standardization of preanalytical conditions and implementation of quality control steps is extremely important for reliable liquid biopsy analysis, and a prerequisite for routine applications in the clinic. PMID- 30018057 TI - Immuno-MALDI-TOF-MS in the Clinic. PMID- 30018058 TI - A decade lost: does educational success mitigate the increased risks of premature death among children with experience of out-of-home care? AB - BACKGROUND: Past research has consistently identified children with out-of-home care (OHC) experience as a high-risk group for premature mortality. While many have argued that educational success is a key factor in reducing these individuals' excessive death risks, empirical evidence has hitherto been limited. The aim of the current study was therefore to examine the potentially mitigating role of educational success in the association between OHC experience and premature mortality. METHODS: Drawing on a Stockholm cohort born in 1953 (n=15 117), we analysed the associations among placement in OHC (ages 0-12), school performance (ages 13, 16 and 19) and premature all-cause mortality (ages 20-56) by means of Cox and Laplace regression analyses. RESULTS: The Cox regression models confirmed the increased risk of premature mortality among individuals with OHC experience. Unadjusted Laplace regression models showed that, based on median survival time, these children died more than a decade before their majority population peers. However, among individuals who performed well at school, that is, those who scored above-average marks at the age of 16 (grade 9) and at the age of 19 (grade 12), the risks of premature mortality did not significantly differ between the two groups. CONCLUSION: Educational success seems to mitigate the increased risks of premature death among children with OHC experience. PMID- 30018059 TI - Acronyms, CINAC, ACN, KDUCAL or NUCAL and so on are inappropriate to use for describing CKDu. PMID- 30018061 TI - Kv2 potassium channels meet VAP. PMID- 30018060 TI - Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria. AB - Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear. Here, we report the structural features and functional behavior of a phosphomimetic cytochrome c mutant, which was generated by site-specific incorporation at position 97 of p-carboxymethyl-l-phenylalanine using the evolved tRNA synthetase method. We found that the point mutation does not alter the overall folding and heme environment of cytochrome c, but significantly affects the entire oxidative phosphorylation process. In fact, the electron donation rate of the mutant heme protein to cytochrome c oxidase, or complex IV, within respiratory supercomplexes was higher than that of the wild-type species, in agreement with the observed decrease in reactive oxygen species production. Direct contact of cytochrome c with the respiratory supercomplex factor HIGD1A (hypoxia-inducible domain family member 1A) is reported here, with the mutant heme protein exhibiting a lower affinity than the wild-type species. Interestingly, phosphomimetic cytochrome c also exhibited a lower caspase-3 activation activity. Altogether, these findings yield a better understanding of the molecular basis for mitochondrial metabolism in acute diseases, such as brain ischemia, and thus could allow the use of phosphomimetic cytochrome c as a neuroprotector with therapeutic applications. PMID- 30018062 TI - Stem cell-derived clade F AAVs mediate high-efficiency homologous recombination based genome editing. AB - The precise correction of genetic mutations at the nucleotide level is an attractive permanent therapeutic strategy for human disease. However, despite significant progress, challenges to efficient and accurate genome editing persist. Here, we report a genome editing platform based upon a class of hematopoietic stem cell (HSC)-derived clade F adeno-associated virus (AAV), which does not require prior nuclease-mediated DNA breaks and functions exclusively through BRCA2-dependent homologous recombination. Genome editing is guided by complementary homology arms and is highly accurate and seamless, with no evidence of on-target mutations, including insertion/deletions or inclusion of AAV inverted terminal repeats. Efficient genome editing was demonstrated at different loci within the human genome, including a safe harbor locus, AAVS1, and the therapeutically relevant IL2RG gene, and at the murine Rosa26 locus. HSC-derived AAV vector (AAVHSC)-mediated genome editing was robust in primary human cells, including CD34+ cells, adult liver, hepatic endothelial cells, and myocytes. Importantly, high-efficiency gene editing was achieved in vivo upon a single i.v. injection of AAVHSC editing vectors in mice. Thus, clade F AAV-mediated genome editing represents a promising, highly efficient, precise, single-component approach that enables the development of therapeutic in vivo genome editing for the treatment of a multitude of human gene-based diseases. PMID- 30018064 TI - Biogeographic regions and events of isolation and diversification of the endemic biota of the tropical Andes. AB - Understanding the spatial and temporal evolution of biota in the tropical Andes is a major challenge, given the region's topographic complexity and high beta diversity. We used a network approach to find biogeographic regions (bioregions) based on high-resolution species distribution models for 151 endemic bird taxa. Then, we used dated molecular phylogenies of 14 genera to reconstruct the area history through a sequence of allopatric speciation processes. We identified 15 biogeographical regions and found 26 events of isolation and diversification within their boundaries that are independently confirmed with disjunct distributions of sister taxa. Furthermore, these events are spatially congruent with six geographical barriers related to warm and/or dry river valleys, discontinuities in elevation, and high peaks separating fauna from different range slopes. The most important barrier is the Maranon River Valley, which limits the boundaries of four bioregions and is congruent with eight phylogenetic distribution breaks, separating the Central and Northern Andes, where the most bioregions are found. We also show that many bioregions have diffuse and overlapping structures, with contact and transition zones that challenge previous conceptions of biogeographical regions as spatially simple in structure. This study found evidence that the drivers of our identified bioregions were processes of Andean uplift and mountain dispersal facilitated by temperature oscillations of the Pleistocene. Therefore, Andean bioregions were not formed from one simple biogeographical event in a certain time frame, but from a combination of vicariance and dispersal events, which occurred in different time periods. PMID- 30018063 TI - Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. AB - We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and a prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin not found in the single-headed S1 myosin motor fragment. We determined this by measuring cardiac myosin actin activated and actin-independent ATPase and single-ATP turnover kinetics. A two headed myosin fragment exhibits distinct autoinhibited ATP turnover kinetics compared with a single-headed fragment. Mavacamten enhanced this autoinhibition. It also enhanced autoinhibition of ADP release. Furthermore, actin changes the structure of the autoinhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state. PMID- 30018066 TI - Primary and metastatic brain tumours in adults: summary of NICE guidance. PMID- 30018065 TI - Combined computational and experimental investigation of the La2CuO4-x S x (0 <= x <= 4) quaternary system. AB - The lack of a mechanistic framework for chemical reactions forming inorganic extended solids presents a challenge to accelerated materials discovery. We demonstrate here a combined computational and experimental methodology to tackle this problem, in which in situ X-ray diffraction measurements monitor solid-state reactions and deduce reaction pathways, while theoretical computations rationalize reaction energetics. The method has been applied to the La2CuO4-x S x (0 <= x <= 4) quaternary system, following an earlier prediction that enhanced superconductivity could be found in these new lanthanum copper(II) oxysulfide compounds. In situ diffraction measurements show that reactants containing Cu(II) and S(2-) ions undergo redox reactions, leaving their ions in oxidation states that are incompatible with forming the desired new compounds. Computations of the reaction energies confirm that the observed synthetic pathways are indeed favored over those that would hypothetically form the suggested compounds. The consistency between computation and experiment in the La2CuO4-x S x system suggests a role for predictive theory: to identify and to explicate new synthetic routes for forming predicted compounds. PMID- 30018067 TI - Sleep quality and noise: comparisons between hospital and home settings. AB - BACKGROUND: Children and their parents report poor sleep in hospital and complain about noise. OBJECTIVE: To measure sleep quality and noise levels in hospital and compare these with the home environment. DESIGN: Observational within case controlled study. SETTING: Paediatric medical wards at Southampton Children's Hospital and bedrooms at home. PARTICIPANTS AND METHODS: Participants were children aged 3-16 years and their co-sleeping parents. Sleep quality was measured using actigraphy for a maximum of 5 nights in each setting. Median sound levels at the bedside were monitored overnight in a subgroup in both settings. MAIN OUTCOME MEASURES: Total sleep time, sleep efficiency, median sound levels overnight. RESULTS: 40 children and 16 mothers completed actigraphy in both settings. Children had on average 62.9 min, and parents 72.8 min, per night less sleep in hospital than at home. Both children and parents had poorer sleep quality in hospital than at home: mean sleep efficiency 77.0% vs 83.2% for children and 77.1% vs 88.9% for parents, respectively. Median sound levels in hospital measured in 8 children averaged 48.6 dBA compared with 34.7 dBA at home and exceeded World Health Organization recommendations of 30 dB. CONCLUSIONS: Children and their mothers have poor quality sleep in paediatric wards. This may affect the child's behaviour, recovery and pain tolerance. Sleep deprivation adds to parental burden and stress. Sound levels are significantly raised in hospital and may contribute to poor sleep. Reduction in the level of noise might lead to an improvement in sleep, affecting the quality of stay of both parent and child. PMID- 30018068 TI - Children who abuse animals: when should you be concerned about child abuse? A review of the literature. AB - Animal abuse by children is common, with 3-44% of children being reported to abuse animals at some point during their childhood. Much of this behaviour may be regarded as an extension of exploratory behaviour in a younger child; however, the apparent link between child and animal abuse is an area of increasing interest; with children who abuse animals being 2-3 times more likely to be directly abused themselves. How concerned should a health professional be that a child who abuses animals could themselves be the victim of abuse? We reviewed the literature on the subject, finding that abuse to an animal that is perpetrated by an older child (>10 years) is more likely to be associated with child abuse. Animal abuse is less common in girls compared with boys and there is some suggestion that child abuse may be more likely in these cases. Some papers have reported a higher prevalence of animal abuse in children with attention deficit hyperactivity disorder, developmental delay and conduct disorder, but the relationship with child abuse in these cases is unknown. Information on both child and animal abuse needs to be shared between the veterinary, medical and social care teams in order to protect both children and animals who are vulnerable. PMID- 30018069 TI - Long-term outcomes after group B streptococcus infection: a cohort study. AB - OBJECTIVE: To describe the risk of death and hospitalisation until adolescence of children after group B streptococcus (GBS) infection during infancy. DESIGN: Population-based cohort study. SETTING: New South Wales, Australia. PATIENTS: All registered live births from 2000 to 2011. INTERVENTIONS: Comparison of long-term outcomes in children with the International Statistical Classification of Diseases and Related Health Problems-10th Revision discharge codes corresponding to GBS infections and those without. MAIN OUTCOME MEASURES: Death and hospitalisation. RESULTS: A total of 1206 (0.1%) children (936 (77.6%)>=37 weeks' gestation) were diagnosed with GBS infection. Over the study period, infection rates decreased from 2.1 (95% CI 1.8 to 2.4) to 0.7 (95% CI 0.5 to 0.9) per 1000 live births. Infants with GBS infection were born at lower gestation (mean 37.6 vs 39.0 weeks), were more likely very low birth weight (<1500 g, OR 9.1(95% CI 7.4 to 11.3)), born premature (OR 3.9(95% CI 3.4 to 4.5)) and have 5 min Apgar scores <=5 (OR 6.7(95% CI 5.1 to 8.8)). Children with GBS had three times the adjusted odds of death (adjusted OR (AOR) 3.0(95% CI 2.1 to 4.3)) or rehospitalisations (AOR 3.1(95% CI 2.7 to 3.5)). Thirty-six (3.0%) with GBS died, with >50% of deaths occurring <28 days. Children with GBS were hospitalised more frequently (median 2 vs 1), for longer duration (mean 3.7 vs 2.2 days) and were at higher risk for problems with genitourinary (OR 3.1(95% CI 2.8 to 3.5)) and nervous (OR 2.0 (95% CI1.7 to 2.3)) systems. CONCLUSIONS: Despite decreasing GBS rates, the risk of poor health outcomes for GBS-infected children remains elevated, especially during the first 5 years. Survivors continue to be at increased risk of death and chronic conditions requiring hospitalisations, such as cerebral palsy and epilepsy. PMID- 30018071 TI - Clinical associations and expression pattern of the autoimmunity susceptibility factor DIORA-1 in patients with primary Sjogren's syndrome. PMID- 30018072 TI - Deprescribing cardiovascular drugs in low-risk patients increases the risk of uncontrolled blood pressure and LDL-cholesterol. PMID- 30018070 TI - Quality of life of children and adolescents with chronic kidney disease: a cross sectional study. AB - OBJECTIVE: The aim was to compare quality of life (QoL) among children and adolescents with different stages of chronic kidney disease (CKD) and determine factors associated with changes in QoL. DESIGN: Cross-sectional. SETTING: The Kids with CKD study involved five of eight paediatric nephrology units in Australia and New Zealand. PATIENTS: There were 375 children and adolescents (aged 6-18 years) with CKD, on dialysis or transplanted, recruited between 2013 and 2016. MAIN OUTCOME MEASURES: Overall and domain-specific QoL were measured using the Health Utilities Index 3 score, with a scale from -0.36 (worse than dead) to 1 (perfect health). QoL scores were compared between CKD stages using the Mann-Whitney U test. Factors associated with changes in QoL were assessed using multivariable linear and ordinal logistic regression. RESULTS: QoL for those with CKD stages 1-2 (n=106, median 0.88, IQR 0.63-0.96) was higher than those on dialysis (n=43, median 0.67, IQR 0.39-0.91, p<0.001), and similar to those with kidney transplants (n=135, median 0.83, IQR 0.59-0.97, p=0.4) or CKD stages 3-5 (n=91, 0.85, IQR 0.60-0.98). Reductions were most frequent in the domains of cognition (50%), pain (42%) and emotion (40%). The risk factors associated with decrements in overall QoL were being on dialysis (decrement of 0.13, 95% CI 0.02 to 0.25, p=0.02), lower family income (decrement of 0.10, 95% CI 0.03 to 0.15, p=0.002) and short stature (decrement of 0.09, 95% CI 0.01 to 0.16, p=0.02). CONCLUSIONS: The overall QoL and domains such as pain and emotion are substantially worse in children on dialysis compared with earlier stage CKD and those with kidney transplants. PMID- 30018073 TI - CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis. AB - The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle and is required for mitotic and S phase progression. The NEDD8-targeting drug MLN4924, which inactivates cullin ring-finger ubiquitin ligases (CRLs), has been examined in clinical trials for various types of lymphoma and acute myeloid leukemia. However, the essential role of CRL4DCAF2 in primary myeloid cells remains poorly understood. MLN4924 treatment, which mimics DCAF2 depletion, also promotes the severity of mouse psoriasis models, consistent with the effects of reduced DCAF2 expression in various autoimmune diseases. Using transcriptomic and immunological approaches, we showed that CRL4DCAF2 in dendritic cells (DCs) regulates the proteolytic fate of NIK and negatively regulates IL-23 production. CRL4DCAF2 promoted the polyubiquitination and subsequent degradation of NIK independent of TRAF3 degradation. DCAF2 deficiency facilitated NIK accumulation and RelB nuclear translocation. DCAF2 DC-conditional knockout mice displayed increased sensitivity to autoimmune diseases. This study shows that CRL4DCAF2 is crucial for controlling NIK stability and highlights a unique mechanism that controls inflammatory diseases. PMID- 30018074 TI - Impact of immunopathology on the antituberculous activity of pyrazinamide. AB - In the 1970s, inclusion of pyrazinamide (PZA) in the drug regimen of tuberculosis (TB) patients for the first 2 mo achieved a drastic reduction of therapy duration. Until now, however, the mechanisms underlying PZA's unique contribution to efficacy have remained controversial, and animal efficacy data vary across species. To understand how PZA kills bacterial populations present in critical lung lesion compartments, we first characterized a rabbit model of active TB, showing striking similarities in lesion types and fates to nonhuman primate models deemed the most appropriate surrogates of human TB. We next employed this model with lesion-centric molecular and bacteriology readouts to demonstrate that PZA exhibits potent activity against Mycobacterium tuberculosis residing in difficult-to-sterilize necrotic lesions. Our data also indicate that PZA is slow acting, suggesting that PZA administration beyond the first 2 mo may accelerate the cure. In conclusion, we provide a pharmacodynamic explanation for PZA's treatment-shortening effect and deliver new tools to dissect the contribution of immune response versus drug at the lesion level. PMID- 30018077 TI - AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation. AB - AMP-activated protein kinase (AMPK) alpha1 is activated in platelets on thrombin or collagen stimulation, and as a consequence, phosphorylates and inhibits acetyl CoA carboxylase (ACC). Because ACC is crucial for the synthesis of fatty acids, which are essential for platelet activation, we hypothesized that this enzyme plays a central regulatory role in platelet function. To investigate this, we used a double knock-in (DKI) mouse model in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser212 on ACC2 were mutated to prevent AMPK signaling to ACC. Suppression of ACC phosphorylation promoted injury-induced arterial thrombosis in vivo and enhanced thrombus growth ex vivo on collagen-coated surfaces under flow. After collagen stimulation, loss of AMPK-ACC signaling was associated with amplified thromboxane generation and dense granule secretion. ACC DKI platelets had increased arachidonic acid-containing phosphatidylethanolamine plasmalogen lipids. In conclusion, AMPK-ACC signaling is coupled to the control of thrombosis by specifically modulating thromboxane and granule release in response to collagen. It appears to achieve this by increasing platelet phospholipid content required for the generation of arachidonic acid, a key mediator of platelet activation. PMID- 30018076 TI - Independent effects of dietary fat and sucrose content on chondrocyte metabolism and osteoarthritis pathology in mice. AB - Obesity is one of the most significant risk factors for knee osteoarthritis. However, therapeutic strategies to prevent or treat obesity-associated osteoarthritis are limited because of uncertainty about the etiology of disease, particularly with regard to metabolic factors. High-fat-diet-induced obese mice have become a widely used model for testing hypotheses about how obesity increases the risk of osteoarthritis, but progress has been limited by variation in disease severity, with some reports concluding that dietary treatment alone is insufficient to induce osteoarthritis in mice. We hypothesized that increased sucrose content of typical low-fat control diets contributes to osteoarthritis pathology and thus alters outcomes when evaluating the effects of a high-fat diet. We tested this hypothesis in male C57BL/6J mice by comparing the effects of purified diets that independently varied sucrose or fat content from 6 to 26 weeks of age. Outcomes included osteoarthritis pathology, serum metabolites, and cartilage gene and protein changes associated with cellular metabolism and stress response pathways. We found that the relative content of sucrose versus cornstarch in low-fat iso-caloric purified diets caused substantial differences in serum metabolites, joint pathology, and cartilage metabolic and stress response pathways, despite no differences in body mass or body fat. We also found that higher dietary fat increased fatty acid metabolic enzymes in cartilage. The findings indicate that the choice of control diets should be carefully considered in mouse osteoarthritis studies. Our study also indicates that altered cartilage metabolism might be a contributing factor to how diet and obesity increase the risk of osteoarthritis. PMID- 30018078 TI - Noncovalent inhibition of C481S Bruton tyrosine kinase by GDC-0853: a new treatment strategy for ibrutinib-resistant CLL. AB - The clinical success of ibrutinib validates Bruton tyrosine kinase (BTK) inhibition as an effective strategy for treating hematologic malignancies, including chronic lymphocytic leukemia (CLL). Despite ibrutinib's ability to produce durable remissions in patients, acquired resistance can develop, mostly commonly by mutation of C481 of BTK in the ibrutinib binding site. Here, we characterize a novel BTK inhibitor, GDC-0853, to evaluate its preclinical efficacy in ibrutinib-naive and ibrutinib-resistant CLL. GDC-0853 is unique among reported BTK inhibitors in that it does not rely upon covalent reaction with C481 to stabilize its occupancy within BTK's adenosine triphosphate binding site. As with ibrutinib, GDC-0853 potently reduces B-cell receptor signaling, viability, NF-kappaB-dependent transcription, activation, and migration in treatment naive CLL cells. We found that GDC-0853 also inhibits the most commonly reported ibrutinib-resistant BTK mutant (C481S) both in a biochemical enzyme activity assay and in a stably transfected 293T cell line and maintains cytotoxicity against patient CLL cells harboring C481S BTK mutations. Additionally, GDC-0853 does not inhibit endothelial growth factor receptor or ITK, 2 alternative targets of ibrutinib that are likely responsible for some adverse events and may reduce the efficacy of ibrutinib-antibody combinations, respectively. Our results using GDC-0853 indicate that noncovalent, selective BTK inhibition may be effective in CLL either as monotherapy or in combination with therapeutic antibodies, especially among the emerging population of patients with acquired resistance to ibrutinib therapy. PMID- 30018075 TI - Germline-activating mutations in PIK3CD compromise B cell development and function. AB - Gain-of-function (GOF) mutations in PIK3CD, encoding the p110delta subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110delta inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110delta inhibitors. PMID- 30018079 TI - Structure of an extended beta3 integrin. AB - Cells use adhesion receptor integrins to communicate with their surroundings. Integrin activation and cellular signaling are coupled with change from bent to extended conformation. beta3 integrins, including alphaIIbbeta3, which is essential for the function of platelets in hemostasis and thrombosis, and alphaVbeta3, which plays multiple roles in diverse cell types, have been prototypes in understanding integrin structure and function. Despite extensive structural studies, a high-resolution integrin structure in an extended conformation remains to be determined. The human beta3 Leu33Pro polymorphism, located at the PSI domain, defines human platelet-specific alloantigens 1a and 1b (HPA-1a/b), immune response to which is a cause of posttransfusion purpura and fetal/neonatal alloimmune thrombocytopenia. Leu33Pro substitution has also been suggested to be a risk factor for thrombosis. Here we report the crystal structure of the beta3 headpiece in either Leu33 or Pro33 form, both of which reveal intermediate and fully extended conformations coexisting in 1 crystal. These were used to build high-resolution structures of full-length beta3 integrin in the intermediate and fully extended states, agreeing well with the corresponding conformations observed by electron microscopy. Our structures reveal how beta3 integrin becomes extended at its beta-knee region and how the flexibility of beta-leg domains is determined. In addition, our structures reveal conformational changes of the PSI and I-EGF1 domains upon beta3 extension, which may affect the binding of conformation-dependent anti-HPA-1a alloantibodies. Our structural and functional data show that Leu33Pro substitution does not directly alter the conformation or ligand binding of beta3 integrin. PMID- 30018080 TI - CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis. AB - The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic cells in systemic mastocytosis (SM). We found that clonal CD34+/CD38- stem cells, CD34+/CD38+ progenitor cells, and CD117++/CD34- MCs invariably express CD44 in patients with indolent SM (ISM), SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia (MCL). In addition, all human MCL-like cell lines examined (HMC-1, ROSA, and MCPV-1) displayed cytoplasmic and cell-surface CD44. We also found that expression of CD44 in neoplastic MCs depends on RAS-MEK and STAT5 signaling and increases with the aggressiveness of SM. Correspondingly, higher levels of soluble CD44 were measured in the sera of patients with advanced SM compared with ISM or cutaneous mastocytosis and were found to correlate with overall and progression-free survival. To investigate the functional role of CD44, a xenotransplantation model was employed using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and a short hairpin RNA (shRNA) against CD44. In this model, the shRNA-mediated knockdown of CD44 resulted in reduced MC expansion and tumor formation and prolonged survival in SCID mice compared with HMC-1.2 cells transduced with control shRNA. Together, our data show that CD44 is a RAS-MEK/STAT5-driven MC invasion receptor that correlates with the aggressiveness of SM. Whether CD44 can serve as therapeutic target in advanced SM remains to be determined in forthcoming studies. PMID- 30018081 TI - Unique BIR domain sets determine inhibitor of apoptosis protein-driven cell death and NOD2 complex signal specificity. AB - The mammalian IAPs, X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), play pivotal roles in innate immune signaling and inflammatory homeostasis, often working in parallel or in conjunction at a signaling complex. IAPs direct both nucleotide-binding oligomerization domain-containing 2 (NOD2) signaling complexes and cell death mechanisms to appropriately regulate inflammation. Although it is known that XIAP is critical for NOD2 signaling and that the loss of cIAP1 and cIAP2 blunts NOD2 activity, it is unclear whether these three highly related proteins can compensate for one another in NOD2 signaling or in mechanisms governing apoptosis or necroptosis. This potential redundancy is critically important, given that genetic loss of XIAP causes both very early onset inflammatory bowel disease and X-linked lymphoproliferative syndrome 2 (XLP-2) and that the overexpression of cIAP1 and cIAP2 is linked to both carcinogenesis and chemotherapeutic resistance. Given the therapeutic interest in IAP inhibition and the potential toxicities associated with disruption of inflammatory homeostasis, we used synthetic biology techniques to examine the functional redundancies of key domains in the IAPs. From this analysis, we defined the features of the IAPs that enable them to function at overlapping signaling complexes but remain independent and functionally exclusive in their roles as E3 ubiquitin ligases in innate immune and inflammatory signaling. PMID- 30018083 TI - Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid MU-opioid receptor desensitization. AB - G protein receptor kinases (GRKs) and beta-arrestins are key regulators of MU opioid receptor (MOR) signaling and trafficking. We have previously shown that high-efficacy opioids such as DAMGO stimulate a GRK2/3-mediated multisite phosphorylation of conserved C-terminal tail serine and threonine residues, which facilitates internalization of the receptor. In contrast, morphine-induced phosphorylation of MOR is limited to Ser375 and is not sufficient to drive substantial receptor internalization. We report how specific multisite phosphorylation controlled the dynamics of GRK and beta-arrestin interactions with MOR and show how such phosphorylation mediated receptor desensitization. We showed that GRK2/3 was recruited more quickly than was beta-arrestin to a DAMGO activated MOR. beta-Arrestin recruitment required GRK2 activity and MOR phosphorylation, but GRK recruitment also depended on the phosphorylation sites in the C-terminal tail, specifically four serine and threonine residues within the 370TREHPSTANT379 motif. Our results also suggested that other residues outside this motif participated in the initial and transient recruitment of GRK and beta-arrestins. We identified two components of high-efficacy agonist desensitization of MOR: a sustained component, which required GRK2-mediated phosphorylation and a potential soluble factor, and a rapid component, which was likely mediated by GRK2 but independent of receptor phosphorylation. Elucidating these complex receptor-effector interactions represents an important step toward a mechanistic understanding of MOR desensitization that leads to the development of tolerance and dependence. PMID- 30018082 TI - Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia. AB - The protein tyrosine phosphatase PTPN11 is implicated in the pathogenesis of juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and other malignancies. Activating mutations in PTPN11 increase downstream proliferative signaling and cell survival. We investigated the signaling upstream of PTPN11 in JMML and AML cells and found that PTPN11 was activated by the nonreceptor tyrosine/serine/threonine kinase TNK2 and that PTPN11-mutant JMML and AML cells were sensitive to TNK2 inhibition. In cultured human cell-based assays, PTPN11 and TNK2 interacted directly, enabling TNK2 to phosphorylate PTPN11, which subsequently dephosphorylated TNK2 in a negative feedback loop. Mutations in PTPN11 did not affect this physical interaction but increased the basal activity of PTPN11 such that TNK2-mediated activation was additive. Consequently, coexpression of TNK2 and mutant PTPN11 synergistically increased mitogen activated protein kinase (MAPK) signaling and enhanced colony formation in bone marrow cells from mice. Chemical inhibition of TNK2 blocked MAPK signaling and colony formation in vitro and decreased disease burden in a patient with PTPN11 mutant JMML who was treated with the multikinase (including TNK2) inhibitor dasatinib. Together, these data suggest that TNK2 is a promising therapeutic target for PTPN11-mutant leukemias. PMID- 30018086 TI - Human genome editing is not unethical, says Nuffield Council. PMID- 30018085 TI - Whole Genome Sequence of the Parasitoid Wasp Microplitis demolitor That Harbors an Endogenous Virus Mutualist. AB - Microplitis demolitor (Hymenoptera: Braconidae) is a parasitoid used as a biological control agent to control larval-stage Lepidoptera and serves as a model for studying the function and evolution of symbiotic viruses in the genus Bracovirus Here we present the M. demolitor genome (assembly version 2.0), with a genome size of 241 Mb, and a N50 scaffold and contig size of 1.1 Mb and 14 Kb, respectively. Using RNA-Seq data and manual annotation of genes of viral origin, we produced a high-quality gene set that includes 18,586 eukaryotic and 171 virus derived protein-coding genes. Bracoviruses are dsDNA viruses with unusual genome architecture, in which the viral genome is integrated into the wasp genome and is comprised of two distinct components: proviral segments that are amplified, circularized, and packaged into virions for export into the wasp's host via oviposition; and replication genes. This genome assembly revealed that at least two scaffolds contain both nudivirus-like genes and proviral segments, demonstrating that at least some of these components are near each other in the genome on a single chromosome. The updated assembly and annotation are available in several publicly accessible databases; including the National Center for Biotechnology Information and the Ag Data Commons. In addition, all raw sequence data available for M. demolitor have been consolidated and are available for visualization at the i5k Workspace. This whole genome assembly and annotation represents the only genome-scale, annotated assembly from the lineage of parasitoid wasps that has associations with bracoviruses (the 'microgastroid complex'), providing important baseline knowledge about the architecture of co opted virus symbiont genomes. PMID- 30018084 TI - Rapid Low-Cost Assembly of the Drosophila melanogaster Reference Genome Using Low Coverage, Long-Read Sequencing. AB - Accurate and comprehensive characterization of genetic variation is essential for deciphering the genetic basis of diseases and other phenotypes. A vast amount of genetic variation stems from large-scale sequence changes arising from the duplication, deletion, inversion, and translocation of sequences. In the past 10 years, high-throughput short reads have greatly expanded our ability to assay sequence variation due to single nucleotide polymorphisms. However, a recent de novo assembly of a second Drosophila melanogaster reference genome has revealed that short read genotyping methods miss hundreds of structural variants, including those affecting phenotypes. While genomes assembled using high-coverage long reads can achieve high levels of contiguity and completeness, concerns about cost, errors, and low yield have limited widespread adoption of such sequencing approaches. Here we resequenced the reference strain of D. melanogaster (ISO1) on a single Oxford Nanopore MinION flow cell run for 24 hr. Using only reads longer than 1 kb or with at least 30x coverage, we assembled a highly contiguous de novo genome. The addition of inexpensive paired reads and subsequent scaffolding using an optical map technology achieved an assembly with completeness and contiguity comparable to the D. melanogaster reference assembly. Comparison of our assembly to the reference assembly of ISO1 uncovered a number of structural variants (SVs), including novel LTR transposable element insertions and duplications affecting genes with developmental, behavioral, and metabolic functions. Collectively, these SVs provide a snapshot of the dynamics of genome evolution. Furthermore, our assembly and comparison to the D. melanogaster reference genome demonstrates that high-quality de novo assembly of reference genomes and comprehensive variant discovery using such assemblies are now possible by a single lab for under $1,000 (USD). PMID- 30018087 TI - The growing and important collaboration between BASHH and IUSTI-Europe. PMID- 30018088 TI - Inflammatory cytokine biomarkers of asymptomatic sexually transmitted infections and vaginal dysbiosis: a multicentre validation study. AB - OBJECTIVES: Vaginal dysbiosis and STIs are important drivers of the HIV epidemic and reproductive complications. These conditions remain prevalent, partly because most cases are asymptomatic. We have shown that inflammatory cytokines interleukin (IL)-1alpha, IL-1beta and interferon-gamma-induced protein (IP)-10 are biomarkers for detecting asymptomatic STIs and vaginal dysbiosis (bacterial vaginosis (BV) or intermediate microbiota). This study aimed to validate the performance of these biomarkers in African women recruited regardless of symptoms. METHODS: IL-1alpha, IL-1beta and IP-10 were measured in menstrual cup secretions, endocervical, lateral vaginal wall and vulvovaginal swabs from 550 women from Pretoria, Soweto and Cape Town, South Africa and Bondo, Kenya using Luminex and ELISA. STIs were assessed by PCR, BV by Nugent scoring and vaginal microbiota by 16S rRNA sequencing. RESULTS: Across four study populations and four types of genital specimens, the performance of IL-1alpha, IL-1beta and IP-10 for identification of women with STIs, BV or intermediate microbiota was consistent. Of the genital samples assessed, biomarkers measured in lateral vaginal wall swabs performed best, correctly classifying 76%(95% CI 70% to 81%) of women according to STI, BV or intermediate microbiota status (sensitivity 77%, specificity 71%) and were more accurate than clinical symptoms (sensitivity 41%, specificity 57%) (p=0.0003). Women incorrectly classified as STI/BV positive using the biomarkers had more abundant dysbiosis-associated bacteria, including Prevotella bivia and Gardnerella sp, detected by 16S rRNA sequencing, but not Nugent scoring. Including vaginal pH with the cytokine biomarkers improved the accuracy of the test (82% (95% CI 75% to 88%) correctly classified), although pH alone had poor specificity (61%). CONCLUSIONS: An inexpensive, point-of-care screening test including IL-1alpha, IL-1beta and IP-10 (and potentially pH) could be used in resource-limited settings to identify women with asymptomatic STIs and dysbiosis. These women could then be referred for aetiological testing, followed by specific treatment. PMID- 30018089 TI - Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites. AB - The regulated expansion of membrane contact sites, which mediate the nonvesicular exchange of lipids between organelles, requires the recruitment of additional contact site proteins. Yeast Vps13 dynamically localizes to membrane contacts that connect the ER, mitochondria, endosomes, and vacuoles and is recruited to the prospore membrane in meiosis, but its targeting mechanism is unclear. In this study, we identify the sorting nexin Ypt35 as a novel adaptor that recruits Vps13 to endosomal and vacuolar membranes. We characterize an interaction motif in the Ypt35 N terminus and identify related motifs in the prospore membrane adaptor Spo71 and the mitochondrial membrane protein Mcp1. We find that Mcp1 is a mitochondrial adaptor for Vps13, and the Vps13-Mcp1 interaction, but not Ypt35, is required when ER-mitochondria contacts are lost. All three adaptors compete for binding to a conserved six-repeat region of Vps13 implicated in human disease. Our results support a competition-based model for regulating Vps13 localization at cellular membranes. PMID- 30018092 TI - Deprescribing in primary care in Portugal (DePil17-20): a three-phase observational and experimental study protocol. AB - INTRODUCTION: Polypharmacy is commonly defined as the simultaneous taking of five or more drugs. Deprescribing is the process of tapering or stopping medications with the aim of improving patient outcomes and optimising current therapy, and there are several tools aiming at identifying potentially inappropriate medications, especially in the elderly. The direct involvement of patients and their caregivers in the choice and administration of drugs has long been known to be very important, but it is not usually applied. The aim of this study is to assess the knowledge of older adults about deprescription, the effect on willingness to have regular medications deprescribed and its quality-of-life outcome. METHODS AND ANALYSIS: This study protocol comprises three phases. The first two phases will be nationwide and aim to evaluate the prevalence and patterns of polypharmacy and assess the barriers and facilitators of deprescribing perceived by older adults, as well as their willingness to have regular medications deprescribed and to self-medicate. The third and last phase will be a non-pharmacological randomised clinical study to measure older patients' acceptance to have regular medications deprescribed and related quality of life. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles expressed in the Declaration of Helsinki. It has been approved by the Ethics Committee of the University of Beira Interior and Portuguese National Data Protection Commission. Study results will be published in peer-reviewed journals and presented at national and international conferences. In short, no action will be taken without written consent from patients and doctors. TRIAL REGISTRATION NUMBER: > NCT03283735. PMID- 30018090 TI - Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. AB - It is not clear to what extent starvation-induced autophagy affects the proteome on a global scale and whether it is selective. In this study, we report based on quantitative proteomics that cells during the first 4 h of acute starvation elicit lysosomal degradation of up to 2-3% of the proteome. The most significant changes are caused by an immediate autophagic response elicited by shortage of amino acids but executed independently of mechanistic target of rapamycin and macroautophagy. Intriguingly, the autophagy receptors p62/SQSTM1, NBR1, TAX1BP1, NDP52, and NCOA4 are among the most efficiently degraded substrates. Already 1 h after induction of starvation, they are rapidly degraded by a process that selectively delivers autophagy receptors to vesicles inside late endosomes/multivesicular bodies depending on the endosomal sorting complex required for transport III (ESCRT-III). Our data support a model in which amino acid deprivation elicits endocytosis of specific membrane receptors, induction of macroautophagy, and rapid degradation of autophagy receptors by endosomal microautophagy. PMID- 30018091 TI - Non-canonical Ret signaling augments p75-mediated cell death in developing sympathetic neurons. AB - Programmed cell death (PCD) is an evolutionarily conserved process critical in sculpting many organ systems, yet the underlying mechanisms remain poorly understood. Here, we investigated the interactions of pro-survival and pro apoptotic receptors in PCD using the sympathetic nervous system as a model. We demonstrate that Ret, a receptor tyrosine kinase required for the survival of many neuronal populations, is restricted to a subset of degenerating neurons that rapidly undergo apoptosis. Pro-apoptotic conditions induce Ret to associate with the death receptor p75. Genetic deletion of p75 within Ret+ neurons, and deletion of Ret during PCD, inhibit apoptosis both in vitro and in vivo. Mechanistically, Ret inhibits nerve growth factor (NGF)-mediated survival of sympathetic neurons. Removal of Ret disrupts NGF-mediated TrkA ubiquitination, leading to increased cell surface levels of TrkA, thereby potentiating survival signaling. Additionally, Ret deletion significantly impairs p75 regulated intramembrane proteolysis cleavage, leading to reduced activation of downstream apoptotic effectors. Collectively, these results indicate that Ret acts non-canonically to augment p75-mediated apoptosis. PMID- 30018093 TI - Cross-sectional analysis of ethnic differences in fall prevalence in urban dwellers aged 55 years and over in the Malaysian Elders Longitudinal Research study. AB - OBJECTIVES: Falls represent major health issues within the older population. In low/middle-income Asian countries, falls in older adults remain an area which has yet to be studied in detail. Using data from the Malaysian Elders Longitudinal Research (MELoR), we have estimated the prevalence of falls among older persons in an urban population, and performed ethnic comparisons in the prevalence of falls. DESIGN: Cross-sectional analysis was carried out using the first wave data from MELoR which is a longitudinal study. SETTING: Urban community dwellers in a middle-income South East Asian country. PARTICIPANTS: 1565 participants aged >=55 years were selected by simple random sampling from the electoral rolls of three parliamentary constituencies. OUTCOME MEASURES: Consenting participants from the MELoR study were asked the question 'Have you fallen down in the past 12 months?' during their computer-assisted home-based interviews. Logistic regression analyses were conducted to compare the prevalence of falls among various ethnic groups. RESULTS: The overall estimated prevalence of falls for individuals aged 55 years and over adjusted to the population of Kuala Lumpur was 18.9%. The estimated prevalence of falls for the three ethnic populations of Malays, Chinese and Indian aged 55 years and over was 16.2%, 19.4% and 23.8%, respectively. Following adjustment for ethnic discrepancies in age, gender, marital status and education attainment, the Indian ethnicity remained an independent predictor of falls in our population (relative risk=1.45, 95% CI 1.08 to 1.85). CONCLUSION: The prevalence of falls in this study is comparable to other previous Asian studies, but appears lower than Western studies. The predisposition of the Indian ethnic group to falls has not been previously reported. Further studies may be needed to elucidate the causes for the ethnic differences in fall prevalence. PMID- 30018094 TI - Short-term postoperative outcomes of colorectal cancer among patients with chronic liver disease: a national population-based study. AB - OBJECTIVE: Patients with colorectal carcinoma (CRC) with pre-existing chronic liver disease (CLD) had a significantly higher 30-day mortality after CRC surgery compared with healthy controls. This study investigated the factors associated with postoperative complications and in-hospital mortality in patients with CRC with coexisting CLD (excluding cirrhosis) who underwent colorectal surgery. DESIGN: A retrospective, observational, population-based study. SETTING: Data were sourced from the National Inpatient Sample database, a part of the Healthcare Cost and Utilisation Project. PARTICIPANTS: This study analysed 7463 inpatients with CRC who underwent colorectal surgery on admission between 2005 and 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint of this study was the prevalence of postoperative complications, and the secondary endpoint was in-hospital mortality. RESULTS: In the CLD group, 36.27% of patients had chronic hepatitis C, 28.36% had non-alcoholic fatty liver disease and 31.19% had other types of CLD. The median hospital stay was 7.0 (5.0-10.0) days in patients with no postoperative complications vs 17.0 (10.0-26.0) days, 8.0 (6.0 12.0) days, 8.0 (6.0-17.0) days, 9.0 (8.0-14.0) days and 10.5 (7.0-17.0) days for patients with postoperative infection, postoperative bleeding, cardiac arrest/heart failure, respiratory complications and digestive complications, respectively (all p<0.05). The presence of CLD was significantly associated with higher risk of postoperative bleeding (adjusted OR (aOR)=1.64, 95% CI 1.15 to 2.34, p=0.007). The presence of CLD (aOR=1.98, 95% CI 1.39 to 2.82, p<0.001) and length of hospital stay (aOR=1.06, 95% CI 1.04 to 1.08, p<0.001) were significantly associated with higher risk of in-hospital mortality. However, hyperlipidaemia was associated with a significantly lower risk of mortality (aOR=0.46, 95% CI 0.28 to 0.75, p=0.002). CONCLUSIONS: Postoperative complications prolonged the length of hospital stay. The presence of CLD and hyperlipidaemia were important factors impacting postoperative complications and in-hospital mortality in patients with CRC with underlying CLD. PMID- 30018095 TI - Short-term and long-term revision rates after lumbar spine discectomy versus laminectomy: a population-based cohort study. AB - BACKGROUND/OBJECTIVE: Degenerative diseases of the lumbar spine were managed with discectomy or laminectomy. This study aimed to compare these two surgical treatments in the postoperative revision rates. DESIGN: A population-based cohort study from analysis of a healthcare database. SETTING: Data were gathered from the Taiwan National Health Insurance Research Database (NHIRD). PARTICIPANTS: We enrolled 16 048 patients (4450 women and 11 598 men) with a mean age of 40.34 years who underwent lumbar discectomy or laminectomy for the first time between 1 January 1997 and 31 December 2007. All patients were followed up for 5 years or until death. RESULTS: Revision rate within 3 months of the index surgery was significantly higher in patients who underwent discectomy (2.75%) than in those who underwent laminectomy (1.18%; p<0.0001). This difference persisted over the first year following the index surgery (3.38% vs 2.57%). One year afterwards, the revision rates were similar between the discectomy (9.75%) and laminectomy (9.69%) groups. The final spinal fusion surgery rates were also similar between the groups (11.25% vs 12.08%). CONCLUSION: The revision rate after lumbar discectomy was higher than that after laminectomy within 1 year of the index surgery. However, differences were not identified between patient groups for the two procedures with respect to long-term revision rates and the proportion of patients who required final spinal fusion surgery. PMID- 30018096 TI - Could listening to music during pregnancy be protective against postnatal depression and poor wellbeing post birth? Longitudinal associations from a preliminary prospective cohort study. AB - OBJECTIVES: This study explored whether listening to music during pregnancy is longitudinally associated with lower symptoms of postnatal depression and higher well-being in mothers post birth. DESIGN: Prospective cohort study. PARTICIPANTS: We analysed data from 395 new mothers aged over 18 who provided data in the third trimester of pregnancy and 3 and 6 months later (0-3 and 4-6 months post birth). PRIMARY AND SECONDARY OUTCOME MEASURES: Postnatal depression was measured using the Edinburgh Postnatal Depression Scale, and well-being was measured using the Short Warwick-Edinburgh Mental Well-being Scale. Our exposure was listening to music and was categorised as 'rarely; a couple of times a week; every day <1 hour; every day 1-2 hours; every day 3-5 hours; every day 5+hrs'. Multivariable linear regression analyses were carried out to explore the effects of listening to music during pregnancy on depression and well-being post birth, adjusted for baseline mental health and potential confounding variables. RESULTS: Listening during pregnancy is associated with higher levels of well-being (beta=0.40, SE=0.15, 95% CI 0.10 to 0.70) and reduced symptoms of postnatal depression (beta= 0.39, SE=0.19, 95% CI -0.76 to -0.03) in the first 3 months post birth. However, effects disappear by 4-6 months post birth. These results appear to be particularly found among women with lower levels of well-being and high levels of depression at baseline. CONCLUSIONS: Listening to music could be recommended as a way of supporting mental health and well-being in pregnant women, in particular those who demonstrate low well-being or symptoms of postnatal depression. PMID- 30018097 TI - GP-OSMOTIC trial protocol: an individually randomised controlled trial to determine the effect of retrospective continuous glucose monitoring (r-CGM) on HbA1c in adults with type 2 diabetes in general practice. AB - INTRODUCTION: Optimal glycaemia can reduce type 2 diabetes (T2D) complications. Observing retrospective continuous glucose monitoring (r-CGM) patterns may prompt therapeutic changes but evidence for r-CGM use in T2D is limited. We describe the protocol for a randomised controlled trial (RCT) examining intermittent r-CGM use (up to 14 days every three months) in T2D in general practice (GP). METHODS AND ANALYSIS: General Practice Optimising Structured MOnitoring To achieve Improved Clinical Outcomes is a two-arm RCT asking 'does intermittent r-CGM in adults with T2D in primary care improve HbA1c?' PRIMARY OUTCOME: Absolute difference in mean HbA1c at 12 months follow-up between intervention and control arms. SECONDARY OUTCOMES: (a) r-CGM per cent time in target (4-10 mmol/L) range, at baseline and 12 months; (b) diabetes-specific distress (Problem Areas in Diabetes). ELIGIBILITY: Aged 18-80 years, T2D for >=1 year, a (past month) HbA1c>5.5 mmol/mol (0.5%) above their individualised target while prescribed at least two non-insulin hypoglycaemic therapies and/or insulin (therapy stable for the last four months). Our general glycaemic target is 53 mmol/mol (7%) (patients with a history of severe hypoglycaemia or a recorded diagnosis of hypoglycaemia unawareness will have a target of 64 mmol/mol (8%)).Our trial compares r-CGM use and usual care. The r-CGM report summarising daily glucose patterns will be reviewed by GP and patient and inform treatment decisions. Participants in both arms are provided with 1 hour education by a specialist diabetes nurse.The sample (n=150/arm) has 80% power to detect a mean HbA1c difference of 5.5 mmol/mol (0.5%) with an SD of 14.2 (1.3%) and alpha of 0.05 (allowing for 10% clinic and 20% patient attrition). ETHICS AND DISSEMINATION: University of Melbourne Human Ethics Sub-Committee (ID 1647151.1). Dissemination will be in peer-reviewed journals, conferences and a plain-language summary for participants. TRIAL REGISTRATION NUMBER: >ACTRN12616001372471; Pre-results. PMID- 30018098 TI - How to measure cultural competence when evaluating patient-centred care: a scoping review. AB - OBJECTIVES: The purpose of this study was to identify patient-centred quality indicators (PC-QI) and measures for measuring cultural competence in healthcare. DESIGN: Scoping review. SETTING: All care settings. SEARCH STRATEGY: A search of CINAHL, EMBASE, MEDLINE, PsycINFO, Social Work Abstracts and SocINDEX, and the grey literature was conducted to identify relevant studies. Studies were included if they reported indicators or measures for cultural competence. We differentiated PC-QIs from measures: PC-QIs were identified as a unit of measurement of the performance of the healthcare system, which reflects what matters to patients and families, and to any individual that is in contact with healthcare services. In contrast, measures evaluate delivery of patient-centred care, in the form of a survey and/or checklist. Data collected included publication year and type, country, ethnocultural groups and mention of quality indicator and/or measures for cultural competence. RESULTS: The search yielded a total of 786 abstracts and sources, of which 16 were included in the review. Twelve out of 16 sources reported measures for cultural competence, for a total of 10 measures. Identified domains from the measures included: physical environment, staff awareness of attitudes and values, diversity training and communication. Two out of 16 sources reported PC-QIs for cultural competence (92 structure and process indicators, and 48 outcome indicators). There was greater representation of structure and process indicators and measures for cultural competence, compared with outcome indicators. CONCLUSION: Monitoring and evaluating patient-centred care for ethnocultural communities allows for improvements to be made in the delivery of culturally competent healthcare. Future research should include development of PC-QIs for measuring cultural competence that also reflect cultural humility, and the involvement of ethnocultural communities in the development and implementation of these indicators. PMID- 30018099 TI - Sex differences in the 1-year risk of dying following all-cause and cause specific hospital admission after age 50 in comparison with a general and non hospitalised population: a register-based cohort study of the Danish population. AB - OBJECTIVES: We examine the mortality of men and women within the first year after all-cause and cause-specific hospital admission to investigate whether the sex differences in mortality after hospitalisation are higher than in the corresponding general and non-hospitalised population. DESIGN: This is a population-based, longitudinal study with nationwide coverage. The study population was identified by linking the National Patient Register with the Central Population Register using a 5% random sample of the Danish population. SETTING: The population born between 1898 and 1961, who was alive and residing in Denmark after 1977, was followed up between 1977 and 2011 with respect to hospital admissions and mortality while aged 50-79. PRIMARY OUTCOME MEASURES: The absolute sex differences in the 1-year risk of dying after all-cause and cause specific hospital admission. The hospitalised population sex differentials were then compared with the sex differences in a general and a non-hospitalised population, randomly matched by age, sex and hospitalisation status. RESULTS: The risk of dying was consistently higher for hospitalised men and women. At all ages, the absolute sex differences in mortality were largest in the hospitalised population, were smaller in the general population and were smallest in the non hospitalised population. This pattern was consistent across all-cause admissions, and with respect to admissions for neoplasms, circulatory diseases and respiratory diseases. For all-cause hospital admissions, absolute sex differences in the 1-year risk of dying resulted in 43.8 excess male deaths per 1,000 individuals within the age range 50-79, while the levels were lower in the general and the non-hospitalised population, at levels of 13.5 and 6.6, respectively. CONCLUSIONS: This study indicates a larger male disadvantage in mortality following hospitalisation, pointing towards an association between the health status of a population and the magnitude of the female advantage in mortality. PMID- 30018100 TI - Qualitative study of barriers to clinical trial retention in adults with recently diagnosed type 1 diabetes. AB - OBJECTIVES: Regular physical exercise may preserve beta cell function in newly diagnosed adults with type 1 diabetes (T1D). However, clinical trials to test this theory require the recruitment and retention of adults with new-onset T1D, which can be challenging. We sought to determine the overall experiences of newly diagnosed adults with T1D in an exercise study, to understand issues that influence the retention of trial participants in such studies. DESIGN: Qualitative methodology using individual face-to-face (n=6) and telephone interviews (n=14). Interview transcripts were thematically analysed using the framework method. SETTING: The study took place at five participating UK hospitals. PARTICIPANTS: Twenty participants, aged 19-55 years, in the Exercise for Type 1 Diabetes study were interviewed to explore their study experiences and identify motivators and deterrents towards the study. Participants in control and intervention arms were interviewed, as were people with T1D who had completed (n=16) and withdrawn (n=4). RESULTS: Participants revealed barriers and facilitators to retention; the majority were generalisable to clinical trials of people with newly diagnosed T1D. Coming to terms with a diagnosis of T1D, lack of time, work pressures, level of health professional support, volume, clarity and consistency of information and feedback and a desire for knowledge about their condition were all cited as influencing factors to trial retention. CONCLUSIONS: To our knowledge, this is the first qualitative study to examine the experience of being involved in an exercise trial by people with T1D. Findings suggest appointments could be shorter, available outside of working hours and planned longer in advance; study information should be clear, consistent and in electronic and paper formats; questionnaires need minimising; healthcare support and feedback needs providing regularly; thought is required around how to support non-exercising arm participants. These considerations may improve participant retention rates in new-onset T1D studies. PMID- 30018101 TI - Addressing multiple modifiable risks through structured community-based Learning Clubs to improve maternal and infant health and infant development in rural Vietnam: protocol for a parallel group cluster randomised controlled trial. AB - INTRODUCTION: Optimal early childhood development is an international priority. Risks during pregnancy and early childhood have lasting effects because growth is rapid. We will test whether a complex intervention addressing multiple modifiable risks: maternal nutrition, mental health, parenting capabilities, infant health and development and gender-based violence, is effective in reducing deficient cognitive development among children aged two in rural Vietnam. METHODS AND ANALYSIS: The Learning Clubs intervention is a structured programme combining perinatal stage-specific information, learning activities and social support. It comprises 20 modules, in 19 accessible, facilitated groups for women at a community centre and one home visit. Evidence-informed content is from interventions to address each risk tested in randomised controlled trials in other resource-constrained settings. Content has been translated and culturally adapted for Vietnam and acceptability and feasibility established in pilot testing.We will conduct a two-arm parallel-group cluster-randomised controlled trial, with the commune as clustering unit. An independent statistician will select 84/112 communes in Ha Nam Province and randomly assign 42 to the control arm providing usual care and 42 to the intervention arm. In total, 1008 pregnant women (12 per commune) from 84 clusters are needed to detect a difference in the primary outcome (Bayley Scales of Infant and Toddler Development Cognitive Score <1 SD below standardised norm for 2 years of age) of 15% in the control and 8% in the intervention arms, with 80% power, significance 0.05 and intracluster correlation coefficient 0.03. ETHICS AND DISSEMINATION: Monash University Human Research Ethics Committee (Certificate Number 20160683), Melbourne, Victoria, Australia and the Institutional Review Board of the Hanoi School of Public Health (Certificate Number 017-377IDD- YTCC), Hanoi, Vietnam have approved the trial. Results will be disseminated through a comprehensive multistranded dissemination strategy including peer-reviewed publications, national and international conference presentations, seminars and technical and lay language reports. TRIAL REGISTRATION NUMBER: ACTRN12617000442303; Pre-results. PMID- 30018103 TI - Metabolism of Anethole Dithiolethione by Rat and Human Liver Microsomes: Formation of Various Products Deriving from Its O-Demethylation and S-Oxidation. Involvement of Cytochromes P450 and Flavin Monooxygenases in These Pathways. AB - A study of the metabolism of anethole dithiolethione (ADT, 5-(p-methoxyphenyl)-3H 1,2-dithiole-3-thione) by rat and human liver microsomes showed the formation of the corresponding S-oxide and the S-oxide of desmethyl-ADT (dmADT, 5-(p hydroxyphenyl)-3H-1,2-dithiole-3-thione), and of p-methoxy-acetophenone (pMA) and p-hydroxy-acetophenone (pHA), in addition to the previously described metabolites, dmADT, anethole dithiolone (ADO, 5-(p-methoxyphenyl)-3H-1,2-dithiole 3-one) and its demethylated derivative dmADO [5-(p-hydroxyphenyl)-3H-1,2-dithiole 3-one]. The microsomal metabolism of ADO under identical conditions led to dmADO and to pMA and pHA. The metabolites of ADT derive from two competing oxidative pathways: an O-demethylation catalyzed by cytochromes P450 and an S-oxidation mainly catalyzed by flavin-dependent monooxygenases (FMO) and, to a minor extent, by CYP enzymes. The most active human CYP enzymes for ADT demethylation appeared to be CYP1A1, 1A2, 1B1, 2C9, 2C19, and 2E1. ADT S-oxidation is catalyzed by FMO 1 and 3, and to a minor extent by CYP enzymes such as CYP3A4. PMID- 30018104 TI - A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi. AB - Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages.IMPORTANCE Emerging multidrug resistance (MDR) in pathogenic filamentous fungi is a significant threat to human health and agricultural production. Understanding mechanisms of MDR is essential to combating fungal pathogens; however, there is still limited information on MDR mechanisms conferred by xenobiotic detoxification. Here, we report for the first time that overexpression of phase I drug-metabolizing monooxygenases (cytochrome P450s) and phase III ATP-binding cassette efflux transporters is regulated by a gain-of-function mutation in the fungus-specific transcription factor in the MDR strains of the filamentous plant-pathogenic fungus Sclerotinia homoeocarpa This study establishes a novel molecular mechanism of MDR through the xenobiotic detoxification pathway in filamentous fungi, which may facilitate the discovery of new antifungal drugs to control pathogenic fungi. PMID- 30018102 TI - Root stem cell niche organizer specification by molecular convergence of PLETHORA and SCARECROW transcription factor modules. AB - Continuous formation of somatic tissues in plants requires functional stem cell niches where undifferentiated cells are maintained. In Arabidopsis thaliana, PLETHORA (PLT) and SCARECROW (SCR) genes are outputs of apical-basal and radial patterning systems, and both are required for root stem cell specification and maintenance. The WUSCHEL-RELATED HOMEOBOX 5 (WOX5) gene is specifically expressed in and required for functions of a small group of root stem cell organizer cells, also called the quiescent center (QC). PLT and SCR are required for QC function, and their expression overlaps in the QC; however, how they specify the organizer has remained unknown. We show that PLT and SCR genetically and physically interact with plant-specific teosinte-branched cycloidea PCNA (TCP) transcription factors to specify the stem cell niche during embryogenesis and maintain organizer cells post-embryonically. PLT-TCP-SCR complexes converge on PLT-binding sites in the WOX5 promoter to induce expression. PMID- 30018105 TI - Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans. AB - Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts-/- mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans To better understand the immunological mechanisms underlying the enhanced resistance of Sts-/- mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts-/- mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts-/ marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts-/- BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts-/- cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis.IMPORTANCE Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recently, the Sts phosphatases were established as key regulators of the host antifungal immune response. In particular, genetic inactivation of Sts significantly enhanced survival of mice infected intravenously with Candida albicans The Sts-/-in vivo resistance phenotype is associated with reduced fungal burden and an absence of inflammatory lesions. To understand the underlying mechanisms, we studied phagocyte responses. Here, we demonstrate that Sts-/- phagocytes have heightened responsiveness to C. albicans challenge relative to wild-type cells. Our data indicate the Sts proteins negatively regulate phagocyte activation via regulating selective elements of the Dectin-1-Syk tyrosine kinase signaling axis. These results suggest that phagocytes lacking Sts respond to fungal challenge more effectively and that this enhanced responsiveness partially underlies the profound resistance of Sts-/- mice to systemic fungal challenge. PMID- 30018106 TI - A Proteolytic Complex Targets Multiple Cell Wall Hydrolases in Pseudomonas aeruginosa. AB - Carboxy-terminal processing proteases (CTPs) occur in all three domains of life. In bacteria, some of them have been associated with virulence. However, the precise roles of bacterial CTPs are poorly understood, and few direct proteolytic substrates have been identified. One bacterial CTP is the CtpA protease of Pseudomonas aeruginosa, which is required for type III secretion system (T3SS) function and for virulence in a mouse model of acute pneumonia. Here, we have investigated the function of CtpA in P. aeruginosa and identified some of the proteins it cleaves. We discovered that CtpA forms a complex with a previously uncharacterized protein, which we have named LbcA (lipoprotein binding partner of CtpA). LbcA is required for CtpA activity in vivo and promotes its activity in vitro We have also identified four proteolytic substrates of CtpA, all of which are uncharacterized proteins predicted to cleave the peptide cross-links within peptidoglycan. Consistent with this, a ctpA null mutant was found to have fewer peptidoglycan cross-links than the wild type and grew slowly in salt-free medium. Intriguingly, the accumulation of just one of the CtpA substrates was required for some DeltactpA mutant phenotypes, including the defective T3SS. We propose that LbcA-CtpA is a proteolytic complex in the P. aeruginosa cell envelope, which controls the activity of several peptidoglycan cross-link hydrolases by degrading them. Furthermore, based on these and other findings, we suggest that many bacterial CTPs might be similarly controlled by partner proteins as part of a widespread mechanism to control peptidoglycan hydrolase activity.IMPORTANCE Bacterial carboxy-terminal processing proteases (CTPs) are widely conserved and have been associated with the virulence of several species. However, their roles are poorly understood, and few direct substrates have been identified in any species. Pseudomonas aeruginosa is an important human pathogen in which one CTP, known as CtpA, is required for type III secretion system function and for virulence. This work provides an important advance by showing that CtpA works with a previously uncharacterized binding partner to degrade four substrates. These substrates are all predicted to hydrolyze peptidoglycan cross-links, suggesting that the CtpA complex is an important control mechanism for peptidoglycan hydrolysis. This is likely to emerge as a widespread mechanism used by diverse bacteria to control some of their peptidoglycan hydrolases. This is significant, given the links between CTPs and virulence in several pathogens and the importance of peptidoglycan remodeling to almost all bacterial cells. PMID- 30018107 TI - Moving Forward: Recent Developments for the Ferret Biomedical Research Model. AB - Since the initial report in 1911, the domestic ferret has become an invaluable biomedical research model. While widely recognized for its utility in influenza virus research, ferrets are used for a variety of infectious and noninfectious disease models due to the anatomical, metabolic, and physiological features they share with humans and their susceptibility to many human pathogens. However, there are limitations to the model that must be overcome for maximal utility for the scientific community. Here, we describe important recent advances that will accelerate biomedical research with this animal model. PMID- 30018108 TI - Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication. AB - Gammaherpesviruses are oncogenic pathogens that persist in ~95% of the adult population. Cellular metabolic pathways have emerged as important regulators of many viral infections, including infections by gammaherpesviruses that require several lipid synthetic pathways for optimal replication. Liver X receptors (LXRs) are transcription factors that are critical regulators of cellular fatty acid and cholesterol synthesis pathways. Not surprisingly, LXRs are attractive therapeutic targets in cardiovascular disease. Here we describe an antiviral role for LXRs in the context of gammaherpesvirus infection of primary macrophages. We show that type I interferon increased LXR expression following infection. Surprisingly, there was not a corresponding induction of LXR target genes. Rather, LXRs suppressed the expression of target genes, leading to decreased fatty acid and cholesterol synthesis, two metabolic pathways that support gammaherpesvirus replication. This report defines LXR-mediated restriction of cholesterol and lipid synthesis as an intrinsic metabolic mechanism to restrict viral replication in innate immune cells.IMPORTANCE Fatty acid and cholesterol synthesis pathways of the host play important roles in diverse biological systems. Importantly, these two metabolic pathways are also usurped by a number of viruses to facilitate viral replication. In this report, we show that suppression of these pathways by liver X receptors in primary macrophages creates an intrinsic antiviral state that attenuates gammaherpesvirus replication by limiting viral access to the two metabolic pathways. PMID- 30018109 TI - Staphylococcus aureus Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages. AB - Macrophages are critical to innate immunity due to their ability to phagocytose bacteria. The macrophage phagolysosome is a highly acidic organelle with potent antimicrobial properties, yet remarkably, ingested Staphylococcus aureus replicates within this niche. Herein we demonstrate that S. aureus requires the GraXRS regulatory system for growth within this niche, while the SaeRS and AgrAC two-component regulatory systems and the alpha-phenol soluble modulins are dispensable. Importantly, we find that it is exposure to acidic pH that is required for optimal growth of S. aureus inside fully acidified macrophage phagolysosomes. Exposure of S. aureus to acidic pH evokes GraS signaling, which in turn elicits an adaptive response that endows the bacteria with increased resistance to antimicrobial effectors, such as antimicrobial peptides, encountered inside macrophage phagolysosomes. Notably, pH-dependent induction of antimicrobial peptide resistance in S. aureus requires the GraS sensor kinase. GraS and MprF, a member of the GraS regulon, play an important role for bacterial survival in the acute stages of systemic infection, where in murine models of infection, S. aureus resides within liver-resident Kupffer cells. We conclude that GraXRS represents a vital regulatory system that functions to allow S. aureus to evade killing, prior to commencement of replication, within host antibacterial immune cells.IMPORTANCES. aureus can infect any site of the body, including the microbicidal phagolysosome of the macrophage. The ability of S. aureus to infect diverse niches necessitates that the bacteria be highly adaptable. Here we show that S. aureus responds to phagolysosome acidification to evoke changes in gene expression that enable the bacteria to resist phagolysosomal killing and to promote replication. Toxin production is dispensable for this response; however, the bacteria require the sensor kinase GraS, which transduces signals in response to acidic pH. GraS is necessary for phagolysosomal replication and survival of S. aureus in the acute stage of systemic infection. Disruption of this S. aureus adaptation would render S. aureus susceptible to phagocyte restriction. PMID- 30018110 TI - Need for Laboratory Ecosystems To Unravel the Structures and Functions of Soil Microbial Communities Mediated by Chemistry. AB - The chemistry underpinning microbial interactions provides an integrative framework for linking the activities of individual microbes, microbial communities, plants, and their environments. Currently, we know very little about the functions of genes and metabolites within these communities because genome annotations and functions are derived from the minority of microbes that have been propagated in the laboratory. Yet the diversity, complexity, inaccessibility, and irreproducibility of native microbial consortia limit our ability to interpret chemical signaling and map metabolic networks. In this perspective, we contend that standardized laboratory ecosystems are needed to dissect the chemistry of soil microbiomes. We argue that dissemination and application of standardized laboratory ecosystems will be transformative for the field, much like how model organisms have played critical roles in advancing biochemistry and molecular and cellular biology. Community consensus on fabricated ecosystems ("EcoFABs") along with protocols and data standards will integrate efforts and enable rapid improvements in our understanding of the biochemical ecology of microbial communities. PMID- 30018111 TI - Temporal Viral Genome-Protein Interactions Define Distinct Stages of Productive Herpesviral Infection. AB - Herpesviruses utilize multiple mechanisms to redirect host proteins for use in viral processes and to avoid recognition and repression by the host. To investigate dynamic interactions between herpes simplex virus type 1 (HSV-1) DNA and viral and host proteins throughout infection, we developed an approach to identify proteins that associate with the infecting viral genome from nuclear entry through packaging. To accomplish this, virus stocks were prepared in the presence of ethynyl-modified nucleotides to enable covalent tagging of viral genomes after infection for analysis of viral genome-protein interactions by imaging or affinity purification. Affinity purification was combined with stable isotope labeling of amino acids in cell culture (SILAC) mass spectrometry to enable the distinction between proteins that were brought into the cell by the virus or expressed within the infected cell before or during infection. We found that input viral DNA progressed within 6 h through four temporal stages where the genomes sequentially (i) interacted with intrinsic antiviral and DNA damage response proteins, (ii) underwent a robust transcriptional switch mediated largely by ICP4, (iii) engaged in replication, repair, and continued transcription, and then (iv) transitioned to a more transcriptionally inert state engaging de novo-synthesized viral structural components while maintaining interactions with replication proteins. Using a combination of genetic, imaging, and proteomic approaches, we provide a new and temporally compressed view of the HSV-1 life cycle based on input genome-proteome dynamics.IMPORTANCE Herpesviruses are highly prevalent and ubiquitous human pathogens. Studies of herpesviruses and other viruses have previously been limited by the ability to directly study events that occur on the viral DNA throughout infection. We present a new powerful approach, which allows for the temporal investigation of viral genome protein interactions at all phases of infection. This work has integrated many results from previous studies with the discovery of novel factors potentially involved in viral infection that may represent new antiviral targets. In addition, the study provides a new view of the HSV-1 life cycle based on genome proteome dynamics. PMID- 30018112 TI - The Main Role of Srs2 in DNA Repair Depends on Its Helicase Activity, Rather than on Its Interactions with PCNA or Rad51. AB - Homologous recombination (HR) is a mechanism that repairs a variety of DNA lesions. Under certain circumstances, however, HR can generate intermediates that can interfere with other cellular processes such as DNA transcription or replication. Cells have therefore developed pathways that abolish undesirable HR intermediates. The Saccharomyces cerevisiae yeast Srs2 helicase has a major role in one of these pathways. Srs2 also works during DNA replication and interacts with the clamp PCNA. The relative importance of Srs2's helicase activity, Rad51 removal function, and PCNA interaction in genome stability remains unclear. We created a new SRS2 allele [srs2(1-850)] that lacks the whole C terminus, containing the interaction site for Rad51 and PCNA and interactions with many other proteins. Thus, the new allele encodes an Srs2 protein bearing only the activity of the DNA helicase. We find that the interactions of Srs2 with Rad51 and PCNA are dispensable for the main role of Srs2 in the repair of DNA damage in vegetative cells and for proper completion of meiosis. On the other hand, it has been shown that in cells impaired for the DNA damage tolerance (DDT) pathways, Srs2 generates toxic intermediates that lead to DNA damage sensitivity; we show that this negative Srs2 activity requires the C terminus of Srs2. Dissection of the genetic interactions of the srs2(1-850) allele suggest a role for Srs2's helicase activity in sister chromatid cohesion. Our results also indicate that Srs2's function becomes more central in diploid cells.IMPORTANCE Homologous recombination (HR) is a key mechanism that repairs damaged DNA. However, this process has to be tightly regulated; failure to regulate it can lead to genome instability. The Srs2 helicase is considered a regulator of HR; it was shown to be able to evict the recombinase Rad51 from DNA. Cells lacking Srs2 exhibit sensitivity to DNA-damaging agents, and in some cases, they display defects in DNA replication. The relative roles of the helicase and Rad51 removal activities of Srs2 in genome stability remain unclear. To address this question, we created a new Srs2 mutant which has only the DNA helicase domain. Our study shows that only the DNA helicase domain is needed to deal with DNA damage and assist in DNA replication during vegetative growth and in meiosis. Thus, our findings shift the view on the role of Srs2 in the maintenance of genome integrity. PMID- 30018113 TI - Structure-Function Analysis of the Curli Accessory Protein CsgE Defines Surfaces Essential for Coordinating Amyloid Fiber Formation. AB - Curli amyloid fibers are produced as part of the extracellular biofilm matrix and are composed primarily of the major structural subunit CsgA. The CsgE chaperone facilitates the secretion of CsgA through CsgG by forming a cap at the base of the nonameric CsgG outer membrane pore. We elucidated a series of finely tuned nonpolar and charge-charge interactions that facilitate the oligomerization of CsgE and its ability to transport unfolded CsgA to CsgG for translocation. CsgE oligomerization in vitro is temperature dependent and is disrupted by mutations in the W48 and F79 residues. Using nuclear magnetic resonance (NMR), we identified two regions of CsgE involved in the CsgE-CsgA interaction: a head comprising a positively charged patch centered around R47 and a stem comprising a negatively charged patch containing E31 and E85. Negatively charged residues in the intrinsically disordered N- and C-terminal "tails" were not implicated in this interaction. Head and stem residues were mutated and interrogated using in vivo measurements of curli production and in vitro amyloid polymerization assays. The R47 head residue of CsgE is required for stabilization of CsgA- and CsgE mediated curli fiber formation. Mutation of the E31 and E85 stem residues to positively charged side chains decreased CsgE-mediated curli fiber formation but increased CsgE-mediated stabilization of CsgA. No single-amino-acid substitutions in the head, stem, or tail regions affected the ability of CsgE to cap the CsgG pore as determined by a bile salt sensitivity assay. These mechanistic insights into the directed assembly of functional amyloids in extracellular biofilms elucidate possible targets for biofilm-associated bacterial infections.IMPORTANCE Curli represent a class of functional amyloid fibers produced by Escherichia coli and other Gram-negative bacteria that serve as protein scaffolds in the extracellular biofilm matrix. Despite the lack of sequence conservation among different amyloidogenic proteins, the structural and biophysical properties of functional amyloids such as curli closely resemble those of amyloids associated with several common neurodegenerative diseases. These parallels are underscored by the observation that certain proteins and chemicals can prevent amyloid formation by the major curli subunit CsgA and by alpha-synuclein, the amyloid forming protein found in Lewy bodies during Parkinson's disease. CsgA subunits are targeted to the CsgG outer membrane pore by CsgE prior to secretion and assembly into fibers. Here, we use biophysical, biochemical, and genetic approaches to elucidate a mechanistic understanding of CsgE function in curli biogenesis. PMID- 30018114 TI - Information management goals and process failures during home visits for middle aged and older adults receiving skilled home healthcare services after hospital discharge: a multisite, qualitative study. AB - BACKGROUND: Middle-aged and older adults requiring skilled home healthcare ('home health') services following hospital discharge are at high risk of experiencing suboptimal outcomes. Information management (IM) needed to organise and communicate care plans is critical to ensure safety. Little is known about IM during this transition. OBJECTIVES: (1) Describe the current IM process (activity goals, subactivities, information required, information sources/targets and modes of communication) from home health providers' perspectives and (2) Identify IM related process failures. METHODS: Multisite qualitative study. We performed semistructured interviews and direct observations with 33 home health administrative staff, 46 home health providers, 60 middle-aged and older adults, and 40 informal caregivers during the preadmission process and initial home visit. Data were analysed to generate themes and information flow diagrams. RESULTS: We identified four IM goals during the preadmission process: prepare referral document and inform agency; verify insurance; contact adult and review case to schedule visit. We identified four IM goals during the initial home visit: assess appropriateness and obtain consent; manage expectations; ensure safety and develop contingency plans. We identified IM-related process failures associated with each goal: home health providers and adults with too much information (information overload); home health providers without complete information (information underload); home health coordinators needing information from many places (information scatter); adults' and informal caregivers' mismatched expectations regarding home health services (information conflict) and home health providers encountering inaccurate information (erroneous information). CONCLUSIONS: IM for hospital-to-home health transitions is complex, yet key for patient safety. Organisational infrastructure is needed to support IM. Future clinical workflows and health information technology should be designed to mitigate IM-related process failures to facilitate safer hospital-to home health transitions. PMID- 30018115 TI - Transforming concepts in patient safety: a progress report. AB - In 2009, the National Patient Safety Foundation's Lucian Leape Institute (LLI) published a paper identifying five areas of healthcare that require system-level attention and action to advance patient safety.The authors argued that to truly transform the safety of healthcare, there was a need to address medical education reform; care integration; restoring joy and meaning in work and ensuring the safety of the healthcare workforce; consumer engagement in healthcare and transparency across the continuum of care. In the ensuing years, the LLI convened a series of expert roundtables to address each concept, look at obstacles to implementation, assess potential for improvement, identify potential implementation partners and issue recommendations for action. Reports of these activities were published between 2010 and 2015. While all five areas have seen encouraging developments, multiple challenges remain. In this paper, the current members of the LLI (now based at the Institute for Healthcare Improvement) assess progress made in the USA since 2009 and identify ongoing challenges. PMID- 30018117 TI - Cachectic Cancer Patients: Immune to Checkpoint Inhibitor Therapy? AB - Immune checkpoint inhibition is dramatically improving patient outcomes in diverse cancers, many of which responded poorly to traditional cytotoxic agents. Drivers of heterogeneous response to immune checkpoint therapy are poorly characterized. Cachectic cancer patients exhibit elevated pembrolizumab clearance and poor response, highlighting the immense therapeutic challenge posed by cancer cachexia.See related article by Turner et al., p. 5841. PMID- 30018116 TI - Protective Effect of a Locked Retinal Chromophore Analog against Light-Induced Retinal Degeneration. AB - Continuous regeneration of the 11-cis-retinal visual chromophore from all-trans retinal is critical for vision. Insufficiency of 11-cis-retinal arising from the dysfunction of key proteins involved in its regeneration can impair retinal health, ultimately leading to loss of human sight. Delayed recovery of visual sensitivity and night blindness caused by inadequate regeneration of the visual pigment rhodopsin are typical early signs of this condition. Excessive concentrations of unliganded, constitutively active opsin and increased levels of all-trans-retinal and its byproducts in photoreceptors also accelerate retinal degeneration after light exposure. Exogenous 9-cis-retinal iso-chromophore can reduce the toxicity of ligand-free opsin but fails to prevent the buildup of retinoid photoproducts when their clearance is defective in human retinopathies, such as Stargardt disease or age-related macular degeneration. Here we evaluated the effect of a locked chromophore analog, 11-cis-6-membered ring-retinal against bright light-induced retinal degeneration in Abca4-/-Rdh8-/- mice. Using in vivo imaging techniques, optical coherence tomography, scanning laser ophthalmoscopy, and two-photon microscopy, along with in vitro histologic analysis of retinal morphology, we found that treatment with 11-cis-6-membered ring-retinal before light stimulation prevented rod and cone photoreceptor degradation and preserved functional acuity in these mice. Moreover, additive accumulation of 11-cis-6 membered ring-retinal measured in the eyes of these mice by quantitative liquid chromatography-mass spectrometry indicated stable binding of this retinoid to opsin. Together, these results suggest that eliminating excess of unliganded opsin can prevent light-induced retinal degeneration in Abca4-/-Rdh8-/- mice. PMID- 30018118 TI - Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non-small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, >=20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D-binding protein (DBP) and survival were also examined.Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089-97. (c)2018 AACR. PMID- 30018119 TI - Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers. AB - Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice.Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection.Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFalpha levels correlated positively with SD at week 8 (P < 0.01).Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845-56. (c)2018 AACR. PMID- 30018120 TI - Sixty seconds on . . . probiotics. PMID- 30018122 TI - Checking our blind spots: current status of research evidence summaries in ME/CFS. PMID- 30018121 TI - Factors associated with additional anterior cruciate ligament reconstruction and register comparison: a systematic review on the Scandinavian knee ligament registers. AB - OBJECTIVE: To present an overview of the Scandinavian knee ligament registers with regard to factors associated with additional ACL reconstruction, and studies comparing the Scandinavian registers with other knee ligament registers. DESIGN: Systematic review. DATA SOURCES: Four electronic databases: PubMed, EMBASE, the Cochrane Library and AMED were searched, and 157 studies were identified. Two reviewers independently screened titles, abstracts and full-text studies for eligibility. A modified version of the Downs and Black checklist was applied for quality appraisal. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible studies were those published since the establishment of the Scandinavian registers in 2004, which reported factors associated with additional ACL reconstruction and compared data from other registers. RESULTS: Thirty-one studies met the inclusion criteria and generally displayed good reporting quality. Adolescent age (<20 years) was the most common factor associated with additional ACL reconstruction. The choice of hamstring tendon graft compared with patella tendon, transportal femoral tunnel drilling, smaller graft diameter and utilisation of suspensory fixation devices were associated with additional ACL reconstruction. Concomitant cartilage injury decreased the likelihood of additional ACL reconstruction. Patient sex alone did not influence the likelihood. The demographics of patients undergoing ACL reconstruction in the Scandinavian registers are comparable to registers in other geographical settings. However, there are differences in surgical factors including the presence of intra-articular pathology and graft choice. SUMMARY: The studies published from the Scandinavian registers in general have a high reporting quality when regarded as cohort studies. Several factors are associated with undergoing additional ACL reconstruction. The results from the registers may help facilitate treatment decisions. PMID- 30018123 TI - Evaluating the Feasibility of Incorporating In-Person Interpreters on Family Centered Rounds: A QI Initiative. AB - OBJECTIVES: No best practice has been defined for incorporating in-person interpreters into family-centered rounds (FCRs) for patients with limited English proficiency (LEP). We hypothesized that addressing barriers to scheduling in person interpreters would make FCR encounters more likely, and thus ensure more equitable care for LEP patients. METHODS: A quality improvement initiative was conducted from October 2014 to March 2016 to arrange in-person interpreters for LEP patients during FCRs on the inpatient pediatric service of a large, urban, tertiary care center in Boston. Main interventions included establishing a protocol for scheduling interpreters for rounds and the implementation of a form to track process adherence. Our primary outcome was the percentage of FCR encounters with LEP patients with an interpreter present. Our balancing measures were patient satisfaction, which was assessed using validated surveys administered weekly by nonphysician team members through convenience sampling of families present on the wards, and rounds duration. RESULTS: There were 614 encounters with LEP patients during the intervention, 367 of which included in person interpreters. The percentage of encounters with LEP patients involving interpreters increased from 0% to 63%. Form completion, our primary process measure, reached 87% in the most recent phase. English-proficient and LEP patients reported similar satisfaction with their rounding experience amid a modest increase in rounds duration (preintervention, 105 minutes; postintervention, 130 minutes; P = .056). CONCLUSIONS: Using quality improvement as a framework to address key barriers, we successfully implemented a process that increased the participation of in-person interpreters on FCRs on a busy pediatric service. PMID- 30018124 TI - Alan Bennett brings life into geriatric ward. PMID- 30018125 TI - Surgeon who failed to tell patient of error is struck off. PMID- 30018126 TI - Core Concept: Amazingly precise optical atomic clocks are more than timekeepers. PMID- 30018128 TI - Sleep quality with WHO Step III opioid use for cancer pain. AB - OBJECTIVE: Sleep is often disturbed in patients with advanced cancer. There is limited knowledge about sleep in patients with cancer treated with strong opioids. This study examines sleep quality in patients with advanced cancer who are treated with a WHO Step III opioid for pain. METHODS: An international, multicentre, cross-sectional study with 604 adult patients with cancer pain using WHO Step III opioids. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) global score (range; 0-21; score >5 indicates poor sleep). PSQI includes sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications and daytime dysfunction. Pain and quality of life were assessed by Brief Pain Inventory and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core30. RESULTS: The median age was 62 years, 42% were female, mean Karnofsky performance score (KPS) was 62.5 (+/-14.2) and mean oral daily morphine equivalent dose was 303 mg/24 hours (+/-543.8 mg). The mean PSQI global score was 8.8 (+/-4.2) (range 0 20). Seventy-eight per cent were poor sleepers. All PSQI components were affected, and 44% reported trouble sleeping caused by pain. In the multiple regression model, predictors of PSQI global scores were pain intensity, emotional function, constipation, financial difficulties and KPS (adjusted R2=0.21). CONCLUSION: The majority (78%) of these patients with cancer treated with Step III opioids experienced poor sleep quality. Pain intensity, emotional function, constipation, financial difficulties and KPS predicted poor PSQI global scores. The clinical implication is that healthcare personnel should routinely assess and treat sleep disturbance in patients with advanced cancer disease. PMID- 30018129 TI - FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia. AB - On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-of-care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single-arm trial of blinatumomab in patients with Ph-positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph-negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph-positive and Ph-negative precursor B-cell R/R ALL. IMPLICATIONS FOR PRACTICE: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7 month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single-arm trial of blinatumomab for treatment of relapsed or refractory Ph-positive precursor B-cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B-cell ALL that is Ph positive or Ph negative. PMID- 30018130 TI - Machine Learning for Better Prognostic Stratification and Driver Gene Identification Using Somatic Copy Number Variations in Anaplastic Oligodendroglioma. AB - BACKGROUND: 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. MATERIALS AND METHODS: A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. RESULTS: Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. CONCLUSION: Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. IMPLICATIONS FOR PRACTICE: Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction. PMID- 30018132 TI - A Case of Nivolumab-Induced Bullous Pemphigoid: Review of Dermatologic Toxicity Associated with Programmed Cell Death Protein-1/Programmed Death Ligand-1 Inhibitors and Recommendations for Diagnosis and Management. AB - : Immunotherapy has emerged as a highly effective treatment for numerous cancers. Use of checkpoint inhibitors against various molecules including programmed cell death protein-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated protein-4 have become widespread in clinical practice. Compared with conventional chemotherapy, immunotherapy is associated with a unique set of immune reactions known collectively as immune-related adverse events (irAEs). Of known irAEs, cutaneous toxicity is among the most frequently observed in patients treated with immunotherapy. Although often mild, dermatologic toxicity can occasionally be high grade and potentially life threatening. In this article, we report a case of PD-1 inhibitor-induced bullous pemphigoid-a serious adverse event that has been increasingly observed with use of PD-1/PD-L1 inhibitors. We will also review diagnosis and management of low grade cutaneous irAEs and bullous disease with checkpoint inhibitors. KEY POINTS: PD-1/PD-L1 inhibitor-induced bullous pemphigoid (BP) is a rare but potentially serious dermatologic toxicity associated with checkpoint inhibitorsIn patients with pruritus or rash that is refractory to topical steroids, physicians should have a greater index of suspicion for higher-grade cutaneous immune-related adverse events.There is no standardized treatment algorithm for management of PD 1/PD-L1 inhibitor-induced BP, but patients frequently require topical and systemic steroids. PMID- 30018131 TI - Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors. AB - BACKGROUND: The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (<=45 years) and older patients (>=65). SUBJECTS, MATERIALS, AND METHODS: In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next-generation sequencing (NGS), immunohistochemistry, and in situ hybridization. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed by NGS. RESULTS: Younger patients (n = 350), when compared with older patients (n = 776), showed higher mutation rates in genes associated with cancer-predisposing syndromes (e.g., Lynch syndrome), such as MSH6 (4.8% vs. 1.2%, p = .005), MSH2 (2.7% vs. 0.0%, p = .004), POLE (1.6% vs. 0.0%, p = .008), NF1 (5.9% vs. 0.5%, p < .001), SMAD4 (14.3% vs. 8.3%, p = .024), and BRCA2 (3.7% vs. 0.5%, p = .002). Genes involved in histone modification were also significantly more mutated: KDM5C (1.9% vs. 0%, p = .036), KMT2A (1.1% vs. 0%, p = .033), KMT2C (1.6% vs. 0%, p = .031), KMT2D (3.8% vs. 0.7%, p = .005), and SETD2 (3.2% vs. 0.9%, p = .039). Finally, TMB-high (9.7% vs. 2.8%, p < .001) and MSI-high (MSI-H; 8.1% vs. 1.9%, p = .009) were more frequent in younger patients. CONCLUSION: Our findings highlight the importance of genetic counseling and screening in younger CRC patients. MSI-H and TMB-high tumors could benefit from immune-checkpoint inhibitors, now approved for the treatment of MSI H/deficient mismatch repair metastatic CRC patients. Finally, histone modifiers could serve as a new promising therapeutic target. With confirmatory studies, these results may influence our approach to younger adults with CRC. IMPLICATIONS FOR PRACTICE: The increasing rate of colorectal cancers (CRC), primarily distal tumors, among young adults poses a global health issue. This study investigates the molecular differences between younger (<=45 years old) and older (>=65) adults with left-sided CRCs. Younger patients more frequently harbor mutations in genes associated with cancer-predisposing syndromes. Higher rates of microsatellite instability-high and tumor mutational burden-high tumors occur in younger patients, who could benefit from immune-checkpoint inhibitors. Finally, histone modifiers are more frequently mutated in younger patients and could serve as a new promising therapeutic target. This study provides new insights into mutations that may guide development of novel tailored therapy in younger CRC patients. PMID- 30018133 TI - Selection of Protein Kinase Inhibitors Based on Tumor Tissue Kinase Activity Profiles in Patients with Refractory Solid Malignancies: An Interventional Molecular Profiling Study. AB - LESSONS LEARNED: Clinically applicable tools are needed for treatment selection and repurposing of available protein kinase inhibitors (PKIs) in patients with advanced solid tumors refractory to standard treatment.Using a tyrosine kinase peptide substrate microarray, observed inhibitory activity in vitro could not sufficiently predict clinical benefit of treatment with the selected PKI. BACKGROUND: This exploratory molecular profiling study determined the feasibility and benefit of the selection of protein kinase inhibitors (PKIs) based on kinase activity profiling in patients with refractory solid malignancies. METHODS: Adult patients with biopsy-accessible refractory solid tumors were eligible. Per patient, the inhibitory potency of sunitinib, dasatinib, erlotinib, sorafenib, everolimus, and lapatinib was determined in tumor lysates from fresh biopsies using a tyrosine kinase peptide substrate microarray. The most active PKI in this in vitro assay was selected for treatment. RESULTS: Thirteen patients were enrolled in the feasibility part and underwent tumor biopsy. Of 12 patients in whom kinase activity profiling was performed, 11 started treatment with a selected PKI: dasatinib in 8, sunitinib in 2, and erlotinib in 1 patient(s). Eight patients were evaluable for response. One patient had stable disease (SD) >4 months on sunitinib; one patient had SD at 6 weeks but progressive disease (PD) at 12 weeks. The remaining patients had PD after 6 weeks of treatment. CONCLUSION: Kinase inhibition profiles of multiple PKIs can be reliably determined using fresh tumor biopsies from patients with refractory solid tumors. However, the current in vitro microarray selection approach insufficiently predicted clinical benefit of PKI treatment in these patients. PMID- 30018134 TI - Adjuvant Subcutaneous Trastuzumab for HER2-Positive Early Breast Cancer: Subgroup Analyses of Safety and Active Medical Conditions by Body Weight in the SafeHer Phase III Study. AB - BACKGROUND: This SafeHer subgroup analysis assessed the safety of fixed-dose subcutaneous trastuzumab (H SC) as an adjuvant therapy in HER2-positive early breast cancer (EBC) by body weight. PATIENTS AND METHODS: Patients with HER2 positive EBC not previously treated with anti-HER2 therapy received H SC 600 mg (every 3 weeks for 18 cycles), with neoadjuvant or adjuvant chemotherapy or without adjuvant chemotherapy. Adverse events (AEs) were assessed throughout treatment and at final follow-up (28 +/-5 days after last treatment). Subgroups were categorized by body weight, Asian origin, and chemotherapy administration. All analyses were descriptive. RESULTS: Of 2,577 patients enrolled, 2,573 received >=1 dose of study medication and were included in this safety analysis. Median body weight at baseline was 67.0 kg (range 33.6-150.0 kg). Any-grade AEs occurred in 88.7% (2,282/2,573) of the overall population, versus 87.1% (590/677) of the lowest bodyweight quartile (<=59 kg), 90.0% (561/623) of the highest quartile (>77 kg), and 86.5% (327/378) of the Asian population. Grade >=3 AEs occurred in 23.2% (596/2,573) of the overall population, 17.9% (121/677) of the lowest bodyweight quartile, 26.8% (167/623) of the highest quartile, and 15.3% (58/378) of the Asian population. The highest bodyweight quartile had the highest incidence of medical conditions at baseline (highest quartile, 75.6%; lowest quartile, 56.1%). CONCLUSION: These data support the use of fixed-dose H SC as an adjuvant therapy in HER2-positive EBC and confirm the comparable safety profile of H SC in patients with low body weight or of Asian origin versus the overall population in SafeHer. ClinicalTrials.gov: NCT01566721. IMPLICATIONS FOR PRACTICE: The safety profile of fixed-dose subcutaneous trastuzumab (H SC) was comparable between patients in the lowest bodyweight subgroup and the overall patient population, and also between patients of Asian origin (of whom a higher proportion often fall within the lower bodyweight quartiles) and the overall population. The safety data from this SafeHer subgroup analysis therefore support the use of fixed-dose H SC 600 mg administered every 3 weeks as an adjuvant therapy for patients with HER2-positive early breast cancer across different bodyweight subgroups and in the Asian patient population. PMID- 30018135 TI - VAMP-associated protein-A and oxysterol-binding protein-related protein 3 promote the entry of late endosomes into the nucleoplasmic reticulum. AB - The endocytic pathway plays an instrumental role in recycling internalized molecules back to the plasma membrane or in directing them to lysosomes for degradation. We recently reported a new role of endosomes-the delivery of components from extracellular vesicles (EVs) to the nucleoplasm of recipient cells. Using indirect immunofluorescence, FRET, immunoisolation techniques, and RNAi, we report here a tripartite protein complex (referred to as the VOR complex) that is essential for the nuclear transfer of EV-derived components by orchestrating the specific localization of late endosomes into nucleoplasmic reticulum. We found that the VOR complex contains the endoplasmic reticulum localized vesicle-associated membrane protein (VAMP)-associated protein A (VAP A), the cytoplasmic oxysterol-binding protein-related protein 3 (ORP3), and late endosome-associated small GTPase Rab7. The silencing of VAP-A or ORP3 abrogated the association of Rab7-positive late endosomes with nuclear envelope invaginations and, hence, the transport of endocytosed EV-derived components to the nucleoplasm of recipient cells. We conclude that the VOR complex can be targeted to inhibit EV-mediated intercellular communication, which can have therapeutic potential for managing cancer in which the release of EVs is dysregulated. PMID- 30018136 TI - Activation of Smoothened in the Hedgehog pathway unexpectedly increases Galphas dependent cAMP levels in Drosophila. AB - Hedgehog (Hh) signaling plays a key role in the development and maintenance of animal tissues. This signaling is mediated by the atypical G protein-coupled receptor (GPCR) Smoothened (Smo). Smo activation leads to signaling through several well-characterized effectors to activate Hh target gene expression. Recent studies have implicated activation of the heterotrimeric G protein subunit Galphai and the subsequent decrease in cellular cAMP levels in promoting the Hh response in flies and mammals. Although Hh stimulation decreases cAMP levels in some insect cell lines, here using a bioluminescence resonance energy transfer (BRET)-based assay we found that this stimulation had no detectable effect in Drosophila S2-R+ cells. However, we observed an unexpected and significant Galphas-dependent increase in cAMP levels in response to strong Smo activation in Smo-transfected cells. This effect was mediated by Smo's broadly conserved core, and was specifically activated in response to phosphorylation of the Smo C terminus by GPCR kinase 2 (Gprk2). Genetic analysis of heterotrimeric G protein function in the developing Drosophila wing revealed a positive role for cAMP in the endogenous Hh response. Specifically, we found that mutation or depletion of Galphas diminished low-threshold Hh responses in Drosophila, whereas depletion of Galphai potentiated them (in contrast to previous findings). Our analysis suggested that regulated cAMP production is important for controlling the sensitivity of cellular responses to Hh in Drosophila. PMID- 30018137 TI - Amyloid-beta fibrils assembled on ganglioside-enriched membranes contain both parallel beta-sheets and turns. AB - Some protein and peptide aggregates, such as those of amyloid-beta protein (Abeta), are neurotoxic and have been implicated in several neurodegenerative diseases. Abeta accumulates at nanoclusters enriched in neuronal lipids called gangliosides in the presynaptic neuronal membrane, and the resulting oligomeric and/or fibrous forms accelerate the development of Alzheimer's disease. Although the presence of Abeta deposits at such nanoclusters is known, the mechanism of their assembly and the relationship between Abeta secondary structure and topography are still unclear. Here, we first confirmed by atomic force microscopy that Abeta40 fibrils can be obtained by incubating seed-free Abeta40 monomers with a membrane composed of sphingomyelin, cholesterol, and the ganglioside GM1. Using Fourier transform infrared (FTIR) reflection-absorption spectroscopy, we then found that these lipid-associated fibrils contained parallel beta-sheets, whereas self-assembled Abeta40 molecules formed antiparallel beta-sheets. We also found that the fibrils obtained at GM1-rich nanoclusters were generated from turn Abeta40 Our findings indicate that Abeta generally self-assembles into antiparallel beta-structures but can also form protofibrils with parallel beta sheets by interacting with ganglioside-bound Abeta. We concluded that by promoting the formation of parallel beta-sheets, highly ganglioside-enriched nanoclusters help accelerate the elongation of Abeta fibrils. These results advance our understanding of ganglioside-induced Abeta fibril formation in neuronal membranes and may help inform the development of additional therapies for Alzheimer's disease. PMID- 30018138 TI - Plasminogen activation triggers transthyretin amyloidogenesis in vitro. AB - Systemic amyloidosis is a usually fatal disease caused by extracellular accumulation of abnormal protein fibers, amyloid fibrils, derived by misfolding and aggregation of soluble globular plasma protein precursors. Both WT and genetic variants of the normal plasma protein transthyretin (TTR) form amyloid, but neither the misfolding leading to fibrillogenesis nor the anatomical localization of TTR amyloid deposition are understood. We have previously shown that, under physiological conditions, trypsin cleaves human TTR in a mechano enzymatic mechanism that generates abundant amyloid fibrils in vitro In sharp contrast, the widely used in vitro model of denaturation and aggregation of TTR by prolonged exposure to pH 4.0 yields almost no clearly defined amyloid fibrils. However, the exclusive duodenal location of trypsin means that this enzyme cannot contribute to systemic extracellular TTR amyloid deposition in vivo Here, we therefore conducted a bioinformatics search for systemically active tryptic proteases with appropriate tissue distribution, which unexpectedly identified plasmin as the leading candidate. We confirmed that plasmin, just as trypsin, selectively cleaves human TTR between residues 48 and 49 under physiological conditions in vitro Truncated and full-length protomers are then released from the native homotetramer and rapidly aggregate into abundant fibrils indistinguishable from ex vivo TTR amyloid. Our findings suggest that physiological fibrinolysis is likely to play a critical role in TTR amyloid formation in vivo Identification of this surprising intersection between two hitherto unrelated pathways opens new avenues for elucidating the mechanisms of TTR amyloidosis, for seeking susceptibility risk factors, and for therapeutic innovation. PMID- 30018139 TI - Deficiency in Fpr2 results in reduced numbers of Lin-cKit+Sca1+ myeloid progenitor cells. AB - The Lin-c-Kit+ Sca-1+ cell population in the bone marrow (BM) serves as the direct precursor for differentiation of myeloid cells. In this study, we report that deficiency in Fpr2, a G protein-coupled chemoattractant receptor in mice, is associated with reduced BM nucleated cells, including CD31+Ly6C+ (granulocytes and monocytes), CD31-/Ly6Cint (granuloid cells), and CD31-/Ly6Chigh (predominantly monocytes) cells. In particular, the number of Lin-c-Kit+Sca-1+ (LKS) cells was reduced in Fpr2-/- mouse BM. This was supported by observations of the reduced incorporation of intraperitoneally injected bromodeoxyuridine by cells in the c-Kit+ population from Fpr2-/- mouse BM. Purified c-Kit+ cells from Fpr2-/- mice showed reduced expansion when cultured in vitro with stem cell factor (SCF). SCF/c-Kit-mediated phosphorylation of P38, STAT1, Akt (Thr-308), and Akt (Ser-473) was also significantly reduced in c-Kit+ cells from Fpr2-/- mice. Furthermore, Fpr2 agonists enhanced SCF-induced proliferation of c-Kit+ cells. Colony-forming unit assays revealed that CFU-granulocyte-macrophage formation of BM cells from Fpr2-/- mice was significantly reduced. After heat inactivated bacterial stimulation in the airway, the expansion of c-kit+ Sca-1+ cells in BM and recruitment of Ly6G+ cells to the lungs and CD11b+Ly6C+TNFalpha+ cells to the spleen of Fpr2-/- mice was significantly reduced. These results demonstrate an important role for Fpr2 in the development of myeloid lineage precursors in mouse BM. PMID- 30018140 TI - "Mallostery"-ligand-dependent protein misfolding enables physiological regulation by ERAD. AB - HMG-CoA reductase (HMGR) undergoes regulated degradation as part of feedback control of the sterol pathway. In yeast, the stability of the HMGR isozyme Hmg2 is controlled by the 20-carbon isoprenoid geranylgeranyl pyrophosphate (GGPP). Increasing GGPP levels cause more efficient degradation by the HMG-CoA reductase degradation (HRD) pathway, allowing for feedback regulation of HMGR. The HRD pathway is critical for the endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded ER proteins. Here, we have explored GGPP's role in HRD dependent Hmg2 degradation. We found that GGPP potently regulates Hmg2 levels in vivo and causes reversible Hmg2 misfolding at nanomolar concentrations in vitro These GGPP-mediated effects were absent in several stabilized or nonregulated Hmg2 mutants. Consistent with its high potency, GGPP's effects were highly specific such that other structurally related molecules were ineffective in altering Hmg2 structure. For instance, two closely related GGPP analogues, 2F GGPP and GGSPP, were completely inactive at all concentrations tested. Furthermore, GGSPP antagonized GGPP's effects in vivo and in vitro Chemical chaperones reversed GGPP's effects on Hmg2 structure and degradation, suggesting that GGPP causes selective Hmg2 misfolding. These results indicate that GGPP functions in a manner similar to an allosteric ligand, causing Hmg2 misfolding through interaction with a reversible, specific binding site. Consistent with this, the Hmg2 protein formed multimers, typical of allosteric proteins. We propose that this "allosteric misfolding," or mallostery, observed here for Hmg2 may be a widely used tactic of biological regulation with potential for development of therapeutic small molecules that induce selective misfolding. PMID- 30018142 TI - Plant mitochondrial protein import: the ins and outs. AB - The majority of the mitochondrial proteome, required to fulfil its diverse range of functions, is cytosolically synthesised and translocated via specialised machinery. The dedicated translocases, receptors, and associated proteins have been characterised in great detail in yeast over the last several decades, yet many of the mechanisms that regulate these processes in higher eukaryotes are still unknown. In this review, we highlight the current knowledge of mitochondrial protein import in plants. Despite the fact that the mechanisms of mitochondrial protein import have remained conserved across species, many unique features have arisen in plants to encompass the developmental, tissue-specific, and stress-responsive regulation in planta. An understanding of unique features and mechanisms in plants provides us with a unique insight into the regulation of mitochondrial biogenesis in higher eukaryotes. PMID- 30018141 TI - GRK2 mediates TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that drives PI3Kgamma/PREX1 signaling and T cell cytokine secretion. AB - The immune system includes abundant examples of biologically-relevant cross regulation of signaling pathways by the T cell antigen receptor (TCR) and the G protein-coupled chemokine receptor, CXCR4. TCR ligation induces transactivation of CXCR4 and TCR-CXCR4 complex formation, permitting the TCR to signal via CXCR4 to activate a phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1)-dependent signaling pathway that drives robust cytokine secretion by T cells. To understand this receptor heterodimer and its regulation, we characterized the molecular mechanisms required for TCR-mediated TCR-CXCR4 complex formation. We found that the cytoplasmic C-terminal domain of CXCR4 and specifically phosphorylation of Ser-339 within this region were required for TCR CXCR4 complex formation. Interestingly, siRNA-mediated depletion of G protein coupled receptor kinase-2 (GRK2) or inhibition by the GRK2-specific inhibitor, paroxetine, inhibited TCR-induced phosphorylation of CXCR4-Ser-339 and TCR-CXCR4 complex formation. Either GRK2 siRNA or paroxetine treatment of human T cells significantly reduced T cell cytokine production. Upstream, TCR-activated tyrosine kinases caused inducible tyrosine phosphorylation of GRK2 and were required for the GRK2-dependent events of CXCR4-Ser-339 phosphorylation and TCR CXCR4 complex formation. Downstream of TCR-CXCR4 complex formation, we found that GRK2 and phosphatidylinositol 3-kinase gamma (PI3Kgamma) were required for TCR stimulated membrane recruitment of PREX1 and for stabilization of cytokine mRNAs and robust cytokine secretion. Together, our results identify a novel role for GRK2 as a target of TCR signaling that is responsible for TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that signals via PI3Kgamma/PREX1 to mediate cytokine production. Therapeutic regulation of GRK2 or PI3Kgamma may therefore be useful for limiting cytokines produced by T cell malignancies or autoimmune diseases. PMID- 30018143 TI - Higher Expectations for a Vaccine To Prevent Congenital Cytomegalovirus Infection. PMID- 30018144 TI - Reply to Gantt et al., "Higher Expectations for a Vaccine To Prevent Congenital Cytomegalovirus Infection". PMID- 30018145 TI - Correction for Kumar et al., "Inflammasome Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD (ASC) Is Critical for the Immune Response and Survival in West Nile Virus Encephalitis". PMID- 30018146 TI - Weight(s) of complicity. AB - International non-governmental organisations (INGO) face a dilemma when deciding whether to intervene in crisis situations where their efforts can be exploited or co-opted by others: intervene and risk becoming complicit with wrongdoing or sit on the sidelines and consign vulnerable people to the ravages of neglect or oppression. In "'He who helps the guilty, shares the crime'? INGOs, moral narcissism and complicity in wrongdoing," Buth et al argue that concerns about complicity often stifle ethical debate and encourage moral narcissism. We argue that neglecting concerns about complicity can foster a different form of moral narcissism and that where worries of complicity are present, aid efforts face three types of risk: risks to others created by contributing to wrongful acts or bad outcomes; risks to the moral integrity of the INGO and its personnel; and risks to social trust in the INGO. In the end, we challenge the assumption that there is a unique, ethically best way to reconcile these values. We suggest that the causes of justice and humanity might be better served by a diverse community of INGOs who each gives different weight to these concerns, than if each INGO adopts the same framework for reconciling these competing demands. PMID- 30018147 TI - Vitamin D and its pathway genes in myopia: systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis of the association of blood vitamin D (25-hydroxyvitamin D, 25(OH)D) concentration and vitamin D pathway genes with myopia. METHODS: We searched the MEDLINE and EMBASE databases for studies published up to 29 January 2018. Cross-sectional or cohort studies which evaluated the blood 25(OH)D concentration, blood 25(OH)D3 concentration or vitamin D pathway genes, in relation to risk of myopia or refractive errors were included. Standard mean difference (SMD) of blood 25(OH)D concentrations between the myopia and non-myopia groups was calculated. The associations of blood 25(OH)D concentrations and polymorphisms in vitamin D pathway genes with myopia using summary ORs were evaluated. RESULTS: We summarised seven studies involving 25 008 individuals in the meta-analysis. The myopia group had lower 25(OH)D concentration than the non-myopia group (SMD=-0.27 nmol/L, p=0.001). In the full analysis, the risk of myopia was inversely associated with blood 25(OH)D concentration after adjusting for sunlight exposure or time spent outdoors (adjusted odds ratio (AOR)=0.92 per 10 nmol/L, p<0.0001). However, the association was not statistically significant for the <18 years subgroup (AOR=0.91 per 10 nmol/L, p=0.13) and was significant only for 25(OH)D3 (likely to be mainly sunlight derived), but not total 25(OH)D (AOR=0.93 per 10 nmol/L, p=0.00007; AOR=0.91 per 10 nmol/L, p=0.15). We analysed four single nucleotide polymorphisms in the VDR gene from two studies; there was no significant association with myopia. CONCLUSIONS: Lower 25(OH)D is associated with increased risk of myopia; the lack of a genetic association suggests that 25(OH)D level may be acting as a proxy for time outdoors. PMID- 30018148 TI - Borderline Ovarian Tumors Share Familial Risks with Themselves and Invasive Cancers. AB - Background: Borderline ovarian tumors (BOTs) are a subgroup of ovarian malignancies with low malignant potential. Very limited earlier data are available on familial clustering of BOTs with other cancers. We aim to explore histology-specific familial associations among BOTs and associations between BOTs and any invasive cancers.Methods: On the basis of 16.1 million individuals in the Swedish Family-Cancer Database, we estimated familial risks for overall or histology-specific patients with BOT considering both BOT and any invasive cancers in first-degree relatives (parents or siblings), as well as familial risks for invasive cancers considering family history of BOTs.Results: A total of 4,199 BOT cases were found in the offspring generation; among them, 34 (0.8%) cases had first-degree relatives diagnosed with any BOT, and 2,489 (59.3%) cases with any invasive cancers. A family history of BOT was associated with risks for all BOTs (RR = 2.20, P < 0.001). Papillary BOT in first-degree relatives was associated with the increased risk of having the same type of BOT (RR = 10.10, P < 0.001). BOTs showed familial associations with some invasive cancers, most consistently with colorectal, ovarian, pancreatic, lung, and bone cancers, and with leukemia. In histologic analyses, associations of BOT with even rare cancers of the anus, thyroid, and endocrine glands were noted.Conclusions: BOTs may share susceptibility with themselves and a number of invasive cancers.Impact: These results provide insight into familial associations of BOT for the first time, which may help with the etiologic mechanism and preventive strategy of BOTs, as well as the genetic counseling for patients with BOT. Cancer Epidemiol Biomarkers Prev; 27(11); 1358-63. (c)2018 AACR. PMID- 30018149 TI - The National Cancer Institute Cohort Consortium: An International Pooling Collaboration of 58 Cohorts from 20 Countries. AB - Cohort studies have been central to the establishment of the known causes of cancer. To dissect cancer etiology in more detail-for instance, for personalized risk prediction and prevention, assessment of risks of subtypes of cancer, and assessment of small elevations in risk-there is a need for analyses of far larger cohort datasets than available in individual existing studies. To address these challenges, the NCI Cohort Consortium was founded in 2001. It brings together 58 cancer epidemiology cohorts from 20 countries to undertake large-scale pooling research. The cohorts in aggregate include over nine million study participants, with biospecimens available for about two million of these. Research in the Consortium is undertaken by >40 working groups focused on specific cancer sites, exposures, or other research areas. More than 180 publications have resulted from the Consortium, mainly on genetic and other cancer epidemiology, with high citation rates. This article describes the foundation of the Consortium; its structure, governance, and methods of working; the participating cohorts; publications; and opportunities. The Consortium welcomes new members with cancer oriented cohorts of 10,000 or more participants and an interest in collaborative research. Cancer Epidemiol Biomarkers Prev; 27(11); 1307-19. (c)2018 AACR. PMID- 30018152 TI - Margaret McCartney: Health technology and the modern inverse care law. PMID- 30018150 TI - An Epidemiological Review of Diet and Cutaneous Malignant Melanoma. AB - Incidence of cutaneous malignant melanoma has continued to rise despite public efforts to promote sun protection behaviors among populations at risk. However, dietary factors may also affect the development of melanoma. In the past few decades, findings from epidemiologic and experimental research have linked consumption of several foods and other nutrients to the risk of melanoma. Caffeine has been associated with a lower risk of melanoma, and citrus fruits and alcohol with increased risk. Associations between polyunsaturated fatty acid, niacin/nicotinamide, folate, and vitamin D with melanoma remain controversial. Diet likely influences melanoma development through several potential mechanisms, such as enhancing UV-induced apoptosis and increasing photosensitivity. We conducted a narrative review to summarize recent epidemiologic studies of diet and melanoma based on published literature. Given the high prevalence of the food items and nutrients covered in this review and the decades-long rising melanoma incidence worldwide, the associations we discuss may have important public health implications in terms of reducing melanoma incidence through dietary modification. Cancer Epidemiol Biomarkers Prev; 27(10); 1115-22. (c)2018 AACR. PMID- 30018154 TI - Visual and Hearing Impairments After Preterm Birth. AB - OBJECTIVES: Our aim was to determine and compare the incidences of sensory impairments among very preterm (VP) (<32 + 0/7 weeks), moderately preterm (MP) (32 + 0/7-33 + 6/7 weeks), late preterm (LP) (34 + 0/7-36 + 6/7 weeks), and term infants (>=37 weeks) and to establish risk factors of neurosensory disabilities. METHODS: This national register study included all live-born infants in Finland between 1991 and 2008. Infants who died before the age of 1 year, who had any major congenital anomaly, or had missing data were excluded (n = 21 007; 2.0%). A total of 1 018 256 infants were analyzed. Incidences of hearing loss, visual disturbances or blindness, other ophthalmologic disorders, and retinopathy of prematurity were determined for gestational age (GA) groups. Risk factors of hearing loss and visual disturbances or blindness were analyzed. RESULTS: The incidences of sensory impairments decreased with advancing GA at birth (P < .001). The most prominent factors associated with increased risks of hearing loss and visual impairment were intracranial hemorrhage and convulsions. VP (odds ratio [OR] 2.34; 95% confidence interval [CI] 1.75-3.14) and LP (OR 1.26; 95% CI 1.04-1.52) births were associated with an increased risk of hearing loss, and VP (OR 1.94; 95% CI 1.55-2.44), MP (OR 1.42; 95% CI 1.11-1.80), and LP (OR 1.31; 95% CI 1.16-1.49) births predicted an increased risk of visual impairment. CONCLUSIONS: Incidences of sensory impairment decreased with increasing GA at birth. The most prominent risk factors predictive of sensory disabilities were intracranial hemorrhage and convulsions. VP and LP births were associated with an increased risk of hearing loss, and VP, MP, and LP births were associated with an increased risk of visual impairment. PMID- 30018155 TI - Angel Unaware and Down Syndrome Awareness. PMID- 30018153 TI - PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow. AB - Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro-inflammatory, suggesting that the establishment of endothelial polarity elicits an anti-inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR-3, is an essential gatekeeper of GSK3beta activity in response to laminar blood flow. We show that flow-induced spatial distribution of PAR-3/aPKClambda and aPKClambda/GSK3beta complexes controls local GSK3beta activity and thereby regulates endothelial planar polarity. The spatial information for GSK3beta activation is essential for flow-dependent polarity to the flow axis, but is not necessary for flow-induced anti-inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies. PMID- 30018158 TI - Effects of hypoxia on swimming and sensing in a weakly electric fish. AB - Low dissolved oxygen (hypoxia) can severely limit fish performance, especially aerobically expensive behaviours including swimming and acquisition of sensory information. Fishes can reduce oxygen requirements by altering these behaviours under hypoxia, but the underlying mechanisms can be difficult to quantify. We used a weakly electric fish as a model system to explore potential effects of hypoxia on swim performance and sensory information acquisition, which enabled us to non-invasively record electric signalling activity used for active acquisition of sensory information during swimming. To quantify potential effects of hypoxia, we measured critical swim speed (Ucrit) and concurrent electric signalling activity under high- and low-dissolved oxygen concentrations in a hypoxia tolerant African mormyrid fish, Marcusenius victoriae Fish were maintained under normoxia for 6 months prior to experimental treatments, and then acclimated for 8 weeks to normoxia or hypoxia and tested under both conditions (acute: 4 h exposure). Acute hypoxia exposure resulted in a significant reduction in both Ucrit and electric signalling activity in fish not acclimated to hypoxia. However, individuals acclimated to chronic hypoxia were characterized by a higher Ucrit under both hypoxia and normoxia than fish acclimated to normoxia. Following a 6 month re-introduction to normoxia, hypoxia-acclimated individuals still showed increased performance under acute hypoxic test conditions, but not under normoxia. Our results highlight the detrimental effects of hypoxia on aerobic swim performance and sensory information acquisition, and the ability of fish to heighten aerobic performance through acclimation processes that can still influence performance even months after initial exposure. PMID- 30018159 TI - Length of stimulus presentation and visual angle are critical for efficient visual PER conditioning in the restrained honey bee, Apis mellifera. AB - Learning visual cues is an essential capability of bees for vital behaviors such as orientation in space and recognition of nest sites, food sources and mating partners. To study learning and memory in bees under controlled conditions, the proboscis extension response (PER) provides a well-established behavioral paradigm. While many studies have used the PER paradigm to test olfactory learning in bees because of its robustness and reproducibility, studies on PER conditioning of visual stimuli are rare. In this study, we designed a new setup to test the learning performance of restrained honey bees and the impact of several parameters: stimulus presentation length, stimulus size (i.e. visual angle) and ambient illumination. Intact honey bee workers could successfully discriminate between two monochromatic lights when the color stimulus was presented for 4, 7 and 10 s before a sugar reward was offered, reaching similar performance levels to those for olfactory conditioning. However, bees did not learn at shorter presentation durations. Similar to free-flying honey bees, harnessed bees were able to associate a visual stimulus with a reward at small visual angles (5 deg) but failed to utilize the chromatic information to discriminate the learned stimulus from a novel color. Finally, ambient light had no effect on acquisition performance. We discuss possible reasons for the distinct differences between olfactory and visual PER conditioning. PMID- 30018160 TI - Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice. AB - Background and Purpose- Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological therapy available for patients with ischemic stroke. However, the percentage of patients who may receive this therapy is limited by the risk of hemorrhagic transformation (HT)-the main complication of ischemic stroke. Our aim is to establish whether iron overload affects HT risk, to identify mechanisms that could help to select patients and to prevent this devastating complication. Methods- Mice fed with control or high-iron diet were subjected to thromboembolic stroke, with or without tPA therapy at different times after occlusion. Blood samples were collected for determination of malondialdehyde, matrix metalloproteinases, and fibronectin. Brain samples were collected 24 hours after occlusion to determine brain infarct and edema size, hemorrhage extension, IgG extravasation, and inflammatory and oxidative markers (neutrophil infiltration, 4-hydroxynonenal, and matrix metalloproteinase-9 staining). Results- Despite an increased rate of recanalization, iron-overload mice showed less neuroprotection after tPA administration. Importantly, iron overload exacerbated the risk of HT after early tPA administration, accelerated ischemia-induced serum matrix metalloproteinase-9 increase, and enhanced basal serum lipid peroxidation. High iron increased brain lipid peroxidation at most times and neutrophil infiltration at the latest time studied. Conclusions- Our data showing that iron overload increases the death of the compromised tissues, accelerates the time of tPA-induced reperfusion, and exacerbates the risk of HT may have relevant clinical implications for a safer thrombolysis. Patients with stroke with iron overload might be at high risk of HT after fibrinolysis, and, therefore, clinical studies must be performed to confirm our results. PMID- 30018161 TI - Experience, the Name We Give Our Mistakes. PMID- 30018157 TI - Nonselective Chemical Inhibition of Sec7 Domain-Containing ARF GTPase Exchange Factors. AB - Small GTP-binding proteins from the ADP-ribosylation factor (ARF) family are important regulators of vesicle formation and cellular trafficking in all eukaryotes. ARF activation is accomplished by a protein family of guanine nucleotide exchange factors (GEFs) that contain a conserved catalytic Sec7 domain. Here, we identified and characterized Secdin, a small-molecule inhibitor of Arabidopsis thaliana ARF-GEFs. Secdin application caused aberrant retention of plasma membrane (PM) proteins in late endosomal compartments, enhanced vacuolar degradation, impaired protein recycling, and delayed secretion and endocytosis. Combined treatments with Secdin and the known ARF-GEF inhibitor Brefeldin A (BFA) prevented the BFA-induced PM stabilization of the ARF-GEF GNOM, impaired its translocation from the Golgi to the trans-Golgi network/early endosomes, and led to the formation of hybrid endomembrane compartments reminiscent of those in ARF GEF-deficient mutants. Drug affinity-responsive target stability assays revealed that Secdin, unlike BFA, targeted all examined Arabidopsis ARF-GEFs, but that the interaction was probably not mediated by the Sec7 domain because Secdin did not interfere with the Sec7 domain-mediated ARF activation. These results show that Secdin and BFA affect their protein targets through distinct mechanisms, in turn showing the usefulness of Secdin in studies in which ARF-GEF-dependent endomembrane transport cannot be manipulated with BFA. PMID- 30018162 TI - Tenecteplase Knocking on the Door. PMID- 30018156 TI - The Inhibitor Endosidin 4 Targets SEC7 Domain-Type ARF GTPase Exchange Factors and Interferes with Subcellular Trafficking in Eukaryotes. AB - The trafficking of subcellular cargos in eukaryotic cells crucially depends on vesicle budding, a process mediated by ARF-GEFs (ADP-ribosylation factor guanine nucleotide exchange factors). In plants, ARF-GEFs play essential roles in endocytosis, vacuolar trafficking, recycling, secretion, and polar trafficking. Moreover, they are important for plant development, mainly through controlling the polar subcellular localization of PIN-FORMED transporters of the plant hormone auxin. Here, using a chemical genetics screen in Arabidopsis thaliana, we identified Endosidin 4 (ES4), an inhibitor of eukaryotic ARF-GEFs. ES4 acts similarly to and synergistically with the established ARF-GEF inhibitor Brefeldin A and has broad effects on intracellular trafficking, including endocytosis, exocytosis, and vacuolar targeting. Additionally, Arabidopsis and yeast (Saccharomyces cerevisiae) mutants defective in ARF-GEF show altered sensitivity to ES4. ES4 interferes with the activation-based membrane association of the ARF1 GTPases, but not of their mutant variants that are activated independently of ARF GEF activity. Biochemical approaches and docking simulations confirmed that ES4 specifically targets the SEC7 domain-containing ARF-GEFs. These observations collectively identify ES4 as a chemical tool enabling the study of ARF-GEF mediated processes, including ARF-GEF-mediated plant development. PMID- 30018163 TI - Front of house drug testing by the Loop is essential in reducing future harm. PMID- 30018164 TI - Proton pump inhibitors increase the risk of cholecystitis: a population-based case-control study. PMID- 30018165 TI - Improving Delivery of Secondary Prophylaxis for Rheumatic Heart Disease in a High Burden Setting: Outcome of a Stepped-Wedge, Community, Randomized Trial. AB - BACKGROUND: Health system strengthening is needed to improve delivery of secondary prophylaxis against rheumatic heart disease. METHODS AND RESULTS: We undertook a stepped-wedge, randomized trial in northern Australia. Five pairs of Indigenous community clinics entered the study at 3-month steps. Study phases comprised a 12 month baseline phase, 3 month transition phase, 12 month intensive phase and a 3- to 12-month maintenance phase. Clinics received a multicomponent intervention supporting activities to improve penicillin delivery, aligned with the chronic care model, with continuous quality-improvement feedback on adherence. The primary outcome was the proportion receiving >=80% of scheduled penicillin injections. Secondary outcomes included "days at risk" of acute rheumatic fever recurrence related to late penicillin and acute rheumatic fever recurrence rates. Overall, 304 patients requiring prophylaxis were eligible. The proportion receiving >=80% of scheduled injections during baseline was 141 of 304 (46%)-higher than anticipated. No effect attributable to the study was evident: in the intensive phase, 126 of 304 (41%) received >=80% of scheduled injections (odds ratio compared with baseline: 0.78; 95% confidence interval, 0.54-1.11). There was modest improvement in the maintenance phase among high-adhering patients (43% received >=90% of injections versus 30% [baseline] and 28% [intensive], P<0.001). Also, the proportion of days at risk in the whole cohort decreased in the maintenance phase (0.28 versus 0.32 [baseline] and 0.34 [intensive], P=0.001). Acute rheumatic fever recurrence rates did not differ between study sites during the intensive phase and the whole jurisdiction (3.0 versus 3.5 recurrences per 100 patient-years, P=0.65). CONCLUSIONS: This strategy did not improve adherence to rheumatic heart disease secondary prophylaxis within the study time frame. Longer term primary care strengthening strategies are needed. CLINICAL TRIAL REGISTRATION: URL: www.anzctr.org.au. Unique identifier: ACTRN12613000223730. PMID- 30018166 TI - Qualitative Evaluation of a Complex Intervention to Improve Rheumatic Heart Disease Secondary Prophylaxis. AB - BACKGROUND: Rheumatic heart disease is a high-burden condition in Australian Aboriginal communities. We evaluated a stepped-wedge, community, randomized trial at 10 Aboriginal communities from 2013 to 2015. A multifaceted intervention was implemented using quality improvement and chronic care model approaches to improve delivery of penicillin prophylaxis for rheumatic heart disease. The trial did not improve penicillin adherence. This mixed-methods evaluation, designed a priori, aimed to determine the association between methodological approaches and outcomes. METHODS AND RESULTS: An evaluation framework was developed to measure the success of project implementation and of the underlying program theory. The program theory posited that penicillin delivery would be improved through activities implemented at clinics that addressed elements of the chronic care model. Qualitative data were derived from interviews with health-center staff, informants, and clients; participant observation; and project officer reports. Quantitative data comprised numbers and types of "action items," which were developed by participating clinic staff with project officers to improve delivery of penicillin injections. Interview data from 121 health-center staff, 22 informants, and 72 clients revealed barriers to achieving the trial's aims, including project-level factors (short trial duration), implementation factors (types of activities implemented), and contextual factors (high staff turnover and the complex sociocultural environment). Insufficient actions were implemented addressing "self-management support" and "community linkage" streams of the chronic care model. Increased momentum was evident in later stages of the study. CONCLUSIONS: The program theory underpinning the study was sound. The limited impact made by the study on adherence was attributable to complex implementation challenges. PMID- 30018167 TI - Improving the Diagnostic Performance of 18F-Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography in Prosthetic Heart Valve Endocarditis. AB - BACKGROUND: 18F-Fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) was recently introduced as a new tool for the diagnosis of prosthetic heart valve endocarditis (PVE). Previous studies reporting a modest diagnostic accuracy may have been hampered by unstandardized image acquisition and assessment, and several confounders, as well. The aim of this study was to improve the diagnostic performance of FDG PET/CT in patients in whom PVE was suspected by identifying and excluding possible confounders, using both visual and standardized quantitative assessments. METHODS: In this multicenter study, 160 patients with a prosthetic heart valve (median age, 62 years [43-73]; 68% male; 82 mechanical valves; 62 biological; 9 transcatheter aortic valve replacements; 7 other) who underwent FDG PET/CT for suspicion of PVE, and 77 patients with a PV (median age, 73 years [65-77]; 71% male; 26 mechanical valves; 45 biological; 6 transcatheter aortic valve replacements) who underwent FDG PET/CT for other indications (negative control group), were retrospectively included. Their scans were reassessed by 2 independent observers blinded to all clinical data, both visually and quantitatively on available European Association of Nuclear Medicine Research Ltd-standardized reconstructions. Confounders were identified by use of a logistic regression model and subsequently excluded. RESULTS: Visual assessment of FDG PET/CT had a sensitivity/specificity/positive predictive value/negative predictive value for PVE of 74%/91%/89%/78%, respectively. Low inflammatory activity (C-reactive protein <40 mg/L) at the time of imaging and use of surgical adhesives during prosthetic heart valve implantation were significant confounders, whereas recent valve implantation was not. After the exclusion of patients with significant confounders, diagnostic performance values of the visual assessment increased to 91%/95%/95%/91%. As a semiquantitative measure of FDG uptake, a European Association of Nuclear Medicine Research Ltd-standardized uptake value ratio of >=2.0 was a 100% sensitive and 91% specific predictor of PVE. CONCLUSIONS: Both visual and quantitative assessments of FDG PET/CT have a high diagnostic accuracy in patients in whom PVE is suspected. FDG PET/CT should be implemented early in the diagnostic workup to prevent the negative confounding effects of low inflammatory activity (eg, attributable to prolonged antibiotic therapy). Recent valve implantation was not a significant predictor of false-positive interpretations, but surgical adhesives used during implantation were. PMID- 30018168 TI - Megakaryocytic Leukemia 1 (MKL1) Bridges Epigenetic Activation of NADPH Oxidase in Macrophages to Cardiac Ischemia-Reperfusion Injury. AB - Background -Excessive accumulation of reactive oxygen species (ROS), catalyzed by the NADPH oxidases (NOX), is involved in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying epigenetic mechanism remains elusive. Methods -We evaluated the potential role of megakaryocytic leukemia 1, or MKL1, as a bridge linking epigenetic activation of NOX to ROS production and cardiac ischemia reperfusion injury. Results -Following I/R injury, MKL1 deficient (KO) mice exhibited smaller myocardial infarction along with improved heart function compared to wild type (WT) littermates. Similarly, pharmaceutical inhibition of MKL1 with CCG-1423 also attenuated myocardial infarction and improved heart function in mice. Amelioration of I/R injury as a result of MKL1 deletion or inhibition was accompanied by reduced ROS in vivo and in vitro In response to I/R, MKL1 levels were specifically elevated in macrophages, but not in cardiomyocytes, in the heart. Of note, macrophage-specific deletion (MphicKO), instead of cardiomyocyte-restricted ablation (CMcKO), of MKL1 in mice led to similar improvements of infarct size, heart function, and myocardial ROS generation. Reporter assay and ChIP assay revealed that MKL1 directly bound to the promoters of NADPH oxidase (NOX) genes to activate NOX transcription. Mechanistically, MKL1 recruited the histone acetyltransferase MOF to modify the chromatin structure surrounding the NOX promoters. Knockdown of MOF in macrophages blocked hyoxia/re-oxygenation-induced NOX transactivation and ROS accumulation. Of importance, pharmaceutical inhibition of MOF with MG-149 significantly down-regulated NOX1/NOX4 expression, dampened ROS production, and normalized myocardial function in mice exposed to I/R injury. Finally, administration of a specific NOX1/4 inhibitor GKT137831 dampened ROS generation and rescued heart function following I/R in mice. Conclusions -Our data delineate an MKL1-MOF-NOX axis in macrophages that contributes to I/R injury and as such have provided novel therapeutic targets in the treatment of ischemic heart disease. PMID- 30018169 TI - Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults. AB - BACKGROUND: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (n=155; age, 72+/-7 years; 59% male) or mild cognitive impairment (n=115; age, 73+/-7 years; 57% male). Aortic pulse wave velocity (PWV; meters per second) was quantified from cardiac magnetic resonance. Resting CBF (milliliters per 100 g per minute) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudocontinuous arterial spin labeling magnetic resonance imaging. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes mellitus, smoking, left ventricular hypertrophy, prevalent cardiovascular disease, atrial fibrillation), hypertension, body mass index, apolipoprotein E4 ( APOE epsilon4) status, and regional tissue volume. Models were repeated testing PWV* APOE epsilon4 interactions. Sensitivity analyses excluded participants with prevalent cardiovascular disease and atrial fibrillation. RESULTS: Among participants with normal cognition, higher aortic PWV related to lower frontal lobe CBF (beta=-0.43; P=0.04) and higher CVR in the whole brain (beta=0.11; P=0.02), frontal lobes (beta=0.12; P<0.05), temporal lobes (beta=0.11; P=0.02), and occipital lobes (beta=0.14; P=0.01). Among APOE epsilon4 carriers with normal cognition, findings were more pronounced with higher PWV relating to lower whole brain CBF (beta=-1.16; P=0.047), lower temporal lobe CBF (beta=-1.81; P=0.004), and higher temporal lobe CVR (beta=0.26; P=0.08), although the last result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among participants with mild cognitive impairment, higher aortic PWV related to lower CBF in the occipital lobe (beta=-0.70; P=0.02), but this finding was attenuated when participants with prevalent cardiovascular disease and atrial fibrillation were excluded. Among APOE epsilon4 carriers with mild cognitive impairment, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (beta=-1.20; P=0.02). CONCLUSIONS: Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity. PMID- 30018170 TI - ANN1 and ANN2 Function in Post-Phloem Sugar Transport in Root Tips to Affect Primary Root Growth. AB - Annexins are a multigene family of calcium-dependent membrane-binding proteins that play important roles in plant cell signaling. Annexins are multifunctional proteins, and their function in plants is not comprehensively understood. Arabidopsis (Arabidopsis thaliana) annexins ANN1 and ANN2 are 64% identical in their primary structure, and both are highly expressed in seedlings. Here, we showed that ann-mutant seedlings grown in the absence of sugar show decreased primary root growth and altered columella cells in root caps; however, these mutant defects are rescued by Suc, Glc, or Fru. In seedlings grown without sugar, significant up-regulation of photosynthetic gene expression and chlorophyll accumulation was found in ann-mutant cotyledons compared to that in wild type, which indicates potential sugar starvation in the roots of ann-mutant seedlings. Unexpectedly, the overall sugar content of ann-mutant primary roots was significantly higher than that of wild-type roots when grown without sugar. To examine the diffusion of sugar along the entire root to the root tip, we examined the unloading pattern of carboxyfluorescein dye and found that post-phloem sugar transport was impaired in ann-mutant root tips compared to that in wild type. Increased levels of ROS and callose were detected in the root tips of ann-mutant seedlings grown without Suc, the latter of which would restrict plasmodesmal sugar transport to root tips. Our results indicate that ANN1 and ANN2 play an important role in post-phloem sugar transport to the root tip, which in turn indirectly influences photosynthetic rates in cotyledons. This study expands our understanding of the function of annexins in plants. PMID- 30018171 TI - The Regulation of Sporopollenin Biosynthesis Genes for Rapid Pollen Wall Formation. AB - Sporopollenin is the major component of the outer pollen wall (sexine). It is synthesized using a pathway of approximately eight genes in Arabidopsis (Arabidopsis thaliana). MALE STERILITY188 (MS188) and its direct upstream regulator ABORTED MICROSPORES (AMS) are two transcription factors essential for tapetum development. Here, we show that all the sporopollenin biosynthesis proteins are specifically expressed in the tapetum and are secreted into anther locules. MS188, a MYB transcription factor expressed in the tapetum, directly regulates the expression of POLYKETIDE SYNTHASE A (PKSA), PKSB, MALE STERILE2 (MS2), and a CYTOCHROME P450 gene (CYP703A2). By contrast, the expression of CYP704B1, ACYL-COA SYNTHETASE5 (ACOS5), TETRAKETIDE a-PYRONE REDUCTASE1 (TKPR1) and TKPR2 are significantly reduced in ams mutants but not affected in ms188 mutants. However, MS188 but not AMS can activate the expression of CYP704B1, ACOS5, and TKPR1 In ms188, dominant suppression of MS188 homologs reduced the expression of these genes, suggesting that MS188 and other MYB family members play redundant roles in activating their expression. The expression of some sporopollenin synthesis genes (PKSA, PKSB, TKPR2, CYP704B1, and ACOS5) was rescued when MS188 was expressed in ams Therefore, MS188 is a key regulator for activation of sporopollenin synthesis, and AMS and MS188 may form a feed-forward loop that activates the expression of the sporopollenin biosynthesis pathway for rapid pollen wall formation. PMID- 30018172 TI - Diffusion of CO2 across the Mesophyll-Bundle Sheath Cell Interface in a C4 Plant with Genetically Reduced PEP Carboxylase Activity. AB - Phosphoenolpyruvate carboxylase (PEPC), localized to the cytosol of the mesophyll cell, catalyzes the first carboxylation step of the C4 photosynthetic pathway. Here, we used RNA interference to target the cytosolic photosynthetic PEPC isoform in Setaria viridis and isolated independent transformants with very low PEPC activities. These plants required high ambient CO2 concentrations for growth, consistent with the essential role of PEPC in C4 photosynthesis. The combination of estimating direct CO2 fixation by the bundle sheath using gas exchange measurements and modeling C4 photosynthesis with low PEPC activity allowed the calculation of bundle sheath conductance to CO2 diffusion (gbs ) in the progeny of these plants. Measurements made at a range of temperatures suggested no or negligible effect of temperature on gbs depending on the technique used to calculate gbs Anatomical measurements revealed that plants with reduced PEPC activity had reduced cell wall thickness and increased plasmodesmata (PD) density at the mesophyll-bundle sheath (M-BS) cell interface, whereas we observed little difference in these parameters at the mesophyll-mesophyll cell interface. The increased PD density at the M-BS interface was largely driven by an increase in the number of PD pit fields (cluster of PDs) rather than an increase in PD per pit field or the size of pit fields. The correlation of gbs with bundle sheath surface area per leaf area and PD area per M-BS area showed that these parameters and cell wall thickness are important determinants of gbs It is intriguing to speculate that PD development is responsive to changes in C4 photosynthetic flux. PMID- 30018173 TI - The Value of Measuring Inspiratory Capacity in Subjects With Cystic Fibrosis. AB - BACKGROUND: Inspiratory capacity (IC) is often overlooked as an important measured index of spirometry in patients with cystic fibrosis (CF). Abnormally low IC may indicate the onset of static/dynamic hyperinflation, which may be accompanied by dyspnea and an increase in the work of breathing. This cross sectional study sought to determine whether measuring IC during spirometry, may add clinical value to FEV1 measurements in CF subjects. METHODS: Anthropometric, clinical, spirometry, and static lung volume data were gathered retrospectively from 98 of 165 subjects with CF (mean +/- SD age 26.8 +/- 11.0 y) registered in The Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Israel. We compared the IC (% predicted) to FEV1, static lung volumes, and hospitalization days/year. RESULTS: IC decreased alongside FEV1 decline but at a slower pace (r2 = 0.32). Incremental trapped air, as measured by residual volume (RV), and a rapid elevation in the ratio of RV to total lung capacity occurred when IC deteriorated below 60% predicted values. The unique combination of IC < 50% predicted and FEV1 > 40% predicted induced an increase of up to 125 hospitalization days/year compared to subjects having IC > 50% predicted (up to 73 d/y, P < .001). CONCLUSIONS: Measuring IC in CF subjects may reveal silent worsening of lung function as indicated by a decline in IC < 50% predicted while FEV1 is still > 40% predicted. This condition may lead to inefficient breathing at high lung volumes, which may explain a subjective sensation of breathlessness and lead to an increase in hospitalization days/year. PMID- 30018174 TI - Assessment of Maximum Dynamic Inspiratory Pressure. AB - BACKGROUND: Inspiratory muscle strength has been considered an important marker of ventilatory capacity and a predictor of global performance. A new tool has become available for dynamically evaluating the maximum inspiratory pressure (the S-Index). However, the proper assessment of this parameter needs to be determined. Thus, the aim of the present study was to investigate the number of inspiratory maneuvers necessary to reach a maximum and reliable S-Index and the influence of inspiratory muscle warm-up on this assessment. METHOD: We performed a retrospective study from the database of 432 healthy subjects who underwent S Index tests and inspiratory muscle warm-up or sham. The effect of repeated maneuvers on the S-Index and the impact of inspiratory muscle warm-up were analyzed by using the intraclass correlation coefficient and unpaired t test. RESULTS: We analyzed 81 subjects, (55% men), mean +/- SD age 38.1 +/- 9.6 y, 43 subjects in the inspiratory muscle warm-up group. Maximum and reliable S-Indexes were reached at the eighth maneuver in both groups preceding inspiratory muscle warm-up or sham, 102 cm H2O (95% CI 95-109 cm H2O); intraclass correlation coefficient 0.96; P < .001. Only the inspiratory muscle warm-up group presented a significant increase in the S-Index after warm-up, 13.5 cm H2O (95% CI 10-17), P < .001. CONCLUSIONS: Eight maneuvers were necessary to reach maximum and reliable values of the S-Index preceding inspiratory muscle warm-up or sham. Moreover, inspiratory muscle warm-up preceding S-Index assessment improved inspiratory muscle performance. PMID- 30018175 TI - Effects of Mechanical Insufflation-Exsufflation on Airway Mucus Clearance Among Mechanically Ventilated ICU Subjects. AB - BACKGROUND: Few studies have evaluated the effects of mechanical insufflation exsufflation (MI-E) in subjects on mechanical ventilation. Therefore, this study aimed to evaluate the effectiveness of MI-E on airway mucus clearance among mechanically ventilated ICU subjects. METHODS: A randomized, parallel-group, open label trial was conducted between June and November 2017 in a single, mixed ICU. Adult ICU subjects receiving mechanical ventilation for > 24 h with stable ventilatory and hemodynamic status were randomized to receive either standard respiratory physiotherapy alone (control group) or respiratory physiotherapy by using an MI-E device (intervention group). The primary outcome was the weight of aspirated airway mucus after study interventions. Secondary outcomes included variation in static lung compliance (DeltaCL), airway resistance (DeltaRaw), work of breathing (DeltaWOB) in relation to the pre-intervention period, and hemodynamic and ventilator complications during the procedures. RESULTS: There were 90 subjects in each group. The mean +/- SD weight of the aspirated airway mucus was higher in the intervention group than in the control group (2.42 +/- 2.32 g vs 1.35 +/- 1.56 g, P < .001). The DeltaCL values in the intervention group were higher than those in the control group (1.76 +/- 4.90 mL/cm H2O vs 0.57 +/- 4.85 mL/cm H2O, P = .001). The DeltaRaw and DeltaWOB values were similar between the groups. No hemodynamic or ventilatory complications were observed. CONCLUSIONS: Among the general ICU subjects receiving mechanical ventilation, use of an MI-E device during respiratory physiotherapy resulted in a larger amount of airway mucus clearance than respiratory physiotherapy alone. (ClinicalTrials.gov registration NCT03178565.). PMID- 30018176 TI - Adherence to Endotracheal Tube Depth Guidelines and Incidence of Malposition in Infants and Children. AB - BACKGROUND: Adherence to guidelines for endotracheal tube (ETT) insertion depth may not be sufficient to prevent malposition or harm to the patient. To obtain an estimate of ETT malpositioning, we evaluated initial postintubation chest radiographs and hypothesized that many ETTs in multiple intubation settings would be malpositioned despite adherence to Pediatric Advanced Life Support and Neonatal Resuscitation Program guidelines. METHODS: In a random subset (randomization table) of 2,000 initial chest radiographs obtained from January 1, 2009, to May 5, 2012, we recorded height, weight, age, sex, ETT inner diameter, and cm marking at the lip from the electronic health record. Chest radiographs of poor quality and with spinal or skeletal deformities were excluded. We defined adherence to Pediatric Advanced Life Support or Neonatal Resuscitation Program guidelines as the difference between predicted and actual ETT markings at the lip as +/- 0.25, +/- 0.50, or +/- 1.0 cm for ETTs of 2.5-4, 4.5-6.0, or >6.5 mm inner diameter, respectively. We defined the proper position as the ETT tip being below the thoracic inlet (superior border of the clavicular heads) and >=1 cm above the carina. Descriptive statistics reported demographics, guideline adherence, and malposition incidence. The chi-square test was used to assess relationships among intubation setting, malposition, and depth guideline adherence (P < .05, significant). RESULTS: We reviewed 507 records, 477 of which met inclusion criteria and had sufficient data for analysis. Fifty-six percent of the subjects were male, with median (interquartile range) age 15.2 (3.4-59.4) months, and 330 ETTs (69%) were malpositioned: 39 above the thoracic inlet, and 291 < 1 cm above the carina. Of 79 ETTS (17%) that adhered to depth guidelines, 56 (74%) were malpositioned. Three-hundred seventy-three ETTs (83%) did not meet guidelines. Two-hundred sixty-four (68%) were malpositioned. The intubation setting did not influence malposition or guideline adherence (P = .54). CONCLUSIONS: In infants and children, a high proportion of ETTs were malpositioned on the first postintubation chest radiograph, with little influence of guideline adherence. PMID- 30018177 TI - Airway Clearance With an Optimized Mechanical Insufflation-Exsufflation Maneuver. AB - BACKGROUND: Standard mechanical insufflation-exsufflation (MI-E) therapy is applied with fast insufflation-exsufflation pressures to achieve high peak expiratory flows (PEF) and assist airway clearance. No attention is given to the resultant high peak inspiratory flows (PIF), although it may impair secretion removal. It has been proposed that an expiratory flow bias (ie, PEF higher than PIF) might be the key determinant for mucus clearance instead of the PEF alone. We examined the effects of 2 MI-E maneuvers, standard versus optimized, with fast and slow insufflation, respectively, along with different MI-E pressure settings on secretion displacement in 3 lung-impedance scenarios that simulated a patient on mechanical ventilation. METHODS: The MI-E device was connected to a lung model that simulated a patient on mechanical ventilation. Known quantities of mucus simulant were injected into the system and exposed to various MI-E ventilation conditions. Mucus movement was examined with image-analysis software. RESULTS: The optimized MI-E maneuver resulted in a much lower PIF (37.5 L/min [interquartile range, 24.9-47.9 L/min] vs 101.8 L/min [interquartile range, 89.1 115.7 L/min], P < .001). Consequently, the expiratory flow bias, expressed by PEF:PIF and the PEF-PIF difference, was much higher in the optimized maneuver. The higher expiratory flow bias in the optimized maneuver displaced the mucus outward, with a difference of 2.6 cm compared with the standard maneuver. Multivariate analysis revealed that the type of maneuver (optimized vs standard), PEF-PIF difference and MI-E pressure gradient were significantly correlated with mucus displacement (r2 = 0.817, P < .001), whereas the PEF was not. PEF:PIF and the PEF-PIF difference were lower in the obstructive lung scenario when compared with the restrictive and normal lung scenarios. CONCLUSIONS: The optimized MI-E maneuver, applied with slow insufflation, resulted in a higher expiratory flow bias, which made the therapy more effective at moving mucus outward, compared with the standard MI-E maneuver, typically applied with fast insufflation. PMID- 30018178 TI - Imposed Work of Breathing During High-Frequency Oscillatory Ventilation in Spontaneously Breathing Neonatal and Pediatric Models. AB - BACKGROUND: High-frequency oscillatory ventilation (HFOV) is used in cases of neonatal and pediatric acute respiratory failure, sometimes even as the primary ventilatory mode. Allowing patients (at least neonates) on HFOV to breathe spontaneously soon after intubation has been shown to be feasible, and this is becoming a more generally used approach for infants and small children. However, such an approach may increase the imposed work of breathing (WOB), raising the question of whether the imposed WOB varies with the use of newer-generation HFOV devices, which operate according to different functional principles. METHODS: A bench test was designed to compare the pressure-time product (PTP), a surrogate marker of the imposed WOB, produced with the use of 7 HFOV devices. Scenarios corresponding to various age groups (preterm newborn [1 kg], term newborn [3.5 kg], infant [10 kg], and child [25 kg]) and 2 respiratory system conditions (physiologic and pathologic) were tested. RESULTS: The PTP varied between devices and increased with the oscillation frequency for all devices, independent of the respiratory system condition. Furthermore, the PTP increased with age and was higher for physiologic than for pathologic respiratory system conditions. We considered a change of >= 20% as being of clinically relevant; the effect of oscillation frequency was the most important parameter influencing imposed WOB during spontaneous breathing. CONCLUSIONS: Variations in imposed WOB, as expressed by PTP values, during spontaneous breathing depend mainly on the oscillator frequency, respiratory system condition, and, though to a lesser extent, on the device itself. PMID- 30018180 TI - Caloric restriction effects on liver mTOR signaling are time-of-day dependent. AB - The regulation of mechanistic target of rapamycin (mTOR) signaling contributes to the metabolic effects of a calorie restriction (CR) diet. We assayed the effect of CR on the activity of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) in the liver of mice at six different times across the day. CR effects on mTORC1 and mTORC2 activities were time-of-day dependent. CR induced mTORC1 activity at one time, reduced at two times and has no effect during other times. CR induced mTORC2 activity at one time of the day and has no effects at other times. Circadian clocks are implemented in the regulation of mTOR signaling in mammals and mechanisms of CR. We assayed the effect of CR on mTOR signaling in the liver of mice deficient for circadian transcriptional regulators BMAL1 and CRYs. The CR induced suppression of mTORC1 activity was observed in both clock mutants, while up regulation of mTORC2 was observed in the liver of CRY deficient but not in the liver of BMAL1 deficient mice. Our finding revealed that CR has different time dependent effect on the activity of mTOR complexes 1 and 2 and suggest that circadian clock protein BMAL1 is involved in the up regulation of mTORC2 upon CR in mammals. PMID- 30018182 TI - Acoustic and mechanical characterization of 3D-printed scaffolds for tissue engineering applications. AB - The acoustic and mechanical properties of 3D-printed porous poly-(ethylene glycol)-diacrylate (PEGDA) hydrogel scaffolds were investigated using an ultrasound pulse echo technique on different scaffold microstructures (solid, hexagonal and square pores). Acoustic parameters such as speed of sound, acoustic impedance and attenuation coefficient as well as physical parameters such as the pore structure, effective density and elastic moduli were determined. The results show that microstructure (porosity and pore geometry) plays a crucial role in defining properties of 3D-printed scaffolds, achieving the highest attenuation for the scaffold with hexagonal pores and showing a decrease in sound speed and elastic moduli with increasing porosity. The properties were also found to be similar to those of soft tissues, making PEGDA scaffolds a suitable candidate for tissue engineering applications. To evaluate their cellular performance, adhesion and proliferation of human mesenchymal stem cells (hMSCs) in these scaffolds were investigated. The porous scaffolds performed better than the solid one, recording the highest cell attachment and growth for the scaffold with the square pores. PMID- 30018179 TI - A three-long non-coding RNA-expression-based risk score system can better predict both overall and recurrence-free survival in patients with small hepatocellular carcinoma. AB - Growing evidence indicates that long non-coding RNAs (lncRNAs) may be potential biomarkers and therapeutic targets for many disease conditions, including cancer. In this study, we constructed a risk score system of three lncRNAs (LOC101927051, LINC00667 and NSUN5P2) for predicting the prognosis of small hepatocellular carcinoma (sHCC) (maximum tumor diameter <=5 cm). The prognostic value of this sHCC risk model was confirmed in TCGA HCC samples (TNM stage I and II). Stratified survival analysis revealed that the suitable patient groups of the sHCC lncRNA-signature included HBV-infected and cirrhotic patients with better physical conditions yet lower levels of albumin and higher levels of alpha fetoprotein preoperatively. Besides, Asian patients with no family history of HCC or history of alcohol consumption can be predicted more precisely. Molecular functional analysis indicated that PYK2 pathway was significantly enriched in the high-risk patients. Pathway enrichment analysis indicated that the two lncRNAs (LINC00667 and NSUN5P2) associated with poor prognosis were closely related to cell cycle. The nomogram based on the lncRNA-signature for RFS prediction in sHCC patients exhibited good performance in recurrence risk stratification. In conclusion, we identified a novel three-lncRNA-expression-based risk model for predicting the prognosis of sHCC. PMID- 30018181 TI - Aging exacerbates mortality of Acinetobacter baumannii pneumonia and reduces the efficacies of antibiotics and vaccine. AB - Pneumonia caused by Acinetobacter baumannii has become a serious threat to the elderly. However, there are no experimental studies on the relevance between aging and A. baumannii infections. Here, we established an aged pneumonia mouse model by non-invasive intratracheal inoculation with A. baumannii. Higher mortality was observed in aged mice along with increased bacterial burdens and more severe lung injury. Increased inflammatory cell infiltration and enhanced pro-inflammatory cytokines at 24 hours post infection were detected in aged mice than those in young mice. Moreover, infected aged mice had lower myeloperoxidase levels in lungs and less reactive oxygen species-positive neutrophils in bronchoalveolar lavage fluid compared with infected young mice. Reduced efficacy of imipenem/cilastatin against A. baumannii was detected in aged mice. Vaccination of formalin-fixed A. baumannii provided 100% protection in young mice, whereas the efficacy of vaccine was completely diminished in aged mice. In conclusion, aging increased susceptibility to A. baumannii infection and impaired efficacies of antibiotics and vaccine. The aged mice model of A. baumannii pneumonia is a suitable model to study the effects of aging on A. baumannii infection and assess the efficacies of antibiotics and vaccines against A. baumannii for the elderly. PMID- 30018183 TI - Non-rectangular waveforms are more charge-efficient than rectangular one in eliciting network-mediated responses of ON type retinal ganglion cells. AB - OBJECTIVE: For individuals blinded by outer retinal degenerative diseases, retinal prostheses would be a promising option to restore sight. Unfortunately, however, the best performance of existing devices is still far removed from normal vision. One possible reason for the shortcoming is thought to be suboptimal stimulation conditions such as the waveform shape of electric stimulus. In this study, we explored the effects of varying waveforms on network mediated responses arising in retinal ganglion cells (RGCs). APPROACH: We used a cell-attached patch clamp technique to record RGC spiking activities in the isolated mouse retina. ON alpha RGCs were targeted by soma size and their light responses to stationary spot flashes. Spiking in targeted RGCs was measured in response to an epiretinally-delivered cathodal current pulse in four waveforms: rectangular, center triangular, increasing and decreasing ramp shapes. Each waveform was tested at three durations (20, 10, and 5 ms) with adjusted amplitude for a range of total charges (50-400 nC). MAIN RESULTS: ON alpha RGCs always generated two bursts of spikes in responses to all stimuli conditions we tested. However, at a given charge, effects of differing waveforms were distinct in the two bursts. For the first burst, the increasing ramp was most effective among the four waveforms (p < 0.05 for all pairwise comparisons with other waveforms). For example, in responses arising from 20 ms-long stimuli, the increasing ramp evoked ~44% more spikes on average than the rectangular shape which is the typical choice of neural stimulation. Also, the rectangular stimulus evoked the weakest response in the delayed burst arising from pulses of every duration. For instance, 20 ms-long stimuli in the three non-rectangular waveforms showed ~23% or more increment in spike counts compared to response arising from the rectangular one; but there was no statistical difference in response magnitudes across the non-rectangular waveforms. SIGNIFICANCE: Although the rectangular waveform has been primarily used in retinal prostheses our results indicate that rectangular stimulus is not optimal for network-mediated responses of ON alpha RGCs. Instead, non-rectangular waveforms evoke stronger responses at a given charge, indicating higher charge-efficiency. Therefore, non-rectangular waveforms are expected to enhance clinical efficacy of retinal prostheses. PMID- 30018184 TI - Hydrodynamic properties of biomimetic shark skin: effect of denticle size and swimming speed. AB - Biomechanists and biologists alike have yet to fully understand the complex morphology and function of shark denticles, morphologically intricate tooth-like structures embedded into the skin of sharks. Denticles vary in many ways (such as size and shape) depending on shark species, and studies on denticle hydrodynamics have suggested that they may aid in drag reduction as well as increase both lift and thrust. Although previous studies have analyzed the effect of different denticle patterns on hydrodynamic performance, no previous work has focused on the effects of denticle size. Here, we report on the hydrodynamic properties of 3D printed shark skin foils with rigid denticles embedded into a flexible substrate. The patterning of these denticles was based on previously reported designs exhibiting the greatest hydrodynamic performance (which also most closely mimics real shark skin). The size of the denticles and the speed of the flow were varied, and the foils were evaluated under both static and dynamic conditions. Static tests showed drag reduction compared to a smooth control foil (without denticles) for the smallest denticle size, while medium and large denticles exhibited increased drag. Under dynamic testing conditions, the smallest denticles increased the self-propelled swimming speed, while the largest denticles reduced swimming performance. At higher speeds, the smallest denticles were also able to reduce power consumption compared to the control, demonstrating that their hydrodynamic effect depends on both denticle size and swimming speed. Our results thus provide new insights into the role of denticle size in shark swimming hydrodynamics across a range of locomotory modes, while simultaneously providing new design guidelines for the production of high performance low drag surface coatings for aquatic and aerospace applications. PMID- 30018185 TI - The relationship between healthcare providers' performance regarding women experiencing domestic violence and their demographic characteristics and attitude towards their management. AB - BACKGROUND: Domestic violence (DV) can threaten women's health. Healthcare providers (HCPs) may be the first to come into contact with a victim of DV. Their appropriate performance regarding a victim of DV can decrease its complications. The aim of the present study was to investigate the relationship between HCPs' performance regarding women experiencing DV, demographic characteristics, and attitudes towards their management. METHODS: In this cross-sectional study, 300 emergency and maternity HCPs were selected using quota random sampling from February to May 2016. All hospitals affiliated to Isfahan University of Medical Sciences (Iran), which are referral centers for DV cases, were selected according to a census. The inclusion criteria included 1 year or more of professional experience and at least 1 encounter with a woman experiencing DV. Data were collected using a researcher-made questionnaire. SPSS was used to analyze the data. Cronbach's alpha was utilized to assess the reliability of the questionnaire. In order to obtain a general description of the data (variables, mean, and standard deviation), the table of frequencies was designed. Moreover, to determine the relationships between variables, chi-square test was applied. RESULTS: The results showed that there were no associations between HCPs' performance regarding DV and their demographic characteristics except their age, professional experience, and economic status. However, there was a significant association between HCPs' attitudes towards providing services (P=0.017) and their performance regarding women experiencing DV (P less than 0.001). CONCLUSIONS: To improve HCPs' performance regarding DV, paying attention to other related factors (i.e., training, employing HCPs with high professional experience, and codifying guidelines) is essential. Moreover, elements which result in the creation of positive attitudes and taking care of DV victims should be encouraged. PMID- 30018186 TI - Amphibian (Xenopus laevis) Tadpoles and Adult Frogs Differ in Their Use of Expanded Repertoires of Type I and Type III Interferon Cytokines. AB - While amphibians around the globe are facing catastrophic declines, in part because of infections with pathogens such as the Frog Virus 3 (FV3) ranavirus; the mechanisms governing amphibian susceptibility and resistance to such pathogens remain poorly understood. The type I and type III interferon (IFN) cytokines represent a cornerstone of vertebrate antiviral immunity, while our recent work indicates that tadpoles and adult frogs of the amphibian Xenopus laevis may differ in their IFN responses to FV3. In this respect, it is notable that anuran (frogs and toads) tadpoles are significantly more susceptible to FV3 than adult frogs, and thus, gaining greater insight into the differences in the tadpole and adult frog antiviral immunity would be invaluable. Accordingly, we examined the FV3-elicited expression of a panel of type I and type III IFN genes in the skin (site of FV3 infection) and kidney (principal FV3 target) tissues and isolated cells of X. laevis tadpoles and adult frogs. We also examined the consequence of tadpole and adult frog skin and kidney cell stimulation with hallmark pathogen-associated molecular patterns (PAMPs) on the IFN responses of these cells. Together, our findings indicate that tadpoles and adult frogs mount drastically distinct IFN responses to FV3 as well as to viral and non-viral PAMPs, while these expression differences do not appear to be the result of a distinct pattern recognition receptor expression by tadpoles and adults. PMID- 30018187 TI - New ABCC2 rs3740066 and rs2273697 Polymorphisms Identified in a Healthy Colombian Cohort. AB - Multidrug resistance-associated proteins (MRP) 1 and 2 belong to the ABC (ATP Binding Cassette) transporters. These transport proteins are involved in the removal of various drugs and xenobiotics, as well as in multiple physiological, pathological, and pharmacological processes. There is a strong correlation between different polymorphisms and their clinical implication in resistance to antiepileptic drugs, anticancer, and anti-infective agents. In our study, we evaluated exon regions of MRP1 (ABCC1)/MRP2 (ABCC2) in a Colombian cohort of healthy subjects to determine single nucleotide polymorphisms (SNPs) and to determine the allelic and genomic frequency. Results showed there are SNPs in our population that have been previously reported for both MRP1/ABCC1 (rs200647436, rs200624910, rs150214567) and MRP2/ABCC2 (rs2273697, rs3740066, rs142573385, rs17216212). Additionally, 13 new SNPs were identified. Evidence also shows a significant clinical correlation for polymorphisms rs3740066 and rs2273697 in the transport of multiple drugs, which suggests a genetic variability in regards to that reported in other populations. PMID- 30018191 TI - Multi-Scale Stress Wave Simulation for Aggregates Segregation Detection of Concrete Core in Circular CFST Coupled with PZT Patches. AB - In this study, the numerical investigation of the detectability of concrete aggregate segregation in circular concrete-filled steel tubulars (CCFST) based on piezoelectric lead zirconate titanate (PZT) measurement is performed. The stress wave propagation in the concrete core of circular CCFST excited with a surface mounted PZT actuator is studied with multi-scale and multi-physical field coupling analysis. The piezoelectric effect of PZT patches and its coupling effect with CFSTs are considered. Numerical concrete modeling technology is employed to construct the concrete core composed of randomly distributed aggregates with and without aggregate segregation at different levels, mortar, and an interfacial transition zone (ITZ). The effects of the random distribution of elliptical aggregates, aggregate segregation, and the existence of ITZ in the concrete core on the wave fields in the cross-section and the corresponding voltage response of the embedded PZT sensor are discussed. An evaluation index based on wavelet packet analysis on the output voltage response is defined, and its sensitivity to concrete aggregate segregation is systematically investigated. The multi-scale and multi-physics coupling simulation results indicate that concrete aggregate segregation in the concrete core of CFST members can be efficiently detected based on the stress wave measurement with a PZT sensor. PMID- 30018190 TI - Use of an E2SFCA Method to Measure and Analyse Spatial Accessibility to Medical Services for Elderly People in Wuhan, China. AB - Current studies on measuring the accessibility of medical services for the elderly (AMSE) have ignored the potential competition among supply and demand and the distance decay laws. Hence, an enhanced two-step floating catchment area (E2SFCA) method (i.e., the road network-based Gaussian 2SFCA method) is proposed to calculate AMSE scores after considering different types of roads, including urban rail transit, freeways, major roads, minor roads and rural roads. Based on the first National Geographic Conditions Monitoring (NGCM) data, this study took Wuhan, China, as a case study and assessed the variation of AMSE using two different threshold times (i.e., Platinum Ten and Golden Hour). Next, global (i.e., sensitivity and hot spot analysis) and local analyses (i.e., three regional area internal comparisons) of AMSE scores were conducted to accurately identify details in the variation of spatial accessibility. It was observed that the E2SFCA method could be easily applied to measure AMSE. The results showed that 48.63% of the elderly population in Wuhan had a higher or the highest level of medical accessibility in "Platinum Ten", while 72.97% had a higher or the highest level in the "Golden Hour", and hot spots of AMSE scores were located in central urban areas and presented an enclosure structure using both threshold travel times, which could provide guidance to governments or planners on issues of spatial planning and identifying elderly medical services shortage areas. PMID- 30018189 TI - Exercising in Air Pollution: The Cleanest versus Dirtiest Cities Challenge. AB - Background: Aerobic exercise is recommended to improve health. However, the increased ventilation might increase the doses of inhaled air pollutants, negating the health benefits in highly polluted areas. Our objective was to estimate the inhaled dose of air pollutants during two simulated exercise sessions at cleanest and dirtiest cities reported by World Health Organization (WHO) considering air quality. Methods: Minute ventilation data were extracted from laboratory-based exercise of 116 incremental running tests and used to calculate total ventilation of a hypothetical 30-min moderate continuous exercise routine. Afterwards, total ventilation values were combined with particulate matter (PM) data reported by the WHO for the 10 cleanest and 10 dirtiest cities, to calculate inhaled doses and the relative risk of all-cause mortality by exercising in different air pollution concentrations. Findings: The dirtiest cities are located at less developed countries compared to cleanest cities. The inhaled dose of PM2.5 and PM10 were significantly higher in the dirtiest cities compared to the cleanest cities at rest and exercise, and significantly higher during exercise compared to the rest at dirtiest cities. The relative risk of all cause mortality analysis showed that, while exercise in the cleanest cities improved health benefits throughout up to 90 min, there were no further health benefits after 15 min of exercise in the dirtiest cities, and the air pollution health risks surpassed the exercise benefits after 75 min. Interpretation: Our findings suggest that a traditional 30-min of moderate aerobic exercise session might induce inhalation of high levels of pollutants when performed at dirtiest cities. Considering several adverse health effects from air pollutants inhalation, so the results suggest that the air pollution levels of the cities should be taken into account for physical exercise recommendations. PMID- 30018193 TI - Relationship between Methods of Loading and Unloading, Carcass Bruising, and Animal Welfare in the Transportation of Extensively Reared Beef Cattle. AB - In Uruguay, extensive, welfare-friendly beef production is a substantial part of the economy and culture. Transport of beef cattle to slaughterhouse compromises animal welfare. The objective of this study was to assess transport conditions related to carcass bruising. A total of 242 trucks with 8132 animals were assessed on loading, transport, unloading conditions, and carcass bruising. Average loading time was 26 min and 21 s and the perception of the truck drivers was correlated with the time took for loading and the use of devices. In 39.3% of the loadings only a flag was used. The average unloading time was 5 min and 54 s with a significant difference in time for the use of devices; only flag 3 min 51 s, cattle prod 6 min 43 s and sticks 8 min 09 s. Of the carcasses observed, 772 (9.5%) had no bruises, 873 (10.7%) had one bruise, 1312 (16.1%) two, 1231 (15.1%) three and 3944 (48.5%) had four or more bruises. Prevalence of bruises were highest on the Tuber-coxea (hip) (29.3%) following forequarter (22.4%), Tuber ischiadicum (rear) (17.3%), ribs/flank (14.1%), rump/round (10.1%) and loin (6.8%). Bruises were 68.7% grade 1 and 31.3 % grade 2; there were no grade 3, the deepest ones, observed. It appeared that animal welfare training of truck drivers worked out well and the use of flags increased compared to a previous study in 2008. PMID- 30018192 TI - Characterization of the Chloroplast Genome Sequence of Acer miaotaiense: Comparative and Phylogenetic Analyses. AB - Acer miaotaiense is an endangered species within the Aceraceae family, and has only a few small natural distributions in China's Qingling Mountains and Bashan Mountains. Comparative analyses of the complete chloroplast genome could provide useful knowledge on the diversity and evolution of this species in different environments. In this study, we sequenced and compared the chloroplast genome of Acer miaotaiense from five ecological regions in the Qingling and Mashan Regions of China. The size of the chloroplast genome ranged from 156,260 bp to 156,204 bp, including two inverted repeat regions, a small single-copy region, and a large single-copy region. Across the whole chloroplast genome, there were 130 genes in total, and 92 of them were protein-coding genes. We observed four genes with non-synonymous mutations involving post-transcriptional modification (matK), photosynthesis (atpI), and self-replication (rps4 and rpl20). A total of 415 microsatellite loci were identified, and the dominant microsatellite types were composed of dinucleotide and trinucleotide motifs. The dominant repeat units were AT and AG, accounting for 37.92% and 31.16% of the total microsatellite loci, respectively. A phylogenetic analysis showed that samples with the same altitude (Xunyangba, Ningshan country, and Zhangliangmiao, Liuba country) had a strong bootstrap value (88%), while the remaining ones shared a similar longitude. These results provided clues about the importance of longitude/altitude for the genetic diversity of Acer miaotaiense. This information will be useful for the conservation and improved management of this endangered species. PMID- 30018188 TI - The Nefarious Nexus of Noncoding RNAs in Cancer. AB - The past decade has witnessed enormous progress, and has seen the noncoding RNAs (ncRNAs) turn from the so-called dark matter RNA to critical functional molecules, influencing most physiological processes in development and disease contexts. Many ncRNAs interact with each other and are part of networks that influence the cell transcriptome and proteome and consequently the outcome of biological processes. The regulatory circuits controlled by ncRNAs have become increasingly more relevant in cancer. Further understanding of these complex network interactions and how ncRNAs are regulated, is paving the way for the identification of better therapeutic strategies in cancer. PMID- 30018195 TI - Waterborne Disease Outbreak Detection: A Simulation-Based Study. AB - Waterborne disease outbreaks (WBDOs) remain a public health issue in developed countries, but to date the surveillance of WBDOs in France, mainly based on the voluntary reporting of clusters of acute gastrointestinal infections (AGIs) by general practitioners to health authorities, is characterized by low sensitivity. In this context, a detection algorithm using health insurance data and based on a space-time method was developed to improve WBDO detection. The objective of the present simulation-based study was to evaluate the performance of this algorithm for WBDO detection using health insurance data. The daily baseline counts of acute gastrointestinal infections were simulated. Two thousand simulated WBDO signals were then superimposed on the baseline data. Sensitivity (Se) and positive predictive value (PPV) were both used to evaluate the detection algorithm. Multivariate regression was also performed to identify the factors associated with WBDO detection. Almost three-quarters of the simulated WBDOs were detected (Se = 73.0%). More than 9 out of 10 detected signals corresponded to a WBDO (PPV = 90.5%). The probability of detecting a WBDO increased with the outbreak size. These results underline the value of using the detection algorithm for the implementation of a national surveillance system for WBDOs in France. PMID- 30018194 TI - Anisotropy of Transport Properties Correlated to Grain Boundary Density and Quantified Texture in Thick Oriented Ca3Co4O9 Ceramics. AB - The misfit-layered Ca3Co4O9 oxide is being seen as a potential thermoelectric (TE) candidate for high-temperature power generation in air. Given the very small size and low strength exhibited by single crystals, grain-oriented Ca3Co4O9 ceramics are worth elaborating to capitalize on their anisotropy. However, the usual textured pellets are too thin to probe the TE properties along their principal crystallographic directions. In this paper, we report on the anisotropy of TE properties in the 350-860 K range within thick textured Ca3Co4O9 ceramics fabricated by moderately pressing at 1173 K stacks of pellets primarily textured using spark plasma sintering (SPS), spark plasma texturing (SPT), and hot pressing (HP). The texture was quantitatively assessed, and the influent microstructural parameters were identified, particularly the grain boundary density parallel (GBDc) and perpendicular (GBDab) to the mean c*-axis. We found that the edge-free processing fostered material texturing and (a,b) plane grain growth, thereby dropping GBDab and increasing GBDc. This resulted in a resistivity rhoab reduction, leading to a marked enhancement in power factor PFab, which reached 520 MUW.m-1.K-2 at 800 K for the HP sample. The anisotropy rhoc/rhoab was substantially promoted as the texture was reinforced and the GBDc/GBDab ratio increased, with rhoc/rhoab (HP) > rhoc/rhoab (SPT) > rhoc/rhoab (SPS). The Seebeck coefficient S also revealed an anisotropic behavior, with a ratio Sc/Sab >1 for the SPS-processed materials. This behavior was reversed (Sc/Sab <1) for the more textured SPT and HP specimens. It therefore resulted in a PF anisotropy PFc/PFab (HP) < PFc/PFab (SPT) < PFc/PFab (SPS). The PFab/PFc ratio attained 13.6 at 800 K for the thick HP sample, which is the largest ratio recorded thus far on undoped Ca3Co4O9 ceramics. PMID- 30018196 TI - Temporal Profiles and Dose-Responsiveness of Side Effects with Escitalopram and Duloxetine in Treatment-Naive Depressed Adults. AB - Side effect profiles of antidepressants are relevant to treatment selection and adherence among patients with major depressive disorder (MDD), but several clinically-relevant characteristics of side effects are poorly understood. We aimed to compare the side effect profiles of escitalopram and duloxetine, including frequencies, time to onset, duration, dose responsiveness, and impact on treatment outcomes. Side effects occurring in 211 treatment-naive patients with MDD randomized to 12 weeks of treatment with flexibly-dosed escitalopram (10 20 mg/day) or duloxetine (30-60 mg/day) as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study were evaluated. Escitalopram- and duloxetine-treated patients experienced a similar mean number of overall side effects and did not differ in terms of the specific side effects observed or their temporal profile. Experiencing any side effect during the first 2 weeks of treatment was associated with increased likelihood of trial completion (86.7% vs. 73.7%, p = 0.045). Duloxetine-treated patients who experienced dry mouth were significantly more likely to achieve remission than those who did not (73.7% vs. 44.8%, p = 0.026). Side effects that resolved prior to a dose increase were unlikely to recur after the increase, but only about 45% of intolerable side effects that required a dose reduction resolved within 30 days of the reduction. At the doses used in this study, escitalopram and duloxetine have similar side effect profiles. Understanding characteristics of side effects beyond simple frequency rates may help prescribers make more informed medication decisions and support conversations with patients to improve treatment adherence. PMID- 30018197 TI - Evaluation of Mesenchymal Stem Cell Sheets Overexpressing BMP-7 in Canine Critical-Sized Bone Defects. AB - The aim of this study was to investigate the in vitro osteogenic capacity of bone morphogenetic protein 7 (BMP-7) overexpressing adipose-derived (Ad-) mesenchymal stem cells (MSCs) sheets (BMP-7-CS). In addition, BMP-7-CS were transplanted into critical-sized bone defects and osteogenesis was assessed. BMP-7 gene expressing lentivirus particles were transduced into Ad-MSCs. BMP-7, at the mRNA and protein level, was up-regulated in BMP-7-MSCs compared to expression in Ad-MSCs. Osteogenic and vascular-related gene expressions were up-regulated in BMP-7-CS compared to Ad-MSCs and Ad-MSC sheets. In a segmental bone-defect model, newly formed bone and neovascularization were enhanced with BMP-7-CS, or with a combination of BMP-7-CS and demineralized bone matrix (DBM), compared to those in control groups. These results demonstrate that lentiviral-mediated gene transfer of BMP-7 into Ad-MSCs allows for stable BMP-7 production. BMP-7-CS displayed higher osteogenic capacity than Ad-MSCs and Ad-MSC sheets. In addition, BMP-7-CS combined with demineralized bone matrix (DBM) stimulated new bone and blood vessel formation in a canine critical-sized bone defect. The BMP-7-CS not only provides BMP-7 producing MSCs but also produce osteogenic and vascular trophic factors. Thus, BMP-7-CS and DBM have therapeutic potential for the treatment of critical-sized bone defects and could be used to further enhance clinical outcomes during bone-defect treatment. PMID- 30018199 TI - A Perspective on Rabies in the Middle East-Beyond Neglect. AB - Rabies is a neglected but preventable viral zoonosis that poses a substantial threat to public health. In this regard, a global program has been initiated for the elimination of human rabies caused by rabid dogs through the mass vaccination of canine populations. Geographic areas vary greatly towards attainment of this objective. For example, while dog-mediated and wildlife rabies have been largely controlled in major parts of the Americas and Western Europe, the Middle East still grapples with human rabies transmitted by unvaccinated dogs and cats. Rabies prevention and control in the Middle East is quite difficult because the region is transcontinental, encompassing portions of Africa, Asia, and Europe, while consisting of politically, culturally, and economically diverse countries that are often subject to war and unrest. Consequently, one over-riding dilemma is the misinformation or complete lack of rabies surveillance data from this area. This communication is an attempt to provide an overview of rabies in the Middle East, as a cohesive approach for the honing of disease management in each area, based on data compiled from multiple sources. In addition, the related regional transboundary movement of rabies was investigated through phylogenetic studies of available viral gene sequences. Thereafter, the epidemiological status of rabies was assessed for the region. Finally, localities were classified first by the Stepwise Approach towards Rabies Elimination framework and then categorized into four different groups based on management theme: "rabies free"; owned dog and domestic animal vaccination; community dog vaccination; and wildlife vaccination. The classification system proposed herein may serve as a baseline for future efforts. This is especially important due to the severe lack of rabies information available for the Middle East as a whole and a need for a comprehensive program focusing on the entirety of the region in light of renewed international commitment towards canine rabies elimination. PMID- 30018200 TI - A Smart Sensing Architecture for Domestic Monitoring: Methodological Approach and Experimental Validation. AB - Smart homes play a strategic role for improving life quality of people, enabling to monitor people at home with numerous intelligent devices. Sensors can be installed to provide a continuous assistance without limiting the resident's daily routine, giving her/him greater comfort, well-being and safety. This paper is based on the development of domestic technological solutions to improve the life quality of citizens and monitor the users and the domestic environment, based on features extracted from the collected data. The proposed smart sensing architecture is based on an integrated sensor network to monitor the user and the environment to derive information about the user's behavior and her/his health status. The proposed platform includes biomedical, wearable, and unobtrusive sensors for monitoring user's physiological parameters and home automation sensors to obtain information about her/his environment. The sensor network stores the heterogeneous data both locally and remotely in Cloud, where machine learning algorithms and data mining strategies are used for user behavior identification, classification of user health conditions, classification of the smart home profile, and data analytics to implement services for the community. The proposed solution has been experimentally tested in a pilot study based on the development of both sensors and services for elderly users at home. PMID- 30018198 TI - The Air Sac Primordium of Drosophila: A Model for Invasive Development. AB - The acquisition of invasive properties preceding tumor metastasis is critical for cancer progression. This phenomenon may result from mutagenic disruption of typical cell function, but recent evidence suggests that cancer cells frequently co-opt normal developmental programs to facilitate invasion as well. The signaling cascades that have been implicated present an obstacle to identifying effective therapeutic targets because of their complex nature and modulatory capacity through crosstalk with other pathways. Substantial efforts have been made to study invasive behavior during organogenesis in several organisms, but another model found in Drosophilamelanogaster has not been thoroughly explored. The air sac primordium (ASP) appears to be a suitable candidate for investigating the genes and morphogens required for invasion due to the distinct overlap in the events that occur during its normal growth and the development of metastatic tumor cells. Among these events are the conversion of larval cells in the trachea into a population of mitotically active cells, reduced cell-cell contact along the leading edge of the ASP, and remodeling of the extracellular matrix (ECM) that surrounds the structure. Here, we summarize the development of ASPs and invasive behavior observed therein. PMID- 30018202 TI - Can Parietin Transfer Energy Radiatively to Photosynthetic Pigments? AB - The main role of lichen anthraquinones is in protection against biotic and abiotic stresses, such as UV radiation. These compounds are frequently deposited as crystals outside the fungal hyphae and most of them emit visible fluorescence when excited by UV. We wondered whether the conversion of UV into visible fluorescence might be photosynthetically used by the photobiont, thereby converting UV into useful energy. To address this question, thalli of Xanthoria parietina were used as a model system. In this species the anthraquinone parietin accumulates in the outer upper cortex, conferring the species its characteristic yellow-orange colouration. In ethanol, parietin absorbed strongly in the blue and UV-B and emitted fluorescence in the range 480-540 nm, which partially matches with the absorption spectra of photosynthetic pigments. In intact thalli, it was determined by confocal microscopy that fluorescence emission spectra shifted 90 nm towards longer wavelengths. Then, to study energy transfer from parietin, we compared the response to UV of untreated and parietin-free thalli (removed with acetone). A chlorophyll fluorescence kinetic assessment provided evidence of UV induced electron transport, though independently of the presence of parietin. Thus, a role for anthraquinones in energy harvesting is not supported for X. parietina under presented experimental conditions. PMID- 30018201 TI - Gold Nanocage-Based Electrochemical Sensing Platform for Sensitive Detection of Luteolin. AB - A simple and sensitive electrochemical sensor was developed for the detection of tracelevels of luteolin. The sensoris based on a novel type of chemically modified electrode: gold nanocage (AuNCs)-modified carbon ionic liquid electrode (CILE). To construct this electrochemical sensing platform for luteolin, CILE is initially prepared by using 1-hexylpyridinium hexafluorophosphate as the binder and then AuNCs are coated on the surface of CILE to fabricate AuNCs-modified CILE (AuNCs/CILE). Electrochemical studies have shown that AuNCs/CILE can exhibit enhanced electrocatalytic activity toward the redox reaction of luteolin, therefore, the redox peak current of luteolin can be greatly improved, resulting in the high sensitivity of the developed sensor. Under the optimal conditions, the oxidation peak currents of the sensor increase linearly with an increase in the luteolin concentration in a range from 1 to 1000 nM with a detection limit of 0.4 nM, which is lower than those of most reported electrochemical luteolin sensors. Moreover, the reproducibility, precision, selectivity, and stability of this sensor are excellent. Finally, the sensing system was applied to the analysis of luteolin-spiked drug samples and the recovery in all cases was 95.0 96.7%, indicating the potential application of this simple, facile, and sensitive sensing system in pharmaceutical analysis. PMID- 30018204 TI - Experimental Verification of the Pumping Effect Caused by the Micro-Tapered Hole in a Piezoelectric Atomizer. AB - In this study, we examined the use of a dynamic micro-tapered hole as a micro scale tapered flow tube valveless piezoelectric pump. Firstly, we obtained photographs of a micro-tapered hole by using an environmental scanning electron microscope (ESEM). Then, we explained the pump effect of the micro-tapered hole, and derived the atomization rate equation. Furthermore, we reported an atomization rate measurement experiment that eliminated the atomization caused by a pressure increase, and demonstrated that a change in the volume of a micro tapered hole could produce atomization. The experimental results indicate that, under the same voltage, the forward atomization rate is much higher than the reverse atomization rate and that the atomization rate increases with the micro tapered hole volume. The experimental results show that the atomization of the micro-tapered aperture atomizer is caused by its pumping effect. Moreover, the flow resistance and volume of the micro-tapered hole can affect the atomization rate. PMID- 30018203 TI - Understanding the Influence of Crop Residue Burning on PM2.5 and PM10 Concentrations in China from 2013 to 2017 Using MODIS Data. AB - In recent years, particulate matter (PM) pollution has increasingly affected public life and health. Therefore, crop residue burning, as a significant source of PM pollution in China, should be effectively controlled. This study attempts to understand variations and characteristics of PM10 and PM2.5 concentrations and discuss correlations between the variation of PM concentrations and crop residue burning using ground observation and Moderate Resolution Imaging Spectroradiometer (MODIS) data. The results revealed that the overall PM concentration in China from 2013 to 2017 was in a downward tendency with regional variations. Correlation analysis demonstrated that the PM10 concentration was more closely related to crop residue burning than the PM2.5 concentration. From a spatial perspective, the strongest correlation between PM concentration and crop residue burning existed in Northeast China (NEC). From a temporal perspective, the strongest correlation usually appeared in autumn for most regions. The total amount of crop residue burning spots in autumn was relatively large, and NEC was the region with the most intense crop residue burning in China. We compared the correlation between PM concentrations and crop residue burning at inter-annual and seasonal scales, and during burning-concentrated periods. We found that correlations between PM concentrations and crop residue burning increased significantly with the narrowing temporal scales and was the strongest during burning-concentrated periods, indicating that intense crop residue burning leads to instant deterioration of PM concentrations. The methodology and findings from this study provide meaningful reference for better understanding the influence of crop residue burning on PM pollution across China. PMID- 30018205 TI - Inhibition Effect of Three-Dimensional (3D) Nanostructures on the Corrosion Resistance of 1-Dodecanethiol Self-Assembled Monolayer on Copper in NaCl Solution. AB - A novel and simple method to improve the corrosion resistance of copper by constructing a three-dimensional (3D) 1-dodecanethiol self-assembled monolayer (SAM) in 3.5% NaCl solution is reported in this study. Several drops of 1% H3PO4 solution are thinly and uniformly distributed on copper surface to form a 3D nanostructure constituted by Cu3(PO4)2 nanoflowers. The anticorrosion properties of 1-dodecanethiol SAM on copper surface and on copper surface that is treated with H3PO4 solution were evaluated. Results demonstrated that 1-dodecanethiol SAM on bare copper surface exhibits good protection capacity, whereas a copper surface that is pretreated with H3PO4 solution can substantially enhance the corrosion resistance of 1-dodecanethiol SAM. PMID- 30018206 TI - Inactivation, Aggregation and Conformational Changes of Polyphenol Oxidase from Quince (Cydonia oblonga Miller) Juice Subjected to Thermal and High-Pressure Carbon Dioxide Treatment. AB - Polyphenol oxidase (PPO) causes the browning reaction in fruits and vegetables and deteriorates the quality. Thermal treatment for enzyme inactivation may result in defects as opposed to high pressure CO2 (HPCD) processing. In this study, the changes in activity, dissociation, aggregation and conformation of purified PPO from thermal and HPCD treated juice were investigated. HPCD exhibited inactivation of PPO at 55-65 degrees C whereas thermal processing alone at the same temperature resulted in PPO still showing activity. Under thermal treatment at 25 and 65 degrees C, the browning degree was higher (0.39 and 0.24) than for HPCD-treated juice (0.23 and 0.12). Fluorescence and circular dichroism spectral results indicated that HPCD induced large decreases in intensities, revealing a rearrangement of the secondary structure and destruction of the native configuration of the PPO molecule. The particle size distribution (PSD) pattern revealed structural modification leading to initial dissociation and subsequent aggregation of PPO after HPCD treatment. Polyacrylamide gel electrophoresis (PAGE) analysis exhibited that molecular size of protein was 40 kDa. In conclusion, the HPCD method was found to be more effective than thermal treatment to inactivate PPO. Structural modifications provided better insights into the phenomena of activation and inactivation of PPO. PMID- 30018208 TI - Single Pass Laser Process for Super-Hydrophobic Flexible Surfaces with Micro/Nano Hierarchical Structures. AB - Wetting has been studied in various fields: chemical industry, automobile manufacturing, food companies, and even life sciences. In these studies, super hydrophobic surfaces have been achieved through complex steps and processes. To realize super-hydrophobicity, however, we demonstrated a simple and single pass laser process for the fabrication of micro/nano hierarchical structures on the flexible polytetrafluoroethylene (PTFE, Teflon) surface. The fabricated hierarchical structures helped increase the hydrophobicity by augmenting the surface roughness and promoting air-trapping. In addition, we employed a low-cost and high-throughput replication process producing numerous polydimethylsiloxane (PDMS) replicas from the laser-processed PTFE film. Thanks to the anti-adhesive characteristics of PTFE and the elasticity of PDMS, the structure perfectly transferred to the replica without any mechanical failure. Moreover, our designed mesh patterns offered the possibility of large area applications through varying the process parameters (pitch, beam spot size, laser fluence, and scan speed). Even though mesh patterns had relatively large pitch (190 MUm), we were able to achieve high contact angle (>150 degrees ). Through pneumatically deformed structure, we clearly showed that the shape of the droplets on our laser processed super-hydrophobic surface was spherical. Based on these outcomes, we can expect our single laser pulse exposure process can overcome many drawbacks and offer opportunities for advancing applications of the wetting phenomena. PMID- 30018209 TI - Could the Visual Differential Attention Be a Referential Gesture? A Study on Horses (Equus caballus) on the Impossible Task Paradigm. AB - In order to explore the decision-making processes of horses, we designed an impossible task paradigm aimed at causing an expectancy violation in horses. Our goals were to verify whether this paradigm is effective in horses by analyzing their motivation in trying to solve the task and the mode of the potential helping request in such a context. In the first experiment, 30 horses were subjected to three consecutive conditions: no food condition where two persons were positioned at either side of a table in front of the stall, solvable condition when a researcher placed a reachable reward on the table, and the impossible condition when the food was placed farther away and was unreachable by the horse. Eighteen horses were used in the second experiment with similar solvable and impossible conditions but in the absence of people. We measured the direction of the horse's ear cup as an indicator of its visual attention in terms of visual selective attention (VSA) when both ears were directed at the same target and the visual differential attention (VDA) when the ears were directed differentially to the persons and to the table. We also included tactile interaction toward table and people, the olfactory exploration of the table, and the frustration behaviors in the ethogram. In the first experiment, the VDA was the most frequent behavior following the expectancy violation. In the second experiment, horses showed the VDA behavior mostly when people and the unreachable resource were present at the same time. We speculate that the VDA could be a referential gesture aimed to link the solution of the task to the people, as a request for help. PMID- 30018207 TI - Anomeric O-Functionalization of Carbohydrates for Chemical Conjugation to Vaccine Constructs. AB - Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates is increasing and developing methods for stereoselective conjugation these polar head groups to proteins and lipids is critically important for pharmaceutical applications. The aim of this review is to provide an overview of commonly employed strategies for installing a functionalized linker at the anomeric position as well as examples of further transformations that have successfully led to glycoconjugation to vaccine constructs for biological evaluation as carbohydrate-based therapeutics. PMID- 30018210 TI - Amplitude-Based Filtering for Video Magnification in Presence of Large Motion. AB - Video magnification reveals important and informative subtle variations in the world. These signals are often combined with large motions which result in significant blurring artifacts and haloes when conventional video magnification approaches are used. To counter these issues, this paper presents an amplitude based filtering algorithm that can magnify small changes in video in presence of large motions. We seek to understand the amplitude characteristic of small changes and large motions with the goal of extracting accurate signals for visualization. Based on spectrum amplitude filtering, the large motions can be removed while small changes can still be magnified by Eulerian approach. An advantage of this algorithm is that it can handle large motions, whether they are linear or nonlinear. Our experimental results show that the proposed method can amplify subtle variations in the presence of large motion, as well as significantly reduce artifacts. We demonstrate the presented algorithm by comparing to the state-of-the-art and provide subjective and objective evidence for the proposed method. PMID- 30018212 TI - Pathogenic Escherichia coli Strains Recovered from Selected Aquatic Resources in the Eastern Cape, South Africa, and Its Significance to Public Health. AB - The prevalence of pathogenic microorganisms, as well as the proliferation of antimicrobial resistance, pose a significant threat to public health. However, the magnitude of the impact of aquatic environs concerning the advent and propagation of resistance genes remains vague. Escherichia coli (E. coli) are widespread and encompass a variety of strains, ranging from non-pathogenic to highly pathogenic. This study reports on the incidence and antibiotic susceptibility profiles of E. coli isolates recovered from the Nahoon beach and its canal waters in South Africa. A total of 73 out of 107 (68.2%) Polymerase chain reaction confirmed E. coli isolates were found to be affirmative for at least one virulence factor. These comprised of enteropathogenic E. coli 11 (10.3%), enteroinvasive E. coli 14 (13.1%), and neonatal meningitis E. coli 48 (44.9%). The phenotypic antibiogram profiles of the confirmed isolates revealed that all 73 (100%) were resistant to ampicillin, whereas 67 (91.8%) of the pathotypes were resistant to amikacin, gentamicin, and ceftazidime. About 61 (83.6%) and 51 (69.9%) were resistant to tetracycline and ciprofloxacin, respectively, and about 21.9% (16) demonstrated multiple instances of antibiotic resistance, with 100% exhibiting resistance to eight antibiotics. The conclusion from our findings is that the Nahoon beach and its canal waters are reservoirs of potentially virulent and antibiotic-resistant E. coli strains, which thus constitute a potent public health risk. PMID- 30018211 TI - Unilateral Botulinum Neurotoxin-A Injection into the Striatum of C57BL/6 Mice Leads to a Different Motor Behavior Compared with Rats. AB - Different morphological changes in the caudate-putamen (CPu) of naive rats and mice were observed after intrastriatal botulinum neurotoxin-A (BoNT-A) injection. For this purpose we here studied various motor behaviors in mice (n = 46) longitudinally up to 9 months after intrastriatal BoNT-A administration as previously reported for rats, and compared both outcomes. Apomorphine- and amphetamine-induced rotational behavior, spontaneous motor behavior, as well as lateralized neglect were studied in mice after the injection of single doses of BoNT-A into the right CPu, comparing them with sham-injected animals. Unilateral intrastriatal injection of BoNT-A in mice induced significantly increased contralateral apomorphine-induced rotations for 1 to 3 months, as well as significantly increased contralateral amphetamine-induced rotations 1 to 9 months after injection. In rats (n = 28), unilateral BoNT-A injection also induced significantly increased contralateral apomorphine-induced rotations 3 months after injection, but did not provoke amphetamine-induced rotations at all. Lateralized sensorimotor integration, forelimb preference, and forelimb stepping were significantly impaired on the left side. The differences in motor behaviors between rats and mice may be caused by different BoNT-A effects on cholinergic and catecholaminergic fibers in rat and mouse striata, interspecies differences in striatal receptor densities, and different connectomes of the basal ganglia. PMID- 30018215 TI - Fast Visual Odometry for a Low-Cost Underwater Embedded Stereo System ?. AB - This paper provides details of hardware and software conception and realization of a stereo embedded system for underwater imaging. The system provides several functions that facilitate underwater surveys and run smoothly in real-time. A first post-image acquisition module provides direct visual feedback on the quality of the taken images which helps appropriate actions to be taken regarding movement speed and lighting conditions. Our main contribution is a light visual odometry method adapted to the underwater context. The proposed method uses the captured stereo image stream to provide real-time navigation and a site coverage map which is necessary to conduct a complete underwater survey. The visual odometry uses a stochastic pose representation and semi-global optimization approach to handle large sites and provides long-term autonomy, whereas a novel stereo matching approach adapted to underwater imaging and system attached lighting allows fast processing and suitability to low computational resource systems. The system is tested in a real context and shows its robustness and promising future potential. PMID- 30018213 TI - Biomimetic Membranes as a Technology Platform: Challenges and Opportunities. AB - Biomimetic membranes are attracting increased attention due to the huge potential of using biological functional components and processes as an inspirational basis for technology development. Indeed, this has led to several new membrane designs and applications. However, there are still a number of issues which need attention. Here, I will discuss three examples of biomimetic membrane developments within the areas of water treatment, energy conversion, and biomedicine with a focus on challenges and applicability. While the water treatment area has witnessed some progress in developing biomimetic membranes of which some are now commercially available, other areas are still far from being translated into technology. For energy conversion, there has been much focus on using bacteriorhodopsin proteins, but energy densities have so far not reached sufficient levels to be competitive with state-of-the-art photovoltaic cells. For biomedical (e.g., drug delivery) applications the research focus has been on the mechanism of action, and much less on the delivery 'per se'. Thus, in order for these areas to move forward, we need to address some hard questions: is bacteriorhodopsin really the optimal light harvester to be used in energy conversion? And how do we ensure that biomedical nano-carriers covered with biomimetic membrane material ever reach their target cells/tissue in sufficient quantities? In addition to these area-specific questions the general issue of production cost and scalability must also be treated in order to ensure efficient translation of biomimetic membrane concepts into reality. PMID- 30018216 TI - Accelerating the K-Nearest Neighbors Filtering Algorithm to Optimize the Real Time Classification of Human Brain Tumor in Hyperspectral Images. AB - The use of hyperspectral imaging (HSI) in the medical field is an emerging approach to assist physicians in diagnostic or surgical guidance tasks. However, HSI data processing involves very high computational requirements due to the huge amount of information captured by the sensors. One of the stages with higher computational load is the K-Nearest Neighbors (KNN) filtering algorithm. The main goal of this study is to optimize and parallelize the KNN algorithm by exploiting the GPU technology to obtain real-time processing during brain cancer surgical procedures. This parallel version of the KNN performs the neighbor filtering of a classification map (obtained from a supervised classifier), evaluating the different classes simultaneously. The undertaken optimizations and the computational capabilities of the GPU device throw a speedup up to 66.18* when compared to a sequential implementation. PMID- 30018214 TI - A MicroRNA Perspective on Cardiovascular Development and Diseases: An Update. AB - In this review, we summarize the latest research pertaining to MicroRNAs (miRs) related to cardiovascular diseases. In today's molecular age, the key clinical aspects of diagnosing and treating these type of diseases are crucial, and miRs play an important role. Therefore, we have made a thorough analysis discussing the most important candidate protagonists of many pathways relating to such conditions as atherosclerosis, heart failure, myocardial infarction, and congenital heart disorders. We approach miRs initially from the fundamental molecular aspects and look at their role in developmental pathways, as well as regulatory mechanisms dysregulated under specific cardiovascular conditions. By doing so, we can better understand their functional roles. Next, we look at therapeutic aspects, including delivery and inhibition techniques. We conclude that a personal approach for treatment is paramount, and so understanding miRs is strategic for cardiovascular health. PMID- 30018217 TI - Resilience in Children: Developmental Perspectives. AB - Advances in developmental resilience science are highlighted with commentary on implications for pediatric systems that aspire to promote healthy development over the life course. Resilience science is surging along with growing concerns about the consequences of adverse childhood experiences on lifelong development. Resilience is defined as the capacity of a system to adapt successfully to challenges that threaten the function, survival, or future development of the system. This definition is scalable across system levels and across disciplines, applicable to resilience in a person, a family, a health care system, a community, an economy, or other systems. Robust findings on resilience in childhood underscore the importance of exposure dose; fundamental adaptive systems embedded in the lives of individuals and their interactions with other systems; developmental timing; and the crucial role of healthcare practitioners and educators as well as family caregivers in nurturing resilience on the "front lines" of lived childhood experience. Resilience science suggests that human resilience is common, dynamic, generated through myriad interactions of multiple systems from the biological to the sociocultural, and mutable given strategic targeting and timing. Implications for pediatric practice and training are discussed. PMID- 30018218 TI - Analytical and Sample Preparation Protocol for Therapeutic Drug Monitoring of 12 Thiopurine Metabolites Related to Clinical Treatment of Inflammatory Bowel Disease. AB - Thiopurines (TP) represent an important therapeutic tool for the treatment of inflammatory bowel diseases (IBD) in the current situation of rising incidence and health care costs. The results of multiple clinical studies aimed at finding correlations between levels of TP metabolites and response of IBD patients to the treatment are, however, often controversial due to variability in analytical and sample preparation procedures among these studies. In this work, therefore, an updated analytical and sample preparation procedure for therapeutic drug monitoring (TDM) of TP metabolites in blood samples obtained from patients with IBD was proposed to establish a unified protocol. An advanced analytical method based on ion-exchange liquid chromatography hyphenated with tandem mass spectrometry (IEC-ESI-MS/MS) was used for the determination of the profiles of 12 individual TP metabolites in the particular steps of sample preparation procedure including blood collection, red blood cells (RBC) isolation, lysis, and storage. Favorable performance parameters of the IEC-ESI-MS/MS method (LLOQs 1-10 nmol/L, accuracy 95-105%, intra-day and inter-day precision < 10%, selectivity demonstrated via no sample matrix interferences) and acceptable stability (peak area fluctuations < 15%) of clinical samples under the proposed sample preparation conditions {(i) EDTA anticoagulant tube for the blood collection; (ii) 4 degrees C and 4 h between the sample collection and RBC isolation; (iii) phosphate-buffered saline for RBC washing and re-suspendation; (iv) -20 degrees C for RBC lysis and short-term storage; (v) 50 mmol/L phosphate buffer, pH 7.4, 10 mmol/L DTT as a stabilizing medium for TPN in RBC lysates} demonstrated the suitability of such protocol for a well-defined and reliable routine use in studies on thiopurines TDM. PMID- 30018219 TI - Structural Divergence in O-GlcNAc Glycans Displayed on Epidermal Growth Factor like Repeats of Mammalian Notch1. AB - Extracellular O-GlcNAc is a novel class of modification catalyzed by epidermal growth factor-like (EGF)-domain specific O-GlcNAc transferase (EOGT). In mammals, EOGT is required for ligand-mediated Notch signaling for vascular development. Previous studies have revealed that O-GlcNAc in mammalian cultured cells is subject to subsequent glycosylation, which may impose additional layers of regulation. This study aimed to analyze the O-GlcNAc glycans of Drosophila EGF20 as model substrates and mouse Notch1 EGF repeats by mass-spectrometry. The analysis of Drosophila EGF20 expressed in HEK293T cells revealed that the majority of the proteins are modified with an elongated form of O-GlcNAc glycan comprising terminal galactose or sialic acid residues. In contrast, recombinant Notch1 EGF repeats isolated from HEK293T cells revealed structural divergence of O-GlcNAc glycans among the different EGF domains. Although the majority of Notch1 EGF2 and EGF20 domains contained the extended forms of the glycan, the O-GlcNAc in many other domains mostly existed as a monosaccharide irrespective of the exogenous EOGT expression. Our results raised a hypothesis that an array of O GlcNAc monosaccharides may impact the structure and function of Notch receptors. PMID- 30018220 TI - Bioaccessibility and Bioavailability of a Marine-Derived Multimineral, Aquamin Magnesium. AB - Introduction: Magnesium is an essential mineral involved in a range of key biochemical pathways. Several magnesium supplements are present on the market and their degree of bioavailability differs depending on the form of magnesium salt used. Aquamin-Mg is a natural source of magnesium, containing 72 additional trace minerals derived from the clean waters off the Irish coast. However, the in vitro bioaccessibility and bioavailability of Aquamin-Mg in comparison with other supplement sources of magnesium has yet to be tested. Method: Aquamin-Mg, magnesium chloride (MgCl2) and magnesium oxide (MgO) were subjected to gastrointestinal digestion according to the harmonized INFOGEST in vitro digestion method and in vitro bioavailability tested using the Caco-2 cell model. Magnesium concentration was measured by atomic absorption spectrophotometry (AAS). Results: Magnesium recovery from both Aquamin-Mg and MgCl2 was greater than for MgO. Magnesium from all three sources was transported across the epithelial monolayer with Aquamin-Mg displaying a comparable profile to the more bioavailable MgCl2. Conclusions: Our data support that magnesium derived from a marine-derived multimineral product is bioavailable to a significantly greater degree than MgO and displays a similar profile to the more bioavailable MgCl2 and may offer additional health benefits given its multimineral profile. PMID- 30018221 TI - Impact of a Pilot School-Based Nutrition Intervention on Dietary Knowledge, Attitudes, Behavior and Nutritional Status of Syrian Refugee Children in the Bekaa, Lebanon. AB - This study evaluated the impact of a 6-month school nutrition intervention on changes in dietary knowledge, attitude, behavior (KAB) and nutritional status of Syrian refugee children. A quasi-experimental design was followed; Syrian refuge children in grades 4 to 6 were recruited from three informal primary schools (two intervention and one control) located in the rural Bekaa region of Lebanon. The intervention consisted of two main components: classroom-based education sessions and provision of locally-prepared healthy snacks. Data on household socio demographic characteristics, KAB, anthropometric measures and dietary intake of children were collected by trained field workers at baseline and post intervention. Of the 296 school children enrolled, 203 (68.6%) completed post intervention measures. Significant increases in dietary knowledge (beta = 1.22, 95% CI: 0.54, 1.89), attitude (beta = 0.69, 95% CI: 0.08, 1.30), and body mass index-for-age-z-scores (beta = 0.25, 95% CI = 0.10, 0.41) were observed among intervention vs. control groups, adjusting for covariates (p < 0.05). Compared to the control, the intervention group had, on average, significantly larger increases in daily intakes of total energy, dietary fiber, protein, saturated fat, and several key micronutrients, p < 0.05. Findings suggest a positive impact of this school-based nutrition intervention on dietary knowledge, attitude, and nutritional status of Syrian refugee children. Further studies are needed to test the feasibility and long-term impact of scaling-up such interventions. PMID- 30018223 TI - Sensitivity-Improved Ultrasonic Sensor for 3D Imaging of Seismic Physical Model Using a Compact Microcavity. AB - A sensitivity-improved ultrasonic sensor is proposed and demonstrated experimentally in this present study. The device is comprised only a fiber-optic microcavity that is formed by discharging a short section of hollow core fiber (HCF). The key to ensuring the success of the sensor relies on the preprocessing of hydrogen loading for HCF. When discharging the HCF, the hydrogen is heated up during the formation of the air bubble, which enlarges the bubble diameter, smoothens its surfaces simultaneously and decreases Young's modulus of the material of the bubble. Ultimately, this results in the probe being highly sensitive to ultrasound with a SNR of 69.28 dB. Once the compact air cavity is formed between the end face of the leading-in fiber and the top wall of the bubble, a well-defined interference spectrum is achieved based on the Fabry-Perot interference. By using spectral side-band filtering technology, we detect the ultrasonic waves reflected by the seismic physical model (SMF) and then reconstruct its three-dimensional image. PMID- 30018224 TI - Comparison of Accuracy of NUTRIC and Modified NUTRIC Scores in Predicting 28-Day Mortality in Patients with Sepsis: A Single Center Retrospective Study. AB - The NUTRIC (Nutrition Risk in the Critically Ill) and modified NUTRIC scores are nutrition risk assessment tools specifically for intensive care unit (ICU) patients. A modified NUTRIC score is composed of all variables except for IL-6 level in the NUTRIC score. Their use in qualifying critically ill patients at nutritional risk has been extensively evaluated, although not in studies of patients with sepsis, when interleukin 6 levels, which are not included in the modified NUTRIC score, may be elevated. The present study was a retrospective comparison of the accuracy of the NUTRIC and modified NUTRIC scores in predicting 28-day mortality of 482 adult patients with sepsis who were admitted to the medical ICU of a tertiary referral hospital in South Korea between January 2011 and June 2017 and who had ICU stays longer than 24 h. The NUTRIC and modified NUTRIC scores were calculated using data from the patients' electronic medical records relating to the first 24 h of admission to the ICU. The area under the curve of the NUTRIC Score for predicting 28-day mortality was 0.762 (95% confidence interval (CI): 0.718-0.806) and of the modified NUTRIC Score 0.757 (95% CI: 0.713-0.801). There was no significant difference between the two scores (p = 0.45). The modified NUTRIC score was a good nutritional risk assessment tool for critically ill septic patients. PMID- 30018225 TI - Highly Efficient and Reusable Montmorillonite/Fe3O4/Humic Acid Nanocomposites for Simultaneous Removal of Cr(VI) and Aniline. AB - Recyclable nanomaterials are in great need to develop clean technology for applications in the removal of water contaminants. In this work, easily separable montmorillonite/Fe3O4/humic acid (MFH) nanocomposites were fabricated through a facile hydrothermal route. It was found the adsorption ability and stability of MFH was significantly enhanced due to the synergistic effects between montmorillonite, Fe3O4 nanoparticles and humic acid. The MFH nanocomposites are highly efficient and recyclable as they can remove at least 82.3% of Cr(VI) and 95.1% of aniline in six consecutive runs. The adsorption mechanism was investigated by analyzing the kinetic parameters of pseudo first-order, pseudo second-order, and intraparticle diffusion models and describing the equilibrium isotherms of Langmuir and Freundlich models. Results indicated different adsorption mechanisms of Cr(VI) and aniline by MFH. The readily synthesized MFH nanocomposites can act as effective and practical materials for environmental applications. PMID- 30018226 TI - Oxidative Stability of Selected Edible Oils. AB - The aim of the study was to examine and compare oxidative stability of refined (peanut, corn, rice bran, grapeseed, and rapeseed) oils. The oils were subject a Schaal Oven Test (temperature 63 +/- 1 degrees C) and a Rancimat test (temperature 120 degrees C) and their stability was compared at the 1st and 12th month of storage. Changes in the peroxide (PV) and anisidine (AnV) values in the thermostat test were the fastest in rapeseed oil and grapeseed oil. The best quality was preserved by peanut and corn oils both in the first and the twelfth month of storage. The induction times for the rice bran, corn, peanut, and rapeseed oils were similar from 4.77 h to 5.02 h in the first month and from 3.22 h to 3.77 h in the twelfth month. The shortest induction times were determined for grapeseed oil: 2.4 h and 1.6 h, respectively. A decrease of oxidative stability of about 30% was found in all the oils after 12 months of storage. The PV of 10, determined in the thermostat and Rancimat tests, were achieved at the latest in corn oil and the fastest in rice bran oil. PMID- 30018222 TI - Mitochondrial Dysfunctions in Type I Endometrial Carcinoma: Exploring Their Role in Oncogenesis and Tumor Progression. AB - Type I endometrial cancer (EC) is the most common form of EC, displaying less aggressive behavior than type II. The development of type I endometrial cancer is considered a multistep process, with slow progression from normal endometrium to hyperplasia, the premalignant form, and endometrial cancer as a result of an unopposed estrogenic stimulation. The role of mitochondria in type I EC tumor progression and prognosis is currently emerging. This review aims to explore mitochondrial alterations in this cancer and in endometrial hyperplasia focusing on mitochondrial DNA mutations, respiratory complex I deficiency, and the activation of mitochondrial quality control systems. A deeper understanding of altered mitochondrial pathways in type I EC could provide novel opportunities to discover new diagnostic and prognostic markers as well as potential therapeutic targets. PMID- 30018227 TI - Dietary Patterns Prior to Pregnancy and Associations with Pregnancy Complications. AB - Few studies have explored pre-pregnancy diet and its relationship with pregnancy outcomes. The objectives of this study were to: (1) derive pre-pregnancy dietary patterns for women enrolled in a prospective cohort in the province of Alberta, Canada; (2) describe associations between dietary patterns and socio-demographic characteristics; and (3) describe associations between dietary patterns and pregnancy complications. Upon enrolment into the Alberta Pregnancy Outcomes and Nutrition (APrON) study (median age of gestation, 17 weeks), women (n = 1545) completed a validated 142-item food frequency questionnaire recording food and beverages consumed "in the 12 months prior to pregnancy". Other assessments included pre-pregnancy body mass index (BMI), gestational weight gain, gestational hypertension, gestational diabetes, and socio-demographic characteristics. Dietary patterns were derived using principal components analysis. Scores were calculated to represent adherence with each dietary pattern retained. Four dietary patterns were retained, accounting for 22.9% of the variation in the overall diet. Dietary patterns were named the "healthy", "meat and refined carbohydrate", "beans, cheese and salad" or "tea and coffee" patterns. Higher "healthy" pattern scores prior to pregnancy were associated with lower odds of developing gestational hypertension during pregnancy (adjusted Odds Ratio (OR): 0.6, 95% Confidence Intervals (CI): 0.4, 0.9). Diet prior to pregnancy is an important target for interventions and may reduce the likelihood of developing complications such as gestational hypertension during pregnancy. PMID- 30018228 TI - Preparation, Characterization, Pharmacokinetics and Biodistribution of Baicalin Loaded Liposome on Cerebral Ischemia-Reperfusion after i.v. Administration in Rats. AB - The dry root of Scutellaria baicalensis, has traditionally been applied in the treatment of cerebral ischemia in Chinese clinics. Baicalin (BA) is considered the key ingredient in it for the brain protection effects. The bioavailability of BA is very low because of its poor lipid and water solubility, which limits the therapeutic effects and clinical application. The aim of the present study was to develop a novel BA-loaded liposome (BA-LP) formulation to improve the drug lipophilicity and further to enhance the drug-concentration in the brain tissues. This study is also designed to investigate the pharmacokinetics of BA in the pathological conditions of stroke and evaluate the pharmacokinetic differences of BA caused by stroke after intravenous administration with BA and BA-LP. In this study, the novel BA-LP prepared in early stage were characterized by morphology, size, zeta potential, encapsulation rate and the in vitro release. The pharmacokinetics and biodistribution of BA and BA-LP were investigated by intravenous administration in rats with middle cerebral artery occlusion (MCAO) model and normal group respectively. BA-LP had a mean particle size of 160-190 nm, zeta potential of -5.7 mV, and encapsulation efficiency of 42 +/- 1%. The BA LP showed a sustained-release behavior, the in vitro drug-release kinetic model of BA-LP fit well with the biphasic dynamic model equation: Q = 1 - (60.12e0.56t 59.08e0.0014t). Pharmacokinetic behavior in MCAO rats is not consistent with that of normal rats. The middle cerebral artery occlusion rats got higher Cmax and AUC0-t, which were about 1.5-2 times to normal rats both in BA and liposome groups. In addition, it got especially higher distribution in brain, while BA were not detected in brain tissues on normal rats. The Cmax and AUC0-t values were significantly greater with liposome than BA on both normal and MCAO rats. The tissue distribution behavior was significantly altered in the case of liposome administrated in comparison with BA, which the concentrations in the heart, liver, spleen, lungs and brain were all increased after administrated liposome, but decreased in kidneys. The TI values showed that the target of liposome was improved especially to heart, spleen and brain, and the brain's target was higher in striatum and cerebellum. In conclusion, BA-LP might be a potential drug delivery system to improve the therapeutic efficacy of BA. In addition, these results also suggest that the pathological damages of ischemia reperfusion have a significant impact on the pharmacokinetic traits of BA. PMID- 30018229 TI - Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs. AB - BACKGROUND: The MEK (mitogen-activated protein kinase)-inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. METHODS: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b 3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. RESULTS: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. CONCLUSIONS: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR 146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC. PMID- 30018230 TI - Immunogenicity and Induction of Functional Antibodies in Rabbits Immunized with a Trivalent Typhoid-Invasive Nontyphoidal Salmonella Glycoconjugate Formulation. AB - Typhoid fever due to Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) infections caused by serovars Enteritidis (SE) and Typhimurium (STm) are major pediatric health problems in sub-Saharan Africa. Typhoid has high complication rates, and iNTS infections have high case fatality rates; moreover, emerging antimicrobial resistance is diminishing treatment options. Vi capsule-based typhoid conjugate vaccine (Typbar-TCVTM), licensed in India and pre-qualified by the World Health Organization, elicits durable immunity when administered to infants, but no iNTS vaccines are licensed or imminent. We have developed monovalent SE and STm glycoconjugate vaccines based on coupling lipopolysaccharide-derived core-O polysaccharide (COPS) to phase 1 flagellin protein (FliC) from the homologous serovar. Herein, we report the immunogenicity of multivalent formulations of iNTS COPS:FliC conjugates with Typbar-TCVTM. Rabbits immunized with the trivalent typhoid-iNTS glycoconjugate vaccine generated high titers of serum IgG antibody to all three polysaccharide antigens for which anti-COPS IgG antibodies were directed primarily against serogroup specific OPS epitopes. Responses to SE and STm FliC were lower relative to anti COPS titers. Post-vaccination rabbit sera mediated bactericidal activity in vitro, and protected mice after passive transfer against challenge with virulent SE or STm Malian blood isolates. These results support accelerated progression to clinical trials. PMID- 30018232 TI - Authentication of Herbal Medicines Dipsacus asper and Phlomoides umbrosa Using DNA Barcodes, Chloroplast Genome, and Sequence Characterized Amplified Region (SCAR) Marker. AB - Dried roots of Dipsacus asper (Caprifoliaceae) are used as important traditional herbal medicines in Korea. However, the roots are often used as a mixture or contaminated with Dipsacus japonicus in Korean herbal markets. Furthermore, the dried roots of Phlomoides umbrosa (Lamiaceae) are used indiscriminately with those of D. asper, with the confusing Korean names of Sok-Dan and Han-Sok-Dan for D. asper and P. umbrosa, respectively. Although D. asper and P. umbrosa are important herbal medicines, the molecular marker and genomic information available for these species are limited. In this study, we analysed DNA barcodes to distinguish among D. asper, D. japonicus, and P. umbrosa and sequenced the chloroplast (CP) genomes of D. asper and D. japonicus. The CP genomes of D. asper and D. japonicus were 160,530 and 160,371 bp in length, respectively, and were highly divergent from those of the other Caprifoliaceae species. Phylogenetic analysis revealed a monophyletic group within Caprifoliaceae. We also developed a novel sequence characterised amplified region (SCAR) markers to distinguish among D. asper, D. japonicus, and P. umbrosa. Our results provide important taxonomic, phylogenetic, and evolutionary information on the Dipsacus species. The SCAR markers developed here will be useful for the authentication of herbal medicines. PMID- 30018231 TI - Chlamydomonas Basal Bodies as Flagella Organizing Centers. AB - During ciliogenesis, centrioles convert to membrane-docked basal bodies, which initiate the formation of cilia/flagella and template the nine doublet microtubules of the flagellar axoneme. The discovery that many human diseases and developmental disorders result from defects in flagella has fueled a strong interest in the analysis of flagellar assembly. Here, we will review the structure, function, and development of basal bodies in the unicellular green alga Chlamydomonas reinhardtii, a widely used model for the analysis of basal bodies and flagella. Intraflagellar transport (IFT), a flagella-specific protein shuttle critical for ciliogenesis, was first described in C. reinhardtii. A focus of this review will be on the role of the basal bodies in organizing the IFT machinery. PMID- 30018233 TI - TRPA1 Modulating C14 Polyacetylenes from the Iranian Endemic Plant Echinophora platyloba. AB - Phytochemical investigation of the apolar extract obtained from aerial parts of the Iranian endemic plant Echinophora platyloba DC (Apiaceae) resulted in the characterization of the polyacetylene fraction of this plant. This resulted to be composed of the known echinophorins A and B, embedding the very rare alpha-pyrone terminal, and of the new echinophorin D (3), including also three conjugated triple bonds. The chemical structures of these compounds were secured by detailed inspection of MS and 1D/2D NMR spectra. The isolated polyacteylenes were evaluated for their modulation of six thermo-TRP channels and they revealed a selective activity on TRPA1, an ion channel involved in the mediation of neuropathic and inflammatory pain. This is the first report on the activity of plant polyacetylenes on transient receptor potential (TRP) channels. PMID- 30018234 TI - Micromechanical Modeling of the Elasto-Viscoplastic Behavior and Incompatibility Stresses of beta-Ti Alloys. AB - Near beta titanium alloys can now compete with quasi-alpha or alpha/beta titanium alloys for airframe forging applications. The body-centered cubic beta-phase can represent up to 40% of the volume. However, the way that its elastic anisotropy impacts the mechanical behavior remains an open question. In the present work, an advanced elasto-viscoplastic self-consistent model is used to investigate the tensile behavior at different applied strain rates of a fully beta-phase Ti alloy taken as a model material. The model considers crystalline anisotropic elasticity and plasticity. It is first shown that two sets of elastic constants taken from the literature can be used to well reproduce the experimental elasto-viscoplastic transition, but lead to scattered mechanical behaviors at the grain scale. Incompatibility stresses and strains are found to increase in magnitude with the elastic anisotropy factor. The highest local stresses are obtained toward the end of the elastic regime for grains oriented with their <111> direction parallel to the tensile axis. Finally, as a major result, it is shown that the elastic anisotropy of the beta-phase can affect the distribution of slip activities. In contrast with the isotropic elastic case, it is predicted that {112} <111> slip systems become predominant at the onset of plastic deformation when elastic anisotropy is considered in the micromechanical model. PMID- 30018236 TI - Ultraviolet Radiation Albedo and Reflectance in Review: The Influence to Ultraviolet Exposure in Occupational Settings. AB - Ultraviolet (UV) albedo and UV reflectance are defined, compared and contrasted, to explain their roles and place in studies focusing on UV radiation and exposure measurements, in the context of localised albedo measurement and human UV exposure studies. This review recommends that the term UV albedo be used when investigating natural horizontal surfaces when the albedo is not known to change significantly over time. The term UV reflectance should be mostly used for non natural surfaces and non-horizontal measurements and will change with respect to the geometry of the irradiances reflected and received, and due to the intrinsic nature of the surface itself. UV albedo measurements made in the literature have been compiled, in both broadband and spectral UV albedo measurements. Broadband measurements have been tabulated and spectral UV measurements have been displayed visually. The methodology of measurements is briefly discussed. Finally, studies that consider how high albedo or reflectance sites influence UV exposure are reviewed. It was concluded that there is currently no known relationship between the albedo or reflectance of a surface and the resulting influence it has on individual UV exposure. This presents an opportunity for researchers to continue exploring the influence of reflective UV surfaces. PMID- 30018235 TI - Production of beta-Lactamase Inhibitors by Streptomyces Species. AB - beta-Lactamase inhibitors have emerged as an effective alternative to reduce the effects of resistance against beta-lactam antibiotics. The Streptomyces genus is known for being an exceptional natural source of antimicrobials and beta lactamase inhibitors such as clavulanic acid, which is largely applied in clinical practice. To protect against the increasing prevalence of multidrug resistant bacterial strains, new antibiotics and beta-lactamase inhibitors need to be discovered and developed. This review will cover an update about the main beta-lactamase inhibitors producers belonging to the Streptomyces genus; advanced methods, such as genetic and metabolic engineering, to enhance inhibitor production compared with wild-type strains; and fermentation and purification processes. Moreover, clinical practice and commercial issues are discussed. The commitment of companies and governments to develop innovative strategies and methods to improve the access to new, efficient, and potentially cost-effective microbial products to combat the antimicrobial resistance is also highlighted. PMID- 30018237 TI - Valence and Intensity of Video Stimuli of Dogs and Conspecifics in Sheep: Approach-Avoidance, Operant Response, and Attention. AB - Stimuli are often presumed to be either negative or positive. However, animals' judgement of their negativity or positivity cannot generally be assumed. A possibility to assess emotional states in animals elicited by stimuli is to investigate animal preferences and their motivation to gain access to these stimuli. This study's aim was to assess the valence of social stimuli in sheep. We used silent videos of varying intensity of dogs as negative versus conspecifics as positive stimuli in three approaches: (1) an approach-avoidance paradigm; (2) operant conditioning using the video stimuli as reinforcers; and (3) an attention test. In the latter, we assessed differential attention of sheep to simultaneous projections by automatically tracking sheep head and ear postures and recording brain activity. With these approaches, it was difficult to support that the sheep's reactions varied according to the stimuli's presumed valence and intensity. The approach-avoidance paradigm and attention test did not support the assumption that dog videos were more negative than sheep videos, though sheep reacted to the stimuli presented. Results from the operant conditioning indicated that sheep were more prone to avoid videos of moving dogs. Overall, we found that standard video images may not be ideal to represent valence characteristics of stimuli to sheep. PMID- 30018239 TI - An Evolutionary Mechanism for the Generation of Competing RNA Structures Associated with Mutually Exclusive Exons. AB - Alternative splicing is a commonly-used mechanism of diversifying gene products. Mutually exclusive exons (MXE) represent a particular type of alternative splicing, in which one and only one exon from an array is included in the mature RNA. A number of genes with MXE do so by using a mechanism that depends on RNA structure. Transcripts of these genes contain multiple sites called selector sequences that are all complementary to a regulatory element called the docking site; only one of the competing base pairings can form at a time, which exposes one exon from the cluster to the spliceosome. MXE tend to have similar lengths and sequence content and are believed to originate through tandem genomic duplications. Here, we report that pre-mRNAs of this class of exons have an increased capacity to fold into competing secondary structures. We propose an evolutionary mechanism for the generation of such structures via duplications that affect not only exons, but also their adjacent introns with stem-loop structures. If one of the two arms of a stem-loop is duplicated, it will generate two selector sequences that compete for the same docking site, a pattern that is associated with MXE splicing. A similar partial duplication of two independent stem-loops produces a pattern that is consistent with the so-called bidirectional pairing model. These models explain why tandem exon duplications frequently result in mutually exclusive splicing. PMID- 30018238 TI - Environmentally Sustainable and Ecosafe Polysaccharide-Based Materials for Water Nano-Treatment: An Eco-Design Study. AB - Nanoremediation, which is the use of nanoparticles and nanomaterials for environmental remediation, is widely explored and proposed for preservation of ecosystems that suffer from the increase in human population, pollution, and urbanization. We herein report a critical analysis of nanotechnologies for water remediation by assessing their sustainability in terms of efficient removal of pollutants, appropriate methods for monitoring their effectiveness, and protocols for the evaluation of any potential environmental risks. Our purpose is to furnish fruitful guidelines for sustainable water management, able to promote nanoremediation also at European level. In this context, we describe new nanostructured polysaccharide-based materials obtained from renewable resources as alternative efficient and ecosafe solutions for water nano-treatment. We also provide eco-design indications to improve the sustainability of the production of these materials, based on life-cycle assessment methodology. PMID- 30018240 TI - Dietary Acid Load, IGF-1 Single Nucleotide Polymorphism and Bone Resorption among Postmenopausal Chinese Women. AB - The interaction of dietary and genetic factors may affect the development of bone deterioration. This study investigated whether the effects of dietary acid load (DAL) on bone loss in postmenopausal Chinese women were moderated by the insulin like growth factor-1 (IGF-1) single nucleotide polymorphism, a known gene that plays a role in the regulation of bone formation and bone remodeling. A total of 217 healthy participants were recruited from the National Council of Senior Citizens Organizations Malaysia. Serum collagen type 1 cross-linked C-telopeptide was used as a surrogate bone marker to assess bone resorption and Agena(r) MassARRAY genotyping analysis was used to identify the signaling of IGF-1 rs35767. The dietary acid load was measured by potential renal acid load score while physical activity was ascertained using the Global Physical Activity Questionnaire. Hierarchical regression was applied to test the main and interaction effects of DAL and IGF-1 genotypes in bone resorption. The result supported the diet-dependent acid-base balance theory that higher DAL was positively associated with bone resorption (beta = 0.152, p = 0.031, F(6,207) = 2.11, sig-F = 0.036, R2 = 0.079). However, the results indicated that there was no significant correlation between IGF-1 and bone resorption, or any significant interaction between DAL and IGF-1. In conclusion, there was no moderating effect of IGF-1 on the relationship between DAL and bone resorption. PMID- 30018241 TI - Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake. AB - Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity. PMID- 30018242 TI - The Effects of High-Intensity Interval Training vs. Moderate-Intensity Continuous Training on Heart Rate Variability in Physically Inactive Adults. AB - Physically inactive adults are prevalent worldwide. This study compared the effects of short-term high-intensity interval training (HIIT) versus moderate intensity continuous training (MICT) on heart rate variability (HRV) in physically inactive adults as a preliminary study. Thirteen physically inactive male adults (27.5 +/- 3.80 years) were randomly assigned to HIIT (N = 7) or MICT (N = 6). The HIIT program consisted of 20 min of interval training with cycling to rest ratio of 10/50 s at >=90% HRpeak, while the MICT program consisted of 40 min of continuous cycling at 60-75% HRpeak. Both groups completed eight sessions of training within two weeks. Time and frequency domains of HRV were measured for 20 min with Actiwave-Cardio monitor (CamNtech, UK). The number of R-R interval and inter-beat interval (IBI) were significantly improved (p < 0.05) in both HIIT and MICT programs following eight sessions of training. A significant interaction effect for group by time was found in the lnLF/HF ratio (p < 0.05) where it was only improved in the HIIT group from pre- to post-test. The HIIT program is superior to MICT in improving HRV in physically inactive adults. The HIIT program can be applied as a time-efficient program for improving cardiac-autoregulation. PMID- 30018243 TI - Regional Variation in Pharmacist Perception of the Financial Impact of Medicare Part D. AB - The objective of this study was to perform a nationwide investigation of the financial performance of community pharmacies in the United States since the inception of Medicare Part D. A nationwide, cross-sectional survey of pharmacists was conducted in 2013. The 43-item online survey collected information about demographics, financial implications of Part D on community pharmacy and patients, provision of Medication Therapy Management (MTM) services and opinions about Medicare Part D 2010 updates. The adjusted response rate was 22.3% (419/1885). A majority of respondents (75.6%) reported a stable or increased prescription volume since 2006 but only 40.4% indicated that the financial performance of their pharmacy as either excellent or good during the same period. Owners and part-owners of rural independent pharmacies were more likely to report a below average or poor financial performance (75.0%). The provision of MTM services was not related to the financial performance of the pharmacy. Nearly half (44.7%) of pharmacy owners or part-owners indicated that they were considering selling their pharmacy, with most (94.1%) reporting that their decision to sell was due to the Part D financial pressures. However, the decision to sell was not related to the change in financial performance since 2006 or the volume of prescriptions dispensed. PMID- 30018244 TI - Shared Decision-Making and Women's Adherence to Breast and Cervical Cancer Screenings. AB - We examined the effect of shared decision-making (SDM) on women's adherence to breast and cervical cancer screenings and estimated the prevalence and adherence rate of screenings. The study used a descriptive cross-sectional design using the 2017 Health Information National Trends Survey (HINTS) data collected by the National Cancer Institute. Adherence was defined based on the guidelines from the American Cancer Society and the composite measure of shared decision-making was constructed using three items in the data. Multivariable logistic regression was performed to examine the association between the SDM and adherence, controlling for cancer beliefs and socio-demographic variables. The analysis included 742 responses. Weighted to represent the U.S. population, 68.1% adhered to both breast and cervical cancer screening guidelines. The composite measure of SDM was reliable (alpha = 0.85), and a higher SDM score was associated with women's screening adherence (b = 0.17; p = 0.009). There were still women who did not receive cancer screenings as recommended. The results suggest that the use of the SDM approach for healthcare professionals' communication with patients can improve screening adherence. PMID- 30018245 TI - Health Management Decision of Sensor System Based on Health Reliability Degree and Grey Group Decision-Making. AB - Metal Oxide Semiconductor (MOS) gas sensor has been widely used in sensor systems for the advantages of fast response, high sensitivity, low cost, and so on. But, limited to the properties of materials, the phenomenon, such as aging, poisoning, and damage of the gas sensitive material will affect the measurement quality of MOS gas sensor array. To ensure the stability of the system, a health management decision strategy for the prognostics and health management (PHM) of a sensor system that is based on health reliability degree (HRD) and grey group decision making (GGD) is proposed in this paper. The health management decision-making model is presented to choose the best health management strategy. Specially, GGD is utilized to provide health management suggestions for the sensor system. To evaluate the status of the sensor system, a joint HRD-GGD framework is declared as the health management decision-making. In this method, HRD of sensor system is obtained by fusing the output data of each sensor. The optimal decision-making recommendations for health management of the system is proposed by combining historical health reliability degree, maintenance probability, and overhaul rate. Experimental results on four different kinds of health levels demonstrate that the HRD-GGD method outperforms other methods in decision-making accuracy of sensor system. Particularly, the proposed HRD-GGD decision-making method achieves the best decision accuracy of 98.25%. PMID- 30018247 TI - An Advanced View on Baculovirus per Os Infectivity Factors. AB - Baculoviruses are arthropod-specific large DNA viruses that orally infect the larvae of lepidopteran, hymenopteran and dipteran insect species. These larvae become infected when they eat a food source that is contaminated with viral occlusion bodies (OBs). These OBs contain occlusion-derived viruses (ODVs), which are released upon ingestion of the OBs and infect the endothelial midgut cells. At least nine different ODV envelope proteins are essential for this oral infectivity and these are denoted per os infectivity factors (PIFs). Seven of these PIFs form a complex, consisting of PIF1, 2, 3 and 4 that form a stable core complex and PIF0 (P74), PIF6 and PIF8 (P95) that associate with this complex with lower affinity than the core components. The existence of a PIF complex and the fact that the pif genes are conserved in baculovirus genomes suggests that PIF proteins cooperatively mediate oral infectivity rather than as individual functional entities. This review therefore discusses the knowledge obtained for individual PIFs in light of their relationship with other members of the PIF complex. PMID- 30018249 TI - Development of Wheel Pressure Control Algorithm for Electronic Stability Control (ESC) System of Commercial Trucks. AB - This paper presents a wheel cylinder pressure control algorithm for application to the vehicle electronic stability control (ESC) systems for commercial trucks. An ESC system is an active system that improves the driving stability by distributing the appropriate braking pressure to each wheel, which is an essential system for safe driving. It is important that the ESC system, through proper braking pressure supply, delivers the correct pressure under control. However, to reduce the cost involved, commercial trucks use a solenoid valve of the on/off-type, rather than a proportional valve that has good pressure control capability. The performance of a proposed wheel pressure control system based on an on/off solenoid valve control was verified by means of experiments conducted using the wheel pressure control algorithm presented in this paper. PMID- 30018246 TI - A Sterol from Soft Coral Induces Apoptosis and Autophagy in MCF-7 Breast Cancer Cells. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that plays a key role in regulating cellular metabolism, and is a therapeutic target for cancer therapy. To search for potential PPARgamma activators, a compound library comprising 11 marine compounds was examined. Among them, a sterol, 3beta,11-dihydroxy-9,11-secogorgost-5-en-9-one (compound 1), showed the highest PPARgamma activity with an IC50 value of 8.3 MUM for inhibiting human breast adenocarcinoma cell (MCF-7) growth. Western blotting experiments showed that compound 1 induces caspase activation and PARP cleavage. In addition, compound 1 modulated the expression of various PPARgamma-regulated downstream biomarkers including cyclin D1, cyclin-dependent kinase (CDK)6, B-cell lymphoma 2 (Bcl-2), p38, and extracellular-signal-regulated kinase (ERK). Moreover, compound 1 increased reactive oxygen species (ROS) generation, upregulated the phosphorylation and expression of H2AX, and induced autophagy. Interestingly, pre-treatment with the autophagy inhibitor 3-methyladenine rescued cells from compound 1-induced growth inhibition, which indicates that the cytotoxic effect of compound 1 is, in part, attributable to its ability to induce autophagy. In conclusion, these findings suggest the translational potential of compound 1 in breast cancer therapy. PMID- 30018248 TI - Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs. AB - Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre malignant immortalised cells, we ectopically expressed telomerase in telomere compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period-aggravated by p53 deficiency-and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy. PMID- 30018250 TI - The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors. AB - BACKGROUND: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. METHODS: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. RESULTS: From the 46 GCs, 27 tested MSI-high/EBV-, 15 tested MSS/EBV+ and four tested MSS/EBV-. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV- GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV- GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD 1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. CONCLUSIONS: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications. PMID- 30018252 TI - An Ultrahigh Sensitivity Acetone Sensor Enhanced by Light Illumination. AB - Au:SmFe0.9Zn0.1O3 is synthesized by a sol-gel method and annealed at 750 degrees C. Through XRD, SEM and XPS analysis methods, the microstructure of the material has been observed. The average particle size is about 50 nm. The sensor shows a high sensitivity toward acetone vapor. As the relative humidity increases, the resistance and sensitivity of the sensor decline. To obtain a low optimum operating temperature, light illumination with different wavelengths has been introduced. The sensitivity toward acetone is improved at lower operating temperature when the sensor is irradiated by light. The smaller the wavelengths, the better the sensitivity of the sensor. Compared with other gases, the sensor shows excellent selectivity to acetone vapor, with better sensitivity, selectivity and stability when under light illumination. PMID- 30018253 TI - Anti-glycation, Carbonyl Trapping and Anti-inflammatory Activities of Chrysin Derivatives. AB - The aim of this study was searching anti-glycation, carbonyl trapping and anti inflammatory activities of chrysin derivatives. The inhibitory effect of chrysin on advanced glycation end-products (AGEs) was investigated by trapping methylglyoxal (MGO), and MGO-conjugated adducts of chrysin were analyzed using LC MS/MS. The mono- or di-MGO-conjugated adducts of chrysin were present at 63.86 and 29.69% upon 48 h of incubation at a chrysin:MGO ratio of 1:10. The MGO adducted positions on chrysin were at carbon 6 or 6 & 8 in the A ring by classic aldol condensation. To provide applicable knowledge for developing chrysin derivatives as AGE inhibitors, we synthesized several O-alkyl or ester derivatives of chrysin and compared their AGE formation inhibitory, anti inflammatory, and water solubility characteristics. The results showed that 5,7 di-O-acetylchrysin possessed higher AGE inhibitory and water solubility qualities than original chrysin, and retained the anti-inflammation activity. These results suggested that 5,7-di-O-acetylchrysin could be a potent functional food ingredient as an AGE inhibitor and anti-inflammatory agent, and promotes the development of the use of chrysin in functional foods. PMID- 30018251 TI - Antiulcer Agents: From Plant Extracts to Phytochemicals in Healing Promotion. AB - In this narrative review, we have comprehensively reviewed the plant sources used as antiulcer agents. From traditional uses as herbal remedies, we have moved on to preclinical evidence, critically discussing the in vitro and in vivo studies focusing on plant extracts and even isolated phytochemicals with antiulcerogenic potential. A particular emphasis was also paid to Helicobacter pylori activity, with emphasis on involved mechanisms of action. Lastly, the issue of safety profile of these plant products has also been addressed. PMID- 30018254 TI - Protective Effect of Sulfated Polysaccharides from Celluclast-Assisted Extract of Hizikia fusiforme Against Ultraviolet B-Induced Skin Damage by Regulating NF kappaB, AP-1, and MAPKs Signaling Pathways In Vitro in Human Dermal Fibroblasts. AB - Our previous study evaluated the antioxidant activities of sulfated polysaccharides from Celluclast-assisted extract of Hizikia fusiforme (HFPS) in vitro in Vero cells and in vivo in zebrafish. The results showed that HFPS possesses strong antioxidant activity and suggested the potential photo protective activities of HFPS. Hence, in the present study, we investigated the protective effects of HFPS against ultraviolet (UV) B-induced skin damage in vitro in human dermal fibroblasts (HDF cells). The results indicate that HFPS significantly reduced intracellular reactive oxygen species (ROS) level and improved the viability of UVB-irradiated HDF cells in a dose-dependent manner. Furthermore, HFPS significantly inhibited intracellular collagenase and elastase activities, remarkably protected collagen synthesis, and reduced matrix metalloproteinases (MMPs) expression by regulating nuclear factor kappa B (NF kappaB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPKs) signaling pathways in UVB-irradiated HDF cells. These results suggest that HFPS possesses strong UV protective effect, and can be a potential ingredient in the pharmaceutical and cosmetic industries. PMID- 30018255 TI - Realization of Lasing Emission from One Step Fabricated WSe2 Quantum Dots. AB - Two-dimensional (2D) transition-metal dichalcogenides (TMDCs) quantum dots (QDs) are the vanguard due to their unique properties. In this work, WSe2 QDs were fabricated via one step ultrasonic probe sonication. Excitation wavelength dependent photoluminescence (PL) is observed from WSe2 QDs. Room-temperature lasing emission which benefits from 3.7 times enhancement of PL intensity by thermal treatment at ~470 nm was achieved with an excitation threshold value of ~3.5 kW/cm2 in a Fabry-Perot laser cavity. To the best of our knowledge, this is the first demonstration of lasing emission from TMDCs QDs. This indicates that TMDCs QDs are a superior candidate as a new type of laser gain medium. PMID- 30018256 TI - Breast Cancer Stem Cells. AB - Breast cancer stem cells (BCSC) have been implicated in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. The origins of BCSCs remain controversial due to tumor heterogeneity and the presence of such small side populations for study, but nonetheless, cell surface markers and their correlation with BCSC functionality continue to be identified. BCSCs are driven by persistent activation of developmental pathways, such as Notch, Wnt, Hippo, and Hedgehog and new treatment strategies that are aimed at these pathways are in preclinical and clinical development. PMID- 30018258 TI - Establishment and Characterization of the Novel High-Grade Serous Ovarian Cancer Cell Line OVPA8. AB - High-grade serous ovarian carcinoma (HGSOC) is the most frequent histological type of ovarian cancer and the one with worst prognosis. Unfortunately, the majority of established ovarian cancer cell lines which are used in the research have unclear histological origin and probably do not represent HGSOC. Thus, new and reliable models of HGSOC are needed. Ascitic fluid from a patient with recurrent HGSOC was used to establish a stable cancer cell line. Cells were characterized by cytogenetic karyotyping and short tandem repeat (STR) profiling. New generation sequencing was applied to test for hot-spot mutations in 50 cancer associated genes and fluorescence in situ hybridization (FISH) analysis was used to check for TP53 status. Cells were analyzed for expression of several marker genes/proteins by reverse-transcription polymerase chain reaction (RT-PCR), fluorescence-activated cell sorting (FACS), and immunocytochemistry (ICC). Functional tests were performed to compare OVPA8 cells with five commercially available and frequently used ovarian cancer cell lines: SKOV3, A2780, OVCAR3, ES2, and OAW42. Our newly-established OVPA8 cell line shows morphologic and genetic features consistent with HGSOC, such as epithelial morphology, multiple chromosomal aberrations, TP53 mutation, BRCA1 mutation, and loss of one copy of BRCA2. The OVPA8 line has a stable STR profile. Cells are positive for EpCAM, CK19, and CD44; they have relatively low plating efficiency/ability to form spheroids, a low migration rate, and intermediate invasiveness in matrigel, as compared to other ovarian cancer lines. OVPA8 is sensitive to paclitaxel and resistant to cisplatin. We also tested two FGFR inhibitors; OVPA8 cells were resistant to AZD4547 (AstraZeneca, London, UK), but sensitive to the new inhibitor CPL304-110-01 (Celon Pharma, Lomianki/Kielpin, Poland). We have established and characterized a novel cell line, OVPA8, which can be a valuable preclinical model for studies on high-grade serous ovarian cancer. PMID- 30018257 TI - Synthesis and Biological Activity of Sterol 14alpha-Demethylase and Sterol C24 Methyltransferase Inhibitors. AB - Sterol 14alpha-demethylase (SDM) is essential for sterol biosynthesis and is the primary molecular target for clinical and agricultural antifungals. SDM has been demonstrated to be a valid drug target for antiprotozoal therapies, and much research has been focused on using SDM inhibitors to treat neglected tropical diseases such as human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis. Sterol C24-methyltransferase (24-SMT) introduces the C24-methyl group of ergosterol and is an enzyme found in pathogenic fungi and protozoa but is absent from animals. This difference in sterol metabolism has the potential to be exploited in the development of selective drugs that specifically target 24 SMT of invasive fungi or protozoa without adversely affecting the human or animal host. The synthesis and biological activity of SDM and 24-SMT inhibitors are reviewed herein. PMID- 30018260 TI - Optical Strain Measurement with Step-Index Polymer Optical Fiber Based on the Phase Measurement of an Intensity-Modulated Signal. AB - Polymer optical fibers (POFs) have been proposed for optical strain sensors due to their large elastic strain range compared to glass optical fibers (GOFs). The phase response of a single-mode polymer optical fiber (SM-POF) is well-known in the literature, and depends on the physical deformation of the fiber as well as the impact on the refractive index of the core. In this paper, we investigate the impact of strain on a step-index polymer optical fiber (SI-POF). In particular, we discuss the responsivity of an optical strain sensor which is based on the phase measurement of an intensity-modulated signal. In comparison to the phase response of an SM-POF, we must take additional influences into account. Firstly, the SI-POF is a multi-mode fiber (MMF). Consequently, we not only consider the strain dependence of the refractive index, but also its dependency on the propagation angle thetaz. Second, we investigate the phase of an intensity modulated signal. The development of this modulation phase along the fiber is influenced by modal dispersion, scattering, and attenuation. The modulation phase therefore has no linear dependency on the length of the fiber, even in the unstrained state. For the proper consideration of these effects, we rely on a novel model for step-index multi-mode fibers (SI-MMFs). We expand the model to consider the strain-induced effects, simulate the strain responsivity of the sensor, and compare it to experimental results. This led to the conclusion that the scattering behavior of a SI-POF is strain-dependent, which was further proven by measuring the far field at the end of a SI-POF under different strain conditions. PMID- 30018259 TI - Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents. AB - Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (B. subtilis, S. aureus) and three Gram-negative (P. aeruginosa, S. typhi, K. pneumonia) pathogenic strains. A molecular docking study, performed in the crystal structure of 50S ribosomal unit of Haloarcula marismortui, indicated that pyrimidine-oxazolidin-2-arylimino hybrids 8c and 8h exhibited a high binding affinity (-9.65 and -10.74 kcal/mol), which was in agreement with their good antibacterial activity. The obtained results suggest that the combination of pyrimidine and oxazolidone moieties can be considered as a valid basis to develop new further modifications towards more efficacious antibacterial compounds. PMID- 30018261 TI - Biomarker Evaluation and Toxic Effects of an Acute Oral and Systemic Fumonisin Exposure of Pigs with a Special Focus on Dietary Fumonisin Esterase Supplementation. AB - The mycotoxin fumonisin B1 (FB1) is a frequent contaminant of feed. It causes a disruption of sphingolipid metabolism and pulmonary, hepatic, and immunological lesions in pigs depending on the exposure scenario. One sensitive biomarker for FB1 exposure is the sphinganine (Sa) to sphingosine (So) ratio in blood. The fumonisin esterase FumD, which can be used as a feed additive, converts FB1 into the much less toxic metabolite hydrolyzed FB1 (HFB1). We conducted a single-dose study with barrows allocated to one of five treatments: (1) control (feed, 0.9% NaCl intravenously iv), (2) 139 nmol FB1 or (3) HFB1/kg BW iv, (4) 3425 nmol FB1/kg BW orally (po), or (5) 3321 nmol FB1/kg BW and 240 U FumD/kg feed po. The Sa/So ratio of iv and po FB1 administered groups was significantly elevated in blood and Liquor cerebrospinalis, but no fumonisin-associated differences were reflected in other endpoints. Neither clinical lung affections nor histopathological pulmonary lesions were detected in either group, while some parameters of hematology and clinical biochemistry showed a treatment-time interaction. FumD application resulted in Sa/So ratios comparable to the control, indicating that the enzymatic treatment was effectively preventing the fumonisin induced disruption of sphingolipid metabolism. PMID- 30018264 TI - A Pilot Study Investigating a Novel Non-Linear Measure of Eyes Open versus Eyes Closed EEGSynchronization in People with Alzheimer's Disease and Healthy Controls AB - BACKGROUND: The incidence of Alzheimer disease (AD) is increasing with the ageing population. The development of low cost non-invasive diagnostic aids for AD is a research priority. This pilot study investigated whether an approach based on a novel dynamic quantitative parametric EEG method could detect abnormalities in people with AD. METHODS: 20 patients with probable AD, 20 matched healthy controls (HC) and 4 patients with probable fronto temporal dementia (FTD) were included. All had detailed neuropsychology along with structural, resting state fMRI and EEG. EEG data were analyzed using the Error Reduction Ratio-causality (ERR-causality) test that can capture both linear and nonlinear interactions between different EEG recording areas. The 95% confidence intervals of EEG levels of bi-centroparietal synchronization were estimated for eyes open (EO) and eyes closed (EC) states. RESULTS: In the EC state, AD patients and HC had very similar levels of bi-centro parietal synchronization; but in the EO resting state, patients with AD had significantly higher levels of synchronization (AD = 0.44; interquartile range (IQR) 0.41 vs. HC = 0.15; IQR 0.17, p < 0.0001). The EO/EC synchronization ratio, a measure of the dynamic changes between the two states, also showed significant differences between these two groups (AD ratio 0.78 versus HC ratio 0.37 p < 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075; IQR 0.03, p < 0.0001). However, the EO/EC ratio was not informative in the FTD group due to very low levels of synchronization in both states (EO and EC). CONCLUSION: In this pilot work, resting state quantitative EEG shows significant differences between healthy controls and patients with AD. This approach has the potential to develop into a useful non-invasive and economical diagnostic aid in AD. PMID- 30018262 TI - Interactions between Vitamin D Status, Calcium Intake and Parathyroid Hormone Concentrations in Healthy White-Skinned Pregnant Women at Northern Latitude. AB - Adverse effects of low vitamin D status and calcium intakes in pregnancy may be mediated through functional effects on the calcium metabolic system. Little explored in pregnancy, we aimed to examine the relative importance of serum 25 hydroxyvitamin D (25(OH)D) and calcium intake on parathyroid hormone (PTH) concentrations in healthy white-skinned pregnant women. This cross-sectional analysis included 142 participants (14 +/- 2 weeks' gestation) at baseline of a vitamin D intervention trial at 51.9 degrees N. Serum 25(OH)D, PTH, and albumin corrected calcium were quantified biochemically. Total vitamin D and calcium intakes (diet and supplements) were estimated using a validated food frequency questionnaire. The mean +/- SD vitamin D intake was 10.7 +/- 5.2 MUg/day. With a mean +/- SD serum 25(OH)D of 54.9 +/- 22.6 nmol/L, 44% of women were <50 nmol/L and 13% <30 nmol/L. Calcium intakes (mean +/- SD) were 1182 +/- 488 mg/day and 23% of participants consumed <800 mg/day. The mean +/- SD serum albumin-adjusted calcium was 2.2 +/- 0.1 mmol/L and geometric mean (95% CI) PTH was 9.2 (8.4, 10.2) pg/mL. PTH was inversely correlated with serum 25(OH)D (r = -0.311, p < 0.001), but not with calcium intake or serum calcium (r = -0.087 and 0.057, respectively, both p > 0.05). Analysis of variance showed that while serum 25(OH)D (dichotomised at 50 nmol/L) had a significant effect on PTH (p = 0.025), calcium intake (<800, 800-1000, >=1000 mg/day) had no effect (p = 0.822). There was no 25(OH)D-calcium intake interaction effect on PTH (p = 0.941). In this group of white-skinned women with largely sufficient calcium intakes, serum 25(OH)D was important for maintaining normal PTH concentration. PMID- 30018266 TI - The Spatio-Temporal Disparities of Areas Benefitting from the Wind Erosion Prevention Service. AB - Ecosystem services are closely linked to human welfare. The flow of ecosystem service can establish spatio-temporal relationships between ecosystem service provision areas (SPAs) and service beneficiary areas (SBAs). In this study, the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model was used to simulate the spatial flow path of the wind erosion prevention (WEP) service in Yanchi County. The frequency at which the simulated trajectories passed through each grid cell was used as a proxy for spatio-temporal disparities in SBAs, and the distribution of benefitting land cover, population, and gross domestic product (GDP) reflected the effects of the WEP flow. The flow paths of the Yanchi County WEP in 2010 mainly extended to eastern and central China, North Korea, South Korea, Japan, Mongolia, and eastern Russia, and were more intensive and longer in spring and winter than in autumn and winter. The SBAs covered an area of 1153.2 * 104 km2 in 2010, with dominant service beneficiary areas (DSBAs) comprising 185.1 * 104 km2 and accounting for 16.1% of the total beneficiary area of the year. The areas through which the flow paths passed with a high frequency (>=10%) were mainly located in Shaanxi, Shanxi, Henan, western Shandong, Hebei, Beijing, and northern Hubei, and the spatial scale of these areas varied, demonstrating obvious seasonal changes, and was the largest in spring. The benefitting land cover was mainly cropland across all of the SBAs, with one billion benefitting people (accounting for 77.11% of the total population of China) associated with a gross domestic product (GDP) of 26.8 trillion RMB (Chinese currency; as of 2018-06-22, 6.497 RMB = US $1, accounting for 87.90% of the total GDP of China). Furthermore, the population and socio-economic development in the DSBAs (21 million people and 0.53 trillion RMB GDP) were no longer affected by wind erosion from Yanchi County. This study revealed the spatio-temporal disparities of the SBAs of WEP in Yanchi County from an ecosystem services flow perspective and provides a scientific and effective basis for policymakers to perform standard ecological compensation accounting and to formulate ecological protection policies. PMID- 30018267 TI - Dissimilarity Metric Based on Local Neighboring Information and Genetic Programming for Data Dissemination in Vehicular Ad Hoc Networks (VANETs). AB - This paper presents a novel dissimilarity metric based on local neighboring information and a genetic programming approach for efficient data dissemination in Vehicular Ad Hoc Networks (VANETs). The primary aim of the dissimilarity metric is to replace the Euclidean distance in probabilistic data dissemination schemes, which use the relative Euclidean distance among vehicles to determine the retransmission probability. The novel dissimilarity metric is obtained by applying a metaheuristic genetic programming approach, which provides a formula that maximizes the Pearson Correlation Coefficient between the novel dissimilarity metric and the Euclidean metric in several representative VANET scenarios. Findings show that the obtained dissimilarity metric correlates with the Euclidean distance up to 8.9% better than classical dissimilarity metrics. Moreover, the obtained dissimilarity metric is evaluated when used in well-known data dissemination schemes, such as p-persistence, polynomial and irresponsible algorithm. The obtained dissimilarity metric achieves significant improvements in terms of reachability in comparison with the classical dissimilarity metrics and the Euclidean metric-based schemes in the studied VANET urban scenarios. PMID- 30018265 TI - Stachys sieboldii Extract Supplementation Attenuates Memory Deficits by Modulating BDNF-CREB and Its Downstream Molecules, in Animal Models of Memory Impairment. AB - Cholinergic dysfunction, impaired brain-derived neurotrophic factor and cAMP response element binding protein (BDNF-CREB) signaling are one of the major pathological hallmarks of cognitive impairment. Therefore, improving cholinergic neurotransmission, and regulating the BDNF-CREB pathway by downregulating apoptosis genes is one strategy for inhibiting the etiology of dementia. This study evaluates the potential effects of Stachys sieboldii MIQ (SS) extract against cognitive dysfunction and its underlying mechanisms. SS supplementation for 33 days improved scopolamine-induced memory impairment symptoms in Morris water maze test and Y-maze test. SS reduced the acetylcholineesterase activity and significantly increase acetylcholine and cholineacetyltransferase activity in the brain. In the subsequent mechanism study, SS regulated the mRNA expression level of neuronal plasticity molecules such as (nerve growth factor) NGF, BDNF, CREB, and its downstream molecules such as Bcl-2 and Egr-1 by downregulating the neuronal apoptosis targets in both hippocampus and frontal cortex. Additionally, inward currents caused by SS in hippocampal CA1 neurons was partially blocked by the GABA receptor antagonist picrotoxin (50 MUM), suggesting that SS acts on synaptic/extrasynaptic GABAA receptors. These findings indicate that SS may function in a way that is similar to nootropic drugs by inhibiting cholinergic abnormalities, and neuronal apoptosis targets and ultimately increasing the expression of BDNF-CREB. PMID- 30018263 TI - Gut Microbiota and Mucosal Immunity in the Neonate. AB - Gut microbiota colonization is a complex, dynamic, and step-wise process that is in constant development during the first years of life. This microbial settlement occurs in parallel with the maturation of the immune system, and alterations during this period, due to environmental and host factors, are considered to be potential determinants of health-outcomes later in life. Given that host-microbe interactions are mediated by the immune system response, it is important to understand the close relationship between immunity and the microbiota during birth, lactation, and early infancy. This work summarizes the evidence to date on early gut microbiota colonization, and how it influences the maturation of the infant immune system and health during the first 1000 days of life. This review will also address the influence of perinatal antibiotic intake and the importance of delivery mode and breastfeeding for an appropriate development of gut immunity. PMID- 30018268 TI - Experimental Evaluation on Depth Control Using Improved Model Predictive Control for Autonomous Underwater Vehicle (AUVs). AB - Due to the growing interest using model predictive control (MPC), there are more and more researches about the applications of MPC on autonomous underwater vehicle (AUV), and these researches are mainly focused on simulation and simple application of MPC on AUV. This paper focuses on the improvement of MPC based on the state space model of an AUV. Unlike the previous approaches using a fixed weighting matrix, in this paper, a coefficient, varied with the error, is introduced to adjust the control increment vector weighting matrix to reduce the settling time. Then, an analysis on the effect of the adjustment to the stability is given. In addition, there is always a lag between the AUV real trajectory and the desired trajectory when the AUV tracks a continuous trajectory. To solve this problem, a simple re-planning of the desired trajectory is developed. Specifically, the point certain steps ahead from current time on the desired trajectory is treated as the current desired point and input to the controller. Finally, experimental results for depth control are given to demonstrate the feasibility and effectiveness of the improved MPC. Experimental results show that the method of real-time adjusting control increment weighting matrix can reduce settling time by about 2 s when tracking step trajectory of 1 m, and the simple re-planning of the desired trajectory method can reduce the average of absolute error by about 15% and standard deviation of error by about 17%. PMID- 30018270 TI - Impact-Sliding Tribology Behavior of TC17 Alloy Treated by Laser Shock Peening. AB - Outer particle collision with certain dynamic objects is not a pure impact wear behavior; it is typically accompanied by sliding wear phenomena. This study is aimed at investigating the impact-sliding wear performance of three different TC17 titanium alloys. One was untreated, and the other two were subjected to laser shock peening (LSP) by 5 and 7 J pulse energy, respectively. The wear test was performed on a novel impact-sliding wear testing rig, which can realize multiple impact-sliding motions by changing motion parameters in the x and z directions. Present results showed that wear resistance of both treated samples improved compared with the untreated alloy. Given the increase in wear cycles, increment in wear rate of the untreated sample was constantly higher than those of the treated samples. All results can be attributed to the increase in surface hardness of the material and residual compressive stress, which was also introduced after LSP. PMID- 30018269 TI - High-Resolution PTP1B Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of PTP1B Inhibitors from Miconia albicans. AB - Protein tyrosine phosphatase 1B (PTP1B) is an intracellular enzyme responsible for deactivation of the insulin receptor, and consequently acts as a negative regulator of insulin signal transduction. In recent years, PTP1B has become an important target for controlling insulin resistance and type 2 diabetes. In the present study, the ethyl acetate extract of leaves of Miconia albicans (IC50 = 4.92 ug/mL) was assessed by high-resolution PTP1B inhibition profiling combined with HPLC-HRMS-SPE-NMR for identification of antidiabetic compounds. This disclosed eleven PTP1B inhibitors, including five polyphenolics: 1-O-(E)-caffeoyl 4,6-di-O-galloyl-beta-d-glucopyranose (2), myricetin 3-O-alpha-l-rhamnopyranoside (3), quercetin 3-O-(2"-galloyl)-alpha-l-rhamnopyranoside (5), mearnsetin 3-O alpha-l-rhamnopyranoside (6), and kaempferol 3-O-alpha-l-arabinopyranoside (8) as well as eight triterpenoids: maslinic acid (13), 3-epi-sumaresinolic acid (14), sumaresinolic acid (15), 3-O-cis-p-coumaroyl maslinic acid (16), 3-O-trans-p coumaroyl maslinic acid (17), 3-O-trans-p-coumaroyl 2alpha-hydroxydulcioic acid (18), oleanolic acid (19), and ursolic acid (20). These results support the use of M. albicans as a traditional medicine with antidiabetic properties and its potential as a source of PTP1B inhibitors. PMID- 30018271 TI - The Frequency of Focal Thyroid Incidental Findings and Risk of Malignancy Detected by 18F-Fluorodeoxyglucose Positron Emission Tomography in an Iodine Deficient Population. AB - Incidental focal uptake of 18F-fluorodeoxyglucose (FDG) in the thyroid on positron emission tomography (PET/CT) is rare but often associated with malignancy. The epidemiology of thyroid incidentalomas has only to some extent been described in countries with iodine deficiency. Here we report data from Denmark, a country with known iodine deficiency and wide access to PET/CT. All FDG PET/CT comprising the head and neck region, during 2014, were retrospectively reviewed, and patients with focal FDG uptake in the thyroid gland were identified. A total of 2451 patients had an FDG PET/CT of which 59 (2.4%) patients presented with FDG-avid focal lesions in the thyroid gland. Among the 59 patients with FDG-avid lesions, 33 patients (56%) received work up with ultrasound, thyroid technetium scintigraphy, fine needle aspiration, and/or histology of which 20 patients had a conclusive pathology report. Ten patients with FDG-avid lesions were identified with thyroid malignancy. The risk of thyroid malignancy was 16.9% among patient with incidental FDG-avid thyroid lesions. Our findings indicated a similar frequency of FDG thyroid incidentalomas and malignancy rates in an iodine deficient population compared to summary data from prior studies, studies mostly performed in geographical areas of normal or excess iodine supplementation. PMID- 30018272 TI - Young Workers' Access to and Awareness of Occupational Safety and Health Services: Age-Differences and Possible Drivers in a Large Survey of Employees in Italy. AB - Young workers are in particular need of occupational safety and health (OSH) services, but it is unclear whether they have the necessary access to such services. We compared young with older workers in terms of the access to and awareness of OSH services, and examined if differences in employment conditions accounted for age-differences. We used survey data from Italy (INSuLA 1, 2014), with a sample of 8000 employed men and women aged 19 to 65 years, including 732 young workers aged under 30 years. Six questions measured access to services, and five questions assessed awareness of different OSH issues. Several employment conditions were included. Analyses revealed that young workers had less access and a lower awareness of OSH issues compared with older workers. For instance, odds ratios (OR) suggest that young workers had a 1.44 times higher likelihood [95%-confidence interval 1.21-1.70] of having no access to an occupational physician, and were more likely (2.22 [1.39-3.38]) to be unaware of legal OSH frameworks. Adjustment for selected employment conditions (company size, temporary contract) substantially reduced OR's, indicating that these conditions contribute to differences between older and younger workers. We conclude that OSH management should pay particular attention to young workers in general and, to young workers in precarious employment, and working in small companies in particular. PMID- 30018273 TI - In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs. AB - To discover new inhibitors against the human colon carcinoma HCT116 cell line, two quantitative structure-activity relationship (QSAR) studies using molecular and nuclear magnetic resonance (NMR) descriptors were developed through exploration of machine learning techniques and using the value of half maximal inhibitory concentration (IC50). In the first approach, A, regression models were developed using a total of 7339 molecules that were extracted from the ChEMBL and ZINC databases and recent literature. The performance of the regression models was successfully evaluated by internal and external validations, the best model achieved R2 of 0.75 and 0.73 and root mean square error (RMSE) of 0.66 and 0.69 for the training and test sets, respectively. With the inherent time-consuming efforts of working with natural products (NPs), we conceived a new NP drug hit discovery strategy that consists in frontloading samples with 1D NMR descriptors to predict compounds with anticancer activity prior to bioactivity screening for NPs discovery, approach B. The NMR QSAR classification models were built using 1D NMR data (1H and 13C) as descriptors, from 50 crude extracts, 55 fractions and five pure compounds obtained from actinobacteria isolated from marine sediments collected off the Madeira Archipelago. The overall predictability accuracies of the best model exceeded 63% for both training and test sets. PMID- 30018274 TI - Dynamic Light Scattering of Biopharmaceutics-Can Analytical Performance Be Enhanced by Laser Power? AB - BACKGROUND: Dynamic light scattering (DLS) is an important tool to characterize colloidal systems and adequate sizing is particularly critical in the field of protein formulations. Among the different factors that can influence the measurement result, the effect of laser power has so far not been studied thoroughly. METHODS: The sensitivity of a DLS instrument was first considered on a theoretical level, followed by experiments using DLS instruments, equipped with two different lasers of (nominal) 45 mW, and 100 mW, respectively. This work analyzes dilute colloidal dispersions of lysozyme as model protein. RESULTS: Theoretical findings agreed with experiments in that only enhanced laser power of 100 mW laser allowed measuring a 0.1 mg/mL protein dispersion in a reliable manner. Results confirmed the usefulness of the presented theoretical considerations in improving a general understanding of the limiting factors in DLS. CONCLUSIONS: Laser power is a critical aspect regarding adequate colloidal analysis by DLS. Practical guidance is provided to help scientists specifically with measuring dilute samples to choose both an optimal instrument configuration as well as a robust experimental procedure. PMID- 30018275 TI - Levenberg-Marquardt Neural Network Algorithm for Degree of Arteriovenous Fistula Stenosis Classification Using a Dual Optical Photoplethysmography Sensor. AB - This paper proposes a noninvasive dual optical photoplethysmography (PPG) sensor to classify the degree of arteriovenous fistula (AVF) stenosis in hemodialysis (HD) patients. Dual PPG measurement node (DPMN) becomes the primary tool in this work for detecting abnormal narrowing vessel simultaneously in multi-beds monitoring patients. The mean and variance of Rising Slope (RS) and Falling Slope (FS) values between before and after HD treatment was used as the major features to classify AVF stenosis. Multilayer perceptron neural networks (MLPN) training algorithms are implemented for this analysis, which are the Levenberg-Marquardt, Scaled Conjugate Gradient, and Resilient Back-propagation, to identify the degree of HD patient stenosis. Eleven patients were recruited with mean age of 77 +/- 10.8 years for analysis. The experimental results indicated that the variance of RS in the HD hand between before and after treatment was significant difference statistically to stenosis (p < 0.05). Levenberg-Marquardt algorithm (LMA) was significantly outperforms the other training algorithm. The classification accuracy and precision reached 94.82% and 92.22% respectively, thus this technique has a potential contribution to the early identification of stenosis for a medical diagnostic support system. PMID- 30018276 TI - Pediatric Deep Brain Stimulation Using Awake Recording and Stimulation for Target Selection in an Inpatient Neuromodulation Monitoring Unit. AB - Deep brain stimulation (DBS) for secondary (acquired, combined) dystonia does not reach the high degree of efficacy achieved in primary (genetic, isolated) dystonia. We hypothesize that this may be due to variability in the underlying injury, so that different children may require placement of electrodes in different regions of basal ganglia and thalamus. We describe a new targeting procedure in which temporary depth electrodes are placed at multiple possible targets in basal ganglia and thalamus, and probing for efficacy is performed using test stimulation and recording while children remain for one week in an inpatient Neuromodulation Monitoring Unit (NMU). Nine Children with severe secondary dystonia underwent the NMU targeting procedure. In all cases, 4 electrodes were implanted. We compared the results to 6 children who had previously had 4 electrodes implanted using standard intraoperative microelectrode targeting techniques. Results showed a significant benefit, with 80% of children with NMU targeting achieving greater than 5-point improvement on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), compared with 50% of children using intraoperative targeting. NMU targeting improved BFMDRS by an average of 17.1 whereas intraoperative targeting improved by an average of 10.3. These preliminary results support the use of test stimulation and recording in a Neuromodulation Monitoring Unit (NMU) as a new technique with the potential to improve outcomes following DBS in children with secondary (acquired) dystonia. A larger sample size will be needed to confirm these results. PMID- 30018279 TI - Cellular Simulation for Distributed Sensing over Complex Terrains. AB - Long-range radio transmissions open new sensor application fields, in particular for environment monitoring. For example, the LoRa radio protocol enables connecting remote sensors at a distance as long as ten kilometers in a line-of sight. However, the large area covered also brings several difficulties, such as the placement of sensing devices in regards to topology in geography, or the variability of communication latency. Sensing the environment also carries constraints related to the interest of sensing points in relation to a physical phenomenon. Thus, criteria for designs are evolving a lot from the existing methods, especially in complex terrains. This article describes simulation techniques based on geography analysis to compute long-range radio coverages and radio characteristics in these situations. As radio propagation is just a particular case of physical phenomena, it is shown how a unified approach also allows for characterizing the behavior of potential physical risks. The case of heavy rainfall and flooding is investigated. Geography analysis is achieved using segmentation tools to produce cellular systems which are in turn translated into code for high-performance computations. The paper provides results from practical complex terrain experiments using LoRa, which confirm the accuracy of the simulation, and scheduling characteristics for sample networks. Performance tables are produced for these simulations on current Graphics Processing Units (GPUs). PMID- 30018278 TI - Paeonol-Loaded Ethosomes as Transdermal Delivery Carriers: Design, Preparation and Evaluation. AB - Paeonol exhibits a wide range of pharmacological activities, such as anti inflammatory, antidiabetic as well as pain-relieving activities. However, its intrinsic properties, such as low water solubility, poor stability and low oral bioavailability, restrict its clinical application. The current study aimed to optimize paeonol-loaded ethosomal formulation and characterize it in terms of encapsulation efficiency (EE), vesicle size (VS), zeta potential (ZP) and polydispersity index (PDI), in addition to differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT IR) studies. Here, paeonol-loaded ethosomes were prepared by the injection method and optimized by the single-factor test and central composite design-response surface methodology. The optimized paeonol-loaded ethosomes had an EE of 84.33 +/ 1.34%, VS of 120.2 +/- 1.3 nm, negative charge of -16.8 +/- 0.36 mV, and PDI of 0.131 +/- 0.006. Ethosomes showed a spherical morphology under the transmission electron microscope (TEM). DSC, XRD and FT-IR results indicated that paeonol was successfully incorporated into the ethosomes. In-vitro transdermal absorption and skin retention of paeonol from paeonol-loaded ethosomes were 138.58 +/- 9.60 ug/cm2 and 52.60 +/- 7.90 ug/cm2, respectively. With reasonable skin tolerance, ethosomes could be a promising vehicle for transdermal delivery of paeonol. PMID- 30018277 TI - The Dietary Antioxidant Piceatannol Inhibits Adipogenesis of Human Adipose Mesenchymal Stem Cells and Limits Glucose Transport and Lipogenic Activities in Adipocytes. AB - Phenolic compounds are among the most investigated herbal remedies, as is especially the case for resveratrol. Many reports have shown its anti-aging properties and the ability to reduce obesity and diabetes induced by high-fat diet in mice. However, such beneficial effects hardly translate from animal models to humans. The scientific community has therefore tested whether other plant phenolic compounds may surpass the effects of resveratrol. In this regard, it has been reported that piceatannol reproduces in rodents the anti-obesity actions of its parent polyphenol. However, the capacity of piceatannol to inhibit adipocyte differentiation in humans has not been characterized so far. Here, we investigated whether piceatannol was antiadipogenic and antilipogenic in human preadipocytes. Human mesenchymal stem cells (hMSC), isolated from adipose tissues of lean and obese individuals, were differentiated into mature adipocytes with or without piceatannol, and their functions were explored. Fifty MUM of piceatannol deeply limited synthesis/accumulation of lipids in both murine and hMSC-derived adipocytes. Interestingly, this phenomenon occurred irrespective of being added at the earlier or later stages of adipocyte differentiation. Moreover, piceatannol lowered glucose transport into adipocytes and decreased the expression of key elements of the lipogenic pathway (PPARgamma, FAS, and GLUT4). Thus, the confirmation of the antiadipogenic properties of piceatanol in vitro warrants the realization of clinical studies for the application of this compound in the treatment of the metabolic complications associated with obesity. PMID- 30018281 TI - Endovascular Management of an Acquired Carotid-Jugular Fistula in a Child. AB - BACKGROUND There is a paucity of published literature on carotid-jugular fistulae in children. These injuries are uncommon in the pediatric age group and most of the current practice in managing such injuries is extrapolated from similar injuries in the adult population. CASE REPORT We report a case of an acquired carotid-jugular fistula (CJF) following penetrating neck trauma in a 12-year-old male, treated by minimally invasive endovascular covered stent. Successful endovascular management was achieved in this case with anatomical and symptomatic resolution at 6 weeks and normal duplex ultrasound at 18 months. CONCLUSIONS The rarity of carotid-jugular fistulae in children means there is a lack of consensus for the appropriate management in the available literature. This case report adds to the evidence for endovascular management of this condition in a pediatric population. PMID- 30018280 TI - Collapsin Response Mediator Protein-2 Ameliorates Sevoflurane-Mediated Neurocyte Injury by Targeting PI3K-mTOR-S6K Pathway. AB - BACKGROUND Collapsin response mediator protein-2 (CRMP-2) is the first member of the CRMP family that has been identified in primary neuronal cells; it was originally found and identified in the regulation of microtubule dimerization into microtubules. MATERIAL AND METHODS In the present study, we aimed to investigate the roles and mechanisms of CRMP-2 in sevoflurane-induced neurocyte injury. Cell viability, proliferation, and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Colorimetry was performed to measure the activity of caspase-3. Western blot and quantitative real-time reverse transcription assays were used to evaluate the related mRNAs and proteins expression. RESULTS We found that CRMP-2 reversed the inhibitory effect of sevoflurane on the viability of nerve cells. Moreover, CRMP-2 accelerated the proliferation and suppressed the apoptosis of sevoflurane-induced nerve cells. CRMP-2 modulated the expression levels of apoptosis-associated protein in sevoflurane-induced nerve cells. Furthermore, it was demonstrated that CRMP-2 impacted the PI3K-mTOR-S6K pathway. CONCLUSIONS CRMP2 ameliorated sevoflurane mediated neurocyte injury by targeting the PI3K-mTOR-S6K pathway. Thus, CRMP2 might be an effective target for sevoflurane-induced neurocyte injury therapies. PMID- 30018282 TI - Creating two self-assembly micro-environments to achieve supercrystals with dual structures using polyhedral nanoparticles. AB - Organizing nanoparticles into supercrystals comprising multiple structures remains challenging. Here, we achieve one assembly with dual structures for Ag polyhedral building blocks, comprising truncated cubes, cuboctahedra, truncated octahedra, and octahedra. We create two micro-environments in a solvent evaporation-driven assembly system: one at the drying front and one at the air/water interface. Dynamic solvent flow concentrates the polyhedra at the drying front, generating hard particle behaviors and leading to morphology dependent densest-packed bulk supercrystals. In addition, monolayers of nanoparticles adsorb at the air/liquid interface to minimize the air/liquid interfacial energy. Subsequent solvent evaporation gives rise to various structurally diverse dual-structure supercrystals. The topmost monolayers feature distinct open crystal structures with significantly lower packing densities than their densest-packed supercrystals. We further highlight a 3.3-fold synergistic enhancement of surface-enhanced Raman scattering efficiency arising from these dual-structure supercrystals as compared to a uniform one. PMID- 30018283 TI - Persistent spin texture enforced by symmetry. AB - Persistent spin texture (PST) is the property of some materials to maintain a uniform spin configuration in the momentum space. This property has been predicted to support an extraordinarily long spin lifetime of carriers promising for spintronics applications. Here, we predict that there exists a class of noncentrosymmetric bulk materials, where the PST is enforced by the nonsymmorphic space group symmetry of the crystal. Around certain high symmetry points in the Brillouin zone, the sublattice degrees of freedom impose a constraint on the effective spin-orbit field, which orientation remains independent of the momentum and thus maintains the PST. We illustrate this behavior using density-functional theory calculations for a handful of promising candidates accessible experimentally. Among them is the ferroelectric oxide BiInO3-a wide band gap semiconductor which sustains a PST around the conduction band minimum. Our results broaden the range of materials that can be employed in spintronics. PMID- 30018284 TI - Author Correction: The global view of mRNA-related ceRNA cross-talks across cardiovascular diseases. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30018285 TI - Socioeconomic determinants of sarcopenic obesity and frail obesity in community dwelling older adults: The Seniors-ENRICA Study. AB - Information on the association between socioeconomic status (SES) throughout life and sarcopenic obesity is scarce, whereas no study has been focused on the association between SES and frail obesity. This analysis estimated the prevalence of sarcopenic obesity and frail obesity, and their associations with SES in older adults. Data were collected in 2012 from 1,765 non-institutionalized individuals aged >=65 participating in the Seniors-ENRICA study in Spain, by using standardized techniques and equipment. SES throughout life was evaluated with the father's occupation, participant's educational level, former own occupation, and current poor housing condition. Overall, 17.2% of participants had sarcopenic obesity, and 4.0% frail obesity. No association was found between SES and sarcopenic obesity. In contrast, the prevalence of frail obesity was higher in those with lower education, having worked in manual job, and currently having poor housing condition. Having >=1 social disadvantages throughout life was associated with higher prevalence of frail obesity. The prevalence of this disorder increased by 1.49 (95% CI: 1.21-1.85) times for each social disadvantage added. The OR (95% CI) of frail obesity was 3.13 (1.71-5.7) for those having 3 or 4 vs. 0 or 1 social disadvantages, implying a more complex process beginning early in life. PMID- 30018286 TI - Electric pulse characteristics can enable species recognition in African weakly electric fish species. AB - Communication is key to a wide variety of animal behaviours and multiple modalities are often involved in this exchange of information from sender to receiver. The communication of African weakly electric fish, however, is thought to be predominantly unimodal and is mediated by their electric sense, in which species-specific electric organ discharges (EODs) are generated in a context dependent and thus variable sequence of pulse intervals (SPI). While the primary function of the electric sense is considered to be electrolocation, both of its components likely carry information regarding identity of the sender. However, a clear understanding of their contribution to species recognition is incomplete. We therefore analysed these two electrocommunication components (EOD waveform and SPI statistics) in two sympatric mormyrid Campylomormyrus species. In a set of five playback conditions, we further investigated which components may drive interspecific recognition and discrimination. While we found that both electrocommunication components are species-specific, the cues necessary for species recognition differ between the two species studied. While the EOD waveform and SPI were both necessary and sufficient for species recognition in C. compressirostris males, C. tamandua males apparently utilize other, non-electric modalities. Mapped onto a recent phylogeny, our results suggest that discrimination by electric cues alone may be an apomorphic trait evolved during a recent radiation in this taxon. PMID- 30018288 TI - Applying causal diagrams in pediatrics to improve research, communication, and practice. PMID- 30018289 TI - Maternal and infant vitamin B12 status and development. PMID- 30018287 TI - Various roles of heme oxygenase-1 in response of bone marrow macrophages to RANKL and in the early stage of osteoclastogenesis. AB - Heme oxygenase-1 (HO-1; encoded by Hmox1), a downstream target of the Nrf2 transcription factor, has been postulated to be a negative regulator of osteoclasts (OCLs) differentiation. Here, we further explored such a hypothesis by examining HO-1 effects in different stages of osteoclastogenesis. We confirmed the inhibition of the expression of OCLs markers by Nrf2. In contrast, both the lack of the active Hmox1 gene or HO-1 silencing in OCLs precursor cells, bone marrow macrophages (BMMs), decreased their differentiation towards OCLs, as indicated by the analysis of OCLs markers such as TRAP. However, no effect of HO 1 deficiency was observed when HO-1 expression was silenced in BMMs or RAW264.7 macrophage cell line pre-stimulated with RANKL (considered as early-stage OCLs). Moreover, cobalt protoporphyrin IX (CoPPIX) or hemin, the known HO-1 inducers, inhibited OCLs markers both in RANKL-stimulated RAW264.7 cells and BMMs. Strikingly, a similar effect occurred in HO-1-/- cells, indicating HO-1 independent activity of CoPPIX and hemin. Interestingly, plasma of HO-1-/- mice contained higher TRAP levels, which suggests an increased number of bone resorbing OCLs in the absence of HO-1 in vivo. In conclusion, our data indicate that HO-1 is involved in the response of bone marrow macrophages to RANKL and the induction of OCLs markers, but it is dispensable in early-stage OCLs. However, in vivo HO-1 appears to inhibit OCLs formation. PMID- 30018290 TI - Water-dispersible PEG-curcumin/amine-functionalized covalent organic framework nanocomposites as smart carriers for in vivo drug delivery. AB - Covalent organic frameworks (COFs) as drug-delivery carriers have been mostly evaluated in vitro due to the lack of COFs nanocarriers that are suitable for in vivo studies. Here we develop a series of water-dispersible polymer-COF nanocomposites through the assembly of polyethylene-glycol-modified monofunctional curcumin derivatives (PEG-CCM) and amine-functionalized COFs (APTES-COF-1) for in vitro and in vivo drug delivery. The real-time fluorescence response shows efficient tracking of the COF-based materials upon cellular uptake and anticancer drug (doxorubicin (DOX)) release. Notably, in vitro and in vivo studies demonstrate that PEG-CCM@APTES-COF-1 is a smart carrier for drug delivery with superior stability, intrinsic biodegradability, high DOX loading capacity, strong and stable fluorescence, prolonged circulation time and improved drug accumulation in tumors. More intriguingly, PEG350-CCM@APTES-COF-1 presents an effective targeting strategy for brain research. We envisage that PEG-CCM@APTES COF-1 nanocomposites represent a great promise toward the development of a multifunctional platform for cancer-targeted in vivo drug delivery. PMID- 30018291 TI - Author Correction: Generation and characterization of ultrathin free-flowing liquid sheets. AB - The original version of this article omitted the following from the Acknowledgements:'P.B. was funded by the ELI Extreme Light Infrastructure Phase 2 (CZ.02.1.01/0.0/0.0/15008/0000162) from the European Regional Development Fund and the EUCALL project funded from the EU Horizon 2020 research and innovation programme under grant agreement No 654220,' which replaces the previous 'P.B. was funded by the ELI Extreme Light Infrastructure Phase 2 (CZ.02.1.01/0.0/0.0/15008/0000162) from the European Regional Development Fund.'This has been corrected in both the PDF and HTML versions of the article. PMID- 30018293 TI - Publisher Correction: FGF signalling controls the specification of hair placode derived SOX9 positive progenitors to Merkel cells. AB - The originally published version of this Article contained an error in Figure 2. In panel e, the blue bar was incorrectly labelled 'KRT8(+)/TOMATO(-)'. Furthermore, during the process of preparing a correction, the publication date of the Article was inadvertently changed to June 20th 2018. Both of these errors have been corrected in the PDF and HTML versions of the Article. PMID- 30018294 TI - APC2 controls dendrite development by promoting microtubule dynamics. AB - Mixed polarity microtubule organization is the signature characteristic of vertebrate dendrites. Oppositely oriented microtubules form the basis for selective cargo trafficking in neurons, however the mechanisms that establish and maintain this organization are unclear. Here, we show that APC2, the brain specific homolog of tumor-suppressor protein adenomatous polyposis coli (APC), promotes dynamics of minus-end-out microtubules in dendrites. We found that APC2 localizes as distinct clusters along microtubule bundles in dendrites and that this localization is driven by LC8-binding and two separate microtubule interacting domains. Depletion of APC2 reduces the plus end dynamics of minus-end out oriented microtubules, increases microtubule sliding, and causes defects in dendritic morphology. We propose a model in which APC2 regulates dendrite development by promoting dynamics of minus-end-out microtubules. PMID- 30018292 TI - An intercross population study reveals genes associated with body size and plumage color in ducks. AB - Comparative population genomics offers an opportunity to discover the signatures of artificial selection during animal domestication, however, their function cannot be directly revealed. We discover the selection signatures using genome wide comparisons among 40 mallards, 36 indigenous-breed ducks, and 30 Pekin ducks. Then, the phenotypes are fine-mapped based on resequencing of 1026 ducks from an F2 segregating population generated by wild * domestic crosses. Interestingly, the two key economic traits of Pekin duck are associated with two selective sweeps with fixed mutations. A novel intronic insertion most possibly leads to a splicing change in MITF accounted for white duck down feathers. And a putative long-distance regulatory mutation causes continuous expression of the IGF2BP1 gene after birth which increases body size by 15% and feed efficiency by 6%. This study provides new insights into genotype-phenotype associations in animal research and constitutes a promising resource on economically important genes in fowl. PMID- 30018296 TI - Clustering and separation of hydrophobic nanoparticles in lipid bilayer explained by membrane mechanics. AB - Small hydrophobic gold nanoparticles with diameter lower than the membrane thickness can form clusters or uniformly distribute within the hydrophobic core of the bilayer. The coexistence of two stable phases (clustered and dispersed) indicates the energy barrier between nanoparticles. We calculated the distance dependence of the membrane-mediated interaction between two adjacent nanoparticles. In our model we consider two deformation modes: the monolayer bending and the hydroxycarbon chain stretching. Existence of an energy barrier between the clustered and the separated state of nanoparticles was predicted. Variation analysis of the membrane mechanical parameters revealed that the energy barrier between two membrane embedded nanoparticles is mainly the consequence of the bending deformation and not change of the thickness of the bilayer in the vicinity of nanoparticles. It is shown, that the forces between the nanoparticles embedded in the biological membrane could be either attractive or repulsive, depending on the mutual distance between them. PMID- 30018295 TI - Peptide Sequence Influence on the Conformational Dynamics and DNA binding of the Intrinsically Disordered AT-Hook 3 Peptide. AB - The intrinsically disordered ATHP3 was studied at native conditions and in complex with DNA using single amino acid substitutions and high-resolution ion mobility spectrometry coupled to mass spectrometry (trapped IMS-MS). Results showed that ATHP3 can exist in multiple conformations at native conditions (at least 10 conformers were separated), with a variety of proline cis/trans orientations, side chain orientations and protonation sites. When in complex with AT rich DNA hairpins, the -RGRP- core is essential for stabilizing the ATHP3: DNA complex. In particular, the arginine in the sixth position plays an important role during binding to AT-rich regions of hairpin DNA, in good agreement with previous NMR and X-ray data. Mobility based correlation matrices are proposed as a way to reveal differences in structural motifs across the peptide mutants based on the conformational space and relative conformer abundance. PMID- 30018297 TI - Deciphering the biology of Cryptophyllachora eurasiatica gen. et sp. nov., an often cryptic pathogen of an allergenic weed, Ambrosia artemisiifolia. AB - A little known, unculturable ascomycete, referred to as Phyllachora ambrosiae, can destroy the inflorescences of Ambrosia artemisiifolia, an invasive agricultural weed and producer of highly allergenic pollen. The fungus often remains undetectable in ragweed populations. This work was conducted to understand its origin and pathogenesis, a prerequisite to consider its potential as a biocontrol agent. The methods used included light and transmission electron microscopy, nrDNA sequencing, phylogenetic analyses, artificial inoculations, and the examination of old herbarium and recent field specimens from Hungary, Korea, Ukraine and USA. The Eurasian and the North American specimens of this fungus were to represent two distinct, although closely related lineages that were only distantly related to other lineages within the Ascomycota. Consequently, we describe a new genus that includes Cryptophyllachora eurasiatica gen. et sp. nov. and C. ambrosiae comb. nov., respectively. The pathogenesis of C. eurasiatica was shown in A. artemisiifolia. No evidence was found for either seed-borne transmission or systemic infection. Two hypotheses were developed to explain the interaction between C. eurasiatica and A. artemisiifolia: (i) as yet undetected seed-borne transmissions and latent, systemic infections; or (ii) alternative hosts. PMID- 30018299 TI - MASTER OF THE UNIVERSE: SCORSESE'S "THE WOLF OF WALL STREET" THROUGH A PSYCHOANALYTIC LENS. AB - In this essay I wish to present some reflections on Jordan Belfort, the protagonist of the movie "The Wolf of Wall Street" from a psychoanalytic prism. The movie, "The Wolf of Wall Street", is a 2013 black comedy film directed by Martin Scorsese and adapted by Terence Winter from Belfort's memoir (2007) of the same name. This movie has already been analyzed from cultural and historical perspectives, with the protagonist representing American culture of the 1980s. I will first summarize some of these views, and then present my psychoanalytic perspective of Jordan's wish to become "Master of the Universe" (Wolfe, 1987; Grunberger, 1993), as expressed through his abuse of drugs, hyper-sexuality, and his aggressive and self-destructive behavior. As the craving for omnipotence and immortality is a universal wish that has existed from time immemorial, I will draw an analogy between certain aspects and symbolic elements in "The Wolf of Wall Street" and Wagner's (1848-1872) four epic operas "Der Ring des Nibelungen." I will conclude with a brief reference to the charismatic appeal of a man like Jordan to the general public. PMID- 30018300 TI - Applying a prevention framework to address homelessness as a population health issue. AB - This paper presents a population health framework for homelessness prevention. Rooted in the Los Angeles County Homeless Initiative, the framework includes strategies that affect social determinants of health that influence a broad range of health outcomes prevalent among the homeless. For each prevention level, we consider the purpose of prevention, the sub-population of interest, and evidence of the effectiveness of interventions in addressing factors that affect health and health outcomes. Our review highlights the importance of cross-cutting strategies and the limits of our knowledge about more targeted preventive interventions. We note that a prevention orientation requires attention to the social and physical environments that affect homelessness plus connections between the homelessness services sector and mainstream systems of care and support. PMID- 30018298 TI - Lethal and sub-lethal effects of the insecticide fipronil on juvenile brown shrimp Farfantepenaeus aztecus. AB - Chemical pesticides are widely used around the world, but at the same time, they may cause direct or indirect risks to many non-target organisms. Recent increased use of insecticides in coastal areas, for example to control invasive tawny crazy ants, raises concern that insecticides may affect ecologically and/or commercially important species found in estuaries. Here, we investigated the lethal and sub-lethal effects of fipronil on juvenile brown shrimp Farfantepenaeus aztecus over 29 days at five different nominal concentrations (0.1, 1.0, 3.0, 6.4, and 10.0 ug/L) in a laboratory experiment. Exposure to all of the fipronil treatments resulted in all individuals dying before the end of the experiment; whereas, no individual died in the control (0.0 ug/L). The 96 hour LC50 was determined to be 1.3 ug/L. Shrimp also experienced weight loss under all of the fipronil treatments. Inter-moult interval was increased from 12.2 +/- 1.64 day in the control group to 15.5 +/- 0.53 day in the 1.0 MUg/L treatment. Lipid content of shrimp increased significantly in a concentration dependent manner. Finally, behavioral and body color changes were also observed under the fipronil treatments. We conclude F. aztecus is very sensitive to fipronil and monitoring is needed in coastal areas. PMID- 30018302 TI - Yield effect of applying earthworm castings produced during the oilseed rape growing season in rice-oilseed rape cropping fields to rice. AB - In-field earthworm density can be increased by planting oilseed rape during the non-rice growing season as compared to maintaining the rice-growing fields in fallow. This study was conducted to determine the effect on rice yield of earthworm castings produced during the oilseed rape-growing season in rice oilseed rape cropping fields and to identify the critical factors that contribute to the yield effect. Field microplot experiments were conducted in 2016 and 2017. In 2016, a rice cultivar was grown under a factorial combination of absence (EC0: 0 kg m-2) and presence of earthworm castings (EC1: 17 kg m-2) with three N application rates (9, 12 and 15 g m-2). In 2017, nine rice cultivars were grown under EC0 and EC1 with the moderate N rate as was used in 2016. Results showed that application of earthworm castings produced during the oilseed rape-growing season in rice-oilseed rape cropping fields had a significant positive yield effect on rice. This was attributed to increased panicle m-2 and total aboveground biomass while spikelets panicle-1, spikelet filling percentage, grain weight, and harvest index were not affected. Our study indirectly provides a new evidence that oilseed rape is an excellent previous crop for cereals. PMID- 30018303 TI - Disparities in Access to Direct Acting Antiviral Regimens for Hepatitis C Virus (HCV): The Impact of Race and Insurance Status. AB - Despite highly effective and well-tolerated regimens for treating hepatitis C virus (HCV), patients face barriers in accessing treatment. In addition to suboptimal HCV screening programs and lack of effective linkage-to-care, other barriers include strict requirements from some payers to cover treatment. This study reports insurance status and Hispanic ethnicity as predictors of not receiving treatment. These barriers occur despite the fact that HCV is the most common indication for liver transplantation and cause of hepatocellular carcinoma in the U.S. Therefore, it is critical that policymakers bring all the stakeholders together and develop a national policy to eradicate HCV infection from the U.S. PMID- 30018301 TI - A monocyte gene expression signature in the early clinical course of Parkinson's disease. AB - Microglia are the main immune cells of the brain and express a large genetic pattern of genes linked to Parkinson's disease risk alleles. Monocytes like microglia are myeloid-lineage cells, raising the questions of the extent to which they share gene expression with microglia and whether they are already altered early in the clinical course of the disease. To decipher a monocytic gene expression signature in Parkinson's disease, we performed RNA-seq and applied the two-sample Kolmogorov-Smirnov test to identify differentially expressed genes between controls and patients with Parkinson's disease and changes in gene expression variability and dysregulation. The gene expression profiles of normal human monocytes and microglia showed a plethora of differentially expressed genes. Additionally, we identified a distinct gene expression pattern of monocytes isolated from Parkinson's disease patients at an early disease stage compared to controls using the Kolmogorov-Smirnov test. Differentially expressed genes included genes involved in immune activation such as HLA-DQB1, MYD88, REL, and TNF-alpha. Our data suggest that future studies of distinct leukocyte subsets are warranted to identify possible surrogate biomarkers and may lead to the identification of novel interventions early in the disease course. PMID- 30018304 TI - Hereditary Pancreatitis in the United States: Survival and Rates of Pancreatic Cancer. AB - OBJECTIVES: Hereditary pancreatitis (HP), an autosomal dominant disease typically caused by mutations in PRSS1, has a broad range of clinical characteristics and high cumulative risk of pancreatic cancer. We describe survival and pancreatic cancer risk in the largest HP cohort in the US. METHODS: HP probands and family members prospectively recruited from 1995 to 2013 completed medical and family history questionnaires, and provided blood for DNA testing. Overall survival (until 12/31/2015) was determined from the Social Security Death Index (SSDI), National Death Index (NDI), and family members. Cause of death was obtained from the NDI. RESULTS: 217 PRSS1 carriers (181 symptomatic) formed the study cohort. The most frequently detected mutations were p.R122H (83.9%) and p.N29I (11.5%). Thirty-seven PRSS1 carriers (30 symptomatic, 7 asymptomatic) were deceased at conclusion of the study (5 from pancreatic cancer). Median overall survival was 79.3 years (IQR 72.2-85.2). Risk of pancreatic cancer was significantly greater than age- and sex- matched SEER data (SIR 59, 95% CI 19-138), and cumulative risk was 7.2% (95% CI 0-15.4) at 70 years. DISCUSSION: We confirm prior observations on survival and pancreatic cancer SIR in PRSS1 subjects. Although risk of pancreatic cancer was significantly high in these patients, its cumulative risk was much lower than previous reports. PMID- 30018305 TI - Injectable antibacterial conductive nanocomposite cryogels with rapid shape recovery for noncompressible hemorrhage and wound healing. AB - Developing injectable antibacterial and conductive shape memory hemostatic with high blood absorption and fast recovery for irregularly shaped and noncompressible hemorrhage remains a challenge. Here we report injectable antibacterial conductive cryogels based on carbon nanotube (CNT) and glycidyl methacrylate functionalized quaternized chitosan for lethal noncompressible hemorrhage hemostasis and wound healing. These cryogels present robust mechanical strength, rapid blood-triggered shape recovery and absorption speed, and high blood uptake capacity. Moreover, cryogels show better blood-clotting ability, higher blood cell and platelet adhesion and activation than gelatin sponge and gauze. Cryogel with 4 mg/mL CNT (QCSG/CNT4) shows better hemostatic capability than gauze and gelatin hemostatic sponge in mouse-liver injury model and mouse tail amputation model, and better wound healing performance than TegadermTM film. Importantly, QCSG/CNT4 presents excellent hemostatic performance in rabbit liver defect lethal noncompressible hemorrhage model and even better hemostatic ability than Combat Gauze in standardized circular liver bleeding model. PMID- 30018306 TI - Exchange-biasing topological charges by antiferromagnetism. AB - Geometric Hall effect is induced by the emergent gauge field experienced by the carriers adiabatically passing through certain real-space topological spin textures, which is a probe to non-trivial spin textures, such as magnetic skyrmions. We report experimental indications of spin-texture topological charges induced in heterostructures of a topological insulator (Bi,Sb)2Te3 coupled to an antiferromagnet MnTe. Through a seeding effect, the pinned spins at the interface leads to a tunable modification of the averaged real-space topological charge. This effect experimentally manifests as a modification of the field-dependent geometric Hall effect when the system is field-cooled along different directions. This heterostructure represents a platform for manipulating magnetic topological transitions using antiferromagnetic order. PMID- 30018307 TI - Squamate reptiles challenge paradigms of genomic repeat element evolution set by birds and mammals. AB - Broad paradigms of vertebrate genomic repeat element evolution have been largely shaped by analyses of mammalian and avian genomes. Here, based on analyses of genomes sequenced from over 60 squamate reptiles (lizards and snakes), we show that patterns of genomic repeat landscape evolution in squamates challenge such paradigms. Despite low variance in genome size, squamate genomes exhibit surprisingly high variation among species in abundance (ca. 25-73% of the genome) and composition of identifiable repeat elements. We also demonstrate that snake genomes have experienced microsatellite seeding by transposable elements at a scale unparalleled among eukaryotes, leading to some snake genomes containing the highest microsatellite content of any known eukaryote. Our analyses of transposable element evolution across squamates also suggest that lineage specific variation in mechanisms of transposable element activity and silencing, rather than variation in species-specific demography, may play a dominant role in driving variation in repeat element landscapes across squamate phylogeny. PMID- 30018308 TI - Soluble Triggering Receptor Expressed on Myeloid Cells 1 in lung cancer. AB - Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) can be found in the sera of patients with infectious, autoimmune and malignant diseases. The primary objective of this study was to investigate the prognostic significance of sTREM-1 in lung cancer patients. We analyzed the sera of 164 patients with lung cancer of all histologies and all stages at the time of diagnosis. We employed an ELISA using the anti-TREM-1 clone 6B1.1G12 mAb and recombinant human TREM-1. Patient data was collected retrospectively by chart review. In ROC-analysis, a sTREM-1 serum level of 163.1 pg/ml showed the highest Youden-Index. At this cut off value sTREM-1 was a marker of short survival in patients with NSCLC (median survival 8.5 vs. 13.3 months, p = 0.04). A Cox regression model showed stage (p < 0.001) and sTREM-1 (p = 0.011) to indicate short survival. There were no differences in sTREM-1 serum values among patients with or without infection, pleural effusion or COPD. sTREM-1 was not associated with metastasis at the time of diagnosis and was not a predictor of subsequent metastasis. In SCLC patients sTREM-1 levels were lower than in NSCLC patients (p = 0.001) and did not predict survival. sTREM-1 did not correlate with CRP or the number of neutrophils. In non small cell lung cancer patients, sTREM-1 in serum has prognostic significance. PMID- 30018310 TI - Reply: Bariatric surgery and chronic kidney disease: much hope, but proof is still awaited. PMID- 30018309 TI - Differentially Methylated Genes in Saliva are linked to Childhood Stress. AB - Chronic and severe stress exposure in early childhood is associated with the development of psychiatric disorders. Yet, the molecular mechanisms underlying this relationship remain poorly understood. Here, we profile molecular marks (DNA methylation and gene expression) throughout the human genome to determine the associations between childhood stress exposure and gene regulation. To do so, we collected saliva tissue from prepubertal girls (mean age 10.9 +/- 1.26 years) who had experienced different levels of childhood adversity, ranging from mild to severe. We found 122 differentially methylated genes (FDR P-value < 0.05) associated with high childhood stress exposures that affect brain development. Of these differentially methylated genes, 12 also differed in gene expression. To further investigate the potential effects of stress exposure on gene regulation, we examined the DNA sequences flanking all the differentially methylated loci. This analysis revealed enrichment of known binding sites for transcription factors, suggesting that DNA methylation may regulate gene expression by mediating transcription factor binding on these genes. Together, these findings indicate a possible neuromolecular mechanism linking children's social experiences with risk for anxiety and depressive disorders. PMID- 30018311 TI - Bariatric surgery and chronic kidney disease: much hope, but proof is still awaited. PMID- 30018312 TI - Peripherally administered melanocortins induce mice fat browning and prevent obesity. AB - BACKGROUND/OBJECTIVES: The browning of white adipose tissue (WAT) has been in the spotlight during the last years, becoming an attractive approach to combat obesity. Melanocortin neuropeptides, such as alpha-melanocyte-stimulating hormone (alpha-MSH), are well-known regulators of appetite at the central nervous system, but its role in adipocyte metabolism is poorly elucidated. This study sought to verify if alpha-MSH can induce transdifferentiation of white to brown/beige adipocytes and to determine whether it can ameliorate the obesity phenotype. METHODS: The browning effect of alpha-MSH was determined in isolated adipocytes using the 3T3-L1 cell line and in inguinal subcutaneous adipose tissue (ingWAT) of diet-induced obese (DIO) mice by quantifying the expression of browning hallmark genes, oxygen consumption, and mitochondrial biogenesis. alpha-MSH protection from diet-induced obesity was evaluated by analyzing mice body weight, fat mass, and lipid and glucose serum profiles. RESULTS: Here, we report that alpha-MSH activates a thermogenic gene program and increases the mitochondrial respiratory rate in 3T3-L1 adipocytes and ingWAT of DIO mice. Without affecting food intake, peripheral administration of alpha-MSH decreases body weight and ingWAT mass, promoting a significant rise in the number of smaller adipocytes, whereas it lowered the larger ones. Additionally, there was an increase in the mass of brown adipose tissue. Browning activation occurs concomitantly with improvement on serum lipid profile, insulin resistance, and glucose homeostasis. CONCLUSIONS: This study highlights the anti-obesity properties of melanocortins by promoting ingWAT browning and provides new perspectives for future designing of more effective therapeutic strategies. PMID- 30018313 TI - Electrical resistivity of liquid Fe to 12 GPa: Implications for heat flow in cores of terrestrial bodies. AB - Electrical and thermal transport properties of liquid Fe under high pressure have important implications for the dynamics and thermal evolution of planetary cores and the geodynamo. However, electrical resistivity (rho) and thermal conductivity (k) of liquid Fe at high pressure still remain contentious properties. To date, only two experimental investigations of rho of liquid Fe in the pressure region below 7 GPa are reported in literature. Here we report the results of measurements of rho for solid and liquid Fe (inversely proportional to k through the Wiedemann-Franz law) at pressures from 3 to 12 GPa, using a large multi-anvil press. We show that rho of liquid Fe decreases as a function of pressure up to the delta-gamma-liquid triple point at ~5.2 GPa, and subsequently remains invariant from 6 to 12 GPa, which is consistent with an earlier study on liquid Ni. Our results demonstrate an important effect of solid phase on the structure and properties of liquid Fe. Our values of rho for solid and liquid Fe are used to calculate k in Mercury's solid inner core and along the adiabat in the liquid outer cores of Moon, Ganymede, Mercury and Mars. Our robust values of thermal conductivity place the focus on uncertainties in thermal expansion as the cause of variation in values of core conducted heat. Except for Mercury, our adiabatic heat flux values in these terrestrial cores validate the use of similar values used in several previous studies. Our high values of core adiabatic heat flux in Mercury would provide a stabilizing effect on, and lead to an increase in thickness of, the thermally stratified layer at the top of the core. PMID- 30018314 TI - Heterogeneity and interplay of the extracellular vesicle small RNA transcriptome and proteome. AB - Extracellular vesicles (EVs) mediate cell-to-cell communication by delivering or displaying macromolecules to their recipient cells. While certain broad-spectrum EV effects reflect their protein cargo composition, others have been attributed to individual EV-loaded molecules such as specific miRNAs. In this work, we have investigated the contents of vesicular cargo using small RNA sequencing of cells and EVs from HEK293T, RD4, C2C12, Neuro2a and C17.2. The majority of RNA content in EVs (49-96%) corresponded to rRNA-, coding- and tRNA fragments, corroborating with our proteomic analysis of HEK293T and C2C12 EVs which showed an enrichment of ribosome and translation-related proteins. On the other hand, the overall proportion of vesicular small RNA was relatively low and variable (2-39%) and mostly comprised of miRNAs and sequences mapping to piRNA loci. Importantly, this is one of the few studies, which systematically links vesicular RNA and protein cargo of vesicles. Our data is particularly useful for future work in unravelling the biological mechanisms underlying vesicular RNA and protein sorting and serves as an important guide in developing EVs as carriers for RNA therapeutics. PMID- 30018315 TI - Virtual environments as memory training devices in navigational tasks for older adults. AB - Cognitive training approaches using virtual environments (VEs) might counter age related visuospatial memory decline and associated difficulties in wayfinding. However, the effects of the visual design of a VE in route learning are not fully understood. Therefore, we created a custom-designed VE optimized for route learning, with adjusted levels of realism and highlighted landmark locations (MixedVE). Herein we tested participants' route recall performance in identifying direction of turn at the intersection with this MixedVE against two baseline alternatives (AbstractVE, RealisticVE). An older vs. a younger group solved the tasks in two stages (immediate vs. delayed recall by one week). Our results demonstrate that the MixedVE facilitates better recall accuracy than the other two VEs for both age groups. Importantly, this pattern persists a week later. Additionally, our older participants were mostly overconfident in their route recall performance, but the MixedVE moderated this potentially detrimental overconfidence. Before the experiment, participants clearly preferred the RealisticVE, whereas after the experiment, most of the younger, and many of the older participants, preferred the MixedVE. Taken together, our findings provide insights into the importance of tailoring visualization design in route learning with VEs. Furthermore, we demonstrate the great potential of the MixedVE and by extension, of similar VEs as memory training devices for route learning, especially for older participants. PMID- 30018316 TI - Microphotonic needle for minimally invasive endoscopic imaging with sub-cellular resolution. AB - Ultra-compact micro-optical elements for endoscopic instruments and miniaturized microscopes allow for non-invasive and non-destructive examination of microstructures and tissues. With sub-cellular level resolution such instruments could provide immediate diagnosis that is virtually consistent with a histologic diagnosis enabling for example to differentiate the boundaries between malignant and benign tissue. Such instruments are now being developed at a rapid rate; however, current manufacturing technologies limit the instruments to very large sizes, well beyond the sub-mm sizes required in order to ensure minimal tissue damage. We show here a platform based on planar microfabrication and soft lithography that overcomes the limitation of current optical elements enabling single cell resolution. We show the ability to resolve lithographic features that are as small as 2 MUm using probes with a cross section that is only 100 microns in size. We also show the ability to image individual activated neural cells in brain slices via our fabricated probe. PMID- 30018317 TI - The membrane-associated fraction of cyclase associate protein 1 translocates to the cytosol upon platelet stimulation. AB - Platelets undergo profound shape changes upon adhesion to damaged blood vessel walls that are mediated by reorganisation of the actin cytoskeleton in response to receptor-mediated signalling cascades. The highly conserved 56 kDa multidomain cyclase associated protein 1 (CAP1) works in concert with cofilin and profilin to modulate actin filament turnover by facilitating cofilin-mediated actin filament severing and depolymerisation and catalysing profilin-mediated regeneration of actin monomers for reutilisation in growing filaments. CAP1 is abundant in platelets but its roles remain unexplored. We report that in suspended platelets CAP1 localises predominantly at the cell cortex whereas in spread platelets it is uniformly distributed in the cytoplasm, with enrichment at the cell cortex and the periphery of actin nodules. Upon subcellular fractionation most CAP1 was found cytosolic but part associated to the membrane fraction in an actin independent manner. Interestingly, upon stimulation with thrombin a significant proportion of the membrane-associated CAP1 translocates to the cytosol. This relocalisation was prevented by prior treatment with PGI2 or the nitric oxide donor GSNO, or by inhibition of GSK3. Our results place CAP1 at a crossroad of signalling pathways that control platelet activation by contributing to actin remodelling at the cell cortex and actin nodules during platelet spreading. PMID- 30018318 TI - Evidence of vitamin D synthesis in insects exposed to UVb light. AB - Vertebrates obtain the prohormone vitamin D primarily by endogenous cutaneous synthesis under ultraviolet b (UVb) exposure. To date, endogenous synthesis of vitamin D in insects has never been investigated. In an initial experiment, we exposed four insect species which differ in ecology and morphology (migratory locusts, house crickets, yellow mealworms and black soldier fly larvae (BSFL)) to a low irradiance UVb source. In a second experiment we exposed these species to a higher UV irradiance, and in a third we tested the effect of exposure duration on vitamin D concentrations in yellow mealworms. Low irradiance UVb tended to increase vitamin D3 levels in house crickets, vitamin D2 levels in BSFL and vitamin D2 and D3 in yellow mealworms. Higher UVb irradiance increased vitamin D3 levels in all species but BSFL. Both BSFL and migratory locusts had increased vitamin D2 levels. Longer UVb exposure of yellow mealworms increased vitamin D2 and increased vitamin D3 until a plateau was reached at 6400 IU/kg. This study shows that insects can synthesize vitamin D de novo and that the amounts depend on UVb irradiance and exposure duration. PMID- 30018319 TI - Author Correction: Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. AB - In this Letter, the authors neglected to acknowledge funding from the Yonsei University Future-leading Research Initiative of 2017 (2017-22-007) awarded to H.W.P. PMID- 30018320 TI - Publisher Correction: Early lineage segregation of multipotent embryonic mammary gland progenitors. AB - In the version of this Article originally published, ref. 52 was incorrectly only attributed to its corresponding author, Fre, S., and an older title was used. The correct citation should have been: Lilja, A. M. et al. Clonal analysis of Notch1 expressing cells reveals the existence of unipotent stem cells that retain long term plasticity in the embryonic mammary gland. Nat. Cell Biol. https://doi.org/10.1038/s41556-018-0108-1 (2018)'. This has now been amended in all online versions of the Article. PMID- 30018321 TI - Author Correction: Structure of the core of the type III secretion system export apparatus. AB - In the version of this article initially published, the PDB code associated with the study was given as 6F2E but should have been 6F2D in Table 1 and the data availability statement. The error has been corrected in the HTML and PDF versions of the article. PMID- 30018322 TI - Highly active enzymes by automated combinatorial backbone assembly and sequence design. AB - Automated design of enzymes with wild-type-like catalytic properties has been a long-standing but elusive goal. Here, we present a general, automated method for enzyme design through combinatorial backbone assembly. Starting from a set of homologous yet structurally diverse enzyme structures, the method assembles new backbone combinations and uses Rosetta to optimize the amino acid sequence, while conserving key catalytic residues. We apply this method to two unrelated enzyme families with TIM-barrel folds, glycoside hydrolase 10 (GH10) xylanases and phosphotriesterase-like lactonases (PLLs), designing 43 and 34 proteins, respectively. Twenty-one GH10 and seven PLL designs are active, including designs derived from templates with <25% sequence identity. Moreover, four designs are as active as natural enzymes in these families. Atomic accuracy in a high-activity GH10 design is further confirmed by crystallographic analysis. Thus, combinatorial-backbone assembly and design may be used to generate stable, active, and structurally diverse enzymes with altered selectivity or activity. PMID- 30018323 TI - Self-healing and superstretchable conductors from hierarchical nanowire assemblies. AB - It is still a great challenge to improve deformability and fatigue-resistance of stretchable conductors when maintaining their high-level conductivity for practical use. Herein, a high-performance stretchable conductor with hierarchically ternary network and self-healing capability is demonstrated through in situ polymerizing N-isopropylacrylamide (NIPAM) on well-defined sulfur containing molecule-modified Ag nanowire (AgNW) aerogel framework. Owing to hierarchical architecture from nanoscale to microscale and further to macroscale and strong interactions of polymer chains and AgNWs, the composite exhibits good conductivity of 93 S cm-1, excellent electromechanical stability up to superhigh tensile strain of 800% and strong fatigue-resistant ability through well accommodating the applied deformations and sharing external force in the network. Furthermore, the composite delivers a fast and strong healing capability induced by reversible Ag-S bonds, which enables the healed conductor to hold an impressive electromechanical property. These prominent demonstrations confirm this material as top performer for use as flexible, stretchable electronic devices. PMID- 30018324 TI - Author Correction: Zebrafish and medaka offer insights into the neurobehavioral correlates of vertebrate magnetoreception. AB - Text for Correction. PMID- 30018325 TI - Adding chemically selective subtraction to multi-material 3D additive manufacturing. AB - Existing photoresists for 3D laser lithography that can be removed after development in a subtractive manner typically suffer from harsh cleavage conditions. Here, we report chemoselectively cleavable photoresists for 3D laser lithography based on silane crosslinkers, allowing the targeted degradation of 3D printed microstructures under mild conditions. Three bifunctional silane crosslinkers carrying various substitutions on the silicon atom are synthesized. The photoresists are prepared by mixing these silane crosslinkers with pentaerythritol triacrylate and a two-photon photoinitiator. The presence of pentaerythritol triacrylate significantly enhances the direct laser written structures with regard to resolution, while the microstructures remain cleavable. For the targeted cleavage of the fabricated 3D microstructures, simply a methanol solution including inorganic salts is required, highlighting the mild cleavage conditions. Critically, the photoresists can be cleaved selectively, which enables the sequential degradation of direct laser written structures and allows for subtractive manufacturing at the micro- and nanoscale. PMID- 30018326 TI - Large ice loss variability at Nioghalvfjerdsfjorden Glacier, Northeast-Greenland. AB - Nioghalvfjerdsfjorden is a major outlet glacier in Northeast-Greenland. Although earlier studies showed that the floating part near the grounding line thinned by 30% between 1999 and 2014, the temporal ice loss evolution, its relation to external forcing and the implications for the grounded ice sheet remain largely unclear. By combining observations of surface features, ice thickness and bedrock data, we find that the ice shelf mass balance has been out of equilibrium since 2001, with large variations of the thinning rates on annual/multiannual time scales. Changes in ice flux and surface ablation are too small to produce this variability. An increased ocean heat flux is the most plausible cause of the observed thinning. For sustained environmental conditions, the ice shelf will lose large parts of its area within a few decades and ice modeling shows a significant, but locally restricted thinning upstream of the grounding line in response. PMID- 30018327 TI - Assessment of the efficacy of different procedures that remove and disassemble alpha-synuclein, tau and A-beta fibrils from laboratory material and surfaces. AB - alpha-synuclein fibrillar polymorphs, Tau and Abeta 1-42 fibrillar assemblies have been shown to propagate, amplify and trigger the formation of protein deposits reminiscent of those present within the central nervous system of patients developing synucleinopathies, tauopathies and amyloid plaques after injection intracerebrally, intramuscularly, intraperitoneally or within the blood stream of model animals. They are thus hazardous and there is need for decontamination and inactivation procedures for laboratory surfaces and non disposable material. We assessed the effectiveness of different reagents to clean and disassemble potentially pathogenic assemblies adsorbed on non-disposable materials in laboratories. We show that commercial detergents and SDS are way more suited to detach alpha-synuclein fibrillar polymorphs, Tau and Abeta 1-42 fibrillar assemblies from contaminated surfaces and disassemble the fibrils than methods designed to decrease PrP prion infectivity. Our observations reveal that the choice of the most adapted cleaning procedure for one given protein assembly or fibrillar polymorph should integrate detergent's cleaning efficiency, material compatibility and capacity to dismantle assemblies. We provide an integrated representation where desorption and neutralization efficacy and surface compatibility are combined to facilitate the choice of the most adapted decontamination procedure. This representation, together with good laboratory practices, contributes to reducing potential health hazards associated to manipulating protein assemblies with prion-like properties. PMID- 30018329 TI - Culture of haploid blastocysts in FGF4 favors the derivation of epiblast stem cells with a primed epigenetic and transcriptional landscape. AB - Pluripotent stem cells within the inner cell mass and epiblast of mammalian embryos have the capacity to form all lineages in the adult organism, while multipotent trophoblast stem (TS) cells derived from the trophectoderm are capable of differentiating into fetal lineages of the placenta. While mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) exhibit distinct expression patterns and utilize distinct external signaling pathways for self renewal, because mouse EpiSCs resemble human ES cells they are a useful model to investigate mechanisms of human ES cell self-renewal and differentiation. Recent studies have shown that haploid embryos and ES cells can be generated from chemically-activated unfertilized mouse oocytes. However, it is unclear whether EpiSCs or TS cells can be derived from haploid embryos. Here, we describe the derivation of EpiSCs from haploid blastocyst-stage embryos using culture conditions that promote TS cell self-renewal. Maternal (parthenogenetic/gynogenetic) EpiSCs (maEpiSCs) functionally and morphologically resemble conventional EpiSCs. Established maEpiSCs and conventional EpiSCs are diploid and exhibit a normal number of chromosomes. Moreover, global expression analyses and epigenomic profiling revealed that maEpiSCs and conventional EpiSCs exhibit similarly primed transcriptional programs and epigenetic profiles, respectively. Altogether, our results describe a useful experimental model to generate EpiSCs from haploid embryos, provide insight into self-renewal mechanisms of EpiSCs, and suggest that FGF4 is not sufficient to derive TS cells from haploid blastocyst-stage embryos. PMID- 30018328 TI - Shared endo-phenotypes of default mode dsfunction in attention deficit/hyperactivity disorder and autism spectrum disorder. AB - Categorical diagnoses from the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) manuals are increasingly found to be incongruent with emerging neuroscientific evidence that points towards shared neurobiological dysfunction underlying attention deficit/hyperactivity disorder and autism spectrum disorder. Using resting-state functional magnetic resonance imaging data, functional connectivity of the default mode network, the dorsal attention and salience network was studied in 1305 typically developing and diagnosed participants. A transdiagnostic hierarchical Bayesian modeling framework combining Indian Buffet Processes and Latent Dirichlet Allocation was proposed to address the urgent need for objective brain-derived measures that can acknowledge shared brain network dysfunction in both disorders. We identified three main variation factors characterized by distinct coupling patterns of the temporoparietal cortices in the default mode network with the dorsal attention and salience network. The brain-derived factors were demonstrated to effectively capture the underlying neural dysfunction shared in both disorders more accurately, and to enable more reliable diagnoses of neurobiological dysfunction. The brain-derived phenotypes alone allowed for a classification accuracy reflecting an underlying neuropathology of 67.33% (+/ 3.07) in new individuals, which significantly outperformed the 46.73% (+/-3.97) accuracy of categorical diagnoses. Our results provide initial evidence that shared neural dysfunction in ADHD and ASD can be derived from conventional brain recordings in a data-led fashion. Our work is encouraging to pursue a translational endeavor to find and further study brain-derived phenotypes, which could potentially be used to improve clinical decision-making and optimize treatment in the future. PMID- 30018331 TI - A Universal Live Cell Barcoding-Platform for Multiplexed Human Single Cell Analysis. AB - Single-cell barcoding enables the combined processing and acquisition of multiple individual samples as one. This maximizes assay efficiency and eliminates technical variability in both sample preparation and analysis. Remaining challenges are the barcoding of live, unprocessed cells to increase downstream assay performance combined with the flexibility of the approach towards a broad range of cell types. To that end, we developed a novel antibody-based platform that allows the robust barcoding of live human cells for mass cytometry (CyTOF). By targeting both the MHC class I complex (beta-2-microglobulin) and a broadly expressed sodium-potassium ATPase-subunit (CD298) with platinum-conjugated antibodies, human immune cells, stem cells as well as tumor cells could be multiplexed in the same single-cell assay. In addition, we present a novel palladium-based covalent viability reagent compatible with this barcoding strategy. Altogether, this platform enables mass cytometry-based, live-cell barcoding across a multitude of human sample types and provides a scheme for multiplexed barcoding of human single-cell assays in general. PMID- 30018330 TI - Stromal PTEN determines mammary epithelial response to radiotherapy. AB - The importance of the tumor-associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk. PMID- 30018333 TI - Differences in biochemical markers between Heart-transplanted and Left Ventricular Assist Device implanted patients, during cardiac rehabilitation. AB - Heart transplant (HTx) and left ventricular assist device (LVAD) implant are the best options for symptomatic end stage heart failure, but LVAD patients show lower rehabilitative outcome than HTx patients. To investigate the causes, we compared biomarkers levels and their association with rehabilitative outcome in 51 HTx and in 46 LVAD patients entering the same cardiac rehabilitation program. In both groups, routine biomarkers were measured at start (T1) and end (T2) of cardiac rehabilitation while homocysteine, leptine and IGF-1 were measured at T1 only. HTx patients had lower lymphocyte, platelets, glucose, total proteins and albumin at T1; differences with LVAD patients vanished during rehabilitation when new cases of diabetes were observed in HTx. By contrast, total cholesterol, LDL and HDL fractions, leptin and IGF-1 were higher in HTx patients. The increase from T1 to T2 in six-minute walking test distance, measure of functional rehabilitation outcome, was positively associated with homocysteine and IGF-1 levels in HTx patients. In conclusion, during rehabilitation care should be paid to the early occurrence of dyslipidemia and hyperglycemia in HTx patients, which also require a proper protein dietary support. IGF-1, dangerously low in LVAD patients, might contribute to their lower rehabilitative outcome. PMID- 30018332 TI - Improved G-AgarTrap: A highly efficient transformation method for intact gemmalings of the liverwort Marchantia polymorpha. AB - Liverworts are key species for studies of plant evolution, occupying a basal position among the land plants. Marchantia polymorpha has emerged as a highly studied model liverwort, and many relevant techniques, including genetic transformation, have been established for this species. Agrobacterium-mediated transformation is widely used in many plant species because of its low cost. Recently, we developed a simplified Agrobacterium-mediated method for transforming M. polymorpha, known as AgarTrap (agar-utilized transformation with pouring solutions). The AgarTrap procedure, which involves culturing the liverwort tissue in various solutions on a single solid medium, yields up to a hundred independent transformants. AgarTrap is a simple procedure, requiring minimal expertise, cost, and time. Here, we investigated four factors that influence AgarTrap transformation efficiency: (1) humidity, (2) surfactant in the transformation buffer, (3) Agrobacterium strain, and (4) light/dark condition. We adapted the AgarTrap protocol for transforming intact gemmalings, achieving an exceptionally high transformation efficiency of 97%. The improved AgarTrap method will enhance the molecular biological study of M. polymorpha. Furthermore, this method provides new possibilities for improving transformation techniques for a variety of plant species. PMID- 30018334 TI - Feasibility and safety of shared EEG/EOG and vision-guided autonomous whole-arm exoskeleton control to perform activities of daily living. AB - Arm and finger paralysis, e.g. due to brain stem stroke, often results in the inability to perform activities of daily living (ADLs) such as eating and drinking. Recently, it was shown that a hybrid electroencephalography/electrooculography (EEG/EOG) brain/neural hand exoskeleton can restore hand function to quadriplegics, but it was unknown whether such control paradigm can be also used for fluent, reliable and safe operation of a semi-autonomous whole-arm exoskeleton restoring ADLs. To test this, seven abled bodied participants (seven right-handed males, mean age 30 +/- 8 years) were instructed to use an EEG/EOG-controlled whole-arm exoskeleton attached to their right arm to perform a drinking task comprising multiple sub-tasks (reaching, grasping, drinking, moving back and releasing a cup). Fluent and reliable control was defined as average 'time to initialize' (TTI) execution of each sub-task below 3 s with successful initializations of at least 75% of sub-tasks within 5 s. During use of the system, no undesired side effects were reported. All participants were able to fluently and reliably control the vision-guided autonomous whole-arm exoskeleton (average TTI 2.12 +/- 0.78 s across modalities with 75% successful initializations reached at 1.9 s for EOG and 4.1 s for EEG control) paving the way for restoring ADLs in severe arm and hand paralysis. PMID- 30018335 TI - Detection and Discrimination of Bacterial Colonies with Mueller Matrix Imaging. AB - The polarization imaging technique is a powerful approach to probe microstructural and optical information of biological structures (e.g., tissue samples). Here, we have studied the polarization properties of different bacterial colonies in order to evaluate the possibility of bacterial detection and discrimination. In this regard, we have taken the backscattering Mueller matrix images of four different bacteria colonies (i.e., Escherichia coli, Lactobacillus rhamnosus, Rhodococcus erythropolis, and Staphylococcus aureus). Although the images have the potential to distinguish qualitatively different bacterial colonies, we explored more accurate and quantitative parameters criteria for discrimination of bacterial samples; more specifically, we have exploited the Mueller matrix polar decomposition (MMPD),frequency distribution histogram (FDH), and central moment analysis method. The outcomes demonstrated a superior capacity of Mueller matrix imaging, MMPD, and FDH in bacterial colonies identification and discrimination. This approach might pave the way for a reliable, efficient, and cheap way of identification of infectious diseases. PMID- 30018336 TI - Downregulated NDR1 protein kinase inhibits innate immune response by initiating an miR146a-STAT1 feedback loop. AB - Interferon (IFN)-stimulated genes (ISGs) play crucial roles in the antiviral immune response; however, IFNs also induce negative regulators that attenuate the antiviral response. Here, we show that both viral and bacterial invasion downregulate Nuclear Dbf2-related kinase 1 (NDR1) expression via the type I IFN signaling pathway. NDR1 promotes the virus-induced production of type I IFN, proinflammatory cytokines and ISGs in a kinase-independent manner. NDR1 deficiency also renders mice more susceptible to viral and bacterial infections. Mechanistically, NDR1 enhances STAT1 translation by directly binding to the intergenic region of miR146a, thereby inhibiting miR146a expression and liberating STAT1 from miR146a-mediated translational inhibition. Furthermore, STAT1 binds to the miR146a promoter, thus decreasing its expression. Together, our results suggest that NDR1 promotion of STAT1 translation is an important event for IFN-dependent antiviral immune response, and suggest that NDR1 has an important role in controlling viral infections. PMID- 30018337 TI - Enhancement of collagen deposition and cross-linking by coupling lysyl oxidase with bone morphogenetic protein-1 and its application in tissue engineering. AB - Cultured cell-derived extracellular matrices (ECM)-based biomaterials exploit the inherent capacity of cells to create highly sophisticated supramolecular assemblies. However, standard cell culture conditions are far from ideal given the fact that the diluted microenvironment does not favor the production of ECM components, a circumstance particularly relevant for collagen. An incomplete conversion of procollagen by C-proteinase/bone morphogenetic protein 1 (BMP1) has been proposed to severely limit in vitro collagen deposition. BMP1 also catalyzes the proteolytic activation of the precursor of the collagen cross-linking enzyme, lysyl oxidase (LOX) to yield the active form, suggesting a deficit in cross linking activity under standard conditions. We hypothesized that the implementation of fibroblast cultures with LOX and BMP1 may be an effective way to increase collagen deposition. To test it, we have generated stable cell lines overexpressing LOX and BMP1 and studied the effect of supernatants enriched in LOX and BMP1 on collagen synthesis and deposition from fibroblasts. Herein, we demonstrate that the supplementation with LOX and BMP1 strongly increased the deposition of collagen onto the insoluble matrix at the expense of the soluble fraction in the extracellular medium. Using decellularization protocols, we also show that fibroblast-derived matrices regulate adipogenic and osteogenic differentiation of human mesenchymal stem cells (MSC), and this effect was modulated by LOX/BMP1. Collectively, these data demonstrate that we have developed a convenient protocol to enhance the capacity of in vitro cell cultures to deposit collagen in the ECM, representing this approach a promising technology for application in tissue engineering. PMID- 30018338 TI - Parkinson's disease and bacteriophages as its overlooked contributors. AB - Recent studies suggest that alterations in the gut phagobiota may contribute to pathophysiological processes in mammals; however, the association of bacteriophage community structure with Parkinson's disease (PD) has not been yet characterized. Towards this end, we used a published dataset to analyse bacteriophage composition and determine the phage/bacteria ratio in faecal samples from drug-naive PD patients and healthy participants. Our analyses revealed significant alterations in the representation of certain bacteriophages in the phagobiota of PD patients. We identified shifts of the phage/bacteria ratio in lactic acid bacteria known to produce dopamine and regulate intestinal permeability, which are major factors implicated in PD pathogenesis. Furthermore, we observed the depletion of Lactococcus spp. in the PD group, which was most likely due to the increase of lytic c2-like and 936-like lactococcal phages frequently present in dairy products. Our findings add bacteriophages to the list of possible factors associated with the development of PD, suggesting that gut phagobiota composition may serve as a diagnostic tool as well as a target for therapeutic intervention, which should be confirmed in further studies. Our results open a discussion on the role of environmental phages and phagobiota composition in health and disease. PMID- 30018339 TI - P31-43, an undigested gliadin peptide, mimics and enhances the innate immune response to viruses and interferes with endocytic trafficking: a role in celiac disease. AB - Celiac disease (CD) is an autoimmune disease characterized by inflammation of the intestinal mucosa due to an immune response to wheat gliadins. Some gliadin peptides are resistant to intestinal digestion (e.g., A-gliadin P31-43) and induce a stress/innate immune response, but the reason why they are dangerous in the intestines of patients with CD is unknown. In the present study, P31-43 activated IFN-alpha, a mediator of the innate immune response in CD, in the intestine of subjects with CD and an enterocyte cell line, CaCo-2. P31-43 cooperated with a viral ligand to activate the TLR7 pathway by interfering with endocytic trafficking. Based on these results, the vesicular pathway regulates the innate/inflammatory response to viral ligands and bioactive dietary peptides. Suggesting that together with viral infections, alimentary proteins able to mimic and potentiate the innate immune response to viruses, can trigger an autoimmune disease such as CD. PMID- 30018340 TI - A Multiwell-Based Detection Platform with Integrated PDMS Concentrators for Rapid Multiplexed Enzymatic Assays. AB - We report an integrated system for accelerating assays with concentrators in a standard 12-well plate (ISAAC-12) and demonstrate its versatility for rapid detection of matrix metalloproteinase (MMP)-9 expression in the cell culture supernatant of breast cancer cell line MDA-MB-231 by accelerating the enzymatic reaction and end-point signal intensity via electrokinetic preconcentration. Using direct printing of a conductive ion-permselective polymer on a polydimethylsiloxane (PDMS) channel, the new microfluidic concentrator chip can be built without modifying the underlying substrate. Through this decoupling fabrication strategy, our microfluidic concentrator chip can easily be integrated with a standard multiwell plate, the de facto laboratory standard platform for high-throughput assays, simply by reversible bonding on the bottom of each well. It increases the reaction rate of enzymatic assays by concentrating the enzyme and the reaction product inside each well simultaneously for rapid multiplexed detection. PMID- 30018342 TI - Instructive power of senescence. PMID- 30018341 TI - Single cell transcriptome profiling of retinal ganglion cells identifies cellular subtypes. AB - Retinal ganglion cells (RGCs) convey the major output of information collected from the eye to the brain. Thirty subtypes of RGCs have been identified to date. Here, we analyze 6225 RGCs (average of 5000 genes per cell) from right and left eyes by single-cell RNA-seq and classify them into 40 subtypes using clustering algorithms. We identify additional subtypes and markers, as well as transcription factors predicted to cooperate in specifying RGC subtypes. Zic1, a marker of the right eye-enriched subtype, is validated by immunostaining in situ. Runx1 and Fst, the markers of other subtypes, are validated in purified RGCs by fluorescent in situ hybridization (FISH) and immunostaining. We show the extent of gene expression variability needed for subtype segregation, and we show a hierarchy in diversification from a cell-type population to subtypes. Finally, we present a website for comparing the gene expression of RGC subtypes. PMID- 30018344 TI - Incidence of bladder cancer in Benghazi, Libya over the past three decades. AB - There are limited data on the disease of bladder cancer in Libya. The objective of this study was to assess the pattern of incidence and clinical presentation of bladder cancer in Benghazi, Libya. This study was a retrospective cohort analysis conducted among consecutive individuals who were diagnosed and/or were treated for bladder cancer from January 1st 1983 to December 31st 2009. A total of 835 cases of bladder tumour were recorded. The world age-standardized incidence rate was 13.1 and 1.9 per 100,000 for males and females, respectively. The mean (standard deviation) age of all patients was 63.7 (14.7). The majority of patients (n = 750, 89.8%) were male, two-thirds of which (n = 594, 79.2%) were smokers while all female patients were non-smokers. Hematuria was the most frequent presenting symptom. Most tumours were well differentiated, and transitional cell carcinoma was the most frequent histological type. The incidence of bladder cancer in Libya is lower than most developed countries, increases by aging, and is more prevalent among males. The incidence of this disease is expected to grow in developing countries such as Libya because of increase in smoking popularity, the shift to sedentary life, diabetes mellitus, and obesity. PMID- 30018343 TI - An integrative, multi-omics approach towards the prioritization of Klebsiella pneumoniae drug targets. AB - Klebsiella pneumoniae (Kp) is a globally disseminated opportunistic pathogen that can cause life-threatening infections. It has been found as the culprit of many infection outbreaks in hospital environments, being particularly aggressive towards newborns and adults under intensive care. Many Kp strains produce extended-spectrum beta-lactamases, enzymes that promote resistance against antibiotics used to fight these infections. The presence of other resistance determinants leading to multidrug-resistance also limit therapeutic options, and the use of 'last-resort' drugs, such as polymyxins, is not uncommon. The global emergence and spread of resistant strains underline the need for novel antimicrobials against Kp and related bacterial pathogens. To tackle this great challenge, we generated multiple layers of 'omics' data related to Kp and prioritized proteins that could serve as attractive targets for antimicrobial development. Genomics, transcriptomics, structuromic and metabolic information were integrated in order to prioritize candidate targets, and this data compendium is freely available as a web server. Twenty-nine proteins with desirable characteristics from a drug development perspective were shortlisted, which participate in important processes such as lipid synthesis, cofactor production, and core metabolism. Collectively, our results point towards novel targets for the control of Kp and related bacterial pathogens. PMID- 30018346 TI - Author Correction: Choosing the future of Antarctica. AB - On page 234 of this Perspective, '50% decrease' has been corrected online to '50% increase' in the sentence "The pH of surface waters south of 60 degrees S decreased by 0.2 between 2017 and 2070, equivalent to a 50% increase in the concentration of hydrogen ions since the pre-industrial period1." PMID- 30018345 TI - A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling. AB - Detection of viral genomes by the innate immune system elicits an antiviral gene program mediated by type I interferons (IFNs). While viral RNA and DNA species induce IFN via separate pathways, the mechanisms by which these pathways are differentially modulated are unknown. Here we show that the positive regulator of IFN in the RNA pathway, TRAF3, has an inhibitory function in the DNA pathway. Loss of TRAF3 coincides with increased expression of the alternative NF-kappaB inducing molecule, NIK, which interacts with the DNA pathway adaptor, STING, to enhance IFN induction. Cells lacking NIK display defective IFN activation in the DNA pathway due to impaired STING signaling, and NIK-deficient mice are more susceptible to DNA virus infection. Mechanistically, NIK operates independently from alternative NF-kappaB signaling components and instead requires autophosphorylation and oligomerization to activate STING. Thus a previously undescribed pathway for NIK exists in activating IFN in the DNA pathway. PMID- 30018347 TI - Endemic fish species structuring oceanic intertidal reef assemblages. AB - Intertidal reef environments are facing a global crisis as climate changes are causing sea-level rise. Synergistically, other human-induced impacts (e.g., sewage, habitat loss) caused by concentration of human populations near the coast increase the natural vulnerability of intertidal ecosystems. However, the effect of these threats have long been neglected due, in part, to a limited knowledge of some aspects of intertidal fish ecology. We tested what are the main differences and drivers in fish assemblages structure between tidepools in three oceanic and three continental shelf (coastal) sites of the tropical southwestern Atlantic (Brazilian Province) using standardized sampling methods. Oceanic and coastal fish assemblages were distinctly structured at the trophic and composition levels. The noteworthy endemism species rate (38-44%) and high densities in oceanic sites are supported by resident species restricted to mid and high-shore tidepools where herbivores were the major trophic group. The coastal sites, on the other hand, were dominated by widely distributed and carnivore species. Physical (substrate type, pool height, subtidal distance and rock coverage), biological (sessile animal coverage) and chemical (salinity) parameters act as the driving forces influencing fish spatial occupancy. Here, clear evidences of high fish endemism and importance of endemics structuring oceanic communities may act as the last straw in favor of the conservation of oceanic intertidal reefs. PMID- 30018350 TI - Author Correction: The interplay of social group biases in social threat learning. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30018349 TI - Cell fate potentials and switching kinetics uncovered in a classic bistable genetic switch. AB - Bistable switches are common gene regulatory motifs directing two mutually exclusive cell fates. Theoretical studies suggest that bistable switches are sufficient to encode more than two cell fates without rewiring the circuitry due to the non-equilibrium, heterogeneous cellular environment. However, such a scenario has not been experimentally observed. Here by developing a new, dual single-molecule gene-expression reporting system, we find that for the two mutually repressing transcription factors CI and Cro in the classic bistable bacteriophage lambda switch, there exist two new production states, in which neither CI nor Cro is produced, or both CI and Cro are produced. We construct the corresponding potential landscape and map the transition kinetics among the four production states. These findings uncover cell fate potentials beyond the classical picture of bistable switches, and open a new window to explore the genetic and environmental origins of the cell fate decision-making process in gene regulatory networks. PMID- 30018348 TI - Maintaining bovine satellite cells stemness through p38 pathway. AB - Isolating and maintaining the appropriate stem cell for large scale cell culture is essential in tissue engineering or food production. For bovine satellite cells an optimized isolation and purification protocol is lacking and there is also no detailed understanding on the factors that maintain stemness of these cells. Here, we set up a fluorescence-activated cell sorting strategy to enrich bovine satellite cells. We found that p38-MAPK signalling is activated and PAX7 expression is gradually lost during satellite cell proliferation. The p38 inhibitor (SB203580) treatment maintained PAX7 expression but inhibited the fusion of satellite cells in a concentration-dependent way in short-term incubation. The mechanism of p38 inhibition was confirmed by inhibiting canonical p38 signalling, i.e. HSP27. Long-term culture with an appropriate concentration of p38i enhanced the proliferation and PAX7 expression, while the differentiation capacity recovered and was enhanced compared to vehicle control. These studies indicate that bovine satellite cells maintenance depends on cell purity and p38 MAPK signalling. Inhibition of p38 MAPK signaling is a promising strategy to facilitate large scale cell expansion of primary cells for tissue engineering and cultured meat purposes. PMID- 30018352 TI - Optical calibration and performance of the adaptive secondary mirror at the Magellan telescope. AB - In this paper we describe the procedure for the optical calibration of large size deformable mirrors, acting as wavefront correctors for adaptive optics systems. Adaptive optics compensate the disturbance due to the atmospheric turbulence to restore the telescope resolution. We will showcase in particular the activities performed for the Adaptive Secondary Mirror (ASM) of the Magellan Adaptive Optics system (MagAO), which is an instrument for the 6.5 m Magellan Clay Telescope, located at Las Campanas Observatory, in Chile. The MagAO ASM calibration is part of the MagAO-2K project, a major MagAO upgrade that started in 2016 with the goal of boosting adaptive optics (AO) correction at visible wavelengths to image exoplanets. For the first time, the optical quality of MagAO mirror is reported. We describe the procedures developed to achieve high SNR interferometric measurements of the ASM modes under the presence of dome convection noise and telescope vibrations. These measurements were required to produce an improved control matrix with up to 500 modes to close the AO loop on sky with enhanced performances. An updated slaving algorithm was developed to improve the control of actuators vignetted by the central obscuration. The calibrations yielded also a new ASM flattening command, updating the one in use since the MagAO commissioning in 2013. With the new flattening command, a 22 nm RMS surface error was achieved. Finally, we present on-sky results showing the MagAO performance achieved with the new calibrations. PMID- 30018351 TI - A combined computational-experimental approach to define the structural origin of antibody recognition of sialyl-Tn, a tumor-associated carbohydrate antigen. AB - Anti-carbohydrate monoclonal antibodies (mAbs) hold great promise as cancer therapeutics and diagnostics. However, their specificity can be mixed, and detailed characterization is problematic, because antibody-glycan complexes are challenging to crystallize. Here, we developed a generalizable approach employing high-throughput techniques for characterizing the structure and specificity of such mAbs, and applied it to the mAb TKH2 developed against the tumor-associated carbohydrate antigen sialyl-Tn (STn). The mAb specificity was defined by apparent KD values determined by quantitative glycan microarray screening. Key residues in the antibody combining site were identified by site-directed mutagenesis, and the glycan-antigen contact surface was defined using saturation transfer difference NMR (STD-NMR). These features were then employed as metrics for selecting the optimal 3D-model of the antibody-glycan complex, out of thousands plausible options generated by automated docking and molecular dynamics simulation. STn specificity was further validated by computationally screening of the selected antibody 3D-model against the human sialyl-Tn-glycome. This computational experimental approach would allow rational design of potent antibodies targeting carbohydrates. PMID- 30018353 TI - Retraction Note: Identification of a novel Na+-coupled Fe3+-citrate transport system, distinct from mammalian INDY, for uptake of citrate in mammalian cells. AB - This paper has been retracted at the request of the authors. PMID- 30018354 TI - Author Correction: Dopamine transients are sufficient and necessary for acquisition of model-based associations. AB - In the version of this article initially published, the laser activation at the start of cue X in experiment 1 was described in the first paragraph of the Results and in the third paragraph of the Experiment 1 section of the Methods as lasting 2 s; in fact, it lasted only 1 s. The error has been corrected in the HTML and PDF versions of the article. PMID- 30018355 TI - Author Correction: Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. AB - In the version of this article initially published, the catalog numbers for BoNT A and B were given in the Methods section as T0195 and T5644; the correct numbers are B8776 and B6403. The error has been corrected in the HTML and PDF versions of the article. PMID- 30018358 TI - Delivery of the gut microbiome. PMID- 30018356 TI - A potentially abundant junctional RNA motif stabilized by m6A and Mg2. AB - N6-Methyladenosine (m6A) is an abundant post-transcriptional RNA modification that influences multiple aspects of gene expression. In addition to recruiting proteins, m6A can modulate RNA function by destabilizing base pairing. Here, we show that when neighbored by a 5' bulge, m6A stabilizes m6A-U base pairs, and global RNA structure by ~1 kcal mol-1. The bulge most likely provides the flexibility needed to allow optimal stacking between the methyl group and 3' neighbor through a conformation that is stabilized by Mg2+. A bias toward this motif can help explain the global impact of methylation on RNA structure in transcriptome-wide studies. While m6A embedded in duplex RNA is poorly recognized by the YTH domain reader protein and m6A antibodies, both readily recognize m6A in this newly identified motif. The results uncover potentially abundant and functional m6A motifs that can modulate the epitranscriptomic structure landscape with important implications for the interpretation of transcriptome-wide data. PMID- 30018359 TI - Observation of nuclear quantum effects and hydrogen bond symmetrisation in high pressure ice. AB - Hydrogen bond symmetrisations in H-bonded systems triggered by pressure-induced nuclear quantum effects (NQEs) is a long-known concept but experimental evidence in high-pressure ices has remained elusive with conventional methods. Theoretical works predicted quantum-mechanical tunneling of protons within water ices to occur at pressures above 30 GPa, and the H-bond symmetrisation transition to occur above 60 GPa. Here we used 1H-NMR on high-pressure ice up to 97 GPa, and demonstrate that NQEs govern the behavior of the hydrogen bonded protons in ice VII already at significantly lower pressures than previously expected. A pronounced tunneling mode was found to be present up to the highest pressures of 97 GPa, well into the stability field of ice X, where NQEs are not anticipated in a fully symmetrised H-bond network. We found two distinct transitions in the NMR shift data at about 20 GPa and 75 GPa attributed to the step-wise symmetrisation of the H-bond. PMID- 30018357 TI - Exploring hidden diversity in Southeast Asia's Dermogenys spp. (Beloniformes: Zenarchopteridae) through DNA barcoding. AB - Members of the freshwater halfbeak genus Dermogenys are hard to identify to the species level, despite several previous attempts to isolate fixed meristic, morphometric and colour pattern differences. This has led to ongoing confusion in scientific literature, records of species occurrence, and entries in museum collections. Here, a DNA barcoding study was conducted on the genus to gain further understanding of its taxonomic status across the Southeast Asian region. Fish were collected from 33 localities, spanning freshwater and brackish habitats in Malaysia, Western Indonesia, Thailand and Vietnam. In total, 290 samples of Dermogenys spp. were amplified for a 651 base pair fragment of the mitochondrial cytochrome oxidase c subunit I (COI) gene. Analysis was able to successfully differentiate the three species: D. collettei, D. siamensis, D. sumatrana; reveal the presence of a new putative species, Dermogenys sp., that was sampled in sympatry with D. collettei at three locations; as well as uncovering two genetic lineages of a fifth species, D. bispina, that display non-overlapping geographical distributions in drainages of northern Borneo; Kudat and Sandakan. This study expands the barcode library for Zenarchopteridae, demonstrates the efficacy of DNA barcoding techniques for differentiating Dermogenys species, and the potential thereof in species discovery. PMID- 30018360 TI - Ontogenetic transition from specialized root hairs to specific root-fungus symbiosis in the dominant Mediterranean seagrass Posidonia oceanica. AB - Terrestrial plants typically take up nutrients through roots or mycorrhizae while freshwater plants additionally utilize leaves. Their nutrient uptake may be enhanced by root hairs whose occurrence is often negatively correlated with mycorrhizal colonization. Seagrasses utilize both leaves and roots and often form root hairs, but seem to be devoid of mycorrhizae. The Mediterranean seagrass Posidonia oceanica is an exception: its adults commonly lack root hairs and regularly form a specific association with a single pleosporalean fungus. Here we show that at two sites in the southern Adriatic, all its seedlings possessed abundant root hairs with peculiar morphology (swollen terminal parts) and anatomy (spirally formed cell walls) as apparent adaptations for better attachment to the substrate and increase of breaking strain. Later on, their roots became colonized by dark septate mycelium while root hairs were reduced. In adults, most of terminal fine roots possessed the specific fungal association while root hairs were absent. These observations indicate for the first time that processes regulating transition from root hairs to root fungal colonization exist also in some seagrasses. This ontogenetic shift in root traits may suggests an involvement of the specific root symbiosis in the nutrient uptake by the dominant Mediterranean seagrass. PMID- 30018362 TI - Insightful classification of crystal structures using deep learning. AB - Computational methods that automatically extract knowledge from data are critical for enabling data-driven materials science. A reliable identification of lattice symmetry is a crucial first step for materials characterization and analytics. Current methods require a user-specified threshold, and are unable to detect average symmetries for defective structures. Here, we propose a machine learning based approach to automatically classify structures by crystal symmetry. First, we represent crystals by calculating a diffraction image, then construct a deep learning neural network model for classification. Our approach is able to correctly classify a dataset comprising more than 100,000 simulated crystal structures, including heavily defective ones. The internal operations of the neural network are unraveled through attentive response maps, demonstrating that it uses the same landmarks a materials scientist would use, although never explicitly instructed to do so. Our study paves the way for crystal structure recognition of-possibly noisy and incomplete-three-dimensional structural data in big-data materials science. PMID- 30018361 TI - Mie-coupled bound guided states in nanowire geometric superlattices. AB - All-optical operation holds promise as the future of computing technology, and key components include miniaturized waveguides (WGs) and couplers that control narrow bandwidths. Nanowires (NWs) offer an ideal platform for nanoscale WGs, but their utility has been limited by the lack of a comprehensive coupling scheme with band selectivity. Here, we introduce a NW geometric superlattice (GSL) that allows narrow-band guiding in Si NWs through coupling of a Mie resonance with a bound-guided state (BGS). Periodic diameter modulation creates a Mie-BGS-coupled excitation that manifests as a scattering dark state with a pronounced scattering dip in the Mie resonance. The frequency of the coupled mode, tunable from the visible to near-infrared, is determined by the pitch of the GSL. Using a combined GSL-WG system, we demonstrate spectrally selective guiding and optical switching and sensing at telecommunication wavelengths, highlighting the potential to use NW GSLs for the design of on-chip optical components. PMID- 30018363 TI - Genetic variations for egg quality of chickens at late laying period revealed by genome-wide association study. AB - With the extension of the egg-laying cycle, the rapid decline in egg quality at late laying period has aroused great concern in the poultry industry. Herein, we performed a genome-wide association study (GWAS) to identify genomic variations associated with egg quality, employing chicken 600 K high-density SNP arrays in a population of 1078 hens at 72 and 80 weeks of age. The results indicated that a genomic region spanning from 8.95 to 9.31 Mb (~0.36 Mb) on GGA13 was significantly associated with the albumen height (AH) and the haugh unit (HU), and the two most significant SNPs accounted for 3.12 ~ 5.75% of the phenotypic variance. Two promising genes, MSX2 and DRD1, were mapped to the narrow significant region, which was involved in embryonic and ovary development and found to be related to egg production, respectively. Moreover, three interesting genes, RHOA, SDF4 and TNFRSF4, identified from three significant loci, were considered to be candidate genes for egg shell colour. Findings in our study could provide worthy theoretical basis and technological support to improve late stage egg quality for breeders. PMID- 30018364 TI - Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice. AB - Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), is classified into two subgroups, Stx1 and Stx2. Clinical data clearly indicate that Stx2 is associated with more severe toxicity than Stx1, but the molecular mechanism underlying this difference is not fully understood. Here, we found that after being incorporated into target cells, Stx2, can be transported by recycling endosomes, as well as via the regular retrograde transport pathway. However, transport via recycling endosome did not occur with Stx1. We also found that Stx2 is actively released from cells in a receptor-recognizing B-subunit dependent manner. Part of the released Stx2 is associated with microvesicles, including exosome markers (referred to as exo-Stx2), whose origin is in the multivesicular bodies that formed from late/recycling endosomes. Finally, intravenous administration of exo-Stx2 to mice causes more lethality and tissue damage, especially severe renal dysfunction and tubular epithelial cell damage, compared to a free form of Stx2. Thus, the formation of exo-Stx2 might contribute to the severity of Stx2 in vivo, suggesting new therapeutic strategies against EHEC infections. PMID- 30018366 TI - Involvement of leptin signaling in the development of cannabinoid CB2 receptor dependent mirror image pain. AB - Neuropathic pain typically appears in a region innervated by an injured or diseased nerve and, in some instances, also on the contralateral side. This so called mirror image pain is often observed in mice lacking CB2 receptors after sciatic nerve injury, but the underlying mechanisms for this phenotype largely remain unclear. Here we focused on peripheral leptin signaling, which modulates neuropathic pain development and interacts with the endocannabinoid system. Leptin production is induced at the site of nerve injury in CB2-deficient mice (CB2-KO) mice and wild type controls (WT). However, induction of leptin receptor expression was only observed in the injured nerve of CB2-KO mice. This was paralleled by a stimulation of the leptin receptor-downstream STAT3 signaling and an infiltration of F4/80-positive macrophages. Interestingly, an upregulation of leptin receptor expression STAT3 activity and macrophage infiltration was also observed on the non-injured nerve of CB2-KO mice thus reflecting the mirror image pain in CB2-KO animals. Importantly, perineurally-administered leptin neutralizing antibodies reduced mechanical hyperalgesia, blocked mirror image pain and inhibited the recruitment of F4/80-positive macrophages. These results identify peripheral leptin signaling as an important modulator of CB2 signaling in neuropathic pain. PMID- 30018365 TI - Unconventional fractional quantum Hall states and Wigner crystallization in suspended Corbino graphene. AB - Competition between liquid and solid states in two-dimensional electron systems is an intriguing problem in condensed matter physics. We have investigated competing Wigner crystal and fractional quantum Hall (FQH) liquid phases in atomically thin suspended graphene devices in Corbino geometry. Low-temperature magnetoconductance and transconductance measurements along with IV characteristics all indicate strong charge density dependent modulation of electron transport. Our results show unconventional FQH phases which do not fit the standard Jain's series for conventional FQH states, instead they appear to originate from residual interactions of composite fermions in partially filled Landau levels. Also at very low charge density with filling factors [Formula: see text], electrons crystallize into an ordered Wigner solid which eventually transforms into an incompressible Hall liquid at filling factors around nu <= 1/7. Building on the unique Corbino sample structure, our experiments pave the way for enhanced understanding of the ordered phases of interacting electrons. PMID- 30018367 TI - Cytonuclear integration and co-evolution. AB - The partitioning of genetic material between the nucleus and cytoplasmic (mitochondrial and plastid) genomes within eukaryotic cells necessitates coordinated integration between these genomic compartments, with important evolutionary and biomedical implications. Classic questions persist about the pervasive reduction of cytoplasmic genomes via a combination of gene loss, transfer and functional replacement - and yet why they are almost always retained in some minimal form. One striking consequence of cytonuclear integration is the existence of 'chimeric' enzyme complexes composed of subunits encoded in two different genomes. Advances in structural biology and comparative genomics are yielding important insights into the evolution of such complexes, including correlated sequence changes and recruitment of novel subunits. Thus, chimeric cytonuclear complexes provide a powerful window into the mechanisms of molecular co-evolution. PMID- 30018368 TI - Breeding for soil-borne pathogen resistance impacts active rhizosphere microbiome of common bean. AB - Over the past century, plant breeding programs have substantially improved plant growth and health, but have not yet considered the potential effects on the plant microbiome. Here, we conducted metatranscriptome analysis to determine if and how breeding for resistance of common bean against the root pathogen Fusarium oxysporum (Fox) affected gene expression in the rhizobacterial community. Our data revealed that the microbiome of the Fox-resistant cultivar presented a significantly higher expression of genes associated with nutrient metabolism, motility, chemotaxis, and the biosynthesis of the antifungal compounds phenazine and colicin V. Network analysis further revealed a more complex community for Fox resistant cultivar and indicated Paenibacillus as a keystone genus in the rhizosphere microbiome. We suggest that resistance breeding in common bean has unintentionally co-selected for plant traits that strengthen the rhizosphere microbiome network structure and enrich for specific beneficial bacterial genera that express antifungal traits involved in plant protection against infections by root pathogens. PMID- 30018369 TI - Role of disordered bipolar complexions on the sulfur embrittlement of nickel general grain boundaries. AB - Minor impurities can cause catastrophic fracture of normally ductile metals. Here, a classic example is represented by the sulfur embrittlement of nickel, whose atomic-level mechanism has puzzled researchers for nearly a century. In this study, coupled aberration-corrected electron microscopy and semi-grand canonical-ensemble atomistic simulation reveal, unexpectedly, the universal formation of amorphous-like and bilayer-like facets at the same general grain boundaries. Challenging the traditional view, the orientation of the lower-Miller index grain surface, instead of the misorientation, dictates the interfacial structure. We also find partial bipolar structural orders in both amorphous-like and bilayer-like complexions (a.k.a. thermodynamically two-dimensional interfacial phases), which cause brittle intergranular fracture. Such bipolar, yet largely disordered, complexions can exist in and affect the properties of various other materials. Beyond the embrittlement mechanism, this study provides deeper insight to better understand abnormal grain growth in sulfur-doped Ni, and generally enriches our fundamental understanding of performance-limiting and more disordered interfaces. PMID- 30018370 TI - Impact of Edible Cricket Consumption on Gut Microbiota in Healthy Adults, a Double-blind, Randomized Crossover Trial. AB - Edible insects are often considered a nutritious, protein-rich, environmentally sustainable alternative to traditional livestock with growing popularity among North American consumers. While the nutrient composition of several insects is characterized, all potential health impacts have not been evaluated. In addition to high protein levels, crickets contain chitin and other fibers that may influence gut health. In this study, we evaluated the effects of consuming 25 grams/day whole cricket powder on gut microbiota composition, while assessing safety and tolerability. Twenty healthy adults participated in this six-week, double-blind, crossover dietary intervention. Participants were randomized into two study arms and consumed either cricket-containing or control breakfast foods for 14 days, followed by a washout period and assignment to the opposite treatment. Blood and stool samples were collected at baseline and after each treatment period to assess liver function and microbiota changes. Results demonstrate cricket consumption is tolerable and non-toxic at the studied dose. Cricket powder supported growth of the probiotic bacterium, Bifidobacterium animalis, which increased 5.7-fold. Cricket consumption was also associated with reduced plasma TNF-alpha. These data suggest that eating crickets may improve gut health and reduce systemic inflammation; however, more research is needed to understand these effects and underlying mechanisms. PMID- 30018371 TI - Direct observation of DNA target searching and cleavage by CRISPR-Cas12a. AB - Cas12a (also called Cpf1) is a representative type V-A CRISPR effector RNA-guided DNA endonuclease, which provides an alternative to type II CRISPR-Cas9 for genome editing. Previous studies have revealed that Cas12a has unique features distinct from Cas9, but the detailed mechanisms of target searching and DNA cleavage by Cas12a are still unclear. Here, we directly observe this entire process by using single-molecule fluorescence assays to study Cas12a from Acidaminococcus sp. (AsCas12a). We determine that AsCas12a ribonucleoproteins search for their on target site by a one-dimensional diffusion along elongated DNA molecules and induce cleavage in the two DNA strands in a well-defined order, beginning with the non-target strand. Furthermore, the protospacer-adjacent motif (PAM) for AsCas12a makes only a limited contribution of DNA unwinding during R-loop formation and shows a negligible role in the process of DNA cleavage, in contrast to the Cas9 PAM. PMID- 30018372 TI - Dry Spin Graphene Oxide Fibers: Mechanical/Electrical Properties and Microstructure Evolution. AB - Dry-spinning method is extensively employed in fiber industry, comparing to the counter-part of wet-spinning process, it has advantages of environmentally friendly, high yield rate and no need for purification. Here, we report the synthesis of graphene oxide (GO) fibers via dry spinning GO inks with extremely high concentrations. The proper rheology properties of such GO inks allow us to dry spin GO fiber directly. Various dry spinning conditions are investigated, and the relationship between mechanical performance and micro-structure of the obtained GO fiber are established. We found that the existence of larger GO liquid crystal domains does not necessarily result to higher mechanical properties, and it is because those large GO liquid crystal domains evolve into thick GO films during drying process and thus prevent the intimate compaction of the whole GOF and leave behind gaps. This is detrimental for the mechanical properties, and thus the dry spin GOF are much weaker than that of wet spin ones. Importantly, Barus effects, that generally arise during the melt spinning of polymers, were not observed, indicating that caution must be taken when classical polymer rheology theories are applied to investigate the dynamic behaviors of GO solution. PMID- 30018373 TI - Cold deep subduction recorded by remnants of a Paleoproterozoic carbonated slab. AB - The absence of low-thermal gradients in old metamorphic rocks (<350 degrees C GPa-1) has been used to argue for a fundamental change in the style of plate tectonics during the Neoproterozoic Era. Here, we report data from an eclogite xenolith in Paleoproterozoic carbonatite in the North China craton that argues for cold subduction as early as 1.8 Ga. The carbonatite has a sediment-derived C isotope signature and enriched initial Sr-Nd isotope composition, indicative of ocean-crust components in the source. The eclogite records peak metamorphic pressures of 2.5-2.8 GPa at 650-670 degrees C, indicating a cold thermal gradient, 250(+/-15) degrees C GPa-1. Our data, combined with old low temperature events in the West African and North American cratons, reveal a global pattern that modern-style subduction may have been established during the Paleoproterozoic Era. Paleoproterozoic carbonatites are closely associated with granulites and eclogites in orogens worldwide, playing a critical role in the Columbia supercontinent amalgamation and deep carbon cycle through time. PMID- 30018375 TI - Stem-cell therapy restores heart function after MI in macaques. PMID- 30018374 TI - The associations between maternal lifestyles and antenatal stress and anxiety in Chinese pregnant women: A cross-sectional study. AB - The study aimed to investigate the associations between maternal lifestyles and antenatal stress and anxiety. 1491 pregnant women were drawn from the Guangxi birth cohort study (GBCS). A base line questionnaire was used to collect demographic information and maternal lifestyles. The Pregnancy Stress Rating Scale (PSRS) and Self-Rating Anxiety Scale (SAS) were used to assess prenatal stress and anxiety, respectively. Regression analyses identified the relationship between maternal lifestyles and prenatal stress and anxiety: (1) Hours of phone use per day was positively correlated to prenatal stress and anxiety and increased with stress and anxiety levels (all P trend < 0.05). In addition, not having baby at home was positively correlated to prenatal stress. (2) Self reported sleep quality was negative with prenatal stress and anxiety, and decreased with stress and anxiety levels (all P trend < 0.01). Moreover, not frequent cooking was negatively correlated to prenatal stress and having pets was negatively correlated to prenatal anxiety (P < 0.05). However, having pets was not correlated to prenatal stress (P > 0.05). Our results showed that adverse lifestyles increase the risk of antenatal stress and anxiety, a regular routine and a variety of enjoyable activities decreases the risk of prenatal stress and anxiety. PMID- 30018376 TI - A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis. AB - Cyclopropanation of unactivated olefinic bonds via addition of a reactive one carbon species is well developed in synthetic chemistry, whereas natural cyclopropane biosynthesis employing this strategy is very limited. Here, we identify a two-component cyclopropanase system, composed of a HemN-like radical S adenosyl-L-methionine (SAM) enzyme C10P and a methyltransferase C10Q, catalyzes chemically challenging cyclopropanation in the antitumor antibiotic CC-1065 biosynthesis. C10P uses its [4Fe-4S] cluster for reductive cleavage of the first SAM to yield a highly reactive 5'-deoxyadenosyl radical, which abstracts a hydrogen from the second SAM to produce a SAM methylene radical that adds to an sp2-hybridized carbon of substrate to form a SAM-substrate adduct. C10Q converts this adduct to CC-1065 via an intramolecular SN2 cyclization mechanism with elimination of S-adenosylhomocysteine. This cyclopropanation strategy not only expands the enzymatic reactions catalyzed by the radical SAM enzymes and methyltransferases, but also sheds light on previously unnoticed aspects of the versatile SAM-based biochemistry. PMID- 30018378 TI - Calibration of force detection for arbitrarily shaped particles in optical tweezers. AB - Force measurement with an optical trap requires calibration of it. With a suitable detector, such as a position-sensitive detector (PSD), it is possible to calibrate the detector so that the force can be measured for arbitrary particles and arbitrary beams without further calibration; such a calibration can be called an "absolute calibration". Here, we present a simple method for the absolute calibration of a PSD. Very often, paired position and force measurements are required, and even if synchronous measurements are possible with the position and force detectors used, knowledge of the force-position curve for the particle in the trap can be highly beneficial. Therefore, we experimentally demonstrate methods for determining the force-position curve with and without synchronous force and position measurements, beyond the Hookean (linear) region of the trap. Unlike the absolute calibration of the force and position detectors, the force position curve depends on the particle and the trapping beam, and needs to be determined in each individual case. We demonstrate the robustness of our absolute calibration by measuring optical forces on microspheres as commonly trapped in optical tweezers, and other particles such a birefringent vaterite microspheres, red blood cells, and a deformable "blob". PMID- 30018377 TI - Differential profiling of lacrimal cytokines in patients suffering from thyroid associated orbitopathy. AB - The aim was to investigate the levels of cytokines and soluble IL-6R in the tears of patients with thyroid-associated orbitopathy (TAO) disease. Schirmer's test was adopted to collect tears from TAO patients (N = 20, 17 women, mean age (+/ SD): 46.0 years (+/-13.4)) and healthy subjects (N = 18, 10 women, 45.4 years (+/ 18.7)). Lacrimal cytokines and soluble IL-6R (sIL-6R) were measured using a 10 plex panel (Meso Scale Discovery Company) and Invitrogen Human sIL-6R Elisa kit, respectively. Tear levels of IL-10, IL-12p70, IL-13, IL-6 and TNF-alpha appeared significantly higher in TAO patients than in healthy subjects. Interestingly, IL 10, IL-12p70 and IL-8 levels increased in tears whatever the form of TAO whereas IL-13, IL-6 and TNF-alpha levels were significantly elevated in inflammatory TAO patients, meaning with a clinical score activity (CAS) >= 3, compared to controls. Furthermore, only 3 cytokines were strongly positively correlated with CAS (IL-13 Spearman coeff. r: 0.703, p = 0.0005; IL-6 r: 0.553, p = 0.011; IL-8 r: 0.618, p = 0.004, respectively). Finally, tobacco use disturbed the levels of several cytokines, especially in patient suffering of TAO. The differential profile of lacrimal cytokines could be useful for the diagnosis of TAO patients. Nevertheless, the tobacco use of these patients should be taken into account in the interpretation of the cytokine levels. PMID- 30018379 TI - Quantifying hormones in exhaled breath for physiological assessment of large whales at sea. AB - Exhaled breath analysis is a non-invasive assessment tool that has shown promise in human diagnostics, and could greatly benefit research, management, and conservation of large whales. However, hormone assessment of whale respiratory vapor (blow) has been challenged by variable water content and unknown total volume of collected samples. To advance this technique, we investigated urea (a compound present in narrow range in circulation) as a normalizing factor to correct for blow sample concentration. Normalized progesterone, testosterone, and cortisol concentrations of 100 blow samples from 46 photo-identified North Atlantic right whales (Eubalaena glacialis) were more biologically relevant compared to absolute estimates, varying by sex, age class, or individual. Progesterone was elevated in adult females compared with other cohorts and highest in one independently confirmed pregnant female. For both sexes, testosterone was two-fold higher in reproductively mature whales but studied adult females showed the widest variation. Cortisol was present in relatively low concentrations in blow and demonstrated variation between individual whales, suggesting potential for studies of individual differences in adrenal activity. Incorporation of methodologies that normalize sample concentration are essential for blow hormone analysis of free-swimming whales, and measurement of urea could be used to optimize non-invasive physiological assessment of whales. PMID- 30018380 TI - Integrated genetic and epigenetic analysis of myxofibrosarcoma. AB - Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1, and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS. PMID- 30018381 TI - Dynamic and programmable morphology and size evolution via a living hierarchical self-assembly strategy. AB - Recent advances in the preparation of shape-shifting and size-growing nanostructures are hot topics in development of nanoscience, because many intelligent functions are always relied on their shape and dimension. Here we report a tunable manipulation of sequential self-assembled transformation in situ via a hierarchical assembly strategy based on a living thiol-disulfide exchange reaction. By tailoring the external stimuli, the reactive points can be generated at the ends of initially unimolecular micelles, which subsequently drive the pre assemblies to periodically proceed into the hierarchically micellar connection, axial growth, bending, and cyclization processes from nanoscopic assemblies to macroscopic particles. Of particular interest would be systems that acquired the shape control and size adjustment of self-assemblies after termination or reactivation of disulfide reshuffling reaction by regulating external stimuli whenever needed. Such a hierarchical strategy for self-assembled evolution is universally applicable not only for other disulfide-linked dendritic polymers but also for exploitation of biological applications. PMID- 30018382 TI - Itching and its related factors in subtypes of eczema: a cross-sectional multicenter study in tertiary hospitals of China. AB - Itching is a leading symptom of eczema or dermatitis and has a great impact on patients' lives. Previous studies on itching have focused mostly on atopic dermatitis (AD). A cross-sectional multicenter study was conducted among outpatients with eczema from 39 tertiary hospitals in mainland China from July 1 to September 30, 2014. This work elaborates on itching in different types of eczema. Itching was very common (97%, 8499/8758) in outpatients with eczema. The severity of the itch increased with age and disease duration (P < 0.001). The top three subtypes of dermatitis with severe itching were atopic dermatitis (30.4%), widespread eczema (30.1%), and asteatotic eczema (27.9%). Widespread eczema refers to the involvement of more than three body parts, without clinical features of other specific types of eczema. The proportion of outpatients without itching was highest in hand eczema (6.8%). Positive correlations were observed between the severity of itching and the proportions of different diseases based on trend tests, including atopic dermatitis (P < 0.001), widespread eczema (P < 0.001), asteatotic eczema (P < 0.001), and autosensitization dermatitis (P < 0.001). Eczema outpatients with older age, longer disease duration, and, especially, a history of allergic diseases might be more prone to itching. PMID- 30018383 TI - Altered protein turnover signaling and myogenesis during impaired recovery of inflammation-induced muscle atrophy in emphysematous mice. AB - Exacerbations in Chronic obstructive pulmonary disease (COPD) are often accompanied by pulmonary and systemic inflammation, and are associated with an increased susceptibility to weight loss and muscle wasting. As the emphysematous phenotype in COPD appears prone to skeletal muscle wasting, the aims of this study were to evaluate in emphysematous compared to control mice following repetitive exacerbations (1) changes in muscle mass and strength and, (2) whether muscle mass recovery and its underlying processes are impaired. Emphysema was induced by intra-tracheal (IT) elastase instillations, followed by three weekly IT-LPS instillations to mimic repetitive exacerbations. Loss of muscle mass and strength were measured, and related to analyses of muscle protein turnover and myogenesis signaling in tissue collected during and following recovery. Emphysematous mice showed impaired muscle mass recovery in response to pulmonary inflammation-induced muscle atrophy. Proteolysis and protein synthesis signaling remained significantly higher in emphysematous mice during recovery from LPS. Myogenic signaling in skeletal muscle was altered, and fusion capacity of cultured muscle cells treated with plasma derived from LPS-treated emphysematous mice was significantly decreased. In conclusion, repetitive cycles of pulmonary inflammation elicit sustained muscle wasting in emphysematous mice due to impaired muscle mass recovery, which is accompanied by aberrant myogenesis. PMID- 30018384 TI - The sources of high airborne radioactivity in cryoconite holes from the Caucasus (Georgia). AB - Cryoconite granules are mixtures of mineral particles, organic substances and organisms on the surface of glaciers where they decrease the ice albedo and are responsible for formation of water-filled holes. The contaminants are effectively trapped in the cryoconite granules and stay there for many years. This study evaluates the contamination level of artificial and natural radionuclides in cryoconite holes from Adishi glacier (Georgia) and identifies the sources of contamination based on activity or mass ratios among artificial radionuclides. Results revealed high activity concentrations of fallout radionuclides reaching 4900 Bq/kg, 2.5 Bq/kg, 107 Bq/kg and 68 Bq/kg for 137Cs, 238Pu, 239+240Pu and 241Am, respectively. The main source of Pu is global fallout, but the low 240Pu/239Pu atomic ratios also indicated local tropospheric source of 239Pu, probably from the Kapustin Yar nuclear test site. Also, high activity ratios of 241Am/239+240Pu could originate from Kapustin Yar. The natural radionuclides originate from the surrounding rocks and were measured to control the environmental processes. 210Pb in cryoconite granules comes predominantly from the atmospheric deposition, and its activity concentrations reach high values up to 12000 Bq/kg. PMID- 30018385 TI - Combined Metabarcoding and Multi-locus approach for Genetic characterization of Colletotrichum species associated with common walnut (Juglans regia) anthracnose in France. AB - Juglans regia (walnut) is a species belonging to the family Juglandaceae. Broadly spread in diverse temperate and subtropical regions, walnut is primarily cultivated for its nuts. In France, Colletotrichum sp. on walnut was detected for the first time in 2007; in 2011 the disease led to 50-70% losses in nut production. A combined approach of metabarcoding analysis and multi-locus genetic characterization of isolated strains has been used for taxonomic designation and to study the genetic variability of this pathogen in France. Evidence indicates that four Colletotrichum species are associated with walnut in France: 3 belong to the C. acutatum species complex and 1 to the C. gloeosporioides species complex. Results also show that C. godetiae is the most abundant species followed by C. fioriniae; while C. nymphaeae and another Colletotrichum sp. belonging to the C. gloeosporioides complex are found rarely. Representative isolates of detected species were also used to confirm pathogenicity on walnut fruits. The results show a high variability of lesion's dimensions among isolates tested. This study highlights the genetic and pathogenic heterogeneity of Colletotrichum species associated with walnut anthracnose in France providing useful information for targeted treatments or selection of resistant cultivars, in order to better control the disease. PMID- 30018386 TI - Addendum: Heliconical smectic phases formed by achiral molecules. PMID- 30018387 TI - Buparlisib is a brain penetrable pan-PI3K inhibitor. AB - Characterization of the genomic landscapes of intracranial tumours has revealed a clear role for the PI3K-AKT-mTOR pathway in tumorigenesis and tumour maintenance of these malignancies, making phosphatidylinositol 3-kinase (PI3K) inhibition a promising therapeutic strategy for these tumours. Buparlisib is a novel pan-PI3K inhibitor that is currently in clinical development for various cancers, including primary and secondary brain tumours. Importantly however, earlier studies have revealed that sufficient brain penetration is a prerequisite for antitumor efficacy against intracranial tumours. We therefore investigated the brain penetration of buparlisib using a comprehensive set of in vitro and in vivo mouse models. We demonstrate that buparlisib has an excellent brain penetration that is unaffected by efflux transporters at the blood-brain barrier, complete oral bioavailability and efficient intracranial target inhibition at clinically achievable plasma concentrations. Together, these characteristics make buparlisib the ideal candidate for intracranially-targeted therapeutic strategies that involve PI3K inhibition. PMID- 30018389 TI - Organic and inorganic carbon and their stable isotopes in surface sediments of the Yellow River Estuary. AB - Studying the carbon dynamics of estuarine sediment is crucial to understanding of carbon cycle in the coastal ocean. This study is to evaluate the mechanisms regulating the dynamics of organic (TOC) and inorganic carbon (TIC) in surface sediment of the Yellow River Estuary (YRE). Based on data of 15 surface sediment cores, we found that TIC (6.3-20.1 g kg-1) was much higher than TOC (0.2-4.4 g kg 1). Both TOC and TIC were generally higher to the north than to the south, primarily due to the differences in kinetic energy level (i.e., higher to the south). Our analysis suggested that TOC was mainly from marine sources in the YER, except in the southern shallow bay where approximately 75% of TOC was terrigenous. The overall low levels of TOC were due to profound resuspension that could cause enhanced decomposition. On the other hand, high levels of TIC resulted partly from higher rates of biological production, and partly from decomposition of TOC associated with sediment resuspension. The isotopic signiture in TIC seems to imply that the latter is dominant in forming more TIC in the YRE, and there may be transfer of OC to IC in the water column. PMID- 30018388 TI - Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides. AB - Thrombin-derived C-terminal peptides (TCPs) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed interaction between TCPs and human CD14. Further, we show that TCPs bind to the LPS-binding hydrophobic pocket of CD14 and identify the peptide region crucial for TCP interaction with LPS and CD14. Taken together, our results demonstrate the role of structural transitions in LPS complex formation and CD14 interaction, providing a molecular explanation for the previously observed therapeutic effects of TCPs in experimental models of bacterial sepsis and endotoxin shock. PMID- 30018390 TI - Molecular identification and characterization of rhodaneses from the insect herbivore Pieris rapae. AB - The association of cabbage white butterflies (Pieris spec., Lepidoptera: Pieridae) with their glucosinolate-containing host plants represents a well investigated example of the sequential evolution of plant defenses and insect herbivore counteradaptations. The defensive potential of glucosinolates, a group of amino acid-derived thioglucosides present in plants of the Brassicales order, arises mainly from their rapid breakdown upon tissue disruption resulting in formation of toxic isothiocyanates. Larvae of P. rapae are able to feed exclusively on glucosinolate-containing plants due to expression of a nitrile specifier protein in their gut which redirects glucosinolate breakdown to the formation of nitriles. The release of equimolar amounts of cyanide upon further metabolism of the benzylglucosinolate-derived nitrile suggests that the larvae are also equipped with efficient means of cyanide detoxification such as beta cyanoalanine synthases or rhodaneses. While insect beta-cyanoalanine synthases have recently been identified at the molecular level, no sequence information was available of characterized insect rhodaneses. Here, we identify and characterize two single-domain rhodaneses from P. rapae, PrTST1 and PrTST2. The enzymes differ in their kinetic properties, predicted subcellular localization and expression in P. rapae indicating different physiological roles. Phylogenetic analysis together with putative lepidopteran rhodanese sequences indicates an expansion of the rhodanese family in Pieridae. PMID- 30018391 TI - Stress related epigenetic changes may explain opportunistic success in biological invasions in Antipode mussels. AB - Different environmental factors could induce epigenetic changes, which are likely involved in the biological invasion process. Some of these factors are driven by humans as, for example, the pollution and deliberate or accidental introductions and others are due to natural conditions such as salinity. In this study, we have analysed the relationship between different stress factors: time in the new location, pollution and salinity with the methylation changes that could be involved in the invasive species tolerance to new environments. For this purpose, we have analysed two different mussels' species, reciprocally introduced in antipode areas: the Mediterranean blue mussel Mytilus galloprovincialis and the New Zealand pygmy mussel Xenostrobus securis, widely recognized invaders outside their native distribution ranges. The demetylathion was higher in more stressed population, supporting the idea of epigenetic is involved in plasticity process. These results can open a new management protocols, using the epigenetic signals as potential pollution monitoring tool. We could use these epigenetic marks to recognise the invasive status in a population and determine potential biopollutants. PMID- 30018392 TI - Traces Of Laboratory Earthquake Nucleation In The Spectrum Of Ambient Noise. AB - The short-term forecast of earthquakes associated with fault rupture is a challenge in seismology and rock mechanics. The evolution of mechanical characteristics of a local fault segment may be encoded in the ambient noise, thus, converting the ambient noise to an efficient source of information about the fault stress-strain conditions. In laboratory experiments we investigate micro-vibrations of a block-fault system induced by weak external disturbances with the purpose of getting reliable evidence of how the system transits to the metastable state. We show that precursory changes of spectral characteristics of micro-vibrations are observed for the complete spectrum of failure modes. In the course of experiments we systematically change the properties of interface to perform the transition from stick-slip to steady sliding and observe the characteristics of micro-vibrations of the laboratory block-fault system. Detected were systematical alterations of the system natural frequency and those alterations were determined by the evolution of fault stiffness. The detected regularities suggest that the final stage of seismic event preparation can be revealed in analyzing the spectral characteristics of ambient noise. The detection of natural oscillations of a block-fault system can be a new useful tool to monitor active faults in real time. PMID- 30018394 TI - IL-6 mediates high-fat diet-induced tumour growth. PMID- 30018393 TI - Subcellular Imaging of Liquid Silicone Coated-Intestinal Epithelial Cells. AB - Surface contamination and the formation of water bridge at the nanoscopic contact between an atomic force microscope tip and cell surface limits the maximum achievable spatial resolution on cells under ambient conditions. Structural information from fixed intestinal epithelial cell membrane is enhanced by fabricating a silicone liquid membrane that prevents ambient contaminants and accumulation of water at the interface between the cell membrane and the tip of an atomic force microscope. The clean and stable experimental platform permits the visualisation of the structure and orientation of microvilli present at the apical cell membrane under standard laboratory conditions together with registering subcellular details within a microvillus. The method developed here can be implemented for preserving and imaging contaminant-free morphology of fixed cells which is central for both fundamental studies in cell biology and in the emerging field of digital pathology. PMID- 30018395 TI - Temporal evolution of hydroclimatic teleconnection and a time-varying model for long-lead prediction of Indian summer monsoon rainfall. AB - Several cases of failure in the prediction of Indian Summer Monsoon Rainfall (ISMR) are the major concern for long-lead prediction. We propose that this is due to the temporal evolution of association/linkage (inherent concept of temporal networks) with various factors and climatic indices across the globe, such as El Nino-Southern Oscillation (ENSO), Equatorial Indian Ocean Oscillation (EQUINOO), Atlantic Multidecadal Oscillation (AMO), North Atlantic Oscillation (NAO), Pacific Decadal Oscillation (PDO) etc. Static models establish time invariant (permanent) connections between such indices (predictors) and predictand (ISMR), whereas we hypothesize that such systems are temporally varying in nature. Considering hydroclimatic teleconnection with two major climate indices, ENSO and EQUINOO, we showed that the temporal persistence of the association is as low as three years. As an application of this concept, a statistical time-varying model is developed and the prediction performance is compared against its static counterpart (time-invariant model). The proposed approach is able to capture the ISMR anomalies and successfully predicts the severe drought years too. Specifically, 64% more accurate performance (in terms of RMSE) is achievable by the recommended time-varying approach as compared to existing time-invariant concepts. PMID- 30018396 TI - Network-based genetic investigation of virulence-associated phenotypes in methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus is a gram-positive bacterium that causes a wide range of infections. Recently, the spread of methicillin-resistant S. aureus (MRSA) strains has seriously reduced antibiotic treatment options. Anti-virulence strategies, the objective of which is to target the virulence instead of the viability of the pathogen, have become widely accepted as a means of avoiding the emergence of new antibiotic-resistant strains. To increase the number of anti virulence therapeutic options, it is necessary to identify as many novel virulence-associated genes as possible in MRSA. Co-functional networks have proved useful for mapping gene-to-phenotype associations in various organisms. Herein, we present StaphNet (www.inetbio.org/staphnet), a genome-scale co functional network for an MRSA strain, S. aureus subsp. USA300_FPR3757. StaphNet, which was constructed by the integration of seven distinct types of genomics data within a Bayesian statistics framework, covers approximately 94% of the coding genome with a high degree of accuracy. We implemented a companion web server for network-based gene prioritization of the phenotypes of 31 different S. aureus strains. We demonstrated that StaphNet can effectively identify genes for virulence-associated phenotypes in MRSA. These results suggest that StaphNet can facilitate target discovery for the development of anti-virulence drugs to treat MRSA infection. PMID- 30018398 TI - The Oddity of Heterogeneity: A Blessing in Disguise. AB - Damage accumulation is widely accepted as the central dogma of ageing, and it has been a long-standing belief that tobacco smokers must experience a faster rate of ageing than non-smokers. It is therefore puzzling as to why proportional hazard model is a popular choice in longitudinal studies given that its assumption assumes a constant hazard with increasing time. If the rate of ageing is accelerated, the hazard gradient of smokers d(log(MU(x)))/dx obtained from frailty parametric fit has to be steeper than non-smokers. This study examines the relative derivative for mortality d(log(MU(x)))/dx of British doctors born 1900-1909, and obtained estimates indicate that the rate of ageing is similar between smokers and non-smokers. A brief theorem is also elaborated to present the difference in life-years gained from interventions and policies by life detrimental risk exposure; e.g. smokers 0.8; non-smokers 5.3 mins/day. The controversial assumption made in the central dogma of ageing, heterogeneity axiom and the application of proportional hazard models are unveiled in this condensed parametric analyses. PMID- 30018397 TI - Association between low-grade inflammation and Breast cancer and B-cell Myeloma and Non-Hodgkin Lymphoma: findings from two prospective cohorts. AB - Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Beta-cell Non Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (beta = -1.28, p = 0.012), and, to lesser, extent with BC (beta = 0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers. PMID- 30018399 TI - Task-specific and variability-driven activation of cognitive control processes during motor performance. AB - It has long been postulated that cognitive and motor functions are functionally intertwined. While the idea received convincing support from neuroimaging studies providing evidence that motor and cognitive processes draw on common neural mechanisms and resources, findings from behavioral studies are rather inconsistent. The purpose of the present study was to identify and verify key factors that act on the link between cognitive and motor functions. Specifically we investigated whether it is possible to predict motor skills from cognitive functions. While our results support the idea that motor and cognitive functions are functionally intertwined and different motor skills entail distinct cognitive functions, our data also strongly suggest that the impact of cognitive control processes on motor skill proficiency depends on performance variability, i.e. on how challenging a motor task is. Based on these findings, we presume that motor skills activate specific cognitive control processes on two levels: basic processes that are solely related to the type of the motor task, and variability driven processes that come into play when performance variability is high. For practitioners, these findings call for specific and challenging motor training interventions to directly tap into the to-be-improved cognitive skills and to involve a maximum of cognitive processes. PMID- 30018400 TI - The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses. AB - The skin represents a physical and chemical barrier against invading pathogens, which is additionally supported by restriction factors that provide intrinsic cellular immunity. These factors detect viruses to block their replication cycle. Here, we uncover the Myb-related transcription factor, partner of profilin (MYPOP) as a novel antiviral protein. It is highly expressed in the epithelium and binds to the minor capsid protein L2 and the DNA of human papillomaviruses (HPV), which are the primary causative agents of cervical cancer and other tumors. The early promoter activity and early gene expression of the oncogenic HPV types 16 and 18 is potently silenced by MYPOP. Cellular MYPOP-depletion relieves the restriction of HPV16 infection, demonstrating that MYPOP acts as a restriction factor. Interestingly, we found that MYPOP protein levels are significantly reduced in diverse HPV-transformed cell lines and in HPV-induced cervical cancer. Decades ago it became clear that the early oncoproteins E6 and E7 cooperate to immortalize keratinocytes by promoting degradation of tumor suppressor proteins. Our findings suggest that E7 stimulates MYPOP degradation. Moreover, overexpression of MYPOP blocks colony formation of HPV and non-virally transformed keratinocytes, suggesting that MYPOP exhibits tumor suppressor properties. PMID- 30018402 TI - Mass spawning by the date mussel Lithophaga lithophaga. AB - Lithophaga lithophaga is one of the commonest bivalves in the Mediterranean Sea and is present in almost every subtidal calcareous rock. Its reproductive cycle is known only from laboratory studies. Herein, we present data on the species reproductive activities based on localised but mass synchronized spawning events. The species reproduces at the end of the northern hemisphere summer and the majority of significant spawning events occur during the period between full moon and its last quarter. Calm seas are an important pre-requisite for the development of such co-ordinated mass spawning events. 'Gamete to gamete' induction seems to be the most likely proximate cue in synchronising gamete release. Spawning begins with a few individuals but spreads progressively along the coastline. In observed situations, reproductive waves finally affect between 10 and >400 m of coastline from 0 to 10 m depth and last longer than three days. In the reproductive zone, dense gamete clouds reduce visibility to zero over tens of metres along the shallow sea bed. No spawning events of such dimensions have been reported upon before for any bivalve. PMID- 30018401 TI - Proteomic Analysis and Functional Characterization of P4-ATPase Phospholipid Flippases from Murine Tissues. AB - P4-ATPases are a subfamily of P-type ATPases that flip phospholipids across membranes to generate lipid asymmetry, a property vital to many cellular processes. Mutations in several P4-ATPases have been linked to severe neurodegenerative and metabolic disorders. Most P4-ATPases associate with one of three accessory subunit isoforms known as CDC50A (TMEM30A), CDC50B (TMEM30B), and CDC50C (TMEM30C). To identify P4-ATPases that associate with CDC50A, in vivo, and determine their tissue distribution, we isolated P4-ATPases-CDC50A complexes from retina, brain, liver, testes, and kidney on a CDC50A immunoaffinity column and identified and quantified P4-ATPases from their tryptic peptides by mass spectrometry. Of the 12 P4-ATPase that associate with CDC50 subunits, 10 P4 ATPases were detected. Four P4-ATPases (ATP8A1, ATP11A, ATP11B, ATP11C) were present in all five tissues. ATP10D was found in low amounts in liver, brain, testes, and kidney, and ATP8A2 was present in significant amounts in retina, brain, and testes. ATP8B1 was detected only in liver, ATP8B3 and ATP10A only in testes, and ATP8B2 primarily in brain. We also show that ATP11A, ATP11B and ATP11C, like ATP8A1 and ATP8A2, selectively flip phosphatidylserine and phosphatidylethanolamine across membranes. These studies provide new insight into the tissue distribution, relative abundance, subunit interactions and substrate specificity of P4-ATPase-CDC50A complexes. PMID- 30018404 TI - Dual-organ invasion is associated with a lower survival rate than single-organ invasion distal bile duct cancer: A multicenter study. AB - The revised criteria of the 8th American Joint Committee on Cancer (AJCC) cancer staging system consider depth of invasion as one of the factors that determine stage in distal bile duct (DBD) cancer, but exclude adjacent organ invasion. The aims were to evaluate the association between adjacent organ invasion and relapse free survival (RFS) and overall survival (OS) after curative surgical resection of DBD cancer and to propose optimal criteria for predicting clinical outcomes. In this retrospective cohort study, 378 patients with DBD cancer treated in multi institutions between 1996 and 2013 were investigated. This study evaluated the relationship between clinicopathologic parameters and adjacent organ invasion and used organ invasion to compare the survival times of each group. Among 204 patients with adjacent organ invasion, 152 were in the single-organ invasion group and 52 were in the dual-organ invasion group based on a review of microscopic slides. In univariate and multivariate analyses, patients with dual organ invasion had a shorter RFS and OS time than those with single-organ invasion. Organ invasion should be included as one of the factors that determine the AJCC stage; this might ultimately help to predict better the survival rate of patients with DBD cancer. PMID- 30018403 TI - Microbial Community Composition Reveals Spatial Variation and Distinctive Core Microbiome of the Weaver Ant Oecophylla smaragdina in Malaysia. AB - The weaver ant Oecophylla smaragdina is an aggressive predator of other arthropods and has been employed as a biological control agent against many insect pests in plantations. Despite playing important roles in pest management, information about the microbiota of O. smaragdina is limited. In this work, a number of O. smaragdina colonies (n = 12) from Malaysia had been studied on their microbiome profile using Illumina 16S rRNA gene amplicon sequencing. We characterized the core microbiota associated with these O. smaragdina and investigated variation between colonies from different environments. Across all 12 samples, 97.8% of the sequences were assigned to eight bacterial families and most communities were dominated by families Acetobacteraceae and Lactobacillaceae. Comparison among colonies revealed predominance of Acetobacteraceae in O. smaragdina from forest areas but reduced abundance was observed in colonies from urban areas. In addition, our findings also revealed distinctive community composition in O. smaragdina showing little taxonomic overlap with previously reported ant microbiota. In summary, our work provides information regarding microbiome of O. smaragdina which is essential for establishing healthy colonies. This study also forms the basis for further study on microbiome of O. smaragdina from other regions. PMID- 30018405 TI - Enhancing enterocyte fatty acid oxidation in mice affects glycemic control depending on dietary fat. AB - Studies indicate that modulating enterocyte metabolism might affect whole body glucose homeostasis and the development of diet-induced obesity (DIO). We tested whether enhancing enterocyte fatty acid oxidation (FAO) could protect mice from DIO and impaired glycemic control. To this end, we used mice expressing a mutant form of carnitine palmitoyltransferase-1a (CPT1mt), insensitive to inhibition by malonyl-CoA, in their enterocytes (iCPT1mt) and fed them low-fat control diet (CD) or high-fat diet (HFD) chronically. CPT1mt expression led to an upregulation of FAO in the enterocytes. On CD, iCPT1mt mice had impaired glycemic control and showed concomitant activation of lipogenesis, glycolysis and gluconeogenesis in their enterocytes. On HFD, both iCPT1mt and control mice developed DIO, but iCPT1mt mice showed improved glycemic control and reduced visceral fat mass. Together these data indicate that modulating enterocyte metabolism in iCPT1mt mice affects glycemic control in a body weight-independent, but dietary fat dependent manner. PMID- 30018406 TI - A possible approach to improving the reproducibility of urinary concentrations of phthalate metabolites and phenols during pregnancy. AB - In epidemiologic studies, classifying episodic exposures to chemicals with short half-lives, such as phthalates and phenols, is challenging. We assessed whether accounting for sources of variability unrelated to exposure pathways would improve the reproducibility of urine concentrations of select phthalate metabolites and phenols. In 2011, a subset of pregnant women (n = 19) enrolled in a prospective study provided first morning urine samples every 3-4 weeks between 16 and 36 weeks gestation. At the time of collection, we identified potential contributors to variations in urinary concentrations: weight gain, gestational age, time slept, time since awoke, time since last food/drink, and time since last void. We estimated intraclass correlation coefficients (ICCs) among repeat urine concentrations with and without adjustment for sources of variability using a random intercept linear mixed model. Concentrations of monoethyl phthalate, butyl, and propyl parabens were the most reproducible (ICCs: 0.68, 0.56, and 0.56, respectively). However, adjustment for potential sources of variability unrelated to exposure pathways did not materially improve reproducibility nor the ability of a single sample to predict exposure based on average biomarker concentrations across pregnancy. Future studies should carefully consider the exposure timeframe and the reliability of using biomarker concentrations from a single time point to represent exposures over pregnancy. PMID- 30018408 TI - AR-V7 detection guides treatment. PMID- 30018407 TI - Association of Decreased Handgrip Strength with Reduced Cortical Thickness in Japanese Female Patients with Type 2 Diabetes Mellitus. AB - LD-100, a quantitative ultrasonic device, allows us to measure cortical thickness (CoTh). Patients with type 2 diabetes mellitus (T2DM) show high prevalence of sarcopenia. This study aimed to clarify the association of handgrip strength (HGS) with cortical porosis, a major risk for fracture of DM. CoTh and trabecular bone mineral density (TrBMD) at the 5.5% distal radius were assessed in T2DM female patients (n = 122) and non-DM female controls (n = 704) by LD-100. T2DM patients aged older 40 years showed significantly lower HGS and CoTh, but not TrBMD, than non-DM counterparts. Although HGS was significantly and positively correlated with CoTh and TrBMD in T2DM patients, multivariate analysis revealed HGS as an independent factor positively associated with CoTh, but not TrBMD, in T2DM patients, suggesting the preferential association of HGS with cortical, but not trabecular, bone component in T2DM female patients. In conclusion, the present study demonstrated an early decline of HGS in T2DM female patients as compared with non-DM healthy controls after the age of 40 years, which is independently associated with thinner CoTh, but not TrBMD in T2DM patients, and thus suggested that reduced muscle strength associated with DM might be a major factor for cortical porosis development in DM patients. PMID- 30018410 TI - Tidally disrupted stars as a possible origin of both cosmic rays and neutrinos at the highest energies. AB - Tidal Disruption Events (TDEs) are processes where stars are torn apart by the strong gravitational force near to a massive or supermassive black hole. If a jet is launched in such a process, particle acceleration may take place in internal shocks. We demonstrate that jetted TDEs can simultaneously describe the observed neutrino and cosmic ray fluxes at the highest energies if stars with heavier compositions, such as carbon-oxygen white dwarfs, are tidally disrupted and these events are sufficiently abundant. We simulate the photo-hadronic interactions both in the TDE jet and in the propagation through the extragalactic space and we show that the simultaneous description of Ultra-High Energy Cosmic Ray (UHECR) and PeV neutrino data implies that a nuclear cascade in the jet is developed by photo-hadronic interactions. PMID- 30018409 TI - Evaluation of in vitro neuronal platforms as surrogates for in vivo whole brain systems. AB - Quantitatively benchmarking similarities and differences between the in vivo central nervous system and in vitro neuronal cultures can qualify discrepancies in functional responses and establish the utility of in vitro platforms. In this work, extracellular electrophysiology responses of cortical neurons in awake, freely-moving animals were compared to in vitro cultures of dissociated cortical neurons. After exposure to two well-characterized drugs, atropine and ketamine, a number of key points were observed: (1) significant differences in spontaneous firing activity for in vivo and in vitro systems, (2) similar response trends in single-unit spiking activity after exposure to atropine, and (3) greater sensitivity to the effects of ketamine in vitro. While in vitro cultures of dissociated cortical neurons may be appropriate for many types of pharmacological studies, we demonstrate that for some drugs, such as ketamine, this system may not fully capture the responses observed in vivo. Understanding the functionality associated with neuronal cultures will enhance the relevance of electrophysiology data sets and more accurately frame their conclusions. Comparing in vivo and in vitro rodent systems will provide the critical framework necessary for developing and interpreting in vitro systems using human cells that strive to more closely recapitulate human in vivo function and response. PMID- 30018411 TI - First insights into the movements of young-of-the-year white sharks (Carcharodon carcharias) in the western North Atlantic Ocean. AB - In recent years, white sharks (Carcharodon carcharias) have become more accessible to researchers off the northeastern U.S. as feeding aggregation sites have emerged and the population has increased. However, there has been limited research on young-of-the-year (YOY) sharks relative to older age classes in this region. Previous research indicated that YOY white sharks were most frequently observed in the New York Bight, suggesting the region serves a nursery role. To further examine the species' use of this area, we deployed satellite and acoustic tags on ten YOY white sharks (138-166 cm total length) off Long Island, New York. The sharks remained resident in New York Bight waters through summer (August through October), further supporting the notion that the region is a nursery area. Southward movements were observed during fall, with overwintering habitat identified off North and South Carolina shelf waters. Return migrations toward the New York Bight were observed in some individuals the following spring. YOY white sharks in this heavily-populated region are exposed to anthropogenic impacts such as fisheries bycatch and coastal habitat degradation. As juvenile survival rates are important for long-term population sustainability, further research is necessary to assess the potential impacts of these activities on the western North Atlantic white shark population. PMID- 30018412 TI - Rotation of stress fibers as a single wheel in migrating fish keratocytes. AB - Crawling migration plays an essential role in a variety of biological phenomena, including development, wound healing, and immune system function. Keratocytes are wound-healing cells in fish skin. Expansion of the leading edge of keratocytes and retraction of the rear are respectively induced by actin polymerization and contraction of stress fibers in the same way as for other cell types. Interestingly, stress fibers in keratocytes align almost perpendicular to the migration-direction. It seems that in order to efficiently retract the rear, it is better that the stress fibers align parallel to it. From the unique alignment of stress fibers in keratocytes, we speculated that the stress fibers may play a role for migration other than the retraction. Here, we reveal that the stress fibers are stereoscopically arranged so as to surround the cytoplasm in the cell body; we directly show, in sequential three-dimensional recordings, their rolling motion during migration. Removal of the stress fibers decreased migration velocity and induced the collapse of the left-right balance of crawling migration. The rotation of these stress fibers plays the role of a "wheel" in crawling migration of keratocytes. PMID- 30018413 TI - Author Correction: The effects of Antibody Engineering CH and CL in Trastuzumab and Pertuzumab recombinant models: Impact on antibody production and antigen binding. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30018416 TI - Crowd control. PMID- 30018415 TI - Generation of hydroxyl radicals from reactions between a dimethoxyhydroquinone and iron oxide nanoparticles. AB - The hydroxyl radical (.OH) is a powerful oxidant that is produced in a wide range of environments via the Fenton reaction (Fe2+ + H2O2 -> Fe3+ + .OH + OH-). The reactants are formed from the reduction of Fe3+ and O2, which may be promoted by organic reductants, such as hydroquinones. The aim of this study was to investigate the extent of .OH formation in reactions between 2,6 dimethoxyhydroquinone (2,6-DMHQ) and iron oxide nanoparticles. We further compared the reactivities of ferrihydrite and goethite and investigated the effects of the O2 concentration and pH on the generation of .OH. The main finding was that the reactions between 2,6-DMHQ and iron oxide nanoparticles generated substantial amounts of .OH under certain conditions via parallel reductive dissolution and catalytic oxidation reactions. The presence of O2 was essential for the catalytic oxidation of 2,6-DMHQ and the generation of H2O2. Moreover, the higher reduction potential of ferrihydrite relative to that of goethite made the former species more susceptible to reductive dissolution, which favored the production of .OH. The results highlighted the effects of surface charge and ligand competition on the 2,6-DMHQ oxidation processes and showed that the co adsorption of anions can promote the generation of .OH. PMID- 30018417 TI - Dopamine gets lit. PMID- 30018414 TI - Vitamin D, Folate and the Intracranial Volume in Schizophrenia and Bipolar Disorder and Healthy Controls. AB - Vitamin D and folate deficiency are considered risk factors for schizophrenia and bipolar disorders, but it is unknown how vitamin D and folate influence the growing brain, cranium or the clinical phenotype. Serum vitamin D and folate levels are in part genetically regulated. We investigated whether adult vitamin D and folate levels are associated with the intracranial volume (ICV) under the hypothesis that developmental vitamin D or folate levels influence neurodevelopment and that current levels are associated with ICV. Ninety patients with severe mental disorders and 91 healthy controls underwent 3 T magnetic resonance imaging and serum sampling. Multiple linear regression was used to assess the contribution of serum vitamin D, folate and patient-control status on ICV. We show that vitamin D levels were within lower range for patients and controls (48.8 +/- 22.1 nmol/l and 53.4 +/- 20.0 nmol/l, respectively). A significant positive association was found between vitamin D and ICV (p = 0.003, r = 0.22), folate was trend-significantly associated with ICV. Folate and vitamin D were significantly associated (p = 0.0001, r = 0.28). There were nonsignificant patient-control differences and no interaction effects. The results suggest that Vitamin D is associated with ICV as detected in the adult. Further studies are warranted for replication and to investigate possible mechanisms and genetic associations. PMID- 30018418 TI - Caught in the act. PMID- 30018419 TI - 3D interaction hubs. PMID- 30018420 TI - Antigen processing movers and shakers. PMID- 30018421 TI - A remote control for switching. PMID- 30018422 TI - A novel SLC9A1 mutation causes cerebellar ataxia. AB - The mammalian Na+/H+ exchanger isoform one (NHE1), encoded by Solute Carrier Family 9, member 1 (SLC9A1), consists of 12 membrane domains and a cytosolic C terminal domain. NHE1 plays an important role in maintaining intracellular pH homeostasis by exchanging one intracellular proton for one extracellular sodium ion. Mice with a homozygous null mutation in Slc9a1 (Nhe1) exhibited ataxia, recurrent seizures, and selective neuronal cell death. In humans, three unrelated patients have been reported: a patient with a homozygous missense mutation in SLC9A1, c.913G>A (p.Gly305Arg), which caused Lichtenstein-Knorr syndrome characterized by cerebellar ataxia and sensorineural hearing loss, a patient with compound heterozygous mutations, c.1351A>C (p.Ile451Leu) and c.1585C>T (p.His529Tyr), which caused a neuromuscular disorder, and a patient with de novo mutation, c.796A>C (p.Asn266His) which associated multiple anomalies. In this study, using whole exome sequencing, we identified a novel homozygous SLC9A1 truncating mutation, c.862del (p.Ile288Serfs*9), in two affected siblings. The patients showed cerebellar ataxia but neither of them showed sensorineural hearing loss nor a neuromuscular phenotype. The main clinical feature was similar to Lichtenstein-Knorr syndrome but deafness may not be an essential phenotypic feature of SLC9A1 mutation. Our report expands the knowledge of clinical features of SLC9A1 mutations. PMID- 30018423 TI - Additional alpha-glucosidase inhibitors from Malbranchea flavorosea (Leotiomycetes, Ascomycota). AB - From the rice-based culture of Malbranchea flavorosea, three new compounds namely flavoroseoside B (5-desoxy-5-chloro-flavoroseoside) (2), 4-hydroxy-2-O-alpha ribofuranosyl-5-methylacetophenone (3), and (S)-3,4-dihydro-3-(1H-indol-3 ylmethyl)-4-methyl-1H-1,4-benzodiazepine-2,5-dione (4), along with three known compounds, rosigenin (5), massarilactone B (6), and riboxylarinol B (7) were obtained. The structures were determined by spectroscopic methods. Compound 4 and its synthetic analog 3,4-dihydro-3-(1H-indol-3-ylmethyl)-1-methyl-1H-1,4 benzodiazepine-2,5-dione (9) inhibited the activity of Ruminococus obeum alpha glucosidase enzyme. Molecular docking and dynamic studies revealed that compounds 4 and 9 might bind to this alpha-glucosidase at the catalytic center. Phylogenetic analysis using internal transcribed spacer region revealed that Malbranchea flavorosea ATCC 34529 is related to Myxotrichum spp. PMID- 30018424 TI - Quinomycins H1 and H2, new cytotoxic antibiotics from Streptomyces sp. RAL404. AB - Two new cytotoxic antibiotics designated quinomycins H1 (2) and H2 (3) were isolated from the culture broth of Streptomyces sp. RAL404. The molecular formula of both compounds was established as C52H65N11O13S2 by electrospray ionization mass spectrometry (ESI-MS). Their structures were determined as echinomycin (1) derivatives containing a 3-hydoxyquinaldic acid molecule in place of one of the two quinoxaline-2-carboxylic acid chromophores. Quinomycins H1 (2) and H2 (3) showed selective cytotoxicity against RG-E1-4 cells bearing the adenovirus oncogenes with IC50s of 11 nM and 12 nM, respectively. PMID- 30018433 TI - Single subatomic particle illuminates mysterious origins of cosmic rays. PMID- 30018436 TI - Science journals end open-access trial with Gates Foundation. PMID- 30018426 TI - Globular-shaped variable lymphocyte receptors B antibody multimerized by a hydrophobic clustering in hagfish. AB - In hagfish and lampreys, two representative jawless vertebrates, the humoral immunity is directly mediated by variable lymphocyte receptors B (VLRBs). Both monomeric VLRBs are structurally and functionally similar, but their C-terminal tails differ: lamprey VLRB has a Cys-rich tail that forms disulfide-linked pentamers of dimers, contributing to its multivalency, whereas hagfish VLRB has a superhydrophobic tail of unknown structure. Here, we reveal that VLRBs obtained from hagfish plasma have a globular-shaped multimerized form (approximately 0.6 to 1.7 MDa) that is generated by hydrophobic clustering instead of covalent linkage. Electron microscopy (EM) and single-particle analysis showed that the multimerized VLRBs form globular-shaped clusters with an average diameter of 28.7 +/- 2.2 nm. The presence of VLRBs in the complex was confirmed by immune-EM analysis using an anti-VLRB antibody. Furthermore, the hydrophobic hagfish C terminus (HC) was capable of triggering multimerization and directing the cellular surface localization via a glycophosphatidylinositol linkage. Our results strongly suggest that the hagfish VLRB forms a previously unknown globular-shaped antibody. This novel identification of a structurally unusual VLRB complex may suggest that the adaptive immune system of hagfish differs from that of lamprey. PMID- 30018439 TI - AI can be sexist and racist - it's time to make it fair. PMID- 30018440 TI - China expands surveillance of sewage to police illegal drug use. PMID- 30018425 TI - The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin. AB - Cell cycle progression in mammals is modulated by two ubiquitin ligase complexes, CRL4 and SCF, which facilitate degradation of chromatin substrates involved in the regulation of DNA replication. One member of the CRL4 complex, the WD-40 containing protein RepID (DCAF14/PHIP), selectively binds and activates a group of replication origins. Here we show that RepID recruits the CRL4 complex to chromatin prior to DNA synthesis, thus playing a crucial architectural role in the proper licensing of chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase, SKP2-containing SCF, to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, which triggered massive genome re-replication. Both RepID and SKP2 interact with distinct, non-overlapping groups of replication origins, suggesting that selective interactions of replication origins with specific CRL components execute the DNA replication program and maintain genomic stability by preventing re-initiation of DNA replication. PMID- 30018442 TI - Gene therapy in mouse fetuses treats deadly disease. PMID- 30018445 TI - How retirement can give your career a new lease of life. PMID- 30018443 TI - Sluggish Atlantic circulation could cause global temperatures to surge. PMID- 30018446 TI - Jupiter has 10 more moons we didn't know about - and they're weird. PMID- 30018447 TI - Why I testified in the Argentina abortion debate. PMID- 30018448 TI - With Pruitt gone, Trump and his allies continue to threaten the EPA. PMID- 30018449 TI - Thresholds of lake and reservoir connectivity in river networks control nitrogen removal. AB - Lakes, reservoirs, and other ponded waters are ubiquitous features of the aquatic landscape, yet their cumulative role in nitrogen removal in large river basins is often unclear. Here we use predictive modeling, together with comprehensive river water quality, land use, and hydrography datasets, to examine and explain the influences of more than 18,000 ponded waters on nitrogen removal through river networks of the Northeastern United States. Thresholds in pond density where ponded waters become important features to regional nitrogen removal are identified and shown to vary according to a ponded waters' relative size, network position, and degree of connectivity to the river network, which suggests worldwide importance of these new metrics. Consideration of the interacting physical and biological factors, along with thresholds in connectivity, reveal where, why, and how much ponded waters function differently than streams in removing nitrogen, what regional water quality outcomes may result, and in what capacity management strategies could most effectively achieve desired nitrogen loading reduction. PMID- 30018450 TI - Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome. AB - Kabuki Syndrome (KS) is a rare disorder characterized by distinctive facial features, short stature, skeletal abnormalities, and neurodevelopmental deficits. Previously, we showed that loss of function of RAP1A, a RAF1 regulator, can activate the RAS/MAPK pathway and cause KS, an observation recapitulated in other genetic models of the disorder. These data suggested that suppression of this signaling cascade might be of therapeutic benefit for some features of KS. To pursue this possibility, we performed a focused small molecule screen of a series of RAS/MAPK pathway inhibitors, where we tested their ability to rescue disease relevant phenotypes in a zebrafish model of the most common KS locus, kmt2d. Consistent with a pathway-driven screening paradigm, two of 27 compounds showed reproducible rescue of early developmental pathologies. Further analyses showed that one compound, desmethyl-Dabrafenib (dmDf), induced no overt pathologies in zebrafish embryos but could rescue MEK hyperactivation in vivo and, concomitantly, structural KS-relevant phenotypes in all KS zebrafish models (kmt2d, kmd6a and rap1). Mass spectrometry quantitation suggested that a 100 nM dose resulted in sub-nanomolar exposure of this inhibitor and was sufficient to rescue both mandibular and neurodevelopmental defects. Crucially, germline kmt2d mutants recapitulated the gastrulation movement defects, micrognathia and neurogenesis phenotypes of transient models; treatment with dmDf ameliorated all of them significantly. Taken together, our data reinforce a causal link between MEK hyperactivation and KS and suggest that chemical suppression of BRAF might be of potential clinical utility for some features of this disorder. PMID- 30018451 TI - Mild Maternal Obstructive Sleep Apnea in Non-obese Pregnant Women and Accelerated Fetal Growth. AB - The prevalence of obstructive sleep apnea (OSA) during pregnancy is rising. OSA during pregnancy has been associated with hypertensive disorders of pregnancy and gestational diabetes. The effect of maternal OSA on the fetus, particularly on fetal growth, is less apparent. Most of the currently available human data is based on non-objective assessment of OSA and includes heterogeneous populations with inadequate control on confounders, such as maternal obesity and pregnancy complications. Using objective tools in non-obese women with uncomplicated pregnancies, we aimed to investigate the association between maternal OSA and fetal growth. A total of 155 non-obese pregnant women were recruited. Birth weight percentile of the newborns of women with mild OSA was significantly higher compared with the newborns of non-OSA controls (72% vs. 57%, respectively, P < 0.01). Birth-length and triceps thickness measurements were significantly higher among the newborns of women with OSA compared with controls (P = 0.02 for both). The proportion of large for gestational age (LGA) newborns was higher among women with OSA compared with controls (28% vs. 8%, respectively, P = 0.04). Our results suggest that maternal OSA during the third trimester of pregnancy - even in a mild form -is associated with accelerated fetal growth. PMID- 30018452 TI - Molecular characterization and functional differentiation of three pheromone binding proteins from Tryporyza intacta. AB - Insect pheromone-binding proteins (PBPs) have been proposed to capture and transport hydrophobic sex pheromone components emitted by con-specific insects to pheromone receptors in the hemolymph of male antennal sensilla. In this study, field trapping results indicate that a mixture of E11-16: Ald and Z11-16: Ald can effectively attract a great number of male Tryporyza intacta. Real-time PCR results suggest that the transcript levels of three TintPBP1-3 genes are mainly expressed in the adult antennae. Fluorescence competitive binding experiments show that TintPBP1-3 proteins have great binding affinities to their major sex pheromones. Moreover, TintPBPs clearly cannot bind to other four kinds of sex pheromone components released by another sugarcane borer, Chilo venosatus and Chilo infuscatellu, which have the same host plant and live in similar habitats like T. intacta. The molecular docking results demonstrate that six amino acid residues of the three TintPBPs are crucial for the specific perception of the sex pheromone components. These results will provide a foundation for the development of novel sex pheromone analogues and blocking agents for biological control of sugarcane pests, improving their efficient monitoring and integrated management strategies in the sugarcane field. PMID- 30018454 TI - Chance favours the prepared mind. PMID- 30018453 TI - Changes in low-level neural properties underlie age-dependent visual decision making. AB - Aging typically slows down cognitive processes, specifically those related to perceptual decisions. However, the neurobiological mechanisms underlying these age-associated changes are still elusive. To address this, we studied the effect of aging on both perceptual and binocular rivalry in various presentation conditions. Two age groups of participants reported their spontaneous percept switches during continuous presentation and percept choices during intermittent presentation. We find no significant age effect on the mean and cumulative frequencies of percept switch durations under continuous presentation. However, the data show a significant age effect on coefficient of variation, ratio of standard deviation to mean of percept durations. Our results also reveal that the alternation rate for percept choices significantly declines at an older age under intermittent presentation. The latter effect is even more pronounced at shorter inter-stimulus durations. These results together with the predictions of existing neural models for bistable perception imply that age-dependency of visual perceptual decisions is caused by shifts in neural adaptation and noise, not by a change in inhibition strength. Thus, variation in the low-level neural properties, adaptation and noise, cause age-dependent properties in visual perceptual decisions. PMID- 30018455 TI - Development of nsP2 protease based cell free high throughput screening assay for evaluation of inhibitors against emerging Chikungunya virus. AB - Chikungunya virus has emerged as one of the most important global arboviral threats over the last decade. Inspite of large scale morbidity, with long lasting polyarthralgia, so far no licensed vaccine or antiviral is available. CHIKV nsP2 protease is crucial for processing of viral nonstructural polypeptide precursor to release enzymes required for viral replication, thus making it a promising drug target. In this study, high cell density cultivation (HCDC) of Escherichia coli in batch process was carried out to produce rCHIKV nsP2pro in a cost effective manner. The purified nsP2pro and fluorogenic peptide substrate have been adapted for fluorescence resonance energy transfer (FRET) based high throughput screening (HTS) assay with Z' value and CV of 0.67 +/- 0.054 and <10% respectively. We used this cell free HTS system to screen panel of metal ions and its conjugate which revealed zinc acetate as a potential candidate, which was further found to inhibit CHIKV in Vero cells. Scale-up process has not been previously reported for any of the arboviral nonstructural enzymes. The successful scale-up method for viral protease together with a HTS assay could lead to the development of industrial level large-scale screening platform for identification of protease inhibitors against emerging and re-emerging viruses. PMID- 30018457 TI - Plasma concentrations of anserine, carnosine and pi-methylhistidine as biomarkers of habitual meat consumption. AB - BACKGROUND/OBJECTIVES: Dietary intake of red and processed meat has been associated with disease risk. Since dietary intake assessment methods are prone to measurement errors, identifying biomarkers of meat intake in bio-samples could provide more valid intake estimates. We examined associations of habitual red and processed meat, poultry, fish, and dairy products consumption with plasma concentrations of anserine, carnosine, pi-methylhistidine (Pi-MH), tau methylhistidine (T-MH), and the ratio of T-MH to Pi-MH in a cross-sectional study. SUBJECTS/METHODS: Plasma anserine, carnosine, Pi-MH, and T-MH concentrations were measured using ion-pair LC-MS/MS in 294 participants in the second Bavarian Food Consumption Survey (BVS II). Habitual food consumption was assessed using three 24-h dietary recalls. Associations between plasma metabolites concentrations and meat, fish, eggs, and dairy products consumption were assessed by fitting generalized linear model, adjusted for age, sex, and BMI. RESULTS: Total meat intake was associated with plasma concentrations of anserine, carnosine, Pi-MH and, the ratio of T-MH to Pi-MH. Red meat intake was related to carnosine (p-trend = 0.0028) and Pi-MH plasma levels (p-trend = 0.0493). Poultry (p-trend = 0.0006) and chicken (p-trend = 0.0003) intake were associated with Pi-MH. The highest anserine concentrations were observed in individuals consuming processed meat or turkey. For T-MH we did not observe any association with meat intake. CONCLUSIONS: Our results indicate an association between habitual meat consumption and plasma concentrations of anserine, carnosine, Pi-MH and the ratio of T-MH to Pi-MH. Intervention studies should clarify whether the analyzed plasma metabolites are indicative for a specific type of meat before proposing them as biomarkers of habitual meat intake in epidemiologic studies. PMID- 30018456 TI - Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis. AB - Lymphatic metastasis is known to contribute to worse prognosis of biliary tract cancer (BTC). Recently, sphingosine-1-phosphate (S1P), a bioactive lipid mediator generated by sphingosine kinase 1 (SPHK1), has been shown to play an important role in lymphangiogenesis and lymph node metastasis in several types of cancer. However, the role of the lipid mediator in BTC has never been examined. Here we found that S1P is elevated in BTC with the activation of ceramide-synthetic pathways, suggesting that BTC utilizes SPHK1 to promote lymphatic metastasis. We found that S1P, sphingosine and ceramide precursors such as monohexosyl-ceramide and sphingomyelin, but not ceramide, were significantly increased in BTC compared to normal biliary tract tissue using LC-ESI-MS/MS. Utilizing The Cancer Genome Atlas cohort, we demonstrated that S1P in BTC is generated via de novo pathway and exported via ABCC1. Further, we found that SPHK1 expression positively correlated with factors related to lymphatic metastasis in BTC. Finally, immunohistochemical examination revealed that gallbladder cancer with lymph node metastasis had significantly higher expression of phospho-SPHK1 than that without. Taken together, our data suggest that S1P generated in BTC contributes to lymphatic metastasis. PMID- 30018458 TI - Reappraisal of attenuated insulin sensitivity in the evolution of non-alcoholic fatty liver disease. AB - BACKGROUND/OBJECTIVES: It has been unknown if attenuated insulin sensitivity (Si) in non-alcoholic fatty liver disease (NAFLD) is a cause or a result. We examined the impact of attenuated Si on NAFLD evolution. SUBJECTS/METHODS: We observed 4856 NAFLD- and diabetes-free participants for a mean 2.9 years. Si was indexed by single point insulin sensitivity estimator (SPISE = [600 * HDL-c0.185]/[TG0.2 * BMI1.338]), correlating with 1/HOMA-IR in an independent cohort (n = 1537, Spearman rho = 0.519, P < 0.01). Fatty liver (FL) was diagnosed by ultrasonography and diabetes by fasting plasma glucose (FPG) >= 7 mmol/L and/or glycohemoglobin A1c >= 6.5%. Multinominal comparison was performed with incident FL (FLw/oDM, n = 486), diabetes (DMw/oFL, n = 171), and FL plus diabetes (FL/diabetes, n = 58) as targets; none of the above (n = 4,138) was the control. SPISE was taken as a predictor with adjustment for covariates. Trajectory of SPISE during the 5 years before development of each condition was also assessed. RESULTS: With SPISE tertile 3 (>10.06) as the reference, tertile 1 (<8.07) was related to incident FLw/oDM and FL/diabetes with OR (95% CI) 3.47 (2.60-4.63) and 1.78 (1.10-2.87), respectively, and tertile 2 (8.07-10.06) related to FLw/oDM with OR (95% CI) 1.38 (1.03-1.85). Low SPISE was not significantly related to incident diabetes. At -5 years, SPISE was 12% (P < 0.05) and 13% (P < 0.01) lower in those developed FLw/oDM and FL/diabetes, respectively, than the control. At year 0, SPISE in the two groups was 18% and 21% lower than the control, respectively (P < 0.01). CONCLUSIONS: Attenuation of Si indexed by SPISE was a risk factor for NAFLD. PMID- 30018459 TI - Comment on "Body weight difference between dual-energy X-ray absorptiometry and multi-frequency bioelectrical impedance analysis attenuates the equivalence of body composition assessment". PMID- 30018460 TI - Author's reply to: Incorrect analyses were used in "Different enteral nutrition formulas have no effect on glucose homeostasis but on diet-induced thermogenesis in critically ill medical patients: a randomized controlled trial" and corrected analyses are requested. PMID- 30018462 TI - Effect of Self-Assembly of Oxalamide Based Organic Compounds on Melt Behavior, Nucleation, and Crystallization of Isotactic Polypropylene. AB - We report on the effect of an aliphatic oxalamide based nucleating agent (OXA3,6) on the melt and crystallization behavior of isotactic polypropylene (iPP) under defined shear conditions. Through polarized optical microscopy, we demonstrate that OXA3,6 self-assembles from the iPP melt into rhombic crystals whereas their size and distribution proved highly dependent on the employed cooling rates. The presence of 0.5 wt % of OXA3,6 in iPP results in a significant suppression in iPP melt viscosity, which could not be explained via molecular modeling. A possible cause for the drop in viscosity in the presence of OXA3,6 is attributed to the interaction (absorption) of high molecular weight iPP chains with the nucleating agent, thereby suppressing their contribution to the viscoelastic response of the melt. This proposed mechanism for the suppression in melt viscosity appears similar to that encountered by the homogeneous distribution of nanoparticles such as CNTs, graphene, and silica. Shear experiments, performed using a slit flow device combined with small-angle X-ray diffraction measurements, indicate that crystallization is significantly enhanced in the presence of OXA3,6 at relatively low shear rates despite its lowered sensitivity to shear. This enhancement in crystallization is attributed to the shear alignment of the rhombic OXA3,6 crystals that provide surface for iPP kebab growth upon cooling. Overall, the suppression in melt viscosity in combination with enhanced nucleation efficiency at low as well as high shear rates makes this self-assembling oxalamide based nucleating agent a promising candidate for fast processing. PMID- 30018461 TI - Effects of Surfactant and Urea on Dynamics and Viscoelastic Properties of Hydrophobically Assembled Supramolecular Hydrogel. AB - Physically associated hydrogels based on strong hydrophobic interactions often have attractive mechanical properties that combine processability with elasticity. However, there is a need to study such interactions and understand their relation to the macroscopic hydrogel properties. Therefore, we use the surfactant sodium dodecyl sulfate (SDS) and urea as reagents that disrupt hydrophobic interactions. The model hydrogel is based on a segmented copolymer between poly(ethylene glycol) (PEG) and hydrophobic dimer fatty acid (DFA). We show that both agents influence viscoelastic properties, dynamics, and relaxation processes of the model hydrogel. In particular, the relaxation time is significantly reduced by urea, as compared to SDS, whereas the surfactant causes a decrease of the modulus of the hydrogel more efficiently. The reversibility of the effects of SDS and urea can be exploited, for instance, by using an injectable sol that solidifies when the SDS or urea diffuses out of the sample. Surfactant-induced processability may be advantageous in future applications of hydrophobically assembled physical hydrogels. PMID- 30018463 TI - Linear Viscoelasticity of Weakly Hydrogen-Bonded Polymers near and below the Sol Gel Transition. AB - Supramolecular polymers bearing weak hydrogen bonds (sticker) can express outstanding dynamic properties due to their labile association. Studying the linear viscoelasticity (LVE) of this type of polymer can provide us with sufficient knowledge to design polymeric materials for applications that need dynamic properties such as self-healing. Using different compositions of flexible weak stickers, LVE analysis showed scalings corresponding to a transition from a linear precursor to a cluster. By introducing one sticker per repeating unit of the precursor polymer, the effect of sticker distribution along the chain as well as phase separation is excluded. However, even a fully functionalized polymer could not show any network formation, whereas surprisingly, a stable cluster was formed. This proves that weakly associated networks do not dissociate rapidly and can relax as a cluster at extended time before the dissociation of stickers can lead to the relaxation of linear analogous (slow kinetics similar to strong physical or even chemical bonds.) On the other hand, the absence of a gel even in fully sticker-functionalized polymers shows that the weakness of these polymers can be described as their weakness in complete association (thermodynamically not favored). PMID- 30018464 TI - PEE POWER(r) urinal II - Urinal scale-up with microbial fuel cell scale-down for improved lighting. AB - A novel design of microbial fuel cells (MFC) fuelled with undiluted urine was demonstrated to be an efficient power source for decentralised areas, but had only been tested under controlled laboratory conditions. Hence, a field-trial was carried out to assess its feasibility for practical implementation: a bespoke stack of 12 MFC modules was implemented as a self-sufficient lit urinal system at UK's largest music festival. Laboratory investigation showed that with a hydraulic retention time (HRT) of 44 h, a cascade of 4 modules (19.2 L displacement volume) was continuously producing ~150 mW. At the same HRT, the chemical oxygen demand (COD) was reduced from 5586 mg COD.L-1 to 625 mg COD.L-1. Field results of the system under uncontrolled usage indicate an optimal retention time for power production between 2h30 and ~9 h. When measured (HRT of ~11h40), the COD decreased by 48% and the total nitrogen content by 13%. Compared to the previous PEE POWER(r) field-trial (2015), the present system achieved a 37% higher COD removal with half the HRT. The 2016 set-up produced ~30% more energy in a third of the total volumetric footprint (max 600 mW). This performance corresponds to ~7-fold technological improvement. PMID- 30018465 TI - Silver-modified octahedral anatase particles as plasmonic photocatalyst. AB - Octahedral anatase particles (OAPs) were modified with silver nanoparticles (NPs) by photodeposition method. The properties of OAPs influenced the properties of silver deposits, and thus the photocatalytic activity of the obtained silver modified OAPs. Photocatalytic activities were tested under UV and vis irradiation for oxidative decomposition of acetic acid and oxidation of 2-propanol, respectively. The properties of silver-modified OAPs were investigated by XRD, STEM, DRS, XPS and time-resolved microwave conductivity (TRMC) method. It was found that electron traps (ETs) worked as nucleation sites for silver, resulting in formation of smaller silver NPs on smaller OAPs with larger content of ETs. The modification with silver resulted in enhanced photocatalytic activity under both UV and vis irradiation. It was found that larger crystallite size of silver NPs, and thus larger polydispersity of silver deposits resulted in broad and intense plasmon resonance peak causing enhanced visible activity. The correlation between photocatalytic activity and TRMC data, e.g., slower decay of TRMC signal for more active samples, allowed discussion on property-governed photocatalytic activities of silver-modified titania. PMID- 30018466 TI - Option pricing in the moderate deviations regime. AB - We consider call option prices close to expiry in diffusion models, in an asymptotic regime ("moderately out of the money") that interpolates between the well-studied cases of at-the-money and out-of-the-money regimes. First and higher order small-time moderate deviation estimates of call prices and implied volatilities are obtained. The expansions involve only simple expressions of the model parameters, and we show how to calculate them for generic local and stochastic volatility models. Some numerical computations for the Heston model illustrate the accuracy of our results. PMID- 30018467 TI - Germline Stem Cells in Myocardial Regeneration - A new hope worth a delve. PMID- 30018468 TI - The Role of microRNAs in Embryonic and Induced Pluripotency. AB - Research on stem cells is one of the fastest growing areas of regenerative medicine that paves the way for a comprehensive solution to cell therapy. Today, stem cells are precious assets for generating different types of cells derived from either natural embryonic stem (ES) cells or induced pluripotent stem (iPS) cells. The iPS technology can revolutionize the future of clinics by offering personalized medicine, which will provide the future treatment for curing untreatable diseases. Although iPS cell therapy is now at its infancy, promising research has motivated scientists to pursue this therapeutic approach. In this article, we provide information regarding similarities and differences between ES and iPS cells, and focus on the non-integrating methods of iPS generation via RNA molecules, especially microRNAs with an emphasis on the elucidation of their role and importance in pluripotency. PMID- 30018470 TI - Cardiomyogenic Heterogeneity of Clonal Subpopulations of Human Bone Marrow Mesenchymal Stem Cells. AB - We have evaluated the cardiomyogenic potential of clonal populations of human bone marrow mesenchymal stem cells (BM-MSC). Four rapidly proliferating clones of BM-MSC were obtained from the BM of a healthy donor which were then treated with 5-azacytidine and evaluated for the expression of GATA-4, NKx-2.5, FOG-2, TDGF-1, beta-MHC, MEF2D and NPPA genes and cTnT, Desmin and beta-MHC proteins. Of the four clones (i) Clone-1 had high expression of GATA-4 (1.89 fold (p<0.05), Nkx2.5 (2.29 fold; p<0.05), FOG2 (2.76 fold; p<0.05), TDGF1 (6.97 fold, p<0.005), betaMHC (10.22 fold; p<0.005), MEF-2D (1.91 fold; p<0.005) and NPPA (1.65 fold; p<0.005); (ii) clone-2 had up-regulation of Nkx2.5 (1.98 fold; p<0.05) but down regulation of rest of the genes; (iii) clone-3 had up-regulation of Nkx2.5 (2.11 fold; p<0.05), TDGF1 (1.88 fold; p<0.05), MEF-2D (1.30 fold; p<0.05) and NPPA (1.21 fold; p<0.05), down regulation of GATA-4 and Fog-2 but no change in betaMHC gene; and (iv) clone-4 had up-regulation of MEF-2D (1.17 fold; p<0.05) and down regulation of GATA-4, Nkx2.5 but no change in other genes compared to untreated cells of the clones. At the protein level, clone-1 expressed cTnT, Desmin, and betaMHC; clone-2 Desmin only while clones-3 and 4 each expressed cTnT, Desmin, and betaMHC. Our data shows that BM-MSC are a heterogenous population of stem cells with sub-populations exhibiting a marked difference in the expression of cardiac markers both at gene and protein levels. This highlights that administering selected sub-populations of BM-MSC with a cardiomyogenic potential may be more efficacious than whole population of cells for cardiac regeneration. PMID- 30018469 TI - Re-Defining Stem Cell-Cardiomyocyte Interactions: Focusing on the Paracrine Effector Approach. AB - Stem cell research for treating or curing ischemic heart disease has, till date, culminated in three basic approaches: the use of induced pluripotent stem cell (iPSC) technology; reprogramming cardiac fibroblasts; and cardiovascular progenitor cell regeneration. As each approach has been shown to have its advantages and disadvantages, exploiting the advantages while minimizing the disadvantages has been a challenge. Using human germline pluripotent stem cells (hgPSCs) along with a modified version of a relatively novel cell-expansion culture methodology to induce quick, indefinite expansion of normally slow growing hgPSCs, it was possible to emphasize the advantages of all three approaches. We consistently found that unipotent germline stem cells, when removed from their niche and cultured in the correct medium, expressed endogenously, pluripotency genes, which induced them to become hgPSCs. These cells are then capable of producing cell types from all three germ layers. Upon differentiation into cardiac lineages, our data consistently showed that they not only expressed cardiac genes, but also expressed cardiac-promoting paracrine factors. Taking these data a step further, we found that hgPSC-derived cardiac cells could integrate into cardiac tissue in vivo. Note, while the work presented here was based on testes-derived hgPSCs, data from other laboratories have shown that ovaries contain very similar types of stem cells that can give rise to hgPSCs. As a result, hgPSCs should be considered a viable option for eventual use in patients, male or female, with ischemic heart disease. PMID- 30018471 TI - Generation of dopamine neuronal-like cells from induced neural precursors derived from adult human cells by non-viral expression of lineage factors. AB - Reprogramming technology holds great promise for the study and treatment of Parkinson's disease (PD) as patient-specific ventral midbrain dopamine (vmDA) neurons can be generated. This should facilitate the investigation of early changes occurring during PD pathogenesis, permitting the identification of new drug targets and providing a platform for drug screening. To date, most studies using reprogramming technology to study PD have employed induced pluripotent stem cells. Research into PD using direct reprogramming has been limited due to an inability to generate high yields of authentic human vmDA neurons. Nevertheless, direct reprogramming offers a number of advantages, and development of this technology is warranted. Previous reports have indicated that induced neural precursors (iNPs) derived from adult human fibroblasts by lineage factor-mediated direct reprogramming can give rise to dopamine neurons expressing tyrosine hydroxylase (TH+). Using normal adult human fibroblasts, the present study aimed to extend these findings and determine the capacity of iNPs for generating vmDA neurons, with the aim of utilising this technology for the future study of PD. While iNPs expressed late vmDA fate markers such as NURR1 and PITX3, critical early regional markers LMX1A, FOXA2 and EN1 were not expressed. Upon differentiation, iNPs gave rise to dopamine neuronal-like cells expressing TUJ1, TH, AADC, DAT, VMAT2 and GIRK2. To induce an authentic A9 phenotype, a series of experiments investigated temporal exposure to patterning factors. Exposure to SHH C24II, purmorphamine, CHIR99021 and/or FGF8b during or after reprogramming was insufficient to induce expression of early vmDA regional markers. Addition of LMX1A/FOXA2 to the transfection cocktail did not induce a sustained vmDA iNP phenotype. This study reports for the first time that iNPs derived from healthy adult human cells by non-viral expression of lineage factors can give rise to dopamine neuronal-like cells. Direct-to-iNP reprogramming could be a suitable strategy for modelling PD in vitro using aged donor-derived cells. PMID- 30018473 TI - Granulation tissue-derived mesenchymal stromal cells: a potential application for burn wound healing in pediatric patients. AB - Objective: Multipotential cells are mobilized into peripheral blood in response to trauma, in particular in severe burns. These cells migrate to the site of injury in response to chemotactic signals to modulate inflammation, repair damaged tissue and facilitate tissue regeneration. We evaluated the possibility of isolating and in vitro expand mesenchymal stromal cells (MSCs) from granulation tissue (GT) during debridement of a burn wound, as a persective strategy to improve skin regeneration. Methods: GT obtained from a 12-month-old burn patient was in vitro cultured. Expanded MCSs were characterized for morphology, immunophenotype, differentiation capacity and proliferative growth. Antifibrotic features were also evaluated. Results: It was possible to isolate and in vitro expand cells from GT with the morphology, phenotype, proliferative and differentiation capacity typical of MSC, these cells were defined as GT-MSC. GT-MSCs exhibited antifibrotic features by releasing soluble factors, this activity was superior to that observed in BM-MSC. Conclusions: Successful isolation and expansion of MSCs from GT is reported. Considering their functional characteristics, GT-MSCs could be considered a good candidate adjuvant therapy to improve burn wound healing, particularly in pediatrics. PMID- 30018472 TI - Proliferation, migration and differentiation potential of human mesenchymal progenitor cells derived from osteoarthritic subchondral cancellous bone. AB - Background: For regenerative therapies in the orthopedic field, one prerequisite for therapeutic success in the treatment of cartilage defects is the potential of body's own cells to migrate, proliferate and differentiate into functional cells. While this has been demonstrated for mesenchymal stem and progenitor cells (MPC) from healthy tissue sources, the potential of cells from degenerative conditions is unclear. In this study the regenerative potential of MPC derived from subchondral cancellous bone with diagnosed osteoarthritis is evaluated in vitro. Methods: OaMPC isolated from bone chips of three individual patients with Kellgren grade 3 osteoarthritis were characterized by analysis of cell surface antigen pattern. Cell proliferation was evaluated by doubling time and population doubling rate. Cell migration was assessed using a multi-well migration assay. Multi-lineage potential was evaluated by histological staining of adipogenic, osteogenic and chondrogenic markers. In addition, chondrogenic differentiation was verified by qPCR. Results: OaMPC showed a stable proliferation and a typical surface antigen pattern known from mesenchymal stem cells. Cell migration of oaMPC can be induced by human blood serum. OaMPC were capable of adipogenic, osteogenic and chondrogenic differentiation comparable to MPC derived from healthy conditions. Conclusion: OaMPC derived from knee joints affected by osteoarthritic conditions showed regeneration potential regarding migration, proliferation and chondrogenic differentiation. This suggests that oaMPC are able to contribute to cartilage repair tissue formation. PMID- 30018474 TI - Letter: Safety and Feasibility of Autologous Mesenchymal Stem Cell Transplantation in Chronic Stroke in Indian patients. A four-year follow up. PMID- 30018476 TI - Current clinical management of gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors (GISTs) are the most common malignant subepithelial lesions (SELs) of the gastrointestinal tract. They originate from the interstitial cells of Cajal located within the muscle layer and are characterized by over-expression of the tyrosine kinase receptor KIT. Pathologically, diagnosis of a GIST relies on morphology and immunohistochemistry [KIT and/or discovered on gastrointestinal stromal tumor 1 (DOG1) is generally positive]. The prognosis of this disease is associated with the tumor size and mitotic index. The standard treatment of a GIST without metastasis is surgical resection. A GIST with metastasis is usually only treated by tyrosine kinase inhibitors without radical cure; thus, early diagnosis is the only way to improve its prognosis. However, a GIST is usually detected as a SEL during endoscopy, and many benign and malignant conditions may manifest as SELs. Conventional endoscopic biopsy is difficult for tumors without ulceration. Most SELs have therefore been managed without a histological diagnosis. However, a favorable prognosis of a GIST is associated with early histological diagnosis and R0 resection. Endoscopic ultrasonography (EUS) and EUS-guided fine needle aspiration (EUS-FNA) are critical for an accurate diagnosis of SELs. EUS-FNA is safe and effective in enabling an early histological diagnosis and adequate treatment. This review outlines the current evidence for the diagnosis and management of GISTs, with an emphasis on early management of small SELs. PMID- 30018475 TI - Liver transplantation and alcoholic liver disease: History, controversies, and considerations. AB - Alcohol consumption accounts for 3.8% of annual global mortality worldwide, and the majority of these deaths are due to alcoholic liver disease (ALD), mainly alcoholic cirrhosis. ALD is one of the most common indications for liver transplantation (LT). However, it remains a complicated topic on both medical and ethical grounds, as it is seen by many as a "self-inflicted disease". One of the strongest ethical arguments against LT for ALD is the probability of relapse. However, ALD remains a common indication for LT worldwide. For a patient to be placed on an LT waiting list, 6 mo of abstinence must have been achieved for most LT centers. However, this "6-mo rule" is an arbitrary threshold and has never been shown to affect survival, sobriety, or other outcomes. Recent studies have shown similar survival rates among individuals who undergo LT for ALD and those who undergo LT for other chronic causes of end-stage liver disease. There are specific factors that should be addressed when evaluating LT patients with ALD because these patients commonly have a high prevalence of multisystem alcohol related changes. Risk factors for relapse include the presence of anxiety or depressive disorders, short pre-LT duration of sobriety, and lack of social support. Identification of risk factors and strengthening of the social support system may decrease relapse among these patients. Family counseling for LT candidates is highly encouraged to prevent alcohol consumption relapse. Relapse has been associated with unique histopathological changes, graft damage, graft loss, and even decreased survival in some studies. Research has demonstrated the importance of a multidisciplinary evaluation of LT candidates. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including 12-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Nutritional therapy helps to reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. For muscular recovery, supervised physical activity has been shown to lead to a gain in muscle mass and improvement of functional activity. Early LT for acute alcoholic hepatitis has been the subject of recent clinical studies, with encouraging results in highly selected patients. The survival rates after LT for ALD are comparable to those of patients who underwent LT for other indications. Patients that undergo LT for ALD and survive over 5 years have a higher risk of cardiorespiratory disease, cerebrovascular events, and de novo malignancy. PMID- 30018478 TI - Bowel preparation quality scales for colonoscopy. AB - Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the United States. Colonoscopy is widely preferred for CRC screening and is the most commonly used method in the United States. Adequate bowel preparation is essential for successful colonoscopy CRC screening. However, up to one-quarter of colonoscopies are associated with inadequate bowel preparation, which may result in reduced polyp and adenoma detection rates, unsuccessful screens, and an increased likelihood of repeat procedure. In addition, standardized criteria and assessment scales for bowel preparation quality are lacking. While several bowel preparation quality scales are referred to in the literature, these differ greatly in grading methodology and categorization criteria. Published reliability and validity data are available for five bowel preparation quality assessment scales, which vary in several key attributes. However, clinicians and researchers continue to use a variety of bowel preparation quality measures, including nonvalidated scales, leading to potential confusion and difficulty when comparing quality results among clinicians and across clinical trials. Optimal clinical criteria for bowel preparation quality remain controversial. The use of validated bowel preparation quality scales with stringent but simple scoring criteria would help clarify clinical trial data as well as the performance of colonoscopy in clinical practice related to quality measurements. PMID- 30018477 TI - Biomarkers of gastric cancer: Current topics and future perspective. AB - Gastric cancer (GC) is one of the most prevalent malignant types in the world and an aggressive disease with a poor 5-year survival. This cancer is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Although the incidence is declining, the outcome of patients with GC remains dismal. Thus, the detection at an early stage utilizing useful screening approaches, selection of an appropriate treatment plan, and effective monitoring is pivotal to reduce GC mortalities. Identification of biomarkers in a basis of clinical information and comprehensive genome analysis could improve diagnosis, prognosis, prediction of recurrence and treatment response. This review summarized the current status and approaches in GC biomarker, which could be potentially used for early diagnosis, accurate prediction of therapeutic approaches and discussed the future perspective based on the molecular classification and profiling. PMID- 30018479 TI - Current practices and future prospects for the management of gallbladder polyps: A topical review. AB - A gallbladder polyp is an elevation of the gallbladder mucosa that protrudes into the gallbladder lumen. Gallbladder polyps have an estimated prevalence in adults of between 0.3%-12.3%. However, only 5% of polyps are considered to be "true" gallbladder polyps, meaning that they are malignant or have malignant potential. The main radiological modality used for diagnosing and surveilling gallbladder polyps is transabdominal ultrasonography. However, evidence shows that other modalities such as endoscopic ultrasound may improve diagnostic accuracy. These are discussed in turn during the course of this review. Current guidelines recommend cholecystectomy for gallbladder polyps sized 10 mm and greater, although this threshold is lowered when other risk factors are identified. The evidence behind this practice is relatively low quality. This review identifies current gaps in the available evidence and highlights the necessity for further research to enable better decision making regarding which patients should undergo cholecystectomy, and/or radiological follow-up. PMID- 30018480 TI - New horizons in the endoscopic ultrasonography-based diagnosis of pancreatic cystic lesions. AB - Pancreatic cystic lesions (PCLs) are increasingly being identified because of the widespread use of high-resolution abdominal imaging. These cysts encompass a spectrum from malignant disease to benign lesions, and therefore, accurate diagnosis is crucial to determine the best management strategy, either surgical resection or surveillance. However, the current standard of diagnosis is not accurate enough due to limitations of imaging and tissue sampling techniques, which entail the risk of unnecessary burdensome surgery for benign lesions or missed opportunities of prophylactic surgery for potentially malignant PCLs. In the last decade, endoscopic innovations based on endoscopic ultrasonography (EUS) imaging have emerged, aiming to overcome the present limitations. These new EUS based technologies are contrast harmonic EUS, needle-based confocal endomicroscopy, through-the-needle cystoscopy and through-the needle intracystic biopsy. Here, we present a comprehensive and critical review of these emerging endoscopic tools for the diagnosis of PCLs, with a special emphasis on feasibility, safety and diagnostic performance. PMID- 30018481 TI - Total polysaccharides of the Sijunzi decoction attenuate tumor necrosis factor alpha-induced damage to the barrier function of a Caco-2 cell monolayer via the nuclear factor-kappaB-myosin light chain kinase-myosin light chain pathway. AB - AIM: To explore the protective effects and underlying mechanisms of total polysaccharides of the Sijunzi decoction (TPSJ) on the epithelial barriers in vitro. METHODS: Caco-2 cell monolayers were treated with or without TPSJ in the presence or absence of TNF-alpha, and paracellular permeability and transepithelial electrical resistance (TEER) were measured to evaluate the epithelial barrier function. Immunofluorescence and western blotting were respectively used to evaluate the distribution and expression of the tight junction proteins claudin 1, claudin 2, zo3, and occludin in Caco-2 cells. Western blotting was also used to evaluate the cellular expression of myosin light chain (MLC), phosphorylated MLC (pMLC), MLC kinase (MLCK), and nuclear factor (NF)-kappaB p65. RESULTS: TPSJ promoted the proliferation of Caco-2 cells and inhibited TNF-alpha-induced secretion of pro-inflammatory cytokines. Furthermore, TPSJ significantly ameliorated both the reduction of TEER and the increased paracellular permeability observed in tumor necrosis factor (TNF)-alpha damaged Caco-2 monolayers. Furthermore, TPSJ remarkably attenuated TNF-alpha induced morphological changes, downregulated the expression of claudin 1, claudin 2, zo3, and occludin, and markedly suppressed TNF-alpha-mediated upregulation of p-MLC and MLCK expression. Finally, TPSJ inhibited the activation and expression of NF-kappaB p65. CONCLUSION: Our results demonstrate that TPSJ alleviates the TNF-alpha-induced impairment of the intestinal epithelial cell barrier function by suppressing NF-kappaB p65-mediated phosphorylation of MLCK and MLC. PMID- 30018482 TI - Efficacy and safety of endoscopic submucosal tunnel dissection for superficial esophageal squamous cell carcinoma and precancerous lesions. AB - AIM: To evaluate the clinical outcomes of patients who underwent endoscopic submucosal tunnel dissection (ESTD) for esophageal squamous cell carcinoma (ESCC) and precancerous lesions. METHODS: ESTD was performed in 289 patients. The clinical outcomes of the patients and pathological features of the lesions were retrospectively reviewed. RESULTS: A total of 311 lesions were included in the analysis. The en bloc rate, complete resection rate, and curative resection rate were 99.04%, 81.28%, and 78.46%, respectively. The ESTD procedure time was 102.4 +/- 35.1 min, the mean hospitalization time was 10.3 +/- 2.8 d, and the average expenditure was 3766.5 +/- 846.5 dollars. The intraoperative bleeding rate was 6.43%, the postoperative bleeding rate was 1.61%, the perforation rate was 1.93%, and the postoperative infection rate was 9.65%. Esophageal stricture and positive margin were severe adverse events, with an incidence rate of 14.79% and 15.76%, respectively. No tumor recurrence occurred during the follow-up period. CONCLUSION: ESTD for ESCC and precancerous lesions is feasible and relatively safe, but for large mucosal lesions, the rate of esophageal stricture and positive margin is high. PMID- 30018483 TI - Impact of the number of examined lymph nodes on outcomes in patients with lymph node-negative gallbladder carcinoma. AB - AIM: To determine whether the number of examined lymph nodes (LNs) is correlated with the overall survival of gallbladder carcinoma (GBC) patients. METHODS: Patients were collected from the Surveillance Epidemiology and End Results database (2004-2013) and categorized by the number of LNs into six groups: 1 LN, 2 LNs, 3 LNs, 4 LNs, 5 LNs, and >= 6 LNs. Survival curves for overall survival were plotted with a Kaplan-Meier analysis. The log-rank test was used for univariate comparisons. RESULTS: In a cohort of 893 patients, the median number of examined LNs was two for the entire cohort. The survival for the 1 LN group was significantly poorer than those of the stage I and II disease groups and for the entire cohort. By dichotomizing the number of LNs from 1 to 6, we found that the minimum number of LNs that should be examined was four for stage I, four or five for stage II, and six for stage IIIA disease. Therefore, for the entire cohort, the number of examined LNs should be at least six, which is exactly consistent with the American Joint Committee on Cancer criteria. CONCLUSION: The examination of higher numbers of LNs is associated with improved survival after resection surgery for N0 GBC. The guidelines for GBC surgery, which recommend that six LNs be examined at least, are statistically valid and should be applied in clinical practice widely. PMID- 30018484 TI - Upper gastrointestinal tract capsule endoscopy using a nurse-led protocol: First reported experience. AB - AIM: To test the feasibility and performance of a novel upper gastrointestinal (GI) capsule endoscope using a nurse-led protocol. METHODS: We conducted a prospective cohort analysis of patients who declined gastroscopy (oesophagogastroduodenoscopy, OGD) but who consented to upper GI capsule endoscopy. Patients swallowed the upper GI capsule following ingestion of 1 liter of water (containing simethicone). A series of positional changes were used to exploit the effects of water flow and move the upper GI capsule from one gravity dependent area to another using a nurse-led protocol. Capsule transit time, video reading time, mucosal visualisation, pathology detection and patient tolerance was evaluated. RESULTS: Fifty patients were included in the study. The mean capsule transit times in the oesophagus and stomach were 28 s and 68 min respectively. Visualisation of the following major anatomical landmarks was achieved (graded 1-5: Poor to excellent): Oesophagus, 4.8 (+/- 0.5); gastro oesophageal junction (GOJ), 4.8 (+/- 0.8); cardia, 4.8 (+/- 0.8); fundus, 3.8 (+/ 1.2); body, 4.5 (+/- 1); antrum, 4.5 (+/- 1); pylorus, 4.7 (+/- 0.8); duodenal bulb, 4.7 (+/- 0.7); second part of the duodenum (D2), 4.7 (+/- 1). The upper GI capsule reached D2 in 64% of patients. The mean video reading time was 48 min with standard playback mode and 20 min using Quickview (P = 0.0001). No pathology was missed using Quickview. Procedural tolerance was excellent. No complications were seen with the upper GI capsule. CONCLUSION: The upper GI capsule achieved excellent views of the upper GI tract. Future studies should compare the diagnostic accuracy between upper GI capsule and OGD. PMID- 30018486 TI - Gastric adenocarcinoma of fundic gland type with signet-ring cell carcinoma component: A case report and review of the literature. AB - A depressed lesion was found at a gastric angle of 76-year-old Japanese woman by esophagogastroduodenoscopy. Four years prior, she was diagnosed with a Helicobacter pylori infection but no eradication was performed. The pathological diagnosis of biopsy specimens was signet-ring cell carcinoma. Endoscopic submucosal dissection (ESD) was performed. Histopathological examination of the ESD specimen revealed proliferation of well-differentiated tubular adenocarcinoma mimicking fundic gland cells at the deep layer of the lamina propria mucosae. These tumor cells expressed focally pepsinogen-I, diffusely MUC6, and scattered H+/K+ ATPase according to immunohistochemistry. Therefore, we diagnosed this tumor as gastric adenocarcinoma of fundic gland type (GA-FG). Adjacent to the GA FG, proliferation of signet-ring cell carcinoma which diffusely expressed MUC 2 and MUC 5AC was observed. Intestinal metaplasia was focally observed in the surrounding mucosa of the signet-ring cell carcinoma. To the best of our knowledge, this is the first case report of GA-FG with a signet-ring cell carcinoma component. The origin of signet-ring cell carcinoma, i.e., whether it accidentally arose from a non-neoplastic mucosa and coexisted with the GA-FG or dedifferentiated from the GA-FG is unclear at present. We expect the accumulation of similar cases and further analysis to clarify this issue. PMID- 30018485 TI - Role of band ligation for secondary prophylaxis of variceal bleeding. AB - AIM: To summarize and critically examine the role of band ligation in secondary prophylaxis of variceal bleeding in patients with cirrhosis. METHODS: A literature review was performed using the MEDLINE and PubMed databases. The search terms consisted of the words "endoscopic band ligation" OR "variceal band ligation" OR "ligation" AND "secondary prophylaxis" OR "secondary prevention" AND "variceal bleeding" OR "variceal hemorrhage" AND "liver cirrhosis". The data collected from relevant meta-analyses and from the most recent randomized studies that were not included in these meta-analyses were used to evaluate the role of endoscopic band ligation in an effort to demonstrate the most recent advances in the treatment of esophageal varices. RESULTS: This study included 11 meta analyses published from 2002 to 2017 and 10 randomized trials published from 2010 to 2017 that evaluated the efficacy of band ligation in the secondary prophylaxis of variceal bleeding. Overall, the results proved that band ligation was superior to endoscopic sclerotherapy. Moreover, the use of beta-blockers in combination with band ligation increased the treatment effectiveness, supporting the current recommendations for secondary prophylaxis of variceal bleeding. The use of transjugular intrahepatic portosystemic shunt was superior to combination therapy regarding rebleeding prophylaxis, with no difference in the survival rates; however, the results concerning the hepatic encephalopathy incidence were conflicting. Recent advances in the management of secondary prophylaxis of variceal bleeding have targeted a decrease in portal pressure based on the pathophysiological mechanisms of portal hypertension. CONCLUSION: This review suggests that future research should be conducted to enhance current interventions and/or to develop innovative treatment options with improved clinical endpoints. PMID- 30018487 TI - Odor alters color preference in a foraging jumping spider. AB - In many prey taxa with aposematic coloration, prey defenses also involve signals in other modalities (odors, sounds, etc.), yet the selective forces that have driven multimodality in warning displays are not well understood. One potential hypothesis that has recently received support in the avian literature (but has yet to be examined in invertebrates) is that different signal components may interact synergistically, such that one component of a signal (odor) may trigger a predator's aversion to another component of a signal (color). Here, we gave jumping spiders (Habronattus trimaculatus) the choice between red or black prey (artificially colored termites) in either the presence or absence of odor from the chemically defended coreid bug (Acanthocephala femorata). When the odor was present, spiders were more likely to avoid the color red compared with when the odor was absent. Interestingly, this pattern only held up when the odor was novel; subsequent exposure to the odor had no effect on color preference. Moreover, this pattern only held for the color red (a color typically used as a warning color and often paired with odor). We replicated this experiment giving spiders the choice between green or black prey, and found that the presence of the odor had no effect on the spiders' responses to the color green. We discuss these findings in the context of predator psychology and the evolution of prey coloration. PMID- 30018488 TI - Influence of Cooking, Storage Period, and Re-heating on Production of Cholesterol Oxides in Chicken Meat. AB - The objective of present study was to investigate the effect of cooking and their combinations with re-heating methods on the formation of cholesterol oxidation products (COPs) in stored chicken thigh meat. Pan roasting, steaming, oven grilling, charcoal grilling, and microwaving were used for cooking. Re-heating of samples was done using the same cooking methods or microwaving after 3 and 6 d of refrigerated storage. Cooking and re-heating resulted in reduction of crude fat and cholesterol contents of chicken thigh meat depending on storage period before re-heating. Cooking and storage period had no influence on the total amount of COPs. The highest total amount of COPs was observed in meat samples cooked by steaming and reheated by microwaving after 6 d of storage, which showed similar value to raw chicken meat stored for 6 days. However, different re-heating methods formed different types of COPs depending on storage period before re heating. The high amount (p<0.05) of 25-hydroxycholesterol or alpha-epoxide was detected in meat samples reheated by steaming or microwaving at 3 or 6 d of storage after steamed cooking, respectively. As a result, the combination of steaming and re-heating with microwaving could increase the total amount of COPs in chicken thigh meat and different cooking/re-heating methods could form different types of COPs, even though no significant difference in the total amount of COPs depending on storage period. PMID- 30018489 TI - Development and Validation of Predictive Model for Salmonella Growth in Unpasteurized Liquid Eggs. AB - Liquid egg products can be contaminated with Salmonella spp. during processing. A predictive model for the growth of Salmonella spp. in unpasteurized liquid eggs was developed and validated. Liquid whole egg, liquid yolk, and liquid egg white samples were prepared and inoculated with Salmonella mixture (approximately 3 Log CFU/mL) containing five serovars (S. Bareilly, S. Richmond, S. Typhimurium monophasic, S. Enteritidis, and S. Gallinarum). Salmonella growth data at isothermal temperatures (5, 10, 15, 20, 25, 30, 35, and 40 degrees C) was collected by 960 h. The population of Salmonella in liquid whole egg and egg yolk increased at above 10 degrees C, while Salmonella in egg white did not proliferate at all temperature. These results demonstrate that there is a difference in the growth of Salmonella depending on the types of liquid eggs (egg yolk, egg white, liquid whole egg) and storage temperature. To fit the growth data of Salmonella in liquid whole egg and egg yolk, Baranyi model was used as the primary model and the maximum growth rate and lag phase duration for each temperature were determined. A secondary model was developed with maximum growth rate as a function of temperature. The model performance measures, bias factor (B f , 0.96-0.99) and r2 (0.96-0.99) indicated good fit for both primary and secondary models. In conclusion, it is thought that the growth model can be used usefully to predict Salmonella spp. growth in various types of unpasteurized liquid eggs when those are exposed to various temperature and time conditions during the processing. PMID- 30018490 TI - Biochemical, Microbiological, and Sensory Characteristics of Stirred Yogurt Containing Red or Green Pepper (Capsicum annuum cv. Chungyang) Juice. AB - Hot pepper has anti-obesity effects by controlling appetite and reducing blood fat level. To reduce the pungency of capsaicin, red or green hot pepper juice was fermented with Bacillus licheniformis SK1230. Fermented hot pepper juice was then added into yogurt at different ratios. The pH of yogurt added with hot pepper juice was decreased from 4.61 to 4.48. Titratable acidity and counts of lactic acid bacteria were increased with increasing amount of pepper juice added. However, the viscosity was decreased significantly compared to the control. On chromaticity test, when more pepper juice was added, L*-value was decreased whereas a*- and b*- values were increased significantly (p<0.05). The spectrum of antimicrobial activity of yogurt was slightly changed compared to using pepper juice. Total polyphenol contents and antioxidant activity were increased with increasing amount of pepper juice added. Stirred yogurt added with fermented red pepper juice at 3% or green pepper juice at 1% showed high scores in flavor, appearance, texture, and overall acceptance in sensory test. Yogurt added with fermented pepper juice with reduced pungency showed also good palatability during storage at 4 degrees C. Yogurt with added hot pepper juice can be play an important role in functional food relative to anti-obesity. PMID- 30018491 TI - Effect of Sea Buckthorn (Hippophae rhamnoides L.) Seed Supplementation on Egg Quality and Cholesterol of Rhode Island Red*Fayoumi Laying Hens. AB - The present trial was carried out to study the effect of sea buckthorn seed supplementation on egg quality of laying birds. A total of 160 Rhode Island Red* Fayoumi layers was divided into four groups of 40 birds each, which was further replicated four times with 10 hens per replicate. Group one was kept as a control, while other three groups were supplemented with sea buckthorn seed powder at a dose rate of 1 (T1), 2 (T2) and 3 (T3) g/kg of feed. The results showed that egg production was significantly (p<0.05) higher in T3 at the end of the study. Egg weight was significantly (p<0.05) high in T2 and T3 during week 39 and 40. Egg yolk weight was significantly (p<0.05) in T3 compared to the control. Significantly (p<0.01) lower egg cholesterol was recorded in T2 and T3. From the results of the present study, we concluded that laying hens supplemented with sea buckthorn at the rate of 2 and 3 g/kg improved the egg quality parameters and egg cholesterol. PMID- 30018492 TI - Effect of Homogenization Pressure and Supplementation with Sucrose Fatty Acid Ester on the Physical Properties of Dairy Cream-based Emulsions. AB - In this study, the droplet size distribution, rheological properties, and stability of dairy cream-based emulsions homogenized with different sucrose fatty acid ester (SFAE, a non-ionic small-molecule emulsifier) concentrations (0.08%, 0.16%, and 0.24% w/w) at different homogenization pressures (10 MPa and 20 MPa) were examined. Homogenization at a high pressure resulted in a smaller droplet size and narrower droplet size distribution. The D[4,3] (volume-weighted mean) and D[3,2] (surface-weighted mean) values of the emulsions decreased with an increase in the SFAE concentration. The flow properties of the emulsions homogenized with SFAE showed shear-thinning (n=0.21-0.46) behavior. The apparent viscosity (etaa,10) and consistency index (K) of the homogenized emulsions were lower than those of the control sample that is non-homogenized and without SFAE, and decreased with an increase in SFAE concentration. The storage modulus (G') and loss modulus (G") of all emulsions homogenized with SFAE were also lower than those of the control sample. The stability of all emulsions with SFAE did not show any significant change for 30 d at 5 degrees C. However, the emulsions stored at 40 degrees C were unstable over the storage period. Therefore, the addition of SFAE enhanced the stability of dairy cream emulsions during storage at refrigeration temperature (5 degrees C). PMID- 30018493 TI - Effect of Chlorine Dioxide Gas Application to Egg Surface: Microbial Reduction Effect, Quality of Eggs, and Hatchability. AB - Controlling of microorganisms in the industrial process is important for production and distribution of hatching and table eggs. In the previous study, we reported that chlorine dioxide (ClO2) gas of a proper concentration and humidity can significantly reduce the load of Salmonella spp. on eggshells. In this study, we compared microbial reduction efficacy on egg's surface using hatching eggs and table eggs, internal quality of table eggs, and hatchability after both the conventional method (washing and UV expose, fumigation with formalin) and ClO2 gas disinfection. Application of 40 ppm ClO2 gas to the table and hatching eggs, respectively, reduced the aerobic plate count (APC) with no statistical difference compared with the conventional methods. Additionally, we didn't observed that any significant difference in albumin height, Haugh unit (HU), and yolk color, this result confirms that 40 ppm ClO2 had no effect on the internal quality of the table eggs, when comparing with the UV treatment method. The hatchability of hatching eggs was not statistical different between formaldehyde fumigation and 80 ppm ClO2 gas treatment, though the value was decreased at high concentration of 160 ppm ClO2 gas. From these results, we recommend that ClO2 gas can be used as a safe disinfectant to effectively control egg surface microorganisms without affecting egg quality. PMID- 30018494 TI - Effects of Foot-and-mouth Disease Vaccination Location and Injection Device on the Incidence of Site Lesions in Pork. AB - This study was aimed to investigate the effects of the type O foot-and-mouse disease vaccine (FMDV) on the incidence of abnormal meat such as granuloma or abscess formation at the injection site in pork and its associated economic losses. At 56 d of age, piglets were inoculated with FMDV by one of three administration routes: N-Neck (a conventional needle-syringe injection into the neck), N-Ham (a conventional needle-syringe injection into the ham), and Non-Neck (injection with a needle-free device into the neck). The injection sites were visually examined for the presence of a granuloma or abscess, and the incidence rate of abnormal meat was calculated. The gross weight of the portion of the pork carcasses condemned because of granuloma or abscess formation was measured and multiplied by the weekly sales price to calculate the total economic losses. After implementation of FMDV, the economic losses were approximately six times higher than before implementation. Granuloma or abscess formation was significantly higher in the N-Neck and Non-Neck groups, in which the vaccine was inoculated into the neck area, than in the N-Ham group (N-Neck and N-Ham vs Non Neck, p<0.05). These results suggest that the incidence of lesions could be reduced if the ham route was used for vaccination. PMID- 30018495 TI - Effects of Different Marination Conditions on Quality, Microbiological Properties, and Sensory Characteristics of Pork Ham Cooked by the Sous-vide Method. AB - The aim of this study was to evaluate the effects of marinade under different conditions (temperature and vacuum) on pork ham cooked by the sous-vide method (61 degrees C and 98.81% vacuum for 45 min). Control group was non-marinade pork ham. The samples were marinated under 1 of 4 conditions: 4 degrees C, 98.81% vacuum (treatment group T1); 4 degrees C, atmospheric pressure (T2); 20 degrees C, 98.81% vacuum (T3); and 20 degrees C, atmospheric pressure (T4). The pH value was higher in the control (6.02) than in the treatment groups (4.30-4.42, p<0.001). Shear force was the lowest in the control: 18.14 N. Lightness and redness values were higher in the control (p<0.001). The chroma value significantly decreased from 12.74 to 7.55 with marinade (p<0.001). Total viable and coliform counts of raw meat were 84.6 and 3.67 Log CFU/g, respectively. After the marinade, the total viable count decreased to 3.00-14.67 Log CFU/g (p<0.001). Coliforms were not detected. After sous-vide cooking, no viable microorganisms were detected in any group. Treatment groups generally showed high scores on consumer preference. The marinade and sous-vide cooking had a positive effect on sensory characteristics. They provided safe conditions for sanitary evaluation. As a result, it appears that marinade at refrigeration temperature is better than that at room temperature. PMID- 30018496 TI - Effect of the Calpain System on Volatile Flavor Compounds in the Beef Longissimus lumborum Muscle. AB - The present study was designed to investigate the effects of calpain system on the formation of volatile flavor compounds in Hanwoo beef. In the first experiment (exp.1), Longissimus lumborum (LL) muscle samples were injected with solutions containing 50 mM CaCl2 or 50 mM ZnCl2 and 154 mM NaCl respectively, and aged for 7 d at 4 degrees C. In the second experiment (exp.2), the ground LL muscle was incubated with the aforementioned solutions containing cathepsin inhibitor. The injection with CaCl2 solution greatly elevated the calpain activity and concomitantly, significantly decreased the Warner-Bratzler shear force (p<0.05). The pH, meat color and cooking loss did not differ (p>0.05) between the treatment groups. A total of 51 volatile compounds were identified using the solid phase microextraction with gas chromatography (SPME-GC). Results on volatile analyses from the both experiments showed that the injection with calcium ions led to significant increase (p<0.05) concentrations of pyrazines and sulfuric compounds. These results coincide with a higher rate of protein degradation due to the CaCl2 injection as compared to the control group. Significantly (p<0.05) higher levels of lipid oxidation derived-aldehydes were found in the samples with ZnCl2. The exp.1 showed that cathepsin inhibitors had no effect on the formation of volatile flavor components after 7 d of aging. These results imply that the proteolytic activity of the calpain system is associated with generation of volatile compounds of chiller-aged beef, while the role of cathepsins is likely very limited. PMID- 30018497 TI - Determination of the Effect of Different Ground Mustard Seeds on Quality Characteristics of Meatballs. AB - This study investigated the effect of yellow, black, and brown mustard seeds on color, lipid oxidation (thiobarbituric acid-reactive substances [TBARS]), and micro-biological and sensory qualities of meatballs during storage. Heat treatment of mustard seeds affected the TBARS value of meatball samples (p<0.0001). The addition of mustard seeds decreased TBARS value of meatball samples (p<0.0001). Heat treatment of mustard seeds decreased the L*, a* and b* values of meatball samples (p<0.0001). The meatball samples with mustard seeds increased b* value of meatball samples however it decreased a* value of meatball samples (p<0.0001). The addition of mustard seeds decreased aerobic mesophilic bacteria count (p<0.0001), Enterobacteriaceae count (p<0.0001), psychrophilic bacteria count (p<0.0001) and yeast and mold count of meatball samples (p<0.0001). On a given storage day, the yellow mustard added meatballs sample was given higher color, appearance, flavor, acceptability ratings than those added black and brown mustard. Regarding sensory and microbiological properties, mustard seed contributed to microbiological quality and sensorial properties of meatball samples. PMID- 30018498 TI - Effects of Sex and Breed on Meat Quality and Sensory Properties in Three-way Crossbred Pigs Sired by Duroc or by a Synthetic Breed Based on a Korean Native Breed. AB - This study was conducted to determine the effects of breed and sex on meat quality and sensory properties of the loin in three-way crossbred pigs: Landrace* Yorkshire*Duroc (LYD) and Landrace*Yorkshire*Woori (LYW) black pig synthesized by Korean native breed. Carcass traits did not differ by breed. Carcass weight and backfat thickness were higher in castrates than in gilts (p<0.01). LYW showed significant high values in fat content, cooking loss, and water-holding capacity (WHC) than LYD (p<0.05). Redness and yellowness of the meat were higher in LYW than in LYD (p<0.01). Further, LYW had lower pH and shear force than LYD (p<0.001). Significant high scores in color and flavor were obtained in LYW or gilts compared to LYD or castrates by sensory panel, respectively (p<0.05). However, other sensory traits did not differ by breed or sex. Capric acid (C10:0) was higher in LYD than LYW (p<0.001). However, stearic acid (C18:0) and saturated fatty acid (SFA) contents were higher in LYW than LYD (p<0.05). Eicosenoic acid (C20:2) and the n6/n3 ratio were higher in gilts than in castrates, whereas SFA content was higher in castrates than in gilts. These results suggest that certain physicochemical qualities of meat and sensory properties are improved in LYW compared to LYD. This study could provide basic data on meat quality of crossbred pigs with Woori black pig as a terminal sire. PMID- 30018499 TI - Physiological Characteristics and Anti-obesity Effect of Lactobacillus plantarum K10. AB - This study aimed to investigate the physiological characteristics and anti obesity effects of Lactobacillus plantarum K10. The alpha-amylase inhibitory activity, alpha-glucosidase inhibitory activity, and lipase inhibitory activity of L. plantarum K10 was 94.66+/-4.34%, 99.78+/-0.12%, and 87.40+/-1.41%, respectively. Moreover, the strain inhibited the adipocyte differentiation of 3T3 L1 cells (32.61+/-8.32%) at a concentration of 100 ug/mL. In order to determine its potential for use as a probiotic, we investigated the physiological characteristics of L. plantarum K10. L. plantarum K10 was resistant to gentamycin, kanamycin, streptomycin, ampicillin, ciprofloxacin, tetracycline, vancomycin, and chloramphenicol. It also showed higher Leucine arylamidase, Valine arylamidase, and beta-galactosidase activities. Moreover, it was comparatively tolerant to bile juice and acid, exhibiting resistance to Escherichia coli, Salmonella Typhimurium, Listeria monocytogenes, and Staphylococcus aureus with rates of 90.71%, 11.86%, 14.19%, and 23.08%, respectively. The strain did not produce biogenic amines and showed higher adhesion to HT-29 cells compared to L. rhamnosus GG. As a result of the animal study, L. plantarum K10 showed significantly lower body weight compared to the high-fat diet group. The administration of L. plantarum K10 resulted in a reduction of subcutaneous fat mass and mesenteric fat mass compared to the high fat diet (HFD) group. L. plantarum K10 also showed improvement in gut permeability compared to the HFD positive control group. These results demonstrate that L. plantarum K10 has potential as a probiotic with anti-obesity effects. PMID- 30018500 TI - Antioxidative Properties of Amaranth Cauline Leaf and Suppressive Effect against CT-26 Cell Proliferation of the Sausage Containing the Leaf. AB - The study investigated antioxidative properties and rectal cancer cell inhibition effect of amaranth (Amaranthus cruentus L.) cauline leaves (ACL) to produce the sausage with ACL powder (ACLP). Antioxidative effects of ACLP prepared with different stem lengths (10-45 cm) were evaluated through DPPH, ABTS, reducing power, total phenol, and total flavonoid. Inhibition effect on rectal cancer cells growth was also examined with CT-26 cell. To determine appropriate ACL amounts in sausage formula, response surface methodology was used. The sausages without ACL (control) and the sausage with ACL (ACLP sausage) were the subjected to the examinations of antioxidation, growth inhibition on CT-26, and physicochemical properties (pH and water content). ACLP made from the leaf with 15 cm length stem generally showed the highest antioxidative effect through results of DPPH, ABTS, reducing power, total phenol, and total flavonoid. ACLP also showed inhibition effect on the proliferation of CT-26, depending on concentration of ACLP. The surface response model showed that 4.87 g of ACLP was optimized amount for sausage production. Physicochemical properties between optimized ACLP and control sausages were not significantly different. Higher antioxidative effect of optimized ACLP sausage extract was observed (p<0.05) in antioxidation tests than control sausage extract except for DPPH. Cell viability of CT-26 cells were higher (p<0.05) in ACLP than in control sausage extracts. These results indicate that ACLP has functional effects on antioxidation activity and growth inhibition on CT-26 cell, and thus, it should be useful as a supplement in sausage, which may some effect as ACLP itself. PMID- 30018501 TI - Formula Optimization of a Perilla-canola Oil (O/W) Emulsion and Its Potential Application as an Animal Fat Replacer in Meat Emulsion. AB - The formulation of an oil/water (o/w) emulsion made up of a mixture of perilla oil and canola oil (30/70 w/w) was optimized using a response surface methodology to find a replacement for animal fat in an emulsion-type meat product. A 12 run Plackett-Burman design (PBD) was applied to screen the effect of potential ingredients in the (o/w) emulsion, including polyglycerol polyricinoleate (PGPR), fish gelatin, soy protein isolate (SPI), sodium caseinate, carrageenan (CR), inulin (IN) and sodium tripolyphosphate. The PBD showed that SPI, CR and IN showed promise but required further optimization, and other ingredients did not affect the technological properties of the (o/w) emulsion. The PBD also showed that PGPR played a critical role in inhibiting an emulsion break. The level of PGPR was then fixed at 3.2% (w/w total emulsion) for an optimization study. A central composite design (CCD) was applied to optimize the addition levels of SPI, CR or IN in an (o/w) emulsion and to observe their effects on emulsion stability, cooking loss and the textural properties of a cooked meat emulsion. Significant interactions between SPI and CR increased the cooking loss in the meat emulsion. In contrast, IN showed interactions with SPI leading to a reduction in cooking loss. Thus, CR was also removed from the formulation. After optimization, the level of SPI (4.48% w/w) and IN (14% w/w) was validated, leading to a perilla-canola oil (o/w) emulsion with the ability to replace animal fat in an emulsion-type meat products. PMID- 30018502 TI - Antioxidant and Antimicrobial Efficacy of Sapota Powder in Pork Patties Stored under Different Packaging Conditions. AB - The present study was undertaken to assess the efficacy of sapota powder (SP) as natural preservatives and its better utilization in food processing with the incorporation of various levels of SP (2, 4, and 6%) by replacing lean meat. Based on the sensory attributes, pork patties with 4% incorporation of SP was found optimum and selected for further storage studies with control under aerobic and modified atmosphere packaging at refrigeration temperature (4+/-1 degrees C) for 42 days for assessing its antioxidant and antimicrobial efficiency. During entire storage period, indicators of lipid oxidative parameters such as thiobarbituric acid reactive substances (TBARS), free fatty acids (FFA) and peroxide value (PV) followed an increasing trend for control as well as treated products; however, treated product showed a significantly (p<0.05) lower value than control. A significantly lower (p<0.05) microbial count in treated patties than control was noted during entire storage. The sensory attributes are better retained in treated product as compared to control and even on 42nd day, overall acceptability of treated patties was found to fall in moderately acceptable category (5.95 in aerobic packets and 5.91 in modified atmosphere packets). Therefore SP has potential to enhance antioxidant and antimicrobial properties of pork patties during storage. PMID- 30018503 TI - Comparison of Marbling Fleck Characteristics and Objective Tenderness Parameters with Different Marbling Coarseness within Longissimus thoracis Muscle of High marbled Hanwoo Steer. AB - It is important to understand how marbling traits and tenderness differ among beef steaks from the carcass grading site and other regions within the longissimus thoracis (LT) muscle, as these characteristics are closely associated with consumer acceptability and willingness to purchase. Thus, the aim of this study was to compare the marbling fleck traits and objective tenderness parameters in the groups classified by the coarseness index (CI) of marbling fleck (high and low groups) at the carcass grading site (13th thoracic vertebra; 13T) and three different locations (13T, 9T, and 6T) within the LT muscle from well-marbled (marbling score 7 to 9) Hanwoo steer. Image analysis showed that the longitudinal locations had a significant effect on marbling fleck traits. The total area of large marbling fleck divided by the total marbling area (coarseness) was higher at the central region (13T to 12T) compared to the front thoracic region (6T to 5T) in the high CI group (0.23 vs. 0.17, p<0.05), whereas no significant differences were observed in the total number of marbling fleck within the LT muscle in the high or low CI groups (p>0.05). Location effect on objective tenderness parameters within the LT muscle was somewhat limited, although the high CI group had a lower Warner-Bratzler shear force (WBS) value than did the low group (p<0.05). Taken together, the degree of coarseness of marbling fleck decreased from the carcass grading site to the front thoracic site, whereas the objective tenderness parameters, including WBS and hardness, of the grading site did not differ from the other regions within the LT muscle. PMID- 30018504 TI - The Functional Properties of Preserved Eggs: From Anti-cancer and Anti inflammatory Aspects. AB - Preserved egg, a kind of alkaline-fermented food, is a traditional egg product in China. Here, we investigated the nutritional functions of preserved eggs by in vivo and in vitro experiments. The results of in vivo studies showed that the levels of triglycerides (TG), total cholesterol (TCHO) and low-density lipoprotein cholesterol/high density lipoprotein cholesterol (LDL-C/HDL-C) were significantly decreased (p<0.05) in the liver of rats treated with preserved eggs. Meanwhile, the levels of two important cancer markers, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were also significantly decreased (p<0.05) in treated rats. In vitro studies were performed on Caco-2 cells, a human epithelial colorectal adenocarcinoma cell line. It demonstrated that the gastrointestinal (GI) digests of preserved eggs significantly accelerated (p<0.05) the apoptosis by upregulating caspase-3 in the Caco-2 cells. Besides, after treated with preserved eggs, the half maximal inhibitory concentration (IC50) of preserved eggs digests to Caco-2 cells was 5.75 mg/mL, indicating the significant inhibition of cell proliferation provided by preserved eggs (p<0.05). The results shown in this study demonstrated that preserved eggs may be a novel functional food involved with antilipemic, anti-inflammatory activity as well as the effect on accelarating the apoptosis of Caco-2 cells. PMID- 30018505 TI - Investigating Meat Quality of Broiler Chickens Fed on Heat Processed Diets Containing Corn Distillers Dried Grains with Solubles. AB - The present study investigated the effects of feed form and distiller's dried grain with solubles (DDGS) on meat quality and fatty acids profile of broiler chickens. A total of 720 broilers (Ross 308; average BW [body weight] 541+/-5.7 g) were randomly allotted to six treatments. Birds were fed three different feed forms (mash; SP, simple pellet; EP, expanded pellet) and DDGS (0 or 200 g kg-1) in a 3*2 factorial arrangement. The addition of DDGS and EP to the diet resulted in increased shear force of breast meat. Moreover, DDGS inclusion in the diet reduced the concentration of stearic acid and behenic acid in thigh meat. Pelleting (SP and EP) of the diets increased palmitic acid content in the thigh, whereas the linolenic acid content decreased. The breast mass was higher with EP and SP diets than with the mash diet. Feed processing led to increased pectoralis muscle and drum mass compared to mash-fed chickens. In conclusion, our results demonstrated that EP decreased thigh linolenic acid and meat shear force. In addition, DDGS supplementation in broiler hampers meat quality by increasing the shear force. PMID- 30018507 TI - Genera of the Protura of the World: diagnosis, distribution, and key. AB - Protura are known all over the world with more than 800 described species belonging to three different orders (Acerentomata, Sinentomata, and Eosentomata) and seven families (Hesperentomidae, Protentomidae, Acerentomidae, Fujientomidae, Sinentomidae, Eosentomidae, and Antelientomidae). At present 76 genera are known worldwide. In this paper a description of the diagnostic characters of these genera and an updated key for their identification are reported. PMID- 30018506 TI - Optimization of Processing Conditions of Chinese Smoke-cured Bacon (Larou) with a New Natural Coating Solution during Storage Period. AB - The study aims to determine the optimum sterilization rate and water activity of Chinese traditional smoke-cured bacon product (Larou) in the preservation with natural coating solution. With the response surface methodology (RSM), we analyzed 3 factors of processing conditions (the concentration of lysozyme, concentration of sodium alginate, and concentration of chitosan) and 2 response factors (sterilization rate and water activity). Sterilization rate and water activity of Larou were largely affected by the concentration of lysozyme, concentration of sodium alginate, and concentration of chitosan. The final optimum concentrations of lysozyme, sodium alginate, and chitosan were 0.09, 1.40, and 1.60% and realized the high sterilization rate. Water activity of sliced Larou was significantly correlated with the sterilization rate. Low-field nuclear magnetic resonance analysis verified the optimum processing conditions. The coating resulted in 99.69% rate of reducing bacteria after 30-day storage. The data of the total number of colony, peroxidation value, moisture content, pH, and sensory evaluation provided the theoretical basis for extending the shelf life of Chinese traditional smoke-cured bacon product (Larou) with natural coating solution. PMID- 30018508 TI - Updated list of the insect parasitoids (Insecta, Hymenoptera) associated with Lobesia botrana (Denis & Schiffermuller, 1775) (Lepidoptera, Tortricidae) in Italy. 2. Hymenoptera, Ichneumonidae, Anomaloninae and Campopleginae. AB - In this second review of the parasitoids recorded on Lobesia botrana (EGVM) in Italy, an updated list and summary of the information available on 14 taxa of Ichneumonidae belonging to the subfamilies Anomaloninae and Campopleginae are provided. For each taxon, geographic distributions, host ranges, ecological role in viticulture and/or in other crops, and taxonomy are provided and discussed. For the most interesting species, tables summarizing the parasitization rates recorded in the field on EGVM or other lepidopteran pests are given. Identification mistakes and wrong synonymies that have generated great confusion and often made geographic distributions and host ranges unreliable are highlighted. A list of four Anomaloninae and 27 Campopleginae recorded on EGVM in Europe is also provided. Among the species examined, Campoplex capitator Aubert is the only potential candidate for biological control of EGVM. PMID- 30018509 TI - New species and records of Sericini scarab beetles from the Indian subcontinent (Coleoptera, Scarabaeidae). AB - The current paper presents new locality records, including first state records for Mizoram, of 92 species of Sericini (Coleoptera: Scarabaeidae: Melolonthinae) from the Indian subcontinent. Eight new species are described herein: Maladera alloservitritasp. n., M. kolasibensissp. n., M. mizoramensissp. n., Neoserica radhanagariensissp. n., Serica (s. str.) basantapurensis sp. n., S. (s. str.) mahakaliensis sp. n., S. (s. str.) therathumensis sp. n., and S. (s. str.) zianii sp. n. PMID- 30018510 TI - A contribution to Dongodytes (s. str.) Deuve, 1993 (Coleoptera, Carabidae, Trechinae). AB - The hypogean genus Dongodytes Deuve, 1993, one of the most cave-adapted genera of ground beetles, is distributed in northern Guangxi, ranging from Mashan through Du'an, Bama, and Fengshan to Tian'e. Review of nominate subgenus Dongodytes Deuve, 1993, with new records for D. fowleri Deuve, 1993 and D. grandis Ueno, 1998 are provided. Meanwhile, Dongodytes tonywhittenisp. n. is described from a limestone cave in Bama County. This interesting species is dedicated to the late Dr. Tony Whitten, a well-known cave biodiversity conservationist in Asia. A key to all species of Dongodytes (s. str.) is also provided. PMID- 30018511 TI - Three new species of Argyra from China (Diptera, Dolichopodidae, Diaphorinae). AB - Previously, there were ten known species in the genus Argyra Macquart from China. In this paper, the following three species from Sichuan Province of China are described as new to science: Argyra longicornissp. n., Argyra pingwuensissp. n. and Argyra sichuanensissp. n. A key to the known species of Argyra from China is provided. PMID- 30018512 TI - Review of the Japanese records of an endangered grouper, Epinephelus tukula, with comments on its population status (Teleostei, Serranidae). AB - The Potato Grouper, Epinephelus tukula, is relatively rare worldwide. Records from the northernmost part of its range (Japan) have been few, resulting in a "Critically Endangered" listing on the Red List for Japan. The Japanese records were revised by examining literature, new specimens, photographs, and the internet, and a continuous distribution pattern from the tropical Ryukyu Islands (including adult individuals) to temperate regions affected by the Kuroshio Current were delineated; this suggests the species inhabits tropical Japan and can spread to temperate regions via the warm current. The species possibly reproduces in Japanese waters but further reproductive ecology research is required. PMID- 30018513 TI - Presurgical Identification of Uterine Smooth Muscle Malignancies through the Characteristic FDG Uptake Pattern on PET Scans. AB - The unidentified presence of uterine smooth muscle malignancies poses a tremendous risk in women planning surgery for presumed benign leiomyomas. We sought to investigate whether preoperative FDG PET may be useful to identify leiomyosarcomas (LMS) and smooth muscle tumors of uncertain malignant potential (STUMP). Methods. We investigated patients with rapidly growing uterine masses which were suspected of being malignant on ultrasound or MRI. Among the 21 patients who underwent FDG PET, we identified 7 LMS, 1 STUMP, and 13 leiomyomas. PET-derived parameters and FDG uptake patterns were analyzed retrospectively. Results. The SUVmax values of LMS/STUMP (range: 3.7-11.8) were significantly higher than those observed in leiomyomas (range: 2.0-9.4; P=0.003) despite a significant overlap. The metabolic tumor/necrosis ratio was significantly higher in LMS/STUMP than in leiomyomas (P < 0.001), with no significant intergroup overlaps. All LMS/STUMP revealed a characteristic pattern of FDG uptake, identifying a specific "hollow ball" sign (corresponding to areas of coagulative tumor necrosis). In contrast, this sign was invariably absent in patients with leiomyomas. Conclusion. The characteristic FDG uptake pattern instead of SUV on PET images allows identifying LMS/STUMP in patients with rapidly growing uterine masses, avoiding the deleterious consequences of regular surgery for presumed benign leiomyomas. PMID- 30018514 TI - Radiotherapy of Glioblastoma 15 Years after the Landmark Stupp's Trial: More Controversies than Standards? AB - Background: The current standard of care of glioblastoma, the most common primary brain tumor in adults, has remained unchanged for over a decade. Nevertheless, some improvements in patient outcomes have occurred as a consequence of modern surgery, improved radiotherapy and up-to-date management of toxicity. Patients from control arms (receiving standard concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide) of recent clinical trials achieve better outcomes compared to the median survival of 14.6 months reported in Stupp's landmark clinical trial in 2005. The approach to radiotherapy that emerged from Stupp's trial, which continues to be a basis for the current standard of care, is no longer applicable and there is a need to develop updated guidelines for radiotherapy within the daily clinical practice that address or at least acknowledge existing controversies in the planning of radiotherapy.The goal of this review is to provoke critical thinking about potentially controversial aspects in the radiotherapy of glioblastoma, including among others the issue of target definitions, simultaneously integrated boost technique, and hippocampal sparing. Conclusions: In conjunction with new treatment approaches such as tumor treating fields (TTF) and immunotherapy, the role of adjuvant radiotherapy will be further defined. The personalized approach in daily radiotherapy practice is enabled with modern radiotherapy systems. PMID- 30018515 TI - Ultrasound Elastography can Detect Placental Tissue Abnormalities. AB - Background: In this prospective cohort study, we examined the utility of elastography to evaluate the fetus and placenta. Patients and methods: Pregnant women in their third trimester of pregnancy, by which time the placenta has formed, were included in this study. A total of 111 women underwent ultrasound examinations, including elastography. Elastographic evaluation was performed using two protocols. First, the placental index (PI) was measured, which quantitatively assesses the hardness of tissue. Second, regions of interest (ROI) were categorized into 3-step scores according to the frequency of the blue area (hardness of placental tissue score [HT score]), which is a qualitative method. After delivery, 40 of the 111 placentas were pathologically examined. Results: The average PI was 44.3 (+/- 29.4) in the in utero SGA group, which was significantly higher than that in the normal group (8.8 (+/- 10.0); p < 0.01) during pregnancy. There was a significant correlation between the PI and z score for estimated fetal weight (EFW) (r = -0.55; p < 0.01). Moreover, a significant positive correlation was observed between the PI and the z score of birth weight (r = -0.39; p < 0.01). Pathological ischemia findings of the placenta were identified in 67% of the HT score 3 group, representing 6 of the 9 patients, and in 20% of the HT score 1 group, representing only 3 of the 15 patients. Conclusions: Placental hardness, as determined by elastography, correlates with both lower estimated fetal body weight and birth weight. These results suggest that ultrasound elastography in the placenta may be an additional marker of intrauterine fetal well-being. PMID- 30018516 TI - Is Carotid Stiffness a Possible Surrogate for Stroke in Long-term Survivors of Childhood Cancer after Neck Radiotherapy? AB - Background: The risk for cerebrovascular late effects among childhood cancer survivors is considerable. According to recent studies it is not clear which marker could be reliable for the screening of cerebrovascular diseases among the long-term survivors of childhood cancer. The purpose of this study is to analyse arterial stiffness and intima-media thickness as possible early markers of later occurring stroke in long-term survivors of childhood cancer after neck radiotherapy. Patients and methods: Twenty-three patients, treated for Hodgkin disease (HD) in childhood, were included. They had received radiation therapy to the neck with 20-65 (median 30) Gy. Twenty-six healthy controls, matched in age, sex, body mass index, arterial hypertension, smoking history and total cholesterol levels were compared. Highresolution colour-coded duplex sonography and power Doppler sonography of the carotid arteries were performed and intima media thickness, number and quality of plaques were measured. Arterial stiffness indices were calculated. Results: Plaque deposits and/or arterial wall calcinations were found in 24 out of 43 (55.8%) irradiated vessels in cancer survivors group and 0 out of 52 vessels in the group of healthy controls (p < 0.01). We found significant group differences for all the stiffness parameters we used (P < 0.05), but there was no difference in intima-media thickness between cases and controls (p = 0.92). In a multivariate model, carotid pulse wave velocity was positively associated with smoking. Conclusions: The arterial stiffness has appeared as a possible surrogate marker for stroke in long-term survivors of childhood cancer. Smoking habit might have an additional negative influence on vascular aging in the group of patients after neck radiotherapy. PMID- 30018517 TI - Perfusion Magnetic Resonance Imaging Changes in Normal Appearing Brain Tissue after Radiotherapy in Glioblastoma Patients may Confound Longitudinal Evaluation of Treatment Response. AB - Background: The aim of this study was assess acute and early delayed radiation induced changes in normal-appearing brain tissue perfusion as measured with perfusion magnetic resonance imaging (MRI) and the dependence of these changes on the fractionated radiotherapy (FRT) dose level. Patients and methods: Seventeen patients with glioma WHO grade III-IV treated with FRT were included in this prospective study, seven were excluded because of inconsistent FRT protocol or missing examinations. Dynamic susceptibility contrast MRI and contrast-enhanced 3D-T1-weighted (3D-T1w) images were acquired prior to and in average (standard deviation): 3.1 (3.3), 34.4 (9.5) and 103.3 (12.9) days after FRT. Pre-FRT 3D-T1w images were segmented into white- and grey matter. Cerebral blood volume (CBV) and cerebral blood flow (CBF) maps were calculated and co-registered patient-wise to pre-FRT 3D-T1w images. Seven radiation dose regions were created for each tissue type: 0-5 Gy, 5-10 Gy, 10-20 Gy, 20-30 Gy, 30-40 Gy, 40-50 Gy and 50-60 Gy. Mean CBV and CBF were calculated in each dose region and normalised (nCBV and nCBF) to the mean CBV and CBF in 0-5 Gy white- and grey matter reference regions, respectively. Results: Regional and global nCBV and nCBF in white- and grey matter decreased after FRT, followed by a tendency to recover. The response of nCBV and nCBF was dose-dependent in white matter but not in grey matter. Conclusions: Our data suggest that radiation-induced perfusion changes occur in normal-appearing brain tissue after FRT. This can cause an overestimation of relative tumour perfusion using dynamic susceptibility contrast MRI, and can thus confound tumour treatment evaluation. PMID- 30018518 TI - In Silico Selection Approach to Develop DNA Aptamers for a Stem-like Cell Subpopulation of Non-small Lung Cancer Adenocarcinoma Cell Line A549. AB - Background: Detection of circulating lung cancer cells with cancer-stem like characteristics would represent an improved tool for disease prognosis. However, current antibodies based methods have some disadvantages and therefore cell SELEX (Systematic Evolution of Ligands by Exponential Enrichment) was used to develop DNA aptamers, recognizing cell surface markers of non-small lung carcinoma (NSLC) cells. Materials and methods: The human adenocarcinoma cell line A549 was used for selection in seven cell SELEX cycles. We used human blood leukocytes for negative selection, and lung stem cell protein marker CD90 antibody binding A549 cells for positive selection. Results: The obtained oligonucleotide sequences after the seventh SELEX cycle were subjected to in silico selection analysis based on three independent types of bioinformatics approaches, selecting two closely related aptamer candidates in terms of consensus sequences, structural motifs, binding affinity (Kd) and stability (DeltaG). We selected and identified the aptamer A155_18 with very good binding characteristics to A459 cells, selected for CD90 antibody binding. The calculated phylogenetic tree showed that aptamers A155_18 and the known A549 cell aptamer S6 have a close structural relationship. MEME sequence analysis showed that they share two unique motifs, not present in other sequences. Conclusions: The novel aptamer A155_18 has strong binding affinity for A549 lung carcinoma cell line subpopulation that is expressing stem cell marker CD90, indicating a possible stemness, characteristic for the A459 line, or a subpopulation present within this cell line. This aptamer can be applied as diagnostic tool, identifying NSLC circulating cells. PMID- 30018519 TI - Matrix Metalloproteinases Polymorphisms as Baseline Risk Predictors in Malignant Pleural Mesothelioma. AB - Background: Malignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases. Matrix metalloproteinases (MMPs) have been identified as modulators of the tumour microenvironment and carcinogenesis. Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM. The aim of our study was to investigate selected MMP polymorphisms as baseline risk predictors in MM development in combination with other well known risk factors, such as asbestos exposure. Patients and methods: The study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%-75%), while frequencies were used to describe categorical variables. Deviation from the Hardy Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Results: Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44-1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35-0.86; P = 0.009). None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma. Conclusions: The MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction. PMID- 30018520 TI - Glioblastoma in Patients over 70 Years of Age. AB - Background: Glioblastoma has in last 20 years seen the steady increase of incidence, which is most prominent in the group of older patients. These older than 70 years have significantly poorer prognosis than other patients and are considered a distinct group of glioblastoma patients. Modified prognostic factors are being used in these patients and this information is lately supplemented with the genetic and epigenetic information on tumour. The therapy is now often tailored accordingly. The aim of our study was to analyse the current treatment of the glioblastoma patients over 70 years of age to determine the impact of clinical prognostic factors. Patients and methods: Among patients treated at the Institute of Oncology Ljubljana between 1997 and 2015, we found that 207 were older than 70 years. We analysed their survival, clinical prognostic factors (age, performance status) treatment modalities (extent of surgery, radiation dose, chemotherapy). Results: Median survival of patients older than 70 years was 5.3 months which was statistically significant inferior to the survival of younger patients (p < 0.001). The clinical prognostic factors that influenced survival the most were performance status (p < 0.001), extent of surgical resection (p < 0.001), addition of temozolomide (p < 0.001) and addition of radiotherapy (p = 0.006). Patients receiving concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide, had same median survival as patients receiving adjuvant temozolomide after completion of radiotherapy. Conclusions: The increase of the number of older patients with glioblastoma corresponds to the increase in the life expectancy but in Slovenia also to the increased availability of diagnostic procedures. Clinical prognostic markers are helpful in decision on the aggressiveness of treatment. Radiotherapy and temozolomide have the biggest impact on survival, but the radiotherapy dose seems to be of secondary importance. In selected patients, chemotherapy alone might be sufficient to achieve an optimal effect. Patients that were fitter, had more aggressive surgery, and received temozolomide fared the best. The scheduling of the temozolomide seems to have limited impact on survival as in our study, there was no difference weather patients received temozolomide concomitant with radiotherapy or after the radiotherapy. Thus far, our findings corroborate the usefulness of recursive partitioning analysis (RPA) classes in clinical decisions. PMID- 30018521 TI - Comparative Analysis of Clinical and Pathological Lymph Node Staging Data in Head and Neck Squamous Cell Carcinoma Patients Treated at the General Hospital Vienna. AB - Background: Results from publications evaluating discrepancies between clinical staging data in relation to pathological findings demonstrate that a significant number of head and neck squamous cell carcinoma (HNSCC) patients are not correctly staged. The aim of this retrospective study was to analyze potential discrepancies of radiological assessment versus pathological data of regional lymph node involvement and to compare the results with data published in the literature. Patients and methods: In a retrospective analysis we focused on patients with HNSCC routinely treated by surgery plus postoperative radiotherapy between 2002 and 2012. For inclusion, complete pre-operative clinical staging information with lymph node status and patho-histological information on involved lymph node regions as well as survival outcome data were mandatory. We included 87 patients (UICC stage III-IV 90.8%) for which the aforementioned data obtained by CT or MRI were available. Overall survival rates were estimated by the Kaplan Meier method. The Pearson correlation coefficient and Spearman's rank correlation coefficient (non-linear relationship) was calculated. Results: Discrepancies at the level of overall tumour stage assessment were noticed in 27.5% of all cases. Thereof, 5.7% were assigned to patho-histological up-staging or down-staging of the primary tumour. At the lymph node level, 11.5% of the patients were downstaged, and 10.3% were upstaged. Conclusions: The study showed that in approximately one-fifth (21.8%) of the patients, lymph node assessment by CT or MRI differs from the pathologic staging, an outcome that corresponds well with those published by several other groups in this field. PMID- 30018522 TI - A Population-based Study of the Effectiveness of Stereotactic Ablative Radiotherapy Versus Conventional Fractionated Radiotherapy for Clinical Stage I Non-small Cell Lung Cancer Patients. AB - Background: Stereotactic ablative radiotherapy (SABR) is a promising option for non-operated early-stage non-small cell lung cancer (NSCLC) compared to conventional fractionated radiotherapy (CFRT). However, results from conclusive randomized controlled trials are not yet available. The aim of our study was to explore the effectiveness of SABR vs. CFRT for non-operated early-stage NSCLC. Patients and methods: We used a comprehensive population-based database to identify clinical stage I non-operated NSCLC patients in Taiwan diagnosed from 2007 to 2013 who were treated with either SABR or CFRT. We used inverse probability weighting and the propensity score as the primary form of analysis to address the nonrandomization of treatment. In the supplementary analyses, we constructed subgroups based on propensity score matching to compare survival between patients treated with SABR vs. CFRT. Results: We identified 238 patients in our primary analysis. A good balance of covariates was achieved using the propensity score weighting. Overall survival (OS) was not significantly different between those treated with SABR vs. CFRT (SABR vs. CFRT: probability weighting adjusted hazard ratio [HR] 0.586, 95% confidence interval 0.264-1.101, p = 0.102). However, SABR was significantly favored in supplementary analyses. Conclusions: In this population-based propensity-score adjusted analysis, we found that OS was not significantly different between those treated with SABR vs. CFRT in the primary analysis, although significance was observed in the supplementary analyses. Our results should be interpreted with caution given the database (i.e., nonrandomized) approach used in our study. Overall, further studies are required to explore these issues. PMID- 30018523 TI - Survival and Stability of Patients with Urothelial Cancer and Spinal Bone Metastases after Palliative Radiotherapy. AB - Background: The aim of the study was to analyze survival and stability of patients with urothelial cell cancer and spinal bone metastases (SBM) after radiotherapy (RT). Furthermore, to assess the effects of RT on bone mineral density (BMD) as a local response in SBM after RT. Patients and methods: Survival of 38 patients with 132 SBM from urothelial cancer, treated from January 2000 to January 2012, was calculated. Stability of irradiated thoracic and lumbar SBM was retrospectively evaluated in computed tomography (CT) scans using the validated Taneichi et al. score. Difference in BMD, measured in Hounsfield units (HU), of the SBM before and at 3 and 6 months after RT was analyzed. Results: All patients died during follow-up. Overall survival (OS) after 6 months, 1 year and 2 years was 90%, 80% and 40%, respectively. Bone survival (BS) was 85%, 64% and 23% after 6 months, 1 year and 2 years, respectively. Survival from start of RT (RTS) was 42% after 6 months, 18% after 1 year and 5% after 2 years. Only 11% received bisphosphonates. Stability did not improve at 3 or 6 months after RT. BMD increased by 25.0 HU +/- 49.7 SD after 3 months (p = 0.001) and by 24.2 HU +/- 52.2 SD after 6 months (p = 0.037). Pain relief (> 2 points on the visual analogue scale) was achieved in only 27% of patients. Conclusions: Benefit from palliative RT of painful or unstable SBM is limited in these patients and they should be carefully selected for RT. Shorter fractionation schedules may be preferred and outcome may improve with concomitant bisphosphonates. PMID- 30018524 TI - Prognostic Value of Plasma EBV DNA for Nasopharyngeal Cancer Patients during Treatment with Intensity-modulated Radiation Therapy and Concurrent Chemotherapy. AB - Background: Plasma EBV DNA concentrations at the time of diagnosis (pre-EBV) and post treatment (post-EBV) have significant value for predicting the clinical outcome of nasopharyngeal cancer (NPC) patients. However, the prognostic value of the EBV concentration during radiation therapy (mid-EBV) has not been vigorously studied. Patients and methods: This was a post hoc analysis of 105 detectable pre EBV NPC patients from a phase II/III study comparing sequential (SEQ) versus simultaneous integrated boost (SIB) intensity-modulated radiation therapy (IMRT). Plasma EBV DNA concentrations were measured by PCR before commencement of IMRT, at the 5th week of radiation therapy and 3 months after the completion of IMRT. The objective was to identify the prognostic value of mid-EBV to predict overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). Results: A median pre-EBV was 6880 copies/ml. Mid-EBV and post EBV were detectable in 14.3% and 6.7% of the patients, respectively. The median follow-up time was 45.3 months. The 3-year OS, PFS and DMFS rates were 86.0% vs. 66.7% (p = 0.043), 81.5% vs. 52.5% (p = 0.006), 86.1% vs. 76.6% (p = 0.150), respectively, for those with undetectable mid-EBV vs. persistently detectable mid EBV. However, in the multivariate analysis, only persistently detectable post-EBV was significantly associated with a worse OS (hazard ratio (HR) = 6.881, 95% confident interval (CI) 1.699-27.867, p = 0.007), PFS (HR = 5.117, 95% CI 1.562 16.768, p = 0.007) and DMFS (HR = 129.071, 95%CI 19.031-875.364, p < 0.001). Conclusions: Detectable post-EBV was the most powerful adverse prognostic factor for OS, PFS and DMFS; however, detectable mid-EBV was associated with worse OS, PFS especially Local-PFS (LPFS) and may facilitate adaptive treatment during the radiation treatment period. PMID- 30018525 TI - Early Cardiotoxicity after Adjuvant Concomitant Treatment with Radiotherapy and Trastuzumab in Patients with Breast Cancer. AB - Background: The purpose of the study was to find out whether there is a difference in the early parameters of cardiotoxicity (left ventricular ejection fraction [LVEF] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) between the two groups of patients: the patients treated for left breast cancer (left breast cancer group) and those treated for the right breast cancer (right breast cancer group), after the treatment had been completed. Patients and methods: The study included 175 consecutive patients with human epidermal growth factor receptor-2 (HER2) positive early breast cancer, treated concurrently with trastuzumab and radiotherapy (RT), between June 2005 and December 2010. Echocardiography with LVEF measurement was performed before adjuvant RT (LVEF0) and after the completed treatment (LVEF1,). After the treatment NT-proBNP measurement was done as well. The difference (Delta) between LVEF0 and LVEF1 was analysed (Delta LVEF = LVEF0 - LVEF1) and compared between the two groups. Results: There were 84 patients in the left and 91 in the right breast cancer group. Median observation time was 57 (37-71) months. Mean Delta LVEF (%) was 1.786% in the left and -2.607% in the right breast cancer group (p = 0.562, CI: 2.004 to 3.648). Median NT-proBNP were 111.0 ng/l in the left and 90.0 ng/l in the right breast cancer group (p = 0.545). Echocardiography showed that the patients in the left breast cancer group did not have significantly worse systolic and diastolic left ventricular function in comparison with the patients in the right breast cancer group, but, they had higher incidence of pericardial effusion (9 [11%] vs. 1 [1%]) (p = 0.007). Conclusions: We did not find any significant differences in the early parameters of cardiotoxicity (LVEF, NT proBNP) between the observed groups. Patients who received left breast/chest wall irradiation had higher incidence of pericardial effusion. PMID- 30018526 TI - Ocular Changes in Metastatic Melanoma Patients Treated with MEK Inhibitor Cobimetinib and BRAF Inhibitor Vemurafenib. AB - Background: Mitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combination with vemurafenib. Patients and methods: In the prospective, observational study, patients with BRAF-mutated metastatic melanoma treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to participate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT). Results: Five out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid macular edema. Conclusions: Multiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, including the discontinuance of a potentially life-prolonging therapy. PMID- 30018527 TI - Sclerosing Melanocytic Lesions (sclerosing Melanomas with Nevoid Features and Sclerosing Nevi with Pseudomelanomatous Features) - An Analysis of 90 Lesions. AB - Background: Sclerosing melanocytic lesions, which are characterized by either focal or diffuse sclerosis in the dermal component and atypical proliferation of predominantly nevoid melanocytes, remain poorly defined. Our aim was to analyze systematically their morphologic spectrum, especially the distinction between sclerosing melanocytic nevus and sclerosing melanoma, which has not been well documented. Patients and methods: We collected 90 sclerosing melanocytic lesions, occurring in 82 patients (49 male, 33 female; age range from 21 to 89 years). A four probe fluorescent in situ hybridization (FISH) assay was performed in 41 lesions to substantiate the diagnosis of sclerosing melanomas. Results: A prominent full-thickness pagetoid spread of melanocytes was identified in 44 (48%) lesions, and a melanoma in situ adjacent to the sclerosis in 55 (61%) lesions. In the intrasclerotic component, maturation was absent in 40 (44%) and mitotic figures were identified in 18 (20%) lesions. Of the 90 lesions, 26 (29%) were diagnosed morphologically as nevi and 64 (71%) as melanomas (Breslow thickness from 0.4 to 1.8 mm), including 45 (50%) melanomas with an adjacent nevus. A four-probe FISH assay was positive in the sclerotic component in 14 of 25 lesions diagnosed morphologically as melanomas and none of 16 nevi. A sentinel lymph node biopsy was performed for 17 lesions and was negative in all cases. Conclusions: Sclerosing melanocytic lesions form a morphologic spectrum and include both nevi and melanomas. The pathogenesis of sclerosis remains obscure but seems to be induced by melanocytes or an unusual host response in at least a subset of lesions. PMID- 30018528 TI - An Evaluation of the ICON(r) Mask Fixation: Curing Characteristics of the Thermoplastic Fixation and Implications for Patient Workflow. AB - Background: Thermoplastic mask immobilization is used to perform hypo fractionated treatments with the Gamma Knife ICON(r). Materials and methods: We evaluated the curing characteristics of the ICON(r) Nanor mask using force sensing resistors coupled with a data logging tool designed by us. Results: For patients being treated with masks made the same day as the treatment, often in the same sitting with no removal and replacement of the patient from the treatment cradle, based on the curves 80% of the force of fixation is reached at 30 minutes. Conclusions: Allowing for curing over 10-15 minutes and the subsequent localizing and delivery Cone beam CT (CBCT)s as well as the plan evaluation this is a reasonable time to start of therapy. For more exacting targets that are still requiring hypo-fractionation a cure period of 15 hours or greater will ensure that maximum rigidity of fixation is achieved. PMID- 30018529 TI - From ERPs to MVPA Using the Amsterdam Decoding and Modeling Toolbox (ADAM). AB - In recent years, time-resolved multivariate pattern analysis (MVPA) has gained much popularity in the analysis of electroencephalography (EEG) and magnetoencephalography (MEG) data. However, MVPA may appear daunting to those who have been applying traditional analyses using event-related potentials (ERPs) or event-related fields (ERFs). To ease this transition, we recently developed the Amsterdam Decoding and Modeling (ADAM) toolbox in MATLAB. ADAM is an entry-level toolbox that allows a direct comparison of ERP/ERF results to MVPA results using any dataset in standard EEGLAB or Fieldtrip format. The toolbox performs and visualizes multiple-comparison corrected group decoding and forward encoding results in a variety of ways, such as classifier performance across time, temporal generalization (time-by-time) matrices of classifier performance, channel tuning functions (CTFs) and topographical maps of (forward-transformed) classifier weights. All analyses can be performed directly on raw data or can be preceded by a time-frequency decomposition of the data in which case the analyses are performed separately on different frequency bands. The figures ADAM produces are publication-ready. In the current manuscript, we provide a cookbook in which we apply a decoding analysis to a publicly available MEG/EEG dataset involving the perception of famous, non-famous and scrambled faces. The manuscript covers the steps involved in single subject analysis and shows how to perform and visualize a subsequent group-level statistical analysis. The processing pipeline covers computation and visualization of group ERPs, ERP difference waves, as well as MVPA decoding results. It ends with a comparison of the differences and similarities between EEG and MEG decoding results. The manuscript has a level of description that allows application of these analyses to any dataset in EEGLAB or Fieldtrip format. PMID- 30018530 TI - No Differential Effects of Two Different Alpha-Band Electrical Stimulation Protocols Over Fronto-Parietal Regions on Spatial Attention. AB - In a previous study using transcranial alternating current stimulation (tACS), we found preliminary evidence that phase coherence in the alpha band (8-12 Hz) within the fronto-parietal network may critically support top-down control of spatial attention (van Schouwenburg et al., 2017). Specifically, synchronous alpha-band stimulation over the right frontal and parietal cortex (0 degrees relative phase) was associated with changes in performance and fronto-parietal coherence during a spatial attention task as compared to sham stimulation. In the current study, we firstly aimed to replicate these findings with synchronous tACS. Second, we extended our previous protocol by adding a second tACS condition in which the right frontal and parietal cortex were stimulated in a desynchronous fashion (180 degrees relative phase), to test the specificity of the changes observed in our previous study. Participants (n = 23) were tested in three different sessions in which they received either synchronous, desynchronous, or sham stimulation over the right frontal and parietal cortex. In contrast to our previous study, we found no spatially selective effects of stimulation on behavior or coherence in either stimulation protocol compared to sham. We highlight some of the differences in study design that may have contributed to this discrepancy in findings and more generally may determine the effectiveness of tACS. PMID- 30018531 TI - Muscle Strength and Neuromuscular Control in Low-Back Pain: Elite Athletes Versus General Population. AB - The purpose of the study was to investigate the athletic-based specificity of muscle strength and neuromuscular control of spine stability in chronic non specific low-back pain (LBP). Thirty elite athletes and 29 age-matched non athletes with (15 athletes and 15 non-athletes) and without LBP (15 athletes and 14 non-athletes) participated in the study. Muscle strength was measured during maximal isometric trunk flexion and trunk extension contractions. The neuromuscular control of spine stability was analyzed by determining trunk stiffness, trunk damping, and onset times of the lumbar and thoracic erector spinae muscles after sudden perturbations (quick release experiments) as well as maximum Lyapunov exponents (local dynamic stability) using non-linear time series analysis of repetitive lifting movements. LBP was assessed using the visual analog scale. We found lower maximal trunk extension moments (p = 0.03), higher trunk damping (p = 0.018) and shorter onset times (p = 0.03) of the investigated trunk muscles in LBP patients in both athletes and non-athletes. Trunk stiffness and the local dynamic stability did not show any differences (p = 0.136 and p = 0.375, respectively) between LBP patients and healthy controls in both groups. It can be concluded that, despite the high-level of training in athletes, both athletes and non-athletes with LBP showed the same deconditioning of the lumbar extensor muscles and developed similar strategies to ensure spine stability after sudden perturbations to protect the spine from pain and damage. The findings highlight that specific training interventions for the trunk muscles are not only crucial for individuals of the general population, but also for well-trained athletes. PMID- 30018532 TI - 5-HT1a Receptor Involvement in Temporal Memory and the Response to Temporal Ambiguity. AB - It has previously been demonstrated that rats trained on the peak-interval procedure to associate two different cues with two different fixed interval schedules will generate a scalar peak function at an intermediate time when presented with the compound cue. This response pattern has been interpreted as resulting from the simultaneous retrieval of different temporal memories, and a consequential averaging process to resolve the ambiguity. In the present set of studies, we investigated the role that serotonin 1a receptors play in this process. In Experiment 1, rats were trained on a peak-interval procedure to associate the interoceptive states induced by saline and the 5-HT1a agonist, 8-OH DPAT, with a 5 s or 20 s fixed-interval schedule signaled by the same tone cue (counter-balanced). While peak functions following administration of saline were centered at the appropriate time (5 s or 20 s), peak functions following administration of the agonist were centered around 7 s, irrespective of the reinforced time during training, suggesting agonist-induced disruption in selective temporal memory retrieval, resulting in increased ambiguity regarding the appropriate time at which to respond. In Experiment 2, rats were trained in a peak-interval procedure to associate a tone cue with a 10 s fixed interval and a light cue with a 20 s fixed interval. Administration of the 5-HT1a antagonist, WAY-100635, had no impact on timing when single cues were presented, but altered the intermediate, scalar, response to the stimulus compound, suggesting antagonist-induced disruption in the processes used to deal with temporal memory ambiguity. Together, these data suggest that manipulations of 5HT transmission at the 5-HT1a receptor cause changes in the temporal pattern of responding that are consistent with alterations in temporal memory processes and responses to temporal ambiguity. PMID- 30018533 TI - Chemical Proteomic Analysis of Serine Hydrolase Activity in Niemann-Pick Type C Mouse Brain. AB - The endocannabinoid system (ECS) is considered to be an endogenous protective system in various neurodegenerative diseases. Niemann-Pick type C (NPC) is a neurodegenerative disease in which the role of the ECS has not been studied yet. Most of the endocannabinoid enzymes are serine hydrolases, which can be studied using activity-based protein profiling (ABPP). Here, we report the serine hydrolase activity in brain proteomes of a NPC mouse model as measured by ABPP. Two ABPP methods are used: a gel-based method and a chemical proteomics method. The activities of the following endocannabinoid enzymes were quantified: diacylglycerol lipase (DAGL) alpha, alpha/beta-hydrolase domain-containing protein 4, alpha/beta-hydrolase domain-containing protein 6, alpha/beta-hydrolase domain-containing protein 12, fatty acid amide hydrolase, and monoacylglycerol lipase. Using the gel-based method, two bands were observed for DAGL alpha. Only the upper band corresponding to this enzyme was significantly decreased in the NPC mouse model. Chemical proteomics showed that three lysosomal serine hydrolase activities (retinoid-inducible serine carboxypeptidase, cathepsin A, and palmitoyl-protein thioesterase 1) were increased in Niemann-Pick C1 protein knockout mouse brain compared to wild-type brain, whereas no difference in endocannabinoid hydrolase activity was observed. We conclude that these targets might be interesting therapeutic targets for future validation studies. PMID- 30018534 TI - Altered Spontaneous Regional Brain Activity in the Insula and Visual Areas of Professional Traditional Chinese Pingju Opera Actors. AB - Recent resting-state fMRI studies have revealed neuroplastic alterations after long-term training. However, the neuroplastic changes that occur in professional traditional Chinese Pingju opera actors remain unclear. Twenty professional traditional Chinese Pingju opera actors and 20 age-, sex-, and handedness-matched laymen were recruited. Resting-state fMRI was obtained by using an echo-planar imaging sequence, and two metrics, amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo), were utilized to assess spontaneous neural activity during resting state. Our results demonstrated that compared with laymen, professional traditional Chinese Pingju actors exhibited significantly decreased ALFF in the bilateral calcarine gyrus and cuneus; decreased ReHo in the bilateral superior occipital and calcarine gyri, cuneus, and right middle occipital gyrus; and increased ReHo in the left anterior insula. In addition, no significant association was found between spontaneous neural activity and Pingju opera training duration. Overall, the changes observed in spontaneous brain activity in professional traditional Chinese Pingju opera actors may indicate their superior performance of multidimensional professional skills, such as music and face perception, dancing, and emotional representation. PMID- 30018535 TI - mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis. AB - A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes. PMID- 30018536 TI - Evolution of Excitation-Inhibition Ratio in Cortical Cultures Exposed to Hypoxia. AB - In the core of a brain infarct, neuronal death occurs within minutes after loss of perfusion. In the penumbra, a surrounding area with some residual perfusion, neurons initially remain structurally intact, but hypoxia-induced synaptic failure impedes neuronal activity. Penumbral activity may recover or further deteriorate, reflecting cell death. Mechanisms leading to either outcome remain ill-understood, but may involve changes in the excitation to inhibition (E/I) ratio. The E/I ratio is determined by structural (relative densities of excitatory and inhibitory synapses) and functional factors (synaptic strengths). Clinical studies demonstrated excitability alterations in regions surrounding the infarct core. These may be related to structural E/I changes, but the effects of hypoxia /ischemia on structural connectivity have not yet been investigated, and the role of structural connectivity changes in excitability alterations remains unclear. We investigated the evolution of the structural E/I ratio and associated network excitability in cortical cultures exposed to severe hypoxia of varying duration. 6-12 h of hypoxia reduced the total synaptic density. In particular, the inhibitory synaptic density dropped significantly, resulting in an elevated E/I ratio. Initially, this does not lead to increased excitability due to hypoxia induced synaptic failure. Increased excitability becomes apparent upon reoxygenation after 6 or 12 h, but not after 24 h. After 24 h of hypoxia, structural patterns of vesicular glutamate stainings change. This possibly reflects disassembly of excitatory synapses, and may account for the irreversible reduction of activity and stimulus responses seen after 24 h. PMID- 30018538 TI - The Drosophila melanogaster Na+/Ca2+ Exchanger CALX Controls the Ca2+ Level in Olfactory Sensory Neurons at Rest and After Odorant Receptor Activation. AB - CALX, the Na+/Ca2+ exchanger in Drosophila, is highly expressed in the outer dendrites of olfactory sensory neurons (OSNs) which are equipped with the odorant receptors (ORs). Insect OR/Orco dimers are nonselective cation channels that pass also calcium which leads to elevated calcium levels after OR activation. CALX exhibits an anomalous regulation in comparison to its homolog in mammals sodium/calcium exchanger, NCX: it is inhibited by increasing intracellular calcium concentration [Ca2+]i. Thus, CALX mediates only Ca2+ efflux, not influx. The main goal of this study was to elucidate a possible role of this protein in the olfactory response. We first asked whether already described NCX inhibitors were capable of blocking CALX. By means of calcium imaging techniques in ex-vivo preparations and heterologous expression systems, we determined ORM-10962 as a potent CALX inhibitor. CALX inhibition did not affect the odor response but it affected the recovery of the calcium level after this response. In addition, CALX controls the calcium level of OSNs at rest. PMID- 30018537 TI - Autophagic Degradation Deficit Involved in Sevoflurane-Induced Amyloid Pathology and Spatial Learning Impairment in APP/PS1 Transgenic Mice. AB - The adverse effects of anesthetics on elderly people, especially those with brain diseases are very concerning. Whether inhaled anesthetics have adverse effects on Alzheimer's disease (AD), which is the most common form of dementia with brain degenerative changes, remains controversial. Autophagy, a crucial biological degradation process, is extremely important for the pathogenesis of AD. In this study, the inhaled anesthetic sevoflurane elicited many enlarged autolysosomes and impaired the overall autophagic degradation in the hippocampus of an AD mouse model, which is involved in the accumulation of amyloid-beta (Abeta) and spatial learning deficits. However, rapamycin treatment counteracted all these effects. The results suggested that inhaled anesthetics may accelerate the pathological process of AD, and enlarged autolysosomes may be a new marker for prediction and diagnosis of the neurotoxicity of anesthetics in AD. PMID- 30018540 TI - Octopamine Shifts the Behavioral Response From Indecision to Approach or Aversion in Drosophila melanogaster. AB - Animals must make constant decisions whether to respond to external sensory stimuli or not to respond. The activation of positive and/or negative reinforcers might bias the behavioral response towards approach or aversion. To analyze whether the activation of the octopaminergic neurotransmitter system can shift the decision between two identical odor sources, we active in Drosophila melanogaster different sets of octopaminergic neurons using optogenetics and analyze the choice of the flies using a binary odor trap assay. We show that the release of octopamine from a set of neurons and not acetylcholine acts as positive reinforcer for one food odor source resulting in attraction. The activation of a subset of these neurons causes the opposite behavior and results in aversion. This aversion is due to octopamine release and not tyramine, since in Tyramine-beta-hydroxylase mutants (Tbetah) lacking octopamine, the aversion is suppressed. We show that when given the choice between two different attractive food odor sources the activation of the octopaminergic neurotransmitter system switches the attraction for ethanol-containing food odor to a less attractive food odor. Consistent with the requirement for octopamine in biasing the behavioral outcome, Tbetah mutants fail to switch their attraction. The execution of attraction does not require octopamine but rather initiation of the behavior or a switch of the behavioral response. The attraction to ethanol also depends on octopamine. Pharmacological increases in octopamine signaling in Tbetah mutants increase ethanol attraction and blocking octopamine receptor function reduces ethanol attraction. Taken together, octopamine in the central brain orchestrates behavioral outcomes by biasing the decision of the animal towards food odors. This finding might uncover a basic principle of how octopamine gates behavioral outcomes in the brain. PMID- 30018539 TI - Behavioral Aversion to AITC Requires Both Painless and dTRPA1 in Drosophila. AB - There has been disagreement over the functional roles of the painless gene product in the detection and subsequent behavioral aversion to the active ingredient in wasabi, allyl isothiocyanate (AITC). Originally, painless was reported to eliminate the behavioral aversion to AITC, although subsequent reports suggested that another trpA homolog, dTRPA1, was responsible for AITC aversion. We re-evaluated the role of the painless gene in the detection of AITC, employing several different behavioral assays. Using the proboscis extension reflex (PER) assay, we observed that AITC did not reduce PER frequencies in painless or dTRPA1 mutants but did in wild-type genotypes. Quantification of food intake showed a significant decline in food consumption in the presence of AITC in wild-type, but not painless mutants. We adapted an oviposition choice assay and found wild-type oviposit on substrates lacking AITC, in contrast to painless and dTRPA1 mutants. Lastly, tracking individual flies relative to a point source of AITC, showed a consistent clustering of wild-type animals away from the point source, which was absent in painless mutants. We evaluated expression patterns of both dTRPA1 and painless, which showed expression in distinct central and peripheral populations. We identified the transmitter phenotypes of subsets of painless and dTRPA1 neurons and found similar neuropeptides as those expressed by mammalian trpA expressing neurons. Using a calcium reporter, we observed AITC evoked responses in both painless and dTRPA1 expressing neurons. Collectively, these results reaffirm the necessity of painless in nociceptive behaviors and suggest experiments to further resolve the molecular basis of aversion. PMID- 30018541 TI - Transcranial Direct Current Stimulation Altered Voluntary Cooperative Norms Compliance Under Equal Decision-Making Power. AB - Social norms play an essential role in human interactions and the development of the evolution of human history. Extensive studies corroborate that compliance with social norms typically requires a punishment threat as almost always specific individuals have self-interests that tempt them to violate the norm. Neural imaging studies demonstrate that lateral orbitofrontal cortex (LOFC) and right dorsolateral prefrontal cortex (rDLPFC) are activated when individuals decide to increase social norm compliance when punishment is possible. Moreover, rDLPFC is affirmed to be involved in social norm compliance with or without external punishment threats in a series of transcranial direct current stimulation (tDCS) research. However, these neuroscience studies are based on the ultimatum game (UG) in which the decision-making power between the proposer and the responder is unequal, and no studies support the causal relationship between rDLPFC and voluntary cooperative norms compliance among the equal decision-making power of subjects. Whether modulating the excitability of rDLPFC, which plays a role in norm compliance, alters the extent of compliance with voluntary cooperative norms under equal decision-making power and how norms from different types with asymmetric endowment influence compliance remain unknown. The present study aimed to provide evidence of a direct link between the neural and behavioral results through the application of tDCS over rDLPFC on compliance with voluntary cooperative norms under equal decision-making power. Results verified that activating rDLPFC altered voluntary cooperative norms compliance of all our participants and significant effect over different initial endowments was observed. The role of norm.own and norm.other in compliance was changed in the anodal treatment. Findings validate that enhancing the excitability of the rDLPFC using tDCS leads to high compliance in voluntary cooperation and this effect is specific to equal decision-making power rather than unequal decision-making power. PMID- 30018542 TI - Neural Correlates of Feedback Processing in Visuo-Tactile Crossmodal Paired Associate Learning. AB - Previous studies have examined the neural correlates for crossmodal paired associate (PA) memory and the temporal dynamics of its formation. However, the neural dynamics for feedback processing of crossmodal PA learning remain unclear. To examine this process, we recorded event-related scalp electrical potentials for PA learning of unimodal visual-visual pairs and crossmodal visual-tactile pairs when participants performed unimodal and crossmodal tasks. We examined event-related potentials (ERPs) after the onset of feedback in the tasks for three effects: feedback type (positive feedback vs. negative feedback), learning (as the learning progressed) and the task modality (crossmodal vs. unimodal). The results were as follows: (1) feedback type: the amplitude of P300 decreased with incorrect trials and the P400/N400 complex was only present in incorrect trials; (2) learning: progressive positive voltage shifts in frontal recording sites and negative voltage shifts in central and posterior recording sites were identified as learning proceeded; and (3) task modality: compared with the unimodal PA learning task, positive voltage shifts in frontal sites and negative voltage shifts in posterior sites were found in the crossmodal PA learning task. To sum up, these results shed light on cortical excitability related to feedback processing of crossmodal PA learning. PMID- 30018543 TI - Modeling Transcranial Direct-Current Stimulation-Induced Electric Fields in Children and Adults. AB - Transcranial direct-current stimulation (tDCS) is a form of non-invasive brain stimulation that induces electric fields in neuronal tissue, modulating cortical excitability. Therapeutic applications of tDCS are rapidly expanding, and are being investigated in pediatrics for various clinical conditions. Anatomical variations are among a host of factors that influence the effects of tDCS, and pronounced anatomical differences between children and adults suggest that induced electric fields may be substantially different across development. The aim of this study was to determine the strength and distribution of tDCS-induced electric fields across development. Typically developing children, adolescents, and adults were recruited. Individualized finite-element method modeling of primary motor cortex (M1) targeting tDCS was performed. In the largest pediatric sample to date, we found significantly higher peak and mean M1 electric field strength, and more expansive electric field spread for children compared to adults. Electric fields were often comparable between adolescents and adults. Our results suggest that these differences may be associated with age-related differences in skull and extra-axial space thickness, as well as developmental changes occurring in gray and white matter. Individualized current modeling may be a valuable tool for personalizing effective doses of tDCS in future pediatric clinical trials. PMID- 30018544 TI - Virtual Orientation Overrides Physical Orientation to Define a Reference Frame in Spatial Updating. AB - Previous studies showed that people could use either an egocentric or allocentric reference frame in spatial updating with body-based cues (i.e., physical body movements), but the adopted reference frame was anchored by the physical egocentric front when body-based cues were constrained. A recent study (He et al., 2018) showed that even without body-based cues, the orientation participants initially faced in the virtual environment (VE; initial heading) could be used to establish a reference frame, suggesting that the physical egocentric front could be overridden by a virtual orientation. In the current project, we aimed to: (a) replicate He et al.'s (2018) finding; (b) examine when the reference frame defined by the virtual initial heading was established; and (c) investigate the cognitive processes in establishing the initial heading as a reference frame. In four experiments, we were able to replicate the previous findings and found that the reference frame defined by the initial heading was established during spatial updating. More importantly, the reference frame defined by the initial heading was egocentric and participants did not need to know the orientation of their initial heading at the beginning of spatial updating to be able to use it. We discuss the cognitive processes of reference frame selection in spatial updating when body-based cues are absent. PMID- 30018545 TI - Overlapping but Divergent Neural Correlates Underpinning Audiovisual Synchrony and Temporal Order Judgments. AB - Multisensory processing is a core perceptual capability, and the need to understand its neural bases provides a fundamental problem in the study of brain function. Both synchrony and temporal order judgments are commonly used to investigate synchrony perception between different sensory cues and multisensory perception in general. However, extensive behavioral evidence indicates that these tasks do not measure identical perceptual processes. Here we used functional magnetic resonance imaging to investigate how behavioral differences between the tasks are instantiated as neural differences. As these neural differences could manifest at either the sustained (task/state-related) and/or transient (event-related) levels of processing, a mixed block/event-related design was used to investigate the neural response of both time-scales. Clear differences in both sustained and transient BOLD responses were observed between the two tasks, consistent with behavioral differences indeed arising from overlapping but divergent neural mechanisms. Temporal order judgments, but not synchrony judgments, required transient activation in several left hemisphere regions, which may reflect increased task demands caused by an extra stage of processing. Our results highlight that multisensory integration mechanisms can be task dependent, which, in particular, has implications for the study of atypical temporal processing in clinical populations. PMID- 30018547 TI - Know Your Body Through Intrinsic Goals. AB - The first "object" that newborn children play with is their own body. This activity allows them to autonomously form a sensorimotor map of their own body and a repertoire of actions supporting future cognitive and motor development. Here we propose the theoretical hypothesis, operationalized as a computational model, that this acquisition of body knowledge is not guided by random motor babbling, but rather by autonomously generated goals formed on the basis of intrinsic motivations. Motor exploration leads the agent to discover and form representations of the possible sensory events it can cause with its own actions. When the agent realizes the possibility of improving the competence to re activate those representations, it is intrinsically motivated to select and pursue them as goals. The model is based on four components: (1) a self organizing neural network, modulated by competence-based intrinsic motivations, that acquires abstract representations of experienced sensory (touch) changes; (2) a selector that selects the goal to pursue, and the motor resources to train to pursue it, on the basis of competence improvement; (3) an echo-state neural network that controls and learns, through goal-accomplishment and competence, the agent's motor skills; (4) a predictor of the accomplishment of the selected goals generating the competence-based intrinsic motivation signals. The model is tested as the controller of a simulated simple planar robot composed of a torso and two kinematic 3-DoF 2D arms. The robot explores its body covered by touch sensors by moving its arms. The results, which might be used to guide future empirical experiments, show how the system converges to goals and motor skills allowing it to touch the different parts of own body and how the morphology of the body affects the formed goals. The convergence is strongly dependent on competence based intrinsic motivations affecting not only skill learning and the selection of formed goals, but also the formation of the goal representations themselves. PMID- 30018548 TI - EEG Characteristics of Dementia With Lewy Bodies, Alzheimer's Disease and Mixed Pathology. AB - Introduction: Previous studies on electroencephalography (EEG) to discriminate between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) have been promising. These studies did not consider the pathological overlap of the two diseases. DLB-patients with concomitant AD pathology (DLB/AD+) have a more severe disease manifestation. The EEG may also be influenced by a synergistic effect of the two pathologies. We aimed to compare EEG characteristics between DLB/AD+, "pure" DLB (DLB/AD-) and AD. Methods: We selected probable DLB patients who had an EEG and cerebrospinal fluid (CSF) available, from the Amsterdam Dementia Cohort (ADC). Concomitant AD-pathology was defined as a CSF tau/Abeta-42 ratio > 0.52. Forty-one DLB/AD+ cases were matched for age (mean 70 (range 53-85)) and sex (85% male) 1:1 to DLB/AD- and AD-patients. EEGs were assessed visually, with Fast Fourier Transform (FFT), network- and connectivity measures. Results: EEG visual severity score (range 1-5) did not differ between DLB/AD- and DLB/AD+ (2.7 in both groups) and was higher compared to AD (1.9, p < 0.01). Both DLB groups had a lower peak frequency (7.0 Hz and 6.9 Hz in DLB vs. 8.2 in AD, p < 0.05), more slow-wave activity and more prominent disruptions of connectivity and networks, compared to AD. No significant differences were found between DLB/AD+ and DLB/AD-. Discussion: EEG abnormalities are more pronounced in DLB, regardless of AD co-pathology. This emphasizes the valuable role of EEG in discriminating between DLB and AD. It suggests that EEG slowing in DLB is influenced more by the alpha-synucleinopathy, or the associated cholinergic deficit, than by amyloid and tau pathology. PMID- 30018546 TI - Modulation of Spike-Timing Dependent Plasticity: Towards the Inclusion of a Third Factor in Computational Models. AB - In spike-timing dependent plasticity (STDP) change in synaptic strength depends on the timing of pre- vs. postsynaptic spiking activity. Since STDP is in compliance with Hebb's postulate, it is considered one of the major mechanisms of memory storage and recall. STDP comprises a system of two coincidence detectors with N-methyl-D-aspartate receptor (NMDAR) activation often posited as one of the main components. Numerous studies have unveiled a third component of this coincidence detection system, namely neuromodulation and glia activity shaping STDP. Even though dopaminergic control of STDP has most often been reported, acetylcholine, noradrenaline, nitric oxide (NO), brain-derived neurotrophic factor (BDNF) or gamma-aminobutyric acid (GABA) also has been shown to effectively modulate STDP. Furthermore, it has been demonstrated that astrocytes, via the release or uptake of glutamate, gate STDP expression. At the most fundamental level, the timing properties of STDP are expected to depend on the spatiotemporal dynamics of the underlying signaling pathways. However in most cases, due to technical limitations experiments grant only indirect access to these pathways. Computational models carefully constrained by experiments, allow for a better qualitative understanding of the molecular basis of STDP and its regulation by neuromodulators. Recently, computational models of calcium dynamics and signaling pathway molecules have started to explore STDP emergence in ex and in vivo-like conditions. These models are expected to reproduce better at least part of the complex modulation of STDP as an emergent property of the underlying molecular pathways. Elucidation of the mechanisms underlying STDP modulation and its consequences on network dynamics is of critical importance and will allow better understanding of the major mechanisms of memory storage and recall both in health and disease. PMID- 30018549 TI - Danhong Injection Reversed Cardiac Abnormality in Brain-Heart Syndrome via Local and Remote beta-Adrenergic Receptor Signaling. AB - Ischemic brain injury impacts cardiac dysfunction depending on the part of the brain affected, with a manifestation of irregular blood pressure, arrhythmia, and heart failure. Generally called brain-heart syndrome in traditional Chinese medicine, few mechanistic understanding and treatment options are available at present. We hypothesize that considering the established efficacy for both ischemic stroke and myocardial infarction (MI), Danhong injection (DHI), a multicomponent Chinese patent medicine, may have a dual pharmacological potential for treating the brain-heart syndrome caused by cerebral ischemic stroke through its multi-targeted mechanisms. We investigated the role of DHI in the setting of brain-heart syndrome and determined the mechanism by which it regulates this process. We induced Ischemia/Reperfusion in Wistar rats and administered intravenous dose of DHI twice daily for 14 days. We assessed the neurological state, infarct volume, CT scan, arterial blood pressure, heart rhythm, and the hemodynamics. We harvested the brain and heart tissues for immunohistochemistry and western blot analyses. Our data show that DHI exerts potent anti-stroke effects (infarct volume reduction: **p < 0.01 and ***p < 0.001 vs. vehicle. Neurological deficit correction: *p < 0.05 and ***p < 0.001 vs. vehicle), and effectively reversed the abnormal arterial pressure (*p < 0.05 vs. vehicle) and heart rhythm (**p < 0.01 vs. vehicle). The phenotype of this brain-heart syndrome is strikingly similar to those of MI model. Quantitative assessment of hemodynamic in cardiac functionality revealed a positive uniformity in the PV loop after administration with DHI and valsartan in the latter. Immunohistochemistry and western blot results showed the inhibitory effect of DHI on the beta-adrenergic pathway as well as protein kinase C epsilon (PKCepsilon) (**p < 0.01 vs. model). Our data showed the underlying mechanisms of the brain heart interaction and offer the first evidence that DHI targets the adrenergic pathway to modulate cardiac function in the setting of brain-heart syndrome. This study has made a novel discovery for proper application of the multi-target DHI and could serve as a therapeutic option in the setting of brain-heart syndrome. PMID- 30018550 TI - Proanthocyanidin Polymer-Rich Fraction of Stryphnodendron adstringens Promotes in Vitro and in Vivo Cancer Cell Death via Oxidative Stress. AB - Cervical cancer is the fourth most common cancer that affects women, mainly through human papilloma virus (HPV) infection with high-risk HPV16 and HPV18. The present study investigated the in vitro anticancer activity and mechanism of action of a proanthocyanidin polymer-rich fraction of Stryphnodendron adstringens (F2) in cervical cancer cell lines, including HeLa (HPV18-positive), SiHa (HPV16 positive), and C33A (HPV-negative) cells, and also evaluated in vivo anticancer activity. In vitro, cell viability was determined by the MTT assay. Cell migration was determined by the wound healing assay. The mechanism of action was investigated by performing ultrastructural analysis and evaluating reactive oxygen species (ROS) production, mitochondrial metabolism, lipoperoxidation, BCL 2 family expression, caspase expression, and DNA and cell membrane integrity. In vivo activity was evaluated using the murine Ehrlich solid tumor model. F2 time- and dose-dependently reduced cell viability and significantly inhibited the migration of cervical cancer cells. HeLa and SiHa cells treated with F2 (IC50) exhibited intense oxidative stress (i.e., increase in ROS and decrease in antioxidant species) and mitochondrial damage (i.e., mitochondrial membrane potential depolarization and a reduction of intracellular levels of adenosine triphosphate). Increases in the Bax/BCL-2 ratio and caspase 9 and caspase 3 expression, were observed, with DNA damage that was sufficient to trigger mitochondria-dependent apoptosis. Cell membrane disruption was observed in C33A cells (IC50 and IC90) and HeLa and SiHa cells (IC90), indicating progress to late apoptosis/necrosis. The inhibition of ROS production by N-acetylcysteine significantly suppressed oxidative stress in all three cell lines. In vivo, F2 significantly reduced tumor volume and weight of the Ehrlich solid tumor, and significantly increased lipoperoxidation, indicating that F2 also induces oxidative stress in the in vivo model. These findings indicate that the proanthocyanidin polymer-rich fraction of S. adstringens may be a potential chemotherapeutic candidate for cancer treatment. PMID- 30018551 TI - Pharmacodynamics of the Glutamate Receptor Antagonists in the Rat Barrel Cortex. AB - Epipial application is one of the approaches for drug delivery into the cortex. However, passive diffusion of epipially applied drugs through the cortical depth may be slow, and different drug concentrations may be achieved at different rates across the cortical depth. Here, we explored the pharmacodynamics of the inhibitory effects of epipially applied ionotropic glutamate receptor antagonists CNQX and dAPV on sensory-evoked and spontaneous activity across layers of the cortical barrel column in urethane-anesthetized rats. The inhibitory effects of CNQX and dAPV were observed at concentrations that were an order higher than in slices in vitro, and they slowly developed from the cortical surface to depth after epipial application. The level of the inhibitory effects also followed the surface-to-depth gradient, with full inhibition of sensory evoked potentials (SEPs) in the supragranular layers and L4 and only partial inhibition in L5 and L6. During epipial CNQX and dAPV application, spontaneous activity and the late component of multiple unit activity (MUA) during sensory-evoked responses were suppressed faster than the short-latency MUA component. Despite complete suppression of SEPs in L4, sensory-evoked short-latency multiunit responses in L4 persisted, and they were suppressed by further addition of lidocaine suggesting that spikes in thalamocortical axons contribute ~20% to early multiunit responses. Epipial CNQX and dAPV also completely suppressed sensory-evoked very fast (~500 Hz) oscillations and spontaneous slow wave activity in L2/3 and L4. However, delta oscillations persisted in L5/6. Thus, CNQX and dAPV exert inhibitory actions on cortical activity during epipial application at much higher concentrations than in vitro, and the pharmacodynamics of their inhibitory effects is characterized by the surface-to-depth gradients in the rate of development and the level of inhibition of sensory-evoked and spontaneous cortical activity. PMID- 30018552 TI - Identifying the Species of Seeds in Traditional Chinese Medicine Using DNA Barcoding. AB - Seed is not only the main reproductive organ of most of herbal plants but also an important part of Traditional Chinese Medicine (TCM). Seed TCMs possess important medicinal properties and have been widely used as components of pharmaceutical products. In parallel with the increasing popularity and accessibility of seeds as medicinal products in recent years, numerous substitutes and adulterants have also appeared on the market. Due to the small volume and similar appearances of many seed TCMs, they are very difficult to accurately identify the constituent plant species through organoleptic methods. Usage of the wrong herb may be ineffective or may worsen the condition and even cause death. Correct identification of seed herbal medicines is therefore essential for their safe use. Here, we acquired 177 ITS2 sequences and 15 psbA-trnH sequences from 51 kinds of seed TCMs belonging to 64 species that have been described in the Chinese Pharmacopoeia. Tree-building analysis showed that the ITS2 sequences of 48 seed TCMs can be differentiated from each other, and they formed distinct, non overlapping groups in the maximum-likelihood tree. Furthermore, all of the sequences acquired in this study have been submitted to the public DNA barcoding system for herbal medicine, and this integrated database was used to identify 400 seed TCM samples purchased from medicinal markets, drug stores, and the Internet, enabling the identification of 7.5% of the samples as containing non-declared species. This study provides a brief operating procedure for the identification of seed TCMs found in herbal medicine. In the future, researchers and traditional herbal medicine enterprises can use this system to test their herbal materials. PMID- 30018553 TI - Will Widespread Synthetic Opioid Consumption Induce Epigenetic Consequences in Future Generations? AB - A growing number of evidence demonstrates that ancestral exposure to xenobiotics (pollutants, drugs of abuse, etc.) can perturb the physiology and behavior of descendants. Both maternal and paternal transmission of phenotype across generations has been proved, demonstrating that parental drug history may have significant implications for subsequent generations. In the last years, the burden of novel synthetic opioid (NSO) consumption, due to increased medical prescription of pain medications and to easier accessibility of these substances on illegal market, is raising new questions first in term of public health, but also about the consequences of the parental use of these drugs on future generations. Besides being associated to the neonatal abstinence syndrome, in utero exposure to opioids has an impact on neuronal development with long-term repercussions that are potentially transmitted to subsequent generations. In addition, recent reports suggest that opioid use even before conception influences the reactivity to opioids of the progeny and the following generations, likely through epigenetic mechanisms. This review describes the current knowledge about the transgenerational effects of opioid consumption. We summarize the preclinical and clinical findings showing the implications for the subsequent generations of parental exposure to opioids earlier in life. Limitations of the existing data on NSOs and new perspectives of the research are also discussed, as well as clinical and forensic consequences. PMID- 30018554 TI - Combining Zebrafish and CRISPR/Cas9: Toward a More Efficient Drug Discovery Pipeline. AB - The use of zebrafish larvae in basic and applied research has grown exponentially during the last 20 years. The reasons for this success lay in its specific experimental advantages: on the one hand, the small size, the large number of progeny and the fast life cycle greatly facilitate large-scale approaches while maintaining 3Rs amenability; on the other hand, high genetic and physiological homology with humans and ease of genetic manipulation make zebrafish larvae a highly robust model for understanding human disease. Together, these advantages allow using zebrafish larvae for performing high-throughput research, both in terms of chemical and genetic phenotypic screenings. Therefore, the zebrafish larva as an animal model is placed between more reductionist in vitro high throughput screenings and informative but low-throughput preclinical assays using mammals. However, despite its biological advantages and growing translational validation, zebrafish remains scarcely used in current drug discovery pipelines. In a context in which the pharmaceutical industry is facing a productivity crisis in bringing new drugs to the market, the combined advantages of zebrafish and the CRISPR/Cas9 system, the most powerful technology for genomic editing to date, has the potential to become a valuable tool for streamlining the generation of models mimicking human disease, the validation of novel drug targets and the discovery of new therapeutics. This review will focus on the most recent advances on CRISPR/Cas9 implementation in zebrafish and all their potential uses in biomedical research and drug discovery. PMID- 30018555 TI - Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia. AB - Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample. PMID- 30018557 TI - A Method for Rapid Screening of Anilide-Containing AMPK Modulators Based on Computational Docking and Biological Validation. AB - Adenosine 5'-monophsphate-activated protein kinase (AMPK) is a crucial energy sensor for maintaining cellular homeostasis. Targeting AMPK may provide an alternative approach in treatment of various diseases like cancer, diabetes, and neurodegenerations. Accordingly, novel AMPK activators are frequently identified from natural products in recent years. However, most of such AMPK activators are interacting with AMPK in an indirect manner, which may cause off-target effects. Therefore, the search of novel direct AMPK modulators is inevitable and effective screening methods are needed. In this report, a rapid and straightforward method combining the use of in silico and in vitro techniques was established for selecting and categorizing huge amount of compounds from chemical library for targeting AMPK modulators. A new class of direct AMPK modulator have been discovered which are anilides or anilide-like compounds. In total 1,360,000 compounds were virtually screened and 17 compounds were selected after biological assays. Lipinski's rule of five assessment suggested that, 13 out of the 17 compounds are demonstrating optimal bioavailability. Proton acceptors constituting the structure of these compounds and hydrogen bonds with AMPK in the binding site appeared to be the important factors determining the efficacy of these compounds. PMID- 30018558 TI - Multiple Sessions of Transcranial Direct Current Stimulation (tDCS) Reduced Craving and Relapses for Alcohol Use: A Randomized Placebo-Controlled Trial in Alcohol Use Disorder. AB - Background: Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has been studied as an adjunctive therapeutic agent for alcohol dependence. In a previous study, we showed that five consecutive sessions of tDCS applied bilaterally over the dorsolateral prefrontal cortex (dlPFC) reduced relapse to the use of alcohol in alcohol use disorder (AUD) outpatients. However, no changes on craving scores were observed. In the present study, we investigated if an extended number of sessions of the same intervention would reduce craving and relapses for alcohol use in AUD inpatients. Methods: Thus, a randomized, double-blind, sham-controlled, clinical trial with parallel arms was conducted (https://clinicaltrials.gov/ct2/show/NCT02091284). AUD patients from two private and one public clinics for treatment of drug dependence were randomly allocated to two groups: real tDCS (5 * 7 cm2, 2 mA, for 20 min, cathodal over the left dlPFC, and anodal over the right dlPFC) and sham-tDCS. Real or sham-tDCS was applied once a day, every other day, in a total of 10 sessions. Craving was monitored by a 5-item obsessive compulsive drinking scale once a week (one time before, three times during and once after brain stimulation) over about 5 weeks. Results: Craving scores progressively decreased over five measurements in both groups but were significantly reduced only in the real tDCS group after treatment. Corrected Hedges' within-group (initial and final) effect sizes of craving scores were of 0.3 for the sham-tDCS and of 1.1 for the real tDCS group. Effect size was 3-fold larger in the real tDCS group. In addition, the between group analysis on craving score difference was nearly significant, and the effect size was 0.58, in favor for a larger effect in the real tDCS group when compared to sham-tDCS. Furthermore, in a 3-months follow-up after intervention, 72.2% of sham-tDCS group relapsed to the alcohol use whereas 72.7% of tDCS group were abstinent. Conclusions: Multiple sessions of bilateral prefrontal tDCS were well tolerated with no significant adverse events. Thus, extended repetitive bilateral tDCS over the dlPFC is a promising adjunctive clinical tool that could be used to reduce alcohol craving and relapses and facilitate alcoholism cessation. PMID- 30018556 TI - Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and beta-amyloid Aggregation. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple etiologies. Beta-amyloid (Abeta) self-aggregation and overexpression of class IIa histone deacetylases (HDACs) are strongly implicated with AD pathogenesis. In this study, a series of novel diarylheptanoid derivatives were designed, synthesized and evaluated for use as dual Abeta self-aggregation and class IIa HDAC inhibitors. Among these compounds, 4j, 5c, and 5e displayed effective inhibitions for Abeta self-aggregation, HDAC5 activity and HDAC7 activity with IC50 values of <10 MUM. The compounds contain three common features: (1) a catechol or pyrogallol moiety, (2) a carbonyl linker and (3) an aromatic ring that can function as an HDAC cap and create hydrophobic interactions with Abeta1-42. Furthermore, compounds 4j, 5c, and 5e showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H2O2-induced toxicity. Overall, these promising in vitro data highlighted compounds 4j, 5c, and 5e as lead compounds that are worthy for further investigation. PMID- 30018559 TI - Association Between Cholangiocarcinoma and Proton Pump Inhibitors Use: A Nested Case-Control Study. AB - Background: The present study aimed to examine the odds of cholangiocarcinoma (CCA) in patients with proton pump inhibitors (PPIs) use. Methods: A nested case control study design was employed using data obtained from Taiwan's National Health Insurance Research Database. In total, 2,293 patients with confirmed diagnosis of CCA were identified and served as the CCA group. The CCA patients were propensity score-matched with 2,293 subjects without CCA who served as the control group. The cumulative defined daily dose (DDD) of PPIs was calculated based on the total supply in days and quantity of individual PPIs. Univariable and multivariate logistic regression models were used to determine the odds of CCA, and calculated odds ratios (ORs) and 95% confidence intervals (CI) were used to assess PPIs use and odds of CCA. Results: The overall adjusted OR of PPIs use associated CCA was 2.58 (95% CI 2.27, 2.93). The adjusted OR of CCA by cumulative DDD dose of PPIs and CCA was analyzed and revealed those odds of CCA are associated with all types of PPIs. Conclusions: There were odds of intrahepatic and extrahepatic CCA among PPIs users. All PPIs use was associated with odds of CCA. Analyses of larger numbers of cases are needed to confirm these findings. PMID- 30018560 TI - Osmoregulation in the Plotosidae Catfish: Role of the Salt Secreting Dendritic Organ. AB - Unlike other marine teleosts, the Plotosidae catfishes reportedly have an extra branchial salt secreting dendritic organ (DO). Salinity acclimation [brackishwater (BW) 3aaa, seawater (SWcontrol) 34aaa, and hypersaline water (HSW) 60aaa] for 14 days was used to investigate the osmoregulatory abilities of Plotosus lineatus through measurements of blood chemistry, muscle water content (MWC), Na+/K+-ATPase (NKA) specific activity and ion transporter expression in gills, DO, kidney and intestine. Ion transporter expression was determined using immunoblotting, immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR). HSW elevated mortality, plasma osmolality and ions, and hematocrit, and decreased MWC indicating an osmoregulatory challenge. NKA specific activity and protein levels were significantly higher in DO compared to gill, kidney and intestine at all salinities. NKA specific activity increased in kidney and posterior intestine with HSW but only kidney showed correspondingly higher NKA alpha-subunit protein levels. Since DO mass was greater in HSW, the total amount of DO NKA activity expressed per gram fish was greater indicating higher overall capacity. Gill NKA and V-ATPase protein levels were greater with HSW acclimation but this was not reflected in NKA activity, mRNA or ionocyte abundance. BW acclimation resulted in lower NKA activity in gill, kidney and DO. Cl- levels were better regulated and the resulting strong ion ratio in BW suggests a metabolic acidosis. Elevated DO heat shock protein 70 levels in HSW fish indicate a cellular stress. Strong NKA and NKCC1 (Na+:K+:2Cl- cotransporter1) co-localization was observed in DO parenchymal cells, which was rare in gill ionocytes. NKCC1 immunoblot expression was only detected in DO, which was highest at HSW. Cystic fibrosis transmembrane regulator Cl- channel (CFTR) localize apically to DO NKA immunoreactive cells. Taken together, the demonstration of high NKA activity in DO coexpressed with NKCC1 and CFTR indicates the presence of the conserved secondary active Cl- secretion mechanism found in other ion transporting epithelia suggesting a convergent evolution with other vertebrate salt secreting organs. However, the significant osmoregulatory challenge of HSW indicates that the DO may be of limited use under more extreme salinity conditions in contrast to the gill based ionoregulatory strategy of marine teleosts. PMID- 30018561 TI - Dexamethasone Administration During Late Gestation Has No Major Impact on Lipid Metabolism, but Reduces Newborn Survival Rate in Wistar Rats. AB - A rise in plasma triacylglycerol levels is a common physiological occurrence during late gestation and excess of glucocorticoids (GCs) has been shown to impair lipid metabolism. Based on those observations, we investigated whether the administration of dexamethasone during the late gestational period could exacerbate this pregnancy associated hypertriacylglycerolemia in rats. For this, female Wistar rats were treated with dexamethasone (0.2 mg/kg of body mass in the drinking water on days 14-19 of pregnancy; DP group) or equivalent days in the virgin rats (DV group). Untreated pregnant rats (control pregnant group) and age matched virgin rats (control virgin group) were used as controls. Functional, biochemical, and molecular analyses were carried out after treatment with GC and in the control groups. Euthanasia was performed on day 20 of pregnancy. The metabolic parameters of the mothers (dams) at the time of weaning and 6 months later, as well as newborn survival, were evaluated. We observed that neither dexamethasone nor pregnancy affected blood glucose or glucose tolerance. Hypertriacylglycerolemia associated with lipid intolerance or reduced hepatic triacylglycerol clearance was observed during the late gestational period. GC treatment caused a further increase in basal plasma triacylglycerol levels, but did not have a significant effect on lipid tolerance and hepatic triacylglycerol clearance in pregnant rats. GC, but not pregnancy, caused few significant changes in mRNA expression of proteins involved in lipid metabolism. Dexamethasone during pregnancy had no impact on lipid metabolism later in the dams' life; however, it led to intra-uterine growth restriction and reduced pup survival rate. In conclusion, GC exposure during the late gestational period in rats has no major impact on maternal lipid homeostasis, soon after parturition at weaning, or later in the dams' life, but GC exposure is deleterious to the newborn when high doses are administered at late gestation. These data highlight the importance of performing an individualized and rigorous control of a GC treatment during late pregnancy considering its harmful impact on the fetuses' health. PMID- 30018562 TI - A Preclinical Systematic Review and Meta-Analysis of Astragaloside IV for Myocardial Ischemia/Reperfusion Injury. AB - Astragaloside IV (AS-IV), the major pharmacological extract from Astragalus membranaceus Bunge, possesses a variety of biological activities in the cardiovascular systems. Here, we aimed to evaluate preclinical evidence and possible mechanism of AS-IV for animal models of myocardial ischemia/reperfusion (I/R) injury. Studies of AS-IV in animal models with myocardial I/R injury were identified from 6 databases from inception to May, 2018. The methodological quality was assessed by using CAMARADES 10-item checklist. All the data were analyzed using Rev-Man 5.3 software. As a result, 22 studies with 484 animals were identified. The quality score of studies ranged from 3 to 6 points. Meta analyses showed AS-IV can significantly decrease the myocardial infarct size and left ventricular ejection fraction, and increase shortening fraction compared with control group (P < 0.01). Significant decreasing of cardiac enzymes and cardiac troponin and increasing of decline degree in ST-segment were reported in one study each (P < 0.05). Additionally, the possible mechanisms of AS-IV for myocardial I/R injury are promoting angiogenesis, improving the circulation, antioxidant, anti-inflammatory and anti-apoptosis. Thus, AS-IV is a potential cardioprotective candidate for further clinical trials of myocardial infarction. PMID- 30018563 TI - Neuromuscular Control and Performance Differences Associated With Gender and Obesity in Fatiguing Tasks Performed by Older Adults. AB - Obesity rates in the geriatric population have emerged as a serious health concern in recent decades. Yet, obesity-related differences in neuromuscular performance and motor control during fatiguing tasks, and how they are modified by gender, specifically among older adults, are still largely unexplored. The first aim of this study was to understand obesity and gender-related differences in endurance time among older adults. Motor variability has been linked with inter-individual differences in the rate of fatigue development, and as potentially revealing underlying mechanisms of neuromuscular control. Hence, the second and third aims of this study were to investigate to what extent motor variability at baseline could predict inter-individual differences in endurance time, and whether systematic obesity and gender differences exist in motor variability among older adults. Fifty-nine older adults (65 years or older) were recruited into four groups: obese male, obese female, non-obese male, and non obese female. Participants performed submaximal intermittent isometric knee extensions until exhaustion. Knee extension force and muscle activation signals (surface electromyography) of a primary agonist muscle, the Vastus Lateralis (VL), were collected. Endurance time and metrics quantifying both the size and structure of variability were computed for the force and EMG signals, using coefficient of variation (within cycles and between cycles) and sample entropy measures. While group differences in endurance time were primarily associated with gender, adding individual motor variability measures as predictor variables explained significantly more variance in endurance time, thus highlighting the relevance of motor variability in understanding neuromotor control strategies. Males exhibited longer endurance times, higher EMG CV, lower EMG SaEn, lower force CV, and higher force SaEn than females. These findings are interpreted to indicate males as using a motor strategy involving better "distribution" of the neural efforts across synergists and antagonists to achieve better performance during the knee extension task. No obesity-related changes in endurance time were found. However, obese individuals exhibited a greater cycle-to-cycle variability in muscle activation, indicating a larger alteration in the recruitment of motor units across successive contractions and potentially increased neural costs, which may have contributed to comparable endurance time and performance as non obese older adults. PMID- 30018564 TI - Engineered Flock House Virus for Targeted Gene Suppression Through RNAi in Fruit Flies (Drosophila melanogaster) in Vitro and in Vivo. AB - RNA interference (RNAi) is a powerful tool to study functional genomics in insects and the potential of using RNAi to suppress crop pests has made outstanding progress. However, the delivery of dsRNA is a challenging step in the development of RNAi bioassays. In this study, we investigated the ability of engineered Flock House virus (FHV) to induce targeted gene suppression through RNAi under in vitro and in vivo condition. As proxy for fruit flies of agricultural importance, we worked with S2 cells as derived from Drosophila melanogaster embryos, and with adult stages of D. melanogaster. We found that the expression level for all of the targeted genes were reduced by more than 70% in both the in vitro and in vivo bioassays. Furthermore, the cell viability and median survival time bioassays demonstrated that the recombinant FHV expressing target gene sequences caused a significantly higher mortality (60-73% and 100%) than the wild type virus (24 and 71%), in both S2 cells and adult insects, respectively. This is the first report showing that a single stranded RNA insect virus such as FHV, can be engineered as an effective in vitro and in vivo RNAi delivery system. Since FHV infects many insect species, the described method could be exploited to improve the efficiency of dsRNA delivery for RNAi-related studies in both FHV susceptible insect cell lines and live insects that are recalcitrant to the uptake of naked dsRNA. PMID- 30018565 TI - Oxidative Stress: A Major Player in Cerebrovascular Alterations Associated to Neurodegenerative Events. AB - The brain is one of the most exquisite organs in the body with high metabolic demands, and requires a tight regulation of the surrounding environment. This tight control is exerted by the neurovascular unit (NVU) comprising different cell types, where endothelial cells play the commander-in-chief role. Thus, it is assumable that even slight perturbations in NVU might affect, in some cases irreversibly, brain homeostasis and health. In this line, recent findings support the two-hit vascular hypothesis for neurodegenerative conditions, where vascular dysfunction underlies the development of neurodegenerative diseases, such as Alzheimer's disease (AD). Knowing that endothelial cells are rich in mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, two major reactive oxygen species (ROS) sources, this review aims to gather information on how oxidative stress is in the front line of vascular alterations observed in brain aging and neurodegenerative conditions, particularly AD. Also, a brief discussion about the therapeutic strategies aimed to protect against cerebrovascular diseases is included. PMID- 30018567 TI - Bed Rest, Exercise Countermeasure and Reconditioning Effects on the Human Resting Muscle Tone System. AB - The human resting muscle tone (HRMT) system provides structural and functional support to skeletal muscle and associated myofascial structures (tendons, fascia) in normal life. Little information is available on changes to the HRMT in bed rest. A set of dynamic oscillation mechanosignals ([Hz], [N/m], log decrement, [ms]) collected and computed by a hand-held digital palpation device (MyotonPRO) were used to study changes in tone and in key biomechanical and viscoelastic properties in global and postural skeletal muscle tendons and fascia from a non exercise control (CTR) and an exercise (JUMP) group performing reactive jumps on a customized sledge system during a 60 days head-down tilt bed rest (RSL Study 2015-2016). A set of baseline and differential natural oscillation signal patterns were identified as key determinants in resting muscle and myofascial structures from back, thigh, calf, patellar and Achilles tendon, and plantar fascia. The greatest changes were found in thigh and calf muscle and tendon, with little change in the shoulder muscles. Functional tests (one leg jumps, electromyography) showed only trends in relevant leg muscle groups. Increased anti-Collagen-I immunoreactivity found in CTR soleus biopsy cryosections was absent from JUMP. Results allow for a muscle health status definition after chronic disuse in bed rest without and with countermeasure, and following reconditioning. Findings improve our understanding of structural and functional responses of the HRMT to disuse and exercise, may help to guide treatment in various clinical settings (e.g., muscle tone disorders, neuro-rehabilitation), and promote monitoring of muscle health and training status in personalized sport and space medicine. PMID- 30018566 TI - Potential Mechanisms of Action for Vitamin C in Cancer: Reviewing the Evidence. AB - Whether vitamin C (ascorbate) has a role to play as an anti-cancer agent has been debated for decades. Ascorbate has been used by cancer patients in an unregulated environment, either as a dietary supplement or in pharmacological doses administered by infusion, with numerous reports of clinical benefit, but in the absence of rigorous clinical trial data. The design of appropriate clinical trials has been hindered by a lack of understanding of the mechanism(s) of action that would inform the choice of effective dose, timing of administration and likely responsive cancer models. More recently, expanded understanding of the biological activities of ascorbate has led to a number of plausible hypotheses for mechanisms of anti-cancer activity. Prominent among these are the generation of significant quantities of hydrogen peroxide by the autoxidation of supra physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate dependent dioxygenase family of enzymes (2-OGDDs) that have a cofactor requirement for ascorbate. Hydrogen peroxide generation is postulated to generate oxidative stress that preferentially targets cancer cells. The 2-OGDDs include the hydroxylases that regulate the hypoxic response, a major driver of tumor survival, angiogenesis, stem cell phenotype and metastasis, and the epigenetic histone and DNA demethylases. The latter are of particular interest, with recent studies suggesting a promising role for ascorbate in the regulation of the ten eleven translocase (TET) DNA demethylases in hematological cancers. Support for these proposed mechanisms has come from many in vitro studies, and xenograft animal models have consistently shown an anti-cancer effect of ascorbate administration. However, decisive evidence for any particular mechanism(s) of action is not yet available from an in vivo setting. With a number of early phase clinical trials currently underway, evidence for potential mechanism(s) of action is required to inform the most appropriate study design and choice of cancer model. Hopefully such information will result in sound clinical data that will avert adding any further controversy to this already contentious debate. PMID- 30018568 TI - Urocortin-2 Prevents Dysregulation of Ca2+ Homeostasis and Improves Early Cardiac Remodeling After Ischemia and Reperfusion. AB - Aims: Urocortin-2 (Ucn-2) is a potent cardioprotector against Ischemia and Reperfusion (I/R) injuries. However, little is known about its role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca2+]i handling. Methods and Results: Cardiac Wistar rat model of I/R was induced by transient ligation of the left coronary artery and experiments were conducted 1 week after surgery in tissue and adult cardiomyocytes isolated from risk and remote zones. We observed that I/R promoted significant alteration in cardiac contractility as well as an increase in hypertrophy and fibrosis in both zones. The study of confocal [Ca2+]i imaging in adult cardiomyocytes revealed that I/R decreased the amplitude of [Ca2+]i transient and cardiomyocytes contraction in risk and remote zones. Interestingly, intravenous infusion of Ucn 2 before heart's reperfusion recovered significantly cardiac contractility and prevented fibrosis, but it didn't affect cardiac hypertrophy. Moreover, Ucn-2 recovered the amplitude of [Ca2+]i transient and modulated the expression of several proteins related to [Ca2+]i homeostasis, such as TRPC5 and Orai1 channels. Using Neonatal Rat Ventricular Myocytes (NRVM) we demonstrated that Ucn 2 blunted I/R-induced Store Operated Ca2+ Entry (SOCE), decreased the expression of TRPC5 and Orai1 as well as their interaction in reperfusion. Conclusion: Our study provides the first evidences demonstrating that Ucn-2 addition at the onset of reperfusion attenuates I/R-induced adverse cardiac remodeling, involving the [Ca2+]i handling and inhibiting the expression and interaction between TRPC5 and Orai1. PMID- 30018569 TI - Every Breath You Take: Non-invasive Real-Time Oxygen Biosensing in Two- and Three Dimensional Microfluidic Cell Models. AB - Knowledge on the availability of dissolved oxygen inside microfluidic cell culture systems is vital for recreating physiological-relevant microenvironments and for providing reliable and reproducible measurement conditions. It is important to highlight that in vivo cells experience a diverse range of oxygen tensions depending on the resident tissue type, which can also be recreated in vitro using specialized cell culture instruments that regulate external oxygen concentrations. While cell-culture conditions can be readily adjusted using state of-the-art incubators, the control of physiological-relevant microenvironments within the microfluidic chip, however, requires the integration of oxygen sensors. Although several sensing approaches have been reported to monitor oxygen levels in the presence of cell monolayers, oxygen demands of microfluidic three dimensional (3D)-cell cultures and spatio-temporal variations of oxygen concentrations inside two-dimensional (2D) and 3D cell culture systems are still largely unknown. To gain a better understanding on available oxygen levels inside organ-on-a-chip systems, we have therefore developed two different microfluidic devices containing embedded sensor arrays to monitor local oxygen levels to investigate (i) oxygen consumption rates of 2D and 3D hydrogel-based cell cultures, (ii) the establishment of oxygen gradients within cell culture chambers, and (iii) influence of microfluidic material (e.g., gas tight vs. gas permeable), surface coatings, cell densities, and medium flow rate on the respiratory activities of four different cell types. We demonstrate how dynamic control of cyclic normoxic-hypoxic cell microenvironments can be readily accomplished using programmable flow profiles employing both gas-impermeable and gas-permeable microfluidic biochips. PMID- 30018571 TI - A Machine Learning Aided Systematic Review and Meta-Analysis of the Relative Risk of Atrial Fibrillation in Patients With Diabetes Mellitus. AB - Background: Meta-analysis is a widely used tool in which weighted information from multiple similar studies is aggregated to increase statistical power. However, the exponential growth of publications in key areas of medical science has rendered manual identification of relevant studies increasingly time consuming. The aim of this work was to develop a machine learning technique capable of robust automatic study selection for meta-analysis. We have validated this approach with an up-to-date meta-analysis to investigate the association between diabetes mellitus (DM) and new-onset atrial fibrillation (AF). Methods: The PubMed online database was searched from 1960 to September 2017 where 4,177 publications that mentioned both DM and AF were identified. Relevant studies were selected as follows. First, publications were clustered based on common text features using an unsupervised K-means algorithm. Clusters that best matched the selected set of potentially relevant studies (a "training" set of 139 articles) were then identified by using maximum entropy classification. The 139 articles selected automatically on this basis were screened manually to identify potentially relevant studies. To determine the validity of the automated process, a parallel set of studies was also assembled by manually screening all initially searched publications. Finally, detailed manual selection was performed on the full texts of the studies in both sets using standard criteria. Quality assessment, meta-regression random-effects models, sensitivity analysis and publication bias assessment were then conducted. Results: Machine learning assisted screening identified the same 29 studies for meta-analysis as those identified by using manual screening alone. Machine learning enabled more robust and efficient study selection, reducing the number of studies needed for manual screening from 4,177 to 556 articles. A pooled analysis using the most conservative estimates indicated that patients with DM had ~49% greater risk of developing AF compared with individuals without DM. After adjusting for three additional risk factors i.e., hypertension, obesity and heart disease, the relative risk was 23%. Using multivariate adjusted models, the risk for developing AF in patients with DM was similar for all DM subtypes. Women with DM were 24% more likely to develop AF than men with DM. The risk for new-onset AF in patients with DM has also increased over the years. Conclusions: We have developed a novel machine learning method to identify publications suitable for inclusion in meta-analysis.This approach has the capacity to provide for a more efficient and more objective study selection process for future such studies. We have used it to demonstrate that DM is a strong, independent risk factor for AF, particularly for women. PMID- 30018570 TI - Significant Acute Response of Brain-Derived Neurotrophic Factor Following a Session of Extreme Conditioning Program Is Correlated With Volume of Specific Exercise Training in Trained Men. AB - Several studies have demonstrated an acute and chronic increase of brain-derived neurotrophic factor (BDNF) in relation to different types of physical exercise. Currently, many individuals seek physical training strategies that present different types of stimulation and volume/intensity. Thus, the extreme conditioning methodology has gained great notoriety in the scientific and non scientific environment. Knowing that BDNF values increase in an effort-dependent manner, it is necessary to study the effects of this strategy on BDNF levels. This study aimed to evaluate the acute response of BDNF in trained men submitted to an extreme conditioning program (ECP) session. Ten volunteers underwent an acute ECP session using the "as many reps as possible" (WOD-AMRAP) method, including three types of exercise (clean, wall ball and double or single-unders) for 9 min. BDNF was measured in the plasma, being collected baseline and immediately after the session. Total load of the clean exercise was five times greater than wall ball exercise (p < 0.05; 2096.1 +/- 387.4 kg vs 415.8 +/- 81.03 kg), which influenced little in the total load (p < 0.05, 2511.9 +/- 358.52 kg) used. For the total volume, practitioners averaged 1.7 times more repetitions in the wall ball exercise compared to clean (46.2 +/- 9 vs 29.5 +/- 3.8 repetitions). The volunteers averaged 75.7 +/- 12.6 double-unders repetitions, bringing the total volume of training to 151.4 +/- 23.7 repetitions. Regarding the BDNF values, there was a significant difference (p = 0.05) between the pre- vs post-moments (11209.85 +/- 1270.4 vs 12132.96 +/- 1441.93 pg/ml). Effect size for this change as moderate (ES = 0.79). We found a positive correlation between total volume of clean exercise and delta BDNF values (p = 0.049). In conclusion, a single extreme conditioning session, through the practice of the WOD-AMRAP method, is capable of increasing the acute concentrations of plasma BDNF. In practical terms, we may suggest that future studies evaluate the effect of ECP as a strategy in the treatment of disorders associated with central degenerative changes. PMID- 30018574 TI - Psilocybin and Mental Health-Don't Lose Control. PMID- 30018573 TI - Cerebellar Structural Abnormalities Associated With Cognitive Function in Patients With First-Episode Psychosis. AB - Introduction: The fundamental role of the cerebellum in higher cognitive processing has recently been highlighted. However, inconsistent findings exist in schizophrenia with respect to the exact nature of cerebellar structural abnormalities and their associations with cognitive and clinical features. Materials and Methods: We undertook a detailed investigation of cerebellar lobular volumes in 40 patients with first-episode psychosis (FEP) and 40 healthy controls (HCs) using the spatially unbiased atlas template of the cerebellum (SUIT). We examined the functional significance of cerebellar structural abnormalities in relation to cognitive and clinical outcomes in patients. Results: We found that left cerebellar lobules VI and X volumes were lower in FEP patients, compared to HCs. Smaller left lobules VI and X volumes were associated with fewer number of categories completed on the Wisconsin Card Sorting Test (WCST) in patients. In addition, smaller left lobule X volume was related to performance delay on the Trail Making Test (TMT) Part B in patients. Conclusion: Our results demonstrate that cerebellar structural abnormalities are present at the early stage of schizophrenia. We suggest functional associations of cerebellar structural changes with non-verbal executive dysfunctions in FEP. PMID- 30018572 TI - Comparative Phospho- and Acetyl Proteomics Analysis of Posttranslational Modifications Regulating Intestine Regeneration in Sea Cucumbers. AB - Sea cucumbers exposed to stressful circumstances eviscerate most internal organs, and then regenerate them rapidly under favorable environments. Reversible protein phosphorylation and acetylation are major modifications regulating protein function. Herein, for the first time, we perform quantitative phospho- and acetyl proteomics analyses of intestine regeneration in a sea cucumber species Apostichopus japonicus. We identified 1,862 phosphorylation sites in 1,169 proteins, and 712 acetylation sites in 470 proteins. Of the 147 and 251 proteins differentially modified by phosphorylation and acetylation, respectively, most were related to cytoskeleton biogenesis, protein synthesis and modification, signal recognition and transduction, energy production and conversion, or substance transport and metabolism. Phosphorylation appears to play a more important role in signal recognition and transduction than acetylation, while acetylation is of greater importance in posttranslational modification, protein turnover, chaperones; energy production and conversion; amino acid and lipid transport and metabolism. These results expanded our understanding of the regulatory mechanisms of posttranslational modifications in intestine regeneration of sea cucumbers after evisceration. PMID- 30018575 TI - Risk Factors for Recent Suicide Attempts in Major Depressive Disorder Patients in China: Results From a National Study. AB - Objective: To analyze the factors associated with recent suicide attempts including socio-demographic and clinical characteristics in major depressive disorder (MDD) patients in China. Methods: The data were from a nationwide sample from 13 major psychiatric hospitals or the psychiatric units of general hospitals in China, from September 1, 2010 to February 28, 2011. Melancholic features and suicide attempts in the past month were defined according to the melancholic feature module and the suicide module of the Mini International Neuropsychiatric Interview (MINI). Socio-demographic and clinical characteristics were compared between MDD patients with and without recent suicide attempts. Further analyses regarding the factors associated with recent suicide attempts in MDD patients were performed via multivariate logistic regression analysis. Results: Among 1,172 MDD patients, 57 (4.9%) were reported to have made a suicide attempt in the past month. Compared to the MDD patients without recent suicide attempt, significantly higher percentage of patients in the recent suicide attempters group had previous suicide attempts (chi2 = 171.861, p < 0.001) and depressive episodes with melancholic features (chi2 = 22.837, p < 0.001). Logistic regression analysis indicated that previous suicide attempts (OR = 20.81, 95% CI: 11.12-38.94, p < 0.001) and depressive episodes with melancholic features (OR = 4.43, 95% CI: 2.09-9.43, p < 0.001) were independently associated with recent suicide attempts in MDD patients. Limitations: Cross-sectional design, retrospective recall of suicide attempt data. Conclusion: Recent suicide attempts are associated with melancholic features and previous suicide attempts in MDD patients in China. These data may help clinicians to identify MDD patients at high risk of suicide attempt behavior. PMID- 30018576 TI - "The Penny Drops": Investigating Insight Through the Medium of Cryptic Crosswords. AB - A new protocol for eliciting insight ("Aha!"/Eureka) moments is proposed, involving the solving of British-style cryptic crosswords. The mechanics of cryptic crossword clues are briefly explained, and the process is set into the insight literature, with parallels being drawn between several different types of cryptic crossword clues and other insight-triggering problems such as magic, jokes, anagrams, rebus, and remote association puzzles (RAT), as well as "classic" thematic or spatial challenges. We have evidence from a previous survey of cryptic crossword solvers that the "Aha!" moment is the most important driver of continued participation in this hobby, suggesting that the positive emotional "payback" has an energizing effect on a participant's motivation to continue solving. Given the success with which a good quality cryptic crossword elicits "Aha!" moments, cryptics should prove highly valuable in exploring insight under lab conditions. We argue that the crossword paradigm overcomes many of the issues which beset other insight problems: for example, solution rates of cryptic crossword clues are high; new material can easily be commissioned, leading to a limitless pool of test items; and each puzzle contains clues resembling a wide variety of insight problem types, permitting a comparison of heterogeneous solving mechanisms within the same medium. Uniquely among insight problems, considerations of expertise also come into play, allowing us to explore how crossword solving experts handle the deliberate misdirection of the cryptic clue more effectively than non-expert, but equally experienced, peers. Many have debated whether there is such a thing as an "insight problem" per se: typically, problems can be solved with or without insight, depending on the context. We argue that the same is true for cryptic crosswords, and that the key to the successful triggering of insight may lie in both the difficulty of the challenge and the degree to which misdirection has been used. Future research is outlined which explores the specific mechanisms of clue difficulty. This opens the way to an exploration of potential links between solving constraints and the experiencing of the "Aha!" moment, which may shed light on the cognitive processes involved in insight solution. PMID- 30018577 TI - Neural Activity Is Dynamically Modulated by Memory Load During the Maintenance of Spatial Objects. AB - Visuospatial working memory (WM) is a fundamental but severely limited ability to temporarily remember selected stimuli. Several studies have investigated the underlying neural mechanisms of maintaining various visuospatial stimuli simultaneously (i.e., WM load, the number of representations that need to be maintained in WM). However, two confounding factors, namely verbal representation and encoding load (the number of items that need to be encoded into WM), have not been well controlled in previous studies. In this study, we developed a novel delayed-match-to-sample task (DMST) controlling for these two confounding factors and recorded scalp EEG signals during the task. We found that behavioral performance deteriorated severely as memory load increased. Neural activity was modulated by WM load in a dynamic manner. Specifically, higher memory load induced stronger amplitude in occipital and central channel-clusters during the early delay period, while the inverse trend was observed in central and frontal channel-clusters during late delay. In addition, the same inverse memory load effect, that was lower memory load induced stronger amplitude, was observed in occipital channel-cluster alpha power during late delay. Finally, significant correlations between neural activity and individual reaction time showed a role of late-delay central and frontal channel-cluster amplitude in predicting behavioral performance. Because the occipital cortex is important for visual information maintenance, the decrease in alpha oscillation was consistent with the cognitive role that is "gating by inhibition." Together, our results from a well-controlled DMST suggest that WM load not exerted constant but dynamic effect on neural activity during maintenance of visuospatial objects. PMID- 30018578 TI - Interacting Effect of Catechol-O-Methyltransferase (COMT) and Monoamine Oxidase A (MAOA) Gene Polymorphisms, and Stressful Life Events on Aggressive Behavior in Chinese Male Adolescents. AB - Numerous studies have demonstrated that both catechol-O-methyltransferase (COMT) gene and monoamine oxidase A (MAOA) gene have been involved in aggressive behavior, as have stressful life events (SLEs). However, most of available evidence was based upon single gene or single gene-environment design, which is limited in accounting for the variance of aggressive behavior, a complex phenotype. This study examined the possible gene * gene * environment interactions between SLE (interpersonal problems and academic pressure) and two genetic polymorphisms (MAOA T941G and COMT Ala22/72Ser) correlated with aggressive behaviors in a sample of 658 Chinese male adolescents. Mothers and teachers reported on adolescents' aggressive behavior using Achenbach's Child Behavior Checklist and Teacher Report Form, respectively. Adolescents completed Self-Rating Life Events Checklist. Saliva samples were collected for DNA analysis. The results revealed no main effects of MAOA T941G and COMT Ala22/72Ser polymorphisms on male adolescents' aggressive behaviors. However, a two-way interactive effect of interpersonal problems and MAOA T941G genotype on teacher reported aggressive behavior was observed: adolescents with lower activity of MAOA T allele, but not those with MAOA G allele, exhibited greater aggressive behavior with an increase in interpersonal problems. A three-way interaction among COMT Ala22/72Ser and MAOA T941G polymorphisms, and SLE in the academic pressure on aggressive behavior was also identified. Among adolescents with lower activity of COMT GT/TT genotype and MAOA T allele, the higher level of academic pressure was significantly linked with an amplification of aggressive behavior, whereas this association didn't exist among those with other genotypes. The present study presents the first evidence of COMT * MAOA * SLE interaction effect on male adolescents' aggressive behavior, highlights the importance of considering distinct domains of stressful events and information bias when examining the effect of MAOA and COMT on aggressive behavior, and thereby contributes to MAOA gene-aggression and COMT gene-aggression literature. PMID- 30018579 TI - Emotional Labor and Occupational Well-Being: Latent Profile Transition Analysis Approach. AB - This study used the latent profile transition analysis (LPTA) to analyze whether emotional labor profiles change across time and how these profiles relate to occupational well-being (i.e., job satisfaction, quality of work life, psychological distress, and work-family conflict). A total of 155 full-time Chinese employees completed the questionnaire survey at two time points. Three latent profiles were identified at Time 1 and the same profiles were replicated at Time 2. We determined that the majority of the participants retained the original profiles. Lastly, occupational well-being differed significantly across the identified profiles. The limitations and implications of this study were also provided. PMID- 30018580 TI - Testing Measurement and Factor Structure Invariance of the Physical Activity and Leisure Motivation Scale for Youth Across Gender. AB - Measurement equivalence is often assumed across comparison groups, a pervasive problem related to many self-report instruments. Measurement equivalence, also known as measurement invariance, implies that a measure has the same meaning across different groups of people. In this study, we aimed to examine the measurement and structural invariance among gender of the Malay version of the Physical Activity and Leisure Motivation Scale for Youth (PALMS-Y-M). Seven hundred-and-eighty-three secondary school students (female = 57.3%, male = 42.7%) with mean age 14.5 years (standard deviation = 1.25) from Kota Bharu, Malaysia, volunteered to participate in this study and completed the PALMS-Y-M, consisting of 28 items with seven subscales. We conducted the confirmatory factor analysis (CFA) and invariance tests on the seven motives of the PALMS-Y-M model. The hypothesized model consisted of 28 observed items and seven latent variables. We used estimator robust to maximum likelihood, MLR to examine the hypothesized measurement and structural invariance. Measurement invariance was tested for three different levels. We first established the configural invariance model, then we compared the metric invariance model and the scalar invariance model with the less restrictive model. Then structural invariance was tested for factor variance, covariance, and means. Findings provided evidence for full measurement and structural invariance of the PALMS-Y-M in males and females. The final CFA model fit the data well for males [comparative fit index (CFI) = 0.922, root mean square error of approximation (RMSEA) = 0.048, standardized root mean residual (SRMR) = 0.050] and females (CFI = 0.922, RMSEA = 0.047, SRMR = 0.053). When invariance of both factor loadings and item intercepts holds in PALMS-Y-M, underlying factors consisting of different motives for participating in PA can be meaningfully compared across gender. Accurate and valid measurement of PALMS-Y-M across comparison groups is crucial for future research that involves examining motives to physical activity in different genders and other socio-cultural variables. PMID- 30018581 TI - Television Is Still "Easy" and Print Is Still "Tough"? More Than 30 Years of Research on the Amount of Invested Mental Effort. AB - We provide a literature overview of 30 years of research on the amount of invested mental effort (AIME, Salomon, 1984), illuminating relevant literature in this field. Since the introduction of AIME, this concept appears to have vanished. To obtain a clearer picture of where the theory of AIME has diffused, we conducted a literature search focusing on the period 1985-2015. We examined scientific articles (N = 244) that cite Salomon (1984) and content-analyzed their keywords. Based on these keywords, we identified seven content clusters: affect and motivation, application fields, cognition and learning, education and teaching, media technology, learning with media technology, and methods. We present selected works of each content cluster and describe in which research field the articles had been published. Results indicate that AIME was most commonly (but not exclusively) referred to in the area of educational psychology indicating its importance regarding learning and education, thereby investigating print and TV, as well as new media. From a methodological perspective, research applied various research methods (e.g., longitudinal studies, experimental designs, theoretical analysis) and samples (e.g., children, college students, low income families). From these findings, the importance of AIME for further research is discussed. PMID- 30018582 TI - Using Overt and Covert Items in Self-Report Personality Tests: Susceptibility to Faking and Identifiability of Possible Fakers. AB - Self-report personality tests widely used in clinical, medical, forensic, and organizational areas of psychological assessment are susceptible to faking. Several approaches have been developed to prevent or detect faking, which are based on the use of faking warnings, ipsative items, social desirability scales, and validity scales. The approach proposed in this work deals with the use of overt items (the construct is clear to test-takers) and covert items (the construct is obscure to test-takers). Covert items are expected to be more resistant to faking than overt items. Two hundred sixty-seven individuals were presented with an alexithymia scale. Two experimental conditions were considered. Respondents in the faking condition were asked to reproduce the profile of an alexithymic individual, whereas those in the sincere condition were not asked to exhibit a particular alexithymia profile. The items of the scale were categorized as overt or covert by expert psychotherapists and analyzed through Rasch models. Respondents in the faking condition were able to exhibit measures of alexithymia in the required direction. This occurred for both overt and covert items, but to a greater extent for overt items. Differently from overt items, covert items defined a latent variable whose meaning was shared between respondents in the sincere and faking condition, and resistant to deliberate distortion. Rasch fit statistics indicated unexpected responses more often for respondents in the faking condition than for those in the sincere condition and, in particular, for the responses to overt items by individuals in the faking condition. More than half of the respondents in the faking condition showed a drift rate (difference between the alexithymia levels estimated on the responses to overt and covert items) significantly larger than that observed in the respondents in the sincere condition. PMID- 30018583 TI - The Contagion of Unethical Pro-organizational Behavior: From Leaders to Followers. AB - Unethical pro-organizational behavior is a common phenomenon in businesses, and one that can cause great damage to them as well as to wider society. Although prior studies have investigated why individuals engage in unethical pro organizational behavior, little research has been undertaken into why such behavior might be commonplace in organizations. The present study focuses on the downstream contagion of unethical pro-organizational behavior from leaders to followers. Drawing on social identity theory, we consider why leaders' unethical pro-organizational behavior brings about corresponding behavior in their employees. Moreover, we predict that leader identification and moral identity will moderate this relationship. Using a time-lag study design, we collected a sample of 227 multisource time-lagged data with which to test our hypotheses. The results show that there is a significant positive relationship between leaders' and employees' unethical pro-organizational behavior, and that this relationship is stronger when employees have higher leader identification and lower moral identity levels. The theoretical and practical implications of our findings are discussed in this paper, as are the limitations of the study. PMID- 30018584 TI - Emotional Differences in Young and Older Adults: Films as Mood Induction Procedure. AB - Film clips are proven to be one of the most efficient techniques in emotional induction. However, there is scant literature on the effect of this procedure in older adults and, specifically, the effect of using different positive stimuli. Thus, the aim of the present study was to examine emotional differences between young and older adults and to know how a set of film clips works as mood induction procedure in older adults, especially, when trying to elicit attachment related emotions. To this end, we use this procedure to analyze differences in subjective emotional response between young and older adults. A sample of 57 older adults and 83 young adults watched a film set previously validated in young population. Their responses were studied in an individual laboratory session to elicit 6 target emotions (disgust, fear, sadness, anger, amusement and tenderness) and neutral state. Self-reported emotional experience was measured using the Self-Assessment Manikin (SAM). Our results show that film clips are capable of evoking positive and negative emotions in older adults. Furthermore, older adults experienced more intensely negative emotions than young adults, especially in response to disgust and fear clips. They also reported higher arousal than young adults, especially in the case of sadness, anger and tenderness clips. Nevertheless, the older adults recovered more easily from the effects of the emotion induction. The young adults reported higher arousal ratings than older adults in response to amusement film clips. On the other hand, this study reflects the importance of controlling the baseline state to study the real strength of mood induction. Overall, current data suggests significant differences occur in emotional response in adult age and that film clips are an effective tool for studying positive and negative emotions in aging research. PMID- 30018585 TI - The Potential Role for Cognitive Training in Sport: More Research Needed. AB - Sports performance at the highest level requires a wealth of cognitive functions such as attention, decision making, and working memory to be functioning at optimal levels in stressful and demanding environments. Whilst a substantial research base exists focusing on psychological skills for performance (e.g., imagery) or therapeutic techniques for emotion regulation (e.g., cognitive behavioral therapy), there is a scarcity of research examining whether the enhancement of core cognitive abilities leads to improved performance in sport. Cognitive training is a highly researched method of enhancing cognitive skills through repetitive and targeted exercises. In this article, we outline the potential use of cognitive training (CT) in athlete populations with a view to supporting athletic performance. We propose how such an intervention could be used in the future, drawing on evidence from other fields where this technique is more fruitfully researched, and provide recommendations for both researchers and practitioners working in the field. PMID- 30018586 TI - Estimation of Energy Expenditure in Wheelchair-Bound Spinal Cord Injured Individuals Using Inertial Measurement Units. AB - A healthy lifestyle reduces the risk of cardio-vascular disease. As wheelchair bound individuals with spinal cord injury (SCI) are challenged in their activities, promoting and coaching an active lifestyle is especially relevant. Although there are many commercial activity trackers available for the able bodied population, including those providing feedback about energy expenditure (EE), activity trackers for the SCI population are largely lacking, or are limited to a small set of activities performed in controlled settings. The aims of the present study were to develop and validate an algorithm based on inertial measurement unit (IMU) data to continuously monitor EE in wheelchair-bound individuals with a SCI, and to establish reference activity values for a healthy lifestyle in this population. For this purpose, EE was measured in 30 subjects each wearing four IMUs during 12 different physical activities, randomly selected from a list of 24 activities of daily living. The proposed algorithm consists of three parts: resting EE estimation based on multi-linear regression, an activity classification using a k-nearest-neighbors algorithm, and EE estimation based on artificial neural networks (ANNs). The mean absolute estimation error for the ANN based algorithm was 14.4% compared to indirect calorimeter measurements. Based on reference values from the literature and the data collected within this study, we recommend wheeling 3 km per day for a healthy lifestyle in wheelchair-bound SCI individuals. Combining the proposed algorithm with a recommendation for physical activity provides a powerful tool for the promotion of an active lifestyle in the SCI population, thereby reducing the risk for secondary diseases. PMID- 30018587 TI - Hyperchloremia Is Associated With Poorer Outcome in Critically Ill Stroke Patients. AB - Background and Purpose: This study aims to explore the cause and predictive value of hyperchloremia in critically ill stroke patients. Materials and Methods: We conducted a retrospective study of a prospectively collected database of adult patients with first-ever acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) admitted to the neurointensive care unit (NICU) of a university-affiliated hospital, between January 2013 and December 2016. Patients were excluded if admitted beyond 72 h from onset, if they required neurocritical care for less than 72 h, and were treated with hypertonic saline within 72 h or had creatinine clearance less than 15 mL/min. Results: Of 405 eligible patients, the prevalence of hyperchloremia ([Cl-] >= 110 mmol/L) was 8.6% at NICU admission ([Cl-]0) and 17.0% within 72 h ([Cl-]max). Thirty-eight (9.4%) patients had new-onset hyperchloremia and 110 (27.1%) had moderate increase in chloride (Delta[Cl-] >= 5 mmol/L; Delta[Cl-] = [Cl-]max - [Cl-]0) in the first 72 h after admission, which were found to be determined by the sequential organ failure assessment score in multivariate logistic regression analysis. Neither total fluid input nor cumulative fluid balance had significant association with such chloride disturbance. New-onset hyperchloremia and every 5 mmol/L increment in Delta[Cl-] were both associated with increased odds of 30-day mortality and 6-month poor outcome, although no independent significance was found in multivariate models. Conclusion: Hyperchloremia tends to occur in patients more severely affected by AIS and ICH. Although no independent association was found, new-onset hyperchloremia and every 5 mmol/L increment in Delta[Cl-] were related to poorer outcome in critically ill AIS and ICH patients. Subject terms: clinical studies, intracranial hemorrhage, ischemic stroke, mortality/survival, quality and outcomes. PMID- 30018588 TI - Predictive Factors for Early Initiation of Artificial Feeding in Patients With Sporadic Creutzfeldt-Jakob Disease. AB - Background: Akinetic mutism has often been used as the predictor of sporadic Creutzfeldt-Jacob disease (sCJD) endpoints, but it may be difficult for general physcians to assess. Nasogastric (NG) tube insertion is indicated for many neurodegenerative diseases with a clinical course of swallowing failure, and can be more easily identified than akinetic mutism by general physicians. Therefore, the aim of this study was to identify whether there are predictive factors for early initiation of artificial feeding in patients with sCJD who require enteral nutrition due to swallowing failure. Methods: We retrospectively reviewed the medical records of all patients diagnosed with probable sCJD who were admitted to the neurology ward at a medical center in Taiwan from January 2002 to July 2017. We used Pearson's chi-squared test to detect the correlation of initial symptoms, neurological signs, brain magnetic resonance imaging (MRI), electroencephalography (EEG), and increased levels of 14-3-3 protein in cerebrospinal fluid (CSF) analysis. The Cox proportional hazards model was used to detect prognostic factors for early initiation of NG tube insertion in sCJD patients. Results: The onset age ranged from 51 to 83 years, and mostly ranged from 60 to 79 years. Akinetic mutism was correlated with pyramidal tract signs, myoclonus, and extrapyramidal signs. Furthermore, myoclonus was revealed to be associated with pyramidal tract signs. Multivariate Cox regression analysis showed that myoclonus and elevated CSF levels of 14-3-3 protein are predictive of early NG insertion. Conclusions: Increased levels of 14-3-3 protein in CSF and the presence of myoclonus at diagnosis are predictive of early swallowing difficulty and indicate rapid deterioration in probable sCJD. In addition to akinetic mutism, early initiation of artificial feeding can be used to predict early deterioration in sCJD. PMID- 30018589 TI - Pre-surgical Brain Mapping: To Rest or Not to Rest? PMID- 30018592 TI - Changes in Serial D-Dimer Levels Predict the Prognoses of Trousseau's Syndrome Patients. AB - Background: The development of acute multiple embolic infarctions (AMEI) resulting from cancer is known as Trousseau's syndrome (TS). At present, however, there is no good marker for predicting the prognosis of TS patients. In the present study, we evaluated the use of serial D-dimer levels as a prognostic marker for TS. Methods: This retrospective cohort study included 1,409 consecutive acute ischemic stroke patients. We selected a group of patients with TS showing AMEI (n = 38; TS group) and a group of patients with atrial fibrillation (Af) and AMEI (n = 35; Af group) as controls. Serial D-dimer levels were measured between days 7 and 28 after stroke (sub-acute phase) in 21 patients of the TS group and 24 patients of the Af group. Results: D-dimer levels at onset (acute phase) were significantly higher in the TS group (8.45 +/- 1.79 MUg/mL, n = 38) compared with the Af group (1.14 +/- 0.14 MUg/mL, n = 35) (p < 0.0001). In patients for whom serial D-dimer measurements were made, D-dimer levels measured at the sub-acute phase decreased to 0.48 +/- 0.12 MUg/mL (n = 24) in the Af group, but remained elevated in the TS group during the sub-acute phase (11.20 +/ 2.77 MUg/mL, n = 21) (p < 0.0001). In all TS patients in whom serial D-dimer measurements were made, D-dimer levels in 17 patients who died within 500 days (13.31 +/- 3.23 MUg/mL) were significantly higher than those of the four surviving patients (2.23 +/- 0.38 MUg/mL) (cut-off D-dimer level = 3.0 MUg/mL) during this period. Moreover, serial D-dimer levels of 10 patients who died within 90 days (17.78 +/- 4.60 MUg/mL) were significantly higher than those of the 11 patients who survived up to 90 days (5.21 +/- 2.12 MUg/mL) (p < 0.05). Conclusions: Serial D-dimer levels may be a good biomarker for TS as well as a useful predictor of the prognosis of TS patients. PMID- 30018590 TI - Neuroprotective Drugs in Infants With Severe Congenital Heart Disease: A Systematic Review. AB - Background: Perinatal and perioperative brain injury is a fundamental problem in infants with severe congenital heart disease undergoing neonatal cardiac surgery with cardiopulmonary bypass. An impaired neuromotor and neurocognitive development is encountered and associated with a reduction in quality of life. New neuroprotective drugs during surgery are described to reduce brain injury and improve neurodevelopmental outcome. Therefore, our aim was to provide a systematic review and best-evidence synthesis on the effects of neuroprotective drugs on brain injury and neurodevelopmental outcome in congenital heart disease infants requiring cardiac surgery with cardiopulmonary bypass. Methods: A systematic search was performed in PubMed, Embase and the Cochrane Library (PRISMA statement). Search terms were "infants," "congenital heart disease," "cardiac surgery," "cardiopulmonary bypass," and "neuroprotective drug." Data describing the effects on brain injury and neurodevelopmental outcome were extracted. Study quality was assessed with the Cochrane Risk of Bias Tool. Two reviewers independently screened sources, extracted data and scored bias. Disagreements were resolved by involving a third researcher. Results: The search identified 293 studies of which 6 were included. In total 527 patients with various congenital heart diseases participated with an average of 88 infants (13 318) per study. Allopurinol, sodium nitroprusside, erythropoietin, ketamine, dextromethorphan and phentolamine were administered around cardiac surgery with cardiopulmonary bypass. Allopurinol showed less seizures, coma, death and cardiac events in hypoplastic left heart syndrome (HLHS) infants (OR: 0.44; 95%-CI:0.21 0.91). Sodium nitroprusside resulted in lower post cardiopulmonary bypass levels of S100beta in infants with transposition of the great arteries after 24 (p < 0.01) and 48 (p = 0.04) h of treatment. Erytropoietin, ketamine and dextromethorphan showed no neuroprotective effects. Phentolamine led to higher S100beta-levels and cerebrovascular resistance after rewarming and at the end of surgery (both p < 0.01). Risk of bias varied between studies, including low (sodium nitroprusside, phentolamine), moderate (ketamine, dextromethorphan), and high (erytropoietin, allopurinol) quality. Conclusions: Allopurinol seems promising for future trials in congenital heart disease infants to reduce brain injury given the early neuroprotective effects in hypoplastic left heart syndrome infants. Larger well-designed trials are needed to assess the neuroprotective effects of sodium nitroprusside, erytropoietin, ketamine and dextromethorphan. Future neuroprotective studies in congenital heart disease infants should not only focus on the perioperative period, however also on the perinatal period, since significant brain injury already exists before surgery. PMID- 30018591 TI - The Clinical and Radiological Spectrum of Hippocampal Pathology in Amyotrophic Lateral Sclerosis. AB - Hippocampal pathology in Amyotrophic Lateral Sclerosis (ALS) remains surprisingly under recognized despite compelling evidence from neuropsychology, neuroimaging and neuropathology studies. Hippocampal dysfunction contributes significantly to the clinical heterogeneity of ALS and requires structure-specific cognitive and neuroimaging tools for accurate in vivo evaluation. Recent imaging studies have generated unprecedented insights into the presymptomatic and longitudinal processes affecting this structure and have contributed to the characterisation of both focal and network-level changes. Emerging neuropsychology data suggest that memory deficits in ALS may be independent from executive dysfunction. In the era of precision medicine, where the development of individualized care strategies and patient stratification for clinical trials are key priorities, the comprehensive review of hippocampal dysfunction in ALS is particularly timely. PMID- 30018593 TI - Exposure to Perchlorate in Lactating Women and Its Associations With Newborn Thyroid Stimulating Hormone. AB - Background: Perchlorate, thiocyanate, and nitrate can block iodide transport at the sodium iodide symporter (NIS) and this can subsequently lead to decreased thyroid hormone production and hypothyroidism. NIS inhibitor exposure has been shown to reduce iodide uptake and thyroid hormone levels; therefore we hypothesized that maternal NIS inhibitor exposure will influence both maternal and newborn thyroid function. Methods: Spot urine samples were collected from 185 lactating mothers and evaluated for perchlorate, thiocyanate, and nitrate concentrations. Blood and colostrum samples were collected from the same participants in the first 48 h after delivery. Thyroid hormones and thyroid related antibodies (TSH, fT3, fT4, anti-TPO, anti-Tg) were analyzed in maternal blood and perchlorate was analyzed in colostrum. Also, spot blood samples were collected from newborns (n = 185) between 48 and 72 postpartum hours for TSH measurement. Correlation analysis was performed to assess the effect of NIS inhibitors on thyroid hormone levels of lactating mothers and their newborns in their first 48 postpartum hours. Results: The medians of maternal urinary perchlorate (4.00 MUg/g creatinine), maternal urinary thiocyanate (403 MUg/g creatinine), and maternal urinary nitrate (49,117 MUg/g creatinine) were determined. Higher concentrations of all three urinary NIS inhibitors (MUg/g creatinine) at their 75th percentile levels were significantly correlated with newborn TSH (r = 0.21, p < 0.001). Median colostrum perchlorate level concentration of all 185 participants was 2.30 MUg/L. Colostrum perchlorate was not significantly correlated with newborn TSH (p > 0.05); however, there was a significant correlation between colostrum perchlorate level and maternal TSH (r = 0.21, p < 0.01). Similarly, there was a significant positive association between colostrum perchlorate and maternal urinary creatinine adjusted perchlorate (r = 0.32, p < 0.001). Conclusion: NIS inhibitors are ubiquitous in lactating women in Turkey and are associated with increased TSH levels in newborns, thus signifying for the first time that co-exposure to maternal NIS inhibitors can have a negative effect on the newborn thyroid function. PMID- 30018594 TI - Genome Plasticity in Cultured Leishmania donovani: Comparison of Early and Late Passages. AB - Leishmania donovani possesses a complex heteroxenic life cycle where infective metacyclic promastigotes are pre-adapted to infect their host and cope up with intracellular stress. Exploiting the similarities between cultured and sandfly derived promastigotes, we used early and late passage cultured promastigotes to show specific changes at genome level which compromise pathogen fitness reflected in gene expression and infection studies. The pathogen loses virulence mostly via transcriptional and translational regulations and long-time cultivation makes them struggle to convert to virulent metacyclics. At the genomic level very subtle plasticity was observed between the early and the late passages mostly in defense-related, nutrient acquisition and signal transduction genes. Chromosome Copy number variation is seen in the early and late passages involving several genes that may be playing a role in pathogenicity. Our study highlights the importance of ABC transporters and calpain like cysteine proteases in parasite virulence in cultured promastigotes. Interestingly, these proteins are emerging as important patho-adaptive factors in clinical isolates of Leishmania. We found that the currently available genome of Leishmania in the NCBI database are from late passages. Our early passage genome can act as a reference for future studies on virulent isolates of Leishmania. The annotated leads from this study can be used for virulence surveillance and therapeutic studies in the Indian subcontinent. PMID- 30018596 TI - On the Natural History of Flavin-Based Electron Bifurcation. AB - Electron bifurcation is here described as a special case of the continuum of electron transfer reactions accessible to two-electron redox compounds with redox cooperativity. We argue that electron bifurcation is foremost an electrochemical phenomenon based on (a) strongly inverted redox potentials of the individual redox transitions, (b) a high endergonicity of the first redox transition, and (c) an escapement-type mechanism rendering completion of the first electron transfer contingent on occurrence of the second one. This mechanism is proposed to govern both the traditional quinone-based and the newly discovered flavin based versions of electron bifurcation. Conserved and variable aspects of the spatial arrangement of electron transfer partners in flavoenzymes are assayed by comparing the presently available 3D structures. A wide sample of flavoenzymes is analyzed with respect to conserved structural modules and three major structural groups are identified which serve as basic frames for the evolutionary construction of a plethora of flavin-containing redox enzymes. We argue that flavin-based and other types of electron bifurcation are of primordial importance to free energy conversion, the quintessential foundation of life, and discuss a plausible evolutionary ancestry of the mechanism. PMID- 30018598 TI - Chemotaxonomy of Mycotoxigenic Small-Spored Alternaria Fungi - Do Multitoxin Mixtures Act as an Indicator for Species Differentiation? AB - Necrotrophic as well as saprophytic small-spored Alternaria (A.) species are annually responsible for major losses of agricultural products, such as cereal crops, associated with the contamination of food and feedstuff with potential health-endangering Alternaria toxins. Knowledge of the metabolic capabilities of different species-groups to form mycotoxins is of importance for a reliable risk assessment. 93 Alternaria strains belonging to the four species groups Alternaria tenuissima, A. arborescens, A. alternata, and A. infectoria were isolated from winter wheat kernels harvested from fields in Germany and Russia and incubated under equal conditions. Chemical analysis by means of an HPLC-MS/MS multi Alternaria-toxin-method showed that 95% of all strains were able to form at least one of the targeted 17 non-host specific Alternaria toxins. Simultaneous production of up to 15 (modified) Alternaria toxins by members of the A. tenuissima, A. arborescens, A. alternata species-groups and up to seven toxins by A. infectoria strains was demonstrated. Overall tenuazonic acid was the most extensively formed mycotoxin followed by alternariol and alternariol mono methylether, whereas altertoxin I was the most frequently detected toxin. Sulfoconjugated modifications of alternariol, alternariol mono methylether, altenuisol and altenuene were frequently determined. Unknown perylene quinone derivatives were additionally detected. Strains of the species-group A. infectoria could be segregated from strains of the other three species-groups due to significantly lower toxin levels and the specific production of infectopyrone. Apart from infectopyrone, alterperylenol was also frequently produced by 95% of the A. infectoria strains. Neither by the concentration nor by the composition of the targeted Alternaria toxins a differentiation between the species-groups A. alternata, A. tenuissima and A. arborescens was possible. PMID- 30018595 TI - Candida Infections and Therapeutic Strategies: Mechanisms of Action for Traditional and Alternative Agents. AB - The Candida genus comprises opportunistic fungi that can become pathogenic when the immune system of the host fails. Candida albicans is the most important and prevalent species. Polyenes, fluoropyrimidines, echinocandins, and azoles are used as commercial antifungal agents to treat candidiasis. However, the presence of intrinsic and developed resistance against azole antifungals has been extensively documented among several Candida species. The advent of original and re-emergence of classical fungal diseases have occurred as a consequence of the development of the antifungal resistance phenomenon. In this way, the development of new satisfactory therapy for fungal diseases persists as a major challenge of present-day medicine. The design of original drugs from traditional medicines provides new promises in the modern clinic. The urgent need includes the development of alternative drugs that are more efficient and tolerant than those traditional already in use. The identification of new substances with potential antifungal effect at low concentrations or in combination is also a possibility. The present review briefly examines the infections caused by Candida species and focuses on the mechanisms of action associated with the traditional agents used to treat those infections, as well as the current understanding of the molecular basis of resistance development in these fungal species. In addition, this review describes some of the promising alternative molecules and/or substances that could be used as anticandidal agents, their mechanisms of action, and their use in combination with traditional drugs. PMID- 30018599 TI - Synergistic Effect of Newly Introduced Root Canal Medicaments; Ozonated Olive Oil and Chitosan Nanoparticles, Against Persistent Endodontic Pathogens. AB - This study was conducted to investigate the antimicrobial-biofilm activity of chitosan (Ch-NPs), silver nanoparticles (Ag-NPs), ozonated olive oil (O3-oil) either separately or combined together against endodontic pathogens. While testing the antimicrobial activity, Ch-NPs showed the least minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values exerting eightfold higher bactericidal activity than O3-oil against both Enterococcus faecalis and Streptococcus mutans as well as fourfold higher fungicidal activity against Candida albicans. Antimicrobial synergy test revealed synergism between O3-oil and Ch-NPs against the test pathogens (FIC index <= 0.5). Ch-NPs was superior at inhibiting immature single and mixed-species biofilm formations by 97 and 94%, respectively. Both of O3-oil and Ch-NPs had a complete anti-fibroblast adherent effect. The safety pattern results showed that O3-oil was the safest compound, followed by Ch-NPs. The double combination of Ch-NPs and O3-oil reduced the mature viable biofilm on premolars ex vivo model by 6-log reductions, with a fast kill rate, indicating potential use in treating root canals. Therefore, the double combination has the potential to eradicate mature mixed-species biofilms and hence it is potent, novel and safe. PMID- 30018600 TI - Analysis on Metabolic Functions of Stored Rice Microbial Communities by BIOLOG ECO Microplates. AB - Microbial contamination has been a pervasive issue during the rice storage and triggers extensive researches. The metabolism of microorganisms was proved as an indicator to mirror the degree of microbial contamination. It is necessary to develop a scientific method to analyze the metabolism of rice microbial communities, thereby monitoring the microbial contamination. In this study, the metabolism of rice microbial communities in different storing-year were investigated by BIOLOG ECO microplates. The three rice samples were respectively stored for 1-3 years. The related indicators of BIOLOG ECO microplates were determined, including average well-color development (AWCD) of carbon sources and three metabolic functional diversity indices. The results showed that there were significant differences in the AWCD of all carbon sources among the three rice microbial communities (p < 0.05), and the functional diversity indices except Simpson index showed significant differences (p < 0.05). Additionally, the three rice microbial communities differed significantly in the metabolic utilization of carboxylic acids and miscellaneous (p < 0.05), and there were, however, no significant differences in the other four types of carbon sources. Furthermore, principal component analysis revealed that the microbial communities of stored rice had obviously different metabolic functions in different storage period. Therefore, the study indicated that the BIOLOG ECO microplate was applicable to evaluate the metabolic functions of rice microbial communities, and carboxylic acids and miscellaneous were two crucial parameters of carbon sources to identify the metabolic differences of microbial communities, a case in which it reflected the conditions of rice microbial contamination. PMID- 30018597 TI - Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis. AB - The emergence of multi- and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the "instruction manual" of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's "rule of five" and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes. PMID- 30018601 TI - Stoichiometric Shifts in Soil C:N:P Promote Bacterial Taxa Dominance, Maintain Biodiversity, and Deconstruct Community Assemblages. AB - Imbalances in C:N:P supply ratios may cause bacterial resource limitations and constrain biogeochemical processes, but the importance of shifts in soil stoichiometry are complicated by the nearly limitless interactions between an immensely rich species pool and a multiple chemical resource forms. To more clearly identify the impact of soil C:N:P on bacteria, we evaluated the cumulative effects of single and coupled long-term nutrient additions (i.e., C as mannitol, N as equal concentrations NH4+ and NO3-, and P as Na3PO4) and water on communities in an Antarctic polar desert, Taylor Valley. Untreated soils possessed relatively low bacterial diversity, simplified organic C sources due to the absence of plants, limited inorganic N, and excess soil P potentially attenuating links between C:N:P. After 6 years of adding resources, an alleviation of C and N colimitation allowed one rare Micrococcaceae, an Arthrobacter species, to dominate, comprising 47% of the total community abundance and elevating soil respiration by 136% relative to untreated soils. The addition of N alone reduced C:N ratios, elevated bacterial richness and diversity, and allowed rare taxa relying on ammonium and nitrite for metabolism to become more abundant [e.g., nitrite oxidizing Nitrospira species (Nitrosomonadaceae), denitrifiers utilizing nitrite (Gemmatimonadaceae) and members of Rhodobacteraceae with a high affinity for ammonium]. Based on community co-occurrence networks, lower C:P ratios in soils following P and CP additions created more diffuse and less connected communities by disrupting 73% of species interactions and selecting for taxa potentially exploiting abundant P. Unlike amended nutrients, water additions alone elicited no lasting impact on communities. Our results suggest that as soils become nutrient rich a wide array of outcomes are possible from species dominance and the deconstruction of species interconnectedness to the maintenance of biodiversity. PMID- 30018602 TI - Evaluating the Antibiotic Susceptibility of Chlamydia - New Approaches for in Vitro Assays. AB - Pigs are the natural hosts of Chlamydia suis, the only Chlamydia species known to spontaneously acquire homotypic resistance conferred by a class C tetracycline resistance gene. Various susceptibility assays have existed for several years, but there is no widely accepted, standardized assay to determine chlamydial antibiotic susceptibility. In this study, we developed new approaches to determine the in vitro susceptibility of Chlamydia to different antibiotics in view of existing protocols. Specifically, the minimal inhibitory concentration (MIC) is based on a consensus of both inclusion number reduction and alteration of inclusion size and morphology upon antibiotic exposure. In addition to these, we employed a recovery assay, allowing observation of the chlamydial response to drug removal and subsequent recovery, as compared to both continued exposure and to the unexposed control. We propose a simple and fast screening method to detect tetracycline resistant C. suis strains within 2 to 3 days with minimal use of consumables. For proof of principle, we evaluated the susceptibility of three C. suis field strains and the reference strain S45/6 to tetracycline, sulfamethoxazole, and penicillin, antibiotics commonly used to prevent respiratory and gastrointestinal diseases on fattening pig farms. We found that tetracycline sensitive strains can easily be distinguished from resistant strains using the evaluation parameters proposed in this study. Moreover, we report that S45/6 is sensitive to sulfamethoxazole while all evaluated C. suis field strains showed some degree of sulfamethoxazole resistance. Finally, we confirm that Penicillin G induces the chlamydial stress response in all evaluated C. suis strains. PMID- 30018604 TI - Leishmanicidal and Immunomodulatory Activities of the Palladacycle Complex DPPE 1.1, a Potential Candidate for Treatment of Cutaneous Leishmaniasis. AB - The present study focused on the activity of the palladacycle complex DPPE 1.1 on Leishmania (Leishmania) amazonensis. Promastigotes of L. (L.) amazonensis were destroyed in vitro by nanomolar concentrations of DPPE 1.1, whereas intracellular amastigotes were killed at drug concentrations fivefold less toxic than those harmful to macrophages. L. (L.) amazonensis-infected BALB/c mice were treated by intralesional injection of DPPE 1.1. Animals treated with 3.5 and 7.0 mg/kg of DPPE 1.1 showed a significant decrease of foot lesion sizes and a parasite load reduction of 93 and 99%, respectively, when compared to untreated controls. Furthermore, DPPE 1.1 was non-toxic to treated animals. The cathepsin B activity of L. (L.) amazonensis amastigotes was inhibited by DPPE 1.1 as demonstrated spectrofluorometrically by use of a specific fluorogenic substrate. Analysis of T cells populations in mice treated with DPPE 1.1 and untreated controls was performed by fluorescence-activated cell sorter (FACS). IFN-gamma was measured in supernatants of lymphocytes from popliteal and inguinal lymph nodes isolated from treated and untreated mice and stimulated with L. (L.) amazonensis amastigotes extract and active TGF-beta was evaluated in supernatants of foot lesions; both dosages were carried out by means of a double-sandwich ELISA assay. A significant increase of TCD4+ and TCD8+ lymphocytes and IFN-gamma secretion was displayed in mice treated with DPPE 1.1 compared to untreated animals, whereas a significant reduction of active TGF-beta was observed in treated mice. These findings open perspectives for further investment in DPPE 1.1 as an alternative option for the chemotherapy of cutaneous leishmaniasis. PMID- 30018603 TI - Fullerenes Influence the Toxicity of Organic Micro-Contaminants to River Biofilms. AB - Organic micro-contaminants (OMCs) enter in freshwaters and interact with other contaminants such as carbon nanoparticles, becoming a problem of unknown consequences for river ecosystems. Carbon nanoparticles (as fullerenes C60) are good adsorbents of organic contaminants and their interaction can potentially affect their toxicity to river biofilms. We tested the C60 interactions with selected OMCs and their effects on river biofilms in different short-term experiments. In these, river biofilms were exposed to C60 and three OMCs (triclosan, diuron, or venlafaxine) and their respective mixtures with fullerenes (C60 + each OMC). The effects were evaluated on structural, molecular, and functional descriptors of river biofilms. Our results showed that C60 did not cause toxic effects in river biofilms, whereas diuron and triclosan significantly affected the heterotrophic and phototrophic components of biofilms and venlafaxine affected only the phototrophic component. The joint exposure of C60 with venlafaxine was not producing differences with respect to the former response of the toxicant, but the overall response was antagonistic (i.e., decreased toxicity) with diuron, and synergistic (i.e., increased toxicity) with triclosan. We suggest that differences in the toxic responses could be related to the respective molecular structure of each OMC, to the concentration proportion between OMC and C60, and to the possible competition between C60 pollutants on blocking the receptors of the biological cell membranes. We conclude that the presence of C60 at low concentrations modified the toxicity of OMC to river biofilms. These interactions should therefore be considered when predicting toxicity of OMC in river ecosystems. PMID- 30018605 TI - Herbaspirillum seropedicae Differentially Expressed Genes in Response to Iron Availability. AB - Herbaspirillum seropedicae Z67 is a nitrogen-fixing endophyte that colonizes many important crops. Like in almost all organisms, vital cellular processes of this endophyte are iron dependent. In order to efficiently acquire iron to fulfill its requirements, this bacterium produces the siderophores serobactins. However, the presence in its genome of many others iron acquisition genes suggests that serobactins are not the only strategy used by H. seropedicae to overcome metal deficiency. The aim of this work was to identify genes and proteins differentially expressed by cells growing in low iron conditions in order to describe H. seropedicae response to iron limitation stress. For this purpose, and by using a transcriptomic approach, we searched and identified a set of genes up regulated when iron was scarce. One of them, Hsero_2337, codes for a TonB dependent transporter/transducer present in the serobactins biosynthesis genomic locus, with an unknown function. Another TonB-dependent receptor, the one encoded by Hsero_1277, and an inner membrane ferrous iron permease, coded by Hsero_2720, were also detected. By using a proteomic approach focused in membrane proteins, we identified the specific receptor for iron-serobactin internalization SbtR and two non-characterized TonB-dependent receptors (coded by genes Hsero_1277 and Hsero_3255). We constructed mutants on some of the identified genes and characterized them by in vitro growth, biofilm formation, and interaction with rice plants. Characterization of mutants in gene Hsero_2337 showed that the TonB dependent receptor coded by this gene has a regulatory role in the biosynthesis of serobactins, probably by interacting with the alternative sigma factor PfrI, coded by gene Hsero_2338. Plant colonization of the mutant strains was not affected, since the mutant strain normally colonize the root and aerial part of rice plants. These results suggest that the strategies used by H. seropedicae to acquire iron inside plants are far more diverse than the ones characterized in this work. In vivo expression studies or colonization competition experiments between the different mutant strains could help us in future works to determine the relative importance of the different iron acquisition systems in the interaction of H. seropedicae with rice plants. PMID- 30018607 TI - Enzymatic Study of Linoleic and Alpha-Linolenic Acids Biohydrogenation by Chloramphenicol-Treated Mixed Rumen Bacterial Species. AB - In the rumen, dietary polyunsaturated fatty acids (PUFA) are reduced by a multistage reaction called biohydrogenation (BH). BH leads to a high proportion of saturated fat in ruminant products, but also products some potential bioactive intermediates like conjugated linoleic and linolenic acids. BH is composed of two kinds of reactions: first an isomerization of PUFA followed by reductions (two for linoleic acid, C18:2n-6; three for alpha-linolenic acid, C18:3n-3). There is little knowledge about BH enzymes as BH bacterial species are the subject of a lot of studies. Nevertheless, both aspects must be explored to control BH and enhance the fatty acids profile of ruminant products. In the present study, an alternative approach was developed to study the enzymes produced in vivo by mixed ruminal bacteria, using inactivation of bacteria by chloramphenicol, an inhibitor of protein synthesis in prokaryotes, before in vitro incubation. To study C18:2n 6 and C18:3n-3 BH several experiments were used: (1) with different incubation durations (0 to 3) to estimate average rates and efficiencies of all BH reactions, and intermediates production; and (2) with different initial quantities of PUFA (0.25 to 2 mg) to estimate Michaelis-Menten enzymatic parameters, Km and Vmax. A last experiment explored the effect of pH buffer and donor cow diet on C18:2n-6 isomerization pathways. Concerning C18:2n-6 BH, this study confirmed the high saturability of its isomerization, the inhibition of both trans11 and trans10 pathways by a low pH, and the last reduction to stearic acid as the limiting-step. Concerning C18:3n-3, its BH was faster than C18:2n-6, in particular its isomerization (Vmax = 3.4 vs. 0.6 mM/h, respectively), and the limiting-step was the second reduction to t11-C18:1. Besides, our mixed isomerases had a higher affinity for C18:2n-6 than for C18:3n-3 (Km = 2.0 * 10-3 vs. 4.3 * 10-3 M, respectively), but due to their high saturability by C18:2n-6, they had a lower efficiency to isomerize C18:2n-6 than C18:3n-3. Chloramphenicol treated ruminal fluid would be a meaningful method to study the BH enzymes activities. PMID- 30018608 TI - Phomopsis longanae Chi-Induced Disease Development and Pericarp Browning of Harvested Longan Fruit in Association With Energy Metabolism. AB - Longan fruit is a popular subtropical fruit with a relatively short shelf life at room temperature mainly due to pericarp browning and fungal infection. This study aimed to investigate the infection of Phomopsis longanae Chi in longan fruit and its effects on the storability and shelf life of longan fruit. The relationship between the energy metabolism of harvested longan fruit and disease development and pericarp browning was elucidated. Results show that P. longanae-inoculation accelerated the deterioration of longan fruit and caused pericarp browning. It also led to the energy deficit in pericarp of longan fruit, which was reflected as lower contents of ATP and ADP, higher AMP content, and lower energy charge as compared to the control samples. Additionally, P. longanae-infection reduced the activities of H+-ATPase, Ca2+-ATPase, and Mg2+-ATPase in plasma, vacuolar, and mitochondrial membranes during the storage period. The results demonstrate that P. longanae-infection led to disease development and pericarp browning in harvested longan fruit, which were due to the infection-induced energy deficit and low ATPase activity that caused disorders of ion transport and distribution, and damaged the structure and function of vacuole, mitochondria, and eventually the whole cells of fruit tissues. PMID- 30018606 TI - A Novel Silver Bioactive Glass Elicits Antimicrobial Efficacy Against Pseudomonas aeruginosa and Staphylococcus aureus in an ex Vivo Skin Wound Biofilm Model. AB - Biofilm infection is now understood to be a potent contributor to the recalcitrant nature of chronic wounds. Bacterial biofilms evade the host immune response and show increased resistance to antibiotics. Along with improvements in antibiotic stewardship, effective new anti-biofilm therapies are urgently needed for effective wound management. Previous studies have shown that bioactive glass (Bg) is able to promote healing with moderate bactericidal activity. Here we tested the antimicrobial efficacy of a novel BG incorporating silver (BgAg), against both planktonic and biofilm forms of the wound-relevant bacteria Pseudomonas aeruginosa and Staphylococcus aureus. BgAg was stable, long lasting, and potently effective against planktonic bacteria in time-kill assays (6-log reduction in bacterial viability within 2 h) and in agar diffusion assays. BgAg reduced bacterial load in a physiologically relevant ex vivo porcine wound biofilm model; P. aeruginosa (2-log reduction) and S. aureus (3-log reduction). BgAg also conferred strong effects against P. aeruginosa biofilm virulence, reducing both protease activity and virulence gene expression. Co-culture biofilms appeared more resistant to BgAg, where a selective reduction in S. aureus was observed. Finally, BgAg was shown to benefit the host response to biofilm infection, directly reducing host tissue cell death. Taken together, the findings provide evidence that BgAg elicits potent antimicrobial effects against planktonic and single-species biofilms, with beneficial effects on the host tissue response. Further investigations are required to elucidate the specific consequences of BG administration on polymicrobial biofilms, and further explore the effects on host-microbe interactions. PMID- 30018609 TI - Transcriptome Study of an Exophiala dermatitidis PKS1 Mutant on an ex Vivo Skin Model: Is Melanin Important for Infection? AB - The black yeast Exophiala dermatitidis is a polyextremophilic human pathogen, especially known for growing in man-made extreme environments. Reported diseases caused by this fungus range from benign cutaneous to systemic infections with 40% fatality rate. While the number of cases steadily increases in both immunocompromised and immunocompetent people, detailed knowledge about infection mechanisms, virulence factors and host response are scarce. To understand the impact of the putative virulence factor melanin on the infection, we generated a polyketide synthase (PKS1) mutant using CRISPR/Cas9 resulting in a melanin deficient strain. The mutant and the wild-type fungus were inoculated onto skin explants using an ex vivo skin organ culture model to simulate in vivo cutaneous infection. The difference between the mutant and wild-type transcriptional landscapes, as assessed by whole RNA-sequencing, were small and were observed in pathways related to the copper homeostasis, cell wall genes and proteases. Seven days after inoculation the wild-type fungus completely colonized the stratum corneum, invaded the skin and infected keratinocytes while the mutant had only partially covered the skin and showed no invasiveness. Our results suggest that melanin dramatically improves the invasiveness and virulence of E. dermatitidis during the first days of the skin infection. PMID- 30018611 TI - The Effects of Arbuscular Mycorrhizal Fungal Colonisation on Nutrient Status, Growth, Productivity, and Canker Resistance of Apple (Malus pumila). AB - We assess whether arbuscular mycorrhizal fungi (AMF) improve growth, nutritional status, phenology, flower and fruit production, and disease resistance in woody perennial crops using apple (Malus pumila) as a study system. In a fully factorial experiment, young trees were grown for 3 years with or without AMF (Funneliformis mosseae and Rhizophagus irregularis), and with industrial standard fertiliser applications or restricted fertiliser (10% of standard). We use two commercial scions (Dabinett and Michelin) and rootstocks (MM111 and MM106). Industrial standard fertiliser applications reduced AMF colonisation and root biomass, potentially increasing drought sensitivity. Mycorrhizal status was influenced by above ground genotypes (scion type) but not rootstocks, indicating strong interactions between above and below ground plant tissue. The AMF inoculation significantly increased resistance to Neonectria ditissima, a globally economically significant fungal pathogen of apple orchards, but did not consistently alter leaf nutrients, growth, phenology or fruit and flower production. This study significantly advances understanding of AMF benefits to woody perennial crops, especially increased disease resistance which we show is not due to improved tree nutrition or drought alleviation. Breeding programmes and standard management practises can limit the potential for these benefits. PMID- 30018610 TI - GPD1 and ADH3 Natural Variants Underlie Glycerol Yield Differences in Wine Fermentation. AB - Glycerol is one of the most important by-products of alcohol fermentation, and depending on its concentration it can contribute to wine flavor intensity and aroma volatility. Here, we evaluated the potential of utilizing the natural genetic variation of non-coding regions in budding yeast to identify allelic variants that could modulate glycerol phenotype during wine fermentation. For this we utilized four Saccharomyces cerevisiae strains (WE - Wine/European, SA - Sake, NA - North American, and WA - West African), which were previously profiled for genome-wide Allele Specific Expression (ASE) levels. The glycerol yields under Synthetic Wine Must (SWM) fermentations differed significantly between strains; WA produced the highest glycerol yields while SA produced the lowest yields. Subsequently, from our ASE database, we identified two candidate genes involved in alcoholic fermentation pathways, ADH3 and GPD1, exhibiting significant expression differences between strains. A reciprocal hemizygosity assay demonstrated that hemizygotes expressing GPD1WA , GPD1SA , ADH3WA and ADH3SA alleles had significantly greater glycerol yields compared to GPD1WE and ADH3WE . We further analyzed the gene expression profiles for each GPD1 variant under SWM, demonstrating that the expression of GPD1WE occurred earlier and was greater compared to the other alleles. This result indicates that the level, timing, and condition of expression differ between regulatory regions in the various genetic backgrounds. Furthermore, promoter allele swapping demonstrated that these allele expression patterns were transposable across genetic backgrounds; however, glycerol yields did not differ between wild type and modified strains, suggesting a strong trans effect on GPD1 gene expression. In this line, Gpd1 protein levels in parental strains, particularly Gpd1pWE, did not necessarily correlate with gene expression differences, but rather with glycerol yield where low Gpd1pWE levels were detected. This suggests that GPD1WE is influenced by recessive negative post-transcriptional regulation which is absent in the other genetic backgrounds. This dissection of regulatory mechanisms in GPD1 allelic variants demonstrates the potential to exploit natural alleles to improve glycerol production in wine fermentation and highlights the difficulties of trait improvement due to alternative trans-regulation and gene-gene interactions in the different genetic background. PMID- 30018612 TI - Sewage Sludge Microbial Structures and Relations to Their Sources, Treatments, and Chemical Attributes. AB - Sewage sludges generation and their disposal have become one of the greatest challenges of the 21st century. They have great microbial diversity that may impact wastewater treatment plant (WWTP) efficiency and soil quality whether used as fertilizers. Therefore, this research aimed to characterize microbial community diversity and structure of 19 sewage sludges from Sao Paulo, Brazil, as well as to draw their relations to sludge sources [domestic and mixed (domestic+industrial)], biological treatments (redox conditions and liming), and chemical attributes, using molecular biology as a tool. All sludges revealed high bacterial diversity, but their sources and redox operating conditions as well as liming did not consistently affect bacterial community structures. Proteobacteria was the dominant phylum followed by Bacteroidetes and Firmicutes; whereas Clostridium was the dominant genus followed by Treponema, Propionibacterium, Syntrophus, and Desulfobulbus. The sludge samples could be clustered into six groups (C1 to C6) according their microbial structure similarities. Very high pH (>=11.9) was the main sludge attribute segregating C6, that presented very distinct microbial structure from the others. Its most dominant genera were Propionibacterium > > Comamonas > Brevundimonas > Methylobacterium ~Stenotrophomonas ~Cloacibacterium. The other clusters' dominant genera were Clostridium > > Treponema > Desulfobulbus ~Syntrophus. Moreover, high Fe and S were important modulators of microbial structure in certain sludges undertaking anaerobic treatment and having relatively low N-Kj, B, and P contents (C5). However, high N-Kj, B, P, and low Fe and Al contents were typical of domestic, unlimed, and aerobically treated sludges (C1). In general, heavy metals had little impact on microbial community structure of the sludges. However, our sludges shared a common core of 77 bacteria, mostly Clostridium, Treponema, Syntrophus, and Comamonas. They should dictate microbial functioning within WWTPs, except by SS12 and SS13. PMID- 30018613 TI - Outer Membrane Lipoprotein Lip40 Modulates Adherence, Colonization, and Virulence of Actinobacillus pleuropneumoniae. AB - Bacterial lipoproteins are a set of membrane proteins with various functions; many of which are virulence factors of pathogenic bacteria. In the present study, we investigated the role of an outer membrane lipoprotein Lip40 in the pathogenesis of Actinobacillus pleuropneumoniae. A mutant strain (Deltalip40) lacking Lip40 and a complemented strain (CDeltalip40) were constructed. Deltalip40 exhibited reduced adherence to the St. Jude porcine lung cells. The ability of the Deltalip40 mutant to colonize the mouse lung tissues was significantly impaired compared to that of the wild type and complementation strains. Furthermore, an infection assay revealed that pigs infected with Deltalip40 showed fewer clinical signs and lung lesions, indicating that Lip40 contributed to the development of porcine pleuropneumonia. Collectively, our data suggest that Lip40 is involved in the virulence of A. pleuropneumoniae. PMID- 30018615 TI - High Tidal Volume Induces Mitochondria Damage and Releases Mitochondrial DNA to Aggravate the Ventilator-Induced Lung Injury. AB - Objective: This study aimed to determine whether high tidal volume (HTV) induce mitochondria damage and mitophagy, contributing to the release of mitochondrial DNA (mtDNA). Another aim of the present study was to investigate the role and mechanism of mtDNA in ventilator-induced lung injury (VILI) in rats. Methods: Rats were tracheotomized and allowed to breathe spontaneously or mechanically ventilated for 4 h. After that, lung injury was assessed. Inhibition of toll-like receptor 9 (TLR9), named ODN2088, was used to determine the involvement of TLR9/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappaB (NF-kappaB) signaling pathway in VILI. The mitochondrial damage and release of mtDNA were assessed. Pharmacological inhibition of mtDNA (chloroquine) was used to determine whether mtDNA trigger inflammation via TLR9 in VILI. EDU-labeled mtDNA deriving from mitophagy was assessed by immunofluorescence. The role of mitophagy in VILI was shown by administration of antimycin A and cyclosporine A. Main results: Rats subjected to HTV showed more severe pulmonary edema and inflammation than the other rats. The decreased expression of TLR9, MyD88, and NF-kappaB were observed following the use of ODN2088. Mechanical ventilation (MV) with HTV damaged mitochondria which resulted in dysfunctional ATP synthesis, accumulation of reactive oxygen species, and loss of mitochondrial membrane potential. Moreover, the results of distribution of fluorescence in rats upon HTV stimulation indicated that mtDNA cleavage was associated with mitophagy. The expression levels of mitophagy related genes (LC3B-II/LC3B-I, PINK1, Parkin, and mitofusin 1) in animals ventilated with HTV were significantly upregulated. Administration of antimycin A aggregated the histological changes and inflammation after MV, but these effects were attenuated when administered in the presence of cyclosporine A. Conclusion: MV with HTV induces mitochondrial damage and mitophagy, contributing to the release of mtDNA, which may be induced VILI in rat via TLR9/MyD88/NF-kappaB signaling pathway. PMID- 30018616 TI - Necrosis Driven Triglyceride Synthesis Primes Macrophages for Inflammation During Mycobacterium tuberculosis Infection. AB - Pulmonary tuberculosis (TB) exhibits granulomatous inflammation, a site of controlling bacterial dissemination at the cost of host tissue damage. Intrigued by the granuloma type-dependent expression of inflammatory markers in TB, we sought to investigate underlying metabolic changes that drive amplification of inflammation in TB. Here, we show an association of higher inflammation in necrotic granulomas with the presence of triglyceride (TG)-rich foamy macrophages. The conspicuous absence of these macrophages in solid granulomas identified a link between the ensuing pathology and the metabolic programming of foamy macrophages. Consistent with in vivo findings, in vitro infection of macrophages with Mycobacterium tuberculosis (Mtb) led to increase in TG synthesis only under conditions of ~60% necrosis. Genetic and pharmacologic intervention that reduced necrosis prevented this bystander response. We further demonstrate that necrosis independent of Mtb also elicits the same bystander response in human macrophages. We identified a role for the human enzyme involved in TG synthesis, diacylglycerol O-acyltransferase (DGAT1), in this phenomenon. The increased TG levels in necrosis-associated foamy macrophages promoted the pro inflammatory state of macrophages to infection while silencing expression of diacylglycerol O-acyltransferase (DGAT1) suppressed expression of pro inflammatory genes. Our data thus invoke a role for storage lipids in the heightened host inflammatory response during infection-associated necrosis. Our data provide a functional role to macrophage lipid droplets in host defense and open new avenues for developing host-directed therapies against TB. PMID- 30018614 TI - Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions. AB - Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases. PMID- 30018618 TI - Therapeutic Prospects of Extracellular Vesicles in Cancer Treatment. AB - Extracellular vesicles (EVs) are released by all cells within the tumor microenvironment, such as endothelial cells, tumor-associated fibroblasts, pericytes, and immune system cells. The EVs carry the cargo of parental cells formed of proteins and nucleic acids, which can convey cell-to-cell communication influencing the maintenance and spread of the malignant neoplasm, for example, promoting angiogenesis, tumor cell invasion, and immune escape. However, EVs can also suppress tumor progression, either by the direct influence of the protein and nucleic acid cargo of the EVs or via antigen presentation to immune cells as tumor-derived EVs carry on their surface some of the same antigens as the donor cells. Moreover, dendritic cell-derived EVs carry major histocompatibility complex class I and class II/peptide complexes and are able to prime other immune system cell types and activate an antitumor immune response. Given the relative longevity of vesicles within the circulation and their ability to cross blood brain barriers, modification of these unique organelles offers the potential to create new biological-tools for cancer therapy. This review examines how modification of the EV cargo has the potential to target specific tumor mechanisms responsible for tumor formation and progression to develop new therapeutic strategies and to increase the efficacy of antitumor therapies. PMID- 30018619 TI - Nuclear Factor kappaB Activation in a Type V Pityriasis Rubra Pilaris Patient Harboring Multiple CARD14 Variants. AB - Pityriasis rubra pilaris (PRP) is a rare papulosquamous skin disorder, which is phenotypically related to psoriasis. Some familial PRP cases show autosomal dominant inheritance due to CARD14 mutations leading to increased nuclear factor kappaB (NFkappaB) activation. Moreover, CARD14 polymorphisms have also been implicated in sporadic PRP. A Hungarian PRP patient with childhood onset disease showing worsening of the symptoms in adulthood with poor therapeutic response underwent genetic screening for the CARD14 gene, revealing four genetic variants (rs117918077, rs2066964, rs28674001, and rs11652075). To confirm that the identified genetic variants would result in altered NFkappaB activity in the patient, functional studies were carried out. Immunofluorescent staining of the NFkappaB p65 subunit and NFkappaB-luciferase reporter assay demonstrated significantly increased NFkappaB activity in skin samples and keratinocytes from the PRP patient compared to healthy samples. Characterization of the cytokine profile of the keratinocytes and peripheral blood mononuclear cells demonstrated that the higher NFkappaB activation in PRP cells induces enhanced responses to inflammatory stimuli. These higher inflammatory reactions could not be explained solely by the observed CARD14 or other inflammation-related gene variants (determined by whole exome sequencing). Thus our study indicates the importance of investigations on other genetic factors related to PRP and their further functional characterization to bring us closer to the understanding of cellular and molecular background of disease pathogenesis. PMID- 30018617 TI - Respiratory Mononuclear Phagocytes in Human Influenza A Virus Infection: Their Role in Immune Protection and As Targets of the Virus. AB - Emerging viruses have become increasingly important with recurrent epidemics. Influenza A virus (IAV), a respiratory virus displaying continuous re-emergence, contributes significantly to global morbidity and mortality, especially in young children, immunocompromised, and elderly people. IAV infection is typically confined to the airways and the virus replicates in respiratory epithelial cells but can also infect resident immune cells. Clearance of infection requires virus specific adaptive immune responses that depend on early and efficient innate immune responses against IAV. Mononuclear phagocytes (MNPs), comprising monocytes, dendritic cells, and macrophages, have common but also unique features. In addition to being professional antigen-presenting cells, MNPs mediate leukocyte recruitment, sense and phagocytose pathogens, regulate inflammation, and shape immune responses. The immune protection mediated by MNPs can be compromised during IAV infection when the cells are also targeted by the virus, leading to impaired cytokine responses and altered interactions with other immune cells. Furthermore, it is becoming increasingly clear that immune cells differ depending on their anatomical location and that it is important to study them where they are expected to exert their function. Defining tissue-resident MNP distribution, phenotype, and function during acute and convalescent human IAV infection can offer valuable insights into understanding how MNPs maintain the fine balance required to protect against infections that the cells are themselves susceptible to. In this review, we delineate the role of MNPs in the human respiratory tract during IAV infection both in mediating immune protection and as targets of the virus. PMID- 30018620 TI - Linkage Disequilibrium and Population Structure in Wild and Cultivated Populations of Rubber Tree (Hevea brasiliensis). AB - Among rubber tree species, which belong to the Hevea genus of the Euphorbiaceae family, Hevea brasiliensis (Willd. ex Adr.de Juss.) Muell. Arg. is the main commercial source of natural rubber production worldwide. Knowledge of the population structure and linkage disequilibrium (LD) of this species is essential for the efficient organization and exploitation of genetic resources. Here, we obtained single-nucleotide polymorphisms (SNPs) using a genotyping-by-sequencing (GBS) approach and then employed the SNPs for the following objectives: (i) to identify the positions of SNPs on a genetic map of a segregating mapping population, (ii) to evaluate the population structure of a germplasm collection, and (iii) to detect patterns of LD decay among chromosomes for future genetic association studies in rubber tree. A total of 626 genotypes, including both germplasm accessions (368) and individuals from a genetic mapping population (254), were genotyped. A total of 77,660 and 21,283 SNPs were detected by GBS in the germplasm and mapping populations, respectively. The mapping population, which was previously mapped, was constructed with 1,062 markers, among which only 576 SNPs came from GBS, reducing the average interval between two adjacent markers to 4.4 cM. SNPs from GBS genotyping were used for the analysis of genetic structure and LD estimation in the germplasm accessions. Two groups, which largely corresponded to the cultivated and wild populations, were detected using STRUCTURE and via principal coordinate analysis. LD analysis, also using the mapped SNPs, revealed that non-random associations varied along chromosomes, with regions of high LD interspersed with regions of low LD. Considering the length of the genetic map (4,693 cM) and the mean LD (0.49 for cultivated and 0.02 for wild populations), a large number of evenly spaced SNPs would be needed to perform genome-wide association studies in rubber tree, and the wilder the genotypes used, the more difficult the mapping saturation. PMID- 30018621 TI - Fire and Plant Diversification in Mediterranean-Climate Regions. AB - Despite decades of broad interest in global patterns of biodiversity, little attention has been given to understanding the remarkable levels of plant diversity present in the world's five Mediterranean-type climate (MTC) regions, all of which are considered to be biodiversity hotspots. Comprising the Mediterranean Basin, California, central Chile, the Cape Region of South Africa, and southwestern Australia, these regions share the unusual climatic regime of mild wet winters and warm dry summers. Despite their small extent, covering only about 2.2% of world land area, these regions are home to approximately one-sixth of the world vascular plant flora. The onset of MTCs in the middle Miocene brought summer drought, a novel climatic condition, but also a regime of recurrent fire. Fire has been a significant agent of selection in assembling the modern floras of four of the five MTC regions, with central Chile an exception following the uplift of the Andes in the middle Miocene. Selection for persistence in a fire-prone environment as a key causal factor for species diversification in MTC regions has been under-appreciated or ignored. Mechanisms for fire-driven speciation are diverse and may include both directional (novel traits) and stabilizing selection (retained traits) for appropriate morphological and life-history traits. Both museum and nursery hypotheses have important relevance in explaining the extant species richness of the MTC floras, with fire as a strong stimulant for diversification in a manner distinct from other temperate floras. Spatial and temporal niche separation across topographic, climatic and edaphic gradients has occurred in all five regions. The Mediterranean Basin, California, and central Chile are seen as nurseries for strong but not spectacular rates of Neogene diversification, while the older landscapes of southwestern Australia and the Cape Region show significant components of both Paleogene and younger Neogene speciation in their diversity. Low rates of extinction suggesting a long association with fire more than high rates of speciation have been key to the extant levels of species richness. PMID- 30018622 TI - Elemental Profiling of Rice FOX Lines Leads to Characterization of a New Zn Plasma Membrane Transporter, OsZIP7. AB - Iron (Fe) and zinc (Zn) are essential micronutrients required for proper development in both humans and plants. Rice (Oryza sativa L.) grains are the staple food for nearly half of the world's population, but a poor source of metals such as Fe and Zn. Populations that rely on milled cereals are especially prone to Fe and Zn deficiencies, the most prevalent nutritional deficiencies in humans. Biofortification is a cost-effective solution for improvement of the nutritional quality of crops. However, a better understanding of the mechanisms underlying grain accumulation of mineral nutrients is required before this approach can achieve its full potential. Characterization of gene function is more time-consuming in crops than in model species such as Arabidopsis thaliana. Aiming to more quickly characterize rice genes related to metal homeostasis, we applied the concept of high throughput elemental profiling (ionomics) to Arabidopsis lines heterologously expressing rice cDNAs driven by the 35S promoter, named FOX (Full Length Over-eXpressor) lines. We screened lines expressing candidate genes that could be used in the development of biofortified grain. Among the most promising candidates, we identified two lines ovexpressing the metal cation transporter OsZIP7. OsZIP7 expression in Arabidopsis resulted in a 25% increase in shoot Zn concentrations compared to non-transformed plants. We further characterized OsZIP7 and showed that it is localized to the plasma membrane and is able to complement Zn transport defective (but not Fe defective) yeast mutants. Interestingly, we showed that OsZIP7 does not transport Cd, which is commonly transported by ZIP proteins. Importantly, OsZIP7-expressing lines have increased Zn concentrations in their seeds. Our results indicate that OsZIP7 is a good candidate for developing Zn biofortified rice. Moreover, we showed the use of heterologous expression of genes from crops in A. thaliana as a fast method for characterization of crop genes related to the ionome and potentially useful in biofortification strategies. PMID- 30018624 TI - miR394 Acts as a Negative Regulator of Arabidopsis Resistance to B. cinerea Infection by Targeting LCR. AB - Gray mold of tomato is caused by the pathogen Botrytis cinerea. MicroRNAs play a crucial role in the biotic and abiotic stress responses of plants and regulate their targets by gene silencing. miR394 is an ancient and conserved miRNA in plants, and it participates in the regulation of plant development and stress responses. In our previous study, miR394 was found to respond to B. cinerea infection in tomato, but the roles and regulatory mechanisms of miR394 in B. cinerea-infected tomato remain unclear. miR394 was down-regulated in tomato in response to B. cinerea infection, showing an expression pattern opposite to the previous finding that miR394 was up-regulated in tomato cv. Jinpeng 1 infected by B. cinerea. We obtained transgenic Arabidopsis overexpressing miR394, which resulted in low expression levels of its target LEAF CURLING RESPONSIVENESS (LCR). Leaf lesion size and trypan blue staining showed that miR394 overexpression led to increased sensitivity of transgenic Arabidopsis to B. cinerea compared to wild type. We also detected changes in the expression levels of stress-related miRNAs, including miR159, miR156, miR168, and miR172. In the transgenic plants, it indicated potential cross talk between these miRNAs and miR394, except for miR159. miR394 also enhanced the expression of ARGONAUTE 1 (AGO1), DSRNA-BINDING PROTEIN 4 (DRB4) and the RNA-binding protein gene DAWDLE (DDL), which are involved in the pathways of miRNA biosynthesis and regulation, suggesting that miR394 overexpression has a feedback effect on these genes. Our data indicate that overexpression of miR394 in Arabidopsis increased the susceptibility of plants to B. cinerea by affecting the expression of its target gene LCR along with a number of key genes involved in plant miRNA metabolism (AGO1). Thus, miR394 is a negative regulator of Arabidopsis resistance to B. cinerea infection by targeting LCR. PMID- 30018623 TI - GhSNAP33, a t-SNARE Protein From Gossypium hirsutum, Mediates Resistance to Verticillium dahliae Infection and Tolerance to Drought Stress. AB - Soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) proteins mediate membrane fusion and deliver cargo to specific cellular locations through vesicle trafficking. Synaptosome-associated protein of 25 kDa (SNAP25) is a target membrane SNARE that drives exocytosis by fusing plasma and vesicular membranes. In this study, we isolated GhSNAP33, a gene from cotton (Gossypium hirsutum), encoding a SNAP25-type protein containing glutamine (Q)b- and Qc-SNARE motifs connected by a linker. GhSNAP33 expression was induced by H2O2, salicylic acid, abscisic acid, and polyethylene glycol 6000 treatment and Verticillium dahliae inoculation. Ectopic expression of GhSNAP33 enhanced the tolerance of yeast cells to oxidative and osmotic stresses. Virus-induced gene silencing of GhSNAP33 induced spontaneous cell death and reactive oxygen species accumulation in true leaves at a later stage of cotton development. GhSNAP33 deficient cotton was susceptible to V. dahliae infection, which resulted in severe wilt on leaves, an elevated disease index, enhanced vascular browning and thylose accumulation. Conversely, Arabidopsis plants overexpressing GhSNAP33 showed significant resistance to V. dahliae, with reduced disease index and fungal biomass and elevated expression of PR1 and PR5. Leaves from GhSNAP33 transgenic plants showed increased callose deposition and reduced mycelia growth. Moreover, GhSNAP33 overexpression enhanced drought tolerance in Arabidopsis, accompanied with reduced water loss rate and enhanced expression of DERB2A and RD29A during dehydration. Thus, GhSNAP33 positively mediates plant defense against stress conditions and V. dahliae infection, rendering it a candidate for the generation of stress-resistant engineered cotton. PMID- 30018626 TI - Evaluation of the Potential for Genomic Selection to Improve Spring Wheat Resistance to Fusarium Head Blight in the Pacific Northwest. AB - Fusarium Head Blight (FHB) has emerged in spring wheat production in Pacific Northwest during the last decade due to factors including climate changes, crop rotations, and tillage practices. A breeding population with 170 spring wheat lines was established and screened over a 2-year period in multiple locations for FHB incidence (INC), severity (SEV), and deposition of the mycotoxin, deoxynivalenol (DON). A genome-wide association study suggested that the detectable number of genetic loci and effects are limited for marker-assisted selection. In conjunction with the success of breeding on FHB resistance in other programs, genomic selection (GS) was suggested as a better option. To evaluate the prediction accuracy of GS in the current breeding population, we conducted a variety of validations by varying proportions of testing populations and cohorts based on both FHB resistance and market class, including soft white spring (SWS), hard white spring (HWS), and hard red spring (HRS). We found that INC had higher heritability, higher correlation across years and locations, and higher prediction accuracy than SEV and DON. Prediction accuracy varied among the scenarios that restricted the testing population to a certain cohort. For a small set of newly developed or introduced lines (<17), prediction accuracy will be about 60% if the lines have similar genetic relationships as those among the current 170-line training population. However, we expect a lower prediction accuracy if new lines are selected for a specific characteristic, such as FHB resistance or market class. With the exception of DON in the SWS lines, the current training population is capable of making reasonably accurate predictions for FHB-resistant lines in most of the major market classes. For SWS, adding more lines or further phenotyping is required to improve prediction accuracy. These results demonstrate the potential and challenges of GS, especially for developing FHB-resistant varieties in the SWS market class. PMID- 30018625 TI - Expression of the Intracellular COPT3-Mediated Cu Transport Is Temporally Regulated by the TCP16 Transcription Factor. AB - Copper is an essential element in plants. When scarce, copper is acquired from extracellular environment or remobilized from intracellular sites, through members of the high affinity copper transporters family COPT located at the plasma membrane and internal membrane, respectively. Here, we show that COPT3 is an intracellular copper transporter, located at a compartment of the secretory pathway, that is mainly expressed in pollen grains and vascular bundles. Contrary to the COPT1 plasma membrane member, the expression of the internal COPT3 membrane transporter was higher at 12 h than at 0 h of a neutral photoperiod day under copper deficiency. The screening of a library of conditionally overexpressed transcription factors implicated members of the TCP family in the COPT3 differential temporal expression pattern. Particularly, in vitro, TCP16 was found to bind to the COPT3 promoter and down-regulated its expression. Accordingly, TCP16 was mainly expressed at 0 h under copper deficiency and induced at 12 h by copper excess. Moreover, TCP16 overexpression resulted in increased sensitivity to copper deficiency, whereas the tcp16 mutant was sensitive to copper excess. Both copper content and the expression of particular copper status markers were altered in plants with modified levels of TCP16. Consistent with TCP16 affecting pollen development, the lack of COPT3 function led to altered pollen morphology. Furthermore, analysis of copt3 and COPT3 overexpressing plants revealed that COPT3 function exerted a negative effect on TCP16 expression. Taken together, these results suggest a differential daily regulation of copper uptake depending on the external and internal copper pools, in which TCP16 inhibits copper remobilization at dawn through repression of intracellular transporters. PMID- 30018627 TI - Precrop Functional Group Identity Affects Yield of Winter Barley but Less so High Carbon Amendments in a Mesocosm Experiment. AB - Nitrate leaching is a pressing environmental problem in intensive agriculture. Especially after the crop harvest, leaching risk is greatest due to decomposing plant residues, and low plant nutrient uptake and evapotranspiration. The specific crop also matters: grain legumes and canola commonly result in more leftover N than the following winter crop can take up before spring. Addition of a high carbon amendment (HCA) could potentially immobilize N after harvest. We set up a 2-year mesocosm experiment to test the effects of N fertilization (40 or 160 kg N/ha), HCA addition (no HCA, wheat straw, or sawdust), and precrop plant functional group identity on winter barley yield and soil C/N ratio. Four spring precrops were sown before winter barley (white lupine, faba bean, spring canola, spring barley), which were selected based on a functional group approach (colonization by arbuscular mycorrhizal fungi [AMF] and/or N2-fixing bacteria). We also measured a subset of faba bean and spring barley for leaching over winter after harvest. As expected, N fertilization had the largest effect on winter barley yield, but precrop functional identity also significantly affected the outcome. The non-AMF precrops white lupine and canola had on average a positive effect on yield compared to the AMF precrops spring barley and faba bean under high N (23% increase). Under low N, we found only a small precrop effect. Sawdust significantly reduced the yield compared to the control or wheat straw under either N level. HCAs reduced nitrate leaching over winter, but only when faba bean was sown as a precrop. In our setup, short-term immobilization of N by HCA addition after harvest seems difficult to achieve. However, other effects such as an increase in SOM or nutrient retention could play a positive role in the long term. Contrary to the commonly found positive effect of AMF colonization, winter barley showed a greater yield when it followed a non-AMF precrop under high fertilization. This could be due to shifts of the agricultural AMF community toward parasitism. PMID- 30018628 TI - Melatonin Mitigates Salt Stress in Wheat Seedlings by Modulating Polyamine Metabolism. AB - Melatonin, a small molecular weight indoleamine molecule, is involved in various biological processes and responses to environmental cues in plants. However, its function in abiotic stress response and the underlying mechanisms is less clear. In this study, we investigated the effect of melatonin on wheat seedlings growth under salt stress condition. Exogenous melatonin pretreatment partially mitigated the salt-induced inhibition of whole-plant growth as judged from shoot dry weight, IAA content, leaf photosynthesis rate, maximum photochemistry efficiency of photosystem II, and chlorophyll. The mitigation was also observed in reduced accumulation of H2O2 in melatonin-pretreated wheat seedlings exposed to salt stress. Exogenous melatonin increased endogenous melatonin content by evaluating the levels of TaSNAT transcript, which encodes a key regulatory enzyme in the melatonin biosynthetic pathway. Furthermore, melatonin increased polyamine contents by accelerating the metabolic flow from the precursor amino acids arginine and methionine to polyamines; melatonin also decreased the degradation of salt-induced polyamines. Taken together, these results provide the evidence that melatonin mitigates salt stress mainly through its regulation on polyamine metabolism of wheat seedlings. PMID- 30018630 TI - Efficient Multiplex Genome Editing Induces Precise, and Self-Ligated Type Mutations in Tomato Plants. AB - Several expression systems for multiple guide RNA (gRNAs) have been developed in the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) system to induce multiple-gene modifications in plants. Here, we evaluated mutation efficiencies in the tomato genome using multiplex CRISPR/Cas9 vectors consisting of various Cas9 expression promoters with multiple gRNA expression combinations. In transgenic tomato calli induced with these vectors, mutation patterns varied depending on the promoters used to express Cas9. By using the tomato ELONGATION FACTOR-1alpha (SlEF1alpha) promoter to drive Cas9, occurrence of various types of mutations with high efficiency was detected in the tomato genome. Furthermore, sequence analysis showed that the majority of mutations using the multiplex system with the SlEF1alpha promoter corresponded to specific mutation pattern of deletions produced by self-ligation at two target sites of CRISPR/Cas9 with low mosaic mutations. These results suggest that optimizing the Cas9 expression promoter used in CRISPR/Cas9-mediated mutation improves multiplex genome editing, and could be used effectively to disrupt functional domains precisely in the tomato genome. PMID- 30018631 TI - Genome Reduction in Tetraploid Potato Reveals Genetic Load, Haplotype Variation, and Loci Associated With Agronomic Traits. AB - The cultivated potato (Solanum tuberosum) has a complex genetic structure due to its autotetraploidy and vegetative propagation which leads to accumulation of mutations and a highly heterozygous genome. A high degree of heterozygosity has been considered to be the main driver of fitness and agronomic trait performance in potato improvement efforts, which is negatively impacted by genetic load. To understand the genetic landscape of cultivated potato, we constructed a gynogenic dihaploid (2n = 2x = 24) population from cv. Superior, prior to development of a high-density genetic map containing 12,753 single nucleotide polymorphisms (SNPs). Common quantitative trait loci (QTL) were identified for tuber traits, vigor and height on chromosomes 2, 4, 7, and 10, while specific QTL for number of inflorescences per plant, and tuber shape were present on chromosomes 4, 6, 10, and 11. Simplex rather than duplex loci were mainly associated with traits. In general, the Q allele (main effect) detected in one or two homologous chromosomes was associated with lower mean trait values suggesting the importance of dosage allelic effects, and the presence of up to two undesired alleles in the QTL region. Loss of heterozygosity has been associated with a lower rate of fitness, yet no correlation between the percent heterozygosity and increased fitness or agronomic performance was observed. Based upon linkage phase, we reconstructed the four homologous chromosome haplotypes of cv. Superior. revealing heterogeneity throughout the genome yet nearly duplicate haplotypes occurring among the homologs of particular chromosomes. These results suggest that the potentially deleterious mutations associated with genetic load in tetraploid potato could be mitigated by multiple loci which is consistent with the theory that epistasis complicates the identification of associations between markers and phenotypic performance. PMID- 30018632 TI - TLHNMDA: Triple Layer Heterogeneous Network Based Inference for MiRNA-Disease Association Prediction. AB - In recent years, microRNAs (miRNAs) have been confirmed to be involved in many important biological processes and associated with various kinds of human complex diseases. Therefore, predicting potential associations between miRNAs and diseases with the huge number of verified heterogeneous biological datasets will provide a new perspective for disease therapy. In this article, we developed a novel computational model of Triple Layer Heterogeneous Network based inference for MiRNA-Disease Association prediction (TLHNMDA) by using the experimentally verified miRNA-disease associations, miRNA-long noncoding RNA (lncRNA) interactions, miRNA function similarity information, disease semantic similarity information and Gaussian interaction profile kernel similarity for lncRNAs into an triple layer heterogeneous network to predict new miRNA-disease associations. As a result, the AUCs of TLHNMDA are 0.8795 and 0.8795 +/- 0.0010 based on leave one-out cross validation (LOOCV) and 5-fold cross validation, respectively. Furthermore, TLHNMDA was implemented on three complex human diseases to evaluate predictive ability. As a result, 84% (kidney neoplasms), 78% (lymphoma) and 76% (prostate neoplasms) of top 50 predicted miRNAs for the three complex diseases can be verified by biological experiments. In addition, based on the HMDD v1.0 database, 98% of top 50 potential esophageal neoplasms-associated miRNAs were confirmed by experimental reports. It is expected that TLHNMDA could be a useful model to predict potential miRNA-disease associations with high prediction accuracy and stability. PMID- 30018629 TI - An Overview of Biomembrane Functions in Plant Responses to High-Temperature Stress. AB - Biological membranes are highly ordered structures consisting of mosaics of lipids and proteins. Elevated temperatures can directly and effectively change the properties of these membranes, including their fluidity and permeability, through a holistic effect that involves changes in the lipid composition and/or interactions between lipids and specific membrane proteins. Ultimately, high temperatures can alter microdomain remodeling and instantaneously relay ambient cues to downstream signaling pathways. Thus, dynamic membrane regulation not only helps cells perceive temperature changes but also participates in intracellular responses and determines a cell's fate. Moreover, due to the specific distribution of extra- and endomembrane elements, the plasma membrane (PM) and membranous organelles are individually responsible for distinct developmental events during plant adaptation to heat stress. This review describes recent studies that focused on the roles of various components that can alter the physical state of the plasma and thylakoid membranes as well as the crucial signaling pathways initiated through the membrane system, encompassing both endomembranes and membranous organelles in the context of heat stress responses. PMID- 30018634 TI - Factors Influencing Patient Decisions Regarding Treatments for Skin Growths: A Cross-Sectional Study. AB - Variations in treatment modalities for skin growths contribute substantially to overall healthcare spending within dermatology. However, little is known regarding factors impacting patient decision-making when choosing a treatment modality. In this survey-based, cross-sectional study (n = 375, 81.9% response rate), we asked patients to rate the importance of different treatment parameters for a nonfacial skin growth, further classified into five domains: efficacy, appearance, financial impact, visit duration, and productivity. Although patients generally prioritized treatment efficacy when selecting a treatment modality, they emphasized different aspects of the treatment experience as a function of age, gender, race, insurance status, and history of malignancy. Patients over age 50 were less likely to consider treatment impact on finances as being "important", but more so efficacy and visit duration. Women were more likely to value efficacy and appearance. Patients without private insurance were more likely to cite efficacy and impact on productivity as being "important". While the underlying reasons for these variations differ across patients, these findings help explain variations in treatment selection among patients choosing between treatments for skin growths and may ultimately lead to improved shared decision-making. PMID- 30018633 TI - Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment. AB - Systemic inflammation and brain pathologies are known to be linked. In the periphery, the inflammation and coagulation systems are simultaneously activated upon diseases and infections. Whether this well-established interrelation also counts for neuroinflammation and coagulation factor expression in the brain is still an open question. Our aim was to study whether the interrelationship between coagulation and inflammation factors may occur in the brain in the setting of systemic inflammation. The results indicate that systemic injections of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and coagulation factors in the brain. The activity of the central coagulation factor thrombin was tested by a fluorescent method and found to be significantly elevated in the hippocampus following systemic LPS injection (0.5 +/- 0.15 mU/mg versus 0.2 +/- 0.03 mU/mg in the control). A panel of coagulation factors and effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the hippocampus, isolated microglia, and N9 microglia cell by Western blot and real time PCR and found to be modulated by LPS. One central finding is a significant increase in FX expression level following LPS induction both in vivo in the hippocampus and in vitro in N9 microglia cell line (5.5 +/- 0.6- and 2.3 +/- 0.1 fold of increase, resp.). Surprisingly, inhibition of thrombin activity (by a specific inhibitor NAPAP) immediately after LPS injection results in a reduction of both the inflammatory (TNFalpha, CXL9, and CCL1; p < 0.006) and coagulation responses (FX and PAR1; p < 0.004) in the brain. We believe that these results may have a profound clinical impact as they might indicate that reducing coagulation activity in the setting of neurological diseases involving neuroinflammation may improve disease outcome and survival. PMID- 30018635 TI - Dietary Habits in Patients with Chronic Spontaneous Urticaria: Evaluation of Food as Trigger of Symptoms Exacerbation. AB - Background: Many patients with chronic spontaneous urticaria (CSU) identify different foods as triggers of their symptoms and frequently make dietary restrictions without enough information. Objective: To explore the diet habits of CSU patients and estimate the clinical impact of the foods most frequently reported to be suspect. Methodology: Patients were interrogated about their clinical history of urticaria. Skin prick test and sIgE serum were done for most frequently reported foods by patients. Food challenge test was also performed. A group of healthy subjects was included to compare the dietary habits and the results of the diagnostic tests. Results: Patients with CSU (n 245) and healthy (n 127) subjects were included. 164 (66%) subjects from CSU group and 31 (24%) from the control group reported at least one adverse reaction with foods. Food IgE sensitization was similar in both groups (17.5% versus 16.5%, respectively). 410 food challenge tests in 164 CSU patients and 38 in 38 control subjects were performed. 1.2% in CSU group and 0.7% in control group had a positive oral challenge test. Conclusion: Despite the high frequency of self-report by patients, foods are uncommon triggers of CSU. Nevertheless, food challenge tests have to be offered early during medical evaluation to avoid unnecessary restrictions. PMID- 30018636 TI - The Antibacterial Effect In Vitro of Honey Derived from Various Danish Flora. AB - The mechanism behind the biologic actions of honey as a wound remedy has been intensively studied; however, there is no published data regarding any antibacterial effect of honey derived from Danish flora. We surveyed 11 honeys of various Danish floral sources for their antibacterial activity and compared them to a culinary processed commercial honey (Jakobsens) and a raw and a medical grade Manuka (Leptospermum scoparium) honey using the agar-well diffusion method. We tested the effect on three gram-positive bacteria (two strains of Staphylococcus aureus and one strain of Staphylococcus epidermidis) and two gram negative bacteria (Pseudomonas aeruginosa and Escherichia coli). All samples, except the commercial honey, exhibited antibacterial activity, and samples derived from Water Mint (Mentha aquatica), Organic 2 (mixed organic flora), and Linden (Tilia cordata) honey had consistent effects on all bacteria tested and showed greater effect than medical grade and raw Manuka (L. scoparium) honey. The content of methylglyoxal was low in the Danish honey (< 2 MUg/mL) and significantly (p<0.05) higher in both the raw and the medical grade Manuka (L. scoparium) honey, where the concentrations were, respectively, 6.29 MUg/mL and 54.33 MUg/mL. The antibacterial effect of Danish honeys was mostly due to hydrogen peroxide. We conclude that honeys derived from Danish flora possess antibacterial effect, probably by a hurdle effect of viscosity, osmolality, acidity, bioactive peptides, and most importantly the content of hydrogen peroxide. These findings indicate that honeys of various Danish floral sources may have clinical potential, although further studies are necessary to elucidate this in order to determine whether the results of our in vitro experiments also apply to a clinical setting. PMID- 30018637 TI - Neurotoxicity of Inhalation Anesthetics in the Neonatal Rat Brain: Effects on Behavior and Neurodegeneration in the Piriform Cortex. AB - There is concern that clinical use of anesthetic drugs may cause neurotoxicity in the developing brain and subsequent abnormal neurobehavior. We therefore evaluated neurotoxic effects of inhalation anesthetics in the neonatal rat brain, using in vivo histological and neurobehavioral outcomes. Wistar rats (n=79, postnatal day 15) were subjected to a clinically relevant single exposure of urethane, isoflurane, sevoflurane, or placebo, without surgery. At 48 h and 96 h, behavioral parameters were recorded and the animals were sacrificed. In cryosectioned brains, total cells and dying cells in layer II of the piriform cortex were counted using unbiased stereology. At 48 h, cell numbers in layer II of the piriform cortex of all drug-treated animals were reduced versus controls (p=0.01). The effect persisted at 96 h in isoflurane- and urethane-exposed animals. Piriform cortical layer II neurons undergoing degeneration, detected histologically by pyknotic nuclei and eosinophilic cytoplasm, were increased in the animals treated with isoflurane (1.9 +/- 0.7 at 96 h) and urethane (2.4 +/- 0.8 at 96 h) versus sevoflurane (0.8 +/- 0.3 at 96 h) and controls (0.9 +/- 0.2 at 96 h). Sevoflurane- and isoflurane-treated animals exhibited increased activity and decreased suckling compared with controls, and sevoflurane-exposed animals also displayed increased rearing behavior at both timepoints. PMID- 30018638 TI - Value of Apoptotic, Antiapoptotic, and Cell Proliferation Markers in the Treatment of Graves' Disease. AB - To better understand the genesis of autoimmunity in Graves' disease (GD), it is essential to study the mechanism of apoptosis and cell proliferation in thyroid cells and intrathyroidal lymphocytic infiltrate of GD patients. Methods. A cross sectional, observational study performed by evaluating histopathological samples of thyroidectomy products from GD patients using immunohistochemistry. New histological sections were prepared for immunohistochemical analysis with markers of cell proliferation, antiproliferation, apoptosis, and antiapoptosis. Results. Patients with GD who underwent radioiodine therapy (RIT) had a lower lymphocytic expression level of p27Kip1, and those who took beta-blockers had higher expression levels of BID (BH3-interacting domain) and a lower Ki-67 expression level in thyrocytes than those who did not. The association of a shorter diagnostic time with a lower expression level of MCL-1 in thyroid cells suggests that the hyperthyroid state was related to a lower antiapoptotic effect on thyrocytes. In comparison to patients with GD not using antithyroid drugs (ATD), we found a lower expression level of BID in lymphocytes for those who used ATD. Conclusion. In GD, the hyperthyroid state was associated with a lower antiapoptotic effect on thyroid cells. RIT, beta-blockers, and thionamide act by stimulating apoptosis of thyrocytes by intrathyroidal lymphocytes. PMID- 30018640 TI - Advancing Parental Age and Risk of Solid Tumors in Children: A Case-Control Study in Peru. AB - Background: The causes of childhood cancer are not well known, but the advanced age of the parents has been suggested as a risk factor for childhood cancer in several observational studies. In this study, we examine a possible link between parental age and childhood solid tumors. Methods: We conducted a hospital-based case-control study (310 cases and 620 controls, matched by age and gender) at Rebagliati Hospital, Lima, Peru. Odd ratio was used to compare categories of advancing maternal and paternal age with and without adjusting for possible confounding factors were calculated. Results: The risk of childhood retinoblastoma was significantly higher among children of mothers aged> 35 years (adjusted OR 1.21; 95% CI, 1.09-6.08) and fathers aged> 35 years (OR 1.17; 1.01 16.33). A significant trend with increasing mother's age (p = 0.037) and father's age (p = 0.005) was found. There were more risks to development of non-Hodgkin's lymphoma (p = 0.047) and gonadal germ cell tumors (p = 0.04) for advanced paternal age. There was a strong protective effect of increasing parity on risk of solid tumors in children (p=0.0015). Conclusion: Our results suggest that advanced parental age is associated with the risk for the development of retinoblastoma. Advanced paternal age increases the risk of non-Hodgkin lymphoma and gonadal germ cell tumor. The higher the order of birth of the children, the less the chance of developing any neoplasm. PMID- 30018641 TI - Alternanthera mosaic potexvirus: Several Features, Properties, and Application. AB - Alternanthera mosaic virus (AltMV) is a typical member of the Potexvirus genus in its morphology and genome structure; still it exhibits a number of unique features. They allow this virus to be considered a promising object for biotechnology. Virions and virus-like particles (VLPs) of AltMV are stable in a wide range of conditions, including sera of laboratory animals. AltMV VLPs can assemble at various pH and ionic strengths. Furthermore, AltMV virions and VLPs demonstrate high immunogenicity, enhancing the immune response to the target antigen thus offering the possibility of being used as potential adjuvants. Recently, for the first time for plant viruses, we showed the structural difference between morphologically similar viral and virus-like particles on AltMV virions and VLPs. In this review, we discuss the features of AltMV virions, AltMV VLP assembly, and their structure and properties, as well as the characteristics of AltMV isolates, host plants, infection symptoms, AltMV isolation and purification, genome structure, viral proteins, and AltMV-based vectors. PMID- 30018642 TI - Structural Study of Europium Doped Gadolinium Polyphosphates LiGd(PO3)4 and Its Effect on Their Spectroscopic, Thermal, Magnetic, and Optical Properties. AB - Alkali metal-rare earth polyphosphates LiGd(1-x)Eux(PO3)4 (LGP:Eu3+) (where x= 0, 0.02 and 0.04) were synthesized by solid-state reaction. The Rietveld refinement showed the following cell parameters: I 2/a space group, a=9.635(3) A, b=7.035(3) A, c=13.191(3) A, beta=90.082 degrees , V= 894.214A3, and Z=4. The similarity between RF=4.21% and RB=4.31% indicated that the realized refinement is reliable. The crystal structure consists of infinite zig-zag chains of (PO4)3- tetrahedra, linked by bridging oxygen. The acyclic structure of polyphosphates is confirmed by infrared and Raman (IR) spectroscopies. A good thermal stability up to 940 degrees C and paramagnetic behavior of these compounds were also proved by thermal analyses and magnetic susceptibility measurements, respectively. Excitation spectra revealed the charge transfer phenomenon between O2- and Eu3+ (CTB), the energy transfer from Gd3+ to Eu3+, and the intrinsic 4f-4f transitions of Eu3+ where the electronic transitions were also identified. Moreover, LGP:Eu3+ can emit intense reddish orange light under excitation at 394 nm. The strongest tow at 578 and 601 nm can be attributed to the transitions from excited state 5D0 to ground states 7F1 and 7F2, respectively. PMID- 30018643 TI - Musculoskeletal Disorders in Patients with Diabetes Mellitus: A Cross-Sectional Study. AB - Introduction: A variety of musculoskeletal disorders (MS) have been associated with diabetes mellitus (DM). This study aimed at assessing the prevalence and associated factors of MS disorders in Moroccan diabetic patients. Methods: A cross-sectional study enrolled consecutive patients with DM. We recorded demographic features of patients and characteristics of DM. MS disorders and vascular complications were assessed by clinical examinations and investigations. Associated factors of MS disorders were assessed by univariate and multivariate analyses. Result: 376 subjects were included; 84.6% had type 2 DM. The participants' median age was 54 years [45-62]; 41% had one or more vascular complications. 34.4% had one or more MS disorders. Osteoarthritis was present in 19.4% of patients. Hand disorders were seen in 14.4%. Shoulder capsulitis was present in 12.5%. Long duration of diabetes and dyslipidemia were associated with increased prevalence of hand abnormalities (P = 0.017; P = 0.019, respectively). Age and dyslipidemia were associated with shoulder capsulitis (P = 0.019; P = 0.047, respectively). Female gender, overweight, and nephropathy were associated with increased odds of osteoarthritis (P = 0.009, P = 0.004, and P = 0.032, respectively). Conclusion: MS disorders are frequent in this population and associated with various factors. HbA1c level does not appear to be associated with development of MS disorders. PMID- 30018639 TI - Chicken Is a Useful Model to Investigate the Role of Adipokines in Metabolic and Reproductive Diseases. AB - Reproduction is a complex and essential physiological process required by all species to produce a new generation. This process involves strict hormonal regulation, depending on a connection between the hypothalamus-pituitary-gonadal axis and peripheral organs. Metabolic homeostasis influences the reproductive functions, and its alteration leads to disturbances in the reproductive functions of humans as well as animals. For a long time, adipose tissue has been recognised as an endocrine organ but its ability to secrete and release hormones called adipokines is now emerging. Adipokines have been found to play a major role in the regulation of metabolic and reproductive processes at both central and peripheral levels. Leptin was initially the first adipokine that has been described to be the most involved in the metabolism/reproduction interrelation in mammals. In avian species, the role of leptin is still under debate. Recently, three novel adipokines have been discovered: adiponectin (ADIPOQ, ACRP30), visfatin (NAMPT, PBEF), and chemerin (RARRES2, TIG2). However, their mode of action between mammalian and nonmammalian species is different due to the different reproductive and metabolic systems. Herein, we will provide an overview of the structure and function related to metabolic and reproductive mechanisms of the latter three adipokines with emphasis on avian species. PMID- 30018644 TI - In Vitro Uptake of Hydroxyapatite Nanoparticles and Their Effect on Osteogenic Differentiation of Human Mesenchymal Stem Cells. AB - There have been many applications in biomedical fields based on hydroxyapatite nanoparticles (HA NPs) over the past decades. However, the biocompatibility of HANPs is affected by exposure dose, particle size, and the way of contact with cells. The objective of this study is to investigate the effect of HA NPs with different sizes on osteogenesis using human mesenchymal stem cells (hMSCs). Three different-sized HA NPs (~50, ~100, and ~150 nm, resp.) were synthesized to study the cytotoxicity, cellular uptake, and effect on osteogenic differentiation of hMSCs. The results clearly showed that each size of HA NPs had dose-dependent cytotoxicity on hMSCs. It was found that HA NPs could be uptaken into hMSCs. The osteogenic differentiation of hMSCs was evaluated through alkaline phosphatase (ALP) activity measurement, ALP staining, immunofluorescent staining for osteopontin (OPN), and real-time polymerase chain reaction (RT-PCR) examination. As expected, HA NPs of all sizes could promote the differentiation of hMSCs towards osteoblast lineage. Among the three sizes, smaller-sized HA NPs (~50 and ~100 nm) appeared to be more effective in stimulating osteogenic differentiation of hMSCs. PMID- 30018646 TI - The Association between the Parents' Knowledge of Carbohydrate Counting and the Glycaemic Control of the Children with Type 1 Diabetes. AB - Background: Medical nutritional therapy is an important component of type 1 diabetes (T1D) care in children and carbohydrate counting is one such method. We aimed to evaluate the knowledge of carbohydrate counting among parents of children with T1D from Sri Lanka and study its association with the child's glycaemic control. Methods: A descriptive cross-sectional study was conducted among parents of children with T1D. HbA1c measurement was used to assess glycaemic control. Knowledge of parent regarding carbohydrate counting was assessed based on a 24-hour dietary recall. Carbohydrate counting knowledge was defined using ratio of carbohydrate content estimated by parents to actual carbohydrate content calculated by researchers (Total, Breakfast, Lunch, Dinner, and Snacks). Ratios obtained were also divided into three groups, underestimation (<0.9), accurate estimation (0.9-1.1), and overestimation (>1.1). A multivariate regression analysis was performed to determine contribution of carbohydrate counting accuracy to glycaemic control (HbA1c). Results: Sample size was 181 and mean age of the parents was 38.8+/-5.9 years. Mean duration of diabetes in the children was 3.7+/-2.6 years and mean HbA1c level was 8.3+/-0.9%. On average, parents estimates of carbohydrate count for the total meal were 0.88+/-0.27 (88%) (range 0.38-1.47) of the actual carbohydrate count. Only 30.5% (n=55) of parents were grouped in the "accurate" estimation category for the total carbohydrate count. Parents of children with diabetes for <=3 years estimated total carbohydrate count more accurately than the counterparts (p<0.05). Mean HbA1c value of those who "underestimated" was significantly higher than those with "accurate" estimation. In the multivariate analysis accuracy of carbohydrate estimation was associated with a lower HbA1c (beta = -0.36; p=0.03). Conclusions: Overall knowledge of carbohydrate counting among parents was inadequate. Better knowledge was associated with improved glycaemic control in children and lower incidence of hypoglycaemic episodes. An inverse association was observed between knowledge and duration of diabetes. PMID- 30018645 TI - The Use of Insecticide-Treated Curtains for Control of Aedes aegypti and Dengue Virus Transmission in "Fraccionamiento" Style Houses in Mexico. AB - Dengue, chikungunya, yellow fever, and Zika viruses transmitted by Aedes aegypti mosquitoes are major public health threats in the tropical and subtropical world. In Mexico, construction of large tracts of "fraccionamientos" high density housing to accommodate population growth and urbanization has provided fertile ground for Ae. aegypti-transmitted viruses. We investigated the utility of pyrethroid-treated window curtains to reduce both the abundance of Ae. aegypti and to prevent dengue virus (DENV) transmission in fraccionamiento housing. Windows and doors of fraccionamiento homes in urban/suburban areas, where Ae. aegypti pyrethroid resistance associated with the Ile1016 knock down resistance (kdr) mutation in the voltage gated sodium channel gene was high, and in rural areas, where kdr resistance was low, were fitted with either insecticide-treated curtains (ITCs) or non-treated curtains (NTCs). The homes were monitored for mosquito abundance and DENV infection. ITCs reduced the indoor abundance of Ae. aegypti and the number of DENV-infected mosquitoes in homes in rural but not in urban/suburban study sites. The presence of non-treated screens also was associated with reduced numbers of mosquitoes in homes. "Super-infested" homes, yielding more than 50 mosquitoes, including DENV-infected mosquitoes, provide a significant public health risk to occupants, visitors, and people in neighboring homes. PMID- 30018648 TI - 'Not My Child': Parents' Denial About Adolescent Sexuality in Harare, Zimbabwe. AB - Objective: To find out adult views on adolescent sexualities in Zimbabwe and how adults construct sexual cultures that deny adolescence access to sex. Materials and methods: The paper uses qualitative methodologies, with purposively selected parents and key informants. A total of ten in depth interviews, four focus groups and six key informant interviews with purposively sampled male and female respondents were conducted. Key informants included a headmaster, teacher, social worker, nurses and a member of traditional healers association. Results: Parents that were interviewed denied that their adolescent children were sexually active. This denial of adolescent sexuality was seen throughout the interviews. The denial of adolescent sexuality was linked to the other themes that emerged including sexual surveillance and sexual communication, school pregnancy, STIs and sexual education, and adult anxiety on adolescent sex. Conclusion: The denial of youth sexuality has serious impacts on youths' access to information and ability to protect themselves from sexually transmitted diseases and HIV. We argue that government policies and lack of comprehensive sex education in schools are based on this denial of adolescent sexuality and should be addressed. PMID- 30018647 TI - Self-Reported Occupational Injuries and Perceived Occupational Health Problems among Latino Immigrant Swine Confinement Workers in Missouri. AB - Swine production has changed dramatically, and in the United States production often takes place in concentrated animal feeding operations (CAFOs). Because of the size and density of these types of facilities, workers may be exposed to serious occupational health risks such as noxious gases, agricultural dusts, elevated noise levels, and zoonotic diseases. This descriptive study examines self-reported occupational injuries and perceived occupational health problems among a convenience sample of 40 Latino immigrant swine confinement workers (92.5% male; M age = 36.1 years; SD = 10.0) in Missouri. Results indicated that seventeen workers (42.5%) rated their health as fair or poor, thirteen (32.5%) had experienced an occupational injury, and eleven (28.2%) reported occupational health problems such as burning eyes, muscular pain, headaches, coughing, nausea, nasal congestion, and sneezing. The majority of workers did not perceive their job to be dangerous. Clearly, more must be done to protect workers, especially immigrant workers, who may not have the same access to information, training, or other protections. Health and safety should be a priority for both farmworkers and farm employers. Practical and policy-based implications and recommendations are discussed. PMID- 30018649 TI - The Relationship Between Factors Related to Divorce Request and Mental Health Among Divorce Applicant Women Referred to Legal Medicine Organization in Ahvaz, Iran. AB - Objective: This study aimed to investigate the relationship between factors related to divorce request with mental health among divorce applicant women in order to understand the effect of these factors on women's mental health. Materials and methods: This study was a cross-sectional study performed on 434 divorce applicant women who referred to legal medicine department of Ahvaz in 2013 based on convenience sampling. Information was collected by using researcher made questionnaire for factors affecting divorce and symptom checklist-25 (SCL 25) standard questionnaire. The data were analyzed using SPSS ver.18. Results: The results showed that among the social factors, life skills and communication, family and individual factors had a significant relationship with mental health among divorce applicant women (p < 0.05). No relationship was seen with economic and cultural factors affecting divorce request (p > 0.05). Conclusion: Regarding the negative effects of various causative factors of divorce on mental health of women including social, life skills, communication, family and individual factors strategies for prevention and reduction of these factors should be seriously considered for prevention and early treatment of mental health problems. These strategies include counseling before marriage, after marriage and during the divorce process. PMID- 30018650 TI - Factors Affecting Fertility Rate in Iran (Panel Data 1966-2013): A Survey Study. AB - Objective: Population and its corresponding problems are among multidimensional and complicated issues of human communities and their related features are the basis for making any plan or policy. Fertility, as one of the principle components of population growth, is an issue that has always been taken into consideration and extensive research has been carried out to recognize factors affecting on it. Therefore, the authors decided to study the most important factors influencing fertility rate in Iran by conducting a longitudinal study and considering the effect of various time periods on its population changes. Materials and methods: This is a descriptive-analytic study. Its required information is a combination of cross-sectional and time series data (panel data) that were extracted from 1966 to 2013 from Iran's population categorized by the country's 24 provinces and from statistical yearbooks of Statistical Center of Iran and Organization of Civil Registration. The final estimations were made using Eviews 7 and STATA 12 software. Findings showed that variables of marriage, women's level of education, unemployment, population policies, Sunni population, economic policies and annual expenses of households have influenced the fertility rate. Results: Based on the research results, marriage and women's level of education respectively had the most positive and the most negative effects on the fertility rate. Then, unemployment, family planning policies, policies of paying cash subsidies and total annual household expenses had reverse effects on the fertility rate and the policies of paying cash subsidies and Sunni population had positive effects on the fertility rate. Conclusion: In order to make policies of increasing fertility rate effective by governmental and politicians' planning, more attention should be paid to providing conditions for marriage and reducing unemployment. PMID- 30018651 TI - Comparing the Efficiency of Three Protocols in Isolation of Cell Free Fetal DNA From Maternal Blood. AB - Objective: Recent advances in non-invasive prenatal diagnosis (NIPD) through cell free fetal DNA (cffDNA) has highlighted cffDNA purification as a critical initial step. Herein, we aimed to compare the efficiency of one proposed protocol with two commercial kits for isolation of cffDNA. Materials and methods: cffDNA was isolated from whole blood of 50 normal pregnancies using one proposed manual protocol compared with QIAamp DNA Blood Mini and Bioneer Kits. Methylated DNA immunoprecipitation real time polymerase chain reaction (MeDIP-Real time PCR) was performed to quantify three fetal specific sequences. Results: Maximum cffDNA quantity was obtained by suggested protocol (248.79 +/- 14.07 ng/ul) and the best quality was achieved by Bioneer Kit (OD ratio: 260/280 nm/nm: 1.69 +/- 0.09, 260/230 nm/nm: 1.15 +/- 0.13) (p < 0.001). Enrichment of fetal specific sequences was significantly higher when proposed protocol was used to isolate cffDNA (p = 0.01). Conclusion: Inhibitory effect of NaI on nucleases and double digestion of DNA associated proteins may be the main reasons behind the superiority of suggested protocol. Significantly higher amplification of fetal specific sequences in suggested protocol would be a strong evidence on recovery of small fetal fragments as demonstrated with its maximum total DNA quantity and amplification in different PCR reactions. PMID- 30018652 TI - Comparing Formation or Non-Formation of Bladder Flap at Cesarean Section on Perioperative and Postoperative Complications: Double-Blind Clinical Trial. AB - Objective: To investigating formation or non-formation of bladder flap at Cesarean section on the complications during and after surgery. Materials and methods: This is a double-blind clinical trial study conducted during February 2014 to May 2015 on 64 pregnant women with gestational age of 36 weeks or more who were delivered by Cesarean section for the first time. They were randomly divided into two groups (intervention group: non-formation of bladder flap; control group: formation of bladder flap). The time to cut out the baby by Cesarean section, total duration of operation, bladder injury, intraoperative bleeding, hematocrit changes expected prior to during and following operation, postoperative pain, macroscopic and microscopic hematuria, postoperative complications and duration of hospitalization were compared between two groups. The data were analyzed with SPSS version 16 using and statistics tests. p < 0.05 was considered significant. Results: Time to cut out the baby for the intervention group (124.9 +/- 40.5 seconds and for control group 155.1 +/- 42.9 seconds) and total duration of the operation (intervention group: 27.7 +/- 5.2 min and control group: 34 +/- 4.73 min) were significantly different (p = 0.000). Number of gauze consumption during operation and postoperative hematocrit drop in the intervention group was significantly lower in the intervention group compared the control group (p = 0.000). The postoperative pain score in the intervention group (4.8 +/- 1.1) and in control group (6.3 +/- 0.9) were significantly different (p = 0.000). Conclusion: Omission of the bladder flap at Cesarean section leads to short-term benefits such as reducing the time to cut out the fetus, duration of surgery, decreasing postoperative bleeding and lowering pain. PMID- 30018653 TI - Prediction of Birth Type Based on the Health Belief Model. AB - Objective: To anticipate the type of childbirth according to the health belief model. Materials and methods: The present cross-sectional research was conducted on 222 primiparous women visiting the healthcare center in Khorram Abad. A combination of simple randomization and clustering was used to do the sampling. The data collection instrument was a validated four-part questionnaire the first part of which contained demographic information. The second part was comprised of awareness questions while the third dealt with the constructs of the health belief model. The final part consisted of the behavioral intention derived from the logical action theory. SPSS 16 was used to statistically analyze the data and the significance level was set at p ? 0.05. Results: The average age of the participants was 27.40 +/- 6.07 years. Intention to go for a vaginal birth showed to be significantly correlated with awareness, perceived sensitivity, intensity, barriers and benefits (p ? 0.001) as well as self-efficacy (p = 0.025). The best predictor of the type of childbirth turned out to be the perceived barriers (OR = 1.153, p ? 0.001) and only then awareness (OR = 1.108, p ? 0.001). Conclusion: Strategies to remove the barriers of preferring vaginal childbirth, raising women's awareness of the side effects of C-section and the benefits of vaginal birth, strategies to enhance women's beliefs in their capability of natural childbirth can be used to reduce the prevalence of unnecessary C-sections. PMID- 30018654 TI - Exploring the Challenges of Adolescent Mothers From Their Life Experiences in the Transition to Motherhood: A Qualitative Study. AB - Objective: Early motherhood and its impact on mothers, children, families and communities is a prevalent health challenge in developing countries that needs to be urgently explored. The aim of this study was exploring the challenges encountered by Iranian adolescent mothers during the transition to motherhood. Materials and methods: Inductive conventional content analysis approach was used in this qualitative study. Face to face in-depth semi-structured interviews were conducted with 16 Iranian teenage mothers in the Kerman province of Iran from March to December2016. Data collection continued until the point of data saturation and MAXQDA software was utilized in the analysis of the data. Results: Six main categories increasing burden of responsibility, experiencing physical problems, receiving insufficient support, inefficiency in maternal role, emotional and mental distress; and role conflict and 18 sub-categories were extracted from the data analysis. Conclusion: The findings of this study showed that adolescent mothers experience many physical, psychological, mental and social challenges. Therefore, it is expedient that special attention and care support is made available to them by health care providers. A comprehensive understanding of the challenges encountered by adolescent mothers, will aid the development of culturally appropriate health promotion guidelines and strategie. PMID- 30018655 TI - Xantogranulomatous Salpingo Oophritis, Lessons Learnt: Report of Two Cases With Unusual Presentation. AB - Xanthogranulomatous inflammation is a rare form of chronic inflammatory response consisting of macrophages, lymphocytes, plasma cells and neutrophils too. Due to its locally destructive nature and mass forming capacity as a result of adhesions, this type of inflammation may mimic malignancy or tuberculosis both clinically and radiologically. We present a report of two such cases, one mimicking tuberculosis and the other mimicking malignancy clinically. Awareness of this condition and a higher index of suspicion among clinicians, radiologists and pathologists can help in early diagnosis and more appropriate treatment of this potentially destructive disorder. PMID- 30018656 TI - Gypenosides Attenuate Lipopolysaccharide-Induced Neuroinflammation and Memory Impairment in Rats. AB - Neuroinflammation is deliberated a major factor in various neurodegenerative diseases. Gypenosides (GPS) have pharmacological properties with multiple beneficial effects including anti-inflammatory, antioxidative, and protective properties. In the present study, whether GPS could improve cognitive dysfunction and chronic inflammation caused by injecting lipopolysaccharide (LPS) in the hippocampus was investigated. Effects of GPS on inflammatory factors in the hippocampus and the downstream mechanisms of these effects were also examined. Induction of LPS into the lateral ventricle caused inflammatory reactions and memory impairment on the rats. Every day treatment of GPS (25, 50, and 100 mg/kg) for 21 consecutive days attenuated spatial recognition, discrimination, and memory deficits. GPS treatment significantly decreased proinflammatory mediators such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and nuclear factor kappaB (NF-kappaB) levels in the brain. Furthermore, GPS reduced LPS-induced elevated levels of inducible nitric oxide synthase (iNOS) and toll-like receptor 4 (TLR4) mRNA and inhibition of brain-derived neurotrophic factor (BDNF) mRNA level. Collectively, these results showed that GPS may improve cognitive function and provide a potential therapy for memory impairment caused by neuroinflammation. Based on these, GPS may be effective in inhibiting the progress of neurodegenerative diseases by improving memory functions due to its anti-inflammatory activities and appropriate modulation of NF kappaB/iNOS/TLR4/BDNF. PMID- 30018658 TI - Demand, End-Uses, and Conservation of Alpine Medicinal Plant Neopicrorhiza scrophulariiflora (Pennell) D. Y. Hong in Central Himalaya. AB - Neopicrorhiza scrophulariiflora (Pennell) D. Y. Hong of Scrophulariaceae family (hereinafter referred to as Neopicrorhiza) has medicinally important rhizomes with high levels of trade. What factors drive demand for Neopicrorhiza in Central Himalaya is unknown. In this context, a nationwide comprehensive survey was conducted from September 2016 to March 2017 to assess demand, end-uses, and conservation of dry Neopicrorhiza rhizomes in Nepal. A total of 2313 herbal products were surveyed for Neopicrorhiza as an ingredient in 38 retailer shops. Processing industries of Neopicrorhiza in Nepal were interviewed using structured questionnaire. There were 23 herbal industries manufacturing 45 types of ayurvedic medicines as end-products containing Neopicrorhiza. The volume and value of annual demand for dry rhizomes of Neopicrorhiza in Nepal were found as 6076 kg and NRs 8573236 (USD 83235.30), respectively, in 2015/016 with average 264.17 kg/industry and NRs 1410.87 (USD 13.69) per kg. The major uses of ayurvedic medicines containing Neopicrorhiza were to treat a number of disease categories: cardiovascular system/liver (17), cardiovascular system/blood (6), nervous system (6), dermatological system (4), musculoskeletal system (3), digestive system (2), respiratory system (2), genitourinal system (4), and others (1). Despite changing legal regulation, trade and consumption of Neopicrorhiza exist in Nepal. It can be concluded that domestic consumption is not the major cause of resource depletion of Neopicrorhiza in Nepal. PMID- 30018657 TI - Sini Decoction Improves Adrenal Function and the Short-Term Outcome of Septic Rats through Downregulation of Adrenal Toll-Like Receptor 4 Expression. AB - Background: Sini Decoction (SND) is composed of Aconitum carmichaelii Debeaux, Zingiber officinale Roscoe, and Glycyrrhiza uralensis Fisch, having been used in China for centuries for collapsing phrase of disease. Studies reported that SND could alleviate inflammatory response, ameliorate microcirculatory disturbances, and improve shock reversal and adrenal gland glucocorticoid stress response during sepsis shock, yet the underlying mechanism is still elusive. Toll-like receptor (TLR) 4 is demonstrated to be crucially correlated with the corticosterone secretion and the impaired adrenal glucocorticoid responses in sepsis. Materials and Methods: SND at dose of 10 g/kg (in low-dose SND group, LD SND) and 20 g/kg (in high-dose SND group, HD-SND) was administered to CLP rats. Four days later, overall survival rates of rats were calculated; rat serum and adrenal glands were collected. Basic serum corticosterone levels were determined, and the increase of corticosterone after 0.8 ug/kg ACTH injection was checked to detect the adrenocortical sensitivity to ACTH. The protein and mRNA expression of TLR4 in adrenal glands were measured to study the impact of SND on TLR4 expression. mRNA levels of IL-10 and TNF-a in adrenal glands and IL-10 and TNF-a levels in serum were also determined to study the cytokines profile. Results: SND improved the cumulative survival rate of CLP rats up to 4 days (P < 0.05 with HD SND) and adrenocortical sensitivity to 0.8 ug/kg ACTH stimulation (P < 0.05 at 60 mins, 31.02 +/- 19.23 ng/ml in LD-SND group and 32.18 +/- 14.88 ng/ml in HD-SND group versus 5.03 +/- 13.34 ng/ml in CLP group), with a significant decrease of protein (P < 0.05, 29.6% in LD-SND group and 27.8% in HD-SND group), mRNA expression of TLR4 (P < 0.05, 32.9% in LD-SND group and 36.1% in HD-SND group), mRNA expression of IL-10 (P < 0.05, 32.0% in LD-SND group and 29.6% in HD-SND group), TNF-a in adrenal glands (P < 0.05, 26.0% in LD-SND group and 25.3% in HD SND group), and TNF-a level in serum (P < 0.05, 100.20 +/- 19.41 pg/ml in LD-SND group and 92.40 +/- 11.66 pg/ml in HD-SND group versus 134.40 +/- 27.87 pg/ml in CLP group). Conclusion: SND increased overall survival rate within 4 days and attenuated adrenal insufficiency in septic rats by downregulating TLR4 mRNA and protein expression in adrenal tissue, inhibiting adrenal production of TNF-alpha and IL-10, and improving adrenal responsiveness. Our results suggest that SND is able to ameliorate adrenal stress responses in a local immune-adrenal crosstalk way involving downregulated expression of TLR4 in adrenal tissue. SND might be a promising treatment for adrenal insufficiency prevention in prolonged sepsis. PMID- 30018659 TI - Systemic Administration of Curcumin Affect Anxiety-Related Behaviors in a Rat Model of Posttraumatic Stress Disorder via Activation of Serotonergic Systems. AB - Posttraumatic stress disorder (PTSD) is a trauma-induced psychiatric disease characterized by impaired hyperarousal, fear extermination, depression, anxiety, and amnesic symptoms that may include the release of monoamines in the dread circuit. Curcumin (CUR), a major diarylheptanoid and polyphenolic component of Curcuma longa, reportedly possesses several pharmacological features, including antidiabetic, antiatherosclerotic, anticancer, and neuropsychiatric actions. But the anxiolytic-like effects of CUR and its mechanism of action in PTSD are unclear. The current research measured some anxiety-related behavioral responses to examine the effects of CUR on symptoms of anxiety in rats after single prolonged stress (SPS) exposure by reversing the serotonin (5-HT) dysfunction. Rats received CUR (20, 50, or 100 mg/kg, i.p., once daily) for 14 days after SPS exposure. Administration of CUR significantly increased the number of central zone crossings in the open field test and reduced grooming behavior in the elevated plus maze (EPM) test and increased the number of open-arm visits on the EPM test. CUR administration significantly reduced freezing response to contextual fear conditioning. CUR recovered neurochemical abnormalities and SPS induced decreased 5-HT tissue levels in the hippocampus, amygdala, and striatum. These results suggested that CUR has anxiolytic-like effects on biochemical and behavioral symptoms associated with anxiety. Thus, CUR may be a useful agent to alleviate or treat psychiatric disorders similar to those observed in patients with PTSD. PMID- 30018660 TI - Transition versus Continuous Slope Walking: Adaptation to Change Center of Mass Velocity in Young Men. AB - During continuous uphill walking (UW) or downhill walking, human locomotion is modified to counteract the gravitational force, aiding or impeding the body's forward momentum, respectively. This study aimed at investigating the center of mass (COM) and center of pressure (COP) velocities and their relative distance during the transition from uphill to downhill walking (UDW) to determine whether locomotor adjustments differ between UDW and UW. Fourteen participants walked on a triangular slope and a continuous upslope of 15 degrees . The kinematics and COPs were obtained using a force plate and a motion capture system. The vertical velocity of the COM in the propulsion phase, the horizontal distance between the COM and COP at initial contact, and the duration of the subphases significantly differed between UDW and UW (all p < 0.05). Compared with the results of UW, longer durations and the deeper downward moving COM in the propulsion phase were observed during UDW (all p < 0.05). Additionally, a shorter horizontal distance between the COM and COP at initial contact was associated with a slower vertical COM velocity in the propulsion phase during UDW. The reduced velocity is likely a gait alteration to decrease the forward momentum of the body during UDW. PMID- 30018661 TI - Inverse association of ApoB and HSP60 antibodies with coronary artery disease in Indian population. AB - Objective: Atherosclerosis is an autoimmune condition and the underlying cause of coronary artery disease (CAD). Circulating antibodies to self-antigens can have a pathogenic or protective function in atherosclerosis. The objective of the study was to understand the association of autoantibody levels with CAD and its correlation with circulating immune cells. Methods: We assessed antigen concentration and antibodies to apolipoprotein B (ApoB) and heat shock protein (HSP)60 by ELISA in 252 acute coronary syndromes (ACS), 112 patients with stable angina (SA) and 203 healthy controls from Indian population. T cells in peripheral blood mononuclear cells (PBMC) were enumerated by flow cytometry. Cytokine concentrations were measured by multiplex assay. Results: IgG and IgM antibodies to ApoB and HSP60 proteins were significantly lower in patients with ACS while only IgG levels to ApoB were lower in patients with SA, compared with control. Subjects in the highest tertile of antibodies showed significantly lower OR for ACS (IgG 0.52, 95% CI 0.31 to 0.88, p=0.02 and IgM 0.58, 95% CI 0.34 to 0.98, p=0.04), ApoB100 (IgG 0.52, 95% CI 0.31 to 0.88, p=0.02 and IgM 0.58, 95% CI 0.34 to 0.99, p=0.04) and HSP60, respectively. Interestingly, T helper 17 (TH17) cells showed an inverse relationship with ApoB and HSP60 IgG antibodies (r2=-0.17, p<0.001 and r2=-0.20, p<0.001, respectively), while interleukin 17 concentrations were negatively correlated with IgM antibodies to the proteins. Conclusion: This study shows that higher antibodies to ApoB and HSP60 proteins are less often associated with ACS and that these antibodies are inversely associated with inflammatory Th17 cells. PMID- 30018663 TI - An efficient synthesis of 1,6-anhydro-N-acetylmuramic acid from N acetylglucosamine. AB - A novel synthesis of 1,6-anhydro-N-acetylmuramic acid is described, which proceeds in only five steps from the cheap starting material N-acetylglucosamine. This efficient synthesis should enable future studies into the importance of 1,6 anhydromuramic acid in bacterial cell wall recycling processes. PMID- 30018662 TI - Clinical implication of LAVI over A' ratio in patients with acute coronary syndrome. AB - Purpose: The ratio of the left atrial volume index (LAVI) and late diastolic mitral annular velocity (A') is a useful echocardiographic index for identifying advanced left ventricular (LV) diastolic dysfunction in patients with dyspnoea. We investigated the clinical implications and prognostic value of the aforementioned ratio (LAVI/A') in patients with ST elevation (STE) or non-STE (NSTE) acute coronary syndrome (ACS). Methods: We studied 212 patients with ACS. All patients underwent electrocardiography, echocardiography and measurement of plasma B-type natriuretic peptide (BNP) level on admission. The study endpoints were hospitalisation and mortality because of heart failure (HF). Results: There was a significant, moderate positive correlation between LAVI/A' and natural logarithm (Ln) BNP level among the participants (r=0.48, p<0.0001). During a mean follow-up of 17 months, eight patients died and nine patients were hospitalised because of HF. The receiver operating characteristics curve indicated that LAVI/A'>=3.0 predicted these events (log-rank, p=0.0021). A significant and moderate positive correlation existed between LAVI/A' and Ln BNP level in the NSTE-ACS group (n=128; r=0.58, p<0.0001). However, the correlation between LAVI/A' and Ln BNP level was weaker in the STE-ACS group (n=84; r=0.33, p=0.0017). Conclusion: LAVI/A' was related to plasma BNP levels in patients with ACS, particularly in those with NSTE-ACS. This index was useful for predicting cardiac events in patients with ACS. PMID- 30018664 TI - Preparation and isolation of isobenzofuran. AB - The synthesis, isolation and characterization of isobenzofuran are described in this publication. Isobenzofuran is of general interest in synthetic and physical organic chemistry because it is one of the most reactive dienes known. A number of synthetic pathways have been published which all suffer from disadvantages such as low yields and difficult purification. We present a synthetic pathway to prepare isobenzofuran in laboratory scale with high yields, from affordable, commercially available starting materials. PMID- 30018666 TI - CF3SO2X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF3SO2Cl. AB - The recent progresses of the application of trifluoromethanesulfonyl chloride, CF3SO2Cl, in the formation of C-CF3, C-SCF3, C-SOCF3, and C-Cl bonds are summarised in this second part of a two-part review published back-to-back on both sodium trifluoromethanesulfinate, CF3SO2Na, (Part 1) and trifluoromethanesulfonyl chloride, CF3SO2Cl (Part 2). There are many reactions in common between these two reagents but it should be noted that CF3SO2Cl reacts under reductive conditions while CF3SO2Na requires oxidative conditions. Electrophilic chlorination is obviously the exclusive preserve of CF3SO2Cl that has been exploited with emphasis in enantioselective chlorination. PMID- 30018665 TI - CF3SO2X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF3SO2Na. AB - Sodium trifluoromethanesulfinate, CF3SO2Na, and trifluoromethanesulfonyl chloride, CF3SO2Cl, are two popular reagents that are widely used for the direct trifluoromethylation of a large range of substrates. Further, these two reagents are employed for the direct trifluoromethylsulfenylation and trifluoromethylsulfinylation, the introduction of the SCF3 and the S(O)CF3 group, respectively. In addition to the aforementioned reactions, the versatility of these two reagents is presented in other reactions such as sulfonylation and chlorination. This first part is dedicated to sodium trifluoromethanesulfinate. PMID- 30018668 TI - The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers. AB - The diastereoselective synthesis of fluorinated building blocks that contain chiral fluorine substituents is of interest. Here we describe optimisation efforts in the synthesis of anti-2,3-difluorobutane-1,4-diol, as well as the synthesis of the corresponding syn-diastereomer. Both targets were synthesised using an epoxide opening strategy. PMID- 30018667 TI - Synthetic mRNA capping. AB - Eukaryotic mRNA with its 5'-cap is of central importance for the cell. Many studies involving mRNA require reliable preparation and modification of 5'-capped RNAs. Depending on the length of the desired capped RNA, chemical or enzymatic preparation - or a combination of both - can be advantageous. We review state-of the art methods and give directions for choosing the appropriate approach. We also discuss the preparation and properties of mRNAs with non-natural caps providing novel features such as improved stability or enhanced translational efficiency. PMID- 30018670 TI - Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia. AB - Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6 hydroxypyrimidine (DAHP), a guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5 triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl 2, COX-2, and TNF-alpha protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-alpha. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis. PMID- 30018669 TI - Xiao-Xu-Ming Decoction Reduced Mitophagy Activation and Improved Mitochondrial Function in Cerebral Ischemia and Reperfusion Injury. AB - We investigated whether Xiao-Xu-Ming decoction reduced mitophagy activation and kept mitochondrial function in cerebral ischemia-reperfusion injury. Rats were randomly divided into 5 groups: sham, ischemia and reperfusion (IR), IR plus XXMD (60 g/kg/day) (XXMD60), IR plus cyclosporin A (10 mg/kg/day) (CsA), and IR plus vehicle (Vehicle). Focal cerebral ischemia and reperfusion models were induced by middle cerebral artery occlusion (MCAO). Cerebral infarct areas were measured by triphenyl tetrazolium chloride staining. Cerebral ischemic injury was evaluated by hematoxylin and eosin staining (HE) and Nissl staining. Ultrastructural features of mitochondria and mitophagy in the penumbra of the ischemic cortex were observed by transmission electron microscopy. Mitophagy was detected by immunofluorescence labeled with LC3B and VDAC1. Autophagy lysosome formation was observed by immunofluorescence labeled with LC3B and Lamp1. The expression of LC3B, Beclin1, and Lamp1 was analyzed by Western blot. The rats subjected to MCAO showed worsened neurological score and cell ischemic damage. These were all significantly reversed by XXMD or CsA. Moreover, XXMD/CsA notably downregulated mitophagy and reduced the increase in LC3, Beclin1, and Lamp1 expression induced by cerebral ischemia and reperfusion. The findings demonstrated that XXMD exerted neuroprotective effect via downregulating LC3, Beclin1, Lamp1, and mitochondrial p62 expression level, thus leading to the inhibition of mitophagy. PMID- 30018671 TI - MST1 Suppression Reduces Early Brain Injury by Inhibiting the NF-kappaB/MMP-9 Pathway after Subarachnoid Hemorrhage in Mice. AB - Background: Mammalian sterile 20-like kinase 1 (MST1), the key component of the Hippo-YAP pathway, exhibits an important role in the pathophysiological process of various neurological disorders, including ischemic stroke and spinal cord injury. However, during subarachnoid hemorrhage, the involvement of MST1 in the pathophysiology of early brain injury remains unknown. Methods: We employed intravascular filament perforation to establish the subarachnoid hemorrhage (SAH) mouse model. The MST1 inhibitor XMU-MP-1 was intraperitoneally injected at 1 h after SAH, followed by daily injections. MST1 in vivo knockdown was performed 3 weeks prior to SAH via intracerebroventricular injection of adeno-associated virus (AAV) packaged with MST1 shRNA. The SAH grade, behavioral deficits, TUNEL staining, Evans blue dye extravasation and fluorescence, brain water content, protein and cytokine expressions by Western blotting, immunofluorescence, and proteome cytokine array were evaluated. Results: Following SAH, the phosphorylation level of MST1 was upregulated at 12 h, with a peak at 72 h after SAH. It was colocalized with the microglial marker Iba1. Both XMU-MP-1 and MST1 shRNA alleviated the neurological deficits, blood-brain barrier (BBB) disruption, brain edema, neuroinflammation, and white matter injury, which were induced by SAH in association with nuclear factor- (NF-) kappaB p65 and matrix metallopeptidase-9 (MMP-9) activation and downregulated endothelial junction protein expression. Conclusions: The current findings indicate that MST1 participates in SAH-induced BBB disruption and white matter fiber damage via the downstream NF-kappaB-MMP-9 signaling pathway. Therefore, MST1 antagonists may serve as a novel therapeutic target to prevent early brain injury in SAH patients. PMID- 30018673 TI - Galectin-3 as a Predictor of Left Ventricular Reverse Remodeling in Recent-Onset Dilated Cardiomyopathy. AB - Objectives: Studies have evaluated the association of galectin-3 and outcome in patients with heart failure. However, there is still scarce evidence concerning the clinical usefulness and predictive value of galectin-3 for left ventricular reverse remodeling (LVRR) in patients with recent-onset dilated cardiomyopathy (RODCM). Patients and Methods: Baseline galectin-3 was measured in 57 patients with RODCM. All patients were followed for at least 12 months. The study end point was LVRR at 12 months, defined as an absolute improvement of the left ventricular ejection fraction of >=10% to a final value of >=35%, accompanied by a decrease in the left ventricular end diastolic diameter of at least 10%, as assessed by echocardiography. In receiver operating characteristic curve analysis, the optimum cut-off value for baseline galectin-3 with the highest Youden index was 59 ng/ml. Results: Overall, LVRR at 12 months was observed in 38 patients (66%). In a univariate analysis, NYHA functional class and baseline galectin-3 levels were associated with LVRR. After adjustment for covariates, galectin-3 remained an independent predictor for LVRR. Conclusions: Our study suggests that baseline galectin-3 is an independent predictor of LVRR. Low levels of galectin-3 may be regarded a useful biomarker of favorable ventricular remodeling in patients with RODCM. PMID- 30018672 TI - REM Sleep Behavior Disorder (RBD) in Dementia with Lewy Bodies (DLB). AB - Rapid eye movement sleep behavior disorder (RBD) is a parasomnia, with abnormal dream-enacting behavior during the rapid eye movement (REM) sleep. RBD is either idiopathic or secondary to other neurologic disorders and medications. Dementia with Lewy bodies (DLB) is the third most common cause of dementia, and the typical clinical presentation is rapidly progressive cognitive impairment. RBD is one of the core features of DLB and may occur either in advance or simultaneously with the onset of DLB. The association between RBD with DLB is widely studied. Evidences suggest that both DLB and RBD are possibly caused by the shared underlying synucleinopathy. This review article discusses history, clinical manifestations, possible pathophysiologies, and treatment of DLB and RBD and provides the latest updates. PMID- 30018674 TI - Clinical Impact and Prognostic Role of KRAS/BRAF/PIK3CA Mutations in Stage I Colorectal Cancer. AB - Stage I colorectal carcinoma has excellent prognosis, with 5-year survival rate up to 95%. The occurrence of lymphovascular invasion, tumor budding, high number of PDC, or lymph node micrometastases is associated with tumor progression. The aim of this study was to evaluate the mutational status of 62 stage I colorectal carcinomas (CRC) (taken from 37 patients surviving more than five years since the initial diagnosis and from 25 patients who died of disease) and to correlate it with histopathological features and the clinical outcome. Mutations of KRAS, NRAS, BRAF, and PIK3CA genes were analyzed through Myriapod Colon Status Kit, using the high-throughput genotyping platform Sequenom MassARRAY System. Mutations in those genes were found in 31 cases (50%) and mainly in those with poor prognosis. The most frequent mutations occurred at codons 12 and 13 of the KRAS gene (40% of cases). We found concomitant PIK3CA mutations in 5 cases (8%). The presence of PIK3CA mutations was mainly observed in tumors with poor prognosis and with unfavorable histopathological prognostic features. High PDC grade (P = 0.0112), the presence of tumor budding (P = 0.0334), LVI (P < 0.0001), KRAS mutations (P = 0.0228), PIK3CA mutations (P = 0.0214), multiple genetic mutations in KRAS and PIK3CA genes (P = 0.039), and nodal micrometastases (P < 0.0001) were significant prognostic variables for CSS. The presence of LVI was the only independent and statistically significant prognostic variable for CSS in our cohort of pTNM stage I CRCs. The analysis of KRAS/PIK3CA mutational status may be used to identify patients with stage I CRC at high risk of bad outcome and who may need additional treatments, including biological therapies. PMID- 30018675 TI - Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy. AB - Objective: To investigate the ratios of creatine kinase (CK) to aminotransferases as biomarkers of acute liver injury in dystrophinopathy. Methods: C57 and mdx (dystrophic) mice were treated with a hepatotoxic reagent D-galactosamine (D GalN). The degrees of liver and muscle injury were assessed using histological examinations. To examine whether serum CK-adjusted aminotransferase levels could indicate liver status in dystrophic mice, the CK/alanine aminotransferase (ALT) and CK/aspartate aminotransferase (AST) ratios were analyzed. Furthermore, we enrolled 658 male patients with dystrophinopathy and 378 male patients without muscle and liver injury as control, whose serum ALT, AST, and CK levels were examined. Results: Animal experiments indicated that D-GalN treatment could induce acute liver injury but not muscle injury. Additionally, D-GalN decreased the CK/ALT and CK/AST ratios in both C57 mice and mdx mice (P < 0.001). However, there was an overlap of the CK/AST ratio between dystrophic mice with and without acute liver injury. In patients with dystrophinopathy, CK-adjusted ALT diminished the variability associated with age, genotype, clinical phenotype, and motor function (P > 0.05). Conclusions: CK/ALT is a potential biomarker for the differential evaluation of acute liver injury in dystrophic mice, which highlights the value to further evaluate the practice of CK/ALT in dystrophinopathy patients. PMID- 30018676 TI - Platelet Distribution Width at First Day of Hospital Admission in Patients with Hemorrhagic Fever with Renal Syndrome Caused by Hantaan Virus May Predict Disease Severity and Critical Patients' Survival. AB - Thrombocytopenia is one of the main characteristics of hemorrhagic fever with renal syndrome (HFRS). This study aimed to evaluate the associations of platelet distribution width (PDW) with the disease severity and critical patients' survival of HFRS. The demographics, clinical data, and white blood cell and platelet parameters including PDW in 260 patients hospitalized for HFRS were analyzed. The results showed that PDW on the first day (PDW1) was positively associated with the disease severity (p = 0.005). Multiple regression analysis showed that in addition to age (odds ratio [OR], 1.091; 95% confidence interval [CI], 1.015-1.172) and occurrence of sepsis (OR, 22.283; 95% CI, 2.985-166.325), PDW1 (OR, 0.782; 95% CI, 0.617-0.992) was a risk factor of the mortality, having an area under the receiver operating characteristic curve of 0.709 (95% CI, 0.572 0.846, p = 0.013) for predicting mortality, with a sensitivity of 70% and a specificity of 67% at a cutoff of 16.5 fL, in patients with critical HFRS. These results suggest the potential of PDW at the first day of hospitalization as a valuable parameter for evaluating the severity of HFRS and a moderate parameter for predicting the prognosis of critical HFRS patients. A prospective study in large patient population is needed to validate these findings. PMID- 30018678 TI - Critical and courageous thinking in medical education: truth-telling, an antidote to tradition. PMID- 30018679 TI - Smoking cessation counselling training in the pre-clerkship curriculum of Canadian medical schools: A national survey. AB - Background: Cigarette use is Canada's leading cause of preventable disease, disability, and death. The Medical Council of Canada requires that physicians be able to address tobacco-use, however smoking cessation counselling (SCC) training remains largely neglected in the pre-clerkship curricula of many Canadian medical schools. Methods: Between July and October of 2015, Canada's 17 medical schools were invited to participate in an administrative survey: The Canadian Medical School Assessment of Smoking Cessation Counselling in the Pre-Clerkship Curriculum. Each was asked to comment on the presence of 28 tobacco-related topics in their curricula, including: time devoted to source material; year(s) of training during which medical students were exposed to related content; methods of teaching and examination; and, the attitudes, policies, and barriers relevant to the presence of smoking cessation counselling (SCC) training in the curriculum.A second short survey: Assessing Medical Students Attitudes toward Smoking Cessation Education was distributed to 100 University of Ottawa medical students to assess comfort level and perceived confidence toward addressing smoking cessation with patients. Results: Eleven of 17 medical schools completed the administrative survey. The results demonstrated substantial deficits and inconsistencies in the delivery of SCC training in the pre-clerkship curricula of Canada's medical schools. The short survey revealed perceived discomfort regarding smoking cessation discussion, consistent with the potential curriculum deficits suggested in the larger national survey. Conclusion: The results of both surveys suggest an unfortunate oversight given the devastating impact of tobacco related diseases. Institutional commitment and enhanced inter-university collaboration could facilitate the development of a national undergraduate medical education program to enhance the delivery of SCC training within the pre clerkship curricula of Canadian medical schools. PMID- 30018677 TI - Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes. AB - The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs. PMID- 30018680 TI - Personality distribution of Canadian medical students: A first look. AB - Background: Personality is one of the key elements in professional identity formation and is self-identified as one of the top two influences for Canadian medical graduates when making a specialty choice yet little is known about the personalities of Canadian medical students. This study is the first to report personality data regarding Canadian medical students. Methods: Personality is one of the key elements in professional identity formation and is self-identified as one of the top two influences for Canadian medical graduates when making a specialty choice yet little is known about the personalities of Canadian medical students. This study is the first to report personality data regarding Canadian medical students. Results: The data were analyzed using Chi square. The distribution of personalities [Guardian, Idealist, Artisan, Rational] for medical students differs from the distribution reported for the general Canadian population. The distribution of personalities is similar for each Canadian medical school. Conclusion: Results from this first national accounting of the personalities of Canadian medical students suggest either that the personalities of medical school applicants differ from the general population or that personality affects medical school admissions success. Knowing the personalities of medical students could be important for medical schools in such areas as admissions, career counselling and professional identity formation. PMID- 30018681 TI - Use of portfolios for assessment of global health residents: qualitative evaluation of design and implementation. AB - Background: When the Global Health training program was created at the University of Calgary, residents were encouraged to seek learning experiences that met their career goals and individualized objectives. An assessment tool was sought that could be reliable, valid, yet flexible. A portfolio process was chosen, but research was necessary to determine whether it was robust. Methods: A qualitative study was conducted with academic experts in Canadian residency training, as well as directors and residents involved in Global Health study in order to assess the validity and benefit of such a tool. Through an online survey, interviews, and focus groups, views on the portfolio and intended content were collected and coded thematically. Results: Multiple themes emerged from the content analysis. Overall, all stakeholders (residents and faculty) were supportive of the use of portfolios for summative assessment, mentioning authentic and varying assessments, reflective and narrative components, and mentor interaction as positive attributes, but they did have many recommendations. Conclusion: This qualitative evaluation validated the use of portfolios for this cohort of students while yielding comments and suggestions that will further enhance the interactive and flexible nature of this seldom used assessment tool. These findings contribute to the understanding of how Global Health assessment can remain individualized yet rigorous. PMID- 30018682 TI - Ethical globalization? Decolonizing theoretical perspectives for internationalization in Canadian medical education. AB - Background: Internationalization is a process being undertaken at institutions of post-secondary education worldwide in response to globalization. The resulting imperatives for medical education include re-thinking Canadian positionality within uneven, problematic Global North-South relations. Members of the medical education community are in need of training and tools to navigate this complex situation. Methods: Using a decolonial theoretical perspective, a literature review was conducted and framed with three ethical questions posed to stimulate collective conversations about internationalization among all members of the health professions education community in Canada. Results: This study identifies analytical gaps in discussions on the role of medical education in the context of colonial, neoliberal, unjust Global North-South relations. The results point to the need for deeper examination of medical curricula for problematic representations and theorization of inequities and racialization. They also suggest that practices for International Medical Electives and the involvement of International Medical Graduates should be evaluated in light of the ethical concerns identified. Conclusion: During this moment of internationalization and globalization in all health professional education, reflexivity and self awareness are important strategies for engaging with decolonizing theoretical perspectives that are critical of Global North-South relations like neoliberal globalization and colonialism. Increased inclusion of pluralistic ways of approaching both processes are necessary for combatting growing health inequities in Canada and globally. PMID- 30018683 TI - Community engagement in global health education supports equity and advances local priorities: an eight year Ecuador-Canada partnership. AB - Background: Global health education initiatives inconsistently balance trainee growth and benefits to host communities. This report describes a global health elective for medical trainees that focuses on community engagement and participatory research to provide mutually beneficial outcomes for the communities and trainees. Methods: An eight-year university-community partnership, the Chilcapamba to Montreal Global Health Elective is a two-month shared decision-making research and clinical observership experience in rural Ecuador for medical trainees at McGill University, Canada. Research topics are set by matching community-identified priorities with skillsets and interests of trainees, taking into consideration local potential impact. Results: Community outcomes included development of a Community Health Worker program, new collaborations with local organizations, community identification of health priorities, and generation of health improvement recommendations. Collaborative academic outputs included multiple bursary awards, conference presentations and published manuscripts. Conclusion: This medical global health elective engages communities using participatory research to prioritise socially responsible and locally beneficial outcomes. PMID- 30018684 TI - Plain language communication as a priority competency for medical professionals in a globalized world. AB - This brief report aims to highlight the impact of globalization - the international movement of goods, people, and ideas - on patient-provider communication in medical training and practice, and how the implementation of plain language communication training as a core competency for care providers can mitigate this impact. Globalization influences both patient and provider population diversity, which presents challenges with regard to patient-provider communication, particularly in cases of limited health literacy. Plain language communication - the delivery of information in a simple, succinct, and accurate manner - can help address these challenges. Training in plain language communication, however, is not a part of standard education for health care providers. Based on a synthesis of relevant literature pertaining to globalization, plain language communication, and medical education curricula, it is hoped that the information presented establishes the need for plain language communication as a core competency in medical education to enable providers to better meet the needs of an increasingly globalized health system. PMID- 30018685 TI - Characterizing a community health partnership in Dominican Republic: Network mapping and analysis of stakeholder perceptions. AB - Background: Medical trainees complete learning experiences abroad to fulfil global health curricular elements, but this participation has been steadily criticized as fulfilling learner objectives at the cost of host communities. This study uses network and qualitative analyses in characterizing a community coalition in order to better understand its various dimensions and to explore the perceived benefits it provided towards optimizing community outcomes. Methods: Data from a semi-structured survey was used for network and qualitative analyses. Partner linkages were assessed using network analysis tool UCINET 6 (version 6.6). Thematic analysis was conducted on qualitative responses around the perceived coalition strengths and weaknesses. Results: Network analysis confirmed that local member organizations were key network influencers based on reported formal agreements, general interactions, and information shared. While sharing of resources was rare, qualitative analysis suggested that information sharing contributed to engagement, enthusiasm, and communication that allowed visiting partners to expand their understanding of community needs and shift their focus beyond learner objectives. Conclusion: Global health programs for medical students should consider the use of community health coalitions to optimally align the work undertaken by learners on global health experiences abroad. Network mapping can help educators and coalition partners visualize interactions and identify value. PMID- 30018686 TI - Students working against tobacco: A novel educational program to improve Canadian medical students' tobacco counselling skills. AB - Background: Medical professionals should be appropriately trained in the field of smoking cessation counseling and be familiar with related tobacco-control issues. Sadly, Canadian medical students receive little education regarding smoking cessation. Methods: University of Ottawa medical students created Students Working Against Tobacco (SWAT), a program that provides its members with tobacco education and opportunities to discuss tobacco use, smoking prevention and cessation with elementary-school students. Surveys assessing student knowledge and confidence in addressing tobacco issues were administered to the participating students at the start of the program and following their delivery of a school presentation. Results: Students initially lacked knowledge, skills and experience in addressing tobacco issues and discussing smoking prevention and cessation counselling. Following their involvement in the SWAT program, students' smoking cessation counselling knowledge and skills improved, and they expressed confidence in becoming more engaged in this important preventive health issue. Conclusion: Until smoking cessation is incorporated into undergraduate medical education programs, gaps will remain in the preparation of tomorrow's physicians regarding the provision of effective smoking cessation counselling and their broader understanding of this important health issue. Currently, there are constraints limiting the number of medical undergraduates that SWAT is able to involve and influence. PMID- 30018687 TI - Ethics in radiology: A case-based approach. AB - Background: Ethics training is required for all radiology residents in Canada, but this may be difficult to provide as radiology departments may not have radiologists with formal ethics training, and may not have access to educational resources focussed on teaching ethics to radiologists. We describe the implementation of a case-based approach to teaching and learning ethics, designed for Canadian radiologists. This approach can be adapted for use in other specialties through development of specialty-specific ethics case scenarios. Methods: Ethics case study rounds specific to Canadian radiologic practice were presented at two different institutions, and using two different methods within one institution. In one method, we requested that the residents read the case study and questions ahead of time; in the other, the rounds were presented without any expectation of residents doing prior preparation. Results: The participants, as a group, agreed with all seven survey statements describing the value of the experience. The opportunity to read the case ahead of time seemed helpful for some residents, but was not found to be overall more useful than discussing the case without prior review. Indeed, more than half of the resident participants in this group indicated that they did not make use of the advance materials at all. Conclusion: Resident feedback indicates that ethics case study rounds are a useful and valuable experience, especially when the case is specifically tailored to their medical practice. Prior preparation was not necessary for residents to benefit from these rounds. PMID- 30018688 TI - Physician workforce planning in Ontario must move from short-term reactivity to long-term proactivity. PMID- 30018689 TI - The unmatched. PMID- 30018690 TI - Canadian Federation of Medical Students (CFMS) response to: The unmatched by Dr. Amit Persad. PMID- 30018691 TI - Association of Faculties of Medicine of Canada response to: The unmatched by Dr. Amit Persad. PMID- 30018692 TI - On call. PMID- 30018694 TI - Distribution of label spacings for genome mapping in nanochannels. AB - In genome mapping experiments, long DNA molecules are stretched by confining them to very narrow channels, so that the locations of sequence-specific fluorescent labels along the channel axis provide large-scale genomic information. It is difficult, however, to make the channels narrow enough so that the DNA molecule is fully stretched. In practice, its conformations may form hairpins that change the spacings between internal segments of the DNA molecule, and thus the label locations along the channel axis. Here, we describe a theory for the distribution of label spacings that explains the heavy tails observed in distributions of label spacings in genome mapping experiments. PMID- 30018695 TI - Flow-induced deformation in a microchannel with a non-Newtonian fluid. AB - In this work, we have fabricated physiologically relevant polydimethylsiloxane microfluidic phantoms to investigate the fluid-structure interaction that arises from the interaction between a non-Newtonian fluid and the deformable wall. A shear thinning fluid (Xanthan gum solution) is used as the blood analog fluid. We have systematically analyzed the steady flow characteristics of the microfluidic phantom using pressure drop, deformation, and flow visualization using micro-PIV (Particle Image Velocimetry) to identify the intricate aspects of the pressure as well as the velocity field. A simple mathematical formulation is introduced to evaluate the flow induced deformation. These results will aid in the design and development of deformable microfluidic systems and provide a deeper understanding of the fluid-structure interaction in microchannels with special emphasis on biomimetic in-vitro models for lab-on-a-chip applications. PMID- 30018696 TI - Vascular-targeted particle binding efficacy in the presence of rigid red blood cells: Implications for performance in diseased blood. AB - The field of drug delivery has taken an interest in combating numerous blood and heart diseases via the use of injectable vascular-targeted carriers (VTCs). However, VTC technology has encountered limited efficacy due to a variety of challenges associated with the immense complexity of the in vivo blood flow environment, including the hemodynamic interactions of blood cells, which impact their margination and adhesion to the vascular wall. Red blood cell (RBC) physiology, i.e., size, shape, and deformability, drive cellular distribution in blood flow and has been shown to impact VTC margination to the vessel wall significantly. The RBC shape and deformability are known to be altered in certain human diseases, yet little experimental work has been conducted towards understanding the effect of these alterations, specifically RBC rigidity, on VTC dynamics in physiological blood flow. In this work, we investigate the impact of RBCs of varying stiffnesses on the adhesion efficacy of particles of various sizes, moduli, and shapes onto an inflamed endothelial layer in a human vasculature-inspired, in vitro blood flow model. The blood rigid RBC compositions and degrees of RBC stiffness evaluated are analogous to conditions in diseases such as sickle cell disease. We find that particles of different sizes, moduli, and shapes yield drastically different adhesion patterns in blood flow in the presence of rigid RBCs when compared to 100% healthy RBCs. Specifically, up to 50% reduction in the localization and adhesion of non-deformable 2 MUm particles to the vessel wall was observed in the presence of rigid RBCs. Interestingly, deformable 2 MUm particles showed enhanced vessel wall localization and adhesion, by up to 85%, depending on the rigidity of RBCs evaluated. Ultimately, this work experimentally clarifies the importance of considering RBC rigidity in the intelligent design of particle therapeutics and highlights possible implications for a wide range of diseases relating to RBC deformability. PMID- 30018698 TI - van der Waals Interaction Activated Strong Electronic Coupling at the Interface between Chloro Boron-Subphthalocyanine and Cu(111). AB - In this article, we investigate the interface between shuttlecock-shaped chloro boron-subphthalocyanine molecules and the Cu(111) surface. We highlight how molecular planarization induced by van der Waals forces can fundamentally alter the interface properties and how it can enable a particularly strong hybridization between molecular and metal states. In our simulations, we start from a situation in which we disregard van der Waals forces and then introduce them gradually by rescaling the interaction parameter, thereby "pulling" the molecule toward the surface. This reveals two adsorption regimes with significantly different adsorption distances, molecular conformations, and adsorbate-induced changes of the work function. Notably, the above-mentioned massive hybridization of electronic states, also observed in photoelectron spectroscopy, is obtained solely for one of the regimes. We show that this regime is accessible only as a consequence of the planarization of the molecular backbone resulting from the van der Waals attraction between the molecule and the surface. The results of this study indicate that for certain metal-molecule combinations unusually strong interfacial electronic interactions can be triggered by van der Waals forces creating a situation that differs from the usually described cases of physisorptive and chemisorptive interactions. PMID- 30018697 TI - Barriers-on-chips: Measurement of barrier function of tissues in organs-on-chips. AB - Disruption of tissue barriers formed by cells is an integral part of the pathophysiology of many diseases. Therefore, a thorough understanding of tissue barrier function is essential when studying the causes and mechanisms of disease as well as when developing novel treatments. In vitro methods play an integral role in understanding tissue barrier function, and several techniques have been developed in order to evaluate barrier integrity of cultured cell layers, from microscopy imaging of cell-cell adhesion proteins to measuring ionic currents, to flux of water or transport of molecules across cellular barriers. Unfortunately, many of the current in vitro methods suffer from not fully recapitulating the microenvironment of tissues and organs. Recently, organ-on-chip devices have emerged to overcome this challenge. Organs-on-chips are microfluidic cell culture devices with continuously perfused microchannels inhabited by living cells. Freedom of changing the design of device architecture offers the opportunity of recapitulating the in vivo physiological environment while measuring barrier function. Assessment of barriers in organs-on-chips can be challenging as they may require dedicated setups and have smaller volumes that are more sensitive to environmental conditions. But they do provide the option of continuous, non invasive sensing of barrier quality, which enables better investigation of important aspects of pathophysiology, biological processes, and development of therapies that target barrier tissues. Here, we discuss several techniques to assess barrier function of tissues in organs-on-chips, highlighting advantages and technical challenges. PMID- 30018699 TI - Electronic Structure Analysis of the Diels-Alder Cycloaddition Catalyzed by Alkali-Exchanged Faujasites. AB - The Diels-Alder cycloaddition (DAC) reaction is a commonly employed reaction for the formation of C-C bonds. DAC catalysis can be achieved by using Lewis acids and via reactant confinement in aqueous nanocages. Low-silica alkali-exchanged faujasite catalysts combine these two factors in one material. They can be used in the tandem DAC/dehydration reaction of biomass-derived 2,5-dimethylfuran (DMF) with ethylene toward p-xylene, in which the DAC reaction step initiates the overall reaction cycle. In this work, we performed periodic density functional theory (DFT) calculations on the DAC reaction between DMF and C2H4 in low-silica alkali(M)-exchanged faujasites (MY; Si/Al = 2.4; M = Li+, Na+, K+, Rb+, Cs+). The aim was to investigate how confinement of reactants in MY catalysts changed their electronic structure and the DAC-reactivity trend among the evaluated MY zeolites. The conventional high-silica alkali-exchanged isolated site model (MFAU; Si/Al = 47) served as a reference. The results show that confinement leads to initial-state (IS) destabilization and transition-state (TS) stabilization. Among the tested MY, most significant IS destabilization is found in RbY. Only antibonding orbital interactions between the reactants/reactive complex and cations were found, indicating that TS stabilization arises from ionic interactions. Additionally, in RbY the geometry of the transition state is geometrically most similar to that of the initial and final state. RbY also exhibits an optimal combination of the confinement-effects, resulting in having the lowest computed DAC-activation energy. The overall effect is a DAC-reactivity trend inversion in MY as compared to the trend found in MFAU where the activation energy correlates with the Lewis acidity of the exchangeable cations. PMID- 30018700 TI - The Kinetoplast of Trypanosomatids: From Early Studies of Electron Microscopy to Recent Advances in Atomic Force Microscopy. AB - The kinetoplast is a specialized region of the mitochondria of trypanosomatids that harbors the most complex and unusual mitochondrial DNA found in nature. Kinetoplast DNA (kDNA) is composed of thousands of circular molecules topologically interlocked to form a single network. Two types of DNA circles are present in the kinetoplast: minicircles (0.5-10 kb) and maxicircles (20-40 kb). Knowledge of kinetoplast architecture is crucial to understanding the replication and segregation of kDNA circles because the molecules involved in these processes are precisely positioned in functional domains throughout the kinetoplast. The fine structure of the kinetoplast was revealed in early electron microscopy (EM) studies. However, an understanding of the topological organization of kDNA was only demonstrated after the development of protocols to separate kDNA from nuclear DNA, followed by EM observations. Electron microscopy analysis of thin sections of trypanosomatids, spreading of isolated kDNA networks onto EM grids, deep-etching studies, and cytochemical and immunocytochemical approaches are examples of techniques that were useful for elucidating the structure and replication of the kinetoplast. Recently, atomic force microscopy has joined this set of techniques and improved our knowledge about the kDNA network and revealed new details about kDNA topology in trypanosomatids. PMID- 30018702 TI - The lentiviral-mediated Nurr1 genetic engineering mesenchymal stem cells protect dopaminergic neurons in a rat model of Parkinson's disease. AB - Nuclear receptor-related factor 1 (Nurr1) has a crucial role in the development and maturation of mesencephalic dopamine (DA) neurons and also plays a protective role in maintenance of DA neurons by inhibiting the activation of microglia and astrocyte. Moreover, the mutations in Nurr1 gene are associated with familial Parkinson's disease (PD), suggested that Nurr1 modulation is a potential therapeutic target for PD. This study examines the therapeutic effects of transplantation of Nurr1 gene-modified bone marrow mesenchymal stem cells (MSCs) on 6-hydroxydopamine (6-OHDA)-induced PD rat models. MSCs were transduced with lentivirus expressing Nurr1 gene and then intrastriatally transplanted into PD rats. Our results showed that Nurr1 gene-modified MSCs overexpress and secrete Nurr1 protein in vitro and also survive and migrate in the brain. Four weeks after transplantation Nurr1 gene-modified MSCs dramatically ameliorated the abnormal behavior of PD rats and increased the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and TH-positive fibers in the striatum, inhibited the activation of glial cells, and reduced the expression of inflammatory factors in the SN. Taken together, these findings suggest that intrastriatal transplantation of lentiviral vector mediated Nurr1 gene-modified MSCs has notable therapeutic effect for PD rats. PMID- 30018701 TI - The progress of circular RNAs in various tumors. AB - Circular RNAs (circRNAs), a novel type of non-coding RNAs, presented as covalently closed continuous loops. Recent researches had found that circRNAs could function as microRNA sponges, regulators of gene transcription and encoding proteins. They were relatively stable and expressed widely in cytoplasm, which played important roles in carcinogenesis of cancers, such as esophageal cancer, gastric cancer, colorectal cancer, hepatocarcinoma, bladder cancer, glioma, breast cancer, osteosarcoma and so on. Furthermore, they were involved in many biological functions, like cell proliferation, drug resistance, cell cycle, invasion and metastasis. Therefore, the further studies were meaningful on the mechanism of cancers and circRNAs. In the review, we will summarize the current biogenesis of circRNAs and the roles of them in various cancers, which might be a novel biomarker and therapeutic avenue. PMID- 30018704 TI - Endovascular treatment for hemorrhagic cerebral venous sinus thrombosis: experience with 9 cases for 3 years. AB - AIM: We experienced a series of patients with hemorrhagic CVST, who were successfully treated with endovascular treatment (EVT). The aim was to explore the best scheme for the future through our treatment data of hemorrhagic CVST. MATERIAL AND METHODS: A retrospective analysis was conducted, selecting nine hemorrhagic CVST patients, who were mainly treated with EVT. Characteristics of hemorrhagic CVST were recorded, including risk factors, thrombus location, presenting symptoms, and treatment details included type of EVT. We also recorded clinical outcomes, degree of sinus recanalization, thrombus recurrences, periprocedural complications, degree of neurological deficit at last follow-up. RESULTS: Catheter thrombolysis and mechanical thrombectomy were applied in all of the nine hemorrhagic CVST patients, stent retriever was used in 7 patients, one of them combined with balloon-assisted thrombectomy. Besides EVT, two patients accepted emergency surgical decompression, one in the local hospital, and the other in our hospital. The follow-up duration ranged from 4 to 28 months. All of them have a neurological and symptomatic improvement, 6 patients have a good outcome, the rest 3 patients have a poor outcome, no thrombus recurrences and death in them. Seven patients had complete recanalization and two patients had partial recanalization at last follow-up. CONCLUSION: EVT is an effective and safe procedure for potentially catastrophic hemorrhagic cerebral venous sinus thrombosis. PMID- 30018703 TI - An immune-competent rat split thickness skin graft model: useful tools to develop new therapies to improve skin graft survival. AB - Skin grafting is the routine standard of care to manage third degree burns and problematic skin defects. Several commercially available dermal substitutes and biologic skin equivalents are placed in the wound bed to facilitate the healing process of the skin grafts, as well as to provide mechanical support for the cells to grow and to delay the contracture. To study pathology and develop new therapies, an immune-competent rat model is required. We have created two different skin graft animal models to mimic the clinical skin grafting operation, the dorsum skin grafting (DG) and inguinal skin grafting (IG). To create a recipient site, a full-thickness, round excision wound was created on the dorsum between rats' scapular angles, covered with DG or IG. Graft contraction was quantified and tissue was harvested on predetermined time points for analysis. Histologic staining was performed to differentiate between DG and IG. Collagen deposition was assessed with Masson's trichrome staining. Mast cells were detected with Toluidine blue. Macrophages were stained with CD68 immune. Vascularity was assessed with functional vessels numbers. Cell proliferation was assessed with Ki67 immune. This model has all the advantages of murine models, such as an abundance of genetic variants and applicable tools, low cost, and practical housing techniques, all of which will promote the development of new therapies and testing new biologic skin equivalents and dermal substitutes. PMID- 30018705 TI - Egr1 deficiency disrupts dynamic equilibrium of chondrocyte extracellular matrix through PPARgamma/RUNX2 signaling pathways. AB - BACKGROUND: This study is to investigate the effect of Egr1 on the mineralization and accumulation of chondrocyte extracellular matrix. METHODS: The femoral heads of patients of various heights were collected. Egr1 knockout mice were used. Their limb lengtha nd body weight were assessed. The bone characteristics were detected by micro-CT scan and histological staining. Immature murine articular chondrocytes (iMACs) were isolated. Gross morphology was observed by histological staining. Relevant mRNA and protein expression were detected by qRT-PCR and Western blot, respectively. the related proteins were observed by immunohistochemical staining and immunofluorescence assay. Chromatin immunoprecipitation and reporter gene assay were also used. TUNEL was used to detect apoptosis. RESULTS: It was found that shorter patients had reduced Egr1 expression levels in the hypertrophic cartilage zone of the femoral head. In addition, Egr1 knockout mice exhibited reduced body size. Micro-CT analysis showed that these mice also had reduced bone volume. Safranin-O staining showed that the extracellular matrix of these mice exhibited a relatively limited degree of mineralization, and TUNEL staining showed reduced cell apoptosis levels. After transfecting the iMACs with dominant-negative Egr1 adenoviruses to inhibit Egr1, the enzymes of Adamst4, Adamst5, Mmp3 and Mmp13 were significantly upregulated. ChIP and luciferase assays revealed that Egr1 might regulate the chondrocyte extracellular matrix by the PPARgamma/RUNX2 signaling pathways. CONCLUSION: Egr1 has an important regulatory effect on the dynamic equilibrium of the chondrocyte extracellular matrix, which may be achieved through the PPARgamma/RUNX2 signaling pathways. PMID- 30018706 TI - Identification of proteins interacting with pORF5 in the pathogenesis of C. trachomatis. AB - OBJECTIVE: This study is to identify and investigate the proteins interacting with pORF5 implicated in the pathogenesis of C. trachomatis. METHODS: The isobaric tags for relative and absolute quantitation (iTRAQ) approach combined with nano liquid chromatography-tandem mass spectrometry (NanoLC-MS/MS) analysis was applied to identify and quantify the differentially expressed proteins in the pORF5-transfected HeLa (pORF5-HeLa) cells and the control vector-transfected HeLa (vector-HeLa) cells. Quantitative real-time PCR (qRT-PCR) and Western blot analysis were performed to detect the mRNA and protein expression levels. RESULTS: Totally 3355 proteins were quantified by employing biological replicates, 314 of which were differentially expressed between the pORF5-HeLa and vector-HeLa cells. Nine differentially expressed proteins (HIST1H1C, HBA1, PARK7, HMGB1, HMGB2, CLIC1, KRT7, SFN, and CDKN2A) were subjected to qRT-PCR, and two over-expressed proteins (HMGB1 and PRAK7) were subjected to the Western blot analysis, to validate the proteomic results. The results from the qRT-PCR and Western blot analysis were consistent with the findings from the proteomic analysis. Moreover, pORF5 could inhibit the TNF-alpha-induced apoptosis in HeLa cells. Through siRNA-mediated functional screening, the high-mobility group box 1 (HMGB1) was shown to be relevant to the inhibition of the apoptotic response in the host cells. CONCLUSION: Identification of key proteins interacting with pORF5 could contribute to the understanding and further exploration of the function of pORF5 in the pathogenic mechanisms of C. trachomatis. PMID- 30018707 TI - Exosome-related lncRNAs as predictors of HCC patient survival: a prognostic model. AB - OBJECTIVES: Accumulating evidence suggests that long non-coding RNA (lncRNA) may affect hepatocellular carcinoma (HCC) progression. However, the mechanism remains unclear. Previous studies have shown that exosomes may promote tumor progression by transporting proteins. Our study aimed to determine the prognostic value of lncRNAs in HCC and the underlying mechanism. METHODS: A dataset comprising a HCC cohort of 364 patients from The Cancer Genome Atlas (TCGA) was analyzed to identify lncRNAs with prognostic value. Co-expression and competing endogenous RNA (ceRNA) networks were constructed to investigate the mechanism of exosome related lncRNAs. To confirm the bioinformatics analysis results, 95 pairs of clinical samples were evaluated by digoxigenin-labeled chromogenic in situ hybridization (CISH). RESULTS: Five lncRNAs (CTD-2116N20.1, AC012074.2, RP11 538D16.2, LINC00501 and RP11-136I14.5) with significant differences were identified (P<0.001). A prognostic nomogram was constructed with a C-index of 0.701. The co-expression and ceRNA networks showed possible mechanisms for CTD 2116N20.1 and RP11-538D16.2. The CISH results confirmed that CTD-2116N20.1 and RP11-538D16.2 were correlated with a poor prognosis for HCC patients. CONCLUSION: Our findings provide an independent and effective prognostic model to predict the survival rate of HCC patients. RP11-538D16.2 and CTD-2116N20.1 are highlighted as important exosome-related lncRNAs. PMID- 30018708 TI - Topiramate exhibits anti-tumorigenic and metastatic effects in ovarian cancer cells. AB - Ovarian cancer is one of the leading causes of cancer related deaths among women worldwide, with an overall 5-year survival of only 30-40%. Carbonic anhydrases are up-regulated in many types of cancer and play an important role in tumor progression and metastasis. Carbonic anhydrase 9 has been implicated as a potential anti-tumorigenic target. Topiramate (TPM) is a potent inhibitor of carbonic anhydrase isozymes, including carbonic anhydrase 9, and has been shown to have anti-tumorigenic activity in several cancer types. Our goal was to evaluate the effect of TPM on cell proliferation and to identify possible mechanisms by which TPM inhibits cell growth in ovarian cancer. TPM significantly inhibited ovarian cancer cell proliferation and induced cell cycle G1 arrest, cellular stress and apoptosis through the AKT/mTOR and MAPK pathways. TPM also exerted anti-metastatic effects by decreasing the adhesion and invasion of ovarian cancer cells and affecting the expression of critical regulators of the epithelial-mesenchymal transition (EMT). Our findings demonstrate that TPM has anti-tumorigenic effects in ovarian cancer and is worthy of further exploration in clinical trials. PMID- 30018710 TI - Hsa_circ_0103809 promotes cell proliferation and inhibits apoptosis in hepatocellular carcinoma by targeting miR-490-5p/SOX2 signaling pathway. AB - BACKGROUND: Circular RNAs (circRNAs) represent a class of non-coding RNAs that are emerging as important regulators during tumorigenesis and provide potential targets for cancer intervention. However, the expression profiles and functions of circRNAs in hepatocellular carcinoma (HCC) have not been completely clarified. Herein, the role of hsa_circ_0103809 was investigated in HCC tissues and cell lines. METHODS: High-throughput circRNA sequencing was performed to detect the expression profiles of circRNA in HCC tissues. The CCK-8, wound healing and flow cytometry were performed to measure the cell viability, migration and apoptosis in HCC cells. The expression levels of gene and protein in HCC tissues and cell lines were assayed by RT-qPCR and western blotting, respectively. Immunohistochemical staining was used to assess the protein expression of SOX2 in HCC tissues. RESULTS: We discovered that hsa_circ_0103809 was significantly increased in HCC tissues and cell lines. Knockdown of hsa_circ_0103809 inhibited proliferation and migration and induced apoptosis in HCC cell lines. Investigation to the molecular mechanisms of hsa_circ_0103809 in HCC cells had revealed that hsa_circ_0103809 directly suppressed miR-490-5p, which targeted to the 3'-UTR of SOX2. Hsa_circ_0103809 loss-of-function could increase the expression of miR-490-5p as well as decreased the expression of SOX2. Furthermore, we found that si-0103809 induced growth and migration inhibition and apoptosis could be reversed by transfected with miR-490-5p inhibitors or SOX2 in HCC cells. CONCLUSION: Our findings suggested that hsa_circ_0103809 might facilitate HCC malignant progression, at least partially, by regulating miR-490 5p/SOX2 signaling pathway. PMID- 30018709 TI - Interleukin enhancer binding factor 2 is a prognostic biomarker for breast cancer that also predicts neoadjuvant chemotherapy responses. AB - Interleukin enhancer binding factor 2 (ILF2) participates in several aspects of DNA and RNA metabolism and regulates gene expression at multiple levels; however, its role in breast cancer remains undefined. The variant statuses of ILF2 in human breast cancer were evaluated using the COSMIC database. Altered ILF2 expression in normal breast tissue relative to cancer tissue and in breast cancer patients with different clinicopathological characteristics, molecular subtypes, clinical outcomes and chemotherapy responses were examined using the Oncomine, GOBO, Kaplan-Meier plotter and GEO datasets. To explore possible biological networks connected to ILF2 in breast cancer, we performed ingenuity pathway analysis on ILF2-related differentially expressed genes. We found that many breast cancers had increased ILF2 copy number variations and increased ILF2 expression. We also observed that elevated ILF2 expression was correlated with aggressive features, such as high histological grade, BRCA1 mutations, and the triple-negative/basal-like subtype, which resulted in shorter survival in these cases. Moreover, ILF2 expression predicted responses to anthracycline/taxane based treatment. Ingenuity pathway analysis revealed that ILF2-related biological functions included promoting cell survival, viability, and proliferation, as well as cell cycle progression and DNA repair. Certain well-known oncogenes (MYC and HGF), cytokines (CSF2, IFNG and IL5) and microRNAs (miR-21, miR-155-5p and let-7) may participate in the ILF2 expression network in breast cancer. In summary, ILF2 is involved in the development and progression of breast cancer and may be a predictive biomarker for better responses to anthracycline/taxane-based treatments. PMID- 30018711 TI - HOXB5 promotes retinoblastoma cell migration and invasion via ERK1/2 pathway mediated MMPs production. AB - Homeobox genes (HOX genes) have been implicated in many tumors. As a member of HOX genes, HOXB5 is overexpressed in bladder cancer and contributes to the proliferation and invasion of breast cancer cells. However, functions of HOXB5 in retinoblastoma remain elusive. In this study, we found that HOXB5 expression is upregulated in retinoblastoma cell lines and tissues. Overexpression of HOXB5 promoted retinoblastoma cell migration and invasion, but knockdown of HOXB5 suppressed the migration and invasion. Moreover, HOXB5 induced the activation of ERK1/2 and upregulated the production of MMP-3 and MMP-13. In addition, ERK1/2 pathway was required for HOXB5-mediated retinoblastoma cell migration and invasion. Taken together, our study suggests that HOXB5 promotes the migration and invasion of retinoblastoma cells by inducing the activation of ERK1/2 and increasing the production of MMP-3 and MMP-13. Therefore, HOXB5 may represent an effective target for treatment of retinoblastoma. PMID- 30018712 TI - NADH protect against radiation enteritis by enhancing autophagy and inhibiting inflammation through PI3K/AKT pathway. AB - Radiotherapy is an important method for cancer treatment but it has serious side effects at high doses. One of the greatest challenges in radiotherapy is that radiation affects both healthy tissue and cancer tissues. For abdominal or pelvic lesions, the bowel is the most easily injured by irradiation. Radiation may cause radiation enteritis, intestinal inflammatory infiltration, or intestinal perforation. Coenzyme NADH involves in energy metabolism and transportation of nucleic acid, proteins and carbohydrates. In our study, NADH was used to protect the intestinal wall from irradiation injury in IEC-6 normal intestinal epithelial cells. By flow cytometry, we found that NADH can inhibit the cell death and the producing of reactive oxygen species (ROS). The immunofluorescence assay showed that cell autophagy was increased in the NADH group. Western blot data indicated that NADH promoted the microtubule associated protein 1A/1B-light chain 3(LC3)-I to LC3II and the expression of IL-1beta and TNFalpha decreased in a dose dependent manner. Interestingly, a specific PI3K/AKT inhibitor (3MA) decreased the expression of inflammatory factors. In the animal experiment, after 12 Gy radiation, there were less TNFalpha and more LC3II in the RT+NADH group than that of RT group. Compared with the mock, there was no significant damage in the NADH group. Thus, our study provides the evidence that NADH may protect against radiation enteritis by suppressing inflammation and enhancing autophagy through PI3K/AKT pathway in normal intestinal cells. PMID- 30018713 TI - Repair mechanism of mesenchymal stem cells derived from nasal mucosa in orbital fracture. AB - OBJECTIVE: Mesenchymal stem cells (MSCs) derived from nasal mucosa are featured by high division and differentiation capacity, with large nuclei, obvious nucleoli and weak cytoplasmic basophily. Imaging examination, typically CT scan, is the gold standard for the diagnosis of orbital fracture. METHODS: We isolated MSCs derived from goat nasal mucosa and built the calcification model so as to investigate the repair mechanism of nasal mucosa-derived MSCs in orbital fracture. Expressions of osteogenic markers Runx2, OCN, OPN and BSP were detected using western blot. RESULTS: Nasal mucosa-derived MSCs were successfully isolated and passaged. Nestin was detected by immunofluorescence assay in the cells of the third generation. It was further confirmed that the isolated cells were nasal mucosa-derived MSCs. As indicated by alizarin red staining, the calcification model in nasal mucosa-derived MSCs was successfully built. The relative expressions of Runx2 and OCN reached the highest level after osteogenic induction for 7 d, and the expressions of OPN and BSP were also high. But at 10 d, the expressions of all markers declined somewhat. At 14 d, the expressions of OPN and BSP reached the peak, but without significant differences compared with those at 7 d. CONCLUSION: The present study suggested that the repair effect of nasal mucosa-derived MSCs in orbital fracture is achieved by facilitating the expressions of osteogenic markers Runx2, OCN, OPN and BSP. However, the pathways of actions are unknown and further studies are required to elucidate the concrete mechanism. PMID- 30018714 TI - Application of three-dimensional visualization technique in preoperative planning of progressive hilar cholangiocarcinoma. AB - OBJECTIVE: This study aims to investigate the role of three-dimensional visualization technique in the diagnosis and treatment of progressive hilar cholangiocarcinoma. METHODS: From January 2014 to February 2017, a three dimensional visualization model was set up in 23 patients with progressive hilar cholangiocarcinoma. The distributions and variations of the hepatic portal ducts were observed. The tumors were classified based on Bismuth classification. The simulation operation was performed and the operation plan was established. RESULTS: All 23 patients revealed a clear relationship between the intrahepatic and extrahepatic ducts, as well as the tumors and ducts. An individualized surgery program was established through the accurate calculation of liver volume and residual liver volume. Among these patients, 13 patients completed radical resection of hilar cholangiocarcinoma combined with massive hepatectomy. No bile leakage occurred and no operative death was found. CONCLUSION: For patients with progressive hilar cholangiocarcinoma, the optimized three-dimensional visualization technique can accurately demonstrate the dilated biliary tract system, provide a new standard to determine the presence of tumor and peripheral vascular invasion, help in establishing a reasonable individualized operation plan, reduce the incidence of bile leakage and liver failure after the operation, and improve the success rate of operation. PMID- 30018715 TI - Immunization with glypican-3 nanovaccine containing TLR7 agonist prevents the development of carcinogen-induced precancerous hepatic lesions to cancer in a murine model. AB - BACKGROUND: Glypican-3 (GPC3) is one of the key tissue markers that could discriminate malignant precancerous lesions from benign hepatic lesions in cirrhotic patients. We aimed to develop a GPC3 cancer vaccine to induce specific T cells to intervene in hepatocellular carcinoma (HCC) development. METHODS: Synthesizing mannosylated liposomes (LPMan) as vaccine delivery system, incorporating one Toll-like receptor (TLR)-7/8 agonist CL097 as adjuvant, we prepared a GPC3 nanovaccine, LPMan-GPC3/CL097. We injected 25 mg/kg diethylnitrosamine intraperitoneally to induce autochthonous HCC in HBV transgenic mice, which persistently express hepatitis B surface antigen in hepatocytes. Starting from week 8 after diethylnitrosamine injection when malignant hepatocytes generated, we immunized the mice subcutaneously every 2 weeks 4 times with LPMan-GPC3/CL097 containing 5 ug of GPC3 plus 5 ug of CL097. RESULTS: The vaccine efficiently targeted draining lymph nodes where naive T cells reside and enhanced the expression of molecules involved in antigen presentation in migratory dendritic cells (DCs). Antigen was professionally processed in endoplasmic reticulum-Golgi system of DCs, subsequently priming both CD4+ and CD8+ T cells. The LPMan-GPC3/CL097 immunization generated significantly more GPC3-specific CD4+ IFNgamma- and CD8+ IFNgamma-producing T cells in mice spleens and livers, which specifically eliminated GPC3-expressing tumor cells. One week after last immunization (week 15 after diethylnitrosamine), 5/5 un immunized, 5/5 sham (LPMan-CL097) and 1/5 LPMan-GPC3/CL097-immunized mice developed HCC. By week 20 after diethylnitrosamine, significantly less HCC developed in LPMan-GPC3/CL097-immunized mice than in sham-immunized mice (P<0.01). CONCLUSIONS: LPMan-GPC3/CL097 immunization induced de novo generation of specific T cells against tumor-associated antigen GPC3 that could prevent HCC development in cirrhotic liver. PMID- 30018716 TI - Catalpol alleviates renal damage by improving lipid metabolism in diabetic db/db mice. AB - OBJECTIVE: To evaluate the protective effect of catalpol against diabetic nephropathy in db/db mouse. METHODS: 8 week old C57BLKS/J db/db mice (type 2 diabetic mouse model) were divided into three groups to feed for 16 weeks on chow diet with or without catalpol supplementation. Their food intake, water consumption, body weight, and fasting glucose levels were recorded every 4 weeks. At the end of study, urine and blood samples were examined for several metabolic variables, and kidneys were harvested for structural characterization and microarray analysis. RESULTS: Catalpol efficiently lowers the fasting glucose and the 24 h urinary albumin excretion rate. Catalpol significantly lowers serum triglycerides, increases high-density lipoproteins, and improves serum creatinine and urea nitrogen. Catalpol-fed mice preserve their kidney structure and renal function better than chow fed db/db mice. Microarray data indicates that lipid metabolism is a potential target of catalpol in exerting protective effect. CONCLUSION: Catalpol has a renal protective effect in diabetic db/db mice. PMID- 30018717 TI - GAG and collagen II attenuate glucocorticoid-induced osteoporosis by regulating NF-kappaB and MAPK signaling. AB - As a component of collagen II, glycosaminoglycan (GAG) has a relatively close relationship with bone metabolism. GAG and collagen II have been proven to promote connection of the bone trabecular structure. However, the exact mechanism remains unknown. In this study, we aimed to determine the concrete effect and the mechanism of GAG and collagen II on glucocorticoid-induced osteoporosis. We implanted prednisolone pellets subcutaneously in mice to mimic glucocorticoid induced osteoporosis. GAG was administered intragastrically every day for 60 days. The results demonstrated a protective effect of GAG and collagen II on glucocorticoid-induced osteoporosis. Trabecular number and connection density increased after treatment with GAG and collagen II. We generated bone marrow derived macrophages to explore the effect of GAG and collagen II on osteoclast differentiation. We collected cell protein and RNA in the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator for nuclear factor kappaB ligand (RANKL) and found that GAG and collagen II inhibited the NF-kappaB and MAPK pathways, thereby down-regulating osteoclast differentiation molecules such as matrix metallopeptidase 9 (MMP 9) and nuclear factor of activated T cells, cytoplasmic 1 (NFATc-1). Our findings suggest that GAG and collagen II may have therapeutic potential of patients with glucocorticoid-induced osteoporosis in clinical settings. PMID- 30018718 TI - Ginkgo biloba extract 761 enhances 5-fluorouracil chemosensitivity in colorectal cancer cells through regulation of high mobility group-box 3 expression. AB - Although the standard ginkgo biloba extract EGb 761 exhibits antioxidative, anti apoptotic, and anticancer properties, there is no research focusing on the chemopreventive effects of EGb 761 in colorectal cancer (CRC). The present study investigated whether EGb 761 could increase 5-fluorouracil (5FU) sensitivity in CRC and its potential mechanism. We found that combined EGb 761 and 5FU treatment significantly elevated the chemosensitivity of CRC cells to 5FU in 5FU-resistant (5FUR) CRC cells, whereas no obvious cytotoxicity of EGb 761 was observed in parental cells. Then, real-time PCR and western blotting revealed that EGb 761 notably attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (increased E-cadherin and decreased vimentin). In addition, we found that EGb 761 significantly inhibited 5FU-induced upregulation of high mobility group-box 3 (HMGB3) expression in 5FUR CRC cells both at mRNA and protein levels. Knockdown of HMGB3 effectively reversed 5FU-induced EMT and attenuated 5FU-induced cytotoxicity in 5FUR CRC cells while overexpression of HMGB3 achieved the opposite results. Moreover, we found that knockdown of HMGB3 effectively reversed the EGb 761-induced inhibition of the Wnt/beta-catenin pathway. The results of the current study collectively demonstrated that EGb 761 can chemosensitize 5FUR CRC cells by inhibiting an EMT phenotype via regulation of HMGB3 expression, suggesting it to be a novel chemoprotective agent in CRC. PMID- 30018719 TI - FOXK1 promotes cell growth through activating wnt/beta-catenin pathway and emerges as a novel target of miR-137 in glioma. AB - Glioma is the most common primary malignant brain tumor in adults. Forkhead box k1 (FOXK1) was reported to be dysregulated and play important roles in multiple human cancers. However, the expression pattern and roles of FOXK1 in glioma has never been investigated. In this study, we firstly observed that the expression of FOXK1 was significantly increased in glioma tissue samples and cell lines. Functional assays demonstrated that overexpression of FOXK1 promoted proliferation, cell cycle transition and inhibited apoptosis in glioma cell lines. On the contrary, knockdown of FOXK1 exhibited an opposite effect on glioma cells proliferation, cell cycle and apoptosis. Data of western blot indicated that FOXK1 overexpression increased while FOXK1 knockdown decreased the levels of beta-catenin, c-myc and cyclinD1 in glioma cells. Moreover, we demonstrated that FOXK1 was a novel target of miR-137 in glioma and FOXK1 restoration abolished the tumor suppressive effect of miR-137 in glioma cells. Statistical analysis showed that the mRNA level of FOXK1 was inversely correlated with miR-137 expression in glioma tissues. In conclusion, the present study demonstrated that FOXK1 promoted cell growth through activating wnt/beta-catenin pathway and is negatively regulated by miR-137 in glioma. PMID- 30018720 TI - PKM2 functions as a potential oncogene and is a crucial target of miR-148a and miR-326 in thyroid tumorigenesis. AB - In this study, we investigated the biological function of pyruvate kinase M2 (PKM2) and its regulation by deregulated microRNAs (miRNAs) in thyroid cancer (TC). The mRNA and protein expression of PKM2 was examined by quantitative reverse transcription PCR and western blot. The biological role of PKM2 was demonstrated through small interfering RNA-mediated knockdown experiments. The regulation of PKM2 by miR-148a and miR-326 was confirmed by western blot, dual luciferase activity assays, and rescue experiments. PKM2 was overexpressed in TC tissues and cell lines. The knockdown of PKM2 in TC cells suppressed cell proliferation, reduced colony formation, and inhibited cell invasion and migration significantly. Luciferase reporter assays revealed that PKM2 is a direct target of two tumor-suppressive miRNAs, miR-148a and miR-326. Re-expressed PKM2 rescued the anticancer effects of miR-148a. Taken together, these data strongly suggest that, apart from gene amplification and mutation, the activation of PKM2 in TC is partly due to the down-regulation of the tumor-suppressive miRNAs miR-148a and miR-326. Thus, PKM2 is overexpressed and plays an oncogenic role in thyroid carcinogenesis. PMID- 30018721 TI - Activation of the CXCL16/CXCR6 pathway promotes lipid deposition in fatty livers of apolipoprotein E knockout mice and HepG2 cells. AB - Non-alcoholic fatty liver disease (NAFLD), characterised by early lipid accumulation and subsequent inflammation in the liver, is becoming a worldwide challenge due to its increasing prevalence in developing and developed countries. This study aimed to investigate the role of CXC chemokine ligand 16 (CXCL16) and its receptor CXC chemokine receptor 6 (CXCR6) in NAFLD under inflammation. We used IL-1beta stimulation in human hepatoblastoma cell line (HepG2) for in vitro studies and casein injection in apolipoprotein E knockout mice in vivo to induce inflammatory stress. The effects of inflammation on cholesterol accumulation were examined by histochemical staining and a quantitative intracellular cholesterol assay. The gene and protein expression of molecules involved in CXCL16/CXCR6 pathway and extracellular matrix (ECM) were examined by real-time polymerase chain reaction (PCR) and Western blotting. The fluorescence intensity of reactive oxygen species (ROS) was assessed by flow cytometry. Results showed that significantly elevated levels of serum amyloid protein A in casein-injected mice confirmed the successful induction of inflamed NAFLD model. Inflammation significantly increased lipid accumulation in livers compared with the high-fat diet group and the controls. Furthermore, inflammation increased the expression of CXCL16, CXCR6, and adisintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in livers, accompanied with increased ECM expression and ROS production. These effects were further confirmed by in vitro studies. Interestingly, CXCL16 gene knockdown in HepG2 cells induced by CXCL16 siRNA resulted in decreased lipid accumulation, ECM excretion, and ROS production. These findings demonstrated that inflammation-mediated activation of CXCL16/CXCR6 is involved in the progression of NAFLD. PMID- 30018722 TI - Apolipoprotein B-100 peptide 210 antibody inhibits atherosclerosis by regulation of macrophages that phagocytize oxidized lipid. AB - Immunization with peptides derived from apolipoprotein B-100 (ApoB-100) has been shown to ameliorate atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice. However, the exact mechanism underlying the therapeutic effects remains elusive. To shed light on this mechanism, we immunized ApoE-/- mice that were fed a Western diet with either malondialdehyde-modified ApoB-100 peptide 210 (P210) emulsified in Freund's adjuvant or anti-malondialdehyde-modified P210 antibody (P210-Ab). Mice immunized with Freund's adjuvant or bovine serum albumin served as controls. Macrophages were incubated in vitro with oxidized low-density lipoprotein (ox-LDL) or ox-LDL plus P210-Ab. Our results show that P210-Ab promoted cholesterol efflux, inhibited lipid accumulation in vitro, and reduced plasma levels of high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). Furthermore, dramatically increased the expression of Fc receptors (FcR) on peripheral blood mononuclear macrophages, suggesting that the mechanism of phagocytosis of ox-LDL by mononuclear macrophages may rely more on FcR than the cluster of differentiation 36 (CD36) scavenger receptor with P210 Ab. Both in vitro and in vivo, P210-Ab triggered the promoter of ATP-binding cassette transporter A1 (ABCA1) to increase peroxisome proliferator-activated receptor alpha (alpha) activity and inhibit the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) pathway. In addition, P210-Ab significantly attenuated macrophage infiltration and markedly improved the stability of atheromatous plaque. In conclusion, the anti-atherosclerotic effect of P210-Ab is related to its preferential inhibition of inflammation and reversion of cholesterol transportation by altering the pathway by which macrophages phagocytize ox-LDL. PMID- 30018723 TI - The effect of ozone on hypoxia, hemolysis and morphological change of blood from patients with aortic dissection (AD): a preliminary in vitro experiment of ozonated autohemotherapy for treating AD. AB - This study aimed to investigate the effect of ozone on hypoxia, hemolysis and morphological change of blood from aortic dissection (AD) patients for providing preliminary evidence of application of ozonated autohemotherapy (Ozone-AHT) in AD patients. 20 AD patients and 20 healthy volunteers were consecutively included, and blood samples were collected from all participants and ozonized in vitro. PO2, SO2, malondialdehyde (MDA), superoxide dismutase (SOD), malformation percentage, morphology change and spatial distribution of filamentous actin (F actin) in erythrocytes at different ozone concentrations were evaluated. After ozonation of whole blood, the median levels of PO2 and SO2 increased under Ozone concentrations at 40 MUg/mL, 80 MUg/mL and 160 MUg/mL compared with samples exposed to 0 MUg/mL in both AD group and control group. The MDA level was similar in samples exposed to 0 MUg/mL, 40 MUg/mL and 80 MUg/mL ozone, while the levels of SOD increased in samples exposed to 40 MUg/mL and 80 MUg/mL in both AD group and control group. Compared with the samples exposed to 0 MUg/mL ozone, FHb level only increased in samples exposed to 80 MUg/mL and 160 MUg/mL Ozone in both AD group and control group. In addition, overdosed ozone (160 MUg/mL) but not therapeutic ozone concentrations (0 MUg/mL, 40 MUg/mL and 80 MUg/mL) increased malformation percentage and morphology change of erythrocytes in both AD group and control group. In conclusion, Ozone improves oxygen content and reduces oxidative damage in blood from AD patients, and therapeutic dose ozone do not induce hemolysis and morphology change of erythrocytes. PMID- 30018724 TI - Adenosine and lidocaine (AL) combination dilates intimally damaged rat thoracic aortic rings and guinea pig mesenteric arteries: possible significance to cardiac surgery. AB - New pharmacotherapies are required to improve vessel graft protection and prevent vasoconstriction and spasm in CABG surgery. Previously we have studied adenosine (A) and lidocaine (L) relaxation in rat aortic rings, and reported a possible crosstalk between L relaxation and adenosine A2a receptor inhibition. The aim of the present study was to examine the effect of AL combination compared to A and L alone on relaxation in intact and denuded rat aortic rings and in guinea-pig pressurized mesenteric arterial segments. Aortic rings were harvested from Sprague-Dawley rats and equilibrated in an organ bath containing modified Krebs Henseleit (KH) solution, pH 7.4, 37 degrees C. Rings were pre-contracted sub maximally with 0.3 uM norepinephrine, and the effects of increasing AL, A or L (up to 1.0 mM) were examined in intact and denuded rings. Mesenteric artery segments were isolated from guinea-pigs and mounted in an arteriograph containing KH solution and pressurised to 60 mmHg. Arteries were preconstricted with 10-8 M vasopressin and AL, A, or L was administered luminally or abluminally. Diameters were measured using video-microscopy. We report in intact rat aortic rings, AL increased relaxation from 21 to 100% (0.1-1.0 mM) and relaxation was endothelium independent. Adenosine alone was also a potent relaxant of aortic rings but, unlike AL relaxation, it was partially endothelium-dependent. In intact mesenteric artery segments, increasing luminal AL produced a potent endothelium independent dilation (up to 90%). Adenosine dilation was endothelium-independent but not lidocaine, which produced 33% dilation only after endothelial removal. Extra-luminal AL and A led to 76% and 80% dilationin intact segments respectively, whereas L resulted in constriction (10-17%). In conclusion, we show that AL can dilate aortic rings and mesenteric artery segments by up to 90% regardless of whether the endothelium is intact. We discuss the potential translational significance of AL to improve conduit protection in cardiac surgery, and other major surgeries. PMID- 30018725 TI - Quantitative measurement of breast carcinoma fibrosis for the prediction in the risk of bone metastasis. AB - BACKGROUND: Previous studies have shown the poor prognosis of metastatic breast cancer including bone metastasis. The early prediction and intervention of invasive breast carcinoma with bone metastasis are crucial to the outcomes of patients. The purpose of our study is to test the hypothesis that the collagen deposition of primary breast cancer can be used as a quantitative biomarker for the early prediction of bone metastasis. METHODS: A total of sixty breast cancer patients were included in our study, and the surgical specimens of these patients were divided into three groups: patients with no metastasis (group 1), lymph node metastasis (group 2), and bone metastasis (group 3). Masson's trichrome staining and hematoxylin and eosin staining were applied to all primary breast cancers. Collagen area percentage and tumor cell measurement of each sample were measured by HistoQuest software. RESULTS: Measurement results of collagen area percentage (%) in primary breast tumors were 32.39 +/- 13.30, 25.37 +/- 11.10, and 22.71 +/- 8.91 for groups 1, 2, and 3, respectively. The corresponding P values were 0.0779 (group 1 vs. group 2), 0.4086 (group 2 vs. group 3), and 0.0102 (group 1 vs. group 3). The correlation between collagen area percentage and tumor cell measurement were group 1 (P = 0.5927, r = -0.1273), group 2 (P = 0.5711, r = 0.1348), and group 3 (P = 0.0003, r = -0.7253). CONCLUSIONS: The collagen deposition of primary breast cancer can be used as a quantitative biomarker for the early prediction of bone metastasis. PMID- 30018726 TI - Impact of sentinel lymph node biopsy in newly diagnosed invasive breast cancer patients with suspicious node: a comparative accuracy survey of fine-needle aspiration biopsy versus core-needle biopsy. AB - Comparing diagnostic accuracy study between ultrasonography (US) guided fine needle aspiration biopsy (FNAB) and core-needle biopsy (CNB) of the Sentinel lymph nodes (SLNs) in newly diagnosed invasive breast cancer patients. We selected 289 newly diagnosed invasive breast cancer patients from June 2015 to July 2017. Ultrasound (US) guided fine-needle aspiration cytology (FNA) and core needle biopsy (CNB) was performed to identify patients with suspicious sentinel lymph node (SLN). Patients with a cortical thickness > 2 mm or atypical morphological characteristics were recommended FNA and CNB. Axillary lymph node dissection (ALND) was applied to patients with biopsy-proven metastasis, and sentinel lymph node biopsy (SLNB) was applied to FNA or CNB negative patients. ALND was also performed when SNB is positive. Out of 289 patients, only 131 patients met final study criteria. Lymph node status was evaluated by FNA, CNB, SLND, and ALND. Among 131 patients, 45 were deemed positive for metastasis and 86 were determined to be negative with CNB, whereas 38 were deemed positive for metastasis and 93 were determined to be negative by using FNAB. CNB was used to correctly identify seven axillae as positive for metastasis that were deemed negative by using FNAB. There were no positive FNAB results in axillae that were negative for metastasis with CNB. All patients underwent SLNB and those with biopsy-proved axillary metastases were assigned directly to ALND as the primary staging procedure. The final histopathologic assessment indicated that 50 (38.2%) of the 131 axillae studied had axillary LN metastases. Axillary US-guided CNB was used to correctly identify 45 (90.0%) of the 50 LN-positive axillae, whereas axillary US-guided FNAB was used to correctly identify 38 (76.0%, P < 0. 001). There were no false-positive results. CNB netted 5 false-negative results, and FNAB resulted in 12. There was significantly different accuracy between different diagnostic tools. In our study, we demonstrated that CNB is a more reliable approach than FNA for the preoperative diagnosis of SLN metastasis. PMID- 30018727 TI - Identification of miR-18a-5p as an oncogene and prognostic biomarker in RCC. AB - BACKGROUND: RCC is a malignant tumor that originates from renal tubular epithelial cells, accounting for nearly 90% of renal malignancies and 3% of adult malignancies. It was reported that more than 30-40% of patients with early localized RCC still have recurrence and metastasis after receiving radical surgery. miRNAs are an endogenous non-coding small RNAs that play an important role in the regulation of tumor cell proliferation, differentiation and apoptosis. METHODS: In our study, RT-qPCR, CCK-8 assay, wound scratch assay, transwell assay and flow cytometry assay were designed to identify the expression and functions of miR-18a-5p in RCC. Moreover, we collected the survival data from The Cancer Genome Atlas to predict and clarify the prognostic functions of miR 18a-5p in RCC. The correlation between miR-18a-5p expression and clinicopathological variables or overall survival was analyzed by 42 formalin fixed paraffin-embedded (FFPE) renal cancer samples. RESULTS: The expression of miR-18a-5p in RCC tissues and cell lines was elevated. Further researches suggested that upregulation of miR-18a-5p had a positive effect on RCC cell proliferation, migration, invasion and inhibition of apoptosis, while down regulation of miR-18a-5p neutralized the effect. In addition, Data of TCGA and prognostic analysis of FFPE RCC samples revealed that high miR-18a-5p expression patients had significantly poorer survival. CONCLUSIONS: These results demonstrated that miR-18a-5p functioned as an oncogene and prognostic biomarker in RCC. PMID- 30018728 TI - Mitochondrial-targeted antioxidant MitoQ provides neuroprotection and reduces neuronal apoptosis in experimental traumatic brain injury possibly via the Nrf2 ARE pathway. AB - Mitoquinone (MitoQ) is a powerful mitochondrial-targeted antioxidant whose neuroprotective effects have been shown in a variety of animal models of neurological diseases. However, its roles in traumatic brain injury (TBI) remain unexplored. The primary objective of this study was to investigate the neuroprotection afforded by MitoQ in a mouse model of TBI, and the involvement of the Nrf2-ARE signaling pathway in the putative neuroprotective mechanism. Mice were randomly divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + MitoQ group. MitoQ (4 mg/kg, administered intraperitoneally) or an equal volume of vehicle was given at 30 min after TBI. After 24 h, brain samples were harvested for analysis. The results demonstrated that treatment with MitoQ significantly improved neurological deficits, alleviated brain edema and inhibited cortical neuronal apoptosis. Furthermore, MitoQ administration increased the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), whereas it decreased the malondialdehyde (MDA) content. In addition, MitoQ treatment reduced Bax protein translocation to mitochondria and cytochrome c release into the cytosol. Moreover, MitoQ greatly accelerated the Nrf2 nuclear translocation and subsequently upregulated the expression of Nrf2 downstream proteins, including heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (Nqo1). In conclusion, the results in the study demonstrate that MitoQ exerts neuroprotective effects in the mouse model of TBI, possibly by activating the Nrf2-ARE pathway. PMID- 30018729 TI - The use of allogenic adipose-derived stem cells in combination with platelet-rich fibrin for the treatment of cartilage defects in rabbit ear. AB - The current study aims to assess the efficacy of allogenic adipose-derived stem cells (ADSCs) together with platelet-rich fibrin (PRF) for the treatment of rabbit ear cartilage defects. For this study, 12 New Zealand white rabbits were randomly allocated into 4 groups. Two full-thickness cartilage defects were created in the rabbit ears. Group 1 was left untreated; Group 2 was treated with allogenic ADSCs, Group 3 was treated with PRF; Group 4 was treated with allogenic ADSCs and PRF. Macroscopic observation, hematoxylin and eosin staining, and Alcian blue staining after 3 months suggested that the allogenic ADSCs/PRF significantly accelerated cartilage regeneration compared to other groups and this was associated with increased expression of collagen II relative to the other groups. Expression of genes associated with immune response such as cluster of differentiation 4 and 8 (CD4, CD8), and interleukin 2 and 4 (IL-2, IL-4) displayed no significant statistical difference compared to Group 1. In conclusion, these results suggest that allogenic ADSCs in combination with PRF can accelerate regeneration in full-thickness cartilage defects in the rabbit ear model without causing a significant immune response. The results suggest that allogenic ADSCs with PRF could successfully be used for cartilage regeneration. PMID- 30018730 TI - GPX3 suppresses tumor migration and invasion via the FAK/AKT pathway in esophageal squamous cell carcinoma. AB - Although an increasing number of findings have proven that glutathione peroxidase 3 (GPX3) is methylated and down-regulated in various cancers, the underlying mechanism of its occurrence in esophageal squamous cell carcinoma (ESCC) remains unknown. In the present study, we found that the methylation rate in advanced cancers was significantly higher than that in early stage cancers by a methylation-specific polymerase chain reaction. Furthermore, the proliferation and migration capacities of KYSE-510 cells were inhibited after up-regulating GPX3 expression by GPX3 lentivirus transfection. As expected, the proliferation and migration capacities of KYSE-150 cells were promoted after down-regulating GPX3 expression with siRNA interfering. Moreover, we found that GPX3 might have deactivated the FAK/AKT signaling pathway to lower the expression of MMP-9 to suppress the migration and invasive capacities of KYSE-150 and KYSE-510 cells. Our findings suggested that GPX3 played a pivotal role in the suppression of carcinogenesis and progression in ESCC, and GPX3 has the potential as a novel biomarker in the diagnosis of ESCC. PMID- 30018731 TI - Improved approach for normothermic machine perfusion of cold stored kidney grafts. AB - Normothermic machine perfusion can decrease reperfusion injury in renal transplantation. Clinical procurement logistics include retrieval and initial transport of the graft using static cold storage. Therefore, use and benefits of brief normothermic reconditioning by machine perfusion should be investigated in the initially cold preserved graft. Porcine kidneys (6 per group) were retrieved 20 min after cardiac standstill. After 20 h of static cold preservation some grafts were put on a machine perfusion circuit and normothermically perfused for 2 h at 35 degrees C (NMP). Another group was subjected to controlled oxygenated rewarming (COR), starting perfusion at 8 degrees C and elevating temperature and pressure slowly up to 35 degrees C and 75 mmHg during the first 90 min of 2 h perfusion. Control kidneys were only cold stored (CS). Post implant graft function was evaluated afterwards in an established in vitro reperfusion model. During graft reconditioning, COR reduced oxygen free radical production and formation of 4-hydroxy-2-nonenal (HNE), an activator of mitochondrial uncoupling proteins, in comparison to NMP. Upon reperfusion, NMP only led to a slight improvement of renal function (clearance of creatinine, fractional excretion of Na and glucose) compared to controls. But 2-3 fold improvements of renal function were seen after COR, which also significantly improved aerobic efficiency (total Na absorption/VO2) upon reperfusion. A slow and controlled increase in temperature up to normothermia improves mitochondrial recovery and oxygen utilization efficiency, resulting in better functional recovery, possibly through a more mild and adapted increase of cellular metabolism. PMID- 30018732 TI - Erratum: Protective effect of asiatic acid in an experimental cerulein-induced model of acute pancreatitis in mice. AB - [This corrects the article on p. 3842 in vol. 9, PMID: 28861174.]. PMID- 30018733 TI - Gene-environment interactions and predictors of breast cancer in family-based multi-ethnic groups. AB - Breast cancer (BC) is the most common cancer in women worldwide and second leading cause of cancer-related death. Understanding gene-environment interactions could play a critical role for next stage of BC prevention efforts. Hence, the purpose of this study was to examine the key gene-environmental factors affecting the risks of BC in a diverse sample. Five genes in one-carbon metabolism pathway including MTHFR 677, MTHFR 1298, MTR 2756, MTRR 66, and DHFR 19bp together with demographics, lifestyle, and dietary intake factors were examined in association with BC risks. A total of 80 participants (40 BC cases and 40 family/friend controls) in southern California were interviewed and provided salivary samples for genotyping. We presented the first study utilizing both conventional and new analytics including ensemble method and predictive modeling based on smallest errors to predict BC risks. Predictive modeling of Generalized Regression Elastic Net Leave-One-Out demonstrated alcohol use (p = 0.0126) and age (p < 0.0001) as significant predictors; and significant interactions were noted between body mass index (BMI) and alcohol use (p = 0.0027), and between BMI and MTR 2756 polymorphisms (p = 0.0090). Our findings identified the modifiable lifestyle factors in gene-environment interactions that are valuable for BC prevention. PMID- 30018734 TI - The immune-related microRNA miR-146b is upregulated in glioblastoma recurrence. AB - Background: Glioblastoma (GBM) has a high rate of local recurrence despite chemoradiotherapy (CRT). Genome-wide expression profiling was performed on patient tumors before and after chemoradiotherapy to identify genes and gene pathways associated with recurrence. Results: Median time to recurrence was 8.9 months with median time to second surgery of 9.6 months. The microRNA (miRNA) analysis identified 9 oncologic and immune-related miRNAs to be differentially expressed, including the hypoxia-related miR-210 and the immune-modulatory miR 146b. More than 1200 differentially-expressed genes were identified with RNA sequencing (RNA-seq). Gene set enrichment analysis (GSEA) identified p53 signaling, Notch, Wnt, VEGF, and MEK gene sets enriched in recurrent GBM. Consistent with the miRNA profiling data, the miR-146b target gene set from GSEA analysis was also associated with recurrence. Methods: Fourteen patients with GBM recurrence after CRT who had available tumor tissue from the initial diagnosis as well as recurrence were selected. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens. Genome-wide expression profiling using RT-PCR for miRNA analysis and RNA-seq for messenger RNA (mRNA) analysis were conducted to identify differentially-expressed genes. GSEA was performed on the differential expression data. Conclusions: Genome-wide expression profiling identifies multiple oncologic and immune-related gene sets associated with GBM recurrence. In particular, immune-related miR-146b is upregulated in recurrence and deserves further investigation. PMID- 30018735 TI - Oral inflammation promotes oral squamous cell carcinoma invasion. AB - Oral squamous cell carcinoma (OSCC) represents 95% of oral malignancies and invasion, and metastasis underlies disease morbidity and mortality. We recently established a direct link between oral inflammation and cancer invasion by showing that neutrophils increase OSCC invasion through a tumor necrosis factor (TNFalpha)-dependent mechanism. The objective of this study was to characterize OSCC-associated inflammation and to determine the molecular mechanisms underlying inflammation-mediated OSCC invasion. Our results showed a significant increase in neutrophil infiltration, the neutrophil-to-lymphocyte ratio in the OSCC microenvironment and increased inflammatory markers, particularly TNFalpha in saliva. We performed next-generation sequencing of the TNFalpha-treated OSCC cells and showed marked overexpression of over 180 genes distributed among clusters related to neutrophil recruitment, invasion, and invadopodia. At the molecular level, TNFalpha treatment increased phosphoinositide 3-kinase (PI3K) mediated invadopodia formation and matrix metalloproteinase (MMP)-dependent invasion. We show here that TNFalpha promotes a pro-inflammatory and pro-invasion phenotype leading to the recruitment and activation of inflammatory cells in a paracrine mechanism. Increased TNFalpha in the tumor microenvironment tips the balance towards invasion leading to decreased overall survival and disease-free survival. This represents a significant advancement of oral cancer research and will support new treatment approaches to control OSCC invasion and metastasis. PMID- 30018736 TI - A multiomics analysis of S100 protein family in breast cancer. AB - The S100 gene family is the largest subfamily of calcium binding proteins of EF hand type, expressed in tissue and cell-specific manner, acting both as intracellular regulators and extracellular mediators. There is a growing interest in the S100 proteins and their relationships with different cancers because of their involvement in a variety of biological events closely related to tumorigenesis and cancer progression. However, the collective role and the possible coordination of this group of proteins, as well as the functional implications of their expression in breast cancer (BC) is still poorly known. We previously reported a large-scale proteomic investigation performed on BC patients for the screening of multiple forms of S100 proteins. Present study was aimed to assess the functional correlation between protein and gene expression patterns and the prognostic values of the S100 family members in BC. By using data mining, we showed that S100 members were collectively deregulated in BC, and their elevated expression levels were correlated with shorter survival and more aggressive phenotypes of BC (basal like, HER2 enriched, ER-negative and high grading). Moreover a multi-omics functional network analysis highlighted the regulatory effects of S100 members on several cellular pathways associated with cancer and cancer progression, expecially immune response and inflammation. Interestingly, for the first time, a pathway analysis was successfully applied on different omics data (transcriptomics and proteomics) revealing a good convergence between pathways affected by S100 in BC. Our data confirm S100 members as a promising panel of biomarkers for BC prognosis. PMID- 30018737 TI - An evaluation in vitro of the efficacy of nutlin-3 and topotecan in combination with 177Lu-DOTATATE for the treatment of neuroblastoma. AB - Targeted radiotherapy of metastatic neuroblastoma using the somatostatin receptor (SSTR)-targeted octreotide analogue DOTATATE radiolabelled with lutetium-177 (177Lu-DOTATATE) is a promising strategy. This study evaluates whether its effectiveness may be enhanced by combination with radiosensitising drugs. The growth rate of multicellular tumour spheroids, derived from the neuroblastoma cell lines SK-N-BE(2c), CHLA-15 and CHLA-20, was evaluated following treatment with 177Lu-DOTATATE, nutlin-3 and topotecan alone or in combination. Immunoblotting, immunostaining and flow cytometric analyses were used to determine activation of p53 signalling and cell death. Exposure to 177Lu-DOTATATE resulted in a significant growth delay in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Nutlin-3 enhanced the spheroid growth delay induced by topotecan in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Importantly, the combination of nutlin-3 with topotecan enhanced the spheroid growth delay induced by X-irradiation or by exposure to 177Lu-DOTATATE. The efficacy of the combination treatments was p53-dependent. These results indicate that targeted radiotherapy of high risk neuroblastoma with 177Lu-DOTATATE may be improved by combination with the radiosensitising drugs nutlin-3 and topotecan. PMID- 30018738 TI - InDePTH: detection of hub genes for developing gene expression networks under anticancer drug treatment. AB - It has been difficult to elucidate the structure of gene regulatory networks under anticancer drug treatment. Here, we developed an algorithm to highlight the hub genes that play a major role in creating the upstream and downstream relationships within a given set of differentially expressed genes. The directionality of the relationships between genes was defined using information from comprehensive collections of transcriptome profiles after gene knockdown and overexpression. As expected, among the drug-perturbed genes, our algorithm tended to derive plausible hub genes, such as transcription factors. Our validation experiments successfully showed the anticipated activity of certain hub gene in establishing the gene regulatory network that was associated with cell growth inhibition. Notably, giving such top priority to the hub gene was not achieved by ranking fold change in expression and by the conventional gene set enrichment analysis of drug-induced transcriptome data. Thus, our data-driven approach can facilitate to understand drug-induced gene regulatory networks for finding potential functional genes. PMID- 30018741 TI - PARP1-Erk synergism in proliferating cells. AB - A synergism between PARP1 and phosphorylated Erk mediating IEG (immediate early gene) expression has been recently reported in cerebral neurons and cardiomyocytes. Stimulation induced PARP-Erk synergism was required for IEG expression underlying synaptic plasticity and long-term memory acquisition during learning. It was similarly required for cardiomyocytes development. Here, we identified this mechanism in Erk-induced gene expression promoting proliferation. This mechanism can be targeted in malignant cells. PMID- 30018740 TI - Integrative landscape of dysregulated signaling pathways of clinically distinct pancreatic cancer subtypes. AB - Despite modern therapeutic advances, the survival prospects of pancreatic cancer patients have remained poor. Besides being highly metastatic, pancreatic cancer is challenging to treat because it is caused by a heterogeneous array of somatic mutations that impact a variety of signaling pathways and cellular regulatory systems. Here we use publicly available transcriptomic, copy number alteration and mutation profiling datasets from pancreatic cancer patients together with data on disease outcomes to show that the three major pancreatic cancer subtypes each display distinctive aberrations in cell signaling and metabolic pathways. Importantly, patients afflicted with these different pancreatic cancer subtypes also exhibit distinctive survival profiles. Within these patients, we find that dysregulation of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways, and p53 mediated disruptions of cell cycle processes are apparently drivers of disease. Further, we identify for the first time the molecular perturbations of signalling networks that are likely the primary causes of oncogenesis in each of the three pancreatic cancer subtypes. PMID- 30018739 TI - Resveratrol prevents p53 aggregation in vitro and in breast cancer cells. AB - One potential target for cancer therapeutics is the tumor suppressor p53, which is mutated in more than 50% of malignant tumors. Loss of function (LoF), dominant negative (DN) and gain of function (GoF) mutations in p53 are associated with amyloid aggregation. We tested the potential of resveratrol, a naturally occurring polyphenol, to interact and prevent the aggregation of wild-type and mutant p53 in vitro using fluorescence spectroscopy techniques and in human breast cancer cells (MDA-MB-231, HCC-70 and MCF-7) using immunofluorescence co localization assays. Based on our data, an interaction occurs between resveratrol and the wild-type p53 core domain (p53C). In addition, resveratrol and its derivatives pterostilbene and piceatannol inhibit mutant p53C aggregation in vitro. Additionally, resveratrol reduces mutant p53 protein aggregation in MDA-MB 231 and HCC-70 cells but not in the wild-type p53 cell line MCF-7. To verify the effects of resveratrol on tumorigenicity, cell proliferation and cell migration assays were performed using MDA-MB-231 cells. Resveratrol significantly reduced the proliferative and migratory capabilities of these cells. Our study provides evidence that resveratrol directly modulates p53, enhancing our understanding of the mechanisms involved in p53 aggregation and its potential as a therapeutic strategy for cancer treatment. PMID- 30018742 TI - Regulation of the interferon-gamma (IFN-gamma) pathway by p63 and Delta133p53 isoform in different breast cancer subtypes. AB - The TP53 family consists of three sets of transcription factor genes, TP53, TP63 and TP73, each of which expresses multiple RNA variants and protein isoforms. Of these, TP53 is mutated in 25-30% of breast cancers. How TP53 mutations affect the interaction of TP53 family members and their isoforms in breast cancer is unknown. To investigate this, 3 independent breast cancer cohorts were stratified into 4 groups based on oestrogen receptor (ER) and TP53 mutation status. Using bioinformatic methodologies, principal signalling pathways associated with the expression of TP53 family members were identified. Results show an enrichment of IFN-gamma signalling associated with TP63 RNA in wild type TP53 (wtTP53), ER negative (ER-) tumours and with Delta133TP53 RNA in mutant TP53 (mTP53) ER positive (ER+) tumours. Moreover, tumours with low IFN-gamma signalling were associated with significantly poorer patient outcome. The predicted changes in expression of a subset of RNAs involved in IFN-gamma signalling were confirmed in vitro. Our data show that different members of the TP53 family can drive transcription of genes involved in IFN-gamma signalling in different breast cancer subgroups. PMID- 30018743 TI - Collaborating genomic, transcriptomic and microbiomic alterations lead to canine extreme intestinal polyposis. AB - Extreme intestinal polyposis in pet dogs has not yet been reported in literature. We identified a dog patient who developed numerous intestinal polyps, with the severity resembling human classic familial adenomatous polyposis (FAP), except the jejunum-ileum junction being the most polyp-dense. We investigated this dog, in comparison with 22 other dogs with spontaneous intestinal tumors but no severe polyposis, and with numerous published human cancers. We found, not APC mutation, but three other alteration pathways as likely reasons of this canine extreme polyposis. First, somatic truncation mutation W411X of FBXW7, a component of an E3 ubiquitin ligase, over-activates MYC and cell cycle-promoting network, accelerating crypt cell proliferation. Second, genes of protein trafficking and localization are downregulated, likely associated with germline mutation G406D of STAMBPL1, a K63-deubiquitinase, and MYC network activation. This inhibits epithelial apical-basolateral polarity establishment, preventing crypt cell differentiation. Third, Bacteroides uniformis, a commensal gut anaerobe, thrives and expresses abundantly thioredoxin and nitroreductase. These bacterial products could reduce oxidative stress linked to host germline mutation R51X of CYB5RL, a cytochrome b5 reductase homologue, decreasing cell death. Our work emphasizes the close collaboration of alterations across the genome, transcriptome and microbiome in promoting tumorigenesis. PMID- 30018744 TI - Survivin as a potential therapeutic target of acetylsalicylic acid in pituitary adenomas. AB - Acetylsalicylic acid (ASA) is known as a cancer preventing agent, but there is no data available regarding the effect of ASA on pituitary cells. We investigated 66 nonfunctioning (NFPA) and growth hormone (GH)-producing adenomas and 15 normal pituitary samples. Functional assays (cell viability, proliferation, flow cytometry cell cycle analysis, caspase-3 activation and DNA degradation) were applied to explore the effect of ASA, YM155 (survivin inhibitor), survivin targeting siRNA and TNF-related apoptosis-inducing ligand (TRAIL) in RC-4B/C and GH3 cells. Pituitary adenoma xenografts were generated in immunocompromised mice. We found that survivin was overexpressed and TRAIL was downregulated in NFPAs compared to normal pituitary tissue. ASA decreased proliferation but did not induce apoptosis in pituitary cells. Additionally, ASA treatment decreased cells in S phase and increased cells in G2/M phase of the cell cycle. Inhibition of survivin using an inhibitor or siRNA-mediated silencing reversed the ASA-induced growth inhibition partially. In addition, we also found survivin-independent effects of ASA on the cell cycle that were mediated through inhibition of cyclin A, cyclin dependent kinase 2 (CDK2) and phospho-CDK2. We also aimed to test the effect of acetylsalicylic acid in an animal model using RC-4 B/C cells, but in contrast to GH3 cells, RC-4 B/C cells failed to adhere and grow a xenograft. We concluded that ASA inhibited the growth of pituitary adenoma cells. Survivin inhibition is a key mechanism explaining its antineoplastic effects. Our results suggest that inhibition of survivin with small molecules or ASA could serve as potential therapeutic agents in NFPA. PMID- 30018745 TI - BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition. AB - While several systemic therapies are approved for cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma of skin-homing T cells that may involve lymph nodes and peripheral blood in advanced stages, relapses are common. Mutational analysis of CTCL cells has revealed frequent amplification of the MYC oncogene, and bromodomain and extraterminal (BET) protein inhibitors have been shown to repress MYC expression in various malignancies. Towards a potential novel therapy, we thus sought to examine the effect of BET inhibition on CTCL cells in vitro. Each of the four tested BET inhibitors (JQ1, ABBV-075, I-BET762, CPI-0610) consistently induced dose-dependent decreases in viability of isolated patient derived CTCL cells and established CTCL cell lines (MyLa, Sez4, HH, Hut78). This effect was synergistically potentiated by combination of BET inhibition with BCL2 inhibition (e.g. venetoclax) or histone deacetylase (HDAC) inhibition (e.g. vorinostat or romidepsin). There was also a marked increase in caspase 3/7 activation when JQ1 was combined with either vorinostat or romidepsin, confirming that the observed synergies are due in major part to induction of apoptosis. Furthermore, MYC and BCL2 expression were each synergistically repressed when CTCL cells were treated with JQ1 plus HDAC inhibitors, suggesting cooperative activities at the level of epigenetic regulation. Taken together, these data indicate that targeting BET proteins in CTCL represents a promising novel therapeutic strategy that may be substantially potentiated by combination with BCL2 or HDAC inhibition. PMID- 30018746 TI - Circular RNA CpG island hypermethylation-associated silencing in human cancer. AB - Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5' 3' ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors. To tackle this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in conjuction with circRNA expression microarrays. We have found that the loss of DNA methylation provokes a release of circRNA silencing. In particular, we have identified that promoter CpG island hypermethylation of the genes TUSC3 (tumor suppressor candidate 3), POMT1 (protein O-mannosyltransferase 1), ATRNL1 (attractin-like 1) and SAMD4A (sterile alpha motif domain containing 4A) is linked to the transcriptional downregulation of both linear mRNA and the hosted circRNA. Although some circRNAs regulate the linear transcript, we did not observe changes in TUSC3 mRNA levels upon TUSC3 circ104557 overexpression. Interestingly, we found circRNA-mediated regulation of target miRNAs and an in vivo growth inhibitory effect upon TUSC3 circ104557 transduction. Data mining for 5'-end CpG island methylation of TUSC3, ATRNL1, POMT1 and SAMD4A in cancer cell lines and primary tumors showed that the epigenetic defect was commonly observed among different tumor types in association with the diminished expression of the corresponding transcript. Our findings support a role for circRNA DNA methylation associated loss in human cancer. PMID- 30018747 TI - Development of an integrated CRISPRi targeting DeltaNp63 for treatment of squamous cell carcinoma. AB - TP63 encodes TAp63, which is functionally similar to the tumor suppressor TP53, and DeltaNp63, which lacks the transcription-activating domain of TAp63 and appears potently oncogenic in squamous cell carcinomas (SCCs). In this study, we developed an integrated CRISPR interference (CRISPRi) system to selectively suppress DeltaNp63 (CRISPRiDeltaNp63). We engineered this CRISPRi using tandemized guide RNA expression cassettes that targeted the 50 to 100 bp downstream of the transcription start site of DeltaNp63 in combination with inactivated Cas9 linked to the transcription repression module Kruppel-associated box repressor domain. The plasmid vector harboring CRISPRiDeltaNp63 repressed DeltaNp63 transcription in lung and esophageal SCC cells. Likewise, Ad CRISPRiDeltaNp63, an all-in-one adenoviral vector containing the tandemized gRNAs and dCas9/KRAB expression cassette suppressed DeltaNp63 expression in SCC cells. Ad-CRISPRiDeltaNp63 also effectively decreased cell proliferation and colony formation and induced apoptosis in lung and esophageal SCC cells in vitro and significantly inhibited tumor growth in a mouse lung SCC xenograft model in vivo. These results indicate that DeltaNp63 suppression using CRISPRiDeltaNp63 may be an effective strategy for treating lung and esophageal SCC. PMID- 30018748 TI - Evaluation of modified carbapenem inactivation method for suspected carbapenemase among Enterobacteriaceae clinical isolates. AB - Modified carbapenem inactivation method (mCIM) testing was currently recommended by Clinical and Laboratory Standards Institute (CLSI) for detection of carbapenemase among Enterobacteriaceae clinical isolates. In this study, a panel of 145 clinical strains were collected for evaluating the mCIM for detection of carbapenemase. Antimicrobial susceptibility testing were performed by microbroth dilution and the results were interpreted according to CLSI guidelines. All strains were resistant to ertapenem with high MIC50 and MIC90 (64 mg/L ->128 mg/L). For blaNDM-1-positive or blaOXA-232-positive strains, the zone of inhibition of meropenem were all 6 mm despite the incubation time of 6 h, 18 h or 24 h. For 6 h, the zone of meropenem inhibition for most of carbapenemase positive isolates were meet the positive criteria 6-15 mm. However, for carbapenemase-negative isolates, the zone of meropenem inhibition were 16-18 mm after 6 h incubation which should be considered indeterminate for standard incubating time such as 18 h or 24 h. After incubating for 18 h or 24 h, the zone of meropenem inhibition were 22-25 mm for carbapenemase-negative isolates and meet the negative criteria. Our study indicate mCIM is a simple and effective method to identify the carbapenemases producers among Enterobacteriaceae clinical isolates. PMID- 30018749 TI - Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants. AB - Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke. We conducted a literature search to review the current state of OAs pharmacogenomics, focusing on Genome Wide Association Studies (GWAs) in patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). VKAs: Warfarin, acenocoumarol, fluindione and phenprocoumon have long been used, but their interindividual variability and narrow therapeutic/safety ratio makes their dosage difficult. GWAs have been useful in finding genetic variants associated with VKAs response. The main genes involved in VKAs pharmacogenetics are: VKORC1, CYP2C19 and CYP4F2. Variants in these genes have been included in pharmacogenetic algorithms to predict the VKAs dose individually in each patient depending on their genotype and clinical variables. DOACs: Dabigatran, apixaban, rivaroxaban and edoxaban have been approved for patients with AF. They have stable pharmacokinetics and do not require routine blood checks, thus avoiding most of the drawbacks of VKAs. Except for a GWAs performed in patients treated with dabigatran, there is no Genome Wide pharmacogenomics data for DOACs. Pharmacogenomics could be useful to predict the better clinical response and avoid adverse events in patients treated with anticoagulants, identifying the most appropriate anticoagulant drug for each patient. Current pharmacogenomics data show that the polymorphisms affecting VKAs or DOACs are different, concluding that personalized medicine based on pharmacogenomics could be possible. However, more studies are required to implement personalized medicine in clinical practice with OA and based on pharmacogenetics of DOACs. PMID- 30018751 TI - Papillary thyroid microcarcinoma (Black Ink). AB - We report a case of a 58-year-old Caucasian woman affected by papillary thyroid microcarcinoma (PTMC) of the left-lobe of the gland with very small size (O 0.3 cm). The characteristics with the Diagnostic Imaging using Ultrasonography, ADF (Advanced Dynamic Flow), and fine-needle-aspiration cytology (FNAC) are discussed, comprising a very small micro-focus of radial shape, with markedly hypoechoic echostructure, irregular margins, supplemented by peripheral vessel formation. It acquires an image which appears similar to a brisk visualization of a dark ink stain in the normal thyroid weave. We call such a pattern "Black Ink" with ultrasonographic image and believe consistent with the infiltrating variant of papillary thyroid microcarcinoma if associated with malignant cytology after FNA. PMID- 30018752 TI - Correction: Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal. AB - [This corrects the article DOI: 10.18632/oncotarget.4754.]. PMID- 30018750 TI - Medicinal mushrooms as an attractive new source of natural compounds for future cancer therapy. AB - Medicinal mushrooms have been used throughout the history of mankind for treatment of various diseases including cancer. Nowadays they have been intensively studied in order to reveal the chemical nature and mechanisms of action of their biomedical capacity. Targeted treatment of cancer, non-harmful for healthy tissues, has become a desired goal in recent decades and compounds of fungal origin provide a vast reservoir of potential innovational drugs. Here, on example of four mushrooms common for use in Asian and Far Eastern folk medicine we demonstrate the complex and multilevel nature of their anticancer potential, basing upon different groups of compounds that can simultaneously target diverse biological processes relevant for cancer treatment, focusing on targeted approaches specific to malignant tissues. We show that some aspects of fungotherapy of tumors are studied relatively well, while others are still waiting to be fully unraveled. We also pay attention to the cancer types that are especially susceptible to the fungal treatments. PMID- 30018753 TI - Correction: Evaluating prognosis by CK7 differentiating renal cell carcinomas from oncocytomas can be used as a promising tool for optimizing diagnosis strategies. AB - [This corrects the article DOI: 10.18632/oncotarget.10225.]. PMID- 30018754 TI - Adaptation to drought in arid and semi-arid environments: Case of the Zambezi Valley, Zimbabwe. AB - Small-scale rain-fed agriculture is the main livelihood in arid to semi-arid regions of sub-Saharan Africa. The area is characterised by erratic rainfall and frequent droughts, making the capacity for coping with temporal water shortages essential for smallholder farmers. Focusing on the Zambezi Valley, Zimbabwe, this study investigates the impact of drought on food security and the strategies used by smallholder farmers to cope with drought. We used meteorological data and interviews to examine the rainfall variability in the study area and the drought coping mechanisms employed by smallholder famers respectively. The results show that there are various strategies used by smallholder farmers to cope with the impact of drought. These strategies include drought-tolerant crop production, crop variety diversification, purchasing cereals through asset sales, non governmental organisations' food aid and gathering wild fruit. However, consecutive droughts have resulted in high food insecurity and depletion of household assets during droughts. Smallholder farmers in the valley have also resorted to a number of measures taken before, during and after the drought. Still, these strategies are not robust enough to cope with this uncertainty. PMID- 30018755 TI - Comparison of Machine-Learning Classification Models for Glaucoma Management. AB - This study develops an objective machine-learning classification model for classifying glaucomatous optic discs and reveals the classificatory criteria to assist in clinical glaucoma management. In this study, 163 glaucoma eyes were labelled with four optic disc types by three glaucoma specialists and then randomly separated into training and test data. All the images of these eyes were captured using optical coherence tomography and laser speckle flowgraphy to quantify the ocular structure and blood-flow-related parameters. A total of 91 parameters were extracted from each eye along with the patients' background information. Machine-learning classifiers, including the neural network (NN), naive Bayes (NB), support vector machine (SVM), and gradient boosted decision trees (GBDT), were trained to build the classification models, and a hybrid feature selection method that combines minimum redundancy maximum relevance and genetic-algorithm-based feature selection was applied to find the most valid and relevant features for NN, NB, and SVM. A comparison of the performance of the three machine-learning classification models showed that the NN had the best classification performance with a validated accuracy of 87.8% using only nine ocular parameters. These selected quantified parameters enabled the trained NN to classify glaucomatous optic discs with relatively high performance without requiring color fundus images. PMID- 30018756 TI - Toleration games: compensatory growth by plants in response to enemy attack is an evolutionarily stable strategy. AB - Damage to plants from natural enemies is a ubiquitous feature of the natural world. Accordingly, plants have evolved a variety of strategies to deal with attack from enemies including the ability to simply tolerate attack. Tolerance often involves some form of compensatory response, such as the regrowth of tissues following damage. While ecological models of defence are common, there has been less effort to make predictions about the evolutionary stability of tolerance. Here, we present and experimentally test a game theoretic model of tolerance to herbivory. Plants in the model have a vector strategy which includes both root and shoot production, and herbivores in the model have a scalar strategy which is time spent foraging. The evolutionarily stable strategy (ESS) is the set of root growth, shoot growth and herbivore foraging which simultaneously maximizes all player's fitness. Compensatory growth is not guaranteed, but it may emerge as an ESS if it maximizes plant fitness. We also experimentally tested the model predictions using wheat and simulated herbivory by clipping 0, 15, 30, 45 or 60 % of shoot production, and measured root, shoot and fruit production at senescence. The model predicted that compensatory growth was often an ESS when herbivores were either above- or below-ground. Plants in the experiment followed model predictions. Specifically, plants produced more tissues than expected based on damage, and for 15 % damage this allowed them to maintain equal fitness compared to undamaged plants. The model allows for above- and below-ground herbivory to be modelled, and predicts their impact on whole plant growth and reproduction. For example, we can predict the effects of shoot damage on root growth. When combined with other advances in predicting plant ecology with evolutionary game theory, we anticipate that this will be a valuable tool for generating further testable hypotheses. PMID- 30018757 TI - Consequences of habitat fragmentation on the reproductive success of two Tillandsia species with contrasting life history strategies. AB - Fragmentation of natural habitats generally has negative effects on the reproductive success of many plant species; however, little is known about epiphytic plants. We assessed the impact of forest fragmentation on plant pollinator interactions and female reproductive success in two epiphytic Tillandsia species with contrasting life history strategies (polycarpic and monocarpic) in Chamela, Jalisco, Mexico, over three consecutive years. Hummingbirds were the major pollinators of both species and pollinator visitation rates were similar between habitat conditions. In contrast, the composition and frequency of floral visitors significantly varied between habitat conditions in polycarpic and self-incompatible T. intermedia but not in monocarpic self compatible T. makoyana. There were no differences between continuous and fragmented habitats in fruit set in either species, but T. makoyana had a lower seed set in fragmented than in continuous forests. In contrast, T. intermedia had similar seed set in both forest conditions. These results indicate that pollinators were effective under both fragmented and continuous habitats, possibly because the major pollinators are hummingbird species capable of moving across open spaces and human-modified habitats. However, the lower seed set of T. makoyana under fragmented conditions suggests that the amount and quality of pollen deposited onto stigmas may differ between habitat conditions. Alternatively, changes in resource availability may also cause reductions in seed production in fragmented habitats. This study adds to the limited information on the effects of habitat fragmentation on the reproductive success of epiphytic plants, showing that even related congeneric species may exhibit different responses to human disturbance. Plant reproductive systems, along with changes in pollinator communities associated with habitat fragmentation, may have yet undocumented consequences on gene flow, levels of inbreeding and progeny quality of dry forest tillandsias. PMID- 30018758 TI - Laparoscopic approach for a presacral myelolipoma resembling a liposarcoma. AB - Myelolipomas are rare benign tumors that are commonly found in the adrenal glands. Extra-adrenal locations are rare, and presacral myelolipomas represent the most common extra-adrenal location. The differential diagnosis of malignant presacral neoplasms is very challenging. We present a case of a presacral neoplasm that was completely removed with a laparoscopic approach and diagnosed as a myelolipoma only after pathological examination. PMID- 30018759 TI - A rare case of percutaneous endoscopic gastrostomy causing a small bowel obstruction and subsequent bowel erosion. AB - Gastrostomy tubes can be used to provide long-term nutrition and feeding when oral intake is not adequate. A rare but serious complication includes iatrogenic small bowel injury. The incidence of this is infrequent due to its position of the small bowel beneath the omentum, however, injury leading to obstruction and volvulus has been previously described in the literature. We present an unusual case of gastrostomy tube transection into omental fat causing a kink in the small bowel allowing for a transition point of obstruction and subsequent erosion of the gastrostomy tube into the small bowel. PMID- 30018760 TI - Case series of two falciform ligament incisional hernias and their laparoscopic repair. AB - Incisional hernias involving the falciform ligament have only been reported in two case reports in the English literature. This is the first reported case series of two falciform ligament incisional hernias. Both patients had undergone a prior cholecystectomy. Laparoscopic transabdominal pre-peritoneal repair was performed with an uneventful recovery in both patients. In the previously published reports both patients underwent an open herniorrhaphy with an underlay mesh repair. These are the first two documented laparoscopic repairs of a falciform ligament incisional hernia. The laparoscopic repair also included intra corporeal suturing of the hernia necks with a non-absorbable suture. We extrapolated this data from the component separation technique which reconstituted the abdominal musculature in their normal anatomical position resulting in a reduced hernia recurrence rate. PMID- 28184279 TI - Design of chemical space networks incorporating compound distance relationships. AB - Networks, in which nodes represent compounds and edges pairwise similarity relationships, are used as coordinate-free representations of chemical space. So called chemical space networks (CSNs) provide intuitive access to structural relationships within compound data sets and can be annotated with activity information. However, in such similarity-based networks, distances between compounds are typically determined for layout purposes and clarity and have no chemical meaning. By contrast, inter-compound distances as a measure of dissimilarity can be directly obtained from coordinate-based representations of chemical space. Herein, we introduce a CSN variant that incorporates compound distance relationships and thus further increases the information content of compound networks. The design was facilitated by adapting the Kamada-Kawai algorithm. Kamada-Kawai networks are the first CSNs that are based on numerical similarity measures, but do not depend on chosen similarity threshold values. PMID- 30018762 TI - The effects of body region, season and external arsenic application on hair cortisol concentration. AB - Hair cortisol analysis has been used to quantify hormone levels in circulation in several mammal species. Hair remains stable for decades or centuries, allowing researchers to use archived hair samples to investigate hormone levels that span long time periods. However, several studies have found that intra-individual variability, driven by the body region from which a sample is derived, confounds measurements of systemic glucocorticoid hormone concentrations. In addition, the external application of chemical agents to hair can remove or concentrate molecules of interest. These may preclude the use of samples that have been collected opportunistically and/or those that have been housed in museum collections. Using a captive population of Vancouver Island marmots (Marmota vancouverensis), we found a strong effect of body region on the concentration of cortisol within hair, as well as an effect of season. Using a collection of American mink (Neovison vison) pelts, we found that application of the preservative arsenic in the form of a soap does not cause a significant decrease in cortisol. The marmot results suggest that intra-individual variability is not stable through time. The reason for these seasonal effects is not clear and further study is necessary. Researchers using samples from an unknown body region should exercise caution in interpreting their results. The mink results suggest that samples held in museum collections can be used to quantify cortisol, even when arsenic preservation is suspected. PMID- 30018763 TI - Juvenile rockfish show resilience to CO2-acidification and hypoxia across multiple biological scales. AB - California's coastal ecosystems are forecasted to undergo shifting ocean conditions due to climate change, some of which may negatively impact recreational and commercial fish populations. To understand if fish populations have the capacity to respond to multiple stressors, it is critical to examine interactive effects across multiple biological scales, from cellular metabolism to species interactions. This study examined the effects of CO2-acidification and hypoxia on two naturally co-occurring species, juvenile rockfish (genus Sebastes) and a known predator, cabezon (Scorpaenichthys marmoratus). Fishes were exposed to two PCO2 levels at two dissolved oxygen (DO) levels: ~600 (ambient) and ~1600 (high) MUatm PCO2 and 8.0 (normoxic) and 4.5 mg l-1 DO (hypoxic) and assessments of cellular metabolism, prey behavior and predation mortality rates were quantified after 1 and 3 weeks. Physiologically, rockfish showed acute alterations in cellular metabolic enzyme activity after 1 week of acclimation to elevated PCO2 and hypoxia that were not evident in cabezon. Alterations in rockfish energy metabolism were driven by increases in anaerobic LDH activity, and adjustments in enzyme activity ratios of cytochrome c oxidase and citrate synthase and LDH:CS. Correlated changes in rockfish behavior were also apparent after 1 week of acclimation to elevated PCO2 and hypoxia. Exploration behavior increased in rockfish exposed to elevated PCO2 and spatial analysis of activity indicated short-term interference with anti-predator responses. Predation rate after 1 week increased with elevated PCO2; however, no mortality was observed under the multiple-stressor treatment suggesting negative effects on cabezon predators. Most noteworthy, metabolic and behavioral changes were moderately compensated after 3 weeks of acclimation, and predation mortality rates also decreased suggesting that these rockfish may be resilient to changes in environmental stressors predicted by climate models. Linking physiological and behavioral responses to multiple stressors is vital to understand impacts on populations and community dynamics. PMID- 30018764 TI - Validation of the Saint George's Respiratory Questionnaire in Uganda. AB - Introduction: Chronic obstructive pulmonary disease (COPD) will soon be the third leading global cause of death and is increasing rapidly in low/middle-income countries. There is a need for local validation of the Saint George's Respiratory Questionnaire (SGRQ), which can be used to identify those experiencing lifestyle impairment due to their breathing. Methods: The SGRQ was professionally translated into Luganda and reviewed by our field staff and a local pulmonologist. Participants included a COPD-confirmed clinic sample and COPD positive and negative members of the community who were enrolled in the Lung Function in Nakaseke and Kampala (LiNK) Study. SGRQs were assembled from all participants, while demographic and spirometry data were additionally collected from LiNK participants. Results: In total, 103 questionnaires were included in analysis: 49 with COPD from clinic, 34 community COPD-negative and 20 community COPD-positive. SGRQ score varied by group: 53.5 for clinic, 34.4 for community COPD-positive and 4.1 for community COPD-negative (p<0.001). The cross-validated c statistic for SGRQ total score predicting COPD was 0.87 (95% CI 0.75 to 1.00). SGRQ total score was associated with COPD severity (forced expiratory volume in 1 s per cent of predicted), with an r coefficient of -0.60 (-0.75, -0.39). SGRQ score was associated with dyspnoea (OR 1.05/point; 1.01, 1.09) and cough (1.07; 1.03, 1.11). Conclusion: Our Luganda language SGRQ accurately distinguishes between COPD-positive and negative community members in rural Uganda. Scores were correlated with COPD severity and were associated with odds of dyspnoea and cough. We find that it can be successfully used as a respiratory questionnaire for obstructed adults in Uganda. PMID- 30018765 TI - No association between DNA methylation and COPD in never and current smokers. AB - Introduction: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with cigarette smoke as the main risk factor for its development. Since not every smoker develops COPD, other factors likely underlie differences in susceptibility to develop COPD. Here, we tested if DNA methylation may be such a factor by assessing the association between DNA methylation levels and COPD in never and current smokers from the general population. Methods: For the current study, 1561 subjects were non-randomly selected from the LifeLines cohort study. We included 903 never smokers and 658 current smokers with and without COPD, defined as pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <70%. Subsequently, we performed robust regression analysis on whole blood DNA methylation levels of 420 938 CpG sites with COPD as outcome. Results: None of the CpG sites in both the never and the current smokers were genome-wide significantly associated with COPD. CpG site cg14972228 annotated to SIPAL3 was most significant (p=5.66*10-6) in the never smokers, while CpG site cg08282037 annotated to EPS8L1 was most significant (p=1.45*10-5) in the current smokers. Conclusion: In contrast to a previous, smaller study, we did not observe any significant association between DNA methylation levels and the presence of COPD, independent of smoking status. Apparently, DNA methylation studies are highly variable. PMID- 30018766 TI - Transitions and touchpoints in idiopathic pulmonary fibrosis. AB - Patients with idiopathic pulmonary fibrosis (IPF) face a poor prognosis and endure intrusive symptoms that impair quality of life. Many patients with IPF will require supplemental oxygen (O2) at some point in the course of their illness, and although it can improve blood oxygen and symptoms, O2 creates physical and emotional challenges for patients and their loved ones. Four events in the course of IPF-the first occurs at the time of diagnosis and the other three are related to O2-herald periods of transition for patients and their caregivers and mark touchpoints when they need extra care and support from practitioners. PMID- 30018767 TI - Analgesic effects of intravenous flunixin and intrafunicular lidocaine or their combination for castration of lambs. AB - Objective: To analyse the effectiveness of intrafunicular lidocaine and intravenous flunixin for reducing pain and signs of stress in lambs undergoing surgical castration. Design: Randomised controlled trial. Setting: One university teaching hospital in Italy. Participants: 30 healthy male lambs, 9-12 weeks old. Intervention: Allocation to five groups: a control group (C), undergoing general anaesthesia but not castration; a surgery group (S), undergoing orchiectomy without analgesic treatment; a surgery-lidocaine group (SL), undergoing orchiectomy and receiving intrafunicular 2 per cent lidocaine solution; a surgery flunixin group (SF), undergoing orchiectomy and receiving intravenous flunixin; a surgery-flunixin-lidocaine group (SFL), undergoing orchiectomy and receiving both intrafunicular lidocaine and intravenous flunixin. Main outcome measures: Nociception and stress were assessed through intraoperative indicators, serum cortisol concentration, glycaemia, behaviour, immune response and clinical evaluation of the heart rate (HR), respiratory rate and rectal temperature after surgery. Results: Groups S and SL showed increased values of intraoperative HR, mean arterial pressure and postoperative cortisol concentration. In group SFL, cortisol values were similar to those of group C. No other difference could be detected. Conclusions: The combination of intravenous flunixin and intrafunicular lidocaine reduced the pain and discomfort of lambs castrated under general anaesthesia. Intrafunicular lidocaine alone did not prevent pain or discomfort associated with castration. Trial registration number: 30/2012/CEISA/COM. PMID- 30018768 TI - Psychosocial and clinical outcomes of percutaneous versus surgical pulmonary valve implantation. AB - Objective: This prospective non-randomised study was performed to compare the psychosocial function and clinical outcomes following surgical and percutaneous implantation of a pulmonary valve at 3 months and 1 year after treatment. Methods: All patients were consecutively admitted for treatment by either method from June 2011 to October 2014. The data of 20 patients treated with the percutaneous technique and 14 patients treated with open heart surgery were compared. Psychosocial function was measured by the Achenbach System of Empirically Based Assessment (ASEBA). We used linear mixed-effect models to investigate group changes between the psychosocial function and clinical data of 34 patients with congenital pulmonary valve disease. Results: A significant difference in favour of the percutaneous pulmonary valve implantation group was observed regarding the ASEBA scores, specifically in the Thought problems subscale at 1 year (p=0.015), Attention problems subscale at 3 months (p=0.016) and 1 year (p=0.007) after treatment. After adjustment for the right ventricle to pulmonary artery pressure gradient at 3 months, a significant change in the Attention problems subscale (p=0.038) was noted in the percutaneous group. The New York Heart Association functional score significantly improved in both groups. The measured right ventricle to pulmonary artery pressure gradient was reduced significantly in both groups at 1 year. Conclusions: Both methods led to significant clinical improvement. Thought and attention problems such as intrusive behaviour significantly decreased only in patients who underwent the percutaneous procedure. Complications as reintervention, bleeding and arrhythmia were only observed in the open surgery group. PMID- 30018770 TI - Correction: Obesity is associated with impaired long-term success of pulmonary vein isolation: a plea for risk factor management before ablation. AB - [This corrects the article DOI: 10.1136/openhrt-2017-000771.]. PMID- 30018769 TI - Efficacy and safety of dabigatran versus warfarin from the RE-LY trial. AB - Background: Current data for atrial fibrillation (AF) and stroke are predominantly derived from North American and European patients. Although the burden of AF is high in Latin America (LA), little is known about current management of AF in the region. Methods: We aimed to assess the consistency of efficacy and safety outcomes associated with dabigatran etexilate (DE) versus warfarin in patients with AF in LA from the RE-LY (Randomised Evaluation of Long Term Anticoagulant Therapy) trial. Data from 956 LA patients and 17 157 non-LA patients were included in this analysis. chi2 test and Cox proportional regression analysis were performed. The primary efficacy outcome included all strokes or systemic embolism (SE). Main safety outcome was major bleeding. Results: LA patients were more often female, had higher proportion of permanent AF and lower creatinine clearance, among other characteristics. Vitamin K antagonist use at randomisation and time in therapeutic range were lower in LA than in non-LA patients (44% vs 63%, p<0.001; and 61.3+/-22.6% vs 64.6+/-19.6%, p=0.015, respectively). Efficacy endpoints were 0.91% versus 1.68% for DE 150 mg twice daily versus warfarin, respectively. Stroke/SE risk was lower in LA patients treated with DE 150 mg twice daily compared with warfarin, although not significant (HR 0.54; 95% CI 0.18 to 1.62). The annual stroke/SE rates for DE 110 mg twice daily versus warfarin were 1.82 versus 1.68, also not significantly different (HR 1.09; CI 0.44 to 2.67). There were no treatment-by-region interactions for either dose of DE on efficacy and safety outcomes. Conclusion: Despite differences in the clinical profile and AF management, the efficacy and safety benefits of dabigatran over warfarin in LA patients relative to non-LA patients are consistent with those observed in the main RE-LY trial. PMID- 30018771 TI - Role of dietary histidine in the prevention of obesity and metabolic syndrome. PMID- 30018773 TI - The introduction of refined carbohydrates in the Alaskan Inland Inuit diet may have led to an increase in dental caries, hypertension and atherosclerosis. PMID- 30018772 TI - Magnesium for the prevention and treatment of cardiovascular disease. PMID- 30018774 TI - Differences of in-hospital outcomes within patients undergoing percutaneous coronary intervention at institutions with high versus low procedural volume: a report from the Japanese multicentre percutaneous coronary intervention registry. AB - Objective: We aimed to determine the relationship between the prevalence of in hospital complications and annual institutional patient volume in a population of patients undergoing percutaneous coronary intervention (PCI). Methods: Clinical data of patients receiving PCI between January 2010 and June 2015 were collected from 14 academic institutions in the Tokyo area and subsequently used for analysis. We employed multivariate hierarchical logistic regression models to determine the effect of institutional volume on several in-hospital outcomes, including in-hospital mortality and procedure-related complications. Results: A total of 14 437 PCI cases were included and categorised as receiving intervention from either lower-volume (<200 procedures/year, n=6 hospitals) or higher-volume (>=200 procedures/year, n=8 hospitals) institutions. Clinical characteristics differed significantly between the two patient groups. Specifically, patients treated in higher-volume hospitals presented with increased comorbidities and complex coronary lesions. Unadjusted mortality and complication rate in lower volume and higher-volume hospitals were 1.3% and 1.2% (p=0.0614) and 6.2% and 8.1% (p=0.001), respectively. However, multivariate hierarchical logistic regression models adjusting for differences in the patient characteristics demonstrated that institutional volume was not associated with adverse clinical outcomes. Conclusions: In conclusion, we observed no significant association between annual institutional volume and in-hospital outcomes within the contemporary PCI multicentre registry. Trial registration number: UMIN R000005598. PMID- 30018775 TI - Direct oral anticoagulants versus standard triple therapy in atrial fibrillation and PCI: meta-analysis. AB - The coexistence of coronary artery disease and atrial fibrillation (AF) in the same individuals raises great concern about the co-treatment with different antithrombotic agents in the case of percutaneous coronary interventions (PCI). The advent of direct oral anticoagulants (DOACs) revolutionised the therapy of AF; less is known, however, about the safety and efficacy of therapy with DOACs in combination with antiplatelet agents after PCI. We performed a meta-analysis of randomized controlled studies enrolling patients with nonvalvular AF undergoing PCI. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for any bleeding (AB), cardiovascular events (CVE), major bleeding (MB), myocardial infarction (MI), and stent thrombosis (ST) at follow-up: 4849 patients have been included in the analysis. When compared with patients receiving standard triple therapy (vitamin-K antagonists plus double antiplatelet therapy [VKAs plus DAPT]), patients receiving DOACs (rivaroxaban/dabigatran plus either one or two antiplatelet agents) had a statistically significant lower risk of AB (RR, 0.66; 95% CI, 0.59-0.75, p<0.00001), as well as of MB (RR, 0.59; 95% CI, 0.47-0.73, p<0.00001). Equivalent efficacy was found about CVE (RR, 1.03; 95% CI, 0.89-1.19, p=0.69), MI (RR, 1.09; 95% CI, 0.81-1.45, p=0.57), while slight although non-statistically significant increased risk of ST was found (RR, 1.46; 95% CI, 0.86-2.48, p=0.16). In conclusion, DOACs are safer than and as effective as warfarin when used in patients with AF undergoing PCI; dual therapy with DOACs is comparable to triple therapy in terms of safety and efficacy. PMID- 30018777 TI - Revascularisation of left main stem disease: a prospective analysis of modern practice and outcomes in a non-surgical centre. AB - Purpose: In this study, we sought to prospectively analyse the management and long term outcomes associated with revascularisation of left main stem disease via percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in our centre. Methods: This prospective study enrolled all patients with unprotected left main stem disease undergoing revascularisation from January 2013 to June 2014. Baseline characteristics, hospital presentation and hospital stay length were collected. Patients were followed up at 1, 2 and 3 years. Primary outcomes of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) were defined as death, Q wave myocardial infarction, stroke, repeat revascularisation and readmission within 30 days. Results: 56 patients with significant left main stem coronary artery disease were identified from the clinical registry. 27 patients underwent PCI (median age 67.7) and 29 CABG (median age 68.6). PCI patients had a higher surgical risk as measured by mean euroSCORE (4.95+/-5.8 vs 3.11+/-3.85). At 3 years, total MACCE occurred in 29.6% of the PCI cohort and 27.5% of the CABG cohort. Death occurred in three patients in the PCI group within the first 6 months. Death occurred in one patient in the CABG group over 2 years postprocedure. Two patients in the CABG cohort presented with Transient Ischemic Attacks (TIAs) at 2-year follow-up. At 3 years, revascularisation occurred in three patients in the PCI cohort. There were no revascularisation events in the CABG cohort. Conclusions: PCI with modern drug eluting stents is a reasonable treatment option for unprotected left main stem disease in a non surgical centre. PMID- 30018776 TI - Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease. AB - Objectives: Current guidelines highlight important therapy implications of cardiac fibrosis in patients with Fabry disease (FD). However, association between morphological and functional impairments with cardiac fibrosis in hereditary cardiomyopathies remains elusive. We investigated the association between echocardiography-determined cardiac dysfunction and cardiac MRI (cMRI) detected myocardial fibrosis (late gadolinium enhancement, LE) in patients with FD with preserved left ventricular ejection fraction (>=50%). Methods: 146 patients with FD (aged 39+/-14 years, 57 men) were analysed, all receiving echocardiography and cMRI within a 1 week interval. Longitudinal systolic strain (LS_sys), strain rate (LSr_sys) and diastolic strain rate (LSr_E/LSr_A) were assessed using speckle-tracking imaging. Receiver operating characteristic (ROC) analysis was performed to identify the diagnostic performance of various markers for LE. Results: LE was detected in 57 (39%) patients with FD. LV wall thickness, left atrial volume, septal E/e', diastolic dysfunction grade, global LS_sys and E/LSr_E, mid-lateral LS_sys and LSr_E, as well as N-terminal pro-brain natriuretic peptide were all associated with LE independent of age, sex, body mass index, New York Heart Association functional class and kidney function. In ROC curve analysis, septal E/e' performed best (area under the curve=0.86, 95% CI=0.79 to 0.92). Septal E/e'>14.8 was strongly associated with LE (specificity=97.8% and sensitivity=49.1%). In 9% of patients, localised LE was present even though no other cardiac or kidney abnormalities were detected. Conclusions: Echocardiography-derived diastolic dysfunction is closely linked to LE in FD. Septal E/e' ratio is the best echocardiographic marker suggestive of LE. Diastolic dysfunction is not a prerequisite for LE in FD, since LE can be detected in the absence of measurable cardiac functional impairments. Trial registration number: ClinicalTrials.gov Identifier (NCT03362164). PMID- 30018778 TI - The HASTE Protocol: a standardised CT Coronary Angiography service operated from a District General Hospital. AB - Introduction: CT coronary angiography (CTCA) has excellent sensitivity but lacks specificity when compared with invasive coronary angiography (ICA) particularly in patients with a high coronary calcium burden. CTCA has been shown in large trials to decrease the requirement for diagnostic ICA and provide diagnostic clarity. We describe the methodology used to provide a standardised CTCA service established in a District General Hospital, which may assist other hospitals aiming to develop a cardiac CT service. Methods: Scan request forms, authorisation and patient instruction were recorded. Patient preparation prior to CTCA as well as exclusion and inclusion criteria were documented. Scans were interpreted using a multidisciplinary team (MDT) approach in order to organise follow-up, medication and further investigation. Results: Over 6 months, 157 consecutive scans were performed. CTCA was completed in 88% (n=138/157) and considered of diagnostic quality in 82% (n=129/157). The median radiation dose was 3.42 mSv. Overall, 64% of patients had evidence of coronary calcium. Following MDT review, 72% (n=113/157) of patients were discharged without requiring invasive angiography. 15% (n=24/157) of patients went on to have invasive angiography showing non-obstructive disease and 13% (20/157) of patients underwent percutaneous coronary intervention (11%) or bypass surgery (1%). Discussion: Appropriate referrals, patient preparation and scan quality remain significant factors in running a CTCA service. Despite this, the vast majority of patients can be discharged on the basis of the CTCA alone. An MDT approach is key to the delivery of a cardiac CT service. PMID- 30018780 TI - Performance of a Framingham cardiovascular risk model among Indians and Europeans in New Zealand and the role of body mass index and social deprivation. AB - Objectives: To evaluate a Framingham 5-year cardiovascular disease (CVD) risk score in Indians and Europeans in New Zealand, and determine whether body mass index (BMI) and socioeconomic deprivation were independent predictors of CVD risk. Methods: We included Indians and Europeans, aged 30-74 years without prior CVD undergoing risk assessment in New Zealand primary care during 2002-2015 (n=256 446). Risk profiles included standard Framingham predictors (age, sex, systolic blood pressure, total cholesterol/high-density lipoprotein ratio, smoking and diabetes) and were linked with national CVD hospitalisations and mortality datasets. Discrimination was measured by the area under the receiver operating characteristics curve (AUC) and calibration examined graphically. We used Cox regression to study the impact of BMI and deprivation on the risk of CVD with and without adjustment for the Framingham score. Results: During follow-up, 8105 and 1156 CVD events occurred in Europeans and Indians, respectively. Higher AUCs of 0.76 were found in Indian men (95% CI 0.74 to 0.78) and women (95% CI 0.73 to 0.78) compared with 0.74 (95% CI 0.73 to 0.74) in European men and 0.72 (95% CI 0.71 to 0.73) in European women. Framingham was best calibrated in Indian men, and overestimated risk in Indian women and in Europeans. BMI and deprivation were positively associated with CVD, also after adjustment for the Framingham risk score, although the BMI association was attenuated. Conclusions: The Framingham risk model performed reasonably well in Indian men, but overestimated risk in Indian women and in Europeans. BMI and socioeconomic deprivation could be useful predictors in addition to a Framingham score. PMID- 30018779 TI - Effect of exercise therapy on established and emerging circulating biomarkers in patients with heart failure: a systematic review and meta-analysis. AB - Background: Biomarkers are important in the diagnosis, risk stratification and management of patients with heart failure (HF). The established biomarkers of myocardial stretch, brain natriuretic peptide (BNP) and amino (N) portion of BNP (NT-proBNP) have been extensively studied, and early analyses have demonstrated response to exercise training. Several other biomarkers have been identified over the last decade and may provide valuable and complementary information which may guide treatment strategies, including exercise therapy. Methods: A systematic search of PubMed, EMBASE and Cochrane Trials Register to 31 October 2017 was conducted for exercise-based rehabilitation trials in HF. Randomised and controlled trials that reported biomarkers, BNP, NT-proBNP, soluble ST2, galectin 3, mid-regional atrial natriuretic peptide, mid-regional adrenomedullin and copeptin, were included. Results: Forty-three studies were included in the systematic review, with 27 studies suitable for meta-analyses. Data pooling was only possible for NT-proBNP and BNP. Meta-analyses of conventional training studies demonstrated a statistically significant improvement in NT-proBNP (pmol/L); mean difference (MD) -32.80 (95% CI -56.19 to -9.42), p=0.006 and in BNP (pmol/L); MD -17.17 (95% CI -29.56 to -4.78), p=0.007. Pooled data of non conventional training failed to demonstrate any statistically significant improvements. Conclusion: Pooled data indicated a favourable effect of conventional exercise therapy on the established biomarkers, NT-proBNP and BNP; however, this was in contrast to a number of studies that could not be pooled. Limited evidence exists as to the effect of exercise training on emerging biomarkers. PMID- 30018781 TI - HIV-associated cardiovascular disease: importance of platelet activation and cardiac fibrosis in the setting of specific antiretroviral therapies. AB - HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015-March 2018. We uncovered three themes: (1) a critical role for the HIV protease inhibitor (PI) ritonavir and certain other PI-based regimens. (2) The importance of platelet activation. Virtually all PIs, and one nucleoside reverse transcriptase inhibitor, abacavir, activate platelets, but a role for this phenomenon in clinical CVD risk may require additional postactivation processes, including: release of platelet transforming growth factor-beta1; induction of oxidative stress with production of reactive oxygen species from vascular cells; suppression of extracellular matrix autophagy; and/or sustained proinflammatory signalling, leading to cardiac fibrosis and dysfunction. Cardiac fibrosis may underlie an apparent shift in the character of HIV-linked CVD over the past decade from primarily left ventricular systolic to diastolic dysfunction, possibly driven by cART. (3) Recognition of the need for novel interventions. Switching from cART regimens based on PIs to contemporary antiretroviral agents such as the integrase strand transfer inhibitors, which have not been linked to clinical CVD, may not mitigate CVD risk assumed under prior cART. In conclusion, attention to the effects of specific antiretroviral drugs on platelet activation and related profibrotic signalling pathways should help: guide selection of appropriate anti-HIV therapy; assist in evaluation of CVD risk related to novel antiretrovirals; and direct appropriate interventions. PMID- 30018782 TI - Impact of early treatment with intravenous vasodilators and blood pressure reduction in acute heart failure. AB - Objective: Although vasodilators are used in acute heart failure (AHF) management, there have been no clear supportive evidence regarding their routine use. Recent European guidelines recommend systolic blood pressure (SBP) reduction in the range of 25% during the first few hours after diagnosis. This study aimed to examine clinical and prognostic significance of early treatment with intravenous vasodilators in relation to their subsequent SBP reduction in hospitalised AHF. Methods: We performed post hoc analysis of 1670 consecutive patients enrolled in the Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure. Intravenous vasodilator use within 6 hours of hospital arrival and subsequent SBP changes were analysed. Outcomes were gauged by 1-year mortality and diuretic response (DR), defined as total urine output 6 hours posthospital arrival per 40 mg furosemide-equivalent diuretic use. Results: Over half of the patients (56.0%) were treated with intravenous vasodilators within the first 6 hours. In this vasodilator-treated cohort, 554 (59.3%) experienced SBP reduction <=25%, while 381 (40.7%) experienced SBP reduction >25%. In patients experiencing <=25% drop in SBP, use of vasodilator was associated with greater DR compared with no vasodilators (p<0.001). Moreover, vasodilator treatment with <=25% drop in SBP was independently associated with lower all-cause mortality compared with those treated without vasodilators (adjusted HR 0.74, 95% CI 0.57 to 0.96, p=0.028). Conclusions: Intravenous vasodilator therapy was associated with greater DR and lower mortality, provided SBP reduction was less than 25%. Our results highlight the importance in early administration of intravenous vasodilators without causing excess SBP reduction in AHF management. Clinical trial registration: URL: http://www.umin.ac.jp/ctr/ Unique identifier: UMIN000014105. PMID- 30018784 TI - Prospective cohort study on injuries and health problems among circus arts students. AB - Aim: The amount of injuries, illnesses and mental health problems was calculated among circus arts students, using a method designed to capture more than just time-loss and/or medical injuries. Furthermore, injury incidence rate, injury incidence proportions, anatomical injury location and severity of injuries were assessed. Methods: A total of 44 first-year, second-year and third-year circus arts students were prospectively followed during one academic year. Every month, all students were asked to complete questionnaires by using the online Performing Artist and Athlete Health Monitor, which includes the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Results: In total, 41 students completed the entire follow-up period. The response rate was 82.9%. During the academic year, all (100%) students reported a health problem. A total of 261 health problems were reported consisting of 184 injuries (70.5%), 51 illnesses (19.5%), 15 mental problems (5.0%) and 11 other health problems (3.1%). The injury incidence rate was 3.3 injuries per 1000 hours (95% CI 2.7 to 3.9). Monthly incidence proportion for substantial injuries (ie, problems leading to moderate or severe reductions in training volume or in performance or complete inability to participate in activities) ranged from 6.8% to 34.1%. Shoulder (n=51; 27.7%), lower back (n=29; 15.8%), wrist (n=26; 14.1%) and ankle (n=17; 9.2%) were the most reported injuries. The average duration of the injuries was 6.9 days (median=2.0; SD=15.0). Conclusions: We implemented a new registration method for circus artists, which captures a complete picture of the burden of health problems in circus students. Our study showed that the burden of injuries is high in this population. PMID- 30018783 TI - Haemodynamic outcomes following aortic valve-in-valve procedure. AB - Background and objectives: Transcatheter aortic valve-in-valve implantation (ViV) has emerged as a valuable technique to treat failed surgical bioprostheses (BPs) in patients with high risk for redo surgical aortic valve replacement (SAVR). Small BP size (<=21 mm), stenotic pattern of degeneration and pre-existing prosthesis-patient mismatch (PPM) have been associated with worse clinical outcomes after ViV. However, no study has evaluated the actual haemodynamic benefit associated with ViV. This study aims to compare haemodynamic status observed at post-ViV, pre-ViV and early after initial SAVR and to determine the factors associated with worse haemodynamic outcomes following ViV, including the rates of high residual gradient and 'haemodynamic futility'. Methods: Early post SAVR, pre-ViV and post-ViV echocardiographic data of 79 consecutive patients who underwent aortic ViV at our institution were retrospectively analysed. The primary study endpoint was suboptimal valve haemodynamics (SVH) following ViV defined by the Valve Academic Research Consortium 2 as the presence of high residual aortic mean gradient (>=20 mm Hg) and/or at least moderate aortic regurgitation (AR). Haemodynamic futility of ViV was defined as <10 mm Hg decrease in mean aortic gradient and no improvement in AR compared with pre-ViV. Results: SVH was found in 61% of patients (57% high residual gradient, 4% moderate AR) after ViV versus 24% early after SAVR. Pre-existing PPM and BP mode of failure by stenosis were independently associated with the primary endpoint (OR: 2.87; 95% CI 1.08 to 7.65; p=0.035 and OR: 3.02; 95% CI 1.08 to 8.42; p=0.035, respectively) and with the presence of high residual gradient (OR: 4.38; 95% CI 1.55 to 12.37; p=0.005 and OR: 5.37; 95% CI 1.77 to 16.30; p=0.003, respectively) following ViV. Criteria of ViV haemodynamic futility were met in 7.6% overall and more frequently in patients with pre-existing PPM and stenotic BP (18.5%) compared with other patients (2.0%). ViV restored haemodynamic function to early post-SAVR level in only 34% of patients. Conclusion: Although ViV was associated with significant haemodynamic improvement compared with pre ViV in >90% of patients, more than half harboured SVH outcome. Furthermore, only one-third of patients had a restoration of valve haemodynamic function to the early post-SAVR level. Pre-existing PPM and stenosis pattern of BP degeneration were the main factors associated with SVH and haemodynamic futility following ViV. These findings provide strong support for the prevention of PPM at the time of initial SAVR and careful preprocedural patient screening. PMID- 30018785 TI - Trends in the theory that inflammation plays a causal role in tendinopathy: a systematic review and quantitative analysis of published reviews. AB - Background/aims: The contribution of inflammation to tendinopathy has been debated in the scientific literature. Several factors may contribute to this lack of clarity, including inconsistent definitions of inflammation. We hypothesised that the adoption and/or rejection of a causal link between inflammation and tendinopathy varied as a function of the 'inflammatory component' (eg, immune cell and molecular mediators included in published reviews). Methods: Twenty data items were collected from each review to determine conclusions about the role of inflammation in tendinopathy, specific definitions of the 'inflammatory component,' quality of the review and other potential correlates. Associations between correlates and a review's conclusion about the role of inflammation in tendinopathy were tested using binomial logistic regression. The database searches retrieved 2261 unique publications: 137 fulfilled inclusion criteria after full text screenings. Results: There has been little support for an inflammatory component to tendinopathy until recently (2012-2015). Prior to 2012, the majority of published reviews did not discuss monocytes, macrophages or lymphocytes in tendinopathy; rather they focused on the lack of neutrophils, often referred to as 'the inflammatory infiltrate', or immune cells were not discussed. Reviews including monocytes and lymphocytes in their discussions were 5.23 times more likely to conclude inflammation was important than reviews that did not, p<0.001. Conclusions: Data collected show growing support for an inflammatory component to tendinopathy, particularly among high-quality reviews and those that used more robust definitions of inflammation. This finding may have implications for explaining dissonance in the literature regarding a causal role for inflammation in the pathogenesis of tendinopathy. PMID- 30018786 TI - Who is coaching the coach? Knowledge of depression and attitudes toward continuing education in coaches. AB - Background: The rate of depression among collegiate athletes ranges from 16% to 23%, with particularly high findings of prevalence in track and field athletes (34%). Collegiate athletes have also been found to underuse mental health resources. Given this high prevalence of depression and demonstrated reluctance to seek help, it is important to explore the awareness and understanding of depression among the individuals who work most closely with this population. Objective: To assess coaches' knowledge and awareness of depression among their athletes and describe their level of interest in receiving continuing education. Method: All National Collegiate Athletic Association Division I cross-country and track and field coaches were invited to participate in an online survey. The sample consisted of 253 participants, of whom 56 (25%) identified themselves as female and 170 (75%) as male with 14 (+/-10.4) years of coaching experience. Respondents completed the Adolescent Depression Awareness Program (ADAP) questionnaire and related questions. Differences in depression knowledge and interest in continuing education were calculated by gender, event specialty, length of coaching experience and certification history using analysis of variance and chi2 analysis. Results: The mean score on the ADAP depression questionnaire was 83%. Significant differences were not observed by gender, length of coaching experience, coaching title or certification history. Distance coaches scored significantly higher on the test than sprints coaches. Coaches estimated that 11% of their former and current student-athletes have struggled with depression. 77% of coaches indicated a 'strong interest' in receiving continuing education. Conclusions: The findings of this study indicate the participating coaches have a good knowledge of depression for individuals without formal education on the topic but may lack depression awareness. This hypothesis is supported by the finding that coaches in the sample found out an athlete was suffering from depression most often by the athlete self-reporting. PMID- 30018787 TI - Effect of Holmich protocol exercise therapy on long-standing adductor-related groin pain in athletes: an objective evaluation. AB - Aim: To objectively evaluate the effect of Holmich protocol-based exercise therapy on long-standing adductor-related groin pain (LSAGP). Methods: We reproduced the Holmich protocol of exercise therapy and objectively evaluated its effect on 17 male athletes (mean age, 25.07+/-4.96 years) suffering from LSAGP, of whom 14 participants completed the 10 weeks treatment period. The study was designed as a single-blinded, before-and-after clinical trial. Main outcome measures included pain, functional ability, hip range of motion (ROM), hip abductor and adductor muscle strength, and successful return to sports activity. Results: Eleven athletes (78.57%) returned to their sports activities in a mean time of 14.2 weeks (range, 10-20 weeks). Visual analogue scale pain score, hip abductor and adductor muscles strength, and function scores improved significantly. Although hip abduction ROM did not show any significant changes (p = 0.609), the extent of progress in the hip internal rotation ROM was significant (p = 0.001). The ratio of hip adduction to abduction strength did not change significantly (p = 0.309 for the isometric and p = 0.957 for the eccentric ratio). Conclusions: Exercise therapy according to the Holmich programme may be an effective treatment for LSAGP. However, more emphasis should be paid to the hip adductor muscles' eccentric strength. Trial registration number: IRCT2016080829269N1. PMID- 30018788 TI - Risk factors associated with injury and concussion in sanctioned amateur and professional mixed martial arts bouts in Calgary, Alberta. AB - Background: There is limited literature that examines risk factors for injury and mild traumatic brain injury (mTBI) in mixed martial arts (MMA). An examination of previously unstudied bout and athlete characteristics that may pose health risks while partaking in this sport is warranted. Hypothesis/purpose: To determine the incidence of injury and concussion, along with the identification of risk factors that contribute to injury and mTBI in amateur and professional MMA bouts in Calgary, Alberta. Study design: A retrospective cohort study with case-control design. Methods: Calgary amateur and professional MMA records were examined from 1 January 2010 to 31 December 2015. Descriptive statistics were used to describe the incidence of injury and concussion, along with univariate and multivariable logistic regression to identify risk factors for injury and mTBI. Results: The injury rate per 100 athlete exposure (AE), the injury rate per 100 min of exposure and the concussion rate per 100 AE were 23.6 (95% CI 20.5 to 27.0), 4.1 (95% CI 3.48 to 4.70) and 14.7 (95% CI 11.8 to 17.2), respectively. The most common location of injury was the head and mTBI was the most common type of injury. Athletes whose bout was finished by a knockout/technical knockout, corner stoppage, draw, no contest or physician, and those whose country of origin was non-Canadian, were more likely to sustain an injury. No risk factors for concussion were shown to be significant. Conclusion: Engaging in MMA exposes athletes to inherent risk and several recommendations are proposed to reduce these risks. Future prospective investigations are necessary to better delineate the findings in this study. PMID- 30018789 TI - Effects of a novel exercise training protocol of Wingate-based sprint bouts dispersed over a day on selected cardiometabolic health markers in sedentary females: a pilot study. AB - Purpose: Sprint interval training (SIT) provides a strong stimulus for improving cardiovascular fitness, which is among the key markers for premature mortality. Recent literature demonstrated that SIT protocols with as few as two stacked 20 s Wingate Anaerobic Test (WAnT) cycle sprints provide sufficient training stimulus for a robust increase in maximal aerobic power. However, this effect is lost when only one bout is performed. This suggests training adaptation is still dependent on the volume of SIT. Therefore, the purpose of this study was to determine the effects of three dispersed 30 s WAnT bouts, done over a day but interspersed with 4 hours of recovery time, on selected cardiometabolic health markers. Methods: Eighteen sedentary women, age 36+/-8 years, were recruited and underwent 8 weeks of supervised training using the WAnT protocol, 3 days a week. Criterion measure of cardiovascular fitness (ie, VO2peak), skinfolds and blood lipids such as triglyceride, low density lipoprotein (LDL) and high density lipoprotein (HDL) were measured before and after training intervention. Results: VO2peak improved by a mean of 14.0% after training (21.7+/-5.7 vs 24.7+/-5.7 mL/kg/min, p<0.01). No significant change was observed for body fat and lipid profile. Conclusion: Performing three dispersed WAnT bouts with a 4-hour recovery period between bouts throughout a day, 3 days per week for 8 weeks provides sufficient training stimulus for a robust increase in VO2peak, which is comparable with other previous SIT protocols with very short recovery intervals. However, no other changes in the other cardiometabolic health markers were detected. PMID- 30018790 TI - Changes in the microRNA expression profile during blood storage. AB - Objectives: For several decades, autologous blood doping (ABD) in sports has been a major problem, and even today there is still no reliable method for satisfactorily detecting ABD. For this kind of doping, stored individual erythrocytes are used to increase stamina and endurance caused by a higher erythrocyte level in the athlete's body. Since there is growing evidence that these cells are enriched with microRNAs (miRNAs), this study has been carried out to discover and validate all miRNAs occurring in fresh blood as well as in stored blood. Methods: Therefore, small RNA Next Generation Sequencing has been performed, which allows untargeted detection of all miRNAs in a blood sample. The focus of this investigation has been to find miRNA alterations in blood bags after erythrocyte processing and during storage, as compared with fresh blood directly withdrawn from subjects. Blood samples were obtained from 12 healthy, recreationally active male subjects three times before blood donation and from blood bags at several time points after blood processing. Results: 189 miRNAs have been considered stable over two consecutive weeks. A further analysis revealed a complex biomarker signature of 28 miRNAs, consisting of 6 miRNAs that altered during 6 weeks of storage and 22 miRNAs that altered due to processing. Conclusion: These results suggest that the identified miRNA biomarker signature may be used for the detection of ABD. These 28 miRNA candidates are tested and verified currently in a follow-up study, a human transfusion clinical trial in healthy sportsmen. PMID- 30018791 TI - Prevalence and burden of overuse injuries in elite junior handball. AB - Aim: To record overuse injuries among male junior handball players throughout a handball season. Design: Prospective cohort study. Methods: Ten Norwegian junior male handball teams (145 players aged 16-18 years) were followed for one 10-month season. All players were sent the Oslo Sports Trauma Research Center Overuse Injury Questionaire every second week to record overuse injuries located in the shoulder, elbow, lower back and knee. The relative burden of overuse injuries was calculated in each anatomical area represented, defined as the proportion of the total cumulative severity score. Results: The average prevalence of all overuse injury problems was 39% (95% CI 29% to 49%) across all anatomical areas. The average prevalence of substantial overuse injury problems, defined as those leading to moderate or large reductions in training volume or sports performance, or to complete inability to participate, was 15% (95% CI 13% to 17%). Over the duration of the study, the cumulative incidence of overuse injury problems was 91% (133 players). Shoulder problems were the most prevalent (average prevalence 17%, 95% CI 16% to 19%), whereas knee problems had the greatest relative burden. Conclusion: Overuse injuries, particularly in the shoulder and knee, have a substantial impact on junior handball players' training participation and performance. Interventions to prevent overuse injuries among male junior handball players should focus on these areas. PMID- 30018792 TI - Study protocol of a 52-week Prospective Running INjury study in Gothenburg (SPRING). AB - Introduction: It is assumed that a running-related (overuse) injury occurs when a specific structure of the human body is exposed to a load that exceeds that structures' load capacity. Therefore, monitoring training load is an important key to understanding the development of a running-related injury. Additionally, other distribution, magnitude and capacity-related factors should be considered when aiming to understand the causal chain of injury development. This paper presents a study protocol for a prospective cohort study that aims to add comprehensive information on the aetiology of running-related injuries and present a new approach for investigating changes in training load with regard to running-related injuries. Methods and analysis: This study focused on recreational runners, that is, runners exposed to a minimum weekly average of 15 km for at least 1 year. Participants will undergo baseline tests consisting of a clinical/anthropometrical examination and biomechanical measurements. Furthermore, participants will log all training sessions in a diary on a weekly basis for 1 year. The primary exposure variable is changes in training load. A medical practitioner will examine runners suffering from running-related pain and, if possible, make a clear diagnosis. Finally, additional time-varying exposure variables will be included in the main analysis, whereas the analysis for the secondary purpose is based on time-fixed baseline-related risk factors. Ethics and dissemination: Ethical approval (DNR: 712-15) for the study and its design was obtained from the Gothenburg regional ethical review board. The results of the study will be published in peer-reviewed journals. PMID- 30018794 TI - A little bit more about Popper's philosophy. PMID- 30018793 TI - Musculoskeletal pain and its association with maturity and sports performance in 14-year-old sport school students. AB - Objectives: In youth sports, musculoskeletal pain is often studied from the standpoint of sports injuries, but little is known about pain conditions in which athletes still participate. The aim was to study the frequency of pain and associations with maturity offset, health status and sports performance in 14 year-old sport school students. Methods: Cross-sectional design. One hundred and seventy-eight students (108 boys and 70 girls) completed anthropometric measures for maturity offset (height, weight and sitting height), questionnaires (pain mannequin and EQ-5D for health status) and sports performance tests (sprint, agility, counter-movement jump and grip strength). Differences between groups were analysed with Student's t-test and analysis of covariance. Results: Thirty one students (18.6%) reported infrequent pain, 85 (50.9%) frequent pain and 51 (30.5%) constant pain. Students in the constant pain group had worse health status than those in the infrequent pain group. Boys with constant pain (n=27) had a lower mean maturity offset (-0.38 vs 0.07 years; p=0.03) than boys with infrequent pain (n=22), and pain was associated with worse sports performance. There was no difference in maturity or sports performance between girls with constant pain (n=24) and girls with infrequent pain (n=9). Conclusion: Musculoskeletal pain is common in sport school students and coincides with worse health status and with a younger biological age in boys. The high prevalence of pain should be acknowledged by coaches and student healthcare workers in order to promote a healthy and sustainable development in young athletes. PMID- 30018795 TI - Feasibility of a postacute structured aerobic exercise intervention following sport concussion in symptomatic adolescents: a randomised controlled study. AB - Objective: The utility of structured exercise for rehabilitation purposes early in the postacute phase (ie, beyond the initial 24-48 hours of advised rest) following sport-related concussion (SRC) remains largely unexplored. This study examined the feasibility of implementing a standardised aerobic exercise (AE) intervention in the postacute stage of SRC recovery in a sample of adolescent students with SRC compared with usual care. Methods: Symptomatic adolescents with SRC were randomised to one of two groups: Aerobic Exercise (n=8) or Usual Care (n=7). The AE intervention, beginning on day 6 postinjury, comprised eight sessions with progressive increases in intensity and duration on a cycle ergometer. Usual care consisted of rest followed by physician-advised progressions in activity levels in an unsupervised setting. All participants were evaluated by physician at weeks 1, 2, 3 and 4 postconcussion. Outcome measures included: (1) Intervention feasibility: symptom status pre-post exercise sessions and completion of intervention and (2) Clinical recovery: symptom status at weeks 1, 2, 3 and 4 postinjury and medical clearance date. Results: All participants completed the exercise sessions as part of the AE intervention and symptom exacerbation was not associated with any exercise session. The AE group experienced greater symptom resolution compared with the Usual Care Group across the recovery timeline. Conclusion: A structured AE protocol appears to be safe and feasible to administer in the postacute stage of SRC recovery in adolescents and should be explored as part of a full Phase III Clinical Trial. PMID- 30018796 TI - Haematopoietic stem cell transplantation in systemic sclerosis. AB - Three randomised controlled trials of haematopoietic stem cell transplantation (HSCT) in systemic sclerosis (SSc) demonstrated long-term survival benefits, induction of clinically meaningful, sustained improvement of forced vital capacity with improvements in skin thickening, vasculopathy and health-related quality of life, in contrast to a clinical decline in standard of care control groups. These benefits, however, must be weighed against the increased risk of transplant-related mortality. Further, with disease progression, severe extensive internal organ involvement and damage ensues, constituting an exclusion criterion for safety reasons, leaving a limited window whereby patients with SSc are eligible for HSCT. Although autologous HSCT offers the possibility of drug-free remission, relapse can occur, requiring re-initiation of disease modifying antirheumatic drugs. HSCT is also associated with secondary autoimmune diseases and gonadal failure. HSCT should be proposed for carefully selected patients with early rapidly progressive diffuse SSc whose clinical picture portends a poor prognosis for survival, but yet lacks advanced organ involvement. PMID- 30018797 TI - Osteoporosis in psoriatic arthritis: a cross-sectional study of an outpatient clinic population. AB - Background: The risk of osteoporosis in patients with psoriatic arthritis (PsA) still remains unclear. The aim of this study was to investigate bone mineral density (BMD) at the hip and lumbar spine measured by dual-energy X-ray absorptiometry in patients with PsA. Methods: From an outpatient clinic in southern Norway, 140 patients with PsA were consecutively recruited and assessed for osteoporosis as part of a prospective study from January 2013 to May 2014. An extensive data collection was performed including demographic data and measures reflecting disease activity and health status. Results: Mean age was 52.4 years and 71 (50.7%) were women. Median disease duration was 7.8 years. The proportion of patients with low BMD (defined as Z score<=-1.0 SD) was comparable to the expected value of 16%, according to the normal distribution of the Z score in the population. Osteoporosis was only found in 6.4% (95% CI3% to 11%) of the patients. No significant associations were found between BMD and disease activity measures. Conclusion: The prevalence of PsA patients with osteoporosis or low BMD was low and in the range seen in the reference population. This supports that patients with PsA are not at high risk for osteoporosis compared with the general population. Therefore, clinicians may follow the general population guidelines for monitoring of osteoporosis for patients with PsA. PMID- 30018798 TI - Depressive mood and low social support are not associated with arthritis development in patients with seropositive arthralgia, although they predict increased musculoskeletal symptoms. AB - Objective: Studies on the role of psychosocial vulnerability in the development of arthritis must be performed early in the disease course to exclude the reverse explanation that arthritis leads to psychological symptoms. Therefore, the objective of this study was to investigate the longitudinal (5-year) association between depressive mood, daily stressors, avoidance coping and social support as predictors, and the development of arthritis and other clinical parameters as outcomes, in persons with seropositive arthralgia at risk of developing rheumatoid arthritis. Methods: Five-year follow-up data of 231 patients from the Reade seropositive arthralgia cohort were used. Clinical and psychological data were collected using physical examinations and questionnaires. Mixed models and Cox regression analyses were used to assess the 5-year associations between depressive mood, daily stressors, avoidance coping or social support, and the development of arthritis or clinical parameters (tender joint count, Visual Analogue Scale (VAS) pain, VAS morning stiffness and erythrocyte sedimentation rate (ESR)). Results: Higher scores for depressive mood and lower scores for social support were not associated with the development of arthritis nor with ESR. However, they were longitudinally associated with an increase in pain (p<0.001), morning stiffness (p<0.01) and tender joint count (p<0.001). No consistent associations were found between daily stressors, avoidance coping and the development of arthritis or other clinical parameters. Conclusion: Although an effect on the development of arthritis could not be demonstrated, a strong longitudinal association was found between high depressive mood, low social support and clinical parameters. In persons with seropositive arthralgia, depressive symptoms and low social support may increase musculoskeletal symptoms. PMID- 30018799 TI - Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies. AB - Objective: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. Methods: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. Results: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks. Conclusion: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years. Trial registration numbers: NCT01172938, NCT01212757 and NCT01212770. PMID- 30018800 TI - Non-classical human leucocyte antigens in ankylosing spondylitis: possible association with HLA-E and HLA-F. AB - Objectives: Ankylosing spondylitis (AS) is the most prevalent form of spondyloarthritis, with a known genetic association with the HLA-B27 molecule. The aim of this study was to assess the contribution of the HLA-G, HLA-E and HLA F to AS susceptibility/protection in Portuguese patients with HLA-B27 AS and HLA B27 unaffected controls. Methods: High-resolution typing of HLA-G, HLA-E and HLA F was performed in 228 patients with HLA-B27 AS and 244 HLA-B27 unaffected controls. Allelic, genotypic and haplotypic frequencies were compared between cohorts. To replicate the results, single nucleotide polymorphisms (SNPs) in HLA E and HLA-F genes were typed in Australian cohorts. For further confirmation, a group of European-descent patients with AS and unaffected controls were genotyped for Major Histocompatibility Complex SNPs using the Illumina microarray. Results: In the Portuguese population, no significant differences were found in HLA-G. For HLA-E, a significant difference was detected for the genotype HLA E*01:01:01/01:03:01 (p=0.009; pc=0.009; OR=0.51), with a protection effect. For HLA-F, significant differences were detected in the allele HLA-F*01:01:02 (p=0.0049; pc=0.0098; OR=0.60) and corresponding SNP rs2075682 (p=0.0004; pc=0.0008; OR=0.53), suggesting protection and in the genotype HLA F*01:01:01/01:03:01 (p=0.011; pc=0.043; OR=2.00), suggesting a susceptibility effect. Three G-E-F haplotypes with significant differences were detected but occur in a very small number of individuals. The only significant differences detected in the replication studies were for HLA-E rs1059510 in the Australians and for HLA-F rs1736924 in the European-descent cohorts. Conclusion: Our results reveal suggestive AS protective and susceptibility effects from both HLA-E and HLA-F loci, however with population differences. To our knowledge, this is the first study showing association of HLA-F with AS. PMID- 30018801 TI - Employment and the role of personal factors among patients with ankylosing spondylitis: a Dutch cross-sectional case-control study. AB - Objectives: To update the knowledge on employment and the role of mastery, a personal factor reflecting the level of control over life and disease, among Dutch patients with ankylosing spondylitis (AS) compared to general population subjects. Methods: Data of persons <=65 years participating in a Dutch cross sectional multicentre study on social participation in AS were used. Being employed was the main outcome. Standardised employment ratios (SERs) were calculated using indirect standardisation after adjusting for age, gender and education and repeated after stratification by symptom duration tertiles. Modified Poisson regressions were performed to understand the role of mastery (Pearlin's scale) independent of sociodemographic and health-related factors. Results: 214 patients and 470 controls (127 (59.3%) and 323 (68.7%) males; mean age 48.3 (SD 10.4) and 39.3 (SD 12.7) years, respectively) completed an online questionnaire. SER (95%CI) in patients was 0.83 (0.69-0.98); 0.84 (0.67-1.04) in males; 0.83 (0.59-1.07) in females. Adjusted absolute employment of patients compared to controls was 69% versus 84%; 73% versus 86% for males; 62% versus 78% for females. In multivariable analyses stratified for patients and controls, mastery was associated with being employed in patients, but only in those with low education. In controls, not mastery but higher education was associated with being employed. Conclusion: Our study reveals that patients suffering from AS compared to population controls are less likely to be employed. Mastery is an important personal factor associated with employment in patients but not in controls. Interventions aimed at improving employment of patients with AS should likely account for mastery. PMID- 30018802 TI - Latent profile analysis approach to the relationship between patient and physician global assessments of rheumatoid arthritis activity. AB - Objective: Patients and physicians commonly differ in their assessments of rheumatoid arthritis (RA) activity. Clinically meaningful discordance thresholds or validation of their ability to predict functional outcomes are lacking. We explored whether an unbiased, person-centred latent profile analysis (LPA) approach could classify cases based on patient global assessment (PtGA) and physician global assessment (MDGA) assessments of RA activity. We further examined whether the LPA groups displayed greater differences in clinical outcomes compared with traditional threshold-based groups. Finally, we evaluated whether LPA yielded higher explanatory power for clinical outcomes. Methods: LPA was performed in 618 patients with established RA from a single centre. A threshold-based discordance definition was used as a comparator, with patients classified into concordant (PtGA-MDGA within +/- 3 cm), positively discordant (PtGA-MDGA >=3 cm) and negatively discordant groups (PtGA-MDGA <=-3 cm). Results: LPA yielded five distinct groups: low PtGA/low MDGA (35.9%), moderate PtGA/moderate MDGA (18.6%), high PtGA/high MDGA (14.7%), high PtGA/low MDGA (23.3%) and low PtGA/high MDGA (7.4%). Groups differed across clinical, physical function, pain, fatigue, health-related quality of life, work productivity and activity impairment outcomes (p<0.001). Concordance groups, in particular, displayed marked heterogeneity in outcomes depending on the magnitude of disease activity reported, with the low/low group faring the best (p<0.001). The LPA solution demonstrated superior explanatory power for all outcomes (p<0.001). Conclusions: We confirmed the validity and advantages of LPA in characterising the relationship between PtGA and MDGA over a conventional threshold-based definition. LPA yielded optimally distinct, clinically meaningful and cohesive groupings, demonstrating superior explanatory power for disease-related outcomes of interest. PMID- 30018803 TI - Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis. AB - Background: Ankylosing spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of human leucocyte antigen (HLA)-B27 alleles. HLA-E molecules are non-classical major histocompatibility complex (MHC) class I molecules that specifically interact with the natural killer receptors NKG2A (inhibitory) and NKG2C (activating), and have been recently proposed to be involved in AS pathogenesis.''. Objective: To analyse the expression of HLA-E and the CD94/NKG2 pair of receptors in HLA-B27-positive patients with AS and healthy controls (HC) bearing the AS-associated B*2705 and the non-AS-associated B*2709 alleles. Methods: The level of surface expression of HLA-E molecules on CD14+ peripheral blood mononuclear cell was evaluated in 21 HLA-B*2705 patients with AS, 12 HLA-B*2705 HC, 12 HLA-B*2709 HC and 6 HLA-B27-negative HC using the monoclonal antibody MEM-E/08 by quantitative cytofluorimetric analysis. The percentage and density of expression of HLA-E ligands NKG2A and NKG2C were also measured on CD3-CD56+ NK cells. Results: HLA-E expression in CD14+ cells was significantly higher in patients with AS (587.0, IQR 424-830) compared with B*2705 HC (389, IQR 251.3-440.5; p=0.0007), B*2709 HC (294.5, IQR 209.5-422; p=0.0004) and HLA-B27-negative HC (380, IQR 197.3-515.0; p=0.01). A higher number of NK cells expressing NKG2A compared with NKG2C were found in all cohorts analysed, as well as a higher cell surface density. Conclusion: The higher surface level of HLA-E molecules in patients with AS compared with HC, concurrently with a prevalent expression of NKG2A, suggests that the crosstalk between these two molecules might play a role in AS pathogenesis, accounting for the previously reported association between HLA-E and AS. PMID- 30018806 TI - Increased B-cell activating factor (BAFF)/B-lymphocyte stimulator (BLyS) in primary antiphospholipid syndrome is associated with higher adjusted global antiphospholipid syndrome scores. PMID- 30018804 TI - Depression as a risk factor for the development of rheumatoid arthritis: a population-based cohort study. AB - Objectives: Major depressive disorder (MDD) is associated with increased levels of systemic proinflammatory cytokines, including tumour necrosis factor alpha. As these cytokines are pathogenic in autoimmune diseases such as rheumatoid arthritis (RA), our aim was to explore on a population-level whether MDD increases the risk of developing RA. Methods: A retrospective cohort study was conducted using The Health Improvement Network (THIN) database (from 1986 to 2012). Observation time was recorded for both the MDD and referent cohorts until patients developed RA or were censored. Cox proportional hazards models were used to determine the risk of developing RA among patients with MDD, accounting for age, sex, medical comorbidities, smoking, body mass index and antidepressant use. Results: A cohort of 403 932 patients with MDD and a referent cohort of 5 339 399 patients without MDD were identified in THIN. Cox proportional hazards models revealed a 31% increased risk of developing RA among those with MDD in an unadjusted model (HR=1.31, 95% CI 1.25 to 1.36, p<0.0001). When adjusting for all covariates, the risk remained significantly increased among those with MDD (HR=1.38, 95% CI 1.31 to 1.46, p<0.0001). Antidepressant use demonstrated a confounding effect that was protective on the association between MDD and RA. Conclusion: MDD increased the risk of developing RA by 38%, and antidepressants may decrease this risk in these patients. Future research is necessary to confirm the underlying mechanism of MDD on the pathogenesis of RA. PMID- 30018805 TI - Recovery after unilateral knee replacement due to severe osteoarthritis and progression in the contralateral knee: a randomised clinical trial comparing daily 2000 IU versus 800 IU vitamin D. AB - Objective: To test whether daily high-dose vitamin D improves recovery after unilateral total knee replacement. Methods: Data come from a 24-month randomised, double-blind clinical trial. Adults aged 60 and older undergoing unilateral joint replacement due to severe knee osteoarthritis were 6-8 weeks after surgery randomly assigned to receive daily high-dose (2000 IU) or standard-dose (800 IU) vitamin D3. The primary endpoints were symptoms (Western Ontario and McMaster Universities Arthritis Index pain and function scores) assessed at baseline, 6, 12, 18 and 24 months in both knees, and the rate of falls over 24 months. The secondary outcomes were sit-to-stand performance, gait speed, physical activity and radiographic progression in the contralateral knee. Results: We recruited 273 participants, 137 were randomised to receive 2000 IU and 136 were randomised to receive 800 IU vitamin D per day. 2000 IU vitamin D increased 25-hydroxyvitamin D levels to 45.6 ng/mL and 800 IU vitamin D to 37.1 ng/mL at month 24 (p<0.0001). While symptoms improved significantly in the operated knee and remained stable in the contralateral knee over time, none of the primary or secondary endpoints differed by treatment group over time. The rate of falls over 24 months was 1.05 with 2000 IU and 1.07 with 800 IU (p=0.84). 30.5% of participants in the 2000 IU and 31.3% of participants in the 800 IU group had radiographic progression in the contralateral knee over 24 months (p=0.88). Conclusions: Our findings suggest that a 24-month treatment with daily 2000 IU vitamin D did not show greater benefits or harm than a daily standard dose of 800 IU among older adults undergoing unilateral total knee replacement. PMID- 30018807 TI - Does a mandatory non-medical switch from originator to biosimilar infliximab lead to increased use of outpatient healthcare resources? A register-based study in patients with inflammatory arthritis. AB - Objectives: National Danish guidelines in May 2015 dictated a mandatory switch from originator infliximab (INX) to biosimilar CT-P13 in patients with inflammatory rheumatic disease. We investigated if this non-medical switch changed use of outpatient hospital resources. Methods: Observational cohort study. Switchers were identified in DANBIO. Rheumatic outpatient contacts, visits and services were identified in the National Patient Registry. The 6-month rate for (1) number of visits (or services) and (2) days with >=1 visit (or service) were compared before/after switching (paired t-tests). Visits per week per patient before/after the switch date were analysed with graphical interrupted time-series analysis. Results: In 769 switchers (372 males, median age 54 years (IQR 44-66)), 1484 outpatient contacts, 6718 visits and 9243 days with services (693 on switch date) were identified. Mean visit rate was 3.89 before and 3.95 after switch (p=0.35). Total number of services was 19 752 (2019 on switch date). Mean rates before/after switch for 16 service categories were small and differences close to zero. Visits per week per patient appeared similar before/after switch with peaks every ~8 weeks (standard INX infusion interval). Conclusion: Changes were marginal with no clinically relevant increase in use of outpatient health care resources 6 months after compared with 6 months before mandatory switch from originator to biosimilar infliximab. PMID- 30018808 TI - Gout and the risk of incident atrial fibrillation in older adults: a study of US Medicare data. AB - Objective: To assess the association of gout with new-onset atrial fibrillation (AF) in the elderly. Methods: We used the 5% Medicare data from 2005 to 2012 to assess whether a diagnosis of gout was associated with incident AF. We used multivariable Cox regression adjusted for demographics, Charlson-Romano comorbidity index, common cardiovascular medications, allopurinol and febuxostat use, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Among 1 647 812 eligible people, 9.8% had incident AF. The mean age was 75 years, 42% were male, 86% were white and the mean Charlson-Romano index score was 1.52. We noted 10 604 incident AF cases in people with gout and 150 486 incident AF cases in people without gout. The crude incidence rates of AF in people with and without gout were 43.4 vs 16.3 per 1000 patient-years, respectively. After multivariable-adjustment, gout was associated with a higher HR of incident AF, 1.92 (95% CI 1.88 to 1.96), with minimal attenuation of HR in sensitivity models that replaced the Charlson-Romano index score with a categorical variable, HR was 1.91 (95% CI 1.87 to 1.95). In another model that adjusted for AF-specific risk factors including hypertension, hyperlipidaemia and coronary artery disease and individual Charlson-Romano index comorbidities, the HR was slightly attenuated at 1.71 (95% CI 1.67 to 1.75). Older age, male sex, white race and higher Charlson-Romano index score were each associated with higher hazard of incident AF. Conclusion: A diagnosis of gout almost doubled the risk of incident AF in the elderly. Future studies should explore the pathogenesis of this association. PMID- 30018809 TI - Postoperative chemotherapy with single-agent fluoropyrimidines after resection of colorectal cancer liver metastases: a meta-analysis of randomised trials. AB - : Surgical resection is the only option of cure for patients with metastatic colorectal cancer. Risk of recurrence after metastasectomy is around 75%. Use of adjuvant chemotherapy after metastasectomy is controversial. Aim: To address whether adjuvant systemic therapy after colorectal cancer metastasectomy offers any survival benefit compared with surgery alone. Methods: Systematic review of literature and meta-analysis of all available randomised evidence. Relative hazards (RHs) were summarised across trials and heterogeneity was assessed with the Q and I2 statistics. Results: Five trials were eligible. Three trials, all using single-agent fluoropyrimidine chemotherapy, presented data valuable for analyses. 482 patients were included in the meta-analysis: 238 randomly assigned to receive postoperative chemotherapy and 244 to metastasectomy only. We found no overall survival (OS) benefit with the use of postoperative single-agent fluoropyrimidines compared with surgery alone, even if a trend for benefit was observed (relative hazard (RH)=0.781, 95% CI 0.593 to 1.030, p=0.080). Significant disease-free survival benefit with the use of postoperative chemotherapy was observed (RH=0.645, 95% CI 0.509 to 0.818, p=0.001). No quality of life (QL) data were available. All trials showed accrual delay, two stopped and one recruiting after 10 years. Long follow-up needs were evidenced since OS curves split only after 3.5 years. Conclusions: No OS benefit was documented from the use of postoperative monochemotherapy. Metastasectomy alone continues to be the standard of care. Combination chemotherapy regimens should be evaluated along with QL assessment in future trials appropriately designed for long-term accrual and follow-up. PMID- 30018810 TI - Potential new biomarkers for squamous carcinoma of the uterine cervix. AB - Aim: An in silico pathway analysis was performed in an attempt to identify new biomarkers for cervical carcinoma. Methods: Three publicly available Affymetrix gene expression data sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total 9 cervical cancer cell lines, 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples. An Agilent data set (GSE7410; 5 normal cervical samples, 35 samples from invasive cervical cancer) was selected as a validation set. Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. We compared the lists of differentially expressed genes between normal and CIN3 samples on the one hand (n=1923) and between CIN3 and invasive cancer samples on the other hand (n=628). Results: Seven probe sets were identified that were significantly overexpressed (at least 2 fold increase expression level, and false discovery rate <5%) in both CIN3 samples respective to normal samples and in cancer samples respective to CIN3 samples. From these, five probes sets could be validated in the Agilent data set (P<0.001) comparing the normal with the invasive cancer samples, corresponding to the genes DTL, HMGB3, KIF2C, NEK2 and RFC4. These genes were additionally overexpressed in cervical cancer cell lines respective to the cancer samples. The literature on these markers was reviewed. Conclusion: Novel biomarkers in combination with primary human papilloma virus (HPV) testing may allow complete cervical screening by objective, non-morphological molecular methods, which may be particularly important in developing countries. PMID- 30018811 TI - Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours. AB - Purpose: TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab's antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX. Patients and methods: A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12-720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose. Results: No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263+/-99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7-26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively. Conclusion: TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2-3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343). PMID- 30018813 TI - Questions asked in the everyday practice: immune checkpoint inhibitors. PMID- 30018812 TI - 2018 ESMO Sarcoma and GIST Symposium: 'take-home messages' in soft tissue sarcoma. AB - The 7th edition of the 'ESMO Sarcoma and GIST Symposium' was held in Milan in February 2018. For the first time, the Symposium brought together representatives from the European Reference Network on rare adult solid cancer (EURACAN) joined by sarcoma experts from the USA, Japan and patient advocacy groups, to share insights and discuss future directions in this rare condition. This commentary will summarise the highlights in soft tissue sarcomas. PMID- 30018814 TI - TRIPLETE: a randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer. AB - Background: FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. Methods: This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, L-leucovorin 200 mg/m2, 5-fluoruracil 2400 mg/m2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5 fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. Discussion: The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. Clinical trial information: NCT03231722. PMID- 30018815 TI - Patient-reported outcomes in a phase II, North American study of alectinib in patients with ALK-positive, crizotinib-resistant, non-small cell lung cancer. AB - Background: In a phase II North American study (NP28761; NCT01871805), the anaplastic lymphoma kinase (ALK) inhibitor alectinib demonstrated both systemic and central nervous system (CNS) efficacy with good tolerability in patients with ALK-positive non-small cell lung cancer. We describe patient-reported outcomes (PROs) from the NP28761 study. Patients and methods: PROs and health-related quality of life (HRQoL) benefits were assessed using two self-administered questionnaires (the European Organisation for Research and Treatment of Cancer 30 Item Quality of Life Questionnaire-Core (EORTC QLQ-C30), and the 13-item EORTC QLQ-lung cancer-specific module) at enrolment and every 6 weeks until week 66, disease progression or death. Results: Clinically meaningful mean improvements (>=10 point change from baseline) were observed in 10 domains, including global health status (GHS), role and social functioning, fatigue, pain, dyspnoea, and appetite loss. A clinically meaningful improvement was observed in GHS from the first assessment (6 weeks) until week 60. Alectinib demonstrated a rapid effect, with a median time to symptom improvement, using the composite endpoint of cough, dyspnoea and pain in the chest, of 1.4 months (6.1 weeks) (95% CI 1.4 to 1.6) and a median time to symptom deterioration of 5.1 months (22.1 weeks) (95% CI 2.8 to 6.8). Patients with CNS metastases at baseline experienced comparable HRQoL over the duration of the study as patients without CNS metastases. Exploratory analysis showed that the occurrence of an objective response may be associated with a better HRQoL. Conclusions: Patients treated with alectinib in this phase II study achieved clinically meaningful improvements in HRQoL and symptoms and had delayed time to symptom deterioration. PMID- 30018816 TI - Indicators of integration at ESMO Designated Centres of Integrated Oncology and Palliative Care. AB - Background: A recent international consensus panel identified 13 major indicators to assess the level of integration between oncology and palliative care. We examined these indicators among European Society for Medical Oncology (ESMO) Designated Centres (ESMO-DCs) of Integrated Oncology and Palliative Care (PC) and determined the centre characteristics associated with greater integration. Methods: This is a preplanned secondary analysis of a recent survey to characterise the structure, processes and outcomes of the palliative care programmes at ESMO-DCs. We assessed the level of integration using 13 major indicators. We calculated two Palliative Care and Oncology Integration Indexes consisting of all 13 indicators (PCOI-13, range 0-13) and 9 of the 13 indicators (PCOI-9, range 0-9), with a higher index indicating greater integration. Results: The survey response rate was 152/184 (83%). Among the 13 major indicators, interdisciplinary team was most likely to be achieved (95%), while early referral to palliative care (median time from referral to death >6 months before death) was only present in 24 (20%) of ESMO-DCs. The median PCOI-13 was 7.8 (IQR 6.4 9.6) and the median PCOI-9 was 6 (IQR 5-7). The presence of dually trained palliative oncologists was associated with higher PCOI-13 (median 8.4 vs 7.0; p=0.01) and PCOI-9 (median 6 vs 5; p=0.03). Non-tertiary hospitals generally had higher PCOI-13 (median 8.6 vs 7.2; p=0.01) and ESMO-DCs outside of Europe had higher PCOI-9 (median 7 vs 6; p=0.03). Conclusions: Assessment of the level of integration at ESMO-DCs with PCOIs highlighted strengths, areas for further development and how double-boarded palliative oncologists may promote integration. PMID- 30018817 TI - Choosing wisely in oncology: necessity and obstacles. AB - In the last decades, the survival of many patients with cancer improved thanks to modern diagnostic methods and progresses in therapy. Still for several tumours, especially when diagnosed at an advanced stage, the benefits of treatment in terms of increased survival or quality of life are at best modest when not marginal, and should be weighed against the potential discomfort caused by medical procedures. As in other specialties, in oncology as well the dialogue between doctor and patient should be encouraged about the potential overuse of diagnostic procedures or treatments. Several oncological societies produced recommendations similar to those proposed by other medical disciplines adhering to the Choosing Wisely (CW) campaign. In this review, we describe what was reported in the medical literature concerning adequacy of screening, diagnostic, treatment and follow-up procedures and the potential impact on them of the CW. We only marginally touch on the more complex topic of treatment appropriateness, for which several evaluation methods have been developed (including the European Society for Medical Oncology-magnitude of clinical benefit scale). Finally, we review the possible obstacles for the development of CW in the oncological setting and focus on the strategies which could allow CW to evolve in the cancer field, so as to enhance the therapeutic relationship between medical professionals and patients and promote more appropriate management. PMID- 30018818 TI - Early Results with a New Posterior Chamber Phakic Intraocular Lens in Patients with High Myopia. AB - Purpose: To report clinical results of a foldable, hydrophilic acrylic, single piece, injectable, posterior chamber phakic intraocular lens (pIOL). Material and Methods: Medical records of patients who underwent posterior chamber phakic IOL (Eyecryl Phakic IOL, Biotech Vision Care, Ahmedabad, India) implantation for surgical correction of myopia were retrospectively reviewed. Only patients with at least a one-year follow-up were included. Manifest refraction, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), endothelial cell density (ECD), and pIOL vault were analyzed at 1, 3, 6, and 12 months after surgery. Complications observed during and after surgery were also recorded. Results: The study included 58 eyes of 29 patients. Mean patient age was 32 +/- 7 years. Spherical equivalent of manifest refraction was -13.41 +/- 3.23 D preoperatively and -0.44 +/- 0.55 D postoperatively. Preoperative CDVA was 0.29 +/- 0.71 logMAR. Postoperative UDVA and CDVA were 0.21 +/- 0.66 and 0.15 +/- 0.69 logMAR, respectively, at the 12-month visit. At the 12-month visit, the efficacy index was 1.20 and the safety index was 1.39. Mean ECD was 2713 +/- 339 cells/mm2 at the preoperative visit and 2608 +/- 362 cells/mm2 at the 12-month visit (3.9% loss, p < 0.001). ECD loss from 3 months to 12 months was not statistically significant. No significant cataract formation, significant endothelial cell loss, glaucoma, uveitis, or any other vision-threatening complication was observed. Conclusion: Based on postoperative experience, we have found that Eyecryl Phakic IOL is safe and effective for treating high myopia. PMID- 30018819 TI - Predictors of Noncompliance to Antihypertensive Therapy among Hypertensive Patients Ghana: Application of Health Belief Model. AB - This study determined noncompliance to antihypertensive therapy (AHT) and its associated factors in a Ghanaian population by using the health belief model (HBM). This descriptive cross-sectional study conducted at Kintampo Municipality in Ghana recruited a total of 678 hypertensive patients. The questionnaire constituted information regarding sociodemographics, a five-Likert type HBM questionnaire, and lifestyle-related factors. The rate of noncompliance to AHT in this study was 58.6%. The mean age (SD) of the participants was 43.5 (+/-5.2) years and median duration of hypertension was 2 years. Overall, the five HBM constructs explained 31.7% of the variance in noncompliance to AHT with a prediction accuracy of 77.5%, after adjusting for age, gender, and duration of condition. Higher levels of perceived benefits of using medicine [aOR=0.55(0.36 0.82),p=0.0001] and cue to actions [aOR=0.59(0.38-0.90),p=0.0008] were significantly associated with reduced noncompliance while perceived susceptibility [aOR=3.05(2.20-6.25), p<0.0001], perceived barrier [aOR=2.14(1.56 2.92), p<0.0001], and perceived severity [aOR=4.20(2.93-6.00),p<0.0001] were significantly associated with increased noncompliance to AHT. Participant who had completed tertiary education [aOR=0.27(0.17-0.43), p<0.0001] and had regular source of income [aOR=0.52(0.38-0.71), p<0.0001] were less likely to be noncompliant. However, being a government employee [aOR=4.16(1.93-8.96), p=0.0002)] was significantly associated increased noncompliance to AHT. Noncompliance to AHT was considerably high and HBM is generally reliable in assessing treatment noncompliance in the Ghanaian hypertensive patients. The significant predictors of noncompliance to AHT were higher level of perceived barriers, susceptibility, and severity. Intervention programmes could be guided by the association of risk factors, HBM constructs with noncompliance to AHT in clinical practice. PMID- 30018820 TI - Identification and Characterization of Families That Are Positively Deviant for Childhood Obesity in a Latino Population: A Case-Control Study. AB - Background: Childhood obesity is a complex public health challenge that requires innovative, sustainable solutions. Positive deviance, inspired by the science of complexity, is an approach that examines what allows certain individuals to succeed despite being predicted to fail. This study is aimed at identifying and defining positive deviants for early childhood obesity. Methods: This case control study used medical record data to identify Latino children aged 2-5 and classify them using their longitudinal weight change. Parents of children with trajectories toward a healthy weight from an obese weight (cases) and parents of children with stable obese weight trajectories over time (controls) were recruited. Mixed-methods analyses were used including a semistructured interview and quantitative surveys evaluating diet, physical activity, sleep, feeding practices, and self-efficacy. Qualitative description was applied to the qualitative data; quantitative data were analyzed using descriptive statistics and logistic regression modeling. Results: Of eligible Latino children identified from the overall data set (n=1,621), 257 (16%) had trajectories toward a healthy weight, and among these, 21 positively deviant cases completed the study with 23 matched controls. Positive deviant families were characterized by lower education, higher self-efficacy, and a more Mexican cultural orientation. Findings suggest that effective engagement of other caregivers and creating healthy food environments were important determinants of healthy weight outcomes. Conclusions: Positive deviants (cases) were distinct from controls in several parenting strategies such as creating healthy food environments and engaging caregivers. They had higher self-efficacy despite lower education. There were fewer differences in diet and physical activity than expected. PMID- 30018821 TI - Prevalence and Associated Factors of Perinatal Depression in Ethiopia: A Systematic Review and Meta-Analysis. AB - Background: There is no pooled evidence regarding the prevalence and potential associated factors of perinatal depression in Ethiopian community. Hence, the current review aimed to examine the prevalence and associated factors of perinatal depression in Ethiopia. Method: A computerized systematic literature search was made in MEDLINE, Scopus, PubMed, ScienceDirect, and Google Scholar. Each database was searched from its start date to January 2018. All included articles were published in English, which evaluated prevalence and associated factors of perinatal depression in Ethiopia. Pooled estimations with 95% confidence interval (CI) were calculated with DerSimonian-Laird (DL) random effects model. Publication bias was evaluated by using inspection of funnel plots and statistical tests. Result: Eight observational studies with an overall sample size of 4624 mothers were included in the review. The pooled prevalence of perinatal depression from these studies reported that the prevalence of perinatal depression in Ethiopia is 25.8% [95% CI, 24.6%-27.1%]. A pervious history of depression [RR: 3.78 (95% CI, 2.18-6.57), I2 = 41.6%], poor socioeconomic status [RR: 4.67 (95% CI, 2.89-7.53), I2 = 0%], not living with spouse [RR: 3.76 (95% CI, 1.96-7.38), I2 = 36.4%], having obstetric complications in previous and/or this pregnancy [RR: 2.74 (95% CI, 1.48-5.06), I2 = 67.7%], and having unplanned pregnancy [RR: 2.73 (95% CI, 2.11-3.53), I2 = 0%] were the major factors associated with perinatal depression. Conclusion: The pooled prevalence of perinatal depression in Ethiopia is far above most developed as well as developing countries. Hence, to realize the sustainable development goals (SDGs) outlined by united nation, much attention should be given to improve maternal mental health through reduction of identified modifiable factors. Maternal health programs, polices, and activities should incorporate maternal mental health as a core component. PMID- 30018822 TI - Association between Obesity, Surgical Route, and Perioperative Outcomes in Patients with Uterine Cancer. AB - Objective: To study temporal trends of hysterectomy routes performed for uterine cancer and their associations with body mass index (BMI) and perioperative morbidity. Methods: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) 2005-2013 databases was conducted. All patients who were 18 years old and older with a diagnosis of uterine cancer and underwent hysterectomy were identified using ICD-9-CM and CPT codes. Surgical route was classified into four groups: total abdominal hysterectomy (TAH), total vaginal hysterectomy (TVH), laparoscopic assisted vaginal hysterectomy (LAVH), and total laparoscopic hysterectomy (TLH) including both conventional and robotically assisted. Patients were then stratified according to BMI. Results: 7199 records were included in the study. TLH was the most commonly performed route of hysterectomy regardless of BMI, with proportions of 50.9%, 48.9%, 50.4%, and 51.2% in ideal, overweight, obese, and morbidly obese patients, respectively. The median operative time for TAH was 2.2 hours compared to 2.7 hours for TLH (p < 0.01). The median length of stay for TAH was 3 days compared to 1 day for TLH (p < 0.01). The percentage of patients with an adverse outcome (composite indicator including transfusion, deep venous thrombosis, and infection) was 17.1 versus 3.7 for TAH and TLH, respectively (p < 0.01). Conclusion: During the last decade, TLH has been increasingly performed in women with uterine cancer. The increased adoption of TLH was seen in all BMI subgroups. PMID- 30018823 TI - Activation, Inhibition, or Something Else: An Exploratory Study on Response Priming Using Moving Dots as Primes in Middle-Aged and Old Adults. AB - Response priming refers to the finding that a prime stimulus preceding a target stimulus influences the response to the following target stimulus. With young subjects, using moving dot stimuli as primes indicated faster responses to compatible targets (i.e., prime and target are associated with the same response) with short stimulus onset asynchronies (SOAs). In contrast, with longer SOAs, participants responded faster to incompatible targets. In the present study, we extended the evidence by comparing middle-aged (50-65 years) and old (66-87 years) adults. With two different motion types, the result found in young participants was replicated in the middle-aged adults. In contrast, old adults showed large positive compatibility effects with the short SOA but neither activation nor inhibition effects with the longer SOA. We discuss our findings in light of several theoretical accounts (i.e., inhibitory deficit, deautomatization, evaluation window account, attention, rapid decay). PMID- 30018824 TI - Validation of Activity Tracking Procedures in Elderly Patients after Operative Treatment of Proximal Femur Fractures. AB - Background: Early postoperative physical activity in elderly patients suffering from proximal femoral fractures may reduce mortality. We hypothesized that activity trackers can reliably and objectively monitor the in-hospital mobilization, correlating with functional independence and quality of life. Methods: Three different tracker types (FitbitTM flex, MisfitTM Shine, and Axivity AX3) at three locations (wrist, ankle, and femur) recorded steps and signal vector magnitudes (SVM) in 22 patients. They were 81 +/- 8 years old, were equally distributed between the sexes, and had an ASA score of 2.5 +/- 0.6. Single protocoled activity events (n = 191) were clinically categorized into 4 levels and correlated with the monitored signals. Additionally, 2 +/- 1 and 8 +/- 3 days after the operation, the EuroQol-5D and the Barthel-20 index supplemented this data. Results: All measurements at the wrist (Fitbit, Misfit) resulted in unacceptable accuracy; however, sensitivity and specificity reached around 90% using the Misfit at the ankle. Applying this combination, the correlation between real and measured steps (R2 = 0.99) and the category discrimination were statistically significant (p < 0.002). A discriminant analysis featured the calculation of four activity levels based on SVM measurements using the Axivity tracker at the femur. A cluster analysis showed a 100% agreement between the clinically observed and the calculated activity levels. The amount of active minutes or periods and both the EuroQol-5D and the Barthel-20 indices significantly increased between the analyzed time points after the operation. However, only the Barthel-20 was associated with the measured activity levels (p < 0.01). Conclusion: The Misfit and the Axivity trackers can reliably monitor activity in elderly patients after operative treatment of proximal femur fractures. However, the wear location is decisive. Objectively measured activity correlated with functional independence and quality of life. PMID- 30018825 TI - Comparisons of the Health Benefits of Strength Training, Aqua-Fitness, and Aerobic Exercise for the Elderly. AB - Objective: To compare strength training, aqua-fitness, and aerobic exercise programs to discern the differences in the benefits achieved by each of the activities in older people. Design: Double-blind randomized trial. Setting: Controlled clinical environment. Participants: 108 people: 54 female paired with a male of the same age (average age of 65.5 +/- 5.6 years). Interventions: Three exercise programs (aqua-fitness, aerobic exercise, and strength training) for six months. Main Outcome Measures: Body Mass Index, Senior Fitness Test (which evaluated functional fitness), and the SF-12 Health Survey. Results: Men showed greater positive changes in the aerobic exercise group for general self-perceived mental health, leg strength, and flexibility of legs and arms. The largest improvements in overall self-perceived physical health and upper limb strength were in the men of the strength training group. The women participants in the strength training group obtained greater benefits, especially in self-perceived mental and physical health and in the strength of the four limbs. Conclusions: To maximise benefits, older people, in general, may want to consider participating in aerobic activity. Furthermore, older women would benefit greatly, both emotionally and physically, from exercise that includes strength training. PMID- 30018826 TI - Investigations into Isoniazid Treated Mycobacterium tuberculosis by Electrospray Mass Spectrometry Reveals New Insights into Its Lipid Composition. AB - Many of the earlier studies involving the effect of isoniazid (INH) treatment have solely focused on the fatty acyl (FA) category of Mycobacterium tuberculosis (MTB) lipids. This motivated us with the major interest to examine the impact of INH on various other categories of MTB lipids. Towards this, we chose to interpret our mass spectral data (LC-ESI-MS) by a standalone software, MS-LAMP, in which "Mtb LipidDB" was integrated. Analysis by MS-LAMP revealed that INH treatment can alter the composition of "glycerolipids (GLs)" and "glycerophospholipids (GPLs)" categories of MTB lipids, in addition to the variations to FA category. Interpretation by "MycoMass" database yielded similar results as that of Mtb LipidDB, except that significant alterations to polyketides (PKs) category also were observed. Probing biosynthetic pathways of certain key lipids belonging to any of GLs, GPLs, and PKs categories can be attractive target(s) for drug discovery or can be useful to identify means to overcome drug resistance or to obtain insights into the causal factors of virulence. To the best of our knowledge, this is the first report hinting at the influence of INH on GLs, GPLs, and PKs of MTB. PMID- 30018828 TI - A Rare Presentation of Cardiac Tamponade from Metastatic Urothelial Carcinoma of the Bladder. AB - A 62-year-old man presented with 2 weeks of progressive dyspnea and chest pain. He was previously diagnosed with high-grade invasive urothelial carcinoma (UC) of the bladder and underwent neoadjuvant chemotherapy followed by radical cystectomy 10 months earlier, resulting in pathologic complete remission. Clinical evaluation and echocardiographic imaging was consistent with a diagnosis of cardiac tamponade. Due to a history of malignancy, the patient was referred for a surgical pericardial window, to include biopsy of the pericardium. Pericardial fluid and pericardial biopsy specimens were consistent with metastatic UC. Cardiac tamponade due to metastatic UC is a rare presentation, and, to our knowledge, there have been only 5 cases reported in the English literature. We report a rare case of cardiac tamponade due to isolated pericardial metastases from high grade UC of the bladder and discuss the symptoms, treatment, and prognosis of this pathologic condition. We also present a brief review of previously published literature. Through this discussion, we would like to emphasize the (1) consideration of cardiac metastases in the differential diagnosis for patients with a history of UC presenting with cardiac or pulmonary symptoms and (2) improved diagnostics with pericardial biopsy and pericardiocentesis over pericardiocentesis alone. PMID- 30018827 TI - Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition. AB - Triple positive breast cancers overexpress both the human epidermal growth factor receptor 2 (HER2) oncogene and the hormonal receptors (HR) to estrogen and progesterone. These cancers represent a unique therapeutic challenge because of a bidirectional cross-talk between the estrogen receptor alpha (ERalpha) and HER2 pathways leading to tumor progression and resistance to targeted therapy. Attempts to combine standard of care HER2-targeted drugs with antihormonal agents for the treatment of HR+/HER2+ breast cancer yielded encouraging results in preclinical experiments but did improve overall survival in clinical trial. In this review, we dissect multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarize prior clinical trials of targeted agents, and describe novel rational drug combinations that include antihormonal agents, HER2 targeted drugs, and CDK4/6 inhibitors for treatment of the HR+/HER2+ breast cancer subtype. PMID- 30018829 TI - Effect of Hemoadsorption for Cytokine Removal in Pneumococcal and Meningococcal Sepsis. AB - Bacterial meningitis and septicemia are invasive bacterial diseases, representing a significant cause of morbidity and mortality worldwide. Both conditions are characterized by an impressive inflammatory response, resulting rapidly in cerebral edema, infarction, hydrocephalus, and septic shock with multiple organ failure. Despite advances in critical care, outcome and prognosis remain critical. Available adjunctive treatments to control the inflammatory response have shown encouraging results in the evolution of patients with sepsis and systemic inflammation, but meningococcal or pneumococcal infection has not been investigated. We herein report five patients with similar critical pathological conditions, characterized by pneumococcal or meningococcal sepsis and treated with hemoadsorption for cytokine removal. All patients showed a progressive stabilization in hemodynamics along with a rapid and marked reduction of catecholamine dosages, a stabilization in metabolic disorders, and less-than expected loss of extremities. Therapy proved to be safe and well tolerated. From this first experience, extracorporeal cytokine removal seems to be a valid and safe therapy in the management of meningococcal and pneumococcal diseases and may contribute to the patient stabilization and prevention of severe sequelae. Further studies are required to confirm efficacy in a larger context. PMID- 30018830 TI - Acquired Factor VIII Inhibitor Presenting as Occult GI Bleeding. AB - An acquired coagulation factor deficiency is characterized by acquired autoantibodies against specific clotting factors in those without diagnosed hemophilia. It is a relatively rare condition with an incidence of approximately one case per million per year. We present a case report of an elderly male who initially presented with an occult GI bleed that was identified with a positive fecal occult blood test result. This is the first case reported to our knowledge of an acquired factor inhibitor deficiency presenting in this manner. We postulate the importance of acquired factor inhibitors in the setting of unexplained anemia given absence of overt clinical symptoms that could contribute to aggravate an established GI bleed, especially in the elderly population. PMID- 30018831 TI - Pyogenic Liver Abscess Caused by Methicillin-Susceptible Staphylococcus aureus in a 21-Year-Old Male. AB - Liver abscesses are the most common types of visceral abscesses. Pyogenic liver abscesses, a particular type of liver abscesses, are uncommonly encountered. We present a rare case of pyogenic liver abscess caused by methicillin-susceptible Staphylococcus aureus in a young man. A 21-year- old man presented from prison to the hospital with fever, nausea, vomiting, diarrhea, and abdominal pain for five days. Labs were significant for leukocytosis with predominant neutrophilia and elevated liver enzymes. CT abdomen with contrast revealed an 8.4 cm multiloculated right hepatic mass extending to the kidney. Patient was started on broad spectrum antibiotics, given septic presentation. Peripheral blood cultures returned positive for methicillin-susceptible Staphylococcus aureus (MSSA). The culture from percutaneous drainage also revealed MSSA. He received a total of four weeks of IV Nafcillin therapy along with drainage of his abscess via percutaneous catheter. Follow-up revealed clinical resolution. This case highlights the importance of obtaining an aspirate from the liver abscess to better guide treatment strategy. Clinicians must consider broadening antibiotic coverage to include gram-positive organisms if the patient presents with severe illness and risk factors for Staphylococcus aureus infections. PMID- 30018832 TI - A Case of Recurrent Erysipelas Caused by Streptococcus mitis Group. AB - The aetiology of erysipelas remains poorly defined though beta-haemolytic streptococci are considered as the main causative pathogens. We describe a case of a 70-year-old woman with recurrent erysipelas in her left arm due to infection with streptococci of the mitis group. Her past medical history includes lymphoedema of the left arm secondary to lymph node dissection due to breast cancer surgery. On seven different occasions during a decade, she has presented a clinical picture of erysipelas and in three of them with Streptococcus mitis group bacteraemia. The results indicate that two cases were caused by Streptococcus mitis and one case was caused by Streptococcus oralis. This is, to our knowledge, the first reported cases of S. mitis and of S. oralis as the causative agents of erysipelas. PMID- 30018833 TI - Successful Pregnancy Outcome after Open Strassman Metroplasty for Bicornuate Uterus. AB - Introduction: Mullerian duct anomalies represent a group of congenital malformations that result from failure to complete bilateral paramesonephric duct elongation, fusion, canalization, or septal resorption. These anomalies are rare in the general population with a bicornuate or didelphys uterus being among the common ones. Bicornuate uterine malformations are of clinical significance due to their adverse reproductive outcomes. Metroplasty has been shown to improve reproductive outcomes of bicornuate uterine malformations. We document a case of bicornuate uterus that was managed with Strassman metroplasty and a subsequent successful pregnancy outcome. Case: A Black African lady was seen with a history of six prior miscarriages. Her diagnostic workup revealed a bicornuate uterus for which she had a Strassman metroplasty performed. She later conceived and was followed up to term with a successful live birth. Conclusion: Strassman metroplasty is a rare procedure in Sub-Saharan Africa and this case seeks to add to the body of knowledge on surgical management of Mullerian duct anomalies specifically bicornuate uterus in this region. This case report aims to increase the awareness of Mullerian duct abnormalities specifically bicornuate uterus in cases of recurrent miscarriages and highlight the diagnostic strategies to investigate and to demonstrate management options in low resource settings. PMID- 30018835 TI - Arthroscopic Osteosynthesis for the Treatment of Coronoid Process Fractures: A Case Series. AB - The treatment strategy and surgical indication for coronoid process fractures are not clear. Many methods of surgery have been described. We report on the use of arthroscopic osteosynthesis for this type of fracture. This method is minimally invasive and effective for confirming the reduction, and it is advantageous for postoperative pain and early recovery after surgery. PMID- 30018834 TI - Bilateral Multiligamentous Knee Injuries: A Case Report and Technique Review. AB - Bilateral knee dislocations are rare musculoskeletal injuries. We report a case of a patient who sustained traumatic bilateral knee dislocations resulting in multiligamentous injuries to both knees. The patient subsequently underwent acute ligamentous reconstructions of both knees performed at 2 weeks and 3 weeks after the initial injury. One year after these procedures, the patient has achieved excellent functional outcomes and has returned to recreational sports. PMID- 30018836 TI - Fracture of a Femoral Revision Stem following a Technical Failure. AB - We report about a fracture of a modular, uncemented femoral revision stem (Zimmer, Revitan(r)) due to a not previously described intraoperative technical problem. During implantation, a small ring, part of the proximal part of the trial stem, was left on the distal part of the definite stem. Following this, the top screwcap of the proximal part of the definite stem could not be tightened properly. However, the stem was thought to be stable, and the situation left. Two and a half years later, the proximal part of the stem fractured and the situation became unstable. It is very useful to know about this ring and that it should always be removed, otherwise, there is possibility that it may be left on the definite distal part of the stem with the possibility of a later fracture. PMID- 30018838 TI - The System Is All Holes and No Cheese. AB - A recent article in the Chicago Tribune revealed systematic failures among many retail pharmacies in detecting drug-drug interactions. This begs questions of what gaps exist in the current system of prescribing oral oncolytics and what advanced practitioners can do to keep patients safe. PMID- 30018837 TI - Retrospondyloptosis of the Spine Secondary to Nonaccidental Trauma. AB - Spinal fracture rates from NAT have been reported in <1-3% of spinal injury cases. We present a 13-month-old female who presented with signs of spinal cord injury and was found to have complete retrospondylolisthesis of T12 vertebra and multiple rib fractures in various stages of healing due to NAT. This case reports an extremely severe spinal injury due to NAT of which there are few in the literature and highlights the importance of suspicion of NAT when pediatric patients present with neurologic symptoms and spinal trauma without plausible mechanism of injury. PMID- 30018839 TI - The Federal 'Right To Try' Act: An Answer to New Treatments During Terminal Illness? AB - The newly proposed Federal "Right to Try" Act permits terminally ill patients to try experimental therapies that have completed phase I testing but have not been approved by the FDA. However, there are concerning provisions of the legislature regarding liability and costs. PMID- 30018840 TI - The Relationship Between Zinc and Quality of Life in Patients With Upper GI Cancer on Chemotherapy. AB - This is a pilot study aimed at evaluating the prevalence of zinc deficiency and how zinc levels affect the quality of life (QOL) of patients with upper gastrointestinal (GI) cancers receiving systemic chemotherapy. The data collection was completed on 40 patients. Although the primary objective of a positive prevalence of zinc deficiency in upper GI cancer patients at diagnosis and after receiving chemotherapy is not statistically significant, we found a statistically significant association between zinc level and certain QOL factors. There is a significantly positive association with satisfaction of social contact at baseline only, sexual pleasure at baseline and at 2 months, QOL at baseline only, and troublesome sweating at baseline, and from baseline to 2 months corresponding with change in other skin problems. Conversely, there is a significantly negative association corresponding changes in enjoyment of physical activities, how the patient usually feels, sexual pleasure, the way in which the patient approaches food, QOL, rashes on the face, and other skin problems. Neutropenia grades were reflective of decreased zinc at baseline but did not show decreased zinc correlating with a weakened immune system. PMID- 30018841 TI - Comparison of Outcome Measures for Traditional and Online Support Groups for Breast Cancer Patients: An Integrative Literature Review. AB - Despite widespread use of support groups in the breast cancer patient population, there are heterogeneous outcome measurements and inconsistencies in their perceived benefits. The purpose of this integrative literature review is to compare the efficacies of traditional and online support groups for breast cancer survivors through analysis of outcome measurements and determination of strengths and weaknesses. After examining the literature, it was found that online support groups are ideal for women who require additional support or who are unable to attend a traditional group. Alternatively, traditional support groups allow for discussion and support tailored to specific cultures and are especially beneficial when a breast cancer survivor is included in the process. These findings suggest that because both traditional and online support groups have unique roles in the psychosocial support of female breast cancer survivors, individual preferences and needs should be considered when determining which support groups will be beneficial. PMID- 30018842 TI - Integrating Emerging Data Into Clinical Practice: A Case-Based Approach for Multiple Myeloma. AB - Selected Patient Cases From the APSHO Regional Lecture SeriesINTRODUCTION As the official publication of the Advanced Practitioner Society for Hematology and Oncology (APSHO), JADPRO is pleased to offer Part 2 of an accredited educational activity based on the recently concluded APSHO Regional Lecture Series. Hosted in collaboration with major cancer centers around the country, the APSHO Regional Lecture Series brought case-based didactic presentations and skills workshops to advanced practitioners. In the spirit of JADPRO, three accredited Grand Rounds articles by Beth Eaby-Sandy, MSN, CRNP, OCN(r) (non-small cell lung cancer) and Sandra Kurtin, PhDc, ANP-C, AOCN(r) (multiple myeloma and chronic lymphocytic leukemia)-program chairs for the regional lecture series-offer the same practice changing information and strategies for advanced practitioners. In this Grand Rounds article, program chair Sandra Kurtin gives a comprehensive overview of the most recent developments in multiple myeloma research from the 2016 American Society of Hematology (ASH) Annual Meeting and clinical insight in the management of patients with this disease. You can read Part 1 in the March 2017 issue of JADPRO or online at advancedpractitioner.com, and be sure to keep an eye out for Part 3 in a future issue of JADPRO. Check out apsho.org/lectures for information on registering for upcoming JADPRO Regional Lectures this year at a location near you. PMID- 30018843 TI - Palliative Chemotherapy: Does It Only Provide False Hope? The Role of Palliative Care in a Young Patient With Newly Diagnosed Metastatic Adenocarcinoma. AB - Case Study A 48-year-old female with recent diagnosis of adenocarcinoma of unknown origin and metastatic disease to the peritoneum initially presented to a nearby academic hospital with abdominal pain. She underwent exploratory laparotomy with tumor debulking surgery at that time. Shortly thereafter, she was readmitted to the same hospital with evidence of partial small bowel obstruction and treated conservatively with bowel rest, nasogastric (NG) tube placement, and intravenous (IV) fluid administration. Eventually the NG tube was removed, and she was discharged home. The following day, she received cycle one of palliative chemotherapy with cisplatin and gemcitabine at her local outpatient oncology clinic. She experienced persistent nausea and intermittent vomiting throughout the night and presented to our local community hospital for evaluation. At the time of admission, she was passing minimal flatus and had passed only a small bowel movement that morning. She had experienced nausea, vomiting, and poor oral intake for over a week. Other presenting symptoms included mild to moderate abdominal pain involving the upper abdomen. Upon evaluation, abdominal x-ray revealed dilated loops of small bowel, consistent with partial small bowel obstruction. An NG tube was placed, and the patient's symptoms were initially improved with bowel rest. Her medical history was significant for pulmonary embolism detected at the time of her adenocarcinoma diagnosis, and she was on oral anticoagulation and home oxygen. She also had a history of depression and total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO) due to fibroids. Her social history revealed she was an office worker and married with two sons, ages 18 and 24. The 18-year-old son lived at home with the patient and her husband. The patient was eagerly awaiting the birth of a granddaughter, due in a few weeks' time. Her mother and father were also present daily during her hospitalization and were a major source of support for her and her family. At the time of hospital admission, a surgical team consultation concluded she was not a candidate for palliative surgery due to extensive disease burden. She was seen in consultation by medical oncology, who recommended resuming chemotherapy once the acute partial small- bowel obstruction resolved. Palliative Care Consult A palliative care consultation was requested to assist with symptom management, including pain and nausea relief. At the time of consultation, the patient appeared in mild distress due to abdominal pain and distention. Vital signs were stable. Physical exam was significant for absent bowel sounds and a mildly distended but nontender abdomen. The NG tube was in place, draining bilious gastric fluid. She had mild nonpitting edema involving the bilateral lower extremities. Discussion with the patient revealed values consistent with improving symptoms and extending life expectancy as long as possible. The patient expressed wishes for "aggressive treatment," which she defined as continuation of chemotherapy and full resuscitation. The palliative care team discussed symptom management options with the patient. Nonsurgical management of partial bowel obstruction was continued, including bowel rest, NG tube decompression, and IV fluids. Pain was controlled initially with IV morphine as needed. After symptom improvement and evidence of bowel function recovery, the NG tube was removed. However, after a short time, she required NG tube replacement due to recurrent nausea and vomiting. Discussion was initiated with the patient, who opted for placement of a venting gastrostomy tube (G-tube) and total parenteral nutrition (TPN), with the goal of symptom relief and administration of nutrition, which would allow for continuation of chemotherapy. During placement of the venting G tube, the gastroenterology (GI) team noted extensive tumor involving the stomach, which made placement of the tube difficult. Additionally, anticoagulation was held during G-tube placement, and postoperatively, the patient experienced acute, right-sided chest pain and shortness of breath. Computed tomography (CT) scan with pulmonary embolus (PE) protocol revealed a new PE, and anticoagulation was changed to enoxaparin. Shortly thereafter, she became febrile and developed leukocytosis. Blood cultures revealed coagulase-negative staphylococcus from a Port-a-Cath source. She was treated with appropriate antibiotic therapy; however, follow-up blood cultures revealed persistent coagulase-negative staphylococcus bacteremia. Her indwelling Port-a-Cath was removed. After appropriate antibiotic therapy, a peripherally inserted central catheter line was inserted and TPN restarted. Reinstituting Palliative Chemotherapy Palliative care discussion with the patient confirmed her desire to reinstitute palliative chemotherapy, with the goal of restoring bowel function and returning home. Chemotherapy was resumed on day 15, despite concerns and even objections from several nursing staff members. The patient experienced treatment side effects, including prolonged thrombocytopenia. A platelet function antibody returned positive, consistent with heparin-induced thrombocytopenia. Enoxaparin was discontinued, and fondaparinux (Arixtra) was initiated. Platelet count recovered shortly thereafter. The patient required intense symptom management due to intractable abdominal pain and nausea and vomiting despite adequate venting G-tube decompression. Medical management was maximized with antiemetics, antisecretory agents, steroids, and antipsychotic agents, and symptoms eventually improved after cycle 2 of chemotherapy. Thereafter, the patient was discharged home. At the time of discharge, her symptoms were well controlled on minimal pain medications. She was still experiencing intermittent nausea but was passing flatus. By reducing the tumor burden, chemotherapy significantly improved her quality of life. She spent a total of 7 weeks in the hospital. During that time, she received two cycles of chemotherapy plus best supportive care and symptom management. Despite intermittent nausea and vomiting, administration of palliative chemotherapy allowed this patient to achieve her primary goals, which included returning home to her family and regaining some bowel function. Over the next several months, she received several more cycles of outpatient palliative chemotherapy. She experienced mild to moderate nausea and intermittent vomiting despite G-tube venting. Eventually, her disease progressed, and the patient chose to forgo any further intervention or chemotherapy. She was enrolled in hospice care and died comfortably at home surrounded by her family. PMID- 30018844 TI - The Challenges of Clinical Research in Rare Cancers: Bevacizumab Use in Low-Grade Serous Ovarian and Primary Peritoneal Cancers. AB - There are challenges to conducting rare cancer clinical trials due to issues surrounding clinical trial design, patient recruitment, and analysis of the study outcomes. This article highlights the challenges of research and data analysis in rare cancers and proposes future study directions using less traditional approaches. PMID- 30018845 TI - Atypical Femoral Fractures: Implications for the Advanced Practitioner in Oncology. AB - Bone-health issues may arise for oncology patients as a side effect of their treatments. One of these may be the development of an atypical femoral fracture. Advanced practitioners should be aware of the risk factors for atypical femoral fractures, and be able to promptly recognize signs, provide patient education, and manage them competently. PMID- 30018846 TI - Ixazomib: An Oral Proteasome Inhibitor for the Treatment of Multiple Myeloma. AB - The FDA approval of ixazomib for use in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least one prior therapy signalled the arrival of the first oral proteasome inhibitor, allowing advanced practitioners to provide multiple myeloma patients an exclusively oral triplet therapy. PMID- 30018847 TI - Establishing an Individual Writing Practice. AB - Do you have a topic in mind for a manuscript but can't find the time or motivation to write it? This article provides step-by-step directions to encourage you to prioritize and plan your writing schedule. PMID- 30018848 TI - Intracellular Deprotection Reactions Mediated by Palladium Complexes Equipped with Designed Phosphine Ligands. AB - Discrete palladium(II) complexes featuring purposely designed phosphine ligands can promote depropargylation and deallylation reactions in cell lysates. These complexes perform better than other palladium sources, which apparently are rapidly deactivated in such hostile complex media. This good balance between reactivity and stability allows the use of these discrete phosphine palladium complexes in living mammalian cells, whereby they can mediate similar transformations. The presence of a phosphine ligand in the coordination sphere of palladium also provides for the introduction of targeting groups, such as hydrophobic phosphonium moieties, which facilitate the accumulation of the complexes in mitochondria. PMID- 30018849 TI - Use of design of experiments to optimize the production of microbial probiotic biofilms. AB - Here, we describe the production of a probiotic biofilm through three intermediate steps: (1) measurement of the adhesion capacity of 15 probiotic strains to evaluate their tendency to form biofilm on different surfaces (stainless steel, glass, and polycarbonate); (2) evaluation of the effects of pH, temperature, cellular growth phase, agitation, and presence of surfactants on probiotic biofilm formation (BF) through the Design of Experiments (DoE) approach; (3) study of the effects of pH, temperature and surfactants concentration on probiotic BF using the Central Composite Design. Finally, we show that biofilms pre-formed by selected probiotics can delay the growth of pathogens, such as Listeria monocytogenes chosen as model organism. Among the tested strains, Bifidobacterium infantis DSM20088 and Lactobacillus reuteri DSM20016 were found to be as the probiotics able to ensure the greatest adhesion (over 6 Log CFU cm2) to the surfaces tested in a very short time (<24 h). Cellular growth phase and agitation of the medium were factors not affecting BF, pH exerted a very bland effect and a greater tendency to adhesion was observed when the temperature was about 30 degrees C. The results obtained in the last experimental phase suggest that our probiotic biofilms can be used as an efficient mean to delay the growth of L. monocytogenes: the lambda phase length, in fact, was longer in samples containing probiotic biofilms (0.30-1.02 h) against 0.08 h observed in the control samples. A reduction of the maximum cell load was also observed (6.99-7.06 Log CFU mL-1 against about 8 Log CFU mL-1 observed in the control samples). PMID- 30018850 TI - 3D skeletal muscle fascicle engineering is improved with TGF-beta1 treatment of myogenic cells and their co-culture with myofibroblasts. AB - Background: Skeletal muscle wound healing is dependent on complex interactions between fibroblasts, myofibroblasts, myogenic cells, and cytokines, such as TGF beta1. This study sought to clarify the impact of TGF-beta1 signaling on skeletal muscle cells and discern between the individual contributions of fibroblasts and myofibroblasts to myogenesis when in co-culture with myogenic cells. 3D tissue engineered models were compared to equivalent 2D culture conditions to assess the efficacy of each culture model to predictively recapitulate the in vivo muscle environment. Methods: TGF-beta1 treatment and mono-/co-cultures containing human dermal fibroblasts or myofibroblasts and C2C12 mouse myoblasts were assessed in 2D and 3D environments. Three culture systems were compared: cell monolayers grown on 2D dishes and 3D tissues prepared via a self-assembly method or collagen 1-based hydrogel biofabrication. qPCR identified gene expression changes during fibroblast to myofibroblast and myoblast differentiation between culture conditions. Changes to cell phenotype and tissue morphology were characterized via immunostaining for myosin heavy chain, procollagen, and alpha-smooth muscle actin. Tissue elastic moduli were measured with parallel plate compression and atomic force microscopy systems, and a slack test was employed to quantify differences in tissue architecture and integrity. Results: TGF-beta1 treatment improved myogenesis in 3D mono- and co-cultures containing muscle cells, but not in 2D. The 3D TGF-beta1-treated co-culture containing myoblasts and myofibroblasts expressed the highest levels of myogenin and collagen 1, demonstrating a greater capacity to drive myogenesis than fibroblasts or TGF beta1-treatment in monocultures containing only myoblasts. These constructs possessed the greatest tissue stability, integrity, and muscle fiber organization, as demonstrated by their rapid and sustained shortening velocity during slack tests, and the highest Young's modulus of 6.55 kPA, approximate half the stiffness of in situ muscle. Both self-assembled and hydrogel-based tissues yielded the most multinucleated, elongated, and aligned muscle fiber histology. In contrast, the equivalent 2D co-culture model treated with TGF-beta1 completely lacked myotube formation through suppression of myogenin gene expression. Discussion: These results show skeletal muscle regeneration can be promoted by treating myogenic cells with TGF-beta1, and myofibroblasts are superior enhancers of myogenesis than fibroblasts. Critically, both TGF-beta1 treatment and co culturing skeletal muscle cells with myofibroblasts can serve as myogenesis accelerators across multiple tissue engineering platforms. Equivalent 2D culture systems cannot replicate these affects, however, highlighting a need to continually improve in vitro models for skeletal muscle development, discovery of therapeutics for muscle regeneration, and research and development of in vitro meat products. PMID- 30018851 TI - Evidence of avian-mediated long distance dispersal in American tardigrades. AB - Terrestrial tardigrades, commonly known as "water bears", are part of a phylum of microscopic, aquatic invertebrates famous for cryptobiosis and space travel, but little is known about their modes of dispersal on Earth. Wind is assumed, but not truly demonstrated, to be the major method of global dispersal. Yet, some water bear distribution patterns cannot be explained by patterns of prevailing winds. Mammals and birds have been proposed as potential animal vectors. Importantly, most nearctic-neotropical migrant birds move north and south, with many crossing the equator, whereas prevailing winds move west to east or east to west but do not cross the equator. When multiplied by billions of birds over tens of millions of years, if the ectozoochory of tardigrades by birds is true then both regional and intercontinental patterns can be better explained. To test for the potential role of birds in tardigrade dispersal, the nests of 10 species for birds were examined. Seventy percent of nests were positive for tardigrades, demonstrating that some birds are in a position for transference. The carcasses of eight birds (six species) found dead from window strikes and a Sandhill Crane (Grus canadensis) found dead during routine surveys were also examined. Of the birds examined, 66% yielded tardigrades from two classes, three orders, and five species, including juveniles, adults, and eggs, suggesting that many bird species are potential vectors for many species of tardigrades. Our data support the hypothesis of avian-mediated long distance dispersal of tardigrades and provide evidence that further investigation is warranted. PMID- 30018852 TI - MIRU-profiler: a rapid tool for determination of 24-loci MIRU-VNTR profiles from assembled genomes of Mycobacterium tuberculosis. AB - Background: Tuberculosis (TB) resulted in an estimated 1.7 million deaths in the year 2016. The disease is caused by the members of Mycobacterium tuberculosis complex, which includes Mycobacterium tuberculosis, Mycobacterium bovis and other closely related TB causing organisms. In order to understand the epidemiological dynamics of TB, national TB control programs often conduct standardized genotyping at 24 Mycobacterial-Interspersed-Repetitive-Units (MIRU)-Variable Number-of-Tandem-Repeats (VNTR) loci. With the advent of next generation sequencing technology, whole-genome sequencing (WGS) has been widely used for studying TB transmission. However, an open-source software that can connect WGS and MIRU-VNTR typing is currently unavailable, which hinders interlaboratory communication. In this manuscript, we introduce the MIRU-profiler program which could be used for prediction of MIRU-VNTR profile from WGS of M. tuberculosis. Implementation: The MIRU-profiler is implemented in shell scripting language and depends on EMBOSS software. The in-silico workflow of MIRU-profiler is similar to those described in the laboratory manuals for genotyping M. tuberculosis. Given an input genome sequence, the MIRU-profiler computes alleles at the standard 24 loci based on in-silico PCR amplicon lengths. The final output is a tab-delimited text file detailing the 24-loci MIRU-VNTR pattern of the input sequence. Validation: The MIRU-profiler was validated on four datasets: complete genomes from NCBI-GenBank (n = 11), complete genomes for locally isolated strains sequenced using PacBio (n = 4), complete genomes for BCG vaccine strains (n = 2) and draft genomes based on 250 bp paired-end Illumina reads (n = 106). Results: The digital MIRU-VNTR results were identical to the experimental genotyping results for complete genomes of locally isolated strains, BCG vaccine strains and five out of 11 genomes from the NCBI-GenBank. For draft genomes based on short Illumina reads, 21 out of 24 loci were inferred with a high accuracy, while a number of inaccuracies were recorded for three specific loci (ETRA, QUB11b and QUB26). One of the unique features of the MIRU-profiler was its ability to process multiple genomes in a batch. This feature was tested on all complete M. tuberculosis genome (n = 157), for which results were successfully obtained in approximately 14 min. Conclusion: The MIRU-profiler is a rapid tool for inference of digital MIRU-VNTR profile from the assembled genome sequences. The tool can accurately infer repeat numbers at the standard 24 or 21/24 MIRU-VNTR loci from the complete or draft genomes respectively. Thus, the tool is expected to bridge the communication gap between the laboratories using WGS and those using the conventional MIRU-VNTR typing. PMID- 30018853 TI - Effects of environmental hypoxia and hypercarbia on ventilation and gas exchange in Testudines. AB - Background: Ventilatory parameters have been investigated in several species of Testudines, but few species have had their ventilatory pattern fully characterized by presenting all variables necessary to understand changes in breathing pattern seen under varying environmental conditions. Methods: We measured ventilation and gas exchange at 25 degrees C in the semi-aquatic turtle Trachemys scripta and the terrestrial tortoise Chelonoidis carbonarius under normoxia, hypoxia, and hypercarbia and furthermore compiled respiratory data of testudine species from the literature to analyze the relative changes in each variable. Results: During normoxia both species studied showed an episodic breathing pattern with two to three breaths per episode, but the non-ventilatory periods (TNVP) were three to four times longer in T. scripta than in C. carbonarius. Hypoxia and hypercarbia significantly increased ventilation in both species and decreased TNVP and oxygen consumption in T. scripta but not in C. carbonarius. Discussion: Contrary to expectations, the breathing pattern in C. carbonarius did show considerable non-ventilatory periods with more than one breath per breathing episode, and the breathing pattern in T. scripta was found to diverge significantly from predictions based on mechanical analyses of the respiratory system. A quantitative analysis of the literature showed that relative changes in the ventilatory patterns of chelonians in response to hypoxia and hyperbarbia were qualitatively similar among species, although there were variations in the magnitude of change. PMID- 30018854 TI - 'We like it wet': a comparison between dissection techniques for the assessment of parity in Anopheles arabiensis and determination of sac stage in mosquitoes alive or dead on collection. AB - Background: The determination of parous rates in mosquitoes, despite numerous shortcomings, remains a tool to evaluate the effectiveness of control programs and to determine vectorial capacity in malaria vectors. Two dissection techniques are used for this. For one, the tracheoles of dried ovaries are examined with a compound microscope and in the other the follicular stalk of ovaries is examined, wet, with a stereomicroscope. The second method also enables the sac stage of parous insects (which provides information on the duration of the oviposition cycle) and the mated status of insects to be determined. Despite widespread use the two techniques have not previously been compared. Methods: We compared the two dissection techniques using Anopheles arabiensis, collected with a tent-trap in Eritrea. The paired ovaries were removed in water and one was examined by each method. From a separate set of dissections from Tanzania, we also determined if the sac stages of Anopheles gambiae s.l. (83% of 183 identified by PCR being Anopheles arabiensis the remainder being A. gambiae) that were alive on collection were different to those that died on collection and what the implications for vectorial capacity estimation might be. Results: Seven per cent of the dry ovaries could not be classified due to granulation (yolk) in the ovariole that obscured the tracheoles. The sensitivity of the dry dissection was 88.51% (CI [79.88-94.35%]) and the specificity was 93.55% (CI [87.68-97.17%]) among the 211 ovaries that could be classified by the dry technique and compared to the ovaries dissected wet. 1,823 live and 1,416 dead from Furvela tent-traps, CDC light-trap and window-trap collections were dissected 'wet' from Tanzania. In these collections parous insects were more likely to die compared to nulliparous ones. The proportion of parous mosquitoes with 'a' sacs (indicative of recent oviposition) was significantly greater in insects that were dead (0.36) on collection in the morning compared to those that were alive (0.12) (Chi square 138.93, p < 0.001). There was a preponderance of newly emerged virgin insects in the outdoor collection (Chi sq = 8.84, p = 0.003). Conclusions: In anophelines the examination of mosquito ovaries using transmitted light in a 'wet' dissection is a more useful and informative technique than examination of dry ovaries. In order to correctly estimate the duration of the oviposition cycle mosquitoes should be dissected as soon as possible after collection. Younger insects were more likely to attempt to feed outdoors rather than indoors. PMID- 30018855 TI - Exercise can improve sleep quality: a systematic review and meta-analysis. AB - Background: Insomnia is common. However, no systematic reviews have examined the effect of exercise on patients with primary and secondary insomnia, defined as both sleep disruption and daytime impairment. This systematic review and meta analysis aimed to examine the effectiveness/efficacy of exercise in patients with insomnia. Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to identify all randomized controlled trials that examined the effects of exercise on various sleep parameters in patients with insomnia. All participants were diagnosed with insomnia, using standard diagnostic criteria or predetermined criteria and standard measures. Data on outcome measures were subjected to meta-analyses using random-effects models. The Cochrane Risk of Bias Tool and Grading of Recommendations, Assessment, Development, and Evaluation approach were used to assess the quality of the individual studies and the body of evidence, respectively. Results: We included nine studies with a total of 557 participants. According to the Pittsburgh Sleep Quality Index (mean difference [MD], 2.87 points lower in the intervention group; 95% confidence interval [CI], 3.95 points lower to 1.79 points lower; low-quality evidence) and the Insomnia Severity Index (MD, 3.22 points lower in the intervention group; 95% CI, 5.36 points lower to 1.07 points lower; very low-quality evidence), exercise was beneficial. However, exercise interventions were not associated with improved sleep efficiency (MD, 0.56% lower in the intervention group; 95% CI, 3.42% lower to 2.31% higher; moderate-quality evidence). Only four studies noted adverse effects. Most studies had a high or unclear risk of selection bias. Discussion: Our findings suggest that exercise can improve sleep quality without notable adverse effects. Most trials had a high risk of selection bias. Higher quality research is needed. PMID- 30018856 TI - Evaluation of standard imaging techniques and volumetric preservation of nervous tissue in genetically identical offspring of the crayfish Procambarus fallax cf. virginalis (Marmorkrebs). AB - In the field of comparative neuroanatomy, a meaningful interspecific comparison demands quantitative data referring to method-specific artifacts. For evaluating the potential of state-of-the-art imaging techniques in arthropod neuroanatomy, micro-computed X-ray microscopy (MUCT) and two different approaches using confocal laser-scanning microscopy (cLSM) were applied to obtain volumetric data of the brain and selected neuropils in Procambarus fallax forma virginalis (Crustacea, Malacostraca, Decapoda). The marbled crayfish P. fallax cf. virginalis features a parthogenetic reproduction generating genetically identical offspring from unfertilized eggs. Therefore, the studied organism provides ideal conditions for the comparative analysis of neuroanatomical imaging techniques and the effect of preceding sample preparations of nervous tissue. We found that wet scanning of whole animals conducted with MUCT turned out to be the least disruptive method. However, in an additional experiment it was discovered that fixation in Bouin's solution, required for MUCT scans, resulted in an average tissue shrinkage of 24% compared to freshly dissected and unfixed brains. The complete sample preparation using fixation in half-strength Karnovsky's solution of dissected brains led to an additional volume decrease of 12.5%, whereas the preparation using zinc-formaldehyde as fixative resulted in a shrinkage of 5% in comparison to the volumes obtained by MUCT. By minimizing individual variability, at least for aquatic arthropods, this pioneer study aims for the inference of method-based conversion factors in the future, providing a valuable tool for reducing quantitative neuroanatomical data already published to a common denominator. However, volumetric deviations could be shown for all experimental protocols due to methodological noise and/or phenotypic plasticity among genetically identical individuals. MicroCT using undried tissue is an appropriate non-disruptive technique for allometry of arthropod brains since spatial organ relationships are conserved and tissue shrinkage is minimized. Collecting tissue based shrinkage factors according to specific sample preparations might allow a better comparability of volumetric data from the literature, even if another technique was applied. PMID- 30018857 TI - Progress in the discovery of amphipod crustaceans. AB - At present, amphipod crustaceans comprise 9,980 species, 1,664 genera, 444 subfamilies, and 221 families. Of these, 1,940 species (almost 20%) have been discovered within the last decade, including 18 fossil records for amphipods, which mostly occurred in Miocene amber and are probably all freshwater species. There have been more authors describing species since the 1950s and fewer species described per author since the 1860s, implying greater taxonomic effort and that it might be harder to find new amphipod species, respectively. There was no evidence of any change in papers per author or publication life-times of taxonomists over time that might have biased apparent effort. Using a nonhomogeneous renewal process model, we predicted that by the year 2100, 5,600 to 6,600 new amphipod species will be discovered. This indicates that about two thirds of amphipods remain to be discovered which is twice the proportion than for species overall. Amphipods thus rank amongst the least well described taxa. To increase the prospect of discovering new amphipod species, studying undersampled areas and benthic microhabitats are recommended. PMID- 30018858 TI - Experimental and molecular approximation to microbial niche: trophic interactions between oribatid mites and microfungi in an oligotrophic freshwater system. AB - Mite-fungal interactions play a key role in structuring core ecosystem processes such as nutrient dynamics. Despite their ecological relevance, these cross kingdom interactions remain poorly understood particularly in extreme environments. Herein, we investigated feeding preferences of a novel genetic lineage of aquatic oribatids obtained from an oligotrophic freshwater system in the Cuatro Cienegas Basin (CCB) within the Chihuahuan Desert, Mexico. During in vitro diet preference bioassays, transient aquatic microfungi (Aspergillus niger, Talaromyces sp., and Pleosporales sp.) recovered from the same mesocosm samples were offered individually and simultaneously to mites. Gut content was analyzed using classic plating and culture-independent direct PCR (focusing on the fungal barcoding region) methods. Our results indicated that oribatids fed on all tested fungal isolates, yet the profusely developing A. niger was preferentially consumed with all fungal components being digested. This feeding habit is particularly interesting since A. niger has been reported as an unsuitable dietary element for population growth, being consistently avoided by mites in previous laboratory experiments. It is possible that our mites from the CCB have adapted to exploit available resources within this oligotrophic site. This work confirms the trophic relationship between microfungi and mites, two rarely investigated major components of the microbial community, shedding light on the niche dynamics under low-nutrient conditions. PMID- 30018859 TI - Nickel and cobalt resistance properties of Sinorhizobium meliloti isolated from Medicago lupulina growing in gold mine tailing. AB - Sinorhizobium meliloti CCNWSX0020, isolated from root nodules of Medicago lupulina growing in gold mine tailings in the northwest of China, displayed multiple heavy metal resistance and growth promotion of M. lupulina. In our previous work, the expression level of dmeR and dmeF genes were induced by Cu2+ through comparative transcriptome approach. Based on protein analysis, the dmeF encoded for a protein which showed a 37% similarity to the cation transporter DmeF of Cupriavidus metallidurans, whereas dmeR encoded transcriptional regulator which was highly homologous with DmeR belonging to RcnR/CsoR family metal responsive transcriptional regulator. In addition to copper, quantitative real time PCR analysis showed that dmeR and dmeF were also induced by nickel and cobalt. To investigate the functions of dmeR and dmeF in S. meliloti CCNWSX0020, the dmeR and dmeF deletion mutants were constructed. The dmeF mutant was more sensitive to Co2 + and Ni2 + than the wild type strain. Pot experiments were carried out to determine whether the growth of M. lupulina was affected when the dmeF gene was knocked out in the presence of nickel or cobalt. Results indicated that the nodule number of the host plant inoculated with the dmeF deletion mutant was significantly less than the S. meliloti CCNWSX0020 wild-type in the presence of Co2 + or Ni2 +. However, when standardized by nodule fresh weight, the nitrogenase activities of nodules infected by the dmeF deletion mutant was similar to nitrogenase activity of the wild type nodule. PMID- 30018860 TI - Digging the compromise: investigating the link between limb bone histology and fossoriality in the aardvark (Orycteropus afer). AB - Bone microstructure has long been known as a powerful tool to investigate lifestyle-related biomechanical constraints, and many studies have focused on identifying such constraints in the limb bones of aquatic or arboreal mammals in recent years. The limb bone microstructure of fossorial mammals, however, has not been extensively described. Furthermore, so far, studies on this subject have always focused on the bone histology of small burrowers, such as subterranean rodents or true moles. Physiological constraints associated with digging, however, are known to be strongly influenced by body size, and larger burrowers are likely to exhibit a histological profile more conspicuously influenced by fossorial activity. Here, we describe for the first time the limb bone histology of the aardvark (Orycteropus afer), the largest extant burrowing mammal. The general pattern is very similar for all six sampled limb bones (i.e., humerus, radius, ulna, femur, tibia, and fibula). Most of the cortex at midshaft is comprised of compacted coarse cancellous bone (CCCB), an endosteal tissue formed in the metaphyses through the compaction of bony trabeculae. Conversely, the periosteal bone is highly resorbed in all sections, and is reduced to a thin outer layer, suggesting a pattern of strong cortical drift. This pattern contrasts with that of most large mammals, in which cortical bone is of mostly periosteal origin, and CCCB, being a very compliant bone tissue type, is usually resorbed or remodeled during ontogeny. The link between histology and muscle attachment sites, as well as the influence of the semi-arid environment and ant eating habits of the aardvark on its bone microstructure, are discussed. We hypothesize that the unusual histological profile of the aardvark is likely the outcome of physiological constraints due to both extensive digging behavior and strong metabolic restrictions. Adaptations to fossoriality are thus the result of a physiological compromise between limited food availability, an environment with high temperature variability, and the need for biomechanical resistance during digging. These results highlight the difficulties of deciphering all factors potentially involved in bone formation in fossorial mammals. Even though the formation and maintaining of CCCB through ontogeny in the aardvark cannot be unambiguously linked with its fossorial habits, a high amount of CCCB has been observed in the limb bones of other large burrowing mammals. The inclusion of such large burrowers in future histological studies is thus likely to improve our understanding of the functional link between bone growth and fossorial lifestyle in an evolutionary context. PMID- 30018861 TI - Avian community characteristics and demographics reveal how conservation value of regenerating tropical dry forest changes with forest age. AB - Expansion of secondary forests following the abandonment of agriculture may have important implications for bird conservation, but few studies have examined the dynamics of this process. We studied bird use of a chronosequence of differently aged abandoned pastures regenerating to dry forest to better understand how the value of these habitats to birds changes over time. In a five year study on Hispaniola, we recorded 7,315 net captures of 60 species of landbirds in sites that began the study at two, five, 10, and 20 years post-abandonment, and in mature native dry forest. Twenty-five species made up 97% of all net captures. Highest capture rates were in the two youngest sites. These early-successional habitats had many over-wintering Neotropical migrants; among residents, granivores and frugivores predominated. In contrast, both the twenty-year-old and mature forest sites had few migrants, more resident insectivores and omnivorous species, and a greater proportion of endemics. Age and sex ratios, body condition and site persistence suggest early successional sites were sub-optimal for most over-wintering migrants, but habitat improved with age for three migratory species; results for permanent residents varied among species. Remnant trees and understory shrubs in the agroecological matrix likely contributed to avian diversity in regenerating dry forest sites, and proximity to mature forest also likely affected the diversity and abundance of birds in regenerating habitat. Our study shows that regenerating forests do not fully compensate for loss of mature dry forest habitat, even after 24 years of regeneration; natural restoration of complex microhabitats in dry forest sites converted to agriculture may take decades or longer. The highest value of regenerating forests may be as habitat for some over-wintering Neotropical migrants, and in creating a buffer zone that enhances biodiversity conservation by re-integrating these lands into the protected tracts of mature forest needed by the islands more unique and endemic bird species. PMID- 30018862 TI - Linkages between soil carbon, soil fertility and nitrogen fixation in Acacia senegal plantations of varying age in Sudan. AB - Background: Over the last decades sub-Saharan Africa has experienced severe land degradation and food security challenges linked to loss of soil fertility and soil organic matter (SOM), recurrent drought and increasing population. Although primary production in drylands is strictly limited by water availability, nutrient deficiencies, particularly of nitrogen (N) and phosphorus (P), are also considered limiting factors for plant growth. It is known that SOM (often measured as soil organic carbon (SOC)) is a key indicator of soil fertility, therefore, management practices that increase SOM contents, such as increasing tree cover, can be expected to improve soil fertility. The objectives of this study were to investigate the effect of Acacia senegal (Senegalia senegal) trees on soil nitrogen, phosphorus and potassium (K) in relation to SOC, the potential of A. senegal for N2 fixation, and to identify possible N and P ecosystem limitations. Methods: Soil nutrient (total N, P, K and available P and exchangeable K) concentrations and stocks were determined for the 0-10, 10-20,20 30 and 30-50 cm layers of A. senegal plantations of varying age (ranging from 7 to 24-years-old) and adjacent grasslands (reference) at two sites in semi-arid areas of Sudan. At both sites, three plots were established in each grassland and plantation. The potential of A. senegal for N2 fixation in relation to plantations age was assessed using delta15N isotopic abundances and nutrient limitations assessed using C:N:P stoichiometry. Results: Soil concentrations of all studied nutrients were relatively low but were significantly and directly correlated to SOC concentrations. SOC and nutrient concentrations were the highest in the topsoil (0-10 cm) and increased with plantations age. Acacia foliage delta15N values were >60/00 and varied little with plantations age. Soil C:N and C:P ratios did not differ between grassland and plantations and only 0-10 cm layer N:P ratios showed significant differences between grassland and plantations. Discussion: The results indicated that soil fertility in the Sahel region is strongly related to SOM contents and therefore highlighting the importance of trees in the landscape. The higher mineral nutrient concentrations in the topsoil of the plantations may be an indication of 'nutrient uplift' by the deeper roots. The high foliar delta15N values indicated that N2 fixation was not an important contributor to soil N contents in the plantations. The accretion of soil N cannot be explained by deposition but may be related to inputs of excreted N brought into the area annually by grazing and browsing animals. The soil C:N:P stoichiometry indicated that the plantations may be limited by P and the grasslands limited by N. PMID- 30018863 TI - Identification and expression analysis of EDR1-like genes in tobacco (Nicotiana tabacum) in response to Golovinomyces orontii. AB - ENHANCED DISEASE RESISTANCE1 (EDR1) encodes a Raf-like mitogen-activated protein kinase, and it acts as a negative regulator of disease resistance and ethylene induced senescence. Mutations in the EDR1 gene can enhance resistance to powdery mildew both in monocotyledonous and dicotyledonous plants. However, little is known about EDR1-like gene members from a genome-wide perspective in plants. In this study, the tobacco (Nicotiana tabacum)EDR1-like gene family was first systematically analyzed. We identified 19 EDR1-like genes in tobacco, and compared them to those from Arabidopsis, tomato and rice. Phylogenetic analyses divided the EDR1-like gene family into six clades, among them monocot and dicot plants were respectively divided into two sub-clades. NtEDR1-1A and NtEDR1-1B were classified into clade I in which the other members have been reported to negatively regulate plant resistance to powdery mildew. The expression patterns of tobacco EDR1-like genes were analyzed after plants were challenged by Golovinomyces orontii, and showed that several other EDR1-like genes were induced after infection, as well as NtEDR1-1A and NtEDR1-1B. Expression analysis showed that NtEDR1-13 and NtEDR1-16 had exclusively abundant expression patterns in roots and leaves, respectively, and the remaining NtEDR1-like members were actively expressed in most of the tissue/organ samples investigated. Our findings will contribute to further study of the physiological functions of EDR1-like genes in tobacco. PMID- 30018864 TI - Taxonomic annotation errors incorrectly assign the family Pseudoalteromonadaceae to the order Vibrionales in Greengenes: implications for microbial community assessments. AB - Next-generation sequencing has provided powerful tools to conduct microbial ecology studies. Analysis of community composition relies on annotated databases of curated sequences to provide taxonomic assignments; however, these databases occasionally have errors with implications for downstream analyses. Systemic taxonomic errors were discovered in Greengenes database (v13_5 and 13_8) related to orders Vibrionales and Alteromonadales. These orders have family level annotations that were erroneous at least one taxonomic level, e.g., 100% of sequences assigned to the Pseudoalteromonadaceae family were placed improperly in Vibrionales (rather than Alteromonadales) and >20% of these sequences were indeed Vibrio spp. but were improperly assigned to the Pseudoalteromonadaceae family (rather than to Vibrionaceae). Use of this database is common; we identified 68 peer-reviewed papers since 2013 that likely included erroneous annotations specifically associated with Vibrionales and Pseudoalteromonadaceae, with 20 explicitly stating the incorrect taxonomy. Erroneous assignments using these specific versions of Greengenes can lead to incorrect conclusions, especially in marine systems where these taxa are commonly encountered as conditionally rare organisms and potential pathogens. PMID- 30018865 TI - Genetic flow among olive populations within the Mediterranean basin. AB - Background: The olive tree is a typical crop of the Mediterranean basin where it shows a wide diversity, accounting for more than 2,600 cultivars. The ability to discriminate olive cultivars and determine their genetic variability is pivotal for an optimal exploitation of olive genetic resources. Methods: We investigated the genetic diversity within 128 olive accessions belonging to four countries in the Mediterranean Basin (Italy, Algeria, Syria, and Malta), with the purpose of better understanding the origin and spread of the olive genotypes across Mediterranean Basin countries. Eleven highly polymorphic simple sequence repeat (SSR) markers were used and proved to be very informative, producing a total of 179 alleles. Results: Cluster analysis distinguished three main groups according to their geographical origin, with the current sample of Maltese accessions included in the Italian group. Phylogenetic analysis further differentiated Italian and Maltese olive accessions, clarifying the intermediate position of Maltese accessions along the x/y-axes of principal coordinate analysis (PCoA). Model-based and neighbor clustering, PCoA, and migration analysis suggested the existence of two different gene pools (Algerian and Syrian) and that the genetic exchange occurred between the Syrian, Italian and Maltese populations. Discussion: The close relationship between Syrian and Italian and Maltese olives was consistent with the historical domestication and migration of olive tree from the North Levant to eastern Mediterranean basin. This study lays the foundations for a better understanding of olive genetic diversity in the Mediterranean basin and represents a step toward an optimal conservation and exploitation of olive genetic resources. PMID- 30018866 TI - Paradoxical Embolism in a Patient with Aortic Valve Endocarditis: A Case Report. AB - This report describes a case of aortic valve endocarditis with systemic and paradoxical pulmonary embolism in a patient with congenital interventricular communication. The patient underwent cardiac surgery and did not have a favorable outcome, presenting refractory cardiogenic shock and subsequently dying while in the hospital. This is an extremely rare case of paradoxical embolism in a patient with infective endocarditis; only four similar cases have been reported in the literature. PMID- 30018867 TI - Risk Factors for Opioid Use Disorders in Adult Postsurgical Patients. AB - The use of opioids in the treatment of chronic pain is one of the most controversial topics in medicine today. Many studies have proposed that the postoperative period is a vulnerable time for patients at risk for developing an opioid use disorder. Many patients are prescribed opioids for management of their postsurgical pain and continue using them for prolonged amounts of time following their surgeries. Some populations are more likely to develop an opioid use disorder following exposure to opioid medications than others. In this review, the authors discuss the patient-level risk factors for the abuse of these drugs in postsurgical patients. PMID- 30018868 TI - Fungal networks and orchid distribution: new insights from above- and below ground analyses of fungal communities. AB - Orchids are critically dependent on fungi for seedling establishment and growth, so the distribution and diversity of orchids might depend on the associated fungal communities. We characterised the communities associated with eight orchid species in three Mediterranean protected areas, using a combination of above ground analyses of sporophores and below-ground molecular analyses of orchid root samples. In three years of sporophore collection in 25 plots around flowering orchid plants, 268 macrofungal species belonging to 84 genera were observed. Statistical analyses indicated a correlation between macrofungal diversity and orchid community variation, regardless of the effect of environmental and spatial factors characterizing the investigated orchid sites. Fungal ITS-DNA PCR amplification, cloning, and sequencing revealed Rhizoctonia-like fungi belonging to Ceratobasidiaceae (26 %), Tulasnellaceae (22.5 %), and Sebacinaceae (3.5 %), as well as other basidiomycetes and ascomycetes, in the roots of 99 orchid plants. Mycorrhizal specificity was low but co-occurring orchid species showed preferences for different partners. The diverse macrofungal communities found in the sites may contribute to orchid community variation without colonizing the orchid roots. Molecular analyses revealed a segregation of associated fungi, which may contribute to Mediterranean orchid coexistence in nature. PMID- 30018869 TI - Karyotype evolution in Fusarium. AB - The germ tube burst method (GTBM) was employed to examine karyotypes of 33 Fusarium species representative of 11 species complexes that span the phylogenetic breadth of the genus. The karyotypes revealed that the nucleolar organizing region (NOR), which includes the ribosomal rDNA region, was telomeric in the species where it was discernible. Variable karyotypes were detected in eight species due to variation in numbers of putative core and/or supernumerary chromosomes. The putative core chromosome number (CN) was most variable in the F. solani (CN = 9-12) and F. buharicum (CN = 9+1 and 18-20) species complexes. Quantitative real-time PCR and genome sequence analysis rejected the hypothesis that the latter variation in CN was due to diploidization. The core CN in six other species complexes where two or more karyotypes were obtained was less variable or fixed. Karyotypes of 10 species in the sambucinum species complex, which is the most derived lineage of Fusarium, revealed that members of this complex possess the lowest CN in the genus. When viewed in context of the species phylogeny, karyotype evolution in Fusarium appears to have been dominated by a reduction in core CN in five closely related complexes that share a most recent common ancestor (tricinctum and incarnatum-equiseti CN = 8-9, chlamydosporum CN = 8, heterosporum CN = 7, sambucinum CN = 4-5) but not in the sister to these complexes (nisikadoi CN = 11, oxysporum CN = 11 and fujikuroi CN = 10-12). CN stability is best illustrated by the F. sambucinum subclade, where the only changes observed since it diverged from other fusaria appear to have involved two independent putative telomere to telomere fusions that reduced the core CN from five to four, once each in the sambucinum and graminearum subclades. Results of the present study indicate a core CN of 4 may be fixed in the latter subclade, which is further distinguished by the absence of putative supernumerary chromosomes. Karyotyping of fusaria in the not too distant future will be done by whole-genome sequencing such that each scaffold represents a complete chromosome from telomere to telomere. The CN data presented here should be of value to assist such full genome assembling. PMID- 30018871 TI - Mitochondrial introgression and interspecies recombination in the Fusarium fujikuroi species complex. AB - The Fusarium fujikuroi species complex (FFSC) is an economically important monophyletic lineage in the genus Fusarium. Incongruence observed among mitochondrial gene trees, as well as the multiple non-orthologous copies of the internal transcribed spacer region of the ribosomal RNA genes, suggests that the origin and history of this complex likely involved interspecies gene flow. Based on this hypothesis, the mitochondrial genomes of non-conspecific species should harbour signatures of introgression or introgressive hybridization. The aim of this study was therefore to search for recombination between the mitochondrial genomes of different species in the FFSC. Using methods based on mt genome sequence similarity, five significant recombinant regions in both gene and intergenic regions were detected. Using coalescent-based methods and the sequences for individual mt genes, various ancestral recombination events between different lineages of the FFSC were also detected. These findings suggest that interspecies gene flow and introgression are likely to have played key roles in the evolution of the FFSC at both ancient and more recent time scales. PMID- 30018872 TI - Ustilago species causing leaf-stripe smut revisited. AB - Leaf-stripe smuts on grasses are a highly polyphyletic group within Ustilaginomycotina, occurring in three genera, Tilletia, Urocystis, and Ustilago. Currently more than 12 Ustilago species inciting stripe smuts are recognised. The majority belong to the Ustilago striiformis-complex, with about 30 different taxa described from 165 different plant species. This study aims to assess whether host distinct-lineages can be observed amongst the Ustilago leaf-stripe smuts using nine different loci on a representative set. Phylogenetic reconstructions supported the monophyly of the Ustilago striiformis-complex that causes leaf stripe and the polyphyly of other leaf-stripe smuts within Ustilago. Furthermore, smut specimens from the same host genus generally clustered together in well supported clades that often had available species names for these lineages. In addition to already-named lineages, three new lineages were observed, and described as new species on the basis of host specificity and molecular differences: namely Ustilago jagei sp. nov. on Agrostis stolonifera, U. kummeri sp. nov. on Bromus inermis, and U. neocopinata sp. nov. on Dactylis glomerata. PMID- 30018870 TI - Multiple independent origins for a subtelomeric locus associated with growth rate in Fusarium circinatum. AB - Fusarium is a diverse assemblage that includes a large number of species of considerable medical and agricultural importance. Not surprisingly, whole genome sequences for many Fusarium species have been published or are in the process of being determined, the availability of which is invaluable for deciphering the genetic basis of key phenotypic traits. Here we investigated the distribution, genic composition, and evolutionary history of a locus potentially determining growth rate in the pitch canker pathogen F. circinatum. We found that the genomic region underlying this locus is highly conserved amongst F. circinatum and its close relatives, except for the presence of a 12 000 base pair insertion in all of the examined isolates of F. circinatum. This insertion encodes for five genes and our phylogenetic analyses revealed that each was most likely acquired through horizontal gene transfer from polyphyletic origins. Our data further showed that this region is located in a region low in G+C content and enriched for repetitive sequences and transposable elements, which is situated near the telomere of Chromosome 3 of F. circinatum. As have been shown for other fungi, these findings thus suggest that the emergence of the unique 12 000 bp region in F. circinatum is linked to the dynamic evolutionary processes associated with subtelomeres that, in turn, have been implicated in the ecological adaptation of fungal pathogens. PMID- 30018873 TI - Competing sexual and asexual generic names in Pucciniomycotina and Ustilaginomycotina (Basidiomycota) and recommendations for use. AB - With the change to one scientific name for pleomorphic fungi, generic names typified by sexual and asexual morphs have been evaluated to recommend which name to use when two names represent the same genus and thus compete for use. In this paper, generic names in Pucciniomycotina and Ustilaginomycotina are evaluated based on their type species to determine which names are synonyms. Twenty-one sets of sexually and asexually typified names in Pucciniomycotina and eight sets in Ustilaginomycotina were determined to be congeneric and compete for use. Recommendations are made as to which generic name to use. In most cases the principle of priority is followed. However, eight generic names in the Pucciniomycotina, and none in Ustilaginomycotina, are recommended for protection: Classicula over Naiadella, Gymnosporangium over Roestelia, Helicobasidium over Thanatophytum and Tuberculina, Melampsorella over Peridermium, Milesina over Milesia, Phragmidium over Aregma, Sporobolomyces over Blastoderma and Rhodomyces, and Uromyces over Uredo. In addition, eight new combinations are made: Blastospora juruensis, B. subneurophyla, Cronartium bethelii, C. kurilense, C. sahoanum, C. yamabense, Milesina polypodii, and Prospodium crusculum combs. nov. PMID- 30018874 TI - NGS barcode sequencing in taxonomy and diagnostics, an application in "Candida" pathogenic yeasts with a metagenomic perspective. AB - Species identification of yeasts and other Fungi is currently carried out with Sanger sequences of selected molecular markers, mainly from the ribosomal DNA operon, characterized by hundreds of tandem repeats of the 18S, ITS1, 5.8S, ITS2 and LSU loci. The ITS region has been recently proposed as a primary barcode marker making this region the most used one in taxonomy, phylogeny and diagnostics. The introduction of NGS is providing tools of high efficacy and relatively low cost to amplify two or more markers simultaneously with great sequencing depth. However, the presence of intra-genomic variability between the repeats requires specific analytical procedures and pipelines. In this study, 286 strains belonging to 11 pathogenic yeasts species were analysed with NGS of the region spanning from ITS1 to the D1/D2 domain of the LSU encoding ribosomal DNA. Results showed that relatively high heterogeneity can hamper the use of these sequences for the identification of single strains and even more of complex microbial mixtures. These observations point out that the metagenomics studies could be affected by species inflection at levels higher than currently expected. PMID- 30018875 TI - Panama, a hot spot for Hermatomyces (Hermatomycetaceae, Pleosporales) with five new species, and a critical synopsis of the genus. AB - Five new species belonging to Hermatomyces (Hermatomycetaceae, Pleosporales) are described based on morphological investigations of specimens collected on rotten twigs and stems of various plants in Panama as well as phylogenetic analyses of sequence data of nuclear ribosomal and protein coding genes (EF1-alpha, RPB2, beta-TUB). The new species are described as: Hermatomyces bifurcatus, H. constrictus, H. megasporus, H. sphaericoides, and H. verrucosus spp. nov. Previously described species such as H. sphaericus and H. tucumanensis were identified among the studied specimens. The new combination, H. reticulatus, is made for Subicularium reticulatum based on examination of the holotype and fresh collections. Hermatomyces subiculosus, originally described from Thailand, is reduced to synonymy with H. reticulatus; H. tectonae is synonymized under H. sphaericus based on morphological and molecular evidence; and H. chiangmaiensis and H. thailandicus are considered later synonyms of H. krabiensis and H. indicus, respectively. The type material of Scyphostroma mirum was found to be conspecific with H. tucumanensis and, therefore, the generic name Hermatomyces should be conserved or protected against the older name Scyphostroma and the binomial H. tucumanensis against S. mirum. Sixteen species of Hermatomyces are recognized, their distinctive characteristics are highlighted in line drawings and a key is provided for their identification. The peculiar morphology and consistent phylogeny of new and previously known Hermatomyces species supports the recognition of the recently introduced monotypic family Hermatomycetaceae as a well delimited monophyletic taxon within the order Pleosporales. PMID- 30018876 TI - Formal description of sequence-based voucherless Fungi: promises and pitfalls, and how to resolve them. AB - There is urgent need for a formal nomenclature of sequence-based, voucherless Fungi, given that environmental sequencing has accumulated more than one billion fungal ITS reads in the Sequence Read Archive, about 1,000 times as many as fungal ITS sequences in GenBank. These unnamed Fungi could help to bridge the gap between 115,000 to 140,000 currently accepted and 2.2 to 3.8 million predicted species, a gap that cannot realistically be filled using specimen or culture based inventories. The Code never aimed at placing restrictions on the nature of characters chosen for taxonomy, and the requirement for physical types is now becoming a constraint on the advancement of science. We elaborate on the promises and pitfalls of sequence-based nomenclature and provide potential solutions to major concerns of the mycological community. Types of sequence-based taxa, which by default lack a physical specimen or culture, could be designated in four alternative ways: (1) the underlying sample ('bag' type), (2) the DNA extract, (3) fluorescent in situ hybridization (FISH), or (4) the type sequence itself. Only (4) would require changes to the Code and the latter would be the most straightforward approach, complying with three of the five principal functions of types better than physical specimens. A fifth way, representation of the sequence in an illustration, has been ruled as unacceptable in the Code. Potential flaws in sequence data are analogous to flaws in physical types, and artifacts are manageable if a stringent analytical approach is applied. Conceptual errors such as homoplasy, intragenomic variation, gene duplication, hybridization, and horizontal gene transfer, apply to all molecular approaches and cannot be used as a specific argument against sequence-based nomenclature. The potential impact of these phenomena is manageable, as phylogenetic species delimitation has worked satisfactorily in Fungi. The most serious shortcoming of sequence-based nomenclature is the likelihood of parallel classifications, either by describing taxa that already have names based on physical types, or by using different markers to delimit species within the same lineage. The probability of inadvertently establishing sequence-based species that have names available is between 20.4 % and 1.5 % depending on the number of globally predicted fungal species. This compares favourably to a historical error rate of about 30 % based on physical types, and this rate could be reduced to practically zero by adding specific provisions to this approach in the Code. To avoid parallel classifications based on different markers, sequence-based nomenclature should be limited to a single marker, preferably the fungal ITS barcoding marker; this is possible since sequence-based nomenclature does not aim at accurate species delimitation but at naming lineages to generate a reference database, independent of whether these lineages represent species, closely related species complexes, or infraspecies. We argue that clustering methods are inappropriate for sequence based nomenclature; this approach must instead use phylogenetic methods based on multiple alignments, combined with quantitative species recognition methods. We outline strategies to obtain higher-level phylogenies for ITS-based, voucherless species, including phylogenetic binning, 'hijacking' species delimitation methods, and temporal banding. We conclude that voucherless, sequence-based nomenclature is not a threat to specimen and culture-based fungal taxonomy, but a complementary approach capable of substantially closing the gap between known and predicted fungal diversity, an approach that requires careful work and high skill levels. PMID- 30018878 TI - Ten reasons why a sequence-based nomenclature is not useful for fungi anytime soon. AB - The large number of species still to be discovered in fungi, together with an exponentially growing number of environmental sequences that cannot be linked to known taxa, has fuelled the idea that it might be necessary to formally name fungi on the basis of sequence data only. Here we object to this idea due to several shortcomings of the approach, ranging from concerns regarding reproducibility and the violation of general scientific principles to ethical issues. We come to the conclusion that sequence-based nomenclature is potentially harmful for mycology as a discipline. Additionally, a classification based on sequences as types is not within reach anytime soon, because there is a lack of consensus regarding common standards due to the fast pace at which sequencing technologies develop. PMID- 30018879 TI - Sequence-based nomenclature: a reply to Thines et al. and Zamora et al. and provisions for an amended proposal "from the floor" to allow DNA sequences as types of names. AB - We reply to two recently published, multi-authored opinion papers by opponents of sequence-based nomenclature, namely Zamora et al. (IMA Fungus9: 167-175,2018) and Thines et al. (IMA Fungus9: 177-183, 2018). While we agree with some of the principal arguments brought forward by these authors, we address misconceptions and demonstrate that some of the presumed evidence presented in these papers has been wrongly interpreted. We disagree that allowing sequences as types would fundamentally alter the nature of types, since a similar nature of abstracted features as type is already allowed in the Code (Art. 40.5), namely an illustration. We also disagree that there is a high risk of introducing artifactual taxa, as this risk can be quantified at well below 5 %, considering the various types of high-throughput sequencing errors. Contrary to apparently widespread misconceptions, sequence-based nomenclature cannot be based on similarity-derived OTUs and their consensus sequences, but must be derived from rigorous, multiple alignment-based phylogenetic methods and quantitative, single marker species recognition algorithms, using original sequence reads; it is therefore identical in its approach to single-marker studies based on physical types, an approach allowed by the Code. We recognize the limitations of the ITS as a single fungal barcoding marker, but point out that these result in a conservative approach, with "false negatives" surpassing "false positives"; a desirable feature of sequence-based nomenclature. Sequence-based nomenclature does not aim at accurately resolving species, but at naming sequences that represent unknown fungal lineages so that these can serve as a means of communication, so ending the untenable situation of an exponentially growing number of unlabeled fungal sequences that fill online repositories. The risks are outweighed by the gains obtained by a reference library of named sequences spanning the full array of fungal diversity. Finally, we elaborate provisions in addition to our original proposal to amend the Code that would take care of the issues brought forward by opponents to this approach. In particular, taking up the idea of the Candidatus status of invalid, provisional names in prokaryote nomenclature, we propose a compromise that would allow valid publication of voucherless, sequence-based names in a consistent manner, but with the obligate designation as "nom. seq." (nomen sequentiae). Such names would not have priority over specimen- or culture-based names unless either epitypified with a physical type or adopted for protection on the recommendation of a committee of the International Commission on the Taxonomy of Fungi following evaluation based on strict quality control of the underlying studies based on established rules or recommendations. PMID- 30018881 TI - Management of Brain Metastases in Epidermal Growth Factor Receptor Mutant Non Small-Cell Lung Cancer. AB - Lung cancer remains a leading cause of mortality with 1.69 million deaths worldwide. Activating mutations in epidermal growth factor receptor (EGFR), predominantly exon 19 deletions and exon 21 L858R mutations, are known oncogenic drivers identified in 20-40% of non-small-cell lung cancers (NSCLC). 70% of EGFR mutant NSCLC patients develop brain metastases (BM), compared to 38% in EGFR wild type patients. First-generation tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib have proven to be superior to chemotherapy in the front line treatment of EGFR-mutant NSCLC, as has afatinib, a second-generation TKI. The most common acquired resistance mechanism is the development of a gatekeeper mutation in exon 20 T790M. Osimertinib has emerged as a third-generation EGFR TKI with proven activity in the front-line setting as well as in patients with a T790M acquired resistance mutation with remarkable CNS activity. As long-term survival outcomes in EGFR-mutant NSCLC continue to improve, the burden of BM becomes a greater challenge. Here, we review the literature related to the management of BM in EGFR-mutant NSCLC including the role of the three generations of EGFR TKIs, immunotherapy, and brain radiation. PMID- 30018880 TI - IMA Genome-F 9: Draft genome sequence of Annulohypoxylon stygium, Aspergillus mulundensis, Berkeleyomyces basicola (syn. Thielaviopsis basicola), Ceratocystis smalleyi, two Cercospora beticola strains, Coleophoma cylindrospora, Fusarium fracticaudum, Phialophora cf. hyalina, and Morchella septimelata. AB - Draft genomes of the species Annulohypoxylon stygium, Aspergillus mulundensis, Berkeleyomyces basicola (syn. Thielaviopsis basicola), Ceratocystis smalleyi, two Cercospora beticola strains, Coleophoma cylindrospora, Fusarium fracticaudum, Phialophora cf. hyalina and Morchella septimelata are presented. Both mating types (MAT1-1 and MAT1-2) of Cercospora beticola are included. Two strains of Coleophoma cylindrospora that produce sulfated homotyrosine echinocandin variants, FR209602, FR220897 and FR220899 are presented. The sequencing of Aspergillus mulundensis, Coleophoma cylindrospora and Phialophora cf. hyalina has enabled mapping of the gene clusters encoding the chemical diversity from the echinocandin pathways, providing data that reveals the complexity of secondary metabolism in these different species. Overall these genomes provide a valuable resource for understanding the molecular processes underlying pathogenicity (in some cases), biology and toxin production of these economically important fungi. PMID- 30018883 TI - Myelolipoma of the Pelvis: A Case Report and Review of Literature. AB - Myelolipomas are uncommon, benign tumors which typically occur in the adrenal glands and consist of mature adipose tissue and benign hematopoietic components. Myelolipomas can occur outside of the adrenal glands, but the presacral region, retroperitoneum, pelvis, and mediastinum are unusual locations for these tumors. It is important to recognize this entity in these locations since they can attain massive sizes leading to pressure symptoms and need to be differentiated from the malignant tumors like liposarcomas. We present a myelolipoma case in the presacral region. Our case illustrates the clinical approach of these tumors in such unusual locations. PMID- 30018882 TI - Beyond the Blood:Brain Barrier: The Importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, Including Diffuse Intrinsic Pontine Glioma. AB - Over the past decade, we have made considerable progress in establishing diffuse intrinsic pontine glioma (DIPG) as a disease entity and developing preclinical tools to interrogate potential therapeutics. However, translation to improved clinical outcomes in children with DIPG has not yet been realized. This is in part due to difficulties encountered in delivering active drugs adequately to the tumor site. However, most preclinical evaluations gloss over the fundamental concepts of central nervous system (CNS) pharmacokinetics and requirements needed to optimize drug delivery and exposure and translate this into efficacious therapy. This article discusses not only the blood:brain barriers but additional barriers to drug delivery for CNS tumors and pharmacokinetic principles that need to be addressed and considered. PMID- 30018884 TI - Neutralization of Streptolysin S-Dependent and Independent Inflammatory Cytokine IL-1beta Activity Reduces Pathology During Early Group A Streptococcal Skin Infection. AB - The bacterial pathogen Group A Streptococcus (GAS) has been shown to induce a variety of human diseases ranging in severity from pharyngitis to toxic shock syndrome and necrotizing fasciitis. GAS produces a powerful peptide toxin known as Streptolysin S (SLS). Though long recognized as a potent cytolysin, recent evidence from our lab has shown that SLS-dependent cytotoxicity is mediated through activation of the pro-inflammatory mediators p38 MAPK and NFkappaB. These findings led us to hypothesize that activation of p38 MAPK and NFkappaB signaling drive the production of pro-inflammatory cytokines which, in turn, serve as positive feedback signals to initiate cytotoxicity in infected host cells. To address this hypothesis, we utilized a cytokine array to characterize the SLS dependent pro-inflammatory cytokine response to GAS infection in human keratinocytes. From these studies, IL-1beta was found to be markedly upregulated in the presence of SLS, and further investigation revealed that this cytokine contributes to cytotoxicity in human keratinocytes during infection. Subcutaneous infection studies were performed in mice to address the physiological impact of increased IL-1beta production. These studies demonstrated that IL-1beta is produced during GAS skin infection in an SLS-dependent manner. Furthermore, inhibition of this cytokine and the upstream kinases and other signaling mediators that drive its production reduced SLS-mediated lesion formation early in the infection process. Together, our findings indicate that pharmacological inhibition of this inflammatory axis holds promise as a therapeutic strategy to reduce tissue destruction during severe invasive Group A Streptococcal infections. PMID- 30018885 TI - Dietary Sodium to Potassium Ratio and the Incidence of Chronic Kidney Disease in Adults: A Longitudinal Follow-Up Study. AB - The aim of this study was to explore the association of dietary sodium to potassium (Na/K) ratio and the risk of chronic kidney disease (CKD) in general Iranian adults. In this prospective cohort study, 1,780 adults, free of baseline CKD with complete follow-up data, were selected from among participants of the Tehran Lipid and Glucose Study and followed for 6.3 years for development of CKD. Dietary sodium and potassium were assessed using a valid and reliable 168-item food frequency questionnaire. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation, and CKD was defined as eGFR <60 mL/min/1.73 m2. Mean dietary intakes of sodium and potassium were 4,547+/-3,703 and 3,753+/-1,485 mg/d, respectively, and their ratio was 1.35+/-1.29. No significant association was found between dietary intakes of sodium and potassium and the risk of CKD after 6.3 y of follow-up, whereas in the case of dietary Na/K ratio, participants in the highest compared to lowest tertile (2.43 vs 1.61) had a significantly increased risk of CKD (odds ratio=1.52, 95% confidence interval=1.01~2.30); an increasing trend in the risk of CKD across tertiles of dietary sodium to potassium ratio was also observed (P for trend=0.05). Present findings demonstrate that the dietary Na/K ratio is a stronger predictor of CKD than the dietary sodium or potassium per se. Decreased dietary Na/K ratio may be considered as an effective dietary approach to modify the risk of kidney dysfunction. PMID- 30018886 TI - Presence of Dental Caries Is Associated with Food Insecurity and Frequency of Breakfast Consumption in Korean Children and Adolescents. AB - Dental caries remains one of the most common chronic diseases affecting children worldwide with a multi-factorial etiology. The objective of the study was to evaluate the association between socioeconomic status (SES), dietary intake, food insecurity (FI), and dental caries in Korean children and adolescents. The study utilized data from the 2-year Korean National Health and Nutrition Examination Survey (KNHANES) conducted with 1,559 Korean boys and 1,391 girls aged 2 to 18 years from 2012 to 2013. Fathers' education (P=0.017), mothers' education (P<0.001), and household income (P=0.049) were all significantly associated with dental caries among Korean boys. As for dietary practices, both eating breakfast (P<0.001) and frequency of eating out (P<0.001) were strongly associated with dental caries (P<0.001). Three models of FI were used and no differences were found regarding genders. In model 3, both food insecure male [odds ratio (OR)=1.682, 95% confidence interval (CI): 0.999~2.832] and female (OR=1.900, 95% CI: 1.094~3.299) subjects had higher odds of developing dental caries than food secure subjects after adjusting the confounding factors. The present study showed a strong association between FI mediated by SES and dental caries. Nutrition education programs targeting low-socioeconomic families are necessary as a tool to prevent dental caries in Korea. PMID- 30018888 TI - The Effects of a Flavonoid-Rich Diet on Oxidative Stress, Inflammation, and Lipid Profile after Elective Percutaneous Coronary Intervention: A Randomized Clinical Trial. AB - Antioxidant-rich foods may decrease oxidative stress and have a direct impact on atherosclerosis by reducing low-density lipoprotein (LDL) oxidation. Our aim was to assess the impact of a flavonoid-rich diet on oxidative stress, inflammatory response, and lipid profile in patients with coronary artery disease submitted to elective percutaneous coronary intervention (PCI). Thirty-three patients submitted to elective PCI were randomly allocated to follow either a flavonoid rich antioxidant (AOX) diet or a control diet based on National Cholesterol Education Program Adult Treatment Panel III recommendations. Patients were followed for 6 months. Dietary intake was recorded at the start and at the end of the follow-up period, as were oxidative stress markers (ferric reducing ability of plasma and protein sulphydryl) and C-reactive protein (CRP). Patients randomized to follow the AOX diet had a reduction in energy, carbohydrate, and lipid intake, as well as increased flavonoid intake. Compared to the control group, there were no changes in oxidative stress markers or CRP in the patients following the AOX diet, but these patients had a significant decrease in LDL cholesterol levels. In conclusion, the findings of this study suggest that a flavonoid-based antioxidant-rich diet is not associated with reductions in oxidative stress or inflammatory markers 6 months after percutaneous coronary intervention. Nonetheless, patients in the intervention group experienced significant reductions in LDL cholesterol, which may indicate cardiovascular benefits of AOX diets despite of inflammation and oxidative stress markers. PMID- 30018887 TI - Phaseolus vulgaris Exerts an Inhibitory Effect on Platelet Aggregation through AKT Dependent Way. AB - The Phaseolus vulgaris (common bean), a worldwide vegetable of high consumption, can act as a nutritional supplement in the diet of oversized individuals to reduce weight. Studies have demonstrated the existence of molecules capable of inhibiting the breakdown of carbohydrates via inhibition of both alpha-amylases and glycosidases. Here, we describe a novel property of the Phaseolus vulgaris: inhibition of thrombotic cardiovascular events. Using assays to test platelet aggregation and secretion, and flow cytometry against the surface expression of P Selectin. We show that bean extracts significantly reduced adenosine 5' diphosphate and arachidonic acid induced-platelet aggregation. The mechanism underlying such effect appears to be mediated by AKT, since AKT hypo phosphorylation decreases the "inside out" activation of platelets. In sum, our results support the hypothesis that common beans are nutritional ingredients that help reduce the risk of cardiovascular diseases associated with platelet hyper reactivity. PMID- 30018889 TI - Supplementation of Type 1 Diabetic Rats with Carrot Powder Lowers Blood Glucose without Improving Cardiac Structure and Function. AB - Foods and food bioactives have shown to be effective in preventing some human disease conditions. In this study, we examined the effects of carrot powder, rich in carotenoids, as a dietary supplement for the prevention of cardiac anomalies in streptozotocin (STZ) induced type 1 diabetic rats. Male Wistar rats were fed either control or carrot powder containing diet for 3 weeks. Type 1 diabetes was induced with STZ injection (65 mg/kg body weight) in half of the rats in each group. All rats were continued on their respective diet for a further 9 weeks. Cardiac structural and functional parameters were measured using echocardiography at 8 weeks post STZ administration. In comparison to non-diabetic rats, diabetic rats showed significant increase in isovolumetric relaxation time and a significant decrease in systolic function parameter, cardiac output. Left ventricular internal dimension and left ventricular posterior wall thickness were significantly higher in diabetic animals. Blood glucose levels were significantly lower in carrot supplemented diabetic rats when compared with non-treated diabetic rats. Diabetic rats treated and untreated had elevated level of lipid peroxidation. Catalase levels were significantly elevated in the carrot powder supplemented diabetic rats when compared to the control rats. Carrot supplementation lowered blood glucose levels significantly but did not normalize it to control levels. It had no effect on cardiac abnormalities and anti-oxidant status in rats with type 1 diabetes. PMID- 30018890 TI - Sargassum sagamianum Extract Alleviates Postprandial Hyperglycemia in Diabetic Mice. AB - In this study, we investigated the postprandial hypoglycemic effect of Sargassum sagamianum extract (SSE) in streptozotocin-induced diabetic mice. Freeze-dried S. sagamianum was extracted with 80% ethanol and concentrated. The inhibition of postprandial hyperglycemia was determined by the inhibitory activity against alpha-glucosidase and alpha-amylase as well as the measurement of postprandial blood glucose levels. SSE demonstrated a high inhibitory activity against alpha glucosidase and alpha-amylase. The IC50 value of SSE against alpha-glucosidase and alpha-amylase was 0.095 mg/mL and 0.199 mg/mL, respectively, and thus it was significantly more efficacious than the pharmaceutical acarbose (0.115 mg/mL and 0.229 mg/mL, respectively). The postprandial blood glucose levels in the SSE administered group were significantly lower than those in the control group. Furthermore, the area under the curve significantly decreased following the administration of SSE. These results indicate that SSE can be used as an alpha glucosidase and alpha-amylase inhibitor and can delay the absorption of dietary carbohydrates. PMID- 30018891 TI - Inhibitory Effects of Apium graveolens on Xanthine Oxidase Activity and Serum Uric Acid Levels in Hyperuricemic Mice. AB - Celery (Apium graveolens) is traditionally used to treat rheumatism and cardiovascular disorders. Hyperuricemia is considered as a predisposing factor for gout and is also suggested to be associated with coronary artery disease. In the present study, the effect of hydroalcoholic extracts from A. graveolens (AGE) against potassium oxonate (PO)-induced hyperuricemia was investigated in mice. AGE (250, 500, and 1,000 mg/kg) or allopurinol (5 mg/kg, as positive control) were orally administrated 1 h after PO injection (250 mg/kg, ip) for two weeks. After that, the serum uric acid level and hepatic xanthine dehydrogenase (XDH) and xanthine oxidase (XO) activities were measured. In addition, the antioxidant activity of AGE was determined by assessment of hepatic lipid peroxidation, in vivo and the ferric reducing/antioxidant power assay, in vitro. The extract exhibited good capacity to reduce ferric ion to ferrous ion with mean value of 63.8+/-8.5 MUmol/g. The data also showed that oxonate treatment produced a significant increase in serum uric acid level (4.6 vs. 2.3 mg/ dL, P<0.001), liver XO/XDH activities (P<0.01 and P<0.001, respectively), and hepatic lipid peroxides levels (about two fold, P<0.01), compared to the healthy mice. AGE significantly decreased the serum uric acid level, hepatic XO/XDH activities, and lipid peroxidation, in a dose-dependent manner. Oral administration of 1,000 mg/kg AGE for two weeks reversed the elevated serum uric acid level (2.7 vs. 4.6 mg/dL, P<0.001) and significantly inhibited liver XO/XDH activities (P<0.001) and diminished hepatic lipid peroxidation (0.45 vs. 0.82 nmol/mg protein, P<0.05), compared with hyperuricemic mice. AGE (1,000 mg/kg) per se did not significantly modify these parameters. Our results demonstrated that AGE could reduce the serum uric acid level via inhibition of hepatic XDH/XO and indicated its potential utility as an effective hypouricemic bioactive agent or functional food. PMID- 30018892 TI - Evaluation of In Vitro Antioxidant Activity of the Water Extract Obtained from Dried Pine Needle (Pinus densiflora). AB - Antioxidant activities of water extracts obtained from dried pine needle (Pinus densiflora) were measured at 0, 4, 20, 100, 500, 1,000, and 1,200 ppm and compared with those of phenolic compounds of butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, ferulic acid, and alpha-tocopherol. The activity was determined as the ability to scavenge 1,1-diphenyl-2-picrylhydrazyl radical and hydrogen peroxide, reductive power, and inhibition of lipid peroxidation in a linoleic acid system using the ferric thiocyanate method and thiobarbituric acid method, respectively. Pine needle water extract (PNWE) exhibited antioxidant activity in a concentration-dependent mode at the same parameters mentioned above, and a significant difference (P<0.05) was observed at 1,000 ppm. The protective activity of PNWE as a potent antioxidant in a non cellular system was compared with that of phenolics at 150.67 MUg/mL in the two assays using biological cellular systems, namely 2,2'-azobis(2-amidinopropane) dihydrochloride-initiated hemolysis and Fe2+-induced lipid peroxidation, using rat red blood cells and rat brain homogenate, respectively. The PNWE showed a strong power comparable to those of commercial phenolic compounds in biological systems. These results indicated that the protective activity of PNWE could be due to the presence of naturally-occurring phenolic compounds, which act as potent in vitro antioxidants in both non-cellular and cellular systems. PMID- 30018893 TI - Effect of Drying Conditions on Nutritional Quality and In Vitro Antioxidant Activity of Traditional Doenjang. AB - Doenjang, a major traditional Korean condiment, is often dried to reduce volume and thereby shipping cost while increasing shelf life. However, changes of nutritional and sensory properties of doenjang during processing have not been well understood. Therefore, this study aimed to evaluate how drying processes influence the nutritional and chemical properties of doenjang. When two drying methods, hot air drying and freeze drying were compared from the nutritional point of view, air-dried doenjang at 60 degrees C or lower showed similar quality parameters including sensory scores, proximate composition, antioxidant capacity, amino acid composition, amino nitrogen, and acid value to freeze-dried doenjang. In contrast, the sample dried at 80 degrees C and 100 degrees C showed lower quality parameters than the freeze-dried one. Ferric reducing antioxidant potential (FRAP), total phenolics content, amino acid composition, and acid value were shown to reflect the sensory and physical properties of dried doenjang. In particular, the FRAP value of dried doenjang was sensitively responsive to drying temperatures and may be utilized as an early biomarker for quality deterioration of dried doenjang. PMID- 30018895 TI - Quality Improvement and Antioxidant Activity of Sugar-Snap Cookies Prepared Using Blends of Cereal Flour. AB - In this study, we investigated the changes in quality and antioxidant activity of sugar-snap cookies prepared with different blends of refined wheat (WHF) and oat flour (OAF). The crude protein contents of OAF and WHF were 12.24% and 7.17%, respectively, and the fiber contents of were 3.45% and 0.31%, respectively; both were increased by adding OAF. However, the total starch contents were decreased by adding OAF. The beta-glucan content of the samples increased considerably upon the addition of OAF. The water-holding capacity was increased after adding OAF compared to WHF (79.21%). Water binding in wet gluten contents decreased on the addition of OAF. Final viscosity increased on the addition of OAF. Antioxidant activity and total phenolic acid were increased upon the addition of OAF. The thickness of cookies prepared with OAF, WHF, 20% of WHF with OAF (WOB20), and WOB40 were 11.28, 12.35, 9.74, and 9.81 mm, respectively. The hardness of cookies prepared with WHF and WOF20 did not differ significantly, and analysis of the appearance of cookies showed that the cookies were increasingly cracked as the OAF content increased. Therefore, substituting WHF with OAF improved the quality and nutrient value of the cookies. PMID- 30018894 TI - Changes in Some Antinutritional Components and In Vitro Multienzymes Protein Digestibility during Hydrothermal Processing of Cassia hirsutta. AB - The seed of Cassia hirsutta was subjected to aqueous soaking and four hydrothermal processing techniques (atmospheric boiling, atmospheric steaming, pressure boiling, and pressure steaming). Soaking of the seed to varying hydration levels before hydrothermal treatments induced the reduction in the concentration of the antinutritional components. The lowest concentration of each of the antinutritional components was observed at 100% hydration level. The effects of hydrothermal techniques on the antinutritional components and protein digestibility were investigated. All the hydrothermal techniques caused significant reduction (P<0.05) in the antinutritional components. Boiling at elevated pressure resulted in greater reduction of antinutrients. The hydrothermal techniques caused total elimination of trypsin inhibitor activity. Reduction in the concentration of the antinutritional components after hydrothermal processing led to the increase in in vitro protein digestibility. The highest in vitro protein digestibility of 86.82% was observed after the legume seed was boiled at elevated pressure. Adoption of this underutilised legume will strengthen dietary diversity, improve feeding patterns, and prevent protein energy malnutrition especially in developing countries since the seed is a good source of nutritionally important nutrients. PMID- 30018896 TI - Structural Characterization of Cellulose Obtained from Extraction Wastes of Graviola (Annona muricata) Leaf. AB - Cellulose is one of the most common functional ingredients in food products and has been widely used as fat replacers and stabilizers. In the present study, the structural properties of cellulose obtained from extraction wastes of graviola (Annona muricata.) leaf (CWG) were characterized via scanning electron microscope (SEM), X-ray diffraction (XRD), fourier transform-infrared (FTIR), and 13C nuclear magnetic resonance (NMR) analyses. Extraction and purification of CWG were accomplished by alkali treatment and bleaching processes. An elongated, fibrous structure of CWG was observed in SEM analysis. The XRD, FTIR, and 13C NMR spectra of CWG were compared with microcrystalline cellulose (control cellulose) and it was found that CWG exhibited similar structural characteristics to the control. XRD diffractogram of CWG showed typical peaks (2theta=15 degrees and 22.6 degrees ) of cellulose I. According to the specific peaks (898, 1,057, and 1,430 cm-1) and chemical shifts (104.5, 88.5, 72~75, and 64.6 ppm) obtained by FTIR and NMR analyses, respectively, it was cofirmed that cellulose was successfully extracted from CWG. PMID- 30018898 TI - Fertility preservation for adolescent and young adult cancer patients in Japan. AB - Adolescent and young adult (AYA) patients are generally defined as being from 15 to 39 years old. For preservation of fertility in AYA cancer patients, the best known guideline in this field was released by the American Society of Clinical Oncology (ASCO) in 2006. However, the ASCO guideline is not necessarily applicable to Japanese cancer patients. The Japan Society for Fertility Preservation (JSFP) was formed in 2012, and a system and guideline for fertility preservation in Japanese AYA cancer patients plus children was released in July 2017. According to this guideline, patients should receive psychological and social support from health care providers such as doctors, nurses, psychologists, pharmacists, and social workers. In 2013, the American Society for Reproductive Medicine stated that freezing oocytes is a method that has passed beyond the research stage. However, freezing ovarian tissue is still a research procedure. While slow freezing of ovarian tissue is generally performed, rapid freezing (vitrification) is more popular in Japan. We have developed a new closed technique for ovarian tissue cryopreservation. It has been suggested that optical coherence tomography might be applied clinically to measure the true ovarian reserve and localize follicles in patients undergoing ovarian tissue transplantation. Combining gonadotropin-releasing hormone agonist therapy with anticancer agents might be useful for ovarian protection and it is expected that discussion of such combined treatment will continue in the future. This article outlines practical methods of fertility preservation using assisted reproductive techniques for AYA cancer patients in Japan. PMID- 30018897 TI - Ovarian tissue cryopreservation and transplantation in patients with cancer. AB - Chemotherapy and radiotherapy improved survival rates of patients with cancer. However, they can cause ovarian failure and infertility in women of reproductive age. Infertility following cancer treatment is considered a major quality of life issue. Ovarian tissue cryopreservation and transplantation is an important option for fertility preservation in adult patients with cancer who need immediate chemotherapy or do not want to undergo ovarian stimulation. Ovarian tissue freezing is the only option for preserving the fertility of prepubertal patients with cancer. In a recent review, it was reported that frozen-thawed ovarian transplantation has lead to about 90 live births and the conception rate was about 30%. Endocrine function recovery was observed in 92.9% between 3.5 and 6.5 months after transplantation. Based on our review, ovarian tissue cryopreservation and transplantation may be carefully considered before cancer treatment in order to preserve fertility and endocrine function in young cancer survivors. PMID- 30018899 TI - Change in rates of prenatal tests for chromosomal abnormality over a 12-year period in women of advanced maternal age. AB - Objective: In 2007, the American College of Obstetricians and Gynecologists (ACOG) recommended that all pregnant women be offered screening or diagnostic tests for chromosomal abnormalities regardless of their age. Noninvasive prenatal testing (NIPT) for common chromosomal aneuploidies was introduced as a screening test in case of high-risk pregnancies. We assessed the rates of prenatal tests in women aged 35 years and older. Methods: A retrospective study was conducted to compare the rates of amniocentesis, chorionic villus sampling (CVS), serum screening, and NIPT from January 2005 through March 2017 in women aged 35 years and older. We divided the initial 12 months after NIPT introduction into 4-month intervals, beginning in April 2016 through March 2017. Results: The rates of amniocentesis were 56% before the ACOG statement, 38% between the ACOG statement and NIPT introduction, and 10% after NIPT introduction (P=0.001). The rates of CVS during the same periods were 0.5%, 2.1%, and 4.3% (P=0.016), respectively. The rates of serum screening were 44.2%, 61.3%, and 55.1% (P=0.049), respectively. During the 3 quarters after NIPT introduction, the rates of amniocentesis were 16.2%, 12.3%, and 7.3% (P=0.002), respectively; the rates of serum screening were 62%, 54%, and 46% (P=0.03), respectively; and the rates of NIPT were 19.9%, 30.3%, and 39.5% (P=0.007), respectively. The rates of CVS over the same periods were not significantly different. Conclusion: The ACOG statement and NIPT introduction significantly decreased the rate of amniocentesis in women of advanced maternal age. NIPT also reduced the rate of serum screening. PMID- 30018901 TI - The comparison of surgical outcomes and learning curves of radical hysterectomy by laparoscopy and robotic system for cervical cancer: an experience of a single surgeon. AB - Objective: The aim of this study was to compare and determine the feasibility, surgical outcomes, learning curves of robotic radical hysterectomy with lymph node dissection (RRHND) to conventional laparoscopic radical hysterectomy with lymph node dissection (LRHND) performed by a single surgeon, in patients with cervical cancer. Methods: Between April 2009 and March 2013, 22 patients underwent LRHND and 19 patients underwent RRHND. Variables such as age, body mass index, International Federation of Gynecology and Obstetrics stage, histological results, number of dissected lymph nodes, operative time, estimated blood loss, days of hospitalization and complications were reviewed. Learning curves of operation time was obtained using cumulative sum (CUSUM) method. Results: Both groups showed similar patient and tumor characteristics. In surgical outcome analysis, RRHND (51.8+/-10.4 minutes) showed longer preparing time than LRHND (42.5+/-14.1 minutes). In the LRHND group, 8 patients experienced postoperative complications (5 void difficulty, 1 postoperative bleeding, 1 right basal ganglia infarction, 1 fever). On the other hand, in the RRHND group, 4 patients experienced a postoperative complication (2 bleeding, 1 peritonitis, 1 dehiscence of trocar site). Using CUSUM method, the learning curves were obtained by plotting the cumulative sequential differences between each data point and the average operation time, and showed two distinct phases in both type of operations. Conclusion: RRHND would be appropriate surgical approach in patients with cervical cancer with favorable outcome of less voiding difficulty. A minimum of 13 cases of robotic radical hysterectomies are required to achieve surgical improvement in the treatment of cervical cancer. PMID- 30018900 TI - Fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome treatment: initial experience in tertiary reference center in Brazil. AB - Objective: To evaluate the initial maternal and perinatal outcomes of fetoscopic laser photocoagulation for the treatment of twin-to-twin transfusion syndrome (TTTS) in a referral center in Brazil. Methods: This prospective observational study analyzed 24 fetoscopic laser photocoagulation procedures at 18-26 weeks of gestation. TTTS severity was determined using the Quintero classification. Blood vessels that crossed the interamniotic membrane were nonselectively photocoagulated. The chi2 test and Mann-Whitney U test were used for the statistical analysis. Results: The mean (+/-standard deviation) age of pregnant women, gestational age at surgery, surgical time, gestational age at birth, and newborn weight were 32.2+/-4.1 years, 20.7+/-2.9 weeks, 51.8+/-16.7 minutes, 30.5+/-4.1 weeks, and 1,531.0+/-773.1 g, respectively. Using the Quintero classification, there was a higher percentage of cases in stage III (54.2%), followed by stages IV (20.8%), II (16.7%), and I (8.3%). Ten (41.7%) donor fetuses died and 14 (58.3%) donor fetuses survived until the end of gestation. Placental insertion location (anterior vs. posterior) did not affect the incidence of iatrogenic septostomy, surface bleeding, and premature rupture of membranes until the end of gestation. The death rate of donor and recipient fetuses before 24th gestational week increased with severity of TTTS. Conclusion: The maternal and perinatal outcomes resulting from the implementation of a new minimally invasive surgical technique are in line with those obtained in major centers worldwide, considering the learning curves and infrastructures. PMID- 30018902 TI - Clinical factors that affect diagnostic discrepancy between colposcopically directed biopsies and loop electrosurgical excision procedure conization of the uterine cervix. AB - Objective: This study aimed to determine the factors affecting pathologic discrepancy and final diagnosis between colposcopic biopsy and pathology by loop electrosurgical excision procedure (LEEP). Methods: Between 2004 and 2016, 1,200 patients who underwent LEEP were enrolled for this study. 667 underwent cervical cytology, human papillomavirus (HPV) test, colposcopic biopsy, and LEEP. We analyzed patient's age, menopausal status, number of delivery, abortion times, cervical cytology, number of punch biopsies, HPV type, LEEP, and interval between colposcopic biopsy and LEEP. Results: Logistic regression analysis of the final diagnosis showed that age 30-39 years and other high HPV group types were associated with cancer diagnosis, whereas atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H), high-grade squamous intraepithelial lesion (HSIL), and HPV type 16 affected the diagnosis of cervical intraepithelial neoplasia (CIN) 2. The overall concordance rate of histopathology between punch biopsy and LEEP was 43.3%. The rates of detecting a more severe lesion by LEEP than those by biopsy were 23.1%. The rates of a less severe lesion detected by LEEP than those by biopsy were 33.6%. Factors related with biopsy underestimation were as follows: <1 vaginal delivery, HSIL, number of punch biopsies and HPV type. Punch biopsy number is a unique factor of biopsy overestimation. Conclusion: Patients with ASC-H, HSIL, and HPV type 16 may undergo conization immediately without colposcopic biopsy. We suggest that colposcopically directed 3 to 5 punch biopsies may be used to determine the need for conization. PMID- 30018903 TI - Comparison of the clinical outcome of frozen-thawed embryo transfer with and without pretreatment with a gonadotropin-releasing hormone agonist. AB - Objective: To describe the clinical outcomes of frozen-thawed embryo transfer (FET) with artificial preparation of the endometrium, using a combination of estrogen (E2) and progesterone (P4) with or without a gonadotropin-releasing hormone agonist (GnRHa), and the modified natural cycle (MNC) with human chorionic gonadotropin (hCG) trigger. Methods: In this retrospective study, we evaluated 187 patients during 3 years (February 2012-April 2015). The patients were allocated to the following treatment groups: group A, comprising 113 patients (181 cycles) who received GnRHa+E2+P4; group B, comprising 49 patients (88 cycles) who received E2+P4; and group C, comprising 25 patients (42 cycles) who received hCG+P4. The inclusion criteria were regular menstrual cycles (length 24-35 days) and age 21-45 years. Results: The primary outcome of the study - implantation rate (IR) per embryo transferred - was not statistically different among the 3 groups. Similar results were found for the IRs with fetal heartbeat per embryo transferred (68/181 [37.6%] in group A vs. 22/88 [25.0%] in group B vs. 14/42 [33.3%] in group C) and for the live birth rates (LBRs) per embryo transferred (56/181 [30.9%] in group A vs. 18/88 [20.5%] in group B vs. 11/42 [26.2%] in group C). Conclusion: Although the pregnancy outcomes were better in the hormone therapy with GnRHa group, hormone therapy FET with GnRHa for pituitary suppression did not result in significantly improved IRs and LBRs when compared with hormone therapy FET without GnRHa or MNC FET. PMID- 30018905 TI - Correlation between the posterior vaginal wall and apex in pelvic organ prolapse. AB - Objective: The aim of our study is to reveal the correlation between the posterior vaginal wall and apex in pelvic organ prolapse. Methods: We retrospectively reviewed the records of all new patient visits to a urogynecology clinic between January 2013 and December 2015. Results: Four hundred five cases were enrolled in our study. When all POP stages were included, the Bp (pelvic organ prolapse quantification point) had a moderate correlation with the C (Pearson's r=0.419; P<0.001). Cases where Bp was stage 3 and above presented strong positive correlations with C (Spearman's rho=0.783; P<0.001). Cases where C was stage 3 and above presented also strong positive correlations with Bp (Spearman's rho=0.718; P<0.001). Conclusion: Posterior vaginal wall prolapse and apical prolapse were correlated with each other, and this correlation was more prominent as stage increased. Therefore, when admitting a patient suspected of posterior vaginal wall prolapse or apical prolapse, it is necessary to evaluate both conditions. Especially in cases more severe or equal to stage 3, it is a must to suspect both conditions as the 2 are strongly correlated. PMID- 30018904 TI - Clinical outcomes of frozen embryo transfer cycles after freeze-all policy to prevent ovarian hyperstimulation syndrome. AB - Objective: To compare the clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR) in frozen embryo transfers (FETs) following either freeze-all policy to prevent ovarian hyperstimulation syndrome (OHSS; freeze-all group) or excess embryo cryopreservation after fresh embryo transfer (surplus group). Methods: The freeze-all group comprised 44 FET cycles performed in 25 women between 2010 and 2016. The surplus group comprised 53 FET cycles performed in 47 women during the same period. The cumulative CPR and OPR according to duration of cryopreservation (interval between cryopreservation and FET) was estimated using Kaplan-Meier plots. Cox regression analysis was used for identifying factor to affect to cryopreservation duration in cycles with pregnancy. Results: In day 2-4 transfer cycles, the crude CPR (40% vs. 18.2%) and OPR (20% vs. 4.5%) were similar between the 2 groups. In day 5 transfer, the crude CPR (33.3% vs. 38.7%) and OPR (33.3% vs. 29%) were also similar between the 2 groups. The cumulative CPR (100% vs. 47.5%) and OPR (100% vs. 33.3%) in day 2-4 transfer as well as the cumulative CPR (46.7% vs. 100%) and OPR (46.7% and 74.8%) in day 5 transfer were also similar between the 2 groups. The median duration of cryopreservation was significantly shorter in the freeze-all group than in the surplus group (19.8 vs. 36.9 weeks, P=0.04). Previous history of delivery was the only factor associated with a shorter cryopreservation duration in cycles with pregnancy (hazard ratio, 0.18; 95% confidence interval, 0.05-0.65; P=0.01). Conclusion: Freezing embryos to prevent OHSS and transferring the frozen embryos later may guarantee an acceptable reproductive outcome. PMID- 30018906 TI - Aberrant uterine leiomyomas with extrauterine manifestation: intravenous leiomyomatosis and benign metastasizing leiomyomas. AB - Objective: Intravenous leiomyomatosis (IVL) and benign metastasizing leiomyoma (BML) are uncommon variants of benign uterine leiomyomas with extrauterine manifestations. Categorizing the extent of disease allows clinicians to delineate the clinical spectrum and the level of sophistication for complete surgical resection. Methods: Twelve patients with IVL and BML were reviewed. They were divided into early versus late stage disease groups, and initial manifestation, clinical characteristics, laboratory values, surgical pathology, and follow up data were summarized. Results: Patients were mostly pre- or peri-menopausal and parous. Patients with late stage disease were more likely to present with cardiac symptoms or abnormal findings on chest X-ray, whereas those with early stage disease presented with classical leiomyoma symptoms including heavy menstrual bleeding, increased myoma size, or lower abdominal discomfort. Tumor marker levels were within normal ranges. A trend of higher neutrophil to leukocyte ratio was observed in the late versus the early stage group (10.4 vs. 1.51, P=0.07); the platelet leukocyte ratio was statistically higher in patients with late stage IVL (0.23 vs. 0.13, P=0.04). The overall recurrence rate was 25%. No recurrence was observed in stage I or stage III IVL groups, while 50% of the stage II IVL group showed recurrence in the pelvic cavity. Conclusion: IVL and BML are benign myoma variants with paradoxically metastatic clinical presentation. Careful inquiry of systemic symptoms, the presence of underlying systemic inflammation, and a high index of suspicion are required for preoperative diagnosis. Furthermore, a multidisciplinary approach is necessary to improve outcomes of surgical resection. PMID- 30018907 TI - Extra-adrenal paraganglioma masquerading as severe preeclampsia. AB - Paraganglioma in pregnancy is an extremely rare condition and its diagnosis is often delayed because the clinical symptoms can mimic those of preeclampsia or gestational hypertension. Here, we report the case of a 32-year-old, gravida 2, para 1 woman who presented with severe headache, palpitation, and sweating at 37 weeks' gestation. Although emergent cesarean section was performed on the assumption of severe preeclampsia, blood pressure fluctuated and heart rate remained tachycardiac. We suspected that she might have thromboembolic lesion in the chest or pheochromocytoma. Chest and abdominal computed tomography revealed a 4 cm mass in the left para-aortic space. Serum and urinary catecholamine levels were found to be significantly increased. She underwent laparoscopic mass removal and the pathology confirmed paraganglioma. When typical paroxysmal hypertension is accompanied by headache, palpitation, and sweating during pregnancy, adrenal tumors should be considered. PMID- 30018908 TI - Primary malignant melanoma of the uterine cervix treated with pembrolizumab after radical surgery: a case report and literature review. AB - Malignant melanoma of the genital tract is a rare disease that is usually diagnosed by chance. When a definite diagnosis is delayed, the prognosis is very poor without standardized treatment. Herein, we describe a 40-year-old patient who presented with a history of bloody vaginal discharge for 7 months. Gynecological examination showed an exophytic, hard and pigmented cervical mass involving the upper vagina. The patient was diagnosed with cervical melanoma after a punch biopsy and underwent a radical hysterectomy, upper vaginectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. After surgeries, the patient underwent 2-cycles of adjuvant immunotherapy with pembrolizumab, but died within 8 months. In this report, treatment with pembrolizumab after radical surgery was not effective for this patient who had a primary cervical melanoma that metastasized to bone and lung tissue. We do not know why pembrolizumab was ineffective for this patient, but there are several possible explanations; further research is needed. PMID- 30018909 TI - An unusual presentation of ovarian dermoid cyst: a case report and review of literature. AB - Dermoid cysts or mature cystic teratoma are the most common type of ovarian germ cell tumor. It may be complicated by torsion, rupture, chemical peritonitis and malignant change but is rarely complicated by infection. We present a case of an ovarian dermoid cyst with super-infection caused by Schistosoma haematobium (S. haematobium). We present here a case of incidental finding of S. haematobium eggs in an infected cystic teratoma of the ovary because of the rare occurrence of this lesion. A 45-year-old Moroccan woman admitted to the gynecological department because of abdominal pain and fever. Gynecological examination, ultrasonography, and abdominopelvic computed tomography scan revealed an ovarian mass thought to be a dermoid cyst. The pathological evaluation suggested infected ovarian dermoid cyst with the presence of adult worm in the tumor, contains same eggs of S. haematobium. Super-infection of an ovarian dermoid cyst is a rare event, and the association with S. haematobium is extremely rare in the literature. PMID- 30018910 TI - Vaginal sling implant misdiagnosed as rectal subepithelial tumor. AB - As cosmetic procedures receive increasing attention from the media, female genital cosmetic surgery (FGCS) has become quite popular in Korea. The safety and efficacy of these surgeries and procedures have yet to be thoroughly documented. We report a case of a 47-year-old woman who underwent a vaginal sling implantation, which resulted in the misdiagnosis of a rectal subepithelial tumor during endoscopic mucosal resection (EMR). This patient suffered an iatrogenic rectal perforation during the EMR, which necessitated an exploratory operation. The sling implant was removed via the vaginal approach, and a primary repair of the vaginal and rectal walls was performed. The patient subsequently showed no sign of complication at her 6-month follow-up. Patients need to be educated about the importance of reporting a history of FGCS prior to undergoing surgical or endoscopic procedures. Also, physicians have to check the medical history of patient thoroughly to avoid misdiagnoses and unnecessary treatment. PMID- 30018911 TI - Erratum: Correction of Acknowledgements. AB - [This corrects the article on p. 328 in vol. 61, PMID: 29780774.]. PMID- 30018912 TI - Exercise rehabilitation new genre pioneering. PMID- 30018913 TI - Urology as rehabilitation medicine: a literature review. AB - As a urologist, we usually encounter with two representative functional behaviors, namely, voiding and sexual function. These are not only important but also complex and synchronized so if these functions are impaired, patients need active functional rehabilitation to recover. These functional impairments should be recognized and corrected early because they could not only cause direct damage to the affected functions but also have harmful consecutive consequences such as kidney damage due to voiding abnormality and self-esteem damage due to decreased sexual function. Numerous rehabilitative methods are currently available, which help minimize the negative effects of these functional impairments. In terms of voiding function, pelvic floor muscle exercise, biofeedback, functional magnetic stimulation, neuromodulation, and clean intermittent self-catheterization are representative rehabilitation modalities. In case of children, extra-attention should be paid because this might affect their entire life. In impairment of sexual function, early intervention to maintain male erection is the main target of rehabilitation to prevent corporal fibrosis and penile deformity and increase recovery chance in patients who underwent radical prostatectomy or major surgery. In this review, we will elucidate various rehabilitation methods in urology to further increase our understanding of the rehabilitative characteristics of urology and widen our view of rehabilitation medicine. PMID- 30018915 TI - Treadmill exercise with bone marrow stromal cells transplantation facilitates neuroprotective effect through BDNF-ERK1/2 pathway in spinal cord injury rats. AB - Transplantation of bone marrow stromal cells (BMSCs) has been known as one of the effective therapeutic methods for functional recovery of spinal cord injury (SCI). Treadmill exercise also facilitates the functional recovery of SCI. Previously, we reported that combination of BMSCs transplantation with treadmill exercise potentiated the locomotor function in SCI rats. In the present study, we investigated whether recovery effect of BMSCs transplantation or treadmill exercise appears through the brain-derived neurotrophic factor (BDNF) extracellular signal-regulated kinases 1/2 (ERK1/2) pathway. The spinal cord contusion injury was performed at the T9-T10 level using the impactor. Cultured BMSCs were transplanted directly into the lesion 1 week after SCI. Treadmill exercise was performed 6 days per a week for 6 weeks. Western blot for Bax, Bcl 2, BDNF, tyrosine kinase B (TrkB), and phosphorylated ERK1/2 (p-ERK1/2), phosphorylated JNK was performed. In the present results, combination of BMSCs transplantation with tread-mill exercise potently decreased Bax expression, potently increased Bcl-2 expression, and potently enhanced BDNF and TrkB expressions in the injured spinal cord. Combination of BMSCs transplantation with treadmill exercise further facilitated p-ERK1/2 and p-c-Jun expression levels. The present findings demonstrated the synergistic effect of treadmill exercise on neuroregenerative effect of BMSCs transplantation appeared through the activation of BDNF-ERK1/2 pathway in SCI. PMID- 30018914 TI - Late starting treadmill exercise improves spatial leaning ability through suppressing CREP/BDNF/TrkB signaling pathway following traumatic brain injury in rats. AB - Traumatic brain injury (TBI) causes deficit in spatial learning and memory function. Physical activity ameliorates neurological dysfunction after TBI. We investigated the effect of late starting treadmill exercise on spatial learning ability in relation with cAMP-response element binding protein (CREB)/brain derived neurotrophic factor (BDNF) signaling pathway using TBI rats. For this study, radial 8-arm maze test, TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labeling) staining, caspase-3 immunohistochemistry, and western blot for Bax, Bcl-2, BDNF, tyrosine kinase B (TrkB), CREB, and phosphorylated CREP (p-CREB) were performed. TBI was induced by an electromagnetic-controlled cortical impact. The rats in the exercise groups were scheduled to run on a treadmill for 30 min once a day for 8 weeks starting 3 weeks after TBI. TBI impaired spatial learning ability and increased caspase-3 expression in the hippocampal dentate gyrus. TBI enhanced Bax expression and suppressed Bcl-2 expression in the hip-pocampus. TBI increased BDNF and TrkB expressions, resulted in the enhancement of p-CREB/CREB ratio in the hippocampus. However, treadmill exercise improved spatial learning ability, decreased caspase 3 expression, suppressed Bax expression, and increased Bcl-2 expression. Treadmill exercise alleviated TBI-induced over-expression of BDNF and TrkB, which suppressed phosphorylation of CREB in the hippocampus. In the present study, late starting treadmill exercise improved spatial learning ability through suppressing TBI-induced activation of CREB/BDNF/TrkB signaling pathway after TBI. PMID- 30018916 TI - Simulated altitude exercise training damages small intestinal mucosa barrier in the rats. AB - This study investigated the effect of simulated altitude training on the changes of small intestinal mucosa barrier, bacterial overgrowth and inflammatory response in the small intestine of rat. Male 8-week-old Sprague-Dawley rats were randomly divided into four groups: normal oxygen sedentary group (n=30), normal oxygen exercise group (n=30), low oxygen sedentary group (n=30) and low oxygen exercise group (n=30). Exercise training was on a treadmill for 1 hr per day on days 3, 6, and 9 in the hypoxia condition. Hematological profiles, hematolxylin and eosin staining, fluorescence in situ hybridization, reverse transcription polymerase chain reaction and Western blot were used to analyze the effect of simulated altitude training on the amount of bacteria, and expression of mRNA and protein. Simulated exercise training significantly increased red blood cells and hematocrit. The small intestinal mucosa barrier was significantly injured by the simulated altitude exercise training. Comparatively more bacterial growth was evident in the small intestine by the simulated altitude exercise training. mRNA levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) and protein expression of nuclear factor-kappa B (NF-kappaB) were significantly elevated by simulated altitude exercise training. These results suggest that the simulated altitude exercise training may impair the small intestinal mucosa barrier via elevation of bacterial growth and inflammatory cytokines (IL-6, TNF alpha) and the up-regulation of NF-kappaB in the rats. PMID- 30018917 TI - Relationship between attention and balance: a dual-task condition study in children. AB - This study explored the relationship between motor functions and attention in children aged 4-5 years. A sample of 85 children was collected from a primary school (44 boys and 41 girls). We applied a standardized continuous attention performance test, the Kiddie Continuous Performance Test, under two conditions (sitting and balancing). Data were collected from two standardized balance tests, the Battelle and Pediatric Balance Scale. There was a significant relationship between attention and balance and gender differences that may condition the way to address balance issues in boys and girls. Gender should be considered when addressing balance problems to get efficient interventions. Balance skill may be a contributing factor in attention-deficit/hyperactivity disorder. PMID- 30018918 TI - The effectiveness on sociality and social relationship by therapeutic recreation based on partner and group activity in the institutionalized elderly. AB - This research examined the effects on sociality and social relationship of therapeutic recreation program (TRP) based on partner and group activity in the institutionalized elderly as the level of psycho-social rehabilitations. TRP sessions were designed to encourage interaction and social relationship between two people or groups performing different types of tasks applied on Mosey's 5 step interaction skills. TRP was conducted for a total of 8 sessions, once a week, for 8 weeks. Using a pre-post experimental design, eight volunteer's data were analyzed to examine changes in sociality and social relationship. As the result, the degree of sociality was significantly changed from 3.14 to 3.73 (P= 0.002), as well as notable improvements of social relationships were found to have statistically increased from 3.27 to 4.10 (P=0.001). Therefore, this study suggests that partner and group-based recreation programs while considering how and when facilitate interaction between participants should be applied as a way to solve the social problems and isolation of the elderly in the future. PMID- 30018920 TI - Applications of psychological skills training for Paralympic table tennis athletes. AB - This study examined effects of psychological skills training (PST) for Korean national table tennis athletes with spinal cord injuries (SCI), who were training for the 2012 London Paralympics. Participants were three male table tennis players with level two SCI, and all participants attended a total of eight sessions of PST over a period of 3 months. The PST consisted of self-talk, imagery, cognitive reconstructing, and routine. To examine the effectiveness of mental coaching, the Test of Performance Strategies questionnaire was administered over three different periods of time: pre-PST, post-PST, and postcompetition. Pre- and posttest outcomes indicated that there were positive changes in self-talk, emotional control, and goal setting of athletes with SCI. With the exception of relaxation, Athlete 1 was able to maintain and use all of the improved mental skills in Paralympic competitions. However, although the mental skills of the athletes 2 and 3 generally improved, they were not able to take full advantage of these improvements in Paralympic competitions. PST can be developed and effectively utilized by athletes with SCI. Disability-specific issues should be considered to provide a better intervention program. PMID- 30018919 TI - The effect of the type of physical activity on the perceived stress level in people with activity limitations. AB - The purpose of this study was to investigate the effect of the type of physical activity that people with activity limitations participate in on their perceived stress level. We analyzed the data of the Korean National Health and Nutrition Examination Survey (KNHANES) conducted annually from 2007 to 2015. The subjects of the study were adults aged 19 or older who had activity limitations. The data analysis was done using the SPSS ver. 18.0 program, and complex sampling design frequencies analysis and logistic regression analysis were conducted. The statistical significance level was set at P<0.05. The results of this study are as follows: First, in the case of males with activity limitations, the odds ratio (OR) for the perceived stress level for those who participated in walking exercise compared to those who did not was 0.707 (95% confidence interval [CI], 0.535-0.934; P<0.05). Second, for males with activity limitations, the OR for the perceived stress level for those who participated in walking exercise for 5 days or more compared to the nonparticipation group was 0.630 (95% CI, 0.472-0.841; P<0.05). Third, for females with activity limitations, the OR for the perceived stress level for those who participated in flexibility exercise compared to those who did not was 0.869 (95% CI, 0.727-1.039; P<0.05). Fourth, for females with activity limitations, the OR for the perceived stress level for those who participated in flexibility exercise for 5 days or more compared to the nonparticipation group was 0.672 (95% CI, 0.539-0.838; P<0.05). PMID- 30018921 TI - Progressive muscle relaxation technique on anxiety and depression among persons affected by leprosy. AB - Anxiety and depression have been found to be increasing among people with leprosy and it may lead to decreased social participation. The progressive muscle relaxation technique (PMRT) is widely used today in choice of treatment for reducing the anxiety and depression. This study aimed to assess the effectiveness of PMRT in reducing anxiety and depression among the hospitalized leprosy affected person in a tertiary care centre. This study is a case series of 50 leprosy affected people aged between 18-60 years who were admitted for leprosy complications in tertiary leprosy referral hospital. The Anxiety-Depression scale was developed and validated by the investigators and administered before intervention of PMRT and after 2 weeks. The follow-up assessment was done at 6 weeks after the initial intervention. The finding shows that a statistically significant difference was observed on anxiety domain before and after application of PMRT. The anxiety means score showed steady decline from 6.76 at pretest to 3.0 (t=25.068, P<=0.001) at post test and 1.12 (t=22.679, P<=0.001) at follow-up. In depression domain, a statistically significant difference was seen in before and after application of PMRT. The depression means score showed steady decline from 6.92 at pre test to 3.28 (t=16.082, P<=0.001) at post test and to 1.16 (t=18.918, P<=0.001) at follow-up. This study proved that the PMRT as a valid treatment option for hospitalized person with leprosy in minimizing the anxiety and depression related symptoms and to benefit the psychosocial wellbeing of leprosy affected patients. PMID- 30018922 TI - The influence of environmental constraints within hospitals on physical activity level of cancer patients. AB - This study aims to examine the influence of hospital environmental constraints on physical activity level of cancer patients. The subjects of this study were 194 cancer patients from five general hospitals in the Seoul metropolitan area (Seoul, Gyeonggi-do, and Incheon). The collected data was analyzed by using SPSS ver. 23.0. As a result of analyzing the effect of environmental constraints on the physical activity level of cancer patients, the constraints related to hospital facilities and programs had no effect on patients' time spent in a hospital bed and their time spent on daily. However, the time cancer patients spend on intentional physical movements is affected by hospital facilities or programs. This means that hospital facilities or programs play an important role in patients' intentional physical activities. In conclusion, for hospitalized cancer patients, physical activity levels are influenced by environmental constraints in the hospital. Therefore, it is important to improve the hospital environment to increase physical activities such as walking and physical exercise, which are an important factor for cancer recovery and prevention of recurrence. PMID- 30018923 TI - Factors associated with physical activity of women aged over 75 in South Korea. AB - Physical activity (PA) and the activity-related factors of aged women dwelling in a city community of Korea were examined for 253 participants aged over 75, regarding their socio-demographic characteristics, health status, physical performance, depression, cognitive function, self-efficacy, outcome expectations, and PA. Descriptive statistics, analysis of covariance, Pearson correlation, and multiple regressions were performed to analyze cross-sectional data. The data indicated the participants carry out low-intensity physical activities, such as house chores, light gardening, and walking for pleasure. Moderate and vigorous intensity physical activities were performed rare. The frequency per week was 15.62+/-8.60 for all listed activities. Frequency of PA decreased significantly in participants aged over 80, of poor perceived health, depression, and cognitive decline. There was a negative correlation between PA and the figure 8 walks (r= 0.20, P=0.002). PA showed significantly positive correlation with self-efficacy (r=0.34, P=0.001) and outcome expectations (r=0.36, P=0.001). In a regression analysis, explanation rate of factors influencing PA was 21.9 % (P=0.001). Outcome expectations (beta=0.23), cognitive function (beta= -0.20), and self efficacy (beta=0.19) influenced the PA. These findings indicate that interventions stimulating cognitive function and enhancing positive expectation and self-confidence should be included for PA promotion of older women aged 75 years and over. PMID- 30018924 TI - Meta-analysis on the effect of combined exercise program intervention on Korean middle-aged women. AB - The purpose of this study is to present a basis of application of an exercise program through a systematic analysis of the effect of combined exercise program for middle-aged women using meta-analysis. It appears that the overall effect size (0.606) of the combined exercise program was positive for improving physical strength and physiological function. The physiologically related variables showed an effect size which is equal to or greater than a middle level. This may be an objective basis to prove that the combined exercise program is an effective intervention method to overcome loss of functions and weakened functions by improving physical strength and preventing reduction of hormones. The combined exercise program was found to be most effective when it was conducted two times a week; for over 1 hr and 30 min to 2 hr; and at intensity of 40% or more for an 8 week period. As the combined exercise program showed an effect of a middle level or higher for all the middle-aged women in their age of 40 to 65, it appeared that this exercise program is very effective for middle-aged women. The results of this study suggest that the combined exercise program for middle-aged women is a very effective intervention method. This study can reduce inefficiencies of overly redundant studies regarding an effect of an exercise program, and can be grounds for the basic work for the integrated classification of the physiological variables. PMID- 30018925 TI - Postexercise hypotension and autonomic modulation response after full versus split body resistance exercise in trained men. AB - To investigate the effects of full versus split body resistance exercise on postexercise hypotension and autonomic modulation in trained men. Sixteen resistance recreationally trained males (age, 24.9+/-5.3 years) performed three randomized trials: upper body (UB), lower body (LB), and full body (FB) conditions. Blood pressure and heart rate variability were collected at rest, immediately postexercise, post-10, and post-30 min during recovery. For systolic blood pressure, delta (30 min minus rest) was lower for the FB condition compared to the UB (-10.1+/-7.4 mmHg [FB] vs. -3.3+/-12.6 mmHg [LB] vs. -1.9+/-8.1 mmHg [UB], P=0.004). For diastolic blood pressure (-8.2+/-10.9 mmHg [FB] vs. -1.5+/ 9.8 mmHg [LB] vs. -8.7+/-11.4 mmHg [UB], P=0.038) and mean blood pressure delta during recovery (-11.7+/-14 mmHg [FB] vs. -2.2+/-10.6 mmHg [LB] vs. -5.2+/-6.8 mmHg [UB], P=0.045), there were statistically significant lower values in the FB condition in relation to the LB condition. Regarding heart rate variability, there were no significant differences between conditions, however, the square root of the mean squared difference between adjacent RR intervals presented an increase until post-30 during recovery (P<0.001), and there was a higher values of low frequency and lower values of high frequency across time (P<0.001). Postexercise hypotension was influenced by the amount of muscle mass involved in a bout of resistance exercise, with the FB condition inducing lower systolic blood pressure in relation to the UB after exercise, as well as a great decrease in postexercise diastolic and mean blood pressure compared with the LB. The autonomic modulation response was similar between conditions during recovery. PMID- 30018926 TI - An analysis of the characteristics of sports activities and injury experiences of leisure sports participants. AB - The purpose of this study is to analyze exercise injury experiences of sports participants and the characteristics of sporting activities depending on whether they have injured or not. The subjects of this study included the 107 people who have experienced exercise injuries and the 103 people who have not have experienced exercise injuries with aged between the 20s and 40s. The questionnaire with household interviews was used for this research. The results of this study that the female participants who have experienced an injury while exercise was outnumbered by their male counterparts and it is found that sports participants in their 40s represented the highest ratio and that the two most popular sports the participants who have experienced injury did were body building and golf. It has been surveyed that the number of hospital care due to exercise injury per year is 2.01 times on average and the amount of money spent on the medical care is 34,252 Korean won on average. It is identified that the level of sports activities that keeping health and perception by the impact of sports activities depending on the participants' exercise injured. It is worthy of notice that those who have experienced exercise injuries tended to show a high level of confidence in which they could benefit from sports activity. In addition, it is interesting to note that bodybuilding and golf were the two sports with a great number of exercise injuries. PMID- 30018927 TI - Determination of the relationship between core endurance and isokinetic muscle strength of elite athletes. AB - Muscle strength and core endurance are both factors contributing to athletes' performance and prevalence of injuries. There are no studies indicating the relationship between muscle strength around the shoulder and knee joints and core endurance. The aim of our study is to determine the relationship between core endurance and isokinetic muscle strength of knees and shoulders of elite athletes. Seventy-one elite athletes (weight lifting, boxing, taekwondo, biathlon, and ice skating) (age, 18.13+/-2.9 years) were included in the study. Isokinetic muscle strength of shoulder internal-external rotation and knee flexion-extension were determined by using an Isomed 2000 device. Core endurance of athletes was assessed using the Mcgill Core Endurance Tests. There was a relationship between the shoulder internal rotation and external rotation peak torque/body weight (PT/W) and all endurance tests except extension endurance tests. There was also a relationship between knee flexion PT/W and all core endurance tests. While there was a relationship between knee extension PT/W and extension endurance and the lateral bridge test, this relationship was not found with the flexor endurance test. These results indicate that the upper and lower extremity muscle strength and core endurance of athletes are related with each other and must be evaluated and trained as a whole with each other. PMID- 30018928 TI - The difference effect of estrogen on muscle tone of medial and lateral thigh muscle during ovulation. AB - The purpose of this study was to investigate the difference effect of estrogen on muscle tone of medial and lateral thigh muscle during ovulation (OV). Twenty eight untrained eumenorrheic healthy women tested muscle stiffness and frequency of vastus medialis, vastus lateralis, semitendinosus, and biceps femoris during menstrual cycle (MC). MC were divided into menses (MS), OV, and luteal phase (LP). The muscle frequency of vastus medialis and semitendinosus were significant higher in OV (13.83+/-1.58 Hz, 15.62+/-2.39 Hz) than LP (13.18+/-0.85 Hz, 14.67+/ 1.62 Hz). Also the muscle stiffness of vastus medialis and semitendinosus were significant higher in OV (211.74+/-46.03 N/m, 241.95+/-48.35 N/m) than LP (184.26+/-26.09 N/m, 215.42+/-35.29 N/m). The present study showed the highest muscle stiffness and frequency at OV and this might be due to the rapid increase of sole hormone in estrogen. Especially, medial part of quadriceps and hamstrings might be influenced during the MC with high concentration of estrogen at OV. PMID- 30018929 TI - Comparative kinematic analysis of the baseball pitching motions of high school athletes in relation to pitching conditions. AB - To analyze changes in pitching motions in relation to pitching conditions during practice versus game comparatively, seven high school over-throwing pitchers served as subjects in this study, who then performed pitches in various conditions. Data were processed using the statistical analysis program SPSS 21.0, and the moving distances and angles of the joints at the point of ball release were analyzed using repeated measurements one-way analysis of variance, followed by Bonferroni post hoc tests. Statistical significance was determined at P<0.05, and the following conclusion was obtained. According to the pitching conditions, the elbow joint was lengthened, and the torso leaned towards the nonpitching arm during pitching. Further, the pitching stride increased, causing the forward transfer of the landing foot and the pitching hand. Based on these observations, it is important to establish a pitching training method that minimizes inconsistency in pitching motions by simulating game-like conditions during pitching practices and developing various training programs. Further investigation is required for a comprehensive mechanical analysis of muscle usage and damage in pitching motions in relation to various pitching conditions. PMID- 30018930 TI - Changes in lower extremity function and pitching performance with increasing numbers of pitches in baseball pitchers. AB - Compared to upper extremity function, the changes in lower extremity function with increasing numbers of pitches have not fully been investigated in baseball pitchers. In addition, little is known about the correlation between lower extremity function and pitching performance. The purpose of this study was to evaluate the effect of fatigue on lower extremity function and pitching performance in a simulated baseball game. Eighteen collegiate baseball pitchers threw 117 pitches in 9 innings (13 pitches per inning) with 5-min rest between innings at an official pitching distance in a simulated game. Isometric hip muscle strength (abduction and adduction) and squat jump performance (height, mean/peak power, and mean/peak velocity) were measured before and after the game. The mean ball velocity and pitching accuracy were assessed per inning. Ball velocity significantly decreased in the 7th (P=0.026) and 9th (P=0.001) innings compared to the 1st inning, but pitching accuracy did not change significantly. Hip abduction (P=0.009) and adduction (P=0.001) strength significantly decreased after the game, but squat jump performance did not significantly change before and after the game. A significant correlation between decreased ball velocity in the 9th inning and decreased hip adduction strength was found (P=0.011, r=0.583). Our findings suggest that hip abduction and adduction strength are susceptible to fatigue owing to repetitive throwing motions and that hip adduction strength, especially, is an important physical fitness factor for maintaining ball velocity during a game in baseball pitchers. PMID- 30018931 TI - Effects of weighted baseball throwing during warm-up on ball velocity and upper extremity muscle activation in baseball pitchers. AB - The objective of this study was to investigate the changes in the muscle activation of high school and college baseball pitchers during throwing of the ball with maximum effort (TBME) using a regular baseball (RB) subsequent to using a light baseball (LB), RB, and overweight baseball (OB) during warm-up (WU) and the resulting changes in the pitch velocity. The study aimed to use the findings in providing basic data for a training program designed to increase the pitch velocity of baseball pitchers. The study population consisted of 12 high school and college baseball players. The study measured and analyzed the upper extremity muscle activation and ball velocity in the stride, arm cocking, and acceleration phases during TBME using an RB subsequent to using an LB, RB, and OB during WU. During WU, the ball velocity was higher when pitching with an LB than with an RB or OB and when pitching with an RB than with an OB. However, there were no significant differences in the ball velocity when pitching with an RB during TBME. In conclusion, WU using weighted baseballs resulted in varying muscle activations, and although the velocity decreased when pitching with an OB, no difference was found during TBME using an RB. Therefore, it is believed that using weighted baseballs during WU does not have an effect on the ball velocity during TBME; future studies are needed on the effects through long-term training. PMID- 30018932 TI - Effect of hip position and breathing pattern on abdominal muscle activation during curl-up variations. AB - Recent studies have indicated that applying different breathing pattern and changes of extremity positions could be a useful way of performing challenging exercises that include coactivation of the abdominal muscles. The aim of this study was to investigate the effects of changes of breathing pattern and hip position on abdominal muscle activity during curl-up exercises. Surface electromyography responses of the rectus abdominis (RA), internal oblique (IO), external oblique (EO) muscles and rectus femoris (RF), and Borg rating of perceived exertion (Borg RPE) score were investigated during the curl up exercises. A total of 20 healthy, physically active male volunteers completed two hip positions (45 degrees and 90 degrees hip flexion) and three breath types (slow expiration, maximal inspiration, and maximal expiration) for curl-up variations. The curl-up with 90 degrees of hip flexion significantly increased the muscular activities of IO, EO, RF, and Borg RPE score (P<0.05). The curl-up with maximal expiration significantly elevated the IO and EO activity, compared to other breathing conditions. There were no significant difference in RA activities (P>0.05). The present study showed both the hip position and breathing pattern affect abdominal muscle activities during the curl-up exercise, especially of the oblique muscles. Among the breathing patterns investigated herein, the curl-up with maximum expiration produced greater activation of the oblique muscles compared to slow expiration and maximum inspiration. PMID- 30018933 TI - Skin temperature changes during muscular static stretching exercise. AB - This study aimed to investigate the acute effects of stretching exercise on skin temperature, flexibility, passive muscle stiffness, and pain during hamstring stretching in healthy young subjects. Thirty-one participants (n=31) were randomly divided into 2 groups: an experimental group (EG, n=15), which was submitted to hamstring stretching exercise for 180 sec, and the control group (n=16), which was not exercised. Skin temperature (TsK) was collected in subjects' posterior thigh using a thermographic camera at 7 time points with intervals of 30 sec each: T0 (rest), T30, T60, T90, T120, T150, and T180. In addition, the knee range of motion, passive stiffness and muscle soreness (visual analogue scale) were recorded during the stretching procedure at the same times. The EG presented a small but progressive increase in TsK (30.8 degrees C+/-0.6 degrees C to 31.1 degrees C+/-0.6 degrees C, P<0.01), with an increased range of motion (P<0.01) and muscle soreness levels (P<0.01) during the gradual hamstring stretching protocol. Additionally, there was an increment of passive stiffness (P<0.01) that was partially reversed toward the end of the stretching period. This research presents evidence that constant, passive and progressive stretching of the hamstrings progressively increased the local TsK by about 0.3 degrees C after 180 sec of stretching. These findings may help to understand the effects of repeated stress on the muscle-tendon unit and the role of muscle stretching in warm-up protocols and rehabilitation. PMID- 30018934 TI - Effect of circuit training on body composition, physical fitness, and metabolic syndrome risk factors in obese female college students. AB - The purpose of this study was to investigate the effect of a 12-week circuit training program on health-related physical fitness and metabolic syndrome risk factors in obese female college students. Twenty subjects with over 30% of accumulated body fat voluntarily participated and were randomly allocated to the control group (n=10) or circuit training group (n=10). The circuit training program consisted of 10 types of resistance and aerobic exercise and was performed 3 times per week for 12 weeks. Health-related physical fitness and metabolic syndrome risk factors were analyzed to elucidate the effect of the circuit training. Significant differences between groups were determined with two way repeated analysis of variance and paired t-test. As a result of this study, body weight, % body fat, and body mass index in the circuit training group was significantly decreased compared to the control group. All health-related physical fitness indicators such as back strength, sit-up, sit-and-reach, and 1,600 m running time showed relative effects between groups or over time. Among the metabolic syndrome risk factors, waist measurement, triglyceride, and total cholesterol were significantly decreased but blood glucose, high-density lipo protein cholesterol and low-density lipoprotein cholesterol did not show any significant difference. Therefore, the present data suggested that circuit training for 12 weeks may be effective in improving physical fitness and preventing metabolic diseases. PMID- 30018935 TI - Wushu Nanquan training is effective in preventing obesity and improving heart function in youth. AB - This study examined the differences of heart rate (HR) and body composition in elementary students who practiced two different styles of Wushu: Nanquan (NQ) and Changquan (CQ). A total of 40 subjects between the ages of 8 and 12 participated in this study who were grouped into NQ (n=20) and CQ (n=17). The results showed that the decreased body weight, increased basal metabolic rate, and higher physical efficiency index were due to the higher real-time HRs of NQ training compared with those of CQ training from 25 to 40 sec. Therefore, this study confirmed that Wushu NQ training can help to prevent obesity and improve heart function in elementary students. PMID- 30018937 TI - A study on the characteristics of standing posture of elderly women with sarcopenia in Korea. AB - This study intended to analyze the characteristics of standing posture and factors related to sarcopenia of elderly women in Korea to provide basic data for the development of rehabilitation programs designed to prevent and control of the sarcopenia of elderly women. A total of 194 elderly women, aged over 65 years old, living in Gyeonggi-do, were selected to diagnose the presence of sarcopenia through bioelectrical impedance analysis (BIA) and muscle function test (gait speed and grip strength). The subjects were then distinguished into normal group (NG=92), presarcopenia group (PG=86), and sarcopenia group (SG=16); the standing posture of elderly women was captured with the three-dimensional (3D) imaging technique (PA200), and an analysis of variance (ANOVA) was carried out for the collected data through IBM SPSS Statistics ver. 23.0. The frontal measurements of standing posture, the pelvic level, R-patella center, and L-patella center, appeared with significant differences from each other whereas, the side measurements of standing posture, the R-earhole position, L-earhole position, R shoulder position, L-shoulder position, R-pelvic angle, L-pelvic angle, R-knee position, and L-knee position, were also found with significant differences from each other. As a consequence, an intervention to be focusing on obese control was found necessary to prevent or to delay the presence of sarcopenia of elderly women. The positional displacement found from head, knee, and pelvis also necessitates the introduction of rehabilitation program customized for elderly women suffering the sarcopenia. PMID- 30018936 TI - Effectiveness of combined and conventional exercise trainings on the biochemical responses of stroke patients. AB - Stroke is the topmost cause of mortality and disability in Ghana. Conventional exercise is mostly used aside pharmacological management technique but the complimentary effects of combined exercise training (CET) have not been reported. This study investigated the effectiveness of combined and conventional exercise trainings on lipid-cardiovascular profiles and body composition among stroke patients in Kumasi. Thirteen stroke survivors between ages 35-68 years (mean+/ standard deviation: age, 59.88+/-10.88 years; duration of illness, 18.11+/-7.72 years) participated in the study. Participants were randomly assigned to CET and conventional exercise group. The CET had 10 weeks of 3 types of exercise trainings, 3 days/wk; conventional exercise group monitored for daily conventional activities during the same period. Post weight (P= 0.003), body mass index (P=0.004), systolic blood pressure (P=0.022), diastolic blood pressure (P=0.004), heart rate (P=0.003), and total cholesterol (P=0.044) of the CET were significantly improved. CET significantly improved total cholesterol (P=0.005) and low-density lipoprotein (P=0.006) better than the conventional exercises. Effectiveness of CET to positively enhance biochemical responses in the management of strove patients was established. PMID- 30018938 TI - Synaptophysin and caspase-3 expression on lumbar segments of spinal cord after sensorimotor restriction during early postnatal period and treadmill training. AB - The purpose of the current study was to investigate whether locomotor stimulation training could have beneficial effects on spinal cord plasticity consequent to sensorimotor restriction (SR). Male Wistar rats were exposed to SR from postnatal day 2 (P2) to P28. Control and experimental rats underwent locomotor stimulation training in a treadmill from P31 to P52. The intensity of the synaptophysin and caspase-3 immunoreaction was determined on ventral horn of spinal cord. The synaptophysin immunoreactivity was lower in the ventral horn of sensorimotor restricted rats compared to controls animals and was accompanied by an increased caspase-3 immunoreactivity. Those alterations were reversed at the end of the training period. Our results suggest that immobility affects the normal developmental process that spinal cord undergoes in early postnatal life influencing both pro-apoptotic and synapse markers. Also, we demonstrated that this phenomenon was reversed by 3 weeks of treadmill training. PMID- 30018939 TI - Potential for foot dysfunction and plantar fasciitis according to the shape of the foot arch in young adults. AB - This study investigated potential for foot dysfunction and plantar fasciitis according to the shape of the foot arch in young adults. Fifty-two participants were required for the present study design to achieve 80% power, 0.8 effect size (eta2), and an alpha level of 0.05. This study recruited 52 young adults (30 men and 22 women). All participants voluntarily agreed to participate in the study after hearing explanations about the purpose and process of the study. They were divided into two groups of 26 according to the shape of foot with and without flat foot using the navicular drop test. The participants were measured the foot function index (FFI), range of motion (ROM) of ankle, and four-way ankle strength. Additionally, the thickness of the plantar fascia was measured using ultrasonography. Intraclass correlation coefficient (ICC) was used to verify the inter- and intrarater reliability of ultrasonography. The inter- and intrarater reliability was excellent (ICC2,1=0.88, ICC3,1=0.93). There were significant differences in dorsi-flexion of ankle ROM, FFI, dorsi-flexion and eversion of ankle strength, and the thickness of the plantar fascia between the two groups (P<0.05). Based on the results, the group with flat foot may gradually generate potential of the foot dysfunction and plantar fasciitis. Therefore, the interventions are necessary to improve the foot dysfunction and plantar fasciitis in people with flat foot. PMID- 30018877 TI - Considerations and consequences of allowing DNA sequence data as types of fungal taxa. AB - Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN. PMID- 30018940 TI - Ipsilateral proprioceptive neuromuscular facilitation patterns improve overflow and reduce foot drop in patients with demyelinating polyneuropathy. AB - The purpose of this study was to evaluate the response of the tibialis anterior muscle (TAm) using surface electromyography in patients with Charcot-Marie-Tooth disease (CMT-IA), after ipsilateral proprioceptive neuromuscular patterns (PNF). Thirteen CMT-IA patients (both sexes) were treated twice a week, for 5 weeks, with bilateral PNF pattern, four times per treatment. During the execution of the patterns, we recorded the bilateral activation of the TAm in root mean square (RMS). We used the Student paired t-test for the first and last treatments, P value set at <0.05. Clinical significance (CS) was obtained by subtracting the values of the first treatment from the last. Chopping pattern to the right side increased RMS for the right (t=-3.52, CS=52%), but not the left TAm (t= -3.35). Flexion-abduction with external rotation pattern to the right (t= -2.46, CS=55%) and left (t=-2.07, CS=53%) significantly increased RMS for TAm on both sides. Extension-adduction with internal rotation pattern to the right (t=-0.25) and left (t=-1.84) did not produce any changes in TAm. Ipsilateral PNF patterns selectively produce TAm overflow in peripheral polyneuropathy patients and can be successfully used as supportive therapy for foot drop. PMID- 30018941 TI - Neck pain and low back pain in relation to functional disability in different sport activities. AB - This population-based, cross-sectional study aimed to determine the frequency of neck pain, low back pain (LBP) and also the LBP related functional disability in five sport categories including football, volleyball, basketball, wrestling, and other sports in one of the Iranian sport Olympiads. The prevalence of neck pain and LBP in different time points was evaluated with the use of an interview questionnaire. A visual analogue scale was used to evaluate the athlete's current pain. Furthermore, the functional disability related to LBP was assessed by the Athletes Disability Index Questionnaire (ADI). A total of 452 male athletes aging between 12 and 20 were screened. Three hundred seventy-seven participants responded to the questionnaires in which their mean age (standard deviation) was 15.95 (1.25). Collectively, the life-time prevalence of neck pain and LBP in all the athletes was 38.8% and 42.0%, respectively. The highest risk of neck pain at all-time points was observed among basketball players compared to other sport groups (P<0.05). The risk of LBP in most time points was the least among wrestlers (P<0.05). The ADI score was significantly higher among basketball players (13.89%) compared to volleyball players and wrestlers (P<0.05). Our study revealed a high prevalence of neck pain and LBP among Iranian young male athletes. A higher risk of neck pain and LBP among basketball players predisposes this sport at high risk of developing spine injuries which needs further consideration. PMID- 30018942 TI - Effects of pulse ultrasound and kneading massage in managing individual with incessant pain at lower region of back using random allocation. AB - The study examined the effect of pulsed therapeutic ultrasound in management of patients with incessant pain at lower region of the back (PWIPLB) in comparison with kneading massage (KM). Fifty PWIPLB recruited purposively were randomly assigned into ultrasound group (USG) and KM group (KMG) equally. Subjects received back extension exercises as baseline treatment. USG received pulse ultrasound (PUS) while KMG was treated using KM. The treatments were administered 2 times weekly for a 6-week period. Severity of pain (SP) and inability of patient (IoP) were evaluated at baseline, 3rd week and 6th week of treatment. Values of the variables obtained were classified and the implications were summarised. A significant change was observed in precompared with posttreatment SP (F=32.6, P=0.000) and IoP (F=2.5, P<0.021) in USG. A significant change was observed in precompared with posttreatment IoP (F=4.1, P<0.05) but not in SP (F=2.9, P<0.086). In the 6th week, there was a significant reduction of SP in the USG relative to SP in the KMG (F=11.98, P=0.000), and there was improvement significantly in the IoP in the KMG relative to that in the USG (F=2.58, P=0.05). PUS may be better than KM in management of SP but KM is better than PUS in IoP with PWCPLB. PMID- 30018943 TI - The effects of early-stage neurodevelopmental treatment on the growth of premature infants in neonatal intensive care unit. AB - The purpose of this study was to investigate the effects of early-stage neurodevelopmental treatment on the growth of premature infants in the neonatal intensive care unit. A total of 85 premature infants were included in this study. Infants with a birth weight of less than 2.5 kg and of 2.5 kg or higher were classified as premature infants with a high risk of growth delay and with a low risk of growth delay respectively. Of the 55 premature infants with a high risk of growth delay, 27 premature infants were placed in the intervention group and 28 were placed in the control group according to their hospitalization time. Thirty premature infants with a low risk of growth delay were included in the comparative group. The same general nursing care of the neonatal intensive care unit was provided to the intervention group, the control group, and the comparative group, but an additional neurodevelopmental treatment program was given only to the intervention group, for 15 min per session, 4 times a week, up to 40 weeks after conception. As growth indicators, the body weight and head circumference were measured before and 2 weeks after the intervention, and at 40 weeks after conception when the intervention was completed. The body weight and head circumference of the intervention group, which received the neurodevelopmental treatment, were significantly improved compared to the control group (P<0.05), but they were not significantly different from those of the comparative group. However, the body weight and head circumference of the control. PMID- 30018944 TI - Effect of knee positions on cardiac compression variables in cardiopulmonary resuscitation of rescuer; Manikin study. AB - The aim of the study was to analyze the effect of knee positions on cardiac compression variables in cardiopulmonary resuscitation (CPR) using the manikin. Adult with career of CPR instructor (n=9; mean age, 27.11+/-6.60 years; mean heights, 177.39+/-4.40 cm; mean weights, 69.45+/-14.85 kg) participated in the experiment, and each participant performed cardiac compression from two different knee positions. Cardiac compression was 30 times per minute for each position with order of position randomized. The results obtained from variables of cardiac compression force were composed of compression velocity, elapsed time, decay rate, and loading rate in maximum and minimum medial-lateral, anterior-posterior (AP), vertical direction respectively. The above variables in 20.3 cm of knee position showed effective result than that of 50 cm of knee position, while maximum AP compression force increased. Given the often predictable setting of sports and exercise rehabilitation related with cardiac arrest, CPR relative to change of knee position were significantly associated with more efficient cardiac compression variables. These data have significant implications for health services program in fields of sports and exercise rehabilitation. PMID- 30018945 TI - Erratum: Effects of exercise training on stroke risk factors, homocysteine concentration, and cognitive function according the APOE genotype in stroke patients. AB - [This corrects the article on p. 267 in vol. 14, PMID: 29740562.]. PMID- 30018946 TI - The Molecular Basis and Therapeutic Potential of Let-7 MicroRNAs against Colorectal Cancer. AB - Although a number of studies have revealed the underlying mechanisms which regulate the development of colorectal cancer (CRC), we have not completely overcome this disease yet. Accumulating evidence has shown that the posttranscriptional regulation by the noncoding RNAs such as microRNAs plays an important role in the development or progression of CRC. Among a number of microRNAs, the let-7 microRNA family that was first discovered in C. elegans and conserved from worms to humans has been linked with the development of many types of cancers including CRC. The expression level of let-7 microRNAs is temporally low during the normal developmental processes, while elevated in the differentiated tissues. The let-7 microRNAs regulate the cell proliferation, cell cycle, apoptosis, metabolism, and stemness. In CRC, expressions of let-7 microRNAs have been reported to be reduced, and so let-7 microRNAs are considered to be a tumor suppressor. In this review, we discuss the mechanisms regulating the let-7 microRNA expression and the downstream targets of let-7 in the context of intestinal tumorigenesis. The application of let-7 mimics is also highlighted as a novel therapeutic agent. PMID- 30018948 TI - The Shisong Cardiac Center in Cameroon: An Example of a Long-Term Collaboration/Cooperation Toward Autonomy. AB - Congenital heart diseases (CHD) are present in nearly 1% of live births; according to WHO, there are 1. 5 million newborns affected by CHD per year and more than 4 million children waiting for cardiac surgery treatment worldwide. The majority of these children (~90%) could be treated, saved and subsequently have a good quality of life but unfortunately, in developing countries with a suboptimal care or no access to care, they are destined to die. Cameroon, one of the 40 poorest countries in the world, is a typical example of this dramatic scenario and this is why we started a collaboration project with a local religious partner (Tertiary Sisters of Saint Francis) in 2001 with the aim of establishing the first cardiac surgery center in this country. There are various well-known organizational models to start a cooperation project in pediatric cardiac surgery in a developing country. In our case, the project included a long-term collaboration with a stable local partner, a big financial investment and a long period of development (10 years or more). It is probably the most difficult model but it is the only one with the greatest guarantee of success in terms of sustainability and autonomy. The aim of this study is to analyze the constructive and problematic aspects of the 17-year collaboration in this project, and to assess possible solutions regarding its critical issues. Although much has been done during this 17-year we are aware that there is still a lot that needs to be done. PMID- 30018947 TI - Vesicoamniotic Shunting Improves Outcomes in a Subset of Prune Belly Syndrome Patients at a Single Tertiary Center. AB - Objective: Review outcomes of Prune Belly Syndrome (PBS) with the hypothesis that contemporary management improves mortality. Methods: A retrospective chart review of inpatient and outpatient PBS patients referred between 2000 and 2018 was conducted to assess outcomes at our institution. Data collected included age at diagnosis, concomitant medical conditions, imaging, operative management, length of follow-up, and renal function. Results: Forty-five PBS patients presented during these 18 years. Prenatal diagnoses were made in 17 (39%); 65% of these patients underwent prenatal intervention. The remaining patients were diagnosed in the infant period (20, 44%) or after 1 year of age (8, 18%). Twelve patients died from cardiopulmonary complications in the neonatal period; the neonatal mortality rate was 27%. The mean follow-up among patients surviving the neonatal period was 84 months. Forty-two patients had at least one renal ultrasound (RUS); of the 30 patients with NICU RUSs, 26 (89%) had hydronephrosis and/or ureterectasis. Of the 39 patients who underwent voiding cystourethrogram (VCUG), 28 (62%) demonstrated VUR. Fifty-nine percent had respiratory distress. Nine patients (20%) were oxygen-dependent by completion of follow up. Thirty-eight patients (84%) had other congenital malformations including genitourinary (GU) 67%, gastrointestinal (GI) 52%, and cardiac 48%. Sixteen patients (36%) had chronic kidney disease (CKD) of at least stage 3; three patients (7%) had received renal transplants. Eighty-four percent of patients had at least one surgery (mean 3.4, range 0-6). The most common was orchiopexy (71%). The next most common surgeries were vesicostomy (39%), ureteral reimplants (32%), abdominoplasty (29%), nephrectomy (25%), and appendicovesicostomy (21%). After stratifying patients according to Woodard classification, a trend for 12% improvement in mortality after VAS was noted in the Woodard Classification 1 cohort. Conclusions: PBS patients frequently have multiple congenital anomalies. Pulmonary complications are prevalent in the neonate while CKD (36%) is prevalent during late childhood. The risk of CKD increased significantly with the presence of other congenital anomalies in our cohort. Mortality in childhood is most common in infancy and may be as low as 27%. Contemporary management of PBS, including prenatal interventions, reduced the neonatal mortality rate in a subset of our cohort. PMID- 30018950 TI - Dispersed Ag2O/Ag on CNT-Graphene Composite: An Implication for Magnificent Photoreduction and Energy Storage Applications. AB - A simple hydrothermal route assisted by a triblock copolymer was used to synthesize Ag2O/Ag nanoparticles on a robotic support consists of functionalized MWCNTs and graphene composite (Ag2O/Ag/CNT-graphene). The composites together with the individual analog of Ag/CNT and Ag/graphene were characterized by means of XRD, TEM-SAED, N2 sorptiometry, Raman, FTIR, UV-Vis, and photoluminescence spectroscopy. These nanomaterials were then tested for the catalytic reduction of 4-nitrophenol (4-NP) to the technologically beneficial 4-aminophenol (4-AP). The Ag2O@Ag@CNT-graphene composite calcined at 400 degrees C has shown fascinating reduction performances for 4-NP either in the dark (k = 0.014 s-1) or under visible light illumination (k = 0.039 s-1) in the presence of 5 mM NaBH4 compared to Ag/CNT (0.0112 s-1) and Ag/graphene (0.010 s-1) catalysts. This was chiefly because Ag2O@Ag@CNT-graphene comprises the highest pore volume (0.49 cm3/g) and involves three types of pores in the margin from 1.8 to 4.0 nm in front of only one modal type of pores for the rest of the catalysts and thus maximizes the adsorptive capacity of the reactants (4-NP and NaBH4). Moreover, the former composite exhibits the highest concentration of the Ag2O component as established by numerous techniques in addition to the cyclic voltammetry, proposing it's facile reaction with 4-NP along with the simultaneous transfer of surface hydrogen and electrons from NaBH4 ions to produce 4-AP. The promotion of the p-n junction evaluated using the Mott-schottky equation on Ag2O@Ag@CNT-graphene assisted by charges separation and surface plasmon resonance bands of Ag and Ag2O are found to be advantageous for 4-NP reduction. The latter composite delivers a specific capacitance of 355 F g-1 at 1.0 A g-1 exceeding those of Ag/CNT (230 F g 1) and Ag/graphene (185 F g-1). The EIS study establishes the high electronic conductivity of the metallic Ag and Ag2O moieties, low internal resistance of CNT graphene as well as the marked ionic transfer facilitated by the composite porous nature. PMID- 30018949 TI - Selenazolyl-hydrazones as Novel Selective MAO Inhibitors With Antiproliferative and Antioxidant Activities: Experimental and In-silico Studies. AB - The novel approach in the treatment of complex multifactorial diseases, such as neurodegenerative disorders and cancer, requires a development of efficient multi targeting oriented drugs. Since oxidative stress significantly contributes to the pathogenesis of cancer and neurodegenerative disorders, potential drug candidates should possess good antioxidant properties. Due to promising biological activities shown for structurally related (1,3-thiazol-2-yl)hydrazones, a focused library of 12 structurally related benzylidene-based (1,3-selenazol-2 yl)hydrazones was designed as potential multi-targeting compounds. Monoamine oxidases (MAO) A/B inhibition properties of this class of compounds have been investigated. Surprisingly, the p-nitrophenyl-substituted (1,3-selenazol-2 yl)hydrazone 4 showed MAO B inhibition in a nanomolar concentration range (IC50 = 73 nM). Excellent antioxidant properties were confirmed in a number of different in vitro assays. Antiproliferative activity screening on a panel of six human solid tumor cell lines showed that potencies of some of the investigated compounds was comparable or even better than that of the positive control 5 fluorouracil. In-silico calculations of ADME properties pointed to promising good pharmacokinetic profiles of investigated compounds. Docking studies suggest that some compounds, compared to positive controls, have the ability to strongly interact with targets relevant to cancer such as 5'-nucleotidase, and to neurodegenerative diseases such as the small conductance calcium-activated potassium channel protein 1, in addition to confirmation of inhibitory binding at MAO B. PMID- 30018951 TI - Carbon Dioxide and Water Electrolysis Using New Alkaline Stable Anion Membranes. AB - The recent development and market introduction of a new type of alkaline stable imidazole-based anion exchange membrane and related ionomers by Dioxide Materials is enabling the advancement of new and improved electrochemical processes which can operate at commercially viable operating voltages, current efficiencies, and current densities. These processes include the electrochemical conversion of CO2 to formic acid (HCOOH), CO2 to carbon monoxide (CO), and alkaline water electrolysis, generating hydrogen at high current densities at low voltages without the need for any precious metal electrocatalysts. The first process is the direct electrochemical generation of pure formic acid in a three-compartment cell configuration using the alkaline stable anion exchange membrane and a cation exchange membrane. The cell operates at a current density of 140 mA/cm2 at a cell voltage of 3.5 V. The power consumption for production of formic acid (FA) is about 4.3-4.7 kWh/kg of FA. The second process is the electrochemical conversion of CO2 to CO, a key focus product in the generation of renewable fuels and chemicals. The CO2 cell consists of a two-compartment design utilizing the alkaline stable anion exchange membrane to separate the anode and cathode compartments. A nanoparticle IrO2 catalyst on a GDE structure is used as the anode and a GDE utilizing a nanoparticle Ag/imidazolium-based ionomer catalyst combination is used as a cathode. The CO2 cell has been operated at current densities of 200 to 600 mA/cm2 at voltages of 3.0 to 3.2 respectively with CO2 to CO conversion selectivities of 95-99%. The third process is an alkaline water electrolysis cell process, where the alkaline stable anion exchange membrane allows stable cell operation in 1 M KOH electrolyte solutions at current densities of 1 A/cm2 at about 1.90 V. The cell has demonstrated operation for thousands of hours, showing a voltage increase in time of only 5 MUV/h. The alkaline electrolysis technology does not require any precious metal catalysts as compared to polymer electrolyte membrane (PEM) design water electrolyzers. In this paper, we discuss the detailed technical aspects of these three technologies utilizing this unique anion exchange membrane. PMID- 30018952 TI - "Born to Run"? Not Necessarily: Species and Trait Bias in Persistent Free-Living Transgenic Plants. AB - The possibility of transgenes from engineered plants ending up in unmanaged populations with undesirable consequences has been a long-term biosafety concern. Experience with traditionally improved plants reveals that most cases of such gene escape have been of little consequence, but on occasion they have led to the evolution of problematic plants or have resulted in an increased extinction risk for wild taxa. Three decades have passed since the first environmental release of transgenic plants, and more than two decades since their first commercialization. Examples of transgenes gone astray are increasingly commonplace. Transgenic individuals have been identified in more than a thousand free-living plant populations. Here I review 14 well-documented consolidated "cases" in which transgenes have found their way into free-living plant populations. Some as transient volunteers; others appear to be persistent transgenic populations. The species involved in the latter are not representative of the current commercialized transgenic crops as whole. They tend to share certain traits that are absent or rare in the transgenic crops that do not exist as persistent populations. The traits commonly occurring in species with persistent transgenic free-living populations are the following, in descending order of importance: (1) a history of occurring as non-transgenic free-living plants, (2) fruits fully or partially shattering prior to harvest, (3) have small or otherwise easily dispersed seeds, either spontaneously or by seed spillage along the supply chain from harvest to consumer, (4) ability to disperse viable pollen, especially to a kilometer or more, (5) perennial habit, and (6) the transgene's fitness effects in the recipient environment are beneficial or neutral. Based on these observations, a thought experiment posits which species might be the next to be reported to occur as free-living transgenic populations. PMID- 30018953 TI - A Review of FOXI3 Regulation of Development and Possible Roles in Cancer Progression and Metastasis. AB - Development and cancer share a variety of functional traits such as EMT, cell migration, angiogenesis, and tissue remodeling. In addition, many cellular signaling pathways are noted to coordinate developmental processes and facilitate aspects of tumor progression. The Forkhead box superfamily of transcription factors consists of a highly conserved DNA binding domain, which binds to specific DNA sequences and play significant roles during adult tissue homoeostasis and embryogenesis including development, differentiation, metabolism, proliferation, apoptosis, migration, and invasion. Interestingly, various studies have implicated the role of key Fox family members such as FOXP, FOXO, and FOXA during cancer initiation and metastases. FOXI3, a member of the Forkhead family affects embryogenesis, development, and bone remodeling; however, no studies have reported a role in cancer. In this review, we summarize the role of FOXI3 in embryogenesis and bone development and discuss its potential involvement in cancer progression with a focus on the bone metastasis. Moreover, we hypothesize possible mechanisms underlying the role of FOXI3 in the development of solid tumor bone metastasis. PMID- 30018954 TI - Synovial Predictors of Differentiation to Definite Arthritis in Patients With Seronegative Undifferentiated Peripheral Inflammatory Arthritis: microRNA Signature, Histological, and Ultrasound Features. AB - Objectives: To examine synovial tissue (ST) predictors of clinical differentiation in patients with seronegative undifferentiated peripheral inflammatory arthritis (UPIA). Methods: Fourty-two patients with IgA/IgM Rheumatoid Factor and anti-citrullinated peptide antibodies negative UPIA, naive to Disease-Modifying Anti-Rheumatic Drugs, underwent Gray Scale (GSUS) and power Doppler (PDUS) evaluation and Ultrasound (US) guided ST biopsy. CD68, CD3, CD21, CD20, and CD31 synovial expression was evaluated by immunohistochemistry. Whole ST microRNA expression was assessed using miScript miRNA PCR Array. Peripheral blood (PB) and synovial fluid (SF) IL-6, VEGF-A, and VEGF-D levels were measured by ELISA and ST TNF expression was assessed by RT-PCR. Each patient was prospectively monitored and classified at baseline and within 1 year as UPIA, Rheumatoid Arthritis (RA), Spondyloarthritis (SpA) or Psoriatic Arthritis (PsA), respectively. Results: At baseline, CD68+ cells were the most common cells within the lining layer (p < 0.001) in seronegative UPIA, directly correlating with GSUS (R = 0.36; p = 0.02) and PDUS (R = 0.55; p < 0.001). Synovial CD31+ vessels count directly correlated with GSUS (R = 0.41; p = 0.01) and PDUS (R = 0.52; p < 0.001). During the follow-up, 6 (14.3%) UPIA reached a definite diagnosis (2 RA, 2 SpA and 2 PsA, respectively). At baseline, UPIA who differentiated had higher GSUS (p = 0.01), PDUS scores (p = 0.02) and higher histological scores for CD68+ (p = 0.005 and p = 0.04 for lining and sublining respectively), sublining CD3+ cells (p = 0.002), CD31+ vessels count (p < 0.001) and higher IL-6 PB levels (p = 0.01) than patients who remained as UPIA. MiRNA PCR Array showed that among the 86 tested miRNA species, at baseline, miR-346 and miR-214 were significantly down regulated (p = 0.02 for both) in ST of UPIA who differentiated than in patients who remained as UPIA, inversely correlating with the lining CD68+ cells IHC score (R = -0.641; p = 0.048) and CD31+ vessels count (R = -0.665; p = 0.036) and with higher baseline ST expression of TNF (p = 0.014). Finally, logistic regression analysis demonstrated that baseline GSUS and PDUS scores >=1.5 [OR:22.93 (95%CI:0.98-534.30)] and CD31+ vessels count >=24.3 [OR:23.66 (95%CI:1.50 373.02)] were independent factors associated with the development of definite arthritis. Conclusions: MiRNA signature, histological and US features of ST may help in the identification of seronegative UPIA with high likelihood of clinical differentiation toward definite seronegative arthritis. PMID- 30018957 TI - Editorial: Comorbidity Burden in Rheumatic Diseases. PMID- 30018955 TI - The Role of Long Non-coding RNAs in the Pathogenesis of RA, SLE, and SS. AB - Rheumatoid diseases are a group of systemic autoimmune diseases which affect multiple organs with largely unknown etiology. In the past decade, long non coding RNAs (lncRNAs) have emerged as important regulators of biological processes and contribute deeply to immune cell development and immune responses. Substantial evidences have been accumulated showing that LncRNAs involved in the pathogenesis of the rheumatoid diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). In this review, we summarize literature combined with bioinformatics methods to analyze the unique and common lncRNAs patterns in rheumatoid diseases and try to reveal the important function of lncRNAs in RA, SLE and SS. PMID- 30018956 TI - Impact of Bradykinin Generation During Thrombolysis in Ischemic Stroke. AB - Ischemic stroke is one of the leading causes of death and disability worldwide. Current medical management in the acute phase is based on the activation of the fibrinolytic cascade by intravenous injection of a plasminogen activator (such as tissue-type plasminogen activator, tPA) that promotes restauration of the cerebral blood flow and improves stroke outcome. Unfortunately, the use of tPA is associated with deleterious effects such as hemorrhagic transformation, symptomatic brain edema, and angioedema, which limit the efficacy of this therapeutic strategy. Preclinical and clinical evidence suggests that intravenous thrombolysis generates large amounts of bradykinin, a peptide with potent pro inflammatory, and pro-edematous effects. This tPA-triggered generation of bradykinin could participate in the deleterious effects of thrombolysis and is a potential target to improve neurological outcome in tPA-treated patients. The present review aims at summarizing current evidence linking thrombolysis, bradykinin generation, and neurovascular damage. PMID- 30018959 TI - The Coming of Age of Inflammatory Bowel Diseases in Asia. PMID- 30018958 TI - Structural and Functional Insights Into Lysostaphin-Substrate Interaction. AB - Lysostaphin from Staphylococcus simulans and its family enzymes rapidly acquire prominence as the next generation agents in treatment of S. aureus infections. The specificity of lysostaphin is promoted by its C-terminal cell wall targeting domain selectivity toward pentaglycine bridges in S. aureus cell wall. Scission of these cross-links is carried out by its N-terminal catalytic domain, a zinc dependent endopeptidase. Understanding the determinants affecting the efficiency of catalysis and strength and specificity of interactions lies at the heart of all lysostaphin family enzyme applications. To this end, we have used NMR, SAXS and molecular dynamics simulations to characterize lysostaphin structure and dynamics, to address the inter-domain interaction, the enzyme-substrate interaction as well as the catalytic properties of pentaglycine cleavage in solution. Our NMR structure confirms the recent crystal structure, yet, together with the molecular dynamics simulations, emphasizes the dynamic nature of the loops embracing the catalytic site. We found no evidence for inter-domain interaction, but, interestingly, the SAXS data delineate two preferred conformation subpopulations. Catalytic H329 and H360 were observed to bind a second zinc ion, which reduces lysostaphin pentaglycine cleaving activity. Binding of pentaglycine or its lysine derivatives to the targeting domain was found to be of very low affinity. The pentaglycine interaction site was located to the N-terminal groove of the domain. Notably, the targeting domain binds the peptidoglycan stem peptide Ala-d-gamma-Glu-Lys-d-Ala-d-Ala with a much higher, micromolar affinity. Binding site mapping reveals two interaction sites of different affinities on the surface of the domain for this peptide. PMID- 30018960 TI - How Does the Epidemiology of Inflammatory Bowel Disease Differ between East and West? A Korean Perspective. AB - Background: Though low compared with those in Western countries, the incidence and prevalence of inflammatory bowel disease (IBD) are rapidly increasing in Asia. If we could understand the differences in IBD epidemiology between Asian and Western countries, we might gain insights into the etiopathogenesis of IBD as well as guidance for personalized therapy. Summary: In Asia, unlike in the West, Crohn's disease (CD) predominantly occurs in men and involves a high prevalence of perianal fistulas. Moreover, in Korean CD patients, ileocolonic involvement is predominant, whereas isolated colonic involvement is very uncommon. In both ulcerative colitis (UC) and CD, extraintestinal manifestations, such as primary sclerosing cholangitis, as well as a positive family history of IBD are less frequent in Asian patients. However, as the prevalence of IBD rises in Korea, so does the frequency of a positive family history. While the colectomy rate among Korean UC patients is lower, the intestinal resection rate in CD patients is similar in Korea and in the West. Infectious problems that can adversely influence IBD management are usually more common in Asia. Key Messages: IBD in Asians differs from that in Westerners in many aspects, including demographic and clinical characteristics, prognosis, and associated problems. PMID- 30018962 TI - Gut Microbiome in Inflammatory Bowel Disease and Other Chronic Immune-Mediated Inflammatory Diseases. AB - Background: Since the description of the normal human gut microbiome in healthy individuals using broad-range polymerase chain reaction, there has been great advancement in the techniques used to conduct microbiome research and applications of this research across health, gastrointestinal diseases, and nongastrointestinal diseases. Summary and Key Messages: In inflammatory bowel disease (IBD), studies have reported gut dysbiosis meaning that the microbial composition, diversity, and richness are altered. Persons with IBD harbor on average 25% fewer microbial genes than healthy persons. Reduced diversity has been reported in both the fecal and mucosal microbiome of IBD. Crohn disease and ulcerative colitis are systemic diseases with immunological alterations in both intestinal and circulating compartments. As knowledge about the impact of the gut microbiome on the intestinal and systemic immune response has grown, researchers have begun exploring how the gut microbiome may impact on other systemic conditions. Considering the role of microbes especially on regulatory T cells, it was plausible that the gut microbiome may have a role in other chronic immune mediated inflammatory diseases. In this review, studies of the gut microbiome in other chronic immune-mediated inflammatory diseases are discussed including how the information can inform our understanding of the gut microbiome in IBD. PMID- 30018961 TI - Epidemiology of Inflammatory Bowel Disease in India: The Great Shift East. AB - Background: Inflammatory bowel disease (IBD), once considered to be a Western disease, is increasingly being reported from India and other Asian countries. The present review summarizes epidemiology and disease characteristics of IBD in India with reference to other Asian countries and the West. Summary: India is projected to have one of the highest disease burden of IBD across the globe. The overall genetic risk and microbial signature in Indian IBD patients are similar to those of patients in the West as demonstrated by the similar incidence of IBD in second-generation Indian immigrants and matching perturbations in the structural and functional component of gut microbiota in Indian studies. The concept of the hygiene hypothesis continues to remain controversial with Indian studies demonstrating contradictory findings. The disease characteristics, long term outcomes including the risk of colorectal cancer, and the effect of pregnancy on IBD and vice versa in Indian patients with IBD are in general similar with few differences. Unlike patients in the West, very few Indian patients have a positive family history. Key Message: The Indian disease pattern is going through a phase of epidemiological transition with a surge in the incidence of IBD. The epidemiology and disease characteristics of IBD mirror the patterns observed in the West. PMID- 30018964 TI - The Efficacy and Safety of Golimumab as Third- or Fourth-Line Anti-TNF Therapy in Patients with Refractory Crohn's Disease: A Case Series. AB - Background: The TNF-alpha antagonist golimumab is approved for the treatment of ulcerative colitis but not for Crohn's disease (CD). We herein report a case series of 8 difficult-to-treat patients with severe and refractory CD receiving golimumab as an off-label rescue medication and fourth-line anti-TNF agent in our tertiary referral inflammatory bowel disease center. Methods: We performed a retrospective analysis of clinical, biochemical, and radiological as well as endoscopic parameters. The patients all suffered from severe refractory CD with ongoing symptoms. Moreover, all 8 patients had previously been treated with all 3 other TNF-alpha antagonists approved for CD in Switzerland (infliximab, adalimumab, and certolizumab pegol) without durable clinical response. Results: Three out of 8 patients showed a primary nonresponse. Among the 5 patients responding after induction, 1 patient showed a loss of response, and in 1 patient, treatment was terminated due to side effects. Three patients have a continuous clinical response under golimumab. We did not observe any severe adverse events during golimumab administration. Conclusions: A considerable fraction of this highly selected subgroup of difficult-to-treat CD patients responded to golimumab, indicating a promising potential for refractory CD patients, including those with multiple previous anti-TNF exposures. PMID- 30018963 TI - The Impact of Cold Spells on the Incidence of Infectious Gastroenteritis and Relapse Rates of Inflammatory Bowel Disease: A Retrospective Controlled Observational Study. AB - Goals: We aimed to assess the impact of very cold days on inflammatory bowel disease (IBD) flares and infectious gastroenteritis (IG). We defined a cold day using the World Meteorological definition of an ice day, which is a day with a maximum temperature below 0 degrees C. Background: Recently, we have shown that heat waves increase the risk for IG and IBD flares. Study: We retrospectively collected data from 738 IBD and 786 IG patients admitted to the University Hospital of Zurich between 2001 and 2005 and from 506 patients with other noninfectious chronic intestinal inflammations as controls. Climate data were received by the Swiss Federal Office for Meteorology and Climatology. Results: There was no evidence for an increased risk of IBD flares (relative risk, RR = 0.99, 95% confidence interval, CI: 0.72-1.33, p = 0.94) or IG flares (RR = 1.16, 95% CI: 087-1.52, p = 0.30) on very cold days. This negative finding was confirmed in alternative formulations with lagged or cumulative (possibly lagged) effects. Conclusion: In this retrospective controlled observational study, no evidence for an increase in hospital admissions due to flares of IBD and IG during cold days was observed. This may be attributed to not relevantly altered bacterial growth conditions during cold days compared to heat waves. PMID- 30018965 TI - Cyclophosphamide Pulse Therapy in Severe Refractory Crohn's Disease: A Retrospective Multicenter Case Series. AB - Background and Aims: In Crohn's disease (CD) patients still remain refractory to current regimens, including biologicals. Previous data from small single-center studies indicated cyclophosphamide pulse therapy (CPT) to be effective for induction of remission at least in steroid-refractory cases. The aim of the present study was to study the efficacy and safety of CPT in mainly tumor necrosis factor (TNF)-refractory complicated CD patients. Methods: Patients with refractory CD undergoing CPT were identified in 13 centers of the German IBD Study Group and retrospectively registered. In total, 41 patients (12 male, 29 female, median age 36 years, range 18-72 years) were included for analysis. Seventy-eight percent of these had previously been treated with thiopurines and 90% had previously received anti-TNF antibodies. Former steroid treatment was found throughout the cohort. Results: Patients received a median number of 5 (1 13) pulses every 28 (13-54) days in a period of 120 (12-411) days. A median dose of 766 (600-1,200) mg and a median cumulative dose of 4,500 (750-9,750) mg was given. A clinical response (reduction in the Harvey-Bradshaw Index [HBI] >=2 points) was found in 68% of the patients and clinical remission (HBI <5 points) in 32%. Steroids could be reduced from 31 to 12 mg per day over all patients. Side effects were recorded in 71% (n = 29) of the patients. Three patients terminated CPT due to side effects. No patient died. Conclusion: Our data point to CPT as a therapeutic alternative for induction of remission in patients with severe refractory courses of CD including TNF antagonists. CPT might serve as bridging for maintenance treatment. PMID- 30018966 TI - Cohort Profile: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS). AB - Background and Aims: The prospective, observational Swiss Eosinophilic Esophagitis Cohort Study (SEECS) was set up in 2015 with the following goals in mind: (1) to provide up-to-date epidemiologic data; (2) to assess the appropriateness of care; (3) to evaluate the psychosocial impact; and (4) to foster translational research projects. Data capture relies on validated instruments to assess disease activity and focuses on epidemiologic variables and biosamples (esophageal biopsies and blood specimens). An annual inclusion of 70 new patients with eosinophilic esophagitis (EoE) or proton pump inhibitor responsive esophageal eosinophilia (PPI-REE) is intended. We herein describe the SEECS cohort profile. Methods: The SEECS includes adult patients (age >=18 years) with EoE or PPI-REE diagnosed according to published criteria. After inclusion, the patients are typically seen once a year for a clinical and endoscopic/histologic follow-up examination. Data are captured using validated questionnaires. Biosamples from patients with gastroesophageal reflux disease (GERD) and controls with a healthy esophagus are collected as well. Results: From January 2016 to July 2017, a total of 111 patients with EoE and 10 patients with PPI-REE were recruited. In addition, esophageal biopsies and blood samples from 11 patients with GERD and 20 controls with a healthy esophagus were collected. The mean age of the patients with EoE and those with PPI-REE was 39.6 +/- 12.9 and 44.6 +/- 15.6 years, respectively. A male predominance was found among both the patients with EoE (77.5%) and those with PPI-REE (70%). Concomitant allergic disorders were found in 79.3% of the patients with EoE and 90% of the patients with PPI-REE. At inclusion, the EoE patients were treated with the following therapeutic regimens: no therapy (0.9%), PPI (36%), swallowed topical corticosteroids (82.9%), elimination diets (15.3%), and esophageal dilation (19.8%). Conclusions: The SEECS is the first national cohort study of patients with EoE or PPI-REE. The SEECS will provide up-to-date epidemiologic data and foster translational research projects. PMID- 30018967 TI - Low Discontinuation Rate of Infliximab Treatment in Steroid-Dependent/Refractory Crohn's Disease Patients. AB - Background: Many patients with moderate to severe Crohn's disease (CD) are treated with infliximab (IFX). As most of these patients experience a long lasting therapy, the outcome and withdrawal of IFX treatment are important clinical questions. Methods: In this retrospective study, we analyzed the treatment outcome in moderate to severe CD patients with a steroid dependent/refractory disease course started on IFX. Withdrawal of IFX was evaluated in patients with deep remission defined as clinical (Harvey-Bradshaw Index <=4), biochemical (fecal calprotectin [FC] <=150 MUg/g stool) over a period of 2 years, and endoscopic and histological remission before discontinuation of IFX. Results: After induction with IFX, clinical remission was observed in 45/109 patients (41.3%) and clinical response in 61/109 patients (56.0%). Only 8/109 patients (7.3%) achieved deep remission and therefore could be discontinued from IFX therapy. In 4 of these patients (50%), relapse was observed after discontinuation of IFX treatment. FC decreased in these 8 patients in deep remission from 652 +/- 168 MUg/g stool (mean +/- SE) at baseline to 24.9 +/- 8.1 MUg/g stool at 14 weeks. When compared to patients in deep remission, FC had decreased significantly less at 14 weeks in patients in clinical remission after induction with IFX (n = 31; 154 +/- 55 MUg/g stool; p = 0.01), in patients with clinical response after induction achieving clinical remission during the maintenance phase (n = 11; 352 +/- 67 MUg/g stool; p = 0.004), or in patients with chronic active disease course on maintenance therapy (n = 50; 645 +/- 93 MUg/g stool; p < 0.001). Conclusion: A low discontinuation rate was observed for steroid-dependent/refractory moderate to severe CD patients with IFX treatment. As FC showed a more or less pronounced decrease depending on the response to the IFX treatment, monitoring of FC may become a noninvasive tool for tailoring biological therapy in CD patients. PMID- 30018968 TI - Case Study: Intra-Patient Heterogeneity of Aneurysmal Tissue Properties. AB - Introduction: Current recommendations for surgical treatment of abdominal aortic aneurysms (AAAs) rely on the assessment of aortic diameter as a marker for risk of rupture. The use of aortic size alone may overlook the role that vessel heterogeneity plays in aneurysmal progression and rupture risk. The aim of the current study was to investigate intra-patient heterogeneity of mechanical and fluid mechanical stresses on the aortic wall and wall tissue histopathology from tissue collected at the time of surgical repair. Methods: Finite element analysis (FEA) and computational fluid dynamics (CFD) simulations were used to predict the mechanical wall stress and the wall shear stress fields for a non-ruptured aneurysm 2 weeks prior to scheduled surgery. During open repair surgery one specimen partitioned into different regions was collected from the patient's diseased aorta according to a pre-operative map. Histological analysis and mechanical testing were performed on the aortic samples and the results were compared with the predicted stresses. Results: The preoperative simulations highlighted the presence of altered local hemodynamics particularly at the proximal segment of the left anterior area of the aneurysm. Results from the post operative assessment on the surgical samples revealed a considerable heterogeneity throughout the aortic wall. There was a positive correlation between elastin fragmentation and collagen content in the media. The tensile tests demonstrated a good prediction of the locally varying constitutive model properties predicted using geometrical variables, i.e., wall thickness and thrombus thickness. Conclusions: The observed large regional differences highlight the local response of the tissue to both mechanical and biological factors. Aortic size alone appears to be insufficient to characterize the large degree of heterogeneity in the aneurysmal wall. Local assessment of wall vulnerability may provide better risk of rupture predictions. PMID- 30018969 TI - TAVI and Post Procedural Cardiac Conduction Abnormalities. AB - Transcatheter aortic valve implantation (TAVI) is a worldwide accepted alternative for treating patients at intermediate or high risk for surgery. In recent years, the rate of complications has markedly decreased except for new onset atrioventricular and intraventricular conduction block that remains the most common complication after TAVI. Although procedural, clinical, and electrocardiographic predisposing factors have been identified as predictors of conduction disturbances, new strategies are needed to avoid such complications, particularly in the current TAVI era that is moving quickly toward the percutaneous treatment of low-risk patients. In this article, we will review the incidence, predictive factors, and clinical implications of conduction disturbances after TAVI. PMID- 30018971 TI - Effect of the Essential Oil of Minthostachys verticillata (Griseb.) Epling and Limonene on Biofilm Production in Pathogens Causing Bovine Mastitis. AB - Bovine mastitis causes large annual economic losses around the world. Different microorganisms are associated with the disease. The capacity of pathogens to adhere to bovine mammary epithelial cells is associated with biofilm production which leads to antibiotic resistance. Research is now leading to search alternative control methods and medicinal plants constitute a natural, safe, effective and inexpensive option. Minthostachys verticillata is an autochthonous medicinal plant of Argentina with multiple ethnobotanical properties. In a previous study, we demonstrated that the essential oil (EO) of this species and limonene, one of its compounds, inhibited the growth of mastitis pathogens. The objective of the present work was to determine the inhibitory effect of the essential oil of M. verticillata and limonene, on biofilm formation and on mature biofilm produced by pathogens isolated from bovine mastitis. Time kill assay and bacterial lysis were also determined. Furthermore, RAPD-PCR assays were performed to determine changes in bacterial DNA after EO and limonene exposition. Bacterial isolates were identified as Escherichia coli (EC3 and EC9), Bacillus pumilus (BP5, BP6, and BP7) and Enterococcus faecium (EF1) by rRNA 16S sequencing and MALDI-TOF MS. All the strains were able to form biofilm. Addition of both lactose and sucrose did not affect biofilm production. MIC values for EO were 3.6 mg/ml for E. faecium; 0.9 mg/ml for E. coli (EC3), 14.5 mg/ml for E. coli (EC9), 1.8 mg/ml for B. pumilus (BP7), 3.63 mg/ml for B. pumilus (BP6) and 29.0 mg/ml for B. pumilus (BP7). MIC values for limonene were 6.6 mg/ml for B. pumilus (BP6) and 105 mg/ml for B. pumilus (BP5). These results demonstrated that EO was more effective than limonene, showing also bactericidal action against E. faecium (minimal inhibitory concentration (MBC) = 29.0 mg/ml). This result was corroborated by time of death assay, observing a cell decrease after at 6 h, and then by bacterial lysis assay. Both EO and limonene affected mature biofilm of isolated strains. The results contribute to the study of EO and limonene which may serve as a therapy against bovine mastitis pathogens inhibiting the development of pathogenic bacteria. PMID- 30018972 TI - Brucellosis Control in Malta and Serbia: A One Health Evaluation. AB - Brucellosis, also known as "undulant fever" or "Malta fever", is a zoonotic infection caused by microorganisms belonging to Brucella, a genus of gram negative coccobacilli that behave as facultative intracellular pathogens of ruminants, swine and other animals. Brucellosis is a threat to public health, hence identifying the optimal way of preventing disease spread is important. Under certain circumstances, integrated, multidisciplinary "One Health" (OH) initiatives provide added value compared to unidisciplinary or conventional health initiatives. Conceptualizing and conducting evaluations of OH approaches may help facilitate decisions on resource allocation. This article historically describes and compares Malta's 1995-1997 with Serbia's 2004-2006 brucellosis control programmes and quantitatively assesses the extent to which they were compliant with a OH approach. For both case studies, we describe the OH initiative and the system within which it operates. Characteristic OH operations (i.e., thinking, planning, working) and supporting infrastructures (to allow sharing, learning and systemic organization) were evaluated. We scored the different aspects of these programmes, with values ranging from zero to one (1 = strong integration of OH). Malta demonstrated a higher OH index (0.54) and ratio (1.37) than Serbia (0.49 and 1.14 respectively). We conclude that context and timing are key to determining how, when and why a One Health approach should be applied. The adoption of a true OH approach that involved systemic organization, leadership clarity and transdisciplinary communication, collaboration, and co ordination was essential to Malta's successful eradication of brucellosis after several failed attempts. In contrast, contextual factors in Serbia permitted the successful adoption of a primarily sectorial approach for short term control of brucellosis. However, while a fully-fledged transdisciplinary OH approach was not initially required, it is likely to be key to maintenance of brucellosis control in the medium and long term. Through these two case studies, we demonstrate that One Health initiatives should be applied at the right place, at the right time, with the right people and using the appropriate conditions/infrastructure. Lastly, OH evaluations should include economic assessments to identify optimal of resources in these situations, thereby justifying funding and political support required. PMID- 30018970 TI - Future Perspectives on the Role of Stem Cells and Extracellular Vesicles in Vascular Tissue Regeneration. AB - Vascular tissue engineering is an area of regenerative medicine that attempts to create functional replacement tissue for defective segments of the vascular network. One approach to vascular tissue engineering utilizes seeding of biodegradable tubular scaffolds with stem (and/or progenitor) cells wherein the seeded cells initiate scaffold remodeling and prevent thrombosis through paracrine signaling to endogenous cells. Stem cells have received an abundance of attention in recent literature regarding the mechanism of their paracrine therapeutic effect. However, very little of this mechanistic research has been performed under the aegis of vascular tissue engineering. Therefore, the scope of this review includes the current state of TEVGs generated using the incorporation of stem cells in biodegradable scaffolds and potential cell-free directions for TEVGs based on stem cell secreted products. The current generation of stem cell seeded vascular scaffolds are based on the premise that cells should be obtained from an autologous source. However, the reduced regenerative capacity of stem cells from certain patient groups limits the therapeutic potential of an autologous approach. This limitation prompts the need to investigate allogeneic stem cells or stem cell secreted products as therapeutic bases for TEVGs. The role of stem cell derived products, particularly extracellular vesicles (EVs), in vascular tissue engineering is exciting due to their potential use as a cell-free therapeutic base. EVs offer many benefits as a therapeutic base for functionalizing vascular scaffolds such as cell specific targeting, physiological delivery of cargo to target cells, reduced immunogenicity, and stability under physiological conditions. However, a number of points must be addressed prior to the effective translation of TEVG technologies that incorporate stem cell derived EVs such as standardizing stem cell culture conditions, EV isolation, scaffold functionalization with EVs, and establishing the therapeutic benefit of this combination treatment. PMID- 30018973 TI - Post-migration follow-up programme for migrants at increased risk of developing tuberculosis: a cohort study. AB - Following pre-migration screening for tuberculosis (TB), migrants who are deemed to be at a high risk of developing TB must attend post-entry follow-up in Australia. We aimed to evaluate the effectiveness of post-migration TB follow-up in the state of New South Wales to diagnose TB in these high-risk migrants. In this retrospective cohort study, we assessed the risk of TB in migrants who arrived in New South Wales between 2000 and 2015 and were referred for post migration follow-up. Clinical notes were examined for a nested cohort to determine whether TB was diagnosed via the follow-up programme or via passive case finding. Of the 32 550 migrants referred for follow-up, 428 (1.3%) developed TB. The incidence of TB was 436 per 100 000 person-years (95% CI 384-491 per 100 000 person-years) in the first 2 years after arrival and 128 per 100 000 person years (95% CI 116-140 per 100 000 person-years) over the mean study observation period of 10.3 years. An estimated 63% of cases were diagnosed via follow-up. TB notifications occurred 0.55 years earlier since time of arrival in Australia in migrants who attended follow-up than in those who did not. Post-migration follow up detected 63% of TB cases in high-risk migrants and potentially prevented delay of TB diagnosis. PMID- 30018974 TI - Prevalence and Associated Factors of Depression among Prisoners in Jimma Town Prison, South West Ethiopia. AB - Background: Mental disorder is one of the greatest challenges that current and future generations will face. Currently among all people suffering from depression, 85% of them live in low- and middle-income countries. Previous studies reported the global burden/prevalence of depression to be five to ten times higher among prisoners than the general population. However, the prevalence of depression among prisoners in our study area is not known. Objective: This study therefore aimed to assess the prevalence and associated factors of depression among prisoners in Jimma town in 2017. Method: A cross-sectional study design was employed on 332 prisoners selected by systematic random sampling method. Data was collected by a face to face interview using Beck Depression Inventory (BDI-II) scale. Data analysis was done using SPSS version 20. Result: The study revealed that 41.9% (n = 139) of participants among prisoners had depression. Having family history of mental illness (AOR = 6.05, 95% CI = 2.6, 13.8), having chronic physical illness (AOR = 2.87, 95% CI = 1.29, 6.41), having history of previous incarceration (AOR = 3.26, 95% CI = 1.02, 10.64), lack of job in the prison (AOR = 4.96, 95% CI = 2.09, 11.8), lifetime alcohol use (AOR = 3.61, 95% CI = 1.8, 7.26), thinking life to be a difficult one after release from prison (AOR = 2.07, 95% CI = 1.2, 3.6), having age between 21 and 25 years (AOR = 2.04, 95% CI = 1.06, 3.89), and having poor social support (AOR = 2.2, 95% CI = 1.27, 3.82) had significant association with depression in the fully adjusted final regression model. Conclusion: This study has shown that the prevalence of depression among prisoners was very high. Having family history of mental illness, having chronic physical illness, having previous incarceration, lack of job in prison, lifetime alcohol use, thinking life to be difficult one after release from prison, having age between 21 and 25 years old, and having poor social support were found to have an impact on the prevalence of depression. PMID- 30018976 TI - Portable and Wearable Brain Technologies for Neuroenhancement and Neurorehabilitation. PMID- 30018975 TI - In Vivo Study of the Effects of ERbeta on Apoptosis and Proliferation of Hormone Independent Prostate Cancer Cell Lines PC-3M. AB - Objective: To evaluate the in vivo therapeutic effects of attenuated Salmonella carrying PCDNA3.1-ERbeta plasmid in hormone-independent prostatic cancer in nude mice and to clarify the mechanism by which estrogen receptor beta (ERbeta) induces apoptosis and proliferation in prostatic cancer cells in mice. Methods: The orthotopic prostatic cancer models of mice were randomly divided as follows: MOCK group, treated with PBS, PQ group, treated with attenuated Salmonella alone, PQ-PCDNA3.1 group, treated with attenuated Salmonella carrying PCDNA3.1 plasmid, and PQ-PCDNA3.1-ERbeta group, treated with the attenuated Salmonella carrying PCDNA3.1-ERbeta plasmid. Then, 10 MUl of the plasmid-containing solution, comprising 1 * 107 cfu of the bacteria, was administered via intranasal delivery to each group except the MOCK group. The experimental methods included flow cytometry and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assay, immunohistochemistry, and western blotting. Results: Compared with the MOCK, PQ, and PQ-PCDNA3.1 groups, the weights of tumors in the PQ-PCDNA3.1-ERbeta group were significantly reduced. The results of flow cytometry and TUNEL assay revealed that the number of apoptotic cells in the PQ-PCDNA3.1-ERbeta group significantly increased. Compared with PQ-PCDNA3.1 group, the protein expression levels of ERbeta, Bad, p-caspase 9, p-caspase 3, and cleaved PARP in the PQ-PCDNA3.1-ERbeta group were significantly increased, while the expression levels of Akt, p-Akt, and Bcl-xl were decreased (P < 0.05). Conclusion: The attenuated Salmonella carrying PCDNA3.1-ERbeta plasmid could inhibit the growth of orthotopic prostatic cancer in mice by increasing the expression of ERbeta. PMID- 30018977 TI - Pleurotus albidus Modulates Mitochondrial Metabolism Disrupted by Hyperglycaemia in EA.hy926 Endothelial Cells. AB - Hyperglycaemia exacerbates the production of reactive oxygen species (ROS), contributing to the multiple complications associated with diabetes. Mitochondrial dysfunction is also known to be associated with diabetes. Therefore, the aim of this work was to study the effect of Pleurotus albidus extract on the mitochondrial dysfunction induced by hyperglycaemia in EA.hy926 endothelial cells. The results showed that P. albidus treatment prevented the increase in the activity of complex I of the electron transport chain and minimized the ROS production induced by hyperglycaemia. In addition, the extract minimized oxidative damage to lipids and proteins, caused an imbalance in the antioxidant enzyme activities of superoxide dismutase and catalase, and decreased the nitric oxide levels induced by hyperglycaemia. These data contribute to our understanding of the mitochondrial disorder induced by hyperglycaemia as well as establishing the conditions required to minimize these alterations. PMID- 30018978 TI - Effect of Multilaminate Small Intestinal Submucosa as a Barrier Membrane on Bone Formation in a Rabbit Mandible Defect Model. AB - A barrier membrane (BM) is essential for guided bone regeneration (GBR) procedures. Absorbable BMs based on collagen have been widely applied clinically due to their excellent biocompatibility. The extracellular matrix (ECM) provides certain advantages that can compensate for the rapid degradation and insufficient mechanical strength of pure collagen membrane due to the porous scaffold structure. Recently, small intestinal submucosa (SIS), one of the most widely used ECM materials, has drawn much attention in bone tissue engineering. In this study, we adopted multilaminate SIS (mSIS) as a BM and evaluated its in vivo and in vitro properties. mSIS exhibited a multilaminate structure with a smooth upper surface and a significantly coarser bottom layer according to microscopic observation. Tensile strength was 13.10 +/- 2.56 MPa. In in vivo experiments, we selected a rabbit mandibular defect model and subcutaneous implantation to compare osteogenesis and biodegradation properties with one of the most commonly used commercial collagen membranes. mSIS was retained for up to 3 months and demonstrated longer biodegradation time than commercial collagen membrane. Quantification of bone regeneration revealed significant differences in each group. Micro-computed tomography (micro-CT) revealed that the quantity and maturity of bones in the mSIS group were significantly higher than those in the blank control group (P < 0.05) and were similar to those in a commercial collagen membrane group (P > 0.05) at 4 and 12 weeks after surgery. Hematoxylin and eosin staining revealed large amounts of mature lamellar bone at 12 weeks in mSIS and commercial collagen membrane groups. Therefore, we conclude that mSIS has potential as a future biocompatible BM in GBR procedures. PMID- 30018979 TI - Assessment of Disability and Factors Determining Disability among Inhabitants of South-Eastern Poland Aged 71-80 Years. AB - Introduction: The aim of the study was to assess the level of disability in a sample of older people in south-eastern Poland and to identify any potential relationship between their profile of functioning and a complex set of variables including activities, participation, and contextual factors. Materials and Methods: The study included 800 people aged 71-80 years. The WHODAS 2.0 questionnaire was applied for the assessment of disability. Results: A total of 43.88% of the interviewees showed a moderate level of disability, while 17.75% had severe or extremely high levels of disability. In addition, 7.75% of the interviewees had no functional limitations and 30.62% demonstrated a mild level of disability. The studied individuals reported the greatest difficulties with life activities such as cleaning, cooking, or shopping, followed by Limited Participation and then getting along. Age, number of chronic diseases, a low level of education, a low level of physical activity, poor living conditions, and lack of opportunities for daily help significantly contributed to higher levels of disability. Conclusions: Measures intended to reduce the level of disability in older adults should focus on improving medical care, health education, increasing physical activity, adapting housing to the needs of everyday functioning, and providing daily help. PMID- 30018980 TI - Use of a Total Variation Minimization Iterative Reconstruction Algorithm to Evaluate Reduced Projections during Digital Breast Tomosynthesis. AB - Purpose: We evaluated the efficacies of the adaptive steepest descent projection onto convex sets (ASD-POCS), simultaneous algebraic reconstruction technique (SART), filtered back projection (FBP), and maximum likelihood expectation maximization (MLEM) total variation minimization iterative algorithms for reducing exposure doses during digital breast tomosynthesis for reduced projections. Methods: Reconstructions were evaluated using normal (15 projections) and half (i.e., thinned-out normal) projections (seven projections). The algorithms were assessed by determining the full width at half-maximum (FWHM), and the BR3D Phantom was used to evaluate the contrast-to-noise ratio (CNR) for the in-focus plane. A mean similarity measure of structural similarity (MSSIM) was also used to identify the preservation of contrast in clinical cases. Results: Spatial resolution tended to deteriorate in ASD-POCS algorithm reconstructions involving a reduced number of projections. However, the microcalcification size did not affect the rate of FWHM change. The ASD-POCS algorithm yielded a high CNR independently of the simulated mass lesion size and projection number. The ASD-POCS algorithm yielded a high MSSIM in reconstructions from reduced numbers of projections. Conclusions: The ASD-POCS algorithm can preserve contrast despite a reduced number of projections and could therefore be used to reduce radiation doses. PMID- 30018983 TI - The Central Neck Dissection or the Modified Sistrunk Procedure in the Treatment of the Thyroglossal Duct Cysts in Children: Our Experience. AB - Background: The aim of the study was to present the surgical techniques providing the lowest recurrence rate in treatment of the primary and recurrent thyroglossal duct cyst (TGDC) in children. Methods: The study included 73 patients operated on because of TGDC in years 2011-2016. Ultrasound was performed in all patients preoperatively. In 8 patients with the recurrence of the disease, the CT or MR was carried out before the surgery. Children with the primary disease underwent the modified Sistrunk procedure. In the revision cases the central neck dissection was a method of choice. Results: In 45 children, the modified Sistrunk procedure was performed and 28 underwent the central neck dissection. In 2 patients, hematoma occurred after the modified Sistrunk procedure with the need of the surgical revision in one. No complications were observed after the central neck dissection. Conclusions: A modified Sistrunk procedure is method of choice in the treatment of the uncomplicated TGDC. In selected cases of the TGDC with a history of infected cyst or incision of an abscess or in revision cases the central neck dissection should be considered in order to avoid the risk of the further recurrences. PMID- 30018982 TI - Characteristic of HPV Integration in the Genome and Transcriptome of Cervical Cancer Tissues. AB - High-risk HPV is clearly associated with cervical cancer. HPV integration has been confirmed to promote carcinogenesis in the previous studies. In our study, a total of 285 DNA breakpoints and 287 RNA breakpoints were collected. We analyzed the characteristic of HPV integration in the DNA and RNA samples. The results revealed that the patterns of HPV integration in RNA and DNA samples differ significantly. FHIT, KLF5, and LINC00392 were the hotspot genes integrated by HPV in the DNA samples. RAD51B, CASC8, CASC21, ERBB2, TP63, TEX41, RAP2B, and MYC were the hotspot genes integrated by HPV in RNA samples. Breakpoints of DNA samples were significantly prone to the region of INTRON (P < 0.01, Chi-squared test), whereas in the RNA samples, the breakpoints were prone to EXON. Pathway analysis had revealed that the breakpoints of RNA samples were enriched in the pathways of transcriptional misregulation in cancer, cancer pathway, and pathway of adherens junction. Breakpoints of DNA samples were enriched in the pathway of cholinergic synapse. In summary, our data helped to gain insights into the HPV integration sites in DNA and RNA samples of cervical cancer. It had provided theoretical basis for understanding the mechanism of tumorigenesis from the perspective of HPV integration in the HPV-associated cervical cancers. PMID- 30018984 TI - Targeting Oxidative Stress in Diabetic Complications: New Insights. PMID- 30018985 TI - Sagittal Abdominal Diameter, Waist Circumference, and BMI as Predictors of Multiple Measures of Glucose Metabolism: An NHANES Investigation of US Adults. AB - The objective was to compare associations between sagittal abdominal diameter (SAD), waist circumference, and BMI to the oral glucose tolerance test (OGTT), along with fasting glucose, HbA1c, and HOMA-IR, in a nationally representative sample of 3582 US adults. The study also analyzed the effect of multiple covariates on the anthropometric and glucose metabolism associations. A cross sectional design was used. SAD was assessed using an abdominal caliper. All other data were collected following strict NHANES protocols. The OGTT was the primary variable used to index glucose metabolism. Fasting glucose, HbA1c, and HOMA-IR were also evaluated. Results showed that mean +/- SE values were as follows: SAD: 22.3 +/- 0.1 cm, waist circumference: 98.0 +/- 0.4 cm, BMI: 28.6 +/- 0.2 kg/m2, OGTT: 113.9 +/- 1.0 mg/dL, fasting glucose: 99.6 +/- 0.3 mg/dL, HbA1c: 5.4 +/- 0.01%, and HOMA-IR: 3.2 +/- 0.1. Compared to waist circumference and BMI, SAD consistently emerged as the best predictor of glucose metabolism, before and after adjusting for the covariates, and with the sample stratified by gender, race, or age. SAD was not a better predictor of OGTT among normal-weight adults or non-Hispanic Black adults. Due to the ease of taking SAD measurements, we recommend that healthcare providers use this simple method to more precisely predict diabetes risk, especially among overweight and obese adults. PMID- 30018981 TI - Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases. AB - Insulin-like growth factor-1 (IGF-1) was firstly identified as a hormone that mediates the biological effects of growth hormone. Accumulating data have indicated the role of IGF-1 signaling pathway in lung development and diseases such as congenital disorders, cancers, inflammation, and fibrosis. IGF-1 signaling modulates the development and differentiation of many types of lung cells, including airway basal cells, club cells, alveolar epithelial cells, and fibroblasts. IGF-1 signaling deficiency results in alveolar hyperplasia in humans and disrupted lung architecture in animal models. The components of IGF-1 signaling pathways are potentiated as biomarkers as they are dysregulated locally or systemically in lung diseases, whereas data may be inconsistent or even paradoxical among different studies. The usage of IGF-1-based therapeutic agents urges for more researches in developmental disorders and inflammatory lung diseases, as the majority of current data are collected from limited number of animal experiments and are generally less exuberant than those in lung cancer. Elucidation of these questions by further bench-to-bedside researches may provide us with rational clinical diagnostic approaches and agents concerning IGF-1 signaling in lung diseases. PMID- 30018986 TI - Extracellular Vesicles: A Novel Target for Exercise-Mediated Reductions in Type 2 Diabetes and Cardiovascular Disease Risk. AB - Regular exercise is important for reducing type 2 diabetes (T2D) and/or cardiovascular disease (CVD) risk. However, only about 40-50% of this CVD risk reduction is accounted for by adiposity, hyperglycemia, hypertension, and dyslipidemia. Herein, we present the novel hypothesis that extracellular vesicles (EVs) are candidate biomarkers that may relate to impaired endothelial function and insulin resistance independent of obesity risk factors. EVs are small membrane-bound particles that are generated by cells following stimulation, stress, or activation. They carry markers of their parent cell and are thought to be potent bioactivators and communicators. We discuss the underlying physiology of specific cell type EVs, as well as examine how acute and chronic exercise interventions impact EV count and phenotype. We also propose that current gaps in the field are in part related to use of different detection techniques and the lack of standardized measurements of EV affecting the pre- and postanalytical phase. Ultimately, improving the understanding of how EVs impact cardiometabolic health and their function will lead to improved approaches for enhancing diagnostic options as well as designing exercise interventions that treat and/or prevent T2D and CVD. PMID- 30018987 TI - Lymph Node-Targeting Nanovaccine through Antigen-CpG Self-Assembly Potentiates Cytotoxic T Cell Activation. AB - Therapeutic vaccines that arouse the cytotoxic T cell immune response to reject infected cells have been investigated extensively for treating disease. Due to the large amounts of resident antigen-presenting cells (APCs) and T cells in lymph nodes, great efforts have been made to explore the strategy of targeting lymph nodes directly with nanovaccines to activate T cells. However, these nanovaccines still have several problems, such as a low loading efficiency and compromised activity of antigens and adjuvants derived from traditional complicated preparation. There are also safety concerns about materials synthesized without FDA approval. Herein, we construct an assembled nanoparticle composed of an antigen (ovalbumin, OVA) and adjuvant (CpG) to ensure its safety and high loading efficiency. The activity of both components was well preserved due to the mild self-assembly process. The small size, narrow distribution, negative charge, and good stability of the nanoparticle endow these nanovaccines with superior capacity for lymph node targeting. Correspondingly, the accumulation at lymph nodes can be improved by 10-fold. Subsequently, due to the sufficient APC internalization and maturation in lymph nodes, ~60% of T cells are stimulated to proliferate and over 70% of target cells are specifically killed. Based on the effective and quick cellular immune response, the assembled nanoparticles exhibit great potential as therapeutic vaccines. PMID- 30018988 TI - Mortality in a Cohort of HIV-Infected Children: A 12-Month Outcome of Antiretroviral Therapy in Makurdi, Nigeria. AB - Introduction: Recognizing the predictors of mortality among HIV-infected children will allow for concerted management that can reduce HIV-mortality in Nigeria. Methodology: A retrospective cohort study in children aged 0-15 years, between October 2010 and December 2013, at the Federal Medical Centre, Makurdi, Nigeria. Kaplan-Meier method analysed the cumulative probability of early mortality (EM) occurring at or before 6 months and after 6 months of follow-up (late mortality LM) on a 12-month antiretroviral therapy (ART). Multivariate Cox proportional regression models were used to test for hazard ratios (HR). Results: 368 children were included in the analysis contributing 81 children per 100 child-years to the 12-month ART follow-up. A significant reduction in EM rates was noted at 17.3 deaths per 100 child-years (30 deaths) to LM rates of 3.0 deaths per 100 child years (10 deaths), p < 0.01. At multivariate analysis, children with a high pretreatment viral load (>=10,000 copies/ml) were found to be at risk of EM (aHR; 18. 089, 95% CI; 2.428-134.77, p=0.005). Having severe immunosuppression at/or before 6 months of ART was the predictor of LM (aHR; 17.28, 95% CI; 3.844-77.700, p <= 0.001). Conclusions: Although a lower mortality rate is seen at 12 months of ART in our setting, predictors of HIV mortality are having high pretreatment HIV viral load and severe immunosuppression. While primary prevention of HIV infection is paramount, early identification of these predictors among our HIV infected children for an early ART initiation can reduce further the mortality in our setting. In addition, measures to ensure a good standard of care and retention in care for a sustained virologic suppression cannot be ignored and are hereby underscored. PMID- 30018989 TI - Aquatic Insect from Iran for Possible Use of Biological Control of Main Vector Borne Disease of Malaria and Water Indicator of Contamination. AB - Iran has a wide variety of zoogeographical regions and different seasons. Here are some important mosquito-borne diseases. Mosquitoes normally live in waters. Its aquatic insect fauna is highly unexplored. To being resolved this faunal gap, a variety of literature records from previous century in different parts of Iran was reviewed. In some southern and southeastern foci in Iran, Malaria is still a main endemic disease which is unstable with two seasonal spring and autumn peaks even though Iran is lunching Malaria elimination. This review article showed the wide variety of aquatic insects throughout the country. Researchers can discuss water pollutant and its quality by using aquatic insect fauna as well as biological control for vectors. Types of aquatic insects and macroinvertebrates sampling can be useful for water quality monitoring as indicators. Looking at aquatic insects' life in water could be one of the most cost-effective and the easiest method to assess the water contaminations by different pollutants and will provide a guideline for scientific communities and environmental agencies for decision making. PMID- 30018990 TI - Pathogenic Fungal Species Associated with Digestive System of Periplaneta americana (Blattaria: Blattidae) Trapped from Residential Dwellings in Ahvaz City, Southwestern Iran. AB - Background: Cockroaches are the most prevalent domestic pests of a worldwide distribution. They were recognized as possible vectors of pathogenic bacteria, viruses, fungi and parasites in residential dwellings and hospital environments. The present study isolated and identified yeasts and filamentous fungi from digestive tract of American cockroaches, collected from three different residential regions of Iran. Methods: Seventy cockroaches were sampled using direct collection (hand catch), vacuum cleaner and sticky traps in Ahvaz, Iran in 2009-2010. Their medically important fungal microorganisms were isolated from digestive tract using standard mycological methods. Filamentous fungi were identified by macroscopic and microscopic examination. Yeasts were identified by API ID32C-32100 kit. Results: A high percentage of cockroaches (88.6%) were detected to carry fungi of medical importance. Overall, 23 fungi species/genera were isolated from the American cockroaches' alimentary tract. The fungi isolated from cockroaches, from the residential regions were species of Aspergillus, Rhizopus, Penicillium, Mucorales, Alternaria, Cladosporium, Mycelia, Chrysosporium, Candida, Rhodotorula, Zygosaccharomyces, and Debaryomyces. Candida spp. (41.4%), Aspergillus spp. (37.1%) and Rhodotorula spp (27.1%) were the most common fungi recovered on cockroaches. Candida albicans and Candida glabrata were the commonest species of the genus Candida. In addition, Aspergillus niger and A. flavus were the most frequent species of the genus Aspergillus. Conclusion: American cockroaches may carry pathogenic fungi in the urban areas of Ahvaz. PMID- 30018991 TI - High Resistance of Vector of West Nile Virus, Culex pipiens Linnaeus (Diptera: Culicidae) to Different Insecticides Recommended by WHO in Northern Iran. AB - Background: Culex pipiens is a mosquito species distributed in different parts of Iran. It is known as vector of some diseases as well as a nuisance insect. A successful control campaign needs to study the biology, ecology and susceptibility status of the target pest. The aim of this study was to investigate the susceptibility status of Culex pipiens to some insecticides recommended by WHO in north of Iran. Methods: Larvae were collected from different breeding places in Sari County by standard dipping method. They were reared to adult stage in an under standard condition. World Health Organization (WHO) standard test kits and the diagnostic dose of 12 imagicides were used for adults, while two larvicides were used against larvae. Results: The least and highest mortality rates after exposure to insecticides were 4.7% (Propoxur 0.1%) and 76.4% (Etofenprox 0.5%), respectively. Larvae showed high resistance to temephos (19.19%) and malathion (54.63%). Culex pipiens was found to be resistant to all used insecticides/larvicides at diagnostic dose. Conclusion: Intensive use of pesticides against agriculture and urban pests increased the resistance level of this species to different insecticides, although currently there is no control program against it. Study on the mechanisms of resistant in this species to different insecticides is recommended. PMID- 30018992 TI - Hemodynamic Changes in Experimentally Envenomed Anaesthetized Rats by Intravenous Injection of Hemiscorpius lepturus Venom. AB - Background: We investigated the hemodynamic changes (Inotropic, chronotropic and arrhythmogenic) in intravenously envenomed anesthetized rats with Hemiscorpius lepturus venom. The neutralizing potencies of different drugs and commercial antivenom were assessed simultaneously. Methods: Different doses of the crude venom (100, 200 and 400MUg/rat) were injected during five minutes via the femoral vein and cardiovascular changes were recorded in rats in Razi Institute Corporation, Karaj, Iran in 2017. The drugs (Atropine, lidocaine, propranolol and prazosin) were injected before the venom for determination of the counteracting effects. Different volumes (100, 500 and 1000MUl) of the antivenom were pre envenomed to neutralize cardiovascular changes. Results: Temporary hypertension and bradycardia with no arrhythmogenic effects were depicted within twenty minutes. There was a difference in arterial pressure between the venom (400MUg/rat) and the vehicle at 8 minutes (114.68+/-5.1mmHg versus 70.2+/ 4.3mmHg). Elevation of the mean arterial pressure was inhibited by propranolol (2 mg/kg) and neutralized by prazosin (1mg/kg) while lidocaine (4mg/kg) and atropine (1mg/kg) had no effects. Premedication with Iranian commercial antivenom (1000MUl) produced surprisingly temporary hypertension compared to the vehicle (140.84+/-4.5 versus 84.3+/-3.2). It had no neutralizing properties on blood pressure variation before the venom injection. Volume-expanded hypertension phenomenon was ruled out in a parallel study. Conclusion: This venom has vasoconstrictive effects in rats probably due to the presence of norepinephrine like materials in its content or liberated from adrenal gland inhibited by prazosin premedication. The neutralizing effects of antivenom on venom-induced hypertension are questionable. PMID- 30018993 TI - Modeling of Environmental Factors Affecting the Prevalence of Zoonotic and Anthroponotic Cutaneous, and Zoonotic Visceral Leishmaniasis in Foci of Iran: a Remote Sensing and GIS Based Study. AB - Background: Leishmaniasis is a re-emerging serious international public health problem, and both visceral and cutaneous types of leishmaniasis became important endemic diseases in Iran. In this study, the relationships between environmental factors (vegetation and elevation) and the prevalence of diseases have been investigated. Methods: All international and national online databases were searched by terms such as leishmaniasis, incidence, prevalence and other related words attributed to Iran and published until first quarter of 2015. The developed database in Excel, later imported to the ArcMap for spatial analyst and mapping. Afterwards, the software was used for modeling the relationship between the prevalence/incidence and environmental variables (vegetation and elevation) by both linear and nonlinear regression. Results: After mapping the prevalence data from 144 studies, considering non-parametric ANOVA, the tendency of zoonotic visceral leishmaniasis to presence in high elevation and high vegetation was more than Anthroponotic and zoonotic cutaneous leishmaniasis. While linear regression showed weaker results for modeling, however, additive nonparametric regression analysis suggested that 10km buffers for elevation, and 10 as well as 50km buffers for vegetation could contribute in better fitness in modeling of these variables. Conclusion: The detailed maps for distribution of disease concluded. The nonlinear regression is a reliable predictor of the relationship between environmental factors and disease incidence, although more and wide researchers are needed to confirm it. PMID- 30018994 TI - Molecular-Based Detection of Leishmania infantum in Human Blood Samples in a New Focus of Visceral Leishmaniasis in Lorestan Province, Iran. AB - Background: The fatal form of leishmaniasis is visceral form (VL), found in some of the countries in the world. Visceral leishmaniasis has been reported sporadically from all provinces in Iran, including Lorestan. This study aimed to characterize parasite species in DAT positive and some of the DAT negative human blood samples of Delfan district, Lorestan Province, central Iran. Methods: Blood samples were collected from different geographical areas of Delfan. Serum was used for DAT test and remained part of molecular study. DNA was extracted by using DNG-plus extracted kit (Cinagen, Iran). Polymerase chain reaction amplification of Leishmania kDNA and PCR-RFLP of ITS1 was done to identify Leishmania species. Some amplicons were sequenced, submitted to GenBank and analyzed by BLASTn. Results: Expected band of kDNA for L. infantum (720bp) was amplified in 16 out of 186 (8.6%) samples which showed previously anti-Leishmania antibody at different titers or were negative serologically. Using BLASTn, 93% similarity with L. infantum has been shown. The rDNA-ITS1 was amplified only in 9 samples (4.7%). RFLP pattern was similar to what expected for L. infantum. Conclusion: A new emerging hypo-endemic focus, caused by L. infantum, is going to be established in Delphan District, Lorestan Province. Further studies on vector and reservoirs are necessary for the region and other parts of Lorestan Province. PMID- 30018995 TI - Situational Analysis of Cutaneous Leishmaniasis in an Endemic Focus of the Disease, Southeastern Iran. AB - Background: Leishmaniasis is one of the most important vector-borne diseases in Iran, existing in a variety of forms ranging from cutaneous to visceral forms. Jask County has been recognized as an endemic focus of the disease in the southeastern region of Iran. This study analyzed the situation of cutaneous leishmaniasis (CL) during 2006-2014. Methods: This cross-sectional analytical study was conducted on CL data got from health sector. ArcGIS 10.3 was exploited for the spatial analysis of CL. Potential high-risk areas of the disease regarding its' current geographical distribution were considered. Results: Overall, 874 CL cases had been registered in the district health center, implying an average incidence of 162.5per 100000. More than 90% of the cases emerged from rural areas. The disease is geographically distributed in the southeastern regions of Jask County. Over one-third of the total study area can be classified as high-risk areas, involving 61 villages with a total population of about 18000. Remarkably, altitude and total precipitation were realized to play key roles in CL transmission within the study area. Conclusion: Although the national protocol for the control of ZCL recommends the substantial destruction of rodent colonies serving as reservoirs of the disease in infected foci, critical improvement of the knowledge of the residents in these areas is crucial for community-based management of the disease in Jask County. PMID- 30018998 TI - Malaria Eliminating: What Lies Ahead of Iran? PMID- 30018997 TI - Melanization of Dirofilaria immitis Larvae in Different Culicid Species. AB - Background: Dirofilaria immitis is an important filarioid transmitted by culicids. The vector role of these arthropods may be influenced by biological events as melanization against D. immitis larvae. This study aimed to detect the occurrence of melanization in Culex quinquefasciatus, Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus experimentally infected with D. immitis. Methods: Five populations (Cx. quinquefasciatus RECIFE (P1), Ae. albopictus RECIFE (P2), Ae. aegypti RECIFE (P3), Ae. aegypti CAMPINAS (P4) and Ae. aegypti ROCKEFELLER (P5)) were artificially fed with infected blood containing D. immitis microfilariae. Ten mosquitoes per day from each population were dissected for 14 days. Results: Melanized larvae of D. immitis were observed in all population except in P3. The period in which melanized larvae were found varied from the third to the 14th day post-infection. Difference in the number of these larvae was observed between P5 and P2-P3 (P< 0.01), and between P5 and P4 (P< 0.05). Third-stage larvae of D. immitis were detected in all population 14 d post infection, except in P3, which presented high mortality 24 h post-infection. The melanization observed in the populations herein studied did not indicate refractory since third-stage larvae were observed at the end of the experiment. Most likely, this immune response aimed to control the number of larvae, in order to maintain the equilibrium between vector-parasite. Conclusion: The melanization did not seem to be a limiting factor to the development of this filarioid in these local Brazilian Culicidae populations. PMID- 30018996 TI - Larvicidal Activity of Bunium persicum Essential Oil and Extract against Malaria Vector, Anopheles stephensi. AB - Background: Malaria, a mosquito-transmitted disease, is still a major human health problem all over the world. Larviciding is a component of comprehensive control program to overcome the disease. Negative aspects of synthetic insecticides application, such as environmental safety concerns, have favored use of natural insecticides. Methods: Larvicidal activity of essential oil, extracts and fractions of a wild grown and a cultivated type of Bunium persicum fruits against malaria vector Anopheles stephensi was assessed according to the method described by WHO. Results: Bunium persicum showed remarkable potency against An. stephensi larvae. LC 50 values for essential oil, total extract, petroleum ether fraction and methanol fraction were 27.4284, 64.9933, 85.9933 and 255.7486ppm for wild type, and 21.3823, 63.2580, 62.7814 and 152.6357ppm for cultivated one. Conclusion: The results of this study suggest B. persicum as a valuable source of natural insecticides against malaria vector Anopheles stephensi. PMID- 30018999 TI - Infectious Diseases Physicians' Perspectives Regarding Injection Drug Use and Related Infections, United States, 2017. AB - Background: In the context of the opioid epidemic, injection drug use (IDU) related infections are an escalating health issue for infectious diseases (ID) physicians in the United States. Methods: We conducted a mixed methods survey of the Infectious Diseases Society of America's Emerging Infections Network between February and April 2017 to evaluate perspectives relating to care of persons who inject drugs (PWID). Topics included the frequency of and management strategies for IDU-related infection, the availability of addiction services, and the evolving role of ID physicians in substance use disorder (SUD) management. Results: More than half (53%, n = 672) of 1273 network members participated. Of these, 78% (n = 526) reported treating PWID. Infections frequently encountered included skin and soft tissue (62%, n = 324), bacteremia/fungemia (54%, n = 281), and endocarditis (50%, n = 263). In the past year, 79% (n = 416) reported that most IDU-related infections required >=2 weeks of parenteral antibiotics; strategies frequently employed for prolonged treatment included completion of the entire course in the inpatient unit (41%, n = 218) or at another supervised facility (35%, n = 182). Only 35% (n = 184) of respondents agreed/strongly agreed that their health system offered comprehensive SUD management; 46% (n = 242) felt that ID providers should actively manage SUD. Conclusions: The majority of physicians surveyed treated PWID and reported myriad obstacles to providing care. Public health and health care systems should consider ways to support ID physicians caring for PWID, including (1) guidelines for providing complex care, including safe provision of multiweek parenteral antibiotics; (2) improved access to SUD management; and (3) strategies to assist those interested in roles in SUD management. PMID- 30019000 TI - Health-Related Quality of Life in Outpatient Parenteral Antimicrobial Therapy. AB - Health-related quality of life (HRQoL) in outpatient parenteral antimicrobial therapy (OPAT) has not been well characterized in the United States. In an OPAT cohort, the short-form-12's median physical component score and mental component score were 40.3 and 54.4, respectively. HRQoL measures could be helpful in studies of OPAT cost-effectiveness. PMID- 30019001 TI - Effect of Hepatocellular Carcinoma on Mortality Among Individuals With Hepatitis B or Hepatitis C Infection in New York City, 2001-2012. AB - Background: Hepatocellular carcinoma (HCC) is a complication of chronic hepatitis B and C virus (HBV and HCV) infection. New York City (NYC) has a high prevalence of HBV and HCV, and infected persons likely face increased mortality from HCC and other causes. We describe the mortality profile of NYC residents with HBV or HCV, emphasizing the contributions of HCC and HIV coinfection. Methods: Two existing data sets were combined to examine all individuals diagnosed with HBV or HCV in NYC first reported to the Health Department during 2001-2012 and their HCC, HIV, and vital status. Logistic regression was used to calculate the odds of HCC diagnosis by viral hepatitis status, whereas Cox proportional hazard regression was used to estimate the hazard of death by HCC/HIV status. Results: In total, 120 952 and 127 933 individuals were diagnosed with HBV or HCV, respectively. HCV infected individuals had 17% higher odds of HCC diagnosis than HBV-infected individuals and 3.2 times higher odds of HIV coinfection. Those with HCV were twice as likely to die during the study period (adjusted hazard ratio, 2.04; 95% confidence interval, 1.96-2.12). The risk of death increased for those with HIV or HCC and was highest for those with both conditions. Conclusions: HCC and HIV represent substantial risks to survival for both HBV- and HCV-infected individuals. Individuals with HBV need close monitoring and treatment, when indicated, and routine HCC screening. Those with HCV need increased, timely access to curative medications before developing liver disease. PMID- 30019004 TI - Quantification of Starch in Guard Cells of Arabidopsis thaliana. AB - In this protocol, we describe how to quantify starch in guard cells of Arabidopsis thaliana using the fluorophore propidium iodide and confocal laser scanning microscopy. This simple method enables monitoring, with unprecedented resolution, the dynamics of starch in guard cells. PMID- 30019003 TI - Human Serum With High Neutralizing Antibody Titers Against Both Zika and Dengue Virus Shows Delayed In Vitro Antibody-Dependent Enhancement of Dengue Virus Infection. AB - Zika virus infection in a dengue virus-naive subject was associated with the induction of high levels of cross-reactive binding antibodies. These responses were, however, largely non-neutralizing and displayed a capacity to enhance dengue infection in vitro at significantly low dilution (1:10). In contrast, a subject who had high levels of neutralizing antibodies against both dengue and Zika viruses enhanced infection at a dilution of 1:10 000. These results suggest that high levels of dengue cross-neutralizing antibodies could potentially prevent the enhancement of dengue infection in Zika virus-convalescent individuals. PMID- 30019002 TI - Cellular Immune Responses 6 Years Following 1, 2, or 3 Doses of Quadrivalent HPV Vaccine in Fijian Girls and Subsequent Responses to a Dose of Bivalent HPV Vaccine. AB - Background: This study examined the cellular immunity of 0, 1, 2, and 3 doses of Gardasil vaccine (4vHPV) in girls after 6 years and their responses to a subsequent dose of Cervarix vaccine (2vHPV). Methods: A subset of girls (n = 59) who previously received 0, 1, 2, or 3 doses of 4vHPV 6 years earlier were randomly selected from a cohort study of Fijian girls (age 15-19 years). Blood was collected before and 28 days after a dose of 2vHPV. The HPV16- and HPV18 specific cellular immune response was determined by IFNgamma-ELISPOT and by measurement of cytokines in peripheral blood mononuclear cell supernatants. Results: Six years after 4vHPV vaccination, HPV18-specific responses were significantly lower in the 1- (1D) or 2-dose (2D) recipients compared with 3-dose recipients (2D: IFNgamma-ELISPOT: P = .008; cytokines, IFNgamma: P = .002; IL-2: P = .022; TNFalpha: P = .016; IL-10: P = .018; 1D: IL-2: P = .031; IL-10: P = .014). These differences were no longer significant post-2vHPV. No significant differences in HPV16 responses (except IL-2, P < .05) were observed between the 2 or 1-dose recipients and 3-dose recipients. Conclusions: These data suggest that cellular immunity following reduced-dose schedules was detectable after 6 years, although the responses were variable between HPV types and dosage groups. The clinical significance of this is unknown. Further studies on the impact of reduced dose schedules are needed, particularly in high-disease burden settings. PMID- 30019005 TI - Pulsatile Chemotherapeutic Delivery Profiles Using Magnetically Responsive Hydrogels. AB - Pulsatile chemotherapeutic delivery profiles may provide a number advantages by maximizing the anticancer toxicity of chemotherapeutics, reducing off-target side effects, and combating adaptive resistance. While these temporally dynamic deliveries have shown some promise, they have yet to be clinically deployed from implantable hydrogels, whose localized deliveries could further enhance therapeutic outcomes. Here, several pulsatile chemotherapeutic delivery profiles were tested on melanoma cell survival in vitro and compared to constant (flatline) delivery profiles of the same integrated dose. Results indicated that pulsatile delivery profiles were more efficient at killing melanoma cells than flatline deliveries. Furthermore, results suggested that parameters like the duration of drug "on" periods (pulse width), delivery rates during those periods (pulse heights), and the number/frequency of pulses could be used to optimize delivery profiles. Optimization of pulsatile profiles at tumor sites in vivo would require hydrogel materials capable of producing a wide variety of pulsatile profiles (e.g., of different pulse heights, pulse widths, and pulse numbers). This work goes on to demonstrate that magnetically responsive, biphasic ferrogels are capable of producing pulsatile mitoxantrone delivery profiles similar to those tested in vitro. Pulse parameters such as the timing and rate of delivery during "on" periods could be remotely regulated through the use of simple, hand held magnets. The timing of pulses was controlled simply by deciding when and for how long to magnetically stimulate. The rate of release during pulse "on" periods was a function of the magnetic stimulation frequency. These findings add to the growing evidence that pulsatile chemotherapeutic delivery profiles may be therapeutically beneficial and suggest that magnetically responsive hydrogels could provide useful tools for optimizing and clinically deploying pulsatile chemotherapeutic delivery profiles. PMID- 30019006 TI - Neighborhood Disadvantage and Telomere Length: Results from the Fragile Families Study. AB - Telomeres are repetitive nucleotide sequences located at the ends of chromosomes that protect genetic material. We use data from the Fragile Families and Child Wellbeing Study to analyze the relationship between exposure to spatially concentrated disadvantage and telomere length for white and black mothers. We find that neighborhood disadvantage is associated with shorter telomere length for mothers of both races. This finding highlights a potential mechanism through which the unique spatially concentrated disadvantage faced by African Americans contributes to racial health disparities. We conclude that equalizing the health and socioeconomic status of black and white Americans will be very difficult without reducing levels of residential segregation in the United States. PMID- 30019007 TI - Clinical Effects of Piribedil in Adjuvant Treatment of Parkinson's Disease: A Meta-Analysis. AB - OBJECTIVE: To evaluate the clinical effects of piribedil in adjuvant treatment of Parkinson's Disease (PD) by pooling previously openly published studies. METHODS: The related electronic databases of Medline (1960~2017.5), Cochrane central register of controlled trials (CENTRAL), EMBASE (1980~2017.5) and Wanfang (1986~20175.5) were searched by two reviewers (Lu Peihua and Wang Jianqian) independently for publications including the topic of prospective randomized controlled trials about clinical effects of piribedil in adjuvant treatment of PD. The data of each included study was extracted and pooled by Stata11.0 software (for meta-analysis). The statistical heterogeneity across the studies was evaluated by I2 test and the publication bias was calculated by begg's funnel plot and Egger's line regression test. RESULTS: After searching the related electronic databases of Medline, CENTRAL, EMBSE and Wanfang databases, 11 clinical studies were included in this meta-analysis. The pooled RR (random effect model) of clinical efficacy was 1.29 (95%CI:1.18~1.41, P=4*10-3) indicating the clinical efficacy of piribedil group was signficat higher than those of control group. The standard mean difference (SMD) for UPDRS score changed before and after treatment was pooled by random effect model. The combined SMD was -0.41 (95%CI:-0.75~-0.06). For piribedil related side effects, the combined data indicated that there was no statistical difference for nausea and vomiting (RR=0.43, 95%CI:0.41~1.69, P=0.61), mental disorders (RR=0.85, 95%CI:0.45~1.59, P=0.61) and other toxicities (RR=0.32, 95%CI:0.09~1.16, P=0.08). CONCLUSION: Piribedil combined with Levodopa in adjuvant treatment of PD is more effective than Levodopa alone without increasing the drug related toxicity. PMID- 30019008 TI - Identification of a Novel BRAF Thr599dup Mutation in Lung Adenocarcinoma. AB - BRAF mutations are known as oncogenic drivers of non-small cell lung cancer (NSCLC). BRAF inhibition has demonstrated anti-tumor activity in patients with BRAF V600E mutant NSCLC. Further molecular screening for novel BRAF thr599dup mutation is warranted. The novel BRAF Thr599dup gene mutation, for which the repeat amino acid-tyrosine is inserted between the 599th amino acid and the 600th amino acid in exon 15 of BRAF, was identified by next-generation sequencing (NGS) during routine clinical care in a lung carcinoma sample from an Asian never smoker. Other putative driver alterations including EGFR, ALK were not found in that patient. BRAF Thr599dup gene mutation analysis was consistent with BRAF v600E gene mutation. Here we report a novel BRAF gene mutation with molecular characteristics consistent with those in BRAF-driven NSCLC. Our case expands the scope of BRAF gene mutations and provides broader molecular profiling for optimizing therapeutic options for patients with NSCLC. The new BRAF gene mutation has important clinical meaning for cancer patients. PMID- 30019009 TI - Use of an educational, audiovisual podcast to maximise safety with variable rate intravenous insulin infusions. AB - Variable rate intravenous insulin infusions (VRIII) are used to maintain stable blood glucose in hospitalised patients with diabetes who are unable to eat or have a severe illness where good glycaemic control is paramount. With VRIII it is important to prescribe an adequate substrate to avoid hypoglycaemia and maintain electrolyte balance. Traditionally the substrate would have been varied to achieve this; current guidelines advise varying the infusion rate rather than the type of substrate. The local hospital Trust updated their VRIII prescription chart to reflect the Joint British Diabetes Societies' suggestions for inpatient care in October 2014. A local audit in January 2015 highlighted that 48% of patients on VRIII were prescribed the correct fluid as per the guideline. A questionnaire to assess prescriber knowledge regarding VRIII showed 40.4% of prescribers selected appropriate fluid for a patient with normal renal function and 11.5% of prescribers selected appropriate fluid for a patient with renal failure. An educational podcast was devised to explain the rationale behind appropriate fluid prescription with VRIII; this was shown to prescribers. Following the podcast, 75.8% of prescribers selected appropriate fluids for normal renal function and 54.5% for renal failure. Questionnaires were completed to assess prescriber knowledge prepodcast and postpodcast. Following the podcast, there was a significant increase in questionnaire scores, indicating improved prescriber knowledge surrounding VRIII. A reaudit of prescriptions for VRIII showed improvement in practice, where 63% of patients on VRIII were prescribed correct fluids. The use of a simple audiovisual podcast on VRIII led to a significant improvement in prescriber knowledge. Podcasts are an ideal medium to raise awareness around safety issues, including safe prescription of insulin. Further work will include the follow-up of participants to evaluate sustained knowledge and improvements of prescriptions in practice, with the overall aim of improving patient safety. PMID- 30019010 TI - Quality improvement of delirium status communication and documentation for intensive care unit patients during daily multidisciplinary rounds. AB - Delirium is a key quality metric identified by The Society of Critical Care Medicine for intensive care unit (ICU) patients. If not recognised early, delirium can lead to increased length of stay, hospital and societal costs, ventilator days and risk of mortality. Clinical practice guidelines recommend ICU patients be assessed for delirium at least once per shift. An initial audit at our urban tertiary care hospital in Illinois, USA determined that delirium assessments were only being performed 31% of the time. Nurses completed simulation based education and were trained using delirium screening videos. After the educational sessions, delirium documentation increased from 40% (12/30) to 69% (41/59) (two-proportion test, p<0.01) for dayshift nurses and from 27% (8/30) to 61% (36/59) (two-proportion test, p<0.01) during the nightshift. To further increase the frequency of delirium assessments, the delirium screening tool was standardised and a critical care progress note was implemented that included a section on delirium status, management strategy and discussion on rounds. After the documentation changes were implemented, delirium screening during dayshift increased to 93% (75/81) (two-proportion test, p<0.01). Prior to this project, physicians were not required to document delirium screening. After the standardised critical care note was implemented, documentation by physicians was 95% (106/111). Standardising delirium documentation, communication of delirium status on rounds, in addition to education, improved delirium screening compliance for ICU patients. PMID- 30019011 TI - See You in 7: improving acute myocardial infarction follow-up care. AB - Acute myocardial infarction (AMI) follow-up care is a crucial part of the AMI recovery process. The American College of Cardiology's 'See You in 7 Challenge' advocates that all patients discharged with a diagnosis of AMI have a cardiac rehabilitation referral made and outpatient cardiac rehabilitation appointment scheduled to occur within 7 days of hospital discharge. A streamlined AMI cardiac rehabilitation referral and appointment scheduling process was not in place at this urban academic medical centre. To develop the streamlined processes, a Six Sigma project was initiated. Four months before the intervention, 1/38 patients with AMI (2.6%) were scheduled to have the initial outpatient cardiac rehabilitation appointment occur within 7 days of hospital discharge, with an average 18.7 days from hospital discharge to the scheduled initial outpatient cardiac rehabilitation appointment. To reduce the time to this initial appointment, availability of outpatient cardiac rehabilitation appointments was increased, additional staff were trained in appointment scheduling and insurance verification processes and appointments were scheduled prior to hospital discharge. After intervention, the number of patients scheduled to attend an outpatient cardiac rehabilitation appointment within 7 days of hospital discharge improved to 72/79 (91.1%) (two-proportion test, p<0.001). Days from hospital discharge to first scheduled outpatient cardiac rehabilitation appointment were reduced from 18.7 days to 6.3 days (a 66.3% reduction) (Mann-Whitney U test, p<0.01). Initial outpatient cardiac rehabilitation attendance within 7 days of hospital discharge increased from 1/38 (2.6%) to 42/79 (53.2%) (a 50.6% increase) (two-proportion test, p<0.001). PMID- 30019012 TI - Interprofessional, student-led intervention to improve insulin prescribing to patients in an Acute Surgical Receiving Unit. AB - Our aim was to test the feasibility of interprofessional, workplace-based learning about improvement through a 4-week placement for one medical and two pharmacy final year students in an Acute Surgical Receiving Unit (ASRU). The target was insulin because this is a common, high-risk medicine in this ASRU and the intervention was medicines reconciliation. Baseline data were collected from 10 patients and used to construct a cause and effect diagram and a process map through feedback and discussions with staff. Hypoglycaemia occurred in four patients but hyperglycaemia occurred in eight patients, of whom six were placed on intravenous insulin infusion (IVII). We estimated that L2454 could be saved by preventing one patient from going on IVII. The students designed and tested a sticker to improve medicines reconciliation for insulin patients. An online form was created to capture clinician feedback on the layout and usability of the sticker. The intervention was associated with improvements in the reliability of medicines reconciliation. The students' work contributed to a larger project to reduce the risk of hypoglycaemia in the ASRU. This proved beneficial in enabling the students to engage with the clinical team. Nonetheless, it was challenging for students from two Universities to get a shared understanding of improvement methods and work effectively with the clinical team. The students said that they learnt more about quality improvement in a working healthcare environment than they would ever learn in a classroom and they valued the opportunity to work with students from other healthcare backgrounds in practice. Despite the additional staff time required to support students from two Universities, both have supported continuation of this work. PMID- 30019013 TI - EMR-based handoff tool improves completeness of internal medicine residents' handoffs. AB - Background: The majority of adverse events in healthcare involve communication breakdown. Physician-to-physician handoffs are particularly prone to communication errors, yet have been shown to be more complete when systematised according to a standardised bundle. Interventions that improve thoroughness of handoffs have not been widely studied. Aim: To measure the effect of an electronic medical record (EMR)-based handoff tool on handoff completeness. Intervention: This EMR-based handoff tool included a radio button prompting users to classify patients as stable, a 'watcher' or unstable. It automatically pulled in EMR data on the patient's 24-hour vitals, common lab tests and code status. Finally, it provided text boxes labelled 'Active Issues', 'Action List (To-Dos)' and 'If/Then' to fill in. Implementation and evaluation: Written handoffs from general and specialty (haematology, oncology, cardiology) Internal Medicine resident-run inpatient wards were evaluated on a randomly chosen representative sample of days in April and May 2015 at Stanford University Medical Center, focusing on a predefined set of content elements. The intervention was then implemented in June 2015 with postintervention data collected in an identical fashion in August to September 2016. Results: Handoff completeness improved significantly (p<0.0001). Improvement in inclusion of illness severity was notable for its magnitude and its importance in establishing a consistent mental model of a patient. Elements that automatically pulled in data and those prompting users to actively fill in data both improved. Conclusion: A simple EMR based handoff tool providing a mix of frameworks for completion and automatic pull-in of objective data improved handoff completeness. This suggests that EMR based interventions may be effective at improving handoffs, possibly leading to fewer medical errors and better patient care. PMID- 30019014 TI - Enhancing acute stroke services: a quality improvement project. AB - Background: In a busy stroke centre in Ireland, care for acute stroke was provided by a mixture of general physicians. In acute ischaemic stroke, speed is essential for good outcomes. Aim: To improve acute stroke services and decrease door-to-needle (DTN) time to less than 60 min by December 2016 in patients with acute ischaemic stroke who are eligible for intravenous thrombolysis.Design: A quality improvement (QI) project was undertaken in a 438 bed, acute, university hospital. Methods: Mixture of qualitative and quantitative data collected. A process map and driver diagram were created. Interventions tested with Plan-Do Study-Act cycles. Times compared between July and December 2015, January and July 2016, July and December 2016, when a new stroke team and pathway were introduced. Results: Between July and December 2015, the total number of ischaemic strokes was 216. 17 were thrombolysed (7.8%). Median door-to-CT (DTCT) time was 36 min (range 21-88). Median DTN time was 99 min (range 52-239). Between July and December 2016, there were 214 ischaemic strokes. 29 were thrombolysed (13.5%). 9 were seen directly by the stroke team during normal hours. With stroke team involvement, median DTCT time was 34 min (range 14-60) and DTN time was 43.5 min (range 24-65). Conclusions: This project led to a significant and sustained improvement in acute stroke care in our hospital with the use of quality improvement techniques. A comprehensive protocol, recurrent and ongoing staff education, and good communication helped to mitigate delays and further enhance care provided to patients presenting with stroke. The approach described may be valuable to the improvement of other services.' PMID- 30019015 TI - Improving wait time from referral to opiate replacement therapy in a drug recovery service. AB - While the reported incidence of heroin use in the UK has reduced, related hospital admissions and associated mortality have continued to increase. Prompt access to treatment (opiate replacement therapy (ORT) and counselling support) have been shown to reduce risk and offer clients the optimal route to recovery. The Specialist Drug and Alcohol Recovery Service (Osprey House) within National Health Service Highland had lengthy delays from referral to commencing ORT (median wait 56 days), which this project aimed to reduce. A rapid process improvement workshop (RPIW) was undertaken to redesign the patient pathway from referral to recovery. The RPIW consisted of three phases: phase I, planning and preparation (12 weeks before the workshop week); phase II, the workshop week; and phase III, the follow-up. Metrics included the lead time from referral to initiating ORT and other process measures at baseline, and then repeated at 30, 60, 90 and 180 days, respectively. Additionally, data were routinely collected on the percentage of clients treated within 3 weeks, as was weekly data on the new process of screening clients within 1 day of referral. Multiple lean tools and techniques, including Plan, Do, Study, Act cycles, were used to test and implement new ways of working. Results at 180 days found the median time from referral to initiating ORT improved from a baseline of 56 to 21 days (63% improvement), room usage improved from 49% to 65% (32% increase) and standard work improved from level 1 to level 3. Increases in the number of clients treated within 3 weeks were demonstrated. Other metrics remained static or reported fluctuations too inconsistent to claim improvement at this point. By applying the Lean principles of removing waste and increasing value, we have redesigned our service, reducing the length of time clients with drug problems wait from referral to commencing ORT. PMID- 30019017 TI - Screen time behaviours and caffeine intake in US children: findings from the cross-sectional National Health and Nutrition Examination Survey (NHANES). AB - Background: Screen time (ST) behaviours, for example, television (TV) watching and computer use, among youth are associated with unhealthy eating, and these patterns track over time. A positive association between ST and TV watching with consumption of caffeinated foods and beverages has been described in national samples of children in a few European countries. The association of ST behaviours with caffeine intake has not been previously reported. We examined whether ST behaviours were associated with caffeine intake on a given day (% consumers and amount consumed) in a nationally representative sample of US children. Methods: Data on 3421 children (ages 6-11 years) from the cross-sectional National Health and Nutrition Examination Survey 2007-2012 were used. Time spent on TV watching and computer use was determined using questionnaires. Dietary intake was assessed using a 24-hour recall by trained interviewers. Caffeine intake (mg) was estimated by using updated food and nutrient databases. Caffeine consumption was examined in relation to time spent (>=2 vs<2 hours/day) on ST behaviours. Results: Children who watched TV >=2 hours/day had significantly higher (~45% more) caffeine intake. Total ST or computer use was not associated with caffeine consumption in school-aged children. Conclusion: TV watching was positively associated with caffeine intake in school-aged children, suggesting the need for continued monitoring of ST and caffeine intake behaviours in children and adolescents as well as examining the correlates of these behaviours to inform nutrition and health policies. PMID- 30019016 TI - Implementation of a whole of hospital sepsis clinical pathway in a cancer hospital: impact on sepsis management, outcomes and costs. AB - : Infection and sepsis are common problems in cancer management affecting up to 45% of patients and are associated with significant morbidity, mortality and healthcare utilisation. Objective: To develop and implement a whole of hospital clinical pathway for the management of sepsis (SP) in a specialised cancer hospital and to measure the impact on patient outcomes and healthcare utilisation. Methods: A multidisciplinary sepsis working party was established. Process mapping of practices for recognition and management of sepsis was undertaken across all clinical areas. A clinical pathway document that supported nurse-initiated sepsis care, prompt antibiotic and fluid resuscitation was implemented. Process and outcome measures for patients with sepsis were collected preimplementation (April-December 2012), postimplementation cohorts (April December 2013), and from January to December 2014. Results: 323 patients were evaluated (111 preimplementation, 212 postimplementation). More patients with sepsis had lactate measured (75.0% vs 17.2%) and appropriate first dose antibiotic (90.1% vs 76.1%) (all p<0.05). Time to antibiotics was halved (55 vs 110 min, p<0.05). Patients with sepsis had lower rates of intensive care unit admission (17.1% vs 35.5%), postsepsis length of stay (7.5 vs 9.9 days), and sepsis-related mortality (5.0% vs 16.2%) (all p<0.05). Mean total hospital admission costs were lower in the SP cohort, with a significant difference in admission costs between historical and SP non-surgical groups of $A8363 (95% CI 81.02 to 16645.32, p=0.048) per patient on the pathway. A second cohort of 449 patients with sepsis from January to December 2014 demonstrated sustained improvement. Conclusions: The SP was associated with significant improvement in patient outcomes and reduced costs. The SP has been sustained since 2013, and has been successfully implemented in another hospital with further implementations underway in Victoria. PMID- 30019018 TI - Feed thickeners in gastro-oesophageal reflux in infants. PMID- 30019019 TI - Antacid therapy for gastroesophageal reflux in preterm infants: a systematic review. AB - Background: Gastro-oesophageal reflux is prevalent in preterm infants. Despite widespread use in clinical practice, there is still much controversy over the efficacy and safety of drug interventions, particularly antacid therapy. Objective: To systematically review the effects of antacid therapy on preterm infants with symptoms of gastro-oesophageal reflux, and to assess the safety of these interventions. Methods: We carried out an electronic search of the Cochrane central register of controlled trials (CENTRAL, The Cochrane Library), MEDLINE (1966-present), EMBASE (1980-present) and CINAHL (1982-present) as well as other online sources. Participants were preterm infants (<37 weeks gestation) with gastro-oesophageal reflux disease who were receiving care on a neonatal unit. We assessed the effects of histamine-2 receptor antagonists, proton pump inhibitors and alginates against placebo, primarily to see if they reduced the symptoms of reflux. Results: Six studies were included in this review. Meta-analysis could not be carried out due to a lack of studies assessing the same intervention with the same outcomes. Omeprazole therapy significantly reduced the oesophageal acid exposure percentage time with pH<4 (p<0.01) and sodium alginate significantly decreased gastro-oesophageal reflux episodes (p=0.024). Metoclopramide and ranitidine showed a significant increase in gastro-oesophageal reflux disease symptoms versus placebo (p<0.04). No significant results were found for the use of esomeprazole or lansoprazole versus placebo. Conclusions: There is insufficient evidence available to conclude whether antacid therapy is effective or safe when treating gastro-oesophageal reflux disease in preterm infants. Further research is needed into this topic and caution should be taken when administering antacids to preterm infants. Trial registration number: CRD42017078778. PMID- 30019020 TI - Pancreatic mucinous cystic neoplasm masquerading as pseudocyst. PMID- 30019021 TI - Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques. AB - An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The current study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-beta/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair housed, juvenile male rhesus macaques were inoculated with SIVmac239; 4 weeks postinoculation, they were treated with weekly injections of 10 mg/kg ActRIIB.Fc or saline for 12 weeks. Myocardial mass and function were evaluated using two dimensional echocardiography at baseline and after 12 weeks. The administration of ActRIIB.Fc was associated with a significantly greater increase in thickness of left ventricular posterior wall and interventricular septum both in diastole and systole. Cardiac output and cardiac index increased with time, more in animals treated with ActRIIB.Fc than in those treated with saline, but the difference was not statistically significant. The changes in ejection fraction, fractional shortening, and stroke volume did not differ significantly between groups. The changes in end-diastolic and end-systolic volumes did not differ between groups. In addition to a large reduction in IGF1 mRNA expression in the ActRIIB.Fc-treated animals, complex changes were detected in the myocardial expression of proteins related to calcium transport and storage. In conclusion, ActRIIB.Fc administration for 12 weeks was associated with increased myocardial mass but did not adversely affect myocardial function in juvenile SIV-infected rhesus macaques. Further studies are necessary to establish long-term cardiac safety. PMID- 30019022 TI - Elevated Levels of Organochlorine Pesticides in South Asian Immigrants Are Associated With an Increased Risk of Diabetes. AB - Objective: Rates of diabetes mellitus are higher in South Asians than in other populations and persist after migration. One unexplored cause may be higher exposure to persistent organic pollutants associated with diabetes in other populations. We compared organochlorine (OC) pesticide concentrations in South Asian immigrants and European whites to determine whether the disease was positively associated with OC pesticides in South Asians. Research Design and Methods: South Asians of Tamil or Telugu descent (n = 120) and European whites (n = 72) were recruited into the London Life Sciences Population Study cohort. Blood samples as well as biometric, clinical, and survey data were collected. Plasma levels of p,p'-dichlorodiphenyldichloroethylene (DDE), p,p'- dichlorodiphenyltrichloroethane, beta-hexachlorohexane (HCH), and polychlorinated biphenyl-118 were analyzed by gas chromatography-mass spectrometry. South Asian cases and controls were categorized by binary exposure (above vs below the 50th percentile) to perform logistic regression. Results: Tamils had approximately threefold to ninefold higher levels of OC pesticides, and Telugus had ninefold to 30-fold higher levels compared with European whites. The odds of exposure to p,p' DDE above the 50th percentile was significantly greater in South Asian diabetes cases than in controls (OR: 7.00; 95% CI: 2.22, 22.06). The odds of exposure to beta-HCH above the 50th percentile was significantly greater in the Tamil cases than in controls (OR: 9.35; 95% CI: 2.43, 35.97). Conclusions: South Asian immigrants have a higher body burden of OC pesticides than European whites. Diabetes mellitus is associated with higher p,p'-DDE and beta-HCH concentrations in this population. Additional longitudinal studies of South Asian populations should be performed. PMID- 30019023 TI - Structural Biology Helps Interpret Variants of Uncertain Significance in Genes Causing Endocrine and Metabolic Disorders. AB - Context: Variants of uncertain significance (VUSs) lack sufficient evidence, in terms of statistical power or experimental studies, to allow unequivocal determination of their damaging effect. VUSs are a major burden in performing genetic analysis. Although in silico prediction tools are widely used, their specificity is low, thus urgently calling for methods for prioritizing and characterizing variants. Objective: To assess the frequency of VUSs in genes causing endocrine and metabolic disorders, the concordance rate of predictions from different in silico methods, and the added value of three-dimensional protein structure analysis in discerning and prioritizing damaging variants. Results: A total of 12,266 missense variants reported in 641 genes causing endocrine and metabolic disorders were analyzed. Among these, 4123 (33.7%) were VUSs, of which 2010 (48.8%) were predicted to be damaging and 1452 (35.2%) were predicted to be tolerated according to in silico tools. A total of 5383 (87.7%) of 6133 disease-causing variants and 823 (55.8%) of 1474 benign variants were correctly predicted. In silico predictions were noninformative in 5.7%, 14.4%, and 16% of damaging, benign, and VUSs, respectively. A damaging effect on 3D protein structure was present in 240 (30.9%) of predicted damaging and 40 (9.7%) of predicted tolerated VUSs (P < 0.001). An in-depth analysis of nine VUSs occurring in TSHR, LDLR, CASR, and APOE showed that they greatly affect protein stability and are therefore strong candidates for disease. Conclusions: In our dataset, we confirmed the high sensitivity but low specificity of in silico predictions tools. 3D protein structural analysis is a compelling tool for characterizing and prioritizing VUSs and should be a part of genetic variant analysis. PMID- 30019024 TI - Sonographic Presentation of Metastases to the Thyroid Gland: A Case Series. AB - Incidental sonographic discovery of thyroid nodules is an increasingly common event. The vast majority is benign, and those that are malignant, are generally associated with an indolent course and low mortality. Sonographic scoring systems have been developed to help clinicians identify nodules that warrant prompt fine needle aspiration cytology (FNAC), but they are based largely on experience with papillary thyroid cancers. We analyzed the performance of four scoring systems widely used for this purpose (American Thyroid Association Guidelines, American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines, European Thyroid Imaging Reporting and Data System, and Korean Thyroid Imaging Reporting and Data System) in patients whose nodules proved to be metastases from other solid cancers. Such nodules reportedly account for 0.2% to 3% of all thyroid malignancies. Each scoring system was used to assess retrospectively the malignancy risk and indications for FNAC of five patients' thyroid nodules that were ultimately diagnosed as metastases (from renal cell carcinoma, breast cancer, and lung cancer in two cases and esophageal cancer). The primaries identified in these cases are those most commonly reported to metastasize to the thyroid. In two cases, the thyroid metastases were the first sign of undetected neoplastic disease. Although sonography alone cannot distinguish thyroid metastases from primary thyroid malignancies, all four scoring systems classified the metastatic nodules as suspicious enough to require FNAC. The five cases accounted for 0.2% of those cytologically examined in our center. In most cases, cytology provided useful guidance for the subsequent management of these lesions, which differs from that of primary thyroid cancers and requires multidisciplinary input. PMID- 30019025 TI - Broccoli Sprouts Delay Prostate Cancer Formation and Decrease Prostate Cancer Severity with a Concurrent Decrease in HDAC3 Protein Expression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice. AB - Background: Cruciferous vegetables have been associated with the chemoprevention of cancer. Epigenetic regulators have been identified as important targets for prostate cancer chemoprevention. Treatment of human prostate cancer cells with sulforaphane (SFN), a chemical from broccoli and broccoli sprouts, inhibits epigenetic regulators such as histone deacetylase (HDAC) enzymes, but it is not known whether consumption of a diet high in broccoli sprouts impacts epigenetic mechanisms in an in vivo model of prostate cancer. Objective: In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we tested the hypothesis that a broccoli sprout diet suppresses prostate cancer, inhibits HDAC expression, alters histone modifications, and changes the expression of genes regulated by HDACs. Methods: TRAMP mice were fed a 15% broccoli sprout or control AIN93G diet; tissue samples were collected at 12 and 28 wk of age. Results: Mice fed broccoli sprouts had detectable amounts of SFN metabolites in liver, kidney, colon, and prostate tissues. Broccoli sprouts reduced prostate cancer incidence and progression to invasive cancer by 11- and 2.4-fold at 12 and 28 wk of age, respectively. There was a significant decline in HDAC3 protein expression in the epithelial cells of prostate ventral and anterior lobes at age 12 wk. Broccoli sprout consumption also decreased histone H3 lysine 9 trimethylation in the ventral lobe (age 12 wk), and decreased histone H3 lysine 18 acetylation in all prostate lobes (age 28 wk). A decline in p16 mRNA levels, a gene regulated by HDAC3, was associated with broccoli sprout consumption, but no significant changes were noted at the protein level. Conclusions: Broccoli sprout intake was associated with a decline in prostate cancer occurrence and HDAC3 protein expression in the prostate, extending prior work that implicated loss of HDAC3/ corepressor interactions as a key preventive mechanism by SFN in vivo. PMID- 30019026 TI - Household Food Security and Birth Size of Infants: Analysis of the Bangladesh Demographic and Health Survey 2011. AB - Background: More than one-third of the population in Bangladesh is affected by household food insecurity in a setting where child survival and well-being are under threat. The relation between household food security and birth size of infants is an important area to explore given its explicit effect on mortality and morbidity. Objective: Our study aims to estimate the association between household food security and birth size of infants. Methods: For the analysis we used a nationally representative cross-sectional survey of 8753 households with a live birth between 2006 and 2011, collected under the Bangladesh Demographic and Health Survey (BDHS) 2011. We investigated the association of small birth size with the following potential explanatory variables: sex of the child; birth interval; mother's age at birth, height, body mass index (BMI), anemia status, parity, previous pregnancy loss, antenatal care visits, exposure to television, and participation in health care decisions; cooking fuel; parents' education level; region; place of residence; and wealth index using Pearson's chi-square test. We then constructed a multivariable logistic regression model of birth size on food security after controlling for all potential confounders as well as the cluster sampling design. The odds ratio (OR) was reported for each of the covariates; a P value <0.05 was interpreted as statistically significant. Results: A total of 1485 (17.3%) children were reported as small at the time of birth and more than one-third of households (35.7%) experienced some degree of food insecurity. Mothers from food-insecure households had 38% higher odds of having small-size infants compared to food-secure households (adjusted OR: 1.38; 95% CI: 1.19, 1.59; P < 0.001). Conclusion: Household food security is one of the key factors associated with small birth size. Interventions to increase birth size should target women belonging to food-insecure households. PMID- 30019027 TI - Iron Absorption from Iron-Enriched Aspergillus oryzae Is Similar to Ferrous Sulfate in Healthy Female Subjects. AB - Background: Iron deficiency anemia (IDA) remains a global health issue, affecting mainly children and adolescent and pregnant women. Because of problems associated with current iron compounds used in both supplementation and fortification areas, there is an emerging interest in new natural iron sources to combat IDA. Objective: The objective of this study was to compare the iron absorption of iron enriched Aspergillus oryzae [Aspiron (ASP)] with FeSO4 in humans. Methods: Iron absorption was assessed using stable isotope and serum iron response methods after oral intake of iron by healthy women in 2 separate studies. In the first study, ASP was intrinsically labelled with 58Fe into a dry form containing 8% iron. Subjects (n = 16, 18-35 y) were randomly assigned to consume liquid semipurified meals labelled with 2 stable iron isotopes, 57FeSO4 (10 mg) and ASP containing 2 mg 58Fe and 8 mg natural abundance iron, in 2 visits. Isotope enrichment was measured 2 wk after the last meal was eaten. In the second study, 17 subjects were randomly assigned to consume a test meal with 3 iron supplements during 3 separate visits: FeSO4, 10 mg Fe, and ASP in 2 iron doses, 10 mg and 20 mg. Changes in serum iron were measured at regular intervals for 4 h after supplementation. Results: The first study showed that the difference in iron absorption from FeSO4 and ASP was not significant (17.18% +/- 14.2% compared to 15.14% +/- 12.3%; P = 0.07). The results of the second study suggested that the iron from ASP was released slowly compared to FeSO4 and the area under the curve did not reflect the absorption of ASP iron, but rather the rate of iron release. Conclusions: Iron-enriched A. oryzae has high relative bioavailability and may cause lower iron surges into the blood compared to FeSO4. PMID- 30019028 TI - Health Effects and Sources of Prebiotic Dietary Fiber. AB - Prebiotic dietary fibers act as carbon sources for primary and secondary fermentation pathways in the colon, and support digestive health in many ways. Fructooligosaccharides, inulin, and galactooligosaccharides are universally agreed-upon prebiotics. The objective of this paper is to summarize the 8 most prominent health benefits of prebiotic dietary fibers that are due to their fermentability by colonic microbiota, as well as summarize the 8 categories of prebiotic dietary fibers that support these health benefits. Although not all categories exhibit similar effects in human studies, all of these categories promote digestive health due to their fermentability. Scientific and regulatory definitions of prebiotics differ greatly, although health benefits of these compounds are uniformly agreed upon to be due to their fermentability by gut microbiota. Scientific evidence suggests that 8 categories of compounds all exhibit health benefits related to their metabolism by colonic taxa. PMID- 30019029 TI - Dietary Bovine Lactoferrin Reduces Staphylococcus aureus in the Tissues and Modulates the Immune Response in Piglets Systemically Infected with S. aureus. AB - Background: Bovine lactoferrin (bLf) reduces Staphylococcus aureus infection in premature infants and promotes the growth of Bifidobacterium infantis, a predominant infant gut species. We hypothesized that bLf in combination with B. infantis would reduce the severity of systemic S. aureus infection. Objective: The aim was to determine the effects of oral administration of bLf and B. infantis on the course of systemic S. aureus infection. Methods: Colostrum deprived piglets were fed formulas containing 4 g whey/L (CON group) or bLf (LF group). One-half of the piglets in each group were gavaged with B. infantis (109 colony-forming units/d), resulting in 2 additional groups (BI or COMB, respectively). On day 7, piglets were intravenously injected with S. aureus. Blood samples were collected preinfection and every 12 h postinfection for immune analyses. Tissue samples were collected on day 12 for analysis of bacterial abundance and gene expression. Results: Preinfection, LF piglets had lower serum interleukin 10 (IL-10), a higher percentage of lymphocytes, and a lower percentage of neutrophils than BI or COMB piglets. After infection, dietary bLf increased piglet weight gain, reduced staphylococcal counts in the kidneys, and tended to lower staphylococcal counts in the lungs and heart. Dietary bLf also decreased kidney IL-10 and increased lung interferon gamma (IFN-gamma) mRNA. B. infantis increased splenic IFN-gamma expression. Renal Toll-like receptor 2 was upregulated in BI piglets but not in COMB piglets. Postinfection, BI piglets had increased serum IL-10 and decreased memory T cell populations. LF and COMB piglets had fewer circulating monocytes and B cells than CON or BI piglets. Conclusions: Dietary bLf and B. infantis produced independent and tissue-specific effects. Piglets fed bLf alone or in combination with B. infantis mounted a more effective immune response and exhibited lower bacterial abundance. This study provides biological underpinnings to the clinical benefits of bLf observed in preterm infants but does not support B. infantis administration during S. aureus infection. PMID- 30019030 TI - Delivering Vitamin A Supplements to Children Aged 6-59 Months: Comparing Delivery through Campaigns and through Routine Health Services in Senegal. AB - Background: Using twice-yearly campaigns such as Child Health Days to deliver vitamin A supplements has been a key strategy over the last 2 decades, and was an important component in helping reach the Millennium Development Goals in child health. As countries move to strengthen their routine health services under the Sustainable Development Goals, efforts are underway to shift supplementation from campaign to routine delivery. Objective: The aim of this study was to compare cost, coverage, and user satisfaction between twice-yearly campaigns and routine delivery of vitamin A supplements in Senegal. Methods: Information was collected on cost, coverage, and user satisfaction with both types of delivery, using administrative data, interviews at various levels in the health system, and focus group discussions with caregivers. Both qualitative and quantitative information were obtained, for 2 regions using routine delivery and 2 regions using campaign delivery. Results: Routine delivery receives fewer dedicated resources. Coverage is lower, especially of children >12 mo of age. Districts undertake outreach ("mini-campaigns") to try to improve coverage in regions using routine delivery, in effect using a hybrid approach. Some mothers prefer the administration of supplements at a health facility as it is perceived as more hygienic and involving professional health workers, but others, especially those living further away, prefer house-to-house delivery which was the norm for the campaign mode. Conclusions: Advance planning for the shift to routine delivery is important in maintaining coverage, as is strengthening the primary health care system by having an appropriate ratio of salaried workers to population. When the system relies heavily on volunteers, and the small incentive payments to volunteers are discontinued, coverage suffers. Routine delivery also relies on good record-keeping and hence literacy. Community understanding of, and support for, supplementation are even more important for routine than for campaign delivery. PMID- 30019031 TI - Capacity of the US Food System to Accommodate Improved Diet Quality: A Biophysical Model Projecting to 2030. AB - Background: Increasing Americans' diet quality will require changes to the food supply. Due to the complex nature of the food system, this is not as straightforward as simply increasing the production of healthy foods and decreasing the production of unhealthy foods. Little is known about whether the US food system can produce enough food, given finite agricultural resources, to support shifts toward healthier eating patterns. Objective: The aim of this study was to model the capacity of the US food system to accommodate a shift toward a healthier diet by 2030. Methods: A biophysical simulation model estimated the proportion of the US population that could be fed a given diet based on food system constraints, currently and projected to 2030. The model accepted data inputs on food intake, crop yields, and population size. Linear and nonlinear regression models were used to estimate projected food intake and crop yields based on recent historical data (1980-2014). Diet quality was estimated using the Healthy Eating Index-2015. Results: The US agricultural system can produce enough food to feed 146% of the population by 2030. A greater proportion of the population can be fed a high-quality diet than a low-quality diet (178% compared to 119%). To accommodate increased diet quality, substantial increases in cropland acreage would be needed for fruits (P < 0.001), vegetables (P = 0.002), legumes (P = 0.002), and nuts (P = 0.007); and decreased cropland acreage would be needed for grains (P = 0.002) and sweeteners (P < 0.001). Conclusions: The US can produce more than enough food to accommodate a shift toward a healthier diet pattern, but even moderate shifts in diet quality would require major transitions in cropland use. The success of this transition is dependent on several factors, like individuals' ease of entry into the agricultural sector, producers' ability to shift production to other crops, and modifications to the food supply chain. PMID- 30019032 TI - Growth-Promoting and Antioxidant Effects of Magnolia Bark Extract in Chickens Uninfected or Co-Infected with Clostridium perfringens and Eimeria maxima as an Experimental Model of Necrotic Enteritis. AB - Background: Magnolia tree bark has been widely used in traditional Asian medicine. However, to our knowledge, no studies have been reported investigating the effects of dietary supplementation with magnolia bark extract in chickens. Objective: We tested the hypothesis that dietary supplementation of chickens with a Magnolia officinalis bark extract would increase growth performance in uninfected and Eimeria maxima/Clostridium perfringens co-infected chickens. Methods: A total of 168 chickens were fed from hatch either a standard diet or a diet supplemented with 0.33 mg or 0.56 mg M. officinalis bark extract/kg (M/H low or M/H high, respectively) from days 1 to 35. At day 14, half of the chickens were orally infected with E. maxima, followed by C. perfringens infection at day 18 to induce experimental avian necrotic enteritis. Daily feed intake, feed conversion ratio, body weight gain, and final body weight were measured as indicators of growth performance. Serum alpha1-acid glycoprotein (AGP) concentrations were measured as an indicator of systemic inflammation, and intestinal lesion scores were determined as a marker of disease progression. Transcript levels for catalase, heme oxygenase 1, and superoxide dismutase in the intestine, liver, spleen, and skeletal muscle were measured as indicators of antioxidant status. Results: Growth performance increased between days 1 and 35 in uninfected and E. maxima/C. perfringens co-infected chickens fed M/H-low or M/H-high diets compared with unsupplemented controls. Gut lesion scores were decreased, whereas AGP concentrations were unchanged, in co-infected chickens fed magnolia-supplemented diets compared with unsupplemented controls. In general, transcripts for antioxidant enzymes increased in chickens fed magnolia supplemented diets compared with unsupplemented controls, and significant interactions between dietary supplementation and co-infection were observed for all antioxidant enzyme transcript levels. Conclusion: Magnolia bark extract might be useful for future development of dietary strategies to improve poultry health, disease resistance, and productivity without the use of antibiotic growth promoters. PMID- 30019035 TI - ASN Science Policy Fellows Advocate for Medical Research. PMID- 30019033 TI - Soy Protein Isolate Suppresses Bone Resorption and Improves Trabecular Microarchitecture in Spontaneously Hyperphagic, Rapidly Growing Male OLETF Rats. AB - Background: Traditionally, milk proteins have been recommended for skeletal health; recently, soy proteins have emerged as popular alternatives. Excess adiposity appears detrimental to skeletal health, as obese adolescents have increased fracture rates compared with healthy controls. However, soy protein effects on skeletal health during excess adiposity remain unknown. Objective: The study objective was to examine the effects of isocaloric diets containing milk protein isolate (MPI), soy protein isolate (SPI), or a 50/50 combination (MIX) as the sole protein source on metabolic health indicators and bone outcomes in rapidly growing, hyperphagic, male Otsuka Long Evans Tokushima Fatty (OLETF) rats. Methods: OLETF rats, aged 4 wk, were randomly assigned to 3 treatment groups (MPI, SPI, or MIX, n = 20 per group) and provided with access to experimental diets ad libitum for 16 wk. Results: Body mass did not differ between the groups, but SPI had lower percentage body fat than MPI (P = 0.026). Insulin was lower in MPI than in MIX (P = 0.033) or SPI (P = 0.044), but fasting blood glucose was not different between the groups. SPI significantly reduced serum cholesterol compared with MPI (P = 0.001) and MIX (P = 0.002). N-terminal propeptide of type I collagen (P1NP) was higher in MIX than MPI (P = 0.05); C terminal telopeptide of type 1 collagen (CTx) was higher in MPI than SPI (P < 0.001) and MIX (P < 0.001); the P1NP to CTx ratio was significantly higher in SPI and MIX than in MPI (P < 0.001). Trabecular separation was reduced in SPI compared with MPI (P = 0.030) and MIX (P = 0.008); trabecular number was increased in SPI compared with MIX (P = 0.038). No differences were seen in cortical geometry and biomechanical properties. Conclusions: In the context of excess adiposity, soy- and milk-based proteins have comparable effects on cortical bone geometry and biomechanical properties, whereas soy-based proteins favorably affect the trabecular microarchitecture, and the combination of both proteins may offer additional benefits to bone remodeling in rapidly growing male OLETF rats. PMID- 30019034 TI - The Effect of Feeding Cocoa Powder and Lactobacillus rhamnosus on the Composition and Function of Pig Intestinal Microbiome. AB - Background: Dietary habits have been linked with variability of gut microbiota composition and disease risk. Objective: The aim of this study was to evaluate the effect of feeding a cocoa powder with or without a probiotic on the composition and function of the fecal microbiome of pigs. Methods: Four groups of 8 pigs each were fed a standard growth diet supplemented with cocoa powder, Lactobacillus rhamnosus (LGG), cocoa powder + LGG, or an equal amount of fiber similar to that found in cocoa powder (control group). Fecal samples were collected prior to and 4 wk after initiation of the dietary intervention. Microbiota composition was determined after amplification of the first 2 variable regions of the 16S ribosomal DNA (rDNA). Predictions of metagenomic function were calculated using 16S rDNA sequence data through Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Results: After 4 wk of treatment, bacterial abundance analysis demonstrated a prebiotic effect of cocoa powder on endogenous Bifidobacteriaceae and Lactobacillaceae and increased abundance of saccharolytic butyrate-producing bacteria like Roseburia. An increased bacterial evenness, Shannon diversity index, and diverse metabolic profile were detected in microbiomes of pigs fed the cocoa powder + LGG (P < 0.05) but not in pigs in the other 3 groups. Conclusion: The data generated from this work demonstrated that 4-wk dietary treatment with cocoa powder alone or in combination with LGG probiotic had an impact on the composition and function of the fecal microbiota of healthy pigs. PMID- 30019036 TI - Evidence for the synthesis of an unusual high spin (S = 7/2) [Cu-3Fe-4S] cluster in the radical-SAM enzyme RSAD2 (viperin). AB - We demonstrate the synthesis and spectroscopic characterization of an unusual high spin (S = 7/2) [Cu-3Fe-4S] cluster in a member of the radical-SAM enzymes. This is the first step in using synthetic [Me-3Fe-4S] clusters for obtaining new insight into the mechanism of radical-SAM catalysis. PMID- 30019037 TI - Structures of FEC-containing electrolytes and the stabilization mechanism at high voltage and elevated temperature. AB - The performance of lithium-ion batteries is strongly dependent on the properties of electrolytes. Understanding of the role of electrolytes is significant for the performance improvement of batteries. In this work, classical molecular dynamic simulations were used to examine the solvation effects of ions and structures of fluoroethylene carbonate (FEC)-containing electrolytes. Density functional theory (DFT) calculations were also used to predict the oxidation stabilities of such electrolytes. The FEC-related species have higher oxidation potentials (Eox) than traditional carbonate electrolytes, indicating their good oxidation stability in high-voltage systems at elevated temperatures. The ratios of species are calculated to be used as a semi-quantitative reference for selecting the representative components of electrolytes. Then, DFT calculations on the representative components show that the oxidation potentials of coordinating species are significantly lower than those of isolated molecules when oxidation is coupled with H-transfer. Ratios of species and corresponding Eox values should be considered to accurately predict the oxidation stability of electrolytes with different solvents. PMID- 30019038 TI - Structural superlubricity in graphite flakes assembled under ambient conditions. AB - To date, structural superlubricity in microscale contacts is mostly observed in intrinsic graphite flakes that are cleaved by shearing from HOPG mesas in situ or friction pairs assembled in vacuum due to the high requirement of ultra clean interface for superlubricity, which severely limits their practical applications. Herein, we report observations on microscale structural superlubricity in graphite flake pairs assembled under ambient conditions, where contaminants are inevitably present at the interfaces. For such friction pairs, we find a novel running-in phenomenon, where the friction decreases with reciprocating motions, but no morphological or chemical changes can be observed. The underlying mechanism for the new running-in process is revealed to be the removal of third bodies confined between the surfaces. Our results improve the understanding of microscale superlubricity and may help extend the practical applications of superlubricity. PMID- 30019039 TI - Enhancement of photoredox catalytic properties of porphyrinic metal-organic frameworks based on titanium incorporation via post-synthetic modification. AB - Porphyrinic metal-organic frameworks could be endowed with greatly improved photocatalytic activity for both oxidation and reduction, based on the incorporation of titanium via a facile cation-exchange strategy. PMID- 30019040 TI - Synthesis of amphiphilic graphitic silver nanoparticles with inherent internal standards: an efficient strategy for reliable quantitative SERS analysis in common fluids. AB - An efficient strategy for reliable quantitative SERS analysis in common fluids was proposed by amphiphilic functionalization of graphitic silver nanoparticles with inherent internal standards by azides, and has the merits of high accuracy, enhanced dispersity and outstanding stability in fluids. PMID- 30019041 TI - Ordered silica mineralization by regulating local reaction conditions. AB - Using cationic peptides with tetramethyl orthosilicate, a silica nano-film >100 MUm in size with <100 nm thickness was constructed under physiological conditions. Control of silica nucleation speed and location was found to be the dominant factor affecting the ordered architecture. Our approach adds new insight into bottom-up nanomaterial construction and contributes to evaluating the silica mineralization system in living organisms. PMID- 30019042 TI - Nitrogen-doped graphene-like carbon nanosheets from commercial glue: morphology, phase evolution and Li-ion battery performance. AB - We report a two-step process to synthesize nitrogen-doped graphene-like carbon nanosheets (N-CNS), using commercially available ethyl cyanoacrylate based super glue as a carbon precursor. In this process, super glue is polymerized in aqueous NaCl solution, followed by carbonization at 1000 degrees C. Scanning electron microscopy (SEM) and high resolution transmission electron microscopy (HRTEM) studies show that the resultant material consists of micron-sized carbon nanosheets with a wrinkled morphology. HRTEM, X-ray diffraction (XRD), XPS and Raman spectroscopic studies confirm the formation of nanocrystalline and graphitic, nitrogen-doped carbon nanosheets. A detailed FTIR analysis of the degradation products of the polymeric precursor (polyethyl cyanoacrylate) at various heat treatment temperatures under an inert atmosphere reveals that the polymer undergoes a cyclization process similar to polyacrylonitrile (PAN) during carbonization to yield the N-CNS. The N-CNS used as an anode for a lithium-ion battery shows stable reversible capacities of 480 mA h g-1 for 100 cycles, which indicates that N-CNS are promising materials for lithium-ion battery applications. In a broader perspective, a unique chemical transformation of polyethyl cyanoacrylate to graphitic carbon may be useful to design new nanostructured carbons for a plethora of applications. PMID- 30019043 TI - Iron-sulphur cluster biogenesis via the SUF pathway. AB - Iron-sulphur (Fe-S) clusters are versatile cofactors, which are essential for key metabolic processes in cells, such as respiration and photosynthesis, and which may have also played a crucial role in establishing life on Earth. They can be found in almost all living organisms, from unicellular prokaryotes and archaea to multicellular animals and plants, and exist in diverse forms. This review focuses on the most ancient Fe-S cluster assembly system, the sulphur utilization factor (SUF) mechanism, which is crucial in bacteria for cell survival under stress conditions such as oxidation and iron starvation, and which is also present in the chloroplasts of green microalgae and plants, where it is responsible for plastidial Fe-S protein maturation. We explain the SUF Fe-S cluster assembly process, the proteins involved, their regulation and provide evolutionary insights. We specifically focus on examples from Fe-S cluster synthesis in the model organisms Escherichia coli and Arabidopsis thaliana and discuss in an in vivo context the assembly of the [FeFe]-hydrogenase H-cluster from Chlamydomonas reinhardtii. PMID- 30019044 TI - Systematic study of the structural parameters affecting the self-assembly of cyclic peptide-poly(ethylene glycol) conjugates. AB - Self-assembling cyclic peptides (CP) consisting of amino acids with alternating d and l-chirality form nanotubes by hydrogen bonding, hydrophobic interactions, and pi-pi stacking in solution. These highly dynamic materials are emerging as promising supramolecular systems for a wide range of biomedical applications. Herein, we discuss how varying the polymer conformation (linear vs. brush), as well as the number of polymer arms per peptide unimer affects the self-assembly of PEGylated cyclic peptides in different solvents, using small angle neutron scattering. Using the derived information, strong correlations were drawn between the size of the aggregates, solvent polarity, and its ability to compete for hydrogen bonding interactions between the peptide unimers. Using these data, it could be possible to engineer cyclic peptide nanotubes of a controlled length. PMID- 30019045 TI - A 3D MoOx/carbon composite array as a binder-free anode in lithium-ion batteries. AB - Molybdenum(vi) oxide (MoO3) nanorod arrays were synthesized employing a template assisted method. A polycarbonate membrane as a template was vacuum infiltrated with an aqueous solution of ammonium heptamolybdate. Template removal by oxygen plasma etching and calcination leads to the formation of highly crystalline 3D MoO3 nanorod arrays as a negative replica of the template. By applying sucrose as the carbon precursor, the mantling of the MoO3 nanorods with a thin carbon coating is obtained. Simultaneously, the direct and binder-free contact between the 3D MoOx nanorod arrays and the current collector resulting from the carbon coating could be achieved and leads to high capacities of up to 1376, 783, 856, 804 and 324 mA h g-1 for cycles 1, 2, 20, 50 and 200 as well as a coulombic efficiency of 99% for such 3D MoOx/C composite electrodes. The cycling performance of this 3D MoOx/C composite material is even more impressive, when comparing the determined experimental capacities with the theoretical capacities of graphite (372 mA h g-1) and MoO2 (838 mA h g-1). Additionally, MoO3 nanorod array electrodes without such an encapsulating carbon coating show an average capacity of only 175 mA h g-1 between cycles 20 and 200. Thus, the carbon coating of the MoO3 nanorod array can increase the electrochemical performance of a lithium-ion cell compared to conventional carbon additives when using MoO3 as the active anode material. This emphasizes the positive effects of the intimate and efficient electron transport and large surface area of the electrode material based on a minimal footprint architecture in Li-ion cells. PMID- 30019046 TI - Two-dimensional tellurium nanosheets for photoacoustic imaging-guided photodynamic therapy. AB - We report the synthesis of two-dimensional Te nanosheets through a facile liquid exfoliation method. The as-synthesized Te nanosheets can produce reactive oxygen species under light irradiation and show high photoacoustic imaging performance due to their strong near-infrared absorbance, and can be engineered as a nanoplatform for simultaneous photoacoustic imaging and photodynamic therapy. PMID- 30019047 TI - Normal and abnormal NHC coordination in cationic hydride iodide complexes of aluminium. AB - The mixed N-heterocyclic carbene (NHC) complexes NHCAlHxI3-x, where NHC is IDip or IMes ((HCNAr)2C:, Ar = 2,6-iPr2C6H3 = Dip (IDip); or 2,4,6-Me3C6H2 = Mes (IMes)), x = 1 or 2, were either prepared from NHCAlH3 and NHCAlI3 or by halogenation of NHCAlH3 with MeI. Reaction of [(IDip)AlHxI3-x], with x = 0-3, with another equivalent of IDip afforded either fluxional equilibria in benzene solution for x = 0, no reaction for x = 3, or the new mixed normal-abnormal NHC coordinated ionic complexes [(IDip)AlH2(aIDip)]I (9) and [(IDip)AlHI(aIDip)]I (10), where aIDip is the abnormal IDip carbene tautomer bonded through its 4 position. The molecular structures of 9 and 10 were determined and show slightly shorter Al-C(aIDip) than Al-C(IDip) distances. In addition, a complex containing [(IDip)AlI2(aIDip)]I (11) was structurally characterized though could not intentionally be synthesised. Possible formation mechanisms for 9-11 are discussed and the normal and abnormal IDip coordination to the aluminium(iii) centre is believed to occur for steric reasons. PMID- 30019048 TI - Electrically conductive MEH-PPV:PCL electrospun nanofibres for electrical stimulation of rat PC12 pheochromocytoma cells. AB - The purpose of this study was to prepare an electrically conducting poly[2 methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV) based nanofibrous scaffold and to investigate the synergetic effect of nanofibre structure and electrical stimulation on neuronal growth for possible use in nerve repair. Nanofibres were produced by electrospinning of blended MEH-PPV with polycaprolactone (PCL) at a ratio of 20 : 80, 40 : 60, 50 : 50 and 60 : 40 (v/v). A better electrical conductivity was achieved by using core-sheath structured nanofibres of PCL (core) and MEH-PPV (sheath) produced using the coaxial electrospinning technique. The highest electrical conductivity was observed in the core-sheath nanofibres, while it increased with increasing concentration of MEH-PPV for the blended electrospun nanofibres. The biocompatibility of the electrospun nanofibres was confirmed by MTS and live-dead staining assays using 3T3 fibroblasts and a neuronal rat pheochromocytoma (PC12) cell line. Beta (III) tubulin immunochemistry showed that PC12 cells differentiated into sympathetic neurons on these porous and stiffer electrospun nanofibres coated with collagen I. Improved cell morphology and attachment on the collagen I coated electrospun meshes has been confirmed by SEM analysis. Significant enhancement in neurite formation and neurite outgrowth of PC12 cells on the conductive scaffolds under electrical potential of 500 mV cm-1 for 2 h day-1 suggests the potential use of these scaffolds for nerve repair. PMID- 30019049 TI - Irradiation with 310 nm and 340 nm ultraviolet light-emitting-diodes can improve atopic dermatitis-like skin lesions in NC/Nga mice. AB - Ultraviolet (UV) light produces an immunomodulatory effect on the skin and is widely used for the treatment of chronic inflammatory skin diseases. UV light emitting diodes (UV-LEDs) are a new and promising source of UV radiation. However, their mechanism of action remains largely unknown. In this study, we tested the safety and effectiveness of UV-LED irradiation for the treatment of atopic dermatitis (AD) in an NC/Nga mouse model. Mice were divided into seven groups of eight mice each. Application of Dermatophagoides farinae (Df) extract ointment for four weeks induced AD-like skin lesions. Subsequently, the mice were exposed to UV-LEDs, narrow band UVB, or UVA irradiation three times per week. We assessed the immunosuppressive effects of 310 nm (50 mJ cm-2) and 340 nm (5 J cm 2) UV-LED irradiation. Histological analyses using hematoxylin-eosin, toluidine blue, and immunohistochemical staining were performed. In addition, the serum levels of IgE, inflammatory cytokines and chemokines were measured using enzyme linked immunosorbent assays (ELISAs). UV-LED irradiation significantly alleviated AD-like skin symptoms, including edema, erythema, dryness, and itching, by modulating Th1 and Th2 responses, transepidermal water loss (TEWL), and scratching behavior in NC/Nga mice. These results suggest that UV-LEDs can improve the treatment of inflammatory skin diseases. PMID- 30019050 TI - Silver nanowire net knitted anisotropic aerogel as an ultralight and sensitive physiological activity monitor. AB - Inherent highly ordered anisotropic aerogels were prepared through a facile celery-carbonization process. The subsequent modification of silver nanowire knitted nets endowed the prepared carbonaceous aerogel with several valuable properties, including broad-spectrum antibacterial activity, near-infrared responsive heating, lightweight cushioning and anisotropic pressure-sensitive conductivity. With the aid of 3D printing technology, this versatile material could be applied as an ultralight monitor to realize the visualized detection of different physiological activities, such as ankle movements and cardiac arrhythmias. PMID- 30019052 TI - Oxide/sulfide-based hybrid arrays as robust electrocatalysts for water splitting. AB - It is imperative to develop bifunctional electrocatalysts with good activity and stability for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). In this paper, a hierarchical NiCo2O4/Ni3S2 hybrid is synthesized by direct growth on nickel foam (NF) using co-precipitation and sulfuration as a general two-step method. When the NiCo2O4/Ni3S2/NF material is used as an electrode, it displays high activity and perfect stability for OER. A low overpotential of only 360 mV is obtained at 40 mA cm-2, comparable to the benchmark of IrO2 electrodes (330 mV overpotential at 40 mA cm-2), benefiting from the particular hybrid structure of NiCo2O4/Ni3S2/NF with large surface area and fast electron transfer. In addition, the NiCo2O4/Ni3S2/NF sample also reveals a superior elevated HER activity compared to NiCo2O4/NF and NF catalysts individually, for which a low overpotential of only 143 mV is obtained at 10 mA cm-2. Beyond that, NiCo2O4/Ni3S2/NF is also used as a bifunctional water splitting catalyst, for which a very low cell voltage of 1.58 V is acquired at 10 mA cm-2 in 1.0 M KOH. The results reveal that oxide/sulfide-based materials can be used as a perfect electrode candidate and afford the advantage of the synergy strategy, which opens a new route toward desired water splitting electrochemical devices of high activity and environmentally friendly electrode materials. PMID- 30019051 TI - In vivo tailor-made protein corona of a prodrug-based nanoassembly fabricated by redox dual-sensitive paclitaxel prodrug for the superselective treatment of breast cancer. AB - Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized via different redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivo compared to marketed Abraxane(r) and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy. PMID- 30019053 TI - Sublimation thermodynamics aspects of adamantane and memantine derivatives of sulfonamide molecular crystals. AB - A number of new sulfonamide compounds with adamantane and memantine fragments were synthesized and characterized. Thermodynamic functions of sublimation processes have been determined on the basis of experimental values of saturated vapor pressures measured by the transpiration method in a wide temperature range. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the considered substances were studied using the DSC method. Correlation equations linking the thermodynamic characteristics of sublimation with melting points and packing densities of crystals have been proposed. PMID- 30019054 TI - The mechanism difference between CO2 and pH stimuli for a dual responsive wormlike micellar system. AB - To indicate the difference between pH and CO2 stimuli mechanisms, a dual responsive system is constructed with the aid of N-[3 (dimethylamino)propyl]docosanamide (NDPD) and sodium salicylate (NaSal), which is responsive to pH and CO2. The dual responsive system is characterized by rheometry, cryo-TEM and 1H NMR spectroscopy. After bubbling CO2 or adjusting the pH, the rheological properties indicate the formation of wormlike micelles. The cyro-TEM images also confirmed wormlike micelles. The effect of temperature is also clarified. By comparing the rheological properties of the wormlike micelles with pH and CO2 stimuli conditions, combined with cryo-TEM and 1H NMR results, the stimuli mechanisms of pH and CO2 to the dual responsive system are shown. Through this work, we expect to deepen our understanding of the responsiveness of a self-assembled system. PMID- 30019055 TI - A novel organic electrochromic device with hybrid capacitor architecture towards multicolour representation. AB - Despite the application of electrochromic (EC) technologies in various optical modulating devices, the challenge to achieve multicolour EC behavior in a single device still remains. However, because almost all EC materials exhibit a single colour change, only a few organic materials are able to undergo multiple colour switching within a single device. The development of multicolour EC applications is therefore highly limited. In this research, we fabricated an EC device (ECD) with the simple hybrid capacitor architecture, i.e. with a flat ITO electrode as the working side and an ITO particle-modified electrode as the counter side. We also employed an electrolyte containing both anodic and cathodic EC materials consisting of small organic molecules. In this novel ECD, each EC material successfully undergoes individual colour switching from light yellow to light green and magenta. The mechanism of a multicolour system represents a significant breakthrough towards a full-colour ECD, thereby expanding the potential of EC technology. PMID- 30019056 TI - Cobalt(ii)-catalyzed regioselective C-H halogenation of anilides. AB - A cobalt-catalyzed regioselective C-H halogenation methodology is reported herein. The highlight of this work is the highly selective C-H functionalization of anilides, which results in high-yielding, versatile, and practical halogenated products. Thereby, brominations, chlorinations and iodinations of many electron rich and electron-deficient anilides were achieved in a highly selective fashion. Mechanistic studies with respect to the pathway of the reaction are also described. PMID- 30019062 TI - Ferritin encapsulation of artificial metalloenzymes: engineering a tertiary coordination sphere for an artificial transfer hydrogenase. AB - Ferritin, a naturally occuring iron-storage protein, plays an important role in nanoengineering and biomedical applications. Upon iron removal, apoferritin was shown to allow the encapsulation of an artificial transfer hydrogenase (ATHase) based on the streptavidin-biotin technology. The third coordination sphere, provided by ferritin, significantly influences the catalytic activity of an ATHase for the reduction of cyclic imines. PMID- 30019063 TI - Probing the pi -> pi* photoisomerization mechanism of trans-azobenzene by multi state ab initio on-the-fly trajectory dynamics simulations. AB - Global nonadiabatic switching on-the-fly trajectory surface hopping simulations at the 5SA-CASSCF(6,6)/6-31G quantum level have been employed to probe the photoisomerization mechanism of trans-azobenzene upon pipi* excitation within four coupled singlet low-lying electronic states (S0, S1, S2, and S3). We have performed 586 sampling trajectories (331 starting from S2 and 255 from S3), and we found about half of the sampling trajectories staying on S1 or S2 states as resonances and the other half of them ending on the ground S0 state as active trajectories. The present simulation has demonstrated that there are six distinct photoisomerization pathways which can be summarized as three categories; one is the newly opened inversion-inversion nonreactive isomerization pathway accounting for 40% (34%) of active trajectories at a time constant of 80 fs (320 fs), the other is the inversion-torsion reactive and nonreactive isomerization pathways accounting for 40% (20%) of active trajectories at a time constant of 880 fs (1700 fs), and the third is the torsion-torsion reactive and nonreactive isomerization pathways accounting for 20% (46%) of active trajectories at a time constant of 780 fs (1000 fs) upon S2 (S3) pipi* excitation. The simulated total reactive quantum yield for trans-azobenzene photoisomerization upon S2 (S3) pipi* excitation is about 0.11 (0.13) which is in good agreement with recent experimental results of 0.09-0.20. Furthermore, the newly opened inversion inversion nonreactive isomerization pathway from the present simulation agrees well with cascade experimental measurements of the Sn -> S1 -> S0 relaxation mechanism in both branching ratio and time constant. PMID- 30019064 TI - Editorial to 'Triple Vessel Coronary Artery Disease and Retinal Nerve Fibre Layer Thickness'. PMID- 30019065 TI - The Influence of Ethnicity on Exclusively Breast-Fed Infants' Anthropometry in a Multiethnic Asian Population. AB - INTRODUCTION: We studied the effects of ethnicity on early infant growth patterns in exclusively breast-fed (EBF) infants from a Singaporean multiethnic population. This was a prospective cohort study conducted in National University Hospital, Singapore. MATERIALS AND METHODS: Healthy, EBF infants born at-term completing 37 weeks and above, and whose birthweight was appropriate for gestational age (>10th centile, <90th centile) were recruited. Infants were required to be EBF at least until the minimum age of weaning. All infants who were preterm and premature, formula-fed, required Intensive/High Dependency care, or born with major congenital anomalies were excluded. A multivariable linear regression analysis was conducted at 5 predetermined time-points (birth; 4-8 weeks; 3-4, 5-8, 12 months) to study the effects of antenatal/parental factors on infant growth. RESULTS: A total of 213 infants were recruited. Maternal age, height and body mass index positively influenced birthweights while maternal hypertension and paternal smoking negatively influenced birthweights. Mean duration of breastfeeding was 8.9 months. Chinese ethnicity did not influence birth anthropometry, but was the single consistent factor that significantly increased weight and length Z-scores from 4-8 weeks until 8 months of life. Chinese ethnicity did not influence head growth throughout the first year of life. CONCLUSION: EBF Chinese infants have increased weights and lengths compared to non-Chinese infants until 8 months' age, despite similar birth anthropometry. This period of discrepant growth coincides with the average duration of breastfeeding. We hypothesise that ethnic variations in breast milk macronutrient composition influence early somatic growth in infants. PMID- 30019066 TI - Apnoeic and Hypopnoeic Load in Obstructive Sleep Apnoea: Correlation with Epworth Sleepiness Scale. AB - INTRODUCTION: Patients with obstructive sleep apnoea (OSA) often present with excessive daytime sleepiness (EDS) as measured by the Epworth Sleepiness Scale (ESS). However, the relationship between EDS and OSA severity as measured by the apnoea-hypopnoea index (AHI) remains inconsistent. We hypothesise that this may be due to the usage and equal weightage of apnoea and hypopnoea events used in determining AHI and that apnoea and hypopnoea load as measured by their total durations may be a better metric to use. We sought to investigate if apnoea or hypopnoea load can display better correlation with ESS. MATERIALS AND METHODS: Retrospective analysis of 821 patients with AHI >=5, who underwent in-laboratory polysomnogram for suspected OSA from January 2015-December 2015, was performed. Objective factors on polysomnogram were correlated with ESS. RESULTS: ESS was correlated with age (r = -0.148, P <0.001), number of apnoeas (r = 0.096, P = 0.006), apnoea load (r = 0.102, P = 0.003), apnoea index (r = 0.075, P = 0.032), number of desaturations (r = 0.081, P = 0.020), minimum SpO2 (r = -0.071, P = 0.041), time SpO2 <85% (r = 0.075, P = 0.031) and REM sleep duration (r = 0.099, P = 0.004). Linear regression analysis found age (P <0.001), apnoea load (P = 0.005), REM (P = 0.021) and stage 1 sleep duration (P = 0.042) as independent factors correlated to ESS. The apnoea load calculated using duration in apnoea correlate with ESS in patients with severe OSA by AHI criteria compared to the mild category. CONCLUSION: AHI does not correlate with ESS. Younger age, longer apnoea, stage 1 and REM sleep were independently related to higher ESS though the correlations were weak. Apnoea load should be taken into account when determining OSA severity. PMID- 30019067 TI - Normotensive Scleroderma Renal Crisis. PMID- 30019068 TI - Triple Vessel Coronary Artery Disease and Retinal Nerve Fibre Layer Thickness. PMID- 30019069 TI - Physiologic Limits of Cardiac Remodelling in Asian Competitive Athletes - A Single Centre Study. PMID- 30019070 TI - Effectiveness of the eCARE Programme: A Short Message Service (SMS) for Asthma Monitoring. PMID- 30019071 TI - Epidemiological Characteristics of Non-Simultaneous Bilateral Fragility Hip Fractures in an Elderly Singaporean Population. PMID- 30019072 TI - No difference in sensory outcome between vertical and oblique incisions for hamstring graft harvest during ACL reconstruction. AB - PURPOSE: To compare the incidence, extent of sensory loss, its clinical effect and natural course caused by sensory nerve injury, during two different skin incisions used for autogenous hamstring graft harvest during ACL reconstruction. METHODS: This randomized prospective study was carried out on 84 patients, divided into two groups, all of them underwent arthroscopic ACL reconstruction using hamstring tendon graft with two incisions; a vertical incision used in 43 patients, and an oblique incision in 41 patients. The location and area of sensory loss were evaluated during follow-up as well as the degree of improvement and patient satisfaction. RESULTS: The average age in this study was 29.8 +/- 7.2 in the vertical group and 29.9 +/- 6.3 in the oblique group. Both semitendinosus and gracilles were harvested in 34 patients, semitendinosus in 49 patients and gracilles in one patient. In the vertical group, a higher incidence of sensory loss was recorded with 21 patients (51.2%), relative to the oblique group with 18 patients (41.9%). However, there was no statistically significant difference (p = n.s). Most of the sensory loss affected the distribution of the IPBSN (infrapatellar branch of saphenous nerve) in 27 patients (69.2%) in both groups, and to a lesser extent in the lower medial area [distribution of SBSN (sartorial branch of saphenous nerve)] in 12 patients (30.8%). CONCLUSION: This study clearly revealed the high incidence of nerve injury particularly the IPBSN during hamstring graft harvest, but did not prove a difference between oblique and vertical incisions, with regard to postoperative sensory loss. It was clear that harvesting the semitendinosus alone is not a factor that can diminish nerve injury. LEVEL OF EVIDENCE: II. PMID- 30019073 TI - Popliteal neurovascular bundle is safe during inside-out repair of medial meniscus without a safety incision. AB - PURPOSE: There is a theoretical risk of injury to neurovascular structures during inside-out meniscal repair without a safety incision, although there are limited studies assessing this risk. This simulation study on archival MRI films was performed to assess the risk for the popliteal neurovascular bundle and the peroneal nerve during passage of needles for inside-out meniscus repair without a "safety incision", thereby defining a "safe zone" of the menisci that can be safely repaired using this technique. METHODS: Archival MRI scans (n = 50) were retrieved and axial sections through the menisci were used for simulation. The needle passage was simulated for different points on the posterior horn and body of lateral and medial menisci at "half-hour" intervals using clock method (15 degrees intervals) with three different portals and two different needle cannulas, resulting in six different scenarios of needle passage for each point on the meniscus. The distance of the needle in each scenario was measured from popliteal vessels (n = 50) and peroneal nerve (n = 10). The value "mean-3SD" was calculated for positive means and "Mean + 3SD" was calculated if the mean was negative. An additional 2 mm was defined as "safe distance". Thus, simulation models in which the mean - 3SD was less than 2 mm (or mean + 3SD was greater than - 2 mm for negative means) were labelled as "unsafe". RESULTS: Needle passage through medial meniscus at and medial to 1 o'clock position for a right knee (or 11 o'clock position for a left knee) was safe, irrespective of the portal and needle type. For the lateral meniscus, only the equatorial region was found to be safe with this method. CONCLUSIONS: The popliteal neurovascular bundle is safe during the inside-out medial meniscal repair without a safety incision. For the terminal-most part of the posterior horn, the AM portal and the straight cannula should be avoided. However, this method without safety incision cannot be recommended for lateral meniscus because of the risk to the popliteal vessels and the peroneal nerve. Instead, the inside-out method with a safety incision, or an all-inside method should be used for lateral meniscus. LEVEL OF EVIDENCE: III. PMID- 30019075 TI - Open reconstruction with autologous spongiosa grafts and matrix-induced chondrogenesis for osteochondral lesions of the talus can be performed without medial malleolar osteotomy. AB - PURPOSE: To evaluate complication rates and postoperative outcomes in patients with osteochondral lesions of the talus who underwent an autologous matrix induced chondrogenesis (AMIC) procedure with autologous spongiosa grafting without malleolar osteotomy. METHODS: A total of 23 patients with a mean age of 35.6 +/- 13.9 years were included in this study. The mean follow-up was 33.5 +/- 10.4 months (range 24-52.9 months). The clinical outcomes were evaluated using the visual analog scale (VAS) and the Foot Function Index (FFI). Postoperatively, lesion healing was assessed using the magnetic resonance observation of cartilage repair tissue (MOCART) protocol. RESULTS: There were no intraoperative or perioperative complications. In one patient, arthroscopic arthrolysis was performed due to painful arthrofibrosis. The mean VAS significantly decreased from 7.6 +/- 1.1 (range 4.2-9.3) to 1.4 +/- 2.2 (range 0-7.4) (P < 0.001). The mean FFI significantly improved from 46.8 +/- 14.3 (range 24.3-80.8) to 15.9 +/- 11.4 (range 10.0-51.7) (P < 0.001). The mean MOCART score at 1-year follow-up was 74.1 +/- 12.4 (range 50-95). Both preoperative and postoperative pains were significantly higher for smokers when compared to non-smokers. CONCLUSIONS: The results of the present study study indicate that AMIC procedure can be performed through the anterolateral and anteromedial arthrotomy without malleolar osteotomy. Thus, the possible complications associated with malleolar osteotomy can be avoided. The AMIC procedure without a malleolar osteotomy can be considered a safe and reliable procedure in patients with osteochondral lesions localized anterior to the midline in the sagittal plane. LEVEL OF EVIDENCE: Therapeutic case series, Level IV. PMID- 30019074 TI - Comparable clinical and structural outcomes after arthroscopic rotator cuff repair in diabetic and non-diabetic patients. AB - PURPOSE: To compare clinical outcome and rotator cuff integrity after arthroscopic rotator cuff repair (ARCR) in patients with and without diabetes mellitus. METHODS: This retrospective study involved 264 consecutive patients who underwent ARCR from 2012 to 2015. Inclusion criteria were a medium or large-sized tear and a minimum of 1-year follow-up. Clinical outcome measures included range of motion (ROM) and the Japanese Orthopaedic Association (JOA) and University of California, Los Angeles (UCLA) scores preoperatively and at final follow-up. Rotator cuff retear was evaluated with magnetic resonance imaging at 3 months post-surgery and final follow-up. Diabetic patients with poor control were pre operatively hospitalized for intensive diabetic control. RESULTS: Our inclusion criteria were met by 30 diabetic patients and 126 non-diabetic patients. Demographic data were not significantly different between the groups, except body mass index (p = 0.021). Preoperative JOA and UCLA scores of the diabetic patients were significantly lower than those of the non-diabetic patients (p < 0.001, and p = 0.006, respectively); however, the scores at final follow-up were not different. ROM was significantly restricted in the diabetic patients before surgery (forward flexion, abduction, internal rotation: p < 0.001, external rotation: p = 0.035), but at the final follow-up, there was no significant difference except for internal rotation (p = 0.005). The retear rate in diabetic patients (23.3%) was not significantly different from that in non-diabetic patients (15.1%). CONCLUSIONS: Diabetic patients who had good perioperative glycemic control showed clinical and structural outcomes comparable to non diabetic patients after ARCR. Intensive perioperative glycemic control and patient education are recommended for preoperative uncontrolled diabetic patients. LEVEL OF EVIDENCE: III. PMID- 30019077 TI - [German social courts confirm: reduction of basic urological flat rate erred]. PMID- 30019076 TI - [Spin echo and gradient echo : Methodological duo of MRI]. AB - Clinical magnetic resonance imaging (MRI) offers a multitude of different techniques with which anatomical, functional and metabolic information can be gained. The technical basis of an MRI method is the so-called pulse sequence, which determines the manner in which data is acquired. Pulse sequences are differentiated between gradient and spin echo sequences. The aim of this article is to present the principal physical properties of both techniques. From these properties, specific applications arise that are routinely used in clinical practice. PMID- 30019078 TI - [Federal social court: GOP 26315 EBM not billable in addition to the oncology agreement]. PMID- 30019079 TI - [Revision of S 303 Sect. 4 SGB V to prevent improper diagnosis manipulation]. PMID- 30019080 TI - [On the requirement of histological examination and/or image documentation in circumcisions]. PMID- 30019081 TI - [A rare renal tumour : Ectopic thyroid tissue in the kidney]. AB - During a nephrectomy of a nonfunctioning, tumour-bearing kidney we found ectopic thyroid tissue in the kidney. This location of ectopic thyroid tissue has not been described before. In general, ectopic thyroid tissue is uncommon and rather found in the cervical region or upper mediastinum. A 131-iodine whole-body scan is the most precise method to detect the presence of ectopic thyroid tissue. It is often difficult to distinguish between benign and differentiated malignant thyroid tissue. PMID- 30019082 TI - Analyte-driven self-assembly of graphene oxide sheets onto hydroxycamptothecin functionalized upconversion nanoparticles for the determination of type I topoisomerases in cell extracts. AB - Type I topoisomerases (TOPOI), a potential diagnostic biomarker and a target for chemotherapeutic agents, play essential roles in DNA replication, transcription, chromosome segregation, and recombination. It is essential to develop analytical methods for accurate detection of TOPOI in biological fluids for early diagnosis of diseases. Here we show an assay for TOPOI on the basis of the target-induced self-assembly of graphene oxide (GO) sheets onto hydroxycamptothecin functionalized upconversion nanoparticles (HCPT-UCNPs). The dipole-dipole coupling of HCPT-UCNPs (donor) and GO (acceptor) regulated by TOPOI enables Forster resonance energy transfer between the donor and the acceptor. Integration of minimal autofluorescence and highly specific affinity into the developed nanosensor allows reliable detection of TOPOI in the nanomolar range with the detection limit of 0.29 nM. The detection of TOPOI in breast cancer cells with recoveries from 96.3 to 103.7% shows the availability of the proposed assay in complicated samples. Graphical abstract ?. PMID- 30019083 TI - Modulating receptor-ligand binding in biorecognition by setting surface wettability. AB - Modulation of support wettability used for microarray format biosensing has led to an improvement of results. Hydrophobicity of glass chips was set by derivatizing with single vinyl organosilanes of different chain length and silane mixtures. Thiol-ene photochemical linking has been used as effective chemistry for covalent anchoring of thiolated probes. Lowest unspecific binding and highest signal intensity and SNR were obtained with large hydrocarbon chain (C22) silanes or a shorter one (C10) containing fluorine atoms. SNR resulting values are improved, reaching levels higher than 1500 in some cases, when using vinyl silanes modified with 1% C10 alkyl fluorinated one, because mild hydrophobicity was achieved (water contact angle ca. 110 degrees ) for all silanes, including the short C2 and C3, thus giving rise to smaller and better defined array spots. In addition, unspecific binding of reagents and targets was totally withdrawn. Hence, good-performing surfaces for biosensing applications can be built using appropriate organosilane reagent selection, including fluorinated ones. Graphical abstract ?. PMID- 30019085 TI - Early transient asymptomatic neutropenia associated with alemtuzumab treatment in multiple sclerosis: a case report. PMID- 30019084 TI - LRP5 gene polymorphisms and radiographic joint damage in rheumatoid arthritis patients. AB - : Rheumatoid arthritis (RA) is characterized by increased bone resorption and impaired bone formation. Osteoblast function is regulated by the canonical LRP5/Wnt/beta-catenin pathway. Bone mineral density and RA joint destruction are partially inherited. In line with this, we found significant associations between LRP5 SNPs (p.A1330V, p.N740N, p.V667M) and RA radiographic damage severity. INTRODUCTION: Increased bone resorption and impaired bone formation characterize rheumatoid arthritis (RA). Canonical Wnt/beta-catenin pathway, signalled by lipoprotein receptor-related protein-5 (LRP5), regulates osteoblast function. Since bone mineral density (BMD) and RA joint destruction are partially inherited, we studied their association with LRP5 single nucleotide polymorphisms (SNPs). METHODS: Clinical data and peripheral blood for biomarkers assessment and LRP5 genotyping were collected from 208 RA patients. Hands and feet X-rays were scored [modified Sharp/van der Heijde Score (SHS), joint space narrowing (JSN), and erosion scores]. Lumbar spine, total left proximal femur, and left hand BMD were assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: TT genotypes for p.A1330V and p.N740N LRP5 SNPs associated with total SHS, erosion score, and hands erosion score; the same for p.A1330V with feet JSN score and p.N740N with hands total score. AG genotype for p.V667M associated with sclerostin and hands JSN score. Femoral BMD associated with TC genotype for p.N740N. Multiple test correction precluded a few of these associations. Among V667M-N740N-A1330V haplotypes: GTT associated with higher feet JSN score (OR = 3.80; p = 0.016) and ATT with higher JSN score (OR = 4.60; p = 0.032), hands total score (OR = 5.65; p = 0.022), and total SHS (OR = 6.74; p = 0.024). CONCLUSION: Significant associations between LRP5 SNPs (p.A1330V, p.N740N, and p.V667M) and the severity of radiographic damage reinforce the evidence of bone destruction heritability in RA. PMID- 30019086 TI - Validity of a triaxial accelerometer and simplified physical activity record in older adults aged 64-96 years: a doubly labeled water study. AB - BACKGROUND: The aim was to examine the validity of a triaxial accelerometer (ACCTRI) and a simplified physical activity record (sPAR) in estimating total energy expenditure (TEE) and physical activity level (PAL) in older adults with the doubly labeled water (DLW) method. METHODS: A total of 44 Japanese elderly individuals (64-96 years), of which 28 were community-dwelling healthy adults with or without sporting habits (S or NS group) and 16 were care home residents with frailty (F group), were included in the study. Basal metabolic rate (BMR) was measured by indirect calorimetry, TEE was obtained by the DLW method, and PAL was calculated as TEE/BMR. Daily step count was monitored by a pedometer (Lifecorder). The 24-h average metabolic equivalent was assessed by ACCTRI and sPAR. RESULTS: The TEEDLW in men was 2704 +/- 353, 2308 +/- 442, and 1795 +/- 338 kcal d-1, and that in women was 2260 +/- 208, 1922 +/- 285, and 1421 +/- 274 kcal d-1 for the S, NS, and F groups, respectively. ACCTRI and sPAR systematically underestimated actual TEE (- 14.2 +/- 11.6 and - 15.3 +/- 12.3% for ACCTRI and sPAR, respectively). After diet-induced thermogenesis was taken into account for ACCTRI and sPAR, TEEDLW was significantly correlated with TEEACCTRI (R2 = 0.714) and TEEsPAR (R2 = 0.668). PALDLW was also significantly correlated with PALACCTRI (R2 = 0.438) and PALsPAR (R2 = 0.402). CONCLUSIONS: Age, living conditions, frailty, and sporting habits contribute to TEE and PAL in the elderly population. ACCTRI and sPAR underestimated TEE and PAL, and adequate corrections are required. The corrected ACCTRI and sPAR are both useful tools to estimate TEE and PAL. PMID- 30019088 TI - Improved adherence to Mediterranean Diet in adults with type 1 diabetes mellitus. AB - PURPOSE: We aimed to assess food intake and adherence to the Mediterranean Diet in patients with T1D compared with nondiabetic individuals. METHODS: This was an observational, multicenter study in 262 T1D subjects and 254 age- and sex-matched nondiabetic subjects. A validated food-frequency questionnaire was administered. The alternate Mediterranean Diet Score (aMED) and alternate Healthy Eating Index (aHEI) were assessed. The clinical variables were also collected. The analysis of data included comparisons between groups and multivariate models. RESULTS: Compared to the controls, the patients with T1D had a higher intake of dairy products (p < 0.001), processed meat (p = 0.001), fatty fish (p = 0.009), fruits and vegetables (p < 0.001), nuts (p = 0.011), legumes (p < 0.001), potatoes (p = 0.045), and bread (p = 0.045), and a lower intake of seafood (p = 0.011), sweets (p < 0.001), and alcohol drinks (p = 0.025). This intake pattern resulted in a higher consumption of complex carbohydrates (p = 0.049), fiber (p < 0.001), protein (p < 0.001), polyunsaturated fatty acids (PUFA) (p = 0.007), antioxidants (p < 0.001), vitamins (p < 0.001), and minerals (p < 0.001). The frequency of patients with T1D and low aMED score (23.2%) was lower than that of the controls (35.4%; p = 0.019). The overall multivariate analysis showed that, among other factors, being a T1D subject was associated with improved aMED and aHEI scores (p = 0.006 and p < 0.001). In patients with T1D, residing in a nonurban area was associated with improved aMED and aHEI scores (p = 0.001 and p < 0.001). CONCLUSIONS: Adult patients with T1D showed healthier dietary habits and a higher adherence to the Mediterranean Diet than nondiabetic subjects. Residing in a nonurban area is associated with an improved dietary pattern. PMID- 30019089 TI - Association between dietary total antioxidant capacity and hepatocellular ballooning in nonalcoholic steatohepatitis: a cross-sectional study. AB - PURPOSE: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, ballooning, and in some cases, fibrosis, which can progress to cirrhosis and carcinoma. The progression of NASH is closely related to oxidative stress. Dietary intake of antioxidants has been suggested in protection against oxidative damage and related clinical complications. Thus, we evaluated the potential association of dietary total antioxidant capacity (TAC) with disease severity in NASH patients, as well as with anthropometric and body composition markers and biochemical parameters. METHODS: Thirty-three outpatients with a mean age of 48.4 +/- 1.9 years were evaluated. Dietary TAC was estimated from a quantitative food frequency questionnaire. NASH severity, determined by liver biopsy, lifestyle characteristics, occurrence of comorbidities, anthropometry, body composition, and biochemical parameters were assessed. RESULTS: NASH patients who had a higher dietary TAC had fewer ballooned hepatocytes compared to those with a lower TAC (p = 0.024). The patients with the highest dietary TAC had a reduction of approximately 20% in the risk of having many ballooned hepatocytes (OR 0.791; 95% CI 0.643-0.974; p = 0.027). There was no association of steatosis, lobular inflammation, and fibrosis with dietary TAC. The same occurred for lifestyle characteristics, occurrence of comorbidities, anthropometry, body composition, and biochemical parameters. CONCLUSION: Dietary TAC is higher in patients with lower hepatic injury (ballooning), suggesting a possible role of food intake naturally high in its antioxidant capacity in reducing free radical production and, consequently, oxidative stress. PMID- 30019087 TI - Nuclear actin: ancient clue to evolution in eukaryotes? AB - Until recently it was widely accepted that the dynamic cytoskeletal matrix is exclusive to the cytoplasm of eukaryotes, evolving before the emergence of the cell nucleus to enable phagocytosis, cell motility and the sophisticated functioning of the endomembrane system within the cytosol. The discovery of the existence of a prokaryotic cytoskeleton has changed this picture significantly. As a result, the idea has taken shape that the appearance of actin occurred in the very first cell; therefore, the emergence of microfilaments precedes that of the eukaryotic cytoskeleton. The discovery of nuclear actin opened new perspective on the field, suggesting that the nuclear activities of actin reflect the functions of primordial actin-like proteins. In this paper, we review the recent literature to explore the evolutionary origin of nuclear actin. We conclude that both ancient and eukaryotic features of the actin world can be detected in the nucleus today, which supports the idea that the cytoskeleton attained significant eukaryotic innovations before the tandem evolution of the cytoskeleton and nucleus occurred. PMID- 30019091 TI - Cloning of a putative sodium/calcium exchanger gene in the crayfish. AB - Crayfish is a common model animal for different experimental purposes. However, the lack of information about the genetic properties of the animal limits its use in comparison to other model animals. In the present study, a putative crayfish sodium/calcium exchanger gene has firstly been cloned in ganglia cDNA samples by conducting a series of PCR experiments, where a set of degenerate and specific primers and RACE method were used. The complete sequence is 2955 bp, and the ORF is 2718 bp in length. Molecular properties of the calculated peptide were similar to the sodium/calcium exchangers reported in the other species. Analysis of the qPCR data indicated that the putative gene has the highest expression level in the ganglia. However, an apparently elevated level of expression is observed in highly active tissues like heart, muscle and intestine, while the least expression level was observed in the stomach samples. It was proposed that the cloned gene may code the sodium/calcium exchanger protein in the crayfish. PMID- 30019090 TI - Vitamin D deficiency in patients with cluster headache: a preliminary study. AB - BACKGROUND: Cluster headache is famous for attacks with seasonal and diurnal periodicity. This diurnal and seasonal variation might be related to sunlight and vitamin D metabolism. We investigated the serum vitamin D levels in patients with cluster headache. METHODS: We enrolled patients with cluster headache and age- and sex-matched migraineurs and normal controls. From October 2016 to March 2018, non-fasting serum 25(OH)D concentrations were measured using a chemiluminescent immunoassay. Vitamin D deficiency was defined as a concentration < 20 ng/mL. RESULTS: The study enrolled 28 patients with cluster headache, 36 migraineurs, and 36 normal controls. In the patients with cluster headache, the serum 25(OH)D concentration averaged 14.0 +/- 3.9 ng/mL and 92.8% had vitamin D deficiency. There was no significant difference among the patients with cluster headache, migraineurs, and controls. In the patients with cluster headache, there was no difference in the serum 25(OH)D concentrations between men and women, cluster and remission periods, first and recurrent attack, presence and absence of daily or seasonal periodicity, and 3-month recurrence. In the 14 patients with seasonal periodicity, patients with periodicity of winter to spring had a trend of lower serum 25(OH)D concentrations than those with periodicity of summer to autumn (12.30 +/- 1.58 vs. 16.96 +/- 4.69 ng/mL, p = 0.097). CONCLUSIONS: Vitamin D deficiency is common in patients with cluster headache, but the role of vitamin D deficiency is uncertain, except for its seasonal influence. PMID- 30019092 TI - Effects of Size and Aggregation/Agglomeration of Nanoparticles on the Interfacial/Interphase Properties and Tensile Strength of Polymer Nanocomposites. AB - In this study, several simple equations are suggested to investigate the effects of size and density on the number, surface area, stiffening efficiency, and specific surface area of nanoparticles in polymer nanocomposites. In addition, the roles of nanoparticle size and interphase thickness in the interfacial/interphase properties and tensile strength of nanocomposites are explained by various equations. The aggregates/agglomerates of nanoparticles are also assumed as large particles in nanocomposites, and their influences on the nanoparticle characteristics, interface/interphase properties, and tensile strength are discussed. The small size advantageously affects the number, surface area, stiffening efficiency, and specific surface area of nanoparticles. Only 2 g of isolated and well-dispersed nanoparticles with radius of 10 nm (R = 10 nm) and density of 2 g/cm3 produce the significant interfacial area of 250 m2 with polymer matrix. Moreover, only a thick interphase cannot produce high interfacial/interphase parameters and significant mechanical properties in nanocomposites because the filler size and aggregates/agglomerates also control these terms. It is found that a thick interphase (t = 25 nm) surrounding the big nanoparticles (R = 50 nm) only improves the B interphase parameter to about 4, while B = 13 is obtained by the smallest nanoparticles and the thickest interphase. PMID- 30019093 TI - Correction to: Factors Predictive of Complete Excision of Large Colorectal Neoplasia Using Hybrid Endoscopic Submucosal Dissection: A KASID Multicenter Study. AB - The original version of the article unfortunately contained errors in author affiliation. Affiliation of third and ninth author was incorrectly assigned. PMID- 30019095 TI - An audit of discharge summaries from secondary to primary care. AB - BACKGROUND: Health is information-intensive. Reliable health care depends on access to this information in a timely and accurate manner. A standardised data set for clinical discharge summaries is essential to optimise the care the patient receives, particularly at discharge. The Irish Health Information and Quality Authority (HIQA) have recently developed a national standard for patient discharge summaries. AIMS: Our aim was to assess the current quality of discharge summaries being received, determine the main areas of concern and establish the areas to improve patient safety. METHODS: We studied 60 discharge summaries received at 3 general practices in the Mid-West of Ireland. We used HIQA "National Standard for Patient Discharge Summary" 2013 as our audit standard. RESULTS: Mandatory fields including Surname, Forename and date of birth were present in 100%, missing in 0%. The patient's address was missing in 7% (n = 4). Gender was missing in 82% (n = 50). Source of referral was missing in 52% (n = 32). No method of admission was documented in 70% (n = 43). Whilst principal diagnosis was documented in 100% (n = 60), no co-morbidities were documented in 28% (n = 17). No medication was documented in 30% (n = 18), and there was no documentation of medication changed in 39% (n = 24). Details of the person completing the discharge summary were incomplete as follows: 85% (n = 52) had no specialty documentation, 36% (n = 22) had no registration number and 38% (n = 23) had no contact number. CONCLUSIONS: This audit shows deficits in adhering to HIQA standards. These must be addressed as a matter of urgency. PMID- 30019094 TI - Design and synthesis of novel 3-(thiophen-2-yl)-1,5-dihydro-2H-pyrrol-2-one derivatives bearing a hydrazone moiety as potential fungicides. AB - BACKGROUND: Tetramic acid, thiophene and hydrazone derivatives were found to exhibit favorable antifungal activity. Aiming to discover novel template molecules with potent antifungal activity, a series of novel 3-(thiophen-2-yl) 1,5-dihydro-2H-pyrrol-2-one derivatives containing a hydrazone group were designed, synthesized, and evaluated for their antifungal activity. RESULTS: The structures of 3-(thiophen-2-yl)-1,5-dihydro-2H-pyrrol-2-one derivatives bearing a hydrazone group were confirmed by FT-IR, 1H NMR, 13C NMR, 1H-1H NOESY, EI-MS and elemental analysis. Antifungal assays indicated that some title compounds exhibited antifungal activity against Fusarium graminearum (Fg), Rhizoctorzia solani (Rs), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc) in vitro. Strikingly, the EC50 value of 5e against Rs was 1.26 ug/mL, which is better than that of drazoxolon (1.77 ug/mL). Meanwhile, title compounds 5b, 5d, 5e-5g, 5n-5q and 5t exhibited remarkable anti-Cc activity, with corresponding EC50 values of 7.65, 9.97, 6.04, 6.66, 7.84, 7.59, 9.47, 5.52, 6.41 and 7.53 ug/mL, respectively, which are better than that of drazoxolon (19.46 ug/mL). CONCLUSIONS: A series of 3-(thiophen-2-yl)-1,5-dihydro-2H-pyrrol-2-one derivatives bearing a hydrazone group were designed, synthesized and evaluated for their antifungal activity against Fg, Rs, Bc and Cc. Bioassays indicated that some target compounds exhibited obvious antifungal activity against the above tested fungi. These results provide a significant basis for the further structural optimization of tetramic acid derivatives as potential fungicides. PMID- 30019096 TI - Physical activity and mental health in an Irish population. AB - BACKGROUND: Physical activity represents a modifiable behaviour which may be associated with increased likelihood of experiencing positive mental health. AIMS: The aim of this study was to examine the association between self-rated physical activity and subjective indicators of both positive and negative mental health in an Irish adult population. METHODS: Based on data from a population based, observational, cross-sectional study, participants were categorised using the International Physical Activity Questionnaire (IPAQ) into those who reported that they did and did not meet recommended physical activity requirements. Self reported positive and negative mental health indicators were assessed using the Energy and Vitality Index (EVI) and the Mental Health Index-5 (MHI-5) from the SF 36 Health Survey Instrument, respectively. Binary logistic regression was used to identify variables independently associated with self-reported positive and negative mental health. RESULTS: A total of 7539 respondents were included in analysis. Overall, 32% reported that they met recommended minimal physical activity requirements. Self-reported positive and negative mental health were reported by 16 and 9% of respondents, respectively. Compared with those who reported meeting-recommended physical activity requirements, those performing no physical activity were three times less likely to report positive mental health (adjusted odds ratio (OR) 0.39, 95% confidence interval (CI) 0.28-0.55) and three times more likely to report negative mental health (OR 3.27, 95% CI 2.38-4.50). CONCLUSION: Compared with those who do not, those who report meeting-recommended physical activity requirements are more and less likely to report experiencing positive and negative mental health, respectively. Future policy development around physical activity should take cognisance of the impact of this activity on both physical and mental health outcomes. PMID- 30019097 TI - Modified capture-recapture estimates of the number of families with Lynch syndrome in Central Ohio. AB - Past methods for estimating the population frequency of familial cancer syndromes have used cases and controls ignoring the familial nature of genetic disease. In this study we modified the capture-recapture method from ecology to estimate the number of families in central Ohio with Lynch syndrome (LS). We screened 1566 colorectal cancer cases and 545 endometrial cancer cases in central Ohio from 1999 to 2005 and identified 58 with LS. We screened an additional 3346 colorectal and 342 endometrial cancer cases from 2013 to 2016 and identified 149 with LS. We found 12 LS mutations shared between families observed in the first and second studies. We identified three individuals between studies who were closely related and eight who were more distantly related. We used identified family relationships and genetic test results to estimate family size and structure. Applying a modified capture-recapture method we estimate 1693 3-generation families in the area who have 288 unique LS causing mutations. Comprehensive colorectal and endometrial cancer screening will take about 20 years to identify 50% of families with LS. This is the first time that the capture-recapture method has been applied to estimate the burden of families with a specific heritable disease. Family structure reveals the potential extent of prevention and the time necessary to identify a proportion of families with LS. PMID- 30019098 TI - Electrocardiographic Findings in Mortalities Due to Pure Methadone Toxicity. AB - We aimed to evaluate electrocardiographic (ECG) abnormalities in mortalities due to pure methadone toxicity in ICU patients since methadone-related mortality may be due to cardiac complications even in acute toxicities. In a retrospective single-center study, files of all patients who had died with confirmed diagnosis of pure methadone toxicity between 2011 and 2016 were evaluated. Autopsy was performed in all cases. A cardiologist measured all ECG quantitative and qualitative indices. Fifty-one deaths were recorded. Forty-two dead patients were males. Median [IQR] age of the patients was 44 [30, 60] years. Of them, 38 (69%) were methadone-dependent and were significantly older than methadone-naive patients (p = 0.008 and p = 0.001, respectively). ECG abnormalities were detected in all cases. ST-T abnormalities were found in 33 (64.7%) patients. Except longer PR interval in dependent patients (p = 0.017) and specific ST elevation in naive cases (p = 0.008), other ECG indices were similar in two groups. No correlation was found between ST-T abnormalities and coronary disease in autopsy. ECG abnormalities irrelevant to coronary artery diseases are common in methadone related mortalities. Methadone toxicity may affect myocardium and play a role in death. Further prospective studies to evaluate other cardiac indices in methadone poisoned patients are recommended. PMID- 30019100 TI - Chemosensitivity of various peritoneal cancer cell lines to HIPEC and PIPAC: comparison of an experimental duplex drug to standard drug regimens in vitro. AB - We performed an in-vitro study testing the chemosensitivity of peritoneal cancer cell lines (SW620, HCT116, MKN45, 23,132/87, OAW42) to various cytostatic drug regimens. A duplex drug, characterized by reversible linking of the antimetabolites 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), was compared to oxaliplatin or to cisplatin plus doxorubicin. The experiments were designed to reflect the conditions of intraperitoneal chemotherapy. CASY(r) (Cell Analysis System) technology was used to compare the impact of incubation temperature/duration and drug concentration on the viability of the cancer cell lines versus normal human dermal fibroblasts. Two incubation scenarios were explored: (i) hyperthermic intraperitoneal chemotherapy (HIPEC) with 1 h of incubation at 42 degrees C, and (ii) pressurized intraperitoneal aerosol chemotherapy (PIPAC) with several successive incubations at 37 degrees C. Under HIPEC conditions, oxaliplatin induced a potent temperature-dependent growth inhibition of colon cancer cells not seen with the duplex drug. Under PIPAC conditions, the duplex drug achieved the same growth inhibition at a fraction of the dose level required with oxaliplatin. Gastric and ovarian cancer cells were more sensitive to cisplatin plus doxorubicin than to the duplex drug under PIPAC conditions. The duplex drug suggests itself, notably in cases of platinum resistance, as an alternative or addition to intraperitoneal chemotherapies when platinum-based PIPAC technology is used. Using it with HIPEC technology is not recommended. Higher doses of the duplex drug will enhance growth inhibition, albeit at the cost of a severely reduced difference in chemosensitivity between tumor and normal cells. Our findings provide orientation for PIPAC-based personalized intraperitoneal chemotherapy. PMID- 30019099 TI - Design, synthesis and antiproliferative evaluation of novel sulfanilamide-1,2,3 triazole derivatives as tubulin polymerization inhibitors. AB - Microtubule as an important target in the cancer therapy was used to design novel tubulin polymerization inhibitors. Sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and their antiproliferative activity against three selected cancer cell lines (BGC-823, MGC-803 and SGC-7901) were evaluated. All sulfanilamide-1,2,3-triazole hybrids displayed potent inhibitory activity against all cell lines. In particular, compound 10b showed the most excellent inhibitory effect against MGC-803 cells, with an IC50 value of 0.4 MUM. Cellular mechanism studies elucidated that 10b induced apoptosis by decreasing the expression level of Bcl-2 and Parp and increasing the expression level of BAX. 10b inhibited the epithelial-mesenchymal transition process by up regulating E-cadherin and down-regulating N-cadherin. Furthermore, the tubulin polymerization inhibitory activity in vitro of 10b was 2.4 MUM. In vivo anticancer assay, 10b effectively inhibited MGC-803 xenograft tumor growth without causing significant loss of body weight. These sulfanilamide-1,2,3 triazole hybrids as potent tubulin polymerization inhibitors might be used as promising candidates for cancer therapy. PMID- 30019101 TI - Hand-foot-skin reaction of grade >= 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC. AB - Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time dependent receiver operating characteristic curves, the development of a hand foot-skin reaction >= grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43-0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58-0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half. PMID- 30019102 TI - Increased inflammatory potential of diet is associated with increased odds of prostate cancer in Argentinian men. AB - PURPOSE: Various aspects of diet, including specific food items and nutrients, have been shown to modulate inflammation and have been implicated in the etiology of prostate cancer (PrCA). No study examining the role of diet-associated inflammation in PrCA has been conducted in Latin America. METHOD: We examined the association between the Dietary Inflammatory Index (DII(r)) and PrCA in a population-based case-control study in Cordoba, Argentina. A total of 153 incident cases of PrCA and 309 controls frequency matched on sex, age (+/- 5 years), and place of residence were recruited from 2008 to 2015. The DII was developed to determine the inflammatory potential of individuals' diets and was computed from a validated food frequency questionnaire using nutrient data from diet only. Multi-level logistic regression models were fit to evaluate the association between DII scores and PrCA, adjusting for age, body mass index, energy intake, and occupational exposure as first-level covariates and family history of prostate cancer as the second-level variable. Odds ratios were estimated in all subject and stratified by BMI (< 30 vs. >= 30 kg/m2). RESULTS: Men in the most pro-inflammatory group (tertile 3) had 50% higher odds of having PrCA compared to men in the most anti-inflammatory group (tertile 1) (ORtertile3 vs. tertile1 1.50; 95% CI 1.24-1.80). The odds of prostate cancer were higher in obese men (n = 109, ORtertile3 vs. tertile1 1.81; 95% CI 1.45-2.27), while no association was found among non-obese men (n = 375, ORtertile3 vs. tertile1 0.93; 95% CI 0.25-3.51). CONCLUSIONS: A pro-inflammatory diet, reflected by higher DII scores, was positively associated with PrCA occurrence. Based on these results and those from other studies, steps should be taken to promote a diet rich in anti-inflammatory foods, in order to reduce risk of PrCA and other chronic diseases. Future studies should explore this association in a prospective setting. PMID- 30019103 TI - Identification of candidate microRNA biomarkers in diabetic nephropathy: a meta analysis of profiling studies. AB - AIMS: The aim was to perform a meta-analysis on the miRNA expression profiling studies in diabetic nephropathy (DN) to identify candidate diagnostic biomarkers. METHODS: A comprehensive literature search was done in several databases and 53 DN miRNA expression studies were selected. To identify significant DN-miR meta signatures, two meta-analysis methods were employed: vote-counting strategy and the robust rank aggregation method. The targets of DN-miRs were obtained and a gene set enrichment analysis was carried out to identify the pathways most strongly affected by dysregulation of these miRNAs. RESULTS: We identified a significant miRNA meta-signature common to both meta-analysis approaches of three up-regulated (miR-21-5p, miR-146a-5p, miR-10a-5p) and two down-regulated (miR-25 3p and miR-26a-5p) miRNAs. Besides that, subgroup analyses divided and compared the differentially expressed miRNAs according to species (human and animal), types of diabetes (T1DN and T2DN) and tissue types (kidney, blood and urine). Enrichment analysis confirmed that DN-miRs supportively target functionally related genes in signaling and community pathways in DN. CONCLUSION: Five highly significant and consistently dysregulated miRNAs were identified, and future studies should focus on discovering their potential effect on DN and their clinical value as DN biomarkers and therapeutic mediators. PMID- 30019104 TI - Testosterone in renal transplant patients: effect on body composition and clinical parameters. AB - BACKGROUND: Clinical studies have demonstrated that, after renal transplantation (TX), testosterone deficiency (TD) at the time of the procedure is independently associated with lower survival of the patient and graft. However, data between TD and the functional CAG polymorphism of the androgen receptor promoter (AR) are discordant. We investigated the prevalence of TD and its association with body composition, biochemical parameters, the Aging Males' Symptoms rating scale (AMS) domains and AR polymorphism. METHODS: In 112 TX patients, we assessed the AMS, biochemical/hormonal (FSH/LH/TT) anthropometric/bioimpedance analysis parameters, and AR CAG polymorphism of AR by gene sequencing. RESULTS: Median values of total testosterone (TT) were 340 ng/dl and 52% of TX patients were affected by TD. Significant correlations between TT and FSH and FSH and LH (p = 0.005, p < 0.0001, respectively) were found. TD patients had lower estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) (p = 0.034, p = 0.022 respectively) and showed higher values of C-reactive protein (p = 0.023) and fat tissue index/adipose tissue mass (p = 0.034 and p = 0.021, respectively), and lower values of serum albumin (p = 0.003) and high-density lipoprotein-cholesterol (p = 0.038) levels. Significant differences were found in the number of patients on mammalian target of rapamycin inhibitors immunosuppressant therapy (p = 0.045). Logistic regression analysis did not show any correlation between age, AMS scores, TT or CAG repeat length, gonadotropins, time of the transplant, and dialysis. CONCLUSIONS: Our results suggest that in TX recipients an appropriate sexual hormonal evaluation should be performed, as we found a high prevalence of TD. However, further studies are needed to clarify the association between TD and patient and graft survival. PMID- 30019105 TI - Training in Endoscopy. AB - PURPOSE OF THE REVIEW: Progress towards the goal of high-quality endoscopy across health economies has been founded on high-quality structured training programmes linked to credentialing practice and ongoing performance monitoring. This review appraises the recent literature on training interventions, which may benefit performance and competency acquisition in novice endoscopy trainees. RECENT FINDINGS: Increasing data on the learning curves for different endoscopic procedures has highlighted variations in performance amongst trainees. These differences may be dependent on the trainee, trainer and training programme. Evidence of the benefit of knowledge-based training, simulation training, hands on courses and clinical training is available to inform the planning of ideal training pathway elements. The validation of performance assessment measures and global competency tools now also provides evidence on the effectiveness of training programmes to influence the learning curve. The impact of technological advances and intelligent metrics from national databases is also predicted to drive improvements and efficiencies in training programme design and monitoring of post-training outcomes. Training in endoscopy may be augmented through a series of pre-training and in-training interventions. In conjunction with performance metrics, these evidence-based interventions could be implemented into training pathways to optimise and quality assure training in endoscopy. PMID- 30019108 TI - About hemangioma and vascular malformations. PMID- 30019106 TI - A coarse-grained approach to studying the interactions of the antimicrobial peptides aurein 1.2 and maculatin 1.1 with POPG/POPE lipid mixtures. AB - In the present work we investigated the differential interactions of the antimicrobial peptides (AMPs) aurein 1.2 and maculatin 1.1 with a bilayer composed of a mixture of the lipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1' rac-glycerol) (POPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE). We carried out molecular dynamics (MD) simulations using a coarse-grained approach within the MARTINI force field. The POPE/POPG mixture was used as a simple model of a bacterial (prokaryotic cell) membrane. The results were compared with our previous findings for structures of 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC), a representative lipid of mammalian cells. We started the simulations of the peptide-lipid system from two different initial conditions: peptides in water and peptides inside the hydrophobic core of the membrane, employing a pre-assembled lipid bilayer in both cases. Our results show similarities and differences regarding the molecular behavior of the peptides in POPE/POPG in comparison to their behavior in a POPC membrane. For instance, aurein 1.2 molecules can adopt similar pore-like structures on both POPG/POPE and POPC membranes, but the peptides are found deeper in the hydrophobic core in the former. Maculatin 1.1 molecules, in turn, achieve very similar structures in both kinds of bilayers: they have a strong tendency to form clusters and induce curvature. Therefore, the results of this study provide insight into the mechanisms of action of these two peptides in membrane leakage, which allows organisms to protect themselves against potentially harmful bacteria. Graphical Abstract Aurein pore structure (green) in a lipid bilayer composed by POPE (blue) and POPG (red) mixture. It is possible to see water beads (light blue) inside the pore. PMID- 30019107 TI - Early post-procedural patients compliance and VAS after UAE through transradial versus transfemoral approach: preliminary results. AB - PURPOSE: The aim of our study is to verify VAS and patient compliance in the immediate post-procedural time, in patients undergoing UAE through radial approach versus femoral procedure. METHODS: Between January and September 2017, 30 consecutive patients (age range 28-47, average 32 years) were enrolled for the study. UAE was performed by two interventional radiologists with more than 10 years of experience and more than 100 cases of UAE done. Patients were divided into two groups: transfemoral approach (group a, n = 15 patients) and transradial approach (group b, n = 15 patients). After procedure, patients were questioned about the compliance using the questionnaire at 24 h and VAS rating at 6, 12, 18 and 24 h. RESULTS: The average of VAS in group b was lower than in group a in each evaluation at 6 h (p < 0.20), 12 h (p < 0.07), 18 h (p < 0.02) and 24 h (p < 0.22) on the basis of Mann-Whitney U test, however, without a clear scientific evidence. Also the compliance score at 24 h had better results in the group b (average 14.0, range 13.0-16.0) in comparison with group a (average 18.0, range 17.0-21.4) (p < 0.001). CONCLUSION: Transradial approach improves the compliance and VAS of patients undergone to UAE. PMID- 30019110 TI - Spring and Late Summer Phytoplankton Biomass Impact on the Coastal Sediment Microbial Community Structure. AB - Two annual Baltic Sea phytoplankton blooms occur in spring and summer. The bloom intensity is determined by nutrient concentrations in the water, while the period depends on weather conditions. During the course of the bloom, dead cells sink to the sediment where their degradation consumes oxygen to create hypoxic zones (< 2 mg/L dissolved oxygen). These zones prevent the establishment of benthic communities and may result in fish mortality. The aim of the study was to determine how the spring and autumn sediment chemistry and microbial community composition changed due to degradation of diatom or cyanobacterial biomass, respectively. Results from incubation of sediment cores showed some typical anaerobic microbial processes after biomass addition such as a decrease in NO2- + NO3- in the sediment surface (0-1 cm) and iron in the underlying layer (1-2 cm). In addition, an increase in NO2- + NO3- was observed in the overlying benthic water in all amended and control incubations. The combination of NO2- + NO3- diffusion plus nitrification could not account for this increase. Based on 16S rRNA gene sequences, the addition of cyanobacterial biomass during autumn caused a large increase in ferrous iron-oxidizing archaea while diatom biomass amendment during spring caused minor changes in the microbial community. Considering that OTUs sharing lineages with acidophilic microorganisms had a high relative abundance during autumn, it was suggested that specific niches developed in sediment microenvironments. These findings highlight the importance of nitrogen cycling and early microbial community changes in the sediment due to sinking phytoplankton before potential hypoxia occurs. PMID- 30019109 TI - Expression kinetics of human periodontal ligament fibroblasts in the early phases of orthodontic tooth movement. AB - PURPOSE: Human periodontal ligament (hPDL) fibroblasts play a crucial mediating role in orthodontic tooth movement (OTM). In this study, we investigated the expression kinetics of genes associated with OTM in its early phase to obtain better insight into the timing and regulation of molecular and cellular signalling and transformation processes occurring in compressive areas of the periodontal ligament during OTM. METHODS: Adherent hPDL fibroblasts were stimulated with physiological orthodontic compressive forces of 2 g/cm2 for 24, 48, 72, and 96 h under cell culture conditions. At each time point, we quantified relative gene expression of genes involved in bone remodelling (ALPL), inflammation (COX2, IL-6), extracellular matrix reorganization (COL1A2, P4HA1, FN1, MMP8) and angiogenesis (VEGF-A) by means of RT-qPCR as well as protein expression of osteoclastogenesis-regulating RANK-L and OPG relative to pressure untreated controls incubated for corresponding time periods. In addition, coculture experiments with osteoclast precursor cells were performed to determine the extent of hPDL-fibroblast-mediated osteoclastogenesis (TRAP staining). RESULTS: As primary response to compressive forces within 24 h, we observed an induction of genes associated with angiogenesis, inflammation, osteoblastogenesis, and the remodelling of the extracellular matrix, with RANK-L expression at first slightly inhibited and only increased after 48 h. Major hPDL mediated osteoclastogenesis was observed after 72 h with minor, non-RANK-L dependent osteoclastogenesis occurring as early as 24 h after compressive force application. CONCLUSIONS: hPDL fibroblasts seem to play a major mediating role in the early phase of OTM with a differentiated, time-dependent regulation and expression pattern of cytokines and other mediators. PMID- 30019112 TI - A case of symmetric retrograde thromboembolic cerebral infarction in an 8-year old child due to arterial thoracic outlet syndrome. AB - Arterial type of thoracic outlet syndrome belongs to the most unusual mechanisms of stroke in children in the first decade of life. We present a case diagnosed for bilateral and symmetric changes due to retrograde thromboembolic phenomenon. Regarding the age of the patient, the appropriate diagnostics and management are still a matter of debate in pediatric and neurological literature. PMID- 30019113 TI - Giant arachnoid granulation in a child with benign intracranial hypertension: an unusual case. AB - CASE PRESENTATION: A 6-year-old girl complained of diplopia and headache over a 2 week period after sustaining a minor head injury. Her neurological examinations were normal, but visual examination identified bilateral papilledema. Magnetic resonance imaging of the brain revealed a protruding nodular lesion causing compression within the anterior superior sagittal sinus in the midline, showing high signal intensity on T2-weighted imaging (T2WI) and low signal intensity on T1WI, similar to that of cerebrospinal fluid. Enhanced T1WI showed irregular narrowing of the anterior superior sagittal sinus adjacent to this lesion. The cortical vein drained to the frontal pole of the arachnoid granulation lesion and into the superior sagittal sinus. No other parenchymal abnormality was noted. A lumbar puncture showed increased opening pressure (30 mmHg), and the laboratory findings were normal. Based on the imaging and clinical findings, benign intracranial venous hypertension with giant arachnoid granulation was diagnosed. The patient's symptoms were reduced satisfactorily following daily treatment with 750 mg acetazolamide. CONCLUSION: We report a case of giant arachnoid granulation involving the anterior superior sagittal sinus in a 6-year-old girl who presented with benign intracranial hypertension. Clinicians should be aware of this rare anatomic variant to avoid unnecessary invasive procedures or examinations in children with benign intracranial hypertension. PMID- 30019114 TI - Resting Motor Threshold, MEP and TEP Variability During Daytime. AB - Humans show a variation in physiological processes during the day. To reliably assess (changes in) cortical excitability with transcranial magnetic stimulation (TMS), it is relevant to know the natural variation in TMS readouts during the day. In case of significant daytime variations, this should be taken into account when scheduling (follow-up) measurements. This study aims to evaluate the influence of the time of day on the resting motor threshold (RMT), motor evoked potential (MEP) and TMS evoked potential (TEP) in healthy controls. TMS-EMG-EEG was recorded in 16 healthy subjects. At both motor cortices, we administered 75 pulses at an intensity of 110% RMT. Subjects were stimulated during five sessions in one day (8:00 AM, 10:30 AM, 1:00 PM, 3:30 PM and 6:00 PM) while keeping the stimulation intensity constant. We compared the TEP waveforms between the five sessions with a cluster-based permutation analysis, and the RMT and MEP amplitude with rmANOVA. In general there were no significant differences between the five sessions in the RMT, MEP amplitude or TEP. Only for the left side, N100 amplitude was larger at 3:30 PM than 10:30 AM. The standard deviation of the P30 and N100 amplitude was significantly higher between subjects within one session than within single subjects during the day. The TEP is highly reproducible during the day, with a low intra-individual variation compared to the inter-individual variation. In addition, we found no significant variation of the RMT and MEP amplitude between multiple sessions on one day. PMID- 30019111 TI - Cricket Injury Epidemiology in the Twenty-First Century: What is the Burden? AB - BACKGROUND: At the turn of the century, a new format of cricket [Twenty20 (T20)] was introduced that has led to more matches being played. Since then, it has been debated whether T20 cricket has increased the risk of overuse injuries. OBJECTIVES: The primary aim of this study was to meta-analyse the cricket injury rates in the twenty-first century. The secondary aims were to explore the risk factors and mechanisms of injury by analysing correlates such as age, format, era of play, country, player type, etc., and to conduct a qualitative analysis of the published studies. METHODS: Several databases were searched using keywords "cricket" and "injur*" and 24 papers reporting cricket injuries fitted the inclusion criteria. Fifteen papers included data on exposure time and were used to calculate injury rates to perform sub-group analysis. RESULTS: Pooled data on 12,511 players revealed 7627 injuries, and the 1.12 million hours of cricket play from 15 studies reporting exposure time showed an injury rate of 53.16 (95% confidence interval 51.84-54.52) per 10,000 h of play. There were no statistically significant differences in injury rates based on age, format, era of play, country, player type and injury definitions. Bowling biomechanics and workload were identified as the major risk factors for bowling injuries. CONCLUSIONS: This review shows that injury rates in junior and amateur cricket are higher than the injury rates of comparable cohorts playing other popular non contact or quasi-contact team sports. There is not enough evidence to conclude that T20 cricket has increased injury rates. PMID- 30019115 TI - [High-resolution 3D mapping : Opportunities and limitations of the RhythmiaTM mapping system]. AB - Three-dimensional mapping systems are used for the characterization and treatment of complex arrhythmias, such as atrial reentrant tachycardias, atrial fibrillation, or ventricular tachycardia. The RhythmiaTM mapping system (Boston Scientific, Natick, MA, USA) belongs to a novel generation of mapping systems that are able to rapidly create high-density and high-resolution three dimensional maps in an automated manner. Mapping is performed with a magnetic- and impedance-based tracked bidirectional deflectable 64-pole basket catheter (IntellaMap OrionTM, Boston Scientific). Based on previous studies, the system is effective and safe for the treatment of complex atrial and ventricular arrhythmias. PMID- 30019116 TI - Introduction to the Special Issue of the Journal of Urban Health on Incarceration and Health. PMID- 30019118 TI - Medical Care Costs Associated with Genital Warts for Commercially Insured US Patients. AB - INTRODUCTION: Genital warts are caused by infection with human papillomavirus (HPV) and are associated with significant morbidity. Primary prevention of genital warts is possible through HPV vaccination, but vaccination rates remain low in the USA. When deciding to implement HPV vaccination programs, public health officials and policy makers rely on cost-effectiveness studies that accurately reflect costs associated with morbidity and mortality. However, previous information on the cost of treating genital warts was outdated. OBJECTIVES: We estimated the mean direct medical care costs associated with genital warts in the USA. METHODS: This was a retrospective case-control study of patients diagnosed with genital warts and matched controls. We used commercial healthcare claims data from 2011 through 2014 to estimate total 1- and 2-year costs from date of diagnosis. We used a generalized linear model to identify factors associated with monthly costs. RESULTS: We identified 34,686 eligible cases of genital warts during the period 2011-2014. The first 2-year mean direct medical cost differences between cases and controls were US$6737 for the USA. Costs were significantly higher in the first 3 months following diagnosis and were higher among older individuals, women, those with co-morbidities or psychiatric illnesses, and those located in the south and southwest USA. CONCLUSIONS: The mean direct cost of treating genital warts is approximately US$6700 in the first 2 years after diagnosis in the USA. These data can assist policy makers in decisions with respect to allocation of resources to implement HPV vaccine programs. PMID- 30019120 TI - Correction to: Cerebral oximetry for cardiac surgery: a preoperative comparison of device characteristics and pitfalls in interpretation. AB - In the original publication, the length unit of the SCD in Table 1 and Fig. 2 has been incorrectly published as cm. The correct length unit is mm. PMID- 30019119 TI - Self-assembled nanoparticles for cellular delivery of peptide nucleic acid using amphiphilic N,N,N-trimethyl-O-alkyl chitosan derivatives. AB - Peptide nucleic acid (PNA) holds enormous potentials as antisense/antigenic drug due to its specific binding ability and biostability with DNA or RNA. However, the poor cellular delivery is the key obstacle in development of PNA therapy. To overcome this difficulty, we developed self-assembled nanoparticles (NPs) for delivery of PNA to living cells using amphiphilic CS derivatives. A series of N,N,N-trimethyl-O-alkyl chitosans (TMACs) with different lengths of alkyl chains were synthesized. The structures of these synthesized chemicals were characterized with FT-IR and 1H NMR. We found that the TMACs were all able to self-assemble in aqueous condition to form nano-size NPs. These nano-size NPs are spherical shape with a size range of around 100 nm and a zeta potential above +30 mV. PNA was easily encapsulated into chitosan derivative NPs by an ultrasonic method with entrapment efficiency up to 75%. The PNA-loaded TMAC NPs released the drug in a sustained manner in PBS (pH 7.4) at 37 degrees C. N,N,N-trimethyl-O cetyl chitosan (TMCC) showed the best in vitro hemocompatibility and cell viability. These TMCC based NPs were able to dramatically increase the cellular uptake of PNA, specifically, 66-fold higher compared to without using these nanoparticles. The results suggest that the designed TMCC NPs might be a promising solution for improving cellular delivery of PNA. PMID- 30019121 TI - Nuclear Localization of Robo is Associated with Better Survival in Bladder Cancer. AB - The Slit-Robo pathway has shown to be altered in several malignant diseases. However, its role in bladder cancer is poorly understood. Therefore, we aimed to assess the tissue expression of Robo1 and Robo4 as well as their ligand Slit2 in different stages of bladder cancer to explore possible changes of Slit-Robo signalling during the progression of bladder cancer. Robo1, Robo4 and Slit2 gene expressions were analyzed in 92 frozen bladder cancer tissue samples by using reverse transcription quantitative real-time PCR. Immunohistochemical analyses were performed on 149 formalin-fixed and paraffin-embedded bladder cancer tissue samples. Results were correlated with the clinical and follow-up data by performing both univariable and multivariable analyses. Robo1 and Robo4 nuclear staining intensitiy was significantly higher in low stage and low grade bladder cancer. Elevated Robo1 nuclear staining was associated with better disease specific survival (DSS) (p = 0.045). Similarly, stronger Robo4 nuclear staining tended to be associated with longer DSS (p = 0.061). We found higher Robo1 and Slit2 gene expression levels in advanced stages of bladder cancer (p = 0.007 and p < 0.001). High Slit2 gene expression was correlated with significantly shorter DSS (p < 0.005), while Robo1 and Robo4 gene expressions were not associated with patients' prognosis. Our results demonstrate that the nuclear expression of Robo1 and Robo4 is associated with a favourable prognosis suggesting that its translocation into the nucleus represent a posttranslational regulation process which may exhibit an antitumor effect in bladder cancer. PMID- 30019117 TI - The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease. AB - With the recent advance in genome-wide association studies (GWAS), disease associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 * 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles. PMID- 30019123 TI - Correction to: Left atrial myocardial dysfunction after chronic abuse of anabolic androgenic steroids: a speckle tracking echocardiography analysis. AB - In the original publication of the article, the seventh author name "Giampaolo Tocci" has been misspelt. The correct name is given in this. PMID- 30019122 TI - Relationship between cardiovascular risk factors and myocardial strain values of both ventricles in asymptomatic Asian subjects: measurement using cardiovascular magnetic resonance tissue tracking. AB - The purpose of this study was to evaluate the association between myocardial deformation parameters and cardiovascular risk factors in asymptomatic Asian subjects and to provide reproducibility for deformation parameters of both ventricles using cardiovascular magnetic resonance (CMR) tissue tracking (TT). We enrolled 129 asymptomatic healthy adults who underwent CMR and assessed the cardiovascular risk factors in all individuals. All subjects had normal left ventricular systolic function. Commercial software was used to derive myocardial deformation parameters of both ventricles from short-axis cine images and long axis cine images with two-, three-, and four-chamber views. Linear regression analysis was performed for evaluation of the association with all strain parameters for each age and systolic blood pressure. Intra class correlation was also calculated in CMR-TT to determine interobserver variability. In all 129 patients, the strain values for the left ventricle (LV) were 48.90 +/- 9.05 for radial strain (RS, %), - 22.30 +/- 2.33 for circumferential strain (CS, %), and - 19.76 +/- 2.22 for longitudinal strain (LS, %). The strain values for the right ventricle (RV) were 18.63 +/- 6.52 for RS, - 10.60 +/- 3.33 for CS, and - 25.06 +/- 3.01 for LS. In all 129 patients (male, n = 105), all strain parameters of LV and RV was significantly different among males and females (all p values < 0.05). The LV strain parameters were significantly associated with age by univariate linear regression analysis: RS, beta = 0.219, p = 0.002; CS, beta = - 0.668, p = 0.014 (except for LS, beta = - 0.104, p = 0.720). With regard to hypertension, diabetes mellitus and dyslipidemia, the values of all strain parameters in both ventricles were not significantly different between individuals with or without risk factors. Inter-observer agreement for three strain variables of LV and RV was 0.915 and 0.715 by iota index, and intra-observer agreement of LV and RV was 0.955 and 0.959 by iota index. The strain parameters by CMR-TT showed an association with age and significant difference in gender, on the other hands, not significantly different between with or without of the other conventional cardiovascular risk factors. The reproducibility of three LV strain parameters was higher than that of the respective RV strain parameters. PMID- 30019124 TI - The Effects of a Primary Care Transformation Initiative on Primary Care Physician Burnout and Workplace Experience. AB - BACKGROUND: Physician burnout is associated with deleterious effects for physicians and their patients and might be exacerbated by practice transformation. OBJECTIVE: Assess the effect of the Comprehensive Primary Care (CPC) initiative on primary care physician experience. DESIGN: Prospective cohort study conducted with about 500 CPC and 900 matched comparison practices. Mail surveys of primary care physicians, selected using cross-sectional stratified random selection 11 months into CPC, and a longitudinal design with sample replacement 44 months into CPC. PARTICIPANTS: Primary care physicians in study practices. INTERVENTION: A multipayer primary care transformation initiative (October 2012-December 2016) that required care delivery changes and provided enhanced payment, data feedback, and learning support. MAIN MEASURES: Burnout, control over work, job satisfaction, likelihood of leaving current practice within 2 years. KEY RESULTS: More than 1000 physicians responded (over 630 of these in CPC practices) in each round (response rates 70-81%, depending on round and research group). Physician experience outcomes were similar for physicians in CPC and comparison practices. About one third of physician respondents in CPC and comparison practices reported high levels of burnout in each round (32 and 29% in 2013 [P = 0.59], and 34 and 36% in 2016 [P = 0.63]). Physicians in CPC and comparison practices reported some to moderate control over work, with an average score from 0.50 to 0.55 out of 1 in 2013 and 2016 (CPC-comparison differences of 0.04 in 2013 [95% CI - 0.08-0.00, P = 0.07], and - 0.03 in 2016 [95% CI - 0.03 0.02, P = 0.19]). In 2016, roughly three quarters of CPC and comparison physicians were satisfied with their current job (77 and 74%, P = 0.77) and about 15% planned to leave their practice within 2 years (14 and 15%, P = 0.17). CONCLUSIONS: Despite requiring substantial practice transformation, CPC did not affect physician experience. Research should track effects of other transformation initiatives on physicians and test new ways to address burnout. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02320591. PMID- 30019125 TI - Clinical and radiographic outcomes of laser pulpotomy in vital primary teeth: a systematic review and meta-analysis. AB - AIM: This was to compare clinical and radiographic success rates of laser pulpotomy with those of other pulpotomy techniques in primary teeth. METHODS: PubMed, SCOPUS, EMBASE, Cochrane and ISI Web of Knowledge databases were searched electronically without time or language limitations. Clinical trials in which laser pulpotomy was compared with at least one other pulpotomy modality in primary teeth were selected. The bibliographic reference lists of eligible articles were also hand-searched. Odds ratios, risk differences and 95% confidence intervals were calculated with the aid of Comprehensive Meta-Analysis software (Version 2.2.050, Biostat, Englewood, NJ, USA). The methodological quality of articles included in the meta-analysis was determined using the Jadad scale. RESULTS: Twelve pulpotomy studies were selected for systematic review and underwent data extraction. Of these studies, statistical analysis was conducted on 11. All clinical trials had low to moderate risks of methodological bias. The meta-analysis showed no significant differences in clinical and radiographic pulpotomy outcomes with laser compared with other techniques (p > 0.05). Likewise, no differences were found in the outcomes at 1, 3, 6, 9, 12 or >= 18 months (all p > 0.05). CONCLUSIONS: For primary molar pulpotomy, the laser technique showed comparable clinical and radiographic results to other conventional pulpotomy medicaments, including formocresol and mineral trioxide aggregate. PMID- 30019126 TI - The patellar pubic percussion test: a simple bedside tool for suspected occult hip fractures. AB - PURPOSE: Patellar finger tapping produces a typical sound that can be detected by a stethoscope positioned on the pubic bone (patellar pubic percussion test (PPPT)). Characteristics of this sound are determined by continuity of bone between patella and pelvis. We hypothesized that a PPPT was able to detect overt hip fractures and occult hip fractures that may not be determined by a standard radiological examination. METHODS: Two independent observers performed a PPPT in patients with a suspected hip or pelvic fracture, just before a conventional radiograph (X-ray) was performed. The PPPT test was scored as negative (similar to contralateral side) or positive (different). Patients with a positive PPPT but with a negative X-ray underwent an additional CT scan. RESULTS: One hundred and ninety-one patients with suspected hip or pelvic fracture were included. A total of 161 patients (84%) were diagnosed with a fracture (hip, n = 142; pelvic, n = 19). An 85% sensitivity, a 70% specificity, a 0.94 positive predictive value, and a 0.47 negative predictive value of the PTTT were calculated. The inter-observer reliability (kappa) was 0.7. Eleven CT scans as indicated by a mismatch between PPPT (positive) and X-ray (no fracture) identified eight fractures (73%). A multivariate analysis demonstrated that a painful passive movement and the PPPT predicted a hip fracture. CONCLUSION: The PPPT is a simple bedside diagnostic tool that is sensitive in detecting clinically straight forward hip fractures as well as occult hip fractures. The PPPT can support decision-making for additional radiological examinations in case of potential occult pelvis or hip fractures. PMID- 30019127 TI - Safety and efficacy of elbasvir and grazoprevir in Japanese hemodialysis patients with genotype 1b hepatitis C virus infection. AB - BACKGROUND: The prevalence of hepatitis C virus (HCV) infection in hemodialysis patients is high and results in a poor prognosis. Thus, safer and more effective treatment regimens are required. In this prospective multicenter study, we investigated the efficacy and safety of the novel HCV-NS5A-inhibitor, elbasvir, and protease inhibitor, grazoprevir in Japanese hemodialysis patients with genotype 1b HCV infection. METHODS: This study is registered at the UMIN Clinical Trials Registry as UMIN00002578. A total of 23 Japanese dialysis patients with genotype 1b HCV infection who were treated with elbasvir and grazoprevir between January 2017 and March 2018 and followed for more than 12 weeks after treatment completion were included. We evaluated the sustained virologic response at 12 weeks after treatment completion (SVR12) and safety during treatment. RESULTS: Of the 23 patients, 7 had advanced liver fibrosis and 2 had a signature resistance associated variant of NS5A (NS5A RAVs)-L31M/V or Y93H at baseline. All patients completed therapy, and 96.7% (22/23) of the patients achieved SVR12. All patients with advanced liver fibrosis and signature NS5A RAVs at baseline achieved SVR12 with a high safety profile. No patient experienced lethal or severe adverse events during therapy, and the most common adverse event was anemia. One patient, who was a non-responder to this therapy, had a history of failure with daclatasvir and asunaprevir therapies and had NS5A RAVs of A92K at baseline, but not signature NS5A RAVs. CONCLUSIONS: Grazoprevir and elbasvir combination is highly effective and safe for hemodialysis patients with genotype 1b HCV infection. PMID- 30019128 TI - PD-1 genotype of the donor is associated with acute graft-versus-host disease after HLA-identical sibling donor stem cell transplantation. AB - Programmed death 1 (PD-1) activation triggers an immune checkpoint resulting in inhibition of T cells that leads to peripheral tolerance. Some PD-1 polymorphisms have been described and associated with the development of autoimmune diseases or cancer predisposition, but there are few data concerning the relevance of such polymorphisms on the clinical outcome after allogeneic hematopoietic stem cell transplant (alloHSCT). We analyzed the distribution of the SNPs PD-1.1G/A (rs36084323) and PD-1.3G/A (rs11568821) genotypes of the donor in a cohort of 1485 alloHSCT from HLA-identical sibling donors. We found an increased risk of grades II to IV graft-versus-host disease (GvHD) in patients receiving grafts from donors homozygous for the G allele at the rs36084323 SNP (P = 0.033; hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.1 to 4.8) and also from donors homozygous for the A allele at the rs11568821 position (P < 0.001; HR 4.5, 95%CI 2.0 to 10.1). In contrast, the PD-1 genotype of the donor did not show association with overall survival or relapse incidence. These results suggest that the PD-1 genotype of the donor plays an important role for the development of acute GvHD after alloHSCT from HLA-identical sibling donors. PMID- 30019130 TI - Correction to: Serum fatty acid-binding protein 4 (FABP4) as a novel biomarker to predict gestational diabetes mellitus. AB - The title "Plasma fatty acid-binding protein 4 (FABP4) as a novel biomarker to predict gestational diabetes mellitus" should be replaced by "Serum fatty acid binding protein 4 (FABP4) as a novel biomarker to predict gestational diabetes mellitus". PMID- 30019129 TI - Congenital diaphragmatic hernia: a scientometric analysis of the global research activity and collaborative networks. AB - Despite a growing interest to clinicians and scientists, there is no comprehensive study that examines the global research activity on congenital diaphragmatic hernia (CDH). A search strategy for the Web of ScienceTM database was designed to identify scientific CDH publications. Research output of countries, institutions, individual authors, and collaborative networks was analyzed. Semi-qualitative research measures including citation rate and h-index were assessed. Choropleth mapping and network diagrams were employed to visualize results. A total of 3669 publications were found, originating from 76 countries. The largest number was published by the USA (n = 1250), the UK (n = 279), and Canada (n = 215). The USA combined the highest number of cooperation articles (n = 152), followed by Belgium (n = 115) and the Netherlands (n = 93). The most productive collaborative networks were established between UK/Belgium (n = 53), Belgium/Spain (n = 47), and UK/Spain (n = 34). Canadian publications received the highest average citation rate (22.8), whereas the USA had the highest country specific h-index (72). Eighty-five (2.3%) articles were published by international multicenter consortiums and national research networks. The most productive institutions and authors were based in North America and Europe. Over the past decades, CDH research has increasingly become multidisciplinary and numerous innovative therapeutic strategies were introduced. CDH-related research has constantly been progressing, involving today many disciplines with main research endeavors concentrating in a few high-income countries. Recent advances in prenatal interventions and regenerative medicine therapy hold the promise of improving CDH outcome in the 21st century. International collaborations and translational research should be strengthened to allow further evolution in this field. PMID- 30019131 TI - Contact-Dependent Growth Inhibition Proteins in Acinetobacter baylyi ADP1. AB - Bacterial contact-dependent growth inhibition (CDI) systems are two-partner secretion systems in which toxic CdiA proteins are exported on the outer membrane by cognate transporter CdiB proteins. Upon binding to specific receptors, the C terminal toxic (CT) domain, detached from CdiA, is delivered to neighbouring cells. Contacts inhibit the growth of not-self-bacteria, lacking immunity proteins co-expressed with CdiA, but promote cooperative behaviours in "self" bacteria, favouring the formation of biofilm structures. The Acinetobacter baylyi ADP1 strain features two CdiA, which differ significantly in size and have different CT domains. Homologous proteins sharing the same CT domains have been identified in A. baumannii. The growth inhibition property of the two A. baylyi CdiA proteins was supported by competition assays between wild-type cells and mutants lacking immunity genes. However, neither protein plays a role in biofilm formation or adherence to epithelial cells, as proved by assays carried out with knockout mutants. Inhibitory and stimulatory properties may be similarly uncoupled in A. baumannii proteins. PMID- 30019132 TI - Investigation on spatiotemporal distribution of aerosol optical properties over two oceanic regions surrounding Indian subcontinent during summer monsoon season. AB - Columnar spectral aerosol optical depths (AODs) and total suspended particulate matter (TSPM) concentrations were collected on board the Oceanographic Research Vessel (ORV) of Sagar Kanya (SK) during 7-21 June 2014 (SK-313) and 31 July-14 August 2015 (SK-323) over the Arabian Sea (AS) and Bay of Bengal (BoB), respectively, for the two successive years during summer monsoon season. AOD measured at 500 nm (AOD500) varied significantly from 0.08 to 0.66 (0.07 to 0.60), with a mean of 0.48 +/- 0.13 (0.34 +/- 0.13) over the BoB (AS) during SK 313 (SK-323). It simply implies that aerosol load was higher over BoB, not variability as the standard deviations of AOD over both oceans are identical (0.13). Daily AOD500 ranged between 0.15 and 0.60 accounted for 70-75% of the total occurrences over two oceanic regions. Mean Angstrom exponent (alpha or alpha) and Angstrom turbidity coefficient (beta or beta) were found to be 0.43 +/ 0.17 (0.39 +/- 0.19) and 0.37 +/- 0.15 (0.27 +/- 0.13), respectively, which are higher over the AS during SK-323 (SK-313) that indicate predominance of coarse relative to fine-mode particles. On the other hand, the spectral curvature and second derivative of alpha (alpha') also showed significant contribution of coarse-mode particles over fine during the two campaigns. Further, column aerosol size distribution (CSD) derived from the King's inversion also exhibited bimodal distribution with a predominant peak observed in the coarse mode (~1.0 MUm) compared to the fine mode at a geometric mean radius at ~0.1 MUm over two oceans. The observed data showed that the two marine regions are significantly influenced by various types of aerosols with a predominance of mixed type (MT) of aerosols. From the morphological study, it is inferred that the particles are a flake, spherical, irregular, and in flower and aggregated shapes conducted for the TSPM samples collected during SK-323 over the AS. Finally, the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model is used to study the impact of long-distance transported aerosols and identify their sources. PMID- 30019133 TI - Performance of ceria/iron oxide nano-composites based on chitosan as an effective adsorbent for removal of Cr(VI) and Co(II) ions from aqueous systems. AB - A novel chitosan/ceria/iron oxide (CS/ceria/Fe3O4) nano-composite adsorbent was synthesized for removal of Cr(VI) and Co(II) ions from aqueous systems in a batch system. The adsorbents were characterized by field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), thermal gravimetric analysis (TGA), and Brunauer- Emmett-Teller (BET) analyses. The behavior of swelling kinetics was also studied. The effect of several adsorption parameters including CeO2 and Fe3O4 contents, initial pH, contact time, initial Cr(VI) and Co(II) concentration, and temperature on the adsorption capacity was studied. The double exponential model revealed a better fit with the kinetic data of Cr(VI) and Co(II) ions. The Cr(VI) and Co(II) adsorption process well fitted the Langmuir model. The maximum adsorption capacities estimated from Langmuir isotherm model were 315.4 and 260.6 mg/g for Cr(VI) and Co(II) ions, respectively. Also, thermodynamic parameters were used to distinguish the nature of Cr(VI) and Co(II) adsorption. The reusability of CS/ceria/Fe3O4 nano-composite was evaluated with stripping agents of 0.1 M NaOH and 0.1 M HNO3. Finally, the evaluation of Cr(VI)-Co(II) coexisting system confirmed that the presence of Co(II) ions played an inhibitor role on the Cr(VI) adsorption. PMID- 30019134 TI - Surfactants in the sea surface microlayer, subsurface water and fine marine aerosols in different background coastal areas. AB - This study aims to determine the concentrations of surfactants in the surface microlayer (SML), subsurface water (SSW) and fine mode aerosol (diameter size < 1.5 MUm) at different coastal stations in Peninsular Malaysia. The concentrations of anionic and cationic surfactants were determined through colorimetric methods as methylene blue active substances (MBAS) and disulphine blue active substances (DBAS), respectively. Water-soluble ions, for the determination of fine mode aerosol sources, were determined using ion chromatography (IC) for anions (SO42-, NO3-, Cl- and F-) and cations (Na+, K+, Ca2+ and Mg2+). Principal component analysis (PCA), combined with multiple linear regression (MLR), was used to identify the possible sources of surfactants in fine aerosol. The results showed the concentrations of surfactants as MBAS and DBAS in the SML ranged between 0.23 +/- 0.03 and 0.35 +/- 0.01 MUmol L-1 and between 0.21 +/- 0.02 and 0.29 +/- 0.01 MUmol L-1, respectively. The enrichment factors (Efs) ratios between MBAS and DBAS in the SML and SSW ranged between 1.04 +/- 0.01 and 1.32 +/- 0.04, respectively. The station that is located near to tourism and industrial activities recorded the highest concentrations of surfactants in SML and SSW. The concentrations of surfactants in fine aerosol ranged between 62.29 and 106.57 pmol m-3. The three possible sources of fine aerosol during the northeast monsoon were aged sea spray/biomass burning (which accounted for 69% of the atmospheric aerosol), nitrate/mineral dust (23%) and sulphate/fresh sea salt (8%). During the southwest monsoon, the three main sources of atmospheric aerosol were biomass burning (71%), secondary inorganic aerosol (23%) and sea spray (6%). This study suggests anthropogenic sources are main contributors to the concentrations of surfactants in SML, SSW and fine aerosols. PMID- 30019135 TI - Ecological and human health risk assessments in the context of soil heavy metal pollution in a typical industrial area of Shanghai, China. AB - The purpose of this study was to identify the concentrations, sources, and potential ecological and health risks of heavy metals in soils from a typical industrial area in Shanghai, China. A total of 28 surface soil samples were collected and analyzed for As, Cd, Cr, Cu, Pb, Ni, Zn, and Hg from the BAO steel industry in June and July 2016. Classic multivariate statistical and geostatistical analysis methods were used to detect the sources of heavy metals, and the ecological risk index (RI) and hazard index (HI) were calculated to assess the potential ecological and health risks. The results showed significant pollution levels, which were derived from the industrial production process and closely related to the spatial layout of the functional areas of the industry. The ecological risk assessment indicated that a very high concentration zone with values ranging from 2045 to 3417 mg kg-1 represented considerable ecological risk in the range of 300 to 600. The main dominant factor affecting the ecological risk is toxicity rather than concentration. The health risk assessment indicated that noncarcinogenic risk was mainly caused by Cr, and the average HI value for adults was 6.48, while it was 39.01 for children. Thus, children face higher threats to heavy metals in soils. The average carcinogenic risk values for Ni, Cr, Cd, and As were 7.97E-09, 5.2E-07, 2.1E-10, and 2.1E-09, respectively, all of which were below the threshold values (1.0E - 04). These results provide basic information for the control and environmental management of heavy metal pollution in steel industrial regions. PMID- 30019136 TI - Impact of desertification and land degradation on Colombian children. AB - OBJECTIVES: Desertification affected more than 24% of Colombia's land mass in 2012. The study aims to establish the singular impact of desertification on under five mortality in Colombia. METHODS: Descriptive statistics and multivariate logit regressions are applied to the population of live births and under-five deaths in Colombia 2008-2011. RESULTS: Children have a higher probability to die in rural communities and among mothers with low education who also have inferior health insurance. Controlling for those, desertification below about 50% of the land, lowers child mortality and increases it after that percentage. The impact of extraction of hydrocarbons is 12.45, metals 5.73 and others 4.91 times higher in municipalities with more than 50% of desertification territory. Rural areas with high desertification have 2.25 times higher risk of mortality due to malnutrition. CONCLUSIONS: In the short term, when mines have less or no effect on desertification, living conditions may improve and reduce child mortality. In the long term, however, as desertification intensifies affecting the ecosystem, child mortality increases. More research is needed, and policy formulated accordingly. PMID- 30019137 TI - Aptamer based voltammetric biosensor for Mycobacterium tuberculosis antigen ESAT 6 using a nanohybrid material composed of reduced graphene oxide and a metal organic framework. AB - The 6-kDa early secretory antigenic target referred to as ESAT-6 is a virulence factor secreted by Mycobacterium tuberculosis (MTB). This work describes a voltammetric aptasensor for ultrasensitive detection of ESAT-6. Reduced graphene oxide doped with metal-organic framework (MOF-rGO) was deposited on a glassy carbon electrode (GCE). This increases the immobilization of electroactive Toluidine Blue (TB) and facilitates the electron transfer from TB to the modified GCE. Platinum/gold core/shell (Pt@Au) nanoparticles were used to assemble thiolated ESAT-6 binding aptamer (EBA) on a modified electrode and to further amplify the response to TB. The modified GCE, typically operated at -0.36 V (vs. SCE), has a linear response in 1.0 * 10-4 to 2.0 * 102 ng?mL-1 ESAT-6 concentration range, and the limit of detection (LOD) for ESAT-6 is as low as 3.3 * 10-5 ng?mL-1. It exhibits satisfactory specificity and reproducibility when analyzing spiked human serum. Graphical abstract Schematic presentation of a voltammetric aptasensor for Mycobacterium tuberculosis antigen ESAT-6 using a glassy carbon electrode modified with reduced graphene oxide (rGO) and a metal organic framework (MOF). The limit of detection for ESAT-6 is as low as 3.3 * 10 5 ng/mL. PMID- 30019138 TI - The Impact of Patent Expiry on Drug Prices: A Systematic Literature Review. AB - OBJECTIVE: The aim of this study was to evaluate the impact of patent expiry on drug prices by means of a systematic literature review. METHODS: A systematic literature search was performed in PubMed to identify all published literature on the impact of patent expiration on drug prices. Additional literature was identified using a less distinct syntax in Google Scholar and EconLit. Data extraction followed a standardized assessment form containing the domains study type, study aim, reported outcomes, number of drugs and drug classes assessed, and originators or generics assessed. RESULTS: The 16 identified studies that assessed impact of patent expiry on drug prices showed that price developments after patent expiration varied between countries. The included studies assessed price developments for the USA, Canada, Australia, the UK, the Netherlands, Germany and France, Spain, Italy, Norway, Sweden and Denmark. The number of drugs included within different studies ranged between 1 and 219. The identified studies indicated that drug prices decreased significantly after patent expiry with drug price ratios ranging from 6.6 to 66% 1-5 years after patent expiry. CONCLUSION: Drug prices decrease significantly after patent expiry. The extent of this price reduction varied greatly between products and countries. For this reason, country-specific analyses on price developments after patent expiry should be used when these are considered in decision making. Future research should be dedicated to gathering more country-specific data to reduce the uncertainty with regard to price developments. PMID- 30019139 TI - Age and sex effects on the relationship between body composition and hip geometric structure in males and females from East China. AB - : The study finds bone mineral density is the principal determinant of hip geometry and lean mass is a better determinant than fat mass in Chinese. Moreover, the impact of fat on skeleton differs with age, with a negative effect in young people but a more positive effect in elderly. PURPOSE: The aim of this study was to examine whether the correlation between body composition including bone mineral density (BMD), lean mass (LM) and fat mass (FM), and hip geometric structure change with aging in males and females from East China. METHODS: It was a cross-section study. A total of 1168 healthy male and 1066 healthy females in Shanghai were divided into six groups based on their age and sex. All participants were evaluated by assessing the BMD of lumber spine and proximal hip, total LM, total FM, and geometric parameters of the hip such as the cross sectional area (CSA), average cortical thickness (ACT), and the buckling ratio (BR) at the narrow neck (NN), the intertrochanter (IT), and the shaft (FS). RESULTS: Among the three body composition, the correlation between hip BMD and hip geometric structure was strongest. LM showed significantly positive correlations with CSA. FM showed negative or little positive correlation with hip geometry in the young group. However, the degree of the contribution of FM to hip geometric structure became substantially positive with aging. Limb LM produced the largest positive contribution to CSA and ACT at all three regions in young males. However, in older males the trunk LM produced the largest positive contribution to CSA and ACT. CONCLUSIONS: Among all body composition parameters, hip BMD showed the largest correlation with hip geometric structure, with LM showing the second largest. The impact of FM and LM on hip geometry changed with aging and with different distributions of lean mass and fat mass. PMID- 30019140 TI - The role of wall shear stress in the parent artery as an independent variable in the formation status of anterior communicating artery aneurysms. AB - OBJECTIVES: The study aimed to determine which hemodynamic parameters independently characterize anterior communicating artery (AcomA) aneurysm formation and explore the threshold of wall shear stress (WSS) of the parent artery to better illustrate the correlation between the magnitude of WSS and AcomA aneurysm formation. METHODS: Eighty-one patients with AcomA aneurysms and 118 patients without intracranial aneurysms (control population), as confirmed by digital subtraction angiography (DSA) from January 2014 to May 2017, were included in this cross-sectional study. Three-dimensional-DSA was performed to evaluate the morphologic characteristics of AcomA aneurysms. Local hemodynamic parameters were obtained using transcranial color-coded duplex (TCCD). Multivariate logistic regression and a two-piecewise linear regression model were used to determine which hemodynamic parameters are independent predictors of AcomA aneurysm formation and identify the threshold effect of WSS of the parent artery with respect to AcomA aneurysm formation. RESULTS: Univariate analyses showed that the WSS (p < 0.0001), angle between the A1 and A2 segments of the anterior cerebral artery (ACA) (p < 0.001), hypertension (grade II) (p = 0.007), fasting blood glucose (FBG; > 6.0 mmol/L) (p = 0.005), and dominant A1 (p < 0.001) were the significant parameters. Multivariate analyses showed a significant association between WSS of the parent artery and AcomA aneurysm formation (p = 0.0001). WSS of the parent artery (7.8-12.3 dyne/cm2) had a significant association between WSS and aneurysm formation (HR 2.0, 95% CI 1.3 2.8, p < 0.001). CONCLUSIONS: WSS ranging between 7.8 and 12.3 dyne/cm2 independently characterizes AcomA aneurysm formation. With each additional unit of WSS, there was a one-fold increase in the risk of AcomA aneurysm formation. KEY POINTS: * Multivariate analyses and a two-piecewise linear regression model were used to evaluate the risk factors for AcomA aneurysm formation and the threshold effect of WSS on AcomA aneurysm formation. * WSS ranging between 7.8 and 12.3 dyne/cm 2 was shown to be a reliable hemodynamic parameter in the formation of AcomA aneurysms. The probability of AcomA aneurysm formation increased one-fold for each additional unit of WSS. * An ultrasound-based TCCD technique is a simple and accessible noninvasive method for detecting WSS in vivo; thus, it can be applied as a screening tool for evaluating the probability of aneurysm formation in primary care facilities and community hospitals because of the relatively low resource intensity. PMID- 30019141 TI - Pre-procedural CT angiography inferior vena cava measurements: a predictor of mortality in patients undergoing transcatheter aortic valve implantation. AB - OBJECTIVES: To assess the value of pre-procedural computed tomography angiography (CTA) measurements of the suprahepatic inferior vena cava (IVC) to detect elevated central venous pressure (CVP) assessed by right heart catheterisation (RHC), and to predict post-procedural 1-year mortality in a cohort of patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: We retrospectively evaluated 408 consecutive patients undergoing CTA before TAVI between January 2011 and December 2014. Two hundred and five patients were included in the RHC cohort, who underwent RHC and CTA within <=1 day prior to TAVI. Two hundred and three patients not fulfilling this requirement were included in the validation cohort. Measurements of the IVC were performed between diaphragm and right atrium on axial slices. Receiver operating characteristic (ROC) analyses, Kaplan-Meier analyses and Cox regression analyses were performed. RESULTS: In the RHC cohort, ROC curve analyses for IVC area measurements indicated an AUC of 0.77 (p < 0.001) to detect CVP >=10mmHg and an area under the ROC curve (AUC) of 0.72 (p < 0.001) to predict 1-year mortality. An IVC area cut off of >=665 mm2 predicted 1-year mortality with a specificity of 84% and a sensitivity of 63%. Kaplan-Meier analysis showed that patients with an IVC area >=665 mm2 had a significantly higher post-procedural 1-year mortality (38% versus 7%, log-rank p < 0.001) with a hazard ratio of 5.5 (95% CI, 2.2-13.6; p < 0.001). Applying this cut-off value to the validation cohort confirmed a significantly higher 1-year mortality after TAVI (34% versus 11%; log-rank p = 0.004) for patients with an IVC area >=665 mm2. CONCLUSIONS: Pre-procedural enlargement of the suprahepatic IVC is a predictor of post-procedural 1-year mortality in patients evaluated for TAVI. KEY POINTS: * IVC measurements are moderate predictors of an elevated CVP in TAVI patients. * Pre-procedural IVC enlargement is a predictor of 1-year mortality after TAVI. * IVC enlargement is associated with right heart dysfunction in TAVI patients. PMID- 30019142 TI - Dose reference levels and clinical determinants in stroke neuroradiology interventions. AB - OBJECTIVES: To establish dose reference levels (RLs) for stroke interventions while carefully analysing the impact of clinical and technical parameters on patient exposure. METHODS: The study retrospectively analysed data from 377 stroke patients prospectively collected between 15 October 2015 and 30 March 2017 at a single, level-3 stroke centre equipped with Philips Allura Clarity systems. Local dose RLs were first derived as the 75th percentile of the dose area product (DAP), cumulative air kerma (Ka,r), fluoroscopy time (FT) and the number of images (NI). Univariate and multivariate negative binomial regressions were considered for the statistical analysis to investigate the dose variability with clinical and technical parameters such as patient's age and sex, occlusion removal technique, number of passages, single-plane or biplane equipment, etc. RESULTS: Local stroke dose RLs were derived in terms of total DAP (162 Gy cm2), Ka,r (854 mGy), FT (42 min) and NI (559). Gender (relative dose multiplier (RDM) 1.31; 95% CI 1.12-1.45), number of passages (RDM 1.22 per passage; 95% CI 1.10 1.22) and procedure success (RDM 0.52, 95% CI 0.55-0.80) proved to be key parameters affecting patient dose. Meanwhile the statistical analysis did not find any difference in relative dose received by patients owing to age, baseline NIHSS score, occlusion removal technique, posterior circulation, support of an anaesthesiologist or use of biplane equipment. CONCLUSIONS: Stroke dose RLs introduced in this work promote the optimisation of patient doses. Male gender, number of passages and success of recanalisation are independent key parameters affecting patient dose. KEY POINTS: * Stroke dose RLs derived in terms of total DAP (162 Gy cm 2 ), K a,r (854 mGy), FT (42 min) and NI (559) will help optimise the radiation safety of patients treated with mechanical thrombectomy. * Male gender (relative dose multiplier 1.31; 95% CI 1.12-1.45), number of passages (RDM 1.22 per passage; 95% CI 1.10-1.22) and success of recanalisation TICI score > 2b (RDM 0.52, 95% CI 0.55-0.80) are independent key parameters affecting patient dose. * Stent retriever or aspiration technique showed no significant difference in terms of the dose delivered to the patient; neither technique should be favoured for dosimetric reasons provided that there is no difference regarding clinical outcomes. PMID- 30019143 TI - Diffusion and perfusion MRI quantification in ileal Crohn's disease. AB - OBJECTIVES: To quantify intravoxel incoherent motion (IVIM)-DWI and dynamic contrast-enhanced (DCE)-MRI parameters in normal and abnormal ileal segments in Crohn's disease (CD) patients and to assess the association of these parameters with clinical and MRI-based measurements of CD activity. METHODS: In this prospective study, 27 CD patients (M/F 18/9, mean age 42 years) underwent MR enterography, including IVIM-DWI and DCE-MRI. IVIM-DWI and DCE-MRI parameters were quantified in normal and abnormal small bowel segments, the latter identified by the presence of inflammatory changes. MRI parameter differences between normal and abnormal bowel were tested using Wilcoxon signed-rank tests. IVIM-DWI and DCE-MRI parameters were correlated with clinical data (C-reactive protein, Harvey-Bradshaw Index), conventional MRI parameters (wall thickness, length of involvement) and MRI activity scores (MaRIA, Clermont). Diagnostic performance of (combined) parameters for differentiation between normal and abnormal bowel was determined using ROC analysis. RESULTS: The DCE-MRI parameters peak concentration Cpeak, upslope, area-under-the-curve at 60s (AUC60), Ktrans and ve were significantly increased (p<0.023), while IVIM-DWI parameters perfusion fraction (PF) and ADC were significantly decreased (p<0.001) in abnormal bowel segments. None of the DCE-MRI and IVIM-DWI parameters correlated with clinical parameters (p>0.105). DCE-MRI parameters exhibited multiple significant correlations with wall thickness (Cpeak, upslope, AUC60, Ktrans; r range 0.431-0.664, p<0.025) and MaRIA/Clermont scores (Cpeak, AUC60, Ktrans; r range 0.441-0.617, p<0.021). Combined Ktrans+ve+PF+ADC showed highest AUC (0.963) for differentiation between normal and abnormal bowel, while ADC performed best for individual parameters (AUC=0.800). CONCLUSIONS: DCE-MRI and IVIM-DWI, particularly when used in combination, are promising for non-invasive evaluation of small bowel CD. KEY POINTS: * IVIM-DWI and DCE-MRI parameters were significantly different between normal and abnormal bowel segments in CD patients. * DCE-MRI parameters showed a significant association with wall thickness and MRI activity scores. * Combination of IVIM-DWI and DCE-MRI parameters led to the highest diagnostic performance for differentiation between normal and abnormal bowel segments, while ADC showed the highest diagnostic performance of individual parameters. PMID- 30019144 TI - Assessment of Cardiac Lead Perforation: Comparison Among Chest Radiography, Transthoracic Echocardiography and Electrocardiography-gated Contrast-enhanced Cardiac CT. AB - OBJECTIVES: Cardiac lead perforation is a rare but potentially life-threatening event. The purpose of this study was to investigate the diagnostic performances of chest radiography, transthoracic echocardiography (TTE) and electrocardiography (ECG)-gated contrast-enhanced cardiac CT in the assessment of cardiac lead perforation. METHODS: This retrospective study was approved by the ethics review board of Sun Yat-Sen Memorial Hospital at Sun Yat-Sen University (Guangzhou, China), and the need to obtain informed consent was waived. Between May 2010 and Oct 2017, 52 patients were clinically suspected to have a cardiac lead perforation and received chest radiography, TTE and ECG-gated contrast enhanced cardiac CT. Among them, 13 patients were identified as having cardiac lead perforation. The diagnostic performances of these three modalities were evaluated by receiver-operating characteristic (ROC) curves using a composite reference standard of surgical and electrophysiological results and clinical follow-up. The areas under ROCs (AUROCs) were compared with the McNemar test. RESULTS: The accuracies of chest radiography, TTE and ECG-gated contrast-enhanced cardiac CT imaging for the diagnosis of cardiac lead perforation were 73.1%, 82.7% and 98.1%, respectively. ECG-gated contrast-enhanced cardiac CT had a higher AUROC than chest radiography (p < 0.001) and TTE (p < 0.001). CONCLUSIONS: ECG-gated contrast-enhanced cardiac CT is superior to both chest radiography and TTE imaging for the assessment of cardiac lead perforation. KEY POINTS: * ECG gated contrast-enhanced cardiac CT has an accuracy of 98.1% in the diagnosis of cardiac lead perforation. * The AUROC of ECG-gated contrast-enhanced cardiac CT is higher than those of chest radiography and TTE imaging. * ECG-gated contrast enhanced cardiac CT imaging has better diagnostic performance than both chest radiography and TTE imaging for the assessment of cardiac lead perforation. PMID- 30019145 TI - Topical antimicrobial prophylaxis in colorectal surgery for the prevention of surgical wound infection: a systematic review and meta-analysis. AB - BACKGROUND: Among the techniques investigated to reduce the risk of surgical wound infection or surgical space infection (SSI) in patients having colorectal surgery are topical application of antimicrobials (antibiotics and antiseptics) to the open wound or immediately after closure. The aim of the present study was to perform a systematic review of the literature on those treatments, with the exception of antibiotic ointments applied to closed skin, which are adequately assessed elsewhere, and a meta-analysis. METHODS: Only randomized trials of patients having only colorectal surgery were included in this review. Studies were sought in MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, Clinical Trials.gov, and the World Health Organization Internet clinical trials register portal. In addition, reference lists of included studies and other published reviews were screened. Meta-analysis was performed for all included studies and subgroup analyses done for each individual intervention. Risk of bias was assessed for each included study, paying particular attention to the preoperative antibiotic prophylaxis used in each study. Sensitivity analyses were done to investigate heterogeneity of the analyses, excluding those studies with a significant risk of bias issues. Absolute risk reduction (RR) was calculated. The overall quality of the evidence for each individual intervention was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and was classified as high, moderate, low or very low. RESULTS: A total of 30 studies are included in this review with 5511 patients, 665 of whom had SSI. The interventions included: 10 studies of gentamicin impregnated sponge or beads wound inlays, 4 studies of chlorhexidine impregnated suture, 11 studies of direct wound lavage or powder application or injection of antibiotics before closure, 4 studies of ionized silver dressing applied to the closed skin, and 1 study of vitamin E oil applied to the open wound. All but one study used preoperative antibiotic prophylaxis in addition to topical procedures, although, in some studies, the systemic antibiotic prophylaxis was not the same between groups or varied significantly from the recommended guidelines. Use of gentamycin sponge did not decrease SSI (RR 0.93, 95% CI 0.75-1.16; low-quality evidence) even after including only the studies of abdominal wounds (RR 1.02, 95% CI 0.80 1.30; low-quality evidence). However, sensitivity analysis excluding studies at high risk of bias decreased the heterogeneity and increased the effect of the prophylaxis for all wounds (RR 0.5, 95% CI 0.33-0.78; low-quality evidence) and for abdominal wounds only (RR 0.38, 95% CI 0.20-0.72; moderate-quality evidence). Chlorhexidine impregnated suture showed no effect on SSI (RR 0.79, 95% CI 0.56 1.10; low-quality evidence) and an increased efficacy after sensitivity analysis (RR 0.42, 95% CI 0.22-0.79; low-quality evidence). Antibiotic lavage showed a significant decrease in SSI (RR 0.45, 95% CI 0.26-0.79; low-quality evidence) which increased after sensitivity analysis (RR 0.33, 95% CI 0.15-0.72; moderate quality evidence). Application of silver dressing to the closed wound resulted in a decrease of SSI (RR 0.55, 95% CI 0.35-0.85; moderate-quality evidence). The one study of topical vitamin E oil applied to the open wound showed a significant risk reduction (RR 0.22, 95% CI 0.05-0.98; low-quality evidence). CONCLUSIONS: Each of these interventions appears to be effective in decreasing SSI, but the number of studies for each is small and the quality of evidence is very low to moderate. Within the various outcomes of GRADE assessment, even a moderate classification suggests that further studies may well have very different results.. No randomized trials exist of combinations of two or more of the above interventions to see if there is a combined effect. Future studies should make sure that the antibiotic used preoperatively is uniform within a study and is consistent with the current guidelines. Deviation from this leads to a significant heterogeneity and risk of bias. PMID- 30019146 TI - Naturally produced type I IFNs enhance human myeloid dendritic cell maturation and IL-12p70 production and mediate elevated effector functions in innate and adaptive immune cells. AB - There has recently been a paradigm shift in the field of dendritic cell (DC) based immunotherapy, where several clinical studies have confirmed the feasibility and advantageousness of using directly isolated human blood-derived DCs over in vitro differentiated subsets. There are two major DC subsets found in blood; plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), and both have been tested clinically. CD1c+ mDCs are highly efficient antigen-presenting cells that have the ability to secrete IL-12p70, while pDCs are professional IFN-alpha-secreting cells that are shown to induce innate immune responses in melanoma patients. Hence, combining mDCs and pDCs poses as an attractive, multi-functional vaccine approach. However, type I IFNs have been reported to inhibit IL-12p70 production and mDC-induced T-cell activation. In this study, we investigate the effect of IFN-alpha on mDC maturation and function. We demonstrate that both recombinant IFN-alpha and activated pDCs strongly enhance mDC maturation and increase IL 12p70 production. Co-cultured mDCs and pDCs additionally have beneficial effect on NK and NKT-cell activation and also enhances IFN-gamma production by allogeneic T cells. In contrast, the presence of type I IFNs reduces the proliferative T-cell response. The mere presence of a small fraction of activated pDCs is sufficient for these effects and the required ratio between the subsets is non-stringent. Taken together, these results support the usage of mDCs and pDCs combined into one immunotherapeutic vaccine with broad immunostimulatory features. PMID- 30019148 TI - Early adolescent aggression predicts antisocial personality disorder in young adults: a population-based study. AB - Modestly prevalent in the general population (~ 4%), but highly prevalent in prison populations (> 40%), the diagnosis of antisocial personality disorder (ASPD) involves aggression as one of several possible criteria. Using multiple informants, we aimed to determine if general aggression, as well as direct and indirect subtypes, assessed in early adolescence (ages 12, 14) predict young adulthood ASPD in a population-based sample. Using data from a Finnish population based longitudinal twin cohort study with psychiatric interviews available at age 22 (N = 1347), we obtained DSM-IV-based ASPD diagnoses. Aggression measures from ages 12 (parental and teacher ratings) and 14 (teacher, self, and co-twin ratings) were used to calculate odds ratios (OR) of ASPD from logistic regression models and the area under the curve (AUC) from receiver operating characteristic curve analysis. Analyses were adjusted for sex, age, and family structure. All informants' aggression ratings were significant (p < 0.05) predictors of ASPD (OR range 1.3-1.8; AUC range 0.65-0.72). Correlations between informants ranged from 0.13 to 0.33. Models including two or more aggression ratings, particularly age 14 teacher and self ratings, more accurately predicted ASPD (AUC: 0.80; 95% confidence interval 0.73-0.87). Direct aggression rated by all informants significantly predicted ASPD (OR range 1.4-1.9), whereas only self-rated indirect aggression was significantly associated with ASPD (OR = 1.4). Across different informants, general and direct aggression at ages 12 and 14 predicted ASPD in a population-based sample. Psychiatric, social, and parenting interventions for ASPD prevention should focus on children and adolescents with high aggression levels, with an aim to gather information from multiple informants. PMID- 30019149 TI - Radiotherapy for cutaneous head and neck cancer and parotid tumours: a prospective investigation of treatment-related acute swallowing and toxicity patterns. AB - PURPOSE: Reports of acute treatment-related dysphagia and toxicities for patients with parotid tumours or cutaneous head and neck cancer (HNC) are limited. This study aimed to describe the severity and timing of dysphagia and related toxicities experienced during radiotherapy for cutaneous HNC and parotid tumours, to inform the nature of future speech pathology (SP) service models required during treatment. METHODS: Prospective study of 32 patients with parotid tumours and 36 with cutaneous HNC undergoing curative non-surgical management. Dysphagia and acute toxicity data was collected weekly during treatment and at 2, 4 and 12 weeks post-treatment using the Functional Oral Intake Scale, diet descriptors and CTCAE v4.0. RESULTS: In both groups, minimal treatment toxicities (grades 0-1) were observed. Xerostomia and dysgeusia were the most frequently reported grade 2 toxicities. Only 3% of parotid patients and 6% with cutaneous HNC experienced grade 3 dysphagia. Full or soft texture diets were maintained by > 70% of patients in both groups. Symptoms peaked in the final week of treatment and rapidly improved thereafter. Apart from xerostomia < 10% of patients had any grade 2 toxicity at 12 weeks post-treatment. CONCLUSION: Patients in these subgroups of HNC experienced minimal treatment-related toxicity during radiotherapy. As such, the need for supportive symptom management by SP is low. Models that involve interdisciplinary surveillance of symptoms with referral to SP only when required may be best suited for these individuals to ensure issues are identified whilst minimising patient burden created by unnecessary routine SP appointments. PMID- 30019150 TI - Mixed-phenotype acute leukemia characteristics: first report from Iran. AB - Mixed-phenotype acute leukemia (MPAL) is the infrequent type of acute leukemia characterized by immunophenotypic and/or cytochemical features of both lineages, but the diagnosis of this disease still is a challenge. In this study, we analyzed immunophenotyping, cytochemistry and frequency of MPAL patients to better diagnosis of MPAL characteristics according to WHO 2016 criteria for the first time in Iran. In this retrospective study, 27 patients were diagnosed as MPAL based on WHO 2016 criteria during 2014-2017. Flow cytometric immunophenotyping was performed on PB and BM samples evaluation of different CD marker expressions in MPAL subsets. RT-PCR was performed for the analyses of BCR/ABL1 fusion in MPAL subsets. Among 27 cases, (70.4%) 19 cases were B + My, (22.22%) 6 cases were T + My, and 2 cases (7.40%) were B + T + My. CD34, CD19, HLA-DR, TdT, CD22, iMPO were positive in majority of B + My cases. CD45, iMPO, iCD3, CD7, CD2 and CD5 were positive in majority of T + My cases. HLA-DR, TdT, CD10, CD22, iCD79a, iMPO, CD45, iCD3, CD7, CD3, CD2, CD5 were positive in majority of B + T + My cases. BCR/ABL1 fusion was positive for 3 cases (11.1%) of p190 fusion and 2 cases (7.4%) of p210 fusion in B + My cases. WHO 2016 criteria are the current standard for diagnosing MPAL. Also, evaluation of TdT, CD2, CD5, CD7 expressions by flow cytometry in EGIL criteria is useful for the better diagnosis of MPAL subsets. In addition, evaluation of BCR/ABL1 and MLL rearrangements in patients should be part of standard work-up in MPAL. PMID- 30019147 TI - Neurotransmitter, Peptide, and Steroid Hormone Abnormalities in PTSD: Biological Endophenotypes Relevant to Treatment. AB - PURPOSE OF REVIEW: This review summarizes neurotransmitter, peptide, and other neurohormone abnormalities associated with posttraumatic stress disorder (PTSD) and relevant to development of precision medicine therapeutics for PTSD. RECENT FINDINGS: As the number of molecular abnormalities associated with PTSD across a variety of subpopulations continues to grow, it becomes clear that no single abnormality characterizes all individuals with PTSD. Instead, individually variable points of molecular dysfunction occur within several different stress responsive systems that interact to produce the clinical PTSD phenotype. Future work should focus on critical interactions among the systems that influence PTSD risk, severity, chronicity, comorbidity, and response to treatment. Effort also should be directed toward development of clinical procedures by which points of molecular dysfunction within these systems can be identified in individual patients. Some molecular abnormalities are more common than others and may serve as subpopulation biological endophenotypes for targeting of currently available and novel treatments. PMID- 30019151 TI - Assessment of alteration in liver 18F-FDG uptake due to steatosis in lymphoma patients and its impact on the Deauville score. PMID- 30019152 TI - Metabolic engineering of Pichia pastoris GS115 for enhanced pentose phosphate pathway (PPP) flux toward recombinant human interferon gamma (hIFN-gamma) production. AB - In the present study, the effects of individual as well as multiple genes of pentose phosphate pathway (PPP) on human interferon gamma (hIFN-gamma) production were analyzed. With overexpression of 6-phosphogluconate dehydrogenase (GND2), 1.9-fold increase in hIFN-gamma was achieved, while synergetic effect of 6 phosphogluconolactonase (SOL3) and D-ribulose-5-phosphate 3-epimerase (RPE1) resulted in 2.56-fold increase in hIFN-gamma as compared to control. Fed batch fermentation using mixed feeding of gluconate and methanol (carbon source) was carried out, resulting in 80 and 123 mg L-1 of hIFN-gamma enhancement in recombinant Pichia GS115 strain encoding codon optimized hIFN-gamma (GS115/hIFN gamma) and Pichia GS115 strain encoding codon optimized hIFN-gamma with co expressed 6-phosphogluconolactonase(SOL3) and D-ribulose-5-phosphate 3-epimerase (RPE1) (GS115/hIFN-gamma/SR) respectively. To get more insight of the flux distribution towards hIFN-gamma, studies were carried out by applying flux balance analysis during methanol fed batch phase for both strains. In both strains (GS115/hIFN-gamma and GS115/hIFN-gamma/SR) more than 95% of formaldehyde flux is directed towards assimilatory pathway. The analysis revealed that with the overexpression of SOL3 and RPE1 the flux towards PPP triggering the alleviation in hIFN-gamma production. PMID- 30019153 TI - CXCL13 polymorphism is associated with essential hypertension in Tatars from Russia. AB - Essential arterial hypertension is a disease with distinct yet unexplored inflammatory component. Our aim was to assess the role of chemokine genes and their interaction in its development. Genotyping of polymorphic markers in six chemokine genes (CXCL13, CCL8, CCL16, CCL17, CCL18, and CCL23) was performed in the group of 522 men of Tatar ethnic origin from the Republic of Bashkortostan, Russia (213 patients with essential hypertension and 309 healthy individuals without history of cardiovascular disease). We found a strong association of CXCL13 rs355689*C allele with essential hypertension under additive (OR 0.56, PFDR = 0.008) and dominant (OR 0.41, PFDR 4.38 * 10- 4) genetic model. The analysis of gene-gene interactions revealed 12 allele/genotype combinations that remained significantly associated with essential hypertension after correction for multiple testing was applied, and each of these combinations included CXCL13 rs355689 polymorphism. Our results indicate that CXCL13 rs355689 polymorphism is strongly associated with essential hypertension in the ethnic group of Tatars, alone and in combination with polymorphic markers in other chemokine genes. PMID- 30019154 TI - Culturable symbionts associated with the reproductive and digestive tissues of the Neotropical brown stinkbug Euschistus heros. AB - Symbionts are widely distributed in eukaryotes, and potentially affect the physiology, ecology and evolution of their host. Most insects harbour free-living bacteria in their haemocoel and gut lumen, intracellular-living bacteria in a range of tissues or bacteria in host-derived specialized cells. Stinkbugs, as do many arthropods, harbour extracellular bacteria in the gut that may affect the fitness of their host. This study identified the culturable symbionts associated with the ovaries, spermatheca, seminal vesicle and posterior midgut region (V4) of males and females of Euschistus heros (F.) (Hemiptera: Pentatomidae). Several culture media were used to isolate the bacteria associated with these structures. The selected colonies (morphotypes) were cultured in liquid medium, subjected to genomic DNA extraction, 16S rRNA gene amplification, and restriction fragment length polymorphism (RFLP) analyses. Morphotypes with distinct RFLP patterns were purified and sequenced, and the sequences obtained were used for putative identification and phylogenetic analysis. Comparison of the sequences with those available in the EzTaxon-e database and the use of a matrix of paired distances grouped the isolates in phylotypes belonging to the Phylum Proteobacteria. Proteobacteria was represented by gamma-Proteobacteria phylotypes belonging to Enterobacteriaceae, while Firmicutes had Bacilli phylotypes distributed in Enterococcaceae and Staphylococcaceae. Some of the phylotypes identified were associated exclusively with single structures, such as ovaries, spermatheca and the V4 midgut region of males and females. All culturable bacteria associated with the seminal vesicle were also associated with other tissues. PMID- 30019155 TI - State Requirements for Prenatal Syphilis Screening in the United States, 2016. AB - Objectives This study assesses U.S. state laws related to prenatal syphilis screening, including whether these laws align with CDC screening recommendations and include legal penalties for failing to screen. Methods Statutes and regulations regarding syphilis screening during pregnancy and at delivery effective in 2016 were examined for all 50 U.S. states and the District of Columbia (DC). Targeted search terms were used to identify laws in legal research databases. The timing of the screening mandates for each state law was coded for: (1) first visit, (2) third trimester, and (3) delivery. Descriptive statistics were calculated to examine the number of states with each type of requirement and whether requirements adhered to the CDC STD treatment guidelines. Results Only six states (11.8%) do not require prenatal syphilis screening. Of states with screening requirements (n = 45), the majority (84.3%) require testing at first prenatal visit or soon after. 17 states (33.3%) require screening during the third trimester with five requiring screening only if the patient is considered at high risk. 8 (15.7%) states require screening at delivery with five requiring testing only if the woman is at high risk. 14 (27.5%) states include punishments for failing to screen (civil penalties, criminal penalties and license revocation). Conclusions for Practice Most states had prenatal syphilis screening requirements; a minority corresponded to or extended CDC recommendations. States vary in when they require testing, who must be tested, and whether a failure to screen could result in a punishment for the provider. PMID- 30019156 TI - Maternal Depression Scale: Do "Drop-In" Laborist Patients Have Increased Postpartum Screening Risks Compared to Patients with Adequate Prenatal Care? AB - Objectives The Edinburgh Postnatal Depression Scale (EPDS) identifies women with depressive symptoms in pregnancy. Our primary objective was to determine the prevalence of EPDS screen-positive women delivering on our no prenatal care (laborist) service and to compare these patients to private patients delivering with prenatal care. Methods Retrospective cohort analysis of EPDS scores during January 1, 2015 to June 18, 2015 was conducted. Scores >= 10 were considered at risk. Results were analyzed as an aggregate and then as no prenatal care versus prenatal care. Characteristics for patients with at-risk scores (EPDS >= 10) versus low-risk scores (EPDS < 10) were quantified. Results Analysis occurred on 970 women. EPDS >= 10 occurred in 12.4% (n = 120/970). Positive EPDS score was 21.1% without prenatal care versus 10.9% with adequate prenatal care (P = 0.003). Maternal demographics and delivery characteristics were clinically similar in patients with prenatal care compared to no prenatal care. Private insurance was more common in patients with prenatal care compared to no prenatal care (23.5 versus 8.1%, P = 0.0001). However, analysis of patients with EPDS > 10 showed non significant distributions of ethnicity, private insurance, Medicaid, or no insurance compared to patients with EPDS < 10. Conclusion for Practice Patients without prenatal care who arrive solely for urgent "drop-in" delivery have a measurable increased risk factor for postpartum depressive symptoms. Ethnicity and payor status were related to adequacy of prenatal care but were not significant variables when analyzing patients with EPDS > 10. Laborist services providing care to "drop-in" patients should recognize this increased risk and develop policies for screening, referral and follow-up of at-risk patients. PMID- 30019157 TI - Examining Temporal Trends in Documentation of Pregnancy Intentions in Family Planning Health Centers Using Electronic Health Records. AB - Objectives Few studies have examined the extent to which providers assess pregnancy intentions during clinical encounters. Our objective was to assess temporal trends in documentation of patient pregnancy intentions in electronic health records (EHR). Methods In this retrospective observational study using EHR data from 627,399 female patients visiting 214 family planning centers in 2012 2014, we assessed changes in the prevalence of pregnancy intention documentation with piecewise log-binomial regression models. We examined bivariate associations between patient/visit characteristics and pregnancy intention documentation in each year, and associations between patients' pregnancy intentions and contraceptive methods. Results The proportion of patients with a documented pregnancy intention increased sharply from the end of 2012 (42%) to the midpoint of 2013 (85%; adjusted quarterly prevalence ratio [APR] = 1.40, 95% CI 1.36 1.45). Thereafter, the rate of change slowed as documentation approached the maximum possible frequency (93%; APR = 1.01, 95% CI 1.00-1.02). Documentation varied by all patient/visit characteristics in 2012 and 2013; in 2014, there were no clinically significant differences. Among patients with a documented intention, 97% were not planning a pregnancy in the next year. Women not planning a pregnancy were more likely to use a most/moderately effective contraceptive method than those planning a pregnancy (73 vs. 35%, p < 0.0001). Conclusions for Practice Improvements in pregnancy intention documentation co-occurred with changes to EHR templates (e.g., placement of structured data fields) and with provider-focused initiatives promoting reproductive life planning. Patients' pregnancy intentions aligned with contraceptive use; however, these findings cannot address whether assessment of intentions affects contraceptive use. PMID- 30019158 TI - Sexual Orientation Disparities in Pregnancy and Infant Outcomes. AB - Objectives Little is known about maternal and infant health among sexual minority women (SMW), despite the large body of research documenting their multiple preconception risk factors. This study used data from the 2006-2015 National Survey of Family Growth (NSFG) to investigate sexual orientation inequities in pregnancy and birth outcomes, including miscarriage, stillbirth, preterm birth, and birth weight. Methods Women reported 19,955 study eligible pregnancies and 15,996 singleton live births. Sexual orientation was measured using self-reported identity and histories of same-sex sexual experiences (heterosexual-WSM [women who only report sex with men]; heterosexual-WSW [women who report sex with women]; bisexual, and lesbian). Logistic regression models were used that adjusted for several maternal characteristics. Results Compared to heterosexual WSM, heterosexual-WSW (OR 1.25, 95% CI 1.00-1.58) and bisexual and lesbian women (OR 1.77, 95% CI 1.34-2.35) were more likely to report miscarriage, and bisexual and lesbian women were more likely to report a pregnancy ending in stillbirth (OR 2.85, 95% CI 1.40-5.83). Lesbian women were more likely to report low birth weight infants (OR 2.64, 95% CI 1.38-5.07) and bisexual and lesbian women were more likely to report very preterm births (OR 1.84, 95% CI 1.11-3.04) compared to heterosexual-WSM. Conclusions for Practice This study documents significant sexual orientation inequities in pregnancy and birth outcomes. More research is needed to understand the mechanisms that underlie disparate outcomes and to develop interventions to improve sexual minority women's maternal and infant health. PMID- 30019159 TI - [painApp-mobile pain monitoring in the home care setting]. AB - BACKGROUND: The use of a scientifically developed App for pain management in the home care setting is not yet established in Germany. The documentation of pain specific data by the patients and the transfer into a web portal to be examined by the attending physician can help close the existing communication gap in pain management between consultations. OBJECTIVES: The aim of the study was to develop a mobile health (mHealth) solution for optimizing pain management in the home care setting. The research questions focus on design and technical issues concerning layout and navigation of the painApp as well as user-relevant questions concerning pain management, such as pain at rest and pain during movement, taking pain medication and patient satisfaction with their pain situation. MATERIALS AND METHODS: Within a 12-month period, the user-centered development and practice-based testing of the application painApp involved patients aged >= 65 years. Within a formative evaluation, a total of four data collections and a final survey took place. During the same period, a web portal was developed and tested the documentation of the patient pain-specific data from the painApp with the participation of general practitioners. RESULTS AND CONCLUSIONS: The development of the painApp as a prototype was realized in the study with high acceptability by the patients. The painApp is able to establish digital communication with the general practitioner without any technical problems and allows the physician access to patient data in real time. PMID- 30019161 TI - Whole body vibration with rest days could improve bone quality of distal femoral metaphysis by regulating trabecular arrangement. AB - Low-magnitude, high-frequency vibration (LMHFV) with rest days (particularly seven rest days) was considerably effective in improving the morphological and mechanical properties of rat proximal femur. However, current knowledge is limited regarding the possible benefit of this mechanical regimen to other bone sites and whether the optimal rest days are the same. This study followed our previous experiment on LMHFV loading with rest days for three-month-old male Wistar rats. The experiment involved seven groups, namely, vibrational loading for X day followed with X day rest (X=1, 3, 5, 7), daily vibrational loading, tail suspension and baseline control. Micro-computed tomography (micro-CT) scanning was used to evaluate the microarchitecture of the distal femoral trabecular bone. Micro-CT image-based microfinite element analysis was performed for each distal femoral metaphysis. LMHFV with rest days substantially changed the trabecular arrangement from remarkably plate-like to rod-like. Vibrational loading with 1 day rest was substantially effective in improving the architecture and apparent- and tissuelevel mechanical properties of the rat distal femoral metaphysis. This study may provide an improved understanding of the sitespecific responses of bone tissue to LMHFV with rest days for a substantially effective therapy of a targeted bone site. PMID- 30019160 TI - Anesthetic Treatment of Cardiac Disease During Pregnancy. AB - PURPOSE OF REVIEW: This review summarizes the pathophysiology, peripartum treatment, and anesthetic management of parturients with cardiac disease. Valvular disease, coronary disease, and cardiomyopathy are specifically addressed in the context of the normal physiologic changes of pregnancy. We offer recommendations for anesthetic approaches, hemodynamic goals with an emphasis on interdisciplinary planning between anesthesiologists, cardiologists, cardiothoracic surgeons, obstetricians, maternal fetal medicine specialists, and neonatologists. RECENT FINDINGS: Vaginal delivery with neuraxial analgesia can be well tolerated by many pregnant patients with cardiac disease when coordinated by an interdisciplinary team of experts. Cardiac disease in pregnancy can present a significant challenge for the interdisciplinary care team. A detailed understanding of each patient's cardiac pathology and the physiologic changes of pregnancy are critical to ensure a safe and successful labor and delivery. Optimized medical therapy in the peripartum period and neuraxial anesthesia with the judicious use of vasoactive agents can be of great benefit for these parturients. As is generally the case, cesarean delivery should be primarily reserved for obstetric indications and maternal wellbeing, with careful consideration of the fetus to guide best practices. PMID- 30019163 TI - Measurements of Atmospheric Proteinaceous Aerosol in the Arctic Using a Selective UHPLC/ESI-MS/MS Strategy. AB - In this article, an analytical methodology to investigate the proteinaceous content in atmospheric size-resolved aerosols collected at the Zeppelin observatory (79 degrees N, 12 degrees E) at Ny Alesund, Svalbard, from September to December 2015, is proposed. Quantitative determination was performed after acidic hydrolysis using ultrahigh-performance liquid chromatography in reversed-phase mode coupled to electrospray ionization tandem mass spectrometry. Chromatographic separation, as well as specificity in the identification, was achieved by derivatization of the amino acids with N-butyl nicotinic acid N hydroxysuccinimide ester prior to the analysis. The chromatographic run was performed within 11 min and instrumental levels of detection (LODs) were between 0.2 and 8.1 pg injected on the column, except for arginine which exhibited an LOD of 37 pg. Corresponding method LODs were between 0.01 and 1.9 fmol/m3, based on the average air sampling volume of 57 m3. The sum of free amino acids and hydrolyzed polyamino acids was shown to vary within 6-2914 and 0.02-1417 pmol/m3 for particles in sizes < 2 and 2-10 MUm in equivalent aerodynamic diameter, respectively. Leucine, alanine, and valine were the most abundant among the amino acids in both aerosol size fractions. In an attempt to elucidate source areas of the collected aerosols, 5- to 10-day 3D backward trajectories reaching the sampling station were calculated. Overall, the method described here provides a first time estimate of the proteinaceous content, that is, the sum of free and polyamino acids, in size-resolved aerosols collected in the Arctic. Graphical Abstract ?. PMID- 30019162 TI - Combined Short-Term Glucose Starvation and Chemotherapy in 3D Colorectal Cancer Cell Culture Decreases 14-3-3 Family Protein Expression and Phenotypic Response to Therapy. AB - Short-term glucose starvation prior to chemotherapy has the potential to preferentially weaken cancer cells, making them more likely to succumb to treatment, while protecting normal cells. In this study, we used 3D cell cultures of colorectal cancer and assessed the effects of short-term glucose starvation and chemotherapy compared to treatment of either individually. We evaluated both phenotypic changes and protein expression levels. Our findings indicate that the combined treatment results in more significant phenotypic responses, including decreased cell viability and clonogenicity. These phenotypic responses can be explained by the decreased expression of LDHA and 14-3-3 family proteins, which were found only in the combined treatment groups. This study indicates that short term glucose starvation has the potential to increase the efficacy of current cancer treatment regimes. Graphical Abstract ?. PMID- 30019164 TI - Feasibility of robotic resection of gastrointestinal stromal tumors along the entire gastrointestinal tract. AB - Robotic surgery has been proposed over the last decade as a valid option to treat gastrointestinal malignancies in a minimally invasive method, yielding encouraging results. The authors examine the outcomes of a consecutive series of patients with stromal gastrointestinal neoplasms who were operated on using a totally robotic technique. There were 36 patients in the study, with median age 70 years. Resected tumors were located in the esophagus, stomach, duodenum, small intestine and rectum. Perioperative morbidity was 8% and no mortality occurred. R0 resection was achieved in all cases. At a median follow-up of 25 months, 35 patients were disease free while there was one case of death related to metastatic disease. Robotic surgery is a valid option to resect gastrointestinal stromal tumors anywhere along the gastrointestinal tract in a minimally invasive manner. PMID- 30019166 TI - Comprehensive analysis of serum microRNAs in hepatic sinusoidal obstruction syndrome (SOS) in rats: implication as early phase biomarkers for SOS. AB - Sinusoidal obstruction syndrome (SOS) is a liver injury caused by clinical chemotherapy, of which pathogenesis is associated with the damage in liver sinusoidal endothelial cells (LSEC). The unavailability of appropriate specific biomarkers for the early diagnosis of SOS may potentially overlook SOS patients. In this study, we sought to find serum microRNAs (miRNAs) as non-invasive biomarkers for investigating SOS in rats. Male Sprague-Dawley rats were orally administered monocrotaline, and then, their livers and sera were collected after 0.25, 0.5, 1, 2, 4, and 7 days. The rats showed a typical SOS phenotype including LSEC damage as early as day 0.25, followed by severe hepatocyte damage on day 2, and developed hepatic fibrosis from days 4 to 7. The miRNA microarray showed that 65 serum miRNAs were increased in their levels on day 0.25, when LSEC damage was observed, while hepatocyte damage was absent. Among the increased serum miRNAs on days 0.25-1, miR-511-3p was enriched in normal LSECs and miR-21-5p was in both LSECs and hepatocytes, suggesting that they were released into blood from the damaged LSECs. The miR-122-5p, miR-192-5p, and miR-101b-3p, which were enriched in hepatocytes, reached the highest levels in serum on day 2, suggesting their utility as indicators for hepatocyte damage. No miRNA showing an increasing trend from days 4 to 7 was found as a biomarker for fibrosis. In conclusion, we found that LSEC-derived miR-21-5p and especially miR-511-3p in serum would serve as early phase biomarkers for SOS in response to LSEC damage. PMID- 30019167 TI - Deglucosylation of zearalenone-14-glucoside in animals and human liver leads to underestimation of exposure to zearalenone in humans. AB - Zearalenone-14-glucoside (ZEN-14G), the modified mycotoxin of zearalenone (ZEN), has attracted considerable attention due to its high potential to be hydrolyzed into ZEN, which would exert toxicity. It has been confirmed that the microflora could metabolize ZEN-14G to ZEN. However, the metabolic profile of ZEN-14G and whether it could be deglucosidated in the liver are unknown. To thoroughly investigate the metabolism of ZEN-14G, in vitro metabolism including phase I and phase II metabolism was studied using liquid chromatography coupled to high resolution mass spectrometry. Additionally, in vivo metabolism of ZEN-14G was conducted in model animals, rats, by oral administration. As a result, 29 phase I metabolites and 6 phase II metabolites were identified and significant inter species metabolic differences were observed as well. What is more, ZEN-14G could be considerably deglucosidated into its free form of ZEN after the incubation with animals and human liver microsomes in the absence of NADPH, which was mainly metabolized by human carboxylesterase CES-I and II. Furthermore, results showed that the major metabolic pathways of ZEN-14G were deglucosylation, hydroxylation, hydrogenation and glucuronidation. Although interspecies differences in the biotransformation of ZEN-14G were observed, ZEN, alpha-ZEL-14G, beta-ZEL-14G, alpha-ZEL, ZEN-14G-16GlcA and ZEN-14GlcA were the major metabolites of ZEN-14G. Additionally, a larger yield of 6-OH-ZEN-14G and 8-OH-ZEN-14G was also observed in human liver microsomes. The obtained data would be of great importance for the safety assessment of modified mycotoxin, ZEN-14G, and provide another perspective for risk assessment of mycotoxin. PMID- 30019165 TI - Management of Subdural Hematomas: Part II. Surgical Management of Subdural Hematomas. AB - PURPOSE OF REVIEW: Management of patients with subdural hematomas starts with Emergency Neurological Life Support guidelines. Patients with acute or chronic subdural hematomas (SDHs) associated with rapidly deteriorating neurologic exam, unilaterally or bilaterally dilated nonreactive pupils, and extensor posturing are considered imminently surgical; likewise, SDHs more than 10 mm in size or those associated with more than 5-mm midline shift are deemed operative. RECENT FINDINGS: While twist drill craniostomy and placement of subdural evacuating vport system (SEPS) are quick, bedside procedures completed under local anesthesia and appropriate for patients with chronic SDH or patients that cannot tolerate anesthesia, these techniques are not optimal for patients with acute SDH or chronic SDH with septations. Burr hole SDH evacuation under conscious sedation or general anesthesia is an analogous technique; however, it requires basic surgical equipment and operating room staff, with a focus on a closed system with burr hole followed by rapid drain placement to avoid introduction of air into the subdural space, or multiple burr holes with extensive irrigation to reduce pneumocephalus and continue SDH evacuation via drain for several days. Acute SDH associated with significant mass effect and cerebral edema requires aggressive decompression via craniotomy with clot evacuation and frequently a craniectomy. Chronic SDHs that fail conservative management and progress clinically or radiographically are addressed with craniotomy with or without membranectomy. Surgical SDH management is variable depending on its characteristics and etiology, patient's functional status, comorbidities, goals of care, institutional preferences, and availability of specialized surgical equipment and adjunct therapies. Rapid access to surgical suites and trained staff to address surgical hemorrhages in a timely manner, with appropriate post-operative care by a specialized team including neurosurgeons and neurointensivists, is of paramount importance for successful patient outcomes. Here, we review various aspects of surgical SDH management. PMID- 30019168 TI - Inverse agonist of ERRgamma reduces cannabinoid receptor type 1-mediated induction of fibrinogen synthesis in mice with a high-fat diet-intoxicated liver. AB - Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRgamma as key regulator of hepatocytic fibrinogen gene expression in human. In a therapeutic approach, we now tested ERRgamma inverse agonist GSK5182 as regulator of fibrinogen levels in mouse hyperfibrinogenemia caused by diet-induced obesity and in mouse hepatocytes. ACEA, a CB1R agonist, up-regulated transcription of mouse fibrinogen via induction of ERRgamma, whereas knockdown of ERRgamma attenuated the effect of ACEA (10 uM) on fibrinogen expression in AML12 mouse hepatocytes. Deletion analyses of the mouse fibrinogen gamma (FGG) gene promoter and ChIP assays revealed binding sites for ERRgamma on the mouse FGG promoter. ACEA or adenovirus ERRgamma injection induced FGA, FGB and FGG mRNA and protein expression in mouse liver, while ERRgamma knockdown with Ad-shERRgamma attenuated ACEA-mediated induction of fibrinogen gene expression. Moreover, mice maintained on a high-fat diet (HFD) expressed higher levels of fibrinogen, whereas cannabinoid receptor type 1 (CB1R)-KO mice fed an HFD had nearly normal fibrinogen levels. Finally, GSK5182 (40 mg/kg) strongly inhibits the ACEA (10 mg/kg) or HFD-mediated induction of fibrinogen level in mice. Taken together, targeting ERRgamma with its inverse agonist GSK5182 represents a promising therapeutic strategy for ameliorating hyperfibrinogenemia. PMID- 30019169 TI - Pathogenesis of IgG4-related disease: a critical review. AB - Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown etiology. Histopathologic examination is the key to diagnosis of IgG4-RD. The histopathologic features of IgG4-RD are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. As for fewer than 15 years, IgG4-RD has been recognized as a unified diagnostic entity. CD4+ T and B cells, which likely cause organ damage and disabling tissue fibrosis, constitute the major inflammatory cell population in patients with IgG4 RD. Affected patients with active, untreated disease have a marked expansion of IgG4-secreting plasmablasts in the blood. Important mechanistic insights regarding the pathogenesis of IgG4-RD have been gradually disclosed in recent years. Exploring the role of interactions between these CD4+ T and B cells in patients with IgG4-RD is a highly promising field of investigation. In this review, we focus on CD4+ T cell subsets and the T-cell clones that are involved in the pathogenesis of IgG4-RD. PMID- 30019170 TI - A 5-year prospective clinical trial on short implants (6 mm) for single tooth replacement in the posterior maxilla: immediate versus delayed loading. AB - The aim of this paper was to demonstrate the treatment outcomes following immediate functional loading concept of short implants inserted for single tooth replacement in the posterior maxilla. The study was performed on 63 patients who received short (6 mm) implants for single tooth replacement in the posterior maxilla. Forty-eight patients underwent immediate functional concept, whereas 15 of the implants were loaded 3 months after insertion. The patients were evaluated for up to 5 years after prosthesis completion. The endpoints included the evaluation of implant survival rate, crown length, bone resorption, plaque accumulation (PI), bleeding on probing (BOP), periodontal probing depth (PPD) and assessment of oral health impact profile (OHIP). At the end of the follow-up period of 5 years, three implants (6.3%) from the immediate loading group have failed during the observation period. Bone loss was significantly lower in the delayed loading group compared to the immediately loaded implants. At the end of the second year, BOP values were higher in the immediately loaded group. Throughout the observation period, PI values in the group with immediate loading were higher. PPD increased consistently and during the first 3 years in the immediate loading group. As a conclusion, short implants inserted for single tooth replacement at the posterior maxilla presented with satisfactory clinical outcomes in both immediate and delayed loading concepts. However, immediately loaded implants presented with an increased bone loss and higher BOP values. As assessed by the OHIP score, a subjective improvement was observed in both groups without significant differences. PMID- 30019171 TI - Healthcare Workers: Occupational Health Promotion and Patient Safety. AB - The purpose of the present study was to explore the relation of work-related risk factors and well-being among healthcare workers and the impact on patient safety, using the Health and Work Survey (INSAT) and Mental Health Continuum - Short Form (MHC-SF). A sample of 361 Portuguese healthcare workers participated in this study. The results indicate some significant work-related risk factors: for emotional well-being, Impossible to express myself (beta = -0.977), Not having recognition by superiors (beta = -1.028) and Have to simulate good mood and/or empathy (beta = -1.007); for social well-being, Exposed to the risk of sexual discrimination (beta = -2.088), Career progress is almost impossible (beta = 1.518), and Have to hide my emotions (beta = -2.307); finally for psychological well-being Exposed to the risk of sexual discrimination (beta = -2.153), Career progress is almost impossible (beta = -1.377), and Have to simulate good mood and/or empathy (beta = -3.201). The results showed high levels of well-being despite the exposure of several risk factors at workplace. Regarding the work related risk factors, the study showed that most of the participants are exposed to several risk factors at workplace (ranging from environmental risk factors, biological to physical), although psychosocial risk factors (work relations with superiors and colleagues, employment relations, and emotional demands) are the ones that most impact on well-being. PMID- 30019173 TI - Synergistic bacterial inactivation by combining antibiotics with nanosecond electric pulses. AB - Antibiotic resistance mechanisms render current antibiotics ineffective, requiring higher concentrations of existing drugs or the development of more powerful drugs for infection treatment. This study demonstrates the synergistic inactivation of a gram-positive (Staphylococcus aureus) and a gram-negative (Escherichia coli) bacteria by combining either tobramycin or rifampicin with 300 ns electric pulses (EPs). For EPs depositing the same total energy density into the sample with no drug, higher electric fields induced greater inactivation, indicating a threshold for irreversible electroporation at these fields and membrane recovery in between lower intensity EPs. Synergistic inactivation generally increased with increasing drug concentration up to 20 MUg/mL compared to strictly EP treatment. Combining even 1/20 of the clinical dose of tobramycin with a train of EPs induced between 2.5 and 3.5 log inactivation after only 10 min of exposure compared to hours to induce inactivation with a clinical dose with no EPs. Similarly, combining a train of EPs with a clinically relevant dose of rifampicin induced 7 to 9 log inactivation over the same time of exposure. These results indicate the promise of combining EPs with antibiotics to rapidly inactivate antibiotic-resistant bacteria in localized treatment areas. PMID- 30019174 TI - Gender differences in the effects of job insecurity on psychological distress in Japanese workers: a population-based panel study. AB - PURPOSE: This study aimed to examine effects of persistence or change in job insecurity on psychological distress (PD) among Japanese community dwellers. METHODS: The sample comprised 889 men and 762 women aged 25-50 years who were employed and completed both wave 1 (2010) and wave 2 (2012) surveys of the Japanese Study on Stratification, Health, Income, and Neighborhood (J-SHINE). Job insecurity, a perception of threat of job loss, was self-reported in both waves to define persistence and change of the status. Logistic regression analysis was performed to compare PD (K6 score >= 5) at wave 2 for employees whose job security changed or who remained insecure with that of those who remained secure. RESULTS: Persistent job insecurity was associated with PD (for men, OR 1.64, 95% CI 1.03-2.63; for women OR 1.65, 95% CI 1.02-2.65), after adjustment for confounders. Additionally, change from secure to insecure perception was also associated with PD in men, while change from insecure to secure was associated with PD in women. Regardless of gender, these effects were observable among workers with children but not among those without children. CONCLUSIONS: Persistent job insecurity and change in job insecurity has adverse effects on PD, especially for workers with children. Gender differences in the effects of change in job security on PD might be explained by the social norms of gender roles and labor market gender segregation. Policy makers should consider dependent family and gender inequalities when developing policies to reduce job insecurity and its negative health effects. PMID- 30019176 TI - Phenotyping of isogenic chlorophyll-less bread and durum wheat mutant lines in relation to photoprotection and photosynthetic capacity. AB - In our experiments, we examined high light responses and photosynthetic capacity of chlorophyll-less isogenic mutant lines of hexaploid bread wheat (Triticum aestivum L.) and tetraploid durum wheat (Triticum durum L.) in comparison to parental lines representing the wild type (WT), in two growth phases and two environments. In young plants, we observed a typical yellow-green phenotype with low chlorophyll content, significantly lower CO2 assimilation rate, elevated chlorophyll a-to-b ratio and insufficient regulation of linear electron transport. In the mutants grown in a moderate light in the growth chamber, a typical "chlorina" phenotype almost disappeared or, at least, was significantly alleviated in later growth stages, including the values of CO2 assimilation and the majority of the measured parameters related to photoprotective responses. On the other hand, in the case of the mutant lines grown in direct sunlight and fluctuating environment, the chlorophyll-less phenotype was evident also in latter growth phases. The chlorophyll-less phenotype was more severe in the durum wheat mutant lines compared to the bread wheat. For example, the durum wheat mutant lines grown outdoors expressed lower flexibility of photoprotective responses, including lower non-photochemical quenching and low rate of cyclic electron flow compared to WT or bread wheat mutants. Based on the analyses, we have identified a set of parameters providing information on the specific photosynthetic traits typical for the chlorophyll-less phenotype. Thus, the proposed way of phenotyping may serve for efficient selection of mutant genotypes for future research or screening activities. As a general result, we observed that the decrease of the chlorophyll content due to mutation was always associated with improper regulation of linear electron transport and a limited ability to prevent over-reduction of PSI acceptor side, regardless of the genotype, environment, and growth stage. This can partly explain why the low chlorophyll mutants were not successful in the evolution of higher plants, despite the photosynthetic capacity observed is high enough and they are fully competitive with wild-type plants in non-fluctuating controlled environment. PMID- 30019175 TI - The relation between social capital and burnout: a longitudinal study. AB - OBJECTIVES: Although social capital approach has showed its merits in predicting well-being and health in the working environment, studies examining the relation between social capital and burnout are scarce and limited to cross-sectional studies in the health care sector. This study aims to explore the longitudinal relationship between workplace social capital and burnout in a Belgian company in the energy sector. An additional aim was to assess whether the relation between workplace social capital and the dimensions of burnout was independent of job characteristics, i.e., the level of decision-making autonomy and task variety, and demographical variables. METHODS: Analyses are conducted on the questionnaire data of 473 workers who participated at the two waves (2013 and 2014) of a longitudinal study. RESULTS: The results showed a negative relation between social capital and distance and a positive relation between social capital and competence, after 1-year follow-up and after adjustments for baseline levels of the respective burnout dimension. In contrast with the literature, no relation between social capital and emotional exhaustion was found after adjustment for baseline level of emotional exhaustion. After additional adjustments were made for the job characteristics 'decision-making autonomy' and 'task variety', the relation between social capital and competence disappeared. CONCLUSIONS: This study delivered evidence for the lagged relation between social capital and distance, even after controlling for demographical and job characteristics. Therefore, the findings suggest that organizations should pay attention to strategies enhancing social interaction, enabling to increase the levels of support, reciprocity, sharing and trust, in the prevention of burnout. PMID- 30019172 TI - Clinical Pharmacokinetics and Pharmacodynamics of Propofol. AB - Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia. Many pharmacokinetic (PK) and pharmacodynamic (PD) models for propofol exist. Some are used to inform drug dosing guidelines, and some are also implemented in so-called target-controlled infusion devices, to calculate the infusion rates required for user-defined target plasma or effect-site concentrations. Most of the models were designed for use in a specific and well defined patient category. However, models applicable in a more general population have recently been developed and published. The most recent example is the general purpose propofol model developed by Eleveld and colleagues. Retrospective predictive performance evaluations show that this model performs as well as, or even better than, PK models developed for specific populations, such as adults, children or the obese; however, prospective evaluation of the model is still required. Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids. PD interactions are the most clinically significant, and, with other hypnotics, tend to be additive, whereas interactions with opioids tend to be highly synergistic. Response surface modelling provides a tool to gain understanding and explore these complex interactions. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects. In this review, we provide an overview of the PK and PD of propofol in order to refresh readers' knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made. PMID- 30019177 TI - Efficacy of palliative radiotherapy and chemo-radiotherapy for unresectable gastric cancer demonstrating bleeding and obstruction. AB - BACKGROUND: Bleeding and obstruction are common localized symptoms in patients with unresectable gastric cancer. Although there are several reports about surgical and endoscopic therapies for gastric cancer, there are few regarding palliative radiation therapy. METHODS: We retrospectively analyzed data for 23 gastric cancer patients who underwent palliative radiation between April 2006 and March 2014, with either localized bleeding (n = 18) or upper gastric obstruction (n = 10). RESULTS: The median (range) total dose and fraction (Fr) of radiotherapy (RT) were 42 (18-60) Gy and 20 (9-30) Fr, respectively. The response rates were 88.8% (bleeding) and 80% (obstruction). The median event-free survival times of the bleeding and obstruction groups from the start of radiation were 103 and 104 days, respectively. Adverse events with RT and chemo-radiotherapy (CRT) were grade 2 nausea (n = 4) and grade 2 esophagitis (n = 3) and grade 2 neutropenia (n = 3). In univariate analysis, the antrum as the gastric primary site (p = 0.063) and peritoneal metastasis (p = 0.054) occurred more frequently in the non-responders (n = 4) than the responders (n = 19). PMID- 30019178 TI - Psychometric Properties of Visuoperceptual Measures of Videofluoroscopic and Fibre-Endoscopic Evaluations of Swallowing: A Systematic Review. AB - Fibreoptic Endoscopic Evaluation of Swallowing (FEES) and Videofluoroscopic Swallow Studies (VFSS) are instrumental assessments of dysphagia which provide videos of the internal structures of swallowing. They are commonly regarded as 'gold-standard' assessments; however, there is no consensus regarding a gold standard measure to analyse the video recordings that they produce. Measures require sound psychometric properties to be suitable for clinical or research purposes. To date, no review of psychometric properties of FEES and VFSS measures has been undertaken or formally reported. This review assessed the quality of the psychometric properties of visuoperceptual measures of FEES and VFSS. Electronic databases were searched for studies reporting on psychometric qualities of visuoperceptual measures which are used to analyse recordings from FEES and VFSS. All dates until February 2017 were included. The Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist was used to evaluate the methodical quality of studies. The measures' overall quality was then assessed by combining COSMIN ratings with quality criteria. Forty-five studies, reporting on 39 measures, met the inclusion criteria for this review. Data about the measures' psychometric properties were very limited. Twenty-one measures had information available about reliability only, while 18 had information on up to five of the possible nine psychometric properties categorised within the COSMIN framework. The majority of the FEES and VFSS measures' psychometric properties were rated as 'indeterminate' overall, due to the small number of studies, issues with design, statistical analyses, and reporting practices of extant studies. There is insufficient evidence to recommend any individual measure included in this review as valid and reliable to interpret VFSS and FEES recordings. Further research, which utilises robust methodological design and reporting, is needed to examine the psychometric properties of measures for FEES and VFSS. PMID- 30019179 TI - Correction to: Phonological and graphotactic influences on spellers' decisions about consonant doubling. AB - Please note that, because of an error in the production process, many of the International Phonetic Alphabet symbols were missing from the originally published pdf version of the article, both in the main text and in the Appendix. PMID- 30019180 TI - Predicting others' knowledge: Knowledge estimation as cue utilization. AB - Predicting what others know is vital to countless social and educational interactions. For example, the ability of teachers to accurately estimate what knowledge students have has been identified as a crucial component of effective teaching. I propose the knowledge estimation as cue-utilization framework, in which judges use a variety of available and salient metacognitive cues to estimate what others know. In three experiments, I tested three hypotheses of this framework: namely, that participants do not automatically ground estimates of others' knowledge in their own knowledge, that judgment conditions shift how participants weight different cues, and that participants differentially weight cues based upon their diagnosticity. Predictions of others' knowledge were dynamically generated by judges who weighed a variety of available and salient cues. Just as the accuracy of metacognitive monitoring of one's own learning depends upon the conditions under which judgments of self are elicited, the bases and accuracy of metacognitive judgments for others depends upon the conditions under which they are elicited. PMID- 30019181 TI - Differential Effectiveness of a Middle School Social and Emotional Learning Program: Does Setting Matter? AB - There is a lack of studies in the literature addressing the differential effectiveness of Social and Emotional Learning according to their implementation setting. This study compared the effectiveness of an upper middle school Social and Emotional Learning program applied in two different settings: within school and after-school hours, while controlling for individual and class-level variables. There were 837 students (Mage = 12.70; SD = 0.98; 47.6% were female): 246 in the control group, 319 in the after-school intervention group and 272 in the within school schedule intervention group, assessed at pretest, post-test and follow-up seven months later. Multilevel analyses identified more positive intervention results in on self-esteem, self-control, and social awareness for students in the within school schedule groups. Girls gained more in social awareness in both program settings. This study highlights the importance of analyzing Social and Emotional Learning program's differential effectiveness in order to optimize it. PMID- 30019182 TI - Effect of novel bioresorbable scaffold composed of poly-L-lactic acid and amorphous calcium phosphate nanoparticles on inflammation and calcification of surrounding tissues after implantation. AB - To study the effect of novel bioresorbable scaffold composed of poly-L-lactic acid (PLLA) and amorphous calcium phosphate (ACP) nanoparticles on inflammation and calcification of surrounding tissues after implantation. Ninety six PLLA/ACP scaffolds and 96 PLLA scaffolds were randomly implanted in the back muscle tissue of 48 SD rats. At the 1st, 2nd, 4th, and 12th weeks after implantation, the calcium, phosphorus, and alkaline phosphatase levels in the blood serum and the contents of calcium and alkaline phosphatase in the tissue surrounding the scaffolds were measured. Hematoxylin-eosin staining was performed to count the inflammatory cells. Von kossa staining was performed to observe calcification of the surrounding tissue around the scaffold. NF-kappaB staining was performed by immunohistochemistry to calculate the positive expression index of inflammatory cells. Western blot was used to detect the expression of IL-6 and BMP-2 in the tissues surrounding the scaffolds. At the 1st, 2nd, 4th, and 12th weeks after scaffold implantation, there were no significant difference in the serum concentration of calcium, phosphorus, alkaline phosphatase and in the tissue homogenate concentration of alkaline phosphatase between the two groups (P > 0.05). The level of calcium in tissue homogenates was lower in the PLLA/ACP group than in the PLLA group at 12-week (P < 0.05). The hematoxylin-eosin staining results showed that the inflammatory cell count in the PLLA/ACP group was lower than the PLLA group at 4-week and 12-week (P < 0.05). The results of NF-kB positive expression index showed that the PLLA group was significantly more than the PLLA/ACP group at 4-week and 12-week (P < 0.01). Western blot results showed that IL-6 expression levels in the PLLA/ACP group scaffolds were significantly lower than those in the control group at the 2-week, 4-week and 12-week (P < 0.05). The expression of BMP-2 in the PLLA group was significantly lower than that in the control group at 4-week and 12-week (P < 0.05). The PLLA/ACP composite material has good histocompatibility. The integration of nanoscale ACPs reduces the inflammatory response induced by acidic metabolites of PLLA material and may inhibit tissue calcification by reducing the amount of calcification factors in the body. PMID- 30019184 TI - May: a month of myths. PMID- 30019183 TI - The role of parent and offspring sex on risk for externalizing psychopathology in offspring with parental alcohol use disorder: a national Swedish study. AB - PURPOSE: The substantial literature showing that offspring of parents with alcohol use disorder (AUD) is at increased risk for externalizing psychopathology rarely examines the differential effects of parental and offspring sex. This literature also has other important limitations, such as modest sample sizes and use of unrepresentative samples. Using a large, nationwide Swedish sample, we aim to investigate the roles of parental and offspring sex in externalizing psychopathology among offspring with parental AUD. METHODS: AUD diagnosis and externalizing measures were obtained from national registries. Associations between outcomes and parental AUD were examined using logistic regressions. Parental and offspring sex effects were examined with interaction terms. RESULTS: Risks for externalizing disorders were increased in sons and daughters with parental AUD, with significant differences between sons and daughters for criminal behavior; maternal AUD had a greater impact than paternal AUD (regardless of offspring sex), but having two parents with AUD increased risk for all outcomes substantially more than having one parent; and maternal AUD increased risk of drug abuse for daughters more than sons, while paternal AUD increased risk of AUD and criminal behavior for sons more than daughters. CONCLUSIONS: Offspring of parents with AUD are at increased risk for externalizing psychopathology. Maternal and paternal AUD differentially affected sons' vs. daughters' risks for AUD, drug abuse, and criminal behavior. The transmission of psychopathology within the externalizing spectrum appears to have sex-specific elements. PMID- 30019185 TI - Cathepsin B inhibition ameliorates the non-alcoholic steatohepatitis through suppressing caspase-1 activation. AB - Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease. NLRP3 inflammasome activation has been widely studied in the pathogenesis of NAFLD. Cathepsin B (CTSB) is a ubiquitous cysteine cathepsin, and the role of CTSB in the progression and development of NAFLD has received extensive concern. However, the exact roles of CTSB in the NAFLD development and NLRP3 inflammasome activation are yet to be evaluated. In the present study, we used methionine choline-deficient (MCD) diet to establish mice NASH model. CTSB inhibitor (CA-074) was used to suppress the expression of CSTB. Expressions of CTSB and caspase-1 were evaluated by immunohistochemical staining. Serum IL-1beta and IL-18 levels were also determined. Palmitic acid was used to stimulate Kupffer cells (KCs), and protein expressions of CTSB, NLRP3, ASC (apoptosis associated speck-like protein containing CARD), and caspase-1 in KCs were detected. The levels of IL-1beta and IL-18 in the supernatant of KCs were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that CTSB inhibition improved the liver function and reduced hepatic inflammation and ballooning, and the levels of pro-inflammatory cytokines IL-1beta and IL-18 were decreased. The expressions of CTSB and caspase-1 in liver tissues were increased in the NASH group. In in vitro experiments, PA stimulation could increase the expressions of CTSB and NLRP3 inflammasome in KCs, and CTSB inhibition downregulated the expression of NLRP3 inflammasome in KCs, when challenged by PA. Moreover, CTSB inhibition effectively suppressed the expression and activity of caspase-1 and subsequently secretions of IL-1beta and IL-18. Collectively, these results suggest that CTSB inhibition limits NLRP3 inflammasome-dependent NASH formation through regulating the expression and activity of caspase-1, thus providing a novel anti-inflammatory signal pathway for the therapy of NAFLD. PMID- 30019186 TI - Marine Bacterial Compounds Evaluated by In Silico Studies as Antipsychotic Drugs Against Schizophrenia. AB - Schizophrenia (SCZ) is one of the brain disorders which affects the thinking and behavioral skills of patients. This disorder comes along with an overproduction of kynurenic acid in the cerebrospinal fluid and the prefrontal cortex of SCZ patients. In this study, marine bacterial compounds were screened for their suitability as antagonists against human kynurenine aminotransferase (hKAT-1) which causes the synthesis of kynurenic acid downstream which ultimately causes the SCZ disorder according to the kynurenic hypothesis of SCZ. The marine actinobacterial compound bonactin shows more promising results than other tested marine compounds such as the histamine H2 blocker famotidine and indole-3-acetic acid (IAC) from docking and in silico toxicological studies carried out here. The obtained results of the Grid-based Ligand Docking with Energetics (Glide) scores of extra-precision (XP) Glide against the target protein hKAT-1 on IAC, famotidine, and bonactin were - 6.581, - 6.500 and - 7.730 kcal/mol where Glide energies were - 29.84, - 28.391, and - 47.565 kcal/mol, respectively. Bonactin is known as an antibacterial and antifungal compound being extracted from a marine Streptomyces sp. Comparing tested compounds against the drug target hKAT-1, bonactin alone showed the best Glide score and Glide energy on the target protein hKAT-1. PMID- 30019187 TI - A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist. AB - Extracellular nucleotides can regulate the production/drainage of the aqueous humor via activation of P2 receptors, thus affecting the intraocular pressure (IOP). We evaluated 5-OMe-UDP(alpha-B), 1A, a potent P2Y6-receptor agonist, for reducing IOP and treating glaucoma. Cell viability in the presence of 1A was measured using [3-(4, 5-dimethyl-thiazol-2-yl) 2, 5-diphenyl-tetrazolium bromide] (MTT) assay in rabbit NPE ciliary non-pigmented and corneal epithelial cells, human retinoblastoma, and liver Huh7 cells. The effect of 1A on IOP was determined in acute glaucomatous rabbit hyaluronate model and phenol-induced chronic glaucomatous rabbit model. The origin of activity of 1A was investigated by generation of a homology model of hP2Y6-R and docking studies. 1A did not exert cytotoxic effects up to 100 mM vs. trusopt and timolol in MTT assay in ocular and liver cells. In normotensive rabbits, 100 MUM 1A vs. xalatan, trusopt, and pilocarpine reduced IOP by 45 vs. 20-30%, respectively. In the phenol animal model, 1A (100 MUM) showed reduction of IOP by 40 and 20%, following early and late administration, respectively. Docking results suggest that the high activity and selectivity of 1A is due to intramolecular interaction between Palpha-BH3 and C5-OMe which positions 1A in a most favorable site inside the receptor. P2Y6 receptor agonist 1A effectively and safely reduces IOP in normotense, acute, and chronic glaucomatous rabbits, and hence may be suggested as a novel approach for the treatment of glaucoma. PMID- 30019188 TI - Allogenic vs. synthetic granules for bone tissue engineering: an in vitro study. AB - The aim of this study was to compare human dental pulp stem cells' (DPSCs) attachment, proliferation and osteogenic differentiation on allogenic and synthetic biphasic bone granules. In this in vitro study, two types of bone granules were used: allograft [freeze-dried bone allograft (FDBA)] and biphasic granules [hydroxyapatite/beta-tricalcium phosphate (HA/beta-TCP)]. By isolation of DPSCs, their attachment to bone granules was observed by scanning electron microscope (SEM) at day 1 and 7 of cultivation. Vital cells were measured by MTT assay at 1, 3, and 7 days of cell culture. Comparison of vital cells at different time points was considered as cell proliferation. Finally, differentiation of DPSCs was evaluated by measurement of alkaline phosphatase (ALP) activity 3, 7, 14, and 21 days after cell seeding in standard and osteogenic media. Data were analyzed using two-way ANOVA with a significant level of 0.05. Attachment of DPSCs on FDBA granules seemed relatively stronger. The number of cells (based on MTT values) and ALP activity of the cells cultured on both study groups increased between time points (p <= 0.001). FDBA granules had more cells compared to HA/beta-TCP granules (p < 0.001). There was no significant difference between ALP activity of two study groups cultured in the standard medium (p = 0.347) and they were both higher than the control group (p < 0.05). In the osteogenic medium, FDBA group had significantly higher ALP activity compared to HA/beta-TCP (p = 0.035) and control (p = 0.001) groups while there was no significant difference between ALP activity of HA/beta-TCP and control groups (p = 0.645). In conclusion, current in vitro study revealed that FDBA granules have more potential in supporting DPSCs attachment and proliferation and inducing their ALP activity compared to HA/beta-TCP granules. Therefore, FDBA could serve as a proper bone substitute material. PMID- 30019189 TI - Effects of family environment features on cochlear-implanted children. AB - PURPOSE: The role of cochlear implant in deaf children development is well-known. However, the results are highly variable and depend on several factors. The most important role belongs to the family, family environment in which the child develops. The aim of the study was to evaluate the features of the family environment in which cochlear-implanted children develop. METHODS: The questionnaire "Family Environment Scale" was sent to 108 families who had cochlear-implanted child with more than 6 months of experience. One of the parents was asked to fill out the questionnaire which also included general information about the child and the family. RESULTS: A total of 58 families responded to the questionnaire and accepted to participate in the study. Mean values were higher compared with normal families in the areas of cohesion, expressiveness, intellectual-cultural orientation and organization, but the cohesion and organization score mean value exceeded the normal values (between 40 and 60). The independence and the conflict areas had lower values than normal families but did not exceed the lower limit of normal (40). CONCLUSIONS: The relationship between the family and the auditory-verbal development potential of the cochlear-implanted child is obvious. However, further studies are needed to establish correlations between the characteristics of the family environment and the level of auditory-verbal and psycho-cognitive development of the cochlear implanted child so we can act on the family environment through education or therapy, to get maximum benefit with these children. PMID- 30019190 TI - Intra and interobserver agreement of narrow band imaging for the detection of head and neck tumors. AB - BACKGROUND: Narrow band imaging (NBI) in combination with white light endoscopy (WLE) has improved the accuracy for the diagnosis and follow-up of head and neck carcinomas by identifying changes in the vascular patterns of the mucosa. However, NBI evaluation is explorer-dependent and may be influenced by the learning curve. The aim of this study is to assess the intra and interobserver agreement of NBI and WLE at the office, under local anaesthesia, by either experienced or non-experienced observers. METHODS: Eighty-seven images of head and neck lesions were routinely collected under WLE and NBI. A group of three experienced otolaryngologists and three medical students assessed the images after a brief training. No additional patient information was provided. The same protocol was repeated after three weeks. Intra and interobserver agreement were calculated with the kappa index. RESULTS: NBI intraobserver agreement was substantial (kappa = 0.62) and better than with WLE alone, which was moderate (kappa = 0.57) in both groups. Interobserver agreement was moderate with WLE (kappa = 0.58) and substantial with NBI (kappa = 0.63). Both groups improved intraobserver and interobserver agreement with the implementation of NBI. CONCLUSIONS: Intra and interobserver agreement with NBI for the evaluation of head and neck lesions are substantial, and improve the results of WLE alone in both, professionals and trainees. PMID- 30019191 TI - Clinicopathological significance of cancer-associated fibroblasts in papillary thyroid carcinoma: a predictive marker of cervical lymph node metastasis. AB - PURPOSE: Most tumors have obvious biologically active fibroblasts known variously as myofibroblasts or cancer-associated fibroblasts (CAFs) in the stroma. CAFs have been known as an important factor of cancer invasion and metastasis. This study aimed to investigate the presence of CAFs in patients with papillary thyroid carcinoma (PTC) and evaluate the correlation between CAFs and cervical lymph node (LN) metastasis in PTC through immunohistochemistry. METHODS: The medical records of 128 patients who were diagnosed with PTC from January 1, 2010 to December 31, 2010 were reviewed, and 78 patients who underwent total thyroidectomy with or without neck dissection, were included in this study. A retrospective pathological evaluation was performed to verify the presence of CAFs. CD34 and alpha-smooth muscle actin (SMA) were used as markers of CAFs. RESULTS: Among 78 patients with PTC, 65 had desmoplastic stromal reaction around the PTC. Through immunohistochemical study of anti-CD34 and alpha-SMA antibodies, CAFs were found in 42 (64.6%) cases with desmoplastic stroma around the PTC. Univariate analysis showed that tumor size and CAFs were the risk factors of LN metastasis in patients with PTC, while multivariate analysis revealed that CAFs were the only independent risk factor of LN metastasis in patients with PTC. CONCLUSION: This study revealed the presence of CAFs in PTC. Furthermore, CAFs were found to be a risk factor of LN metastasis in PTC. Therefore, CAFs may be used as a predictive marker for LN metastasis in patients with PTC. PMID- 30019192 TI - Adhesion and mechanical properties of nanocrystalline hydroxyapatite coating obtained by conversion of atomic layer-deposited calcium carbonate on titanium substrate. AB - The purpose of this study was to evaluate the mechanical properties of nanocrystalline hydroxyapatite coating by tensile adhesion testing and scratch testing. The coating was manufactured on titanium substrate by converting atomic layer-deposited (ALD) calcium carbonate thin film in dilute phosphate solution. The tensile adhesion testing was performed with hydraulic testing device in accordance with ISO 4624 and ISO 16276-1. Scratch testing was done according to SFS-EN 13523-12 with spherical 10 um scratching tip. Characterization of the samples was done with light and electron microscopy after which they were stained with alizarin red and the failure modes and loadings were analyzed. The highest obtained tensile adhesion value was 6.71 MPa produced with 4000 ALD cycles, converted to hydroxyapatite in alkaline solution, and annealed for 30 min in 700 degrees C. The annealing improved the adhesion values by approximately 0.8 MPa, but examining the samples with electron microscopy showed intact coating in both annealed and non-annealed samples. Samples produced with 4000 cycles performed better in testing than 2000 cycle samples, and better adhesion was also achieved with alkaline conversion solution compared to neutral solution. PMID- 30019193 TI - Facile synthesis of N- (4-bromophenyl)-1- (3-bromothiophen-2-yl)methanimine derivatives via Suzuki cross-coupling reaction: their characterization and DFT studies. AB - A variety of imine derivatives have been synthesized via Suzuki cross coupling of N-(4-bromophenyl)-1-(3-bromothiophen-2-yl)methanimine with various arylboronic acids in moderate to good yields (58-72%). A wide range of electron donating and withdrawing functional groups were well tolerated in reaction conditions. To explore the structural properties, Density functional theory (DFT) investigations on all synthesized molecules (3a-3i) were performed. Conceptual DFT reactivity descriptors and molecular electrostatic potential analyses were performed by using B3LYP/6-31G(d,p) method to explore the reactivity and reacting sites of all derivatives (3a-3i). PMID- 30019194 TI - Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers. AB - PURPOSE: To report our initial experience of fully percutaneous deep venous arterialization (pDVA) for the treatment of chronic critical limb ischemia (cCLI) after failed distal angioplasty. MATERIALS AND METHODS: pDVA was performed in five consecutive patients by creating an arteriovenous fistula (AVF) between a below the knee artery and its satellite deep vein. In this early experience, only patients with failed prior interventional attempts at establishing flow with no distal targets for an arterial bypass were selected. Early technical success was defined as successful AVF creation and retrograde venous perfusion of the wound site. Patient demographics, procedural details, morbidity/mortality and wound healing outcomes were assessed prospectively. Patients were followed up in wound care centers, and graft patency was documented on duplex ultrasound. RESULTS: All five consecutive patients (mean age 58 years) underwent successful pDVA without any procedural complications. There were neither 30-day major adverse limb events nor major cardiovascular complications. Three out of the five patients (60%) had clinical improvement as observed by resolution of rest pain and complete wound healing. At the 1-month FU, one patient died and one patient received a major amputation. The median wound healing time was 39 weeks. CONCLUSION: pDVA is a safe and feasible vascularization alternative in patients with end-stage/no option CLI. The early experience highlights the need for a multidisciplinary approach including a dedicated wound care service. PMID- 30019196 TI - Unreliable and Difficult-to-Access Food for Those in Need: A Qualitative and Quantitative Study of Urban Food Pantries. AB - For individuals who are food insecure, food pantries can be a vital resource to improve access to adequate food. Access to adequate food may be conceptualized within five dimensions: availability (item variety), accessibility (e.g., hours of operation), accommodation (e.g., cultural sensitivity), affordability (costs, monetary or otherwise), and acceptability (e.g., as related to quality). This study examined the five dimensions of access in a convenience sample of 50 food pantries in the Bronx, NY. The design was cross-sectional. Qualitative data included researcher observations and field notes from unstructured interviews with pantry workers. Quantitative data included frequencies for aspects of food access, organized by the five access dimensions. Inductive analysis of quantitative and qualitative data revealed three main inter-related findings: (1) Pantries were not reliably open: only 50% of pantries were open during hours listed in an online directory (several had had prolonged or indefinite closures); (2) Even when pantries were open, all five access dimensions showed deficiencies (e.g., limited inventory, few hours, pre-selected handouts without consideration of preferences, opportunity costs, and inferior-quality items); (3) Open pantries frequently had insufficient food supply to meet client demand. To deal with mismatch between supply and demand, pantries developed rules for food provision. Rules could break down in cases of pantries receiving food deliveries, leading to workarounds, and in cases of compelling client need, leading to exceptions. Adherence to rules, versus implementation of workarounds and/or exceptions, was worker- and situation-dependent and, thus, unpredictable. Overall, pantry food provision was unreliable. Future research should explore clients' perception of pantry access considering multiple access dimensions. Future research should also investigate drivers of mismatched supply and demand to create more predictable, reliable, and adequate food provision. PMID- 30019195 TI - Leptin stimulates tissue rat mast cell pro-inflammatory activity and migratory response. AB - OBJECTIVE: The aim of this study was to determine whether leptin, a member of the adipocytokines involved in immune and inflammatory response regulation, may influence some aspects of mast cell biology. MATERIALS AND METHODS: Experiments were done in vitro on fully mature tissue rat mast cells isolated from the peritoneal cavity, and leptin was used at concentrations 0.001-100 ng/ml. The effect of leptin on mast cell degranulation (histamine release assay), intracellular Ca2+ level (fluorimetry), pro-inflammatory mediator release (ELISA technique), surface receptor expression (flow cytometry and confocal microscopy), and migration (Boyden microchamber assay) was estimated. RESULTS: Leptin was found to stimulate mast cells to degranulation and histamine release. It induced the intracellular Ca2+ increase, as well. In response to leptin stimulation, mast cells generated and released cysLTs and chemokine CCL3. Leptin-induced upregulation of CYSLTR1 and CYSLTR2 surface expression was observed. Moreover, this adipocytokine stimulated mast cells to migratory response, even in the absence of extracellular matrix (ECM) proteins. CONCLUSIONS: Our observations clearly documented that leptin promotes the pro-inflammatory activity of mast cells, and it thereby engages these cells in the inflammatory processes. PMID- 30019197 TI - A Comparison of Infant Sleep Safety Guidelines in Nine Industrialized Countries. AB - Many countries have guidelines that recommend safety practices for infant sleep. However, it is not known whether guidelines between countries are similar or different. The purpose of this paper is to compare national public health infant sleep safety guidelines among highly developed countries. Criteria for inclusion were: countries defined by United Nations as "very high human development," guideline related to infant sleep position and safety practices, evidence of it being a national guideline, and published in English. Guidelines from nine countries met inclusion criteria, and data were extracted across 13 categories. All guidelines recommended the supine sleep position and avoidance of smoke exposure. While most guidelines addressed the remaining 11 categories, specific recommendations varied among guidelines. These findings can inform the broad context of SIDS reduction work, offer opportunities for collaboration among countries, and promote multi-country and global conversations about how research evidence is translated into recommendations for practice. PMID- 30019198 TI - Students' Alcohol Use, Sexual Behaviors, and Contraceptive Use While Studying Abroad. AB - College study abroad students may represent a subgroup at risk for increased alcohol use and sexual activity while traveling. The present study explored student's alcohol use, sexual activity, and the interrelationship between the two while abroad. A sample of 372 students (Mage abroad = 20, SD = 3.3, 68% women) who had traveled abroad in the past 3 years were recruited from a large, southern university. Students completed an online survey of demographics, alcohol use, sexual behaviors, and contraceptive use. Students reported consuming an average of six drinks in one sitting, and 76% of women and men met criteria for 'hazardous drinking' while abroad. Students who met criteria for 'hazardous drinking' were more likely to engage in sexual activity; however, they also had a greater likelihood of wearing a condom. Our findings show students engage in problematic drinking and this is related to their engagement in sexual activity while abroad. Findings extend previous research and suggest study abroad programs should address norms around drinking and sexual activity prior to travel to ensure students' safety while abroad. PMID- 30019199 TI - The ancient history of dementia. AB - OBJECTIVE: This paper presents dementia, as studied in the ancient Greek and Byzantine bibliography, aiming at clarifying whether there was an early differentiation between dementia and senile dementia. METHODS: Numerous references of the terms morosis, delirium (pialpharhoalphalambdaetarhoetaMUalpha) or "leros" (lambdaetarhoomicronsigma), and anoia were found in the writings of authors from the seventh century BC up to the fourteenth century AD. The references were studied and those referring to everyday use of the words were eliminated from the corpus, which is, thus, formed solely by the terms with medical connotations. RESULTS: The ancient history of dementia may be separated in two periods: before and after Posidonius, who differentiated two medical ontologies relating to dementia: dementia appearing due to old age called lambdaetarhoomicronsigma and dementia appearing due to other reasons called morosis. During the first period, we mainly have authors referring to dementia due to old age or due to cold black bile, defined as a deterioration of memory and reasoning. In all cases, the etiology and the clinical manifestations are presented while we make an attempt to correlate the ancient descriptions to modern medical entities. CONCLUSIONS: The study of the ancient texts proves that dementia was distinguished from senile dementia early in history. This differentiation was manifested even with a shift in the use of specific terminology. Finally, the attempt to correlate modern medical entities with dementia-related issues results in interesting hypotheses. PMID- 30019202 TI - Reactive transport of arsenic-enriched geothermal spring water into a sedimentary aquifer. AB - The movement of high-arsenic (As)-concentration Beitou geothermal spring water up to 4600 MUg/L from the upstream area may affect the downstream Guandu plain and Guandu wetland. The major As pathway is via the subsurface flow. The study assesses the fate and transport of As-enriched geothermal spring water in the Beitou-Guandu area. The groundwater head and flow field velocity are first simulated by using HYDROGEOCHEM-fluid flow model. The steady state flow field is well-calibrated with root mean square error 1.73 m and R2 = 0.992. The spatial temporal distributions of As in the Beitou-Guandu area are simulated by the HYDROGEOCHEM reactive transport model using the calibrated steady state flow field. The results show that high As concentration (250 MUg/L) in groundwater of Guandu plain was caused by the movement of high As concentration from the Beitou geothermal spring water. In contrast, the low As concentration (5-50 MUg/L) in Guandu wetland was mitigated by the tidal water dilution. The simulated As concentrations increase in the first 3 years, and then gradually decrease due to the adsorption of As on the iron oxide minerals ferrihydrite and iron sulfide minerals pyrite. Furthermore, the hydrogeochemical transport model is applied to assess the effect of bioaccumulation of As by the mangrove plants of Guandu wetland. The dominant mangrove plants, Kandelia obovata, can reduce about 5-30 MUg/L As concentration in groundwater. It may be one of sinks of As in Guandu wetland. The inclusion of K. obovata can uptake the aqueous As and allow the simulated As concentration further close to the field measurement in the Guandu wetland. The study successfully models the reactive chemical transport of As by considering both geochemical reactions and biochemical uptakes in the Beitou Guandu area. The result demonstrates that the complex biogeochemical transport can be quantified by the sophisticated HYDROGEOCHEM model. Moreover, the salient features of the biogeochemical reactions can be recovered and elucidated through a series of systematic simulation. PMID- 30019200 TI - Analysis of the clinical features of early Parkinson's disease with comparatively integrated intestinal function. AB - OBJECTIVE: Constipation is among the most frequently delineated nonmotor symptoms (NMS) with a high occurrence in Parkinson's disease (PD). The purpose of our study was to investigate whether PD with comparatively integrated intestinal function (without constipation) in the early stage had different clinical features compared to constipated PD. METHOD: We conducted a study of 105 consecutive de novo as well as early treated (treated for shorter than 3 months), aged 50 years or older outpatients. Subjects were administered motor and nonmotor questionnaires as well as constipation associated examinations. Then, we explored the distinctive features of nonconstipated contrasted to constipated PD by using univariate, multiple regression analysis and correlation analysis. RESULTS: Nonconstipated PD tended to have fewer motor deficits, as well as lower Hoehn and Yahr (H&Y) stage and they mainly presented as tremor-dominant (TD), while constipated group had a higher occurrence of posture instability and gait difficulty (PIGD); nonconstipated patients were inclined to live in urban area, the NMSloads and prevalence of NMS were lower compared to constipated ones. Correlation analysis found a discord between NMSloads and disease severity based on H&Y stage and motor scores in nonconstipated PD. CONCLUSIONS: These results suggest that PD without constipation in early stage may represent a unique clinical phenotype, which may be more benign than PD with constipation. PMID- 30019201 TI - Optic nerve sheath diameter measured sonographically as non-invasive estimator of intracranial pressure: a systematic review and meta-analysis. AB - PURPOSE: Although invasive intracranial devices (IIDs) are the gold standard for intracranial pressure (ICP) measurement, ultrasonography of the optic nerve sheath diameter (ONSD) has been suggested as a potential non-invasive ICP estimator. We performed a meta-analysis to evaluate the diagnostic accuracy of sonographic ONSD measurement for assessment of intracranial hypertension (IH) in adult patients. METHODS: We searched on electronic databases (MEDLINE/PubMed(r), Scopus(r), Web of Science(r), ScienceDirect(r), Cochrane Library(r)) until 31 May 2018 for comparative studies that evaluated the efficacy of sonographic ONSD vs. ICP measurement with IID. Data were extracted independently by two authors. We used the QUADAS-2 tool for assessing the risk of bias (RB) of each study. A diagnostic meta-analysis following the bivariate approach and random-effects model was performed. RESULTS: Seven prospective studies (320 patients) were evaluated for IH detection (assumed with ICP > 20 mmHg or > 25 cmH2O). The accuracy of included studies ranged from 0.811 (95% CI 0.678-0.847) to 0.954 (95% CI 0.853-0.983). Three studies were at high RB. No significant heterogeneity was found for the diagnostic odds ratio (DOR), positive likelihood ratio (PLR) and negative likelihood ratio (NLR), with I2 < 50% for each parameter. The pooled DOR, PLR and NLR were 67.5 (95% CI 29-135), 5.35 (95% CI 3.76-7.53) and 0.088 (95% CI 0.046-0.152), respectively. The area under the hierarchical summary receiver-operating characteristic curve (AUHSROC) was 0.938. In the subset of five studies (275 patients) with IH defined for ICP > 20 mmHg, the pooled DOR, PLR and NLR were 68.10 (95% CI 26.8-144), 5.18 (95% CI 3.59-7.37) and 0.087 (95% CI 0.041-0.158), respectively, while the AUHSROC was 0.932. CONCLUSIONS: Although the wide 95% CI in our pooled DOR suggests caution, ultrasonographic ONSD may be a potentially useful approach for assessing IH when IIDs are not indicated or available (CRD42018089137, PROSPERO). PMID- 30019203 TI - [Revised version of the 4th edition of the WHO classification of malignant lymphomas : What is new?] AB - After 8 years, the WHO has now published the updated version of the 4th edition of the classification of hematopoietic and lymphoid tumors. This update provides a conceptual rewrite of existing entities as well as some new provisional entities and categories, particularly among the aggressive B-cell lymphomas. Important new diagnostic categories include the high-grade B-cell lymphomas, the large B-cell lymphoma with IRF4 rearrangement, and the Burkitt-like lymphoma with 11q aberrations. Of particular importance, new concepts concerning the taxonomy and classification of early lymphoid lesions or precursor lesions are included, such as the in situ follicular neoplasia or the in situ mantle cell neoplasia. In addition, the concept of indolent lymphoproliferations, such as breast-implant associated anaplastic large cell lymphoma and the indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, has been strengthened. Finally, diagnostic criteria for existing lymphoma entities have been refined. PMID- 30019204 TI - Application of the fluctuation theorem to motor proteins: from F1-ATPase to axonal cargo transport by kinesin and dynein. AB - The fluctuation theorem is a representative theorem in non-equilibrium statistical physics actively studied in the 1990s. Relating to entropy production in non-equilibrium states, the theorem has been used to estimate the driving power of motor proteins from fluctuation in their motion. In this review, usage of the fluctuation theorem in experiments on motor proteins is illustrated for biologists, especially those who study mechanobiology, in which force measurement is a central issue. We first introduce the application of the fluctuation theorem in measuring the rotary torque of the rotary motor protein F1-ATPase. Next, as an extension of this application, a recent trial estimating the force generated during cargo transport in vivo by the microtubule motors kinesin and dynein is introduced. Elucidation of the physical mechanism of such transport is important, especially for neurons, in which deficits in cargo transport are deeply related to neuronal diseases. Finally, perspectives on the fluctuation theorem as a new technique in the field of neuroscience are discussed. PMID- 30019206 TI - How medicinal chemists learned about log P. AB - Although log P is now recognized to be a key factor that determines the bioactivity of a molecule, the focus of medicinal chemists on hydrophobicity and log P started with the quantitative structure-activity relationships (QSAR) publications of Hansch and Fujita. Their original publication represents a dramatic change of focus to incorporate consideration of log P after a decade of work unsuccessfully attempting to use the Hammett equation to explain the structure-activity relationships of plant growth regulators. QSAR allows one to explore the quantitative relationship between log P and biological activity even when other factors also influence potency. In particular, Hansch's publications of thousands of QSAR equations demonstrate that a relationship of biological activity with log P is indeed a general phenomenon. Hansch's group also provided data and tools that enable others to explore the relationship between log P and the biological activity of compounds of interest. PMID- 30019205 TI - Role of ion channels in heart failure and channelopathies. AB - Heart failure (HF) is a complication of multiple cardiac diseases and is characterized by impaired contractile and electric function. Patients with HF are not only limited by reduced contractile function but are also prone to life threatening ventricular arrhythmias. HF itself leads to remodeling of ion channels, gap junctions, and intracellular calcium handling abnormalities that in combination with structural remodeling, e.g., fibrosis, produce a substrate for an arrhythmogenic disorders. Not only ventricular life-threatening arrhythmias contribute to increased morbidity and mortality but also atrial arrhythmias, especially atrial fibrillation (AF), are common in HF patients and contribute to morbidity and mortality. The distinct ion channel remodeling processes in HF and in channelopathies associated with HF will be discussed. Further basic research and clinical studies are needed to identify underlying molecular pathways of HF pathophysiology to provide the basis for improved patient care and individualized therapy based on individualized ion channel composition and remodeling. PMID- 30019208 TI - Health Risk Assessment for Human Exposure to Trace Metals and Arsenic via Consumption of Hen Egg Collected from Largest Poultry Industry in Iran. AB - The relative contribution of foodstuffs to intake of heavy metal is still equivocal, and thus, available data are rare. Here, the concentration of ten heavy metals and arsenic were measured in the content of hen egg from five strains of commercial laying hens to evaluate contamination level and potential health risk among local and international consumers in Iran. The estimated daily intake (EDI) of all heavy metals was significantly lower than the provisional tolerable daily intake (PTDI) and respective tolerable daily intake (TDI). The non-carcinogenic and carcinogenic risk values for eating eggs were in the safe range for all consumers, indicating that the no health risk for consumers due to the daily intake of either arsenic or heavy metals. Therefore, intake of heavy metal exposure through the consumption of commercial egg product in Iran is completely safe for both national and international consumers. PMID- 30019207 TI - Antagonising Wnt/beta-catenin signalling ameliorates lens-capsulotomy-induced retinal degeneration in a mouse model of diabetes. AB - AIMS/HYPOTHESIS: Cataract surgery in diabetic individuals worsens pre-existing retinopathy and triggers the development of diabetic ocular complications, although the underlying cellular and molecular pathophysiology remains elusive. We hypothesise that lens surgery may exaggerate pre-existing retinal inflammation in diabetes, which may accelerate neurovascular degeneration in diabetic eyes. METHODS: Male heterozygous Ins2Akita mice (3 months of age) and C57BL/6 J age matched siblings received either lens capsulotomy (to mimic human cataract surgery) or corneal incision (sham surgery) in the right eye. At different days post surgery, inflammation in anterior/posterior ocular tissues was assessed by immunohistochemistry and proinflammatory gene expression in the retina by quantitative PCR (qPCR). Degenerative changes in the retina were evaluated by electroretinography, in vivo examination of retinal thickness (using spectral domain optical coherence tomography [SD-OCT]) and morphometric analysis of retinal neurons. The therapeutic benefit of neutralising Wnt/beta-catenin signalling following lens capsulotomy was evaluated by intravitreal administration of monoclonal antibody against the co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) (Mab2F1; 5 MUg/MUl in each eye). RESULTS: Lens capsulotomy triggered the early onset of retinal neurodegeneration in Ins2Akita mice, evidenced by abnormal scotopic a- and b-wave responses, reduced retinal thickness and degeneration of outer/inner retinal neurons. Diabetic Ins2Akita mice also had a higher number of infiltrating ionised calcium binding adapter molecule 1 (IBA1)/CD68+ cells in the anterior/posterior ocular tissues and increased retinal expression of inflammatory mediators (chemokine [C C motif] ligand 2 [CCL2] and IL-1beta). The expression of beta-catenin was significantly increased in the inner nuclear layer, ganglion cells and infiltrating immune cells in Ins2Akita mice receiving capsulotomy. Neutralisation of Wnt/beta-catenin signalling by Mab2F1 ameliorated ocular inflammation and prevented capsulotomy-induced retinal degeneration in the Ins2Akita mouse model of diabetes. CONCLUSIONS/INTERPRETATION: Targeting the canonical Wnt/beta-catenin signalling pathway may provide a novel approach for the postoperative management of diabetic individuals needing cataract surgery. PMID- 30019209 TI - Assessing Essential Trace Elements in Cave Nectar Bat (Eonycteris spelaea): A Study in Barak Valley of Assam, India. AB - This study investigated trace elements in the different organs of Eonycteris spelaea, a hill cave from the Bhuban Hills of Sonai Reserve Forest, Cachar, Assam (India). Six bats were collected from the site and concentrations of four trace elements (Cu, Zn, Fe, and Mn) were examined from the tissues of liver, lungs, kidney, and patagium using graphite furnace atomic absorption spectrometer (graphite furnace model-Analytic Jena Vario-6). The results of the study revealed that concentration of essential trace elements in the body tissues of E. spelaea were less than the maximum permissible limit. During the study, it was found that the concentration of copper in all the four organs are of the following order: liver (3 +/- 0.11 MUg/g dw) > lungs (2.4 +/- 0.14 MUg/g dw) > kidney (1.8 +/- 0.10 MUg/g dw) > patagium (1.8 +/- 0.06 MUg/g dw). For zinc, this sequence was kidney (61.8 +/- 0.32 MUg/g dw) > liver (61.2 +/- 0.14 MUg/g dw) > lungs (58.8 +/ 0.19 MUg/g dw) > patagium (46.8 +/- 0.16 MUg/g dw). For manganese, kidney (1.2 +/- 0.15 MUg/g dw) > lungs (0.6 +/- 0.13 MUg/g dw) > liver (0.6 +/- 0.11 MUg/g dw) > patagium (0.6 +/- 0.10 MUg/g), and for iron, it was liver (98.4 +/- 0.22 MUg/g) > lungs (78.6 +/- 0.47 MUg/g dw) > kidney (25.8 +/- 0.23 MUg/g dw) > patagium (16.2 +/- 0.26 MUg/g dw). Analysis of variance revealed significant differences (d.f. = 15, F = 44.84, P < 0.01) in the accumulation pattern in all the studied tissues of Eonycteris spelaea. PMID- 30019210 TI - Brain serotonin critically contributes to the biological effects of electroconvulsive seizures. AB - Compounds targeting serotonin (5-HT) are widely used as antidepressants. However, the role of 5-HT in mediating the effects of electroconvulsive seizure (ECS) therapy remains undefined. Using Tph2-/- mice depleted of brain 5-HT, we studied the effects of ECS on behavior and neurobiology. ECS significantly prolonged the start latency in the elevated O-Maze test, an effect that was abolished in Tph2-/ mice. Furthermore, in the absence of 5-HT, the ECS-induced increase in adult neurogenesis and in brain-derived neurotrophic factor signaling in the hippocampus were significantly reduced. Our results indicate that brain 5-HT critically contributes to the neurobiological responses to ECS. PMID- 30019211 TI - Systematic review and meta-analysis of perioperative and long-term outcomes in patients receiving statin therapy before carotid endarterectomy. AB - BACKGROUND: Carotid endarterectomy (CEA) is associated with perioperative stroke and mortality in a minority of cases. The aim of this systematic review and meta analysis was to investigate the effect of pre-operative statins on perioperative outcomes in patients undergoing CEA for internal carotid artery (ICA) stenosis. METHODS: A systematic review of PubMed, Medline, and the Cochrane Database of Systematic Reviews was performed. Studies were included which reported perioperative stroke and/or survival outcomes following CEA for ICA stenosis and compared patients who were and were not taking pre-operative statins. Relevant data were extracted and pooled using meta-analysis. RESULTS: Seven studies met the inclusion criteria, comprising 21,387 patients. A total of 68.9% (14,976) were administered statins and 31.1% (6657) were statin-free. Pre-operative statin use was higher in patients with a history of cardiac disease (12.2 vs. 23.6% in the statin-free group), diabetes (31.6 vs. 25.1% in the statin-free group), and hypertension (83.5 vs. 72.2% in the statin-free group), while a greater proportion of statin-free patients had symptomatic disease (44.9 vs. 55.5% in the statin-free group). Statins were associated with reduced perioperative stroke in all patients (OR 0.57; 95% CI 0.34-0.95; p = 0.03) and in symptomatic patients (OR 0.57; 95% CI 0.35-0.93; p = 0.03). A trend towards lower perioperative mortality (OR 0.54; 95% CI 0.29, 1.03; p = 0.06) and significantly improved overall survival was observed in the statin group (HR 0.69; 95% CI 0.59-0.81; p < 0.001) at a mean follow-up of 62 months (range 27-76 months). CONCLUSIONS: Administration of statins before CEA is associated with lower rates of perioperative stroke and improved overall survival. Compliance with optimal medical treatment associated with the use of pre-operative statins may limit the clinical significance of these findings. Future investigation to characterize the potential benefit of statin therapy in patients undergoing CEA for ICA stenosis is warranted. PMID- 30019212 TI - Evaluating tacrolimus pharmacokinetic models in adult renal transplant recipients with different CYP3A5 genotypes. AB - PURPOSE: Numerous studies have been conducted on the population pharmacokinetics of tacrolimus in adult renal transplant recipients. It has been reported that the cytochrome P450 (CYP) 3A5 genotype is an important cause of variability in tacrolimus pharmacokinetics. However, the predictive performance of population pharmacokinetic (PK) models of tacrolimus should be evaluated prior to their implementation in clinical practice. The aim of the study reported here was to test the predictive performance of these published PK models of tacrolimus. METHODS: A literature search of the PubMed and Web of Science databases ultimately led to the inclusion of eight one-compartment models in our analysis. We collected a total of 1715 trough concentrations from 174 patients. Predictive performance was assessed based on visual and numerical comparison bias and imprecision and by the use of simulation-based diagnostics and Bayesian forecasting. RESULTS: Of the eight one-compartment models assessed, seven showed better predictive performance in CYP3A5 extensive metabolizers in terms of bias and imprecision. Results of the simulation-based diagnostics also supported the findings. The model based on a Chinese population in 2013 (model 3) showed the best and most stable predictive performance in all the tests and was more informative in CYP3A5 extensive metabolizers. As expected, Bayesian forecasting improved model predictability. Diversity among models and between different CYP3A5 genotypes of the same model was also narrowed by Bayesian forecasting. CONCLUSIONS: Based on our results, we recommend using model 3 in CYP3A5 extensive metabolizers in clinical practice. All models had a poor predictive performance in CYP3A5 poor metabolizers, and they should be used with caution in this patient population. However, Bayesian forecasting improved the predictability and reduced differences, and thus the models could be applied in this latter patient population for the design of maintenance dose. PMID- 30019213 TI - Worm expulsion of Gymnophalloides seoi from C57BL/6 mice: role of metacercarial exosomes in upregulating TLR2 and MUC2 expression in intestinal tissues. AB - Gymnophalloides seoi worms were rapidly expelled from C57BL/6 mice within days 3 6 post-infection probably due to operation of mucosal innate immunity. To understand better the mucosal immunity related to worm expulsion from the host, we isolated exosomes of G. seoi metacercariae and investigated their role in induction of mRNA and protein expression of several Toll-like receptors and mucin related factors in vitro. G. seoi-secreted exosomes were collected using differential ultracentrifugation, and cellular internalization of the exosomes into HT-29 intestinal epithelial cells was visualized by confocal microscopy. The expression of TLR2 and MUC2 in HT-29 cells was up-regulated in stimulation with the exosomes. We suggest that G. seoi-secreted exosomes offer a new point of view in the mechanism of worm expulsion from the host through enhancement of TLR2 and MUC2 expression. PMID- 30019214 TI - Migraine and greater pain symptoms at 10-year follow-up among patients with major depressive disorder. AB - BACKGROUND: No study has investigated the associations of migraine with pain symptoms over a ten-year period among outpatients with major depressive disorder (MDD). This study aimed to investigate this issue. METHODS: At baseline, the study enrolled 290 outpatients with MDD and followed-up the patients at six month, two-year, and ten-year time points. MDD and anxiety comorbidities were diagnosed using the Structured Clinical Interview for DSM-IV-text revision. Migraine was diagnosed based on the International Classification of Headache Disorders. The bodily pain subscale of the Short Form 36 (SF-BP) and the pain subscale (PS) of the Depression and Somatic Symptoms scale were also used. Generalized Estimating Equation models were employed to investigate the longitudinal impacts of migraine on pain symptoms. RESULTS: MDD patients with migraine had lower SF-BP and higher PS scores than those without. Depression, anxiety, and headache indices were significantly correlated with SF-BP and PS scores. The higher the frequency of migraine, the more often patients suffered from pain symptoms. Patients with migraine at all investigated time points suffered from pain symptoms most of the time (ranging from 60.0% to 73.7%) over the 10 years. After controlling for depression and anxiety, migraine was independently associated with a decreased SF-BP score (by 8.93 points) and an increased PS score (by 1.33 points). CONCLUSION: Migraine was an important comorbidity associated with greater severities of pain symptoms during long-term follow-up. Migraine treatment should be integrated into the treatment of depression to improve pain symptoms and quality of life in the pain dimension. PMID- 30019215 TI - eIF2A, an initiator tRNA carrier refractory to eIF2alpha kinases, functions synergistically with eIF5B. AB - The initiator tRNA (Met-tRNA i Met ) at the P site of the small ribosomal subunit plays an important role in the recognition of an mRNA start codon. In bacteria, the initiator tRNA carrier, IF2, facilitates the positioning of Met-tRNA i Met on the small ribosomal subunit. Eukarya contain the Met-tRNA i Met carrier, eIF2 (unrelated to IF2), whose carrier activity is inhibited under stress conditions by the phosphorylation of its alpha-subunit by stress-activated eIF2alpha kinases. The stress-resistant initiator tRNA carrier, eIF2A, was recently uncovered and shown to load Met-tRNA i Met on the 40S ribosomal subunit associated with a stress-resistant mRNA under stress conditions. Here, we report that eIF2A interacts and functionally cooperates with eIF5B (a homolog of IF2), and we describe the functional domains of eIF2A that are required for its binding of Met-tRNA i Met , eIF5B, and a stress-resistant mRNA. The results indicate that the eukaryotic eIF5B-eIF2A complex functionally mimics the bacterial IF2 containing ribosome-, GTP-, and initiator tRNA-binding domains in a single polypeptide. PMID- 30019216 TI - Responses of Patients with Disorders of Consciousness to Habit Stimulation: A Quantitative EEG Study. AB - Whether habit stimulation is effective in DOC patient arousal has not been reported. In this paper, we analyzed the responses of DOC patients to habit stimulation. Nineteen DOC patients with alcohol consumption or smoking habits were recruited and 64-channel EEG signals were acquired both at the resting state and at three stimulation states. Wavelet transformation and nonlinear dynamics were used to extract the features of EEG signals and four brain lobes were selected to investigate the degree of EEG response to habit stimulation. Results showed that the highest degree of EEG response was from the call-name stimulation, followed by habit and music stimulations. Significant differences in EEG wavelet energy and response coefficient were found both between habit and music stimulation, and between habit and call-name stimulation. These findings prove that habit stimulation induces relatively more intense EEG responses in DOC patients than music stimulation, suggesting that it may be a relevant additional method for eliciting patient arousal. PMID- 30019217 TI - Finger or Light: Stimulation Sensitivity of Visual Startle in the Coma Recovery Scale-Revised for Disorders of Consciousness. PMID- 30019218 TI - Comprehensive Proteomic Profiling of Patients' Tears Identifies Potential Biomarkers for the Traumatic Vegetative State. AB - The vegetative state is a complex condition with unclear mechanisms and limited diagnostic, prognostic, and therapeutic methods. In this study, we aimed to explore the proteomic profile of tears from patients in a traumatic vegetative state and identify potential diagnostic markers using tears-a body fluid that can be collected non-invasively. Using iTRAQ quantitative proteomic technology, in the discovery phase, tear samples collected from 16 patients in a traumatic vegetative state and 16 normal individuals were analyzed. Among 1080 identified tear proteins, 57 were upregulated and 15 were downregulated in the patients compared to the controls. Bioinformatics analysis revealed that the differentially-expressed proteins were mainly involved in the wound response and immune response signaling pathways. Furthermore, we verified the levels of 7 differentially-expressed proteins in tears from 50 traumatic vegetative state patients and 50 normal controls (including the samples used in the discovery phase) using ELISA. The results showed that this 7-protein panel had a high discrimination ability for traumatic vegetative state (area under the curve = 0.999). In summary, the altered tear proteomic profile identified in this study provides a basis for potential tear protein markers for diagnosis and prognosis of the traumatic vegetative state and also provides novel insights into the mechanisms of traumatic vegetative state. PMID- 30019220 TI - Laparoscopic pyloroplasty versus endoscopic per-oral pyloromyotomy for the treatment of gastroparesis. AB - BACKGROUND: Gastroparesis is a debilitating functional disorder of the stomach characterized by delayed gastric emptying absent an obstructive etiology. Surgical or endoscopic disruption of the pylorus has been utilized to treat this disease, but there is little evidence comparing laparoscopic pyloroplasty (LP) with endoscopic per-oral pyloromyotomy (POP). Herein we describe our experience at our institution using a propensity-matched cohort study to compare outcomes between these procedures. METHODS: All patients who underwent LP for the treatment of gastroparesis from October 2014 through September 2017 at our institution were retrospectively reviewed. Propensity scoring was used to match these patients 1:1 to patients undergoing POP during this time period based on gender, age, and etiology of gastroparesis. Symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI), scintigraphic gastric emptying studies (GES), and perioperative outcomes were compared between matched cohorts. Thirty patients underwent LP for gastroparesis during the study period which were matched 1:1 with patients undergoing POP. The etiology of gastroparesis was 63.3% idiopathic (n = 19), 20.0% post-surgical (n = 6), and 16.7% diabetic (n = 5) in both cohorts. RESULTS: Patients who underwent LP had a longer average length of stay (4.6 vs. 1.4 days, p = 0.003), operative time (99.3 vs. 33.9 min, p < 0.001), and estimated blood loss (12.9 vs. 0.4 mL, p < 0.001). There were more complications in the LP cohort (16.7 vs. 3.3%, p = 0.086), which included surgical site infection (6.7 vs. 0%, p = 0.153), pneumonia (6.7 vs. 0.0%, p = 0.153), and unplanned ICU admission (10.0 vs. 0.0%, p = 0.078). LP and POP both resulted in similar, significant improvements in both in GCSI scores and objective gastric emptying. CONCLUSIONS: Per-oral endoscopic pyloromyotomy (POP) is safe and effective for the treatment of medical refractory gastroparesis. POP has less perioperative morbidity compared to LP with comparative functional outcomes. PMID- 30019219 TI - Heterogeneity within the PF-EPN-B ependymoma subgroup. AB - Posterior fossa ependymoma comprise three distinct molecular variants, termed PF EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies. PMID- 30019222 TI - Longitudinal Links Between Adolescent Social Anxiety and Depressive Symptoms: Testing the Mediational Effects of Cybervictimization. AB - This study focuses on the temporal sequence between social anxiety and depressive symptoms, and whether cybervictimization might mediate these links. We used a longitudinal sample of 501 early adolescents (51.9% girls; Mage = 13.96) followed at three time points. Using a cross-lagged path model in MPlus, we found that social anxiety predicted depressive symptoms over time, but not the other way around. Time-1 depressive symptoms also predicted cybervictimization, but only for boys and not for girls. No mediating effects of cybervictimization emerged; however, Time-2 social anxiety was a significant mediator between Time-1 social anxiety and depressive symptoms, whereas Time-2 depressive symptoms significantly mediated the link between Time-1 social anxiety and Time-3 depressive symptoms. In sum, social anxiety was a strong predictor of depressive symptoms over time but not vice versa-irrespective of cybervictimization. PMID- 30019223 TI - Cognitive-Affective Pathways to Child Depressive and Anxious Symptoms: Role of Children's Discipline Attributions. AB - Children's maladaptive cognitive attributions may elicit affective reactions that contribute to depressive and anxious symptoms. This study investigated cognitive affective pathways in depressive and anxious symptoms in a sample of 110 prepubertal children, evaluating children's specific appraisals of experiences of parental discipline as well as general attributional style, along with their hopelessness, self-esteem, and shame. Pathways toward depressive and anxious symptoms were tested simultaneously to identify potential unique etiological mechanisms. Results suggested that lower self-esteem strongly contributed to depressive and anxious symptoms, whereas shame related to depression only and hopelessness related to depression only marginally. Additionally, general negative attributional style and low sense of control over discipline related to all three affective elements. Lastly, low sense of discipline control directly predicted depressive symptoms, whereas beliefs that discipline was undeserved directly predicted anxious symptoms. Future work should continue to examine the role of children's discipline-specific attributions, which appear important in internalizing symptoms. PMID- 30019221 TI - Minimally invasive surgery techniques in pelvic exenteration: a systematic and meta-analysis review. AB - BACKGROUND: Pelvic exenteration is potentially curative for locally advanced and recurrent pelvic cancers. Evolving technology has facilitated the use of minimally invasive surgical (MIS) techniques in selected cases. We aimed to compare outcomes between open and MIS pelvic exenteration. METHODS: A review of comparative studies was performed. Firstly, we evaluated the differences in surgical techniques with respect to operative time, blood loss, and margin status. Secondly, we assessed differences in 30-day morbidity and mortality rates, and length of hospital stay. RESULTS: Four studies that directly compared open and MIS exenteration were included. Analysis was performed on 170 patients; 78.1% (n = 133) had open pelvic exenteration, while 21.8% (n = 37) had a MIS exenteration. The median age for open exenteration was 57.7 years versus 63 years for MIS exenteration. Even though the operative time for MIS exenteration was 83 min longer (p < 0.001), it was associated with a median of 1,750mls less blood loss. The morbidity rate for MIS exenterative group was 56.7% (n = 21/37) versus 88.5% (n = 85/96) in the open exenteration group, with pooled analysis observing a 1.17 relative risk increase in 30-day morbidity (p = 0.172) in the open exenteration group. In addition, the MIS cohort had a 6-day shorter length of hospital stay (p = 0.04). CONCLUSION: MIS exenteration can be performed in highly selective cases, where there is favourable patient anatomy and tumour characteristics. When feasible, it is associated with reduced intra-operative blood loss, shorter length of hospital stay, and reduced morbidity. PMID- 30019224 TI - Denosumab in the treatment of glucocorticoid-induced osteoporosis. AB - Glucocorticoid therapy is the number one cause of secondary osteoporosis particularly effecting young individuals. Possessing an increased risk for fractures, glucocorticoid-induced osteoporosis might interfere with patients' well-being and quality of life. Therefore, proper treatment of bone loss and prevention from fractures are of great importance. There are a limited number of therapeutic and preventative options for glucocorticoid-induced osteoporosis. Denosumab, with its high anti-resorptive potential, has been studied several times among patients on glucocorticoid therapy. However, a comprehensive look analysing the current data is lacking. Thus, the objective of the current article is to evaluate the current evidence on the efficacy, as well as the safety profile of denosumab in glucocorticoid-induced osteoporosis. Pubmed/MEDLINE, Scopus and Web of Science databases were searched for the terms denosumab, glucocorticoid-induced osteoporosis, steroid-induced osteoporosis, glucocorticoids and osteoporosis. Relevant data regarding the efficacy and safety of denosumab among patients with glucocorticoid-induced osteoporosis was analysed. Denosumab contributes to increased bone mineral density and decreased bone-turnover marker levels among glucocorticoid users. It is an effective therapeutic option with a favourable safety profile in glucocorticoid-induced osteoporosis. PMID- 30019226 TI - Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. AB - Autoinflammatory diseases are characterized by fever attacks of varying durations, associated with variety of symptoms including abdominal pain, lymphadenopathy, polyserositis, arthritis, etc. Despite the diversity of the clinical presentation, there are some common features that make the differential diagnosis of the autoinflammatory diseases challenging. Familial Mediterranean fever (FMF) is the most commonly seen autoinflammatory conditions, followed by syndrome associated with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). In this review, we aim to evaluate disease characteristics that make a diagnosis of FMF and PFAPA challenging, especially in a regions endemic for FMF. The ethnicity of patient, the regularity of the disease attacks, and the involvement of the upper respiratory systems and symphonies could be helpful in differential diagnosis. Current data from the literature suggest the use of biological agents as an alternative for patients with FMF and PFAPA who are non responder classic treatment options. More controlled studies are needed to evaluate the efficacy and safety of this strategy. PMID- 30019227 TI - Iron Deficiency in Heart Failure: to Treat or Not to Treat? AB - PURPOSE OF REVIEW: This review will highlight the frequency and prognostic importance of iron deficiency in patients with chronic heart failure. An overview of the evidence surrounding the use of both oral and intravenous iron will be presented together with discussion around what further data are required to establish what is the optimal long-term treatment strategy. RECENT FINDINGS: Several recent randomised controlled studies have suggested that intravenous iron therapy in iron deficient patients with chronic heart failure and reduced ejection fraction can improve symptoms and quality of life, at least in the short term. There is no evidence of benefit from oral iron. Iron deficiency is common in patients with chronic heart failure and is associated with a worse prognosis. Whilst oral iron therapy has been shown to be of no benefit, randomised controlled trials suggest significant improvement in symptoms and quality of life with intravenous iron treatment over 6-12 months. Data are lacking on long-term efficacy, safety and impact on hard outcomes such as death and hospitalisation. Four large trials are currently recruiting patients and will provide definitive answers to these outstanding questions. PMID- 30019225 TI - Regulation of energy metabolism in the growth plate and osteoarthritic chondrocytes. AB - Osteoarthritis (OA) is a chronic disorder associated mainly with pain, limited range of motion, stiffness, low-grade systemic inflammation, and articular cartilage destruction. Recent studies have demonstrated the involvement of chondrocyte differentiation (hypertrophy) as one of the mechanisms in cartilage degradation in OA. This implicates the involvement of principal changes in the regulation of cellular function associated with profound alterations in chondrocyte energy metabolism in the course of cartilage resorption. Therefore, this review describes the major energy-generating pathways and their regulatory molecules used by the growth plate chondrocytes during endochondral ossification and by articular chondrocytes in OA. These regulatory molecules facilitate either the glycolytic pathway of energy generation, which controls cell proliferation, or mitochondrial oxidative phosphorylation promoted by AMPK and sirtuins and responsible for tissue regeneration. Consideration of the disturbances in energy metabolic pathways associated with OA might provide an approach to disclose the primary causes of the disease's development and progression. Medline/PubMed was searched for publications in English using key words: osteoarthritis, epiphyseal growth plate, articular cartilage, glycolysis, oxidative phosphorylation, and regulation of energy metabolism. PMID- 30019228 TI - Robotic laparoendoscopic single-site radical prostatectomy (R-LESS-RP) with daVinci Single-Site(r) platform. Concept and evolution of the technique following an IDEAL phase 1. AB - To describe the evolution of robotic laparoendoscopic single-site radical prostatectomy (R-LESS-RP) performed with the daVinci Single-Site Platform(r) and a home-made multiport aimed to overcome classical drawbacks of LESS, still present with this platform. Between 09/2015 and 06/2017 12 patients underwent R LESS RP for clinical localized prostate cancer. Following a "phase 1 (development stage)" innovation, development, exploration, assessment, long-term study (IDEAL) framework, different solutions were drawn to overcome drawbacks of daVinci Single Site Platform(r), included 3 (A, B, and C) multi-ports developed and evaluated in term of advantages/drawbacks concerning ergonomy. The end points of this study were: feasibility, safety, efficacy, by reporting rational description of multiports configuration, demographics, perioperative variables, functional and oncological results. Semi-flexible robotic 5-mm needle-holder instead of Maryland forceps, 30 degrees lenses up and barbed-suture allowed overcoming limits of robotic-platform. Multiport-C (GelPOINT Advanced-Access(r) and an extra 8-mm robotic trocar outside the multiport) showed the best compromise to ensure both surgeon and bed-side assistant to reproduce a standard robotic procedure. No conversion to either standard robotic or open technique or intraoperative complications occur in any case. Two patients experienced "high-grade" Clavien Dindo complications. After 12.4 months follow-up, all patients were continent without any sign of biochemical relapse and among 5 preoperative potent patients submitted to nerve-sparing dissection, 4 reported good erectile-function. R-LESS RP is feasible and safe in the hands of experienced minimally-invasive surgeons. Do date, we recommend a hybrid solution with a home-made multiport and use of an additional standard robotic trocar which allows the use endowrist(r) technology instruments. PMID- 30019229 TI - Weight Management in Patients with Type 2 Diabetes: a Multidisciplinary Real world Approach. AB - PURPOSE OF REVIEW: Obesity and type 2 diabetes (T2D) are closely linked metabolic diseases. Most individuals with T2D are overweight or obese, which raises their cardiovascular risk. The etiology of both diseases is multifaceted, thus requiring a multidisciplinary approach to control them. This review describes the most effective multidisciplinary approach to weight management in patients with T2D in real-world clinical practice. RECENT FINDINGS: Weight management programs in real-world clinical settings lead to long-term weight loss for up to 5 years. Multidisciplinary approach to manage obesity and T2D through weight reduction is feasible in real-world clinical practice and is recommended as part of the treatment plan for patients with T2D who are overweight or obese. Recent data demonstrates that multidisciplinary approach to weight management in patients with T2D results in long-term weight loss and is associated with improved cardiovascular risk factors. PMID- 30019230 TI - Increased thalamic glutamate/glutamine levels in migraineurs. AB - BACKGROUND: Increased cortical excitability has been hypothesized to play a critical role in various neurological disorders, such as restless legs syndrome, epilepsy and migraine. Particularly for migraine, local hyperexcitability has been reported. Levels of regional excitatory and inhibitory neurotransmitters are related to cortical excitability and hence may play a role in the origin of the disease. Consequently, a mismatch of the excitatory-inhibitory neurotransmitter network might contribute to local hyperexcitability and the onset of migraine attacks. In this study we sought to assess local levels of glutamate / glutamine (GLX) and gamma-aminobutyric acid (GABA) in the occipital cortex and right thalamus of migraineurs and healthy subjects. METHODS: We measured interictally local biochemical concentrations in the occipital lobe and the right thalamus in patients with migraine (without aura) and healthy controls (HCs) using proton magnetic resonance spectroscopy at 3 T. GLX levels were acquired using PRESS and GABA levels using the GABA-sensitive editing sequence MEGA-PRESS. Regional GLX and GABA levels were compared between groups. RESULTS: Statistical analyses revealed significantly increased GLX levels in both the primary occipital cortex and thalamus. However, we found no group differences in GABA levels for these two regions. Correlation analyses within the migraine group revealed no significant correlations between pain intensity and levels of GLX or GABA in either of the two brain regions. CONCLUSIONS: Further research is needed to investigate the role of GABA/GLX ratios in greater depth and to measure changes in neurotransmitter levels over time, i.e. during migraine attacks and interictally. PMID- 30019231 TI - Social network changes during space restriction in zoo chimpanzees. AB - Several studies across anthropoid species have demonstrated how primates respond to the increased risk of conflict during space restriction with various behavioral strategies. Three strategies have been proposed relating to tension regulation, conflict avoidance, and inhibition. Prior research supporting these strategies has focused on individual- and dyadic-level analyses, yet group-living animals live within a web of inter-individual connections. Here, for the first time, we used a network approach to investigate how social structure and individuals' connectedness change during space restriction. We collected grooming and aggression data during a 6-week control period and a 5-week period of space restriction in a large group of zoo chimpanzees. We compared network density and individual centrality measures (degree, eigenvector, and betweenness centrality) between these two periods using permutation tests. The density of the unidirectional grooming network was significantly lower during space restriction, indicating fewer grooming partners and a less cohesive network. This was mainly due to a reduction in females' grooming partners (degree) and an increase in females' betweenness centrality. We found no differences in the mutual grooming or aggression networks. Our findings are consistent with a conflict avoidance strategy and complement previous findings from the same dataset based on individual behavioral rates that supported a selective inhibition strategy. The results highlight the dynamic nature of social structure and its inherent flexibility to respond effectively to short-term changes in the environment. PMID- 30019232 TI - Predation of army ants by Toppin's titi monkey, Plecturocebus toppini Thomas 1914 (Primates: Pitheciidae), in an urban forest fragment in eastern Acre, Brazil. AB - The predation of army ants (Eciton rapax) was recorded during an observational study of the feeding behavior of a group of titi monkeys (Plecturocebus toppini) in an urban fragment of forest in Acre, Brazil. During one observed event, the group's adult female used its tail to retrieve ants, a type of behavior not observed previously in this genus. All incidents of on-forest floor foraging occurred during the dry season, when fruit was least abundant in the forest, while on other occasions, the ants were captured from tree branches and leaves. The observation of predation and ground-level foraging recorded in this study reinforce the adaptive capacity of P. toppini for survival in fragmented forests, and this was also the first record of the predation of army ants by this titi species. PMID- 30019233 TI - [Diagnostics and treatment of lacrimal duct diseases : A structured patient centred care concept]. AB - BACKGROUND: The cardinal symptom of lacrimal stenosis is epiphora and a subjective high level of discomfort due to continuous dacryorrhea. OBJECTIVE: The aim of the current paper is to present a structured review of common diagnostic and therapeutic strategies for lacrimal stenosis. MATERIALS AND METHODS: The most important diagnostic and therapeutic approaches are analysed using the existing literature and by reporting the authors' own experiences. RESULTS: A detailed patient history is crucial for diagnosis of lacrimal disorders. Precise inspection and palpation of the lacrimal and lid region may confirm lacrimal stenosis. Examinations of tear production, tear quality and the properties of the ocular surface are helpful. The most important diagnostic tool is lacrimal duct probing and syringing. Therapy is guided by underlying pathologies. Treatment of congenital lacrimal stenosis follows a staged concept. Epiphora in adults without signs of dacryocystitis should be treated with dacryoendoscopy. Dacryoendoscopy is also a therapeutic option for chronic dacryocystitis, but dacryocystorhinostomy may also be required. Lacrimal trauma should be reconstructed rapidly after the incident by lacrimal intubation. Neoplasia of the lacrimal excretory system requires histological classification to enable multidisciplinary management. CONCLUSION: Basic ophthalmologic diagnostics are complemented by special symptom-based examinations. Due to ongoing improvement of available diagnostic and therapeutic options, patients' care is becoming increasingly individualised. PMID- 30019234 TI - Balance in multiple sclerosis: relationship to central brain regions. AB - Dizziness, postural instability, and ataxia are among the most debilitating symptoms of multiple sclerosis (MS), reflecting, in large part, dysfunctional integration of visual, somatosensory, and vestibular sensory cues. However, the role of MS-related supratentorial lesions in producing such symptoms is poorly understood. In this study, motor control test (MCT) and dynamic sensory organization test (SOT) scores of 58 MS patients were compared to those of 72 healthy controls; correlations were determined between the MS scores of 49 patients and lesion volumes within 26 brain regions. Depending upon platform excursion direction and magnitude, MCT latencies, which were longer in MS patients than controls (p < 0.0001), were correlated with lesion volumes in the cortex, medial frontal lobes, temporal lobes, and parietal opercula (r's ranging from 0.20 to 0.39). SOT test scores were also impacted by MS and correlated with lesions in these same brain regions as well as within the superior frontal lobe (r's ranging from - 0.28 to - 0.40). The strongest and most consistent correlations occurred for the most challenging tasks in which incongruent visual and proprioceptive feedback were given. This study demonstrates that supratentorial lesion volumes are associated with quantitative balance measures in MS, in accord with the concept that balance relies upon highly convergent and multimodal neural pathways involving the skin, muscles, joints, eyes, and vestibular system. PMID- 30019235 TI - Fast periodic visual stimulation to study tool-selective processing in the human brain. AB - Because tools are manipulated for the purpose of action, they are often considered to be a specific object category that associates perceptual and motor properties. Their neural processing has been studied extensively by comparing the cortical activity elicited by the separate presentation of tool and non-tool objects, assuming that observed differences are solely due to activity selective for processing tools. Here, using a fast periodic visual stimulation (FPVS) paradigm, we isolated EEG activity selectively related to the processing of tool objects embedded in a stream of non-tool objects. Participants saw a continuous sequence of tool and non-tool images at a 3.7 Hz presentation rate, arranged as a repeating pattern of four non-tool images followed by one tool image. We expected the stimulation to generate an EEG response at the frequency of image presentation (3.7 Hz) and its harmonics, reflecting activity common to the processing of tool and non-tool images. Most importantly, if tool and non-tool images evoked different neural responses, we expected this differential activity to generate an additional response at the frequency of tool images (3.7 Hz/5 = 0.74 Hz). To ensure that this response was not due to unaccounted for systematic differences in low-level visual features, we also tested a phase-scrambled version of the sequence. The periodic insertion of tool stimuli within a stream of non-tool stimuli elicited a significant EEG response at the tool-selective frequency and its harmonics. This response was reduced when the images were phase scrambled. We conclude that FPVS is a promising technique to selectively measure tool-related activity. PMID- 30019237 TI - Physiology-based ERPs in normal and abnormal states. AB - Evoked response potentials (ERPs) and other transients are modeled as impulse responses using physiology-based neural field theory (NFT) of the corticothalamic system of neural activity in the human brain that incorporates synaptic and dendritic dynamics, firing response, axonal propagation, and corticocortical and corticothalamic pathways. The properties of model-predicted ERPs are explored throughout the stability zone of the corticothalamic system, and predicted time series and wavelet spectra are also analyzed. This provides a unified treatment of predicted ERPs for both normal and abnormal states within the brain's stability zone, including likely parameters to represent abnormal states of reduced arousal. PMID- 30019236 TI - Structure and properties of composite surface layers produced on NiTi shape memory alloy by a hybrid method. AB - A hybrid process that combines oxidation under glow-discharge conditions with ion beam-assisted deposition (IBAD) has been applied to mechanically polished NiTi shape memory alloy in order to produce composite surface layers consisting of a TiO2 layer and an external carbon coating with an addition of silver. The produced surface layers a-C(Ag) + TiO2 type have shown increased surface roughness, improved corrosion resistance, altered wettability, and surface free energy, as well as reduced platelet adhesion, aggregation, and activation in comparison to NiTi alloy in initial state. Such characteristics can be of great benefit for cardiac applications. PMID- 30019238 TI - A mathematical model of angiogenesis and tumor growth: analysis and application in anti-angiogenesis therapy. AB - The purpose of this paper is to develop a new coupled mathematical model of angiogenesis (new blood vessel growth) and tumor growth to study cancer development and anti-angiogenesis therapy. The angiogenesis part assumes the capillary to be a viscoelastic continuum whose stress depends on cell proliferation or death, and the tumor part is a Darcy's law model regarding the tumor mass as an incompressible fluid where the nutrient-dependent growth elicits volume change. For the coupled model, we provide both an inviscid analysis and a parameter sensitivity analysis of the angiogenesis model in response to a stationary hypoxic tumor, and a steady state analysis of the tumor growth in response to a fixed and long blood capillary. The analysis shows that the stable steady state tumor with an invading blood capillary exists if and only if the nutrient release rate divided by the decay rate is less than the tumor viable limit, and the full tumor encloses one part of the capillary in this steady state. Afterwards, we use the coupled model to simulate vascularized tumor growth and anti-angiogenesis therapy. The simulations show that the tumor tends to maximize the nutrient transfer by blood vessel co-option and the anti angiogenesis treatment by using growth factor neutralizing antibodies would regress the neovasculature and shrink the tumor size. However, the shrunken tumor mass could survive by feeding on mature blood vessels that resist the treatment. This implies the limited efficacy of the anti-angiogenesis monotherapy and its effect on vessel normalization. PMID- 30019240 TI - The Relation Between the Lower Lateral Cartilages and the Function of the External Nasal Valve. AB - INTRODUCTION: The position of the lower lateral cartilages (LLC) is closely related to the function of the external nasal valve (ENV). When there is a cephalic malposition of these cartilages, the nasal alae have inadequate support, which leads to ENV insufficiency during deep inspiration. METHODS: Retrospective study with 60 patients evaluated: the positioning of the LLC and the occurrence of ENV insufficiency; the effectiveness of structuring the medial and lateral walls of the ENV; and the frequency of the grafts used for structuring it. RESULTS: Of the 60 operated cases, 37 patients (62%) had ENV insufficiency, in 23 cases there was cephalic malposition of the LLC, and in the latter group 17 patients (74%) presented this insufficiency. A structured ENV was effective in the treatment of this insufficiency (p = 0.001). A lateral crural strut graft was performed in 24 cases (40%) of 60 patients operated. The alar contour graft was performed from 2013 to 2015 in 4 patients (22%) of 18 cases operated, and between 2016 and 2018 it was performed in 29 patients (69%) out of 42 cases. The columellar strut was routinely used from 2013 to mid-2016 in 33 cases (100%), and after that period until the present day the tongue-in-groove technique was performed in 11 cases (41%) and in the remaining 16 cases (59%) the caudal septal extension graft was performed. CONCLUSION: Cephalic malposition of the LLC is an important red flag of ENV insufficiency. This insufficiency should be treated by structuring the walls of the ENV. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30019239 TI - Update on systemic therapy for advanced cutaneous melanoma and recent development of novel drugs. AB - Malignant melanoma is generally chemo- and radio-resistant, and patients with advanced melanoma have a poor prognosis. However, with our increased understanding of the checkpoint immune molecules and genetic alterations of melanoma cells, more effective immunotherapy, such as anti CTLA4 antibody and anti PD-1 antibodies, and targeted drug therapy, such as BRAF inhibitors and MEK inhibitors, have been developed, resulting in improved overall survival and quality of life of patients with advanced melanoma. In addition, emerging technologies to develop prognostic and predictive biomarkers for response to systemic therapy could help clinicians make more accurate assessments of the disease and formulate more effective treatment plans. In this review, current standard systemic therapy options and recently developed novel drugs for advanced melanoma are discussed. PMID- 30019241 TI - A Randomized, Placebo-Controlled, Double-Blind, Prospective Clinical Trial of Botulinum Toxin Type A in Prevention of Hypertrophic Scar Development in Median Sternotomy Wound. AB - BACKGROUND: Linear hypertrophic scar is a common surgical problem that can be difficult to manage, especially for the median sternotomy scar. Botulinum toxin type A (BTA) is widely used in cosmetic surgery and has been shown to improve scar quality recently. The aim of this study was to evaluate the efficacy of BTA injected in the early postoperative of median sternotomy on preventing scar formation. METHODS: In this prospective randomized controlled trial, 19 consecutive patients who underwent median sternotomy were enrolled. The median sternotomy wound in each patient was divided into the upper half and the lower half. Both halves of the wound were randomized to receive the treatment with either BTA or normal saline. At 6-month follow-up, scars were assessed using the Vancouver Scar Scale, scar widths were measured, and patients were asked to evaluate their overall satisfaction. RESULTS: Seventeen patients with median sternotomy wounds completed the entire study. At 6-month follow-up, the mean Vancouver Scar Scale score for the BTA-treated group was 3.44 +/- 1.68 and for the normal saline control group was 6.29 +/- 2.39, and there was a statistically significant difference between the two groups (P < 0.05). There were also significant improvements in scar width and patient satisfaction for the BTA treated halves of the wounds (P < 0.05). CONCLUSIONS: The study demonstrates that early postoperative BTA injection can decrease scar formation and reduce scar width in median sternotomy wounds, and the overall appearance is more satisfactory. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30019242 TI - Systematic Review of Quality-of-Life Measurement After Aesthetic Rhinoplasty. AB - INTRODUCTION: The assessment of outcomes in aesthetic rhinoplasty is highly relevant because patient satisfaction and improved health-related quality of life (QoL) are the predominant factors in determining success. The patient-reported outcome measures (PROMs) employed in rhinoplasty research studies are remarkably diverse, thus yielding difficulties with data analysis. The aim of this article is to provide a comprehensive review of the literature to reveal the relevance of the QoL assessment for rhinosurgeons. METHODS: A systematic literature search with the terms "Rhinoplasty" and "Quality of Life" was conducted using PubMed/MEDLINE, Google Scholar and Cochrane databases. Primarily, all publications related to QoL following aesthetic rhinoplasty between 2002 and 2017 were identified. As a secondary selection, we focused on articles with a prospective study design, a significant cohort size (at least 50 patients) and a follow-up period of at least 6 months after aesthetic rhinoplasty. RESULTS: A total of 62 PROM studies assessing QoL following aesthetic rhinoplasties were obtained. We ascertained an increasing publication rate of QoL articles over the last 15 years. Only 17 studies satisfied comprehensive inclusion criteria of a high qualitative study selection. The Rhinoplasty Outcome Evaluation was the most frequently used QoL questionnaire of the secondary selection (70.6%). The total number of 16 various questionnaires exhibit high heterogeneity. CONCLUSION: Our data strengthen the increasing importance of the assessment of QoL after rhinoplasty. Despite a lack of reliable publications with considerable heterogeneity and large variability in outcomes, functional-aesthetic rhinoplasty leads to a significant improvement of patient's health-related QoL. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30019243 TI - Religion and the Plastic Surgeon: an Imam, a Minister, and a Rabbi Walk into a Surgical Centre. AB - Cultural competency has become a keystone in forming a successful doctor-patient relationship to provide culturally appropriate services that respect patients' ethno-cultural beliefs, values, attitudes, and conventions. In cosmetic surgery, an often-overlooked aspect of a patient's cultural is his and her religious beliefs. In response to this paucity of resources for cosmetic surgeons to enable them to properly service their religious patients, this project was undertaken. This review article covers the three main Abrahamic religions (Judaism, Christianity, and Islam) and was written with the assistance of a prominent bioethicist from each religion (see Acknowledgements). In discussing each religion, the article has been divided into two sections. The first section is a general overview of the religion's relationship with cosmetic surgery as summary provided by the consulting bioethicist. The second portion is an annotated review of additional resources providing the reader further details on that religion. For example, our bioethicists provide a general perspective on Christianity as a whole, and the annotated review focuses on differences between Catholics and Protestants. We recognize the heterogeneity that is inherent in religion and the cultural and geographic biases that affect it. However, we aim to provide the reader a broad and basic foundation of the relationship between Judaism, Christianity, and Islam with cosmetic surgery to begin to create common ground between the physician and the patient and improve the process of shared decision making and thus our outcomes. This paper should be seen as a foundation to build upon rather than an authoritative source, and specific patient concerns should be addressed with the patient's own religious advisor. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30019244 TI - Growth performance and rumen development in Malabari kids reared under different production systems. AB - In order to investigate the effect of rearing systems on growth and rumen development in Malabari male kids, 14 pre-weaned Malabari male kids of uniform morphological characters were randomly divided into two equal groups as T1 and T2. Both the groups were reared intensively for 12 weeks whereby kids under T1 group were allowed to suckle their dams and provided green grass ad libitum. The kids under T2 were weaned at the age of 7 days and provided formulated semi-solid broiler goat concentrate diet through the feeding bottle and were not offered any grass/roughage. Parameters like live weight gain, daily weight gain and body measurements were studied to evaluate the growth performance. However, gastrointestinal tract morphometric studies and qualitative morphological analysis of rumen papillae were undertaken to measure the rumen development. The daily weight gain of kids under T2 was significantly (P <= 0.01) higher than the daily weight gain of kids under T1. Also, the body measurements like height at withers, heart girth and body length were significantly (P <= 0.01) higher in T2 than in T1. The rumen and abomasum were comparatively more developed in T2 than in T1. The morphology of rumen papillae in both groups was different in size, shape and colour. The length, width, density and surface area of rumen papillae among kids in T2 were significantly (P <= 0.01) higher than those kids in T1. The results of the present study indicated that the feeding of semi-solid broiler goat concentrate diet improved growth performance and early rumen development in kids. PMID- 30019245 TI - Seroprevalence of bluetongue and presence of viral antigen and type-specific neutralizing antibodies in goats in Tripura, a state at Indo-Bangladesh border of northeastern India. AB - Bluetongue (BT) is a notifiable multiple species transboundary viral disease of domestic and wild ruminants. Though the disease is enzootic in India, little is known of the disease burden and prevalent serotypes in Tripura, a hilly state of northeastern India sharing a vast porous border with Bangladesh. A surveillance study was conducted to understand the disease burden in goats in Tripura. Serum (n = 1240) and blood (n = 194) samples were collected during the year 2014 to 2017 from all the eight districts of Tripura. The overall prevalence of BT seroconversion was 47.58% whereas the presence of viral antigen was 20.61% at the individual level. Percent seroconversion was found more (50.47 +/- 4.00, CI 41.31 to 49.47) in adult goats in comparison to the younger animals where it was 45.39 +/- 2.08, CI 42.63 to 58.31. Presence of neutralizing antibodies in selected serum samples (n = 72) was investigated by serum neutralization test (SNT) against six bluetongue virus (BTV) serotypes and BTV-1 was found as most predominant (65.27%) followed by BTV-16 (26.38%), BTV-10 (20.83%), BTV-9 and 23 (13.88%), and BTV-2 (6.94%). To the best of our knowledge, this is the first study conducted in Tripura to investigate the presence of BTV antigen and type specific neutralizing antibodies in apparently healthy goats. PMID- 30019246 TI - Incisional hernia after surgery for colorectal cancer: a population-based register study. AB - BACKGROUND: Our knowledge on the incidence of incisional hernia and risk factors for developing incisional hernia following surgery for colorectal cancer is far from complete. METHODS: All procedures registered in the Swedish Colorectal Cancer Register (SCRCR) 2007-2013 were identified. Patients with comorbid disease diagnoses, registered at admissions and visits prior to the procedure and relevant to this study, were obtained from the National Patient Register (NPR). These diagnoses included cardiovascular disease, connective tissue disorders, liver cirrhosis, renal failure, diabetes, chronic obstructive lung disease and chronic inflammatory conditions. Data on occurrence of incisional hernias were obtained by combining data from the SCRCR and the NPR (International Classification of Diseases code). RESULTS: During 2007-2013, 39,984 procedures were registered in the SCRCR. After excluding laparoscopic procedures, procedures repeated on the same patient, procedures with concomitant liver resection and procedures without laparotomy, 28,913 cases remained for analysis. Five years after surgery, the cumulative incidence of incisional hernia was 5.3%. In multivariate proportional hazard analysis, significantly increased risk for incisional hernia was found for the male gender (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.21-1.62), operation time exceeding 180 min (HR 1.25, CI 1.08-1.45), body mass index (BMI) > 30 (HR 1.78, CI 1.51-2.09), age < 70 years (HR 1.34, CI 1.16-1.56) and postoperative wound complication (HR 2.09, CI 1.70 2.58). DISCUSSION: Men, patients younger than 70 years and patients with BMI > 30 face a higher risk for incisional hernia. The risk is also increased in cases where the procedure takes longer than 3 h or where postoperative wound complications occur. These patients will benefit from measures aimed at preventing the development of incisional hernia. PMID- 30019247 TI - Microbial responses to transient shock loads of quaternary ammonium compounds with different length of alkyl chain in a membrane bioreactor. AB - Extensive applications of quaternary ammonium compounds (QACs) in household and industrial products inevitably lead to their release into wastewaters; however, little attention has been paid to the acute effects on activated sludge. In this work, we investigated the responses of microorganisms in a membrane bioreactor (MBR) to transient shock loads of QACs with different alkyl chain length and their impacts on MBR performance. Results showed that QACs affected microbial viability and caused damage to key enzymes (e.g., ammonium monooxygenase and nitrite oxidoreductase), inhibiting organic matter degradation and nitrogen removal. The presence of QACs also caused negative influences on dehydrogenase activity, catalase and superoxide dismutase, thus increasing the production of reactive oxygen species. Moreover, QACs with longer alkyl chains and/or benzyl groups bonded to the nitrogen atom could induce a more severe damage to cell integrity and microbial viability. The interaction with QACs also induced the release of organic matters and the changes of adhesion properties of microbial products, resulting in aggravated membrane fouling in MBRs. Our results demonstrate the acute negative effects of QACs on activated sludge, and special attention should be paid to the performance of biological wastewater treatment processes subject to the shock loads of QAC-bearing industrial streams. PMID- 30019248 TI - MicroRNA-92a-1-5p influences osteogenic differentiation of MC3T3-E1 cells by regulating beta-catenin. AB - Osteoblastic differentiation is a complex process that is critical for proper bone formation. An increasing number of studies have suggested that microRNAs (miRNAs) are pivotal regulators in various physiological and pathological processes, including osteogenesis. Here, we discuss the influence of miRNA-92a-1 5p on osteogenic differentiation. We found that miR-92a-1-5p was obviously downregulated during osteogenic differentiation of MC3T3-E1 cells. Gain-of function and loss-of-function experiments revealed that miR-92a-1-5p was a negative regulator of osteogenic differentiation. Experimental validation demonstrated that beta-catenin, which acts as a positive regulator of osteogenic differentiation, was negatively regulated by miR-92a1-5p. The findings of this study provide new insights into the possibility of miR-92a1-5p being a potential therapeutic target in the management of bone regeneration-related diseases. PMID- 30019249 TI - Study design of multi-center, open-label randomized controlled, head-to-head trial comparing minodronic acid and raloxifene: Japanese Osteoporosis Intervention Trial (JOINT)-04. AB - We planned to conduct multi-center, open-labeled, blinded-endpoints, head-to-head randomized trial of minodronate and raloxifene to compare incidences of vertebral and non-vertebral fractures. The study is the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-4). Here, we present the pre-fixed study design. The inclusion criteria are ambulatory older women with osteoporosis, aged > 60 years, and without pre-specified risk factors for secondary osteoporosis and dementia. The subjects who meet selection criteria will be randomly allocated to the raloxifene (60 mg/day) or minodronate (1 mg/day or 50 mg/4 weeks) groups using the central registry. The co-primary endpoints are osteoporotic (vertebral, humeral, femoral, and radial), vertebral, and major osteoporotic (clinical vertebral, humeral, femoral, and radial) fractures. Furthermore, we plan to use the Hochberg procedure to preserve an overall type 1 error rate. In addition, changes in bone mineral density (BMD), hip-structure analysis (HSA) variables, height, bone turnover markers, serum cholesterol and triglyceride concentrations, dental health questionnaire, fall frequency, fall risk index, nursing care level, physical function, quality of life (QOL), and safety profiles were assessed as secondary endpoints. To detect 24% reduction of major osteoporotic fractures with 80% power and a two-sided significance level of 5% with a 2-year observation period, 1734 patients/treatment arm would be required. Subgroup analysis stratified to the following factors age, body mass index, BMD, 25-hydroxyvitamin D concentration, estimated glomerular filtration rate (eGFR), prevalent vertebral fracture number, hypertension status, and diabetes mellitus is pre-specified. The protocol is registered in the trial registry system, and the trial identification number is UMIN000005433. PMID- 30019250 TI - Postoperative pulmonary complications and thoracocentesis associated with early versus late chest tube removal after thoracic esophagectomy with three-field dissection: a propensity score matching analysis. AB - PURPOSE: To evaluate the safety of early chest tube removal after thoracic esophagectomy with three-field dissection. METHODS: This prospective cohort study evaluated patients who underwent thoracic esophagectomy with three-field dissection during 2013-2015. Patients were divided into two groups according to whether they underwent early or late chest tube removal. Propensity score matching in a 1:1 ratio was applied. We compared the incidences of postoperative pulmonary complications and thoracocentesis in the two groups. RESULTS: After propensity score matching, 89 patients in each group were analyzed. There was no significant difference between the groups in the incidences of pulmonary complications or thoracocentesis. Significantly more patients achieved first mobilization within 15 h postoperatively in the early removal group (89.8%) than in the late removal group (52%, p < 0.01). Multivariate analysis revealed that early chest tube removal was not a risk factor for pulmonary complications or thoracocentesis. Independent risk factors for pulmonary complications were a history of pulmonary disease (odds ratio: 0.81 [0.63-0.98]; p = 0.02) and neoadjuvant chemotherapy (odds ratio: 0.67 [0.32-0.96]; p = 0.04). CONCLUSION: Early chest tube removal is as safe and feasible as late chest tube removal after thoracic esophagectomy with three-field dissection. PMID- 30019251 TI - Fibrinogen binding-dependent cytotoxicity and degradation of single-walled carbon nanotubes. AB - Carbon nanotubes are widely used in the area of biomedicine, and the binding of protein to carbon nanotubes are believed to play an important role in the potential cytotoxicity of nanomaterials. In this work, we investigated the effects of human fibrinogen-surface coatings on the biodegradation and cytotoxicity of carboxylated single-walled carbon nanotubes (SWCNTs). It was found that the electrostatic and pi-pi stacking interactions might be the crucial factors in stabilizing the binding of fibrinogen with SWCNTs by both theoretical and experimental approaches. Although naked SWCNTs could induce significant toxicity to macrophages, coating these nanomaterials with fibrinogen could greatly attenuate their toxicity. On the other hand, although SWCNTs and fibrinogen-preincubated SWCNTs were resistant to biodegradation in resting macrophages, both naked and fibrinogen-coated SWCNTs could be effectively and similarly degraded through myeloperoxidase (MPO) and peroxynitrite (ONOO-) dependent pathways in activated macrophages, where NADPH oxidase played a determinant role in the biodegradation process. Importantly, degraded SWCNTs by ONOO- pathway in vitro induced less cytotoxicity than non-degraded nanotubes. These findings demonstrated that the binding of fibrinogen to SWCNTs could reduce cytotoxicity without affecting the biodegradation of nanotubes in activated inflammatory cells, providing a new route to design the safer nanotubes for future biomedical applications. PMID- 30019254 TI - Expert's comment concerning Grand Rounds case entitled "Traumatic atlantoaxial rotatory fixation in an adult patient" by MA Garcia-Pallero, et al. (Eur Spine J, 2017; DOI 10.1007/s00586-016-4916-3). PMID- 30019252 TI - Mesenteric ischemia in acute aortic dissection. AB - Despite improved outcomes in acute aortic dissection in Japan, mesenteric ischemia remains a problem. This is largely due to difficulties in early diagnosis and treatment. To address this problem, this article will review several diagnostic modalities such as ultrasound and near-infrared spectroscopy, as well as surgical treatments. Ultrasound is useful for assessing mesenteric ischemia because it can be performed at bedside and it provides information on both morphology and perfusion in real time without exposure to radiation or contrast media. Malperfusion can be assessed at four sites between the aorta and intestine. Two causes of malperfusion, aortic type and branch type, can be assessed. Lack of intestinal movement can also indicate ischemia. Near-infrared light assesses regional oxygen saturation in the tissue, while fluorescent visualization using indocyanin green demonstrates vessels and tissue perfusion. Information provided by these imaging modalities can help guide treatment strategies. Future treatments include endovascular interventions combined with conventional surgical procedures. The hybrid OR may be helpful for such sophisticated treatments. PMID- 30019253 TI - Minimally invasive cardiac surgery in Japan: history and current status. AB - This review examines the historical and current status of minimally invasive cardiac surgery (MICS) in Japan, based on reports that have been published in English. Although enthusiasm for MICS in Japan increased during the 1990s, it waned during the early 2000s because of various limitations. However, the introduction of minimally invasive mitral valve surgery, aortic valve replacement, atrial septal defect closure, and coronary artery bypass has led to the resurgence of MICS in Japan during recent years. Academic societies and a national registry system will play an important role in ensuring that this new wave of MICS is implemented safely and effectively. Off-the-job training and team building are also key factors for implementing a successful MICS program. PMID- 30019255 TI - Personalized image-based tumor growth prediction in a convection-diffusion reaction model. AB - Inter-individual heterogeneity of tumors leads to non-effectiveness of unique therapy plans. This issue has caused a growing interest in the field of personalized medicine and its application in tumor growth evaluation. Accordingly, in this paper, a framework of personalized medicine is presented for growth prediction of brain glioma tumors. A convection-diffusion-reaction model is used as the patient-specific tumor growth model which is associated with multimodal magnetic resonance images (MRIs). Two parameters of intracellular area fraction (ICAF) and metabolic rate have been used to incorporate the physiological data obtained from medical images into the model. The framework is tested on the data of two cases of glioma tumors to document the approach; parameter estimation is made using particle swarm optimization (PSO) and genetic algorithm (GA) and the model is evaluated by comparing the predicted tumors with the observed tumors in terms of root mean square error of the ICAF maps (IRMSE), relative area difference (RAD) and Dice's coefficient (DC). Results show the differences of IRMSE, RAD and DC in 4.1 ? 1.15%, 0.099 ? 0.041 and 85.5 ? 7.5%, respectively. Survival times are estimated by assuming the tumor radius of 35 mm as the fatal burden. Results confirm that less-diffusive tumors lead to higher survival times. The represented framework makes it possible to personally predict the growth behavior of glioma tumors only based on patients' routine MRIs and provides a basis for modeling the personalized therapy and walking in the path of personalized medicine. PMID- 30019256 TI - Theoricity, observation and homology: a response to Pearson. AB - An interesting metatheoretical controversy took place during the 1980's and 1990's between pattern and phylogenetic cladists. What was always at stake in the discussion was not how work in systematics should be carried out, but rather how this practice should be metatheoretically interpreted. In this article, we criticize Pearson's account of the metatheoretical factors at play in this discussion. Following him, we focus on the issue of circularity, and on the role that phylogenetic hypotheses play in the determination of "primary homologies". Pearson argues that the recognition of primary homologies cannot be achieved without recourse to previous phylogenetic knowledge, and that to claim otherwise is to state that primary homologies are observable. To show why that view would be inadequate, he appeals to Hanson's views about theory-laden observation, alongside with a specific case study, which allegedly illustrates the more complex relation between observation and theory. We will argue that the pattern cladists' point (at least regarding the issue of homology) is better addressed by taking a quite different approach: instead of thinking in terms of observability, the topic can be tackled by paying attention to the way in which concepts are determined. We will take the notion of T-theoricity from metatheoretical structuralism and show that, once the issue is discussed with the appropriate metatheoretical framework, the alleged counterexample brought up by Pearson is not problematic at all for pattern cladism. PMID- 30019257 TI - The weight of weight self-stigma in unhealthy eating behaviours: the mediator role of weight-related experiential avoidance. AB - Weight stigma plays a damaging role in the life of the individuals with overweight and obesity who may internalise the widespread stigmatisation messages. Weight self-stigma is defined as personal experiences of shame, negative self-evaluations as well as perceived discrimination. It has been found to be related to experiential avoidance patterns and poorer outcomes. The current study aims to conduct a confirmatory factor analysis (CFA) on the Weight Self Stigma Questionnaire (WSSQ) and explore its psychometric properties. Furthermore, the mediator role of weight-related experiential avoidance on the relationship between weight self-stigma and unhealthy eating behaviour was analysed. Concerning the CFA, the sample comprised 331 women with overweight and obesity seeking nutritional treatment. A second independent sample of 58 overweight and obese women was used to assess WSSQ's temporal validity and internal responsiveness. Results supported the WSSQ two-factor structure and good psychometric properties and responsiveness to change. Also, evidence was found for the mediator role of weight-related experiential avoidance on the relationship between BMI, weight self-stigma and unhealthy eating patterns in women with overweight and obesity. Overall, the current study showed that WSSQ is a reliable measure and highlights the important role of weight self-stigma and weight-related experiential avoidance in women with overweight and obesity. Level of evidence: Level V, descriptive studies. PMID- 30019258 TI - Comparing internalization of appearance ideals and appearance-related pressures among women from the United States, Italy, England, and Australia. AB - Researchers have observed variation in levels of body image disturbance and eating pathology among women from different Western countries. Examination of cross-cultural differences in the established risk factors (i.e., thin-ideal internalization, muscular-ideal internalization, and appearance pressures from family, peers, and media) for negative outcomes may help to elucidate the prominence of specific risk factors within a given Western society and guide associated interventions. Women from the United States (US), Italy, England, and Australia completed the Sociocultural Attitudes Towards Appearance Questionnaire 4 (SATAQ-4). Analysis of covariance controlling for age and BMI indicated significant cross-country differences for all SATAQ-4 subscales. Results typically indicated higher levels of appearance-ideal internalization and appearance pressures in the US and lower levels in Italy; however, associated effect sizes were generally small. A medium effect of country was observed for peer-appearance pressures, which were highest in the US compared with all other countries. Repeated-measures analysis of variance and paired samples t tests conducted within each country identified thin-ideal internalization and media appearance pressures as the predominant risk factors for all four countries. Overall, findings suggest more cross-country similarities than differences, and highlight the importance of delivering interventions to address thin-ideal internalization and media appearance pressures among women from Western backgrounds.Level of evidence Descriptive study, Level V. PMID- 30019259 TI - Psychological inflexibility in overweight and obese people from the perspective of acceptance and commitment therapy (ACT). AB - PURPOSE: To identify the psychological inflexibility (PI) processes (experiential avoidance, cognitive fusion, poor contact with the present moment, unclear personal values and lack of commitment to action) associated with body mass index (BMI), depression, anxiety and stress symptoms and binge eating in overweight and obese people by drawing on the acceptance and commitment therapy (ACT) framework. METHODS: A cross-sectional study of 243 people with a BMI of at least 25 and aged from 18 to 60 years old. The following instruments were used: Acceptance and Action Questionnaire II (AAQ-II), Acceptance and Action Questionnaire-Weight (AAQ W), Valued Living Questionnaire (VLQ), Cognitive Fusion Questionnaire (CFQ-7), Cognitive Fusion Questionnaire-Body Image (CFQ-BI), Mindful Eating Questionnaire (MEQ), Binge Eating Scale (BES) and Depression, Anxiety and Stress Scale (DASS 21). Data were analyzed using one-way ANOVA and t tests. RESULTS: There were no differences between BMI categories with respect to PI variables, but PI was positively related to the severity of binge eating and to symptoms of depression, anxiety and stress. CONCLUSION: The development of interventions focused on psychological inflexibility can be useful for the treatment of symptoms associated with overweight and obesity. LEVEL OF EVIDENCE: Level V, cross sectional descriptive study. PMID- 30019260 TI - Partial sleep deprivation and food intake in participants reporting binge eating symptoms and emotional eating: preliminary results of a quasi-experimental study. AB - : Sleep deprivation consistently increases food intake. This study aimed to evaluate the effect of partial sleep deprivation on food intake in individuals reporting binge eating, controlling for self-reported depressive emotional eating. Fourteen young adults reporting binge eating symptoms and 14 controls denying any eating disorders symptoms were offered a large and varied breakfast after a night of habitual sleep (HN) and after a night of partial sleep deprivation (DN). Food intake was unobtrusively measured while daily food intake was measured via a food diary. Results revealed only a significant effect of the Night on fibre consumed at breakfast and on the amount of daily snacks: both groups consumed less fibre and more snacks after DN compared to after HN. However, when controlling for depressive emotional eating, results showed that individuals reporting low depressive emotional eating ate less after DN than after HN at breakfast, but then they ate more throughout the day. Partial sleep deprivation may decrease fibre consumption and increase daily snacks regardless of binge eating symptoms, while daily food intake may increase only in individuals who do not report emotional eating. LEVEL OF EVIDENCE: Experimental study, Level 1. PMID- 30019261 TI - What do I look like? Perceptual confidence in bulimia nervosa. AB - : Cognitive confidence, a type of metacognition referring to confidence in one's cognitive abilities (e.g., memory, perception, etc.), has been identified as relevant to eating disorders (EDs) using self-report measures. Repeated checking has been found to elicit decreases in perceptual confidence in obsessive compulsive disorder (OCD). The purpose of the present study was to experimentally investigate perceptual confidence, a type of cognitive confidence, in EDs. Specifically, this construct was investigated in the context of body checking, a behaviour with similarities to compulsive checking as observed in OCD. Women with bulimia nervosa (BN; n = 21) and healthy controls (HC; n = 24) participated in the study. There were no group differences with regards to perceptual confidence at baseline F(1, 43) = 0.5, p = 0.48, etap2 = 0.01, but a significant difference was observed post-checking F(1, 43) = 7.79, p = 0.008, etap2 = 0.15, which was accounted for by significant decreases in perceptual confidence in the BN group F(1, 43) = 13.31, p < 0.001, etap2 = 0.24. Similar to compulsive checking in OCD, body checking may paradoxically decrease confidence regarding one's appearance. LEVEL OF EVIDENCE: Level I, experimental study. PMID- 30019262 TI - A nanosystem composed of upconversion nanoparticles and N, N-diethyl-p phenylenediamine for fluorimetric determination of ferric ion. AB - A system composed of upconversion nanoparticles (UCNPs) and N,N-diethyl-p phenylenediamine (EPA) is shown to be a useful probe for highly sensitive and selective fluorometric determination of ferric ion. The fluorescence of the UCNPs (under the 980 nm excitation) has peaks at 546, 657, 758 and 812 nm. EPA is readily oxidized by Fe(III) to generate a dye with a peak at 552 nm. This causes an inner filter effect on the fluorescence peaks at 546 nm, whereas the emissions at 657, 758 and 812 nm remained unchanged. Therefore, the iron concentration can be quantified by measurement of the ratio of fluorescence at 546 and 758. Under optimal condition, the ratio drops linearly in the 0.25 to 50 MUM. Fe(III) concentration ranges, with a detection limit of 0.25 MUM. The method is highly selective and was applied to the analysis of spiked samples (wastewater) where it gave recoveries of between 100.9 and 107.3%; and RSD values between 0.8 and 1.4%. Results are approximately the same as those obtained by AAS. Graphical abstract A method is presented for fluorimetric determination of Fe(III). Fe(III) reacts with N,N-diethyl-p-phenylenediamine (EPA) to generate EPA oxide. The fluorescence peaking at 546 nm is reduced in presence of oxidized EPA via an inner filter. PMID- 30019263 TI - Femtosecond laser settings for optimal bracket bonding to zirconia. AB - Bonding orthodontic brackets to ceramic materials is a challenging procedure; femtosecond (FS) laser conditioning could provide improved results, but the ideal settings for effective bracket-zirconia bonding have never been established. This study aimed to analyze the differences in surface roughness and shear bond strength (SBS) produced by different femtosecond laser settings and establish a protocol to prepare zirconia surfaces for optimal adhesion to metal orthodontic brackets. One hundred eighty zirconia samples were assigned to six groups according to surface treatment: (1) control; (2) air-particle abrasion (APA); (3) FS laser irradiation (300 mW output power, 60 MUm inter-groove distance); (4) FS laser irradiation (200 mW, 100 MUm); (5) FS laser irradiation (40 mW, 60 MUm); and (6) FS laser irradiation (200 mW, 60 MUm). Surface roughness was measured. Orthodontic brackets were bonded to the zirconia specimens, and SBS was measured. SBS in groups 3 and 6 was significantly higher than the other groups (5.92 +/- 1.12 MPa and 5.68 +/- 0.94 MPa). No significant differences were found between groups 1, 2, 4, and 5 (3.87 +/- 0.77 MPa, 4.25 +/- 0.51 MPa, 3.74 +/- 0.10 MPa, and 3.91 +/- 0.53 MPa). Surface roughness was significantly greater for FS laser than for control and APA groups (p = 1.28 * 10-8). FS laser at 200 mW, 60 MUm can be recommended as the ideal settings for treating zirconia surfaces, producing good SBS and more economical energy use. PMID- 30019264 TI - Acute kidney injury is linked to higher mortality in elderly hospitalized patients with non-valvular atrial fibrillation. AB - AIM: Renal insufficiency is associated with medical complications in patients with non-valvular atrial fibrillation (NVAF). However, data for elderly patients are scarce. Thus, the main objectives of the present study were to analyze the characteristics of elderly patients with NVAF and acute or chronic renal disease, describe their management in real-life conditions, and detect factors associated with complications. METHODS: The NONAVASC registry includes patients > 75 years with NVAF, hospitalized by any cause in 64 Spanish Internal Medicine departments. Patients were categorized into acute kidney injury (AKI), chronic kidney disease (CKD) or preserved renal function (PRF). All variables associated with in hospital mortality with P < 0.10 in univariate analysis were included to develop a multivariate logistic-regression model. RESULTS: The study included 804 patients (53.9% women), 352 (43.8%) of whom met diagnostic criteria for CKD. AKI was detected in 119 (14.8%) patients. AKI was associated with greater length of stay, higher mortality and an increased rate of patient transfer to nursing homes. After logistic-regression analysis, we found an association between mortality and AKI (OR 2.4, 95% CI 1.03-5.53; P = 0.045). The increase in creatinine values (OR 1.8, 95% CI 1.19-2.73; P = 0.005) and the decrease in albumin values (OR 2.0, 95% CI 1.05-3.73; P = 0.033) were also linked to mortality. CONCLUSIONS: Our study shows the relationship between AKI and creatinine value increase and a higher mortality in elderly patients with NVAF. In light of our findings, the detection of renal function impairment in these patients should alert physicians and consider them as high-risk patients. PMID- 30019265 TI - Adapted physical activity to promote active and healthy ageing: the PoliFIT pilot randomized waiting list-controlled trial. AB - BACKGROUND: Physical activities can prevent disability in elderly. AIMS: To evaluate the feasibility and impact on physical function of an adapted physical activity (APA) programme in community-dwelling people of >= 70 years old. METHODS: Non-blinded randomized trial with a waiting list control. Eligible people (n = 186) were randomly allocated to 4 months of weekly APA classes of 45 min or in control group performing usual lifestyle activity. PRIMARY OUTCOME: time to walk 400 m. SECONDARY OUTCOMES: short physical performance battery (SPPB), pain (visual analogic scale, McGill Questionnaire), Oswestry Disability Index (ODI), Geriatric Depression Scale (GDS), handgrip strength, accesses to Emergency Department and falls. RESULTS: Participants were allocated to the intervention (n = 130) or to the control (n = 56) group (80% females aged 75.6 +/ 4.6 years). We found statistically significant difference in the time to walk 400 m only in the subgroup intervention with the lower performance at baseline (p for interaction 0.031). SPPB improved and VAS decreased more in the intervention group. No significant differences for McGill questionnaire, ODI, GDS, accesses to ER and falls were showed. DISCUSSION: Despite the good rate of attendance (71%) and satisfaction (97%), our APA programme was associated with no benefit on the time to walk 400 m and small benefit on SPPB and VAS. The efficacy of the intervention was likely limited by the short duration and low intensity and by the already good performance of our population at baseline. CONCLUSIONS: We designed this initiative as a pilot study intending to implement research of this type in the future. PMID- 30019266 TI - Therapeutic effects of probiotics on neurotoxicity induced by clindamycin and propionic acid in juvenile hamsters. AB - The present study investigated the therapeutic effects of probiotics on brain intoxication induced by clindamycin and propionic acid (PPA) in hamsters. Fifty golden Syrian hamsters were randomly divided into five experimental groups of ten animals each: (A) control group receiving phosphate buffered saline; (B) oral buffered PPA-treated group being administered with a neurotoxic dose of 250 mg/kg PPA during three days; (C) oral clindamycin-treated group receiving a single dose of 30 mg clindamycin/kg; and (D, E) the two therapeutic groups being administered the same doses of clindamycin and PPA followed by probiotics for three weeks at a daily dose of 0.2 g/kg. Biochemical parameters of energy metabolism and oxidative stress were examined in brain homogenates from all hamsters. The development of pathogenic bacteria was monitored on stool samples from all hamsters. Descriptive changes in fecal microbiota and overgrowth of Clostridium species in clindamycin and PPA treated hamsters were recorded. Interestingly, probiotics were shown effective to restore normal gut microbiota. Clindamycin and PPA treatments caused an elevation in lipid peroxidation and catalase activity, as oxidative stress markers, together with a reduction in GST activity and GSH level. Energy metabolism impairment was ascertained via the activation of creatine kinase and a decrease of lactate dehydrogenase. These findings suggest that bacteria overgrowth caused by PPA and clindamycin was efficient to illustrate signs of neuronal toxicity. The present study indicates that probiotic treatment can improve poor detoxification, oxidative stress, and altered gut microbiota as mechanisms implicated in the etiology of many neurological disorders. PMID- 30019268 TI - Individual differences in processing resources modulate bimanual interference in pointing. AB - Coordinating both hands during bimanual reaching is a complex task that can generate interference during action preparation as often indicated by prolonged reaction times for movements that require moving the two hands at different amplitudes. Individual processing constraints are thought to contribute to this interference effect. Most importantly, however, the amount of interference seems to depend considerably on overall task demands suggesting that interference increases as the available processing resources decrease. Here, we further investigated this idea by comparing performance in a simple direct cueing and a more difficult symbolic cueing task between three groups of participants that supposedly vary in their processing resources, i.e., musicians, young adults and older adults. We found that the size of interference effects during symbolic cueing varied in the tested groups: musicians showed the smallest and older adults the largest interference effects. More importantly, a regression model, using processing speed and processing capacity as predictor variables, revealed a clear link between the available processing resources and the size of the interference effect during symbolic cueing. In the easier direct cueing task, no reliable interference was observed on a group level. We propose that the susceptibility to bimanual interference is modulated by the task-specific processing requirements in relation with the available processing resources of an individual. PMID- 30019267 TI - Antidepressant-like action of agmatine in the acute and sub-acute mouse models of depression: a receptor mechanism study. AB - Previous studies have shown that agmatine, a potential neuromodulator or co transmitter, exhibited antidepressant-like action in animal models, yet its mechanism, especially the receptor mechanism, remains unclear. In the present study, using efaroxan, a preferential antagonist of I1 imidazoline receptor (I1R) and yohimbine, an antagonist of alpha2 adrenergic receptor (alpha2AR), we investigated the roles of I1R and alpha2AR in agmatine's antidepressant-like effect in acute and sub-acute depression models in mice. We found that in the tail-suspension test (TST) and the forced swimming test (FST), acute administration of agmatine (20 and 40 mg/kg, p.o.) significantly shortened the immobility time. Concurrent administration of efaroxan (1 mg/kg, i.p.) completely abolished the antidepressant-like effects of agmatine (40 mg/kg, p.o.) whereas yohimbine (5 mg/kg, i.p.) failed to exert similar effects, suggesting that the acute antidepressant-like effects of agmatine was mainly mediated by I1R but not alpha2AR. Additionally, in the learned helplessness (LH) test, repeated administration of agmatine (20 mg/kg, p.o., q.d.) for 5 days significantly decreased the escape latency and the number of escape failure, and these effects were respectively abolished by concurrent administration of efaroxan (0.5 mg/kg,i.p., q.d.) and yohimbine (3 mg/kg, i.p., q.d.) for 5 days, suggesting that the antidepressant-like action of agmatine in the LH test was achieved via the activation of both I1R and alpha2AR. In summary, we found that the antidepressant like effects of agmatine in the TST and the FST were mediated by activating I1R and in the sub-acute LH test were mediated by activating both I1R and alpha2AR. PMID- 30019269 TI - Volitional media multitasking: awareness of performance costs and modulation of media multitasking as a function of task demand. AB - In two experiments, we sought to determine whether (a) people are aware of the frequently observed performance costs associated with engaging in media multitasking (Experiment 1), and (b) if so, whether they modulate the extent to which they engage in multitasking as a function of task demand (Experiment 2). In Experiment 1, participants completed a high-demand task (2-back) both independently and while a video was simultaneously presented. To determine whether people were sensitive to the impact that the concurrent video had on primary-task performance, subjective estimates of performance were collected following both trial types (No-Video vs. Video trials), as were explicit beliefs about the influence of the video on performance. In Experiment 2, we modified our paradigm by allowing participants to turn the video on and off at their discretion, and had them complete either a high-demand task (2-back) or a low demand task (0-back). Findings from Experiment 1 indicated that people are sensitive to the magnitude of the decrement that media multitasking has on primary-task performance. In addition, findings from Experiment 2 indicated that people modulate the extent to which they engage in media multitasking in accordance with the demands of their primary task. In particular, participants completing the high-demand task were more likely to turn off the optional video stream compared to those completing the low-demand task. The results suggest that people media multitask in a strategic manner by balancing considerations of task performance with other potential concerns. PMID- 30019270 TI - Training and transfer effects of extensive task-switching training in students. AB - The capacity to switch between tasks is a central component of executive functioning. Previous studies assessing effects of task-switch training have revealed mixed results, both in terms of processes that may be improved and the extent of beneficial effects on non-trained tasks. These studies primarily used few training sessions, which may have limited training and transfer effects. Here, 31 students were trained for 21 days on a cued switching task. Both the trained group and an active control group (n = 29) performed a number of cognitive tasks before and after training. Training reduced both switch and mixing costs, which mostly reached an asymptote after approximately four to six training sessions, although there were residual costs at the end of training. The switch cost reduction was restricted to trials with a short cue-stimulus onset interval (CSI). Training benefitted performance on another switching task, reflecting near transfer. However, this benefit was limited to the switch cost and to trials with a short CSI. There were no beneficial effects on far-transfer tasks measuring interference control, response inhibition, working memory, and general IQ. The results suggest that the present extensive training protocol, implicating overtraining, specifically enhanced the efficiency of processes involved in preparing for the relevant upcoming task set and/or inhibition of the previous task set. However, the lack of beneficial far-transfer effects is in line with previous cognitive training studies employing fewer training sessions, suggesting that the extent of training is not critical for (not) finding transfer effects. PMID- 30019271 TI - Left bundle branch block-induced left ventricular remodeling and its potential for reverse remodeling. AB - With the emergence of cardiac resynchronization therapy (CRT) as a powerful tool to reverse left ventricular dysfunction in patients with left bundle branch block (LBBB), there is increasing awareness that LBBB-induced dyssynchrony may be a primary cause of heart failure with reduced ejection fraction (HFrEF). Current guidelines for implanting CRT require at least 3 months of guideline-directed medical therapy (GDMT) before device implantation in the hopes that medications will reverse cardiomyopathy and obviate the need for device therapy. However, no randomized controlled trial demonstrating efficacy of medications ever stratified outcomes by patients with conduction abnormalities. Consequently, CRT, not GDMT, may be a more effective first-line therapy for patients with LBBB and HFrEF. This review evaluates the evidence for LBBB-induced cardiomyopathy, examines the rationale for GDMT in this population, and presents the evidence for direct implantation of CRT. It is likely that many patients would benefit from earlier intervention with CRT, though about 25% of patients with LBBB and HFrEF may respond to GDMT. PMID- 30019273 TI - Roles, Strengths and Challenges of Using Robots in Interventions for Children with Autism Spectrum Disorder (ASD). AB - The aim of this research was to study roles, strengths and challenges of robot mediated interventions using robot KASPAR for children with autism spectrum disorder (ASD). Twelve focus group sessions were organized in which 70 ASD care and/or education professionals participated. Six roles for KASPAR were identified: provoker, reinforcer, trainer, mediator, prompter, and diagnostic information provider. Strengths of KASPAR are related to personalisation possibilities, its playfulness, the action-reaction principle, its neutral expression, consistent and repetitive application of actions, possibilities to vary behaviour in a controlled manner and having an extra hand. Challenges of working with KASPAR were: limited reaction possibilities, possibility of children being scared of KASPAR, difficulties with generalisation or transfer and finally potential dependence on KASPAR. PMID- 30019272 TI - Mechanistic implication of decreased plasma atrial natriuretic peptide level for transient rise in the atrial capture threshold early after ICD or CRT-D implantation. AB - PURPOSE: Despite the use of steroid-eluting leads, a transient but not persistent rise in the atrial/ventricular capture threshold (TRACT/TRVCT) can occur early after pacemaker implantation in patients with sick sinus syndrome. This study aimed to assess the prevalence, predictors, and mechanisms of TRACT/TRVCT in patients with heart failure undergoing implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) implantation. METHOD: One hundred twenty consecutive patients underwent ICD (N = 70) or CRT (N = 50) implantation. Capture threshold was measured at implantation, 7-day, 1-month, and 6-month post-implantation. TRACT/TRVCT was defined as a threshold rise at 7 days by more than twice the height of the threshold at implantation, with full recovery during follow-up. Atrial and brain natriuretic peptide (ANP and BNP) levels were measured before implantation. RESULTS: TRACT and TRVCT were observed in 13 (11%) and 10 (8%) patients, respectively. Patients with TRACT had lower ANP level (median 72 [42-105] vs. 99 [49-198] pg/mL, P = 0.06), lower ANP/BNP ratio (0.29 [0.20-0.36] vs. 0.50 [0.33-0.70], P < 0.01), lower atrial sensing amplitude (2.0 +/- 0.8 vs. 2.7 +/- 1.3 mV, P = 0.02), and lower left ventricular ejection fraction (32 +/- 12 vs. 40 +/- 14%, P = 0.04) than those without TRACT. TRACT recovered within 1 month, whereas TRVCT recovered within 6 months. In multivariable analysis, ANP/BNP ratio was the only independent predictor of TRACT (OR, 0.018; 95% CI, 0.001-0.734; P = 0.034). CONCLUSIONS: Atrial degenerative change characterized by lower ANP/BNP ratio was associated with the occurrence of TRACT in patients with heart failure. TRVCT could also occur, but it required a longer recovery time than TRACT. PMID- 30019275 TI - Higher Tactile Temporal Resolution as a Basis of Hypersensitivity in Individuals with Autism Spectrum Disorder. AB - Many individuals with autism spectrum disorder (ASD) have symptoms of sensory hypersensitivity. Several studies have shown high individual variations in temporal processing of tactile stimuli. We hypothesized that these individual differences are linked to differences in hyper-reactivity among individuals with ASD. Participants performed two tasks as to vibrotactile stimuli: One is a temporal order judgement task, and another is a detection task. We found that individuals with ASD with higher temporal resolution tended to have more severe hypersensitivity symptoms. In contrast, the tactile detection threshold/sensitivity were related to the severities of stereotyped behaviour and restricted interests, rather than to hypersensitivity. Our findings demonstrate that higher temporal resolution to sensory stimuli may contribute to sensory hypersensitivity in individuals with ASD. PMID- 30019276 TI - Brief Report: Using the Social Communication Questionnaire to Identify Young People Residing in Secure Children's Homes with Symptom Complexes Compatible with Autistic Spectrum Disorder. AB - Autistic Spectrum Disorder (ASD) affects approximately 1% of the general population. The prevalence of ASD, or symptom complexes compatible with ASD, amongst young people residing within Secure Children's Homes (SCH's) remains ill understood. There are critical implications for the resourcing and understanding of the management of young people with social/communication difficulties. This paper describes a preliminary investigation of the prevalence of ASD within SCH's in the UK. The Social Communication Questionnaire (SCQ) was completed with support workers for 113 adolescents admitted to two SCH's in England as a screen for ASD. The SCQ identified 15 (13.3%) young people with symptoms compatible with an ASD presentation; differences in gender, legal status and a history of Child Sexual Exploitation (CSE) are discussed. PMID- 30019274 TI - Psychometric Evaluation of the Short Sensory Profile in Youth with Autism Spectrum Disorder. AB - The Short Sensory Profile (SSP) is one of the most commonly used measures of sensory features in children with autism spectrum disorder (ASD), but psychometric studies in this population are limited. Using confirmatory factor analysis, we evaluated the structural validity of the SSP subscales in ASD children. Confirmatory factor models exhibited poor fit, and a follow-up exploratory factor analysis suggested a 9-factor structure that only replicated three of the seven original subscales. Secondary analyses suggest that while reliable, the SSP total score is substantially biased by individual differences on dimensions other than the general factor. Overall, our findings discourage the use of the SSP total score and most subscale scores in children with ASD. Implications for future research are discussed. PMID- 30019277 TI - McGurk Effect by Individuals with Autism Spectrum Disorder and Typically Developing Controls: A Systematic Review and Meta-analysis. AB - By synthesizing existing behavioural studies through a meta-analytic approach, the current study compared the performances of Autism spectrum disorder (ASD) and typically developing groups in audiovisual speech integration and investigated potential moderators that might contribute to the heterogeneity of the existing findings. In total, nine studies were included in the current study, and the pooled overall difference between the two groups was significant, g = - 0.835 (p < 0.001; 95% CI - 1.155 to - 0.516). Age and task scoring method were found to be associated with the inconsistencies of the findings reported by previous studies. These findings indicate that individuals with ASD show weaker McGurk effect than typically developing controls. PMID- 30019278 TI - Correction to: The Association Between Emotional and Behavioral Problems in Children with Autism Spectrum Disorder and Psychological Distress in Their Parents: A Systematic Review and Meta-analysis. AB - The original version of this article contains additional supplementary material which was omitted during the initial submission and it was not published. These are graphical representations of the studies and effect sizes in each meta analysis. Please note that there is no change to the main body of the article, data entered, or conclusions drawn from the meta-analyses. PMID- 30019279 TI - Gender Dysphoria, Sexuality and Autism Spectrum Disorders: A Systematic Map Review. AB - In this systematic map review, we aimed (1) at identifying studies including the co-occurrence of autism spectrum disorders (ASD) and gender dysphoria (GD) between 1946 and 2018, and (2) to present the papers included in this systematic map review to provide authors in the field of GD, sexuality and ASD with an important database of studies focusing on this very complex topic. The field is of emerging interest, as observed by the large increase of studies over the past decades, especially since 2015. However, future challenges are to be addressed in future studies. PMID- 30019281 TI - Bariatric Surgery for a Medical Complex Condition. PMID- 30019280 TI - No Difference in Ghrelin-Producing Cell Expression in Obese Versus Non-obese Stomach: a Prospective Histopathological Case-Control Study. AB - BACKGROUND: To understand the role of ghrelin in the mechanism of action of laparoscopic sleeve gastrectomy (LSG), a prospective cohort case-control study to assess the expression of ghrelin-producing cells (GPC) in two groups of patients was designed. METHODS: Specimens of resected stomach from 26 obese patients who underwent LSG (group A), were compared by immunohistochemistry to control stomach samples from 26 non-obese patients (group B) resected for other pathologies or during autopsy; (GIST: 6 cases, inflammatory diseases: 4 cases, post-mortem autopsy cases with stomachs from healthy persons victims of traumatic accidents: 16 cases). Immunohistochemistry investigation was performed with the use of Ventana Benchmark ultra, anti-ghrelin antibody NOVUS, mouse monoclonal 2F4, diluted at 1:100. RESULTS: No significant difference in the expression of GPC number between group A and B was found (p = 0.87). No significant correlation between patients presenting a GPC number above (subgroup 1) or below (subgroup 2) the average, and EWL% changes, both at 1 and 6 years of follow-up, was recorded. CONCLUSIONS: Our study has shown that the expression of GPC is similar in the stomach of obese and non-obese controls, being mostly influenced by the inflammatory status of the gastric mucosa. A variation in the preoperative number of GPC has not influenced the weight loss in patients who underwent LSG. PMID- 30019282 TI - PEGylated lipid microspheres loaded with cabazitaxel for intravenous administration: stability, bioavailability, antitumor efficacy, and toxicity. AB - This paper aimed to develop a novel lipid microsphere delivering cabazitaxel (CTX) using phosphatidylcholine combined with DSPE-PEG2000 as emulsifier, and evaluate its stability, pharmacokinetics, antitumor efficacy, and toxicity. The pegylated cabazitaxel-loaded lipid microspheres (CTX-PLMs) were prepared by high pressure homogenization methods; the biological samples were analyzed by the UPLC MS/MS method. CTX-PLMs had a drug concentration of 1.2 mg/ml and a mean particle size of 180.0 +/- 51.119 nm. CTX-PLMs showed a superior physical stability as it could remain nearly intact after 1-year storage. The AUC0-t of the CTX-PLMs was 1562.6 +/- 520.1 MUg h L-1 compared with the CTX-solution of 860.734 +/- 312.4 MUg h L-1. CTX-PLMs exhibited a strong antitumor efficacy against NCI-N87 and DU145 tumor models with tumor growth inhibition rates of 93.5 and 88.5%, respectively. The LD50 of CTX-PLMs in rats was 20.89 mg/kg. As for the long-term toxicity, the thymus, mesenteric lymph nodes, and bone marrow were the main toxic target organs and systemic toxicity induced by CTX-PLMs was alleviated relative to that of the CTX-solution. Safety assessment studies including hemolysis test, dermal sensitization test, systemic anaphylaxis, and vascular stimulation test indicated that CTX-PLMs is safe enough for intravenous administration. In a word, CTX-PLMs are a promising carrier for intravenous administration with satisfactory stability, stronger tumor inhibition, and superior safety profile. PMID- 30019283 TI - Oncoplastic approach to excisional breast biopsies: a randomized controlled, phase 2a trial. AB - BACKGROUND: Oncoplastic surgery has been used in breast cancer patients for better cosmetic outcome over the last decades. The aim of this prospective randomized study is to show its place in excisional breast biopsy. METHODS: An oncoplastic approach excision was compared with conventional excisional breast biopsies. The study included 80 patients, of whom half received oncoplastic intervention and half received the conventional. The primary endpoint was the cosmetic result. Patient, surgeon and independent observers rated the results on a four-point scale. Scores other than self-perceived were based on third-month medical photographs. RESULTS: Between May 20, 2015 and April 27, 2016, 40 patients were randomly assigned to oncoplastic biopsy and 40 patients were assigned to conventional excisional biopsy. Median follow-up was 5.6 months (IQR 3.0-6.0). Self-perceived perfect scoring for general cosmetic outcome was found significantly higher after oncoplastic biopsy (73 0.5%) comparing with control group (32.4%) (p = 0.001). This impact did not change after adjusting patients for potential confounders. Margin clearance rates in malignant cases were comparable in both arms (p = 0.999); four patients in oncoplastic biopsy group (40%) and three patients in control group (33%) had positive margins. CONCLUSIONS: The oncoplastic biopsy achieved better cosmetic results with similar surgical margin positivity rates when compared with conventional breast biopsy. It may be a better biopsy option used for patients requiring excisional breast biopsy. PMID- 30019284 TI - Arteriovenous Malformations: Syndrome Identification and Vascular Management. AB - PURPOSE OF REVIEW: Vascular malformations represent a poorly understood set of conditions that create considerable diagnostic and therapeutic confusion. Historically, extensive surgical resections yielded poor results. More recently, the treatment paradigm has shifted to endovascular therapy such that embolization and sclerotherapy are now considered the first line of treatment. Although there is still a role for traditional surgical techniques, it is now most commonly integrated with endovascular therapies in a hybrid fashion. The goal of this review is to provide a greater understanding of the diagnosis and treatment of vascular malformations. RECENT FINDINGS: Vascular malformations can be high-flow (arteriovenous shunting) or low-flow (venous or lymphatic). Clinical presentation and treatment is different for each. Treatment of high-flow lesions must be directed at reducing or eliminating the nidus, usually via super-selective catheterization and embolization. Low-flow lesions are usually treated by direct injection of sclerosing agents under fluoroscopic or ultrasound guidance. The cornerstone of managing patients with vascular malformations is making the proper diagnosis, which is often challenging. Even after a diagnosis is made, therapy itself may be challenging and generate frustration among patients and providers. Frequently, the treatment of vascular malformations is characterized by only slow and incremental improvements without complete lesion eradication. By combining a thorough understanding of the vascular malformation disease process with an array of endovascular techniques, vascular interventionalists may contribute greatly to the care of these patients. PMID- 30019285 TI - Technical feasibility, radiation dosimetry and clinical use of 18F-sodium fluoride (NaF) in evaluation of metastatic bone disease in pediatric population. AB - PURPOSE: The role of 18F-fluoride (18F-NaF) PET-CT for the detection of bone metastases in adults is well established and is considered superior to conventional bone scintigraphy. However, data pertaining use of 18F-NaF PET-CT in pediatric oncology is relatively sparse. The aim of the present study is to retrospectively analyze and share a single-center experience of 18F-NaF PET-CT in pediatric population and to provide preliminary information regarding imaging technique, feasibility of this modality in young patients and radiation dosimetry measurements in pediatric oncology cases. MATERIALS AND METHODS: Twenty-four pediatric patients (mean age 8.0 +/- 3.9) were included in the study for retrospective analysis. All patients were referred for primary staging or restaging for potential osseous metastatic disease and PET-CT scan was performed by injecting 2.2 MBq/kg (0.06 mCi/kg) of 18F-NaF. RESULTS: Nine patients were imaged for primary staging and in all cases increase osteoblastic activity was seen in the primary tumor and of these, metastatic bone disease was identified in 2/9 patients. In the restaging group comprising 15/24 patients, metastatic deposits were identified in 3/15 whilst no disease was seen in the remaining 12 patients. Patients were injected a mean dose of 90.35 +/- 22.9 MBq with an estimated mean effective absorbed doses of 2.98 +/- 0.75 mSv for 18F-NaF and 3.37 +/- 2.4 mSv for CT alone. Mean cumulative effective dose of 18F-NaF PET-CT scan was 5.11 +/- 2.7 mSv. CONCLUSIONS: 18F-NaF PET-CT may be a feasible alternative to 99mTc MDP for radionuclide bone scintigraphy in the evaluation of pediatric bone pathology. Due to its better pharmacokinetics, there is potential that osseous staging can be achieved with relatively low doses and with a similar radiation burden as with 99mTc-MDP imaging. PMID- 30019286 TI - Real-world cost-effectiveness of cetuximab in the third-line treatment of metastatic colorectal cancer based on patient chart review in the Netherlands. AB - OBJECTIVE: To assess the cost effectiveness of cetuximab in third-line treatment of patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) in routine clinical practice compared with best supportive care (BSC). METHODS: Patients (n = 287) with KRAS wt mCRC treated with cetuximab or BSC in eight hospitals in the Netherlands between 2009 and 2012 were included in our real world study. Outcome measures were costs per life-year (LY) and costs per quality adjusted LY (QALY) gained. A Markov model was developed, and a time horizon of four years was applied. Outcomes were calculated from Kaplan-Meier survival curves from patient-level data and literature. Direct medical costs were estimated in all centers (2013 values), and incremental cost-effectiveness ratios (ICERs) were calculated. Results were discounted, and a probabilistic sensitivity analysis was performed. RESULTS: Administration of cetuximab in third-line treatment of mCRC resulted in a gain of 0.29 LYs and 0.25 QALYs compared with BSC. In the four-year study period, average discounted healthcare costs were ?36,637 in the cetuximab group vs. ?3648 in the BSC group. The discounted ICERs of cetuximab vs. BSC in the real-world setting were ?114,907and ?133,527 per LY and QALY gained, respectively. CONCLUSIONS: Results of this cost-effectiveness analysis showed that third-line treatment with cetuximab for patients with KRAS (exon 2) wt mCRC offered clinical benefits at additional cost. The real-world ICERs were in line with those of previously published cetuximab and panitumumab cost-utility models. PMID- 30019287 TI - Intraoperative transvaginal ultrasound examination during myomectomy. PMID- 30019288 TI - Ultrasound facilitates the diagnosis of tarsal tunnel syndrome: intraneural ganglion cyst of the tibial nerve. AB - The tibial nerve intraneural ganglion cyst-which presents with fluid accumulated inside the nerve epineurium-is a rare etiology of tarsal tunnel syndrome. We report a case with insidious onset of numbness over his left medial ankle. Ultrasound imaging revealed that the tibial nerve was encircled by crescent shaped anechoic substances, spanning from the distal leg to the sole. Magnetic resonance imaging disclosed a thickened tibial nerve wrapped by hyperintense materials in the tarsal tunnel. Some effusion was observed besides the tibialis posterior and flexor digitorum tendons as well. The patient underwent a surgical treatment and an intraneural ganglion cyst was confirmed. This report elaborated the clinical and imaging presentations of a tibial nerve intraneural ganglion cyst and highlighted the usefulness of ultrasound in exploring the cause of compressive neuropathy at the ankle region. PMID- 30019289 TI - Cardiac Adaption to Exercise Training: the Female Athlete. AB - PURPOSE OF REVIEW: The number of female athletes participating in sports has increased exponentially over the past century. While cardiac adaptations to exercise have been well described, female athletes have been underrepresented in many prior studies. More recently, important research has embraced gender as an important biologic variable. We will review this work in order to examine how gender influences the impact of exercise on the heart. RECENT FINDINGS: Exercise induced cardiac remodeling (EICR) manifests slightly differently in male and female athletes. Specifically, female athletes have fewer signs of EICR on the electrocardiogram than male athletes, though are more likely to have anterior T wave inversions in the absence of cardiac disease. Cardiac enlargement due to exercise follows a different pattern in female versus male athletes, with females having similar chamber size when adjusted for body size but lower left ventricular mass. Recent research also suggests that female masters athletes may be less likely to have excess coronary disease, atrial fibrillation, and myocardial fibrosis, all of which have been posited though not proven to be sequelae of long-term endurance exercise in males. Gender appears to be an important modifier of the relationship between exercise and associated cardiac remodeling. The biological mechanisms underlying gender-based differences in EICR are poorly understood and will be an important area of future research. PMID- 30019291 TI - Modulation of lipid metabolism in juvenile yellow catfish (Pelteobagrus fulvidraco) as affected by feeding frequency and environmental ammonia. AB - In the intensive culture systems, excessive feeding leads to ammonia accumulation, which results in lipid metabolism disorder. However, little information is available on the modulation of lipid metabolism in fish as affected by feeding frequency and ammonia stress. In this study, weight gain increased as feeding frequency increased from one to four times daily, but feed conversion ratio is opposite. The highest survival was found in ammonia group when fish was fed two times daily. Liver ammonia content increased as feeding frequency increased from one to four times daily, and the highest brain ammonia content was found when fish was fed four times daily. The highest liver 6-phospho gluconate dehydrogenase (6PGD), fatty acid synthase (FAS), carnitine palmitoyltransferase (CPT), and lipoprotein lipase (LPL) contents were found in control group when fish was fed four times daily; in comparison, the highest liver 6PGD, FAS, CPT, and LPL contents were found in ammonia group when fish was fed two times daily. Liver 6PGD, FAS, CPT 1, SREBP-1, and PPARalpha mRNA expression in control group increased significantly as feeding frequency increased from one to four times daily, and the highest expression of 6PGD, G6PD, and FAS was observed in ammonia group when fish was fed two times daily. This study indicated that the optimal feeding frequency is two times daily when yellow catfish exposed to ammonia. PMID- 30019292 TI - Autonomic involvement in Guillain-Barre syndrome: an update. AB - BACKGROUND: Guillain-Barre syndrome (GBS), an inflammatory, usually demyelinating polyradiculopathy, is characterized by ascending symmetrical limb weakness, sensory disturbances, and absent or reduced deep tendon reflexes. There is extensive literature suggesting that GBS is associated with autonomic dysfunction in up to two-thirds of patients. However, it is interesting that there is still no consensus amongst medical professionals regarding whether GBS patients should be routinely screened for autonomic nervous system (ANS) neuropathy. This is an important issue, as the mortality rate from presumed ANS abnormalities now exceeds that of respiratory failure. Given the long interval since this literature was last comprehensively reviewed, an update on this topic is warranted. METHODS: A PubMed search yielded 193 results with the terms "GBS or Guillain-Barre syndrome and autonomic symptoms" and 127 results with the terms "GBS or Guillain-Barre syndrome and dysautonomia." RESULTS: This review will summarize the current literature involving GBS and autonomic dysfunction in terms of presentation, management, and a brief discussion of prognosis. We also examine prospective approaches that may be helpful and update a proposed management plan. PMID- 30019290 TI - Psammomys obesus: a Natural Diet-Controlled Model for Diabetes and Cardiovascular Diseases. AB - PURPOSE OF REVIEW: This review specifically summarises and reports terrestrial mammals of the gerbil subfamily, known as Israeli sand rats or Psammomys obesus (P. obesus) as a diet-controlled, unique, polygenic rodent model for research in the areas of obesity, type 2 diabetes, and cardiovascular diseases. The animal model closely mimics phenotypic and pathophysiological resemblance with human populations. RECENT FINDINGS: The physiological status and biochemical composition in P. obesus can be manipulated effectively by controlling its nutritional intake, making it a natural model for cardiovascular and diabetic research. Humans exhibit remarkable disparity in physiology and pathology, which are inter-dependent factors. However, variations in these factors in most animal models currently being used for cardiovascular/diabetes research are insignificant. Consequently, it is a necessity to identify and develop animal models exhibiting physiological variations mimicking human pathological conditions. We have compiled research developments conducted with this rodent model manifesting pathophysiology, closely mimicking that in human beings, thereby enabling better translation of novel therapeutic and diagnostic discoveries. PMID- 30019293 TI - Neurogenic hypertension: introduction to the series. PMID- 30019294 TI - Simulation of the power transmission of bone-conducted sound in a finite-element model of the human head. AB - Bone conduction (BC) sound is the perception of sound transmitted in the skull bones and surrounding tissues. To better understand BC sound perception and the interaction with surrounding tissues, the power transmission of BC sound is investigated in a three-dimensional finite-element model of a whole human head. BC sound transmission was simulated in the FE model and the power dissipation as well as the power flow following a mechanical vibration at the mastoid process behind the ear was analyzed. The results of the simulations show that the skull bone (comprises the cortical bone and diploe) has the highest BC power flow and thereby provide most power transmission for BC sound. The soft tissues was the second most important media for BC sound power transmission, while the least BC power transmission is through the brain and the surrounding cerebrospinal fluid (CSF) inside the cranial vault. The vibrations transmitted in the skull are mainly concentrated at the skull base when the stimulation is at the mastoid. Other vibration transmission pathways of importance are located at the occipital bone at the posterior side of the head while the transmission of sound power through the face, forehead and vertex is minor. The power flow between the skull bone and skull interior indicate that some BC power is transmitted to and from the skull interior but the transmission of sound power through the brain seem to be minimal and only local to the brain-bone interface. PMID- 30019296 TI - Magnetic resonance imaging findings of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion in adults: a pilot study. AB - PURPOSE: The purpose of the study was to retrospectively analyze MRI findings of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2/TFE RCC) in adults. METHODS: Sixteen patients with Xp11.2/TFE RCC were reviewed retrospectively. The clinical characteristics and imaging features were assessed and then compared between metastatic and non-metastatic subgroups. RESULTS: The mean age at diagnosis was 47.4 (20-76) years. Seven (44 %) patients were men, and nine (56 %) patients were women. The lesions predominantly exhibited an endophytic distribution (n = 14, 88 %) with a capsule (n = 16, 100 %), accompanied by solid and cystic patterns (n = 12, 75%) and hemorrhage (n = 11, 69 %). The tumors prevalently appeared hyper- to isointense on T1WI (n = 14, 88 %), hypointense on T2WI (n = 13, 81 %), and hyperintense on DWI (n = 16, 100 %) with a lower ADC (P < 0.001) than that of the surrounding tissue. The tumors were less enhanced than the normal renal cortex in all phases with a prolonged enhancement pattern (P <= 0.001). In addition, six patients (38 %) developed recurrence or metastases. The RCCs with metastases showed an irregular shape (P = 0.013), an incomplete capsule (P = 0.018), heterogeneous solid-cystic patterns (P = 0.034), and hemorrhage (P = 0.037) than non-metastatic subgroups. CONCLUSIONS: MRI provides valuable information for the diagnosis of adult Xp11.2/TFE RCCs. Features including irregular shape, incomplete capsule, mixed solid-cystic pattern, and hemorrhage may indicate the occurrence of recurrence or metastases. PMID- 30019297 TI - Indirect percutaneous core needle biopsy of solid pancreatic or peripancreatic lesions. AB - Solid pancreatic or peripancreatic lesions comprise a heterogeneous group of diseases that rely on a multimodality imaging approach for subsequent tissue procurement. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA)/biopsy is an effective and safe method for tissue diagnosis in this region. The failure to obtain adequate tissue for diagnosis under EUS guidance is still a rare but important issue. Percutaneous core needle biopsy (CNB) provides an alternative pathway for adequate specimen acquisition. Because of the deep retroperitoneal location, the percutaneous biopsy of pancreatic or peripancreatic lesions may inevitably pass through visceral organs. The procedure is relatively risky and difficult for general radiologists, particularly beginners, and an adequate knowledge of the abdominal anatomy and biopsy technique is indispensable. In this review, various aspects of percutaneous CNB for solid pancreatic or peripancreatic lesions using different trans-organ approaches are reviewed to increase the chance of successful biopsy. PMID- 30019295 TI - Co-expression of caspase-3 or caspase-8 with galanin in the human stomach section affected by carcinoma. AB - Neoplastic process may cause distinct changes in the morphology, i.e. size and number of the neurons of the neuronal plexuses forming the enteric nervous system (ENS) of the human intestine. Moreover, it was also reported that these changes were not directly associated with apoptosis. Thus, the main aim of this study was to determine the atrophic changes of myenteric plexuses (MPs) in the vicinity of cancer invasion and the potential reason which may be responsible for these changes if they occur. Tissue samples from the stomach were collected from ten patients which undergo organ resection due to cancer diagnosis. Samples were taken from the margin of cancer invasion and from a macroscopically-unchanged part of the stomach wall. Triple-immunofluorescence staining of the 10-um-thick cryostat sections was used to visualize the co-expression of caspase-3 (CASP3) or caspase-8 (CASP8) with galanin (GAL) in the MPs of ENS. Microscopic observations of MPs located closely to gastric cancer invasion showed that they were significantly smaller than plexuses located distally. The percentage of neurons containing CASP3 within MPs located close to cancer-affected regions of the stomach was higher, while containing CASP8 was lower compared to the unchanged regions. Additionally, elevated high expression of CASP3 or CASP8 in the neurons from MPs was accompanied by a decreased expression of GAL. To our knowledge, this is the first report describing the decomposition of MPs within cancer-affected human stomach wall and the possible role of apoptosis in this process. PMID- 30019298 TI - Markers for Severity of Problems in Interpersonal Relationships of Crack Cocaine Users from a Brazilian Multicenter Study. AB - Crack cocaine users frequently report difficulties regarding having healthy and rewarding relationships. Factors other than the use of crack cocaine itself may be at play when it comes to being able to develop healthier connections with partners, adult relatives and close friends. To verify which factors, including demographics, substance abuse related factors and psychiatric comorbidities could be markers for a higher severity of problems in interpersonal relationships of crack cocaine users seeking for treatment. This was a cross-sectional study, conducted between April 2011 and November 2012. Participants were 407 crack cocaine users seeking treatment in specialized public facilities of six Brazilian capitals. The relationship of severity of problems in the family/social area and the prevalence of psychiatric disorders, exposure to stressful events, substance use related factors and practice of illicit activities were explored through multivariate analyses. Number of days using crack cocaine in the last 30 days, age of first time using alcohol and feeling its effects, a diagnosis of alcohol abuse, posttraumatic stress disorder, antisocial personality disorder and attention-deficit/hyperactivity disorder were significantly associated with a higher severity of problems in interpersonal relationships with partners, adult relatives and friends. Problems in interpersonal relationships are strongly related to specific psychiatric comorbidities and the frequency of crack cocaine use. Factors identified by this study can make the paths to recovery more challenging. These results support psychosocial interventions that focus in the improvement of interpersonal relationships of crack cocaine users. PMID- 30019299 TI - RACK1 deficiency synergizes with all-trans retinoic acid to induce apoptosis in human acute promyelocytic leukemia cells. AB - As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome-autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL. PMID- 30019300 TI - Molecular changes to the rat renal cotransporters PEPT1 and PEPT2 due to ageing. AB - Renal PEPT1 and PEPT2 cotransporters play an important role in the balance of circulating body oligopeptides and selected peptidomimetic drugs. We aim to comprehensively characterise age-related changes of the renal PEPT cotransporters at the gene, protein, and functional level. Brush border membrane vesicles (BBMV) and outer medulla membrane vesicles (OMMV) were isolated from the kidneys of young, middle-aged and old rats. The protein expression of PEPT1 was not only increased in BBMV from old rats, but PEPT1 also appeared in OMMV from middle-aged and old rats. SLC15A1 gene expression in the renal cortex increased in middle aged group. PEPT2 protein expression was not only increased with ageing, but PEPT2 also was found in BBMV from middle-aged and old groups. SLC15A2 gene expression in the renal outer medulla increased in the old group. These changes in the expressions and localisations of PEPT1 and PEPT2 could explain the changes to transport activity in BBMV and OMMV. These findings provide novel insights that would be useful for maintaining protein nutrition and optimising the delivery of some peptidomimetic drugs in elderly individuals. PMID- 30019302 TI - Unusual Techniques for Preserving Surgical and Oncologic Safety in Hepatectomy of Advanced Adrenal Malignancy with Vena Cava and Liver Invasion. AB - BACKGROUND: Status in terms of major vascular structure invasion is a crucial factor for successful major hepatic resection. In particular, surgery for advanced tumors with inferior vena cava (IVC) invasion is difficult and may even be dangerous for the patient, having high risk of massive bleeding and greater chance of embolic complications such as stroke, bowel ischemia, and pulmonary venous thrombosis. For such reasons, many surgeons hesitate to carry out such surgical resection, and even if they do so, may not totally remove the tumor including the part inside the IVC, achieving R1 resection. For safe and radical surgery, various surgical techniques are required. We report herein three cases of major hepatectomy with IVC invasion and discuss several surgical tips. PATIENTS AND METHODS: From March 2011 to February 2014, we retrospectively reviewed three cases of adrenal malignancy with liver and IVC invasion. Based on the severity of the malignant tumor, each case illustrates a different method to address surgical complications and maintain oncologic safety. Case 1: A 34-year old woman was diagnosed with adrenocortical tumor during medical examination. Tumor invaded the right lobe of the liver and very close to the IVC. Fortunately, there was little thrombosis inside the IVC; we performed right hemihepatectomy and adrenalectomy, then resected the IVC wall close to the tumor and repaired the IVC side wall using 4-0 Prolene. Case 2: A 54-year-old woman who complained of abdominal discomfort visited our hospital. Abdominal computed tomography (CT) scan revealed huge adrenal mass with liver and IVC invasion. Thrombosis inside the IVC extended to the right atrium. We decided to carry out veno-veno bypass during operation in collaboration with heart surgeon. After application of veno veno bypass, the right atrium wall was opened and the tumor thrombus removed. We then carried out right hemihepatectomy and adrenalectomy. Supra- and infrahepatic vena cava were clamped during tumor thrombectomy to prevent embolic complications. Case 3: A 51-year-old woman who complained of headache and hypertension visited our hospital and was diagnosed with huge adrenal tumor. Tumor invaded to the right lobe of the liver and encased the IVC. The tumor totally invaded the IVC, and massive bleeding was expected during dissection. We resected the tumor including IVC en bloc, and reconstructed IVC with artificial graft (Dacron) under veno-veno bypass. RESULTS: In case 1, there was no surgical complication. The patient was discharged 7 days postoperatively and underwent adjuvant chemotherapy (Mitotane) after discharge. Unfortunately, multiple hepatic metastases were identified 4 months after operation. She died 6 months after surgery. In case 2, there was no surgical complication after surgery. The patient was discharged 10 days postoperatively. Multiple liver and lung metastases were identified 4 months after operation, and pulmonary embolism was also diagnosed on chemotherapy. She died 16 months after operation. In case 3, the patient had no surgical complication in the immediate postoperative period and was discharged 14 days after surgery. Pheochromocytoma was confirmed in pathologic report. One month after discharge, she underwent interventional balloon dilatation due to short segmental collapse of suprahepatic IVC. At 42 months after surgery, she was still alive with no relapse. DISCUSSION: In advanced-stage malignant tumor, the conflict between achieving oncologic R0 resection and patient safety remains an unsolved issue. In particular, more advanced surgical technique is required when the tumor invades large vessels such as the vena cava. Previous reports on cases of advanced tumor invading liver and IVC have described the technical difficulties.1,2 Wakayama et al. reported cases of successful thrombectomy under veno-veno bypass in hepatocellular carcinoma with IVC and right atrium invasion,3 and Vicente et al.4 reported surgical resection of IVC thrombus without cardiopulmonary bypass. Major vascular invasion of the tumor is known to be a poor prognostic factor for survival. However, some reports state that, if the tumor invades major vascular structure, complete tumor removal might be helpful for patient survival due to the biologic features of the tumor.2,5,6 This video report does not describe any new techniques, but is more helpful for junior surgeons in educational terms. The limitation of this report is that we could not show good oncologic long-term survival after surgery. However, no fatal complications related to the surgical procedure occurred, by managing the tumor thrombus during the operation. We present three techniques with differing aggressiveness. The techniques illustrated in this video represent a good option to achieve patient surgical safety. PMID- 30019301 TI - Genetic characterization of extraintestinal Escherichia coli isolates from chicken, cow and swine. AB - Phenotypic determination of antimicrobial resistance in bacteria is very important for diagnosis and treatment, but sometimes this procedure needs further genetic evaluation. Whole-genome sequencing plays a critical role in deciphering and advancing our understanding of bacterial evolution, transmission, and surveillance of antimicrobial resistance. In this study, whole-genome sequencing was performed on nineteen clinically extraintestinal Escherichia coli isolates from chicken, cows and swine and showing different antimicrobial susceptibility. A total of 44 different genes conferring resistance to 11 classes of antimicrobials were detected in 15 of 19 E. coli isolates (78.9%), and 22 types of plasmids were detected in 15/19 (78.9%) isolates. In addition, whole-genome sequencing of these 19 isolates identified 111 potential virulence factors, and 53 of these VFDB-annotated genes were carried by all these 19 isolates. Twelve different virulence genes were identified while the most frequent ones were gad (glutamate decarboxylase), iss (increased serum survival) and lpfA (long polar fimbriae). All isolates harbored at least one of the virulence genes. The findings from comparative genomic analyses of the 19 diverse E. coli isolates in this study provided insights into molecular basis of the rising multi-drug resistance in E. coli. PMID- 30019303 TI - De Novo Stage 4 Metastatic Breast Cancer: A Surgical Disease? PMID- 30019304 TI - Prognostic Value of Preoperative Systemic Immunoinflammatory Measures in Patients with Esophageal Cancer. AB - BACKGROUND: It is reported that several systemic immunoinflammatory measures, including systemic immune-inflammatory index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and C-reactive protein (CRP)-to albumin ratio (CAR), are associated with survival in patients with various types of cancer. OBJECTIVE: The aim of the present study was to clear which systemic immunoinflammatory measures had the greatest prognostic values. In addition, we examined which component had the greatest prognostic power in patients with esophageal cancer. METHODS: Preoperative systemic immunoinflammatory measures were evaluated in 143 patients undergoing esophageal resection for esophageal cancer from 2009 to 2014. Univariate and multivariate analyses were performed to determine the prognostic significance of these markers. Receiver operating characteristic (ROC) curves were plotted, and the area under the ROC curves (AUROCs) were compared to verify the accuracy of each measure in predicting overall survival (OS). RESULTS: In univariate analysis, preoperative SII, NLR, and CAR were the predictors of OS in patients who underwent esophagectomy for esophageal cancer (p < 0.05, respectively), whereas in multivariate analysis, CAR and pathological tumor depth were the significant predictors of OS (hazard ratio [HR] 1.994, p = 0.03 vs. HR 1.967, p = 0.02, respectively). According to AUROC, the CRP (0.66) and albumin levels (0.66) were more important systemic immunoinflammatory measures than neutrophil (0.58), lymphocyte (0.63), and platelet (0.56) levels. CONCLUSION: Among systemic immunoinflammatory measures, CAR was the most significant predictor of OS in patients with esophageal cancer. CRP and albumin levels were more important components of systemic immunoinflammatory measures. PMID- 30019305 TI - Streamlining Decision Making in Contralateral Risk-Reducing Mastectomy: Impact of PREDICT and BOADICEA Computations. AB - INTRODUCTION: Patients with sporadic breast cancer (BC) have low contralateral breast cancer risk (CLBCR; approximately 0.7% per annum) and contralateral prophylactic mastectomy (CPM) offers no survival advantage. CPM with autologous reconstruction (AR) has major morbidity and resource implications. OBJECTIVE: The aim of this study was to review the impact of PREDICT survival estimates and lifetime CLBCR scores on decision making for CPM in patients with unilateral BC. METHODS: Of n = 272 consecutive patients undergoing mastectomy and AR, 252 were included. Five- and 10-year survival was computed with the PREDICT(V2) online prognostication tool, using age and clinicopathological factors. Based on family history (FH) and tumor biology, CLBCR was calculated using validated BODICEA web based software. Survival scores were correlated against CLBCR estimates to identify patients receiving CPM with 'low' CLBCR (< 30% lifetime risk) and poor prognosis (5-year survival < 80%). Patients with 'high' CLBCR receiving unilateral mastectomy (UM) were similarly identified (UK National Institute of Health and Care Excellence [NICE] criteria for CPM, >= 30% lifetime BC risk). Justifications motivating CPM were investigated. RESULTS: Of 252 patients, 215 had UM and 37 had bilateral mastectomy and AR. Only 23 (62%) patients receiving CPM fulfilled the NICE criteria. Of 215 patients, 5 (2.3%) failed to undergo CPM despite high CLBCR and good prognosis. CPMs were performed, at the patient's request, for no clear justification (n = 8), contralateral non-invasive disease, and/or FH (n = 5), FH alone (n = 4) and ipsilateral cancer recurrence-related anxiety (n = 3). CONCLUSION: In the absence of prospective risk estimates of CLBCR and prognosis, certain patients receive CPM and reconstruction despite modest CLBCR, yet a proportion of patients with good prognoses and substantial risk are not undergoing CPM. PMID- 30019306 TI - Lack of functional remission in Cushing's syndrome. AB - INTRODUCTION: Hypercortisolism leads to severe clinical consequences persisting after the onset of remission. These physical sequelae of cortisol exposure are known to profoundly impact the patient's quality of life. As psychological factors may be correlated with this quality of life, our objective was to determine the specific weight of psychological determinants of quality of life in patients in remission from hypercortisolism. PATIENTS AND METHODS: In an observational study, 63 patients with hypercortisolism in remission were asked to complete exhaustive self-administered questionnaires including quality of life (WHOQoL-BREF and Cushing QoL), depression, anxiety, self-esteem, body image, and coping scales. Multivariate analyses were performed. Psychological variables relevant to the model were: anxiety, depression, self-esteem, body image, and positive thinking dimension of the Brief-COPE. Cortisol deficiency was defined as a potential confounder. RESULTS: The median time since remission was 3 years. Patients had significantly lower quality of life and body satisfaction score than the French population and patients with chronic diseases. Depression significantly impaired all WHOQoL and Cushing QoL domains. A low body satisfaction score significantly impaired social relationships quality of life score. In total, 42.9% of patients still needed working arrangements, 19% had disability or cessation of work. CONCLUSION: Patients in biological remission of hypercortisolism can rarely be considered as functionally cured: this is evidenced by altered quality of life, working arrangements, and chronic depression. A multidisciplinary management of these patients is thus mandatory on a long-term basis. PMID- 30019308 TI - The Limb-Girdle Muscular Dystrophies: Is Treatment on the Horizon? AB - There has been an ever-expanding list of the Limb-Girdle Muscular Dystrophies (LGMD). There are currently 8 subtypes of autosomal dominant (AD) and 26 subtypes of autosomal recessive (AR) LGMD. Despite continued research efforts to conquer this group of genetic neuromuscular disease, patients continue to be treated symptomatically with the aim of prevention or addressing complications. Mouse models have been helpful in clarifying disease pathogenesis as well as strategizing pathways for treatment. Discoveries in translational research as well as molecular therapeutic approaches have kept clinicians optimistic that more promising clinical trials will lead the way to finding the cure for these devastating disorders. It is well known that the challenge for these rare diseases is the ability to assemble adequate numbers of patients for a clinically meaningful trial, but current efforts in developing patient registries have been encouraging. Natural history studies will be essential in establishing and interpreting the appropriate outcome measures for clinical trials. Nevertheless, animal studies continue to be key in providing proof of concept that will be necessary in moving research along. This review will briefly discuss each type of LGMD, highlighting their distinguishing features, then focus on research efforts that have been published in the literature for the past few years, many of which are still in the preclinical trial stage. PMID- 30019307 TI - Primary hyperparathyroidism: findings from the retrospective evaluation of cases over a 6-year period from a regional UK centre. AB - BACKGROUND: Although there are international guidelines on diagnosis and management of primary hyperparathyroidism (PHPT), clinical practice varies in different centres. Periodic review of diagnostic work-up, surgical treatment by parathyroidectomy (PTX) and clinical surveillance in nonsurgical treatment group among patients with PHPT is expected to improve the quality of care. We report a retrospective study of cases with PHPT managed at a regional centre in the United Kingdom. METHODS: Clinical data of cases with calcium >=2.6 mmol/L and parathyroid hormone (PTH) >=9.0 pmol/L was procured from biochemistry database from January 2011 to December 2016. Laboratory parameters, imaging studies for renal stones, osteoporosis and localisation of parathyroid adenomas, type of treatment received (PTX or nonsurgical), complications of treatment, other medical co-morbidities and mortality during follow-up was recorded in each case to examine the outcomes of care of patients with PHPT. RESULTS: The study included 160 patients: 127 (79%) females and 33 (21%) males. Median age was 70 years in females and 74 in males. Thirty cases (19% of 159) had renal stones and 47 (37.3% of 126) had osteoporosis. Eighty-one cases (51%) received PTX. Logistic regression analysis showed that higher calcium levels (odds ratio (OR) = 73.991; p < 0.001), peak PTH (OR = 1.023; p = 0.025), peak alkaline phosphatase (OR = 0.985, p < 0.001), lower age (OR = 0.985, p < 0.001) and male gender (OR = 0.209, p < 0.002) as statistically significant predictors for patients receiving PTX. Higher age at diagnosis of PHPT was associated with increased risk of co-existent hypertension (OR = 10.904, p = 0.001) and fractures (OR = 1.067, p = 0.004). Higher peak calcium concentration was an independent predictor of acute kidney injury (OR = 9.631, p = 0.011). PTX cured 76 cases (94%) with only 7 (9%) postoperative complications. Twenty-four cases (15%) died from the entire cohort (only one from PTX group) during a median follow-up period of 3.6 years (interquartile range = 1.5). CONCLUSIONS: PTX treatment is associated with cure of disease in patients with PHPT with acceptable risk of complications. Improvements in diagnostic work-up and follow-up care should improve the morbidity from PHPT. PMID- 30019309 TI - 25-hydroxycholesterol reduces inflammation, viral load and cell death in ZIKV infected U-87 MG glial cell line. AB - Zika virus (ZIKV) infection is a global health issue due to its worldwide diffusion and to the related effects on neural progenitor cells with severe consequences on developing brain as well as on the central nervous system of adults. Previous studies showed that ZIKV infection induces an increment of IL1B expression in the central nervous system and also in the blood. IL-1beta is a pro inflammatory cytokine essential for cellular defence, tissue repair and neuroinflammation, a mechanism seen to be associated with several neuroinflammatory diseases. 25-hydroxycholesterol (25-HC) is a natural oxysterol, derived from hydroxylation of cholesterol, possessing important antiviral activity possibly correlated to its ability to alter host membrane structures. Furthermore, 25-HC is involved in the modulation of IL1B gene expression, being able to suppress IL-1beta driven inflammation probably by blocking the activation of the SREB proteins. In our study, we analysed the antiviral action of 25-HC in ZIKV-infected U-87 MG cells, also evaluating its impact on inflammation and cell death. We demonstrated that 25-HC is able to reduce inflammation and cell death caused by ZIKV infection and also to diminish intracellular ZIKV load in U-87 MG glial cell line. Considering its antiviral activity and its ability to penetrate blood-brain barrier, 25-HC could be proposed, based on our results and literature findings, as a potential anti-ZIKV agent. PMID- 30019311 TI - Coming of Age of IAP 2015 Growth Charts: The Way Forward. PMID- 30019310 TI - Topical rectal antiseptic at time of prostate biopsy: how a resident patient safety project has evolved into institutional practice. AB - PURPOSE: To report outcomes 5 years after a resident quality initiative incorporated topical rectal antiseptic into our ultrasound-guided prostate needle biopsy (TRUS PNB) protocol. METHODS: A chart review was conducted on 1007 men who underwent TRUS PNB between 2010 and 2017. Comparison groups include those who received a topical rectal antiseptic (N = 437) compared to those who did not (N = 570). Povidone-iodine (N = 303) or 4% chlorhexidine solution without alcohol (N = 134) were topical agents. Outcomes of interest included post-biopsy infection (urinary tract infection and/or sepsis), hospital admission, and need for ICU monitoring. RESULTS: Median age and PSA of men included in this study were 64 years and 12 ng/mL. Almost 90% of patients were Caucasian, 13% had diabetes, 3% were on immunosuppression, 32% had at least one prior biopsy, 14% received antibiotics, and 7% were hospitalized in the past 6 months. 22 patients (2.2%) developed a post-biopsy infection with a significant reduction in the group receiving topical rectal antiseptic (0.8 vs. 3.3%, p = 0.01). Post-biopsy UTI rates (p = 0.04) and hospital admission (p = 0.03) were also lower in the topical antiseptic group with trends to reduction in sepsis and need for ICU monitoring. CONCLUSIONS: What started as a resident quality safety project 5 years ago has demonstrated a reduction in infections and hospital admissions following TRUS PNB. Our institutional practice now routinely uses povidone-iodine or chlorhexidine as an adjunct to oral quinolones for TRUS PNB perioperative prophylaxis. PMID- 30019312 TI - Autism and Allergy - Are They Linked? PMID- 30019313 TI - Epidemiology, clinical and laboratory features of 24 consecutive cases of leptospirosis at a German infectious disease center. AB - To determine epidemiological, clinical and laboratory characteristics of leptospirosis, 24 consecutive patients diagnosed with the infection between 2011 and 2017 at the University Medical Center Hamburg-Eppendorf were retrospectively analyzed. The majority of patients were male travelers who returned from Southeast Asia and had a history of freshwater-associated activities. Considering the lack of discriminatory clinical or clinical chemistry parameters, leptospirosis should be regarded as differential diagnosis in any patient with acute febrile illness, especially with a history of travel to tropical and subtropical regions or freshwater exposure. PMID- 30019314 TI - Relationship between environmental factors and the spatial distribution of Spermophilus dauricus during 2000-2015 in China. AB - The Spermophilus dauricus is a rodent species that feeds on the tender parts of plants and seeds. It is also a natural carrier of the hepatitis B virus and the main host of the plague bacillus Yersinia pestis threatening human health and the cultivated ecosystems. Based on ecological niche modeling (ENM) for the MaxEnt model and ArcGIS for the Spatial Analyst model, we quantified the potential risk zone and spatial pattern of the S. dauricus outbreak during 2000-2015. We analyze the temporal and spatial variation for different levels of risk zones. The results showed that the S. dauricus was primarily distributed in the North China with arid and semi-arid regions. The suitable habitat of S. dauricus includes an annual precipitation of 250-700 mm year-1, a temperature of - 3 to 14 degrees C, the normalized differential vegetation index (NDVI) of 0.05-0.65, and an elevation of < 3800 m. Although the NDVI and precipitation were significantly increasing, the potential risk zone did not expand. But, this result can not mean the S. dauricus outbreak had been controlled, and the substantial additional efforts in the form of observational and/or experimental investigations are needed to explore the relationships between environmental factors and the habitat of the S. dauricus, ideally by including the influences from land cover, vegetation characteristics, and artificial disturbances. PMID- 30019315 TI - Differing Effects of Parathyroid Hormone, Alendronate, and Odanacatib on Bone Formation and on the Mineralization Process in Intracortical and Endocortical Bone of Ovariectomized Rabbits. AB - Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as mineral crystals accrue and are modified; this continues until bone remodeling renews that site. Pharmacological agents for osteoporosis differ in their effects on bone remodeling, and we hypothesized that they may differently modify bone mineral accrual. We, therefore, assessed newly formed bone in mature ovariectomized rabbits treated with the anti-resorptive bisphosphonate alendronate (ALN-100u g/kg/2*/week), the anabolic parathyroid hormone (PTH (1-34)-15u g/kg/5*/week), or the experimental anti-resorptive odanacatib (ODN 7.5 uM/day), which suppresses bone resorption without suppressing bone formation. Treatments were administered for 10 months commencing 6 months after ovariectomy (OVX). Strength testing, histomorphometry, and synchrotron Fourier-transform infrared microspectroscopy were used to measure bone strength, bone formation, and mineral accrual, respectively, in newly formed endocortical and intracortical bone. In Sham and OVX endocortical and intracortical bone, three modifications occurred as the bone matrix aged: mineral accrual (increase in mineral:matrix ratio), carbonate substitution (increase in carbonate:mineral ratio), and collagen molecular compaction (decrease in amide I:II ratio). ALN suppressed bone formation but mineral accrued normally at those sites where bone formation occurred. PTH stimulated bone formation on endocortical, periosteal, and intracortical bone surfaces, but mineral accrual and carbonate substitution were suppressed, particularly in intracortical bone. ODN treatment did not suppress bone formation, but newly deposited endocortical bone matured more slowly with ODN, and ODN-treated intracortical bone had less carbonate substitution than controls. In conclusion, these agents differ in their effects on the bone matrix. While ALN suppresses bone formation, it does not modify bone mineral accrual in endocortical or intracortical bone. While ODN does not suppress bone formation, it slows matrix maturation. PTH stimulates modelling based bone formation not only on endocortical and trabecular surfaces, but may also do so in intracortical bone; at this site, new bone deposited contains less mineral than normal. PMID- 30019316 TI - Use of Emergency Medication in Adult Patients with Epilepsy: A Multicentre Cohort Study from Germany. AB - BACKGROUND: Emergency treatment with benzodiazepines is indicated in prolonged seizures, seizure clusters and status epilepticus. OBJECTIVE: The aim of this study was to evaluate the use of emergency medication in adult patients with epilepsy. PATIENTS AND METHODS: All adult epilepsy patients attending the epilepsy outpatient clinics of the university hospitals in Frankfurt and Marburg in 2015 were asked to participate in this questionnaire-based, retrospective survey. RESULTS: A total of 481 patients with a mean age of 43.4 years (range 18 94 years, 54% female) participated in the study. Among them, 134 patients (27.9%) reported on the prescription of an emergency medication during the last year. Patients receiving emergency medication were younger and exhibited a lower age at epilepsy onset, a higher seizure frequency and a higher number of regularly taken antiepileptic drugs. The most frequently taken emergency drugs were oral lorazepam tablets (65.7%; n = 88 out of 134), followed by buccal midazolam (23.9%, n = 32) and rectal diazepam (17.9%, n = 24). The most common indications for administering the emergency medication were seizures continuing for several minutes (35.1%, n = 47), but almost the same number of patients (33.6%, n = 45) stated that the rescue medication was given during or after every seizure. Regarding adverse events, sedation was named as a major (18.7%, n = 25) or moderate (29.1%; n = 39) problem by a substantial number of patients. Difficulties in administration were reported by 17 (13%) patients. Two-thirds assessed the efficacy of their emergency medication as good (50.7%, n = 68) or as very good (15.7%, n = 21). For multivariate logistic regression analysis, aspects such as young age at onset, active epilepsy, structural etiology, presence of generalised tonic-clonic seizures, past medical history of status epilepticus and living with another person independently predicted prescription of emergency medication. CONCLUSIONS: In most cases, unsuitable benzodiazepines with slow absorption due to oral administration were prescribed, or buccal midazolam solution was used off-label in adults. Furthermore, inappropriate use of emergency medication at every seizure was reported by a substantial number of participating patients. PMID- 30019317 TI - A facile modification to improve the biocompatibility and adsorbability of activated carbon with zwitterionic hydrogel. AB - In this work, poly(carboxybetaine methacrylate) hydrogel (pCBMA) was employed to modify the activated carbon (AC) for improving the biocompatibility and adsorption capacity of AC in biological environments. First, size-controlled hydrogel beads and hydrogel coated AC (pCBMA-AC) were fabricated with a homemade device, and the preparation conditions were optimized. Then the physical and biological properties of pCBMA-AC with different diameters were investigated. 2 mm pCBMA-AC dispalyed excellent stability with leakage rate only 0.16% after 72 h shaking incubation, as well as remarkable biocompatibility with merely 0.13% hemolysis rate and 3.41% cell death, while 14.72% and 70.11% for the bare AC, respectively, indicating the acceptable lower hemolysis and cytotoxicity according to ISO 10993. Furthermore, the adsorption capacities of pCBMA-AC were evaluated in biological environments with methylene blue as model molecules. The pCBMA-AC displayed 93.50% and 97.32% adsorption rates in BSA solution and FBS, respectively, but only 70.33% and 40.26% for the uncoated AC. These results indicated that pCBMA endows AC remarkable biocompatibility and adsorption capacity, which could extend the applications of AC in biological environments. PMID- 30019318 TI - Clinical validation of the next-generation sequencing-based Extended RAS Panel assay using metastatic colorectal cancer patient samples from the phase 3 PRIME study. AB - PURPOSE: To validate a next-generation sequencing (NGS)-based companion diagnostic using the MiSeqDx(r) sequencing instrument to simultaneously detect 56 RAS mutations in DNA extracted from formalin-fixed paraffin-embedded metastatic colorectal cancer (mCRC) tumor samples from the PRIME study. The test's ability to identify patients with mCRC likely to benefit from panitumumab treatment was assessed. METHODS: Samples from PRIME, which compared first-line panitumumab + FOLFOX4 with FOLFOX4, were processed according to predefined criteria using a multiplex assay that included input DNA qualification, library preparation, sequencing, and the bioinformatics reporting pipeline. NGS mutational analysis of KRAS and NRAS exons 2, 3, and 4 was performed and compared with Sanger sequencing. RESULTS: In 441 samples, positive percent agreement of the Extended RAS Panel with Sanger sequencing was 98.7% and negative percent agreement was 97.6%. For clinical validation (n = 528), progression-free survival (PFS) and overall survival (OS) were compared between patients with RAS mutations (RAS Positive) and those without (RAS Negative). Panitumumab + FOLFOX4 improved PFS in RAS Negative patients (P = 0.02). Quantitative interaction testing indicated the treatment effect (measured by the hazard ratio of panitumumab + FOLFOX4 versus FOLFOX4) differed for RAS Negative versus RAS Positive for PFS (P = 0.0038) and OS (P = 0.0323). CONCLUSIONS: NGS allows for broad, rapid, highly specific analyses of genomic regions. These results support use of the Extended RAS Panel as a companion diagnostic for selecting patients for panitumumab, and utilization is consistent with recent clinical guidelines regarding mCRC RAS testing. Overall, approximately 13% more patients were detected with the Extended RAS Panel versus KRAS exon 2 alone. CLINICAL TRIAL REGISTRY IDENTIFIER: NCT00364013 (ClinicalTrials.gov). PMID- 30019320 TI - Purely neuroendoscopic resection of intraventricular tumors with an endoscopic ultrasonic aspirator. AB - Surgery for intraventricular tumors remains a controversial and evolving field, with endoscopic resection becoming more popular. We present a series of nine consecutive cases of purely endoscopic resection of intraventricular tumors with the aid of an ultrasonic aspirator specific for neuroendoscopy. Nine patients (five men, four women) aged 18-74 years (mean 43.7) underwent surgery. The most common symptom was headache. In all cases, magnetic resonance imaging showed single supratentorial intraventricular lesions (five lateral ventricle, four third ventricle). The average maximum diameter was 20.5 mm (range 11-42). Associated hydrocephalus was found in eight cases at diagnosis. Five patients underwent complete macroscopic resection. Three underwent subtotal resection and one underwent partial resection (two thirds of the tumor). The mean endoscopic procedure time was 70 min (37-209). The eight patients with associated hydrocephalus also underwent endoscopic septostomy to improve cerebral spinal fluid circulation, with one patient additionally requiring endoscopic third ventriculostomy and another requiring Monro foraminoplasty. One patient required ventriculoperitoneal shunting. The mean post-operative follow-up was 15.1 months (range 2-33). At the time of analysis, no patient showed recurrence or regrowth of the operated lesion. The histological diagnoses and degree of resection were three subependymomas with complete resection, three colloid cysts with two complete and one subtotal resection, one pilocytic astrocytoma with partial resection (approximately two thirds of the lesion), one epidermoid tumor with subtotal resection, and one central neurocytoma with subtotal resection. The endoscopic ultrasonic surgical aspirator can be a safe and effective tool for the removal of intraventricular tumors, even in firmer solid lesions. PMID- 30019319 TI - Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Significant improvement in survival outcome with the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors has been shown in advanced non-small cell lung cancer (NSCLC) patients compared with chemotherapy. However, the full spectrum of toxic events of PD-1/PD-L1 inhibitors was not well characterized. We conducted a comprehensive meta-analysis to state the safety profile of PD-1/PD-L1 inhibitors in NSCLC, and identify the exact incidence and relative risk (RR) of both summary and detailed AEs. MATERIALS AND METHODS: Electronic databases (PubMed, EMBASE and the Cochrane library databases) and major conference proceedings were systematically searched for all clinical trials in lung cancer using PD-1/PD-L1 inhibitors. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients reporting all-grade (1-4) or high-grade (3-4) AEs [toxic symptoms, hematologic toxicities, and immune-related AEs (irAEs)], treatment discontinuation due to toxicities, or toxic deaths. The pooled incidence, RR, and corresponding 95% confidence interval (CI) of toxicity outcomes were calculated. RESULTS: A total of 4413 patients from 8 RCTs (3 with nivolumab; 2 with atezolizumab, and 3 with pembrolizuma) were included. In terms of summary toxic events, PD-1/PD-L1 inhibitors had a significantly lower risk of any all-grade AEs (66.20 vs. 86.08%; RR 0.77) and high-grade AEs (14.26 vs. 43.53%; RR 0.32), treatment discontinuation (5.94 vs. 13.92%; RR 0.44), and toxic deaths (0.48 vs. 1.12%; RR 0.45) than chemotherapy. With regard to detailed toxic events, the risk of toxic symptoms (including all-grade fatigue, nausea, constipation, diarrhea and peripheral sensory neuropathy; high-grade fatigue, anorexia, diarrhea and peripheral sensory neuropathy) and hematologic toxicities (including all-grade and high-grade neutropenia, thrombocytopenia, and anemia) from PD-1/PD-L1 inhibitors was significantly lower than from chemotherapy. However, there was a small but significantly increased risk of irAEs, including all-grade rash, pruritus, colitis, hypothyroidism, hyperthyroidism, ALT/AST elevations and pneumonitis, as well as high-grade pneumonitis. CONCLUSION: PD-1/PD-L1 inhibitors are generally safer and better tolerated than chemotherapy for patients with NSCLC with regard to summary toxic events, detailed toxic symptoms and hematologic toxicities. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and several of them can be severe and even life-threatening. Clinicians should be aware of the risk of these AEs, as they may have a potentially negative impact on the patients' quality of life and survival outcome. PMID- 30019321 TI - Evolutionarily Related Dihydrofolate Reductases Perform Coequal Functions Yet Show Divergence in Their Trajectories. AB - The enzyme dihydrofolate reductase (DHFR) catalyzes NADPH dependent reduction of dihydrofolate to tetrahydrofolate. It plays a crucial role in the DNA synthesis. The investigation of evolution of DHFR generates immense curiosity. It aids in predicting how the enzyme has adapted to the surroundings of various cell types. In spite of great similarity in the structure of E. coli DHFR and human DHFR, their primary sequences are divergent to a great extent, which is evident in variations in the kinetics mechanism of their catalysis. In presence of physiological levels of ligands, they possess distinct kinetics and different rate limiting steps. We have reviewed the process of their unfolding and refolding, their behaviour in denaturing conditions and in presence of various chaperones. Although there is structural similarity between these two homologous enzymes yet they have established distinct mechanisms to accomplish the coequal functions. PMID- 30019323 TI - Can intensive fish farming for 20 years induce changes in benthic ecosystems on a scale of waterbody? An assessment from Cephalonia bay (Ionian Sea). AB - The environmental impacts of fish farming on benthic ecosystems beneath the fish cages have been widely addressed the past decades. However, the chronic release of nutrients can cause a shift in local primary productivity and a chronic increase in the sedimentation of organic material at a large spatial scale which could be reflected in benthic ecosystems. In this context, the indirect effects of aquaculture on the benthic ecosystem were studied in a semi-closed bay (Cephalonia, Ionian Sea) where a relatively large fish farm has been operating since 1982. Results from the present sampling were compared to historical data obtained in 1996 and 2001, in order to detect if nutrient release that could impact phytoplankton dynamics in the bay could indirectly alter benthic communities, as well. Macrofaunal communities have not shown deterioration but rather a small, yet statistically significant, improvement in diversity indices and ecological status indicators, and no significant change regarding bioturbation potential. This indicated that processes involved in nutrient consumption and transfer are highly effective in such an oligotrophic environment. PMID- 30019325 TI - T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: Report of the First Case in the Mandible. AB - T-cell/histiocyte-rich large B-cell lymphoma (THRBCL) is an uncommon subtype of non-Hodgkin's lymphoma. It is a predominant nodal neoplasm; however, extranodal sites, such as the spleen, liver and bone marrow, can be involved at diagnosis. However, only one case of primary THRLBCL in the jaws have been reported. We herein describe a 29-year-old female patient who presented with a swelling of the right mandible that had grown rapidly over the previous 2 months. Periapical and panoramic radiographs showed a multilocular osteolytic lesion located in the mandibular periapical region of the canine and premolar teeth and molar region. Preoperative examination and incisional biopsy were performed. Immunohistochemistry was applied to confirm the diagnosis of THRBCL in the jaw. The treatment consisted of CHOP therapy and radiotherapy. After complete tumor remission following initial treatment, additional sites of the disease appeared in the lung, abdomen and long bones. The patient died within 2 months. THRLBCL is an uncommon and aggressive malignant neoplasm that can involve the jaws, mimicking a periapical disease. PMID- 30019324 TI - Comprehensive investigation of a dye-decolorizing peroxidase and a manganese peroxidase from Irpex lacteus F17, a lignin-degrading basidiomycete. AB - Irpex lacteus F17 is well-known for its ability to degrade recalcitrant aromatic pollutants, which mainly results from the action of the manganese peroxidase (MnP) that it is able to produce. Recently, the genome sequencing and annotation of this strain provided comprehensive picture of the ligninolytic peroxidase gene family. In addition to revealing the presence of 13 MnPs, genes for five dye decolorizing peroxidases (DyPs) were also discovered in the I. lacteus F17 genome, which are unrelated to the fungal class II peroxidases. In the present study, amino acid sequences of five DyPs and 13 MnPs, representing two different families of heme peroxidases, were analyzed. Of these, two enzymes, a DyP (Il DyP4) and a MnP (Il-MnP6) were expressed respectively in Escherichia coli, and were characterized by comparing their molecular models, substrate specificities, and catalytic features. The results showed that Il-DyP4 possessed a higher catalytic efficiency for some representative substrates, and a stronger decolorizing ability to a wide range of synthetic dyes in acidic conditions. Based on electrochemical measurements, Il-DyP4 was found to have a high redox potential of 27 mV at pH 3.5, which was superior to that of Il-MnP6 (- 75 mV), thereby contributing to its ability to oxidize high redox potential substrates, such as veratryl alcohol and polymeric dye Poly R-478. The results highlighted the potential of Il-DyP4 for use in industrial and environmental applications. PMID- 30019326 TI - Main challenges in the control of zoonoses and related foodborne diseases in the South Mediterranean and Middle East region. AB - In the South Mediterranean and Middle East region, interactions between humans, animals, and the surrounding environment are frequently close. This fact is mainly manifested in traditional farming settings (by sedentary, semi-sedentary, and nomadic communities) as well as where livestock intensification has been introduced. A combination of complex factors in these settings (e.g. challenges in country infrastructures and cross-sectoral collaboration/ coordination, traditional habits, poor social information, etc.) contribute to the emergence and, occasionally, to the endemic pattern of zoonoses. The phenomenal growth of international travel and trade, population displacement, and unhygienic settlements has increased the speed and ease with which pathogens and vectors can cross continents and cause outbreaks and epidemics. Programmes for the prevention and control of zoonoses have been implemented in several countries in this region; however, the expected results have not always been realised. The conflicts and civil unrest affecting certain countries in this region during the last decade, together with the mass displacement of people seeking refuge, have resulted in serious epidemiological and social impacts. Zoonoses and related food borne diseases are, indeed, a worldwide challenge, whose prevention and control mainly depend on the actions of national authorities. Once peace has been established in this region, authorities need to address the burden of these diseases through resource mobilisation, the implementation of international agencies? technical guidance, and inter-country collaboration. PMID- 30019327 TI - Cross-reactivity in serological tests for brucellosis: a comparison of immune response of Escherichia coli O157:H7 and Yersinia enterocolitica O:9 vs Brucella spp. AB - According to European Union (EU) regulations, the serological tests for the eradication of bovine and ovine brucellosis are the Rose Bengal Test, Complement Fixation Test, and i-ELISA. These methods, also recommended by the World Organization for Animal Health (OIE) for international trades, have limitations related to the use of suspensions of smooth Brucellae or LPS extracts. Limitations include false-positive serological reactions to brucellosis, which in turn impedes accurate diagnosis in some herds. False positive reactions should be considered carefully during the final stages of an eradication programme and for surveillance purposes in brucellosis-free areas. In this study, we produced specific sera through the experimental infection of sheep with Y. enterocolitica O:9 and E. coli O157:H7. These are the most important cross-reactive bacteria with Brucella. We then evaluated the antibody response of groups of sheep that had been immunised towards homologous antigens and official antigens for brucellosis, in order to identify a differential diagnostic protocol to distinguish cross-reaction in Brucella-infected animals. PMID- 30019328 TI - The prevalence, characterisation, and antimicrobial resistance of Yersinia enterocolitica in pigs from Central Italy. AB - Widely spread in nature, Yersinia enterocolitica (YE) is a foodborne pathogen of major health and economic significance in developed countries. The aim of this study is to analyse YE strains isolated from 400 slaughtered pigs from the Abruzzo region, Italy, using biochemical tests and a multiplex polymerase chain reaction PCR detecting 6 chromosomal genes (ystA, irp2, 16s, ail, inv, hemR) and one plasmid-borne virulence gene (yadA). Antimicrobial susceptibility was evaluated and pulsed-field gel electrophoresis (PFGE) was also performed in order to assess phylogenetic diversity. In total, 56 samples of porcine tonsils (14%) were found to be positive for the presence of pathogenic YE. All YE belonged to the pathogenic bioserotype 4/O:3. All YE samples were positive for the chromosomal virulence genes ystA, ail, and inv, whereas results for the presence of yadA and hemR were variable. This study found that YE isolates were resistant to ampicillin (100%), streptomycin (26.79%), sulfisoxazole (19.65%), tetracycline (16.08%), nalidixic acid (14.30%), and chloramphenicol (10.72%). The strains characterised by PFGE showed a high similarity. This study demonstrates the usefulness of multiplex polymerase chain reaction (PCR) compared with conventional phenotypic assays for the identification of pathogenic YE isolates and the limitations of PFGE for the molecular typing of YE bioserotype 4/O:3. PMID- 30019329 TI - Detection and characterisation of potentially pathogenic species of Vibrio in the Vibrata river, Abruzzo Region, Italy. AB - This study aimed to isolate, define the genetic profile, assess potential pathogenicity and evaluate the seasonal distribution of Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus strains isolated from the Vibrata river (Abruzzo Region, Italy) during a monitoring period of one year. Detection was performed according to ISO/TS 21872-1-2:2007. Species identification and characterisation were achieved using molecular methods. Vibrio spp. were detected in 50% (23) of the water samples. In particular, V. cholerae, V. parahaemolyticus, and V. vulnificus were isolated in 18 (39.1%), 4 (8.7%), and 2 (4.3%) samples, respectively. All V. parahaemolyticus strains were tdh gene negative, 75% were positive for trh gene. In 30 V. cholerae isolates, the polymerase chain reaction (PCR) assay for detecting virulence and regulatory genes (ctxA, toxR, tcpA, ompU, hlyA, tcpI, zot, and stn/sto) revealed 6 genotypes associated to different levels of pathogenicity. Pulsed-field gel electrophoresis (PFGE) characterisation of the V. cholerae strains identified 13 different pulsotypes. A greater degree of similarity was shown for strains isolated in the same period of the year. Results of our study reveal a potential health risk associated with the waters of the Vibrata river, which are used for irrigation and next to the swimming areas of Abruzzo coastline. PMID- 30019330 TI - Comparison of automated extraction methods for the detection of hepatitis A virus and norovirus in mussels. AB - Noroviruses and hepatitis A virus are the pathogens most frequently involved in non-bacterial gastroenteritis and hepatitis worldwide. They are mainly transmitted via the faecal-oral route, direct person-to-person contact or through the consumption of contaminated water and foods. In food virology, detection methods of these viruses are currently based on real-time reverse transcription polymerase chain reaction (RT-PCR). A crucial step in this process is the acid nucleic extraction, since its performance can negatively influence viral detection and thus give false negative results. The aim of this study is to evaluate the efficiency of 2 automated extraction systems, MagMAX Express and EZ1 Advanced XL, in recovering hepatitis A virus and norovirus RNA from mussels. In the present study, we used mengovirus as a process control to assess the efficiency of the extraction process. Samples were tested for mengovirus, hepatitis A, and norovirus by real time one-step RT-PCR assay. Our data indicates the MagMax Express is the better system to extract hepatitis A and norovirus RNA from mussels since its extraction efficiency was higher (p<0.05) than EZ1 Advanced XL. PMID- 30019331 TI - Exuberant granulation tissue in a horse: successful treatment by the intralesional injection of 4% formaldehyde solution. AB - The healing of wounds located on the equine distal limbs can often be impaired, which can result in exuberant granulation tissue and its associated aesthetic alteration and functional failures. Although a number of therapies have been developed and assessed, the treatment of these wounds still presents challenges. This report describes the treatment of exuberant granulation tissue in a horse using an intra-lesional injection of 4% formaldehyde solution. The successful outcome of this treatment suggests that further investigations are required in order to better evaluate its efficacy, as well as the incidence and the severity of any adverse reaction. PMID- 30019332 TI - Heart valve pathology in regularly slaughtered horses. AB - In this study we examined macroscopic and microscopic lesions in the mitral valves of 50 regularly slaughtered horses in Italy. Macroscopically the results were minor. Microscopic lesions to the valve were found in both young and elderly subjects, confirming that there is no correlation between age and onset of lesions. We set out to evaluate whether the lesions correspond to valve disorder during the life of the animal. PMID- 30019333 TI - Reproductive disorders in domestic canaries (Serinus canarius domesticus): a retrospective study on bacterial isolates and their antimicrobial resistance in Italy from 2009 to 2012. AB - Reproductive disorders are responsible for significant economic losses in canary aviculture due to embryo and newborn chick mortality. Most of the time, deaths are caused by bacterial pathogens, however little published data exist about the prevalence of bacterial isolates that are identified during diagnostic protocols. This study reports on data collected from previous investigations carried out on cloacal swabs (n 456), unhatched eggs (n 52), and dead newborn chicks (n 68) collected from canary aviaries with a history of reproductive disorders. Of the examined samples, 41% were positive for the presence of pathogenic or potentially pathogenic bacteria, with particular regard to Gram negative species during bacteriological investigations. The most prevalent microorganisms were Gram negative (55%). A predominance of Klebsiella, Escherichia, and Pantoea genera was observed. These are usually associated to pathological conditions in pet birds. Among Gram-positive bacteria, Bacillus spp. and Staphylococcus spp. were most prevalent. The antimicrobial susceptibility testing carried out on bacterial isolates showed a multiple resistance, especially against amoxycillin, erythromycin, spiramycin, tiamulin, and tylosin. This study represents a first attempt to provide an update on microbial causes of embryonic and neonatal mortality in canary aviaries in Italy; in addition, it provides further understandings about the efficacy of antimicrobial therapy. PMID- 30019334 TI - Veterinary forensic sciences to solve a fatal case of predation on flamingos (Phoenicopterus roseus). AB - The present case study concerns a case of predation of 4 individuals of captive pink flamingo in Emilia Romagna Region, Northeastern Italy. The pink flamingo (Phoenicopterus roseus) is a species included in the Red List of Threatened Species established by the International Union for Conservation of Nature (IUCN) which lists species in danger of extinction. During the Winter of 2013, 4 flamingos (2 in the Comacchio area, and 2 from Argenta and Codigoro oases - Ferrara province) were found dead some of them headless, with their bodies severely bitten. At first, a fox (Vulpes vulpes) was suspected to be the predator responsible for the killing and the birds were taken to the laboratory for further investigations. The investigations included: field observations, study of the predator behaviour, necropsy examinations, assessment of the intercanine distance, and genetic analysis on the predator's traces. The intercanine distance indicated that the predator could not have been a fox. The analysis of salivary DNA samples enabled us to establish that the predator was in fact a dog. This case highlights the importance of co-operation among the various branches of forensic sciences and the great usefulness of the roles filled by other veterinary forensic experts involved in solving crime. PMID- 30019336 TI - Effect of internalized stigma on functional recovery in patients with schizophrenia. AB - PURPOSE: This cross-sectional study was conducted to determine the effect of internalized stigma on functional recovery in patients with schizophrenia. DESIGN AND METHODS: As a result of the power analysis performed, the sample size of the study that reflect population was determined to be 250 patients. Patient Information Form, Functional Recovery Scale in Schizophrenia (FROGS), and Internalized Stigma of Mental Illness Scale (ISMIS) were used for data collection. FINDINGS: It was determined that the mean FROGS subscale and total scores of the patients participating in the study were low. The mean ISMIS subscale and total scores of the patients were high. PRACTICE IMPLICATIONS: It was found that the level of internalized stigma was high and the level of functional recovery was low patients with schizophrenia. PMID- 30019337 TI - A randomized intraindividual comparative study of methyl-5-aminolaevulinate vs. 5 aminolaevulinic acid nanoemulsion (BF-200 ALA) in photodynamic therapy for actinic keratosis of the face and scalp. PMID- 30019335 TI - GABA beyond the synapse: defining the subtype-specific pharmacodynamics of non synaptic GABAA receptors. AB - KEY POINTS: Physiologically relevant combinations of recombinant GABAA receptor (GABAR) subunits were expressed in HEK293 cells. Using whole-cell voltage clamp and rapid drug application, we measured the GABAR-subtype-specific properties to convey either synaptic or extrasynaptic signalling in a range of physiological contexts. alpha4betadelta GABARs are optimally tuned to submicromolar tonic GABA and transient surges of micromolar GABA concentrations. alpha5beta2gamma2l GABARs are better suited to higher tonic GABA levels, but also convey robust responses to brief synaptic and perisynaptic GABA fluctuations. alpha1beta2/3delta GABARs function well at prolonged, micromolar (>2 MUm) GABA levels, but not to low tonic (<1 MUm GABA) or synaptic/transient GABAergic signalling. These results help illuminate the context- and isoform-specific modes of GABAergic signalling in the brain. ABSTRACT: GABAA receptors (GABARs) mediate a remarkable diversity of signalling modalities in vivo. Yet most published work characterizing responses to GABA has focused on the properties needed to convey fast, phasic synaptic inhibition. We therefore aimed to characterize the most prevalent (alpha4betadelta, alpha5beta3gamma2L) and least prevalent (alpha1beta2delta) non synaptic GABAR currents, using whole-cell voltage clamp recordings of recombinant GABAR expressed in HEK293 cells and drug application protocols to recapitulate the GABA concentration profiles occurring during both fast synaptic and slow extrasynaptic signalling. We found that alpha4betadelta GABARs were very sensitive to submicromolar GABA, with a rank order potency of alpha4beta2delta >= alpha4beta1delta ~ alpha4beta3delta GABARs. In comparison, the GABA EC50 was up to 20 times higher for alpha1beta2gamma2L GABARs, with alpha1beta2delta and alpha5beta3gamma2L GABARs having intermediate GABA potency. Both alpha4betadelta and alpha5beta3gamma2L GABAR currents exhibited slow, but substantial, desensitization as well as prolonged rates of deactivation. These GABAR current properties defined distinct 'dynamic ranges' of responsiveness to changing GABA for alpha4beta2delta (0.1-1 MUm), alpha5beta3gamma2L (0.5-7 MUm) and alpha1beta2gamma2L (0.6-9 MUm) GABARs. Finally, alpha1beta2delta GABARs were notable for their relative lack of desensitization and extremely quick deactivation. In summary, our results help delineate the roles that specific GABARs may play in mediating non-synaptic GABA signals. Since ambient GABA levels may be altered during development as well as by drugs and disease states, these findings may help future efforts to understand disrupted inhibition underlying a variety of neurological illnesses, such as epilepsy. PMID- 30019338 TI - Sympathoexcitation by hypothalamic paraventricular nucleus neurons projecting to the rostral ventrolateral medulla. AB - KEY POINTS: Causal relationships between central cardiovascular pathways and sympathetic vasomotor tone have not been evidenced. This study aimed to verify the sympathoexcitatory role of hypothalamic paraventricular nucleus neurons that project to the rostral ventrolateral medulla (PVN-RVLM neurons). By using optogenetic techniques, we demonstrated that stimulation of PVN-RVLM glutamatergic neurons increased renal sympathetic nerve activity and arterial pressure via, at least in part, stimulation of RVLM C1 neurons in rats. This monosynaptic pathway may function in acute sympathetic adjustments to stressors and/or be a component of chronic sympathetic hyperactivity in pathological conditions such as heart failure. ABSTRACT: The rostral ventrolateral medulla (RVLM), which is known to play an important role in regulating sympathetic vasomotor tone, receives axonal projections from the hypothalamic paraventricular nucleus (PVN). However, no studies have proved that excitation of the PVN neurons that send axonal projections to the RVLM (PVN-RVLM neurons) causes sympathoexcitation. This study aimed to directly examine the sympathoexcitatory role of PVN-RVLM neurons. Male rats received microinjections into the PVN with an adeno-associated virus (AAV) vector that encoded a hybrid of channelrhodopsin-2/1 with the reporter tdTomato (ChIEF-tdTomato), or into the RVLM with a retrograde AAV vector that encoded a channelrhodopsin with green fluorescent protein (ChR2 GFPretro ). Under anaesthesia with urethane and alpha-chloralose, photostimulation (473 nm wavelength) of PVN-RVLM neurons, achieved by laser illumination of either RVLM of ChIEF-tdTomato rats (n = 8) or PVN of ChR2 GFPretro rats (n = 4), elicited significant renal sympathoexcitation. Immunofluorescence confocal microscopy showed that RVLM adrenergic C1 neurons of ChIEF-tdTomato rats were closely associated with tdTomato-labelled, PVN-derived axons that contained vesicular glutamate transporter 2. In another subset of anaesthetized ChIEF-tdTomato rats (n = 6), the renal sympathoexcitation elicited by photostimulation of the PVN was suppressed by administering ionotropic glutamate receptor blockers into the RVLM. These results demonstrate that excitation of PVN-RVLM glutamatergic neurons leads to sympathoexcitation via, at least in part, stimulation of RVLM C1 neurons. PMID- 30019339 TI - Highly divergent Mollicutes symbionts coexist in the scorpion Androctonus australis. AB - Androctonus australis is one of the most ubiquitous and common scorpion species in desert and arid lands from North Africa to India and it has an important ecological role and social impact. The bacterial community associated to this arachnid is unknown and we aimed to dissect its species composition in the gut, gonads, and venom gland. A 16S rRNA gene culture-independent diversity analysis revealed, among six other taxonomic groups (Firmicutes, Betaproteobacteria, Gammaproteobacteria, Flavobacteria, Actinobacteria, and Cyanobacteria), a dominance of Mollicutes phylotypes recorded both in the digestive tract and the gonads. These related Mollicutes include two Spiroplasma phylotypes (12.5% of DGGE bands and 15% of clones), and a new Mycoplasma cluster (80% of clones) showing 16S rRNA sequence identities of 95 and 93% with Mollicutes detected in the Mexican scorpions Centruroides limpidus and Vaejovis smithi, respectively. Such scorpion-associated Mollicutes form a new lineage that share a distant ancestor with Mycoplasma hominis. The observed host specificity with the apparent phylogenetic divergence suggests a relatively long co-evolution of these symbionts with the scorpion hosts. From the ecological point of view, such association may play a beneficial role for the host fitness, especially during dormancy or molt periods. PMID- 30019340 TI - Non-heavy drinking and worsening of non-invasive fibrosis markers in nonalcoholic fatty liver disease: A cohort study. AB - : The effect of modest alcohol consumption on fibrosis progression in the general population with NAFLD remains unclear. We examined the association of non-heavy alcohol consumption with worsening of non-invasive fibrosis indices in a large scale, low-risk population with non-alcoholic fatty liver disease (NAFLD). A cohort study was performed in 58,927 Korean adults with NAFLD and low fibrosis scores who were followed for a median of 8.3 years. Non-, light, and moderate drinkers were defined as 0 g/day, 1-9.9 g/day, and 10-29.9 g/day (10-19.9 g/day for women), respectively. Progression from low to intermediate or high probability of advanced fibrosis was assessed using non-invasive indices including NAFLD fibrosis score (NFS) and FIB-4. Parametric proportional hazards model was used to estimate the multivariate-adjusted hazard ratios and 95% confidence intervals. During 347,925.4 person-years of follow-up, 5,630 subjects with low FIB-4 progressed to intermediate or high FIB-4. The multivariable adjusted HRs (95% CI) for worsening of FIB-4 comparing light-drinkers and moderate-drinkers with non-drinkers were 1.06 (0.98-1.16) and 1.29 (1.18-1.40), respectively. Similarly, using NFS, corresponding HRs (95% CI) comparing light drinkers and moderate-drinkers with non-drinkers were 1.09 (1.02-1.16) and 1.31 (1.23-1.40), respectively. Furthermore, the association of moderate drinkers with worsening of either FIB-4 or NFS remained significant after introducing alcohol use and confounders treated as time-varying covariates. CONCLUSION: In this large scale cohort of young and middle aged individuals with NAFLD, non-heavy alcohol consumption, especially moderate alcohol consumption, was significantly and independently associated with worsening of noninvasive markers of fibrosis, indicating that even moderate alcohol consumption might be harmful. This article is protected by copyright. All rights reserved. PMID- 30019341 TI - Anticoagulation management services in community pharmacy: Feasibility of implementing a quality improvement programme through a practice-based research network. AB - WHAT IS KNOWN AND OBJECTIVE: The literature has reported suboptimal real-world use of oral anticoagulants in patients with atrial fibrillation (AF). Anticoagulation management services (AMSs) in community pharmacy have rarely been evaluated, and no formal process is available to enable pharmacists to evaluate and improve their clinical practices. Our objective was to assess the feasibility of implementing, through a practice-based research network (PBRN), a quality improvement programme on AMSs by community pharmacists for AF patients and explore its impact on the quality of clinical practices and pharmacists' knowledge. METHODS: An uncontrolled pre/post-pilot study was conducted through a PBRN. Pharmacists identified 5-20 AF patients on oral anticoagulants per pharmacy and completed questionnaires at baseline (T0) and after 6 months (T6). Clinical practices were evaluated using a set of quality indicators (QIs). QI scores ranged from 0% (no QI achieved) to 100% (all QIs achieved). The programme included an audit and feedback based on QIs and a personalized training programme (including online videos). Participation rates and satisfaction were documented. Mean changes (T6-T0), with 95% confidence interval (CI), in QIs and knowledge scores were computed. RESULTS AND DISCUSSION: A total of 37 pharmacies (50 pharmacists) identified 222 patients who had received either vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), or both. All pharmacies received their baseline quality report (audit), and facilitators contacted by phone 97% of pharmacies (feedback). Each of the six online videos was completed by at least 48% of pharmacists. Baseline mean global QI scores for VKAs and DOACs were 39.1% (95% CI: 35.7%-42.4%) and 12.3% (7.8%-16.8%), respectively. Over a 6 month period, they increased by 12.5% points (7.5%-17.5%) and 9.9% points (3.8% 16.1%), respectively. Baseline mean global knowledge score was 68.7% (65.4% 72.0%) and increased by 4.3% points (1.2%-7.4%). WHAT IS NEW AND CONCLUSION: Implementing a quality improvement programme for AMS in community pharmacy is relevant and feasible and may improve pharmacists' practices and knowledge. PMID- 30019342 TI - On the data acquisition, image reconstruction, cone beam artifacts, and their suppression in axial MDCT and CBCT - A review. AB - PURPOSE: In the clinic, computed tomography (CT) has evolved into an essential modality for diagnostic imaging by multidetector row CT (MDCT) and image guided intervention by cone beam CT (CBCT). Recognizing the increasing importance of axial MDCT/CBCT in clinical and preclinical applications, and the existence of CB artifacts in MDCT/CBCT images, we provide a review of CB artifacts' root causes, rendering mechanisms and morphology, and possible solutions for elimination and/or reduction of the artifacts. METHODS: By examining the null space in Radon and Fourier domain, the root cause of CB artifacts (i.e., data insufficiency) in axial MDCT/CBCT is analytically investigated, followed by a review of the data sufficiency conditions and the "circle +" source trajectories. The rendering mechanisms and morphology of CB artifacts in axial MDCT/CBCT and their special cases (e.g., half/short scan and full scan with latitudinally displaced detector) are then analyzed, followed by a survey of the potential solutions to suppress the artifacts. The phenomenon of imaged zone indention and its variation over FBP, BPF/DBPF, two-pass and iterative CB reconstruction algorithms and/or schemes are discussed in detail. RESULTS: An interdomain examination of the null space provides an insightful understanding of the root cause of CB artifacts in axial MDCT/CBCT. The decomposition of CB artifacts rendering mechanisms facilitates understanding of the artifacts' behavior under different conditions and the potential solutions to suppress them. An inspection of the imaged zone intention phenomenon provides guidance on the design and implementation of CB image reconstruction algorithms and schemes for CB artifacts suppression in axial MDCT/CBCT. CONCLUSIONS: With increasing importance of axial MDCT/CBCT in clinical and preclinical applications, this review article can update the community with in-depth information and clarification on the latest progress in dealing with CB artifacts and thus increase clinical/preclinical confidence. PMID- 30019343 TI - Communicative and pedagogical strategies in nurses' and surgeons' discharge consultations with patients undergoing surgery for colorectal cancer. AB - AIM: To describe the structure, content, and the communicative and pedagogic strategies in discharge consultations between patients and professionals after colorectal cancer surgery. BACKGROUND: Both nurses and surgeons play an important role in preparing patients for discharge from hospital following surgery for colorectal cancer (CRC). DESIGN: An explorative quantitative and qualitative research based on analysis of transcriptions of 13 audio-taped discharge consultations between patients and nurses and patients and surgeons conducted between January - March 2012. METHODS: In the quantitative analysis, the structure of each consultation was described in phases, subtopics, and main topics. The proportion of the main topics in relation to the whole conversation was counted in percentages. The text from the consultations was then analysed qualitatively with the support from Ricoeur's theory of interpretation. RESULTS: The language constituted the essence in the consultations regardless of other communicative and pedagogical strategies. The pedagogic strategies used were explanation model, information transfer, task orientation, and dialogue. Topics occurring in the consultations were Operation, Symptoms, Medication, Thromboprophylaxis, Recovery after surgery, Bowel function, Spreading, and Follow up. The surgeons and nurses used similar topics, but the surgeons used more communicative and pedagogic strategies. CONCLUSION: Language was fundamental for communication and independent of the communicative and pedagogical strategies. Using preparedness communication more consistent in discharge consultation can help patients to better understand the recovery process after CRC surgery and regain control over their life. It is important that the consultations build on the patient as an active and learning person. PMID- 30019344 TI - Essential preanalytics in PD-L1 immunocytochemistry. PMID- 30019345 TI - I am the chosen one: Narcissism in the backdrop of self-determination theory. AB - OBJECTIVE: This theoretical article discusses the relevance of self-determination theory (SDT) for narcissism, a classic topic in self-theory. METHOD AND RESULTS: The trait of narcissism reflects a self-aggrandizing, dominant, and manipulative interpersonal orientation that feeds on exaggerated perceptions of agency, but not communion. The article embeds narcissism in the five mini-theories of SDT (organismic integration, causality orientations, basic needs, cognitive evaluation, and goal contents) and considers research directions that can explore synergies between key constructs from SDT and narcissism. CONCLUSIONS: SDT can serve as a foundation for a deeper understanding of narcissism. From the other end, narcissism can enrich SDT by explaining variations in motivational processes. PMID- 30019347 TI - Practical and statistical challenges in driving research. AB - Driving is an integral aspect of many modern societies, and motor vehicle safety is an important public health issue. With advances in sensor technology, more and more driving data are being collected by researchers, insurers, and automobile companies, which has increased the need and opportunities for statisticians to be involved in driving research. This report discusses several practical and statistical challenges in driver-level studies, including the process of defining meaningful driving metrics, issues related to "Big Data" aspects of driving research, and the principle of reproducible research. PMID- 30019346 TI - A protocol to measure the impact of intentional changes to nurse staffing and skill-mix in medical and surgical wards. AB - AIM: The aim of this research is to measure the impact that planned changes to nurse staffing and skill-mix have on patient, nurse, and organizational outcomes. BACKGROUND: It has been highlighted that there are several design limitations in studies that explore the relationship between nurse staffing and patient, nurse and organizational outcomes; not least that the vast majority of research in this area emanates from studies that are predominantly observational in design. There are limited studies that measure nurse, patient, organizational, and economic outcomes using a longitudinal design following a planned change in nurse staffing. DESIGN: The research will employ a longitudinal, multimethod approach to evaluate the impact that planned changes in nurse staffing and skill-mix have on wards in three pilot hospitals. METHODS: Administrative data collection will take place on a shift-by-shift basis prospectively over a three-year period including the measurement of nursing sensitive outcomes: cross-sectional patient experience data and nurse outcomes (nursing work, job satisfaction, burnout, missed care) will be collected at intervals prior to, during and after the implementation of planned changes in nurse staffing and skill-mix. Data will be analysed using interrupted time-series models, adjusted for key hospital, ward and patient-level factors. An economic costing of the changes will further investigate the resources required for the intervention that can then be aggregated to a national level for future roll-out plans. DISCUSSION: The study aims to provide evidence on the impact of planned changes to nurse staffing and skill-mix based on a systematic approach using a longitudinal design and to determine the extent to which the approach can be implemented at a national level. PMID- 30019348 TI - The influence of adherence to the Mediterranean diet on academic performance is mediated by sleep quality in adolescents. AB - AIM: This study examined the association of adherence to the Mediterranean diet with academic performance and tested whether this association was mediated by sleep in Spanish adolescents. METHODS: We recruited 269 adolescents (52% boys) aged 13.9 +/- 0.3 years from the Deporte, ADOlescencia y Salud study of 38 secondary schools and sport clubs in Castellon, Spain, between February and May 2015. Adherence to the Mediterranean diet was assessed by the KIDMED questionnaire, sleep quality was evaluated with the Pittsburgh Sleep Quality Index test and sleep duration was objectively computed using a wrist-worn accelerometer. Academic performance was assessed through final school grades and a validated test. RESULTS: Greater adherence to the Mediterranean diet was associated with higher scores in language, core subjects, grade point average and verbal ability (p < 0.05). Sleep quality acted as a significant mediator of the association between adherence to the Mediterranean diet and final grades in maths, language, core subjects and the grade point average. CONCLUSION: Our data show that the influence of adherence to the Mediterranean diet on academic performance was mediated by sleep quality in adolescents. Education and public health professionals should work together to achieve both improved health status and academic performance in adolescents. PMID- 30019349 TI - Unexplained fever after pancreas transplantation. AB - BACKGROUND: Fever occurs frequently early after pancreas transplant, however, the exact cause is often undetermined. Limited data are available on pancreas recipients experiencing unexplained, noninfectious fever. This study aims to characterize unexplained fever (UF) in pancreas recipients and its effect on patient and graft outcomes. METHODS: We performed a retrospective cohort study of UF among consecutive pancreas or simultaneous pancreas-kidney transplant recipients from 1 January 2011 to 31 August 2015. Classification of UF was based on the absence of positive cultures, radiologic findings, and other diagnostic features of infection or rejection. RESULTS: Twenty-three of 92 (25%) patients experienced UF. The UF episode first occurred at a mean of 31 +/- 17 days post transplant and accounted for 34 admissions with an average length of stay of 5.1 +/- 3.4 days. Intravenous corticosteroid was administered following confirmation of negative diagnostic tests in 77% of patients, with fever resolution occurring in all. No differences were seen in rates of biopsy-proven rejection, graft loss, death, or documented infections compared to UF-free patients during the first year post-transplant. CONCLUSION: UF is a common cause for readmission following pancreas transplantation. While the etiology of UF remains difficult to identify, UF occurrence was not associated with adverse outcomes during the first-year post transplant. PMID- 30019350 TI - Guns, Obesity, and Opioids: A Population Health Science Perspective on 3 Contemporary Epidemics. PMID- 30019351 TI - Tibial nerve axonal excitability in type 1 diabetes mellitus. AB - INTRODUCTION: The aim of this study was to determine alterations in axonal excitability in tibial nerve as compared with median nerve axonal excitability in patients with diabetic polyneuropathy. METHODS: Six patients with diabetic polyneuropathy and 10 patients with diabetes mellitus without polyneuropathy were enrolled. RESULTS: Compared with diabetic patients without polyneuropathy, the tibial nerve strength-duration time constant was significantly longer and supernormality was lower in those with polyneuropathy. Threshold electrotonus studies showed abnormalities in patients with diabetic polyneuropathy, in which smaller threshold changes from long-depolarizing and hyperpolarizing conditioning, termed "fanning-in," were found. DISCUSSION: This study confirms that axonal excitability is significantly altered in the tibial nerve of patients with diabetic polyneuropathy. Evaluating the axonal excitability of the median and tibial nerves may reveal the presence of length-dependent polyneuropathy at an early stage. Muscle Nerve, 2018. PMID- 30019352 TI - WHO-5 and BDI-II are acceptable screening instruments for depression in people with diabetes. AB - AIMS: To investigate the acceptability of two questionnaires, the five item WHO Well-being Index (WHO-5) and the Beck Depression Inventory II (BDI-II), which differ in length and focus, by comparing three screening groups: (1) WHO-5, (2) BDI-II and (3) WHO-5 and BDI-II. METHODS: A total of 699 individuals with diabetes were approached to participate in the study, of whom 95 completed the WHO-5, 254 completed the BDI-II and 350 completed both the WHO-5 and the BDI-II questionnaires. Five facets of acceptability were compared, including objective aspects (response rate and completion level) and subjective aspects (appreciation, agreeableness and accuracy of the screening questionnaire). Data were analysed using logistic regression analysis and (multivariate) analysis of covariance. RESULTS: The overall response rate was 65% (453 out of 699). No differences between the three groups were found with respect to the response rate (WHO-5: 66%; BDI-II: 63%; WHO-5 and BDI-II: 66%; P >= 0.19) and completion level (WHO-5: 99.5%; BDI-II: 97.8%; WHO-5 and BDI-II: 98.7%; P=0.45). The three groups did differ significantly in their scores on two of the three subjective indicators (P<0.03), i.e. appreciation (P=0.002) and agreeableness (P=0.035), with those completing only the WHO-5 reporting greater appreciation and agreeableness. CONCLUSIONS: A brief well-being questionnaire, such as the WHO-5, results in greater appreciation of mood screening and appreciation of completing the questionnaire, but this does not result in a better response rate and higher questionnaire completion. Given these results, either or both questionnaires can be used to screen for depressive symptoms in people with diabetes in clinical practice. PMID- 30019353 TI - Development and validation of the Moral Distress in Dementia Care Survey instrument. AB - AIMS: To report on the development and validation of the Moral Distress in Dementia Care Survey instrument. BACKGROUND: Despite growing awareness of moral distress among nurses, little is known about the moral distress experiences of nursing staff in dementia care settings. To address this gap, our research team developed a tool for measuring the frequency, severity and effects of moral distress in nursing staff working in dementia care. DESIGN: The research team employed an exploratory sequential mixed method design to generate items for the moral distress questionnaire. Data were collected between January 2013 - June 2014. In this paper, we report on the development and validation of the Moral Distress in Dementia Care Survey instrument. METHODS: The Moral Distress in Dementia Care Survey instrument was piloted with a portion of the target population prior to a broader implementation. Appropriate statistical analyses and psychometric testing were completed. RESULTS: The team collected 389 completed surveys from registered nurses, licensed practical nurses and healthcare aides, representing a 43.6% response rate across 23 sites. The Moral Distress in Dementia Care Survey emerged as a reliable and valid instrument to measure the frequency, severity and effects of moral distress for nursing staff in dementia care settings. The relative value of the Moral Distress in Dementia Care Survey as a measurement instrument was superseded by its clinical relevance for dementia care staff. CONCLUSION: The Moral Distress in Dementia Care Survey is a potentially useful tool for estimating the frequency, severity and effects of moral distress in nursing staff working in dementia care settings and for the evaluation of measures taken to mitigate moral distress. PMID- 30019354 TI - Monomeric Rare-Earth Metal Silyl-Thiophosphinoyl-Alkylidene Complexes: Synthesis, Structure, and Reactivity. AB - A series of monomeric rare-earth metal silyl-thiophosphinoyl-alkylidene complexes [LLn{C(SiR3 )PPh2 S}] (5: Ln=Lu, R=Me; 6: Ln=Lu, R=Ph; 7: Ln=Y, R=Me; 8: Ln=Y, R=Ph; 9: Ln=Sm, R=Ph; 10: Ln=Sm, R=Me; 11: Ln=La, R=Ph; L=[MeC(NDIPP)CHC(Me)(NCH2 CH2 N(Me)2 )]- , DIPP=2,6-(iPr)2 C6 H3 ) have been synthesized and structurally characterized. The influences of rare-earth metal ions, ancillary ligands, and alkylidene groups on the reactivity of complexes 5-11 and the related scandium complexes [LSc{C(SiR3 )PPh2 S}] (1: R=Me; 2: R=Ph) and [L'Sc{C(SiR3 )PPh2 S}] (3: R=Me; 4: R=Ph; L'=[MeC(NDIPP)CHC(Me)(NCH2 CH2 N(iPr)2 )]- ) have been studied. Reactions of these rare-earth metal alkylidene complexes with PhCN give four kinds of products, the formation of which is dependent on the rare-earth metal ions, ancillary ligands, and alkylidene groups of the complexes. In the reactions with tBuNC, unusual C-P bond cleavage of the alkylidene group and C=C triple bond formation occur. Complexes 10 and 11 also react with PhSiH3 to form hydrides, which subsequently undergo Ln-H addition to the C=N bond of the ancillary ligand L. DFT calculations have been used to analyze the bonding in complex 10, which exhibits a polarized three centers Sm-C-P pi interaction, and to rationalize the reactivity by computing reaction mechanisms. The difference in reactivity of PhCN and tBuNC is due to the electron density delocalization that is enabled by the phenyl group rather than the tBu group. PMID- 30019355 TI - The imbroglio of the physiological Cra effector clarified at last. AB - Owing to its role in controlling carbon and energy metabolism, the catabolite repressor/activator protein Cra has been one of the most studied prokaryotic regulators of the last 30 years. Yet, a key mechanistic detail of its biological function - i.e. the nature of the metabolic effector that rules its DNA-binding ability - has remained controversial. Despite the high affinity of Cra for fructose-1-phosphate (F1P), the prevailing view claimed that fructose-1,6 biphosphate (FBP) was the key physiological effector. Building on such responsiveness to FBP, Cra was proposed to act as a glycolytic flux sensor and central regulator of critical metabolic transactions. At the same time, data raised on the Cra protein of Pseudomonas putida ruled out that FBP could be an effector - but instead suggested that it was the unintentional carrier of a small contamination by F1P, the actual signal molecule. While these data on the P. putida Cra were received with skepticism - if not dismissal - by the community of the time, the paper by (Bley-Folly et al, 2018) now demonstrates beyond any reasonable doubt that the one and only effector of E. coli Cra is F1P and that every action of FBP on this regulator can be traced to its systematic mix with the authentic binder. PMID- 30019356 TI - Designing Explosive Poly(Ionic Liquid)s as Novel Energetic Polymers. AB - The development of ionic-liquid-derived functional materials would be vital for stimulation of the interdisciplinary research in the fields of ionic liquid chemistry and material science. Here, a series of novel poly(ionic liquid)s with explosive capability were designed and prepared by introducing the energetic nitrato group and nitro-rich anions, such as nitrate, dinitramide, and nitroform into the polymeric chains. The as-synthesized explosive poly(ionic liquid)s (E PILs) were fully characterized, and their physicochemical and detonation properties were investigated. All E-PILs show higher detonation performances than state-of-the-art energetic polymers including glycidyl azide polymer (GAP) and poly(glycidyl nitrate) [poly(GLYN)]. Some E-PILs exhibit higher calculated detonation velocities and pressures than 2,4,6-trinitrotoluene (TNT). These E PILs are promising candidates for applications as new high-performance energetic polymers. PMID- 30019357 TI - Masticatory muscle stretching for the management of sleep bruxism: A randomised controlled trial. AB - BACKGROUND: Sleep bruxism is a phenomenon associated with masticatory muscle hyperactivity. While stretching of limb and trunk muscles has been extensively studied for musculoskeletal disorders, little is known about the effectiveness of stretching of masticatory muscles in the management of bruxism. OBJECTIVE: The aim of this study is to determine the effectiveness of stretching of the masticatory muscles for sleep bruxism. METHODS: Twenty four pain-free individuals with sleep bruxism were randomly assigned to either an intervention group or a control group. Both groups were given sleep hygiene advice and the intervention group additionally received muscle-stretching exercises for 10 days. Primary outcome measures, bruxism bursts and episodes per hour of sleep, were measured by ambulant polysomnography. Secondary outcome measures were among others pain-free active maximum mouth opening (MMO) and masseter pressure pain threshold (PPT). RESULTS: The number of bruxism episodes per hour of sleep increased more in the intervention group than in the control group (by 1.1 episodes, P = 0.066), as did the number of bruxism bursts per hour of sleep (by 8.6 bursts, P = 0.049). MMO and PPT increased significantly more in the intervention group (by 3.2 mm, P = 0.020; and by 1.0 kg/cm2 , P = 0.036, respectively). CONCLUSION: Static stretching of the masticatory muscles resulted in a minor increase in sleep bruxism episodes (not significant) and bursts (significant). It also led to a significant increase in MMO and PPT. Therefore, masticatory muscle stretching was not effective in reducing sleep bruxism in the absence of pain and/or dysfunction. PMID- 30019358 TI - Noninvasive analysis and minimally invasive in vivo experimental challenges of the skin barrier. AB - In this review, we aim to give a concise and selective overview of noninvasive biophysical analysis techniques for skin barrier analysis (transepidermal water loss, electrical methods, confocal Raman microspectroscopy, sebumeter, reflectance spectrophotometry, tristimulus colorimetry, diffuse reflectance spectroscopy and reflectance confocal microscopy), including advantages and limitations. Rather than giving an exhaustive description of the many techniques currently available, we show the usefulness of a representative selection of techniques in the functional and morphological evaluation of the skin barrier. Furthermore, we introduce human minimally invasive skin challenging models as a means to study the mechanisms regulating skin homoeostasis and disease and subsequently show how biophysical analysis techniques can be combined with these in vivo skin challenging models in the functional and morphological evaluation of the skin barrier in healthy human skin. We are convinced that the widespread application of biophysical analysis techniques in dermatological practice and in cosmetic sciences will prove invaluable in offering personalized and noninvasive skin treatment solutions. Furthermore, combining the human in vivo challenging models with these novel noninvasive techniques will provide valuable methodology and tools for detailed characterization of the skin barrier in health and disease. PMID- 30019359 TI - On the design and efficacy assessment of self-assembling peptide-based hydrogel glycosaminoglycan mixtures for potential repair of early stage cartilage degeneration. AB - Peptide-based hydrogels are of interest for their potential use in regenerative medicine. Combining these hydrogels with materials that may enhance their physical and biological properties, such as glycosaminoglycans, has the potential to extend their range of biomedical applications, for example in the repair of early cartilage degeneration. The aim of this study was to combine three self assembling peptides (P11 -4, P11 -8, and P11 -12) with chondroitin sulphate at two molar ratios of 1:16 and 1:64 in 130 and 230 mM Na+ salt concentrations. The study investigates the effects of mixing self-assembling peptide and glycosaminoglycan on the physical and mechanical properties at 37 degrees C. Peptide alone, chondroitin sulphate alone, and peptide in combination with chondroitin sulphate were analysed using Fourier transform infrared spectroscopy to determine the beta-sheet percentage, transmission electron microscopy to determine the fibril morphology, and rheology to determine the elastic and viscous modulus of the materials. All of the variables (peptide, salt concentration, and chondroitin sulphate molar ratio) had an effect on the mechanical properties, beta-sheet formation, and fibril morphology of the hydrogels. P11 -4 and P11 -8-chondroitin sulphate mixtures, at both molar ratios, were shown to have a high beta-sheet percentage, dense entangled fibrillar networks, as well as high mechanical stiffness in both (130 and 230 mM) Na+ salt solutions when compared with the P11 -12/chondroitin sulphate mixtures. These peptide/chondroitin sulphate hydrogels show promise for biomedical applications in glycosaminoglycan depleted tissues. PMID- 30019360 TI - High field magnetic resonance imaging anatomy of feline carpal ligaments is comparable to plastinated specimen anatomy. AB - Feline carpal ligament injuries are often diagnosed indirectly using palpation and stress radiography to detect whether there is instability and widening of joint spaces. There are currently no reports describing normal feline carpal ligament anatomy and the magnetic resonance imaging (MRI) appearance of the carpal ligaments. The objective of this prospective, anatomic study was to describe normal feline carpal ligament anatomy using gross plastinated specimens and MRI. We hypothesized that MRI could be used to identify the carpal ligaments as previously described in the dog, and to identify species specific variations in the cat. The study was conducted using feline cadaver antebrachii that were radiographed prior to study inclusion. Three limbs were selected for MRI to confirm repeatability of anatomy between cats. The proton density weighted pulse sequence was used and images were acquired in transverse, dorsal, and sagittal planes. Following MRI, the limbs were plastinated and a collagen stain was used to aid in identification of carpal ligament anatomy. These limbs were sliced in sagittal section, and a further six paired limbs were included in the study and sliced in transverse and dorsal planes. Anatomic structures were initially described using MRI and then subjectively compared with gross plastinated specimens. Readers considered the transverse MRI plane to be most useful for visualizing the majority of the carpal ligaments. Findings indicated that MRI anatomy of the carpal ligaments was comparable to plastinated anatomy; therefore MRI appears to be a beneficial imaging modality for exploration of feline carpal pathology. PMID- 30019361 TI - Factors contributing to cancer-related suicide: A study of root-cause analysis reports. AB - OBJECTIVE: Vast efforts are directed toward curing or prolonging the life of patients with cancer. However, less attention is given to mental health aspects of cancer care, and there is elevated incidence of death by suicide in this population. Evaluating Root Cause Analyses (RCAs) of cancer-related suicides may further our understanding of system-level factors that may contribute to suicide in patients with cancer and highlight strategies to mitigate this risk. METHODS: We searched the Veterans Health Administration National Center for Patient Safety RCA database for cancer-related suicides between 2002 and 2017 to evaluate the context of the suicides and identify root causes and suggested actions. These variables were coded by consensus and evaluated using descriptive statistics. RESULTS: We identified 64 RCA reports involving cancer-related suicide; 100% were males of older age. Many suicides occurred during treatment with palliative intent (44%, N = 28). Depression (59%, N = 38), medical comorbidities (59%, N = 38), and pain (47%, N = 30) were common suicide risk factors identified. Most suicides occurred within 7 days of a medical visit (67%, N = 43), especially within the first 24 hours (41%, N = 26). Root causes included a need to improve recognition of triggers for assessment and interdisciplinary communication. CONCLUSION: This analysis uncovers opportunities to mitigate risk of death by suicide among patients with cancer. Suggested actions include use of comprehensive cancer centers and development of a distress checklist using information from the National Comprehensive Cancer Network Guidelines. Further studies should assess additional factors that may increase the risk of other adverse mental health outcomes in this population. PMID- 30019362 TI - The beta-adrenoceptor blocker propranolol ameliorates compulsive-like gambling behaviour in a rodent slot machine task: implications for iatrogenic gambling disorder. AB - Previous work has shown that chronic administration of the dopamine D2/3 receptor agonist ropinirole invigorates performance on a rodent slot machine task (rSMT). This behavioural change appears superficially similar to the iatrogenic gambling disorder (GD) observed in a sub-set of patients with Parkinson's disease (PD), and has been associated with increased activation of the intra-cellular signalling proteins GSK3beta and CREB in the striatum. Here, we wanted to determine whether this response to ropinirole could be attenuated by targeting these signalling proteins, and if the loss of dopaminergic innervation characteristic of PD would alter ropinirole's effects on the rSMT. Male Long Evans rats were trained on the rSMT. Dopaminergic terminals innervating the dorsolateral striatum were then lesioned bilaterally using the neurotoxin 6 hydroxydopamine hydrochloride (6-OHDA). Subsequently animals were implanted with osmotic mini-pumps delivering ropinirole. Lastly, animals were given dietary lithium (Li+ ), to inhibit the activation of GSK3beta, or injections of the beta adrenoceptor antagonist propranolol, which potently inhibits CREB as a secondary mechanism of action, and any changes in ropinirole-induced increases in compulsive-like engagement in the rSMT evaluated. Chronic ropinirole increased the number of trials animals completed, reproducing our original finding. This increase in task engagement was not altered in animals with 6-OHDA lesions, a putative model of early PD. In addition, the effects of ropinirole were not attenuated by administration of Li+ , but were ameliorated by propranolol. These data suggest that propranolol may represent a potential pharmacotherapy for the treatment of iatrogenic gambling. PMID- 30019363 TI - PDT and BF-200 ALA: The therapy option for the treatment of Poikiloderma of Civatte. AB - Poikiloderma is a chronic skin condition affecting middle-age men and women that comprises cutaneous atrophy, telangiectasias, and changes in the pigmentation of the skin usually of mottled appearance (both hyper- and hypopigmentation). There is no specific medical treatment for Poikiloderma of Civatte (PC), but the use of photoprotector/sunscreen + SPF 50 to avoid prolonged sun exposure is highly recommended in these patients. Some authors recommend the use of topical corticoids in early stages; however, the results have not been satisfactory. Multiple topical (retinoids, dimethyl sulfoxide, or calcineurin inhibitors), systemic (cyclophosphamide), and physical (dermabrasion, phototherapy, and fractional photothermolysis) treatments have been described with unequal and inconsistent responses or unsatisfactory. This report underlies the combination of BF-200 ALA and photodynamic therapy (PDT) with positive results at the clinical level: significant improvement of pigmentary changes and telangiectasias after two PDT sessions. PMID- 30019364 TI - Highly-focused ultrasound in non-invasive body contouring: Long-term follow-up in Korean patients. PMID- 30019365 TI - Intralesional 5-fluorouracil to treat extensive molluscum contagiosum in an immunocompromised patient: A novel therapeutic modality. PMID- 30019366 TI - Oral Isotretinoin for the treatment of Aripiprazol-induced acneiform rash. AB - Acneiform rash is a commonly reported side effect to certain types of medications, including antipsychotic agents. Its clinical presentation consists mainly of papulopustular lesions. Other types of lesions, such as nodular or cystic, can also be observed. Body distribution of the lesions follows a similar pattern to acne vulgaris. Depending on the severity of the case, drug-induced acne may be treated in different ways. In mild cases, the use of topical antibiotics and retinoids in combination is usually effective. With more severe forms, it may be necessary to add oral antibiotics, such as tetracyclines, but a good response is not always achieved. Identification of the drug responsible for the side-effect is mandatory in refractory eruptions. Herein, we present the case of an Aripiprazole-induced acneiform rash successfully treated with oral Isotretinoin. The treatment was effective and well tolerated and there was no need to discontinue the psychopharmacological medication. This is the first study to report this modality of treatment. PMID- 30019367 TI - GC-MS aroma characterization of vegetable matrices: Focus on 3-alkyl-2 methoxypyrazines. PMID- 30019368 TI - Beyond medical expulsive therapy: evolution to supported stone passage for ureteric stones. AB - OBJECTIVE: To evaluate the impact of removing tamsulosin from standardized ureteric stone clinical protocols on rate of stone surgery. PARTICIPANTS AND METHODS: We conducted a single-centre, comparison of all patients with unilateral, <1 cm ureteric stones presenting to a stone clinic after discharge from the emergency department during consecutive years. In the initial year, patients were initially offered medical expulsive therapy (MET) with tamsulosin. In the subsequent year, the protocol was modified to focus on symptom control without tamsulosin; this was termed 'supported stone passage' (SSP). The primary outcome was rate of stone surgery within 90 days of the initial clinic encounter. RESULTS: Among 723 patients (360 MET, 363 SSP), the rate of attempted stone passage increased from 65% to 74%, between the initial and the subsequent year (P < 0.016). Tamsulosin prescription in patients to attempting stone passage decreased from 84% to 13% (P < 0.001). In patients attempting stone passage, the rate of stone surgery was 26% in the METand 19% in the SSP group (P = 0.066). The overall surgery rate decreased from 51% in the MET group to 40% in the SSP group (P = 0.003). Multivariable analysis, controlling for age, sex and stone burden, did not demonstrate a difference in either rate of attempting to pass stones or in rate of failure of passage according to care protocol. We were unable to demonstrate an independent effect of tamsulosin on failure of passage. Overall, surgical intervention was less likely in the SSP phase than in the MET phase, with an odds ratio of 0.64 (confidence interval) 0.44-0.91; P = 0.013). CONCLUSIONS: Removing tamsulosin from clinical protocols did not impair stone passage in patients attempting to pass stones. PMID- 30019369 TI - Papuloerythroderma of Ofuji successfully treated with methotrexate. PMID- 30019370 TI - Developing a generic tool to routinely measure the impact of health libraries. AB - BACKGROUND: Health libraries contribute to many activities of a health care organisation. Impact assessment needs to capture that range of contributions. OBJECTIVES: To develop and pilot a generic impact questionnaire that: (1) could be used routinely across all English NHS libraries; (2) built on previous impact surveys; and (3) was reliable and robust. METHODS: This collaborative project involved: (1) literature search; (2) analysis of current best practice and baseline survey of use of current tools and requirements; (3) drafting and piloting the questionnaire; and (4) analysis of the results, revision and plans for roll out. FINDINGS: The framework selected was the International Standard Methods And Procedures For Assessing The Impact Of Libraries (ISO 16439). The baseline survey (n = 136 library managers) showed that existing tools were not used, and impact assessment was variable. The generic questionnaire developed used a Critical Incident Technique. Analysis of the findings (n = 214 health staff and students), plus comparisons with previous impact studies indicated that the questionnaire should capture the impact for all types of health libraries. CONCLUSIONS: The collaborative project successfully piloted a generic impact questionnaire that, subject to further validation, should apply to many types of health library and information services. PMID- 30019372 TI - Life-history evolution under fluctuating density-dependent selection and the adaptive alignment of pace-of-life syndromes. AB - We present a novel perspective on life-history evolution that combines recent theoretical advances in fluctuating density-dependent selection with the notion of pace-of-life syndromes (POLSs) in behavioural ecology. These ideas posit phenotypic co-variation in life-history, physiological, morphological and behavioural traits as a continuum from the highly fecund, short-lived, bold, aggressive and highly dispersive 'fast' types at one end of the POLS to the less fecund, long-lived, cautious, shy, plastic and socially responsive 'slow' types at the other. We propose that such variation in life histories and the associated individual differences in behaviour can be explained through their eco evolutionary dynamics with population density - a single and ubiquitous selective factor that is present in all biological systems. Contrasting regimes of environmental stochasticity are expected to affect population density in time and space and create differing patterns of fluctuating density-dependent selection, which generates variation in fast versus slow life histories within and among populations. We therefore predict that a major axis of phenotypic co-variation in life-history, physiological, morphological and behavioural traits (i.e. the POLS) should align with these stochastic fluctuations in the multivariate fitness landscape created by variation in density-dependent selection. Phenotypic plasticity and/or genetic (co-)variation oriented along this major POLS axis are thus expected to facilitate rapid and adaptively integrated changes in various aspects of life histories within and among populations and/or species. The fluctuating density-dependent selection POLS framework presented here therefore provides a series of clear testable predictions, the investigation of which should further our fundamental understanding of life-history evolution and thus our ability to predict natural population dynamics. PMID- 30019371 TI - Disordered linkers in multidomain allosteric proteins: Entropic effect to favor the open state or enhanced local concentration to favor the closed state? AB - There are many multidomain allosteric proteins where an allosteric signal at the allosteric domain modifies the activity of the functional domain. Intrinsically disordered regions (linkers) are widely involved in this kind of regulation process, but the essential role they play therein is not well understood. Here, we investigated the effect of linkers in stabilizing the open or the closed states of multidomain proteins using combined thermodynamic deduction and coarse grained molecular dynamics simulations. We revealed that the influence of linker can be fully characterized by an effective local concentration [B]0 . When Kd is smaller than [B]0 , the closed state would be favored; while the open state would be preferred when Kd is larger than [B]0 . We used four protein systems with markedly different domain-domain binding affinity and structural order/disorder as model systems to understand the relationship between [B]0 and the linker length as well as its flexibility. The linker length is the main practical determinant of [B]0 . [B]0 of a flexible linker with 40-60 residues was determined to be in a narrow range of 0.2-0.6 mM, while a too short or too long length would dramatically decrease [B]0 . With the revealed [B]0 range, the introduction of a flexible linker makes the regulation of weakly interacting partners possible. PMID- 30019373 TI - Shifts in the dynamics of productivity signal ecosystem state transitions at the biome-scale. AB - Understanding ecosystem dynamics and predicting directional changes in ecosystem in response to global changes are ongoing challenges in ecology. Here we present a framework that links productivity dynamics and ecosystem state transitions based on a spatially continuous dataset of aboveground net primary productivity (ANPP) from the temperate grassland of China. Across a regional precipitation gradient, we quantified spatial patterns in ANPP dynamics (variability, asymmetry and sensitivity to rainfall) and related these to transitions from desert to semi arid to mesic steppe. We show that these three indices of ANPP dynamics displayed distinct spatial patterns, with peaks signalling transitions between grassland types. Thus, monitoring shifts in ANPP dynamics has the potential for predicting ecosystem state transitions in the future. Current ecosystem models fail to capture these dynamics, highlighting the need to incorporate more nuanced ecological controls of productivity in models to forecast future ecosystem shifts. PMID- 30019374 TI - Cellular microbiology interview-Dr. Duncan Wilson. PMID- 30019375 TI - Dissection of hepatic versus extra-hepatic insulin clearance: Ethnic differences in childhood. AB - AIMS: Adult African American (AA) women have one third of the hepatic insulin clearance of European American (EA) women. This lower hepatic (but not extra hepatic) insulin clearance in AA individuals is associated with higher plasma insulin concentrations. This study aims to understand whether impairment of hepatic insulin clearance is seen in AA individuals since childhood, possibly suggesting that genetic/epigenetic factors, rather than lifestyle only, contribute to this. MATERIALS AND METHODS: A total of 203 children (105 male and 98 female (55 AA, 88 EA and 60 Hispanic American [HA]; ages, 7-13 years; mean BMI, 19 kg/m2 )) underwent the frequently applied intravenous glucose tolerance test (FSIGT) at the University of Alabama at Birmingham, General Clinical Research Center and Department of Nutrition Sciences. Glucose, insulin and C peptide levels were measured and hepatic and extra-hepatic insulin clearances were calculated using mathematical modelling. RESULTS: Fractional hepatic insulin extraction (FEL ) was lower in AA than in EA children (mean (SD), 19% (20%) vs 33% (20%); P = 0.0007). Adjusting for age, Tanner stage and body fat, FEL was lower in AA than in EA children (P = 0.0012), and there was a slight sex-related difference (FEL, 24% (10%) vs 29% (10%) in boys vs girls; P = 0.04). Extra hepatic insulin clearance did not differ with ethnicity (27 (12), 21 (12) and 24 (28) mL/kg/min for AA, HA and EA children, respectively; P > 0.05). CONCLUSIONS: At a young age, FEL is lower in AAs than in EAs, which does not rule out genetic/epigenetic factors. These differences are related to hyperinsulinaemia and, over time, could possibly contribute to metabolic disorders in AA individuals. PMID- 30019376 TI - Development and validation of a liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of serotonin and thromboxane B2 from activated platelets. AB - INTRODUCTION: Availability of a rapid and reliable platelet activation assay avoiding limitations of current techniques would be valuable to diagnose heparin induced thrombocytopenia and platelet secretion disorders. OBJECTIVES: The first aim was to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify in a single run TxB2 synthesized and serotonin released from platelets. The second aim was to use our method in association with light transmission aggregometry (LTA) to select good platelet responders for the diagnosis of HIT. METHODS: Electrospray ionization and chromatographic separation were optimized for the simultaneous dosage of serotonin and TxB2. The method was validated according to the European Medicines Agency (EMA) guideline for bioanalytical method validation. LTA was performed with monoclonal anti-CD9 (clone ALB6) as platelet activator to select good responders. RESULTS: Detection was performed using a tandem mass spectrometer with alternated positive and negative electrospray ionization. The total run time was 6 minutes. The method was validated for calibration curves, precision, accuracy, lower limit of quantification, carry-over, selectivity, and matrix effect. Platelet response to ALB6 was highly variable among donors. CONCLUSION: We developed and validated a UHPLC-MS/MS method for the simultaneous quantification of TxB2 and serotonin. PMID- 30019377 TI - Subclinical hypothyroidism and long QT. PMID- 30019378 TI - Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure. AB - OBJECTIVE: To evaluate the efficacy and safety of Nit-Occlud Le VSD Coil versus Duct Occluders for percutaneous closure of perimembranous ventricular septal defect (pmVSD). INTRODUCTION: VSD closure using conventional pmVSD occluders has been largely abandoned because of an unacceptable high rate of complete heart block (CHB). The advantages of Duct Occluders and VSD Coil are supposed to reduce the drawbacks of previous devices, especially CHB complications. METHOD: Patients underwent percutaneous pmVSD closure were divided into Coil group (using VSD Coil, n = 71) and DO group (using Duct Occluders, n = 315). Patient demographics, clinical presentations, echocardiography measurements, procedure details and follow-up data were collected. RESULT: The procedure success rate was high in both DO group (95.6%) and Coil group (97.2%, P = .53). The closure rate immediately after procedure in the DO group was higher than that in the Coil group (76.8% vs. 58.0%, P < .01). After 6 months, the closure rate was not significantly different between the 2 groups (DO group 91.3% vs. Coil group 84.1%, P = .07). The mean follow-up time was 61.4 +/- 24.1 months. The major complication rate was low in both groups (DO group 1.9% vs. Coil group 1.4%, P = .78). Two patients (0.7%) in the DO group and one patient (1.4%) in the Coil group with CHB needed permanent pacemaker (P = .5). Device embolization (3 patients, 1.0%) and endocarditis (1 patient, 0.3%) occurred only in the DO group. There was no death, disability or other major complications detected in either group. CONCLUSION: Percutaneous pmVSD closure using either Nit-Occlud Le VSD Coil or Duct Occluders is feasible, safe and efficacious in selected patients. The main problems of Duct Occluders are unsuitable defect anatomy and device embolization while VSD Coil disadvantages are residual shunt and hemolysis. PMID- 30019379 TI - Risk factor analysis for a complicated postoperative course after neonatal arterial switch operation: The role of troponin T. AB - OBJECTIVE: To find risk factors for a complicated early postoperative course after arterial switch operation (ASO) in neonates with d-transposition of the great arteries (dTGA). In addition to anatomical and surgical parameters, the predictive value of early postoperative troponin T (TnT) values in correlation to the early postoperative course after ASO is analyzed. METHODS: Seventy-nine neonates (57 (72%) male) with simple dTGA treated by ASO between 2009 and 2016 were included in the analysis. A complicated early postoperative course (30 days) was defined by one of the following criteria: (A) moderate to severe cardiac dysfunction without rhythm disturbances, (B) rhythm disturbances causing hemodynamic instability with the need for medical treatment, (C) signs for ischemia in ECG, (D) need for surgical or catheter interventional reinterventions other than diagnostic, or (E) other reasons. RESULTS: Forty of 79 patients (51%) showed a complicated early postoperative course after ASO, with 2 patients dying after 13 and 16 days. Patients with a complicated early postoperative course had a longer PICU stay (P < .001), needed longer mechanical ventilator support (P = .001) and longer inotropic support (P = .03), and more reinterventions (surgical or catheter interventional) were necessary (P = .001). Only the presence of a VSD (P = .001) and longer surgery duration (P = .026) were associated to a complicated postoperative course. TnT values only showed a trend toward higher values in patients with a complicated postoperative course (P = .06). A secondary rise in TnT was seen in 10 patients, ranging from 11.6% to 410.2%, of whom 7 could be classified in the complicated postoperative group. CONCLUSIONS: The postoperative course after ASO in dTGA neonates is influenced by other cardiac comorbidities like a VSD with the need for surgical treatment, influencing surgery duration. Postoperative higher TnT values reflect a longer and more vulnerable intraoperative course with limited predictive value on the early postoperative course. PMID- 30019380 TI - Platelet activation markers in children with congenital heart disease associated with pulmonary arterial hypertension. AB - BACKGROUND: Mean platelet volume (MPV), platecrit, and platelet distribution width (PDW) are markers of platelet activation. Previous studies have found that platelet activation occurs in patients with pulmonary arterial hypertension. Platelet indices including MPV, PDW, and platecrit have not been studied in children with congenital heart disease associated pulmonary arterial hypertension (APAH-CHD) who survived and those who died. OBJECTIVE: The objective of this study to investigate the value of platelet indices with clinical and hemodynamic indicators predicting the disease severity and survival in children with APAH CHD. METHODS: This was a nested case-control study. MPV, platecrit, and PDW levels measured in 37 patients with APAH-CHD and 43 healthy subjects at the beginning of the study. Right heart catheterization was performed in all 37 patients. Clinical and hemodynamic data were collected. All patients were followed from the date of laboratory testing. The study was conducted between March 2012-July 2015. The comparison of clinical, hemodynamic data and platelet indices were made between patients with APAH-CHD who died than APAH-CHD patients who survived. RESULTS: Of 37 patients, after a mean follow-up duration of 67.90 +/- 47.90 months, 11 patients died. MPV (12.10 femoliter [fL; 8.20-12.50] vs 8.70 fL [6.40-9.70], P = .007), PDW (16.88 +/- 1.09% vs 15.75 +/- 1.58%, P = .04) and platecrit (0.28 +/- 0.31 vs 0.22 +/- 0.27, P = .01) were significantly higher in the patients with APAH-CHD who died than those who survived. Pearson's correlation analysis showed that MPV correlated with mean pulmonary artery pressure (r = 0.332, P = .04) and correlated negatively with six-minute walking distance (r = -0.600. P = .00). PDW and platecrit correlated positively with mean pulmonary artery pressure (r = 0.373, P = .02; r = 0.389, P = .01, respectively). CONCLUSION: Our results showed that MPV, platecrit and PDW were increased in children with APAH-CHD. They might give clue about disease severity. PMID- 30019381 TI - Non-coronary predictors of elevated high-sensitive cardiac troponin T (hs-cTnT) levels in an unselected emergency patient cohort. AB - BACKGROUND: Aim of this study was to evaluate the predictors of hs-cTnT in a non ACS patient cohort admitted to the emergency department. HYPOTHESIS: Atrial fibrillation and hypertension may not always be sufficient for elevation for hs cTnT. METHODS: We performed a retrospective, single center study encompassing in total 1003 patients. Individuals were retrospectively divided in ACS- and non-ACS patients by two independent investigators reviewing the medical records. In order to identify predictors of hs-cTnT elevation hazard ratios were calculated for age, gender, vital signs, cardiovascular risk factors, LVEF, serum levels of CRP, hemoglobin, and creatinine. Elevation of hs-cTnT was defined by exceeding 14 ng/L (upper reference limit [URL]). RESULTS: About 987 patients were included while 25 patients were excluded because of missing data. 307 patients (31.4%) met the current guideline requirements of diagnosing an ACS, whereas 671 patients (68.6%) were hospitalized with excluded ACS. In the multivariate analysis age, anemia, CRP, creatinine, and reduced systolic left ventricular ejection fraction were independent predictors of elevated troponin T levels in the non-ACS group. However, hypertensive systolic blood pressure, atrial fibrillation and tachycardia were not predictive for Troponin T elevation in non-ACS patients in this multivariate analysis. CONCLUSIONS: In an unselected, non-ACS patient cohort age, chronic renal failure, inflammatory state, and reduced left ventricular systolic function were associated with hs-cTnT levels above the upper reference limit. Rather, often supposed predictors as atrial fibrillation, hypertension, and tachycardia cannot sufficiently explain increased hs-cTnT in our study. Hence, further studies are needed to assess whether isolated hypertension, tachycardia, or atrial fibrillation sufficiently explain elevated hs-cTnT. PMID- 30019382 TI - Increased brain and behavioural susceptibility to portion size in children with loss of control eating. AB - BACKGROUND: Portion size influences intake (i.e. the portion size effect [PSE]), yet determinants of susceptibility to the PSE are unclear. OBJECTIVE: We tested whether children who reported an episode of loss of control (LOC) eating over the last 3 months would be more susceptible to the PSE and would show differential brain responses to food cues compared with children with no-LOC. METHODS: Across five sessions, children (n = 47; 7-10 years) consumed four test meals at 100%, 133%, 167% and 200% conditions for portion size and completed a functional magnetic resonance imaging scan while viewing pictures of foods varied by portion size and energy density (ED). Incidence of LOC over the past 3 months was self reported. Random coefficient models were tested for differences in the shape of the PSE curve by LOC status. A whole-brain analysis was conducted to determine response to food cues during the functional magnetic resonance imaging. RESULTS: Reported LOC (n = 13) compared with no-LOC (n = 34) was associated with increased susceptibility to the PSE, as evidenced by a positive association with the linear slope (P < 0.005), and negative association with the quadratic slope (P < 0.05) of the intake curve. Children who reported LOC compared with no-LOC showed increased activation in the left cerebellum to small relative to large portions (P < 0.01) and right cerebellum to High-ED relative to Low-ED food cues (P < 0.01). CONCLUSION: Children who reported LOC were more susceptible to the PSE and showed alterations in food-cue processing in the cerebellum, a hindbrain region implicated in satiety signalling. PMID- 30019383 TI - Mechanism of Charge Separation and Frontier Orbital Structure in Graphitic Carbon Nitride and Graphene Quantum Dots. AB - Graphene quantum dots (GQDs) and carbon nitride quantum dots (CNQDs), the latest addition to the carbon material family, are promising materials for numerous novel applications in optical sensing, photocatalysis, biosensing, and photovoltaics. However, understanding the photocatalytic capability of CNQDs compared to GQDs requires investigations of the charge behavior on the excited state energy surface. In this work, through time-dependent density functional tight binding (TD-DFTB) calculations, we show that CNQDs exhibit superior ground state frontier orbitals (FOs) localization. Strong localization of the FOs and excited state charge separation observed in the first excited state are caused by the relaxation of the structure. Excited energy surface investigations reveal spatial confinement of FOs to the stretched C-N bonds due to excited state structural relaxation. On the other hand, no such localized FOs structure was found for GQDs, presumably caused by its strong pi-conjugated configuration not allowing large structural changes upon excitation. The optical absorption and emission of CNQDs is sensitive to size and does not show large variations with the shape of the QD. Our approach provides an explanation for the origin of the enhanced photocatalytic performance of CNQDs over GQDs and their characteristic FOs localization. PMID- 30019384 TI - A microvenular hemangioma with a rare expression of progesterone receptor immunocreativity and a review of the literature. AB - Microvenular hemangioma (MVH) is a rare benign vascular tumor with a controversial etiology, but hormone receptor alterations might be involved. We report a case of MVH in a 41-year-old Taiwanese woman who presented with a 1.5 * 1 cm violaceous plaque on left thigh that had appeared 1 year previously. She had taken oral contraceptives for several years and stopped 1 year prior to presentation. Histologically, the tumor was composed of small and compressed venous structures infiltrating in the dermis and subcutis. Immunohistochemically, the tumor cells displayed negative immunoreactivity for human herpesvirus-8 and positive immunoreactivity for smooth muscle actin and progesterone receptor (PR). Taken together with the patient's medical hormone therapy history and the evidence of PR immunoreactivity, our findings support that progesterone may be associated with the tumorigenesis of MVH. PMID- 30019385 TI - Household chaos during infancy and infant weight status at 12 months. AB - BACKGROUND: Infancy is a critical period for obesity prevention. Emerging evidence links household chaos to poor health outcomes, yet its impact on obesity in infancy is unknown. OBJECTIVES: We examined associations between household chaos when infants were 6 and 12 months and weight-for-length (WFL) z-score at 12 months, exploring potential mediation by infant sleep and screen time. METHODS: We examined 401 predominately Black women and infants in the southeastern United States. We conducted multivariable linear regressions examining household chaos and infant WFL z-score, assessing breastfeeding, sleep, screen time as potential mediators. RESULTS: Among infants, 69.7% were Black and 49.0% were female. Mean breasting duration was 3.7 months. Over half (50.4%) of families had annual household incomes <$20 000. After adjustment for potential confounders, household chaos was associated with infant WFL z-score (0.02; 95% CI 0.001, 0.04; p = 0.04) at 12 months. We did not observe associations between chaos and infant breastfeeding, sleep or screen time. CONCLUSIONS: Higher household chaos was associated with greater infant weight at 12 months, but there was no evidence of mediation by breastfeeding, sleep or screen time. PMID- 30019386 TI - Protective effect of melatonin versus montelukast in cisplatin-induced seminiferous tubule damage in rats. AB - We compared the protective effects of melatonin and montelukast against cisplatin induced testicular damage. Adult male rats were assigned to one of four groups: a control group, a cisplatin (Cis) group treated with a single intraperitoneal injection of 7 mg/kg cisplatin, a cisplatin + melatonin group (Cis-Mel) and a cisplatin + montelukast group (Cis-Mon) each treated with the same dose of cisplatin together with either oral melatonin (20 mg/kg) or oral montelukast (10 mg/kg) in 2 ml water from day 1 to day 10 starting on the day of the cisplatin injection. Cisplatin-induced oxidative stress, with a significant increase in testicular malonedialdehyde (MDA), decreased testicular glutathione (GSH), histological testicular damage and body weight loss. Additionally, increased abnormal sperm forms and decreased count and motility were noted. Melatonin and montelukast both rescued GSH concentrations, increased sperm count and motility and decreased abnormal forms. Montelukast resulted in better rescue of weight loss, while greater improvement in sperm count and testicular pathology, and a trend for decreased MDA were noted with melatonin. These findings suggest that melatonin and montelukast protect against different aspects of cisplatin-induced toxicity. Future studies should assess whether both drugs may have additive benefit when used in combination. PMID- 30019387 TI - Financial burden among older, long-term cancer survivors: Results from the LILAC study. AB - BACKGROUND: Increasing attention is being paid to financial burdens of cancer survivorship, but little is known about the prevalence and predictors of these burdens in older, long-term survivors. METHODS: We used data from 6012 participants diagnosed with cancer since enrolling in the Women's Health Initiative, and who participated in the Life and Longevity After Cancer (LILAC) ancillary study to estimate prevalence and identify predictors of financial burden. We used logistic regression to identify sociodemographic, socioeconomic, health- and cancer-related factors associated with financial burden and backward selection to build a final multivariable model. RESULTS: Average age at LILAC participation was 79 and 9.2 years had elapsed since cancer diagnosis. Overall, 6% experienced some form of financial burden, including having an insurance company refuse a claim (2.6%), being denied loans or insurance due to cancer history (2.2%), or experiencing significant indebtedness (1.8%, including facing large debts or bills or declaring bankruptcy). Eight predictors remained associated (P < 0.05) with financial burden in the fully-adjusted model: younger age, shorter time since diagnosis, African-American race, household income <$20 000/year, modified Charlson comorbidity score >=2, receipt of chemotherapy, regional stage at diagnosis, and no private health insurance. Education, cancer site, social support, receipt of radiation, and receipt of hormone therapy were not associated with financial burden. Predictors differed between types of financial burden experienced and age at diagnosis (<65 vs 65+). CONCLUSION: Cancer-related financial burden was rare in this population of older, female long term cancer survivors. The identification of several socioeconomic, health related and demographic predictors of financial burden may suggest targets of intervention to reduce financial burdens. PRECIS: Financial burden was uncommon in older, female, long-term survivors. Predictors of financial burden included age, race, income, comorbidities, time since diagnosis, stage, insurance, and receipt of chemotherapy. PMID- 30019389 TI - MiR-335-5p restores cisplatin sensitivity in ovarian cancer cells through targeting BCL2L2. AB - OBJECTIVE: Our study was designed to explore the association miR-335-5p and BCL2L2 and to investigate the influence of miR-335-5p/BCL2L2 axis on cisplatin resistant ovarian cancer cells. METHODS: Microarray analysis was used to determine differentially expressed microRNAs in primary and cisplatin-resistant A2780 cells. Cell function experiments were conducted to investigate the effect of miR-335-5p on the cisplatin sensitivity of A2780 cells. The targeted relationship between BCL2L2 mRNA and miR-335-5p was validated through luciferase assay. Tumor xenograft was performed to confirm the function of miR-335-5p in restoring the cisplatin sensitivity of the ovarian cancer cells. RESULTS: MiR-335 5p was lowly expressed in cisplatin-resistant A2780 cells. Overexpression of miR 335-5p reduced cell survival and enhanced cisplatin-induced cell apoptosis. BCL2L2 mRNA was a target of miR-335-5p, and silencing of BCL2L2 showed the similar results on the cell viability as miR-335-5p overexpression. CONCLUSION: Upregulation of miR-335-5p expression enhanced the cisplatin sensitivity of ovarian cancer cells through suppressing BCL2L2, suggesting the potential of miR 335-5p/BCL2L2 axis as a therapeutic target for the cisplatin resistance of patients with ovarian cancer. PMID- 30019388 TI - Coexpression of CD5 and CD43 predicts worse prognosis in diffuse large B-cell lymphoma. AB - Both CD5 and CD43 are expressed on the surface of B lymphocytes of definite phase and associated with the adverse outcome in diffuse large B-cell lymphoma (DLBCL). However, the relationship between CD5 and CD43 expression and the prognostic value of CD5/CD43 coexpression in DLBCL are unknown. We herein determined the correlation between CD5 and CD43 expression, as separate factors or in combination, with the clinicopathological features and survival of 200 patients with DLBCL receiving standard chemotherapy with or without rituximab. Among these DLBCL patients, CD5 expression, CD43 expression, and CD5/CD43 coexpression were detected in 18 (9%), 57 (27%), and 10 (5%) patients, respectively, and all were positively correlated with advanced age and nongerminal cell type. CD5-positive and CD43-positive DLBCL patients had poorer event-free survival (EFS, P < 0.001) and overall survival (OS, P < 0.001) than CD5-negative and CD43-negative patients, respectively. CD5/CD43 coexpression was correlated with a significantly worse prognosis than CD5 or CD43 expression alone. Univariate analysis showed that CD5 expression, CD43 expression, and CD5/CD43 coexpression were all adverse prognostic factors for DLBCL patient survival, and CD5/CD43 coexpression was associated with a greater relative risk for recurrence and death than either CD5 or CD43 expression alone. Multivariate analysis demonstrated that CD5/CD43 coexpression was an independent prognostic factor for EFS (P < 0.001) and OS (P < 0.001) in DLBCL. In conclusion, our data indicate that DLBCL patients with CD5/CD43 coexpression represent a specific subgroup with a significantly worse prognosis than those expressing either marker alone. PMID- 30019390 TI - Obstacles to mineralocorticoid receptor antagonists in a community-based heart failure population. AB - AIM: Previous studies and national assessments indicate an undertreatment of mineralocorticoid receptor antagonists (MRA) in heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate why MRA is not used to full extent. METHODS: A complete community-based heart failure population was studied. Several variables were collected, and medical records were scrutinized to identify reasons for not prescribing MRA. RESULTS: Of 2029 patients, 812 had EF <=40%. Five hundred and fifty-three patients (68%) tried MRA at some point but 184 of these (33%) discontinued therapy. There were 259 patients that never tried MRA with 177 with a listed explanation or contraindication. Eighty-two patients, 10% of the total HFrEF population, had no clear contraindications. They were older and had less HF hospitalizations compared to patients on MRA (P < 0.05) and 32% did not have any follow-up at the cardiology clinic. Contraindications to MRA were renal dysfunction (93 patients), hypotension (28 patients), and hyperkalemia (25 patients). Only six patients had hyperkalemia without renal dysfunction. Of the patients with renal dysfunction, 66 (72%) had eGFR >30 mL/min. CONCLUSIONS: The reasons why MRA are underutilized were mainly because of contraindications. However, the data suggest that physicians are overly cautious about moderately reduced kidney function. There seems to be a 10%-18% avoidable undertreatment with MRA, especially for elderly patients that are admitted to the hospital for other reasons than heart failure. This suggests that patients with heart failure would benefit from routine follow-up at a cardiology clinic. PMID- 30019391 TI - Complications and survival rates of inlays and onlays vs complete coverage restorations: A systematic review and analysis of studies. AB - OBJECTIVE: The aim of this study was to identify if different types of indirect restorations used for single teeth had different biological and technical complications, as well as survival rates. METHOD: An electronic search was performed in various electronic databases to identify articles, published between 1980 and 2017. The search terms were categorised into 4 groups: inlay, onlay, inlay/onlay and crown. Manual searches of published full-text articles and related reviews were also performed. RESULTS: A total number of 2849 papers were retrieved initially. After a detailed assessment for eligibility, 9 studies were selected for inclusion. The heterogeneity of the studies did allow neither a meta analysis nor any meaningful comparison between types of restorations or materials. Only some pooling was performed for representative reasons. The mean survival rate of inlays was 90.89%, while for onlays and crowns it was 93.50% and 95.38%, respectively. For the fourth study group, consisting of both inlays and onlays, the survival rate was found to be 99.43%. Statistical analysis demonstrated caries to be the main biological complication for all types of restorations, followed by a root and/or tooth fracture incidence (11.34%) and endodontic incidence. Ceramic fractures represented the most common technical complication, followed by loss of retention and porcelain chipping. CONCLUSION: The 5-year survival rate for crowns and inlays/onlays is very high, exceeding 90%. An association between the kind of complications and different types of restorations could not be established. Nevertheless, a relatively high failure rate due to caries and ceramic fractures was noted. PMID- 30019392 TI - Synthesis and characterization of a poly(p-phenylenediamine)-based electrospun nanofiber for the micro-solid-phase extraction of organophosphorus pesticides from drinking water and lemon and orange juice samples. AB - A new micro-solid-phase extraction sorbent was synthesized by electrospinning poly(p-phenylenediamine)/poly(vinyl alcohol) in the presence of cetyltrimethylammonium bromide. The modified nanofiber was prepared by removing the majority of the poly(vinyl alcohol) from the nanofiber blend by exposing it to the hot water. Scanning electron microscopy and surface analysis were performed to study the homogeneity and porosity of the electrospun nanofiber. In addition, Fourier transform infrared spectroscopy was applied for more characterization. The capability of the new nanofiber was explored by applying it in the extraction and preconcentration of organophosphorus pesticides from aqueous medium. After solvent desorption, the extracted analytes were analyzed by high-performance liquid chromatography with diode array detection. Under the optimum conditions, the relative standard deviation values at the concentration level of 50 ng/mL were in the range of 4.8-8.3%. The calibration curve showed linearity in the range of 0.5-500 ng/mL, and the limits of detection (S/N = 3) for the studied compounds were 0.15 ng/mL. By analyzing Tehran drinking water, lemon juice, sour lemon juice, orange juice and sour orange juice, the applicability of the presented method was investigated and the relative recoveries were in the range of 76-102%. PMID- 30019393 TI - Interventions to promote mental health in nursing students: A systematic review and meta-analysis of randomized controlled trials. AB - AIMS: The aim of this study was to systematically examine the efficacy of interventions aimed at improving nursing students' mental health and to identify which form of interventions was effective. BACKGROUND: Recent research has demonstrated mental disorders in common among nursing students and may lead to adverse consequences like low self-efficacy and poor academic performance. DESIGN: According to the recommendations of the Cochrane Collaboration, a systematic review and meta-analysis was conducted. DATA SOURCES: PubMed, EMBase, the Cochrane central register of randomized controlled trials, PsycINFO and Web of Science were used to identify potential studies (January 1990-April 2017). REVIEW METHODS: A systematic review of the literature and meta-analysis of randomized controlled trials on the efficacy of interventions on reducing mental disorders in nursing students. Review Manager version 5.3 was used to obtain pooled results. RESULTS: Twelve studies with a total sample size of 651 participants met the inclusion criteria. Interventions included psychotherapy, exercise, training programme and other forms of intervention. The results of subgroup analysis showed that depression benefit more from psychotherapy, anxiety benefit from psychotherapy and non-psychotherapy. Interventions were effective in managing stress and systolic blood pressure. Improvements on self-efficacy and diastolic blood pressure was not observed. CONCLUSION: Psychotherapy should be chosen to reduce depression and anxiety of nursing students. There is a need for further studies should explore more potential value of psychotherapy on stress and biological change. PMID- 30019394 TI - Updated definition of epsilon waves. PMID- 30019395 TI - Family dynamics in transthyretin-related familial amyloid polyneuropathy Val30Met: Does genetic risk affect family functioning? AB - Adult-onset, chronic, genetic diseases like transthyretin-related familial amyloid polyneuropathy Val30Met (TTR-FAP Val30Met), have a major psychosocial impact not only on patients, but also on families. Genetic risk may therefore be an increased factor in psychosocial impact of the disease on these families' functioning. To evaluate impact of genetic risk, a study was conducted to perceive the impact of the illness on families' functioning. Groups of TTR-FAP Val30Met patients, pre-symptomatic carriers, partners and patients with multiple sclerosis (MS), a non-hereditary disease, were studied. Sample included 190 adults: 87 patients and 28 pre-symptomatic carriers for TTR-FAP Val30Met, 41 partners and 34 patients with MS. Family Adaptability and Cohesion Scale IV (FACES IV) and a social-demographic questionnaire were applied. No significant differences were observed between patients and pre-symptomatic carriers and both these and their partners regarding cohesion and flexibility. MS patients scored significantly higher in median scores for balanced scales. Satisfaction and communication levels were also lower in patients with TTR-FAP Val30Met than with MS. Family functioning was perceived as balanced by most TTR-FAP Val30Met patients and pre-symptomatic carriers. These families may be considered as mostly healthy. Difficulties in family communication should be taken into account when caring for these families. PMID- 30019396 TI - Nanocatalyst Complex Can Dephosphorylate Key Proteins in MAPK Pathway for Cancer Therapy. AB - Controlling phosphorylation processes of proteins is a facile way for manipulating cell fates. Herein, a synergistic therapeutic strategy utilizing a near-infrared (NIR)-responsive nanocatalyst (NC) complex is presented, which is comprised of photoactive NC and protein phosphatase 2A (PP2A), to synergistically inhibit hyperphosphorylation of mitogen-activated protein kinase (MAPK) pathway for cancer therapy, as an example of many biological processes this approach can apply to. NIR-triggered release of PP2A specially dephosphorylates and inactivates mitogen-activated protein kinase kinase (MAP2K, also known as MEK) and extracellular regulated protein kinases (ERK) in the MAPK pathway, meanwhile, the NIR-triggered activation of NC decreases the level of intracellular adenosine triphosphate to attenuate protein phosphorylation of MEK and ERK. The synergistic therapeutics effectively suppress melanoma progression by inhibiting hyperphosphorylation of the MAPK pathway. In addition, the nanocatalyst complex reduces the risk of drug-resistance through inhibiting a rebound of RAS-GTP. The NIR-responsive nanocatalyst complex paves a novel way for cancer therapeutics. PMID- 30019397 TI - Postoperative pain management after sinus surgery: a survey of the American Rhinologic Society. AB - BACKGROUND: Postoperative pain management is controversial as there are no current guidelines to direct clinical practice. The purpose of this study was to demonstrate prescribing patterns for pain management after functional endoscopic sinus surgery (FESS). METHODS: A 15-item web-based survey was electronically distributed to 1770 members of the American Rhinologic Society (ARS). Linear regression analysis was used to determine associations between providers and prescribing patterns. RESULTS: The survey was completed by 168 members (9.49%), representing all regions of the United States. The most commonly prescribed medications were opioid/non-opioid combination pills. One hundred fifty-seven of 168 members (94.05%) prescribed at least one kind of opioid after FESS, with an average of 27.38 pills. The majority of surveyed members worked in private or academic settings. Academic physicians were less likely to prescribe ibuprofen (p = 0.0407), and nonsteroidal anti-inflammatory drugs (NSAIDs) in general (p = 0.032). Physicians in private practice were less likely to refer patients to pain management (p = 0.0117), but more likely to refer patients to nontraditional forms of pain management (p = 0.0164). Academic physicians were more likely to refer patients to pain management (p = 0.00121). There was no association between perception of pain control and the prescription of NSAIDs or with number of opioid pills prescribed. CONCLUSION: Most providers prescribed opioids after FESS. There was no significant difference in the number of opioids prescribed based on geography or practice setting. There was significant heterogeneity in the adjuvant pain management strategy between academic and private practitioners. Most members provided patient education and few reported poor pain control. However, there was a gap in understanding of appropriate medication disposal and evidence-based postoperative pain management. PMID- 30019399 TI - Association of fish and long-chain omega-3 fatty acids intakes with total and cause-specific mortality: prospective analysis of 421 309 individuals. AB - BACKGROUND: Prevailing dietary guidelines recommend regular fish consumption. However, the associations of fish and long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFAs) intakes with mortality remain unclear. OBJECTIVES: To examine the associations of fish and LCn-3 PUFAs intakes with total and cause-specific mortality. METHODS: A total of 240 729 men and 180 580 women from NIH-AARP Diet and Health Study were prospectively followed-up for 16 years. Dietary intakes were assessed using a validated NIH Diet History Questionnaire. RESULTS: A total of 54 230 men and 30 882 women died during 6.07 million person-years of follow up. Higher fish and LCn-3 PUFAs intakes were significantly associated with lower total mortality (P < 0.0001). Comparing the highest with lowest quintiles of fish intake, men had 9% (95% confidence interval, 6-11%) lower total mortality, 10% (6 15%) lower cardiovascular disease (CVD) mortality, 6% (1-10%) lower cancer mortality, 20% (11-28%) lower respiratory disease mortality and 37% (17-53%) lower chronic liver disease mortality, while women had 8% (5-12%) lower total mortality, 10% (3-17%) lower CVD mortality and 38% (20-52%) lower Alzheimer's disease mortality. Fried fish consumption was not related to mortality in men whereas positively associated with mortality from all causes (P = 0.011), CVD and respiratory disease in women. LCn-3 PUFAs intake was associated with 15% and 18% lower CVD mortality in men and women across extreme quintiles, respectively. CONCLUSION: Consumption of fish and LCn-3 PUFAs was robustly associated with lower mortality from major causes. Our findings support current guidelines for fish consumption while advice on non-frying preparation methods is needed. PMID- 30019398 TI - GLP-1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract. AB - Glutamatergic neurons that express pre-proglucagon (PPG) and are immunopositive (+) for glucagon-like peptide-1 (i.e., GLP-1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP-1 neurons give rise to an extensive central network in which GLP-1 receptor (GLP-1R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via GLP-1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP-1R, whereas PPG neurons do not. In this study, confocal microscopy in rats confirmed that prolactin-releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP-1+ axonal varicosities. Surprisingly, GLP-1+ appositions were also observed on dendrites of PPG/GLP-1+ neurons in both species, and electron microscopy in rats revealed that GLP-1+ boutons form asymmetric synaptic contacts with GLP-1+ dendrites. However, RNAscope confirmed that rat GLP-1 neurons do not express GLP 1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP-1, and a mouse crossbreeding strategy revealed that <1% of PPG neurons co-express GLP-1R. Collectively, these data suggest that GLP-1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local "feed-forward" synaptic network among GLP-1 neurons that apparently does not use GLP-1R signaling. This local GLP-1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP-1 neural populations that shape behavioral and physiological responses to internal and external challenges. PMID- 30019400 TI - Volatile compounds in different parts of the fruit Psidium guajava L. cv. "Media China" identified at distinct phenological stages using HS-SPME-GC-QTOF/MS. AB - INTRODUCTION: Determination of the volatile organic compounds (VOCs) emitted by immature fruits furthers our understanding of plant-pest interactions and by fruits in a ripe state concerns food quality. OBJECTIVES: To apply headspace solid-phase microextraction gas chromatography quadrupole time-of-flight mass spectrometry (HS-SPME-GC-QTOF/MS) to compare the volatiles emitted by different parts of guava (Psidium guajava L. cv. "Media China") at different maturation stages. METHODOLOGY: HS-SPME combined with GC-QTOF/MS was used to characterise the VOCs of entire guavas in the orchard and under laboratory conditions. For chemical analysis X-ray fluorescence spectroscopy, refractometry, titration, complexometry, diode array detector high-performance liquid chromatography (DAD HPLC) and refractive index detector (RI)-HPLC were used. RESULTS: The guava variety was rich in potassium and poor in sodium. A total of 44 VOCs were identified in different phenological stages and parts of the fruits. Release of VOCs was influenced by the temperature in the plantation, and transformation of innate fruit VOCs started immediately after cutting. CONCLUSION: The most abundant VOC released by the immature fruit in the plantation overnight was (S) limonene, and it concentrated in the outer skin (pericarp). The esters ethyl benzoate, ethyl octanoate, butyl-2-methylbutanoate, ethyl hexanoate, cis-3 hexenyl acetate, and ethyl butanoate were emitted by ripe whole fruits. During ripening ethyl benzoate reached a maximum production after three to five days, while the formation of the aldehydes benzaldehyde, hexanal and trans-2-hexen-1-al started thereafter. PMID- 30019401 TI - Comparison of cross-sectional areas and distal-proximal nerve ratios in amyotrophic lateral sclerosis. AB - INTRODUCTION: This study explored potential diagnostic markers of nerve ultrasound in differentiating amyotrophic lateral sclerosis (ALS) from mimic disorders. METHODS: Ultrasound of the median, ulnar, and tibial nerves was conducted in 53 patients with ALS, 32 patients with ALS-mimic disorders, and 30 controls. Nerve cross-sectional area (CSA) and distal-proximal ratios were calculated. RESULTS: The median nerve CSA in the upper arm was decreased (7.9 +/- 1.3 mm2 vs. 9.0 +/- 1.4 mm2 , P < 0.05), and the median nerve wrist-upper arm ratio was increased in ALS patients compared with controls (1.3 +/- 0.4 vs. 1.1 +/- 0.2; P < 0.01). In differentiating ALS from mimic presentations, assessment of median nerve CSA in the upper arm and comparison of a median and ulnar nerve CSA distal-proximal ratio provide diagnostic potential. DISCUSSION: Assessment of nerve CSA combined with calculation of nerve CSA distal-proximal ratio provides a useful marker to aid in the diagnosis of ALS. Muscle Nerve, 2018. PMID- 30019402 TI - Fine-needle aspiration in all thyroid incidentalomas at 18 F-FDG PET/CT: Can EU TIRADS revise the dogma? AB - OBJECTIVE: Focal thyroid incidentalomas (TIs) are observed in 2% of 18 F-FDG PET/CT representing malignancy in one-third of cases. Currently, due to the lack of evidence on their optimal management, guidelines suggest fine-needle aspiration cytology (FNAC). The study aim was to evaluate the role of ultrasound evaluation according to EU-TIRADS to assess the risk of TIs and inform FNAC prescriptions. DESIGN: We retrospectively reviewed 18 F-FDG PET/CT TIs recorded during the period 2014-2017. Enrolled were TIs with histological outcome and autonomous nodules. Cases with uncertain matching between 18 F-FDG PET/CT, ultrasound and histology were excluded. RESULTS: According to the selection criteria, 75 TIs, being 13 (17.3%) malignant and 62 (82.7%) benign, were included. Cancers had significantly higher SUVmax and SUVmax ratio (Mann-Whitney P < 0.01) than benign, and the most accurate cut-offs were >7.1 and >3.65, respectively. At ultrasound, the cancer rate was 0% in EU-TIRADS 2, 2.9% in EU TIRADS 3, 4.2% in EU-TIRADS 4% and 78.6% in EU-TIRADS 5 (chi-squared P < 0.001). Sensitivity, specificity, PPV, NPV and accuracy for malignancy were 92%, 64%, 35%, 98% and 69% for SUVmax; 85%, 68%, 36%, 96% and 71% for SUVmax ratio; and 85%, 95%, 79%, 97% and 93% for EU-TIRADS, respectively. The absence of all these three features reached a specificity of 97.1%. CONCLUSIONS: EU-TIRADS, within a clinical careful approach, can discriminate with significant accuracy lesions at high risk of malignancy from those at low risk among TIs at 18 F-FDG PET/CT. Additionally, a centre-based threshold for SUV parameters should be useful for the initial assessment of these lesions during PET/CT reading and reporting. PMID- 30019403 TI - Caregivers' perceptions of aggressive behaviour in nursing home residents living with dementia: A meta-ethnography. AB - AIM: To explore how formal caregivers perceive and interpret aggressive behaviour in nursing home residents living with dementia, by synthesizing knowledge from published qualitative studies. BACKGROUND: Nursing home caregivers are exposed to aggressive behaviour from residents living with dementia. The way caregivers perceive aggressive behaviour may affect their feelings and actions related to situations and thus nursing care. Knowledge about caregivers' perceptions of aggressive behaviour has previously not been synthesized. DESIGN: Noblit and Hare's interpretative meta-ethnography. DATA SOURCES: A systematic literature search in CINAHL, PubMed and Scopus supplemented by manual search strategies, were completed. Nine studies from five countries, published between 2001 - 2015, met the research objective and inclusion criteria and were included. FINDING: Five themes describing formal caregivers' perceptions and interpretation of residents' aggressive behaviour emerged: "A manifestation of the disease"; "a way to express themselves and their needs"; "a reaction to caregivers" attitude and approach"; "a reaction to a stressful and demanding environment"; and "an unavoidable situation that seems impossible to solve". Themes were synthesized into the metaphor: 'tailoring using unpredictable patterns' and visualized in a model. CONCLUSION: Caregivers perceive and interpret aggressive behaviour related to the resident's illness and person, the caregiver's attitude and approach, or a demanding environment. Further research and theoretical development is important, as shown by different perceptions and interpretations, as well as central definitions in research publications. The study informs evidence-based practice and health-policy by showing the importance of developing reflective relational nursing care, knowledge, and competence in nursing homes. PMID- 30019404 TI - Autonomic responses to tooth clenching in migraineurs-augmented trigeminocardiac reflex? AB - BACKGROUND: Systemic autonomic changes are well known in migraineurs. Also, masticatory disorders are reported to be associated with migraine. However, if those phenomena are interrelated, and how, is unclear. Moreover, the knowledge on the autonomic responses to masticatory stimuli in migraineurs is limited. OBJECTIVE: To investigate tooth clenching-related cardiac autonomic regulation in migraineurs. METHODS: We compared maximal tooth clenching-induced systemic autonomic responses, indicated by heart rate variability and blood pressure changes, in headache-free migraineurs (n = 17) and control subjects (n = 22). RESULTS: Levels of high-frequency power, reflecting vagal activity, were lower in migraineurs at baseline but increased after tooth clenching whereas in controls they returned to baseline (P < 0.05, mixed model analysis). In multivariate regression model, the presence of migraine predicted the baseline levels of low- and high-frequency power and sympathovagal balance, and the post-test increase in high-frequency power, with the attack frequency and side of headache as the modifiers of the measured changes in migraineurs. The painful signs of temporomandibular disorders, found in clinical oral examination, enhanced both maximal changes in RR intervals and post-test vagal responses to tooth clenching only in migraineurs. CONCLUSION: The enhanced post-clenching vagal activation may represent a marker of the augmented trigeminocardiac reflex to stimulation of trigeminal area, sensitised in migraineurs. Our results support an involvement of autonomic mechanisms in migraine pathophysiology and are interesting in terms of interactions between migraine and masticatory disorders, elucidating one potential way how masticatory disorders may aggravate migraine. PMID- 30019405 TI - Profile of exhaled-breath volatile organic compounds to diagnose pancreatic cancer. AB - BACKGROUND: Pancreatic cancer has a very poor prognosis as most patients are diagnosed at an advanced stage when curative treatments are not possible. Breath volatile organic compounds (VOCs) have shown potential as novel biomarkers to detect cancer. The aim of the study was to quantify differences in exhaled breath VOCs of patients with pancreatic cancers compared with cohorts without cancer. METHODS: Patients were recruited to an initial development cohort and a second validation cohort. The cancer group included patients with localized and metastatic cancers, whereas the control group included patients with benign pancreatic disease or normal pancreas. The reference test for comparison was radiological imaging using abdominal CT, ultrasound imaging or endoscopic ultrasonography, confirmed by histopathological examination as appropriate. Breath was collected from the development cohort with steel bags, and from the validation cohort using the ReCIVATM system. Analysis was performed using gas chromatography-mass spectrometry. RESULTS: A total of 68 patients were recruited to the development cohort (25 with cancer, 43 no cancer) and 64 to the validation cohort (32 with cancer, 32 no cancer). Of 66 VOCs identified, 12 were significantly different between groups in the development cohort on univariable analysis. Receiver operating characteristic (ROC) curve analysis using significant volatile compounds and the validation cohort produced an area under the curve of 0.736 (sensitivity 81 per cent, specificity 58 per cent) for differentiating cancer from no cancer, and 0.744 (sensitivity 70 per cent, specificity 74 per cent) for differentiating adenocarcinoma from no cancer. CONCLUSION: Breath VOCs may distinguish patients with pancreatic cancer from those without cancer. PMID- 30019406 TI - 2-Arylsilacyclobutane as a Latent Carbanion Reacting with CO2. AB - An electronically neutral 2-arylsilacyclobutane generates a nucleophilic carbanion at room temperature through cleavage of the benzylic C-Si bond when simply dissolved in polar aprotic solvents such as N,N-dimethylformamide (DMF). The nucleophilic species is capable of capturing carbon dioxide to furnish a silalactone. The carboxylation reaction is unique in that no additional activating agents are required. PMID- 30019407 TI - Ecthyma contagiosum (Orf): Reflectance confocal microscopy and histopathological correlates. PMID- 30019408 TI - Extracellular adenosine reversibly inhibits the activation of human regulatory T cells and negatively influences the achievement of the operational tolerance in liver transplantation. AB - The artificial induction of tolerance in transplantation is gaining strength. In mice, a differential role of extracellular adenosine (eADO) for regulatory and effector T cells (Tregs and Teffs, respectively) has been proposed: inhibiting Teffs and inducing Tregs. The aim of this study was to analyze the action of extracellular nucleotides in human T cells and, moreover, to examine the influence of CD39 and CD73 ectonucleotidases and subsequent adenosine signaling through adenosine 2 receptor (A2 R) in the induction of clinical tolerance after liver transplant. The action of extracellular nucleotides in human T cells was analyzed by in vitro experiments with isolated T cells. Additionally, 17 liver transplant patients were enrolled in an immunosuppression withdrawal trial, and the differences in the CD39-CD73-A2 R axis were compared between tolerant and nontolerant patients. In contrast to the mice, the activation of human Tregs was inhibited similarly to Teffs in the presence of eADO. Moreover, the expression of the enzyme responsible for the degradation of ADO, adenosine deaminase, was higher in tolerant patients with respect to the nontolerant group along the immunosuppression withdrawal. Our data support the idea that eADO signaling and its degradation may play a role in the complex system of regulation of liver transplant tolerance. PMID- 30019410 TI - Allergic contact cheilitis caused by lauryl PCA. PMID- 30019409 TI - Ecological correlates of the spatial co-occurrence of sympatric mammalian carnivores worldwide. AB - The composition of local mammalian carnivore communities has far-reaching effects on terrestrial ecosystems worldwide. To better understand how carnivore communities are structured, we analysed camera trap data for 108 087 trap days across 12 countries spanning five continents. We estimate local probabilities of co-occurrence among 768 species pairs from the order Carnivora and evaluate how shared ecological traits correlate with probabilities of co-occurrence. Within individual study areas, species pairs co-occurred more frequently than expected at random. Co-occurrence probabilities were greatest for species pairs that shared ecological traits including similar body size, temporal activity pattern and diet. However, co-occurrence decreased as compared to other species pairs when the pair included a large-bodied carnivore. Our results suggest that a combination of shared traits and top-down regulation by large carnivores shape local carnivore communities globally. PMID- 30019411 TI - Glucocorticoids induce corneal allograft tolerance through expansion of monocytic myeloid-derived suppressor cells. AB - Glucocorticoids (GCs) are the most widely used drugs to prevent transplant rejection; however, it is not yet clear how GCs induce immune tolerance in transplantation. Here, we demonstrate that GCs induce tolerance to corneal allografts in mice through expansion of MHC class II- CD11b+ Ly6C+ monocytes in the bone marrow and mobilization of the cells to spleen, draining lymph nodes, and graft site. The GC-induced CD11b+ Ly6C+ monocytes inhibited T cell proliferation in vitro, and adoptive transfer of the cells improved the survival of corneal allografts. Depletion of CD11b+ Ly6C+ cells in mice during GC treatment abrogated the effects of GCs in prevention of immune rejection. Together, the results identify monocytic myeloid-derived suppressor cells as crucial mediators of the GC-induced tolerance in transplantation. PMID- 30019412 TI - Fire on ice and frozen trees? Inappropriate radiocarbon dating leads to unrealistic reconstructions. PMID- 30019414 TI - Development of Bioink from Decellularized Tendon Extracellular Matrix for 3D Bioprinting. AB - Using decellularized extracellular matrix (dECM) hydrogels as bioinks has been an important step forward for bioprinting of functional tissue constructs, considering their rich microenvironment and their high degree of biomimicry. However, directly using dECM hydrogels as bioinks may not be suitable for bioprinting processes because of the loss of shape fidelity and geometrical precision of bioprinted structure due to their slow gelation kinetics. In this article, the development and direct bioprinting of dECM hydrogel bioink from bovine Achilles tendon were presented. The developed bioink is used for a microcapillary-based bioprinting process without any support structure and/or any additional cross-linker components. The reported decellularization and solubilization methods yield dECM pre-gels which turn into stable hydrogels in a short time at physiological conditions. The gelation kinetics and mechanical strength of bioinks with different concentrations and digestion times are characterized. A support structure-free 3D bioprinting of the developed bioink is shown by aspirating dECM bioinks and then in situ gelation and extrusion through a fine microcapillary nozzle. The viability assays indicate that the developed dECM bioink has no cytotoxic effect on encapsulated NIH 3T3 cells and the cells show lineage-specific morphology in the early days of culture as well. PMID- 30019413 TI - In vitro characterization of intrinsic properties and local synaptic inputs to pyramidal neurons in macaque primary motor cortex. AB - Primates (including humans) have a highly developed corticospinal tract, and specialized motor cortical areas which differ in key ways from rodents. Much work on motor cortex has therefore used macaque monkeys as a good animal model for human motor control. However, there is a paucity of data describing the fundamental functional architecture of primate primary motor cortex, which is best addressed with in vitro approaches. In this study we examined the cellular properties and the micro-circuitry of the adult macaque primary motor cortex by carrying out in-vitro intracellular recordings. We aimed to characterize the basic properties of the cortical circuitry by studying the intrinsic properties of its pyramidal neurons and their physiological interconnectivity. We studied the passive and active electrophysiological properties of pyramidal neurons in both superficial and deep cortical layers. Both superficial and deep pyramidal neurons exhibited bursting behaviour that could act as powerful excitation for downstream targets. Synaptic connections were lamina specific. Neurons in the deep layers had convergent excitatory inputs from all cortical layers whereas superficial neurons had only significant inputs from superficial layers. This sheds light on the functional architecture of the primate primary motor cortex and how its output is shaped. We also took the unique opportunity in our recording technique to characterize the relationship between intracellular and extracellular spike waveforms, with implications for cell-type identification in studies in awake behaving monkey. Our results will aid the interpretation of primate studies into motor control involving extracellular spike recordings and electrical stimulation in primary motor cortex. PMID- 30019415 TI - Band Structure Perfection and Superconductivity in Type-II Dirac Semimetal Ir1-x Ptx Te2. AB - The discovery of a new type-II Dirac semimetal in Ir1-x Ptx Te2 with optimized band structure is described. Pt dopants protect the crystal structure holding the Dirac cones and tune the Fermi level close to the Dirac point. The type-II Dirac dispersion in Ir1-x Ptx Te2 is confirmed by angle-resolved photoemission spectroscopy and first-principles calculations. Superconductivity is also observed and persists when the Fermi level aligns with the Dirac points. Ir1-x Ptx Te2 is an ideal platform for further studies on the exotic properties and potential applications of type-II DSMs, and opens up a new route for the investigation of the possible topological superconductivity and Majorana physics. PMID- 30019416 TI - Independent association of serum vitamin D with anti-Mullerian hormone levels in women with polycystic ovary syndrome. AB - OBJECTIVE: This study aimed at investigating the association of serum vitamin D (25(OH)D) and anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) as well as non-PCOS healthy ovulatory women and the possible confounding effects of adiposity and androgen. METHOD: This was a cross-sectional study conducted on serum samples collected from 451 women diagnosed with PCOS as well as 244 age-matched healthy ovulatory women in a tertiary gynaecology out patient clinic and a family planning clinic. RESULTS: Serum 25(OH)D level was significantly higher in women recruited during summer and autumn than those recruited in winter and spring. Both serum 25(OH)D and AMH levels peaked during summer in women with PCOS. In ovulatory women, only serum 25(OH)D but not AMH level showed such seasonal variation. Serum 25(OH)D level in women with PCOS significantly correlated positively with AMH, AMH/antral follicle count (AFC) ratio, serum total testosterone, sex-hormone-binding globulin and quantitative insulin-sensitivity check index and inversely with body mass index (BMI), insulin, triglycerides and homeostatic model assessment of insulin resistance. After controlling for BMI, 25(OH)D level remained significantly correlated positively with serum AMH, AMH/AFC and total testosterone, and inversely with triglycerides. 25(OH)D level was an independent predictor of serum AMH level after controlling for age, BMI and free androgen index in women with PCOS. CONCLUSION: Serum 25(OH)D level is an independent factor significantly associated with AMH level in women with PCOS but not in ovulatory women. PMID- 30019417 TI - APC2 associates with the actin cortex through a multipart mechanism to regulate cortical actin organization and dynamics in the Drosophila ovary. AB - The actin cortex that lines the plasma membrane of most eukaryotic cells resists external mechanical forces and plays critical roles in a variety of cellular processes including morphogenesis, cytokinesis, and cell migration. Despite its ubiquity and significance, we understand relatively little about the composition, dynamics, and structure of the actin cortex. Adenomatous polyposis coli (APC) proteins regulate the actin and microtubule cytoskeletons through a variety of mechanisms, and in some contexts, APC proteins are cortically enriched. Here we show that APC2 regulates cortical actin dynamics in the follicular epithelium and the nurse cells of the Drosophila ovary and in addition affects the distribution of cortical actin at the apical side of the follicular epithelium. To understand how APC2 influences these properties of the actin cortex, we investigated the mechanisms controlling the cortical localization of APC2 in S2 cultured cells. We previously showed that the N-terminal half of APC2 containing the Armadillo repeats and the C-terminal 30 amino acids (C30) are together necessary and sufficient for APC2's cortical localization. Our work presented here supports a model that cortical localization of APC2 is governed in part by self-association through the N-terminal APC Self-Association Domain (ASAD) and a highly conserved coiled-coil within the C30 domain. PMID- 30019418 TI - Response of basal cell carcinoma to imiquimod was associated with the Gli1 : Gli3 expression ratio. PMID- 30019419 TI - Liver-selective mmp-9 inhibition in the rat eliminates ischemia-reperfusion injury and accelerates liver regeneration. AB - : Recruitment of liver sinusoidal endothelial cell progenitor cells, so-called sprocs, from the bone marrow by VEGF-sdf1 signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP 9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or would be detrimental. RESULTS: Liver-selective MMP-9 inhibition accelerated liver regeneration after partial hepatectomy by 40%, whereas systemic MMP inhibition impaired liver regeneration. Liver-selective MMP-9 inhibition largely abolished warm ischemia reperfusion injury. In the extended hepatectomy model, liver-selective MMP-9 inhibition restored liver sinusoidal endothelial cell integrity, enhanced liver regeneration, and reduced ascites. Liver-selective MMP-9 inhibition markedly increased recruitment and engraftment of bone marrow sprocs, whereas systemic MMP inhibition impaired mobilization of bone marrow sprocs and their hepatic engraftment. Hepatic MMP-9 proteolytically cleaved VEGF after partial hepatectomy. Liver-selective MMP-9 inhibition prevented VEGF cleavage and doubled protein expression of VEGF and its downstream signaling partner sdf-1. In contrast, systemic MMP inhibition enhanced recruitment and engraftment of infused allogeneic progenitors. CONCLUSION: Liver-selective MMP inhibition prevents proteolytic cleavage of hepatic VEGF, which enhances recruitment and engraftment of bone marrow sprocs after liver injury. This ameliorates injury and accelerates liver regeneration. Liver-selective MMP-9 inhibition may be a therapeutic tool for liver injury that damages the vasculature, whereas systemic matrix metalloproteinase inhibition can enhance the benefit of stem cell therapy with endothelial progenitor cells. This article is protected by copyright. All rights reserved. PMID- 30019420 TI - Copper-Catalyzed Tandem Hydrocupration and Diastereo- and Enantioselective Borylalkyl Addition to Aldehydes. AB - We report the copper-catalyzed stereoselective addition of in situ generated chiral boron-alpha-alkyl intermediates to various aldehydes including alpha,beta unsaturated aldehydes under mild conditions. This tandem and multicomponent method facilitated the synthesis of enantiomerically enriched 1,2 hydroxyboronates bearing contiguous stereocenters in good yield with high diastereo- and enantioselectivity up to a ratio greater than 98:2. In particular, alpha,beta-unsaturated aldehydes were successfully used as electrophiles in Cu-H catalysis through 1,2-addition without significant reduction. The resulting 1,2 hydroxyboronates were used in various transformations. PMID- 30019421 TI - Economic evaluation of smoking cessation in Ontario's regional cancer programs. AB - Quitting smoking after a diagnosis of cancer results in greater response to treatment and decreased risk of disease recurrence and second primary cancers. The objective of this study was to evaluate the potential cost-effectiveness of two smoking cessation approaches: the current basic smoking cessation program consisting of screening for tobacco use, advice, and referral; and a best practice smoking cessation program that includes the current basic program with the addition of pharmacological therapy, counseling, and follow-up. A Markov model was constructed that followed 65-year-old smokers with cancer over a lifetime horizon. Transition probabilities and mortality estimates were obtained from the published literature. Costs were obtained from standard costing sources in Ontario and reports. Probabilistic and deterministic sensitivity analyses were conducted to address parameter uncertainties. For smokers with cancer, the best practice smoking cessation program was more effective and more costly than the basic smoking cessation program. The incremental cost-effectiveness ratio of the best practice smoking cessation program compared to the basic smoking cessation program was $3367 per QALY gained and $5050 per LY gained for males, and $2050 per QALY gained and $4100 per LY gained for females. Results were most sensitive to the hazard ratio of mortality for former and current smokers, the probability of quitting smoking through participation in the program and smoking-attributable costs. The study results suggested that a best practice smoking cessation program could be a cost-effective option. These findings can support and guide implementation of smoking cessation programs. PMID- 30019422 TI - Feasibility of a nurse-led intervention for the early management of depression after stroke in hospital. AB - AIM: To explore the feasibility of the Post-Stroke Depression toolkit in terms of fidelity and acceptability in daily nursing practice. BACKGROUND: Depression after stroke is common and influences patients' recovery significantly. Although stroke guidelines recommend early depression screening and treatment, depressive symptoms remain unrecognized. To enhance adoption of evidence into the context of the daily practice of stroke treatment, we developed the Post-Stroke Depression toolkit, an evidence-based nurse-led intervention for the early management of depressive symptoms after a stroke for use in the hospital setting. DESIGN: An explanatory mixed-methods before-and-after study design. METHODS: Data were collected continuously from March 2012 - June 2013 during three phases: pre implementation, the implementation phase (where implementation strategies guided the implementation) and the sustainability phase (executed without the implementation strategies) and involved patient chart audits and surveys and individual and focus group interviews with nurses. RESULTS: A total of 775 patient charts were audited to examine fidelity. Implementation of the Post Stroke Depression toolkit during the implementation phase resulted in an increase in depression screening (+72.9%) and more patients receiving nursing interventions (+11.1%). During the sustainability phase, screening for depression decreased (-16.3%), while the application of the nursing interventions remained unchanged (+0.6%). The acceptability of the toolkit was judged to be good. CONCLUSIONS: The Post-Stroke Depression toolkit was found to be feasible in terms of fidelity and acceptability, improving structural screening for depressive symptoms as well as the application of nursing interventions in case of a positive screening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03500250. PMID- 30019423 TI - A robust intensity modulated proton therapy optimizer based on Monte Carlo dose calculation. AB - PURPOSE: Accuracy of dose calculation models and robustness under various uncertainties are key factors influencing the quality of intensity modulated proton therapy (IMPT) plans. To mitigate the effects of uncertainties and to improve the dose calculation accuracy, an all-scenario robust IMPT optimization based on accurate Monte Carlo (MC) dose calculation was developed. METHODS: In the all-scenario robust IMPT optimization, dose volume histograms (DVHs) were computed for the nominal case and for each uncertainty scenario. All scenarios were weighted by DVH values dynamically throughout optimization iterations. In contrast, probabilistic approach weighted scenarios with fixed scenario weights and worst case optimizations picked one single scenario - the worst scenario for each iteration. Uncertainties in patient setup and proton range were considered in all clinical cases studied. Graphics processing unit (GPU) computation was employed to reduce the computational time in both the MC dose calculation and optimization stages. A previously published adaptive quasi-Newton method for proton optimization was extended to include robustness. To validate the all scenario algorithm extension, it was compared with the single scenario optimization target volume (OTV) based approach in clinical cases of three different disease sites. Additional comparisons with worst case optimization methods were conducted to evaluate the performance of the all-scenario robust optimization against other robust optimizations. RESULTS: The all-scenario robust IMPT optimization spared organs at risk (OARs) better than the OTV-based method while maintaining target coverage and improving the robustness of targets and OARs. Compared with composite and voxel-wise worst case optimization, the all scenario robust optimization converged faster, and arrived at solutions of tighter DVH robustness spread, better target coverage and lower OAR dose. CONCLUSION: An all-scenario robust IMPT treatment planning system was developed using an adaptive quasi-Newton optimization method. The optimization system was GPU-accelerated and based on MC dose calculation. Improved performance was observed in clinical cases when compared with worst case optimization methods. PMID- 30019424 TI - Obesity in women who have experienced intimate partner violence. AB - AIMS: The aim of this study was to examine the pathway through which intimate partner violence (IPV) severity and child abuse severity influence obesity among women who have experienced IPV. BACKGROUND: Intimate partner violence is a public health issue that is found to be related to obesity. Yet, little is known about the pathways that link both IPV and child abuse experiences to obesity. The roles of posttraumatic stress disorder and depressive symptoms in the relations between IPV and obesity are still not well known. DESIGN: A cross-sectional study of 299 women who have experienced IPV. METHODS: A convenience sample of abused women was recruited from nine primary healthcare centres in Saudi Arabia. Data were collected in 2015, using self-report questionnaires and physical measures for obesity. Non-parametric analysis of variance was conducted to explore group differences. Structural equation modelling was used to examine the hypothesized model. RESULTS: Among the sample, 52.5% was classified as obese based on body mass index. Obese women had significantly higher levels of IPV, physical child abuse, depressive symptoms and posttraumatic stress disorder symptoms. The study showed that both IPV severity and child abuse severity indirectly influenced obesity through depressive symptoms. CONCLUSION: The alarming rate of obesity among abused women suggests that these women are at great risk for obesity, which necessitates clinical consideration. The study findings highlight the need to treat depressive symptoms to manage and prevent obesity among IPV and child abuse survivors. Specifically, nurses should tailor interventions that address mental health outcomes of abuse in managing obesity. PMID- 30019425 TI - Chemical Constituents from Chloranthus anhuiensis and Their Cytotoxic Activities. AB - Three hiherto unknown phenylpropanoid compounds, namely (7S,8R)-1-(1-ethoxy-2 hydroxypropyl)-2-methoxy-3,4-(methylenedioxy)benzene (1), (7S,8S)-1-(1-ethoxy-2 hydroxypropyl)-2-methoxy-3,4-(methylenedioxy)benzene (2), and (7S,8R)-1-(1 methoxy-2-hydroxypropyl)-2-methoxy-3,4-(methylenedioxy)benzene (3), along with 12 known compounds (4 - 15) were obtained from the extract of whole plant of Chloranthus anhuiensis. Among them, 7 and 13 were obtained from nature for the first time. The structures of these natural compounds were characterized by extensive spectroscopic analysis and calculated electronic circular dichroism (ECD) data. Furthermore, their cytotoxic and neuroprotective activities were evaluated using MDA-MB-231, 4T1, HepG2, and PC12 cell lines. Compounds 8 and 13 exhibited moderate cytotoxic activities against MDA-MB-231 cell line with the IC50 values of 39.7 and 25.8 MUm, respectively. And all the isolated compounds have no neuroprotective activities. PMID- 30019426 TI - Development of psoriasis by continuous neutrophil infiltration into the epidermis. AB - Remarkable effects of anti-IL-17A and anti-IL-23 antibodies on psoriasis indicate deep involvement of IL-23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen-presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, "detachment-mediated cell proliferation." This passing is continuously repeated and leads to elongation of rete ridges. The IL-23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL-17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL-23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL-23 and IL-1beta. In this manner, the framework of the IL-23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL-17A production by neutrophils and ending in IL-17A production by nTh17 cells. Therapeutic mechanisms of anti-IL-17A and anti-IL-23 antibodies, targeting neutrophils, were also described. PMID- 30019427 TI - Use of stochastic patch-occupancy models in the California red-legged frog for Bayesian inference regarding past events and future persistence. AB - Assessing causes of population decline has critical importance for management of threatened species. Stochastic patch occupancy models (SPOMs) are popular tools for understanding spatial and temporal dynamics of populations when presence/absence data in multiple habitat patches are available. We develop a Bayesian Markov chain method that extends existing SPOMs by focusing on past environmental changes that might have altered occupancy patterns prior to the beginning of data collection. We apply the method to assess causes of population decline in the California red-legged frog in three creeks: in situ die-off, or residual impact of past source population loss. Despite having no occupancy data for the 20-30 years between the hypothetical event leading to population decline and the first data, we discriminate among hypotheses, finding evidence of increased in situ die-off in two creeks. Although the creeks have comparably many occupied segments, owing to different extinction-colonization dynamics, we predict an eightfold difference in persistence probabilities of their populations to 2030. Adding a source population leads to a greater predicted persistence probability than does decreasing the in situ die-off, emphasizing that reversing the deleterious impacts of a disturbance need not be the most efficient management strategy. We expect that the method will be useful for studying dynamics and evaluating management strategies of many species. Article impact statement: Patch-occupancy data can be used to detect disturbances and to predict the impact of management strategies. This article is protected by copyright. All rights reserved. PMID- 30019428 TI - Quantifying and presenting overall evidence in network meta-analysis. AB - Network meta-analysis (NMA) has become an increasingly used tool to compare multiple treatments simultaneously by synthesizing direct and indirect evidence in clinical research. However, many existing studies did not properly report the evidence of treatment comparisons and show the comparison structure to audience. In addition, nearly all treatment networks presented only direct evidence, not overall evidence that can reflect the benefit of performing NMAs. This article classifies treatment networks into three types under different assumptions; they include networks with each treatment comparison's edge width proportional to the corresponding number of studies, sample size, and precision. In addition, three new measures (ie, the effective number of studies, the effective sample size, and the effective precision) are proposed to preliminarily quantify overall evidence gained in NMAs. They permit audience to intuitively evaluate the benefit of performing NMAs, compared with pairwise meta-analyses based on only direct evidence. We use four case studies, including one illustrative example, to demonstrate their derivations and interpretations. Treatment networks may look fairly differently when different measures are used to present the evidence. The proposed measures provide clear information about overall evidence of all treatment comparisons, and they also imply the additional number of studies, sample size, and precision obtained from indirect evidence. Some comparisons may benefit little from NMAs. Researchers are encouraged to present overall evidence of all treatment comparisons, so that audience can preliminarily evaluate the quality of NMAs. PMID- 30019430 TI - PKC epsilon signaling effect on actin assembly is diminished in cardiomyocytes when challenged to additional work in a stiff microenvironment. AB - The stiffness of the microenvironment surrounding a cell can result in cytoskeletal remodeling, leading to altered cell function and tissue macrostructure. In this study, we tuned the stiffness of the underlying substratum on which neonatal rat cardiomyocytes were grown in culture to mimic normal (10 kPa), pathological stiffness of fibrotic myocardium (100 kPa), and a nonphysiological extreme (glass). Cardiomyocytes were then challenged by beta adrenergic stimulation through isoproterenol treatment to investigate the response to acute work demand for cells grown on surfaces of varying stiffness. In particular, the PKCE signaling pathway and its role in actin assembly dynamics were examined. Significant changes in contractile metrics were seen on cardiomyocytes grown on different surfaces, but all cells responded to isoproterenol treatment, eventually reaching similar time to peak tension. In contrast, the assembly rate of actin was significantly higher on stiff surfaces, so that only cells grown on soft surfaces were able to respond to acute isoproterenol treatment. Forster Resonance Energy Transfer of immunofluorescence on the cytoskeletal fraction of cardiomyocytes confirmed that the molecular interaction of PKCE with the actin capping protein, CapZ, was very low on soft substrata but significantly increased with isoproterenol treatment, or on stiff substrata. Therefore, the stiffness of the culture surface chosen for in vitro experiments might mask the normal signaling and affect the ability to translate basic science more effectively into human therapy. PMID- 30019429 TI - Nogo-B promotes tumor angiogenesis and provides a potential therapeutic target in hepatocellular carcinoma. AB - Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti-angiogenic therapeutic targets. We found that the expression level of Nogo-B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo-B depletion inhibited tumor angiogenesis, Nogo-B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo-B regulates tumor angiogenesis based on its association with integrin alphav beta3 and activation of focal adhesion kinase. Moreover, Nogo-B antibody successfully abolished the function of Nogo-B in tumor angiogenesis in vitro and in vivo. Collectively, our results strongly suggest that Nogo-B is an important tumor angiogenic factor and blocking Nogo-B selectively inhibits tumor angiogenesis. PMID- 30019431 TI - Prenatal management and timing of delivery of uncomplicated monochorionic monoamniotic twin pregnancy: the MONOMONO study. AB - BACKGROUND: Monoamniotic twins are at increased risk of perinatal complications. Perinatal mortality has been reported to be high, primarily related to cord entanglement. International guidelines made no recommendation regarding whether these women should be managed in the hospital or can be safely managed in outpatient settings. Moreover, timing of planned delivery in these women is also a subject of debate. OBJECTIVE: To compare the perinatal outcomes of inpatient versus outpatient fetal surveillance approaches employed among 22 participating study centers; and to calculate the fetal and neonatal death rate according to gestational age in non-anomalous monoamniotic twins from 26 weeks' gestation. STUDY DESIGN: The MONOMONO study was a multinational cohort study. Clinical records of all consecutive women with monochorionic monoamniotic twin pregnancies, who were referred to 22 university hospitals in Italy, the United States, the United Kingdom, and Spain, from January 2010 to January 2017, were included in the study. Only non-anomalous uncomplicated monoamniotic twins with both fetuses alive at 26 0/7 weeks were included in the study. Management of monoamniotic twins was different in the different included centers. In 10 centers all monoamniotic twins were routinely managed inpatient. In 12 centers all monoamniotic twins were routinely managed as outpatients. The primary outcome was intrauterine fetal death in the inpatient versus outpatient group. We also planned to assess the fetal death rate and the neonatal death rate according to gestational age per 1-week interval. Outcomes were presented as odds ratio (OR) with the 95% of confidence interval (CI). In addition to the standard logistic regression analysis, we used a generalized mixed model approach, with twin pair as the cluster unit. This model was used because the outcomes of each twin were not independent of the co-twin. RESULTS: 195 consecutive pregnant women with non anomalous uncomplicated monoamniotic twin gestations (390 fetuses) were included. Of them, 75 (38.5%) were managed as inpatients and 120 (61.5%) were managed as outpatients. The overall perinatal loss rate was 10.8% (42/390) with the peak fetal death rate occurring at 29 weeks gestation (15/348, 4.3%). There was no significant difference in mean gestation age at delivery (31 weeks), birth weight (~1.6 kg), or emergency delivery rate between the inpatient and outpatient surveillance groups. There was no statistically significant difference in fetal death rates between inpatient surveillance protocols commencing from around 26 weeks compared with outpatient surveillance protocols from 30 weeks (3.3% vs 10.8%; adjusted OR 0.21, 95% CI 0.04 to 1.17). Maternal LOS in the hospital was 42.1 days in the inpatient group, and 7.4 days in the outpatient group (MD 34.70 days, 95% CI 31.31 to 38.09). From 32 0/7 to 36 6/7 weeks, no fetal or neonatal death in either group was recorded. 46 fetuses delivered after 34 0/7 weeks, and none of them died in utero or within the first 28 days of life. CONCLUSION: In uncomplicated monoamniotic twins, when compared with outpatient management, inpatient surveillance is associated with similar fetal mortality. After 31 6/7 weeks there were no intrauterine fetal deaths or neonatal deaths even up to 36 6/7 weeks. This article is protected by copyright. All rights reserved. PMID- 30019433 TI - Nurses' experiences of undertaking fertility-related discussions with teenagers and young adults with cancer: An interpretive phenomenological analysis. AB - AIMS: The aim of this study was to explore and interpret nurses' experiences, feelings and associated meanings attached to undertaking fertility-related discussions with teenagers and young adults with cancer. The study also aims to advance an understanding of factors which facilitate or hinder such discussions, to progress clinical practice. BACKGROUND: Improved cancer treatments have increased survival rates for many teenagers and young adults. However, as a side effect of treatment, infertility may result. International and UK studies suggest this patient population may not be provided with adequate opportunities to discuss this important issue. Little is known about nurses' experiences of undertaking fertility-related discussions. DESIGN: Qualitative Interpretive Phenomenological Analysis. METHODS: Eleven semistructured interviews were conducted between February and May 2016 with purposively selected nurses working in a Teenage Cancer Trust Unit in a UK hospital. Interviews were recorded and transcribed verbatim. Data were analysed using Interpretive Phenomenological Analysis. FINDINGS: Nurses experienced a perceived lack of knowledge resulting in avoidance of raising fertility issues. Nurses expressed a specific need for more knowledge and education which was viewed as an essential prerequisite to their participation in discussions. The limited time frame for female patients to preserve fertility prior to commencement of treatment was felt to inhibit both fertility-related discussion and fertility preservation. CONCLUSION: Ongoing education and support for nurses may ensure teenage and young adult cancer patients' reproductive needs are met. Nurses need to consider ways to ensure female patients benefit from improved information regarding infertility risks and preservation options to support their reproductive needs. PMID- 30019434 TI - A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department. AB - BACKGROUND: Opioids are commonly prescribed in the emergency department (ED) for the treatment of acute pain. Analgesic alternatives are being explored in response to an epidemic of opioid misuse. Low-dose ketamine (LDK) is one opioid alternative for the treatment of acute pain in the ED. OBJECTIVES: This systematic review and meta-analysis sought to quantify whether LDK is an effective and safe opioid alternative for acute pain reduction in adults in the ED setting. (PROSPERO Registration Number CRD42017065303). METHODS: This was a systematic review of randomized controlled trials comparing intravenous opioids to LDK for relief of acute pain in the ED. Studies where the control group initially received opioids prior to ketamine were excluded. A research librarian designed the electronic search strategy. Changes in visual analog scale or numeric rating scale pain scales were analyzed to determine the relative effects of LDK and opioids in the treatment of acute pain. RESULTS: Three studies met the criteria for inclusion in this meta-analysis. Compared to pain scale reduction with morphine, ketamine was not inferior (relative reduction = 0.42, 95% confidence interval = -0.70 to 1.54). No severe adverse events were reported in any study, but higher rates of nonsevere adverse events were observed with ketamine. CONCLUSIONS: Ketamine is noninferior to morphine for the control of acute pain, indicating that ketamine can be considered as an alternative to opioids for ED short-term pain control. PMID- 30019432 TI - Changes of motor corticobulbar projections following different lesion types affecting the central nervous system in adult macaque monkeys. AB - Functional recovery from central nervous system injury is likely to be partly due to a rearrangement of neural circuits. In this context, the corticobulbar (corticoreticular) motor projections onto different nuclei of the ponto-medullary reticular formation (PMRF) were investigated in 13 adult macaque monkeys after either, primary motor cortex injury (MCI) in the hand area, or spinal cord injury (SCI) or Parkinson's disease-like lesions of the nigro-striatal dopaminergic system (PD). A subgroup of animals in both MCI and SCI groups was treated with neurite growth promoting anti-Nogo-A antibodies, whereas all PD animals were treated with autologous neural cell ecosystems (ANCE). The anterograde tracer BDA was injected either in the premotor cortex (PM) or in the primary motor cortex (M1) to label and quantify corticobulbar axonal boutons terminaux and en passant in PMRF. As compared to intact animals, after MCI the density of corticobulbar projections from PM was strongly reduced but maintained their laterality dominance (ipsilateral), both in the presence or absence of anti-Nogo-A antibody treatment. In contrast, the density of corticobulbar projections from M1 was increased following opposite hemi-section of the cervical cord (at C7 level) and anti-Nogo-A antibody treatment, with maintenance of contralateral laterality bias. In PD monkeys, the density of corticobulbar projections from PM was strongly reduced, as well as that from M1, but to a lesser extent. In conclusion, the densities of corticobulbar projections from PM or M1 were affected in a variable manner, depending on the type of lesion/pathology and the treatment aimed to enhance functional recovery. PMID- 30019435 TI - Murine type VII collagen distorts outcome in human skin graft mouse model for dystrophic epidermolysis bullosa. AB - Human skin graft mouse models are widely used to investigate and develop therapeutic strategies for the severe generalized form of recessive dystrophic epidermolysis bullosa (RDEB), which is caused by biallelic null mutations in COL7A1 and the complete absence of type VII collagen (C7). Most therapeutic approaches are focused on reintroducing C7. Therefore, C7 and anchoring fibrils are widely used as readouts in therapeutic research with skin graft models. In this study, we investigated the expression pattern of human and murine C7 in a grafting model, in which human skin is reconstituted out of in vitro cultured keratinocytes and fibroblasts. The model revealed that murine C7 was deposited in both human healthy control and RDEB skin grafts. Moreover, we found that murine C7 is able to form anchoring fibrils in human grafts. Therefore, we advocate the use of human-specific antibodies when assessing the reintroduction of C7 using RDEB skin graft mouse models. PMID- 30019436 TI - Transcription factor ABI3 auto-activates its own expression during dehydration stress response. AB - The transcription factor abscisic acid insensitive 3 (ABI3) has recently been shown to mediate the dehydration stress response in nonseed and seed plants by regulation of several downstream genes. Here, we show how ABI3 autoregulates its transcription in response to dehydration stress signalling. Autoactivation is primarily through the Sph/RY element CATGCA present at the promoter region of ABI3. Along with other known cis-elements found at the ABI3 promoter, CATGCA remains occluded by nucleosomes during transcription repression. The nucleosomes tend to reposit during active transcription and are associated with several histone modifications, such as H3K9 and K27 acetylations and H3K4 trimethylation. This work thus, reveals the genetic and epigenetic essentials required for expression of the ABI3 gene, a crucial factor regulating dehydration stress signalling in Arabidopsis thaliana. PMID- 30019437 TI - Topical micronutrients in atopic dermatitis-An evidence-based review. AB - The role of dietary factors is an important and controversial topic in the pathogenesis of atopic dermatitis (AD). Despite the preponderance of consumer products utilizing oral micronutrients supplementation for relief AD symptoms, less attention has been paid on the utility of topical micronutrients, specifically for individuals with AD. We review evidence on topical formulations of vitamins (A, B, C, D, and E) and trace minerals (magnesium, manganese, zinc, and iodine) for treatment of AD. While topical B, C, and E formulations appear to provide some benefit to AD individuals, topical vitamin A has no utility, and topical vitamin D may exacerbate symptoms. Magnesium, zinc, and iodine all appear to improve AD through anti-inflammatory and anti-microbial effects, though future studies must evaluate their use as monotherapy. The exposition of the effects that topical micronutrients have on AD offers an adjuvant treatment modality for this common inflammatory dermatosis. PMID- 30019438 TI - Auditory motion does not modulate spiking activity in the middle temporal and medial superior temporal visual areas. AB - The integration of multiple sensory modalities is a key aspect of brain function, allowing animals to take advantage of concurrent sources of information to make more accurate perceptual judgments. For many years, multisensory integration in the cerebral cortex was deemed to occur only in high-level "polysensory" association areas. However, more recent studies have suggested that cross-modal stimulation can also influence neural activity in areas traditionally considered to be unimodal. In particular, several human neuroimaging studies have reported that extrastriate areas involved in visual motion perception are also activated by auditory motion, and may integrate audiovisual motion cues. However, the exact nature and extent of the effects of auditory motion on the visual cortex have not been studied at the single neuron level. We recorded the spiking activity of neurons in the middle temporal (MT) and medial superior temporal (MST) areas of anesthetized marmoset monkeys upon presentation of unimodal stimuli (moving auditory or visual patterns), as well as bimodal stimuli (concurrent audiovisual motion). Despite robust, direction selective responses to visual motion, none of the sampled neurons responded to auditory motion stimuli. Moreover, concurrent moving auditory stimuli had no significant effect on the ability of single MT and MST neurons, or populations of simultaneously recorded neurons, to discriminate the direction of motion of visual stimuli (moving random dot patterns with varying levels of motion noise). Our findings do not support the hypothesis that direct interactions between MT, MST and areas low in the hierarchy of auditory areas underlie audiovisual motion integration. PMID- 30019439 TI - Synthesis of Cyclic Compounds via Photoinduced Radical Cyclization Cascade of C=C bonds. AB - Cyclic compounds constitute a great important class of substances in the science of medicine and biology, which renders the research on facile and efficient construction of such complex scaffolds from simple starting materials to be hot and appealing. Recently, the radical cascade reaction involving multiple bond formation/cleavage has emerged as an ideal and powerful route to give high-value cyclic products, along with diminished cost and waste. As a simple and benign methodology, photoredox catalysis offers a readily available access to the generation of radical species. Alkenes have been recognized as one of the most valuable building blocks for the reason they allow installation of different functional groups simultaneously through addition to the C=C bonds. This account summarizes the recent advances in photoinduced radical cascade cyclization to the synthesis of cyclic compounds with C=C bonds working as the initial radical acceptors, and emphasis is put on the related reaction mechanisms. PMID- 30019440 TI - Remote monitoring of implanted cardiac devices: A guide for patients and families. PMID- 30019441 TI - Same Redox Evidence But Different Physiological "Stories": The Rashomon Effect in Biology. AB - The Rashomon effect - a phenomenon studied in the arts and social sciences - occurs when the same event is given contradictory interpretations by different individuals involved. The effect was named after Akira Kurosawa's 1950 film Rashomon, in which a murder is described in four contradictory ways by four witnesses. In the film, a samurai has been killed under mysterious circumstances. Four people give contradictory reports about the crime. In particular, the samurai's wife claims that she was sexually abused by a bandit, fainted, and then awoke to find her husband dead; the bandit claims that he seduced the wife and challenged the samurai in a battle to victory or at least to an honorable death; the woodcutter (who may have been an onlooker) claims that he witnessed the rape and murder but was not involved; and the dead samurai's spirit claims that he committed suicide. The Rashomon effect is not only about constructing different versions of the world based on differences in perspective; it occurs when such differences appear together with the absence of evidence to assess any version of the truth, plus "the social pressure for closure on the question." In this commentary, we describe the relevance of the Rashomon effect beyond the arts and social sciences, namely in the field of biology. We use examples from redox biology, which is full of contradictions, thus making it fertile ground on which to apply reasoning derived from the Rashomon effect. PMID- 30019442 TI - A systematic review of strategies to reduce sugar-sweetened beverage consumption among 0-year to 5-year olds. AB - OBJECTIVE: The objective of this study is to summarize evidence for strategies designed to reduce sugar-sweetened beverage (SSB) consumption among children aged 0 to 5 years. DATA SOURCES: PubMed, Web of Science, EMBASE, CINAHL, ERIC, Cab Abstracts and the Cochrane Central Register of Controlled Trials are the electronic databases searched in this systematic review. STUDY SELECTION: Each included study evaluated an intervention to reduce SSB consumption in children aged 0 to 5 years, was conducted in a high-income country and was published between 1 January 2000 and 15 December 2017. DATA SYNTHESIS: Twenty-seven studies met the inclusion criteria. The primary intervention settings were healthcare (n = 11), preschool/daycare (n = 4), home (n = 3), community venues (n = 3) and other settings (n = 6). Overarching strategies which successfully reduced SSB consumption included (i) in-person individual education, (ii) in-person group education, (iii) passive education (e.g. pamphlets), (iv) use of technology, (v) training for childcare/healthcare providers and (vi) changes to the physical access of beverages. Studies were of moderate methodological quality (average score of 20.7/29.0 for randomized studies; 3.1/9.0 for non-randomized studies). CONCLUSIONS: Evidence suggests that interventions successful at reducing SSB consumption among 0-year to 5-year olds often focused on vulnerable populations, were conducted in preschool/daycare settings, specifically targeted only SSBs or only oral hygiene, included multiple intervention strategies and had higher intervention intensity/contact time. PMID- 30019443 TI - Iranian HIV/AIDS patients with oropharyngeal candidiasis: identification, prevalence and antifungal susceptibility of Candida species. AB - : Oropharyngeal candidiasis is the commonest mucocutaneous infection in HIV positive individuals. Herein, samples were taken from oral cavities of 150 HIV infected patients and cultured on Sabouraud-dextrose agar; 89 (59.3%) of 150 patients had positive culture for Candida and presented clinical sign of classical oral candidiasis. Totally, 102 morphologically distinct colonies were isolated from Candida positive cultures and subsequently identified by polymerase chain reaction and sequencing assay, presenting the following frequency: 54 C. albicans (52.9%), 16 C. dubliniensis (15.7%), 12 C. tropicalis (11.8%), 9 C. glabrata (8.8%), 7 C. kefyr (6.9%) and 4 C. africana (3.9%). Additionally, multiple Candida species were co-isolated from 13.5% (12/89) patients. Regarding the antifungal susceptibility test, which was performed by CLSI protocol (M27 A3/M27-S3), all Candida isolates were susceptible to amphotericin B and caspofungin, while some of them were resistant to fluconazole (17.6%; 16 C. albicans, 1 C. dubliniensis and 1 C. glabrata), itraconazole (16.7%; 15 C. albicans, 1 C. dubliniensis and 1 C. tropicalis) and voriconazole (5.9%; 5 C. albicans and 1 C. tropicalis). Collectively, our findings reinforce the urgent necessity to find new therapeutic agents to treat oral candidiasis in HIV positive patients, especially due to the high incidence of azole-resistant Candida strains and the increased frequency of non-C. albicans species. SIGNIFICANCE AND IMPACT OF THE STUDY: The Candida species recovered from oral cavity of 150 Iranian HIV/AIDS patients and their antifungal susceptibility profiles were reported. Candida albicans was the commonest Candida species, followed by C. dubliniensis, C. tropicalis, C. glabrata, C. kefyr and C. africana. All Candida isolates were susceptible to amphotericin B and caspofungin, while resistance to azoles was detected. The growing drug-resistance profile reported in clinical isolates of C. albicans and non-C. albicans strains is a serious problem in hospitals worldwide. Consequently, the suitable antifungal choice to treat the HIV/AIDS population with oral candidiasis needs to be rethought and new therapeutic options must urgently arise. PMID- 30019444 TI - A systematic approach toward comparing electrospray ionization efficiencies of derivatized and non-derivatized amino acids and biogenic amines. AB - Ionization efficiency (IE) in mass spectrometry (MS) has been studied for many different compounds, and different IE scales have been constructed in order to quantitatively characterize IE. In the case of MS, derivatization has been used to increase the sensitivity of the method and to lower the limits of detection. However, the influence of derivatization on IE across different compounds and different derivatization reagents has not been thoroughly researched, so that practitioners do not have information on the IE-enhancing abilities of different derivatization reagents. Moreover, measuring IE via direct infusion of compounds cannot be considered fully adequate. Since derivatized compounds are in complex mixtures, a chromatographic method is needed to separate these compounds to minimize potential matrix effects. In this work, an IE measurement system with a chromatographic column was developed for mainly amino acids and some biogenic amines. IE measurements with liquid chromatography electrospray ionization mass spectrometry (LC/ESI/MS) were carried out, and IE scales were constructed with a calibration curve for compounds with and without derivatization reagent diethyl ethoxymethylenemalonate. Additionally, eluent composition effects on ionization were investigated. Results showed that derivatization increases IE for most of the compounds (by average 0.9 and up to 2-2.5 logIE units) and derivatized compounds have more similar logIE values than without derivatization. Mobile phase composition effects on ionization efficiencies were negligible. It was also noted that the use of chromatographic separation instead of flow injection mode slightly increases IE. In this work, for the first time, IE enhancement of derivatization reagents was quantified under real LC/ESI/MS conditions and obtained logIE values of derivatized compounds were linked with the existing scale. PMID- 30019445 TI - Relationship between gerotranscendence and oral health-related quality of life. AB - OBJECTIVES: The purpose of our cross-sectional study was to investigate the relationship between gerotranscendence and oral health-related quality of life (OHR-QOL). To our knowledge, this is the first study to investigate the relationship between gerotranscendence and OHR-QOL. METHODS: Participants (total n = 1969; 70-year-old group, n = 999; 80-year-old group, n = 970) were drawn from resident lists in four areas of Japan: one urban area and one rural area in each of two geographical regions. OHR-QOL was measured using the Geriatric Oral Health Assessment Index (GOHAI). Measurement of occlusal force was performed using pressure-sensitive sheets. Gerotranscendence was assessed with the Japanese Gerotranscendence Scale Revised (JGS-R). We used multiple linear regression analysis to examine the relationships among OHR-QOL and other variables. RESULTS: Geriatric Oral Health Assessment Index score was significantly correlated with occlusal force, number of teeth, financial status and JGS-R score on linear regression analysis. CONCLUSION: Degree of gerotranscendence was significantly and independently correlated with degree of OHR-QOL in our sample. PMID- 30019446 TI - Systematic review of the changing pattern of the oral manifestations of HIV. AB - The purpose of the present study paper was to review the reported prevalence of the oral manifestations of HIV (OM-HIV) worldwide since 1980, and to determine the global variation in its prevalence over time. PubMed, Scopus, Embase and Google Scholar were searched. The filter "English" was used. The timeframe searched was 1980- 2015. The PRISMA flow chart was used. Data were extracted using the Joanna Briggs Institute standardized data extraction form and transferred to SPSS version 22 for analysis. The systematic review of 97 studies (70 low bias risk) showed that the prevalence of OM-HIV continue to be significant in developing countries. Globally and through all the decades, oral candidiasis remained the most commonly encountered OM-HIV, including among patients on antiretroviral therapy (ART) (26.2%). Hairy leukoplakia was more prevalent in Europe and America compared with Africa and Asia. Oral warts were reported more often in studies on patients receiving ART. Interestingly, salivary gland disease decreased in the developed world and increased in developing countries over time. Despite the changing pattern of these conditions over time, there is no evidence that the OM-HIV have become of less significance globally. Maintaining the drive for high-quality research in the subject will have an impact on less developed countries to help address oral health inequalities. PMID- 30019449 TI - Anti-tumour actions of cannabinoids. AB - The endocannabinoid system has emerged as an important target for the treatment of many diverse diseases. In addition to the well-established palliative effects of cannabinoids in cancer therapy, phytocannabinoids, synthetic cannabinoid compounds and inhibitors of endocannabinoid degradation have attracted attention as possible systemic anticancer drugs. Results emerging from preclinical studies suggest cannabinoids elicit effects at different levels of cancer progression, including inhibition of proliferation, neovascularization, invasion and chemoresistance, induction of apoptosis and autophagy as well as enhancement of tumour immune surveillance. Although the clinical use of cannabinoid receptor ligands is limited by their psychoactivity, non-psychoactive compounds, such as cannabidiol, have gained attention due to preclinically established anticancer properties and a favourable risk-to-benefit profile. Thus, cannabinoids may complement the currently used collection of chemotherapeutic agents, as a broadly diversified option for cancer treatment, while counteracting some of their severe side effects. PMID- 30019448 TI - Comparison of hemagglutination inhibition, single radial hemolysis, virus neutralization assays, and ELISA to detect antibody levels against seasonal influenza viruses. AB - BACKGROUND: The immunological response to influenza vaccine and/or natural infection is evaluated by serological techniques, the most common being hemagglutination inhibition (HI), single radial hemolysis (SRH), and virus neutralization assays, which is commonly used in a micro-neutralization (MN) format. ELISA is not officially required; however, this assay is able to measure different class-specific antibodies. The four assays identify different sets or subsets of antibodies. OBJECTIVES: The aim of this study was to establish the correlation among four serological assays using four seasonal influenza strains. METHODS: The HI, SRH, MN assays, and ELISA were performed on four seasonal influenza strains. RESULTS: A strong positive correlation was found between HI and MN and between SRH and MN assays for influenza A strains. The B strains also showed good correlations among the three assays. A positive correlation was also found between ELISA and the "classical" assays for all strains. Concerning the correlates of protection, as defined by HI >= 40 and SRH >= 25 mm2 , good agreement was observed for the influenza A strains. By contrast, the agreement for the B strains was very low. CONCLUSIONS: There is a positive strong correlation among the four serological assays for both A and B strains, especially for the HI and MN assays. There is good agreement on correlates of protection between HI and SRH assays for the A strains, but very low agreement for the B strains, suggesting higher sensitivity of SRH than HI assay in detecting antibodies against the influenza B viruses. PMID- 30019450 TI - Taking stock of anaesthetic databases: enough data, time for action! PMID- 30019447 TI - The underestimated role of basophils in Ph+ chronic myeloid leukaemia. AB - Chronic myeloid leukaemia (CML) is a hematopoietic neoplasm defined by the chromosome translocation t(9;22) and the related oncogene, BCR-ABL1. In most patients, leukaemic cells can be kept under control using BCR-ABL1-targeting drugs. However, many patients relapse which remains a clinical challenge. In particular, patients with advanced (accelerated or blast phase) CML have a poor prognosis. So far, little is known about molecular and cellular interactions and features that contribute to disease progression and drug resistance in CML. One key prognostic factor at diagnosis is marked basophilia. However, although basophils are well-known multifunctional effector cells, their impact in CML remains uncertain. In this article, we discuss the potential role of basophils as active contributors to disease evolution and progression in CML. In particular, basophils serve as a unique source of inflammatory, angiogenic and fibrogenic molecules, such as vascular endothelial growth factor or hepatocyte growth factor. In addition, basophils provide vasoactive substances, like histamine as well as the cytokine-degrading enzyme dipeptidyl-peptidase IV which may promote stem cell mobilization and the extramedullary spread of stem and progenitor cells. Finally, basophils may produce autocrine growth factors for myeloid cells. Understanding the role of basophils in CML evolution and progression may support the development of more effective treatment concepts. PMID- 30019451 TI - The effect of intrapulmonary percussive ventilation in pediatric patients: A systematic review. AB - BACKGROUND: Intrapulmonary percussive ventilation (IPV) is frequently used in clinical practice to enhance sputum evacuation and lung recruitment. However, the evidence in different respiratory pathologies, especially in children, is still lacking. This systematic review aims to enlist the effectiveness of IPV as an airway clearance technique in pediatric patients. DATA SOURCES: A systematic literature search was performed in PubMed, Web of Science, and the Cochrane Library databases. STUDY SELECTION: Studies were included if the subjects suffered from a respiratory disease requiring airway clearance and the mean age of the sample was <18 years. After screening, nine articles remained for further analysis. RESULTS: Three of the nine articles examined patients with cystic fibrosis (CF). No significant differences in lung function or expectorated mucus were found compared to conventional chest physiotherapy. On the other hand, significant beneficial results were found for the treatment or prevention of atelectasis in non-CF patients using IPV. Similar results were seen when comparing therapies for neuromuscular/neurological patients. One study found that IPV reduced hospital stay and improved the clinical status of children with acute bronchiolitis compared to no physiotherapy. Severe adverse events did not occur in the included studies. CONCLUSION: A limited number of studies investigated IPV in the pediatric population. Despite the heterogeneity across the studies and the small sample sizes, the results seem promising. IPV is suggested to be a safe and effective alternative for airway clearance. Future research is required to confirm these results and to further analyze the possible benefits in different respiratory pathologies. PMID- 30019452 TI - Translational regulation in response to stress in Saccharomyces cerevisiae. AB - The budding yeast Saccharomyces cerevisiae must dynamically alter the composition of its proteome in order to respond to diverse stresses. The reprogramming of gene expression during stress typically involves initial global repression of protein synthesis, accompanied by the activation of stress-responsive mRNAs through both translational and transcriptional responses. The ability of specific mRNAs to counter the global translational repression is therefore crucial to the overall response to stress. Here we summarize the major repressive mechanisms and discuss mechanisms of translational activation in response to different stresses in S. cerevisiae. Taken together, a wide range of studies indicate that multiple elements act in concert to bring about appropriate translational responses. These include regulatory elements within mRNAs, altered mRNA interactions with RNA binding proteins and the specialization of ribosomes that each contribute towards regulating protein expression to suit the changing environmental conditions. PMID- 30019453 TI - Entrapment of "PV-Tracker" guidewire in the pulmonary veins during atrial fibrillation ablation with PVAC Gold. AB - We report the entrapment of Pulmonary Vein Ablation Catheter (Medtronic, Minneapolis, MN, USA) and its guidewire within the right pulmonary veins in two patients. The catheters could be retrieved without complications but they were disabled in both cases. This nondescribed incident should be recognized by PVAC users since it may be a source of potential severe complications during pulmonary vein isolation procedures. PMID- 30019454 TI - Neural processing of food cues in pre-pubertal children. AB - BACKGROUND/OBJECTIVES: Neuroimaging investigations of brain pathways involved in reward and motivation have primarily focused on adults. This study sought to identify brain responses to visual food cues and explore its relationships with adiposity and sex in pre-pubertal children. METHODS: Brain responses to palatable food vs. non-food cues were measured in 53 children (age: 8.18 +/- .66 years; sex: 22 boys, 31 girls) after an overnight fast. Whole-brain analysis (cluster correction Z > 2.3, P < .05) was performed to examine brain food cue reactivity and its relationships with adiposity and sex. RESULTS: Greater brain activity in response to food vs. non-food cues was observed in regions implicated in reward (orbital frontal cortex, striatum), taste (insula, postcentral gyrus), appetite (hypothalamus), emotion (amygdala), memory (hippocampus), visual processing (occipital cortex) and attention (parietal cortex). A negative association was found between percent body fat and food cue reactivity in the medial prefrontal cortex and lateral orbital frontal cortex adjusting for age and sex. Boys compared with girls had increased food cue reactivity in right hippocampus and visual cortex. CONCLUSIONS: These data suggest that body fat and sex are important moderators of brain food cue reactivity in children. PMID- 30019455 TI - Worker feedback on occupational skin disease awareness posters. PMID- 30019456 TI - Factors associated with professional identity, job satisfaction and burnout for occupational therapists working in eating disorders: A mixed methods study. AB - BACKGROUND: Occupational therapists employed within eating disorder services provide unique and valuable interventions. However, existing literature suggests that occupational therapists in this area may be at substantial risk of experiencing poor work-related wellbeing (e.g., high levels of burnout and low levels of job satisfaction). Despite these risks, no previous studies have explored the work-related experiences of occupational therapists in this specialist area of practice. OBJECTIVES: To explore challenges faced by occupational therapists working in eating disorders, their sense of professional identity, burnout and job satisfaction. METHOD: A mixed methods sequential design was adopted. Australian occupational therapists working in eating disorder services were invited to complete a survey exploring job challenges, burnout, professional identity and job satisfaction. Follow-up interviews were conducted and analysed using Braun and Clarke's method of thematic analysis. RESULTS: Ten occupational therapists (representing approximately 50% of the workforce in this specialist area in Australia) participated. There were strong correlations between challenges from the client group and exhaustion (a component of burnout), and moderate correlations between stronger professional identity, pressure to adopt generalist approaches and exhaustion. Qualitative analysis suggested job challenges arose from structural, personal and client-related sources, especially underutilisation of occupational therapy and pressure to adopt non-occupation based practices. Participants reported using strategies such as maintaining an occupation focus, supervision, professional interactions and maintaining work life balance to mitigate job stress. CONCLUSION: Occupational therapists working in eating disorders do face challenges. These are particularly related to the lack of evidence base for occupational therapy in this area. Future research should focus on developing further evidence for occupational therapy in eating disorders and designing outcome measures that capture improvements in daily functioning. These efforts would strengthen the role of occupational therapy and may reduce the risk of burnout and improve job satisfaction and sense of professional identity. PMID- 30019458 TI - A rare case of duplicated vas deferens discovered accidentally during varicocelectomy. AB - Congenital anomalies of the male urogenital tract include a variety of structural abnormalities. These abnormalities could affect either the male external genitalia, internal genitalia or both. Congenital anomalies of the vas deferens are rare and may include unilateral or bilateral (agenesis, atresia, duplication, ectopy or diverticulum) that could be complete or segmental. In addition, they may be isolated anomalies of the vas deferens or may be associated with other congenital anomalies elsewhere especially in the male urogenital tract. Those anomalies may be discovered during genital examination (either clinically or radiologically) or even during inguinal surgeries as in hernia repair, vasectomy, orchiopexy and varicocelectomy. Thus, proper evaluation should be made for the cases of duplicated vas deferens to avoid the accidental injury during the operation and to exclude other associated congenital anomalies. Besides that, the undiagnosed cases may lead to failure of vasectomy procedure. Here, we report a case of duplication of the vas deferens in a 33-year-old male that was accidentally discovered during spermatic cord dissection for varicocelectomy. PMID- 30019457 TI - Association of mood disorders with cardiovascular disease risk factors in overweight and obese youth with elevated blood pressure. AB - The American Heart Association defines mood disorders (MDO) as a tier-II cardiovascular disease risk factor in children. Cross-sectional analysis of overweight/obese children referred to an obesity hypertension clinic revealed 37% had a MDO (defined by clinical diagnosis or Patient Health Questionnaire-9/-A score >=10), 55% had confirmed hypertension, and 75% left ventricular hypertrophy (LVH). Children with MDOs were older, had greater measures of adiposity, and had a greater prevalence of hypertension (78%) than those without MDOs (42%; P = .04). Hypertensive children were 2.8 times more likely to have a MDO than those without (52% vs 18%; P = .02). Multivariable logistic regression revealed a statistically significant independent association of MDOs with hypertension (Odds Ratio [OR] 6.3, P = .048), but not LVH (LVMI >= 51 g/m2.7 ; OR 1.13, P = .88). Overall, the prevalence of MDOs in this group of overweight/obese children with elevated blood pressure was well above national averages, suggesting that at-risk youth, particularly those with confirmed hypertension, should be regularly screened for MDOs. PMID- 30019459 TI - Long noncoding RNA LINC00261 regulates endometrial carcinoma progression by modulating miRNA/FOXO1 expression. AB - : Long noncoding RNA LINC00261 was reported to be downregulated in multiple cancers. LINC00261 overexpression inhibits cancer cell proliferation, migration, and invasion. But the expression and function of LIN00261 in endometrial carcinoma are still elusive. We found that LINC00261 mRNA levels were downregulated in endometrial carcinoma, and LINC00261 overexpression inhibited endometrial carcinoma cell proliferation, migration, and invasion. miRNAs, including miR-182, miR-183, miR-153, miR-27a, and miR-96, were predicted to bind LINC00261 and FOXO1, and functioned to attenuate expression of LINC00261 and FOXO1. Overexpressed LINC00261 lowered these dissociative miRNAs, resulting in increase of FOXO1 protein levels. The knockdown of FOXO1 eliminated the suppression effect of overexpressed LINC00261 on endometrial carcinoma cell aggressiveness. LINC00261 promotes FOXO1 expression through reducing FOXO1 targeted miRNAs to suppress endometrial carcinoma cell proliferation, migration, and invasion. SIGNIFICANCE OF THE STUDY: LINC00261 is downregulated in endometrial carcinoma and associated with metastasis of this cancer. LINC00261 elevates FOXO1 protein levels through reducing FOXO1-targeted miRNAs to suppress endometrial carcinoma cell proliferation, migration, and invasion. PMID- 30019461 TI - 10th International Conference of Jordanian Society of Dermatology, Venereology, Dermatosurgery & Laser, Amman, Kingdom of Jordan. PMID- 30019460 TI - Switches of tyrosine-kinase inhibitors in chronic phase of chronic myeloid leukemia in real life. PMID- 30019462 TI - Key considerations for selecting instruments when evaluating healthcare professionals' evidence-based practice competencies: A discussion paper. AB - AIM: A discussion of key considerations related to selecting instruments and tools for evaluating healthcare professionals' evidence-based practice (EBP) competencies. DESIGN: A discussion paper. DATA SOURCES: Articles published in international peer-reviewed journals from January 2000 - November 2017 on validated instruments for assessing healthcare professionals' performance-based EBP competencies. IMPLICATIONS FOR NURSING: Validated EBP competency instruments based on actual performance to evaluate the EBP competencies of healthcare professionals are currently available in the field of medicine. Although some of these instruments have already been adapted for use in physical and occupational therapy, their modification for use in nursing has begun only in the last few months. CONCLUSION: A concerted effort on modifying and validating objective measures of actual performance for use in nursing should be commenced to evaluate directly measurable EBP competencies, instead of continuing to rely on nurses' self-assessments. Future studies focusing on development and validation of objective instruments to evaluate EBP competencies based on actual performance and exploring the modification of currently available objective instruments from medicine are urgently needed in nursing. IMPACT: Instead of measuring actual EBP competencies, the majority of competency evaluations in nursing are still being conducted via self-assessments, despite growing evidence of their poor accuracy in evaluating directly measurable constructs such as evidence-based practice knowledge and skills. Accurate measurement of nurses' EBP competencies is essential to increasing systematic implementation of EBP in healthcare organizations, thus promoting the attainment of improved care quality and patient outcomes in healthcare delivery. PMID- 30019463 TI - Continuation versus discontinuation of antiplatelet therapy for bleeding and ischaemic events in adults undergoing non-cardiac surgery. AB - BACKGROUND: Antiplatelet agents are recommended for people with myocardial infarction and acute coronary syndromes, transient ischaemic attack or stroke, and for those in whom coronary stents have been inserted. People who take antiplatelet agents are at increased risk of adverse events when undergoing non cardiac surgery because of these indications. However, taking antiplatelet therapy also introduces risk to the person undergoing surgery because the likelihood of bleeding is increased. Discontinuing antiplatelet therapy before surgery might reduce this risk but subsequently it might make thrombotic problems, such as myocardial infarction, more likely. OBJECTIVES: To compare the effects of continuation versus discontinuation for at least five days of antiplatelet therapy on the occurrence of bleeding and ischaemic events in adults undergoing non-cardiac surgery under general, spinal or regional anaesthesia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1), MEDLINE (1946 to January 2018), and Embase (1974 to January 2018). We searched clinical trials registers for ongoing studies, and conducted backward and forward citation searching of relevant articles. SELECTION CRITERIA: We included randomized controlled trials of adults who were taking single or dual antiplatelet therapy, for at least two weeks, and were scheduled for elective non-cardiac surgery. Included participants had at least one cardiac risk factor. We planned to include quasi-randomized studies.We excluded people scheduled for minor surgeries under local anaesthetic or sedation in which bleeding that required transfusion or additional surgery was unlikely. We included studies which compared perioperative continuation of antiplatelet therapy versus discontinuation of antiplatelet therapy or versus substitution of antiplatelet therapy with a placebo for at least five days before surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, assessed risk of bias and synthesized findings. Our primary outcomes were: all-cause mortality at longest follow-up (up to six months); all-cause mortality (up to 30 days). Secondary outcomes included: blood loss requiring transfusion of blood products; blood loss requiring further surgical intervention; risk of ischaemic events. We used GRADE to assess the quality of evidence for each outcome MAIN RESULTS: We included five RCTs with 666 randomized adults. We identified three ongoing studies.All study participants were scheduled for elective general surgery (including abdominal, urological, orthopaedic and gynaecological surgery) under general, spinal or regional anaesthesia. Studies compared continuation of single or dual antiplatelet therapy (aspirin or clopidogrel) with discontinuation of therapy for at least five days before surgery.Three studies reported adequate methods of randomization, and two reported methods to conceal allocation. Three studies were placebo-controlled trials and were at low risk of performance bias, and three studies reported adequate methods to blind outcome assessors to group allocation. Attrition was limited in four studies and two studies had reported prospective registration with clinical trial registers and were at low risk of selective outcome reporting bias.We reported mortality at two time points: the longest follow-up reported by study authors up to six months, and time point reported by study authors up to 30 days. Five studies reported mortality up to six months (of which four studies had a longest follow-up at 30 days, and one study at 90 days) and we found that either continuation or discontinuation of antiplatelet therapy may make little or no difference to mortality up to six months (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.34 to 4.27; 659 participants; low-certainty evidence); the absolute effect is three more deaths per 1000 with continuation of antiplatelets (ranging from eight fewer to 40 more). Combining the four studies with a longest follow-up at 30 days alone showed the same effect estimate, and we found that either continuation or discontinuation of antiplatelet therapy may make little or no difference to mortality at 30 days after surgery (RR 1.21, 95% CI 0.34 to 4.27; 616 participants; low-certainty evidence); the absolute effect is three more deaths per 1000 with continuation of antiplatelets (ranging from nine fewer to 42 more).We found that either continuation or discontinuation of antiplatelet therapy probably makes little or no difference in incidences of blood loss requiring transfusion (RR 1.37, 95% CI 0.83 to 2.26; 368 participants; absolute effect of 42 more participants per 1000 requiring transfusion in the continuation group, ranging from 19 fewer to 119 more; four studies; moderate-certainty evidence); and may make little or no difference in incidences of blood loss requiring additional surgery (RR 1.54, 95% CI 0.31 to 7.58; 368 participants; absolute effect of six more participants per 1000 requiring additional surgery in the continuation group, ranging from seven fewer to 71 more; four studies; low certainty evidence). We found that either continuation or discontinuation of antiplatelet therapy may make little or no difference to incidences of ischaemic events (to include peripheral ischaemia, cerebral infarction, and myocardial infarction) within 30 days of surgery (RR 0.67, 95% CI 0.25 to 1.77; 616 participants; absolute effect of 17 fewer participants per 1000 with an ischaemic event in the continuation group, ranging from 39 fewer to 40 more; four studies; low-certainty evidence).We used the GRADE approach to downgrade evidence for all outcomes owing to limited evidence from few studies. We noted a wide confidence in effect estimates for mortality at the end of follow-up and at 30 days, and for blood loss requiring transfusion which suggested imprecision. We noted visual differences in study results for ischaemic events which suggested inconsistency. AUTHORS' CONCLUSIONS: We found low-certainty evidence that either continuation or discontinuation of antiplatelet therapy before non-cardiac surgery may make little or no difference to mortality, bleeding requiring surgical intervention, or ischaemic events. We found moderate-certainty evidence that either continuation or discontinuation of antiplatelet therapy before non-cardiac surgery probably makes little or no difference to bleeding requiring transfusion. Evidence was limited to few studies with few participants, and with few events. The three ongoing studies may alter the conclusions of the review once published and assessed. PMID- 30019464 TI - Emergency department neuroimaging for epileptic seizures. AB - OBJECTIVE: To determine the frequency and yield of neuroimaging in patients with known seizure disorders presenting to the emergency department (ED) with recurrent (nonindex) seizures. METHODS: We reviewed 822 consecutive ED visits for nonindex seizures at the Oregon Health & Science University and the VA Portland Health Care System. For each visit, we abstracted details of the clinical presentation, whether neuroimaging was obtained, the results of neuroimaging, and the results of previous neuroimaging studies, when available. We determined whether ED neuroimaging led to an acute change in patient management (yield). Clinical factors associated with obtaining ED neuroimaging, and with the yield of neuroimaging, were evaluated by multivariate logistic regression. RESULTS: A majority (78%) of ED seizure visits were for nonindex seizures. Neuroimaging was obtained in 381 of 822 nonindex seizure visits (46%). Of these, 11 imaging studies (3%) led to an acute change in patient management, 8 (2%) after excluding false-positive scans. Acute head trauma, prolonged alteration of consciousness, and a focal neurologic examination at presentation were associated with an increased yield of ED neuroimaging. Absent any of these 3 clinical factors the true positive yield of neuroimaging was zero. SIGNIFICANCE: ED neuroimaging was performed in nearly half of all patients presenting with nonindex seizures. A more conservative use of ED neuroimaging for nonindex seizures, based on clinical factors at presentation, could decrease imaging frequency with minimal loss of yield. PMID- 30019465 TI - Maintenance of tight junction barrier integrity in cell turnover and skin diseases. AB - The skin forms a life-sustaining barrier between the organism and the physical environment. The physical barrier of the skin is mainly comprised of the stratum corneum (SC) and tight junctions (TJs). In recent years, there have been significant advances in our understanding of the epidermal TJ function, composition and regulation. In contrast to the SC, TJs are highly dynamic structures. It was discovered that spatiotemporal regulation of dynamic TJ replacement from cell to cell maintains the TJ barrier homeostasis of the skin, despite continuous cellular turnover. This review summarizes current knowledge about how TJ barrier homeostasis is maintained in simple and stratified epithelia, and how diseases and other conditions affect the TJ barrier in the skin. PMID- 30019466 TI - Trimetazidine suppresses oxidative stress, inhibits MMP-2 and MMP-9 expression, and prevents cardiac rupture in mice with myocardial infarction. AB - BACKGROUND/AIMS: Cardiac rupture (CR) is a catastrophic complication of acute myocardial infarction (MI). At present, there are no effective pharmacological strategies for preventing post-MI rupture. Here we investigated the effect of trimetazidine (TMZ) on post-MI CR. METHODS: MI models were induced by left coronary artery ligation in male C57BL/6 mice. Animals allocated to the rupture incidence were closely monitored for 7 days; autopsy was performed once animals were found dead to determine the reason of death. Heart function was detected by echocardiography. Oxidative stress markers and matrix metalloproteinases (MMPs) were analyzed by Western Blotting. RESULTS: TMZ markedly reduced the post-MI CR incidence of mice. We found that the expression of metalloproteinase (MMP) -2 and MMP-9 in the TMZ-treated group was significantly lower than the saline-treated group. Further, TMZ markedly attenuated MI-induced oxidative stress. To investigate the mechanism of the effect of TMZ on CR, we pretreated H9c2 cells with H2 O2 and found that TMZ treatment markedly decreased H2 O2 -induced MMP-2 and MMP-9 expression. TMZ prevents CR through inhibition of oxidative stress, which is attributable to the down-regulation of MMP-2, MMP-9 expression. CONCLUSIONS: Our findings indicate that TMZ suppresses oxidative stress, inhibits MMP-2 and MMP-9 expression, and prevents CR in mice with MI. PMID- 30019468 TI - Setting off firecrackers: An economic way to release inner stress for patients with depression. AB - PURPOSE: To advocate an economic way to release inner stress for patients with depression. CONCLUSIONS: Setting off firecrackers has psychological value. It is not merely for fun, but is more an economic and easy behavioral therapy in psychiatric care, even risking a little bit noise and air pollution, especially for patients with depression. PRACTICE IMPLICATIONS: In routine psychiatric care practice, patient with depression were encouraged to set off firecrackers to release their stress. PMID- 30019467 TI - Management of patients with advanced prostate cancer in the Asia Pacific region: 'real-world' consideration of results from the Advanced Prostate Cancer Consensus Conference (APCCC) 2017. AB - OBJECTIVE: The Asia Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2018) brought together 20 experts from 15 APAC countries to discuss the real-world application of consensus statements from the second APCCC held in St Gallen in 2017 (APCCC 2017). FINDINGS: Differences in genetics, environment, lifestyle, diet and culture are all likely to influence the management of advanced prostate cancer in the APAC region when compared with the rest of the world. When considering the strong APCCC 2017 recommendation for the use of upfront docetaxel in metastatic castration-naive prostate cancer, the panel noted possible increased toxicity in Asian men receiving docetaxel, which would affect this recommendation in the APAC region. Although androgen receptor-targeting agents appear to be well tolerated in Asian men with metastatic castration resistant prostate cancer, access to these drugs is very limited for financial reasons across the region. The meeting highlighted that cost and access to contemporary treatments and technologies are key factors influencing therapeutic decision-making in the APAC region. Whilst lower cost/older treatments and technologies may be an option, issues of culture and patient or physician preference mean, these may not always be acceptable. Although generic products can reduce cost in some countries, costs may still be prohibitive for lower income patients or communities. The panellists noted the opportunity for a coordinated approach across the APAC region to address issues of access and cost. Developments in technologies and treatments are presenting new opportunities for the diagnosis and treatment of advanced prostate cancer. Differences in genetics and epidemiology affect the side-effect profiles of some drugs and influence prescribing. CONCLUSIONS: As the field continues to evolve, collaboration across the APAC region will be important to facilitate relevant research and collection and appraisal of data relevant to APAC populations. In the meantime, the APAC APCCC 2018 meeting highlighted the critical importance of a multidisciplinary team-based approach to treatment planning and care, delivery of best-practice care by clinicians with appropriate expertise, and the importance of patient information and support for informed patient choice. PMID- 30019469 TI - Incidence and outcome of Guillain-Barre syndrome in Iceland: A population-based study. AB - OBJECTIVE: In this study, we determine the incidence and outcomes of Guillain Barre syndrome (GBS) in Iceland over a 20-year period. METHOD: Cases were identified from the records of both referral hospitals in the country. All cases met the Brighton Criteria for GBS. Disability was assessed at diagnosis, peak of symptoms, discharge, and follow-up using the Guillain-Barre Disability Scale. RESULTS: Sixty-three individuals fulfilled the diagnostic criteria with an average age of onset of 46 years (range 1-89 years) and a male:female ratio of 1. The average annual incidence was 1.1 per 100 000 person-years. Nerve conduction studies were consistent with demyelinating polyneuropathy in 87% of cases, acute motor axonal neuropathy (AMAN) in 4%, and were normal in 9%. Treatment was received by 89% of patients and included IVIG (84%), plasmapheresis (8%), or both treatments (3%). Mechanical ventilation was required by 22% of patients. Long term follow-up with an average length of 6.5 years was available for 98% of patients, and the average GBS disability score at follow-up was 0.9. Four deaths related to GBS (6%) were observed. CONCLUSION: We believe we have identified all patients diagnosed with GBS in Iceland during the study period, with an incidence comparable to recent studies from well-defined populations around the world. Our reported mortality is similar to or higher than other population-based studies. At follow-up, 13% of patients still required a walking aid, but most survivors (74%) had minor or no symptoms. PMID- 30019470 TI - Malaria in pregnancy shapes the development of foetal and infant immunity. AB - Malaria, particularly Plasmodium falciparum, continues to disproportionately affect pregnant women. In addition to the profoundly deleterious impact of maternal malaria on the health of the mother and foetus, malaria infection in pregnancy has been shown to affect the development of the foetal and infant immune system and may alter the risk of malaria and nonmalarial outcomes during infancy. This review summarizes our current understanding of how malaria infection in pregnancy shapes the protective components of the maternal immune system transferred to the foetus and how foetal exposure to parasite antigens impacts the development of foetal and infant immunity. It also reviews existing evidence linking malaria infection in pregnancy to malaria and nonmalarial outcomes in infancy and how preventing malaria in pregnancy may alter these outcomes. A better understanding of the consequences of malaria infection in pregnancy on the development of foetal and infant immunity will inform control strategies, including intermittent preventive treatment in pregnancy and vaccine development. PMID- 30019471 TI - Profiling of Hura crepitans L. latex by ultra-high-performance liquid chromatography/atmospheric pressure chemical ionisation linear ion trap Orbitrap mass spectrometry. AB - INTRODUCTION: The phytochemistry of the latex of Hura crepitans L. (Euphorbiaceae), a widespread tree in the Amazonian forest having many uses, is little known. Only huratoxin, a daphnane diterpene orthoester, has been described despite the high pharmacological potential of this kind of compounds. Glucosphingolipids (cerebrosides) are also known to be distributed in Euphorbiaceae latexes. OBJECTIVE: To tentatively identify daphnanes diterpenes and cerebrosides in the latex of H. crepitans. METHODS: An ethanolic extract of the lyophilised latex of H. crepitans was analysed by ultra-high-performance liquid chromatography (UHPLC) coupled with positive and negative atmospheric pressure chemical ionisation high-resolution mass spectrometry (APCI-HRMS) method using a quadrupole/linear ion trap/Orbitrap (LTQ-Orbitrap). Tandem mass spectrometry (MS/MS) spectra were recorded by two different fragmentation modes: collision induced dissociation (CID) and higher-energy collisional dissociation (HCD). RESULTS: The analysis of CID- and HCD-MS/MS spectra allowed to propose fragmentation patterns for daphnane esters and cerebrosides and highlight diagnostic ions in positive and negative ion modes. A total of 34 compounds including 24 daphnane esters and 10 cerebrosides have been tentatively annotated. Among them, 17 daphnane diterpenes bearing one or two acyl chains are new compounds and the cerebrosides are described in the genus Hura for the first time. CONCLUSION: This study revealed the chemical constituents of the latex of H. crepitans and particularly its richness and chemical diversity in daphnane diterpenes, more frequently encountered in the species of Thymelaeaceae. PMID- 30019472 TI - A translational analysis of ABA and ABC renewal of operant behavior. AB - Following reduction, behavior may recur when organisms are exposed to new or different environments. Such recurrences, called treatment relapse, are characterized by an increase of a previously reduced behavior. Renewal is a type of treatment relapse resulting from changes in stimulus contexts despite the ongoing maintenance of treatment. Renewal types include varying arrangements, such as ABA and ABC renewal, where each letter represents a different context. In the present series of translational analyses, we evaluated both ABA and ABC renewal and assessed whether these two renewal arrangements may be present in a single participant's behavior. Results produced evidence of both ABA and ABC renewal, and both types of renewal were detected in an individual participant's behavior. PMID- 30019473 TI - Neural mechanisms of sensorimotor transformation and action selection. AB - Ray Guillery made major contributions to our understanding of the development and function of the brain. One of his principal conceptual insights, developed together with Murray Sherman [S.M. Sherman & R.W. Guillery (2001) Exploring the Thalamus. Elsevier, Amstrerdam; S. Sherman & R. Guillery (2006) Exploring the Thalamus and Its Role in Cortical Functioning. Academic Press, New York, NY; S.M. Sherman & R.W. Guillery (2013) Functional Connections of Cortical Areas: A New View from the Thalamus. MIT Press, Cambridge, MA and then in his last book (R. Guillery (2017) The Brain as a Tool: A Neuroscientist's Account. Oxford University Press, Oxford, UK)], was that the brain is a 'tool' to understand the world. In this view, the brain does not passively process sensory information and use the result to inform motor outputs. Rather, sensory and motor signals are widely broadcast and inextricably linked, with ongoing sensorimotor transformations serving as the basis for interaction with the outside world. Here, we describe recent studies from our laboratory and others which demonstrate this astute framing of the link among sensation, perception, and action postulated by Guillery and others [G. Deco & E.T. Rolls (2005) Prog Neurobiol, 76, 236-256; P. Cisek & J.F. Kalaska (2010) Annu Rev Neurosci, 33, 269-298]. Guillery situated his understanding in the deeply intertwined relationship between the thalamus and cortex, and importantly in the feedback from cortex to thalamus which in turn influences feed-forward drive to cortex [S.M. Sherman & R.W. Guillery (2001) Exploring the Thalamus. Elsevier, Amstrerdam; S. Sherman & R. Guillery (2006) Exploring the Thalamus and Its Role in Cortical Functioning. Academic Press, New York, NY]. We extend these observations to argue that brain mechanisms for sensorimotor transformations involve cortical and subcortical circuits that create internal models as a substrate for action, that a key role of sensory inputs is to update such models, and that a major function of sensorimotor processing underlying cognition is to enable action selection and execution. PMID- 30019475 TI - Characteristics and Treatment of Chronic Chikungunya Virus: Comment on the Article by Chang et al. PMID- 30019474 TI - Hyaluronic acid filler for skin rejuvenation: The role of diet on outcomes. A pilot study. PMID- 30019476 TI - Recent Advances in the Design of Targeted Iridium(III) Photosensitizers for Photodynamic Therapy. AB - Photodynamic therapy (PDT) is a noninvasive treatment for certain types of cancer, bacterial, fungal and viral infections, and skin diseases. In recent years, adaptation of this treatment so as to achieve more specific targeted cancer therapy in particular has attracted significant attention. We focus herein on the design of novel iridium-based photosensitizers (PSs) with tunable photophysical and photobiological properties as efficient PDT agents. We highlight the ability of some IrIII photosensitizers to target specific cellular components, including their activation by one- and two-photon irradiation. PMID- 30019477 TI - Relationships between leadership, structural empowerment, and engagement in nurses. AB - AIM: The aim of this study was to analyse the relationships among structural empowerment, the leadership style of managers, and the engagement of nurses in a health organization of Spain. BACKGROUND: Transformational leadership has an impact on patient security and satisfaction as well as the well-being and engagement of healthcare workers. Empowerment is a management practice that is fundamental for professional growth and positively affects the quality of patient care. DESIGN: A cross-sectional study. METHODS: Randomized sample of 131 nurses recruited from 11 health centres with different levels of care was surveyed to assess managers' leadership style, nurse empowerment, and work engagement. The data were analysed by descriptive and correlational statistics and hierarchical mediated regression. RESULTS: The transformational leadership of the nurse manager directly and positively influences the structural empowerment of nurses. The structural empowerment of nurses directly and positively influences engagement. The transformational leadership of managers positively influences nurse engagement through the mediating effect of structural empowerment. CONCLUSION: The structural empowerment of nurses acts as a mediator between the transformational leadership of nurse managers and nurse engagement. PRACTICAL IMPLICATION: The transformational leadership of nurse managers at the unit level has a double impact on staff nurses: first, increasing empowerment and second, increasing the engagement of the nurse staff. PMID- 30019478 TI - Has Access to HCV Therapy Changed for Patients with Mental Health or Substance Use Disorders in the DAA Period? AB - BACKGROUND: Direct-acting antivirals (DAA) for hepatitis C virus (HCV) became available in 2014, but the role of mental health or substance use disorders (MH/SUD) on access to treatment is unknown. OBJECTIVE: To examine extent and predictors of HCV treatment in the pre-DAA and post-DAA periods in 4 large, diverse health care settings in the United States (US). METHODS: Retrospective analysis of 29,544 adults with chronic HCV who did or did not receive treatment from 1/1/11-2/28/17. Kaplan Meier curve was used to examine cumulative risk for receiving HCV treatment stratified by MH/SUD. Predictors of HCV treatment in the pre-DAA (1/1/11-12/31/13) and post-DAA (1/1/14-2/28/17) cohorts were analyzed using multivariate generalized estimating equations (GEE) and a modified Poisson models. RESULTS: Overall 21.7% (2,879/13,240) of those with chronic HCV post-DAA were treated compared to 3.5% (574/16,304) in the pre-DAA period. Compared to non Hispanic Whites, Hispanic Whites (AOR 0.36, 95% CI: 0.25, 0.52) were less likely to be treated in the post-DAA period. Those with concurrent nonalcoholic fatty liver disease (AOR 1.39, 95% CI: 1.05, 1.83), cirrhosis (AOR 2.00, 95% CI: 1.74, 2.31), and liver transplant (AOR 2.72, 95% CI: 1.87, 3.94) were more likely to be treated post-DAA. Those with MH/SUD were less likely to be treated both before (AOR 0.46, 95% CI: 0.36, 0.60) and after (AOR 0.63, 95% CI:0.55,0.71) DAA therapy was available. Overall, the cumulative risk for receiving HCV treatment from 2011 17 among those with vs. without MH/SUD was 13.6% vs. 21.6%, respectively, (P <0.001). CONCLUSIONS: The volume of patients treated for HCV has increased in the post-DAA period especially among those with liver-related co-morbidities, but disparities in access to treatment continue among those with MH/SUD. This article is protected by copyright. All rights reserved. PMID- 30019480 TI - Paternal lifestyle factors in relation to semen quality and in vitro reproductive outcomes. AB - This prospective-cohort study aimed at investigating the influence of paternal lifestyle factors on semen parameters and intracytoplasmic sperm injection (ICSI) outcomes. The influence of paternal lifestyle factors on seminal quality and ICSI outcomes was investigated in male patients undergoing conventional semen analysis. Cigarette smoking negatively influenced semen volume (B: -0.417, slope: 1.570, p = 0.047), sperm count/ml (B: -7.363, slope: 52.298, p = 0.014), total sperm count (B: -4.43, slope: 178.165, p = 0.023), total motile sperm count (B: 1.38, slope: 100.276, p = 0.045) and SDF (B: 0.014, slope: 9.767, p = 0.033). Alcohol consumption negatively influenced sperm count/ml (B: -12.527, slope: 42.255, p = 0.040) and sperm DNA fragmentation (B: 5.833, slope: 9.680, p = 0.002). There were no significant influences of other paternal lifestyle factors. Cigarette smoking negatively influenced the fertilisation rate (B: -1.349, slope: 21.950, p = 0.039) and the blastocyst formation rate (B: -14.244, slope: 28.851, p = 0.025). Alcohol consumption negatively influenced fertilisation rate (B: 3.617, slope: 20.138, p = 0.041) and blastocyst formation rate (B: -34.801, slope: 30.044, p = 0.042). Cigarette smoking and alcohol consumption appear to reduce semen quality, fertilisation and blastocyst formation rates; thus, it would be wise to recommend that male partners reconsider their lifestyle during in vitro reproduction treatment. PMID- 30019479 TI - Perception scores of siblings and parents of children with hypoplastic left heart syndrome. AB - OBJECTIVES: Siblings of children with chronic medical conditions endorse a lower quality of life compared to age-matched peers. Caregiver and sibling-self report of adjustment are often discordant. Congenital heart disease significantly affects family life. To date, there have been no studies addressing the functioning of siblings of children with hypoplastic left heart syndrome, one of the most severe forms of congenital heart disease. The goal of this study was to assess the impact of hypoplastic left heart syndrome on sibling's quality of life as well as the caregiver's perception of this effect. STUDY DESIGN: Cross sectional study using a web-based survey distributed via various listservs targeted towards families of children with hypoplastic left heart syndrome. Employed the Sibling Perception Questionnaire, designed to assess sibling and caregiver perceptions of adjustment to chronic illness. A Negative Adjustment Composite Score was calculated for each respondent, with higher values representing more negative adjustment. RESULTS: Thirty-five caregivers responded. Majority of caregivers were female (74%), white (86%) and college educated (54%). Thirty-two siblings participated, ranging in age from 7 to 30 years of age (12.5 +/- 6.3). Most children with hypoplastic left heart syndrome (73%) had undergone the third stage of palliation. Forty-two caregiver-sibling pairs were examined. Caregiver Negative Adjustment Composite Scores were significantly higher than sibling scores, with caregivers reporting more adjustment problems (2.4 +/- 0.4) than siblings (2.3 +/- 0.3, P < .05). Sibling age was correlated with worse caregiver and sibling scores (r 0.35, P < .05). CONCLUSIONS: Caregivers of children with hypoplastic left heart syndrome perceive their siblings as struggling more than the children self-report. Siblings tend to report worse adjustment as they get older. These data suggest that programs should include support for the entire family through all ages to optimize quality of life. PMID- 30019481 TI - Crystal structure of plasma kallikrein reveals the unusual flexibility of the S1 pocket triggered by Glu217. AB - : Serine proteases play important roles in numerous physiological and pathophysiological processes. Moreover, serine proteases are classical subjects for studies of catalytic and inhibitory mechanisms of enzymes. Here, we determined the crystal structures of a serine protease, murine plasma kallikrein (mPK), and its complex with a peptidic inhibitor. Although mPK in the complex adopts a canonical protease structure, the apo-mPK exhibits a previously unobserved structural feature: the entrance of the intact S1 pocket is blocked by Glu217. In addition, molecular dynamics simulations and functional assays support the flexibility of Glu217 and suggest that this flexibility plays a role in regulating the activity of serine proteases. ENZYMES: EC: 3.4.21.34. PMID- 30019482 TI - Quantitative Analysis of Surface Electromyography for Pediatric Neuromuscular Disorders. AB - INTRODUCTION: Needle electromyography (EMG) has been an important diagnostic tool, although discomfort may limit its use in some children. We investigated the diagnostic utility of the clustering index (CI) method, a quantitative analysis for surface EMG (SEMG), in children. METHODS: SEMG was recorded from the tibialis anterior muscle. Discriminant analysis between patients with neurogenic disorders and patients with myopathy was performed for whole epochs by using the CI and area values. RESULTS: Forty-five children (29 with myopathy, 16 with neurogenic disorders; age 9 +/- 3.9 years) were enrolled. The mean discriminant function value of the neurogenic group was 0.58 +/- 0.88 (-0.48-2.30), whereas that of the myopathic group was -0.55 +/- 0.70 (-2.38-0.68). When the cutoff value was set at the limit of the other group, 17 of 29 children with myopathy and 7 of 16 children with neurogenic disorders were correctly classified. DISCUSSION: The CI method can be a useful noninvasive diagnostic tool in children with neuromuscular disorders. Muscle Nerve, 2018. PMID- 30019483 TI - Identification of spoilage by Alicyclobacillus bacteria in tomato-based products by UHPLC-MS/MS. AB - In recent years, there have been some cases of alteration of tomato derivatives by Alicyclobacilli spp. The spoilage was reported by consumers who felt odors and abnormal tastes ("bad") of products. In this work, an untarget approach with Q ExactiveTM Quadrupole-Orbitrap Mass Spectrometer has been used to identify metabolites associated with the alteration of tomato puree by Alicyclobacillus bacteria. The study was carried out on tomato puree found positive for the presence of Alicyclobacillus spores. The germination and growth of native spores were induced through incubation at 65 degrees C under static conditions for 5 days. For microbial concentration below 100 ufc/mL, negative growth was considered. The samples arising from incubation were submitted to UHPL-HRMS/MS analysis. To find compounds related to microbial growth, data obtained by UHPLC MS/MS analysis were processed with Thermo Fisher Compound DiscovererTM 2.0 software. We compared samples grouped according to microbial growth: positive growth vs negative growth. Five compounds were identified and confirmed by analysis performed on authentic standards. To other compounds, we have assigned a putative identity. The HRMS approach using Q-ExactiveTM Quadrupole-Orbitrap Mass Spectrometer has proven to be an important and powerful tool for identification of compounds which could be used as marker molecules in cases of suspected spoilage by Alicyclobacillus bacteria in tomato derivatives. PMID- 30019485 TI - Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin via ERK1/2 and mTOR pathways in vitro and in vivo. AB - Psoriasis is a chronic inflammatory disease, affecting more than millions of people in the world. Recently, the mTOR inhibitor rapamycin (RAPA) was reported to be involved in the pathogenesis of psoriasis. However, the underlying mechanism remains unclear. Haematoxylin and eosin staining was used to examine the effects of RAPA on inflammatory level of lesional tissues from patients with psoriasis and animal models. Quantitative real-time PCR, immunohistochemistry and western blot assay were performed to assess the effects of RAPA on tropomyosins (TPMs) expression in patients with psoriasis, cell models and animal models. Phalloidin staining was used to assess the RAPA effects on cell skeleton. The effects of RAPA on cell proliferation and cell cycle were detected by CCK-8 assay, EdU staining and flow cytometry. Methylation status of TPMs was analysed by methylation-specific PCR. The expression of TPM1 and TPM2 was significantly downregulated, while their methylation level was obviously higher in the lesional tissues, cell models and animal models of psoriasis. After treated with RAPA, the expression and methylation levels of TPMs were all restored in the cell models and animal models of psoriasis. RAPA inhibited cell proliferation and decreased the ratio of S phase cell in Hacat or human epidermal keratinocytes cell models of psoriasis. Finally, the activated ERK1/2 and mTOR pathways in the cell model and animal model of psoriasis were suppressed by the treatment of RAPA. RAPA could be used as an effective agent for the treatment of psoriasis by decreasing the methylation level of TPM1 and TPM2 via inhibiting the ERK1/2 and mTOR signalling pathways. PMID- 30019484 TI - Comparative effectiveness of management options for patients with small renal masses: a prospective cohort study. AB - OBJECTIVES: To explore the comparative effectiveness of partial nephrectomy (PN), radical nephrectomy (RN), ablative therapies (ablation) and active surveillance (AS) for small renal masses (SRMs; tumour diameter <=4.0 cm) in the domains of survival, renal function and quality of life (QoL) using the prospectively maintained Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry. PATIENTS AND METHODS: Estimated glomerular filtration rate (eGFR) was calculated from creatinine values to determine renal function. QoL was measured using the Short Form 12 (SF-12) questionnaire. The Kaplan-Meier method and Cox proportional hazards regression were used for survival analysis. The mixed effects model was used for renal function and QoL analysis. RESULTS: Of 638 patients, 231 (36.2%) chose PN, 41 (6.4%) RN, 27 (4.2%) ablation and 339 (53.1%) AS. Cancer-specific survival at 7 years was 98.8% in PN patients and 100% in all other groups. Overall survival (OS) at 7 years was 87.9%, 90.2%, 83.5% and 66.1% in PN, RN, ablation and AS patients, respectively. The OS rate was significantly worse in the AS group than other groups and likely attributable to older age and increased comorbidities. The eGFR was lowest in RN patients but comparable in all other groups. QoL was lowest in AS patients due to lower physical health scores, but mental health scores were similar in all groups. CONCLUSIONS: With excellent oncological outcomes in all groups, nephron-sparing approaches, like PN and ablation, are preferred over RN when intervention is indicated for SRMs. AS is a reasonable option for select patients, given the comparable oncological and mental health outcomes. PMID- 30019487 TI - Serotonin transporter (5-HTTLPR) genotypes and trinucleotide repeats of androgen receptor exert a combinatorial effect on hormonal milieu in patients with lifelong premature ejaculation. AB - Premature ejaculation is one of the most common sexual disorders in men due to uncontrolled modulation of spinal reflexes controlled by cortico-limbic centers in the brain. In this study, we investigate the combinatorial effects of trinucleotide repeats of androgen receptor and allelic variants of the 5-HTTLPR gene on sex steroids, hypophyseal hormones, sexual performance, and premature ejaculation assessment parameters among evidence-based lifelong premature ejaculation subjects. A total of 271 outpatients (age 26.6 +/- 1.9) consulting for evidence-based lifelong premature ejaculatory dysfunction were selected in this study. The control group consists of 155 men with normal IELT (>4 min). The study revealed that the subjects who have the highest (>=26) CAG stretches depicted a significantly higher serum oxytocin levels (102.1 pg/ml; n = 126, p < 0.001) compared with the control group (71.2 pg/ml; n = 75, p = <0.001) and patients which have medium (22-25) and short (<=21) CAG stretches (76.63 ng/ml; n = 64, p < 0.001 vs. 77.4 ng/ml; n = 81, p < 0.001). Almost 33 (26.1%) lifelong premature ejaculatory patients had AR variant of longer (>=26) CAG repeats was homozygous for S alleles (SS), 45 (35.7%) was homozygous for L allele (LL), and 48 (38%) had the L/S or S/L genotype of 5-HTTLPR gene. Homozygous (SS) alleles have a significant positive correlation (r = 0.44, p < 0.0001) with the high score of BDI-II (39.1, n = 126, p < 0.001). However, LL alleles have shown a significant positive correlation with PEDT (r = 0.46, p < 0.001) and negative correlation with self-estimated IELT and intercourse satisfaction (r = -0.35, p < 0.001). The innovative study design elaborates that androgen receptor trinucleotide repeats and 5-HTTLPR genotypes have combinatorial impact on hormonal milieu and sexual function regarding evidence-based lifelong premature ejaculatory dysfunction patients. PMID- 30019486 TI - Social media in nursing and midwifery education: A mixed study systematic review. AB - AIM: To synthesize evidence on the effectiveness of social media in nursing and midwifery education. BACKGROUND: Social media are being explored to see if these online tools can support teaching, learning, and assessment. DESIGN: A mixed study systematic review. DATA SOURCES: A systematic search of PubMed, MEDLINE, CINAHL, Scopus, and ERIC was run in January 2016. An updated search was run in June 2017. No date limits were applied. METHODS: Titles, abstracts, and full papers were screened against inclusion criteria by two independent reviewers, who extracted and quality assessed data. Synthesis followed a sequential explanatory approach. RESULTS: Twelve studies were included. Social media seemed to support students to acquire new knowledge and skills. The learning process centred on the interactive nature of the platforms which allow information to be dynamically shared and discussed in near real time. The characteristics of social media enabled social support and a more student-centred setting, which appeared to enhance collaborative learning, although information quality was sometimes problematic. Learning via social media was underpinned by how well the educational interventions were organized, digital literacy and e-Professionalism of students and faculty, the accessibility of the online applications, and personal motivation. CONCLUSION: This review provides the first rigorous synthesis of social media in nursing and midwifery education. A new Social Media Learning Model was conceptualized to aid our understanding of learning via this technology. Knowledge gaps are identified and recommendations on how to capitalize on social media to improve learning in higher and continuing education provided. PMID- 30019488 TI - Hepatitis B therapy as HIV prevention in Africa: a case series from Zambia. AB - In East and Southern Africa, where 5-10% have chronic hepatitis B virus (HBV) infection, incidence of human immunodeficiency virus (HIV) infection remains unacceptably high. This introduces challenges and opportunities for implementation of HBV care and treatment. We now describe new HIV diagnoses made within an HBV monoinfection cohort in Zambia and their relevance to broader HBV policy implementation. This article is protected by copyright. All rights reserved. PMID- 30019490 TI - The 13th International Pan Arab League of Dermatology Conference Held Jointly with the Ninth Dermopolitan Congress Jordan at the Dead Sea, Jordan. PMID- 30019489 TI - Changes in ganglioside GM1 expression in glaucomic retina. PMID- 30019491 TI - The fragmented QRS and epsilon wave in arrhythmogenic right ventricular dysplasia: Does before-and-after the end of the QRS complex matter? PMID- 30019492 TI - Temporomandibular disorder symptoms and their association with quality of life, emotional states and sleep quality in South-East Asian youths. AB - Population studies on the prevalence of temporomandibular disorders (TMD) and their associations with quality of life (QoL), emotional states and sleep quality in South-East Asian youths are not available. This cross-sectional study assessed the presence of TMD and their relationships to QoL, depression, anxiety, stress and sleep quality in a cohort of South-East Asian adolescents/young adults. Three hundred and sixty-two students from a polytechnic were enrolled in the study and completed an online questionnaire consisting of the Fonesca's Anamnestic Index (FAI), Oral Health Impact Profile for TMD (OHIP-TMD), Depression, Anxiety and Stress Scales-21 (DASS-21) and Pittsburgh Sleep Quality Index. The FAI appraises TMD severity while OHIP-TMD determines the effect of TMD on oral health-related QoL. Statistical analysis was performed using chi-square test for categorical data whilst one-way ANOVA/post hoc Bonferroni's tests were employed for numerical scores (P < 0.05). Of the 244 participants who completed the questionnaires in their entirety (37 males; 207 females, mean age 20.1 +/- 3.2 years), 32.4% had mild TMD, 9.4% had moderate TMD and 58.2% were TMD free. The total prevalence of TMD was 41.8% (n = 102) and most OHIP-TMD domains including functional limitation (P = 0.000), physical pain (P = 0.000), handicapped (P = 0.000) and psychological discomfort (P = 0.001) showed significant differences in mean scores depending on TMD severity. A similar trend was observed for DASS-21. The majority of participants with TMD (69.6%; n = 71) had poor sleep quality (P = 0.004). TMD appear to be prevalent in South-East Asian youths with varying severity. Severity of TMD had some bearing on QoL, emotional states as well as sleep quality. PMID- 30019494 TI - Strong cytoskeleton activity on millisecond timescales upon particle binding revealed by ROCS microscopy. AB - Cells change their shape within seconds, cellular protrusions even on subsecond timescales enabling various responses to stimuli of approaching bacteria, viruses or pharmaceutical drugs. Typical response patterns are governed by a complex reorganization of the actin cortex, where single filaments and molecules act on even faster timescales. These dynamics have remained mostly invisible due to a superposition of slow and fast motions, but also due to a lack of adequate imaging technology. Whereas fluorescence techniques require too long integration times, novel coherent techniques such as ROCS microscopy can achieve sufficiently high spatiotemporal resolution. ROCS uses rotating back-scattered laser light from cellular structures and generates a consistently high image contrast at 150 nm resolution and frame rates of 100 Hz-without fluorescence or bleaching. Here, we present an extension of ROCS microscopy that exploits the principles of dynamic light scattering for precise localization, visualization and quantification of the cytoskeleton activity of mouse macrophages. The locally observed structural reorganization processes, encoded by dynamic speckle patterns, occur upon distinct mechanical stimuli, such as soft contacts with optically trapped beads. We find that a substantial amount of the near-membrane cytoskeleton activity takes place on millisecond timescales, which is much faster than reported ever before. PMID- 30019495 TI - Temporal information in tones, broadband noise, and natural vocalizations is conveyed by differential spiking responses in the superior paraolivary nucleus. AB - Communication sounds across all mammals consist of multiple frequencies repeated in sequence. The onset and offset of vocalizations are potentially important cues for recognizing distinct units, such as phonemes and syllables, which are needed to perceive meaningful communication. The superior paraolivary nucleus (SPON) in the auditory brainstem has been implicated in the processing of rhythmic sounds. Here, we compared how best frequency tones (BFTs), broadband noise (BBN), and natural mouse calls elicit onset and offset spiking in the mouse SPON. The results demonstrate that onset spiking typically occurs in response to BBN, but not BFT stimulation, while spiking at the sound offset occurs for both stimulus types. This effect of stimulus bandwidth on spiking is consistent with two of the established inputs to the SPON from the octopus cells (onset spiking) and medial nucleus of the trapezoid body (offset spiking). Natural mouse calls elicit two main spiking peaks. The first spiking peak, which is weak or absent with BFT stimulation, occurs most consistently during the call envelope, while the second spiking peak occurs at the call offset. This suggests that the combined spiking activity in the SPON elicited by vocalizations reflects the entire envelope, that is, the coarse amplitude waveform. Since the output from the SPON is purely inhibitory, it is speculated that, at the level of the inferior colliculus, the broadly tuned first peak may improve the signal-to-noise ratio of the subsequent, more call frequency-specific peak. Thus, the SPON may provide a dual inhibition mechanism for tracking phonetic boundaries in social-vocal communication. PMID- 30019493 TI - Angiotensin converting enzyme inhibitors and interstage failure in infants with hypoplastic left heart syndrome. AB - INTRODUCTION: Angiotensin converting enzyme inhibitors are commonly prescribed medications after the Norwood procedure. There are little data that can be used to determine if angiotensin converting enzyme inhibitors improve interstage outcomes in children with single ventricle defects. The objective of this study was to investigate the relationship between angiotensin converting enzyme inhibitors and interstage failure among infants born with hypoplastic left heart syndrome. METHODS: We conducted a retrospective cohort study using data from the National Pediatric Cardiology Quality Improvement Collaborative database (collected between 2008 and 2015). We used logistic regression models to assess the exposure-outcome associations and propensity score matching to account for differences in baseline patient characteristics associated with use of angiotensin converting enzyme inhibitors. RESULTS: A total of 1 487 neonates participated in the study. Thirty-nine percent of patients were prescribed angiotensin converting enzyme inhibitors after the Norwood procedure; 11% experienced interstage failure (death, heart transplantation, and not being a candidate for the second-stage surgery). Before propensity score matching, patients receiving angiotensin converting enzyme inhibitors were significantly more likely to experience interstage failure, compared to patients not on angiotensin converting enzyme inhibitors (OR = 1.44; 95% CI: 1.04, 1.99; P = 0.03). Although there was an increased odds of interstage failure among patients receiving angiotensin converting enzyme inhibitors compared to patients not receiving angiotensin converting enzyme inhibitors in the propensity score matched cohort, this association was not significantly different (adjusted OR = 1.29; 95% CI: 0.88, 1.95; P = 0.18). CONCLUSION: Angiotensin converting enzyme inhibitor therapy did not demonstrate a beneficial effect on interstage failure among infants with hypoplastic left heart syndrome, even when patient characteristics associated with the use of angiotensin converting enzyme inhibitors were considered. PMID- 30019496 TI - Determinants of organ donation registration. AB - Rates of organ donor registration range from 20% to 60% throughout the United States. The purpose of this study was to examine sociogeographic differences in organ donor registration rates throughout Missouri to identify varying patterns The organ donor registration rate from each Department of Motor Vehicle office in Missouri was extracted from the National Organ Registration database, office locations were geocoded, and census tract level sociodemographic characteristics were extracted. Spatial regression analyses were conducted to identify relationships between location of DMV offices and census tract-level concentrated disadvantage. Census tract-level concentrated disadvantage (education attainment, poverty, single-headed households) had a significant negative relationship with organ donor registration rates. Yet, census tract-level African American/Black resident concentration was not significantly related to organ donor registration rates. These findings suggest that race-based interventions to recruit organ donors may no longer be necessary. Yet, identifying how characteristics of concentrated disadvantage may be more influential in determining organ donor registration. Gaining a better understanding of how individual decisions are made is integral in the context of increased life expectancy in conjunction with the complex management of chronic conditions. PMID- 30019497 TI - Nontechnical skills of the operating theatre circulating nurse: An ethnographic study. AB - AIM: This paper aims to uncover circulating nurses' nontechnical skills-namely, the cognitive and social skills that floor nurses need to deliver patient care in the operating room. BACKGROUND: Previous studies have shown that nontechnical skills play a key role in the safe execution of high-risk health practices, such as anaesthesia, resuscitation, and surgery. Regarding the surgical team, research has thus far focused on the nontechnical skills of anaesthesiologists, surgeons, and scrub nurses, leaving unexplained the cognitive and social skills that circulating nurses need to acquire and use. DESIGN: Ethnographic study. METHODS: Empirical materials were collected in the operating department of a hospital located in northern Italy, drawing on direct observation, document analysis and informal interviews with the circulating nurses. Data collection lasted 3 months, from May - July 2017. RESULTS: Nontechnical skills of circulating nurses can be described using five categories: leadership, situation awareness, task management, communication, and teamwork. CONCLUSION: This paper explicitly addresses circulating nontechnical skills needed to support the design of educational and training pathways for nurses. PMID- 30019498 TI - A randomized clinical trial of the efficacy and safety of sitagliptin compared with dapagliflozin in patients with type 2 diabetes mellitus and mild renal insufficiency: The CompoSIT-R study. AB - AIM: To compare the efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin with the sodium-glucose transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes and mild renal insufficiency. MATERIALS AND METHODS: Patients with HbA1c >=7.0 to <=9.5% (>=53 to <=80 mmol/mol) and estimated glomerular filtration rate >=60 to <90 mL/min/1.73m2 on metformin (>=1500 mg/d) +/- sulfonylurea were randomized to sitagliptin 100 mg (n = 307) or dapagliflozin 5 mg titrated to 10 mg (n = 306) once daily for 24 weeks. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is non-inferior to dapagliflozin in reducing HbA1c at Week 24, with superiority to be tested if non-inferiority is met. ClinicalTrials.gov NCT02532855. RESULTS: Baseline mean HbA1c (% [mmol/mol]) was 7.7 (60.9) and 7.8 (61.2), and mean eGFR (mL/min/1.73m2 ) was 79.4 and 76.9 for the sitagliptin and dapagliflozin groups, respectively. After 24 weeks, the between-group difference in least squares mean (95% CI) changes from baseline in HbA1c was -0.15% (-0.26, 0.04) (-1.67 mmol/mol [-2.86, -0.48]), P = 0.006, meeting the prespecified criteria for declaring both non-inferiority and superiority of sitagliptin versus dapagliflozin. The HbA1c goal of <7% (<53 mmol/mol) was met by 43% (sitagliptin) and 27% (dapagliflozin) of patients. No meaningful between-group difference was observed in a pre-specified analysis of 2-hour incremental postprandial glucose excursion. A review of adverse events (AEs) was notable for a lower incidence of drug-related AEs with sitagliptin compared with dapagliflozin. CONCLUSIONS: In patients with type 2 diabetes, mild renal insufficiency and inadequate glycaemic control on metformin +/- sulfonylurea, sitagliptin treatment resulted in greater improvement in glycaemic control compared with dapagliflozin and was generally well tolerated. PMID- 30019499 TI - SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease. AB - AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus. PMID- 30019500 TI - Alcohol intake and semen variables: cross-sectional analysis of a prospective cohort study of men referring to an Italian Fertility Clinic. AB - BACKGROUND: The association between alcohol intake and male reproductive function is still controversial. In the frame of a prospective cohort study, designed to investigate the relation between life style and fertility, we performed a cross sectional analysis of semen quality. METHODS: Men of subfertile couples, referring to an Italian Infertility Unit and eligible for assisted reproductive techniques (ARTs), were asked about their lifestyle: BMI, smoking, caffeine intake, occupational and leisure physical activity (PA) and alcohol intake in the last year before ART procedure. Semen volume, sperm concentration, total sperm count and sperm motility were determined. Age, risk factors for impaired male fertility, caffeine, smoking, leisure PA, days of abstinence and daily calories intake were accounted for in the analyses. RESULTS: Between September 2014 and December 2016, we enrolled 323 male patients, mean age 39.3 years. Thirty-one (9.6%) were abstainers, 97 (30.0%) drank <1-3, 98 (30.3%) 4-7 and 97 (30.0%) >=8 alcohol units per week. As compared to men drinking <1-3 units per week, median semen volume was higher in the 4-7 units/week group (3.0 mL, interquartile range, IQR, 2.0-4.0 vs. 2.4 mL, IQR 1.7-3.5), as well as total sperm count (87.9 mil/mL, IQR 20.2-182.1 vs. 51.5 mil/mL, IQR 15.2-114.7). Association with sperm concentration was also significant, with a U-shaped trend in groups of alcohol intake. After adjusting for potential confounders, these relations were confirmed. Similar patterns were observed in subgroups of leisure PA and risk factors for impaired male fertility, although these estimates often lacked statistical significance, presumably because of low sample size. CONCLUSIONS: Moderate alcohol intake appears positively associated to semen quality in male partners of infertile couples undergoing ARTs. PMID- 30019501 TI - What is dyslexia? An exploration of the relationship between teachers' understandings of dyslexia and their training experiences. AB - Given that an estimated 5-10% of the worldwide population is said to have dyslexia, it is of great importance that teachers have an accurate understanding of what dyslexia is and how it effects their students. Using results from a large scale survey of teachers in England and in Wales (N ~ 2,600), this paper demonstrates that teachers held a basic understanding of dyslexia, based on the behavioural issues that it is associated with. Teachers lacked the knowledge of the biological (i.e., neurological) and cognitive (i.e., processing) aspects of dyslexia. Moreover, a number of teachers mentioned visual factors in their description of dyslexia, despite there being inconclusive evidence to suggest a direct relationship between visual functioning and dyslexia. Further findings demonstrate the importance of good-quality teacher training in increasing teachers' confidence working with those with dyslexia, while increasing their knowledge of the cognitive aspects of dyslexia. This paper argues that evidence based teacher training, which informs teachers of the up-to-date research on the biological, cognitive, and behavioural aspects of dyslexia, is essential to combat misconceptions and ensure that teachers have more nuanced and informed understandings of dyslexia. PMID- 30019503 TI - Does allergy explain why some children have severe asthma? AB - Asthma is a common disease in childhood with a minority of affected children having severe therapy-resistant asthma (STRA). Children with STRA can be differentiated from those with mild-moderate disease by greater allergic sensitization, increased eosinophilic airway inflammation, increased airway remodelling and reduced corticosteroid responsiveness. The aetiology of STRA in children is multifactorial but allergy seems to play a key role. Many children with asthma have coexisting allergic disease, and severe rhinitis seems to be an important driver of STRA in children. Allergies to foods, moulds, pollen and pets have also been associated with severe asthma exacerbations. Identifying allergens that are driving asthma symptoms in children with STRA may provide additional strategies for improving their disease control. Avoidance strategies may be possible. Additional monoclonal antibody therapy with Omalizumab or Mepolizumab may be helpful in children with clinically important polysensitization. PMID- 30019504 TI - Amplifying Strength, Toughness, and Auxeticity via Wavy Sutural Tessellation in Plant Seedcoats. AB - Protective armors are widespread in nature and often consist of periodic arrays of tile-like building blocks that articulate with each other through undulating interfaces. To investigate the mechanical consequences of these wavy tessellations, especially in instances where the amplitude of the undulations is near the scale of the constituent tiles as is found in the seedcoats of many plant species, an approach that integrates parametric modeling and finite element simulations with direct mechanical testing on their 3D-printed multi-material structural analogues is presented. Results from these studies demonstrate that these tiled arrays of largely isotropic star-like unit cells exhibit an unusual combination of mechanical properties including auxeticity and mutually amplified strength and toughness which can be systematically tuned by varying the waviness of the sutural tessellation. PMID- 30019502 TI - Determination of four main components of gentamicin in animal tissues after solid phase extraction by high-performance liquid chromatography/tandem mass spectrometry. AB - RATIONALE: An analytical method for gentamicin in animal tissues was developed and validated. An alkaline mobile phase with an HPH C8 column was selected so that all the four gentamicin components were retained and eluted without using fluorinated ion-pairing reagents. METHODS: The method is sufficiently sensitive and highly selective, using a strong cation-exchange solid-phase extraction cartridge (PCX) to clean up the samples. Different types of solid-phase extraction columns and membranes were considered to obtain a high recovery. The method was validated on spiking samples, recovery, inter- and intra-assay variation, to ensure its accuracy and precision. RESULTS: The LOQ (S/N >= 10) for gentamicin in goat meat, liver, kidney and adipose tissue was 25, 50, 30 and 30 ng/g, respectively; the LOD (S/N >= 3) was 5, 10, 10 and 10 ng/g, respectively. The recoveries were between 88% and 106%. The method in all animal tissues was calibrated from 10 to 1000 MUg/L in the matrix-assisted standard solution. CONCLUSIONS: The novelty of this method is that the commonly used fluorinated ion pairing reagent was not used in the mobile phase in our analysis, greatly reducing the contamination of the ESI source in negative mode. Moreover, the four gentamicin components were clearly separated via chromatographic separation. PMID- 30019507 TI - Mass spectrometry in drug metabolism and pharmacokinetics: Current trends and future perspectives. AB - Drug Metabolism and Pharmacokinetics (DMPK) is a core scientific discipline within drug discovery and development as well as post-marketing. It helps to design and select the most promising drug candidate and obtain advanced insights on the processes that control absorption, distribution, metabolism and excretion (ADME) of the final drug candidate. Mass spectrometry is one of the key technologies applied in DMPK. Therefore, the continuous advances made in the field of mass spectrometry also directly impact the way in which we investigate the ADME properties of a compound, providing us with new tools to gather more information or improve our efficiency. An overview will be given of some important current trends and future perspectives in the field. PMID- 30019506 TI - A 4-bp deletion promoter variant (rs984225803) is associated with mild OCA4 among Japanese patients. AB - Oculocutaneous albinism (OCA) type 4 is one of the most common types of albinism among Japanese population. In some patients who were clinically diagnosed with OCA, we have found a heterozygous pathological mutation in the coding region of SLC45A2, the gene responsible for OCA4, not leading to a DNA-based diagnosis. In this study, we evaluated pathological variants in the promoter region of SLC45A2 in these patients. The results indicated that the majority of the patients had a 4-bp deletion in the said region (c.-492_489delAATG; GenBank accession number: NM_016180; rs984225803) in the contralateral allele. These patients displayed a mild phenotype, especially regarding eye manifestations. The results of the luciferase reporter assay and electrophoretic mobility shift assay supported the pathological role of the variant. In addition, four of 220 alleles in Japanese normal control subjects also showed the deletion variant, indicating that this variant could possibly be a skin color-associated variant. PMID- 30019505 TI - What is the role of apical ventriculotomy in children and young adults with hypertrophic cardiomyopathy? AB - BACKGROUND: The transapical approach has been utilized in adult HCM patients with either midventricular obstruction or a small LV cavity; however, there are little data on its use in children. METHODS: We retrospectively reviewed all patients (age <21 years) with HCM who underwent a transapical myectomy from January 2002 to December 2016. Indication for surgery was midventricular obstruction in 19/23 (83%) and small LV cavity in 4 (17%). Preoperative symptoms included: dyspnea (96%), chest pain (65%), presyncope (61%), and syncope (35%). The mean age at the time of operation was 14 +/- 4.0 years (range, 4-20). RESULTS: Overall, 23 patients (12 males) underwent transapical myectomy. A concomitant transaortic approach was performed in 16/19 (84%) with obstruction. The intraventricular gradient decreased from 71 mm Hg (IQR 44-92 mm Hg) preoperatively to 18 mm Hg (IQR 8-34 mm Hg, P < .0001) after myectomy. In patients with a small LV cavity, the mean left ventricular end diastolic dimension (LVEDD) increased from 40 +/- 3 mm to 46 +/- 3 mm (P = .05) after myectomy. There were no early deaths. Postoperative morbidity included complete heart block in 3 patients, 2 of which required pacemakers. Median follow up was 3.5 years (IQR 1.6-5.6). Symptoms improved in 95% of patients; the number of patients in NYHA class 3 or 4 heart failure decreased from 10/23 (43%) preoperatively to 3/23 (13%) postoperatively (P < .0001). Overall survival at 5 years postsurgery was 100%. Transplant-free survival was 91% and 87% at 1 and 5 years, respectively. CONCLUSION: In children with HCM, transapical myectomy is an effective adjunct to a transaortic approach to abolish midventricular obstruction and it effectively increases LV stroke volume in patients with small LV cavities and nonobstructive HCM. It may be beneficial for these patients with significant symptoms and who have failed medical therapy as a treatment alternative to cardiac transplantation. PMID- 30019508 TI - Factors associated with molar-incisor hypomineralisation in schoolchildren aged 8 10 years: a case-control study. AB - BACKGROUND: The aetiology of molar-incisor hypomineralisation (MIH) is multifactorial and may involve genetic and environmental factors. AIM: To verify the factors associated with MIH in schoolchildren from 8 to 10 years of age. DESIGN: This is a case-control study with a sample consisting of children aged 8 to 10 years, paired by gender and school type, in a ratio of 1:3. The case group included 186 children with MIH and the control included 558 children without MIH. Data were collected through a semi-structured questionnaire and clinical examination. Chi-square, linear-by-linear, Mann-Whitney, and logistic regression tests were conducted. A value of P < 0.05 was considered significant. RESULTS: The prevalence of mild MIH was 19.5%, moderate MIH 2.2% and severe MIH 3.2%. An association was observed between MIH with treatment need and a higher mean DMF-T and decayed and missing teeth (P < 0.05). According to the aetiological factors studied, mothers who presented a fever during pregnancy had a 2.54 times greater chance of having children with severe MIH than mothers who did not present a fever (P = 0.045). CONCLUSION: The presence of fever during pregnancy and the need for treatment were associated with MIH. PMID- 30019509 TI - Recent Advances in Tracking the Transplanted Stem Cells Using Near-Infrared Fluorescent Nanoprobes: Turning from the First to the Second Near-Infrared Window. AB - Stem cell-based regenerative medicine has attracted tremendous attention for its great potential to treat numerous incurable diseases. Tracking and understanding the fate and regenerative capabilities of transplanted stem cells is vital for improving the safety and therapeutic efficacy of stem cell-based therapy, therefore accelerating the clinical application of stem cells. Fluorescent nanoparticles (NPs) have been widely used for in vivo tracking of the transplanted stem cells. Among these fluorescent NPs, near-infrared (NIR) NPs have greatly improved the sensitivity, tissue penetration depth, spatial and temporal resolutions of the fluorescence imaging-based stem cell tracking technologies due to the reduced absorption, scattering, and autofluorescence of NIR fluorescence in tissues. Here, this review summarizes the recent studies regarding the tracking of transplanted stem cells using NIR NPs and emphasizes the recent advances of fluorescence imaging in the second NIR window (NIR-II, 1000-1700 nm). Furthermore, the challenges and future prospects of the NIR NP based technologies are also discussed. PMID- 30019511 TI - Organocatalytic Asymmetric Cascade Reactions Based on Gamma-Nitro Carbonyl Compound. AB - The significant advancements in asymmetric organocascade reactions have been accomplished during the past decades, paving the way to the efficient and stereoselective construction of structurally complex scaffolds from simple and readily available starting materials. Nitro-containing cyclic compounds have become a privileged molecular library given their broad and promising activities in various therapeutic areas. In various approaches to build these valuable scaffolds, the utility of gamma-nitrocarbonyl intermediates is one of the most efficient approaches due to its high efficiency, reliability and versatility. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of nitro-containing cyclic molecules via organocascade strategies based on gamma-nitrocarbonyl intermediates. Various organocatalysts with distinct activation modes have found application in providing these sophisticated compounds. This review is organized according to the types of organocatalyst. These methods are of importance for the construction of complex chiral cyclic frameworks and the design of new pharmaceutical compounds. We believe that compounds based on nitro-containing cyclic skeletons have the potential to provide novel therapeutic agents and useful biological tools. PMID- 30019510 TI - Cancer of unknown primary-Epidemiological trends and relevance of comprehensive genomic profiling. AB - BACKGROUND: Cancer of unknown primary (CUP) is a distinct clinicopathological entity with poor prognosis, frequently resistant to chemotherapy. Comprehensive genomic profiling (CGP) by next-generation sequencing potentially identifies novel treatment options for CUP patients. The objective of this study was to determine incidence and survival trends and to discuss the value of CGP in CUP patients. METHODS: Age-standardized incidence rates (ASR) per 100 000 were calculated for 2935 CUP patients from 1981 to 2014 using cancer registry data of the canton of Zurich, Switzerland. Kaplan-Meier survival curves were estimated for sex, age, and histological groups. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR). A literature review was conducted to assess the current use of CGP in CUP patients. RESULTS: ASR of CUP increased from 10.3 to 17.6 between 1981 and 1997 and decreased to 5.8/100 000 in 2014. Mean overall survival remained stable. Mortality was significantly lower for patients with squamous cell carcinoma (HR 0.48 [95% CI, 0.41-0.57]) and neuroendocrine carcinoma (0.75 [0.63-0.88]) and higher for unclassified neoplasms (1.25 [1.13-1.66]) compared to adenocarcinomas. The literature review identified 10 studies using CGP of CUP tissue. Clinically relevant mutations were identified in up to 85% of CUP patients, of which 13%-64% may benefit from currently available drugs. CONCLUSIONS: CUP incidence decreased probably due to improved diagnostics, but mortality did not improve over the last 34 years. CGP testing may help to identify molecular signatures in CUP patients and enable targeted treatment. PMID- 30019512 TI - Analysis of volatile organic compounds in crumb and crust of different baked and toasted gluten-free breads by direct PTR-ToF-MS and fast-GC-PTR-ToF-MS. PMID- 30019513 TI - Phytoestrogens in soy-based meat substitutes: Comparison of different extraction methods for the subsequent analysis by liquid chromatography-tandem mass spectrometry. AB - This paper presents the development of an efficient extraction procedure followed by a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of five phytoestrogens (genistein, daidzein, formononetin, biochanin A, and coumestrol) in soy-based meat substitutes. Phytoestrogens are considered endocrine disrupting compounds, and their quantification is important in soy-based products, whose diffusion is increasing nowadays. The HPLC-MS/MS method, with electrospray ionization (ESI) source, was optimized to obtain high specificity and sensitivity, as well as rapidity of the analysis. Three extraction techniques were applied to soy burgers and compared: ultrasound assisted extraction, ultrasound assisted extraction followed by solid phase extraction and the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) methodology. Both ultrasound assisted extraction and QuEChERS proved to be suitable for the determination of phytoestrogens, showing high recoveries, in the range of 86% to 99% and 75% to 105%, respectively. Matrix effect was evaluated, and ion suppression was observed for coumestrol and formononetin, demonstrating the importance of matrix effect assessment when complex samples are analyzed by HPLC-ESI-MS. The complete analytical protocols provided limits of detection and quantitation in soy-burgers at the ng g-1 level for all the considered phytoestrogens. Some soy burger samples were analyzed by both ultrasound assisted extraction and QuEChERS followed by HPLC-MS/MS. High concentration levels of daidzein and genistein (2-59 MUg g-1 and 2-72 MUg g-1 , respectively) were found; formononetin was in the range of 5 to 26 ng g-1 , while biochanin A and coumestrol were under the limit of quantitation in all samples. The results obtained with the two different sample treatment were in good agreement, proving the precision and accuracy of the described techniques. PMID- 30019514 TI - Is Sexual Abuse a Unique Predictor of Sexual Risk Behaviors, Pregnancy, and Motherhood in Adolescence? AB - This study tested sexual abuse as a unique predictor of subsequent adolescent sexual behaviors, pregnancy, and motherhood when in company with other types of maltreatment (physical abuse, neglect) and alternative behavioral, family, and contextual risk factors in a prospective, longitudinal study of maltreated (n = 275) and comparison (n = 239) nulliparous females aged 14-19 years old assessed annually through 19 years old. Hierarchical regression was used to disentangle risk factors that account for the associations of maltreatment type on risky sexual behaviors at 19 years old, adolescent pregnancy, and adolescent motherhood. Findings indicate that sexual and physical abuse remain significant predictors of risky sexual behaviors, and that sexual abuse remains a significant predictor of adolescent motherhood when alternative explanatory variables are controlled. PMID- 30019515 TI - Novel SUZ12 mutations in Weaver-like syndrome. AB - SUZ12 is a core component of polycomb repressive complex 2 (PRC2) along with EZH2 and EED. Recently, germline mutations in the SUZ12, EZH2 and EED genes have been reported in Weaver syndrome (WS) or Weaver-like syndrome, suggesting a functional link between PRC2 deficits and WS. However, only one case of a SUZ12 mutation presenting with Weaver-like syndrome has been reported. Here, we report a missense and a frameshift mutation in SUZ12 (c.1797A>C; p.Gln599His and c.844_845del; p.Ala282Glnfs*7), both of which are novel, in two individuals. Their clinical features included postnatal overgrowth, increased bifrontal diameter, large ears, round face, horizontal chin crease and skeletal anomalies, but did not fulfill the WS diagnostic criteria. These data provide strong evidence that SUZ12 mutations cause Weaver-like syndrome. PMID- 30019516 TI - Evaluation of Quality of Life Using EORTC QLQ-BM22 in Patients with Bone Metastases after Treatment with Magnetic Resonance Guided Focused Ultrasound. AB - OBJECTIVE: To reveal the alterations in quality of life (QOL) in bone metastases patients after magnetic resonance guided focused ultrasound (MRgFUS). METHODS: This retrospective study enrolled 26 patients diagnosed with bone metastases. Patients had various primary malignant tumors and tumor lesions in different locations. All patients received MRgFUS for bone metastasis. Each focal spot sonication pulse that was applied to create energy deposition lasted 20 s and was performed at a frequency of 1.05 MHz. The visual analog scale (VAS) was used to measure pain level and the EORTC QLQ-BM22 was applied to evaluate QOL for 12 months. The lower the QLQ-BM22 score, the better the QOL of patients. RESULTS: The painful site subscale of the EORTC QLQ-BM22 was observed without significant change. Significant reductions in the functional subscales were observed after therapy compared with the baseline. The functional interference was reduced significantly during the first 12 months. From the 2-month time point onwards, the pain characteristics subscale also decreased significantly. VAS scores had decreased by 40.8% 1 month after the operation and had decreased 10.9% compared with VAS scores preoperation. Scores for pain characteristics decreased by 28.8% after the operation and the scores were still down by 10.8% 1 year after the treatment. VAS scores indicated a significant reduction in pain over the course of the research until the 12-month time point follow-up compared with the baseline. CONCLUSION: MRgFUS therapy improved the QOL of patients with bone metastasis by relieving bone pain. PMID- 30019518 TI - Occupational systemic allergic dermatitis in a football player sensitized to colophonium. PMID- 30019517 TI - Pulmonary complications after liver transplantation in children: risk factors and impact on early post-operative morbidity. AB - Liver transplantation (LT) is associated with high post-operative morbidity, despite excellent survival rates. With this retrospective study, we report the incidence of early and late pulmonary complications (PC) after LT, identify modifiable risk factors for PC and analyzed the role of PC in post-operative ventilation duration and hospital length of stay. In a series of 79 children (0 16 years) with LT over a 12 years period, early (<3 months post-LT) and/or late (>3 months post-LT) PC occurred in 68 patients (86%). Sixty-four percent (64%) developed early major complications such as pulmonary edema, atelectasis, or pleural effusion. Atelectasis requiring an intervention (P <= .02), pulmonary edema (P <= .02), or elevated PELD/MELD scores (P = .05) were associated with an increase in total ventilation duration and length of stay in the ICU. Risk factors for early PC included preoperative hypoxemia (P = .005), low serum albumin at LT admission (P = .003), or early rejection (P = .002). About 20% of patients experienced late PC of which 81% were infections. Risk factor assessment prior to LT may ultimately help reduce early PC thereby possibly minimizing post operative morbidity and ICU length of stay. PMID- 30019519 TI - Photosensitised Multiheme Cytochromes as Light-Driven Molecular Wires and Resistors. AB - Multiheme cytochromes possess closely packed redox-active hemes arranged as chains spanning the tertiary structure. Here we describe five variants of a representative multiheme cytochrome engineered as biohybrid phototransducers for converting light into electricity. Each variant possesses a single Cys sulfhydryl group near a terminus of the heme chain, and this was efficiently labelled with a RuII (2,2'-bipyridine)3 photosensitiser. When irradiated in the presence of a sacrificial electron donor (SED) the proteins exhibited different types of behaviour. Certain proteins were rapidly and fully reduced. Other proteins were rapidly semi-reduced but resisted complete photoreduction. These findings reveal that photosensitised multiheme cytochromes can be engineered to act as resistors, with intrinsic regulation of light-driven electron accumulation, and also as molecular wires with essentially unhindered photoreduction. It is proposed that the observed behaviour arises from interplay between the site of electron injection and the distribution of heme reduction potentials along the heme chain. PMID- 30019520 TI - Pulmonary interstitial glycogenosis: Diagnostic evaluation and clinical course. AB - OBJECTIVES: We sought to describe the phenotype for patients with P.I.G. including presentation, evaluation, cardiac co-morbidities, high resolution computed tomography findings, and outcomes. METHODS: With institutional review board approval, we performed a retrospective review of patients with biopsy proven P.I.G. Biopsies, high resolution chest computed tomography, and cardiac evaluations were reviewed and characterized by experts in each field. RESULTS: Sixty-two percent of the patients were male. The median gestational age was 37 weeks (range 27-40). The median age at biopsy was 1.6 months (range 0.3-6 months). Structural heart disease was present in 63% of patients. Pulmonary hypertension (diagnosed by echocardiogram and/or cardiac catheterization) was noted in 38% of patients. Alveolar simplification was present in 79% of patients. Fifty percent of available biopsies revealed patchy disease. An increase in age at biopsy was associated with patchy (vs diffuse) disease. Ninety-two percent of patients were treated with systemic corticosteroids. Median age at last follow-up was 1234 days with a range of 37 days to 15 years. At the time of last follow-up, 12 patients were off all support, eight were on supplemental oxygen, two were mechanically ventilated, one underwent lung transplantation, and one died. CT findings commonly included ground glass opacities (86%) and cystic change (50%). CONCLUSIONS: The P.I.G. phenotype has not been comprehensively described, and poor recognition and misconceptions about P.I.G. persist. P.I.G. is a disease that presents in early infancy, requires significant medical intervention, and frequently is seen in association with alveolar simplification and/or cardiovascular disease. CT findings include ground glass opacities and cysts. Patients should be monitored for pulmonary hypertension. Without life-threatening comorbidities, many patients do well over time, although respiratory symptoms may persist into adolescence. PMID- 30019521 TI - Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD). AB - Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that 3 reperfusion strategies mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset-provoke mitochondrial changes that may underlie their cardioprotective effects. Using an isolated, working rat heart model of DCD, we demonstrate that all 3 strategies improve oxygen-consumption-cardiac-work coupling and increase tissue adenosine triphosphate content, in parallel with increased functional recovery. These reperfusion strategies, however, differentially affect mitochondria; mild hypothermia also increases phosphocreatine content, while mechanical postconditioning stimulates mitochondrial complex I activity and reduces cytochrome c release (marker of mitochondrial damage), whereas hypoxia upregulates the expression of peroxisome proliferator-activated receptor-gamma coactivator (regulator of mitochondrial biogenesis). Characterization of the role of mitochondria in cardioprotective reperfusion strategies should aid in the identification of new, mitochondrial based therapeutic targets and the development of effective reperfusion strategies that could ultimately facilitate DCD heart transplantation. PMID- 30019523 TI - Mifepristone in the treatment of the ectopic adrenocorticotropic hormone syndrome. AB - OBJECTIVES: Mifepristone, a glucocorticoid receptor antagonist, can be used to manage hypercortisolism in patients with ectopic adrenocorticotropic hormone syndrome (EAS) when surgical cure is not feasible. Outcomes of EAS patients treated with mifepristone have been limited to reports of isolated cases. We aimed to determine the efficacy and limitations of mifepristone in the treatment of EAS and to compare outcomes with those of patients who underwent bilateral adrenalectomy. METHOD: A retrospective cohort study of EAS patients from the University of Michigan between 1997 and 2017 was conducted. RESULTS: Of the 55 patients with EAS, 16 were treated with mifepristone: eight neuroendocrine tumours, two carcinomas and six occult tumours. Treatment with mifepristone was most commonly prompted by psychosis, uncontrolled glucose and/or hypertension. The median maintenance dose was 600 mg/d. Amelioration of psychosis was observed within 48 hours in 3/3 patients, and the glycaemic control was improved in 14/16 patients. The median duration of treatment was 9 months, and three patients were treated for more than 24 months. The overall survival at 24 months was equivalent between patients with EAS treated with mifepristone vs bilateral adrenalectomy (N = 12) (P = 0.6). CONCLUSIONS: Mifepristone is effective in treating EAS for over 2 years, and survival was not different from that of patients treated with bilateral adrenalectomy. Aggressive concomitant therapy for hypokalaemia and hypertension is necessary. PMID- 30019524 TI - It's not just what you have, but how you use it: solar-positional and behavioural effects on hummingbird colour appearance during courtship. AB - Animals exhibit a diversity of colours that can play key roles in mating interactions. However, we presently lack an understanding of the relative importance of the environment, behaviour and natural reflective properties of colourful ornaments in shaping an individual's colour appearance during mating displays. We investigated interactions among structurally based plumage, display environments and courtship shuttle displays of male Costa's hummingbirds (Calypte costae) to test how these elements may differentially contribute to colour appearance during shuttles. Male position relative to the sun was the strongest predictor of colour appearance, with shuttle behaviours and feather reflectance playing smaller roles. Furthermore, male solar orientation and shuttling behaviour (e.g. shuttle width) were repeatable among displays, whereas male colour appearance mostly was not. These results emphasise the contributions of behaviour and environment to colour-signalling and suggest that relying on reflectance measurements of colourful ornaments alone provides an incomplete picture of ecologically relevant visual phenotypes of displaying animals. PMID- 30019522 TI - Secretion and fusion of biogeochemically active archaeal membrane vesicles. AB - Microbes belonging to the genus Metallosphaera oxidize sulfidic minerals. These organisms thrive at temperature extremes and are members of the archaeal phylum Crenarchaeota. Because they can employ a lithoautotrophic metabolism, energy availability likely limits their activity raising questions about how they conduct biogeochemical activity. Vesicles are membrane encapsulated structures produced by all biological lineages but using very different mechanisms. Across the Crenarchaeota, it has been proposed that a eukaryotic-like Endosomal Sorting Complex Required for Transport system promotes formation of these structures but in response to unknown signals and for undefined purposes. To address such questions, Metallosphaera sedula vesicle formation and function were studied under lithoautotrophic conditions. Energy deprivation was evaluated and found to stimulate vesicle synthesis while energy excess repressed vesicle formation. Purified vesicles adhered rapidly to the primary copper ore, chalcopyrite, and formed compact monolayers. These vesicle monolayers catalyzed iron oxidation and solubilization of mineralized copper in a time-dependent process. As these activities were membrane associated, their potential transfer by vesicle fusion to M. sedula cells was examined. Fluorophore-loaded vesicles rapidly transferred fluorescence under environmentally relevant conditions. Vesicles from a related archaeal species were also capable of fusion; however, this process was species specific as vesicles from different species were incapable of fusion. In addition, vesicles produced by a copper-resistant M. sedula cell line transferred copper extrusion capacity along with improved viability over mutant M. sedula cells lacking copper transport proteins. Membrane vesicles may therefore play a role in modulating energy-related traits in geochemical environments by fusion mediated protein delivery. PMID- 30019525 TI - Male-pattern baldness, common latent viruses, and microcompetition. AB - Many studies link the development of androgen-related disorders to the overexpression of two proteins, 5alpha-reductase and androgen receptor (AR). In this commentary, we use microcompetition to explain how common latent viruses can cause transcription factor deficiency, overexpression of 5alpha-reductase and AR, and male-pattern baldness. PMID- 30019526 TI - RadAA: A Command-line Tool for Identification of Radical Amino Acid Changes in Multiple Sequence Alignments. AB - High-throughput sequencing has revolutionised biology and medicine. Numerous genomes and transcriptome assemblies are now available, and these genomic data sets lend themselves to comparisons between species, strains, and other strata. Researchers often need to rapidly identify changes, in particular amino acid substitutions that could confer biological function in their system of interest. However, we are not aware of an easy-to-use tool that can be used to detect such changes, and researchers currently rely on idiosyncratic computer code. We present RadAA, a command-line tool which screens multiple sequence alignments for radical amino acid changes in a stratum/strata by classifying residues into groups by charge (with cysteine in its own group). RadAA is easy to use, even for researchers with little experience in computational biology. It can be run on most operating systems - including MacOS, Windows, and Linux - and integrated into high-performance computing environments. The RadAA source code and executable binaries are freely available at https://github.com/sciseim/RadAA. PMID- 30019527 TI - Missense variants in ALAS2 gene in five patients. PMID- 30019528 TI - Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective, randomised, multi-centre clinical trial in 80 patients. AB - Amnion and chorion allografts have shown great promise in healing diabetic foot ulcers (DFUs). Results from an interim analysis of 40 patients have demonstrated the accelerated healing ability of a novel aseptically processed, dehydrated human amnion and chorion allograft (dHACA). The goal of this study was to report on the full trial results of 80 patients where dHACA was compared with standard of care (SOC) in achieving wound closure in non-healing DFUs. After a 2-week screening period, during which patients with DFUs were unsuccessfully treated with SOC, patients were randomised to either SOC alone or SOC with dHACA applied weekly for up to 12 weeks. At 12 weeks, 85% (34/40) of the dHACA-treated DFUs healed, compared with 33% (13/40) treated with SOC alone. Mean time to heal within 12 weeks was significantly faster for the dHACA- treated group compared with SOC, 37 days vs 67 days in the SOC group (P = .000006). Mean number of grafts used per healed wound during the same time period was 4.0, and mean cost of the tissue to heal a DFU was $1771. The authors concluded that aseptically processed dHACA heals DFUs significantly faster than SOC at 12 weeks. PMID- 30019529 TI - Hereditary neuralgic amyotrophy in childhood caused by duplication within the SEPT9 gene: A family study. AB - Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with episodic, recurrent, and painful neuropathies affecting the nerves of the brachial plexus. In this study, we report on a family of Lebanese descent with HNA onset in early childhood. The affected family members presented with platelet dysfunction. Platelet aggregation was reduced after stimulation with the agonists ADP and epinephrine in all affected family members. Flow cytometric analyses revealed impaired platelet delta-secretion. The index patient and one brother suffered from kidney cysts. Molecular genetic analysis revealed a heterozygous duplication of exon 2 within the septin 9 (SEPT9) gene in all the affected family members. Such a young child with HNA (aged 2 years) caused by SEPT9 duplication has not been described so far. PMID- 30019530 TI - Timing of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients. AB - AIMS: Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long-term CAV progression and clinical outcomes in a large contemporary HT cohort. METHODS AND RESULTS: We analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow-up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES (<2 years after HT) and the LS (>2 years after HT) groups. During a median follow-up of 8.2 years, ES resulted in significantly lower change (Delta) of plaque index (+3.8% +/- 1.7% vs. +8.2% +/- 3.6%; P = 0.0008) and PV (+0.8 +/- 0.3 vs. +1.9 +/- 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV-associated events (hazard ratio 0.48, 95% confidence interval: 0.27-0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all-cause mortality and CAV-associated events (hazard ratio 0.58, 95% confidence interval: 0.38-0.91; P = 0.019). CONCLUSIONS: Early initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV-related events and mortality. PMID- 30019531 TI - Reflectance confocal microscopy for the noninvasive diagnosis of cutaneous juvenile xanthogranuloma. AB - Juvenile xanthogranuloma is the most common type of non-Langerhans cell histiocytosis. It appears primarily in infancy, where its differential diagnosis includes Spitz nevus, dermal nevus and molluscum contagiosum. We report the case of a 2-year-old boy with juvenile xanthogranuloma, as diagnosed using real-time, in vivo reflectance confocal microscopy. PMID- 30019532 TI - The novel HLA-DRB1*15:149 allele discovered in a Taiwanese individual. AB - One nucleotide substitution at residue 85 of HLA-DRB1*15:02:01:01 results in a new allele, HLA-DRB1*15:149. PMID- 30019535 TI - Zolpidem ameliorates motor impairments in the unilaterally 6-hydroxydopamine lesioned rat. AB - Nuclei within the basal ganglia-such as the globus pallidus external segment, subthalamic nucleus, and substantia nigra pars reticulata-have been shown to exhibit synchronous bursting activity entrained to excessive cortical beta oscillations following dopamine depletion. Zolpidem binds to GABAA receptors with selectivity for those expressing the alpha1 subunit, potentiating inhibitory postsynaptic currents and increasing the time decay of channel opening. Interestingly, zolpidem-sensitive nuclei within the basal ganglia circuitry are also those that have been shown to exhibit hyperexcitation in a dopamine-depleted state. We hypothesized that a drug with selectivity for these nuclei may improve motor impairments associated with Parkinson's disease. In order to determine the threshold dose at which zolpidem might encumber motor behavior, a dose-response experiment was performed in intact rats using rotarod. Next, we tested whether subthreshold doses (0.1, 0.25, 0.5 mg/kg; i.p.) of zolpidem improved volitional motor behavior/coordination using the rotarod balance beam and cylinder/paw preference tests in unilaterally 6-hydroxydopamine-lesioned rats. It was found that 0.1 mg/kg zolpidem significantly improved rotarod performance and significantly reduced forelimb use asymmetry compared to undrugged post-lesion conditions. Here, we present the first translational evidence for a role of zolpidem-sensitive GABAA receptors in the treatment of PD motor symptoms. Our data show that zolpidem improves both motor coordination and volitional forelimb use in the unilateral 6-hydroxydopamine lesion model of PD, and thus suggest that zolpidem-sensitive GABAA receptors may represent a novel therapeutic target for the treatment of motor symptoms of Parkinson's disease. PMID- 30019533 TI - Effects of thoracic radiotherapy timing and duration on progression-free survival in limited-stage small cell lung cancer. AB - Concurrent chemoradiotherapy (CRT) has been recommended and applied widely as the standard treatment for limited-stage small cell lung cancer (LS-SCLC). However, controversies remain regarding the optimal timing and treatment duration of thoracic radiotherapy (TRT), and their effects on patient survival. To evaluate prognostic values of TRT timing and duration on progression-free survival (PFS) in LS-SCLC and their dependence on TRT fractionation and clinicopathological characteristics, we retrospectively analyzed 197 LS-SCLC patients receiving CRT from 2000 to 2016 at Sun Yat-sen University Cancer Center. Based on the optimal cut-off values of TRT timing and duration generated by Cutoff Finder, patients were divided into early TRT/late TRT group and short TRT/long TRT group respectively. Univariate and multivariate Cox analysis were performed to assess correlations of TRT timing, duration, fractionation, and clinicopathological characteristics with PFS. Univariate analysis revealed that early-initiated TRT (P = 2.54 * 10-4 ) and short TRT (P = .001) significantly correlated with longer PFS. Their PFS benefits persisted in patients receiving hyperfractionated TRT and etoposide-cisplatin (EP) chemotherapy, but were less prominent in those receiving once-daily TRT and non-EP chemotherapy. Multivariate analysis further identified early initiated TRT (P = .004) and short TRT (P = .017) as independent prognostic factors for longer PFS in LS-SCLC. Our study confirmed that early-initiated TRT and short TRT had positive prognostic roles in LS-SCLC, especially in patients receiving hyperfractionated TRT and etoposide-cisplatin chemotherapy. TRT fractionation was not an independent prognostic factor in LS-SCLC. PMID- 30019534 TI - Biology-Oriented Drug Synthesis (BIODS) Approach towards Synthesis of Ciprofloxacin-Dithiocarbamate Hybrids and Their Antibacterial Potential both in Vitro and in Silico. AB - A novel series of ciprofloxacin-dithiocarbamate hybrids 7a - 7l were designed, synthesized, and evaluated against Gram-positive and Gram-negative bacteria. A significant part of the title compounds showed considerable antibacterial activity against Gram-positive species. The most potent compound against Gram positive bacteria was 2-chloro derivative 7h and the most potent derivative against Gram-negative bacteria was 3-chloro compound 7i. In vitro antibacterial evaluation of compound 7h against clinically isolated bacteria methicillin resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) showed that this compound acted better than ciprofloxacin against the latter bacteria. Docking study of compound 7h in the active site of S. aureus DNA gyrase revealed that this ciprofloxacin-dithiocarbamate derivative interacted with the main components of the active site of the enzyme. PMID- 30019536 TI - Characterization of septin expression in normal and fibrotic kidneys. AB - Chronic kidney disease (CKD) is characterized by the loss of nephrons and worsening organ-fibrosis that leads to deterioration and ultimately the total breakdown of kidney function. Renal fibrosis has become a major public health problem worldwide and necessitates hemodialysis and kidney transplantation in affected patients. CKD is mainly characterized by the activation and proliferation of interstitial fibroblasts and by excessive synthesis and accumulation of extracellular matrix components, causing the disruption of the normal tissue architecture of the kidney. Septins are GTPase proteins associated with membranes, actin filaments, and microtubules and are undoubtedly crucial for cytoskeleton organization. Although some septins are involved in liver fibrosis, they have not been investigated in the context of renal fibrosis. Here, we show that numerous septins are expressed in the healthy kidney and demonstrate in fibrotic mouse kidneys that various septins are remarkably up-regulated in the tubulointerstitium compared to contralateral control kidneys. We observed the same findings in human fibrotic kidneys. In both healthy and fibrotic kidneys, septins are coexpressed with extracellular matrix components, reinforcing the structural function of septins as cytoskeletal components. Furthermore, we could show in septin 8-deficient mice that septin 8 is dispensable for the formation of renal fibrosis, and that no other septin was compensatory changed in kidneys compared to wild-type mice. PMID- 30019537 TI - Effects of maternity yoga on the autonomic nervous system during pregnancy. AB - AIM: To elucidate the changes in the daily variation seen in the autonomic nervous system during pregnancy brought about by maternity yoga and to evaluate how maternal yoga affects stress and sleep. METHODS: A prospective, longitudinal study was conducted between January 2013 and December 2014. Pregnant women who were attending maternity yoga classes at Palmore Hospital between 20 and 23 weeks' gestation were enrolled as the yoga group, and a matched control group was also enrolled. Study participants completed questionnaires, including a perceived stress scale and sleep logs, during their second and third trimesters. Heart rate variability and salivary alpha-amylase levels were evaluated as stress indices at 20-23 weeks' gestation, 28-31 weeks' gestation and 36-40 weeks' gestation. RESULTS: A total of 38 women were in the yoga group, with 53 in the control group. At 28-31 weeks' gestation, heart rate variability during night and late night periods was significantly higher in the yoga group than in the control group. At 36-40 weeks' gestation, variability between the morning, afternoon and late night was significantly higher in the yoga group. Salivary alpha-amylase levels decreased significantly immediately after practicing yoga during all evaluation periods in the yoga group. Night-time sleep duration was significantly longer in the yoga group. CONCLUSION: Our results suggest that practicing yoga activates the parasympathetic nervous system during the third trimester of pregnancy, consolidating sleep during the night and decreasing alpha-amylase levels, which indicates reduced stress. PMID- 30019539 TI - Transgender HIV status, self-perceived dental care barriers, and residents' stigma, willingness to treat them in a community dental outreach program: Cross sectional study. AB - AIM: Assess the association between high risk transgender (TG) HIV status, self perceived barriers toward oral care, and the residents' stigma and willingness to treat during community dental outreach. METHODS: Demographics, tobacco habits, HIV status, willingness for rapid HIV testing, and self- perceived oral health, barriers toward oral care were assessed in a cross-sectional study among 212 transgender in South India. Further, the residents' stigma across three subscales and residents' willingness to treat the transgender was evaluated. RESULTS: Overall, 88% had begging as the sole income, and 93% lived in slums and used some form of tobacco. Oral health was perceived to be poor by more than half, and the mean probing pocket depth (PPD) and decayed, missing, or filled teeth (DMFT) was 4.2 mm and 3.67, respectively. The residents reported significantly low regard and willingness to treat TG irrespective of high/low stigma and when the transgender HIV status was positive/do not know. Residents with greater fear of exposure expressed least regard and willingness to treat TG (P < 0.05). CONCLUSION: The self-perceived oral health of transgender' was poor corresponding to the clinical examination findings. Moreover, the stigmatizing attitude and low regard to provide oral care is rampant among the dental residents, which further frustrates dental care. PMID- 30019538 TI - A fine-needle aspiration-based protein signature discriminates benign from malignant breast lesions. AB - There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and to follow-up personalized cancer therapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissues; however, the minute sample amounts require sensitive multiplex molecular analysis to achieve clinical utility. We have applied proximity extension assays (PEA) and NanoString (NS) technology for analyses of proteins and of RNA, respectively, in FNA samples. Using samples from patients with breast cancer (BC, n = 25) or benign lesions (n = 33), we demonstrate that these FNA-based molecular analyses (a) can offer high sensitivity and reproducibility, (b) may provide correct diagnosis in shorter time and at a lower cost than current practice, (c) correlate with results from routine analysis (i.e., benchmarking against immunohistochemistry tests for ER, PR, HER2, and Ki67), and (d) may also help identify new markers related to immunotherapy. A specific 11-protein signature, including FGF binding protein 1, decorin, and furin, distinguished all cancer patient samples from all benign lesions in our main cohort and in smaller replication cohort. Due to the minimally traumatic sampling and rich molecular information, this combined proteomics and transcriptomic methodology is promising for diagnostics and evaluation of treatment efficacy in BC. PMID- 30019540 TI - Organizational readiness for implementing change in acute care hospitals: An analysis of a cross-sectional, multicentre study. AB - AIM: To assess nurse-reported organizational readiness for implementing change in acute care hospitals. BACKGROUND: An organization's success at implementing new policies and programmes depends largely on its stakeholders' readiness for change. Organizational readiness is a multilevel, multifaceted construct associated with staffing, leadership and quality of care. DESIGN: This is a secondary analysis of the cross-sectional multicentre "Matching Registered Nurse Services with Changing Care Demands" study. METHODS: In 23 acute care hospitals across Switzerland, 1,833 nurses working in 124 units completed a survey between September 2015 and January 2016. Organizational readiness was measured with two subscales: "change commitment" and "change efficacy". Work environment factors were assessed using the Practice Environment Scale of the Nursing Work Index. RESULTS: Nurses were positive about implementing change in their hospitals. Intraclass correlation was higher at the unit level than at the hospital level for both change commitment and change efficacy. Nursing foundation for quality of care and supportive leadership were positively associated with readiness, change commitment and change efficacy. However, staffing and resource adequacy was positively associated only with change efficacy. No association was found with standardized staffing. CONCLUSION: While organizational readiness scores vary among hospitals and units, they are positively associated with supportive leadership and a foundation for quality of care. Further research should consider organizational readiness as an important factor of change and ultimately of the quality of care. PMID- 30019541 TI - Ultrafiltration behavior of partially retained proteins and completely retained proteins using equally-staged single pass tangential flow filtration membranes. AB - This work examines the ultrafiltration behavior of partially retained proteins like lysozyme and completely retained proteins like monoclonal antibodies using single pass tangential flow filtration (SPTFF) modules with different screen channels and molecular weight cut-offs. When the staging of the SPTFF used the same membrane area in each stage, there was no impact of the module screened channel or the buffer matrix on the final concentration achieved for completely retained monoclonal antibodies. A hybrid configuration containing 30 kDa membranes and 50 kDa membranes increased the maximum achievable concentration for both the monoclonal antibodies used in this work, at the same time, allowing a two-fold to four-fold increase in normalized feed flow-rate through the system compared to only the 30 kDa or only the 50 kDa membranes. The sieving coefficient of lysozyme measured and calculated using SPTFF was lower than those measured during conventional recirculation TFF indicating a more complicated concentration polarization effect than conventional recirculation TFF. Moreover, the sieving coefficients of lysozyme were the same for the 10 kDa regenerated cellulose and 50 kDa PES membranes while it was higher for the 30 kDa regenerated cellulose membrane. The difference in TFF and SPTFF behavior is important when the product of interest is desired to be permeated. This work presents the first body of data for partially and completely retained solutes together in the SPTFF mode and provides a strategy to increase protein concentration at higher feed flow rates. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018 (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1137-1148, 2018. PMID- 30019542 TI - Assessing the skin barrier via corneocyte morphometry. AB - The skin barrier is an inevitable physiological function. Virtually all skin diseases exhibit an altered barrier. Because of its diversity, this vital function cannot be assessed adequately by a single method. Preference in both pharmaceutical and cosmetic testing is given to noninvasive assays, mostly macroscopic methods like optical or electrical or mechanical measurements. The present review focuses on advances in ultrastructural assays based on corneocytes obtained via tape stripping-highlighting candidates for automated processing. Among these are electron microscopic (EM) and atomic force microscopic (AFM) analyses, which are discussed with respect to clinical signs and skin hydration, as assessed by Raman spectroscopy or by concentration of natural moisturizing factor. PMID- 30019543 TI - Mapping of fine-scale rat prefrontal cortex connections: Evidence for detailed ordering of inputs and outputs connecting the temporal cortex and sensory-motor regions. AB - Cerebral cortex structure is crucially important for cortical organization and function. The organization of prefrontal cortex (PFC) is controversial and here we seek to understand it more clearly through the study of fine-scale cortical connections. To determine the ordering of microscale input and output connections in the rat PFC, we injected small volumes (20-30 nl) of anterograde (Fluro-Ruby) and retrograde (Fluoro-Gold) neuroanatomical tracers into PFC. These injections revealed several connected regions of the brain but here we report findings restricted to PFC to temporal cortex and sensory-motor cortex pathways. In agreement with previous studies incorporating larger injection volumes we found that smaller injection volumes revealed a more detailed, fine-scale ordering of both prefrontal inputs and output connections to the temporal cortex and sensory motor cortex regions. These findings are also supported by labelling observed from additional tracer injections made into corresponding regions of temporal cortex. The topography observed reflected the ordering seen at a larger level (i.e., with larger injection volumes) but there were some differences in the topography, such as in relation to the direction of ordering. In agreement with earlier work, we found that fine-scale input and output connections were not always aligned with respect to one another. These results provide evidence for topographically arranged inputs and outputs in two distinct PFC pathways, along with evidence for different connectional patterns within the same pathways. Based on theories of functional connectivity, these findings provide evidence for prefrontal cortical regions residing within networks that contribute to different cognitive functions. PMID- 30019544 TI - ESI-TOF mass spectrometry of cationic carbosilane dendrimers: A potent tool for characterization of structural defects. AB - Macromolecular polyelectrolytes are gaining considerable attention for the application in medicine that implies their detailed characterization. We have successfully applied electrospray ionization mass spectrometry (ESI MS) to the analysis of defects in the structure of three generations of polycationic carbosilane dendrimers bearing series of quarternary phosphonium groups at their periphery. Besides expected defects caused by incomplete conversion of particular reaction steps during the synthesis of dendritic scaffold and subsequent peripheral functionalization, also, several products of side reactions were observed together with defects created in the course of measurement (particularly ion exchange products). Defective molecules can be to some extent separated by means of gel permeation chromatography that proves that they are not products of in source fragmentation processes. Within the reaction sequence used for the synthesis of dendrimers under study, hydrosilylation was the source of most defects; the effectivity of quarternization depends on the type of phosphine. Results confirm high sensitivity of ESI MS towards defects, stability of the carbosilane skeleton towards fragmentation under the conditions of ESI ionization, and capability to detect both lower- and higher-molecular weight impurities arising from the synthetic sequence in the same m/z range as the target dendrimer, thus providing valuable view of the polydispersity. PMID- 30019545 TI - MITF and UV responses in skin: From pigmentation to addiction. AB - Ultraviolet radiation (UVR) has numerous effects on skin, including DNA damage, tanning, vitamin D synthesis, carcinogenesis, and immunomodulation. Keratinocytes containing damaged DNA secrete both alpha-melanocyte-stimulating hormone (alpha MSH), which stimulates pigment production by melanocytes, and the opioid beta endorphin, which can trigger addiction-like responses to UVR. The pigmentation (tanning) response is an adaptation that provides some delayed protection against further DNA damage and carcinogenesis, while the opioid response may be an evolutionary adaptation for promoting sun-seeking behavior to prevent vitamin D deficiency. Here, we review the pigmentation response to UVR, driven by melanocytic microphthalmia-associated transcription factor (MITF), and evidence for UVR-induced melanomagenesis and addiction. We also discuss potential applications of a novel approach to generate protective pigmentation in the absence of UVR (sunless tanning) using a topical small-molecule inhibitor of the salt-inducible kinase (SIK) family. PMID- 30019546 TI - Application of Multifunctional Nanomaterials in Radioprotection of Healthy Tissues. AB - Radiotherapy has been extensively used in clinic for malignant tumors treatment. However, a severe challenge of it is that the ionizing radiation needed to kill tumors inevitably causes damage to surrounding normal tissues. Although some of the molecular radioprotective drugs, such as amifostine, have been used as clinical adjuvants to radio-protect healthy tissues, their shortcomings such as short systemic circulation time and fast biological clearing from the body largely hinder the sustained bioactivity. Recently, with the rapid development of nanotechnology in the biological field, the multifunctional nanomaterials not only establish powerful drug delivery systems to improve the molecular radioprotective drugs' biological availability, but also open a new route to develop neozoic radioprotective agents because some nanoparticles possess intrinsic radioprotective abilities. Therefore, considering these overwhelming superiorities, this review systematically summarizes the advances in healthy tissue radioprotection applications of multifunctional nanomaterials. Furthermore, this review also points out a perspective of nanomaterial designs for radioprotection applications and discusses the challenges and future outlooks of the nanomaterial-mediated radioprotection. PMID- 30019547 TI - [Analysis of schistosomiasis prevention and control model of Yujiang: in-sights from governmental supply of rural public goods]. AB - This article analyzes the influencing factors of rural public service supply of schistosomiasis prevention and control in China and the successful experiences of schistosomiasis prevention and pattern of Yujiang from an angle of view of rural public goods. This article points out the short supply of rural public goods in the service of schistosomiasis prevention and control in the traditional small scale peasant economy, and the possibility of promoting the rural public goods in the cooperation economic model. The essential features of the schistosomiasis prevention and control pattern of Yujiang include strengthening the leadship of the Communist Party of China, improving health education, adjusting the measures to local condition, and so on. PMID- 30019548 TI - [Studies on colonization risk and potential geographical distribution of Biomphalaria glabrata as an intermediate host of Schistosoma mansoni in Mainland China]. AB - OBJECTIVE: To predict the colonization risk and potential geographical distribution of Biomphalaria glabrata in the Mainland China based on the past period temperature data. METHODS: The survival extreme high temperatures and low temperatures of B. glabrata eggs, young and adult B. glabrata snails and the average effective accumulated temperature of generation development were determined in laboratory conditions. The temperature data in January and July from 1955 to 2010 were collected from the national meteorological monitoring sites in the southern part of China, including Chongqing, Zhejiang, Yunnan, Sichuan, Jiangxi, Hunan, Hainan, Guizhou, Guangdong, Guangxi and Fujian provinces (11 provinces). A database of ambient temperature related to B. glabrata was established based on the Geographic Information System (GIS). The colonization risk and potential geographical distribution of B. glabrata in the southern part of China were analyzed and predicted by ArcGIS 10.1 software. RESULTS: The half lethal low temperatures of B. glabrata eggs, young and adult B. glabrata snails were 6.80, 6.34 C and 6.60 C respectively; the half lethal high temperatures of B. glabrata eggs, young and adult B. glabrata snails were 35.99, 33.59 C and 32.20 C, respectively. The developmental threshold temperature was 7.16 C; the average effective accumulated temperature of generation development was (1 970.07 +/- 455.10) days-degree. The GIS overlay analysis of the half lethal low and high temperatures of B. glabrata showed that the local temperature conditions in all Hainan and part regions in Yunnan, Guangxi, Guangdong and Fujian were conformed to the survival temperature of B. glabrata snails. The regions, where the average effective accumulated temperature was more than the average effective accumulated temperature of generation development of B. glabrata, were Guangdong and Hainan, and part regions of other 9 provinces. The overlay analysis of GIS maps of the survival extreme high temperatures and low temperatures of B. glabrata with the GIS map of the average effective accumulated temperature of generation development in 2010 showed that the whole region of Hainan and part regions of Guangdong, Guangxi, Yunnan and Fujian were potential geographical distribution regions of colonization risk of B. glabrata. The overlay analysis of GIS maps of the survival extreme high temperatures and low temperatures of B. glabrata with the GIS map of the average effective accumulated temperature of generation development from 1955 to 2010 showed that the potential geographical distribution regions of B. glabrata was expanding from the whole region of Hainan and part regions of Guangdong in 1955 to the whole region of Hainan and part regions of Guangdong, Guangxi, Yunnan and Fujian in 2010. CONCLUSIONS: If B. glabrata snails were introduced into the Mainland China, the potential geographical distribution regions would be the whole region of Hainan and part regions of Guangdong, Guangxi and Yunnan. The changes of risk range and risk intensity present the trends of expanding and increasing from the south to the north gradually. PMID- 30019549 TI - [Strategy of transmission interruption of schistosomiasis and its effects in Runzhou District, Zhenjiang City, Jiangsu Province]. AB - OBJECTIVE: To evaluate the effects of the strategy of transmission interruption of schistosomiasis in Runzhou District, Zhenjiang City, Jiangsu Province. METHODS: The comprehensive prevention and control strategy was carried out in RunzhouDistrict, Zhenjiang City, Jiangsu Province. The strategy was relied mainly on the Oncomelania hupensis snail control, extended chemotherapy of schistosomiasis in residents and the health education. The infection rate of schistosomiasis in residents, area with snails, area with snails controlled, and the rates of awareness and correct behavior of schistosomiasis were as evaluation indexes. RESULTS: The area with snails controlled was 7 091.50 hm2 in Runzhou District, Zhenjiang City from 2001 to 2016. The area with snails reduced year by year from 2001 to 2016. There was a negative correlation between the coverage intensity of snail control and the area with snails (r = -0.874, P = 0). There were 1 703 serum positive and 199 fecal positive people of schistosomiasis in the permanent residents from 2001 to 2016. These serum and fecal positive people of schistosomiasis were all treated with praziquantel. The serum positive rate of schistosomiasis in the permanent residents dropped to below 1.0% after 2005. The fecal positive patients were not found in 2004 and later. Totally 189 639 people received the questionnaire survey for the knowledge of schistosomiasis control from 2001 to 2016. The rates of awareness and correct behavior of schistosomiasis were raised in the residents year by year. The goal of the transmission interruption of schistosomiasis came to true in Runzhou District, Zhenjiang City in 2016. CONCLUSIONS: The comprehensive prevention and control strategy including mainly the snail control, extended chemotherapy of schistosomiasis and health education could achieve the goal of transmission interruption of schistosomiasis in the areas of marshland along the Yangtze River. PMID- 30019550 TI - [Endemic features and space - time clustering of schistosomiasis in Xinjian District, Nanchang City from 2009 to 2014]. AB - OBJECTIVE: To understand the endemic situation and distribution features of schistosomiasis in Xinjian District, Nanchang City, Jiangxi Province from 2009 to 2014, so as to provide a reference for the prevention and control of schistosomiasis in the future. METHODS: The endemic data of schistosomiasis in Xinjian District were collected by taking the village as a unit from 2009 to 2014. An endemic database was established, and the SaTScan software was applied to analyze the spatiotemporal aggregation areas of Schistosoma japonicum infection in crowd, Oncomelania hupensis snails and cattle. RESULTS: The S. japonicum infection rate of crowd was decreased from 0.10% in 2009 to 0.000 68% in 2014. The infection rate of O. hupensis snails was greatly fluctuated from 2009 to 2014, the highest was 1.04% in 2012, but it fell to 0 in 2014. The highest infection rate of cattle was 1.98% in 2012, and it fell to 0 in 2014. The spatial temporal clustering detection showed that three areas of crowd infection were mainly concentrated in 20 villages of Changyi Township, Lianyu Township and Songhu Town; two areas of snail infection were mainly concentrated in five villages of Changyi Township and Nanji Township; one area of cattle infection was mainly concentrated in three villages of Changyi Township. CONCLUSIONS: The endemic situation of schistosomiasis presents a declining trend in Xinjian District from 2009 to 2014 as a whole. However, the potential risks of the rebound of the disease still exist, and the six clustering areas of infection are still the key areas for the prevention and control of schistosomiasis in the future. PMID- 30019551 TI - [Analysis of schistosomiasis endemic situation of national surveillance sites in Yunnan Province from 2005 to 2016]. AB - OBJECTIVE: To analyze the dynamic endemic situation of schistosomiasis in Yunnan Province, and evaluate the effectiveness of the prevention and control interventions. METHODS: Four schistosomiasis heavy endemic villages (each of 4 endemic counties) from 2005 to 2014 and 18 villages (each of 18 counties) in 2015 and 2016 were selected as survey sites. Then, the serological screening and etiological tests were carried out in the residents and floating population. The infection status of the livestock and relevant information of field feces and Oncomelania hupensis snails were surveyed. RESULTS: The serum positive rate was 8.40% to 25.40% in the local residents, and the rate of the female was higher than that of the male, the rates of 30 to 60 year age groups were higher than those of the other age groups, and the rates of peasants were higher. The feces positive rate was 0 to 6.59%, and the corrected infection rate was 0 to 1.67% in the local residents. The serum positive rate was 0 to 25.00% in the floating population. The infection rate in the livestock was 0 to 10.29%, and the main infected animals were the cattle, buffalo, dog, equine and pig. Totally 1 642 feces were tested, and no positives were found. The area with snail habitats was 753.97 hm2, and the density of living snails was 0.013 9 to 0.631 5 snails/0.1 m2. A total of 64 positive snails were found. The snail control rate was 100%. Totally 161 schistosomiasis patients and 269 schistosome-infected animals were treated. CONCLUSIONS: The schistosomiasis epidemic situation has been effectively controlled, and is at a low prevalence status in Yunnan Province. In order to block the transmission of schistosomiasis and eliminate schistosomiasis, the comprehensive control measures should be strengthened continually. PMID- 30019552 TI - [Effect of cystatin from Schistosoma japonicum on DSS - induced ulcerative colitis in mice]. AB - OBJECTIVE: To investigate the effect of cysteine protease inhibitor derived from Schistosoma japonicum (SjCystatin) on dextran sodium sulfate (DSS)-induced acute ulcerative colitis in mice. METHODS: Eighteen C57BL/6 mice were randomly divided into three groups: a control group treated with PBS (Group A), a DSS-induced colitis group treated with PBS (Group B), and a DSS-induced-colitis group treated with SjCystatin (Group C). Colitis was induced in mice by giving 3% DSS orally for 7 days. During this period, the mice were daily injected with 10 MUg of SjCystatin or PBS only as a control intraperitoneally. The mice were monitored daily for their clinical manifestations and given scores based on disease activity index (DAI). The severity of colonic inflammation was monitored by the macroscopic score and pathological change. The cytokine profile including TNF alpha, IL-4, IL-6 and IL-10 in the supernatants of colon homogenate was detected by ELISA. RESULTS: Compared with Group A (0.50 +/- 0.28), the DAI score increased significantly in Group B (9.30 +/- 1.30) (F = 86.86, P < 0.01), with remarkable pathological damages seen in colon tissues. and the levels of TNF-alpha and IL-6 were (321.33+/-67.01) and (403.58 +/-180.51) pg/mL. The DAI score significantly reduced in Group C (6.67+/-1.57) as compared to Group B (F = 86.86, P < 0.01), with improvements in the macroscopic and microscopic pathology in mouse colon specimens. As compared to Group B, the levels of TNF-alpha [(188.14 +/- 40.14) pg/mL] and IL-6 ([ 209.71 +/- 48.47) pg/mL] significantly decreased (F = 17.46 and 9.89, both P < 0.01). CONCLUSIONS: SjCystatin has a significantly inhibitory effect for alleviating DSS-induced acute ulcerative colitis in C57BL/6 mice. PMID- 30019553 TI - [Establishment of a recombinase-aided isothermal amplification technique to detect Schistosoma japonicum specific gene fragments]. AB - OBJECTIVE: To establish a novel method for the detection of Schistosoma japonicum specific gene fragments by recombinase aided isothermal amplification (RAA). METHODS: The gene fragment SjG28 of S. japonicum was selected as the target gene fragment to be detected, and the primers were designed according to the mechanism of RAA reaction. The reaction of isothermal amplification of S. japonicum was established and optimized. Then this method was applied to amplify and detect the specific gene fragment in the gradient diluent SjG28-recombiant plasmids and different concentrations of S. japonicum genomic DNA to estimate the sensitivity of this method. The samples were also detected by polymerase chain reaction (PCR) in parallel as control. This method was applied to detect the genomic DNA of S. mansoni, Ascaris lumbricoides, and Ancylostoma duodenale to evaluate the specificity. RESULTS: The specific gene fragment was amplified from genomic DNA of adult worms and eggs of S. japonicum by recombinase aided isothermal amplification reaction established in this study. The reaction can be completed within 30 minutes and the minimum detectable template was 20 copies of plasmids or 0.5 ng of genomic DNA per microliter. Other parasites'genomic DNAs, such as S. mansoni, A. lumbricoides, An. duodenale and healthy human blood genomic DNA were not able to be detected by this method. CONCLUSIONS: A novel method for the detection of S. japonicum specific gene fragments by recombinase aided isothermal amplification is established in this study, which can be carried out conveniently and rapidly with a considerable sensitivity and specificity, showing the prospect for application in the diagnosis of schistosomiasis japonica. PMID- 30019554 TI - [Study on effect of clinical pathway implementation in advanced schistosomiasis with ascites]. AB - OBJECTIVE: To evaluate the effect of clinical pathway (CP) on the implementation of advanced schistosomiasis patients with ascites. METHODS: Totally 1 129 cases of advanced schistosomiasis patients with ascites but without other complications were selected randomly from the Performance Evaluation and Management System for Medical Treatment of Advanced Schistosomiasis Patients in Hubei Province from year 2011 to 2013. Among the patients, 754 cases were treated by CP (CP group), and 375 cases were treated with traditional methods (NCP group), and the hospitalization days, hospitalization expenses, medicine proportions, treatment outcomes and degrees of satisfaction and health knowledge rates of the two groups were compared. Meanwhile, the variation of CP was calculated. RESULTS: The average length of hospital days of the CP group and NCP group were (13.85 +/- 5.60) d and (17.92 +/- 5.80) d, respectively, and the average hospitalization costs of the two groups were (4 699.14 +/- 1 520.59) Yuan and (5 692.01 +/- 1 616.66) Yuan, respectively, both the differences were statistically significant (both P < 0.05). Also the hospitalization cost structures of the two groups were remarkably different, the composition ratios of the inspection fee and accommodation fee in the CP group were lower than those in the NCP group, but the constituent ratios of the examination fee, diagnosis and treatment fee, drug charges and other expenses were higher than those in the NCP group (all P < 0.05). The awareness rate of health knowledge in the CP group was higher than that in the NCP group (P < 0.05), but there were no statistically significant differences in the treatment outcome and the degree of satisfaction between the two groups (both P > 0.05). The variation rate of CP was 9.02% (68/754). CONCLUSIONS: The implementation of CP can decrease the days of hospital stay and medical expenses, improve the awareness rate on health knowledge of the patients. The CP treatment with low variation rate is applicable to advanced schistosomiasis patients with ascites but without complications. PMID- 30019555 TI - [Epidemiological characteristics of echinococcosis death cases in China from 2008 to 2016]. AB - OBJECTIVE: To understand the epidemiological characteristics of death cases of echinococcosis in China from 2008 to 2016, so as to provide an important reference for the prevention and control of echinococcosis. METHODS: The death information registration and management system data were selected to analyze the epidemiological characteristics of the death cases of echinococcosis. The data were analyzed by SPSS 21.0 and the map was drawn by ArcGIS 10.1 software. RESULTS: From 2008 to 2016, a total of 367 death cases of echinococcosis were reported in China, and the number of deaths in turn was 33, 30, 21, 32, 35, 54, 55, and 81 in each year, with an annual average crude mortality of 129.29 /105. The average age of death was (56 +/- 18) years; the sex ratio of male to female was 100?94. There was no statistical difference between the male and female death cases (chi2 = 0.33, P > 0.05).The death cases of echinococcosis were mainly distributed in endemic areas of Qinghai, Sichuan, Ningxia, Xinjiang, Gansu, Inner Mongolia, Yunnan and non-endemic areas of Heilongjiang, Jiangsu, Henan and Shandong. The death cases in the first eleven provinces accounted for 87.5% (321/367) of the total death cases, among which the highest proportions of the nationality, occupation, educational level, highest diagnostic units, and the place of death were Han (52.0%, 191/367), farmer (46.6%, 171/367), junior high school or below (57.2%, 210/367), provincial or three-level hospitals (46.6%, 171/367), and at home (59.9%, 220/367). CONCLUSIONS: Since 2014, the death cases of echinococcosis in China have been increasing year by year, indicating that the prevention and treatment of echinococcosis is still very serious. The causes for the rise of the fatality rate remain to be further studied. PMID- 30019557 TI - [Effect of Cryptosporidium parvum infection on Toll-like receptors of intestinal mucosa in mice]. AB - OBJECTIVE: To investigate the mechanism of Toll-like receptor in intestinal mucosal injury induced by Cryptosporidium parvum infection in mice. METHODS: Totally 30 male BALB/c mice were randomly divided into a normal control group, 1week infection group and 2-week infection group. The mice of the 1-week and 2 week infection groups were sacrificed 7 days and 14 days after the infection respectively, and the mice of the normal control group were sacrificed 14 days after the infection. The model of intestinal infection of C. parvum in mice was built by using the immunosuppressive method and oocyst intragastric administration. The pathological changes of the intestinal mucosa of mice were observed with a light microscope and the villus height, crypt depth and ratio of villus height/crypt depth were measured. The ultrastructure of the intestinal mucosa of mice was observed by a transmission electron microscope (TEM). The expressions of TLR2 and TLR4 in the intestinal mucosa were tested by qPCR and Western blotting. RESULTS: Under the light microscope, the intestinal villi were dropsical, obviously atrophied and shortened, and the submucosal structure was dropsical. The height of chorionic villi and the ratio of villus height to crypt depth in the jejunum of the 1-week and 2-week infection groups were significantly lower than those in the normal control group (all P < 0.05), while the depth of the recess of the former two was significantly increased (all P < 0.05). With the extension of the infection time, the villus height and the ratio of villus height to crypt depth in the jejunum of mice decreased significantly (both P < 0.05), and the crypt depth increased significantly (P < 0.01). The TEM observation showed that the structure of the oocyst of C. parvum in the jejunum of the infected mouse was intact, the villi around the oocyst were abscission seriously, and the oocyst wall was fused with the epithelial cell membrane. The qPCR observation showed that compared with the normal control group, the expressions of TLR2 mRNA and TLR4 mRNA in the intestinal mucosa of the 1-week and 2-week infection groups were significantly higher (all P < 0.05). In addition, the expressions of TLR2 and TLR4 mRNA in the 2-week infection group were significantly higher than those in the 1-week infection group (both P < 0.05). The Western blotting showed that the expressions of TLR2 protein and TLR4 protein in the intestinal mucosa of the 1-week and 2-week infection groups were significantly higher than those of the normal control group (all P < 0.05). Furthermore, the expressions of TLR2 and TLR4 protein in the 2week infection group were significantly higher than those in the 1-week infection group (both P < 0.05). CONCLUSIONS: TLR2 and TLR4 are important receptors for intestinal mucosal recognition of C. parvum. The C. parvum infection may lead to intestinal mucosal damage possibly via the mechanisms associated with the up-regulation of TLR2 and TLR4 expressions. PMID- 30019556 TI - [Epidemic situation of imported malaria and diagnostic capabilities of medical institutions in Wuhan City from 2008 to 2017]. AB - OBJECTIVE: To understand the epidemiological characteristics of imported malaria and the control and diagnostic capacities of the medical institutions in Wuhan City, so as to offer the evidence for formulating the surveillance and control strategies. METHODS: From 2008 to 2017, the epidemiological data of imported malaria were collected. The information including gender, age, distribution, vocational background, positive rate of fever patients, and time of final diagnosis was analyzed with the descriptive statistic method. The Plasmodium species composition and infection source were analyzed by chi square test. The initial and confirmed diagnosis abilities of medical institutions were analyzed by rank sum test. RESULTS: Totally, 424 imported malaria cases were reported, including 301 falciparum malaria cases (70.99%). The male population aged 20 to 49 years was the main morbidity group, and the incidence was not related to seasons. For the parasite species, there was a significant difference between African countries and Southeast Asian countries (chi2 = 205.83, P < 0.01). Plasmodium ovale and P. malariae were all imported from sub-Saharan Africa. For diagnostic capacities of the medical institutions at different levels, the initial diagnosis (Z = -3.89, P < 0.01) and confirmed diagnosis (chi2 = 53.88, P < 0.01) were significantly different, respectively. The ability of malaria diagnosis was improved rapidly in the clinical laboratory after 2008 and achieved to 100% in 2010. The detection rate within 24 hours increased to at least 90% and the detection rate within 6 days decreased to 0 in 2016. CONCLUSIONS: Although the medical institutions in Wuhan City have strong ability to treat imported malaria, they are still faced with a serious situation for malaria control and elimination. The capacity building should be strengthened constantly. PMID- 30019558 TI - [Dynamics of routine blood tests in BALB/c mice with Babesia microti infection]. AB - OBJECTIVE: To understand the changes in body weight, spleen weight and complete blood cells in BALB/c mice infected with Babesia microti. METHODS: For the infection group, six weeks old BALB/c mice were injected intraperitoneally with a dose of 100 MUL of B. microti infected blood (20% RBC infection rate, each mouse). For the determination of the progression of B. microti infection up to 28 days of the infection, the microscopic visualization of thin blood smears of tail blood stained with Giemsa staining was performed in the infection group. The experiment was carried out at different intervals on days 0, 7, 14, 21, and 28 after the infection, respectively. The mice were sacrificed, and spleens were collected and weighed, and the body weight of the mice was also determined. The blood cells of the mice were analyzed by using Mindray BC-5300 Vet animal automatic hematology analyzer. RESULTS: On the first day after the infection, B. microti was visualized in RBC of the infection group. The significantly highest infection rate (55%) appeared on the seventh day of the infection, and then steadily decreased; the mice attained the latent infection phase on the 28th day post-infection, when the parasite could not be visualized in the peripheral blood. The mice in the infected group acquired a significantly lowest body weight on the 7th day of the infection, and then gradually returned to normal. The weight of the spleen was the significantly highest on the 14th day of the infection, and then consistently decreased. On the 28th day of infection, the spleen weight was still higher than that of the control group. There were no significant changes in the number of white blood cells (WBC), lymphocytes, and eosinophils in the infected mice; and altered levels were all within the normal mouse reference range. The number of red blood cells, hemoglobin, and platelet count in the infected mice were decreased to the lowest level when the B. microti infection rate achieved to the highest, and then gradually returned to the normal levels. CONCLUSIONS: B. microti infection can cause body weight loss, splenic weight gain, and reduction in the number of erythrocytes and platelets in whole blood of the mice. Besides, the whole blood cell analyzer has a diagnostic significance in the identification of babesiosis. PMID- 30019559 TI - [Establishing evaluation system for health education products of parasitic diseases by Delphi method]. AB - OBJECTIVE: To establish an evaluation system for health education products of parasitic diseases by using a Delphi method, so as to provide references for the evaluation of health education products. METHODS: An expert panel was established and evaluation indicators were determined by brainstorming and face-to-face discussion, then the weight of each evaluation indicator was determined through a two-round Delphi method and the evaluation system was established. RESULTS: The evaluation indicators for material products, graphic design products and audio visual products were established respectively by expert panel. Four first indicators and 12 second indicators were included in each type of products. The consensus was achieved following the two rounds of expert consultation among 23 knowledgeable and experienced experts, who considered "scientificity" and "acceptability" to be the most important of all the first indicators, and "information accuracy" and "behavioral guidance" of all the second indicators. CONCLUSIONS: A scientific and rational evaluation system is established, and it can be used in comprehensive evaluation of health education products for parasitic diseases. PMID- 30019560 TI - [Sequential analysis of genome of Thelazia callipaeda]. AB - OBJECTIVE: To investigate the molecular characteristics of genome sequence of Thelazia callipaeda (T. cp). METHODS: The obtained T. cp genome assembling data were annotated by using a combination of ab initio gene by softwares, GeneMark and GeneID, and the homology of the experimentally confirmed genes was predicted by software GeMoMa. The results were integrated by software EVM to predict all genes of genome. The obtained genes were annotated in the common public database and three dedicated databases (CAZyme, TCDB and PHI), respectively. RESULTS: The Scaffolds and Contigs gene structure of T. cp genome (79.34 Mb) was analyzed, and a total of 6 333 genes were obtained. The sequence search was conducted in the public databases using BLASTx, of which 97.85% of the genes could be annotated. The genes annotated in the NR database were the most (98.69%), and those enriched in the KEGG pathway were the least (50.50%). The functional genes were blasted by KOG database and totally 4 517 genes were found. The three special databases (CAZyme, TCDB and PHI) were used to annotate all the genes, and 136, 139 and 1 498 genes were assigned respectively, and the number of genes in the PHI database was the largest. In the cytochrome proprietary database, 238 cytochrome P450 genes were predicted. CONCLUSIONS: We have preliminarily revealed the T. cp genome structure characteristics and annotation information, and totally 6 333 genes are obtained. PMID- 30019561 TI - [Development of a novel method for UPLC-QTOF-MS analysis of anti-schistosomiasis heterocyclic compounds]. AB - OBJECTIVE: To develop an ultra-performance liquid chromatography/quadrupole-time of flight mass spectrometry (UPLC-QTOF-MS) method for the determination of an oxadiazole-2-oxide heterocyclic compound F-2015-14. METHODS: Mouse plasma and liver homogenate specimens were extracted with ethyl acetate and chromatographed on a Waters CORTECS column (C18, 1.6 MUm, 2.1 mm * 150 mm) by using a mobile phase of 10% acetonitrile-0.1% formic acid with by a volume fractionation by gradient elution. Then, UPLC-QTOF-MS was performed to determine F-2015-14 in mouse plasma and liver homogenate specimens. RESULTS: The linearity of F-2015-14 in plasma ranged from 12.5 to 250 mg/mL with a correlation coefficient of 0.990 and a detection limit of 8.8 mg/mL. F-2015-14 in liver homogenates ranged from 12.5 to 250 mg/mL. The linearity was good with a correlation coefficient of 0.992 and a limit of detection of 5.6 mg/mL. If the concentration of plasma and liver homogenate specimens was 12.5 mg/mL, the accuracy and the matrix effect were 80% to 120%, and the inter-day and intra-day precision was within 20%. If the concentrations of plasma and liver homogenate specimens were 100 mg/mL and 200 mg/mL, the accuracy and the matrix effect were 85% to 115%, and the inter-day and intra-day precision was within 15%. CONCLUSIONS: The UPLC-QTOF-MS established in this study has a high sensitivity and good reproducibility for the determination of F-2015-14, which provides bases for the development of novel anti schistosomiasis drugs. PMID- 30019562 TI - [Investigation on Toxoplasma gondii infection in liver disease patients in Hangzhou City]. AB - OBJECTIVE: To understand the Toxoplasma gondii infection in liver disease patients in Hangzhou City. METHODS: A total of 1 200 patients with liver diseases were enrolled, including 300 patients with liver cancer, 300 cases with hepatitis B, 300 cases with hepatic fibrosis and 300 cases with fatty degeneration of the liver, while 1 200 healthy people served as controls. The serum anti-T. gondii IgG and IgM antibodies were detected in the subjects using ELISA assay. RESULTS: The seropositive rates of anti-T. gondii IgG and IgM antibodies were 24.00% (288/1 200) and 1.17% (14/1 200) in the liver disease patients, and 11.42% (137/1 200) and 1.08% (13/1 200) in the healthy controls, respectively. There was a significant difference in the seropositive rate of anti-T. gondii IgG antibody between the liver disease patients and controls (chi2 = 65.19, P < 0.01), and no significant difference was seen in the seropositive rate of anti-T. gondii IgM antibody between the liver disease patients and controls (chi2 = 0.04, P > 0.05). The seropositive rates of anti-T. gondii IgG antibody were 26.00%, 25.00%, 23.33% and 21.67% in the patients with liver cancer, hepatitis B, hepatic fibrosis and fatty degeneration of the liver, respectively, and no significant difference was detected among these patients with four types of liver diseases (chi2 = 1.79, P > 0.05). CONCLUSIONS: The seropositive rate of anti-T. gondii IgG antibody is high in liver disease patients in Hangzhou City, and the management and health education of toxoplasmosis should be given to patients with liver diseases. PMID- 30019563 TI - [Study on community of acaroid mites breeding in home storages in Linquan Area, Anhui Province]. AB - OBJECTIVE: To investigate the species and diversity of acaroid mites community in home storages in Linquan area, Anhui Province. METHODS: The samples of 48 kinds of storages from the residents in Linquan County were collected, and the mites in them were separated in a microscope directly. RESULTS: Totally 19 species of acaroid mites belonging to 14 genera of 6 families were obtained from the 48 kinds of samples. The diversity analysis showed that the number of species, the species richness index and species diversity index of mites in the habitats were in the order of the other storages > drysaltery > grains. CONCLUSIONS: The quantities of breeding acaroid mites in storages in Linquan area are much larger, meanwhile the species are also very rich, thus in order to reduce the harm of acaroid mites, we should take active measures to control their breeding. PMID- 30019564 TI - [Seasonal fluctuations of mosquitoes and application of two surveillance tools in Taibai Lake area of Jining City]. AB - OBJECTIVE: To investigate the seasonal fluctuations of mosquitoes in Taibai Lake area of Jining City, and evaluate the application effects of two mosquito trapping tools (Gongfu Xiaoshuai mosquito lamp and WJ-C mosquito sampler), so as to provide references for the effective surveillance, prevention and control of local mosquito vectors. METHODS: The overnight capture of mosquitoes with a man bait net trap, Gongfu Xiaoshuai mosquito lamp, and WJ-C mosquito sampler was performed to collect mosquitoes. The species of adult mosquitoes and seasonal fluctuations were investigated and analyzed. RESULTS: A total of 10 914 mosquitoes belonging to 13 species, 5 genera were collected with the overnight capture of mosquitoes with the man-bait net trap, and Culex tritaeniorhynchus, Cx. pipiens palllen and Mansonia uniformis were the dominant species, accounting for 77.41% of the total. The proportion of Coquillettidia ochracea increased significantly. All the adult mosquitoes appeared in June, and reached the density peak in July and August. Both of the two surveillance tools showed relatively sensitive capture performance against mosquitoes. The trapping results of WJ-C mosquito sampler were basically the same as the man-bait trapping method, however, the amount of Mansonia uniformis and Coquillettidia ochracea collected by Gongfu Xiaoshuai mosquito lamp was significantly lower than that of the man bait trapping method. CONCLUSIONS: The mosquito species are varied in Taibai Lake area of Jining City. Therefore, monitoring should be strengthened. In addition, the two mosquito trapping tools are sensitive, but they have both advantages and disadvantages, thus we should better pay attention to the consistency of monitoring methods in use. PMID- 30019565 TI - [Survey of prevention knowledge and behavior of echinococcosis and influencing factors in residents in agricultural and pastoral areas of Maerkang City]. AB - OBJECTIVE: To master the prevention knowledge and behavior of echinococcosis and the influencing factors in residents in agricultural and pastoral areas of Maerkang City, so as to provide the reference for formulating the policy and strategy of echinococcosis prevention and control. METHODS: In April, 2017, 796 residents in agricultural and pastoral areas of Maerkang City were selected by the multi-stage stratified random sampling method, and surveyed with questionnaires. The main questions included the prevention knowledge and related behaviors of echinococcosis. RESULTS: The awareness rate of prevention knowledge of echinococcosis was 70.1% (558/796). The awareness rate was the lowest in the group aged 15 to 25 years. The difference of knowledge awareness rate was statistically significant among the different age groups (chi2 = 16.408, P < 0.01). The knowledge awareness rate of the people with middle school or above educational level was higher than that of the people with primary school or below educational level (chi2 = 4.869, P = 0.027). The knowledge awareness rate of the dog owners was lower than that of the people without a dog (chi2 = 11.384, P = 0.001). The knowledge awareness rate in the people who received the knowledge training of three times or more was higher than that in the people who received the knowledge training of two times or less (chi2 = 11.439, P = 0.003). The logistic regression showed that the age, educational level, training times and dog raising were the main influencing factors. The related behavior survey showed that 32.7% (260/796) of residents did not drink unboiled water, 37.0% (61/165) of dog owners tied the dog, 43.6% (72/165) of dog owners fed the dogs with anthelmintic regularly, and only 10.3% (17/165) of dog owners buried the dog's dung. CONCLUSIONS: The awareness rate of echinococcosis prevention knowledge in Maerkang City should be improved. The health education should be focused on the young people, people with low educational level, and people who have dogs. The behaviors of drinking unboiled water, tying dogs, feeding dogs with anthelmintic regularly, and burying dog' s dung should be advocated. PMID- 30019566 TI - [Acaroid mite breeding in ground rice in Wenchang area]. AB - OBJECTIVE: To investigate the breeding of acaroid mites in the stored grains in Wenchang area, Hainan Province, China. METHODS: The breeding mites from the samples were separated by a shake-sieve and microscope directly. The isolations were used for slide preparation based on previous literature, and then under a light microscope, the identification and counting of the acaroid mites were performed. RESULTS: Twelve species of mites were identified from 20 categories of grains. They belonged to 10 genera of 4 families. Among the 12 grain samples, the breeding rates were higher of Blomia tropicalis and Tyrophagus putrescentiae. Among the 20 samples collected, a total of 5 885 mites were found, with an average breeding density of 29.43/g. CONCLUSIONS: The infestation of acaroid mites appears serious in the stored grains in Wenchang area, which should be taken measures to prevent and control. PMID- 30019567 TI - [Tracking evaluation on implementation of Criteria for Control and Elimination of Malaria (GB 26345-2010) in Yunnan Province]. AB - OBJECTIVE: To understand the knowledge, usage, applicability of the standard and the suggestions on the implementation of Criteria for Control and Elimination of Malaria (GB 26345-2010) among malaria prevention and control staff of disease control and medical institutions at all levels in Yunnan Province, so as to provide the evidence for the implementation and revision of the standard. METHODS: Malaria prevention and control workers at 192 institutions in 16 prefectures and cities of Yunnan Province were surveyed. The malaria prevention and treatment workers at county-level center for disease control and prevention (CDCs), county-level medical institutions and township hospitals in Tengchong City and Yingjiang County of Yunnan Province were investigated on the spot. The knowledge and usage, problems and recommendations encountered in the implementation of the standard were collected. RESULTS: Totally 444 questionnaires were collected, of which 428 were valid and the valid rate of questionnaires was 96.4%. Among them, the proportion of those who knew the standard was 86.7% (371/428), and the channel of knowledge acquirement was mainly the education and training, accounting for 50.7% (188/371). The total awareness rate of objective indicators in the standard content was 65.9% (282/428). Among the frequency of utilization, the "occasional use" of this standard was the majority, accounting for 33.6% (144/428). Among the applications, the highest proportion of applying to the "regular malaria prevention and control work" was 59.3% (191/322), and only 19.3% (62/322) applied to the "assessment for malaria elimination". In the standard suitability assessment, the proportion of considering the standard to be fully applicable was 91.3% (391/428), and the proportion of considering the standard to be revised was 8.7% (37/428). The agencies where the respondents were located have taken corresponding measures to promote the implementation of the standard. A total of 43 proposals for the implementation of the standard were collected, relating to personnel and supporting conditions. CONCLUSIONS: Combined with the actual situation, the standard should be strengthened practically. At the same time, the standard learning, training, and publicity should be strengthened to raise the implementation level. Its implementation in Yunnan Province should be sequentially consolidated and steadily promoted. PMID- 30019568 TI - [Historical Oncomelania hupensis snail environments in Baoshan District, Shanghai City]. AB - OBJECTIVE: To understand the distribution and characteristics of historical Oncomelania hupensis snail environments in Baoshan District, Shanghai City, so as to provide the reference for adjusting and formulating the monitoring program of the snail situation in the future. METHODS: A retrospective survey and a field survey were conducted to collect the information of historical O. hupensis snail environments and set up the database. The distribution and characteristics of them were analyzed. RESULTS: There were 53 historical O. hupensis snail environments which distributed in three towns, and the accumulative area was 1 635 530 m2 in Baoshan District, Shanghai City. Class I, II, III and IV accounted for 73.58%, 5.66%, 16.98% and 3.77% respectively. The complete transformation (Class I and Class II) was done in 42 places which covered the area of 1 622 043 m2, in which Class I environments and Class II environments accounted for 79.25% and 99.18% of the total, respectively. CONCLUSIONS: There has been a great change in the historical O. hupensis snail environments in Baoshan District, Shanghai City. The information of the field investigation should be enriched and updated at different times to guide the investigation of O. hupensis snails in the future. PMID- 30019569 TI - [Surveillance results of national monitoring sites for soil-transmitted nematode infections in Xinchang County from 2009 to 2017]. AB - OBJECTIVE: To understand the infection status of soil-transmitted nematodes in Xinchang County, so as to offer the evidence for the formulation of control measures. METHODS: The infection of soiltransmitted nematodes in residents was investigated by using the Kato-Katz method and cellophane anal swab. RESULTS: A total of 3 069 people were examined in 2009, 2012 and 2017, of which 1 520 people were male and 61 people were infected, with the infection rate of 4.01%; 1 549 were women and 54 people were infected, with the infection rate of 3.48%. The infection rates of soil-transmitted nematodes in 2009, 2012 and 2017 were 4.60%, 4.29% and 2.35%, respectively, and the total infection rates were decreased (chi2 = 7.151, P < 0.05). CONCLUSIONS: The rate of soil-transmitted nematode infection in Xinchang County is declining, and it is at a low epidemic level. PMID- 30019570 TI - [Investigation on knowledge, attitude and practice (KAP) of college students on foodborne parasitic diseases in Wuhu City]. AB - OBJECTIVE: To understand the status of knowledge, attitude and practice (KAP) on foodborne parasitic diseases and the influencing factors among college students in Wuhu City, so as to provide the evidence for the development of strategies on health education. METHODS: A total of 1 685 college students from five colleges were selected through the randomly stratified cluster sampling method, and then they were investigated by questionnaires to understand their KAP on foodborne parasitic diseases. Chi-square test was performed and regression models were constructed to analyze the influencing factors of knowledge on food-borne parasitic diseases. RESULTS: Among the 1 685 college students surveyed the awareness rates of knowledge about foodborne parasitic diseases and their harms were 33.5% (565 cases) and 31.4% (529 cases). There were statistically significant differences among/between the grades, schools, places of origin, family incomes, whether or not having the male or female friends, whether or not having the medical personnel in the family, whether or not having the insistence on the annual physical examination, whether or not receiving the health education, and whether or not having the history of parasitic diseases (all P < 0.05). The logistic regression analysis showed that the school, receiving the health education, having the insistence on the annual physical examination, and the history of parasitic diseases were the independent influencing factors of the awareness rate of knowledge on foodborne parasitic diseases (all P < 0.01). CONCLUSIONS: The awareness rate, healthy behavior and correct attitude formation about foodborne parasitic diseases are low among the college students in Wuhu City, and therefore, it is necessary to offer the courses related to foodborne parasitic diseases in colleges and universities. PMID- 30019571 TI - [Evolution and evaluation of schistosomiasis prevention and control institutions in China]. AB - Schistosomiasis is one of a few endemic and infectious diseases, which are controlled by the specific prevention and control institutions in China. Through the review of historical data, this paper describes the construction, continuation and changes of schistosomiasis prevention and control institutions in different historical periods and systems, and analyzes and evaluates its historical function, contribution and status. PMID- 30019572 TI - [Anemia due to hookworm disease: a case report]. AB - This paper reports one case of anemia due to hookworm disease. The case was diagnosed through the stool routine examination, in which the hookworm ova were found. It is suggested that the role of stool routine examination in the diagnosis of hookworm disease should be paid much attention. PMID- 30019573 TI - [Differentiating the morphology of infective larvae between two human hookworms]. AB - The morphological differentiation of the infective larvae between human Ancylostoma duodenale and Necator americanus is of great significance for the epidemiological survey of hookworm diseases and human parasitology teaching. Understanding of features of the oral spear and transverse lines on the tunica vaginalis is able to accurately differentiate the infective larvae between these two human hookworms. PMID- 30019574 TI - Recalcitrant and recurrent bacterial folliculitis during anti-IL17 therapy in a psoriatic patient. PMID- 30019575 TI - Digital myxoid cysts: 12-year experience from two Italian Dermatology Units. AB - BACKGROUND: Digital mucous cysts (DMCs) are benign, translucent, fluid-filled asymptomatic, slow-growing, dome-shaped nodules overlying a joint or tendon sheath on the distal dorsal side of the fingers or, more rarely, on the toes. They are degenerative in nature and are often associated with interphalangeal joint arthritis. Although DMCs are usually solitary, multiple cysts have been observed to develop simultaneously. They can sometimes be painful, confer a reduction in motility, and cause weakness and deformity in the nails. Spontaneous regression is rare, and intervention using surgical or non-surgical treatment is advisable. METHODS: We analyzed 53 DMCs of 51 patients treated in two Italian Dermatology Units between January 2004 and March 2015. The aim of this study was to evaluate the most salient clinical, histopathological and dermoscopic features, in addition to the response to treatment. We then compared the data to assess whether the histological type (ganglion-type or focal dermal mucinosis type) or immunohistochemical phenotype of DMCs is correlated with the likelihood of relapse. All the patients have been treated with simple surgical excision with a cure rate of 72.6% at a mean recurrence time of 160 days with a mean follow-up of 3.6 years. RESULTS: Histopathological examination, performed in 11 out of the 53 cysts, revealed 7 cases of ganglion-type cysts and 4 cases of focal cutaneous mucinosis-type cysts. No correlation was detected between histopathological type and recurrence. CONCLUSIONS: Digital dermoscopy confirmed the pattern recently reported in the literature, providing confidence in the clinical diagnosis and reducing the need for preoperative radiography or ultrasound imaging. PMID- 30019576 TI - Suicidality among psoriasis patients: a critical evidence synthesis. AB - Psoriasis is a chronic inflammatory skin disease with under-investigated and underappreciated links to psychiatric comorbidities, including anxiety, depression, and suicidality. In this review, we synthesize and discuss the literature investigating the association between psoriasis and three measures of suicidality: suicidal ideation, suicide attempts, and completed suicide. Studies have shown that psoriasis is significantly linked to all three measures of suicidality, but the available data on suicide attempts and completed suicides is limited and less consistent. Studied risk factors for suicidality in psoriasis patients include age, gender, and severity of psoriasis. Younger patients and patients with more severe psoriasis are at significantly higher risk of suicidality; gender was not associated with suicidality in most studies. Higher levels of psoriasis-related stressors and decrements to quality of life were significantly associated with suicidality in psoriasis patients. Most biologic treatments for psoriasis appear to be helpful in decreasing rates of depression, but data on their impact on suicidality is less well known. Understanding the risk of suicidality in psoriasis patients is key to engaging all stakeholders to screen psoriasis patients for mental health conditions. Clinicians may incorporate simple screening tools to screen for suicidal ideation and refer appropriately. PMID- 30019577 TI - Xenon-anaesthesia and beyond: pros-contras. AB - Xenon is a colourless and odourless noble gas, licensed for human use as an anaesthetic gas as well as a radiological marker. The MAC of this gas is about 63% but Xenon anaesthesia is associated with fast recovery of cognitive function and cardiovascular stability. Nevertheless, Postoperative nausea and vomiting (PONV) incidence for xenon anaesthesia is very high. Xenon has been reported to have cytoprotective effects that may have therapeutic values in both CNS protection, and in organ graft preservation. Currently, there are few studies about the effect of Xenon on ischaemia reperfusion injury of transplantable organs and insufficient clinical data upon its effect on intracranial and cerebral perfusion pressure. We shortly review pros and contras of Xenon, as an anaesthetic agent. PMID- 30019579 TI - Toward Super-Tough Poly(l-lactide) via Constructing Pseudo-Cross-link Network in Toughening Phase Anchored by Stereocomplex Crystallites at the Interface. AB - We demonstrated a novel strategy to toughen poly(l-lactide) (PLLA) by constructing pseudo-cross-link networks based on chain entanglements of long chain branched structure in the toughening phase, which were anchored by stereocomplex (SC) crystallites at the interface. The formation of pseudo-cross link network was achieved by simple blending of the copolymer of long-chain branched polycaprolactone and poly(d-lactide) (LB-PCL- b-DLA) with PLLA without introducing any chemical cross-linking structure or nonbiodegradable component. The microscopic morphology analysis suggests that the interface-formed SC crystallites not only enhanced the interfacial interaction between LB-PCL and PLLA but also obviously increased the matrix crystallization rate. Different from those blends without SC crystallites or long-chain branched structures, nano microgels were observed in chloroform solution of the PLLA/LB-PCL- b-DLA blend, suggesting the formation of pseudo-cross-link network. The pseudo-cross-link network in LB-PCL toughening phase endows PLLA a significantly improved impact toughness (49.5 kJ/m2), which is almost 13 times than that of neat PLLA. Moreover, matrix crystallinity and spherulite size of the PLLA matrix also play significant roles in toughening. Only sufficiently crystallized PLLA with proper spherulite size can effectively trigger the matrix shear yielding, meanwhile, facilitate the energy dissipating. PMID- 30019580 TI - Diastereoselective and Enantioselective Synthesis of Barbiturate-Fused Spirotetrahydroquinolines via Chiral Palladium(0)/Ligand Complex Catalyzed [4 + 2] Cycloaddition of Vinyl Benzoxazinanones with Barbiturate-Based Olefins. AB - Under the catalysis of chiral palladium(0)/ligand complex, the [4 + 2] cycloaddition between vinyl benzoxazinanones and barbiturate-based olefins proceeded readily and provided barbiturate-fused spirotetrahydroquinolines in up to 96% chemical yield with up to >99:1 dr and 97% ee. The absolute configuration of barbiturate-fused spirotetrahydroquinolines was clearly identified by X-ray single crystal structure analysis. The reaction mechanism was proposed to shed light on the enantioselective formation of barbiturate-fused spirotetrahydroquinolines. PMID- 30019578 TI - Traditional Tibetan Medicine Induced High Methylmercury Exposure Level and Environmental Mercury Burden in Tibet, China. AB - Highly elevated concentrations of total mercury (THg) and methylmercury (MeHg) were found in the municipal sewage in Tibet. Material flow analysis supports the hypothesis that these elevated concentrations are related to regular ingestion of Hg-containing Traditional Tibetan Medicine (TTM). In Tibet in 2015, a total of 3600 kg of THg was released from human body into the terrestrial environment as a result of TTM ingestion, amounting to 45% of the total THg release into the terrestrial environment in Tibet, hence substantially enhancing the environmental Hg burden. Regular ingestion of TTM leads to chronic exposure of Tibetans to inorganic Hg (IHg) and MeHg, which is 34 to 3000-fold and 0-12-fold higher than from any other known dietary sources, respectively. Application of a human physiology model demonstrated that ingestion of TTM can induce high blood IHg and MeHg levels in the human body. Moreover, 180 days would be required for the MeHg to be cleared out of the human body and return to the initial concentration i.e. prior to the ingestion of 1 TTM pill. Our analysis suggests that high Hg level contained in TTM could be harmful to human health and elevate the environmental Hg burden in Tibet. PMID- 30019581 TI - Topological Phase Buried in a Chalcogenide Superlattice Monitored by Helicity Dependent Kerr Measurement. AB - Chalcogenide superlattices (SLs), formed by the alternate stacking of GeTe and Sb2Te3 layers, also referred to as interfacial phase-change memory (iPCM), are a leading candidate for spin-based memory device applications. Theoretically, the iPCM structure has been predicted to form a three-dimensional topological insulator or Dirac semimetal phase depending on the constituent layer thicknesses. Here, we experimentally investigate the topological insulating nature of chalcogenide SLs using a helicity-dependent time-resolved Kerr measurement. The helicity-dependent Kerr signal is observed to exhibit a four cycle oscillation with pi/2 periodicity, suggesting the existence of a Dirac-like cone in some chalcogenide SLs. Furthermore, we found that increasing the thickness of the GeTe layer dramatically changed the periodicity, indicating a phase transition from a Dirac semimetal into a trivial insulator. Our results demonstrate that thickness-tuned chalcogenide SLs can play an important role in the manipulation of topological states, which may open up new possibilities for spintronic devices based on chalcogenide SLs. PMID- 30019582 TI - Presence of the Carcinogen N'-Nitrosonornicotine in Saliva of E-cigarette Users. AB - Many harmful constituents are present in e-cigarettes at much lower levels than in cigarette smoke, and the results of analysis of urinary biomarkers in e cigarette users are consistent with these findings. However, understanding the health effects of chronic exposures to e-cigarette aerosols may require thinking beyond these comparisons. In this study, we investigated the endogenous formation of the tobacco-specific oral and esophageal carcinogen N'-nitrosonornicotine (NNN) in e-cigarette users. Salivary NNN, nornicotine, and nicotine as well as urinary tobacco biomarkers, including total NNN, were analyzed in 20 e-cigarette users, 20 smokers, and 19 nonsmokers. Nornicotine and NNN levels in e-cigarettes used by the study participants were also analyzed. The mean of NNN in saliva of e cigarette users was 14.6 (+/-23.1) pg/mL, ranging from nonquantifiable (below the limit of quantitation, LOQ) to 76.0 pg/mL. In smokers, salivary NNN ranged from below LOQ to 739 pg/mL, with 80% of smokers having salivary NNN in the range of levels found in e-cigarette users. Consistent with a previous report, very low levels of urinary total NNN were present in only 5 out of 20 e-cigarette users (ranging from 0.001 to 0.01 pmol/mL urine). Only trace levels of NNN were found in e-cigarette liquids. Together, our findings demonstrate that NNN is formed endogenously in e-cigarette users. While the overall exposure to NNN in e cigarette users is dramatically lower than in smokers, the known carcinogenic potency of NNN warrants further investigations into the potential consequences of its endogenous formation. Salivary NNN, rather than urinary total NNN, which accounts for only 1-3% of the NNN dose, should be used to monitor e-cigarette users' exposure to this carcinogen. PMID- 30019583 TI - Facile Synthesis of Highly Dispersed Co3O4 Nanoparticles on Expanded, Thin Black Phosphorus for a ppb-Level NO x Gas Sensor. AB - Expanded few-layer black phosphorus nanosheets (FL-BP NSs) were functionalized by branched polyethylenimine (PEI) using a simple noncovalent assembly to form air stable overlayers (BP-PEI), and a Co3O4@BP-PEI composite was designed and synthesized using a hydrothermal method. The size of the highly dispersed Co3O4 nanoparticles (NPs) on the FL-BP NSs can be controlled. The BP-C5 (190 degrees C for 5 h) sensor, with 4-6 nm Co3O4 NPs on the FL-BP NSs, exhibited an ultrahigh sensitivity of 8.38 and a fast response of 0.67 s to 100 ppm of NO x at room temperature in air, which is 4 times faster than the response of the FL-BP NS sensor, and the lower detection limit reached 10 ppb. This study points to a promising method for tuning properties of BP-based composites by forming air stable overlayers and highly dispersed metal oxide NPs for use in high performance gas sensors. PMID- 30019584 TI - Correction to Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo beta-lactamase-1. PMID- 30019585 TI - Ionothermal Synthesis of Open-Framework Metal Phosphates Using a Multifunctional Ionic Liquid. AB - Two crystalline metal phosphates (metal = Be and Al) were prepared under ionothermal conditions using a multifunctional ionic liquid as a solvent, a structure-directing agent, and a phosphorus source. The beryllium phosphate has a three-dimensional structure with intersecting 24-membered ring (24 MR) channels. The aluminum phosphate has a two-dimensional structure containing 8 MR windows. It displays exceptional hydrothermal stability and shows a high proton conductivity on the order of 10-3 S cm-1 at 25 degrees C under high humidity conditions. PMID- 30019586 TI - Insight Analysis of Promiscuous Estrogen Receptor alpha-Ligand Binding by a Novel Machine Learning Scheme. AB - Estrogen receptor alpha (ERalpha) plays a significant role in occurrence of breast cancer and may cause various adverse side-effects when ERalpha is an off target protein. A theoretical model was derived to predict the binding affinity of ERalpha using the pharmacophore ensemble/support vector machine (PhE/SVM) scheme to consider the promiscuous characteristic of ERalpha. The estimations by PhE/SVM were discovered to be in good agreement with the observed values for those training molecules ( n = 31, r2 = 0.80, qCV2 = 0.77, RMSE = 0.57, s = 0.58), test molecules ( n = 179, q2 = 0.91-0.96, RMSE = 0.33, s = 0.26) and outliers ( n = 15, q2 = 0.80-0.86, RMSE = 0.56, s = 0.49). When subjected to various statistical validations, the PhE/SVM model consistently fulfilled the strictest criteria. A mock test also asserted its predictivity. When compared with crystal structures, the calculated results are consistent with the reported ERalpha-ligand co-complex structure, and the plasticity nature of ERalpha is also disclosed. Consequently, this precise, fast, and robust model can be adopted to predict ERalpha-ligand binding affinities and to design safer non-ERalpha targeted pharmaceuticals in the process of drug discovery and development. PMID- 30019588 TI - Elevated serum YKL-40 correlates with clinical characteristics in patients with polymyositis or dermatomyositis. AB - Background Serum YKL-40 has been proved to be a promising biomarker for estimating the disease activity of several autoimmune diseases. However, its utility in polymyositis or dermatomyositis has not been established. The aim of this study was to investigate the utility of YKL-40 in patients with polymyositis/dermatomyositis. Method Patients with definite polymyositis/dermatomyositis who visited the Second People's Hospital of Wuxi between April 2016 and March 2017 were prospectively enrolled. Eighty-seven healthy individuals were set as a control. Serum YKL-40 of all participants was determined using ELISA. The associations between YKL-40 and clinical characteristics of polymyositis/dermatomyositis were analysed using the Student's t-test, Mann-Whitney test and receiver operating characteristic curve analysis. Results A total of 99 patients with polymyositis/dermatomyositis were enrolled. The patients with polymyositis/dermatomyositis had significantly higher serum YKL 40 concentration. Patients with interstitial lung disease had significantly higher YKL-40 concentration than those without. Serum YKL-40 was positively correlated with myositis disease activity assessment visual analogue scale, C reactive protein, erythrocyte sedimentation rate and ferritin. The area under receiver operating characteristic curve of YKL-40 for identifying interstitial lung disease was 0.82. Conclusions Serum YKL-40 is a useful biomarker for estimating disease activity or severity of polymyositis/dermatomyositis. PMID- 30019587 TI - Development and Optimization of an In Vitro Multienzyme Synthetic System for Production of Kaempferol from Naringenin. AB - An in vitro multienzyme synthetic system was developed and optimized to efficiently produce kaempferol in a single reaction tube. Two key genes, Atf3h and Atfls1, in the biosynthetic pathway of kaempferol were cloned into a prokaryotic expression vector and overexpressed in Escherichia coli. The recombinant proteins were purified through affinity chromatography and showed activities of flavanone 3-hydroxylase and flavonol synthase, respectively, followed by development of an in vitro synthetic system for producing kaempferol. The system contains 8.2 mM alpha-ketoglutaric acid, 0.01 mM ferrous ion, 0.4% sodium ascorbate, 25 MUg/mL of each recombinant enzyme, and 10% glycerol in 100 mM Tris-HCl (pH 7.2). When the reaction was carried out at 40 degrees C for 40 50 min, the yield of kaempferol was 37.55 +/- 1.62 mg/L and the conversion rate from NRN to KMF was 55.89% +/- 2.74%. Overall, this system provides a promising and efficient approach to produce kaempferol economically. PMID- 30019589 TI - Prospective analysis of phoned potassium results and what general practitioners do with them: a pilot study. AB - Background Communicating abnormal results to requesting clinicians is an essential part of clinical authorisation. Guidance from the Royal College of Pathologists on communication of critical/unexpected results is issued as 'advice to pathologists'. The 2017 guidelines advise rapid communication of serum potassium results <=2.5 mmol/L and >=6.5 mmol/L. Little is known about what happens after the results have been communicated. We wished to establish answers to the following questions: Are phoned results acted on? If so, when? What is the outcome of any action taken? Methods A prospective study of primary care potassium results authorised out of hours was undertaken. Potassium requests from primary care were retrieved from the laboratory information management system. The potassium result was recorded, along with other data. Data were analysed for potassium results that were validated out of hours (18:00 h-08:00 h). Results Over six months, 220 potassium results <3.1 mmol/L and >5.9 mmol/L from primary care were validated out of hours. A subset of these (27) were phoned to the general practice out of hours 'hub', and 16 patients referred to hospital out of hours, on account of the potassium results. The remaining potassium results phoned out of hours were acted on subsequently. Conclusions Critical potassium results were phoned urgently and are acted on, although not always out of hours. For potassium results phoned out of hours, the most frequent action was to refer to hospital out of hours. Different actions occurred for similar potassium results, reflecting the fact that actions taken and their urgency depend on the patient, the clinician and the practice policy for handling results. PMID- 30019590 TI - Targeted therapy for metastatic colorectal cancer. AB - INTRODUCTION: Outcomes in metastatic colorectal cancer are improving, with better understanding and use of targeted therapies. Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This article reviews the current evidence for targeted therapies in advanced colorectal cancer, including up-to-date data regarding anti-epidermal growth factor receptor (EGFR) and anti vascular endothelial growth factor (VEGF) agents, the relevance of primary tumor location and novel subgroups such as BRAF mutated, HER2 amplified, and mismatch repair-deficient cancers. Expert commentary: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for metastatic colorectal cancer (mCRC). The use of EGFR-targeted antibodies should be restricted to patients with extended RAS wild-type profiles, and there is evidence that they should be further restricted to patients with left-sided tumors. Clinically, mCRC can be divided into subgroups based on RAS, BRAF, HER2, and MMR status, each of which have distinct treatment pathways. PMID- 30019591 TI - Assessment of pasteurisation of edible insects using enzymatic tests (activity of alkaline phosphatase and lactoperoxidase) applied in dairy products. AB - Industrialising edible insects goes along with quality control and hazard analysis and critical control points. One of those steps is assessing heat treatment. For the present contribution, the potential of enzymatic heat assessment tests used in the dairy industry (alkaline phosphatase and lactoperoxidase) to detect heat treatment in several insect species ( Acheta domesticus, Gryllus assimilis, Gryllus bimaculatus, Locusta migratoria, Schistocerca gregaria, Chilecomadia moorei, Galleria mellonella, Bombyx mori, Pachnoda marginata, Tenebrio molitor, Zophobas atratus, Apis mellifera, and Hermetia illucens) was evaluated. Insect material was homogenised, diluted, and the enzymatic tests (Lactognost(r), Peroxtesmo(r)) were carried with these liquids as if they were milk. All species but C. moorei, B. mori, P. marginata, and A. mellifera showed alkaline phosphatase activity in raw samples and none in heated (10 min at 100 C) ones, while only G. mellonella, T. molitor, and Z. atratus reacted accordingly with lactoperoxidase. In trial 2 focusing only on alkaline phosphatase activity, inactivation of the enzyme after 5, 10, and 15 min of heating occurred species specific within a range of 60-86 C, i.e. within ordinary pasteurisation schemes. Thus and for the time being, heat treatment in many edible insect species can be assessed using alkaline phosphatase activity test kits. In contrast to milk samples, positive results may display bluish or greenish colours, and the time until a reliable reading is possible is extended to 1-1.5 h (24 h in the case of Gryllidae). PMID- 30019592 TI - Cluster-status migrainosus with a weekly periodicity responsive to high-flow oxygen: A case report. AB - Background There are cases in the headache literature described as "cluster migraine," but none of stereotyped cases of cluster headache evolving into status migrainosus. We believe this is the first documented case of "cluster-status migrainosus". Case A 54 year-old female hospital administrator presented with headaches with a unique periodicity and semiology that were acutely responsive to high-flow oxygen. She experienced cluster headache attacks every Thursday morning at 3-4 am, which would evolve into status migrainosus lasting through Sunday evening. These attacks were preceded by prodromal depressed mood changes and fluid retention, and later followed by postdromal euphoria and auto-diuresis. These attacks initially occurred every other week and progressed to weekly attacks for 1.5 years. These headaches did not respond to trials of propanolol, sodium valproate, topiramate, amitriptyline, gabapentin, and carbamazepine for preventive treatment or to oral sumatriptan and butalbital-acetaminophen-caffeine for acute treatment. We started her on high-flow 100% oxygen for cluster headache, which successfully aborted greater than 80% of her weekly cluster headache attacks and prevented them from evolving into status migrainosus. Conclusion We believe this is the first case of "cluster-status migranosus" described in the medical literature. High-flow oxygen both aborted the cluster headaches and prevented the ensuing status migrainosus. PMID- 30019593 TI - Hallux Interphalangeal Arthrodesis Following First Metatarsophalangeal Arthrodesis. AB - BACKGROUND: Hallux interphalangeal (IP) arthritis can occur after first metatarsophalangeal (MTP) arthrodesis. IP arthrodesis is a standard treatment, but in the setting of prior MTP surgery there will be increased stress on the IP joint. This may result in diminished potential for bone healing. This investigation assessed the outcomes of hallux IP arthrodesis after first MTP arthrodesis. METHODS: Charts were retrospectively reviewed for patients who underwent interphalangeal arthrodesis between January 1, 2007, and April 3, 2017, and who had a minimum of 12 weeks of follow-up. We compared patients with and without prior ipsilateral first MTP arthrodesis. There were 42 patients whose median follow-up was 9 (range, 3-135) months. RESULTS: Median time from previous first MTP arthrodesis until IP arthrodesis was 54 months. Six nonunions (35.3%) occurred in 17 patients with prior first MTP arthrodesis. Only 2 nonunions (8.0%) occurred in 25 patients with isolated IP arthrodesis. The multivariable risk difference of nonunion was 53.3% ( P = .001). Prior first MTP arthrodesis also was more likely to have complications (52.9% vs 24.0%, respectively). The multivariable risk difference of complications was 35.7% ( P = .082). The speed of bone healing was significantly different, with a multivariable rate ratio of 0.21 ( P = .012). Conclusion Prior first MTP arthrodesis resulted in 4.8 times slower bone healing for IP arthrodesis. It increased the risks of nonunion and any other complications. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 30019594 TI - Adenocarcinoma histology is a poor prognostic factor in locally advanced cervical cancer. AB - OBJECTIVE: This retrospective study aimed to compare prognostic factors and survival between adenocarcinoma (AC) and squamous cell carcinoma (SCC) in locally advanced cervical cancer treated at a single center. METHODS: All medical records of cervical cancer patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB or IIIA,B, treated between 2004 and 2012, were reviewed. We treated patients with chemoradiotherapy (CRT) followed by brachytherapy (BT). Multivariate logistic regression and Cox proportional hazard models were used to analyze clinicopathological characteristics, patterns of care and outcomes. RESULTS: We included in the analysis 161 patients (52 AC; 109 SCC). Patients with AC were younger (age 50 vs. 55 years), more likely to die from the disease (HR: 1.60; 95% CI: 1.26-2.58; p = .001) and to have disease recurrence (HR: 1.69; 95% C.I: 1.21-2.12; p = .004) than those with SCC. The other significant prognostic factors for overall survival (OS) and recurrence-free survival (RFS) in AC were FIGO stage (p = .001; p = .002), WHO status (0 vs. 1-3; p = .003; p = .04), and hemoglobin level (<12 g/dl>; p = .04; p = .02). The 5 year overall survival for stage II of AC and SCC was 63% and 82% (p = .03), and for IIIA,B it was 33.6% and 73% (p = .0005). The 5 year RFS for AC and SCC stage FIGO IIIA,B was 24% and 57% (p = .001). CONCLUSIONS: Adenocarcinoma histology negatively impacts OS and RFS for advanced cervical cancer. Histology-specific therapy may be an opportunity for survival improvement in these women. PMID- 30019595 TI - Age, Daily Stress Processes, and Allostatic Load: A Longitudinal Study. AB - OBJECTIVE: The present study examined age differences in the association between daily stressors and allostatic load. METHOD: Participants consisted of 317 adults (34-84 years) who participated in Waves 1 (1996-1997) and 2 (between 2005 and 2009) of the Midlife Development in the United States Survey. During Wave 1, participants reported the stressors they encountered across eight consecutive days. Within-person affective reactivity slopes indexing change in negative affect from a nonstressor day to a stressor day were calculated for each participant. Affective reactivity and stressor exposure scores at Wave 1 were used to predict allostatic load at Wave 2. RESULTS: Heightened levels of affective reactivity at Wave 1 predicted elevated levels of allostatic load at Wave 2 but only among older adults who also reported high levels of stressor exposure. No significant associations emerged for younger adults. DISCUSSION: Daily stress processes may be one pathway through which age-related physical health declines occur. PMID- 30019596 TI - Reducing the radiation exposure from CT scanning in children with shunts: a nationwide survey and a departmental CT protocol. AB - INTRODUCTION: Low dose ionising radiation such as from CT scans carries a low but cumulative risk of cancer and children are particularly sensitive. Children with VP Shunts often undergo multiple CT scans. We developed a CT protocol with reduced radiation for paediatric patients with shunts and compared it with the current practice in the other neurosurgical units in the UK and ROI by conducting a nationwide survey. METHODS: An email questionnaire was send to the superintendent radiographer in every Neurosurgical unit in the UK and the ROI. RESULTS: The response rate was 70%. Only 5 (19%) of the responding units used a dedicated CT shunt protocol with reduced radiation. Radiation was reduced by lowering the tube current. In comparison, our protocol uses a combination of less tube current and fewer slices. This reduced the radiation exposure of a CT head significantly with sufficient image quality to make a diagnosis. CONCLUSION: Radiation from CT for paediatric shunt patients scans can and should be reduced. This can be achieved by using reduced radiation protocols. A national paediatric CT shunt protocol could lead to significant reduction in effective radiation dose. PMID- 30019597 TI - Determination of the Depth- and Time- Dependent Mechanical Behavior of Mouse Articular Cartilage Using Cyclic Reference Point Indentation. AB - Mouse models of osteoarthritis and cartilage degeneration are important and powerful tools for investigating the molecular mechanisms of the disease pathology. Because of the vast number of genetically modified mouse models that are available for research, the ability to use these models is particularly attractive for the mechanobiologic interactions in the pathogenesis of osteoarthritis. However, the very small scale of mouse articular cartilage, where the healthy tissue is only 80 um in thickness, poses challenges in quantifying mechanical characteristics of the tissue. We introduce here a novel approach that combines experimental and analytical methods to quantify the nuanced mechanical changes during cartilage degeneration at this scale. Cyclic reference point indentation is used to directly test the murine articular cartilage to obtain the force-deformation and the phase-shift characteristics of the tissue. The cartilage zonal thicknesses are confirmed from histology. These data are then fitted to a parallel spring model to determine the depth-dependent tissue stiffness and modulus. Using this approach, we investigated the effects of trypsin degradation on the zonal mechanical behavior of mouse articular cartilage. We observe a decline of the superficial zone stiffness coupled with the loss of the superficial layer. Subsequent degradation by trypsin allowed the identification of middle- and deep- zone properties. Taken together, this approach can be a useful tool for understanding the disease mechanisms of cartilage homeostasis and degeneration, and for monitoring of therapies for osteoarthritis. PMID- 30019598 TI - Does Nox2 Overactivate in Children with Nonalcoholic Fatty Liver Disease? AB - It is unknown whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) activation is early associated with endotoxemia and liver damage in nonalcoholic fatty liver disease (NAFLD). To address this issue, we evaluated Nox2 activation, oxidative stress, gut permeability, and lipopolysaccharide (LPS) serum levels in 67 children with biopsy-proven NAFLD and 73 controls. Compared with controls, NAFLD patients had higher Nox2 activity, isoprostane, zonulin, and LPS levels. Multivariate linear regression analysis showed that triglycerides, high-density lipoprotein (HDL), homeostatic model assessment-estimated insulin resistance (HOMA-IR), LPS, and isoprostanes were independently associated with Nox2-derivative peptide (sNox2-dp) levels. Within the NAFLD group, patients with nonalcoholic steatohepatitis (NASH) had significant higher levels of sNox2-dp, isoprostanes, LPS, triglycerides, HOMA-IR, fasting glucose and insulin, and lower HDL than those without NASH. Furthermore, sNox2-dp levels were linearly associated with the histological grading of steatosis, inflammation, ballooning, fibrosis, and NAFLD activity score. This study provides evidence that children with NAFLD have Nox2 overactivation compared with controls and significant association with the degree of liver damage. The close relationship between Nox2 and LPS serum levels leads to hypothesize a potential role for gut-derived LPS in eliciting systemic Nox2 activation. Antioxid. Redox Signal. 00, 000-000. PMID- 30019599 TI - Prevalence and Correlates of Criminal Behavior Among the Non-institutionalized Elderly: Results From the National Survey on Drug Use and Health. AB - OBJECTIVES: First to explore the prevalence of criminal behavior committed by the non-institutionalized geriatric American population. Second to determine the correlates of criminal behavior among this population. METHODS: We used data of the non-institutionalized adults aged >=65 years in the National Survey on Drug Use and Health from 2008 through 2014. We compared socio-demographic and mental health profiles of arrestees to non-arrestees and lawbreakers to non-lawbreakers and then determined the correlates of being arrested and breaking the law through regression analyses. RESULTS: Around 0.4% of the population reported being arrested, and 5% reported breaking the law in the past year. The most prevalent offense was driving while intoxicated. Arrestees were significantly more likely to be male and to have had an alcohol or a drug(s) use disorder in the past year. Lawbreakers had a significant likelihood of being male, having a high educational level, and having an alcohol or a drug(s) use disorder in the past year. CONCLUSIONS: Elderly lawbreakers seem to have distinct characteristics that not just separate them from non-offenders but also probably from younger lawbreakers. PMID- 30019600 TI - The potential value of rapid, cloud-enabled onsite testing for the diagnosis of rheumatoid arthritis in the United States. AB - AIMS: Improvements in information technology have granted the recent development of rapid, cloud-enabled, onsite laboratory testing for rheumatoid arthritis (RA). This study aims to quantify the value to payers of such technologies. MATERIALS AND METHODS: To calculate the value of rapid, cloud-enabled, onsite laboratory testing to diagnose RA relative to traditional, centralized laboratory testing, an Excel-based decision tree model was created that simulated potential cost savings to payers who cover routine evaluations of RA patients in the US. First, a conceptual framework was created to identify the value components of rapid, cloud-enabled onsite testing. Second, value associated with patient time savings, savings on visit fees, change in treatment costs, and QALY improvements was measured, leveraging existing literature and information from an observational study. Lastly, these value components were combined to estimate the total incremental value accruing to payers per patient-year relative to centralized laboratory testing. RESULTS: Rapid, cloud-enabled, onsite testing is estimated to save one office and 1.81 laboratory visits during the evaluation period for the average patient. Results from an observational study found that rapid, cloud enabled testing increased the likelihood of completing diagnostic orders from 84.5% to 97%, resulting in an increased probability of early treatment (3.5 percentage points) with disease-modifying anti-rheumatic drugs among patients eligible for treatment. The combined total value was $5,648 per evaluated patient year. This value is primarily attributed to health benefits of early treatment ($5,048), fewer visit payments ($459), and patient time savings due to fewer office ($216) and laboratory visits ($255). LIMITATIONS AND CONCLUSIONS: Data on the impact of rapid, cloud-enabled, onsite testing on patient health, care delivery, and clinical decision-making is scarce. More robust real-world data would confirm the validity of our model. Rapid, cloud-enabled, onsite testing has the potential to generate significant value to payers. PMID- 30019601 TI - In vitro study for the evaluation of transluminal aspiration as a novel treatment option for thrombosis in the HeartWare HVAD. AB - INTRODUCTION:: Pump thrombosis of left ventricular assist devices remains a devastating complication with high morbidity and mortality. Despite the improvements made, the matter affects many patients and the treatment options are limited to thrombolysis and surgical replacement. An alternative approach using the aspiration Indigo catheter was tested. METHODS:: An Indigo thrombectomy catheter was used within an in vitro model to assess the direct aspiration of prefabricated clots from three different positions within the HeartWare HVAD (inlet, outlet, and housing). The experiments were conducted with a straight and an angled catheter. The aspiration pressure was constant. The flow, power consumption, and pressure head of the left ventricular assist devices were measured at pre-defined measuring points. RESULTS:: The device was more effective (success rate 71%) at inlet and outlet of the left ventricular assist device. In addition, the duration of aspiration and the aspiration volume were shorter in comparison to the aspiration in the housing (inlet M = 19.75 s, outlet M = 60.50 s, and housing M = 38.75 s). Moreover, the aspiration volume was associated with the aspiration duration and the weight of thrombi but not with their volume. Noteworthy, the angled catheter showed an improved performance compared to the straight one (67%-33%). The recorded parameters showed no major changes during the use of the catheter. After application of the Indigo catheter, flow and pressure head of the pump could be restored. CONCLUSIONS:: The aspiration system showed promising results under specific conditions for the treatment of pump thrombosis in an in vitro model. However, further examination, including in vivo experiments, will justify its effectiveness. PMID- 30019602 TI - Ten-Year Trends in Physical Dating Violence Victimization Among Adolescent Boys and Girls in British Columbia, Canada. AB - Physical dating violence (PDV) victimization among adolescents is a serious global problem. Although knowledge of trends in PDV victimization can help guide programming and health policies, little research has examined whether the prevalence of PDV victimization has increased, decreased, or remained stable over time among non-U.S.-based samples of youth. In addition, few studies have directly tested whether disparities in PDV victimization between boys and girls have narrowed, widened, or remained unchanged in recent years. To address these gaps, we used school-based data from the British Columbia Adolescent Health Survey (BC AHS) of 2003, 2008, and 2013 ( n boys = 18,441 and n girls = 17,459) to examine 10-year trends in PDV victimization. We also tested whether trends differed across self-reported sex. Data from the 2003 to 2013 BC AHS revealed that recent PDV victimization rates had significantly decreased among youth overall (5.9%-5.0%) and boys (8.0%-5.8%), but not girls (5.3%-4.2%). Although boys had steeper declines than girls in PDV victimization rates, year-by-sex interactions indicate that the sex gap in PDV victimization had not significantly narrowed. Moreover, rates of PDV victimization over the 10-year period indicated significantly higher rates of PDV victimization among boys compared with girls. Despite positive declines in recent rates of PDV victimization among youth, important differences in rates of PDV victimization between boys and girls remain. These findings underscore the need for greater attention to sex differences in research and programming and health policies to reduce PDV victimization and the sex disparities therein. PMID- 30019603 TI - Sardiovascular mortality during heat waves in temperate climate: an association with bioclimatic indices. AB - The authors studied the relative predictive powers of several bioclimatic indices as predictors of population mortality during heat waves. Daily mean and maximum values of air temperature, Humidex, apparent, and physiological equivalent temperatures (PETs) were examined. The numbers of daily deaths and daily meteorological data in Rostov-on-Don (southern Russia) were used. The study period spanned April-September between 1999 and 2011. The eight selected bioclimatic indices were used to identify heat waves and calculate the expected increases in mortality during such events from Poisson generalized linear model of daily death counts. All of the bioclimatic indices considered were positively and significantly associated with mortality during heat waves. The best predictor was chosen from a set of similar models by maximization of relative mortality risk estimates. Having compared the relative increases and their significance levels in several cause- and age-specific mortality rates, the authors concluded that PET was the most powerful predictor. PMID- 30019604 TI - Agreement on Reporting Intimate Partner Violence Among Nepalese Couples: A Cross Sectional Study. AB - When intimate partner violence (IPV) data are collected from only one partner, they are often subject to considerable reporting bias. However, it is not easy to collect such data from couples, and inaccuracies might result in discrepancies, which needs a resolution. We assessed the concordance on reports of lifetime and previous year physical, sexual, and emotional IPV against wives, as reported by both Nepalese wives and husbands. The association of possible risk factors with discordant reporting of IPV was also analyzed. We conducted a cross-sectional study in two areas in Nepal between August and September 2011. We collected data from 717 randomly selected couples on lifetime and previous year experience of physical, sexual, and emotional IPV against wives, as well as their sociodemographic characteristics. We calculated the kappa coefficients and agreement percentage to assess the concordance on wives' reports of IPV victimization and husbands' reports of IPV perpetration. We also performed multiple logistic regressions to identify the factors associated with discordant reporting of IPV among couples. Levels of concordance between wives' and husbands' reports of IPV were significantly low, as indicated by kappa coefficients, ranging from .20 (sexual and emotional IPV) to .24 (physical IPV) in lifetime experience and from .15(sexual IPV) to .18 (physical IPV) in previous year experience. Wives' caste, husbands' age and education, household income, and place of residence were significantly associated with discordance in IPV reports among Nepalese couples. Discordant reporting about IPV is common among Nepalese couples. Collecting information from both partners might be important to obtain more reliable data on IPV in the Nepalese context. PMID- 30019605 TI - Wear Characteristics of Conventional Ultrahigh-Molecular-Weight Polyethylene Versus Highly Cross-Linked Polyethylene in Total Ankle Arthroplasty. AB - BACKGROUND:: The aim of this study was to compare the polyethylene wear rate, particle size, and particle shape of primary semiconstrained, fixed-bearing, bone sparing total ankle arthroplasty using conventional ultrahigh-molecular-weight polyethylene (CPE) versus highly cross-linked polyethylene (HXLPE) by applying a level walking input using a joint simulator. METHODS:: Two fixed-bearing total ankle replacement systems with different types of polyethylene liners were tested: (1) CPE sterilized in ethylene oxide, and (2) HXLPE sterilized with gas plasma after electron beam irradiation. Three implants for each design underwent wear testing using gravimetric analysis over 5 million simulated walking cycles. A fourth implant was used as a load soak control. Equivalent circle diameter (ECD) and equivalent shape ratio (ESR) were computed to determine particle size and particle shape, respectively. RESULTS:: The mean wear rate from 1.5 to 5 million cycles (MC) was 2.0 +/- 0.3 mg/MC for HXLPE and 16.7 +/- 1.3 mg/MC for CPE ( P < .001). The total number of particles per cycle generated for HXLPE and CPE were 0.17 * 106 particles/cycle and 0.53 * 106 particles/cycle, respectively ( P < .001). The mean ECD of HXLPE particles (0.22 +/- 0.11 MUm) was significantly smaller than the mean ECD of CPE particles (0.32 +/- 0.14 MUm) ( P < .001). HXLPE particles were significantly more round than CPE particles ( P < .001). CONCLUSIONS:: HXLPE liners had a significantly lower wear rate and produced significantly fewer and rounder particles than CPE liners. The results of this study suggest that HXLPE has more favorable wear characteristics for total ankle arthroplasty. CLINICAL RELEVANCE:: Polyethylene wear particles have been linked to osteolysis after total ankle arthroplasty. There is no consensus on the importance of highly cross-linked polyethylene in total ankle arthroplasty with regard to implant wear. This is the first nonindustry study to compare the polyethylene wear rate, particle size, and particle shape of fixed-bearing total ankle arthroplasty conventional polyethylene versus highly cross-linked polyethylene. The lower wear rate and different particle size/morphology of highly cross-linked polyethylene could be beneficial in vivo to decrease osteolysis. PMID- 30019606 TI - Risk of Damaging Anatomical Structures During Minimally Invasive Hallux Valgus Correction (Bosch Technique): An Anatomical Study. AB - BACKGROUND:: Percutaneous, transverse distal metatarsal osteotomy with K-wire fixation (the Bosch technique) is an established technique for hallux valgus correction. Nevertheless, the risk of damaging the anatomical structures during the operation is unknown. METHODS:: Forty fresh-frozen anatomical foot specimens with hallux valgus deformity underwent a percutaneous corrective procedure. Specimens of group A (n = 20) were operated by an experienced surgeon while specimens of group B (n = 20) were done by untrained residents. RESULTS:: The dorsal cutaneous nerve was injured in 1 of 20 cases in group A and 6 of 20 cases in group B ( P = .037). There was a significant difference in overall complication rate between specimens of group A and group B ( P = .043). CONCLUSIONS:: The results show an increased risk of perioperative injury of the dorsal cutaneous branch of the deep peroneal nerve as well as a significant effect of the surgeon's experience on the overall complication rate. CLINICAL RELEVANCE:: Results of this study are highly relevant for all surgeons who perform percutaneous, minimally invasive hallux valgus surgery to avoid damage to the peripheral nerves. In addition, the data suggest an intensive training for surgeons before minimally invasive hallux valgus surgery is performed without supervision. PMID- 30019607 TI - Health checks for cardiometabolic diseases in primary care: One size does not fit all. PMID- 30019608 TI - Meta-analysis of efficacy and safety of dual antiplatelet therapy versus aspirin monotherapy after coronary artery bypass grafting. PMID- 30019609 TI - Influences of Extended Family on Intimate Partner Violence: Perceptions of Pakistanis in Pakistan and the United Kingdom. AB - Limited research has been undertaken on the role of extended family members in Intimate Partner Violence (IPV). This study uniquely explores the perspective of Pakistani men and women about the role of a husband and wife's families in relation to marital conflict and IPV. For this qualitative study, data were collected through 41 individual interviews, including 20 from Pakistan and 21 from the United Kingdom. The findings are presented in four themes, including "privacy and personal space," "interference and instigation of problems," "conflicting and uncommunicated expectations," and "adjustment facilitation." A lack of privacy and personal space within a family home shared with extended family on the husband's side, interference in terms of mothers-in-law and sisters in-law making complaints about the wife, and the couple's differing expectations of the husband's responsibility for his extended family could cause tension and conflict that could lead to IPV. The husband's family could also have a positive effect by minimizing conflict through offering the couple personal time and helping the wife to adjust to her new family. The wife's family was perceived as having a much more passive role in terms of not interfering, but instead allowing her to adjust to her new extended family. In conclusion, the husband's extended family can have a considerable impact on conflict within couples. Public health prevention initiatives for IPV in Pakistani people should address the role of the husband's extended family. The findings of the study are not only important for the population studied, which is part of an international diaspora, but also for other communities worldwide that value close family structure due to cultural and religious preferences. PMID- 30019610 TI - Experimental investigations of the aerated polymethylmethacrylate-based vertebral cement flow in capillaries. AB - INTRODUCTION: A constant growth in the population suffering from osteoporotic vertebral weakening is observed. As a result, vertebroplasty procedures become more and more common. Unfortunately, they may be associated with several complications occurring during bone cement injection, including its leakage or overheating of tissues. Despite several experimental studies, there is a lack of data related to random aeration of the bone cement. Therefore, the main objective of the following investigations was to emphasize that random aeration of the bone cement, and, consequently, a compressibility factor, could not be treated as a negligible factor during the vertebroplasty procedure and had to be taken into account in the development of the mathematical model. MATERIALS AND METHODS: A special test rig to reproduce the vertebroplasty procedure was designed and built. The authors conducted numerous experiments on polymethylmethacrylate-based bone cement flows, analyzing different flow conditions, such as volume flow rate and flow channel diameter. Time periods of the flow front between characteristic sections and pressures (differential and gauge) were measured. RESULTS: All investigations revealed that bone cements mixed in special mixing kits were characterized by a random level of aeration which led to varied flow parameters. Comparing the experimental results with the theoretical values of the continuity equation, the highest difference in the flow duration reached 140%. DISCUSSION: It has been proven that the aeration of the bone cement alters the flow dynamics. Therefore, much more data are required for statistical analysis to validate a mathematical model of the bone cement flow. PMID- 30019611 TI - Factors Associated With Uncertainty in Illness Among People With Parkinson's Disease. AB - People with Parkinson's disease (PD) reported to experience uncertainty because of gradually progressive disease characteristics with no cure, and variably manifesting and unpredictable symptoms. This study was designed to identify illness-related variables influencing uncertainty in PD patients and to analyze direct and indirect paths between these variables. Data were collected from 206 participants using a structured questionnaire. Path analysis revealed the direct and/or indirect effects of economic status, disease severity, social support, and resilience on uncertainty in people with PD. Disease severity, social support, and resilience were shown to have significant direct effects on uncertainty. Economic status and disease severity had indirect effects on uncertainty, which were mediated by social support. Disease severity and social support also had indirect effects on uncertainty, which were mediated by resilience. Therefore, the efforts of health care professionals should be directed not only toward managing PD symptoms, but also toward facilitating social support and resilience. PMID- 30019612 TI - Tracking Tregs: Translocation of CD49b/LAG-3+ Type 1 T Regulatory Cells to the Gut-Associated Lymphoid Tissue of HIV+ Patients. AB - The gastrointestinal mucosa [gut-associated lymphoid tissue (GALT)] represents the largest site of chronic immune activation and HIV replication. Important cellular agents in the immunopathogenesis of an HIV infection are, in particular, CD49b/LAG-3+ type 1 T regulatory cells (Tr1), which secrete large amounts of IL 10 (interleukin-10), and plasmacytoid dendritic cells, the main producers of IFN alpha (interferon-alpha). However, the distribution of CD49b/LAG-3+ Tr1 cells along the GALT is unknown. PMID- 30019613 TI - Treatment of an incarcerated inguinal hernia associated with abdominal tuberculosis in an adult patient. AB - The incidence of tuberculosis is increasing worldwide, especially in developing countries. The prevalence of abdominal tuberculosis has been found to be as high as 12% in people with extrapulmonary tuberculosis. Peritoneal thickening and intestinal adhesions can occur in patients with abdominal tuberculosis. Inguinal hernias are extremely rare in people with abdominal tuberculosis; only 11 cases have been reported in the English-language literature, half of which involved pediatric patients. No definitive guideline on the management of such cases is available. In this report, we describe the unusual finding of an incarcerated inguinal hernia in an adult with abdominal tuberculosis and propose a therapy to treat this complicated disease based on our successful experience. PMID- 30019614 TI - Postincident Interpersonal Difficulty Among Adolescent Victims of Violent Crime. AB - Adolescents are exposed to high levels of violence in the United States. Exposure to violence at this point in the life course can have both short- and long-term consequences for young victims that include socioemotional distress and depression, substance abuse, and delinquency. Prior research indicates that positive, productive, and supportive reactions on the parts of those close to targets of violence attenuate feelings of distress and social anomie that many victims report. However, less attention has been devoted to the attributes of criminal violence that may stress the postincident interpersonal relationships of victims and their family members, friends, or peers. The disquieting effects of violence and bodily injury may influence how victims characterize their social connections in the wake of violent crime. This study uses data from the National Crime Victimization Survey ( N = 1,652) to assess whether characteristics of violent acts and victims predict reports of postincident interpersonal difficulties made by violent crime victims aged 12 to 20. The findings are that more severe forms or levels of violence (e.g., robberies and sexual assaults) and reports of physical injuries are linked to perceptions of relationship difficulties with members of social networks by adolescent victims of violent crime. This study makes a contribution to our understanding of victimization by identifying levels of violence and injury as independent stressors on victims' perceptions of their relationships and as relevant components of how younger victims see themselves or are perceived by others. It also represents a direct test of whether attributes of violent acts undermine adolescents' perceptions of the quality of their relationships. The results of the study could also aid in the development of interventions that better address the needs of both young victims and their supporters. PMID- 30019615 TI - Improving advance care planning for care home residents with dementia: Evaluation of simulation training for care home workers. AB - The importance of effective advance care planning is often underestimated by professionals caring for care home residents. Using a simulated scenario, this model aimed to highlight the importance of timely advance care planning for care home residents. An adapted simulation effectiveness tool was used to evaluate a simulated scenario of a resident with advanced dementia. Feedback from this tool, N = 28 (response rate 82%), suggests this model was well received and that simulation training delivered by a multi-professional faculty, effectively demonstrates the benefits of early advance care planning for residents with dementia. PMID- 30019617 TI - Association of Acute Increase in Plasma Neurofilament Light with Repetitive Subconcussive Head Impacts: A Pilot Randomized Control Trial. AB - The purpose of the study was to examine an association of repetitive subconcussive head impacts with changes in plasma neurofilament light (NF-L) levels following 10 bouts of controlled soccer heading. In this randomized control trial, 37 healthy adult soccer players were randomly assigned into either a heading (n = 19) or kicking-control group (n = 18). The heading group executed 10 headers with soccer balls projected at a velocity of 25 mph over 10 min. Plasma samples were obtained at pre-heading baseline, 0 h, 2 h, and 24 h post heading. The kicking-control group followed the same protocol with 10 kicks. Plasma NF-L was measured using ultrasensitive single-molecule array technology. Data from 34 subjects were eligible for analysis (heading n = 18 and kicking n = 16). Ten subconcussive head impacts induced a gradual increase in plasma NF-L expression for the heading group (beta = 0.0297, standard error [SE] = 0.01, p = 0.0049), whereas there was no significant time effect for the kicking-control group. A follow-up analysis revealed that a significant difference appeared at 24 h post-heading (3.68 +/- 0.30 pg/mL) compared with pre-heading (3.12 +/- 0.29 pg/mL, p = 0.0013; Cohen's d = 1.898). At the 24 h post-heading time-point, the plasma NF-L level for the heading group was significantly higher than that of the kicking-control group with an estimated mean difference of 0.66 pg/mL (SE = 0.22, p = 0.0025). The data suggest that the increased level of plasma NF-L was driven by repetitive subconcussive head impacts and required longer than 2 h after the head impacts for the increase to be detected. Plasma NF-L levels may serve as an objective marker to monitor acute axonal burden from subconcussive head impacts. PMID- 30019618 TI - Detection of Hyperexcitability by Functional Magnetic Resonance Imaging after Experimental Traumatic Brain Injury. AB - Diagnosis of ongoing epileptogenesis and associated hyperexcitability after brain injury is a major challenge. Given that increased neuronal activity in the brain triggers a blood oxygenation level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI), we hypothesized that fMRI could be used to identify the brain area(s) with hyperexcitability during post-injury epileptogenesis. We applied fMRI to detect onset and spread of BOLD activation after pentylenetetrazol (PTZ)-induced seizures (PTZ, 30 mg/kg, intraperitoneally) in 16 adult male rats at 2 months after lateral fluid percussion (FPI)-induced traumatic brain injury (TBI). In sham-operated controls, onset of the PTZ-induced BOLD response was bilateral and first appeared in the cortex. After TBI, 5 of 9 (56%) rats exhibited ipsilateral perilesional cortical BOLD activation, followed by activation of the contralateral cortex. In 4 of 9 (44%) rats, onset of BOLD response was bilateral. Interestingly, latency from the PTZ injection to onset of the BOLD response increased in the following order: sham-operated controls (ipsilateral 132 +/- 57 sec, contralateral 132 +/- 57 sec; p > 0.05) < TBI with bilateral BOLD onset (ipsilateral 176 +/- 54 sec, contralateral 178 +/- 52 sec; p > 0.05) < TBI with ipsilateral BOLD onset (ipsilateral 406 +/- 178 sec, contralateral 509 +/- 140 sec; p < 0.05). Cortical lesion area did not differ between rats with ipsilateral versus bilateral BOLD onset (p > 0.05). In the group of rats with ipsilateral onset of PTZ-induced BOLD activation, none of the rats showed a robust bilateral thalamic BOLD response, only 1 of 5 rats had robust ipsilateral thalamic calcifications, and 4 of 5 rats had perilesional astrocytosis. These findings suggest the evolution of the epileptogenic zone in the perilesional cortex after TBI, which is sensitive to PTZ-induced hyperexcitability. Further studies are warranted to explore the evolution of thalamo-cortical pathology as a driver of epileptogenesis after lateral FPI. PMID- 30019616 TI - Preformed Vascular Networks Survive and Enhance Vascularization in Critical Sized Cranial Defects. AB - Vascular networks provide nutrients, oxygen, and progenitor cells that are essential for bone function. It has been proposed that a preformed vascular network may enhance the performance of engineered bone. In this study vascular networks were generated from human umbilical vein endothelial cell and mesenchymal stem cell spheroids encapsulated in fibrin scaffolds, and the stability of preformed vascular networks and their effect on bone regeneration were assessed in an in vivo bone model. Under optimized culture conditions, extensive vessel-like networks formed throughout the scaffolds in vitro. After vascular network formation, the vascularized scaffolds were implanted in a critical sized calvarial defect in nude rats. Immunohistochemical staining for CD31 showed that the preformed vascular networks survived and anastomosed with host tissue within 1 week of implantation. The prevascularized scaffolds enhanced overall vascularization after 1 and 4 weeks. Early bone formation around the perimeter of the defect area was visible in X-ray images of samples after 4 weeks. Prevascularized scaffolds may be a promising strategy for engineering vascularized bone. PMID- 30019619 TI - Impact of ex-vivo extracorporeal membrane oxygenation circuitry on daptomycin. AB - BACKGROUND:: The objective was to determine the alterations of daptomycin (DAP) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation (ECMO) circuit including the Quadrox-i(r) oxygenator. METHODS:: Quarter-inch and 3/8-inch, simulated, closed-loop, ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. A one-time dose of DAP was administered into the circuit and serial pre- and post-oxygenator concentrations were obtained at 0-5 minutes and 1, 2, 3, 4, 5, 6 and 24-hour time points. DAP was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS:: For both the 1/4 inch and 3/8-inch circuits, there was no significant DAP loss at 24 hours. Additionally, the reference DAP concentrations remained relatively constant during the entire 24-hour study period. CONCLUSION:: This ex-vivo investigation demonstrated no significant DAP loss within an ECMO circuit with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of DAP in the setting of ECMO may be anticipated with current recommended doses, depending on the amount of extracorporeal volume needed for circuit maintenance in comparison to the patient's apparent volume of distribution. Additional studies with a larger sample size are needed to confirm these findings. PMID- 30019620 TI - An engineered novel lentivector specifically transducing dendritic cells and eliciting robust HBV-specific CTL response by upregulating autophagy in T cells. AB - Dendritic cells (DCs) play a predominant role in initiating cell immune responses. Here we generated a DC-targeting lentiviral vector (LVDC-UbHBcAg LIGHT) and evaluated its capacity to elicit HBV-specific cytotoxic T lymphocyte (CTL) responses. DC-SIGN-mediated specific transduction using this construct was confirmed in DC-SIGN-expressing 293T cells and ex vivo-cultured bone marrow cells. LVDC-UbHBcAg-LIGHT-loaded DCs were highly effective in inducing HBV specific CTLs. Mechanistic studies demonstrated autophagy blocking led to a significant increase in apoptosis and obvious inhibition of CD8 + T cells entry into S-phase, correspondingly attenuated LVDC-UbHBcAg-LIGHT-loaded DC-induced T cell responses. This observation was supported by accumulation of pro-apoptotic proteins and the main negative cell cycle regulator-CDKN1B that otherwise would be degraded in activated T cells where autophagy preferentially occured. Our findings revealed an important role of autophagy in the activation of T cells and suggested LVDC-UbHBcAg-LIGHT may potentially be used as a therapeutic strategy to combat persistent HBV infection with higher security. PMID- 30019622 TI - Combining Brain Microdialysis and Translational Pharmacokinetic Modeling to Predict Drug Concentrations in Pediatric Severe Traumatic Brain Injury: The Next Step Toward Evidence-Based Pharmacotherapy? AB - Evidence-based analgosedation in severe pediatric traumatic brain injury (pTBI) management is lacking, and improved pharmacological understanding is needed. This starts with increased knowledge of factors controlling the pharmacokinetics (PK) of unbound drug at the target site (brain) and related drug effect(s). This prospective, descriptive study tested a pediatric physiology-based pharmacokinetic software model by comparing actual plasma and brain extracellular fluid (brainECF) morphine concentrations with predicted concentration-time profiles in severe pTBI patients (Glasgow Coma Scale [GCS], <=8). Plasma and brainECF samples were obtained after legal guardian written consent and were collected from 8 pTBI patients (75% male; median age, 96 months [34.0-155.5]; median weight, 24 kg [14.5-55.0]) with a need for intracranial pressure monitoring (GCS, <=8) and receiving continuous morphine infusion (10-40 MUg/kg/h). BrainECF samples were obtained by microdialysis. BrainECF samples were taken from "injured" and "uninjured" regions as determined by microdialysis catheter location on computed head tomography. A previously developed physiology based software model to predict morphine concentrations in the brain was adapted to children using pediatric physiological properties. The model predicted plasma morphine concentrations well for individual patients (97% of data points within the 90% prediction interval). In addition, predicted brainECF concentration-time profiles fell within a 90% prediction interval of microdialysis brainECF drug concentrations when sampled from an uninjured area. Prediction was less accurate in injured areas. This approach of translational physiology-based PK modeling allows prediction of morphine concentration-time profiles in uninjured brain of individual patients and opens promising avenues towards evidence-based pharmacotherapies in pTBI. PMID- 30019623 TI - Traumatic Injury Leads to Inflammation and Altered Tryptophan Metabolism in the Juvenile Rabbit Brain. AB - Neuroinflammation after traumatic brain injury (TBI) contributes to widespread cell death and tissue loss. Here, we evaluated sequential inflammatory response in the brain, as well as inflammation-induced changes in brain tryptophan metabolism over time, in a rabbit pediatric TBI model. On post-natal days 5-7 (P5 P7), New Zealand white rabbit littermates were randomized into three groups: naive (no injury), sham (craniotomy alone), and TBI (controlled cortical impact). Animals were sacrificed at 6 h and 1, 3, 7, and 21 days post-injury for evaluating levels of pro- and anti-inflammatory cytokines, as well as the major components in the tryptophan-kynurenine pathway. We found that 1) pro- and anti inflammatory cytokine levels in the brain injury area were differentially regulated in a time-dependent manner post-injury; 2) indoleamine 2,3 dioxygeenase 1 (IDO1) was upregulated around the injury area in TBI kits that persisted at 21 days post-injury; 3) mean length of serotonin-staining fibers was significantly reduced in the injured brain region in TBI kits for at least 21 days post-injury; and 4) kynurenine level significantly increased at 7 days post-injury. A significant decrease in serotonin/tryptophan ratio and melatonin/tryptophan ratio at 21 days post-injury was noted, suggesting that tryptophan metabolism is altered after TBI. A better understanding of the temporal evolution of immune responses and tryptophan metabolism during injury and repair after TBI is crucial for the development of novel therapeutic strategies targeting these pathways. PMID- 30019624 TI - Toxic Stress and Vulnerable Mothers: A Multilevel Framework of Stressors and Strengths. AB - Toxic stress is associated with poor health outcomes that extend across the life span. Although caregivers can protect their children from toxic stress through supportive caregiving, this can be challenging for vulnerable mothers living in socioeconomically disadvantaged environments. We aim to advance the science of toxic stress prevention by exploring the stressors and strengths experienced by vulnerable mothers through application of a theoretical framework, Bronfenbrenner's bioecological model. Following Arksey and O'Malley's five-stage scoping study framework, 179 articles were included. Key information was abstracted and each article was reviewed for relevance to the bioecological model. Results revealed that the sources of stress and strength are multilayered, transactional, and have a complex influence on caregiving in families at risk of toxic stress. Future research should include empirical investigations of the complex relationships among these stressors and strengths, and the development of preventive interventions to support vulnerable families at risk of toxic stress. PMID- 30019625 TI - Effect of Excess Iodine Intake from Iodized Salt and/or Groundwater Iodine on Thyroid Function in Nonpregnant and Pregnant Women, Infants, and Children: A Multicenter Study in East Africa. AB - BACKGROUND: Acute excess iodine intake can damage the thyroid, but the effects of chronic excess iodine intake are uncertain. Few data exist for pregnant and lactating women and infants exposed to excessive iodine intake. METHODS: This was a multicenter cross-sectional study. At study sites in rural Kenya and urban Tanzania previously reporting iodine excess in children, urinary iodine concentration (UIC), thyrotropin, total thyroxine, and thyroglobulin (Tg) were measured in school-age children (SAC), women of reproductive age, pregnant (PW) and lactating women, and breast-feeding and weaning infants. In a national study in Djibouti, UIC was measured in SAC and PW. At all sites, daily iodine intake was estimated based on UIC, and iodine concentration was measured in household salt and drinking water. RESULTS: The total sample size was 4636: 1390, 2048, and 1198 subjects from Kenya, Tanzania, and Djibouti, respectively. In Kenya and Tanzania: (i) median UIC was well above thresholds for adequate iodine nutrition in all groups and exceeded the threshold for excess iodine intake in SAC; (ii) iodine concentrations >40 mg of iodine/kg were found in approximately 55% of household salt samples; (iii) iodine concentrations >=10 MUg/L were detected in 9% of drinking water samples; (iv) Tg was elevated in all population groups, but the prevalence of thyroid disorders was negligible, except that 5-12% of women of reproductive age had subclinical hyperthyroidism and 10-15% of PW were hypothyroxinemic. In Djibouti: (i) the median UIC was 335 MUg/L (interquartile range [IQR] = 216-493 MUg/L) in SAC and 265 MUg/L (IQR = 168-449 MUg/L) in PW; (ii) only 1.6% of Djibouti salt samples (n = 1200) were adequately iodized (>15 mg/kg); (iii) the median iodine concentration in drinking water was 92 MUg/L (IQR = 37-158 MUg/L; n = 77). In all countries, UIC was not significantly correlated with salt or water iodine concentrations. CONCLUSIONS: Although iodine intake was excessive and Tg concentrations were elevated, there was little impact on thyroid function. Chronic excess iodine intake thus appears to be well tolerated by women, infants, and children. However, such high iodine intake is unnecessary and should be avoided. Careful evaluation of contributions from both iodized salt and groundwater iodine is recommended before any review of iodization policy is considered. PMID- 30019621 TI - The established and the predicted roles of dynein light chain in the regulation of mitochondrial apoptosis. AB - The mitochondrial pathway of apoptosis is regulated by the interplay between the members of Bcl-2 family. Within this family, BH3-only proteins are the sensors of apoptotic stimuli and can trigger apoptosis either by inhibiting the anti apoptotic Bcl-2-family proteins or by directly activating the effectors Bax and Bak. An expanding body of research suggests that a number of non-Bcl-2 proteins can also interact with Bcl-2 proteins and contribute to the decision of cell fate. Dynein light chain (LC8, DYNLL or DLC), a hub protein and a dimerizing engine has been proposed to regulate the pro-apoptotic activity of two BH3-only proteins, Bim and Bmf. Our recent work has provided insight into the mechanisms through which DLC1 (DYNLL1) modulates Bim activity. Here we discuss the present day understanding of Bim-DLC interaction and endeavor to evaluate this interaction in the light of information from studies of DLC with other binding partners. PMID- 30019626 TI - T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes. AB - BACKGROUND:: Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown. OBJECTIVES:: To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS. METHODS:: Children <18 years with a first demyelinating event were prospectively included and followed. Soluble CD27 was determined in CSF using an enzyme-linked immunosorbent assay (ELISA). Cox regression analyses were used to calculate hazard ratios (HRs) for CDMS. RESULTS:: A total of 94 ADS children were included (ADS with encephalopathy (ADS+) n = 33 and ADS without encephalopathy (ADS-) n = 61). Of the 61 ADS- children, 21 (48%) were diagnosed with CDMS during follow-up. At baseline, sCD27 levels were higher in patients with a future CDMS diagnosis ( n = 29) than in monophasic ADS+ ( n = 30), monophasic ADS- ( n = 28) and relapsing non-MS patients ( n = 7; p < 0.001). In ADS- patients, sCD27 was associated with CDMS (HR = 1.8 per 100 U/mL increase in sCD27 levels, p = 0.031), after adjustments for age, oligoclonal bands and the presence of dissemination in space on baseline magnetic resonance imaging (MRI). CONCLUSION:: CSF sCD27 levels at first attack of demyelination were associated with CDMS diagnosis in children. This makes sCD27 a potential clinically relevant quantitative marker when performing routine CSF diagnostics. PMID- 30019627 TI - Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia. AB - Rationale Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke. Design TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a >=8-point improvement in NIHSS score, or NIHSS 0-1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 ug subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose. Conclusion TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia. Trial registration: ClinicalTrials.gov/ANZCTR NTA1127. PMID- 30019628 TI - Factor Structure for Chronic Stress Before and During Pregnancy by Racial/Ethnic Group. AB - This study aimed to explore race/ethnicity-specific dimensionalities of chronic stress before and during pregnancy for non-Hispanic (N-H) White, N-H Black, Hispanic, and Asian women in the United States. This study analyzed the data among 6,850 women from the New York City and Washington State Pregnancy Risk Assessment Monitoring System (2004-2007) linked with birth certificates. Separate exploratory factor analysis was conducted by race/ethnicity using a maximum likelihood extraction method with 26 chronic stress items before and during pregnancy. Correlations and internal consistency reliabilities among items and latent factors determined race/ethnicity-specific factor structures of chronic stress. Chronic stress was race/ethnicity-distinctive and multidimensional with low correlations among the factors ( r = .07-.28, p < .05). Despite financial hardship, perceived isolation, and physical violence underlying chronic stress among the racial/ethnic groups, intergroup variations existed under each group's cultural or sociopolitical contexts. This study could help develop targeted strategies to intervene with women's chronic stressors before childbirth. PMID- 30019629 TI - Safety and predictors of stroke mimics in The Norwegian Tenecteplase Stroke Trial (NOR-TEST). AB - Background Stroke mimics are frequently treated with thrombolysis in clinical practice and thrombolytic trials. Although alteplase in stroke mimics has proven to be safe, safety of tenecteplase in stroke mimics has not been assessed in an ischemic stroke study setting. We aimed to assess clinical characteristics and safety of stroke mimics treated with thrombolysis in the Norwegian Tenecteplase Stroke Trial. We also aimed to identify possible predictors of stroke mimics as compared to patients with acute cerebral ischemia. Methods Norwegian Tenecteplase Stroke Trial was a phase-3 trial investigating safety and efficacy of tenecteplase vs. alteplase in patients with suspected acute cerebral ischemia. Two groups were defined based on diagnose at discharge: patients with a different diagnose than ischemic stroke or transient ischemic attack (stroke mimics group) and patients diagnosed with ischemic stroke or transient ischemic attack (acute cerebral ischemia group). Logistic regression analyses were performed with stroke mimics vs. acute cerebral ischemia as dependent variable to identify predictors of stroke mimics. Results Of 1091 randomized patients, 181 (16.6%) were stroke mimics. Migraine (22.2%) and peripheral vertigo (11.4%) were the two most frequent stroke mimic-diagnoses. There was no symptomatic intracerebral hemorrhage in the stroke mimics group. Stroke mimics were independently associated with age <=60 years (OR 2.75, p < 0.001), female sex (OR 1.48, p = 0.026), no history of myocardial infarction (OR 2.03, p = 0.045), systolic BP <= 150 mmHg (OR 2.33, p < 0.001), NIHSS <= 6 points (OR 1.83, p = 0.011), sensory loss (OR 1.55, p = 0.015), and no facial paresis (OR 2.41, p < 0.001) on admission. Conclusion Thrombolysis with tenecteplase seems to be as safe as with alteplase in stroke mimics. Predictors were identified for stroke mimics which may contribute to differentiate stroke mimics from acute cerebral ischemia in future stroke trials. PMID- 30019630 TI - Effects of Electrical Stimulation in Tinnitus Patients: Conventional Versus High Definition tDCS. AB - BACKGROUND: Contradictory results have been reported for transcranial direct current stimulation (tDCS) as treatment for tinnitus. The recently developed high definition tDCS (HD tDCS) uses smaller electrodes to limit the excitation to the desired brain areas. OBJECTIVE: The current study consisted of a retrospective part and a prospective part, aiming to compare 2 tDCS electrode placements and to explore effects of HD tDCS by matched pairs analyses. METHODS: Two groups of 39 patients received tDCS of the dorsolateral prefrontal cortex (DLPFC) or tDCS of the right supraorbital-left temporal area (RSO-LTA). Therapeutic effects were assessed with the tinnitus functional index (TFI), a visual analogue scale (VAS) for tinnitus loudness, and the hyperacusis questionnaire (HQ) filled out at 3 visits: pretherapy, posttherapy, and follow-up. With a new group of patients and in a similar way, the effects of HD tDCS of the right DLPFC were assessed, with the tinnitus questionnaire (TQ) and the hospital anxiety and depression scale (HADS) added. RESULTS: TFI total scores improved significantly after both tDCS and HD tDCS (DLPFC: P < .01; RSO-LTA: P < .01; HD tDCS: P = .05). In 32% of the patients, we observed a clinically significant improvement in TFI. The 2 tDCS groups and the HD tDCS group showed no differences on the evolution of outcomes over time (TFI: P = .16; HQ: P = .85; VAS: P = .20). CONCLUSIONS: TDCS and HD tDCS resulted in a clinically significant improvement in TFI in 32% of the patients, with the 3 stimulation positions having similar results. Future research should focus on long-term effects of electrical stimulation. PMID- 30019631 TI - Longitudinal Developmental Outcomes after Traumatic Brain Injury in Young Children: Are Infants More Vulnerable Than Toddlers? AB - Children under 4 years of age have the highest incidence of traumatic brain injury (TBI) among the non-elderly and may be at high risk of poor developmental outcomes. We prospectively enrolled a cohort of children injured before 31 months old with TBI or orthopedic injury (OI), from 2013 to 2015 at two pediatric level 1 trauma centers to study very young children's developmental outcomes after injury. We used Ages & Stages-3 and Ages & Stages: Social-Emotional screening tools to measure children's development at pre-injury and 3 and 12 months post injury. The cohort included 123 children with TBI categorized as mild (n = 48), complicated-mild or moderate (n = 54), and severe (n = 21) and 45 children with OI. Generalized linear models examined effects of injury severity and age at injury controlling for pre-injury ratings. Children with mild or complicated mild/moderate TBI generally remained on developmental track. Compared to OI, children with severe TBI tended to have a negative developmental trajectory with decrements in communication (-7.07; 95% confidence interval [CI], -13.7, -0.48), gross motor (-15.2; 95% CI, -21.1, -9.19), problem solving (-11.6; 95% CI, -17.9, -5.29), personal-social (-16.8; 95% CI, -22.8, -10.8), and social-emotional (21.0; 95% CI, 7.32, 34.7) domains 12 months post-injury. Developmental effects from TBI differed by age at injury: Infants had more difficulties than older children in communication and problem-solving domains. Despite low developmental scores in 28% of the cohort, only 5% were receiving Early Childhood Intervention (ECI) services 12 months after injury. Early age at injury is a vulnerability factor after TBI. Young age and severe injury should prompt evaluation for ECI. PMID- 30019632 TI - Hospital case-volume is associated with case-fatality after aneurysmal subarachnoid hemorrhage. AB - Background Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures. Aims To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007-2014. Hospitals were categorized by annual case-volume (low volume: <41/year; intermediate: 41 70/year; high: >70/year). Primary outcome was 14-day in-hospital case-fatality. We calculated proportions, and used multiple logistic regression to adjust for age, sex, differences in comorbidity or disease severity, aneurysm treatment modality, and hospital. Results We included 8525 patients (2363 treated in low volume hospitals, 3563 treated in intermediate volume hospitals, and 2599 in high volume hospitals). Crude 14-day case-fatality for hospitals with low case-volume was 10.4% (95% confidence interval (CI) 9.2-11.7%), for intermediate volume 7.0% (95% CI 6.2-7.9%; adjusted odds ratio (OR) 0.63 (95%CI 0.47-0.85)) and for high volume 5.4% (95% CI 4.6-6.3%; adjusted OR 0.50 (95% CI 0.33-0.74)). In patients with clipped aneurysms, adjusted OR for 14-day case-fatality was 0.46 (95% CI 0.30-0.71) for hospitals with intermediate case-volume and 0.42 (95% CI 0.25 0.72) with high case-volume. In patients with coiled aneurysms, adjusted OR was 0.77 (95% CI 0.55-1.07) for hospitals with intermediate case-volume and 0.56 (95% CI 0.36-0.87) with high case-volume. Conclusions Even within a subset of large, tertiary care centers, intermediate and high hospital case-volume is associated with lower case-fatality after aSAH regardless of treatment modality, supporting centralization to higher volume centers. PMID- 30019633 TI - RecoverNow: A patient perspective on the delivery of mobile tablet-based stroke rehabilitation in the acute care setting. AB - BACKGROUND/AIM: We previously reported the feasibility of RecoverNow (a mobile tablet-based post-stroke communication therapy in acute care). RecoverNow has since expanded to include fine motor and cognitive therapies. Our objectives were to gain a better understanding of patient experiences and recovery goals using mobile tablets. METHODS: Speech-language pathologists or occupational therapists identified patients with stroke and communication, fine motor, or cognitive/perceptual deficits. Patients were provided with iPads individually programmed with applications based on assessment results, and instructed to use it at least 1 h/day. At discharge, patients completed a 19-question quantitative and open-ended engagement survey addressing intervention timing, mobile device/apps, recovery goals, and therapy duration. RESULTS: Over a six-month period, we enrolled 33 participants (three did not complete the survey). Median time from stroke to initiation of tablet-based therapy was six days. Patients engaged in therapy on average 59.6 min/day and preferred communication and hand function therapies. Most patients (63.3%) agreed that therapy was commenced at a reasonable time, although half expressed an interest in starting sooner, 66.7% reported that using the device 1 h/day was enough, 64.3% would use it after discharge, and 60.7% would use it for eight weeks. Sixty-seven percent of patients expressed a need for family/friend/caregiver to help them use it. CONCLUSION: Our results suggest that stroke patients are interested in mobile tablet-based therapy in acute care. Patients in the acute setting prefer to focus on communication and hand therapies, are willing to begin within days of their stroke and may require assistance with the tablets. PMID- 30019634 TI - Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: Study protocol. AB - RATIONALE: Unruptured intracranial aneurysms are currently left untreated if the presumed complication risk of preventive endovascular or neurosurgical intervention is higher than the risk of rupture. Aneurysm wall inflammation and blood pressure are attractive modifiable risk factors of aneurysm rupture and growth. AIM: To investigate in patients with an unruptured intracranial aneurysm who do not qualify for preventive endovascular or neurosurgical intervention whether a treatment strategy of acetylsalicylic acid 100 mg/day plus intensive blood pressure treatment (targeted systolic blood pressure < 120 mmHg, monitored with a home blood pressure measuring device) reduces the risk of aneurysm rupture or growth compared with care as usual (no acetylsalicylic acid, targeted office systolic blood pressure < 140 mmHg, no home blood pressure measuring device). SAMPLE SIZE: We aim to randomize 776 patients 1:1 to the intervention arm or care as usual. DESIGN: Bi-national (Germany and the Netherlands) multicenter, prospective, randomized, open-label phase III trial with blinded outcome assessment. OUTCOMES: The primary outcome is aneurysm rupture or growth (increase in any aneurysm diameter by >= 1 mm) on repeated MR or CT angiography within 36 +/- 6 months after randomization. DISCUSSION: The Prospective Randomized Open label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms (PROTECT-U) is the first randomized trial to investigate if a medical strategy reduces the risk of rupture or growth of intracranial aneurysms in patients not undergoing preventive endovascular or neurosurgical aneurysm treatment. Clinical trial Registration: NCT03063541. PMID- 30019635 TI - Urinary bladder matrix protects host from bacterial-induced lung infection. AB - The extracellular matrix (ECM) is composed of a complex mixture of structural and functional macromolecules that are important during growth, development, and wound repair. In this study, we seek to determine if an ECM derived from the porcine urinary bladder, specifically urinary bladder matrix (UBM), can act to prevent bacterial infection in the context of lung injury. Here, we examined a digested form of UBM, which prevented bacterial biofilm formed by both Gram positive bacteria (GPB) such as methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria (GNB) including Pseudomonas aeruginosa (PA) and Klebsiella pneumoniae (KP) in vitro. Furthermore, exogenously administered UBM digest exhibited host protection from MSSA, MRSA, and PA-induced respiratory infection in a murine infection model. The protection against both GPB- and GNB-induced infection demonstrated by UBM suggests the antibacterial function is likely through biofilm prevention. In addition, two potential off the shelf UBM product forms (pre formulated digested UBM and intact UBM particulate) showed significant protection from acute severe respiratory infection. Taken together, our results support further study of the use of UBM as an alternative treatment to attenuate bacterial-induced infection. PMID- 30019636 TI - Relationships between certain individual characteristics and occupational accidents. AB - BACKGROUND: Work accidents and injuries are an occupational health and safety problem. METHODS: This cross-sectional study was conducted for 404 frontline workers who were randomly selected from the Arya Sasol Petrochemical Company in Bushehr, Iran, during 2016. A statistical analysis was performed using the chi2 test and the logistic regression model with SPSS version 18. RESULTS: The overall occupational accident rate among the participants was found to be 9.2%. Statistically significant differences were observed for body mass index, education, job experience, smoking habit, consumption of sedative pills and presence of sleep disorders. Three factors had significant adjusted odds ratios (ORs): body mass index (OR 2.41, 95% confidence interval [CI] [1.16, 5.04]), education (OR 0.25, 95% CI [0.07, 0.85]) and job experience (OR 0.29, 95% CI [0.15, 0.57]). CONCLUSIONS: Preventive programs should be implemented for industrial workers, especially young workers, workers who smoke, overweight workers and workers with psychosomatic disease. PMID- 30019637 TI - Protein and Peptide Markers in Reproduction. PMID- 30019638 TI - Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases. AB - Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO 1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer's Disease (AD), Parkinson's Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review. PMID- 30019639 TI - Parkinson's Disease: Alpha Synuclein, Heme Oxygenase and Biotherapeutic Countermeasures. AB - Neurodegenerative disorders have been and remain persistent sources of enormous suffering throughout human history. The tragedy of their impact on human relationships, physical vitality, and fundamental dignity cannot be understated. Parkinson's disease (PD), one of the most common of these terrible illnesses, has a global incidence of approximately two-to-four percent of the human population, along with devastating social and economic impact. The present review analyzes aspects of PD pathophysiology that offer particularly attractive strategies for the development of improved prevention and therapy. The occurrence, symptoms, pathogenesis, and etiology of PD are considered, with focus on how the Alpha synuclein protein, which normally regulates neurotransmitter release, is aggregated by oxidative stressors into toxic inclusions, prominently including Lewy bodies and insoluble fibrils that disrupt the organization of brain areas responsible for motor control. The contribution to a progressively prooxidant tissue environment resulting from interaction between advanced glycation end products (AGEs) and their cognate receptors (RAGEs) is examined here as a significant driver of PD. This review also explores strategies currently being developed by a U.S.-Russian team that may reduce the risk and severity of PD by use of recombinant atoxic derivatives (ad) of botulinum neurotoxins (BoNT/A ad), that traffic inducers of the cytoprotective enzyme heme oxygenase to selected midbrain neurons, at which Alpha synuclein aggregation occurs. Considered together, the topic material presented here provides both researchers and clinicians with a short but concise overview of the current understanding of PD pathology and approaches to biotherapeutic (precision) countermeasures to its onset and progression. PMID- 30019640 TI - Heme Oxygenase and the Skin in Health and Disease. AB - The skin is often introduced as the largest organ of the human body which - being uniquely exposed to external stress - faces several types of challenges, from physical, chemical, biological, and immunological origin. Therefore, the skin is also a site where inflammation, oxidative stress and cellular damage occurs regularly. Heme oxygenase (HO), primarily functioning in the catabolism of heme, is a very important cytoprotective enzyme that has antioxidant, anti-inflammatory and anti-apoptotic properties. Given the need for an enzyme with such a combination of attributes in the skin, it is not surprising that HO is involved in physiological processes as well as pathological conditions of the skin. In the recent decade, a huge effort was undertaken to identify treatments that modify HO activity for the treatment of inflammatory or malignant skin diseases. In this review, we highlight the role of HO in the skin in physiological conditions as well as in relevant dermatological diseases such as atopic dermatitis, psoriasis and melanoma. PMID- 30019641 TI - New Developments in Pichia pastoris Expression System, Review and Update. AB - BACKGROUND: Although Pichia pastoris is an outstanding host among conventional expression systems for production of recombinant proteins, a new interest has been emerged to this system due to the inherent advantages and new developments in this expression host. The potential for secretory and soluble expression of heterologous glycoproteins in P. pastoris proposed this system as a candidate for the production of complex eukaryotic proteins. METHODS: Several new developments have occurred in different areas related to P. pastoris expression system including hosts, vectors, glycosylation pattern and fermentation technology. Strain engineering using Crispr/Cas9 technology to produce human-like glycoproteins and protease deficient strains are two new areas of development with high importance. RESULTS: This review is dedicated to discuss the most important characteristics of P. pastoris with emphasis on new developments, especially in the field of glycoengineering, efficient expression vectors and promoters. CONCLUSION: New developments that occurred in the P. pastoris expression system converted this system to a versatile host for the production of complex proteins. This progress paved the way for several proteins to enter the clinical trials or industrial processes with this valuable expression host. PMID- 30019642 TI - Low Doses of G-CSF Prevent Cerebral Infarction and Maintain Muscle Strength in an Experimental Model of Global Ischemic Stroke. AB - BACKGROUND: Stroke is a major cause of severe and long-term disability in adult individuals. Treatment of this disease is limited by the narrow therapeutic window in which intervention is crucial. An alternative therapy for stroke could be cellular growth factors, which participate in several pathways that mediate neuronal cell death. METHODS: We evaluated the neuroprotective ability of different doses of granulocyte colonystimulating factor (G-CSF; 5, 50 and 100 MUg/kg/day) in the mouse model of global cerebral ischemia induced by bilateral occlusion of the common carotid arteries for 80 minutes. The control group received vehicle (5% glucose solution) and the treated group was administered with G-CSF at two postsurgery time-points: immediately after and 24 hours after. Subsequently, muscle strength, leukocyte count, infarcted cortical area, and apoptosis/TUNEL were evaluated. RESULTS: The global ischemia promoted an impairment of the strength (16%) and a cerebral infarction (0.437+/-0.08 cm2) which were accompanied by apoptosis evaluated by TUNEL in control mice. In mice treated with G-CSF the strength function was maintained, the infarcted area (~70%) and apoptosis were decreased in a similar magnitude in all treated groups. Accordingly, the cytokine activities were confirmed by blood leukocyte count that was increased approximately 2-fold than that observed in the control group. CONCLUSION: The results indicate a neuroprotective effect of G-CSF, even in small doses, in mice subjected to global cerebral ischemia, thereby reducing the neurofunctional impairment caused by stroke, when considering the maintenance of muscle strength in the treated animals. PMID- 30019643 TI - Emerging Role of Polyamines in Plant Stress Tolerance. AB - Plants, being sessile organisms, are challenged by variety of stresses in the form of abiotic and biotic components of environment. In such adverse conditions, plants evolve various adaptive strategies in order to survive. Among these strategies, accumulation of polyamines in plants helps to combat stress. Polyamines are ubiquitous low molecular weight compounds, which are now known to be involved in stress tolerance as suggested by various pieces of evidence during abiotic and biotic stress. The anti-stress properties of polyamines in plants are illustrated by their roles in modulation of morphological growth parameters, elevation of photosynthetic pigments, as well as declined content of stress indices, antioxidative enzymes, and non-enzymatic antioxidants content. The emerging role of polyamines in plant stress tolerance has been discussed in the present review. PMID- 30019644 TI - Novel Benzylidenehydrazide-1,2,3-Triazole conjugates as Antitubercular Agents: Synthesis and Molecular Docking. AB - Novel 1,2,3-triazole based benzylidenehydrazide derivatives were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (MTB) H37Ra, M. bovis BCG and cytotoxic activity. Most of the derivatives exhibited promising in vitro potency against MTB characterized by lower MIC values. Among all the synthesized derivatives, compound 6a and 6j were the most active against active and dormant MTB H37Ra, respectively. Compound 6d was significantly active against dormant and active M. bovis BCG. The structure activity relationship has been explored on the basis of anti-tubercular activity data. The active compounds were also tested against THP-1, A549 and Panc-1 cell lines and showed no significant cytotoxicity. Further, the synthesized compounds were found to have potential antioxidant with IC50 range = 11.19-56.64 MUg/mL. The molecular docking study of synthesized compounds was performed against DprE1 enzyme of MTB to understand the binding interactions. Moreover, synthesized compounds were also analysed for ADME properties and from all the experimental results, the potency of compounds indicate that, this series considered as starting point for the developement of novel and more potent anti-tubercular agents in future. PMID- 30019645 TI - Pivotal Pathogenic and Biomarker Role of Chlamydia Pneumoniae in Neurovascular Diseases. AB - Chlamydia Pneumoniae (C. Pn) is an obligatory intracellular bacterium that is associated with respiratory tract infections like pneumonia, pharyngitis and bronchitis. It has also been implicated in cerebrovascular (stroke) as well as cardiovascular diseases. The most possible pathway via which C. Pn elicits its pathogenesis could be via activation of Human Vascular Smooth Muscle Cells (VSMCs) proliferation resulting in the stimulation of Toll-Like Receptor-4 (TLR 4) and/or phospho-44/42(p44/p42) Mitogen-Activated Protein Kinases (MAPK). It is also established that tyrosine phosphorylation of IQ domain GTPase-activating protein 1 (IQGAP1) also contributed to C. Pn infection-triggered Vascular Endothelial Cell (VEC) movements via the SRC tyrosine kinase inhibitor PP2 (4 amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) resulting in angiogenesis. It is also proven that restricted inflammatory cell infiltrates as well as apoptosis have been linked to C. Pn or C. Pn-specific proteins in atherosclerotic plaques of patients with stroke. It is further an evidence that C. Pn enters the cerebral vasculature during the initial infection and worsen atherosclerosis either directly or indirectly. Chronic, persistent C. Pn infection is also capable of triggering the secretion of Chlamydial Heat Shock Protein 60 (cHSP60) in the vessel wall resulting in augmentation of inflammation. C. Pn also aids in the activation of explicit cell-intermediated immunity within plaques. Macrophages in the carotid plaques co-exist with CD4+ lymphocytes which are capable of triggering the release of pro-inflammatory cytokines resulting in the augmentation of atherogenic development during C. Pn infection. C. Pn actively participated in the modification of both histones H3 and H4 during chromatin analysis via the interleukin 8(IL-8) gene facilitator as well as conscription of nuclear factor kappa-B(NF-kappaB) or NF- kappaB/p65 complex and polymerase II (Pol II). This review, therefore, focuses on the crucial involvement of C. Pn in the pathogenesis of cerebrovascular events. PMID- 30019646 TI - Therapeutic potential of Citronella Essential Oil: a review. AB - Mosquito borne diseases such as malaria, filariasis, chikunguniya, yellow fever, dengue and Japanese encephalitis are the major cause of remarkable morbidity and mortality in livestock and humans worldwide. Since ancient times, aromatic plants are used for their medicinal value. Essential oils derived from these plants may be used as effective alternatives/adjuvents in pharmaceuticals, biomedical, cosmetic, food, veterinary and agriculture applications. These oils have also gained popularity and interest for prevention and treatment of various disorders. However, several reports on adverse effects including skin eruption, contact artricaria or toxic encephalopathy in children are available for synthetic repellent in literature. Thus, natural insect repellents like essential oils have been explored recently as an alternative. One such essential oil studied widely, is citronella oil, extracted mainly from Cymbopogon nardus. This essential oil has exhibited good efficacy against mosquitoes. It is a mixture of components including citronellal, citronellol, geraniol as major constituents contributing to various activities (antimicrobial, anthelmintic, antioxidant, anticonvulsant antitrypanosomal and wound healing), besides mosquito repellent action. Citronella essential oil is registered in US EPA (Environmental protection agency) as insect repellent due to its high efficacy, low toxicity and customer satisfaction. However, poor stability in the presence of air and high temperature limits its practical applications. Since, specific knowledge on properties and chemical composition of oil is fundamental for its effective application, the present review compiles and discusses biological properties of citronella oil. It also sheds light on various formulations and applications of this essential oil. PMID- 30019647 TI - Anti-Ophidian Properties Of Herbal Medicinal Plants: Could It Be A Remedy For Snake Bite Envenomation? AB - Snake bite envenoming cause high rates of morbidity and mortality and is one of the serious health related concern all over the globe. Around 3200 species of snakes have been discovered till date. Amid these species, about 1300 species of snakes are venomous. On account of its severity, World Health Organization (WHO) recently included snake bite envenoming in the list of neglected tropical diseases. Immunotherapy has partially solved the issues related to snake bite envenomation. However, it is associated with numerous adverse effects, due to which alternative treatment strategies are required for the treatment of snake bite. Traditionally, a large repository of herbal medicinal plants is known to possess activity against snake venom. An exploration of the therapeutic benefits of these medicinal plants used for the treatment of snake bites reveals the presence of various potential phytochemicals. The aim of the present review is to provide an outline regarding poisonous snakes all over the world, various compositions of snake venom, adverse effects related to anti-snake venom and numerous medicinal plants used for anti ophidian activity. PMID- 30019648 TI - Metformin one in a million efficient medicines for rheumatoid arthritis complications: inflammation, Osteoblastogenesis, Cardiovascular disease, Malignancies. AB - BACKGROUND: Rheumatoid arthritis is a widespread autoimmune disease and inflammation and bone destruction are two main issues in rheumatoid arthritis. OBJECTIVE: To discussing metformin effects on rheumatoid arthritis complications. METHOD: We conducted a narrative literature search including clinical trials, experimental studies on laboratory animals and cell lines. Our search covered Medline, PubMed and Google Scholar databases from 1999 until 2018. We used the terms" Metformin; Rheumatoid arthritis; Cardiovascular disease; Cancer; Osteoblastogenesis. DISCUSSION: Inflammatory pro-cytokines such as Interlukin-6 play important roles in T.helper17 cell lineage differentiation. Interlukin-6 and Tumor Necrosis Factor-alpha activate Janus kinase receptors signal through Signaling transducer and activator of transcription signaling pathway which plays important role in inflammation, bone destruction and cancer in rheumatoid arthritis patients. Interlukin-6 and Tumor Necrosis Factor-alpha synergistically activate Signaling transducer and activator of transcription and Nuclear Factor kbeta pathways and both cytokines increase the chance of cancer development in rheumatoid arthritis patients. Metformin is AMPK activators that can suppress mTOR, STAT3 and HIF-1 so AMPK activation plays important role in suppressing inflammation and osteoclastogenesis and decreasing cancer. CONCLUSION: Metformin effect on AMPK and mTOR pathways gives the capability to changes Treg/Th17 balance and decrease Th17 differentiation and inflammation, osteoclastogenesis and cancers in RA patients. Metformin can be useful in protecting bones especially in first stages of RA and it can decrease inflammation, CVD and cancer in RA patients so Metformin beside DAMARs can be useful in increasing RA patients' life quality with the less harm and cost. PMID- 30019649 TI - Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity. AB - BACKGROUND: Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity. Target compounds were synthesized, and investigated for their in vitro anticancer activity. RESULT: Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 uM) and MCF7 (IC50 of 29.4 uM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 uM), HEPG2 (IC50 of 16.4 uM) and MCF7 (IC50 of 32.8 uM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7uM). Both 8b and 10 exhibited good potency regarding inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with IC50 of 14.00 and 21.62 nM, respectively. CONCLUSION: The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site. PMID- 30019650 TI - Significance of Mir-15a-5p and Cnksr3 as Novel Prognostic Biomarkers in Non-Small Cell Lung Cancer. AB - Background In recent years, targeted cancer treatment methods at various molecular levels have been developed for non-small cell lung cancer (NSCLC), one of two major subtypes of lung cancer. miRNA-based clinical trials are currently the preferred targeted therapeutic strategy. Also, ceRNAs (competing endogenous RNA) would be the newest and the most effective approach to uncover novel interactions between mRNAs and miRNAs in NSCLC carcinogenesis. There are many factors influencing on efficiency of a miRNA to suppress or silence translation of the target mRNA. The most effective event is the presence of other RNAs showing ceRNA activity. These RNAs contain binding sites for specific miRNAs and enable miRNAs to bind these pseudo targets, instead of the original binding sites on the target mRNA. Therefore, the mRNA of the target gene is less affected by this miRNA, while the amount of miRNA remains the same in the media. Method For this project, we determined that five clinically important different oncogenes (PDL1, FGFR1, DDX3X, SLC1A5, FXR1) are involved in the pathogenesis of NSCLC. For this purpose, we transfected model NSCLC cell line, A549, with miRNAs (miR-150 5p, miR-15a-5p, miR-503-5p) targeting these oncogenes to investigate whether these oncogenes will be suppressed at the mRNA level and also how the suppression efficiency of these miRNA on the oncogenes will be affected by possible ceRNA (CNKSR3, POU2F1, HIPK2) activities. Results miR-15a-5p was determined to have the most suppressive effect on the five genes and three potential ceRNAs (p<0.05). Furthermore, CNKSR3 was the ceRNA most affected by all three miRNAs (p<0.05). Conclusion CNKSR3 was affected more than the oncogenes known to act on NSCLC and this might make it a stronger and novel marker for use in possible treatment regimens designed using miR-15a-5p silencing effect on oncogenes in NSCLC pathogenesis. According to literature, this is the first study associating NSCLC with miR-15a-5p and CNKSR3. PMID- 30019651 TI - One Pot Synthesis of Triazolo Heterolignans: Biological Evaluation and Molecular Docking Studies as Tubulin Inhibitors. AB - BACKGROUND: The anti mitotic activity of podophyllotoxin derivative targeting tubulin enzyme proved them as strong polymerization inhibitors. The introduction of heteroatom along with different heteroaryl systems in naturally obtained lignans created a latitude for design of bioactive components. A novel one pot sequential propargylation/cycloaddition reaction strategy has been followed to synthesize triazolo-heterolignans. OBJECTIVE: To screen anti-proliferative activity of novel heterolignans and to determine their mode of action Methods: SRB assay, Cytotoxicity evaluation, PI uptake for analysis of cell cycle, caspase 3 activity, Western blot analysis and Immunofluorescence and molecular docking studies. RESULTS: SRB assay of synthesised compounds were provided compound 3a and 5f to be highly active among the synthesized compounds. The Compound 3a showed cell cycle arrest at G2/M phase and 5f arrest the cells at G1 phase. Compound 5f displayed caspase 3 mediated apoptotic effect at lower levels. Compound 3a and 5f displayed microtubule disassembly inhibition same as paclitaxel and found to be occupying colchicine binding site of tubulin, both ligands were depicted pi cation interaction with Lys352 residue and triazole ring accommodated at the lactone binding site. CONCLUSION: A novel one pot sequential propargylation/cycloaddition reaction has been developed for the synthesis of triazolo-heterolignans. Compound 3a and 5f were displayed good cytotoxic activities and found to inhibit microtubule disassembly. The importance of triazole ring of heterolignans has been studied by molecular docking experiments and results were compared. PMID- 30019652 TI - Exploring the lapse in druggability: Sequence Analysis, Structural Dynamics and binding site characterization of K-RasG12C variant, a feasible oncotherapeutics target. AB - The difficulty in druggability has presented a hurdle in the treatment of cancer diseases associated with dysfunctional mutant K-ras. This has so far impeded the emergence of suitable inhibitors to discontinue its aberrant activities. Despite the identification of different interactive sites, limited information exists in literature about their characteristics that could aid the design and development of appropriate inhibitors that could bind at its catalytic or effector binding sites, thereby disrupting oncogenic activities. While binding of inhibitors at the K-ras catalytic site could alter activity switch, targeting effector binding regions would disrupt its association with effector proteins such as Raf. Moreover, identification and cross validation of druggable sites on mutant K-ras coupled with characterization would aid the design of characteristic chemical compounds for such sites. Herein, we carried out a comprehensive study of K-ras G12C mutant to identify, cross-validate and characterize its binding sites for potential druggability, coupled with the elucidation of alterations in 3D conformations and dynamics. From our results, the identified druggable sites were selected based on cross-validation and were characterized based on site attributes to provide insights for suitable ligands. Conformational studies revealed that the mutant exhibited notable structural instability, increased flexibility and a strongly anti-correlated movement compared to the inactive and active wildtype forms. Furthermore, identified druggable sites served as the basis of defining lead compounds with nucleophilic and electrophilic attributes for each site. These findings will contribute to the development of site-specific K-ras inhibitors for the treatment of cancer diseases associated with oncogenic K ras activities. PMID- 30019653 TI - Clinical application of polysialylated therapeutic proteins. AB - While protein therapeutics are invaluable in managing numerous diseases, many require frequent injections to maintain therapeutically effective concentrations, due to their short half-life in circulation. PolyXenTM, a platform technology employing biodegradable, non-immunogenic and hydrophilic polysialic acids (PSA) for drug delivery, is being utilized to overcome such limitations, thereby enabling the clinical utility of a broad range of protein therapeutics. Here, we report the recent progress on two development candidates, polysialylated erythropoietin (PSA-EPO) and polysialylated deoxyribonuclease I (PSA-DNase). Polysialylation led to a significantly prolonged circulating half-life (e.g., t1/2 of PSA-EPO = ~400 h in patients after subcutaneous administration, vs. t1/2 of EPO = ~22 h), improved stability against proteases and thermal stress, reduced clearance, and enhanced in vivo efficacy. This approach has been clinically validated in phase I and II studies of PSA-EPO for managing anemia in patients with chronic kidney disease (CKD). PMID- 30019654 TI - Complications of Diabetes: An Insight into Genetic Polymorphism and Role of Insulin. AB - BACKGROUND: Diabetes Mellitus (DM) is an advanced and chronic endocrine disorder characterized by an insufficiency of insulin secretion from pancreatic beta-cells and liver, adipose tissues, and skeletal muscles. OBJECTIVE: The main objective of this study is to understand the mechanism and genes which are responsible for the prevalence of diabetes. The study also covers various types of diabetic complications with special reference to insulin role and defects. METHODS: The scientific literature and patents were reviewed and analyzed based on their suitability and relevance to the theme of the study. The scientific literature was covered from the authentic databases such as Elsevier, Springer, and Bentham Science. The patents were reviewed from http://www.freepatentsonline.com. RESULTS: Glucokinase (ATP: D-glucose-6-phosphotransferase; GCK), initiates glycolysis and acts as a glucose sensor and metabolic signal producer in liver and pancreas. PCR-sequencing showed qualitative differences in diabetic patients in comparison to healthy subjects. Glucokinase is the most important component in glucose detection of pancreatic islet beta cells in diabetes because glucokinase mutations can be one of the most common single gene disorders described. It is known that a genetic variation of a human glucokinase gene, including a point mutation, causes MODY, the concentration of plasma glucose increased and it is supposed to be the cause of diabetes of the present study subjects. Owing to hyperglycemia and individual components of the insulin resistance (metabolic) syndrome, people with Type II DM are prone to the high threat for microvascular complications (including nephropathy, retinopathy, and neuropathy) and macrovascular complications (such as Ischemic Heart Disease). There were also significant differences (P < 0.0001) in glycation levels (0.90, 0.4838mole/mole), random blood sugar (348.8, 105.8mg/dL), cholesterol levels (235.3, 161.8mg/dL), low density lipoprotein in diabetic subjects (155.3, 28.46mg/dL) and in healthy donors. GCK gene mutations were found in 70% of the patients while 30% are non mutated. CONCLUSION: In conclusion, lipids, glucose, and protein play an essential role in the initiation of AGE's or diabetic complications (Micro and Macrovascular Complications). The importance of the clinical results should also be recognized in the genetic analysis of heterogeneous disorders as NIDDM/ Type II DM. PMID- 30019655 TI - Pensions and low sodium salt: a qualitative evaluation of a new strategy for managing hypertension in rural South Africa. AB - Background This paper describes a pilot study to assess the feasibility of a novel intervention to improve the management of hypertension among older people in rural South Africa. Older South Africans have the highest rates of uncontrolled hypertension recorded for any country. Notably, South Africa has a widely-available old age grant (pension), which is delivered on a monthly basis to citizens living in rural villages. Methods We assessed the feasibility of engaging with older people at the point of pension delivery in the Agincourt sub district of Mpumalanga Province. This included providing information about hypertension, measuring blood pressure, referral to primary care services, and providing a monthly supply of low sodium salt. We recruited 20 people aged 60 and over to participate in the pilot intervention, which was conducted over three months in two villages. Towards the end of the intervention, we conducted focus groups with study participants and held a meeting with local stakeholders, including the district health office and the state social security agency. Results The pilot study demonstrated (i) Sustained engagement with the original 20 participants. Of these, 19 continued to participate in the intervention during subsequent monthly pension days. (ii) A high level of acceptance of the low sodium salt product, reflected in repeat usage and comments made in the focus groups. (iii) Strong support for the intervention and a willingness to collaborate by local stakeholders. (iv) A perception among participants that symptoms they associated with hypertension had abated. This is supported by blood pressure readings made over the three months of follow-up. Conclusion Though limited in scope, this pilot study provided evidence of the feasibility of the intervention and justification for it to be tested on a larger and more robust basis. PMID- 30019656 TI - The Effect of Coconut Jelly with Stevia as a Natural Sweetener on Blood Glucose, Insulin and C-Peptide Responses in Twelve Healthy Subjects. AB - BACKGROUND: Coconut jelly is a popular dessert among Asian people. However, it contains high levels of sugar. The recent patents on steviol glycoside (WO2015014969A1), steviol glycoside compositions for oral ingestion or use (WO2017095932A1) and sweetener composition for preventing and improving obesity, containing glycolysis inhibitor ingredient (EP2756764B1) help to select the sweetener for development of coconut jelly. OBJECTIVE: Therefore, the purposes of this study were to develop a healthier coconut jelly formula by using stevia as a natural sweetener as well as to investigate the short-term effects of Modified Coconut Jelly (MCJ) compared to Control Formula (CCJ) consumption on glycemic and insulin responses in twelve healthy participants. METHODS: The sensory evaluation found that MCJ with 50% sugar replacement using stevia obtained the highest acceptability score compared to other formulas. In a cross-over design, participants were required to consume MCJ and CCJ containing 50 g of available carbohydrates. Blood samples were collected at 0 (baseline), 30, 60, 90 and 120 minutes for postprandial blood glucose, insulin, and C-peptide. RESULTS: The incremental Areas Under the Curve (iAUC) of blood glucose and insulin of MCJ had a lower trend than CCJ by 15.7 and 5.4 percent, respectively. MCJ consumption had blood glucose slowly decline after 60 to 120 minute. MCJ tended to decrease in postprandial blood glucose level without inducing insulin secretion. CONCLUSION: This might be an effect of stevia. Nutrient composition is lower in total sugar and higher in fiber, which has been reported as antihyperglycemia in humans. Therefore, MCJ might be an optional food product for healthy people or patients with Non-Communicable Diseases (NCDs) such as diabetes mellitus. PMID- 30019658 TI - Ischemic Strokes in a Man with Congenital Afibrinogenemia. PMID- 30019657 TI - Methicillin-resistant Staphylococcus aureus colonisation: epidemiological and molecular characteristics in an acute-care tertiary hospital in Singapore. AB - Current knowledge of methicillin-resistant Staphylococcus aureus (MRSA) colonisation in relation to epidemiological characteristics is incomplete. We conducted a cross-sectional study at an acute-care tertiary infectious diseases hospital of MRSA isolates identified through routine surveillance from January 2009 to December 2011. We randomly selected 205 MRSA isolates (119 inpatients) from 798 isolates (427 inpatients) for molecular profiling using multilocus sequence typing. Multilevel multinomial logistic regression was used to estimate odds ratio (OR) assessing the predilection of MRSA strains for anatomic sites, and associations of strains with human immunodeficiency virus (HIV) infection. The most frequent sequence types (STs) were 239, 22 and 45. The proportion of ST22 increased over the sampling period, replacing ST239 as the dominant lineage. However, ST239 remained the most prevalent among HIV-seropositive individuals who were six times more likely to be colonised with this strain than non-HIV patients (adjusted OR (aOR) 6.44, 95% confidence interval (CI) 1.94-21.36). ST45 was >24 times more likely to be associated with perianal colonisation than in the nares, axillae and groin sites (aOR 24.20, 95% CI 1.45-403.26). This study underlines the clonal replacement of MRSA in Singapore as previously reported but revealed, in addition, key strain differences between HIV-infected and non-infected individuals hospitalised in the same environment. PMID- 30019659 TI - Use of real-time semiquantitative PCR data in management of a neonatal intensive care unit adenovirus outbreak. AB - OBJECTIVE: To describe an adenovirus outbreak in a neonatal intensive care unit (NICU), including the use of qualitative and semiquantitative real-time polymerase chain reaction (qPCR) data to inform the outbreak response. DESIGN: Mixed prospective and retrospective observational study. SETTING: A level IV NICU in the southeastern United States.PatientsTwo adenovirus cases were identified in a NICU. Screening of all inpatients with qPCR on nasopharyngeal specimens revealed 11 additional cases.InterventionsOutbreak response procedures, including enhanced infection control policies, were instituted. Serial qPCR studies were used to screen for new infections among exposed infants and to monitor viral clearance among cases. Changes to retinopathy of prematurity (ROP) exam procedures were made after an association was noted in those patients. At the end of the outbreak, a retrospective review allowed for comparison of clinical factors between the infected and uninfected groups. RESULTS: There were no new cases among patients after outbreak identification. One adenovirus-infected patient died; the others recovered their clinical baselines. The ROP exams were associated with an increased risk of infection (odds ratio [OR], 84.6; 95% confidence interval [CI], 4.5-1,601). The duration of the outbreak response was 33 days, and the previously described second wave of cases after the end of the outbreak did not occur. Revisions to infection control policies remained in effect following the outbreak. CONCLUSIONS: Retinopathy of prematurity exams are potential mechanisms of adenovirus transmission, and autoclaved or single-use instruments should be used to minimize this risk. Real-time molecular diagnostic and quantification data guided outbreak response procedures, which rapidly contained and fully terminated a NICU adenovirus outbreak. PMID- 30019660 TI - Pulmonary artery to left atrial fistula: haemodynamic changes traced from fetus to infancy until its interventional closure. AB - Communications between the pulmonary artery and left atrium cause cyanosis. The images document serial haemodynamic changes in such a fistula from fetal life to the postnatal period with a successful transcatheter intervention. PMID- 30019661 TI - Kinds of individuals defined by patterns of variables. AB - This paper argues that investigators should consider replacing the popular practice of comparing individuals varying in gender, social class, and/or ethnicity on one or more continuous measures with a search for kinds of individuals defined by patterns of properties that include not only their values on outcome measures but also their gender, social class, and ethnicity. Investigators who believe that a particular predictor contributes to an outcome independent of the gender, class, or ethnicity of the participants often implement statistical procedures that promise to remove the contributions of the above categories. These analyses lead to misleading conclusions when the controlled category is correlated with the dependent measures. The final sections summarize the properties of genders, classes, and ethnic groups that make distinctive contributions to many psychological outcomes. The paper ends by noting that a society's ethical beliefs constitute a defensible basis for ignoring the biological properties associated with these categories in order to allow members of these groups access to whatever educational or occupational goals they desire. PMID- 30019662 TI - The Going to Stay at Home program: combining dementia caregiver training and residential respite care. AB - : ABSTRACTBackground:Caring for persons with dementia is stressful for family caregivers. Caregiver training programs and respite care can reduce this stress and help maintain persons with dementia living longer in the community. We evaluated a program that combines caregiver training with a residential respite stay. METHODS: In total, 90 dyads of persons with dementia and their caregivers, in groups of 3-6 dyads, volunteered to participate in a five-day residential training program and were followed-up 6 and 12 months later. The primary outcome was caregiver depression; secondary outcomes were measures of caregiver burden, unmet needs, person with dementia behavioral symptoms, and the quality of life and function. RESULTS: Caregiver depression and burden were unchanged, despite decreasing function in persons with dementia. Caregivers' unmet needs and behavioral symptoms in persons with dementia decreased significantly. Compared to a group of persons with dementia admitted for routine residential respite care, there was a marked reduction in permanent placement over 12 months. CONCLUSIONS: The Going to Stay at Home Program is a feasible and practicable model with benefits for caregivers and persons with dementia. It may lead to delay in institutionalization and may be applicable to other chronic conditions. PMID- 30019664 TI - Computed tomography versus magnetic resonance imaging in paediatric cochlear implant assessment: a pilot study and our experience at Great Ormond Street Hospital. AB - BACKGROUND: To date, there is a lack of consensus regarding the use of both computed tomography and magnetic resonance imaging in the pre-operative assessment of cochlear implant candidates. METHODS: Twenty-five patients underwent high-resolution computed tomography and magnetic resonance imaging. 'Control scores' describing the expected visualisation of specific features by computed tomography and magnetic resonance imaging were established. An independent radiological review of all computed tomography and magnetic resonance imaging scan features was then compared to the control scores and the findings recorded. RESULTS: Agreement with control scores occurred in 83 per cent (20 out of 24) of computed tomography scans and 91 per cent (21 out of 23) of magnetic resonance imaging scans. Radiological abnormalities were demonstrated in 16 per cent of brain scans and 18 per cent of temporal bone investigations. CONCLUSION: Assessment in the paediatric setting constitutes a special situation given the likelihood of congenital temporal bone abnormalities and associated co morbidities that may be relevant to surgery and prognosis following cochlear implantation. Both computed tomography and magnetic resonance imaging contribute valuable information and remain necessary in paediatric cochlear implant pre operative assessment. PMID- 30019665 TI - Cochlear orientation: pre-operative evaluation and intra-operative significance. AB - OBJECTIVE: The study primarily aimed to calculate the orientation of the cochlea pre-operatively, using high-resolution computed tomography of the temporal bone, and predict the ease of electrode insertion. METHODS: Pre-operatively, high resolution computed tomography scans were conducted on children scheduled for cochlear implantation, and two angles, alpha and beta, were calculated. The values of alpha and beta were then correlated with intra-operative difficulty in insertion of the electrode array. RESULTS: Ninety-six children were included in the study. Of the seven patients who had an alpha angle of less than 50 degrees, the surgeon experienced difficulties in electrode insertion. However, there were four patients with an alpha angle of more than 50 degrees for whom the surgeon also experienced difficulties in electrode insertion. In all these patients, the beta angle was more than 20 degrees. CONCLUSION: Calculation of cochlear orientation and its angle with the surgical axis (alpha and beta) can aid the planning of surgery, particularly with regard to the cochleostomy site and preservation of residual hearing. PMID- 30019663 TI - Change in Cognitive Performance From Midlife Into Old Age: Findings from the Midlife in the United States (MIDUS) Study. AB - OBJECTIVES: A substantial body of research has documented age-related declines in cognitive abilities among adults over 60, yet there is much less known about changes in cognitive abilities during midlife. The goal was to examine longitudinal changes in multiple cognitive domains from early midlife through old age in a large national sample, the Midlife in the United States (MIDUS) study. METHODS: The Brief Test of Adult Cognition by Telephone (BTACT) was administered on two occasions (MIDUS 2, MIDUS 3), an average of 9 years apart. At MIDUS 3, those with the cognitive assessment (N=2518) ranged in age from 42 to 92 years (M=64.30; SD=11.20) and had a mean education of 14.68 years (SD=2.63). The BTACT includes assessment of key aging-sensitive cognitive domains: immediate and delayed free recall, number series, category fluency, backward digit span, processing speed, and reaction time for attention switching and inhibitory control, which comprise two factors: episodic memory and executive functioning. RESULTS: As predicted, all cognitive subtests and factors showed very small but significant declines over 9 years, with differences in the timing and extent of change. Processing speed showed the earliest and steepest decrements. Those with higher educational attainment scored better on all tests except reaction time. Men had better executive functioning and women performed better on episodic memory. CONCLUSIONS: Examining cognitive changes in midlife provides opportunities for early detection of cognitive impairments and possibilities for preventative interventions. (JINS, 2018, 24, 805-820). PMID- 30019666 TI - Preliminary outcomes of endoscopic middle-ear surgery in 103 cases: a UK experience. AB - BACKGROUND: Totally endoscopic ear surgery and endoscope-assisted microsurgery are still new concepts, with relatively few centres in the UK performing them. Advantages include better visualisation of difficult to reach areas, such as the sinus tympani, and limited external incisions. This paper reports our short-term outcomes for endoscopic middle-ear surgery. METHODS: A prospective review was conducted of the first 103 consecutive patients undergoing totally endoscopic ear surgery or endoscope-assisted microsurgery in 1 centre performed by 1 operator. The outcomes assessed were: tympanic membrane healing, audiological data and complications. RESULTS: Twenty-five patients underwent endoscope-assisted microsurgery, while 78 had totally endoscopic ear surgery. There were no reported cases of dead ear or permanent facial nerve palsy. The average air-bone gap following stapedectomy was 7.38 dB. The tympanic membrane healing rate was 89 per cent. CONCLUSION: Our results confirm that endoscopic middle-ear surgery is safe, and the short-term outcomes are comparable with conventional surgery. PMID- 30019667 TI - White matter lesions in magnetic resonance imaging of the brain in 56 patients with visual vertigo. AB - BACKGROUND: Visual vertigo is defined as a condition in which there is worsening or triggering of vestibular symptoms in certain visual environments. Previous studies have associated visual vertigo with an increased prevalence of underlying white matter lesions on brain imaging. METHOD: This study evaluated the magnetic resonance imaging scans of the brain from a cohort of patients with visual vertigo, and compared the outcomes to an age- and gender-matched group of healthy volunteers.Results and conclusionWhite matter lesions were observed in 17.9 per cent of the patient group and in 16.3 per cent of the control group. The prevalence of white matter lesions in the patient group was not too different to that expected based on age. PMID- 30019668 TI - Quality of online otolaryngology health information. AB - OBJECTIVE: Up to 70 per cent of the population search online for medical or health-related information. This study aimed to assess the quality of online health resources available to educate patients on a variety of otolaryngological conditions. METHODS: Two clinicians independently analysed the quality and content of educational websites (patient.co.uk and wikipedia.org) for common and uncommon diagnoses, with cancerresearchuk.org also used to assess two head and neck cancers. RESULTS: Cancerresearchuk.org, followed by patient.co.uk, scored most highly in their ability to inform readers on a selection of otolaryngological conditions. Although wikipedia.org was less likely to include all relevant information and was more difficult to read, it still provided mostly accurate information. CONCLUSION: Where possible, patients should be advised to access professionally maintained health information websites (patient.co.uk and cancerresearchuk.org). However, wikipedia.org can provide adequate information, although it lacks depth and can be difficult to understand. PMID- 30019669 TI - Is the use of a bone conduction hearing device on a softband a useful tool in the pre-operative assessment of suitability for other hearing implants? AB - OBJECTIVE: To assess whether pre-operative assessment with a bone conduction hearing device on a softband is an accurate predictor of performance with one of two transcutaneous hearing implants.Study designCohort study comparing pre-and post-operative speech audiometry using correlation analysis. METHODS: Pre operative pure tone audiometry and aided half optimum speech recognition thresholds were compared with post-operative aided results for each ear that had undergone implantation. Data were collected prospectively. RESULTS: Full data were available in 24 ears. In 19 out of 24 ears (79 per cent), the difference between pre- and post-operative speech scores was less than 10 dB, demonstrating a good clinical correlation. The Pearson correlation coefficient was calculated at 0.66 (95 per cent confidence interval = 0.357-0.842), indicating a strong statistical correlation. CONCLUSION: Pre-operative softband testing shows good clinical correlation and strong statistical correlation with hearing implant performance. The findings suggest there is value in using the test to predict performance and guide patients' expectations. PMID- 30019670 TI - Imaging in autoimmune inner-ear disease and endolymphatic hydrops, bone cement for improving hearing outcomes in stapes surgery, and the reporting of results. External ear canal cholesteatoma: a hypothesis. PMID- 30019671 TI - Regeneration of the tympanic membrane using fibroblast growth factor-2. AB - OBJECTIVE: A systematic review was conducted to investigate the effectiveness of fibroblast growth factor-2 on the regeneration of tympanic membrane perforation. METHODS: The PubMed database was searched for relevant studies. Experimental studies, human randomised controlled trials, prospective single-arm studies and retrospective studies reporting acute and chronic tympanic membrane perforations in relation to two healing outcomes (success rate and closure time), were selected. RESULTS: All 11 clinical studies investigating the effect of fibroblast growth factor-2 on traumatic tympanic membrane perforations in humans reported a success rate of 89.3-100 per cent, with a closure time of around 2 weeks. Three studies of fibroblast growth factor-2 combined with Gelfoam showed that the success rate of chronic tympanic membrane perforation was 83-98.1 per cent in the fibroblast growth factor-2 group, but 10 per cent in the gelatine sponge groups. CONCLUSION: Fibroblast growth factor-2 with or without biological material patching promotes regeneration in cases of acute and chronic tympanic membrane perforation, and is safe and efficient. However, the best dosage, application time and administration pathway of fibroblast growth factor-2 are still to be elucidated. PMID- 30019673 TI - Acute critical illness and cancer risk: Implications from a nationwide population based study in Asia. AB - OBJECTIVE: The objective of this study was to identify the risk of incident cancer among patients with acute critical illness. METHODS: The study applied the big database from the National Health Research Institutes in Taiwan. The risk of incident cancer over a 12-year period in patients with 4 types of newly diagnosed acute critical illness (septicemia/septic shock, acute myocardial infarction, hemorrhagic stroke and ischemic stroke) was investigated using Cox proportional hazards regression model with further controlling for the competing risk of death. RESULTS: This study included 42,675 patients in the acute critical illness cohort and 42,675 patients in the age- and sex-matched comparison cohort. Correlation between the incidence of cancer and critical illness was found after adjusting for age, sex, comorbidities and further controlling for death [adjusted subhazard ratio (aSHR) = 1.73, 95% confidence interval (CI) = 1.63-1.84]. Five common incident cancers associated with acute critical illness were hematologic malignancy (aSHR = 4.00, 95% CI = 3.11-5.14), cancers of liver (aSHR = 2.25, 95% CI = 1.93-2.63), uterus (aSHR = 1.86, 95% CI = 1.32-2.61), head and neck (aSHR = 1.79, 95% CI = 1.39-2.30) and esophagus (aSHR = 1.62, 95% CI = 1.09-2.42). Among these cancers, septicemia/septic shock was found to confer a higher risk of incident cancer compared to other subtypes of acute critical illness. CONCLUSIONS: This research is the first to tackle this clinically relevant issue regarding the types of acute critical illness most associated with cancer development with a very large sample size and robust methods. After adjustment for the potential confounding factors and consideration of the competing risk of death, the association between having an acute critical illness and incident cancer was noted. PMID- 30019674 TI - Methadone use and asymptomatic common bile duct dilation: Re-examining the link. AB - Opiates have long been implicated in causing common bile duct (CBD) dilation but few studies have been done to look at the association between synthetic opiates - methadone - and asymptomatic CBD dilation. The mechanism by which methadone could cause CBD dilation is poorly understood, but it has been postulated that increase in biliary pressures from contraction of the sphincter of Oddi is likely. In the below article, we review all the evidence pertaining towards methadone causing common bile duct dilation. PMID- 30019675 TI - High-altitude treatment in severe asthma: Effective and needed in an era of precision medicine. PMID- 30019672 TI - Regenerating hair cells in vestibular sensory epithelia from humans. AB - Human vestibular sensory epithelia in explant culture were incubated in gentamicin to ablate hair cells. Subsequent transduction of supporting cells with ATOH1 using an Ad-2 viral vector resulted in generation of highly significant numbers of cells expressing the hair cell marker protein myosin VIIa. Cells expressing myosin VIIa were also generated after blocking the Notch signalling pathway with TAPI-1 but less efficiently. Transcriptomic analysis following ATOH1 transduction confirmed up-regulation of 335 putative hair cell marker genes, including several downstream targets of ATOH1. Morphological analysis revealed numerous cells bearing dense clusters of microvilli at the apical surfaces which showed some hair cell-like characteristics confirming a degree of conversion of supporting cells. However, no cells bore organised hair bundles and several expected hair cell markers genes were not expressed suggesting incomplete differentiation. Nevertheless, the results show a potential to induce conversion of supporting cells in the vestibular sensory tissues of humans. PMID- 30019676 TI - Iodine status during pregnancy and lactation: a pilot study in the Netherlands. AB - BACKGROUND: Iodine deficiency occurs in West European countries. Iodine is important for brain development of the foetus and infant. The current iodine status of pregnant and lactating Dutch women is unknown. METHODS: In a pilot study we examined the iodine status of 36 women. From 20 gestational weeks (GW) until 4 weeks postpartum, they ingested 150 MUg iodine/day in the form of a multivitamin supplement for pregnant and lactating women. Twenty-four hour urine samples were collected at 20 and 36 GW and at 4 weeks postpartum. A breast milk sample was collected at 4 weeks postpartum. Iodine concentrations were analysed by inductively coupled plasma-mass spectrometry. Cut-off values for the urinary iodine concentration (UIC) for pregnant and lactating women are 150 and 100 MUg/l, respectively. Adequate intakes (AI) of iodine for infants aged 0-6 months are 1.1 MUmol/l (Institute of Medicine recommendations) or 0.5 MUmol/l (Nordic Councilrecommendations). RESULTS: The median UICs (percentages below cut-off) were 102 MUg/l (83%) at 20 GW, 144 MUg/l (56%) at 36 GW and 112 MUg/l (40%) at 4 weeks postpartum. The median breast milk iodine concentration was 1.2 MUmol/l (range 0.5-3.0); 33% and 0% of the infants had estimated iodine intakes below the IOM-AI and Nordic-AI, respectively. CONCLUSION: This pilot study suggested a high prevalence of iodine deficiency during pregnancy. Daily supplementation of 150 MUg iodine from 20 GW might be insufficient to reach maternal iodine adequacy. The median breast milk iodine concentration seems adequate. Further studies, using a representative sample of the Dutch population, are needed to establish the current Dutch iodine status of pregnant and lactating women. PMID- 30019677 TI - Predictors of benefit from high-altitude climate therapy in adults with severe asthma. AB - BACKGROUND: High-altitude climate therapy has been shown to benefit patients with severe asthma but it is not known which patients benefit most from this treatment. In the current study we aimed to identify clinical, functional and inflammatory predictors of favourable outcome of high-altitude climate therapy. METHODS: This is a secondary analysis of a prospective cohort including 136 adult patients with a diagnosis of severe refractory asthma, referred to the Dutch Asthma Centre in Davos (1600 metres above sea level), Switzerland. They had assessments of medication usage, asthma-related quality of life (Asthma-related Quality of Life Questionnaire, AQLQ), asthma control, body mass index (BMI), sino nasal symptoms, fatigue, lung function (forced expiratory volume in one second, FEV1), exercise tolerance, allergy and inflammation (fraction of exhaled nitric oxide, blood eosinophils) at entry and after 12 weeks of treatment. Five clinically relevant outcomes were considered: AQLQ, oral corticosteroid dose, FEV1, body mass index and blood eosinophils. Independent predictors of beneficial outcome were identified by multiple linear regression analysis. RESULTS: Lower blood eosinophil counts (p < 0.01), younger age (p = 0.02) and poorer asthma control (p < 0.01) were independently associated with greater reduction in the dose of oral corticosteroids. Lower fatigue score at baseline (p = 0.01) was associated with greater weight loss (reduction in BMI). Higher levels of total IgE at baseline (p < 0.01), and higher doses of inhaled corticosteroids (p = 0.03) were associated with greater decreases in blood eosinophils. There were no predictors for improvement in AQLQ or FEV1. CONCLUSIONS: The beneficial effect of high-altitude climate therapy in adults with severe asthma can be predicted by patient characteristics, such as age, blood eosinophils and degree of asthma control before admission. PMID- 30019678 TI - Clinical predictors of escalating care in hepatic and renal cyst infection in autosomal dominant polycystic kidney and liver disease. AB - BACKGROUND: Cyst infection may occur in autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD). Antimicrobial agents often fail to control infection, leading to invasive action. We aimed to identify factors predicting escalation of care. METHODS: ADPKD and ADPLD patients were identified from local/national databases (2001-2013). Records were screened for patients meeting criteria for cyst infection (positive cyst aspirate and/or clinical findings). Factors that predict escalated care were identified with multivariate modified Poisson regression. RESULTS: We screened 1773 patients. A total of 77 patients with cyst infection (4.3%) were included for analysis (hepatic 36%; male 49%; age 54 +/-; 13 years; ADPKD 95%; dialysis 9%, diabetes 18%, renal transplant 56%, eGFR [IQR 24-78] ml/min/1.73 m2 (excluding patients with a history of renal transplant or receiving dialysis)). A pathogen was identified in 71% of cases. Escherichia coli was the most common pathogen and accounted for 69% of cases. Initial treatment was limited to antibiotics in 87% of patients (n = 67), 40% included a fluoroquinolone. Ultimately, 48% of patients underwent some form of invasive action (escalation of care). Increasing white blood cell count (WBC) (RR 1.04 95%-CI 1.01-1.07, p = 0.008) was associated with escalating care, whereas an increase in time between transplant and infection (RR 0.92 95% CI 0.86-0.97, p = 0.005) and E. coli isolation (RR 0.55 95% CI 0.34-0.89, p = 0.02) were protective. CONCLUSION: High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients. PMID- 30019679 TI - Rifampin levels in daily practice: the accuracy of a single measurement. AB - BACKGROUND: Measurement of rifampin levels is not part of routine practice. However, low levels are associated with failure of tuberculosis treatment. The clinical relevance of serum levels in daily practice is unclear. The objective was to evaluate rifampin serum concentrations and factors associated with insufficient concentrations. METHODS: Patients with at least one rifampin concentration drawn 3 hours after intake (C3) between 2005 and 2014 were included. Data on demographic and clinical characteristics were collected, including side effects and dose adjustments. Two different criteria were used to define adequate concentrations (criterion 1: C3 a nd C 6 >= 3 mg/l; criterion 2: C3 or C6 >= 5 mg/l). RESULTS: Of 63 patients, 66% and 76% had a sufficient level according to criterion 1 or 2, respectively. C3 exceeded C6 in most patients, while a late maximum was significantly associated with diabetes mellitus (p = 0.003). A dose adjustment was made in 19% of cases, more frequently in patients with insufficient levels (p = 0.02) or with >= 2 side effects (p = 0.03). CONCLUSION: Rifampin levels varied but were mostly adequate and a single measurement at 3 hours after intake provided the required information in most cases, indicating that full AUC0-24 measurements could be limited to specific situations. PMID- 30019680 TI - A case of late-onset systemic sclerosis with ruptured silicone breast implants. AB - BACKGROUND: It is still unresolved whether there is a relationship between silicone breast implants (SBIs) and late-onset systemic sclerosis (SSc). CASE DESCRIPTION: A 83-year-old female was diagnosed with limited cutaneous SSc. During follow-up the presence of ruptured SBIs was confirmed. We provide a literature review concerning SBIs and development of SSc, particularly in relation to age of onset. CONCLUSION: Data about age of onset are incomplete and no details on the rupture of SBIs are reported; however, an association between SSc and SBIs possibly exists. PMID- 30019681 TI - 'Transformation' from amyloid light chain amyloidosis to symptomatic multiple myeloma. AB - Amyloid light chain (AL) amyloidosis and multiple myeloma (MM) are both clonal plasma cell disorders, and may be concurrently present in patients. However, symptomatic MM seldom develops in patients with AL amyloidosis, while the other way around is common. With this case report, we discuss the difficulties in the differential diagnosis between AL amyloidosis and MM, and extend on the possible mechanisms involved in the development of these overlapping disorders. In addition, we provide clinicians with tools that may help improve their management and monitoring of such patients. PMID- 30019682 TI - Cytomegalovirus-associated thrombosis. AB - Cytomegalovirus (CMV) infections are often asymptomatic, but symptoms can range from a mononucleosis-like syndrome to a severe, disseminated infection in immunocompromised patients. We present two cases of immunocompetent patients with acute CMV infection directly followed by portal vein thrombosis in one and pulmonary embolism in the other patient. Thromboembolism may be a severe complication of acute CMV infection, with possible therapeutic implications. PMID- 30019684 TI - Answer to Photo Quiz: A case of progressive abdominal angina. PMID- 30019683 TI - A case of progressive abdominal angina. PMID- 30019685 TI - Traumatic occlusion of the renal artery. PMID- 30019686 TI - Answer to Photo Quiz: Traumatic occlusion of the renal artery. PMID- 30019687 TI - An unusual cause of hyperammonaemia. PMID- 30019688 TI - Answer to Photo Quiz: An unusual cause of hyperammonaemia. PMID- 30019689 TI - Evaluation of a toolkit for standardizing clinical measures of muscle tone. AB - OBJECTIVE: To evaluate a new portable toolkit for quantifying upper and lower extremity muscle tone in patients with upper motor neuron syndrome (UMNS). APPROACH: Cross-sectional, multi-site, observational trial to test and validate a new technology. SETTING: Neurorehabilitation clinics at tertiary care hospitals. PARTICIPANTS: Four cohorts UMNS patient, >6 mo post acquired brain injury, spinal cord injury, multiple sclerosis and cerebral palsy, and a sample of healthy age matched adult controls. MEASURES: Strength: grip, elbow flexor and extensor, and knee extensor; range of motion (ROM): passive ROM (contracture) and passive active ROM (paresis); objective spasticity: stretch-reflex test for elbow, and pendulum test for knee; subjective spasticity: modified Ashworth scale scores for elbow and knee flexors and extensors. RESULTS: Measures were acquired for 103 patients from three rehabilitation clinics. Results for patient cohorts were consistent with the literature. Grip strength correlated significantly with elbow muscle strength and all patient populations were significantly weaker in upper- and lower-extremity compared to controls. Strength and paresis were correlated for elbow and knee but neither correlated with contracture. Elbow spasticity correlated with strength and paresis but not contracture. Knee spasticity correlated with strength, and subjective spasticity correlated with contracture. SIGNIFICANCE: The BioToneTM toolkit provided comprehensive objective measures for assessing muscle tone in patients with UMNS. The toolkit could be useful for standardizing outcomes measures in clinical trials and for routine practice. PMID- 30019690 TI - Strategies to optimise occupational radiation protection in interventional cardiology using simultaneous registration of patient and staff doses. AB - The International Commission on Radiological Protection recommends that occupational protection and patient protection be managed in an integrated approach. This paper describes the experience and the initial results of a system able to register and to process simultaneously staff and patient doses in interventional cardiology and the practical use of this system in the optimisation of occupational exposure. The system used simultaneously collects and manages patient and staff doses for all radiation events. The personal electronic dosimeters worn over the protective apron of health professionals working inside catheterisation laboratories can send (wireless) doses and dose rate values to an X-hub and provide the operators inside the catheterisation rooms with real-time information. Individual and global reports for all the health professionals may be periodically obtained from the system to help with the optimisation. The results for eight cardiologists, one fellow and four nurses for a total of 2468 interventional cardiology procedures and 3207 occupational dose values collected over one year are presented here. Annual doses Hp(10) measured over the apron for cardiologists ranged from 0.3 to 6.3 mSv. For the cardiologist, the ratio between occupational doses (over the apron) and patient doses ranged from 0.05 to 0.23 MUSv Gy-1 cm-2, with a mean value of 0.12 MUSv Gy 1 cm-2. The system allows defining optimisation strategies by comparing the results between the different operators while considering the workload and complexity of the procedures (based on the total Kerma Area Product managed by the different operators). The registration of the date and time of the occupational radiation doses allows auditing the use of the personal dosimeters worn by the various operators. PMID- 30019691 TI - Intermittent locomotion of a fish-like swimmer driven by passive elastic mechanism. AB - The intermittent locomotion performance of a fish-like elastic swimmer is studied numerically in this paper. The actuation is imposed only at the head and the locomotion is indirectly driven by passive elastic mechanism. For intermittent swimming, certain time durations of passive coasting are interspersed between two half-periods of active bursting. To facilitate the comparison of energy efficiencies in continuous and intermittent swimming at the same cruising speed, we consider both intermittent swimming at various duty cycles and also continuous swimming at reduced actuation frequencies. The result indicates that the intermittent style is more economical than the continuous style only when the cruising Reynolds number is sufficiently large and the duty cycle is moderate. We also explore the passive tail-beating pattern and wake structure for intermittent swimming. It is found that the kinematics of the tail contains a preparatory burst phase which lies in between the active bursting and the passive coasting phases. Three vortex streets are found in the wake structures behind the intermittent swimmers. The two oblique streets consist of strong vortex dipoles and the horizontal street is made up of weak vortices. The results of this study can provide some insight into the burst-and-coast swimming of fish and also inform the design of efficient bio-mimetic under-water vehicles. PMID- 30019692 TI - Asymmetric detrended fluctuation analysis in neonatal stress. AB - OBJECTIVE: To detect stress in newborns by observing heart rate (HR) variability utilizing an asymmetric detrended fluctuation analysis (ADFA), we sought to determine the fractal structure of the series of inter-beat intervals, so as to distinguish the periods of acceleration of the HR from decelerations. Thus, two scaling exponents, alpha + and alpha -, representing decelerations and accelerations respectively, are obtained. APPROACH: Forty healthy term newborns were included in this study, undergoing two different types of stress stimuli: routine heel lance blood sampling for metabolic screening purposes, and its simulation by applying dull pressure on the heel. MAIN RESULTS: It appears that when newborns face stress, the scaling exponent related to accelerations significantly increases and becomes higher than the deceleration scaling exponent. To test the diagnostic properties of the scaling exponents, an ROC curve analysis was applied; alpha - showed good diagnostic performance with an AUC between 0.626 and 0.826, depending on the length of the time series. The joint use of alpha + and alpha - further increased the diagnostic performance, in particular for shorter series of RR intervals, with an AUC between 0.691 and 0.833. SIGNIFICANCE: ADFA, particularly of the acceleration scaling exponent, may be a useful clinical diagnostic tool for monitoring neonatal stress. PMID- 30019693 TI - Influence of the SPECT calibration source position on the absorbed dose calculation for 131I-NaI therapy using GATE simulations. AB - Many research groups have studied nuclear medicine image quantification to improve its accuracy in dose estimation. This work aims to evaluate the influence of the source calibration position for absorbed dose calculation for a 131I-NaI therapy using Monte Carlo (MC) simulations. The calibration approach consisted of a cylindrical phantom filled with water. A cylindrical 131I source with 361.1 +/- 3.6 kBq ml-1 was positioned at the center of the phantom and its outer part. Images were acquired with 150 00 counts per projection image acquired with SPECT detector (high counts density-HCD) and 3000 counts per projection (low counts density-LCD). MC simulations, performed with GATE code, were validated by comparing the S values of a water sphere uniformly filled with 131I, as from the sphere model of OLINDA/EXM 1.1. Calibration factors deviation between central and peripheral calibrations is more significant for HCD (18.3%) than for LCD images (3.7%). The 3D dose distribution map obtained from GATE resulted in a dose factor equal to 1.5 * 10-3 mGy/(MBq.s). For both HCD and LCD images, the commonly used approach, which employs the central source calibration to obtain the dose from a peripheral source, resulted in dose overestimation. Results suggest that organ dose calculation can be improved considering the organ position in the field of view. Finally, patients' radiation protection in dosimetry studies could be improved considering the calibration source position, due to the superior accuracy in dose calculation. PMID- 30019694 TI - Free and confined Brownian motion in viscoelastic Stokes-Oldroyd B fluids. AB - We linearize the Stokes-Oldroyd B model for small perturbations and instantaneous hydrodynamic friction to simulate the environment for a free and confined Brownian particle. We use the standard Green's function approach to determine the viscoelasticity, and show that the expression obtained for the frequency dependent viscosity is similar to that given by the Jeffrey's model, though the latter describes viscoelasticity by the bulk storage and loss moduli that is represented by a complex elastic modulus [Formula: see text] of the fluid concerned. In contrast, we consider the characteristics of the polymer chains and the Newtonian solvent of the complex fluid individually, and determine an expression for frequency-dependent viscosity that would be useful for microrheology performed from Brownian trajectories measured in experiments. Finally, we evaluate the trajectory of a free Brownian particle in a viscoelastic environment using our formalism, and calculate various important parameters quantifying Brownian dynamics, which we then extend to the particle confined in a harmonic potential as provided by optical tweezers. PMID- 30019696 TI - Publisher Correction: Store-independent modulation of Ca2+ entry through Orai by Septin 7. AB - This corrects the article DOI: 10.1038/ncomms11751. PMID- 30019695 TI - Additional Diagnostic Value of Growth Differentiation Factor-15 (GDF-15) to N Terminal B-Type Natriuretic Peptide (NT-proBNP) in Patients with Different Stages of Heart Failure. AB - BACKGROUND Growth differentiation factor-15 (GDF-15) is a promising biomarker of cardiac remodeling. The purpose of this study was to explore the diagnostic value of plasma GDF-15 levels in different stages of heart failure (HF) and to assess the relationship with ventricular remodeling. MATERIAL AND METHODS We enrolled 219 HF patients from the Department of Cardiology in Tianjin Union Medical Center as the HF group and 32 healthy subjects as the control group. Circulating GDF-15, NT-proBNP, procollagen I C-terminal propeptide (PICP), and N-terminal procollagen III propeptide (PIIINP) levels were measured using ELISA. Associations between GDF-15 and clinical indicators in cardiac remodeling were assessed using receiver operating characteristic (ROC) curves and Spearman correlation. All the patients were followed up for 1 year. RESULTS The level of plasma GDF-15 in HF patients was higher than in the control group (P<0.05) and increased with higher ACCF/AHA and NYHA classification (P<0.05). Patients with HFrEF had higher GDF-15 levels compared to patients with HFmrEF (P<0.05). GDF-15 and left ventricular mass index (LVMI) were significantly increased as early as the pre-clinical HF stage. Also, GDF-15 levels were positively correlated to LVMI (r=0.433, P<0.05), PICP (r=0.378, P<0.001) and PIIINP (r=0.382, P<0.001). ROC curves were constructed and GDF-15 plus NT-proBNP (AUC=0.905, 95%CI: 0.868-0.942, P<0.001) was superior to NT proBNP (AUC=0.869, 95%CI: 0.825-0.913, P<0.001) in identifying HF. GDF-15 levels did not predict prognosis after a 1-year follow-up period. CONCLUSIONS GDF-15 combined with NT-proBNP significantly improves the accuracy of diagnosing HF. Plasma GDF-15 levels can indirectly reflect the degree of cardiac remodeling and fibrosis. PMID- 30019697 TI - Publisher Correction: Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma. AB - This corrects the article DOI: 10.1038/ncomms14278. PMID- 30019698 TI - Publisher Correction: Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. AB - This corrects the article DOI: 10.1038/ncomms11773. PMID- 30019699 TI - Corrigendum: One Step Quantum Key Distribution Based on EPR Entanglement. AB - This corrects the article DOI: 10.1038/srep28767. PMID- 30019700 TI - The gut microbiota in neuropsychiatric disorders. AB - The purpose of this review is to summarize current knowledge about the gut microbiota in neuropsychiatric disorders. It is estimated that the human gut is colonized by up to 1018 microorganisms, mostly anaerobic bacteria. The gut microbiome is responsible for multiple functions, e.g. tightness of the intestine barrier, digestion and absorption. The correlation between gut dysbiosis and development of psychiatric, autoimmune and allergic diseases as well as bidirectional communication between brain and gut microflora have been shown. Recent findings suggest that specific bacteria can be involved in the development of clinical conditions, such as Autism Spectrum Disorders, depression and schizophrenia, and microbiota may be a target for therapeutic intervention providing novel treatment strategies. PMID- 30019701 TI - Fos immunoreactivity in the intermediolateral nucleus induced by tendon vibration of the m. triceps surae in rats pretreated with a nitric oxide blocker or precursor. AB - We investigated neuronal activation of the rat intermediolateral (IML) nucleus of the thoracolumbar spinal cord, initiated by Achilles tendon vibration, after intramuscular (m. triceps surae) administration of 7-nitroindazole (7-NI) or L arginine (LA). The spindle afferent response to vibratory stimuli induced a distinct bilateral increase in the activation of c-Fos immunoreactivity in the spinal neurons in three groups of rats (tendon-vibrated, tendon-vibrated + 7-NI and tendon-vibrated + LA). The T5/T13 segments in tendon-vibrated +7-NI animals showed the highest increase of Fos-immunoreactive neurons. This increase was two times higher than that in tendon only-vibrated control rats and endon-vibrated + LA animals. The highest mean number of labelled neurons were observed in the IML nucleus and in layers 4 and 7 of the T5-L3 segments in tendon-vibrated and tendon vibrated + 7-NI animals, and in the IML nucleus and layer 4 in tendon-vibrated + LA rats. The highest mean number of activated neurons was found ipsilaterally in the IML nucleus of the T5/T13 segment. These results indicate that decreased nitric oxide release after injection of 7-NI was accompanied by a potentiation of the early c-fos gene expression induced by muscle proprioceptive activity within the thoracolumbar region of the rat spinal cord. Thus, enhanced c-Fos immunoreactivity in the IML nucleus indicated that the sympathetic nervous system can exert a direct influence on the muscle spindles. PMID- 30019702 TI - The relationship between alpha burst activity and the default mode network. AB - Alpha rhythm, described by Hans Berger, is mainly recorded from the occipital cortex (OCC) of relaxed subjects with their eyes closed.Early studies indicated the thalamo-cortical circuit as the origin of alpha rhythm. Recent works suggest an additional relationship between alpha rhythm and the Default Mode Network (DMN). We simultaneously recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) signals in 36 young males asked to alternately close and open their eyes in 30-s blocks. Using an EEG source channel montage (the recorded signal was interpolated to designated source positions corresponding to certain brain regions) we found an alpha rhythm sub-activity composed of its intrinsic events, called alpha bursting segments (ABS). More ABS were observed on source channels related to the DMN than those located over the OCC. Similarly, both the beamformer source analysis and fMRI indicated that the specific ABS activity detected on the posterior cingulate cortex/precuneus (PCC) source channel was less related to the OCC than to the DMN source channels. The fMRI analysis performed using the PCC-ABS as a general linear model regressor indicated an increased blood oxygenation level-dependent signal change in DMN nodes - precuneus and prefrontal cortex. These results confirm the OCC source of alpha activity a nd additional specific sources of ABS in the DMN. PMID- 30019703 TI - Face processing in a case of high functioning autism with developmental prosopagnosia. AB - The ability to "read" the information about facial identity, expressed emotions, and intentions is crucial for non-verbal social interaction. Neuroimaging and clinical studies consequently link face perception with fusiform gyrus (FG) and occipital face area (OFA) activity. Here we investigated face processing in an adult, patient PK, diagnosed with both high functioning autism spectrum disorder (ASD) and developmental prosopagnosia (DP). Both disorders have a significant impact on face perception and recognition, thus creating a unique neurodevelopmental condition. We used eye-tracking and functional magnetic resonance imaging (fMRI) method. Eye-tracking and fMRI results of PK were compared to results of control subjects. Patient PK showed atypical gaze-fixation strategy during face perception and typical patterns of brain activations in the FG and OFA. However, a significant difference between PK and control subjects was found in the left anterior superior temporal sulcus/middle temporal gyrus (aSTS/MTG). In PK the left aSTS/MTG was hypo-activated in comparison to the control subjects. Additionally, functional connectivity analysis revealed decreased inter-hemispheric connectivity between right and left aSTS/MTG in 'ASD and DP' patient during face recognition performance as compared to the control subjects. The lack of activity in the left aSTS/MTG observed in the case of the clinical subject, combined with the behavioral, eye-tracking, and neuropsychological results, suggests that impairment of the cognitive mechanism of face recognition involves higher level of processing. It seems to be related to insufficient access to semantic knowledge about the person when prompted by face stimuli. PMID- 30019704 TI - Administration of muscarinic antagonists induce changes in passive avoidance learning and in synaptic transmission in the CA1 area of the hippocampus. AB - Muscarinic acetylcholine receptors (mAChR) are known to be related to learning and memory processes. Inactivation of mAChR by cholinergic antagonists have been shown to produce amnesia in a variety of behavioral tasks. In this study, we investigated the role of M1 and M2 AChR on passive avoidance learning and plasticity of synapses formed by Schaffer collaterals in freely moving rats. Experiments were performed using Wistar male rats. Seven days before testing, a recording electrode was lowered in the CA1 region under chloral hydrate anaesthesia to record the field excitatory postsynaptic potential (fEPSP) in response to Schaffer collateral stimulation. Selective M2 receptor antagonists methoctramine and selective M1 receptors antagonist pirenzepine were intraperitoneally injected immediately after training. The effects on memory retention were examined using passive avoidance training. We measured latency of the first entry into a dark compartment of the chamber. fEPSP amplitude and slope ratio were measured before shock presentation, 90 min after the shock, and 24 hour after the shock. Methoctramine significantly impaired behavior in the passive avoidance test but pirenzepine did not induce any changes compared to control. Our results showed that pirenzepine but not methoctramine supressed the amplitude of fEPSPs. On the other hand, intracerebroventricular methoctramine administration impaired passive avoidance learning and increased the amplitude of fEPSP. PMID- 30019705 TI - Influence of age on speech intelligibility in babble noise. AB - Problems with hearing aids, particularly with regard to speech intelligibility in the presence of noise, are commonly reported by older individuals in everyday practice. The main goal of this study was to measure differences in speech intelligibility between older and younger people and to establish how speech intelligibility in competitive noise differs between younger and older populations with similar hearing status. More than 400 persons were tested using the Czech Test of Sentence Intelligibility in Babble Noise and divided into younger (40-65 years) and older (66-85 years) age groups. Test performance was compared between age groups based on subgroups stratified by SRT values (speech reception threshold in word audiometry in silence). Results showed a significant correlation between older age and diminished sentence intelligibility in competitive noise. Evaluation using a nonparametric U-test showed a statistical difference between the younger and older groups in sentence intelligibility, with a speech signal presented at 65 dB sound pressure level (SPL) and competitive babble noise also presented at 65 dB SPL. Increased difficulty in the use of hearing aids in older users is related, among other things, to a reduced ability to discriminate speech not only in silence but particularly in competitive variable noise due both to their aging auditory functions and to a diminished capacity to differentiate the time factors of sounds. It is probably connected with the diminished function of inhibitory neurons. PMID- 30019706 TI - Summation of two illusions of extent. AB - In the present visual psychophysical study, the Oppel-Kundt and and Muller-Lyer illusion magnitudes were measured separately (by single figures) and in combination (by two patterns superposed spatially). Data for 30 subjects revealed extensive variability both for the separate and combined illusion strength. Nevertheless, the effect of addition of the perceived length distortions was established. The combined illusions were significantly stronger than the separate ones. Dynamics of the misperceptions summation was studied by varying length of the Muller-Lyer wings in the superposed stimuli. According to the experimental data obtained, the two misperceptions in length occurred and combined into sensory response varying in dependence on the spatial parameters of the superposed stimuli and on the individual experimental accomplishment. The data supported an explanation for the origin of the filled/unfilled illusion: overestimate of a filled interval length developed due to the spatiotemporal integration along a continuous excitation path elicited by the real or imaginary contours of the filling. PMID- 30019707 TI - The influence of mood on visual perception of neutral material. AB - In the study we investigated how current mood affects spontaneous perceptual processes of neutral stimuli of low-arousal, unrelated to any specific task. Two separate but similar procedures were carried out: one using functional magnetic resonance imaging (fMRI), the other using electroencephalography based source localization. In both experiments, sessions of passive viewing of neutral pictures were preceded by either a negative or positive mood induction. In response to neutral stimuli, we observed higher activation of visual areas after positive mood induction and lower activations in medial prefrontal and right frontotemporal regions after negative mood induction. We conclude that in relatively safe laboratory conditions, after being exposed to negative emotional content, automatic processes of affective control are recruited by the prefrontal cortex. This results in attenuation of processing of incoming stimuli, as the stimuli do not carry salient information with respect to bottom-up or top-down processes. The observed effects may therefore represent an implicit mechanism of perceptual modulation. PMID- 30019708 TI - Changes in neurogenesis with post-hatching age in the male Japanese quail (Cortunix japonica) brain. AB - Most avian neurogenesis studies have previously focused on the song control system and little attention has been given to non-song birds. The objective of this study was to assess changes in neurogenesis associated with post-hatching age (3-12 weeks) in the Japanese quail brain using proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunohistochemistry. PCNA-immunoreactive (ir) cells were observed mainly in the olfactory bulb ventricular zone, telencephalic ventricular zones and cerebellum. Fewer PCNA-ir cells were also observed in the hypothalamus, thalamus and bed nucleus of the stria terminalis. In telencephalic ventricular zones, PCNA-ir cells were concentrated ventrally and dorsally adjacent to the mesopallium and medial striatum, respectively. DCX-ir cells were observed in the olfactory bulb, telencephalon and cerebellum. Furthermore, DCX-ir cells were scattered throughout the pallium except in the entopallium and arcopallium, septal nuclei and striatum. Fewer DCX-ir cells were also observed in the hippocampus and bed nucleus of stria terminalis. The density of PCNA-ir cells and DCX-ir cells in all brain areas declined with post-hatching age. In conclusion, cell proliferation appears to be restricted to the ventricular zones whereas neuronal recruitment is more widespread in the olfactory bulb, telencephalon and cerebellum. Postnatal neuronal incorporation appears to be absent in the diencephalon and mesencephalon. PMID- 30019709 TI - Effective nerve cell modulation by electrical stimulation of carbon nanotube embedded conductive polymeric scaffolds. AB - Biomimetic biomaterials require good biocompatibility and bioactivity to serve as appropriate scaffolds for tissue engineering applications. Recent developments demonstrated that the unique properties of carbon nanotubes (CNTs) can enhance neural cell growth and axon organization. We previously developed a promising nerve conduit manufactured from biodegradable polycaprolactone fumarate (PCLF) for use in peripheral nerve regeneration applications. In the present study, we fabricated conductive PCLF-CNT scaffolds using ultraviolet (UV) induced photocrosslinking. We confirmed the successful incorporation of CNTs into the PCLF-CNT scaffolds which exhibited improved surface roughness compared with plain PCLF by scanning electronic microscopy, transmission electronic microscopy, and atomic force microscopy examinations. The PCLF-CNT substrates also had reduced impedance by electrochemical measurements. Enhanced PC-12 cell growth and differentiation were observed on PCLF-CNT sheets compared with PCLF sheets, indicating the beneficial effects of embedding CNTs into PCLF. Electrical stimulation not only enhanced PC-12 cell proliferation and neurite extension, but also promoted cellular migration and intracellular connections, which are all critical cellular behaviours for nerve regeneration. Overall, this study provides a new promising strategy for using electrically conductive PCLF-CNT nerve scaffolds in regenerative medicine. PMID- 30019710 TI - An electrochemical biosensor for rapid detection of anti-dsDNA antibodies in absolute scale. AB - Autoimmune diseases are chronic inflammatory pathologies that are characterized by the presence of antibodies against the body's own epitopes in serum (autoantibodies). Systemic lupus erythematosus (SLE) is a common autoimmune pathology characterized by the presence of antinuclear antibodies (ANAs). These include anti-dsDNA (alpha-dsDNA) antibodies, which are widely used for diagnosis and disease monitoring. Their determination is carried out using traditional techniques such as Indirect Immunofluorescence (IFI) or Enzyme-Linked Immunosorbent Assay (ELISA), which are time consuming, require qualified technicians, and are not compatible with decentralized analysis outside a laboratory facility. Here, we show a sandwich-format electrochemical biosensor based method for alpha-dsDNA determination in a rapid and simple manner. The total assay time is only 30 minutes, and the sensor is capable of detecting 16 ng (8 MUg mL-1) of alpha-dsDNA antibodies. Using the current derived from the detection limit of the method as a cut-off, we could discriminate positive from negative serum samples with 90% sensitivity and 100% specificity. Using monoclonal antibodies for calibration curves, our results are presented in absolute scale (i.e., concentration instead of serum titer) which will help us to perform comparisons between methods and carry out further improvements of this protocol. In an effort to render the sensor compatible with automation, we minimized the manipulation steps without compromising the analytical performance, even in complex samples such as serum. PMID- 30019711 TI - Schiff-base coordination complexes with plutonium(iv) and cerium(iv). AB - PuL2 and CeL2 (L = N,N'-bis[(4,4'-diethylamino)salicylidene]-1,2 phenylenediamine) have been synthesized, and characterized by single crystal X ray diffraction, UV/vis/NIR spectroscopy, and cyclic voltammetry. These studies reveal the enhanced stabilization of Pu(iv) versus Ce(iv) with this Schiff base, and quasi-reversible redox behaviour only with the plutonium complex. PMID- 30019712 TI - Iodine catalyzed reduction of quinolines under mild reaction conditions. AB - A reduction of quinolines to synthetically versatile tetrahydroquinoline molecules with I2 and HBpin is described. In the presence of iodine (20 mol%) as a catalyst, reduction of quinolines and other N-heteroarenes proceeded readily with hydroboranes as the reducing reagents. The broad functional-group tolerance, good yields and mild reaction conditions imply high practical utility. PMID- 30019713 TI - Silver-catalyzed stereoselective formation of glycosides using glycosyl ynenoates as donors. AB - A silver-catalyzed glycosylation reaction employing readily accessible and stable glycosyl ynenoates is developed. This reaction is mostly high yielding and exhibits varying levels of stereoinversion at the anomeric position. Compared to established and versatile Yu's gold catalysis, this chemistry features the use of substantially cheaper AgNTf2. PMID- 30019714 TI - Tailored transition metal-doped nickel phosphide nanoparticles for the electrochemical oxygen evolution reaction (OER). AB - Foreign transition metals are doped into the hexagonal nickel phosphide structure through a simple and facile bottom-up wet-chemical synthesis process via stabilization with oleylamine, trioctylphosphine (TOP), and trioctylphosphine oxide (TOPO): the as-prepared transition metal-doped nickel phosphide nanoparticles show a high level of doping but create no significant distortion of the crystal structure and morphology against pristine nickel phosphide nanoparticles, which exhibit excellent activity in the electrochemical oxygen evolution reaction (OER), having overpotential as small as 330 mV at 20 mA cm-2 with a low Tafel slope value of 39 mV dec-1. PMID- 30019715 TI - "Calix[4]-box" cages promote the formation of amide bonds in water in the absence of coupling reagents. AB - The present work shows that encapsulation can be used to promote amide bond formation in water under mild conditions, in the absence of carbodiimide coupling agents. PMID- 30019716 TI - Cyano-tryptophans as dual infrared and fluorescence spectroscopic labels to assess structural dynamics in proteins. AB - The steady state and time-resolved fluorescence and infrared (IR) properties of 4 and 5-cyanotryptophan (CNTrp) are investigated and compared, and the tryptophan (Trp) analogs are found to be very attractive to study structural and dynamic properties of proteins. The position of the nitrile substitution as well as the solvent environment influences the spectroscopic properties (solvatochromism). Similar to native Trp, electronic (nanosecond) lifetime and emission spectra are modulated by the environment, making CNTrps attractive fluorescent probes to study the structural dynamics of proteins in complex media. The nitrile absorption in the IR region can provide local structural information as it responds sensitively to changes in electrostatics and hydrogen bond (HB) interactions. Importantly, we find that 4CNTrp exhibits a single absorption in the nitrile stretch region, while the model compound 4CN-indole (4CNI) shows two. Even though the spectrum of the model compound is perturbed by a Fermi resonance, we find that 4CNTrp itself is a useful IR label. Moreover, if the nitrile group is substituted at the 5 position, the Trp analog predominantly reports on its HB status. Because the current literature on similar compounds is too limited for a detailed solvatochromic analysis, we extend the available data significantly. Only now are microscopic details such as the mentioned sensitivity to electrostatics coming to light. The vibrational lifetime of the CN moiety (acting on a picosecond time scale in contrast to the nanosecond time scale for fluorescent emission) allows for its application in 2D-IR spectroscopy in the low picosecond range. Taken together, the benefits of CNTrps are that they absorb and emit separately from the naturally occurring Trp and that in these dual fluorescence/vibrational labels, observables of IR and fluorescence spectroscopy are modulated differently by their surroundings. Because IR absorption and fluorescence operate on different time and length scales, they thus provide complementary structural information. PMID- 30019717 TI - Strategic design of thiophene-fused nickel dithiolene derivatives for efficient NLO response. AB - The NLO properties of two synthesized aryl extended thiophene fused nickel dithiolenes have been studied theoretically. Based on these two systems, a systematic modification has been made by substituting neutral and zwitterionic donor-acceptor groups at the aryl (phenyl and thenyl) ring to enlarge their NLO responses. Among the four designed systems, the zwitterionic donor-acceptor group significantly reduces the HOMO-LUMO energy gap, resulting in an enormous increase in the first hyperpolarizability (beta) values. To judge their high NLO response, transition dipole moment (TDM) density values have been plotted and it has been found that electron dissipation occurs from one donor part to the acceptor part with a high Deltar index value. It should be noted that the high Deltar index values are a quantitative measurement to understand the type of transitions, and we noticed that a charge transfer transition occurs in the case of zwitterionic systems. Hence, a relationship between the first hyperpolarizability and TDM has been established. In order to highlight the NLO active segment in a molecule, a density analysis has also been done. We anticipate that as our designed systems possess high beta values, they should have significance in optical uses. PMID- 30019721 TI - Ionic columnar clustomesogens: associations between anionic hexanuclear rhenium clusters and liquid crystalline triphenylene tethered imidazoliums. AB - Providing several functionalities to a single material is an emerging challenge with many industrial prospects in materials sciences. Self-assembled organic inorganic hybrid materials endowed with emission properties are part of these new materials. While the inorganic moieties provide emissivity, the organic part confers nanostructuration and processability. Here we describe how columnar arrangements can be obtained by assembling, via electrostatic interactions, isometric anionic inorganic nanoemitters, namely [Re6Se8(CN)6]4-, with imidazolium counter cations bearing triphenylene units. The resulting hybrids combine the emission of both components and energy transfer has been evidenced between both entities. Hole charge mobilities of the hybrid organic-inorganic columnar mesophases were also evaluated by the space charge limited current (SCLC) method. PMID- 30019723 TI - Structures, electronic properties, reactivity and dynamic studies of three new polyoxometalate compounds. AB - We report a complex study on the crystal structures, electronic properties, reactivity and dynamics of three polyoxometalate compounds (C6NH8)4[H2P2Mo5O23].5H2O (1), (C2H8N)5[HP2Mo5O23].(C3H9NO2)0.5.(H2O)1.5 (2) and (C2H8N)3[PMo12O40].(H2O)0.34 (3). These compounds were synthesized using a solution method and characterized by single-crystal X-ray diffraction. Crystallography confirmed three distinct symmetries P1[combining macron], P21/c and R3[combining macron]c for 1, 2, and 3, respectively, and unit cell constants a = 12.5609(2) A, b = 13.2470(2) A, c = 14.0353(2) A, alpha = 107.1568(14) degrees , beta = 101.2854(13) degrees , gamma = 92.1445(14) degrees for 1, a = 15.8583(6) A, b = 17.3578(5) A, c = 14.8499 (4) A, beta = 114.933(3) degrees for 2, and a = 16.3798(3) A, c = 50.2781(5) A for 3. Semi-empirical calculations applied on the compounds provided information about their reactivity and electronic structures. In this context, several discussions concerning the frontier molecular orbitals, molecular electrostatic potential, thermodynamic properties and local ionization potential were mentioned. We also conducted molecular dynamics analysis in order to elucidate the dynamics of cations and anions and their energy variation. PMID- 30019725 TI - Stabilizing intramolecular cobalt-imidazole coordination with a remote methyl group in the backbone of a cofactor B12-protein model. AB - This communication describes the stabilizing effect (DeltaDeltaG degrees = -4 kJ mol-1) of a remote methyl group in the backbone of a cobalamin-enzyme mimic on intramolecular imidazole-cobalt coordination. For this purpose, two B12 derivatives with an appended imidazole base were synthesized and analysed with spectrophotometric pH titrations. Qualitative conformation analysis of the backbone structure suggests that a thermodynamically unfavoured gauche interaction in the base-off form of a model containing an (R)-configured CH3 group at position C176 of the linker between the corrin ring and the terminal imidazole ligand steers the base toward cobalt coordination. PMID- 30019726 TI - Oxidatively stable ferrocenyl-pi-bridge-titanocene D-pi-A complexes: an electrochemical and spectroscopic investigation of the mixed-valent states. AB - The synthesis, spectroscopic, and electrochemical characterization of oxidatively stable D-pi-A compounds of the form (Me2CpC2Fc)2TiCl2 and RCp2Ti(C2Fc)2CuX (where Fc = ferrocenyl) are reported. Oxidative stability enabled by the addition of CuX is evidenced by voltammagrams of the RCp2Ti(C2Fc)2CuX compounds which all display two chemically-reversible 1e- FeIII/II couples, indicative of electronic communication between the Fc- termini. Differential pulse voltammetry (DPV) in CH2Cl2/[n-Bu4N][PF6], demonstrated that the redox potential difference between the two 1e- FeIII/II couples (DeltaE1/2) is between 112 mV and 146 mV, being most pronounced with the electron rich Cp*2Ti(C2Fc)2CuBr. The DeltaE1/2 values were unaffected by solvent (THF) and displayed only a small dependence on the identity of the counterion, either PF6- or B(C6F5)4-. For each complex with a measurable DeltaE1/2 value, spectroelectrochemical experiments were performed in CH2Cl2/[n Bu4N][PF6] and gave clear evidence of both the one-electron oxidized mixed-valent (MV) state and the two-electron oxidized state, each with distinct spectroscopic signatures. The MV states of these complexes showed absorbance between 820 and 940 nm which were replaced with a higher energy feature following a second oxidation. A very similar absorption band was also observed in the one-electron oxidized state of an analogue with only a single Fc substituent, namely TMSCp2Ti(C2Fc)(C2Ph)CuBr, suggesting this feature is not an FeII/FeIII intravalence charge-transfer (IVCT) band. Despite DFT calculations suggesting a pathway exists for electronic coupling, NIR spectroscopy on the MV states gave no evidence of an FeII/FeIII IVCT. Possible contributions to DeltaE1/2 from inductive effects and a superexchange mechanism are discussed. PMID- 30019727 TI - Covalently linking CuInS2 quantum dots with a Re catalyst by click reaction for photocatalytic CO2 reduction. AB - Covalently linking photosensitizers and catalysts in an inorganic-organic hybrid photocatalytic system is beneficial for efficient electron transfer between these components. However, general and straightforward methods to covalently attach molecular catalysts on the surface of inorganic semiconductors are rare. In this work, a classic rhenium bipyridine complex (Re catalyst) has been successfully covalently linked to the low toxicity CuInS2 quantum dots (QDs) by click reaction for photocatalytic CO2 reduction. Covalent bonding between the CuInS2 QDs and the Re catalyst in the QD-Re hybrid system is confirmed by UV-visible absorption spectroscopy, Fourier-transform infrared spectroscopy and energy-dispersive X-ray measurements. Time-correlated single photon counting and ultrafast time-resolved infrared spectroscopy provide evidence for rapid photo-induced electron transfer from the QDs to the Re catalyst. Upon photo-excitation of the QDs, the singly reduced Re catalyst is formed within 300 fs. Notably, the amount of reduced Re in the linked hybrid system is more than that in a sample where the QDs and the Re catalyst are simply mixed, suggesting that the covalent linkage between the CuInS2 QDs and the Re catalyst indeed facilitates electron transfer from the QDs to the Re catalyst. Such an ultrafast electron transfer in the covalently linked CuInS2 QD-Re hybrid system leads to enhanced photocatalytic activity for CO2 reduction, as compared to the conventional mixture of the QDs and the Re catalyst. PMID- 30019728 TI - Correction: Development of a microparticulate system containing Brazilian propolis by-product and gelatine for ascorbic acid delivery: evaluation of intestinal cell viability and radical scavenging activity. AB - Correction for 'Development of a microparticulate system containing Brazilian propolis by-product and gelatine for ascorbic acid delivery: evaluation of intestinal cell viability and radical scavenging activity' by Lizziane Maria Belloto de Francisco et al., Food Funct., 2018, DOI: 10.1039/c8fo00863a. PMID- 30019729 TI - Preparation of a fermentation solution of grass fish bones and its calcium bioavailability in rats. AB - In this study, with grass fish bones as the substrate, after flavourzyme treatment, and fermentation with Leuconostoc mesenteroides, a fermentation solution with a high content of soluble calcium was obtained. High performance liquid chromatography and GC-MS analysis indicated that free calcium (11.29 mmol L-1) in the fermentation solution was composed of calcium lactate (3.89 mmol L 1), calcium acetate (6.21 mmol L-1), calcium amino acids and small peptide calcium. Animal experiments show that the fermentation solution of grass fish bones could promote the growth and development of calcium-deficient rats. Complex organic calcium could be well absorbed and utilized by rats so that serum calcium, alkaline phosphatase levels, femur weight and other indicators in calcium-deficient rats could be returned to normal levels. The fermentation solution of grass fish bones can avoid the waste of aquatic proteins and fish bone calcium, and it exhibited high calcium bioavailability. Therefore, the fermentation solution of grass fish bones might be used as a new efficient calcium supplement. PMID- 30019730 TI - BiVO4 quantum dot-decorated BiPO4 nanorods 0D/1D heterojunction for enhanced visible-light-driven photocatalysis. AB - Herein, we report a BiVO4 quantum dot (QDs)-decorated BiPO4 nanorods 0D/1D heterojunction via an in situ growth method. It showed enhanced visible-light driven photocatalytic activity for degrading Rhodamine B (Rh B) compared to its pristine counterparts in composite. The mass ratio of BiVO4/BiPO4 was then varied from 3 wt% to 50 wt% and the optimum value was found to be 30 wt%, showing 8.3 fold and 6.3-fold apparent reaction rates higher than those of pristine BiPO4 and BiVO4, respectively. Moreover, all of the reduced Rh B was transformed into CO2 and H2O during the photocatalysis, thus showing the good mineralization ability (almost 100%) of the composite. Furthermore, the photocatalytic mechanism of the composite was also investigated here by the zeta potential, scavenger experiments, electron paramagnetic resonance (EPR), photoluminescence spectroscopy (PL), transient photocurrent and electrochemical impedance spectroscopy (EIS). Results show that (i) OH was the main reactive species and (ii) BiVO4 could form a heterojunction with BiPO4, thus widening the response range to the visible region and accelerating the charge separation and transfer. PMID- 30019731 TI - Design and fabrication of a liver-on-a-chip platform for convenient, highly efficient, and safe in situ perfusion culture of 3D hepatic spheroids. AB - Spheroid-based three-dimensional (3D) liver culture models, offering a desirable biomimetic microenvironment, are useful for recapitulating liver functions in vitro. However, a user-friendly, robust and specially optimized method has not been well developed for a convenient, highly efficient, and safe in situ perfusion culture of spheroid-based 3D liver models. Here, we have developed a biomimetic and reversibly assembled liver-on-a-chip (3D-LOC) platform and presented a proof of concept for long-term perfusion culture of 3D human HepG2/C3A spheroids for building a 3D liver spheroid model. On the basis of a fast and reversible seal of concave microwell-based PDMS-membrane-PDMS sandwich multilayer chips, it enables a high-throughput and parallel perfusion culture of 1080 cell spheroids in a high mass transfer and low fluid shear stress biomimetic microenvironment as well as allowing the convenient collection and analysis of the cell spheroids. In terms of reducing spheroid loss and maintaining cell morphology and viability in long-term perfusion culture, the cell spheroids in the 3D-LOC were more safe and efficient. Notably, the polarisation, liver specific functions, and metabolic activity of the cell spheroids in 3D-LOC were also remarkably improved and exhibited better long-term maintenance over conventional perfusion methods. Additionally, a robust micromilling method that incorporates secondary PDMS coating techniques (SPCs) for fabricating V-shaped concave microwells was also developed. The V-shaped concave microwell arrays exhibited a higher distribution density and aperture ratio, making it easy to form large-scale and uniform-sized cell spheroids with minimum cell loss. In summary, the proposed 3D-LOC could provide a convenient and robust solution for the long-term safe perfusion culture of hepatic spheroids and be beneficial for a variety of potential applications including development of bio-artificial livers, disease modeling, and drug toxicity screening. PMID- 30019732 TI - A Cu(ii) metallocycle for the reversible self-assembly of coordination-driven polyrotaxane-like architectures. AB - We report the design and synthesis of a Cu(ii) metallocycle (1) and use the possibility to expand the Cu(ii) coordination sphere to self-assemble mechanically interlocked species via interpenetration. Metallocycle 1 can be used as a platform to reversibly assemble a 1D + 1D -> 1D coordination-driven polyrotaxane (3), where 1 acts as the hosting ring as well as the stopper, and 4,4'-bipyridine is the guest-axle. A coordinating solvent can substitute the 4,4' bipyridine axle to disassemble the polyrotaxane (3 -> 2) that is easily restored by further adding 4,4'-bipyridine (2 -> 3). Other polyrotaxanes can be isolated by reacting 1 with pyridine (4) and phenylpyridine (5). Interconversion among the presented species is demonstrated and ensured by the open position of each copper center in platform 1. PMID- 30019733 TI - Heterometallic CuIIFeIII and CuIIMnIII alkoxo-bridged complexes revealing a rare hexanuclear M6(MU-X)7(MU3-X)2 molecular core. AB - The novel hexanuclear complexes [Cu4Fe2(OH)(Piv)4(tBuDea)4Cl].0.5CH3CN (1) and [Cu4Mn2(OH)(Piv)4(tBuDea)4Cl] (2) were prepared through one-pot self-assembly reactions of copper powder and iron(ii) or manganese(ii) chloride with N-tert butyldiethanolamine (H2tBuDea) and pivalic acid (HPiv) in acetonitrile. Crystallographic studies revealed the uncommon molecular core type M6(MU-X)7(MU3 X)2 in 1 and 2, which can be viewed as a combination of two trimetallic M3(MU X)2(MU3-X) fragments joined by three bridging atoms. The analysis and classification of the hexanuclear complexes having a M3(MU-X)2(MU3-X) moiety as a core forming fragment using data from the Cambridge Structural Database (CSD) were performed. Variable-temperature (1.8-300 K) magnetic susceptibility measurements of 1 showed a decrease of the effective magnetic moment value at low temperature, indicative of antiferromagnetic coupling between the magnetic centres (JFe-Cu/hc = -6.9 cm-1, JCu-Cu/hc = -4.1 cm-1, JFe-Fe/hc = -24.2 cm-1). Complex 1 acts as a catalyst in the reaction of mild oxidation of cyclohexane with H2O2, showing the yields of products, cyclohexanol and cyclohexanone, up to 17% using pyrazinecarboxylic acid as a promoter. In the oxidation of cis-1,2 dimethylcyclohexane with m-chloroperoxybenzoic acid (m-CPBA), 70% of retention of stereoconfiguration was observed for tertiary alcohols. Compound 1 also catalyses the amidation of cyclohexane with benzamide. In all three catalytic reactions the by-products were investigated in detail and discussed. PMID- 30019734 TI - Facilitating tumor spheroid-based bioassays and in vitro blood vessel modeling via bioinspired self-formation microstructure devices. AB - Non-planar microstructure-based tissue culture devices have emerged as powerful tools to mimic in vivo physiological microenvironments in a wide range of medical applications. Here we report a spontaneous aqueous molding approach - inspired by Stenocara gracilipes beetles - to rapidly fabricate non-planar microstructure devices for facilitating tissue-based bioassays. The device fabrication is determined from the self-assembled liquid morphology, which is induced by condensation or guided by surface tension. Through experiments and modeling, we reveal that the molding mainly comprises two typical circular and striped domains, highlighting versatile applications for bioengineering. In addition, the molding characteristic is dependent on the geometry of the patterned wetting surfaces, the working volume of the liquid, and the interaction between the liquid and the substrate. The theoretical model, based on the geometry of the patterned liquid, is highly consistent with experimental data. We also demonstrate that our approach can facilitate the culturing of tumor spheroids incorporated with biomimic nano-cilia, rapid high-throughput drug screening, tumor spheroid migration assay, and in vitro modeling of blood vessels. Remarkably, the delivery of multiple concentrations of drugs and their associate mixtures (a total of 25 test spots in one device) can be carried out simultaneously within seconds. Taken together, these insights may offer new opportunities to tailor non-planar microstructures, and our proposed methodology can be applicable for the emerging needs in tumor cell biology and tissue engineering. PMID- 30019735 TI - Phase-selective synthesis of self-supported RuP films for efficient hydrogen evolution electrocatalysis in alkaline media. AB - Large-scale hydrogen production through alkaline water electrolysis requires highly active and less expensive materials to replace platinum as a catalyst for the hydrogen evolution reaction (HER). Ruthenium, as the cheapest platinum-group element, has recently been demonstrated to exhibit excellent activity toward the HER. However, achieving better HER activity of ruthenium-based materials by selecting a more active phase is still unexplored. Herein, we report the fabrication of self-supported RuP and RuP2 catalyst films on carbon cloth (RuP/CC and RuP2/CC) via a facile, potentially scalable, and phase-controllable synthetic method. RuP/CC displays superior catalytic activity with a low overpotential of 13 mV at 10 mA cm-1, outperforming RuP2/CC (33 mV at 10 mA cm-1) and most non-Pt HER catalysts. Moreover, good electrochemical stability and faradaic efficiency of nearly 100% are also demonstrated for RuP/CC. Density functional theory calculations reveal that RuP with a higher charge density at the Ru site is more favorable for the chemisorption of hydrogen, thereby exhibiting better HER activity than RuP2. PMID- 30019736 TI - Synthesis of alpha-oxygenated beta,gamma-unsaturated ketones by a catalytic rearrangement strategy. AB - A straightforward two-step entry to alpha-oxgenated beta,gamma-unsaturated ketones from readily available alpha,beta-unsaturated ketones is disclosed. It was found that bis(allylic) alcohols undergo a skeletal rearrangement in the presence of 1 mol% of cheap and non-corrosive p-toluenesulfonic acid. Computational studies were conducted to support the mechanism and to rationalise the influence of the catalyst acidity on the product selectivity. PMID- 30019737 TI - ? PMID- 30019738 TI - [Model fidelity of flexible assertive community treatment (F-ACT) teams: five years of audit results]. AB - BACKGROUND: The Flexible act (f-act) has been introduced in the Netherlands since 2004, alongside the Assertive Community Treatment (act) model. An estimate of 400 (f-)act teams concurrently provide care to approximately 70.000 people with serious mental illness. The ccaf has been assessing the model fidelity of act and f-act teams since 2009 to promote the quality and transparency of healthcare for clients with serious mental illness. OBJECTIVE To describe the state of implementation of f-act and associated trends in the Netherlands.
METHOD: Analysis of the ccaf database, which holds the data of audits conducted between 2009 and 2014.
RESULTS: The audits conducted by ccaf between 2009 and 2014 indicated an adequate implementation of f-act. The team foundations were well organized, featuring a multidisciplinary team structure, management of medication, practical support and investment in healthcare continuity, including during an admission. However, the results regarding participation and recovery were unsatisfactory. Furthermore, the results depicted a decline in the scores concerning a number of areas, including outreach and support of participation and recovery. CONCLUSIONS Although the data indicates an on average satisfactory implementation of f-act in the Netherlands, there are signs that the implementation of f-act is under pressure with relatively fewer home visits, a rising caseload and a reduced investment in recovery and participation. The findings are in accordance with the signs and arguments to adjust the emphasis on reducing hospital admissions, prioritizing the consolidation of outpatient care instead. PMID- 30019739 TI - [Text message reminders in the hospital-psychiatry outpatient setting - a quasi experimental study on cost aspects]. AB - BACKGROUND: During their specialty training program residents are stimulated to think and work in a goal-oriented way. Patient 'no shows' are quite common in the mental healthcare system, consequently causing the ineffective use of healthcare services.
AIM: To reduce the amount of 'no shows' in an outpatient clinic for hospital psychiatry by sending reminders via text messaging.
METHOD: A quasi-experimental study was conducted at an outpatient clinic for hospital psychiatry in 2016, in which 101 patients were included. Eventually, 50 patients received a text message to remind them of their appointment, while 46 did not. We used a chi2 test to evaluate group differences. The effect size was expressed in the 'number needed to cash' (nnc), similar to the number needed to treat (nnt). Routinely available hospital-data was used to estimate lost revenue per year.
RESULTS: A significant group difference was found in the number of outpatient clinic visits in favour of sending a text message reminder (74% vs. 92%, p = 0.018). This corresponded to a nnc of 5.53, i.e. 6 text messages need to be sent in order to accomplish one extra patient showing up for their intake. Based on hospital-data from 2016 the estimated lost revenue was ? 53.017,38 / year at our outpatient clinic.
CONCLUSION: Sending reminders via text messaging is effective in reducing the number of 'no shows' at an outpatient clinic for hospital psychiatry. PMID- 30019740 TI - [Patients of a F-ACT youth team: juveniles with severe mental illness]. AB - BACKGROUND: While three quarters of all psychiatric disorders develop before the age of eighteen, mental health services are barely enlisted by adolescents. This population is increasingly targeted by F-ACT youth teams (flexible assertive community treatment) in the Netherlands, considering regular mental health services often encounter difficulty in reaching out to them. It remains unknown how severe their psychopathology can be.
AIM: To describe the adolescents being treated in a F-ACT youth team, outlining their problems and needs. To answer the question whether youngsters under the age of eighteen can meet the criteria of severe mental illness (SMI).
METHOD: An inventory was made of all adolescents referred to our F-ACT youth team regarding psychiatric diagnosis and limitations in social functioning. Two case reports were included as subsequent illustration.
RESULTS: The juvenile population treated by our F ACT youth team (n = 30) were predominantly males (n = 20). They suffered from various psychiatric problems, often coinciding with longstanding social limitations. Three quarters of these youths could meet the criteria of SMI.
CONCLUSION: It was established that a substantial amount of juveniles under the age of eighteen meet the criteria of SMI. This could facilitate the provision of targeted care for youths. However, there is also the risk of stigmatisation. PMID- 30019741 TI - [Mental health in Bonaire - an inspiration for the Dutch New Mental Health Movement]. AB - BACKGROUND: In 2010 the bes-islands in the Caribbean became a special municipality of the Netherlands. Healthcare was upgraded to match Dutch standards over a short period of time. With a population of 15,518 inhabitants in 2010 (19,408 in 2016), Bonaire received its own fact-team (flexible assertive community treatment). It subsequently became a unique experiment for the Dutch New Mental Health Movement.
AIM: To describe the development of a modern mental health care system in a limited geographic area.
METHOD: Site visitation, interviews and analysis of historical data sources.
RESULTS: The local mental health team takes integral responsibility for all the mh care needs in Bonaire. There is no intricate diagnostic referral system. Consultation access lines are short. The team was able to dramatically reduce the need for hospitalization. Collaboration with the somatic hospital and general practitioners runs smoothly and the facilities offer complementary care. Societal integration is insured due to mental health professionals living interspersed in the neighborhood, the low threshold allowing them to respond to signals efficiently. There is a natural development of the following three domains of care: reduction of symptoms, societal participation and personal remission.
CONCLUSION: Integrated mental health services in a geographically small area, as presented by the Dutch New Mental Health Movement, enables the possibility of recovery oriented care. PMID- 30019742 TI - [The diagnosis of unipolar versus bipolar disorders using neuroimaging]. AB - BACKGROUND: Clinical differentiation between unipolar and bipolar depression can be a challenge. Additional diagnostic tools based on biomarkers could help resolve ambiguous cases. In this article we discuss studies from the dissertation 'Bipolar or unipolar? A brain teasing question', investigating to which extent neuroimaging could contribute to such detection.
AIM: To investigate whether neuroimaging can aid in differentiating between uni- and bipolar disorder.
METHOD: An analysis of the brain anatomy and functioning in medication-free uni- and bipolar participants and healthy controls using magnetic resonance imaging (MRI).
RESULTS: The results indicate that there are differences regarding both brain structure and functioning when comparing unipolar and bipolar patients. The nature of these differences corresponded with the present mood state. Diagnosis could also be predicted on an individual level. However, direct implementation during clinical practice is currently not possible, in part due to the heterogeneity of the findings and the limitations inherent to MRI-research.
CONCLUSION: Neuroimaging may be a promising technique for development of additional diagnostic tools to differentiate between unipolar and bipolar disorder. PMID- 30019743 TI - [Treatment-resistant constipation and the need for chronic use of laxatives following lithium administration]. AB - Just a few days after the introduction of lithium therapy to treat a 35-year old man suffering from a bipolar disorder, complaints of constipation arose. The issue persisted despite numerous trials with first and second line laxatives at adequate dose and duration over a period of several weeks. After the singular administration of highly dosed macrogol laxatives with electrolytes, a lower dosage was established as maintenance treatment, yielding promising results. However, the potential interactions as well as the possible fluctuations in serum lithium levels when combining a maintenance treatment of both lithium and laxatives remains to be evaluated. PMID- 30019744 TI - [A boy with treatment-resistant psychiatric problems: X-linked adrenoleukodystrophy]. AB - In this case report we describe a 17-year-old boy with severe behavioural disorders, apathy and cognitive decline who was eventually diagnosed with X linked adrenoleukodystrophy (x-ald). If a patient presents with a combination of psychiatric and neurological problems, metabolic diseases such as x-ald should be included in the differential diagnosis. PMID- 30019745 TI - Ultrastructure and 3D transmission electron tomography of collagen fibrils and proteoglycans of swollen human corneal stroma. AB - BACKGROUND: The transparency of the cornea is regulated by the unique organization of collagen fibrils (CFs) which is maintained by proteoglycans (PGs). The interlacing of CF lamellae in the anterior stroma provides the biomechanical properties of the cornea. OBJECTIVE: To investigate the alterations of CFs and PGs in the swollen cornea, with special reference to the anterior stroma by using electron microscopy and 3D ultrastructural tomography. METHOD: Nine healthy normal scleral corneal rings (age from 40 to 65 years) were hydrated individually in deionised water to induce swelling in the cornea. Three of them were hydrated for 2hr whereas the other three were hydrated for 48hr. The remaining three scleral normal corneal rings were used as a control.The corneas were processed for electron microscopy (EM) to study the CFs and PGs. Ultrathin sections were observed using transmission electron microscopy (JOEL 1400) and digital images of CFs, PGs and lamellae were captured using a bottom mounted Quemesa camera and iTEM Soft Imaging System. The software program 'Composer-x64, version 3.4.2.0' was used to construct individual 3D images from 120 digital images taken from -60 to + 60 degree angles. RESULTS: The 3D tomography showed the degeneration of microfibrils within the CFs of the swollen cornea. The CF diameter was significantly reduced and the interfibrillar spacing significantly increased in both the 2hr and 48hr hydrated corneas compared to the normal cornea. Within the hydrated corneas, the CF diameter was smaller and the interfibrillar spacing was increased in the middle and posterior stroma compared to the anterior stroma. The PG area in both the 2hr and the 48hr hydrated cornea was reduced in the anterior stroma, whereas it was increased in middle and posterior stroma compared to the normal cornea. The density of the PGs in both the 2hr and the 48hr samples, was reduced compared to the density of PGs in the normal cornea. CONCLUSION: The CFs, PGs and lamellae had degenerated, caused by swelling. 3D imaging demonstrated that the impairment of the microfibrils and PGs within the CF, is caused by the excessive hydration or swelling in the anterior as well as in the middle and posterior stroma. The lamellae of the anterior stroma which provides the biomechanical strength in the normal cornea, had degenerated in the swollen corneas due to the presence of the damaged CFs and PGs. PMID- 30019746 TI - Host use dynamics in a heterogeneous fitness landscape generates oscillations in host range and diversification. AB - Colonization of novel hosts is thought to play an important role in parasite diversification, yet little consensus has been achieved about the macroevolutionary consequences of changes in host use. Here, we offer a mechanistic basis for the origins of parasite diversity by simulating lineages evolved in silico. We describe an individual-based model in which (i) parasites undergo sexual reproduction limited by genetic proximity, (ii) hosts are uniformly distributed along a one-dimensional resource gradient, and (iii) host use is determined by the interaction between the phenotype of the parasite and a heterogeneous fitness landscape. We found two main effects of host use on the evolution of a parasite lineage. First, the colonization of a novel host allowed parasites to explore new areas of the resource space, increasing phenotypic and genotypic variation. Second, hosts produced heterogeneity in the parasite fitness landscape, which led to reproductive isolation and therefore, speciation. As a validation of the model, we analyzed empirical data from Nymphalidae butterflies and their host plants. We then assessed the number of hosts used by parasite lineages and the diversity of resources they encompass. In both simulated and empirical systems, host diversity emerged as the main predictor of parasite species richness. PMID- 30019747 TI - The effect of high-flow nasal oxygen on hospital length of stay in cardiac surgical patients at high risk for respiratory complications: a randomised controlled trial. AB - There has been increased interest in the prophylactic and therapeutic use of high flow nasal oxygen in patients with, or at risk of, non-hypercapnic respiratory failure. There are no randomised trials examining the efficacy of high-flow nasal oxygen in high-risk cardiac surgical patients. We sought to determine whether routine administration of high-flow nasal oxygen, compared with standard oxygen therapy, leads to reduced hospital length of stay after cardiac surgery in patients with pre-existing respiratory disease at high risk for postoperative pulmonary complications. Adult patients with pre-existing respiratory disease undergoing elective cardiac surgery were randomly allocated to receive high-flow nasal oxygen (n = 51) or standard oxygen therapy (n = 49). The primary outcome was hospital length of stay and all analyses were carried out on an intention-to treat basis. Median (IQR [range]) hospital length of stay was 7 (6-9 [4-30]) days in the high-flow nasal oxygen group and 9 (7-16 [4-120]) days in the standard oxygen group (p=0.012). Geometric mean hospital length of stay was 29% lower in the high-flow nasal group (95%CI 11-44%, p = 0.004). High-flow nasal oxygen was also associated with fewer intensive care unit re-admissions (1/49 vs. 7/45; p = 0.026). When compared with standard care, prophylactic postoperative high-flow nasal oxygen reduced hospital length of stay and intensive care unit re admission. This is the first randomised controlled trial examining the effect of prophylactic high-flow nasal oxygen use on patient-centred outcomes in cardiac surgical patients at high risk for postoperative respiratory complications. PMID- 30019748 TI - De-escalation techniques for managing non-psychosis induced aggression in adults. AB - BACKGROUND: Aggression occurs frequently within health and social care settings. It can result in injury to patients and staff and can adversely affect staff performance and well-being. De-escalation is a widely used and recommended intervention for managing aggression, but the efficacy of the intervention as a whole and the specific techniques that comprise it are unclear. OBJECTIVES: To assess the effects of de-escalation techniques for managing non-psychosis-induced aggression in adults in care settings, in both staff and service users. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and 14 other databases in September 2017, plus three trials registers in October 2017. We also checked references, and contacted study authors and authorities in the field to identify additional published and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing de escalation techniques with standard practice or alternative techniques for managing aggressive behaviour in adult care settings. We excluded studies in which participants had psychosis. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: This review includes just one cluster-randomised study of 306 older people with dementia and an average age of 86 years, conducted across 16 nursing homes in France. The study did not measure any of our primary or secondary outcomes but did measure behavioural change using three measurement scales: the Cohen Mansfield Agitation Inventory (CMAI; 29-item scale), the Neuropsychiatric Inventory (NPI; 12-item scale), and the Observation Scale (OS; 25-item scale). For the CMAI, the study reports a Global score (29 items rated on a seven-point scale (1 = never occurs to 7 = occurs several times an hour) and summed to give a total score ranging from 29 to 203) and mean scores (evaluable items (rated on the same 7-point scale) divided by the theoretical total number of items) for the following four domains: Physically Non-Aggressive Behaviour, such as pacing (13 items); Verbally Non-Aggressive Behaviour, such as repetition (four items); Physically Aggressive Behaviour, such as hitting (nine items); and Verbally Aggressive Behaviour, such as swearing (three items). Four of the five CMAI scales improved in the intervention group (Global: change mean difference (MD) 5.69 points, 95% confidence interval (CI) -9.59 to -1.79; Physically Non Aggressive: change MD -0.32 points, 95% CI -0.49 to -0.15; Verbally Non Aggressive: change MD -0.44 points, 95% CI -0.69 to -0.19; and Verbally Aggressive: change MD -0.16 points, 95% CI -0.31 to -0.01). There was no difference in change scores on the Physically Aggressive scale (MD -0.08 points, 95% CI -0.37 to 0.21). Using GRADE guidelines, we rated the quality of this evidence as very low due to high risk of bias and indirectness of the outcome measures. There were no differences in NPI or OS change scores between groups by the end of the study.We also identified one ongoing study. AUTHORS' CONCLUSIONS: The limited evidence means that uncertainty remains around the effectiveness of de-escalation and the relative efficacy of different techniques. High-quality research on the effectiveness of this intervention is therefore urgently needed. PMID- 30019749 TI - Frequent 911 Fall Calls in Older Adults: Opportunity for Injury Prevention Strategies. AB - OBJECTIVES: To evaluate the utility of monitoring emergency medical services (EMS) call patterns to identify older adults who may benefit from targeted fall prevention and medical monitoring strategies. DESIGN: Retrospective chart review of EMS fall-related care. The HealthEMS database for the community surveyed was queried from January 1, 2007, through December 31, 2016. Fall-related calls for individuals aged 60 and older were identified and used to determine which individuals had subsequent fall calls and needed transport to the hospital over the study time period. SETTING: Medium-sized suburban community. PARTICIPANTS: Community-dwelling adults aged 60 and older with fall-related calls. MEASUREMENTS: Descriptive EMS cell data. RESULTS: Over the 10-year period, 37,324 EMS call data were recorded, with 11% (N=4,084) identified as fall-related calls that occurred for individuals aged 60 and older. Twenty-nine percent (n=685) of individuals who called for a fall called at least one more time within the study period. Time between calls substantially decreased the more frequently an individual called (p<.001). Fifteen percent (n=107) of repeat callers called 5 or more times for falls, and these individuals were transported to the hospital only 21% of the time (vs 75% of first-time callers, p <.001). CONCLUSION: Certain older individuals are at risk of having multiple fall-related calls to EMS over short periods of time, sometimes within hours of previous calls. In our current healthcare system, no significant intervention or follow-up is offered or available by emergency first response teams to prevent subsequent falls. This study demonstrates the need for a paradigm change in our healthcare system that helps reduce resource utilization for the first responder community for fall related calls in older adults and re-directs those resources to implement nationwide fall-prevention strategies to decrease fall related disability and death. PMID- 30019750 TI - Metabolic engineering of Escherichia coli for the enhanced production of l tyrosine. AB - Despite wide applications of l-tyrosine in the market, microbial overproduction of l-tyrosine has been a great challenge due to the complex gene regulations involved in its biosynthetic pathway. To this end, effects of knocking out tyrR on the l-tyrosine production were further explored during the strain development. Also, blocking cellular uptake of l-tyrosine by knocking out tyrosine transporters was examined with respect to l-tyrosine production. Using feedback resistant aroG and tyrA genes (aroGfbr and tyrAfbr hereafter) as initial overexpression targets, which encode 3-deoxy-7-phosphoheptulonate synthase and chorismate mutase or prephenate dehydrogenase, respectively, various combinations of genes were subsequently overexpressed in the Escherichia coli wild-type and tyrR knockout strain, and their effects on the l-tyrosine production were examined. Co-overexpression of aroGfbr , aroL and tyrC, a gene from Zymomonas mobilis functionally similar to tyrAfbr , but insensitive to l-tyrosine, led to the greatest l-tyrosine production regardless of the strains and plasmid constructs examined in this study. The strain BTY2.13 overexpressing the abovementioned three genes together with the removal of the l-tyrosine-specific transporter (tyrP) produced 43.14 g/L of l-tyrosine by fed-batch fermentation using the exponential feeding followed by DO-stat feeding method. This outcome suggested that the tyrR gene knockout was not mandatory for the l-tyrosine overproduction, but the production performance of strains having tyrR appeared to be highly affected by vector systems and feeding methods. With an optimal vector system and a feeding method, tyrP knockout appeared to be more effective in enhancing the l-tyrosine than tyrR knockout. PMID- 30019751 TI - Effect of aspirin in vascular surgery in patients from a randomized clinical trial (POISE-2). AB - BACKGROUND: In the POISE-2 (PeriOperative ISchemic Evaluation 2) trial, perioperative aspirin did not reduce cardiovascular events, but increased major bleeding. There remains uncertainty regarding the effect of perioperative aspirin in patients undergoing vascular surgery. The aim of this substudy was to determine whether there is a subgroup effect of initiating or continuing aspirin in patients undergoing vascular surgery. METHODS: POISE-2 was a blinded, randomized trial of patients having non-cardiac surgery. Patients were assigned to perioperative aspirin or placebo. The primary outcome was a composite of death or myocardial infarction at 30 days. Secondary outcomes included: vascular occlusive complications (a composite of amputation and peripheral arterial thrombosis) and major or life-threatening bleeding. RESULTS: Of 10 010 patients in POISE-2, 603 underwent vascular surgery, 319 in the continuation and 284 in the initiation stratum. Some 272 patients had vascular surgery for occlusive disease and 265 had aneurysm surgery. The primary outcome occurred in 13.7 per cent of patients having aneurysm repair allocated to aspirin and 9.0 per cent who had placebo (hazard ratio (HR) 1.48, 95 per cent c.i. 0.71 to 3.09). Among patients who had surgery for occlusive vascular disease, 15.8 per cent allocated to aspirin and 13.6 per cent on placebo had the primary outcome (HR 1.16, 0.62 to 2.17). There was no interaction with the primary outcome for type of surgery (P = 0.294) or aspirin stratum (P = 0.623). There was no interaction for vascular occlusive complications (P = 0.413) or bleeding (P = 0.900) for vascular compared with non-vascular surgery. CONCLUSION: This study suggests that the overall POISE 2 results apply to vascular surgery. Perioperative withdrawal of chronic aspirin therapy did not increase cardiovascular or vascular occlusive complications. Registration number: NCT01082874 ( http://www.clinicaltrials.gov). PMID- 30019752 TI - Influence of dentine debris and organic tissue on the properties of sodium hypochlorite solutions. AB - AIM: To determine the free available chlorine of 2.5% sodium hypochlorite (NaOCl) alone and combined with 9% etidronic acid (HEDP) in the presence of inhibitors, organic tissue and organic tissue plus dentine debris; to evaluate the influence of dentine debris on the tissue-dissolving capacity of both NaOCl solutions; and to determine the antimicrobial action of these solutions when in contact with organic tissue and organic tissue plus dentine debris. METHODOLOGY: The available chlorine of the solutions over time in the absence and presence of the inhibitors was measured using a titration method. The organic tissue dissolution by the solutions alone and in the presence of dentine powder was evaluated by weighing bovine tissue specimens before and after exposure to the solutions for 3 and 10 min. For the antimicrobial activity, biofilms of Enterococcus faecalis were exposed to the solutions for 3 min in the absence and presence of organic tissue and organic tissue + dentine debris. The biovolume and percentage of damaged membrane cells of the biofilm were measured by means of confocal microscopy and the live/dead technique. Nonparametric tests were used to determine statistical differences (P < 0.05). RESULTS: Both inhibitors consumed the free available chlorine of the solutions over time. The presence of dentine debris significantly reduced the tissue dissolution capacity of the NaOCl solutions (P < 0.05). The percentages of biovolume reduction were not affected by the presence of the inhibitors in the two NaOCl solutions, whereas the percentage of damaged membrane cells was significantly reduced (P < 0.001). Overall, a similar behaviour was observed in the NaOCl and NaOCl/HEDP groups. CONCLUSIONS: The presence of organic tissue and organic tissue + dentine debris favoured rapid consumption of the free chlorine of NaOCl and NaOCl/HEDP. This resulted in a decreased ability to dissolve organic tissue without affecting the short-term antimicrobial activity. PMID- 30019753 TI - ABRE-BINDING FACTORS play a role in the feedback regulation of ABA signaling by mediating rapid ABA induction of ABA co-receptor genes. AB - Group A protein phosphatase 2Cs (PP2Cs) are abscisic acid (ABA) co-receptors that negatively regulate the ABA signaling pathway by inhibiting the downstream SnRK2 protein kinases. It has long been observed that exogenous ABA treatments dramatically induce the expression of group A PP2C genes, but the underlying molecular mechanisms and the biological significance remain largely unknown. Here, by using GUS reporter transgenic lines in which various lengths of ABI1 and ABI2 promoters were used to drive GUS gene expression, we defined the promoter fragments that confer ABA inducibility to ABI1 and ABI2. We further showed that ABRE-binding factors (ABFs), the bZIP family transcription factors, directly bind to the promoters of group A PP2C genes, and mediate rapid induction of their expression on exogenous ABA treatments. Moreover, our data indicated that ABA dramatically induces the expression of ABF genes and the accumulation of endogenous ABF proteins, and that ABFs themselves are involved in this induction, thus providing another layer of ABA regulation towards ABF proteins in addition to the well-characterized ABA-induced phosphorylation by SnRK2 protein kinases. Together, our data demonstrate that ABFs mediate rapid ABA induction of group A PP2C genes, thus playing a role in the negative feedback regulation of ABA signaling. PMID- 30019754 TI - Rice PPS1 encodes a DYW motif-containing pentatricopeptide repeat protein required for five consecutive RNA-editing sites of nad3 in mitochondria. AB - The pentatricopeptide repeat (PPR) protein family is a large family characterized by tandem arrays of a degenerate 35-amino-acid motif whose members function as important regulators of organelle gene expression at the post-transcriptional level. Despite the roles of PPRs in RNA editing in organelles, their editing activities and the underlying mechanism remain obscure. Here, we show that a novel DYW motif-containing PPR protein, PPS1, is associated with five conserved RNA-editing sites of nad3 located in close proximity to each other in mitochondria, all of which involve conversion from proline to leucine in rice. Both pps1 RNAi and heterozygous plants are characterized by delayed development and partial pollen sterility at vegetative stages and reproductive stage. RNA electrophoresis mobility shift assays (REMSAs) and reciprocal competition assays using different versions of nad3 probes confirm that PPS1 can bind to cis elements near the five affected sites, which is distinct from the existing mode of PPR-RNA binding because of the continuity of the editing sites. Loss of editing at nad3 in pps1 reduces the activity of several complexes in the mitochondrial electron transport chain and affects mitochondrial morphology. Taken together, our results indicate that PPS1 is required for specific editing sites in nad3 in rice. PMID- 30019755 TI - Initial Cholinesterase Inhibitor Therapy Dose and Serious Events in Older Women and Men. AB - OBJECTIVES: To examine dose-related prescribing and short-term serious events associated with initiation of cholinesterase inhibitor (ChEI) therapy. DESIGN: Retrospective, population-based cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Women (n=47,829) and men (n=32,503) aged 66 and older who initiated a ChEI between April 1, 2010, and June 30, 2016. MEASUREMENTS: All-cause serious events (emergency department (ED) visits, inpatient hospitalizations, death) within 30 days of ChEI initiation. Multivariable Cox proportional hazards models were used to estimate adjusted rates of serious events. RESULTS: Overall, 4.8% of older adults were dispensed a lower-than-recommended ChEI starting dose, 87.9% a recommended dose, and 7.3% a higher-than-recommended starting dose. Eight thousand six hundred seventy-one (10.8%) individuals experienced a serious event within 30 days of initiating therapy, primarily ED visits (8,540, 10.6%). Relative to those initiated on a recommended starting dose, those initiated on a higher dose had a significantly increased rate of serious events (women adjusted hazard ratio (aHR) 1.50, 95% confidence interval (CI) =1.38-1.63; men aHR 1.31, 95% CI=1.19-1.45). Similar patterns were found for ED visits and inpatient hospitalizations but not death. The relative effect of higher-than-recommended starting dose dispensed vs. recommended starting dose dispensed was greater in women than it was in men: the number needed to harm was 22 (95% confidence interval (CI)=18-29) for women and 36 (95% CI= 26-61) for men. CONCLUSION: Serious events immediately after initiation of ChEIs were associated with starting ChEI dose. This association was stronger in women. PMID- 30019756 TI - A System for Managing Staff and Quality of Dementia Care in Assisted Living Facilities. AB - OBJECTIVES: To describe a staff management and quality improvement system implemented in an assisted-living facility (ALF) that provides dementia care. DESIGN: Prospective quality improvement project over 13 consecutive months. SETTING: One ALF that provides dementia care services. PARTICIPANTS: ALF residents with dementia (N=57). INTERVENTION: A staff management and quality improvement system was implemented for 3 aspects of daily care: morning and evening activity of daily living (ADL) care, nutritional care, and activity engagement. MEASUREMENTS: Supervisory staff monitored the quality of daily care processes of all residents and direct care staff using standardized observations. Observational data were summarized into quality measures for each of the 3 daily care areas and ranged from 0% to 100%, with a higher score indicative of better quality. These quality measures were shared with direct care staff in weekly huddles at which feedback was provided about areas in need of improvement. The management team also reviewed the data weekly to discuss strategies for improvement. RESULTS: The quality measures in each of the 3 areas improved or remained consistently high over the 13 study months: morning and evening ADL care (83-96%), quality nutritional of care during meals (74-95%), activity engagement (69-97%). CONCLUSION: A staff management and quality improvement system that relies on standardized observations of quality of care, weekly review by managers, and feedback to direct care staff informs areas in need of improvement and supports consistent implementation of quality of care over time for ALF residents receiving dementia care. PMID- 30019758 TI - Effects of cornstarch on the gel properties of black bean protein isolate. AB - The effects of common starch (CS) and high amylopectin starch (HAS) from corn on the properties of heat induced black bean protein isolate (BBPI) gels prepared by heating at 95 degrees C for 30 min were investigated by using dynamic oscillatory rheometer, texture analyzer, and scanning electron microscopy (SEM). Compared with BBPI alone, the presence of cornstarch (1-4%, wt/vol) could improve storage modulus (G') and textural properties of BBPI (10%, wt/vol) gels. The mixed system of BBPI and 4% (wt/vol) HAS exhibited the highest G' and formed the gel faster and more easily, which resulted in firmer and more elastic gel than BBPI-CS at all starch concentrations. It was possible that HAS had lower pasting temperature and higher viscosity than CS, which was beneficial to the formation of BBPI gel network and strengthened the stability of network structure. Moreover, it might also be related to the synergistic effect between protein and starch. The CS and HAS existed in the BBPI gel network could bind water, leading to the increase in the water-holding capacity (WHC) of mixed gels, especially 4% (wt/vol) HAS, which was related to homogeneous and compact microstructure with small pores. PMID- 30019759 TI - Modelling of focused ion beam induced increases in sample temperature: a case study of heat damage in biological samples. AB - : Ion beam induced heat damage in soft materials and biological samples is not yet well understood in Focused Ion Beam systems (FIBs). The work presented here discusses the physics behind the ion beam - sample interactions and the effects which lead to increases in sample temperature and potential heat damage. A model by which heat damage can be estimated and which allows parameters to be determined that reduce/prevent heat damage was derived from Fourier's law of heat transfer and compared to finite element simulations, numerical modelling results and experiments. The results suggests that ion beam induced heat damage can be prevented/minimised by reducing the ion beam current (local dose rate), decreasing the beam overlap (reduced local ion dose) and by introducing a blur (increased surface cross-section area, reduced local dose) while sputtering, patterning or imaging soft material and nonresin-embedded biological samples using FIBs. LAY DESCRIPTION: FIB/SEMs, which combine a scanning electron microscope with a focused ion beam in a single device, have found increasing interest biological research. The device allows to cut samples at precisely selected areas and reveal sub surface information as well as preparing transmission electron microscope samples from bulk materials. Preparing biological samples has proven to be challenging due to the induced heat damage. This work explores the physics behind the sample cutting and proposes a model and a method, based on physical principles which allows the user to estimate the induced heat during the cutting process and to select cutting parameters which avoid heat damage in the sample. PMID- 30019757 TI - Identification of discrete, intermingled hypocretin neuronal populations. AB - Neurons in the lateral hypothalamic area that express hypocretin (Hcrt) neuropeptides help regulate many behaviors including wakefulness and reward seeking. These neurons project throughout the brain, including to neural populations that regulate wakefulness, such as the locus coeruleus (LC) and tuberomammilary nucleus (TMN), as well as to populations that regulate reward, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA). To address the roles of Hcrt neurons in seemingly disparate behaviors, it has been proposed that Hcrt neurons can be anatomically subdivided into at least two distinct subpopulations: a "medial group" that projects to the LC and TMN, and a "lateral group" that projects to the NAc and VTA. Here, we use a dual retrograde tracer strategy to test the hypotheses that Hcrt neurons can be classified based on their downstream projections and medial/lateral location within the hypothalamus. We found that individual Hcrt neurons were significantly more likely to project to both the LC and TMN or to both the VTA and NAc than would be predicted by chance. In contrast, we found that Hcrt neurons that projected to the LC or TMN were mostly distinct from Hcrt neurons that projected to the VTA or NAc. Interestingly, these two populations of Hcrt neurons are intermingled within the hypothalamus and cannot be classified into medial or lateral groups. These results suggest that Hcrt neurons can be distinguished based on their downstream projections but are intermingled within the hypothalamus. PMID- 30019760 TI - Sex-specific density of ventricular SK currents: is this a general feature of SK channel function? PMID- 30019761 TI - Bubble-echo based deconvolution of contrast-enhanced ultrasound imaging: Simulation and experimental validations. AB - PURPOSE: Improvement of both the imaging resolution and the contrast-to-tissue ratio (CTR) is a current emphasis of contrast-enhanced ultrasound (CEUS) for microvascular perfusion imaging. Based on the strong nonlinear characteristics of contrast agents, the CTRs have been significantly enhanced using various advanced CEUS methods. However, the imaging resolution of these methods is limited by the finite bandwidth of the imaging process. This study aimed to propose a bubble echo based deconvolution (BED) method for CEUS with both improved resolution and CTR. METHOD: The method is built on a modified convolution model and uses novel bubble-echo based point-spread-functions to reconstruct the images by regularized inverse Wiener filtering. Performances of the proposed BED for three CEUS modes are investigated through simulations and in vivo perfusion experiments. RESULTS: BED of fundamental imaging was found to have the highest improvement in imaging resolution with the resolution gain up to 2.0 +/- 0.2 times, which was comparable to the approved cepstrum-based deconvolution (CED). BED of second-harmonic imaging had the best performance in CTR with an enhancement of 9.8 +/- 2.3 dB, which was much higher than CED. Pulse inversion BED had both a better resolution and a higher CTR. CONCLUSION: All results indicate that BED could obtain CEUS image with both an improved resolution and a high CTR, which has important significance to microvascular perfusion evaluation in deep tissue. PMID- 30019763 TI - The factor structure and psychometric properties of an Arabic-translated version of the Body Appreciation Scale-2. AB - PURPOSE: The conduct of body image studies with Arab populations is hindered by a lack of psychometrically sound assessment measures. We examined the psychometric properties of an Arabic translation of the most frequently employed measure of body appreciation, the Body Appreciation Scale-2 (BAS-2). DESIGN AND METHODS: A sample of college-aged women from the United Arab Emirates (UAE) (n = 256) completed the Arabic BAS-2, and measures of aesthetic and functional body image, authentic body pride, and self-reported body mass index (BMI). RESULTS: Exploratory factor analysis revealed that the Arabic BAS-2 had a one-dimensional factor structure. BAS-2 scores were positively correlated with body image and body pride, but not with BMI. PRACTICE IMPLICATIONS: A psychometrically sound BAS 2 may now facilitate the conduct of cross-cultural work that includes the Arabic speaking population, an often-neglected ethnic group in most body image studies. PMID- 30019762 TI - Improving Nursing Facility Care Through an Innovative Payment Demonstration Project: Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care Phase 2. AB - Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) is a 2-phase Center for Medicare and Medicaid Innovations demonstration project now testing a novel Medicare Part B payment model for nursing facilities and practitioners in 40 Indiana nursing facilities. The new payment codes are intended to promote high-quality care in place for acutely ill long-stay residents. The focus of the initiative is to reduce hospitalizations through the diagnosis and on-site management of 6 common acute clinical conditions (linked to a majority of potentially avoidable hospitalizations of nursing facility residents): pneumonia, urinary tract infection, skin infection, heart failure, chronic obstructive pulmonary disease or asthma, and dehydration. This article describes the OPTIMISTIC Phase 2 model design, nursing facility and practitioner recruitment and training, and early experiences implementing new Medicare payment codes for nursing facilities and practitioners. Lessons learned from the OPTIMISTIC experience may be useful to others engaged in multicomponent quality improvement initiatives. PMID- 30019764 TI - Navigating a fine balance in the treatment of amyotrophic lateral sclerosis. PMID- 30019765 TI - Omega-6 fats for the primary and secondary prevention of cardiovascular disease. AB - BACKGROUND: Omega-6 fats are polyunsaturated fats vital for many physiological functions, but their effect on cardiovascular disease (CVD) risk is debated. OBJECTIVES: To assess effects of increasing omega-6 fats (linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA)) on CVD and all-cause mortality. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to May 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher versus lower omega-6 fat intake in adults with or without CVD, assessing effects over at least 12 months. We included full texts, abstracts, trials registry entries and unpublished studies. Outcomes were all-cause mortality, CVD mortality, CVD events, risk factors (blood lipids, adiposity, blood pressure), and potential adverse events. We excluded trials where we could not separate omega-6 fat effects from those of other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias of included trials. We wrote to authors of included studies. Meta-analyses used random-effects analysis, while sensitivity analyses used fixed-effects and limited analyses to trials at low summary risk of bias. We assessed GRADE quality of evidence for 'Summary of findings' tables. MAIN RESULTS: We included 19 RCTs in 6461 participants who were followed for one to eight years. Seven trials assessed the effects of supplemental GLA and 12 of LA, none DGLA or AA; the omega-6 fats usually displaced dietary saturated or monounsaturated fats. We assessed three RCTs as being at low summary risk of bias.Primary outcomes: we found low-quality evidence that increased intake of omega-6 fats may make little or no difference to all-cause mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.12, 740 deaths, 4506 randomised, 10 trials) or CVD events (RR 0.97, 95% CI 0.81 to 1.15, 1404 people experienced events of 4962 randomised, 7 trials). We are uncertain whether increasing omega-6 fats affects CVD mortality (RR 1.09, 95% CI 0.76 to 1.55, 472 deaths, 4019 randomised, 7 trials), coronary heart disease events (RR 0.88, 95% CI 0.66 to 1.17, 1059 people with events of 3997 randomised, 7 trials), major adverse cardiac and cerebrovascular events (RR 0.84, 95% CI 0.59 to 1.20, 817 events, 2879 participants, 2 trials) or stroke (RR 1.36, 95% CI 0.45 to 4.11, 54 events, 3730 participants, 4 trials), as we assessed the evidence as being of very low quality. We found no evidence of dose-response or duration effects for any primary outcome, but there was a suggestion of greater protection in participants with lower baseline omega-6 intake across outcomes.Additional key outcomes: we found increased intake of omega-6 fats may reduce myocardial infarction (MI) risk (RR 0.88, 95% CI 0.76 to 1.02, 609 events, 4606 participants, 7 trials, low-quality evidence). High-quality evidence suggests increasing omega-6 fats reduces total serum cholesterol a little in the long term (mean difference (MD) -0.33 mmol/L, 95% CI -0.50 to -0.16, I2 = 81%; heterogeneity partially explained by dose, 4280 participants, 10 trials). Increasing omega-6 fats probably has little or no effect on adiposity (body mass index (BMI) MD -0.20 kg/m2, 95% CI -0.56 to 0.16, 371 participants, 1 trial, moderate-quality evidence). It may make little or no difference to serum triglycerides (MD -0.01 mmol/L, 95% CI -0.23 to 0.21, 834 participants, 5 trials), HDL (MD -0.01 mmol/L, 95% CI -0.03 to 0.02, 1995 participants, 4 trials) or low-density lipoprotein (MD -0.04 mmol/L, 95% CI -0.21 to 0.14, 244 participants, 2 trials, low-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-6 fats on cardiovascular health, mortality, lipids and adiposity to date, using previously unpublished data. We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI, where 53 people may need to increase omega-6 fat intake to prevent 1 person from experiencing MI. Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity. PMID- 30019766 TI - Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. AB - BACKGROUND: Researchers have suggested that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) benefit cardiovascular health. Guidelines recommend increasing omega-3 rich foods, and sometimes supplementation, but recent trials have not confirmed this. OBJECTIVES: To assess effects of increased intake of fish- and plant-based omega-3 for all-cause mortality, cardiovascular (CVD) events, adiposity and lipids. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to September 2016, with no language restrictions. We handsearched systematic review references and bibliographies and contacted authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. MAIN RESULTS: We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet.Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (RR 0.98, 95% CI 0.90 to 1.03, 92,653 participants; 8189 deaths in 39 trials, high-quality evidence), cardiovascular mortality (RR 0.95, 95% CI 0.87 to 1.03, 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR 0.99, 95% CI 0.94 to 1.04, 90,378 participants; 14,737 people experienced events in 38 trials, high-quality evidence), coronary heart disease (CHD) mortality (RR 0.93, 95% CI 0.79 to 1.09, 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR 1.06, 95% CI 0.96 to 1.16, 89,358 participants; 1822 strokes in 28 trials) or arrhythmia (RR 0.97, 95% CI 0.90 to 1.05, 53,796 participants; 3788 people experienced arrhythmia in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR 0.93, 95% CI 0.88 to 0.97, 84,301 participants; 5469 people experienced CHD events in 28 RCTs); however, this was not maintained in sensitivity analyses - LCn3 probably makes little or no difference to CHD event risk. All evidence was of moderate GRADE quality, except as noted.Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20, 19,327 participants; 459 deaths, 5 RCTs),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25, 18,619 participants; 219 cardiovascular deaths, 4 RCTs), and it may make little or no difference to CHD events (RR 1.00, 95% CI 0.80 to 1.22, 19,061 participants, 397 CHD events, 4 RCTs, low-quality evidence). However, increased ALA may slightly reduce risk of cardiovascular events (from 4.8% to 4.7%, RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low quality evidence), and probably reduces risk of CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants; 193 CHD deaths, 3 RCTs), and arrhythmia (3.3% to 2.6%, RR 0.79, 95% CI 0.57 to 1.10, 4,837 participants; 141 events, 1 RCT). Effects on stroke are unclear.Sensitivity analysis retaining only trials at low summary risk of bias moved effect sizes towards the null (RR 1.0) for all LCn3 primary outcomes except arrhythmias, but for most ALA outcomes, effect sizes moved to suggest protection. LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes towards null for most primary outcomes. There were no dose or duration effects in subgrouping or meta regression.There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity or lipids, although LCn3 slightly reduced triglycerides and increased HDL. ALA probably reduces HDL (high- or moderate-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event risk, CHD mortality and arrhythmia. PMID- 30019767 TI - Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease. AB - BACKGROUND: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests that increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. OBJECTIVES: To assess effects of increasing total PUFA intake on cardiovascular disease and all-cause mortality, lipids and adiposity in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without cardiovascular disease that assessed effects over 12 months or longer. We included full texts, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, cardiovascular disease mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included trials for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. MAIN RESULTS: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Eleven included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA.Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 7.8% vs 7.6%, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 19,290 participants in 24 trials), but probably slightly reduces risk of coronary heart disease events from 14.2% to 12.3% (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants) and cardiovascular disease events from 14.6% to 13.0% (RR 0.89, 95% CI 0.79 to 1.01, 17,799 participants in 21 trials), all moderate-quality evidence. Increasing PUFA may slightly reduce risk of coronary heart disease death (6.6% to 6.1%, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) andstroke (1.2% to 1.1%, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants, though confidence intervals include important harms), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, 16 trials, 15,107 participants) all low-quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality.Increasing PUFA intake slightly reduces total cholesterol (mean difference (MD) -0.12 mmol/L, 95% CI -0.23 to -0.02, 26 trials, 8072 participants) and probably slightly decreases triglycerides (MD -0.12 mmol/L, 95% CI -0.20 to -0.04, 20 trials, 3905 participants), but has little or no effect on high-density lipoprotein (HDL) (MD 0.01 mmol/L, 95% CI -0.02 to 0.01, 18 trials, 4674 participants) or low-density lipoprotein (LDL) (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, 15 trials, 3362 participants). Increasing PUFA probably causes slight weight gain (MD 0.76 kg, 95% CI 0.34 to 1.19, 12 trials, 7100 participants).Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. AUTHORS' CONCLUSIONS: This is the most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids or adiposity. Increasing PUFA intake probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke (though not ruling out harms), but has little or no effect on all-cause or cardiovascular disease mortality. The mechanism may be via lipid reduction, but increasing PUFA probably slightly increases weight. PMID- 30019768 TI - Effects of Active Learning on Health Literacy and Behavior in Older Adults: A Randomized Controlled Trial. AB - OBJECTIVES: To investigate the effects of active learning education on health literacy, cognitive and physical function, physical activity, and dietary habits in older adults. DESIGN: Randomized controlled trial. SETTING: Rural community in Japan. PARTICIPANTS: Individuals aged 65 and older (N=84) randomly assigned to a health education intervention group (n=42) or a control group (n=42). INTERVENTION: The intervention group attended a weekly 90-minute active learning program on exercise, diet and nutrition, and cognitive activity for health promotion in older age for 24 weeks. Active learning included exploratory learning, group work, and self-planning for behavioral change, which promoted a healthy lifestyle. MEASUREMENTS: Outcome measures were obtained at baseline before randomization and at 24 weeks. Comprehensive health literacy was assessed as the primary outcome using the Health Literacy Scale-14 (HLS-14) and the 16 item European Health Literacy Survey Questionnaire (HLS-EU-Q16). Cognitive function was evaluated in 4 domains: processing speed, verbal fluency, working memory, and memory. Physical function and amounts of physical activity were also objectively measured. RESULTS: HLS-14, the disease prevention domain of the HLS EU-Q16, category verbal fluency test, Scenery Picture Memory Test, and Timed Up and Go test scores; gait speed; number of steps per day; physical activity levels; and dietary variety scores were significantly improved in the intervention group than the control group. CONCLUSION: This study suggests that health education through active learning is effective in enhancing comprehensive health literacy, verbal fluency, memory, gait speed, balance ability, physical activity, and dietary variety in older adults. PMID- 30019769 TI - Lefamulin: Review of a Promising Novel Pleuromutilin Antibiotic. AB - The emergence and spread of antimicrobial resistance have led to a global public health emergency requiring development of new antimicrobial classes. Lefamulin (formally BC-3781) is a novel pleuromutilin antibiotic currently undergoing Food and Drug Administration review for community-acquired bacterial pneumonia (CABP) as intravenous (IV) and oral (PO) formulations. Although pleuromutilin antibiotics were first developed in the 1950s, lefamulin is the first to be used for systemic treatment of bacterial infections in humans. Lefamulin exhibits a unique mechanism of action through inhibition of protein synthesis by binding to the peptidyl transferase center of the 50S bacterial ribosome, thus preventing the binding of transfer RNA for peptide transfer. Lefamulin displays activity against gram-positive and atypical organisms associated with CABP (i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded gram positive spectrum including Staphylococcus aureus (i.e., methicillin-resistant, vancomycin-intermediate, and heterogeneous strains) and vancomycin-resistant Enterococcus faecium. Lefamulin was also shown to retain activity against multidrug-resistant Neisseria gonorrhoeae and Mycoplasma genitalium. Lefamulin exhibits time-dependent killing, and the pharmacodynamic target best associated with antibacterial activity is fAUC0-24 /MIC (minimum inhibitory concentration [MIC]). Preclinical and phase II trials indicate that lefamulin concentrates in lung tissue are well tolerated at an IV dose of 150 mg twice/day over 1 hour or a PO dose of 600 mg twice/day, and preliminary phase III data suggest similar efficacy when compared with moxifloxacin with or without linezolid in CABP. Documented resistance and cross-resistance with other gram-positive antibacterials remains low. Additional published in vitro, in vivo, and preclinical trial data suggest further exploration of lefamulin in various infectious disease states (e.g., acute bacterial skin and skin structure infections, and sexually transmitted infections). This review discusses the pertinent bacterial spectrum of activity, preclinical and ongoing clinical data, and potential roles in therapy for lefamulin. PMID- 30019770 TI - beta-Strand twisting/bending in soluble and transmembrane beta-barrel structures. AB - The majority of beta-strands in globular proteins have a right-handed twist and bend. The dominant driving force for beta-strand twisting is thought to be inter strand hydrogen bonds. We previously demonstrated that for water-soluble proteins, both the twisting and bending of beta-strand are suppressed by the polar side chains of serine, threonine, and asparagine residues. To determine whether this also holds for transmembrane beta-strands, we calculated and statistically analyzed the twist and bend angles of four-residue frames of beta strands in both transmembrane and water-soluble beta-barrel proteins with known three-dimensional structures. In the case of transmembrane beta-strands, we found that twisting was suppressed even for frames not containing serine, threonine, or asparagine residues. The suppression of twisting in transmembrane beta-strands could be attributed to the propagation of the suppressive effect of serine, threonine, and asparagine residues within a frame to the neighboring, hydrogen bonded strands under the restriction that all strands in the closed barrel structure must have similar twist angles. A similar tendency was also observed for water-soluble beta-barrel proteins. We previously showed that the dominant driving force for beta-strand bending is hydrophobic interactions involving aromatic residues within and outside the strand. Transmembrane beta-barrels have no hydrophobic core; however, rather hydrophilic residues predominate inside the barrel or the beta-strands of transmembrane beta-barrels have larger bend angles than those of water-soluble beta-barrels. Our results reveal that, in transmembrane beta-barrel proteins, the glycine-aromatic ring motif is important for generating the beta-strand bending necessary for barrel formation. PMID- 30019771 TI - A protocol for early childhood caries diagnosis and risk assessment. AB - The global Early Childhood Caries (ECC) burden is of concern to the World Health Organisation (WHO), but the quantification of this burden and risk is unclear, partly due to difficulties in accessing young children for population surveys and partly due to diagnostic criteria for ECC experience. The WHO criterion for caries diagnosis is the late stage event of dentine cavitation. Earlier stages of the caries lesion are clinically detectable and should be registered earlier in the life of children and arrested/remineralized before lesions progress to the cavitation stage. A protocol for ECC diagnosis is proposed to guide those engaged in clinical dentistry in their characterization of the ECC lesion. As management of early lesions is a critical step to reduce risk of their progression to later stage lesions, a practical method for assessing ECC risk is proposed also. Risk assessment is very important because it determines (a) urgency for interventions aimed to arrest lesion progression; (b) the frequency of such interventions and (c) the need to enhance the primary prevention of ECC. The guidelines are set out separately for ECC diagnosis for ongoing clinical care and for epidemiologic purposes. Similarly, guidelines are set out for ECC risk assessment and ongoing monitoring. PMID- 30019772 TI - Monitoring transient events in infrared spectra using local mode analysis. AB - Time-resolved Fourier transformed infrared (FTIR) spectroscopy of chemical reactions is highly sensitive to minimal spatiotemporal changes. Structural features are decoded and represented in a comprehensible manner by combining FTIR spectroscopy with biomolecular simulations. Local mode analysis (LMA) is a tool to connect molecular motion based on a quantum mechanics simulation with infrared (IR) spectral features and vice versa. Here, we present the python-based software tool of LMA and demonstrate the novel feature of LMA to extract transient structural details and identify the related IR spectra at the case example of malonaldehyde (MA). Deuterated MA exists in two almost equally populated tautomeric states separated by a low barrier for proton transfer so IR spectra represent a mixture of both states. By state-dependent LMA, we obtain pure spectra for each tautomeric state occurring within the quantum mechanics trajectory. By time-resolved LMA, we obtain a clear view of the transition between states in the spectrum. Through local mode decomposition and the band pass filter, marker bands for each state are identified. Thus, LMA is beneficial to analyze the experimental spectra based on a mixture of states by determining the individual contributions to the spectrum and motion of each state. PMID- 30019773 TI - Computational characterization of the binding mode between oncoprotein Ets-1 and DNA-repair enzymes. AB - The Ets-1 oncoprotein is a transcription factor that promotes target gene expression in specific biological processes. Typically, Ets-1 activity is low in healthy cells, but elevated levels of expression have been found in cancerous cells, specifically related to tumor progression. Like the vast majority of the cellular effectors, Ets-1 does not act alone but in association with partners. Given the important role that is attributed to Ets-1 in major human diseases, it is crucial to identify its partners and characterize their interactions. In this context, two DNA-repair enzymes, PARP-1 and DNA-PK, have been identified recently as interaction partners of Ets-1. We here identify their binding mode by means of protein docking. The results identify the interacting surface between Ets-1 and the two DNA-repair enzymes centered on the alpha-helix H1 of the ETS domain, leaving alpha-helix H3 available to bind DNA. The models highlight a hydrophobic patch on Ets-1 at the center of the interaction interface that includes three tryptophans (Trp338, Trp356, and Trp361). We rationalize the binding mode using a series of computational analyses, including alanine scanning, molecular dynamics simulation, and residue centrality analysis. Our study constitutes a first but important step in the characterization, at the molecular level, of the interaction between an oncoprotein and DNA-repair enzymes. PMID- 30019774 TI - Human telomerase protein: Understanding how the catalytic activity is suppressed under single substitutions of some conserved residues. A computational study. AB - The reverse transcriptase domain in telomerase proteins contains the essential conserved residues to catalyze the addition of a single nucleotide to the ends of DNA strands of most eukaryotic cells. In human telomerase protein, mutations in the conserved residues K902, R631, K626, D712, D868, and D869 are known to suppress catalytic activity. To understand these results, a computational model was constructed to simulate a ternary complex consisting of a model of the protein reverse transcriptase domain, a DNA/RNA double helix, an incoming dNTP, and two Mg2+ ions. Three independent Molecular Dynamics Simulations were performed for the wild type and the mutated K902N, R631Q, D712A, D868A, and D869A complexes. Binding Free Energies and alanine-scanning studies were also performed. Using the two-metal-ion mechanism for the nucleotide addition, deviations from the wild type which stop the activity of the human protein, were identified in each mutated complex. The K902N and R631Q mutations might stop the catalytic activity preventing the exit of the pyrophosphate from the catalytic pocket. Additionally, evidence that the same mechanism probably applies to the K626A, R631A, and K902A mutations is presented. For D712A mutation, the pentavalent intermediate state might not form; therefore, the catalytic reaction might not even begin. For the D868A mutation, the O3'-hydroxyl might lose coordination with the Mg ion and the reaction might not either start. Finally, from the limited sampling carried out in this work, we did not obtain any evidence to identify the mechanism by which the D869A mutation cancels the activity of telomerase. PMID- 30019775 TI - AFM-based nanomechanical characterization of bronchoscopic samples in asthma patients. AB - Asthma is not a single disease, but recently, it is considered as a syndrome characterized through various clinical presentations and different etiopathologies. Large degree of the disease heterogeneity manifests in distinct characteristics that translate into variability of properties at single cell and molecular levels. Here, we conducted measurements of mechanical properties of bronchial tissue samples collected from patients suffering from asthma. The results obtained from different applied protocols for sample preparation may indicate that deep freezing and storage in liquid nitrogen, followed by consecutive unfreezing of tissue samples, preserve tissue mechanical properties as indicated by a parameter referred here as a tissue relative stiffness index. Tissue relative stiffness index quantifies both the degree of heterogeneity and deformability of tissue samples regarding healthy one. These studies demonstrate that the freezing protocol, optimized towards asthma tissue, can facilitate atomic force microscopy use what, together with recent findings on standardization of elasticity measurements, enables the measurements of large group of samples with minimized influence of errors stemming from the applied methodology of tissue stiffness determination. PMID- 30019776 TI - Transluminal antegrade endoscopic lithotripsy for pancreatic duct stones (with video). PMID- 30019777 TI - Coil conversion to beta-strand induced by dimerization. AB - Most molecular processes in living organisms rely on protein-protein interactions, many of which are mediated by beta-sheet interfaces; this study investigates the formation of beta-sheet interfaces through the conversion of coils into beta-strands. Following an exhaustive search in the Protein Data Bank, the corresponding structural dimorphic fragments were extracted, characterized, and analyzed. Their short strand lengths and specific amino acid profiles indicate that dimorphic beta-strand interfaces are likely to be less stable than standard ones and could even convert to coil interfaces if their environment changes. Moreover, the construction of a simple classifier able to discriminate between the sequences of dimorphic and standard beta-strand interfaces suggests that the nature of those dimorphic sequences could be predicted, providing a novel means of identifying proteins capable of forming dimers. PMID- 30019778 TI - Singular value decomposition for the correlation of atomic fluctuations with arbitrary angle. AB - Many proteins exhibit a critical property called allostery, which enables intra molecular transmission of information between distal sites. Microscopically, allosteric response is closely related to correlated atomic fluctuations. Conventional correlation analysis correlates the atomic fluctuations at two sites by taking the dot product (DP) between the fluctuations, which accounts only for the parallel and antiparallel components. Here, we present a singular value decomposition (SVD) method that analyzes the correlation coefficient of fluctuation dynamics with an arbitrary angle between the correlated directions. In a model allosteric system, the second PDZ domain (PDZ2) in the human PTP1E protein, approximately one third of the strong correlations have near perpendicular directions, which are underestimated in the conventional method. The discrimination becomes more prominent for residue pairs with larger separation. The results of the proposed SVD method are more consistent with the experimentally determined PDZ2 dynamics than those of conventional method. In addition, the SVD method improved the prediction accuracy of the allosteric sites in a dataset of 23 known allosteric monomer proteins. The proposed method may inspire extended investigation not only into allostery, but also into protein dynamics and drug design. PMID- 30019779 TI - Correlation between attention-deficit/hyperactivity disorder, its pharmacotherapy and thyroid dysfunction: A nationwide population-based study in Taiwan. AB - OBJECTIVE: The aim of this study was to examine the comorbid rates of thyroid dysfunction among patients with attention-deficit/hyperactivity disorder (ADHD) and the general population. We further examined whether pharmacotherapy affects ADHD patients' risk of developing thyroid dysfunction. DESIGN AND MEASUREMENT: We recruited 75 247 newly diagnosed ADHD patient and 75 247 healthy controls between January 1999 and December 2011 from the National Health Insurance database in Taiwan. We compared hyperthyroidism, hypothyroidism and other common paediatric psychiatric diseases between ADHD patients and controls. We carried out logistic regression analysis to identify an independent factor for predicting thyroid dysfunction. Furthermore, we analysed the time sequence of the diagnosis and the risk of developing a thyroid disorder after receiving pharmacotherapy. RESULTS: Compared to the control group, the ADHD group had higher comorbidity rates of both hyperthyroidism (1.1% of ADHD vs 0.7% of controls, aOR: 1.72, P < 0.001) and hypothyroidism (0.6% of ADHD vs 0.2% of controls, aOR: 2.23, P < 0.001). Of the ADHD patients with comorbid thyroid dysfunction, about two-thirds and half of patients were diagnosed with ADHD prior to their diagnosis of hyperthyroidism and hypothyroidism, respectively. Furthermore, pharmacotherapy had no significant influence on the risk of developing hyperthyroidism (aHR: 1.09, P = 0.363) or hypothyroidism (aHR: 0.95, P = 0.719) among ADHD patients. CONCLUSION: Patients with ADHD had greater comorbid rates with thyroid dysfunction than the control subjects, but pharmacotherapy for treating ADHD did not affect thyroid dysfunction later in life. However, these findings should be further verified using a clinical cohort with comprehensive laboratory assessment in future. PMID- 30019780 TI - Survey of disease awareness, treatment behavior and treatment satisfaction in patients with atopic dermatitis in Korea: A multicenter study. AB - In Korea, there is a high dependency on oriental medicine and folk remedies (Korean J Asthma Allergy Clin Immunol, 25, 2005, 110). In addition, inaccurate information available through the Internet is increasing (Korean J Dermatol, 44, 2006, 137). So, there is always a possibility that patients may have difficulty obtaining accurate information about atopic dermatitis (AD). The aim was to determine the awareness, treatment behavior and treatment satisfaction of patients with AD and their caregivers. In October 2017, patients diagnosed with AD at nine hospitals were enrolled in this study. A questionnaire was completed by each patient. A total of 371 subjects were surveyed. In response to the question asking about knowledge of AD, the correct answer rate was 55.4%. Bathing using soap, body scrub and moisturizer showed favorable outcomes. A total of 54.9% patients responded that they were reluctant to use steroid ointment. When asked about their previous treatment, 39.6% reported using oriental medicine and 26.5% had tried folk remedies. The hospital treatment satisfaction score was 6.6. Patients usually applied their knowledge in their daily lives. However, there was a lot of inaccurate knowledge. Therefore, it is important for patients to understand the characteristics of this disease and obtain correct information. PMID- 30019781 TI - Bridge-Caging Strategy in Phosphorus-Substituted Rhodamine for Modular Development of Near-Infrared Fluorescent Probes. AB - Replacement of the bridging oxygen atom in rhodamine with phosphorus is one of the most efficient ways for bright near-infrared (NIR) fluorophores with wavelengths over 700 nm. However, the organophosphorus bridge is more versatile than just being a spectrum tuner, it is also a profound solubility booster and photostability enhancer, as proved by a series of phosphorus-substituted rhodamines (PRBs). A unique bridge-caging strategy for efficiently manipulating fluorescence has further been innovated in example PRB2. Consistent with theoretical calculations, the formation of organophosphinate by a caging group as a fluorescence-controller locks the spirolactone into a colorless and nonfluorescent form, whereas decaging, a process induced by a specific stimulus, results in a ring-opened form, which yields strong fluorescence. The bridge caging strategy is feasible for the modular development of NIR probes. Efficient in vivo imaging of photoillumination, hydrogen peroxide, and enzyme have been achieved on the PRB2 scaffold as a photoactivatable fluorophore, PRB2-hnu; fluorescent indicator, PRB2-H2 O2 ; and fluorogenic enzyme substrate, PRB2-NTR, respectively. PMID- 30019782 TI - Extremely Long Lived Localized Singlet Diradicals in a Macrocyclic Structure: A Case Study on the Stretch Effect. AB - Localized singlet diradicals have attracted much attention, not only in the field of bond-homolysis chemistry, but also in nonlinear optical materials. In this study, an extremely long lived localized singlet diradical was obtained by using a new molecular design strategy in which it is kinetically stabilized by means of a macrocycle that increases the molecular strain of the corresponding sigma bonded compound. Notably, the lifetime of this diradical (14 MUs) is two orders of magnitude longer than that of a standard singlet diradical without a macrocyclic structure (~0.2 MUs) at 293 K. The species is persistent below a temperature of 100 K. In addition to the kinetic stabilization of the singlet diradical, the spontaneous oxidation of its corresponding ring-closed compound at 298 K produced oxygenated products under atmospheric conditions. Apparently, the "stretch effect" induced by the macrocyclic structure plays a crucial role in extending the lifetime of localized singlet diradicals and increasing the reactivity of their corresponding sigma-bonded compounds. PMID- 30019783 TI - Investigating the Low Temperature Formation of CuII -(N,O) Species on Cu-CHA Zeolites for the Selective Catalytic Reduction of NOx. AB - In this work, we show the potentiality of operando FTIR spectroscopy to follow the formation of CuII -(N,O) species on Cu exchanged chabazite zeolites (Cu-CHA), active for the selective catalytic reduction of NOx with NH3 (NH3 -SCR). In particular, we investigated the reaction of NO and O2 at low temperature (200 and 50 degrees C) on a series of Cu-CHA zeolites with different composition (Si/Al and Cu/Al ratios), to investigate the nature of the formed copper nitrates, which have been proposed to be key intermediates in the oxidation part of the SCR cycle. Our results show that chelating bidentate nitrates are the main structures formed at 200 degrees C. At lower temperature a mixture of chelating and monodentate nitrates are formed, together with the nitrosonium ion NO+ , whose amount was found to be proportional to the zeolite Bronsted site concentration. Nitrates were found to mainly form with CuII ions stabilized by one negative framework charge (Z), Z-[Cu(OH]I or Z-[Cu(O2 ]I , without involvement of Z2 -CuII ones. This evidence, together with the absence of bridging nitrates in samples with high probability for Cu-Cu pairs, indicate that the nitrate ligands are not able to mobilize copper ions, at variance with what recently reported for NH3 . Finally, water was found to replace preformed chelating copper nitrates and deplete NO+ (though with different kinetics) at both temperatures, while favouring the presence of monodentate ones. PMID- 30019784 TI - "Extracellular matrix remodelling in the liver of rats subjected to dietary choline deprivation and/or thioacetamide administration". AB - Choline deprivation is a recognized experimental approach to nonalcoholic steatohepatitis, while thioacetamide (TAA)-induced liver fibrosis resembles alcoholic liver fibrogenesis. In order to elucidate the effect of TAA on liver extracellular matrix composition under choline deprivation due to choline deficient diet (CDD) administration, we evaluated the transcriptional and immunohistochemical (IHC) pattern of major hepatic matrix metalloproteinases (namely, MMP-2, -9) and their tissue inhibitors (TIMP-1, -2) in adult male albino Wistar rats at 30, 60 and 90 days. In the CDD+TAA group, IHC showed an early progressive increase in MMP-2 expression, while MMP-9 initially exhibited a significant increase followed by a gradual decrease; TIMP-1 and TIMP-2 IHC expressions showed gradual increase throughout the experiment. The MMPs-TIMPs regulation at the transcriptional level was found to be increased in all groups throughout the experiment. The increased MMP-2/TIMP-2 and suppressed MMP-9/TIMP-1 ratios in IHC and in real-time polymerase chain reaction (RT-PCR) seemed to correlate with the degree of liver fibrosis. These results support the important role of MMPs and TIMPs in controlling the hepatic pathogenesis and shed more light on the recently described experimental approach to liver disease (steatohepatitis) under the impact of two insults (TAA and CDD). PMID- 30019785 TI - Australian community pharmacist experiences with smoking cessation and opinions of health warnings on individual cigarette sticks. AB - OBJECTIVES: We aimed to identify the experiences of Australian community pharmacists with smokers and their associated perceptions of effective health warnings on individual cigarette sticks. METHODS: A mixed-methods online survey was distributed to Australian pharmacists through pharmacy-specific social media pages, and the Pharmaceutical Society of Australia, followed by semi-structured face-to-face interviews with pharmacists in Townsville, Australia, who were purposively sampled. The interviews continued until data saturation was achieved. Participants described their experiences with smokers, perceptions and effectiveness ratings of current cigarette packaging warnings, and 12 text warnings (divided into four themes) on individual cigarette sticks, and their general opinions on effective anti-tobacco health warnings. KEY FINDINGS: Seventy pharmacists participated in the survey and 17 pharmacists in the interviews. Both groups of pharmacists cited smoking-related personal or close-contact illness, pressure by family members or physicians and the financial costs of smoking as being the main drivers for quit attempts. Most interviewed pharmacists interact with smokers several times per week. Cigarette stick warnings describing mortality consequences (especially the 'minutes of life lost' warning) and the financial consequences of tobacco use were rated as significantly more effective than current packaging warnings (odds ratio [OR] = 2.23; 95% confidence interval [CI]: 1.12-4.12, P = 0.02, and 1.97; 95%CI: 1.01-3.84, P = 0.04, respectively). CONCLUSIONS: Pharmacists have considerable experience assisting smokers with quitting and based on these experiences believe that novel and tangible health warnings on cigarette sticks may be an effective future measure to combat tobacco use. Further research on the opinions of a more diverse range of health professionals and the general community will generate more robust findings regarding this method of intervention. PMID- 30019786 TI - A Novel Top-Down Synthesis of Ultrathin 2D Boron Nanosheets for Multimodal Imaging-Guided Cancer Therapy. AB - Single atom nonmetal 2D nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) are prepared through a novel top-down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform is developed, which exhibits multiple promising features for cancer therapy and imaging, including: i) efficient NIR-light-to-heat conversion with a high photothermal conversion efficiency of 42.5%, ii) high drug-loading capacity and triggered drug release by NIR light and moderate acidic pH, iii) strong accumulation at tumor sites, iv) multimodal imaging properties (photoacoustic, photothermal, and fluorescence imaging), and v) complete tumor ablation and excellent biocompatibility. As far as it is known, this is the first report on the top-down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multimodal imaging-guided drug delivery platform. The newly prepared B NSs are also expected to provide a robust and useful 2D nanoplatform for various biomedical applications. PMID- 30019787 TI - Resonance-Enhanced Absorption in Hollow Nanoshell Spheres with Omnidirectional Detection and High Responsivity and Speed. AB - Optical resonance formed inside a nanocavity resonator can trap light within the active region and hence enhance light absorption, effectively boosting device or material performance in applications of solar cells, photodetectors (PDs), and photocatalysts. Complementing conventional circular and spherical structures, a new type of multishelled spherical resonant strategy is presented. Due to the resonance-enhanced absorption by multiple convex shells, ZnO nanoshell PDs show improved optoelectronic performance and omnidirectional detection of light at different incidence angles and polarization. In addition, the response and recovery speeds of these devices are improved (0.8 and 0.7 ms, respectively) up to three orders of magnitude faster than in previous reports because of the existence of junction barriers between the nanoshells. The general design principles behind these hollow ZnO nanoshells pave a new way to improve the performance of sophisticated nanophotonic devices. PMID- 30019788 TI - Iron Vacancies Induced Bifunctionality in Ultrathin Feroxyhyte Nanosheets for Overall Water Splitting. AB - Exploring of new catalyst activation principle holds a key to unlock catalytic powers of cheap and earth-abundant materials for large-scale applications. In this regard, the vacancy defects have been proven to be effective to initiate catalytic active sites and endow high electrocatalytic activities. However, such electrocatalytically active defects reported to date have been mostly formed by anion vacancies. Herein, it is demonstrated for the first time that iron cation vacancies induce superb water splitting bifunctionality in alkaline media. A simple wet-chemistry method is developed to grow ultrathin feroxyhyte (delta FeOOH) nanosheets with rich Fe vacancies on Ni foam substrate. The theoretical and experimental results confirm that, in contrast to anion vacancies, the formation of rich second neighboring Fe to Fe vacancies in delta-FeOOH nanosheets can create catalytic active centers for both hydrogen and oxygen evolution reactions. The atomic level insight into the new catalyst activation principle based on metal vacancies is adaptable for developing other transition metal electrocatalysts, including Fe-based ones. PMID- 30019789 TI - Health professionals' dealing with hope in palliative patients with cancer, an explorative qualitative research. AB - Hope is important for individuals with cancer in palliative care. Health professionals' perspective on hope affects the communication with palliative patients. The aim of this study was to explore how Dutch health professionals deal with palliative patients with cancer who hope for prolongation of life. Focus group discussions (FGD) were conducted. An interpretive description approach was used to understand the interpretation of and reaction to hopefulness in palliative patients with cancer by health professionals. Three FGDs were held, each consisting of five to ten health professionals working with palliative patients recruited in a general Dutch hospital and homecare organisation. The ways in which the participating health professionals interpret hope in palliative individuals with cancer and their behaviour towards these hopeful palliative patients are shaped by their reliance on their own normative ideas. Patients' hopefulness generally violates these norms and is, therefore, considered a problem that requires intervention. Hope that does not correspond with the medical facts is experienced as problematic by Dutch health professionals who therefore believe they should intervene and do something about it. Health professionals are challenged to face and address patients' and families' perceptions of hope, especially when those perceptions might differ from their own as professionals. PMID- 30019790 TI - Amateur endurance athletes' use of non-steroidal anti-inflammatory drugs: a cross sectional survey. AB - OBJECTIVE: To explore amateur endurance athletes' use and views about non steroidal anti-inflammatory drugs (NSAIDs). METHODS: An online cross-sectional survey of amateur athletes at four athletic clubs. KEY FINDINGS: Of a sample of 129 of amateur athletes, 68% (n = 88) reported using NSAIDs in the previous 12 months (84.4% in triathletes, 70.9% in runners and 52.5% in cyclists). Overall, ibuprofen was the most popular drug (n = 48). There was a lack of knowledge of adverse drug reactions, with only 26% of use advised by a doctor or pharmacist. CONCLUSIONS: There is high usage of NSAIDs in amateur athletes, including before and during events, largely without professional health advice. Informational needs of amateur athletes are not being met. PMID- 30019791 TI - Diminishing Kidney Reserve and the "Pseudo"normal Creatinine. PMID- 30019792 TI - The impact of a reduction in fluoride concentration in the Malaysian water supply on the prevalence of fluorosis and dental caries. AB - OBJECTIVE: To assess the prevalence and severity of dental fluorosis and caries among Malaysian children following the reduction in fluoride concentration from 0.7 to 0.5 parts per million (ppm) in the public water supply. METHODS: This study involved lifelong residents aged 9- and 12-year-olds in fluoridated and nonfluoridated areas in Malaysia (n = 1155). In the fluoridated area, children aged 12 years and 9 years were exposed to 0.7 and 0.5 ppm, respectively, at the times when maxillary central incisors developed. Standardized photographs of maxillary central incisors were blind scored for fluorosis using Dean's criteria. Dental caries was examined using ICDAS-II criteria. RESULTS: The prevalence of fluorosis (Dean's score >= 2) among children in the fluoridated area (35.7%, 95% CI: 31.9%-39.6%) was significantly higher (P < 0.001) than children in the nonfluoridated area (5.5%, 95% CI: 3.6%-7.4%). Of those in the fluoridated area, the prevalence of fluorosis decreased from 38.4% (95% CI: 33.1%-44.3%) for 12 year-olds to 31.9% (95% CI: 27.6%-38.2%) for 9-year-olds, although this difference was not statistically significant (P = 0.139). The mean caries experience in the permanent dentition was significantly lower in the fluoridated area than in the nonfluoridated area for both age groups (P < 0.05). In the multivariate models, the difference in the differences of caries experience between fluoridated and nonfluoridated areas remained statistically significant. This suggests that caries-preventive effect is still maintained at 0.5 ppm. CONCLUSION: Findings indicate that the change in fluoride level from 0.7 to 0.5 ppm has reduced fluorosis and maintains a caries-preventive effect. Although there is a reduction in fluorosis prevalence, the difference was not statistically significant. PMID- 30019793 TI - Referring Hospital Characteristics Associated With Potentially Avoidable Emergency Department Transfers. AB - OBJECTIVE: Many emergency department (ED) transfers of children may be avoidable. Identifying hospital-level variables associated with avoidable transfers may guide system-level interventions to improve pediatric emergency care. We sought to examine hospital characteristics associated with ED transfers deemed "probably avoidable" in a large state Medicaid program. METHODS: We performed a retrospective cohort study using 2009 to 2013 claims data for Pennsylvania Medicaid beneficiaries. We categorized all ED transfers of children < 17 years old as "probably avoidable," "possibly avoidable", or "unavoidable" based on ultimate disposition and procedures (including subspecialty consultations) at the receiving ED. Using descriptive statistics and multivariable regression, we examined hospital characteristics associated with probably avoidable transfers. RESULTS: Among 2,839,379 pediatric visits to EDs across 158 Pennsylvania hospitals, 20,304 resulted in transfer. Among these, 3,764 (18.5%) were categorized as probably avoidable and 6,091 (30.0%) as possibly avoidable transfers. In adjusted analysis, compared to hospitals with no pediatric-specific capabilities, probably avoidable transfers were less likely from referring hospitals with pediatric-specific EDs and no other pediatric-specific capabilities (adjusted odds ratio [aOR] = 0.38, 95% confidence interval [CI] = 0.21-0.71) and from referring hospitals with pediatric-specific EDs and inpatient capabilities (aOR = 0.36, 95% CI = 0.20-0.64). Probably avoidable transfers were more likely from referring hospitals in large metropolitan areas (aOR = 2.64, 95% CI = 1.46-4.80) compared to those in rural areas. CONCLUSIONS: Among pediatric emergency transfers in a large state Medicaid program with a nearly 20% probably avoidable transfer rate, there was significant hospital-level variation in the proportion of probably avoidable transfers. Transfers from hospitals in large metropolitan areas and transfers from hospitals without pediatric-specific capabilities had increased odds of being probably avoidable transfers, such that these hospitals may represent targets for interventions to reduce these transfers. PMID- 30019794 TI - Neurocognitive assessment of children with neurodevelopmental disorders: Preliminary findings. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention and hyperactivity/impulsivity, and is often treated pharmacologically. It is necessary to use both subjective and objective assessments to diagnose and determine the efficacy of pharmacological treatment in children with ADHD, but cognitive assessment tools for ADHD are scarce. We examined a computer-administered, brief, and repeatable cognitive assessment tool: CogHealth. The aims of this study were to use the CogHealth battery, an objective assessment tool, to compare cognitive function between children with ADHD or ADHD + autism spectrum disorder (ASD) and healthy children and to assess improvements in cognitive function following pharmacological treatment. METHODS: We measured the cognitive function of nine children with ADHD or ADHD + ASD using CogHealth and compared the results with those of 33 age-matched children from the community. Cognitive function comparisons were made before and after psychostimulant treatment with methylphenidate. RESULTS: We detected significant cognitive abnormalities in the children with ADHD, compared with the control subjects. The children with pre-treatment ADHD had significantly more errors on the detection task (DT), and more anticipatory errors in the one card learning task, compared with control children. The children with ADHD significantly improved their accuracy on the one back test (OBT), and had significantly fewer errors, anticipatory errors, and shorter reaction times after osmotic-release oral system methylphenidate treatment. CONCLUSION: The DT is a useful neurocognitive function assessment for children with ADHD, and the OBT can measure pharmacological treatment effectiveness in children with ADHD. PMID- 30019795 TI - Priorities to Overcome Barriers Impacting Data Science Application in Emergency Care Research. AB - For a variety of reasons including cheap computing, widespread adoption of electronic medical records, digitalization of imaging and biosignals, and rapid development of novel technologies, the amount of health care data being collected, recorded, and stored is increasing at an exponential rate. Yet despite these advances, methods for the valid, efficient, and ethical utilization of these data remain underdeveloped. Emergency care research, in particular, poses several unique challenges in this rapidly evolving field. A group of content experts was recently convened to identify research priorities related to barriers to the application of data science to emergency care research. These recommendations included: 1) developing methods for cross-platform identification and linkage of patients; 2) creating central, deidentified, open-access databases; 3) improving methodologies for visualization and analysis of intensively sampled data; 4) developing methods to identify and standardize electronic medical record data quality; 5) improving and utilizing natural language processing; 6) developing and utilizing syndrome or complaint-based based taxonomies of disease; 7) developing practical and ethical framework to leverage electronic systems for controlled trials; 8) exploring technologies to help enable clinical trials in the emergency setting; and 9) training emergency care clinicians in data science and data scientists in emergency care medicine. The background, rationale, and conclusions of these recommendations are included in the present article. PMID- 30019796 TI - Sodium Acetate, Sodium Acid Pyrophosphate, and Citric Acid Impacts on Isolated Peripheral Lymphocyte Viability, Proliferation, and DNA Damage. AB - The present study examined the impacts of sodium acetate (SA), sodium acid pyrophosphate (SAPP), and citric acid (CA) on the viability, proliferation, and DNA damage of isolated lymphocytes in vitro. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays were adopted to evaluate cell viability, while comet assay was employed to assess the genotoxic effects. The cells were incubated with different levels of SA (50, 100, and 200 mM), SAPP (25, 50, and 100 mM/L), or CA (100, 200, and 300 MUg/mL). The lymphocytes treated with the tested food additives showed concentration dependent decreases in both cell viability and proliferation. A concentration dependent increase in LDH release was also observed. The comet assay results indicated that SA, SAPP, and CA increased DNA damage percentage, tail DNA percentage, tail length, and tail moment in a concentration-dependent manner. The current results showed that SA, SAPP, and CA are cytotoxic and genotoxic to isolated lymphocytes in vitro. PMID- 30019797 TI - Unidirectional barbed suture for vaginal cuff closure without backward stitch in total laparoscopic hysterectomy. AB - AIM: To evaluate the safety and efficacy of unidirectional barbed suture technique for vaginal cuff closure in total laparoscopic hysterectomy (TLH). METHODS: In a retrospective chart review, data were analyzed from 165 patients who underwent a TLH with an unidirectional barbed suture technique for vaginal cuff closure from January 2012 to June 2016 at tertiary-care university-based teaching hospital and academic affiliated hospital. Vaginal cuff was closed by single layer 3/0 V-Loc unidirectional 9", 180 day Absorbable Wound Closure Device (Covidien Healthcare, Mansfield, MA) and the suture was not stitched backward to secure distal end. RESULTS: A total of 165 patients were included and the median age was 50 years (range, 35-84 years). The median completion time for hysterectomy time was 100 min (range, 40-240 min) and the median vaginal cuff closure time was 7 min (range, 4-15 min). The median estimated blood loss was 87.8 mL (range 30-250 mL) and the median uterine weight was 200 g (range, 40-900 g). Intraoperative complication included bladder perforation (1.2%) and postoperative complications were vaginal cuff dehiscence (1.8%), cuff cellulitis (0.6%), vesicovaginal fistula (0.6%) and unexplained fever (0.6%). CONCLUSION: According to the results of current study, the use of unidirectional barbed suture without backward stitching appears to be safe for the vaginal cuff closure in TLH. PMID- 30019798 TI - Perceptions of nurses working with psychiatric consumers regarding the elimination of seclusion and restraint in psychiatric inpatient settings and emergency departments: An Australian survey. AB - Seclusion and restraint continue to be used across psychiatric inpatient and emergency settings, despite calls for elimination and demonstrated efficacy of reduction initiatives. This study investigated nurses' perceptions regarding reducing and eliminating the use of these containment methods with psychiatric consumers. Nurses (n = 512) across Australia completed an online survey examining their views on the possibility of elimination of seclusion, physical restraint, and mechanical restraint as well as perceptions of these practices and factors influencing their use. Nurses reported working in units where physical restraint, seclusion, and, to a lesser extent, mechanical restraint were used. These were viewed as necessary last resort methods to maintain staff and consumer safety, and nurses tended to disagree that containment methods could be eliminated from practice. Seclusion was considered significantly more favourably than mechanical restraint with the elimination of mechanical restraint seen as more of a possibility than seclusion or physical restraint. Respondents accepted that use of these methods was deleterious to relationships with consumers. They also felt that containment use was a function of a lack of resources. Factors perceived to reduce the likelihood of seclusion/restraint included empathy and rapport between staff and consumers and utilizing trauma-informed care principles. Nurses were faced with threatening situations and felt only moderately safe at work, but believed they were able to use their clinical skills to maintain safety. The study suggests that initiatives at multiple levels are needed to help nurses to maintain safety and move towards realizing directives to reduce and, where possible, eliminate restraint use. PMID- 30019799 TI - Low serum folate status in the second trimester increase the risk of low birthweight in Chinese women. AB - AIM: This study aimed to explore the influence of maternal folate and vitamin B12 (B12) status during pregnancy on the incidence of low birthweight (LBW) infants. METHODS: A total of 6203 eligible women registered in seven hospitals in southern China, and 230 cases with singleton live births and 382 controls were matched for further analyses. The concentrations of serum folate and B12 were detected with chemiluminescence microparticle immunoassay on ARCHITECT i2000-1. Conditional logistic regression was used to evaluate the effects of folate and B12 levels on LBW. RESULTS: Maternal serum folate levels increased basically with increasing the period of folic acid supplementation (P trend <0.001). Moreover, maternal serum folate and B12 levels gradually decreased with the increase of gestational age (P < 0.001). Conditional logistic regressions analysis results showed increased odds ratios (OR) for LBW from the fourth to first folate quartiles (P trend <0.01) in the second trimester. Compared with the women in the highest quartile, those in the lowest quartile of serum folate in the second trimester were found with higher risk of LBW (adjusted OR = 1.67, 95% confidence interval [CI]: 1.02-2.73). However, no significant association was observed between serum folate and LBW in the first trimester or third trimester. In addition, serum B12 exhibited no significant association with LBW. CONCLUSIONS: Low serum folate levels in the second trimester significantly increases the risk of LBW amongst Chinese women with singleton pregnancies. PMID- 30019800 TI - cPCET versus HAT: A Direct Theoretical Method for Distinguishing X-H Bond Activation Mechanisms. AB - Proton-coupled electron transfer (PCET) events play a key role in countless chemical transformations, but they come in many physical variants which are hard to distinguish experimentally. While present theoretical approaches to treat these events are mostly based on physical rate coefficient models of various complexity, it is now argued that it is both feasible and fruitful to directly analyze the electronic N-electron wavefunctions of these processes along their intrinsic reaction coordinate (IRC). In particular, for model systems of lipoxygenase and the high-valent oxoiron(IV) intermediate TauD-J it is shown that by invoking the intrinsic bond orbital (IBO) representation of the wavefunction, the common boundary cases of hydrogen atom transfer (HAT) and concerted PCET (cPCET) can be directly and unambiguously distinguished in a straightforward manner. PMID- 30019802 TI - Injury-based Geographic Access to Trauma Centers. AB - OBJECTIVE: Previous studies examining access to trauma care use patient residence as a proxy for location and need for services, which could result in a flawed understanding of access to trauma centers. The objective of this study was to examine the geographic access of the U.S. population to trauma centers based on trauma incident locations. METHODS: We conducted a cross-sectional study using 9 1-1 emergency medical services activations associated with traumatic injury from the 2014 National Emergency Medical Services Information System and trauma centers participating in the 2014 American Hospital Association Annual Survey. The measures included the percentage of trauma incidents that could reach a trauma center within 60 minutes by ground ambulance, capacity-to-demand ratio for each trauma center, and overall trauma care accessibility ratio for each U.S. zip code. RESULTS: A total of 92.9% of all trauma incidents could be transported to an existing trauma center within 60 minutes by ground ambulance, and 85.3% could be transported to a Level I or II trauma center within this time frame in the 32 study states. While 94.7% of trauma incidents in the Northeast area could be transported to a Level I or II trauma center within a 60-minute driving time, the capacity-to-demand ratios of trauma centers in this region were low, indicating high utilization of those trauma center resources. By using the accessibility measure, we found that some Midwestern and Southern states had higher amounts of accessible trauma center resources relative to the number of injuries than Northeastern states. CONCLUSIONS: These findings suggest that greater access to trauma care and significant variations can be observed throughout the 32 study states when using trauma incident location rather than patient residence to calculate access to trauma care. The proposed capacity-to-demand ratio and accessibility ratio can be applied to many other needs assessments in health care. PMID- 30019801 TI - Potential risk factors associated with prognosis of neoadjuvant chemotherapy followed by interval debulking surgery in stage IIIc-IV high-grade serous ovarian carcinoma patients. AB - AIM: No consensus has been achieved on the prognostic factors for patients with advanced stage epithelial ovarian cancer who underwent neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). This study aimed to investigate the prognostic factors for the patients diagnosed as International Federation of Gynecology and Obstetrics stage IIIc-IV high-grade serous ovarian cancer (HG-SOC). METHODS: A total of 200 patients histologically diagnosed as IIIc-IV stage HG-SOC were retrospectively analyzed. All patients underwent platinum-NAC followed by IDS treatment between January 2003 and December 2013. The potential predictive factors (including preoperative ascites volume, cancer antigen 125 [CA-125] and CA-125 decreasing kinetics, NAC and adjuvant chemotherapy cycle number as well as tumor characteristics) for optimal cytoreduction by IDS and for progression free survival (PFS) and overall survival (OS) were assessed. RESULTS: Optimal cytoreduction by IDS was achieved in 78% of HG-SOC patients who underwent NAC. The median number of NAC cycle was 3 (range 1 8). No ascites regression (P < 0.01, odds ratio [OR] = 2.28, 95% confidence interval [CI]: 1.41-3.69), and worse CA-125 decreasing kinetics (P < 0.01, OR = 2.01, 95% CI: 1.37-2.93) were independent predictive factors for suboptimal cytoreduction by IDS. Multivariate regression analysis revealed that PFS and OS were independently associated with preoperative ascites (P < 0.01, hazard ratio [HR] = 2.13, 95% CI: 1.38-3.28 and P < 0.01, HR = 2.33, 95% CI: 1.27-4.26, respectively) and CA-125 decreasing kinetics (P = 0.01, HR = 1.10, 95% CI: 1.02 1.18 and P < 0.01, HR = 1.22, 95% CI: 1.08-1.37, respectively). PFS of patients who underwent more than four NAC cycles was shorter than those of patients who received four or less number of NAC cycles; however, no difference was observed for OS. CONCLUSION: Ascites regression and CA-125 decreasing kinetics were independently associated with the optimal cytoreduction rate and survival of patients diagnosed with advanced stage HG-SOC and treated with NAC/IDS. PMID- 30019803 TI - Torsion of normal-sized ovary during late pregnancy: A case report and review of the literature. AB - Adnexal torsion is one of the most common gynecologic surgical emergencies. All age groups can be affected, but torsion of normal-sized ovary that happens during late pregnancy is rare and challenging to be diagnosed. The objective of this article is to present a case of adnexal torsion in a normal-sized ovary suspected by magnetic resonance imaging (MRI) in the third trimester of pregnancy. A 36 year-old woman at 32 + 5 weeks gestational age was admitted to hospital due to recurrent severe left lower abdominal pain. Doppler ultrasound failed to demonstrate the ovarian diseases, while MRI scan suspected the diagnosis of adnexal torsion. The patient received emergent exploratory laparotomy, and the left adnexa with a necrotic ovary was removed. Tocolytic therapy was used before and after surgery. Finally, she delivered a healthy full-term infant via cesarean section. Adnexal torsion occurring in a normal-sized ovary was quite rare in the third trimester pregnancy. MRI might be better than ultrasound in the early diagnosis of ovarian torsion. PMID- 30019804 TI - Blood Group O->A Transformation by Chemical Ligation of Erythrocytes. AB - Agglutination of red blood cells (RBCs) remains the only practical method for routine use for ABH typing in clinical practice. However, exact mechanistic details of agglutination are not yet thoroughly studied. In this research, RBCs of blood group O were converted to blood group A through two approaches: by chemical ligation of the cells' glycocalyx with synthetic blood group A tetrasaccharide, and by insertion of synthetic glycolipid carrying the same A antigen into the cells' membranes. The O->A ligated RBCs and natural A RBCs showed comparable agglutination characteristics with antibodies. As expected, RBCs with inserted glycolipid showed lower agglutination scores. This approach could help cell biologists in site-specific and cell-friendly modification of glycocalyx by other ligands. PMID- 30019805 TI - Relationship between sarcopenia and depression in older patients with diabetes: An investigation using the Japanese version of SARC-F. AB - AIM: The purpose of the present study was to investigate the relationship between sarcopenia and depression in older patients with diabetes using the Japanese version of SARC-F. METHODS: Participants included patients with diabetes aged >=65 years who were undergoing outpatient treatment at the Ise Red Cross Hospital, Ise, Japan. Depression was measured using the Japanese version of the Patient Health Questionnaire 9, which is a nine-item questionnaire. Sarcopenia was assessed using the Japanese version of SARC-F, a self-administered questionnaire comprising five question items. Multiple logistic regression analysis with depression as the dependent variable and sarcopenia as the explanatory variable was used to calculate the odds ratio for depression in patients with sarcopenia. RESULTS: A total of 275 patients (167 men, 108 women) were the study participants. The adjusted odds ratio for depression in male patients with sarcopenia was 5.76 (95% CI 1.83-18.12, P = 0.003). The adjusted odds ratio for depression in female patients with sarcopenia was 2.62 (95% CI 0.68-10.05, P = 0.159). CONCLUSIONS: A statistically significant relationship was shown between sarcopenia and depression in older male patients with diabetes. We believe that drawing the attention of physicians to sarcopenia prevalence by using the Japanese version of SARC-F will contribute to the detection of depression in older male patients with diabetes. Geriatr Gerontol Int 2018; 18: 1318-1322. PMID- 30019806 TI - A Practical and General Amidation Method from Isocyanates Enabled by Flow Technology. AB - The addition of carbon nucleophiles to isocyanates represents a conceptually flexible and efficient approach to the preparation of amides. This general synthetic strategy has, however, been relatively underutilized owing to narrow substrate tolerance and the requirement for less favourable reaction conditions. Herein, we disclose a high-yielding, mass-efficient, and scalable method with appreciable functional group tolerance for the formation of amides by reaction of Grignard reagents with isocyanates. Through the application of flow chemistry and the use of substoichiometric amounts of CuBr2 , this process has been developed to encompass a broad range of substrates, including reactants found to be incompatible with previously published procedures. PMID- 30019807 TI - Simultaneous CRISPR/Cas9-mediated editing of cassava eIF4E isoforms nCBP-1 and nCBP-2 reduces cassava brown streak disease symptom severity and incidence. AB - Cassava brown streak disease (CBSD) is a major constraint on cassava yields in East and Central Africa and threatens production in West Africa. CBSD is caused by two species of positive-sense RNA viruses belonging to the family Potyviridae, genus Ipomovirus: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Diseases caused by the family Potyviridae require the interaction of viral genome-linked protein (VPg) and host eukaryotic translation initiation factor 4E (eIF4E) isoforms. Cassava encodes five eIF4E proteins: eIF4E, eIF(iso)4E-1, eIF(iso)4E-2, novel cap-binding protein-1 (nCBP-1), and nCBP 2. Protein-protein interaction experiments consistently found that VPg proteins associate with cassava nCBPs. CRISPR/Cas9-mediated genome editing was employed to generate ncbp-1, ncbp-2, and ncbp-1/ncbp-2 mutants in cassava cultivar 60444. Challenge with CBSV showed that ncbp-1/ncbp-2 mutants displayed delayed and attenuated CBSD aerial symptoms, as well as reduced severity and incidence of storage root necrosis. Suppressed disease symptoms were correlated with reduced virus titre in storage roots relative to wild-type controls. Our results demonstrate the ability to modify multiple genes simultaneously in cassava to achieve tolerance to CBSD. Future studies will investigate the contribution of remaining eIF4E isoforms on CBSD and translate this knowledge into an optimized strategy for protecting cassava from disease. PMID- 30019808 TI - Total Synthesis of Keramamides A and L from a Common Precursor by Late-Stage Indole Synthesis and Configurational Revision. AB - The marine natural products keramamide A and L, members of the class of anabaenopeptin-type peptides, were synthesized for the first time by a convergent and flexible route. The installation of the substituted tryptophan moieties was accomplished at the very end of the synthesis on the cyclic peptides, and thus enabled the synthesis of both natural products from one common precursor. The preparation of several epimers clearly indicates that the originally proposed relative configurations of both Keramamides A and L were not correct. PMID- 30019809 TI - An Environmentally Friendly and Flexible Aqueous Zinc Battery Using an Organic Cathode. AB - Rechargeable batteries have been used to power various electric devices and store energy from renewables, but their toxic components (namely, electrode materials, electrolyte, and separator) generally cause serious environment issues when disused. Such toxicity characteristic makes them difficult to power future wearable electronic devices. Now an environmentally friendly and highly safe rechargeable battery, based on a pyrene-4,5,9,10-tetraone (PTO) cathode and zinc anode in mild aqueous electrolyte is presented. The PTO-cathode shows a high specific capacity (336 mAh g-1 ) for Zn2+ storage with fast kinetics and high reversibility. Thus, the PTO//Zn full cell exhibits a high energy density (186.7 Wh kg-1 ), supercapacitor-like power behavior and long-term lifespan (over 1000 cycles). Moreover, a belt-shaped PTO//Zn battery with robust mechanical durability and remarkable flexibility is first fabricated to clarify its potential application in wearable electronic devices. PMID- 30019810 TI - Tailored Cobalt-Catalysts for Reductive Alkylation of Anilines with Carboxylic Acids under Mild Conditions. AB - The first cobalt-catalyzed hydrogenative N-methylation and alkylation of amines with readily available carboxylic acid feedstocks as alkylating agents and H2 as ideal reductant is described. Combination of tailor-made triphos ligands with cobalt(II) tetrafluoroborate significantly improved the efficiency, thus promoting the reaction under milder conditions. This novel protocol allows for a broad substrate scope with good functional group tolerance, even in the presence of reducible alkenes, esters, and amides. PMID- 30019811 TI - The caring behaviours of Danish pharmaconomists: insight for pharmacy technician practice around the world. AB - OBJECTIVES: Pharmacy workforce support personnel are being accorded greater scopes of practice, especially Danish pharmaconomists [pharmacy technician, experts in pharmaceuticals with a 3-year degree]. The aims of this study were to assess pharmaconomists' caring behaviours and identify factors related to those behaviours. METHODS: A self-administered survey was distributed to a random sample of pharmaconomists in Denmark. The survey assessed caring behaviours using the Caring Behaviours Assessment and acquired data to ascertain their employers' culture, respondent's need for achievement, personality traits, commitment and work-related characteristics. Descriptive statistics provided insight into pharmacomomists' predispositions, and bivariate analyses were used to identify associations of pharmaconomists' caring with other variables under study. KEY FINDINGS: Over 300 pharmaconomists responded (52.2% response rate). Pharmaconomists reported generally high levels (well above the median on the 5 point scale) of caring behaviours. They reported higher levels (upper range of 5 point scale) of empathic behaviours, such as treating patients with respect and seeing things from the patient's point of view but somewhat lower levels of encouraging the patient to talk about how they feel and praising the patient's efforts, which could otherwise help patients cope with and improve their self efficacy for disease management. Pharmaconomist caring was associated with practice setting, organisational culture and commitment to their employer. CONCLUSIONS: Pharmaconomists reported performing behaviours that were empathic, but less frequently those associated with facilitating greater patient autonomy. Caring behaviours were associated with a number of variables related to practice setting. The findings can help to inform educational pedagogy and pharmacy personnel management. PMID- 30019812 TI - Readiness and recovery: Transferring between methadone and buprenorphine/naloxone for the treatment of opioid use disorder. AB - Long-acting opioids are prescribed as part of treatment for opioid use disorders; methadone and buprenorphine are well researched and commonly prescribed for the treatment of opioid use disorder. Meta-analysis suggests that buprenorphine has a slightly poorer retention rate in treatment as compared to methadone. Benefits of buprenorphine/naloxone include greater ease in ceasing treatment and less use of illicit opioids while in treatment as compared to methadone. There are a number of qualitative and mixed-method studies that ask patients about their experiences of methadone maintenance and buprenorphine maintenance treatment. This research aimed to understand perspectives of receiving buprenorphine/naloxone for the treatment of opioid use disorder. A qualitative descriptive approach was used. Seven participants with a current diagnosis of opioid use disorder treated with buprenorphine/naloxone were interviewed. Thematic analysis extracted four themes: drivers for opioid substitution treatment change; readiness for buprenorphine/naloxone substitution treatment; absence of effect from buprenorphine/naloxone; and an increased sense of citizenship on buprenorphine/naloxone. This study identified a number of factors influencing participants' decision-making in transferring between methadone and buprenorphine/naloxone for the treatment of their opioid use disorder. Methadone was preferred by those seeking sedation and wishing to continue using other opioids, and buprenorphine/naloxone was most effective for participants no longer wishing to experience sedation and seeing opioid abstinence as an end point in their recovery. Changing treatment expectations are important to consider when determining medication selection and highlight the importance of quality information when determining the most suitable medication for the treatment of opioid use disorder. PMID- 30019814 TI - Non-pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome: a Cochrane systematic review. AB - OBJECTIVES: To assess the effects of non-pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). PATIENTS AND METHODS: We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was August 2017. We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available non pharmacological interventions. Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. The primary outcomes were prostatitis symptoms and adverse events. The secondary outcomes were sexual dysfunction, urinary symptoms, quality of life, anxiety and depression. RESULTS: We included 38 unique studies with 3290 men with CP/CPPS across 23 comparisons, reporting outcomes mostly on short-term follow-up. Acupuncture probably leads to clinically meaningful reduction in prostatitis symptoms compared with sham procedure (mean difference (MD) in total NIH-CPSI score -5.79, 95% confidence interval (CI) -7.32 to -4.26, moderate QoE). Acupuncture may result in little to no difference in adverse events (low QoE). Acupuncture may also lead to a clinically meaningful reduction in prostatitis symptoms compared with standard medical therapy (MD -6.05, 95% CI -7.87 to -4.24, two studies, 78 participants, low QoE). Lifestyle modifications may be associated with a reduction in prostatitis symptoms compared with control (risk ratio (RR) for improvement in NIH-CPSI scores 3.90, 95% CI 2.20 to 6.92, very low QoE). We found no information regarding adverse events. A physical activity programme may cause a small reduction in prostatitis symptoms compared with control (NIH-CPSI score MD -2.50, 95% CI -4.69 to -0.31, low QoE). We found no information regarding adverse events. We are uncertain whether the prostatic massage reduces or increases prostatitis symptoms compared with control (very low QoE). We found no information regarding adverse events. Extracorporeal shockwave therapy reduces prostatitis symptoms compared with control (NIH-CPSI score MD -6.18, 95% CI -7.46 to -4.89, high QoE). These results may not be sustained at medium-term follow-up (low QoE). This treatment may not be associated with a greater incidence of adverse events (low QoE). Transrectal thermotherapy alone or in combination with medical therapy may decrease prostatitis symptoms slightly when compared with medical therapy alone (NIH-CPSI score MD -2.50, 95% CI -3.82 to -1.18, low QoE). One included study reported that participants may experience transient adverse events. CONCLUSIONS: Based on the findings of moderate to high-quality evidence, this review found that some non-pharmacological interventions such as acupuncture and extracorporeal shockwave therapy are likely to result in a decrease in prostatitis symptoms and may not be associated with a greater incidence of adverse event. The QoE for most other comparisons was predominantly low. Future clinical trials should include a full report of their methods including adequate masking, consistent assessment of all patient-important outcomes including potential treatment-related adverse events and appropriate sample sizes. This article is protected by copyright. All rights reserved. PMID- 30019815 TI - Cellular Microbiology Interview - Dr Jessica Quintin. PMID- 30019813 TI - Association between exposure to antiretroviral drugs and the incidence of hypertension in HIV-positive persons: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. AB - OBJECTIVES: Previous studies have suggested that hypertension in HIV-positive individuals is associated primarily with traditional risk factors such as older age, diabetes and dyslipidaemia. However, controversy remains as to whether exposure to antiretroviral (ARV) drugs poses additional risk, and we investigated this question in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort. METHODS: The incidence of hypertension [systolic blood pressure (BP) > 140 and/or diastolic BP > 90 mmHg and/or initiation of antihypertensive treatment] was determined overall and in strata defined by demographic, metabolic and HIV-related factors, including cumulative exposure to each individual ARV drug. Predictors of hypertension were identified using uni- and multivariable Poisson regression models. RESULTS: Of 33 278 included persons, 7636 (22.9%) developed hypertension over 223 149 person-years (PY) [incidence rate: 3.42 (95% confidence interval (CI) 3.35-3.50) per 100 PY]. In univariable analyses, cumulative exposure to most ARV drugs was associated with an increased risk of hypertension. After adjustment for demographic, metabolic and HIV-related factors, only associations for nevirapine [rate ratio 1.07 (95% CI: 1.04-1.13) per 5 years] and indinavir/ritonavir [rate ratio 1.12 (95% CI: 1.04-1.20) per 5 years] remained statistically significant, although effects were small. The strongest independent predictors of hypertension were male gender, older age, black African ethnicity, diabetes, dyslipidaemia, use of lipid-lowering drugs, high body mass index (BMI), renal impairment and a low CD4 count. CONCLUSIONS: We did not find evidence for any strong independent association between exposure to any of the individual ARV drugs and the risk of hypertension. Findings provide reassurance that screening policies and preventative measures for hypertension in HIV-positive persons should follow algorithms used for the general population. PMID- 30019816 TI - Loneliness and Adolescents' Neural Processing of Self, Friends, and Teachers: Consequences for the School Self-Concept. AB - The present interdisciplinary study explored whether perceived loneliness is associated with ventromedial prefrontal cortex (vMPFC) activation during self- and social judgments (friends and teachers) in adolescents. Moreover, we examined how vMPFC activity is related to the academic self-concept (ASC). Results of manifest path analysis indicated that high perceived loneliness was related to lower neural response to self-judgments. In turn, high neural response to self judgments was positively associated with the ASC, whereas there was a trendwise negative association between high neural response to teacher-related judgments and ASC. This study reveals associations between perceived loneliness and neural processing of the self, underlining the idea that feeling isolated from others may hinder self-insight and, by extension, the formation of a stable academic self-concept. PMID- 30019817 TI - Impella-assisted chronic total occlusion percutaneous coronary interventions: A multicenter retrospective analysis. AB - INTRODUCTION: Patients with coronary chronic total occlusions (CTO) often have concurrent higher-risk anatomy and physiology (significant calcium, left ventricular dysfunction, multivessel disease) that increase their procedural risk. We present a retrospective multicenter case series describing use of the Impella percutaneous ventricular assist device (p-VAD) during CTO PCI. METHODS: We performed a retrospective analysis of self-reported data from five large referral centers from 2013 to 2017 and identified patients that underwent elective, hemodynamically supported CTO PCI with the Impella p-VAD device (2.5 or CP). Preprocedural demographics, procedural invasive hemodynamics and characteristics, and in-hospital outcomes were reported. RESULTS: About 57 patients (2% of the overall CTO volume of these centers) were included in this retrospective cohort. The primary indication in the majority (78.9%) of cases was chronic angina; in 21.1% the primary indication was for chronic congestive heart failure because of an ischemic cardiomyopathy. The median LVEF was 20% (15%, 30%) and 63.2% were surgical turndowns. Significant proportions of the group underwent multivessel PCI (91.2%), intervention on an unprotected left main or last remaining conduit vessel (35.1%), and/or atherectomy (17.5%). Technical success was 87.7%. In-hospital procedural complications included: vascular injury (5.3%), all-cause death (5.3%), major bleeding (3.5%), stroke (1.8%), and coronary perforation resulting in tamponade (1.8%). CONCLUSION: Impella-assisted CTO PCI can be performed with high technical success rates. However, assiduous attention to appropriate case selection is critical, given the periprocedural complication rates reported in this patient population. PMID- 30019818 TI - Broken arrow: Successful retrieval of a dislodged coronary orbital atherectomy microtip. AB - A 68-year-old female with a history of coronary artery disease and prior bypass surgery presented for staged percutaneous coronary intervention (PCI) to a calcified and angulated ostial left circumflex (LCX) artery lesion after PCI of the anastomosis of the left internal mammary artery - to left anterior descending artery. Orbital atherectomy of the LCX was performed at a speed of 80,000 RPM with multiple passes, and was complicated by device microtip dislodgement and entrapment within the vessel. After advancing a "buddy" wire beyond the microtip, a tapered microcatheter was advanced over the ViperWire and into the edge of the broken microtip and torqued into the microtip with forward pressure using the 0.014 in ViperWire tip as a "backstop." The guidewire, microcatheter, and microtip were then successfully removed as a unit and the intervention with stent placement was completed over the "buddy" wire. Scanning electron microscopy of the shaft revealed evidence of cyclic fatigue, indicating that the fracture occurred while spinning. The fracture when performing atherectomy in a model coronary artery with a radius of approximately 6 mm. This represents a first case of microtip dislodgement and entrapment during the use of a coronary orbital atherctomy device.short. PMID- 30019819 TI - Comparison of devices used in carotid artery stenting: A vascular quality initiative analysis of commonly used carotid stents and embolic protection devices. AB - BACKGROUND: Data regarding efficacy of various stent and embolic protection device (EPD) combinations to prevent stroke during carotid artery stenting (CAS) is limited. We compared post-procedure inpatient neurologic outcomes across various carotid stent-EPD platforms recorded in the Vascular Quality Initiative (VQI) registry. METHODS: We analyzed 13,786 consecutive CAS procedures in the VQI registry performed between January 1, 2005 and December 31, 2015. The most commonly used stent-EPD combinations (n = 5407) were included in the analysis. Post-procedure inpatient neurologic outcomes included (1) ipsilateral stroke/transient ischemic attack (TIA) and (2) any stroke/TIA. Multivariate generalized estimating equation regression analysis was performed, adjusting for age, sex, tobacco use, coronary artery disease, congestive heart failure, prior stroke/TIA, hypertension, history of carotid revascularization, and presence of a second ipsilateral stenosis >70%, to determine whether risk of outcomes differed according to device. RESULTS: Of 13,786 CAS procedures, Xact-Emboshield (n = 2,438, 17.6%), Precise-Angioguard (n = 1,480, 10.7%), Acculink-Accunet (n = 829, 6.01%), and Acculink-Emboshield (n = 660, 4.8%) were the most commonly used combinations, accounting for a total of 5,407 procedures. Inpatient event rates for ipsilateral stroke/TIA and any stroke/TIA were 1.9 and 2.7% in the Accunet Acculink, 3.0 and 3.2% in Acculink-Emboshield, 3.2 and 4.1% in Precise-Angioguard and 2.2 and 3.0% in Xact-Emboshield. There was no evidence of difference in risk of ipsilateral stroke/TIA or any stroke/TIA across device combinations (P = 0.15 and P = 0.16, respectively). CONCLUSION: CAS with current carotid stent-EPD combinations is associated with low rates of inpatient stroke/TIA. There is no statistically significant difference in rates of inpatient stroke/TIA across device combinations. PMID- 30019820 TI - Long-term outcomes and predictors of morbi-mortality according to age in stemi patients with multivessel disease: Impact of an incomplete revascularization. AB - BACKGROUND: Optimal management strategy for patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD) still remains unclear, especially in the elderly population. The aim of this study was to assess long-term outcomes and predictors of morbi-mortality according to age in patients with a STEMI and MVD. METHODS: We prospectively included 381 consecutive patients with a STEMI who underwent primary angioplasty and showed MVD in the angiogram. 111 (29.1%) patients were older than 75 (>=75) years and 270 (70.9%) were younger than 75 (<75) years. The co-primary outcomes were the incidence of all-cause mortality and major adverse cardiac events (MACE) during follow-up. RESULTS: During a median follow-up of 22 months, patients >=75 years showed a higher incidence of all-cause mortality and MACE, as compared to younger patients. On multivariate analysis, incomplete revascularization (IR) was only an independent predictor of MACE (HR = 3.1, CI 95%:1.9-4.7; P = .02) in younger patients; whereas in the elderly group severely depressed ejection fraction was the unique independent predictor of MACE (HR = 2.7, CI 95%:1.5-4.8; P = .001). IR was not associated with the risk of all-cause mortality in any group. CONCLUSION: This study confirms the relevant prevalence of MVD in STEMI patients, as well as the difference in outcomes of an IR strategy between both age-groups, being only independently associated with MACE in younger patients. This finding supports that a routine complete revascularization (CR) strategy seems to be the best therapeutic option in younguer patients, whereas in the elderly population may not confer a clear clinical benefit during a long-term follow-up. PMID- 30019821 TI - Embolization of a complex coronary to pulmonary artery fistula using balloon assisted liquid embolic injection: A novel technique. AB - Complex Coronary artery to Pulmonary artery fistulas (CPFs) can be difficult to manage with embolization or ligation. An 88-year-old woman with exertional angina was found to have a complex precordial CPF, severe Mitral regurgitation, and Pulmonary Hypertension. CPF treatment was recommended prior to minimally invasive mitral valve replacement (to avoid postoperative myocardial ischemia from worsened steal). The CPF was supplied by multiple branches from the LAD and RCA, and formed a complex common varicosity with multiple drainage channels to the pulmonary artery. The CPF was treated by injecting a liquid embolic agent, Ethylene Vinyl Alcohol Copolymer (Onyx, Medtronic, MN), into two of the feeding arteries arising from the RCA through a Scepter C Dual lumen balloon micro catheter (Microvention, Aliso Viejo, CA. This resulted in complete obliteration of the fistula, and the patient subsequently underwent successful mitral valve replacement surgery. PMID- 30019822 TI - Is two better than one? Re-evaluating the surgical approval process for TAVR. PMID- 30019823 TI - Early collapse causing stenosis in a resorbable magnesium scaffold. AB - We report a case of early in-stent restenosis due to collapse of a Magmaris resorbable magnesium scaffold. PMID- 30019824 TI - Real clinical experiences of dual versus triple antithrombotic therapy after percutaneous coronary intervention. AB - OBJECTIVES: We aimed to assess the impact of omitting aspirin on clinical outcomes in a real-world collective of patients receiving oral anticoagulation (OAC) therapy who were treated with a current-generation drug-eluting stent (DES) or an everolimus-eluting bioresorbable vascular scaffold (BVS). BACKGROUND: Limited data are available regarding the clinical benefit of triple antithrombotic therapy (TAT) with aspirin compared with dual antithrombotic therapy (DAT) without aspirin in patients undergoing percutaneous coronary intervention (PCI) and requiring OAC. METHODS: In total, 237 patients were analyzed. The primary outcome was a composite of major adverse cardiac and cerebrovascular events (MACCE) within 1 year after PCI. Secondary outcomes were the individual components of the primary endpoint, cardiovascular death, and any bleeding according to Bleeding Academic Research Consortium (BARC) or Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: Eighty-nine patients (37.6%) received DAT, and 148 (62.4%) received TAT. The rate of MACCE was significantly higher in DAT patients than in TAT patients (16 (18%) vs. 11 (7.4%); hazard ratio [HR] 2.73, 95% confidence interval [CI] 1.24-6.03; P = 0.01). The results of the multivariable Cox proportional hazards model including corrections for imbalances in baseline characteristics confirmed a significant independent association between DAT and MACCE (HRadj 3.14, 95% CI 1.31-7.54; P = 0.01). Major bleeding did not differ significantly between treatment groups. CONCLUSION: DAT was associated with a significantly higher rate of MACCE than TAT after DES or BVS implantation. Further studies are required to evaluate the safety and efficacy of dual versus TAT after PCI in clinical practice. PMID- 30019825 TI - The interplay between permanent pacemaker implantation and mortality in patients treated by transcatheter aortic valve implantation: A systematic review and meta analysis. AB - BACKGROUND: Previous implantation of a permanent pacemaker (PPM) is common among patients undergoing transcatheter aortic valve implantation (TAVI). Moreover, onset of conduction disturbances needing new PPM implantation after TAVI is frequent. The interplay of pre-existing and new-PPM on mortality after TAVI remains controversial. METHODS: We performed a systematic review and study-level meta-analysis on the influence of PPM on mortality after TAVI. Patients were divided into 3 groups: pre-existing PPM, new-PPM (implantation within 30 days after TAVI) and no-PPM (without PPM up to 30 days after TAVI). Outcomes were compared using pairwise and network meta-analysis. RESULTS: A total of 28 studies including 40,016 subjects were eligible. Patients of the no-PPM group had a lower mortality outcome compared to the rest of the study population (relative risk [RR] 0.76, 95% confidence interval [CI] 0.68-0.85, P < 0.0001) at median follow up of 16.3 months. In particular, patients with a pre-existing PPM (RR 1.43, 95% CI 1.26-1.62, P < 0.0001), but not those with a newly implanted PPM (RR 1.08, 95% CI 0.99-1.18, P = 0.10), had a significantly higher mortality compared to patients of the no-PPM group. Moreover, meta-regression analysis showed that the transapical approach rate had a detrimental interaction with pre-existing PPM on mortality (P = 0.03). CONCLUSION: Compared to patients without PPM, those with a pre-existing PPM before TAVI had higher mortality, in particular if treated by the transapical approach. New-PPM implantation did not have a negative relation on mid-term outcome. PMID- 30019826 TI - Metallic Cobalt-Carbon Composite as Recyclable and Robust Magnetic Photocatalyst for Efficient CO2 Reduction. AB - CO2 conversion into value-added chemical fuels driven by solar energy is an intriguing approach to address the current and future demand of energy supply. Currently, most reported surface-sensitized heterogeneous photocatalysts present poor activity and selectivity under visible light irradiation. Here, photosensitized porous metallic and magnetic 1200 Co?C composites (PMMCoCC-1200) are coupled with a [Ru(bpy)3 ]Cl2 photosensitizer to efficiently reduce CO2 under visible-light irradiation in a selective and sustainable way. As a result, the CO production reaches a high yield of 1258.30 uL with selectivity of 64.21% in 6 h, superior to most reported heterogeneous photocatalysts. Systematic investigation demonstrates that the central metal cobalt is the active site for activating the adsorbed CO2 molecules and the surficial graphite carbon coating on cobalt metal is crucial for transferring the electrons from the triplet metal-to-ligand charge transfer of the photosensitizer Ru(bpy)32+ , which gives rise to significant enhancement for CO2 reduction efficiency. The fast electron injection from the excited Ru(bpy)32+ to PMMCoCC-1200 and the slow backward charge recombination result in a long-lived, charge-separated state for CO2 reduction. More impressively, the long-time stability and easy magnetic recycling ability of this metallic photocatalyst offer more benefits to the photocatalytic field. PMID- 30019827 TI - Comparison of short-term clinical outcomes of proximal versus nonproximal lesion location in patients treated with primary percutaneous coronary intervention for ST-elevation myocardial infarction: The PROXIMITI study. AB - OBJECTIVES: The objective of this study was to investigate the association of proximal and nonproximal location of culprit coronary lesions with clinical outcomes of patients presenting with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI). BACKGROUND: Proximal culprit lesion location in patients presenting with STEMI is associated with increased mortality when compared to distal culprit lesions in the thrombolytic era. The impact of lesion location on clinical outcomes in the era of PCI remains unclear. METHODS: We analyzed 3,283 patients with STEMI who enrolled in the Victorian Cardiac Outcomes Registry. We compared outcomes in those with proximal lesion location versus patients with nonproximal location. RESULTS: Of 3,283 participants, 1,376 (41.9%) had a proximal lesion location. Patients with proximal lesion location presented with greater rates of cardiogenic shock and out-of-hospital cardiac arrest, and left ventricular systolic dysfunction, all P < .01. Procedural success rates were similar (96% vs. 95%, P = .08). Patients with proximal lesion location had higher rates of in-hospital and 30-day mortality, major adverse cardiac events (MACE; mortality, myocardial infarction, stent thrombosis, and unplanned revascularization) and major adverse cardiac and cerebrovascular events (MACCE; MACE, and stroke) compared to the nonproximal group, all P < .001. However, on multivariable regression analysis, proximal lesion location was not independently associated with MACE during in-hospital stay or at 30-days (OR 1.32, 95% CI 0.95-1.83, P = .09 and OR 1.23, 95% CI 0.92 1.65, P = .15) respectively. CONCLUSIONS: Patients with proximal lesion location had greater hemodynamic instability and higher-risk features; however, proximal lesions per se were not independently associated with worse clinical outcomes compared to nonproximal lesions. PMID- 30019828 TI - Slope of left ventricular filling as an index of valvular and paravalvular regurgitation in native and prosthetic aortic valves. AB - BACKGROUND: Precise quantification of paravalvular aortic regurgitation (PAR) is challenging. Aortic regurgitation index (AR index) has been validated in transcatheter aortic valve replacement (TAVR) cohorts; however, accuracy is limited by heart rate dependency. Diastolic pressure time (DPT) index has been suggested as an alternative and also predicts mortality after TAVR. We chose to evaluate the left ventricular diastolic filling slope (LVDFS) as a surrogate of AR, and suggest it is less heart rate dependent than the AR index and comparable to DPT index. METHODS: For initial validation, we compared the LVDFS between three cohorts of patients with native aortic valves referred for hemodynamic assessment: (1) Patients without AR; (2) moderate AR; and (3) severe AR. We then retrospectively identified TAVR patients between January 2012 and 2017, and compared LVDFS to echocardiographic PAR. RESULTS: In both TAVR patients and those patients with native aortic valve disease, the LVDFS showed a stepwise increase with increasing echocardiographic AR severity. When compared to AR or DPT indices, LVDFS better discriminated the degree of AR in native valves and post TAVR when AR is primarily paravalvular. Additionally, the slope did not considerably change across a spectrum of heart rates in both native and post-TAVR populations. CONCLUSIONS: The LVDFS is a simple, reproducible metric that can be operationalized in patients undergoing TAVR, as well as those with native valve regurgitation. Additional studies are necessary to determine the relationship between LVDFS and post-TAVR outcomes. PMID- 30019829 TI - Assessment of vertical ridge augmentation and labial prominence using buccal versus palatal approaches for maxillary segmental sandwich osteotomy (inlay technique): A randomized clinical trial. AB - BACKGROUND: The aim of this study was to evaluate the final vertical gain at the deficient anterior maxillary alveolar ridges using buccal versus palatal approaches for maxillary segmental sandwich osteotomy (inlay technique). This is a single-institutional randomized comparative clinical trial. MATERIAL AND METHODS: The study population was 16 patients with edentulous anterior maxillary alveolar ridges (40 implant sites). Patients were randomly divided into two equal groups. Both groups received sandwich osteotomy with down fracture of the deficient anterior maxillary alveolar ridge, using buccal approach (control group) and palatal approach (study group) with interpositional alloplastic bone blocks fixed with miniplates. Assessment included the mean percentage of vertical gain at the proposed implant sites after 4 months, taken from cross-sectional cuts of a cone beam computed tomography. RESULTS: All cases showed uneventful wound healing and a total of 40 delayed implant placement were done. Results showed that there was no statistical significance between the 2 groups in terms of bone height (P = .43) and labial prominence (P = .5) CONCLUSION: Both techniques were successful where the mean percentage of 4 months postoperative vertical bone gain of the control group was 79.9% and that of the study group was 76.5%. PMID- 30019830 TI - Microcatheter knuckle technique: A novel technique for negotiating the subintimal space during chronic total occlusion recanalization. AB - OBJECTIVES: To establish if novel microcatheter knuckle technique (MKT) is feasible and efficacious in negotiating the subintimal space in difficult lesions during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: CTOs remain one of the most challenging lesion subsets in PCI. Guidewire manipulation and advancement of equipment within the subintimal space is sometimes challenging and aggressive manipulation in the subintimal space is feared, because of concern of vessel disruption and perforation. Here we introduce the MKT, for negotiating the subintimal space during challenging CTO PCI. METHODS: MKT is performed by creating a wire knuckle with polymer-jacketed guidewire and positioned in the subintimal space. Subsequently, a tapered-tip, kink-resistant microcatheter is advanced towards the knuckled tip of guidewire and the guidewire is simultaneously withdrawn; creating a knuckle-shaped microcatheter tip. The MKT was considered in CTO PCIs that involved subintimal techniques where resistance to guidewire knuckle advancement was encountered. Procedures were performed between March 2013 and June 2017 at our institution. RESULTS: During the study period, a total of 440 CTO PCIs were performed, from which seven were treated with MKT. MKT was successful in six patients and technical success was achieved in all seven patients. The MKT was successfully performed with both the antegrade and retrograde approach. CONCLUSION: We present a novel technique for negotiating the subintimal space in CTO PCI for cases where significant resistance is experienced restricting guidewire or material advancement in antegrade or retrograde dissection. The MKT appears to be efficacious complementing the CTO operator's armamentarium. PMID- 30019831 TI - Impact and trends of intravascular imaging in diagnostic coronary angiography and percutaneous coronary intervention in inpatients in the United States. AB - BACKGROUND: Intravascular imaging with intravascular ultrasound (IVUS) and optical coherence tomography (OCT) is an important adjunct to invasive coronary angiography. OBJECTIVES: The primary objective was to examine the frequency of intravascular coronary imaging, trends in imaging use, and outcomes of patients undergoing angiography and/or percutaneous coronary intervention (PCI) in the United States. METHODS: Adult patients >=18 years of age undergoing in-hospital cardiac catheterization from January 2004 to December 2014 were identified from the National Inpatient Sample (NIS). International Classification of Diseases, Ninth Revision (ICD-9) diagnosis and procedure codes were used to identify IVUS and OCT use during diagnostic angiography and PCI. RESULTS: Among 3,211,872 hospitalizations with coronary angiography, intracoronary imaging was performed in 88,775 cases (4.8% of PCI and 1.0% of diagnostic procedures), with IVUS in 98.9% and OCT in 1.1% of cases. Among patients undergoing PCI, the rate of intravascular coronary imaging increased from 2.1% in 2004-2005 to 6.6% in 2013 2014 (P < 0.001 for trend). Use of intravascular coronary imaging was associated with lower in-hospital mortality in patients undergoing PCI (adjusted OR 0.77; 95% CI 0.71-0.83). There was marked variability in intravascular imaging by hospital, with 63% and 13% of facilities using intravascular imaging in <5% and >15% of PCIs, respectively. CONCLUSIONS: In a large administrative database from the United States, intravascular imaging use was low, increased over time, and imaging was associated with reduced in-hospital mortality. Substantial variation in the frequency of intravascular imaging by hospital was observed. Additional investigation to determine clinical benefits of IVUS and OCT are warranted. PMID- 30019832 TI - Dramatic secular changes in prognosis for kidney transplant candidates in the United States. AB - Over recent decades, numerous clinical advances and policy changes have affected outcomes for candidates of kidney transplantation in the United States. We examined the national Scientific Registry for Transplant Recipients for adult (18+) solitary kidney transplant candidates placed on the waiting list for primary listing from 2001 to 2015. We evaluated rates of mortality, transplantation, and waitlist removal. Among 340 115 candidates there were significant declines in mortality (52 deaths/1000 patient years in 2001-04 vs 38 deaths/1000 patient years in 2012-15) and transplant rates (304 transplants/1000 patient years in 2001-04 vs 212 transplants/1000 patient years in 2012-15) and increases in waitlist removals (15 removals/1000 patient years in 2001-04 vs 25/1000 patient years in 2012-15) within the first year after listing. At 5 years an estimated 37% of candidates listed in 2012-15 were alive without transplant as compared to 22% in 2001-04. Declines in mortality over time were significantly more pronounced among African Americans, candidates with longer dialysis duration, and those with diabetes (P < .001). Cumulatively, results indicate dramatic changes in prognoses for adult kidney transplant candidates, likely impacted by selection criteria, donor availability, regulatory oversight, and clinical care. These trends are important considerations for prospective policy development and research, clinical and patient decision-making, and evaluating the impact on access to care. PMID- 30019833 TI - Initial clinical experience with the FlexPoint Steerable Transseptal Needle in left-sided structural heart procedures. AB - OBJECTIVES: The purpose of this study is to describe the initial clinical experience with a steerable transseptal needle (STSN) for left-sided structural heart procedures. BACKGROUND: Targeted transseptal (TS) puncture is required for many structural heart procedures, and the use of a steerable needle has not previously been described. METHODS: Consecutive patients undergoing structural heart interventions with targeted TS puncture under transesophageal echocardiographic (TEE) and fluoroscopic guidance were studied. The STSN was used in all patients with a standard commercial TS sheath. Deflection of the needle was performed "real time" to achieve localization of the TS puncture site. RESULTS: Twenty-seven patients underwent STSN puncture of the interatrial septum. In all cases, the needle could be deflected in vivo to achieve optimal tenting and localization of the puncture site without having to remove or reshape the needle. The needle was deflected to match a wide range of right atrial diameters (width 4.3 +/- 0.9 cm and length 6.0 +/- 0.9 cm in the 4-chamber view). In two patients with prior mitral valve surgery and a fibrotic septum, assisted crossing was achieved using the piercing stylet in one patient, and Bovie energy in the other. There were no procedural complications, and all patients had successful completion of the intended structural heart procedure. CONCLUSIONS: The STSN needle can be used to target the intended puncture location on the interatrial septum with real-time adjustable deflection without the need to remove and reshape the needle. In all cases crossing was successful and there were no complications. PMID- 30019834 TI - Long-term outcomes of transmesenteric portal vein recanalization for the treatment of chronic portal vein thrombosis after pediatric liver transplantation. AB - Portal vein thrombosis (PVT) may occur at any time following liver transplantation. We describe our experience with portal vein recanalization in cases of thrombosis after liver transplantation. Twenty-eight children (5%) out of 566 liver transplant recipients underwent portal vein recanalization using a transmesenteric approach. All children received left hepatic segments, developed PVT, and had symptoms or signs of portal hypertension. Portal vein recanalization was performed via the transmesenteric route in all cases. Twenty-two (78.6%) patients underwent successful recanalization and stent placement. They received oral anticoagulants after the procedure, and clinical symptoms subsided. Symptoms recurred due to portal vein restenosis/thrombosis in seven patients. On an intention-to-treat basis, the success rate of the proposed treatment was 60.7%. Only 17 out of 28 children with posttransplant chronic PVT retained stent patency (primary + assisted) at the end of the study period. In cases of portal vein obstruction, the transmesenteric approach via minilaparotomy is technically feasible with good clinical and hemodynamic results. It is an alternative procedure to reestablish the portal flow to the liver graft that can be performed in selected cases and a therapeutic addition to other treatment strategies currently used to treat chronic PVT. PMID- 30019835 TI - Hepatic encephalopathy impacts the predictive value of the Fried Frailty Index. AB - Frailty is increasingly recognized as a predictor of poor outcomes in solid organ transplantation. The most widely utilized frailty tool, the Fried Frailty Index (FFI), includes patient-reported exhaustion, weight loss, and physical activity as well as measured walk speed and handgrip. Although hepatic encephalopathy (HE) is common among liver transplant candidates, data are lacking regarding its impact on the interpretation of frailty. We prospectively enrolled 685 patients with cirrhosis during their transplant evaluation, following them until death or transplantation. Our cohort was aged 54.5 +/- 10.3 years, 60% male, with an average MELD score of 14.7 +/- 6.3. A history of HE was present in 39%. Frailty was present in 41%, associated with higher MELD, low albumin, ascites, and HE. HE was associated with frail performance on three components of the FFI-grip (odds ratio 1.41 95% CI, 1.03-1.92), walk speed (1.56 95% CI, 1.14-2.15), and decreased energy (1.44 95% CI, 1.05-1.99). These three components were associated with transplant free survival in the whole cohort: energy (hazard ratio 1.67 95% CI, 1.25-2.28), grip (1.63 95% CI, 1.24-2.16), and walk speed (1.56 95% CI, 1.19 2.04). However, among patients with HE, the FFI was not associated with survival. HE plays a critical role in the frailty phenotype and the implications of frailty among patients with cirrhosis evaluated for liver transplantation. PMID- 30019836 TI - Transradial versus tibiopedal access approach for endovascular intervention of superficial femoral artery chronic total occlusion. AB - BACKGROUND: Improved equipment and techniques have resulted in transition from surgical bypass to endovascular intervention to treat superficial femoral artery (SFA) chronic total occlusions (CTO). A change in access site to radial (TRA) or tibiopedal (TPA) artery for the treatment of these SFA CTO has been reported. The feasibility, efficacy and safety of these two access sites for treatment of SFA CTO have not been reported. METHODS: We performed an as treated analysis of 184 SFA CTO interventions in 161 patients from 01/2014 to 09/2016 using either primary TRA or TPA (operator discretion) at two institutions. Primary end point was 30 day major adverse event (MAE) - death, amputation or target vessel revascularization, secondary endpoint was success of procedure. RESULTS: Primary TRA was used in 46 patients with 47 CTO lesions .Primary TPA was used in 115 patients with 137 CTO lesions. Primary crossing success rate was higher with TRA compared to TPA (74% vs 54%, P = 0.01). Dual TRA-TPA was required in 72 prior uncrossed lesions resulting in a crossing and procedural success of 99% and 96% respectively. The overall crossing and procedural success rate using either of these approaches was 99% and 98% respectively. The 30 day MAE was 5% in TRA arm, 0% in TPA arm and 2% in dual TRA-TPA arm, P = 0.08. All access sites were patent, confirmed by ultrasound. CONCLUSION: The treatment of SFA CTO is feasible and safe using both TRA or TPA approach providing high success rates and no access site complications. PMID- 30019837 TI - Stressful living in lower-quality habitats? Body mass, feeding behaviour and physiological stress levels in wild wood mouse populations. AB - Wild populations are continuously subjected to changes in environmental factors that pose different challenges. Body condition and hormones have been commonly used as health indicators due to their potential correlation with fitness. In the present study, we analyzed whether habitats of different quality, influenced body mass, food intake and physiological stress levels in wild wood mice (Apodemus sylvaticus). Field work was seasonally carried out in Holm oak woods and pine forests in central Spain. 93 wood mice from 4 different populations (2 per habitat type) were live-trapped. From each captured individual we noted body mass and food intake, measured as the amount of bait remaining in each trap. The physiological stress levels were measured non-invasively in collected fresh faeces by quantifying faecal corticosterone metabolites (FCM) with a 5alpha pregnane-3beta,11beta, 21-triol-20-one enzyme immunoassay. Wood mice abundances decreased from spring to summer, were higher in Holm oak woods than in pine forests and also resulted in different age-class distribution between both habitats. Individuals inhabiting pine forests showed a lower body mass and increased food intake probably because the comparatively lower food quality and availability in this habitat. Further, these individuals showed increased physiological stress levels, likely due to the lower quality habitat regarding both food and vegetation cover availability. Overall, besides affecting local wood mouse abundance, our study underscores the effect of habitat quality on body mass, food intake and the endocrine stress response. Considering wood mouse pivotal position in ecosystems, these results could help in the understanding of environmental traits hampering viability of wild populations. This article is protected by copyright. All rights reserved. PMID- 30019838 TI - Effects of FGF21-secreting adipose-derived stem cells in thioacetamide-induced hepatic fibrosis. AB - Mesenchymal stem cells (MSCs) have been investigated to treat liver diseases, but the efficiency of MSCs to treat chronic liver diseases is conflicting. FGF21 can reduce inflammation and fibrosis. We established FGF21-secreting adipose derived stem cells (FGF21_ADSCs) to enhance the effects of ADSCs and transplanted them into thioacetamide (TAA)-induced liver fibrosis mice via the tail vein. Transplantation of FGF21_ADSCs significantly improved liver fibrosis by decreasing serum hyaluronic acid and reducing the expression of fibrosis-related factors such as alpha-smooth muscle actin (alpha-SMA), collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) compared with the Empty_ADSCs by inhibition of p-JNK, NF-kappaB and p-Smad2/3 signalling. alpha-lactoalbumin (LA) and lactotransferrin (LTF), secretory factors produced from FGF21_ADSCs inhibited TGF-beta1-induced expression of alpha-SMA and collagen in LX-2 cells. These results suggest that transplantation of FGF21_ADSCs inhibited liver fibrosis more effectively than Empty_ADSCs, possibly via secretion of alpha-LA and LTF. PMID- 30019839 TI - Predicted magnitude of alternate access in the contemporary transcatheter aortic valve replacement era. AB - OBJECTIVES: We aimed to evaluate the true extent of alternate access in a contemporary cohort of transcatheter aortic valve replacement (TAVR) patients. BACKGROUND: Appropriate access selection for TAVR impacts clinical outcomes. Despite device miniaturization, some patients remain ineligible for transfemoral arterial access. METHODS: Five hundred seventy-five consecutive TAVR patients were classified according to iliofemoral artery diameters measured by computed tomography (<5.0 mm, 5.0-5.4 mm, 5.5-5.9 mm, or >=6 mm) and need for alternate access rate was estimated according to commercially available transcatheter heart valve Instructions For Use (IFU). RESULTS: Based on iliofemoral artery diameters alone, 11.5% of patients were predicted to require alternate access. After patient-level adjustment for the size of the planned THV and severe tortuosity or severe calcification, 14.9% and 20.8% of patients, respectively were predicted to require alternate access. Overall, 87.8% of patients underwent transfemoral TAVR and 12.3% underwent alternate access. There was no difference in the rate of major vascular complications and life threatening or major bleeding between groups, but transfusion rate was higher in smaller vessel groups. CONCLUSIONS: Despite device miniaturization, a substantial minority of contemporary TAVR patients still require alternate access. Most are eligible for newer extrathoracic approaches including transcaval, subclavian, and transcarotid that avoid the morbidity of transthoracic access. PMID- 30019840 TI - Pirfenidone in restrictive allograft syndrome after lung transplantation: A case series. AB - Pirfenidone may attenuate the decline of pulmonary function in restrictive allograft syndrome (RAS) after lung transplantation. We retrospectively assessed all lung transplant recipients with RAS who were treated with pirfenidone for at least 3 months (n = 11) in our lung transplant center and report on their long term outcomes following initiation of pirfenidone. Main outcome parameters included evolution of pulmonary function and overall survival. Pirfenidone appears to attenuate the decline in forced vital capacity and forced expiratory volume in 1 second. Notably, 3 patients were bridged to redo-transplantation with pirfenidone for 11 (5-12) months and are currently alive, while 3 other patients demonstrate long-term stabilization of pulmonary function after 26.6 (range 18.4 46.6) months of treatment. Median overall 3-year survival after RAS diagnosis was 54.5%. Subjective intolerance, mainly anorexia and nausea, necessitating pirfenidone dose de-escalation in 55% of patients, as well as calcineurin dose increase requirements with about 20% are important complications during pirfenidone treatment after lung transplantation. Our findings provide further evidence that pirfenidone appears to be safe and may attenuate the rate of decline in lung function in patients with RAS, but the actual clinical benefit cannot be assessed in the context of this study design and requires further investigation in a larger randomized trial. PMID- 30019842 TI - Antitumor activity of RT2 peptide derived from crocodile leukocyte peptide on human colon cancer xenografts in nude mice. AB - RT2, derived from the leukocyte peptide of Crocodylus siamensis, can kill human cervical cancer cells via apoptosis induction, but no evidence has shown in vivo. In this study, we investigated the antitumor effect of RT2 on human colon cancer xenografts in nude mice. Twenty-four mice were injected subcutaneously with human colon cancer HCT 116 cells. Eleven days after cancer cell implantation, the mice were treated with intratumoral injections of phosphate buffered saline (PBS) or RT2 (0.01, 0.1, and 1 mg/mouse) once every 2 days for a total of 5 times. The effect of a 10-day intratumoral injection of RT2 on body weight, biochemical, and hematological parameters in BALB/c mice showed no significant difference between the groups. Tumor volume showed a significant decrease only in the treatment group with RT2 (1 mg/mouse) at day 6 (P < .05), day 8 (P < .01), and day 10 (P < .01) after the first treatment. The protein expression levels of cleaved poly (ADP-ribose) polymerase (PARP), apoptosis-inducing factor (AIF), and the p53 tumor suppressor protein (p53) in xenograft tumors increased after treatment with RT2 (1 mg/mouse) compared to those in the PBS-injected group. Moreover, RT2 increased the expression of Endo G and Bcl-2 family proteins. Therefore, the peptide RT2 can inhibit tumor growth via the induction of apoptosis in an in vivo xenograft model. PMID- 30019841 TI - Integrative analysis of competing endogenous RNA networks reveals the functional lncRNAs in heart failure. AB - Heart failure has become one of the top causes of death worldwide. It is increasing evidence that lncRNAs play important roles in the pathology processes of multiple cardiovascular diseases. Additionally, lncRNAs can function as ceRNAs by sponging miRNAs to affect the expression level of mRNAs, implicating in numerous biological processes. However, the functional roles and regulatory mechanisms of lncRNAs in heart failure are still unclear. In our study, we constructed a heart failure-related lncRNA-mRNA network by integrating probe re annotation pipeline and miRNA-target interactions. Firstly, some lncRNAs that had the central topological features were found in the heart failure-related lncRNA mRNA network. Then, the lncRNA-associated functional modules were identified from the network, using bidirectional hierarchical clustering. Some lncRNAs that involved in modules were demonstrated to be enriched in many heart failure related pathways. To investigate the role of lncRNA-associated ceRNA crosstalks in certain disease or physiological status, we further identified the lncRNA associated dysregulated ceRNA interactions. And we also performed a random walk algorithm to identify more heart failure-related lncRNAs. All these lncRNAs were verified to show a strong diagnosis power for heart failure. These results will help us to understand the mechanism of lncRNAs in heart failure and provide novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets. PMID- 30019843 TI - Long-term outcomes after treatment of bare-metal stent restenosis with paclitaxel coated balloon catheters or everolimus-eluting stents: 3-year follow-up of the TIS clinical study. AB - BACKGROUND: The efficacy of paclitaxel-eluting balloon catheters (PEB) and drug eluting stents for treatment of bare-metal stent restenosis (BMS-ISR) have been demonstrated in several studies with follow-up times of 9 to 12 months; however, the long-term outcomes of ISR treatment are less defined. OBJECTIVES: We aimed to compare the long-term efficacy of PEB and everolimus-eluting stents (EES) for the treatment of BMS-ISR. METHODS: We analyzed 3-year clinical follow-up data from patients included in the TIS randomized clinical study. A total of 136 patients with BMS-ISR were allocated to receive treatment with either PEB or EES (68 patients with 74 ISR lesions per group). RESULTS: The PEB and EES groups did not significantly differ in major adverse cardiac events-free survival (MACE; P = .211; including individual events: CV death: P = .622; myocardial infarction: P = .650 or target vessel revascularization: P = .286) at 3-year clinical follow-up. No event-free survival differences were found between the groups regarding overall mortality (P = .818), definite stent thrombosis (P = .165) or the second MACE (P = .270). CONCLUSIONS: At the 3-year follow-up, no significant differences in clinical outcomes were found between iopromide-coated PEB and EES for the treatment of BMS-ISR. (ClinicalTrials.gov; https://clinicaltrials.gov; NCT01735825). PMID- 30019844 TI - A Modular Solder System with Hierarchical Morphology and Backward Compatibility. AB - A modular solder system with hierarchical morphology and micro/nanofeatures in which solder nanoparticles are distributed on the surface of template micropowders is reported. A core-shell structure of subsidiary nanostructures, which improved the intended properties of the modular solder is also presented. In addition, polymer additives can be used not only as an adhesive (like epoxy resin) but also to impart other functions. By combining all of these, it is determined that the modular solder system is able to increase reflowability on a heat-sensitive plastic substrate, oxidation resistance, and electrical conductivity. In this respect, the system could be readily modified by changing the structure and composition of each constituent and adopting backward compatibility with which the knowledge and information attained from a previously designed solder can offer feedback toward further improving the properties of a newly designed one. In practice, In-Sn-Bi nanoparticles engineered on the surface of Sn-Zn micropowders result in pronounced reflowing on a flexible Au-coated polyethylene terephthalate (PET) substrate even at the low temperature of 110 degrees C. Depending on their respective concentrations, the incorporation of CuO@CeO2 nanostructures and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) polymers increases oxidation resistance and electrical conductivity of the modular solder. PMID- 30019845 TI - Effects of insect-infestation on rodent-mediated dispersal of Quercus aliena: Results from field and enclosure experiments. AB - Rodents influence plant establishment and regeneration by functioning as both seed predators and dispersers. However, these rodent-plant interactions can vary significantly due to various environmental conditions and the activity of other insect seed-predators. Here, we use a combination of both field and enclosure (i.e, individual cage and semi-natural enclosure) experiments, to determine whether rodents can distinguish sound seeds from those infested with insects. We also demonstrate how such responses to insects are influenced by food abundance and other environmental factors. We presented rodents with two kinds of Quercus aliena seeds (sound and insect-infested seeds) in a subtropical forest in Qinling Mountains, central China, from September to November of 2011 to 2013. The result showed that rodents prefer to hoarded and ate sound seeds than infested seeds in the field and semi-natural enclosure, while they prefer to ate infested seeds than sound seeds in the individual cages. In addition, both hoarding and eating decisions were influenced by food abundance. Rodents hoarded more sound seeds in years of high food abundance while they consume more acorns in years of food shortage. Compared with field results, rodents reduced scatter hoarding behavior in semi-natural enclosures and ate more insect-infested seeds in smaller individual cages. These results further confirm that rodents distinguish infested seeds form non-infested seeds but demonstrate that this behavior varies with conditions (environment and food abundance). We suggest that such interactions will influence the dispersal and natural regeneration of seeds as well as predation rates on insect larvae. This article is protected by copyright. All rights reserved. PMID- 30019846 TI - Shrinkable Nanotubes for Duplex Formation of Short Nucleotides. AB - Molecular monolayer nanotubes produced by self-assembly of an amphiphile modified with a 2-nitrobenzyl group as a photoresponsive unit are able to encapsulate dinucleotides via electrostatic attraction. Upon photoirradiation, the 18 nm inner diameter of the nanotubes shrinks to less than 2 nm as a result of photochemical cleavage of the 2-nitrobenzyl group in the amphiphile. This shrinking of the nanotube channels leads to a propulsive release of the dinucleotides into the bulk solution and simultaneously accelerates formation of the dinucleotide duplexes. The larger nanotube channels without photoirradiation merely release each dinucleotide into the bulk solution, indicating that the squeezing via transportation in the narrow nanotube channels is necessary for duplex formation. In addition to the size effect, water with a lower polarity confined within the narrow nanotube channels helps to stabilize the energetically unfavorable hydrogen-bonded base pair between the dinucleotides. This system should enable researchers to perform biological reactions that occur only in specific environments and conditions in living organisms. PMID- 30019847 TI - A 3-year experience of a simple, novel technique for accurate ostial/non-ostial coronary stenting: The buddy balloon anchor stent technique. AB - OBJECTIVE: To evaluate the safety and efficacy of a new technique for accurate ostial/non-ostial coronary stenting in percutaneous coronary intervention (PCI). BACKGROUND: Accurate stent localization is a key factor impacting the postoperative success of patients undergoing PCI. However, the accurate localization of some lesions, especially ostial lesions, is very difficult to achieve, because they are often complicated by bobbing or to-and-fro movement of the stent during cardiac contractions. METHODS: We report a novel technique of precise ostial/non-ostial stenting based on the buddy balloon anchor stent (BBAS) technique. Between May 2014 and July 2017, 47 patients with significant ostial/non-ostial coronary stenosis that required accurate stenting were included in this study. Of them, 23 patients were treated using the conventional method and the remaining 24 patients were treated using (BBAS) technique. Evaluation was then performed using intravascular ultrasound (IVUS) in the procedural, or coronary computed tomography angiography (CCTA) in the follow up. RESULTS: Using the BBAS technique, the procedural success was achieved in all 24 (100%) cases. IVUS was performed in seven patients (29.17%) and no procedural complications occurred. All six failed cases that occurred among patients with right coronary artery and left anterior descending artery ostial stenosis treated using the conventional method, the lesions were subsequently successfully re-stented using the BBAS technique. After a follow-up of 3-36 months, CCTA was performed in 11 patients (45.83%), all the stents were in the accurate position. There were no major cardiovascular events of death, myocardial infarction, or target lesion revascularization. CONCLUSION: BBAS is a simple, highly successful and safe technique for accurate stenting of difficult ostial/nonostial coronary stenosis lesions. PMID- 30019848 TI - New RANZCR clinical radiology written report guidelines. AB - The Royal Australian and New Zealand College of Radiologists (RANZCR) Radiology Written Report Guideline was first issued in 2011. A survey-based consultation of clinical radiology members of the college in 2015 found that the vast majority of 235 respondents supported all components of the guideline. Since the original guideline was developed, considerable new research has been published about radiology reporting, particularly regarding structured/template reports. In 2016/17 a RANZCR working group used the consultation results, stakeholder feedback and recent research to develop revised guidelines. This article outlines the consultation survey results and guideline revision process as well as some of the supporting evidence from the literature. PMID- 30019849 TI - Food supplementation by an invasive fleshy-fruited shrub sustains body condition of a native frugivorous bird during winter. AB - Birds tend to adjust their behavior and physiology to changes in food availability in their environment. Seasonal fluctuation of food resources may act as an energetic challenge, augmenting hypothalamus-pituitary-adrenal axis (HPA axis) activity, leading to an increase in corticosterone concentrations and promoting the metabolism of energy stores. Plant invasions may alter seasonal food fluctuations by providing a food supply during scarce seasons. This could attenuate the energetic challenge, reducing HPA axis activity and the metabolism of reserves. Using a system with seasonal fluctuation in food availability, we tested if fruit supplementation by the invasive fleshy-fruited Pyracantha angustifolia during the season of native fruit scarcity, decreases the consumption of energy stores via activity attenuation of the HPA axis. We measured changes in body condition and circulating corticosterone (CORT) concentration in Turdus chiguanco occurring at sites both invaded and non-invaded by P. angustifolia over three time periods that correspond to the periods prior to, during, and after highest fruit production of the plant. Fruit scarcity in the ecosystem appears as an energetic challenge for T. chiguanco, given that body mass, fat score and residuals of body mass/tarsus length decreased during winter in a site not invaded by the exotic shrub. Conversely, the presence of the invasive plant seemed to attenuate the metabolism of energetic reserves, as we did not record changes in body condition in birds inhabiting the invaded site. Unexpectedly, plasma CORT concentration did not vary between sites or periods. Further evaluation is required to elucidate how enhanced body condition, resulting from the consumption of a fleshy-fruited invasive plant, affects survivorship and reproductive performance in T. chiguanco. This article is protected by copyright. All rights reserved. PMID- 30019850 TI - Exploring the predictive power of the unspecific risk category of the Basel Screening Instrument for Psychosis. AB - AIM: Ultrahigh risk (UHR) criteria, consisting of brief limited intermittent psychotic symptoms (BLIPS), attenuated psychotic symptoms (APS) and genetic risk and deterioration (GRD) syndrome are the most widely used criteria for assessing the clinical high-risk state for psychosis (CHR-P). The Basel Screening Instrument for Psychosis (BSIP) includes a further risk category, the unspecific risk category (URC). However, little is known about the predictive power of this risk category compared to other risk categories. METHODS: Two hundred CHR-P patients were detected as part of the Fruherkennung von Psychosen (FePsy) study using the BSIP. Transition to psychosis was assessed in regular intervals for up to 7 years. RESULTS: Patients meeting only the URC criterion (n = 40) had a significantly lower risk of transition to psychosis than the UHR group (including BLIPS, APS and GRD) (HR 0.19 [0.05; 0.80] (P = 0.024). Furthermore, the URC only risk group had a lower transition risk than the APS without BLIPS group (P = 0.015) and a trendwise lower risk than the BLIPS group (P = 0.066). However, despite the lower transition risk in the URC only group, there were still two patients (5%) in this group with a later transition to psychosis. CONCLUSIONS: The URC includes patients who have a lower risk of transition than those included by the UHR categories and thereby increases the sensitivity of the BSIP. This offers the possibility of a stratified intervention, with these subjects receiving low intensity follow-up and treatment. PMID- 30019851 TI - Factors associated with vocational disengagement among young people entering mental health treatment. AB - AIM: Most mental disorders have their onset by age 25, disrupting normative vocational engagement. Factors associated with vocational disengagement at first contact with specialist treatment are important for service planning. The aim of this paper was to investigate the association between theoretically important factors and vocational disengagement for youth entering mental health treatment. METHODS: A file audit was used to extract vocational data of 145 young people aged 15 to 25 years entering treatment in 2011 at a public youth mental health service in Melbourne, Australia. Comparisons were made across three specialist programs for: psychosis (n = 50), mood disorders (n = 52) and borderline personality pathology (n = 43). Individual characteristics were entered into univariate and multivariate logistic regressions to investigate their associations with vocational disengagement. RESULTS: Educational disengagement was associated with being older (OR = 4.38, P = 0.004) and not living with parents (OR = 2.87, P = 0.038). Unemployment and being NEET (Not in Education, Employment or Training) were both associated with not having commenced tertiary education (OR = 0.23, P = 0.022; OR = 0.05, P = 0.002; respectively). Being NEET was also associated with being older (OR = 6.18, P = 0.004). Primary diagnostic grouping was not associated with vocational disengagement, once accounting for other factors. CONCLUSIONS: The likelihood of vocational disengagement did not differ across disorder groups, implying that intervention should be "transdiagnostic" and might best target education first, specifically post secondary qualifications. Other domains or variables not measured in this study are also likely to be important, and this might include young people's support systems and symptom severity. Qualitative studies may be useful for exploring further factors relevant to vocational engagement. PMID- 30019852 TI - Effects of maternal stress induced by predator odors during gestation on behavioral and physiological responses of offspring in Brandt's vole (Lasiopodomys brandtii). AB - Maternal effects play a crucial role in regulating populations of small mammals and anti-predator behaviors of offspring. The present study investigated the effects of maternal stress induced by exposure to predator odors during gestation on the behavioral and physiological responses of offspring in Brandt's vole (Lasiopodomys brandtii). Effects included changes in growth, behaviors, hormone levels in serum, and fosB/DeltafosB mRNA and FosB/DeltaFosB protein expression in the hypothalamus. Our results showed that when pregnant voles were exposed to cat and rabbit urine odors for 18 days (1 h/day), the weight of the female offspring decreased; however, the thymus and ovary indices increased, compared with the control group. Male offspring of voles exposed to cat odor spent more time exploring and foraging, and showed a decrease in corticosterone (CORT) compared with voles in the control group. Both fosB/DeltafosB mRNA and FosB/DeltaFosB protein expressions were downregulated in the hypothalamus of male offspring in the cat odor-exposed group compared to that in offspring in the control group. However, the mRNA levels of fosB/DeltafosB in the hypothalamus of female offspring did not decrease in response to cat urine odor. Our findings suggested that maternal stress induced by predator odors during gestation restrained the growth of female offspring and increased the duration of exploring and foraging behaviors of male offspring by regulating the HPA axis, which, in turn, reduced the sensitivity of offspring to unfamiliar environments and increased their probability of becoming prey. PMID- 30019853 TI - Effects of reproductive experience on paternal behavior, levels of testosterone, prolactin in serum and dendritic spines in medial prefrontal cortex of mandarin voles. AB - Maternal behaviors and brains change dramatically with pregnancy, parturition and other mothering experiences. However, whether paternal behavior, brain plasticity and levels of relevant hormones also change along with fathering experience and pups' age remains unclear. Using socially monogamous mandarin voles (Microtus mandarinus), we found that experienced fathers exhibited more active paternal behaviors, such as licking, retrievals and nest building, but less paternal care, such as huddling, than new fathers. The high levels of licking and nest building appeared in the earlier days of their mate's lactation. Experienced fathers retrieved 9-13-day-old pups more frequently. However, these paternal behaviors did not show significant changes with age of pups in new fathers. In addition, experienced fathers had dramatically higher prolactin levels than new fathers but had similar concentrations of testosterone to new fathers. New fathers had lower levels of testosterone but higher levels of prolactin than new paired males. The fathers had higher prolactin levels in the earlier days of their mate's lactation. The new and experienced fathers had similar dendritic length and spine density on pyramidal neurons in the medial prefrontal cortex but displayed higher levels than new paired males. Taken together, these results indicate that reduction of testosterone levels and increase of prolactin levels may be associated with initiation of paternal care. Fathering experience significantly affects levels of parental care and paternal behaviors toward different aged pups, and brain plasticity can also be enhanced by transition to fatherhood. PMID- 30019854 TI - Direct Dehydrative Glycosylation of C1-Alcohols. AB - Due to the central role played by carbohydrates in a multitude of biological processes, there has been a sustained interest in developing effective glycosylation methods to enable more thorough investigation of their essential functions. Among the myriad technologies available for stereoselective glycoside bond formation, dehydrative glycosylation possesses a distinct advantage given the unique properties of C1-alcohols such as straightforward preparation, stability, and a general reactivity compatible with a diverse set of reaction conditions. In this Focus Review, a survey of direct dehydrative glycosylations of C1-alcohols is provided with an emphasis on recent achievements, pervading limitations, mechanistic insights, and applications in total synthesis. PMID- 30019855 TI - In Situ Growth of Zeolitic Imidazolate Framework-67-derived Nanoporous Carbon@K0.5 Mn2 O4 for High-Performance 2.4 V Aqueous Asymmetric Supercapacitors. AB - Aqueous asymmetric supercapacitors (ASCs) with a wide voltage window can effectively improve energy storage capacity of energy storage devices. Zeolitic imidazolate framework-67 (ZIF-67) was used as a precursor to prepare nanoporous carbon (NC), and K0.5 Mn2 O4 nanosheets were subsequently grown on the NC surface through a facile in situ redox process (denoted as NCMO). The electrode potential window of NCMO was extended to 1.2 V in a three-electrode system and the value of the potential window was higher than that of most reported manganese oxides. To assemble the asymmetric supercapacitor with a high voltage range, the as-prepared NCMO and NC (with a potential window of -1.2-0 V) were used as the positive and negative electrode, respectively. A 2.4 V NCMO//NC aqueous ASC was constructed and displayed a large energy density of 60 Wh kg-1 at a power density of 1200 W kg-1 and excellent rate performance (41 Wh kg-1 even at a specific power density of 12.3 kW kg-1 ) as well as good cycling stability (92.6 % capacitance retention over 10 000 cycles at 10 A g-1 ). This work provides new opportunities for the development of high voltage ASCs with a high energy density for further practical application. PMID- 30019856 TI - Seed Value Influences Cache Pilfering Rates by Desert Rodents. AB - Some rodents gather and store seeds. How many seeds they gather and how they treat those seeds is largely determined by seed traits such as mass, nutrient content, hardness of the seed coat, presence of secondary compounds, and germination schedule. Through their consumption and dispersal of seeds, rodents act as agents of natural selection on seed traits, and those traits influence how rodents forage. Many seeds that are scatter hoarded by rodents are pilfered, or stolen, by other rodents, and seed traits also likely influence pilfering rates and seed fates of pilfered seeds. To clarify coevolutionary relationships between rodents and the plants that they disperse, one needs to understand the role of seed traits in rodent foraging decisions. We compared how the seeds of four species of plants that are dispersed by scatter-hoarding animals and that differ in value (singleleaf pinon pine, Pinus monophylla; desert peach, Prunus andersonii; antelope bitterbrush, Purshia tridentata; Utah juniper, Juniperus osteosperma) were pilfered and recached by rodents. One hundred artificial caches of the four seed species (25 per species) were prepared, and removal by rodents was monitored. Rodents pilfered high value seeds more rapidly than the other seeds. Desert peach seeds, which contain toxic secondary compounds, were more frequently recached. Relatively low value seeds like Utah juniper and antelope bitterbrush were pilfered more slowly, were sometimes left at cache sites, and seeds of the latter species were transported shorter distances to new cache sites. The background density of seeds also appeared to influence the relative value of seeds. This article is protected by copyright. All rights reserved. PMID- 30019858 TI - Female mice exhibit both sexual and social partner preferences for vocalizing males. AB - Acoustic signals are widely used as courtship signals in the animal kingdom. It has long been known that male mice emit ultrasonic vocalizations (USVs) in the presence of female mice or in response to female secretions. This observation led to the hypothesis that male USVs play a role in courtship behavior. Although previous studies showed that female mice have a social partner preference for vocalizing males, it is not known if they exhibit a sexual partner preference when given a choice. To address this issue, we examined the copulatory behaviors of female mice with either devocalized males (with or without the playback of the USVs) or sham-operated males in 2 different behavioral paradigms: the no-choice paradigm in the home cage of a male mouse (without choice of mating partners) or the mate-choice paradigm in a 3-chambered apparatus (with choice of mating partners). In the no-choice paradigm, female mice exhibited comparable sexual receptivity with sham-operated and devocalized males. In addition, we found that female mice showed more approach behavior towards devocalized males when male USVs were played back. In the mate-choice paradigm, female mice visited more frequently and stayed longer with sham-operated than devocalized males. Furthermore, we showed that female mice received more intromissions from sham operated males than devocalized males. In summary, our results suggested that, although female mice can copulate equally with both devocalized and vocalizing males when given no choice of mating partner, female mice exhibit both sexual and social partner preferences for vocalizing males in the mate-choice paradigm. PMID- 30019857 TI - Whole-brain atrophy assessed by proportional- versus registration-based pipelines from 3T MRI in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Whole-brain atrophy is a standard outcome measure in multiple sclerosis (MS) clinical trials as assessed by various software tools. The effect of processing method on the validity of such data obtained from high resolution 3T MRI is not known. We compared two commonly used methods of quantifying whole-brain atrophy. METHODS: Three-dimensional T1-weighted and FLAIR images were obtained at 3T in MS (n = 61) and normal control (NC, n = 30) groups. Whole-brain atrophy was assessed by two automated pipelines: (a) SPM8 to derive brain parenchymal fraction (BPF, proportional-based method); (b) SIENAX to derive normalized brain parenchymal volume (BPV, registration method). We assessed agreement between BPF and BPV, as well their relationship to Expanded Disability Status Scale (EDSS) score, timed 25-foot walk (T25FW), cognition, and cerebral T2 (FLAIR) lesion volume (T2LV). RESULTS: Brain parenchymal fraction and BPV showed only partial agreement (r = 0.73) in the MS group, and r = 0.28 in NC. Both methods showed atrophy in MS versus NC (BPF p < 0.01, BPV p < 0.05). Within MS group comparisons, BPF (p < 0.05) but not BPV (p > 0.05) correlated with EDSS score. BPV (p = 0.03) but not BPF (p = 0.08) correlated with T25FW. Both metrics correlated with T2LV (p < 0.05) and cognitive subscales. BPF (p < 0.05) but not BPV (p > 0.05) showed lower brain volume in cognitively impaired (n = 23) versus cognitively preserved (n = 38) patients. However, direct comparisons of BPF and BPV sensitivities to atrophy and clinical correlations were not statistically significant. CONCLUSION: Whole-brain atrophy metrics may not be interchangeable between proportional- and registration-based automated pipelines from 3T MRI in patients with MS. PMID- 30019859 TI - The Greek version of the McMaster Family Assessment Device. AB - The Family Assessment Device (FAD) is a self-report questionnaire, developed to assess the six dimensions of the McMaster Model of Family Functioning. It has been translated into the Greek language but never validated. We aimed to evaluate the psychometric properties of the Greek version of the FAD in a nonclinical sample. In a sample of Greek families, the FAD was administered together with the already validated Family Adaptability and Cohesion Evaluation Scale (FACES-III). In a subsample of 96 individual participants, the scales were administered again after 1 month. The sample of 453 participants (151 families: 194 children and 259 parents) completed both questionnaires. The mean age of the children was 23.62 years (SD = 6.35 years), and 68 (35%) were male. The mean age of the parents was 51.4 years (SD = 8.2 years), and 117 (45.2%) were male. All subscales of the FAD had significant correlation (concurrent validity) with the FACES-III (n = 453, p < .001). Test-retest reliability ranged from .58 to .82 (N = 96, p < .001). Internal consistency (Cronbach's alpha) ranged from .47 to .94. A model with the six factors had a good statistical fit but not all the items were loading in the same components as from the theory assumed. The Greek FAD has good psychometric properties, although its factor structure might differ from the original version. PMID- 30019860 TI - Synteny search identifies Carnivore Y chromosome for evolution of male specific genes. AB - The explosively accumulated mammalian genomes have provided a valuable resource to characterize the evolution of the Y chromosome. Unexpectedly, the Y-chromosome sequence has been characterized in only a small handful of species, with a majority of them being model organisms. Thus, identification of Y-linked scaffolds from unordered genome sequences is becoming more important. Here, we used a syntenic-based approach to generate the scaffolds of male specific region in Y chromosome (MSY) from the genome sequence of 6 male carnivore species. Our results identified 14, 15, 9, 28, 14 and 11 Y-linked scaffolds in polar bear, pacific walrus, red panda, cheetah, ferret and tiger, covering 1.55Mbp, 2.62Mbp, 964Kb, 1.75Mb, 2.17Mbp and 1.84Mb MSY, respectively. All of the candidate Y linked scaffolds in three selected species (red panda, polar bear and tiger) were successfully verified using PCR. We re-annotated these Y-linked scaffolds plus with domestic dog and cat MSY, a total of 11 orthologous genes conserved in at least 7 of the 8 carnivores were identified. These 11 Y-linked genes have significantly higher evolutionary rates compared with their X-linked counterparts, indicating less purifying selection for MSY genes. Taken together, our study shows that the approach of synteny search is a reliable and easily affordable strategy to identify Y-linked scaffolds from unordered carnivore genome and provides a preliminary evolutionary study for carnivore MSY genes. This article is protected by copyright. All rights reserved. PMID- 30019861 TI - Eph Receptor Effector Ephexin Mediates Olfactory Dendrite Targeting in Drosophila. AB - Deciphering the mechanisms of sensory neural map formation is a central aim in neurosciences. Failure to form a correct map frequently leads to defects in sensory processing and perception. The olfactory map develops in subsequent steps initially forming a rough and later a precise map of glomeruli in the antennal lobe (AL), mainly consisting of olfactory receptor neuron (ORN) axons and projection neuron (PN) dendrites. The mechanisms underpinning the later stage of class-specific glomerulus formation are not understood. Recent studies have shown that the important guidance molecule Eph and its ligand ephrin play a role in class-specific PN targeting. Here, we reveal aspects of the mechanism downstream of Eph signaling during olfactory map formation. We show that the Eph-specific RhoGEF Ephexin (Exn) is required to fine tune PN dendrite patterning within specific glomeruli. We provide the first report showing an in vivo neurite guidance defect in an exn mutant. Interestingly, the quality of the phenotypes is different between eph and exn mutants; while loss of Eph leads to strong misprojections of DM3/Or47a neurons along the medial-lateral axis of the antennal lobe (AL), loss of Exn induces ventral ectopic innervation of a neighboring glomerulus. Genetic interaction experiments suggest that differential signaling of the small GTPases Rac1 and Cdc42 mediated by Exn-dependent and -independent Eph signaling fine tunes spatial targeting of PN dendrites within the olfactory map. We propose that their distinct activities on the actin cytoskeleton are required for precise navigation of PN dendrites within the olfactory map. Taken together, our results suggest that the precise connectivity of an individual neuron can depend on different modes of signaling downstream of a single guidance receptor. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018. PMID- 30019862 TI - Manuscript "The metapodials of ancient bison (Bison priscus Boj.) of North Eastern Russia: "stress markers", sex and withers height". AB - 175 metapodials (MP) of Pleistocene and early Holocene bison (Bison priscus Boj.) from the vast area of NE Russia were studied. MP were attributed to males and females both visually and statistically. Data on the withers height of bison from NE Russia are provided. Stress markers were recorded, including so-called "buttresses". With rare exceptions stress markers were not of a pathological nature. The origin and development of the buttresses are age-related; their prevalence in bison females can be considered as the response to an increased load during pregnancy. Changes in the periosteum, found in males, are related to their greater activity. Buttresses are also well-developed on metatarsals of the red deer and the elk; less-developed in the reindeer and not found in the giant deer. A relationship between stress markers, locomotion, and the environment is established. Possible peculiarities of the Rauchua River bison locomotion are discussed. This article is protected by copyright. All rights reserved. PMID- 30019863 TI - Differential altered expression of let-7a and miR-205 tumor-suppressor miRNAs in different subtypes of breast cancer under treatment with Taxol. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs which have been considered as major players in the process of carcinogenesis and drug responsiveness of breast cancer. OBJECTIVES: In this study, we aimed to investigate the expression pattern of let-7a and miR-205 tumorsuppressor miRNAs in breast cancer cell lines under treatment with paclitaxel. MATERIAL AND METHODS: The half maximal inhibitory concentration (IC50) of paclitaxel was determined for 4 breast cancer cell lines, including MCF-7, MDA-MB-231, SKBR-3, and BT-474 by an MTT assay. The expression level of let-7a and miR-205, and their targets, K-RAS and HER3, was determined before and after treatment with paclitaxel, using quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). RESULTS: After treatment, the expression level of both let-7a and miR-205 was significantly increased in HER2- overexpressing cell line BT-474 (26.4- and 7.2-fold, respectively). In contrast, the HER2-negative cell lines MCF 7 and MDA-MB-231 showed a significantly decreased expression of both let-7a (30.3 and 13.5-fold, respectively) and miR-205 (20- and 18.1-fold, respectively). Controversially, SKBR-3 revealed a significantly decreased expression of both let 7a (1.3-fold) and miR-205 (1.3-fold). The expression level of K-RAS as a target of let-7a decreased in all cell lines significantly, but the pattern of alteration in the expression level of HER3 as a target of miR-205 in all cell lines was the reverse of the pattern of alteration in the expression level of miR 205. CONCLUSIONS: Our results confirmed a better response of HER2-overexpressing breast cancer to paclitaxel at the miRNA level. One putative reason could be the upregulation of tumor-suppressor miRNAs after treatment with paclitaxel. On the other hand, HER2-negative breast cancer cell lines showed a significantly decreased expression of tumor-suppressor miRNAs, a putative mechanism of resisting the therapy. PMID- 30019864 TI - Correlation between malnutrition, body mass index and complications in patients with urinary bladder cancer who underwent radical cystectomy. AB - BACKGROUND: Nutrition is the 3rd most important factor in surgery, following anesthesia and asepsis. Until now, it has been a poorly explored field of urology. The relationship between malnutrition and postoperative complications has been proven beyond doubt in general surgery, where 30% of patients are operated in a malnutrition state. OBJECTIVES: The aim of our work was to assess the influence of malnutrition, defined by nutritional risk screening (NRS) scale and body mass index (BMI), on postoperative results in patients with bladder cancer after radical cystectomy. MATERIAL AND METHODS: The research was carried out at 8 urological centers between 2012 and 2014, and included patients with bladder cancer at stage from T2 to T4, who underwent radical cystectomy. The degree of malnutrition was assessed with the aid of the NRS 2002 questionnaire. Other examined parameters were BMI, age, type of operation, and the number of complications, the latter of which were measured by applying the Clavien-Dindo scale. RESULTS: A total of 125 patients were enrolled in our study, out of whom 64 (51.2%) were undernourished. According to the BMI, most of the patients were overweight - 50 (40%) or had normal body weight - 49 (39.2%); 24 (19.2%) were obese, and 2 (1.6%) were underweight. CONCLUSIONS: There was no relationship between malnutrition, defined by the NRS scale, and postoperative complications, and we did not find a significant relationship between the other tested variables. We observed only 1 significant relationship between the nutrition state, measured by BMI scale, and the degree in Clavien-Dindo scale. Body mass index under 18.5 and over 30 increased postoperative complications. Nowadays, the recommended scale is NRS 2002, which is based mostly on loss of weight. In our patients, qualitative malnutrition is more probable than quantitative malnutrition. PMID- 30019865 TI - Phosphorus is an independent risk factor for the progression of diabetic nephropathy. AB - BACKGROUND: Serum phosphorus is thought to be an important risk factor for the progression of chronic kidney disease (CKD). However, the association of serum phosphorus with disease progression in patients with different causes of kidney diseases remains to be elucidated. OBJECTIVES: The aim of this study was to estimate the effect of serum phosphorus on disease progression in 2 cohorts of CKD with different causes. MATERIAL AND METHODS: A total of 591 patients with diabetic nephropathy and 957 patients with IgA nephropathy from the National Clinical Research Center of Kidney Diseases, Nanjing, China, with biopsy-proven kidney disease, stage 1-4 CKD and a follow-up of at least 1 year were recruited. We evaluated the relationship between the baseline phosphorus category and the disease progression in the 2 cohorts. RESULTS: Multivariate Cox regression analyses indicated that the risk of the endpoint event was 1.68-fold higher (95% confidence interval (CI): 0.95-2.91) in IgA nephropathy patients and 2.88-fold higher (95% CI: 1.12-5.04) in diabetic nephropathy patients with the highest quartile of serum phosphorus compared with the risk of those with the lowest quartile. CONCLUSIONS: The association of serum phosphorus with the progression of CKD may vary in specific CKD patient subgroups. Serum phosphorus is independently associated with the progression of kidney disease in patients with diabetic nephropathy. PMID- 30019866 TI - Frequency of isolation and drug susceptibility of bacterial strains isolated from child oncohematological patients 2011-2014: A single center study. AB - BACKGROUND: Infections in pediatric patients with oncohematological diseases pose a huge therapeutic and diagnostic problem. OBJECTIVES: The aim of the study was to investigate the etiology of bacteremia and the antibiotic susceptibility of pathogenic and colonizing bacterial strains in pediatric oncohematological patients. MATERIAL AND METHODS: In the period 2011-2014, 17,209 positive test results, including 1,129 positive blood cultures, were subjected to a detailed analysis. The assessment of drug susceptibility was conducted in accordance with the CLSI (American), EUCAST (European), and KORLD (Polish) recommendations. RESULTS: A high percentage (86-91%) of negative blood culture results was demonstrated. A predominance of Gram-positive bacteria was seen in all years (60 70%) in contrast to Gram-negative strains (30-40%). Coagulase-negative staphylococci (CNS) were the strains most frequently isolated from blood (41-47%) among all bacterial strains. Susceptibility to linezolid and vancomycin was 96 100%, and to teicoplanin 82-96%. Methicyllin-resistant coagulase-negative Staphylococcus (MRCNS) were isolated in 77-86%. All Staphylococcus aureus (S. aureus) strains were susceptible to glycopeptides and linezolid, while Enterococcus spp. was susceptible to linezolid. Apart from the year 2014, no methicillin-resistant S. aureus (MRSA) were isolated. Enterobacteriaceae (EN) were the most susceptible to imipenem and meropenem (91-100%) as well as to amikacin (77-93%). From 2013 to 2014, non-fermentative rods (NF) isolated from blood were less susceptible to imipenem and meropenem (71% and 67-71%, respectively) than to other antibiotics. It has been shown that strains isolated from blood have a statistically significantly different susceptibility to antibiotics (CNS and EN are less and NF is more susceptible) than those existing as colonizing flora. CONCLUSIONS: Our results show that choosing appropriate antibiotics for treating infection in children with oncohematological diseases based on antibiograms for colonizing flora may be difficult because they may not take into account the more resistant strains. According to the antibiotic susceptibility of the strains isolated from blood in our center, the most viable active empirical and carbapenem-saving therapy could be conducted with piperacillin/tazobactam or cefepime. PMID- 30019867 TI - Perioperative standards for the treatment of coagulation disorders and usage of blood products in patients undergoing liver transplantation used in the Clinic for Transplant Surgery in Wroclaw. AB - BACKGROUND: Coagulation system disorders in liver transplantation (ltx) patients are considered a serious issue. Liver cirrhosis leads to decreased synthesis of clotting factors and decreased elimination of waste products, including coagulation proteins. Platelet sequestration and dysfunction in an enlarged spleen additionally worsen these conditions. The resulting state, the most common pathology of the coagulation system, involves the reduction of clotting potential and hyperfibrinolysis. OBJECTIVES: Tackling the problem of impaired hemostasis is a dynamic process. Throughout the whole procedure, consisting of the preanhepatic, the anhepatic and the neohepatic phases, consecutive pathomechanisms disrupt the very balance that anesthesia aims to preserve. MATERIAL AND METHODS: Rotational thromboelastometry (ROTEM), having been introduced in the Clinic of Anesthesiology and Intensive Therapy, Wroclaw Medical University, Poland, enables the efficient and early diagnosis of clotting disorders. An additional major problem which occurs during ltx, namely blood loss, could be solved using a cell separator. RESULTS: In this study, we present the standards introduced to the Transplantology Department of the Vascular Surgery Clinic, Wroclaw Medical University, Poland, that describe blood treatment during ltx procedures. CONCLUSIONS: We conclude that thromboelastometric examination and the use of a cell separator have significantly increased the safety of ltx procedures at our clinic. The introduction of thromboelastometry (TEM) and the implementation of the cell separator recovery method have enabled us to perform the dangerous and complicated surgical procedure of ltx in a much more stable and much safer manner than in the past. PMID- 30019868 TI - Medical Devices; Hematology and Pathology Devices; Classification of Blood Establishment Computer Software and Accessories. Final rule. AB - The Food and Drug Administration (FDA, Agency, or we) is issuing a final rule to classify blood establishment computer software (BECS) and BECS accessories (regulated under product code MMH) into class II (special controls). FDA has identified special controls for BECS and BECS accessories that are necessary to provide a reasonable assurance of safety and effectiveness. FDA is also giving notice that the Agency does not intend to exempt BECS and BECS accessories from premarket notification requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act). PMID- 30019869 TI - Final Determination Regarding Partially Hydrogenated Oils. Notification; declaratory order; extension of compliance date. AB - Based on the available scientific evidence and the findings of expert scientific panels, the Food and Drug Administration (FDA or we) made a final determination that there is no longer a consensus among qualified experts that partially hydrogenated oils (PHOs), which are the primary dietary source of industrially produced trans fatty acids (IP-TFA), are generally recognized as safe (GRAS) for any use in human food. In a declaratory order announcing our final determination, we set a compliance date of June 18, 2018. We are now extending the compliance date for certain uses of PHOs. PMID- 30019870 TI - Hearing Aid Compatibility Standards. Final rule; announcement of effective date. AB - In this document, the Commission announces that the Office of Management and Budget (OMB) has approved, for a period of three years, the information collection associated with rules adopted in the Commission's document Access to Telecommunication Equipment and Services by Persons with Disabilities; Amendment of the Commission's Rules Governing Hearing Aid-Compatible Mobile Handsets et. al., Report and Order and Order on Reconsideration (Order). This document is consistent with the Order, which stated that the Commission would publish a document in the Federal Register announcing the effective date of those rules. PMID- 30019871 TI - Medical Devices; Exemptions From Premarket Notification: Class II Devices. Final order. AB - The Food and Drug Administration (FDA or the Agency) is publishing an order to exempt a list of class II devices from premarket notification (510(k)) requirements, subject to certain limitations. This exemption from 510(k), subject to certain limitations, is immediately in effect for the listed class II devices. This exemption will decrease regulatory burdens on the medical device industry and will eliminate private costs and expenditures required to comply with certain Federal regulations. FDA is also amending the codified language for the listed class II devices to reflect this finaldetermination. FDA is publishing this order in accordance with the section of the Federal Food, Drug, and Cosmetic Act (FD&C Act) permitting theexemption of a device from the requirement to submit a 510(k). PMID- 30019872 TI - Medicare Program; Update to the Required Prior Authorization List of Durable Medical Equipment, Prosthetics, Orthotics, and Supplies (DMEPOS) Items That Require Prior Authorization as a Condition of Payment. Update to list. AB - This document announces the addition of 31 Healthcare Common Procedure Coding System (HCPCS) codes to the Required Prior Authorization List of Durable Medical Equipment, Prosthetics, Orthotics, and Supplies (DMEPOS) Items that require prior authorization as a condition of payment. Prior authorization for these codes will be implemented nationwide. PMID- 30019873 TI - Medical Devices; General and Plastic Surgery Devices; Classification of the Microneedling Device for Aesthetic Use. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the microneedling device for aesthetic use into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the microneedling device for aesthetic use's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 30019874 TI - Medical Devices; Orthopedic Devices; Classification of the In Vivo Cured Intramedullary Fixation Rod. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the in vivo cured intramedullary fixation rod into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the in vivo cured intramedullary fixation rod's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 30019875 TI - Medicare Program; Changes to the Comprehensive Care for Joint Replacement Payment Model (CJR): Extreme and Uncontrollable Circumstances Policy for the CJR Model. Final rule. AB - This final rule finalizes a policy that provides flexibility in the determination of episode spending for Comprehensive Care for Joint Replacement Payment Model (CJR) participant hospitals located in areas impacted by extreme and uncontrollable circumstances for performance years 3 through 5. PMID- 30019876 TI - Process for Department of Veterans Affairs (VA) Physicians To Be Added to the National Registry of Certified Medical Examiners. Final rule. AB - FMCSA amends the Federal Motor Carrier Safety Regulations (FMCSRs) to establish an alternative process for qualified advanced practice nurses, doctors of chiropractic, doctors of medicine, doctors of osteopathy, physician assistants, and other medical professionals who are employed in the VA and are licensed, certified, or registered in a State to perform physical examinations (qualified VA examiners) to be listed on the Agency's National Registry of Certified Medical Examiners, as required by the Fixing America's Surface Transportation (FAST) Act and the Jobs for Our Heroes Act. After successful completion of online training and testing developed by FMCSA, these qualified VA examiners will become certified VA medical examiners who can perform medical examinations of, and issue Medical Examiner's Certificates to, commercial motor vehicle operators who are military veterans enrolled in the VA healthcare system. This rule will reduce the costs for qualified VA examiners to be listed on the National Registry. PMID- 30019877 TI - Black Lung Benefits Act: Medical Benefit Payments. Final rule. AB - This final rule revises the regulations under the Black Lung Benefits Act (BLBA or Act) governing the payment of medical benefits and maintains the level of care available to miners. The final rule establishes methods for determining the amounts that the Black Lung Disability Trust Fund (Trust Fund) will pay for covered medical services and treatments provided to entitled miners. The Department based the rule on payment formulas that the Centers for Medicare & Medicaid Services (CMS) uses to determine payments under the Medicare program, which are similar to the formulas used by other programs that the Office of Workers' Compensation Programs (OWCP) administers. The Department is adopting these payment formulas for the black lung program because they more accurately reflect prevailing community rates for authorized treatments and services than do the internally-derived payment formulas that OWCP currently uses. In addition, the final rule eliminates two obsolete provisions. PMID- 30019878 TI - Transanal transabdominal TME: how far can we push it? AB - Over many decades, advances in surgical technology, such as the use of the electrocautery Bovie, development of minimally invasive and advanced endoscopic platforms and the ability to create and maintain pneumorectum have propelled surgical techniques forward to today, with development of the transanal total mesorectal excision TME (taTME) for en bloc resection of rectal cancers. The transanal platform offers, for now, a viable alternative to perform safe and oncologically sound TME, especially favorable in cases of low rectal lesions in a narrow pelvis post neoadjuvant treatment. The aspiration of the colorectal community remains to continue to push the operative boundaries whilst maintaining safe oncological principals with the best possible functional outcomes for patients. In this article we review this evolving technique and focus on future directions. PMID- 30019879 TI - The "Wandering Spleen" as a rare cause of recurrent abdominal pain: a literature review. AB - INTRODUCTION: Wandering spleen (WS) is a rare and generally acquired condition, resulting from abnormal ligamentous laxity failing to fixate the spleen in its normal location in the left upper quadrant, thus leading to its migration to the pelvis due to gravity. Such migration leads to an elongated vascular pedicle, which is prone to torsion causing splenic infarction; thus, a prompt surgical intervention is recommended. Since this adverse event affects childbearing women or children, it is crucial to choose the most appropriate surgical strategy, such as splenectomy or splenopexy, both effective and widely diffused options. The aim of this paper is to perform a literature review on WS reports treated by surgery. We also present a case of symptomatic WS migrated in pelvis in a young female treated by splenectomy. EVIDENCE ACQUISITION: All relevant articles from 1895 up to December 2017 were identified by literature searches in PubMed, Scopus and Google Scholar. EVIDENCE SYNTHESIS: A total of 376 patients treated with surgical approach for WS were identified. The most common presentations were abdominal pain and abdominal mass, and approximately half of the patients had an acute clinical onset. Radiology is essential for the diagnosis. Surgical strategy changed over the time; splenectomy is the most reported treatment although in the last years there is a increasing trend towards a more conservative strategy, preferring splenopexy or by using a laparoscopic approach. CONCLUSIONS: Surgery is the gold standard strategy, and laparoscopic approach is reccomended, for the treatment of wandering spleen. Both splenopexy or splenectomy are effective and safe surgical options. PMID- 30019880 TI - One anastomosis gastric bypass: key technical features, and prevention and management of procedure-specific complications. AB - INTRODUCTION: One Anastomosis Gastric Bypass (OAGB) is now a recognised mainstream bariatric procedure being adopted by an increasing number of surgeons. The purpose of this review was to present an evidence-based summary of its key technical aspects and prevention and management of its specific complications. EVIDENCE ACQUISITION: We examined PubMed for all published articles on OAGB, including the ones published under one of its various other names. EVIDENCE SYNTHESIS: An ideal OAGB procedure has a long, narrow pouch constructed carefully to avoid going too close to the greater curvature of the stomach especially at the bottom of the pouch, and maintains a safe distance from the angle of His. A Bilio-Pancreatic limb length of 150 cm appears to be safest and a limb length of > 200 cm is associated with a significantly increased incidence of protein calorie malnutrition. We recommend routine closure of Petersen's space to prevent Petersen's hernia and suggest a protocol for micronutrient supplementation. This review also presents evidence-based algorithms for prevention and management of marginal ulcers, protein-calorie malnutrition, and Gastro-Oesophageal Reflux Disease after OAGB. We suggest lifelong supplementation with two multivitamin/mineral supplements (each containing at least 1.0 mg Copper and 15 mg Zinc) daily, 1.5 mg vitamin B12 orally daily or 3-monthly injection with 1 mg vitamin B12, 120 mg elemental iron daily, 1500 mg elemental Calcium daily, and 3000 international units of vitamin D daily. CONCLUSIONS: This review examines key technical steps of OAGB. We also discuss how to prevent and manage its specific complications. PMID- 30019881 TI - Medical Devices; Immunology and Microbiology Devices; Classification of the Brain Trauma Assessment Test. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the brain trauma assessment test into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the brain trauma assessment test's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 30019882 TI - Medical Devices; Gastroenterology-Urology Devices; Classification of the Endoscopic Electrosurgical Clip Cutting System. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the endoscopic electrosurgical clip cutting system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the endoscopic electrosurgical clip cutting system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 30019883 TI - Medical Devices; Gastroenterology-Urology Devices; Classification of the Fluid Jet System for Prostate Tissue Removal. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the fluid jet system for prostate tissue removal into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the fluid jet system for prostate tissue removal's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 30019884 TI - Medical Devices; Immunology and Microbiology Devices; Classification of the Next Generation Sequencing Based Tumor Profiling Test. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the next generation sequencing based tumor profiling test into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the next generation sequencing based tumor profiling test's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 30019885 TI - Medical Care in Foreign Countries and Filing for Reimbursement for Community Care Not Previously Authorized by VA. Final rule. AB - The Department of Veterans Affairs (VA) adopts as final, with no changes, a proposed rule amending its medical regulations related to hospital care and medical services in foreign countries. We simplified and clarified the scope of these regulations, address medical services provided to eligible veterans in the Republic of the Philippines, and removed provisions related to grants to the Republic of the Philippines that are no longer supported by statutory authority. VA also amends its medical regulations related to filing claims for reimbursement of medical expenses incurred for VA care not previously authorized. We provided a 60-day period to receive comments from the public on the proposed changes, and received no comments. VA adopts the proposed rule as final, with no changes. PMID- 30019886 TI - Third Party Billing for Medical Care Provided Under Special Treatment Authorities. Final rule. AB - The Department of Veterans Affairs (VA) is amending its medical regulations to clarify that VA will not bill third party payers for care and services provided by VA under certain statutory provisions, which we refer to as "special treatment authorities." These special treatment authorities direct VA to provide care and services to veterans based upon discrete exposures or experiences that occurred during active military, naval, or air service. VA is authorized, but not required by law, to recover or collect charges for care and services provided to veterans for non-service-connected disabilities. This rule establishes that VA will not exercise its authority to recover or collect reasonable charges from third party payers for care and services provided under the special treatment authorities. PMID- 30019887 TI - Role of Photogenerated Iodine on the Energy-Conversion Properties of MoSe2 Nanoflake Liquid Junction Photovoltaics. AB - Transition metal dichalcogenides (TMDs) such as MoSe2 and WSe2 are efficient materials for converting solar energy to electrical energy in photoelectrochemical photovoltaic cells. One limiting factor of these liquid junction solar cells is that photogenerated oxidation products accumulate on the electrode surface and decrease the photocurrent efficiency. However, it is unclear where the reaction products accumulate on the electrode surface and how they impact the local photoelectrochemical response. This open question is especially important for the structurally heterogeneous TMD nanoflake thin-film electrodes that are promising for large-area solar energy conversion applications. Here, we use a single-nanoflake photoelectrochemical and Raman microscopy approach to probe how the photogenerated I2/I3- products impact the photocurrent collection efficiency and the onset potential in MoSe2-nanoflake|I /I2|Pt photoelectrochemical solar cells. We observed localized I2/I3- deposition on all types of MoSe2 nanoflake surface motifs, including basal planes, perimeter edges, and interior step edges. Illuminated nanoflake spots with the highest photocurrent collection efficiency are the first to be limited by I2/I3- formation under high-intensity illumination. Interestingly, I2/I3- formation occurs on illuminated surface spots that have the lowest photocurrent onset potential for iodide oxidation, corresponding to the highest open circuit voltage ( VOC). The VOC shifts could be attributed to variations in the surface reaction kinetics or doping density across the nanoflake. Our results highlight important limiting factors of nanoflake thin-film TMD liquid junction photovoltaics under concentrated solar illumination intensities. PMID- 30019888 TI - Cu-Thienoquinone Charge-Transfer Complex: Synthesis, Characterization, and Application in Organic Transistors. AB - A facile and unusual reaction between thienoquinone compound QDTBDT2C and copper is reported. The formation of Cu-QDTBDT2C complex is proved by absorption spectra, IR spectra, Raman spectra, and X-ray photoelectron spectroscopy data. This complex can serve as a doping layer at the interface of Cu/QDTBDT2C and greatly improve the performance of organic transistors in which the copper electrode is source/drain electrodes and QDTBDT2C is an active layer. The transistors display an electron mobility of 0.95 cm2 V-1 s-1, to our knowledge, the highest electron mobility reported for copper electrode-based n-type transistors and nearly two times higher than that of the Au electrode-based devices. These results demonstrate the potential applications of Cu-QDTBDT2C complex in organic electronics, and the unique properties of QDTBDT2C (spontaneously reacting with copper) provide a new insight into the design of n type organic semiconductors for copper electrode-based organic transistors. PMID- 30019889 TI - Magnetic Patterning by Electron Beam-Assisted Carbon Lithography. AB - We report on the proof of principle of a scalable method for writing the magnetic state by electron-stimulated molecular dissociative adsorption on ultrathin Co on Re(0001). Intense microfocused low-energy electron beams are used to promote the formation of surface carbides and graphitic carbon through the fragmentation of carbon monoxide. Upon annealing at the CO desorption temperature, carbon persists in the irradiated areas, whereas the clean surface is recovered elsewhere, giving origin to chemical patterns with nanometer-sharp edges. The accumulation of carbon is found to induce an in-plane to out-of-plane spin reorientation transition in Co, manifested by the appearance of striped magnetic domains. Irradiation at doses in excess of 1000 L of CO followed by ultrahigh vacuum annealing at 380 degrees C determines the formation of a graphitic overlayer in the irradiated areas, under which Co exhibits out-of-plane magnetic anisotropy. Domains with opposite magnetization are separated here by chiral Neel walls. Our fabrication protocol adds lateral control to spin reorientation transitions, permitting to tune the magnetic anisotropy within arbitrary regions of mesoscopic size. We envisage applications in the nano-engineering of graphene-spaced stacks exhibiting the desired magnetic state and properties. PMID- 30019890 TI - CO2 Selective PolyActive Membrane: Thermal Transitions and Gas Permeance as a Function of Thickness. AB - It is generally accepted that the melting point of a semicrystalline polymer is associated with the thickness of the crystalline lamellae (Gibbs-Thomson equation). In this study, a commercially available multiblock copolymer PolyActive composed of 77 wt % of poly(ethylene glycol terephthalate) and 23 wt % of poly(butylene terephthalate) was dip-coated on top of a multilayer microporous support. The thickness was changed between 0.2 and 8 MUm using coating solutions containing 0.75-7.5 wt % PolyActive. The surface temperature of the membrane during dip-coating was monitored using an infrared camera. Single gas permeances of N2, H2, CH4, and CO2 were measured between 20 and 80 degrees C at temperature steps of 2 degrees C. Spherulitic superstructures composed of radially directed lamellae were observed in the polarized light microscope in the prepared membranes. Atomic force microscopy studies showed that the thickness of the crystalline lamellae was in the order of 10 nm or 0.01 MUm at the surface of the membrane. Therefore, according to the Gibbs-Thomson equation, the melting point should not change in the thickness range 0.2-8 MUm. However, the gas permeance data showed that the melting point of the polyether domains of the 0.2 MUm PolyActive layer was 10 degrees C lower compared to that of the 8 MUm layer. The results can be explained by considering that the width of many crystalline lamellae significantly reduces as a function of film thickness, thereby reducing the average fold surface free energy/lateral surface free energy ratio. PMID- 30019891 TI - Luminescence and Location of Gd3+ or Tb3+ Ions in Perovskite-Type LaScO3. AB - The luminescence properties of Gd3+ or Tb3+ ions at La and Sc sites were investigated in LaScO3 with a distorted perovskite-type structure (ABO3). Although the luminescence of lanthanide ions located at B sites is not common and has not been examined in detail, Gd3+ or Tb3+ luminescence from B sites and A sites is clearly observed in Gd3+- or Tb3+-doped LaScO3. The differences in the luminescence characteristics concern peak positions, peak shapes, and decay time, which are all influenced by the crystal field and the site symmetry. The UV luminescence of Gd3+ at B sites shows a red shift compared to Gd3+ at A sites, and the green luminescence of Tb3+ at B sites contrasts with the blue-violet and green luminescence of Tb3+ at A sites. The decay time of the luminescence from B sites is systematically longer than that from A sites in both the Gd3+ and Tb3+ cases. PMID- 30019892 TI - Sensitive Detection of Exosomal Proteins via a Compact Surface Plasmon Resonance Biosensor for Cancer Diagnosis. AB - Exosomes are small extracellular vesicles released by cells for cell-cell communication. They play important roles in cancer development, metastasis, and drug resistance. Exosomal proteins have been demonstrated by many studies as promising biomarkers for cancer screening, diagnosis, and monitoring. Among many detection techniques, surface plasmon resonance (SPR) is a highly sensitive, label-free, and real-time optical detection method. Commercial prism-based wavelength/angular-modulated SPR sensors afford high sensitivity and resolution, but their large footprint and high cost limit their adaptability for clinical settings. Recently, a nanoplasmonic exosome (nPLEX) assay was developed to detect exosomal proteins for ovarian cancer diagnosis. However, comparing with conventional SPR biosensors, the broad applications of nanoplasmonic biosensors are limited by the difficult and expensive fabrication of nanostructures. We have developed an intensity-modulated, compact SPR biosensor (25 cm * 10 cm * 25 cm) which uses a conventional SPR sensing mechanism and does not require nanostructure fabrication. Calibration from glycerol showed that the compact SPR biosensor offered sensitivity of 9.258 * 103%/RIU and resolution of 8.311 * 10-6 RIU. We have demonstrated the feasibility of the compact SPR biosensor in lung cancer diagnosis using exosomal epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) as biomarkers. It detected a higher level of exosomal EGFR from A549 nonsmall cell lung cancer (NSCLC) cells than BEAS-2B normal cells. With human serum samples, the compact SPR biosensor detected similar levels of exosomal EGFR in NSCLC patients and normal controls, and higher expression of exosomal PD-L1 in NSCLC patients than normal controls. The compact SPR biosensor showed higher detection sensitivity than ELISA and similar sensing accuracy as ELISA. It is a simple and user-friendly sensing platform, which may serve as an in vitro diagnostic test for cancer. PMID- 30019893 TI - Longer-Lasting Electron-Based Microscopy of Single Molecules in Aqueous Medium. AB - Use of electron-based microscopy in aqueous media has been held back because aqueous samples tend to suffer from water radiolysis and other chemical degradation caused by the high energy of incident electrons. Here we show that aqueous liquid pockets in graphene liquid cells at room temperature display significantly improved stability when using deuterated water, D2O. Reporting transmission electron microscopy (TEM) experiments based on common imaging conditions, we conclude that use of D2O outperforms adding radical scavengers to H2O regardless of imaging details; it increases the lifetime of dissolved organic macromolecules by a factor of 2-5, and it delays by even longer the appearance of radiolysis-induced bubbles, by a factor of time up to 10. We quantify statistically the consequences of minimizing the electron voltage and dose and conclude that the D2O environment increases sample longevity without noticeable sacrifice of contrast that is critical for direct imaging of weakly scattering organic macromolecules and biomolecules. PMID- 30019895 TI - Fast and Selective Detection of Cr(III) in Environmental Water Samples Using Phosphovanadate Y(V0.2P0.8O4):Eu3+ Fluorescence Nanorods. AB - Phosphovanadate Y(V0.2P0.8O4):Eu3+ nanorods have been created via a simple hydrothermal method and used for the highly sensitive and selective fluorescence detection of Cr3+ over other common heavy metal ions within a 10 min period. It was found that the fluorescence intensity of Y(V0.2P0.8O4):Eu3+ linearly decreases with Cr3+ concentrations ranging from 1 * 10-9 to 1.2 * 10-6 M. The sensing mechanism for Cr3+ is ascribed to the aggregation of Y(V0.2P0.8O4):Eu3+ nanorods triggered by Cr3+ ions owing to the high affinity of phosphate groups to metal ions. The excellent chemical stability, photostability over a wide pH range of 3-12, and high salt-tolerance performance with ionic strength from 1* 10-3 to 12 M of Y(V0.2P0.8O4):Eu3+ allow these nanorods to successfully overcome the photobleaching and pH-dependent fluorescence property of traditional organic fluorescence probes. These characteristics ensure their applicability to environmental monitoring of Cr3+. The sensitive determination of Cr3+ in different environmental water samples demonstrated the potential application of Y(V0.2P0.8O4):Eu3+ as a practical environmental probe. With the help of a UV lamp (254 nm), the visual Cr3+ values for dynamic monitoring in industrial wastewater further verified that this method can even exhibit on-site visible features in daytime and night easily. This allows for the direct monitoring of environmental Cr3+. PMID- 30019896 TI - Synthesis of Cinnolines and Cinnolinium Salt Derivatives by Rh(III)-Catalyzed Cascade Oxidative Coupling/Cyclization Reactions. AB - A novel method for the synthesis of cinnolines and cinnolinium salt derivatives via Rh(III)-catalyzed cascade oxidative coupling/cyclization reaction from Boc arylhydrazines and alkynes has been developed. The reactions have a broad substrate scope and high stereoselectivity with readily available starting materials and provides an efficient synthetic route for this kind of compounds. A catalytically competent five-membered rhodacycle has been isolated, thus revealing a key intermediate in the catalytic cycle. PMID- 30019894 TI - Rationally Designed Peptides as Efficient Inhibitors of Nucleic Acid Chaperone Activity of HIV-1 Nucleocapsid Protein. AB - Due to its essential roles in the viral replication cycle and to its highly conserved sequence, the nucleocapsid protein (NCp7) of the human immunodeficiency virus type 1 is a target of choice for inhibiting replication of the virus. Most NCp7 inhibitors identified so far are small molecules. A small number of short peptides also act as NCp7 inhibitors by competing with its nucleic acid (NA) binding and chaperone activities but exhibit antiviral activity only at relatively high concentrations. In this work, in order to obtain more potent NCp7 competitors, we designed a library of longer peptides (10-17 amino acids) whose sequences include most of the NCp7 structural determinants responsible for its specific NA binding and destabilizing activities. Using an in vitro assay, the most active peptide (pE) was found to inhibit the NCp7 destabilizing activity, with a 50% inhibitory concentration in the nanomolar range, by competing with NCp7 for binding to its NA substrates. Formulated with a cell-penetrating peptide (CPP), pE was found to accumulate into HeLa cells, with low cytotoxicity. However, either formulated with a CPP or overexpressed in cells, pE did not show any antiviral activity. In vitro competition experiments revealed that its poor antiviral activity may be partly due to its sequestration by cellular RNAs. The selected peptide pE therefore appears to be a useful tool for investigating NCp7 properties and functions in vitro, but further work will be needed to design pE derived peptides with antiviral activity. PMID- 30019897 TI - Reactions of Cyclopentadienylidenes with CF3I: Electron Bond Donation versus Halogen Bond Donation of the Iodine Atom. AB - The interaction of cyclopentadienylidene and tetrachlorocyclopentadienylidene with the halogen bond donor CF3I has been studied by matrix isolation spectroscopy. The carbenes were produced by photolysis of the corresponding diazo compounds, matrix-isolated in argon doped with 1% CF3I at 3 K. Bimolecular reactions between the carbenes and CF3I were induced by annealing these matrices to 25-30 K to allow for the diffusion of trapped species. Instead of classical halogen-bonded complexes, these carbenes form complexes in which the iodine atom is shared between the carbene center and the CF3 group. Photolysis of the complexes at 3 K yields radical pairs, which reversibly react back to the complexes when the matrices are warmed to 25-30 K. PMID- 30019898 TI - A Data Science Approach to Understanding Water Networks Around Biomolecules: The Case of Tri-Alanine in Liquid Water. AB - Herein, we use recently developed data science algorithms to illustrate the complexity of the water network surrounding the hydrated peptide tri-alanine extracted from molecular dynamics simulations. We estimate the dimensionality of water variables and show that it is sensitive to the underlying secondary structure of the peptide. We show that water wires threading the peptide encode important information on the secondary structure. Interestingly, the free-energy landscape as revealed by the water wires is very rough for alpha-configurations and rather smooth for beta-configurations. The structured nature of the free energy landscape is washed out if one uses more standard collective variables such as the number of hydrogen bonds around the peptide. Our results provide fresh insights into the molecular ingredients behind the coupling of protein and solvent degrees of freedom relevant for many biophysical and chemical processes. PMID- 30019899 TI - Cobalt(III)-Catalyzed C-H Amidation of 7-Azaindoles with Dioxazolones: Synthesis of 7-Azaindole Amidated Derivatives. AB - An efficient cobalt-catalyzed C-H amidation of 7-azaindoles was developed by using dioxazolones as the amidating reagent. A wide scope of substituted 7 azaindoles, even N-vinly groups, is suitable for the reaction, generating 7 azaindoles derivatives with potential properties up to 91% yield under straightforward and strong applicable reaction conditions. PMID- 30019900 TI - Regioselective Arene and Heteroarene Functionalization: N-Alkenoxypyridinium Salts as Electrophilic Alkylating Agents for the Synthesis of alpha-Aryl/alpha Heteroaryl Ketones. AB - A direct regioselective functionalization of arenes and heteroarenes using N alkenoxypyridinium salts as electrophilic alkylating agents for the synthesis of alpha-aryl/heteroaryl ketones has been developed. The method generates alkylating agents from alkynes and N-pyridine oxide followed by site-selective electrophilic substitution with a broad range of arenes and heteroarenes including benzene derivates, phenols, ethers, indoles, pyrroles, furans, and thiophenes in one pot. Kinetic isotope effect measurements and DFT studies reveal that this reaction likely proceeds through a carbon-cation intermediate. PMID- 30019901 TI - Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression. AB - Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date. PMID- 30019902 TI - Optical Chirality Sensing with a Stereodynamic Aluminum Biphenolate Probe. AB - The determination of the enantiopurity and the concentration of chiral compounds by chiroptical sensing with molecular probes is increasingly attractive for high throughput screening applications including streamlined asymmetric reaction development. In this study, we use stereodynamic aluminum biphenolate complexes for quantitative ee and concentration analysis of amino alcohols and alpha hydroxy acids. An important feature of the tropos biphenolate ligand used is the presence of a phenylacetylene antenna for optimal chirality recognition and CD/UV responses at high wavelengths. The complexation-driven chirality amplification yields strong CD signals, which allows quantitative chiroptical sensing with good accuracy. We show that aluminate biphenolate sensors can exhibit linear and nonlinear correlations between the induced CD signals and the enantiomeric composition or concentration of the chiral substrate. PMID- 30019903 TI - Regiospecific Three-Component Aminofluorination of Olefins via Photoredox Catalysis. AB - Direct visible-light-mediated aminofluorination of styrenes has been developed with high regioselectivity. Shelf-stable N-Ts-protected 1-aminopyridine salt was used as the nitrogen-radical precursor, and the commercially available hydrogen fluoride-pyridine was used as the nucleophilic fluoride source. The synthesis of an analogue of LY503430 was performed to demonstrate the synthetic value of this strategy. PMID- 30019904 TI - Semilocal Pauli-Gaussian Kinetic Functionals for Orbital-Free Density Functional Theory Calculations of Solids. AB - Kinetic energy (KE) approximations are key elements in orbital-free density functional theory. To date, the use of nonlocal functionals, possibly employing system-dependent parameters, has been considered mandatory in order to obtain satisfactory accuracy for different solid-state systems, whereas semilocal approximations are generally regarded as unfit to this aim. Here, we show that, instead, properly constructed semilocal approximations, the Pauli-Gaussian (PG) KE functionals, especially at the Laplacian level of theory, can indeed achieve similar accuracy as nonlocal functionals and can be accurate for both metals and semiconductors, without the need for system-dependent parameters. PMID- 30019905 TI - Crude-MS Strategy for in-Depth Proteome Analysis of the Methane-Oxidizing Methylocystis sp. strain SC2. AB - Methylocystis sp. strain SC2 is a representative of the alphaproteobacterial methane oxidizers or type IIa methanotrophs. These microorganisms play a crucial role in methane cycling. Here, we developed an efficient analytical proteomics workflow for strain SC2. It tackles the major challenges related to the high amount of integral membrane proteins that need to be efficiently solubilized and digested for downstream analysis. Each step of the workflow, including cell lysis, protein solubilization and digestion, and MS peptide quantification, was assessed and optimized. Our new crude-lysate-MS approach proved to increase protein quantification accuracy and proteome coverage of strain SC2. It captured 62% of the predicted SC2 proteome, with up to 10-fold increase in membrane associated proteins relative to less effective conditions. The use of crude cell lysate for downstream analysis showed to be highly efficient for SC2 and other members of the family Methylocystaceae. Using two contrasting nitrogen conditions, we further validated our workflow efficiency by analyzing the SC2 proteome for differentially expressed proteins involved in methane and nitrogen metabolism. Our crude-MS approach may be applied to a variety of proteomic workflows incorporating cell types with challenging solubilization properties. Data are available via ProteomeXchange with identifier PXD009027. PMID- 30019906 TI - Triflic Acid Treatment Enables LC-MS/MS Analysis of Insoluble Bacterial Biomass. AB - The lysis and extraction of soluble bacterial proteins from cells is a common practice for proteomics analyses, but insoluble bacterial biomasses are often left behind. Here, we show that with triflic acid treatment, the insoluble bacterial biomass of Gram- and Gram+ bacteria can be rendered soluble. We use LC MS/MS shotgun proteomics to show that bacterial proteins in the soluble and insoluble postlysis fractions differ significantly. Additionally, in the case of Gram- Pseudomonas aeruginosa, triflic acid treatment enables the enrichment of cell-envelope-associated proteins. Finally, we apply triflic acid to a human microbiome sample to show that this treatment is robust and enables the identification of a new, complementary subset of proteins from a complex microbial mixture. PMID- 30019907 TI - Synthetic Studies of the Daphniphyllum Alkaloids: A Cooperative Reaction of Proximal Functional Groups Forming a Tetracyclic System. AB - During the course of synthetic studies of the Daphniphyllum alkaloids, an unusual reaction of a rhodium carbenoid was observed. The bicyclic substrate, in which an alpha-diazo-beta-ketoester moiety was present at the 3-position of a 1,4-diene moiety, was treated with rhodium pivalate to produce an intermediate having diene and ketene moieties. This intermediate underwent an intramolecular [4 + 2] cycloaddition reaction to form a tetracyclic compound. PMID- 30019908 TI - Implementation of an Evidence-Based Care Program Within a Multihospital Health Care System. AB - The need for evidence-based guidance at the local hospital level is challenged by lack of clinician resources to critically appraise and synthesize evidence, and the applicability and timing of external evidence reviews are not always ideal for local settings. BJC HealthCare established an Evidence-Based Care (EBC) program to address evidence synthesis needs within the organization using a standardized rapid review process. From 2012 to 2016, 377 rapid reviews were completed. Common review topics included supplies or technology (23%), infection prevention (20%), and patient safety (18%). The median turnaround time for reviews was 22 calendar days (16 business days). Of the 68% (28/41) of review requestors who responded to a survey, 89% agreed or strongly agreed that EBC's review informed their project or final decision, and 93% indicated that they likely would request a review in the future. Using rapid review methodology, an EBC program delivered timely and relevant evidence for local decision making. PMID- 30019909 TI - Prognostic utility of neutrophil-to-lymphocyte and platelets-to-lymphocyte ratio in predicting biochemical recurrence post robotic prostatectomy. AB - AIM: Utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting biochemical recurrence (BCR) in patients with localized prostate cancer. MATERIALS & METHODS: Retrospective analysis of patients operated by robot-assisted radical prostatectomy. Variables included were: NLR, PLR pre operative prostate specific antigen, pathological Gleason score, surgical margins status, extracapsular extension, seminal vesical invasion, and lymph node status. RESULTS: Out of 321 patients, no association between NLR or PLR and BCR was detected. Predictors of BCR were pathological Gleason score, extracapsular extension and positive surgical margins. On multivariate analysis, the Gleason Score, extracapsular extension and positive surgical margins remained the only predictors of BCR. CONCLUSION: Neither elevated NLR nor PLR predicted an increased risk of BCR. PMID- 30019910 TI - Cardiac myosin-binding protein C: how a novel biomarker could transform chest pain triage. PMID- 30019911 TI - Critical Review of Double-Carbapenem Therapy for the Treatment of Carbapenemase Producing Klebsiella pneumoniae. AB - OBJECTIVE: To review the clinical data on the effectiveness and safety of double carbapenem therapy (DCT) in patients infected with carbapenemase-producing Klebsiella pneumoniae (CP-Kp). DATA SOURCES: A literature search was performed utilizing PubMed and EMBASE (from 1966 to May 2018); bibliographies of the retrieved articles were also searched. STUDY SELECTION AND DATA EXTRACTION: Articles were included if they evaluated patients with infections caused by CP-Kp and were treated with DCT. Meeting abstracts, editorials, and animal and in vitro studies were excluded. DATA SYNTHESIS: The search strategy revealed 8 case reports and 6 clinical studies (total of 171 patients) that evaluated the administration of ertapenem followed by prolonged infusions of meropenem or doripenem. Most patients were critically ill and commonly had infections in the blood, lungs, and urine. Clinical and microbiological success were reported in 70% of the patients and mortality in 24%. Adverse events, which included mostly seizures, sodium disorders, and gastrointestinal symptoms, were reported in 16 patients; none required interruption of treatment. Relevance to Patient Care and Clinical Practice: This review evaluated the clinical experience of DCT in the treatment of CP-Kp infections, based on case reports and clinical studies, for the potential role of DCT as a therapeutic option. CONCLUSION: Despite the limited studies, current data suggest that DCT may be an effective and safe strategy to treat CP-Kp. However, large randomized controlled trials are necessary to clearly define the role of DCT. PMID- 30019912 TI - New Zealand Obese Mice as a Translational Model of Obesity-related Obstructive Sleep Apnea Syndrome. PMID- 30019913 TI - A Psychometric Examination of the Anagram Persistence Task: More Than Two Unsolvable Anagrams May Not Be Better. AB - The purpose of this investigation was to examine a single-anagram, a double anagram, and multi-anagram versions of the Anagram Persistence Task (APT) for factorial validity, reliability, and convergent validity. Additionally, a battery of intelligence tests was administered to examine convergent validity. Based on an unrestricted factor analysis, two factors were uncovered from the 14 anagram (seven very difficult and seven very easy) response times: test-taking persistence and verbal processing speed. The internal consistency reliabilities for the single-anagram, double-anagram, and multi-anagram (seven difficult anagrams) measures were .42, .85, and .86, respectively. Furthermore, all three versions of the APT correlated positively with intelligence test performance ( r ~ .22). However, the double-anagram and multi-anagram versions also evidenced negative, nonlinear effects with intelligence test performance ( r ~ -.15), which suggested the possibility of testee adaptation. Taking psychometrics and administration time into consideration, simultaneously, the double-anagram version of the APT may be regarded as preferred. PMID- 30019914 TI - Prevalence and potential predictors of gambling disorder among people living with HIV. AB - Specific subsets of the adult population are at an increased risk of problem gambling behaviors. Previous research among these subsets has found increased rates of disordered gambling among those with drug use, alcohol use, mood, anxiety, and personality disorders. To what extent this may apply to the HIV population, known to have a high burden of co-occurring substance use and mental disorders, is not known The current study also examined the effectiveness of The Brief Biosocial Gambling Screen (BBGS) for the diagnosis of gambling disorder. This study examined the prevalence of gambling behaviors and disordered gambling in patients enrolled in an urban HIV clinic. 100 people living with HIV (PLWH) were assessed on gambling behaviors, impulsivity, and criterion on disordered gambling. Screening for gambling disorder using the BBGS was compared to the American Psychiatric Association DSM-5 criterion. The mean age was 53, 44% were female, 60% completed high school or above, and 80% self-identified as unemployed/disabled. 13% met four or more criteria for gambling disorder according to DSM-5 criteria. Participants that met criteria were more likely to report marijuana (p = .044) and heroin (p = .002) use, and greater impulsivity (p < 0.00001) when compared to participants who did not meet criteria. The BBGS was able to effectively screen individuals for disordered gambling with a sensitivity of 100%, specificity of 90.8%, positive predictive value of 56.2%, and a negative predictive value of 100%. These results suggest that urban HIV clinics may need to consider actively screening for gambling disorders, and referring to appropriate counseling and treatment for those who screen positive. PMID- 30019915 TI - Effects of SOX15 on the colorectal cancer cells via downregulation of the Wnt/beta-catenin signaling pathway. AB - AIM: To detect the function and mechanism of SOX15 in colorectal cancer. MATERIALS & METHODS: The expression of SOX15 in colorectal cancer (CRC) cells and tissues was detected by real-time PCR, quantitative real-time PCR and immunohistochemistry. The overexpression of SOX15 in cells was tested by western blot, CCK-8, FACS analysis, transwell and clone assay. Moreover, SOX15 regulated Wnt pathway investigated by western blot. RESULTS: We found that SOX15 has a low expression in CRC cells and tissues. Overexpression of SOX15 can inhibit the proliferation, migration and invasion of cells and induce cells apoptosis. Furthermore, SOX15 could be the inhibitor of Wnt/beta-catenin pathway in CRC. CONCLUSION: SOX15 can be a tumor suppressor in CRC by suppressing the Wnt/beta catenin signaling pathway. PMID- 30019916 TI - Need for a Judicious Use of Nonsteroidal Anti-inflammatory Drugs to Avoid Community-Acquired Acute Kidney Injury. AB - Millions of Americans use over-the-counter analgesics on a daily basis, and nearly 100 million nonsteroidal anti-inflammatory drug (NSAID) prescriptions are filled per year. In high-risk patients, these medications can disrupt kidney hemodynamics and precipitate community-acquired acute kidney injury (CA-AKI). The risk of NSAID-associated CA-AKI increases 3- to 5-fold in patients taking renin angiotensin system inhibitors and diuretics concurrently. CA-AKI increases the risk of developing chronic kidney disease (CKD) or accelerating progression of pre-existing CKD. Importantly, many cases of NSAID-induced CA-AKI may be avoided by identifying high-risk patients and providing patient and provider education on when to avoid these medications and minimize risk. PMID- 30019917 TI - Plasmodium falciparum dihydroorotate dehydrogenase: a drug target against malaria. AB - Malaria remains one of the most lethal infectious diseases worldwide, and the most severe form is caused by Plasmodium falciparum. In recent decades, the major challenge to treatment of this disease has been the ability of the protozoan parasite to develop resistance to the drugs that are currently in use. Among P. falciparum enzymes, P. falciparum dihydroorotate dehydrogenase has been identified as an important target in drug discovery. Interference with the activity of this enzyme inhibits de novo pyrimidine biosynthesis and consequently prevents malarial infection. Organic synthesis, x-ray crystallography, high throughput screening and molecular modeling methods such as molecular docking, quantitative structure-activity relationships, structure-based pharmacophore mapping and molecular dynamics simulations have been applied to the discovery of new inhibitors of P. falciparum dihydroorotate dehydrogenase. PMID- 30019919 TI - Introduction to COX inhibitors. PMID- 30019918 TI - Tailoring breast cancer therapies to reduce mortality and improve quality of life: San Antonio Breast Cancer Symposium 2017 (part 1). AB - The 40th annual San Antonio Breast Cancer Symposium was convened in San Antonio, TX, USA on 5-9 December 2017. More than 7500 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, loco-regional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with part 1 focusing on dose-intense radiotherapy, perioperative endocrine therapy, duration of bisphosphonates, immunotherapy, ovarian function suppression and acupuncture. The second part of this report will discuss a range of topics related to de-escalation of loco-regional therapies, the significance of complete pathological response, older patients and CDK 4/6 inhibitors, circulating tumor cells and plasma DNA as a tumor marker. PMID- 30019920 TI - A Concept Analysis of Resistiveness to Care. AB - People with cognitive impairment often require assistance with activities of daily living. It is when providing assistance with these activities that many caregivers experience behaviors that have been categorized as disruptive or problematic and called resistiveness to care. These behaviors are considered to be a source of burden and job burnout for caregivers. Nurses wanting to help caregivers, who manage these trying situations, need to understand the concept of resistiveness to care and communicate this knowledge clearly with health care providers. Therefore, a literature search was conducted in 2012 within the databases CINAHL, Medline (PubMed), ProQuest, and PsychINFO. This produced 40 relevant articles. Because no concept analysis existed for resistiveness to care, a principle-based concept analysis was performed. The analysis helped construct a theoretically defined concept. Further analysis highlighted that more research is needed to advance the concept of resistiveness to care to enhance professional communication surrounding this phenomenon. PMID- 30019921 TI - Comparison of the rates of stroke and acute coronary events in northern France. AB - Background Although stroke and acute coronary events share several risk factors, few studies have compared population-level epidemiological surveillance indicators of the two diseases in the same age range and in the same geographical area. Design The objective of the present study was to compare the rate of acute coronary events with that of stroke among inhabitants aged from 35-74 years in Northern France (Lille). Methods All incident and recurrent acute coronary events and stroke events occurring in men and women over 2008-2014 were recorded using two population-based registries with several overlapping sources of case ascertainment for hospitalised/non-hospitalised and fatal/non-fatal events. Log linear Poisson regression models were used to compare the event and mortality rates. Results The results showed that the incident rates of acute coronary event and stroke were similar except under 60 years. In this group (35-59 years), the incident rate of acute coronary events was 1.6-fold higher than that of stroke. In contrast, the attack (incident and recurrent) rates were higher for acute coronary events than for stroke (1.5-fold; p < 0.0001) - especially in men (1.8 fold; p < 0.0001). The mortality rate was 2.2-fold higher for acute coronary events than for stroke, independent of sex and age group ( p < 0.0001), as was the case-fatality rate (1.5-fold, p < 0.0001). Conclusion In Lille, the overall acute coronary event rate was higher than the stroke rate - especially among men, due to a higher risk of incident acute coronary event under the age of 65 and a higher risk of recurrent acute coronary event in the 65-74 year-old age range. Further efforts should be devoted to primary and secondary prevention strategies after acute coronary events. PMID- 30019922 TI - Unhealthy shift work. PMID- 30019923 TI - Incidence and mortality of myocardial infarction among Catalonian older adults with and without underlying risk conditions: The CAPAMIS study. AB - BACKGROUND: Population-based data about the epidemiology of acute myocardial infarction is limited. This study investigated incidence and mortality of acute myocardial infarction in older adults with specific underlying chronic conditions and evaluated the influence of these conditions in developing acute myocardial infarction. DESIGN AND METHODS: This was a population-based cohort study involving 27,204 individuals >= 60 years of age in Tarragona (Catalonia, Spain). Data on all cases of hospitalised acute myocardial infarction were collected from 1 December 2008-30 November 2011. Incidence rates and 30-day mortality were estimated according to age, sex, chronic illnesses and underlying conditions. Multivariable Cox regression analysis was used to calculate hazard ratios and to estimate the association between baseline conditions and risk of developing acute myocardial infarction. RESULTS: The incidence of acute myocardial infarction was 475 per 100,000 person-years. Maximum rates appeared among individuals with history of coronary artery disease (2839 per 100,000), chronic severe nephropathy (1407 per 100,000), atrial fibrillation (1226 per 100,000), chronic heart disease (1149 per 100,000), history of stroke (1147 per 100,000) and diabetes mellitus (914 per 100,000). Thirty-day mortality was 15.3% overall, reaching 31.6% among patients over 80 years. In the multivariable analysis, history of coronary artery disease, age > 70 years, sex male, chronic heart disease, history of stroke, atrial fibrillation, diabetes mellitus and hypertension emerged as significantly associated with an increased risk of acute myocardial infarction. CONCLUSIONS: The incidence and mortality of acute myocardial infarction remain considerable in our setting. Considering classical major risk factors, diabetes mellitus and hypertension were the underlying conditions most strongly associated with an increased risk in our study population. PMID- 30019924 TI - Rational application of drug promiscuity in medicinal chemistry. AB - 'Drug promiscuity' refers to a drug that can act on multiple molecular targets, exhibiting similar or different pharmacological effects. Drugs may interact with unwanted targets, leading to off-target effects (one of the main reasons for side effects). Thus, intervention to prevent off-target effects in the early stages of drug discovery could reduce the risk of failure. The conversion between target and off-target effects is important for drug repurposing. Drug repurposing strategies could reduce research and development costs. This review details the research progress in the rational application of drug promiscuity for the discovery of multi-target drugs, drug repurposing and improving druggability in medicinal chemistry over the last 5 years. PMID- 30019925 TI - Synthesis & molecular modeling studies of bronchodilatory active indole-pyridine conjugates. AB - AIM: Synthesis of novel bronchodilatory active indole-pyridine conjugates. Results/methodology: Indole-pyridine conjugates (6a-n, 8a-i and 10a-c) were synthesized in a facile pathway through reaction of 2-[(1-alkyl-1H-indol-3 yl)methylene]malononitriles 4a,b with the corresponding ketone-containing compounds (5a-f, 7a-c and 9a,b) in the presence of sodium alkoxide. Single (6l, 8 g) and powder (6k, 8d) x-ray studies supported the structures. RESULTS: Histamine precontracted isolated tracheal rings of guinea pig exhibited the potent bronchodilation properties of 6c (about double-fold potency relative to the standard reference, theophylline). Some of the synthesized conjugates (8d, 6c, 6f and 6e) revealed promising reduction of IL-8 production during lipopolysaccharide induced airway inflammatory bioassay. Computational studies (3D pharmacophore, 2D QSAR 'quantitative structure-activity relationship') showed high approximations to the bronchodilation properties and explained the parameters controlling biological observations. PMID- 30019926 TI - The Experiences of Muslim Family Members of Critically Ill Patients During End-of Life Care in Saudi Arabia: A Qualitative Phenomenological Study. AB - The aim of this study was to identify the needs, beliefs, and practices of Muslim family members during the end-of-life care for a family member in the intensive care unit (ICU) in Saudi Arabia. This was a phenomenological study using in-depth individual interviews to gather data. Ten family members of adult ICU patients receiving end-of-life care were interviewed. The experiences of family members during end-of-life care were reflected in four major themes: (a) the spirituality of death, (b) family's need for information, (c) being there, and (d) the ICU environment. Participants placed high value on religious practices such as prayer, and appreciated when these practices could be accommodated in the ICU. Family participants also detailed their need for frequent communication and opportunities to ask questions about the care of their critically ill loved one. Being able to spend as much time as desired in close proximity to the critically ill patient particularly as the end of life approaches was also important, with participants suggesting that visitation times should be waived. Finally, family participant suggested that changes were needed to the ICU environment to make accommodating large families easier and more comfortable particularly when they wish to spend significant time at the bedside of their loved one. Family should be prioritized as an extension of the care provided to critically ill ICU patients, particularly those approaching end of life. A model of care should be introduced to deliver supportive and holistic care during the end-of-life care journey, supported by appropriate education regarding family care at the end of life. PMID- 30019927 TI - An efficient formulation based on cationic porphyrins to photoinactivate Staphylococcus aureus and Escherichia coli. AB - AIM: Antibiotic resistance is an increasingly serious worldwide problem that needs to be addressed with alternative tools. Antimicrobial photodynamic therapy seems a promising approach but in some cases the synthesis of highly efficient photosensitizers requires laborious processes burdened by extensive chromatographic purifications. In this study, we evaluate the suitability of a formulation (Form-1) containing porphyrins bearing different charges, obtained during the synthesis of the highly efficient photosensitizer 5,10,15-tris(1 methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide. RESULTS: Form 1 was equally effective in the photoinactivation of Escherichia coli and Staphylococcus aureus (reductions >5 log) as the best stand-alone photosensitizer. CONCLUSION: The effective reduction of bacteria with Form-1 provided promising indications supporting its use, leading to a substantial decrease in costs and production time. PMID- 30019929 TI - Prospective relation of adolescent citrate excretion and net acid excretion capacity with blood pressure in young adulthood. AB - Experimental data and observational studies in adults suggest that even subtle changes in acid-base balance, indicative of a higher systemic proton load, are related to higher blood pressure (BP) levels and an increased hypertension risk. However, these associations have not been investigated during growth. The kidney is the central organ in regulating excretion of non-volatile acids and renal citrate excretion has been shown to be a sensitive non-invasive marker of changes in systemic acid-balance. We thus analysed the prospective relation of 24-h citrate excretion as well as net acid excretion capacity (NAEC, a non-invasive indicator of the renal ability to excrete protons) during adolescence (males: 10 15 years, females: 9-14 years) with BP-levels in young adulthood (18-30 years) in 374 healthy participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study. In linear regression analyses adjusted for age, sex, 24-h urinary excretions of sodium and potassium as well as further relevant confounders, a 1 mmol/1.73 m2/d higher adolescent citrate excretion was related to 1.2 mmHg lower systolic BP (P=0.02) but not to diastolic BP (P=0.6). A 10 mEq higher NAEC during adolescence was related to 1.7 mmHg lower systolic BP in young men, but this association was statistically non-significant (P=0.07) after multivariable adjustment. Additional adjustment for adult BMI did not alter these findings. To conclude, subtle changes in systemic acid-base balance during adolescence are already indicative for later BP. Potential sex-differences in these associations should be investigated in further studies. PMID- 30019930 TI - Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data. AB - The mechanisms of cardiovascular and renal protection observed in clinical trials of SGLT2 inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg dapagliflozin once-daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiologic variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of NHE3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects, and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower GFR, suggesting cardiorenal benefits of SGLT2i may be sustained in renally impaired patients. PMID- 30019928 TI - miRNA in a multiomic context for diagnosis, treatment monitoring and personalized management of metastatic breast cancer. AB - Metastatic breast cancer is characterized by aggressive spreading to distant organs. Despite huge multilevel research, there are still several important challenges that have to be clarified in the management of this disease. Therefore, recent investigations have implemented a modern, multiomic approach with the aim of identifying specific biomarkers for not only early detection but also to predict treatment responses and metastatic spread. Specific attention is paid to short miRNAs, which regulate gene expression at the post-transcriptional level. Aberrant miRNA expression could initiate cancer development, cell proliferation, invasion, migration, metastatic spread or drug resistance. An miRNA signature is, therefore, believed to be a promising biomarker and prediction tool that could be utilized in all phases of carcinogenesis. This article offers comprehensive information about miRNA profiles useful for diagnostic and treatment purposes that may sufficiently advance breast cancer management and improve individual outcomes in the near future. PMID- 30019931 TI - CELLS OF NG2 LINEAGE INCREASE IN GLOMERULI OF MICE FOLLOWING PODOCYTE DEPLETION. AB - Under certain circumstances, podocytes can be partially replaced following their loss in disease. The inability of podocytes to proliferate suggests that replacement derives from other cell types. Because Neural/glial antigen 2 (NG2) expressing cells can serve as progenitors in other organs, and because herein we showed increased NG2 staining in podocytes following their loss in experimental FSGS, we used lineage tracing in NG2-CreER tdTomato mice to test the hypothesis that partial podocyte replacement might derive from this cell population. The percentage of glomeruli with RFP-labeled NG2 cells increased following podocyte depletion, which was augmented by enalapril. However, BrdU was not detected in RFP-labeled cells, consistent with the migration of these cells to the glomerulus. Within glomeruli, RFP-labeled cells did not co-express podocyte proteins (p57, synaptopodin, nephrin or podocin), but did co-express markers for mesangial (alpha8 Integrin, PDGFbeta Receptor) and parietal epithelial cells (PAX8, SSeCKS). These results suggest that following podocyte depletion, cells of NG2 lineage do not serve as adult podocyte progenitors, but have the ability to transdifferentiate to mesangial and parietal epithelial cell fates. PMID- 30019932 TI - Soluble (Pro)Renin Receptor as a Potential Therapy for Diabetes Insipidus. AB - The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus, and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs) on the basolateral membrane of principal cells of the collecting duct (CD) to regulate fluid permeability. The VP-evoked endocrine pathway is essential in determining urine concentrating capability. For example, a defect in any component of the VP signaling pathway can result in polyuria, polydipsia, and hypotonic urine, collectively termed diabetes insipidus (DI). A lack of VP production precipitates central diabetes insipidus (CDI) which can be managed effectively by VP supplementation. A majority of cases of nephrogenic diabetes insipidus (NDI) result from V2R mutations that impair receptor sensitivity. No specific therapy is currently available for management of NDI. Evidence is evolving that (Pro)renin receptor (PRR), a newly identified member of the renin angiotensin system, is capable of regulating VP production and action. As such, PRR should be considered strongly as a therapeutic target for treating CDI and NDI. The current review will summarize recent advances in understanding the physiology of renal and central PRR as it relates to the two types of DI. PMID- 30019933 TI - The endocrine disruptor Bisphenol-A is implicated in urinary voiding dysfunction in male mice. AB - Estrogens, acting synergistically with androgens, are known from animal experiments to be important in lower urinary tract symptoms (LUTS) and benign prostate enlargement. Human exposure to environmental estrogens occurs throughout the lifespan, but the urologic health risks in men are largely unknown. Bisphenol A (BPA) is an endocrine disruptor implicated in male urogenital malformations. Given the role of estrogens in male LUTS, we studied the effects of BPA administered in combination with testosterone (T) on the urinary voiding behavior of adult male mice. Adult male mice underwent subcutaneous implantation with slow release pellets of 25 mg BPA or 2.5 mg estradiol-17beta (E2), plus 25 mg T and were compared to untreated (UNT) mice that underwent sham surgery. We studied urinary voiding behavior noninvasively for one month prior to treatment and for four months after treatment. After euthanasia, we evaluated bladder volume and mass. Mice treated with T+BPA had increased bladder volume (p < 0.05) and mass (p < 0.01) compared to UNT mice. After four months of treatment with T+BPA, three of five mice developed voiding dysfunction in the form of droplet voiding or an intermediate pattern of voiding different from both UNT and T+E2 treated mice. Treatment of male mice with BPA or estradiol induces voiding dysfunction that manifests at later time points, implicating the endocrine disruptor, BPA, as a contributor to male LUTS. PMID- 30019934 TI - Reduced bladder responses to capsaicin and GSK1016790A in retired-breeder female rats with diminished volume sensitivity. AB - Literature documents an age related reduction of bladder sensory function. TRPV1 or TRPV4 channels have been implicated in bladder mechano-transduction. To investigate contributions of TRPV1 or TRPV4 to the age related reduction of bladder sensory function, bladder responses to capsaicin (CAP, TRPV1 agonist) and GSK1016790A (GSK, TRPV4 agonist) in retired breeder (RB, 12-15 months) and young adult (2-3 month) female rats were compared using multiple methods. Metabolic cage and continuous infusion cystometry (CMG) recordings revealed that RB rats exhibit larger bladder capacity and lower voiding frequency. RB rats also have a greater intravesical pressure threshold for micturition, however, the voiding contraction strength was equivalent to that in young rats. CAP (1MUM) or GSK (20nM) administered intravesically evoked smaller changes in all CMG parameters in RB rats. In vitro, CAP (1MUM) or GSK (20nM) evoked smaller enhancement of bladder strip contractions, while the muscarinic receptor agonist carbachol (at 100, 300 and 1000 nM) elicited greater amplitude contractions in RB rats. Patch clamp recording revealed smaller CAP (100 nM) induced inward currents in bladder primary sensory neurons, and Ca2+ imaging revealed smaller GSK (20 nM) evoked increases in [Ca2+]i in urothelial cells in RB rats. These results suggest that RB rats have a decreased bladder sensory function commonly observed in elderly women, and could be used as an animal model to study the underling mechanisms. Reduced functional expression of TRPV1 in bladder afferents or reduced functional expression of urothelial TRPV4 may be associated with the diminished sensory function. PMID- 30019935 TI - The Murine Dialysis Fistula Model Exhibits a Senescence Phenotype: Pathobiologic Mechanisms and Therapeutic Potential. AB - There is no therapy that promotes maturation and functionality of a dialysis arteriovenous fistula (AVF). The search for such therapies largely relies on evaluating vascular responses and putative therapies in experimental AVFs. We studied an AVF in mice with chronic kidney disease (CKD). We demonstrate numerous stressors in the vein of the AVF-CKD group, including pathologic shear, mitogenic, inflammatory, and hypoxia-reoxygenation stress. Because stress promotes premature senescence, we examined whether senescence is induced in the vein of the AVF-CKD model. We demonstrate a senescence phenotype in the AVF-CKD model as indicated by increased expression of p16Ink4a, p21Cip1, and p53, and expected changes for certain senescence-associated miRNAs. RNA-Seq analysis demonstrated that approximately 10,000 genes were differentially expressed in the vein of the AVF-CKD group, including upregulation of proinflammatory and proliferative genes. The vein in the AVF-CKD group exhibited telomere erosion and increased senescence-associated beta-galactosidase activity and staining. Senescence was induced in the artery of the AVF-CKD group, and in the vein of the AVF without CKD. Finally, given the rapidly rising clinical interest in senolytics, we provide proof-of-concept of senolytics as a therapeutic approach by demonstrating that senolytics decrease p16Ink4a expression in the AVF-CKD model. This study introduces a novel concept underlying the basis for maturational and functional failure in human dialysis AVFs and identifies a new target for senolytic therapy. PMID- 30019936 TI - Analysis of risk factors of lymph node metastasis in rectal neuroendocrine neoplasms using multicenter data. AB - AIM: This study was conducted to analyze the risk factors associated with lymph node metastasis in rectal neuroendocrine neoplasms (NENs). MATERIALS & METHODS: A total of 419 patients with rectal NENs were enrolled. A univariate analysis of risk factors of lymph node metastasis was conducted using a chi2 test, and a multivariate analysis was conducted using a logistic regression analysis. RESULTS: Univariate and multivariate regression analysis revealed that tumor size, G grade and the depth of tumor invasion were independent risk factors for lymph node metastasis (p < 0.05). CONCLUSION: Rectal NENs patients with a larger tumor size, deeper tumor invasion or a higher G grade had a higher risk of regional lymph node metastasis. PMID- 30019938 TI - From the Editor-in-Chief's Desk. PMID- 30019937 TI - Synthesis and drug efficacy validations of racemic-substituted benzimidazoles as antiulcer/antigastric secretion agents. AB - AIM: Due to their effective binding affinity to receptors which are responsible for various diseases, benzimidazoles are often bioactive. Present study intended and carried out to synthesis, characterize and develop benzimidazole-based antiulcer drugs. Materials & methods: Established 8a-l were evaluated for gastric antisecretory/antiulcer properties using freshly prepared H+-K+-ATPase from goat fundus mucosa. Molecular docking was carried out to unveil best binding affinities with H+-K+-ATPase (protein data bank ID: 2XZB). RESULTS: The obtained least inhibitory constant of 8a-l (18-92 nM) was comparable to the in vitro H+-K+ ATPase inhibition (IC50: 24-122 nM). Furthermore, the lethal effect of 8a-l to colon cancerous cells and nonharm effect to the normal cells was recognized through cytotoxicity studies. CONCLUSION: After all in silico, in vitro experimental and structure-activity relationship predictions, the antiulcer druggability potential of 8a-l was recognized. A future drug development study for the most potent compounds among 8a-l is strongly indorsed. PMID- 30019939 TI - Capturing Exacerbations of Chronic Obstructive Pulmonary Disease with EXACT: A Sub-Analysis of FLAME. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n=457) from the FLAME study used the EXAcerbations of COPD Tool (EXACT(r)) to capture symptom-defined exacerbations. OBJECTIVES: To evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU). METHODS: All patients in FLAME used an e-Diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time-to-first symptom-defined (EXACT) exacerbation, and assessed differences between symptom defined and HCRU events in terms of number, severity and concordance. MEASUREMENTS AND MAIN RESULTS: A non-significant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio: 0.83, 95% CI: 0.60, 1.14, P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with IND/GLY versus SFC (HR 0.76, 95% CI: 0.56, 1.03, P = 0.075). These results were consistent with data from the overall FLAME population. 23.5% of symptom-defined (EXACT) events corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (kappa index 0.24, 95% CI: 0.15, 0.33). CONCLUSIONS: Regardless of the exacerbation definition used, our findings support the use of LABA/LAMAs as the preferred treatment option for patients at risk of future exacerbations. PMID- 30019940 TI - Tailoring breast cancer therapies to reduce mortality and improve quality of life: San Antonio Breast Cancer Symposium 2017 (part 2). AB - The 40th annual San Antonio Breast Cancer Symposium was convened in San Antonio, TX, USA on 5-9 December 2017. More than 7500 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, loco-regional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with part 1 focusing on dose-intense radiotherapy, perioperative endocrine therapy, duration of bisphosphonates, immunotherapy, ovarian function suppression and acupuncture. The second part of this report will discuss a range of topics related to de-escalation of loco-regional therapies, the significance of complete pathological response, older patients and CDK 4/6 inhibitors, circulating tumor cells and plasma DNA as a tumor marker. PMID- 30019941 TI - Drug Repurposing Patent Applications October-December 2017. PMID- 30019942 TI - Drug Repurposing Patent Applications January-March 2018. PMID- 30019943 TI - Drug Repurposing and Artificial Intelligence: From Liaison to Marriage. PMID- 30019944 TI - A Computational Study on the Blocking Ability of Selected Commercially Available Anticancer Drugs and Their Hypothetic Derivatives on the CCR5. AB - Computational studies were done on the complexes between some commercially available anticancer drugs and their hypothetic derivatives and the CCR5 protein. At first step, the docking studies were done to obtain the best ligand that can inhibit the CCR5 protein. Based on the binding energy results obtained from the docking studies, 16 complexes were selected. Molecular dynamic studies were carried out on these structures and then molecular mechanics-generalized Born surface area calculations were done to find the binding energies of the ligands to the CCR5 protein. Based on the investigation of the binding modes of the ligands to the CCR5 protein, the TYR and ALA have more tendency to bind to the ligand moieties. By decomposing of the binding energies, it was found that the van der Waals interactions have the most important role in the binding of ligands to the protein in comparison with the electrostatic and hydrogen bonding interactions. The results of the interaction potential surface map analysis showed that the nitrogen and oxygen atoms have a relatively similar role in the binding of ligands to the CCR5 protein structure. PMID- 30019945 TI - Literature Search and Review. PMID- 30019947 TI - The next generation of therapy for multiple myeloma: a review of ongoing clinical trials utilizing ClinicalTrials.gov. AB - The therapeutic armamentarium for multiple myeloma has grown significantly over the past decade. We characterized ongoing multiple myeloma clinical trials utilizing ClinicalTrials.gov . A search of ClinicalTrials.gov on 21 April 2017 returned 239 therapeutic interventional trials in multiple myeloma. A majority (84.1%) of trials are early-phase (I/II). Immunotherapies are significantly more likely to be studied in Phase I trials than Phase II trials (p = 0.0049). Primary sponsor (academic, cooperative group, industry) is significantly associated with phase of trial (p = 0.0334). Quality of life assessment is included as a secondary objective in only 10.1% of trials. Areas of need are continued advancement of immunotherapies, late-phase studies utilizing a triplet control group, and an objective focus on quality of life. PMID- 30019946 TI - Identification of Novel, Structurally Diverse, Small Molecule Modulators of GPR119. AB - GPR119 drug discovery efforts in the pharmaceutical industry for the treatment of type 2 diabetes mellitus (T2DM) and obesity, were initiated based on its restricted distribution in pancreas and GI tract, and its possible role in glucose homeostasis. While a number of lead series have emerged, the pharmacological endpoints they provide have not been clear. In particular, many lead series have demonstrated loss of efficacy and significant toxic side effects. Thus, we sought to identify novel, potent, positive modulators of GPR119. In this study, we have successfully developed and optimized a high throughput screening strategy to identify GPR119 modulators using a live cell assay format that utilizes a cyclic nucleotide-gated channel as a biosensor for cAMP production. Our high-throughput screening (HTS) approach is unique to that of previous HTS approaches targeting this receptor, as changes in cAMP were measured both in the presence and absence of an EC10 of the endogenous ligand, oleoylethanolamide, enabling detection of both agonists and potential allosteric modulators in a single assay. From these efforts, we have identified positive modulators of GPR119 with similar as well as unique scaffolds compared to existing compounds and similar as well as unique signaling properties. Our compounds will not only serve as novel molecular probes to better understand GPR119 pleiotropic signaling and the underlying physiological consequences of receptor activation, but are also well-suited for translation as potential therapeutic agents. PMID- 30019948 TI - Resonant interaction between electromagnetic fields and proteins: A possible starting point for the treatment of cancer. AB - Samples of human hemoglobin, bovine serum albumin, lysozyme and myoglobin were used as prototype of proteins to investigate their response to exposure to high frequency electromagnetic fields (HF-EMFs), in order to study possible application to the treatment of cancer. To this aim, Fourier-transform infrared spectroscopy was used in the infrared region. The most evident result which appeared after 3 h exposure to HF-EMFs was a significant increase in intensity of the Amide I band and of CH2 bending vibrations, showing that the proteins aligned toward the direction of the field. In addition, proteins' unfolding and aggregation occurred after exposure to HF-EMFs. These findings can be explained assuming a resonance interaction between the natural frequencies of proteins and HF-EMFs, which can induce iperpolarization of cells. Given that cancerous tissues were found to have natural frequencies different from natural frequencies of normal tissues, we can hypothesize to irradiate cancerous tissues using EMFs at natural frequencies of cancer cells, causing resonant interaction with cellular membrane channels, inducing increasing of ions' flux across cellular channels and damaging the cellular functions of cancer cells. PMID- 30019949 TI - Investigational drug therapies in phase I and phase II clinical trials for alcohol use disorders. AB - INTRODUCTION: Alcohol use disorder (AUD) is a complex psychiatric condition characterized by craving, compulsive seeking, loss of control of alcohol consumption as well as the emergence of negative emotional states during withdrawal. Despite the large socioeconomic burden of AUD, therapeutic treatment options lag behind. Areas covered: This review covers pharmacotherapies currently in phase I/II clinical trials for the treatment of AUDs listed on clinicaltrials.gov. We discuss drug therapies that modulate monoamine, GABA/Glutamate, neuropeptide and neuroimmune systems. We examine in depth preclinical and clinical evidence of a select range of these compounds and consider their utility in treating AUDs. Expert opinion: Current therapeutic options to treat AUD are inadequate at a population level. Currently there are 30 different compounds and one compound combination in phase I/II clinical trials for AUD. These compounds target various aspects of neurotransmitter signaling, neuroimmune modulation, and alcohol metabolism. Almost 75% of these compounds under trial are Food and Drug Administration (FDA) approved for other indications, which may save time and costs in treatment development. Further, development of therapeutics focused on genetic biomarkers and behavioral screening may improve how treatment decisions are made in the future on a case-by case basis. PMID- 30019950 TI - Using Electronic Contact to Reduce Homonegative Attitudes, Emotions, and Behavioral Intentions Among Heterosexual Women and Men: A Contemporary Extension of the Contact Hypothesis. AB - The current study experimentally examined the potential for a contemporary extension of the contact hypothesis, known as electronic contact, or E-contact, to reduce sexual prejudice, intergroup anxiety, and avoidant behavioral intentions among heterosexuals. It also extended the sexual minority contact literature by examining the role of participant and interaction partner sex as a possible boundary condition of this contact-prejudice relationship. To test our hypotheses, 140 heterosexual female and male university students were randomly allocated to interact with a homosexual or heterosexual, female or male E-contact partner, in a collaborative and text-only online interaction before completing the outcome measures. Overall, the results demonstrated that interacting online with a female, as opposed to a male, homosexual E-contact partner reduced heterosexual men's feelings of intergroup anxiety, which in turn was associated with lower sexual prejudice and outgroup avoidance. For heterosexual women, however, E-contact did not influence the outcome variables. In the context of sexual prejudice, these results suggest that E-contact may be particularly useful as a prejudice-reduction strategy among individuals who typically require it most: heterosexual men. PMID- 30019951 TI - EDITORIAL RETRACTION. PMID- 30019952 TI - An Unusual Variant of a Floating Forearm Injury: A Case Report and Review. AB - BACKGROUND: "Floating forearm" injuries, perilunate injuries, with an elbow dislocation, are rare and challenging to treat. METHODS: We present the case of an unusual variant of a floating forearm injury, trans-scaphoid perilunate fracture dislocation and elbow dislocation, with a concomitant open both-bone forearm fracture after a fall from a ladder. Treatment involved irrigation and debridement of the forearm wound, open reduction and internal fixation of the forearm and perilunate injury, and closed reduction of the elbow. RESULTS: At final follow-up, he had returned to his previous occupation. Radiographs demonstrated fully healing fractures without evidence of osteonecrosis or degeneration. CONCLUSIONS: A review of the presentation, evaluation, and management of this rare injury pattern is provided. PMID- 30019953 TI - Use of quantitative clinical pharmacology to improve early clinical development success in neurodegenerative diseases. AB - INTRODUCTION: The success rate of pharmaceutical Research & Development (R&D) is much lower compared to other industries such as micro-electronics or aeronautics with the probability of a successful clinical development to approval in central nervous system (CNS) disorders hovering in the single digits (7%). Areas covered: Inspired by adjacent engineering-based industries, we argue that quantitative modeling in CNS R&D might improve success rates. We will focus on quantitative techniques in early clinical development, such as PharmacoKinetic-PharmacoDynamic modeling, clinical trial simulation, model-based meta-analysis and the mechanism based physiology-based pharmacokinetic modeling, and quantitative systems pharmacology. Expert commentary: Mechanism-based computer modeling rely less on existing clinical datasets, therefore can better generalize than Big Data analytics, including prospectively and quantitatively predicting the clinical outcome of new drugs. More specifically, exhaustive post-hoc analysis of failed trials using individual virtual human trial simulation could illuminate underlying causes such as lack of sufficient functional target engagement, negative pharmacodynamic interactions with comedications and genotypes, and mismatched patient population. These insights are beyond the capacity of artificial intelligence (AI) methods as they are many more possible combinations than subjects. Unlike 'black box' approaches in AI, mechanism-based platforms are transparent and based on biologically sound assumptions that can be interrogated. PMID- 30019955 TI - Antioxidative Capacity of and Contaminant Concentrations in Processed Plum Products Consumed in Romania. AB - The bioactive compounds (total phenols, anthocyanins, and flavonoids) and antioxidant activity of plum-based products (prunes, jams, and marmalade) were evaluated based on spectrophotometric assays and acrylamide and 5-hydroxymethyl-2 furaldehyde concentrations to determine the quality and safety of these products in the Romanian marketplace. The total polyphenol concentrations in prunes, marmalade, and jams were 0.93 to 5.63 g of gallic acid equivalent per kg of dry matter, and the antioxidant activity was 3.0 to 17.2 mmol/kg. The concentrations of potentially harmful acrylamide in the plum products ranged from the limit of quantitation (<20 MUg/kg) to 37.44 MUg/kg, and the concentration was higher in prunes (26.66 to 163.72 MUg/kg) than in jams. The 5-hydroxymethyl-2-furaldehyde concentrations in plum products were also variable, at 36 to 2,149 mg/kg. These data revealed a very low concentration of acrylamide in thermally processed plum products, and the results for total polyphenols and the antioxidant activity of prunes and plum jams may be relevant for evaluating these products as important sources of bioactive compounds. PMID- 30019956 TI - Carbapenemases and Extended-Spectrum beta-Lactamase-Producing Multidrug-Resistant Escherichia coli Isolated from Retail Chicken in Peshawar: First Report from Pakistan. AB - We report the prevalence of extended-spectrum beta-lactamases and carbapenemases in Escherichia coli isolated from retail chicken in Peshawar, Pakistan. One hundred E. coli isolates were recovered from retail chicken. Antibiotic susceptibility testing was carried out against ampicillin, chloramphenicol, kanamycin, nalidixic acid, cephalothin, gentamicin, sulfamethoxazole trimethoprim, and streptomycin. Phenotypic detection of beta-lactamase production was analyzed through double disc synergy test using the antibiotics amoxicillin clavulanate, cefotaxime, ceftazidime, cefepime, and aztreonam. Fifty multidrug resistant isolates were screened for detection of sul1, aadA, cmlA, int, blaTEM, blaSHV, blaCTX-M, blaOXA-10, blaVIM, blaIMP, and blaNDM-1 genes. Resistance to ampicillin, nalidixic acid, kanamycin, streptomycin, cephalothin, sulfamethoxazole-trimethoprim, gentamicin, cefotaxime, ceftazidime, aztreonam, cefepime, amoxicillin-clavulanate, and chloramphenicol was 92, 91, 84, 73, 70, 67, 53, 48, 40, 39, 37, 36, and 23% respectively. Prevalence of sul1, aadA, cmlA, int, blaTEM, blaCTX-M, blaIMP, and blaNDM-1 was 78% ( n = 39), 76% ( n = 38), 20% ( n = 10), 90% ( n = 45), 74% ( n = 37), 94% ( n = 47), 22% ( n = 11), and 4% ( n = 2), respectively. blaSHV, blaOXA-10, and blaVIM were not detected. The coexistence of multiple antibiotic resistance genes in multidrug-resistant strains of E. coli is alarming. Hence, robust surveillance strategies should be developed with a focus on controlling the spread of antibiotic resistance genes via the food chain. PMID- 30019957 TI - Development of a Real-Time PCR Assay for Detection of Kudoa iwatai (Myxosporea: Multivalvulida) in Japanese Seabass ( Lateolabrax japonicus). AB - Kudoa iwatai, a myxosporean parasite, has low host fish specificity, and consumers encounter commercial marine fish or marketed marine fish infected with this parasite in Japan. Although the presence of this parasite infection in fish samples is traditionally determined by the microscopic morphological examination of extracted spores, this method lacks sensitivity and specificity. In this study, we developed a real-time PCR assay for the detection of K. iwatai 18S rDNA to achieve the rapid and specific identification of K. iwatai in foreign substance inspection. We also evaluated the usefulness of real-time PCR for Japanese seabass ( Lateolabrax japonicus) with or without K. iwatai cysts. Our real-time PCR assay was able to reliably detect the target plasmid DNA over a 7 log range (from 4.0 * 101 to 4.0 * 107 copies per reaction) and displayed a linear relationship, with a correlation of determination value of 0.9993 and slope of -3.3651. Moreover, the mean value of the intra-assay coefficient of variation was 0.89% in triplicate assays, and the detection limit of this method was 2.5 copies of K. iwatai 18S rDNA per reaction. The sensitivity of the real time PCR was the same or higher than that of an established conventional PCR when DNA extracts from eight Japanese seabass with or without K. iwatai were used as templates. The specificity of the real-time PCR was comparable with that of conventional PCR by using DNA extracts from fish samples infected with nine Kudoa species. Together, these results indicate that our real-time PCR assay is highly sensitive, reproducible, and specific for detecting K. iwatai 18S rDNA in foreign substance inspection. We believe that this highly sensitive real-time PCR may also be useful for understanding the gastrointestinal diseases associated with K. iwatai and for studying the yet unknown life cycle of K. iwatai. PMID- 30019958 TI - Impact of Process Temperature, Humidity, and Initial Product Moisture on Thermal Inactivation of Salmonella Enteritidis PT 30 on Pistachios during Hot-Air Heating. AB - Some thermal processes, such as pistachio roasting, are not yet well characterized with respect to the impact of product and process variables on Salmonella lethality. This study aimed to quantify the effects of process temperature, humidity, and initial product water activity (aw), on Salmonella lethality for in-shell pistachios. In-shell pistachios were inoculated with Salmonella Enteritidis PT 30 (~8.5 log CFU/g), equilibrated (0.45 or 0.65 aw), and heated without soaking ("dry") or after a pure-water or 27% NaCl brining pretreatment ("presoaked"). Inoculated pistachio samples (15 g) were heated in a laboratory-scale, moist-air convection oven at 104.4 or 118.3 degrees C, humidities of ~3, 15, or 30%, v/v (~24.4, 54.4, or 69.4 degrees C dew point), and air speed of 1.3 m/s. Salmonella survivors were quantified at six times during each treatment, targeting total reductions of ~3 to 5 log. Survivor data were analyzed using analysis of variance to identify main effects (time, temperature, humidity, and initial aw) and two-term interactions with time. As expected, lethality increased ( P < 0.05) with temperature and humidity. For example, the time to achieve a 4-log reduction decreased 50 to 80% when humidity increased from ~3 to 30%. When the dry and presoaked treatments were analyzed separately, initial product aw (0.45 versus 0.65 aw or 0.75 versus 0.95 aw) did not affect lethality ( P > 0.05). However, when comparing dry against presoaked treatments, the time to achieve a 4-log reduction decreased 55 to 85% ( P < 0.05) for presoaked pistachios subjected to the same temperature-humidity treatment. Salt had no effect ( P > 0.05) on lethality outcomes. These results, relative to initial aw, process humidity, brining, and salt effects on process lethality, are critically important and must be considered in the design and validation of thermal processes for Salmonella reduction in pistachio processing. PMID- 30019954 TI - Optimal site selection and image fusion guidance technology to facilitate cardiac resynchronization therapy. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) has emerged as one of the few effective treatments for heart failure. However, up to 50% of patients derive no benefit. Suboptimal left ventricle (LV) lead position is a potential cause of poor outcomes while targeted lead deployment has been associated with enhanced response rates. Image-fusion guidance systems represent a novel approach to CRT delivery, allowing physicians to both accurately track and target a specific location during LV lead deployment. Areas covered: This review will provide a comprehensive evaluation of how to define the optimal pacing site. We will evaluate the evidence for delivering targeted LV stimulation at sites displaying favorable viability or advantageous mechanical or electrical properties. Finally, we will evaluate several emerging image-fusion guidance systems which aim to facilitate optimal site selection during CRT. Expert commentary: Targeted LV lead deployment is associated with reductions in morbidity and mortality. Assessment of tissue characterization and electrical latency are critical and can be achieved in a number of ways. Ultimately, the constraints of coronary sinus anatomy have forced the exploration of novel means of delivering CRT including endocardial pacing which hold promise for the future of CRT delivery. PMID- 30019959 TI - Fourier Transform Near-Infrared Spectroscopy and Chemometrics To Predict Zygosacchromyces rouxii in Apple and Kiwi Fruit Juices. AB - This study investigated the capability of near-infrared spectroscopy (NIRS) to predict the concentration of Zygosaccharomyces rouxii in apple and kiwi fruit juices. The yeast was inoculated in fresh kiwi fruit juice ( n = 68), reconstituted kiwi juice ( n = 85), and reconstituted apple juice ( n = 64), followed by NIR spectra collection and plate counting. A principal component analysis indicated direct orthogonal signal correction preprocessing was suitable to separate spectral samples. Parameter optimization algorithms increased the performance of support vector machine regression models developed in a single variety juice system and a multiple variety juice system. Single variety juice models achieved accurate prediction of Z. rouxii concentrations, with the limit of quantification at 3 to 15 CFU/mL ( R2 = 0.997 to 0.999), and the method was also feasible for Hanseniaspora uvarum and Candida tropicalis. The best multiple variety juice model obtained had a limit of quantification of 237 CFU/mL ( R2 = 0.961) for Z. rouxii. A Bland-Altman analysis indicated good agreement between the support vector machine regression model and the plate counting method. It suggests that NIRS can be a high-throughput method for prediction of Z. rouxii counts in kiwi fruit and apple juices. PMID- 30019960 TI - Antibacterial Effect of Essential Oils against Spoilage Bacteria from Vacuum Packed Cooked Cured Sausages. AB - Nonfermented sausages, which have a pH of around 6.0, a low salt concentration, and high moisture with a water activity higher than 0.95, are highly perishable. In this study, culture-dependent techniques and 16S rDNA approaches were used to identify the presumptive spoilage lactic acid bacteria (LAB) in sliced vacuum packed cooked sausage during storage at 4 degrees C. The antibacterial properties of essential oils (EOs) from the medicinal plants Carum carvi, Cinnamomum zeylanicum, Curcuma longa, Citrus medica, and Eugenia caryophyllata against isolated LAB were also investigated. A total of 106 colonies were obtained on de Man Rogosa Sharpe medium after storage of sausages samples, and 16 isolates were identified from conventional morphological analysis of the bacterial populations. DNA extraction and 16S rDNA analysis indicated that Lactobacillus curvatus, Weissella viridescens, Leuconostoc mesenteroides, Enterococcus faecium, Lactobacillus reuteri, Lactobacillus dextrinicus, Lactobacillus sakei, and Pediococcus dextrinicus were the main spoilage LAB. The antibacterial properties of EOs against isolated LAB were indicated by inhibition zones on culture plates of 7.8 to 31 mm, depending on the susceptibility of the tested LAB strain. The MICs and MBCs of five EOs were determined. The most effective EO against the LAB was C. zeylanicum followed by C. carvi and C. medica, and the least effective EO was C. longa. The EO from C. zeylanicum had the highest antimicrobial activity (lowest MICs) against LAB, with EO MICs of 4.66 to 5.33 MUL/mL. The most susceptible isolate was L. mesenteroides, with a MIC of 4.66 MUL/mL for the C. zeylanicum EO. These data indicate that the EO from C. zeylanicum could be used as a natural preservative for vacuum-packed emulsion-type sausage. PMID- 30019961 TI - Toxoplasma gondii Lineages Circulating in Slaughtered Industrial Pigs and Potential Risk for Consumers. AB - Toxoplasma gondii is a cosmopolitan zoonotic protozoan parasite, and the consumption of raw or undercooked pig meat is one of the most important sources of T. gondii infection. Three predominant lineages, types I, II, and III, are widespread in Europe. Although still poorly understood, a relationship between each type and the severity of illness represents a public health issue. To gain further knowledge of the genotypes in circulation and of the potential risk for consumers, one heart sample and one diaphragm sample (206 total) were taken from each of 103 pig carcasses at an abattoir in Italy. Then, we used 529-bp repetitive element PCR and a B1 real-time PCR high-resolution melting assay coupled with sequencing to detect and genotype T. gondii isolates. T. gondii DNA was detected in 14 pigs (13.6%, 95% confidence interval = 7 to 20.2%), and types I (3.9%), II (5.8%), and III (3.9%) were identified. We found that heart tissue had a significantly higher PCR positivity rate for T. gondii than did diaphragm tissue. This is Europe's largest study on genotyping of T. gondii from pigs, and it demonstrates that all three main lineages are present in carcasses of industrially reared pigs in Italy. There is a potential risk to consumers of infection with any or all of the three lineages, and the related clinical consequences should be taken into account. This study suggests that monitoring of T. gondii types in meat is essential, especially in meat that is traditionally eaten raw or that is minimally processed. PMID- 30019962 TI - Assessment of Consumer Perceptions on the Use of Antimicrobials in Production Animals in Chile. AB - Successful treatment of diseases that sicken food-producing animals requires the use of antimicrobials. However, these drugs could result in serious consequences for human, animal, and environmental health. The emergence of antimicrobial resistance requires better communication with consumers to inform them about the risks associated with the use of these drugs, as well as the benefits gained from their rational use. This work studied consumer perceptions about the use of antimicrobials in the production of animal origin foods by questioning 72 consumers in nine focus groups. The participants were all inhabitants of the Metropolitan Region, Chile, and were assigned to focus groups of 5 to 12 individuals each, according to their age: age groups I, II, and III spanned age ranges of 25 to 35, 36 to 50, and older than 50 years, respectively. Consumers regarded the use of antimicrobials in farm animals as a relevant and necessary practice, as long as it was done adequately by veterinarians to ensure productivity and to guarantee food quality and safety. Even though most consumers identified antimicrobial use as a potential risk to their health, only a few recognized that antimicrobial resistance could be transferred from animals to humans via food consumption. Also, consumers complained that they did not have access to enough information about foods of animal origin. Consequently, they stated that food industry and regulatory entities should ensure transparency of production processes and also educate the population on this topic. Consumer perceptions about responsible and judicious use of antimicrobials may become an ally in the effort to reduce and improve the use of these drugs in animal production systems. PMID- 30019963 TI - Rapid and Sensitive Detection of Campylobacter jejuni in Poultry Products Using a Nanoparticle-Based Piezoelectric Immunosensor Integrated with Magnetic Immunoseparation. AB - Campylobacter jejuni is one of the leading causes of foodborne human gastrointestinal diseases. Poultry and poultry products have been identified as the major transmission routes to humans for this pathogenic bacterium. The objective of this research was to develop a rapid and sensitive immunosensor for detection of C. jejuni in poultry products on the basis of a quartz crystal microbalance (QCM) using magnetic nanobeads (MNBs) for separation of target pathogen and gold nanoparticles for amplification of the measurement. A QCM sensor in a flow cell was prepared by immobilizing the mouse anti- C. jejuni monoclonal antibody (mAb1) on the sensor surface to specifically capture C. jejuni. Rabbit anti- C. jejuni polyclonal antibody (pAb1) was conjugated with MNBs to capture and separate C. jejuni from food matrices. MNB-pAb1- C. jejuni complexes were injected into the flow cell to bind with the mAb1 immobilized on the QCM sensor surface. Goat anti-rabbit immunoglobulin G polyclonal antibody conjugated with gold nanoparticles was injected into the flow cell to bind with pAb1 on MNBs. Finally, resonant frequency was measured with a QCM analyzer, and the change in resonant frequency was correlated to the cell number of C. jejuni. The specificity of this immunosensor was confirmed with different strains of Campylobacter, Salmonella, and other foodborne pathogens commonly colonized in the broiler gastrointestinal tract. Samples of broiler carcass wash and ground turkey were spiked with C. jejuni at different concentrations for use in tests. Results showed that the QCM immunosensor could rapidly detect C. jejuni in poultry products, with a detection limit of 20 to 30 CFU/mL without preenrichment, and a total detection time of less than 30 min. Characteristics of C. jejuni captured by the antibody immobilized on the surface of the QCM sensor were visualized by using atomic force microscopy. This highly adaptive and flexible method could provide the poultry industry a more rapid, sensitive, and effective method for detection of major foodborne pathogens in poultry products. PMID- 30019964 TI - Algorithm for comorbidities, associations, length of stay and mortality (ACALM). PMID- 30019965 TI - Three-Dimensional Characterization of Trabecular Bone Mineral Density of the Distal Radius Utilizing Quantitative Computed Tomography. AB - BACKGROUND: Distal radius (DR) fractures demonstrate patterns of predictable fragments. Bone mineral density (BMD) measurements of these regions of interest (ROIs) may guide more precise treatment. METHODS: Computed tomography (CT) scans of the DR of 42 healthy volunteers (23 female) were analyzed using quantitative CT software, measuring BMD within trabecular bone. Seven ROIs were described by alignment with the distal (volar ulnar distal [VUD], dorsal ulnar distal [DUD], volar radial distal [VRD], and dorsal radial distal [DRD]) or proximal (middle ulnar proximal [MUP], middle proximal [MP], and middle radial proximal [MRP]) sigmoid notch. Additional ROIs were the radial styloid (RS) and metadiaphysis (MD). A general estimation equation assessed subject's BMDs with predictive factors of gender, ROI, and age. The interaction between gender, ROI, and age was included in the model to allow for differences in ROI to vary with gender and/or age. RESULTS: Comparing ROIs within the same gender and, separately, within the same age group revealed significantly higher BMD adjacent to the radioulnar and radiocarpal joints. Male and female individuals aged >=50 years (mean: 172.7 mg/cm3 +/- 6.1) had significantly lower BMD than those aged <50 years (mean: 202.7 mg/cm3 +/- 5.8) when all ROIs were considered. Males had higher mean BMD at each ROI compared with females; these differences were significant in 5 of the 9 ROIs: VUD, DUD, DRD, RS, MUP. CONCLUSIONS: Trabecular BMD of the DR is highest adjacent to the radioulnar and radiocarpal joints. Female patients and those >=50 years have lower trabecular BMD. PMID- 30019967 TI - Gastrointestinal pathophysiology and nutrition in cystic fibrosis. AB - INTRODUCTION: Cystic fibrosis (CF) is a severe, progressive, multisystemic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. Optimizing nutrition is critical, as higher growth parameters are associated with better pulmonary function and outcomes, but unfortunately patients with this disease are prone to malnutrition, growth failure, and vitamin deficiencies. The purpose of this review is to provide a timely highlight of the physiologic processes and outcome data to support today's management strategies, as well as review these principles themselves. Areas covered: This review covers the background of the importance of vigilant attention to nutrition and growth in these patients, the underlying physiology leading to an abnormal gastrointestinal tract and its role in CF malnutrition, and current evaluation and management strategies to address nutrition in CF. Analysis of up-to-date relevant literature was performed using PubMed. Expert commentary: Advances in research and clinical developments over the years have improved knowledge of this disease as well as patient outcomes. Of particular importance is optimizing nutrition especially in the early stages of life, as well as accounting for the markedly abnormal CF intestinal milieu when addressing the gastrointestinal and nutritional needs of these patients. PMID- 30019966 TI - N-acetyl cysteine in the treatment of alcohol use disorder in patients with liver disease: Rationale for further research. AB - INTRODUCTION: Alcoholic liver disease (ALD) is the leading cause of alcohol related death and one of the most common forms of liver disease. Abstinence from alcohol is crucial to reducing morbidity and mortality associated with the disease. However, there are few pharmacotherapies for alcohol use disorder suitable for those with significant liver disease. Areas Covered: This paper presents a rationale for investigating the use of N-acetyl cysteine (NAC) to promote abstinence or reduce heavy alcohol consumption for patients with an alcohol use disorder, particularly in the presence of liver disease. NAC is an antioxidant with glutamatergic modulating and anti-inflammatory properties. Evidence is emerging that oxidative stress, neuro-inflammation and dysregulation of glutamatergic neurotransmission play a key role in alcohol use disorder. Similarly, oxidative stress is known to contribute to ALD. We outline the studies that have investigated NAC to reduce alcohol consumption including preclinical and clinical studies. We also review the evidence for NAC in other addictions as well as psychiatric and physical comorbidities associated with alcohol use disorders. Expert Opinion: NAC is low cost, well-tolerated and could have promise for the treatment of alcohol use disorder in the presence of liver disease. Clinical trials directly examining efficacy in this population are required. PMID- 30019969 TI - Pharmacotherapy for Alzheimer's disease: a perspective on treatment strategies in Japan. PMID- 30019968 TI - Optimal prophylaxis of chemotherapy-induced nausea and vomiting for moderately emetogenic chemotherapy: a meta-analysis. AB - AIM: We compare neurokinin-1 receptor antagonist (NK-1RA)-based triple regimen and conventional duplex regimen for antiemetic efficacy for patients with moderately emetogenic chemotherapy (MEC). Patients & methods: Pooled risk ratios (RRs) were used to evaluate the complete response and no significant nausea. The results were separately analyzed for pure MEC regimens, carboplatin-based regimens and oxaliplatin-based regimens. RESULTS: Ten trials focused on MEC involving 2928 cancer patients using NK-1RA triple regimens or conventional duplex regimen were included. NK-1RA-based triple regimen showed significant better complete responses in overall (RR: 1.14; 95% CI: 1.05-1.24), acute (RR: 1.02; 95% CI: 1.00-1.04) and delayed (RR: 1.13; 95% CI: 1.04-1.23) phase compared with duplex regimen in patients with MEC. Similar results were found for no significant nausea. Subgroup analyses showed that triple regimen showed superior antiemetic efficacy significantly in patients with carboplatin-based chemotherapy, instead of oxaliplatin-based chemotherapy. CONCLUSION: NK-1RA is recommended to use in carboplatin-based chemotherapy, not oxaliplatin-based chemotherapy. PMID- 30019970 TI - A randomized, single-blind, study evaluating a 755-nm picosecond pulsed Alexandrite laser vs. a non-ablative 1927-nm fractionated thulium laser for the treatment of facial photopigmentation and aging. AB - BACKGROUND: Laser toning is one of the most popular strategies to treat facial photopigmentation and aging. Several laser modalities, including fractional non ablative, Q-switched (QS) lasers and new generation picosecond lasers have been used for this indication. However, there is paucity of head to head comparisons of older generation of lasers with new ones. OBJECTIVE: To compare a 755 nm picosecond pulsed alexandrite laser with a non-ablative 1927 nm fractionated thulium laser for the treatment of facial photopigmentation and aging through a randomized, single-blind study. MATERIALS AND METHODS: 20 subjects (skin types I IV) were randomized to receive either four 755-nm picosecond alexandrite laser treatments, spaced 3 weeks apart, or two dual wavelength thulium fiber fractionated 1550/1927 nm laser treatments, spaced 6 weeks apart. Follow-up assessment visits occurred 4 and 12 weeks after the last study treatment. RESULTS: At the 4- and 12-week follow-up, both groups showed significant improvement of photoaging, pigmentation, skin quality according to the investigator and subjects assessments. When comparing the two groups, subjects in 755 nm group had statistically significant greater improvement in investigator assessments of photoaging/skin quality and subject satisfaction than those in the 1927 nm group. CONCLUSION: Both the non-ablative 1927 and 755 nm picosecond laser can improve facial photopigmentation, but the latter can yield superior results with less pain and side effects according to patient and investigator assessments. PMID- 30019971 TI - Low-cost multifrequency electrical impedance-based system (MFEIBS) for clinical imaging: design and performance evaluation. AB - Electrical impedance tomography (EIT) is an upcoming and capable imaging modality used for clinical imaging. It is non-invasive, non-ionising and an inexpensive technique. This paper explains the designing and the analysis of a low-cost multifrequency electrical impedance-based system (MFEIBS) having a flexible mechanism of interfacing up to 32 electrodes, suitable for 1 kHz-2 MHz. Various indicators to check the performance of the EIT system were evaluated and presented here. The performance of VCO and VCCS was measured up to 2 MHz. SNR was measured with saline phantom and its mean value is 74 dB for the complete bandwidth. Different combinations of resistors and capacitors were used to find the accuracy of the system, and relative error was less than 0.55% for the entire range. CMRR of the system was calculated and it was found to be maximum 85 dB at 1 kHz frequency. A 16-electrode circular plastic phantom having a diameter of 18 cm was established and connected with a simple MFEIBS. Obtained surface potential was applied to the computer used for image formation using NI USB-6259, 16-bit, 1.25 MS/s M Series High-speed DAQ. Images reconstructed using the system presented in this paper was generated from a 16-electrode plastic phantom filled with NaCl up to 1.2 cm height. PMID- 30019972 TI - A case of herpes simplex virus reactivation after fractional ablative carbon dioxide laser to treat a burn scar. AB - Fractional photothermolysis was initially introduced by Manstein in 2004 .Fractional CO2 laser technology introduced has allowed physicians to obtain good cosmetic results with a lower rate of complications than non-fractionated ablative laser treatment. However, adverse effects may still occur.Reported cases of HSV infection after fractional photothermolysis are rare. A 48-year-old woman with Fitzpatrick skin type III presented with a scar in her perioral area desiring esthetic improvement of her burn scar. She didn't have a history of recurrent herpes simplex virus (HSV) infection periorally. A fractionated resurfacing laser Quadralase (Candela) was used to treat her perioral burn scar. Two sessions were performed with a month interval. Five days after the second session of laser therapy even after she took antiviral prophylaxis based on valacyclovir 500mg twice daily 24 hours before the laser session and 3 days after, she presented with a rash on the perioral area preceded by pain. Correlation of the history and the clinical presentation was consistent with HSV reactivation. Treatment was initiated with acyclovir 10mg/kg/8h administered intravenously for 10 days with a clearing of her vesicular eruption. Fractional CO2 laser is a very safe procedure when used with accepted parameters. Early recognition, close monitoring and careful wound care will prevent long term sequelae when complications occur. PMID- 30019973 TI - Impact and management of iron deficiency and iron deficiency anemia in women's health. AB - INTRODUCTION: Iron deficiency and iron deficiency anemia are highly prevalent among women throughout their lives. Some females are particularly vulnerable to iron deficiency/iron deficiency anemia, including those with heavy menstrual bleeding (HMB) and pregnant/postpartum women. Despite the high prevalence of iron deficiency/iron deficiency anemia in women, the condition is still underdiagnosed and therefore undertreated, with serious clinical consequences. Areas covered: The following review examines the impact of iron deficiency and iron deficiency anemia on clinical outcomes and quality of life in women from adolescence to post menopause, paying particular attention to guidelines and current recommendations for diagnostic tests and management. Expert commentary: There are numerous adverse health consequences of an iron-deficient state, affecting all aspects of the physical and emotional health and well-being of women. Guidelines must be developed to help clinicians better identify and treat women at risk of iron deficiency or iron deficiency anemia, particularly those with HMB, or who are pregnant or postpartum. Replacement therapy with oral or intravenous iron preparations is the mainstay of treatment for iron deficiency/iron deficiency anemia, with red blood cell transfusion reserved for emergency situations. Each iron therapy type is associated with benefits and limitations which impact their use. PMID- 30019974 TI - Uterine artery flow velocity waveforms before and after delivery in hypertensive disorders of pregnancy near term. AB - OBJECTIVE: To compare the uterine artery pulsatility index (UtAPI-AP) before labor and immediate postpartum (UtAPI-PP) in hypertensive disorders of pregnancy (HTNP) and normotensives near term. METHODS: Pregnancies >=36 weeks admitted for labor induction in our institution from October 2015 to October 2017 were included. We excluded active labor, multiple gestations, fetal demise, and those with inadequate uterine artery sampling. Our primary outcome was to compare the UtAPI-AP and UtAPI-PP between subjects with HTNP (gestational hypertension, preeclampsia with and without severe features) and normotensive participants. Our secondary outcomes were to compare the UtAPI-AP and UtAPI-PP by subgroups (severe HNTP, non-severe HTNP, and controls) and the UtAPI-PP in participants while on MgSO4 and after its discontinuation. A linear regression model was applied to test the above associations. A P < .05 was considered significant. RESULTS: We included 108 women (HTNP = 71; controls = 37). The UtAPI-AP was higher in the HTNP group (.85 +/- .3 vs. .71 +/- .2; P < .001); however, the UtAPI-PP was not different between groups (1.11 +/- .3 vs. 1.16 +/- .4; P = .46). The UtAPI-AP was higher in the severe HTNP group than controls (P = .004), but there was no significant difference in the UtAPI-PP between subgroups. Our results remained unchanged after adjusting for confounders. The UtAPI while on MgSO4 and after its discontinuation was similar (P = >.99). CONCLUSION: The increased UtAPI in patients with HTNP resolves soon after delivery. MgSO4 does not seem to have an effect on the UtAPI postpartum. PMID- 30019975 TI - Serum magnesium level in the first trimester of pregnancy as a predictor of pre eclampsia - a pilot study. AB - OBJECTIVES: The aim of this study was to evaluate the importance of serum concentration of magnesium (Mg) in the first trimester of pregnancy for predicting pre-eclampsia (PE). METHODS: This prospective study included 403 pregnant women over 18, with singleton pregnancy (from 11 to 14 weeks of pregnancy). The subjects were divided into a group who subsequently developed PE (PEKT) (n = 61), and a group of healthy pregnancies with no complications and with normal outcomes (TNT) (n = 342). In the first trimester, urea, creatinine, uric acid, Mg, free beta subunit of human chorionic gonadotrophin, plasma protein A related to pregnancy, and C-reactive protein were determined. We followed all subjects until the end of pregnancy. RESULTS: Serum Mg is significantly lower in PEKT than in TNT group (p < 0.001). The serum first trimester Mg level cutoff at <=0.81 mmol/L had a sensitivity of 77.0% and specificity of 71.6% for the detection of women with PEKT. The level of serum Mg has the strongest significant positive correlation (p < 0.05) with the week of gestational outcomes (R = 0.442), weight (R = 0.416), and Apgar score (R = 0.343) of the newborns, and the strongest significant negative correlation with the number of miscarriages (R = 0.413), serum creatinine (R = -0.471), and the number of pregnancies (R = 0.326). The week of gestational outcome is predicted with the greatest reliability by the serum Mg. CONCLUSIONS: Serum Mg level during the first trimester of pregnancy is a significant prediction tool for PE and could also play an important role in predicting the week of gestational outcome and birth weight of newborns. PMID- 30019976 TI - Stigma associated with mental illness and its treatment in the Arab culture: A systematic review. AB - BACKGROUND: Mental health has not had the same public profile as physical health. This has contributed to the stigma associated with mental illness and to its treatments. Research investigating how the traditions and values amongst those with an Arab heritage contribute to stigmatizing beliefs, attitudes or actions in the provision of mental healthcare has not been widely reported. AIM: To systematically review the literature and summarize the findings of studies reporting stigmatizing beliefs, actions and attitudes toward treatment of people with mental illness in the Arab population. METHODS: PubMed, Ovid, Psycharticles and Embase were used to identify original studies of non-institutionalized Arab adults or children reporting findings relevant to stigma toward mental illness. A manual search of the bibliography of all selected original studies was also undertaken. Independent data extraction was performed by two reviewers, who then met to compare data and reach consensus. Findings were classified as stigmatizing beliefs, actions or attitudes toward mental health treatments. RESULTS: A total of 33 articles were retrieved for full review. Those utilizing qualitative methodology provided insight into the many ways mental illness is viewed and defined among those with an Arab heritage. Among the studies using quantitative methodology, most compared stigmatizing beliefs, attitudes toward mental health treatments or stigmatizing actions among different Arab populations, some also investigated correlations between characteristics of the Arab population tested with stigmatizing beliefs, actions and attitudes toward mental health treatments. Findings from studies undertaken in Qatar reported greater stigmatizing beliefs, actions or attitudes toward mental health treatments among Qatari versus non Qatari Arabs. CONCLUSION: A large diversity in the stigmatizing beliefs, actions and attitudes toward treatment of mental illness within the Arab population were identified. The influence of cultural variations on stigma should be explored further and used to tailor anti-stigma interventions in this population. PMID- 30019977 TI - Effect of cabergoline alginate nanocomposite on the transgenic Drosophila melanogaster model of Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Dopamine agonists help the patients with PD by reversing the dopamine depletion and related motor deficits. In the present work, cabergoline, a potent ergot dopamine agonist, was given in the form of cabergoline alginate nanocomposite (CANC) to the PD model flies to study its effects on climbing ability, activity pattern, life span, lipid peroxidation, glutathione (GSH) content, glutathione-S transferase (GST) activity, dopamine content, protein carbonyl content, mean gray scale values, and caspase-3 and caspase-9 activities. Cabergoline alginate nanocomposite was synthesized by adding the cabergoline solution in the warm aqueous solution of sodium alginate; The synthesized CANC was characterized using fourier transform (FTIR) infrared spectroscopy, transmission electron microscopy (TEM), and UV-Visible spectroscopic techniques. The synthesized CANC having the final doses of 1, 2, and 3 MUM was supplemented with diet and the flies were allowed to feed on it for 24 days. Cabergoline alginate nanocomposite significantly increases climbing ability, reduces lipid peroxidation, GST activity, protein carbonyl content, caspase 3/9 activity, mean gray-scale values, and increases the GSH as well as dopamine content in a dose-dependent manner. The results of this study suggest that CANC is potent in delaying and reducing the symptoms of PD. PMID- 30019978 TI - Serum biomarkers for diagnosis and monitoring viral hepatitis and hepatocellular carcinoma. AB - INTRODUCTION: Chronic liver disease due to viral hepatitis continues to be a major global health concern. Timely diagnosis and treatment will prevent cirrhosis, risk of hepatocellular carcinoma (HCC), and requirement for liver transplantation. Numerous serum biomarkers are available for viral hepatitis that are helpful in diagnosis, measuring severity, progression of disease, evaluating the best therapeutic options, and monitoring antiviral treatment response. Determining the clinical use of available diagnostic tests can be challenging for the health care provider. Areas covered: This review article attempts to summarize the established and emerging serological markers for diagnosis and managing viral hepatitis. The literature search was performed in February 2018 and included MEDLINE and Embase databases for recent relevant literature on biomarkers for viral hepatitis. Expert Commentary: Despite the discovery of several candidate biomarkers, translating these to clinical practice in viral hepatitis and HCC remains challenging. While limited availability of the new biomarkers in prevalent geographic areas and significant cost remain major obstacles, there have been exciting developments in this field. Understanding the detection limits and sensitivity of these markers and translating them into clinical use is important in management of viral hepatitis and complications of liver disease such as cirrhosis and hepatocellular cancer. PMID- 30019979 TI - Beyond the individual: population health and physical therapy. AB - Improving the health of populations is critical to meeting global health targets. The purpose of this article is to define population health and differentiate it from related concepts and introduce a framework that can be used to inform the population-based practice of physical therapists. The Population-Based Practice (PBP) Framework is modified from the Public Health Nursing Intervention Wheel and can be used to understand levels (i.e., systems, community, and individual) and types (i.e., screening and outreach, referral and follow-up, health teaching and coaching, consultation and collaboration, advocacy and policy development, and social marketing) of population-based practice. Several physical therapy examples illustrate selected cells within the model. The PBP Framework provides practitioners, educators, and scholars with a new way to envision population based practice for physical therapists. Such a shift in both thinking and practice is needed if physical therapists are to use their unique skills to move beyond the individual, embracing population-based practice to improve health outcomes and reduce health disparities while controlling costs. PMID- 30019980 TI - Early-onset retinal dystrophy and chronic dermatitis in a girl with an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG). AB - PURPOSE: Early-onset retinal dystrophy is usually isolated but can also be the presenting manifestation of an undiagnosed systemic disease. The purpose of this report is to highlight the initial presentation of a girl with early-onset retinal dystrophy and chronic dermatitis who was found to have an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG). METHODS: Retrospective case report. RESULTS: A 13-year-old Baluchi girl was referred for evaluation of low vision since soon after birth. Clinical exam confirmed retinal dystrophy. She also had developmental disability and chronic dermatitis. Brain MRI was normal. Whole exome and confirmatory Sanger sequencing uncovered homozygosity for a SRDA3 deletion (p.Gln96delinsX) that was previously reported in two other Baluchi SRDA3 CDG families with ocular coloboma, optic atrophy, atopic dermatitis, cerebellar hypoplasia, and developmental disability. Early-onset retinal dystrophy was not mentioned in those two families but has since been documented in other SRDA3-CDG families harboring different biallelic variants in the gene. DISCUSSION: Early onset retinal dystrophy with chronic dermatitis should raise suspicion for biallelic SRDA3 mutations, particularly in the context of developmental disability. Exome sequencing can be a useful analysis in retinal dystrophy patients with multisystem disease. Homozygosity for the SRDA3 deletion p.Gln96delinsX is not always associated with ocular coloboma. PMID- 30019981 TI - Giant Cell Poor Extra-Articular Diffuse-Type Tenosynovial Giant Cell Tumor With Extensive Desmin Expression: A Potential Diagnostic Pitfall With Cytogenetic Confirmation. AB - Diffuse-type tenosynovial giant cell tumor can rarely present as an entirely extra-articular mass, which can be misdiagnosed as a sarcoma especially when giant cells are absent, dominated by large dendritic mononuclear cells, and desmin expression is extensive. PMID- 30019982 TI - ACTG2-Associated Visceral Myopathy With Chronic Intestinal Pseudoobstruction, Intestinal Malrotation, Hypertrophic Pyloric Stenosis, Choledochal Cyst, and a Novel Missense Mutation. AB - Primary visceral myopathy caused by a pathogenic mutation in the gene encoding the enteric smooth muscle actin gamma 2 ( ACTG2) affects gastrointestinal and genitourinary tracts and often presents as chronic intestinal pseudoobstruction. We present a case of pediatric onset chronic intestinal pseudoobstruction associated with a novel missense ACTG2 mutation c.439G>T/p.G147C. In addition to the known disease manifestations of feeding intolerance and intestinal malrotation, our patient had a late-onset hypertrophic pyloric stenosis and a late-onset choledochal cyst, the former of which has not previously been described in patients with ACTG2-associated visceral myopathy. PMID- 30019983 TI - An Alternative Treatment Against Acanthocephala ( Prosthenorchis elegans) in Captive Squirrel Monkeys ( Saimiri sciureus) in Mexico. AB - We provide the first report of Acanthocephala ( Prosthenorchis elegans) in Mexican non-human primates. There has been no known treatment against this parasite except for surgical removal, and this has been relatively ineffective because of the small juveniles. We report the presence of P. elegans in a captive breeding colony of squirrel monkeys ( Saimiri sciureus) in Mexico, and we describe a successful treatment protocol. Treatment involved 2 steps: oral administration of the drugs loperamide chlorhydrate (0.5 mg/0.9 kg/3 days) and niclosamide (0.2 mg/0.9 kg/3 days) followed by surgical removal of adult worms from the intestine. Fecal examination during treatment revealed live adults but no living juveniles and no eggs. Surgery after 1 wk of treatment revealed the presence of adults and an absence of juvenile parasites. All adults were physically extracted during the surgery. All subjects recovered from surgery within 1 wk. PMID- 30019984 TI - Remediation of perceptual organisation in schizophrenia. AB - Introduction Impaired perceptual organisation in schizophrenia has been repeatedly described in clinical and research literatures. It has also been associated with problems in more complex aspects of visual function, including visuospatial and visual cognitive test performance. Two therapeutic interventions were developed here that target perceptual organisation: (1) Computer-based training, which emphasized stimulus-driven processing (bottom-up approach), and (2) Instrumental Enrichment therapy, which is a therapist-guided interactive learning method (top-down approach). Methods Twenty-eight patients diagnosed with schizophrenia or schizoaffective disorder participated in a 12-week programme. For both forms of interventions, task difficulty increased progressively, based upon successful performance. The third group of patients, which served as controls, received a similar therapeutic intervention that did not include a perceptual organisation component. Before and after intervention, participants received tests of perceptual organisation, as well as a battery of neuropsychological tests. Results Results indicate that both forms of intervention improved perceptual organisation ability relative to the control condition. In addition, the improvement was found for select neuropsychological tests, although the pattern of improvement did not favour capacities more closely associated with visual organisational or visuospatial function. Conclusions Together, results demonstrate the effectiveness of new remediation protocols that target mid-level visual processing, which generalized to select visual cognitive functions. PMID- 30019985 TI - Persistent Taenia solium Cysticercosis In the State of Morelos, Mexico: Human and Porcine Seroprevalence. AB - Serological tests are needed to estimate the prevalence of Taenia solium cysticercosis in endemic rural areas. The predictive value of serum antibody levels to diagnose porcine cysticercosis and human neurocysticercosis (NC) was herein assessed by ELISA using serum samples from 247 backyard pigs (141 without cysticercosis and 106 with cysticercosis) and 183 human subjects (116 non-NC subjects and 67 NC patients) in central Mexico diagnosed by necropsy and computed tomography, respectively. A sensitivity of 77.3 and 92.5% and a specificity of 88.6 and 100% were found to diagnose porcine and human cysticercosis, respectively. The prevalence of porcine and human cysticercosis in the state of Morelos was estimated by ELISA. Anti-cysticercal antibodies were found in 8.4 and 19.02% of assayed sera from 1,811 humans and 804 pigs, respectively. Marginalization and living in the eastern region were risk factors for humans, whereas free-roaming, medium marginalization levels and living in Sierra de Huautla were risk factors for pigs. These results clearly evidence the persistence of cysticercosis transmission and neurocysticercosis in a region neighboring Mexico City, pointing out the need to apply effective measures already available for its control. PMID- 30019986 TI - A Web of Disheartenment With Hope on the Horizon: Intimate Partner Violence in Rural and Northern Communities. AB - Intimate partner violence (IPV) has become a worldwide epidemic, yet little is known about the experiences of women survivors living in rural and Northern Canadian communities. Existing statistics suggest that women living in rural areas of the Canadian Prairie Provinces and Northwest Territories (NWT) are at a significantly higher risk of experiencing IPV. To better understand the experiences of IPV in these regions, qualitative interviews were conducted with service providers, including the Royal Canadian Mounted Police (RCMP), Victims Services, Shelter Services, counselors, and others (e.g., physicians). In total, 122 participants were interviewed. These interviews were analyzed using a grounded theory approach where the data/results were transformed into a pictorial matrix that documents the struggles that service providers endure. The matrix/results highlight how social issues, such as isolation and poverty, contribute to social oppressions, such as lack of resources, transportation, and/or services. As service providers struggle against these forces, they begin to develop feelings of disheartenment. Yet, they continue to fight because there are opposing forces, such as Emergency Intervention Orders, police transportation, and Victim Services, that demonstrate how societal response is improving the lives and increasing safety in rural and Northern communities. Ultimately, the results suggest that to reduce the incidences of IPV, we must go beyond the violent acts and deal with the social contexts in which IPV resides. PMID- 30019987 TI - The histological spectrum of tubulo-reticular inclusion positive renal biopsies: a tertiary hospital experience and review of the literature. AB - AIM: To identify the underlying diseases with TRI-positive kidney biopsies, and describe the histological pattern and spectrum of TRI-positive kidney biopsies. METHODS: A retrospective analysis of all patients' chart that underwent renal biopsy at King Saud University Medical City between 2012 and 2017 was done. Kidney biopsies that indicated a positive result for tubuloreticular inclusions (TRI's) on electron microscopy were reviewed and the underlying disease and histological pattern was extracted. RESULTS: Of 1,473 native kidney biopsies reviewed, 96 (6.5%) were TRI-positive. Of the 96 TRI-positive kidney biopsies, 87 (90.6%) were TRI-positive lupus nephritis (LN); of which 10 (11.5%) were Class V, 49 (56.3%) were active LN, and 28 (32.2%) were inactive LN. The underlying diseases of the nine non-LN TRI-positive cases included diabetic nephropathy, connective tissue disorders, immune complex mediated Glomerulonephritis (GN), acute thrombotic microangiopathy, rhabdomyolysis, and Wegener's disease. CONCLUSION: LN is a very common finding in TRI-positive kidney biopsies. Active LN and chronic LN are the more common classes of TRI-positive LN kidney biopsies, than pure membranous (Class V) LN. TRI positive kidney biopsies without LN are commonly found in diabetic nephropathy, connective tissue disorders and immune mediated GN's. This study highlights this finding in our patients cohort in opposition to what has been reported in the literature. PMID- 30019988 TI - Stability of Risk Status During Preschool. AB - The current study investigated the stability of children's risk status across the preschool year. A total of 1,102 preschool children attending Title 1 schools ( n = 631) and non-Title 1 schools ( n = 471) participated in this study. Using averaged standard scores for two measures of language, print knowledge, and phonological awareness administered at the beginning of preschool (Time 1) and midyear (Time 2), children were classified as at-risk or not at each time point. Prevalence rates were determined for four categories of risk status: (1) always at risk, (2) only at risk at Time 1, (3) never at risk, and (4) only at risk at Time 2. Univariate and multivariate analyses indicated that the best predictor of children's risk status was their level of skill in the respective literacy domain at the beginning of preschool. These results suggest that children with stable risk can be identified early and may benefit from the early provision of extra instructional support within a response-to-instruction framework. PMID- 30019989 TI - A High-Quality Draft Genome Sequence of Colletotrichum gloeosporioides sensu stricto SMCG1#C, a Causal Agent of Anthracnose on Cunninghamia lanceolata in China. AB - Colletotrichum has a broad host range and causes major yield losses of crops. The fungus Colletotrichum gloeosporioides is associated with anthracnose on Chinese fir. In this study, we present a high-quality draft genome sequence of C. gloeosporioides sensu stricto SMCG1#C, providing a reference genomic data for further research on anthracnose of Chinese fir and other hosts. PMID- 30019990 TI - Non-specific effects of vaccinations in high-income settings: How to address the issue? AB - "Non-specific effects" of vaccines go beyond the specific protective effects against the targeted diseases. They, if real, could theoretically be beneficial, neutral or negative. This article intends to answer the following questions: Do the non-specific effects of vaccines exist? Almost certainly yes, and they can be important in low-income countries Are non-specific effects also present in high income countries? At least to some extent, it seems quite logical Can non specific effects be systematically identified by the current systems of side effects/unintended reactions monitoring? Most likely not Could the Institute of Medicine proposals and some ongoing attempts solve the issue? It seems unlikely Could there be better, feasible and ethically acceptable ways to achieve the aforementioned objective? A proposal is presented about this issue, with the potential both to solve the problem with the most valid methods, and to overcome the ethical problems that have so far precluded the adoption of RCTs to study possible vaccine non-specific effects, monitored by long follow-up. PMID- 30019991 TI - Comparison of Emotional Dispositions Between Street Gang and Non-Gang Prisoners. AB - Effectively recognizing, identifying, and utilizing emotional stimuli is essential for successful social interactions, with deficits in these robustly identified as risk factors for offending. Psychological understanding of street gang membership is limited, particularly surrounding emotional dispositions distinguishing street gang from non-gang offenders. This study examined how street gang members compare with non-gang offenders on trait emotional intelligence (TEI), antisocial personality disorder (ASPD), callous-unemotional traits, anger rumination, and aggression. Recruited through volunteer sampling, participants included 73 (44 street gang and 29 non-gang) male offenders incarcerated at a U.K. Category C prison. Participants completed seven questionnaires assessing emotional dispositions, social desirability, and, consistent with the Eurogang definition, street gang membership. To compare participants' demographics and identify the predictors of street gang membership, chi-square and discriminant function analyses were conducted. With a significant discriminant function, Lambda = .80, chi2(6) = 14.96, p = .021, high levels of ASPD, anger rumination, and aggression and low levels of TEI predict street gang membership. Compared with non-gang prisoners, street gang prisoners did not differ on callous-unemotional traits, age, or ethnicity. Results suggest that, compared with non-gang prisoners, street gang members were more likely to possess dysfunctional emotional dispositions. Findings from this research have important implications in terms of developing interventions for street gang membership. Specifically, this research supports the need for gang-specific early intervention and prevention programs, with emotion-focused components. Ideas for future research are discussed, including the identification of further sociocognitive, personality, and emotional traits distinguishing street gang from non-gang offenders. PMID- 30019992 TI - Seroepidemiology of varicella in Hangzhou, China in the vaccine era. AB - Objective To delineate seroepidemiology of VZV in children aged 1-14 years in Hangzhou, to evaluate immunological response of VarV via 2 dose regimen immunization of VarV, for improving immunization strategy of VarV. Methods From 2014-2016, a multi-stage stratified random sampling method was employed to select participants included via physical examination for children in the Community Health Centre in Hangzhou. Results were compared among 11 various age groups: 1 ,2-,3-,4-,5-,6-,7-,8-,9-,10-,11-14 years. Demographic data and vaccination history of all subjects derived from Zhejiang Information System for Immunization Program. Then, the second dose of the VarV was conducted on children aged 4-6 years who had immunization history of one dose of VarV. ELISA was used to detect VZV IgG in serum samples. Results 895 subjects with available information were included. The rate of VZV IgG seropositivity was 65.59% and the geometric mean concentration (GMC) for VZV IgG was 5.14 +/- 1.89 mIU/ml. The GMC in urban subjects were higher than rural ones. Both the rate of VZV IgG seropositivity and the GMC in children aged 4-6 years groups were statistically lower than participants younger than 4 years and aged 7-14 years (1-,2-,3-,7-,8-,9-,10-,11 14 years). 627 subjects had immunization history of VarV. Both the rate of VZV IgG seropositivity and the GMC in subjects had immunization history of VarV was higher than who had no immunization history.90 subjects were included after the 2nd dose immunization of VarV. Both the rate of VZV IgG seropositivity and the GMC were significantly increased after the immunization of the 2nd dose of VarV. Conclusions The GMC for VZV IgG in children aged 4-6 years were lower than participants groups (1-,2-,3-,7-,8-,9-,10-,11-14 years).2 doses regimen immunization of VarV are effective for increasing both the rate of VZV IgG seropositivity and the GMC in these subjects. PMID- 30019993 TI - Safety, feasibility, and potential efficacy of intraarterial selective cooling infusion for stroke patients treated with mechanical thrombectomy. AB - This is a prospective non-randomized cohort study of 113 consecutive patients to investigate the safety and efficacy of a short-duration intraarterial selective cooling infusion (IA-SCI) targeted into an ischemic territory combined with mechanical thrombectomy (MT) in patients with large vessel occlusion-induced acute ischemic stroke (AIS); 45/113 patients underwent IA-SCI with 350 ml 0.9% saline at 4C for 15 min at the discretion of the interventionalist. Key parameters such as vital signs and key laboratory values, symptomatic and any intracranial hemorrhage, coagulation abnormalities, pneumonia, urinary tract infections and mortality were not significantly different between the two groups. Final infarct volume (FIV) was assessed on noncontrast CT performed at three to seven days. After an adjusted regression analysis, the between-group difference in FIV (19.1 ml; 95% confidence interval (CI) 3.2 to 25.2; P = 0.038) significantly favored the IA-SCI group. At 90 days, no differences were found in the proportion of patients who achieved functional independence (mRS 0-2) (51.1% versus. 41.2%, adjusted odd ratio (aOR) 1.9, 95% CI 0.8-2.6, P = 0.192). Combining short-duration IA-SCI with MT was safe. There was a smaller FIV and trend towards clinical benefit that will need to be further evaluated in randomized control trials. PMID- 30019995 TI - Genetic polymorphisms of CYP2S1, CYP2J2 and CYP2R1 genes in three Chinese populations: Han, Tibetan and Uighur. AB - AIM: Cytochrome P450 enzymes CYP2S1, CYP2J2 and CYP2R1 are of interest due to their unknown enzymatic function and disease-specific expression property. The aim of this study was to investigate the genetic variations of CYP2S1, CYP2J2 and CYP2R1 genes, and their polymorphic distribution in different Chinese populations. MATERIALS & METHODS: All of the exons, exon-intron boundaries and 1 kb 5'-flanking region of the three genes were sequenced in 150 Chinese subjects. RESULTS: There were 21, 15 and nine genetic variants identified in CYP2S1, CYP2J2 and CYP2R1 genes, respectively. The genetic polymorphisms of CYP2S1 and CYP2J2 showed significant difference. Thr353Ala variant in CYP2S1 protein was predicted to be consistently damaged. The hydrogen bond interactions were decreased in two mutants: Thr353Ala and Cys372Ser. -177C >T in CYP2S1 affected transcription factor EGR1 binding site. CONCLUSION: This study highlights the importance of genetic polymorphism information on the CYP2S1, CYP2J2 and CYP2R1 genes in Chinese populations. PMID- 30019994 TI - Utility of the Youth Compendium of Physical Activities. AB - PURPOSE: The purposes of this article are to: (a) describe the rationale and development of the Youth Compendium of Physical Activities (Youth Compendium); and (b) discuss the utility of the Youth Compendium for audiences in research, education, community, health care, public health, and the private sector. METHODS: The Youth Compendium provides a list of 196 physical activities (PA) categorized by activity types, specific activities, and metabolic costs (youth metabolic equivalents of task [METy]) as measured by indirect calorimetry. The utility of the Youth Compendium was assessed by describing ways in which it can be used by a variety of audiences. RESULTS: Researchers can use METy values to estimate PA levels and determine changes in PA in intervention studies. Educators can ask students to complete PA records to determine time spent in physical activities and to identify health-enhancing activities for classroom PA breaks. Community leaders, parents, and health care professionals can identify activity types that promote healthful behaviors. Public health agencies can use the METy values for surveillance and as a resource to inform progress toward meeting national physical activity guidelines. Applications for the private sector include the use of METy in PA trackers and other applications. CONCLUSION: The National Collaborative on Childhood Obesity Research Web site presents the Youth Compendium and related materials to facilitate measurement of the energy cost of nearly 200 physical activities in children and youth. The Youth Compendium provides a way to standardize energy costs in children and youth and has application for a wide variety of audiences. PMID- 30019997 TI - Retrospective survey of owners' experiences with palliative radiation therapy for pets. AB - OBJECTIVE To describe animal owners' experiences with palliative radiation therapy (PRT) of pets and identify factors influencing satisfaction with their pets' treatment. DESIGN Retrospective, cross-sectional study. SAMPLE 118 owners of dogs, cats, or rabbits. PROCEDURES Medical records were searched to identify animals that underwent PRT between 2004 and 2013. Signalment, tumor-related data, and outcome information were recorded. Owners completed an electronic survey assessing satisfaction with treatment (ie, satisfaction with the decision for their pet to undergo PRT and indication that they would choose PRT for their pet again), expectations regarding PRT, and perceptions of their pets' quality of life (QOL) and signs of discomfort from acute adverse radiation effects. Additional data regarding practical aspects of treatment, pet death, communications with veterinarians, and owner demographics were collected. Variables were tested for association with measures of owner satisfaction. RESULTS 92 of 116 (79%) owners were satisfied with the decision to have their pets undergo PRT. Most (92/118 [78%]) owners reported their pet's QOL improved after PRT; these owners were significantly more likely to be satisfied than those who did not report improved QOL. Owners who perceived their pets had discomfort from adverse radiation effects (38/116 [33%]) were significantly less likely to be satisfied than owners who did not report this observation. Measures of satisfaction were not associated with patient survival time. Twenty-one of 118 (18%) owners indicated they expected PRT would cure their pet's tumor. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that short life expectancy should not deter recommendation of PRT for pets. Protocols that minimize risk of acute adverse effects may be advantageous. Veterinarians should attempt to ensure that owners understand the goals of PRT. PMID- 30019996 TI - Risk Factors for Bud Perennation of Podosphaera macularis on Hop. AB - The hop powdery mildew fungus Podosphaera macularis persists from season to season in the Pacific Northwestern United States through infection of crown buds because only one of the mating types needed to produce the ascigerous stage is presently found in this region. Bud infection and successful overwintering of the fungus leads to the emergence of heavily infected shoots in early spring (termed flag shoots). Historical data of flag shoot occurrence and incidence in Oregon and Washington State during 2000 to 2017 were analyzed to identify their association with the incidence of powdery mildew, growers' use of fungicides, autumn and winter temperature, and other production factors. During this period, flag shoots were found on 0.05% of plants evaluated in Oregon and 0.57% in Washington. In Oregon, the incidence of powdery mildew on leaves was most severe and the number of fungicide applications made by growers greatest in yards where flag shoots were found in spring. Similarly, the incidence of plants with powdery mildew in Washington was significantly associated with the number of flag shoots present in early spring, although the number of fungicide applications made was independent of flag shoot occurrence. The occurrence of flag shoots was associated with prior occurrence of flag shoots in a yard, the incidence of foliar powdery mildew in the previous year, grower pruning method, and, in Washington, winter temperature. A census of hop yards in the eastern extent of the Oregon production region during 2014 to 2017 found flag shoots in 27 of 489 yards evaluated. In yards without flag shoots, 338 yards (73.2%) were chemically pruning or not pruned, whereas the remaining 124 (26.8%) were mechanically pruned. Of the 27 yards with flag shoots, 22 were either chemically pruned or not pruned and 4 were mechanically pruned in mid-April, well after the initial emergence of flag shoots. The prevalence of yards with flag shoots also was related to thoroughness of pruning in spring (8.1% of yards with incomplete pruning versus 1.9% of yards with thorough pruning). A Bayesian logistic regression model was fit to the data from the intensively assessed yards in Oregon, with binary risk factors for occurrence of a flag shoot in the previous year, occurrence of foliar mildew in the previous year, and thoroughness of pruning in spring. The model indicated that the median and 95% highest posterior density interval of the probability of flag shoot occurrence was 0.0008 (0.0000 to 0.0053) when a yard had no risk factors but risk increased to 0.0065 (0.0000 to 0.0283) to 0.43 (0.175 to 0.709) when one to all three of the risk factors were present. The entirety of this research indicates that P. macularis appears to persist in a subset of chronically affected hop yards, particularly yards where spring pruning is conducted poorly. Targeted management of the disease in a subset of fields most at risk for producing flag shoots could potentially influence powdery mildew development regionwide. PMID- 30019998 TI - Retrospective study of factors associated with surgical site infection in dogs following tibial plateau leveling osteotomy. AB - OBJECTIVE To identify risk factors associated with surgical site infection (SSI) in dogs following tibial plateau leveling osteotomy (TPLO). DESIGN Retrospective cohort study. ANIMALS 320 dogs that underwent unilateral or bilateral TPLO (n = 405 procedures) between 2007 and 2015 and were reexamined by a veterinarian at least once >= 8 weeks after the procedure. PROCEDURES Data were extracted from medical records regarding signalment, TPLO procedure details, medical history of dermatitis, and SSI status. Logistic regression was performed to identify factors associated with SSI development. RESULTS An SSI developed following 34 (8.4%; 95% confidence interval [CI], 6.1% to 11.5%) procedures. Prophylactic antimicrobial administration was provided following 36.8% (n = 149) of procedures. For 71 (17.5%) procedures, the dog had dermatitis at the time of surgery; 12 of these procedures involved dermatitis at the surgical site. The incidence of SSI following the 12 procedures for dogs with dermatitis at the surgical site was 16.7% (2/12 [95% CI, 3.3% to 54.3%]) and was 10.2% (6/59 [95% CI, 4.5% to 21.3%]) for dogs with dermatitis elsewhere; however, these differences in incidence were not significant. On multivariable analysis, German Shepherd Dogs (vs other breeds), meniscectomy (vs no meniscectomy), and attending surgeon having performed <= 20 (vs > 20) procedures during the study period were associated with increased odds of SSI. CONCLUSIONS AND CLINICAL RELEVANCE SSI following TPLO was associated with the German Shepherd breed, meniscectomy, and surgeon. Prospective studies are needed to investigate the mechanisms underlying these associations. PMID- 30020000 TI - Advocating on behalf of veterinarians, the AVMA, and the veterinary profession. PMID- 30019999 TI - Survey of human-horse relationships and veterinary care for geriatric horses. AB - OBJECTIVE To assess relationships between horse owners (or lessees) and geriatric or nongeriatric horses and to investigate factors influencing veterinary care decision-making. DESIGN Descriptive, cross-sectional, survey-based study. SAMPLE 2,879 people who owned or leased >= 1 horse. PROCEDURES Participants were recruited through social media and online horse forums to participate in an online survey about their horses, including measures of attachment, veterinary care decision-making, and experiences surrounding the death of a horse. Data were collected for primary horses (those respondents interacted with most) and secondary horses. Horses were further categorized as geriatric (>= 20 years of age) and nongeriatric. RESULTS Geriatric primary horses were considered companion animals, retired, or used as part of a business significantly more frequently, and described as competition horses significantly less frequently, than nongeriatric horses. Geriatric horses were owned or leased significantly longer than nongeriatric horses, but the degree of respondents' attachment did not differ for geriatric versus nongeriatric horses. When respondents reported the death of a horse in the previous year, euthanasia was associated with higher levels of bereavement than death by other means. Death of geriatric horses most commonly followed a chronic illness and was associated with significantly higher levels of bereavement than death of nongeriatric horses. Among factors influencing decisions regarding expensive or long-term medical care, the horse's ability to lead a comfortable life was ranked highest. Respondents with geriatric horses made numerous accommodations for their care. CONCLUSIONS AND CLINICAL RELEVANCE Results provided important initial information about the relationships people have with geriatric horses. Understanding how individuals perceive their horses and how they make decisions regarding complex veterinary care is critical in informing effective client communication. PMID- 30020001 TI - Comparison of complication rates following elective arthroscopy performed as inpatient versus outpatient surgery in horses. AB - OBJECTIVE To report complication rates following elective arthroscopy in horses and determine whether postoperative complication rates are higher for outpatient procedures, compared with inpatient procedures. DESIGN Retrospective cohort study. ANIMALS 357 client-owned horses that had undergone 366 elective arthroscopic procedures between January 2008 and February 2015. PROCEDURES Medical records were retrospectively reviewed. Data collected included signalment, travel time to the hospital, clinical signs, joints treated, lesions diagnosed, medications administered, anesthesia and surgery times, details of the procedure (including closure method and surgeons involved), and hospitalization status (inpatient or outpatient). Inpatients were horses that remained hospitalized overnight, and outpatients were horses that were discharged in the afternoon of the day of surgery. The collected data were analyzed along with follow-up information to identify factors associated with postoperative complications and potentially associated with hospitalization status. RESULTS Data were collected on 366 elective arthroscopic procedures (outpatient, n = 168 [46%]; inpatient, 198 [54%]). Complications that occurred included bandage sores, catheter problems, colic, diarrhea, postoperative discomfort, esophageal impaction, fever, incisional drainage, postanesthetic myopathy, persistent synovitis, persistent lameness, septic arthritis, and osteochondral fragments not removed during the original surgery. None of these complications were associated with hospitalization status (outpatient vs inpatient). However, Standardbreds were overrepresented in the outpatient group, and anesthesia and surgery times were longer for the inpatient group. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that outpatient elective arthroscopy in healthy horses could be performed safely and without a higher risk of complications, com pared with similar procedures performed on an inpatient basis. PMID- 30020003 TI - In This Issue * August 1, 2018. PMID- 30020002 TI - What Is Your Neurologic Diagnosis? PMID- 30020004 TI - Risk of anesthesia-related complications in brachycephalic dogs. AB - OBJECTIVE To determine whether brachycephalic dogs were at greater risk of anesthesia-related complications than nonbrachycephalic dogs and identify other risk factors for such complications. DESIGN Retrospective cohort study. ANIMALS 223 client-owned brachycephalic dogs undergoing general anesthesia for routine surgery or diagnostic imaging during 2012 and 223 nonbrachycephalic client-owned dogs matched by surgical procedure and other characteristics. PROCEDURES Data were obtained from the medical records regarding dog signalment, clinical signs, anesthetic variables, surgery characteristics, and complications noted during or following anesthesia (prior to discharge from the hospital). Risk of complications was compared between brachycephalic and nonbrachycephalic dogs, controlling for other factors. RESULTS Perianesthetic (intra-anesthetic and postanesthetic) complications were recorded for 49.1% (n = 219) of all 446 dogs (49.8% [111/223] of brachycephalic and 48.4% [108/223] of nonbrachycephalic dogs), and postanesthetic complications were recorded for 8.7% (39/446; 13.9% [31/223] of brachycephalic and 3.6% [8/223] of nonbrachycephalic dogs). Factors associated with a higher perianesthetic complication rate included brachycephalic status and longer (vs shorter) duration of anesthesia; the risk of perianesthetic complications decreased with increasing body weight and with orthopedic or radiologic procedures (vs soft tissue procedures). Factors associated with a higher postanesthetic complication rate included brachycephalic status, increasing American Society of Anesthesiologists status, use of ketamine plus a benzodiazepine (vs propofol with or without lidocaine) for anesthetic induction, and invasive (vs noninvasive) procedures. CONCLUSIONS AND CLINICAL RELEVANCE Controlling for other factors, brachycephalic dogs undergoing routine surgery or imaging were at higher risk of peri- and postanesthetic complications than nonbrachycephalic dogs. Careful monitoring is recommended for brachycephalic dogs in the perianesthetic period. PMID- 30020005 TI - Anesthesia Case of the Month. PMID- 30020006 TI - Investigation and characterization of Brucella canis infections in pet-quality dogs and associated human exposures during a 2007-2016 outbreak in Michigan. AB - OBJECTIVE To estimate Brucella canis seropositivity rates for purebred dogs being bred by noncommercial breeders, describe epidemiological findings in infected commercial dog-production facilities, and characterize B canis infection in pet dogs and the risk to human health. DESIGN Retrospective descriptive study. SAMPLE 2,799 canine specimens submitted to the Michigan State University Veterinary Diagnostic Laboratory for B canis testing and records of B canis reports provided to the Michigan Department of Agriculture and Rural Development from 2007 through 2016. PROCEDURES Results of B canis laboratory tests and epidemiological findings for reported cases of B canis were reviewed and summarized. Federal and state public health officials were interviewed regarding human B canis infection. State veterinarians were interviewed regarding canine brucellosis reporting and control procedures. RESULTS Estimated B canis seropositivity was 0.4% among purebred Michigan dogs owned by noncommercial breeders. Infection was confirmed in dogs from 17 commercial dog-production facilities, 3 shelters, and 1 rescue agency. Estimated infection prevalence in production facilities ranged from 2 of 22 (9%) to 5 of 6 (83%). Transfer of infected dogs involved 22 Michigan counties and 11 states. Seven of 20 privately owned infected dogs had diskospondylitis; I also had uveitis. Fifty-three veterinary hospital or diagnostic laboratory personnel had inadvertent exposure to the pathogen. Brucella canis was isolated from 1 commercial production facility owner. CONCLUSIONS AND CLINICAL RELEVANCE B canis was uncommon in purebred dogs being bred by noncommercial breeders but endemic in Michigan commercial facilities producing dogs destined to become household pets. Infected pet dogs caused human B canis exposure, and several pet dogs had debilitating disease not associated with the reproductive system. PMID- 30020007 TI - Clients' attitudes toward veterinarians' attire in the small animal emergency medicine setting. AB - OBJECTIVE To determine how veterinarians' attire affected clients' perceptions and trust in the small animal emergency medicine setting. DESIGN Cross-sectional study. SAMPLE 154 clients of a 24-hour small animal emergency clinic in a rural location. PROCEDURES A survey was administered to clients in the waiting room over a 1-month period to elicit their impressions of veterinarians' attire in various clinical scenarios and whether that attire would affect their perceptions. Respondents completed the survey after examining photographs of 1 male and 1 female veterinarian in 5 styles of attire (business, professional, surgical, clinical, and smart casual). RESULTS 83 (53.9%) respondents were female, and 71 (46.1%) were male; age was evenly distributed. Across all clinical scenarios, the most common response was no preference regarding the way a male or female veterinarian was dressed and that this attire would have no effect on the respondents' trust in their veterinarian. Most respondents were indifferent or preferred that their veterinarians not wear neckties and white coats. Twenty-six percent (40/154) of respondents indicated that they believed their veterinarian's attire would influence their opinion of the quality of care their pet received. CONCLUSIONS AND CLINICAL RELEVANCE In this small animal emergency medicine setting, most clients indicated no preference regarding their veterinarian's attire, yet approximately one-fourth indicated this attire would influence their perception of the quality of care their pet received. Further studies are warranted in other practice settings and locations to determine whether these findings are generalizable or unique to this particular setting. PMID- 30020008 TI - What Is Your Diagnosis? PMID- 30020010 TI - Letters to the Editor. PMID- 30020009 TI - Pathology in Practice. PMID- 30020011 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 30020012 TI - Pathology in Practice. PMID- 30020014 TI - Aspiration-related respiratory disorders in dogs. PMID- 30020015 TI - Beta-1,4-galactosyltransferase 2 c.909C>T gene variant is predictive of on clopidogrel platelet reactivity. AB - CYP2C19 genotype influences clopidogrel response but only accounts for a small part of the variability in platelet reactivity. Recently, exome sequencing identified a variant of the gene encoding B4GALT2 as a potential candidate implicated in on-treatment platelet reactivity. Carriers of the B4GALT2 c.909C>T variant have lower platelet reactivity indicating that B4GALT2 could influence clopidogrel sensitivity and could expose to the risk of bleeding events. We undertook this observational retrospective study to determine if B4GALT2 c.909C>T influences P2RY12-specific vasodilator-stimulated phosphoprotein phosphorylation and agonist-induced platelet aggregation in a nonselected cohort of 174 patients under clopidogrel-based antiplatelet therapy. Our results indicate that in individuals under dual antiplatelet therapy, B4GALT2 c.909C>T might be an independent genetic predictor of on-treatment platelet reactivity. PMID- 30020016 TI - Accurately genotyping CYP2D6: not for the faint of heart. PMID- 30020017 TI - Corrigendum. PMID- 30020018 TI - Personality Traits Do Not Predict How We Look at Faces. AB - While personality has typically been considered to influence gaze behaviour, literature relating to the topic is mixed. Previously, we found no evidence of self-reported personality traits on preferred gaze duration between a participant and a person looking at them via a video. In this study, 77 of the original participants answered an in-depth follow-up survey containing a more comprehensive assessment of personality traits (Big Five Inventory) than was initially used, to check whether earlier findings were caused by the personality measure being too coarse. In addition to preferred mutual gaze duration, we also examined two other factors linked to personality traits: number of blinks and total fixation duration in the eye region of observed faces. No significant correlations were found between any of these measures and participant personality traits. We suggest that effects previously reported in the literature may stem from contextual differences or modulation of arousal. PMID- 30020019 TI - Implementation and assessment of vaccination programmes: the importance of vaccination sequence for overall health outcomes. AB - In addition to their effect on the target infections, accumulating evidence indicates that vaccines have non-specific effects. Live measles vaccine (MV) has beneficial NSEs reducing mortality by more than can be explained by preventing measles infection. In contrast, non-live diphtheria-tetanus-pertussis vaccine (DTP) has negative NSEs; in spite of protecting against diphtheria, tetanus and pertussis, it is associated with increased mortality. The most recent vaccine has the strongest effect on child health, and therefore sequence of vaccines is important. There is consistent evidence that DTP with or after MV is associated with increased mortality compared with having MV as the most recent vaccine, but the sequence of vaccines is not considered in the current evaluation and implementation of vaccination programmes. To maximise the impact of current vaccination programmes on child health, increased emphasis should be placed on receiving MV after DTP. Increasing time with live MV as the most recent vaccine through better adherence to the schedule, and modified recommendations for catch up vaccinations for children who do not follow the recommended schedule are likely to result in improvements in child health. PMID- 30020020 TI - Medical adherence in patients with systemic lupus erythematosus in Germany: predictors and reasons for non-adherence - a cross-sectional analysis of the LuLa cohort. AB - Objective Adherence to medication has a major impact on treatment control and success especially in chronic diseases but often remains unrecognized. Besides clinical, socioeconomic, disease-related and treatment-related parameters, general and personal health beliefs, as well as perception of health, can affect adherence. Our aim was to investigate the adherence to lupus-specific medications in German lupus patients and to assess influencing factors including detrimental or beneficial effects of health perceptions and beliefs. Methods The Lupus Erythematosus (LE) Long-Term Study (LuLa-study) is a nationwide longitudinal study among German Caucasian patients with systemic lupus erythematosus who have been assessed annually using a self-reported questionnaire since 2001. In 2013, we included questions concerning medical adherence (Morisky Medication Adherence Scale; MMAS-4), beliefs about medication prescribed (BMQ), illness perception and about the patients' health locus of control (HLC). We present a cross-sectional analysis to assess predictors of adherence using a multivariable stepwise logistic regression. Results Five hundred and seventy-nine patients participated, 81 of whom did not take any lupus-specific medication and 40 of whom did not complete the MMAS-4 and were therefore omitted. Only 62.7% reported high adherence. Unintentional behaviour for low medical adherence exceeded the intentional behaviour by far. The use of azathioprine (OR: 1.85; 95% CI: 1.02 3.34), prednisone <7.5 mg (OR: 1.56; 95% CI: 0.97-2.49), a higher age (OR: 1.06; 95% CI: 1.03-1.08) and higher external HLC (OR: 1.15; 95% CI: 1.01-1.30) proved conducive for high adherence in our multivariable model. On the contrary, the general perception of medication being harmful or addictive (OR: 0.89; 95% CI: 0.82-0.97) was detrimental. Conclusion A low belief that one's own health is determined by healthcare providers (external HLC) and the belief of the harmfulness of medication were independent predictors of low adherence besides age and the choice of the medical agent. The recognition of these potential obstacles in physician-patient relationships is essential to ameliorate adherence. Provision of sufficient information and education might help to reach the best possible outcome. PMID- 30020021 TI - Composite urinary biomarkers to predict pathological tubulointerstitial lesions in lupus nephritis. AB - Objective This study aimed to evaluate the clinical value of urinary biomarkers including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein-1 (MCP-1) in lupus nephritis. Methods A total of 109 biopsy-proven lupus nephritis patients were included and 50 healthy individuals were used as normal controls. Urinary KIM-1, NGAL, and MCP-1 levels were measured by ELISA and their correlations with clinical and histological features were assessed. Receiver operating characteristic curves were performed and the Cox regression model was applied to identify prognostic factors associated with renal outcomes. Results Active lupus nephritis patients exhibited elevated urinary levels of KIM-1, NGAL, and MCP-1 compared with lupus nephritis patients in remission ( P < 0.001) and normal controls ( P < 0.001). The urinary KIM-1 level was correlated with pathological tubular atrophy ( r = 0.208, P < 0.05) and increased significantly in the presence of interstitial inflammatory lesions ( P = 0.031). Urinary KIM-1, NGAL, and MCP-1 levels were higher in patients with active tubulointerstitial lesions than in those with only chronic lesions ( P = 0.015, P = 0.230, and P = 0.086, respectively). A combination of KIM-1, NGAL, and MCP-1 was a good indicator for diagnosing active tubulointerstitial lesions (area under the curve: 0.796). The combination of KIM-1 and NGAL was identified as an independent risk factor for renal outcomes (hazard ratio = 7.491, P < 0.05). Conclusion Urinary KIM-1, NGAL, and MCP-1 levels were associated with kidney injury indices in lupus nephritis. The combination of the three biomarkers showed increased power in predicting tubulointerstitial lesions and renal outcomes. PMID- 30020022 TI - Prognostic nutritional index is correlated with disease activity in patients with systemic lupus erythematosus. AB - The prognostic nutritional index (PNI), which is calculated using serum albumin level and total lymphocyte count in the peripheral blood, is regarded as an index that reflects the immunonutritional status of patients. PNI was calculated in 217 systemic lupus erythematosus (SLE) patients according to the following formula: 10 * serum albumin value (g/dL) + 0.005 * peripheral lymphocyte count (/mm3). Pearson's correlation analysis was used to elucidate the correlation between continuous variables. Linear and logistic regression analyses were performed to assess the correlation between laboratory variables and SLE Disease Activity Index-2000 (SLEDAI-2 K) and to differentiate between active and inactive SLE. Ninety-three patients were classified as active SLE (SLEDAI-2 K >= 5) and 124 as inactive SLE. Patients with active SLE exhibited lower median PNI than those with inactive SLE (39.0 vs. 49.1, p < 0.001). Multivariable logistic regression analysis revealed PNI as an independent predictor of active SLE. Multivariable linear regression analysis revealed that PNI was significantly correlated with laboratory variables of SLEDAI-2 K, erythrocyte sedimentation rate, C-reactive protein and SLEDAI-2 K. Furthermore, in patients who switched from active to inactive SLE after treatment ( n = 55), PNI increased as disease activity improved ( p < 0.001), which suggests that PNI may be useful for estimating SLE activity. PMID- 30020024 TI - Left Atrial Appendage Occlusion Devices. AB - Atrial fibrillation is a very common arrhythmia whose prevalence is expected to increase significantly as the population ages. The associated stroke risk is a major cause of morbidity and mortality. Stroke prevention by anticoagulation carries its own risks, leading to the search for alternative strategies. Multiple techniques have been developed to exclude the left atrial appendage (the main source of thromboembolism in atrial fibrillation) from the circulation. Such techniques offer the hope of stroke prevention without the risks of anticoagulation. This article describes the percutaneous approaches being currently performed in the United States. Particular emphasis is placed on the use of transesophageal echocardiography to guide these procedures. PMID- 30020023 TI - Characteristics of 1555 childhood-onset lupus in three groups based on distinct time intervals to disease diagnosis: a Brazilian multicenter study. AB - Objective The objective of this study was to compare demographic data, clinical/laboratorial features and disease activity at diagnosis in three different groups with distinct time intervals between onset of signs/symptoms and disease diagnosis. Methods A multicenter study was performed in 1555 childhood onset systemic lupus erythematosus (American College of Rheumatology criteria) patients from 27 pediatric rheumatology services. Patients were divided into three childhood-onset systemic lupus erythematosus groups: A: short time interval to diagnosis (<1 month); B: intermediate time interval (>=1 and <3 months); and C: long time interval (>=3 months). An investigator meeting was held to define the protocol. Demographic data, SLICC classification criteria and SLEDAI-2 K were evaluated. Results The number of patients in each group was: A = 60 (4%); B = 522 (33.5%); and C = 973 (62.5%). The median age at diagnosis (11.1 (4.2-17) vs. 12 (1.9-17.7) vs. 12.5 (3-18) years, P = 0.025) was significantly lower in group A compared with groups B and C. The median number of diagnostic criteria according to SLICC (7 (4-12) vs. 6 (4-13) vs. 6 (4-12), P < 0.0001) and SLEDAI-2 K (18 (6 57) vs. 16 (2-63) vs. 13 (1-49), P < 0.0001) were significantly higher in group A than the other two groups. The frequency of oral ulcers in the palate (25% vs. 15% vs. 11%, P = 0.003), pleuritis (25% vs. 24% vs. 14%, P < 0.0001), nephritis (52% vs. 47% vs. 40%, P = 0.009), neuropsychiatric manifestations (22% vs. 13% vs. 10%, P = 0.008), thrombocytopenia (32% vs. 18% vs. 19%, P = 0.037), leucopenia/lymphopenia (65% vs. 46% vs. 40%, P < 0.0001) and anti-dsDNA antibodies (79% vs. 66% vs. 61%, P = 0.01) were significantly higher in group A compared with the other groups. In contrast, group C had a less severe disease characterized by higher frequencies of synovitis (61% vs. 66% vs. 71%, P = 0.032) and lower frequencies of serositis (37% vs. 33% vs. 25%, P = 0.002), proteinuria >500 mg/day (48% vs. 45% vs. 36%, P = 0.002) and low complement levels (81% vs. 81% vs. 71%, P < 0.0001) compared with groups A or B. Conclusions Our large Brazilian multicenter study demonstrated that for most childhood-onset systemic lupus erythematosus patients, diagnosis is delayed probably due to mild disease onset. Conversely, the minority has a very short time interval to diagnosis and a presentation with a more severe and active multisystemic condition. PMID- 30020025 TI - A Mixed-Method Analysis of Persisting Effects Associated with Positive Outcomes Following Ibogaine Detoxification. AB - We examined persisting effects, self-perceived challenges, and potential benefits associated with positive outcomes following ibogaine detoxification using data collected as part of a larger online retrospective study of 73 patients who received treatment for chronic opioid use in Mexico between 2012 and 2015. A mixed-methods design was used comparing treatment responders versus non responders, as well as content coding of themes from open-ended questions. Most participants reported positive persisting effects of ibogaine detoxification (e.g., enhanced personal sense of gratitude and authenticity, and meaning and appreciation for life). Compared to non-responders, treatment responders endorsed greater persisting changes in their ability to tolerate difficult/painful feelings, capacity for coping with stress, and reduced unhealthy anger. Treatment responders reported greater change in subjective levels of inner peace, joy, feelings of love/openheartedness, and experiences of sacredness in life. Qualitative analyses revealed that treatment responders reported a heightened sense of spiritual awareness and greater connection to their intra-/interpersonal relationships after ibogaine detoxification. Notable challenges of ibogaine detoxification included psychological and health-related difficulties during treatment and challenges with post-treatment integration. Findings highlight the persisting effects associated with positive response to ibogaine detoxification and possible post-treatment needs (i.e., more integration/aftercare resources). Future research using rigorous experimental designs is needed. PMID- 30020026 TI - An Examination of Social Support and PTSD Treatment Response During Prolonged Exposure. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) results from exposure to traumatic events. Social support is negatively related to PTSD symptoms in cross sectional and longitudinal studies. It is unclear, however, if social support is associated with treatment response for PTSD. The current study evaluated the extent to which social support was associated with PTSD treatment response among treatment-seeking veterans receiving prolonged exposure (PE). It was hypothesized that social support would improve PTSD treatment response and that PTSD symptom reduction would improve social support. METHOD: A total of 123 veterans were recruited from a Veterans Affairs Medical Center and evaluated for PTSD, diagnostic-related symptoms, and social support. All participants received PE. Data were analyzed using mixed-effects models. RESULTS: Findings suggested that elevated social support during treatment was associated with greater reductions in PTSD symptoms during treatment. Social support also increased during treatment. Increases in social support were not moderated by PTSD symptoms during treatment. CONCLUSIONS: These findings suggest that social support and PTSD symptoms are related throughout treatment. Social support moderated the change in PTSD symptoms, whereas PTSD symptoms did not moderate changes in social support. PMID- 30020027 TI - Challenges to primary healthcare services in the management of non-communicable diseases in marginalised populations on the Thailand-Myanmar border: a pilot survey. AB - Non-communicable diseases (NCDs) are emerging rapidly. This manuscript reports on a pilot survey of NCDs at a primary healthcare level in a marginalised migrant population on the Thailand-Myanmar border in the face of declining rates of malaria. A retrospective audit of routine clinic (2004-2016) and NCD patient survey data (2014-2016) was conducted. The length of follow-up was assessed by Kaplan-Meier analysis. From July 2014 to July 2016, 238 migrant patients were on the NCD register. Hypertension (n = 80) and diabetes mellitus (n = 51) were the most common diagnoses. After the first consultation, 41% (95% confidence interval = 35-47%) were lost to follow-up by 30 days. NCD retention rates were low: 50% of registered patients were lost to follow-up by 80 (95% CI = 49-132) days. After this survey, a novel low-cost insurance scheme for the migrant community has been launched in this area. Development of new schemes involving patients, healthcare providers and funding support are required for improved and sustainable NCD care for marginalised populations. PMID- 30020028 TI - Prevalence of obesity and its risk factors among school children in Karachi, Pakistan. AB - A cross-sectional questionnaire study was conducted during 2012 in private and public-sector schools of Karachi to determine the prevalence and factors influencing overweight and obesity among school children (aged 11-15 years). Sociodemographic characteristics and dietary habits were explored. The CDC Growth Chart was used to record height and weight. Of a total of 887 children, being overweight and frankly obese was found in 169 (19.1%) and 96 (10.8%), respectively. Of these, 176 (66.4%) were from private schools, and significant associations were found in 202 (76.2%) who were spending > 2 h/day watching television and 139 (52.5%) sleeping > 8 h/day. PMID- 30020029 TI - Long-Term Trajectories of Posttraumatic Stress Disorder: Categorical versus Continuous Assessment. AB - OBJECTIVE: Long-term trajectories of posttraumatic stress disorder (PTSD) may fluctuate over time and typically conform to four heterogeneous patterns: resilience, recovery, delayed-onset, and chronic symptomatology. However, such fluctuations are typically short ranged and have rarely been investigated over the course of decades after the trauma. Moreover, existing studies have used a variety of measurements, either employing a categorical Diagnostic and Statistical Manual of Mental Disorders (DSM)-oriented approach or a continuous measure of symptom severity. The aim of this study was to evaluate the two methods of analyzing trajectories of PTSD by examining the level of concordance between them, their sensitivity, and their validity. METHOD: A total of 349 Israeli veterans from the 1973 Yom Kippur War were examined at four time points over more than four decades since the war. A latent class growth analysis (LCGA) was conducted to identify different PTSD trajectories, using both categorical and continuous PTSD assessments. RESULTS: Descriptive results revealed that the four commonly observed patterns of PTSD are insufficient for capturing the range of individual PTSD trajectories. Using a categorical measure in the explorative LCGA yielded three trajectories (resilient, chronic, and delayed onset). The continuous measure yielded five trajectories (resilient, chronic, recovered, and two delayed-onset trajectories), which provided a slightly more nuanced distinction of participants' distress-induced psychosocial dysfunction as compared to the three-trajectory solution. CONCLUSION: These findings suggest that using a continuous PTSD trajectory measure provides a somewhat more sensitive estimation of PTSD trajectories. More specifically, taking into consideration symptom intensity and fluctuation over time may provide a more comprehensive picture of the survivors' distress. PMID- 30020031 TI - Surgical Echocardiography of the Mitral Valve: Focus on 3D. AB - The mitral valve remains a complex structure where multiple forms of pathology can be seen. Mitral regurgitation continues to be one of the most common valvular diseases in the industrialized world. While intraoperative 2-dimensional transesophageal echocardiography has been commonplace for some time, 3 dimensional technology has emerged and has shown great benefit for diagnosis and guidance during mitral valve surgery. In the hands of a trained sonographer, high quality real-time images can easily be obtained and correlate well with gross anatomical findings. The use of multiple angled views and color Doppler within 3 dimensional transesophageal echocardiography has become a valuable asset in the understanding and interpretation of the mitral valve for surgical interventions. PMID- 30020030 TI - No Mystification, Perhaps Some Misunderstanding. PMID- 30020032 TI - Posthospital home visit as teaching tool for internal medicine residents. AB - Internal medicine residency programs consider effectively discharging patients from the hospital an important training milestone. However, it is rare for residents to have the opportunity to follow discharged patients into the community and see discharge plans in action. This curriculum provided residents with the opportunity to evaluate patients in their homes after they were discharged from the hospital to assess the alignment of the discharge plan with patients' real-life circumstances. Thirty-nine internal medicine residents participated in a structured exercise during a posthospital discharge home visit to older patients they cared for during the hospital admission. After completing the exercise, residents were asked what they learned from the experience. We found that by visiting patients' homes, residents were able to better assess patient needs, which highlighted the necessity for more individualized discharge plans with regard to in-home functioning, communication with caregivers, and medication reconciliation. Further, the posthospital visit exercise enhanced residents' awareness of challenges in developing and implementing discharge care plans for complex older patients. PMID- 30020033 TI - How Do Patients With Schizophrenia and Their Families Learn About the Diagnosis? AB - OBJECTIVE: The purpose of the present study was to investigate how patients with schizophrenia and their relatives learn about the diagnosis and to study their feelings and degree of satisfaction with the process of delivering that information. METHOD: A total of 16 individuals who had been recently diagnosed with schizophrenia spectrum disorders and 15 of their relatives were interviewed. The interviews were recorded, transcribed verbatim, and analyzed using grounded theory. RESULTS: Twenty-six (86%) patients and relatives reported having first learned about the diagnosis by reading the patient's release form or during an incidental encounter with personnel. Most patients and their relatives disagreed with the diagnosis and reported negative feelings about the way in which they learned about it. Only four (14%) patients and relatives fully understood why medications were prescribed. Relatives who received the diagnosis incidentally were more dissatisfied with the disclosure process and had poorer adherence to treatment. CONCLUSIONS: Development of empirical-based guidelines for delivering difficult news in psychiatry is needed to improve the way of communicating the diagnosis to patients and their relatives. PMID- 30020034 TI - An Overview of a Hospital-Based Child Advocacy Center's Experience from Turkey. AB - The purpose of the present study was to investigate sociodemographic variables, features of sexual abuse (SA), and first psychiatric evaluation results of abused children, and to analyze the relation of the psychiatric evaluation results to the children's age and gender, type and duration of abuse, abuser-child relationship, and marital status of the children's parents, at one of the most experienced Child Advocacy Centers (CACs) in Turkey. All data were obtained from reports prepared by child and adolescent psychiatrists. The sample of this study consists of 436 child sexual abuse (CSA) cases who admitted Izmir CAC between April 2014 and November 2015. The statistical analyses yielded significant relations between psychiatric symptoms and chronic abuse, the gender of the children, and type of abuse. Suicidal ideation and behaviors due to sexual abuse (SA) were also examined. According to our results, it is fair to say that children exposed to SA benefit from immediate psychiatric help because of their vulnerability for psychiatric disorders due to abuse. In this context, CACs are very important multidisciplinary establishments to determine children's multiple needs to ease their trauma with collaborative teamwork. Psychiatric evaluation should be part of this multidisciplinary context. PMID- 30020035 TI - [Oral nutritional supplement in patients with COPD who completed PR program: six months and one year follow ups]. AB - Introduction: Oral nutritional supplement (ONS), an important part of multidisciplinary pulmonary rehabilitation (PR) program, is indicated according to body composition abnormalities in the patients with chronic obtructive pulmonary disease (COPD). We evaluated efficacy of oral nutritional supplement (ONS) during 5-8 months in patients with COPD who completed PR program. Materials and Methods: The data of 41 patients with stable COPD were recorded after the approval had been taken. Patients were grouped according to ONS duration. Group 1 consisted of patients who took ONS during 2 months, group 2: 5 months, group 3: 8 months. In all patients, pulmonary function tests, quality of life, exercise capacity and body composition datas were recorded before and after PR program, at 3rd, 6th month and in 20 patients 1 year follow-up visit. Result: In all groups, improvements after PR in exercise capacity, dyspnea, and body composition sustained at 3 and 6 month. Quality of life was protected in group 1 during six month, in other groups it was over values before PR despite loss at 6. month. All improvements after PR were similiar between groups. In 20 patients with one year follow up, while the improvements in dyspnea and body composition were preserved, both exercise capacity and quality of life decreased, exercise capacity was lower than values before PR. Conclusions: In patients with COPD, after multidisplinary PR program, the improvements in dyspnea, exercise capacity, quality of life were maintained during six months regardless of body composition and ONS duration. Furthermore, while the improvements in body composition, dyspnea, quality of life were protected, exercise capacity was found to be lower than baseline. PMID- 30020036 TI - Does the neutrophil-to-lymphocyte ratio have any importance between subjects with obstructive sleep apnea syndrome with obesity and without obesity? AB - Introduction: An increase in the incidence of OSAS (obstructive sleep apnoea syndrome) has been seen due to the reported association between OSAS and obesity. Subjects are predisposed to cardiovascular disease due to systemic inflammation caused by the interactions between obesity and OSA. Inflammatory markers could be used to predict the degree of systemic inflammation, which could be a prognostic factor for future adverse events such as metabolic risks. One marker that has recently started being used as an indicator of systemic inflammation is neutrophil-to-lymphocyte ratio (NLR). Materials and Methods: The aim is to evaluate NLR, which is a easily measured parameter of systemic inflammation in OSAS subjects with and without obesity. 155 subjects were assigned to four different groups according to their body mass indices. Comparisons of white blood cell, neutrophil, lymphocyte, NLR values and anthropometric measurements were done for each group. Result: The NLR and neutrophil counts of group 4 were statistically significant and higher than those of groups 1, 2 and 3. The lymphocyte counts of group 4 were the lowest amongst all groups, these values were lower than the lymphocyte counts of groups 1, 2 and 3 with statistically significant differences (p< 001). A positive correlation was found between the body mass index and lymphocyte count values of obese OSAS subjects (r= 0.027, p= 353). Conclusions: The NLR ratio was found to be increasing by obesity grade and reveals that the associated inflammatory response also increases. The NLR ratio might be used as an inflammatory marker in obese OSAS subjects. PMID- 30020037 TI - Occurrence of adverse events in patient receiving community-based therapy for multidrug-resistant tuberculosis in Pakistan. AB - Introduction: Pakistan ranks 4th among 22 multidrug resistant tuberculosis (MDR TB) high burden countries. The increasing rate of MDR-TB in Pakistan underscores the importance of effective treatment programs of drug-resistant TB. Clinical management of MDR-TB requires prolonged multidrug regimens that often cause adverse events (AEs). Materials and Methods: This retrospective case series study include all patients who were enrolled for MDR-TB treatment during January 2014 till April 2015 at Programmatic Management of Drug Resistant TB (PMDT) unit at tertiary care hospital, Lady Reading Hospital (LRH) Peshawar Pakistan. In this study we sought to ascertain the occurrence of treatment related adverse events and factors associated with these events. Here we also examined the frequency of and reasons for changing drug regimens. We further sought to determine whether the occurrence of adverse events negatively impacts the treatment outcome and management of adverse effects without requiring the discontinuation of MDR-TB therapy. Result: At the time of analysis final outcomes of all 200 enrolled patients exist. Among these 52.5% were females and (81.5%) were aged <= 44 years. Among study cases 155 (77.2%) experienced at least one adverse event during treatment. The most commonly reported events were psychiatric issues (70%) whereas the less common was skin rashes (7.5%). A change in drug dose due to adverse events occurred in 16.5% cases, while 13.5% cases had at least one drug discontinued temporarily. Younger age and lung cavities at baseline were positive association with occurrence of adverse events. Association was also found between adverse events and treatment outcomes (OR 0.480, 0.236-0.978, p= 0.041). Conclusions: Adverse events were prevalent among MDR-TB patients treated at PMDT LRH Peshawar. All patients who were younger aged and cavitory lungs should be closely monitored for occurrence of adverse events. PMID- 30020038 TI - Drug resistance pattern in Mycobacterium tuberculosis to the first line drugs of pulmonary tuberculosis patients at Hazara Region, Pakistan. AB - Introduction: Multidrug resistant TB (MDR-TB), defined as resistance to at least rifampicin and isoniazid together, has been rapidly spreading in recent years. In new pulmonary tuberculosis patients, rapid spread of MDR-TB and XDR-TB challenging the effectiveness of national TB control programs especially in many low-income countries. This study was aimed to determine the resistance pattern of Mycobacterium tuberculosis among new cases, cured, failure, relapse, defaulted, treatment completed, treatment not evaluated and suspect to be resistant to first line antitubercular drugs of pulmonary tuberculosis (PTB). Materials and Methods: The study was conducted during 2013-2016 in which 148 patients were enrolled infected with pulmonary TB. Three sputum samples were consecutively collected and transported for drug analysis to the Provincial Reference Laboratory (PRL) at Hayatabad Medical complex Peshawar (HMCP) TB laboratory, within three days of collection at +4 degrees C in a cold box. Using the standard proportion method, drug susceptibility test was performed on 132 (89.2%) sputum samples for rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), and streptomycin (S). Result: Prevalence of resistance to one drug was 5 (3.4%). The highest proportion of mono-drug resistance was observed against E, 3 (2%), followed by H, 1 (0.7%), and R, 1 (0.7%). Pattern of resistant to two drugs was 14 (9.5%). The proportion of poly resistant was 3 (2%). 112 (93.33%) diagnose patients were MDR TB. Conclusions: To formulate an effective regimen, it is important to know drug resistant pattern because drug resistant pattern varies from different period of time also from one place to another. PMID- 30020039 TI - In vitro effects of ciprofloxacin, levofloxacin and moxifloxacin on Mycobacterium tuberculosis isolates. AB - Introduction: Increased tuberculosis prevalence, and isolation of multidrug resistant (MDR) Mycobacterium tuberculosis strains frequently as causative organisms from tuberculosis infections are resulted in increasing need of new anti-tuberculosis drugs. Nowadays, fluoroquinolones known to have fewer side effects than the other drugs used in treatment of tuberculosis are sometimes assessed even as first-line anti-tuberculosis drugs due to their in vitro and in vivo strong activity. It was aimed in this study to investigate phenotypically the fluoroquinolone susceptibility in MDR and non-MDR M. tuberculosis isolates. Materials and Methods: A total of 126 MDR and non-MDR M. tuberculosis isolates from mycobacteriology laboratory of two hospitals in the Aegean Region of Turkey were included in the study. Ciprofloxacin (CIP), levofloxacin (LEV) and moxifloxacin (MXF) susceptibilities were assessed by agar proportion method according to the Clinical and Laboratory Standards Institute (CLSI) recommendations. Result: Twelve (15.2%), 5 (6.3%) and 4 (5.1%) of the MDR M. tuberculosis strains were resistant to CIP, LEV, MXF, respectively [resistance breakpoints (ug/mL); CIP (> 2), LEV (> 1), MXF (> 0.5)] while non-MDR strains were susceptible to CIP, LEV, MXF. Conclusions: Consequently, although high fluoroquinolone susceptibilities were evaluated as a pleasing data in this study, to preserve their efficiency for many years steadily, quinolone usage and resistance increment in MDR M. tuberculosis isolates should be monitored elaborately. PMID- 30020040 TI - Look closer to welders' lung. AB - Introduction: Welding produces miscellaneous gases and particles that has various impact on respiratory system and long term exposure may result "welders'lung". The aim of this study is to describe the radiological findings of welders' and make an awereness for welders radilogical findings. Materials and Methods: The clinical and radiological findings of welders' who had hospital applications with respiratory symptoms between January 2010-January 2017 were evaluated retrospectively. Result: A total of 16 male welders with mean age 37 +/- 8 years had the mean duration of welding occupation 12 +/- 7 years. The most common symptoms were coughing (87%), sputum production (63%) and dyspnoea (63%).Thirteen welders were working in shipyards and 3 in construction business and other workplaces. Three (19%) patients had rhonchi on physical examination and these patients had decreased FEV1/FVC values below 70% on spirometry. Poorly-defined centrilobular micronodules that were not clearly visible on chest radiographs observed on thorax high resolution computed tomography. Bronchoscopy was performed to 7 patients. Iron-positive pigment granules and ferruginous bodies were revealed in 3 patients' bronchoalveolar lavage. Conclusions: Welders' chest X-ray deserve a closer look. In pulmonary radiology, there may be radiographical findings ranging from small ill defined nodules to groundglass opacites. Physcians should look more careful to welders' chest X-ray and incase of suspicious findings best can be detected on high HRCT. An awareness for the radiological findings will also reduce interventional procedures in these patients hereby, occupational history must be included in daily practice of physicians. PMID- 30020041 TI - Smoking attitudes of the patients with allergic rhinitis: a comparison with asthma and chronic obstructive pulmonary disease. Are there differences when only upper airways are involved? AB - Introduction: Despite the well documented relationship between lower airway diseases and smoking, there are limited data about smoking and allergic rhinitis (AR). In this study, we aimed to document the smoking behaviour and environmental tobacco smoke (ETS) exposure of the patients with AR in comparison with patients with asthma, chronic obstructive pulmonary diseases (COPD) and healthy controls (HC). Materials and Methods: Demographics and disease characteristics were recorded from case files whereas smoking history, childhood and current exposures to ETS, as well as the smoking behaviors were investigated by a self reported questionnaire. Result: A total of 937 subjects comprising patients with AR (n= 252), asthma (n= 249), COPD (n= 188) and HCs (n= 248) were enrolled in the study. The rates of active smokers were 35% (HCs), 26% (COPD), 21% (AR), and 11% (asthma). Exposure to ETS while with friends was significantly higher among HCs and AR groups (p< 0.0001). The rate of willingness to quit smoking is high in AR patients (73%) but they did not determined about date of quiting. Conclusions: Our results showed that a significant number of patients with AR actively smoke and neither the patients with AR nor the people in their surroundings were sufficiently aware of the health hazards of smoking with AR. It seems necessary to inform patients with about the health effects of smoking on all respiratory tract diseases. PMID- 30020042 TI - Characteristics of influenza pneumonia patients admitted to the ICU due to hypoxemic respiratory failure. AB - Introduction: Hypoxemic respiratory failure due to influenza pneumonia during epidemic seasons sometimes may require mechanical ventilation support and intensive care unit (ICU) stay. We aimed to evaluate the characteristics and risk factors of influenza pneumonia patients admitted to our ICU due to hypoxemic respiratory failure. Materials and Methods: Patients admitted to our ICU between December 2015 and March 2016 who had hypoxemic respiratory failure due to clinically and radiologically suspected influenza pneumonia were enrolled. Result: Twenty two patients (11 male) met the enrollment criteria. Median age and APACHE II score was 45 (36-63) years and 19 (13-25) respectively. Maximum set PEEP levels during mechanical ventilation was significantly lower in patients who survived [10 (8-10) vs 13 (10-16), p= 0.025)]. Deceased patients spent more time under a PaO2/FiO2 ratio below 100 [72 (24-90) vs. 0 (0-48) hours, p= 0.024]. Survival rate was 88% (7/8) in patients who had noninvasive ventilation (NIV) success while it was only 7% (1/14) in patients who had undergone invasive mechanical ventilation (p< 0.001). Overall mortality was 64%. Conclusions: Viral pneumonia may result in severe hypoxemic respiratory failure and ARDS especially during epidemic seasons. NIV success, time spent under a PaO2/FiO2 ratio below 100 and low serum albumin levels at admission may be predictors of severity of the disease and mortality. PMID- 30020043 TI - Humidification therapy; long-term effects in COPD and OSAS patients. AB - Humidification therapy is widely used in patients during invasive ventilation and the importance of heating and humidifying the inhaled air is well defined in both the acute and long term setting. On the other hand the continuous usage of humidification in noninvasive ventilation is controversial and the long term effects are still not well defined. The usage of noninvasive ventilation is especially important in hypercapnic Chronic obstructive pulmonary disease (COPD) and also the obstructive sleep apnea syndrome (OSAS) patients and compliance to this treatment is essential in long term. Limited number of studies have shown that heated humidification is preferred by COPD patients and might help in mucus clearance, reduce mucus viscosity and help in expectoration, but there was shown no priority as far as concerns the lung function or blood gas parameters. Humidification might also be important in long term oxygen treatment since the inhalation of dry air can lead to ciliary dysfunction, alterations in mucus properties and mucociliary clearance impairment. Studies concerning OSAS patients showed that humidification helps to reduce the nasal symptoms but plays no role in increasing the compliance of patients in long term. Multi-center studies with large number of patients are needed to identify patients' groups who are likely to benefit from the addition of humidification to noninvasive therapy. PMID- 30020044 TI - Management of parapneumonic effusion in pregnant women. AB - Pneumonia and parapneumonic effusion (PPE) are not more common in pregnant women compared to normal population. Pneumonia is considered the second most common infection in pregnant women. PPE is a serious complication of pneumonia and occurs especially in case of treatment delay or inappropriate antibiotic selection. The data on the management of PPE in pregnant women is limited to few case reports. PMID- 30020045 TI - Foreign body aspiration in a pregnant woman: successfully removed roasted chickpea. AB - Foreign body aspiration is a serious health problem in all age groups, and in pregnancy it may cause serious complications for the fetus as well as the pregnant woman. Here we present our case of a 36 years old 22 weeks pregnant woman, accidentally aspirating roasted chickpea upon laughing. She had the complaints of coughing and shortness of breath on admission, bronchoscopy was performed, and the roasted chickpea blocking the entrance of right lower lobe bronchus was removed without any complications. For foreign body aspiration in pregnancy, bronchoscopy is a rather safer procedure when performed by an experienced team. PMID- 30020046 TI - [Lupus-like syndrome in patients treated with anti-TNF-alpha factors]. AB - A 56-year-old male patient presented with history of complaints of night sweats, short ness of breath, cough and yellow sputum, fever. There was a history of tumor neurosis factor-alpha (etanercept) due to ankylosing spondylitis. Postero anterior chest X-ray; the right sinus was blunt, the right diaphragm had linear opacity compatible with atelectasis extending from the diaphragm to the periphery, left pleural effusion, left middle basal paracardiac opacity. In thorax tomography; pleural effusion and pericardial effusion and compressive atelectasis in the adjacent lung parenchyma were detected. Lymphocyte dominance had in cytological examination. Active chronic pleuritis and fibrinous exudate as benign cytology were reported in pleural biopsy. We are thought to develop pleurisy due to anti TNF-induced lupus like syndrome. 100 mg prednol was applied for three days. One month later the control was found toregress in the filter. PMID- 30020047 TI - Difficulty in management of pneumothorax in an octogenarian with pulmonary fibrosis. PMID- 30020048 TI - Is Asthma-COPD overlap an asthma phenotype or a COPD phenotype? PMID- 30020049 TI - Immuno-checkpoint inhibitor-associated hyper-eosinophilia and tumor shrinkage. PMID- 30020051 TI - The AsMA Global Connection Story with ESAM. PMID- 30020052 TI - General Aviation Accidents Involving Octogenarian Airmen: Implications for Medical Evaluation. AB - BACKGROUND: No upper age limit exists at which general aviation pilots are disallowed from exercising their flying privileges. Operating an aircraft, and landing in particular, requires high visual acuity, cognitive function, and eye hand/foot coordination; i.e., functions which commonly deteriorate with age. No studies have addressed flight safety of airmen >= 80 yr of age (octogenarian+ or 80+) or whether such airmen are more landing accident-prone. This research seeks to answer these questions. METHODS: Accidents and private pilot-certificated airmen counts were obtained from the National Transport Safety Board accident database and the U.S. Civil Airmen Statistics, respectively. Contingency tables were used to determine differences in proportions. A Poisson distribution was employed to determine whether airmen count (80+ and 30-39 yr) and their accident rates differed over time. Differences in median values were tested with a Mann Whitney test. RESULTS: The proportion of airmen 80+ years doubled and their accident rate increased (6 and 11 mishaps/1000 airmen, respectively) between 2002 and 2016. Landing accidents were over-represented for octogenarian+ pilots compared with airmen 30-39 yr (31 and 17%, respectively) and did not reflect inferior experience but were often due to an aircraft flaring deficiency. The proportion of fatal accidents was comparable (11 and 13%, respectively) for the older and younger age cohorts. CONCLUSION: A growing population and a climbing accident rate for octogenarian+ airmen were evident. The disproportionate count of pilots involved in landing mishaps raises a concern for an increase in such mishaps for octogenarian airmen opting for BasicMed due to less restrictive/frequent visual acuity tests.Boyd DD. General aviation accidents involving octogenarian airmen: implications for medical evaluation. Aerosp Med Hum Perform. 2018; 89(8):687-692. PMID- 30020053 TI - Local Pressure Application Effects on Neurological and Circulatory Function. AB - BACKGROUND: Pain and discomfort reported during sitting is a significant problem for aviators during prolonged missions. Previous work has determined that areas of local pressure exist during prolonged sitting in UH-60 seat systems; however, no work has examined the effects of this local pressure on measures of neurological and circulatory function. METHODS: A total of 30 healthy subjects completed the study in which focal pressure was applied in three conditions (no pressure, pressure to the ischial tuberosity, and pressure to the posterior thigh). We applied pressure using a purpose-built pressure application system allowing subjects to sit in a position mimicking the sitting position in a UH-60 Black Hawk helicopter and measurements were taken before, during, and after pressure application. We measured neurological function with the soleus Hoffmann reflex and sural nerve conduction velocity, and circulatory function with dynamic infrared thermography. RESULTS: We found a decrease in soleus Hoffmann reflex by 0.87 V and 0.52 V during pressure application at the posterior thigh and ischial tuberosity, respectively. No changes in nerve conduction velocity were found among the conditions during or after pressure application. Limb temperature increased 0.42-0.44 degrees C during pressure application, but began to return to baseline once pressure was removed. DISCUSSION: This study examined the development of neurological and circulatory alterations due to local pressure application in an aviation specific functional position. These results may be used in the development of future interventions to mitigate the negative effects of localized pressure in military aviators.Games KE, Lakin JM, Quindry JC, Weimar WH, Sefton JM. Local pressure application effects on neurological and circulatory function. Aerosp Med Hum Perform. 2018; 89(8):693-699. PMID- 30020054 TI - PERCLOS as an Indicator of Slow-Onset Hypoxia in Aviation. AB - BACKGROUND: PERCLOS is a metric that has been primarily studied in the domain of driver fatigue to predict performance decrements, but there is comparatively less research applying it to aviation, where hypoxia is a safety concern. Hypoxic exposure was expected to increase blink activity, possibly by means of impairing blink inhibition behavior, thereby leading to increased eyelid closure time. METHODS: PERCLOS, blink rate, and blink duration were measured using head-mounted eye-tracking on pilots using a flight simulator inside a hypobaric chamber. Pilot subjects were tasked with programming the autopilot of a G-1000 console according to instructions from a simulated air traffic controller. Data was collected at 5% decrements in blood oxygen saturation (Spo2) through progressive decreases in hypobaric pressure to model slow-onset hypoxia. RESULTS: PERCLOS, blink rate, and blink duration increased significantly and linearly as a function of decreasing Spo2, and largely recovered in the posthypoxia normoxia condition. The greatest change in PERCLOS relative to the prehypoxia baseline occurred in the 80% Spo2 condition, whereas the greatest change in blink rate and duration occurred at 75% Spo2. As Spo2 decreased, a higher frequency of long blink durations was observed. DISCUSSION: The increase in blink rate and duration in the absence of task demand manipulation could suggest hypoxia-induced sympathetic excitation and impairment of adaptive blink inhibition behavior. The effect of hypoxia on oculomotor features is also likely task-specific. In consideration of the extensive demand made upon the visual modality in flight, increased PERCLOS may further tax visual information processing.Thropp JE, Scallon JFV, Buza P. PERCLOS as an indicator of slow-onset hypoxia in aviation. Aerosp Med Hum Perform. 2018; 89(8):700-707. PMID- 30020055 TI - Fatigue Incident Antecedents, Consequences, and Aviation Operational Risk Management Resources. AB - BACKGROUND: Flight crew fatigue is an important factor in aviation, leading organizations to implement fatigue risk management programs to reduce risk. The U.S. Air Force Air Mobility Command (AMC) has implemented the Aviation Operational Risk Management (AvORM) program to aid mission schedulers and flight crews in mitigating flight risks and identifying appropriate levels of risk. The AvORM program uses a scheduling tool and underpinning biomathematical fatigue model. This study examined self-reported fatigue-related incidents within AMC, which provides some indirect and anecdotal evidence as to the effectiveness of the scheduling tool. METHODS: Archival data from the AMC Aviation Safety Action Program (ASAP) Safety Reporting System was examined. Report content themes were created through an inductive approach in terms of fatigue prevalence, antecedents, and consequences. RESULTS: Fatigue was estimated as a factor in 4% of the reports. The two most commonly referenced fatigue antecedents were associated with mission/duty length and mission scheduling/planning factors. Factors associated with aircraft operation violations were the most cited consequences of fatigue. Fatigue was almost twice as likely to be reported as a secondary rather than primary contributing factor. Aircrew reported both positive and negative aspects of AvORM resources in mission planning and fatigue mitigation. DISCUSSION: Examination of ASAP reports suggests that fatigue is a contributing factor to safety incidents. Although the AvORM program highlights potential flight risks by utilizing a scheduling tool built upon an underlying biomathematical fatigue model, human fatigue continues to impact safety, suggesting an ongoing need for improved fatigue risk management and mitigation.Morris MB, Wiedbusch MD, Gunzelmann G. Fatigue incident antecedents, consequences, and aviation operational risk management resources. Aerosp Med Hum Perform. 2018; 89(8):708-716. PMID- 30020056 TI - Quantitative Pupillometry for Detection of Intracranial Pressure Changes During Head-Down Tilt. AB - BACKGROUND: There is a need to develop noninvasive methods to monitor intracranial pressure (ICP). Pupillary reactivity decreases in patients with elevated ICP with demonstrated cerebral edema. We sought to determine whether pupillary reactivity is affected when ICP is elevated in the absence of brain edema. METHODS: Healthy subjects and individuals with idiopathic intracranial hypertension (IIH) underwent pupillometry in different positions (upright, supine, and head-down tilt) and during different physiological maneuvers. A separate group of healthy subjects were tested in the upright resting position only. The pupillary dynamics were measured with a pupillometer. RESULTS: Healthy and IIH subjects were enrolled. In the healthy subjects the change from upright to head-down tilt led to a Neurological Pupil Index (NPI) decrease from 4.30 to 4.12, while maximum pupil size and minimum pupil size increased from 4.74 to 5.19 and 3.04 to 3.44, respectively. In the IIH group the maximum pupil size, minimum pupil size, and latency increased in magnitude with a decline in head tilt. The mean NPI of IIH subjects, 4.37, was greater than the healthy mean, 4.25. Also, the mean IIH Max and Min, 5.02 and 3.25, were greater than the healthy mean, 4.62 and 2.92. DISCUSSION: We observed changes in the pupillary reactivity in all subjects based on changes in position and task. There were also differences between the healthy and IIH subjects. This is consistent with our hypothesis that elevated intracranial pressure may result in decreased pupillary reactivity even in the absence of brain edema.Soeken TA, Alonso A, Grant A, Calvillo E, Gutierrez Flores B, Clark J, Donoviel D, Bershad EM. Quantitative pupillometry for detection of intracranial pressure changes during head-down tilt. Aerosp Med Hum Perform. 2018; 89(8):717-723. PMID- 30020057 TI - Portable Autorefractors for Detecting Axial Length Changes in Space. AB - INTRODUCTION: We evaluated the reproducibility of two portable, self-administered autorefractors (Netra and SVOne Pro) to assess the time course of visual changes on the ISS. METHODS: We measured cycloplegic refractive error at 5 visits at least a week apart in 13 subjects (6 women, 7 men, 30 +/- 9 yr) using both devices seated and also prone with lower body positive pressure (LBPP) applied. Axial length was measured with an optical biometer. Subjects completed a questionnaire on device preferences. RESULTS: The SVOne seated intrasession reproducibility coefficient (RPC) was 0.37 diopters (D), while the Netra's was 0.41 D. Intersession seated results were: RPC = 0.67 D for the SVOne and RPC = 0.54 D for the Netra. The average seated to prone LBPP differences were significantly different from zero for both the SVOne and Netra. The SVOne was preferred in four out of five categories on the questionnaire and took half the time to complete a measurement set compared to the Netra. DISCUSSION: Users preferred the SVOne and it took less time. An SVOne refraction change of 0.67 D from baseline would happen by chance less than 5% of the time. If multiple separate measurements were taken, the detection limit could be reduced (e.g., three repeated measurements could reduce it to 0.38 D). Since astronauts with visual changes show spherical equivalent changes of 0.5 to 1.0 D, in-flight autorefractors could help determine the time course of refractive changes in space from which changes in axial length could be inferred.Masterova KS, Anderson AP, Cowan DR, Fellows AM, Zegans ME, Buckey JC. Portable autorefractors for detecting axial length changes in space. Aerosp Med Hum Perform. 2018; 89(8):724 730. PMID- 30020058 TI - Energy Drink and Nutritional Supplement Beliefs Among Naval Aviation Candidates. AB - INTRODUCTION: The National Academy of Medicine called for increased research on nutritional supplement use among military members. Current research has suggested potential health risks posed by energy drink consumption. The purpose of this study was to examine the relationship of energy drink consumption and beliefs about nutritional supplements in a U.S. military population. METHODS: Data were collected by means of an anonymous 44-item survey that was administered to and completed by 302 naval aviation candidates (100% response rate) enrolled in aviation preflight indoctrination (API) at Naval Air Station Pensacola, FL. RESULTS: Bivariate correlations indicated a statistically significant relationship between beliefs regarding the safety of energy drinks, energy drink consumption frequency, and personal beliefs regarding supplements [r(202) = 0.23]. The negative correlational coefficient indicated an inverse relationship between favorable perceptions on supplements and energy drink consumption. DISCUSSION: This study assessed beliefs about the safety of nutritional supplements among API candidates and to examine if a relationship between nutritional supplement beliefs and energy drink consumption exists. Results indicated a significant inverse relationship between API candidates' beliefs regarding consumption frequency and safety of energy drinks as well as beliefs regarding supplement use. Results also suggested that the more positively an API candidate perceived nutritional supplements, the less frequently energy drinks were consumed. The findings of this study indicated a weak inverse relationship between the beliefs/use of energy drinks and beliefs regarding the effectiveness of nutritional supplement use among naval aviation candidates.Sather TE, Woolsey CL, Delorey DR, Williams RD Jr. Energy drink and nutritional supplement beliefs among naval aviation candidates. Aerosp Med Hum Perform. 2018; 89(8):731-736. PMID- 30020059 TI - Color Vision Tests in Pilots' Medical Assessments. AB - INTRODUCTION: The aim of this study was to evaluate the ability of eight color vision tests to screen for and accurately measure hereditary color-deficiency in order to improve color vision assessment methods for aircraft pilots. METHODS: This prospective study included 29 color-deficient subjects and 23 healthy subjects. All performed the following tests: Ishihara plates, Farnsworth D15, Lanthony desaturated 15 Hue, Munsell 100 Hue, Beyne and Fletcher-Evans CAM lanterns, Nagel anomaloscope, and the Color Assessment and Diagnosis (CAD) test. The sensitivity and specificity of color-deficiency diagnosis were evaluated for each test, as well as the test's relevance for assessing aircraft pilots. RESULTS: The Ishihara plate test demonstrated a sensitivity of 0.97 and a specificity of 1.00 for color-deficiency screening. The CAD test and anomaloscope showed both a sensitivity and specificity of 1.00. The Beyne lantern, Fletcher lantern, Farnsworth D15, and the Lanthony 15 Hue tests all showed a specificity of 1.00 and sensitivities of, respectively, 0.69, 0.97, 0.58, and 0.79. During aircraft pilot selection tests, the CAD test classified 10% of color-deficient subjects as safe to fly, the anomaloscope 17%, and the Beyne and Fletcher lantern tests, respectively, 31% and 3%. DISCUSSION: The discrepancy in results confirms that current color vision test protocols need to be reassessed. The CAD test could be an interesting alternative to the series of tests used to assess flight crew, but it seems more selective than current tests.Marechal M, Delbarre M, Tesson J, Lacambre C, Lefebvre H, Froussart-Maille F. Color vision tests in pilots' medical assessments. Aerosp Med Hum Perform. 2018; 89(8):737-743. PMID- 30020060 TI - Semicircular Canal Size and Shape Influence on Disorientation. AB - INTRODUCTION: Orientation in a 3-dimensional environment increases demands on the vestibular system. The anterior, lateral, and posterior semicircular canals sense pitch, roll, and yaw acceleration, respectively. The macular end organs sense linear acceleration and provide gravity reference. Creatures that evolved to fly (birds) share the same sensory systems and probably the same limitations as creatures that did not evolve to fly. However, bird semicircular canals have been noted for their large size relative to body mass since 1907. METHODS: A brief literature review was conducted regarding the morphological structure of the vestibular systems in birds, and their evolutionary and functional significance as compared to that in humans. RESULTS: For any given body mass, qualitatively more "agile" species have semicircular canals with larger radius of curvature. Specifically, the anterior and lateral canals were found to be preferentially larger than those of nonavian theropods and humans. Avian canals rarely approach circularity and all three canals typically undergo torsional excursions out of their respective planes. DISCUSSION: Increase in the length of the semicircular canal is associated with greater sensitivity to rotational stimuli. Highly maneuverable birds of prey have the largest overall canal dimensions relative to body mass, most plausibly to match the rapid body rotations that characterize variable speed maneuvering during pursuit. By comparison, the semicircular canals in humans are relatively smaller and lack the adaptive morphological asymmetry in agile flying species. This teleological symmetry may present another inherent but less understood vestibular limitation during aerobatic maneuvers, which could lead to spatial disorientation.Cheung B, Ercoline W. Semicircular canal size and shape influence on disorientation. Aerosp Med Hum Perform. 2018; 89(8):744-748. PMID- 30020061 TI - A Case Study of Severe Space Motion Sickness. AB - BACKGROUND: Motion sickness remains a significant and unpredictable problem during spaceflight. One of the major difficulties in understanding the etiology of space motion sickness has been a lack of data at the time the symptoms occur, i.e., immediately after entry into space and during return to Earth; in these phases of the mission is when critical operational tasks are performed. CASE REPORT: We report here the case of a crewmember who experienced severe motion sickness symptoms immediately after launching into space and for several days into the mission. Verbal reports recorded during and immediately after the flight describe in detail the symptoms and their underlying causes. The prominent cause was oscillopsia that was induced by moving the head, wearing prescription eyeglasses, and translating the whole body. DISCUSSION: In this case, space motion sickness was sudden and induced by voluntary or involuntary head or body movements in any plane. These head movements caused a visual disturbance that induced the perception that the environment was oscillating. The exaggerated motion perceptions suggest an increased vestibular sensitivity and/or decreased pursuit-optokinetic mechanisms in orbit and immediately after landing.Reschke MF, Wood SJ, Clement GR. A case study of severe space motion sickness. Aerosp Med Hum Perform. 2018; 89(8):749-753. PMID- 30020062 TI - Medical Guidelines for Airline Travel: Management of In-Flight Cardiac Arrest. AB - INTRODUCTION: Although cardiac arrest during airline flights is relatively uncommon, the unusual setting, limited resources, and the variability of the skills in medical volunteers present unique challenges. Survival in patients who suffer a witnessed arrest with a shockable rhythm who are treated promptly has improved since the advent of widely available automated external defibrillators (AEDs). In general, the chances of survival from an out-of-hospital cardiac arrest (OHCA) are greater when ventricular fibrillation (VF) is seen as the initial rhythm or if there is return of spontaneous circulation (ROSC). Not all in-flight cardiac arrests are witnessed because cabin crew or fellow passengers might simply assume that the victim is sleeping. Based upon a review of the literature on resuscitation after OHCA, we recommend that automatic external defibrillators be carried on all commercial airline flights, regardless of duration. Patients presenting with shockable rhythm (e.g., VF, unstable ventricular tachycardia) have the best prognosis for survival and usually require diversion of the aircraft for advanced cardiac life support (ACLS). Because diversion may require interruption of cardiopulmonary resuscitation (CPR) and may impact flight safety, the volunteer rescuer, cabin crew, flight crew, and medical consultation services should discuss the possible outcome and operational considerations before recommending a diversion for a patient with a nonshockable rhythm. The recommendations in this article were developed by members of the Air Transport Medicine and Aerospace Human Performance Committees and approved by the Council of the Aerospace Medical Association.Ruskin KJ, Ricaurte EM, Alves PM. Medical guidelines for airline travel: management of in-flight cardiac arrest. Aerosp Med Hum Perform. 2018; 89(8):754-759. PMID- 30020063 TI - You're the Flight Surgeon. AB - Nussbaum L. You're the flight surgeon: loss of consciousness while exercising. Aerosp Med Hum Perform. 2018; 89(8):760-762. PMID- 30020065 TI - This Month in Aerospace Medicine History. PMID- 30020064 TI - Ralph N. Greene, M.D.: Second President of the Aero Medical Association. PMID- 30020067 TI - Ortega is President-Elect of AsMA; Vermeiren Installed as President. PMID- 30020066 TI - Abstracts Not Presented. PMID- 30020068 TI - ? PMID- 30020069 TI - [The spinal dural arteriovenous fistula is an underdiagnosed vascular malformation]. AB - The spinal dural arteriovenous fistula is the most common spinal vascular malformation, and it is severely underdiagnosed. The symptoms can mimic those of spinal stenosis. Today, the diagnosis is made by an advantageous combination of MR time-resolved imaging of contrast kinetics and digital subtraction angiography posing low risk to the patient. Treatment is primarily direct microsurgical obliteration. Early treatment is essential, since outcome is dependent on preoperative clinical status. PMID- 30020070 TI - [Gallstones lost during laparoscopic cholecystectomy may cause severe complications]. AB - This review presents the consequences of gallstones lost during laparoscopic cholecystectomy (LC) and left in the peritoneal cavity. The incidence of intraoperative loss of gallstones during LC is estimated to be 1-40%. 1-12% of patients with unretrieved gallstones may develop compli-cations, with intra abdominal abscesses being the most frequent. The presence of pigment stones is correlated to development of complications. Studies show, that 80-83% of surgeons may underestimate the number of potential complications, which indicates, that this subject requires increased clinical attention. PMID- 30020071 TI - [Long delay until correct diagnosis of glomus tumours in the distal phalanx]. AB - Glomus tumours tend to be diagnosed with long delay due to lack of knowledge about the condition. This is a case report of two patients with longstanding symptoms, which remained undiagnosed for several years despite X-ray and MRI. One was operated on without finding the tumour at the initial surgical procedure, and the other had the diagnosis confirmed by ultrasound. Both were cured of the pain, when the subungual tumour was excised. PMID- 30020072 TI - [Should ophtalmologists recommend medical cannabis to patients with glaucoma?] AB - Cannabis has been widely used for various medical purposes since before year 2000 BC. Its effects are mediated by cannabinoids and stimulation of mainly G-protein coupled cannabinoid receptors. In 1971, subjects who smoked marihuana, showed a decrease in the intraocular pressure. Later investigations additionally revealed a neuroprotective effect of both ?-9-tetrahydrocannabinol and cannabidiol (CBD). Furthermore, CBD was found to promote neurogenesis. The aim of this review is to provide an overview of the potential use of cannabinoids in the treatment of glaucoma. PMID- 30020073 TI - [Severely dislocated fracture of neck of talus initially treated outside of trauma centre]. AB - Fracture of the talus is usually the result of a high-energy trauma and can present as an open fracture. This is a case report of an 18-year-old male with an open dislocated fracture of the neck of the talus, and the primary treatment consisted of: administration of antibiotics, tetanus prophylaxis, debridement and wound irrigation, reduction of fracture, immobilisation in external fixation and wound closure. Later, the patient had osteosynthesis of the fracture due to nonunion. PMID- 30020074 TI - [Amyloidosis in larynx]. AB - Localised laryngeal amyloidosis is a rare tumour of the upper respiratory tract, which is characterised by extra-cellular accumulation of proteinaceous material in the submucosa. The aetiology is still unclear. This is a case report of localised multifocal amyloidosis located to larynx and rhinopharynx. A 50-year old women with a history of progressive dysphonia and dyspnoea underwent ear-nose throat and haematological investigation with no signs of systemic involvement. The amyloid deposits in larynx were effectively treated with laser resection in general anaesthesia and regular follow-up. PMID- 30020077 TI - Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction (BASILICA) during transcatheter aortic valve-in-valve implantation with bioprosthetic valve fracturing via the transcaval access. PMID- 30020075 TI - Noncoding RNA-nucleated heterochromatin spreading is intrinsically labile and requires accessory elements for epigenetic stability. AB - The heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high positional precision, or fidelity, following replication. How the spreading reaction contributes to this fidelity is not clear. To resolve the origins of stable inheritance of repression, we probed the intrinsic character of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading triggered by noncoding RNA nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. This lack of stability correlates with high histone turnover. At the mating type locus, this unstable behavior is restrained by an accessory cis-acting element REIII, which represses histone turnover. Further, REIII safeguards epigenetic memory against environmental perturbations. Our results suggest that the most prevalent type of spreading, driven by noncoding RNA-nucleators, is epigenetically unstable and requires collaboration with accessory elements to achieve high fidelity. PMID- 30020076 TI - UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity. AB - Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory. PMID- 30020078 TI - Nanoscale potential fluctuations in nonstoichiometrics tantalum oxide. AB - The atomic and electronic structure of nonstoichiometric amorphous tantalum oxide (TaO x ) films of different composition has been investigated by means of electron microscopy, x-ray photoelectron spectroscopy, Raman and infrared spectroscopy. The dispersion of the absorption coefficient and refraction index has been studied by spectral ellipsometry. The optical spectra were interpreted using the results of a quantum-chemical simulation for crystalline orthorhombic TaO x . It was found that the presence of oxygen vacancies in the oxygen deficient TaO x film show an optical absorption peak at 4.6 eV. It has been established that TaO x consists of stoichiometric Ta2O5, metallic Ta clusters less than 20 nm in size, and tantalum suboxides TaO y (y < 2.5). The model of nanoscale potential fluctuations of TaO x bandgap in the range of 0-4.2 eV is proposed and justified. The design of the flash memory element based on the effect of localization of electrons and holes in Ta metallic nanoclusters in the TaO x matrix is proposed. PMID- 30020079 TI - 4D dose calculation for pencil beam scanning proton therapy of pancreatic cancer using repeated 4DMRI datasets. AB - 4D magnetic resonance imaging (4DMRI) has a high potential for pancreatic cancer treatments using proton therapy, by providing time-resolved volumetric images with a high soft-tissue contrast without exposing the patient to any additional imaging dose. In this study, we aim to show the feasibility of 4D treatment planning for pencil beam scanning (PBS) proton therapy of pancreatic cancer, based on five repeated 4DMRI datasets and 4D dose calculations (4DDC) for one pancreatic cancer patient. To investigate the dosimetric impacts of organ motion, deformation vector fields were extracted from 4DMRI, which were then used to warp a static CT of the patient, so as to generate synthetic 4DCT (4DCT-MRI). CTV motion amplitudes <15 mm were observed for this patient. The results from 4DDC show pronounced interplay effects in the CTV with dose homogeneity d5/d95 and dose coverage v95 being 1.14 and 91%, respectively, after a single fraction of the treatment. An averaging effect was further observed when increasing the number of fractions. Motion effects can become less dominant and dose homogeneity d5/d95 = 1.03 and dose coverage v95 = [Formula: see text] within the CTV can be achieved after 28 fractions. The observed inter-fractional organ and tumor motion variations underline the importance of 4D imaging before and during PBS proton therapy. PMID- 30020081 TI - Application of PDF analysis assisted by MD simulations for determination of the atomic structure and crystal habit of CdSe nanocrystals. AB - A new methodology of performing structural analysis of nanocrystals based on wide angle powder diffraction is proposed. It combines molecular dynamics simulations with the analysis of pair distribution function. The actual analysis was performed on CdSe quantum dots. MD simulations of nanocrystals with shapes defined by low-index atomic planes, (1 0 0), (1 1 0), and (1 1 1) introduced bulk and surface relaxation in initially perfect crystal lattice. In search for the best atomistic model of the actual CdSe nanocrystals, experimental structure functions S(Q) and interatomic distance functions G(r) were matched to those calculated with MD models. Eventually it was concluded that CdSe nanocrystals with dimensions of 2.5-3.5 nm assume the shape of octahedrons terminated by (1 1 1) surfaces. PMID- 30020080 TI - Relative Patlak plot for dynamic PET parametric imaging without the need for early-time input function. AB - The Patlak graphical method is widely used in parametric imaging for modeling irreversible radiotracer kinetics in dynamic PET. The net influx rate of radiotracer can be determined from the slope of the Patlak plot. The implementation of the standard Patlak method requires the knowledge of full-time input function from the injection time until the scan end time, which presents a challenge for use in the clinic. This paper proposes a new relative Patlak plot method that does not require early-time input function and therefore can be more efficient for parametric imaging. Theoretical analysis proves that the effect of early-time input function is a constant scaling factor on the Patlak slope estimation. Thus, the parametric image of the slope of the relative Patlak plot is related to the parametric image of standard Patlak slope by a global scaling factor. This theoretical finding has been further demonstrated by computer simulation and real patient data. The study indicates that parametric imaging of the relative Patlak slope can be used as a substitute of parametric imaging of standard Patlak slope for tasks that do not require absolute quantification, such as lesion detection and tumor volume segmentation. PMID- 30020082 TI - Electron-donor doping enhanced Li storage in electride Ca2N monolayer: a first principles study. AB - It was reported by Hu et al (2015 ACS Appl. Mater. Interfaces 7 24016) that Li adsorption on the Ca2N monolayer is energetically unfavorable, although it was found to be a good candidate for Na storage. In this paper, from first-principles calculations, it is shown that compressive stain can greatly enhance the interactions between Li adsorbate and the Ca2N host, which is beneficial to prevent Li from clustering on the surface and thus Li storage becomes possible. Charge distribution analysis further shows that the enhanced Li-adsorption is a result of the increased surface charge density and the more confined charge distribution under compressive strain. Inspired by this observation, several electron-donor-doped Ca2N materials are considered as anode materials for Li-ion batteries. Results show that the O and F doped Ca2N have the best performance, with predicted Li storage capacity reaching about 567.9 and 565.9 mAh g-1 for O and F doped cases, respectively. It is also demonstrated that electron-donor doping does not change the metallic electronic structures and the low Li-ion migration energy barriers on the surface of the Ca2N monolayer, and thus the rate performance of the doped Ca2N can be as good as the undoped case. Our study offers a deep understanding of the Li interactions with 2D materials and provides an approach of material modification to 2D electrides for battery applications. PMID- 30020083 TI - Spin-fluctuation and spin-relaxation effects of single adatoms from first principles. AB - Single adatoms offer an exceptional playground for studying magnetism and its associated dynamics at the atomic scale. Here we review recent results on single adatoms deposited on metallic substrates, based on time-dependent density functional theory. First we analyze quantum zero-point spin-fluctuations (ZPSF) as calculated from the fluctuation-dissipation theorem, and show how they affect the magnetic stability by modifying the magnetic anisotropy energy. We also assess the impact of ZPSF in the limit of small hybridization to the substrate characteristic of semi-insulating substrates, connecting to recent experimental investigations where magnetic stability of a single adatom was achieved for the first time. Secondly, we inspect further the dynamics of single adatoms by considering the longitudinal and transverse spin-relaxation processes, whose time scales are analyzed and related to the underlying electronic structure of both the adatom and the substrate. Thirdly, we analyze spin-fluctuation modes of paramagnetic adatoms, i.e. adatoms where the Stoner criterion for magnetism is almost fulfilled. Interestingly, such modes can develop well-defined peaks in the meV range, their main characteristics being determined by two fundamental electronic properties, namely the Stoner parameter and the density of states at the Fermi level. Furthermore, simulated inelastic scanning tunneling spectroscopy curves reveal that these spin-fluctuation modes can be triggered by tunneling electrons, opening up potential applications also for paramagnetic adatoms. Lastly, an overview of the outstanding issues and future directions is given. PMID- 30020084 TI - Aggregation of nanoparticles regulated by mechanical properties of nanoparticle membrane system. AB - The aggregation of nanoparticles (NPs) on the cell membrane is crucial for the cellular uptake process and has important biological implications in protein membrane interactions. In this paper, we systematically investigate how the aggregation is regulated by the mechanical properties of the NP-membrane system, including the membrane tension, and the size and shape of the NPs. Results show that when NPs aggregate parallel to the cell membrane, increasing the membrane tension will modulate the membrane-mediated interaction between the NPs from attractive to attractive-repulsive and finally to purely repulsive. In contrast, the membrane-mediated interaction is attractive and independent of the membrane tension when the NPs aggregate to a tubular configuration. For the aggregation of NPs of different sizes, the large-size NP is wrapped to a greater extent than the small-size NP. For the aggregation of nonspherical NPs, low aspect ratio and weak NP-membrane adhesion strength lead to the side-to-side configuration, whereas a system with a high aspect ratio and strong NP-membrane adhesion strength prefers the tip-to-tip configuration. Importantly, NPs of different sizes and anisotropic shapes are found to facilitate the aggregation process by reducing the energy barrier that should be overcome during the aggregation. The results reveal the mechanism of the aggregation of NPs on the cell membrane and provide guidelines to the design of NP-based drug delivery systems. PMID- 30020085 TI - Top-down and sensitive indium oxide nanoribbon field effect transistor biosensor chips integrated with on-chip gate electrodes toward point of care applications. AB - We report a scalable, uniform, and sensitive top-down fabricated indium oxide (In2O3) nanoribbon biosensor platform with integrated on-chip gate electrodes using two photolithographic masks. The purpose of this on-chip gate electrode is to control the operational point of the sensor during biomolecular detection replacing the cumbersome external Ag/AgCl electrode. It exhibits excellent capability in gating transistors in an aqueous condition and high stability during the sensing experiment, which is similar to the Ag/AgCl electrode. Its compactness increases the portability and pushes this platform toward a practical use. To demonstrate its capability for detection of biomolecules, we combine this platform with the electronic enzyme-linked immunosorbent assay (ELISA) technique to amplify the signal and to bypass limitation of the Debye screening effect from high salt concentration of physiological samples. Troponin I, a cardiac marker for diagnosis of acute myocardial infarction (AMI), was selected as the target molecule in this study. The In2O3 nanoribbon device offers a high response of 30% toward 0.1 pg ml-1 troponin I concentration and a lower detection limit than that of the commercial ELISA kit on the market by five orders of magnitude. The total assay time from the sample collection to the data acquisition is about 45 min, which is within the constraint of the emergency care application. With the demonstrated sensitivity, uniformity, scalability, quick turn-around time and ability to be integrated, our In2O3 nanoribbon biosensor platform has high potential toward clinical tests for early diagnosis of AMI. PMID- 30020086 TI - Critical properties of the quasi-two-dimensional metallic ferromagnet Fe2.85GeTe2. AB - We have investigated the critical behavior of Fe2.85GeTe2 single crystals near the paramagnetic-ferromagnetic transition by bulk dc magnetization measurements. The critical exponents beta, gamma and delta, obtained from modified Arrott plot, Kouvel-Fisher method, and critical isothermal magnetization analysis, could fulfill the Widom scaling law. The self-consistency and reliability of these exponents are further verified by the magnetic state equations below and above the Curie temperature at high magnetic field. In addition, the exchange distance deduced from the susceptibility exponent is shown to decay as [Formula: see text]. Based on the observations, we suggest that the competition between direct magnetic exchange and Coulombic and/or RKKY interactions should be responsible for the intrinsic magnetism in this system. PMID- 30020088 TI - Comparison of Preoperative Administration of Pregabalin and Duloxetine on Cognitive Functions and Pain Management After Spinal Surgery: A Randomized, Double-blind, Placebo-controlled Study. AB - STUDY OBJECTIVE: Surgical trauma is known to induce hyperalgesia, and if pain management is insufficient, it contributes to persistent pain in the postoperative period.In this study, our primary aims were to compare the effect of pregabalin and duloxetine on postoperative pain scores and cognitive functions. Our secondary aim was to determine drug-related side effects. DESIGN: This was a prospective, randomized, double-blind, placebo-controlled study. SETTINGS: The study was carried out in the setting of the operating room and the surgical ward. PATIENTS: Ninety-four patients, 18 to 65 years of age, ASA status I-II, scheduled for elective repair of lumbar disc herniation were enrolled in the study. INTERVENTIONS: The patients were randomly divided into 3 groups: the first group received pregabalin 75 mg orally 1 hour before the surgery and at the postoperative 12th and 24th hours. The second group received duloxetine 60 mg orally 1 hour before the surgery. At the postoperative 12th hour, they received a placebo capsule, and, at the 24th hour, they received duloxetine 60 mg again. The third group received placebo capsules orally at all timepoints. MEASUREMENTS: Postoperative pain evaluation was conducted using a Visual Analogue Scale at the postoperative first minute, 30th minute, first hour, and the 12th, 24th, and 48th hours. The preoperative and postoperative sixth hour cognitive functions were evaluated with Montreal Cognitive Assessment (MoCA) test. MAIN RESULTS: There was a significant reduction in mean MoCA scores postoperatively in all groups (P<0.01). The highest MoCA score reduction was in the pregabalin group (1.83+/ 1.31 point), then in the duloxetine group (1.16+/-0.82), and the least decrease was in the control group (0.49+/-0.61). At all timepoints, the mean Visual Analogue Scale scores of the pregabalin and duloxetine groups were similar to each other, and they were lower than that of the control group (P<0.05). CONCLUSIONS: Preoperative use of duloxetine 60 mg can be an useful alternative to pregabalin 75 mg, as it has a similar analgesic effect on postoperative pain, with fewer incidences of drug-related negative effects on cognitive function. PMID- 30020087 TI - Maternal Protective Parenting Accounts for the Relationship Between Pain Behaviors and Functional Disability in Adolescents. AB - INTRODUCTION: A variety of factors influence parent responses to pain behaviors they observe in their adolescents with chronic pain. Certain parental responses to pain, such as attention or overprotection, can adversely impact adolescent adaptive functioning and correspond to poor clinical outcomes. OBJECTIVES: It was hypothesized that the relationship between adolescent pain behaviors and functional disability was mediated by maladaptive parenting (protective, monitoring, solicitousness) responses. MATERIALS AND METHODS: Participants were 303 adolescents and their mothers presenting to a pain clinic. Adolescents completed measures of functional disability and pain intensity; mothers completed measures assessing adolescent pain behaviors, their own catastrophizing about their adolescent's pain, and responses to pain. A path model tested the direct and indirect associations between pain behaviors and disability via 3 parenting responses, controlling for average pain intensity and parent pain catastrophizing. RESULTS: Greater pain behavior was associated with increased protective responses (alpha path, P<0.001); greater protective behavior was associated with increased disability (beta path, P=0.002). Including parenting responses in the model, the path between pain behaviors and disability remained significant (c' path, P<0.001). The indirect path between pain behaviors and disability via parenting responses was significant for protective responses (P<0.02), controlling for pain intensity and parent pain catastrophizing. The indirect effect of protective responses explained 18% of the variance between pain behaviors and disability. DISCUSSION: Observing adolescent pain behaviors may prompt parents to engage in increased protective behavior that negatively impacts adolescents' functioning, even after controlling for the effects of parental pain catastrophizing. PMID- 30020089 TI - Congenital Syphilis: A Discussion of Epidemiology, Diagnosis, Management, and Nurses' Role in Early Identification and Treatment. AB - BACKGROUND: Syphilis is caused by the spirochete bacterium Treponema pallidum. Syphilis left untreated, or inadequately treated during pregnancy, can result in congenital syphilis (CS). Congenital syphilis can lead to severe sequelae or fetal, neonatal, or infant death. PURPOSE: To discuss the epidemiological trends, pathophysiology, diagnosis, and management of CS; the implications of CS upon the infant; as well as the importance of the nurse's role in the prompt identification of CS and the timely interventions needed to minimize sequelae. METHODS: A literature search was completed using ProQuest, CINAHL, Google Scholar, and PubMed. Articles published within the past 10 years were included. FINDINGS: Epidemiological trends of CS in the United States indicate that maternal syphilis infection and CS are on the rise. Risk factors include ethnicity, socioeconomic status, access to prenatal care, and sexual behaviors, as well as compliance with prenatal syphilis screening by prenatal providers. Risks of CS to the developing fetus begin at approximately 14 weeks. Timely treatment is necessary to minimize or eliminate mortality and morbidity. IMPLICATIONS FOR PRACTICE: Evidence-based, interprofessional strategies, which promote a collaborative perinatal/neonatal preventative approach to care of the pregnant female, are indicated to reverse the increasing incidence of CS within the United States. Strategies prioritizing early identification and treatment of at-risk neonates are necessary to reduce/eliminate the devastating long-term consequences of CS upon this vulnerable population. IMPLICATIONS FOR RESEARCH: The paucity of research, which focuses on CS, is most likely due to ethical concerns related to infants as research participants and provides an opportunity for future research. Future research could focus on factors that focus on maternal-fetal/maternal-child transmission of CS. PMID- 30020090 TI - Effect of Exercise on Risk Factors of Diabetic Foot Ulcers: A Systematic Review and Meta-analysis. AB - The objectives of this study were to examine the effectiveness of different types of exercise on risk factors of diabetic foot ulcers, including glycated hemoglobin (HbA1c), peripheral arterial disease (PAD), and diabetic peripheral neuropathy, in people with type 2 diabetes mellitus (T2DM). PubMed, Web of Science, Cochrane Library, Scopus, and CINAHL were searched from inception to January 2018 for relevant articles. Eligible studies were randomized controlled trials (RCTs) that examined effects of exercise on the selected risk factors. Twenty RCTs with 1,357 participants were included in the meta-analyses. The differences in post-intervention values of HbA1c and ankle brachial index (ABI) between exercise and control groups were synthesized, yielding mean differences of -0.45% (P<0.00001) and 0.03 (P=0.002), respectively; the differences in within group changes in HbA1c were synthesized, yielding mean differences of -0.19% (P=0.1), -0.25% (P=0.0006), and -0.64% (P=0.006) for aerobic vs. resistance, combined vs. aerobic, and combined vs. resistance exercise, respectively. Exercise has a significant effect on reducing HbA1c, while combined exercise is more effective compared to aerobic or resistance exercise alone. Exercise also improves ABI. However, evidence regarding the association between exercise and peripheral neuropathy and risks of diabetic foot ulcers in people with T2DM remains insufficient. PMID- 30020091 TI - Evidence-Based Physiatry: Clinical Practice Guideline: Noninvasive Treatments for Low Back Pain. PMID- 30020092 TI - Effects of Video Games-Based Task-Oriented Activity Training (Xbox 360 KinectTM) on Activity Performance and Participation in Patients with Juvenile Idiopathic Arthritis: A Randomized Clinical Trial. AB - OBJECTIVE: The aim of the study was to compare the effects of two different task oriented activity training (TOAT) programs on activity performance and participation in children/adolescents with Juvenile Idiopathic Arthritis (JIA). DESIGN: Sixty-two patients were randomized into group I and group II for TOAT. In group I, activities of daily living (ADL) were practiced using real materials from daily life and, in group II, ADL were practiced using video-based games (Xbox 360 Kinect) for 3 days/a week/8 weeks. Pain by the "Numeric Rating Scale (NRS)", upper extremity muscle, grip, and pinch strengths by a dynamometer, activity performance and participation by the "Childhood Health Assessment Questionnaire (CHAQ)", "Canadian Occupational Performance Measure (COPM)", and "Duruoz Hand Index (DHI)" were evaluated. RESULTS: After treatment in both groups, significant changes were found in the NRS, muscle strength, grips strength, CHAQ, COPM, and DHI (p<0.05). Group II was statistically superior to group I in changes of almost all upper extremity muscle strengths, palmar pinch strength, COPM-satisfaction, and DHI scores (p<0.05). CONCLUSION: Video games based TOAT is an alternative and feasible treatment for children/adolescents with JIA. This new method may have widespread applicability in future research, given the rapidly growing interest in virtual reality-based therapy in rehabilitation. PMID- 30020093 TI - Morphological Changes of the Median Nerve after Carpal Tunnel Release in a Median Nerve Lipofibromatous Hamartoma. PMID- 30020094 TI - Epithelial Inclusions in Gallbladder Specimens Mimic Parasite Infection: Histologic and Molecular Examination of Reported Cystoisospora belli Infection in Gallbladders of Immunocompetent Patients. AB - Recent publications have described epithelial cytoplasmic vacuoles and inclusions incidentally noted within gallbladder epithelium and concluded that they represent coccidian parasite infection, in particular, Cystoisospora belli. We identified 8 gallbladder specimens from our institution in the past 3 years in which this diagnosis was suggested or in which similar epithelial alterations were prominent. Molecular analysis was performed on the 8 gallbladder specimens and on 3 positive control specimens: small bowel biopsies from acquired immunodeficiency syndrome patients with diarrhea. Polymerase chain reaction using primers designed to amplify an internal transcribed spacer (ITS2) in the C. belli ribosomal gene cluster was performed on the DNA samples. All 8 gallbladder specimens were negative for amplification, while a product consistent with C. belli was amplified from all 3 positive controls. Histologically, the gallbladder cytoplasmic inclusions stained diffusely positive for Grocott-Gomori's methenamine silver and Periodic acid-Schiff with diastase. In contrast, sections from a positive control small bowel biopsy demonstrated organisms that were negative for Grocott-Gomori's methenamine silver and showed a distinct capsular and punctate internal staining on Periodic acid-Schiff with diastase in various parasite forms. Together, the lack of molecular evidence of C. belli and the distinct morphologic and special staining patterns in these gallbladders compared with positive control small bowel suggest that these epithelial changes do not represent true C. belli infection. Our results suggest that gallbladders of immunocompetent patients may occasionally show epithelial changes that can morphologically mimic C. belli infection. Pathologists should be aware of this histologic variant to minimize unnecessary treatment, testing, and patient anxiety. PMID- 30020095 TI - Walking endurance and perceived symptom severity after a single maximal exercise test in persons with mild disability because of multiple sclerosis. AB - People with multiple sclerosis (PwMS) are less physically active compared with the general population. This might also be because of the perception of temporary worsening of symptoms during physical activity. Forty-two PwMS with a mild level of disability underwent a maximal exercise test on a bicycle ergometer. Fifteen minutes before and 15 and 75 min after the maximal exercise test, the 6-minute walking test was conducted and the rate of perceived exertion was recorded. Twice before and three times after the maximal exercise test, participants rated the symptom inventory, including symptom domains of general fatigue, muscle fatigue, balance, gait pattern, muscle weakness, spasticity, pain, sensory disturbance, dizziness, and visual impairment. The visual analogue scale was used to rate the perceived symptoms from 0 (no intensity) to 10 (maximal intensity). The 6-minute walking test distance increased significantly over time, whereas the rate of perceived exertion increased temporarily after the maximal exercise test. Immediately after the maximal exercise test, significant temporary increases were found in balance, gait pattern, muscle weakness, and visual impairment. General and muscle fatigue were elevated, compared with the baseline, till 15 and 75 min after the maximal exercise test, respectively. A short-term impact of a single maximal exercise test was considered as the temporary worsening of perceived symptoms, especially (muscle) fatigue and the gait pattern, in PwMS with a mild level of disability. However, a recovery was observed after 75 min. Walking endurance was not affected by the maximal exercise test. PMID- 30020096 TI - How We Do It: "Punch-Pop" Single-Instrument Punch Fenestration of Cartilage to Augment Healing by Granulation, a Video Walkthrough. PMID- 30020098 TI - Commentary on Chlorhexidine Keratitis. PMID- 30020097 TI - Epidermal Fluence Threshold Determination by Real-Time Melanin Measurements. AB - BACKGROUND AND OBJECTIVE: Epidermal preservation is essential during laser treatment for vascular, hair, and benign pigment dyschromias. Epidermal tolerance is determined by epidermal melanin content, fluence, pulse width, wavelength, skin cooling, and spot size. The authors' objective was to determine the maximum epidermal tolerance for the long-pulse alexandrite 755 nm and the long-pulse neodymium-doped yttrium aluminum garnet (Nd:YAG) 1064-nm lasers for varying epidermal melanin content. MATERIALS AND METHODS: Skin melanin measurements were performed at the test sites with a melanin reader, and 0.5 to 1 second of refrigerated air precooled the skin. Then, alexandrite and Nd:YAG laser test spots of 5 to 18 mm were delivered in a series of ascending fluences using 5-, 20 , and 50-ms pulse widths. Skin response at 24 to 48 and 96 hours was scored from 0 to 15 varying from "no reaction" to "severe scabbing." RESULTS: Alexandrite laser, mean threshold fluences increased by a factor of 1.2 increasing from 5 to 20 ms, and by a factor of 1.4 increasing from 5 to 50 ms, among subjects with a melanin index (MI) from 9 to 25 (Fitzpatrick skin phototype I-III). The Nd:YAG fluence to reach epidermal tolerance was 6X the fluence with the alexandrite laser for the same MI in subjects with MI 26 to 35. CONCLUSION: Epidermal melanin measurements are quantitative and objective, therefore, improving treatment setting determination by decreasing the risk of overtreatment or undertreatment. PMID- 30020099 TI - Plasma Exeresis Treatment for Epidermoid Cysts: A Minimal Scarring Technique. AB - BACKGROUND: Epidermoid cysts are cutaneous benign tumors commonly seen in young or middle-aged adults. Plasma exeresis is an innovative technique for several skin conditions: it causes ionization of the atmospheric gas between the proximal tip of the device and the tissue to be treated, creating sublimation of the tissue. OBJECTIVE: To remove the cyst with a novel technique that allows a good cosmetic result. MATERIALS AND METHODS: Patients with clinical diagnosis of at least one epidermal cyst, aged between 18 and 70 years were enrolled. A standardized procedure was used. After administration of topical and sometimes local anesthesia (for cysts bigger than 1 cm), a tiny hole was created with plasma exeresis. The content of the cyst was then extruded and Micro Hartman Alligator Ear Forceps pulled out the loosened capsule. RESULTS: Twenty patients aged between 18 and 68 years were enrolled: 11 males (55%) and 9 females (45%). Twenty-eight cysts were successfully removed. The diameter ranged from 3 to 24 mm. No side effects were observed. The scar measured not more than 3 mm. CONCLUSION: This study suggests that plasma exeresis could represent a good and safe option to remove noninfected cysts on cosmetic areas, although further study is required. PMID- 30020100 TI - Reconstruction of Preauricular Wounds Using a Flipped Island Pedicle Flap: Case Series of 12 Patients. AB - BACKGROUND: Island pedicle flaps (IPFs) are a frequently used reconstructive option in dermatologic surgery. With variations in its execution, the flap can be used for an assortment of facial defects. OBJECTIVE: To describe the execution of a flipped IPF for the reconstruction of medium to large preauricular wounds after Mohs micrographic surgery. MATERIALS AND METHODS: An analysis of the flipped IPF reconstruction of 12 preauricular defects is presented. Patient demographics, surgical defects, aesthetic outcomes, and complications are described. RESULTS: Twelve patients with 12 preauricular tumors (9 basal cell carcinomas, 2 squamous cell carcinomas, and 1 malignant melanoma) were treated using Mohs micrographic surgery. A flipped IPF reconstruction was successfully used with good cosmetic outcomes and no complications in all 12 patients. CONCLUSION: In this series, the authors demonstrate the effective use of flipped IPFs for the reconstruction of medium to large preauricular defects with good aesthetic outcomes and no complications. PMID- 30020101 TI - Reducing the Incidence of Substance Use Disorders in Anesthesiology Residents: 13 Years of Comprehensive Urine Drug Screening. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The incidence of substance use disorders in the United States among residents in anesthesiology is between 1% and 2%. A recent study reported that the incidence of substance use disorders in U.S. anesthesiology residents has been increasing. There are no reports of effective methods to prevent substance use disorder in residents. A comprehensive drug testing program including a random component may reduce the incidence of substance use disorders. METHODS: The authors initiated a comprehensive urine drug screening program of residents, fellows, faculty physicians, and certified nurse anesthetists. The authors performed 3,190 tests over 13 yr. The authors determined the incidence of substance use disorders among residents in our large anesthesiology residency program during the decade before (January 1, 1994, to December 31, 2003) and for the 13 yr after (January 1, 2004 to December 31, 2016) instituting a random urine drug testing program. A total of 628 residents trained in the program over these 23 yr; they contributed a total of 1,721 resident years for analysis. Fewer faculty and certified nurse anesthetists were studied, so we do not include them in our analysis. RESULTS: The incidence of substance use disorders among trainees in our department during the 10 yr before initiation of urine drug screening was four incidents in 719 resident years or 0.0056 incidents per resident-year. In the 13 yr after the introduction of urine drug screening, there have been zero incidents in 1,002 resident years in our residency program (P = 0.0305). CONCLUSIONS: This single-center, comprehensive program including preplacement and random drug testing was associated with a reduction of the incidence of substance use disorders among our residents in anesthesiology. There were no instances of substance use disorders in our residents over the recent 13 yr. A large, multicenter trial of a more diverse sample of academic, government, and community institutions is needed to determine if such a program can predictably reduce the incidence of substance use disorders in a larger group of anesthesiology residents. PMID- 30020102 TI - Acute Adrenal Insufficiency in the Perioperative Period: A Case Report. AB - Acute adrenal insufficiency is a rare but potentially life-threatening event during the perioperative period. The usual manifestations of an acute adrenal crisis can mimic common postoperative complications and a high index of suspicion is required for the diagnosis. Early diagnosis and prompt treatment can be lifesaving. We present the case of a 65-year-old man who, after a partial nephrectomy, developed acute adrenal insufficiency, which remained undiagnosed in the postoperative period, eventually leading to cardiac arrest. This case highlights the need for perioperative physicians to have a watchful eye for diagnosing and treating this uncommon yet lethal condition. PMID- 30020103 TI - The Role of ECMO in the "At-Risk" Tracheal Extubation. AB - Tracheal extubation requires careful planning and preparation. We present the extubation of a patient with severe ankylosing spondylitis after cervical spine surgery. We discuss the use of extracorporeal membrane oxygenation (ECMO) in this "at-risk" extubation, where our ability to oxygenate was uncertain and reintubation was predicted to be difficult. To our knowledge, ECMO has not previously been used in this context. We suggest preparing ECMO for rescue oxygenation when all other fundamental oxygenation techniques are predicted to be difficult or impossible. ECMO could be included in airway management and extubation guidelines. PMID- 30020104 TI - Novel Preoxygenation Technique to Deliver High-Flow Oxygen in a Patient With Facial Trauma: A Case Report. AB - This case demonstrates a novel preoxygenation technique in a patient with difficult access to the airway after a traumatic facial injury. To find a solution, a fusion of oxygenation equipment was trialed by altering and combining a tracheostomy mask and the tubing of an Optiflow circuit from which the nasal cannula component had been removed. This novel combination delivered high-flow humidified oxygen (60 L/min) orally, avoided further facial injury, and was well tolerated by the patient. Effective preoxygenation was confirmed by arterial gas measurements. This study supports the use of this novel Optiflow-tracheostomy mask fusion device in appropriately selected cases. PMID- 30020105 TI - Unilateral Rhinorrhea and Sneezing After Upper Gastrointestinal Endoscopy Under Intravenous Propofol Sedation With Supplemental Oxygen Administered via a Nasal Cannula: A Case Report. AB - We present a rarely described complication of unilateral rhinorrhea and sneezing in a patient who received intravenous sedation with propofol and supplemental oxygen via a nasal cannula during upper gastrointestinal endoscopy. The literature is reviewed and a mechanism is proposed. Mechanical irritation of the nasal mucosa is felt to be the trigger. Suggestions to avoid and to treat are offered. PMID- 30020106 TI - Transesophageal Echocardiographic Observation of Caval Thrombus Followed by Intraoperative Placement of Inferior Vena Cava Filter for Presumed Pulmonary Embolism During Cesarean Hysterectomy for Placenta Percreta: A Case Report. AB - During a cesarean hysterectomy for placenta percreta, transesophageal echocardiography was used to monitor volume status and guide resuscitation. After delivery of the neonate but before massive surgical hemorrhage, a thrombus appeared in the inferior vena cava. Roughly 3 hours later, the patient had hemodynamic changes consistent with an intraoperative pulmonary embolism. Boluses of epinephrine stabilized the patient. An inferior vena cava filter was placed via an in situ internal jugular central venous cannula to prevent further embolic events. We believe transesophageal echocardiography is a useful monitor during surgery for placenta percreta. PMID- 30020107 TI - Methylnaltrexone-Associated Bowel Perforation in Postoperative Opioid-Induced Constipation and Ogilvie Syndrome: A Case Report. AB - Pain management with opioids is often limited by medication side effects. One of the most common and distressing side effects is opioid-induced constipation (OIC), a syndrome that is now getting significant national attention. We report the case of an opioid-dependent 56-year-old man who underwent lumbar decompression for spinal stenosis. Postoperatively, he developed OIC and Ogilvie syndrome, then following treatment with methylnaltrexone experienced an acute bowel perforation. We briefly review the recommended management of OIC as well as indications and contraindications of methylnaltrexone and similar new medications. PMID- 30020108 TI - Electricity: How Much for the Contemporary Tertiary Care Operating Room? AB - Surgery requires many electrically driven devices. Three events occurred recently in an operating room (OR) suite circa the 1980s wherein circuit breakers tripped due to overloaded circuits. This led to us to (1) increase OR electric capacity; (2) record each instrument's power requirements, map their OR location, and determine when during surgery they were used; (3) provide users with instruction and diagrams into which outlet to plug each instrument. When introducing surgeries requiring devices, especially with high electrical power (current or amperage) demands, or renovating older or planning new ORs, it is important to provide ORs with sufficient electric current, circuits, and outlets. PMID- 30020109 TI - Real-Time Assessment of Renal Venous Flow by Transesophageal Echography During Cardiac Surgery. PMID- 30020110 TI - Nutcracker Syndrome-An Unusual Case of Chronic Left Upper Abdominal Pain: A Case Report. AB - A 38-year-old woman presented with a chief complaint of sharp, achy left upper abdominal pain with radiation to the left flank. This pain started approximately one-and-a-half years before she consulted with a pain specialist. Although an extensive workup was completed, no organic cause was established as the cause of her pain. After undergoing successful fluoroscopically guided celiac plexus blocks, an abdominal magnetic resonance imaging scan was obtained that revealed nutcracker phenomenon. The patient was evaluated by an urologist and underwent renal autotransplantation. The patient subsequently had complete relief of her pain. PMID- 30020111 TI - ISMICS Research and Education Fund. PMID- 30020112 TI - Colorectal cancer in young African Americans: clinical characteristics and presentations. AB - PURPOSE: Colorectal cancer (CRC) is the third most common cancer in the USA, and the incidence in young adults has been increasing over the past decade. We studied the clinical characteristics and presentations of CRC in young African American (AA) adults because available data on how age and ethnicity influence its pattern of presentation is limited. PATIENTS AND METHODS: We conducted a retrospective study of 109 young adults (75 African Americans) below 50 years, who were diagnosed with CRC between 1 January 1997 and 31 December 2016. Proximal CRC was defined as lesions proximal to the splenic flexure. Independent t-tests and chi-test or Fisher's exact test were performed where appropriate to determine the differences between AA and non-AA patients. RESULTS: The mean age at diagnosis was 42 years (range: 20-49 years). Compared with non-AAs, AAs had more frequent proximal CRC (38.7 vs. 14.7%, P=0.003), lower hemoglobin (10.5 vs. 12.7 g/dl, P<0.001), and more frequent weight loss (21.3 vs. 2.9% P=0.014). Non-AAs presented more frequently with rectal bleeding (52.9 vs. 32.0% P=0.037). There was no statistically significant difference in histology, stage, grade, tumor size, and carcinoembryonic antigen level between groups. When we stratified between proximal and distal disease among patients with CRC, we found larger tumor size in distal disease, which presented more with rectal bleeding and bowel habit changes. Proximal disease presented more as abdominal pain and weight loss. CONCLUSION: There should be a higher index of suspicion for CRC in young AA adults presenting with anemia, abdominal pain, and weight loss. Early screening colonoscopy should be advocated in AAs because of the predominance of proximal disease. PMID- 30020113 TI - Differences in coronary plaque morphology between East Asian and Western White patients: an optical coherence tomography study. AB - AIMS: Prevalence of coronary artery disease as well as cardiac mortality varies between Asian and White patients. However, the link between race and plaque characteristics in patients with coronary artery disease remains largely unexplored. Thus, we aimed to investigate the detailed culprit plaque characteristics between East Asian and White patients using optical coherence tomography. PATIENTS AND METHODS: A total of 101 East Asians were matched to 101 White patients. Matching parameters included age, sex, clinical presentation, hyperlipidemia, diabetes mellitus, and lesion location. RESULTS: There were no differences in underlying pathology (rupture vs. erosion) of acute coronary syndrome (P=0.935). Lesion length was longer (18.0+/-6.0 vs. 14.6+/-5.4 mm; P<0.002), lipid length was greater (9.4+/-4.6 vs. 7.2+/-3.8 mm; P<0.023), lipid index was higher (1635+/-987 vs. 1104+/-730; P=0.002), and mean reference area was larger (8.1+/-3.0 vs. 6.5+/-2.4 mm; P<0.021) in White patients compared with East Asian patients. CONCLUSION: There are significant differences in plaque morphology between East Asian and White patients even after controlling for confounders. Our findings underscore key differences in atherosclerosis between East Asian and White populations, and may have to be taken into consideration when interpreting the results of future research. PMID- 30020114 TI - The intervention mechanism of folic acid for benzo(a)pyrene toxic effects in vitro and in vivo. AB - Folic acid is a necessary micronutrient for normal human growth and development. Benzo(a)pyrene (BaP) is a ubiquitously distributed environmental pollutant and its metabolite, benzo(a)pyrene-diol-epoxide, is known to exert a strong teratogenic and carcinogenic effect on the body's tissues and cells. The aim of this study was to investigate the mechanism by which folic acid can inhibit the toxic effects of BaP both in vivo and in vitro. We measured changes in 16HBE cell activity affected by the intervention of folic acid on BaP using the cell counting kit-8 assay and that of cell cycle distribution by flow cytometry. At the same time, we assessed the xeroderma pigmentosum group A, xeroderma pigmentosum group C, excision repair cross complementation group 1, cyclinD1, and CKD4 mRNAs, and their related protein expression both in mouse lung tissue and in 16HBE cells. In conclusion, the mechanisms by which this effect is mediated were not entirely elucidated by our study, possibly because folic acid antagonizes the toxic effects of BaP by upregulating the levels of excision repair cross complementation group 1, xeroderma pigmentosum group A, and xeroderma pigmentosum group C gene expression to improve the rate of DNA repair, in turn accelerating the speed of repair for DNA damage caused by BaP. Meanwhile, folic acid could restrain BaP-induced cyclinD1 protein expression, which could help cells return to their normal cell cycle.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0/. PMID- 30020115 TI - Cervical cancer screening uptake in women aged between 15 and 64 years in Mozambique. AB - Cervical cancer is the most common cancer in Mozambique, reflecting the high prevalence of both human papillomavirus and HIV infections. A national screening program for cervical cancer was started in 2009, using the visual inspection with acetic acid and cryotherapy, targeting women aged 30-55 years. We aimed to estimate the self-reported prevalence and determinants of cervical cancer screening uptake in Mozambique. A cross-sectional study of a representative sample of the women aged 15-64 years (n=1888) was carried out in 2014/2015 following the WHO-Stepwise Approach to Chronic Disease Risk Factor Surveillance. The prevalence of screening uptake using visual inspection with acetic acid or cervical cytology, at least once in a lifetime, was 3.0% [95% confidence interval (CI): 2.2-4.1]; the prevalence was the lowest in the center region (1.4%) and the highest in the capital city of Maputo (11.1%). Among women aged 30-55 years, the prevalence was 3.4% (95% CI: 2.3-5.2) and the factors independently associated with a greater frequency of screening uptake were education (>=8 schooling years vs. none: prevalence ratio=5.57, 95% CI: 1.34-23.16) and use of oral contraceptives (prevalence ratio=2.33, 95% CI: 1.05-5.15). This was the first national Mozambican survey on cervical cancer screening uptake ever carried out and it showed a very low prevalence of screening, even in the more urban and affluent areas. There is an urgent need to raise public awareness of cervical cancer screening and to increase the number of screening units and trained personnel throughout the country. PMID- 30020116 TI - Preserving the Shoulder Function of an Elite Paratriathlete. AB - Shoulder pain in wheelchair users that participate in competitive adaptive sports can be a troublesome condition. Shoulder pain not only affects athletic performance but also affects functional activities such as wheelchair propulsion and weight bearing during transfers. Managing pain in these athletes thus presents a unique challenge because of the difficulty in achieving relative rest and the need to modify athletic shoulder-focused rehabilitation strategies. In all athletes, it is vital to establish an early, accurate diagnosis and optimize conservative treatment before considering surgical interventions to avoid excessive shoulder-related morbidity, loss of function, and, worse, loss of independence. PMID- 30020117 TI - Nonoperative Treatments for Knee Osteoarthritis: An Evaluation of Treatment Characteristics and the Intra-Articular Placebo Effect: A Systematic Review. AB - BACKGROUND: Guidelines recommending various nonoperative treatments for patients with knee osteoarthritis remain inconsistent. Much of this controversy relates to what constitutes a clinically important effect. The purposes of the present study were to compare treatment effect sizes from recent meta-analyses evaluating pharmacological or medical device interventions for the treatment of knee osteoarthritis and to further assess the clinical impact that the intra-articular placebo effect may have on intra-articular injection therapies. METHODS: A search of PubMed, MEDLINE, and Embase from the inception date of each database through May 30, 2017 was conducted for all articles involving meta-analyses of pharmacological or medical device knee osteoarthritis treatments compared with controls. Two reviewers independently screened articles for eligibility and extracted data for analysis. We present effect estimates on a standardized mean difference (SMD) scale and compare them all against a threshold for clinical importance of 0.50 standard deviation (SD) unit. RESULTS: Ten meta-analyses (sample size range, 110 to 39,814) providing a total of 19 different effect sizes for pain were included in this review. SMD estimates ranged from 0.08 to 0.79 for various electrical modalities, orthotic devices, topical and oral nonsteroidal anti-inflammatory drugs (NSAIDs), dietary supplements, and intra-articular injection therapies. Seventeen treatments demonstrated significant improvements in terms of pain when patients who had received treatment were compared with controls. After accounting for the intra-articular placebo effect, the greatest effect estimates were those of intra-articular platelet-rich plasma and high molecular weight hyaluronic acid. When these were judged according to our threshold for clinical importance, high molecular weight intra-articular hyaluronic acid was found to have the most precise effect estimate that surpassed this threshold. Platelet-rich plasma was found to provide the greatest point estimate of the treatment effect, but the precision around this estimate had the largest amount of uncertainty across all treatments. CONCLUSIONS: While many nonoperative treatments demonstrated significant improvements in pain, we found the greatest effect estimates for intra-articular treatments. While platelet-rich plasma provided the greatest point estimate of the treatment effect, variability among studies suggests that future research into optimal formulations is required. The strongest current evidence supports clinically important and significant treatment effects with intra-articular hyaluronic acid formulations between 1,500 and >6,000 kDa. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020118 TI - Functional Outcome Assessment in Hip Preservation Surgery. PMID- 30020120 TI - Reappraisal of eligibility criteria in cancer clinical trials. AB - PURPOSE OF REVIEW: We aimed to summarize the recent reflections and collaborative initiatives pertaining to the definition of more appropriate eligibility criteria in cancer clinical trials. RECENT FINDINGS: There is an intrinsic tension between two opposite purposes when it comes to defining eligibility criteria: on the one hand, participants must be protected, and on the other, the study population must be defined as accurately as possible. However, stringent eligibility criteria jeopardize the feasibility of trials, and, consequently, the generalizability of trial results. Therefore, interdisciplinary working groups under the auspices of the American Society of Clinical Oncology and Friends of Cancer Research propose to adapt/relax some of the classical eligibility criteria. SUMMARY: In-depth reflection of the existing eligibility criteria, and implementation of recent recommendations are needed. PMID- 30020121 TI - Clinical Evaluation of Synovial Alpha Defensin and Synovial C-Reactive Protein in the Diagnosis of Periprosthetic Joint Infection. AB - BACKGROUND: Diagnosing periprosthetic joint infection after total joint arthroplasty is often challenging. The alpha defensin test has been recently reported as a promising diagnostic test for periprosthetic joint infection. The goal of this study was to determine the diagnostic accuracy of alpha defensin testing. METHODS: One hundred and eighty-three synovial alpha defensin and synovial fluid C-reactive protein (CRP) tests performed in 183 patients undergoing evaluation for periprosthetic joint infection were reviewed. Results were compared with the Musculoskeletal Infection Society (MSIS) criteria for periprosthetic joint infection. RESULTS: Alpha defensin tests were performed prior to surgical treatment for infection, and 37 of these patients who had these tests were diagnosed by MSIS criteria as having infections. Among this group, the alpha defensin test had a sensitivity of 81.1% (95% confidence interval [CI], 64.8% to 92.0%) and a specificity of 95.9% (95% CI, 91.3% to 98.5%). There were 6 false-positive results, 4 of which were associated with metallosis. There were 7 false negatives, all of which were associated with either draining sinuses (n = 3) or low-virulence organisms (n = 4). A combined analysis of alpha defensin and synovial fluid CRP tests was performed in which a positive result was represented by a positive alpha defensin test and a positive synovial fluid CRP test (n = 28). Among this group, the sensitivity was calculated to be 73.0% (95% CI, 55.9% to 86.2%) and the specificity was calculated to be 99.3% (95% CI, 96.2% to 99.9%). An additional combined analysis was performed where a positive result was represented by a positive alpha defensin test or positive synovial fluid CRP test (n = 64). Among this group, the sensitivity was calculated to be 91.9% (95% CI, 78.1% to 98.3%) and the specificity was calculated to be 79.5% (95% CI, 72.0% to 85.7%). CONCLUSIONS: Alpha defensin in combination with synovial fluid CRP demonstrates very high sensitivity for diagnosing periprosthetic joint infection, but may yield false-positive results in the presence of metallosis or false negative results in the presence of low-virulence organisms. When both alpha defensin and synovial fluid CRP tests are positive, there is a very high specificity for diagnosing periprosthetic joint infection. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020122 TI - Preoperative Opioid Use Is Associated with Higher Readmission and Revision Rates in Total Knee and Total Hip Arthroplasty. AB - BACKGROUND: Prescription opioid use is epidemic in the U.S. Recently, an association was demonstrated between preoperative opioid use and increased health care utilization following abdominal surgeries. Given that primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) are 2 of the most common surgical procedures in the U.S., we examined the association of preoperative opioid use with 30-day readmission and early revision rates. METHODS: We reviewed 2003 to 2014 data from 2 Truven Health MarketScan databases (commercial insurance and Medicare plus commercial supplemental insurance). Subjects were included if they had a Current Procedural Terminology (CPT) code for primary TKA or THA and were continuously enrolled in the database for at least 6 months prior to the index procedure. Preoperative opioid prescriptions were identified using National Drug Codes (NDCs). Rates of 30-day readmissions and revision arthroplasty were identified and compared among patients with stratified durations of preoperative opioid use in the 6 months preceding TKA or THA. RESULTS: The study included 324,154 patients in the 1-year follow-up group and 159,822 patients in the 3-year follow-up group. Opioid-naive TKA patients had a lower revision rate than did those with >60 days of preoperative opioid use (1-year cohort: 1.07% compared with 2.14%, p < 0.001; 3-year cohort: 2.58% compared with 5.00%, p < 0.001). A similar trend was noted among THA patients (1-year: 0.38% compared with 1.10%, p < 0.001; 3-year: 1.24% compared with 2.99%, p < 0.001). These trends persisted after adjusting for age, sex, and Charlson Comorbidity Index (CCI). The 30-day readmission rate after TKA or THA was significantly lower for patients with no preoperative opioid use compared with those with >60 days of preoperative opioid use (TKA: 4.82% compared with 6.17%, p < 0.001; THA: 3.71% compared with 5.85%, p < 0.001). Again, this association persisted after adjusting for age, sex, and CCI. CONCLUSIONS: Preoperative opioid use was associated with significantly increased risk of early revision and significantly increased risk of 30-day readmission after TKA and THA. This study illustrates the increased risk of poor outcomes and increased postoperative health-care utilization for patients with long-term opioid use prior to THA and TKA. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020119 TI - Evaluation of early musculoskeletal disease in patients with haemophilia: results from an expert consensus. AB - : Early joint damage in patients with haemarthrosis often escapes diagnosis because of insufficient investigation of biomechanical changes. Arthropathy in haemophilia requires complex assessment with several tools. Considering the increased emphasis on an integrated approach to musculoskeletal (MSK) outcomes, re-evaluation of MSK assessment to address individual patient needs is warranted. To advise on the optimal use of current assessment tools and strategies for tailored MSK evaluation in patients with haemophilia. A panel of experts in haemophilic arthropathy evaluated internationally recognized assessment tools through published literature and personal expertise. Each tool was considered, scored and ranked for their utility in the clinical assessment of MSK damage. Subsequently, a patient evaluation table detailing advice on type and frequency of assessments for different patient populations was constructed. To obtain a complete MSK assessment, multiple tools must be used to ensure each criterion is evaluated. For patients with haemophilia, clinical examination of the joint, disease-specific structure/function scores, and activity/participation scores including quality of life are important, and should be performed on a regular basis according to age and clinical condition. Joint imaging is recommended in the prevention, diagnosis and follow-up of haemophilic arthropathy and should be used in conjunction with joint structure and function scores. An integrated approach to MSK assessment using combinations of tools will allow earlier management of dysfunction and may improve long-term outcomes. This approach could be used in long-term follow-up of all patients independent of age and disease stage, especially in children to prevent arthropathy. PMID- 30020123 TI - A Prospective Evaluation of Patient-Reported Opioid Utilization After Nonoperative Treatment of Fractures and Dislocations. AB - BACKGROUND: Prescription of opioid analgesics is currently a common practice to relieve pain for musculoskeletal injuries in many regions of the world, especially in the United States and Canada. However, overprescription may underlie opioid misuse. Details on the utilization of prescribed opioids after nonoperative treatment of fractures and dislocations and whether consumption is related to injury location are unknown. METHODS: A total of 1,513 consecutive patients in China who underwent nonoperative treatment of a fracture and/or dislocation and who were prescribed opioids were studied over a 3-month period. Demographic information, alcohol consumption, smoking status, injury location, volume of prescription, and consumption patterns were recorded and were summarized. RESULTS: The mean number of opioid pills prescribed was 14.7, and the mean patient-reported number of pills consumed was 7.2. Overall, 152 patients (10.0%) reported taking no prescribed opioid analgesics, and 924 patients (61.1%) ceased their prescribed opioids prior to completing the regimen. Injury location, alcohol consumption, and type of fracture or dislocation were all significantly associated with the patient-reported number of opioid pills consumed (p < 0.05). Patients with fracture and/or dislocation of the wrist or forearm (9.4 pills for 3.8 days); ankle, tibia, or fibula (9.3 pills for 3.7 days); or elbow or humerus (9.1 pills for 3.7 days) used more opioid pills compared with patients with injuries at other locations (not exceeding 6.4 pills and 3 days). When compared with patients who had no, low, or moderate daily alcohol consumption, there was more opioid use in patients with high daily alcohol consumption (8.5 pills for 3.4 days) and those with very high daily alcohol consumption (11.3 pills for 4.7 days). Patients with a dislocation and/or displaced fracture reported consuming 8.2 pills for 3.3 days, which was more than the consumption in patients with a nondisplaced fracture (6.2 pills for 2.5 days) and patients with an avulsion fracture (6.2 pills for 2.5 days). CONCLUSIONS: Surgeons and patients should try to avoid opioids if possible after nonoperatively treated fractures and dislocations. If opioids are used, surgeons should prescribe the smallest dose for the shortest time after considering the injury location and type of fracture or dislocation. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020124 TI - Three-Dimensional Compared with Two-Dimensional Preoperative Planning of Corrective Osteotomy for Extra-Articular Distal Radial Malunion: A Multicenter Randomized Controlled Trial. AB - BACKGROUND: Malunion is the most frequent complication seen after a fracture of the distal end of the radius. The primary aim of this study was to compare patient-reported outcome measures (PROMs) after corrective osteotomy for malunited distal radial fractures with and without 3-dimensional (3D) planning and use of patient-specific surgical guides. METHODS: From September 2010 to May 2015, 40 adult patients with a symptomatic extra-articular malunited distal radial fracture were randomized to 3D computer-assisted planning or conventional 2-dimensional (2D) planning for corrective osteotomy. The primary outcome was the Disabilities of the Arm, Shoulder and Hand (DASH) score. Secondary outcomes included the Patient-Rated Wrist Evaluation (PRWE) score, pain and satisfaction scores, grip strength, and radiographic measurements at 3, 6, and 12 months postoperatively. RESULTS: From baseline to 12 months of follow-up, the reduction in the mean DASH score was -30.7 +/- 18.7 points for the 3D planning group compared with -20.1 +/- 17.8 points for 2D planning (p = 0.103). Secondary functional outcome by means of the PRWE resulted in a similar reduction of -34.4 +/- 22.9 points for the 3D planning group compared with -26.6 +/- 18.3 points for the 2D planning group (p = 0.226). There were no significant differences in pain, satisfaction, range of motion, and grip strength. Radiographic analysis showed significant differences in the mean residual volar angulation (by 3.3 degrees ; p = 0.04) and radial inclination (by 2.7 degrees ; p = 0.028) compared with the templated side, in favor of 3D planning and guidance. The duration of preoperative planning and surgery as well as complication rates were comparable. CONCLUSIONS: Although there was a trend toward a minimal clinically important difference in PROMs in favor of 3D computer-assisted guidance for corrective osteotomy of extra-articular distal radial malunion, it did not attain significance because of (post hoc) insufficient power. Despite the challenge of feasibility, a trial of large magnitude is warranted to draw definitive conclusions regarding clinical advantages of this advanced, more expensive technology. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020125 TI - Risk-Based Hospital and Surgeon-Volume Categories for Total Hip Arthroplasty. AB - BACKGROUND: Studies of volume-outcome relationships typically subdivide volume via non-evidence-based methods, producing categories that vary widely among studies, preclude the comparison of results, and possibly obscure the true volume outcome relationships. The goal of the current study was to use quantitative methods to derive meaningful, risk-based categories for hospital and surgeon total hip arthroplasty (THA) volume based on relationships with mortality, complications, and revision. METHODS: Using New York statewide patient data (1997 to 2014; n = 187,557), we derived risk-based hospital and surgeon-volume categories for primary THA based on relationships with 90-day complications and mortality and 2-year revision. RESULTS: The following categories, based on relationships with complications, mortality, and revision, were derived for surgeon volume: 0 to 12, 13 to 25, 26 to 72, 73 to 165, 166 to 279, and >=280 THA/year. For hospital volume, the categories derived were 0 to 11, 12 to 54, 55 to 157, 158 to 526, and >=527 THA/year. More than 35% of THA cases in New York State were conducted by surgeons performing <=1 THA/month (0 to 12 THA/year), and these were associated with a 2 to 2.5-fold increase in the risk for complications, mortality, and revision relative to higher-volume surgeons. Similarly, 15% of THA cases in New York State were conducted in hospitals performing <=1 THA/week (0 to 11 or 12 to 54 THA/year), and these were associated with a nearly 1.5-fold increase in complications and between a 4 and 6-fold increase in mortality. Traditional non-evidence-based quartile categories were concentrated at lower volumes, did not capture the full magnitude of the volume related differences, and were a poorer representation of the outcome data, as assessed by several model metrics. Thus, quartiles showed only a <2-fold increase in complications, mortality, and revision for the lowest versus the highest surgeon-volume quartile and failed to show the increased risk for lower versus higher hospital volumes. CONCLUSIONS: The volume-outcome relationships in THA are more pronounced than previously apparent through standard statistical techniques. Volume-based strategies for improving outcomes in THA should use benchmarks that are evidence-based to achieve optimal results. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020126 TI - Gait Mechanics After ACL Reconstruction Differ According to Medial Meniscal Treatment. AB - BACKGROUND: Knee osteoarthritis risk is high after anterior cruciate ligament reconstruction (ACLR) and arthroscopic meniscal surgery, and higher among individuals who undergo both. Although osteoarthritis development is multifactorial, altered walking mechanics may influence osteoarthritis progression. The purpose of this study was to compare gait mechanics after ACLR among participants who had undergone no medial meniscal surgery, partial medial meniscectomy, or medial meniscal repair. METHODS: This was a secondary analysis of data collected prospectively as part of a clinical trial. Sixty-one athletes (mean age of 21.4 +/- 8.2 years) who had undergone primary ACLR participated in the study when they achieved impairment resolution (5.3 +/- 1.7 months postoperatively), including minimal to no effusion, full knee range of motion, and >=80% quadriceps-strength symmetry. Participants were classified by concomitant medial meniscal treatment: no involvement or nonsurgical management of a small, stable tear; partial meniscectomy; or meniscal repair. Participants underwent comprehensive walking analyses. Joint contact forces were estimated using a previously validated, electromyography-driven musculoskeletal model. Variables were analyzed using a mixed-model analysis of variance with group and limb comparisons (alpha = 0.05); group comparisons of interlimb differences in measurements (surgical minus contralateral limb) were performed to determine significant interactions. RESULTS: The participants in the partial meniscectomy group walked with a higher peak knee adduction moment (pKAM) in the surgical versus the contralateral limb as compared with those in the meniscal repair group and those with no medial meniscal surgery (group difference for partial versus repair: 0.10 N-m/kg-m, p = 0.020; and for partial versus none: 0.06 N-m/kg-m, p = 0.037). Participants in the repair group walked with a smaller percentage of medial to total tibiofemoral loading in the surgical limb compared with both of the other groups (group difference for repair versus partial: -12%, p = 0.001; and for repair versus none: -7%, p = 0.011). The participants in the repair group loaded the medial compartment of the surgical versus the contralateral limb 0.5 times body weight less than did the participants in the partial meniscectomy group. CONCLUSIONS: Participants in the partial meniscectomy group walked with higher pKAM and shifted loading toward the medial compartment of the surgical limb, while participants in the repair group did the opposite, walking with lower pKAM and unloading the surgical limb relative to the contralateral limb. These findings may partially explain the conflicting evidence regarding pKAM after ACLR and the elevated risk for osteoarthritis (whether from overloading or underloading) after ACLR with concomitant medial meniscectomy or repair. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020127 TI - Timing of Epiphysiodesis to Correct Leg-Length Discrepancy: A Comparison of Prediction Methods. AB - BACKGROUND: The purpose of this study was to compare the accuracy of different methods used to predict ultimate leg lengths and residual leg-length discrepancy in a group of patients treated with epiphysiodesis at our institution. METHODS: Seventy-seven patients with adequate preoperative radiographs, no postoperative complications, and follow-up to skeletal maturity composed the study group. We compared the predicted lengths of both legs and residual leg-length discrepancy at maturity with actual outcomes using the White-Menelaus, Anderson-Green, Moseley, and multiplier methods. RESULTS: Skeletal age varied >1 year from chronological age in 61 (26%) of 231 observations, including 19 patients (25%) whose average skeletal age from 3 determinations differed by >1 year from chronological age. The prediction accuracy of each method was improved by using skeletal, rather than chronological, age. Error in prediction of the length of the short leg varied from a mean (and standard deviation) of 1.8 +/- 1.2 cm for the straight-line graph to 2.5 +/- 2.0 cm for the multiplier method. Prediction error for the long leg (after epiphysiodesis) varied from a mean of 1.2 +/- 1.1 cm for the straight-line graph to 1.7 +/- 1.5 cm for the multiplier method. Leg length-discrepancy prediction error ranged from a mean of 0.7 +/- 0.6 cm for the White-Menelaus method incorporating a growth inhibition factor to 1.1 +/- 0.9 cm for the multiplier method. The multiplier method was the least accurate of all. All differences were significant. CONCLUSIONS: Determination of skeletal age is clinically relevant in patients being considered for epiphysiodesis to manage leg length inequality. The multiplier method was the least accurate of the prediction methods in this patient population, which may have implications in calculating the appropriate timing of epiphysiodesis. PMID- 30020128 TI - Glenoid Bone Reaction to All-Soft Suture Anchors Used for Shoulder Labral Repairs. AB - BACKGROUND: All-soft suture anchors (ASSAs) are commonly used for shoulder labral repair and capsulorrhaphy in patients with shoulder instability. While these anchors may have some specific advantages over other types of suture anchors, little is known about the prevalence and time-dependence of bone cyst formation and tunnel expansion after implantation of ASSAs. The aim of this study was to quantify the proportions of cyst formation and tunnel expansion around ASSAs and to characterize and test for differences in abnormalities observed at different postoperative time points. METHODS: Thirty patients who were treated with arthroscopic shoulder stabilization surgery with ASSAs (1.4 mm; JuggerKnot, Biomet) underwent a computed tomography (CT) scan of the operatively treated shoulder at 1 month (10 patients), 6 months (10 patients), or 12 months (10 patients) postoperatively. Demographic and operative data were collected, and CT scans were evaluated for cyst formation, tunnel expansion, and tunnel volume measured in cubic millimeters. Statistical analyses were performed to detect differences in these outcomes among the follow-up groups. All shoulders were stable at all time points of the study, and there were no incidents of recurrent instability during the study period. RESULTS: Ninety-one suture anchors were evaluated in 30 patients. Tunnel expansion was identified in the large majority of patients in the 6-month and 12-month follow-up groups, with a significant increase in these proportions compared with the 1-month follow-up group (p = 0.002). Mean tunnel volumes also significantly increased over the study period (p < 0.001). The presence of cyst formation was negligible in all 3 follow-up cohorts. CONCLUSIONS: This study demonstrated low rates of cyst formation but a significantly increased tunnel volume 6 and 12 months after shoulder labral surgery with ASSAs. There was no association with the initial tunnel location. Additional well-controlled studies with longer follow-up are needed to identify potential associations among tunnel expansion, intraoperative technique, and clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020129 TI - Capsular Ligament Function After Total Hip Arthroplasty. AB - BACKGROUND: The hip joint capsule passively restrains extreme range of motion, protecting the native hip against impingement, dislocation, and edge-loading. We hypothesized that following total hip arthroplasty (THA), the reduced femoral head size impairs this protective biomechanical function. METHODS: In cadavers, THA was performed through the acetabular medial wall, preserving the entire capsule, and avoiding the targeting of a particular surgical approach. Eight hips were examined. Capsular function was measured by rotating the hip in 5 positions. Three head sizes (28, 32, and 36 mm) with 3 neck lengths (anatomical 0, +5, and +10 mm) were compared. RESULTS: Internal and external rotation range of motion increased following THA, indicating late engagement of the capsule and reduced biomechanical function (p < 0.05). Internal rotation was affected more than external. Increasing neck length reduced this hypermobility, while too much lengthening caused nonphysiological restriction of external rotation. Larger head sizes only slightly reduced hypermobility. CONCLUSIONS: Following THA, the capsular ligaments were unable to wrap around the reduced-diameter femoral head to restrain extreme range of motion. The posterior capsule was the most affected, indicating that native posterior capsule preservation is not advantageous, at least in the short term. Insufficient neck length could cause capsular dysfunction even if native ligament anatomy is preserved, while increased neck length could overtighten the anterior capsule. CLINICAL RELEVANCE: Increased understanding of soft-tissue balancing following THA could help to prevent instability and improve early function. This study illustrates how head size and neck length influence the biomechanical function of the hip capsule in the early postoperative period. PMID- 30020131 TI - Radiographic and Anatomic Landmarks of the Major Knee Ligaments. PMID- 30020130 TI - Comparison of Long-Term Outcomes of Radial Osteotomy and Nonoperative Treatment for Kienbock Disease: A Systematic Review. AB - BACKGROUND: Radial osteotomy has shown favorable clinical results for early to advanced stages of Kienbock disease. However, it is not clear whether this technique could change the natural course of the disease, or whether its clinical results are actually superior to those of nonoperative treatment. The purpose of this study was to compare radial osteotomy with nonoperative treatment in terms of long-term radiographic and clinical outcomes in patients with Kienbock disease. METHODS: We systematically reviewed retrospective studies of radial osteotomy and nonoperative treatment for Kienbock disease with long-term follow up (mean of >=10 years). A systematic search was conducted across 3 databases (CENTRAL, PubMed, and Embase) and relevant articles were selected. Data regarding patient demographics, treatment details, and radiographic and clinical outcomes were abstracted from the selected studies. RESULTS: Seventeen studies (5 of nonoperative treatment and 12 of radial osteotomy) were included. Before treatment, the mean age of patients and mean proportion of wrists with Lichtman stage III or higher were not significantly different between the 2 groups. Neither the mean proportion of wrists that showed worsening of the Lichtman stage after treatment nor the proportion that showed no change in the stage were significantly different between the 2 groups. However, the mean proportion of wrists that had more than moderate pain at the time of final follow-up was significantly lower in the radial osteotomy group (5.7%; range, 0% to 18.2%) than in the nonoperative treatment group (23.2%; range, 17.4% to 35.3%). In addition, the total arc of wrist motion at the time of final follow-up was significantly greater in the radial osteotomy group (107.4 degrees +/- 10.0 degrees ; range, 93.0 degrees to 126.0 degrees ) than in the nonoperative treatment group (88.8 degrees +/- 13.2 degrees ; range, 68.5 degrees to 103.5 degrees ). CONCLUSIONS: Systematic review of long-term follow-up studies showed that radial osteotomy was not superior to nonoperative treatment in terms of disease progression according to the Lichtman stage. Nevertheless, radial osteotomy was reported to have better outcomes with respect to the extent of pain and range of wrist motion. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30020132 TI - What's New in Musculoskeletal Infection. PMID- 30020133 TI - Small Simple Trials: A Strategy for Orthopaedic Randomized Trials. PMID- 30020134 TI - The General Orthopaedist: Going the Way of the Dinosaur or the Next Subspecialty?: AOA Critical Issues. AB - Orthopaedic specialization has increased substantially over the past several decades, partly due to the desire of residents to improve their clinical expertise and to increase the likelihood that they will obtain a position with better compensation and a more balanced lifestyle. The American Academy of Orthopaedic Surgeons (AAOS) census data support this trend, demonstrating a substantial rise in the percentage of practicing orthopaedic surgeons who identify themselves as specialists rather than as general orthopaedic surgeons. There is a perception that a more narrowed scope of practice may prevent the current orthopaedic workforce from being able to adequately care for populations in rural areas of the United States. Additional consideration should be given to clearly defining the necessary knowledge and skills of a general orthopaedist in the twenty-first century, to understanding their role in musculoskeletal care, and to reevaluating residency educational experiences relative to their ability to prepare graduates to practice general orthopaedics independently. PMID- 30020135 TI - Infection: It's a Numbers Game: Commentary on an article by William Z. Stone, MD, et al.: "Clinical Evaluation of Synovial Alpha Defensin and Synovial C-Reactive Protein in the Diagnosis of Periprosthetic Joint Infection". PMID- 30020136 TI - Insufficient Post Hoc Statistical Power: A Potential Pitfall of a Well-Designed Randomized Controlled Surgical Trial: Commentary on an article by Geert A. Buijze, MD, PhD, et al.: "Three-Dimensional Compared with Two-Dimensional Preoperative Planning of Corrective Osteotomy for Extra-Articular Distal Radial Malunion. A Multicenter Randomized Controlled Trial". PMID- 30020137 TI - More Is Not Always Better: Understanding the Impact of Volume on the Analysis of Outcomes: Commentary on an article by Jayme C.B. Koltsov, PhD, et al.: "Risk Based Hospital and Surgeon-Volume Categories for Total Hip Arthroplasty". PMID- 30020138 TI - Erratum: Predictors and Outcomes of Crossover to Surgery from Physical Therapy for Meniscal Tear and Osteoarthritis. PMID- 30020139 TI - Accelerated Internal Auditory Canal Screening Magnetic Resonance Imaging Protocol With Compressed Sensing 3-Dimensional T2-Weighted Sequence. AB - BACKGROUND AND PURPOSE: High-resolution T2-weighted sequences are frequently used in magnetic resonance imaging (MRI) studies to assess the cerebellopontine angle and internal auditory canal (IAC) in sensorineural hearing loss patients but have low yield and lengthened examinations. Because image content in the Wavelet domain is sparse, compressed sensing (CS) that uses incoherent undersampling of k space and iterative reconstruction can accelerate MRI acquisitions. We hypothesized that an accelerated CS T2 Sampling Perfection with Application optimized Contrasts using different flip angle Evolution (SPACE) sequence would produce acceptable diagnostic quality for IAC screening protocols. MATERIAL AND METHODS: Seventy-six patients underwent 3 T MRI using conventional SPACE and a CS T2 SPACE prototype sequence for screening the IACs were identified retrospectively. Unilateral reconstructions for each sequence were separated, then placed into mixed folders for independent, blinded review by 3 neuroradiologists during 2 sessions 4 weeks apart. Radiologists reported if a lesion was present. Motion and visualization of specific structures were rated using ordinal scales. McNemar, Wilcoxon, Cohen kappa, and Mann-Whitney U tests were performed for accuracy, equivalence, and interrater and intrarater reliability. RESULTS: T2 SPACE using CS reconstruction reduced scan time by 80% to 50 seconds and provided 98.7% accuracy for IAC mass detection by 3 raters. Radiologists preferred conventional images (0.7-1.0 reduction on 5-point scale, P < 0.001), but rated CS SPACE acceptable. The 95% confidence for reduction in any cerebellopontine angle, IAC, or fluid-filled inner ear structure assessment with CS SPACE did not exceed 0.5. CONCLUSIONS: Internal auditory canal screening MRI protocols can be performed using a 5-fold accelerated T2 SPACE sequence with compressed sensing while preserving diagnostic image quality and acceptable lesion detection rate. PMID- 30020140 TI - Which anticoagulants should be used for stroke prevention in non-valvular atrial fibrillation and severe chronic kidney disease? AB - PURPOSE OF REVIEW: Non-valvular atrial fibrillation is common in patients with severe chronic kidney disease (CKD) and historically patients have been treated with vitamin K antagonists (VKA). However, these agents have questionable efficacy and are associated with increased bleeding risk. Non-vitamin K oral anticoagulants (NOAC) have advantages over VKA in early stage CKD. In this review, we sought to establish evidence for best practice in patients with severe CKD (creatinine clearance <30 ml/min including dialysis patients) and nonvalvular atrial fibrillation. RECENT FINDINGS: Registry studies have shown that the relative risk of stroke in untreated atrial fibrillation in dialysis patients is lower than in patients in the general population, but VKA are associated with increased haemorrhagic stroke in this high-risk population. A large meta-analysis of dialysis patients found no benefit of VKA in reducing stroke, but an increased bleeding risk. However, studies from Scandinavia have emphasized that risk of VKA are mitigated by increasing the time in anticoagulant therapeutic range (TTR). The consensus from the Kidney Disease: Improving Global Outcomes conference on arrhythmia in CKD was that if dialysis patients required OAC for atrial fibrillation then apixaban could be considered in preference to VKA. SUMMARY: Best practice prophylaxis against stroke risk in dialysis patients with atrial fibrillation is still an area of uncertainty. If OAC is indicated because of high risk, then treatment options include VKA with careful attention to increased TTR, or reduced dose apixaban, which would be off label in Europe. No RCT evidence currently exists to guide therapy, but RCTS of apixaban versus VKA in dialysis patients are currently underway. PMID- 30020141 TI - Home treatment of acute pulmonary embolism: state of the art in 2018. AB - PURPOSE OF REVIEW: Historically, because of the necessity of parenteral anticoagulation, patients with acute pulmonary embolism are hospitalized until stable oral anticoagulation is achieved. Despite improvements in prognostic risk stratification and the introduction of the direct oral anticoagulants, home treatment is still not widely applied. Main advantages of home treatment involve improvement of quality of life and significant healthcare cost reduction. In this review, we summarized recent published data on home treatment of patients with acute pulmonary embolism. RECENT FINDINGS: Although a significant decrease in mean duration of hospital admission for pulmonary embolism has been demonstrated over the last decade in Europe, most pulmonary embolism patients are currently hospitalized while they might be treated in an outpatient setting. In recent years, five major studies have been performed, in which the decision to initiate home treatment was based on the Hestia criteria in most patients. Over 98% of patients treated at home had an uncomplicated course. SUMMARY: Home treatment of acute pulmonary embolism is suggested to be feasible and safe in 30-55% of all patients. Results of ongoing trials will provide more insight in the optimal strategy to select patients with pulmonary embolism who are eligible for home treatment and likely will result in more widespread application of this practice. PMID- 30020142 TI - New treatment paradigms for connective tissue disease-associated interstitial lung disease. AB - PURPOSE OF REVIEW: Interstitial lung disease (ILD) is frequently observed in connective tissue disease (CTD) and is a major cause of mortality. In CTD-ILD, a marked variability in morphological patterns, time course and severity exists. In many patients, CTD-ILD is limited and inherently stable, although a significant proportion of patients have progressive disease. We review the utility of integration of the recently proposed disease behavior classification into the management of CTD-ILD, and recent advances in treatment approaches. RECENT FINDINGS: Recent studies on scleroderma-ILD (SSc-ILD) staging and short-term lung function trends provide important information, although accurate prognostic markers, particularly in limited/early CTD-ILD, are still needed. Most patients with progressive CTD-ILD stabilize on immunosuppression, as observed in recent SSc-ILD trials and CTD-ILD retrospective series. A minority of patients present with life-threatening acute/subacute ILD, requiring intense immunosuppression, with limited available guidance. A significant minority of CTD-ILD patients have progressive disease despite immunosuppression. Ongoing trials with antifibrotic agents and with biologic agents may reveal a potential role for their use/addition. SUMMARY: Ultimately, further research into the mechanisms linking autoimmunity to fibrosis and randomized controlled clinical trials are needed, with the aim of preventing irreversible damage of lung tissue, while minimizing burden of treatment. PMID- 30020143 TI - Near-infrared spectroscopy in vegetables and humans: An observational study. AB - BACKGROUND: Cerebral near-infrared spectroscopy (NIRS) of tissue oxygen saturation is claimed to be a surrogate marker for global cerebral perfusion. Increasingly, NIRS target-based therapy has been used during cardiac surgery in the hope of decreasing the incidence of adverse neurological outcome. OBJECTIVES: We report NIRS values for some common vegetables and faculty at a world-class medical institution. DESIGN: Observational nonblinded study. SETTING: Single tertiary care institution and local urban vegetable market. PARTICIPANTS: Five yams (Dioscorea cayenensis), five courgettes (Cucurbita pepo) and five butternut squashes (Cucurbita moschata) were studied. Five cardiothoracic surgeons and anaesthesiologists were the control group. INTERVENTIONS: None. MAIN OUTCOME MEASURES: NIRS value of each species. RESULTS: Mean NIRS value for the control group was 71% [95% confidence interval (CI) 68 to 74] and was similar to that of the yellow squashes [75% (95% CI 74 to 76)]. These values were significantly greater than the NIRS measurements of both the butternut squash and yam [63% (95% CI 62 to 64) and 64% (95% CI 63 to 65), respectively, P < 0.01]. CONCLUSION: Commonly eaten vegetables have NIRS measurements similar to those seen in healthy humans. PMID- 30020144 TI - Comparison of a novel clinical score to estimate the risk of REsidual neuromuscular block Prediction Score and the last train-of-four count documented in the electronic anaesthesia record: A retrospective cohort study of electronic data on file. AB - BACKGROUND: Residual neuromuscular block (rNMB) after surgery is not difficult to identify if proper neuromuscular monitoring is used, but many clinicians do not use quantitative neuromuscular monitoring. OBJECTIVE: The aim of this study was to develop a REsidual neuromuscular block Prediction Score (REPS) to predict postoperative rNMB and compare the predictive accuracy of the prediction score with train-of-four count (TOFC) measurement at the end of a surgical case. DESIGN: Retrospective cohort study of data on file. DATA SOURCE: Electronic patient data and peri-operative data on vital signs, administered medications, and train-of-four ratio (TOFR) obtained in the postoperative recovery rooms [postanaesthesia care unit (PACU)] at Massachusetts General Hospital in Boston, Massachusetts, USA. PATIENTS: Quantitative TOFR measurements obtained on admission to the PACU were available from 2144 adult noncardiac surgical patients. MAIN OUTCOME MEASURE: Presence of rNMB at PACU admission, defined as a TOFR of less than 0.9. RESULTS: In the score development cohort (n=2144), rNMB occurred in 432 cases (20.2%). Ten independent predictors for residual paralysis were identified and used for the score development. The final model included: hepatic failure, neurological disease, high-neostigmine dose, metastatic tumour, female sex, short time between neuromuscular blocking agent administration and extubation, aminosteroidal neuromuscular blocking agent, BMI more than 35, absence of nurse anaesthetist and having an experienced surgeon. The model discrimination by C statistics was 0.63, 95% confidence interval (0.60 to 0.66), and risk categories derived from the REPS had a higher accuracy than the last documented intra-operative TOFC for predicting rNMB (net reclassification improvement score 0.26, standard error 0.03, P < 0.001). CONCLUSION: The REPS can be used to identify patients at greater risk of rNMB. This tool may inform anaesthetists better than an intra-operative TOFC and thus enable peri-operative anaesthetic practices to be tailored to the patient and minimise the undesirable effects of rNMB. TRIAL REGISTRY NUMBER: Approved by Partners Human Research Committee (protocol number 2016P000940) at MGH in Boston, Massachusetts, USA on 25 April 2016. PMID- 30020145 TI - Ambulatory Blood Pressure Reactivity as a Moderator in the Association Between Daily Life Psychosocial Stress and Carotid Artery Atherosclerosis. AB - OBJECTIVE: We examined whether associations between daily psychosocial stressor exposures and carotid artery intima-medial thickness (IMT) may be stronger among those showing larger stress-related cardiovascular reactivity (CVR) during the course of daily living. METHODS: A total of 474 healthy working adults (ages 30 54 years) collected ambulatory blood pressure and recorded their daily experiences, using electronic diaries, during two 2-day periods for a week. Measures of mean momentary task strain and social conflict were used as indices of stressor exposure, and partial regression coefficients linking momentary strain and conflict with ambulatory blood pressure fluctuations were used as measures of CVR. IMT was assessed in the carotid arteries using B-mode ultrasound. RESULTS: After covariate adjustment, associations between mean task strain exposure and IMT were significant among those high in CVR to strain (for systolic blood pressure, p = .006, for diastolic blood pressure, p = .011) but not among those low in strain CVR. Similarly, associations involving mean conflict exposure were significant among those high in CVR to social conflict (p < .001 for systolic blood pressure, p = .001 for diastolic blood pressure) but not among low social conflict reactors. Significant moderation effects were more consistently shown for task strain than for social conflict, but the overall pattern of results was robust across two different types of statistical modeling procedures. CONCLUSIONS: Individual differences in CVR may moderate the effects of daily psychosocial stress on subclinical CVD among healthy employed adults. Using ecological momentary assessment to measure stress exposure as well as stress reactivity may facilitate our ability to detect these effects. PMID- 30020146 TI - Not the Last Word: Ponseti Broke the Iron Triangle. PMID- 30020147 TI - Art in Science: King Richard III-Revisited. PMID- 30020148 TI - External Validation and Optimization of the SPRING Model for Prediction of Survival After Surgical Treatment of Bone Metastases of the Extremities. AB - BACKGROUND: Survival predictions before surgery for metastatic bone disease in the extremities (based on statistical models and data of previous patients) are important for choosing an implant that will function for the remainder of the patient's life. The 2008-SPRING model, presented in 2016, enables the clinician to predict expected survival before surgery for metastatic bone disease in the extremities. However, to maximize the model's accuracy, it is necessary to maintain and update the patient database to refit the prediction models achieving more accurate calibration. QUESTIONS/PURPOSES: The purposes of this study were (1) to refit the 2008-SPRING model for prediction of survival before surgery for metastatic bone disease in the extremities with a more modern cohort; and (2) to evaluate the performance of the refitted SPRING model in a population-based cohort of patients having surgery for metastatic bone disease in the extremities. METHODS: We produced the 2013-SPRING model by adding to the 2008-SPRING model (n = 130) a cohort of patients from a consecutive institutional database of patients who underwent surgery for bone metastases in the extremities with bone resection and reconstruction between 2009 and 2013 at a highly specialized surgical center in Denmark (n = 140). Currently the model is only available as the nomogram fully available in the current article, which is sufficient to use in daily clinical work, but we are working on making the tool available online. As such, the 2013 SPRING model was produced using a consecutive cohort of patients (n = 270) treated during an 11-year period (2003-2013) called the training cohort, all treated with bone resection and reconstruction. We externally validated the 2008 SPRING and the 2013-SPRING models in a prospective cohort (n = 164) of patients who underwent surgery for metastatic bone disease in the extremities from May 2014 to May 2016, called the validation cohort. The validation cohort was identified from a cross-section of the Danish population who were treated for metastatic lesions (using endoprostheses and internal fixation) in the extremities at five secondary surgical centers and one highly specialized surgical center. This cross-section is representative of the Danish population and no patients were treated outside the included centers as a result of public healthcare settings. The indications for surgery for training and the validation cohort were pathologic fracture, impending fracture, or intractable pain despite radiation. Exact date of death was known for all patients as a result of the Danish Civil Registration System and no loss to followup existed. In the training cohort, 150 patients (out of 270 [56%]) and in the validation cohort 97 patients (out of 164 [59%]) died of disease within 1 year postoperatively. The 2013 model did not differ from the 2008 model and included hemoglobin, complete fracture/impending fracture, visceral and multiple bone metastases, Karnofsky Performance Status, and the American Society of Anesthesiologists score and primary cancer. The models were evaluated by area under the receiver operating characteristic curve (AUC ROC) and Brier score (the lower the better). RESULTS: The 2013-SPRING model was successfully refitted with a cohort using more patients than the 2008-SPRING model. Comparison of performance in external validation between the 2008 and 2013-SPRING models showed the AUC ROC was increased by 3% (95% confidence interval [CI], 0%-5%; p = 0.027) and 2% (95% CI, 0%-4%; p = 0.013) at 3-month and 6-month survival predictions, respectively, but not at 12 months at 1% (95% CI, 0%-3%; p = 0.112). Brier score was improved by -0.018 (95% CI, -0.032 to -0.004; p = 0.011) for 3-month, -0.028 (95% CI, -0.043 to -0.0123; p < 0.001) for 6-month, and -0.014 (95% CI, -0.025 to -0.002; p = 0.017) for 12 month survival prediction. CONCLUSIONS: We improved the SPRING model's ability to predict survival after surgery for metastatic bone disease in the extremities. As such, the refitted 2013-SPRING model gives the surgeon a tool to assist in the decision-making of a surgical implant that will serve the patient for the remainder of their life. The 2013-SPRING model may provide increased quality of life for patients with bone metastasis because potential implant failures can be minimized by precise survival prediction preoperatively and the model is freely available and ready to use from the current article. LEVEL OF EVIDENCE: Level I, diagnostic study. PMID- 30020149 TI - CORR Insights(r): Risk of Perforation Is High During Corrective Reaming of Retroverted Glenoids: A Computer Simulation Study. PMID- 30020150 TI - Is the Enzyme-linked Immunosorbent Assay More Accurate Than the Lateral Flow Alpha Defensin Test for Diagnosing Periprosthetic Joint Infection? AB - BACKGROUND: Alpha defensin was proposed as a new biomarker in synovial fluid for the diagnostic workup of failed joint prostheses. To our knowledge, no comparative study of the performance of the quantitative enzyme-linked immunosorbent assay (ELISA) and qualitative lateral flow alpha defensin test has been reported. QUESTIONS/PURPOSES: (1) Using the proposed European Bone and Joint Infection Society (EBJIS) criteria for defining periprosthetic joint infection (PJI), is there a difference in the diagnostic accuracy of quantitative ELISA and qualitative lateral flow alpha defensin tests? (2) Is there a difference in the performance of the two alpha defensin tests when using three definition classification systems (Musculoskeletal Infection Society [MSIS], Infectious Diseases Society of America [IDSA], and proposed EBJIS)? METHODS: In this retrospective study of samples collected earlier as part of a related longitudinal study, we included patients in whom aspiration of the prosthetic hip or knee was performed as routine investigation before every revision arthroplasty. Between October 2016 and April 2017, a total of 73 patients were eligible for inclusion. As a result of an insufficient fluid volume for analysis (< 5 mL), two patients were excluded. Among the 71 patients in the final analysis, 54 had a knee and 17 a hip arthroplasty. Using the proposed EBJIS criteria, PJI was diagnosed in 22 patients (31%) and aseptic failure in 49 (69%). The alpha defensin ELISA and lateral flow tests were performed in synovial fluid. Patients were classified as having PJI or aseptic failure using the MSIS, the IDSA, and the proposed EBJIS criteria. Sensitivity and specificity of ELISA and the lateral flow alpha defensin test were calculated. Based on receiver operating characteristic analysis, area under the curve values were compared. RESULTS: When measured against the proposed EBJIS criteria, the sensitivity of alpha defensin ELISA and the lateral flow test was low and not different from one another with the numbers available at 50% (95% confidence interval [CI], 31%-69%) and 46% (95% CI, 27%-65%; p = 0.857), respectively, whereas both methods showed high specificity (98% [95% CI, 88%-100%]; p = 1.000). For sensitivity, the highest values were seen when compared against the MSIS criteria (ELISA: 85% [95% CI, 56% 97%], lateral flow: 77% [95% CI]; p = 0.871), intermediate with IDSA criteria (ELISA: 73% [95% CI, 48%-89%], lateral flow: 67% [95% CI]; p = 0.867), and lowest with proposed EBJIS criteria (ELISA: 50% [95% CI, 31%-69%], lateral flow: 46% [95% CI]; p = 0.763). Specificity, however, was high regardless of the criteria used, where ELISA and lateral flow produced results that were not different (MSIS: 98% [95% CI, 90%-100%], IDSA: 98% [95% CI, 90%-100%], EBJIS: 98% [95% CI, 88%-100%]; p = 1.000). The area under the curve of alpha defensin ELISA and the lateral flow test was similar, regardless of the definition criteria used (EBJIS: p = 0.566; IDSA: p = 0.425; MSIS: p = 0.339). CONCLUSIONS: There is no difference between the quantitative and qualitative alpha defensin test for confirmation of PJI, irrespective of applied definition criteria. Having the advantage of providing results within 10 minutes without the need for a laboratory facility, the qualitative test may be of interest in the intraoperative setting, however, at a cost of higher test expense. LEVEL OF EVIDENCE: Level I, diagnostic study. PMID- 30020151 TI - Reversal of Fatty Infiltration After Suprascapular Nerve Compression Release Is Dependent on UCP1 Expression in Mice. AB - BACKGROUND: In large rotator cuff tears, retraction of the supraspinatus muscle creates suprascapular nerve traction and compression. However, suprascapular nerve transection, when used in previous models, is different from chronic compression of the suprascapular nerve in patients. To define the role of suprascapular nerve chronic injury in rotator cuff muscle atrophy and fatty infiltration, we developed a novel reversible suprascapular nerve compression mouse model. QUESTIONS/PURPOSES: We asked: (1) Can suprascapular nerve injury be induced by compression but reversed after compression release? (2) Can muscle fatty infiltration be induced by suprascapular nerve compression and reversed after compression release? (3) Is white fat browning involved in fatty infiltration resorption? METHODS: Mice in a common strain of C57BL/6J were randomly assigned to suprascapular nerve transection (n = 10), nerve compression (n = 10), nerve compression and release (n = 10), or sham control (n = 10) groups. To study the role or white fat browning on muscle fatty infiltration, additional UCP1 reporter mice (n = 4 for nerve compression and n = 4 for nerve compression release) and knockout mice (n = 4 for nerve compression and n = 4 for nerve compression release) were used. Nerve injury was testified using osmium tetroxide staining and neural muscular junction staining and then semiquantified by counting the degenerating axons and disrupted junctions. Muscle fatty infiltration was evaluated using Oil Red O staining and then semiquantified by measuring the area fraction of fat. Immunofluorescent and Oil Red O staining on UCP1 transgenic mice was conducted to testify whether white fat browning was involved in fatty infiltration resorption. Ratios of UCP1 positively stained area and fat area to muscle cross-section area were measured to semiquantify UCP1 expression and fatty infiltration in muscle by blinded reviewers. Analysis of variance with Tukey post hoc comparisons was used for statistical analysis between groups. RESULTS: Suprascapular nerve injury was induced by compression but reversed after release. The ratios of degenerating axons were: sham control: 6% +/- 3% (95% confidence interval [CI], 3%-10%); nerve compression: 58% +/- 10% (95% CI, 45%-70% versus sham, p < 0.001); and nerve compression and release: 15% +/- 9% (95% CI, 5%-26% versus sham, p = 0.050). The supraspinatus muscle percentage area of fatty infiltration increased after 6 weeks of nerve compression (19% +/- 1%; 95% CI, 18%-20%; p < 0.001) but showed no difference after compression release for 6 weeks (5% +/- 3%; 95% CI, 1%-10%; p = 0.054) compared with sham (2% +/- 1%; 95% CI, 1%-3%). However, the fat area fraction in UCP1 knockout mice did not change after nerve compression release (6% +/- 1%; 95% CI, 4%-8% at 2 weeks after compression and 5% +/- 0.32%; 95% CI, 4%-6% after 2 weeks of release; p = 0.1095). CONCLUSIONS: We developed a clinically relevant, reversible suprascapular nerve compression mouse model. Fatty infiltration resorption after compression release was mediated through white fat browning. CLINICAL RELEVANCE: If the mechanism of browning of white fat in rotator cuff muscle fatty infiltration can be confirmed in humans, a UCP1 agonist may be an effective treatment for patients with suprascapular nerve injury. PMID- 30020152 TI - Classifications in Brief: Tonnis Classification of Hip Osteoarthritis. PMID- 30020153 TI - Outcomes of regional anesthesia in cancer patients. AB - PURPOSE OF REVIEW: To summarize the current evidence on the impact of regional anesthesia or analgesia on cancer recurrence. RECENT FINDINGS: Preclinical investigations suggest that regional anesthesia could have a positive impact on reducing cancer growth and progression. Regional anesthesia is also associated with better immunological and stress-related outcomes in patients undergoing major oncological surgery. Most recent retrospective studies do not show any benefit of regional anesthesia or analgesia on cancer recurrence or recurrence free survival. SUMMARY: The available clinical evidence does not support the use of any anesthesia technique to improve the cancer-related survival after major oncological surgery. The results from four randomized controlled trials will shed light on this critical topic in perioperative medicine. PMID- 30020154 TI - Periprocedural management of patients with subarachnoid hemorrhage. AB - PURPOSE OF REVIEW: Anesthesiologists and intensivists may be involved in the management of aneurysmal subarachnoid hemorrhage (aSAH) patients at various stages of care. This article will review the recent advances in the periprocedural management of aSAH patients. RECENT FINDINGS: New scoring systems to assess gravity and prognosis of aSAH patients have been evaluated and proposed. Rebleeding still remains, with early aneurysmal treatment, a major challenge in the first hours of aSAH management. In the last decades, the treatment of the aSAH has shifted from clipping to coiling and more recently, the use of flow diversion technique has been introduced in selected patients. Although these improvements allow treatment of more complex aneurysms, they have implications for the anesthesiologist, including requiring the management of anticoagulation with its inherent risks. Even though knowledge, monitoring, and management of postprocedural phase of aSAH patients has improved, vasospasm and cerebral-delayed ischemia still remain the major and devastating complications in the postoperative course of aSAH patients. SUMMARY: Despite recent progress in the scoring, diagnosis, and treatment of aSAH patients, the periprocedural management of these patients is still a major challenge for anesthesiologists and intensivists, who are involved from the first phase of the aneurysm rupture through the postoperative phases and vasospasm period. PMID- 30020155 TI - An update on regional analgesia for rib fractures. AB - PURPOSE OF REVIEW: To provide an update on new strategies for pain management after rib fractures utilizing regional analgesia. RECENT FINDINGS: Pain management for patients with rib fractures can be very challenging. Traditionally, intravenous patient-controlled analgesia (IVPCA) with opioids, epidural, and paravertebral blocks have been used. These techniques, however, may be contraindicated or have limited application in certain patient populations. Recently, ultrasound-guided myofascial plane blocks such as the erector spinae plane (ESP) block and the serratus anterior plane (SAP) block have emerged as alternatives; providing excellent analgesia with minimal side effects. These blocks have the flexibility to be employed in a wide variety of circumstances where epidural and paravertebral approaches may not be feasible such as in anticoagulated patients and in patients with vertebral fractures where positioning options are limited. Myofascial blocks are less invasive and allow for broader and earlier application (e.g. in the emergency department). Further research on myofascial plane blocks is a priority. SUMMARY: Until recently, epidural, paravertebral, and intercostal blocks have been advocated as primary management techniques for pain associated with rib fractures. Newer myofascial plane blocks may play a key role in the future as part of alternative pain management strategies. PMID- 30020156 TI - Anesthesia for stroke rescue. AB - PURPOSE OF REVIEW: To highlight the potential implications of recent advances in the management of large vessel occlusions for intraprocedural anesthetic management. RECENT FINDINGS: Stroke remains the leading cause of disability in the United States and the second leading cause of death in the world. Several randomized control trials published within the past decade have helped to make endovascular thrombectomy the standard of care for all eligible patients. However, whether intraprocedural anesthesia care practices may significantly improve in-hospital and out-of-hospital morbidity and mortality outcomes are not clear. SUMMARY: Management strategies that shorten the time to intervention and maintain blood pressure to preserve penumbral tissue may be beneficial. Future well powered studies are necessary to enable inferences on what type of anesthetic management is harmless, neurotoxic, or neural plasticity promoting. PMID- 30020157 TI - Intraoperative neurophysiological monitoring in neuroanesthesia. AB - PURPOSE OF REVIEW: The purpose of this review is to highlight the importance of making informed choices of anesthetics and evaluating the impact of depth of anesthesia, hemodynamic status and other factors capable of interfering with signal capture during intraoperative neurophysiological monitoring (IONM). RECENT FINDINGS: Over the last decades, neuromonitoring has advanced considerably, allowing for insights into neurological function during anesthesia and making it possible to assess intraoperative consciousness and neural integrity in real time. IONM is indicated in surgeries posing risk to targeted neural tissues and adjacent structures. The technique helps correlate surgical maneuvers with neurophysiological changes at high levels of sensitivity and specificity and can identify risk situations early enough to prevent postoperative neurological deficits. SUMMARY: Experience with IONM, the use of an adequate IONM modality, and knowledge of the effect of anesthetic techniques and agents on neurophysiological parameters are fundamental for reliable measurements. The current gold standard in IONM is total intravenous anesthesia without neuromuscular block. PMID- 30020158 TI - What Constitutes a Well-Designed Pilot Study? PMID- 30020160 TI - NANNAHEIM Is the Place to Be This Fall! PMID- 30020162 TI - Comparing N-PASS and NIPS: Improving Pain Measurement in the Neonate. PMID- 30020161 TI - Systematic Review: What Is the Evidence for the Side-Lying Position for Feeding Preterm Infants? AB - BACKGROUND: Side-lying position is an increasingly common feeding strategy used by parents, nurses, and feeding therapists to support oral feeding in preterm infants. Better understanding of the research evidence on the effect of the side lying position will help clinicians make informed decisions and guide future research in this important area. PURPOSE: To identify and summarize the available evidence on the effect of side-lying position on oral feeding outcomes in preterm infants. METHODS/SEARCH STRATEGY: PubMed, CINAHL, Web of Science and PsycINFO were searched for ("preterm" OR "premature") AND "feed*" AND "position*". The full text of 47 articles was reviewed to identify eligible studies that use a quasi-experimental or experimental design to examine the intervention effectiveness; 4 studies met criteria. FINDINGS/RESULTS: Four studies compared the effect of the side-lying position with either the semi-upright, cradle-hold, or semi-reclined positions on various feeding outcomes. The findings were conflicting: 2 studies found the side-lying position to be beneficial for supporting physiologic stability during feeding compared with the semi-upright position whereas 2 studies did not find significant differences in any of their outcomes between the side-lying position and other feeding positions. However, this finding should be interpreted cautiously because of various methodological weaknesses and limited generalizability. IMPLICATIONS FOR PRACTICE: This review does not provide strong or consistent evidence that the side-lying position improves preterm infants' oral feeding outcomes. IMPLICATIONS FOR RESEARCH: A large randomized controlled trial with a diverse group of preterm infants is needed to determine the effects of the side-lying position and identify infants who would receive the most benefit.Video Abstract Available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx. PMID- 30020165 TI - This Month in Anesthesiology. PMID- 30020169 TI - Coca Bitters-Numbing the Fatigue Rather Than the Pain. PMID- 30020167 TI - How Low Can You Go? Minimum Dosage and Safety of Intraneural Sciatic Nerve Blocks. PMID- 30020170 TI - "No Charge" Laughing Gas at Carmichael & Company of Troy, New York. PMID- 30020171 TI - Liebig's Trade Card for Numbing but Toxic Aconite. PMID- 30020172 TI - Planocaine: Procaine by May & Baker Ltd. of Dagenham. PMID- 30020173 TI - Streams of Unconsciousness V: Stability Reflected in the Pyriphlegethon. PMID- 30020175 TI - Retained Central Venous Guidewires: Are We Flushing Them Out? PMID- 30020174 TI - Modeling the Effects of the Locked Pack Procedure to Prevent Guidewire Retention in a Clinical Setting. PMID- 30020176 TI - In Reply. PMID- 30020177 TI - Pharmacokinetic Pharmacodynamic Perspective on the Detection of Signs of Neural Inertia in Humans. PMID- 30020178 TI - Electroencephalogram and Anesthetics. PMID- 30020179 TI - In Reply. PMID- 30020180 TI - Risks of Impaired Organ Protection with Inhibiting Transient Receptor Potential Vanilloid 1. PMID- 30020181 TI - In Reply. PMID- 30020182 TI - Postoperative Analgesia after Shoulder Surgery. PMID- 30020183 TI - Intraoperative Considerations of the Suprascapular Nerve Block. PMID- 30020184 TI - In Reply. PMID- 30020185 TI - Catching a Unicorn: Neostigmine and Muscle Weakness-Not Neostigmine for All, but Quantitative Monitoring for Everyone! PMID- 30020186 TI - In Reply. PMID- 30020187 TI - In Reply. PMID- 30020188 TI - Colloids in Major Abdominal Surgery: Are They Really Better? PMID- 30020189 TI - In Reply. PMID- 30020190 TI - Central Venous Lines in Low-birth-weight Newborns: Watch Out. PMID- 30020191 TI - In Reply. PMID- 30020192 TI - High expression of mitogen-activated and stress-activated protein kinase 1 indicates poor prognosis in patients with glioma. AB - Mitogen-activated and stress-activated protein kinase 1 (MSK1), which belongs to the subfamily of MAPK-activated protein kinase, plays an important role in cell proliferation and neoplastic transformation. It has been recently reported that MSK1 overexpression was closely related to the progression of some tumors such as colorectal cancer. However, the clinical significance of MSK1 in glioma has not been addressed. To investigate the potential role of MSK1 in glioma, we first examined the expression pattern of MSK1 in glioma tissues and normal brain tissues using quantitative RT-PCR, and the results showing that MSK1 expression was significantly elevated in glioma tissues compared with normal brain tissues. The clinical relevance of MSK1 expression level was then analyzed, and we found that high expression of MSK1 was closely related to the larger tumor size and advanced WHO grade. Univariate and multivariate analyses revealed that glioma patients with higher expression of MSK1 had poorer overall survival, and MSK1 was identified as an independent unfavorable prognosis factor. In addition, the effects of MSK1 on glioma cells were tested through cellular experiments, and we demonstrated that MSK1 can promote proliferation and invasion capacities of tumor cells. In conclusion, patients with glioma with higher MSK1 expression were more predisposed to poorer clinical outcomes and unfavorable prognosis, indicating the potential role of MSK1 as a novel clinical biomarker and therapeutic target. PMID- 30020194 TI - Defining Patient Safety Events in Inpatient Psychiatry. AB - OBJECTIVES: The past 20 years have seen the emergence of a national movement to improve hospital-based healthcare safety in the United States. However, much of the foundational work and subsequent research have neglected inpatient psychiatry. The aim of this article was to advance a comprehensive approach for conceptualizing patient safety in inpatient psychiatry as framed by an application of the Institute of Medicine patient safety framework. METHODS: This article develops a framework for characterizing patient safety in hospital-based mental health care. We discuss some of the conceptual and methodological issues related to defining what constitutes a patient safety event in inpatient psychiatry and then enumerate a comprehensive set of definitions of the types of safety events that occur in this setting. RESULTS: Patient safety events in inpatient psychiatry are broadly categorized as adverse events and medical errors. Adverse events are composed of adverse drug events and nondrug adverse events, including self-harm or injury to self, assault, sexual contact, patient falls, and other injuries. Medical errors include medication errors and nonmedication errors, such as elopement and contraband. We have developed clear definitions that would be appropriate for use in epidemiological studies of inpatient mental health treatment. CONCLUSIONS: Psychiatry has not been an integral part of the national safety movement. As a first step toward breaching this chasm, we have considered how psychiatric events fit into the safety framework adopted across much of medicine. Patient safety should become a key part of inpatient psychiatry's mission and pursued rigorously as the subject of research and intervention efforts. PMID- 30020193 TI - Nivolumab Treatment for Cancers in the HIV-infected Population. AB - Nivolumab is a standard treatment option in several advanced malignancies, but safety and efficacy are still unknown in patients with human immunodeficiency virus (HIV) infection. We describe a case series of people living with HIV (PLWH) receiving nivolumab in the Veterans Health Administration (VA) and report responses and toxicities. We identified all PLWH who received nivolumab at any VA facility since 2000 in the Corporate Data Warehouse (CDW), which provides nationwide research access to VA electronic medical records. We identified 16 HIV infected nivolumab recipients. The median number of nivolumab doses received was 6 (range, 1-32). Changes in CD4 count during therapy were variable, with 70% (7/10) of patients experiencing increases. Half of PLWH were treated for non small-cell lung cancer; 2 for Hodgkin lymphoma (HL), 2 for renal cell carcinoma, and 4 for off-label cancers. For non-small-cell lung cancer, 7 patients had evaluable responses. Although 5 of 7 patients immediately progressed, 1 had a partial response and 1 had stable disease, which were both durable. Two of 16 (14%) PLWH had complete responses; both with HL (2/2 HL, 100%). The prevalence of immune-related adverse effects was 40% overall (6/15); 27% (4/15) had pneumonitis. To our knowledge, this is the largest case series reporting outcomes with nivolumab in PLWH. Outcomes were comparable with those seen in studies of HIV-uninfected patients, and particularly interesting for HL. The reason for the high proportions of immune-related adverse effects is unclear, but needs to be confirmed in larger studies. PMID- 30020195 TI - Long-term relative survival from melanoma in Germany 1997-2013. AB - Up-to-date melanoma relative survival (RS) estimates and trend analysis facilitate close monitoring of melanoma patients' prognosis. This study aimed to provide recent 5-year and 10-year RS from melanoma, stratified by prognostic factors, and identify latest survival trends. Data from 12 German cancer registries were analysed. We included patients with primary cutaneous malignant melanoma (ICD-10: C43.X) diagnosed in 1997-2013 who were at least 15 years old. Five-year and 10-year RS were estimated by period analysis. For 10-year RS analyses, we excluded patients who were 75 years of age or older. Analyses were stratified by sex, age, histology, tumour stage, and body site. We included 82 901 patients, of whom 51% were women. The median age at diagnosis was 62 years. Five-year and 10-year RS in 2007-2013 were 92.4 and 90.8%, respectively. RS was higher in women. The prognosis worsened with older age and higher stage. In superficial spreading melanoma and lentigo maligna melanoma, RS was high; it was lower in nodular, acral lentiginous and 'other' melanoma. RS was the highest for melanoma on the arms; RS for melanoma on unknown or overlapping sites of the skin was the lowest. Five-year and 10-year RS increased significantly from 2005-2007 and 2008-2010 to 2011-2013, by 3.5 and 3.3 percentage points, respectively. For melanoma of 'other' histology, 5-year and 10-year RS increased significantly. Ten year RS also increased significantly in men with superficial spreading melanoma and T4 melanoma, and in women with T3 melanoma. Melanoma RS improved, especially in certain subgroups. The reasons for improvements need to be investigated further. PMID- 30020197 TI - Acral melanoma: a retrospective cohort from the Brazilian National Cancer Institute (INCA). AB - Acral melanoma (AM) is a rare subtype of melanoma arising on the palms, soles and subungual areas. In the Brazilian and Latin American populations, the sociodemographic and clinical-pathologic features of AM are unclear. AM tends to be more advanced at presentation because of delayed diagnoses, with poor survival. This study reports on a retrospective AM cohort from the Brazilian National Cancer Institute. We reviewed a database of 529 patients presenting with AM from 1997 to 2014 and analysed the sociodemographic and clinical-pathologic features of AM associated with overall survival and relapse-free survival. All patients were Brazilian, ranging in age from 19 to 101 years (mean 65.4; median 67.0). Two hundred and ninety-four (55.8%) patients were women. The Breslow primary lesion thicknesses ranged from 0.0 to 65.0 mm (mean 8.3 mm; median 5.0 mm). Of these patients, 43.3% had the acral lentiginous histologic subtype. Plantar was the most frequently involved site (68.5%), and ulcers and mitosis were present in 79.0 and 86.4% of these cases, respectively. Multivariate analysis results found that Breslow thickness of 1.03 (95% confidence interval: 1.01-1.05; P=0.01) and ulceration of 2.70 (95% confidence interval: 1.00-7.06; P=0.05) were poor prognostic indicators of overall survival. AM tumours were thick on diagnostic tests and were associated with poorer survival outcomes. Unfavourable prognosis likely derives from the delayed diagnosis compared with other melanoma subtypes. PMID- 30020196 TI - Analysis of MLN4924 (pevonedistat) as a potential therapeutic agent in malignant melanoma. AB - The NEDD8 pathway is a known activator of the ubiquitin-protease system, a complex that is partially responsible for the degradation of proteins involved in cell-cycle regulation and neoplastic growth. In this study, we evaluated the antitumor potential of MLN4924 (pevonedistat), a potent NEDD8 inhibitor. We hypothesized that MLN4924 treatment induces apoptosis in human melanoma cells. A375 and Mel39 BRAF V600E mutant melanoma cell lines were treated in vitro with MLN4924 alone or in combination with interferon-alpha (IFN-alpha) or vemurafenib therapeutic agents utilized on melanoma patients. Annexin/propidium iodine flow cytometry analysis showed that treatment with MLN4924 for 72 h induced apoptosis in A375 and Mel39 melanoma cells with an IC50 of 1200 and 143 nmol/l, respectively. Combination therapy of A375 cells with 10 U/ml IFN-alpha and 1200 nmol/l MLN4924 led to a significant increase in cell death (78.2+/-3.7%) compared with single-agent treatment by IFN-alpha (17.5+/-2.5%) or MLN4924 (50.7+/-1.0%; P<0.005). Treatment of A375 cells with 1 MUmol/l vemurafenib had a notable effect on cell viability. However, the addition of MLN4924 to vemurafenib had an inhibitory effect on apoptosis. Results from MTS proliferation assays indicate that MLN4924 has antiproliferative effects on melanoma cells in vitro, with the addition of IFN-alpha further inhibiting proliferation. Pretreatment with MLN4924 led to A375 cell sensitization to vemurafenib treatment and immunoblot analysis of MLN4924-treated cells revealed cleavage of caspase-3, caspase-7, caspase-9, and poly-ADP-ribose polymerase. These results show that MLN4924 does have an efficacy in treating melanoma in vitro alone or in combination with IFN-alpha, and thus it may have potential use in patients with advanced melanoma. PMID- 30020198 TI - The many faces of CD8+ T cells in atherosclerosis. AB - PURPOSE OF REVIEW: Atherosclerosis and the clinical consequence of cardiovascular disease remain the leading cause of death worldwide. Both an increase in cholesterol levels, as well as immune responses drive the pathogenesis of this disease. Although much is known about the role of many immune cell subsets in atherogenesis, research into the role of CD8 T cells is limited. RECENT FINDINGS: Both atheroprotective and atherogenic functions of CD8 T cells have been reported. On the one hand, the inflammatory cytokines produced by CD8 T cells exacerbate inflammatory responses, and the cytotoxic activity of these cells toward lesion-stabilizing cells such as endothelial cells drives the progression and instability of atherosclerotic lesions. On the other hand, cytotoxic activity toward antigen presenting cells and the presence of regulatory CD8 T-cell subsets dampen immunity and can limit atherosclerosis. SUMMARY: Here we review the different roles of CD8 T cells in atherosclerosis and discuss possible treatment strategies targeting these cells to reduce atherosclerotic lesion burden. PMID- 30020199 TI - Atherosclerosis in the single-cell era. AB - PURPOSE OF REVIEW: The immune system plays a critical role in the development and modulation of atherosclerosis. New high-parameter technologies, including mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq), allow for an encompassing analysis of immune cells. Unexplored marker combinations and transcriptomes can define new immune cell subsets and suggest their functions. Here, we review recent advances describing the immune cells in the artery wall of mice with and without atherosclerosis. We compare technologies and discuss limitations and advantages. RECENT FINDINGS: Both CyTOF and scRNAseq on leukocytes from digested aortae show 10-30 immune cell subsets. Myeloid, T, B and natural killer cells were confirmed. Although cellular functions can be inferred from RNA-Seq data, some subsets cannot be identified based on current knowledge, suggesting they may be new cell types. CyTOF and scRNAseq each identified four B cell subsets and three macrophage subsets in the atherosclerotic aorta. Limitations include cell death caused by enzymatic digestion and the limited depth of the scRNAseq transcriptomes. SUMMARY: High-parameter methods are powerful tools for uncovering leukocyte diversity. CyTOF is currently more powerful at discerning leukocyte subsets in the atherosclerotic aorta, whereas scRNAseq provides more insight into their likely functions. PMID- 30020200 TI - Metabolism of innate immune cells: impact on atherosclerosis. AB - PURPOSE OF REVIEW: It is increasingly recognized that profound metabolic changes occur in activated myeloid cells, which shape their inflammatory phenotype and cellular functions. The purpose of this review is to summarize the accumulating evidence that major metabolic adaptations occur in monocytes and macrophages in the context of atherosclerosis ultimately modulating atherosclerotic plaque formation. RECENT FINDINGS: Plaque macrophages show a profound metabolic reprogramming which is driven by atherogenic factors in the plaque microenvironment, such as damage associated molecular patterns, modified lipoproteins, and hypoxia. In addition, systemic atherogenic factors modulate metabolism of circulating monocytes and their bone marrow progenitors. Activation of glycolysis, the pentose phosphate pathway, and fatty acid synthesis, a reduction of fatty acid oxidation accompanied by complex changes in the lysosomal handling of lipids all appear to facilitate atherogenesis. These processes also drive the development of trained immunity, a phenomenon describing the persistent pro-inflammatory phenotype that develops after brief stimulation of monocytes with pro-atherogenic stimuli. SUMMARY: A pro-atherosclerotic environment reprograms the metabolism of myeloid cells in the various developmental phases of atherosclerosis. Knowledge of these metabolic programs facilitates the development of novel drugs to prevent atherosclerotic cardiovascular disease. PMID- 30020201 TI - Risk Factors and Main Indications for Palivizumab Prophylaxis in a Second Season Population: Results From the German Synagis Registry 2009-2016. AB - BACKGROUND: After national recommendations, palivizumab is administered in Germany to high-risk infants to prevent hospitalizations related to respiratory syncytial virus (RSV) infection. Limited data are available to characterize those children who receive palivizumab in 2 consecutive RSV seasons. METHODS: This was a comparative analysis of data from a postmarketing observational study (German SYNAGIS Registry, AbbVie Germany GmbH & Co.KG, Wiesbaden) detailing RSV-related risk factors and main indications for palivizumab in 920 children who received at >=1 palivizumab injection in a second season between 2010 and 2016 [second season population (SSP)]. RESULTS: Median birth weight and gestational age at birth as well as the proportion of children with hemodynamically significant congenital heart disease, with any form of chronic lung disease of prematurity or with any form of neuromuscular impairment, were significantly higher in the SSP. Accordingly, hemodynamically significant congenital heart disease, chronic lung disease and other reasons (including neuromuscular impairment) and not prematurity were the main indications for palivizumab in the SSP. The RSV-related hospitalization rate confirmed by viral testing in the SSP (receiving palivizumab prophylaxis) was 0.9%. No deaths due to RSV were reported. CONCLUSIONS: Second season recipients of palivizumab differ from one season recipients of palivizumab in terms of risk factors and main indications for prophylaxis. Keeping in mind the limitations of an uncontrolled prospective observational study, these results support the effectiveness of palivizumab (concerning the RSV rehospitalization rate) and do not reveal new safety alerts in a large SSP. PMID- 30020202 TI - Atypical and Severe Nonsuicidal Self-Injury as an Indicator of Severe Psychopathology: Findings From a Sample of High-Risk Community Mental Health Clients. AB - This study examined whether atypical/severe nonsuicidal self-injury (NSSI; e.g., foreign body ingestion, cutting necessitating sutures) serves as a marker of severe psychopathology among 467 adult community mental health clients (n = 33 with an atypical/severe NSSI history). Information regarding psychiatric risk indicators was extracted from participants' psychiatric records. Generalized linear models with negative binomial distribution and log link function, as well as chi-square tests, were used to address study aims. Clients with a lifetime atypical/severe NSSI history met criteria for a significantly greater number of psychiatric risk indicators than clients with a lifetime history of common NSSI only; however, these clients were not significantly more likely to report recent suicidal actions. Individuals with an atypical/severe NSSI history may demonstrate more severe psychopathology than those with a history of common NSSI only. Thus, it may be clinically useful to consider individuals with an atypical/severe NSSI history as a high-risk subgroup. PMID- 30020203 TI - The Emerging Imperative for a Consensus Approach Toward the Rating and Clinical Recommendation of Mental Health Apps. AB - With over 10,000 mental health- and psychiatry-related smartphone apps available today and expanding, there is a need for reliable and valid evaluation of these digital tools. However, the updating and nonstatic nature of smartphone apps, expanding privacy concerns, varying degrees of usability, and evolving interoperability standards, among other factors, present serious challenges for app evaluation. In this article, we provide a narrative review of various schemes toward app evaluations, including commercial app store metrics, government initiatives, patient-centric approaches, point-based scoring, academic platforms, and expert review systems. We demonstrate that these different approaches toward app evaluation each offer unique benefits but often do not agree to each other and produce varied conclusions as to which apps are useful or not. Although there are no simple solutions, we briefly introduce a new initiative that aims to unify the current controversies in app elevation called CHART (Collaborative Health App Rating Teams), which will be further discussed in a second article in this series. PMID- 30020205 TI - Independent Computerized Cognitive Remediation for Psychosis: An Investigation of Patient Experiences. AB - Cognitive remediation (CR) training improves cognition and functioning in patients with psychosis. To date, however, few studies have investigated CR from a subjective patient perspective. We recently conducted a randomized control trial demonstrating the effectiveness of a new, low therapist support, computer based training program. This study aims to assess the service user experience of this program. Twenty CR completers with psychosis were interviewed using both rated and open-ended questions. Thematic analysis identified three broad themes: a) benefits of doing CR, b) costs of doing CR, and c) experience of doing CR. Positive experiences of therapy participation included improved cognition, improved positive self-regard, a development of life skills, and a transfer of benefits to everyday life. Negative experiences included therapy being difficult and tiring, leading to frustration and anxiety. These findings demonstrate the feasibility of low therapist support CR and point to variables that might impact therapy adherence. PMID- 30020204 TI - Care and Discharge Outcome of Acute Stroke in Lebanon: A Hospital-Based Study. AB - The present study was conducted to assess stroke care and outcomes in two Lebanese hospitals. Patients admitted in 2012 and 2013 were retrospectively selected. Data were extracted from medical records for time to hospital arrival, stroke severity, management, and discharge outcomes. A Cox regression analysis was then conducted to predict time to in-hospital death. A total of 201 patients were included (mean age = 69.2 years), among whom 50% arrived within a delay of 3.75 hours. Half underwent brain imaging in the first hour, and nine patients received an acute intervention. Forty-four patients died at the hospital; 142 were discharged home, among whom 98 patients were dependent in their daily activities. Stroke severity on admission and time from onset to arrival were found to be significantly associated to the time to in-hospital death (adjusted hazard ratio [HRa] = 1.13 and HRa = 0.98 respectively; p < 0.05). The study sheds light on high case fatality and dependency rates at discharge among stroke patients in Lebanese hospitals. PMID- 30020206 TI - Social Anxiety and Benign and Toxic Online Self-Disclosures: An Investigation Into the Role of Rejection Sensitivity, Self-Regulation, and Internet Addiction in College Students. AB - This work aimed to explore the relationship between social anxiety with benign and toxic online self-disclosures with the mediating role of rejection sensitivity, self-regulation, and Internet addiction. In this study, 358 students who were active members of social networks at the Mohaghegh Ardabili University, Iran were evaluated in the form of a structural equation model. The results substantiated that social anxiety could explain 47% of the variance in benign online self-disclosure and 27% of toxic online self-disclosure with the mediating role of rejection sensitivity, self-regulation, and Internet addiction. It was found that people with high social anxiety had higher rejection sensitivity and lower self-regulation. Also, people with higher social anxiety had directly higher benign and toxic online self-disclosures. The results indicated that self regulation did not have a direct impact on benign online self-disclosure; however, it had a direct negative impact on toxic online self-disclosure. PMID- 30020207 TI - Less Mindful, More Struggle and Growth: Mindfulness, Posttraumatic Stress Symptoms, and Posttraumatic Growth of Breast Cancer Survivors. AB - Treatment of posttraumatic stress symptoms (PTSSs) and facilitation of posttraumatic growth (PTG) are two encouraging areas of research, yet little is understood about the relationships between dispositional mindfulness, PTSSs, and PTG. The aim of the present study was to investigate whether PTSSs is correlated with PTG among breast cancer patients in China and explore the role of mindfulness in this relationship. A sample of 202 Chinese breast cancer patients voluntarily participated in the study by completing a set of questionnaires. The results revealed that PTSSs were significantly positively correlated with PTG. Structural equation modeling showed that mindfulness did not moderate but mediated the relation between PTSSs and PTG. These findings indicate that breast cancer patients with higher mindfulness may recover from PTSSs through a different process. Posttraumatic growth may not be the only positive indicator of posttraumatic individuals. PMID- 30020208 TI - An Initial Study of Alexithymia and Its Relationship With Cognitive Abilities Among Mild Cognitive Impairment, Mild Alzheimer's Disease, and Healthy Volunteers. AB - The present study examined the degree to which alexithymia is greater in mild Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to healthy volunteers (healthy comparison [HC]), and investigated relationships between alexithymia and cognition. Eighty-five participants (MCI = 30, AD = 21, HC = 34) underwent a comprehensive neuropsychological examination and completed the 20 item Toronto Alexithymia Scale (TAS-20). Relative to HC, MCI and AD reported greater alexithymia total scores and higher scores on the TAS factor difficulty in identifying feelings (DIF). The remaining two factors, difficulty in describing feelings (DDF) and externally oriented thinking showed no significant group differences. In MCI, TAS-20 and DIF were negatively correlated with working and long-term verbal memory. In AD, TAS-20 was negatively correlated with general cognition, attention, memory, and visual spatial constructive and executive abilities. Also in AD, DIF was negatively correlated with general cognition, memory, and executive abilities. The correlation between DIF and long-term verbal memory in both MCI and AD suggests a potential common mechanism for alexithymia in these neurocognitive disorders. Declines in verbal memory may hinder a patient's ability to recall an association between a given sensation and the episodic experience of that sensation, thus leading to difficulty identifying feelings, as measured by the DIF factor of the TAS-20. PMID- 30020209 TI - Single Versus Multiple Suicide Attempts: A Prospective Examination of Psychiatric Factors and Wish to Die/Wish to Live Index Among Military and Civilian Psychiatrically Admitted Patients. AB - Individuals with multiple suicide attempts have a greater risk for eventual suicide death. We investigated clinical differences in participants with single versus multiple suicide attempts. Individuals with multiple attempts were more likely to have severe depressive symptoms, drug use disorder, and a higher wish to die. Borderline personality disorder traits and drug use disorder were significant predictors of multiple attempts when adjusting for other psychiatric disorders. Participants with multiple attempts sustained higher suicidal ideation worst and wish to die/wish to live-worst scores during the 3-month assessment period. Clinical differences between individuals with multiple versus single attempts point to the need of tailored suicide prevention efforts. PMID- 30020210 TI - Change in Children's Self Confidence and the Use of Defense Mechanisms. AB - Change in the personality trait of self-confidence was studied in a group of children from the Berkeley Guidance Longitudinal study. Self-confidence was assessed at age 6 (n = 99) and again at age 10 (n = 97). Results indicated that a change in level of self-confidence was related to the use of defense mechanisms, as assessed from Thematic Apperception Test stories. A decrease in self confidence was positively related to the use of the immature defense of denial and negatively related to the use of the relatively mature defense of identification. In contrast, an increase in self-confidence was unrelated to the use of defense mechanisms. PMID- 30020211 TI - Supernatural Explanations of Neurological and Psychiatric Disorders Among Health Care Professionals at an Academic Tertiary Care Hospital in Saudi Arabia. AB - Saudi society is one of many where supernatural explanations for neurological and psychiatric disorders are prevalent among lay persons. The frequency of such beliefs among health care professionals in this country, however, is unknown. The frequency of supernatural explanations for neurological and psychiatric disorders was assessed in 126 health care professionals at an academic medical center in Jeddah. A high frequency of belief in supernatural factors as a cause for neurological and psychiatric illness, including the evil eye, divine testing and punishment, and sorcery, was found. Younger age and more junior level of training were associated with a higher likelihood of belief in supernatural causation. A surprisingly high prevalence of supernatural explanations was found among these health care professionals, 80% of whom were attending physicians or physicians in training. Future studies should focus on the potential impact of these beliefs on clinical practice. PMID- 30020213 TI - Sickness Absence of Nurses Working in Residential Elder Care: The Essential Role of Psychosocial Job Resources and Home Demands. AB - OBJECTIVES: To elucidate the role and pathways of psychosocial home demands, psychosocial home resources, and psychosocial job resources in relation to sickness absence among nurses working in residential elder care. METHODS: Longitudinal (SEM) analyses with bootstrapping with a 1 year follow-up among 365 nurses were performed. Survey data and registered sickness absence data were used. RESULTS: A complete mediation model showed the best fit. More psychosocial job resources (beta = -1.50) like "work schedule fit with private life" predicted less and more psychosocial home demands (beta = 0.62) predicted more psychosomatic health complaints. The job resources and home demands predicted sickness absence duration and episodes 1-year later mediated through nurses' health. CONCLUSIONS: More attention is needed for nurses' work schedule fit with private life and their home demands to potentially reduce health-related sickness absence among nurses working in residential elder care. PMID- 30020212 TI - Systemic Effects of Segmental Vibration in an Animal Model of Hand-Arm Vibration Syndrome. AB - OBJECTIVE: Epidemiology suggests that occupational exposure to hand-transmitted (segmental) vibration has local and systemic effects. This study used an animal model of segmental vibration to characterize the systemic effects of vibration. METHODS: Male Sprague Dawley rats were exposed to tail vibration for 10 days. Genes indicative of inflammation, oxidative stress, and cell cycle, along were measured in the heart, kidney, prostate, and liver. RESULTS: Vibration increased oxidative stress and pro-inflammatory gene expression, and decreased anti-oxidant enzymes in heart tissue. In the prostate and liver, vibration resulted in changes in the expression of pro-inflammatory factors and genes involved in cell cycle regulation. CONCLUSIONS: These changes are consistent with epidemiological studies suggesting that segmental vibration has systemic effects. These effects may be mediated by changes in autonomic nervous system function, and/or inflammation and oxidative stress. PMID- 30020214 TI - Health and Fitness Benefits But Low Adherence Rate: Effect of a 10-Month Onsite Physical Activity Program Among Tertiary Employees. AB - OBJECTIVE: The aim of this study was to assess the effects of a 10-month structured physical activity intervention implemented within the workplace on overall health indicators among tertiary (office workers) employees. METHODS: In this quasi-experimental study, 224 employees followed a 10-month worksite physical activity program. Overall health was assessed at baseline, after 5 months, and by the end of the intervention. RESULTS: Fat mass percentage decreased significantly. There was a time effect favoring push-ups, abdominal strength, flexibility, heart rate postexercise, heart rate +30 seconds, and heart rate +60 seconds postexercise. Anxiety, depression, and eating habits also improved. In total, 45% of participants completed the whole intervention. CONCLUSION: Although a structured on-site physical activity program supports improved health indicators, adherence remains a concern and requires specialists to develop new strategies. PMID- 30020216 TI - Occupational UV Exposure and Sun-Protective Behaviour in German Outdoor Workers: Results of a Nationwide Study. AB - OBJECTIVE: The aim of the National Cancer Aid Monitoring (NCAM) was to investigate which occupational groups (1) show higher sun exposure time, (2) suffer from sunburn, and (3) use recommended protective measures. METHODS: In 2016, a total of 485 individuals were classified as outdoor workers in accordance with ISCO-08 and asked about exposure time, prevalence of sunburn, and personal sun-protective measures on a sunny summer day. RESULTS: Outdoor workers were exposed to ultraviolet (UV) radiation for a mean time of 23.6 +/- 15.3 hours per week. The 12-month prevalence of getting sunburnt at work was 19%. Only one-third of outdoor workers reported using five of the most important protective measures "often" or "always." CONCLUSION: The NCAM revealed a number of high-risk groups, whose sun-protective behavior has scarcely been studied up to now. PMID- 30020215 TI - Occupational Physical Activity and Cardiovascular Risk Factors Profile in the Adult Population of the Southern Cone of Latin America: Results From the CESCAS I Study. AB - OBJECTIVE: We explore the association between occupational physical activity (OPA) and cardiovascular risk factors in four cities of the Southern Cone. METHODS: Robust multivariable linear regression models were used to examine the associations. RESULTS: The working population was constituted by 1868 men and 1672 women. Men performing high levels of OPA showed higher levels of high density lipoprotein (HDL; mean adj. diff. = 2.24 mg/dL; P = 0.004), lower levels of triglycerides (-24.59 mg/dL; P = 0.006), and total cholesterol (TC)/HDL ratio values (-0.21; P = 0.015) than reference. Women in the highest category of OPA had higher levels of HDL (2.85 mg/dL; P = 0.006), lower TC/HDL (0.27; P = 0.001), and low-density lipoprotein/HDL ratios (-0.18; P = 0.003) than sedentary activities. CONCLUSION: Individuals who performed high levels of OPA did not exhibit a worse cardiovascular risk profile and an improvement on selected biomarkers was observed when compared with those performing sedentary activities. PMID- 30020217 TI - Correlates of Occupational Heat-Induced Illness Costs: Case Study of South Australia 2000 to 2014. AB - OBJECTIVE: To investigate the profile of occupational heat-induced illness costs in South Australia and to examine the association with high temperature. METHODS: Workers' compensation claim data were used to quantify the associations between maximum temperature (Tmax) and occupational heat illness (OHI)-related costs, using time-series analysis after controlling for confounding factors. RESULTS: Four hundred thirty-eight OHI claims in 2000 to 2014 resulted in total medical costs of AU$6,002,840 and 5,036 work days lost. Relatively higher OHI burdens were found in men, those aged 25 to 44 years, new workers, medium-size businesses, and those employed in the mining industry. A 1 degrees C increase in Tmax above about 33 degrees C was associated with a 41.6% increase in medical costs and a 74.8% increase in days lost due to OHI, respectively. CONCLUSIONS: The cost profile of OHI may be used to justify interventions for particular industries, occupations, and worker categories. PMID- 30020218 TI - Redesigning Employee Benefits. PMID- 30020219 TI - The Effects of Lower Extremity Strengthening Delivered in the Workplace on Physical Function and Work-Related Outcomes Among Desk-Based Workers: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to assess the effectiveness of a workplace leg-strengthening program on self-reported function, physical capacity, and work related outcomes among desk-based workers. METHODS: Forty-three desk-based workers were randomized to a 12-week exercise program or no exercise control. The primary outcome was change in self-reported physical function on the Lower Extremity Functional Scale (LEFS) from baseline to follow-up. Secondary outcomes were physical capacity (mobility, strength), self-reported outcomes (pain, depressive symptoms), and work-related outcomes (resilience, work ability). RESULTS: The exercise group showed greater improvements in LEFS and mobility. No significant between-group differences existed in knee strength or remaining self reported and work-related outcomes. CONCLUSION: Workplace implemented leg strengthening exercises are effective at improving self-reported and physical health outcomes of desk-based workers. Moving forward, occupational exercise interventions may be essential to enhance worker longevity among the aging, sedentary workforce. PMID- 30020220 TI - Joint Association of Overweight and Common Mental Disorders With Diagnosis Specific Disability Retirement: A Follow-Up Study Among Female and Male Employees. AB - OBJECTIVE: We examined the joint association of overweight and CMDs (common mental disorders) with diagnosis-specific disability retirement among midlife employees. METHODS: Baseline surveys (n = 8960, response rate 67%) were linked with registers of the Finnish Centre of Pensions. We calculated the hazard ratios (HRs) for disability retirement due to any, musculoskeletal, and mental diagnoses according to the International Classification of Diseases (ICD-10) with Cox regression analysis (mean follow-up 8.3 years) among normal-weight (body mass index 18.5 to 25 kg/m) and overweight (>=25 kg/m) participants with or without CMD (General Health Questionnaire-12 score >=3). RESULTS: Overweight was associated with disability retirement due to any and musculoskeletal diagnoses and CMD with any and mental diagnoses. The risk for disability retirement was additively higher for those with both overweight and CMD. CONCLUSION: Preventing overweight and CMD, and especially considering those with both conditions simultaneously, likely helps maintain work ability. PMID- 30020221 TI - Genetic Polymorphism on Susceptibility to Nephrotoxic Properties of BTEXs Compounds. PMID- 30020222 TI - Reducing Lethal Force Errors by Modulating Police Physiology. AB - OBJECTIVES: The aim of this study was to test an intervention modifying officer physiology to reduce lethal force errors and improve health. METHODS: A longitudinal, within-subjects intervention study was conducted with urban front line police officers (n = 57). The physiological intervention applied an empirically validated method of enhancing parasympathetic engagement (ie, heart rate variability biofeedback) during stressful training that required lethal force decision-making. RESULTS: Significant post-intervention reductions in lethal force errors, and in the extent and duration of autonomic arousal, were maintained across 12 months. Results at 18 months begin to return to pre intervention levels. CONCLUSION: We provide objective evidence for a physiologically focused intervention in reducing errors in lethal force decision making, improving health and safety for both police and the public. Results provide a timeline of skill retention, suggesting annual retraining to maintain health and safety gains. PMID- 30020223 TI - EVAC versus REBOA in a Swine Model of Hemorrhage and Ischemia Reperfusion Injury. AB - BACKGROUND: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is effective at limiting hemorrhage from non-compressible sources and restoring, yet causes progressive distal ischemia, supraphysiologic pressures and increased cardiac afterload. Endovascular Variable Aortic Control (EVAC) addresses these limitations, while still controlling hemorrhage. Previous work demonstrated improved outcomes following a 90-minute intervention period in an uncontrolled hemorrhage model. The present study compares automated EVAC to REBOA over an occlusion period reflective of contemporary REBOA usage. METHODS: Following instrumentation, 12 Yorkshire-cross swine underwent controlled 25% hemorrhage, a 45-minute intervention period of EVAC or REBOA, and subsequent resuscitation with whole blood and critical care for the remainder of a six-hour experiment. Hemodynamics were acquired continuously and laboratory parameters were assessed at routine intervals. Tissue was collected for histopathologic analysis. RESULTS: No differences were seen in baseline parameters. During intervention, EVAC resulted in more physiologic proximal pressure augmentation compared to REBOA (101 mmHg vs 129 mmHg 95CI 105-151, p=0.04). During critical care, EVAC animals required less than half the amount of crystalloid (3450 ml 95CI 1215-5684 vs 7400 ml 95CI 6148-8642, p<0.01) and vasopressors (21.5 ng/kg 95CI 7.5-35.5 vs 50.5 ng/kg 95CI 40.5-60.5, p=0.05) when compared to REBOA animals. EVAC resulted in lower peak and final lactate levels. EVAC animals had less aortic hyperemia from reperfusion with aortic flow rates closer to baseline (36 ml/kg/min 95CI 30-44 vs 51 mL/kg/min 95CI 41-61, p=0.01). CONCLUSION: For short durations of therapy, EVAC produces superior hemodynamics and less ischemic insult than REBOA in this porcine controlled hemorrhage model, with improved outcomes during critical care. This study suggests EVAC is a viable strategy for in-hospital management of patients with hemorrhagic shock from non-compressible sources. Survival studies are needed to determine if these early differences persist over time. LEVEL OF EVIDENCE: 1 STUDY TYPE: Translational Science. PMID- 30020224 TI - A post-traumatic cervical hematoma with emphysema. PMID- 30020225 TI - Design and implementation of the Western Pennsylvania regional Stop the Bleed initiative. AB - BACKGROUND: Hemorrhage is the leading cause of preventable death in trauma, and nearly 40% of prehospital deaths can be attributed to blood loss. The Stop the Bleed program provides a structured curriculum for teaching hemorrhage control and the use of bleeding control kits. To overcome implementation barriers and to achieve the goal of making education on bleeding control as common as cardiopulmonary resuscitation, widespread implementation with outreach to the public and law enforcement is necessary. METHODS: We provide a description and analysis of the implementation of a regional Stop the Bleed program, which includes a step-by-step guide to the design of this program provided as a template to guide attempts at large-scale Stop the Bleed program development. RESULTS: Combining the efforts of regional trauma and nontrauma centers as a hub and-spoke design, a region covering four states, 72 counties, and 30,000 square miles was targeted. A total of 27,291 individuals were trained in a 21-month period including 3,172 trainers, 19,310 lay public, and 4,809 law enforcement officers. A total of 436 bleeding control kits were distributed to 102 public schools, and tourniquets were provided to 4,809 law enforcement officers. Program development and community outreach resulted in official recognition of the program by the Pennsylvania State Senate. CONCLUSIONS: With the use of a multicenter outreach program design with emphasis on law enforcement and public education while developing a train-the-trainer program, widespread and rapid dissemination of Stop the Bleed teaching is feasible. The general steps described in this manuscript may serve as a template for new or developing programs in other areas to increase the national exposure to Stop the Bleed. LEVEL OF EVIDENCE: Economic/Decision study, level IV. PMID- 30020226 TI - Tourniquet use is not associated with limb loss following military lower extremity arterial trauma. AB - BACKGROUND: The effect of battlefield extremity tourniquet (TK) use on limb salvage and long-term complications following vascular repair is unknown. This study explores the influence of TK use on limb outcomes in military lower extremity arterial injury. METHODS: The study database includes cases of lower extremity vascular injury from 2004 to 2012 with data recorded until discharge from military service. We analyzed all limbs with at least one named arterial injury from the femoral to the tibial level. Tourniquet (TK) and no TK (NTK) groups were identified. Univariate analyses were performed with significance set at p <= 0.05. RESULTS: A total of 455 cases were included, with 254 (56%) having a TK for a median of 60 minutes (8-270 minutes). Explosive injuries (53%) and gunshot wounds (26%) predominated. No difference between TK and NTK was present in presence of fracture, level of arterial injury, type of arterial repair, or concomitant venous injury. More nerve injuries were present in the TK group, and Abbreviated Injury Scale extremity and Mangled Extremity Severity Score tended toward greater injury severity. Amputation and mortality rates did not differ between groups, but the incidence of severe edema, wound infection, and foot drop was higher in the TK group. Vascular above-knee amputation, arterial repair complication, and severe edema were higher in the TK group also (p = 0.10). Tourniquet duration of 60 minutes or longer was not associated with increased amputations, but more rhabdomyolysis was present. CONCLUSION: Field TK use is associated with wound infection and neurologic compromise but not limb loss. This may be due to a more severe injury profile among TK limbs. Increased TK times may predispose to systemic, but not limb, complications. LEVEL OF EVIDENCE: Therapeutic/care management, level IV. PMID- 30020227 TI - Association of pain after trauma with long-term functional and mental health outcomes. AB - BACKGROUND: Chronic pain after trauma is associated with serious clinical, social, and economic burden. Due to limitations in trauma registry data and previous studies, the current prevalence of chronic pain after trauma is unknown, and little is known about the association of pain with other long-term outcomes. We sought to describe the long-term burden of self-reported pain after injury and to determine its association with positive screen for posttraumatic stress disorder (PTSD), functional status, and return to work. METHODS: Trauma survivors with moderate or severe injuries and one completed follow-up interview at either 6 months or 12 months after injury were identified from the Functional Outcomes and Recovery after Trauma Emergencies project. Multivariable logistic regression models clustered by facility and adjusting for confounders were used to obtain the odds of positive PTSD screening, not returning to work, and functional limitation at 6 months and 12 months after injury, in trauma patients who reported to have pain on a daily basis compared to those who did not. RESULTS: We completed interviews on 650 patients (43% of eligible patients). Half of patients (50%) reported experiencing pain daily, and 23% reported taking pain medications daily between 6 months and 12 months after injury. Compared to patients without pain, patients with pain were more likely to screen positive for PTSD (odds ratio [OR], 5.12; 95% confidence interval [CI], 2.97-8.85), have functional limitations for at least one daily activity (OR, 2.42; 95% CI, 1.38-4.26]), and not return to work (OR, 1.86; 95% CI, 1.02-3.39). CONCLUSIONS: There is a significant amount of self-reported chronic pain after trauma, which is in turn associated with positive screen for PTSD, functional limitations, and delayed return to work. New metrics for measuring successful care of the trauma patient are needed that span beyond mortality, and it is important we shift our focus beyond the trauma center and toward improving the long-term morbidity of trauma survivors. LEVEL OF EVIDENCE: Therapeutic/Care management, level III. PMID- 30020228 TI - Emergency general surgery in the United Kingdom: A lot of general, not many emergencies, and not much surgery. AB - BACKGROUND: The provision of emergency general surgery services is a global issue, with important implications for patients and workforce. The aim of this study was to analyze the characteristics of emergency general surgical patients in the United Kingdom, with reference to diagnostic case mix, operative workload, comorbidity, discharge destination, and outcomes, to facilitate comparisons and future service development. METHODS: This is a cross-sectional population-based study based in the National Health Service in Scotland, one of the home nations of the United Kingdom. All patients aged 16 or older admitted under the care of a general surgeon, as an emergency, to a National Health Service hospital in Scotland, in 2016, were included. RESULTS: There were 81,446 emergency general surgery admissions by 66,498 patients. Median episode age was 53 years. There were more female patients than male (55% vs 45%, p < 0.0001). The most common diagnoses were nonspecific abdominal pain (20.2%), cholecystitis (7.2%), constipation (3.4%), pancreatitis (3.1%), diverticular disease (3.1%), and appendicitis (3.1%). Only 25% of patients had operations (n = 20,292). The most frequent procedures were appendicectomy (13.1%), endoscopy (11.3%), and drainage of skin lesions (9.7%). Diagnoses and operations differed with age. Overall median length of stay was 1 day. With a 6-month follow-up, patients older than 75 years had a 19.8% mortality rate. CONCLUSIONS: Emergency general surgery in the United Kingdom is a high-volume, diagnostically diverse, and low-operative volume specialty with high short-term mortality rate in elderly patients. Consideration should be given to alternative service delivery models, which make better use of surgeons' skills while also ensuring optimal care for patients who are increasingly elderly and have complex chronic health problems. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 30020229 TI - Targeted Muscle Reinnervation in the Lower Leg: An Anatomical Study. AB - BACKGROUND: Targeted muscle reinnervation reroutes the ends of cut nerves to reinnervate small motor nerves of nearby muscles, with the goal of reducing neuroma pain and/or improving prosthesis function. Anatomical roadmaps for targeted muscle reinnervation have been established in the upper extremity and thigh, but not for the lower leg. METHODS: The major branch points of motor nerves and the motor entry points to muscles of the leg were dissected in five cadaver specimens. Leg length was defined as distance from the lateral femoral condyle to the lateral malleolus. The distances from the lateral femoral condyle to major branch points and motor entry points were recorded as percentages of leg length to identify targets for targeted muscle reinnervation. RESULTS: The tibialis anterior and extensor digitorum longus were both acceptable targets in the anterior compartment, with an average 4.4 motor entry points within 10 to 80 percent and 3.0 motor entry points within 20 to 80 percent leg length, respectively. The peroneus longus was the best target in the lateral compartment, with an average 5.8 motor entry points within 20 to 70 percent leg length. The gastrocnemius and soleus were both acceptable targets in the superficial posterior compartment, with an average 4.4 motor entry points within 0 to 40 percent and 6.2 motor entry points within 20 to 80 percent leg length, respectively for each muscle. The flexor digitorum longus was the best target in the deep posterior compartment, with an average 6.0 motor entry points within 30 to 90 percent leg length. CONCLUSIONS: Targeted muscle reinnervation is technically feasible in the lower leg. This cadaveric study provides a roadmap for incision placement and identification of motor nerve targets. PMID- 30020230 TI - Anatomical Basis of the Gastroepiploic Vascularized Lymph Node Transfer: A Radiographic Evaluation Using Computed Tomographic Angiography. AB - BACKGROUND: The omentum, nourished by the gastroepiploic vessels, has gained popularity as an option for vascularized lymph node transfer. The anatomy of the gastroepiploic vessels, omentum, and lymph nodes has not been investigated. The purpose of this article is to describe the right gastroepiploic artery and related structures by using computed tomographic angiography. METHODS: A retrospective analysis was conducted on 34 patients who underwent computed tomographic angiography. Statistical models were applied to identify right gastroepiploic artery and lymph node anatomical characteristics. RESULTS: The right gastroepiploic artery was identified in 33 of 34 patients. It was found to have a diameter of 2.49 +/- 0.66 mm at its origin. The gastroduodenal artery length before right gastroepiploic artery takeoff was 3.09 +/- 1.31 cm. Twenty five patients had lymph nodes in the right gastroepiploic artery lymphosome. There were 2.7 +/- 2.12 lymph nodes identified per patient. The distance from the right gastroepiploic artery origin to the most proximal lymph node was 3.99 +/- 2.21 cm. The distance from the gastroepiploic artery origin to the third lymph node was 9.12 +/- 5.06 cm. Each lymph node was within 7.00 +/- 6.2 mm of the right gastroepiploic artery. CONCLUSIONS: When using the right gastroepiploic artery donor site for vascularized lymph node transfer, the plastic surgeon should anticipate using a pedicle length of 4 cm, a total flap length of 9 cm, and 3 cm of surrounding tissue to obtain at least three lymph nodes for transfer. Computed tomographic angiography is an effective imaging modality that can be used for patient-specific surgical navigation before vascularized lymph node transfer. PMID- 30020231 TI - Comparison of Pediatric Intercalary Allograft Reconstructions with and without a Free Vascularized Fibula. AB - BACKGROUND: Lower extremity intercalary allograft reconstruction has traditionally been used to facilitate limb salvage. Combining the allograft with a free vascularized fibula graft has been described; however, there is a paucity of data comparing the outcome of these reconstructions. METHODS: Twenty-nine pediatric patients (15 boys and 14 girls) underwent lower extremity limb salvage with the use of intercalary cadaveric allograft at a mean age of 12 years. The most common diagnosis was osteosarcoma (n = 18). Patients underwent reconstruction with an allograft alone (n = 11) or supplemented with a free vascularized fibula graft (n = 18). RESULTS: The mean time to union of the allograft was 11 months, with 10 patients requiring additional bone grafting. There was no difference in the need for an additional bone graft (OR, 0.87; p = 1.0) between patients with a free vascularized fibula graft and those without. The allograft was revised in three patients because of fracture (n = 2) and fracture and infection (n = 1). In all of these patients, the allograft was not supplemented with a free vascularized fibula graft (p < 0.001). Five patients underwent an amputation, most commonly for disease recurrence. At last follow-up, the mean Mankin and Musculoskeletal Tumor Society rating was 90 percent, with 19 patients (66 percent) who achieved a "good" or "excellent" outcome according to the Mankin score. CONCLUSION: Use of an intercalary allograft to reconstruct a lower extremity provides a durable means of reconstruction; however, supplementation with a free vascularized fibula graft reduces the risk of allograft revision. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 30020232 TI - Correlation between Quantity of Transferred Lymph Nodes and Outcome in Vascularized Submental Lymph Node Flap Transfer for Lower Limb Lymphedema. AB - BACKGROUND: Vascularized lymph node transfer has shown promising results in the treatment of lower limb lymphedema, but little is known about the number of lymph nodes needed for the transfer to achieve optimal results. This study investigated the correlation between number of transferred lymph nodes in submental vascularized lymph node transfer and outcomes regarding limb circumference reduction and cellulitis incidence. METHODS: Thirty-five patients who had received vascularized submental lymph node transfer to an ankle for lower limb lymphedema following gynecologic cancer treatment were included in the study. Limb circumference was determined by means of tape measurement preoperatively and postoperatively and was used to calculate the circumferential difference. Ultrasonography was performed postoperatively to determine the number of lymph nodes within the transferred flap. Patients were divided into groups A through C depending on the number of transferred lymph nodes: 1 or 2 (n = 10), 3 or 4 (n = 14), and 5 to 8 (n = 11), respectively. RESULTS: The mean age of the patients was 60.0 +/- 9.2 years. All flaps survived. The mean improvement of circumferential difference for the whole cohort was 19.8 +/- 9.2 percent. Groups B and C both had significantly higher improvements in the circumferential difference than group A (p = 0.04 and p = 0.02, respectively), but when compared to each other, the difference was nonsignificant. All groups had significant reductions in the incidence of cellulitis postoperatively. CONCLUSIONS: Submental vascularized lymph node transfer for lower limb lymphedema reduced the incidence of cellulitis, regardless of the number of transferred lymph nodes. The transfer of three or more lymph nodes provided significantly better outcome regarding limb circumference reduction than the transfer of two or fewer lymph nodes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 30020233 TI - Nonvisualization of Sentinel Lymph Nodes by Lymphoscintigraphy in Primary Cutaneous Melanoma: Incidence, Risk Factors, and a Review of Management Options. AB - BACKGROUND: Lymphoscintigraphy is often performed before sentinel lymph node biopsy, especially in areas likely to have multiple or aberrant drainage patterns. This study aims to determine the incidence and characteristics of melanoma patients with negative lymphoscintigraphic findings and to review the management options and surgical recommendations. METHODS: This is a retrospective study of patients with primary cutaneous melanoma who underwent sentinel lymph node biopsy between 2005 and 2016. Patients with nonvisualized lymph nodes on preoperative lymphoscintigraphy were compared in a 1:4 ratio with a randomly selected unmatched cohort drawn from all melanoma patients who underwent preoperative lymphoscintigraphy within the period of the study. Demographic, clinical, and outcome data were compared between these groups. RESULTS: A negative lymphoscintigraphic scan was seen in 2.3 percent of all cases (25 of 1073). In both univariate and multivariate analyses, predictive patient- and tumor-specific factors for negative lymphoscintigraphy included older age and head and neck location. Patients with a nonvisualized sentinel lymph node had significantly worse overall survival compared with patients who had a visualized sentinel lymph node, but there was no difference in melanoma-specific survival. In 16 of the 25 cases (64 percent), at least one sentinel lymph node was found intraoperatively despite the negative lymphoscintigraphic findings. CONCLUSIONS: Older patients with head and neck melanomas are more likely to experience nodal nonvisualization on lymphoscintigraphy. In patients who have nodal nonvisualization, the surgeon should attempt sentinel lymph node biopsy at the time of excision of the primary lesion because a sentinel lymph node can still be found in a majority of cases, and it offers prognostic information. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 30020234 TI - Influence of Repaired Cleft Lip and Palate on Layperson Perception following Orthognathic Surgery. AB - BACKGROUND: Facial scarring and disharmony caused by clefting are associated with psychosocial stress, which may be improved by orthognathic surgery. The authors examine how clefting influences change in layperson perception of a patient following orthognathic surgery. METHODS: One thousand laypersons were recruited through Mechanical Turk to evaluate patient photographs before and after orthognathic surgery. Nineteen patients-five with unilateral and five with bilateral clefting-were included. Respondents assessed six personality traits, six emotional expressions, and likelihood of seven interpersonal experiences on a scale from 1 to 7. RESULTS: Changes in all aspects of social perception after the procedure differed significantly between cleft versus noncleft cohorts (p < 0.01 for all). Respondents evaluated the change for the cleft cohort compared with the noncleft cohort as more trustworthy, friendly, sad, and afraid; more likely to feel lonely, be teased or bullied by others, or feel anxious around others; less angry, disgusted, threatening, dominant, intelligent, happy, and attractive; and less likely to have romantic relationships, friends, or be praised by others. For unilateral versus bilateral cleft cohorts, change in social perception was significantly different in four of the 19 items (p < 0.05 for all). Social perception change for the unilateral cohort was less surprised, sad, dominant, or happy compared with the bilateral cohort (p < 0.05 for all). CONCLUSIONS: Despite significant improvements in social perception following orthognathic surgery, cleft patients benefit less than noncleft patients. These findings may be useful to counsel postsurgical expectations for cleft patients undergoing orthognathic surgery. PMID- 30020235 TI - Incidents of Mandibular Distraction Osteogenesis for Hemifacial Microsomia. AB - BACKGROUND: This study focused mainly on the safety and unexpected incidents of mandibular distraction osteogenesis in treating patients with hemifacial microsomia. METHODS: Records of 71 patients with hemifacial microsomia treated by mandibular distraction osteogenesis from February of 2010 to March of 2015 were examined in this retrospective study. The modified mandibular osteotomy was conducted under the assistance of three-dimensional reconstruction, computer aided design, and rapid prototyping technique. Distraction was conducted 4 to 7 days postoperatively at a frequency of 1 mm/day; moreover, the distractor was kept in place for 4 to 13 months after the first operation before it was removed. The scope of distraction ranged from 20 to 40 mm. All incidents encountered during and after the mandibular distraction process were documented in the medical records of patients. The patients were followed up for an average of 34.4 months after the second-stage operation. RESULTS: The overall rate of incidents was 36.6 percent. Of them, minor incidents, which could be resolved with or without noninvasive therapy, were observed in 18.3 percent of all procedures in this series. Meanwhile, the rate of moderate incidents necessitating invasive therapy was reported to be 12.7 percent, whereas that of major incidents that could not be resolved with invasive therapy was 5.6 percent. CONCLUSIONS: Mandibular distraction osteogenesis is a widely used procedure for treating patients with hemifacial microsomia. It is extremely important to be fully aware of a variety of incidents occurring during and after the surgical procedure to minimize the frequency of occurrence of such incidents. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 30020236 TI - Interposition Vein Grafting in Head and Neck Free Flap Reconstruction. AB - BACKGROUND: Many surgeons are hesitant to use interposition vein grafting in head and neck microvascular free flap surgery because of concerns for elevated risk of flap loss. METHODS: The authors conducted a review of patients who underwent head and neck free flap reconstruction between 2005 and 2015. The effect of vein grafts on flap compromise and flap loss was analyzed using univariate and multivariate models. RESULTS: A total of 3240 free flaps were performed. Vein grafts were used in 241 flaps (7.4 percent). The free flap compromise rate was 14.5 percent with vein grafts and 3.4 percent without vein grafts (p < 0.001). The free flap loss rate was 6.4 percent with vein grafts and 1.1 percent without vein grafts (p < 0.001). Radiation therapy, chemotherapy, prior neck dissection, prior free flap, osteoradionecrosis, and multiple free flap surgery were more frequent within the vein graft group (all p < 0.001). Despite this, vein grafting was associated with an increased risk of flap compromise (adjusted OR, 4.8; 95 percent CI, 3.2 to 7.3; p < 0.001) and flap loss (adjusted OR, 5.5; 95 percent CI, 3.0 to 10.2; p < 0.001) on multivariable analysis. Individual review of each flap loss within the vein graft group identified no cases of thrombosis caused by anastomotic technical errors, arguing against the requirement of an additional anastomosis as a cause for loss of vein-grafted free flaps. CONCLUSIONS: An increased risk of free flap compromise and loss is associated with use of vein grafts. However, a 93.4 percent success rate was still achieved in notably more challenging cases where vein grafting was deemed necessary taking into consideration the pertinent risks and benefits. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 30020237 TI - Long-Term Results in Isolated Metopic Synostosis: The Oxford Experience over 22 Years. AB - BACKGROUND: Metopic synostosis causing trigonocephaly is treated by fronto orbital advancement and remodeling to correct the deformity and cerebral distortion and to treat intracranial hypertension in a small number of cases. The aim of this study was to evaluate complications, revisions, and long-term outcomes. METHODS: A retrospective chart review was performed on consecutive metopic craniosynostosis patients treated between February of 1995 and February of 2017 at the Oxford Craniofacial Unit. RESULTS: Two hundred forty-five patients with isolated metopic synostosis were seen. Two hundred two patients underwent fronto-orbital advancement and remodeling. Fifty patients were girls and 152 patients were boys. Mean age at surgery was 16.8 months. Mean weight preoperatively was 12 kg. All patients received blood transfusion. Mean postoperative stay was 6 days. Average follow-up time was 8 years (range, 0.5 to 22 years). There were eight major complications (4 percent). Six patients (2.9 percent) required secondary calvarial expansion for late raised intracranial pressure. Thirty-one (15 percent) had other subsequent procedures, including wire removal and forehead shape contouring with alloplastic onlay. Raised intracranial pressure before surgery was confirmed in two cases by intracranial pressure monitoring. CONCLUSIONS: Trigonocephaly is caused by metopic synostosis and is treated by fronto-orbital advancement and remodeling to restore both internal and external skull configuration. After surgery, the authors identified a 2.9 percent risk of late raised intracranial pressure requiring a secondary calvarial expansion, necessitating prolonged follow-up in all cases. Temporal hollowing and forehead contour defects were not uncommon. This is the largest reported series of metopic synostosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 30020238 TI - Sphenoid Dysplasia in Neurofibromatosis: Patterns of Presentation and Outcomes of Treatment. AB - BACKGROUND: Sphenoid wing dysplasia in patients with neurofibromatosis type 1 may result in challenging and significant changes, including ultimately vision loss. The authors describe the radiographic patterns of sphenoid dysmorphology with time and age, and the impact of surgical intervention on preservation of vision. METHODS: A retrospective study was performed at a single pediatric hospital, identifying subjects with neurofibromatosis type 1. Records were reviewed in their entirety for each subject, with attention to ophthalmologic evaluation. Radiographic images were digitally analyzed and scored for sphenoid transformations on a grade of 0 to 3. RESULTS: Fifty-two subjects were identified. On initial imaging, 42.31 percent had a normal sphenoid (grade 0), 32.69 percent had an abnormal contour (grade 1), 11.54 percent had thinning (grade 2), and 13.46 percent had a gross defect (grade 3). Among the 45 subjects with serial imaging, 55.56 percent demonstrated progression of the deformity of at least one grade. Deformity progression correlated with length of imaging interval. Enucleation was noted to occur more often in subjects with a gross sphenoid defect (p < 0.0001). Of subjects identified as having a gross sphenoid defect, 26.7 percent were managed using orbitosphenoid reconstruction with titanium mesh and cranial bone graft, and 33.3 percent were managed with soft tissue debulking and canthopexy only. Vision was more likely to be preserved with early orbitosphenoid reconstruction (p < 0.05). CONCLUSIONS: Sphenoid dysplasia is a progressive disease. Loss of vision is associated with a gross defect, and appears to be better preserved with early orbitosphenoid reconstruction with titanium mesh and cranial bone graft. PMID- 30020239 TI - Association of general and central adiposity with blood pressure among Chinese adults: results from the China National Stroke Prevention Project. AB - BACKGROUND: The American Heart Association concluded that waist circumference was a better predictor of blood pressure risk than BMI in Asians. However, data are inconsistent and information in Chinese, the largest global population group, is limited. METHODS: Data was obtained from the Chinese National Stroke Prevention Project Survey of a nationally representative sample of middle-aged and older Chinese adults. A total of 135 825 individuals not taking any antihypertensive drugs were included in this study. Multiple linear regression analyses were conducted to examine the association between blood pressure and parameters of general adiposity, including BMI, height-adjusted weight, and parameters of central adiposity, including waist circumference, hip circumference, waist-hip ratio, and waist-height ratio. Results were shown as mean difference in blood pressure associated with one standard deviation higher level of adiposity. RESULTS: The overall means +/- standard deviation of BMI and waist circumference were 24.3 +/- 3.18 kg/m and 84.0 +/- 8.88 cm, respectively. BMI seemed more strongly associated with SBP/DBP (4.22 mmHg/SD; 2.60 mmHg/SD) than central adiposity markers. In addition, there were sex differences. For men, waist circumference showed a stronger association with SBP/DBP than BMI (4.04 vs. 3.79, P < 0.05; 2.26 vs. 2.13, P < 0.05). For women, BMI was more closely related to SBP/DBP than central adiposity parameters, such as waist circumference (4.59 vs. 3.41, P < 0.05; 2.98 vs. 2.24, P < 0.05). Additionally, in both urban and rural areas, waist circumference was mostly associated with SBP/DBP among men, whereas it was BMI among women. CONCLUSION: Compared with central adiposity, blood pressure is more strongly associated with general adiposity in Chinese adults. Interestingly, there are significant sex differences in the relationship of blood pressure with general and central adiposity. Waist circumference is the strongest predictor for men but suboptimal for women, and BMI tend to a better predictor of blood pressure for women. In addition, our results for men are consistent with the recommendation of the American Heart Association in 2015 that waist circumference could be used for assessing the risk of blood pressure. PMID- 30020240 TI - Supporting self-management for people with hypertension: a meta-review of quantitative and qualitative systematic reviews. AB - OBJECTIVES: Globally, healthcare policy promotes supported self-management as a strategy for people with long-term conditions. This meta-review aimed to explore how people with hypertension make sense of their condition, to assess the effectiveness of supported self-management in hypertension, and to identify effective components of support. METHODS: From a search of eight databases (January 1993-October 2012; update June 2017) we included systematic syntheses of qualitative studies of patients' experiences, and systematic reviews of randomized controlled trials evaluating the impact of supported self-management on blood pressure and medication adherence. We used meta-ethnography, meta-Forest plots and narrative analysis to synthesise the data. RESULTS: Six qualitative and 29 quantitative reviews provided data from 98 and 446 unique studies, respectively. Self-management support consistently reduced SBP (by between 2 and 6 mmHg), and DBP (by between 1 and 5 mmHg). Information about hypertension and treatment, home BP monitoring (HBPM) and feedback (including telehealth) were widely used in effective interventions. Patients' perceptions of a disease with multiple symptoms contrasted with the professional view of an asymptomatic condition. HBPM, in the context of a supportive patient-professional relationship, changed perceptions of the significance of symptoms and fostered confidence in ability to self-manage hypertension. CONCLUSION: Our systematic qualitative and quantitative meta-reviews tell complementary stories. Supported self-management can improve blood pressure control. Interventions are complex and encompass a broad range of support strategies. HBPM (with or without telehealth) within the context of a supportive patient-professional partnership can bridge the gap between medical and lay perspectives of hypertension and enable effective self-management. PMID- 30020241 TI - Association of imbalanced sex hormone production with excessive procoagulation factor SerpinF2 in preeclampsia. AB - BACKGROUND: Preeclampsia, a serious pregnancy-associated syndrome, is the leading cause of maternal and perinatal morbidity and mortality. Significant exacerbation of the hypercoagulation status as well as imbalanced steroid hormones have been reported in developed preeclampsia. However, it remains unclear whether the two pathological changes are directly associated. METHOD AND RESULTS: Our proteomic analysis revealed a significantly elevated SerpinF2/alpha2-antiplasmin level in preeclampsia plasma. Measurement of the longitudinally gestational change of plasmin-alpha2-antiplasmin (PAP) complex, testosterone, estradiol in preeclampsia patients and normal pregnant women demonstrated that the circulating PAP and testosterone levels in the early-onset preeclampsia (E-PE) patients were substantially higher, whereas estradiol concentration was significantly lower than that in normal pregnant controls from early pregnancy throughout gestation. Correlation analysis revealed that circulating PAP is in positive correlation with the concentration of testosterone, and in negative correlation with estradiol in E-PE patients. In E-PE placenta, the productions and activities of 17beta-hydroxysteroid dehydrogenases 3 and aromatase, the essential enzymes for testosterone and estradiol synthesis, were compromised. In human renal and trophoblastic cells, testosterone and estradiol could regulate SerpinF2 expression in opposite ways. In addition, obvious fibrin deposition was colocalized with SerpinF2 in intervillous spaces and the area surrounding syncytiotrophoblasts in E-PE placenta. CONCLUSION: The findings reveal a tight correlation between the imbalanced steroid hormone production and the procoagulation factor in E-PE patients, which provide potential biomarkers to predict preeclampsia, and bring new insight into the pathogenesis of preeclampsia. PMID- 30020242 TI - Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction. AB - AIM: Although abnormalities in reflex sympathetic neural function represent a hallmark of heart failure, no information is available on the neuroadrenergic and baroreflex function in heart failure with preserved, midrange and reduced ejection fraction. The current study was designed to assess muscle sympathetic nerve traffic (MSNA) and baroreflex function in the clinical classes of heart failure defined by the new European Society of Cardiology/American College of Cardiology Foundation/American Heart Association guidelines. METHODS: In 32 treated heart failure patients aged 69.3 +/- 1.1 (mean +/- SEM) classified according to new heart failure guidelines, we measured MSNA (microneurography), spontaneous baroreflex sensitivity and venous plasma norepinephrine (HPLC). Fourteen age-matched healthy individuals represented the control group. RESULTS: MSNA was progressively and significantly increased from controls to heart failure conditions characterized by preserved, midrange and reduced ejection fraction (40.4 +/- 2.5, 55.6 +/- 2.1, 70.4 +/- 3 and 78.6 +/- 2.6 bursts/100 heart beats, P < 0.01). In contrast, plasma norepinephrine was significantly increased in heart failure with reduced ejection fraction only. Baroreflex sensitivity was significantly reduced in the latter two clinical conditions and almost unaltered in heart failure with preserved ejection fraction. There was an inverse relationship between different markers of adrenergic activity (MSNA, heart rate and plasma norepinephrine), left ventricular ejection fraction and baroreflex function. Brain natriuretic peptides were directly and significantly related to MSNA and plasma norepinephrine. CONCLUSION: Thus clinical categories of heart failure patients defined by the new European Society of Cardiology/American College of Cardiology Foundation/American Heart Association classification share as a common pathophysiological link the marked overactivity of the sympathetic nervous system, whose magnitude is significantly and strongly related to the impairment of the left ventricular ejection fraction. A baroreflex dysfunction accompanies in the more severe heart failure state the neuroadrenergic activation. PMID- 30020244 TI - Fatal Refractory Ventricular Fibrillation Due to Ingestion of Hydrofluoric Acid. AB - Hydrofluoric acid (HF) is a colorless and odorless solution of the hydrogen fluoride in water. It is used in some household products. The rapid onset of severe toxicity and death after the ingestion of HF is not reported often. Also, there is no reported fatal pediatric case after HF ingestion. In this case report, we present a 3.5-year-old girls who unintentionally drunk a rust remover that contained 8% HF. She died in a short period as a result of refractory ventricular fibrillation, which was developed due to fluoride intoxication. PMID- 30020243 TI - Development and validation of subtype prediction scores for the workup of primary aldosteronism. AB - OBJECTIVES: A subtype prediction score for primary aldosteronism has not yet been developed and validated using a large dataset. This study aimed to develop and validate a new subtype prediction score and to compare it with existing scores using a large multicenter database. METHODS: In total, 1936 patients with primary aldosteronism were randomly assigned to the development and validation datasets, constituting 1290 and 646 patients, respectively. Three prediction scores were generated with or without confirmatory tests, using logistic regression analysis. In the validation dataset, new and existing prediction scores were compared using receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement analyses. RESULTS: The new prediction score is simply calculated using serum potassium levels [>3.9 mmol/l (four points); 3.5 3.9 mmol/l (three points)], the absence of adrenal nodules during computed tomography (three points), a baseline plasma aldosterone concentration of <210.0 pg/ml (two points), a baseline aldosterone/renin ratio of less than 620 (two points), and female sex (one point). Using the validation dataset, we found that a new subtype prediction score of at least 8 had a positive predictive value of 93.5% for bilateral hyperaldosteronism. The new prediction score for bilateral hyperaldosteronism was better than the existing prediction scores in the receiver operating characteristic curve and net reclassification improvement analyses. CONCLUSION: The new prediction score has clear advantages over the existing prediction scores in terms of diagnostic accuracy, feasibility, and the potential for generalization in a large population. These data will help healthcare professionals to better select patients who require adrenal venous sampling. PMID- 30020245 TI - Resuscitation With Ringer's Lactate Compared With Normal Saline for Pediatric Diabetic Ketoacidosis. AB - OBJECTIVE: The aims of this study were to describe the use of Ringer's lactate (LR) or normal saline (NS) for resuscitation among children with diabetic ketoacidosis (DKA) and compare the effect of fluid type on cost, length of stay, and rate of cerebral edema (CE). METHODS: This is a retrospective study of 49,737 children aged 0 to 17 years with DKA between January 1, 2005, and September 30, 2015, using data from the Pediatric Health Information System. Treatment with LR or NS was identified. Our primary outcomes were total adjusted cost and length of stay. Our secondary outcome was CE rate per 1000 episodes. RESULTS: The majority of patients were treated with NS (n = 43,841 [88%]) compared with LR (n = 1762 [4%]) or both NS and LR (n = 4134 [8%]). Hospital-year-specific practice patterns were used to investigate the effect of fluid type across resuscitation fluid groups. Total adjusted cost was $1160 less (95% confidence interval, -1468 to 852), or -14.2%, for cases with any episode of LR compared with NS only. Length of stay was not different across groups. The rate of cerebral edema per 1000 episodes was 12.7 for cases with any episode of LR compared with 34.6 NS only (difference, -21.9; 95% confidence interval, -30.4 to -13.3). CONCLUSIONS: Ringer's lactate was infrequently used for resuscitation of pediatric DKA patients. However, resuscitation with LR compared with NS was associated with lower total cost and rates of CE. Further investigation using patient-level clinical and laboratory data is needed to evaluate factors that drive cost and risk of CE development with each fluid. PMID- 30020246 TI - Factors Influencing Pediatric Emergency Department Visits for Low-Acuity Conditions. AB - OBJECTIVES: Emergency department (ED) overcrowding is a growing problem, and pediatric patients are contributing. In this study, we aimed to determine which factors influence parents or guardians to choose the ED over their primary care physician (PCP). METHODS: A cross-sectional, online survey was administered in an academic hospital pediatric ED from September to October 2017. The 21-question survey was offered to the parents or guardians of pediatric patients triaged as low acuity. The survey assessed establishment and availability of their PCP, perception of illness or injury severity, reasons for choosing the ED, and demographic information. RESULTS: A total of 101 surveys were collected, with a 95% completion rate. Most patients had an established PCP. More than two-thirds did not attempt to contact their PCP prior to their ED visit. Nearly half stated their PCP did not offer after-hours or weekend availability. Most did not feel their child's condition was serious. Almost half would have waited to see their PCP if they could be seen within 24 hours. CONCLUSIONS: There appears to be a common misperception that PCPs do not offer extended hours. In addition, the parent or guardian's perception of severity was oftentimes more serious than perceived by medical staff. These results suggest that improving health literacy among our patient population by educating them on PCP availability and capability, ancillary services offered by PCP, and appropriate usage of the ED could potentially reduce nonurgent ED visits. PMID- 30020247 TI - Elevated Heart Rate and Risk of Revisit With Admission in Pediatric Emergency Patients. AB - OBJECTIVE: The aim of this study was to identify emergency department (ED) heart rate (HR) values that identify children at elevated risk of ED revisit with admission. METHODS: We performed a retrospective cohort study of patients 0 to 18 years old discharged from a tertiary-care pediatric ED from January 2013 to December 2014. We created percentile curves for the last recorded HR for age using data from calendar year 2013 and used receiver operating characteristic (ROC) curves to characterize the performance of the percentiles for predicting ED revisit with admission within 72 hours. In a held-out validation data set (calendar year 2014 data), we evaluated test characteristics of last-recorded HR for-age cut points identified as promising on the ROC curves, as well as those identifying the highest 5% and 1% of last recorded HRs for age. RESULTS: We evaluated 183,433 eligible ED visits. Last recorded HR for age had poor discrimination for predicting revisit with admission (area under the curve, 0.61; 95% confidence interval, 0.58-0.63). No promising cut points were identified on the ROC curves. Cut points identifying the highest 5% and 1% of last recorded HRs for age showed low sensitivity (10.1% and 2.5%) with numbers needed to evaluate of 62 and 50, respectively, to potentially prevent 1 revisit with admission. CONCLUSIONS: Last recorded ED HR discriminates poorly between children who are and are not at risk of revisit with admission in a pediatric ED. The use of single-parameter HR in isolation as an automated trigger for mandatory reevaluation prior to discharge may not improve revisit outcomes. PMID- 30020248 TI - Prognostic Factors of Children Admitted to a Pediatric Intensive Care Unit After an Episode of Drowning. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic factors of patients admitted to a pediatric intensive care unit (PICU) after drowning. METHODS: Retrospective observational study from January 1992 to December 2004 and prospective study from January 2005 to December 2015 were conducted in a tertiary children's hospital PICU. The data analyzed refer to the patient, event, type of resuscitation performed, and clinical situation after resuscitation and at arrival to the PICU; results of additional tests; and clinical evolution and neurological status at discharge from the PICU (categorized as death, severe encephalopathy, or normal). The considered potential prognostic factors were whether drowning was witnessed, the type of initial resuscitation, Glasgow Coma Scale score at admission, pupil status and reactivity, and pH. RESULTS: One hundred thirty-one patients were registered. Mortality was 16.7%, and 8.3% had significant neurological sequelae. The clearest factor associated with poor outcome was the type of initial resuscitation performed. All patients who did not require cardiopulmonary resuscitation (CPR), or only basic CPR, had good outcomes; 96.3% of those who required advanced CPR with epinephrine administration had poor outcomes. Patients who needed advanced resuscitation with administration of epinephrine had lower temperature, Glasgow Coma Scale score, pH, and bicarbonate at admission and higher level of glucose. In this group, there was also a higher incidence of seizures, acute respiratory distress syndrome, hemodynamic compromise, and acute renal failure. CONCLUSIONS: The need for advanced CPR with epinephrine administration on the scene predicts poor neurological outcome (severe encephalopathy or death) in drowned children. PMID- 30020249 TI - Measuring Anxiety in the Pediatric Emergency Department. AB - OBJECTIVES: The objective of this study was to evaluate the agreement between the State Trait Anxiety Inventory (STAI) and other anxiety scales to determine whether these shorter to administer scales could replace the STAI. METHODS: This was a prospective cohort study on a convenience sample of children, aged 9 to 17 years, presenting to a pediatric emergency department. Patients were divided into 2 groups: preteens (PT) (aged 9-12 years) completed the pediatric STAI and teens (T) (aged 13-17 years) completed the adult STAI. Participants also completed a visual analog scale (0-100 mm), a Likert scale (1-5), and a short version of the STAI. Intraclass correlation (2-way mixed model, average measures) was used to evaluate agreement between the STAI and the other scales. A sample size of 100 patients per group was estimated as sufficient. RESULTS: The median (interquartile range) STAI state anxiety scores were 33 (28.25-36.75) and 37.5 (32-44), in the PT (n = 100) and T (n = 100) groups, respectively. The median (interquartile range) STAI trait anxiety scores were 33.5 (28-38.75) and 36 (31 44), in the PT and T groups, respectively. Agreements between the STAI and the other scales were poor for all scales. At best, the intraclass correlation was 0.71 for the agreement between the STAI and the short version of the STAI. CONCLUSIONS: There appears to be poor agreement between the STAI and the other scales designed to measure anxiety in children 9 to 17 years presenting to the pediatric emergency department. PMID- 30020250 TI - Practice Variation in Emergency Department Management of Children With Sickle Cell Disease Who Present With Fever. AB - OBJECTIVES: Urgent medical evaluation is recommended for patients with sickle cell disease (SCD) and fever. Clear recommendations exist regarding certain aspects of treatment, but other areas lack evidence. We determined practice variation for children with SCD presenting with fever to the emergency department (ED). METHODS: Retrospective chart review of children ages 3 months to 21 years with SCD presenting to the ED with fever greater than or equal to 38.5 degrees C in the ED or preceding 24 hours. Visits from 3 sickle cell centers were included. Outcomes included blood culture, complete blood count, antibiotic treatment, chest x-ray, urinalysis, electrolytes, and hospital disposition. Differences greater than 10% were considered clinically meaningful. RESULTS: The population included 14,454 visits, of which 4143 (29%) were febrile and met all inclusion criteria. A complete blood count and blood culture were obtained at 94% of visits, and antibiotics were given at 91%, with no differences among sites. Meaningful differences existed for disposition, with 52%, 43%, and 99% of patients admitted to the inpatient units at hospitals A, B, and C, respectively. Differences were seen in obtaining a urinalysis (33%, 17%, and 21%), electrolytes (2%, 50%, and 12%), and chest x-rays for patients 2 years and older (78%, 77%, 64%) for hospitals A, B, and C, respectively. CONCLUSIONS: Significant variation exists in the proportion of children who receive a urinalysis, electrolytes, chest x-ray, and, most importantly, admission to the hospital. These examples of practice variation represent potential opportunities to define best care practices for children with SCD presenting to the ED for fever. PMID- 30020251 TI - Congenital Vallecular Cyst as a Cause of Neonatal Stridor and Apnea. AB - An infant who presents with stridor and apnea constitutes a challenge for emergency physicians in terms of diagnosis and management. Among the rarest of causes for these symptoms, congenital vallecular cysts can cause devastating outcomes if left undiagnosed. Reported here is a case of intermittent episodes of stridor and apnea in a 4-day-old neonate with a previously undiagnosed vallecular cyst. The process by which the infant was stabilized, correctly diagnosed, and successfully treated for a life-threatening airway obstruction is explained. After a discussion of vallecular cysts, methods for preparing for and executing proper airway management in an infant who presents with apnea and stridor are considered. PMID- 30020252 TI - Decreasing sleep-related symptoms through increasing physical activity among Asian American midlife women. AB - OBJECTIVE: The beneficial effects of physical activities on sleep-related symptoms have been reported in the literature, and physical activity has been suggested as an efficient strategy to reduce sleep-related symptoms among midlife women. The effect of Web-based physical activity promotion programs on sleep related symptoms have, however, rarely been explored, especially among midlife racial/ethnic minority women. The purpose of this pilot study was to test the preliminary efficacy of a WPAPP on self-reported sleep-related symptoms and physical activity of Asian American midlife women. METHODS: This pilot study was a randomized repeated measures pretest/posttest control group study (14 in an intervention group and 12 in a control group). Multiple instruments were used to measure background characteristics (eg, sociodemographic and health status), sleep-related symptoms and physical activity experiences at pretest, post 1 month, and post 3 months. The data were analyzed using an intent-to-treat linear mixed-model growth curve analysis. RESULTS: After adjusting for covariates and random intercept, the intervention group showed a significant decrease in the total numbers of psychological (P = 0.0956) and total sleep-related symptoms (P = 0.0733) at post 1 month. Also, both groups showed a significant increase in physical activity (active living habits) at post 3 months (P = 0.0353). CONCLUSIONS: The WPAPP is potentially beneficial in decreasing Asian American midlife women's sleep-related symptoms and promoting their lifestyle physical activity. PMID- 30020253 TI - Risk factors for sexual dysfunction in BRCA mutation carriers after risk-reducing salpingo-oophorectomy. AB - OBJECTIVE: The aim of the study was to identify risk factors for sexual dysfunction in BRCA mutation carriers who have undergone risk-reducing salpingo oophorectomy (RRSO). METHODS: A cross-sectional study was performed. BRCA1/2 mutation carriers with and without RRSO were surveyed to determine sexual function (Female Sex Function Index [FSFI]), demographics, medical history, sleep quality, depression, and anxiety scores. Characteristics of patients with the lowest quartile of FSFI scores (<14 +/- 8.8) were analyzed to identify risk factors for the most severe phenotype. RESULTS: In the 804 women surveyed, 764 underwent RRSO. Of the 529 (69%) carriers with completed FSFI questionnaires in the RRSO cohort, sexual dysfunction was reported in 77.3%. Poor sleep (P = 0.002), hot flashes (P = 0.002), lack of current systemic hormone therapy (HT) use (P = 0.002), depression (P < 0.001), and anxiety (P = 0.001) were associated with sexual dysfunction. In adjusted analyses, depression (adjusted odds ratio [aOR] 2.4, 95% CI, 1.4-4.1) and hot flashes (aOR 1.9, 95% CI, 1.2-3.0) remained significantly associated with sexual dysfunction. Depression was also a significant risk factor for the most severe degree of sexual dysfunction (OR 2.1, 95% CI, 1.3-3.5) and had the greatest impact on Arousal and Satisfaction domain scores of the FSFI. Current systemic HT use seemed to decrease the risk for sexual dysfunction (aOR 0.6, 95% CI, 0.4-1.0). CONCLUSIONS: Sexual dysfunction is highly prevalent in BRCA mutation carriers after RRSO. Depression seems to be a significant risk factor for sexual dysfunction in this patient population and may be under-recognized and undertreated. Patient and provider education on sexual side effects after surgery and risk factors for sexual dysfunction is necessary to decrease postoperative sexual distress. HT may be associated with improved sexual function after surgery. PMID- 30020254 TI - Changes in carotid artery intima-media thickness 3 years after cessation of menopausal hormone therapy: follow-up from the Kronos Early Estrogen Prevention Study. AB - OBJECTIVE: Little is known regarding the progression of preclinical atherosclerosis upon cessation of menopausal hormone therapy (MHT). This study evaluated changes in carotid artery intima-media thickness (CIMT) in a subgroup of participants during 4 years and 3 years after the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: Of the women enrolled in KEEPS at Mayo Clinic (n = 118), a subset (n = 76) agreed to participate in this follow-up study. KEEPS MHT assignments were placebo (PBO), n = 33; transdermal 17beta-estradiol (tE2), n = 23; and oral conjugated equine estrogens group (oCEE), n = 20. CIMT was measured by B-mode ultrasonography. Longitudinal analysis of CIMT was performed using all available data from pre-, on-, and post-treatment periods. RESULTS: At 7 years, median age of participants was 60.2 years; median time since menopause was 8.5 years. The mean difference in rates of increase was significantly greater over the post- than on-treatment period within the oCEE group (0.010 [0.002 0.017] mm/y), but not within the PBO (0.006 [-0.001 to 0.012] mm/y; P = 0.072) or tE2 (0.002 [-0.005 to 0.010] mm/y; P = 0.312) groups. There were, however, no significant treatment differences in the linear trends over those intervals (P = 0.524). CONCLUSIONS: Cessation of MHT at the lower doses and formulations used in KEEPS did not appear to alter the trajectory of CIMT over a 3-year follow-up period. CIMT, however, increased in all groups over the entire 7-year timeframe as expected with age and timing of menopause possibly key contributors.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30020255 TI - Cosmetics and ocular allergy. AB - PURPOSE OF REVIEW: The purpose of this review was to explore recent developments in the study of ocular cosmetics, as they pertain to adverse reactions that can be attributed to them. RECENT FINDINGS: Immunologically mediated adverse reactions to cosmetics are most commonly the result of sensitization to preservatives, fragrances and dyes used in these products. Metals such as nickel, cobalt, chromium and lead are used in products such as eye shadows and eye liners as well as toy makeup sets in amounts greater than the recommended amount of 1 ppm. Cosmetics make up the majority of fragrance-induced contact dermatitis. Recently, a free smartphone app was developed by American Contact Dermatitis Society that holds promise in better enabling patients to utilize their patch test data while shopping for cosmetics. SUMMARY: Both immediate and delayed hypersensitivity reactions linked to cosmetics are often the result of sensitization to preservatives, fragrances and additives in the products themselves. Despite significant advances in our understanding of these reactions, further research will be necessary to elucidate the mechanisms behind these reactions and bring this knowledge to the bedside as to improve patient care with potential cosmetic-based related allergic disorders. PMID- 30020256 TI - Conjunctival provocation tests: prediction of seasonal allergy. AB - PURPOSE OF REVIEW: The conjunctival provocation test (CPT) is often used to clearly identify the specific allergen causing the symptoms of allergic rhinoconjunctivitis but also to assess the clinical efficacy of an allergen immunotherapy (AIT). As there is no consensus about its predictive value, the aim of this publication is to evaluate under which conditions the CPT can predict the symptom severity during the allergy season after previous AIT. RECENT FINDINGS: Three out of four randomized controlled trials (RCTs) showed a correlation between CPT reactivity and symptoms occurring under natural allergen exposure after previous AIT. Furthermore, one RCT found that performing the CPT 4 weeks after initiating AIT can identify early responders who also show a benefit during the season. Another RCT suggested that conducting the CPT prior to starting AIT can be used to identify patients who may benefit more from treatment than others. SUMMARY: The assessment of the reviewed literature led us to the conclusion that the CPT has a predictive value and can consequently be used to assess the efficacy of an administered AIT if performed according to a standardized challenge protocol with high-quality allergen extracts. PMID- 30020257 TI - Seasonal ocular allergy and pollen counts. AB - PURPOSE OF REVIEW: The purpose of the article is to provide a historical overview of literature regarding pollen sensitization and ocular allergy with an emphasis on developments that have occurred over the past 5 years. RECENT FINDINGS: Currently, pollen studies have examined the molecular and cellular pathways involved in initiating allergic conjunctivitis to find targets for therapeutics. Studies have also documented the threshold, linear increase and plateau point in the relationship between pollen levels and allergic conjunctivitis symptoms. SUMMARY: Traditionally, intact pollen grains are counted as a means of correlating patient symptoms to allergen exposure. However, establishing a dose response relationship between pollen grain exposure and allergic conjunctivitis has proven to be difficult. It has been observed that ocular allergies induce a two-fold response including early-phase and late-phase IgE-mediated reactions. Sensitization itself is a combination of pollen exposure over time in genetically predisposed individual. However, symptoms appear to reach an asymptotic point at which clinical severity plateaus. More studies are needed to clearly define differences in pollen sensitization by plant species. PMID- 30020258 TI - Topical antihistamines, mast cell stabilizers, and dual-action agents in ocular allergy: current trends. AB - PURPOSE OF REVIEW: To address the current trends of therapeutic mechanisms for treatment of allergic conjunctivitis (AC), based on topical antihistamines and mast cell stabilizers (MCS). RECENT FINDINGS: The antihistamine drug alcaftadine has H4 receptor inverse agonism, anti-inflammatory and MCS activities. The antihistamines levocabastine and azelastine are more effective than placebo in treatment of AC symptoms in randomized controlled trials (RCTs). The topical dual action antihistamines/MCS olopatadine, azelastine, ketotifen, and epinastine are commonly used in Europe and in the United States for mild subtypes of AC. For the main symptoms of AC, ocular itch and conjunctival hyperemia, epinastine 0.05% was superior to placebo, but equal or more effective than olopatadine 0.1%, while the later was more effective than ketotifen. High concentration olopatadine 0.77% had longer duration of action, better efficacy on ocular itch, and a similar safety profile to low-concentration olopatadine 0.2%. The new formulas of topical dual action agents present longer duration of action, leading to a decreased frequency of use. SUMMARY: The topical dual-action agents are the most effective agents treating signs and symptoms of mild forms of AC. There is superiority to the high concentration olopatadine drug over other agents on ocular itch, with prolonged effect when used once-daily. PMID- 30020259 TI - Adults and children with anaphylaxis in the emergency room: why it is not recognized? AB - PURPOSE OF REVIEW: Despite many international guidelines have been published in the last 10 years, anaphylaxis continues to be underdiagnosed, undernotified, and undertreated. Anaphylactic reactions in adults and children in emergency departments are frequently not recognized, leading to underutilization of epinephrine, and a higher risk of death. RECENT FINDINGS: A few studies have been recently published showing that educational intervention for both physicians and other healthcare professionals improve diagnosis and treatment of anaphylaxis. Moreover, the new International Classification of Diseases, 11th edition improved classification of anaphylaxis, making it easier to be notified. SUMMARY: Anaphylaxis is a life-threatening hypersensitivity reaction that is most frequently seen by emergency physicians and nurses than allergists or immunologists. Education seems to be best strategy to improve management of this severe condition. PMID- 30020260 TI - Globalization and anaphylaxis. AB - PURPOSE OF REVIEW: To understand the impact of globalization in the management of anaphylaxis and identify potential strategies to improve patients' care and prevention. RECENT FINDINGS: Developments in the field of anaphylaxis have been consistently following these globalization trends offering possibilities of collaborations of the allergy community and integrated international initiatives to reach quality care of allergic patients worldwide. SUMMARY: Globalization is the process of interaction and integration between people, companies, and governments worldwide. Developments in the field of anaphylaxis have been following these globalization trends offering possibilities of collaborations and integrated international initiatives to reach quality care of allergic patients worldwide. Complex disorders, such as anaphylaxis, have called for complex integrative strategies, leading to a new acceptance of outside traditions. Allergy is encouraging us to accept holistic and integrative medical practices as viable options. With the dissolution of multinational boundaries and the universal free access to information, the notion of holistic and global-based care is emerging as the new reality of the medicine. We strongly believe that the integrated action plan to the management and prevention of anaphylaxis, just possible through the globalization, is a key health, political and economical move that advocates for the best practice of allergology. PMID- 30020261 TI - The Epidemiology of Vestibular Migraine: A Population-based Survey Study. AB - OBJECTIVES: 1. Describe the epidemiology of vestibular migraine (VM) in the United States, using data from the 2008 National Health Interview Survey (NHIS). 2. Characterize the sociodemographic and clinical attributes of people with VM. STUDY DESIGN: Population-based nationwide survey study of US adults. PATIENTS: Adult respondents to the 2008 NHIS. MAIN OUTCOME MEASURES: The responses of participants in the 2008 NHIS balance and dizziness supplement (n = 21,781) were analyzed using statistical software. A case definition for VM was generated based on consensus criteria for diagnosis, and this was applied to the dataset to ascertain the prevalence, demographic, and clinical characteristics of VM. RESULTS: The 1-year prevalence of a dizziness or balance problem in the United States was 11.9% (2,490 respondents). Of respondents with dizziness, 584 (23.4%) met our case definition of VM, which represents a prevalence of VM in 2.7% of adults. There was a female preponderance (64.1%) and a slightly younger mean age (40.9 yr) for those with VM as compared with all respondents (51.7% females and 46.0 yr, respectively). Multivariate analysis showed that age less than 40, female sex, anxiety, depression, and prior head trauma were all associated with significantly increased odds of experiencing VM. Only 10% of subjects meeting criteria for VM were told that migraine was the cause of their dizziness. CONCLUSION: Using a representative database, we found a much higher prevalence of VM in the United States than previously reported. Results from this study indicate likely under-diagnosis of VM. PMID- 30020262 TI - Audiologic Manifestations of Marshall Syndrome. AB - OBJECTIVE: Marshall syndrome is a genetic disorder caused by mutations in the COL11A1 gene. This syndrome is characterized by skeletal, ophthalmologic, craniofacial, and auditory abnormalities. Hearing loss is among the main manifestations reported in this disorder being observed in approximately 80% of affected individuals.The present study aims to describe the audiologic characteristics of three members of a family with Marshall syndrome and also serves as a review of the literature. STUDY DESIGN: Family study. SETTING: Tertiary care otology and skull base center. PATIENTS: We report the audiologic findings in a family with Marshall syndrome consisting of a mother and her son and daughter. INTERVENTION(S):: The audiologic evaluation included tympanometry, acoustic reflexes testing, auditory brainstem response, transient otoacoustic emissions, pure-tone audiometry, speech audiometry in quiet, and conditioned play audiometry. These methods were applied according to the age of the patients. In addition, we provide a review of the English-language literature in an attempt to clarify the auditory phenotype of this syndrome. RESULTS: All 3 affected individuals had heterozygous c.3816+1G>A mutation in the splicing donor site of intron 50 of the COL11A1 gene. All three patients in our study had bilateral sensorineural hearing loss. Hearing impairment ranged from mild to moderate in the daughter, moderate in the son, and from mild to moderate in their mother. CONCLUSION: The majority of individuals with Marshall syndrome present early onset bilateral sensorineural hearing loss. Hearing impairment is usually detected in early childhood, progresses gradually, and becomes stable in late adulthood, with a severity ranging from mild to severe. PMID- 30020263 TI - Differentiation Between Intralabyrinthine Schwannoma and Contrast-enhancing Labyrinthitis on MRI: Quantitative Analysis of Signal Intensity Characteristics. AB - OBJECTIVE: Distinguishing intralabyrinthine schwannoma (ILS) from labyrinthitis is crucial in deciding patient management between surgery and medication; however, the clinical and radiological differentiation between ILS and labyrinthitis is difficult, especially when labyrinthitis shows contrast enhancement mimicking ILS on magnetic resonance imaging (MRI). This study aimed to evaluate the quantitative characteristics of signal intensity on 3T MRI for differentiating ILS from contrast-enhancing labyrinthitis (CEL). STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center. PATIENTS: Between July 2003 and June 2017, 9 subjects diagnosed with ILS (16 MRI cases) and 9 subjects diagnosed with CEL (9 MRI cases) were enrolled in the study. MAIN OUTCOME MEASURES: Normalized signal intensity on contrast-enhanced T1-weighted image (nCE T1), normalized signal intensity on T2-weighted image (nT2), and normalized signal intensity on contrast-enhanced fluid-attenuated inversion recovery image (nFLAIR) were measured and compared between ILS and CEL. The diagnostic performance of these values was assessed using receiver operating characteristic (ROC) analysis. RESULTS: In ILS, the nCE-T1 and the nT2 were significantly higher and lower, respectively, than in CEL (all, p < 0.05); and the nFLAIR did not significantly differ (p > 0.05). The maximal nCE-T1 achieved the highest area under the curve (AUC) in differentiating ILS and CEL, followed by the mean nCE T1, the mean nT2, and the maximal nT2. Combination of the nCE-T1 and the nT2 showed higher AUC than the nCE-T1 alone, but without statistical significance (p = 0.340). CONCLUSIONS: Quantitative measurement of the signal intensity on MRI can be a viable imaging tool for differentiating ILS from CEL. PMID- 30020264 TI - Intratympanic Gentamicin for Small Vestibular Schwannomas With Intractable Vertigo. AB - OBJECTIVE: To evaluate the objective and subjective effects of intratympanic gentamicin treatment in patients with small vestibular schwannomas who exhibit intractable vertigo. PATIENTS: Individuals diagnosed with small vestibular schwannomas who exhibited intractable vertigo were retrospectively reviewed. INTERVENTIONS: Intratympanic gentamicin injection. MAIN OUTCOME MEASURES: Vertigo control. RESULTS: Eight patients were included in the study. All patients achieved complete or substantial control of vertigo attacks while six patients reported residual imbalance. Three patients experienced significant hearing loss during therapy and follow-up. Only one patient showed a drop from Class B to Class C. Caloric tests and vestibular evoked myogenic potentials showed that all patients exhibited impaired peripheral vestibular function before treatment and that unilateral vestibular deafferentation was achieved during follow-up. Dizziness Handicap Inventory scores decreased over time, indicating an increase in the quality of life. CONCLUSIONS: Intratympanic gentamicin could provide an efficient approach to control intractable vertigo caused by small vestibular schwannoma. Before treatment, a complete physical examination, hearing level evaluation, vestibular function evaluation, and appropriate patient expectations are indispensable. PMID- 30020266 TI - A Prospective Randomized Crossover Study in Single Sided Deafness on the New Non Invasive Adhesive Bone Conduction Hearing System. AB - BACKGROUND: Recently, an adhesive bone conduction hearing system has been developed for conductive hearing loss or single-sided deafness (SSD). In SSD cases, this device may be a good solution for patients who are unsuitable for, or who do not wish to undergo, bone conduction implant or cochlear implant surgery. The study aimed to investigate the hearing outcomes with the adhesive hearing system in SSD. PURPOSE OF THE STUDY: The study aimed to investigate the hearing outcomes with the adhesive hearing system in SSD. METHODS: A randomized crossover study was conducted in 17 SSD participants, using CROS (contralateral routing of signals) hearing aid as a control. Following outcome measurements were administered after a two-week trial: 1) Speech, Spatial and Qualities scale, Audio Processor Satisfaction Questionnaire, and a custom-made questionnaire about the use of the system, 2) sound localization, 3) speech perception in noise. RESULTS: 70% of the SSD subjects reported that the adhesive hearing system was partially useful or better. Using the APSQ, the adhesive test device was evaluated equally as the control device. Sound localization improved with the adhesive test device and deteriorated with the control device. There was no improvement in speech perception in noise measured with the adhesive test device. Speech perception in noise (SSSDNNH) with the control device improved significantly. CONCLUSION: To the best of our knowledge, this is the first study to report on the outcomes of the new adhesive system. Users' satisfaction of the adhesive hearing system was found to be comparable to the control device. Since the hearing outcomes vary highly between patients, trials with applicable hearing systems are recommended in SSD patients. PMID- 30020265 TI - Human Otopathologic Findings in Cases of Folded Cochlear Implant Electrodes. AB - HYPOTHESIS: We hypothesize that human cases of cochlear implantation (CI) with folding of the electrode array will demonstrate greater degrees of intracochlear ossification, lower spiral ganglion neuron (SGN) counts, and poorer audiometric outcomes. BACKGROUND: CI electrode array folding, such folding of the proximal array, is a relatively common surgical complication that can occur with forceful electrode insertion and may be an important and avoidable factor affecting implant outcomes. However, otopathologic findings and audiologic outcomes of human cases where folding of the implant electrode array is observed remain undefined. METHODS: Specimens from a human temporal bone repository having undergone CI during life were evaluated. Specimens with folding of the electrode array on histological analysis constituted study cases. Electrode-matched specimens without array folding constituted controls. All specimens were examined by light microscopy and histopathologically described. Intracochlear fibrosis and osseous tissue, and SGN counts were measured. Pre- and postoperative word recognition scores were also compared. RESULTS: Cases with folded electrodes showed greater volumes of intracochlear osseous tissue than controls, which was most prominent in areas adjacent to array folding. Both cases and controls demonstrated similar amounts of fibrous tissue. Folded cases showed decreased SGNs when compared with the contralateral ear, whereas controls showed stable SGN populations between ears. In this small cohort, postoperative hearing outcomes were similar between groups. CONCLUSION: Atypical fibro-osseous changes and lower SGN counts are observed in cases of CI electrode folding. Future studies are necessary to determine if recognition and correction of folding can prevent long term intracochlear changes. PMID- 30020267 TI - The Application of Parametric Micro-Flow Imaging in the Evaluation of Liver Fibrosis. AB - This study aims to investigate the application of parametric micro-flow imaging in the evaluation of liver fibrosis. From March 2013 to February 2014, 117 participants were recruited in this research prospectively, which includes 97 patients (who have been infected with hepatitis B virus or/and hepatitis C virus and have undergone liver biopsy) and 20 healthy volunteers. Contrast agent was injected as a bolus via the antecubital vein for the participants. Dynamic images of intercostal liver were collected and then divided into 30-second (30s) group and 10-second (10s) group. Color coding and quantitative analysis were performed, and related parameters were obtained and analyzed with the stage of liver fibrosis. The comparison of parameters between the stages of liver fibrosis was that the value of 30s slope reduced and the value of 10s slope increased with the increasing fibrosis stages. The value of 30s ratio at 5 seconds and 10s ratio at 5 seconds both increased with the increasing fibrosis stages. Receiver operating characteristic curves were obtained to evaluate the cutoff values and diagnosibility of parameters to predict F2 and higher or F3 and higher of fibrosis stages. The results show that parametric micro-flow imaging has potential value of guiding antiviral therapy for patients with viral hepatitis and evaluating the degree of improvement in liver fibrosis. PMID- 30020268 TI - Transient Elastography Identifies the Risk of Esophageal Varices and Bleeding in Patients With Hepatitis B Virus-Related Liver Cirrhosis. AB - This study aimed to analyze the diagnostic accuracy of liver stiffness for predicting esophageal variceal grading and the risk of esophageal variceal bleeding (EVB) in cases of cirrhosis. Hematological and biochemical parameters were measured and transient elastography was performed in 88 patients with hepatitis B-related cirrhosis undergoing endoscopy for esophageal varices. Esophageal varices grade was highly correlated with liver stiffness measurement (LSM) and the liver stiffness spleen diameter-to-platelet score in cirrhosis. Compared with those from endoscopy, the LSM and the liver stiffness spleen diameter-to-platelet score for the absence of esophageal varices were as follows: area under the receiver operating characteristic curve (AUROC), 0.894/0.926; sensitivity, 0.836/0.818; and specificity, 0.875/1.000, respectively. The AUROC and the sensitivity and specificity of LSM and the liver stiffness spleen diameter-to-platelet score for predicting grade III esophageal varices were 0.954 and 0.901, respectively. The AUROCs of LSM and the liver stiffness spleen diameter-to-platelet score for discriminating grades II and III from grade I or the absence of esophageal varices were 0.958 and 0.941, respectively. We also found that EVB was closely associated with LSM and spleen diameter. The AUROC, sensitivity, and specificity were 0.855/0.819, 0.857/0.875, and 0.747/0.780, respectively. Meanwhile, LSM and spleen diameter were 2 independent factors for predicting EVB. These data suggest that LSM and the liver stiffness spleen diameter-to-platelet score could accurately rule out cirrhosis without esophageal varices and differentiate high- and low-risk patients. Furthermore, LSM and spleen diameter had excellent abilities to predict EVB. PMID- 30020269 TI - Contrast-Enhanced Ultrasound of Spermatic Cord and Retroperitoneal Liposarcoma. AB - Liposarcoma is the most common paratesticular scrotal malignancy. Ultrasound is the conventional imaging modality for evaluating scrotal masses. Contrast enhanced ultrasound (CEUS) can provide complementary information by identifying distinct enhancement patterns. We present CEUS findings of 2 concurrent soft tissue masses in 1 patient: a spermatic cord well-differentiated liposarcoma and a retroperitoneal dedifferentiated liposarcoma. We review the Doppler ultrasound, computed tomography, and histopathologic appearances of low- versus high-grade liposarcomas in addition to the utility of CEUS with quantitative analysis in potentially grading liposarcomas. PMID- 30020270 TI - Carotid Ultrasound Examinations: Indications Correlated With Abnormal Findings. AB - Our purpose was to evaluate the clinical indications for carotid duplex ultrasonography and determine for each indication how often carotid artery disease was identified.We retrospectively reviewed the consecutive reports for 3191 carotid ultrasound examinations. We tracked 14 indications to determine how often examinations were requested for each indication and correlated each indication with the finding of carotid artery disease.We found 26.5% of all examinations were abnormal; 17.5% of patients showed internal carotid artery disease; 10.9%, a moderate stenosis; 5.2%, a severe stenosis; and 1.4%, a total occlusion. For each of the 14 individual indications, with 1 exception, carotid ultrasound examination showed a 19.7% or greater chance of an abnormal result and an 11.6% or greater chance of finding a flow-limiting stenosis of an internal carotid artery.Our results validate the collaborative position of the American College of Radiology, the American Institute of Ultrasound in Medicine, the Society for Pediatric Radiology, and the Society of Radiologists in Ultrasound that, overall and for almost all indications they enumerate, carotid ultrasound examinations are a proven and useful procedure for evaluating extracranial carotid artery disease. PMID- 30020271 TI - The High-Frequency Ultrasound Detection of Rat Sciatic Nerve in a Crushed Injury Model. AB - OBJECTIVE: This study aimed to visualize sciatic nerve injury in rats using ultrasound imaging in a crushed injury model. METHODS: Adult male Sprague-Dawley rats were subjected to a left sciatic nerve crush operation. Then, high-frequency ultrasound was used to image both sciatic nerves at 2 days and at 1, 2, 3, 4, and 6 weeks after surgery. RESULTS: Normal uninjured nerves have uniform thickness, display a smooth epineurium and inner adventitia, and are oblong in transverse sections. After the crush operation, nerve thickness increased, the inner echo signal decreased, the image of the epineurium became obscured and coarse before becoming smooth again, and transverse sections of the nerve fibers changed from being semicircular to oval in shape before becoming elliptical again. These observations were consistent with pathological changes associated with nerve injury. CONCLUSIONS: High-frequency ultrasound is capable of capturing dynamic changes in rat sciatic nerves in a crushed injury model. This can be used as an auxiliary method of evaluation in traditional peripheral nerve injury experiments. PMID- 30020272 TI - Hepatitis C-Associated B-cell Non-Hodgkin Lymphoma: A Pictorial Review. AB - BACKGROUND AND PURPOSE: Hepatitis C virus (HCV) can induce both hepatic and extrahepatic malignancies. A strong association between HCV and non-Hodgkin lymphomas (NHLs) has been demonstrated. The purpose of this article is to give emphasis on the clinical and imagistic particularities of the hepatitis C associated NHL, revealing the importance of ultrasonography in discovering and characterizing splenic masses. METHODS: We present the cases of 3 women (aged 72, 61, and 56 years, respectively), all of which had a history of chronic hepatitis C and were subsequently diagnosed with different forms of lymphoma. In all 3 cases, conventional ultrasound exploration showed inhomogeneous splenomegaly. Contrast-enhanced ultrasound and computerized tomography were performed soon after admission, both clinical and imaging findings leading to the suspicion of lymphoma. The bone marrow biopsy was relevant for the diagnosis lymphoma in 2 patients, whereas the third woman only presented age-related changes in cellularity. Splenectomy was later performed in this case, for both diagnostic and therapeutic purposes; histopathological examination and immunohistochemistry revealed malignant non-Hodgkin diffuse large B-cell lymphoma. CONCLUSIONS: The cooccurrence of HCV infection and splenic lymphoma is a frequently encountered scenery. Ultrasonography, both conventional and contrast-enhanced, plays an important role in the exploration of the spleen, representing a first-line imagistic method and a valuable means of characterizing different types of splenic lesions. IMPLICATIONS FOR PRACTICE: This article states the importance of ultrasonographic evaluation regarding the splenic pathology, by revealing clinical and imagistic findings in 3 cases of hepatitis C-associated lymphoma. PMID- 30020273 TI - The Extended Fetal Cardiac Examination: Is It Feasible in a High-Risk Practice? AB - The aims of this study were to demonstrate the feasibility of obtaining additional cardiac views as proposed on an extended fetal cardiac examination and to see if there was any variation in individual components of that examination stratified by sonographer training, patient body habitus, or equipment. We retrospectively reviewed 200 consecutive detailed second-trimester high-risk fetal obstetric sonograms that included additional extended cardiac views. We analyzed the percentage of the time individual views were obtained, with variation based on (1) a sonographer with greater than 3 years of training compared with a group with 6 to 12 months of training, (2) 2 different ultrasound units, and (3) different body mass indices. Overall, the highest rate of visualization was achieved with the 4-chamber view (98.2%), whereas the 3-vessel tracheal view had the lowest percentage of visualization (40.2%), among the less experienced sonographers. Differences in successful completion of the extended cardiac views were not statistically different between the sonographer with a level of training greater than 3 years as compared with those with 6 to 12 months' training except for the 3-vessel tracheal view (P < 0.001). There is no statistically significant difference in our ultrasound equipment, when considering only inexperienced sonographers. Increasing body mass index had an inverse relationship with obtaining the components of the detailed cardiac examination. Using state-of-the-art ultrasound equipment and with focused additional training of obstetric sonographers, the majority of extended cardiac views can be obtained. There are exceptions. PMID- 30020274 TI - Effectiveness of Bedside Lung Ultrasound for Clinical Follow-Up of Primary Spontaneous Pneumothorax Patients Treated With Tube Thoracostomy. AB - Primary spontaneous pneumothorax (PSP) is a common cause of presentation to emergency departments and subsequent hospitalization. Patients with large PSP are treated with tube thoracostomy (TT) and followed up with x-rays. In this study, we investigated the efficiency of bedside ultrasound and compared it with x-ray imaging for the clinical follow-up of PSP patients treated with TT.This is a prospective observational study. After ethical committee approval and written informed consent were obtained, patients who were treated with TT because of PSP were screened. In the follow-up of these patients, a bedside lung ultrasound (BLUS) was performed before every chest x-ray by an emergency physician experienced in performing BLUSs. The performance of BLUSs in detecting free air in the pleural cavity was compared statistically with that of x-rays.Sixty-two patients were enrolled in the study. In total, 166 BLUSs and x-rays were compared. The sensitivity of BLUS was 95.65% (85.20-99.50), specificity was 100% (79.40-100.00), positive predictive value was 100% (92-100), negative predictive value was 88.90% (65.30-98.60), and the area under the curve was 0.99 (0.974 1.000; P = 0.001) for detecting air in the pleural cavity. These results showed that there was no statistically significant difference between BLUS and x-ray methods for detecting air in the pleural cavity.Our study revealed that BLUS can be safely used for the follow-up of PSP patients treated with TT to determine if air is present in the pleural cavity. Further studies are needed. PMID- 30020275 TI - HIV DNA: a clinical marker of HIV reservoirs. AB - PURPOSE OF REVIEW: A number studies are currently underway to develop new drugs aimed at reducing the HIV reservoir or achieving ART-free control of HIV infection. Many markers of HIV reservoirs have been proposed, each one having a different meaning. Total HIV DNA dynamics during the course of HIV infection and its predictive value are now well known. This marker allowed to estimate the size of HIV reservoir at different stages of HIV infection in blood, cell subsets and tissues. Therefore, the purpose of this review is timely and relevant, with the objective to discuss how total HIV DNA might be helpful in the clinical settings. RECENT FINDINGS: Among the markers, it appears that HIV DNA is the most well studied, and recent articles confirmed that this marker is easy to use and is precise, specific, practical, robust and reproducible. All these characteristics correspond to what is expected from a helpful clinical marker. SUMMARY: HIV DNA level could be considered as a global marker, and it is usually included in current clinical studies to describe the persistence and dynamics of the HIV reservoir, mainly in treated patients. HIV DNA might be helpful in designing clinical trials and personalized medication for HIV patients in the future. PMID- 30020276 TI - Clinical and Radiological Outcome of a new Total Cervical Disc Replacement Design. AB - STUDY DESIGN: Non-randomized prospective and single center clinical trial of the ProDisc Vivo prosthesis. OBJECTIVE: Investigate the clinical and radiological results of a refined cTDR - the ProDisc Vivo - with two years of follow up (FU). The incidence of implant-related complications was recorded as a secondary outcome variable. SUMMARY OF BACKGROUND DATA: Previous generations of the ProDisc artificial cervical disc replacement generate high primary stability due to keel based designs with opening of the anterior cortex during the implantation and subsequent high rates of heterotopic ossifications. METHODS: Clinical outcome scores included the Neck Disability Index (NDI), Visual Analogue Scale (VAS), arm and neck pain self-assessment questionnaires. The radiological outcome included the range of motion (ROM) and the occurrence of heterotopic ossifications. The incidence of implant-related complications with new implant design was recorded as a secondary outcome variable. RESULTS: A total of 55 patients received a single level treatment with the ProDisc Vivo cTDR between C3/4 and C6/7, with a follow up rate of 78%. The clinical outcome scores improved in all parameters significantly (p = 0.0001) (NDI: 68.3 -> 17.4; VAS arm: 6.3 -> 1.4; VAS neck: 4.9 -> 1.6). The ROM of the index-segment didn't show a significant change (p = 0.26) (7.9 degrees -> 9.2 degrees ). Heterotopic ossifications at the index segment was found as grade 0 in 58%, grade 1 in 22%, grade 2 in 10%, grade 3 (with functional impairment of the prosthesis) in 7% and grade 4 in 3% of the cases. We observed three implant-related complications (5.5%), with two implant dislocations anteriorly and one low-grade infect. CONCLUSION: cTDR with ProDisc Vivo demonstrated a significant and sustained improvement of all clinical outcome parameters. A less-invasive implantation mechanism with lower primary stability of the cTDR might be a reason for a higher dislocation rate compared to the keel based previous generation ProDisc C. LEVEL OF EVIDENCE: 4. PMID- 30020278 TI - Synthesis of glycerol carbonate over a 2D coordination polymer built with Nd3+ ions and organic ligands. AB - In this work, a two-dimensional coordination polymer was synthesized and the structure was determined by single-crystal X-ray diffraction. The crystal structure belongs to the space group Pna21 and was characterized by Raman and FT infrared spectroscopy, powder X-ray diffraction and Brunauer-Emmett-Teller surface area analysis. Catalyst activities were evaluated through the synthesis of glycerol carbonate from glycerol and urea using a batch reactor. After the optimization of both reaction and reaction conditions, the activity results showed that the coordination polymer used as a heterogeneous catalyst has good values of conversions and selectivity for the manufacturing of glycerol carbonate in a fine-chemical process. The analysis of powder X-ray diffraction and spectroscopy for the coordination polymer employed, before and after the reaction, shows that some changes have taken place in the crystal structure during the process, in spite of a recovery at the end of the reaction. The advantages and limitations of the coordination polymer were discussed and compared with those of the previous heterogeneous catalysts in the literature. PMID- 30020277 TI - Impact of Adult Scoliosis on Roussouly's Sagittal Shape Classification. AB - STUDY DESIGN: Retrospective analysis of data collected prospectively in an adult spine deformity multicenter database. OBJECTIVE: To determine the impact of adult scoliosis (AS) on the type of Roussouly's sagittal shape in terms of classification applicability, scoliosis modification of a patient theoretical sagittal shape, and coronal-sagittal deformity associations. SUMMARY OF BACKGROUND DATA: Roussouly described a 4-type sagittal shape classification in healthy individuals, which has been also applied to patients with degenerative spinal disease. However, it remains uncertain if its principles can be applied to AS patients. METHODS: AS patients recorded in a prospective multicenter database of adult spinal deformity were included. Preoperative sagittal radiographs were analyzed using the KEOPS software to measure pelvic parameters, global sagittal alignment, and the various criteria used for the Roussouly classification. The different sagittal shape types were compared using the chi-square and McNemars tests, and ANOVA with Bonferroni correction. RESULTS: The classification was applicable to all of the 190 analyzed AS patients. In addition to Roussouly's criteria, 2 parameters helped differentiate the different shapes: T10-L2 angle (24 degrees +/- 19 type-1; 14 degrees +/- 15 type-2; 3 degrees +/- 15 type-3; 0.4 degrees +/- 14 type-4; P < 0.001), and lordosis distribution index (90% +/- 17 type-1; 83% +/- 16 type-2; 73% +/- 21 type-3; 63% +/- 16 type-4; P < 0.001). AS changed the theoretical shape in 34% of the patients (P < 0.001). Curve etiology and curve pattern were not associated with any particular type of sagittal shape (P > 0.05). Type-1 was associated with older patients (P = 0.02), degenerative curves (P = 0.02), and greater PI-LL mismatch (P = 0.012). Types 3-4 were associated with younger age and idiopathic etiology (P < 0.001). CONCLUSIONS: Roussouly's 4-type sagittal shape classification could be applied to AS patients. AS modified the theoretical type in 1 of every 3 patients. No particular association was found between the sagittal types and specific coronal deformities. Sagittal shape recognition in patients with AS will help restore the appropriate theoretical shape trough surgery, which can eventually lead to better surgical outcomesLevel of evidence: 4. PMID- 30020279 TI - Remote activation of nanoparticulate biomimetic activity by light triggered pH jump. AB - Herein, we report a facile, efficient and versatile method for the photo regulation of pH-dependent activities of artificial enzymes by incorporating flash photolysis reagents. Under light excitation, a persistent pH shift is achieved by proton release from photosensitive 2-nitrobenzaldehyde. Following such change, the controlled activation of oxidase-like activity of nanoceria is successfully demonstrated. PMID- 30020280 TI - Halogen-atom effect on the ultrafast photodissociation dynamics of the dihalomethanes CH2ICl and CH2BrI. AB - A comparative study of the ultrafast photodissociation dynamics of the dihalomethanes CH2ICl and CH2BrI has been carried out at 268 nm, around the maximum of the first absorption band, employing femtosecond velocity map ion imaging in conjunction with high level ab initio electronic structure calculations and full dimension on-the-fly trajectory calculations including surface hopping. Total translational energy distributions and angular distributions of the iodine fragments as well as reaction times for the C-I bond cleavage are presented and discussed along with the computed absorption spectra, potential energy curves and trajectories. The revealed dynamics is mainly governed by absorption to the 5A' state for CH2BrI while two dissociation pathways, through the 4A' or 5A' states, are in competition for CH2lCI. An anchor effect due to the substituent halogen atom (Br or Cl), which implies significant rotational motion of the dissociating molecule, characterizes the photodissociation in both dihalomethanes and leads to a remarkable rotational energy of the radical co-fragment. This energy flux into the internal degrees of freedom of the molecules is the main key factor governing the real time reaction dynamics. PMID- 30020282 TI - Fluorescence anisotropy in indole under two-photon excitation in the spectral range 385-510 nm. AB - This paper presents the detailed study of two-photon excited fluorescence in indole dissolved in propylene glycol produced by two-photon absorption from the molecular ground state to several high lying excited states. The experimental method involved excitation with linearly and circularly polarized femtosecond pulses and time-resolved detection of the polarized fluorescence decay. The fluorescence intensity, anisotropy, excited state lifetime, and rotation diffusion time as function of the excitation light wavelength in the spectral range 385-510 nm were determined in experiment. The theoretical fit of the experimental results obtained demonstrated the contributions of six highly excited molecular states of different symmetry to the two-photon absorption intensity and fluorescence anisotropy. An intense two-photon absorption peak was observed experimentally in the spectral range 385-480 nm and explained as contributions from four high lying electronic excited states. The temporal dependence of fluorescence intensity in indole was satisfactory characterized by a single excited state lifetime tauf and a single rotational diffusion time taurot. As shown, the excited state lifetime tauf depends on the excitation light wavelength, which was explained by taking into account nonradiative relaxation transitions in the molecular vibronic excited states. The rotation diffusion time taurot was found to be equal to taurot = 0.9 +/- 0.5 ns and practically independent of the excitation wavelength. The determined molecular anisotropy changed substantially in the spectral area 385-480 nm taking positive and negative values, and the anisotropies referring to linearly and circularly polarized excitation light changed almost in opposite phases with each other. The experimental results obtained were interpreted using ab initio molecular structure computations and a model based on the Frank-Condon approximation and taking into account vibronic absorption bands. PMID- 30020281 TI - Impact of the lanthanide contraction on the activity of a lanthanide-dependent methanol dehydrogenase - a kinetic and DFT study. AB - Interest in the bioinorganic chemistry of lanthanides is growing rapidly as more and more lanthanide-dependent bacteria are being discovered. Especially the earlier lanthanides have been shown to be preferentially utilized by bacteria that need these Lewis acids as cofactors in their alcohol dehydrogenase enzymes. Here, we investigate the impact of the lanthanide ions lanthanum(iii) to lutetium(iii) (excluding Pm) on the catalytic parameters (vmax, KM, kcat/KM) of a methanol dehydrogenase (MDH) isolated from Methylacidiphilum fumariolicum SolV. Kinetic experiments and DFT calculations were used to discuss why only the earlier lanthanides (La-Gd) promote high MDH activity. Impact of Lewis acidity, coordination number preferences, stability constants and other properties that are a direct result of the lanthanide contraction are discussed in light of the two proposed mechanisms for MDH. PMID- 30020286 TI - Photoelectron shake-ups as a probe of molecular symmetry: 4d XPS analysis of I3- in solution. AB - A combination of multi-configurational restricted active space calculations with a Dyson orbital formalism has been applied for accurate simulations of 4d photo electron spectra of the I3- molecular ion. The analysis based on the occupation numbers of natural orbitals allowed to predict and rationalize the spectral fingerprints of solvent-induced nuclear asymmetry. In particular, it demonstrates how the nuclear asymmetry directly causes an increase of shake-up intensity. The relative intensity of shake-up and main features of the I 4d XPS spectrum could therefore serve as a simplified experimental observable of structural asymmetry, complementary to changes in the shape of the main spectral features. PMID- 30020284 TI - Structural differences between toxic and nontoxic HypF-N oligomers. AB - We have studied two misfolded oligomeric forms of the protein HypF-N, which show similar morphologies but very different toxicities. We measured over 80 intermolecular distance-dependent parameters for each oligomer type using FRET, in conjunction with solution- and solid-state NMR and other biophysical techniques. The results indicate that the formation of a highly organised hydrogen bonded core in the toxic oligomers results in the exposure of a larger number of hydrophobic residues than in the nontoxic species, causing the former to form aberrant interactions with cellular components. PMID- 30020291 TI - Pushing the cycling stability limit of hierarchical metal oxide core/shell nanoarrays pseudocapacitor electrodes by nanoscale interface optimization. AB - Three-dimensional hierarchical metal oxide core/shell nanowire arrays (HMONAs) have become promising pseudocapacitive materials due to their integrated smart architectures. However, these core/shell nanostructures have unsatisfactory structural stability and frequently suffer destruction during their fabrication process and their charge-discharge cycles, thus limiting their application lifespan. Herein, a general strategy based on the minimization of the lattice mismatch between the shell and the backbone at the nanoscale interface has been proposed to improve the cycling stability of the HMONAs. This strategy is achieved by a facile hydrothermal pretreatment under mild acidic condition, where a selective dissolution process occurs for interface optimization. To prove the concept, three typical HMONAs, alpha-MnO2 nanotube@delta-MnO2 nanosheet core/shell arrays, alpha-MnO2 nanotube@NiO nanosheet core/shell arrays and Co3O4@MnO2 core/shell nanoarrays, were synthesized for interface optimization. It was found that these thermodynamically unstable nanostructures in the shells of HMONAs can be selectively dissolved under a hydrothermal process, leading to enhanced stability of HMONAs. The comparison study indicates that all treated HMONAs exhibit excellent capacitance retention of 93.2% (MnO2@MnO2), 94.3% (MnO2@NiO) and 95.3% (Co3O4@MnO2) after 5000 cycles, which are 22.9%, 9.3% and 20.1% higher, respectively, than those of the untreated HMONAs. Furthermore, the symmetrical supercapacitors based on treated MnO2@MnO2 nanoarrays electrodes also demonstrate 92% capacitance retention after 5000 cycles, showing better comprehensive performance than their untreated counterpart (78% capacitance retention). The general strategy of nanoscale interface optimization provides new opportunities in pushing the cycling stability limit of HMONAs. PMID- 30020296 TI - Direct C-OH/P(O)-H dehydration coupling forming phosphine oxides. AB - A t-BuONa-mediated C-OH/P(O)-H cross dehydration coupling to produce alkylphosphine oxides is developed. This reaction employed readily available alcohols and P(O)-H compounds as the starting materials, providing an efficient alternative method for constructing sp3 C-P bonds. A reasonable reaction path involving dehydration and subsequent regio-selective hydrophosphorylation of the resulting alkenes was proposed. PMID- 30020297 TI - Unraveling the discrepancies in size dependence of hardness and thermal stability in crystalline/amorphous nanostructured multilayers: Cu/Cu-Ti vs. Cu/HfO2. AB - Crystalline/amorphous interfaces (CAIs) confer outstanding mechanical properties on crystalline/amorphous nanostructured multilayers (C/ANMs), which are widely used in micro/nanodevices, because their unique interfacial structure possesses high strain compatibility. In this study, Cu/X (X = Cu-Ti, HfO2) C/ANMs with equal layer thicknesses (h) were comparatively investigated in terms of size dependent hardness (H) and thermal stability to uncover the fundamental difference(s) between Cu/Cu-Ti and Cu/HfO2. It was found that both as-deposited Cu/Cu-Ti and Cu/HfO2 C/ANMs exhibited a maximum hardness at a critical thickness of h ~30 nm, which was caused by a transition from confined dislocation gliding to dislocation transmission across the interface. Specifically, the Cu/Cu-Ti C/ANMs exhibited annealing hardening, whereas the Cu/HfO2 C/ANMs exhibited annealing softening associated with a minimum softening at h ~ 30 nm, which was closely correlated with their thermal stability. In comparison with monolithic amorphous X thin films, the glassy X nanolayers in the present Cu/X C/ANMs exhibited reduced thermal stability and a trend that smaller sizes led to higher stability. The underlying mechanism of the size-dependent crystallization behavior of X nanolayers is discussed in terms of the constraining effects of the interface. These findings provide deep insights into the design of Cu/metallic glass and Cu/ceramic-glass C/ANMs with optimal performance. PMID- 30020298 TI - Divergent biosynthesis of indole alkaloids FR900452 and spiro-maremycins. AB - FR900452 and spirocyclic maremycins, including F and G components, are structurally related indole alkaloids, previously identified from different Streptomyces species. These alkaloids feature an indole diketopiperazine motif linked with a cyclopentenone moiety, but the linkage differs in FR900452 and the spirocyclic maremycins. Here, FR900452 and its two new analogues were identified from the fermentation broth of Streptomyces sp. B9173, the producer of maremycins. Gene inactivation and heterologous expression of the mar gene cluster confirmed that production of FR900452 shares the same biosynthetic machinery that produces maremycins. FR900452 was identified as the precursor of maremycin A/B by feeding studies. MarP, a SnoaL-like protein, was demonstrated to differentiate the biosynthesis of FR900452 from that of spiro-form maremycin G. PMID- 30020299 TI - Tunable terahertz photoconductivity of hydrogen functionalized graphene using optical pump-terahertz probe spectroscopy. AB - We show that the terahertz photoconductivity of monolayer graphene following 800 nm femtosecond optical pump excitation can be tuned by different levels of hydrogenation (graphane) and provide a quantitative understanding of the unique spectral dependence of photoconductivity. The real part of terahertz photoconductivity (DeltasigmaRe(omega)), which is negative in doped pristine graphene, becomes positive after hydrogenation. Frequency and electronic temperature Te dependent conductivity sigma(omega, Te) is calculated using the Boltzmann transport equation taking into account the energy dependence of different scattering rates of the hot carriers. It is shown that the carrier scattering rate dominated by disorder-induced short-range scattering, though sufficient for pristine graphene, is not able to explain the observed complex Deltasigma(omega) for graphane. Our results are explained by considering the system to be heterogeneous after hydrogenation where conductivity is a weighted sum of conductivities of two parts: one dominated by Coulomb scattering coming from trapped charge impurities in the underlying substrate and the other dominated by short-range scattering coming from disorder, surface defects, dislocations and ripples in graphene flakes. A finite band gap opening due to hydrogenation is shown to be important in determining Deltasigma(omega). PMID- 30020300 TI - Conformational sensitivity of surface selection rules for quantitative Raman identification of small molecules in biofluids. AB - Biofluid analysis by surface-enhanced Raman scattering (SERS) is usually hindered by nonspecific interferences. It is challenging to drive targeted molecules towards sensitive areas with specific capture and quantitative recognition in complex biofluids. Herein, a highly specific and quantitative SERS analyzer for small molecule dopamine (DA) in serum is demonstrated on a portable Raman device by virtue of a transducer of mercaptophenylboronic acid (MPBA) and a site directed decoration of plasmonic Ag dendrites on a superhydrophobic surface. Theoretical simulations of molecular vibrations and charge distributions demonstrate the predomination of Raman surface selection rules in molecular reorientation upon the binding of DA. This recognition event is translated into ratiometric changes in the spectral profile which evidences excellent capability on SERS quantitation. The rules can well distinguish DA from its common interferents including fructose, glucose, sucrose and ascorbic acid which all generate weak but completely opposite spectral changes. Moreover, benefitting from the wettability difference, the target DA in diluted serum can be specifically enriched on a transducer-capped Ag surface, and the adsorption of other interferences is resisted by superhydrophobic features. It paves a new way for labelling a single SERS tag to simultaneously realize the identification and quantification of small molecules in complex biological media. PMID- 30020301 TI - Optical bio-chemical sensors based on whispering gallery mode resonators. AB - Whispering gallery mode (WGM) resonators have attracted extensive attention and their unique characteristics have led to some remarkable achievements. In particular, when combined with optical sensing technology, the WGM reonator-based sensor offers the advantages of small size, high sensitivity and a real-time dynamic response. At present, this type of sensor is widely applied in the bio chemical sensing field. In this paper, we briefly review the sensing principle, the structures and the sensing applications of optical bio-chemical sensors based on the WGM resonator, with particular focuses on their sensing properties and their advantages and disadvantages. In addition, the existing problems and future development trends of WGM resonator-based optical bio-chemical sensors are discussed. PMID- 30020302 TI - Hierarchical carbon-silicon nanowire heterostructures for the hydrogen evolution reaction. AB - Silicon nanowires (SiNWs) opened up exciting possibilities in a variety of research fields due to their unique anisotropic morphologies, facile tuning capabilities, and accessible fabrication methods. The SiNW-based photoelectrochemical (PEC) conversion has recently been known to provide an efficiency superior to that of various photo-responsive semiconductor heterostructures. However, a challenge still remains in designing optimum structures to minimize photo-oxidation and photo-corrosion of the Si surface in a liquid electrolyte. Here, we report a simple method to synthesize hierarchically branched carbon nanowires (CNWs) on SiNWs utilizing copper vapor as the catalyst in a chemical vapor deposition (CVD) process, which exhibits outstanding photocatalytic activities for hydrogen generation along with excellent chemical stability against oxidation and corrosion. Thus, we believe that the CNW-SiNW photoelectrodes would provide a new route to developing high-performing cost effective catalysts essential for advanced energy conversion and storage technologies. PMID- 30020303 TI - Tunable black phosphorus heterojunction transistors for multifunctional optoelectronics. AB - Many, black phosphorus (BP) based field-effect transistors, homojunctions, and vertical van der Waals structures have been developed for optoelectronic applications, with few studies being conducted on exploring the potential of their naturally formed heterojunctions. Here, we report a novel thickness modulated, gate-tunable BP heterojunction phototransistor for multiple purposes and high performance optoelectronics. Despite its thickness of less than 5 nm, the device, whose fabrication spares the need for split-gate or chemical doping or vertical stacking requirements, achieves an excellent photoresponsivity of 383 A W-1 at 1550 nm under zero gate bias, which is among the best photoresponse performance of all-BP-based photodetectors in this spectral range. Furthermore, it exhibits a shot-noise-limited noise equivalent power (NEPshot) of less than 10 2 pW Hz-1/2, making it very promising for ultra-low power detection. Additionally, owing to the heterojunction-induced built-in electric field, the device can be readily used for infrared photovoltaic devices in the absence of source-drain bias (Vd), a feature that is distinctively superior to traditional phototransistors. The multifunctionality demonstrated in our BP heterojunction transistor paves the way towards realizing tunable improved performance optoelectronics based on 2D materials platform. PMID- 30020304 TI - Reversible fabrication and self-assembly of a gemini supra-amphiphile driven by dynamic covalent bonds. AB - A smart gemini supra-amphiphile behaving with pH/CO2 dual-sensitive hierarchical self-assembly was fabricated under the effect of dynamic covalent bonds. In the presence of an amino-functionalized cation, water-insoluble terephthalaldehyde, and an amphiphilic anion, the benzoic imine bond can initiate the transformation from a single-tailed supra-amphiphile to a gemini supra-amphiphile with increasing pH, followed by the subsequent evolution from micelles to vesicles. Reversible self-assembly and disassembly of the gemini supra-amphiphile can be realized via CO2/N2 treatment, thus inducing the fission and reversion of vesicles. Interestingly, the flexible nature of supra-amphiphiles allows for the hierarchical assembly of vesicles, leading to the formation of aqueous two-phase systems. Multiple responsive supra-amphiphiles have useful applications in the fabrication of smart supra-molecular materials, including self-healing materials, nanocarriers and chemosensors. PMID- 30020308 TI - Antioxidant extract counteracts the effects of aging on cortical spreading depression and oxidative stress in the brain cortex. AB - PURPOSE: To investigate the effects of Murici extract on the brain excitability dependent phenomenon known as cortical spreading depression (CSD) and on brain oxidative stress. METHODS: Adult and aged Wistar rats were supplemented with murici extract (150 mg/kg/day or 300 mg/kg/day) by gavage for fifteen days. Afterwards, the animals were submitted to a CSD electrophysiological recording and to brain oxidative stress evaluation. RESULTS: Our results showed that aging decreased CSD propagation velocity, catalase activity and glutathione/oxidized glutathione ratio (GSH/GSSG) in the brain cortex of the rats, and increased malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity. The highest dose (300 mg/kg/day) of murici extract accelerated CSD, whereas the lowest (150mg/kg/day) decelerated, in both adult and aged animals. In contrast, aged animals supplemented with murici extract in both doses presented low MDA levels and high GSG/GSSG ratio in comparison to the control-aged animals. CONCLUSION: Murici extract supplementation seems to revert detrimental effects in aged brains and could be considered as a strategy in the treatment of pathologies related to aging and cortical spreading depression. PMID- 30020309 TI - Effects of hypothermia on lung inflammation in a rat model of meconium aspiration syndrome. AB - PURPOSE: To evaluate the effects of hypothermia treatment on meconium-induced inflammation. METHODS: Fifteen rats were instilled with human meconium (MEC, 1.5 mL/kg, 65 mg/mL) intratracheally and ventilated for 3 hours. Eight rats that were ventilated and not instilled with meconium served as a sham group. In MEC hypothermia group, the body temperature was lowered to 33+/-0.5 degrees C. Analysis of the blood gases, interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage (BAL) fluid samples, and histological analyses of the lungs were performed. RESULTS: The BAL fluid TNF alpha, IL-1beta, IL-6 and IL-8 concentrations were significantly higher in the MEC-hypothermia group than in the MEC-normothermia (p < 0.001, p < 0.001, p = 0.001, p < 0.001, respectively) and sham-controlled groups (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). CONCLUSION: Meconium-induced inflammatory cytokine production is affected by the body temperature control. PMID- 30020310 TI - Interleukin-4 protects from chemotherapy-induced peripheral neuropathy in mice modal via the stimulation of IL-4/STAT6 signaling. AB - PURPOSE: To investigate the possible role of IL-4 signaling pathway in vincristine-induced peripheral neuropathy. METHODS: The mouse model of vincristine-induced peripheral neuropathy and interleukin (IL)-4 knockout mice were utilized to investigate the possible role of IL-4 signaling pathway in vincristine-induced peripheral neuropathy. Vincristine induced increased sensitivity to mechanical stimulation was measured by von Frey hair test 7 and 14 days after intraperitoneal administration of 0.1 mg/kg vincristine in mice. Relative expression levels of cytokines were detected by quantitative real-time PCR. STAT6 expression following vincristine treatment was assessed with western blotting. RESULTS: We discovered that IL-4/STAT6 signaling was down-regulated in vincristine-treated mice. Deletion of IL-4 in mice increased the sensitivity to mechanical allodynia. IL-4 knockout mice also produced more pro-inflammatory cytokines, including IL-1beta and TNF-alpha. Notably, co-administration of exogenous recombination IL-4 significantly prevented vincristine-induced mechanical allodynia. CONCLUSION: Anti-inflammatory cytokine IL-4 protects rodent model from vincristine-induced peripheral neuropathy via the stimulation of IL 4/STAT6 signaling and inhibition of the pro-inflammatory cytokines. PMID- 30020311 TI - The therapeutic effects of curcumin and capsaicin against cyclophosphamide side effects on the uterus in rats. AB - PURPOSE: To evaluate the impact of systemic cyclophosphamide treatment on the rat uterus and investigate the potential therapeutic effects of natural antioxidant preparations curcumin and capsaicin against cyclophosphamide side effects. METHODS: A 40 healthy adult female Wistar albino rats were used in this study. Rats were randomly divided into four groups to determine the effects of curcumin and capsaicin against Cyclophosphamide side effects on the uterus (n=10 in each group); Group 1 was the control group (sham-operated), Group 2 was the cyclophosphamide group, Group 3 was the cyclophosphamide + curcumin (100mg/kg) group, and Group 4 was the cyclophosphamide + capsaicin (0.5 mg/kg) group. RESULTS: Increased tissue oxidative stress and histological damage in the rat uterus were demonstrated due to the treatment of systemic cyclophosphamide chemotherapy alone. The level of tissue oxidant and antioxidant markers and histopathological changes were improved by the treatment of curcumin and capsaicin. CONCLUSION: Cytotoxic effects of natural alkylating chemotherapeutic agents like cyclophosphamide on the uterus can be prevented by curcumin and capsaicin. PMID- 30020312 TI - An experimental study on the preventive effects of N-acetyl cysteine and ozone treatment against contrast-induced nephropathy. AB - PURPOSE: To compare the preventive effects of N-acetyl cysteine (NAC), ozone preconditioning and ozone treatment against contrast-induced nephropathy (CIN) in an experimental rat model. METHODS: Thirty adult male Wistar rats were randomly distributed into five groups (n=6 for each group). Group I served as control and Group II had only contrast agent, while Group III received NAC and Group IV received intraperitoneal ozone 6 hours before and 6 hours after introduction of contrast agent. Ozone treatment was applied for 5 days after the contrast agent was introduced in Group V. After induction of CIN, groups were compared in terms of serum levels of urea, creatinine, neutrophil gelatinase associated lipocalin, protein carbonyl, total antioxidant capacity (TAC) as well as degree of renal injury at histopathologic level. RESULTS: Groups II-V displayed more obvious histopathological alterations such as hemorrhage and renal tubular injury compared with Group I. TAC (p=0.043) and creatinine (p=0.046) levels increased significantly in Group II after the intervention. In Group III, protein carbonyl level diminished remarkably (p=0.046), while creatinine level was increased (p=0.046) following the intervention. TAC level was higher in Group IV (p=0.028) and Group V (p=0.026) following the procedure. CONCLUSION: The N-acetyl cysteine and ozone treatment may alleviate the biochemical and histopathological deleterious effects of contrast-induced nephropathy via enhancement of total antioxidant capacity and decreasing oxidative stress. PMID- 30020313 TI - Synergistic effect of honey and Nigella sativa on wound healing in rats. AB - PURPOSE: To investigate the therapeutic potential of honey, Nigella sativa (N. sativa) and their combination in rat model of excisional wound healing. METHODS: A circular excision wound was established in the back region of 50 Wistar rats. Subsequently, they were divided into 5 groups and daily topical administration of lanolin in the control group, honey in the honey group, cold-pressed N. sativa seed oil in the N. sativa groups, mix of 1:1 ratio of honey and N. sativa seed oil in the mix group, and phenytoin cream in the phenytoin group were used. Then, wound surface areas were evaluated using digital camera immediately after the injury and at post excision days 5, 10, 15 and 20. RESULTS: Significant reduction in wound surface area was observed within and between the groups (P < 0.001). In the post excision days 5, 10, 15 and 20 the wound surface areas in the mix group were significantly lower than the other groups followed by the phenytoin, honey, N. sativa, and control groups. CONCLUSION: The wound healing may be improved and accelerated by using topical solutions of honey, N. sativa seed oil and especially their mixture. PMID- 30020315 TI - A curcumin derivative J147 ameliorates diabetic peripheral neuropathy in streptozotocin (STZ)-induced DPN rat models through negative regulation AMPK on TRPA1. AB - PURPOSE: To investigate the specific molecular mechanisms and effects of curcumin derivative J147 on diabetic peripheral neuropathy (DPN). METHODS: We constructed streptozotocin (STZ)-induced DPN rat models to detected mechanical withdrawal threshold (MWT) in vivo using Von Frey filaments. In vitro, we measured cell viability and apoptosis, adenosine 5'-monophosphate-activated protein kinase (AMPK) and transient receptor potential A1 (TRPA1) expression using MTT, flow cytometry, qRT-PCR and western blot. Then, TRPA1 expression level and calcium reaction level were assessed in agonist AICAR treated RSC96cells. RESULTS: The results showed that J147reduced MWT in vivo, increased the mRNA and protein level of AMPK, reduced TRPA1 expression and calcium reaction level in AITCR treated RSC96 cells, and had no obvious effect on cell viability and apoptosis. Besides, AMPK negative regulated TRPA1 expression in RSC96 cells. CONCLUSIONS: J147 could ameliorate DPN via negative regulation AMPK on TRPA1 in vivo and in vitro. A curcumin derivative J147might be a new therapeutic potential for the treatment of DPN. PMID- 30020316 TI - Impact of 1,25(OH) 2 D 3 on TG content in liver of rats with type 2 diabetes. AB - PURPOSE: To evaluate the effects of 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) on the content of triglyceride (TG), as well as on the gene and protein expressions of adiponectin receptor 2 (AdipoR2), p38 mitogen-activated protein kinase (P38MAPK), and lipoprotein lipase (LPL) in the liver of rats with type 2 diabetes mellitus (T2DM) so as to provide theoretical basis for exploring the mechanism by which 1,25(OH)2D3 regulates TG. METHODS: Wistar rats were divided into four groups (n=25), with different treatments and detected the gene and protein expressions of AdipoR2, p38MAPK, and LPL in the liver tissue by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Meanwhile, the content of TG in the liver tissue was detected by the Enzyme-linked immunosorbent assay. RESULTS: The expression of AdipoR2, p38MAPK, LPL gene and protein in the liver of VitD intervention group was significantly higher than that in T2DM group (P <0.05), while the TG content was significantly lower than that in T2DM group (P <0.05). CONCLUSION: 1,25(OH)2D3 can decrease the content of TG in the liver, and its mechanism may be achieved by upregulating the expressions of AdipoR2, p38MAPK, and LPL in the liver. PMID- 30020317 TI - Development of a model for laparoscopic cholecystectomy video assisted training. A randomized study. AB - PURPOSE: To identify the surgical trainee benefits through the use of video assisted training (VAT). METHODS: Twelve cases of uncomplicated laparoscopic cholecystectomy (LC) were selected. Edited video segments focused on essential intra-operative anatomical structure identification and critical surgical steps. Evaluation of these videos was constructed on a scoring system based on pre and post-teach tests. RESULTS: The mean value of the pre-teach score was 33.2 +/- 18.0 points and in the post-teach test the mean value was 66.7 +/- 9.7 points. A statistically significant difference was seen when comparing pre and post-teach results (p<.00001). CONCLUSION: The widespread and the systematic use of video assisted learning may be a useful and economic tool in adjunct to the surgical training techniques practiced until now throughout the surgical community. PMID- 30020314 TI - Cardioprotective effect of lipstatin derivative orlistat on normotensive rats submitted to cardiac ischemia and reperfusion. AB - PURPOSE: To evaluate in vivo animal model of cardiac ischemia/reperfusion the cardioprotective activity of pancreatic lipase inhibitor of the orlistat. METHODS: Adult male Wistar rats were anesthetized, placed on mechanical ventilation and underwent surgery to induce cardiac I/R by obstructing left descending coronary artery followed by reperfusion to evaluation of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) with pancreatic lipase inhibitor orlistat (ORL). At the end of reperfusion, blood samples were collected for determination of triglycerides (TG), very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase-MB (CK-MB). RESULTS: Treatment with ORL has been able to decrease the incidence of VA, AVB and LET. Besides that, treatment with ORL reduced serum concentrations of CK and LDL, but did not alter the levels of serum concentration of TG, VLDL and HDL. CONCLUSION: The reduction of ventricular arrhythmias, atrioventricular block, and lethality and serum levels of creatine kinase produced by treatment with orlistat in animal model of cardiac isquemia/reperfusion injury suggest that ORL could be used as an efficient cardioprotective therapeutic strategy to attenuate myocardial damage related to acute myocardial infarction. PMID- 30020318 TI - Curcumin exerts anti-inflammatory and vasoprotective effects through amelioration of NFAT-dependent endothelin-1 production in mice with acute Chagas cardiomyopathy. AB - BACKGROUND: The anti-inflammatory and cardioprotective properties of curcumin (Cur), a natural polyphenolic flavonoid isolated from the rhizomes of Curcuma longa, are increasingly considered to have beneficial effects on the progression of Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi. OBJECTIVE: To evaluate the effects of oral therapy with Cur on T. cruzi-mediated cardiovasculopathy in acutely infected mice and analyse the in vitro response of parasite-infected human microvascular endothelial cells treated with this phytochemical. METHODS: Inflammation of heart vessels from Cur-treated and untreated infected mice were analysed by histology, with benznidazole (Bz) as the reference compound. Parasitaemia was monitored by the direct method. Capillary permeability was visualised by Evans-blue assay. Myocardial ET-1, IL-6, and TNF alpha mRNA expressions were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Microvascular endothelial HMEC-1 cells were infected in vitro with or without addition of Cur or Bz. Induction of the Ca2+/NFAT pathway was assessed by fluorometry, immunoblotting, and reporter assay. FINDINGS: Oral Cur therapy of recently infected mice reduced inflammatory cell infiltration of myocardial arteries without lowering parasite levels. Compared to that of the phosphate-buffered saline-receiving group, hearts from Cur-treated mice showed significantly decreased vessel inflammation scores (p < 0.001), vascular permeabilities (p < 0.001), and levels of IL-6/TNF-alpha (p < 0.01) and ET-1 (p < 0.05) mRNA. Moreover, Cur significantly (p < 0.05 for transcript; p < 0.01 for peptide) downregulated ET-1 secretion from infected HMEC 1 cells. Remarkably, Cur addition significantly (p < 0.05 at 27.0 MUM) interfered with T. cruzi-dependent activation of the Ca2+/NFATc1 signalling pathway that promotes generation of inflammatory agents in HMEC-1 cells. CONCLUSIONS: Oral treatment with Cur dampens cardiovasculopathy in acute Chagas mice. Cur impairs the Ca2+/NFATc1-regulated release of ET-1 from T. cruzi-infected vascular endothelium. These findings identify new perspectives for exploring the potential of Cur-based interventions to ameliorate Chagas heart disease. PMID- 30020319 TI - Analysis of radioprotection and antimutagenic effects of Ilex paraguariensis infusion and its component rutin. AB - DNA repair pathways, cell cycle checkpoints, and redox protection systems are essential factors for securing genomic stability. The aim of the present study was to analyze the effect of Ilex paraguariensis (Ip) infusion and one of its polyphenolic components rutin on cellular and molecular damage induced by ionizing radiation. Ip is a beverage drank by most inhabitants of Argentina, Paraguay, Southern Brazil, and Uruguay. The yeast Saccharomyces cerevisiae (SC7Klys 2-3) was used as the eukaryotic model. Exponentially growing cells were exposed to gamma rays (gamma) in the presence or absence of Ip or rutin. The concentrations used simulated those found in the habitual infusion. Surviving fractions, mutation frequency, and DNA double-strand breaks (DSB) were determined after treatments. A significant increase in surviving fractions after gamma irradiation was observed following combined exposure to gamma+R, or gamma+Ip. Upon these concomitant treatments, mutation and DSB frequency decreased significantly. In the mutant strain deficient in MEC1, a significant increase in gamma sensitivity and a low effect of rutin on gamma-induced chromosomal fragmentation was observed. Results were interpreted in the framework of a model of interaction between radiation-induced free radicals, DNA repair pathways, and checkpoint controls, where the DNA damage that induced activation of MEC1 nodal point of the network could be modulated by Ip components including rutin. Furthermore, ionizing radiation-induced redox cascades can be interrupted by rutin potential and other protectors contained in Ip. PMID- 30020321 TI - Pulmonary metastases in children: are we operating unnecessarily? AB - OBJECTIVE: to determine, in pediatric patients with malignant neoplasms, the characteristics of pulmonary nodules identified on computed tomography, as well as the possibility of differentiating benign lesions from metastases. METHODS: we conducted a retrospective study of patients submitted to pulmonary resections of nodules diagnosed as metastases in a period of seven years. We compared computed tomography and surgery findings, as well as results of anatomopathological examinations. RESULTS: we studied nine patients submitted to 11 surgical interventions. Among the studied variables, only nodule size greater than 12.5mm proved to be statistically significant to predict malignancy. CONCLUSION: among the tomographic characteristics of pulmonary nodules in children with malignant neoplasms, only the size of the lesion was a predictor of malignancy. PMID- 30020320 TI - NLRP3 inflammasome signaling as an early molecular response is negatively controlled by miR-186 in CFA-induced prosopalgia mice. AB - The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most frequently studied in the central nervous system and has been linked to neuropathic pain. In this study, a post-translational mechanism of microRNA (miR) 186 via regulating the expression of NLRP3 in the complete Freund's adjuvant (CFA)-treated mice was investigated. The injection of CFA was used to induce trigeminal neuropathic pain in mice. miRs microarray chip assay was performed in trigeminal ganglions (TGs). CFA treatment significantly increased the mRNA expression of NLRP3, interleukin (IL)-1beta, and IL-18 in TGs compared to the control group. Moreover, 26 miRs were differentially expressed in TGs from trigeminal neuropathic pain mice, and the expression of miR-186 showed the lowest level of all the miRs. Further examination revealed that NLRP3 was a candidate target gene of miR-186. We delivered miR-186 mimics to CFA-treated mice. The head withdrawal thresholds of the CFA-treated mice were significantly increased by miR 186 mimics injection compared with CFA single treatment. The mRNA and protein expression of NLRP3, IL-1beta, and IL-18 in TGs from trigeminal neuropathic pain mice were significantly inhibited by miR-186 mimics treatment compared to the CFA group. miR-186 was able to suppress the neuropathic pain via regulating the NLRP3 inflammasome signaling. PMID- 30020322 TI - Cardiac tamponade by peripherally inserted central catheter in preterm infants: role of bedside ultrasonography and therapeutic approach. AB - OBJECTIVE: to determine the incidence of pericardial effusion with cardiac tamponade in preterm infants in a pediatric intensive care unit, with emphasis on the relationship between pericardial effusion and peripherally inserted central catheter, and to evaluate the role of bedside ultrasound in approaching these cases. METHODS: we conducted a retrospective analysis of patients admitted to a pediatric intensive care unit between July 2014 and December 2016, who presented pericardial effusion with hemodynamic repercussion, evaluated by ultrasonography. RESULTS: we studied 426 patients admitted to the five beds of the neonatal unit. In the period, there were 285 bedside ultrasound exams. We found six cases of pericardial effusion, four of which with obstructive shock and need for pericardial drainage. There was no procedure-related mortality, and all patients evolved with hemodynamic improvement after the procedure. The incidence of pericardial effusion was 2.4 cases per year. CONCLUSION: the incidence of pericardial effusion is low in neonates, but early diagnosis is fundamental due to high morbidity and mortality, especially in cases of abrupt onset. All cases were diagnosed by bedside ultrasonography, demonstrating its importance in the screening of these cases, especially in shocks of uncertain etiology and neonates with sudden onset hemodynamic instability who are using central venous access. PMID- 30020323 TI - Evaluation of quality of life, weight loss and comorbidities of patients undergoing bariatric surgery. AB - OBJECTIVE: to assess the efficacy of weight loss, the evolution of comorbidities, the quality of life and the BAROS protocol (Bariatric Analysis and Reporting Outcome System) in the postoperative period of patients undergoing bariatric surgery. METHODS: we conducted a cross-sectional, quantitative study with 95% true strength (P=0.05), with 103 patients submitted to SLEEVE Vertical Gastrectomy (40) and Roux-en-Y Gastric Bypass (63), from four months after surgery. We carried out the research at the Ambulatory of General Surgery of the Clinics Hospital of the Federal University of Pernambuco, using the BAROS protocol. RESULTS: the majority of the patients were female (89.3%). The mean age was 44.23 years. The mean percentage loss of excess weight was 69.35%. The mean postoperative follow-up time was 41.87 months (+/-37.35). The comorbidities with the highest percentage of resolution were sleep apnea (90.2%), diabetes (80.7%) and hypertension (70.8%). The most frequent complications were hair loss (79.6%), nutritional deficiency (37.9%) and anemia (35%). The BAROS protocol demonstrated that patients positively evaluated quality of life in 93.2% of the cases. The Moorehead-Ardelt questionnaire showed that quality of life "improved" or "improved greatly" for 94.1% of patients. CONCLUSION: bariatric surgery has been shown to be an effective procedure in the treatment of morbid obesity and in the control of comorbidities. Quality of life analysis was evaluated positively through the BAROS protocol. PMID- 30020324 TI - Evidence for varicose vein treatment: an overview of systematic reviews. AB - BACKGROUND: Varicose veins affect nearly 30% of the world's population. This condition is a social problem and needs interventions to improve quality of life and reduce risks. Recently, new and less invasive methods for varicose vein treatment have emerged. There is a need to define the best treatment options and to reduce the risks and costs. Since there are cosmetic implications, treatments for which effectiveness remains unproven present risks to consumers and higher costs for stakeholders. These risks and costs justify conducting an overview of systematic reviews to summarize the evidence. DESIGN AND SETTING: Overview of systematic reviews within the Discipline of Evidence-Based Health, at Universidade Federal de Sao Paulo (UNIFESP). METHODS: Systematic reviews on clinical or surgical treatments for varicose veins were included, with no restrictions on language or publication date. RESULTS: 51 reviews fulfilled the inclusion criteria. Outcomes and comparators were described, and a narrative review was conducted. Overall, there was no evidence that compression stockings should be recommended for patients as the initial treatment or after surgical interventions. There was low to moderate evidence that minimally invasive therapies (endovenous laser therapy, radiofrequency ablation or foam sclerotherapy) are as safe and effective as conventional surgery (ligation and stripping). Among these systematic reviews, only 18 were judged to present high quality. CONCLUSIONS: There was evidence of low to moderate quality that minimally invasive treatments, including foam sclerotherapy, laser and radiofrequency therapy are comparable to conventional surgery, regarding effectiveness and safety for treatment of varicose veins. PMID- 30020325 TI - Prognostic Impact of Iron Metabolism Changes in Patients with Acute Coronary Syndrome. AB - BACKGROUND: Iron metabolism disorders have been associated with an increased risk of cardiovascular events. However, the prognostic impact on patients (pts) with acute coronary syndrome (ACS) has yet to be clarified. OBJECTIVE: To determine the prognostic value of serum iron and ferritin levels in pts with ACS in the short and long-term. METHODS: Consecutive pts admitted to a coronary care unit with a diagnosis of ACS, for a period of 2 years, were evaluated. The population was divided into tertiles of serum iron and ferritin distribution. The primary adverse events were the occurrence of in-hospital death or heart failure (HF) and death or HF at 1 year of follow-up. RESULTS: We studied 280 pts (73% males; mean age 68 +/- 13 years). The mean levels of serum iron and ferritin were 59 +/- 34 mcg/dL and 205 +/- 185 ng/mL, respectively. Patients included in the 1st tertile of serum iron (<= 40 mcg/dL) had a higher rate of adverse events, in-hospital and after 1 year. Lower and higher levels of ferritin (1st and 3rd tertiles, <= 110; >219 ng/ml, respectively) were associated with a higher incidence of HF during hospitalization and death at 1 year. A ferritin value >316 ng /mL was an independent risk factor for death at 1 year (adjusted OR: 14; 95%CI: 2.6 to 75.9). CONCLUSION: In this population, iron metabolism alterations were associated with a higher rate of adverse events and higher ferritin levels constituted an independent mortality predictor in the long-term. PMID- 30020326 TI - Influence of Type 1 Diabetes on the Symbolic Analysis and Complexity of Heart Rate Variability in Young Adults. AB - BACKGROUND: Type 1 diabetes mellitus can cause autonomic changes, which can be assessed by heart rate variability. Among the heart rate variability assessment methods, the symbolic analysis and Shannon entropy, based on the Chaotic dynamics, have gained prominence. OBJECTIVE: To compare heart rate variability indexes, obtained through symbolic analysis and Shannon entropy, in young adults with type 1 diabetes mellitus and healthy young individuals, associated with the analysis of linear indexes; and to verify if there are associations between the indexes obtained by the symbolic analysis and by Shannon entropy and linear indexes in diabetic individuals. METHODS: Heart rate variability data from 39 young adults with type 1 diabetes mellitus and 43 healthy young individuals were analyzed, using a cardio-frequency meter. Linear indexes (standard deviation of all normal RR intervals recorded in a time interval expressed in milliseconds; square root of the mean of the squared differences between adjacent normal RR intervals in a time interval expressed in milliseconds; low and high frequency components in millisecond squared; and normalized units and ratio between low and high frequency components) and nonlinear ones (Shannon entropy and symbolic analysis - standard without variation; with one or two variations; and with two different variations) of the heart rate variability were calculated. The statistical significance was set at 5%, and the confidence interval was 95%. RESULTS: Significantly lower values were observed in the DM1 group compared to healthy young adults for the standard deviation indexes of all normal RR intervals recorded in a time interval [37.30 (29.90) vs. 64.50 (36.20); p = 0.0001], square root of the mean of the squared differences between adjacent normal RR intervals in a time interval [32.73 (17.43) vs. 55.59 (21.60); p = 0.0001], low frequency component [402.00 (531.00) vs. 1,203.00 (1,148.00); p = 0.0001], high frequency component [386.00 (583.00) vs. 963.00 (866.00); p = 0.0001] and the pattern with two different variations [15,33 (9,22) vs. 20.24 (12.73); p = 0.0114], with the effect of this difference being considered large (standard deviation of all normal RR intervals recorded in a time interval, square root of the mean of the squared differences between adjacent normal RR intervals in a time interval and low frequency component), medium (high frequency component) and small (standard with two different variations). The agreement of the associations between the linear and non-linear indexes was considered elevated for the high frequency component index - normalized units (r = -0.776), with the standard index without variation, and moderate for the indexes square root of the mean of the squared differences between adjacent normal RR intervals in a time interval (r = 0.550), standard deviation of all normal RR intervals recorded in a time interval (r = 0.522), high frequency component - normalized units (r = 0.638) with the index standard with two similar variations, as well as for the indexes square root of the mean of the squared differences between adjacent normal RR intervals in a time interval (r = 0.627) and high frequency component - normalized units (r = 0.601) with the index standard with two different variations. CONCLUSION: Type 1 diabetes mellitus influenced linear indexes and symbolic analysis, but not yet in the complexity of heart rate variability. Additionally, heart rate variability indexes correlated with the symbolic dynamics. PMID- 30020328 TI - Perception of users on self-care of lower leg ulcers. AB - OBJECTIVE: To know the perception of users on self-care of ulcers in the lower limbs. METHOD: This is a qualitative, exploratory, and descriptive study conducted with 10 users registered in the complementary programme of a wound care clinic in Canoas, RS, Brazil. Data were collected using information from the medical records of the users and semi-structured interviews conducted between October and November 2016. RESULTS: The results were discussed according to thematic content analysis with three thematic categories: self-care and living with the ulcer, self-care deficit and supporting users with ulcer, and self-care and the ulcer care network, based on the Nursing Self-Care Deficit Theory. CONCLUSIONS: Self-care is the result of dialogue between the user/nurse/health workers and the link they establish when they share care. The support of family members and the service can facilitate or limit care. PMID- 30020327 TI - Persistent Inflammatory Activity in Blood Cells and Artery Tissue from Patients with Previous Bare Metal Stent. AB - BACKGROUND: Studies have pointed out a higher mortality after coronary artery bypass surgery (CABG) in patients with stent. OBJECTIVE: To evaluate inflammatory markers in peripheral blood cells and in coronary artery tissue samples obtained during CABG in patients with stent compared to controls. METHODS: The case series consisted of two groups, one with previous stent implantation (n = 41) and one control (n = 26). The expression of the LIGHT, IL-6, ICAM, VCAM, CD40, NFKB, TNF, IFNG genes was analyzed in peripheral blood cells collected preoperatively. The coronary artery was evaluated for: interleukin-6, ICAM, VCAM, CD40, NFKB, TNF alpha and IFN-gamma by immunohistochemistry. A total of 176 tissue samples were grouped for analysis in: A1- arteries with stent (n = 38); A2- native arteries from patients with stent in another artery (n = 68); and A3- arteries without stent from controls undergoing routinely CABG surgery (n = 70). A significance level of 0.05 was adopted. RESULTS: Patients with stent showed higher TNF (p = 0.03) and lower CD40 gene expression (p = 0.01) in peripheral blood cells than controls without stent. In coronary artery samples, the TNF-alpha protein staining was higher in the group A1, not only in the intima-media layer (5.16 +/- 5.05 vs 1.90 +/- 2.27; p = 0.02), but also in the adipose tissue (6.69 +/- 3.87 vs 2.27 +/- 4.00; p < 0.001). Furthermore, group A1 had a higher interleukin-6 protein staining in adipose tissue than group A3 (p = 0.04). CONCLUSION: We observed a persistently higher systemic TNF expression associated with exacerbated TNF-alpha and interleukin-6 local production in patients with stents. This finding may contribute to a worse clinical outcome. PMID- 30020329 TI - Psychic workload in the process of work of maternity and obstetric centers nurses. AB - OBJECTIVE: To identify the psychic workload present in the work process of nurses working in Maternity and Obstetric Centers. METHOD: A descriptive qualitative study developed with 14 nurses working in obstetric centers and maternity units of two hospitals. The data were collected through a semi-structured interview, developed from October of 2015 to January of 2016, and exploited based on Content Analysis. RESULTS: The results were grouped into two categories: the nurses' working process and their psychic workload; and the maintenance of (in)appropriate practices such as psychic workload, demonstrating that the psychic workload is materialized in multiple elements of the work process, passing through assignments, interpersonal relationship and maintaining inadequate pipelines. CONCLUSIONS: It was identified that the psychic workload in the nurses' work process in the studied context is related to the perpetuation of dehumanized practices and to the challenge of maintaining humanized practices. PMID- 30020330 TI - Laser acupuncture protocol for essential systemic arterial hypertension: randomized clinical trial. AB - OBJECTIVES: to evaluate the efficacy of a laser acupuncture protocol developed and applied by nurses in arterial hypertension patients. METHOD: randomized, multicenter, triple-blind and two-armed clinical trial. The sample consisted of 102 participants, 51 per arm, both sexes, aged between 30 and 75 years, undergoing drug therapy for a year or more, with difficulty to control blood pressure, maintaining regular measures >140x90 mmHg. Participants underwent six standard or simulated laser-acupuncture sessions, for 24 minutes, within a period of six weeks. Descriptive analyzes expressed as frequencies of occurrences, means and medians were used, and analysis of the association between variables was performed using Student's t-test and Anova, using Statistica(r) software, version 12.0. The significance level was set at 5% (alpha=0.05). The comparison between blood pressure measurements was performed using Student's t-test for paired samples and Anova for repeated measures. RESULTS: a significant reduction in systolic (p<0.001) and diastolic (p<0.001) blood pressure was observed among participants in the intervention arm, which was not observed in the simulation arm. CONCLUSION: the results have demonstrated the efficacy of the protocol. Reduction and control of blood pressure have been demonstrated, indicating the possibility of using this technology for the care of patientes with essential systemic arterial hypertension. Brazilian Registry of Clinical Trials. UTN: U1111 1177-1811. Clinical Trials NCT02530853. PMID- 30020331 TI - Direct costs of integrated procedures of conventional hemodialysis performed by nursing professionals. AB - OBJECTIVE: to analyze the mean direct cost of the constituent procedures of conventional hemodialysis, performed in three public teaching and research hospitals. METHOD: quantitative, exploratory-descriptive study, of the multiple case study type. The mean direct cost was calculated by multiplying the time (timed) spent by nursing professionals, on the execution of procedures, by the unit cost of direct labor, added to the cost of materials and solutions/medications. RESULTS: the total mean direct cost, in patients with an arteriovenous fistula corresponded to US$25.10 in hospital A, US$37.34 in hospital B and US$25.01 in hospital C, and in patients with a dual lumen catheter, US$32.07 in hospital A, US$40.58 in hospital B and US$30.35 in hospital C. The weighted mean values obtained were US$26.59 for hospital A, US$38.96 for hospital B and US$27.68 for hospital C. It was noted that the "installation and removal of hemodialysis fistula access" caused a significantly lower economic impact compared to "installation and removal of hemodialysis catheter access". CONCLUSION: with the knowledge developed it will be possible to support hospital managers, technical managers and nursing professionals in the decision making process, with a view to the rational allocation of the necessary inputs for the performance of conventional hemodialysis. PMID- 30020332 TI - Record of the circumstances of falls in the community: perspective in the Iberian Peninsula. AB - OBJECTIVE: to determine the diagnosis of the situation regarding documentation of falls and risk of falls in people older than 75 years in basic health units in Spain and Portugal. METHOD: mixed exploratory study in two stages: (i) quantitative descriptive of randomly selected fall records produced in one year (597 records; 197 Spanish and 400 Portuguese); and (ii) qualitative, with the purpose of knowing the perception of health professionals employing semi structured interviews (72 professionals, 16 Spanish and 56 Portuguese). The study areas were two basic health units in southern Spain and northern Portugal. RESULTS: in the fall records, the number of women was higher. The presence of fall was associated with the variables age, presence of dementia, osteoarticular disease, previous falls and consumption of antivertiginous medication. Health professionals perceived an absence of risk assessment instruments, as well as lack of prevention programs and lack of awareness of this event. CONCLUSION: falls are perceived as an area of priority attention for health professionals. Nonetheless, there is a lack of adherence to the registration of falls and risk assessment, due to organizational, logistical and motivational problems. PMID- 30020333 TI - Difficulties and motivations for physical exercise in women older than 65 years. A qualitative study. AB - OBJECTIVE: to identify difficulties and motivations for the practice of physical exercise in women older than 65 years. METHOD: qualitative study based on the phenomenological theory, with focus groups and in-depth interviews. The nursing staff selected 15 women by intentional sampling using the following criteria: age, time dedicated to physical exercise, independence, and absence of cognitive impairment and contraindication for this activity. Two focus groups were formed (one of them did physical exercise for less than 150 minutes per week and the other at least 150 minutes per week) in addition to conducting five in-depth interviews. Qualitative analysis of the data was performed through transcription, coding, categorization, and verification of results. RESULTS: the difficulties to start and develop physical exercise were circumscribed to the perception of poor health and lack of free time; both circumstances result from care obligation, being represented as a gender imposition. However, the motivations are related to perception of strength, need for socialization, and perception of autonomy and freedom. CONCLUSIONS: the ideological representation of gender determines the women's decision to exercise. Knowing the meaning and significance that women give to health and their role in the socio-family environment allows nurses to develop relationships and interventions to encourage the practice of physical exercise. PMID- 30020334 TI - Results of the implementation of integrated care after cardiorespiratory arrest in a university hospital. AB - OBJECTIVES: to identify the care measures performed after cardiorespiratory arrest (CRA) and to relate them to the neurological status and survival at four moments: within the first 24 hours, at the discharge, six months after discharge, and one year after discharge. METHOD: retrospective, analytical and quantitative study performed at the Emergency Department of a university hospital in Sao Paulo. Eighty-eight medical records of CRA patients who had a return of spontaneous circulation sustained for more than 20 minutes were included and the post-CRA care measures performed in the first 24 hours were identified, as well as its relationship with survival and neurological status. RESULTS: the most frequent post-CRA care measures were use of advanced airway access techniques and indwelling bladder catheterization. Patients who had maintained good breathing and circulation, temperature control and who were transferred to intensive care unit had a better survival in the first 24 hours, after six months and one year after discharge. Good neurological status at six months and one year after discharge was associated with non-use of vasoactive drugs and investigation of the causes of the CRA. CONCLUSION: the identification of good practices in post CRA care may help to reduce the mortality of these individuals and to improve their quality of life. PMID- 30020335 TI - Risk factors for death in patients with non-infectious adverse events. AB - OBJETIVE: to identify risk factors for death in patients who have suffered non infectious adverse events. METHOD: a retrospective cohort study with patients who had non-infectious Adverse Events (AE) in an Intensive Care Unit. The Kaplan Meier method was used to estimate the conditional probability of death (log-rank test 95%) and the risk factors associated with death through the Cox regression. RESULTS: patients over 50 years old presented a risk 1.57 times higher for death; individuals affected by infection/sepsis presented almost 3 times the risk. Patients with a Simplified Acute Physiology Score III (SAPS3) greater than 60 points had four times higher risk for death, while those with a Charlson scale greater than 1 point had approximately two times higher risk. The variable number of adverse events was shown as a protection factor reducing the risk of death by up to 78%. CONCLUSION: patients who had suffered an adverse event and who were more than 50 years of age, with infection/sepsis, greater severity, i.e., SAPS 3>30 and Charlson>1, presented higher risk of death. However, the greater number of AEs did not contributed to the increased risk of death. PMID- 30020336 TI - Direct cost of maintenance of totally implanted central venous catheter patency. AB - OBJECTIVE: to identify the average direct cost of maintaining the patency of totally implanted central venous catheter with heparin at a Day Hospital of a public hospital of high complexity specialized in the treatment of cancer patients, and estimate the average direct cost of replacing heparin with sodium chloride 0.9%. METHOD: quantitative, exploratory-descriptive study, with a sample of 200 non-participant observations of the maintenance of totally implanted central venous catheters with heparin. The average direct cost was calculated by multiplying the (clocked) time spent by professionals to complete the procedure by the direct unit cost of workforce, added to the cost of materials and solutions. RESULTS: the estimated total direct cost of catheter maintenance with heparin was US$ 9.71 (SD=1.35) on average, ranging from US$ 7.98 to US$ 23.28. The estimated total direct cost of maintenance with 0.9% sodium chloride in the place of heparin was US$ 8.81 (SD=1.29) on average, resulting in a reduction of US$ 0.90 per procedure. CONCLUSION: the results contributed to propose strategies to assist in cost containment/minimization in this procedure. The replacement of heparin by 0.9% sodium chloride proved to be an option to reduce the total average direct cost. PMID- 30020337 TI - Reliability analysis of the Manchester Triage System: inter-observer and intra observer agreement. AB - OBJECTIVE: To analyze the reliability of the Manchester Triage System to determine the priority of patients in emergency services. METHOD: This is a reliability study with a sample of 361 nurses. The data were collected in three stages and the questionnaires were applied using the electronic software. The agreement was measured by the evaluation of clinical cases. The outcomes evaluated were agreement with the gold standard and intra-observer in the indication of the flowchart, discriminator, and level of risk. Data were submitted to univariate and bivariate analyses. The agreement was measured by the Kappa index. RESULTS: The external and internal reliability of the protocol ranged from moderate to substantial (Kappa: 0.55-0.78). The time of professional experience as a nurse, in emergency services and in the classification of risk were associated with external and internal reliability. The correct choice of the discriminator influenced the correct indication of the risk level (R2 = 0.77, p <0.0001) more than the correct choice of the flowchart (R2 = 0.16, p <0.0001). CONCLUSION: The reliability of the Manchester Triage System ranged from moderate to substantial and it was influenced by the clinical experience of the nurse. The protocol is safe for defining clinical priorities using different classification flowcharts. PMID- 30020338 TI - Nursing strategies for child health surveillance. AB - OBJECTIVE: to appreciate the strategies promoted by nurses in the context of child health surveillance relevant to early childhood development. METHOD: this is a qualitative study with an inductive thematic analysis of the data, based on the conceptual principles of child health surveillance, and developed through semi-structured interviews with Brazilian nurses working with families in primary health care. RESULTS: the nurses' strategies in favor of child health surveillance focus on actions that anticipate harm with continuous follow-up and monitoring of health indicators. The process of child growth and development is the basis for responses and benefits to health, connection with the daily lives of families, active search, articulations between professionals and services, access to comprehensive care, and intrinsic actions between promotion, prevention and health follow-up. CONCLUSION: child health surveillance actions developed by nurses with families involve knowledge sharing, favor the resolution of problems, increase child health indicators, and strengthen the relationship between health and children's rights, which support the promotion of development in early childhood. PMID- 30020340 TI - Liver transplantation for acute liver failure due to antitubercular drugs - a single-center experience. AB - OBJECTIVES: Patients receiving treatment for tuberculosis are at risk of developing acute liver failure due to the hepatotoxicity of antitubercular drugs. We aimed to describe our experience with liver transplantation from deceased donors in this situation. METHODS: We identified patients undergoing transplantation for acute liver failure due to antitubercular drugs in our prospectively maintained database. RESULTS: Of 81 patients undergoing transplantation for acute liver failure, 8 cases were attributed to antitubercular drugs during the period of 2006-2016. Regarding the time of tuberculosis treatment until the onset of jaundice, patients were on antitubercular drugs for a mean of 64.7 days (21-155 days). The model for end stage liver disease (MELD) score of patients ranged from 32 to 47 (median 38), and seven patients underwent transplantation under vasopressors. The 1-year survival was 50%. Three patients died during the week following transplantation due to septic shock (including a patient with acute liver failure due to hepatic/disseminated tuberculosis), and the remaining patient died 2 months after transplantation due to pulmonary infection. There were 2 cases of mild rejection and 1 case of moderate rejection. Of the surviving patients, all were considered cured of tuberculosis after alternative drugs were given. CONCLUSION: Patients arrived very sick and displayed poor survival after deceased donor transplantation. PMID- 30020341 TI - Is subjective sleep evaluation a good predictor for obstructive sleep apnea? AB - OBJECTIVE: To compare subjective sleep evaluation obtained using four questionnaires with polysomnography results for individuals with and without obstructive sleep apnea. METHODS: Observational and analytical study in which individuals underwent polysomnography were studied retrospectively to investigate sleep disorders. We compared subjective data from a research database used to predict obstructive sleep apnea based on the STOP-BANG questionnaire, evaluation of excessive daytime sleepiness (Epworth Sleepiness Scale), sleep quality questionnaire (Mini Sleep Questionnaire) and Post-Sleep Data Collection Instrument with the self-reported total sleep time and sleep-onset latency for subjects with and without obstructive sleep apnea. RESULTS: The STOP-BANG questionnaire was a good predictor for the diagnosis of obstructive sleep apnea. However, the other instruments did not show a significant difference between healthy and sick individuals. Patients' perceptions of their sleep onset time were significantly lower than the polysomnographic data, but this difference remained for both subjects with and without obstructive sleep apnea. No difference was found between the subjective duration of sleep and the total sleep time assessed by polysomnography in either the healthy subjects or the patients. CONCLUSION: Except for the STOP-BANG questionnaire, subjective evaluation of sleepiness, sleep quality, perception of onset, and total sleep time are not important parameters for the diagnosis of obstructive sleep apnea, which reinforces the need for an active search for better management of these patients. PMID- 30020339 TI - Studies evaluating of health interventions at schools: an integrative literature review. AB - OBJECTIVE: to identify and analyze the available evidence on the strategies used in the studies evaluating health interventions at school. METHOD: this is an integrative review searching in LILACS, CINAHL, CUIDEN, ScienceDirect, and PubMed. From the pre-defined inclusion and exclusion criteria, there were 121 articles chosen to compose the sample. RESULTS: english studies (97.5%), with a quantitative approach (80.2%), related to the interventions carried out in the Region of the Americas (54.6%) and the European Region (23.1%) predominated. For the most part, they are interventions as programs (70.2%), interested in evaluating results (73.5%) from the value judgment (83.4%). Prevalence of interventions focused on efficacy, effects or impact, and activities carried out on interventions were focused on physical activity, healthy eating, sexual and reproductive health, mental health, and use of tobacco, alcohol, and other drugs. They are worked through activities of clinical monitoring, health promotion and disease prevention. CONCLUSION: the evidence indicates that the evaluations of health interventions in the school focus the results produced in programs through the judgment of value. The topics most addressed were healthy eating, physical activity, prevention of alcohol and other drugs, among others. PMID- 30020343 TI - Launching the Latin American Epidemiological Cooperation relating to Noncommunicable Diseases. PMID- 30020342 TI - Comparison of botulinum toxin and propranolol for essential and dystonic vocal tremors. AB - OBJECTIVES: Vocal tremors, which cause social difficulties for patients, may be classified as resting or action tremors. Of the vocal action tremors, essential and dystonic tremors are the most common. Botulinum toxin and oral medications have been used to treat vocal tremors, but no comparative clinical trials have been performed. The aim of this study was to compare the effects of botulinum toxin injection and the oral administration of propranolol in the treatment of essential and dystonic vocal tremors. METHODS: This clinical trial recruited 15 patients, divided into essential and dystonic vocal tremor groups. Patients in both groups received successive treatment with botulinum toxin and propranolol. The treatments were administered at different times; the order of treatment was randomly selected. Patients were assessed with flexible nasofibrolaryngoscopy and with perceptual and acoustic voice evaluations. A statistical significance level of 0.05 (5%) was used. RESULTS: Botulinum toxin produced statistically significant improvements in perceptual measures of vocal instability in patients with dystonic vocal tremors compared with baseline values and treatment with propranolol. The acoustic measure of variability in the fundamental frequency was significantly lower in patients with dystonic vocal tremors after treatment with botulinum toxin. CONCLUSION: Essential and dystonic vocal tremors responded differently to treatment. Dystonic vocal tremors responded significantly to treatment with botulinum toxin but not oral propranolol. Essential vocal tremors did not respond significantly to either treatment, perhaps due to the small number of patients, which is a limitation of this research. PMID- 30020344 TI - Translation and validation of Warmometer, a tool for assessing warmth in patient provider relationships, for use in Brazilian Portuguese. AB - BACKGROUND: Empathy in the patient-provider relationship is associated with important outcomes in healthcare practice. Our aim was to translate and validate Warmometer, a visual tool for assessing warmth in patient-provider relationships, for use in Brazilian Portuguese. DESIGN AND SETTING: Cross-sectional study conducted at an antenatal clinic of a public university hospital in Sao Paulo, Brazil. METHODS: The instrument was translated into Brazilian Portuguese and culturally adapted. It was tested for reliability and validity among 32 pregnant women, between June 2015 and January 2016. To assess construct validity, it was correlated with the Consultation and Relational Empathy (CARE) scale (gold standard for patient-provider relationships) and the Interpersonal Reactivity Index (IRI). RESULTS: The translated version of Warmometer had good face and content validity, low intra-observer reproducibility (intraclass correlation coefficient, ICC: 0.224; 95% confidence interval, CI -0.589 to 0.621;P = 0.242) and high inter-observer reproducibility (ICC: 0.952; 95% CI 0.902 to 0.977; P < 0.001). There was a strong correlation between Warmometer and CARE (r = 0.632) and a weak correlation between Warmometer and IRI (r = 0.105). CONCLUSIONS: Warmometer was translated, culturally adapted and validated for use in Brazilian Portuguese. The translated version is a reliable tool for assessing the degree of empathy perceived by the patient in a patient-provider relationship. PMID- 30020345 TI - Functional capacity measurement: reference equations for the Glittre Activities of Daily Living test. AB - OBJECTIVE: To develop reference equations for the Glittre Activities of Daily Living test (Glittre ADL-test) on the basis of anthropometric and demographic variables in apparently healthy individuals. A secondary objective was to determine the reliability of the equations in a sample of COPD patients. METHODS: This was a cross-sectional study including 190 apparently healthy individuals (95 males; median age, 54.5 years [range, 42-65]; median FEV1 = 97% [range, 91 105.2]; and median FVC = 96% [range, 88.5-102]) recruited from the general community and 74 COPD patients (55 males; mean age, 65 +/- 8 years; body mass index [BMI] = 25.9 +/- 4.7 kg/m2; FEV1 = 36.1 +/- 14.1%; and FVC = 62.7 +/- 16.1%) recruited from a pulmonary rehabilitation center. RESULTS: The mean time to complete the Glittre ADL-test was 2.84 +/- 0.45 min. In the stepwise multiple linear regression analysis, age and height were selected as Glittre ADL-test performance predictors, explaining 32.1% (p < 0.01) of the total variance. Equation 1 was as follows: Glittre ADL-testpredicted = 3.049 + (0.015 * ageyears) + (-0.006 * heightcm). Equation 2 included age and BMI and explained 32.3% of the variance in the test, the equation being as follows: Glittre ADL-testpredicted = 1.558 + (0.018 * BMI) + (0.016 * ageyears). CONCLUSIONS: The reference equations for the time to complete the Glittre ADL-test were based on age, BMI, and height as independent variables and can be useful for predicting the performance of adult individuals. The predicted values appear to be reliable when applied to COPD patients. PMID- 30020346 TI - Hyperimmunoglobulin E syndrome (Job syndrome): chest CT findings. PMID- 30020347 TI - Patient-ventilator asynchrony. AB - Patient-v entilator asynchrony (PVA) is a mismatch between the patient, regarding time, flow, volume, or pressure demands of the patient respiratory system, and the ventilator, which supplies such demands, during mechanical ventilation (MV). It is a common phenomenon, with incidence rates ranging from 10% to 85%. PVA might be due to factors related to the patient, to the ventilator, or both. The most common PVA types are those related to triggering, such as ineffective effort, auto-triggering, and double triggering; those related to premature or delayed cycling; and those related to insufficient or excessive flow. Each of these types can be detected by visual inspection of volume, flow, and pressure waveforms on the mechanical ventilator display. Specific ventilatory strategies can be used in combination with clinical management, such as controlling patient pain, anxiety, fever, etc. Deep sedation should be avoided whenever possible. PVA has been associated with unwanted outcomes, such as discomfort, dyspnea, worsening of pulmonary gas exchange, increased work of breathing, diaphragmatic injury, sleep impairment, and increased use of sedation or neuromuscular blockade, as well as increases in the duration of MV, weaning time, and mortality. Proportional assist ventilation and neurally adjusted ventilatory assist are modalities of partial ventilatory support that reduce PVA and have shown promise. This article reviews the literature on the types and causes of PVA, as well as the methods used in its evaluation, its potential implications in the recovery process of critically ill patients, and strategies for its resolution. PMID- 30020348 TI - ICNP(r) terminology subset for care of women and children experiencing breastfeeding. AB - OBJECTIVE: To describe the development of a terminology subset of the International Classification for Nursing Practice for care of women and children in process of breastfeeding. METHOD: Methodological study developed in six stages according to the guidelines recommended by the International Council of Nurses. RESULTS: Seventy-four nursing diagnoses/outcomes and 213 nursing interventions were performed and classified according to the theoretical model Interactive Theory of Breastfeeding. CONCLUSION: The subset is expected to safely and systematically steer nurses that work in this area, promoting the implementation of the nursing process and quality of care, focusing on women, children and families that are experiencing the breastfeeding process. PMID- 30020350 TI - Effects of diode laser application on inflammation and mpo in periodontal tissues in a rat model. AB - OBJECTIVE: In this study, we aimed to histologically and immunologically evaluate the effect of diode laser treatment when applied adjunctive to scaling and root planing (SRP) in an experimental periodontitis model. MATERIALS AND METHODS: We used Wistar-Albino rats (n=60) with average weight of 230 g. Experimental periodontitis was induced by ligature at the right and left first mandibular molar teeth in all rats. After 11 days, the ligature was removed and rats were divided into two groups. The control group (n=30) received only SRP treatment, while the laser group (n=30) received a diode laser (GaAlAs, 810 nm, 1 W, 10 J, 20 s) treatment adjunctive to SRP. Ten rats in each group were sacrificed after 7, 15, and 30 days. Histopathological examination was performed in the left mandible of rats. Myeloperoxidase (MPO) was evaluated by western blot in the gingival specimens from the right mandible. RESULTS: MPO levels in the laser group were statistically significantly lower compared with the control group (p<=0.05). There was no statistically significance at any time between MPO levels in the control group (p>0.05). MPO levels in the laser group at the 7th day were statistically significantly higher compared to the 15th (p<=0.05) and the 30th day (p<=0.05). Inflammatory cell infiltration decreased over time in both groups and was statistically significantly lower in the laser group than in the control group at all times (p<=0.01). CONCLUSIONS: Within the limits of this study, we suggest that diode laser application is an adjunctive treatment because it reduced inflammation and MPO when applied in addition to SRP. On the other hand, more studies are needed for the assessment of the effects of diode laser application to periodontal tissues. PMID- 30020349 TI - Communicative performance and vocabulary domain in preschool preterm infants. AB - OBJECTIVE: The objective of this study was to evaluate and compare the performance of children in preschool age who were born premature and term, without neurological injury, regarding receptive and expressive language skills, and to reflect on the importance of these skills for performance in preschool. MATERIALS AND METHODS: Two groups named Preterm Group and Comparison Group, each composed by 40 children, as well as 80 legal representatives (mothers) and 80 teachers of the participants. To pair the groups, we considered chronological age (months), sex, educational level, type of school (public or private) and socioeconomic status. To assess the groups we used structured and semi-structured Observation of Communicative Behavior and applied the ABFW Child Language Test - Part B-Vocabulary and the Peabody Picture Vocabulary Test. To assess the legal representatives we applied an anamnesis questionnaire and the MacArthur Communicative Development Inventory. The assessment of the teachers consisted of the MacArthur Communicative Development Inventory and a Student Assessment Protocol developed by the authors. RESULTS: For the observation of communicative behavior, the categories with the highest losses were: narrative, maintaining dialogic activities and attention difficulties. In the ABFW Child Language Test and Peabody Picture Vocabulary Test there were statistically significant differences. In the MacArthur Communicative Development Inventory there were statistically significant differences in expressive vocabulary, but no differences in receptive vocabulary, for both the mothers and the teachers. CONCLUSION: Children born prematurely with low risk of neurological sequelae in preschool age may have greater difficulties in linguistic performance than their peers born to term. PMID- 30020351 TI - Study of the chemical interaction between a high-viscosity glass ionomer cement and dentin. AB - OBJECTIVE: To investigate the chemical interactions between a high-viscosity glass ionomer cement (GIC) (KetacTM Molar Easymix, 3M ESPE, Seefeld, Bavaria, Germany) and human dentin. It was also analyzed the dynamics of GIC setting mechanism based on the time intervals required for the GIC and the GIC mixed with dentin to achieve stability. MATERIAL AND METHODS: Each constituent of GIC - powder (P) and liquid (L) - and powdered dentin (D), as well as the associations P+L, D+L, and P+L+D in the concentrations of 29%, 50%, 65%, 78%, 82%, and 92% of GIC were analyzed with Fourier transform infrared (FTIR) and Raman spectroscopy. RESULTS: New optical absorption bands and/or Raman bands, which were not present in P, L, or D, were observed in the associations. The concentrations of 29% and 50% of GIC showed higher interaction, revealing that the amount of dentin influences the formation of new optical absorption or scattering bands. FTIR bands showed that the setting time to achieve bond stability was longer for the high-viscosity GIC (38+/-7 min) than for the sample with 29% of GIC (28+/-4 min). CONCLUSIONS: The analysis revealed the formation of new compounds or molecular rearrangements resulting from the chemical interactions between GIC and dentin. Moreover, this study provides an effective method to evaluate the dynamics of the setting mechanism of GICs. PMID- 30020353 TI - [Geography of health: historical bases and the present]. PMID- 30020352 TI - Tomographic late evaluation of xenogeneic bone grafts in sockets of impacted third molars. AB - OBJECTIVE: It is necessary to preserve height and thickness of the alveolar bone to facilitate rehabilitation with osteointegratable implants or simply to maintain bone integrity after extraction. Biomaterials associated with resorbable or non-resorbable membranes, when placed in the region of the socket, may contribute to avoid this unwanted reabsorption. OBJECTIVE: The objective of this study was to evaluate the distance of the crest of alveolar ridge to the cementoenamel junction (CEJ) of the lower second molars and the bone density of the third molar socket filled with Gen-Tech(r), 5 years after an exodontia using cone beam computed tomography (CBCT) to visualize the central region of the sockets, without overlapping of the buccal and lingual cortical bones. MATERIAL AND METHODS: A total of 12 individuals from an initial group of 39 patients submitted to extraction of the unruptured lower third molars and grafting of an association of inorganic bovine bone matrix, organic bovine bone matrix, collagen and bone morphogenetic proteins (BMP) (Gen-Tech(r)) on one side and the contralateral sockets filled only by clot, returned to control after 5 years, and were submitted to CBCT. The distance from the crest of alveolar bone to the CEJ and the bone density (BD) were measured using the i-CAT Vision Software. RESULTS: The results showed that the distance from the crest of alveolar bone to the CEJ in the control group was similar to that observed before the exodontia; in the experimental group, this distance was smaller. Considering the BD measurement, a significantly higher density was observed in the experimental group (p<0.05). CONCLUSION: Part of the biomaterial was not absorbed and allowed the stability of the evaluated parameters after 5 years, being able to be used as a bone substitute in the socket. PMID- 30020354 TI - The role of inter-regional flows in the spread of epidemics in a city of regional influence with a tropical climate. AB - The aim of this research was to investigate the origin of imported cases of dengue in the city of Araraquara, Brazil and to describe the disease's main epidemiological characteristics. The study encompassed all confirmed cases of dengue recorded in the Information System for Notifiable Diseases (SINAN) [Sistema de Informacao de Agravos de Notificacao] from 1998 to 2013. Cases whose origin of infection was likely located outside Araraquara were considered imported. The epidemiological study entailed a descriptive analysis of the data, regarding the distribution of cases by sex, age, and classification of imported and autochthonous cases. A geographic information system was used to map flows and estimate distances. There were 6,913 confirmed cases, 419 of which were imported. In most cases, the origin of infection was located in the state of Sao Paulo as well as other Brazilian regions. The results indicate the relevance of imported cases and differences in the epidemiological profile with respect to age and sex. Conclusions indicate the need to increase epidemiological and environmental health surveillance at ports, airports, truck stops, and bus and train terminals. PMID- 30020355 TI - [Development of a georeferenced system for the management, mobility and monitoring of primary care in community health]. AB - Community health agents carry out significant actions on the ground to provide prevention and care and bring health services to families. These practices in the field constitute a constant collective mapping process using the knowledge of the territory that the agents possess. Based on intensive fieldwork starting in 2012 in conjunction with local social organizations and health institutions in Brazil and Argentina, the binational project App+Health (App+Salud in Spanish and App+Saude in Portugues) was initiated. The project's objective was to develop a monitoring and georeferencing system for community health management in the form of an application for cell phones or tablets with internet access, which would take into account the basic conditions of the environment and movement history of users and connect map updating methodologies using social cartography with free collaborative mapping platforms. As a result, the beta version of App+Health was developed, through a heightened process of exchange of interdisciplinary knowledge. PMID- 30020356 TI - Geospatial and environmental analysis of road traffic accidents in the city of Resistencia, Argentina. AB - Traffic accidents are an emerging problem in cities with high mobility and little urban planning. Evidence is lacking in Argentina regarding the relationship between the environment and accident occurrence; we therefore conducted a geospatial analysis and estimated the risk of accidents and their possible association with the characteristics of the physical environment in the city of Resistencia, Argentina occurring in 2012. Kernel density estimates were used for the spatial distribution of accidents and in parallel an observational, analytical study was carried out to analyze the factors associated with accident occurrence. The results show three critical areas (in the northwest, center and south of the city) with greater accident frequency. Environmental factors that were associated with the occurrence of accidents were the presence of street lighting (23% greater), the presence of a tree close to the road (47% greater), the presence of a traffic light (28% greater), and if the road was a major avenue (122% greater) and had curves (129% greater). This study shows the city of Resistencia to be in a situation of urban vulnerability due not only to its socioeconomic status but also to the unequal development compared to neighboring cities, a reality that fosters an unfavorable environment. PMID- 30020357 TI - [Health risk zoning: yellow fever from a geographical perspective in La Macarena, Department of Meta, Colombia]. AB - This paper attempts to zone yellow fever risk in La Macarena (department of Meta, Colombia) in terms of environmental hazards and socio-economic vulnerabilities. An ecological study was carried out, in which data published from 2007 to 2013 on conditions of the municipality were integrated into a geographic information system. Through a superposition of map layers, magnitudes of hazard and vulnerability proportional to the degree of severity were obtained. As a result the spatial heterogeneity of the risk of yellow fever was described, suggesting that the areas surrounding populated centers, roads and rivers present the highest probability of transmission. It is concluded that the cartographic representation of the spatial distribution of risk in the municipality constitutes a methodological contribution to health risk zoning - in concrete geographical areas and based on hazards and vulnerabilities - which facilitates decision-making in public health. PMID- 30020358 TI - [Child malnutrition in Argentina in the first part of the century: a quantitative approach]. AB - Child malnutrition is an important public health problem in Argentina, both as a primary cause of mortality/morbidity and associated with different pathologies that affect children. However, little is known about its magnitude, trends and spatial distribution. This article seeks to detect such situations considering different geographic scales. A quantitative approach was applied, systematizing vital statistics (mortality), hospital discharges (morbidity), and low birth weight (natality) in children 0-4 years of age. Accordingly, the information sources used were mortality statistics (1999-2013), hospital discharge statistical records (2000, 2005-2011) and live birth statistics (1999-2012) provided by the Office of Statistics and Health Information (DEIS) [Direccion de Estadisticas e Informacion de Salud] of the National Ministry of Health. The results show differences according to the scale considered. The conclusions highlight the necessity of integrating the different sources of information analyzed in order to provide a more general overview of a problem that, albeit in decline, still registers high magnitudes in the most vulnerable areas. In this way, certain areas of northern Argentina evidence worse conditions, requiring immediate attention be paid to issues of poverty and child health. PMID- 30020359 TI - [Spatial variation of hypertension treatment coverage in the municipality of Santiago, Chile]. AB - One of the tasks of primary health care is to achieve adequate treatment coverage for patients with arterial hypertension. The aim of this study was to analyze the spatial variation of hypertension treatment coverage in the municipality of Santiago de Chile in 2014, evaluating its relationship with the distance to primary health care establishments and socioeconomic factors using georeferencing techniques and global and geographically weighted Poisson regression models. According to the results, arterial hypertension treatment coverage shows spatial dependence, given that its relationship with the presence of older adults, the proportion of population enrolled, socioeconomic status and the distance to primary health care establishments varied spatially. It is concluded that in order to improve hypertension coverage it is necessary to consider different local realities, a process that can be facilitated by the application of spatial analysis techniques. PMID- 30020360 TI - Childhood cancer: incidence and spatial patterns in the city of Campinas, Brazil, 1996-2005. AB - This article analyzes cancer incidence and spatial patterns in children and adolescents (0-19 years of age) residing in the city of Campinas in Southeastern Brazil who were diagnosed from 1996-2005. Cancers were classified according to the Third International Classification of Childhood Cancer (ICCC-3) Groups. The four most common groups were studied: leukemias, lymphomas, and central nervous system and soft tissue neoplasms. Age-standardized incidence rates were calculated using the world standard population. A spatial Bayesian hierarchical regression model (controlling for data heterogeneity and spatial autocorrelation) was fitted, assuming that the number of cancer cases follows a Poisson distribution. A total of 180 cases were diagnosed during the study period. Overall, the crude incidence rate was 54.2 per million and the age-standardized incidence rate was 56.5 per million. Although some regions present higher incidence rates, considering the spatial heterogeneity and the spatial autocorrelation, no statistically significant differences in the relative risks were observed. PMID- 30020361 TI - [Analysis of the spatial distribution of road accidents attended by the Mobile Emergency Service (SAMU-192) in a municipality of northeastern Brazil]. AB - This study describes the epidemiological characteristics of road accident victims attended by the Brazilian Mobile Emergency Service (SAMU-192) and located in the areas of highest accident density in the municipality of Olinda, (Pernambuco, Brazil). Kernel density estimation was used to detect spatial agglomerations of accidents. In 2015, 724 accidents occurred; of these, 73.48% of the victims were males aged 20-39 years. There was a predominance of accidents involving motorcycles (54.97%). Accident clusters were detected in the main traffic corridors, with run-over accidents located near bus terminals. Spatial analysis proved to be a relevant instrument for the identification of accident clusters and the application of effective prevention and traffic safety improvement measures. PMID- 30020362 TI - [Factors associated with the occurrence of tuberculosis and its spatial distribution in a Brazilian city, 1991-2010]. AB - This article seeks to identify factors associated with the incidence of tuberculosis and the spatial distribution of the disease in Olinda, Pernambuco, from 1991 to 2010. In order to study the factors associated with the disease, Poisson regression was applied and standardized morbidity ratios were utilized for the spatial exploratory analysis. Although a reduction in the average incidence of tuberculosis in Olinda was observed, the rate remains high in comparison with the national average. Mapping according to five-year periods suggests rate increases until 2005, with a decline between 2006 and 2010 and the persistence of high incidence in areas of greater socioeconomic need. The highest tuberculosis incidence rates were associated in each area with the proportions of illiteracy, of heads of household without income, of households lacking water supply and of older adults, as well as with the presence of cases of retreatment and of households with two or more new cases of tuberculosis. Incorporating a spatial component is key for the organization of health services and the planning of epidemiological surveillance for tuberculosis. PMID- 30020363 TI - [Analysis of the territorial patterns of the life contexts of children up to 6 years of age and their potential influence on the coverage of immunization programs in Chile]. AB - The aim of this paper was to analyze selected variables that could be involved in vaccination coverage of children in different communal territories of Chile, including the vaccines bacillus Calmette-Guerin (BCG) at birth, pentavalent at 6 months and measles-mumps-rubella (MMR) at 12 months and 6 years, in the period 2008-2011. The methodology includes three phases. The first corresponds to the operationalization of twenty socio-territorial variables that account the general life contexts of the target population. The second phase involves the definition of a scale of values through a panel of experts to weigh the importance of each of the variables. The third phase integrates the information into a spatial decision support system for the identification of territorial patterns, through multi-criteria evaluation and multivariate cluster analysis. The results indicate that it is feasible to group territories into four types. In general terms, it is possible to observe that as the life context improves, higher levels of coverage can be found for each vaccine. PMID- 30020364 TI - International context and national policies: challenges facing social protection and health systems in a changing world. PMID- 30020365 TI - Sustaining Social Protection and Provision: the front line in the battle for the Good Society. AB - In an era when social policy priorities are subordinated to regressive capitalist agendas, sustaining collective commitments to social protection and social provision defines the front line of the battle for the good society. The conflict manifests itself across a range of arenas, but health is analytically archetypal. This introductory article for the special issue assumes the dynamics of the contradiction between the inherently collective character of health provision and capitalist insistence on using individual consumption valued in market prices to measure societal success. Left unchecked, the elite bloc whose agenda is defined by pursuit of the interests of capital will destroy existing social provision and protection, making societies, especially in the Global South, ugly places to live for ordinary citizens. The articles in this volume leave us with a challenge: how can we construct the oppositional agency necessary to expand and strengthen social provision and protection in an era of regressive capitalist domination? PMID- 30020366 TI - Changing Systems of Social Protection in the Context of the Changing Political Economies since the 1980s. AB - This article provides an overview of the profound changes in the more advanced welfare states in Europe and Latin America over the past 35 years. Deindustrialization, informalization, and the rise of unstable employment, combined with aging populations rendered traditional employment-based models of social protection less effective and at the same time increased demands on the welfare state. The two main responses to these challenges were efforts at cost containment and inclusion in non-contributory social protection schemes and health services of those in marginal labor market positions. The mix of these two responses and the depth of the changes were shaped by the intensity of the economic and demographic pressures, policy legacies, the partisan preferences of governing parties and coalitional constraints, the strength of groups in civil society, the presence of veto points in the political system, and in Latin America the process of democratization, along with the international context. A broad comparison between Latin America and Europe highlights the importance of the international context in the form of a relentless pursuit of neoliberal models by the International Financial Institutions in Latin America in contrast to the model of Social Europe promoted by the European Union. PMID- 30020367 TI - [Is the Welfare State resisting? Recent developments of the social state in OECD countries]. AB - In this paper an attempt was made to analyze some of the main indicators of the evolution of the welfare state in OECD countries between 1980 and 2016. In particular, an assessment was made to evaluate if the so-called Great Recession starting in 2008 led to a contraction of the social state. The analysis focused on three dimensions: social expenditure, funding, and effectiveness. The conclusion drawn was that the twenty-first century has been a period of expansion, both in terms of social expenditure and the catch-up of the latecomers. In particular, all traditional areas of social policy have expanded in tandem with a slight increase in "active" social policies. The rise in social expenditure has been financed by increasing taxation not thoroughly alien to progressivity principles. Overall, it has been translated into an increased effort for redistribution. However, inequality and poverty are advancing at a higher rate. PMID- 30020368 TI - Neoliberal meritocracy and financial capitalism: consequences for social protection and health. AB - There is inherent tension between the idea of health as a social right and of health as a private good. From the latter perspective, healthcare provision is brought closer to the logic of ownership, where access depends on ability to pay. The prioritization of markets (over governments), economic incentives (over social or cultural norms), and entrepreneurship (over collective or community action), one of the hallmarks of neoliberalism, constitutes a project to dismantle the welfare state, defined as a set of policy mechanisms designed to meet collective needs. This article examines the above process and its consequences for social protection and health by reflecting upon two phenomena that threaten the principle of health as a social right: neoliberal ideas and policies; and financial capitalism. We argue that the common good must be defended or insulated from the negative effects of financial capitalism and from the erosion and fragmentation of public institutions and social protection systems caused by neoliberalism. PMID- 30020369 TI - Global technological transformations and asymmetries: development strategy and structural challenges for the Unified Health System. AB - This paper articulates contemporary themes of the development agenda as global phenomena that affect the dissemination and direction of health technical progress, subjecting the sustainability of the Unified Health System (SUS). The evaluation of the external dependence of the Brazilian Health Economic Industrial Complex, the bibliographical review of the literature on economic complexity and its data on Latin America and Brazil and the collection and evaluation of statistical data from the World Intellectual Property Organization and the National Institute of Industrial Property enable us to build an overview of increasing economic and power asymmetries that reiteratesthis centre-periphery pattern in multiple themes and geographical scales. This perspective consolidates the endogenous link between national development patterns and structural possibilities and boundaries for the setting of a Brazilian universal health system. Confronting global technological asymmetries is part of a strategic agenda that conditionsthe advancingof the Unified Health Systemtowards its founding principles of universality, comprehensiveness and equity. PMID- 30020370 TI - The social issue in the BRICS Project. AB - BRICS, the acronym for Brazil, Russia, India, China and South Africa, is the first multilateral group created and run by non-western developed countries. The group aims to influence world geopolitics and market based on the right of developing and emerging countries to participate equitably in development. The social issue lies at the core of the group's justifications to achieve its goals. In this regard, this paper aims to analyze how the social issue has been addressed by BRICS. The methodology was based on bibliographic research and documentary analysis of the Declarations resulting from the nine BRICS Summits held from 2009 to 2017. Findings indicate that the social problem was necessary for the affirmation of the group's project in the global context. While there are advances in some social indicators and poverty has been reduced, the results in many social commitments of the group are weak. This can be attributed to the centrality of national contexts in the social issue, internal differences between countries, the non-mandatory nature of the group's initiatives, or because, while showing powerful strategies for new global arrangements, the social issue remains subsumed to geopolitical and market objectives. PMID- 30020371 TI - [The reshaping of healthcare systems in the age of financialization. Lessons from France and Brazil]. AB - Since the post-War period, social protection systems have experienced continuous reforms, either extending or, more often, reducing the scope and the scale of public provision. This paper seeks to present how healthcare systems have evolved both in France and in Brazil recently, in order to comprehend mechanisms through which financialization has been reshaping public care provision. This comparative analysis unveils distinct financialization dynamics of healthcare systems, built upon universalism principles. After featuring both systems, underlying their private dimension - either complementary or supplementary - the article points out how the financial sector is broadening its share in the supply of healthcare services. In what follows, the sector's process of internationalization/centralization is analyzed and lastly the regulatory role of the State in strengthening private provision is defined. Despite radically different institutional paths, the findings corroborate that in both cases finance is a driving force in reshaping the healthcare sector. PMID- 30020372 TI - Commodification in the reforms of the German, French and British health systems. AB - Since the 1980s, European health systems have undergone several reforms, with emphasis on the tendency of their commodification. The objective of this article is to demonstrate how market mechanisms were implemented in the functioning of these systems, german, british and french - from the 1980s. The "mercantile" reforms were justified on the premise that the insertion of market logic could both reduce the need for public spending and increase the efficiency of existing expenditure. The work presents different forms of commodification implemented in the reforms, with the distinction between processes of explicit commodification, in which there is an effective increase in private, and implicit presence, in which there is incorporation of principles from the private sector in the public system, both in financing and in the provision of health services. In addition to detailing the different ways in which this phenomenon is expressed, the article briefly presents the potential negative effects of this process for health systems, especially in terms of access and equity, stating that the initial assumptions surrounding commodification (cost reduction and efficiency improvement) appear to be false. PMID- 30020373 TI - Social Determinants, Conditions and Performance of Health Services in Latin American Countries, Portugal and Spain. AB - Comparison can be an important resource for identifying trends or interventions that improve the quality of health services. Although Portugal and Spain have accumulated important knowledge in primary health care-PHC driven national systems, the Ibero-American countries have not been object of comparative studies. This paper presents an assessment using an analytical dashboard created by the Ibero-American Observatory on Policies and Health Systems. It discusses aspects that have stood out in monitoring the service systems of Argentina, Brazil, Colombia, Spain, Paraguay, Peru, and Portugal throughout the 21st century's first decade. Forty-five indicators and time series showing the highest completeness degree divided into social determinants, conditions and performance were analyzed. Three trends are common to almost all countries: overweight increase, negative trade balance for pharmaceutical products, and an increase in health system expenditure. This convergence trend reveals the need for changes in the way of regulating, organizing and delivering health services with public policies and practices that guarantee comprehensive care, including health promotion actions enabling systems sustainability. PMID- 30020374 TI - The World Bank, state reform, and the adjustment of social policies in Latin America. AB - This article briefly analyses the central points of the World Bank's agenda for the reform of national states in Latin America, between 1980 and 2017. The text is based on World Bank documents and specialized literature. Initially some relevant aspects of the history of the World Bank and its configuration as a multilateral organization are presented. Next, it discusses the role of the institution in the encouragement of structural adjustment programs for the economies of the region during the 1980s, based on a hyper-market oriented agenda. Afterwards, the process of the renewal and expansion process of the Bank's political agenda from the end of the 1990s is looked at, which was based on the maintenance of the macroeconomic adjustment, the encouragement of institutional reforms, and combatting extreme poverty. Finally, the principal lines in the Bank's social policy reform agenda are discussed, including health. PMID- 30020375 TI - Health Policies in Argentina, Brazil and Mexico: different paths, many challenges. AB - Over recent decades, several Latin American health systems have undergone reforms. This paper analyzes health policies in Argentina, Brazil and Mexico from 1990 to 2014. It explores the reform strategies, explanatory factors and effects on the configuration of each health system. The analytical framework was based on the historical-comparative approach and considered the following aspects: political and economic context; health reform agendas, processes and strategies; changes in the health system configuration in terms of social stratification and de-commodification. The research methods involved literature review, document and data analysis and interviews. In the period, Argentina maintained an employment based and fragmented healthcare system, expanded specific public programs and private health plans. Brazil created a public and universal health system, which coexists with a dynamic and growing private sector. Mexico maintained the employment-based health care and created a popular health insurance. Although the reform influences and strategies varied between the countries, social stratification and commodification persisted in the three health systems, under different arrangements.The transformation of these characteristics is essential to build universal health systems in Latin America. PMID- 30020376 TI - Network integration and care coordination: the case of Chile's health system. AB - The article analyzes the implementation of integrated healthcare networks (RISS) and the strategies for care coordination by PHC in the Chilean public health system. Semi-structured interviews were conducted with policymakers from the public health system and academics, complemented by documentary analysis and bibliographic review. The country stands out for the institutionalization of care coordination instruments widely recognized, such as referral maps, demand manager physician, electronic records and, mainly, definition of protocols, under the strong leadership of the Ministry of Health and conduction by the Servicios de Salud managers, regional space for the construction of RISS. However, segmentation and fragmentation's degrees within the public subsystem were identified, with the maintenance of free-choice for specialized medical appointment and double waiting lists - one for procedures with explicit access guarantees and another for others cases. The Chilean experience demonstrates the need for a greater role for PHC so it will be able to take on the leadership of RISS. In the country, the network seems to orbit around large and powerful hospitals. Elements of a broader context of the health system also condition advances and impasses in the development of the analyzed strategies. PMID- 30020377 TI - Stewardship and governance: structuring dimensions for Implementation Primary Health Care Policies in Paraguay, 2008-2017. AB - This study analyzes the conduction patterns of implementing Primary Health Care (PHC) in Paraguay in three government periods (2008-2012, 2012-2013 and 2013 2017) and three management levels (national, regional and local). This is a qualitative study based on grounded theory. A priori categories on PHC stewardship and governance in Paraguay were analyzed. An open-ended questionnaire was applied to a sample of social, political and technical stakeholders: ministers, coordinators, managers, consultants, and international organizations' experts. Data were processed combining the use of Atlas Ti software and sorting findings in a structured Excel matrix. Gaps in leadership, regulatory mechanisms, technical capacities for health planning and management and financial implementation methods have affected PHC continuous expansion and strengthening process. The findings show limitations and possibilities for the implementation of this health policy in Paraguay, evidencing the need for greater qualification of management and political stability in its conduction. PMID- 30020378 TI - [Decentralization and regionalization of health policy: a historical-comparative approach between Brazil and Spain]. AB - This article discusses the processes of de centralization and regionalization of health policy in Brazil and Spain between 1980 and 2015. The study was developed with contributions of the historical institutionalism and of the historical com parative method, by means of three dimensions of analysis: State context; trajectory and institution ality of the decentralization and regionalization of health; and constraints. The study showed that,in both countries, the more general context of re-democratization and decentralization of the State conditioned the reforms of health systems and their political-administrative organization. In addition, historical, institutional and political factors have had a specific impact in each case, influencing the regional organization of services, the balance of power and the division of responsibilities between the governmental spheres in the management, financing and coordination of health policy. The study suggests that the way these factors interrelated over time is important for understanding the decentralization and regionalization of health systems in different contexts. PMID- 30020379 TI - Health policies in Southern Europe and deregulation of labour relations: a glimpse of Portugal. AB - Under the Troika Memorandum (2011-2015), health policies in Portugal know a political agenda, business and organizational schedule guided by the principles of privatisation, deregulation and underfinancing of public services by the State. In this article, the authors provide a review of the literature on health systems in the countries of the Southern European countries, highlighting the Portuguese situation regarding reform processes and major health inequalities before and during the economic crisis. Complementarily, the testimonies of different professionals of the health sector (doctor, nurse, therapeutics technician, unions and heads of care units) are summoned. Based on an exploratory study, it is our purpose to discuss political-organisational transformations and their consequences in the deregulation and precariousness of labour relations in the health sector. Wage reductions, career freeze, contractual instability, professional demotivation, intensification of the work pace and disqualification of services are some of the most visible signs of a management agenda that conflicts with the missions of a universal National Health System (NHS) at the service of Portuguese society. PMID- 30020380 TI - Challenges for work in healthcare: comparative study on University Hospitals in Algeria, Brazil and France. AB - This study compares the challenges for work in emergency services of publicuniversity hospitals in Algeria, Brazil and France. The description and analysis are organized in three topics: context and trajectory of the health systems; hospitals and emergency services; and the challenges that are faced. The research carried out interviews, surveys, observation and "groupes de rencontre du travail" / GRT. The data analysis was done using participatory appraisal techniques associated to triangulation of sources and data. The main challenges found were: workforce deficit; lack of hospitals beds in inpatient units; deficit of infrastructure and materials; excess of "chronophagic activities"; generational transition; and violence by patients and families.Despite their particularities, the countries coincide regarding the challenges. Measures to rationalize and restrain spending have a greater impact on Algeria and Brazil due to the low level of public funding, but they also occur in France. The hospital management cannot be dissociated from healthcare system planningconsidering the increasing pressures of the demographic and epidemiological transition. In medium term, measures that may mitigate "chronophagic activities", materials deficit and the violence should be considered to improve work in emergencies. PMID- 30020381 TI - Pharmaceutical Services in Mozambique: foreign aid in public provision of medicines. AB - This article examines the activities of national and international actors in Pharmaceutical Services (PS) in Mozambique from 2007 to 2012, focusing on the public provision of HIV/Aids, malaria and tuberculosis medicines. It describes how PS functions in the country, what actors are involved in this area and the relations among them, pursuing salient issues in the modus operandi of partners in cooperation. The methodology combines literature review, document survey and analysis and interviews. The theoretical and analytical framework was given by the policy analysis approach, focusing on the role of the State and its interrelations with other actors in foreign aid in PS, and also by the networks approach. It was concluded that the interactions among the actors involved is complex and characterised by operational fragmentation and overlapping of activities between entities, centralised medicine procurement in the hands of few agents, bypassing of national structures and disregard for the strengthening needed to bolster national health system autonomy. Despite some advances in the provision and availability of medicines for these diseases, external dependence is strong, which undermines the sustainability of PS in Mozambique. PMID- 30020382 TI - [Meanings of Neglected Diseases in the Global Health agenda: the place of populations and territories]. AB - The global health agenda has made significant strides in neglected diseases. In a dynamic movement, throughout the past two decades, it has assumed different priorities, strategies and meanings. Nevertheless, important challenges persist in terms of geopolitical, economic, epistemological and social development. The designation and location of neglected diseases in certain territorial spaces and populations is historically related to some dynamics such as those of a colonial and capitalistic nature. They reveal continuities in the rationality of policies and actions, pervading asymmetries between peoples, institutions and nations. Although it has positively included the debate on neglected diseases, it can be argued the global agenda of public health has yet to assume and evoke the dimension of neglected bodies and populations with more theoretical and methodological vigor, by intensifying the dialogue between biomedical and political-economic fields. It means reinforcing the critical understanding of the historical vulnerabilities of individuals in the production of knowledge, as well as giving prominence and taking into account their ways of leading their lives in conjunmction with local public health priorities and practices. PMID- 30020383 TI - The Right to healthcare and fiscal austerity: the Brazilian case from an international perspective. AB - The article analyzes the implications of the austerity policy in Brazil on the guarantee of universal social rights, focusing on the financing of the Unified Health System (SUS) and the right to health. The effects of the Brazilian austerity policy are analyzed in an international perspective, based on evidence produced in different contexts, identified from a literature review, in order to base the arguments developed in the article. Information on the fiscal austerity measures being implemented in Brazil is presented and its likely impacts on social protection in the country are analyzed in a context of significant economic recession. The austerity policy adopted in Brazil is not universal, since it does not affect all Brazilian society equally, nor does it have temporary effects, since it is not focused on reducing the momentary imbalance in public accounts. Its main objective is to promote the reduction of the size of the Brazilian State. Finally, we show alternative paths to the fiscal austerity policy that has been used to tackle the economic crisis. The authors argue by a national development project that is necessarily linked to social protection for the universe of citizens and based on values of solidarity. PMID- 30020384 TI - Displacement of social security and social disprotection in Brazil. AB - After 30 years in force, CF-88 must be salvaged and commemorated but also evaluated in relation to how much social and political resistance it acquired in the execution of its determinations. These determinations not only conflict with those of the dictatorial period preceding it but were also shown to be minimally attractive to neoliberal forces in Brazil in the late 1980s and early 1990s and are now widely recognized as conservative. One of the main recommendations of CF 88 - the subject of this article - was the notion of universal public State social protection adopted under the basis of security and/or social security and, with it, a social security budget. Over the last 30 years, this idea has shifted from this founding matrix due to forces of conservatism, individualism, and privatization. This has limited the State's role as a provider, thus conditioning access to the consumption capacities of social protection commodities. PMID- 30020385 TI - Harm reduction strategies regarding the misuse of alcohol and other drugs: a review of the literature. AB - The present study attempts to systemize the experiences of those that have been treated in the primary health care system for alcohol and drug abuse with a view to obtaining reductions in the damages caused to Brazil and the world at large. A bibliographical study was conducted of publications in Portuguese and in English over the past ten years on the following databases SciELO, Lilacs, Medline and PsycINFO. After the selection of the corpus, meta-synthesis was carried out in order to integrate the material obtained. It was possible to identify and analyze advances and impasses in the implementation of harm reduction strategies, and to compare the different approaches identified in the services and care activities offered to users. We noticed that Harm Reduction has become consolidated as a prevention and health care strategy; therefore, it is essential that more academic and scientific research in this area is conducted. PMID- 30020386 TI - Social Support patterns in Primary Health Care: differences between having physical diseases or mental disorders. AB - The social support network is a health protective factor involving physical, mental and psychological aspects, providing a better quality of life, favoring better adaptation to adverse conditions, promoting resilience and mobilizing resources for a more effective coping with negative life events that can lead to illness. We aimed to analyze the association between physical diseases, common mental disorders and the social support network of patients serviced at primary care facilities in the cities of Rio de Janeiro and Sao Paulo through a cross sectional study with 1,466 patients in the 18-65 years age group. We used the Social Network Index (SNI) to assess the support network through the categories of isolation and integration. The doctor/nurse completed the questionnaire to evaluate the physical disease diagnosis, while the Hospital Anxiety and Depression Scale was used to detect mental disorders. We found that the pattern of social support was different depending on the presence of physical diseases or mental disorders. Negative associations were found between diabetes and isolation; integration and anxiety; integration and depression. Positive associations were identified between isolation and anxiety and isolation and depression. PMID- 30020387 TI - [Circumstances and consequences of care: a prospective study in palliative care]. AB - The sundry circumstances that affect end-of-life care can have a determining role in the result of this experience, particularly in psychological morbidity levels before and after bereavement. The aim of this study is to describe the prevalence of psychopathological symptoms and overburden among family caregivers in palliative care and to identify the circumstances associated with care provision. An attempt was made to evaluate the progress of psychopathological symptoms, identifying circumstantial factors that can interfere in acute grief. The sample consisted of 75 Portuguese caregivers, mostly women and patients' daughters. The results show that caregivers more involved with patient care bear a greater burden and are more likely to manifest psychopathological symptoms, which persist in acute grief. Moreover, the existence of peritraumatic symptoms seem to contribute significantly to the overall state of distress in acute grief. Social support has a protective effect in the different symptomatologic situations and are closely related to family dynamics. These results suggest the possibility of early identification of the most vulnerable caregivers and the adverse circumstances that affect them. PMID- 30020388 TI - Parents and children suffering from mental distress: coping mechanisms, understanding and fear of the future. AB - The aim of the study was to learn about the parents' coping experiences regarding the mental suffering of their children. This is an ethnographic study. Data was analyzed through content analysis. Three categories have been identified: 1. Coping with everyday situations 2. Understanding of mental suffering as a life situation; 3. Fear of the future, feeling of social and governmental helplessness. Mental suffering imposes situations that need to be quickly resolved on families and arrangements in an attempt to balance the family system; family members coexist with mental suffering in the perspective of a chronic illness, and seek coping mechanisms for day-to-day situations; lastly they fear the future of their sick relatives and feel helpless due to public policies. Research is needed in the area to assess the impact of this issue on the lives of families, institutions and public policies. PMID- 30020389 TI - [Maternal nutritional status and its association with birth weight in high-risk pregnancies]. AB - The clinical and nutritional status of pregnant women are important variables for birth-weight risk inadequacies. Thus, this study sought to evaluate the nutritional status of high-risk pregnant women and its association with birth weight of their offspring. It involved a cross-sectional study with high-risk pregnant women assisted at the university hospital of Maceio in the State of Alagoas and their newborns. The nutritional status of pregnant women and their offspring was evaluated according to body mass index for gestational age and birth weight, respectively. The association between maternal factors (comorbidities and nutritional status) and birth weight was assessed by the chi square test and Pearson correlation, by adopting a confidence level of 95%. One hundred and forty-nine pregnant women were studied, 19.7% of whom were of normal weight; 32% were underweight; and 48.3% were overweight. Among newborns, 39.6% referred to as small for gestational age (SGA); 26.8% appropriate for gestational age (AGA) and 33.6% large for gestational age (LGA). LGA offspring were associated with overweight and the presence of metabolic comorbidities and SGA offspring were associated with insufficient gestational weight gain, whereby interventions are needed to reduce these outcomes. PMID- 30020390 TI - Use of health services and medicines by hypertensive and diabetic patients in the municipality of Rio de Janeiro, Brazil. AB - This study aimed to describe and analyze factors associated with emergency care and hospitalization of hypertensive and diabetic patients in the municipality of Rio de Janeiro, especially those related to the use of medicines. This is across sectional study using secondary database from a household survey that approached hypertensive and diabetic patients. The outcome variables were: 1) seek for emergency careasa resultof complications related to hypertension and diabetes in the 12months preceding the interviews; 2) hospitalizationin the same period andfor the same reasons. Uni and bivariate analysis between exposure variables and each of the outcomes were performed using chi-square test at a significance level of 10%, which originated multivariate logistic regression analysis. Negative self-evaluation of health status was associated with both outcomes in the multivariate analysis. Having stopped taking the medications was associated with hospitalization and having missed a medical appointment in the last six months was associated with search for emergency care. PMID- 30020391 TI - The self-confrontation with own time as an analytical perspective in the study of relations between teams and health. AB - Sociological studies point out a malaise resulting from the use of time in contemporary societies. The present study aimed at developing a device that combines a quantitative instrument on the use of time, with a qualitative interview technique, seeking to reveal possible relations between time and health. A field research was conducted with nurses of a hospital in the metropolitan area of Rio de Janeiro. The subjects registered the length of time activities took to be carried out during an entire week in an activity notebook adapted from time use diaries. Interviews were inspired in self-confrontation, as workers observed a coloured image that describes time taken from the register of activities. The device allowed investigate how workers perceive this time and how they relate it to health, considered in an ample sense. Among the issues brought up by the group as source of discomfort and physical malaise, are the overcharge of professional work and acknowledgement of too much time for the others that are linked to too little time for oneself with a strong component in gender relations. The strength of this device as investigative path of relations of time and health indicates its adequacy in studies with other groups of workers. PMID- 30020392 TI - Breastfeeding of preterm newborn infants following hospital discharge: follow-up during the first year of life. AB - : This paper aims to evaluate the prevalence of breastfeeding among premature infants following hospital discharge. Cohort (< 33 gestation weeks) followed up to 12 months (adjusted age). VARIABLES: breastfeeding, anthropometric measurements, social and family information. The proportion of breastfeeding during follow-up was calculated. Survival analysis was conducted to estimate breastfeeding duration. In total, 242 of the 258 infants (93.7%) returned to follow-up; 170 (69.9%) at 6 months and 139 (57.2%) at 12 months (adjusted age). A history of miscarriages (27.5%), stillbirths (11.7%), neonatal deaths (9.5%) and preterm births (21.1%) was noted in 65.5% of women. At hospital discharge: 5.5% received exclusive breastfeeding, 65.8% breastfeeding and formula, 28.6% formula. At month 1, 81.3% received breastfeeding, decreasing to 68.5% at month 2, 62.4% at month 3, 48.1% at month 4 and 22.4% at month 6 (adjusted age). The median of breastfeeding duration was 4 months. Breastfeeding occurred up to four months adjusted age in almost half of the population. Despite the need to improve these rates, the results could reflect the profile of the Child-Friendly Hospital Initiative Unit. Maintaining breastfeeding amongst preterm infants following hospital discharge is still a challenge, for both mothers and health professionals. PMID- 30020393 TI - Tecobe in Marajo: trend of indicators for the monitoring of primary care before and during the More Physicians for Brazil Program. AB - This study aimed to evaluate the performance of the Family Health Strategy after implementation of the More Physicians Program (MPBP) in the territory of Marajo Pa-Brazil through an historical series of four primary care indicators during 2011-2015: population coverage, proportion of live births to mothers with/without prenatal consultations, hospitalization rates due to primary care sensitive condition (taxas de internacoes por condicoes sensiveis a atencao primaria - ICSAP) and infant mortality rate. A trend of improvement was evident after implementation of the MPBP in 2013, achieving 42.8% of coverage in December 2015. In April 2014, all 16 municipalities had established teams with physicians. The proportion of live births to mothers with/without prenatal consultations showed increasing trends in most municipalities, increasing by 97% on average, predominantly with seven consultations or more and reducing the proportion of live births to mothers without prenatal visits. The infant mortality rate achieved a downward trend starting in 2014. The results indicate improvements in primary care based on the selected indicators, boosting the Family Health Strategy (FHS) in the studied region. PMID- 30020394 TI - Factors associated with sexually transmitted infections: a population based survey in the city of Sao Paulo, Brazil. AB - We determined the prevalence of sexually transmitted infections (STIs), the factors associated with infection and types of counseling received by men and women from health professionals in the City of Sao Paulo. The investigation consisted of a cross-sectional study conducted with men and women aged between 15 and 64 years living in the City of Sao Paulo. Of 4,057 individuals who had engaged in sexual activity, 6.3% reported previous history of a STI: 4.3% of women and 8.2% of men. The factors associated with STI were being aged over 34 years and not using a condom during first sexual intercourse, among men, and being aged over 25 years among women. Protective factors included not having had sexual intercourse with someone from the same sex, among men, and having initiated sexual activity after the age of 15 years and not having a casual sex partner over the last 12 months, among women. Counseling about the importance of HIV and syphilis testing was received by 72.1% and 64.7% of women, respectively, while fewer than half of the men received this type of counseling (40.2% and 38.6 %, respectively). The prevalence of previous history of a STI was high among the population of the City of Sao Paulo. The findings of this study informed the development, implementation, and evaluation of STI policies, including those directed at HIV, leading to a reduction in the barriers that hinder access to and use of condoms and the creation of STI prevention app. PMID- 30020395 TI - Bullying and health-related quality of life in children and adolescent Mexican students. AB - Previous studies have reported a relationship between being a victim of bullying, but no studies have been carried out with Mexican students; notwithstanding the high scores of bullying in Mexico in international rankings. The objective of this study was to analyze the association between being a victim of bullying and lower HRQoL among schoolchildren and adolescents in Mexico. This cross-sectional and correlational study involved 2225 students from 22 elementary, middle and high schools. HRQoL was assessed with the KIDSCREEN-10 questionnaire and bullying with the social adaptation dimension of KIDSCREEN-52. Bivariate associations were evaluated, and a multivariate logistic regression was utilized. The prevalence of victims of bullying was 17.3%. Being a victim of bullying was double the risk of having a lower HRQoL than not being a victim after adjusting for health perception, gender and age, OR 2.3 (1.7-3.1). As the Wilson and Cleary Model of Quality of Life explains, individual characteristics, such as, being a victim of bullying are associated with quality of life. Similar findings in the existing literature imply that bullying is a global phenomenon that impacts the victimized child or adolescent's life in different ways. PMID- 30020396 TI - [Standards of physical activity practices in adolescents in a city of Northeastern Brazil]. AB - The scope of this study was to describe the standards of physical activity practices and analyze its variations as sociodemographic characteristics of adolescents in a city of Northeastern Brazil. The sample consisted of 2,350 adolescents in the city of Joao Pessoa in the Brazilian State of Paraiba. The prevalence of physical activity was determined and the practice scores (minutes/week) calculated: general and types (sports, exercise, active commuting and recreational activities). Multiple linear regression was used to estimate the relative contribution of the types of practice for the general score of physical activity. The physical activities most practiced were active commuting (55.2%) and sports (52.7%). The activities that presented the greatest explanatory capacity for the overall score of practice were: sports (38.1%) and exercises (21.8%). The explanatory capacity of sports was increased in all subgroups, except in female patients. The practice of exercise contributes to the major changes in the general score in female adolescents from private schools. Recreational activities and active commuting had the largest contribution for the female gender. Sports and exercise were the activities that contributed the most to explain the changes in the general practice score. PMID- 30020397 TI - [Concerns in research in the health sector: for a politicized broadening of singular listening approaches]. PMID- 30020398 TI - P3 Component as a Potential Endophenotype for Control Inhibition in Offspring of Alcoholics. AB - Aims: To assess inhibitory processes and the ongoing event-related potential (ERP) activity of offspring of alcoholics (OA) during a Go/No-Go task, with the purpose of characterizing possible psychophysiological endophenotypes for alcohol dependent vulnerability. Short summary: EEG recordings and ERP measurements of young adults with positive and negative family history of alcoholism where obtained while they performed a Go/No-Go task to assess inhibitory processes. Offspring of alcoholics showed a different ERP pattern compared to the control group and exerted greater effort than the control group. Methods: ERP measurements were obtained by electroencephalogram (EEG) recordings of 65 participants divided into two groups: one group of 30 subjects with positive family history of alcoholism and a control group of 35 subjects with negative family history of alcoholism. They performed a Go/No-Go task, where each individual was required to classify visual stimuli by colour (Go) and inhibit their response to a No-Go signal. Results: OA have higher P3 amplitudes during the Go condition in all of the regions analysed and higher No-Go P3 amplitudes than control subjects in the frontal region. Unlike controls, OA have no differences between the P3 amplitudes across conditions. Conclusions: The absence of differences between the P3 Go and No-Go observed in the OA group can be interpreted as a possible alteration related with inhibition, in a way that they may need to recruit similar resources for inhibitory and classificational processes for both conditions. Therefore, the P3 component may be considered as a useful endophenotype and a vulnerability marker to develop addictive behaviour. PMID- 30020399 TI - Fatigue in Prevalent Haemodialysis Patients Predicts All-cause Mortality and Kidney Transplantation. AB - Background: Fatigue affects between 49% and 92% of dialysis patients with considerable repercussions on their functioning and quality of life. Purpose: To evaluate whether fatigue severity and its impact on functioning predict survival (all-cause mortality) and time to transplantation among in-centre haemodialysis patients. Methods: As part of a prospective study of fatigue among in-centre haemodialysis patients, survival data were collected between April 2014 and August 2017. Fatigue severity was measured using the Chalder Fatigue Questionnaire (CFQ) and fatigue-related functional impairment using the Work and Social Adjustment Scale (WSAS). Sociodemographic, clinical, and psychological data were collected. The association between fatigue and outcomes was assessed using proportional hazard survival models, allowing for competing risks, and discrete-time survival models. All models were adjusted for relevant risk factors. Results: The sample consisted of 174 haemodialysis patients. There were 37 deaths and 31 transplantations over 3 years. At 1,095 days (36 months), cumulative survival was 70.5% and the cumulative transplantation rate was 22.2%. In unadjusted models, fatigue was significantly associated with an increased risk of death (CFQ-continuous SHR = 1.06, 95% CI: 1.02 to 1.11; CFQ-dichotomous SHR = 2.18, 95% CI: 1.11 to 4.31; WSAS SHR = 1.03, 95% CI: 1.01 to 1.05) and decreased likelihood of transplantation (CFQ-continuous SHR = 0.92, 95% CI: 0.87 to 0.98; CFQ-dichotomous SHR = 0.33, 95% CI: 0.15 to 0.75; WSAS SHR = 0.96, 95% CI: 0.93 to 0.99). However, these associations ceased to be significant after controlling for covariates. Conclusions: Fatigue was predictive of an increased risk of death and decreased likelihood of transplantation among patients, possibly through distress, impaired functioning, and its consequences, rather than clinical and inflammatory markers. PMID- 30020400 TI - Effect of lentiviral vector-mediated KSR1 gene silencing on the proliferation of renal tubular epithelial cells and expression of inflammatory factors in a rat model of ischemia/reperfusion injury. AB - Renal ischemia/reperfusion (I/R) is a common cause of acute renal failure in many clinical settings. Our study aimed to elucidate the role of lentiviral vector mediated KSR1 gene silencing in inflammatory factor expression and proliferation of renal tubular epithelial cells (RTECs) in a rat model of I/R injury. Male Sprague-Dawley (SD) rats were used for I/R model establishment and subject to different treatments, followed by the measurement of neurological severity score (NSS), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-1beta, 47 kDa heat-shock protein (HSP47), KSR1, and factors related to the Ras/MAPK pathway, as well as cell apoptosis. As compared with the blank group, the neurologic impairment induced by I/R in the siKSR1, U0126, and siKSR1 + U0126 groups was alleviated. Compared with the control group, the other five groups showed increased levels of TNF-alpha, IL-6, IL-1beta, HSP47, N-ras, Raf-1, c-fos, TNF-alpha, IL-6, p38 MAPK, and cell apoptosis, accompanied by a declined mRNA and protein level of Bcl-2. As compared with the blank and NC groups, the siKSR1, U0126, and siKSR1 + U0126 groups showed decreased levels of TNF-alpha, IL-6, IL 1beta, HSP47, N-ras, Raf-1, c-fos, TNF-alpha, IL-6, p38 MAPK, cleaved caspase-3, cleaved caspase-9, p53, and cell apoptosis, accompanied by an increased mRNA and protein level of Bcl-2. Our findings demonstrated that KSR1 gene silencing might inhibit the expression of inflammatory factors in RTECs and promote their proliferation by inactivating the Ras/MAPK pathway in the rat model of I/R injury. PMID- 30020401 TI - Predictors of Adherence to Different Volumes of Exercise in the Breast Cancer and Exercise Trial in Alberta. AB - Background: Exercise demonstrates a dose-response effect on many health outcomes; however, adhering to higher doses of exercise can be challenging, and the predictors of adherence may differ based on exercise volume. Purpose: To examine the predictors of adherence to two different volumes of aerobic exercise within the Breast Cancer and Exercise Trial in Alberta (BETA). Methods: In BETA, we randomized 400 inactive but healthy postmenopausal women to either a moderate volume (150 min/week) or a high volume (300 min/week) of aerobic exercise for 1 year. We collected data on several predictors of exercise adherence at baseline and used linear and mixed-effect models to determine predictors of exercise adherence to exercise volume and overall. Results: Adherence was higher in the moderate-volume group (84.5%) compared with the high-volume group (75.2%; p < .001). There were no statistically significant interactions between predictors of exercise adherence and exercise volume. Overall, we found that exercise adherence was predicted by randomization group, body mass index (BMI), employment status, and physical health. Adherence was 8.6% lower in the high-volume versus moderate volume group, 6.7% lower for women working full time versus not, 0.8% lower per BMI increase of 1 kg/m2, and 0.5% higher per unit of physical health. Conclusions: Adherence to high-volume aerobic exercise was more challenging than for moderate-volume aerobic exercise, but the predictors of adherence were similar. Moreover, few factors were major predictors of exercise adherence in this setting suggesting that well-controlled efficacy trials that produce high adherence rates may reduce the influence of individual characteristics on exercise adherence. Trial Registration: NCT1435005. PMID- 30020402 TI - ACDtool: a web-server for the generic analysis of large data sets of counts. AB - Motivation: More than 20 years ago, our laboratory published an original statistical test (referred to as the Audic-Claverie (AC) test in the literature) to identify differentially expressed genes from the pairwise comparison of counts of "expressed sequence tags" determined in different conditions. Despite its antiquity and the publications of more sophisticated packages, this original publication continued to gather more than 200 citations per year, indicating the persistent usefulness of the simple AC test for the community. This prompted us to propose a fully revamped version of the AC test with a user interface adapted to the diverse and much larger datasets produced by contemporary omics techniques. Results: ACDtool is a freely accessible web service (URL: www.igs.cnrs-mrs.fr/acdtool/) proposing 3 types of analyses: 1) the pairwise comparison of individual counts, 2) pairwise comparisons of arbitrary large lists of counts, 3) the all-at-once pairwise comparisons of multiple datasets. Statistical computations are implemented using standard R functions and can accommodate all practical ranges of counts as generated by modern omic experiments. ACDtool is well suited for large datasets without replicates. Supplementary information: Supplementary informations are available at Bioinformatics online. PMID- 30020403 TI - Dynamic compression schemes for graph coloring. AB - Motivation: Technological advancements in high-throughput DNA sequencing have led to an exponential growth of sequencing data being produced and stored as a byproduct of biomedical research. Despite its public availability, a majority of this data remains hard to query for the research community due to a lack of efficient data representation and indexing solutions. One of the available techniques to represent read data is a condensed form as an assembly graph. Such a representation contains all sequence information but does not store contextual information and metadata. Results: We present two new approaches for a compressed representation of a graph coloring: a lossless compression scheme based on a novel application of wavelet tries as well as a highly accurate lossy compression based on a set of Bloom filters. Both strategies retain a coloring even when adding to the underlying graph topology. We present construction and merge procedures for both methods and evaluate their performance on a wide range of different datasets. By dropping the requirement of a fully lossless compression and using the topological information of the underlying graph, we can reduce memory requirements by up to three orders of magnitude. Representing individual colors as independently stored modules, our approaches can be efficiently parallelized and provide strategies for dynamic use. These properties allow for an easy upscaling to the problem sizes common to the biomedical domain. Availability: We provide prototype implementations in C ++, summaries of our experiments as well as links to all datasets publicly at https://github.com/ratschlab/graph_annotation. PMID- 30020404 TI - A review of metrics measuring dissimilarity for rooted phylogenetic networks. AB - Availability: http://bioinformatics.imu.edu.cn/distance/. Contact: guomaozu@bucea.edu.cn. PMID- 30020406 TI - BIPSPI: a method for the prediction of Partner-Specific Protein-Protein Interfaces. AB - Motivation: Protein-Protein Interactions (PPI) are essentials for most cellular processes and thus, unveiling how proteins interact is a crucial question that can be better understood by identifying which residues are responsible for the interaction. Computational approaches are orders of magnitude cheaper and faster than experimental ones, leading to proliferation of multiple methods aimed to predict which residues belong to the interface of an interaction. Results: We present BIPSPI, a new machine learning-based method for the prediction of partner specific protein-protein interaction sites. Contrary to most binding site prediction methods, the proposed approach takes into account a pair of interacting proteins rather than a single one in order to predict partner specific binding sites. BIPSPI has been trained employing sequence-based and structural features from both protein partners of each complex compiled in the Protein-Protein Docking Benchmark version 5.0 and in an additional set independently compiled. Also, a version trained only on sequences has been developed. The performance of our approach has been assessed by a leave-one-out cross-validation over different benchmarks, outperforming state-of-the-art methods. Availability: BIPSPI web server is freely available at http://bipspi.cnb.csic.es. BIPSPI code is available at https://github.com/bioinsilico/BIPSPI Docker image is available at https://hub.docker.com/r/bioinsilico/bipspi/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30020405 TI - PIM1 overexpression in T-cell lymphomas protects tumor cells from apoptosis and confers doxorubicin resistance by upregulating c-myc expression. AB - T-cell lymphomas (TCLs) are a malignancy characterized by tumor aggression and resistance to traditional chemotherapy. Disruption of the extrinsic cell death pathway is essential for resistance to chemotherapy. PIM1 serves as a crucial modulator in cancers. However, the role of PIM1 in TCLs remains unclear. In this study, we studied the roles of PIM1 in established T-lymphoma cell lines Jurkat and HUT-78. CCK-8 assay was conducted to evaluate cell survival and flow cytometry was performed to evaluate cell death of TCL cells. siRNAs were used to knockdown the expression of PIM1 and c-myc. qRT-PCR was used to evaluate the mRNA expression levels of c-myc and PIM1. Western blot analysis was used to evaluate the protein expression levels of PIM1, c-myc, STAT3, and phospho-STAT3. Doxorubicin was used to determine the effect of PIM1 on apoptosis. Our results showed that PIM1 expression was markedly enhanced and induced c-myc expression in TCL cells. Doxorubicin inhibited the expressions of c-myc and PIM1, and triggered the extrinsic cell death of TCLs by suppressing the JAK-STAT3 signaling pathway. Moreover, PIM1 silencing via siRNA suppressed c-myc expression, promoted the cell death of TCLs, and increased doxorubicin sensitivity. Conversely, PIM1 overexpression in TCL cells induced c-myc expression, suppressed TCL cell death, and promoted doxorubicin resistance. Collectively, our results demonstrate that PIM1 overexpression in TCLs participates in cancer cell protection from apoptosis and leads to doxorubicin resistance by inducing c-myc expression, indicating that PIM1 may be a promising target in TCL treatment. PMID- 30020407 TI - Optimal Intraoperative Assessment of Gastric Margins. AB - Objectives: Intraoperative pathology consultation (IOC) to assess margins is frequently requested during surgery of the stomach and gastroesophageal junction. Methods: We studied 110 consecutive patients undergoing gastrectomy with IOC margin assessment. Results: Gastric margins at IOC utilized the most blocks but were least often positive. In 64% of patients, the entire gastric margin was examined using average six blocks; representative sections were examined in 25% of patients using two blocks. There was no difference in patient outcome between those who had entire vs representative sections of margin examined. Gross variables showing strongest associations with positive margins were tumor size and tumor distance to margin. Tumors sized greater than 2.3 cm had significantly increased risk of positive margin, and tumor distance greater than 4.5 cm to margin was associated with negative margins. Conclusions: We conclude representative sections of the closest gastric margin are sufficient to ensure R0 resection in the majority of cases. PMID- 30020408 TI - Recruitment for a Pragmatic Clinical Trial to Reduce Fall Injuries. PMID- 30020409 TI - Can the Impact of Topiramate on Memory Processes be Related to Its 'Antialcoholic Activity'?-A Preclinical Study. AB - Aims: Topiramate causes the inhibition of alcohol consumption in addicts but the mechanism of this action has not been fully understood yet. Nowadays, it seems that memory may have a role in the development of dependence. In this study, the impact of topiramate and ethanol on the bioelectric activity of the brain in rabbits and on spatial memory in rats was evaluated. Short summary: The aim of the study was to assess the effect of co-administration of topiramate and ethanol on bioelectric activity of the rabbits' brain and on spatial memory in rats. Topiramate decreased ethanol-induced changes in all studied brain structures and improved memory and learning processes. Methods: A pharmaco electroencephalography study was used to examine the effect of topiramate (25 mg/kg/day) co-administered for 6 weeks with ethanol on the bioelectric activity of the rabbits' brain. The influence of the drug was also assessed in first and second weeks of the abstinence period. Spatial memory was evaluated in rats using Morris water maze task. Topiramate (60 mg/kg/day) was administered with the ethanol for 3 weeks and for 2 weeks in the abstinence. Results: After 6 weeks of topiramate and ethanol administration, the drug decreased ethanol-induced changes in the midbrain reticular formation, hippocampus and frontal cortex. In the abstinence, the drug also inhibited the features of neuronal hyperactivity, especially in the hippocampus. Moreover, topiramate co-administered with ethanol for 3 weeks decreased ethanol-induced memory disturbance in rats. This beneficial effect was also observed in the second week of abstinence. Conclusion: These findings reveal that 'antialcoholic' activity of topiramate may be associated with its advantageous effect on memory and learning processes. PMID- 30020410 TI - Scaling read aligners to hundreds of threads on general-purpose processors. AB - Motivation: General-purpose processors can now contain many dozens of processor cores and support hundreds of simultaneous threads of execution. To make best use of these threads, genomics software must contend with new and subtle computer architecture issues. We discuss some of these and propose methods for improving thread scaling in tools that analyze each read independently, such as read aligners. Results: We implement these methods in new versions of Bowtie, Bowtie 2 and HISAT. We greatly improve thread scaling in many scenarios, including on the recent Intel Xeon Phi architecture. We also highlight how bottlenecks are exacerbated by variable-record-length file formats like FASTQ and suggest changes that enable superior scaling. Availability: Experiments for this study: https://github.com/BenLangmead/bowtie-scaling. Bowtie: http://bowtie bio.sourceforge.net. Bowtie 2: http://bowtie-bio.sourceforge.net/bowtie2. HISAT: http://www.ccb.jhu.edu/software/hisat. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30020411 TI - Random Walk with Restart on Multiplex and Heterogeneous Biological Networks. AB - Motivation: Recentyears have witnessed anexponentialgrowthin thenumberof identified interactions between biological molecules. These interactions are usually represented as large and complex networks, callingforthedevelopmentof appropriated toolstoexploitthe functionalinformationtheycontain. Random walk with restart is the state-of-the-art guilt-by-association approach. It explores the network vicinity of gene/protein seeds to study their functions, based on the premise that nodes related to similar functions tend to lie close to each other in the networks. Results: In the present study, we extended the random walk with restart algorithm to multiplex and heterogeneous networks. The walk can now explore different layers of physical and functional interactions between genes and proteins, such as protein-protein interactions and co-expression associations. In addition, the walk can also jump to a network containing different sets of edges and nodes, such as phenotype similaritiesbetween diseases.Wedevisedaleave-one-out cross-validationstrategytoevaluate the algorithms abilities to predict disease-associated genes.We demonstrate the increased performances of the multiplex-heterogeneous random walk with restart as compared to several random walks on monoplex or heterogeneous networks. Overall, our framework is able to leverage the different interaction sourcesto outperform current approaches. Finally,we appliedthealgorithmto predict candidate genesfor the Wiedemann-Rautenstrauch syndrome, andtoexplore the network vicinityof theSHORT syndrome. Availability: The source code is available on GitHub at: https://github.com/albertovaldeolivas/RWR-MH. In addition, an R package is freely available through Bioconductor at: http://bioconductor.org/packages/RandomWalkRestartMH/. PMID- 30020412 TI - Heritability Estimation and Differential Analysis with Generalized Linear Mixed Models in Genomic Sequencing Studies. AB - Motivation: Genomic sequencing studies, including RNA sequencing and bisulfite sequencing studies, are becoming increasingly common and increasingly large. Large genomic sequencing studies open doors for accurate molecular trait heritability estimation and powerful differential analysis. Heritability estimation and differential analysis in sequencing studies requires the development of statistical methods that can properly account for the count nature of the sequencing data and that are computationally efficient for large data sets. Results: Here, we develop such a method, PQLseq (Penalized Quasi-Likelihood for sequencing count data), to enable effective and efficient heritability estimation and differential analysis using the generalized linear mixed model framework. With extensive simulations and comparisons to previous methods, we show that PQLseq is the only method currently available that can produce unbiased heritability estimates for sequencing count data. In addition, we show that PQLseq is well suited for differential analysis in large sequencing studies, providing calibrated type I error control and more power compared to the standard linear mixed model methods. Finally, we apply PQLseq to perform gene expression heritability estimation and differential expression analysis in a large RNA sequencing study in the Hutterites. Availability: PQLseq is implemented as an R package with source code freely available at www.xzlab.org/software.html and https://cran.r-project.org/web/packages/PQLseq/index.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30020413 TI - Rapid rebound of a preexisting CXCR4-tropic HIV variant after allogeneic transplantation with CCR5 delta32 homozygous stem cells. AB - Allogeneic transplantation (alloSCT) of homozygous CCR5delta32 stem cells has once resulted in HIV cure in the case of the "Berlin patient". We have recently reported a viral breakthrough in a similar setting ("Essen patient"). In this study we demonstrate that the rapid rebound after alloSCT was related to a highly replicative CXCR4-tropic HIV variant, which could already be detected prior to alloSCT. PMID- 30020414 TI - SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation. AB - Motivation: Understanding the relationship between the sequence, structure, binding energy, binding kinetics and binding thermodynamics of protein-protein interactions is crucial to understanding cellular signaling, the assembly and regulation of molecular complexes, the mechanisms through which mutations lead to disease, and protein engineering. Results: We present SKEMPI 2.0, a major update to our database of binding free energy changes upon mutation for structurally resolved protein-protein interactions. This version now contains manually curated binding data for 7085 mutations, an increase of 133%, including changes in kinetics for 1844 mutations, enthalpy and entropy changes for 443 mutations, and 440 mutations which abolish detectable binding. Availability: The database is available as supplementary data and at https://life.bsc.es/pid/skempi2/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30020415 TI - Screening, Recruitment, and Baseline Characteristics for the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) Study. AB - Background: We describe the recruitment of participants for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large pragmatic cluster randomized trial that is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Eligible persons were 70 years or older, community-living, and at increased risk for serious fall injuries. The modified goal was to recruit 5,322 participants over 20 months from 86 primary care practices within 10 diverse health care systems across the United States. Methods: The at-risk population was identified using two distinct but complementary screening strategies that included three questions administered centrally via the mail (nine sites) or in the clinic (one site), while recruitment was completed centrally by staff at Yale. Results: For central screening, 226,603 letters mailed to 135,118 patients yielded 28,719 positive screens (12.7% of those mailed and 46.5% of the 61,729 returned). In the clinic, 22,537 screens were completed, leading to 5,732 positive screens (25.4%). Of the 34,451 patients who screened positive for high risk of serious fall injuries, 31,872 were sent a recruitment packet and, of these, 5,451 (17.1%) were enrolled over 20 months (mean age: 80 years; 62% female). The participation rate was 34.0% among eligible patients. The enrollment yields were 3.6% (vs 5% projected) for each patient screened centrally, despite multiple screens, and 10.5% (vs 33.9% projected) for each positive clinic screen. Conclusions: Despite lower-than expected yields, the STRIDE Study exceeded its modified recruitment goal. If the STRIDE intervention is found to be effective, the two distinct strategies for identifying a high-risk population of older persons could be implemented by most health care systems. PMID- 30020417 TI - Bezlotoxumab. AB - C. difficile infection (CDI) is mediated by actions of toxin A and toxin B. Fully human monoclonal antibodies directed against the binding domains of these toxins were developed. Despite pre-clinical studies suggesting efficacy for the anti toxin A monoclonal, actoxumab, the anti-toxin B monoclonoal, bezolotoxumab, alone was shown to be effective in clinical trials. Intravenous infusion of bezlotoxumab at a 10 mg/kg dosage as adjunctive treatment reduced the risk of recurrent CDI over placebo for adult patients at increased risk for CDI recurrence in two large randomized, double-blind trials. Significant benefit was noted for patients with one or more of the following predefined risks; age >65 years, history of CDI, immunocompromise, severe CDI. Overall, bezlotoxumab appeared to be safe, however, an unexplained increased risk of heart failure was noted for patients with underlying congestive heart failure. Further refinement of who would benefit most and when best to administer bezlotoxumab is warranted. PMID- 30020416 TI - Cost estimates for HIV care and patient characteristics for health resource utilisation from linkage of claims data with the Swiss HIV Cohort Study. AB - Background: Comprehensive and representative data on resource use is critical for health policy decision making but often lacking for HIV infection. Privacy preserving probabilistic record linkage of claim and cohort study data may overcome these limitations. Methods: Encrypted dates of birth, gender, study center and antiretroviral therapy (ART) of the Swiss HIV Cohort Study (SHCS) from 2012 and 2013 were linked by privacy preserving probabilistic record linkage with claim data from the largest health insurer covering 15% of the Swiss residential population. We modeled predictors for mean annual costs adjusting for censoring and grouped patients by cluster analysis into 3 risk groups for resource use. Results: The matched subsample of 1196 patients from 9326 SHCS and 2355 claim records was representative for all SHCS patients on ART. Corrected mean total cost (SE) in 2012 and 2013 were USD 30'462 (582) and USD 30'965 (629) and mainly accrued in ambulatory care for ART (70% of mean costs). The low risk group for resource use had mean annual cost of USD 26'772 (536) and USD 26'132 (589) in 2012 and 2013. In the moderate and high risk groups annual costs for 2012 and 2013 were higher by USD 3'526 [1'907; 5'144] (13%) and 4'327 [2'662; 5'992] (17%) and USD 14'026 [8'763; 19'289 (52%) and 13'567[8'844; 18'288] (52%), respectively. Conclusions: In a representative subsample of patients from linkage of SHCS and claim data, ART was the major cost factor but patient profiling allowed to identify factors related to higher resource use. PMID- 30020418 TI - Absorption of foliar-applied Zn in sunflower (Helianthus annuus): importance of the cuticle, stomata and trichomes. AB - Background and Aims: The pathways whereby foliar-applied nutrients move across the leaf surface remain unclear. The aim of the present study was to examine the pathways by which foliar-applied Zn moves across the sunflower (Helianthus annuus) leaf surface, considering the potential importance of the cuticle, stomata and trichomes. Methods: Using synchrotron-based X-ray florescence microscopy and nanoscale secondary ion mass spectrometry (NanoSIMS), the absorption of foliar-applied ZnSO4 and nano-ZnO were studied in sunflower. The speciation of Zn was also examined using synchrotron-based X-ray absorption spectroscopy. Key Results: Non-glandular trichomes (NGTs) were particularly important for foliar Zn absorption, with Zn preferentially accumulating within trichomes in <=15 min. The cuticle was also found to have a role, with Zn appearing to move across the cuticle before accumulating in the walls of the epidermal cells. After 6 h, the total Zn that accumulated in the NGTs was approx. 1.9 times higher than in the cuticular tissues. No marked accumulation of Zn was found within the stomatal cavity, probably indicating a limited contribution of the stomatal pathway. Once absorbed, the Zn accumulated in the walls of the epidermal and the vascular cells, and trichome bases of both leaf sides, with the bundle sheath extensions that connected to the trichomes seemingly facilitating this translocation. Finally, the absorption of nano-ZnO was substantially lower than for ZnSO4, with Zn probably moving across the leaf surface as soluble Zn rather than nanoparticles. Conclusions: In sunflower, both the trichomes and cuticle appear to be important for foliar Zn absorption. PMID- 30020419 TI - Increased Resting Heart Rate on Electrocardiogram Relative to In-office Pulse Rate Indicates Cardiac Overload: The J-HOP Study. AB - BACKGROUND: Heart rate (HR) assessed by electrocardiogram (ECG-HR) and pulse rate (PR) measured in a physician's office (office-PR) are taken with subjects in different body positions-i.e., supine vs. sitting. Although analysis of HR differences according to body position could provide new practical insights, there have been few studies on the subject. We herein investigated whether the difference between office-PR and ECG-HR (delta HR) was associated with brain natriuretic peptide (BNP) levels and left ventricular mass (LVM). METHODS: Among the 4,310 patients with 1 or more cardiovascular risk factors recruited for the Japan Morning Surge-Home Blood Pressure study, we excluded those with atrial fibrillation or a prescribed beta-blocker. We analyzed the 2,972 patients who had ECG-HR, office-PR, and BNP data and 1,061 patients with echocardiography data. RESULTS: In the complete patient series, office-PR was significantly higher than ECG-HR (72.1 +/- 10.3 vs. 66.6 +/- 11.9 bpm, P < 0.001). When we divided patients into quintiles based on the delta HR, the BNP level and LVM index (LVMI) decreased across categories after adjustment for traditional cardiovascular risk factors (each P <= 0.001). In a multiple linear regression analysis, the delta HR was independently and significantly associated with both the log-transformed BNP level (beta = -0.179, P < 0.001) and LVMI (beta = -0.113, P = 0.001) adjusted for covariates. CONCLUSION: A decreased delta HR was positively associated with the BNP level and LVMI. Without the requirement of a special technique, this evaluation might indicate potential cardiac overload and provide a clinical sign related to heart failure. PMID- 30020420 TI - Cryfa: a secure encryption tool for genomic data. AB - Summary: The ever-increasing growth of high-throughput sequencing technologies has led to a great acceleration of medical and biological research and discovery. As these platforms advance, the amount of information for diverse genomes increases at unprecedented rates. Confidentiality, integrity and authenticity of such genomic information should be ensured due to its extremely sensitive nature. In this paper, we propose Cryfa, a fast secure encryption tool for genomic data, namely in Fasta, Fastq, VCF, SAM and BAM formats, which is also capable of reducing the storage size of Fasta and Fastq files. Cryfa uses AES encryption combined with a shuffling mechanism, which leads to a substantial enhancement of the security against low data complexity attacks. Compared to AES Crypt, a general-purpose encryption tool, Cryfa is an industry-oriented tool, which is able to provide confidentiality, integrity and authenticity of data at 4 times more speed; in addition, it can reduce the file sizes to 1/3. Due to the absence of a method similar to Cryfa, we have simulated its behavior with a combination of encryption and compression tools, for comparison purpose. For instance, our tool is 9 times faster than its fastest competitor in Fasta files. Also, Cryfa has a very low memory usage (only a few megabytes), which makes it feasible to run on any computer. Availability: Source codes and binaries are available, under GPLv3, at https://github.com/pratas/cryfa. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30020421 TI - Repurposing an Old Drug for a New Epidemic: Ursodeoxycholic Acid to Prevent Recurrent Clostridioides difficile Infection. AB - Recurrent Clostridioides difficile infection (rCDI) may be mediated in part by secondary bile acids. Here we report salvage therapy with ursodeoxycholic acid (UDCA) to prevent rCDI in 16 high-risk patients. Patients on UDCA had a low observed recurrence rate (12.5%). Controlled trials are needed to confirm these observations. PMID- 30020422 TI - Public Health Detailing for HIV Pre-Exposure Prophylaxis. AB - Despite the promise of HIV pre-exposure prophylaxis (PrEP), PrEP remains underutilized, often due to clinician factors. Academic or public health detailing is a process by which university and/or government groups employ the marketing practices of pharmaceutical companies to improve clinical practice. We describe the novel application of detailing to increase PrEP prescribing and related care in New York City and New England. Detailing can play a crucial role in PrEP implementation. PMID- 30020424 TI - Effectiveness and Safety of Rivaroxaban Versus Warfarin in Nonvalvular Atrial fibrillation Patients with a Non-Sex-Related CHA2DS2-VASc Score of 1. AB - Aims: To compare the effectiveness and safety of standard dose rivaroxaban (20 mg once daily) and warfarin in nonvalvular atrial fibrillation (NVAF) patients with a non-sex-related CHA2DS2-VASc score of 1. Methods and Results: Analysis of United States Truven MarketScan claims from 11/2011-12/2016 for anticoagulant naive NVAF patients with a single non-sex-related stroke risk factor assigned 1 point in the CHA2DS2-VASc score and >=12-months of continuous medical/prescription insurance coverage prior to the qualifying oral anticoagulant dispensing. Standard dose rivaroxaban users were 1:1 propensity matched to warfarin users. Patients were followed until outcome occurrence, insurance disenrollment or end of data availability. Primary outcomes included stroke or systemic embolism and major bleeding and were compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). 3,319 rivaroxaban users were 1:1 propensity-score matched to 3,319 warfarin users. Median (interquartile range) duration of follow-up was 1.6 (0.7, 2) years and the most common qualifying stroke risk factor was hypertension (n = 4532, 68.3%). Rivaroxaban was associated with a significant reduction in the 1 year stroke or systemic embolism versus warfarin (HR = 0.41, 95%CI=0.17-0.98), with no significant difference in overall major bleeding (HR = 0.74, 95%CI=0.44 1.26) or major bleeding subtypes (HR ranging from=0.33-0.78, p > 0.05 for all). Similar results were seen after extending follow-up to 2-years. Conclusions: Rivaroxaban may lower the rate of stroke or systemic embolism versus warfarin in NVAF patients with a non-sex-related CHA2DS2-VASc score of 1 without impacting major bleeding. PMID- 30020425 TI - Blood Pressure Management in Patients with Symptomatic Peripheral Artery Disease: Insights from the PORTRAIT Registry. PMID- 30020423 TI - Acute ketamine dysregulates task-related gamma-band oscillations in thalamo cortical circuits in schizophrenia. AB - Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1-90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63-80 Hz) in occipital regions and upregulated low frequency (5-28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia. PMID- 30020426 TI - Plasma IgA responses against two Salmonella Typhi antigens identify patients with typhoid fever. AB - Background: There is a need for a reliable, simple diagnostic assay for typhoid fever. Available commercial serologic assays for typhoid fever have limited sensitivity and specificity. Using high-throughput immuno-screening technologies, we previously identified several immuno-reactive Salmonella Typhi antigens that appear promising for possible inclusion in a new diagnostic assay: hemolysin E (HlyE); cytolethal distending toxin (CdtB), S. Typhi LPS, and S. Typhi membrane preparation (MP). Methodology: We assessed plasma antibody responses (IgM, IgA, and IgG) to these antigens via ELISA in patients with suspected enteric fever, controls with other febrile illnesses, and healthy controls in Dhaka, Bangladesh and performed Tubex, Typhidot, Widal and the Typhoid/Paratyphoid test (TPTest) on each patient. Using machine learning methods, we identified a parsimonious serology signature to distinguish acute typhoid cases from controls and then validated our findings in an independent test cohort from Nepal of culture confirmed S. Typhi patients and controls with other bacteremic illnesses. Results: We identified anti-MP IgG and IgA plasma responses to HlyE, LPS, and MP as important predictors of acute typhoid in the Bangladesh cohort. Using our Nepalese validation cohort, we demonstrated that the use of two antigens (HlyE and LPS) with one antibody isotype (IgA) could distinguish typhoid from other invasive bacterial infections (AUC 0.95; sensitivity 90%, specificity 92%). Use of a single antigen (HlyE) and isotype (IgA) had an AUC of 0.93. Conclusion: Our results suggest that development of a diagnostic assay for acute typhoid fever focused on detecting IgA responses against HlyE, with or without LPS, is warranted. PMID- 30020427 TI - The cardiothoracic ratio: a neglected preoperative risk-stratified method for patients with rheumatic heart disease undergoing valve replacement surgery. AB - OBJECTIVES: It is common for patients with rheumatic heart disease to have an enlarged heart. We investigated the prognostic value of cardiothoracic ratio (CTR) in patients with rheumatic heart disease undergoing valve replacement surgery. METHODS: A total of 1772 patients were divided into 4 groups based on the quartiles of preoperative CTR: <0.56 (n = 349), 0.56-0.61 (n = 488), 0.61 0.66 (n = 449) and >=0.66 (n = 486). The CTR was measured from postero-anterior chest radiographs. We then investigated the association between the CTR and adverse outcomes. RESULTS: In-hospital mortality was 4.0% (71/1772). Analyses of receiver operating characteristic curves showed that, at a cut-off of 0.6, the CTR exhibited 66.2% sensitivity and 64.0% specificity for detecting in-hospital death (area under curve 0.671, P < 0.001). The prevalence of in-hospital death was 7.1% in males with a CTR >0.6, which was significantly higher in males without a CTR. A similar result was observed in females (1.9 vs 5.1%, P = 0.004). Multivariable regression showed that a CTR >0.6 was an independent predictor of in-hospital (odds ratio 2.36, P = 0.005) and 1-year mortality (hazard ratio 2.06, P = 0.006). Kaplan-Meier curves, for the cumulative rate of 1-year mortality among groups, indicated that the risk of death was increased if the CTR >0.6 (log rank 16.36, P < 0.001). CONCLUSIONS: CTR, as a simple and reproducible indicator, was identified as a prognostic factor for predicting poor outcomes in patients with rheumatic heart disease undergoing valve replacement surgery. PMID- 30020428 TI - Molecular Actions of PPARalpha in Lipid Metabolism and Inflammation. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARalpha also exhibits marked anti-inflammatory capacities. The first-generation PPARalpha agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARalpha works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications. PMID- 30020430 TI - Level of block: atrioventricular node, infra-Hisian, or intramyocardial? PMID- 30020429 TI - The Processes of Anterior Pituitary Hormone Pulse Generation. AB - More than 60 years ago, Geoffrey Harris described his "neurohumoral theory," in which the regulation of pituitary hormone secretion was a "simple" hierarchal relationship, with the hypothalamus as the controller. In models based on this theory, the electrical activity of hypothalamic neurons determines the release of hypophysiotropic hormones into the portal circulation, and the pituitary simply responds with secretion of a pulse of hormone into the bloodstream. The development of methodologies allowing the monitoring of the activities of members of the hypothalamic-vascular-pituitary unit is increasingly allowing dissection of the mechanisms generating hypothalamic and pituitary pulses. These have revealed that whereas hypothalamic input is required, its role as a driver of pulsatile pituitary hormone secretion varies between pituitary axes. The organization of pituitary cells has a key role in the modification of their response to hypophysiotropic factors that can lead to a memory of previous demand and enhanced function. Feedback can lead to oscillatory hormone output that is independent of pulses of hypophysiotropic factors and instead, results from the temporal relationship between pituitary output and target organ response. Thus, the mechanisms underlying the generation of pulses cannot be generalized, and the circularity of feedforward and feedback interactions must be considered to understand both normal physiological function and pathology. We describe some examples of the clinical implications of recognizing the importance of the pituitary and target organs in pulse generation and suggest avenues for future research in both the short and long term. PMID- 30020431 TI - Patent foramen ovale and long-term risk of ischaemic stroke after surgery. AB - Aims: Pre-operatively diagnosed patent foramen ovale (PFO) is associated with an increased risk of ischaemic stroke within 30 days after surgery. This study aimed to assess the PFO-attributable ischaemic stroke risk beyond the perioperative period. Methods and results: This observational study of adult patients without history of stroke undergoing non-cardiac surgery with general anaesthesia examined the association of PFO with ischaemic stroke 1 and 2 years after surgery using multivariable logistic regression. Of the 144 563 patients included, a total of 1642 (1.1%) and 2376 (1.6%) ischaemic strokes occurred within 1 and 2 years after surgery, 54 (4.7%) and 76 (6.6%) among patients with PFO, and 1588 (1.1%) and 2300 (1.6%) among patients without PFO, respectively. The odds of ischaemic stroke within 1 and 2 years after surgery were increased in patients with PFO: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.51-2.69; P < 0.001 and aOR 2.10, 95% CI 1.64-2.68; P < 0.001, respectively. Among patients who underwent contrast transoesophageal echocardiography, the frequency of PFO was 27%, and the increased stroke risk in patients with PFO was robust (aOR 3.80, 95% CI 1.76-8.23; P = 0.001 for year 1). The PFO-attributable risk was mitigated by post-operative prescription of combination antithrombotic therapy (odds ratio 0.41, 95% CI 0.22-0.75; P for interaction = 0.004). Conclusion: Patients with PFO are vulnerable to ischaemic stroke for an extended period of time after surgery. Physicians should consider implementing PFO screening protocols in patients scheduled for major non-cardiac surgery. PMID- 30020432 TI - Paravalvular root abscess with mycotic pseudoaneurysm. PMID- 30020433 TI - Frank's sign: diagonal earlobe crease. PMID- 30020434 TI - Design and evaluation of a sequence capture system for genome-wide SNP genotyping in highly heterozygous plant genomes: a case study with a keystone Neotropical hardwood tree genome. AB - Targeted sequence capture coupled to high-throughput sequencing has become a powerful method for the study of genome-wide sequence variation. Following our recent development of a genome assembly for the Pink Ipe tree (Handroanthus impetiginosus), a widely distributed Neotropical timber species, we now report the development of a set of 24,751 capture probes for single-nucleotide polymorphisms (SNPs) characterization and genotyping across 18,216 distinct loci, sampling more than 10 Mbp of the species genome. This system identifies nearly 200,000 SNPs located inside or in close proximity to almost 14,000 annotated protein-coding genes, generating quality genotypic data in populations spanning wide geographic distances across the species native range. To provide recommendations for future developments of similar systems for highly heterozygous plant genomes we investigated issues such as probe design, sequencing coverage and bioinformatics, including the evaluation of the capture efficiency and a reassessment of the technical reproducibility of the assay for SNPs recall and genotyping precision. Our results highlight the value of a detailed probe screening on a preliminary genome assembly to produce reliable data for downstream genetic studies. This work should inspire and assist the development of similar genomic resources for other orphan crops and forest trees with highly heterozygous genomes. PMID- 30020435 TI - Angiographic derived endothelial shear stress: a new predictor of atherosclerotic disease progression. AB - Aims: To examine the efficacy of angiography derived endothelial shear stress (ESS) in predicting atherosclerotic disease progression. Methods and results: Thirty-five patients admitted with ST-elevation myocardial infarction that had three-vessel intravascular ultrasound (IVUS) immediately after revascularization and at 13 months follow-up were included. Three dimensional (3D) reconstruction of the non-culprit vessels were performed using (i) quantitative coronary angiography (QCA) and (ii) methodology involving fusion of IVUS and biplane angiography. In both models, blood flow simulation was performed and the minimum predominant ESS was estimated in 3 mm segments. Baseline plaque characteristics and ESS were used to identify predictors of atherosclerotic disease progression defied as plaque area increase and lumen reduction at follow-up. Fifty-four vessels were included in the final analysis. A moderate correlation was noted between ESS estimated in the 3D QCA and the IVUS-derived models (r = 0.588, P < 0.001); 3D QCA accurately identified segments exposed to low (<1 Pa) ESS in the IVUS-based reconstructions (AUC: 0.793, P < 0.001). Low 3D QCA-derived ESS (<1.75 Pa) was associated with an increase in plaque area, burden, and necrotic core at follow-up. In multivariate analysis, low ESS estimated either in 3D QCA [odds ratio (OR): 2.07, 95% confidence interval (CI): 1.17-3.67; P = 0.012) or in IVUS (<1 Pa; OR: 2.23, 95% CI: 1.23-4.03; P = 0.008) models, and plaque burden were independent predictors of atherosclerotic disease progression; 3D QCA and IVUS derived models had a similar accuracy in predicting disease progression (AUC: 0.826 vs. 0.827, P = 0.907). Conclusions: 3D QCA-derived ESS can predict disease progression. Further research is required to examine its value in detecting vulnerable plaques. PMID- 30020437 TI - Extracting chemical-protein relations with ensembles of SVM and deep learning models. AB - Mining relations between chemicals and proteins from the biomedical literature is an increasingly important task. The CHEMPROT track at BioCreative VI aims to promote the development and evaluation of systems that can automatically detect the chemical-protein relations in running text (PubMed abstracts). This work describes our CHEMPROT track entry, which is an ensemble of three systems, including a support vector machine, a convolutional neural network, and a recurrent neural network. Their output is combined using majority voting or stacking for final predictions. Our CHEMPROT system obtained 0.7266 in precision and 0.5735 in recall for an F-score of 0.6410 during the challenge, demonstrating the effectiveness of machine learning-based approaches for automatic relation extraction from biomedical literature and achieving the highest performance in the task during the 2017 challenge.Database URL: http://www.biocreative.org/tasks/biocreative-vi/track-5/. PMID- 30020438 TI - Longer-term direct and indirect effects of infant rotavirus vaccination across all ages in the US; 2000 - 2013: analysis of a large hospital discharge dataset. AB - Background: Rotavirus disease dramatically declined among children under 5 years of age since the rotavirus vaccine was introduced in 2006; population-level impacts remain to be fully elucidated. Methods: Data from the Healthcare Cost and Utilization Project State Inpatient Database were used to conduct a time-series analysis of monthly hospital discharges across age groups for acute gastroenteritis and rotavirus from 2000-2013. Rate ratios were calculated comparing pre- and post-vaccine eras. Results: Following vaccine introduction, a decrease in rotavirus hospitalizations occurred with a shift towards biennial patterns across all ages. The 0-4 year age group experienced the largest decrease in rotavirus hospitalizations (RR: 0.14, 95% CI: 0.09 - 0.23). The 5-19 and 20-59 year age groups experienced significant declines in rotavirus hospitalization rates overall; even post-vaccine calendar years were characterized by progressively lower rates while odd post-vaccine years were associated with reductions in rates that diminished over time. Those aged 60 years or older experienced the smallest change in rotavirus hospitalization rates overall, with significant reductions in even post-vaccine years compared to pre-vaccine years (RR: 0.51; 95% CI: 0.39 - 0.66). Conclusions: Indirect impacts of infant rotavirus vaccination are apparent in the emergence of biennial patterns in rotavirus hospitalizations that extend to all age groups ineligible for vaccination. These observations are consistent with the notion that young children are of primary importance in disease transmission and that the initial post-vaccination period of dramatic population-wide impacts will be followed by more complex incidence patterns across the age range in the long-term. PMID- 30020436 TI - realDB: a genome and transcriptome resource for the red algae (phylum Rhodophyta). AB - With over 6000 species in seven classes, red algae (Rhodophyta) have diverse economic, ecological, experimental and evolutionary values. However, red algae are usually absent or rare in comparative analyses because genomic information of this phylum is often under-represented in various comprehensive genome databases. To improve the accessibility to the ome data and omics tools for red algae, we provided 10 genomes and 27 transcriptomes representing all seven classes of Rhodophyta. Three genomes and 18 transcriptomes were de novo assembled and annotated in this project. User-friendly BLAST suit, Jbrowse tools and search system were developed for online analyses. Detailed introductions to red algae taxonomy and the sequencing status are also provided. In conclusion, realDB (realDB.algaegenome.org) provides a platform covering the most genome and transcriptome data for red algae and a suite of tools for online analyses, and will attract both red algal biologists and those working on plant ecology, evolution and development.Database URL: http://realdb.algaegenome.org/. PMID- 30020439 TI - Of mice and human embryos: is there an ethically preferred order of preclinical research on new assisted reproductive technologies? AB - It is widely acknowledged that the responsible introduction of new assisted reproductive technologies (ARTs) requires preclinical safety research, including the use of animal models and human embryos. However, the moral sensitivity of human embryo research has led to regulations and guidance stating that human embryos may only be used for research that cannot also be conducted with animals. We call this the 'use animals first' (UAF) rule. In the field of ART research, this translates into the notion of an ideal chain of consecutive preclinical research steps, where research using human embryos may only be considered as a further step after promising results have been obtained in animals first. This may lead to research ethics committees requiring animal studies that are in fact a waste of time and money, while exposing animals to an infringement of their wellbeing for no good purpose. In this paper, we explore the possible moral arguments behind the UAF-rule and test their validity. We conclude that there are no convincing grounds for upholding this rule and recommend replacing it. PMID- 30020441 TI - Association of childhood stress with late-life dementia and Alzheimer's disease: the KIHD study. AB - Background: There remains a dearth of life-course studies analyzing childhood environment and late-life chronic illness. In particular, few have addressed possible early-life predictors of dementia. This study examines relationships between childhood stress and later-age dementia, specifically Alzheimer's disease (AD). Methods: We used data from 2682 men in the population-based Kuopio Ischemic Heart Disease Risk Factor Study who participated in extensive baseline health examinations and interviews between 1984 and 1989, when they were between 42 and 61 years of age. Childhood events were documented in these structured interviews. We created a composite childhood stress variable that included living in custody or an orphanage, experience of crisis in childhood, having problems with teachers and emigrating because of war. Data on incident cases of dementia, including AD, were obtained through 2014 via national health register linkages. Risk of developing dementia was estimated using Cox regression adjusting for age, education, income and prior/existing diseases at baseline. Results: Childhood stress was associated with increased risk of dementia (HR = 1.86, 95% CI: 1.12 3.10). Associations remained statistically significant after adjustment for age, education, income and other covariates (HR = 1.93, 95% CI: 1.14-3.25). Associations were marginally significant with AD, with HRs of similar magnitude. Conclusions: Childhood stress plays an important role in late-life dementia risk among men. Support systems should be developed for children suffering from stressful conditions. Further research examining childhood social and environmental effects on later morbidity, in diverse populations, is necessary to develop a holistic understanding of life-course disease burden. PMID- 30020442 TI - Neonatal ECG screening and QT correction: the march towards consistency and accuracy. PMID- 30020443 TI - Finnish adolescents' self-efficacy in peer interactions: a critical incident study. AB - Peers play a significant role in influencing adolescent self-efficacy. Self efficacy, in turn, has been considered to influence health behavior. The purpose of this qualitative descriptive study was to describe adolescents' perceptions about their self-efficacy in peer interactions to strengthen the theoretical understanding about the sources of self-efficacy during adolescence. The sample comprised of 155 adolescents (13 - 17 years) in three upper comprehensive schools within two Finnish cities. The data were collected using the critical incident technique with an open-ended questionnaire. Adolescents were asked to describe two situations: one in which they had, and another in which they had not been able to act according to their own choice in peer interactions. Adolescents' written descriptions were analyzed using inductive thematic analysis. The data suggests that adolescents' perceptions about their self-efficacy in peer interactions manifests itself as a dynamic process characterized by debating with oneself and reflecting on information relevant for judging personal abilities. Debating with oneself consisted of five themes which influenced the adolescents' self-efficacy in peer interactions: adolescents' self-identity, social atmosphere, adolescents' cognitive and emotional aspects as well as evaluating the consequences of the intended action. Adolescents' self-identity, which included self-confidence and morals, appeared to be the most solid theme, whereas social atmosphere varied according to the situation. Social atmosphere often diminished the adolescents' self-efficacy in peer interactions. Although the findings are partly consistent with previous literature, they also put more emphasis on adolescents' own active role in the formation of self-efficacy in the context of peer interactions. PMID- 30020440 TI - Primary prevention implantable cardioverter-defibrillator and opportunities for sudden cardiac death risk assessment in non-ischaemic cardiomyopathy. AB - Sudden cardiac death (SCD) accounts for approximately one-third of all deaths among patients with non-ischaemic cardiomyopathy (NICM). Implantable cardioverter defibrillator (ICD) therapy has been the primary intervention for managing individuals at high risk for SCD. However, individual ICD trials in the NICM population have failed to demonstrate a mortality benefit with prophylactic ICD implantation. Current guidelines recommend ICD implantation in NICM patients with symptomatic heart failure and a left ventricular <=35% and are based on meta analyses of multiple trials that span three decades and include the recent Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischaemic Heart Failure on Mortality (DANISH) trial. These pooled analyses report a significant reduction in all-cause mortality with ICD implantation compared with medical therapy alone. In addition, each of these trials has demonstrated consistently a reduction in the risk of SCD compared with medical therapy alone. As a result, a refined approach of risk stratification that selects patients at the highest risk for SCD may lead to a significant improvement in ICD efficacy. In this clinical review, we first discuss the evolution of clinical trials that have evaluated ICDs in the NICM population. We then highlight some key markers of arrhythmia risk that hold promise in personalizing risk stratification for SCD. PMID- 30020444 TI - Assessments of Temporal Variations in Haplotypes of 'Candidatus Liberibacter solanacearum' and Its Vector, the Potato Psyllid, in Potato Fields and Native Vegetation. AB - The potato psyllid, Bactericera cockerelli (Sulc) (Hemiptera: Triozidae), had been known for nearly a century to cause psyllid yellows of solanaceous crops. However, it has only been a decade since the insect was discovered to transmit the bacterium 'Candidatus Liberibacter solanacearum' (Lso), which putatively causes potato zebra chip disease. This project was initiated to quantify temporal incidences of haplotypes of the psyllid (Central, Southwestern, and Western) and Lso (A, B) in potato fields and in native vegetation. Psyllids were collected from native vegetation in Texas (2011-2014), and from potato fields in Texas and New Mexico (2014-2017). Psyllids were tested for Lso and haplotypes of both psyllid and Lso. In Texas, the Central psyllid haplotype was overwhelmingly dominant both in potato fields and in native vegetation regardless of location and time of collection. However, in New Mexico potato fields, although the Southwestern haplotype was overall dominant, the ratios of individual haplotypes varied among years and within a season. The Southwestern psyllid haplotype was greater in incidence than the Central early but declined later in the season in each of the 4 yr, while the Central haplotype was low in incidence early but increased over time. Lso was detected in all three psyllid haplotypes representing the first report in Southwestern psyllid haplotype. In Texas, Lso haplotype A was more frequently detected than B, but in New Mexico the incidence of positive psyllids was not high enough to make definitive conclusions regarding predominant Lso haplotype. PMID- 30020445 TI - Causes of death in Japanese patients with atrial fibrillation: The Fushimi AF Registry. AB - Aims: To investigate the causes of death and the associated clinical factors in patients with atrial fibrillation (AF) in the contemporary clinical practice. Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients since March 2011 in Fushimi-ku, Kyoto. We investigated causes of death and the clinical indicators of cardiovascular (CV) and non-CV death in 4,045 patients with available follow-up data by the end of November 2016. The mean age was 73.6+/-10.9 years and the mean CHA2DS2-VASc score was 3.38+/-1.69. Oral anticoagulants (OAC) were prescribed in 55% of patients. During a median follow-up of 1,105 days, there were 705 all-cause deaths (5.5%/year); 180 CV (26% of total deaths), 381 non-CV (54%), and 144 undetermined causes (20%). The most common causes of CV and non-CV death were heart failure (14.5%), malignancy (23.1%) and infection/sepsis (17.3%), while mortality due to stroke was only 6.5%. Mortality due to infection/sepsis and undetermined causes increased with aging. On multivariate analysis, the strongest indicator of CV death was pre-existing heart failure (hazard ratio [HR]: 2.42, 95% confidence interval [CI]: 1.66-3.54, P < 0.001) and that of non-CV death was anemia (HR: 2.84, 95% CI: 2.22-3.65, P < 0.001). Conclusions: In a Japanese community-based AF cohort, CV death was not mainly related to stroke but to heart failure. Non-CV death, mainly malignancy and infection, comprised more than a half of all deaths, which increased substantially in accordance with aging. Clinical factors that were associated with CV and non-CV death were distinct. PMID- 30020446 TI - Impact of routine cryptococcal antigen screening and targeted pre-emptive fluconazole therapy in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/MUL: a systematic review and meta-analysis. AB - Cryptococcal antigen (CrAg) screening and targeted pre-emptive fluconazole in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/MUL seems promising to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg-positivity (31 studies; 35,644 participants) and asymptomatic CM in CrAg-positives, incidence of CM and all-cause mortality in screened participants. Pooled prevalence of blood CrAg-positivity was 6% (95%CI: 5 - 7) and asymptomatic CM in CrAg-positives was 33% (95%CI: 21 - 45). Incidence of CM without pre-emptive fluconazole was 21.4% (95%CI: 11.6 - 34.4) and 5.7% (95%CI: 3.0 - 9.7) with pre-emptive fluconazole initiated at 800 mg/day. In CrAg positives, post-screening lumbar puncture prior to initiating pre-emptive fluconazole at 800 mg/day further reduced incidence of CM to null and showed some survival benefits. However, all-cause mortality remained significantly higher in CrAg-positives than CrAg-negatives: RR: 2.2 (95%CI: 1.7 - 2.9, p<0.001). PMID- 30020447 TI - A prospective, open-label, randomized trial of doxycycline versus azithromycin for the treatment of uncomplicated murine typhus. AB - Background: Murine typhus, or infection with Rickettsia typhi, is a global but neglected disease without randomised clinical trials to guide antibiotic therapy. Doxycycline is commonly used but without objective evidence for optimum treatment duration. Azithromycin is a potential alternative. Methods: A prospective, open, randomised trial was conducted in non-pregnant, consenting inpatient adults with rapid diagnostic test evidence for uncomplicated murine typhus at two hospitals in Vientiane, Laos. Patients were randomised to seven (D7) or three days (D3) oral doxycycline or three days oral azithromycin (A3). Primary outcome measures were fever clearance time (FCT) and frequencies of treatment failure and relapse. Trial registration ISRCTN47812566. Results: Between 2004-2009, 216 patients (72 per arm) were enrolled; 158 (73.2%) patients had serology/PCR-confirmed murine typhus; 52 (24.1%) were R. typhi PCR-positive. All patients survived to discharge. One patient in each treatment group withdrew. Treatment failure risk was greater following regimen A3 (22.5%, 16/71) compared to D3 (4.2%, 3/71) or D7 (1.4%, 1/71)(p<0.0001). The area under the time-fever curve and FCT, for R. typhi PCR-positive patients, was significantly higher in patients following A3 than D3 (1.8 fold and 1.9 fold, respectively) and D7 (1.5 fold and 1.6 fold, respectively)(p=0.005 & p=0.021). No patients returned with PCR-confirmed R. typhi relapse. Conclusion: In Lao adults azithromycin is inferior to doxycycline for the oral therapy of uncomplicated murine typhus. Three and seven days of doxycycline have similar efficacy. Azithromycin use in murine typhus should be reconsidered. Investigation of genomic and phenotypic markers of R. typhi azithromycin resistance is needed. Trial registration: ISRCTN 47812566. PMID- 30020448 TI - Aberrant expression of genes associated with stemness and cancer in endometria and endometrioma in a subset of women with endometriosis. AB - STUDY QUESTION: Is there molecular evidence for a link between endometriosis and endometriosis-associated ovarian cancers (EAOC)? STUDY ANSWER: We identified aberrant gene expression signatures associated with malignant transformation in a small subgroup of women with ovarian endometriosis. WHAT IS KNOWN ALREADY: Epidemiological studies have shown an increased risk of EAOC in women with ovarian endometriosis. However, the cellular and molecular changes leading to EAOC are largely unexplored. STUDY DESIGN, SIZE, DURATION: CD73+CD90+CD105+ multipotent stem cells/progenitors (SC cohort) were isolated from endometrium (n = 18) and endometrioma (n = 11) of endometriosis patients as well as from the endometrium of healthy women (n = 14). Extensive phenotypic and functional analyses were performed in vitro on expanded multipotent stem cells/progenitors to confirm their altered characteristics. Aberrant gene signatures were also validated in paired-endometrium and -endometrioma tissue samples from another cohort (Tissue cohort, n = 19) of endometriosis patients. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Paired-endometrial and -endometriotic biopsies were obtained from women with endometriosis (ASRM stage III-IV) undergoing laparoscopic surgery. Control endometria were obtained from healthy volunteers. Isolated CD73+CD90+CD105+ SC were evaluated for the presence of known endometrial surface markers, colony forming efficiency, multi-lineage differentiation, cell cycle distribution and 3D-spheroid formation capacity. Targeted RT-PCR arrays, along with hierarchical and multivariate clustering tools, were used to determine both intergroup and intragroup gene expression variability for stem cell and cancer associated markers, in both SC+ and tissue cohorts. MAIN RESULTS AND THE ROLE OF CHANCE: Isolated and expanded SC+ from both control and patient groups showed significantly higher surface expression of W5C5+, clonal expansion and 3D spheroid formation capacity (P < 0.05) compared with SC-. The SC+ cells also undergo mesenchymal lineage differentiation, unlike SC-. Gene expression from paired-endometriosis samples showed significant downregulation of PTEN, ARID1A and TNFalpha (P < 0.05) in endometrioma compared with paired-endometrium SC+ samples. Hierarchical and multivariate clustering from both SC+ and tissue cohorts together identified 4 out of 30 endometrioma samples with aberrant expression of stem cell and cancer-associated genes, such as KIT, HIF2alpha and E cadherin, altered expression ratio of ER-beta/ER-alpha and downregulation of tumour suppressor genes (PTEN and ARID1A). Thus, we speculate that above changes may be potentially relevant to the development of EAOC. LARGE-SCALE DATA: N/A. LIMITATIONS, REASON FOR CAUTION: As the reported frequency of EAOC is very low, we did not have access to those samples in our study. Moreover, by adopting a targeted gene array approach, we might have missed several other potentially relevant genes associated with EAOC pathogenesis. The above panel of markers should be further validated in archived tissue samples from women with endometriosis who later in life developed EAOC. WIDER IMPLICATIONS OF THE FINDINGS: Knowledge gained from this study, with further confirmation on EAOC cases, may help in developing screening methods to identify women with increased risk of EAOC. STUDY FUNDING/COMPETING INTEREST(S): The study is funded by the Swedish Research Council (2012-2844), a joint grant from Stockholm County and Karolinska Institutet (ALF), RGD network at Karolinska Institutet, Karolinska Institutet for doctoral education (KID), Estonian Ministry of Education and Research (IUT34-16), Enterprise Estonia (EU48695), Horizon 2020 innovation program (WIDENLIFE, 692065), European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways funding (IAPP, SARM, EU324509) and MSCA-RISE-2015 project MOMENDO (691058). All authors have no competing interest. PMID- 30020449 TI - Ceftazidime/avibactam, Meropenem/vaborbactam or both? Clinical and formulary considerations. AB - Ceftazidime/avibactam and Meropenem/vaborbactam are changingthe management of invasive infections due to carbapenem-resistant enterobacteriaceae (CRE) leading to higher rates of clinical cure, decreased mortality, and decreased rates of acute kidney injury when compared to colistin-based regimens. However, these two agents are not interchangeable with regards to management of CRE infections, and clinicians need to be aware of their differences. This review focuses on differences in in vitro activity of these agents as a function of mechanism of carbapenem resistance, the clinical data supporting their superiority over colistin-based therapy, and the differences between agents with regards to propensity for selection of resistance. Furthermore, considerations and recommendations for hospital formularies and antibiotic stewardship programs regarding positioning of these agents are discussed. PMID- 30020450 TI - Development and evaluation of 3-dimensional printed models of the human tracheobronchial system for training in flexible bronchoscopy. AB - OBJECTIVES: Training and assessment of proper skills in flexible bronchoscopy are major educational goals for cardiothoracic residents. Therefore, we developed 3 dimensional (3D) printed models of the human tracheobronchial system for training and assessment of cardiothoracic residents in flexible bronchoscopy. METHODS: Three models of normal (size/shape) human tracheobronchial anatomy were generated using a commercially available 3D printer. Ten residents (inexperienced: Group 1; experienced: Group 2) participated in this study with an experimental setting of initial assessment (Model 1), training (15 min, Model 2) and post-training assessment (Model 3). The time needed for flexible bronchoscopy assessment of randomly assigned ostia was recorded before and after training. Additionally, the time for retrieval of a foreign body from the tracheobronchial system was measured before and after training. RESULTS: The average time for intubation of a given ostium (Model 1) at initial assessment was 88 s for Group 1 and 38 s for Group 2 (P < 0.0001). Following training, there was a significant reduction in time for intubation of a given ostium (Model 3) in both groups (P < 0.0001). However, the initial difference between experienced and inexperienced residents was no longer present following training. Additionally, the time for retrieval of a foreign body (cotton wool plug) from the tracheobronchial system was significantly reduced following training in both groups. CONCLUSIONS: Accurate models of the human tracheobronchial system can be generated from representative patient images using 3D engineering software and 3D printing technology. With these models, residents can be effectively trained in flexible bronchoscopy with significant improvement in their proficiency and handling capability. PMID- 30020451 TI - Can We Target Endogenous Anti-inflammatory Responses as a Therapeutic Strategy for Inflammatory Bowel Disease? AB - Inflammatory bowel disease (IBD) describes chronic relapsing remitting inflammation of the gastrointestinal tract including ulcerative colitis and Crohn's disease. The prevalence of IBD is rising across the globe. Despite a growing therapeutic arsenal, current medical treatments are not universally effective, do not induce lasting remission in all, or are accompanied by short- and long-term adverse effects. Therefore, there is a clinical need for novel therapeutic strategies for IBD. Current treatments for IBD mainly manipulate the immune system for therapeutic gain by inhibiting pro-inflammatory activity. There is a robust endogenous immunoregulatory capacity within the repertoire of both innate and adaptive immune responses. An alternative treatment strategy for IBD is to hijack and bolster this endogenous capability for therapeutic gain. This review explores this hypothesis and presents current evidence for this therapeutic direction in immune cell function, cytokine biology, and alternative mechanisms of immunoregulation such as microRNA, oligonucleotides, and the endocannabinoid system. PMID- 30020452 TI - Cephalic vs. subclavian lead implantation in cardiac implantable electronic devices: a systematic review and meta-analysis. AB - Aims: Cephalic vein cutdown (CVC) and subclavian puncture (SP) are widely used techniques for lead insertion of cardiac implantable electronic devices (CIEDs). Whether one technique is superior to the other, is still being debated. The purpose of this study was to compare CVC vs. SP for lead implantation in CIEDs with respect to the incidence of pneumothorax, lead failure, and bleeding. Methods and results: We performed a systematic search of the pertinent literature on lead implantation in CIEDs via PubMed and Cochrane databases published over the last 25 years. Standard meta-analytic methods were applied to compare incidences of outcomes of interest. Sensitivity analysis was conducted to determine the impact of each study on the overall effect size. Risk of publication bias was assessed. A total of 20 studies were included in the analysis. These studies comprised more than 30 000 patients with more than 50 000 leads implanted via CVC or SP. The incidence of pneumothorax was lower with the CVC technique (n = 29/15 065, 0.19% vs. n = 205/15 824, 1.30%) [odds ratio (OR) 0.21, 95% confidence interval (CI) 0.10-0.42, P < 0.001]. With respect to overall lead failure, CVC was associated with better outcomes as compared to SP (n = 10/2002, 0.50% vs. n = 40/2080, 1.92%) (OR 0.25, 95% CI 0.13-0.51, P < 0.001). There was no significant difference in bleeding events (n = 25/811, 3.08% vs. n = 20/2136, 0.94%) (OR 1.69, 95% CI 0.37-7.79, P = 0.50). Conclusion: This comprehensive meta-analysis demonstrates lower risk for pneumothorax and lead failure associated with CVC as compared to SP. Cephalic vein cutdown should constitute the preferred venous access. PMID- 30020453 TI - The epidemiology of herpes simplex virus type 1 in Asia: systematic review, meta analyses, and meta-regressions. AB - Objective: To characterize herpes simplex virus type 1 (HSV-1) epidemiology in Asia by assessing seroprevalence levels and extent to which HSV-1 is isolated from clinically-diagnosed genital ulcer disease (GUD) and genital herpes. Methods: HSV-1 reports in Asia were systematically reviewed and synthesized, and findings reported following PRISMA guidelines. Random-effects meta-analyses were conducted to estimate pooled mean seroprevalence and proportion of HSV-1 detection in GUD and genital herpes. Random-effects meta-regressions were conducted to identify predictors of seroprevalence and sources of between-study heterogeneity. Results: A total of 49 publications with relevant indicators were identified. These included 54 overall seroprevalence measures (and 182 stratified measures), eight proportions of HSV-1 detection in GUD, and 24 proportions of HSV 1 detection in genital herpes. Pooled mean seroprevalence was 50.0% (n=26; 95% CI: 41.3-58.7%) for children and 76.5% (n=151; 95% CI: 73.3-79.6%) for adults. By age group, pooled mean was lowest at 55.5% (n=37; 95% CI: 47.5-63.4%) in individuals aged <20, followed by 67.9% (n=48; 95% CI: 62.4-73.3%) in individuals aged 20-39, and 87.5% (n=44; 95% CI: 83.4-91.1%) in individuals aged >=40. In meta-regression, age was the only major predictor of seroprevalence. Mean proportion of HSV-1 detection was 5.6% (n=8; 95% CI: 0.8-13.6%) in GUD and 18.8% (n=24; 95% CI: 12.0-26.7%) in genital herpes. Conclusions: HSV-1 epidemiology appears to be in transition in Asia. HSV-1 is probably playing an influential role as a sexually transmitted infection explaining one-fifth of genital herpes cases. There is a need for expanded seroprevalence monitoring and GUD and genital herpes etiological surveillance. PMID- 30020454 TI - One-Hour Postload Hyperglycemia: Implications for Prediction and Prevention of Type 2 Diabetes. AB - Context: Recently, a value of 1-hour postload glucose concentration (1-h-PG) >=155 mg/dL (8.6 mmol/L) in individuals with normal glucose tolerance (NGT) has been found to be associated with an increased risk for future type 2 diabetes mellitus (T2DM). In this review, we analyze the implication of 1-h-PG determination in prediction of T2DM and cardiovascular disease. Design: A literature search was performed using MEDLINE. We included all English studies published up to February 2018 in peer-reviewed journals that examined the relationship between 1-h-PG and diabetes, cardiometabolic alterations, organ damage, and cardiovascular disease. Results: Several longitudinal studies have consistently shown that 1-h-PG >=155 mg/dL can recognize individuals at increased risk for future T2DM among subjects with NGT. Additionally, we describe the pathophysiological abnormalities associated with 1-h-PG >=155 mg/dL including impaired insulin sensitivity, beta-cell dysfunction, and increased glucose intestinal absorption, which are known to be involved in T2DM pathogenesis. Importantly, numerous studies have demonstrated that a value of 1-h-PG >=155 mg/dL in individuals with NGT is not only linked to an increased risk for future T2DM, but also able to identify those having a worse cardiovascular phenotype and an increased risk of adverse cardiovascular outcomes. Conclusions: Although 1-h PG determination is not currently recommended by the American Diabetes Association for identifying high-risk individuals, the available evidence indicates that a value of 1-h-PG >=155 mg/dL may be a useful tool to recognize, among subjects with NGT, those at increased risk of T2DM and cardiovascular disease. PMID- 30020455 TI - Societal participation of individuals aged 55-64 years with and without chronic disease. AB - Background: It is unknown whether an increase in societal participation is important for individuals with a chronic disease. This study explores whether having paid work, volunteer activities or informal care giving differs for individuals with a chronic disease and those without. Methods: Respondents (n = 1779) aged 55-64 years who participated in the Longitudinal Ageing Study Amsterdam in 2002/2003 or 2012/2013 were included. We tested differences in (combinations of) performing paid work, volunteer activities or informal care giving between participants with and without a chronic disease by regression analyses, while taking into account sociodemographic confounders and effect modification by year. Results: Having a chronic disease was associated with having paid work in 2002/2003 (OR: 0.5; 95% CI: 04-0.7), but not in 2012/2013 (OR: 0.7; 95% CI: 0.4-1.1). Work participation of participants with (OR: 1.5; 95% CI: 1.0-2.2) and without a chronic disease (OR: 2.3; 95% CI: 1.3-3.9) increased in 2012/2013. Participants with a chronic disease are more likely to participate in volunteer activities than paid work. No statistically significant associations were found between having a chronic disease and informal care giving. Conclusion: Participation in paid work differs between individuals aged 55-64 years with a chronic disease and those without, but participation in informal care giving did not. Individuals with a chronic disease are more likely to participate in volunteer activities than paid work. Future research should focus on differences in societal participation within heterogeneous group of individuals with a chronic disease, since differences may be present in subgroups with specific chronic diseases. PMID- 30020456 TI - Acquired Olfactory Dysfunction in Children and Adolescents: A Systematic Review of the Literature. AB - Olfactory function can be influenced by many factors and olfactory dysfunction is associated with several diseases. But even considering this, the causes of acquired olfactory dysfunction in children are not well understood. This review was conducted to gain an overview of the etiologies of acquired olfactory dysfunction in a pediatric population. Studies were identified using a predefined literature search, including studies if patients were <=18 years of age and results of psychophysical olfactory testing were reported. A total of 44 articles met the inclusion criteria for this review and were included in the qualitative analysis. The influence of 6 disease groups on olfactory function in children was observed (otorhinolaryngology, traumatic brain injury, oncology, psychiatric diseases, environmental factors, and other diseases). The current literature is convincing that diseases in the otorhinolaryngology group and traumatic brain injury can lead to acquired olfactory dysfunction, whereas according to the current literature, the role of other influencing factors such as most psychiatric disorders remains uncertain. A number of diseases and circumstances affect olfactory function in children and may cause acquired olfactory dysfunction in this age group. Nevertheless, more research is needed to better understand the causes of acquired olfactory dysfunction in children. Future research should have the goal of early diagnosis and, if possible, early treatment of the condition to prevent a negative impact of olfactory dysfunction on children and adolescents. PMID- 30020458 TI - Examining the impact of psychological factors on hospital length of stay for burn survivors: A systematic review. AB - Recovery of burn patients may be impeded by mental health problems. By gaining a better understanding of the impact that psychological factors may have on hospital length of stay, providers may be better informed to address the complex needs of burn survivors through effective and efficient practices. This systematic review summarizes existing data on the adverse psychological factors for the length of burn patients' hospitalization, and assesses the methodological quality of the extant literature on mental health conditions of burn survivors. A literature search was conducted in four electronic databases: PubMed, PsychINFO, Science Direct, and the Cumulative Index to Nursing and Allied Health Literature. Results yielded reports published between 1980 and 2016. Methodological quality was assessed by using an 11-item MQS system. 74 studies were identified by search; nineteen articles were eligible for analysis. Findings demonstrate paucity of evidence in the area. Reports indicate longer hospital stay among burn patients with mental health problems. Substance use was the most consistent mental-health predictor of longer hospital stay. Heterogeneity in data on mental health conditions rendered impossible estimation of effect sizes of individual psychological factors on length of hospitalization. Many studies over-relied on retrospective designs, and crude indicators of psychological factors. Findings indicate that mental health problems do have an impact on the trajectory of burn recovery by increasing the length of hospital stay for burn survivors. Inpatient mental health services for burn patients are critically needed. Prospective designs, and more sensitive psychological indicators are needed for future studies. PMID- 30020457 TI - Youth With Type 1 Diabetes Have Adipose, Hepatic, and Peripheral Insulin Resistance. AB - Context: Adolescents with type 1 diabetes (T1D) have difficulty obtaining optimal glucose control, which may relate to insulin resistance (IR), especially during puberty. Moreover, IR increases the risk for cardiovascular disease, the leading cause of death in T1D. However, the tissue specificity of IR in adolescents with T1D has not been fully phenotyped. Objective: To assess adipose, hepatic, and peripheral insulin sensitivity in adolescents with and without T1D. Design and Setting: Thirty-five youth with T1D [median age, 16 (first and third quartiles, 14, 17) years; 53% female; median body mass index (BMI) percentile, 82nd (55th, 96th); late puberty; median hemoglobin A1c, 8.3% (7.3%, 9.4%)] and 22 nondiabetic youth of similar age, BMI, pubertal stage, and level of habitual physical activity were enrolled. Insulin action was measured with a four-phase hyperinsulinemic euglycemic clamp (basal and 10, 16, and 80 mU/m2/min) with glucose and glycerol isotope tracers. Results: Adolescents with T1D had a significantly higher rate of lipolysis (P < 0.0001) and endogenous glucose production (P < 0.001) and lower peripheral glucose uptake (glucose rate of disappearance, 6.9 +/- 2.9 mg/kg/min for patients with T1D vs 11.3 +/- 3.3 for controls; P < 0.0001) during hyperinsulinemia compared with controls. In youth with T1D, glucose rate of disappearance correlated with free fatty acid at the 80 mU/m2/min phase (P = 0.005), markers of inflammation (IL-6; P = 0.012), high sensitivity C-reactive protein (P = 0.001), and leptin (P = 0.008)], but not hemoglobin A1c. Conclusions: Adolescents with T1D have adipose, hepatic and peripheral IR. This IR occurs regardless of obesity and metabolic syndrome features. Youth with T1D may benefit from interventions directed at improving IR in these tissues, and this area requires further research. PMID- 30020459 TI - Impact of drug storage systems: a quasi-experimental study with and without an automated-drug dispensing cabinet. AB - Objective: To compare the costs and benefits of an automated-drug dispensing cabinet (ADC) versus traditional floor stock storage (TFSS). Design: A quasi experimental multicenter study conducted during 2015. Setting: A teaching hospital (814 beds) equipped with 43 ADCs and a not-for-profit teaching hospital (643 beds) equipped with 38 TFSS systems, in Paris, France. Participants: All the wards of the two hospitals were included in the study. Intervention(s): ADC versus TFSS. Main Outcome Measure(s): A composite outcome composed of cost and benefits. Results: The total cost with payback period was substantially higher for the ADCs (574 006? for 41 ADCs) than TFSS (190 305? for 30 TFSS systems). The mean number of costly drugs and units were significantly higher for ADCs (P < 0.001). There was no significant difference in the mean number of overall drugs and units. There were significantly fewer urgent global deliveries with ADCs than TFSS units. Nurses' satisfaction with ADCs was high and the prevalence of medication process errors related to ADCs was low. No event due to storage errors was reported for ADCs and nine events were reported for TFSS units. On the contrary, informatic-related events increased with the use of ADCs, as expected. Conclusions: Overall, ADCs are well-established in wards and are particularly appreciated by nurses. A significant difference in the initial investment cost was confirmed, but it must be adjusted over time. This difference is offset in the long-term by gains in preparation time and fewer medication process errors, securing the medication process. PMID- 30020460 TI - A Cross-Sectional and Longitudinal Analysis of Trabecular Bone Score in Adults With Turner Syndrome. AB - Context: Turner syndrome (TS) is associated with short stature, gonadal failure, and fractures. Spinal trabecular bone score (TBS) is a novel bone imaging modality that has not been evaluated in TS. Objective: To evaluate TBS in TS and its association with bone mineral density (BMD), prevalent fracture, and risk factors. Design and Setting: Longitudinal study of TS from a single tertiary hospital between 2006 and 2017. Patients or Other Participants: Fifty-eight subjects with TS aged 20 to 49 years who underwent dual-energy X-ray absorptiometry (DXA). Main Outcome Measures: TBS, DXA parameters, and prevalent fractures were investigated. Results: Normal, partially degraded, and degraded TBSs were observed in 39 (67%), 15 (26%), and four (7%) subjects, respectively. High rates of prescribed estrogen replacement therapy (ERT) with stable TBS and BMD were observed during follow-up. TBS was positively correlated with spine and femoral neck (FN) BMD and Z-scores (all P < 0.05) and negatively correlated with age (-0.004 per year; P = 0.014) and delay in ERT initiation in women with primary amenorrhea (-0.010 per year; P < 0.001). Fractures were present in 17 (31%) subjects. Low TBS had a significantly higher area under the receiver operator curve for predicting prevalent fracture than low bone mass at either the spine or FN (P < 0.05). Subjects with no history of fracture were more likely to have a normal TBS (P = 0.023). Conclusions: BMD and TBS can be preserved with early initiation and continued use of ERT. TBS may provide additional fracture risk prediction to standard DXA parameters in TS and needs to be validated in larger prospective studies. PMID- 30020461 TI - Combination GLP-1 and Insulin Treatment Fails to Alter Myocardial Fuel Selection vs. Insulin Alone in Type 2 Diabetes. AB - Context: It is unclear if effects of glucagon-like peptide-1 (GLP-1) and clinically available GLP-1 agonists on the heart occur at clinical doses in humans, possibly contributing to reduced cardiovascular disease risk. Objective: To determine whether liraglutide, at clinical dosing, augments myocardial glucose uptake (MGU) alone or combined with insulin compared with insulin alone in metformin-treated type 2 diabetes mellitus (T2D). Design: In a randomized clinical trial of patients with T2D treated with metformin plus oral agents or basal insulin, myocardial fuel use was compared after 3 months of treatment with insulin detemir, liraglutide, or combination detemir plus liraglutide added to background metformin. Main Outcome Measures: Myocardial blood flow (MBF), fuel selection, and rates of fuel use were evaluated using positron emission tomography, powered to demonstrate large effects. Results: MBF was greater in the insulin-treated groups [median (25th, 75th percentile): detemir, 0.64 mL/g/min (0.50, 0.69); liraglutide, 0.52 mL/g/min (0.46, 0.58); detemir plus liraglutide, 0.75 mL/g/min (0.55, 0.77); P = 0.035 comparing three groups, P = 0.01 comparing detemir groups to liraglutide alone]. There were no evident differences among groups in MGU [detemir, 0.040 umol/g/min (0.013, 0.049); liraglutide, 0.055 umol/g/min (0.019, 0.105); detemir plus liraglutide, 0.037 umol/g/min (0.009, 0.046); P = 0.68 comparing three groups]. There were no treatment-group differences in measures of myocardial fatty acid uptake or handling, and no differences in total oxidation rate. Conclusion: These observations argue against large effects of GLP-1 agonists on myocardial fuel metabolism as mediators of beneficial treatment effects on myocardial function and ischemia protection. PMID- 30020463 TI - Differences in Upper and Lower Body Adipose Tissue Oxygen Tension Contribute to the Adipose Tissue Phenotype in Humans. AB - Context and Objectives: Upper and lower body adipose tissue (AT) exhibits opposing associations with obesity-related cardiometabolic diseases. Recent studies have suggested that altered AT oxygen tension (pO2) may contribute to AT dysfunction. Here, we compared in vivo abdominal (ABD) and femoral (FEM) subcutaneous AT pO2 in women who are overweight and have obesity, and investigated the effects of physiological AT pO2 on human adipocyte function. Design: ABD and FEM subcutaneous AT pO2 and AT blood flow (ATBF) were assessed in eight [BMI (body mass index) 34.4 +/- 1.6 kg/m2] postmenopausal women who were overweight with obesity and impaired glucose metabolism. ABD and FEM AT biopsy specimens were collected to determine adipocyte morphology and AT gene expression. Moreover, the effects of prolonged exposure (14 days) to physiological AT pO2 on adipokine expression/secretion, mitochondrial respiration, and glucose uptake were investigated in differentiated human multipotent adipose-derived stem cells. Results: AT pO2 was higher in ABD than FEM AT (62.7 +/- 6.6 vs 50.0 +/- 4.5 mm Hg, P = 0.013), whereas ATBF was comparable between depots. Maximal uncoupled oxygen consumption rates were substantially lower in ABD than FEM adipocytes for all pO2 conditions. Low physiological pO2 (5% O2) decreased proinflammatory gene expression, increased basal glucose uptake, and altered adipokine secretion in ABD and FEM adipocytes. Conclusions: We demonstrated for the first time, to our knowledge, that AT pO2 is higher in ABD than FEM subcutaneous AT in women who are overweight/with obesity, partly due to a lower oxygen consumption rate in ABD adipocytes. Moreover, low physiological pO2 decreased proinflammatory gene expression and improved the metabolic phenotype in differentiated human adipocytes, whereas more heterogeneous effects on adipokine secretion were found. PMID- 30020464 TI - Driving sustainable change in antimicrobial prescribing practice: how can social and behavioural sciences help? AB - Addressing the growing threat of antimicrobial resistance is, in part, reliant on the complex challenge of changing human behaviour-in terms of reducing inappropriate antibiotic use and preventing infection. Whilst there is no 'one size fits all' recommended behavioural solution for improving antimicrobial stewardship, the behavioural and social sciences offer a range of theories, frameworks, methods and evidence-based principles that can help inform the design of behaviour change interventions that are context-specific and thus more likely to be effective. However, the state-of-the-art in antimicrobial stewardship research and practice suggests that behavioural and social influences are often not given due consideration in the design and evaluation of interventions to improve antimicrobial prescribing. In this paper, we discuss four potential areas where the behavioural and social sciences can help drive more effective and sustained behaviour change in antimicrobial stewardship: (i) defining the problem in behavioural terms and understanding current behaviour in context; (ii) adopting a theory-driven, systematic approach to intervention design; (iii) investigating implementation and sustainability of interventions in practice; and (iv) maximizing learning through evidence synthesis and detailed intervention reporting. PMID- 30020462 TI - Diurnal Cortisol Concentrations and Growth Indexes of 12- to 48-Month-Old Children From Mexico City. AB - Context: Early life cortisol plays an important role in bone, muscle, and fat mobilization processes, which could influence body composition, affecting anthropometric indicators such as weight and height. Objective: To explore the association between diurnal cortisol levels and growth indexes in children from 12 to 48 months of age. Design: This study includes data from 404 children from the Programming Research in Obesity, Growth, Environment and Social Stressors Mexican birth cohort. Cortisol was measured in eight saliva samples collected at four time points during the day (from wakeup to bedtime), over 2 days, when the child was either 12, 18, or 24 months old. Total daytime cortisol levels were calculated by averaging the area under the curve (AUC) for the 2 days. Height and weight were measured from 12 to 48 months of age. Growth indexes were constructed according to z scores following World Health Organization standards: weight-for age z score (Z-WFA), height/length-for-age z score, weight-for-height/length z score (Z-WFH), and body mass index-for-age z score (Z-BMIFA). Mixed models were used to analyze the association between cortisol AUC quartiles and growth indexes. Results: Cortisol showed an inverted U-shaped association with the four growth indexes. Compared with the first quartile, all quartiles had a positive association with indexes that include weight, with the second quartile having the strongest association, resulting in an average change of beta (95% CI) 0.38 (0.13 0.64) for Z-WFA, 0.36 (0.10-0.62) for Z-WFH, and 0.43 (0.17-0.69) for Z-BMIFA. Conclusions: Results suggest that early life daytime cortisol levels, as a reflection of hypothalamic-pituitary-adrenal axis development, might influence growth in early infancy. PMID- 30020465 TI - Mitotic spindle orientation in epithelial homeostasis and plasticity. AB - Polarized epithelia are a foundation of organ and appendage structures throughout Metazoa and serve as a physical barrier to preserve physiological functions. In proliferating epithelia, planar cell division occurs by orienting the mitotic spindle within the plane of the epithelium to ensure tissue organization. Conversely, loss of tissue architecture is a hallmark of carcinoma, and aberrant spindle orientation is hypothesized to contribute to tissue disorganization through dysplasia and cell dissemination. Recent in vivo studies have uncovered a role of planar spindle alignment in the robust maintenance of tissue architecture, which accompanies homeostatic mechanisms such as cell delamination and re-integration of misplaced cells following abnormal cell division. Furthermore, perpendicular spindle orientation shifts have been suggested as causes of cell fate change and epithelial plasticity manifested by epithelial-to mesenchymal transition. This review describes the mechanism by which planar spindle orientation is tightly regulated and discusses the roles of mitotic spindle orientation in epithelial development and disease. PMID- 30020466 TI - CLINICAL AND PATHOLOGICAL ASPECTS OF SILENT PITUITARY ADENOMAS. AB - Context: Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. Evidence Acquisition: A comprehensive literature search was performed using MEDLINE and EMBASE databases between January 2000 and March 2018 with the following key words: (i) pituitary adenoma/tumor and non-functioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed and recent advances in the field of silent pituitary adenomas were summarized. Evidence Synthesis: The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas: while some adenomas are truly silent, others may show some evidence of biochemical hypersecretion or may have subtle clinical signs, and therefore may be referred to as clinically silent or 'whispering' adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a higher rate of recurrence. Transcription factors for pituitary cell lineages have been introduced into the 2017 WHO guidelines: SF1 staining for gonadotroph lineage, PIT1 for growth hormone, prolactin and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. Conclusions: A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new WHO classification of pituitary adenomas. New classifications, novel prognostics markers, emerging imaging and therapeutic approaches will need to be evaluated to better serve this unique group of patients. PMID- 30020467 TI - Optimization of Mass-Rearing Methods for Anopheles arabiensis Larval Stages: Effects of Rearing Water Temperature and Larval Density on Mosquito Life-History Traits. AB - Insect mass-rearing is an essential requirement for the sterile insect technique. Production at a large scale requires the development of standardized rearing procedures to produce good quality males able to compete with wild males to mate with wild females. Three sets of experiments (using trays placed on the table, the whole tray-rack system, and climate-controlled chambers) have been conducted aiming to determine the optimal water temperature and number of eggs to aliquot into each larval rearing tray to achieve the highest production of pupae. No difference was found in time to pupation, sex ratio, or male body size as a result of altering larval density. However, higher larval densities resulted in decreased emergence rate and female body size. A constant water temperature of 22 degrees C delayed hatching and did not allow Anopheles arabiensis to complete larval development. Hatching eggs in water at 22 degrees C and then increasing water temperature to 27 degrees C resulted in decreased pupae production compared to eggs hatched and larvae maintained at a water temperature of 27 degrees C throughout. Water temperature and larval density affected the production parameters of An. arabiensis mosquitoes, which has implications for mass release programs. We conclude that 4,000 eggs per 4 liter and a water temperature of 27 degrees C were the optimal conditions for mass-rearing this mosquito species which yielded 105,000 pupae/larval rearing unit. These results are valuable information in the development of standard operation procedures for the efficient large-scale rearing of An. arabiensis mosquitoes. PMID- 30020468 TI - The Association of Maternal Thyroid Autoimmunity During Pregnancy With Child IQ. AB - Context: Thyroperoxidase antibody (TPOAb) positivity is a major risk factor for gestational thyroid dysfunction. During the first 18 to 20 weeks of pregnancy, high concentrations of human chorionic gonadotropin (hCG) stimulate the thyroid to ensure adequate thyroid hormone availability for the developing fetus. However, TPOAb-positive women have an impaired thyroidal response to hCG stimulation. Objective: To study the association of maternal TPOAb positivity during pregnancy with child IQ. Design, Setting, and Participants: This study was embedded in two prospective birth cohorts: Generation R (Rotterdam, the Netherlands) and Avon Longitudinal Study of Parents and Children (ALSPAC; United Kingdom). Mother-child pairs with available data on early pregnancy TPOAb (<=18 weeks of gestation) and offspring IQ were included (n = 3637 for Generation R and n = 2396 for ALSPAC). Main Outcome Measures: Child IQ at 5 to 10 years of age. Results: In Generation R, TPOAb positivity was associated with a 2.0 +/- 0.9 point lower mean child IQ (P = 0.03). Sensitivity analyses showed negative effect estimates already from TPOAb concentrations considerably lower than currently used manufacturer cutoffs. In ALSPAC, neither TPOAb positivity nor TPOAb concentrations below manufacturer cutoffs were associated with child IQ (TPOAb positivity: 0.7 +/- 1.0; P = 0.45). Adjustment for maternal TSH or free T4 concentrations or urinary iodine/creatinine ratio did not change the results. Conclusion: TPOAb positivity during pregnancy was associated with lower child IQ in Generation R but not in ALSPAC. Further studies are needed to elucidate whether differences between the study populations, such as maternal iodine status, could be the underlying cause for these differences. PMID- 30020470 TI - Epithelial-mesenchymal transition in haematopoietic stem cell development and homeostasis. AB - Epithelial-mesenchymal transition (EMT) is a morphogenetic process of cells that adopt an epithelial organization in their developmental ontogeny or homeostatic maintenance. Abnormalities in EMT regulation result in many malignant tumours in the human body. Tumours associated with the haematopoietic system, however, are traditionally not considered to involve EMT and haematopoietic stem cells (HSCs) are generally not associated with epithelial characteristics. In this review, we discuss the ontogeny and homeostasis of adult HSCs in the context of EMT intermediate states. We provide evidence that cell polarity regulation is critical for both HSC formation from embryonic dorsal aorta and HSC self-renewal and differentiation in adult bone marrow. HSC polarity is controlled by the same set of surface and transcriptional regulators as those described in canonical EMT processes. With an emphasis on partial EMT, we propose that the concept of EMT can be similarly applied in the study of HSC generation, maintenance and pathogenesis. PMID- 30020469 TI - Glucocorticoid Receptor Mutations and Hypersensitivity to Endogenous and Exogenous Glucocorticoids. AB - Background: The glucocorticoid receptor (GR) consists of two alternatively spliced isoforms: GRalpha, which activates gene transcription, and GRbeta, a dominant-negative receptor. Theoretically, inactivating variants of GRbeta could result in glucocorticoid hypersensitivity. Design: A 46-year-old woman presented for evaluation of adrenal insufficiency prompted by low plasma cortisol levels and multiple unexplained symptoms but without clinical evidence of glucocorticoid insufficiency. To explain these findings, extensive clinical, genetic, and molecular studies were performed. Methods: Standard clinical methods assessed the patient's hypothalamic-pituitary-adrenal axis. Validated molecular techniques were used for receptor sequencing, stable transfections, stimulation of candidate genes, cDNA arrays, Ingenuity Pathway Analysis, volcano analysis, and isolation and analysis of the patient's mononuclear cells. Results: Clinical studies excluded primary or secondary adrenal insufficiency, established consistently low basal cortisol levels, and demonstrated hypersensitivity to ultra-low-dose dexamethasone. Receptor sequencing identified two variants of GR9beta (A3669G and G3134T) as well as the known Bcl1 polymorphism. Reductionist studies using stable osteosarcoma cell lines transfected with the GRbeta variants demonstrated glucocorticoid hypersensitivity of transcribed genes on cDNA array analysis. The patient's monocytes responded to hydrocortisone with exaggerated stimulation of the candidate genes GILZ and FKBP5. Conclusion: Two variants of the dominant negative GRbeta, in conjunction with a common Bcl1 intron variant, resulted in hypersensitivity to endogenous and exogenous glucocorticoids and, as a reflection of severity, low circulating cortisol levels without clinical evidence of glucocorticoid insufficiency. This prismatic case exemplifies the unique effects of variants of a dominant-negative receptor. PMID- 30020472 TI - Antibacterial effect of ceftolozane/tazobactam in combination with amikacin against aerobic Gram-negative bacilli studied in an in vitro pharmacokinetic model of infection. AB - Objectives: To use a pre-clinical infection model to assess the antibacterial effect of human simulations of dosing with ceftolozane/tazobactam (with or without amikacin) or meropenem against Enterobacteriaceae and Pseudomonas aeruginosa. Methods: An in vitro pharmacokinetic model was used to assess changes in bacterial load and profiles after exposure to mean human serum concentrations over 168 h. Changes in area under the bacterial kill curve (AUBKC; log cfu/mL.h) and growth on 4 * MIC recovery plates were the co-primary outcome measures. Results: Simulations of ceftolozane/tazobactam at 1 g/0.5 g or 2 g/1 g q8h or meropenem 2 g q8h all produced a >4 log reduction in bacterial load of Escherichia coli. Meropenem had smaller AUBKC values, indicating greater reduction in bacterial load than ceftolozane/tazobactam. Meropenem was also more effective than ceftolozane/tazobactam against Klebsiella pneumoniae strains. All regimens were equally effective in reducing P. aeruginosa bacterial load measured by AUBKC but growth on 4 * MIC recovery plates and changes in population profiles were only seen with meropenem. Addition of amikacin at 15 mg/kg q24h or 7.5 mg/kg q12h to 2 g/1 g of ceftolozane/tazobactam produced greater reductions in bacterial load but generated changes in amikacin population profiles with the 7.5 mg/kg q12h amikacin simulation. Conclusions: The doses of ceftolozane/tazobactam simulated were highly effective in reducing the bacterial load of E. coli (MIC <=0.25 mg/L), but less so for K. pneumoniae (MIC 4 mg/L). For both species, meropenem produced an overall greater reduction in pathogen load. Ceftolozane/tazobactam and meropenem were equally effective as monotherapy against P. aeruginosa but emergence of resistance occurred with meropenem. Addition of amikacin to ceftolozane/tazobactam reduced the bacterial load of P. aeruginosa at the expense of emergence of resistance to amikacin. PMID- 30020471 TI - Unmet needs in Primary Care of older clients with mental health concerns. AB - Objective: To examine the unmet needs of older clients with perceived mental health problems who attend primary healthcare services. Design: Unmet needs were derived from (i) the health concerns and caregiver network availability provided by a General Practitioner (GPs) and from (ii) a qualitative analysis of an open question about needs completed by informal caregivers (ICs) of those clients. Participants: The sample comprised 436 clients with mean age of 75.2 years and 110 ICs with mean age of 56.7 years. Setting: Primary healthcare centers in the North of Portugal. Main outcome measure: The Community Assessment of Risk Instrument-CARI (Clarnette RM, Ryan JP, O'Herlihy E, et al. The community assessment of risk instrument: investigation of inter-rater reliability of an instrument measuring risk of adverse outcomes. J Frailty Aging 2015;4: 80-9; O'Caoimh R, Healy E, Connell EO, et al. The Community Assessment of Risk Tool (CART): investigation of inter-rater reliability for a new instrument measuring risk of adverse outcomes in community dwelling older adults. Irish J Med Sci 2012.) and qualitative data about needs. Results: Several needs were observed in relation to (1) mental state (e.g. cognition, anxiety/depression); (2) functionality (e.g. IADLS, bathing, mobility); (3) medical state (e.g. chronic diseases, vision deficits) and (4) IC ability to meet clients' needs. From the categorical analysis of the ICs' answers, an amount of unmet needs not only health related but also related with referrals and legal issues were found. Conclusions: This study shows a large number of unmet needs of older people. The evaluation of the clients combined with the evaluation of the testimonials of ICs enables the understanding of difficulties of both clients and caregivers, and which needs should be prioritized. PMID- 30020473 TI - Evaluation of Insect Pests on Edamame Varieties in Minnesota. AB - Edamame, Glycine max (L.) Merrill, consumption continues to rise in the United States. Improved understanding of production threats, including insect pests, could facilitate increasing production of edamame in the north-central United States. Two years of complimentary field and laboratory experiments were performed to assess insect pest populations on commercially available edamame varieties. Fourteen varieties of edamame and four grain-type soybean varieties were tested in the laboratory with soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), and subsets of these varieties were tested in the field with naturally occurring insect populations. In the laboratory, mean aphid densities on the edamame varieties Agate and Chiba Green did not differ from the aphid-resistant grain-type soybean. Among edamame, aphid densities on Agate, Chiba Green, and Kuroshinju were significantly lower than on Hokkaido Black. In both years of the field experiment, aphid densities were significantly lower on the aphid-resistant grain-type compared to all others varieties. In 2016, aphid populations on edamame varieties did not differ from the aphid-susceptible grain types. However, in 2017 with greater aphid exposure, differences were seen among edamame varieties, and between edamame and aphid-susceptible grain-types. In both years, potato leafhopper, Empoasca fabae (Harris) (Hemiptera: Cicadellidae), densities tended to be higher on edamame varieties compared to grain-types, and varied significantly among edamame varieties. In a laboratory study, differences were seen among varieties in mean density of trichomes, with grain-types generally having more trichomes than edamame. Results of this research will provide a foundation for development of production recommendations for edamame in the north-central United States. PMID- 30020475 TI - Chemical compounds that suppress hypoxia-induced stress granule formation enhance cancer drug sensitivity of human cervical cancer HeLa cells. AB - In eukaryotic cells, when exposed to certain types of stress including hypoxia, eIF2alpha is phosphorylated by several kinases including protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK). Subsequently, protein translation is stopped and stress granules (SGs) are formed. Cancer cells form SGs under hypoxia. SGs accumulate apoptosis-related molecules and play anti apoptotic roles. Thus, hypoxia-induced SG formation contributes to drug resistance in cancer cells. For this reason, inhibition of SG formation is expected to be beneficial in cancer therapy. To prove this concept, chemical reagents that inhibit SG formation are required as experimental tools. We searched for chemical compounds that suppress SG formation and identified that beta-estradiol, progesterone, and stanolone (hereafter described as EPS) inhibit SG formation in human cervical cancer HeLa cells. As it turned out, EPS block PKR but not PERK, thus fail to suppress SG formation in most cancer cells, where SGs are formed via PERK. Nevertheless, in this study, we used HeLa cells as a model and demonstrated that EPS block hypoxia-induced SG formation in HeLa cells and consequently reduce drug resistance that HeLa cells acquire under hypoxia. Our findings support that inhibition of SG formation is a useful method to control cancers. PMID- 30020476 TI - The Association of Thyroid Function With Bone Density During Childhood. AB - Context: Although the skeleton is a well-known thyroid hormone target organ, very little data are available on the association of thyroid function with bone outcomes during childhood. Objective: To study the association of thyroid function with bone mass during childhood. Design, Setting, and Participants: Population-based prospective cohort including 4204 children with TSH and free T4 (FT4) measured at the age of 6 years. Main Outcome Measures: Bone density was assessed by a total body dual-energy X-ray absorptiometry scan at the median age of 6 years (95% range, 5.6 to 7.9) and at the age of 10 years (95% range, 9.0 to 10.9) in 4204 and 3404 participants, respectively. Results: There was an inverse association of TSH with bone mineral density (BMD) at the age of 6 (beta -0.028 +/- 0.011, P = 0.009) and with follow-up measurements at the age of 10 (beta 0.027 +/- 0.011, P = 0.014), but not with bone mineral content (BMC) at the age of 6 (beta -0.028 +/- 0.015, P = 0.06) or for follow-up measurements of BMC at the age of 10 (beta -0.011 +/- 0.015, P = 0.47). There was an inverse association of FT4 with BMD (beta -0.016 +/- 0.006, P = 0.014) and BMC (beta -0.023 +/- 0.009, P = 0.009) cross-sectionally, and also at the age of 10 years (BMD: beta 0.018 +/- 0.007, P = 0.007; BMC: beta -0.021 +/- 0.009, P = 0.020). Conclusion: A higher FT4 concentration is associated with lower bone mass at the age of 6 and at the age of 10 years. These data provide insights into the effects of thyroid function on bone physiology during childhood. PMID- 30020477 TI - Measurement of selected androgens using liquid chromatography-tandem mass spectrometry in reproductive-age women with Type 1 diabetes. AB - STUDY QUESTION: What information does androgen profiling using liquid chromatography tandem mass spectrometry (LC-MS/MS) provide in reproductive-age women with Type 1 diabetes (T1D)? SUMMARY ANSWER: In T1D women, androstenedione proved most useful of the measured androgens in differentiating subgroups based on clinical phenotypes of hyperandrogenism (HA) and polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY: The prevalence of HA and PCOS are increased in women with T1D. These observations are based on measurement of serum androgens using immunoassays, to-date no studies using LC-MS/MS have been reported in reproductive-age women with T1D. STUDY DESIGN, SIZE, DURATION: This was a cross sectional study with recruitment of three groups of reproductive-age women: women with T1D (n = 87), non-diabetic women with (N = 97) and without PCOS (N = 101). PARTICIPANTS/MATERIALS, SETTING, METHODS: Using LC-MS/MS, we aimed to characterize androgen profiles and PCOS status in women with T1D, and interpret findings in relation to cohorts of non-diabetic women with and without PCOS. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to non-diabetic women, dehydroepiandrosterone/dehydroepiandrosterone sulphate (DHEA/DHEAS) ratio was lower (P < 0.05) in women with T1D. Testosterone levels were greater in T1D women with clinical HA and anovulation compared to those without clinical HA and with regular cycles, while androstenedione levels were greater in T1D women with HA and anovulation compared to those with HA and regular cycles and also those without HA and with regular cycles (P < 0.05 for all). Compared to T1D women without PCOS, the 18% of T1D women who had PCOS were younger with lower BMI, an older age of menarche, and were more likely to have a positive family history of PCOS (P < 0.05 for all). Androgen levels did not differ between women with T1D and PCOS compared to BMI-matched non-diabetic women with PCOS, but androstenedione levels were greater in T1D women with PCOS compared to obese women with PCOS (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Relatively small subgroups of patients were studied, reducing the power to detect small differences. Free testosterone levels were not measured using equilibrium dialysis, and were not calculated - commonly used formulae have not been validated in T1D. WIDER IMPLICATIONS OF THE FINDINGS: Androstenedione is a sensitive biochemical marker of clinical hyperandrogenism and PCOS in T1D. T1D women with PCOS are leaner than those without PCOS but are more likely to have a family history of PCOS. Women with T1D and PCOS have a similar biochemical phenotype to lean non-diabetic women with PCOS but differ from obese women with PCOS. The mechanisms underlying PCOS in T1D and its clinical significance require further investigation. STUDY FUNDING/COMPETING INTEREST(S): The study was part funded by the Meath Foundation. The authors have no competing interests. PMID- 30020478 TI - Increased Risk of Influenza and Influenza-Related Complications Among 140,480 Patients With Inflammatory Bowel Disease. AB - Background: Diseases of immune dysregulation are associated with an increased risk of viral infections, some of which may be preventable. To date, there are very limited data on the incidence and risk of influenza and related complications in patients with inflammatory bowel disease (IBD). Furthermore, the impact of immunosuppressive medications on that risk is unclear. Therefore, the aim of this study was to estimate the incidence and severity of influenza infections in IBD patients. In addition, we looked specifically at the effect of medications on influenza risk. Methods: Using the MarketScan Database (January 2008 to December 2011), we conducted a retrospective cohort study to estimate the incidence of influenza and risk of related complications in IBD patients compared with those without IBD. We employed a nested case-control study design to evaluate the potential independent effect of IBD medications on influenza risk. Results: A total of 140,480 patients with IBD and non-IBD controls were studied. There were 2963 patients with influenza compared with 1941 non-IBD subjects. Inflammatory bowel disease patients had an increased influenza risk compared with those without IBD (incidence rate ratio, 1.58; 95% confidence interval [CI], 1.49 1.68). A higher rate of hospitalizations (162/2994 [5.4%] vs 36/1941 [1.85%]; P < 0.001) was noted. Systemic corticosteroids were found to be independently associated with influenza (odds ratio, 1.22; 95% CI, 1.08-1.38). Conclusions: Inflammatory bowel disease patients had an increased risk of influenza compared with those without IBD and were more likely to require hospitalization. Steroids were the only medication class independently associated with flu risk. PMID- 30020479 TI - Parasitic Quill Mites of the Family Syringophilidae (Acariformes: Prostigmata) Associated With Sub-Saharan Sunbirds (Passeriformes: Nectariniidae): Species Composition and Host-Parasite Relationships. AB - We investigated the quill mite fauna of the family Syringophilidae (Acariformes: Prostigmata) associated with Sunbirds (Passeriformes: Nectariniidae) in the Sub Saharan region. Six hundred eleven host individuals belonging to 52 species were examined. Syringophilid parasitization prevalence (44 hosts of 15 species) ranged from 1.4 to 75% in particular host species. In the collected material, we have found seven quill mite species and among them four are new for science: 1) Aulobia afroanthreptes Skoracki & Zmudzinski sp. nov. from Anthreptes neglectus Neumann, 1922 and Anthreptes longuemarei (Lesson, 1831), both from Tanzania; 2) Syringophiloidus nectariniae Skoracki & Zmudzinski sp. nov. from Hedydipna collaris (Vieillot, 1819) from Tanzania; 3) Aulonastus nectariniphilus Skoracki & Zmudzinski sp. nov. from Anthreptes reichenowi Gunning, 1909 from Tanzania and Nectarinia tacazze (Stanley, 1814) from Ethiopia; and 4) Picobia hedydipna Skoracki & Zmudzinski sp. nov. from Hedydipna collaris from Kenya. Representatives of the genera Aulonastus Kethley, 1970 and Syringophiloidus Kethley, 1970 are recorded on Sunbirds for the first time. The following new host species are given: Cinnyris mariquensis Smith, 1836, C. shelleyi Alexander, 1899 and C. regius Reichenov, 1893, all from Tanzania for Aulobia nectariniae Skoracki & Glowska, 2008; A. neglectus and A. longuemarei, both from Tanzania for Neoaulonastus cinnyris Klimovicova et al., 2014; Cyanomitra verreauxii (Smith, 1832) from Tanzania and Cinnyris chalybeus (Linnaeus, 1766) from South Africa for Picobia oritis Skoracki et al., 2009. Additionally, host-parasite relationships are discussed. PMID- 30020480 TI - First Record of Aedes albopictus (Diptera: Culicidae) and Second Record of Aedes japonicus (Diptera: Culicidae) Parasitized by Water Mites (Acari: Hydrachnidiae) in North America. AB - The primary aim of this study was to determine if the Asian tiger mosquito (Aedes albopictus (Skuse)) (Diptera: Culicidae), that vectors a number of arboviruses, is parasitized by water mites (Acari: Prostigmata: Parasitengonina: Hydrachnidiae). Larval water mite parasitism of adult mosquitoes has been shown to reduce mosquito fecundity and life span in the laboratory, and impact some populations in the field. Water mites have been considered for biocontrol purposes and used to age-grade mosquito populations. Consequently, there is interest in water mite-mosquito associations from public health and integrated pest management perspectives. In 2016, the Pennsylvania Department of Environmental Protection West Nile Virus Control Program examined 146,607 mosquitoes representing 31 species for parasitic mites. Ten mosquitoes representing four species rarely or not previously known to be parasitized by mites were saved from destructive West Nile virus and Zika virus testing. Twelve parasitic mites were identified to the lowest taxonomic level possible. An Asian tiger mosquito and an Asian bush mosquito (Aedes japonicus) (Theobald) were each parasitized by a Parathyas sp. Lundblad (Hydryphantoidea: Hydryphantidae: Euthyadinae) water mite, and are the first and second records of these associations in North America, respectively. Two Culex restuans Theobald (Diptera: Culicidae) mosquitoes parasitized by either a Euthyas sp. Piersig (Hydryphantoidea: Hydryphantidae: Euthyadinae) or a Parathyas sp. water mite are new associations, and a Culex pipiens Linnaeus mosquito parasitized by a Parathyas sp. water mite represents a new record for this association in North America. PMID- 30020481 TI - A Gain-of-Function CASR Mutation Causing Hypocalcemia in a Recessive Manner. PMID- 30020482 TI - Herpes Therapy Enters the Molecular Age. PMID- 30020483 TI - The association between body mass index, waist circumference, waist-hip ratio and cognitive disorder in older adults. AB - Purpose: To examine the association between body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and cognitive disorder in older adults. Methods: Cross-sectional data from the mini-mental state examination questionnaire and physical examination of older adults (>=65, n = 1037) were collected and analyzed. Logistic regression examined the odds ratios (ORs) of cognitive performance according to BMI, WC and WHR. Results: The prevalence of cognitive dysfunction in older adults was 13.0%. The BMI-based overweight rate, obesity rate and central obesity rate calculated by either WC or WHR were 39.6, 11.4% and 66.5, 65.6%, respectively. The risk of cognitive impairment was increased in elderly individuals >=70 years old than in those <70 years old (OR = 1.738). In addition, gender, WHR and smoking habit were also significantly different between the two age groups (P < 0.05). We examined the effects of different BMI values and WC/WHR central obesity on cognition impairment in >=70 year-old adults and found that BMI obesity and WC/WHR central obesity had a combined effect on the incidence of cognition impairment (OR = 3.076 and OR = 3.584). Conclusions: BMI obesity and WC/WHR central obesity have a combined effect on cognitive impairment and WHR has a stronger association with cognitive impairment than WC. PMID- 30020484 TI - Herpes Simplex Virus Shedding Rate: Surrogate Outcome for Genital Herpes Recurrence Frequency and Lesion Rates, and Phase 2 Clinical Trials End Point for Evaluating Efficacy of Antivirals. AB - Background: We tested whether genital herpes simplex virus (HSV) shedding is an appropriate surrogate outcome for the clinical outcome of genital herpes lesions in studies of HSV-2 antiviral interventions. Methods: We analyzed prospective data from natural history studies and clinical trials of antiviral agents for HSV 2 in which HSV-2-seropositive participants provided self-collected anogenital swab specimens daily over >=25 days for HSV DNA quantitation by polymerase chain reaction (PCR). Genital recurrences were self-reported. Results: Among 674 participants, genital HSV shedding was detected on 17% of days, and genital lesions were reported on 10% of days. Within the same session, HSV shedding rates were strongly correlated with lesion rates (rho = 0.61, P < .0001). The relative reduction in the recurrence rate was 72% (P = .041) for recipients of the antiviral agent pritelivir as compared to recipients of placebo, but it decreased to 21% (P = .75) after adjustment for HSV shedding rate. When evaluating valacyclovir and acyclovir, adjustment for the HSV shedding rate also led to a reduced association of these antivirals with the recurrence rate. Overall, 40% 82% of the antiviral effect on recurrences was explained by its effect on HSV shedding. Conclusion: HSV genital shedding measured by PCR analysis in swab specimens self-collected daily is an appropriate surrogate outcome for genital herpes lesions because it is in the causal pathway to recurrences. PMID- 30020485 TI - Analysis of DNA methylation alterations in rice seeds induced by different doses of carbon-ion radiation. AB - To investigate the mechanism underlying differences in biological effects induced by low- versus high-dose heavy-ion radiation (HIR) in rice plants, two dimensional gel electrophoresis (2-DE) coupled with methylation-sensitive amplification polymorphism (MSAP) analysis were used to check the expression changes in rice leaf proteome profiles and the changes in DNA methylation after exposure of seeds to ground-based carbon-ion radiation at various cumulative doses (0, 0.01, 0.02, 0.1, 0.2, 1, 2, 5 or 20 Gy; 12C6+; energy, 165 MeV/u; mean linear energy transfer, 30 KeV/MUm). In this study, principal component analysis (PCA) and gene ontology (GO) functional analysis of differentially expressed proteins of rice at tillering stage showed that proteins expressed in rice samples exposed to 0.01, 0.02, 0.1, 0.2 or 1 Gy differed from those exposed to 2, 5 or 20 Gy. Correspondingly, the proportion of hypermethylation was higher than that of hypomethylation at CG sites following low-dose HIR (LDR; 0.01, 0.2 or 1 Gy), whereas this was reversed at high-dose HIR (HDR; 2, 5 or 20 Gy). The hypomethylation changes tended to occur at CHG sites with both low- and high-dose HIR. Furthermore, sequencing of MSAP variant bands indicated that the plants might activate more metabolic processes and biosynthetic pathways on exposure to LDR, but activate stress resistance on exposure to HDR. This study showed that radiation induced different biological effects with low- and high-dose HIR, and that this may have been caused by different patterns of hyper- and hypomethylation at the CG sites. PMID- 30020486 TI - Socioeconomic and psychosocial determinants of adherence to the Mediterranean diet in a general adult Italian population. AB - Background: To evaluate the adherence to Mediterranean diet (MD) and its major socioeconomic and psychosocial determinants in a large sample of the Italian population, covering three main geographical areas of the Country (Southern, Central and Northern). Methods: Data were obtained from the Italian Nutrition & Health Survey (INHES), including a total of 7, 430 participants (age >20) recruited from all over Italy (2010-13). Dietary information was collected by the European Food Propensity Questionnaire. Adherence to MD was assessed by using the MedDietScore based on 11 food groups. Associations were tested by multivariable logistic regression analysis (Odds ratio [OR] with 95% CI). Results: Adherence to MD was higher in Southern Italy as compared with the Northern (OR = 1.34; 95% CI 1.18-1.53), and was closely associated with adult age (OR= 2.40; 1.61-3.58 for those aged > 75 years as compared with 20-34 years) and higher educational level (OR = 1.77; 1.40-2.24 for post-secondary education as opposed to lowest educational attainment). Subjects reporting adverse life events and those with family-related stress were less likely to show an optimal adherence to MD (OR = 0.55; 0.46-0.67 and OR = 0.44; 0.28-0.69, for highest vs. lowest tertile, respectively) as compared with adequate controls. A number of eating behaviours were also inversely associated with MD, such as consuming higher amount of alcohol in the weekend than in week days. Conclusions: Adherence to MD is strongly determined by age, geographical area and educational level. Psychosocial factors and several eating behaviours are also closely associated. PMID- 30020487 TI - Aldosterone Suppression by Dexamethasone in Patients With KCNJ5-Mutated Aldosterone-Producing Adenoma. AB - Context: Aldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown. Objective: To investigate KCNJ5 genotype-specific differences in aldosterone biosynthesis in response to ACTH stimulation. Design and Setting: A cross-sectional study through retrieval of clinical records. Participants: One hundred forty-one patients aged >=20 years with APA were examined. Main Outcome Measures: Associations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)]. Results: KCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group. Conclusion: This report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy. PMID- 30020488 TI - Multiple modes of adaptation: regulatory and structural evolution in a small heat shock protein gene. AB - Thermal tolerance is a key determinant of species distribution. Despite much study, the genetic basis of adaptive evolution of thermal tolerance, including the relative contributions of transcriptional regulation versus protein evolution, remains unclear. Populations of the intertidal copepod Tigriopus californicus are adapted to local thermal regimes across their broad geographic range. Upon thermal stress, adults from a heat tolerant southern population (San Diego) upregulate several heat shock proteins (HSPs) to higher levels than those from a less tolerant northern population (Santa Cruz). Suppression of a specific HSP, HSPB1, significantly reduces T. californicus survival following acute heat stress. Sequencing of HSPB1 revealed population specific nucleotide substitutions in both promoter and coding regions of the gene. HSPB1 promoters from heat tolerant populations contain two canonical heat shock elements (HSEs), the binding sites for heat shock transcription factor (HSF), while less tolerant populations have mutations in these conserved motifs. Allele specific expression of HSPB1 in F1 hybrids between tolerant and less tolerant populations showed significantly biased expression favoring alleles from tolerant populations and supporting the adaptive divergence in these cis-regulatory variants. The functional impact of population-specific non-synonymous substitutions in HSPB1 coding sequences was tested by assessing the thermal stabilization properties of SD versus SC HSPB1 protein variants. Recombinant HSPB1 from the southern SD population showed greater capacity for protecting protein structure under elevated temperature. Our results indicate that both regulatory and protein coding sequence evolution within a single gene appear to contribute to thermal tolerance phenotypes and local adaptation among conspecific populations. PMID- 30020489 TI - Quality of essential surgical care in low- and middle-income countries: a systematic review of the literature. AB - Purpose: Quality of care is an emerging area of focus in the surgical disciplines. However, much of the emphasis on quality is limited to high-income countries. To address this gap, we conducted a systematic review of the literature on the quality of essential surgical care in low- and middle- income countries (LMIC). Data sources: We searched PubMed, Cinahl, Embase and CAB Abstracts using three domains: quality of care, surgery and LMIC. Study selection: We limited our review to studies of essential surgeries that pertained to all three search domains. Data extraction: We extracted data on study characteristics, type of surgery and the way in which quality was studied. Results of data synthesis: 354 studies were included. 281 (79.4%) were single center studies and nearly half (n = 169, 46.9%) did not specify the level of facility. 207 studies reported on mortality (58.47%) and 325 reported on a morbidity (91.81%), most commonly surgical site infection (n = 190, 53.67%). Of the Institute of Medicine domains of quality, studies were most commonly of safety (n = 310, 87.57%) and effectiveness (n = 180, 50.85%) and least commonly of equity (n = 21, 5.93%). Conclusion: We find that while there are numerous studies that report on some aspects of quality of care, much of the data is single center and observational. Additionally, there is variability on which outcomes are reported both within and across specialties. Finally, we find under reporting of parameters of equity and timeliness, which may be critical areas for research moving forward. PMID- 30020490 TI - Injury rates and economic cycles in the Italian manufacturing sector. AB - Background: There is a procyclical relationship between economic growth and occupational injury rates in the short term. Injury rates rise during periods of economic growth and fall during recessions. Aims: To estimate injury rates for the manufacturing sector in Italy between 1994 and 2012 and their correlation with major macroeconomic factors and to identify a possible change in the trend of injury rates at the beginning of the 2008 economic crisis. Methods: Total and annual serious injury rates were calculated for the national sector. We used a linear autoregressive model to assess the relationship between injury rates and unemployment rate/real GDP growth, and a joint-point regression analysis to analyse changes in injury rates over time. Results: After adjusting for the spontaneous dynamic change in injury rates over time, both total and serious injury rates were negatively associated with unemployment rate, and significantly positively associated with real GDP growth. Manufacturing injury rates dropped after 2008. Conclusions: Manufacturing injury rates are associated with major macroeconomic factors. Workplace injury rates declined between 1994 and 2012. This downward trend was further accelerated after 2008. The changes in workforce composition before and after 2008 partly explain the procyclical relationship between business conditions and injury rates. PMID- 30020491 TI - New insights into the plant epitranscriptome. AB - Throughout all kingdoms of life, ribonucleotides are marked with covalent chemical modifications that change the structure and binding properties of modified RNA molecules. These marks are deposited by 'writer' proteins, recognized by 'readers', and removed by 'erasers', thus forming an epitranscriptomic system of marks and binding proteins directly analogous to the epigenome. Recent advances in marrying classical biochemical techniques with high throughput sequencing have enabled detailed mapping of plant epitranscriptomic marks, which in turn yielded insights into how these marks regulate a host of biological processes, from shoot stem cell fate to floral transition and from leaf development to viral activity. In this review, we highlight recent developments in the study of plant epitranscriptomics, with an emphasis on N6 methyladenosine (m6A) and 5-methylcytosine (m5C). These studies have advanced the field beyond descriptive mapping or isolated genetic studies, and produced a more nuanced understanding of how components of the epitranscriptome and their binding proteins directly regulate critical aspects of plant biology. PMID- 30020494 TI - Identification and Distribution of Haplotypes of Diaphorina citri (Hemiptera: Liviidae) in Jamaica and the Caribbean. AB - Diaphorina citri Kuwayama (Hemiptera: Psyllidae), also known as the Asian citrus psyllid, is a vector of the citrus huanglongbing (HLB) disease. D. citri transmits all three known strains of the HLB pathogen: Candidatus Liberibacter africanus, Candidatus Liberibacter americanus, and Candidatus Liberibacter asiaticus. The study involved 92 psyllids representing the Caribbean Basin and reference samples representing countries within Asia, North America, and South America. This study was aimed at characterizing D. citri on a molecular level in order to determine the haplotype diversity and uniqueness within Jamaica and the Caribbean Basin. D. citri-specific primers were used to amplify an 821 bp gene fragment from the mitochondrial cytochrome c oxidase subunit I gene (mtCOI). The statistical parsimony program, TCS, was used to determine the 12 haplotypes found within the Caribbean, with haplotypes H2 and H7 being the most prominent. The H2 haplotype was found to belong to the South Western Asia group originating from India. H2 represented 54% of the sequenced samples and dominated the Greater Antilles, 22% were grouped as H7, dominating the Lesser Antilles, while the remaining 24% of the sequences were grouped in the remaining 10 haplotypes and were variants seen within the Greater and Lesser Antilles. PMID- 30020493 TI - Radiation Exposure From Pediatric CT Scans and Subsequent Cancer Risk in the Netherlands. AB - Background: Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood. Methods: For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided. Results: Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk. Conclusions: We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings. PMID- 30020492 TI - Crystal structure of dimeric human PNPase reveals why disease-linked mutants suffer from low RNA import and degradation activities. AB - Human polynucleotide phosphorylase (PNPase) is an evolutionarily conserved 3'-to 5' exoribonuclease principally located in mitochondria where it is responsible for RNA turnover and import. Mutations in PNPase impair structured RNA transport into mitochondria, resulting in mitochondrial dysfunction and disease. PNPase is a trimeric protein with a doughnut-shaped structure hosting a central channel for single-stranded RNA binding and degradation. Here, we show that the disease linked human PNPase mutants, Q387R and E475G, form dimers, not trimers, and have significantly lower RNA binding and degradation activities compared to wild-type trimeric PNPase. Moreover, S1 domain-truncated PNPase binds single-stranded RNA but not the stem-loop signature motif of imported structured RNA, suggesting that the S1 domain is responsible for binding structured RNAs. We further determined the crystal structure of dimeric PNPase at a resolution of 2.8 A and, combined with small-angle X-ray scattering, show that the RNA-binding K homology and S1 domains are relatively inaccessible in the dimeric assembly. Taken together, these results show that mutations at the interface of the trimeric PNPase tend to produce a dimeric protein with destructive RNA-binding surfaces, thus impairing both of its RNA import and degradation activities and leading to mitochondria disorders. PMID- 30020495 TI - Associations between family and home-related factors and child's snack consumption in a multi-ethnic population. AB - Background: Energy-dense snacks are considered unhealthy due to their high concentrations of fat and sugar and low concentrations of micronutrients. The present study aimed to evaluate associations between family and home-related factors and children's snack consumption. We explored associations within subgroups based on ethnic background of the child. Methods: Cross-sectional data of 644 primary school children (mean age: 9.4 years, 53% girls) from the population-based 'Water Campaign' study conducted in the Netherlands were used. Logistic regression analyses were used to evaluate the associations between family and home-related factors and child's snack intake. Results: Of the children, 28.7% consumed more than one snack per day. Children of parents who expressed more restrictive parenting practices towards the child's snack consumption (odds ratio (OR) = 2.5, P < 0.001), and who modelled snack eating less often (OR = 2.2, P < 0.001) had lower snack intake. Restrictive parenting practices and parental modelling of healthy snacking were significant for children with a Dutch or Moroccan/Turkish ethnic background, but not for children with a Surinamese/Antillean ethnic background. Conclusions: We observed that parenting practices and parental modelling were independently associated with the child's snack intake. Also, the relationships between these factors and the child's snack consumption differed for children with distinct ethnic backgrounds. PMID- 30020496 TI - Using 2D Structural Alerts to Define Chemical Categories for Molecular Initiating Events. AB - Molecular initiating events (MIEs) are important concepts for in silico predictions. They can be used to link chemical characteristics to biological activity through an adverse outcome pathway (AOP). In this work, we capture chemical characteristics in 2D structural alerts, which are then used as models to predict MIEs. An automated procedure has been used to identify these alerts, and the chemical categories they define have been used to provide quantitative predictions for the activity of molecules that contain them. This has been done across a diverse group of 39 important pharmacological human targets using open source data. The alerts for each target combine into a model for that target, and these models are joined into a tool for MIE prediction with high average model performance (sensitivity = 82%, specificity = 93%, overall quality = 93%, Matthews correlation coefficient = 0.57). The result is substantially improved from our previous study (Allen, T. E. H., Goodman, J. M., Gutsell, S., and Russell, P. J. 2016. A history of the molecular initiating event. Chem. Res. Toxicol. 29, 2060-2070) for which the mean sensitivity for each target was only 58%. This tool provides the first step in an AOP-based risk assessment, linking chemical structure to toxicity endpoint. PMID- 30020497 TI - Japanese encephalitis: vaccine options and timing of pre-travel vaccination. PMID- 30020499 TI - Landscape Features Associated With Blacklegged Tick (Acari: Ixodidae) Density and Tick-Borne Pathogen Prevalence at Multiple Spatial Scales in Central New York State. AB - Blacklegged ticks (Ixodes scapularis Say, Acari: Ixodidae) are the most commonly encountered and medically relevant tick species in New York State (NY) and have exhibited recent geographic range expansion. Forests and adjacent habitat are important determinants of I. scapularis density and may influence tick-borne pathogen prevalence. We examined how percent forest cover, dominant land cover type, and habitat type influenced I. scapularis nymph and adult density, and associated tick-borne pathogen prevalence, in an inland Lyme-emergent region of NY. I. scapularis nymphs and adults were collected from edge and wooded habitats using tick drags at 16 sites in Onondaga County, NY in 2015 and 2016. A subsample of ticks from each site was tested for the presence of Borrelia burgdorferi, Borrelia miyamotoi, Anaplasma phagocytophilum, and Babesia microti using a novel multiplex real-time polymerase chain reaction (PCR) assay, and deer tick virus using reverse transcription-PCR. Habitat type (wooded versus edge) was an important determinant of tick density; however, percent forest cover had little effect. B. burgdorferi was the most commonly detected pathogen and was present in ticks from all sites. Ba. microti and deer tick virus were not detected. Habitat type and dominant land cover type were not significantly related to B. burgdorferi presence or prevalence; however, ticks infected with A. phagocytophilum and B. miyamotoi were collected more often in urban environments. Similarity between B. burgdorferi prevalence in Onondaga County and hyperendemic areas of southeastern NY indicates a more rapid emergence than expected in a relatively naive region. Possible mechanistic processes underlying these observations are discussed. PMID- 30020498 TI - PLIN1 Haploinsufficiency Is Not Associated With Lipodystrophy. AB - Context: Monogenic partial lipodystrophy is a genetically heterogeneous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance. Objective: We investigated if null variants in PLIN1 cause lipodystrophy. Methods: As part of a targeted sequencing panel test, we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal. Results: We identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally, 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632; 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. Conclusions: Our study suggests that heterozygous variants that are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy. PMID- 30020500 TI - Molecular Characterization of a Geranyl Diphosphate-Specific Prenyltransferase Catalyzing Stilbenoid Prenylation from Morus alba. AB - Pharmaceutically active compounds from medical plants are attractive as a major source for new drug development. Prenylated stilbenoids with increased lipophilicity are valuable secondary metabolites which possess a wide range of biological activities. So far, many prenylated stilbenoids have been isolated from Morus alba but the enzyme responsible for the crucial prenyl modification remains unknown. In the present study, a stilbenoid-specific prenyltransferase (PT), termed Morus alba oxyresveratrol geranyltransferase (MaOGT), was identified and functionally characterized in vitro. MaOGT recognized oxyresveratrol and geranyl diphosphate (GPP) as natural substrates, and catalyzed oxyresveratrol prenylation. Our results indicated that MaOGT shared common features with other aromatic PTs, e.g. multiple transmembrane regions, conserved functional domains and targeting to plant plastids. This distinct PT represents the first stilbenoid specific PT accepting GPP as a natural prenyl donor, and could help identify additional functionally varied PTs in moraceous plants. Furthermore, MaOGT might be applied for high-efficiency and large-scale prenylation of oxyresveratrol to produce bioactive compounds for potential therapeutic applications. PMID- 30020501 TI - Feeding a Fussy Eater: Examining Longitudinal Bidirectional Relationships Between Child Fussy Eating and Maternal Feeding Practices. AB - Objective: Child fussy eating has been associated with a range of maternal feeding practices; however, whether effects are parent-driven, child-driven, or bidirectional (i.e., both) remains unclear. This study tested for bidirectional relationships between nonresponsive and structure-related maternal feeding practices and child fussy eating at age 2, 3.7, and 5 years using a cross-lagged model approach. Methods: First-time Australian mothers (N = 207) reported four nonresponsive and four structure-related feeding practices and child food fussiness (FF) using validated questionnaires at child age 2, 3.7, and 5 years. Bivariate cross-lagged analyses were conducted for each of the eight feeding practices separately. Results: Both child- and parent-driven associations were observed. Higher FF at 3.7 years predicted higher nonresponsive feeding practices and less structure-related practices at 5 years. Higher structure-related practices at 2 and 3.7 years predicted lower FF at 3.7 and 5 years, respectively. Use of food as a reward for behavior at 3.7 years predicted higher FF at 5 years. Conclusions: Both parent- and child-driven associations explain the relationship between fussy eating and feeding practices. Given that early fussy eating is associated with more nonresponsive feeding, providing parents with anticipatory guidance to manage fussy eating behavior in infants and toddlers may help to avoid the use of these practices. Furthermore, the use of structure-related feeding practices and avoiding the use of food rewards may help to prevent the development of fussy eating. PMID- 30020502 TI - Nalpha-Acetyltransferases 10 and 15 are Required for the Correct Initiation of Endosperm Cellularization in Arabidopsis. AB - The endosperm and embryo originate from the fertilized central cell and egg cell through a programmed series of cell division and differentiation events. Characterization of more vital genes involved in endosperm and embryo development can help us to understand the regulatory mechanism in more depth. In this study, we found that loss of NAA10 and NAA15, the catalytic and auxiliary subunits of Arabidopsis thaliana N-terminal acetyltransferase A (AtNatA), respectively, led to severely delayed and incomplete endosperm cellularization, accompanied by disordered cell division in the early embryo. Studies on the marker genes/lines of the endosperm (AGL62-GFP, pDD19::GFP, pDD22::NLS-GFP and N9185) and embryo (STM, FIL, SCR and WOX5) in naa10/naa15 mutants showed that expression patterns of these markers were significantly affected, which were tightly associated with the defective feature of endosperm cellularization and embryo cell differentiation. Subsequently, embryonic complementation rescued the abortive embryos, but failed to initiate endosperm cellularization properly, further confirming the essential role of AtNatA in both endosperm and embryo development. Moreover, repression of AGL62 in naa10 and naa15 restored the endosperm cellularization, suggesting that NAA10/NAA15 functions in initiation of endosperm cellularization by inhibiting the expression of AGL62 in Arabidopsis. Therefore, NAA10 and NAA15 could be considered as crucial factors involved in promoting endosperm cellularization in Arabidopsis. PMID- 30020504 TI - N-acetylcysteine (NAC) in COPD: benefits often lost in trials. PMID- 30020503 TI - Paradigm Shifts in Nocturnal Glucose Control in Type 2 Diabetes. AB - Context: A better understanding of nocturnal regulation of glucose homeostasis will provide the framework for designing rational therapeutic strategies to improve the management of overnight glucose in patients with type 2 diabetes (T2D). Objective: To establish the nocturnal pattern and regulation of glucose production (EGP) in humans and to determine whether the pattern is dysregulated in people with T2D. Design: Subjects were infused with [3-3H] glucose overnight. Arterial blood samples were drawn for hormones and analytes to estimate EGP throughout the night. Deuterium-labeled water was provided to measure gluconeogenesis (GNG) using the hexamethylenetetramine method of Landau. Setting: Mayo Clinic Clinical Research Trials Unit, Rochester, MN, USA. Participants and Interventions: A total of 43 subjects [23 subjects with T2D and 20 nondiabetic (ND) subjects comparable for age and body mass index] were included in this study. Main Outcome(s) Measure(s): Glucose and EGP. Results: Plasma glucose, C peptide, and glucagon concentrations were higher throughout the night, whereas insulin concentrations were higher in subjects with T2D vs ND subjects at 1:00 and 4:00 am but similar at 7:00 am. EGP was higher in the subjects with T2D than in the ND subjects throughout the night (P < 0.001). Glycogenolysis (GGL) fell and GNG rose, resulting in significantly higher (P < 0.001) rates of GNG at 4:00 and 7:00 am and significantly (P < 0.001) higher rates of GGL at 1:00, 4:00, and 7:00 am in T2D as compared with ND. Conclusions: These data imply that optimal therapies for T2D for nocturnal/fasting glucose control should target not only the absolute rates of EGP but also the contributing pathways of GGL and GNG sequentially. PMID- 30020505 TI - Molecular Identification of the Carrion Beetles (Coleoptera) in Selected Regions of Saudi Arabia. AB - Geographical regions have a major effect on the arrival times of different insect species on carrion. This means that data generated in one region should not be used to determine time of death in a different region. In the present study, we demonstrate the effect of geographical location on the diversity of carrion beetles in Saudi Arabia, whereas the mitochondrial cytochrome c oxidase subunit I (mtCOI) barcodes were used as a marker for molecular identification of the carrion beetles at a dry stage on sheep carrion. We analyzed 819 adult beetles belonging to nine species originating from Riyadh (609 beetles), Jazan (157 beetles), and Arar (53 beetles). In Riyadh, results showed the presence of six species belonging to three different families. On the other hand, in Jazan five species belonging to four families were collected. From Arar, five species belonging to three families were collected. By comparing between individuals of the same species from different regions, individuals of Necrobia rufipes DeGeer (Coleoptera: Cleridae) showed the highest intraspecific variations 0-20%, while individuals of Saprinus splendens Paykull and Saprinus semistriatus Scriba (Coleoptera: Histeridae) showed the lowest intraspecific variations 0-1%. Interspecific variability was also measured between collected and identified species, with differences revealed to be in the range of 3.8-29.8%. The results are important from an ecological point of view and for Medico-Legal Forensic Entomology. PMID- 30020506 TI - Patient Perspectives on Opioids: Views of Inpatient Veterans with Chronic Pain. AB - Objective: To elucidate perspectives on opioids and opioid use from hospitalized veterans with comorbid chronic pain using qualitative methods. Design: This was an analysis of individual qualitative interviews. The semistructured interview guide was developed by a hospitalist with clinical expertise in pain treatment with guidance from a medical anthropologist. Interviews aimed to understand participants' experiences of chronic pain. Setting: A Midwestern Veterans Health Administration inpatient hospital unit. Subjects: Nineteen inpatient veterans with a history of chronic pain or antecedent opioid use. Methods: Recently admitted veterans were screened for chronic pain diagnosis on admission and antecedent opioid use. Eligible veterans were approached to participate in an in person interview during their hospitalization. Results: The following themes were identified in relation to opioid use: other patients as the problem (by misusing opioids resulting in broad limits to opioid access), empathy for providers (perceived to be working under prescribing constraints), and opioids as a last resort. Conclusions: Although participants were not specifically questioned about opioid medications, discussion of opioids was prevalent in discussions of chronic pain. Findings suggest the potential utility of engaging hospitalized veterans in conversations about opioids and alternative pain management strategies. PMID- 30020507 TI - Adiposity, vitamin D requirements, and clinical implications for obesity-related metabolic abnormalities. AB - This review was conducted to clarify both the complex interrelationship between adiposity and vitamin D and the clinical implications of vitamin D status on metabolic abnormalities associated with obesity. Obesity increases the risk of vitamin D deficiency, a finding consistently reported across all ages and in different population groups. According to genetic studies, this is driven by the effect of higher adiposity, which causes a reduction in circulating concentrations of 25-hydroxyvitamin D [25(OH)D, used as an indicator of vitamin D status]. Conversely, higher concentrations of 25(OH)D do not appear to affect the risk of obesity. Evidence from clinical trials using vitamin D supplementation to achieve weight reduction is limited. Some trials, however, have suggested that concomitant supplementation with vitamin D and calcium potentially reduces central fat deposits, especially in individuals with low dietary calcium intakes. Adiposity has important implications for the efficacy of vitamin D supplementation, and increases in 25(OH)D concentrations are generally lower in obese than in normal-weight individuals. Active hormonal vitamin D has many mechanistic effects, both physiologically and biochemically, that could counteract the harmful effects of obesity on metabolism and reduce the risks of metabolic abnormalities and tissue damage consequent to adiposity. Whether improvements in the overall obesogenic metabolic profile can be achieved by vitamin D supplementation, however, is still unknown. PMID- 30020508 TI - Adipose Tissue Inflammation and Adrenomedullin Overexpression Contribute to Lipid Dysregulation in Diabetic Pregnancies. AB - Context: Impaired maternal lipid metabolism in gestational diabetes mellitus (GDM) has detrimental effects on maternal health and fetal growth. We previously reported the excessive expression of adrenomedullin (ADM) and its receptors in GDM adipose tissues compared with normal glucose-tolerant pregnancies. In the present study, we determined the mechanisms underlying enhanced expression of ADM and its receptors. Design: Omental adipose tissue (OAT) samples were collected from women during cesarian section of term pregnancy with nonoverweight (NOW; n = 9), overweight (OW; n = 8), obese (OBS; n = 10), and GDM (n = 10) status. Results: The expression of ADM and its receptors was greater in OATs from GDM than from women who were NOW, OW, and OBS. The expression of adipokines, leptin, and resistin were significantly increased, but adiponectin was decreased in OATs from patients with GDM compared with those without GDM. Macrophage infiltration and TNF-alpha expression were greater in OAT from pregnant women with GDM than in pregnant women without GDM. Furthermore, TNF-alpha dose dependently increased mRNA for ADM and its receptor components calcitonin receptor-like receptor and receptor activity-modifying proteins 2 and 3 in OAT explants from women who were NOW. Human adipocytes treated with ADM significantly increased glycerol release in culture medium, and the increases of glycerol in culture medium of OAT from women with GDM were attenuated by ADM antagonists, ADM22-52. Conclusions: Increased macrophage infiltration and TNF-alpha expression in adipose tissue from GDM, but not from OBS, tissues stimulate ADM and its receptor overexpression, leading to enhanced lipolysis and hyperlipidemia. This might contribute to fetal macrosomia and adiposity in diabetic pregnancies. PMID- 30020509 TI - The role of family absolute and relative income in suicide among Chinese rural young adults: mediation effects of social support and coping strain. AB - Background: suicide is a major public health issue in China. However, research on the impact of absolute and relative economic stats on suicide is scarce among the Chinese population, particularly rural young adults. Using a case-control psychological autopsy study design, we aimed to investigate the effect of family absolute and relative income on suicide among Chinese rural young adults and to further explore the potential mediating mechanism under these associations. Method: the information of 393 suicide cases and 416 community living controls were collected for this study. A Binary Choice Model was used to analyze the association between family absolute and relative income and suicide risk, as well as potential mediating factors for these associations. Results: a much stronger association was found between relative income and suicide than between absolute income and suicide. Social support was a dominant mediator for the association between family relative income and suicide among both female and male young adults. Coping strain emerged as a mediating factor within the link between absolute income and suicide for males. Conclusions: public health interventions to reduce suicide should pay more attention to relative income in addition to absolute income as potential targets for intervention, and how social support and coping strain act as mediating factors. PMID- 30020511 TI - Heart Rate Variability and Cognitive Bias Feedback Interventions to Prevent Post deployment PTSD: Results from a Randomized Controlled Trial. AB - Introduction: There is a long history of pre-deployment PTSD prevention efforts in the military and effective pre-deployment strategies to prevent post deployment PTSD are still needed. Materials and Methods: This randomized controlled trial included three arms: heart rate variability biofeedback (HRVB), cognitive bias modification for interpretation (CBM-I), and control. The hypothesis was that pre-deployment resilience training would result in lower post deployment PTSD symptoms compared with control. Army National Guard soldiers (n = 342) were enrolled in the Warriors Achieving Resilience (WAR) study and analyzed. The outcome was PTSD symptom severity using the PTSD Checklist - Military version (PCL) measured at pre-deployment, 3- and 12-month post-deployment. Due to the repeated measures for each participant and cluster randomization at the company level, generalized linear mixed models were used for the analysis. This study was approved by the Army Human Research Protection Office, Central Arkansas Veterans Healthcare System Institutional Review Board (IRB), and Southeast Louisiana Veterans Health Care System IRB. Results: Overall, there was no significant intervention effect. However, there were significant intervention effects for subgroups of soldiers. For example, at 3-months post-deployment, the HRVB arm had significantly lower PCL scores than the control arm for soldiers with no previous combat zone exposure who were age 30 and older and for soldiers with previous combat zone exposure who were 45 and older (unadjusted effect size -0.97 and 1.03, respectively). A significant difference between the CBM-I and control arms was found for soldiers without previous combat zone exposure between ages 23 and 42 (unadjusted effect size -0.41). Similarly, at 12-months post-deployment, the HRVB arm had significantly lower PCL scores in older soldiers. Conclusion: Pre deployment resilience training was acceptable and feasible and resulted in lower post-deployment PTSD symptom scores in subgroups of older soldiers compared with controls. Strengths of the study included cluster randomization at the company level, use of iPod device to deliver the resilience intervention throughout the deployment cycle, and minimal disruption of pre-deployment training by using self paced resilience training. Weaknesses included self-report app use, study personnel not able to contact soldiers during deployment, and in general a low level of PTSD symptom severity throughout the study. In future studies, it would important for the study team and/or military personnel implementing the resilience training to be in frequent contact with participants to ensure proper use of the resilience training apps. PMID- 30020510 TI - A randomized, open-label, Phase III trial of pertuzumab retreatment in HER2 positive locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab and chemotherapy: the Japan Breast Cancer Research Group-M05 PRECIOUS study. AB - The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one sided 5% level of significance. PMID- 30020512 TI - Comparative efficacy of a 12 week yoga-based lifestyle intervention and dietary intervention on adipokines, inflammation, and oxidative stress in adults with metabolic syndrome: a randomized controlled trial. AB - The present randomized controlled trial (RCT) evaluated the comparative efficacy of 12 week yoga-based lifestyle intervention (YBLI) and dietary intervention (DI) alone on adipokines, inflammation, and oxidative stress in Indian adults with metabolic syndrome (Met S). A parallel, two arm, RCT was conducted in Integral Health Clinic (IHC), All India Institute of Medical Sciences, India from 2012 to 2014. IHC is an outpatient facility conducting YBLI programs for prevention and management of chronic diseases. Two hundred sixty men and women (20-45 years) visiting the outpatient department of a tertiary care hospital were diagnosed with Met S and randomized 1:1 to receive 12 week YBLI (n = 130) or DI (n = 130). Primary outcomes were change in plasma levels of adipokines (leptin, adiponectin, and leptin:adiponectin ratio), markers of inflammation (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6), markers of oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxy-2'-deoxyguanosine [8-OHdG], and superoxide dismutase [SOD]) measured at baseline, 2 weeks, and 12 weeks. YBLI group showed a significant decrease in leptin, leptin:adiponectin ratio, IL-6, 8 OHdG, and TBARS levels, whereas there was a significant increase in adiponectin and SOD levels. No significant changes were noticed in DI alone group. YBLI showed significantly greater reduction in TBARS levels than in DI group, suggestive of reduced oxidative stress in adults with Met S. A 12 week YBLI had a positive impact on oxidative stress versus DI alone in adults with Met S. PMID- 30020514 TI - An Anopheles by Any Other Name ...? AB - The physical characteristics of a nematoceran fly that evokes the image of a mosquito of the genus Anopheles Meigen (Diptera: Culicidae) has existed since the genus was defined in the early part of the twentieth century. Is that image likely to change with the recent proposal to elevate four Neotropical subgenera to generic status based on relationships generated by phylogenetic analyses of mitochondrial protein-coding genes? Reasons for retaining the traditional concept of Anopheles, with its traditionally recognized subgenera, are presented. However, as the ranking of taxa as genera or subgenera is subjective, the choice of rank of a genus-group name may be considered a subjective decision and a matter of user preference. PMID- 30020513 TI - 2-Hydroxyglutarate MR spectroscopy for prediction of isocitrate dehydrogenase mutant glioma: a systemic review and meta-analysis using individual patient data. AB - Background: Noninvasive and accurate modality to predict isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. We aimed to investigate the diagnostic performance of 2-hydroxyglutarate (2HG) magnetic resonance spectroscopy (MRS) for prediction of IDH mutant glioma and provide an optimal cutoff value for 2HG. Methods: A systematic literature search of Ovid-MEDLINE and EMBASE was performed to identify original articles investigating the diagnostic performance of 2HG MRS up to March 20, 2018. Pooled sensitivity and specificity were calculated using a bivariate random-effects model. Subgroup analysis and meta-regression were performed to explain heterogeneity effects. An optimal cutoff value for 2HG was calculated from studies providing individual patient data. Results: Fourteen original articles with 460 patients were included. The pooled sensitivity and specificity for the diagnostic performance of 2HG MRS for prediction of IDH mutant glioma were 95% (95% CI, 85-98%) and 91% (95% CI, 83-96%), respectively. The Higgins I2 statistic demonstrated that heterogeneity was present in the sensitivity (I2 = 50.69%), but not in the specificity (I2 = 30.37%). In the meta-regression, echo time (TE) was associated with study heterogeneity. Among the studies using point-resolved spectroscopy (PRESS), a long TE (97 ms) resulted in higher sensitivity (92%) and specificity (97%) than a short TE (30-35 ms; sensitivity of 90%, specificity of 88%; P < 0.01). The optimal 2HG cutoff value of 2HG using individual patient data was 1.76 mM. Conclusion: 2HG MRS demonstrated excellent specificity for prediction of IDH mutant glioma, with TE being associated with heterogeneity in the sensitivity. Key Points: 1. HG MRS has excellent diagnostic performance in the prediction of IDH mutant glioma. 2. The pooled sensitivity was 95% and the pooled specificity was 91%. 3. Echo time was associated with study heterogeneity in the meta-regression. PMID- 30020516 TI - Russia: thirty years in transition. PMID- 30020515 TI - Multiple myeloma and pepperpot skull. PMID- 30020517 TI - European Public Health News. PMID- 30020519 TI - The special case of left lobe amoebic liver abscess. PMID- 30020518 TI - Reflecting on Alma Ata 1978: forty years on. PMID- 30020520 TI - The Use and Misuse of Statistical Methods in Cytopathology Studies: Review of 6 Journals. AB - Background: The misuse of statistical methods in diagnostic accuracy studies has been criticized in many publications. Objective: To assess the use and misuse of statistical methods in medical journal articles. Methods: We reviewed 141 original articles from 6 cytopathology journals published in 2014. Results: In total, 16 articles used no descriptive statistics and 66 articles used no inferential statistics. Also, 82 articles did not report using any tests for diagnostic accuracy. The most commonly adopted statistical measure for diagnostic accuracy was sensitivity, followed by specificity. The most common inferential statistical methods were chi2 testing, the Fisher exact test, and the Cohen kappa coefficient, respectively. Only 78 articles were free of statistical errors. "No statistics were used although statistical methods were required" was the most common type of error, followed by "failure to select proper statistical methods." Conclusion: Our assessment of use of statistical methods in this subsection of pathology demonstrated a need for improvement. PMID- 30020521 TI - Inflammatory or Neuropathic Pain: Characteristics and Their Relationships with Disease Activity and Functional Status in Axial Spondyloarthritis Patients. AB - Objective: To assess inflammatory back pain (IBP) and neuropathic pain (NP) in patients with axial spondyloarthritis (axSpA) and explore their relationships with disease activity and functional status. Design: Descriptive, cross-sectional study. Setting and Subjects: A convenience sample of 132 patients with axSpA was recruited from a university-affiliated hospital in China. Methods: The presence of IBP or NP, pain intensity and quality, pain interference, disease activity, and functional status were assessed. Univariate analyses and binary logistic regressions were used to identify factors related to IBP or NP. Results: Fifty patients (37.9%) had IBP, and 22 (16.7%) had NP. Scores of pain intensity and pain interference, disease activity, and functional limitation were significantly higher in patients with IBP or NP than those without either (P < 0.05). The quality of IBP or NP was mainly presented as sensory descriptors, and patients with IBP had a higher level of "tiring-exhausting" in affective descriptors (P < 0.05). There was a significant correlation between IBP and disease activity (odds ratio [OR] = 1.813, 95% confidence interval [CI] = 1.196-2.750). NP was related to functional limitation (OR = 1.544, 95% CI = 1.098-2.171). Conclusions: Though pain quality (sensory and affective pain descriptors) show differently in patients with IBP or NP, the axSpA patients with IBP or NP experience more severe pain intensity and pain interference, higher disease activity, and greater functional limitation. The presence of IBP or NP could reflect higher disease activity or greater functional limitation in patients with axSpA. PMID- 30020523 TI - Conceptual and Methodological Considerations on mRNA And Proteins as Intercellular and Long-distance Signals. AB - High throughput studies identified approximately one fifth of Arabidopsis protein encoding transcripts to be graft transmissible and to move over long distances in phloem. In roots, one fifth of transcription factors were annotated as non-cell autonomous moving between cells. Is this massive transport a way of inter-organ and cell-to-cell communication or does it serve different purposes? On the tissue level, many miRNAs and all siRNAs act non-cell autonomously. Why are these RNAs and proteins not just expressed in cells where they exert their function? Short and long distance transport of these macromolecules raises the question whether all mobile mRNAs and transcription factors could be defined as signalling molecules. Since the answer is not clear yet, we will discuss in this review conceptual approaches to this phenomenon using a single mobile signalling macromolecule, FLOWERING LOCUS T, which has been characterized extensively. We conclude that careful individual studies of mobile macromolecules are necessary to uncover their biological function and the observed massive mobility. To stimulate such studies, we provide a review summarizing the resourceful wealth of experimental approaches to this intriguing question and discuss methodological scopes and limits. PMID- 30020522 TI - A Zinc Finger Transcriptional Repressor Confers Pleiotropic Effects on Rice Growth and Drought Tolerance by Down-Regulating Stress-Responsive Genes. AB - The C2H2-type zinc finger proteins (ZFPs) are involved in a wide range of plant development and stress responses. Many studies have shown the positive roles of ZFP genes in stress tolerance. However, overexpression of ZFP genes usually leads to the side effect of growth retardation. Here we report a new member of the ZFP family, Oryza sativa drought-responsive zinc finger protein 1 (OsDRZ1), positively regulating both stress tolerance and plant architecture in rice (Oryza sativa L.). OsDRZ1 was expressed throughout all tissues examined and could be induced by multiple abiotic stresses. OsDRZ1 protein was localized mostly in the nucleus. Unlike most reported rice ZFPs functioning as transcriptional activators, OsDRZ1 is a transcriptional repressor. Overexpression of OsDRZ1 in rice increased seedling drought tolerance and the transgenic plants appeared to accumulate more free proline and fewer reactive oxygen species (ROS), and elevate the activities of antioxidant enzymes. In contrast, RNA interference (RNAi) of OsDRZ1 led to lower activities of antioxidative response and more sensitivity to drought. RNA sequencing analysis revealed that the genes down-regulated by OsDRZ1 were mostly down-regulated by drought, implying the critical role of OsDRZ1 in modulating drought-responsive gene expression. A cupin gene OsGLP1 (germin-like protein1) was identified as one of the potential target genes of OsDRZ1, as suggested by real-time PCR and transient expression analysis in rice protoplasts. Moreover, overexpression of OsDRZ1 did not lead to growth inhibition but the promotion of rice growth, implying the potential application prospective of OsDRZ1 in engineering drought-tolerant crops. PMID- 30020524 TI - Necrotic erythema nodosum leprosum masquerading as cutaneous vasculitis. PMID- 30020525 TI - Health behaviors and illness according to marital status in middle-aged Koreans. AB - Background: Marital status influences health and this association might differ by time and/or country. Divorce rates have increased abruptly in Korea. We investigated relationships between marital status and health behaviors and illness among middle-aged Koreans. Methods: Data from the fifth Korean National Health and Nutrition Examination Survey 2010-12 was used. Participants were middle-aged (40-65 years) Koreans (3015 male and 4498 female) who had been married. Health behaviors and physical and mental health status were evaluated separately for each gender according to marital status (currently married versus separated, divorced or widowed) using logistic regression analyses adjusted for age, income level and region. Results: About 5.4% of men and 13.0% of women lived without their spouses. Odd ratios (ORs) for smoking, binge drinking, inadequate sleep, hypertriglyceridemia and depression were significantly higher in participants not living with their spouses. ORs for non-participation in regular health examinations and cancer screenings, anemia, elevated alanine aminotransferase and suicidal ideation were significantly higher in men not living with their spouses. Conclusions: Health behaviors and illness were significantly worse in middle-aged Koreans not living with their spouses. Men were more susceptible to poor health screening, nutritional deficiencies and mental illness. Preventive services are necessary to improve their health status. PMID- 30020526 TI - Strategies to reduce the burden of HPV disease in HIV-positive men who have sex with men. PMID- 30020527 TI - A big, fat, complicated public health problem. PMID- 30020528 TI - Maternal Lipids at 28 Weeks' Gestation and Offspring Adiposity at Age 5 to 7 Years. AB - Context: Obesity is a global epidemic, and there is a focus on identifying markers of obesity in children with a view to prevention. Objective: We aimed to examine prospectively the association of maternal fasting lipids with adiposity in 5- to 7-year-old offspring in a large observational study. Design: Pregnant women (1612) were recruited to the Belfast center of the Hyperglycemia and Adverse Pregnancy Outcome study in a large tertiary maternity hospital at an average of 28 weeks' gestation. Maternal fasting total cholesterol, low-density lipoprotein-cholesterol, triglycerides, and high-density lipoprotein-cholesterol were estimated at 28 weeks' gestation. Offspring-mother pairs (819) were included in the current study, and adiposity was expressed as body mass index (BMI) z score (1990 British growth standard) and sum of skin-fold (SSF) thicknesses (triceps, subscapular, and suprailiac). Statistical significance was more rigorously defined as P < 0.01 to allow for multiple comparisons. Results: No linear relation was found between maternal lipids and offspring BMI z score or SSFs (P >= 0.01) using correlation analysis. With the use of logistic regression, there was no relation between maternal lipids and offspring adiposity controlled for birthweight z score, offspring age, offspring gender, smoking during pregnancy, offspring energy intake and physical activity, maternal BMI during pregnancy, and fasting glucose during pregnancy (P >= 0.01). Conclusion: Maternal 28-week gestational fasting lipids are not associated with offspring BMI or subcutaneous adiposity at age 5 to 7 years. PMID- 30020529 TI - Diagnosing risk factors alongside mass drug administration using serial diagnostic tests-which test first? AB - Background: When tests are used in series to determine individual risk factors and infection status in a mass drug administration (MDA), the diagnostics, test order and subsequent treatment decisions (the testing algorithm) affect population-level treatment coverage and cost, but there is no existing framework for evaluating which algorithm optimizes any given outcome. Methods: We present a mathematical tool (with spreadsheet implementation) to analyse the effect of test ordering, illustrated using treatment for onchocerciasis in an area where high burden Loa loa co-infections present a known risk factor. Results: The prevalence of the infection and risk factor have a non-linear impact on the optimal ordering of tests. Testing for the MDA infection first always leaves more infected people untreated but fewer people with the risk factor being misclassified. The cost of the treatment given to infected individuals with the risk factor does not affect which algorithm is more cost effective. Conclusions: For a given test and treat algorithm and its costs, the correct strategy depends on the expected prevalence. In most cases, when the apparent prevalence of the target infection is greater than the apparent prevalence of the risk factor, it is cheaper to do the risk factor test first, and vice versa. PMID- 30020531 TI - Prevalence and correlates of non-medical only compared to self-defined medical and non-medical cannabis use, Canada, 2015. AB - BACKGROUND: The Canadian federal government has committed to legalizing non medical cannabis use by adults in 2018. Medical use was legalized in 2001; however, not all people reporting medical use have medical authorization. To prepare for monitoring the effects of the policy change, a greater understanding of the prevalence of cannabis use and the characteristics of all cannabis users is needed. DATA AND METHODS: Data from the 2015 Canadian Tobacco, Alcohol and Drugs Survey (CTADS) were used to estimate prevalence and examine reasons for medical use and factors associated with people who reported using cannabis Non Medically Only (NMO), compared with people who reported Self-Defined Medical and Non-Medical use (SDMNM), including use of other drugs and the non-therapeutic use of psychoactive pharmaceuticals. RESULTS: In 2015, 9.5% of Canadians aged 15 and older reported NMO cannabis use, while another 2.8% reported SDMNM use. Half of Canadians reporting some self-defined medical use cited pain as the primary reason. Daily and near-daily use was significantly more common among SDMNM users (47.2%) than among individuals considered NMO users (26.4%). Past-year cannabis users of any type were more likely to be male and younger, to have used other illicit drugs and at least one of three classes of psychoactive pharmaceutical drugs non-therapeutically, and to be daily smokers or heavy drinkers. SDMNM cannabis use was more common among people reporting worse health (general and mental), use of psychoactive pharmaceuticals, and living in lower-income households. DISCUSSION: Because non-medical cannabis use is common to both user groups analyzed, many similarities were anticipated. Nevertheless, SDMNM users also had several unique characteristics consistent with use to address medical problems. However, because the CTADS does not collect information about whether the individual has received a health care practitioner's authorization to use cannabis for a medical purpose this analysis should not be interpreted as an evaluation of people who access cannabis through Health Canada's medical access program, the Access Cannabis for Medical Purposes Regulations (ACMPR). PMID- 30020532 TI - Tuberculosis-related hospital use among recent immigrants to Canada. AB - BACKGROUND: While the incidence of active tuberculosis (TB) in Canada is among the lowest in the world, the rates of TB among immigrants and Indigenous people remain high. In fact, the majority of new active TB cases are disproportionately found among immigrants. This study profiles TB-related acute care hospitalizations among new immigrants to Canada by selected characteristics. DATA AND METHODS: This study is based on the 2000-to-2013 Longitudinal Immigration Database (IMDB) linked to the Canadian Institute for Health Information's Discharge Abstract Database (DAD) from 2001/2002 to 2013/2014. It examines the timing of first TB-related acute care hospitalization occurring from the fiscal year 2001/2002 to the fiscal year 2013/2014 among immigrants who landed in Canada from 2000 to 2013 outside of Quebec and the territories. Mean and median hospital days and the percentage of total TB hospitalizations incurred by these new immigrants are calculated to measure the burden of hospital care among recent immigrants. RESULTS: From 2001/2002 to 2013/2014, 1,120 out of 2.7 million immigrants arriving between 2000 and 2013 were found to have, in total, 1,340 TB related hospital discharges. The majority of cases (97%) were among immigrants from the Immigration, Refugees and Citizenship Canada (IRCC) designated country list for TB, in which abour three quarters of the cases were from the World Health Organization (WHO) list of high TB-burden countries. Approximately half (45%) of immigrants hospitalized for TB were aged 18 to 34 at the time of hospitalization. Around 10% of all TB patients had been hospitalized before formally landing as immigrants. Mean and median length of hospital stay were 17 days and 11 days, respectively (22 days and 14 days, respectively, for the overall population in Canada). While new immigrants who landed between 2000 and 2013 represent 7% of the overall population of Canada, they incurred 17% of all TB-related hospital discharges occurring during this period. DISCUSSION: This paper demonstrates the value of linked administrative data to understanding immigrant health and is important for future work in this area. Current immigration protocols surrounding TB involve screening for active pulmonary TB and identifying some migrants with latent TB. Results of this study, linking TB related hospitalizations to immigrant landing files, provide unique information that can inform public health action, as well as migration policy and program development to contribute to the efforts to eliminate TB. PMID- 30020530 TI - The Quantitative Genetic Control of Root Architecture in Maize. AB - Roots remain an underexplored frontier in plant genetics despite their well-known influence on plant development, agricultural performance and competition in the wild. Visualizing and measuring root structures and their growth is vastly more difficult than characterizing aboveground parts of the plant and is often simply avoided. The majority of research on maize root systems has focused on their anatomy, physiology, development and soil interaction, but much less is known about the genetics that control quantitative traits. In maize, seven root development genes have been cloned using mutagenesis, but no genes underlying the many root-related quantitative trait loci (QTLs) have been identified. In this review, we discuss whether the maize mutants known to control root development may also influence quantitative aspects of root architecture, including the extent to which they overlap with the most recent maize root trait QTLs. We highlight specific challenges and anticipate the impacts that emerging technologies, especially computational approaches, may have toward the identification of genes controlling root quantitative traits. PMID- 30020533 TI - Oral Administration of Probiotic Lactobacillus Casei Shirota Decreases Pneumonia and Increases Pulmonary Functions after Single Rib Fracture: A Randomized Double Blind, Placebo-Controlled Clinical Trial. AB - : Considerate proportion of elderly patients with a rib fracture is susceptible to pulmonary complications, especially pneumonia. We aimed to assess the effect of oral administration of the probiotic Lactobacillus casei Shirota (LcS) on pneumonia and pulmonary functions among elderly patients with single rib fracture. The current study including 204 eligible elderly patients with a single rib fracture was conducted. Patients were randomly assigned to receive oral administration of skimmed milk containing either a commercial probiotic LcS or placebo daily for 1 mo after the fracture, followed by pneumonia assessments, pulmonary function testing including forced expiratory volume (FEV), negative inspiratory pressure (NIP), and forced vital capacity (FVC), as well as evaluation of potential adverse effects including myocardial infarction, acute kidney injury, nonunion of fractured bone, or stroke. After 1 mo consumption, patients in the LcS group exhibited decreased pneumonia and increased recovery of pulmonary functions, in terms of FEV, FVC, and NIP, compared to the placebo group. No difference was observed in incidence of adverse events between the 2 groups. In patients with a single rib fracture, oral administration of the probiotic LcS was associated with a lower incidence of pneumonia and increased pulmonary functions without causing severe adverse effects. PRACTICAL APPLICATION: To conclude, after 1-mo LcS consumption, in patients with a single rib fracture, oral administration of the probiotic LcS was associated with a lower incidence of pneumonia and increased pulmonary functions without causing severe adverse effects. PMID- 30020534 TI - Effects of three infusion fluids with different sodium chloride contents on steady-state serum concentrations of bromide in dogs. AB - Potassium bromide overdose (bromism) in the management of canine epilepsy has been known. However, a protocol to reduce bromide concentrations rapidly has not been previously established. The effects of three infusion fluids with different chloride contents on the steady-state serum concentrations of bromide in beagles were determined. After stabilization of the serum bromide concentrations, seven dogs were infused with saline (Na+ 154 mmol/L; Cl- 154 mmol/L), lactated Ringer's (Na+ 131 mmol/L; Cl- 110 mmol/L), or maintenance solutions (Na+ 35 mmol/L; Cl- 35 mmol/L) at a rate of 2 or 10 ml kg-1 hr-1 for 5 hr. Serum and urine were collected hourly, and the bromide concentrations were measured. When saline and lactated Ringer's solutions were infused at a rate of 10 ml kg-1 hr-1 for 5 hr, serum bromide concentrations were decreased by 14.24% and urine bromide concentrations by 17.63%, respectively. Of all compositions of infusion fluids, only sodium and chloride contents were associated with the decreased serum concentrations and the increased renal clearance of bromide. In summary, saline and lactated Ringer's solutions reduced serum bromide concentrations in a sodium chloride-dependent manner in dogs were found when infused at 10 ml kg-1 hr-1 for 5 hr. PMID- 30020535 TI - Pharmacokinetic evaluation of marbofloxacin after intravenous administration at different ages in llama crias, and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation. AB - In llama crias (tekes), Escherichia coli and Staphylococcus aureus are major pathogens, and marbofloxacin could be a suitable choice. The objectives of this study were (a) to evaluate the serum pharmacokinetics of marbofloxacin (5 mg/kg) after intravenous administration in tekes and simulate a multidose regimen; (b) to emulate pharmacokinetic profiles after single dose and steady-state conditions by Monte Carlo simulation (c) to determine the MIC of regional strains of Escherichia coli and Staphylococcus aureus; (d) to perform a PK/PD analysis by Monte Carlo simulation. Pharmacokinetics of marbofloxacin was evaluated in six animals at 3, 10, 24, 50, and 80 days after birth. Marbofloxacin were determined by HPLC. A steady-state multi-dose simulation was carried out, and concentration time profiles were generated by Monte Carlo simulation. MIC of marbofloxacin against regional E. coli and S. aureus strains were also determined. Finally, a PK/PD analysis was conducted by Monte Carlo simulation. After pharmacokinetic analysis, clearance showed a trend to increase (0.14 and 0.18 L kg-1 hr-1 ), and AUC (36.74 and 15.21 MUg hr-1 ml-1 ) and Vss (3.06 and 3.37 L/kg) trended to decrease at 3 and 80 days-old, respectively, showing accumulation ~50% in animals with 3 days. All strains tested of E. coli (MIC90 = 0.06 MUg/ml) and S. aureus (MIC90 = 0.25 MUg/ml) were susceptible to marbofloxacin. PK/PD analysis suggests that the therapeutic regimen of marbofloxacin could be effective for infections caused by E. coli strains in animals between 3 and 80 days, with a CFR for Cmax /MIC > 10 of 100% and for AUC24 /MIC > 125 of 99.99%; and for infections produced by S. aureus in animals between 3 and 24 days old, with a CFR for Cmax /MIC > 10 of 93.08% and for AUC24 /MIC > 60 of 97.01%, but a higher dose should be used in older animals, because PK/PD endpoints were not met. PMID- 30020536 TI - Retrospective review of screening for Sturge-Weber syndrome with brain magnetic resonance imaging and electroencephalography in infants with high-risk port-wine stains. AB - BACKGROUND: There is a lack of consensus regarding how best to screen children with facial port-wine stains for Sturge-Weber syndrome. Many favor brain magnetic resonance imaging, and adjunctive electroencephalography is increasingly used. However, the sensitivity, specificity, and negative and positive predictive value of magnetic resonance imaging and electroencephalography and whether screening improves seizure recognition is unclear. METHODS: A retrospective review of children with high-risk port-wine stains presenting consecutively to the outpatient laser clinic of a tertiary pediatric hospital between December 2015 and November 2016 was undertaken. Primary outcome measures were yield, accuracy, age of and protocols for screening magnetic resonance imaging and electroencephalography, type of and age at presenting seizure, and percentage referred to neurology. RESULTS: Of 126 patients with facial port-wine stains, 25.4% (32/126) were at high risk of Sturge-Weber syndrome (hemifacial, median, and forehead PWS phenotypes); 43.7% of these (14/32) underwent screening magnetic resonance imaging. Sturge-Weber syndrome was detected in 7.1% (1/14). Magnetic resonance imaging had false-negative results in 23.1% (3/13) of those screened. Screening magnetic resonance imaging had sensitivity of 25%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 76.9% for the detection of Sturge-Weber syndrome (hemifacial, median and forehead PWS phenotypes). Only one-third of those with false-negative magnetic resonance imaging were referred to neurology. Mean age of first seizure in those with false negative screening magnetic resonance imaging was 28 months, vs 14 months in those not screened. Abnormal electroencephalographic signs were detected in the two infants who underwent presymptomatic electroencephalography. CONCLUSIONS: Findings from this small cohort of individuals with port-wine stains that put them at high risk of Sturge-Weber syndrome suggest that children with positive screening magnetic resonance imaging will almost certainly develop Sturge-Weber syndrome but that negative screening magnetic resonance imaging cannot exclude Sturge-Weber syndrome (in up to 23.1% of cases). False-negative magnetic resonance imaging may delay seizure recognition. Seizure education, monitoring, and consideration of adjunctive electroencephalography are important irrespective of magnetic resonance imaging findings. PMID- 30020537 TI - Infiltration of abdominal striae distensae by Hodgkin's lymphoma. PMID- 30020539 TI - Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity. AB - Guanylate-binding proteins (GBPs) are conserved family of IFN-inducible GTPases that play an important role in the host immunity against bacterial, viral, and protozoan pathogens. GBPs protect the host by associating with intracellular microbes, their vacuolar niche or, in the case of viruses, with their replication complex. This association results in a restriction of the respective pathogen, yet the exact molecular mechanisms of the antimicrobial functions of GBPs are still unclear. Recent work has linked the GBPs with the activation of inflammasomes, multi-protein complexes that assemble upon recognition of pathogen or host-derived signals and that drive the release of cytokines and host cell death. Here, we will focus on the most recent findings that have started to unravel the manifold restriction mechanism controlled by GBPs in mouse and human cells, and that shed light on the molecular cues that control GBP recruitment to bacterial membranes. PMID- 30020538 TI - Mechanochromic Switching between Delayed Fluorescence and Phosphorescence of Luminescent Coordination Polymers Composed of Dinuclear Copper(I) Iodide Rhombic Cores. AB - The synthesis and photophysical properties of two luminescent CuI coordination polymers, [Cu2 I2 (PPh3 )2 (3-tpyb)]n and [Cu2 I2 (PPh3 )2 (4-tpyb)]n (Cu-3-tpyb and Cu-4-tpyb; PPh3 =triphenylphosphine, m-tpyb=1,3,5-tris(m-pyridyl)benzene (m=3, 4)), are described. X-ray structural analysis indicated that one dimensional coordination chains comprising rhombic {Cu2 I2 (PPh3 )2 } cores and m tpyb bridging ligands were formed. Both Cu-3-tpyb and Cu-4-tpyb exhibited blue-to yellow thermally activated delayed fluorescence (TADF) that originated from mixing of the metal-to-ligand and halide-to-ligand charge-transfer excited states and moderate emission quantum yields of 0.29 and 0.27, respectively, at 298 K. Further, mechanochromic luminescence was observed for both complexes. The emission lifetimes indicated that the origin of emission switched from TADF to phosphorescence, which was derived from the triplet cluster-centered (3 CC) emissive state generated by grinding-induced amorphization. PMID- 30020541 TI - Induced linear dermatosis: Koh Kchol. PMID- 30020540 TI - The Associations Between Oral Complex Carbohydrate Sensitivity, BMI, Liking, and Consumption of Complex Carbohydrate Based Foods. AB - Recent work suggests that humans may perceive complex carbohydrates and that their sensitivity to simple carbohydrates (i.e., glucose and sucrose) is independent from tasting complex carbohydrates. The aim of this study was to confirm whether humans could sense complex carbohydrates from a range of concentration levels; and if their oral sensitivity to complex carbohydrate relates to their BMI, liking, and consumption of complex carbohydrate-based foods using a large sample group of adults. Participants' (n = 92 females, age 23.7 +/- 0.5 yr [range, 19 to 47 yr]) oral sensitivity towards complex carbohydrate (maltodextrin) and sweet taste function (glucose) was assessed by measuring detection threshold and suprathreshold intensity perception (gLMS). Participants were asked to complete an online version of a Food Frequency Questionnaire and a Likes and Dislikes Questionnaire. Hedonic ratings for complex carbohydrate and sweet solutions, as well as for a range of complex carbohydrate and sweet prototypical foods, were also measured. Consistent with previous findings, there was large interindividual variation in detection and intensity measures for maltodextrin and glucose. No significant associations were found between oral complex carbohydrate sensitivity, Body Mass Index (BMI), and frequency of consumption of complex carbohydrate-based foods measured. Similarly, no differences were observed between liking of complex carbohydrates, BMI, and food intake. All in, these results from a large sample group further support the proposition that complex carbohydrates are not invisible to the human palate, and can be sensed in the oral cavity even at low concentration levels. PMID- 30020542 TI - Factors predicting remission in thymectomized patients with acetylcholine receptor antibody-positive myasthenia gravis. AB - INTRODUCTION: Although thymectomy is an important therapeutic option for myasthenia gravis (MG), factors predicting remission after thymectomy are not well known. METHODS: We retrospectively reviewed patients with acetylcholine receptor antibody (AChR-Ab)-positive MG who had undergone thymectomy. Prognostic factors predicting remission were investigated. Changes in AChR-Ab titer before and after thymectomy were also evaluated. RESULTS: Among the 179 patients, 52.5% achieved complete stable or pharmacologic remission. Nonthymomatous pathology and mild preoperative status were favorable predictors of remission. The decrease in AChR-Ab titer after thymectomy was significant in nonthymomatous MG but not in thymomatous MG. DISCUSSION: Nonthymomatous pathology and mild preoperative status are prognostic factors that may predict remission after thymectomy. The decrease in AChR-Ab titer after thymectomy was significant in nonthymomatous MG but not in thymomatous MG, suggesting that the pathogenic role of the thymus differs according to pathology. Muscle Nerve, 2018. PMID- 30020543 TI - Bromelain Kinetics and Mechanism on Myofibril from Golden Pomfret (Trachinotus blochii). AB - : Bromelain was used to tenderize golden pomfrets (Trachinotus blochii). The enzyme kinetic model was x=2.447*ln[1+(1332.21*E0S0-1.74)t], which indicated that the degree of hydrolysis (DH, x) was dependent on hydrolysis time (t), the initial concentration of myofibril (S0 ) and bromelain (E0 ). The relationship between the overall hydrolysis rate (v), S0 , E0 , and t is demonstrated as: v=(16.50(E0S0)-1.33)S0 exp {-2.447ln[1+(1332.21E0S0-1.74)t2]}. Sample of 0.40% E0 /S0 was further used to study the effects of hydrolysis time on the changes of proteins, peptides, free amino acids (FAA), and protein nanostructure. SDS-PAGE result showed that myosin heavy chain was degraded dramatically from 22.88% before treatment to 12.03% after 2 min bromelain treatment. Meanwhile, bromelain did not exhibit activity towards actin, trypomyosin, myosin light chain, and troponin C. A general increase of amino acids indicated the increased DH and the preferential cleavage sites of bromelain in the descending order of lysine, glutamic acid, glycine, ornithine, methionine sulfoxide, and alanine. Atomic force microscope images showed that the strip-like structure of myofibril was considerably degraded by bromelain, and the granulation of protein after 20 min indicated possible self-assembling of protein hydrolysate. Confocal laser scanning microscopy further confirmed the degradation of myofibril proteins and formation of protein aggregates. PRACTICAL APPLICATION: Meat of golden pomfrets is tough, thus not idea for fish balls or fish cakes. Tenderization is essential to achieve desired texture and consumer acceptance, especially for this fish meat with intrinsic hard texture. Bromelain can be extracted from pineapple processing waste. Enzymatic kinetics was studied to instruct industry to control the tenderness of the processed fish meat. The microstructural and mechanism study elucidate the process, thus could be applied to improve the quality of the seafood products correspondingly. PMID- 30020545 TI - Postherpetic abdominal pseudohernia. Presentation of a clinical case and literature review. PMID- 30020546 TI - The distinctive cytology and disease evolution of blastic plasmacytoid dendritic cell neoplasm. PMID- 30020544 TI - Synthesis of Lipid-Carbohydrate-Peptidyl-RNA Conjugates to Explore the Limits Imposed by the Substrate Specificity of Cell Wall Enzymes on the Acquisition of Drug Resistance. AB - Conjugation of RNA with multiple partners to obtain mimics of complex biomolecules is limited by the identification of orthogonal reactions. Here, lipid-carbohydrate-peptidyl-RNA conjugates were obtained by post functionalization reactions, solid-phase synthesis, and enzymatic steps, to generate molecules mimicking the substrates of FmhB, an essential peptidoglycan synthesis enzyme of Staphylococcus aureus. Mimics of Gly-tRNAGly and lipid intermediate II (undecaprenyl-diphospho-disaccharide-pentapeptide) were combined in a single "bi-substrate" inhibitor (IC50 =56 nm). The synthetic route was exploited to generate substrates and inhibitors containing d-lactate residue (d Lac) instead of d-Ala at the C-terminus of the pentapeptide stem, a modification responsible for vancomycin resistance in the enterococci. The substitution impaired recognition of peptidoglycan precursors by FmhB. The associated fitness cost may account for limited dissemination of vancomycin resistance genes in S. aureus. PMID- 30020547 TI - Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S fexofenadine. AB - Thirty-two Collies were used to determine the impact of ABCB1 genotype and phenotype on the plasma pharmacokinetics of fexofenadine's (Fex) R- and S enantiomers after bolus Fex administration, as human P-gp exhibits stereoselectivity. Each Collie's ABCB1 genotype and ivermectin (IVM) sensitivity (phenotype) was determined prior to study enrolment. Wild-type (WT) Collies had lower plasma concentrations of the individual enantiomers as compared to heterozygous IVM nonsensitive (HNS), heterozygous IVM-sensitive (HS) and homozygous mutant (MUT) Collies. Based on pairwise statistical comparison, WT Collies had statistically significantly lower (AUC0-last ) and peak (Cmax ) values compared to HS, HNS and MUT Collies. Tmax was not influenced by genotype/phenotype. Inter-individual variability in PK metrics tended to be largest for WT Collies. Although the influence of genotype/phenotype on Fex PK occurred with the individual isomers, impairment of S-Fex absorption, particularly in the MUT dogs, exceeded that associated with R-Fex. Since Fex elimination occurs primarily via biliary excretion via a transporter other than P glycoprotein, and based upon our understanding of Fex absorption kinetics, we attributed these differences primarily to the absorption portion of the profile. These differences are expressed in a stereo-specific manner. These results demonstrate the potential negative impact on estimates of drug effectiveness and toxicity, especially for P-gp substrates that do not exhibit Central Nervous System toxicities. PMID- 30020549 TI - A Novel Family of Polyiodo-Bromoantimonate(III) Complexes: Cation-Driven Self Assembly of Photoconductive Metal-Polyhalide Frameworks. AB - In the presence of different cations, reactions of [SbBr6 ]3- and I2 result in a new family of diverse supramolecular 1D polyiodide-bromoantimonate networks. The coordination number of Sb, as well as geometry of assembling {Ix }n- polyhalide units, can vary, resulting in unprecedented structural types. The nature of I???Br interactions was studied by DFT calculations; estimated energy values are 1.6-6.9 kcal mol-1 . Some of the compounds showed strong photoconductivity in thin films, suggesting multiple feasible applications in optoelectronics and solar energy conversion. PMID- 30020548 TI - Economically Motivated Food Fraud and Adulteration in Brazil: Incidents and Alternatives to Minimize Occurrence. AB - : Brazil is one of the world's largest food producers. Adulteration of foods is often reported and represent an important potential threat to food safety. Because of this, reduction of the vulnerability of foods to adulteration is of high priority to Brazil. This study analyzes economically motivated food fraud and adulterations in Brazil between 2007 and 2017, based on academic journal reports. In addition, alternatives are proposed to minimize these incidents through good practices, traceability systems and the development of methods to detect food fraud and adulteration. Complex supply chains for foods of animal origin, such as milk and dairy products, were the main targets of food fraud and adulterations. Other products prone to fraudulent activities were vegetable oils, especially olive oil, which are high value products. Meat and fish, as well as their respective by-products, were also involved in some food fraud and adulteration, especially substitution. Cases of extraneous ingredient addition were also reported in the coffee and tea sectors. Comprehensive food fraud and adulteration prevention requires the enforcement of regulatory systems, increased sampling and monitoring, training of food producers and handlers, and development of precise, rapid, and cost-effective methods of fraud detection. The availability of robust methods to identify the chemical constituents of foods could be a decisive step, both to detect and prevent fraud in producer countries and to open up new markets to these products. The results of this study can be used to analyze food safety risks and prioritize target areas for food research and policy-making in order to enforce food safety regulations in Brazil. PRACTICAL APPLICATION: A food fraud and adulteration review was conducted based on scientific literature in Brazil. Milk and its products were the main targets of food fraud and adulterations. Food fraud and adulteration causes and suggestions for good practice are presented. The results can be used to analyze food safety and protect consumer rights. PMID- 30020550 TI - Interaction Between Phenolic Compounds and Lipase: The Influence of Solubility and Presence of Particles in the IC50 Value. AB - Obesity is one of the principal human health problems and one of the main treatments against it is the inhibition of pancreatic lipase, the main responsible enzyme of lipid digestion. For that purpose, previous studies have tested several phenolic compounds against lipase, without considering their aggregation behavior in aqueous solutions. Because of this, the present study focuses on understanding how the solubility and the presence of particles affect the IC50 value of the interaction between lipase and phenolic compounds present in beverages like fruit juices and teas. Therefore, the inhibitory capacity against pancreatic lipase and the aggregate formation of 9 phenolic compounds (quercetin, rutin, myricetin, catechin, epigallocatechin gallate, cyanidin, caffeic acid, chlorogenic acid, and vanillic acid) were analyzed. The results obtained together with the solubility data from literature were treated by principal component analysis and indicate that the IC50 value does not correlate with the solubility or aggregate formation of the phenolic compounds. However, the IC50 values of phenolic compounds which aggregate during the assay conditions have low reproducibility. This study shows that the aggregate formation of phenolic compounds plays an important role during in vitro assays for pancreatic lipase inhibition and should be considered in future experiments as it can lead to false positive results. In terms of particle formation, the flavonoids investigated in this study are more prone to aggregation compared to the phenolic acids. PMID- 30020551 TI - Evolutionary couplings and sequence variation effect predict protein binding sites. AB - Binding small ligands such as ions or macromolecules such as DNA, RNA, and other proteins is one important aspect of the molecular function of proteins. Many binding sites remain without experimental annotations. Predicting binding sites on a per-residue level is challenging, but if 3D structures are known, information about coevolving residue pairs (evolutionary couplings) can predict catalytic residues through mutual information. Here, we predicted protein binding sites from evolutionary couplings derived from a global statistical model using maximum entropy. Additionally, we included information from sequence variation. A simple method using a weighted sum over eight scores substantially outperformed random (F1 = 19.3% +/- 0.7% vs F1 = 2% for random). Training a neural network on these eight scores (along with predicted solvent accessibility and conservation in protein families) improved substantially (F1 = 26.2% +/-0.8%). Although the machine learning was limited by the small data set and possibly wrong annotations of binding sites, the predicted binding sites formed spatial clusters in the protein. The source code of the binding site predictions is available through GitHub: https://github.com/Rostlab/bindPredict. PMID- 30020553 TI - A Visible-Light-Induced Strategy To Construct Osmanaphthalynes, Osmaanthracyne, and Osmaphenanthryne. AB - Herein, we describe a novel, green, and efficient synthesis of a series of different substituted osmanaphthalynes (including -H, -Br, -I, -CH3 and -CF3 ) and the first examples of the preparation of alpha-osmaanthracyne and alpha osmaphenanthryne by means of a visible light-induced intramolecular cyclization reaction of their corresponding osmium hydrido alkenylcarbyne complexes. This visible-light-driven method provides an efficient and straightforward approach to afford the desired fused metal heterocyclic complexes constructed with an Os atom as the metal center in high yield under mild conditions. PMID- 30020552 TI - Reproductive phasiRNAs in grasses are compositionally distinct from other classes of small RNAs. AB - Little is known about the characteristics and function of reproductive phased, secondary, small interfering RNAs (phasiRNAs) in the Poaceae, despite the availability of significant genomic resources, experimental data, and a growing number of computational tools. We utilized machine-learning methods to identify sequence-based and positional features that distinguish phasiRNAs in rice and maize from other small RNAs (sRNAs). We developed Random Forest classifiers that can distinguish reproductive phasiRNAs from other sRNAs in complex sets of sequencing data, utilizing sequence-based (k-mers) and features describing position-specific sequence biases. The classification performance attained is > 80% in accuracy, sensitivity, specificity, and positive predicted value. Feature selection identified important features in both ends of phasiRNAs. We demonstrated that phasiRNAs have strand specificity and position-specific nucleotide biases potentially influencing AGO sorting; we also predicted targets to infer functions of phasiRNAs, and computationally assessed their sequence characteristics relative to other sRNAs. Our results demonstrate that machine learning methods effectively identify phasiRNAs despite the lack of characteristic features typically present in precursor loci of other small RNAs, such as sequence conservation or structural motifs. The 5'-end features we identified provide insights into AGO-phasiRNA interactions. We describe a hypothetical model of competition for AGO loading between phasiRNAs of different nucleotide compositions. PMID- 30020554 TI - Decarboxylative Organocatalytic Allylic Amination of Morita-Baylis-Hillman Carbamates. AB - The present study reports the organocatalytic enantioselective allylic amination of Morita-Baylis-Hillman carbamates efficiently catalyzed by a chiral amine in the presence of a Bronsted acid. Chiral allylic amines were produced in high yields (up to 98 %) and enantioselectivities (up to 97 % ee). This method provides an efficient and easily performed route to prepare alpha-methylene-beta lactams, and other optically active beta-lactams, such as the cholesterol lowering drug Ezetimibe. PMID- 30020555 TI - Carbon Nitride Materials for Water Splitting Photoelectrochemical Cells. AB - Graphitic carbon nitride materials (CNs) have emerged as suitable photo- and heterogeneous- catalysts for various reactions thanks to their tunable band gap, suitable energy-band position, high stability under harsh chemical conditions, and low cost. However, the utilization of CN in photoelectrochemical (PEC) and photoelectronic devices is still at an early stage owing to the difficulties in depositing high-quality and homogenous CN layer on substrates, its wide band gap, poor charge-separation efficiency and low electronic conductivity. In this minireview, we discuss the synthetic pathways for the preparation of various structures of CN on substrates, and their underlying photophysical properties and current photoelectrochemical performance. The main challenges for CN incorporation into PEC cell are described, together with possible routes to overcome the standing limitations toward the integration of CN materials in PEC and other photoelectronic devices. PMID- 30020556 TI - Iron related changes in MS lesions and their validity to characterize MS lesion types and dynamics with Ultra-high field magnetic resonance imaging. AB - Iron accumulates with age in the normal human brain. This process is altered at several levels in the brain of multiple sclerosis (MS) patients. Since iron is mainly stored in oligodendrocytes and myelin in the normal brain, its liberation in demyelinating lesions may amplify tissue damage in demyelinating lesions and its uptake in macrophages and microglia may help to more precisely define activity stages of the lesions. In addition, glia cells change their iron import, export and storage properties in MS lesions, which is reflected by alterations in the expression of iron transport molecules. Changes of iron distribution in the brain can be reliably detected by MRI, particularly upon application of Ultra high magnetic field (7 Tesla). Iron-sensitive MRI allows to more accurately distinguish the lesions in MS from those in other inflammatory brain diseases, to visualize a subset of slowly expanding lesions in the progressive stage of MS and to increase the sensitivity for lesion detection in the gray matter, such as the cerebral cortex or deep gray matter nuclei. PMID- 30020557 TI - A Continuously Regenerable Chiral Ammonia Borane for Asymmetric Transfer Hydrogenations. AB - A novel chiral ammonia borane was designed and developed through the dehydrogenation of ammonia borane with a chiral phosphoric acid, which was highly effective for the asymmetric transfer hydrogenation of imines and beta-enamino esters to afford high levels of reactivities and enantioselectivities. Significantly, this chiral ammonia borane can be continuously regenerated during the transfer hydrogenation with the assistance of water and ammonia borane, which made it possible to obtain satisfactory results using only 0.1 mol % of the chiral phosphoric acid. Notably, the role of chiral phosphoric acid is to produce the chiral ammonia borane. PMID- 30020558 TI - Direct N-Alkylation and Kemp Elimination Reactions of 1-Sulfonyl-1H-Indazoles. AB - The reactions of 1-sulfonyl-1H-indazoles under basic conditions are discussed, and the direct N-alkylation and Kemp elimination reactions of these compounds are reported. A series of 2-(p-tosylamino)benzonitriles and N-alkyl indazoles were prepared in good yields. Moreover, the 2-(p-tosylamino)benzonitriles could be transformed into a diverse range of important derivatives in a one-pot reaction. This method was successfully applied to the total syntheses of quindolinone and cryptolepinone; quindolinone was prepared in a one-pot reaction from 1-sulfonyl 1H-indazole. PMID- 30020559 TI - Domino Pd0 -Catalyzed C(sp3 )-H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates. AB - The Pd0 -catalyzed C(sp3 )-H arylation of 2-bromo-N-methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4pi electrocyclic ring-opening and 6pi electrocyclization. The introduction of a bulky, non-activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways. PMID- 30020560 TI - Exploring the heterogeneity of MS lesions using positron emission tomography: a reappraisal of their contribution to disability. AB - The biological mechanisms driving disability worsening in multiple sclerosis (MS) are only partly understood. Monitoring changes in lesion load on MRI has a limited predictive value on the progression of clinical disability, and there is an essential need for novel imaging markers specific for the main candidate mechanisms underlying neurodegeneration which include failing myelin repair, innate immune cell activation and gray matter neuronal damage. Positron Emission Tomography (PET) is an imaging technology based on the injection of radiotracers directed against specific molecular targets, which has recently allowed the selective quantification in-vivo of the key biological mechanisms relevant to MS pathophysiology. Pilot PET studies performed in patients with all forms of MS allowed to revisit the contribution of MS lesions to disability worsening and showed that the evolution of lesions toward chronic activation, together with their remyelination profile were relevant predictors of disability worsening. PET offers the opportunity to bridge a critical gap between neuropathology and in vivo imaging. This technique provides an original approach to disentangle some of the most relevant pathological components driving MS progression, to follow-up their temporal evolution, to investigate their clinical relevance and to evaluate novel therapeutics aimed to prevent disease progression. PMID- 30020561 TI - A clinical and histopathological study of malformations observed in fetuses infected by the Zika virus. AB - BACKGROUND: The recent outbreak of Zika virus (ZIKV) infection and the associated increased prevalence of microcephaly in Brazil underline the impact of viral infections on embryo fetal development. The aim of the present study is to provide a detailed clinical and histopathological study of the fetal disruption caused by the ZIKV, with a special focus on the associated neuropathological findings. METHODS: A detailed feto-placental examination, as well as neuropathological and neurobiological studies were performed on three fetuses collected after pregnancy termination between 22 and 25 weeks of gestation (WG), because brain malformations associated with a maternal and fetal ZIKV infection was diagnosed. RESULTS: In all three cases, the maternal infection occurred during the first trimester of pregnancy. A small head was observed on the ultrasound examination of the second trimester of pregnancy and led to the diagnosis of ZIKV fetopathy and pregnancy termination. The fetal histopathological examination was unremarkable on the viscera but showed on the testis an interstitial lymphocytic infiltrate. The placenta contained a Hofbauer cells hyperplasia with signs of inflammation. Neuropathological findings included a meningoencephalitis and an ex vacuo hydrocephalus. Immunohistochemical studies showed the presence of T lymphocytic and histiocytic meningitis associated with an abundant cerebral astroglial and macrophagic reaction. In situ hybridization demonstrated, abundant ZIKV particles within the cerebral parenchyma mainly in the ventricular/subventricular zone and in the cortical plate. In addition massive cells death and endoplasmic reticulum damage were present. CONCLUSION: The present study reports on the clinical and histopathological findings observed in three fetuses infected by the ZIKV. It emphasizes the severity of brain damages and the minimal visceral and placental changes observed upon ZIKV infection. This confirms the selective neurotropism of ZIKV. Finally, it allows us to describe the cascade of multifactorial developmental defects leading to microcephaly. PMID- 30020562 TI - A Stable Crystalline Copper(I)-N2 O Complex Stabilized as the Salt of a Weakly Coordinating Anion. AB - Nitrous oxide is considered a poor ligand, and therefore only a handful of well defined metal-N2 O complexes are known. Oxidation of copper powder with an extreme oxidant, [Ag2 I2 ][An]2 ([An]- =[Al(OC(CF3 )3 )4 ]- ) in perfluorinated hexane leads to CuI [An], the first auxiliary ligand-free CuI salt of the perfluorinated alkoxyaluminate anion. The compound is capable of forming a stable and crystalline complex with nitrous oxide, Cu(N2 O)[An], where the Cu-N2 O bond is by far the strongest among all other molecular metal-N2 O complexes known. Thorough characterization of the compounds together with the crystal structure of Cu(N2 O)[An] complex supported with DFT calculations are presented. These give insight into the bonding in the Cu+ -N2 O system and confirm N-end coordination of the ligand. PMID- 30020563 TI - MRI of cortical lesions and its use in studying their role in MS pathogenesis and disease course. AB - Cortical grey matter (GM) demyelination is present from the earliest stages of multiple sclerosis (MS) and is associated with physical deficits and cognitive impairment. In particular, the rate of disability progression in MS, both in the relapsing and progressive phases, appears to be strictly associated with degenerative GM demyelination and diffuse cortical atrophy. In the last decade, several histopathological studies and advanced radiological methodologies have contributed to better identify the exact involvement/load of cortical pathology in MS, even if the specific inflammatory features and the precise cell and molecular mechanisms of GM demyelination and neurodegeneration in MS remain still not fully understood. It has been proposed that a combined neuropathology, imaging and molecular approach may help to define a more detailed characterization and precise assessment of the heterogeneous features of GM injury and inflammation in MS. This, in turn, will possibly identify specific imaging and biohumoral (cerebrospinal fluid/serum) correlates of cortical pathology that may have an important role in predicting and monitor the disease evolution. PMID- 30020564 TI - Chiral N,N Ligands Enabling Palladium-Catalyzed Enantioselective Intramolecular Heck-Matsuda Carbonylation Reactions by Sequential Migratory and CO Insertions. AB - Unprecedented enantioselective intramolecular Heck carbonylation reactions of arenediazonium salts were enabled by a chiral N,N ligand. This reaction constitutes the first enantioselective Heck carbonylation that proceeds through migratory insertion followed by CO insertion. The enantioenriched functionalized dihydrobenzofurans were obtained in good to high yields and enantiomeric ratios of up to 98:2 under mild and operationally simple reaction conditions. PMID- 30020565 TI - Pt Nanoparticles Supported on Nitrogen-Doped-Carbon-Decorated CeO2 for Base-Free Aerobic Oxidation of 5-Hydroxymethylfurfural. AB - Currently, the base-free aerobic oxidation of biomass-derived 5 hydroxymethylfurfural (HMF) to produce 2,5-furandicarboxylic acid (FDCA) is attracting intense interest due to its prospects for the green, sustainable, and promising production of biomass-based aromatic polymers. Herein, we have developed a new Pt catalyst supported on nitrogen-doped-carbon-decorated CeO2 (NC CeO2 ) for the aerobic oxidation of HMF in water without the addition of any homogeneous base. It was demonstrated that the small-sized Pt particles could be well dispersed on the surface of the hybrid NC-CeO2 support, and the activity of the supported Pt catalyst depended strongly on the surface structure and properties of the catalysts. The as-fabricated Pt/NC-CeO2 catalyst, with abundant surface defects, enhanced basicity, and favorable electron-deficient metallic Pt species, enabled an almost 100 % yield of FDCA in water with molecular oxygen (0.4 MPa) at 110 degrees C for 8 h without the addition of any homogeneous base, which is indicative of exceptional catalytic performance. Furthermore, this Pt/NC CeO2 catalyst also showed good stability and reusability owing to strong metal support interactions. An understanding of the role of surface structural defects and basicity of the hybrid NC-CeO2 support provides a basis for the rational design of high-performance and stable supported metal catalysts with practical applications in various transformations of biomass-derived compounds. PMID- 30020567 TI - Understanding the human and system factors involved in medication errors. AB - Medication errors involving patients are a serious concern in healthcare practice. Nurses, more than any other healthcare professional group, are principally involved in medicines administration. This article recognises the complexity of why medication errors occur and considers the many factors involved, including those from an individual and organisational system perspective. It adopts a solution-focused approach, based on the evidence underpinning the knowledge of medication errors. PMID- 30020566 TI - Brain responses during strategic online gaming of varying proficiencies: Implications for better gaming. AB - BACKGROUND: Online gaming is a complex and competitive activity. However, little attention has been paid to brain activities relating to gaming proficiency. METHODS: In the current study, fMRI data were obtained from 70 subjects while they were playing online games. Based on their playing, we selected 24 clips from each subject for three levels of gaming proficiency (good, poor, and average), with each clip lasting for 8 seconds. RESULTS: When comparing the brain responses during the three conditions, good-play trials, relative to poor- or average-play trials, were associated with greater activation of the declive, postcentral gyrus, and striatum. In post-hoc analyses taking the identified clusters as regions of interest to calculate their functional connectivity, activation of the declive during good-play conditions was associated with that in the precentral gyrus and thalamus, and activation in the striatum was associated with that in the inferior frontal gyrus and middle frontal cortex. CONCLUSIONS: Taken together, findings suggest specific regional brain activations and functional connectivity patterns involving brain regions and circuits involved in sensory, motor, automatic and executive functioning and their coordination are associated with better gaming. Specifically, for basic functions, such as simple reaction, motor control, and motor coordination, people need to perform them automatically; for highly cognitive functions, such as plan and strategic playing, people need to engage more executive functions in finishing these works. The automatically processed basic functions spare cognitive resources for the highly cognitive functions, which facilitates their gaming behaviors. PMID- 30020568 TI - [If problems arise during palliative sedation: considerations in sedation in the terminal phase]. AB - Palliative sedation is increasingly being utilised when patients are close to death. Despite clear guidelines, its implementation is often problematic. In this clinical lesson we describe two patients in whom sedation did not go according to plan. The first case concerns a relative overdose of the medication which resulted in agitation, and the second case concerns the premature initiation of palliative sedation which caused the period of sedation to last too long. Suggestions are made to prevent these problems occurring. PMID- 30020570 TI - [Dutch Medicines Act also applicable to repurposing]. AB - In this issue of the Dutch Journal of Medicine (NTvG), Strous and Van den Brink argue that Article 68 of the Dutch Medicines Act should be applied to repurposed drugs in a more liberal manner. Medicines prescribed on-label have been authorised by the relevant regulatory authority and are therefore guaranteed to have been substantiated by the necessary evidence and assessed for a positive benefit-risk balance. Article 68 states that medicines may be prescribed off label only if they are described in the relevant professional treatment standards or guidelines. The more liberal application of Article 68 would allow the prescription of drugs that have not been adequately assessed for evidence substantiating their efficacy and safety in the field for which they are being prescribed. This is unwarranted, for repurposed drugs and for any other drug. PMID- 30020569 TI - [Practice variation in the application of remifentanil during labour; an overview of its application in Dutch hospitals]. AB - OBJECTIVE: To survey (a) the frequency of the use of patient-controlled analgesic remifentanil-PCA during labour in the Netherlands; (b) considerations by obstetricians whether or not to offer remifentanil-PCA; (c) target population for remifentanil-PCA and (d) the application of maternal monitoring. DESIGN: Descriptive survey. METHOD: A questionnaire was sent to all 81 Dutch hospitals with a labour ward. The following subjects were covered: (a) available methods for pharmacological pain relief; (b) considerations by obstetricians whether or not to offer remifentanil-PCA; (c) target population for remifentanil-PCA; (d) maternal monitoring and (e) the hospital's birth data for the year 2016. The hospital pharmacist was asked for the number of remifentanil dispensed in 2016 2017. RESULTS: The questionnaire was completed by 81 obstetricians (100% response rate). Remifentanil-PCA was available in 59 out of 81 (73%) of the hospitals with a mean use of 23% of the births (range 16-56%) in those units. In 34 (58%) of these hospitals, remifentanil-PCA is available for all women, and in 25 (42%) it was for a selected group of women. Most frequently mentioned considerations for offering remifentanil-PCA were 'a need for an alternative for epidural analgesia' and 'at the request of pregnant women' reported a respective 55 (93%) and 46 (78%) times. In hospitals where remifentanil-PCA was not offered, the following motives were given for this policy: 'epidural analgesia is the most effective method of pain relief during labour'; 'risk of serious maternal complications'; and 'sufficient monitoring during labour not feasible in delivery rooms'. CONCLUSION: A large variation between Dutch hospitals exists in the application of remifentanil-PCA during labour. In the majority of the hospitals, remifentanil PCA is available for all women. The most common motives mentioned by obstetricians for its use are 'a need for an alternative for epidural analgesia' and 'at the request of pregnant women'. PMID- 30020571 TI - [Interdigital pilonidal sinus of the foot: a peculiar place for a common lesion]. AB - BACKGROUND: Besides the natal cleft, a pilonidal sinus can also occur in other areas of the body. An uncommon place is the interdigital web space of the toes. A sinus can arise due to penetration of the skin by a hair. The only curative treatment is surgical excision. CASE DESCRIPTION: A 55-year-old man was referred by the GP with an inflammation between his toes. On physical examination we saw a skin defect with hairs and granulation tissue between the fourth and fifth toes of the right foot. It was decided to surgically excise the affected area. Histopathological examination showed a chronical, fibrosing inflammation surrounding a free hair structure, consistent with a pilonidal sinus. The lesion was probably caused by dog hairs, in combination with poor personal hygiene. CONCLUSION: This patient had a pilonidal sinus at an uncommon site. In the event of poorly-understood inflammation between the toes, a pilonidal sinus should be considered. PMID- 30020572 TI - [Sharing internal audit results with the Inspectorate; interviews on the possibility and preconditions]. AB - OBJECTIVE: To study to what extent internal audit results of hospitals can be shared with external supervisors and the necessary preconditions for this. DESIGN: Qualitative interview research. METHOD: In 2013-2015, we interviewed 36 individuals from six hospitals: 12 department heads (all medical specialists), 10 department managers; five members of the Board of Directors; five members of the Supervisory Board and the four account-holding hospital inspectors. We also performed a focus group interview with six other hospital inspectors of the Health and Youth Care Inspectorate. The interview data were analysed thematically. RESULTS: The interviewees pointed out that there is no coordination between internal and external supervision. They were in favour of sharing internal audit results with external supervisors to reduce the supervisory burden. They stated that internal audits give insight into quality improvements, how hospital directors govern quality and safety and the culture of improvement within healthcare provider teams. With this information, the Inspectorate can assess to what extent hospitals are learning organisations. The interviewees mentioned the following preconditions for sharing audit results: reliable and risk-based information about quality and safety, collected by expert, trained auditors and careful use of this information by the Inspectorate in order to maintain openness among audited healthcare providers. CONCLUSION: Internal audit results can be shared conditionally with external supervisors like the Health and Youth Care Inspectorate. When internal audit results show that hospitals are open, learning and self-cleansing organisations, the Inspectorate can supervise the hospitals remotely and supervisory burden will probably be reduced. PMID- 30020573 TI - [New indications for existing drugs; repurposing in psychiatry and addiction medicine]. AB - Repurposing is the discovery - whether or not by accident - of a new use for an existing product, for example, a new indication for a drug. In the past, several psychotropic drugs have received their place in the treatment arsenal via this route. Both in psychiatry and addiction medicine, there is an important need for new treatments with new working mechanisms. Potential new uses in both psychiatry and addiction medicine of several drugs that have already been registered for other indications are currently under study. For example, the anaesthetic ketamine is found to have a strong antidepressant effect. In addition, both the anti-epileptic topiramate and the muscle-relaxant baclofen could possibly prevent relapse in addictive behaviours. PMID- 30020574 TI - [Application of flexible transanal port for excision of rectal tumours]. AB - In 2010 the first report of the application of the flexible transanal port ('operation platform') for the excision of rectal tumours was published. Due to the enhanced vision it provides, adenomas and small malignant rectal tumours can be radically resected with significantly fewer recurrences than with endoscopic mucosal resection or transanal excisions done without this platform. The application of this platform is cheaper and more intuitive than transanal endoscopic microsurgery, while the quality of the local resection, the risk of postoperative complications and the functional and oncological outcomes all appear to be comparable. This is the reason that this flexible platform is now in use in most Dutch hospitals. The flexible port has led to an increase in rectum sparing treatment for low-risk T1 rectal carcinoma. Nowadays, this platform is also used for the transanal approach during radical rectal surgery for high-risk rectal carcinomas and for rectal operations in patients with benign conditions in the pelvis minor such as severe endometriosis or Crohn's disease. PMID- 30020575 TI - [Catamenial pneumothorax: an intriguing cause of recurrent pneumothorax in women]. AB - BACKGROUND: Thoracic endometriosis (TE) is one of the causes of secondary pneumothorax in women. According to the literature, 1 in 3 premenopausal women with pneumothorax can be diagnosed with 'catamenial pneumothorax'. The diagnosis is often not or only belatedly made in practice, even though treatment is significantly different than that of primary pneumothorax. CASE DESCRIPTION: A 40 year-old woman came to the emergency department because of dyspnoea and right sided chest pain. The patient had recurrent pneumothorax and chest pain related to the menstrual cycle. Thoracoscopy revealed thoracic endometriosis. The endometriosis lesions were removed and the patient subsequently received hormonal menstrual suppression treatment. CONCLUSION: In premenopausal women with pneumothorax or a recurrence of pneumothorax, it is important to consider catamenial pneumothorax. Infertility, earlier proven abdominal endometriosis and chest pain linked to menstruation are indications of thoracic endometriosis or catamenial pneumothorax. PMID- 30020576 TI - [Engaged caregivers: an empirical-ethical analysis of dignity in palliative care]. AB - The concept of dignity is often used in palliative care, and, in particular, as a concept to illustrate what is important to those involved. However, philosophers, ethicists and laypersons cannot agree on what dignity actually is. In this paper, we analyse what caregivers told us about situations in which they thought dignity was at stake. From two focus group meeting of health care professionals concerning the end of life, we learned that dignity could mean different things, but that there were also shared themes. Dignity was at stake where the situation of the patient threatened the deeply felt values of the caregivers. The caregiver engages him or herself to support the dignity of their patient while simultaneously honouring their own sense of dignity. We recommend that care organisations support caregivers' engagement with dignity by creating time and space for its analysis. PMID- 30020577 TI - [Remifentanil during labour; has its place in pain relief during labour been decided?] AB - Patient-controlled analgesia using remifentanil (remifentanil PCA) has been used as a new form of pain relief during labour since soon after its release on the market. Reduction in pain scores lasts for 1 to 2 hours, and the analgesia is inferior to that of an epidural. Remifentanil PCA can be an alternative for epidural analgesia in cases where the woman cannot or does not want to receive epidural anaesthesia. In some hospitals in the Netherlands remifentanil PCA is being used on a large scale, possibly because of its less invasive character and for logistical reasons. The Netherlands RAVEL study comparing remifentanil with epidural analgesia showed greater satisfaction with pain relief in the epidural group. There is a high risk of hypoventilation during remifentanil PCA use, leading to desaturation; since desaturation can be a late consequence of hypoventilation, adequate monitoring of the woman is essential. It would be ideal to monitor the frequency and depth of ventilation along with peripheral saturation, and one-on-one care of the woman is advised. PMID- 30020578 TI - Federal Employees Health Benefits Program and Federal Employees Dental and Vision Insurance Program: Expiration of Coverage of Children of Same-Sex Domestic Partners; Federal Flexible Benefits Plan: Pre-Tax Payment of Health Benefits Premiums: Conforming Amendments. Final rule. AB - On October 30, 2013, OPM published final regulations in the Federal Register to expand coverage for children of same-sex domestic partners under the Federal Employees Health Benefits (FEHB) Program and the Federal Employees Dental and Vision Insurance Program (FEDVIP). The regulation allowed children of same-sex domestic partners living in states that did not allow same-sex couples to marry to be covered family members under the FEHB and the FEDVIP. Due to a subsequent Supreme Court decision legalizing same-sex marriage in all states, OPM published an interim final regulation on December 2, 2016, that created a regulatory exception that only allowed children of same-sex domestic partners living overseas to maintain their FEHB and FEDVIP coverage until September 30, 2018. OPM recognized that there were additional requirements placed on overseas federal employees that did not apply to other civilian employees with duty stations in the United States making it difficult to travel to the United States to marry their same-sex partners. Understanding that we have provided agencies with additional time for compliance given that overseas federal employees may not have been able to marry immediately following the Supreme Court decision, OPM is issuing a final rule removing references to domestic partners and domestic partnerships from the regulations. Based on the Supreme Court decision and the two additional year's lead time for domestic partners overseas to marry, the current language in the CFR is not needed and may be somewhat confusing. There is no change in coverage for children whose same-sex partners are married. PMID- 30020579 TI - Schedule for Rating Disabilities: Skin. Final rule. AB - On August 12, 2016, VA published in the Federal Register the proposed rule for Schedule for Rating Disabilities: Skin. VA received multiple responses during the 60-day comment period. This final rule implements the Secretary's proposed rule with limited revisions. PMID- 30020580 TI - Fiduciary Activities. Final rule. AB - The Department of Veterans Affairs (VA) amends its fiduciary program regulations, which govern the oversight of beneficiaries, who because of injury, disease, or age, are unable to manage their VA benefits, and the appointment and oversight of fiduciaries for these vulnerable beneficiaries. The amendments will update and reorganize regulations consistent with current law, VA policies and procedures, and VA's reorganization of its fiduciary activities. They will also clarify the rights of beneficiaries in the program, and the roles of VA and fiduciaries in ensuring that VA benefits are managed in the best interest of beneficiaries and their dependents. The amendments to this rulemaking are mostly mandatory to comply with the law. They are also in line with the law's goals to streamline and modernize the fiduciary program and process. These amendments by Congress, reduce unnecessary regulations, streamline and modernize processes, and improve services for Veterans. Furthermore, VA is unable to alter proposed amendments that directly implement mandatory statutory provisions. PMID- 30020581 TI - Controlled Substances Quotas. Final rule. AB - The Drug Enforcement Administration (DEA) is publishing this final rule to strengthen the process for setting controls over diversion of controlled substances and make other improvements in the quota management regulatory system for the production, manufacturing, and procurement of controlled substances. PMID- 30020582 TI - Bladder diverticula with more than 5 cm increases the risk of acute urinary retention in BPH. PMID- 30020583 TI - ICSI with testicular sperm for couples with sperm DNA damage. PMID- 30020584 TI - Testicular versus ejaculated sperm should be used for intracytoplasmic sperm injection (ICSI) in cases of infertility associated with sperm DNA fragmentation | Opinion: Yes. PMID- 30020736 TI - Cannabinoids: emerging evidence in use and abuse. AB - Despite current legal and medical controversies surrounding cannabinoids, it is a fact that emergency departments are seeing an increasing number of patients presenting with symptoms associated with the use of these drugs. This review outlines the pathophysiology of cannabinoids, the potential clinical findings associated with their use, and the current evidence for best-practice management of patients who present to the emergency department with signs of acute intoxication and chronic use. Differences between natural and synthetic cannabinoids are discussed, along with the latest evidence for diagnosing and managing patients presenting with the intractable vomiting of cannabinoid hyperemesis syndrome.Emerging treatments for cannabinoid hyperemesis syndrome are presented, including hot water bathing, early haloperidol administration, and topical capsaicin, in addition to an update on the legal status of medical cannabinoid substances. PMID- 30020737 TI - Emergency department management of dental trauma: recommendations for improved outcomes in pediatric patients. AB - Nearly 50% of children will experience dental trauma by the age of 4 years. Timely and effective care is important in the management of dental injuries, as several studies have shown poor outcomes with delayed treatment. The current evidence in the management of dental injuries is primarily from a dentist's perspective, with limited evidence specific to management in the emergency department. The goal of pediatric dental injury management is dictated largely by whether the dentition is primary or permanent. This issue provides a systematic emergency medicine-based approach to address pediatric dental injuries, along with a review of basic dental procedures that will lead to improved dental outcomes. PMID- 30020738 TI - Costs associated with long-acting insulin analogues in patients with diabetes. AB - OBJECTIVES: The objective of this literature review was to evaluate the costs associated with the use of long-acting insulin analogues (LAIAs) compared with non-LAIA agents, including human insulin, oral antidiabetic drugs, and other injectable therapies, in the treatment of patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). STUDY DESIGN: A systematic review of the medical literature (MEDLINE, EMBASE, Cochrane, EconLit) conducted from 2004 to 2016. METHODS: The review protocol was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria for studies were: patients with T1D and/or T2D, LAIA intervention, and comparators, including oral antidiabetics (OADs) or neutral protamine Hagedorn (NPH). Outcomes of interest were adherence measures; economic outcomes, including total costs, cost savings, and willingness-to-pay; and cost-effectiveness or incremental cost effectiveness analyses. Real-world costs of individual LAIAs were also evaluated and are often compared against those of other LAIAs in the economic analyses. RESULTS: We identified and included 117 relevant studies. Patients using LAIAs had higher drug costs than those using OADs and NPH but had neutral or reduced total and diabetes-related costs compared with patients using non-LAIAs. Use of LAIA pen-delivery systems may lead to improved adherence and reduction in costs. Patients receiving insulin glargine demonstrated higher adherence and persistence than patients on insulin detemir. Economic models suggest that LAIAs are more cost-effective than NPH for T1D; for T2D, insulin glargine is more costly than NPH but less so than insulin detemir. CONCLUSIONS: Despite higher drug costs, the real-world overall medical costs of LAIAs are not significantly different from those of NPH in patients with diabetes. The findings may be helpful for formulary decision making for patients with diabetes in a cost-constrained environment. PMID- 30020585 TI - Testicular versus ejaculated sperm should be used for intracytoplasmic sperm injection (ICSI) in cases of infertility associated with sperm DNA fragmentation | Opinion: No. PMID- 30020739 TI - A gray area for reimbursement: medical foods for non-inborn errors of metabolism. AB - OBJECTIVES: The use of medical foods (MFs) specifically for non-inborn errors of metabolism (non-IEM) is rising. Concomitantly, evidence for the safety and efficacy of these non-IEM MFs is lacking. We examined the current use and costs of non-IEM MFs and determined whether the scientific evidence supporting their effectiveness and medical utility is adequate to warrant public reimbursement. STUDY DESIGN: We employed a qualitative literature review analysis. METHODS: PubMed and MEDLINE databases were searched for all years using relevant keywords, including names of non-IEM MFs identified in the California Workers' Compensation System (CAWCS) claims dataset from 2011 to 2013. The quality of extracted data was scored with the Delfini Evidence Tool Kit. RESULTS: Only 2 (3.2%) of 62 studies were conducted with scientific rigor. These 2 studies were for dietary management of Alzheimer disease, which does not have a distinctive nutritional requirement necessitating an MF. Seventy-one percent of the studies of MFs used by patients in the CAWCS were considered to have uncertain validity. CONCLUSIONS: Most reviewed non-IEM MFs lack evidence to support their safety and efficacy. These non-IEM MFs do not abide by FDA draft guidance, as they do not address a distinct nutritional requirement for a disease and yet often have a National Drug Code or "Rx only" label. Consequently, these products do not meet the statutory definition of an MF. We recommend that CAWCS and other payers not provide insurance coverage for non-IEM MFs until more scientific evidence supports their safety, efficacy, and use for nutritional need of a disease. PMID- 30020740 TI - Disease-modifying antirheumatic drug initiation among patients newly diagnosed with rheumatoid arthritis. AB - OBJECTIVES: To determine the rate of timely disease-modifying antirheumatic drug (DMARD) initiation in patients newly diagnosed with rheumatoid arthritis (RA), as recommended per a quality measure endorsed by the National Quality Forum. STUDY DESIGN: Retrospective analysis of claims data from the Truven Health MarketScan commercial and Medicare claims databases. METHODS: Patients newly diagnosed with RA were identified in the claims databases. Outcomes included rate of nonbiologic or biologic DMARD initiation within 12 months of diagnosis; initiation by year (2009-2012), US state, and prescription drug plan; and time to initiation. Multivariate modeling was performed to identify factors associated with initiation or noninitiation. RESULTS: Of 40,040 newly diagnosed patients, 55.5% initiated RA therapy within 12 months, including 21,154 (52.8%) initiating DMARD therapy and 1051 (2.6%) initiating biologic DMARD therapy. Rates were similar for years 2009 (53.3%), 2010 (55.7%), 2011 (56.3%), and 2012 (56.8%), but they varied widely by US state (range, 33.3%-88.0%) and prescription plan (range, 42.6%-63.5% across 8 largest plans). Mean (SD) time to initiation of any RA therapy was 39 (65) days. Predictors of initiation included point-of-service (odds ratio [OR], 1.18) and consumer-driven/high-deductible (OR, 1.19) plans, comorbid psoriasis (OR, 1.30) or diabetes (OR, 1.17), rheumatoid factor test (OR, 3.02), and diagnosis by a rheumatologist (OR, 3.17). Predictors of noninitiation included female sex (OR, 0.94), preferred provider organization plan (OR, 0.87), higher comorbidity score (OR, 0.94), select comorbidities (OR range, 0.65-0.92), and number of prescriptions for any cause (OR, 0.98). CONCLUSIONS: Only slightly more than half of patients initiated RA therapy within 12 months of diagnosis in this commercially insured population. PMID- 30020741 TI - Cost per response analysis of strategies for chronic immune thrombocytopenia. AB - OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue. PMID- 30020742 TI - 5-ASA to sulfasalazine drug switch program in patients with ulcerative colitis. AB - OBJECTIVES: To switch patients with ulcerative colitis (UC) from costlier 5 aminosalicylic acid compounds to sulfasalazine and assess (1) the cost savings, (2) the barriers to switching, and (3) adverse events (AEs) and adherence at 3 months after the drug switch. STUDY DESIGN: An open-label, pharmacist administered drug switch program coordinated at an academic inflammatory bowel disease center. METHODS: A clinical pharmacist contacted patients with UC who were prescreened by physicians and covered by specific insurers to enroll them in the drug switch program. Enrolled patients were followed for 3 months to assess AEs and medication adherence. Reasons for declining to participate were recorded. RESULTS: A total of 205 eligible patients were identified; only 14 enrolled, and 10 remained on sulfasalazine for the entire 3-month follow-up period. The enrollment rate was only 4.9%, yet a net cost savings of $22,828/3-month to the insurer was achieved (including program administration costs but excluding AE costs), with co-pays reduced by approximately $25 per month per patient. The rate of AEs on sulfasalazine (28.6%) was similar to that found in previous reports. Significant unanticipated barriers to switching were encountered, namely patient desire to not alter an existing effective drug regimen. CONCLUSIONS: A pharmacist administered drug switch program in patients with UC was significantly more difficult than anticipated, with questionable achievement of cost savings. This experience suggests that future drug switches and studies should focus on patient preferences for drug switching, as this may have implications for switching from brand name to biosimilar drugs. PMID- 30020743 TI - Direct oral anticoagulant prescription trends, switching patterns, and adherence in Texas Medicaid. AB - OBJECTIVES: To compare prescription trends, costs, switch patterns, and mean adherence among oral anticoagulants in the Texas Medicaid population. STUDY DESIGN: Secondary analysis of Medicaid prescription claims data. METHODS: All oral anticoagulant prescriptions for patients aged 18 to 63 years with 1 or more prescription claims for an oral anticoagulant from July 1, 2010, to December 31, 2015, were included in utilization and expenditure trend analyses. Switch patterns and adherence, measured by the proportion of days covered (PDC), were analyzed over 1 year for patients newly initiated on oral anticoagulant therapy. RESULTS: Over the 5.5-year study period, direct oral anticoagulant (DOAC) use increased steadily and the proportion of oral anticoagulant prescription expenditures accounted for by DOACs increased substantially. By December 2015, DOACs accounted for one-third of anticoagulant prescription claims and more than 90% of total oral anticoagulant prescription expenditures. The mean cost per prescription was 30 times higher for DOACs than warfarin. A higher proportion of patients with a DOAC as an index drug switched drugs. The overall mean +/- SD PDC was 0.71 +/- 0.21, with no significant differences among patients on dabigatran, rivaroxaban, and apixaban. Using a PDC cutoff point of 0.80 to indicate adherence (vs nonadherence), 42% of patients were categorized as adherent. CONCLUSIONS: Texas Medicaid prescription data show a gradual increase in DOAC use with a rapid increase in prescription expenditures. Further exploration of the causes of higher switch rates among DOAC initiators compared with warfarin initiators and nonadherence to DOACs is needed to understand the challenges related to DOAC adoption in practice and to improve patient outcomes. PMID- 30020744 TI - Two-year adherence and costs for biologic therapy for rheumatoid arthritis. AB - OBJECTIVES: To evaluate adherence to newly initiated biologic disease-modifying antirheumatic drugs (bDMARDs) in effectively treated patients with rheumatoid arthritis (RA). STUDY DESIGN: Retrospective cohort study of administrative claims data (IMS PharMetrics Plus) for services incurred from July 1, 2008, to December 31, 2014. METHODS: Data from patients with RA aged 18 to 64 years with continuous enrollment for at least 30 months and initiating abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab were analyzed. Treatment effectiveness was determined using a validated algorithm. Outcomes included adherence rates (proportion of days covered >=80%) for 1 year and 2 years, year 2 adherence among patients effectively and noneffectively treated in year 1, year 2 adherence predictors, and year 2 costs and cost predictors. RESULTS: Across 10,374 patients, adherence rates were 46% for year 1 and 34% for 2 years; rates were lowest for golimumab and highest for infliximab. In year 1, 3076 (29.7%) patients were considered effectively treated. Year 2 adherence was 59% in effectively treated patients, 32% in patients who failed any effectiveness criteria, and 12% in patients who failed only the adherence criterion. Intravenous bDMARDs, older age, male sex, Northeast region, commercial payer, prior DMARD use, index year 2010 or later, and lower preindex all-cause costs each predicted better adherence. Adjusted year 2 all-cause and RA-related costs were $39,425 and $22,123, respectively, for effectively treated patients and $25,313 and $9250 for noneffectively treated patients. Cost predictors included effective treatment, region, payer, and index year. CONCLUSIONS: Adherence to the first bDMARD was suboptimal even in effectively treated patients, suggesting opportunities to improve adherence in patients with RA initiating biologics. PMID- 30020745 TI - Cost of biologic treatment persistence or switching in rheumatoid arthritis. AB - OBJECTIVES: To estimate total costs among patients with rheumatoid arthritis (RA) who persisted on or switched from newly initiated biologic therapy. STUDY DESIGN: A retrospective claims database analysis. METHODS: This analysis included adults in the HealthCore Integrated Research Database with RA who initiated treatment with a biologic for RA (abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, or tocilizumab) between January 2009 and November 2014. Total healthcare costs (plan- and patient-paid) were estimated for 1 year post index. Treatment persistence was defined as no discontinuation (ie, no refill gap >45 days) and no biologic switch. RESULTS: Of 7468 patients, 45.2% persisted on the index biologic for at least 1 year without a refill gap and 16.7% switched to another biologic in the first year; other patients discontinued the index biologic (23.2%) or restarted after a refill gap (15.0%). Mean 1-year total healthcare costs per patient were $41,901 (95% CI, $40,855-$42,947) among persistent patients and $44,244 (95% CI, $40,820-$47,668) among switchers. In a multivariable analysis of all patients, switchers had 5% higher postindex costs on average than persistent patients (exp(beta) = 1.05; 95% CI, 1.01-1.08), and etanercept had the lowest postindex costs (exp(beta) ranged from 1.03 to 1.51 for other biologics relative to etanercept). CONCLUSIONS: Patients with RA who switched biologic therapy incurred higher 1-year total postswitch healthcare costs compared with patients who were persistent on the index biologic. Healthcare costs were lowest for patients who started on etanercept, particularly those who persisted on etanercept. PMID- 30020746 TI - Impact of medical and/or pharmacy reimbursement on adult vaccination rates. AB - OBJECTIVES: To evaluate whether adults enrolled in commercial health insurance plans that provide reimbursement for herpes zoster vaccine (HZV) and pneumococcal vaccine (PV) through the medical and pharmacy benefits have higher vaccination rates compared with those whose health plans cover vaccines under the medical benefit alone. STUDY DESIGN: Retrospective claims analysis using medical and pharmacy claims data from January 1, 2012, through December 31, 2014. Separate but parallel analyses were conducted for HZV and PV. METHODS: Previously unvaccinated patients were divided into exposed (those in employer groups with both medical and pharmacy benefits for vaccinations) and unexposed (those in employer groups that covered vaccination under the medical benefit only) cohorts. RESULTS: For HZV, 32,506 and 1299 patients received vaccinations in the exposed and unexposed cohorts, respectively. The vaccination rate was significantly higher in the exposed (42 vaccinations per 1000 eligible person-years) than the unexposed cohort (15 vaccinations per 1000 eligible person-years; P <.001). For PV, 16,409 and 1386 received vaccinations in the exposed and unexposed cohorts, respectively. The vaccination rate was significantly higher in the exposed (22 vaccinations per 1000 eligible person-years) than the unexposed cohort (17 vaccinations per 1000 eligible person-years; P <.001). CONCLUSIONS: Among members with commercial health insurance, HZV and PV rates were significantly higher among those whose insurance covered vaccinations under both medical and pharmacy benefits, compared with members whose insurance covered vaccines under the medical benefit only. Pharmacy-based vaccination coverage from commercial health insurance plans may help improve adult vaccination rates. PMID- 30020747 TI - Modeling the impacts of restrictive formularies on patients with HIV. AB - OBJECTIVES: To model the impacts of restrictive formulary designs on outcomes for patients with HIV and to demonstrate the costs of restricting access to novel HIV regimens with better safety and efficacy profiles. STUDY DESIGN: We modified an epidemiological model of HIV incidence, progression, and treatment to simulate the effects of 5 formulary scenarios on patient outcomes in the United States. METHODS: Using a cohort of HIV-susceptible individuals, we followed patients through HIV infection, disease progression, and death. Patients transitioned in and out of treatment states once infected. Treatment discontinuation, efficacy, and the rate of adverse events (AEs; renal failure and bone fracture) in each formulary scenario depended on the treatment path and regimens included. Outcomes of interest included all-cause cumulative deaths, annual rates of AEs, and costs associated with treating those AEs. RESULTS: All outcomes of interest were more favorable in less restrictive formulary scenarios that provided fewer barriers to appropriate treatments. By 2025, more restrictive formularies would have resulted in 171,500 more cumulative bone and renal events among treated patients with HIV compared with an open formulary. This corresponds to AE treatment costs of $3.65 billion in more restrictive formularies compared with $1.43 billion in an open formulary. Finally, compared with an open formulary, there would be an additional 16,200 cumulative deaths in more restrictive formularies. CONCLUSIONS: Less restrictive formulary designs, which allow patients with HIV to initiate potentially safer and more efficacious regimens based on their proclivity to AEs, yield better outcomes and reduce costs. PMID- 30020748 TI - Treatment patterns among adults with ADHD receiving long-acting therapy. AB - OBJECTIVES: To evaluate the treatment patterns among commercially insured adults in the United States with attention-deficit/hyperactivity disorder (ADHD) who received long-acting (LA) combination therapy (CT) or monotherapy for ADHD. STUDY DESIGN: Retrospective observational study. METHODS: Adults with at least 1 ADHD diagnosis and at least 1 LA ADHD medication were identified from the MarketScan claims database (April 1, 2009, to March 31, 2014). The index date was randomly selected among LA medication initiation dates (index treatment). CT was identified if a different ADHD medication was filled within 30 days of the index date and the 2 medications overlapped by 30 days or more; otherwise, the treatment was considered monotherapy. Adherence was measured using proportion of days covered (PDC) during the 1 year post index date and was defined as a PDC of 0.8 or greater. Persistence was defined as time to discontinuation (TTD) (ie, >=30-day supply gap). Adherence and persistence were compared between CT and monotherapy using multivariable logistic and Cox models, respectively, adjusting for baseline characteristics. RESULTS: Of 225,600 eligible patients, 7.3% received LA CT and 92.7% received LA monotherapy (mean age, 29 vs 31 years, respectively). Patients receiving LA CT had significantly lower adherence than those receiving LA monotherapy (mean PDC, 0.33 vs 0.41; adherence rate, 7% vs 16%, respectively; adjusted odds ratio, 0.38; P <.001). They also demonstrated significantly lower persistence than patients receiving LA monotherapy (median TTD, 59 vs 79 days, respectively; adjusted hazard ratio, 1.32; P <.001). CONCLUSIONS: Among US adults with ADHD treated with LA medications, LA CT was associated with significantly lower adherence and persistence compared with LA monotherapy. PMID- 30020749 TI - Insights on site-of-care cancer research: both quality and cost information are necessary to guide policy. AB - The implementation of alternative payment models that successfully capture clinical heterogeneity-without adding unacceptable levels of administrative complexity-may be equally (if not more) important than site-neutral payment policies. PMID- 30020750 TI - Value-based health insurance design: how much does socioeconomic status matter? AB - Socioeconomic status (SES), an important determinant of individual health status, has not been widely incorporated into employer benefits strategies. Recent research has characterized significant differences in healthcare utilization patterns and cost among workers in different wage categories, raising the possibility that SES does influence individual healthcare utilization behaviors. In particular, SES may have appreciable impact on the effectiveness of benefits tactics, including value-based insurance design (VBID). This paper sets forth a hypothesis that low wage status negatively influences individual receptivity to VBID offerings, which may blunt the impact of current VBID initiatives. In contrast, high-wage earners may already be compliant with recommended care, and implementation of a VBID design may not yield incremental increases in their treatment compliance. As a result, wage status may be a significant predictor of a favorable response to VBID. Based on these considerations, the authors offer suggestions for employer actions, including evaluation of benefits enrollee response to VBID tactics by employee wage band as an initial step. Employers may also wish to engage benefits enrollees via survey or focus group activities to understand barriers to a more impactful VBID response and consider some of the included benefits design considerations that may result in more equitable and impactful use of VBID. Further research is needed to better understand the relationship between SES and response to VBID offerings. PMID- 30020751 TI - The development of diabetes complications in GP-centered healthcare. AB - OBJECTIVES: To compare the development of diabetes complications, measured in terms of clinical end points, of patients enrolled in general practitioner (GP) centered healthcare (Hausarztzentrierte Versorgung [HZV]) and patients in usual GP care (non-HZV) over 4 years. STUDY DESIGN: Retrospective closed cohort study based on German claims data. METHODS: The main end points in our evaluation were dialysis, blindness, amputation, stroke, myocardial infarction, cardiovascular disease, hypoglycemia, and mortality. We used Cox proportional hazards regression models for multivariable analysis. RESULTS: We included 217,964 patients in our study: 119,355 were enrolled in HZV and 98,609 were in non-HZV. Compared with non HZV, the HZV group had a 15.6% lower risk of requiring dialysis during the 4 years of observation. Risks were also lower in the HZV group for all other end points except mortality. CONCLUSIONS: The results of the present study indicate that GP-centered healthcare is associated with a delay in the occurrence of serious diabetes complications and reduces the risk of diabetes complications. This may be because GP-centered care is associated with improved coordination of care. PMID- 30020752 TI - Differences in spending on provider-administered chemotherapy by site of care in Medicare. AB - OBJECTIVES: To compare Medicare spending on provider-administered chemotherapy in hospital outpatient departments (HOPDs) and physician offices after controlling for cancer type. STUDY DESIGN: Secondary data analysis. METHODS: We used 2010 2013 claims data for a random sample of Medicare fee-for-service beneficiaries who had cancer and received chemotherapy services either in physician offices or in HOPDs. We constructed 2 spending measures: (1) spending on chemotherapy drugs and (2) spending on chemotherapy administration. Each spending measure was the allowed payment, which includes both Medicare reimbursement and patient out-of pocket spending. We compared the spending measures in the 2 care settings using regression analysis to control for certain patient risk factors, including cancer type. We also compared the number of chemotherapy and administration claims per beneficiary and spending per claim by cancer type to understand differences in utilization patterns in the 2 care settings. RESULTS: Risk-adjusted chemotherapy drug spending per beneficiary was $2451 lower in HOPDs compared with physician offices. Risk-adjusted chemotherapy administration spending was $322 higher in HOPDs than in physician offices. Patients in physician offices received chemotherapy drugs more frequently than those in HOPDs. However, the chemotherapy spending per claim line was higher in HOPDs than physician offices. CONCLUSIONS: Chemotherapy drug spending per Medicare beneficiary was lower in HOPDs than in physician offices, driven by less frequent use of chemotherapy in HOPDs. As the site of provider-administered chemotherapy shifts from physician offices to HOPDs, continuing assessment of cancer care spending by site of care is necessary. PMID- 30020753 TI - Examining differential performance of 3 medical home recognition programs. AB - OBJECTIVES: We examined differences in patient outcomes associated with 3 patient centered medical home (PCMH) recognition programs-National Committee for Quality Assurance (NCQA) Level 3, The Joint Commission (TJC), and Accreditation Association for Ambulatory Health Care (AAAHC)-among Medicare beneficiaries receiving care at federally qualified health centers (FQHCs). STUDY DESIGN: We used data from CMS' FQHC Advanced Primary Care Practice Demonstration, in which participating FQHCs received assistance to achieve NCQA Level 3 PCMH recognition. We assessed the impact of the 3 recognition programs on utilization, quality, and Medicare expenditures using a sample of 1108 demonstration and comparison FQHCs. METHODS: Using propensity-weighted difference-in-differences analyses, we compared changes in outcomes over 3 years for beneficiaries attributed to FQHCs that achieved each type of recognition relative to beneficiaries attributed to FQHCs that did not achieve recognition. RESULTS: Recognized FQHCs, compared with nonrecognized FQHCs, were associated with significant 3-year changes in FQHC visits, non-FQHC primary care visits, specialty visits, emergency department (ED) visits, hospitalizations, a composite diabetes process measure, and Medicare expenditures. Changes varied in direction and strength by recognition type. In year 3, compared with nonrecognized sites, NCQA Level 3 sites were associated with greater increases in ambulatory visits and quality and greater reductions in hospitalizations and expenditures (P <.01), TJC sites were associated with significant reductions in ED visits and hospitalizations (P <.01), and AAAHC sites had changes in the opposite direction of what we anticipated. CONCLUSIONS: Heterogeneous changes in beneficiary utilization, quality, and expenditures by recognition type may be explained by differences in recognition criteria, evaluation processes, and documentation requirements. PMID- 30020754 TI - Prices for physician services in Medicare Advantage versus traditional Medicare. AB - OBJECTIVES: To compare the prices paid to physicians by employer-sponsored Medicare Advantage (MA) plans with those paid by traditional Medicare (TM) and to determine whether the relationship between MA and TM prices is affected by the generosity of MA benchmarks. STUDY DESIGN: Descriptive analysis of medical claims data from the 2014-2015 MarketScan Medicare Claims Database. METHODS: We focus on claims for low-complexity office visits with an established patient (Current Procedural Terminology [CPT] code 99213) and electrocardiograms (CPT code 93000). For a given service, we identify the prices paid by MA plans and by TM in a metropolitan statistical area (MSA), which is our definition of a market. We then construct an MA-to-TM price ratio for each MSA and report the median price ratio. In a subanalysis, we disaggregate the result for office visits by MA benchmark generosity. RESULTS: For both services, the estimated median price ratio is close to 1.00. We also find that even as MA benchmarks (relative to local fee-for service spending) increase, the median price ratio for office visits remains close to 1.00. CONCLUSIONS: After analyzing claims for common physician services, we find that employer-sponsored MA plans pay prices that are similar to TM rates. This holds even as the generosity of MA plan payment changes. Similarity between MA and TM prices appears to be stable over time, despite recent policy changes. Our findings emphasize the important role that TM plays in the MA market and that TM payment changes could have a spillover effect on MA prices and spending. PMID- 30020755 TI - Forgotten patients: ACO attribution omits those with low service use and the dying. AB - OBJECTIVES: Alternative payment models, such as accountable care organizations, hold provider groups accountable for an assigned patient population, but little is known about unassigned patients. We compared clinical and utilization profiles of patients attributable to a provider group with those of patients not attributable to any provider group. STUDY DESIGN: Cross-sectional study of 2012 Medicare fee-for-service beneficiaries 21 years and older. METHODS: We applied the Medicare Shared Savings Program attribution approach to assign beneficiaries to 2 mutually exclusive categories: attributable or unattributable. We compared attributable and unattributable beneficiaries according to demographics, dual eligibility for Medicaid, nursing home residency, clinical comorbidities, annual service utilization, annual spending, and 1- and 2-year mortality. We estimated multivariate regression models describing correlates of attribution status. RESULTS: Most beneficiaries (88%) were attributable to a provider group. The remaining 12% were unattributable. Beneficiaries unattributable to any provider group were more likely to be younger, male, and from a minority group; to have disability as the basis for enrollment; and to live in high-poverty areas. Unattributable beneficiaries included 3 distinct subgroups: nonusers of care, decedents, and those with healthcare service use but no qualifying evaluation and management visits. Many unattributable Medicare beneficiaries had minimal use of healthcare services, with the exception of a small subgroup of beneficiaries who died within the attribution year. CONCLUSIONS: Attribution approaches that more fully capture unattributable patients with low service use and patients near the end of life should be considered to reward population health efforts and improve end-of-life care. PMID- 30020756 TI - Postdischarge engagement decreased hospital readmissions in Medicaid populations. AB - OBJECTIVES: To investigate the effect of managed care organization (MCO) implemented postdischarge engagement, supported by other broadly focused interventions, on 30-day hospital readmissions in 6 at-risk Medicaid populations. STUDY DESIGN: Prospective cohort study. METHODS: One-year follow-up analysis of member claims data was performed following an intervention period from January 1, 2014, to December 31, 2014. Postdischarge engagement, supported by additional MCO initiated interventions, was implemented to reduce 30-day hospital readmissions in Medicaid members having 1 or more dominant chronic conditions. Hospital readmission rates were calculated at baseline and at 1 year post intervention. Bivariable and multivariable generalized estimating equation analysis was used to quantify the likelihood of hospital readmissions. RESULTS: Following implementation, postdischarge engagement rates increased significantly, whereas provider follow-up rates remained unchanged. Increased member engagement resulted in statistically significant reductions in weighted readmission rates enterprise wide (-10.1%; P <.01) and in 3 of 6 MCOs (-3.9% to -15.8%; P <=.05) in 2014. Compared with nonparticipants, members who were successfully reached for postdischarge engagement displayed a 33% decrease in 30-day readmissions enterprise-wide (adjusted odds ratio, 0.67; 95% CI, 0.62-0.73) and a comparable decrease (-23% to -39%) in 5 of the 6 MCOs. In this context, greater frequency of postdischarge engagement was associated with proportionally decreased likelihood of readmissions. CONCLUSIONS: Postdischarge engagement, against the backdrop of multifaceted MCO-implemented interventions, was associated with significantly reduced hospital readmissions in at-risk Medicaid subjects. Reduced likelihood of readmissions was observed at both the enterprise-wide and plan levels in a manner proportional to the frequency of engagement, a novel reported outcome for this population. PMID- 30020757 TI - ACOs with risk-bearing experience are likely taking steps to reduce low-value medical services. AB - OBJECTIVES: Accountable care organizations (ACOs) are groups of healthcare providers responsible for quality of care and spending for a defined patient population. The elimination of low-value medical services will improve quality and reduce costs and, therefore, ACOs should actively work to reduce the use of low-value services. We set out to identify ACO characteristics associated with implementation of strategies to reduce overuse. STUDY DESIGN: Survey analysis. METHODS: We used the National Survey of ACOs to determine the percentage of responding ACOs aware of the Choosing Wisely campaign and to what degree ACOs have taken steps to reduce the use of low-value services. We identified characteristics of ACOs associated with implementing low-value care-reducing strategies using 3 statistical models (stepwise and LASSO logistic regression and random forest). RESULTS: Responding executives of 155 of 267 ACOs (58%) were aware of Choosing Wisely. Eighty-four of those 155 ACO leaders said that their ACOs also actively implemented strategies to reduce the use of low-value services, largely through educating physicians and stimulating shared decision making. All 3 models identified the presence of at least 1 commercial payer contract and prior joint experience pursuing risk-based payment contracts as the most important predictors of an ACO actively implementing strategies to reduce low-value care. CONCLUSIONS: In the first year of implementation, just one-third of ACOs had taken steps to reduce the use of low-value medical services. Safety net ACOs and those with little experience as a risk-bearing organization need more time and support from healthcare payers and the Choosing Wisely campaign to prioritize the reduction of overuse. PMID- 30020758 TI - Trends in primary care encounters across professional roles in PCMH. AB - OBJECTIVES: Team-based care models, including the patient-centered medical home (PCMH), are increasingly promoted to improve the delivery of primary care. However, evaluation measures are often reported at a clinic or primary care provider (PCP) level, creating challenges in describing and analyzing the use and impact of non-PCP clinician team members. Thus, we aimed to measure clinician specific care delivery trends and determine whether trends were responsive to systemwide PCMH implementation. STUDY DESIGN: Interrupted time-series analysis of 57 million primary care encounters among 5 million veterans at 764 Veterans Health Administration primary care clinics from 2009 to 2013. METHODS: Retrospective data identified patient encounters attributable to 12 types of clinicians, yielding an encounters-by-clinician metric. Negative binomial regression modeled the monthly clinic-level rates of encounters for each type of clinician, before and during PCMH implementation. RESULTS: Over 5 years, the percentage of encounters by non-PCP clinicians increased from 29% to 35%. Monthly encounter rates for nurses and social workers significantly increased by 0.5% and 1.3%, respectively, after the introduction of PCMH, whereas PCP encounter rates significantly decreased over time. Encounter trends for pharmacists, nutritionists, and behavioral health clinicians did not significantly change. CONCLUSIONS: This study demonstrated the feasibility of capturing care delivered by a full complement of team members using routinely collected data. Findings suggest that the proportions of care delivered by non-PCP clinicians were sensitive to a change in care delivery model. As team-based care models expand, availability and use of metrics that account for care by all team members are critical for inferring clinician-related effects on outcomes. PMID- 30020759 TI - Inpatient placement: associations with mortality, cost, and length of stay. AB - OBJECTIVES: Tertiary referral centers have created inpatient units to meet the needs of specific patient populations but sometimes are forced to place patients on other units that, although having the basic necessary skillsets for treating the patient, are not focused on that diagnosis area. The objective of this study was to look at outcomes of patients admitted to these different inpatient settings. STUDY DESIGN: Retrospective review of patient data from a single tertiary academic medical center from August 1, 2014, to June 30, 2015, comparing patients admitted to primary versus secondary inpatient services. Patients admitted to the inpatient children's hospital, psychiatric hospital, labor and delivery unit, or subacute transitional care unit were excluded. METHODS: Demographics of patients in the primary versus secondary units were compared to look for systematic differences between the 2 patient populations. To control for confounding variables, a gamma regression analysis was conducted for length of stay (LOS) and total cost, whereas a logistic regression was conducted for mortality. RESULTS: Admitting to the primary unit resulted in 5.5% lower observed LOS, controlling for other patient variables, but it came at a 17.8% higher total cost of care provided compared with secondary units. Mortality was also found to be lower on primary units (odds ratio, 0.864) but did not cross the threshold of statistical significance (P = .101). CONCLUSIONS: Patients admitted to the primary unit had a lower LOS with higher costs of care. There was a trend toward improved mortality, although it was not statistically significant. PMID- 30020760 TI - Defect States Control Effective Band Gap and Photochemistry of Graphene Quantum Dots. AB - Graphene quantum dots (GQDs) have emerged as a new group of quantum-confined semiconductors in recent years, with possible applications as light absorbers, luminescent labels, electrocatalysts, and photoelectrodes for photoelectrochemical water splitting. However, their semiconductor characteristics, such as the effective band gap, majority carrier type, and photochemistry, are obscured by defects in this material. Herein, we use surface photovoltage spectroscopy (SPS) in combination with photoelectrochemical measurements to determine the parameters that are essential to the use of GQDs as next-generation semiconductor devices and photocatalysts. Our results show that ordered GQDs (1-6 nm) behave as p-type semiconductors, based on the positive photovoltage in the SPS measurements on Al, Au, and fluorine-doped tin oxide substrates, and generate mobile charge carriers under excitation of defect states at 1.80 eV and under band gap excitation at 2.62 eV. Chemical reduction with hydrazine removes some defects and increases the effective band gap to 2.92 eV. SPS measurements in the presence of sacrificial electron donor and acceptors show that photochemical charge carriers can be extracted and promote redox reactions. A reduced GQDs photocathode supports an unprecedented photocurrent of 50 MUA cm-2 using K3Fe(CN)6 as sacrificial electron acceptor. Additionally, while pristine GQDs do not photoreduce protons under visible light, hydrazine-treated GQDs generate H2 from aqueous methanol under visible and UV light (0.04% quantum efficiency at 375 nm) without added co-catalysts. These findings are relevant to the use of GQDs in photochemical and photovoltaic energy-conversion systems. PMID- 30020761 TI - Mixed-Valence Cobalt(II/III) Metal-Organic Framework for Ammonia Sensing with Naked-Eye Color Switching. AB - The construction of colorimetric sensing materials with high selectivity, low detection limits, and great stability provides a significant way for facile device implementation of an ammonia (NH3) sensor. Herein, with excellent alkaline stability and exposed N sites in molecule as well as with naked-eye color switching nature generated from changeable cobalt (Co) valence, a three dimensional mixed-valence cobalt(II/III) metal-organic framework (FJU-56) with tris-(4-tetrazolyl-phenyl)amine (H3L) ligand was synthesized for colorimetric sensing toward ammonia. The activated FJU-56 demonstrates a limit of detection of 1.38 ppm for ammonia sensing, with high selectivity in ammonia and water competitive adsorption, and shows outstanding stability and reversibility in the cyclic test. The NH3 or water molecules binding to the exposed N sites with the hydrogen-bond are observed by single-crystal X-ray diffraction, determining that the attachment of guest molecules to the FJU-56 framework changes the valence of Co ions with a naked-eye color switching response, which provides an ocular demonstration for ammonia capture and a valuable insight into ammonia sensing. PMID- 30020762 TI - Expanding Interlayer Spacing of Hard Carbon by Natural K+ Doping to Boost Na-Ion Storage. AB - Heteroatom-doped carbon is an attractive material for anodes in lithium-/sodium ion batteries as a replacement for traditional graphite anodes. However, the complex fabrication process and high cost limit practical applications of these carbon materials. Here, we report a low-cost, natural potassium-doped carbon material, which is directly carbonized from the coconut endocarp-a kind of high potassium-containing biomass material. The obtained carbon structure features an expanded d(002)-spacing (0.4 nm) originating from the superhigh potassium content (6654 mg kg-1). Because of the improvement on charge transfer kinetics and electrical properties, the potassium-doped carbon anode exhibits promising electrochemical performance in sodium-ion batteries, including high initial reversible capacity (314 mAh g-1) and good cycle stability (289 mAh g-1 after 200 cycles). Additionally, this work opens up a new approach for the design of heteroatom-doped carbon materials from the viewpoint of being naturally environmental friendly. PMID- 30020763 TI - High-Performance and Lightweight Thermal Management Devices by 3D Printing and Assembly of Continuous Carbon Nanotube Sheets. AB - Free-standing carbon nanotube films or buckypaper can provide a significant platform to develop practical applications of nanocarbon materials. For this research, buckypaper with high thermal conductivity (20 W/m K) and large surface area (350 m2/g) was mass produced in-house to investigate for use in lightweight thermal management devices. Floating catalyst chemical vapor deposition carbon nanotube sheets were also studied in this work. We introduced two manufacturing techniques to use the sheets for heat dissipation: (1) printing conductive composite ink on the sheets to make lightweight thermal devices, such as heat sinks and (2) assembling the sheets directly into 3D structures that were mounted on the back of heat-generating devices. These manufacturing techniques resulted in extremely lightweight, high-performance heat dissipation devices compared with other heat sink materials. PMID- 30020764 TI - Proton-Rocking-Chair-Type Redox Capacitors Based on Indium Tin Oxide Electrodes with Multilayer Films Containing Ru Complexes. AB - A rechargeable proton-rocking-chair-type redox capacitor was fabricated using scalable layer-by-layer-(LbL)-assembled films composed of two dinuclear Ru complexes that exhibit proton-coupled electron-transfer (PCET) reactions with different Ru(II/III) redox potentials (RuNH-OH and RuCH-OH). RuNH-OH and RuCH-OH contain different coordination environments that involve two phosphonate linker ligands at both ends and bridging 2,6,2',6'-tetrakis(benzimidazol-2-yl)-4,4' bipyridine or 1,3,1',3'-tetrakis(benzimidazol-2-yl)-5,5'-biphenyl ligands, respectively. The molecular units were assembled onto indium tin oxide (ITO) electrodes by complexation between the phosphonate groups and zirconium(IV) ions. The LbL growing process of these multilayer films was monitored by electrochemical or UV-vis spectroscopic measurements. The thus obtained LbL films on the ITO electrodes showed PCET reactions at different potentials, depending on the bridging ligands. The introduction of cyclometalated Ru-C bonds in the bridging ligand of RuCH-OH led to the stabilization of the ruthenium(III) oxidation state, and therefore, RuCH-OH exhibited lower p Ka values for the imino N-H protons in the bridging benzimidazole groups compared to those of the corresponding RuNH-OH complex. The proton movements that accompany the redox reaction in the Ru multilayer films on the ITO electrode were confirmed using a pH indicator probe. For the performance test of a proton-rocking-chair-type redox capacitor, a two-electrode system composed of RuNH-OH and RuCH-OH multilayer films on ITO electrodes was examined in an aqueous solution of NaClO4. Under galvanostatic conditions, stable, reversible, and repeatable charging/discharging processes occurred. The capacitance increased with an increasing number of LbL layers. For comparison, a similar redox capacitor composed of two RuNMe-OH and RuCMe-OH analogues, in which all four imino N-H protons on the benzimidazole moieties are protected by N-Me groups, was constructed and examined. In these complexes, the capacitance decreased by 77% compared to the PCET-type capacitor composed of a cell containing RuNH-OH and RuCH-OH; this result strongly suggests that the proton movement plays a more important role for the charge storage than the anion movement. In such LbL films composed of Ru complexes that exhibit PCET type redox reactions, the capacitance is drastically improved with an increasing number of layers and using protons as charge carriers. PMID- 30020765 TI - Dihydroindenofluorene Positional Isomers. AB - Bridged oligophenylenes are very important organic semiconductors (OSCs) in organic electronics (OE). The fluorene unit, which is a bridged biphenyl, is the spearhead of this class of materials and has, over the last 20 years, led to fantastic breakthroughs in organic light-emitting diodes. Dihydroindenofluorenes belong to the family of bridged terphenyls and can be viewed as the fusion of a fluorene unit with an indene fragment. Dihydroindenofluorenes have also appeared as very promising building blocks for OE applications. In the dihydroindenofluorene family, there are five positional isomers, with three different phenyl linkages ( para/ meta/ ortho) and two different ring bridge arrangements ( anti/ syn). We have focused on the concept of positional isomerism. Indeed, the structural differences of the dihydroindenofluorenyl cores lead to unusual electronic properties, which our group has described since 2006, thanks to the five dispirofluorene-indenofluorene positional isomers (dihydroindenofluorenes substituted on the bridges by fluorenyl units). 6,12 Dihydroindeno[1,2- b]fluorene (the para-anti isomer) is constructed on a p terphenyl core and possesses an anti geometry. Although this isomer has been widely investigated over the last 20 years, studies of the four other isomers remain very scarce. 11,12-Dihydroindeno[2,1- a]fluorene (the para-syn isomer) is also built on a bridged p-terphenyl core but possesses a syn geometry. This particular geometry has been advantageously used by our group to drastically tune the electronic properties, and this isomer has emerged as a promising scaffold to obtain stable blue emission arising from conformationally controllable intramolecular excimers. These preliminary studies have shown the crucial influence of the geometry on the electronic properties of the dihydroindenofluorenes. Modification of the arrangement of the phenyl linkages from para to meta provides the meta isomers, namely, 7,12-dihydroindeno[1,2- a]fluorene (the meta-anti isomer) and 5,7-dihydroindeno[2,1- b]fluorene (the meta syn isomer). With these two regioisomers, the strong impacts of both the linkage and the geometry on the electronic properties have been particularly highlighted over the years. The last positional isomer of the family is 5,8-dihydroindeno[2,1 c]fluorene, which possesses a central o-terphenyl backbone and a syn geometry. This isomer is unique because of its ortho linkage, which induces a particular helicoidal turn of the dihydroindenofluorenyl core. Using a structure-property relationship approach, in the present Account we describe the molecular diversity of the five dispirofluorene-indenofluorene positional isomers and the consequences both in terms of their organic synthesis and electronic properties. This Account shows how positional isomerism can be a powerful tool to tune the electronic properties of OSCs. PMID- 30020766 TI - Tough Reversible Adhesion Properties of a Dry Self-Cleaning Biomimetic Surface. AB - Geckos have one of the world's most efficient reversible adhesion systems. Even walking in dusty conditions, geckos can dislodge up to 80% of contaminants and recover their adhesion capability after walking as few as four steps. Thus far, artificial dry self-cleaning materials inspired by the geckos' hierarchical fibrillar structure have been only able to remove 55% of collected large particle contaminants with 30 steps. Challenges, including low mechanical strength, low stiffness, and short fatigue time keep these materials from being used in practical applications. This study involves the novel fabrication of dry self cleaning surfaces with a high mechanical performance and an outstanding dry self cleaning property. Imposing a load-drag-pull process similar to a gecko's foot adhesion process, our biomimetic surfaces could dislodge up to 59% of microparticles (~8 MUm) with as few as five steps. Furthermore, the surface had an excellent screening ability at low temperatures regardless of the surface roughness similarity. The surfaces were also proven to be scratch resistant. The biomimetic surfaces exhibit enhanced dry self-cleaning and mechanical properties and could be promising in applications such as reusable adhesives, biochips, aerospace satellite waste collection, and screening equipment. PMID- 30020767 TI - Tunable Multipolar Surface Plasmons in 2D Ti3C2 T x MXene Flakes. AB - 2D Ti3C2 T x MXenes were recently shown to exhibit intense surface plasmon (SP) excitations; however, their spatial variation over individual Ti3C2 T x flakes remains undiscovered. Here, we use scanning transmission electron microscopy (STEM) combined with ultra-high-resolution electron energy loss spectroscopy (EELS) to investigate the spatial and energy distribution of SPs (both optically active and forbidden modes) in mono- and multilayered Ti3C2 T x flakes. With STEM EELS mapping, the inherent interband transition in addition to a variety of transversal and longitudinal SP modes (ranging from visible down to 0.1 eV in MIR) are directly visualized and correlated with the shape, size, and thickness of Ti3C2 T x flakes. The independent polarizability of Ti3C2 T x monolayers is unambiguously demonstrated and attributed to their unusual weak interlayer coupling. This characteristic allows for engineering a class of nanoscale systems, where each monolayer in the multilayered structure of Ti3C2 T x has its own set of SPs with distinctive multipolar characters. Moreover, the tunability of the SP energies is highlighted by conducting in situ heating STEM to monitor the change of the surface functionalization of Ti3C2 T x through annealing at temperatures up to 900 degrees C. At temperatures above 500 degrees C, the observed fluorine (F) desorption multiplies the metal-like free electron density of Ti3C2 T x flakes, resulting in a monotonic blue-shift in the SP energy of all modes. These results underline the great potential for the development of Ti3C2 T x-based applications, spanning the visible-MIR spectrum, relying on the excitation and detection of single SPs. PMID- 30020768 TI - Laser Immunotherapy in Combination with Perdurable PD-1 Blocking for the Treatment of Metastatic Tumors. AB - A convenient and feasible therapeutic strategy for malignant and metastatic tumors was constructed here by combining photothermal ablation (PTA)-based laser immunotherapy with perdurable PD-1 blockade immunotherapy. Hollow gold nanoshells (HAuNS, a photothermal agent) and AUNP12 (an anti PD-1 peptide, APP) were co encapsulated into poly(lactic- co-glycolic) acid (PLGA) nanoparticles. Unlike monoclonal PD-1/PD-L1 antibodies, PD-1 peptide inhibitor shows lower cost and immunotoxicity but needs frequent administration due to its rapid clearance in vivo. Our data here showed that the formed HAuNS- and APP-loaded PLGA nanoparticles (AA@PN) could maintain release periods of up to 40 days for the peptide, and a single intratumoral injection of AA@PN could replace the frequent administration of free APP. After the administration of AA@PN and irradiation with a near-infrared laser at the tumor site, an excellent killing effect on the primary tumor cells was achieved by the PTA. The nanoparticles also played a vaccine-like role under the adjuvant of cytosine-phospho-guanine (CpG) oligodeoxynucleotide and generated a localized antitumor-immune response. Furthermore, sustained APP release with laser-dependent transient triggering could induce the blockage of PD-1/PD-L1 pathway to activate T cells, thus subsequently generating a systemic immune response. Our data demonstrated that the PTA combined with perdurable PD-1 blocking could efficiently eradicate the primary tumors and inhibit the growth of metastatic tumors as well as their formation. The present study provides a promising therapeutic strategy for the treatment of advanced cancer with metastasis and presents a valuable reference for obtaining better outcomes in clinical cancer immunotherapy. PMID- 30020769 TI - Enhancing Gas Sorption and Separation Performance via Bisbenzimidazole Functionalization of Highly Porous Covalent Triazine Frameworks. AB - In this paper, a series of bisbenzimidazole-functionalized highly porous covalent triazine frameworks (CTF-BIBs) has been constructed from a new organic building block, 1,4-bis(5-cyano-1 H-benzimidazole-2-yl)benzene, via ionothermal polymerization. The physical porosity and gas adsorption properties of these CTF BIBs were characterized, and the resulting CTF-BIBs exhibit significantly high Brunauer-Emmett-Teller surface areas (1636-2088 m2 g-1) and notable CO2 uptakes (86.4-97.6 cm3 g-1 at 273 K and 1 bar; 48.5-56.8 cm3 g-1 at 298 K and 1 bar). More importantly, these CTF-BIBs exhibit excellent selective separation abilities for CO2/N2, CO2/CH4, C2H6/CH4, and C3H8/CH4, particularly for equimolar mixtures C3H8/CH4 (386.6 for CTF-BIB-1 under 1 bar and 298 K). Furthermore, transient breakthrough simulations were carried out for equimolar CO2/C3H8/C2H6/CH4 mixtures, and CTF-BIBs display good separation performance in industrial fixed bed adsorbers. These results clearly demonstrate that the synthesized CTF-BIBs may serve as potential materials for CO2 capture and adsorptive separation for small hydrocarbons. PMID- 30020771 TI - Nanosizing Noncrystalline and Porous Silica Material-Naturally Occurring Opal Shale for Systemic Tumor Targeting Drug Delivery. AB - Opal shale, as a naturally occurring and noncrystalline silica material with porous structure, has the potential to be a drug delivery carrier. In this study, we obtained opal shale nanoparticles (OS NPs) through the techniques of ultrasonic emulsion and differential centrifugation. The OS NPs exhibited markedly lower cytotoxicity than crystalline mesoporous silica nanoparticles. The highly porous structure and the strong adsorbability endowed OS NPs with the ability of loading and sustained release of doxorubicin (DOX). DOX-loaded OS NPs improved tumor cellular uptake and antiproliferation compared with free drug. Interestingly, OS NPs possessed strong binding with the nuclear envelope, which can be beneficial to the nucleus localization and apoptosis inducing of loaded DOX. We further demonstrated the tumor passive targeting ability, prolonged blood circulation, and enhanced antitumor effect with limited in vivo toxicity. Our results suggest that OS NPs can be applied for tumor targeting drug delivery, which may have a significant influence on the development of silica-based drug delivery system. PMID- 30020770 TI - Effective Neural Photostimulation Using Indium-Based Type-II Quantum Dots. AB - Light-induced stimulation of neurons via photoactive surfaces offers rich opportunities for the development of therapeutic methods and high-resolution retinal prosthetic devices. Quantum dots serve as an attractive building block for such surfaces, as they can be easily functionalized to match the biocompatibility and charge transport requirements of cell stimulation. Although indium-based colloidal quantum dots with type-I band alignment have attracted significant attention as a nontoxic alternative to cadmium-based ones, little attention has been paid to their photovoltaic potential as type-II heterostructures. Herein, we demonstrate type-II indium phosphide/zinc oxide core/shell quantum dots that are incorporated into a photoelectrode structure for neural photostimulation. This induces a hyperpolarizing bioelectrical current that triggers the firing of a single neural cell at 4 MUW mm-2, 26-fold lower than the ocular safety limit for continuous exposure to visible light. These findings show that nanomaterials can induce a biocompatible and effective biological junction and can introduce a route in the use of quantum dots in photoelectrode architectures for artificial retinal prostheses. PMID- 30020772 TI - Pharmacology and Therapeutic Potential of the 5-HT7 Receptor. AB - It is well-documented that serotonin (5-HT) exerts its pharmacological effects through a series of 5-HT receptors. The most recently identified member of this family, 5-HT7, was first identified in 1993. Over the course of the last 25 years, this receptor has been the subject of intense investigation, and it has been demonstrated that 5-HT7 plays an important role in a wide range of pharmacological processes. As a result of these findings, modulation of 5-HT7 activity has been the focus of numerous drug discovery and development programs. This review provides an overview of the roles of 5-HT7 in normal physiology and the therapeutic potential of this interesting drug target. PMID- 30020773 TI - Significantly Improving Lithium-Ion Transport via Conjugated Anion Intercalation in Inorganic Layered Hosts. AB - Layered hydroxides (LHs) have emerged as an important class of functional materials owing to their unusual physicochemical properties induced by various intercalated species. While both the electrochemistry and interlayer engineering of the materials have been reported, the role of interlayer engineering in improving the Li-ion storage of these materials remains unclear. Here, we rationally introduce pillar ions with conjugated anion dicarboxylate groups, cobalt oxalate ions ([CoOx2]2-), into the interlayers of Co(OH)2 nanosheets [denoted as I-Co(OH)2 NSs]. The pillar ion guarantees excellent structural stability, high electrical conductivity, and accelerated Li-ion diffusion. The structure delivers high-rate cycling performance for lithium-ion batteries. This work provides insights for the design of LH-based high-performance electrode materials by a rational interlayer-engineering strategy. PMID- 30020774 TI - Tracking the Sources of Antibiotic Resistance Genes in an Urban Stream during Wet Weather using Shotgun Metagenomic Analyses. AB - Stormwater runoff has been known to cause increases in bacterial loadings in urban streams. However, little is known about its impacts on antibiotic resistance genes (ARGs) in urban watersheds. This study was performed to characterize the ARG composition of various environmental compartments of an urban watershed and to quantify their contributions of microbes and ARGs to an urban stream under wet weather conditions. Shotgun metagenomic results showed that the ARG abundance in wet weather flow was significantly higher than in base flow. Multidrug resistance genes were the most common ARG type across environmental samples. Vancomycin resistance genes were abundant in embankment soil and street sweeping samples. Analyses using SourceTracker estimated storm drain outfall water to be the biggest contributor of microbes (54-57%) and ARGs (82-88%) in the urban stream during wet weather flows. Furthermore, results on street sweepings showed that wash-off from streets was the biggest known contributor of microbes (41-45%) and ARGs (92-96%) in storm drain outfall water. Pantoea and Pseudomonas were associated with the highest numbers of ARGs and were most abundant in stormwater-related samples. Results from this study can advance our knowledge about ARGs in urban streams, an important medium linking environmental ARGs to the general public. PMID- 30020775 TI - Climatic Influence on Temporal Trends of Polychlorinated Biphenyls and Organochlorine Pesticides in Landlocked Char from Lakes in the Canadian High Arctic. AB - Temporal trends and climate related parameters affecting the fate of legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were examined in landlocked Arctic char from four lakes in the Canadian Arctic. Among biological parameters, lipid content was a key factor explaining the concentration of most POPs in Arctic char. Legacy PCBs and OCPs generally showed declining trends of concentrations in Arctic char, consistent with past restriction on uses and emissions of POPs. However, increases in lake primary productivity (measured as chlorophyll a) exerted a dilution effect on POPs concentrations in Arctic char. Concentrations of POPs in char from the last two decades were positively correlated with interannual variations of the North Atlantic Oscillation (NAO). Higher concentrations of POPs in Arctic char were observed in 3 of the 4 lakes during positive NAO phases. This, together with increasing local Arctic temperatures, could lead to increases on POPs concentrations in char from remote Arctic Lakes in future decades. Also, if there are nearby secondary sources as may be the case for Resolute Lake, located near an airport where increasing levels were found for hexachlorobenzene and toxaphene, probably due to the mobilization from secondary sources in soils. PMID- 30020776 TI - Metal Reactivity in Laboratory Burned Wood from a Watershed Affected by Wildfires. AB - We investigated interfacial processes affecting metal mobility by wood ash under laboratory-controlled conditions using aqueous chemistry, microscopy, and spectroscopy. The Valles Caldera National Preserve in New Mexico experiences catastrophic wildfires of devastating effects. Wood samples of Ponderosa Pine, Colorado Blue Spruce, and Quaking Aspen collected from this site were exposed to temperatures of 60, 350, and 550 degrees C. The 350 degrees C Pine ash had the highest content of Cu (4997 +/- 262 mg kg-1), Cr (543 +/- 124 mg kg-1), and labile dissolved organic carbon (DOC, 11.3 +/- 0.28 mg L-1). Sorption experiments were conducted by reacting 350 degrees C Pine, Spruce, and Aspen ashes separately with 10 MUM Cu(II) and Cr(VI) solutions. Up to a 94% decrease in Cu(II) concentration was observed in solution while Cr(VI) concentration showed a limited decrease (up to 13%) after 180 min of reaction. X-ray photoelectron spectroscopy (XPS) analyses detected increased association of Cu(II) on the near surface region of the reacted 350 degrees C Pine ash from the sorption experiments compared to the unreacted ash. The results suggest that dissolution and sorption processes should be considered to better understand the potential effects of metals transported by wood ash on water quality that have important implications for postfire recovery and response strategies. PMID- 30020778 TI - Current State and New Trends in the Use of Cellulose Nanomaterials for Wastewater Treatment. AB - Nanotechnology has been identified as having great potential for improving the efficiency of water prevention and purification while reducing costs. In this field, two applications of nanocellulose have generated attention and have proven to be a sound strategy as an adsorbent and as a membrane for the removal of contaminants. This potential is attributed to its high aspect ratio, high specific surface area, high capacity retention, and environmental inertness. In addition to the aforementioned advantages, the presence of active sites allows the incorporation of chemical moieties that may enhance the binding efficiency of pollutants to the surface. This review paper intends to understand how nanocellulose affects the adsorption behavior of water pollutants, e.g., heavy metal ions, microbes, dyes, and organic molecules, and is divided in two parts. First, a general overview of the different strategies for the preparation of nanocellulose is described, and its specific properties are reported. The second section reports some of its application as adsorbent nanomaterial or separation membrane. It appears that the use of nanocellulose for these applications is very promising for wastewater treatment industries. PMID- 30020777 TI - Selection between Diastereomeric Kinetic vs Thermodynamic Carbonyl Binding Modes Enables Enantioselective Iridium-Catalyzed anti-(alpha-Aryl)allylation of Aqueous Fluoral Hydrate and Difluoroacetaldehyde Ethyl Hemiacetal. AB - Enantioselectivity increases with increasing carbonyl electrophilicity in 2 propanol-mediated reductive couplings of aldehydes with branched aryl-substituted allylic acetates to form products of carbonyl anti-(alpha-aryl)allylation. This unusual phenomenon is caused by aldehyde coordination to diastereomeric kinetic vs thermodynamic carbonyl binding sites that deliver enantiomeric products. Exploiting this effect, anti-diastereo- and enantioselective (alpha aryl)allylations of fluoral hydrate and difluoroacetaldehyde ethyl hemiacetal were developed. PMID- 30020780 TI - Synthesis of Cyclic Organic Carbonates Using Atmospheric Pressure CO2 and Charge Containing Thiourea Catalysts. AB - Cycloadditions of epoxides with CO2 to synthesize cyclic five-membered ring organic carbonates are of broad interest from a synthetic, environmental, and green chemistry perspective, and the development of effective catalysts for these transformations is an ongoing challenge. A series of eight charge-containing thiourea salts that catalyze these reactions under mild conditions (i.e., 60 degrees C and atmospheric CO2 pressure) are reported. Substrate scope and mechanistic studies were also carried out, isotope effects were measured, and a reactive intermediate was isolated revealing a surprising pathway in which a thiourea catalyst serves as a nucleophile in the cleavage of the epoxide ring. PMID- 30020779 TI - Multiresidue Determination of the Anabolic-Agent Residues Steroids, Stilbenes, and Resorcylic Acid Lactones in Bovine Urine by GC-MS/MS with Microwave-Assisted Derivatization. AB - In this work, a GC-MS/MS method was developed for the determination of anabolic agent residues in bovine urine. The optimized sample preparation was as follows: enzymatic hydrolysis by beta-glucuronidase-sulfatase enzyme from Helix pomatia for 16 h at 37.5 degrees C, liquid-liquid extraction with diethyl ether, solid phase extraction with HLB and aminopropylsilane cartridges, and microwave assisted derivatization using 25 MUL of MSTFA/NH4I/ethanethiol and full microwave power for 2 min. The method was validated according to Decision 657/2002/EC, Codex Alimentarius, and Manual da Garantia da Qualidade Analitica guidelines. The acceptability criteria for quantitative analysis were met for alpha ethinylestradiol, alpha-nandrolone, beta-estradiol, beta-zearalanol, beta zearalenol, drostanolone, ethisterone, dienestrol, diethylstilbestrol, hexestrol, megestrol, methyltestosterone, and zearalenone. The analytes alpha-zearalenol, alpha-zearalanol, and norethandrolone were validated for qualitative analysis. PMID- 30020781 TI - Visible-Light Photocatalytic Difluoroalkylation-Induced 1, 2-Heteroarene Migration of Allylic Alcohols in Batch and Flow. AB - A convenient method for the preparation of sp3-rich heterocycles is reported. The method comprises a photocatalytic difluoroalkylation-induced 1,2-heteroarene migration of allylic alcohols. Here we describe for the first time the benefits of using flow to facilitate such migration reactions, including shorter reaction times, higher selectivities, and opportunities to scale the chemistry. PMID- 30020782 TI - Confirmation of the Revised Structure of Samoquasine A and a Proposed Structural Revision of Cherimoline. AB - The identity of the natural product samoquasine A has remained obscure since its isolation from custard apple seeds in 2000. One of the proposed structures, benzo[ f]phthalazin-4(3 H)-one, was prepared in two steps by regioselective ortho lithiation/formylation of N, N-diisopropyl-2-naphthylamide, followed by cyclization with hydrazine, but was shown to be different from the natural product. Perlolidine, another candidate structure, was synthesized by a novel route involving a beta-selective Heck reaction of butyl vinyl ether. Both perlolidine and samoquasine A are converted by trimethylsilyldiazomethane into the same N-methyl derivative. In addition, the 13C NMR spectra of perlolidine and another structurally mis-assigned natural product, cherimoline, are almost identical. Thus, both samoquasine A and cherimoline are actually perlolidine. PMID- 30020783 TI - Structure-Function Analysis of Immune Checkpoint Receptors to Guide Emerging Anticancer Immunotherapy. AB - The modulation of immune checkpoint receptors has been one of the most successful, exciting, and explored approaches for cancer immunotherapy. Currently, several immune checkpoint modulators, mainly monoclonal antibodies, are showing remarkable results. However, the failure to show a response in most patients and the induction of severe immune-related adverse effects are the major drawbacks. Novel approaches concerning the development of immune modulatory small molecules have emerged as an alternative. Nevertheless, the lack of structural information about immune checkpoint receptors has hindered the rational design of those small-molecule modulators by preventing the use of methodologies such as computer-aided drug design. Herein, we provide an overview and critical analysis of the structural and dynamic details of immune checkpoint receptors (cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and glucocorticoid-induced TNFR-related protein (GITR)) and their interaction with known modulators. This knowledge is essential to advance the understanding of their binding mode and guide the design of novel effective targeted anticancer medicines. PMID- 30020784 TI - Copper-Catalyzed Aerobic Oxidative [3+2] Annulation for the Synthesis of 5 Amino/Imino-Substituted 1,2,4-Thiadiazoles through C-N/N-S Bond Formation. AB - A copper-catalyzed aerobic oxidative annulation reaction of 2 aminopyridine/amidine with isothiocyanate has been reported. This strategy involving C-N/N-S bond formations provides various 5-amino/imino-substituted 1,2,4-thiadiazole derivatives under a Cu/O2 catalytic system. This method has demonstrated high reactivity, mild reaction conditions, and a broad substrate scope. Furthermore, the synthetic utilities of the approach are demonstrated by further modifications. PMID- 30020785 TI - Systematic Ligand Effects in the Reactions of Fe+(6D) and FeX+(5Delta) with CF3X (X = Cl, Br, I). Ion Mobility Measurements of FeX+(5Delta) (X = F, Cl, Br, I) in He. AB - The gas phase reactions of Fe+(6D) and FeX+(5Delta) with CF3X (X = Cl, Br, I) were examined using a selected-ion drift cell reactor under near-thermal energetic conditions. All reactions were carried out in a uniform electric field at a total pressure of 3.5 Torr at room temperature. In addition, reduced zero field mobilities were measured for FeX+(5Delta) (X = F, Cl, Br, I) in He, yielding values of 14.2 +/- 0.4, 13.7 +/- 0.3, 13.3 +/- 0.2, and 13.0 +/- 0.3 cm2.V-1.s-1, respectively. Fe+(6D) reacts slowly with CF3Cl and CF3Br, producing an adduct exclusively with the former and FeBr+ with the latter. Conversely, Fe+(6D) exhibits efficient chemistry with CF3I to yield FeI+, FeCF3+, and FeFI+ in parallel reactions. Dependent on the halogen, FeX+(5Delta) reactions display one or more of four different processes: F- abstraction, X- abstraction, halogen switching, and association. In general, the presence of the halogen ligand enhances the rate of reaction over that of Fe+(6D) with the same molecular substrate. With CF3Cl, this ligand effect is observed to vary systematically with the electron-withdrawing capability of the halogen. This is illustrated by the correlation between reaction efficiency and the charge distribution on FeX+(5Delta) as determined from DFT calculations. Specific reaction outcomes for the FeX+(5Delta) reactions lead to upper and lower bounds on XFe-Y bond strengths (X, Y = F, Cl, Br, I) that are generally consistent with one another and with known trends. PMID- 30020786 TI - Green and Black Tea Phenolics: Bioavailability, Transformation by Colonic Microbiota, and Modulation of Colonic Microbiota. AB - Monomeric green tea catechin (GTC) and oligomeric, oxidized black tea phenolic (BTP) have shown promising health benefits, although GTC has been more extensively studied than BTP. We review the current knowledge on bioavailability, colonic transformation, and gut microbiota modulatory effects of GTC and BTP. As a result of their similar poor bioavailability in the small intestine and potentially similar metabolites upon colonic fermentation, it seems as if GTC and BTP have similar health effects, although it cannot be excluded that they have different gut microbiota modulatory effects and that BTP gives a poorer yield of bioactive phenolic metabolites upon colonic fermentation than GTC. PMID- 30020787 TI - The All-Seeing Eye of Resonant Auger Electron Spectroscopy: A Study on Aqueous Solution Using Tender X-rays. AB - X-ray absorption and Auger electron spectroscopies are demonstrated to be powerful tools to unravel the electronic structure of solvated ions. In this work for the first time, we use a combination of these methods in the tender X-ray regime. This allowed us to address electronic transitions from deep core levels, to probe environmental effects, specifically in the bulk of the solution since the created energetic Auger electrons possess large mean free paths, and moreover, to obtain dynamical information about the ultrafast delocalization of the core-excited electron. In the considered exemplary aqueous KCl solution, the solvated isoelectronic K+ and Cl- ions exhibit notably different Auger electron spectra as a function of the photon energy. Differences appear due to dipole forbidden transitions in aqueous K+ whose occurrence, according to the performed ab initio calculations, becomes possible only in the presence of solvent water molecules. PMID- 30020788 TI - Investigation into the Solid-State Properties and Dissolution Profile of Spray Dried Ternary Amorphous Solid Dispersions: A Rational Step toward the Design and Development of a Multicomponent Amorphous System. AB - The formulation of oral amorphous solid dispersions (ASD) includes the use of excipients to improve physical stability and enhance bioavailability. Combinations of excipients (polymers and surfactants) are often employed in pharmaceutical products to improve the delivery of poorly water-soluble drugs. However, additive interactions in multicomponent ASD systems have not been extensively studied and may promote crystallization in an unpredictable manner, which in turn may affect the physical stability and dissolution profile of the product. The main aim of this study was to understand the effect of different surfactant and polymer combinations on the solid-state properties and dissolution behavior of ternary spray-dried solid dispersions of dipyridamole and cinnarizine. The surfactants chosen for this study were sodium dodecyl sulfate and poloxamer 188, and the model polymers used were polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose K100. The spray-dried ternary dispersions maintained higher supersaturation compared to either the crystalline drug equilibrium solubility or their respective physical mixtures. However, rapid and variable dissolution behavior was observed for different formulations. The maximum supersaturation level was observed with drug-polymer-polymer ternary dispersions. On the other hand, incorporating the surfactant into binary (drug polymer) and ternary (drug-polymer-polymer) ASDs adversely affected the physical stability and dissolution by promoting crystallization. On the basis of these observations, a thorough investigation into the impact of combinations of additives on amorphous drug crystallization during dissolution and stability studies is recommended in order to develop optimized formulations of supersaturating dosage forms. PMID- 30020789 TI - Diboron-Catalyzed Dehydrative Amidation of Aromatic Carboxylic Acids with Amines. AB - Tetrakis(dimethylamido)diboron and tetrahydroxydiboron are herein reported as new catalysts for the synthesis of aryl amides by catalytic condensation of aromatic carboxylic acids with amines. The developed protocol is both simple and highly efficient over a broad range of substrates. This method thus represents an attractive approach for the use of diboron catalysts in the synthesis of amides without having to resort to stoichiometric or additional dehydrating agents. PMID- 30020790 TI - Microscopic Mechanism of the Helix-to-Layer Transformation in Elemental Group VI Solids. AB - We study the conversion of bulk Se and Te, consisting of intertwined a helices, to structurally very dissimilar, atomically thin two-dimensional (2D) layers of these elements. Our ab initio calculations reveal that previously unknown and unusually stable delta and eta 2D allotropes may form in an intriguing multistep process that involves a concerted motion of many atoms at dislocation defects. We identify such a complex reaction path involving zipper-like motion of such dislocations that initiate structural changes. With low activation barriers ?0.3 eV along the optimum path, the conversion process may occur at moderate temperatures. We find all one-dimensional (1D) and 2D chalcogen structures to be semiconducting. PMID- 30020791 TI - A Rh-Catalyzed Air and Moisture Tolerable Aldehyde (Ketone)-Directed Fluorosulfonylvinylation of Aryl C( sp2)-H Bonds. AB - The first Rh-catalyzed activation of ortho sp2 C-H bonds of aldehydes (ketones) for monoselective coupling with ethenesulfonyl fluoride was accomplished without covalent or transient preinstallation of imines. The 42 examples revealed that the developed method has the advantage of a wide scope and functional-group tolerability. Application of this method for complicated natural product modification was also accomplished. PMID- 30020792 TI - Amino-Functionalized Mesoporous Silica Particles for Ocular Delivery of Brimonidine. AB - To treat glaucoma, conventional eye drops are often prescribed. However, the eye drops have limited effectiveness as a result of low drug bioavailability due to their rapid clearance from the preocular space. To resolve this, we proposed amino-functionalized mesoporous silica (AMS) particles as delivery carriers of the glaucoma drug, brimonidine. Because of the presence of mesopores, brimonidine (BMD) could be encapsulated in the AMS with a loading amount of 41.73 MUg/mg (i.e., drug loading capacity of about 4.17%) to give the BMD-AMS, which could release the drug in a sustained manner over 8 h. BMD-AMS was also shown to be mucoadhesive due to the presence of both hydroxyl and amino groups in the surface, allowing for formation of hydrogen bonds and an ionic complex with the mucin, respectively. Therefore, when topically administered to rabbit eyes in vivo, BMD-AMS could reside in the preocular space for up to 12 h because of its adherence to the mucous layer. To assess in vivo efficacy, we examined the variance in intraocular pressure (IOP) and brimonidine concentration in the aqueous humor (AH) after applying BMD-AMS to the eye, which was compared with that induced by Alphagan P, the marketed brimonidine eye drops. For BMD-AMS, the duration in the decrease in IOP and the area under the drug concentration in the AH-time curve (AUC) were 12 h and 2.68 MUg.h/mL, respectively, which were about twice as large as those obtained with Alphagan P; this finding indicated enhanced ocular bioavailability of brimonidine with BMD-AMS. PMID- 30020793 TI - Nototronesides A-C, Three Triterpene Saponins with a 6/6/9 Fused Tricyclic Tetranordammarane Carbon Skeleton from the Leaves of Panax notoginseng. AB - Three triterpene saponins, nototronesides A-C (1-3), possessing an unprecedented 6/6/9 fused tricyclic tetranordammarane core, were isolated from the leaves of Panax notoginseng. Their structures were elucidated on the basis of spectroscopic data, and the structure of sapogenin (1a) was further confirmed by X-ray crystallography. The existence of 1-3 adds a new dimension to the diversity of the triterpene family. Moreover, compound 2 showed a moderate neuroprotective effect on serum deficiency-induced cellular damage in PC12 cells. PMID- 30020794 TI - The Role of Glass Transition Temperatures in Coamorphous Drug-Amino Acid Formulations. AB - The improved physical stability associated with coamorphous drug-amino acid (AA) formulations may indicate a decrease in mobility of the amorphous drug molecules, compared to the neat amorphous form of the drug. Since the characteristic glass transition temperatures ( Tgalpha and Tgbeta) represent molecular mobility in amorphous systems, we aimed to characterize Tgalpha and Tgbeta and to determine their role in physical stability as well as their potential usefulness to determine the presence of an excess component (either drug or AA) in coamorphous systems. Indomethacin (IND)-tryptophan (TRP) and carvedilol (CAR)-TRP were used as model coamorphous systems. The analytical techniques used were X-ray powder diffractometry (XRPD) to determine the solid-state form, dynamic mechanical analysis (DMA) to probe Tgalpha and Tgbeta, and differential scanning calorimetry (DSC) to probe thermal behavior of the coamorphous systems. Tgalpha analysis showed a gradual monotonous increase in Tgalpha values with increasing AA concentration, and this increase in the Tgalpha value is not the cause of the improved physical stability. The Tgbeta analysis for the IND-TRP sample with 10% drug had a Tgbeta of 226.8 K, and samples with 20-90% drug had similar Tgbeta values around 212.5 K. For CAR-TRP, samples with 10-40% drug had similar Tgbeta values around 230.5 K, and samples with 50-90% drug had similar Tgbeta values around 223.3 K. The similar Tgbeta values in coamorphous systems at different drug ratios indicate that they in fact are the Tgbeta of the component that is in excess to an ideal drug-AA coamorphous mixture. DSC and XRPD analysis showed that for IND-TRP, IND is in excess if the drug concentration is 30% or above and will eventually recrystallize. For CAR-TRP, CAR is in excess and recrystallizes when the drug concentration is 50% or above. We have proposed a means of estimating, on the basis of Tgbeta, which drug to AA ratios will lead to optimally physically stable coamorphous systems that can be considered for further development. PMID- 30020795 TI - Digital Workflow: From Guided Surgery to Final Full-Arch Implant Prosthesis in Three Visits. AB - The purpose of this article is to report a digital workflow protocol for full arch implant rehabilitation from guided surgery to final prosthesis in only three visits. This expedited protocol allows for implant placement with a surgical template generated from preoperative virtual planning and production of the CAD/CAM prosthodontic rehabilitation using a digital workflow. At the first visit, a guided implant placement protocol with the All-on-4 concept and immediate loading with the conversion prosthesis technique was done. At the same visit, final impression and interocclusal records, cast verification and mounting, as well as digital scanning of the conversion prosthesis were carried out. During the second visit, the framework try-in was performed. Lastly, the third visit included delivery of the final full-arch prosthesis opposed by a maxillary complete denture. PMID- 30020796 TI - Fast-Tracking the Implant Prosthodontic Workflow for Full-Arch Restorations: Case Series. AB - The conventional approach for fabrication of a definitive prosthesis for full arch implant cases requires multiple visits. This article presents a case series highlighting the efficacy of a novel time-saving technique for full-arch implant prosthodontics. The technique is indicated for cases in which an immediate fixed provisional restoration has been delivered on the day of implant placement or within 72 hours of implant placement or for cases where the clinician has made an esthetically and functionally acceptable provisional restoration before starting the prosthetic phase for the definitive restoration. The technique involves taking an impression of the well-adjusted provisional restoration and transferring the jaw relation in a single step, allowing the clinician to circumvent several steps without compromising accuracy or end results. PMID- 30020797 TI - Six-Year Follow-Up of Immature Tooth Revascularization With Enamel Matrix Proteins. AB - Novel endodontic revascularization techniques have been considered as alternative options for treatment of immature teeth affected by apical periodontitis. The continuous development of the root canal has been recognized as a major advantage of these techniques over traditional apexification approaches. This article reports a case in which endodontic revascularization using extracellular matrix proteins (EMPs) as a scaffold was utilized to treat an immature maxillary lateral incisor with history of trauma and chronic apical periodontitis. The root canal was accessed and sequentially irrigated with sodium hypochlorite (NaOCl) (2 mL, 5.25%), saline solution (10 mL), and gluconate chlorhexidine (10 mL, 0.12%). The root canal was then dried, filled with an antibiotic paste (ciprofloxacin, metronidazole, and minocycline), and sealed for 3 weeks. The antibiotic paste was then removed by irrigating the canal with NaOCl (10 mL, 5.25%). The intracanal scaffold was obtained by injecting a commercially available enamel EMP into the newly formed intracanal blood clot. Mineral trioxide aggregate was used to seal the scaffold in place, and a composite resin restoration was then placed using a universal restorative. At 3 and 72 months, clinical and radiographic analyses demonstrated short- and long-term success of the technique presented. The authors' findings indicate revascularization techniques are promising in the treatment of immature teeth with apical periodontitis. Longitudinal clinical trials are necessary to confirm the findings reported herein. PMID- 30020798 TI - Platform Switching and Screw- and Cement-Retained Restorations: Effects on Peri Implant Tissue Health and Disease. AB - As dental implant therapy has evolved since its early days more than five decades ago, its effects have been mostly extremely positive. However, over the course of time, several undesirable, unanticipated consequences have also materialized, most notably peri-implant disease. In this article, the authors propose that many of the challenges clinicians see today regarding increased peri-implant disease represent negative effects of interventions that, though well-intended, had unforeseen shortcomings. Sufficient time has now passed for these adverse effects to manifest, and clinicians today are better able to understand how their attempts to solve problems in some ways produced new challenges. The article also shows how new innovations in engineering and digital technology allow clinicians to address the problems of the past and avoid increasing the risk of peri-implant disease. PMID- 30020799 TI - Implant/Abutment Biomechanics and Material Selection for Predictable Results. AB - Change in crestal bone height and volume around endosseous dental implants is a complex issue involving interactions among many variables such as surgical approach, patient health, volume of hard and soft tissues, and implant configuration. Establishing and maintaining a soft-tissue seal around transmucosal abutments on bone-level implants or on the collar of one-stage tissue-level implants is paramount to maintaining crestal bone height, and failing to do so will result in apical migration of the soft tissue onto the implant. Bone-level implants have been constructed with many connection configurations. Locking-taper conical connection implants have proven superior to buttress joint implants at achieving a tight seal and eliminating the microgap at the implant-to-abutment junction and have demonstrated improvements in crestal bone maintenance. Attaining a transmucosal seal on locking-taper conical connection implants is dependent on the use of proven tissue-compatible materials such as titanium and zirconia. Gold and dental porcelain directly to the bone level implant has been shown to cause tissue recession and bone loss around the implant; use of these materials directly to the implant interface should be confined to one-stage tissue-level implants. Lastly, proper abutment processing and clinical handling finalize the process. Poor dental laboratory processing can lead to loss of the tight locking-taper conical connection seal and screw loosening, while clinicians must keep the abutments clean and sterile. Best practice is for clinicians to inspect all abutments upon receipt from the lab and clean them with soap and water, followed by autoclave sterilization. PMID- 30020800 TI - Removable and Fixed Fully Edentulous Treatment Options for the Aging Patient. AB - As the number of seniors in the United States continues to rise, edentulism remains a serious ailment affecting many elderly patients. Though many seniors are taking fuller dentitions into their later years due to a greater emphasis on oral health maintenance than in the past, this growing population still often requires creative edentulous treatment solutions from skilled clinicians. Fortunately, with the evolution of implant dentistry various possibilities are available to treat edentulous aging patients with removable and/or fixed options. This article will review aging as it relates to the use of dentures and discuss prosthetic restorative alternatives for senior patients. It also will examine the impact of caries, neurosensory disorders, facial esthetics, and chronologic aging on dental treatments. PMID- 30020801 TI - Effective Use of Dental Software Systems to Achieve Predictable Results: A Novel Approach. AB - With an ever-increasing amount of information available through various media, today's prosthodontic patients appear to be more educated about comprehensive dental solutions than ever before. Patient expectations are generally high, and many patients present seeking to remedy sometimes myriad years of dental neglect with healthy, functional, esthetic results. Often times these patients are middle aged, hard-working people who wish to achieve their prosthodontic goals with a minimal financial investment. This can be a challenge to clinicians to utilize their academic resources and experience and formulate a creative, cost-effective solution. This case report demonstrates a pathway to a viable prosthodontic outcome incorporating a workflow of digital technologies that meets the standard of care and addresses patients' needs. PMID- 30020802 TI - Benchmark for Tooth Replacement: Immediate Implant With Immediate Provisional Restoration. Outcome Analytics From 29 Years of Documentation. AB - This article focuses on evidence-based documentation of immediate implant surgery with immediate provisional restoration. Since 1988 the author has documented 14,946 implant surgical sites as to protocol, size of implant, regenerative regimen, outcome, and long-term follow-up. There were 8,319 immediate implant sites: 2,493 were immediate implant/immediate provisional restorations (IIIPR), and 5,826 were immediate implant/no restoration (IINR). The cumulative success rate of IIIPR was 95.1%, while IINR was 94.5%. Patients and dentists were canvassed as to outcome satisfaction of the procedure and final esthetics. The author concludes that IIIPR compares favorably to IINR; IIIPR were reproducible in diverse clinical situations, produced a steady state of bone and soft tissue under loading, and provided high patient satisfaction. PMID- 30020803 TI - Framing the Restorative Result: How Tissue Augmentation and Preservation Maximizes Implant Therapy Outcomes. AB - The role of hard- and soft-tissue augmentation as it pertains to dental implant therapy is often underestimated. If this restorative aspect is neglected during the natural healing process and subsequent remodeling following extraction(s), the long-term outcome of treatment can be catastrophic. Three of the most common opportunities for surgeons to enhance outcomes with regenerative therapy are: reconstruction of edentulous segments of the alveolus, management of extraction sockets, and immediate implant placements. Each has its own unique nuances, which can be quite confounding without an appreciation for the potential biomaterials and techniques currently available for use in these situations. This article will focus on novel methods aimed toward the reconstruction and maintenance of hard- and soft-tissue volumes needed to support functional, hygienic, and esthetic implant restorations. PMID- 30020805 TI - The Impact of Real-World Particulate Matter Air Pollution on the Airways of Susceptible Individuals. PMID- 30020804 TI - Digital Workflow: Helping Clinicians Make Smart Decisions, Achieve Better Outcomes. PMID- 30020806 TI - Lung Function Tracking - Does It Wobble during Adolescence? PMID- 30020807 TI - Pulmonary Vascular Disease Across the Life Span: A Call for Bridging Pediatric and Adult Cardiopulmonary Research and Care. PMID- 30020809 TI - How to Define Early Chronic Obstructive Pulmonary Disease. PMID- 30020810 TI - Sustained Continuous Glucose Monitor Use in Low-Income Youth with Type 1 Diabetes Following Insurance Coverage Supports Expansion of Continuous Glucose Monitor Coverage for All. PMID- 30020811 TI - FaST-LMM for Two-Way Epistasis Tests on High-Performance Clusters. AB - We introduce a version of the epistasis test in FaST-LMM for clusters of multithreaded processors. This new software maintains the sensitivity of the original FaST-LMM while delivering acceleration that is close to linear on 12-16 nodes of two recent platforms, with respect to improved implementation of FaST LMM presented in an earlier work. This efficiency is attained through several enhancements on the original single-node version of FaST-LMM, together with the development of a message passing interface (MPI)-based version that ensures a balanced distribution of the workload as well as a multigraphics processing unit (GPU) module that can exploit the presence of multiple GPUs per node. PMID- 30020812 TI - The Effect of Curcumin on Serum Copper and Zinc and Zn/Cu Ratio in Individuals with Metabolic Syndrome: A Double-Blind Clinical Trial. AB - Metabolic syndrome is a complex disorder with high socioeconomic costs and a high global prevalence. The serum concentrations of some trace elements are higher in people with metabolic syndrome compared to normal individuals. Curcumin is derived from turmeric and has antioxidant and anti-inflammatory properties. Curcumin may therefore have a potential role in the management of cardiovascular risk. The aim of this study was to investigate the effects of curcumin on serum copper (Cu), zinc (Zn), and Zn/Cu ratio levels in patients with metabolic syndrome. A double-blind clinical trial was designed in which 120 individuals with metabolic syndrome were randomly assigned to one of three groups: curcumin 1gr/day, phospholipidated curcumin 1gr/day, or a placebo, each taken for 6 weeks. Serum copper and zinc were measured before and after intervention. At baseline, in addition to obtaining the anthropometric characteristics of participants, a fasting blood sample was taken from each participant, and the concentrations of serum Cu and Zn were measured by atomic absorption (Varian AA 240 FS model). Serum Zn concentrations rose significantly in the phospholipidated curcumin and curcumin groups, being significantly higher (p <.001) in the phospholipidated curcumin group than in the curcumin group (p <.05). Serum Zn concentration fell in the control group (p <.05). Changes in serum Zn level from baseline to the levels after six weeks' intervention were significantly different between the groups, but changes in serum Cu from between baseline until after intervention were not significantly different. The serum Zn/Cu level in phospholipidated curcumin and curcumin groups after intervention was higher than for the control group, but it was more significant in the group taking phospholipidated curcumin (p <.001). Curcumin and phospholipidated curcumin complex, given at a dose of 1 g per day for six weeks, were associated with an increase in serum zinc and consequently zinc-to-copper ratio. PMID- 30020813 TI - Can early intervention with pharmacotherapy reduce the morbidity and mortality of chronic lymphocytic leukemia? PMID- 30020815 TI - Sodium Iodate Disrupted the Mitochondrial-Lysosomal Axis in Cultured Retinal Pigment Epithelial Cells. AB - PURPOSE: Low doses of sodium iodate (NaIO3) impair visual function in experimental animals with selective damage to retinal pigment epithelium (RPE) and serve as a useful model to study diseases caused by RPE degeneration. Mitochondrial dysfunction and defective autophagy have been suggested to play important roles in normal aging as well as many neurodegenerative diseases. In this study, we examined whether NaIO3 treatment disrupted the mitochondrial lysosomal axis in cultured RPE. METHODS: The human RPE cell line, ARPE-19, was treated with low concentrations (<=500 MUM) of NaIO3. The expression of proteins involved in the autophagic pathway and mitochondrial biogenesis was examined with Western blot. Intracellular acidic compartments and lipofuscinogenesis were evaluated by acridine orange staining and autofluorescence, respectively. Mitochondrial mass, mitochondrial membrane potential (MMP), and mitochondrial function were quantified by MitoTracker Green staining, tetramethylrhodamine methyl ester staining, and the MTT assay, respectively. Phagocytosis and the degradation of photoreceptor outer segments (POS) were assessed by fluorescence based approaches and Western blot against rhodopsin. RESULTS: Treatment with low concentrations of NaIO3 decreased cellular acidity, blocked autophagic flux, and resulted in increased lipofuscinogenesis in ARPE-19 cells. Despite increases in protein levels of Sirtuin 1 and PGC-1alpha, mitochondrial function was compromised, and this decrease was attributed to disrupted MMP. POS phagocytic activities decreased by 60% in NaIO3-treated cells, and the degradation of ingested POS was also impaired. Pretreatment and cotreatment with rapamycin partially rescued NaIO3-induced RPE dysfunction. CONCLUSIONS: Low concentrations of NaIO3 disrupted the mitochondrial-lysosomal axis in RPE and led to impaired phagocytic activities and degradation capacities. PMID- 30020816 TI - Advances in stem cell therapy for cartilage regeneration in osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA) is a progressive joint disease that compromises the structural integrity of cartilage tissue. Conventional treatments based on medication or surgery are nowadays inefficient and cell-based therapy has emerged as one of the most promising methods for cartilage regeneration. The first therapy developed for cartilage defects was autologous chondrocyte implantation, but in the last few decades stem cells (SCs) from different sources have been proposed as a possible alternative for OA. Areas covered: SC sources and available delivery procedures (scaffolds/hydrogels) are presented, along with the main issues arisen in this regard. Thereafter, preclinical and clinical trials performed in recent years are reviewed in order to take a glance toward the potential benefits that such therapies could deliver to the patients. Expert opinion: SCs have proven their potential and safety for OA treatment. Nevertheless, there are still many questions to be resolved before their widespread used in clinical practice, such as the treatment mechanism, the best cell source, the most appropriate processing method, the most effective dose and delivery procedure, and their efficacy. In this sense, long-term follow-up and larger randomized controlled trials utilizing standardized and established outcome scores are mandatory to make objective conclusions. PMID- 30020818 TI - Reply to D.L. Kimpel et al. PMID- 30020819 TI - Collaboration Between Rheumatology and Oncology in Immune Checkpoint Inhibitor Therapy. PMID- 30020817 TI - Long Noncoding RNA GAS5 Suppresses 3T3-L1 Cells Adipogenesis Through miR-21a 5p/PTEN Signal Pathway. AB - Emerging studies indicated that both long noncoding RNAs and micro-RNAs play crucial roles in the mediation of adipogenesis, which is closely linked to obesity-related diseases. However, the mechanisms of lncRNA-miRNAs coregulating in adipogenesis are still largely unknown. In this study, we determined that lncRNA growth arrest-specific 5 (GAS5) presented an opposite expression pattern with miR-21a-5p in 3T3-L1 adipocytes development. To explore the role of GAS5 in adipogenesis, pcDNA3.1-GAS5 expression vectors and GAS5-siRNAs were used to perform GAS5 overexpression and knockdown, respectively. Ectopic expression of GAS5 dramatically reduced miR-21a-5p level and suppressed the proliferation of 3T3-L1 preadipocytes, while silencing GAS5 slightly increased miR-21a-5p expression but had no significant influence on the cell viability. In addition, overexpression of GAS5 remarkably decreased the mRNA and protein levels of adipogenic marker genes, and resulted in a notable reduction of lipid accumulation. In contrast, overexpressing miR-21a-5p significantly facilitated differentiation of 3T3-L1 cells. By target gene prediction and luciferase reporter assay, we suggested that GAS5 might indirectly improve the expression of phosphatase and tensin homolog (PTEN) by repressing miR-21a-5p in a miRNA-based regulatory mechanism. Together, GAS5 plays a suppressive role in 3T3-L1 cells adipogenesis, which further highlights the importance of lncRNAs in adipogenesis. PMID- 30020820 TI - Kinesio taping is superior to other taping methods in ankle functional performance improvement: a systematic review and meta-analysis. AB - OBJECTIVE:: To compare the effect of Kinesio taping on ankle functional performance with that of other taping methods (non-elastic taping) in healthy individuals and patients with ankle sprain. METHODS:: A search was performed in electronic databases (MEDLINE, Embase, Cochrane Library, and China National Knowledge Infrastructure) for studies published up to 31 March 2018 using the following keywords: ankle, Kinesio taping, KT, and tape. Studies on ankle functional performance were selected, and data on Star Excursion Balance Test results, vertical jump height, and range of motion were extracted. Meta-analyses (where appropriate and possible) using either fixed or random effects model, standardized mean differences, and tests of heterogeneity were performed. RESULTS:: Ten studies fulfilled the inclusion criteria. The Star Excursion Balance Test results indicated that Kinesio taping was superior to other taping methods (placebo taping or tension-free taping). The mean difference was 3.2 (95% confidence interval (CI): 0.84-5.59, I2 = 5%, P = 0.008). In studies in which vertical jump height was measured, a negative effect was observed for other taping methods (athletic taping or placebo taping), but not for Kinesio taping (mean difference = 1.06, 95% CI: 0.19-0.93, I2 = 15%, P = 0.02). Both Kinesio taping and common taping had no significant effect on range of motion, with no differences between these methods ( I2 = 0%, P = 0.80). CONCLUSION:: Kinesio taping is superior to other taping methods (athletic taping) in ankle functional performance improvement. PMID- 30020821 TI - Propagating and Debunking Conspiracy Theories on Twitter During the 2015-2016 Zika Virus Outbreak. AB - The present study investigates the characteristics of discussion of conspiracy theories about the Zika virus outbreak of 2015-16 on Twitter. Content and social network analysis of a dataset of 25,162 original Tweets about Zika virus conspiracy theories showed that relative to debunking messages, conspiracy theories spread through a more decentralized network, are more likely to invoke supposedly knowledgeable authorities in making arguments, and ask more rhetorical questions. These trends can be understood in the context of previous work on conspiracy theories, including the "just asking questions" style of rhetoric, the importance of sourcing and authority, and the tendency to simultaneously consider many different potential conspiracies that might underlie an important topic or event. PMID- 30020822 TI - Interferon Lambda: Toward a Dual Role in Cancer. AB - Interferon (IFN)-lambda, a type III interferon (IFN), is a member of a new family of pleotropic cytokines that share high similarity with classical IFNs alpha and beta (IFN-alpha/beta), type I IFNs. IFN-lambda acts as an antiviral agent and displays distinct biological functions, including tumor suppression. Although it activates the common Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways, similar to IFN-alpha/beta, IFN-lambda differentially induces the expression of IFN-stimulated genes (ISGs). Novel evidence indicates that IFN-lambda acts quite differently from IFN-alpha/beta under both homeostasis and pathological situations. In contrast to IFN alpha/beta, IFN-lambda is not involved in over-stimulation of the immune response or exacerbation of inflammation. However, the emergence of unexpected characteristics of IFN-lambda, in the control of inflammation and promotion of immune suppression and cancer, reveals novel challenges and offers more strategic opportunities in the context of cancer and beyond. In this article, we discuss new evidence and potential consequences associated with the biology of IFN-lambda and provide a different vision for building novel therapeutic strategies in oncology. PMID- 30020824 TI - Molecular mechanisms of somatostatin-mediated intestinal epithelial barrier function restoration by upregulating claudin-4 in mice with DSS-induced colitis. AB - Intestinal barrier dysfunction plays a crucial role in the pathogenesis of ulcerative colitis (UC). Previous studies have shown somatostatin (SST) can protect intestinal barrier structure possibly through upregulating tight junction (TJ) protein expression, but the mechanisms of this upregulation remain undefined. This study aimed to investigate the molecular mechanisms of interaction of SST with its downstream regulatory elements in DSS-induced colitis mice. In DSS-induced colitis mice, exogenous SST supplement (octreotide) effectively ameliorated disease progression, restored colonic barrier structure and function, and stimulated claudin-4 expression. Similar effects were also observed for SST on Caco-2 cells intervened by TNF-alpha. SST receptor 5 (SSTR5) agonist L-817,818 upregulated the claudin-4 expression whereas the SSTR2 agonist seglitide could not reverse TNF-alpha-induced reduction of claudin-4. SST treatment significantly decreased the phosphorylation levels of ERK1/2 and p38 induced by TNF-alpha. PD-98059 (ERK1/2 pathway inhibitor) but not SB-202190 (p38 pathway inhibitor) could reverse TNF-alpha-induced suppression of claudin-4 expression. Both inhibitors could improve the TJ barrier function damaged by TNF alpha. Our studies suggest that the protective effect of SST on intestinal barrier achieved by upregulating claudin-4 expression through activation of SSTR5 and suppression of the ERK1/2 pathways. These findings will benefit the development of novel treatment regimens for UC. PMID- 30020823 TI - Epigenetic silencing of the tumor suppressor genes SPI1, PRDX2, KLF4, DLEC1, and DAPK1 in childhood and adolescent lymphomas. AB - The aim of the study was to investigate the expression and methylation status of seven distinctive genes with tumor suppressing properties in childhood and adolescent lymphomas. A total of 96 patients with Hodgkin Lymphoma (HL, n = 41), Non-Hodgkin Lymphoma (NHL, n = 15), and reactive lymphoid hyperplasia (RLH, n = 40, as controls) are included in the research. The expression status of CDKN2A, SPI1, PRDX2, DLEC1, FOXO1, KLF4 and DAPK1 genes were measured with QPCR method after the RNA isolation from paraffin blocks of tumor tissue and cDNA conversion. DNA isolation was performed from samples with low gene expression followed by methylation PCR study specific to promoter regions of these genes. We found that SPI1, PRDX2, DLEC1, KLF4, and DAPK1 genes are significantly less expressed in patient than the control group (p = 0.0001). However, expression of CDKNA2 and FOXO1 genes in the patient and control groups were not statistically different. The methylation ratios of all genes excluding the CDKN2A and FOXO1 were significantly higher in the HL and NHL groups than the controls (p = 0.0001). We showed that SPI1, PRDX2, DLEC1, KLF4 and DAPK1 genes are epigenetically silenced via hypermethylation in the tumor tissues of children with HL and NHL. As CDKN2A gene was not expressed in both patient and control groups, we conclude that it is not specific to malignancy. As FOXO1 gene was similarly expressed in both groups, its relationship with malignancy could not be established. The epigenetically silenced genes may be candidates for biomarkers or therapeutic targets in childhood and adolescent lymphomas. PMID- 30020825 TI - Adenosinergic Signaling Inhibits Oxalate Transport by Human Intestinal Caco2-BBE Cells Through the A2B Adenosine Receptor. AB - Most kidney stones (KS) are composed of calcium oxalate, and small increases in urine oxalate affect the stone risk. Intestinal oxalate secretion mediated by anion exchanger SLC26A6 (PAT1) plays a crucial role in limiting net absorption of ingested oxalate; thereby preventing hyperoxaluria and related KS, reflecting the importance of understanding regulation of intestinal oxalate transport. We previously showed that ATP and UTP inhibit oxalate transport by human intestinal Caco2-BBE cells (C2). Since ATP is rapidly degraded to adenosine (ADO), we examined whether intestinal oxalate transport is regulated by ADO. We measured 14C-oxalate uptake in the presence of an outward Cl gradient as an assay of Cl oxalate exchange activity, {greater than or equal to} 49% of which is PAT1 mediated in C2 cells. We found that ADO significantly inhibited oxalate transport by C2 cells, an effect completely blocked by the nonselective ADO receptor antagonist 8-SPT. ADO also significantly inhibited oxalate efflux by C2 cells, which is important since PAT1 mediates oxalate efflux in vivo. Using pharmacological antagonists and A2B adenosine receptor (A2B AR) siRNA knockdown studies, we observed that ADO inhibits oxalate transport through the A2B AR, phospholipase C, and PKC. ADO inhibits oxalate transport by reducing PAT1 surface expression as shown by biotinylation studies. We conclude that ADO inhibits oxalate transport by lowering PAT1 surface expression in C2 cells through signaling pathways including the A2B AR, PKC, and phospholipase C. Given higher ADO levels and overexpression of the A2B AR in IBD, our findings have potential relevance to pathophysiology of IBD-associated hyperoxaluria and related KS. PMID- 30020826 TI - Acute iodine deficiency induces a transient VEGF-dependent microvascular response in mammary glands involving HIF-1, ROS, and mTOR. AB - Iodine deficiency (ID), which affects almost two billion people worldwide, is associated with breast pathologies such as fibrosis in human and induces breast atypia in animal models. Because ID induces vascular activation in the thyroid, another iodide-uptaking organ, and as breast is also sensitive to ID, we aimed to characterize ID-induced effects on the breast microvasculature in vivo and in two different breast cell lines in vitro. Virgin and lactating NMRI mice received an iodide-deficient diet and a Na+/I- symporter inhibitor for 1 to 20 days. Some virgin mice were treated with vascular endothelial growth factor A (VEGF) or VEGF receptor inhibitors. In vitro, ID was induced in MCF7 and MCF12A cells by replacing the iodide-containing medium by an iodide-deficient medium. In vivo, VEGF expression was increased following ID in mammary tissues. Consequently, ID induced a transient increase in mammary gland blood flow, measured after anesthesia, in virgin and lactating mice, which was repressed by VEGF or VEGF receptor inhibitors. In MCF7 cells, ID induced a transient increase in reactive oxygen species, followed by an increase in hypoxia-inducible factor-1alpha (HIF 1alpha) protein and VEGF mRNA expression. Antioxidant N-acetylcysteine and mammalian target of rapamycin (mTOR) inhibitor blocked ID-induced HIF-1alpha protein increase and VEGF transcription. However, mTOR activity was not inhibited by N-acetylcysteine. Similar responses were observed in MCF12A cells. These data indicate that ID activates the canonical VEGF pathway and mTOR in breast tissues, which provides new insights to better understand the correlation between ID, vascular activation, and breast pathologies. PMID- 30020828 TI - Fat storage-inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes. AB - Fat storage-inducing transmembrane protein 2 (FIT2) aids in partitioning of cellular triacylglycerol into lipid droplets. A genome-wide association study reported FITM2-R3H domain containing like-HNF4A locus to be associated with type 2 diabetes (T2DM) in East Asian populations. Mice with adipose tissue (AT) specific FIT2 knockout exhibited lipodystrophic features, with reduced AT mass, insulin resistance, and greater inflammation in AT when fed a high-fat diet. The role of FIT2 in regulating human adipocyte function is not known. Here, we found FIT2 protein abundance is lower in subcutaneous and omental AT obtained from patients with T2DM compared with nondiabetic control subjects. Partial loss of FIT2 protein in primary human adipocytes attenuated their lipid storage capacity and induced insulin resistance. After palmitate treatment, triacylglycerol accumulation, insulin-induced Akt (Ser-473) phosphorylation, and insulin stimulated glucose uptake were significantly reduced in FIT2 knockdown adipocytes compared with control cells. Gene expression of proinflammatory cytokines IL-18 and IL-6 and phosphorylation of the endoplasmic reticulum stress marker inositol requiring enzyme 1alpha were greater in FIT2 knockdown adipocytes than in control cells. Our results show for the first time that FIT2 is associated with T2DM in humans and plays an integral role in maintaining metabolically healthy AT function.-Agrawal, M., Yeo, C. R., Shabbir, A., Chhay, V., Silver, D. L., Magkos, F., Vidal-Puig, A., Toh, S.-A. Fat storage-inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes. PMID- 30020829 TI - Secretory phospholipase A2 group IIA enhances the metabolic rate and increases glucose utilization in response to thyroid hormone. AB - Secretory phospholipase A2 group IIA (PLA2G2A) is a phospholipase which has a role in inflammation, atherogenesis, and host defense. Previously, we found that PLA2G2A protects mice on high-fat diets from weight gain and insulin resistance. Here, we examined the regulation of PLA2G2A and the metabolic changes that occur in response to variations in thyroid status. In particular, the impact of PLA2G2A on the brown adipose tissue (BAT) thermogenic gene expression was explored. We induced hypothyroidism in C57BL/6 and PLA2G2A-overexpressing (IIA+) mice over a 10 wk period or treated them with thyroid hormone (T3) for 5 wk. There were no significant changes in PLA2G2A abundance in response to thyroid status. The energy expenditure of hypothyroid IIA+ mice did not increase; however, the energy expenditure, substrate utilization, insulin sensitivity, and glucose tolerance were all elevated in the IIA+ mice given T3. Moreover, white adipocytes from IIA+ mice were much more prone to "beiging," including increased expression of brown adipose thermogenic markers such as uncoupling protein 1 (UCP1), PR domain containing 16, and early B cell factor 2. Finally, the BAT of IIA+ mice had increased UCP1 and other proteins indicative of mitochondrial uncoupling and nonshivering adaptive thermogenesis. These data reveal a novel role for PLA2G2A on adipose tissue thermogenesis depending on thyroid status.-Kuefner, M. S., Deng, X., Stephenson, E. J., Pham, K., Park, E. A. Secretory phospholipase A2 group IIA enhances the metabolic rate and increases glucose utilization in response to thyroid hormone. PMID- 30020830 TI - Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. AB - The ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR-1a has a complex pharmacology, highlighted by G-protein-dependent and -independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling bias of many GHSR-1a-specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK-0677, L692,585, and [d-Lys3]-growth hormone-releasing peptide-6 (Dlys), JMV2959, and [d-Arg(1),d-Phe(5),d-Trp(7, 9),Leu(11)]-substance P (SP-analog). We investigated their effect on basal GHSR-1a constitutive signaling, ligand-directed downstream GHSR-1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR-1a-beta-arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR-1a antagonist. Moreover, the SP-analog behaved as an inverse agonist increasing G-protein-dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP-analog attenuated beta-arrestin-dependent signaling. Considering the limited success in the clinical development of GHSR-1a targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR-1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR-1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.-Ramirez, V. T., van Oeffelen, W. E. P. A., Torres-Fuentes, C., Chruscicka, B., Druelle, C., Golubeva, A. V., van de Wouw, M., Dinan, T. G., Cryan, J. F., Schellekens, H. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. PMID- 30020827 TI - The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation. AB - Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential function in cell survival and is highly expressed in many cancers. Inhibition of TRPM2 in neuroblastoma by depletion with CRISPR technology or expression of dominant negative TRPM2-S has been shown to significantly reduce cell viability. Here, the role of proline-rich tyrosine kinase 2 (Pyk2) in TRPM2 modulation of neuroblastoma viability was explored. In TRPM2-depleted cells, phosphorylation and expression of Pyk2 and cAMP-responsive element-binding protein (CREB), a downstream target, were significantly reduced after application of the chemotherapeutic agent doxorubicin. Overexpression of wild-type Pyk2 rescued cell viability. Reduction of Pyk2 expression with shRNA decreased cell viability and CREB phosphorylation and expression, demonstrating Pyk2 modulates CREB activation. TRPM2 depletion impaired phosphorylation of Src, an activator of Pyk2, and this may be a mechanism to reduce Pyk2 phosphorylation. TRPM2 inhibition was previously demonstrated to decrease mitochondrial function. Here, CREB, Pyk2, and phosphorylated Src were reduced in mitochondria of TRPM2-depleted cells, consistent with their role in modulating expression and activation of mitochondrial proteins. Phosphorylated Src and phosphorylated and total CREB were reduced in TRPM2-depleted nuclei. Expression and function of mitochondrial calcium uniporter (MCU), a target of phosphorylated Pyk2 and CREB, were significantly reduced. Wild-type TRPM2 but not Ca2+-impermeable mutant E960D reconstituted phosphorylation and expression of Pyk2 and CREB in TRPM2-depleted cells exposed to doxorubicin. Results demonstrate that TRPM2 expression protects the viability of neuroblastoma through Src, Pyk2, CREB, and MCU activation, which play key roles in maintaining mitochondrial function and cellular bioenergetics. PMID- 30020831 TI - Understanding the coupling between DNA damage detection and UvrA's ATPase using bulk and single molecule kinetics. AB - Nucleotide excision repair (NER) protects cells against diverse types of DNA damage, principally UV irradiation. In Escherichia coli, damage is recognized by 2 key enzymes: UvrA and UvrB. Despite extensive investigation, the role of UvrA's 2 ATPase domains in NER remains elusive. Combining single-molecule fluorescence microscopy and classic biochemical methods, we have investigated the role of nucleotide binding in UvrA's kinetic cycle. Measurement of UvrA's steady-state ATPase activity shows it is stimulated upon binding DNA ( kcat 0.71-1.07/s). Despite UvrA's ability to discriminate damage, we find UV-damaged DNA does not alter the steady-state ATPase. To understand how damage affects UvrA, we studied its binding to DNA under various nucleotide conditions at the single molecule level. We have found that both UV damage and nucleotide cofactors affect the attached lifetime of UvrA. In the presence of ATP and UV damage, the lifetime is significantly greater compared with undamaged DNA. To reconcile these observations, we suggest that UvrA uses negative cooperativity between its ATPase sites that is gated by damage recognition. Only in the presence of damage is the second site activated, most likely in a sequential manner.-Barnett, J. T., Kad, N. M. Understanding the coupling between DNA damage detection and UvrA's ATPase using bulk and single molecule kinetics. PMID- 30020832 TI - Proinsulin C-peptide prevents hyperglycemia-induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice. AB - C-peptide has a beneficial effect against diabetic complications, but its role in hyperglycemia-induced metastasis is unknown. We investigated hyperglycemia mediated pulmonary vascular leakage and metastasis and C-peptide inhibition of these molecular events using human pulmonary microvascular endothelial cells (HPMVECs) and streptozotocin-induced diabetic mice. VEGF, which is elevated in the lungs of diabetic mice, activated transglutaminase 2 (TGase2) in HPMVECs by sequential elevation of intracellular Ca2+ and reactive oxygen species (ROS) levels. VEGF also induced vascular endothelial (VE)-cadherin disruption and increased the permeability of endothelial cells, both of which were prevented by the TGase inhibitors monodansylcadaverine and cystamine or TGM2-specific small interfering RNA. C-peptide prevented VEGF-induced VE-cadherin disruption and endothelial cell permeability through inhibiting ROS-mediated activation of TGase2. C-peptide supplementation inhibited hyperglycemia-induced ROS generation and TGase2 activation and prevented vascular leakage and metastasis in the lungs of diabetic mice. The role of TGase2 in hyperglycemia-induced pulmonary vascular leakage and metastasis was further demonstrated in diabetic Tgm2-/- mice. These findings demonstrate that hyperglycemia induces metastasis, and C-peptide prevents the hyperglycemia-induced metastasis in the lungs of diabetic mice by inhibiting VEGF-induced TGase2 activation and subsequent vascular leakage.-Jeon, H.-Y., Lee, Y.-J., Kim, Y.-S., Kim, S.-Y., Han, E.-T., Park, W. S., Hong, S.-H., Kim, Y.-M., Ha, K.-S. Proinsulin C-peptide prevents hyperglycemia-induced vascular leakage and metastasis of melanoma cells in the lungs of diabetic mice. PMID- 30020833 TI - Integrated communications between cyclooxygenase-2 and Alzheimer's disease. AB - Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) are involved in the pathogenesis of Alzheimer's disease (AD), which is characterized by the accumulation of beta-amyloid protein (Abeta) and tau hyperphosphorylation. However, the gaps in our knowledge of the roles of COX-2 and PGs in AD have not been filled. Here, we summarized the literature showing that COX-2 dysregulation obviously influences abnormal cleavage of beta-amyloid precursor protein, aggregation and deposition of Abeta in beta-amyloid plaques and the inclusion of phosphorylated tau in neurofibrillary tangles. Neuroinflammation, oxidative stress, synaptic plasticity, neurotoxicity, autophagy, and apoptosis have been assessed to elucidate the mechanisms of COX-2 regulation of AD. Notably, an imbalance of these factors ultimately produces cognitive decline. The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P. and Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease. PMID- 30020834 TI - The Price of Precision: Genetic Testing and Drug Costs in America. PMID- 30020835 TI - Application of Single-Tube Tri-Primer ARMS-PCR to Detect the NFKB1 ATTG Insertion/Deletion Polymorphism. AB - AIMS: The -94 ATTG insertion/deletion polymorphism (rs28362491) is an important functional polymorphism in the NFKB1 gene. It has been shown that rs28362491 is associated with many diseases. The purpose of this study was to establish a simple and reliable method to detect the ATTG insertion/deletion polymorphism. METHODS: On the basis of the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method, a single-tube tri-primer ARMS-PCR method was developed to detect the ATTG insertion/deletion polymorphism in 93 samples. The results of the single-tube tri-primer ARMS-PCR method were validated by DNA sequencing. RESULTS: After optimization of the PCR conditions, the single-tube tri-primer ARMS-PCR was established to detect the insertion/deletion polymorphism using agarose gel electrophoresis. In 93 volunteers, the genotype frequencies were 30.1% for Ins/Ins, 19.4% for Del/Del, and 50.5% for Ins/Del, respectively. The results of the single-tube tri-primer ARMS-PCR method were consistent with the results of DNA sequencing. CONCLUSIONS: This single-tube tri-primer ARMS-PCR is a reliable, simple, and cost-efficient genotyping method for the detection of the ATTG insertion/deletion polymorphism in the NFKB1 gene. PMID- 30020836 TI - Do postural constraints affect eye, head, and arm coordination? AB - If a whole body reaching task is produced when standing or adopting challenging postures, it is unclear whether changes in attentional demands or the sensorimotor integration necessary for balance control influence the interaction between visuomotor and postural components of the movement. Is gaze control prioritized by the central nervous system (CNS) to produce coordinated eye movements with the head and whole body regardless of movement context? Considering the coupled nature of visuomotor and whole body postural control during action, this study aimed to understand how changing equilibrium constraints (in the form of different postural configurations) influenced the initiation of eye, head, and arm movements. We quantified the eye-head metrics and segmental kinematics as participants executed either isolated gaze shifts or whole body reaching movements to visual targets. In total, four postural configurations were compared: seated, natural stance, with the feet together (narrow stance), or while balancing on a wooden beam. Contrary to our initial predictions, the lack of distinct changes in eye-head metrics; timing of eye, head, and arm movement initiation; and gaze accuracy, in spite of kinematic differences, suggests that the CNS integrates postural constraints into the control necessary to initiate gaze shifts. This may be achieved by adopting a whole body gaze strategy that allows for the successful completion of both gaze and reaching goals. NEW & NOTEWORTHY Differences in sequence of movement among the eye, head, and arm have been shown across various paradigms during reaching. Here we show that distinct changes in eye characteristics and movement sequence, coupled with stereotyped profiles of head and gaze movement, are not observed when adopting postures requiring changes to balance constraints. This suggests that a whole body gaze strategy is prioritized by the central nervous system with postural control subservient to gaze stability requirements. PMID- 30020837 TI - Force dynamics and synergist muscle activation in stick insects: the effects of using joint torques as mechanical stimuli. AB - Many sensory systems are tuned to specific parameters of behaviors and have effects that are task-specific. We have studied how force feedback contributes to activation of synergist muscles in serially homologous legs of stick insects. Forces were applied using conventional half-sine or ramp and hold functions. We also utilized waveforms of joint torques calculated from experiments in freely walking animals. In all legs, forces applied to either the tarsus (foot) or proximal leg segment (trochanter) activated synergist muscles that generate substrate grip and support, but coupling of the depressor muscle to tarsal forces was weak in the front legs. Activation of trochanteral receptors using ramp and hold functions generated positive feedback to the depressor muscle in all legs when animals were induced to seek substrate grip. However, discharges of the synergist flexor muscle showed adaptation at moderate force levels. In contrast, application of forces using torque waveforms, which do not have a static hold phase, produced sustained discharges in muscle synergies with little adaptation. Firing frequencies reflected the magnitude of ground reaction forces, were graded to changes in force amplitude, and could also be modulated by transient force perturbations added to the waveforms. Comparison of synergist activation by torques and ramp and hold functions revealed a strong influence of force dynamics (dF/d t). These studies support the idea that force receptors can act to tune muscle synergies synchronously to the range of force magnitudes and dynamics that occur in each leg according to their specific use in behavior. NEW & NOTEWORTHY The effects of force receptors (campaniform sensilla) on leg muscles and synergies were characterized in stick insects using both ramp and hold functions and waveforms of joint torques calculated by inverse dynamics. Motor responses were sustained and showed reduced adaptation to the more "natural" and nonlinear torque stimuli. Calculation of the first derivative (dF/d t) of the torque waveforms demonstrated that this difference was correlated with the dynamic sensitivities of the system. PMID- 30020838 TI - Biophysical basis of subthalamic local field potentials recorded from deep brain stimulation electrodes. AB - Clinical deep brain stimulation (DBS) technology is evolving to enable chronic recording of local field potentials (LFPs) that represent electrophysiological biomarkers of the underlying disease state. However, little is known about the biophysical basis of LFPs, or how the patient's unique brain anatomy and electrode placement impact the recordings. Therefore, we developed a patient specific computational framework to analyze LFP recordings within a clinical DBS context. We selected a subject with Parkinson's disease implanted with a Medtronic Activa PC+S DBS system and reconstructed their subthalamic nucleus (STN) and DBS electrode location using medical imaging data. The patient-specific STN volume was populated with 235,280 multicompartment STN neuron models, providing a neuron density consistent with histological measurements. Each neuron received time-varying synaptic inputs and generated transmembrane currents that gave rise to the LFP signal recorded at DBS electrode contacts residing in a finite element volume conductor model. We then used the model to study the role of synchronous beta-band inputs to the STN neurons on the recorded power spectrum. Three bipolar pairs of simultaneous clinical LFP recordings were used in combination with an optimization algorithm to customize the neural activity parameters in the model to the patient. The optimized model predicted a 2.4-mm radius of beta-synchronous neurons located in the dorsolateral STN. These theoretical results enable biophysical dissection of the LFP signal at the cellular level with direct comparison to the clinical recordings, and the model system provides a scientific platform to help guide the design of DBS technology focused on the use of subthalamic beta activity in closed-loop algorithms. NEW & NOTEWORTHY The analysis of deep brain stimulation of local field potential (LFP) data is rapidly expanding from scientific curiosity to the basis for clinical biomarkers capable of improving the therapeutic efficacy of stimulation. With this growing clinical importance comes a growing need to understand the underlying electrophysiological fundamentals of the signals and the factors contributing to their modulation. Our model reconstructs the clinical LFP from first principles and highlights the importance of patient-specific factors in dictating the signals recorded. PMID- 30020839 TI - Relationship between vestibular sensitivity and multisensory temporal integration. AB - A single event can generate asynchronous sensory cues due to variable encoding, transmission, and processing delays. To be interpreted as being associated in time, these cues must occur within a limited time window, referred to as a "temporal binding window" (TBW). We investigated the hypothesis that vestibular deficits could disrupt temporal visual-vestibular integration by determining the relationships between vestibular threshold and TBW in participants with normal vestibular function and with vestibular hypofunction. Vestibular perceptual thresholds to yaw rotation were characterized and compared with the TBWs obtained from participants who judged whether a suprathreshold rotation occurred before or after a brief visual stimulus. Vestibular thresholds ranged from 0.7 to 16.5 deg/s and TBWs ranged from 13.8 to 395 ms. Among all participants, TBW and vestibular thresholds were well correlated ( R2 = 0.674, P < 0.001), with vestibular-deficient patients having higher thresholds and wider TBWs. Participants reported that the rotation onset needed to lead the light flash by an average of 80 ms for the visual and vestibular cues to be perceived as occurring simultaneously. The wide TBWs in vestibular-deficient participants compared with normal functioning participants indicate that peripheral sensory loss can lead to abnormal multisensory integration. A reduced ability to temporally combine sensory cues appropriately may provide a novel explanation for some symptoms reported by patients with vestibular deficits. Even among normal functioning participants, a high correlation between TBW and vestibular thresholds was observed, suggesting that these perceptual measurements are sensitive to small differences in vestibular function. NEW & NOTEWORTHY While spatial visual-vestibular integration has been well characterized, the temporal integration of these cues is not well understood. The relationship between sensitivity to whole body rotation and duration of the temporal window of visual vestibular integration was examined using psychophysical techniques. These parameters were highly correlated for those with normal vestibular function and for patients with vestibular hypofunction. Reduced temporal integration performance in patients with vestibular hypofunction may explain some symptoms associated with vestibular loss. PMID- 30020840 TI - To look or not to look? Reward, selection history, and oculomotor guidance. AB - The current eye-tracking study examined the influence of reward on oculomotor performance, and the extent to which learned stimulus-reward associations interacted with voluntary oculomotor control with a modified paradigm based on the classical antisaccade task. Participants were shown two equally salient stimuli simultaneously: a gray and a colored circle, and they were instructed to make a fast saccade to one of them. During the first phase of the experiment, participants made a fast saccade toward the colored stimulus, and their performance determined a (cash) bonus. During the second, participants made a saccade toward the gray stimulus, with no rewards available. On each trial, one of three colors was presented, each associated with high, low or no reward during the first phase. Results from the first phase showed improved accuracy and shorter saccade latencies on high-reward trials, while those from the second replicated well-known effects typical of the antisaccade task, namely, decreased accuracy and increased latency during phase II, even despite the absence of abrupt asymmetric onsets. Crucially, performance differences between phases revealed longer latencies and less accurate saccades during the second phase for high-reward trials, compared with the low- and no-reward trials. Further analyses indicated that oculomotor capture by reward signals is mainly found for saccades with short latencies, while this automatic capture can be overridden through voluntary control with longer ones. These results highlight the natural flexibility and adaptability of the attentional system, and the role of reward in modulating this plasticity. NEW & NOTEWORTHY Typically, in the antisaccade task, participants need to suppress an automatic orienting reflex toward a suddenly appearing peripheral stimulus. Here, we introduce an alternative antisaccade task without such abrupt onsets. We replicate well-known antisaccade effects (more errors and longer latencies), demonstrating the role of reward in developing selective oculomotor biases. Results highlight how reward and selection history facilitate developing automatic biases from goal-driven behavior, and they suggest that this process responds to individual differences in impulsivity. PMID- 30020841 TI - Highlights from the 28th Annual Meeting of the Society for the Neural Control of Movement. PMID- 30020843 TI - Using transcranial magnetic stimulation to investigate the neural mechanisms of inhibitory control. AB - Many everyday actions require inhibitory control. The success of these actions depends on the availability of prior information regarding stopping demands. Using transcranial magnetic stimulation (TMS), Cirillo and colleagues (Cirillo J, Cowie MJ, MacDonald HJ, Byblow WD. J Neurophysiol 119: 877-886, 2018) provide novel neurophysiological evidence for distinct roles of intracortical inhibitory mechanisms underlying inhibitory control. Other, nonexclusive mechanisms such as disfacilitation of excitatory pathways and interhemispheric inhibition may also contribute to inhibitory control. Accordingly, diverse TMS protocols are a valuable assessment tool to investigate these mechanisms. PMID- 30020844 TI - Chronic recording and electrochemical performance of Utah microelectrode arrays implanted in rat motor cortex. AB - Multisite implantable electrode arrays serve as a tool to understand cortical network connectivity and plasticity. Furthermore, they enable electrical stimulation to drive plasticity, study motor/sensory mapping, or provide network input for controlling brain-computer interfaces. Neurobehavioral rodent models are prevalent in studies of motor cortex injury and recovery as well as restoration of auditory/visual cues due to their relatively low cost and ease of training. Therefore, it is important to understand the chronic performance of relevant electrode arrays in rodent models. In this report, we evaluate the chronic recording and electrochemical performance of 16-channel Utah electrode arrays, the current state-of-the-art in pre-/clinical cortical recording and stimulation, in rat motor cortex over a period of 6 mo. The single-unit active electrode yield decreased from 52.8 +/- 10.0 ( week 1) to 13.4 +/- 5.1% ( week 24). Similarly, the total number of single units recorded on all electrodes across all arrays decreased from 106 to 15 over the same time period. Parallel measurements of electrochemical impedance spectra and cathodic charge storage capacity exhibited significant changes in electrochemical characteristics consistent with development of electrolyte leakage pathways over time. Additionally, measurements of maximum cathodal potential excursion indicated that only a relatively small fraction of electrodes (10-35% at 1 and 24 wk postimplantation) were capable of delivering relevant currents (20 uA at 4 nC/ph) without exceeding negative or positive electrochemical potential limits. In total, our findings suggest mainly abiotic failure modes, including mechanical wire breakage as well as degradation of conducting and insulating substrates. NEW & NOTEWORTHY Multisite implantable electrode arrays serve as a tool to record cortical network activity and enable electrical stimulation to drive plasticity or provide network feedback. The use of rodent models in these fields is prevalent. We evaluated chronic recording and electrochemical performance of 16 channel Utah electrode arrays in rat motor cortex over a period of 6 mo. We primarily observed abiotic failure modes suggestive of mechanical wire breakage and/or degradation of insulation. PMID- 30020842 TI - Specificity in the interaction of high-voltage-activated Ca2+ channel types with Ca2+-dependent afterhyperpolarizations in magnocellular supraoptic neurons. AB - Magnocellular oxytocin (OT) and vasopressin (VP) neurons express an afterhyperpolarization (AHP) following spike trains that attenuates firing rate and contributes to burst patterning. This AHP includes contributions from an apamin-sensitive, medium-duration AHP (mAHP) and from an apamin-insensitive, slow duration AHP (sAHP). These AHPs are Ca2+ dependent and activated by Ca2+ influx through voltage-gated Ca2+ channels. Across central nervous system neurons that generate Ca2+-dependent AHPs, the Ca2+ channels that couple to the mAHP and sAHP differ greatly, but for magnocellular neurosecretory cells this relationship is unknown. Using simultaneous whole cell recording and Ca2+ imaging, we evaluated the effect of specific high-voltage-activated (HVA) Ca2+ channel blockers on the mAHP and sAHP. Block of all HVA channels via 400 MUM Cd2+ inhibited almost the entire AHP. We tested nifedipine, conotoxin GVIA, agatoxin IVA, and SNX-482, specific blockers of L-, N-, P/Q-, and R-type channels, respectively. The N-type channel blocker conotoxin GVIA (1 MUM) was the only toxin that inhibited the mAHP in either OT or VP neurons although the effect on VP neurons was weaker by comparison. The sAHP was significantly inhibited by N-type block in OT neurons and by R-type block in VP neurons although neither accounted for the entirety of the sAHP. Thus the mAHP appears to be elicited by Ca2+ from mostly N-type channels in both OT and VP neurons, but the contributions of specific Ca2+ channel types to the sAHP in each cell type are different. Alternative sources to HVA channels may contribute Ca2+ for the sAHP. NEW & NOTEWORTHY Despite the importance of afterhyperpolarization (AHP) mechanisms for regulating firing behavior of oxytocin (OT) and vasopressin (VP) neurons of supraoptic nucleus, which types of high-voltage-activated Ca2+ channels elicit AHPs in these cells was unknown. We found that N-type channels couple to the medium AHP in both cell types. For the slow AHP, N-type channels contribute in OT neurons, whereas R-type contribute in VP neurons. No single Ca2+ channel blocker abolished the entire AHP, suggesting that additional Ca2+ sources are involved. PMID- 30020845 TI - A model of the rat medial gastrocnemius muscle based on inputs to motoneurons and on an algorithm for prediction of the motor unit force. AB - The muscle force is the sum of forces of multiple motor units (MUs), which have different contractile properties. During movements, MUs develop unfused tetani, which result from summation of twitch-shape responses to individual stimuli, which are variable in amplitude and duration. The aim of the study was to develop a realistic muscle model that would integrate previously developed models of MU contractions and an algorithm for the prediction of tetanic forces. The proposed model of rat medial gastrocnemius muscle is based on physiological data: excitability and firing frequencies of motoneurons, contractile properties, and the number and proportion of MUs in the muscle. The MU twitches were modeled by a six-parameter analytical function. The excitability of motoneurons was modeled according to a distribution of their rheobase currents measured experimentally. Processes of muscle force regulation were modeled according to a common drive hypothesis. The excitation signal to motoneurons was modeled by two form types: triangular and trapezoid. The discharge frequencies of MUs, calculated individually for each MU, corresponded to those recorded for rhythmic firing of motoneurons. The force of the muscle was calculated as the sum of all recruited MUs. Participation of the three types of MUs in the developed muscle force was presented at different levels of the excitation signal to motoneurons. The model appears highly realistic and open for input data from various skeletal muscles with different compositions of MU types. The results were compared with three other models with different distribution of the input parameters. NEW & NOTEWORTHY The proposed mathematical model of rat medial gastrocnemius muscle is highly realistic because it is based strictly on experimentally determined motor unit contractile parameters and motoneuron properties. It contains the actual number and proportion of motor units and takes into consideration their different contributions to the whole muscle force, depending on the level of the excitation signal. The model is open for input data from other muscles, and additional physiological parameters can also be included. PMID- 30020846 TI - Continued Avoidance of USPSTF Guidelines for Screening Mammography. PMID- 30020847 TI - Managing Recurrent Urinary Tract Infections in Postmenopausal Women. PMID- 30020848 TI - A Remembrance of Life before Roe v. Wade. PMID- 30020849 TI - Parenteral Opioid Shortage - Treating Pain during the Opioid-Overdose Epidemic. PMID- 30020850 TI - Unoccupied Aircraft Systems in Marine Science and Conservation. AB - The use of unoccupied aircraft systems (UASs, also known as drones) in science is growing rapidly. Recent advances in microelectronics and battery technology have resulted in the rapid development of low-cost UASs that are transforming many industries. Drones are poised to revolutionize marine science and conservation, as they provide essentially on-demand remote sensing capabilities at low cost and with reduced human risk. A variety of multirotor, fixed-wing, and transitional UAS platforms are capable of carrying various optical and physical sampling payloads and are being employed in almost every subdiscipline of marine science and conservation. This article provides an overview of the UAS platforms and sensors used in marine science and conservation missions along with example physical, biological, and natural resource management applications and typical analytical workflows. It concludes with details on potential effects of UASs on marine wildlife and a look to the future of UASs in marine science and conservation. Expected final online publication date for the Annual Review of Marine Science Volume 11 is January 3, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30020851 TI - Antibiotic Prescribing Patterns for Sinusitis Within a Direct-to-Consumer Virtual Urgent Care. AB - BACKGROUND: Direct-to-consumer virtual visits are increasingly popular across both for-profit and nonprofit healthcare systems. INTRODUCTION: Virtual visits offer a convenient affordable way for patients to obtain medical care for simple conditions such as sinusitis and uncomplicated urinary tract infections. However, virtual visits have been associated with increased antibiotic utilization when compared with traditional in-person care. METHODS: In this retrospective cohort study, antibiotic utilization for acute sinusitis was compared between patients treated through a direct-to-consumer virtual urgent care versus a matched cohort treated through traditional urgent care. RESULTS: Fifty-seven patients were treated for acute sinusitis within the virtual care cohort, whereas 100 patients were treated in the traditional care arm. Antibiotic utilization for acute sinusitis was lower when care was delivered virtually using live-interactive video (67%) than when using traditional urgent care (92%) (p < 0.001). When care was delivered virtually, age, gender, and care delivery modality (telephone vs. video) were not associated with antibiotic utilization for acute sinusitis. DISCUSSION: Concerns have been raised that care delivered virtually does not meet expected quality standards when compared with traditional care. Antibiotic utilization has been used as an example of this quality gap. In this study, we demonstrate that antibiotic utilization was lower in a virtual care cohort than when care was delivered by emergency medicine physicians based in an academic setting. This suggests that awareness and sensitivity to prescribing guidelines may be more important than care delivery modality as it relates to antibiotic utilization. CONCLUSIONS: It is possible to deliver care virtually for acute sinusitis without increasing antibiotic utilization. PMID- 30020852 TI - Application of 2'-O-(2-N-Methylcarbamoylethyl) Nucleotides in RNase H-Dependent Antisense Oligonucleotides. AB - An RNase H-dependent antisense oligonucleotide (ASO), having the 2'-O-(2-N methylcarbamoylethyl) (MCE) modification, was evaluated in vitro and in vivo. The antisense activities of an ASO having the MCE modification were comparable with those of an ASO having the 2'-O-methoxyethyl (MOE) modification in both in vitro and in vivo experiments. In contrast, the hepatotoxic potential of the ASO having the MCE modification was lower than that of the ASO having the MOE modification. Thus, these findings suggested that the MCE modification could be used as an alternative to the MOE modification. PMID- 30020853 TI - The control effect of fungicide pyraclostrobin against freckle disease of banana and its residue dynamics under field conditions. AB - Fungicide pyraclostrobin has been widely employed to control plant diseases by inhibiting the mitochondrial respiration of pathogenic fungi. Due to its broad spectrum, the extensive use of pyraclorstrobin was reported to cause emerging resistance on crops. Here, we evaluated the control effect of 250 g L-1 of pyrachlostrobin suspension concentrate (SC) against freckle disease (caused by Phyllosticta spp) on banana. Meanwhile, the dissipation and residue dynamics of pyraclostrobin in banana and soil under field conditions were determined by high performance liquid chromatography (HPLC) with DAD detection in different locations. The analytical method was validated using spiked samples at three levels, which indicated the recoveries ranged from 92.0% to 99.0% with relative standard deviations (RSDs) below 5%, providing a sensitive, precise and reliable method to monitor pyraclostrobin in banana fruit and soil. The dissipation of pyraclostrobine followed the first-order kinetics and its half-lives were 5.25 to 9.90 days. In addition, the terminal residues of pyraclostrobin in banana, banana sarcocarp and soil were below the maximum residue limit (MRL) (0.02 mg kg-1) after a pre-harvest interval (PHI) of 42 days, which suggesting that the use of pyraclostrobin at recommended dosages was safe to banana and the environment. In summary, we demonstrated the integrated evaluation on the disease control capacity of pyraclostrobin and its environmental behavior on banana, aiming to provide solid and basic data for the safe use of fungicide pyraclostrobin. PMID- 30020854 TI - Shear Bond Strength of Nanohybrid Composite to the Resin Matrix Ceramics After Different Surface Treatments. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of different surface treatments on the shear bond strength (SBS) of a composite resin to the various resin matrix ceramics (RMC). BACKGROUND: Clinical applications of physical and chemical surface conditioning methods may be required for RMC to optimize the adhesion of additional resin materials. MATERIALS AND METHODS: Ninety-nine RMC specimens (6 * 6 * 2 mm) were prepared from a resin nanoceramic (RNC), a polymer-infiltrated hybrid ceramic (PIHC), and a flexible hybrid ceramic (FHC) block with a cutting machine under copious water. All specimens divided randomly into three surface treatment subgroups (n = 11): (1) untreated (Cnt), (2) tribochemical silica coated (Tbc), and (3) neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiated with 3 W (150 mJ/pulse, 20 Hz) for 20 sec. A nanohybrid composite resin was layered with a disc-shape mold (2 * 3 mm) onto the ceramics and submitted to thermal cycling (3000 cycles, 5-55 degrees C). The SBS test of specimens was performed using a universal testing machine. Data were statistically analyzed with two-way analysis of variance (ANOVA) and Tukey HSD test (alpha = 0.05). RESULTS: The type of RMC, surface treatments, and their interactions was statistically significant on SBS, according to the ANOVA (p < 0.05). Both the Tbc and Lsr surface treatments significantly increased the SBS values of FHC (p < 0.001), while significant increases were observed only for Lsr0applied RNC and Tbc applied PIHC groups (p < 0.001). CONCLUSIONS: The tribochemical silica coating and laser irradiation techniques may be suitable for improving the surface topography of specific types of RMC. While the same surface treatment technique may not provide similar successful results for all types of RMC, it is recommended to choose the most effective and reliable technique for clinical application. PMID- 30020855 TI - Student Evaluation of Distance Learning for Healthcare Professionals. AB - BACKGROUND: To meet the population's health needs, it is necessary to have health professionals highly trained and updated with the latest skills. The Brazilian government, through the Open University of Brazilian National Health System (UNA SUS), offers continuing education with free access, in distance learning (DL) modality. OBJECTIVE: This study aimed to analyze students' perceptions regarding didactic and pedagogical aspects related to the content and activities, educational resources, and tutoring in a module offered by UNA-SUS/Federal University of Maranhao (UFMA). METHODS: The authors analyzed a sample of 319 students, enrolled in four postgraduate classes, who had completed the communicable diseases module, from 2013 to 2014, and responded to evaluation questions through the Integrated Management System (SIGU) questionnaire, an auxiliary system for processing and interpreting assessments of DL modules offered by UNA-SUS/UFMA. For statistical analysis, evaluation variables were dichotomized into either a positive outcome ("great" and "good") or a negative outcome ("bad" and "insufficient"). Data were analyzed using Statistical Package for the Social Sciences (SPSS; version 18); the significance level was set at 5% (p < 0.05). RESULTS: The authors observed that 99% of the students evaluated the module positively. Regarding the evaluation of the content and activities, 53% (169), 43.6% (139), and 3.4% (11) of students evaluated the item unit workload as great, good, and bad, respectively. The highest rated item was tutor performance, rated as great by 229 (71.8%) students. CONCLUSIONS: The results contributed to the improvement of DL courses offered by UNA-SUS/UFMA from the perspectives of controlling dropout rates and the development of public health services offered in Brazil. PMID- 30020856 TI - Inner Mongolia: A Potential Portal for the Spread of Rabies to Western China. AB - In recent years, the number of human rabies cases in China has decreased annually. However, some western provinces with no human cases for more than 10 years have begun to report rabies cases, and all of the rabies lineages that circulated in western China were found in Inner Mongolia as well. In this study, we generated a phylogenetic tree with all the Inner Mongolia rabies strains available in GenBank and our laboratory, as well as strains from western China and representative viruses from neighboring countries, based on the N gene sequence. Furthermore, the possible relationships underlying the spread of the virus within Inner Mongolia and neighboring regions were analyzed. Three of six rabies lineages of China (China I-VI) were shown to exist in Inner Mongolia, and a spatial cluster analysis supported that the China I lineage, the dominant cluster of China, likely spread to Ningxia from Inner Mongolia. Wild raccoon dog rabies (China IV/Arctic-like-2) may have spread to Inner Mongolia from Russia and likely continued to spread to Qinghai and Tibet. The red fox lineage (China III/Cosmopolitan), which likely spread from Russia and Mongolia, has been shown to circulate in Inner Mongolia and was a serious threat to Xinjiang, which is adjacent to Inner Mongolia. Thus, Inner Mongolia likely became a location where national and international rabies viruses collected and developed into a potential portal for the spread of rabies to western China. To effectively control the spread of rabies in China, both prevention and control of dog and wild animal rabies in Inner Mongolia should be a top priority. PMID- 30020857 TI - Alteration of Surface Glycoproteins After Photodynamic Therapy. AB - BACKGROUND: Cell membranes have been identified as an important intracellular cancer treatment target, since the glycoconjugates present on the cell surface are involved in numerous cell functions. Photodynamic therapy (PDT) is a therapeutic modality employed in the treatment of tumors that uses visible light to activate a photosensitizer. OBJECTIVE: This study analyzed the expression of surface carbohydrates after PDT with two different photosensitizers, 5 aminolevulinic acid (ALA) and Photosan-3. METHODS: Mice were injected subcutaneously with 2 * 105 B16 cells. After 7-10 days, the presence of a tumor with a diameter of 3.6 mm was observed. Photosan-3(r) and 5-aminolevulinic acid ALA were used in the PDT treatment. Control animals (not submitted to either laser treatment or photosensitizer injection) and treated animals were euthanized 15 days post-treatment. The tumors were irradiated with a red diode laser, lambda = 655 nm, energy density of 10 J.cm-2, and power density of 45 mW.cm-2. After 2 weeks of treatment with PDT, the mice were euthanized, the tumors were collected, and the cell surfaces were labeled with lectins concanavalin A (ConA) and wheat germ agglutinin (WGA). RESULTS: Fluorescence microscopy analysis of the cell surfaces with lectins ConA and WGA showed the presence of alpha-mannose and alpha glucose. CONCLUSIONS: The combined effects of either Photosan-3 or ALA and red laser light on melanoma suggest an inhibitory glycosylation action from PDT on the surface of B16-F10 cells. PMID- 30020858 TI - Effect of environmental feedbacks on pacing strategy and affective load during a self-paced 30 min cycling time trial. AB - The purpose of this study was to analyze the pacing strategy and its affective consequences during self-paced cycling time trials (TT) performed at different severity of hypoxia. Eight competitive cyclists performed five 30 min self-paced TTs at their best performance in the following conditions: 1) normobaric normoxia (NNSL); 2) normobaric hypoxia under two simulated altitudes: 2000 m (NH2000) and 3500 m (NH3500) and 3) normobaric hypoxia but the cyclists were deceived and thought to be at sea level for 2000 m (DecNH2000) and 3500 m (DecNH3500). Power Output (PO), oxygen uptake (VO2), and blood lactate concentration ([La]) were recorded to assess exercise intensity and physiological adaptations. The rate of perceived exertion (RPE) and pleasure were measured with a CR10 Borg scale to evaluate the affective load (AL). PO and VO2 decreased with the severity of hypoxia but no significantly difference on performance was measured between deceived and real conditions, except for pacing strategy. The started intensity depends on the exercise expectations, but PO was rapidly adjusted with the physiological constraints and the rate of increase of RPE. Finally, AL did not reach maximal values so that the athletes sustained a physiological and emotional reserve to perform a final spurt. PMID- 30020859 TI - Determinants of healthcare workers' willingness to recommend the seasonal influenza vaccine to diabetic patients: A cross-sectional survey in Ningbo, China. AB - BACKGROUND: Seasonal influenza vaccine uptake among diabetic patients is low in China. Recent studies showed healthcare workers'(HCWs') recommendation is an effective way to promote influenza vaccination. This study aimed to assess HCWs' willingness to recommend influenza vaccine to diabetic patients and identify the predictors of this willingness. METHODS: During Dec 2016-Jan 2017, a self administered questionnaire on perceptions, attitudes and practices related to influenza vaccination for diabetic patients was distributed to 1370 HCWs in 20 hospitals and 20 community health centers in Ningbo. Predictors of HCWs' willingness to recommend influenza vaccine were analyzed by logistic regressions. RESULTS: Of 1340 HCWs who completed the survey, 58.13%(779/1340) participants reported willingness to recommend influenza vaccine to diabetic patients. Factors positively associated with the recommendation willingness included awareness of national influenza vaccination guideline(OR: 6.33; 95%CI: 4.66-8.60) and regional reimbursement policy(OR: 1.62; 95%CI: 1.19-2.20), training on influenza and diabetes (OR: 1.65; 95%CI: 1.21-2.23), influenza vaccination history(OR: 1.35; 95%CI: 1.01-1.79), beliefs in vaccine effects on reducing serious consequences(OR: 1.38; 95%CI: 1.01-1.91), reduction in hospitalization costs(OR: 1.43; 95%CI: 1.05-1.94) caused by influenza, and more than 10 years of practitioner experience(OR: 1.60; 95%CI: 1.04-2.46). Worries about side-effects of influenza vaccine were identified as the barriers of recommendation. CONCLUSION: The present study demonstrates that knowledge about national guideline and reimbursement policies, training programs, perceptions about effectiveness and safety of influenza vaccine increase HCWs' willingness to recommend the influenza vaccination to diabetic patients. These measures should be taken to ensure HCWs' role in the administration of influenza vaccination among diabetic patients. PMID- 30020860 TI - Assessing the Repeatability of Tick Dragging as a Method for Ixodes scapularis Surveillance. AB - Tick dragging is an important tool used by public health for Ixodes scapularis surveillance to identify Lyme disease risk areas in Ontario, Canada. Concerns have been raised on the repeatability of tick dragging due to fluctuations that occur in the tick population in response to micro- and macroclimatic variations. Our objective was to assess the repeatability of tick dragging over a short timescale by examining three outcome measures: presence/absence of ticks, tick abundance, and likelihood of tick establishment based on an indicator developed by Clow et al. ( 2018 ). We conducted tick dragging twice per site within a 1 month period at a total of 15 sites in eastern and southern Ontario. Ixodes scapularis were detected at 11 sites. The outcome of presence/absence was consistent at 13 of 15 sites. Abundance was highly variable, changing between each visit at sites where ticks were detected. The likelihood level was consistent at 13 of 15 sites. Based on the kappa statistic, there was substantial agreement between measurements for the presence/absence and the likelihood levels. Our results indicate that both presence/absence and likelihood levels provide more consistent outcomes for tick dragging than tick abundance alone; however, applying the dragging data to the likelihood indicator provides additional information about the potential risk associated with I. scapularis establishment in the area. PMID- 30020861 TI - Impact of a spleen registry on optimal post-splenectomy vaccination and care. AB - OBJECTIVE: To evaluate quality of patient knowledge and rates of adherence to guidelines amongst splenectomised patients registered to the Spleen Australia registry. METHOD: Registrants recruited for assessment of residual splenic function post-splenectomy also underwent an assessment of quality of knowledge and a review of their long-term management. Eligible patients were >= 18 years of age, registered to the Spleen Australia clinical registry and had been splenectomised at least 1 year prior to their visit. Quality of knowledge was assessed using a validated questionnaire used in similar studies. Receipt of immunisations was validated by record review. Chemoprophylaxis use was self reported by patients. Adherence was evaluated using Australian guidelines. RESULTS: 77 patients were evaluated for education and adherence. 58% were female, mean age was 58 years, and median duration since splenectomy was 14 years. Most common indications for splenectomy were trauma and haematological conditions. 77% had good knowledge of key educational points to reduce chances of infection. Adherence to immunisations varied with poor adherence to vaccines introduced after 2010. Only 6 patients were adherent to all recommended immunisations. Increasing duration since registration was associated with poorer 13vPCV (p = 0.008) and 4vMenCV adherence (p = 0.001). Over 70% either currently or had previously used daily chemoprophylaxis and 66% had a supply of emergency antibiotics. CONCLUSIONS: Although registrants are receiving initial and booster vaccinations, they do not receive newly recommended vaccines. In order to maintain long-term adherence, we recommend streamlining health information systems, improving awareness strategies and improving financial access to vaccinations in the community with additional awareness of the activities of the registry. PMID- 30020862 TI - IL-1alpha and IL-1beta as alternative biomarkers for risk assessment and the prediction of skin sensitization potency. AB - Potential biomarkers of skin sensitization in RAW264.7 mouse macrophages were investigated as alternatives to animal experiments and risk assessment. The concentrations that resulted in a cell viability of 90% (CV90) and 75% (CV75) were calculated by using a water-soluble tetrazolium salt (WST)-1 assay and used to analyze the skin sensitization potency of 23 experimental materials under equivalent treatment conditions. In addition, the expression of interleukin (IL) 1alpha, IL-1beta, IL-31, tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX-2) was analyzed utilizing Western blotting. In the cell viability analysis, skin sensitizers were generally more cytotoxic and exhibited increased skin sensitization potency. However, nonsensitizers did not show any marked cytotoxic tendency. Biomarker analysis demonstrated that IL-1alpha, IL-1beta, and the combination of IL-1alpha and IL-1beta (IL-1alpha + IL-1beta) predicted reliably skin sensitization potential (1) sensitivities of 94.4%, 83.3%, and 83.3%, specificities of 100%, 100%, and 100%, and (2) accuracies of 95.7%, 87%, and 87%, respectively. These observations correlated most reliably as indicators for skin sensitization potency. Data suggest that IL-1alpha and IL-1beta may serve as potential biomarkers for skin sensitization and provide an alternative method to animal experiments for prediction of skin sensitization potency and risk assessment. PMID- 30020863 TI - Linguistic Synchrony Predicts the Immediate and Lasting Impact of Text-Based Emotional Support. AB - Emotional support is critical to well-being, but the factors that determine whether support attempts succeed or fail are incompletely understood. Using data from more than 1 million support interactions enacted within an online environment, we showed that emotional-support attempts are more effective when there is synchrony in the behavior of support providers and recipients reflective of shared psychological understanding. Benefits of synchrony in language used and semantic content conveyed were apparent in immediate measures of support impact (recipient ratings of support effectiveness and expressions of gratitude), as well as delayed measures of lasting change in the emotional impact of stressful life situations (recipient ratings of emotional recovery made at a 1-hr delay). These findings identify linguistic synchrony as a process underlying successful emotional support and provide direction for future work investigating support processes enacted via linguistic behaviors. PMID- 30020864 TI - Advancing the Science on the Biopsychosocial Effects of Human Trafficking. PMID- 30020865 TI - Psychological Consequences of Human Trafficking: Complex Posttraumatic Stress Disorder in Trafficked Children. AB - Trafficked children are frequently exposed to multiple traumatic events, including during their recruitment, transit, and exploitation. It has been hypothesized that such exposures can lead to the development of Complex Posttraumatic Stress Disorder (PTSD). Complex PTSD includes (in addition to the core PTSD symptoms of re-experiencing, avoidance, and hyperarousal) disturbances in affect regulation, dissociation, self-concept, interpersonal relationships, somatization, and systems of meaning. This historical cohort study aimed to investigate Complex PTSD in trafficked children with a diagnosis of PTSD and compare these with nontrafficked controls exposed to single or multiple trauma. Trafficked children were identified by keyword searches of the electronic health records of more than 250,000 mental health service users; a matched cohort of nontrafficked children was randomly selected. Regression models compared the number of Complex PTSD symptoms in trafficked children and non-trafficked children who had experienced multiple or single trauma. Fifty-one trafficked children were identified: eleven with a diagnosis of PTSD (22%). A high proportion of trafficked children with PTSD had Complex PTSD symptoms. Trafficked and non-trafficked children with PTSD who had been exposed to multiple trauma showed a greater number of Complex PTSD symptoms compared to nontrafficked children with PTSD exposed to single-event traumas. Somatic symptoms were noted for almost two-thirds of the trafficked children but only 10%-11% of the nontrafficked children. Child trafficking and multiple trauma exposure are associated with more complex posttraumatic presentations. A thorough clinical assessment at intake is crucial to ensure additional symptoms can be meaningfully incorporated into treatment plans. PMID- 30020866 TI - Human Trafficking Health Research: Progress and Future Directions. PMID- 30020867 TI - Health Issues Associated with Commercial Sexual Exploitation and Sex Trafficking of Children in the United States: A Systematic Review. AB - This article reviews studies examining health issues associated with commercial sexual exploitation and sex trafficking (CSE/ST) of children in the United States. We searched five health and social sciences databases for peer-reviewed articles published in English between January 1990 and April 2017. After independent screening of the records, we identified 27 studies that met the inclusion criteria. Descriptions of the included studies and their definitions of CSE/ST are provided. Most of the studies sampled children and youth in urban, metropolitan areas and employed cross-sectional surveys or reviewed case files and medical records of convenience samples. Studies differed widely in their operationalization of CSE/ST, which limit systematic comparison across studies and the generalizability of findings. Qualitative analysis of the included studies shows that among commercially sexually exploited/trafficked children, there are elevated burdens of substance use and abuse, mental health disorders such as depression, PTSD, suicidal behaviors, and sexual and reproductive health issues including STIs, HIV, and pregnancy. This review underscores the need for more empirical studies, to guide an evidence-based understanding of and response to the range and complexity of the health issues in this population. Of particular utility are studies that address some of the methodological limitations of prior research in this field (e.g., cross-sectional, convenience samples) and those that assess overlooked health issues (e.g., malnutrition, eating disorders, post-trauma growth, and long-term health consequences). PMID- 30020868 TI - Social Support, Dysfunctional Coping, and Community Reintegration as Predictors of PTSD Among Human Trafficking Survivors. AB - Human trafficking exerts psychological effects on survivors that persist after intervention, and even after community reintegration. Effects include anxiety, depression, alienation, disorientation, aggression, suicidal ideation, attention deficit, and posttraumatic stress disorder (PTSD). Community supports and coping mechanisms may mitigate these effects. The report presented here is part of a long-term program of research to develop and test evidence-informed mental health and human capacity-building intervention programs for women and girls who are victims of trafficking. Structural equation modeling was used to assess a conditional process model (moderated mediation) of the effect of social support, coping, and community reintegration on PTSD among n = 144 girls and women. Participants received psychosocial intervention at a residential care facility for trafficking survivors. Results indicate model fit was excellent. Results indicate community reintegration indirectly influenced PTSD through its effect on perceived social support. Survivors who reported more difficulty reintegrating back into the community perceived less social support than those that reported easier community reintegration, and trafficking survivors who perceived less social support indicated more PTSD. Survivors with more PTSD symptoms tended to report using more dysfunctional coping mechanisms. PMID- 30020869 TI - Ethical and Practical Considerations for Collecting Research-Related Data from Commercially Sexually Exploited Children. AB - This article presents seven challenges of collecting primary (i.e., firsthand) data from commercially sexually exploited children (CSEC). We drew on our research team's experience collecting longitudinal data from 28 CSEC survivors with a 12-month follow-up period. We used both face-to-face and electronic group brainstorming methods to nominate a list of research-related challenges. The two main themes that were identified were challenges that can limit data quality and concerns about the impact of research on participants, researchers, and others. The three challenges related to data quality are (1) the age of the research participants; (2) questions about obtaining informed consent from parents or guardians; and (3) the over-interrogation of CSEC youth. The four challenges related to concerns about the impact of research were (4) concerns that research participation may further exploit youth; (5) staying in the role of researcher and refraining from providing advocacy; (6) secondary trauma and burnout experienced by research staff; and (7) the additional burden that research and data collection may place on the advocates and direct service providers. Because the process of collecting data from CSEC youth can be complicated, and rife with ethical and practical challenges, we have relayed our experiences with seven specific research-related challenges in order to stimulate discourse and further progress in the field. PMID- 30020870 TI - Case 256: Breast Implant-associated Anaplastic Large-Cell Lymphoma. AB - History A 57-year-old woman presented with right breast swelling and enlargement and a palpable mass in the right lower inner breast. There was no history of fever, trauma, skin redness, or nipple discharge. The patient had a history of breast augmentation, with retropectoral silicone implants placed 2.5 years ago. Screening mammography (images not shown) 7 months prior revealed bilateral breast implants but no other abnormality. Mammography and US of the right breast were performed at the initial evaluation. Subsequently, fluorine 18 fluorodeoxyglucose PET/CT and MRI were performed. PMID- 30020871 TI - Case 260. AB - History A 31-year-old woman with a history of bilateral orthotopic lung transplantation performed 10 months earlier for cystic fibrosis presented for a routine follow-up appointment, with her chief symptom being a cough. The cough started approximately 1 month prior to this appointment and was minimally productive of clear to yellow phlegm. In addition to her cough, she reported increased sinus congestion and a sensation of "something in her upper chest." She denied shortness of breath, wheezing, hemoptysis, or cigarette smoking. Review of systems was negative for fever, chills, or night sweats. At physical examination, the patient was afebrile, borderline tachycardic (heart rate, 99 beats per minute), and mildly hypertensive (blood pressure, 138/99 mm Hg). Oxygen saturation was 96% on room air. Laboratory evaluation revealed a white blood cell count of 3.5 * 109/L (normal range, 3.2-9.8 * 109/L). Pulmonary function testing was notable for a newly decreased ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of 64% (2.0 and 3.4 L, respectively) (normal FEV1-to-FVC ratio, 80%), suggesting an obstructive lung process. One month prior to presentation, the patient's sputum cultures grew Pseudomonas and methicillin-resistant Staphylococcus aureus. The patient showed no evidence of active infection at the time of bronchoscopy. Thus, the bacteria were favored to reflect colonization, and antibiotic therapy was not administered at that time. The patient was taking an immunosuppression regimen of mycophenalate mofetil (CellCept; Genentech, San Francisco, Calif) (1 g twice daily), prednisone (10 mg daily), and tacrolimus (Prograf; Astellas Pharma US, Northbrook, Ill) (goal therapeutic range, 12-14 ng/mL). The patient was sent for posteroanterior and lateral chest radiography followed by chest CT ( Figs 1 - 3 ) and fluorine 18 fluorodeoxyglucose PET/CT ( Fig 4 ). [Figure: see text][Figure: see text][Figure: see text][Figure: see text]. PMID- 30020872 TI - [The New Medical Licensing Examination in Portugal]. PMID- 30020873 TI - [Physical Activity Counseling: A Proposed Clinical Intervention Flowchart]. PMID- 30020874 TI - [Reuse of Clinical Records for Scientific Research: Legal Issues Related to the Authorization of the Holders and Anonymisation]. PMID- 30020875 TI - [Oral Health - Factors of Non-Adherence to Dental Vouchers: A Case-Control Study]. AB - INTRODUCTION: A dental voucher was created to facilitate the access to oral health care, however the use of these vouchers, by students aged 7, 10 and 13 with dental caries from state schools within the geodemographic area covered by the Community Health Center Group of Western Lisbon and Oeiras, had a low uptake (23%, school year 2014/2015) The aim of this study was to examine the factors associated with this non-use. MATERIAL AND METHODS: A case-control study was carried out involving 270 students (135 cases and 135 controls) from 35 state schools who agreed to participate in the study. A descriptive analysis of the reasons for non-adhesion to the voucher, and a study associating the variables and the use/non-use of the dental vouchers using bivariate and multivariate statistical analysis was made adopting a significance of 0.05. RESULTS: The main reasons for non-use (n = 135) were the use of private dentists outside the dental voucher scheme (23.7%) and forgetting to use the vouchers or exceeding the expiry date (21.5%). The main factor associated with the non-use was students having a private dentist (OR adjusted 2.004, p = 0.012; IC 95%: 1.176 - 3.413) and the main factor associated with the use was having information of dentists accepting dental vouchers (OR adjusted 0.096, p = < 0.001; IC 95%: 0.047 - 0.198). DISCUSSION: Our findings highlight the need to improve the accessibility to dental vouchers. CONCLUSION: It is hoped that the identification of these factors will contribute in the planning of strategies and activities to improve the use of dental vouchers. PMID- 30020876 TI - Clinical Presentation and Long-Term Outcomes of Systemic Sclerosis Portuguese Patients from a Single Centre Cohort: A EUSTAR Registration Initiative. AB - INTRODUCTION: Systemic sclerosis is a complex disorder that requires systematic screening. Our objective is to report the European Scleroderma Trials and Research group centre affiliation and its impact in our clinical practice. MATERIAL AND METHODS: The European Scleroderma Trials and Research group affiliation process, database update and current patient evaluation, with respect to demographic and clinical features. Cumulative mortality was analysed. RESULTS: We identified 19 female patients (which met all the American College of Rheumatology/ European League Against Rheumatism 2013 criteria for systemic sclerosis) under current follow-up, divided according to the LeRoy classification into diffuse cutaneous (n = 5), limited cutaneous (n = 11) and limited (n = 3) types, followed for a median period of 5, 12 and 6 years, respectively. Raynaud's phenomenon and abnormal nailfold capillaries were universally present. Interstitial lung disease was absent in the limited cutaneous form but present in 100% of the diffuse subtype. Pitting scars were more common in the diffuse form. Active disease was also more frequent in the diffuse form, and most patients with active disease were treated with anti-endothelin receptor antagonists. Over 21 years (from 1994 to 2015) the mortality rate was 55% (n = 23/42). Age at time of death was significantly lower in the diffuse subtype. DISCUSSION: Our single centre cohort shares many features with larger and international reports and more specifically is in accordance with patient characteristics described in the European Scleroderma Trials and Research group registries. CONCLUSION: The European Scleroderma Trials and Research group registration motivated our systematic patient characterization and may be used as a tool for homogenous disease registries. PMID- 30020877 TI - [Proposal of a Portuguese Tool for Quality Assessment of Genetic Counselling: a New Tool for Healthcare Professionals]. AB - INTRODUCTION: The lack of tools for quality assessment of genetic counselling is recognized in national and international studies. The correlation of quality of healthcare practice with greater satisfaction of patients and affected families is also well established. The present study describes the development and validation of the first Portuguese scale for quality assessment of genetic counselling practice. It encompasses a proposal of a new tool for the evaluation of the process by professionals. MATERIAL AND METHODS: The definition of an initial pool of items and their organization was based on a literature review and identification of the main genetic counselling dimensions as well as the theoretical dimensions of the Reciprocal Engagement Model. After a pre-test validation the scale was submitted to psychometric validation using a sample of 30 participants who evaluated 81 genetic counselling sessions. RESULTS: Based on statistical and empirical criteria the best items were selected. The final 50 items- version comprises five dimensions: education, counselees' characteristics and decision-making, therapeutic relationship, effects of the process on the counselees and services organization. DISCUSSION: Results showed consistent psychometric properties of the scale supported on theoretical and practice concepts of genetic counseling. The reduced number of participants involved in psychometric validation is a limitation of the study, which reflected the reduced number of professionals in genetic healthcare services. CONCLUSION: The scale proposed at this study is a novel and multidimensional instrument that aimed to contribute to the improvement of genetic counselling practice in Portugal. PMID- 30020878 TI - New Insights Into the Role of Tissue Eosinophils in the Progression of Colorectal Cancer: A Literature Review. AB - INTRODUCTION: Amongst the inflammatory cells implicated in the immune surveillance of colorectal cancer, a growing body of evidence suggests a role for eosinophils in carcinogenesis. We aimed to review the value of tumour-associated tissue eosinophilia (TATE) in the prognosis of colorectal cancer emphasizing the identification and measurement of tissue-infiltrating eosinophils and their association with the clinicopathological features of the disease. MATERIAL AND METHODS: We used PubMed and Web of Science search engines to retrieve studies that looked at the association between tissue eosinophils and colorectal cancer prognosis. RESULTS: We selected 15 studies for our review. In the majority of the studies, eosinophils were identified in hematoxylin-eosin stained sections and scores were generated for analysis. Most of the studies pointed to tumour associated tissue eosinophilia as a favourable prognostic marker in colorectal cancer and found an inverse association between eosinophil count and the metastatic potential of these neoplasms. The association between tumour associated tissue eosinophilia and established prognostic markers of colorectal cancer was assessed in some studies, with inconsistent results. Additionally, tumour-associated tissue eosinophilia decreased with the adenoma-carcinoma progression of colorectal lesions. DISCUSSION: Several mechanisms have been proposed regarding eosinophil chemoatraction to tumour tissues and eosinophil cancer cell cross-talk, suggesting that eosinophils are actively involved in colorectal cancer progression. Although a scoring system is still lacking, tumour associated tissue eosinophilia meets the criteria of a convenient histopathological prognosticator in colorectal cancer. CONCLUSION: Collectively, current evidence associates the presence of eosinophils in the colorectal cancer microenvironment with the modulation of tumour progression. The clinical impact of this finding deserves future research. PMID- 30020879 TI - Posterior Reversible Encephalopathy Syndrome: A Case of Hypercalcemia. AB - Posterior reversible encephalopathy syndrome is an encephalopathy that can be clinically characterized by headache, altered mental status and/or seizures. Neuroimaging demonstrates usually reversible bilateral subcortical vasogenic occipital-parietal edema. Exact pathophysiology remains unclear but is commonly associated with hypertension, renal failure, sepsis and use of immunosuppressive therapy. Its development in the setting of severe hypercalcemia is extremely rare. The authors report a case of posterior reversible encephalopathy syndrome in a normotensive patient with severe hypercalcemia as the only identifiable cause. PMID- 30020880 TI - Fever and Rash: Revisiting Measles. AB - Fever and rash are a common combination of symptoms in the young adult patient. The etiologic investigation is usually oriented towards the most common diseases, but atypical presentations of less frequent conditions should also be recalled. We describe the case of a 44 year-old Portuguese woman who presented with fever, conjunctivitis, cough and rash, rapidly evolving to hepatitis and extensive pneumonia with respiratory failure. Although she claimed to be vaccinated according to the national immunisation schedule, a final diagnosis of primary measles pneumonia was clinically made and confirmed by serology. However, some less typical features mislead us initially. Although the rare form of primary measles pneumonia is more prevalent among immunosuppressed patients, our patient was immunocompetent. Moreover, absence of contagiousness, as was the case, occurs more frequently in atypical measles. This case highlights the need to always confirm the alleged vaccination status in adults and raises attention to some unusual features of typical measles. PMID- 30020881 TI - [Pyoderma Gangrenosum in a Patient with Ulcerative Colitis]. PMID- 30020882 TI - [Protocol for the Prevention of Infections Related to the Treatment of Hematological Malignancies]. AB - Patients with haematological malignancies have a higher incidence of infection compared with the general population. Several factors contribute to this but specially chemotherapy drugs carry different and specific infectious risks. This protocol discusses the prevention of infections in patients who will undergo chemotherapy for the treatment of haematological malignancies. It is divided into: study prior to the initiation of chemotherapy; vaccination and eradication prior to initiation of chemotherapy; antimicrobial prophylaxis during chemotherapy; special situations. The main aims of this protocol are to serve as support to a more systematic and individualized approach to patients undergoing chemotherapy for the treatment of haematological malignancies and by doing so prevent the infectious complications that may arise. PMID- 30020883 TI - [Letter to the Editor: When Judas Got Measles]. PMID- 30020884 TI - A single-center performance evaluation of the fully automated iFlash anti Mullerian hormone immunoassay. PMID- 30020886 TI - Effect of mud pack to eyes on psychological variables in healthy volunteers: a pilot randomized controlled trial. AB - Background Mud pack is one of the fundamental therapeutic procedures used in naturopathy to treat various diseases. There is a lack of scientific evidence for the use of mud-pack application in psychological variables. The present study aims at evaluating the effect of mud pack to eyes on psychological variables in healthy volunteers. Materials and methods Sixty healthy individuals with the age varied from 18 to 21 years were recruited and randomly divided into either mud pack group (n=30) or wet-pack group (n=30). Mud-pack group received mud pack to eyes and wet-pack group received wet pack to eyes for a duration of 30 min/session (a total of 15 sessions). Psychological assessments like Mindful Attention Awareness Scale (MAAS), Perservative Thinking Questionnaire (PTQ) and Positive and Negative Affect Scale (PANAS) were taken before and after the intervention. Statistical analysis was performed using statistical package for the social sciences, version 16. Results Result of this study showed a significant reduction in PTQ score and PANAS negative score in both mud-pack and wet-pack groups. But, a significant increase in MAAS score was observed only in the mud-pack group, unlike wet-pack group. However, there was no significant difference found in between group analysis. Conclusions Result suggests that though both mud pack and wet pack to eyes reduced the scores of PTQ and negative affects, only mud pack to eyes increased the state of mindfulness in healthy individuals. PMID- 30020885 TI - Liraglutide for psychiatric disorders: clinical evidence and challenges. AB - Obesity and diabetes are both risk factors and consequences of psychiatric disorders. Glucagon like peptide 1 (GLP-1) receptor agonists such as liraglutide are widely used in the treatment of diabetes and obesity. There are considerable amounts of preclinical studies showing the effects of liraglutide on promotion of neurogenesis, while preventing apoptosis and oxidation. Preliminary clinical evidence has suggested that liraglutide could decrease weight gain, improve cognition and prevent cognitive decline. Accordingly, liraglutide has been regarded as a potential candidate for the management of psychiatric disorders. Herein, we will discuss the association between obesity/diabetes and psychiatric disorders, and the emerging use of liraglutide in psychiatry. PMID- 30020887 TI - In vitro anticholinesterase, antimonoamine oxidase and antioxidant properties of alkaloid extracts from kola nuts (Cola acuminata and Cola nitida). AB - Background The development of cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for management of neurodegenerative diseases such as Alzheimer's disease (AD) has come with their undesirable side effects. Hence, research for potent but natural ChE and MAO inhibitors with little or no side effects is essential. This study investigated the potentials of alkaloid extracts from two Cola species as nutraceuticals for prevention and management of AD. Methods Alkaloid extracts were obtained from two Cola species (Cola nitida [KN] and Cola acuminata [KA]) by solvent extraction method. The extracts were characterized for their alkaloid contents using gas chromatography (GC). The effects of the extracts on ChE and MAO activities were investigated in vitro. Also, the extracts' ability to inhibit Fe2+-induced lipid peroxidation in rat brain homogenate, scavenge DPPH and OH radicals, as well as chelate Fe2+ were determined. Results GC characterization revealed the presence of augustamine and undulatine as the predominant alkaloids in the extracts. There was no significant (P > 0.05) difference in the inhibitory effects of the extracts on ChE activities. However, KA extract exhibited significantly higher (P < 0.05) MAO inhibitory effect than KN. Also, KA extract inhibited Fe2+- induced malondialdehyde (MDA) production in rat brain homogenate more significantly than KN, while there was no significant difference in DPPH and OH radicals scavenging, as well as Fe2+-chelating abilities of the extracts. Conclusions Our findings revealed that KN and KA alkaloid extracts exhibited significant effect in vitro on biological pathways that may contribute to neuroprotection for the management of neurodegenerative diseases. PMID- 30020888 TI - Testicular and spermatotoxic potential of methanol extract of red cultivar Allium cepa in rats. AB - Background In both human and animals, especially in food and companion animal breeding farms, infertility is normally a challenge of great concern. Males have been found to be solely responsible for about 20-30% of infertility cases. Allium cepa (Onion), being one of the highly consumed spices worldwide, is usually overlooked as a possible reproductive toxicant. Most research on A. cepa document its medicinal effects. This study focused on toxicity potential of A. cepa to the male reproductive system. Spermatozoa morphological characteristics and testicular histopathology of male Wistar rats were accessed following administration of A. cepa methanol extract for 14 and 28 days. Methods The rats (55) were divided into groups A, B and C of 25, 25 and 5 rats, respectively. Group C served as the control and was administered distilled water (10 ml/kg), while groups A and B were subdivided into five groups of five rats each. Group A and B were administered A. cepa extract at various graded doses for 14 days and 28 days, respectively. Results The results revealed significantly increased (p < 0.05) percentage spermatozoa abnormalities, with significantly lower spermatozoa concentration, mass activity and percentage sperm motility when compared with the control group. Conclusions Conclusively, excessive (>100 mg/kg) and prolonged (>7 days) consumption or administration of Allium cepa (onion), including nutraceutical preparations of A. cepa has spermatotoxic effect and may damage germinal epithelial cells of the testicles. Toxicity of A. cepa is dose-dependent and beneficial effects may be maximized at doses <=100 mg/kg for <=7 consecutive days. PMID- 30020889 TI - Neonatal Ogg1/Mutyh knockout mice have altered inflammatory gene response compared to wildtype mice in the brain and lung after hypoxia-reoxygenation. AB - BACKGROUND: 8-Oxoguanine DNA-glycosylase 1 (OGG1) and mutY DNA glycosylase (MUTYH) are crucial in the repair of the oxidative DNA lesion 7,8-dihydro-8 oxoguanine caused by hypoxia-reoxygenation injury. Our objective was to compare the gene expression changes after hypoxia-reoxygenation in neonatal Ogg1-Mutyh double knockout mice (OM) and wildtype mice (WT), and study the gene response in OM after hyperoxic reoxygenation compared to normoxic. METHODS: Postnatal day 7 mice were subjected to 2 h of hypoxia (8% O2) followed by reoxygenation in either 60% O2 or air, and sacrificed right after completed reoxygenation (T0h) or after 72 h (T72h). The gene expression of 44 a priori selected genes was examined in the hippocampus/striatum and lung. RESULTS: We found that OM had an altered gene response compared to WT in 21 genes in the brain and 24 genes in the lung. OM had a lower expression than WT of inflammatory genes in the brain at T0h, and higher expression at T72h in both the brain and lung. In the lung of OM, five genes were differentially expressed after hyperoxic reoxygenation compared to normoxic. CONCLUSION: For the first time, we report that Ogg1 and Mutyh in combination protect against late inflammatory gene activation in the hippocampus/striatum and lung after neonatal hypoxia-reoxygenation. PMID- 30020890 TI - Adenoid Facies. PMID- 30020892 TI - Astro Worms. PMID- 30020891 TI - Risk Factors for Antibiotic-Associated Diarrhea in Critically Ill Patients. AB - BACKGROUND We analyzed the factors related to AAD to inform the rational use of antibiotics in critically ill patients and to reduce the incidence of AAD by providing a reference for antibiotic use in the clinical setting. MATERIAL AND METHODS This study was a retrospective analysis of the clinical data of patients who were hospitalized in the ICU of the First Teaching Hospital of Xi'an Jiaotong University from January 1, 2015 to December 31, 2016. Patients with AAD were assigned to the case group, and all others were assigned to the control group. Basic data were collected for all the selected patients. All the relevant data were analyzed with univariate or multivariate regression analyses, and P<0.05 was considered statistical significance. RESULTS A total of 293 patients were enrolled. Statistical analyses showed that gender (OR 1.915; 95% [CI] 1.061 3.455; P=0.031), parenteral nutrition (OR 1.877; 95% [CI] 1.043-3.377; P=0.036), preventive use of probiotics (OR 0.497; 95% [CI] 0.285-0.866; P=0.014), APACHE II score upon admission to the ICU (OR 0.961; 95% [CI] 0.927-0.998; P=0.037) and use of enzyme-inhibitor antibiotics (OR 1.899; 95% [CI] 1.044-3.420; P=0.016) were associated with AAD. Further subgroup analysis by gender showed that parenteral nutrition (OR 2.144; 95% [CI] 1.064-4.322; P=0.033), preventive use of probiotics (OR 0.367; 95% [CI] 0.186-0.722; P=0.004), and APACHE II score upon admission to the ICU (OR 1.055; 95% [CI] 1.011-1.101; P=0.014) were associated with AAD in critically ill male patients. Age (OR 0.975; 95% [CI] 0.951-0.999; P=0.041) and use of carbapenem antibiotics (OR 4.826; 95% [CI] 1.011-23.030; P=0.048) were associated with AAD in critically ill female patients. CONCLUSIONS Parenteral nutrition, prophylactic use of probiotics, use of enzyme-inhibitor antibiotics, and use of combinations of antibiotics were associated with AAD in critically ill patients. The prophylactic use of probiotics may be a protective factor in AAD. PMID- 30020893 TI - 50, 100 &150 Years Ago. PMID- 30020894 TI - Is the Friend of My Friend My Double? PMID- 30020895 TI - Ba-Boom! There Goes Your Hearing. PMID- 30020896 TI - Caterpillar Heartbeats. PMID- 30020897 TI - Taking Stock of Life. PMID- 30020898 TI - Quick Hits. PMID- 30020899 TI - Underwater. PMID- 30020900 TI - Letters. PMID- 30020901 TI - That's Life. PMID- 30020902 TI - Is Dark Matter Real? PMID- 30020904 TI - Body Sense. PMID- 30020903 TI - Recommended. PMID- 30020905 TI - Collecting Space Rocks. PMID- 30020907 TI - I'll Have My AI Call Your AI. PMID- 30020906 TI - Can Logging Help Jaguars? PMID- 30020908 TI - Monster Waves. PMID- 30020909 TI - Capture That Carbon. PMID- 30020910 TI - Bloodthirsty. PMID- 30020911 TI - Termites and Fairy Circles. PMID- 30020912 TI - The Seventh Sense. PMID- 30020913 TI - Bringing Darwin Back. PMID- 30020914 TI - I(KEA), Robot. PMID- 30020915 TI - A Sense of Discovery. PMID- 30020916 TI - Sunspot Surprise. PMID- 30020917 TI - Prepare for Water Day Zero. PMID- 30020919 TI - Art by the Numbers. PMID- 30020918 TI - 23 and We. PMID- 30020920 TI - Barley heads east: Genetic analyses reveal routes of spread through diverse Eurasian landscapes. AB - One of the world's most important crops, barley, was domesticated in the Near East around 11,000 years ago. Barley is a highly resilient crop, able to grown in varied and marginal environments, such as in regions of high altitude and latitude. Archaeobotanical evidence shows that barley had spread throughout Eurasia by 2,000 BC. To further elucidate the routes by which barley cultivation was spread through Eurasia, simple sequence repeat (SSR) analysis was used to determine genetic diversity and population structure in three extant barley taxa: domesticated barley (Hordeum vulgare L. subsp. vulgare), wild barley (H. vulgare subsp. spontaneum) and a six-rowed brittle rachis form (H. vulgare subsp. vulgare f. agriocrithon (Aberg) Bowd.). Analysis of data using the Bayesian clustering algorithm InStruct suggests a model with three ancestral genepools, which captures a major split in the data, with substantial additional resolution provided under a model with eight genepools. Our results indicate that H. vulgare subsp. vulgare f. agriocrithon accessions and Tibetan Plateau H. vulgare subsp. spontaneum are closely related to the H. vulgare subsp. vulgare in their vicinity, and are therefore likely to be feral derivatives of H. vulgare subsp. vulgare. Under the eight genepool model, cultivated barley is split into six ancestral genepools, each of which has a distinct distribution through Eurasia, along with distinct morphological features and flowering time phenotypes. The distribution of these genepools and their phenotypic characteristics is discussed together with archaeological evidence for the spread of barley eastwards across Eurasia. PMID- 30020921 TI - Hypodermal responses to protein synthesis inhibition induce systemic developmental arrest and AMPK-dependent survival in Caenorhabditis elegans. AB - Across organisms, manipulation of biosynthetic capacity arrests development early in life, but can increase health- and lifespan post-developmentally. Here we demonstrate that this developmental arrest is not sickness but rather a regulated survival program responding to reduced cellular performance. We inhibited protein synthesis by reducing ribosome biogenesis (rps-11/RPS11 RNAi), translation initiation (ifg-1/EIF3G mutation and egl-45/EIF3A RNAi), or ribosome progression (cycloheximide treatment), all of which result in a specific arrest at larval stage 2 of C. elegans development. This quiescent state can last for weeks-beyond the normal C. elegans adult lifespan-and is reversible, as animals can resume reproduction and live a normal lifespan once released from the source of protein synthesis inhibition. The arrest state affords resistance to thermal, oxidative, and heavy metal stress exposure. In addition to cell-autonomous responses, reducing biosynthetic capacity only in the hypodermis was sufficient to drive organism-level developmental arrest and stress resistance phenotypes. Among the cell non-autonomous responses to protein synthesis inhibition is reduced pharyngeal pumping that is dependent upon AMPK-mediated signaling. The reduced pharyngeal pumping in response to protein synthesis inhibition is recapitulated by exposure to microbes that generate protein synthesis-inhibiting xenobiotics, which may mechanistically reduce ingestion of pathogen and toxin. These data define the existence of a transient arrest-survival state in response to protein synthesis inhibition and provide an evolutionary foundation for the conserved enhancement of healthy aging observed in post-developmental animals with reduced biosynthetic capacity. PMID- 30020923 TI - Index or illusion: The case of frailty indices in the Health and Retirement Study. AB - INTRODUCTION: Frailty is a geriatric syndrome that has been defined differently with various indices. Without a uniform definition, it remains unclear how to interpret and compare different frailty indices (FIs). With the advances in index mining, we find it necessary to review the implicit assumptions about the creation of FIs. We are concerned the processing of frailty data may introduce measurement error and bias. We aim to review the assumptions, interpretability and predictive power of FIs regarding mortality. METHODS: Three FIs, the Functional Domains Model proposed by Strawbridge et al. (1998), the Burden Model by Rockwood et al. (2007) and the Biologic Syndrome Model by Fried et al. (2004), were directly compared using the data from the Health and Retirement Study (HRS), a longitudinal study since 1996 mainly following up Americans aged 50 years and over. The FIs were reproduced according to Cigolle et al. (2009) and interpreted with their input variables through forward-stepwise regression. Biases were the residuals of the FIs that could not be explained by own input variables. Any four of the input variables were used to create alternative indices. Discrete-time survival analysis was conducted to compare the predictive power of FIs, input variables and alternative indices on mortality. RESULTS: We found frailty a syndrome not unique to the elderly. The FIs were produced with different degrees of bias. The FIs could not be fully interpreted with the theory-based input variables. The bias induced by the Biological Syndrome Model better predicted mortality than frailty status. A complicated FI, the Burden Model, could be simplified. The input variables better predicted mortality than the FIs. The continuous FIs predicted mortality better than the frailty statuses. At least 6865 alternative indices better predicted mortality than the FIs. CONCLUSION: FIs have been used as outcome in clinical trials and need to be reviewed for adequacy based on our findings. The three FIs are not closely linked to the theories because of bias introduced by data manipulation and excessive numbers of input variables. We are developing new algorithms to develop and validate innovative indices. PMID- 30020922 TI - Stochastic resonance enhances the rate of evidence accumulation during combined brain stimulation and perceptual decision-making. AB - Perceptual decision-making relies on the gradual accumulation of noisy sensory evidence. It is often assumed that such decisions are degraded by adding noise to a stimulus, or to the neural systems involved in the decision making process itself. But it has been suggested that adding an optimal amount of noise can, under appropriate conditions, enhance the quality of subthreshold signals in nonlinear systems, a phenomenon known as stochastic resonance. Here we asked whether perceptual decisions made by human observers obey these stochastic resonance principles, by adding noise directly to the visual cortex using transcranial random noise stimulation (tRNS) while participants judged the direction of coherent motion in random-dot kinematograms presented at the fovea. We found that adding tRNS bilaterally to visual cortex enhanced decision-making when stimuli were just below perceptual threshold, but not when they were well below or above threshold. We modelled the data under a drift diffusion framework, and showed that bilateral tRNS selectively increased the drift rate parameter, which indexes the rate of evidence accumulation. Our study is the first to provide causal evidence that perceptual decision-making is susceptible to a stochastic resonance effect induced by tRNS, and to show that this effect arises from selective enhancement of the rate of evidence accumulation for sub-threshold sensory events. PMID- 30020924 TI - Associations between birth characteristics and age-related cognitive impairment and dementia: A registry-based cohort study. AB - BACKGROUND: There is evidence for long-lasting effects of birth characteristics on cognitive ability in childhood and adulthood. Further, low cognitive ability throughout the lifetime has been linked to age-related cognitive decline and dementia risk. However, little is known about the effects of birth characteristics on cognitive dysfunction late in life. Here we explore potential associations between birth characteristics (weight, head circumference, length, and gestational age), adjusted and not adjusted for gestational age, and cognitive impairment and dementia late in life. METHODS AND FINDINGS: Data from twins in the Swedish Twin Registry born 1926-1960 were merged with information from the Swedish birth, patient, and cause of death registries, resulting in a sample of 35,191 individuals. A subsample of 4,000 twins aged 65 years and older also participated in a telephone cognitive screening in 1998-2002. Associations of birth characteristics with registry-based dementia diagnoses and on telephone assessed cognitive impairment were investigated in the full sample and subsample, respectively. The full sample contained 907 (2.6%) individuals with a dementia diagnosis (an incidence rate of 5.9% per 100,000 person-years), 803 (2.4%) individuals born small for gestational age, and 929 (2.8%) individuals born with a small head for gestational age. The subsample contained 569 (14.2%) individuals with cognitive impairment. Low birth weight for gestational age and being born with a small head for gestational age were significant risk factors for cognitive dysfunction late in life, with an up to 2-fold risk increase (p < 0.001) compared to infants with normal growth and head size, even after controlling for familial factors, childhood socioeconomic status, and education in adulthood. In line with this, each additional 100 g birth weight and each additional millimeter head circumference significantly reduced the risk for dementia (hazard ratio 0.98, 95% confidence interval 0.97 to 0.99, p = 0.004) and cognitive impairment (odds ratio 0.99, 95% confidence interval 0.99 to 1.00, p = 0.004), respectively. Within-pair analyses of identical twins, though hampered by small sample size, suggested that the observed associations between birth characteristics and dementia are likely not due to underlying shared genetic or environmental etiology. A limitation of the present study is that registry-based dementia diagnoses likely miss some of the true dementia cases in the population. Further, a more precise measure of cognitive reserve early in life as well as a date of onset for the cognitive impairment measure in the subsample would have been favorable. CONCLUSIONS: In this study, we found that infants of smaller birth size (i.e., low birth weight or small head circumference adjusted and unadjusted for gestational age) have a significantly higher risk of age-related cognitive dysfunction compared to those with normal growth, highlighting the importance of closely monitoring the cognitive development of such infants and evaluating the potential of early life interventions targeted at enhancing cognitive reserve. PMID- 30020925 TI - Bacterial sensing: A putative amphipathic helix in RsiV is the switch for activating sigmaV in response to lysozyme. AB - Extra Cytoplasmic Function (ECF) sigma factors are a diverse group of alternate sigma factors bacteria use to respond to changes in the environment. The Bacillus subtilis ECF sigma factor sigmaV responds to lysozyme. In the absence of lysozyme, sigmaV is held inactive by the anti-sigma factor, RsiV. In the presence of lysozyme RsiV is degraded via regulated intramembrane proteolysis, which results in the release of sigmaV and thus activation of lysozyme resistance genes. Signal peptidase is required to initiate degradation of RsiV. Previous work indicated that RsiV only becomes sensitive to signal peptidase upon direct binding to lysozyme. We have identified a unique domain of RsiV that is responsible for protecting RsiV from cleavage by signal peptidase in the absence of lysozyme. We provide evidence that this domain contains putative amphipathic helices. Disruption of the hydrophobic surface of these helices by introducing positively charged residues results in constitutive cleavage of RsiV by signal peptidase and thus constitutive sigmaV activation. We provide further evidence that this domain contains amphipathic helices using a membrane-impermeable reagent. Finally, we show that upon lysozyme binding to RsiV, the hydrophobic face of the amphipathic helix becomes accessible to a membrane-impermeable reagent. Thus, we propose the amphipathic helices protect RsiV from cleavage in the absence of lysozyme. Additionally, we propose the amphipathic helices rearrange to form a suitable signal peptidase substrate upon binding of RsiV to lysozyme leading to the activation of sigmaV. PMID- 30020926 TI - Social preferences under chronic stress. AB - Even though chronic stress is a pervasive problem in contemporary societies and is known to potentially precede both adverse psychological as well as physiological conditions, its effects on decision making have not been systematically investigated. In this paper, we focus on the relation between self reported chronic stress and self-reported as well as behaviorally shown social preferences. We measured chronic stress with the Trier Inventory for Chronic Stress. To determine social preferences, participants played a double anonymous dictator game. In order to control for the robustness of social preferences we employed a 2x2x2x2 design where we manipulated four variables: the frame (Give to Recipient vs. Take from Recipient), the decision maker's gender (Female vs. Male), the recipient's gender (Female vs. Male), and the nature of the reward (Real vs. Hypothetical). Results show that perceived chronic stress is not significantly related to social preferences in monetarily rewarded dictator decisions for either gender. However, women's displayed preferences for hypothetical rewards are negatively correlated to chronic stress levels. This indicates that higher chronic stress in women is associated with lower hypothetical transfers but not with altered actual behavior as compared to non stressed women. For men, we do not observe such effects. Our findings suggest that, while chronic stress leaves social preferences unaffected in an incentive compatible task, it might foster what could be interpreted as a decrease in self image promotion in women. Thus, we conclude that in a thoroughly controlled behavioral task differences in reported chronic stress do not entail differences in social preferences, but relate to variation in hypothetical decisions for women. PMID- 30020928 TI - Density propagation based adaptive multi-density clustering algorithm. AB - The performance of density based clustering algorithms may be greatly influenced by the chosen parameter values, and achieving optimal or near optimal results very much depends on empirical knowledge obtained from previous experiments. To address this limitation, we propose a novel density based clustering algorithm called the Density Propagation based Adaptive Multi-density clustering (DPAM) algorithm. DPAM can adaptively cluster spatial data. In order to avoid manual intervention when choosing parameters of density clustering and still achieve high performance, DPAM performs clustering in three stages: (1) generate the micro-clusters graph, (2) density propagation with redefinition of between-class margin and intra-class cohesion, and (3) calculate regional density. Experimental results demonstrated that DPAM could achieve better performance than several state-of-the-art density clustering algorithms in most of the tested cases, the ability of no parameters needing to be adjusted enables the proposed algorithm to achieve promising performance. PMID- 30020927 TI - DNA barcoding Brooklyn (New York): A first assessment of biodiversity in Marine Park by citizen scientists. AB - DNA barcoding is both an important research and science education tool. The technique allows for quick and accurate species identification using only minimal amounts of tissue samples taken from any organism at any developmental phase. DNA barcoding has many practical applications including furthering the study of taxonomy and monitoring biodiversity. In addition to these uses, DNA barcoding is a powerful tool to empower, engage, and educate students in the scientific method while conducting productive and creative research. The study presented here provides the first assessment of Marine Park (Brooklyn, New York, USA) biodiversity using DNA barcoding. New York City citizen scientists (high school students and their teachers) were trained to identify species using DNA barcoding during a two-week long institute. By performing NCBI GenBank BLAST searches, students taxonomically identified 187 samples (1 fungus, 70 animals and 116 plants) and also published 12 novel DNA barcodes on GenBank. Students also identified 7 ant species and demonstrated the potential of DNA barcoding for identification of this especially diverse group when coupled with traditional taxonomy using morphology. Here we outline how DNA barcoding allows citizen scientists to make preliminary taxonomic identifications and contribute to modern biodiversity research. PMID- 30020929 TI - Different megafauna vary in their seed dispersal effectiveness of the megafaunal fruit Platymitra macrocarpa (Annonaceae). AB - The world's largest terrestrial animals (megafauna) can play profound roles in seed dispersal. Yet, the term 'megafauna' is often used to encompass a diverse range of body sizes and physiologies of, primarily, herbivorous animals. To determine the extent to which these animals varied in their seed dispersal effectiveness (SDE), we compared the contribution of different megafauna for the large-fruited Platymitra macrocarpa (Annonaceae), in a tropical evergreen forest in Thailand. We quantified 'seed dispersal effectiveness' by measuring the quantity and quality contributions of all consumers of P. macrocarpa fruit. Seed dispersal quantity was the proportion of the crop consumed by each species. Quality was defined as the proportion of seeds handled by each animal taxon that survived to produce a 2-month seedling. Megafauna (elephants, sambar deer, bears) dispersed 78% of seeds that produced seedlings, with 21% dispersed by gibbons (a medium-sized frugivore). The main megafaunal consumers displayed different dispersal strategies. Elephants were the most effective dispersers (37% of seedlings) and they achieved this by being high-quality and low-quantity dispersers. Bears displayed a similar strategy but were especially rare visitors to the trees (24% of the total seedlings produced). Sambar were high-quantity dispersers, but most seeds they handled did not survive and they were responsible for only 17% of seedlings. Gibbons displayed a high SDE relative to their body size, but they probably cannot match the role of elephants despite being more regular consumers of the fruit. The low density and poor regeneration of P. macrocarpa in the study site suggest that current dispersal rates by megafauna are insufficient, possibly reflecting reduced or missing megafauna populations. We show that different megafaunal species disperse seeds in different ways and may make unique contributions to the reproductive success of the plant species. PMID- 30020930 TI - Effects of visual search training in children with hemianopia. AB - BACKGROUND: This study investigates the effect of a new computer-based visual search training (VST) that was adapted for children with homonymous hemianopia (HH). METHODS: 22 children with HH (median age 11 years, 8 months: 6y6m-19y2m) trained at home for 15 minutes twice/day, 5 days/week, for 6 weeks. To assess performance before training (T1), directly after training (T2) and 6 weeks after the end of training (T3), we measured search times (STs) during on-screen search (with eye tracking), and in a real life search task. Additional variables analyzed during on-screen search were numbers, amplitudes, and durations of saccades, their directional patterns and the proportional number of saccades into the non-seeing field. The latter was the main variable during free viewing. Sixteen healthy age-matched children, who did not undergo the training, served as comparison group. Quality of Life (QoL)-questionnaires were also applied. RESULTS: STs of the patients decreased significantly during the training and all search performance tests. This improvement persisted 6 weeks after the end of the training. Saccade amplitudes increased, total number of saccades to find the target decreased, and the proportional number of saccades to the non-seeing side increased. These changes were maintained at T3. Saccade durations did not change. During free viewing, saccades were equally distributed to both sides before and after training. Patients reported improvements in QoL and activities of daily living. Performance in the healthy children did not change by simply repeating the visual search test. CONCLUSIONS: The improvement in STs in all search tasks, larger and fewer saccades, and an improved search strategy after VST suggests that the children with HH benefited from the training. The maintained improvement at T3 and the improvement in the real life search task indicate that the newly developed search strategy persists and can be applied to everyday life. PMID- 30020931 TI - Peripheral nerve abnormality in HIV leprosy patients. AB - BACKGROUND: The geographical overlap of HIV (human immunodeficiency virus) and leprosy infection has become increasingly frequent and worrying, bringing many clinical issues. Peripheral neuropathy is very frequent in leprosy because of the predilection of its etiologic agent by Schwann cells of the peripheral nervous system, and it also affects individuals with HIV as one of the most common neurological manifestations. METHODOLOGY/PRINCIPAL FINDINGS: The present study compared a cohort of 63 patients diagnosed with leprosy and coinfected with HIV with a cohort of 64 patients with leprosy alone, who were followed at the outpatient clinic of the Nucleus of Tropical Medicine of the Federal University of Para, Brazil. We observed that HIV-coinfected leprosy patients presented greater odds of overall peripheral nerve damage (nerve function impairment-NFI) than patients with leprosy alone. More sensitive damage was observed, especially in patients coinfected with multibacillary forms. Leprosy patients coinfected with HIV presented higher chances of motor damage with improvement over time using multidrug therapy (MDT) and highly active antiretroviral therapy (HAART), along with a greater extent of damage and occurrence of neuritis. The data suggest that in addition to patients presenting possible damage caused by leprosy, they also had a greater damage gradient attributable to HIV disease, but not related to HAART because most of these patients had been on the treatment for less than a year. Neuritis was treated with prednisone at doses recommended by the WHO, and coinfected patients had the highest rate of clinical improvement in the first 60 days. CONCLUSIONS/SIGNIFICANCE: The clinical characteristics of the two diseases should be considered in leprosy patients coinfected with HIV for better diagnosis and treatment of peripheral neuropathy. We suggest that new simplified assessment tools that allow the evaluation of the NFI of these patients be developed for use in the service. PMID- 30020932 TI - Diurnal oscillations in human salivary microRNA and microbial transcription: Implications for human health and disease. AB - The microbiome plays a vital role in human health and disease. Interaction between human hosts and the microbiome occurs through a number of mechanisms, including transcriptomic regulation by microRNA (miRNA). In animal models, circadian variations in miRNA and microbiome elements have been described, but patterns of co-expression and potential diurnal interaction in humans have not. We investigated daily oscillations in salivary miRNA and microbial RNA to explore relationships between these components of the gut-brain-axis and their implications in human health. Nine subjects provided 120 saliva samples at designated times, on repeated days. Samples were divided into three sets for exploration and cross-validation. Identification and quantification of host miRNA and microbial RNA was performed using next generation sequencing. Three stages of statistical analyses were used to identify circadian oscillators: 1) a two-way analysis of variance in the first two sample sets identified host miRNAs and microbial RNAs whose abundance varied with collection time (but not day); 2) multivariate modeling identified subsets of these miRNAs and microbial RNAs strongly-associated with collection time, and evaluated their predictive ability in an independent hold-out sample set; 3) regulation of circadian miRNAs and microbial RNAs was explored in data from autistic children with disordered sleep (n = 77), relative to autistic peers with typical sleep (n = 63). Eleven miRNAs and 11 microbial RNAs demonstrated consistent diurnal oscillation across sample sets and accurately predicted collection time in the hold-out set. Associations among five circadian miRNAs and four circadian microbial RNAs were observed. We termed the 11 miRNAs CircaMiRs. These CircaMiRs had 1,127 predicted gene targets, with enrichment for both circadian gene targets and metabolic signaling processes. Four CircaMiRs had "altered" expression patterns among children with disordered sleep. Thus, novel and correlated circadian oscillations in human miRNA and microbial RNA exist and may have distinct implications in human health and disease. PMID- 30020935 TI - New Saussurea (Asteraceae) species from Bogeda Mountain, eastern Tianshan, China, and inference of its evolutionary history and medical usage. AB - In this study, Saussurea bogedaensis Yu-J. Wang & Jie Chen, a new species from Bogeda Mountain in the eastern part of the Tianshan Mountains, is described and discussed based on evidence in terms of both morphological and genetic data. S. bogedaensis is morphologically similar to S. involucrata, which is distributed in the western part of the Tianshan Mountains, and it is well known because of its beauty, rarity, and medicinal value. The new species is also similar to S. orgaadayi, which is distributed in the nearby Altai Mountains. Our genetic data support the close relationships among these three species. According to their allopathic distributions, we suggest that these three species are derived from the same ancestor but that they differentiated after reaching their current range. In addition, we propose that the new species might serve as an alternative to S. involucrata in medicine due to their very high similarity. However, this species appears to be rare because we only found six mature individuals in the field despite extensive investigations. PMID- 30020933 TI - Combining Wolbachia-induced sterility and virus protection to fight Aedes albopictus-borne viruses. AB - Among the strategies targeting vector control, the exploitation of the endosymbiont Wolbachia to produce sterile males and/or invasive females with reduced vector competence seems to be promising. A new Aedes albopictus transinfection (ARwP-M) was generated by introducing wMel Wolbachia in the ARwP line which had been established previously by replacing wAlbA and wAlbB Wolbachia with the wPip strain. Various infection and fitness parameters were studied by comparing ARwP-M, ARwP and wild-type (SANG population) Ae. albopictus sharing the same genetic background. Moreover, the vector competence of ARwP-M related to chikungunya, dengue and zika viruses was evaluated in comparison with ARwP. ARwP M showed a 100% rate of maternal inheritance of wMel and wPip Wolbachia. Survival, female fecundity and egg fertility did not show to differ between the three Ae. albopictus lines. Crosses between ARwP-M males and SANG females were fully unfertile regardless of male age while egg hatch in reverse crosses increased from 0 to about 17% with SANG males aging from 3 to 17 days. When competing with SANG males for SANG females, ARwP-M males induced a level of sterility significantly higher than that expected for an equal mating competitiveness (mean Fried index of 1.71 instead of 1). The overall Wolbachia density in ARwP-M females was about 15 fold higher than in ARwP, mostly due to the wMel infection. This feature corresponded to a strongly reduced vector competence for chikungunya and dengue viruses (in both cases, 5 and 0% rates of transmission at 14 and 21 days post infection) with respect to ARwP females. Results regarding Zika virus did not highlight significant differences between ARwP-M and ARwP. However, none of the tested ARwP-M females was capable at transmitting ZIKV. These findings are expected to promote the exploitation of Wolbachia to suppress the wild-type Ae. albopictus populations. PMID- 30020934 TI - A biophysically detailed computational model of urinary bladder small DRG neuron soma. AB - Bladder small DRG neurons, which are putative nociceptors pivotal to urinary bladder function, express more than a dozen different ionic membrane mechanisms: ion channels, pumps and exchangers. Small-conductance Ca2+-activated K+ (SKCa) channels which were earlier thought to be gated solely by intracellular Ca2+ concentration ([Ca]i) have recently been shown to exhibit inward rectification with respect to membrane potential. The effect of SKCa inward rectification on the excitability of these neurons is unknown. Furthermore, studies on the role of KCa channels in repetitive firing and their contributions to different types of afterhyperpolarization (AHP) in these neurons are lacking. In order to study these phenomena, we first constructed and validated a biophysically detailed single compartment model of bladder small DRG neuron soma constrained by physiological data. The model includes twenty-two major known membrane mechanisms along with intracellular Ca2+ dynamics comprising Ca2+ diffusion, cytoplasmic buffering, and endoplasmic reticulum (ER) and mitochondrial mechanisms. Using modelling studies, we show that inward rectification of SKCa is an important parameter regulating neuronal repetitive firing and that its absence reduces action potential (AP) firing frequency. We also show that SKCa is more potent in reducing AP spiking than the large-conductance KCa channel (BKCa) in these neurons. Moreover, BKCa was found to contribute to the fast AHP (fAHP) and SKCa to the medium-duration (mAHP) and slow AHP (sAHP). We also report that the slow inactivating A-type K+ channel (slow KA) current in these neurons is composed of 2 components: an initial fast inactivating (time constant ~ 25-100 ms) and a slow inactivating (time constant ~ 200-800 ms) current. We discuss the implications of our findings, and how our detailed model can help further our understanding of the role of C-fibre afferents in the physiology of urinary bladder as well as in certain disorders. PMID- 30020937 TI - Identification of a putative polyketide synthase gene involved in usnic acid biosynthesis in the lichen Nephromopsis pallescens. AB - Usnic acid is a unique polyketide produced by lichens. To characterize usnic acid biosynthesis, the transcriptome of the usnic-acid-producing lichen-forming fungus Nephromopsis pallescens was sequenced using Illumina NextSeq technology. Seven complete non-reducing polyketide synthase genes and nine highly-reducing polyketide synthase genes were obtained through transcriptome analysis. Gene expression results obtained by qPCR and usnic acid detection with LCMS-IT-TOF showed that Nppks7 is probably involved in usnic acid biosynthesis in N. pallescens. Nppks7 is a non-reducing polyketide synthase with a MeT domain that also possesses beta-ketoacyl-ACP synthase, acyl transferase, product template, acyl carrier protein, C-methyltransferase, and Claisen cyclase domains. Phylogenetic analysis shows that Nppks7and other polyketide synthases from lichens form a unique monophyletic clade. Taken together, our data indicate that Nppks7 is a novel PKS in N. pallescens that is likely involved in usnic acid biosynthesis. PMID- 30020938 TI - Passive acoustic surveys for predicting species' distributions: Optimising detection probability. AB - Surveying terrestrial species across diverse habitats is important for predicting species' distributions and implementing conservation actions. For vocalising species, passive acoustic monitoring (PAM) is increasing in popularity; however, survey design rarely considers the factors influencing the timing and occurrence of vocalisations and in turn, how they may influence detectability of the species. Here, we use the koala (Phascolarctos cinereus) as a case study to show how PAM can be used to first examine the factors influencing vocalisations, and then use occupancy modelling to make recommendations on survey design for the species. We used automated recording units to monitor koala vocalisations at ten sites between August 2016 and January 2017. The timing of male koala vocalisations was linked to time of sunset with vocalisations increasing two hours prior to sunset and peaking at four hours after sunset. Vocalisations had a seasonal trend, increasing from the early to middle stage of the breeding season. Koala population density and stage of the breeding season had more influence on detection probability than daily sampling schedule. Where population density was low, and during the early stage of the breeding season, 7 survey nights (recording for 6 hours from 20:00h to 02:00h; i.e. the period of peak bellowing activity) were required to be 95% confident of a site-specific absence. Our study provides an approach for designing effective passive acoustic surveys for terrestrial species. PMID- 30020936 TI - Skin mucosome activity as an indicator of Batrachochytrium salamandrivorans susceptibility in salamanders. AB - Recently emerged fungal diseases, Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal) are an increasing threat to amphibians worldwide. In Europe, the threat of Bsal to salamander populations is demonstrated by the rapid decline of fire salamander populations in Germany, the Netherlands and Belgium. Although most European urodelans are susceptible to infection in infection trials, recent evidence suggests marked interspecific differences in the course of infection, with potentially far reaching implications for salamander conservation. As a salamander's skin is the first line of defense against such pathogens, interspecific differences in innate immune function of the skin may explain differential susceptibility. Here we investigate if compounds present on a salamander's skin can kill Bsal spores and if there is variation among species. We used a non-invasive assay to compare killing ability of salamander mucosomes of four different species (captive and wild Salamandra salamandra and captive Ichtyosaura alpestris, Cynops pyrrhogaster and Lissotriton helveticus) by exposing Bsal zoospores to salamander mucosomes and determining spore survival. In all samples, zoospores were killed when exposed to mucosomes. Moreover, we saw a significant variation in this Bsal killing ability of mucosomes between different salamander host species. Our results indicate that mucosomes of salamanders might provide crucial skin protection against Bsal, and could explain why some species are more susceptible than others. This study represents a step towards better understanding host species variation in innate immune function and disease susceptibility in amphibians. PMID- 30020939 TI - Impact of chlorine dioxide disinfection of irrigation water on the epiphytic bacterial community of baby spinach and underlying soil. AB - The contamination of pathogenic bacteria through irrigation water is a recognized risk factor for fresh produce. Irrigation water disinfection is an intervention strategy that could be applied to reduce the probability of microbiological contamination of crops. Disinfection treatments should be applied ensuring minimum effective doses, which are efficient in inhibiting the microbial contamination while avoiding formation and accumulation of chemical residues. Among disinfection technologies available for growers, chlorine dioxide (ClO2) represents, after sodium hypochlorite, an alternative disinfection treatment, which is commercially applied by growers in the USA and Spain. However, in most of the cases, the suitability of this treatment has been tested against pathogenic bacteria and low attention have been given to the impact of chemical residues on the bacterial community of the vegetable tissue. The aim of this study was to (i) to evaluate the continual application of chlorine dioxide (ClO2) as a water disinfection treatment of irrigation water during baby spinach growth in commercial production open fields, and (ii) to determine the subsequent impact of these treatments on the bacterial communities in water, soil, and baby spinach. To gain insight into the changes in the bacterial community elicited by ClO2, samples of treated and untreated irrigation water as well as the irrigated soil and baby spinach were analyzed using Miseq(r) Illumina sequencing platform. Next generation sequencing and multivariate statistical analysis revealed that ClO2 treatment of irrigation water did not affect the diversity of the bacterial community of water, soil and crop, but significant differences were observed in the relative abundance of specific bacterial genera. This demonstrates the different susceptibility of the bacteria genera to the ClO2 treatment. Based on the obtained results it can be concluded that the phyllosphere bacterial community of baby spinach was more influenced by the soil bacteria community rather than that of irrigation water. In the case of baby spinach, the use of low residual ClO2 concentrations (approx. 0.25 mg/L) to treat irrigation water decreased the relative abundance of Pseudomonaceae (2.28-fold) and Enterobacteriaceae (2.5-fold) when comparing treated versus untreated baby spinach. Members of these two bacterial families are responsible for food spoilage and foodborne illnesses. Therefore, a reduction of these bacterial families might be beneficial for the crop and for food safety. In general it can be concluded that the constant application of ClO2 as a disinfection treatment for irrigation water only caused changes in two bacterial families of the baby spinach and soil microbiota, without affecting the major phyla and classes. The significance of these changes in the bacterial community should be further evaluated. PMID- 30020940 TI - The emerging health impact of voluntary medical male circumcision in Zimbabwe: An evaluation using three epidemiological models. AB - BACKGROUND: Zimbabwe adopted voluntary medical male circumcision (VMMC) as a priority HIV prevention strategy in 2007 and began implementation in 2009. We evaluated the costs and impact of this VMMC program to date and in future. METHODS: Three mathematical models describing Zimbabwe's HIV epidemic and program evolution were calibrated to household survey data on prevalence and risk behaviors, with circumcision coverage calibrated to program-reported VMMCs. We compared trends in new infections and costs to a counterfactual without VMMC. Input assumptions were agreed in workshops with national stakeholders in 2015 and 2017. RESULTS: The VMMC program averted 2,600-12,200 infections (among men and women combined) by the end of 2016. This impact will grow as circumcised men are protected lifelong, and onward dynamic transmission effects, which protect women via reduced incidence and prevalence in their male partners, increase over time. If other prevention interventions remain at 2016 coverages, the VMMCs already performed will avert 24,400-69,800 infections (2.3-5% of all new infections) through 2030. If coverage targets are achieved by 2021 and maintained, the program will avert 108,000-171,000 infections (10-13% of all new infections) by 2030, costing $2,100-3,250 per infection averted relative to no VMMC. Annual savings from averted treatment needs will outweigh VMMC maintenance costs once coverage targets are reached. If Zimbabwe also achieves ambitious UNAIDS targets for scaling up treatment and prevention efforts, VMMC will reduce the HIV incidence remaining at 2030 by one-third, critically contributing to the UNAIDS goal of 90% incidence reduction. CONCLUSIONS: VMMC can substantially impact Zimbabwe's HIV epidemic in the coming years; this investment will save costs in the longer term. PMID- 30020942 TI - Maximizing adaptive power in neuroevolution. AB - In this paper we compare systematically the most promising neuroevolutionary methods and two new original methods on the double-pole balancing problem with respect to: the ability to discover solutions that are robust to variations of the environment, the speed with which such solutions are found, and the ability to scale-up to more complex versions of the problem. The results indicate that the two original methods introduced in this paper and the Exponential Natural Evolutionary Strategy method largely outperform the other methods with respect to all considered criteria. The results collected in different experimental conditions also reveal the importance of regulating the selective pressure and the importance of exposing evolving agents to variable environmental conditions. The data collected and the results of the comparisons are used to identify the most effective methods and the most promising research directions. PMID- 30020941 TI - Determinants for not utilizing trachomatous trichiasis surgery among trachomatous trichiasis patients in Mehalsayint District, North-East Ethiopia. AB - BACKGROUND: Globally, trachoma is the leading cause of infectious blindness. In Ethiopia, the overall Trachomatous Trichiasis (TT) surgical coverage is 41%. Identifying determinants for not utilizing TT surgery among TT patients is important to design and monitor effective intervention programs. Therefore, this study aimed to identify determinants for not utilizing TT surgery among TT patients in Mehalsayint District, North East Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: A community based unmatched case control study was employed from March 30, 2017 to April 13, 2017. A total of 482 study participants (241 cases and 241 controls) with age of >=15 years were included in the study. The data were entered with Epi info version 7.2 software and exported to SPSS version 20 for analysis. Bivariate analysis was fitted to screen candidate variables with p<0.2 for the final model. Finally, multivariable logistic regression analysis was employed to identify significant factors (p<0.05) for not utilizing TT surgery. Respondents' age of 16-30 years (AOR: 10.11; 95% CI: 2.72, 37.59) and widowed respondents (AOR: 0.40; 95% CI: 0.21, 0.77), time to reach the service (AOR: 0.46; 95% CI: 0.24, 0.87), unavailability of TT surgeon (AOR: 5.00; 95% CI: 1.16, 21.38), symptoms of trichiasis (AOR: 7.49; 95% CI: 2.41, 23.26), duration of the problem (AOR: 2.56; 95% CI: 1.44, 4.54), the affected eye (AOR: 2.16; 95% CI: 1.23, 3.80), epilation practice (AOR: 3.22; 95% CI: 1.84, 5.64), and place of TT surgery given (AOR: 4.21; 95% CI: 2.48, 7.14) were significant determinants for not utilizing TT surgical services. CONCLUSIONS/SIGNIFICANCE: In this study, TT surgery against trachoma is very low and TT remains public health problem in the district. Being younger age and widowed, time taken to reach the service, absence of TT surgeon, symptoms of trichiasis, duration of problem, the affected eye, epilation practice, and service place were determinants for the inability of TT surgical services. The findings of this study would help in designing effective interventions to reduce trachoma in that district. PMID- 30020943 TI - Effect of chewing an apple on dental plaque removal and on salivary bacterial viability. AB - OBJECTIVES: Studies on dental plaque removal by chewing an apple are scarce and dated, with conflicting findings. This study aimed to determine whether chewing an apple produced mechanical removal of dental plaque or had any effect on salivary bacterial viability. METHODS: The study group consisted of 20 healthy adults with good oral health status who were randomly assigned to brush their teeth or eat an apple. After 2 weeks, the experiment was repeated with the order reversed. Plaque index (PI) and the bacterial viability (BV) in a sample of whole saliva (spit) were determined before brushing or apple eating (baseline, B), immediately afterward (A) and 24 hours afterward (24). RESULTS: After chewing an apple, PI-A was significantly higher than both PI-B (P < .001) and PI-24 (P < .001). BV-A was significantly lower than BV-B (P < .001), with a return to baseline values at the BV-24 measurement. CONCLUSIONS: Chewing an apple does not remove dental plaque, and may favor plaque regrowth during the first 24 hours, but it does produce an immediate reduction in salivary bacterial viability similar to that after tooth brushing. PMID- 30020944 TI - Decision-making during trial of labour after caesarean; a qualitative study with gynaecologists. AB - OBJECTIVE: The attempt of a woman to deliver vaginally after having had a caesarean in a previous pregnancy is increasingly common in current obstetric practice. During a trial of labour after caesarean, gynaecologists consider whether continuing vaginal birth is safe or, alternately, whether a repeat caesarean is advised. There is large variation in the success rates of women with comparable medical risk factors, requiring better insight in how this assessment is made. As a window of opportunity to intervene in this unexplained variation in practice in specific, and in the globally rising caesarean rate in general, our aim was to increase understanding of gynaecologists' decision-making during trial of labour. STUDY DESIGN: We conducted a constructivist grounded theory study, interviewing Dutch gynaecologists. Data collection and analysis were performed concurrently. Initial convenience sampling shifted to theoretical sampling as the study progressed. Data collection continued until theoretical sufficiency was reached. We applied open and axial codes to transcripts of the interviews, and then assembled the axial codes into themes that built up to an emerging theoretical framework. RESULTS: Nine gynaecologists were interviewed. Data indicated they continuously weighed the chance of a successful outcome of trial of labour against the likelihood of adversities. Patients' opinions, aspects of progress of labour and gynaecologists' personal stances regarding trial of labour played a role in the decision-making process; these factors are influenced by organisational affordances and culture. Variation in the assessment of individuals' chances of success and variable thresholds for a repeat caesarean added to the complexity of the decision-making. CONCLUSION: This study pieced together patient-, delivery-, physician- and society-related factors that result in vitally important decisions during trial of labour after caesarean; it reveals the complexity as well as the repetitive patterns involved in this process. Exposing these factors offers opportunities to incorporate the decision-making process in targeted educational interventions, with the aim of modifying the underlying assumptions and concepts in order to reduce practice variation. PMID- 30020945 TI - Elucidating "lucidum": Distinguishing the diverse laccate Ganoderma species of the United States. AB - Ganoderma is a large, diverse and globally-distributed genus in the Basidiomycota that includes species causing a white rot form of wood decay on a variety of tree species. For the past century, many studies of Ganoderma in North America and other regions of the world have used the name G. lucidum sensu lato for any laccate (shiny or varnished) Ganoderma species growing on hardwood trees or substrates. Molecular studies have established that G. lucidum sensu stricto (Curtis) Karst is native to Europe and some parts of China. To determine the species of the laccate Ganoderma that are present in the United States, we studied over 500 collections from recently collected samples and herbarium specimens from hardwoods, conifers, and monocots. A multilocus phylogeny using ITS, tef1alpha, rpb1 and rpb2 revealed three well-supported clades, similar to previously reported findings. From the U.S. collections, thirteen taxa representing twelve species were identified, including: G. curtisii, G. lucidum sensu stricto, G. martinicense, G. oregonense, G. polychromum, G. ravenelii, G. sessile, G. tsugae, G. tuberculosum, G. cf. weberianum, G. zonatum, and Tomophagus colossus (syn. G. colossus). The species G. meredithiae is synonymized with G. curtisii, and considered a physiological variant that specializes in decay of pines. The designation G. curtisii f.sp. meredithiae forma specialis nov. is proposed. Species such as G. curtisii and G. sessile, once considered as G. lucidum sensu lato, were found to be divergent from one another, and highly divergent from G. lucidum sensu stricto. Morphological characteristics such as context tissue color and features (e.g. melanoid bands), basidiospore shape and size, geographic location, and host preference were found to aid in species identification. Surprisingly, G. lucidum sensu stricto was found in the U.S., but only in geographically restricted areas of northern Utah and California. These collections appear to have resulted from the introduction of this species into the United States possibly from mushroom growers producing G. lucidum outdoors. Overall, this study clarifies the chaotic taxonomy of the laccate Ganoderma in the United States, and will help to remove ambiguities from future studies focusing on the North American species of laccate Ganoderma. PMID- 30020946 TI - Table tennis playing styles require specific energy systems demands. AB - The aim of the present study was to investigate the differences in energy system contributions and temporal variables between offensive and all-round playing styles. Fifteen male table tennis players (Offensive players: N = 7; All-round players: N = 8) participated in the study. Matches were monitored by a portable gas analyzer and the blood lactate responses was also measured. The contributions of the oxidative (WOXID), phosphagen (WPCr), and glycolytic (W[La]) energy systems were assumed as the oxygen consumption measured during the matches above of baseline value, the fast component of excess post-exercise oxygen consumption (EPOCFAST) measured after the matches, and the net of blood lactate concentration (Delta[La]), respectively. Energy systems contributions were not significantly different between the offensive and all-round playing styles (WOXID: 96.1+/-2.0 and 97.0+/-0.6%, P = 0.86; WPCr: 2.7+/-1.7 and 2.0+/-0.6%, P = 0.13; W[La]: 1.2+/ 0.5 and 1.0+/-0.7%, P = 0.95; respectively), however, magnitude-based analysis of WPCr presented Likely higher contribution for offensive compared to all-round players. Regarding temporal variables, only rate of shots presented higher values for offensive when compared to all-round players (P = 0.03), while the magnitude based analysis presented Very likely lower, Likely lower and Likely higher outcomes of rate of shots, WPCr and maximal oxygen consumption, respectively, for all-round players. Strong negative correlation was verified for offensive players between number of shots and WPCr (r = -0.86, P = 0.01), while all-round players showed strong correlations between rally duration, WOXID (r = 0.76, P = 0.03) and maximal oxygen consumption (r = 0.81, P = 0.03). Therefore, despite no differences in energy system contributions for offensive and all-round players, different playing styles seems to requires specific energy systems demands. PMID- 30020948 TI - The osteology of Periptychus carinidens: A robust, ungulate-like placental mammal (Mammalia: Periptychidae) from the Paleocene of North America. AB - Periptychus is the archetypal genus of Periptychidae, a clade of prolific Paleocene 'condylarth' mammals from North America that were among the first placental mammals to radiate after the end-Cretaceous extinction, remarkable for their distinctive dental anatomy. A comprehensive understanding of the anatomy of Periptychus has been hindered by a lack of cranial and postcranial material and only cursory description of existing material. We comprehensively describe the cranial, dental and postcranial anatomy of Periptychus carinidens based on new fossil material from the early Paleocene (Torrejonian) of New Mexico, USA. The cranial anatomy of Periptychus is broadly concurrent with the inferred plesiomorphic eutherian condition, albeit more robust in overall construction. The rostrum is moderately elongate with no constriction, the facial region is broad, and the braincase is small with a well-exposed mastoid on the posterolateral corner and tall sagittal and nuchal crests. The dentition of Periptychus is characterized by strongly crenulated enamel, enlarged upper and lower premolars with a tall centralised paracone/protoconid. The postcranial skeleton of Periptychus is that of a robust, medium-sized (~20 Kg) stout-limbed animal that was incipiently mediportal and adopted a plantigrade stance. The structure of the fore- and hindlimb of Periptychus corresponds to that of a typically terrestrial mammal, while morphological features of the forelimb such as the low tubercles of the humerus, long and prominent deltopectoral crest, pronounced medial epicondyle, and hemispherical capitulum indicate some scansorial and/or fossorial ability. Most striking is the strongly dorsoplantarly compressed astragalus of Periptychus, which in combination with the distal crus and calcaneal morphology indicates a moderately mobile cruropedal joint. The anatomy of Periptychus is unique and lacks any extant analogue; it combines a basic early placental body plan with numerous unique specializations in its dental, cranial and postcranial anatomy that exemplify the ability of mammals to adapt and evolve following catastrophic environmental upheaval. PMID- 30020947 TI - Maternal consumption of green tea extract during pregnancy and lactation alters offspring's metabolism in rats. AB - INTRODUCTION: Green tea extract has anti-inflammatory and antioxidant effects which improve dyslipidemia and decrease adipose tissue depots associated with hyperlipidic diet consumption. OBJECTIVE: To evaluate the effect of green tea extract consumption by rats during pregnancy and lactation on the metabolism of their offspring that received control or high-fat diet with water during 10 weeks after weaning. METHODS: Wistar rats received water (W) or green tea extract diluted in water (G) (400 mg/kg body weight/day), and control diet (10 animals in W and G groups) during pregnancy and lactation. After weaning, offspring received water and a control (CW) or a high-fat diet (HW), for 10 weeks. One week before the end of treatment, oral glucose tolerance test was performed. The animals were euthanized and the samples were collected for biochemical, hormonal and antioxidant enzymes activity analyses. In addition, IL-10, TNF-alpha, IL-6, and IL-1beta were quantified by ELISA while p-NF-kappaBp50 was analyzed by Western Blotting. Repeated Measures ANOVA, followed by Tukey's test were used to find differences between data (p < 0.05). RESULTS: The consumption of high-fat diet by rats for 10 weeks after weaning promoted hyperglycemia and hyperinsulinemia, and increased fat depots. The ingestion of a high-fat diet by the offspring of mothers who consumed green tea extract during pregnancy and lactation decreased the inflammatory cytokines in adipose tissue, while the ingestion of a control diet increased the same cytokines. CONCLUSION: Our results demonstrate that prenatal consumption of green tea associated with consumption of high-fat diet by offspring after weaning prevented inflammation. However, maternal consumption of the green tea extract induced a proinflammatory status in the adipose tissue of the adult offspring that received the control diet after weaning. PMID- 30020949 TI - Valence-space associations in touchscreen interactions: Valence match between emotional pictures and their vertical touch location leads to pictures' positive evaluation. AB - Embodied cognition research suggests that bodily experiences might ground mental representations of emotional valence in the vertical dimension of space (i.e., positive is up and negative is down). Accordingly, recent studies show that upward and downward arm movements may also influence the evaluation of valence laden stimuli, suggesting that upward (downwards) movements lead to more positive (negative) evaluations. Interestingly, these studies typically did not investigate paradigms that require a direct hand interaction with the stimuli. With the advent of touchscreen devices and their use for experimental environments, however, a direct and more natural hand interaction with the stimuli has come to the fore. In this regard, the goal of the present study is to examine how direct hand interaction with valence-laden stimuli on a touchscreen monitor affects their perceived valence. To do so, participants evaluated emotional pictures after touching and moving them either upwards or downwards across a vertically mounted touchscreen. In contrast to previous findings, the results suggest that positive pictures were evaluated as more positive after downward movements while negative pictures were evaluated as less negative following upward movements. This finding may indicate that a matching between the pictures' valence and the valence associated with their vertical touch location leads to more positive evaluations. Thus, the present study extends earlier results by an important point: Touching the emotional pictures during movement may influence their valence processing. PMID- 30020950 TI - Prognostic implication of monocytes in atrial fibrillation: The West Birmingham Atrial Fibrillation Project. AB - BACKGROUND AND OBJECTIVES: High monocyte counts are related to adverse outcomes in cardiovascular disease. Their role in prognostication in patients with atrial fibrillation (AF) is unknown. We investigated whether monocyte counts are useful as a marker of prognosis in patients with AF. METHODS: Monocyte counts were obtained from blood samples in 881 AF patients. Study outcomes were (i) all-cause death; (ii) major adverse cardiovascular events; (iii) stroke, TIA or other systemic embolism (SSE); and (iv) major bleeding. RESULTS: Median follow up was 7.2 years; 44% of patients died, 48% developed MACE; 9% had SSE and 5% had major bleeding. On Cox regression, after adjustment for CHA2DS2-VASc score, the highest quartile of monocyte counts (i.e., >=580 MUL vs. other quartiles) was associated with increased risk of death (hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.31-2.05, p<0.001) and MACE (HR 1.58, 95% CI 1.28-1.96, p<0.001). Persistent monocyte levels >=580 per MUL during follow up were associated with further increase in risk of death (HR 1.52, 95% CI 1.10-2.11, p = 0.01) and MACE (HR 1.54, 95% CI 1.13-2.09, p = 0.006). Persistent monocyte levels >=580 per MUL during were associated with a significant increase in major bleeding events (HR 2.77, 95% CI 1.36-5.67, p = 0.005, after adjustment for HAS-BLED score). CONCLUSION: High monocyte counts independently predict the occurrence of MACE, major bleeding and mortality, but not SSE. Understanding the pathophysiological mechanisms involved would help understand the relationships between monocytes, and adverse thrombotic and bleeding outcomes in AF patients. PMID- 30020951 TI - Assessment of CD52 expression in "double-hit" and "double-expressor" lymphomas: Implications for clinical trial eligibility. AB - "Double-hit" and "double-expressor" lymphomas represent distinct but overlapping subsets of aggressive B-cell non-Hodgkin lymphoma. The high rates of bone marrow involvement by these lymphomas pose a major therapeutic challenge due to the chemotherapy-resistant nature of the bone marrow microenvironment and the limited utility of rituximab-based salvage regimens in patients with relapsed/refractory disease. Preclinical studies utilizing high-dose cyclophosphamide in combination with the anti-CD52 monoclonal antibody alemtuzumab have recently shown promise in the treatment of intramedullary disease, and a Phase I human trial is now underway. In support of such efforts, here we perform CD52 target validation on a series of double-hit (n = 40) and double-expressor (n = 58) lymphomas using immunohistochemistry. CD52 expression levels varied considerably across samples, however positive staining was observed in 75% of both double-hit and double expressor lymphomas. Similarly, high levels of CD52 expression were seen in patients whose disease was associated with high-risk clinical features, including primary refractory status (73%), higher IPI score (76%), and bone marrow involvement (74%). CD52 expression was not significantly correlated with diagnostically relevant pathologic features such as morphology, cytogenetic findings or other immunophenotypic features, but was notably present in all cases lacking CD20 expression (n = 6). We propose that CD52 expression status be evaluated on a case-by-case basis to guide eligibility for clinical trial enrollment. PMID- 30020953 TI - A note on internet use and the 2016 U.S. presidential election outcome. AB - We use data from the American National Election Studies from 1996 to 2016 to study the role of the internet in the 2016 U.S. presidential election outcome. We compare trends in the Republican share of the vote between likely and unlikely internet users, and between actual internet users and non-users. Relative to prior years, the Republican share of the vote in 2016 was as high or higher among the groups least active online. PMID- 30020952 TI - Outcome of patients with acute bacterial meningitis in a teaching hospital in Ethiopia: A prospective study. AB - BACKGROUND: The mortality and neurologic sequelae associated with acute bacterial meningitis (ABM) remain high despite advances in medical care. The main aim of this study was to evaluate short-term outcome in patients treated as bacterial meningitis at a teaching hospital in Ethiopia to identify factors that could be focused on to improve outcome in this setting. METHODS: A hospital based longitudinal study was conducted at Jimma University Hospital in southwest Ethiopia from March 1, 2013 to December 31, 2015. Participants of this study were patients of age 18 years and older who were treated as confirmed or possible cases of ABM. Patients were followed throughout their hospital stay for change in their clinical course and predefined end points. A multivariable analysis was done to identify factors associated with unfavorable outcomes. RESULT: 90 patients admitted with diagnosis of acute bacterial meningitis were included in the study; cerebrospinal fluid was analysed for 85 (94.4%) of them. Causative bacteria were isolated in 26 (28.9%) patients only; most of these isolates (84.6%) were either Streptococcus pneumoniae or Neisseria meningitidis. Patients managed as cases of ABM at the hospital suffered from a high rate of unfavorable outcome (36.7%) and an overall mortality rate of 22.2%. Impaired level of consciousness (AOR = 0.766, 95% CI = 0.589-0.995), dexamethasone therapy (AOR = 4.676, 95% CI = 1.12-19.50) and fever persisting after two days of admission (AOR = 24.226, 95% CI = 5.24-111.96) were found to be independently associated with unfavorable outcome. CONCLUSION: Outcome in patients treated for ABM at the hospital was found to be poor. Impaired mentation, treatment with adjunctive dexamethasone and persistent fever were found to be associated with poor outcome. Thus, development of clinical guidelines for treatment of ABM that suit the local context is essential to improve patient management and outcome. PMID- 30020954 TI - Phylogenetic analysis of canine distemper virus in South African wildlife. AB - Canine distemper virus (CDV) causes a severe contagious disease in a broad range of hosts. This is the first study to genetically characterise CDV strains from four different wildlife species in South Africa. The phylogenetic diversity of CDV is examined, using the haemagglutinin gene. The South African wildlife CDV isolates showed a high degree of similarity to CDV in South African domestic dogs. Phylogenetic analyses confirmed the presence of 12 geographical lineages with CDV strains from South African wildlife falling within the Southern African lineage. The study reveals two possible co-circulating sub-genotypes corresponding to the northern and southern regions of South Africa respectively. CDV strains from the non-canid species were distinct, but similar to CDV isolates from domestic dog and wild canids. Residues at amino acid sites of the SLAM binding region support the notion that CDV strains encoding 519I / 549H are better adapted to non-canid species than canid species. The amino acids present at site 530 are conserved regardless of host species. Strains from South African wild carnivores showed no difference between host species with all strains presenting 530N. All non-canid strains in this study presented the combination 519I/549H. No evidence of host adaptation or lineage grouping was observed for the Nectin-4 binding region. Further studies should include CDV strains isolated from various hosts from a wider geographical range in South Africa. PMID- 30020955 TI - Evidence of a positive association between malpractice climate and thyroid cancer incidence in the United States. AB - The incidence of thyroid cancer has risen dramatically in the past few decades. The cause of this is unclear, but several lines of evidence indicate it is largely due to overdiagnosis, the diagnosis of tumors that would have never manifest clinically if untreated. Practices leading to overdiagnosis may relate to defensive medicine. In this study, we evaluated the association between malpractice climate and incidence of thyroid, breast, prostate, colon, and lung cancer in U.S. states from 1999-2012 using publicly available government data. State-level malpractice risk was quantified as malpractice payout rate, the number of malpractice payouts per 100,000 people per state per year. Associations between state-level cancer incidence, malpractice payout rate, and several cancer risk factors were evaluated. Risk factors included several social determinants of health, including factors predicting healthcare access. States with higher malpractice payout rate had higher thyroid cancer incidence, on both univariate analysis (r = 0.51, P = 0.009, Spearman) and multivariate analysis (P<0.001, multilevel model). In contrast, state-level malpractice payout rate was not associated with incidence of any other cancer type. Malpractice climate may be a social determinant for being diagnosed with thyroid cancer. This may be a product of greater defensive medicine in states with higher malpractice risk, which leads to increased diagnostic testing of patients with thyroid nodules and potential overdiagnosis. Alternatively, malpractice risk may be a proxy for another, unmeasured risk factor. PMID- 30020956 TI - ProfPPIdb: Pairs of physical protein-protein interactions predicted for entire proteomes. AB - MOTIVATION: Protein-protein interactions (PPIs) play a key role in many cellular processes. Most annotations of PPIs mix experimental and computational data. The mix optimizes coverage, but obfuscates the annotation origin. Some resources excel at focusing on reliable experimental data. Here, we focused on new pairs of interacting proteins for several model organisms based solely on sequence-based prediction methods. RESULTS: We extracted reliable experimental data about which proteins interact (binary) for eight diverse model organisms from public databases, namely from Escherichia coli, Schizosaccharomyces pombe, Plasmodium falciparum, Drosophila melanogaster, Caenorhabditis elegans, Mus musculus, Rattus norvegicus, Arabidopsis thaliana, and for the previously used Homo sapiens and Saccharomyces cerevisiae. Those data were the base to develop a PPI prediction method for each model organism. The method used evolutionary information through a profile-kernel Support Vector Machine (SVM). With the resulting eight models, we predicted all possible protein pairs in each organism and made the top predictions available through a web application. Almost all of the PPIs made available were predicted between proteins that have not been observed in any interaction, in particular for less well-studied organisms. Thus, our work complements existing resources and is particularly helpful for designing experiments because of its uniqueness. Experimental annotations and computational predictions are strongly influenced by the fact that some proteins have many partners and others few. To optimize machine learning, recent methods explicitly ignored such a network-structure and rely either on domain knowledge or sequence only methods. Our approach is independent of domain-knowledge and leverages evolutionary information. The database interface representing our results is accessible from https://rostlab.org/services/ppipair/. The data can also be downloaded from https://figshare.com/collections/ProfPPI-DB/4141784. PMID- 30020957 TI - A novel method for quantifying axon degeneration. AB - Axons normally degenerate during development of the mammalian nervous system, but dysregulation of the same genetically-encoded destructive cellular machinery can destroy crucial structures during adult neurodegenerative diseases. Nerve growth factor (NGF) withdrawal from dorsal root ganglia (DRG) axons is a well established in vitro experimental model for biochemical and cell biological studies of developmental degeneration. Definitive methods for measuring axon degeneration have been lacking and here we report a novel method of axon degeneration quantification from bulk cultures of DRG that enables objective and automated measurement of axonal density over the entire field of radial axon outgrowth from the ganglion. As proof of principal, this new method, written as an R script called Axoquant 2.0, was used to examine the role of extracellular Ca2+ in the execution of cytoskeletal disassembly during degeneration of NGF deprived DRG axons. This method can be easily applied to examine degenerative or neuroprotective effects of gene manipulations and pharmacological interventions. PMID- 30020958 TI - Progress in Mozambique: Changes in the availability, use, and quality of emergency obstetric and newborn care between 2007 and 2012. AB - INTRODUCTION: Maternal mortality in Mozambique has not declined significantly in the last 10-15 years, plateauing around 480 maternal deaths per 100,000 live births. Good quality antenatal care and routine and emergency intrapartum care are critical to reducing preventable maternal and newborn deaths. MATERIALS AND METHODS: We compare the findings from two national cross-sectional facility-based assessments conducted in 2007 and 2012. Both were designed to measure the availability, use and quality of emergency obstetric and neonatal care. Indicators for monitoring emergency obstetric care were used as were descriptive statistics. RESULTS: The availability of facilities providing the full range of obstetric life-saving procedures (signal functions) decreased. However, an expansion in the provision of individual signal functions was highly visible in health centers and health posts, but in hospitals, performance was less satisfactory, with proportionally fewer hospitals providing assisted vaginal delivery, obstetric surgery and blood transfusions. All other key indicators showed signs of improvements: the institutional delivery rate, the cesarean delivery rate, met need for emergency obstetric care (EmOC), institutional stillbirth and early neonatal death rates, and cause-specific case fatality rates (CFRs). CFRs for most major obstetric complications declined between 17% and 69%. The contribution of direct causes to maternal deaths decreased while the proportion of indirect causes doubled during the five-year interval. CONCLUSIONS: The indicator of EmOC service availability, often used for planning and developing EmONC networks, requires close examination. The standard definition can mask programmatic weaknesses and thus, fails to inform decision makers of what to target. In this case, the decline in the use of assisted vaginal delivery explained much of the difference in this indicator between the two surveys, as did faltering hospital performance. Despite this backsliding, many signs of improvement were also observed in this 5-year period, but indicator levels continue below recommended thresholds. The quality of intrapartum care and the adverse consequences from infectious diseases during pregnancy point to priority areas for programmatic improvement. PMID- 30020959 TI - The advantages of using drones over space-borne imagery in the mapping of mangrove forests. AB - Satellite data and aerial photos have proved to be useful in efficient conservation and management of mangrove ecosystems. However, there have been only very few attempts to demonstrate the ability of drone images, and none so far to observe vegetation (species-level) mapping. The present study compares the utility of drone images (DJI-Phantom-2 with SJ4000 RGB and IR cameras, spatial resolution: 5cm) and satellite images (Pleiades-1B, spatial resolution: 50cm) for mangrove mapping-specifically in terms of image quality, efficiency and classification accuracy, at the Setiu Wetland in Malaysia. Both object- and pixel based classification approaches were tested (QGIS v.2.12.3 with Orfeo Toolbox). The object-based classification (using a manual rule-set algorithm) of drone imagery with dominant land-cover features (i.e. water, land, Avicennia alba, Nypa fruticans, Rhizophora apiculata and Casuarina equisetifolia) provided the highest accuracy (overall accuracy (OA): 94.0+/-0.5% and specific producer accuracy (SPA): 97.0+/-9.3%) as compared to the Pleiades imagery (OA: 72.2+/-2.7% and SPA: 51.9+/-22.7%). In addition, the pixel-based classification (using a maximum likelihood algorithm) of drone imagery provided better accuracy (OA: 90.0+/-1.9% and SPA: 87.2+/-5.1%) compared to the Pleiades (OA: 82.8+/-3.5% and SPA: 80.4+/ 14.3%). Nevertheless, the drone provided higher temporal resolution images, even on cloudy days, an exceptional benefit when working in a humid tropical climate. In terms of the user-costs, drone costs are much higher, but this becomes advantageous over satellite data for long-term monitoring of a small area. Due to the large data size of the drone imagery, its processing time was about ten times greater than that of the satellite image, and varied according to the various image processing techniques employed (in pixel-based classification, drone >50 hours, Pleiades <5 hours), constituting the main disadvantage of UAV remote sensing. However, the mangrove mapping based on the drone aerial photos provided unprecedented results for Setiu, and was proven to be a viable alternative to satellite-based monitoring/management of these ecosystems. The improvements of drone technology will help to make drone use even more competitive in the future. PMID- 30020961 TI - Utility of high b-value (2000 sec/mm2) DWI with RESOLVE in differentiating papillary thyroid carcinomas and papillary thyroid microcarcinomas from benign thyroid nodules. AB - PURPOSE: The aim of the study was to evaluate the role of high b-value (2000 sec/mm2) diffusion-weighted imaging (DWI) by using Readout Segmentation of Long Variable Echo-trains (RESOLVE) in differentiating papillary thyroid carcinomas (PTCs) and papillary thyroid microcarcinomas (PTMCs) from benign thyroid nodules. MATERIALS AND METHODS: Consecutive patients with thyroid nodules scheduled for surgery underwent high b-value DWI with 3 b-values: 0, 800 and 2000 sec/mm2. Signal intensity ratios (SIRs) of thyroid nodules to adjacent normal thyroid tissue on DWI were measured as: SIRb0, SIRb800 and SIRb2000. Apparent diffusion coefficient (ADC) values based on the 3 different b-values were acquired as: ADCb0-800, ADCb0-2000, and ADCb0-800-2000. The 6 diagnostic indicators were evaluated by receiver operating characteristic (ROC) and diagnostic ability was compared between high b-value DWI and Ultrasound (US). RESULTS: A total of 52 PTCs including 33 PTMCs (38 patients, 8 men and 30 women, aged 45.68 +/- 11.93 years) and 62 benign thyroid nodules (46 patients, 7 men and 39 women, aged 48.73 +/- 11.98 years) were enrolled into the final statistical analysis. ADCb0-800 2000 had the highest diagnostic ability in differentiating PTCs from benign thyroid nodules with area under curve (AUC) of 0.944, sensitivity of 96.15% and specificity of 85.48%, and PTMCs from benign thyroid nodules with AUC of 0.940, sensitivity of 93.94% and specificity of 85.48%. On the strength of lower false positive rates than US (14.52% vs. 32.26% for PTCs and 14.52% vs. 32.26% for PTMCs), ADCb0-800-2000 had significantly better diagnostic ability in PTCs (P = 0.002) and PTMCs (P = 0.005). CONCLUSION: High b-value (2000 sec/mm2) DWI can contribute to differentiating PTCs and PTMCs from benign thyroid nodules and can be potentially used as an active surveillance imaging method for PTMCs. PMID- 30020960 TI - Prevalence and mapping of hepatitis C infections among men who have sex with men in New York City. AB - Emerging sexually transmitted hepatitis C virus (HCV) epidemics among men who have sex with men (MSM) have been reported worldwide, with higher HCV infection rates among those who are HIV-infected. This study aims to determine prevalence of recent and chronic HCV infections among community-recruited MSM in New York City (NYC), map HCV infections by home, social, and sexual neighborhoods, and identify clusters of genetically linked HCV variants using phylogenetic analysis. The NYC M2M study recruited MSM via modified time-space, venue-based sampling and internet/mobile app-based recruitment during 2010-13. Participants completed a Google Earth map on neighborhoods of where they lived, socialized, and had sex in the last 3 months, an ACASI questionnaire, and a sexual network inventory about their sex partners. The men received HIV testing and provided serum samples. Testing on stored serum samples included HCV antibody and RNA viral load, HCV antibody avidity assay (avidity index <30% with positive viral load is considered recently infected), and HCV RNA extraction and amplification to generate a 432 base-pair region of Core/E1 for sequencing and phylogenetic analysis. Historic local controls were included in the phylogenetic analysis. Of 1,028 MSM, 79.7% were HIV-negative and 20.3% HIV-positive. Twenty nine MSM (2.8%) were HCV antibody-positive. MSM who were HCV antibody-positive reported a median of 2 male sex partners in last 3 months, with 6.9% aged 18-24, 17.2% 25-29, 13.8% 30-39, and 62.1% 40 and over. 8.1% of HIV-positive MSM were HCV antibody-positive vs. 1.5% of HIV-negative men (p<0.0001). Of 29 HCV-antibody positive MSM, 12 (41%) were HCV RNA-positive (11 subtype 1a and 1 subtype 1b). Two of 12 HCV RNA positive participants had low antibody avidity values, suggesting recent HCV infection. HCV antibody seropositivity was significantly associated with older age >40 years, adjusted odds ratio (aOR) 3.56 (95% CI 1.57, 8.08), HIV-positive serostatus, aOR 3.18 (95% CI 1.40, 7.22), any sexually transmitted infection (STI) in the last 3 months, aOR 2.81 (95% CI 1.11, 7.13), and injection drug use (IDU) ever, aOR 4.34 (95% CI 1.69, 11.17). Mapping of HCV infections differed slightly by home, social, and sexual neighborhoods. Based on phylogenetic analysis from 12 HCV RNA-positive samples, no evidence of a clustered HCV epidemic was found. Overall HCV seroprevalence was 2.8% among community-recruited MSM in NYC, with higher prevalence among HIV-positive MSM compared to HIV negative MSM. Only two participants were found to have recent HCV infection, with no evidence of a clustered HCV epidemic based on phylogenetic analysis. Our results support testing of HCV infection among HIV-negative MSM if they report having a recent STI and IDU in the past rather than universal HCV testing in all HIV-negative MSM. PMID- 30020962 TI - Assessment of willingness to pay for expanded carrier screening among women and couples undergoing preconception carrier screening. AB - BACKGROUND: Expanded carrier screening can provide risk information for numerous conditions. Understanding how individuals undergoing preconception expanded carrier screening value this information is important. The NextGen study evaluated the use of genome sequencing for expanded carrier screening and reporting secondary findings, and we measured participants' willingness to pay for this approach to understand how it is valued by women and couples planning a pregnancy. METHODS: We assessed 277 participants' willingness to pay for genome sequencing reporting carrier results for 728 gene/condition pairs and results for 121 secondary findings. We explored the association between attitudes and demographic factors and willingness to pay for expanded carrier screening using genome sequencing and conducted interviews with 58 of these participants to probe the reasoning behind their preferences. RESULTS: Most participants were willing to pay for expanded carrier screening using genome sequencing. Willingness to pay was associated with income level and religiosity, but not risk status for a condition in the carrier panel. Participants willing to pay nothing or a small amount cited issues around financial resources, whereas those willing to pay higher amounts were motivated by "peace of mind" from carrier results. CONCLUSION: Women and couples planning a pregnancy value genome sequencing. The potentially high out-of-pocket cost of this service could result in healthcare disparities, since maximum amounts that participants were willing to pay were higher than a typical copay and related to income. PMID- 30020963 TI - It's not all about the Soprano: Rhinolophid bats use multiple acoustic components in echolocation pulses to discriminate between conspecifics and heterospecifics. AB - Acoustic communication plays a pivotal role in conspecific recognition in numerous animal taxa. Vocalizations must therefore have discrete acoustic signatures to facilitate intra-specific communication and to avoid misidentification. Here we investigate the potential role of echolocation in communication in horseshoe bats. Although it has been demonstrated that echolocation can be used to discriminate among con- and hetero-specifics, the specific acoustic cues used in discrimination are still relatively unknown. Furthermore, the Acoustic Communication Hypothesis proposes that in multispecies assemblages, in which echolocation frequencies are likely to overlap, bats partition acoustic space along several dimensions so that each species occupies a discrete communication domain. Thus, multiple echolocation variables may be used in discrimination. The objective of this study was to investigate the potential of various echolocation variables to function as discriminatory cues in echolocation-based species discrimination. Using habituation-dishabituation playback experiments, we firstly tested the ability of Rhinolophus clivosus to discriminate between echolocation pulses of heterospecifics with either discrete or overlapping frequencies. Secondly, to determine whether R. clivosus could use echolocation variables other than frequency, we investigated its ability to discriminate among echolocation pulses differing in only one manipulated parameter. These test variables were identified by their contribution to the dissimilarity among pulses. Our results suggest that R. clivosus could discriminate readily between species using echolocation pulses with discrete frequencies. When frequencies overlapped, the ability of bats to discriminate was dependant on additional acoustic variables that defined the acoustic space occupied by the test signal. These additional acoustic variables included, but may not be restricted to, sweep rate of the FM and duty cycle. Thus, when echolocation pulses share a similar acoustic domain, bats use several cues to reliably discriminate among heterospecifics. PMID- 30020964 TI - Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy. AB - As antiretroviral therapy (ART) expands in resource-limited settings, understanding the impact of ART on pregnancy outcomes is critical. We analyzed women who became pregnant on ART while enrolled in a clinical trial (HPTN 052, ACTG A5208, and ACTG A5175); the majority of women were from Africa, with a median age of 29 years. Eligible women were on ART at conception and had a documented date of a last menstrual period and a pregnancy outcome. The primary outcome was non-live birth (stillbirth; spontaneous abortion; elective termination; or ectopic pregnancy) versus live birth. Preterm birth (<37 weeks completed gestation) was a secondary outcome. We used Cox proportional hazards regression models with time-varying covariates. 359 women became pregnant, of whom 253 (70%) met inclusion criteria: 127 (50%) were on NNRTI-based ART, 118 (47%) on PI-based ART, and 8 (3%) on 3-NRTIs at conception. There were 160 (63%) live births (76 term and 84 preterm), 11 (4%) stillbirths, 51 (20%) spontaneous abortions, 28 (11%) elective terminations, and 3 (1%) ectopic pregnancies. In multivariable analysis adjusted for region, parent study, and pre-pregnancy ART class, only older age was associated with increased hazard of preterm birth [HR: 2.49 for age 25-30 years; 95% CI: 1.18-5.26; p = 0.017]. Women conceiving on ART had high rates of preterm birth and other adverse pregnancy outcomes. Despite the benefits of ART, studies designed to investigate the effects of preconception ART on pregnancy outcomes are needed. PMID- 30020965 TI - Ethnic diversity, poverty and social trust in Germany: Evidence from a behavioral measure of trust. AB - Several scholars have concluded that ethnic diversity has negative consequences for social trust. However, recent research has called into question whether ethnic diversity per se has detrimental effects, or whether lower levels of trust in diverse communities simply reflect a higher concentration of less trusting groups, such as poor people, minorities, or immigrants. Drawing upon a nationally representative sample of the German population (GSOEP), we make two contributions to this debate. First, we examine how ethnic diversity at the neighborhood level specifically the proportion of immigrants in the neighborhood-is linked to social trust focusing on the compositional effect of poverty. Second, in contrast to the majority of current research on ethnic diversity, we use a behavioral measure of trust in combination with fine-grained (zip-code level) contextual measures of ethnic composition and poverty. Furthermore, we are also able to compare the behavioral measure to a standard attitudinal trust question. We find that household poverty partially accounts for lower levels of trust, and that after controlling for income, German and non-German respondents are equally trusting. However, being surrounded by neighbors with immigrant background is also associated with lower levels of social trust. PMID- 30020966 TI - Hypotheses and evidence related to intense sweeteners and effects on appetite and body weight changes: A scoping review of reviews. AB - Observed associations between consumption of diet foods and obesity have sparked controversy over whether intense sweeteners may promote weight gain, despite their negligible energy contribution. We conducted a scoping review of reviews, to obtain an overview of hypotheses, research approaches and features of the evidence on intense sweeteners' potential relationships to appetite and weight changes. We searched for reviews of the scientific literature published from 2006 to May 2017. Two reviewers independently assessed title and abstracts, and full text publications. Arksey and O'Malley's framework for scoping reviews guided the process. We extracted and charted data on characteristics of the reviews and the evidence presented. The 40 included reviews present hypotheses both on how intense sweeteners can reduce or maintain body weight and on how these can promote weight gain. We classified only five publications as systematic reviews; another nine presented some systematic approaches, while 26 reviews did not describe criteria for selecting or assessing the primary studies. Evidence was often presented for intense sweeteners as a group or unspecified, and against several comparators (e.g. sugar, water, placebo, intake levels) with limited discussion on the interpretation of different combinations. Apart from the observational studies, the presented primary evidence in humans is dominated by small studies with short follow-up-considered insufficient to assess weight change. Systematic reviews of animal studies are lacking in this topic area. The systematic evidence only partly explore forwarded hypotheses found in the literature. Primary studies in humans seem to be available for systematic exploration of some hypotheses, but long-term experimental studies in humans appear sparse. With few exceptions, the reviews on intense sweeteners and weight change underuse systematic methodology, and thus, the available evidence. Further studies and systematic reviews should be explicit about the hypothesis explored and elucidate possible underlying mechanisms. PMID- 30020967 TI - No evidence that facial width-to-height ratio (fWHR) is associated with women's sexual desire. AB - Facial width-to-height ratio (fWHR) has been linked to many different behavioral tendencies. However, not all of these correlations have replicated well across samples. Arnocky et al. (in press, Archives of Sexual Behavior) recently reported that sexual desire was correlated with fWHR. The current study aimed to test this relationship in a large sample of women. fWHR was measured from face images of 754 women. Each woman completed the Sexual Desire Inventory, which measures total, dyadic, and solitary sexual desire. Analyses revealed no significant correlations between fWHR and any of our measures of sexual desire. These null results do not support the hypothesis that fWHR is related to women's sexual desire. Additionally, we found no evidence that women's face-shape sexual dimorphism was related to their sociosexual orientation. PMID- 30020968 TI - Predictive gravity models of livestock mobility in Mauritania: The effects of supply, demand and cultural factors. AB - Animal movements are typically driven by areas of supply and demand for animal products and by the seasonality of production and demand. As animals can potentially spread infectious diseases, disease prevention can benefit from a better understanding of the factors influencing movements patterns in space and time. In Mauritania, an important cultural event, called the Tabaski (Aid el Kebir) strongly affects timing and structure of movements, and due to the arid and semi-arid climatic conditions, the season can also influence movement patterns. In order to better characterize the animal movements patterns, a survey was carried out in 2014, and those data were analysed here using social network analysis (SNA) metrics and used to train predictive gravity models. More specifically, we aimed to contrast the movements structure by ruminant species, season (Tabaski vs. Non-Tabaski) and mode of transport (truck vs. foot). The networks differed according to the species, and to the season, with a changed proportion of truck vs. foot movements. The gravity models were able to predict the probability of a movement link between two locations with moderate to good accuracy (AUC ranging from 0.76 to 0.97), according to species, seasons, and mode of transport, but we failed to predict the traded volume of those trade links. The significant predictor variables of a movement link were the human and sheep population at the source and origin, and the distance separating the locations. Though some improvements would be needed to predict traded volumes and better account for the barriers to mobility, the results provide useful predictions to inform epidemiological models in space and time, and, upon external validation, could be useful to predict movements at a larger regional scale. PMID- 30020969 TI - A novel multiplex assay of SNP-STR markers for forensic purpose. AB - Like DIP-STR markers (deletion/insertion polymorphism-short tandem repeat combinations), SNP-STR markers (single nucleotide polymorphism-STR combinations) are also valuable in forensic DNA mixture analysis. In this study, eight SNP-STRs were selected, and a stable and sensitive multiplex polymerase chain reaction (PCR) assay was developed for amplifying these SNP-STRs and the Amelogenin gender marker according to the principle of amplification refractory mutation system (ARMS). This novel multiplex set allows detection of the minor DNA contributor in a DNA mixture of any gender and cellular origin with high resolution (beyond a DNA ratio of 1:20). In addition, SNP-STR haplotype frequencies were estimated based on a survey of 350 unrelated individuals from Chinese Han population, and the combined power of discrimination (PD) and power of exclusion (PE) of the eight SNP-STRs were calculated as 0.99999999965 and 0.9996, which were obviously higher than that of the eight STR loci: 0.9999999954 and 0.9989 respectively. The results indicated that the SNP-STR compound markers have higher application value in forensic identification compared to standard autosomal STRs, especially in the analysis of imbalanced DNA mixtures. PMID- 30020970 TI - Factors associated with lumbar spinal stenosis in a large-scale, population-based cohort: The Wakayama Spine Study. AB - OBJECTIVE: Patients with lumbar spinal stenosis (LSS) who have radiographically similar degrees of stenosis may not necessarily exhibit equivalent symptoms. As part of a cross-sectional study, we examined factors associated with symptomatic LSS (sLSS) in the general population of Japan. METHODS: We evaluated 968 participants (men, 319; women, 649) between 2008 and 2010. Orthopedic surgery specialists diagnosed sLSS using interview results, medical examinations, and imaging findings. LSS was radiographically graded using a 4-level scale. Additionally, we examined basic anthropometry, smoking habits, alcohol consumption, ankle-brachial index values (ABI), and glycosylated hemoglobin (HbA1c) levels. We grouped patients with moderate and severe radiographic LSS, and compared the indicated factors on the basis of the presence/absence of sLSS. Data were evaluated using multiple logistic regression analyses. RESULTS: Radiographically, 451 participants had moderate and 288 severe stenosis. Clinically, 92 participants were diagnosed with sLSS, including 36 with moderate and 52 with severe stenosis. In the moderate stenosis group, participants with sLSS had significantly higher rates of diabetes mellitus (DM) and lower ABIs than did non-LSS participants. Although sLSS participants tended to be older (p = 0.19), there were no significant differences in the sex distribution, body mass index values, or in the percentages of participants who were drinkers/smokers. In the severe stenosis group, there were no differences in any of the evaluated factors. Multiple logistic regression showed that DM (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.52-9.34]) and low ABI (1 SD = 0.09; OR, 1.36; 95% CI, 1.04-1.81) were significantly associated with LSS in the moderate stenosis group. CONCLUSIONS: DM and low ABIs are significantly associated with sLSS in patients with moderate radiographic stenosis. Neither factor is associated with sLSS in patients with severe stenosis. Notably, the effects of intrinsic factors on symptomology may be masked when anatomic stenosis is severe. PMID- 30020971 TI - Nuclear receptor/Wnt beta-catenin interactions are regulated via differential CBP/p300 coactivator usage. AB - Over 400 million years ago, the evolution of vertebrates gave rise to a life cycle in which the organism began to live longer particularly as an adult. To accommodate such a longer lifespan, the organism underwent adaptation, developing a mechanism for long-lived cellular homeostasis. This adaptation required a population of long-lived relatively quiescent somatic stem cells (SSCs) along with a more proliferative differentiated daughter cell population, and was necessary to safeguard the genetic attributes with which SSCs were endowed. Intriguingly, cAMP response element binding protein (CREB)-binding protein (CBP) and E1A-binding protein, 300 kDa (p300), the highly homologous Kat3 coactivators had diverged, through duplication of ancestral Kat3, immediately preceding the evolution of vertebrates, given that both CBP and p300 have been detected in nearly all vertebrates versus non-vertebrates. We now demonstrate that a relatively small, highly evolutionarily conserved, amino terminal 9 amino acid deletion in CBP versus p300, plays a critical role in allowing for both robust maintenance of genomic integrity in stem cells and the initiation of a feed forward differentiation mechanism by tightly controlling the interaction of the nuclear receptor family with the Wnt signaling cascade in either an antagonistic or synergistic manner. PMID- 30020973 TI - Alcohol consumption and future hospital usage: The EPIC-Norfolk prospective population study. AB - BACKGROUND: Heavy drinkers of alcohol are reported to use hospitals more than non drinkers, but it is unclear whether light-to-moderate drinkers use hospitals more than non-drinkers. OBJECTIVE: We examined the relationship between alcohol consumption in 10,883 men and 12,857 women aged 40-79 years in the general population and subsequent admissions to hospital and time spent in hospital. METHODS: Participants from the EPIC-Norfolk prospective population-based study were followed for ten years (1999-2009) using record linkage. RESULTS: Compared to current non-drinkers, men who reported any alcohol drinking had a lower risk of spending more than twenty days in hospital multivariable adjusted OR 0.80 (95%CI 0.68-0.94) after adjusting for age, smoking status, education, social class, body mass index and prevalent diseases. Women who were current drinkers were less likely to have any hospital admissions multivariable adjusted OR 0.84 (95%CI 0.74-0.95), seven or more admissions OR 0.77 (95% CI 0.66-0.88) or more than twenty hospital days OR 0.70 (95%CI 0.62-0.80). However, compared to lifelong abstainers, men who were former drinkers had higher risk of any hospital admissions multivariable adjusted OR 2.22 (95%CI 1.51-3.28) and women former drinkers had higher risk of seven or more admissions OR 1.30 (95%CI 1.01-1.67). CONCLUSION: Current alcohol consumption was associated with lower risk of future hospital usage compared with non-drinkers in this middle aged and older population. In men, this association may in part be due to whether former drinkers are included in the non-drinker reference group but in women, the association was consistent irrespective of the choice of reference group. In addition, there were few participants in this cohort with very high current alcohol intake. The measurement of past drinking, the separation of non-drinkers into former drinkers and lifelong abstainers and the choice of reference group are all influential in interpreting the risk of alcohol consumption on future hospitalisation. PMID- 30020972 TI - Exploring temporal patterns of bacterial and fungal DNA accumulation on a ventilation system filter for a Singapore university library. AB - INTRODUCTION: Ventilation system filters process recirculated indoor air along with outdoor air. This function inspires the idea of using the filter as an indoor bioaerosol sampler. While promising, there remains a need to investigate several factors that could limit the accuracy of such a sampling approach. Among the important factors are the dynamics of microbial assemblages on filter surfaces over time and the differential influence of outdoor versus recirculated indoor air. METHODS: This study collected ventilation system filter samples from an air handling unit on a regular schedule over a 21-week period and analyzed the accumulation patterns of biological particles on the filter both quantitatively (using fluorometry and qPCR) and in terms of microbial diversity (using 16S rDNA and ITS sequencing). RESULTS: The quantitative result showed that total and bacterial DNA accumulated monotonically, rising to 41 ng/cm2 for total DNA and to 2.8 ng/cm2 for bacterial DNA over the 21-week period. The accumulation rate of bacterial DNA correlated with indoor occupancy level. Fungal DNA first rose to 4.0 ng/cm2 before showing a dip to 1.4 ng/cm2 between weeks 6 and 10. The dip indicated a possible artifact of this sampling approach for quantitative analysis as DNA may not be conserved on the filter over the months-long service period. The sequencing results indicate major contributions from outdoor air for fungi and from recirculated indoor air for bacteria. Despite the quantitative changes, the community structure of the microbial assemblages was stable throughout the 21 week sampling period, highlighting the robustness of this sampling method for microbial profiling. CONCLUSION: This study supports the use of ventilation system filters as indoor bioaerosol samplers, but with caveats: 1) an outdoor reference is required to properly understand the contribution of outdoor bioaerosols; and 2) there is a need to better understand the persistence and durability of the targeted organisms on ventilation system filters. PMID- 30020975 TI - Usefulness of polymerase chain reaction for diagnosing Whipple's disease in rheumatology. AB - OBJECTIVES: To determine when Tropheryma whipplei polymerase chain reaction (PCR) is appropriate in patients evaluated for rheumatological symptoms. METHODS: In a retrospective observational study done in rheumatology units of five hospitals, we assessed the clinical and radiological signs that prompted T. whipplei PCR testing between 2010 and 2014, the proportion of patients diagnosed with Whipple's disease, the number of tests performed and the number of diagnoses according to the number of tests, the patterns of Whipple's disease, and the treatments used. Diagnostic ascertainment was based on 1- Presence of at least one suggestive clinical finding; 2- at least one positive PCR test, and 3- a response to antibiotic therapy described by the physician as dramatic, including normalization of C Reactive Protein. RESULTS: At least one PCR test was performed in each of 267 patients. Rheumatic signs were peripheral arthralgia (n = 239, 89%), peripheral arthritis (n = 173, 65%), and inflammatory back pain (n = 85, 32%). Whipple's disease was diagnosed in 13 patients (4.9%). The more frequently positive tests were saliva and stool. In the centres with no diagnoses of Whipple's disease, arthritis was less common and constitutional symptoms more common. The group with Whipple's disease had a higher proportion of males, older age, and greater frequency of arthritis. The annual incidence ranged across centres from 0 to 3.6/100000 inhabitants. CONCLUSION: Males aged 40-75 years with unexplained intermittent seronegative peripheral polyarthritis, including those without constitutional symptoms, should have T. whipplei PCR tests on saliva, stool and, if possible, joint fluid. PMID- 30020974 TI - Role of genetic and electrolyte abnormalities in prolonged QTc interval and sudden cardiac death in end-stage renal disease patients. AB - BACKGROUND: Patients with end-stage renal disease have very high mortality. In individuals on hemodialysis, cardiovascular deaths account for ~50% of all deaths in this population, mostly due to arrhythmia. To determine the causes of these arrhythmic deaths is essential in order to adopt preventive strategies. The main objective of this study was to investigate whether, the presence of QTc interval alterations, from electrolyte abnormalities or presence of rare genetic variants, could have a relationship with sudden arrhythmogenic deaths in end-stage renal disease patients. METHODS: We recorded the pre- and post-dialysis QTc interval in 111 patients undergoing hemodialysis. In 47 of them, we analyzed 24 SCD-related genes including the most prevalent genes associated with long QT syndrome using a custom resequencing panel. RESULTS: We found a positive although not significant association between the presence of long QTc and mortality in a subset of end stage renal disease patients. In addition, in five patients with long QTc only after dialysis (21.7%) we detected rare potentially pathogenic genetic variants. Three out of these five carriers subsequently died suddenly. CONCLUSIONS: Genetic background may be determinant in the risk of sudden cardiac death in these patients. We recommend evaluating the QTc interval before and after hemodialysis, and performing a genetic analysis of individuals with long QTc after hemodialysis. PMID- 30020976 TI - Are older long term care residents accurately prognosticated and consequently informed about their prognosis? Results from SHELTER study data in 5 European countries. AB - BACKGROUND: Informing residents in long term care facilities (LTCFs) about their prognosis can help them prepare for the end of life. This study aimed to examine which proportion of European LTCF residents, close to death, are accurately prognosticated and consequently informed about their prognosis; and to examine factors related to accurate prognostication and discussion of prognosis. METHODS: A subsample of SHELTER study data was used, consisting of: 500 residents from 5 European countries, who died within 6 months after their last assessment, and had a valid answer on the item 'End stage disease, 6 or fewer months to live'. This item was used to indicate whether an accurate prognosis was established and discussed with residents. Generalized estimating equations were used to examine factors related to establishment and discussion of accurate prognosis. RESULTS: 86.4% of residents close to death did not receive an accurate prognosis. Residents with cancer; fatigue; dehydration; and normal mode of nutritional intake were more likely to have an accurate prognosis established and discussed. Accurate prognostication and prognosis discussion was less likely for residents who: had a diagnosis under 'other'; initiated interactions; and residents from Germany, Italy and the Netherlands. CONCLUSIONS: The great majority of residents close to death did not receive an accurate prognosis. Prognostication tools might help clinicians to increase their prognostic accuracy and communication training might help to discuss prognosis with residents. PMID- 30020977 TI - PCV13 vaccination impact: A multicenter study of pneumonia in 10 pediatric hospitals in Argentina. AB - INTRODUCTION: In 2012, PCV13 was introduced into the National Immunization Program in Argentina, 2+1 schedule for children <2 years. Coverage rates for 1st and 3rd doses were 69% and 41.0% in 2012, 98% and 86% in 2013; 99% and 89% in 2014, respectively. The aims of this study were to evaluate impact of PCV13 on Consolidated Pneumonia (CP) and Pneumococcal Pneumonia (PP) burden, and to describe epidemiological-clinical pattern of PP during the three-year period following vaccine introduction. METHODS: Hospital-based study at 10 pediatric surveillance units in Argentina. CP and PP discharge rates per 10,000 hospital discharges were compared between the pre-vaccination period 2007-2011 (preVp), the year of intervention (2012) and the post-vaccination period 2013-2014 (postVp). RESULTS: Significant reduction in CP and PP discharge rates was observed in patients <5 years [% reduction (95%CI)]: 10.2% (6.3; 14.0) in 2012 and 24.8% (21.3; 28.2) in postVp for CP discharge rate; 59.5% (48.0; 68.5) in 2012 and 68.8% (58.3; 76.6) in postVp for PP discharge rate. Significant changes were also observed in children >=5 years, mainly in PP discharge rate. A total of 297 PP cases were studied; 59.3% male; 31.3% <2 years; 42.9% had received PCV13 in 2012 and 84.5% in posVp. Case fatality rate was 3.4%. PCV13 serotypes decreased from 83.0% (39/47) in 2012 to 64.2% (52/81) in postVp, p = 0.039. CONCLUSIONS: After PCV13 introduction, significant reduction in CP and PP discharge rates was observed in hospitalized children <5 years. In patients >=5 years, PP discharge rate also decreased significantly. PMID- 30020978 TI - Decreased trend in hospital mortality from pancreatic cancer despite increase in number of hospital admissions. AB - BACKGROUND AND AIM: Pancreatic cancer is one of the common cancers in US and is associated with high mortality and morbidity. The objectives of our study were to look at the recent trends in the number of hospitalizations with pancreatic cancer. METHODS: We identified patients with a discharge diagnosis of pancreatic cancer in the National Inpatient Sample from 2007 to 2011 using International Classification of Diseases-Clinical Modification, 9th revision (ICD-9-CM) codes. We looked at the yearly trend in the hospitalizations with pancreatic cancer and the outcomes which included length of stay (LOS), hospital charges and in hospital mortality. We also performed multivariate analysis to look for the predictors of mortality. RESULTS: There were 450, 414 patients with discharge diagnosis of pancreatic cancer. There was 18% increase in hospitalizations with pancreatic cancer in 2011 compared to 2007. Most of the patients were Caucasian (63%) with the mean age of 68 +/- 0.14 years, had Medicare (57%) as primary insurance, were from Southern region (35%) and had higher Charlson Comorbidity Index (CCI) (87% with CCI > = 5). 6% underwent Whipple's procedure in the index hospitalization. After the adjustment for inflation, the mean hospital charges increased from $ 47,331 in 20007 to $ 53, 854 in 2011 (p = 0.01). LOS decreased from 7.31 +/- 0.11 days in 2007 to 6.70 +/- 0.09 days in 2011 (<0.001). Despite the increase in the number of hospitalizations of patients with pancreatic cancer, mortality decreased from 9.8% in 2007 to 8.1% in 2011 (p<0.001). On multivariate analysis, the independent factors associated with higher mortality were older age, male sex African-American race, insurance status other than Medicare, higher CCI and enrollment in palliative care. There was regional variation in mortality. Whipple's procedure conferred lower mortality. CONCLUSIONS: Our study showed downward trends in LOS and in-hospital mortality despite increasing hospitalizations with pancreatic cancer. PMID- 30020980 TI - The Cow Milk Symptom Score (CoMiSSTM) in presumed healthy infants. AB - OBJECTIVE: The Cow's Milk-related Symptom Score (CoMiSSTM) was developed as an awareness tool to recognize possible manifestations of cow's milk protein allergy (CMPA). Arbitrarily, a cut-off value of >=12 was defined as a "positive score." The aim of this study was to determine an age-related CoMiSS in healthy infants to minimize the risk of false reassurance or over-diagnosis of CMPA in case of a negative or positive score, respectively. METHODS: General pediatricians determined the CoMiSS in presumed healthy infants aged <=6 months during a routine visit. Exclusion criteria included any known acute or chronic disease, preterm delivery (< 37 weeks), therapeutic formula, any food supplement (except vitamins) or medication. RESULTS: Data from 891 consecutive infants were collected. Complete information was obtained from only 413 (46.4%) infants: Belgium: 31.2%, Italy 18.2%, Poland 19.1% and Spain 31.5%. Since gender (girls vs boys) (p = 0.579) had no influence on the CoMiSS, the data were re-calculated to include those infants with missing gender. The overall median and mean (SD) CoMiSS scores were, respectively, 3.0 and 3.7 (2.9). The 95th percentile was 9. Median crying (p<0.001), regurgitation (p = 0.009) and eczema (p = 0.039) scores differed significantly across the age categories. The other components of the CoMiSS were not age dependent. CONCLUSION: In healthy infants <= 6 months, the median CoMiSS is 3.0. More prospective studies in different sites and comparing healthy and allergic infants are warranted to obtain further evidence on the utility of the CoMiSS. PMID- 30020979 TI - Collagen cross-linking impact on keratoconus extracellular matrix. AB - BACKGROUND: Keratoconus (KC) is a common multifactorial ectatic corneal disease with unknown onset. KC most commonly appears in adolescence and affects approximately 1:400 people worldwide. Treatment options, for advanced KC cases, are collagen cross-linking (CXL) and corneal transplants. CXL is a new KC treatment that helps arrest the disease. Unfortunately, only a fraction of KC patients will qualify for CXL treatment. Our goal, in this study, was to begin to understand how CXL affects the corneal microenvironment and pave the way towards a more patient-driven CXL treatment. METHODS: Primary human corneal fibroblasts from healthy and KC donors were plated on transwell polycarbonate membranes and stimulated by a stable vitamin C. At 4 weeks, riboflavin was added followed by UVA irradiation. Transmission Electron Microscopy (TEM) and western blots were used to assess the effect of CXL on the extracellular matrix (ECM) and the resident cells, pre- and post CXL. RESULTS: Data shows CXL improved lamellar organization showing more organized collagen fibrils decorated with proteoglycans (PGs). The distribution of the collagen fibrils and interfibrillar spacing was also visibly improved, post-CXL. Lumican, mimecan, and decorin were the dominant PGs and were significantly upregulated in post-CXL cultures. ECM degradation proteins, matrix metalloproteinases (MMPs), MMP-1, -3, and -9, but not MMP-2, were significantly downregulated post-CXL. TIMP-1 and -2 were not modulated by CXL. CONCLUSION: The unknown effects of CXL on the human corneal microenvironment have hampered our ability to make CXL available to all KC patients. Our current study provides a deeper understanding on CXL activity, using our unique 3D in vitro model. PMID- 30020981 TI - Analysis of global stock index data during crisis period via complex network approach. AB - Considerable research has been done on the complex stock market, however, there is very little systematic work on the impact of crisis on global stock markets. For filling in these gaps, we propose a complex network method, which analyzes the effects of the 2008 global financial crisis on global main stock index from 2005 to 2010. Firstly, we construct three weighted networks. The physics-derived technique of minimum spanning tree is utilized to investigate the networks of three stages. Regional clustering is found in each network. Secondly, we construct three average threshold networks and find the small-world property in the network before and during the crisis. Finally, the dynamical change of the network community structure is deeply analyzed with different threshold. The result indicates that for large thresholds, the network before and after the crisis has a significant community structure. Though this analysis, it would be helpful to investors for making decisions regarding their portfolios or to regulators for monitoring the key nodes to ensure the overall stability of the global stock market. PMID- 30020982 TI - Lateral movement of the saddle relative to the equine spine in rising and sitting trot on a treadmill. AB - Saddle slip, defined as a progressive lateral displacement of the saddle during ridden exercise, has recently been given attention in the scientific press as a potential sign of lameness. The aim of this study was to objectively quantify the normal lateral movement (oscillations) of the saddle relative to the horse in non lame horses, and associate this movement to the movements of the horse and rider. Data from seven Warmblood dressage horses competing at Grand Prix (n = 6) or FEI Intermediate (n = 1) level, ridden by their usual riders, were used. Simultaneous kinetic, kinematic and saddle pressure measurements were conducted during sitting and rising trot on a force-measuring treadmill. The maximum lateral movement of the caudal part of the saddle relative to the horse's spine (MAX) was determined for each diagonal step. A mixed model was applied, with MAX as outcome, and T6 and S3 vertical position, rigid body rotation angles (roll, pitch, yaw) of the horse's and rider's pelvis, vertical ground reaction forces, saddle force, and rider position (rising in rising trot, sitting in rising trot or sitting in sitting trot) as explanatory variables. The least square means for MAX were 14.3 (SE 4.7) mm and 23.9 (SE 4.7) mm for rising and sitting in rising trot, and 20.3 (SE 4.7) mm for sitting trot. A 10 mm increase in maximum pelvic height at push off increased MAX by 1.4 mm (p<0.0001). One degree increase in rider pelvis roll decreased MAX 1.1 mm, and one degree increase in rider pelvis yaw increased MAX 0.7 mm (both p<0.0001). The linear relationships found between MAX and movements of both horse and rider implies that both horse and rider movement asymmetries are reflected in the lateral movements or oscillations of the saddle in non-lame horses. PMID- 30020983 TI - Does attention bias modification training impact on task performance in the context of pain: An experimental study in healthy participants. AB - Attention has been theorized to play a key role in the experience of pain and associated task interference. Training attention away from pain via attention bias modification (ABM) training techniques has been proposed to improve pain related outcomes, but evidence is inconsistent. In an experimental study, we investigated the impact of a single session ABM training -using a visual probe paradigm with idiosyncratic pain words- on cold pressor test (CPT) pain experience and task interference by pain. Fifty-eight healthy volunteers were randomly assigned to an ABM training group (N = 28; attending away from pain) and a sham training group (N = 30; no training direction). At pre-training, participants performed a baseline Random-Interval-Repetition (RIR) task and the CPT. Participants reported on sensations they experienced during the baseline CPT. Relevant descriptors were integrated in the visual probe paradigm during the training phase. At post-training, participants completed the RIR task again while experiencing CPT pain. Participants also reported on the extent they attended to the pain and the intensity/unpleasantness of the pain. Results indicated that, in contrast with our hypotheses, ABM training did also not reduce task interference due to CPT pain. Furthermore, ABM training did not change self-reported attending to CPT pain. Finally, ABM training did not reduce CPT pain intensity or pain unpleasantness. Overall, the current study provides no support for the effectiveness of a single session ABM training in improving pain-related outcomes. Future research addressing the conditions under which ABM training improves or fails to improve pain-related outcomes is warranted. PMID- 30020985 TI - Monocyte human leukocyte antigen - Antigen D related, neutrophil oxidative burst and cytokine analysis in patients of decompensated cirrhosis with and without acute-on chronic liver failure. AB - BACKGROUND AND AIM: Due to a dysregulated immune response, patients with acute-on chronic liver failure (ACLF) have increased risk of infection and multi organ failure in comparison to compensated cirrhosis. The comparative data on the presence of 'immune paresis' in patients with ACLF and decompensated cirrhosis without ACLF is not available. Aim of the present study was to compare the immunological parameters in patients with decompensated cirrhosis with and without ACLF. METHODOLOGY: In a prospective study, 76 patients with decompensated cirrhosis with (n = 38) and without (n = 38) ACLF and 10 healthy controls (HC) were evaluated for monocytic human leukocyte antigen-antigen D Related (HLA-DR) expression, mean density of HLA-DR expressed on the surface of these cells, neutrophil oxidative burst (NOB) capacity and serum levels of cytokines (IL-1, IL 6, IL-8, IL10, IL-12, and TNF-alpha). RESULTS: Patients of decompensated cirrhosis with and without ACLF demonstrated significantly lower mean percentage of monocytes expressing HLA-DR and quantitative increase in the NOB after stimulation with PMA when compared to HC. However there was no difference in mean percentage of monocytes with HLA-DR expression (43.61+/-26.56% vs. 43.10+/ 20.98%) (p = 0.91), mean density of HLA-DR expression on the surface (30.34+/ 29.32 vs. 41.71+/-52.13) (p = 0.42) and quantitative increase in NOB after stimulation with PMA (16.55+/-11.91 vs. 17.24+/-16.18) (p = 0.47) amongst patients with decompensated cirrhosis with and without ACLF. Patients with ACLF had significantly higher pro-inflammatory and anti-inflammatory cytokines in comparison to patients with decompensated cirrhosis without ACLF. CONCLUSION: Patients with decompensated cirrhosis demonstrate a component of immune-paresis, however there is similar impairment in HLA-DR expression and NOB capacity in patients with and without ACLF. Both inflammatory and anti-inflammatory cytokines are increased in patients with ACLF in comparison to patients with decompensated cirrhosis without ACLF. PMID- 30020984 TI - Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective. AB - The malignant neoplasm of the cervix, cervical cancer, has effects on the reproductive tract. Although infection with oncogenic human papillomavirus is essential for cervical cancer development, it alone is insufficient to explain the development of cervical cancer. Therefore, other risk factors such as host genetic factors should be identified, and their importance in cervical cancer induction should be determined. Although gene expression profiling studies in the last decade have made significant molecular findings about cervical cancer, adequate screening and effective treatment strategies have yet to be achieved. In the current study, meta-analysis was performed on cervical cancer-associated transcriptome data and reporter biomolecules were identified at RNA (mRNA, miRNA), protein (receptor, transcription factor, etc.), and metabolite levels by the integration of gene expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers, tumor suppressors and oncogenes in cervical cancer as well as various receptors (e.g. ephrin receptors EPHA4, EPHA5, and EPHB2; endothelin receptors EDNRA and EDNRB; nuclear receptors NCOA3, NR2C1, and NR2C2), miRNAs (e.g., miR-192-5p, miR-193b-3p, and miR-215-5p), transcription factors (particularly E2F4, ETS1, and CUTL1), other proteins (e.g., KAT2B, PARP1, CDK1, GSK3B, WNK1, and CRYAB), and metabolites (particularly, arachidonic acids) as novel biomarker candidates and potential therapeutic targets. The differential expression profiles of all reporter biomolecules were cross-validated in independent RNA-Seq and miRNA-Seq datasets, and the prognostic power of several reporter biomolecules, including KAT2B, PCNA, CD86, miR-192-5p and miR-215-5p was also demonstrated. In this study, we reported valuable data for further experimental and clinical efforts, because the proposed biomolecules have significant potential as systems biomarkers for screening or therapeutic purposes in cervical carcinoma. PMID- 30020986 TI - A novel one-step lens cleaning device using air and water flow for endoscopic surgery. AB - In a surgical operation requiring endoscopy, it is essential to obtain a clear endoscopic view. However, it is often disturbed by the contamination on the lens during the surgery. No device can clean the lens surface simply and completely. Many surgeons are hampered by the impaired view and the distraction by the repeated cleaning of the lens. Therefore, we developed a novel endoscope cleaning device to address this problem. The device was made of 3D-printed rubber-like plastic. It contains a syringe filled with saline and an aspiration system. It would be used intraoperatively to wash the lens surface in a few seconds with rapid flow of water and air. The cleaning ability of the device was evaluated using mayonnaise with adenosine triphosphate (ATP) as a model contaminant. The gauze-wiping maneuver was selected as control. After each maneuver, the clarity of the endoscopic view was evaluated, and residual contaminants were assessed quantitatively with ATP assay. The cleaning device obtained a crisp and clear view and eliminated the contaminant on the lens every time after a single cleaning maneuver. The gauze-wiping maneuver required for the lens to be wiped at least three times to obtain a clear view, and even then, some contaminants remained. Repeated contamination and cleaning using gauze led to accumulation of contaminants on the lens, which resulted in difficulty in cleaning the lens as the operation proceeded. The cleaning device did not show such accumulation. Our novel cleaning device with air and water flow has been shown to wash out the lens contaminants completely and immediately in a simple manner. It is expected to improve the safety and cost-effectiveness of endoscopic surgery. PMID- 30020987 TI - Five-week yin yoga-based interventions decreased plasma adrenomedullin and increased psychological health in stressed adults: A randomized controlled trial. AB - BACKGROUND: Non-communicable diseases (NCDs, e.g. cardiovascular disease) are responsible for high rates of morbidity and the majority of premature deaths worldwide. It is necessary to develop preventative interventions that can reduce the associated risk factors of NCDs. Researchers have found that the biomarker adrenomedullin (ADM) becomes elevated years before the onset of NCDs and might play an important role in their development. ADM has also been linked to psychological problems such as stress, anxiety, and depression, which are known risk factors of NCDs. In this randomized controlled trial, we examined whether participating in a five-week yoga intervention reduces ADM and increases psychological health in middle-aged adults who self-report as moderately to highly stressed, but who otherwise exhibit no physical complaints. METHODS: One hundred and five adults (78% women; mean age = 53.5, SD = 6.7) were randomly assigned to (1) a five-week Yin yoga intervention, (2) a five-week intervention combining Yin yoga with psychoeducation and mindfulness practice (called the YOMI program), or (3) a control group who did not practice yoga or mindfulness for five weeks. RESULTS: Compared to the control group, we observed significantly greater pre-post reductions in plasma ADM levels (p < .001), anxiety (p <= .002), and sleep problems (p <= .003) in both intervention groups. Furthermore, the YOMI group exclusively showed significantly greater pre-post reductions in stress (p = .012) and depression (p = .021) compared to the control group. Significant correlations (p < .05) were found between pre-post reductions in ADM and anxiety symptoms (p = .02) and depression (p = .04) in the entire sample. CONCLUSION: The five-week Yin yoga-based interventions appeared to reduce both the physiological and psychological risk factors known to be associated with NCDs. The study suggests that incorporating Yin yoga could be an easy and low-cost method of limiting the negative health effects associated with high stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT03428542. PMID- 30020988 TI - Short-term tissue decomposition alters stable isotope values and C:N ratio, but does not change relationships between lipid content, C:N ratio, and Deltadelta13C in marine animals. AB - Measures (e.g. delta15N, delta13C, %C, %N and C:N) derived from animal tissues are commonly used to estimate diets and trophic interactions. Since tissue samples are often exposed to air or kept chilled in ice over a short-term during sample preparation, they may degrade. Herein, we hypothesize that tissue decomposition will cause changes in these measures. In this study, we kept marine fish, crustacean and mollusc tissues in air or ice over 120 h (5 days). We found that tissue decomposition in air enriched delta15N (range 0.60/00 to 1.30/00) and delta13C (0.20/00 to 0.40/00), decreased %N (0.47 to 3.43 percentage points from staring values of ~13%) and %C (4.53 to 8.29 percentage points from starting values of ~43%), and subsequently increased C:N ratio (0.14 to 0.75). In air, while such changes to delta13C were relatively minor and therefore likely tolerable, changes in delta15N, %N, %C and C:N ratio should be interpreted with caution. Ice effectively reduced the extent to which decomposition enriched delta15N (<= 0.40/00) and delta13C (<= 0.20/00), and eliminated decomposition in C:N ratio, %N and %C. In our second experiment, for fish tissues in either air or ice over 120 h, we observed no effects of decomposition on relationships between lipid content, C:N ratio, and Deltadelta13C (change in delta13C after lipid removal), which are employed to correct delta13C for samples containing lipid. We also confirmed that lipid in tissues caused large errors when estimating delta13C (mean +/- standard error = -1.80/00 +/- 0.10/00, range -0.60/00 to -3.80/00), and showed both lipid extraction and mathematical correction performed equally well to correct for lipids when estimating delta13C. We, therefore, recommend that specimens of marine animals should be kept in ice during sample preparation for a short-term, as it is an effective means for minimizing changes of the stable isotope measures in their tissue. PMID- 30020990 TI - Correction: Tensor decomposition-based unsupervised feature extraction applied to matrix products for multi-view data processing. AB - [This corrects the article DOI: 10.1371/journal.pone.0183933.]. PMID- 30020989 TI - Seasonal variation of Cesium-137 concentration in Asian black bear (Ursus thibetanus) and wild boar (Sus scrofa) in Fukushima Prefecture, Japan. AB - To elucidate and reduce the risk of radionuclide contamination in wildlife caused by the Tokyo Electric Power Company Fukushima Dai-ichi Nuclear Power Station accident, it is important to understand radionuclide variations in the wild animal population. Here, we used environmental monitoring data and muscle samples collected from Asian black bear (Ursus thibetanus) and wild boar (Sus scrofa) from May 2011 to March 2016 to examine seasonal variation in radiocesium (137Cs) concentrations in muscle tissues (hereafter, muscle 137Cs) of these important game species in Fukushima Prefecture. We measured muscle 137Cs of bears and wild boars killed by hunters or in animal control culls. First, using a linear mixed model (LMM), we tested for a positive relationship between muscle 137Cs and 137Cs in the soil at the site of capture (hereafter, soil 137Cs) estimated from a soil 137Cs deposition map produced by the Japan Atomic Energy Agency. In the LMM, muscle 137Cs was positively related to estimated soil 137Cs, which corroborates the results of previous studies. The LMM regression coefficients differed between the two species, with wild boar muscle 137Cs being higher than that of bears sampled at the same locations. We then employed a generalized additive mixed model (GAMM) to estimate seasonal variation in the muscle 137Cs of the target species. GAMM showed that muscle 137Cs varied seasonally and that this seasonal variation also differed between the two species. In bears, muscle 137Cs decreased from spring to early autumn, before increasing in winter. Wild boar muscle 137Cs remained low during spring and summer and was high during autumn and early spring. These patterns are likely influenced by differences in diet, habitat use, and physiology between these two species. PMID- 30020991 TI - HLA-A*11:01 is associated with levetiracetam-induced psychiatric adverse events. AB - Levetiracetam (LEV) is effective for focal and generalized epilepsy and is used worldwide because of its relatively few drug interactions and favorable tolerability. However, some psychiatric adverse events (PAEs) have been reported, resulting in drug withdrawal. The pathophysiology of LEV-induced PAE has not yet been elucidated. In this study, we investigated the relationship between PAEs and human leukocyte antigen (HLA) genes. Eleven epilepsy patients, who developed PAEs after the administration of LEV and spontaneously improved after drug withdrawal, were enrolled retrospectively. Genomic DNA from the peripheral blood was extracted, and four-digit allele genotyping of HLA genes was performed. The genotype frequencies of HLA genes were compared to those of 80 patients in which LEV was well tolerated, as well as to 485 individuals from the general Korean population. The frequency of the HLA-A*1101 allele was significantly higher in the LEV-induced PAEs group compared to both the LEV-tolerant group (p = 0.021, OR 4.80, 95% CI 1.30-17.74) and the general Korean population (p = 0.015, OR 4.62, 95% CI 1.38-15.45). This study is the first attempt at investigating the relationship between the HLA system and LEV-induced PAE. The results of this study suggest that the HLA-A*1101 allele could be a risk factor for the development of PAEs. PMID- 30020993 TI - Assessment of heat stress in 7-week old dairy calves with non-invasive physiological parameters in different thermal environments. AB - We estimated thermal stress in 7-week old Holstein bull calves during a warm episode in summer to study acute physiological responses of calves to heat stress. Data were collected over a 5-day period: day 1 (control), day 2 (heat stress), and a 3-day post-stress period in shaded (n = 8) and unshaded (n = 8) thermal environments. On the control day, both groups were shaded. Thermal environment was characterized by relative humidity, ambient temperature, and the temperature-humidity index (THI). Physiological variables included respiratory rate, rectal temperature, ear skin temperature and heart rate. Correlations between animal-based and meteorological indices were calculated, and ambient temperature correlated slightly better with physiological measures than THI. Rectal temperature was the only animal-based parameter that showed stronger correlations with the thermal indices when calculated for the shaded than for the unshaded environment [r = 0.42 vs. r = 0.47, P = 0.032 (ambient temperature), r = -0.39 vs. r = -0.45, P = 0.012 P = 0.015 (relative humidity), r = 0.41 vs. r = 0.46, P = 0.022 (THI)]. No differences were found between groups during the control day for any of the physiological parameters. During days 2 and 3, average and maximal values of respiratory and heart rates were higher in unshaded calves than in shaded ones. Maximal respiratory rates were in average by 25.9, 17.8 and 10.1 breaths/min lower in shaded calves than in unshaded calves for days 2, 3 and 4, respectively (P < 0.001, P < 0.001 and P = 0.024). Maximal heart rate was 127.4 +/- 8.5 vs. 99.2 +/- 6.3 beats/min on the heat stress day (P < 0.001), and 121.0 +/- 6.9 vs. 103.4 +/- 7.7 beats/min on day 3 (P = 0.006) in unshaded and shaded calves, respectively. Maximal body temperatures were higher measured either in the rectum or on the ear skin in unshaded calves than in shaded ones (with 0.5 and 1.6 degrees C, P = 0.040 and P = 0.018, respectively), but only on the heat stress day. Based on our results, shading of young calves may be adequate for alleviating acute heat stress in continental regions. Ambient temperature is appropriate to estimate acute heat stress in dairy calves. PMID- 30020992 TI - Signs of continental ancestry in urban populations of Peru through autosomal STR loci and mitochondrial DNA typing. AB - The human genetic diversity around the world was studied through several high variable genetic markers. In South America the demic consequences of admixture events between Native people, European colonists and African slaves have been displayed by uniparental markers variability. The mitochondrial DNA (mtDNA) has been the most widely used genetic marker for studying American mixed populations, although nuclear markers, such as microsatellite loci (STRs) commonly used in forensic science, showed to be genetically and geographically structured. In this work, we analyzed DNA from buccal swab samples of 296 individuals across Peru: 156 Native Amazons (Ashaninka, Cashibo and Shipibo from Ucayali, Huambiza from Loreto and Moche from Lambayeque) and 140 urban Peruvians from Lima and other 33 urban areas. The aim was to evaluate, through STRs and mtDNA variability, recent migrations in urban Peruvian populations and to gain more information about their continental ancestry. STR data highlighted that most individuals (67%) of the urban Peruvian sample have a strong similarity to the Amazon Native population, whereas 22% have similarity to African populations and only ~1% to European populations. Also the maternally-transmitted mtDNA confirmed the strong Native contribution (~90% of Native American haplogroups) and the lower frequencies of African (~6%) and European (~3%) haplogroups. This study provides a detailed description of the urban Peruvian genetic structure and proposes forensic STRs as a useful tool for studying recent migrations, especially when coupled with mtDNA. PMID- 30020995 TI - Twenty-year trend in mortality among hospitalized patients with pneumococcal community-acquired pneumonia. AB - BACKGROUND: There is only limited information on mortality over extended periods in hospitalized patients with pneumococcal community-acquired pneumonia (CAP). We aimed to evaluate the 30-day mortality and whether is changed over a 20-year period among immunocompetent adults hospitalized with pneumococcal CAP. METHODS: We conducted a retrospective observational study of data that were prospectively collected at the Hospital Clinic of Barcelona of all adult patients hospitalized with diagnosis of pneumococcal CAP over a 20-year period. To aid analysis, results were divided into four periods of 5 years each (1997-2001, 2002-2006, 2007-2011, 2012-2016). The primary outcome was 30-day mortality, but secondary outcomes included intensive care unit (ICU) admission, lengths of hospital and ICU-stays, ICU-mortality, and need of mechanical ventilation. RESULTS: From a cohort of 6,403 patients with CAP, we analyzed the data for 1,120 (17%) adults with a diagnosis of pneumococcal CAP. Over time, we observed decreases in the rates of alcohol consumption, smoking, influenza vaccination, and older patients (age >=65 years), but increases in admissions to ICU and the need for non invasive mechanical ventilation. The overall 30-day mortality rate was 8% (95% confidence interval, 6%-9%; 84 of 1,120 patients) and did not change significantly between periods (p = 0.33). Although, we observed a decrease in ICU mortality comparing the first period (26%) to the second one (10%), statistical differences disappeared with adjustment (p0.38). CONCLUSION: Over time, 30-day mortality of hospitalized pneumococcal CAP did not change significantly. Nor did it change in the propensity-adjusted multivariable analysis. Since mortality in pneumococcal pneumonia has remained unaltered for many years despite the availability of antimicrobial agents with proven in vitro activity, other non antibiotic strategies should be investigated. PMID- 30020994 TI - Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences. AB - In a variety of species, reduced food intake, and in particular protein or amino acid (AA) restriction, extends lifespan and healthspan. However, the underlying epigenetic and/or transcriptional mechanisms are largely unknown, and dissection of specific pathways in cultured cells may contribute to filling this gap. We have previously shown that, in mammalian cells, deprivation of essential AAs (methionine/cysteine or tyrosine) leads to the transcriptional reactivation of integrated silenced transgenes, including plasmid and retroviral vectors and latent HIV-1 provirus, by a process involving epigenetic chromatic remodeling and histone acetylation. Here we show that the deprivation of methionine/cysteine also leads to the transcriptional upregulation of endogenous retroviruses, suggesting that essential AA starvation affects the expression not only of exogenous non-native DNA sequences, but also of endogenous anciently-integrated and silenced parasitic elements of the genome. Moreover, we show that the transgene reactivation response is highly conserved in different mammalian cell types, and it is reproducible with deprivation of most essential AAs. The General Control Non-derepressible 2 (GCN2) kinase and the downstream integrated stress response represent the best candidates mediating this process; however, by pharmacological approaches, RNA interference and genomic editing, we demonstrate that they are not implicated. Instead, the response requires MEK/ERK and/or JNK activity and is reproduced by ribosomal inhibitors, suggesting that it is triggered by a novel nutrient-sensing and signaling pathway, initiated by translational block at the ribosome, and independent of mTOR and GCN2. Overall, these findings point to a general transcriptional response to essential AA deprivation, which affects the expression of non-native genomic sequences, with relevant implications for the epigenetic/transcriptional effects of AA restriction in health and disease. PMID- 30020998 TI - The elusive power of the individual victim: Failure to find a difference in the effectiveness of charitable appeals focused on one compared to many victims. AB - Previous research has offered conflicting findings regarding the influence of help appeals that feature an individual victim compared to a group of victims. Studies examining emotional responses and donation behavior have generally found that help appeals focusing on a single victim elicit more prosocial responses, while studies examining policy support have found the opposite. The present studies investigate these effects while addressing potential confounds that may have arisen in previous research. Study 1 (N = 924) compares the effects of help appeals that focus on either a) an identified individual, b) an identified group, c) statistics describing many individuals, or d) statistics paired with an individual. Study 1 also examines how the location of the individual(s) in need moderates observed effects. Study 2 (N = 1,085) compares the effects of help appeals that describe either an identified individual or statistics about many individuals, while fully crossing the text manipulation with either a) no imagery, b) an image of an individual, or c) a map indicating areas of poverty. In both Study 1 and Study 2 no significant differences were found between the individual and the group conditions. PMID- 30020996 TI - Mitochondrial DNA is critical for longevity and metabolism of transmission stage Trypanosoma brucei. AB - The sleeping sickness parasite Trypanosoma brucei has a complex life cycle, alternating between a mammalian host and the tsetse fly vector. A tightly controlled developmental programme ensures parasite transmission between hosts as well as survival within them and involves strict regulation of mitochondrial activities. In the glucose-rich bloodstream, the replicative 'slender' stage is thought to produce ATP exclusively via glycolysis and uses the mitochondrial F1FO ATP synthase as an ATP hydrolysis-driven proton pump to generate the mitochondrial membrane potential (DeltaPsim). The 'procyclic' stage in the glucose-poor tsetse midgut depends on mitochondrial catabolism of amino acids for energy production, which involves oxidative phosphorylation with ATP production via the F1FO-ATP synthase. Both modes of the F1FO enzyme critically depend on FO subunit a, which is encoded in the parasite's mitochondrial DNA (kinetoplast or kDNA). Comparatively little is known about mitochondrial function and the role of kDNA in non-replicative 'stumpy' bloodstream forms, a developmental stage essential for disease transmission. Here we show that the L262P mutation in the nuclear-encoded F1 subunit gamma that permits survival of 'slender' bloodstream forms lacking kDNA ('akinetoplastic' forms), via FO-independent generation of DeltaPsim, also permits their differentiation into stumpy forms. However, these akinetoplastic stumpy cells lack a DeltaPsim and have a reduced lifespan in vitro and in mice, which significantly alters the within-host dynamics of the parasite. We further show that generation of DeltaPsim in stumpy parasites and their ability to use alpha-ketoglutarate to sustain viability depend on F1-ATPase activity. Surprisingly, however, loss of DeltaPsim does not reduce stumpy life span. We conclude that the L262P gamma subunit mutation does not enable FO independent generation of DeltaPsim in stumpy cells, most likely as a consequence of mitochondrial ATP production in these cells. In addition, kDNA-encoded genes other than FO subunit a are important for stumpy form viability. PMID- 30020997 TI - Healthcare resource utilization and costs among patients with rheumatoid arthritis on biologic therapies in Taiwan: A 1-year mirror-image study using a national claims database. AB - OBJECTIVES: This nationwide population-based study aimed at evaluating healthcare resource utilization and direct medical costs among rheumatoid arthritis (RA) patients receiving biologic therapies in Taiwan. DESIGN AND SETTING: A retrospective cohort of 2,425 RA patients who had received first-line tumor necrosis factor (TNF)-alpha antagonist treatment for at least 6 months (the baseline period) between 2007 and 2011 was identified from the National Health Insurance Research Database in Taiwan. OUTCOME MEASURES: Healthcare resource utilization and direct medical costs of those patients were analyzed and compared 1 year before the index date and during the 1-year follow-up. RESULTS: Analytical results demonstrated that 87.7% of RA patients received the same TNF-alpha antagonist during the 1-year follow-up, 2.4% of the patients switched to another TNF-alpha antagonist after the baseline period, 7.1% of the study cohort received a second-line biologic agent, while the remaining patients discontinued use of any TNF-alpha antagonist. Compared to 1 year before the index date, there were significant reductions in emergency room visits and hospitalization days for RA patients treated with the same TNF-alpha antagonist during the 1-year follow-up. However, there was an increase of outpatient visits among those patients. For those RA patients who switched to another TNF-alpha antagonist or received a second-line biologic agent, they consumed more healthcare resources. Furthermore, the corresponding medication costs went up markedly during the 1-year follow-up, but nearly all total direct medical costs (biologics excluded) were significantly reduced across the study cohort. Lastly, male patients incurred slightly higher medical costs than their counterparts, albeit in a statistically insignificant fashion. CONCLUSIONS: This investigation revealed that RA patients treated with biologics utilized fewer emergency room visits and shorter hospitalization days, but incurred higher costs. In summary, this study provides meaningful information on healthcare resource utilization and medical costs of RA patients for healthcare providers and policymakers. PMID- 30021000 TI - Correction: First detection of Wolbachia in the New Zealand biota. AB - [This corrects the article DOI: 10.1371/journal.pone.0195517.]. PMID- 30020999 TI - Age-related macular degeneration and progression of coronary artery calcium: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Age-related macular degeneration (AMD) shares many similarities with cardiovascular disease (CVD) pathophysiology. We sought to determine the relationship of AMD to the progression of coronary artery calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Our cohort consisted of 5803 adults aged 45 to 84 years free of known cardiovascular disease (CVD). Retinal photographs were taken during visit 2 (Aug 2002-Jan 2004). CAC was measured with computed tomography at visit 1 (July 2000-Aug 2002) and visit 5 (April 2010-Dec 2011) and changes between visits were determined. RESULTS: Participants were categorized as with (n = 244) and without AMD (n = 5559) at visit 2. At visit 5, 92 participants with and 2684 without AMD had CAC scores. Among those with detectable CAC at baseline (>0 at visit 1), CAC progression was greater in persons with compared to those without AMD after multivariable adjustment (530 +/- 537 vs. 339 +/- 426 Agatston units, P<0.01). CONCLUSIONS: The presence of AMD in a diverse population without known clinical CVD independently predicted higher 10-year CAC progression in participants with baseline CAC >0. The retinal exam might be a useful tool for pre-clinical assessment and prevention of CVD events. PMID- 30021001 TI - Phylogenetic analysis of viruses in Tuscan Vitis vinifera sylvestris (Gmeli) Hegi. AB - The health status of the native grapevine Vitis vinifera subsp. sylvestris (Gmeli) Hegi in natural areas in Europe has received little attention. A survey was carried out on wild grapevines in Tuscany (Italy), where isolates of the Grapevine rupestris stem pitting virus (GRSPaV), Grapevine leafroll-associated virus 1 and 3 (GLRaV-1 and GLRaV-3) and Grapevine virus A (GVA) were detected. The complete coat protein (CP) region of these isolates was sequenced to investigate the relationship of the viral variants from Tuscan wild grapevines with isolates from different geographical origins. According to the phylogenetic analyses, GLRaV-1 and GLRaV-3 isolates from Tuscan wild grapevines clustered with isolates from cultivated grapevines with nucleotide sequence identities ranging from 66% to 87% and from 72.5% to 99% respectively, without any correlation between the distribution and geographical origin. Conversely, GRSPaV and GVA isolates clustered together with other Italian isolates from V. vinifera with nucleotide sequence identities ranging from 71.14% to 96.12% and from 73.5% to 92%, respectively. Our analysis of the whole amino acid sequences revealed a high conservation level for the studied proteins explained by a selective pressure on this genomic region, probably due to functional constraints imposed on CP, such as specific interactions with cellular receptors in the insect vectors necessary for successful transmission. In addition, analyses of genetic recombination suggest no significant point mutations that might play a significant role in genetic diversification. The dN/dS ratio also estimated a low number of non silent mutations, highlighting the purifying selective pressure. The widespread distribution of the Rugose wood complex (GRSPaV and GVA associated disease) in comparison with the Grapevine Leafroll associated viruses (GLRaV-1 and -3) could explain the major geographical correlation found for the viral variants detected in Tuscany. PMID- 30021002 TI - Preparation, characterization and utilization of coreshell super paramagnetic iron oxide nanoparticles for curcumin delivery. AB - In this study, super paramagnetic iron oxide nanoparticles (SPIONs) were produced by chemical co-precipitation method, then it was constructed to be a core shell nanoparticle by functionalizing with SDS, loading with curcumin and coating with a biopolymer i.e. chitosan. Each step was analyzed microscopically and spectroscopically. The produced coreshell particles were between 40 and 45nm and these coreshell particles were utilized for drug delivery studies against cervical cancer cell line-HeLa cells. The coreshell SPIONs were found to be releasing curcumin in between 6 and 12 h, which was evidenced by increased apoptotic cells and increased caspase 3 expression in HeLa cells. PMID- 30021003 TI - Correction: Justifying gender discrimination in the workplace: The mediating role of motherhood myths. AB - [This corrects the article DOI: 10.1371/journal.pone.0190657.]. PMID- 30021004 TI - Feline calicivirus- and murine norovirus-induced COX-2/PGE2 signaling pathway has proviral effects. AB - Cyclooxygenases (COXs)/prostaglandin E2 (PGE2) signaling pathways are known to modulate a variety of homeostatic processes and are involved in various pathophysiological conditions. COXs/PGE2 signaling pathways have also been demonstrated to have proviral or antiviral effects, which appeared different even in the same virus family. A porcine sapovirus Cowden strain, a member of genus Sapovirus within the Caliciviridae family, induces strong COX-2/PGE2 but transient COX-1/PGE2 signaling to enhance virus replication. However, whether infections of other viruses in the different genera activate COXs/PGE2 signaling, and thus affect the replication of viruses, remains unknown. In the present study, infections of cells with the feline calicivirus (FCV) F9 strain in the genus Vesivirus and murine norovirus (MNV) CW-1 strain in the genus Norovirus only activated the COX-2/PGE2 signaling in a time-dependent manner. Treatment with pharmacological inhibitors or transfection of small interfering RNAs (siRNAs) against COX-2 enzyme significantly reduced the production of PGE2 as well as FCV and MNV replications. The inhibitory effects of these pharmacological inhibitors against COX-2 enzyme on the replication of both viruses were restored by the addition of PGE2. Silencing of COX-1 via siRNAs and inhibition of COX-1 via an inhibitor also decrease the production of PGE2 and replication of both viruses, which can be attributed to the inhibition COX-1/PGE2 signaling pathway. These data indicate that the COX-2/PGE2 signaling pathway has proviral effects for the replication of FCV and MNV, and pharmacological inhibitors against these enzymes serve as potential therapeutic candidates for treating FCV and MNV infections. PMID- 30021005 TI - Characterization of wheat (Triticum aestivum) TIFY family and role of Triticum Durum TdTIFY11a in salt stress tolerance. AB - The TIFY proteins constitute a plant-specific super-family and they are involved in regulating many plant processes, such as development, defences and stress responses. The Jasmonate-ZIM-Domain (JAZ) proteins, the best-characterized sub group of the TIFY family are key regulator of the jasmonic acid (JA) signalling pathway. Jasmonates regulate several aspects of plant development, and play a primary role in defence mechanisms as well as in plant responses to abiotic stresses. The TIFY family is well studied in dicots but poorly investigated in monocots. The present study reports an extensive genomic identification of TIFY proteins from Triticum aestivum. We identified 49 TIFY genes, which were annotated according to three sub-genomes (AABBDD) of T. aestivum. Following their clustering with Oryza sativa and Brachypodium distachyon, the 49 genes were grouped in 18 different TIFY homeologous subsets. Expression analyses of 6 representative TIFY genes on Tunisian durum wheat seedlings revealed their differential regulation by various stress treatment, including JA, ABA and salt stress. TIFY11a was specifically induced after salt treatment. Transgenic lines over-expressing TdTIFY11a showed higher germination and growth rates under high salinity conditions, compared to wild type plants. In summary, our results outline a relevant role of wheat TIFY proteins in promoting germination under salt stress. PMID- 30021006 TI - Ubiquitination of alpha-synuclein filaments by Nedd4 ligases. AB - Alpha-synuclein can form beta-sheet filaments, the accumulation of which plays a key role in the development of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. It has previously been shown that alpha-synuclein is a substrate for the HECT domain-containing ubiquitin ligase Nedd4, and is subject to ubiquitin-mediated endosomal degradation. We show here that alpha-synuclein filaments are much better substrates for ubiquitination in vitro than monomeric alpha-synuclein, and that this increased susceptibility cannot be mimicked by the mere clustering of monomers. Recognition by Nedd4 family enzymes is not through the conventional binding of PPxY-containing sequences to WW domains of the ligase, but it also involves C2 and HECT domains. The disease-causing alpha synuclein mutant A53T is a much less efficient substrate for Nedd4 ligases than the wild-type protein. We suggest that preferential recognition, ubiquitination and degradation of beta-sheet-containing filaments may help to limit toxicity, and that A53T alpha-synuclein may be more toxic, at least in part because it avoids this fate. PMID- 30021008 TI - Efficient recovery of recombinant CRM197 expressed as inclusion bodies in E.coli. AB - CRM197, which retains the same inflammatory and immune-stimulant properties as diphtheria toxin but with reduced toxicity, has been used as a safe carrier in conjugated vaccines. Expression of recombinant CRM197 in E. coli is limited due to formation of inclusion bodies. Soluble expression attempts in Bacillus subtilis, P. fluorescens, Pichia pastoris, and E. coli were partially unsuccessful or did not generate yields sufficient for industrial scale production. Multiple approaches have been attempted to produce CRM197 in E. coli, which has attractive features such as high yield, simplicity, fast growth, etc., including expression of oxidative host, concurrent expression of chaperones, or periplasmic export. Recently, alternative methods for recovery of insoluble proteins expressed in E. coli were reported. Compared to traditional denaturation/refolding, these methods used the non-denaturing solubilization agent, N-lauroylsarkosine to obtain higher recovery yields of native proteins. Based on this work, here, we focused on solubilization of CRM197 from E. coli inclusion bodies. First, CRM197 was expressed as inclusion bodies by high-level expression of recombinant CRM197 in E. coli (126.8 mg/g dcw). Then bioactive CRM197 was isolated from these inclusion bodies with high yield (108.1 mg/g dcw) through solubilization with N-lauroylsarkosine including Triton X-100 and CHAPS, and purified by Ni-affinity chromatography and size-exclusion chromatography. In this study, we present a cost-effective alternative for the production of bioactive CRM197 and compare our recovery yield with yields in other production processes. PMID- 30021007 TI - Rapid in vitro detection of CTX-M groups 1, 2, 8, 9 resistance genes by LAMP assays. AB - BACKGROUND: The prevalence of bacteria producing CTX-M Extended-Spectrum beta lactamases (ESBLs) has increased around the world and some of them became a major cause of infections such as bloodstream or urinary tract infections (UTI). We developed a loop-mediated isothermal amplification (LAMP) assay for a simple, rapid and sensitive detection of the four most common CTX-M groups, namely CTX-M groups 1, 2, 8 and 9. METHODS: LAMP primers targeting the four ESBLs CTX-M groups were designed using the Primer Explorer V4 software. The detection limit of the method was tested by serial dilution of reference DNAs. The primer specificity of the LAMP reaction was tested on DNA extracted from six strains producing various group of CTX-M and validated using DNA extracted from CTX-M-resistant clinical isolates (isolated from pus, urine, or blood). Results were compared with those of conventional PCR. RESULTS: We were able to detect down to 0.1 pg/ul of DNA using the newly developed LAMP assays whereas the minimal amount detectable for conventional PCR was 50 to 100pg/ul, indicating that the LAMP assay was found to have a detection limit at least 500 to 1000 times lower than the PCR. Additionally, representative genes from the CTX-M groups 1, 2, 8 and 9 were amplified using the designed assay and no cross amplification was observed between the four CTX-M groups, demonstrating the specificity of the LAMP assay. Of the 37 clinical strains tested, the four LAMP assays showed 100% sensitivity and 87%, 97%, 100%, 100% specificity for the CTX-M groups 1, 2, 8 and 9 respectively. CONCLUSION: Being sensitive, specific, rapid and standard methods, the LAMP assays developed in this study have a potential to be beneficial tools in molecular epidemiology and surveillance studies of the four prevalent EBSLs CTX-M groups even in low cost laboratory. PMID- 30021009 TI - Preclinical toxicological assessment of a novel monoclonal antibody targeting human platelet-derived growth factor CC (PDGF-CC) in PDGF-CChum mice. AB - Platelet-derived growth factor CC (PDGF-CC) is important during foetal development but also in pathogenesis of neurologic diseases, cancer and fibrosis. We have previously demonstrated that blocking the PDGF-CC/PDGF receptor alpha (PDGFRalpha) axis resulted in reduction of stroke volume and cerebrovascular permeability after experimentally induced stroke. Recently, we could translate these findings into the clinic showing that imatinib, a small tyrosine kinase inhibitor targeting PDGF receptors, can significantly improve neurological outcome after ischemic stroke in human. Herein we report preclinical toxicological analyses of our newly generated monoclonal anti-human PDGF-CC antibody 6B3 (mAb 6B3) in PDGF-CC humanized mice. Beside histological organ assessment, we also analysed serum, urine, haematological parameters and the general health status of the treated mice. We could not find any indications that mAb 6B3 is toxic or has other significant side effects neither in short, nor in long treatment regimens. Our results indicate that mAb 6B3 can be further developed for clinical use. This opens up the possibility to assess the therapeutic potential of blocking PDGF-CC in diverse pathological conditions such as neurologic diseases, cancer and fibrosis. PMID- 30021010 TI - Correction: Suprafenacine, an Indazole-Hydrazide Agent, Targets Cancer Cells Through Microtubule Destabilization. AB - [This corrects the article DOI: 10.1371/journal.pone.0110955.]. PMID- 30021012 TI - Correction: Enhancing monellin production by Pichia pastoris at low cell induction concentration via effectively regulating methanol metabolism patterns and energy utilization efficiency. AB - [This corrects the article DOI: 10.1371/journal.pone.0184602.]. PMID- 30021011 TI - Development and initial validation of the Morningness-Eveningness Exercise Preference Questionnaire (MEEPQ) in Japanese university students. AB - The aim of this study was to develop a questionnaire to conveniently assess the diurnal preferences of physical activity (PA) in Japanese university students. A total of 219 subjects completed our novel Morningness-eveningness Exercise Preference Questionnaire (MEEPQ). The MEEPQ consisted of 30 items (15 items for the morning and the same 15 items for the evening) rated on a 5-point Likert scale concerning their preference for participating in PA in the morning and evening. The morning score (MS) and evening score (ES) were determined by summing each of the respective 15 items. The internal consistency and construct validity were assessed, and a factor analysis was conducted. To examine the external validity of the MEEPQ, participants wore an accelerometer for seven consecutive days to measure their PA levels objectively. Finally, the test-retest reliability was evaluated at a one-month interval. The MEEPQ showed excellent internal consistency (Cronbach's alpha = 0.896) and construct validity (morning KMO = 0.913, evening KMO = 0.875). A factor analysis showed a three-factor structure involving Physical Wellness (MEEPQ-W), Psychological Well-Being (MEEPQ-P) and Exercise Barrier (MEEPQ-B). The percent of variance was largest for MEEPQ-W in the morning (45.2%) and MEEPQ-P in the evening (40.8%). Test-retest showed that MEEPQ scores had fair repeatability. Significant and positive associations between scores and objectively measured PA levels were found in the MS and 6-9 AM PA and in the ES and 6-9 PM and 9 PM- 0 AM PA (all p<0.05). In summary, the novel MEEPQ showed relatively good agreement and thus can be used for Japanese university student samples. In the MEEPQ, three factors (the physical wellness, psychological well-being and exercise barrier) contributed to a morning or evening PA preference. The summed scores were significantly associated with the objectively measured PA levels in both the morning and evening. Therefore the MEEPQ appears to be a suitable tool for assessing diurnal PA preferences. PMID- 30021013 TI - A qualitative exploration of the misconceptions, knowledge gaps and constructs of leptospirosis among rural and urban communities in Malaysia. AB - This qualitative study aimed to explore the misconceptions, knowledge gaps and constructs of leptospirosis among 72 respondents from rural and urban districts in two states of Malaysia. We conducted focus group discussions and data were examined using thematic analyses. The layman term of 'rat urine disease' contributed the most to the misconceptions regarding leptospirosis. There were gaps in the knowledge among urban and rural respondents in the two states, with the majority of subjects demonstrating a poor understanding of the disease. Construction of knowledge about leptospirosis relied mostly on the information provided by mass and social media; reading materials; word-of-mouth publicity; observations; experiences; and knowledge sharing among families, friends, and communities. The study findings may provide the foundation for the development of educational materials that may reduce the gaps in knowledge, and thereby improve health literacy and enhance preventive health behaviours for avoiding leptospirosis. PMID- 30021014 TI - Analysis of KRT1, KRT10, KRT19, TP53 and MMP9 expression in pediatric and adult cholesteatoma. AB - Cholesteatoma is an epidermal cyst with still unknown pathomechanism. The aim of the current study was to investigate molecular differences in the background of the hyperproliferative property and aggressive behavior typical of the cholesteatoma epithelium. The expression of three cytokeratin genes (KRT1, KRT10 and KRT19), the matrix metalloproteinase 9 gene (MMP9) and the tumor suppressor TP53 gene was measured by qRT-PCR in surgical samples of pediatric and adult cholesteatoma cases and their expression level was compared to that of normal skin samples from the retroauricular region of control individuals. Cholesteatoma samples were stratified according to the age of onset and recurrence for more detailed analysis. Our results showed identical expression pattern for KRT1 and KRT10, their expression was higher in pediatric cases than in adults, especially in pediatric recurrent samples. The expression level of KRT19 was inversely proportional to that of KRT1/KRT10, it was lower in the more invasive recurrent cases both in our pediatric and adult groups. As it was expected from the bone destructive behavior of cholesteatoma, a significantly elevated expression of MMP9 was measured in cholesteatoma samples, the highest level was found in adult recurrent cases. Low expression levels characterize the TP53 gene without significant differences in our samples. These findings demonstrate that cytokeratin expression distinguishes between pediatric/adult, nonrecurrent/recurrent cases, suggesting that distinct differentiation state and cell division potential characterize these cholesteatoma cases. KRT19 with a tumor suppressor potential might restrict the recurrence of cholesteatoma. The differences observed in gene expression profiles between cholesteatoma and control samples support the notion that cholesteatoma is a cystic lesion with tumor-like behavior because it is characterized by invasive, destructive growth and high tendency for recurrence. PMID- 30021015 TI - DNA barcoding for the efficient and accurate identification of medicinal polygonati rhizoma in China. AB - Polygonati rhizoma (PR), a traditional medicinal and edible product with various bioactive components (Polygonatum polysaccharides, saponins, phenols, and flavonoids), is widely consumed in China. However, other species with morphological characteristics similar to those of the actual components are being used to replace or adulterate PR, causing issues with quality control and product safety. The morphological similarity of PR and its substitutes makes classic morphological identification challenging. To address this issue, DNA barcoding based identification using ITS2 and psbA-trnH sequences was applied in this study to evaluate the efficiency and accuracy of this approach in identifying PR samples collected from 39 different regions in China. The identification of PR by this method was confirmed by other methods (phylogeny-based and character-based methods), and all the samples were clearly and accurately distinguished. This study highlights the efficient and accurate nature of DNA barcoding in PR identification. Applying this technique will provide a means to differentiate PR from other altered formulations, thus improving product quality and safety for consumers of PR and its products. PMID- 30021016 TI - Prevalence of diabetes mellitus amongst hospitalized tuberculosis patients at an Indian tertiary care center: A descriptive analysis. AB - BACKGROUND: India has a high prevalence of tuberculosis (TB) as well as diabetes mellitus (DM). DM is a chronic disease caused by deficiency of insulin production by the pancreas. The risk of TB amongst DM patients is three times higher than those without. The estimated national prevalence of DM is 7.3%. Despite the growing burden of DM, there are limited studies describing the prevalence of TB DM in India. OBJECTIVE: Our study estimated the prevalence of DM amongst adult hospitalized TB patients at Kasturba Hospital, Manipal and determined factors associated with the likelihood of DM-TB co-prevalence. METHODS: We conducted a retrospective cohort study at Kasturba Hospital, Manipal Academy of Higher Education. All hospitalized adult patients diagnosed with pulmonary TB (PTB) and extrapulmonary TB (EPTB) between June 1st 2015 and June 30th 2016 were eligible for inclusion. Pediatric and pregnant TB patients were excluded from our study. Data were extracted from medical charts. Descriptive and multivariate analyses were performed in R. Multivariate analysis adjusted for age, gender, type of TB, history of TB, and nutrition (body mass index (BMI)) status. RESULTS: A total of 728 patients met the eligibility criteria, 517 (71%) were male, 210 (29%) female, 406 (56%) had PTB and 322 (44%) had EPTB. Amongst those with a nutritional status, 36 (30%) patients were underweight (BMI <18.4 kg/m2), 73 (40%) had a normal BMI (18.5kg/m2-24.9 kg/m2), 15 (8%) were overweight (BMI 25.0 kg/m2-29.9 kg/m2) and 9 (5%) were obese (BMI >30.0 kg/m2). A total of 720 (98.9%) of TB patients had at least one blood sugar test result. The overall prevalence of DM (n = 184) amongst TB patients was 25.3% (95% CI 22.2%, 28.6%). When stratified, it was 35.0% (30.4%, 39.9%) and 13.0% (9.7%, 17.3%) amongst PTB and EPTB patients respectively. TB patients aged 41-60 years had 3.51 times higher odds (aOR 3.51 (2.08, 6.07)) of having DM than patients 40 years or younger. Patients aged 60 years or older had 2.49 times higher odds (aOR 2.49 (1.28, 4.85)) of having DM than younger patients (<40 years). Females had lower odds (aOR 0.80 (0.46, 1.37)) of developing DM than male TB patients and patients with a history of TB had lower odds (aOR 0.73 (0.39, 1.32)) than newly diagnosed TB patients. Additionally, EPTB patients had significantly lower odds (aOR 0.26 (0.15, 0.43)) compared to PTB patients. Underweight patients also had significantly lower odds (aOR 0.25 (0.14, 0.42)) of having DM than normal weight patients. CONCLUSION: Our study found a higher prevalence of TB-DM than the national average. TB-DM co prevalence was significantly associated with age, type of TB and undernutrition. As India's DM prevalence is expected to rise, TB-DM will become an increasingly important part of the TB epidemic requiring specialized study and care. PMID- 30021017 TI - Long-term serial position effects in cue-based inference. AB - An important theoretical question in decision making concerns the nature of cue generation: What mechanism drives the generation of cues used to make inferences? Most models of decision making assume that the properties of cues, often cue validity, initiate a set of dynamic pre-decision processes. In two studies, we test how memory accessibility affects cue use by manipulating both ecological cue validity and cue accessibility in a stock-forecasting task. Cue accessibility was manipulated by the pattern of accurate cue discriminations within experiment blocks of the learning phase of the experiments. Specifically, we manipulated the serial positions in which the cues accurately discriminated while holding overall cue validity constant. At test, participants preferred cues that discriminated early in the learning phase-a kind of primacy effect. The findings suggest that cue use is influenced by memory retrieval mechanisms and that cue use is not solely determined by cue validity. The results have implications for the development of computational models of heuristic decision-making. PMID- 30021018 TI - A study on the dynamics of temporary HIV treatment to assess the controversial outcomes of clinical trials: An in-silico approach. AB - It is still unclear under which conditions temporary combined antiretroviral therapy (cART) results in a prolonged remission after interruption. Clinical trials have contradicting reposts about the effect of cART during primary HIV infection on the disease progression. Here we propose that the apparent contradiction is due the presence of a window of opportunity for cART treatment observed in the in silico studies. We study non-linear correlations in the HIV dynamics over time using information theory. This approach requires a large dataset of CD4+ T lymphocytes and viral load concentrations over time. Since it is unfeasible to collect the required amount of data in clinical trials we use C ImmSim, a clinically validated in silico model of the HIV infection, to simulate the HIV infection and temporary cART in 500 virtual patients for a period of 6 years post infection in time steps of 8 hours. We validate the results of our model with two published clinical trials of temporary cART in acute infection and analyse the impact of cART on the immune response. Our quantitative analysis predicts a "window of opportunity" of about ten months after the acute phase during which a temporary cART has significantly longer-lasting beneficial effects on the immune system as compared to treatment during the chronic phase. This window may help to explain the controversial outcomes of clinical trials that differ by the starting time and duration of the short-term course cART and provides a critical insight to develop appropriate protocols for future clinical trials. PMID- 30021020 TI - Inheritance and QTL mapping of cucumber mosaic virus resistance in cucumber (Cucumis Sativus L.). AB - The commercial yield of cucurbit crops infected with Cucumber mosaic virus (CMV) severely decreases. Chemical treatments against CMV are not effective; therefore, genetic resistance is considered the primary line of defense. Here, we studied resistance to CMV in cucumber inbred line '02245' using a recombinant inbred line (RIL) population generated from a cross between '65G' and '02245' as susceptible and resistant parents, respectively. Genetic analysis revealed that CMV resistance in cucumber is quantitatively inherited. Analysis of the RIL population revealed that a quantitative trait locus (QTL) was found on chromosome 6; named cmv6.1, this QTL was delimited by SSR9-56 and SSR11-177 and explained 31.7% of the phenotypic variation in 2016 and 28.2% in 2017. The marker SSR11-1, which is close to the locus, was tested on 78 different cucumber accessions and found to have an accuracy of 94% in resistant and moderately resistant lines but only 67% in susceptible lines. The mapped QTL was delimited within a region of 1,624.0 kb, and nine genes related to disease resistance were identified. Cloning and alignment of the genomic sequences of these nine genes between '65G' and '02245' revealed that Csa6M133680 had four single-base substitutions within the coding sequences (CDSs) and two single-base substitutions in its 3'-untranslated region, and the other eight genes showed 100% nucleotide sequence identity in their exons. Expression pattern analyses of Csa6M133680 in '65G' and '02245' revealed that the expression levels of Csa6M133680 significantly differed between '65G' and '02245' at 80 h after inoculation with CMV and that the expression in '02245' was 4.4 times greater than that in '65G'. The above results provide insights into the fine mapping and marker-assisted selection in cucumber breeding for CMV resistance. PMID- 30021021 TI - The mathematics of market timing. AB - Market timing is an investment technique that tries to continuously switch investment into assets forecast to have better returns. What is the likelihood of having a successful market timing strategy? With an emphasis on modeling simplicity, I calculate the feasible set of market timing portfolios using index mutual fund data for perfectly timed (by hindsight) all or nothing quarterly switching between two asset classes, US stocks and bonds over the time period 1993-2017. The historical optimal timing path of switches is shown to be indistinguishable from a random sequence. The key result is that the probability distribution function of market timing returns is asymmetric, that the highest probability outcome for market timing is a below median return. Put another way, simple math says market timing is more likely to lose than to win-even before accounting for costs. The median of the market timing return probability distribution can be directly calculated as a weighted average of the returns of the model assets with the weights given by the fraction of time each asset has a higher return than the other. For the time period of the data the median return was close to, but not identical with, the return of a static 60:40 stock:bond portfolio. These results are illustrated through Monte Carlo sampling of timing paths within the feasible set and by the observed return paths of several market timing mutual funds. PMID- 30021019 TI - Relaxed natural selection contributes to global obesity increase more in males than in females due to more environmental modifications in female body mass. AB - OBJECTIVE: Relaxed natural selection, measured by Biological State Index (Ibs), results in unfavourable genes/mutations accumulation in population. Obesity is partly heritable. We aim to examine and compare the effects of relaxed natural selection on male and female obesity prevalence. METHODS: Data for 191 countries of the world were captured for this ecological study. Curvilinear regressions, bivariate and partial correlations, linear mixed models and multivariate linear regression analyses were used to examine the relationship between Ibs and sex specific obesity prevalence. Per capita GDP, urbanization and caloric intake were controlled for as the confounding factors. Fisher r-to-z transformation, R2 increment in multivariate regression and F-test were used to compare the correlations. RESULTS: Curvilinear regressions, bivariate and partial correlations (controlled for GDP, urbanization and calories) revealed that Ibs was significantly correlated to obesity prevalence of both sexes, but significantly stronger to male than to female obesity prevalence. Curvilinear regression models also showed strong correlations. Mixed linear models, with effects of GDP, urbanisation and caloric intake controlled for, showed that male and female average obesity prevalence rates were significantly higher in countries with greater Ibs value than their equivalents in countries with lower Ibs. Between higher and lower Ibs countries, the gap of male obesity prevalence is 60% greater than the gap of female obesity prevalence. Stepwise multiple regression identified that Ibs was a significant predictor of obesity prevalence of both sexes. Multivariate regression showed that, adding Ibs as an obesity predictor, R2 increment in male model was significantly greater than in female model. CONCLUSIONS: Relaxed natural selection may drive males and females to accumulate metabolic faulty genes equally. Probably due to greater environmental, personal intervention in regulating female body mass, relaxed natural selection shows less contributing effects to female obesity prevalence than to male obesity prevalence. Gene therapy to prevent obesity may need to be also taken into account. PMID- 30021029 TI - Promoting health and physical capacity during productive work: the Goldilocks Principle. AB - Objectives In spite of preventive efforts, organizations and employees face several challenges related to working life and occupational health, such as a substantial prevalence of musculoskeletal disorders, social inequality in health and physical capacity, multi-morbidity, an obesity epidemic and an aging workforce. We argue that a new approach to occupational ergonomics and health is required, going beyond prevention of harm caused by work. We propose the "Goldilocks Principle" for how productive work can be designed to promote health and physical capacity. Methods Physical (in)activity profoundly influences health and physical capacity, with effects depending on the extent and temporal structure of the (in)activity. Like the porridge, chair and bed that needed to be "just right" for Goldilocks in the The Three Bears fairytale, physical activity during productive work needs to be "just right" for promoting rather than deteriorating health and capacity. In many jobs, physical activity is, however, either too much/high/frequent or too little/low/infrequent to give positive biomechanical and cardiometabolic stimuli. Results This paper presents the rationale, concept, development, application and prospects of the Goldilocks Principle for how productive work can be designed to promote health and physical capacity. Conclusions We envision a great potential to promote health and physical capacity by designing productive work according to the Goldilocks Principle, thus leading to benefits with respect to the current challenges related to working life and occupational health for society, organizations and employees. PMID- 30021022 TI - Molecular epidemiology and spatiotemporal dynamics of norovirus associated with sporadic acute gastroenteritis during 2013-2017, Zhoushan Islands, China. AB - A total of 1 590 fecal swabs and stool samples from sporadic acute gastroenteritis patients of all ages were collected from January 2013 to March 2018 in the Zhoushan Islands, China, with 99 (6.23%) samples subsequently identified as human norovirus (HuNoV) positive. Phylogenetic analysis of partial RdRp and VP1 gene regions identified 10 genotypes of the GII genogroup and 3 genotypes of the GI genogroup. The predominant genotype was GII.P17-GII.17 (42.86%, 33/77), followed by GII.Pe-GII.4_Sydney 2012 (24.68%, 19/77) and GII.P16 GII.2 (12.96%, 10/77). However, the prevailing genotype in the Zhoushan Islands has shifted on three separate occasions. The GII.Pe-GII.4_Sydney_2012 strain was dominant in 2013-2014, the GII.P17-17 strain was dominant in 2015-2016, and the GII.P16-GII.2 strain was dominant in 2017. Divergence analysis showed that the re emerging GII.P16-GII.2 strains clustered with the Japanese 2010-2012 GII.P16 GII.2 strains, and the time of the most recent common ancestor was estimated to have occurred in 2012 to 2013. The evolutionary rates of the RdRp gene region of the GII.P16 genotype and the VP1 gene region of the GII.2 genotype were 2.64 * 10 3 (95% HPD interval, 2.17-3.08 * 10-3) and 3.36 * 10-3 (95% HPD interval, 2.66 4.04 * 10-3) substitutions/site/year, respectively. The migration pattern of the HuNoV GII.2 genotype in China demonstrated that the re-emerging GII.P16-GII.2 strains were first introduced into Hong Kong from Japan, and then spread from Hong Kong to other coastal areas. Our results also showed that the GII.P16-GII.2 strains in the Zhoushan Islands were likely introduced from Jiangsu Province, China, in 2016. PMID- 30021023 TI - Improvement of signal-to-noise ratio in parallel neuron arrays with spatially nearest neighbor correlated noise. AB - We theoretically investigate the signal-to-noise ratio (SNR) of a parallel array of leaky integrate-and-fire (LIF) neurons that receives a weak periodic signal and uses spatially nearest neighbor correlated noise. By using linear response theory, we derive the analytic expression of the SNR. The results show that the amplitude of internal noise can be increased up to an optimal value, which corresponds to a maximum SNR. Given the existence of spatially nearest neighbor correlated noise in the neural ensemble, the SNR gain of the collective ensemble response can exceed unity, especially for a negative correlation. This nonlinear collective phenomenon of SNR gain amplification may be related to the array stochastic resonance. In addition, we show that the SNR can be improved by varying the number of neurons, frequency, and amplitude of the weak periodic signal. We expect that this investigation will be useful for both controlling the collective response of neurons and enhancing weak signal transmission. PMID- 30021030 TI - Introduction. PMID- 30021031 TI - When and How to Incorporate Steroids for Persistent Diabetic Macular Edema: A Discussion of Real-World Treatment Optimization Strategies. AB - In the United States, diabetic macular edema (DME) is the leading cause of vision loss among people with diabetic retinopathy. Despite the availability of different therapies for DME, up to half of patients with DME show some persistent edema after anti-vascular endothelial growth factor (VEGF) treatment alone, leaving these patients at high risk for vision loss. However, dosing in a similar fashion to that of pivotal anti-VEGF trials is difficult because of real-life challenges faced in clinical practice. This is particularly true for DME, in that the frequency and burden of anti-VEGF injections are a major challenge to patient care. Research evaluating anti-VEGF therapies has shaped the treatment paradigms for patients with DME, and similar benefits have also been noted in clinical trials evaluating the use of intravitreal steroids. Treatment with a long-term intravitreal corticosteroid, which requires fewer injections than treatment with most short-acting therapies, has been found to reduce inflammation and improve vision in a percentage of patients. This roundtable discussion, which took place during the 2018 annual meeting of the Vit-Buckle Society, reviews the current treatment paradigms for DME and evaluates how to customize and optimize treatment strategies geared toward individualized patient care. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:S5-S15.]. PMID- 30021033 TI - Emerging Gene Therapy Treatments for Inherited Retinal Diseases. PMID- 30021032 TI - Letter to the Editor: Imaging Characteristics and Natural History of Macular Pseudo-Folds Mimicking Full-Thickness Postoperative Macular Folds Following Retinal Detachment Repair. PMID- 30021034 TI - Predictors of Outcome During Eplerenone Therapy in Chronic Central Serous Chorioretinopathy:A Prospective, Open-Label Pilot Clinical Study. AB - BACKGROUND AND OBJECTIVE: To assess the treatment response and predictive factors following eplerenone treatment in chronic central serous chorioretinopathy (CSCR). PATIENTS AND METHODS: A prospective, nonrandomized study involving fixed dose eplerenone was conducted in 22 eyes of 11 consecutive patients with bilateral chronic CSCR. The changes in subretinal fluid (SRF), central macular thickness (CMT), and best-corrected visual acuity (BCVA) were analyzed. RESULTS: A significant reduction in SRF was observed in 13 of 16 eyes with baseline SRF (81.25%) at 3 months (P < .04), with complete resolution in six eyes (37.5%) at 3 months and in 10 eyes (62.5%) at 6 months (P < .006). Baseline BCVA was a significant predictor of final BCVA (P < .001), whereas 3-month SRF height was a weak but significant predictor of the 6-month height (r2 = 0.53; P = .002). CONCLUSION: When treated with eplerenone, chronic CSCR shows a significant reduction in SRF, with baseline BCVA and 3-month SRF height being important predictive factors. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:479-486.]. PMID- 30021035 TI - Quantitative Comparison of Retinal Vascular Features in Optical Coherence Tomography Angiography Images From Three Different Devices. AB - BACKGROUND AND OBJECTIVE: To compare optical coherence tomography angiography (OCTA) images from three different devices. PATIENTS AND METHODS: This was a prospective, observational, cross-sectional study. All eyes (n = 24) were imaged thrice each time with swept-source OCT (DRI OCT Triton Plus; Topcon, Tokyo, Japan), spectral-domain OCTA (AngioVue; Optovue, Fremont, CA), and SD-OCT Angioplex (Cirrus HD-OCT 5000; Carl Zeiss Meditec, Jena, Germany). Outcome measures were foveal avascular zone (FAZ) area, vessel density, spacing between large vessels (SLV), and spacing between small vessels (SSV). They were calculated using local fractal analyses and Frangi filter. RESULTS: The vascular parameters showed good to excellent repeatability (intraclass coefficient > 0.8) in the three devices. The FAZ area (P = .3) and vessel density of the superficial layer (P = .8) were similar between the devices. In the deep layer, vessel density was significantly higher (P = .02) with Angio-Vue images compared to those acquired using the other devices. However, SLV was significantly higher (P < .05) and SSV was significantly lower (P < .05) on Angioplex scans compared to other devices. Vessel parameters were significantly altered in Frangi-filtered images as compared to nonfiltered images. CONCLUSIONS: Vessel density showed good repeatability among the three devices, although there were differences in vessel parameters between the devices. Also, vessel parameters changed significantly after Frangi filtering. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:488 496.]. PMID- 30021036 TI - Findings in Persistent Retinopathy of Prematurity. AB - BACKGROUND AND OBJECTIVE: To determine whether retinopathy of prematurity (ROP) that persists beyond a postmenstrual age (PMA) of 45 weeks has abnormalities that can be documented by fundus photography or fluorescein angiography (FA). PATIENTS AND METHODS: Fundus photographs and FAs were reviewed for all premature infants who underwent FA for persistent ROP after 45 weeks PMA. RESULTS: Of the 487 infants who were screened for ROP, 16 (3.3%) demonstrated ROP beyond 45 weeks. Seven (43.8%) infants received prior treatment with intravitreal bevacizumab (IVB) for Type 1 ROP. FAs were obtained in eight cases; four subjects were previously treated with IVB. Leakage at the vascular-avascular border was demonstrated in seven subjects (87.5%). Shunt vessels, posterior retinal nonperfusion, and absence of the foveal avascular zone was limited to the IVB group. CONCLUSIONS: There are persistent vascular abnormalities among infants with ROP beyond 45 weeks. Findings that may be missed by RetCam fundus photographs were highlighted with FA. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:497-503.]. PMID- 30021037 TI - Treatment of Acute Zonal Occult Outer Retinopathy With Intravitreal Steroids. AB - BACKGROUND AND OBJECTIVE: To report on the use of intravitreal steroids in the management of acute zonal occult outer retinopathy (AZOOR), a rare disorder affecting the outer retina. PATIENTS AND METHODS: Retrospective case series of nine eyes of five patients with AZOOR who received intravitreal triamcinolone acetonide (IVTA), dexamethasone intravitreal implant, and/or fluocinolone acetonide implant. Treatment response was determined by reported symptoms and multimodal imaging findings. Patients were observed for at least 1 year following intravitreal steroid treatment (range: 14 months to 63 months). RESULTS: Seven eyes received IVTA, six eyes received the dexamethasone intravitreal implant, and one eye received the fluocinolone acetonide implant. All patients experienced disease stability or improvement based on symptomatic response and multimodal imaging findings after intravitreal steroids. One eye developed central serous retinopathy, and another eye a choroidal neovascular membrane. Five of nine eyes experienced ocular hypertension. All phakic eyes developed cataracts. CONCLUSION: Intravitreal steroids effectively achieved disease stability in patients with AZOOR. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:504-509.]. PMID- 30021038 TI - Relationship Between Dry Retinal Volume and Visual Acuity in Diabetic Macular Edema. AB - BACKGROUND AND OBJECTIVE: To evaluate the relationship between a novel spectral domain optical coherence tomography (SD-OCT) parameter, predicted dry retinal volume (DRV), and visual acuity (VA) in subjects with diabetic macular edema. PATIENTS AND METHODS: Twenty-eight eyes of 26 subjects with macular edema secondary to diabetic retinopathy (cases) and 10 healthy eyes of normal volunteers (controls) were included. Spectral-domain optical coherence tomography volume scans (512 * 128) were obtained before and 6 months to 12 months after anti-vascular endothelial growth factor therapy. The borders of the neurosensory retina, nerve fiber layer (NFL), and vitreous were manually defined using previously described grading software. NFL reflectivity was used to normalize the signal between eyes, allowing a normalized total retinal intensity to be computed for each eye by summing the brightness of every pixel in the retina on all B scans. Using this normalized retinal intensity, a ratio of retinal intensity of cases over retinal intensity of normal was generated. The predicted DRV was computed by multiplying this calculated ratio with total retinal volume at baseline for each eye. Correlation analysis was performed between DRV at baseline and VA at baseline and final follow-up. RESULTS: The mean +/- standard deviation age of the cohort was 69 years +/- 9.8 years, and 28% were female. Mean best corrected VA (logMAR) improved from 0.56 +/- 0.36 at baseline to 0.44 +/- 0.32 at follow-up (P = .001). The uncorrected ("wet") total retinal volume of 13.25 mm3 +/- 2.73 mm3 at baseline declined significantly to a posttreatment retinal volume of 10.92 mm3 +/- 1.42 mm3. The predicted DRV (10.79 mm3 +/- 1.42 mm3) was statistically similar to the post-treatment, actual retinal volume. No significant correlation was observed between DRV and post-treatment VA. CONCLUSIONS: The predicted DRV at baseline showed good agreement with the actual observed posttreatment retinal volume. Thus, DRV may be a potentially useful parameter to estimate the extent of retinal tissue loss that may be obscured by the presence of concomitant edema. The lack of correlation between DRV and VA, however, suggests that other parameters, such as the integrity of the outer retinal bands, are likely important for visual outcome prediction. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:510-515.]. PMID- 30021039 TI - Characterization of Idiopathic Choroidal Neovascularization Using Fluorescein Angiography, Indocyanine Green Angiography, and Optical Coherence Tomography Angiography. AB - BACKGROUND AND OBJECTIVE: To assess the usefulness of optical coherence tomography angiography (OCTA) in cases of idiopathic choroidal neovascularization (iCNV). PATIENTS AND METHODS: Seven eyes with suspected iCNV were evaluated using OCT, OCTA, fluorescein angiography (FA), and indocyanine green angiography (ICGA) and were followed up between 3 weeks and 4 weeks following an intravitreal anti vascular endothelial growth factor (VEGF) injection. The utility of OCTA in the diagnosis and characterization of morphology of iCNV at baseline and follow-up was assessed. RESULTS: Morphology of vasculature comprising iCNV could be detected in all cases (100%) on OCTA and in 57% cases on ICGA. FA only detected hyperfluorescence and not individual vessel morphology. After anti-VEGF injection, the mean logMAR visual acuity improved from 0.55 to 0.27. A qualitative scale to assess response of therapy is suggested. CONCLUSIONS: OCTA is a useful, noninvasive tool to detect, characterize, and follow-up on cases of suspected iCNV with utility comparable to or even better than traditional angiography techniques. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:516 522.]. PMID- 30021040 TI - Normal Variation of Photoreceptor Outer Segment Volume With Age, Gender, Refractive Error, and Vitreomacular Adhesion. AB - BACKGROUND AND OBJECTIVE: Thickness and volume changes of the photoreceptor outer segment (PROS) layer on spectral-domain optical coherence tomography (SD-OCT) images are associated with various disease states. However, there are limited data on normal anatomical variation. This study evaluates the correlation of PROS volume with age, gender, refractive error, and presence of vitreomacular adhesion (VMA) in healthy subjects. PATIENTS AND METHODS: SD-OCT scans of 68 normal eyes were analyzed. The ellipsoid zone and the apical retinal pigment epithelium boundary were segmented using an automated algorithm. The PROS volume was calculated as the region bounded by these two layers within a 6-mm diameter circle centered at the fovea. A general linear model was used for statistical analysis. RESULTS: PROS volume increased with age to a significant degree (P = .013). Gender, refractive error, and presence of VMA were insignificant factors. CONCLUSION: PROS volume, as measured on routine SD-OCT, increases with age in healthy subjects, after adjusting for gender, refractive error, and VMA. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:523-527.]. PMID- 30021041 TI - New Vital Dye Injection Technique With Vitrectomy Probe. AB - BACKGROUND AND OBJECTIVE: To evaluate a new, safer way to inject vital dye during chromovitrectomy for dye-assisted macular peeling. PATIENTS AND METHODS: Prospective consecutive case series. Enrolled patients underwent macular surgery with a new technique of staining the epiretinal membrane and the internal limiting membrane with vital dyes. Twenty eyes of 20 patients (eight men, 12 women) were affected by idiopathic epiretinal membrane and underwent 25-gauge via pars plana vitrectomy for epiretinal membrane removal. Ten eyes were stained with Membrane Blue-Dual (Brilliant Blue G + trypan blue; DORC, Zuidland, The Netherlands) and 10 eyes were stained with Brilliant Peel (Brillant Blue G; Fluoron GmbH, Ulm, Germany). Preoperatively and postoperatively (1, 3, and 6 months) all patients received a complete ophthalmologic examination with best corrected visual acuity (BCVA) assessment, swept-source optical coherence tomography, and multifocal electroretinography (mfERG). RESULTS: The mean age of the patients was 67.0 years +/- 8.6 years (range: 55 years to 78 years). No statistically significant difference in BCVA improvement or central foveal thickness decrease was observed in either group (P > .05). The mfERG showed an increase in electrical response densities 3 months after surgery. CONCLUSION: The authors describe a new technique to inject vital dye during chromovitrectomy for dye-assisted macular peeling that may help to improve the overall safety of macular surgery. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:528-533.]. PMID- 30021042 TI - Type 2 Choroidal Neovascularization in a Choroidal Granuloma Detected Using Swept Source Optical Coherence Tomography Angiography. AB - The authors describe the imaging characteristics and progression of a type 2 choroidal neovascular membrane (CNV) using swept-source optical coherence tomography (SS-OCTA). A 27-year-old male presented with an active possible tubercular choroidal granuloma associated with exudative retinal detachment in the right eye. The patient received anti-tubercular drugs, oral corticosteroids, and intravitreal bevacizumab and showed complete resolution in 3 months. At the 7 month follow-up, SS-OCTA imaging revealed a type 2 CNV. SS-OCTA is a very useful tool to detect and monitor the growth of CNV in active and healed posterior uveitis without the risks of dye-based angiography. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:534-539.]. PMID- 30021043 TI - Bilateral Macular Choroidal Infarction as a Manifestation of Giant Cell Arteritis. AB - The authors present an unusual case of bilateral macular choroidal infarction as a manifestation of giant cell arteritis (GCA). Due to sequential bilateral presentation, multimodal imaging with spectral-domain optical coherence tomography allows for simultaneous evaluation of progressive stages of outer retinal damage caused by choroidal hypoperfusion seen on fluorescein and indocyanine green angiography. This case report demonstrates that GCA should be considered in the differential diagnosis of placoid maculopathies. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:540-543.]. PMID- 30021044 TI - Spontaneous Attachment of Rhegmatogenous Retinal Detachment Following Vitrectomy for Stage 4B Retinopathy of Prematurity and Atypical Retinal Changes Post Resolution. AB - A prematurely born baby underwent lens-sparing vitrectomy for Stage 4B retinopathy of prematurity (ROP) in the left eye. This child had a stormy neonatal course, referred late, and was treated with intravitreal anti-vascular endothelial growth factor and laser in both eyes in the past. The surgery was uneventful, and the retina was attached until a month after surgery. Later, there was development of a break that led to the occurrence of rhegmatogenous retinal detachment in the operated eye. The retinal detachment increased with time during the course of 6 weeks. Surprisingly, the hole disappeared with spontaneous attachment of retina in the following weeks, with multiple depigmented spots over the posterior pole. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:544-547.]. PMID- 30021045 TI - Novel Mutation in Retinitis Pigmentosa GTPase Regulator Gene Causes Primary Ciliary Dyskinesia and Retinitis Pigmentosa. AB - The majority of X-linked retinitis pigmentosa (XLRP) is due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Determining the pathogenicity of novel variants is important for enrollment of patients into gene therapy trials. Sequencing and analysis of RPGR variants in ORF15 is challenging, as it is highly repetitive and rich in purines. Overlapping reading frames and polymorphic insertions / deletions add further complexity to the detection of mutations. Identifying systemic manifestations in affected males and carrier phenotype in related females expedites confirmation of pathogenic variants. The authors present a 16-year-old boy with a history of primary ciliary dyskinesia presenting with complaints of nyctalopia and visual field constriction. Multimodal imaging found peripheral thinning of the retina and a characteristic foveal hyperautofluorescent ring in the proband, and a carrier phenotype in the asymptomatic mother. A novel c.1059_1059+2delGGT, p.(?) variant in RPGR was identified as hemizygous in the affected boy and heterozygous in his mother. This case study expands the genotypic spectrum of RPGR variants associated with systemic manifestations. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:548 552.]. PMID- 30021046 TI - Parapapillary Optic Nerve Head Drusen in Leber Congenital Amaurosis. AB - A 20-year-old male who was known to have Leber congenital amaurosis was assessed. Best-corrected visual acuity was counting fingers in both eyes (OU). Anterior segment OU revealed poorly reacting pupils and nystagmoid movements. Dilated fundus examination revealed widespread bone spicule pigmentation with "macular coloboma" OU (Figure a and b). Short-wave autofluorescence showed hyperautofluorescent buried optic nerve head drusen and generalized hypoautofluorescence OU (Figure c and d). Additionally, the left eye showed parapapillary drusen resulting from calcification of swollen and disrupted axons at a remote location in the parapapillary area (blue arrows; Figure b and d). The presence of buried optic nerve head drusen OU gives a clue to the diagnosis of parapapillary drusen, which can be easily mistaken for retinal astrocytoma. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:554.]. PMID- 30021047 TI - Getting Better With Age and Time: A Look Back at the European Experience for Liver Transplantation for Pediatric Patients With Wilson's Disease. PMID- 30021048 TI - Calcinosis cutis dermatologic toxicity associated with fibroblast growth factor receptor inhibitor for the treatment of Wilms tumor. AB - Small-molecule inhibitors (nibs) have revolutionized cancer therapy with the emergence of clinically efficacious treatment for advanced-stage malignancies. Fibroblast growth factor receptor (FGFR) inhibitors have shown therapeutic efficacy in malignancies with molecular-genetic alterations in the FGFR/fibroblast growth factor pathway. In a phase 1 clinical trial, erdafitinib, a pan FGFR inhibitor, was well tolerated with a manageable toxicity profile. Hyperphosphatemia was a frequent adverse event in patients treated with erdafitinib; however, no serious complications were observed with this therapy. Here, we report the development of calcinosis cutis dermatologic toxicity in a patient with hyperphosphatemia while treated with a novel selective FGFR inhibitor, INCB 54828-101. Awareness of this form of dermatologic toxicity from an FGFR inhibitor will be important for close monitoring of serum levels of phosphate, FGF23, vitamin D, and calcitriol, the management of adverse serum chemistry with chelators, and treatment decisions to either reduce dose or withhold FGFR inhibitor. PMID- 30021049 TI - Establishing an Organotypic System for Investigating Multimodal Neural Repair Effects of Human Mesenchymal Stromal Stem Cells. AB - Human mesenchymal stromal stem cells (hMSCs) hold regenerative medicine potential due to their availability, in vitro expansion readiness, and autologous feasibility. For neural repair, hMSCs show translational value in research on stroke, spinal cord injury (SCI), and traumatic brain injury. It is pivotal to establish multimodal in vitro systems to investigate molecular mechanisms underlying neural actions of hMSCs. Here, we describe a platform protocol on how to set up organotypic co-cultures of hMSCs (alone or polymer-scaffolded) with explanted adult rat dorsal root ganglia (DRGs) to determine neural injury and recovery events for designing implants to counteract neurotrauma sequelae. We emphasize in vitro hMSC propagation, polymer scaffolding, hMSC stemness maintenance, hMSC-DRG interaction profiling, and analytical formulas of neuroinflammation, trophic factor expression, DRG neurite outgrowth and tropic tracking, and in vivo verification of tailored implants in rodent models of SCI. (c) 2018 by John Wiley & Sons, Inc. PMID- 30021050 TI - Commercially Relevant Orthogonal Multi-Component Supramolecular Hydrogels for Programmed Cell Growth. AB - This study reports the ability of synthetically simple, commercially viable sugar derived 1,3:2,4-dibenzylidenesorbitol-4',4"-diacylhydrazide (DBS-CONHNH2 ) to support cell growth. Simple mixing and orthogonal self-sorting can formulate heparin, agarose, and heparin-binding micelles into these gels-easily incorporating additional function. Interestingly, the components used in the gel formulation, direct the ability of cells to grow, meaning the chemical programming of these multi-component gels is directly translated to the biological systems in contact with them. This simple approach has potential for future development in regenerative medicine. PMID- 30021051 TI - [3,3]-Sigmatropic Rearrangement of Cyclopropenylcarbinyl Cyanates: Access to Alkylidene(aminocyclopropane) Derivatives. AB - Cyclopropenylcarbinyl cyanates, generated in situ by dehydration of the corresponding carbamates, underwent an efficient and stereoselective [3,3] sigmatropic rearrangement leading to the corresponding alkylidene(isocyanatocyclopropanes), which could be converted into various alkylidene(aminocyclopropane) derivatives in a one-pot manner. This transformation complements the repertoire of sigmatropic rearrangements involving cyclopropenylcarbinol derivatives and in particular, the previously reported Overman rearrangement of cyclopropenylcarbinyl trichloroacetimidates. PMID- 30021052 TI - Dissecting the neuronal vulnerability underpinning Alpers' syndrome: a clinical and neuropathological study. AB - Alpers' syndrome is an early-onset neurodegenerative disorder often caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG) which is essential for mitochondrial DNA (mtDNA) replication. Alpers' syndrome is characterized by intractable epilepsy, developmental regression and liver failure which typically affects children aged 6 months-3 years. Although later onset variants are now recognized, they differ in that they are primarily an epileptic encephalopathy with ataxia. The disorder is progressive, without cure and inevitably leads to death from drug-resistant status epilepticus, often with concomitant liver failure. Since our understanding of the mechanisms contributing the neurological features in Alpers' syndrome is rudimentary, we performed a detailed and quantitative neuropathological study on 13 patients with clinically and histologically-defined Alpers' syndrome with ages ranging from 2 months to 18 years. Quantitative immunofluorescence showed severe respiratory chain deficiencies involving mitochondrial respiratory chain subunits of complex I and, to a lesser extent, complex IV in inhibitory interneurons and pyramidal neurons in the occipital cortex and in Purkinje cells of the cerebellum. Diminished densities of these neuronal populations were also observed. This study represents the largest cohort of post-mortem brains from patients with clinically defined Alpers' syndrome where we provide quantitative evidence of extensive complex I defects affecting interneurons and Purkinje cells for the first time. We believe interneuron and Purkinje cell pathology underpins the clinical development of seizures and ataxia seen in Alpers' syndrome. This study also further highlights the extensive involvement of GABAergic neurons in mitochondrial disease. PMID- 30021053 TI - Ultrasound for Hepatocellular Carcinoma Surveillance: Still Looking for the Fortune Teller. PMID- 30021054 TI - Impact of Abdominal Aortic Calcification among Liver Transplant Recipients: A Retrospective Study. AB - Abdominal aortic calcification (AAC) is known as a risk factor of coronary artery disease, stroke, hyperphosphatemia, chronic inflammation, diabetes, and decreased estimated glomerular filtration rate. However, the clinical implications of incidental AAC findings in liver transplantation have not been evaluated in terms of post-transplantation survival and complications. Therefore, we analyzed the relationships between the AAC level and the outcomes following liver transplantation. A total of 156 consecutive patients who underwent liver transplantation between January 2007 and December 2014 were divided into two groups according to their AAC level (< or >= 100 mm3 ), as calculated using the Agatston method. Even after propensity matching, the survival time was significantly longer in the low AAC group compared to that in the high AAC group (median survival time, 4.5 vs 3.0 years, p =0.004). A multivariate analysis identified high AAC level (hazard ratio, 2.2) and old donor age (hazard ratio, 2.2) as prognostic factors for overall survival. In conclusion, high AAC is an independent unfavorable prognostic factor in liver transplantation. This article is protected by copyright. All rights reserved. PMID- 30021055 TI - Fluorooxoborates: Ushering in a New Era of Deep Ultraviolet Nonlinear Optical Materials. AB - Borates are one of the most important classes of functional materials, and several hundreds of artificial borates have been synthesized. The substitution of oxygen by fluorine leads to manifold classes of borates. Fluorooxoborates (also known as fluoroborates), in which the F atoms covalently connect with the B atoms, show additional compositional and structural diversity compared to classic borates. Recently, owing to the large polarizability anisotropy, large HOMO-LUMO gaps, and high hyperpolarizability of the oxyfluoride BOx F4-x building blocks, fluorooxoborates have received unprecedented attention in the search for new ultraviolet (UV) and deep-UV (DUV) nonlinear optical (NLO) materials. Specifically, some compounds have excellent NLO properties that are comparable or superior to KBe2 BO3 F2 , which is the only usable crystal that generates coherent light below 200 nm through a direct second harmonic generation (SHG) process. This Minireview illustrates recent progress on the synthesis, crystal structures, structure-properties relationships and applications of fluorooxoborates. This paper concludes by highlighting the outstanding opportunities offered by NLO fluorooxoborate crystals as an innovative avenue for DUV all solid-state coherent light generation. PMID- 30021057 TI - Predictive Factors for Survival in Children Receiving Liver Transplants for Wilson's Disease: A Cohort Study Using European Liver Transplant Registry Data. AB - Liver transplantation (LT) is a rescue therapy for life-threatening complications of Wilson's disease (WD). However, data on the outcome of WD patients after LT are scarce. The aim of our study was to analyze a large pediatric WD cohort with the aim of investigating the longterm outcome of pediatric WD patients after LT and to identify predictive factors for patient and transplant survival. This is a retrospective cohort study using data of all children (<18 years) transplanted for WD enrolled in the European Liver Transplant Registry from January 1968 until December 2013. In total, 338 patients (57.6% female) transplanted at 80 different European centers (1-26 patients per center) were included in this study. The median age at transplantation was 14.0 years (interquartile range [IQR], 11.2 16.1 years); patients were followed up for a median of 5.4 years (IQR, 1.0-10.9 years) after LT. Overall patient survival rates were high with 87% (1-year survival), 84% (5-year survival), and 81% (10-year survival); survival rates increased considerably with the calendar year (P < 0.001). Early age at LT, living donation, and histidine tryptophan ketoglutarate preservation liquid were identified as risk factors for poor patient survival in the multivariate analysis. LT is an excellent treatment option for pediatric patients with WD and associated end-stage liver disease. Longterm outcome in these patients is similar to other pediatric causes for LT. Overall patient and graft survival rates improved considerably over the last decades. To improve future research in the field, the vast variability of allocation strategies should be harmonized and a generally accepted definition or discrimination of acute versus chronic WD needs to be found. PMID- 30021058 TI - Screening of Detergents for Stabilization of Functional Membrane Proteins. AB - Membrane protein studies usually require use of detergents to extract and isolate proteins from membranes and manipulate them in a soluble context for their functional or structural characterization. However, solubilization with detergent may interfere with MP stability and may directly affect MP function or structure. Moreover, detergent properties can be affected such as critical micellar concentration (CMC) can be affected by the experimental conditions. Consequently, the experimenter must pay attention to both the protein and the behavior of the detergent. This article provides a convenient protocol for estimating the CMC of detergents in given experimental conditions. Then, it presents two protocols aimed at monitoring the function of a membrane protein in the presence of detergent. Such experiments may help to test various detergents for their inactivating or stabilizing effects on long incubation times, ranging from few hours to some days. (c) 2018 by John Wiley & Sons, Inc. PMID- 30021059 TI - Integrating theoretical and experimental permeability estimations for provisional biopharmaceutical classification: Application to the WHO essential medicines. AB - The accuracy of the provisional estimation of the Biopharmaceutics Classification System (BCS) is heavily influenced by the permeability measurement. In this study, several theoretical and experimental models currently employed for BCS permeability classification have been analysed. The experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in an Ussing chamber, the MDCK and Caco-2 cell monolayers, and the parallel artificial membrane (PAMPA). The theoretical models included the octanol-water partition coefficient and the QSPeR (Quantitative Structure-Permeability Relationship) model recently developed. For model validation, a dataset of 43 compounds has been recompiled and analysed for the suitability for BCS permeability classification in comparison with the use of human intestinal absorption and oral bioavailability values. The application of the final model, based on a majority voting system showed a 95.3% accuracy for predicting human permeability. Finally, the present approach was applied to the 186 orally administered drugs in immediate-release dosage forms of the WHO Model List of Essential Medicines. The percentages of the drugs that were provisionally classified as BCS Class I and Class III was 62.4%, suggesting that in vivo bioequivalence (BE) may potentially be assured with a less expensive and more easily implemented in vitro dissolution test, ensuring the efficiency and quality of pharmaceutical products. The results of the current study improve the accuracy of provisional BCS classification by combining different permeability models. PMID- 30021060 TI - Laparoscopic Donor Hepatectomy for Adult Living Donor Liver Transplantation Recipients. AB - Even after 2 decades of experience in laparoscopic hepatectomy, data on purely laparoscopic approach for donor hepatectomy in adult living donor liver transplantation (LDLT) are limited. We report our initial experience of a purely laparoscopic approach for donor hepatectomy for adult recipients to explore its potential application in the management of donors. We did a retrospective data analysis of 54 consecutive patients operated on between May 2013 and February 2015. There were 41 right, 10 extended right, and 3 left hepatectomies. The median operative time was 436 minutes (range 294-684 minutes), and warm ischemia time was 6 minutes (2-12 minutes). Estimated blood loss was 300 mL (10-850 mL), and none of the patients required intraoperative transfusion. Four cases were converted to open laparotomy. The major complication rate was 16.7%, and biliary complication was the most frequent cause. Patients with normal anatomy had a major complication rate of 9.3% as compared with 45.5% in patients with anatomic variations. All patients recovered, and there was no mortality. In conclusion, a purely laparoscopic donor hepatectomy for adult LDLT recipients seems to be a feasible option; with careful patient selection and when performed by experienced surgeons, it may afford results comparable to the open method. PMID- 30021062 TI - Bioinspired Supertough Graphene Fiber through Sequential Interfacial Interactions. AB - Natural nacre exhibits extraordinary functional and structural diversity, combining high strength and toughness. The mechanical properties of nacre are attributed to (i) a highly arranged hierarchical layered structure of inorganic minerals (95 vol %) containing a small amount only of organic materials (5 vol %), (ii) abundant synergistic interfacial interactions, and (iii) formation under ambient temperature. Herein, inspired by these three design principles originating from natural nacre, the supertough bioinspired graphene-based nanocomposite fibers (BGNFs) are prepared under room temperature via sequential interfacial interactions of ionic bonding and pi-pi interactions. The resultant synergistic effect leads to a super toughness of 18.7 MJ m-3 as well as a high tensile strength of 740.1 MPa. In addition, the electrical conductivity of these supertough BGNFs is as high as 384.3 S cm-1. They can retain almost 80% of this conductivity even after 1000 cycles of loading-unloading testing, which makes these BGNFs promising candidates for application in flexible and stable electrical devices, such as strain sensors and actuators. PMID- 30021063 TI - Stretchable, Implantable, Nanostructured Flow-Diverter System for Quantification of Intra-aneurysmal Hemodynamics. AB - Random weakening of an intracranial blood vessel results in abnormal blood flow into an aneurysmal sac. Recent advancements show that an implantable flow diverter, integrated with a medical stent, enables a highly effective treatment of cerebral aneurysms by guiding blood flow into the normal vessel path. None of such treatment systems, however, offers post-treatment monitoring to assess the progress of sac occlusion. Therefore, physicians rely heavily on either angiography or magnetic resonance imaging. Both methods require a dedicated facility with sophisticated equipment settings and time-consuming, cumbersome procedures. In this paper, we introduce an implantable, stretchable, nanostructured flow-sensor system for quantification of intra-aneurysmal hemodynamics. The open-mesh membrane device is capable of effective implantation in complex neurovascular vessels with extreme stretchability (500% radial stretching) and bendability (180 degrees with 0.75 mm radius of curvature) for monitoring of the treatment progress. A collection of quantitative mechanics, fluid dynamics, and experimental studies establish the fundamental aspects of design criteria for a highly compliant, implantable device. Hemocompatibility study using fresh ovine blood captures the device feasibility for long-term insertion in a blood vessel, showing less platelet deposition compared to that in existing implantable materials. In vitro demonstrations of three types of flow sensors show quantification of intra-aneurysmal blood flow in a pig aorta and the capability of observation of aneurysm treatment with a great sensitivity (detection limit as small as 0.032 m/s). Overall, this work describes a mechanically soft flow-diverter system that offers an effective treatment of aneurysms with an active monitoring of intra-aneurysmal hemodynamics. PMID- 30021064 TI - In Vitro Transcription Networks Based on Hairpin Promoter Switches. AB - In vitro transcription networks are analogs of naturally occurring gene regulatory networks that consist of synthetic DNA templates that are cross regulated by their own transcripts. This ability to design and execute in vitro transcription networks has allowed bottom-up construction of complex network topologies with predictable dynamic behavior. Here we describe the simplified design of an in vitro transcription network based on single-stranded synthetic DNA hairpin switches that function similar to molecular beacons, via toehold mediated strand displacement. Systematic construction of increasingly larger circuits was achieved by programming interactions between multiple switches through rational sequence design, and the dynamic behavior of networks was accurately predicted using a simple mathematical model. Ultimately, we engineered a cascade of switches that acted as a Boolean complete NAND gate capable of sensing both DNA and RNA inputs. The tools and framework that have been developed makes the execution of in vitro transcription circuits much simpler, which will enable them to more readily serve as testbeds for nucleic acid computations both in vitro and in vivo. PMID- 30021061 TI - Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients. AB - De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomedecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08-2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09-2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68-3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97-9.48), esophageal (SIR = 4.76; 95% CI, 3.56-6.24), lung (SIR = 2.56; 95% CI, 2.21-2.95), and lip-mouth-pharynx (SIR = 2.20; 95% CI, 1.72-2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT. PMID- 30021065 TI - Covalent Organic Framework-Covalent Organic Framework Bilayer Membranes for Highly Selective Gas Separation. AB - Covalent organic frameworks (COFs) have been proposed as alternative candidates for molecular sieving membranes due to their chemical stability. However, developing COF membranes with narrowed apertures close to the size of common gas molecules is a crucial task for selective gas separation. Herein, we demonstrate a new type of a two-dimensional layered-stacking COF-COF composite membrane in bilayer geometry synthesized on a porous support by successively regulating the growth of imine-based COF-LZU1 and azine-based ACOF-1 layers via a temperature swing solvothermal approach. The resultant COF-LZU1-ACOF-1 bilayer membrane has much higher separation selectivity for H2/CO2, H2/N2, and H2/CH4 gas mixtures than the individual COF-LZU1 and ACOF-1 membranes due to the formation of interlaced pore networks, and the overall performance surpasses the Robeson upper bounds. The COF-LZU1-ACOF-1 bilayer membrane also shows high thermal and long time stabilities. PMID- 30021066 TI - Indolino-Oxazolidine Acido- and Photochromic System Investigated by NMR and Density Functional Theory Calculations. AB - Three addressable indolino-oxazolidine units connected through an isomerizable double bond to a substituted thiophene represent a smart example of a multiaddressable system whose reversible responses could be selectively activated on demand. Experimental and theoretical approaches to push forward the understanding of the system mechanism and set pathways to design optimized compounds for suitable application are here presented. NMR and UV-visible spectroscopies are used for structural and kinetic studies, while density functional theory (DFT) calculations pave the way to highlight energetic and electronic processes that are involved. Substitution and solvent effects toward the reactivity of the compounds are experimentally studied and combined with theoretical calculations. The most efficient and selective stimuli to travel between the four possible states resulting from the ring-opening of indolino[2,1- b]oxazolidine (generally referenced as BOX) derivatives and the trans-cis isomerization of the ethylenic junction are elucidated. PMID- 30021067 TI - Dissolution Behavior and Biodurability of Ingested Engineered Nanomaterials in the Gastrointestinal Environment. AB - Engineered nanomaterials (ENM) are extensively used as food additives in numerous food products, and at present, little is known about the fate of ingested ENM (iENM) in the gastrointestinal (GI) environment. Here, we investigated the dissolution behavior, biodurability, and persistence of four major iENM (TiO2, SiO2, ZnO, and two Fe2O3) in individual simulated GI fluids (saliva, gastric, and intestinal) and a physiologically relevant digestion cascade (saliva -> gastric > intestinal) in the fasted state over physiologically relevant time frames. TiO2 was found to be the most biodurable and persistent iENM in simulated GI fluids with a maximum of only 0.42% (4 MUM Ti4+ ion release) dissolution in cascade digestion, followed by iron oxides, of which the rod-like morphology was more biodurable and persistent (0.7% maximum dissolution, 8.7 MUM Fe3+) than the acicular one (2.27% maximum dissolution, 16.7 MUM Fe3+) in the cascade digestion, respectively. SiO2 and ZnO were less biodurable than Fe2O3, with 65.5% (416 MUM Si4+) and 100% (1718.1 MUM Zn2+) dissolution in the gastric phase, respectively. In the intestinal phase, however, Si4+ ions reprecipitated, possibly due to sudden pH changes, while ZnO remained completely dissolved. These observations were also confirmed using high-resolution particle size and concentration, and electron microscopy, time-dependent analysis. In terms of decreasing biodurability and persistence in the simulated GI environment, the tested nanomaterials can be ranked as follows: TiO2 ? rod-like Fe2O3 > acicular Fe2O3 ? SiO2 > ZnO, which is in agreement with limited animal biokinetics data. Chronic uptake of these iENM as particles or ions by the GI tract, especially in the presence of a food matrix and authentic digestive media, and associated implications for human health warrants further investigation. PMID- 30021068 TI - Fluorescent Guide RNAs Facilitate Development of Layered Pol II-Driven CRISPR Circuits. AB - Efficient clustered regularly interspaced short palindromic repeat (CRISPR) guide RNA (gRNA) expression from RNA Polymerase II (Pol II) promoters will aid in construction of complex CRISPR-based synthetic gene networks. Yet, we require tools to properly visualize gRNA directly to quantitatively study the corresponding network behavior. To address this need, we employed a fluorescent gRNA (fgRNA) to visualize synthetic CRISPR network dynamics without affecting gRNA functionality. We show that studying gRNA dynamics directly enables circuit modification and improvement of network function in Pol II-driven CRISPR circuits. This approach generates information necessary for optimizing the overall function of these networks and provides insight into the hurdles remaining in Pol II-regulated gRNA expression. PMID- 30021069 TI - Mechanisms of Rhodium(III)-Catalyzed C-H Functionalizations of Benzamides with alpha,alpha-Difluoromethylene Alkynes. AB - The rhodium(III)-catalyzed C-H functionalizations of benzamides with alpha,alpha difluoromethylene alkynes have been investigated by means of density functional theory calculations. The computations show that after the formation of seven membered rhodacycle via consecutive N-H deprotonation/C-H activation/migratory insertion, a novel redox-neutral process without the engagement of otherwise widely accepted Rh(V) nitrenoid species has been formulated in the hydroarylation reaction. It turns out that the seven-membered rhodacycle undergoes a concerted Lossen rearrangement/migration of OPiv from N to Rh to generate the isocyanate intermediate, from which the ensuing nucleophilic addition of MeOH and protodemetalation lead to the generation of final products. By preventing formation of Rh(V) nitrenoid species, the intriguing role of fluorine substituents in hydroarylation reaction has also been disclosed. Furthermore, the coordination of carbonyl oxygen of OPiv group to the Rh center proves to be crucial for both [4 + 2] annulation and hydroarylation. However, in the case of using directing group with N-OMe, the lack of such assistance would engender a considerable buildup of energy with respect to the transition state, making both [4 + 2] annulation and hydroarylation processes kinetically unfavorable. Accordingly, the alternative [4 + 1] annulation takes place as the most favored pathway via consecutive twofold beta-F eliminations. PMID- 30021070 TI - Toward a Reliable Description of the Lattice Vibrations in Organic Molecular Crystals: The Impact of van der Waals Interactions. AB - This work assesses the reliability of different van der Waals (vdW) methods to describe lattice vibrations of molecular crystals in the framework of density functional theory (DFT). To accomplish this task, calculated and experimental lattice phonon Raman spectra of a pool of organic molecular crystals are compared. We show that the many-body dispersion (MBD@rsSCS) van der Waals method of Ambrosetti et al. and the pairwise method of Grimme et al. (D3-BJ) outperform the other tested approaches (i.e., the D2 method of Grimme, the TS method of Tkatchenko and Scheffler, and the nonlocal functional vdW-DF-optPBE of Klimes et al.). For the worse-performing approaches the results could not even be fixed by the introduction of scaling parameters, as commonly used for high-energy intramolecular vibrations. Interestingly, when using the experimentally determined unit cell parameters, DFT calculations using the PBE functional without corrections for long-range vdW interactions provide spectra of similar accuracy as the MBD@rsSCS and D3-BJ simulations. PMID- 30021071 TI - Amyloid-beta Peptide Triggers Membrane Remodeling in Supported Lipid Bilayers Depending on Their Hydrophobic Thickness. AB - Amyloid-beta (Abeta) peptide has been implicated in Alzheimer's disease, which is a leading cause of death worldwide. The interaction of Abeta peptides with the lipid bilayers of neuronal cells is a critical step in disease pathogenesis. Recent evidence indicates that lipid bilayer thickness influences Abeta membrane associated aggregation, while understanding how Abeta interacts with lipid bilayers remains elusive. To address this question, we employed supported lipid bilayer (SLB) platforms composed of different-length phosphatidylcholine (PC) lipids (C12:0 DLPC, C18:1 DOPC, C18:1-C16:0 POPC), and characterized the resulting interactions with soluble Abeta monomers. Quartz crystal microbalance dissipation (QCM-D) experiments identified concentration-dependent Abeta peptide adsorption onto all tested SLBs, which was corroborated by fluorescence recovery after photobleaching (FRAP) experiments indicating that higher Abeta concentrations led to decreased membrane fluidity. These commonalities pointed to strong Abeta peptide-membrane interactions in all cases. Notably, time-lapsed fluorescence microscopy revealed major differences in Abeta-induced membrane morphological responses depending on SLB hydrophobic thickness. For thicker DOPC and POPC SLBs, membrane remodeling involved the formation of elongated tubule and globular structures as a passive means to regulate membrane stress depending on Abeta concentration. In marked contrast, thin DLPC SLBs were not able to accommodate extensive membrane remodeling. Taken together, our findings reveal that membrane thickness influences the membrane morphological response triggered upon Abeta adsorption. PMID- 30021072 TI - Does Anchor Placement on the Glenoid Affect Functional Outcome After Arthroscopic Bankart Repair? AB - BACKGROUND: In arthroscopic Bankart repair, anchor positions can affect glenoid labral height and functional outcomes. PURPOSE: To evaluate anchor placement on the glenoid during Bankart lesion repair and determine which placement would lead to better functional outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHOD: This study included 90 patients (74 males, 16 females; average age, 23.7 years; range, 18-47 years) who underwent surgery for Bankart lesions between December 2009 and March 2014. The mean follow-up duration was 32.7 months (range, 26-48 months). We divided anchor positions into 2 groups: on the glenoid face and at the glenoid edge. The anchor position on the glenoid and the labral height were examined with computed tomography (CT) arthrography at 4.5-month follow-up, and Rowe scores were calculated at 2-year follow-up. RESULTS: The group with the anchor placed on the glenoid face contained 63 patients, and the group with the anchor placed at the glenoid edge or rim contained 27 patients. Mean labral heights at 4.5 months postoperatively in the 2 groups were 5.4 +/- 0.22 mm and 3.2 +/- 0.16 mm, respectively ( P < .01), and mean Rowe scores at 2 years were 94.7 and 79.5, respectively ( P < .01). Rowe scores calculated at 2-year follow up were significantly related to anchor position ( P < .01). CONCLUSION: Anchors positioned on the glenoid face resulted in the greatest restored labral height and better functional outcome (Rowe score). Thus, anchor placement on the glenoid face should be considered, as it may yield better functional outcome in arthroscopic Bankart repair. PMID- 30021073 TI - No Difference in the KOOS Quality of Life Subscore Between Anatomic Double-Bundle and Anatomic Single-Bundle Anterior Cruciate Ligament Reconstruction of the Knee: A Prospective Randomized Controlled Trial With 2 Years' Follow-up. AB - BACKGROUND: The double-bundle reconstruction technique was developed to resemble the properties of the native anterior cruciate ligament (ACL) more closely than the conventional single-bundle technique. The clinical benefit of the operative procedure is controversial, and there is a need for studies with a focus on patient-reported outcomes (PROs). STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. HYPOTHESIS: Anatomic double-bundle ACL reconstruction would be superior to anatomic single-bundle reconstruction regarding the change in the Knee injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QoL) subscore from baseline to 2-year follow-up. METHODS: According to sample size calculations, 120 patients aged 18 to 40 years with a primary ACL injury of their knee were randomized to the anatomic double-bundle or anatomic single-bundle reconstruction groups. Patients with posterior cruciate ligament, posterolateral corner, or lateral collateral ligament injuries or with established osteoarthritis were excluded. Patients with residual laxity from a coexistent medial collateral ligament injury were excluded. Data were registered at baseline, 1 year, and 2 years. In 24 patients, postoperative 3-dimensional computed tomography was performed to verify the positioning of the bundles. The outcome measures were the change in KOOS subscores and the International Knee Documentation Committee 2000 subjective score, pivot-shift test result, Lachman test finding, KT-1000 arthrometer measurement, activity level, return-to-sports rate, and osteoarthritic changes on radiographs. A linear mixed model was used for the analysis of all the PROs, including the primary outcome. RESULTS: The change in the KOOS QoL subscore from baseline to 2-year follow-up was not different between the double- and single-bundle groups (mean change, 29.2 points vs 28.7 points, respectively; -0.5-point difference; 95% CI, -8.4 to 7.4 points; P = .91). Neither were there any differences between the 2 groups in the remaining PROs, knee laxity measurements, or activity levels of the patients. Radiological signs of osteoarthritis were found in 2 patients. Eleven patients had a graft rupture: 8 in the single-bundle group and 3 in the double-bundle group ( P = .16). Three-dimensional computed tomography of the knees verified the positioning of the anteromedial bundle, posterolateral bundle, and single-bundle grafts to be within acceptable limits. CONCLUSION: There was no difference in the KOOS QoL subscore, the remaining PROs, knee laxity measurements, or activity levels comparing the double- and single-bundle ACL reconstruction techniques. The number of bundles does not seem to influence clinical and subjective outcomes, as long as the tunnels are adequately positioned. Registration: NCT01033188 ( ClinicalTrials.gov identifier). PMID- 30021074 TI - Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies. AB - INTRODUCTION: Macromolecules with unique effects and potency are increasingly being considered for application in lung pathologies. Numerous delivery strategies for these macromolecules through the lung have been investigated to improve the targeting and overall efficacy. Areas covered: Targeting approaches from delivery devices, formulation strategies and specific targets are discussed. Expert opinion: Although macromolecules are a heterogeneous group of molecules, a number of strategies have been investigated at the macro, micro, and nanoscopic scale for the delivery of macromolecules to specific sites and cells of lung tissues. Targeted approaches are already in use at the macroscopic scale through inhalation devices and formulations, but targeting strategies at the micro and nanoscopic scale are still in the laboratory stage. The combination of controlling lung deposition and targeting after deposition, through a combination of targeting strategies could be the future direction for the treatment of lung pathologies through the pulmonary route. PMID- 30021075 TI - 30-Day readmission following outpatient rotator cuff repair: an analysis of 18,061 cases. AB - OBJECTIVES: The purpose of this study is to identify patient characteristics that increase risk for unplanned readmission within 30 days of an initial hospital stay after outpatient rotator cuff repair (RCR). METHODS: A retrospective cohort study was performed utilizing the National Surgical Quality Improvement Program (ACS NSQIP) datasets from 2012 to 2015. Patients were preliminarily included in the study based on the presence of a primary Common Procedural Terminology code for RCR (23410, 23412, 23420, and 29827). Only non-emergent, outpatient, and elective procedures performed on patients with American Society of Anesthesiologists (ASA) <=4 were considered. The primary outcome variables were 30-day unplanned readmission after outpatient surgery. Secondary analyses were implemented to establish reason and timing of readmission. RESULTS: A total of 18,061 cases were reviewed, and 199 (1%) patients experienced 30-day unplanned readmission. Age >=80 (OR = 2.13, p = 0.0276), COPD (OR = 1.75, p = 0.0354), hypertension requiring medication (OR = 1.67, p = 0.0027), dialysis (OR = 13.46, p < 0.0001) and an ASA classification of 3 (OR = 2.78, p = 0.0143) or ASA 4 (OR = 6.15, p = 0.0012) were identified as major prognosticators for readmission. Female sex was associated with lower odds of readmission (OR = 0.54, p = 0.0001). The most common complications associated with readmission were cardiovascular (29%), infection (19%), and respiratory (17%). CONCLUSIONS: The rate of 30-day unplanned inpatient readmission following outpatient RCR using the NSQIP data was found to be 1%, with advanced age and preexisting medical comorbidities contributing to the highest odds of readmission. Cardiovascular, infectious, and respiratory complications contributed to the majority of readmissions. The ability to identify patients with these risk factors will be of utility in optimizing outcomes and cost-effectiveness of RCR. LEVEL OF EVIDENCE: Level III. PMID- 30021077 TI - Introducing a Virtual Assistant to the Lab: A Voice User Interface for the Intuitive Control of Laboratory Instruments. AB - The introduction of smart virtual assistants (VAs) and corresponding smart devices brought a new degree of freedom to our everyday lives. Voice-controlled and Internet-connected devices allow intuitive device controlling and monitoring from all around the globe and define a new era of human-machine interaction. Although VAs are especially successful in home automation, they also show great potential as artificial intelligence-driven laboratory assistants. Possible applications include stepwise reading of standard operating procedures (SOPs) and recipes, recitation of chemical substance or reaction parameters to a control, and readout of laboratory devices and sensors. In this study, we present a retrofitting approach to make standard laboratory instruments part of the Internet of Things (IoT). We established a voice user interface (VUI) for controlling those devices and reading out specific device data. A benchmark of the established infrastructure showed a high mean accuracy (95% +/- 3.62) of speech command recognition and reveals high potential for future applications of a VUI within the laboratory. Our approach shows the general applicability of commercially available VAs as laboratory assistants and might be of special interest to researchers with physical impairments or low vision. The developed solution enables a hands-free device control, which is a crucial advantage within the daily laboratory routine. PMID- 30021079 TI - Radical Changes for Reproductive Health Care - Proposed Regulations for Title X. PMID- 30021078 TI - Testing Epinephrine for Out-of-Hospital Cardiac Arrest. PMID- 30021080 TI - Adaptive Learning Algorithm Convergence in Passive and Reactive Environments. AB - Although the number of artificial neural network and machine learning architectures is growing at an exponential pace, more attention needs to be paid to theoretical guarantees of asymptotic convergence for novel, nonlinear, high dimensional adaptive learning algorithms. When properly understood, such guarantees can guide the algorithm development and evaluation process and provide theoretical validation for a particular algorithm design. For many decades, the machine learning community has widely recognized the importance of stochastic approximation theory as a powerful tool for identifying explicit convergence conditions for adaptive learning machines. However, the verification of such conditions is challenging for multidisciplinary researchers not working in the area of stochastic approximation theory. For this reason, this letter presents a new stochastic approximation theorem for both passive and reactive learning environments with assumptions that are easily verifiable. The theorem is widely applicable to the analysis and design of important machine learning algorithms including deep learning algorithms with multiple strict local minimizers, Monte Carlo expectation-maximization algorithms, contrastive divergence learning in Markov fields, and policy gradient reinforcement learning. PMID- 30021076 TI - A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Concern about the use of epinephrine as a treatment for out-of hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. METHODS: In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). RESULTS: At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]). CONCLUSIONS: In adults with out-of hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group. (Funded by the U.K. National Institute for Health Research and others; Current Controlled Trials number, ISRCTN73485024 .). PMID- 30021081 TI - An Empirical Evaluation of Rule Extraction from Recurrent Neural Networks. AB - Rule extraction from black box models is critical in domains that require model validation before implementation, as can be the case in credit scoring and medical diagnosis. Though already a challenging problem in statistical learning in general, the difficulty is even greater when highly nonlinear, recursive models, such as recurrent neural networks (RNNs), are fit to data. Here, we study the extraction of rules from second-order RNNs trained to recognize the Tomita grammars. We show that production rules can be stably extracted from trained RNNs and that in certain cases, the rules outperform the trained RNNs. PMID- 30021082 TI - Spiking Elementary Motion Detector in Neuromorphic Systems. AB - Apparent motion of the surroundings on an agent's retina can be used to navigate through cluttered environments, avoid collisions with obstacles, or track targets of interest. The pattern of apparent motion of objects, (i.e., the optic flow), contains spatial information about the surrounding environment. For a small, fast moving agent, as used in search and rescue missions, it is crucial to estimate the distance to close-by objects to avoid collisions quickly. This estimation cannot be done by conventional methods, such as frame-based optic flow estimation, given the size, power, and latency constraints of the necessary hardware. A practical alternative makes use of event-based vision sensors. Contrary to the frame-based approach, they produce so-called events only when there are changes in the visual scene. We propose a novel asynchronous circuit, the spiking elementary motion detector (sEMD), composed of a single silicon neuron and synapse, to detect elementary motion from an event-based vision sensor. The sEMD encodes the time an object's image needs to travel across the retina into a burst of spikes. The number of spikes within the burst is proportional to the speed of events across the retina. A fast but imprecise estimate of the time-to-travel can already be obtained from the first two spikes of a burst and refined by subsequent interspike intervals. The latter encoding scheme is possible due to an adaptive nonlinear synaptic efficacy scaling. We show that the sEMD can be used to compute a collision avoidance direction in the context of robotic navigation in a cluttered outdoor environment and compared the collision avoidance direction to a frame-based algorithm. The proposed computational principle constitutes a generic spiking temporal correlation detector that can be applied to other sensory modalities (e.g., sound localization), and it provides a novel perspective to gating information in spiking neural networks. PMID- 30021083 TI - Computing with Spikes: The Advantage of Fine-Grained Timing. AB - Neural-inspired spike-based computing machines often claim to achieve considerable advantages in terms of energy and time efficiency by using spikes for computation and communication. However, fundamental questions about spike based computation remain unanswered. For instance, how much advantage do spike based approaches have over conventional methods, and under what circumstances does spike-based computing provide a comparative advantage? Simply implementing existing algorithms using spikes as the medium of computation and communication is not guaranteed to yield an advantage. Here, we demonstrate that spike-based communication and computation within algorithms can increase throughput, and they can decrease energy cost in some cases. We present several spiking algorithms, including sorting a set of numbers in ascending/descending order, as well as finding the maximum or minimum or median of a set of numbers. We also provide an example application: a spiking median-filtering approach for image processing providing a low-energy, parallel implementation. The algorithms and analyses presented here demonstrate that spiking algorithms can provide performance advantages and offer efficient computation of fundamental operations useful in more complex algorithms. PMID- 30021085 TI - Recognition Dynamics in the Brain under the Free Energy Principle. AB - We formulate the computational processes of perception in the framework of the principle of least action by postulating the theoretical action as a time integral of the variational free energy in the neurosciences. The free energy principle is accordingly rephrased, on autopoetic grounds, as follows: all viable organisms attempt to minimize their sensory uncertainty about an unpredictable environment over a temporal horizon. By taking the variation of informational action, we derive neural recognition dynamics (RD), which by construction reduces to the Bayesian filtering of external states from noisy sensory inputs. Consequently, we effectively cast the gradient-descent scheme of minimizing the free energy into Hamiltonian mechanics by addressing only the positions and momenta of the organisms' representations of the causal environment. To demonstrate the utility of our theory, we show how the RD may be implemented in a neuronally based biophysical model at a single-cell level and subsequently in a coarse-grained, hierarchical architecture of the brain. We also present numerical solutions to the RD for a model brain and analyze the perceptual trajectories around attractors in neural state space. PMID- 30021084 TI - CosMIC: A Consistent Metric for Spike Inference from Calcium Imaging. AB - In recent years, the development of algorithms to detect neuronal spiking activity from two-photon calcium imaging data has received much attention, yet few researchers have examined the metrics used to assess the similarity of detected spike trains with the ground truth. We highlight the limitations of the two most commonly used metrics, the spike train correlation and success rate, and propose an alternative, which we refer to as CosMIC. Rather than operating on the true and estimated spike trains directly, the proposed metric assesses the similarity of the pulse trains obtained from convolution of the spike trains with a smoothing pulse. The pulse width, which is derived from the statistics of the imaging data, reflects the temporal tolerance of the metric. The final metric score is the size of the commonalities of the pulse trains as a fraction of their average size. Viewed through the lens of set theory, CosMIC resembles a continuous Sorensen-Dice coefficient-an index commonly used to assess the similarity of discrete, presence/absence data. We demonstrate the ability of the proposed metric to discriminate the precision and recall of spike train estimates. Unlike the spike train correlation, which appears to reward overestimation, the proposed metric score is maximized when the correct number of spikes have been detected. Furthermore, we show that CosMIC is more sensitive to the temporal precision of estimates than the success rate. PMID- 30021086 TI - Multiclass Classification and Feature Selection Based on Least Squares Regression with Large Margin. AB - Least squares regression (LSR) is a fundamental statistical analysis technique that has been widely applied to feature learning. However, limited by its simplicity, the local structure of data is easy to neglect, and many methods have considered using orthogonal constraint for preserving more local information. Another major drawback of LSR is that the loss function between soft regression results and hard target values cannot precisely reflect the classification ability; thus, the idea of the large margin constraint is put forward. As a consequence, we pay attention to the concepts of large margin and orthogonal constraint to propose a novel algorithm, orthogonal least squares regression with large margin (OLSLM), for multiclass classification in this letter. The core task of this algorithm is to learn regression targets from data and an orthogonal transformation matrix simultaneously such that the proposed model not only ensures every data point can be correctly classified with a large margin than conventional least squares regression, but also can preserve more local data structure information in the subspace. Our efficient optimization method for solving the large margin constraint and orthogonal constraint iteratively proved to be convergent in both theory and practice. We also apply the large margin constraint in the process of generating a sparse learning model for feature selection via joint [Formula: see text]-norm minimization on both loss function and regularization terms. Experimental results validate that our method performs better than state-of-the-art methods on various real-world data sets. PMID- 30021087 TI - Twitter Tailwinds - Little Capsules of Gratitude. PMID- 30021088 TI - Psychotic Disorders. PMID- 30021089 TI - National Longitudinal Lesbian Family Study - Mental Health of Adult Offspring. PMID- 30021090 TI - Evaluation of Medicare's Bundled Payments Initiative for Medical Conditions. AB - BACKGROUND: The Center for Medicare and Medicaid Innovation (CMMI) launched the Bundled Payments for Care Improvement (BPCI) initiative in 2013. A subsequent study showed that the initiative was associated with reductions in Medicare payments for total joint replacement, but little is known about the effect of BPCI on medical conditions. METHODS: We used Medicare claims from 2013 through 2015 to identify admissions for the five most commonly selected medical conditions in BPCI: congestive heart failure (CHF), pneumonia, chronic obstructive pulmonary disease (COPD), sepsis, and acute myocardial infarction (AMI). We used difference-in-differences analyses to assess changes in standardized Medicare payments per episode of care (defined as the hospitalization plus 90 days after discharge) for these conditions at BPCI hospitals and matched control hospitals. RESULTS: A total of 125 hospitals participated in BPCI for CHF, 105 hospitals for pneumonia, 101 hospitals for COPD, 88 hospitals for sepsis, and 73 hospitals for AMI. At baseline, the average Medicare payment per episode of care across the five conditions at BPCI hospitals was $24,280, which decreased to $23,993 during the intervention period (difference, -$286; P=0.41). Control hospitals had an average payment for all episodes of $23,901, which decreased to $23,503 during the intervention period (difference, -$398; P=0.08; difference in differences, $112; P=0.79). Changes from baseline to the intervention period in clinical complexity, length of stay, emergency department use or readmission within 30 or 90 days after hospital discharge, or death within 30 or 90 days after admission did not differ significantly between the intervention and control hospitals. CONCLUSIONS: Hospital participation in five common medical bundles under BPCI was not associated with significant changes in Medicare payments, clinical complexity, length of stay, emergency department use, hospital readmission, or mortality. (Funded by the Commonwealth Fund.). PMID- 30021091 TI - l-Glutamine and the Dawn of Combination Therapy for Sickle Cell Disease. PMID- 30021092 TI - Case 22-2018: A 64-Year-Old Man with Progressive Leg Weakness, Recurrent Falls, and Anemia. PMID- 30021093 TI - Duty-Hour Flexibility Trial in Internal Medicine. PMID- 30021094 TI - Severe Mitral Stenosis. PMID- 30021095 TI - Cryptococcus neoformans Meningoencephalitis. PMID- 30021097 TI - Tipping Clonal Hematopoiesis into Transformation. PMID- 30021098 TI - The Inevitable Math behind Entitlement Reform. PMID- 30021099 TI - The IARC Perspective on Colorectal Cancer Screening. PMID- 30021100 TI - miR-212 and mTOR form a regulation loop to modulate autophagy in colorectal adenoma HT-29 cells. AB - Autophagy is a conserved lysosomal degradation pathway that regulates cell survival and death in order to maintain cellular homeostasis. Dysfunctional autophagy is associated with different types of cancer, making it an attractive therapeutic target. Mammalian target of rapamycin (mTOR) signaling negatively regulates autophagy and suppresses the efficacy of certain cancer therapeutic agents. NVP-BEZ235 is a dual inhibitor of the PI3K/mTOR signaling pathway and exhibits anti-cancer activities; it also induced autophagy and inhibited proliferation in colorectal adenoma HT-29 cells. Colorectal adenoma and colorectal cancer have been recently shown to have elevated levels of miR-212. In the current study, we examined the role of miR-212 in NVP-BEZ235-induced autophagy in HT-29 cells. NVP-BEZ235 at the concentration as low as of 1 nM effectively induced autophagy and dose-dependently inhibited the expression of microRNA-212 (miR-212) whereas mTOR activator MHY1485 elevated the miR-212 expression. Transfection of miR-212 mimics inhibited autophagy whereas miR-212 inhibitors promoted autophagy as assessed by the LC3B-I conversion to LC3B-II and the expression levels of beclin-1. Furthermore, miR-212 mimics activated mTOR whereas miR-212 inhibitors suppressed mTOR activation as shown by the levels of phospho-mTOR. miR-212 mimics further enhanced the effect of NVP-BEZ235 in reducing the viability of HT-29 cells. Our data support that miR-212 is a target of mTOR signaling as well as an activator of mTOR to negatively regulate autophagy. Thus, miR-212 and mTOR signalings may form a positive regulation loop in maintaining cellular homeostasis. This study warrants further investigation of miR-212 as an effective target of autophagy-based cancer therapeutic strategies. PMID- 30021096 TI - A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. AB - BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell related pain. METHODS: In a multicenter, randomized, placebo-controlled, double blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle beta0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .). PMID- 30021101 TI - Dynamic testing of stimulative and suppressive biomarkers on peripheral blood cells at early stages of immunotherapy predicts response in advanced cancer patients. AB - PURPOSE: Immunotherapy against malignant tumors has shown considerable clinical efficacy, especially agents targeting the programmed death 1 (PD-1) pathway. In this study, we set out to dynamically determine the relationships between clinical benefit and changes in immune biomarkers on peripheral blood monocular cells (PBMCs) and try to establish a model to predict the response at an early stage of treatment. EXPERIMENTAL DESIGN: All patients recruited from December 2016 to July 2017 were treated in the Cancer Center of the Chinese People's Liberation Army General Hospital with nivolumab or pembrolizumab, and with or without chemotherapy. We investigated nine checkpoint molecules PD-1, CTLA-4, TIM 3, LAG-3, BTLA, CD160, Ki-67, OX40, and GITR on CD4+, CD8+, and NK cells by flow cytometry in patients before and after receiving each treatment of anti-PD-1 agents. RESULTS: We found that the responder group showed higher expressions of PD-1 on CD4+ and NK cells than the non-responder group after the first cycle of immunotherapy, and lower expression of CTLA-4, GITR, and OX40 after the second cycle of immunotherapy. A simple model of the combination of biomarkers was generated to predict the immunotherapeutic effect, revealing that elevation of key biomarkers after the first cycle of immunotherapy, followed by a decrease in their expression after the second cycle, was associated with a better outcome from immunotherapy at an early stage of treatment of cancer. CONCLUSION: Our work indicates that by testing biomarkers on patients' PBMCs at an early stage of treatment, the immunotherapeutic effect can be predicted, thus improving patient outcomes and cost efficiency. PMID- 30021102 TI - Applications of vitamin D in sepsis prevention. AB - Vitamin D (VD) is a steroid prohormone that regulates the body's calcium and phosphate levels in bone mineralization. It is also well described as a fat soluble vitamin playing an important role in immunomodulation, regulation of cytokines, and cell proliferation. Thus, VD is a powerful hormone with pleiotropic effects, which acts to maintain optimal health. Recent studies demonstrate that VD deficiency is associated with the development of cardiovascular diseases, autoimmune disorders, and various types of cancer, each associated with increased mortality rates. VD deficiency is commonly seen in the intensive care unit (ICU); it aggravates the incidence and outcome of infectious complications in critically ill patients. In particular, VD deficiency is associated with an increased risk of sepsis and more severe clinical outcomes in patients with sepsis. These patients have dysregulated VD metabolism and frequently present insufficient plasma VD levels, which contribute to the deterioration of their clinical state. In this review, we summarize the role of VD in the immune system, the consequences of its deficiency and we discuss potential perspectives on VD supplementation in preventing sepsis and enhancing patient recovery. Although the relevance of the applications of VD in sepsis is stated, further studies are required to elucidate the optimal VD plasma levels and the recommended daily intake. PMID- 30021103 TI - Re-framing the theory of autoimmunity in the era of the microbiome: persistent pathogens, autoantibodies, and molecular mimicry. AB - The theory of autoimmunity was developed at a time when the human body was regarded as largely sterile. Antibodies in patients with chronic inflammatory disease could consequently not be tied to persistent human pathogens. The concept of the "autoantibody" was created to reconcile this phenomenon. Today, however, the discovery of the human microbiome has revolutionized our understanding of human biology. Humans are superorganisms that harbor trillions of persistent microbial cells. Indeed, vast human microbiomes have been detected in human tissue and blood. These microbial ecosystems harbor thousands of newly identified bacteria, viruses, and other microorganisms -- most of which can act as pathogens under conditions of immunosuppression. The theory of autoimmunity must be revised to account for the human microbiome. Here, we propose a model in which "autoantibodies" are created in response to chronic, persistent microbiome pathogens. The structural homology (molecular mimicry) between pathogen and host proteins can result in "collateral damage" to surrounding human tissue. This calls for a paradigm shift in autoimmune disease treatment. Immunosuppressive medications palliate inflammatory symptoms at the expense of microbiome health and balance. In contrast, treatments that support the immune system in autoimmune disease could allow patients to target pathogens at the root of the disease process. PMID- 30021104 TI - Novel targeted therapies in ovarian and uterine carcinosarcomas. AB - Carcinosarcomas (CSs) of the uterus and ovary are rare biologically aggressive tumors with poor prognosis. The development of novel, effective treatment strategies against CSs of the female genital tract remains an unmet medical need. Whole-exome sequencing studies have recently demonstrated mutations or aberrant activation of multiple genes/pathways in CSs including HER2, PI3K/AKT/mTOR, EGFR, MAPK, genes related to histones and chromatin structure, and genes related to cell-cycle regulation. The carcinomatous component of these biphasic tumors is suggested to be the catalyst in CS tumorigenesis. This article reviews the genetic landscapes and explores novel targeted treatment modalities against this deadly gynecologic tumor. PMID- 30021105 TI - Evaluating Anti-CD32b F(ab) Conformation Using Molecular Dynamics and Small-Angle X-Ray Scattering. AB - Complementary strategies of small-angle x-ray scattering (SAXS) and crystallographic analysis are often used to determine atomistic three-dimensional models of macromolecules and their variability in solution. This combination of techniques is particularly valuable when applied to macromolecular complexes to detect changes within the individual binding partners. Here, we determine the x ray crystallographic structure of a F(ab) fragment in complex with CD32b, the only inhibitory Fc-gamma receptor in humans, and compare the structure of the F(ab) from the crystal complex to SAXS data for the F(ab) alone in solution. We investigate changes in F(ab) structure by predicting theoretical scattering profiles for atomistic structures extracted from molecular dynamics (MD) simulations of the F(ab) and assessing the agreement of these structures to our experimental SAXS data. Through principal component analysis, we are able to extract principal motions observed during the MD trajectory and evaluate the influence of these motions on the agreement of structures to the F(ab) SAXS data. Changes in the F(ab) elbow angle were found to be important to reach agreement with the experimental data; however, further discrepancies were apparent between our F(ab) structure from the crystal complex and SAXS data. By analyzing multiple MD structures observed in similar regions of the principal component analysis, we were able to pinpoint these discrepancies to a specific loop region in the F(ab) heavy chain. This method, therefore, not only allows determination of global changes but also allows identification of localized motions important for determining the agreement between atomistic structures and SAXS data. In this particular case, the findings allowed us to discount the hypothesis that structural changes were induced upon complex formation, a significant find informing the drug development process. The methodology described here is generally applicable to deconvolute global and local changes of macromolecular structures and is well suited to other systems. PMID- 30021107 TI - Direct Evidence for the Effect of Glycerol on Protein Hydration and Thermal Structural Transition. AB - The mechanisms of protein stabilization by uncharged solutes, such as polyols and sugars, have been intensively studied with respect to the chemical thermodynamics of molecular crowding. In particular, many experimental and theoretical studies have been conducted to explain the mechanism of the protective action on protein structures by glycerol through the relationship between hydration and glycerol solvation on protein surfaces. We used wide-angle x-ray scattering (WAXS), small angle neutron scattering, and theoretical scattering function simulation to quantitatively characterize the hydration and/or solvation shell of myoglobin in aqueous solutions of up to 75% v/v glycerol. At glycerol concentrations below ~40% v/v, the preservation of the hydration shell was dominant, which was reasonably explained by the preferential exclusion of glycerol from the protein surface (preferential hydration). In contrast, at concentrations above 50% v/v, the partial penetration or replacement of glycerol into or with hydration-shell water (neutral solvation by glycerol) was gradually promoted. WAXS results quantitatively demonstrated the neutral solvation, in which the replacement of hydrated water by glycerol was proportional to the volume fraction of glycerol in the solvent multiplied by an exchange rate (beta <= 1). These phenomena were confirmed by small-angle neutron scattering measurements. The observed WAXS data covered the entire hierarchical structure of myoglobin, ranging from tertiary to secondary structures. We separately analyzed the effect of glycerol on the thermal stability of myoglobin at each hierarchical structural level. The thermal transition midpoint temperature at each hierarchical structural level was raised depending on the glycerol concentration, with enhanced transition cooperativeness between different hierarchical structural levels. The onset temperature of the helix-to-cross beta-sheet transition (the initial process of amyloid formation) was evidently elevated. However, oligomerization connected to fibril formation was suppressed, even at a low glycerol concentration. PMID- 30021106 TI - Single Proteoliposome High-Content Analysis Reveals Differences in the Homo Oligomerization of GPCRs. AB - G-protein-coupled receptors (GPCRs) control vital cellular signaling pathways. GPCR oligomerization is proposed to increase signaling diversity. However, many reports have arrived at disparate conclusions regarding the existence, stability, and stoichiometry of GPCR oligomers, partly because of cellular complexity and ensemble averaging of intrareconstitution heterogeneities that complicate the interpretation of oligomerization data. To overcome these limitations, we exploited fluorescence-microscopy-based high-content analysis of single proteoliposomes. This allowed multidimensional quantification of intrinsic monomer-monomer interactions of three class A GPCRs (beta2-adrenergic receptor, cannabinoid receptor type 1, and opsin). Using a billion-fold less protein than conventional assays, we quantified oligomer stoichiometries, association constants, and the influence of two ligands and membrane curvature on oligomerization, revealing key similarities and differences for three GPCRs with decidedly different physiological functions. The assays introduced here will assist with the quantitative experimental observation of oligomerization for transmembrane proteins in general. PMID- 30021108 TI - Sequence Reversal Prevents Chain Collapse and Yields Heat-Sensitive Intrinsic Disorder. AB - Sequence patterns of charge, hydrophobicity, hydrogen bonding, and other amino acid physicochemical properties contribute to mechanisms of protein folding, but how sequence composition and patterns influence the conformational dynamics of the denatured state ensemble is not fully understood. To investigate structure sequence relationships in the denatured state, we reversed the sequence of staphylococcal nuclease and characterized its structure, thermodynamic character, and hydrodynamic radius using circular dichroism spectroscopy, dynamic light scattering, analytical ultracentrifugation, and size-exclusion chromatography as a function of temperature. The macromolecular size of "Retro-nuclease" is highly expanded in solution with characteristics similar to biological intrinsically disordered proteins. In contradistinction to a disordered state, Retro-nuclease exhibits a broad sigmoid transition of its hydrodynamic dimensions as temperature is increased, indicating a thermodynamically controlled compaction. Counterintuitively, the magnitude of these temperature-induced hydrodynamic changes exceed that observed from thermal denaturation of folded unaltered staphylococcal nuclease. Undetectable by calorimetry and intrinsic tryptophan fluorescence, the lack of heat capacity or fluorescence changes throughout the thermal transition indicate canonical hydrophobic collapse did not drive the Retro-nuclease structural transitions. Temperature-dependent circular dichroism spectroscopy performed on Retro-nuclease and computer simulations correlate to temperature sensitivity in the intrinsic sampling of backbone conformations for polyproline II and alpha-helix. The experimental results indicate a role for sequence direction in mediating the collapse of the polypeptide chain, whereas the simulation trends illustrate the generality of the observed heat effects on disordered protein structure. PMID- 30021109 TI - Monitoring Unfolding of Titin I27 Single and Bi Domain with High-Pressure NMR Spectroscopy. AB - A complete description of the pathways and mechanisms of protein folding requires a detailed structural and energetic characterization of the folding energy landscape. Simulations, when corroborated by experimental data yielding global information on the folding process, can provide this level of insight. Molecular dynamics (MD) has often been combined with force spectroscopy experiments to decipher the unfolding mechanism of titin immunoglobulin-like single or multidomain, the giant multimodular protein from sarcomeres, yielding information on the sequential events during titin unfolding under stretching. Here, we used high-pressure NMR to monitor the unfolding of titin I27 Ig-like single domain and tandem. Because this method brings residue-specific information on the folding process, it can provide quasiatomic details on this process without the help of MD simulations. Globally, the results of our high-pressure analysis are in agreement with previous results obtained by the combination of experimental measurements and MD simulation and/or protein engineering, although the intermediate folding state caused by the early detachment of the AB beta-sheet, often reported in previous works based on MD or force spectroscopy, cannot be detected. On the other hand, the A'G parallel beta-sheet of the beta-sandwich has been confirmed as the Achilles heel of the three-dimensional scaffold: its disruption yields complete unfolding with very similar characteristics (free energy, unfolding volume, kinetics rate constants) for the two constructs. PMID- 30021110 TI - Light-Driven Chloride Transport Kinetics of Halorhodopsin. AB - Despite growing interest in light-driven ion pumps for use in optogenetics, current estimates of their transport rates span two orders of magnitude due to challenges in measuring slow transport processes and determining protein concentration and/or orientation in membranes in vitro. In this study, we report, to our knowledge, the first direct quantitative measurement of light-driven Cl- transport rates of the anion pump halorohodopsin from Natronomonas pharaonis (NpHR). We used light-interfaced voltage clamp measurements on NpHR-expressing oocytes to obtain a transport rate of 219 (+/- 98) Cl-/protein/s for a photon flux of 630 photons/protein/s. The measurement is consistent with the literature reported quantum efficiency of ~30% for NpHR, i.e., 0.3 isomerizations per photon absorbed. To reconcile our measurements with an earlier-reported 20 ms rate limiting step, or 35 turnovers/protein/s, we conducted, to our knowledge, novel consecutive single-turnover flash experiments that demonstrate that under continuous illumination, NpHR bypasses this step in the photocycle. PMID- 30021111 TI - External Ion Access in the Na/K Pump: Kinetics of Na+, K+, and Quaternary Amine Interaction. AB - Na/K pumps build essential ion gradients across the plasmalemma of animal cells by coupling the extrusion of three Na+, with the import of two K+ and the hydrolysis of one ATP molecule. The mechanisms of selectivity and competition between Na+, K+, and inhibitory amines remain unclear. We measured the effects of external tetrapropylammonium (TPA+) and ethylenediamine (EDA2+) on three different Na/K pump transport modes in voltage-clamped Xenopus oocytes: 1) outward pump current (IP), 2) passive inward H+ current at negative voltages without Na+ or K+ (IH), and 3) transient charge movement reporting the voltage dependent extracellular binding/release of Na+ (QNa). Both amines competed with K+ to inhibit IP. TPA+ inhibited IH without competing with H+, whereas EDA2+ did not alter IH at pH 7.6. TPA+ competed with Na+ in QNa measurements, reducing Na+ apparent affinity, evidenced by a ~-75 mV shift in the charge-voltage curve (at 20 mM TPA+) without reduction of the total charge moved (Qtot). In contrast, EDA2+ and K+ did not compete with Na+ to inhibit QNa; both reduced Qtot without decreasing Na+-apparent affinity. EDA2+ (15 mM) right-shifted the charge-voltage curve by ~+50 mV. Simultaneous occlusion of EDA2+ and Na+ by an E2P conformation unable to reach E1P was demonstrated by voltage-clamp fluorometry. Trypsinolysis experiments showed that EDA2+-bound pumps are much more proteolysis-resistant than Na+-, K+-, or TPA+-bound pumps, therefore uncovering unique EDA2+-bound conformations. K+ effects on QNa and IH were also evaluated in pumps inhibited with beryllium fluoride, a phosphate mimic. K+ reduced Qtot without shifting the charge-voltage curve, indicating noncompetitive effects, and partially inhibited IH to the same extent as TPA+ in non-beryllium-fluorinated pumps. These results demonstrate that K+ interacts with beryllium-fluorinated pumps inducing conformational changes that alter QNa and IH, suggesting that there are two external access pathways for proton transport by IH. PMID- 30021112 TI - Phragmoplast Orienting Kinesin 2 Is a Weak Motor Switching between Processive and Diffusive Modes. AB - Plant development and morphology relies on the accurate insertion of new cell walls during cytokinesis. However, how a plant cell correctly orients a new wall is poorly understood. Two kinesin class-12 members, phragmoplast orienting kinesin 1 (POK1) and POK2, are involved in the process, but how these molecular machines work is not known. Here, we used in vivo and single-molecule in vitro measurements to determine how Arabidopsis thaliana POK2 motors function mechanically. We found that POK2 is a very weak, on average plus-end-directed, moderately fast kinesin. Interestingly, POK2 switches between processive and diffusive modes characterized by an exclusive-state mean-squared-displacement analysis. Our results support a model that POK motors push against peripheral microtubules of the phragmoplast for its guidance. This pushing model may mechanically explain the conspicuous narrowing of the division site. Together, our findings provide mechanical insight into how active motors accurately position new cell walls in plants. PMID- 30021114 TI - Theoretical Analysis of Stress Distribution and Cell Polarization Surrounding a Model Wound. AB - A growing amount of experimental evidence shows that the local elastic field acting on cells governs their spatial organization and polarity in a tissue. Interestingly, experiments on wound healing reveal a universal formation of thick actomyosin bundles around the margins of epithelial gaps. Although the forces involved in this process have been measured, the mechanisms governing cellular alignment and contractile ring formation are still not fully understood. To theoretically investigate this process, we have carried out a self-consistent calculation of the elastic field that is actively generated around a circular gap in a contractile cell monolayer that is adhered to an elastic substrate, taking into account the responsiveness of actomyosin activity to the locally generated stress. We model actomyosin contractility by a radial distribution of point force dipoles that may alter in magnitude and orientation in response to the local elastic stress. In addition, the model takes into account the forces exerted by leader cells on the margins of the cell monolayer. Our model suggests that the presence of a hole in the center of a contractile cell monolayer creates a mechanical tendency for actomyosin forces to polarize tangentially around the hole margin. In addition, it predicts that this tendency optimizes with substrate rigidity, thickness, and strength of cell adhesion to the substrate. Our calculations support the view that the universal formation of a peripheral contractile ring is a consequence of actomyosin contractility in the bulk and its inherent responsiveness to the local stress. PMID- 30021113 TI - Blebbistatin Effects Expose Hidden Secrets in the Force-Generating Cycle of Actin and Myosin. AB - Cyclic interactions between myosin II motors and actin filaments driven by ATP turnover underlie muscle contraction and have key roles in the motility of nonmuscle cells. A remaining enigma in the understanding of this interaction is the relationship between the force-generating structural change and the release of the ATP-hydrolysis product, inorganic phosphate (Pi), from the active site of myosin. Here, we use the small molecular compound blebbistatin to probe otherwise hidden states and transitions in this process. Different hypotheses for the Pi release mechanism are tested by interpreting experimental results from in vitro motility assays and isolated muscle fibers in terms of mechanokinetic actomyosin models. The data fit with ideas that actomyosin force generation is preceded by Pi release, which in turn is preceded by two serial transitions after/coincident with cross-bridge attachment. Blebbistatin changes the rate limitation of the cycle from the first to the second of these transitions, uncovering functional roles of an otherwise short-lived pre-power stroke state that has been implicated by structural data. PMID- 30021116 TI - Formation of a Secretion-Competent Protein Complex by a Dynamic Wrap-around Binding Mechanism. AB - Bacterial virulence is typically initiated by translocation of effector or toxic proteins across host cell membranes. A class of gram-negative pathogenic bacteria including Yersinia pseudotuberculosis and Yersinia pestis accomplishes this objective with a protein assembly called the type III secretion system. Yersinia effector proteins (Yop) are presented to the translocation apparatus through formation of specific complexes with their cognate chaperones (Syc). In the complexes where the structure is available, the Yops are extended and wrap around their cognate chaperone. This structural architecture enables secretion of the Yop from the bacterium in early stages of translocation. It has been shown previously that the chaperone-binding domain of YopE is disordered in its isolation but becomes substantially more ordered in its wrap-around complex with its chaperone SycE. Here, by means of NMR spectroscopy, small-angle X-ray scattering and molecular modeling, we demonstrate that while the free chaperone binding domain of YopH (YopHCBD) adopts a fully ordered and globular fold, it populates an elongated, wrap-around conformation when it engages in a specific complex with its chaperone SycH2. Hence, in contrast to YopE that is unstructured in its free state, YopH transits from a globular free state to an elongated chaperone-bound state. We demonstrate that a sparsely populated YopHCBD state has an elevated affinity for SycH2 and represents an intermediate in the formation of the protein complex. Our results suggest that Yersinia has evolved a binding mechanism where SycH2 passively stimulates an elongated YopH conformation that is presented to the type III secretion system in a secretion-competent conformation. PMID- 30021117 TI - Rational engineering of ornithine decarboxylase with greater selectivity for ornithine over lysine through protein network analysis. AB - Ornithine decarboxylase (ODC) converts C5 ornithine into C4 putrescine, a monomer for polyamide synthesis. However, ODC also has minor activity towards cell metabolite C6 lysine and yields C5 cadaverine. The accumulation of cadaverine in the reaction solution causes increase in the operational cost of subsequent distillation process for putrescine purification. Here, to increase ODC substrate specificity toward ornithine over lysine, molecular modelling and protein network analysis, specifically k-clique community analysis, around the substrate tunnel were performed. This resulted in a mutant with two-fold increase in substrate specificity (ornithine versus lysine) without losing its original activity towards ornithine (kcat/KM = 61.5 s-1 mM-1), compared to the native enzyme. When this mutant was used for putrescine synthesis, 31.6 g/L putrescine (based on 51.5 g/L ornithine) titer was achieved, while 0.007 g/L (based on 2.57 g/L lysine) cadaverine was produced. This corresponds to four-fold decrease in cadaverine yield compared to the native ODC. PMID- 30021115 TI - Antimargination of Microparticles and Platelets in the Vicinity of Branching Vessels. AB - We investigate the margination of microparticles/platelets in blood flow through complex geometries typical for in vivo vessel networks: a vessel confluence and a bifurcation. Using three-dimensional lattice Boltzmann simulations, we confirm that behind the confluence of two vessels, a cell-free layer devoid of red blood cells develops in the channel center. Despite its small size of roughly 1 MUm, this central cell-free layer persists for up to 100 MUm after the confluence. Most importantly, we show from simulations that this layer also contains a significant amount of microparticles/platelets and validate this result by in vivo microscopy in mouse venules. At bifurcations, however, a similar effect does not appear, and margination is largely unaffected by the geometry. This antimargination toward the vessel center after a confluence may explain earlier in vivo observations, which found that platelet concentrations near the vessel wall are seen to be much higher on the arteriolar side (containing bifurcations) than on the venular side (containing confluences) of the vascular system. PMID- 30021118 TI - Combating oxidative stress disorders with citrus flavonoid: Naringenin. AB - The incidence of diseases related to oxidative stress disorders have been increased dramatically. Alternatives medicine or the active compound extracted from the natural products received great attention among researches at the present era. Naringenin (NG), a common dietary flavanone, found in the citrus fruits such as oranges, bergamots, lemons and grapefruit. It is used in the several oxidative stress disorders as the nutraceutical value of the compound emerges. Functionally, the antioxidants effect of NG is primarily attributed by reducing the free radical like reactive oxygen species (ROS) and enhancing the antioxidants activity such as superoxide dismutase (SOD), catalase, glutathione (GSH) in chronic diseases such as cardiovascular, neurodegenerative, diabetes, pulmonary, cancer and nephropathy. The present review article summarised the antioxidant property of NG and its molecular mechanism towards such diseases. Pubmed, Science Direct, Scopus, Web of Science and Google scholar were searched using the terms 'naringenin', 'oxidative stress disorders', 'naringenin and cardiovascular diseases', 'naringenin and diabetes mellitus', 'naringenin and neurodegenerative diseases', 'naringenin and pulmonary diseases', 'naringenin and cancer' and 'naringenin and nephropathy'. There has been special attention on evaluating anti-oxidative effect of NG on neurodegenerative diseases. Although some mechanisms of action remain vague, the current review highlighted the potential use of NG as a oxidative stress reliever which can be used as next prophylaxis compound in the treatment of the various oxidative stress disorders. PMID- 30021119 TI - Intralymphatic allergen immunotherapy against pollen allergy: A 3-year open follow-up study of 10 patients. PMID- 30021120 TI - Closing the gap: Understanding African American asthma knowledge and beliefs. AB - BACKGROUND: African American children are disproportionately affected by asthma (13% vs 8% non-Hispanic white Americans) and experience 30% higher asthma-related deaths than whites. Knowledge regarding asthma and asthma treatment among African Americans has been postulated as a potential contributor to this observed health disparity. Compared with the amount of studies on asthma, few investigations provide insight into the baseline knowledge and beliefs of African Americans regarding asthma. OBJECTIVE: Assess knowledge and beliefs regarding asthma symptoms, diagnosis, treatment, prognosis, and stigmas in a general community sample of African Americans. METHODS: Using community-based participatory research techniques, we developed and implemented a cross-sectional survey to explore asthma knowledge and beliefs among African American adults in a Midwestern city. RESULTS: Among the 158 African American adults who completed the survey, general asthma knowledge was good, with awareness of the genetic contribution to asthma and general asthma symptomatology (eg, 92% aware of nighttime cough as a symptom). However, asthma-related misconceptions were also revealed. Thirty-three percent of respondents were concerned about addiction to asthma medication, and 60% of respondents believed that inhaled corticosteroids were dangerous or did not know. CONCLUSION: This study reveals important insights into asthma knowledge and beliefs among African Americans that may be used to address disparities in asthma outcomes in this population. PMID- 30021121 TI - Leptin restores markers of female fertility in lipodystrophy. AB - OBJECTIVES: Female reproductive dysfunction occurs in patients with pathological loss of adipose tissue, i.e. lipodystrophy (LD). However, mechanisms remain largely unclear and treatment effects of adipocyte-derived leptin have not been assessed in LD animals. METHODS: In the current study, C57Bl/6 LD mice on a low density lipoprotein receptor knockout background were treated with leptin or saline for 8 weeks and compared to non-LD controls. RESULTS: The number of pups born was 37% lower in breeding pairs consisting of LD female mice x non-LD male mice (n = 3.3) compared to LD male mice x non-LD female mice (n = 5.2) (p < 0.05). Mean uterus weight was significantly lower in the saline-treated LD group (18.8 mg) compared to non-LD controls (52.9 mg; p < 0.0001) and increased significantly upon leptin treatment (46.5 mg; p < 0.001). The mean number of corpora lutea per ovary was significantly lower in saline-treated LD animals compared to non-LD controls (p < 0.01) and was restored to non-LD control levels by leptin (p < 0.05). Mechanistically, mRNA expression of ovarian follicle stimulating hormone receptor (p < 0.01) and estrogen receptor beta (p < 0.05), as well as of pituitary luteinizing hormone beta subunit (p < 0.001) and follicle stimulating hormone beta subunit (p < 0.05), was significantly upregulated in LD mice compared to non-LD controls. In addition, mean time to vaginal opening as a marker of puberty onset was delayed by 12.5 days in LD mice (50.9 days) compared to non-LD controls (38.4 days; p < 0.001). CONCLUSIONS: Female LD animals show impaired fertility which is restored by leptin. Future studies should assess leptin as a subfertility treatment in human leptin-deficiency disorders. PMID- 30021122 TI - Future trends in the treatment of non-alcoholic steatohepatitis. AB - With an estimated prevalence of ~25% in Western and Asian countries, non alcoholic fatty liver disease (NAFLD), caused by chronic excessive caloric intake, is the emerging as the most prevalent liver disorder worldwide. NAFLD exists in two clinical entities, non-alcoholic fatty liver disease (NAFL), a relative benign disease that carry on minimal risk of liver-related morbidity but significant risk of cardiovascular complications, and non-alcoholic steatohepatitis (NASH), a progressive liver disorder with a significant risk for development of liver-related morbidities and mortality. While, liver injury in NASH is contributed by lipid overload in hepatocytes, lipotoxicity, the main determinant of disease progression is an inflammation-driven fibrotic response. Here, we review the landscape of emerging pharmacological interventions in the treatment of NAFL and NASH. A consensus exists that, while treating the liver component of NASH requires development of novel pharmacological approaches, the future therapy of NASH needs to be tailored to the single patient and most likely will be a combination of agents acting on specific pathogenic mechanisms at different disease stage. PMID- 30021123 TI - Evaluation of neuregulin-1's neuroprotection against ischemic injury in rats using diffusion tensor imaging. AB - Stroke is a devastating neurovascular disorder that results in damage to neurons and white matter tracts. It has been previously demonstrated that neuregulin-1 (NRG-1) protects neurons from ischemic injury following stroke. Here, diffusion tensor imaging (DTI) was utilized to characterize the effects of NRG-1 treatment on cererbral infarction and integrity of white matter after ischemic insult using a permanent middle celebral artery occlusion (pMCAo) rat model. In the present study, sixteen Sprague-Dawley rats underwent pMCAo surgery and received either a single intra-arterial bolus (20 MUg/kg) dose of NRG-1 or saline immediately prior to pMCAo. MRI including T2-weighted imaging and DTI was performed in the first 3 h post stroke, and repeated 48 h later. It is found that the stroke infarction was significantly reduced in the NRG-1 treated group. Also, NRG-1 prevented the reduction of fractional anisotropy (FA) in white matter tracts of fornix and corpus callosum (CC), indicating its protection of CC and fornix white matter bundles from ischemia insult. As a conclusion, the present DTI results demonstrate that NRG-1 has significantly neuroprotective effects in both cerebral cortex and white matter including corpus callosum and fornix during acute stroke. In particular, NRG-1 is more effective on stroke lesion with mild ischemia. As CC and fornix white matter bundles play critical roles in transcallosal connectivity and hippocampal projections respectively in the central nervous system, the findings could provide complementary information for better understanding the biological mechanism of NRG-1's neuroprotection in ischemic tissues and neurobehavioral effects. PMID- 30021124 TI - Identification of carotid lipid-rich necrotic core and calcification by 3D magnetization-prepared rapid acquisition gradient-echo imaging. AB - BACKGROUND AND PURPOSE: This study sought to investigate the feasibility of three dimensional MPRAGE in identifying the lipid-rich necrotic core (LRNC) and calcification (CA) of carotid atherosclerotic plaques. MATERIALS AND METHODS: Twelve patients (mean age 68.4 +/- 11.8 years; 7 males) with carotid atherosclerotic plaques on ultrasound were included and underwent multicontrast magnetic resonance (MR) vessel wall imaging. The contrast enhanced T1W (CE-T1W) images were considered as reference for identifying LRNC. The signal intensity of LRNC, CA, sterno-cleidomastoid muscle and fibrous tissue (FT) was measured on CE T1W, T1W, T2W, and MPRAGE images, respectively. The relative signal intensity (rSI) of LRNC and CA against muscle or FT was compared among four sequences. Area under the curve (AUC) of rSIs of LRNC, CA and FT against muscle on MPRAGE, T1W and T2W images in discriminating the LRNC or CA from FT and the other plaque component was calculated. RESULTS: Of 352 slices, 88 (25.0%) had LRNC, 31 (8.8%) had CA, 14 (4.0%) had both LRNC and CA, and 247 (70.2%) had no components. Among four imaging sequences, MPRAGE images showed the lowest rSI of LRNC (0.34 +/- 0.18) and CA (0.20 +/- 0.16) against muscle, followed by T1W (0.48 +/- 0.18 and 0.33 +/- 0.21), CE-T1W (0.58 +/- 0.23 and 0.40 +/- 0.21) and T2W (0.71 +/- 0.47 and 0.43 +/- 0.40) images. In addition, the MPRAGE images showed the lowest rSI of LRNC (0.57 +/- 0.26) and CA (0.33 +/- 0.23) against FT. MPRAGE showed greater AUC than T2W and T1W in discriminating the LRNC (0.827 vs. 0.703 vs. 0.635) and CA (0.917 vs. 0.838 vs. 0.825). CONCLUSION: MPRAGE sequence might be a potential non-contrast enhanced imaging tool for identification of carotid LRNC and CA. PMID- 30021125 TI - Respiratory fluctuations in pupil diameter are not maintained during cognitive tasks. AB - Pupil diameter fluctuation throughout the respiratory cycle is autonomically controlled in the resting state, as pupils dilate during inspiration and constrict during expiration. Furthermore, pupil size is differentially modulated by cognitive states between task engagement and disengagement. To determine whether respiratory-dependent fluctuations in pupil size are maintained during a cognitive task, we employed healthy human subjects performing a delayed matching to-sample task with a short delay and measured their pupil sizes and R wave-to-R wave intervals (RRIs). We detected respiratory fluctuations in pupil size and the RRI during the delay period immediately before the discrimination stage of the task. During the discrimination stage, the cognitive state with the higher task engagement yielded more pupil dilation. However, respiratory fluctuations in pupil size were abolished, whereas those in the RRI were still discernible during the discrimination stage. Our results suggest that an alternative control mechanism involving the cognitive state associated with task engagement overrides the respiratory-related autonomic control of pupil diameter. PMID- 30021126 TI - Real-world effectiveness of teriparatide on fracture reduction in patients with osteoporosis and comorbidities or risk factors for fractures: Integrated analysis of 4 prospective observational studies. AB - INTRODUCTION: Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies. METHODS: Patients received teriparatide 20 MUg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age <75 or >=75 years, diabetes, prior bisphosphonates use, rheumatoid arthritis (RA), glucocorticoid use, prior hip, and prior vertebral fracture. RESULTS: The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p < .005) for >6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p = .074, patients <75 years of age responded better), and diabetes for clinical fractures (p = .046, patients with diabetes responded better), although all of these subgroups experienced significant reductions over time. Glucocorticoids, prior bisphosphonate, and prior vertebral fracture were associated with increased CVF, NVF, and clinical fracture rates; RA, prior hip fracture and female gender were associated with higher NVF and clinical fracture rates; increased age was associated with higher CVF and clinical fracture rates. CONCLUSIONS: Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies. PMID- 30021127 TI - Rab and Arf proteins at the crossroad between membrane transport and cytoskeleton dynamics. AB - The intracellular movement and positioning of organelles and vesicles is mediated by the cytoskeleton and molecular motors. Small GTPases like Rab and Arf proteins are main regulators of intracellular transport by connecting membranes to cytoskeleton motors or adaptors. However, it is becoming clear that interactions between these small GTPases and the cytoskeleton are important not only for the regulation of membrane transport. In this review, we will cover our current understanding of the mechanisms underlying the connection between Rab and Arf GTPases and the cytoskeleton, with special emphasis on the double role of these interactions, not only in membrane trafficking but also in membrane and cytoskeleton remodeling. Furthermore, we will highlight the most recent findings about the fine control mechanisms of crosstalk between different members of Rab, Arf, and Rho families of small GTPases in the regulation of cytoskeleton organization. PMID- 30021128 TI - Hemorrhagic Cystitis: Brighter Days Ahead. PMID- 30021129 TI - Complete mitochondrial genome of the first deep-sea spongicolid shrimp Spongiocaris panglao (Decapoda: Stenopodidea): Novel gene arrangement and the phylogenetic position and origin of Stenopodidea. AB - Stenopodidea Claus, 1872 (Crustacea: Decapoda) is one of the major groups of decapods crustaceans. Hitherto, only one complete mitochondrial genome (mitogenome) from the family Stenopodidae is available for the infraorder Stenopodidea. Here, we determined the complete mitogenome of Spongiocaris panglao de Grave and Saito, 2016 using Illumina sequencing, representing the first species from the family Spongicolidae. The 15,909 bp genome is a circular molecule and consists of 13 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes and one control region. Although the overall genome organization is typical for metazoans, the mitogenome of S. panglao shows some derived characters. A + T content of 77.42% in S. pamglao mitogenome is second-highest among the dacapods described to date. The trnR gene exhibit modified secondary structure with the TpsiC loop completely missing, which might be a putative autapomorphy of S. pamglao mitogenome. Compared with the shallow water stenopodidean species S. hispidus, the control region of S. pamglao exhibits three characteristics: larger size, higher A + T content, and more tandem repeat sequences. The gene order exhibited difference from the ancestral mitogenome pattern of the Pancrustacea, with 5 tRNA genes rearrangement. The result from BI was agreed with most morphological characters and molecular evidences, revealing that Stenopodidea and Reptantia had the closest relationship, as the sister group of Caridea. Still, the alternative hypothesis supported from ML topology cannot be completely rejected based on the current data. Estimated times revealed that the two stenopodideans families Stenopodidae and Spongicolidae diverged from each other around 122 Mya. The divergence time of spongicolid shrimp is in good agreement with the origin of their hexactinellid hosts (78-144 Mya). PMID- 30021130 TI - Diverse roles of fatty acid binding proteins (FABPs) in development and pathogenesis of cancers. AB - One of the most importantly involved pathways in cancer development is fatty-acid signaling pathway. Synthesized lipids as energetic sources are consumed by cancer cells for proliferation, growth, survival, invasion and angiogenesis. Fatty acids as signaling compounds regulate metabolic and transcriptional networks, survival pathways and inflammatory responses. Aggregation of fatty acids with fatty acid binding proteins (FABPs) facilitates their transportation to different cell organelles. FABPs, a group of lipid binding proteins modulate fatty acid metabolism, cell growth and proliferation and cancer development. They may be used as tumor marker in some cancers. FABPs are expressed in most malignancies such as prostate, breast, liver, bladder and lung cancer which are associated with the incidence, proliferation, metastasis, invasion of tumors. This review introduces several isoforms of FABPs (FABP1-12) and summarizes their function and their possible roles in cancer development through some proposed mechanisms. PMID- 30021131 TI - Transcriptomic hallmarks of bone remodelling revealed by RNA-Seq profiling in blood of Arabian horses during racing training regime. AB - The impact of exercises on young developing organisms is still of interest to researchers. Similarly like Thoroughbreds, Arabian horses competing at the race track. The high percent of lameness and loss of days in training are often the result of weakness in the condition of the musculoskeletal system. The objective of the presented study was to identify by RNA-Seq method, the possible skeletal system originating transcriptomic profile in peripheral blood of Arabian horses undergoing race training. Obtained results showed that one of the most significantly deregulated pathway involved in bone homeostasis was those involved in osteoclast differentiation. Among the significantly expressed molecules, we recognized twelve genes potentially involved in the metabolism of the skeletal system: BGLAP, CTSK, TYROBP, PDLIM7, SLC9B2, TWSG1, NOTCH2, IL6ST, VAV3, NFATc1, CLEC5A, TXLNG. The panel of identified genes should be evaluated as candidate biomarkers for bone homeostasis indicators of Arabians performing on race tracks to assess bone remodelling states during training for race track competitions. PMID- 30021132 TI - Transcription activity of transposon sequence limits Sleeping Beauty transposition. AB - Sleeping Beauty (SB) transposon based technology has been extensively applied in basic research and biotechnology for routine cell culture gene delivery and vertebrate transgenesis, and it is also investigated in various gene therapy applications. Cell tolerance for the transgene is a key factor during transgenesis and is modulated not only through the type but by the dose of expression. Our experimental results exemplify that transgenes regulated with high activity promoters can reduce the overall success of gene delivery. Observations connected to transposon donors regulated by different promoters have also revealed inverse correlation between transcription activity and the hyperactive variant SB100X excision efficiency. This competition between transcription and transposition was independent of the transgene coding sequence and did not alter the transgenic efficiency in general. However, promoters applied in the transgene cassette can produce different average copy numbers depending on the transcriptional activity of the transposon. Unlike the piggyBac (PB) transposon system, this phenomenon allows a fine balance of expression using the high copy potential SB system that adjusts the copy number of lower activity promoter driven transgenes to a higher expression level. All this contributes to a well-tolerated and satisfactory transgenesis, and would be important to consider in gene therapy applications. PMID- 30021133 TI - Physical stabilities of taro starch nanoparticles stabilized Pickering emulsions and the potential application of encapsulated tea polyphenols. AB - In this research, Pickering emulsion stabilized by taro starch nanoparticles was successfully prepared, and the potential application of encapsulating tea polyphenols was investigated. The nanoparticle size (about 460 nm) and contact angle (81.5 degrees ) of taro starch indicate that it is suitable for adsorbing on the oil-water interface and forming a dense interfacial layer. Emulsion stability at different particle concentrations, oil-water ratios, and sodium chloride concentrations has been systematically studied. By considering the particle size, zeta potential, and stability index of Pickering emulsion, it is considered that the emulsion has the best stability when the particle concentration is 7% and the oil fraction is 0.5. Low concentration of salt ions (0.04 mM NaCl) will cause a slight flocculation to improve the stability, but adding high concentration of salt will make emulsion break. In addition, we found that this Pickering emulsion could encapsulate the tea polyphenols greatly with a retention rate of up to 67%. The findings may have great significance for the design and fabrication of native starch particle stabilized emulsion. PMID- 30021134 TI - Extraction, purification, characterization and antioxidant activities of polysaccharides from Zizyphus jujuba cv. Linzexiaozao. AB - The extraction process, purification and characterization analyses of polysaccharides (LZJP) in Ziziphus jujuba planted in Linze County, Gansu Province were investigated, respectively. The results showed a maximum polysaccharide yield of 5.72% was achieved at a solid/liquid ratio of 1:20 g/mL for 90 min at 80 degrees C. Two homogenous acidic polysaccharides (LZJP3 and LZJP4) were purified successively by DEAE-52 cellulose and Sephadex G-100 column chromatography. LZJP3 is composed of one polymer with galactose while LZJP4 is made up of two different kinds of polymers with xylose and glucose by size-exclusion chromatograph combined with multi-angle laser photometer (HPSEC-LLS) and gas chromatography (GC) analysis. LZJP3 and LZJP4 were beta-pyran polysaccharides with a large number of molecular globular aggregates by FT-IR (Fourier-transform infrared) and AFM (Atomic force microscopy) analysis, and the surface morphology exhibited smooth and filamentous staggered extension in the form of rod-like aggregation with SEM (Scanning electron microscopy) determination. Meanwhile, LZJP3 and LZJP4 exhibited antioxidant activities against DPPH, hydroxyl radical, hydrogen peroxide, superoxide radical and stronger reducing power in vitro with the concentration increasing. The results indicated that LZJPs were worthy of being developed further as a natural antioxidant in food and medicine industries. PMID- 30021135 TI - Amphiphilic ionic complexes of hyaluronic acid with organophosphonium compounds and their antimicrobial activity. AB - Amphiphilic ionic complexes of hyaluronic acid and alkyltrimethylphosphonium soaps with alkyl chains containing even numbers of carbons from 12 to 22 have been produced. The complexes have a nearly stoichiometric composition, are non water soluble, and are stable to heat up to temperatures above 200 degrees C. These complexes are amphiphilic and able to adopt a biphasic structure with the paraffinic and polysaccharide phases ordered arranged with a periodicity ranging between 3 and 5 nm depending on n. The paraffinic phase in complexes with n >= 18 was crystallized and showed melting at temperatures between 58 and 70 degrees C depending on the n value. The complexes decomposed upon incubation in water under physiological conditions, and undergone extensive biodegradation by the action of hyaluronidases. Biocide assays carried out in both solid and liquid media demonstrated a high antimicrobial activity of the complexes against Gram-positive S. aureus but moderate against Gram-negative E. coli and C. albicans fungi. PMID- 30021136 TI - Characterization of a novel psychrophilic and halophilic beta-1, 3-xylanase from deep-sea bacterium, Flammeovirga pacifica strain WPAGA1. AB - beta-1, 3-Xylanase is one of the most important hydrolytic enzymes to prepare oligosaccharides as functional foods in seaweed industry. However, less than five beta-1, 3-xylanases have been experimentally expressed and characterized; moreover, none of them is psychrophilic and salt tolerant. Here, we mined a novel beta-1, 3-xylanase (Xyl512) from the genome of the deep-sea bacterium Flammeovirga pacifica strain WPAGA1 and biochemically characterized it in detail. The Xyl512 did not contain any carbohydrate-binding module; the catalytic domain of it belonged to the glycoside hydrolase family 26. The optimum temperature and pH of the purified beta-1, 3-xylanase was 20 degrees C and pH 7.0 in the condition of no NaCl. However, they shifted to 30 degrees C and 7.5 with 1.5 mol/L NaCl, respectively. In this condition (1.5 mol/L NaCl), the overall activity was 2-fold as high as that without NaCl. Based on the residue interactions and the electrostatic surfaces, we addressed the possible mechanism of its adaption to low temperature and relative high NaCl concentration. The Xyl512 showed significantly reduced numbers of hydrogen bonds leading to a more flexible structure, which is likely to be responsible for its cold adaptation. While the negatively charged surface may contribute to its salt tolerance. The beta-1, 3-xylanase we identified here was the first reported psychrophilic and halophilic one with functionally characterized. It could make new contributions to exploring and studying the beta-1, 3-xylanase for further associated investigations. PMID- 30021137 TI - Optimization of nanofibrillation degree of chitin for induction of plant disease resistance: Elicitor activity and systemic resistance induced by chitin nanofiber in cabbage and strawberry. AB - Chitin has not been extensively used in agriculture owing to its handling difficulties despite its utilizable functions such as induction of disease resistance and growth promotion in plants. Chitin nanofiber (CNF), which has an elicitor activity to induce plant disease resistance, can be handled like a water soluble material, because of its high dispersibility. To determine the potential use of CNF in agriculture, the nanofibrillation degree of chitin for elicitor activity and its effect on the disease resistance against pathogens were examined in cabbage and strawberry plants. The similarity in thickness and length of CNF to that of polymeric chitin was sufficient to induce elicitor activity in both plants. Cabbage and strawberry plants, which were grown in a mixture of soil and CNF with optimized specification, challenged with fungal pathogens showed a reduction in the number of spots caused by Alternaria brassicicola and lesion size by Colletotrichum fructicola, respectively. Gene expression analysis revealed that the defense-related genes in cabbage plant grown in CNF-containing soil were significantly upregulated before and after pathogen infection. These results indicate that CNF can systemically induce disease resistance in cabbage and strawberry plants and is a promising natural-based material to control diseases in cultivated plants. PMID- 30021138 TI - Metal ions increase mechanical strength and barrier properties of collagen-sodium polyacrylate composite films. AB - From the previous experiment, it was confirmed that the incorporation of 0.3 wt% sodium polyacrylate (PAAS) into collagen (Co) fibers can improve the mechanical properties and thermal stability of the composite films. In this study, Ca2+, Fe3+ and Ag+ ranging 0.001-0.004 mol/g were used to improve the properties of Co PAAS blend films based on the rationale of their potential electrostatic interaction with these biopolymers. As expected, Zeta-potential film-forming solutions was decreased to some extent with the addition of metal ions. SEM images presented that the surface of the composites became coarser and internal structure became more stratified as metal ion contents increased. Tensile strength was increased by the addition of these ions with a varied optimal concentration: Ca2+ (0.003 mol/g), Fe3+ (0.002 mol/g) and Ag+ (0.001 mol/g). Water vapor permeability (WVP), solubility and light transmission value of films while causing film thickness no obvious change. In addition, the differential scanning calorimetry (DSC) and thermo-gravimetric analysis (TGA) results indicated that the metal ions improved the thermal stability of the composite film. Therefore, Ca2+, Fe3+ and Ag+ with an appropriate addition amount can be used as a potential alternative to reinforce collagenous composite materials. PMID- 30021139 TI - Splenic Leukocytes Get the Nerves up for Myelopoiesis. AB - The intricate interplay between the immune and the nervous systems has been steadily unveiled at both cellular and molecular levels. In this issue of Immunity, Vasamsetti et al. (2018) show that sympathetic nerves drive catecholamine signaling from leukocytes, thereby promoting splenic granulocyte macrophage progenitor (GMP) proliferation and differentiation. PMID- 30021140 TI - A Tumor Cell-Intrinsic Yin-Yang Determining Immune Evasion. AB - Pancreatic adenocarcinoma (PDAC) is mostly refractory to immunotherapies. In this issue of Immunity, Li et al. (2018) generate a library of clonal PDAC tumors to examine the tumor-intrinsic features shaping the anti-tumor immune response and find that tumor cell-derived CXCL1 directly blunts T cell infiltration and reduces responsiveness to immunotherapy. PMID- 30021141 TI - Hitting HIV's Harpoon. AB - The HIV-1 fusion peptide is a target for broadly neutralizing antibodies. In a recent issue of Nature Medicine, Xu et al. (2018) provide proof-of-concept that vaccination with fusion peptide followed by vaccination with an envelope glycoprotein trimer can induce antibodies in animal models that neutralize diverse HIV-1 viruses. PMID- 30021142 TI - Getting a Taste for Parasites in the Gut. AB - How type 2 immune responses are initiated is obscure. Nadjsombati et al. (2018), along with two other studies (Lei et al., 2018; Schneider et al., 2018), show that tuft cells can initiate type 2 responses by recognizing the metabolite succinate produced by intestinal parasites. PMID- 30021143 TI - Programmed Cell Death in Immune Defense: Knowledge and Presumptions. AB - Cell-culture studies are our main source of knowledge of the various forms of programmed cell death. Yet genetic perturbations of death-protein function in animal models are almost the only source of our knowledge of the physiological roles of these programs. Shortcomings in the state of knowledge acquired by these two experimental approaches are exemplified in this Perspective by reference to research on the contribution of apoptosis to lymphocyte development, a subject on which there is already much knowledge, and on the role of necroptosis in inflammation, about which information is just beginning to emerge. To address these shortcomings, there is need to find ways to verify the notions obtained through the current experimental approaches by directly monitoring death programs within specific cells in vivo. PMID- 30021145 TI - Intestinal Tolerance, with a Little Help from Our Microbial Friends. AB - The intestinal immune system performs a tightrope walk between anti-pathogen immunity and tolerance to innocuous luminal antigens. In this issue of Immunity, Kim et al. (2018) demonstrate that the microbiota is driving tolerance to food antigens and dampening inflammatory responses through CX3CR1+ mononuclear phagocytes. PMID- 30021144 TI - Detection of Succinate by Intestinal Tuft Cells Triggers a Type 2 Innate Immune Circuit. AB - In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. In vivo sensing of the tritrichomonad required SUCNR1, whereas N. brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of other sensing pathways triggering the response to helminths. PMID- 30021147 TI - Viral Infection "Interferes" with Glucose Tolerance. AB - In this issue of Immunity, Sestan et al. (2018) show that viral-induced inflammation leads to insulin resistance in skeletal muscle, followed by compensatory hyperinsulinemia, which promotes the anti-viral effector response of CD8+ T cells. Interestingly, this leads to persistent glucose intolerance and the progression of type 2 diabetes in pre-diabetic animals. PMID- 30021148 TI - Neuroendocrine Cells Take Your Breath Away. AB - Pulmonary neuroimmune networks have emerged as important regulators of lung homeostasis. In a recent issue of Science, Sui et al. show that strategically positioned pulmonary neuroendocrine cells amplify allergic airway responses via group 2 innate lymphoid cells. PMID- 30021149 TI - Matrix metalloprotease-9 expresssion in meningioma: Correlation with growth fraction and role of gender. A pilot immunohistochemical study. AB - OBJECTIVE: Matrix metalloproteases (MMPs), particularly MMP2 and MMP9 increase tumor invasion and edema in meningiomas. Although lesser recognized, MMPs may also enhance cell growth via liberating growth factors or via cleaving inactive growth factors into active isoforms. However, there exist very few studies, which investigated correlation of MMPs with growth fraction in meningiomas. Meningiomas are seen more frequently in women and their growth accelarate during pregnancy. However, no study examined whether MMP-expressions in meningioma differ with gender. PATIENTS AND METHODS: In a pilot immunohistochemical study, we analyzed the correlation of MMP9 expression with Ki67 index and whether gender influences MMP9 expression. We retrospectively selected 24 meningioma cases including 10 cases with WHO Grade-1 tumors and 7 cases each with WHO Grade-2 and 3 tumors, respectively. RESULTS: We separately determined the intensity and area of MMP9 staining and also calculated an expression index by multiplying these two parameters. Spearman correlation analyses revealed that MMP9 staining intensity, staining area and expression index significantly correlated with Ki67 proliferation index. MMP9 staining indices were significantly higher in women specimens. CONCLUSION: If these findings will be confirmed in larger series, MMP inhibitors and female hormone receptor-antagonists may be combined to augment chemotherapy efficacy and to attenuate invasion in high-grade meningiomas. PMID- 30021146 TI - Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock. AB - The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-beta-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways. PMID- 30021150 TI - Influence of sugar beet pulp and paper waste as bulking agents on physical, chemical, and microbial properties during green waste composting. AB - Composting is considered to be a natural, sustainable, and highly beneficial method for solid waste disposal. The objective of this study was to investigate the two-stage composting of green waste (GW) as affected by the addition of sugar beet pulp (SBP; at 0, 25, and 35%) and/or paper waste (PW; at 0, 5, and 10%) as bulking agents. The combination of SBP and PW greatly improved the composting conditions and the final compost quality in terms of composting temperature; pH; emissions of ammonia, nitrite nitrogen, and carbon dioxide; lignocellulose degradation; microbial abundance; enzyme activities; particle-size distribution; the ratio of water-soluble organic carbon to organic nitrogen; and phytotoxicity. The optimal two-stage composting process of GW and the highest quality compost product were obtained with the combination of 25% SBP and 10% PW. This optimal combination of bulking agents produced a mature and stable final compost product in only 20 days. PMID- 30021152 TI - RADX Modulates RAD51 Activity to Control Replication Fork Protection. AB - RAD51 promotes homologous recombination repair (HR) of double-strand breaks and acts during DNA replication to facilitate fork reversal and protect nascent DNA strands from nuclease digestion. Several additional HR proteins regulate fork protection by promoting RAD51 filament formation. Here, we show that RADX modulates stalled fork protection by antagonizing RAD51. Consequently, silencing RADX restores fork protection in cells deficient for BRCA1, BRCA2, FANCA, FANCD2, or BOD1L. Inactivating RADX prevents both MRE11- and DNA2-dependent fork degradation. Furthermore, RADX overexpression causes fork degradation that is dependent on these nucleases and fork reversal. The amount of RAD51 determines the fate of stalled replication forks, with more RAD51 required for fork protection than fork reversal. Finally, we find that RADX effectively competes with RAD51 for binding to single-stranded DNA, supporting a model in which RADX buffers RAD51 to ensure the right amount of reversal and protection to maintain genome stability. PMID- 30021151 TI - Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity. AB - RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins. PMID- 30021153 TI - WAC Promotes Polo-like Kinase 1 Activation for Timely Mitotic Entry. AB - The key mitotic regulator Polo-like kinase 1 (Plk1) is activated during G2 phase by Aurora A kinase (AurkA)-mediated phosphorylation of its activation loop, which is important for timely mitotic entry. The mechanism for Plk1 activation remains incompletely understood. Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. These defects are rescued by exogenous expression of wild-type WAC, but not the Plk1-binding-deficient mutant. WAC also binds AurkA and can enhance Plk1 phosphorylation by AurkA in vitro. Taken together, these results indicate an important role for WAC in promoting Plk1 activation and the timely entry into mitosis. PMID- 30021155 TI - ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor. AB - Mineralocorticoid receptor (MR) signaling regulates both renal Na-Cl reabsorption and K+ excretion. We previously demonstrated that phosphorylation of S843 in the MR ligand-binding domain in renal intercalated cells is involved in the balance of these activities by regulating ligand binding and signaling. However, the kinase that phosphorylates MRS843 is unknown. Using a high-throughput screen assay of 197 kinases, we found that ULK1 is the principal kinase that is responsible for the phosphorylation of MRS843. The results were confirmed by in vitro kinase assay, mass spectrometry, and siRNA knockdown experiments. Notably, phosphorylation at MRS843 was markedly reduced in ULK1/2 double knockout mouse embryonic fibroblasts. Upstream, we show that ULK1 activity is inhibited by phosphorylation induced by angiotensin II via mTOR in cell culture and in vivo. These findings implicate mTOR and ULK1 as regulators of MR activity in intercalated cells, a pathway that is critical for maintaining electrolyte homeostasis. PMID- 30021154 TI - Molecular Deconvolution Platform to Establish Disease Mechanisms by Surveying GPCR Signaling. AB - Despite the wealth of genetic information available, mechanisms underlying pathological effects of disease-associated mutations in components of G protein coupled receptor (GPCR) signaling cascades remain elusive. In this study, we developed a scalable approach for the functional analysis of clinical variants in GPCR pathways along with a complete analytical framework. We applied the strategy to evaluate an extensive set of dystonia-causing mutations in G protein Galphaolf. Our quantitative analysis revealed diverse mechanisms by which pathogenic variants disrupt GPCR signaling, leading to a mechanism-based classification of dystonia. In light of significant clinical heterogeneity, the mechanistic analysis of individual disease-associated variants permits tailoring personalized intervention strategies, which makes it superior to the current phenotype-based approach. We propose that the platform developed in this study can be universally applied to evaluate disease mechanisms for conditions associated with genetic variation in all components of GPCR signaling. PMID- 30021156 TI - The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen. AB - Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1 deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints. PMID- 30021157 TI - Reconstituting Arabidopsis CRY2 Signaling Pathway in Mammalian Cells Reveals Regulation of Transcription by Direct Binding of CRY2 to DNA. AB - In response to blue light, cryptochromes photoexcite and interact with signal partners to transduce signal almost synchronously in plants. The detailed mechanism of CRY-mediated light signaling remains unclear: the photobiochemical reactions of cryptochrome are transient and synchronous, thus making the monitoring and analysis of each step difficult in plant cells. In this study, we reconstituted the Arabidopsis CRY2 signaling pathway in mammalian cells and investigated the biological role of Arabidopsis CRY2 in this heterologous system, eliminating the interferences of other plant proteins. Our results demonstrated that, besides being the light receptor, Arabidopsis CRY2 binds to DNA directly and acts as a transcriptional activator in a blue-light-enhanced manner. Similar to classic transcription factors, we found that the transcriptional activity of CRY2 is regulated by its dimerization and phosphorylation. In addition, CRY2 cooperates with CIB1 to regulate transcription by enhancing the DNA affinity and transcriptional activity of CIB1 under blue light. PMID- 30021158 TI - A Virally Encoded DeSUMOylase Activity Is Required for Cytomegalovirus Reactivation from Latency. AB - A subset of viral genes is required for the long-term latent infection of hematopoietic cells by human cytomegalovirus (HCMV). Here, we show that a latency associated gene product (LUNA) promotes the disruption of cellular PML bodies during latency. Mutation and inhibitor studies reveal that LUNA encodes a deSUMOylase activity responsible for this disruption. Specifically, LUNA encodes a conserved Asp-Cys-Gly motif common to all deSUMOylases. Importantly, mutation of the putative catalytic cysteine is sufficient to reverse LUNA-mediated PML dispersal and markedly reduces the efficiency of viral reactivation. The depletion of PML from cells is sufficient to rescue the reactivation of the LUNA deficient viruses, arguing that targeting PML is an important biological role of LUNA. Finally, we demonstrate that reactivation of naturally latent HCMV is blocked by deSUMOylase inhibitors. Thus, latent HCMV primes the cellular environment for efficient reactivation via the activity of a virally encoded deSUMOylase. PMID- 30021159 TI - OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3 Dependent and Independent Mechanisms. AB - Naive CD4+ T cells can be converted to Foxp3+ T regulatory cells (Tregs) in the periphery (iTregs), where induction of Foxp3 gene expression is central to Treg differentiation. OX40 signaling is known to inhibit Foxp3 expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress Foxp3 expression in freshly activated naive CD4+ T cells. Specifically, OX40 upregulates BATF3 and BATF, which produce a closed chromatin configuration to repress Foxp3 expression in a Sirt1/7-dependent manner. Moreover, OX40 can also activate the AKT-mTOR pathway, especially in the absence of BATF3 and BATF, to inhibit Foxp3 induction, and this is mediated by phosphorylation and nuclear exclusion of the transcription factor Foxo1. Taken together, our results provide key mechanistic insights into how OX40 inhibits Foxp3 expression and Treg induction in the periphery. PMID- 30021160 TI - The Lack of WIP Binding to Actin Results in Impaired B Cell Migration and Altered Humoral Immune Responses. AB - Wiskott-Aldrich syndrome protein (WASp) is a main cytoskeletal regulator in B cells. WASp-interacting protein (WIP) binds to and stabilizes WASp but also interacts with actin. Using mice with a mutated actin binding domain of WIP (WIPDeltaABD), we here investigated the role of WIP binding to actin during B cell activation. We found an altered differentiation of WIPDeltaABD B cells and diminished antibody affinity maturation after immunization. Mechanistically, WIPDeltaABD B cells showed impaired B cell receptor (BCR)-induced PI3K signaling and actin reorganization, likely caused by diminished CD81 expression and altered CD19 dynamics on the B cell surface. WIPDeltaABD B cells displayed reduced in vivo motility, concomitantly with impaired chemotaxis and defective F-actin polarization, HS1 phosphorylation, and polarization of HS1 to F-actin-rich structures after CXCL12 stimulation in vitro. We thus concluded that WIP binding to actin, independent of its binding to WASp, is critical for actin cytoskeleton plasticity in B cells. PMID- 30021162 TI - HDACi Delivery Reprograms Tumor-Infiltrating Myeloid Cells to Eliminate Antigen Loss Variants. AB - Immune recognition of tumor-expressed antigens by cytotoxic CD8+ T cells is the foundation of adoptive T cell therapy (ACT) and has been shown to elicit significant tumor regression. However, therapy-induced selective pressure can sculpt the antigenicity of tumors, resulting in outgrowth of variants that lose the target antigen. We demonstrate that tumor relapse from ACT and subsequent oncolytic viral vaccination can be prevented using class I HDACi, MS-275. Drug delivery subverted the phenotype of tumor-infiltrating CD11b+ Ly6Chi Ly6G- myeloid cells, favoring NOS2/ROS secretion and pro-inflammatory genes characteristic of M1 polarization. Simultaneously, MS-275 abrogated the immunosuppressive function of tumor-infiltrating myeloid cells and reprogrammed them to eliminate antigen-negative tumor cells in a caspase-dependent manner. Elevated IFN-gamma within the tumor microenvironment suggests that MS-275 modulates the local cytokine landscape to favor antitumor myeloid polarization through the IFN-gammaR/STAT1 signaling axis. Exploiting tumor-infiltrating myeloid cell plasticity thus complements T cell therapy in targeting tumor heterogeneity and immune escape. PMID- 30021161 TI - ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation. AB - The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT) associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells. An inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immunocompetent mouse model of breast cancer revealed that ALIX deficient tumors are larger and show an increased immunosuppressive environment. Our data suggest that ALIX modulates immunosuppression through regulation of PD L1 and EGFR and may, therefore, present a diagnostic and therapeutic target for BLBC. PMID- 30021164 TI - COMMD5/HCaRG Hooks Endosomes on Cytoskeleton and Coordinates EGFR Trafficking. AB - COMMD5/HCaRG is involved in tissue repair, and its low expression is associated with tumorigenicity. Cell growth, migration, and differentiation are controlled by COMMD5. We previously reported that COMMD5 inhibited the growth of renal carcinoma cells by regulating expression or phosphorylation of ErbB members. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity. PMID- 30021163 TI - Crosstalk between PKCalpha and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium. AB - Protein kinase C (PKC) isozymes are commonly recognized as oncoproteins based on their activation by tumor-promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCalpha acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKCalpha is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKCalpha is rate limiting for endometrial tumor initiation. PKCalpha tumor suppression involves PP2A-family dependent inactivation of AKT, which can occur even in the context of genetic hyperactivation of PI3K/AKT signaling by coincident mutations in PTEN, PIK3CA, and/or PIK3R1. Together, our data point to PKCalpha as a crucial tumor suppressor in the endometrium, with deregulation of a PKCalpha->PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis. PMID- 30021165 TI - Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca2+/CaM Controls DCV Binding and Liprin-alpha/TANC2 Recruits DCVs to Postsynaptic Sites. AB - Tight regulation of neuronal transport allows for cargo binding and release at specific cellular locations. The mechanisms by which motor proteins are loaded on vesicles and how cargoes are captured at appropriate sites remain unclear. To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-alpha and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-alpha and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. Furthermore, we found that specific TANC2 mutations-reported in patients with different neuropsychiatric disorders-abolish the interaction with KIF1A. We propose a model in which Ca2+/CaM regulates cargo binding and liprin-alpha and TANC2 recruit KIF1A-transported vesicles. PMID- 30021166 TI - Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression. AB - Menin (MEN1) is a critical modulator of tissue development and maintenance. As such, MEN1 mutations are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin is abundantly expressed in the nervous system, little is known with regard to its function in the adult brain. Here, we demonstrate that neuron-specific deletion of Men1 (CcKO) affects dendritic branching and spine formation, resulting in defects in synaptic function, learning, and memory. Furthermore, we find that menin binds to the p35 promoter region to facilitate p35 transcription. As a primary Cdk5 activator, p35 is expressed mainly in neurons and is critical for brain development and synaptic plasticity. Restoration of p35 expression in the hippocampus and cortex of Men1 CcKO mice rescues synaptic and cognitive deficits associated with Men1 deletion. These results reveal a critical role for menin in synaptic and cognitive function by modulating the p35-Cdk5 pathway. PMID- 30021168 TI - Aberrant Deactivation-Induced Gain of Function in TRPM4 Mutant Is Associated with Human Cardiac Conduction Block. AB - A gain-of-function mutation in the Ca2+-activated transient receptor potential melastatin member 4 (TRPM4A432T) is linked to life-threatening cardiac conduction disturbance, but the underlying mechanism is unclear. For deeper insights, we used photolysis of caged Ca2+, quantitative Ca2+, and electrophysiological measurements. TRPM4A432T's 2-fold larger membrane current was associated with 50% decreased plasma membrane expression. Kinetic analysis unveiled 4-fold slower deactivation that was responsible for the augmented membrane current progressively rising during repetitive human cardiac action potentials. Rational mutagenesis of TRPM4 at position 432 revealed that the bulkiness of the amino acid was key to TRPM4A432T's aberrant gating. Charged amino acids rendered the channel non-functional. The slow deactivation caused by an amino acid substitution at position 432 from alanine to the bulkier threonine represents a key contributor to the gain of function in TRPM4A432T. Thus, our results add a mechanism in the etiology of TRP channel-linked human cardiac channelopathies. PMID- 30021167 TI - CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease. AB - Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP beta-cleavage and Abeta production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Abeta production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy. PMID- 30021169 TI - Dual Function of USP14 Deubiquitinase in Cellular Proteasomal Activity and Autophagic Flux. AB - The ubiquitin-proteasome system and the autophagy-lysosome system are two major intracellular proteolytic pathways in eukaryotes. Although several biochemical mechanisms underlying the crosstalk between them have been suggested, little is known about the effect of enhanced proteasome activity on autophagic flux. Here, we found that upregulation of proteasome activity, which was achieved through the inhibition of USP14, significantly impaired cellular autophagic flux, especially at the autophagosome-lysosome fusion step. UVRAG appeared to function as a crucial checkpoint for the proper progression of autophagic flux. Although proteasome activation through USP14 inhibition facilitated the clearance of microtubule-associated protein tau (MAPT) and reduced the amount of its oligomeric forms, the same conditions increased the formation of inclusion bodies from nonproteasomal substrates such as huntingtin with long polyglutamine repeats. Our results collectively indicate that USP14 may function as a common denominator in the compensatory negative feedback between the two major proteolytic processes in the cell. PMID- 30021171 TI - Promoter Activity Buffering Reduces the Fitness Cost of Misregulation. AB - Organisms regulate gene expression through changes in the activity of transcription factors (TFs). In yeast, the response of genes to changes in TF activity is generally assumed to be encoded in the promoter. To directly test this assumption, we chose 42 genes and, for each, replaced the promoter with a synthetic inducible promoter and measured how protein expression changes as a function of TF activity. Most genes exhibited gene-specific TF dose-response curves not due to differences in mRNA stability, translation, or protein stability. Instead, most genes have an intrinsic ability to buffer the effects of promoter activity. This can be encoded in the open reading frame and the 3' end of genes and can be implemented by both autoregulatory feedback and by titration of limiting trans regulators. We show experimentally and computationally that, when misexpression of a gene is deleterious, this buffering insulates cells from fitness defects due to misregulation. PMID- 30021170 TI - Insights into Centromere DNA Bending Revealed by the Cryo-EM Structure of the Core Centromere Binding Factor 3 with Ndc10. AB - The centromere binding factor 3 (CBF3) complex binds the third centromere DNA element in organisms with point centromeres, such as S. cerevisiae. It is an essential complex for assembly of the kinetochore in these organisms, as it facilitates genetic centromere specification and allows association of all other kinetochore components. We determined high-resolution structures of the core complex of CBF3 alone and in association with a monomeric construct of Ndc10, using cryoelectron microscopy (cryo-EM). We identify the DNA-binding site of the complex and present a model in which CBF3 induces a tight bend in centromeric DNA, thus facilitating assembly of the centromeric nucleosome. PMID- 30021172 TI - Differences in Cell Cycle Status Underlie Transcriptional Heterogeneity in the HSC Compartment. AB - Hematopoietic stem cells (HSCs) are considered a heterogeneous cell population. To further resolve the HSC compartment, we characterized a retinoic acid (RA) reporter mouse line. Sub-fractionation of the HSC compartment in RA-CFP reporter mice demonstrated that RA-CFP-dim HSCs were largely non-proliferative and displayed superior engraftment potential in comparison with RA-CFP-bright HSCs. Gene expression analysis demonstrated higher expression of RA-target genes in RA CFP-dim HSCs, in contrast to the RA-CFP reporter expression, but both RA-CFP-dim and RA-CFP-bright HSCs responded efficiently to RA in vitro. Single-cell RNA sequencing (RNA-seq) of >1,200 HSCs showed that differences in cell cycle activity constituted the main driver of transcriptional heterogeneity in HSCs. Moreover, further analysis of the single-cell RNA-seq data revealed that stochastic low-level expression of distinct lineage-affiliated transcriptional programs is a common feature of HSCs. Collectively, this work demonstrates the utility of the RA-CFP reporter line as a tool for the isolation of superior HSCs. PMID- 30021174 TI - Comparison of sorption kinetics of PAHs by sorptive sinks and caco-2 cell and the correlation between bioaccessibility and bioavailability of PAHs in indoor dust. AB - Sorptive sinks are extensively used in the bioaccessibility of organic contaminants, but their suitability for simulating the intestinal cell is seldom reported. In the present study, the sorption efficiency of PAHs by sorptive sinks including silica, poly(ethylene-co-vinyl acetate) (polyE), tenax, and C18 were compared with that by caco-2 cells. The elimination rate constants of phenanthrene, fluoranthene, pyrene, benzo(a)pyrene by caco-2 cell were 0.0417 +/- 0.006 min-1, 0.0411 +/- 0.0074 min-1, 0.0362 +/- 0.006 min-1, and 0.0526 +/- 0.0037 min-1, respectively, which were more closely to that of silica and polyE compared to other materials. This indicated that these materials might be the preferable sorptive sinks to simulate absorption of PAHs by intestinal cells. The bioaccessibility of phenanthrene, fluoranthene, pyrene, benzo(a)pyrene in indoor dust ranged from 15.5-43.5%, 9.10-38.8%, 10.0-37.9%, and 6.00-21.9%, respectively, based on physiologically based extraction test (PBET) and the sorptive sinks added in the intestinal solution led to 1.17 to 8.47-fold enhancement of bioaccessibility. The correlation of in vivo PAHs relative bioavailability (RBA) and in vitro digestion bioaccessibility with or without the sorptive sinks of indoor dust were measured, and the results indicated that silica and polyE were more likely to predict PAHs RBA of indoor dust, which was consistent with the results of sorption kinetics assay. The present results indicate that silica and polyE have the potential to simulate caco-2 cell and the inclusion of these materials in the PBET is likely to predict PAHs RBA in indoor dust. Capsule: Silica and polyE were more likely to simulate absorption of PAHs by intestinal cells, and to predict PAHs RBA of indoor dust. PMID- 30021173 TI - Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism. AB - Thermogenic fat expends energy during cold for temperature homeostasis, and its activity regulates nutrient metabolism and insulin sensitivity. We measured cold activated lipid landscapes in circulation and in adipose tissue by MS/MSALL shotgun lipidomics. We created an interactive online viewer to visualize the changes of specific lipid species in response to cold. In adipose tissue, among the approximately 1,600 lipid species profiled, we identified the biosynthetic pathway of the mitochondrial phospholipid cardiolipin as coordinately activated in brown and beige fat by cold in wild-type and transgenic mice with enhanced browning of white fat. Together, these data provide a comprehensive lipid bio signature of thermogenic fat activation in circulation and tissue and suggest pathways regulated by cold exposure. PMID- 30021175 TI - Leachate from fine root litter is more acidic than leaf litter leachate: A 2.5 year laboratory incubation. AB - Some tree species increase fine root production under soil acidification, thus changing the balance of litter input from leaves and roots. Litter leaches a significant amount of acidic materials during its decomposition, which might facilitate soil acidification. In this context, we focused on dissolved organic matter (DOM) as the major component of acidic materials. We hypothesized that both the quality and quantity of DOM, which control its function (i.e., proton supply), differ between leaf and root litter. To test this hypothesis, we conducted a 2.5-year laboratory incubation experiment using fresh fine roots and fresh green leaves as litter of two coniferous species (Cryptomeria japonica and Chamaecyparis obtusa) and investigated the leachate pH and DOM composition based on the optical properties. After the early stage of decomposition when flash leaching of DOM converged, the amount of dissolved organic carbon (DOC) leached from roots increased again and leachate pH declined. In contrast, DOC concentrations continued to decrease in leaf leachates during the incubation period, and the pH decrease was not as striking as that of root leachates. Optical properties (ultraviolet visible absorption and fluorescence) of DOM revealed that humic-like substances in DOM played a central role in the acidic pH of root leachates. The total amount of protons released from roots of C. japonica and C. obtusa is about 13 and 18 times higher, respectively, than that from leaves. These results imply that the increase of fine root biomass may induce a positive plant-soil feedback in acidic soils, affecting soil biogeochemical functions of terrestrial ecosystems. PMID- 30021176 TI - Retention and remobilization mechanisms of environmentally aged silver nanoparticles in an artificial riverbank filtration system. AB - Riverbank filtration systems are important structures that ensure the cleaning of infiltrating surface water for drinking water production. In our study, we investigated the potential risk for a breakthrough of environmentally aged silver nanoparticles (Ag NP) through these systems. Additionally, we identified factors leading to the remobilization of Ag NP accumulated in surficial sediment layers in order to gain insights into remobilization mechanisms. We conducted column experiments with Ag NP in an outdoor pilot plant consisting of water-saturated sediment columns mimicking a riverbank filtration system. The NP had previously been aged in river water, soil extract, and ultrapure water, respectively. We investigated the depth-dependent breakthrough and retention of NP. In subsequent batch experiments, we studied the processes responsible for a remobilization of Ag NP retained in the upper 10 cm of the sediments, induced by ionic strength reduction, natural organic matter (NOM), and mechanical forces. We determined the amount of remobilized Ag by ICP-MS and differentiated between particulate and ionic Ag after remobilization using GFAAS. The presence of Ag-containing heteroaggregates was investigated by combining filtration with single-particle ICP-MS. Single and erratic Ag breakthrough events were mainly found in 30 cm depth and Ag NP were accumulated in the upper 20 cm of the columns. Soil-aged Ag NP showed the lowest retention of only 54%. Remobilization was induced by the reduction of ionic strength and the presence of NOM in combination with mechanical forces. The presence of calcium in the aging- as well as the remobilizing media reduced the remobilization potential. Silver NP were mainly remobilized as heteroaggregates with natural colloids, while dissolution played a minor role. Our study indicates that the breakthrough potential of Ag NP in riverbank filtration systems is generally low, but the aging in soil increases their mobility. Remobilization processes are associated to co-mobilization with natural colloids. PMID- 30021177 TI - A new framework to estimate spatio-temporal ammonia emissions due to nitrogen fertilization in France. AB - In France, agriculture is responsible for 98% of ammonia (NH3) emissions with over 50% caused by nitrogen (N) fertilization. The current French national inventory is based on default emission factors (EF) and does not account for the main variables influencing NH3 emissions. To model the spatio-temporal variability of NH3 emissions due to mineral and organic N fertilization, we implemented a new method named CADASTRE_NH3. The novelty lies in the combined use of two types of resources: the process-based Volt'Air model and geo-referenced and temporally explicit databases for soil properties, meteorological conditions and N fertilization. Simulation units are the Small Agricultural Regions. Several sources of information were combined to obtain N fertilization management: census and surveys of the French Ministry of Agriculture, statistics on commercial fertilizer deliveries, and French expertise on physicochemical properties of organic manure. The practical interest of this new framework was illustrated for France during the crop year 2005/06. Aggregation at crop year level showed a reasonable agreement between estimated values derived from CADASTRE_NH3 and those from the French inventory method, for N and ammoniacal-N (TAN) application rates, total NH3 emissions and NH3 EF. Discrepancies were large for organic manure only; national TAN application rates and NH3 emissions were 62-63% lower with CADASTRE_NH3. This was due to divergences in the representation of cattle farm yard manure and in the TAN:N ratio of solid manure. Annual emissions for fertilization in France were estimated to be 270 Gg NH3, 29% lower than the French national inventory estimate. At the regional level, organic manure contributed to 73% of field NH3 emissions in intensive livestock husbandry areas and to 41% in the other areas. The CADASTRE_NH3 framework can be seen as a Tier 3 approach able to estimate specific regional EF for different mineral fertilizers and organic manure. PMID- 30021178 TI - Homelessness in the child welfare system: A randomized controlled trial to assess the impact of housing subsidies on foster care placements and costs. AB - Inadequate housing and homelessness among families represent a substantial challenge for child and adolescent well-being. Child welfare services confront housing that threatens placement into foster care with little resources and evidence to guide practice. The present study provides the first rigorous test of the Family Unification Program (FUP) - a federal program that offers housing subsidies for inadequately housed families under investigation for child maltreatment. A randomized controlled trial assesses program impact on foster care placement and costs. The experiment referred intact child welfare-involved families whose inadequate housing threatened foster placement in Chicago, IL to FUP plus housing advocacy (n = 89 families with 257 children) or housing advocacy alone (n = 89 families with 257 children). Families were referred from 2011 to 2013, and administrative data recorded dates and costs of foster placements over a 3-year follow-up. Intent-to-treat analyses suggested families randomly assigned for FUP exhibited slower increases in rates of foster placement following housing intervention compared with families referred for housing advocacy alone. The program generates average savings of nearly $500 per family per year to the foster care system. Housing subsidies provide the foster care system small but significant benefits for keeping homeless families together. Findings inform the design of a coordinated child welfare response to housing insecurity. PMID- 30021179 TI - Metabolite profiling and gene expression of Na/K transporter analyses reveal mechanisms of the difference in salt tolerance between barley and rice. AB - Barley (Hordeum vulgare) and rice (Oryza sativa) differ greatly in their salt tolerance, although both species belong to the Poaceae family. To understand the mechanisms in the difference of salt tolerance between the two species, the responses of ionome, metabolome and gene expression of Na and K transporters to the different salt treatments were analyzed using 4 barley and 4 rice genotypes differing in salt tolerance. In comparison with 4 rice genotypes, four barley genotypes showed better plant growth, lower shoot Na concentration and higher K concentration at the 9 day after salt treatments. There was a dramatic difference in absolute expression levels of SOS, HKT and NHX family genes between barley and rice, which might account for their difference in Na/K homeostasis and salt tolerance. Moreover, rice leaves accumulated excess Na under salt treatments, which caused serious damages to physiological metabolisms based on metabolomic analysis, but barley leaves had lower Na concentration and small changes in the most metabolites. These results provide useful insights into the molecular mechanism in the difference of salt tolerance between rice and barley. PMID- 30021180 TI - PreScription: Factors Related to Drug Waste and Pharmacy Solutions. PMID- 30021181 TI - Compounded Low-dose Naltrexone for the Treatment of Guttate Psoriasis: A Case Report. AB - The ancient autoimmune skin condition psoriasis is still ubiquitous worldwide, produces the same, often-intolerable effects noted in its earliest recorded descriptions, and remains without cure. Management options designed to resolve the itchy, scaly, weeping, erythematous, and often widespread lesions of that disorder are now available, but they vary in efficacy, most are associated with the development of severe adverse effects, and many are prohibitively expensive. In this article, we describe the successful use of a compounded formulation of oral low-dose naltrexone to manage guttate psoriasis in a 75-year-old white male patient. That therapy produced only 1 adverse effect (dry skin near the lesions on the patient's arms and legs) and was relatively inexpensive. The formulation for that preparation and comments from the patient, the pharmacist who suggested its use, the prescriber, and the compounder who prepared it are included. Many clinicians are unaware of the benefits of compounded low-dose naltrexone in treating autoimmune diseases. We hope that this case report will encourage compounding pharmacists to consider and suggest it as an alternative therapy for patients who cannot tolerate or afford manufactured medications to treat psoriasis. PMID- 30021182 TI - Compounding from a Pharmacy Student's Perspective. AB - The International Academy of Compounding Pharmacists' Foundation held a student essay contest in the Spring of 2018. Two great submissions were chosen to receive an award. This article features one of the chosen essays, which discusses the benefits that compounding pharmacies/pharmacists offer patients and discusses the importance and advantages of owning/operating a compounding pharmacy. PMID- 30021183 TI - The History, Symptoms, Causes, Risk Factors, Types, Diagnosis, Treatments, and Prevention of Gout, Part 1. AB - Gout, a common and complex form of inflammatory arthritis, is characterized by abnormally elevated levels of uric acid in the blood. It is estimated that 52.5 million people in the U.S. have arthritis or one of the rheumatic diseases, according to the Centers for Disease Control and Prevention. There are over 100 rheumatic diseases and conditions. In the U.S., the most common types of arthritis or rheumatic diseases are osteoarthritis, gout, fibromyalgia, and rheumatoid arthritis, in that order according to prevalence. This article focuses on gout. Although there is no cure for gout, the disease can be effectively treated and managed with a combination of medication (manufactured and/or compounded) and self-management strategies. PMID- 30021184 TI - Quality Control: Water Activity Considerations for Beyond-use Dates. AB - There are minimum levels of water activity that are required for growth of bacteria and molds. Water activity is the ratio of vapor pressure of water in a product to pure water at the same temperature. Pure distilled water has a water activity of 1. Water activity is also a measure of water in a material that is available to react with or attach itself to other material; it is also called "free" water while the unavailable water is called "bound" water. Higher water activity substances tend to support more microorganisms; bacteria usually require water activity values of at least 0.91 and fungi at least 0.6. Every microorganism has a limit of water activity below which it will not grow. To lower water activity, one can add or change the concentrations of ingredients such as sodium chloride, sucrose, alcohol, propylene glycol, or glycerin so the preparation becomes self-preserving. Also, if the preparation has too high a water activity and the addition of other substances to lower the water activity, then a preservative may be required for the preparation. Nonaqueous liquids or dry solids will not support spore germination or microbial growth due to their low water activity. PMID- 30021185 TI - Basics of Compounding--Nonsterile: Compounding Self-emulsifying Drug Delivery Systems and Other Self-emulsifying Lipid Formulations, Part 2. AB - Self-emulsifying Drug Delivery Systems are being introduced and are increasing in popularity for improving the solubility of lipophilic drugs. They are isotropic mixtures of drug, oil, surfactant and/or cosurfactant, and sometimes cosolvents. There is some overlap of this discussion in the March-April 2018 issue of the International Journal of Pharmaceutical Compounding in an article on the discussion of microemulsions. Self-emulsifying Drug Delivery Systems can be orally administered in hard-gelatin capsules so they can be appropriate for compounding after the formulation has been developed. Their primary advantages include enhanced solubility and bioavailability for lipophilic drugs that provide formulation challenges. Part 1 of this 2-part article was presented in the May June 2018 issue of the International Journal of Pharmaceutical Compounding, which included a discussion on the three main types of Self-emulsifying Drug Delivery Systems. The conclusion of this 2-part article is presented in this issue with additional discussions on the topics of 1) dosage forms utilizing Self emulsifying Drug Delivery Systems, 2) characterization of Self-emulsifying Drug Delivery Systems, and 3) example formulas for Self-nano-emulsifying Drug Delivery Systems and Self-micro-emulsifying Drug Delivery Systems. As will be seen in this 2-part series, there are numerous dosage forms in which Self-emulsifying Drug Delivery Systems can be incorporated. PMID- 30021186 TI - Basics of Sterile Compounding: Criteria for Determining Beyond-use Dating. AB - Compounding pharmacists must separately and collectively evaluate multiple aspects of a compounded sterile preparation when determining their beyond-use date. Considerations include the microbiological risk level, storage temperature, chemical stability, batch size, and whether or not a sterility test will be performed. The United States Pharmacopeia Chapter <797> provides guidance on the maximum beyond-use date allowed solely based on the microbiological risk level associated with the compounding of a sterile preparation. Compounders should select the shortest beyond-use date between the risk-level based beyond-use date and the chemical stability of the compound. When compounding pharmacists intend to provide a compounded sterile preparation with a beyond-use date that exceeds the risk-level based recommendations in United States Pharmacopeia Chapter <797>, they must ensure that their formulations are sterility tested in compliance with United States Pharmacopeia Chapter <71>. United States Pharmacopeia Chapter <71> compliance includes conducting method suitability that is applicable to the strength and batch size that they plan to prepare. Chemical stability must be a separate consideration for each formulation. PMID- 30021187 TI - Stability of Extemporaneously Prepared Sodium Benzoate Oral Suspension. AB - The stability of extemporaneously prepared sodium benzoate oral suspension in cherry syrup and Ora-Sweet was studied. Oral solutions of 250-mg/mL sodium benzoate were prepared in either cherry syrup or Ora-Sweet. To a beaker, 50 grams of Sodium Benzoate Powder USP was dissolved and filtered, the solution was divided equally into two parts, and each aliquot was added into two separate calibrated 100-mL amber vials. In the first vial, cherry syrup was added to make a final volume of 100 mL. In the second vial, Ora-Sweet was added to give a final volume of 100 mL. This process was repeated to prepare three solutions of each kind and all were stored at room temperature. A 250-uL sample was withdrawn immediately after preparation and again at 7, 14, 28, 60, and 90 days for each sample. At each time point, further dilution was made to an expected concentration of 0.25 mg/mL with sample diluent, and the samples were assayed in triplicate by stability-indicating high-performance liquid chromatography. Stability was defined as the retention of at least 90% of the initial concentration. At least 92% of the initial concentration of sodium benzoate in cherry syrup and at least 96% of the sodium benzoate in Ora-Sweet remained throughout the 90-day study period. There were no detectable changes in color and no visible microbial growth in any sample. Extemporaneously compounded suspensions of sodium benzoate in cherry syrup or Ora-Sweet were stable for at least 90 days when stored in a 4-oz amber plastic bottle at room temperature in reduced lighting. PMID- 30021188 TI - Kinetics of Tetracaine Solvolysis in Propylene Glycol. AB - Tetracaine is a potent ester-type local anesthetic. Recent publications describe the use of TC free base in topical anesthetic formulations containing propylene glycol. While solvolysis of tetracaine in propylene glycol solutions has been reported, there are no detailed reports on the kinetics of tetracaine reaction with propylene glycol. The objectives of the study were to characterize the kinetics and temperature dependence of tetracaine solvolysis in PG solutions. In this study, products of tetracaine degradation in propylene glycol solution at 60 degrees C were collected and analyzed by high-performance liquid chromatographymass spectrometry and nuclear magnetic resonance. The kinetics of tetracaine reaction with propylene glycol was studied at 22 degrees C, 30 degrees C, 40 degrees C, and 60 degrees C. The reaction of tetracaine with n-propanol and isopropanol was also studied. Analysis was performed by high-performance liquid chromatography-mass spectrometry with ultraviolet detection using a gradient elution method. Tetracaine concentrations were quantitated using a four-point standard curve. Tetracaine degradation rates were consistent with apparent first order kinetics at all temperatures studied. The data indicated that tetracaine degrades via transesterification with propylene glycol. The rate constants ranged from 2.26 x 10-3 d-1 at 22 degrees C to 7.06 x 10-2 d-1 at 60 degrees C. Arrhenius analysis indicated an activation energy for the reaction of 74.1 kJ/mol, which is similar to published values for the hydrolysis of pharmaceutical esters. PMID- 30021189 TI - Long-term Physicochemical Stability of Concentrated Solutions of Noradrenaline Bitartrate in Polypropylene Syringes for Administration in the Intensive Care Unit. AB - Intensive care units use drug solutions within higher concentrations to avoid fluid overload. The purpose of this study was to evaluate the physicochemical stability of concentrated solutions of noradrenaline bitartrate in polypropylene syringes during 30 days of storage at 5 degrees C +/- 3 degrees C. Five 50-mL syringes containing 0.240 mg/mL of noradrenaline bitartrate in 0.9% sodium chloride were prepared and stored at 5 degrees C +/- 3 degrees C during 30 days. Immediately after preparation and periodically during the storage, noradrenaline concentrations were measured by high-performance liquid chromatography. Spectrophotometric absorbance at different wavelengths, pH measurement, and microscopic observations were also performed. The results showed that all solutions were physicochemically stable during the entire storage period at 5 degrees C +/- 3 degrees C, and no color change, turbidity, precipitation, opacity, significant pH variations, nor optic densities were observed. Microscopic analysis was used to determine if there was any formation of crystals. The concentration of noradrenaline was not found to decrease during the 30 days of storage. Solutions of noradrenaline bitartrate 0.240 mg/mL in syringes of 0.9% sodium chloride were physically and chemically stable for at least 30 days when stored in syringes at 5 degrees C +/- 3 degrees C and may be prepared in advanced by a centralized intravenous additive service. PMID- 30021190 TI - Comparative Stability of Vitamin K1 Oral Liquids Prepared in Sterile Water for Injection and Stored in Amber Glass Bottles and Amber Plastic Syringes. AB - The purpose of this study was to evaluate the stability of vitamin K1 oral liquids in Sterile Water for Injection when stored in amber glass bottles and amber plastic syringes under refrigerated conditions. Four 100-mL batches of vitamin K1 in Sterile Water for Injection were prepared in amber glass bottles to protect from light. One of the batches was divided into 1-mL aliquots, using amber plastic oral syringes, and capped. The prepared bottles and syringes were stored in a laboratory refrigerator. On each day of sampling, 1-mL aliquots were removed from each bottle and mixed with an equal volume of ethanol. Likewise, the contents of sample syringes were mixed with ethanol to achieve an assay concentration of 0.5 mg/mL. Recovery of vitamin K1 in the compounded samples was quantified against a United States Pharmacopeia reference standard. Quantification was achieved using a stability-indicating high-performance liquid chromatography with ultraviolent light detection method. Product stability is defined as 90% to 110% of the initial concentration. The percent recovery in the Sterile Water for Injection preparations in glass bottles remained above 90% for the 105-day duration of the study, but some samples stored in amber plastic syringes fell below 90% on day 21. Furthermore, a statistically significant difference (2-way ANOVA, P < 0.0001) emerged between syringes at day 0 and day 30, and this trend continued through the day 60, 90, and 105 samples. The only statistically significant difference found within the bottle-stored samples occurred on day 105 (versus zero, P = 0.0465), but the recovery on day 105 still exceeded 90%. Vitamin K1 in Sterile Water for Injection, stored in a refrigerated amber glass bottle, is stable for 105 days. This preparation can also be stored in amber plastic syringes, but this decreases the beyond-use date to 14 days. PMID- 30021191 TI - Antineoplastic Drug Contamination on the Outside of Prepared Infusion Bags. AB - Eight Dutch hospital pharmacies took wipe samples of prepared infusion bags containing 5 fluorouracil just before distribution to the wards. The samples were tested with high-performance liquid chromatography and triple quadrupole mass spectroscopy. The limit of detection was 10 ng per swipe. None of the 146 samples had a detectable amount of 5-fluorouracil. The outside of infusion bags containing antineoplastic drugs prepared in these eight Dutch hospital pharmacies were not contaminated and, therefore, were not a risk factor with regard to exposure of hospital workers to antineoplastic drugs. PMID- 30021192 TI - Association Between Hypoxia-Inducible Factor-2alpha (HIF-2alpha) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis. AB - BACKGROUND/AIMS: Although some studies showed that HIF-2alpha expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2alpha expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2alpha expression in CRC. METHODS: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information. RESULTS: HIF-2alpha protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, P < 0.001), higher in male than female CRC patients (OR = 1.47, P = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, P = 0.029). TSA verified the reliability of the above results. HIF-2alpha expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2alpha alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2alpha and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2alpha expression and DFS in other cancers, but HIF-2alpha expression was correlated with a worse DFS of CRC (HR = 1.23, P = 0.037). Moreover, HIF-2alpha expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs < 1, Ps < 0.05). CONCLUSIONS: HIF-2alpha expression may be associated with the carcinogenesis of CRC, which is higher in males than in females, negatively linked to tumor differentiation, and correlated with a worse DFS of CRC. Additional prospective studies are needed. PMID- 30021193 TI - The Role of Canonical Wnt Signaling in Regulating Radioresistance. AB - Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy. PMID- 30021194 TI - Trough-Shaped Audiograms Are Common in Patients with Acoustic Neuroma and Sudden Sensorineural Hearing Loss. AB - Acoustic neuroma sometimes presents with sudden-onset sensorineural hearing loss as a primary symptom. We investigated 848 untreated cases that included 20 cases with acoustic neuroma with sudden-onset sensorineural hearing loss and 828 cases without acoustic neuroma. Fourteen of the 20 acoustic neuroma and 90 of the 828 cases of sudden-onset sensorineural hearing loss showed a trough-shaped audiogram with the greatest amount of hearing loss in the mid-frequency range. The incidence of a trough-shaped audiogram was significantly higher in patients with acoustic neuroma than in those without (p < 0.01). This study suggests that a trough audiogram is a significant finding in patients with sudden-onset sensorineural hearing loss and indicates the presence of acoustic neuroma. PMID- 30021195 TI - Na+-Leak Channel, Non-Selective (NALCN) Regulates Myometrial Excitability and Facilitates Successful Parturition. AB - BACKGROUND/AIMS: Uterine contractility is controlled by electrical signals generated by myometrial smooth muscle cells. Because aberrant electrical signaling may cause inefficient uterine contractions and poor reproductive outcomes, there is great interest in defining the ion channels that regulate uterine excitability. In human myometrium, the Na+ leak channel, non-selective (NALCN) contributes to a gadolinium-sensitive, Na+-dependent leak current. The aim of this study was to determine the role of NALCN in regulating uterine excitability and examine its involvement in parturition. METHODS: Wildtype C57BL/6J mice underwent timed-mating and NALCN uterine expression was measured at several time points across pregnancy including pregnancy days 7, 10, 14, 18 and 19. Sharp electrode current clamp was used to measure uterine excitability at these same time points. To determine NALCN's contribution to myometrial excitability and pregnancy outcomes, we created smooth-muscle-specific NALCN knockout mice by crossing NALCNfx/fx mice with myosin heavy chain Cre (MHCCreeGFP) mice. Parturition outcomes were assessed by observation via surveillance video recording cre control, flox control, smNALCN+/-, and smNALCN-/ mice. Myometrial excitability was compared between pregnancy day 19 flox controls and smNALCN-/- mice. RESULTS: We found that in the mouse uterus, NALCN protein levels were high early in pregnancy, decreased in mid and late pregnancy, and then increased in labor and postpartum. Sharp electrode current clamp recordings of mouse longitudinal myometrial samples from pregnancy days 7, 10, 14, 18, and 19 revealed day-dependent increases in burst duration and interval and decreases in spike density. NALCN smooth muscle knockout mice had reduced myometrial excitability exemplified by shortened action potential bursts, and an increased rate of abnormal labor, including prolonged and dysfunctional labor. CONCLUSIONS: Together, our findings demonstrate that the Na+ conducting channel NALCN contributes to the myometrial action potential waveform and is important for successful labor outcomes. PMID- 30021196 TI - LncRNA NEAT1 Promotes Deterioration of Hepatocellular Carcinoma Based on In Vitro Experiments, Data Mining, and RT-qPCR Analysis. AB - BACKGROUND/AIMS: Accumulated evidence indicates that lncRNA NEAT1 has important roles in various malignant tumors. In this study, we conducted a comprehensive analysis to explore the exact role of NEAT1 in hepatocellular carcinoma (HCC). METHODS: The effects of NEAT1 on cell proliferation, apoptosis, migration, and invasion were measured by in vitro experiments. The expression level and clinical value of NEAT1 in HCC was evaluated based on data from The Cancer Genome Atlas (TCGA), Oncomine, and in-house real-time quantitative (RT-qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses were conducted to investigate the potential molecular mechanisms of NEAT1. RESULTS: NEAT1 siRNA not only inhibited proliferation, migration, and invasion of HCC cells but also induced HCC cell apoptosis. A total of four records from TCGA, Oncomine, and RT-qPCR analysis were combined to assess the expression level of NEAT1 in HCC. The pooled standard mean deviation (SMD) indicated that NEAT1 was up-regulated in HCC (SMD = 0.54; 95% CI, 0.36-0.73; P < 0.0001). The area under the curve value of the summary receiver operating characteristic curve was 0.71. NEAT1 expression was also related to race (P = 0.025) and distant metastasis (P = 0.002). Additionally, the results of GO, KEGG pathway, and PPI network analyses suggest that NEAT1 may promote the progression of HCC by interacting with several tumor-related genes (SP1, MDM4, CREBBP, TRAF5, CASP8, TRAF1, KAT2A, and HIST4H4). CONCLUSIONS: NEAT1 contributes to the deterioration of HCC and provides a potential biomarker for the diagnosis and therapy of HCC. PMID- 30021197 TI - MiR-298 Exacerbates Ischemia/Reperfusion Injury Following Ischemic Stroke by Targeting Act1. AB - BACKGROUND/AIMS: This study investigated the role of the microRNA miR-298 and its target Act1 in ischemic stroke. METHODS: Cell viability was assessed with the 3 (4,5-dimethythiazol-2- yl)-2,5-diphenyl tetrazolium bromide assay. Apoptotic cells were detected by flow cytometry, and mRNA and protein expression were assessed by quantitative real-time PCR and western blotting, respectively. The regulatory relationship between miR-298 and Act1 was evaluated with the luciferase assay. To clarify the role of Act1 following ischemic stroke, the transcript was knocked down by short interfering RNA. The in vitro findings were validated in a mouse model of middle cerebral artery occlusion by administration of miR-298 mimic. RESULTS: Act1 was upregulated whereas miR-298 was downregulated in ischemic stroke. miR-298 overexpression by transfection of a mimic suppressed Act1 protein levels in vitro and in vivo, and the luciferase assay showed that miR-298 directly binds to the 3' untranslated region of the Act1 transcript. miR 298 overexpression enhanced cell apoptosis and autophagy and exacerbated ischemic infarction and neurological deficits, effects that were exerted via negative regulation of Act1/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-kappaB signaling and downstream autophagy pathways. CONCLUSIONS: Upregulation of miR-298 following ischemic stroke promotes brain injury in vitro and vivo by inhibiting the Act1/JNK/NF-kappaB signaling cascade and the downstream autophagy pathway. Therapeutic strategies that target miR-298 could be beneficial for the treatment of ischemic stroke. PMID- 30021198 TI - Ergosterol Attenuates LPS-Induced Myocardial Injury by Modulating Oxidative Stress and Apoptosis in Rats. AB - BACKGROUND/AIMS: Ergosterol (ER) is the primary sterol found in fungi and is named after the ergot fungus. A variety of pharmacological activities have been reported for ER, including antioxidative, anti-proliferative, and anti inflammatory effects, although its role in sepsis remains unclear. METHODS: The protective effect of ER on lipopolysaccharide (LPS)-induced sepsis myocardial injury was evaluated both in vivo and in vitro. Rats were pretreated with ER and then with LPS. Histopathology of heart tissues was first performed. Subsequently, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), creatine kinase MB fraction (CK-MB), and lactate dehydrogenase (LDH) in serum and heart tissues were assessed by enzyme-linked immunosorbent assay kits. Western blotting was further used to evaluate the expression of antioxidant proteins (HO-1 and cytochrome c) and apoptosis associated proteins (Bcl-2, Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP). In addition, the effects of ER on oxidative stress biomarkers and apoptosis proteins were also detected in LPS-treated H9C2 cells. Moreover, small interfering Nrf2 RNA was transfected to H9C2 cells to study the role of Nrf2 signaling in connection with the protective effects of ER. RESULTS: Pretreatment with ER ameliorated the histopathological changes in heart tissue induced by LPS injection, increased SOD activity, and reduced MDA content, and CK-MB and LDH levels. Furthermore, ER restored the expression of Nrf-2 and HO 1 in rat hearts, attenuating apoptotic damage via up-regulation of Bcl-2 in combination with the inhibition of Bax, cytochrome c, cleaved-caspase-3 and 9, and PARP, as revealed by western blot. When Nrf2 was blocked by siRNA, the effects of ER on SOD and MDA activity, as well as the expression of the antioxidant proteins and apoptosis-associated proteins were abolished. CONCLUSIONS: We demonstrated that ER has a cardioprotective effect in LPS-induced sepsis model through modulation of the antioxidant activity and anti-apoptosis effects and this process might be regulated by Nrf2 signaling. PMID- 30021200 TI - Chlorhexidine, a Matrix Metalloproteinase Inhibitor and the Development of Secondary Caries Wall Lesions in a Microcosm Biofilm Model. AB - This study investigated the role of a matrix metalloproteinase (MMP) inhibitor (CHX 2%) in the development of secondary caries wall lesions in different interface conditions with small (run 1) and wider gaps (run 2). Dentin discs were restored and pretreated with or without CHX 2%. In run 1, interfaces were made with gaps of 30, 60, or 90 um. Interfaces with composite placed directly onto the dentin were either bonded (Adper Single Bond 2) or not bonded. In run 2, interfaces were made with gaps of 100 um, with or without adhesive on the composite side (CLEARFIL SE Bond). Interfaces were either bonded or not bonded, as in run 1. Microcosm biofilms were grown on dentin-composite samples for 14 days. Caries lesion outcomes were analyzed by transversal wavelength-independent microradiography at 3 locations: the outer surface, and the interface wall at a distance of 200 and 500 um from the gap entrance. Linear regression analyses showed that pretreatment with MMP inhibitor did not influence progression of the wall lesion at any location (p >= 0.218). Interfaces with intentional gaps showed positive and significant effect on the wall lesion progression at 200 um from the gap entrance (p <= 0.005). A small trend of increase in wall lesion development was observed at the 200-um location when bonding was present on the composite side. In conclusion, the dentin pretreatment with CHX 2% was not able to slow down the development of secondary caries wall lesions in small and wide gaps in this biofilm model. PMID- 30021199 TI - MiR-4319 Suppress the Malignancy of Triple-Negative Breast Cancer by Regulating Self-Renewal and Tumorigenesis of Stem Cells. AB - BACKGROUND/AIMS: High levels of cancer stem cells (CSCs) in patients with triple negative breast cancer (TNBC) correlate with risk of poor clinical outcome and possibly contribute to chemoresistance and metastasis in patients with highly malignant TNBC. Aberrant microRNA expression is associated with the dysfunction of self-renewal and proliferation in cancer stem cells, while there is little information about the TNBC-specific microRNAs in regulating CSC ability. METHODS: Solexa deep sequencing was performed to detect the expression levels of TNBC or non-TNBC stem cells (CSCs) microRNAs. Mammosphere formation assay, qRT-PCR and the xenograft model in nude mice were performed. Bioinformatic analysis and microarray were used to select the target gene, and luciferase reporter assays were used to confirm the binding sites. RESULTS: Solexa sequencing data exhibited differential expression of 193 microRNAs between TNBC and non-TNBC stem cells. The gene ontology analysis and pathways analyses showed that genes were involved in the maintenance of stemness. MiR-4319 could suppress the self-renewal and formation of tumorspheres in TNBC CSCs through E2F2, and also inhibited tumor initiation and metastasis in vivo. Moreover, increased E2F2 could reverse the effect of miR-4319 on the self-renewal in TNBC CSCs. CONCLUSIONS: MiR-4319 suppresses the malignancy of TNBC by regulating self-renewal and tumorigenesis of stem cells and might be a remarkable prognostic factor or therapeutic target for patients with TNBC. PMID- 30021201 TI - The Relationship of Pollen Dispersal with Allergy Symptoms and Immunotherapy: Allergen Immunotherapy Improves Symptoms in the Late Period of Japanese Cedar Pollen Dispersal. AB - BACKGROUND: The severity of symptoms of pollen-induced allergic rhinitis is affected by the amount of scattered pollen. However, the relationships between the pollen dispersal pattern, symptom severity, and treatment efficacy are not clear. METHODS: Between 2007 and 2012, we performed 4 randomized, placebo controlled studies of sublingual immunotherapy (SLIT) on patients with Japanese cedar-induced allergic rhinitis who lived in or around Chiba, Japan. The participants were asked to avoid using rescue medicines during the cedar pollen season as much as possible and to record their nasal symptoms in allergy diaries. The amount of pollen dispersed daily was quantified using the Durham method, and the season was divided into early and late periods based on the pollen count. RESULTS: A total of 721 patients were enrolled in the 4 studies during the 6-year study period. In the placebo group (n = 349), a correlation was observed between the amount of pollen dispersed and the severity of symptoms in the early but not late period of pollen dispersal. Treatment with SLIT (n = 372) significantly improved symptom severity in the late but not early period. CONCLUSION: For patients with Japanese cedar pollen-induced allergic rhinitis, the fluctuation of daily pollen dispersal had a minimal effect on the severity of symptoms during the late period. SLIT was remarkably effective in alleviating symptoms during this period but not in the early period. PMID- 30021202 TI - Single-Centre Experience of Testosterone Therapy for Boys with Hypogonadism. AB - BACKGROUND: Hypogonadism in boys is one of the commonest conditions encountered in paediatric endocrinology. AIMS: To study variations in management in a contemporary group of boys at a single specialist centre. METHODS: Retrospective review of case records of all boys treated with testosterone at a tertiary endocrine service from 2012 to 2017. RESULTS: Of the 358 boys reviewed for hypogonadism, 46 (13%) were initiated on testosterone therapy at a median age (range) of 14.2 years (12.1, 17.7). Indications for therapy included a functional delay of puberty that was constitutional in 17 (37%) or related to chronic disease in 10 (22%) or organic hypogonadism due to primary gonadal failure in 7 (15%), multiple pituitary hormone deficiency in 6 (13%), and isolated hypogonadotropic hypogonadism in 6 (13%). Of the 46 boys, 40 (89%) were started on intramuscular testosterone, 4 (9%) on oral testosterone, and 1 (2%) on transdermal gel. Of the 19 boys (40%) with organic hypogonadism re-quiring long term therapy, 12 (63%) had assessment of liver function, 6 (32%) had a haematocrit, and 2 (11%) had a DXA scan in the year of commencing treatment. CONCLUSIONS: Testosterone therapy is administered in about 13% of boys reviewed for hypogonadism and its monitoring requires standardisation. PMID- 30021203 TI - NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naive Patients with Chronic Hepatitis C. AB - BACKGROUND: Hepatitis C virus (HCV) NS3 resistance-associated substitutions (RASs) reduce HCV susceptibility to protease inhibitors. Little is known about NS3 RASs in viral isolates from the liver of chronic hepatitis C (CHC) patients infected with HCV genotype-1a (G1a). AIM: The objective of this work was to study NS3 variability in isolates from the serum and liver of HCV-G1a-infected patients naive to direct-acting antivirals (DAAs). METHODS: NS3 variability of HCV-G1a isolates from the serum and liver of 11 naive CHC patients, and from sera of an additional 20 naive CHC patients, was investigated by next-generation sequencing. RESULTS: At a cutoff of 1%, NS3 RASs were detected in all the samples examined. At a cutoff of 15%, they were found in 54.5% (6/11) and 27.3% (3/11) of the paired liver and serum samples, respectively, and in 22.5% (7/31) of the overall serum samples examined. Twenty-six out of thirty-one (84%) patients showed NS3 variants with multiple RASs. Phylogenetic analysis showed that NS3 sequences clustered within 2 clades, with 10/31 (32.2%) patients infected by clade I, 15/31 (48.8%) by clade II, and 6/31 (19.3%) by both clades. CONCLUSIONS: Though the number of patients examined was limited, NS3 variants with RASs appear to be major components of both intrahepatic and circulating viral quasispecies populations in DAA-naive patients. PMID- 30021204 TI - Ultrasonography and the American Thyroid Association Ultrasound-Based Risk Stratification Tool: Utility in Pediatric and Adolescent Thyroid Nodules. AB - BACKGROUND: Pediatric thyroid nodules are more likely to be malignant compared to those in adults and may have different concerning ultrasound (US) features. Recent adult guidelines stratify malignancy risk by US features. Our aim is to (1) describe and confirm US features that predict pediatric malignancy, and (2) apply the Adult American Thyroid Association (ATA) Risk Stratification Guidelines to a large pediatric cohort. METHODS: We identified 112 children with 145 thyroid nodules from 1996 to 2015. Two blinded pediatric radiologists independently read all US images, described multiple features, and reported their overall impression: benign, indeterminate, or malignant. Each nodule was assigned an ATA risk stratification category. Radiologists' impressions and ATA risk stratification were compared to histology and cytology results. RESULTS: Multiple US features including a solid composition, presence of microcalcifications, irregular margins, increased blood flow, and hypoechogenicity were associated with increased odds of malignancy. ATA risk stratification correlated with the radiologists' overall impression (p < 0.001). The sensitivity for detecting malignancy was comparable between both ATA stratification (91%) and the radiologists' overall impression (90%). The specificity of the radiologists' malignant overall impression (80%) was better compared to the ATA high risk stratification (54%). CONCLUSIONS: At our institution, pediatric radiologists' overall impressions had similar sensitivity but better specificity for detecting malignancy than the ATA risk stratification tool by our convention. However, neither US-based methods perfectly discriminated benign from malignant nodules, supporting the continued need for fine needle aspiration for suspicious nodules. Further work is needed to develop an US-based scoring system specific to pediatric patients. PMID- 30021205 TI - External Validation and Clinical Usefulness of First Trimester Prediction Models for the Risk of Preeclampsia: A Prospective Cohort Study. AB - INTRODUCTION: This study assessed the external validity of all published first trimester prediction models for the risk of preeclampsia (PE) based on routinely collected maternal predictors. Moreover, the potential utility of the best performing models in clinical practice was evaluated. MATERIAL AND METHODS: Ten prediction models were systematically selected from the literature. We performed a multicenter prospective cohort study in the Netherlands between July 1, 2013, and December 31, 2015. Eligible pregnant women completed a web-based questionnaire before 16 weeks' gestation. The outcome PE was established using postpartum questionnaires and medical records. Predictive performance of each model was assessed by means of discrimination (c-statistic) and a calibration plot. Clinical usefulness was evaluated by means of decision curve analysis and by calculating the potential impact at different risk thresholds. RESULTS: The validation cohort contained 2,614 women of whom 76 developed PE (2.9%). Five models showed moderate discriminative performance with c-statistics ranging from 0.73 to 0.77. Adequate calibration was obtained after refitting. The best models were clinically useful over a small range of predicted probabilities. DISCUSSION: Five of the ten included first trimester prediction models for PE showed moderate predictive performance. The best models may provide more benefit compared to risk selection as used in current guidelines. PMID- 30021206 TI - Abnormal Expression of Long Noncoding RNAs in Primary Immune Thrombocytopenia: A Microarray Related Study. AB - BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) are important regulators of biological processes and they contribute to the pathological developments of various diseases, including autoimmune diseases. To gain the further understanding, we estimate the expression of lncRNAs in primary immune thrombocytopenia (ITP). METHODS: In this study, microarray studies were performed to characterize expression profiles of various lncRNAs and mRNAs in blood samples collected from ITP patients. Quantitative real-time PCR (qRT-PCR) was performed to confirm the results, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene ontology analysis were used to provide functional annotations, co expression network construction (CNC) analysis was made to reveal the relations between lncRNAs and their targeted genes. RESULTS: A total of 1177 and 632 lncRNAs were significantly up-regulated or down-regulated, respectively, in "newly diagnosed ITP" patients versus healthy individuals. In addition, 1182 genes and 737 genes were up-regulated or down-regulated, respectively, in "chronic recurrent ITP" patients versus healthy individuals. In a KEGG analysis, "TNF signaling pathway-Homo sapiens (human)" was a key result. In a gene ontology analysis, "Granulocyte macrophage colony-stimulating factor production (GO: 0032604, ontology: Biological process, P = 1.69577E-05)" and "coreceptor activity (GO: 0015026, ontology: molecular function, P = 4.67594E-06)" were the two most critical results. Data from qRT-PCR and receiver operating characteristic curves further demonstrated that ENST00000440492, ENST00000528366, NR_038920, and ENST00000552576 can efficiently distinguish different stages of ITP, especially NR_038920 and ENST00000528366. In a CNC analysis, four lncRNAs were emphasized, and NR_038920 and ENST00000528366 were both associated with proteins with important roles in autoimmune diseases. CONCLUSIONS: These results suggest that lncRNAs act through targeted genes to mediate their functions and to mediate their functions and affect the pathogenesis of ITP. PMID- 30021207 TI - CXCL12 in Patients with Chronic Kidney Disease and Healthy Controls: Relationships to Ambulatory 24-Hour Blood Pressure and Echocardiographic Measures. AB - BACKGROUND/AIMS: Chronic kidney disease is a pro-inflammatory condition where the interplay between different regulatory pathways and immune cells mediates an unfavorable remodeling of the vascular wall and myocardial hypertrophy. These mechanisms include the action of CXCL12. The aim of this study is to evaluate the association between serum CXCL12 with left ventricular hypertrophy (LVH) and blood pressure control in chronic kidney disease (CKD) patients. METHODS: This single-center observational study involved 90 stable CKD stage 1-5 patients (including 33 renal transplant recipients) and 25 healthy age- and sex-matched control subjects. CXCL12 was quantified by ELISA. 24-h ambulatory blood pressure monitoring was performed in 90 patients and 25 healthy controls. Left ventricular mass index (LVMI) was calculated based on the transthoracic echocardiography measurements in 27 patients out of the CKD population and in the whole control group. RESULTS: CXCL12 correlated significantly with LVMI by multivariate regression analysis (coefficient B = 0.33, p = 0.02) together with age (B = 0.30, p = 0.03) and gender (B = 0.41, p = 0.003). A positive correlation was observed between CXCL12 and average 24-h systolic blood pressure (SBP) (rho = 0.35, p = 0.001), daytime SBP (rho = 0.35, p = 0.001), and nocturnal SBP (rho = 0.30, p = 0.002). Nocturnal hypertension was frequent (46% of CKD patients). CONCLUSIONS: The results of our study point towards a link between CXCL12 and LVH as well as blood pressure control among patients with CKD, supporting the thesis that CXCL12 may be regarded as a new potential uremic toxin. PMID- 30021208 TI - Degradation of Monocyte Chemoattractant Protein-1 by Tryptase Co-Released in Immunoglobulin E-Dependent Activation of Primary Human Cultured Mast Cells. AB - BACKGROUND: Mast cells are key immune effector cells which release chemokines, proteases, and other inflammatory mediators upon activation by immunological stimuli. The aim of this study was to investigate the effects of co-releasing proteases on the kinetics of release of the chemokine monocyte chemoattractant protein-1 (MCP-1) in immunoglobulin E (IgE)-mediated activation of human mast cells. METHODS: Homogenous populations of mature and functional primary human mast cells were generated from CD34+ progenitors originated from buffy coats of healthy adult donors. The releases of MCP-1 from human mast cells in basal conditions and in response to FcepsilonRI cross-linking were assessed at different time points. The effects of different types of protease inhibitors on MCP-1 release from these mast cells under stimulated or unstimulated conditions were also investigated. RESULTS: Cultured human mast cells released MCP-1 in basal conditions and its levels increased in a time-dependent manner. When stimulated by FcepsilonRI cross-linking, the levels of MCP-1 detected in the medium gradually decreased over time after the initial peak induction. Such a decline in MCP-1 levels after IgE-dependent activation was completely prevented by pretreatment with a cocktail of protease inhibitors or the specific tryptase inhibitor APC366. CONCLUSIONS: Direct regulation of MCP-1 expression by co release of tryptase in cultured human mast cells upon IgE-dependent activation demonstrates a role of the serglycin:serine protease axis in modulation of inflammatory reactions through proteolytic degradation of mediators such as chemokines. PMID- 30021210 TI - Prevalence and Clinical Profile of Human Salivirus in Children with Acute Gastroenteritis in Northern Italy, 2014-2015. AB - OBJECTIVE: Human Salivirus (SalV) has been associated with gastroenteritis on all continents. METHODS: This paper presents the real-time RT-PCR assay for the detection of SalV in clinical fecal samples collected from 192 hospitalized children with acute gastroenteritis in Piedmont, Italy. RESULTS: The most commonly detected virus was Norovirus genogroup II (GII) (33.8%), followed by Rotavirus (21.3%), Sapovirus (10.9%), Parechovirus (8%), Norovirus GI (6.7%), and Adenovirus (1%). PCR detected SalV in 1 (0.5%) subject. CONCLUSIONS: Our data show that the detection rate of SalV in diarrheal children (0.5%) is lower than that observed in other countries, where it is reported in diarrheal children in 8.6-1.2% of patients. PMID- 30021209 TI - Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington's Disease. AB - BACKGROUND/AIMS: Huntington's disease (HD) is a heritable neurodegenerative disorder, and there is no cure for HD to date. A type of fibroblast growth factor (FGF), FGF9, has been reported to play prosurvival roles in other neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. However, the effects of FGF9 on HD is still unknown. With many similarities in the cellular and pathological mechanisms that eventually cause cell death in neurodegenerative diseases, we hypothesize that FGF9 might provide neuroprotective functions in HD. METHODS: In this study, STHdhQ7/Q7 (WT) and STHdhQ111/Q111 (HD) striatal knock-in cell lines were used to evaluate the neuroprotective effects of FGF9. Cell proliferation, cell death and neuroprotective markers were determined via the MTT assay, propidium iodide staining and Western blotting, respectively. The signaling pathways regulated by FGF9 were demonstrated using Western blotting. Additionally, HD transgenic mouse models were used to further confirm the neuroprotective effects of FGF9 via ELISA, Western blotting and immunostaining. RESULTS: Results show that FGF9 not only enhances cell proliferation, but also alleviates cell death as cells under starvation stress. In addition, FGF9 significantly upregulates glial cell line derived neurotrophic factor (GDNF) and an anti-apoptotic marker, Bcl-xL, and decreases the expression level of an apoptotic marker, cleaved caspase 3. Furthermore, FGF9 functions through ERK, AKT and JNK pathways. Especially, ERK pathway plays a critical role to influence the effects of FGF9 toward cell survival and GDNF production. CONCLUSIONS: These results not only show the neuroprotective effects of FGF9, but also clarify the critical mechanisms in HD cells, further providing an insight for the therapeutic potential of FGF9 in HD. PMID- 30021211 TI - Reference Ranges and Determinants of Tricuspid Regurgitation Velocity in Healthy Adults Assessed by Two-Dimensional Doppler-Echocardiography. AB - BACKGROUND: Tricuspid regurgitation velocity (TRV) is the most widely used parameter by transthoracic echocardiography (TTE) in the evaluation of patients with suspected pulmonary hypertension (PH). OBJECTIVES: To explore the physiologic range of TRV in healthy adults and to investigate its clinical determinants. METHODS: In the first part of the study, 614 healthy individuals (age 45.7+/- 14.7 years, 60.26% women) were prospectively assessed by TTE. In the second part, a pooled meta-analysis of 16 already published studies with TRV values in healthy subjects (n = 981) was performed. Statistical analysis included the calculation of 95% quantiles for defining reference ranges. RESULTS: In the prospectively enrolled cohort, mean TRV was 2.01 +/- 0.29 m/s (5-95% CI 1.987 2.033 m/s). It was significantly but weakly positively correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, left atrial volume and negative with mitral inflow E/A ratio. No significant differences were found between males and females. The prospectively enrolled data revealed similar values to the literature-based datasets resulting in a mean TRV of 1.96 m/s (95% CI 1.91-2.02 m/s) and a 95% quantile of 2.55 m/s. CONCLUSIONS: To the best of our knowledge, this is the largest dataset to describe reference ranges of TRV and their clinical determinants in healthy adults years. The determined cut-off value of 2.55 m/s of this study has to be confirmed in specific pathologies such as patients at risk of PH. PMID- 30021212 TI - Browning of Pig White Preadipocytes by Co-Overexpressing Pig PGC-1alpha and Mice UCP1. AB - BACKGROUND/AIMS: Brown adipose tissue (BAT) is critical for mammals' survival in the cold environment. BAT-dependent non-shivering thermogenesis is attributed to uncoupling protein 1 (UCP1)'s disengagement of oxidative phosphorylation from ATP synthesis and dissipates energy as heat. Thus individuals with a substantial amount of BAT are better equipped during cold stress and less likely to become obese. Recently, our laboratory has shown pig adipocytes have no UCP1 protein. The inability of newborn piglets to generate heat contributed to its high death rate. Repairing the genetic defect of UCP1 in pig adipocytes has implications in defending against cold for piglets and developing an alternative treatment for human obesity. METHODS: Q-PCR, western blotting (WB) and oxygen consumption measurement were used to enable functional UCP1 protein in preadipocytes. Immunoprecipitation (IP), chromatin immunoprecipitation (CHIP), and dual luciferase reporter assay system were used to clarify the thermogenesis mechanism of functional UCP1. RESULTS: Only co-overexpressing mice UCP1 and pig PGC-1alpha increased not only the mitochondrial number but also the uncoupled respiration rate in the transfected pig adipocytes. The functional mice UCP1 increased the pig PGC-1alpha activity through the AMPK-SIRT1 pathway. The active form PGC 1alpha interacted with transcription factors Lhx8, Zic1, ERRalpha, and PPARalpha to regulate the expression of mitochondrial energy metabolism and adipocytes browning-related genes. CONCLUSION: Our data suggest a model in which pig PGC 1alpha and mice UCP1 work collaboratively to restore uncoupling respiration in pig preadipocytes. These results have great implications for piglet survival and developing an alternative treatment for human obesity in the future. PMID- 30021213 TI - Large-Volume Infusions into the Brain: A Comparative Study of Catheter Designs. AB - BACKGROUND/AIMS: "Whole-brain" infusions have emerged as a potential need with the promise of disease-modifying therapies for neurodegenerative diseases. In addition, several current clinical trials in brain cancer utilize direct delivery of drugs that are required to fill large volumes. Such requirements may not be well served by conventional single port catheters with their "point source" of delivery. Our aim is to examine infusions into large volumes of heterogeneous tissue, aiming for uniformity of distribution. METHODS: A porous catheter (porous brain infusion catheter, PBIC), designed by Twin Star TDS LLC, for brain infusions was developed for this study and compared with another convection enhanced delivery catheter (SmartFlowTM NGS-NC-03 from MRI Interventions, a step end-port catheter, SEPC) in current use in clinical trials. The studies were in vivo in porcine brain. A total of 8 pigs were used: the size of the pig brain limited the porous length to 15 mm. The placements of the tips of the two catheters were chosen to be the same (at the respective brain hemispheres). RESULTS: The PBIC and SEPC both performed comparably and well, with the PBIC having some advantage in effecting larger distributions: p ~ 0.045, with 5 infusions from each. CONCLUSIONS: Given the performance of the PBIC, it would be highly appropriate to use the device for therapeutic infusions in human clinical trials to assess its capability for large-volume infusions. PMID- 30021215 TI - The Aging Process Alters IL-1beta and CD63 Levels Differently in Extracellular Vesicles Obtained from the Plasma and Cerebrospinal Fluid. AB - OBJECTIVE(S): The aim of this study was to investigate exosomal markers and inflammatory cargo of extracellular vesicles (EVs) obtained from cerebrospinal fluid (CSF) and plasma in the aging process. We also studied the inflammatory cargo by quantifying IL-1beta levels. METHODS: Male Wistar rats, aged 3 and 21 months, were used (n = 12 in each group). The CSF and plasma of animals were collected, and isolation of EVs was performed using a commercial kit. Total protein concentration, acetylcholinesterase (AChE) activity, and CD63 and IL 1beta levels were evaluated. RESULTS: AChE activity in EVs increased in both samples, specifically in the circulating EVs and those in the CSF of the older group. An age-related increase was observed in CD63 levels in EVs from the CSF but a decrease was observed in plasma EVs of the older group. Student's t test showed that the young adult rats had significantly higher circulating IL-1beta levels in the EVs compared to the aged ones, without any effect on central content. CONCLUSION: Our data suggest that the normal aging process causes different changes in the profiles of central and circulating EVs. Altered IL 1beta levels in circulating EVs can be linked, at least partly, to age-related inflammatory conditions, and a disruption of the CFS exosomes in aged rats, evaluated by CD63 levels, can be related to susceptibility to neurodegenerative disorders. PMID- 30021214 TI - The Need to Distinguish between Bodily Distress Disorder and Somatic Symptom Disorder. PMID- 30021216 TI - Potential Role of Gr-1+ CD8+ T Lymphocytes as a Source of Interferon-gamma and M1/M2 Polarization during the Acute Phase of Murine Legionella pneumophila Pneumonia. AB - In this study, we analyzed interferon (IFN)-gamma-producing cells and M1/M2 macrophage polarization in Legionella pneumophila pneumonia following anti-Gr-1 antibody treatment. Anti-Gr-1 treatment induced an M1-to-M2 shift of macrophage subtypes in the lungs and weakly in the peripheral blood, which was associated with increased mortality in legionella-infected mice. CD8+ T lymphocytes and natural killer cells were the dominant sources of IFN-gamma in the acute phase, and anti-Gr-1 treatment reduced the number of IFN-gamma-producing CD8+ T lymphocytes. In the CD3-gated population, most Gr-1-positive cells were CD8+ T lymphocytes in the lungs and lymph nodes (LNs) of infected mice. Additionally, the number of IFN-gamma-producing Gr-1+ CD8+ T lymphocytes in the lungs and LNs increased 2 and 4 days after L. pneumophila infection, with anti-Gr-1 treatment attenuating these populations. Antibody staining revealed that Gr-1+ CD8+ T lymphocytes were Ly6C-positive cells rather than Ly6G, a phenotype regarded as memory type cells. Furthermore, the adoptive transfer of Gr-1+ CD8+ T lymphocytes induced increases in IFN-gamma, M1 shifting and reduced bacterial number in the Legionella pneumonia model. These data identified Ly6C+ CD8+ T lymphocytes as a source of IFN-gamma in innate immunity and partially associated with reduced IFN gamma production, M2 polarization, and high mortality in anti-Gr-1 antibody treated mice with L. pneumophila pneumonia. PMID- 30021217 TI - Liposomal Curcumin Targeting Endometrial Cancer Through the NF-kappaB Pathway. AB - BACKGROUND/AIMS: Emerging evidence suggests that curcumin possesses chemopreventive properties against various cancers. However, its poor bioavailability limits its clinical application. In this study, we aimed to utilize encapsulation in liposomes (Lipo) as a strategy for the clinical administration of curcumin for endometrial carcinoma (EC). METHODS: Curcumin was encapsulated in a liposomal delivery system to prepare a formulation of liposomal curcumin (LC). EC cell lines Ishikawa and HEC-1 were treated with the compound and cell proliferation was measured using MTT assay. Hoechst 33258 staining assay and flow cytometry were used to detect apoptosis of the cells. Wound healing and cell invasion assays were employed to monitor cell motility. Underlying target signaling, such as NF-kappaB, caspases, and MMPs, were further studied via qRT PCR and western blot. Thereafter, a zebrafish model was used to assess the toxicity of LC. Finally, a zebrafish transplantation tumor model of EC was grown and treated with LC. Tumors were monitored and harvested to study the expression of NF-kappaB. RESULTS: The formation of LC was successfully developed with excellent purity and physical properties. In vitro, LC resulted in dose-dependent inhibition of proliferation, induction of apoptosis, and suppression of Ishikawa and HEC-1 cell motility. LC treatment also suppressed the activation and/or expression of NF-kappaB, caspase-3, and MMP-9. No demonstrable toxicity was found in the zebrafish model and tumors were suppressed after treatment with LC. PCR analysis also showed down-regulated expression of NF-kappaB. CONCLUSIONS: LC was successfully prepared and played biological roles against EC probably through negative regulation of the NF-kappaB pathway in vitro and in vivo, which demonstrates its potential therapeutic effects in EC. PMID- 30021233 TI - [Treatment of end-of-dose fluctuations: the need for an individualized approach]. AB - Patients with Parkinson's disease show a wide heterogeneity of symptoms and comorbidities, requiring individualized therapeutic strategies, particularly in advanced stages of the disease. This is reflected by the choice of different substance classes and drugs for the treatment of end-of-dose fluctuations. Each of these drugs offers a characteristic profile of effects and unwanted side effects, which has to be taken into consideration. Replacement of a substance by an alternative drug under consideration, for instance, of healthcare economics is possible only to a limited extent, since therapeutic effects as well as tolerability in the individual patient must be taken into account. PMID- 30021234 TI - Common Indications and The Diagnostic Yield of Esophagogastroduodenoscopy in Children with Gastrointestinal Distress. AB - BACKGROUND: The number of inconspicuous results of esophagogastroduodenoscopies (EGDs) in childhood appears to be disturbingly high. The aim of this study was to analyze the diagnostic yield of EGD and to determine its relevance of specific clinical indications. METHODS: We performed a retrospective analysis of 380 consecutive pediatric patients who underwent diagnostic EGD in two German level I pediatric gastroenterology departments in 2015 and 2016. RESULTS: 44% of the 380 patients were male and 17% were younger than 5 years old. 55% of all EGDs (n=210) did not yield a pathological result. 27% (n=104) of all EGDs were performed due to nonspecific symptoms (epigastralgia, nausea). Strikingly, in this group, 88% (n=91) showed normal results and in only 12% a diagnosis was made: reflux esophagitis (n=5), Helicobacter pylori (HP) gastritis (n=6) or hemorrhagic gastritis (n=1). Fewer inconspicuous EGDs were performed in patients with dysphagia (68%) or heartburn and reflux (61%). 59 patients were examined due to serologically elevated celiac antibodies. Here, the diagnosis could be confirmed histopathologically in 78% (n=46). Of the 37 patients with abdominal pain and a previously positive non-invasive HP test, EGD served to establish the diagnosis of HP gastritis in 84%. CONCLUSIONS: The diagnostic yield for EGDs is increased in patients with more specific symptoms (i. e. dysphagia, heartburn, HP, celiac disease). Consequently, as an invasive procedure, EGD warrants a strict indication. PMID- 30021236 TI - Homeopathic Treatment of Insomnia and Symptom Clusters Related to Cerebral Chemotoxicity in Oncology. AB - BACKGROUND: During chemotherapy, the correlation between insomnia and fatigue, anxiety, pain, depressed mood, and cognitive disorders makes these subjective complaints a 'symptom cluster' with common biological mechanisms. The theory of cerebral inflammation following the production of pro-inflammatory cytokines (high level of interleukin 1-beta [IL1-beta], IL6 and tumour necrosis factor alpha) is currently the most generally accepted. Understanding these mechanisms should allow us to propose a chemoprotective homeopathic treatment of the nervous system. METHODS: By retaining the inflammatory aetiology, we combined the rubrics 'Inflammation of the brain', 'Inflammation of the meninges', 'Inflammation of the nerves' with the symptom cluster: insomnia, fatigue, depressive state and memory disorders. RESULTS: After repertorisation, we propose the following homeopathic protocol: Belladonna 15c, Phosphorus 15c, Cerebral cortex 4c and Nerves 4c, two pills of each medicine to be sucked together before breakfast, lunch and dinner, on each day of chemotherapy and for the following 2 days. CONCLUSION: This selected protocol, derived from a physiopathological knowledge of the symptoms, seems to be well suited to the prevention and treatment of post-chemotherapeutic cerebral inflammation. It is essential to start the homeopathic treatment before the chemotherapy session to anticipate the emergence of the 'chemo-brain' side effects. This proposed prevention protocol must be confirmed and quantified by randomised studies. PMID- 30021235 TI - Expression of Peroxisome Proliferator-Activated Receptor Alpha (PPARalpha) in Non Somatotroph Pituitary Tumours and the Effects of PPARalpha Agonists on MMQ Cells. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARalpha in additional phenotypes of pituitary adenomas (PA), the relationship between PPARalpha and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARalpha agonists on lactotroph cells. Seventy-five human PA - 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) - were characterised for PPARalpha and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARalpha was expressed in a majority of PA. PPARalpha immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARalpha expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100-200 MUM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARalpha is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARalpha agonists. PMID- 30021237 TI - Correction: Antihypertensive Effect of Polyphenol-Rich Fraction of Azadirachta indica on Nomega-Nitro-L-Arginine Methyl Ester-Induced Hypertension and Cardiorenal Dysfunction. PMID- 30021238 TI - [Current trends in surgery for benign parotid lesions]. AB - Parotidectomy is the standard procedure for treatment of benign parotid tumors. Nowadays, one of the main objectives of surgery is to minimize morbidity. However, the debate about the appropriate surgical technique in parotid surgery is still ongoing. There is a high level of evidence, that limited parotidectomy techniques are associated with fewer complications and especially with lower prevalence of permanent facial nerve palsy and Frey's syndrome. However, limited parotidectomy requires an accurate pre-selection of patients and a precise preoperative diagnostic work-up. This manuscript describes the current trends in surgery for benign parotid lesions and illustrates the treatment options for major post-parotidectomy complications. PMID- 30021239 TI - [Transoral videoendoscopic resection of head-and-neck Tumors in 4-hand technique]. AB - INTRODUCTION: Videoendoscopic surgery in 4-hand technique is a standard procedure in laparoscopic and also in transsphenoidal pituitary operations. In recent years transoral videoendoscopic resection of head and neck tumours in 4-hand technique (TOVR) gained more and more importance. MATERIALS AND METHODS: From March 2013 28 transoral videoendoscopic resections of oropharyngeal (n = 5)-, hypopharyngeal (n = 12) and laryngeal (n = 11) carcinomas in 4-hand technique werde successfully performed. RESULTS: In all 28 cases a R0-resection without extension to a transcervical surgical approach was achieved transorally. Even in patients with minor mobility of the cervical vertebral column (n = 9) and reduced adjustment facilities of the Kleinsasser laryngoscope or Weerda distending laryngoscope transoral tumor resection could be successfully performed with the use of rigid angular optics. CONCLUSION: TOVR is an effective, cheap and minimally invasive surgical procedure featuring numerous advantages compared to CO2 laser resection and can be considered as real alternative for traditional resection methods of head and neck tumours. PMID- 30021240 TI - Innovative Solution for Grasping Forceps Support Suction to Facilitate Uniportal Video-Assisted Thoracoscopic Surgery. AB - Uniportal video-assisted thoracoscopic surgery has been limited to the use of very few instruments, which but at least include energy device, grasping forceps, and suction. The last two instruments must be temporarily replaced by each other in response to situation. This step prolongs operative duration and potentially impairs the surgical efficiency. We describe a novel instrument design of grasping forceps support suction. Its continuous suction can clear the smoke and blood simultaneously to keep the operative field dry and clean, minimize the requirement to exchange surgical devices, and allow for optimized surgical workflow. PMID- 30021241 TI - Mechanical Heart Valve Replacement in a Low-Middle Income Region in the Modern Era: Midterm Results from a Sub-Saharan Center. AB - BACKGROUND: The management of patients with mechanical heart valves remains a major concern in populations with limited resources and medical facilities. This study reports the clinical outcomes of patients who underwent mechanical valve implantation in a sub-Saharan center over an 8-year period. METHODS: A total of 291 mechanical valves were implanted in 233 patients in our institution between February 2008 and June 2016. A total of 117 patients underwent mitral valve replacement (MVR, 50.2%), 57 had aortic valve replacement (AVR, 24.4%), and 59 underwent both AVR and MVR (double valve replacement [DVR], 25.7%). The mean age at surgery was 27.6 +/- 13.4 years (range, 7-62 years). Rheumatic etiology was found in 80.6% of the patients. Hospital mortality, late deaths, and valve related events were reviewed at follow-up (839 patient-years, range: 1-9.4 years, complete in 93%). RESULTS: The 30-day mortality was 4.7% (11/233). The overall survival at 1 and 6 years for the whole cohort was 88.8 +/- 2.1% and 78.7 +/- 3.3%, respectively. The 6-year survival for AVR, MVR, and DVR was 89.3 +/- 4.8%, 73.2 +/- 5.4%, and 79.3 +/- 5.8%, respectively (p = 0.15). The freedom from neurologic events and anticoagulation-related bleeding at 6 years was 93.1 +/- 2.1% and 78.9 +/- 3.7%, respectively. No patient had reoperation at follow-up. No case of prosthetic valve thrombosis was identified. Eight full-term pregnancies were reported. CONCLUSION: This preliminary experience reports acceptable midterm results after mechanical heart valve implantation in our region. Both accurate surgical evaluation and strategies, either financial or social, facilitating patient's education and medical assistance are crucial to ensure good results. Long-term follow-up and further studies comparing current nonthrombogenic options are warranted to draw reliable conclusions. PMID- 30021242 TI - Impact of a novel biopsy instrument with a 25-mm side-notch needle on the detection of prostate cancer in transrectal biopsy. AB - OBJECTIVES: To evaluate the impact of a novel biopsy instrument that extends the length of the side-notch on the detection of prostate cancer in transrectal needle biopsy. METHODS: We collaborated with a biopsy needle manufacturer and developed a novel biopsy instrument (PRIMECUT II long-notch type) with a 25-mm side-notch length and 28-mm stroke length to take longer tissue cores. The sampled core length, cancer detection rate, pain and complications of 489 patients who underwent transrectal biopsy using the long-notch needle were compared with those of 469 patients who underwent biopsy using a normal instrument with a 19-mm side-notch length and 22-mm stroke length. RESULTS: The mean length of tissue taken by the long-notch needle was significantly longer than that of tissue taken by the normal-notch needle (16.3 vs 22.4 mm, P < 0.001). The overall cancer detection rate was 42.0% for the normal-notch needle and 51.1% for the long-notch needle (P = 0.005). In patients with a prostate volume of 20-40 mL, the cancer detection rate for the long-notch needle was especially higher than that for the normal-notch needle (74.2% vs 47.5%, P < 0.001). Multivariate analysis showed that the long-notch needle improved cancer detection significantly (odds ratio 1.702, P < 0.001). There were no differences of pain during biopsy and complication between the two groups. CONCLUSIONS: The novel biopsy instrument with a 25-mm side-notch can take longer tissue samples safely and has a significantly higher rate of prostate cancer detection in transrectal biopsy. PMID- 30021244 TI - Out-of-hospital arrests attending an Australian tertiary paediatric emergency department over 13 years: An observational study. AB - OBJECTIVE: In paediatric cardiopulmonary arrest, International Liaison Committee on Resuscitation (ILCOR) states, 'there are no simple guidelines to determine when resuscitative efforts become futile'. Considerations to assist this decision making include cause of arrest, pre-existing medical conditions, age, site of arrest, duration of untreated cardiopulmonary arrest, witnessed arrest and presence of shockable rhythm. Outcomes are poor in out-of-hospital cardiac arrests (OHCA), particularly for infants. This single-centre observational study describes the characteristics and outcomes of the subgroup of children presenting to our hospital's ED following OHCA still receiving cardiac compressions, to assist development of guidelines for future resuscitation efforts in our ED, particularly for cessation of cardiopulmonary resuscitation (CPR). METHODS: The ED database was searched for children presenting in cardiopulmonary arrest receiving cardiac compressions. Data were reviewed on pre-hospital, ED and hospital management and outcome, particularly looking at considerations outlined by ILCOR. RESULTS: From January 2000 to December 2013, 60 children were identified: median age 1.71 years; 87% arresting at home; 68% with bystander CPR; median CPR duration pre-hospital 42 min, and in ED 19.5 min; total CPR median 61 min. Fifty patients (83%) died in ED, 10 (17%) were admitted to intensive care but all died within 4 days. CONCLUSION: Children presenting to ED still receiving cardiac compressions following OHCA had a universally poor outcome, regardless of age and underlying cause. This implies resuscitative efforts could be discontinued earlier in this subgroup. A national, multicentre study is needed to determine if this finding is reproducible with a larger population. PMID- 30021243 TI - An accelerated nonlocal Poisson-Boltzmann equation solver for electrostatics of biomolecule. AB - The nonlocal modified Poisson-Boltzmann equation (NMPBE) is one important variant of a commonly used dielectric continuum model, the Poisson-Boltzmann equation (PBE), for computing electrostatics of biomolecules. In this paper, an accelerated NMPBE solver is constructed by finite element and finite difference hybrid techniques. It is then programmed as a software package for computing electrostatic solvation and binding free energies for a protein in a symmetric 1:1 ionic solvent. Numerical results validate the new solver and its numerical stability. They also demonstrate that the new solver has much better performance than the corresponding finite element solver in terms of computer CPU time. Furthermore, they show that the binding free energies produced by NMPBE can match chemical experiment data better than those by PBE. PMID- 30021245 TI - Validated uroflowmetry-based predictive model for the primary diagnosis of urethral stricture disease in men. AB - OBJECTIVES: To define a uroflowmetry-based non-invasive predictive tool for the primary diagnosis of urethral stricture disease. METHODS: A total of 300 male patients (150 with urethral stricture disease and 150 with benign prostatic obstruction), treated surgically between 2005 and 2015, and 75 healthy males were included in this study. Patients were randomly assigned to one of two groups (75 benign prostatic obstruction patients and 75 urethral stricture disease patients in each group). A model, able to objectively differentiate between benign prostatic obstruction and urethral stricture disease, was created by use of original and hybrid uroflowmetry variables in logistic regression in group A (test group). Receiver operating characteristics curve analysis was used for validation in group B (validation group) and to calculate cut-off values to distinguish healthy individuals from benign prostatic obstruction as a result of urethral stricture disease. RESULTS: Receiver operating characteristics area under the curve values of the created model were 0.841 (0.777-0.905) and 0.807 (0.735-0.879) in groups A and B, respectively. Optimal cut-off values were 2.2847 and 0.1182 to distinguish healthy individuals versus benign prostatic obstruction and benign prostatic obstruction versus urethral stricture disease. CONCLUSIONS: A triphasic uroflowmetry-based model is able to objectively distinguish voiding patterns of healthy individuals, benign prostatic obstruction and urethral stricture disease. The probability of urethral stricture disease can be objectively calculated for each individual patient based on a non-invasive uroflowmetry test. Uroflowmetry pattern interpretation by use of statistical models could become a new standard. PMID- 30021246 TI - Profile of the Australian College of Optometry low vision clinic. AB - BACKGROUND: The number of Australians living with vision impairment or blindness is expected to increase substantially due to the ageing population and prevalence of age-related eye disease. In response, the Australian College of Optometry (ACO) commenced a low vision clinic in 2013. The ACO is a not-for-profit organisation providing eye-care services to more than 60,000 Victorians per year experiencing economic or social disadvantage. Consultation fees are bulk-billed to the Australian national health care scheme - Medicare - while spectacles and visual aids are subsidised through the state government-funded Victorian Eyecare Service. The aim of this study was to determine the profile and prescribing patterns of the new optometry-led low vision clinic, and report the findings of a short-term loan magnifier pilot study. METHODS: A retrospective audit of 270 patient records was conducted. Additionally, a short-term loan magnifier program was pilot tested to ascertain the demand for, and benefits of, such a program among this cohort. RESULTS: The median age was 77 years (interquartile range 64 to 85 years), with 52 per cent being female. The main cause of vision impairment was age-related macular degeneration (40 per cent). At least one-third primarily spoke a language other than English. The majority (75 per cent) were referred by the optometrist to the onsite consultant occupational therapist for immediate assistance with activities of daily living and onward referral for additional comprehensive services, as required. Of the 49 participants who completed the loan magnifier study, only nine exchanged the magnifier/s initially prescribed. CONCLUSIONS: The ACO has established a low vision service within a large optometry clinic for people experiencing social and economic disadvantage. Where a program of subsidised low-cost magnifiers is available, there is little benefit to short-term loans of magnifiers. Providing basic affordable low vision aids and rehabilitation within a large primary care optometry setting can facilitate acceptability and uptake of low vision services that increase quality of life. PMID- 30021247 TI - Amyloid precursor protein is overexpressed in bladder cancer and contributes to the malignant bladder cancer cell behaviors. AB - OBJECTIVES: To investigate the expression of amyloid precursor protein in bladder cancer, and to study its role in malignant bladder cancer cell behaviors. METHODS: Immunohistochemistry and western blotting analysis were used to detect the amyloid precursor protein level in bladder cancer tissues and cell lines. The effect of amyloid precursor protein on bladder cancer cell proliferation, migration, invasion and cell cycle was evaluated by using small interfering ribonucleic acid. The levels of RAS, RAF, MEK, phosphorylated MEK, extracellular regulated protein kinases, phosphorylated extracellular regulated protein kinases, protein kinase B and phosphorylated protein kinase B were determined by western blot after amyloid precursor protein knockdown. The effect of amyloid precursor protein on the extracellular regulated protein kinases pathway was further evaluated using extracellular regulated protein kinases pathway agonist, ceramide C6. RESULTS: The expression of amyloid precursor protein was significantly increased in the human bladder cancer tissues compared with matched normal bladder tissues. The overexpression of amyloid precursor protein was significantly associated with tumor stage, tumor size, histological grade and lymph node metastasis. The proliferation, migration and invasion of human bladder cancer cells were significantly inhibited by the silencing of amyloid precursor protein. In addition, knockdown of amyloid precursor protein arrested the cell cycle progression of bladder cancer cells in the G2/M phase. Mechanistic analysis showed that knockdown of amyloid precursor protein significantly decreased the phosphorylation of extracellular regulated protein kinases. Ceramide C6 could rescue the malignant bladder cancer cell behaviors inhibited by the silencing of amyloid precursor protein. CONCLUSIONS: Amyloid precursor protein is upregulated in bladder cancer, and might be closely associated with bladder cancer cell growth and survival. Amyloid precursor protein could potentially be used as a therapeutic target for bladder cancer treatment. PMID- 30021249 TI - Correlation of flow complexity parameter with aneurysm rupture status. AB - Ruptured aneurysms are known to have complex flow patterns and concentrated inflow jet, but a quantifiable measure for the degree of flow complexity in patient-specific geometries has not been established. Previously, we proposed a flow complexity parameter that provides a quantitative description of the complexity of flow patterns through calculated curvature and torsion of the flow field. The purpose of the current study was to provide an analytic solution of the flow complexity parameter and assess a possible correlation with the rupture status of cerebral aneurysms by analyzing the parameter on five ruptured and five unruptured aneurysms from anterior communicating artery. We analyzed the flow complexity parameter in jet and non-jet regions in order to measure the concentration of the jet flow and the complexity of the non-jet flow. We found that on average, in a ruptured case the jet region is significantly less complex (4.5 times) than the jet region in an unruptured case, while the non-jet region is significantly more complex (3.5 times) than the non-jet region in an unruptured case. We also found a strong positive correlation of the non-jet complexity with dome volume in ruptured cases, but no correlation of jet complexity with dome volume. These findings suggest that a ruptured aneurysm has more than 4 times more concentrated inflow jet and more than 3 times more complex flow patterns in non-jet region than an unruptured aneurysm. This newly implemented kinematic parameter provides a measurable degree of complexity of flow patterns in cerebral aneurysms that can better assess aneurysm rupture risk. PMID- 30021248 TI - Environmental and behavioural modifications for improving food and fluid intake in people with dementia. AB - BACKGROUND: Weight loss, malnutrition and dehydration are common problems for people with dementia. Environmental modifications such as, change of routine, context or ambience at mealtimes, or behavioural modifications, such as education or training of people with dementia or caregivers, may be considered to try to improve food and fluid intake and nutritional status of people with dementia. OBJECTIVES: Primary: To assess the effects of environmental or behavioural modifications on food and fluid intake and nutritional status in people with dementia. Secondary: To assess the effects of environmental or behavioural modifications in connection with nutrition on mealtime behaviour, cognitive and functional outcomes and quality of life, in specific settings (i.e. home care, residential care and nursing home care) for different stages of dementia. To assess the adverse consequences or effects of the included interventions. SEARCH METHODS: We searched the Specialized Register of Cochrane Dementia and Cognitive Improvement (ALOIS), MEDLINE, Eembase, PsycINFO, CINAHL, ClinicalTrials.gov and the World Health Organization (WHO) portal/ICTRP on 17 January 2018. We scanned reference lists of other reviews and of included articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating interventions designed to modify the mealtime environment of people with dementia, to modify the mealtime behaviour of people with dementia or their caregivers, or both, with the intention of improving food and fluid intake. We included people with any common dementia subtype. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed the risk of bias of included trials. We assessed the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included nine studies, investigating 1502 people. Three studies explicitly investigated participants with Alzheimer's disease; six did not specify the type of dementia. Five studies provided clear measures to identify the severity of dementia at baseline, and overall very mild to severe stages were covered. The interventions and outcome measures were diverse. The overall quality of evidence was mainly low to very low.One study implemented environmental as well as behavioural modifications by providing additional food items between meals and personal encouragement to consume them. The control group received no intervention. Differences between groups were very small and the quality of the evidence from this study was very low, so we are very uncertain of any effect of this intervention.The remaining eight studies implemented behavioural modifications.Three studies provided nutritional education and nutrition promotion programmes. Control groups did not receive these programmes. After 12 months, the intervention group showed slightly higher protein intake per day (mean difference (MD) 0.11 g/kg, 95% confidence interval (CI) -0.01 to 0.23; n = 78, 1 study; low-quality evidence), but there was no clear evidence of a difference in nutritional status assessed with body mass index (BMI) (MD -0.26 kg/m2 favouring control, 95% CI -0.70 to 0.19; n = 734, 2 studies; moderate quality evidence), body weight (MD -1.60 kg favouring control, 95% CI -3.47 to 0.27; n = 656, 1 study; moderate-quality evidence), or score on Mini Nutritional Assessment (MNA) (MD -0.10 favouring control, 95% CI -0.67 to 0.47; n = 656, 1 study; low-quality evidence). After six months, the intervention group in one study had slightly lower BMI (MD -1.79 kg/m2 favouring control, 95% CI -1.28 to 2.30; n = 52, 1 study; moderate-quality evidence) and body weight (MD -8.11 kg favouring control, 95% CI -2.06 to -12.56; n = 52, 1 study; moderate-quality evidence). This type of intervention may have a small positive effect on food intake, but little or no effect, or a negative effect, on nutritional status.Two studies compared self-feeding skills training programmes. In one study, the control group received no training and in the other study the control group received a different self-feeding skills training programme. For both comparisons the quality of the evidence was very low and we are very uncertain whether these interventions have any effect.One study investigated general training of nurses to impart knowledge on how to feed people with dementia and improve attitudes towards people with dementia. Again, the quality of the evidence was very low so that we cannot be certain of any effect.Two studies investigated vocal or tactile positive feedback provided by caregivers while feeding participants. After three weeks, the intervention group showed an increase in calories consumed per meal (MD 200 kcal, 95% CI 119.81 to 280.19; n = 42, 1 study; low-quality evidence) and protein consumed per meal (MD 15g, 95% CI 7.74 to 22.26; n = 42, 1 study; low quality evidence). This intervention may increase the intake of food and liquids slightly; nutritional status was not assessed. AUTHORS' CONCLUSIONS: Due to the quantity and quality of the evidence currently available, we cannot identify any specific environmental or behavioural modifications for improving food and fluid intake in people with dementia. PMID- 30021250 TI - A Case of Esophageal Squamous Cell Carcinoma in situ Arising from Esophageal Squamous Papilloma. AB - Squamous papilloma is a common benign tumor of the esophagus. Patients with papilloma are usually asymptomatic, and they are diagnosed incidentally during esophagogastroduodenoscopy. Most papillomas are small and easily removed by forceps biopsy. Recurrence of papilloma after removal is rare. Human papilloma virus infection is supposed to play a role in the development of esophageal papilloma; however, malignant transformation of papilloma is extremely unusual. Here, we report a case of malignant transformation of esophageal squamous papilloma at the gastroesophageal junction into squamous cell carcinoma in situ, which was treated by endoscopic submucosal dissection. PMID- 30021252 TI - Effect of Stem Cells and Gene Transfected Stem Cells Therapy on the Pancreas of Experimentally Induced Type 1 Diabetes. AB - Background and Objectives: Insulin secretion entirely depends on Ca2+ influx and sequestration into endoplasmic reticulum (ER) of beta-cells, performed by Sarco ER Ca2+-ATPase 2b (SERCA2b). In diabetes, SERCA2b is decreased in the beta-cells leading to impaired intracellular Ca2+ homeostasis and insulin secretion. Adipose mesenchymal stem cells (AMSCs) play a potential role in transplantation in animal models. The present study aimed at investigating and comparing the therapeutic effect of non-transfected AMSCs and SERCA2b gene transfected AMSCs on the pancreas of induced diabetes type 1 in rat. Methods and Results: 58 adult male albino rats were divided into: Donor group: 22 rats, 2 for isolation, propagation and characterization of AMSCs and SERCA2b transfected AMSCs, in addition 20 for isolated islet calcium level assessment. Group I (Control Group): 6 rats, Group II (Diabetic Group): 10 rats, 50 mg streptozotocin (STZ) were injected intraperitoneal (IP), Group III (AMSCs Group): 10 rats, 1*106 AMSCs were injected intravenous and Group IV (SERCA2b transfected AMSCs Group): 10 rats, 1*106SERCA2b transfected AMSCs were injected as in group III. Groups I, II, III and IV were sacrified 3 weeks following confirmation of diabetes. Serological, histological, morphometric studies and quantitative polymerase chain reaction (qPCR) were performed. Nuclear, cytoplasmic degenerative and extensive fibrotic changes were detected in the islets of group II that regressed in groups III and IV. Isolated islet calcium, blood glucose, plasma insulin and qPCR were confirmative. Conclusions: AMSCs and SERCA2b gene transfected AMSCs therapy proved definite therapeutic effect, more obvious in response to SERCA2b gene transfected AMSCs. PMID- 30021251 TI - Endobronchial Smooth Muscle Tumors: A Series of Five Cases Highlighting Pitfalls in Diagnosis. AB - Background: Primary endobronchial smooth muscle tumors (SMTs), which are extremely rare, include endobronchial leiomyomas and leiomyosarcomas. Clinically, SMTs present with signs and symptoms of bronchial obstruction, and lack specific radiological findings. Thus, histopathological examination is required for accurate diagnosis as well as for tumor grading. We examined the histomorphological and immunohistochemical features of endobronchial SMTs and highlighted pitfalls in diagnosis, particularly when using small biopsies. Methods: Cases of primary endobronchial SMTs diagnosed at our Institute over the last 6 years (2012-2017) were retrieved from the departmental archives. Histopathological features and immunohistochemistry performed for establishing the diagnosis were reviewed. Results: Five cases of SMTs occurring in endobronchial locations were identified. These included three cases of leiomyoma, and two cases of leiomyosarcoma. The age distribution of patients ranged from 13 to 65 years. Leiomyomas showed more consistent staining with smooth muscle markers (smooth muscle actin, desmin, and smooth muscle myosin heavy chain), while tumors of higher grade showed variable, focal staining, leading to erroneous diagnosis, especially on small biopsies. Conclusions: The diagnosis of endobronchial SMTs relies on histopathological examination, for both confirmation of smooth muscle lineage and determination of the malignant potential of the lesion. Appropriate immunohistochemical panels including more than one marker of smooth muscle differentiation are extremely valuable for differential diagnosis from morphological mimics, which is necessary for instituting appropriate management. PMID- 30021253 TI - Pja2 Inhibits Wnt/beta-catenin Signaling by Reducing the Level of TCF/LEF1. AB - Ubiquitination of proteins plays an essential role in various cellular processes, including protein degradation, DNA repair, and cell signaling pathways. Previous studies have shown that protein ubiquitination is implicated in regulating pluripotency as well as fate determination of stem cells. To identify how protein ubiquitination affects differentiation of embryonic stem cells, we analyzed microarray data, which are available in the public domain, of E3 ligases and deubiquitinases whose levels changed during stem cell differentiation. Expression of pja2, a member of the RING-type E3 ligase family, was up-regulated during differentiation of stem cells. Wnt/beta-catenin signaling is one of the most important signaling pathways for regulation of the self-renewal and differentiation of embryonic stem cells. Pja2 was shown to bind to TCF/LEF1, which are transcriptional factors for Wnt/beta-catenin signaling, and regulate protein levels by ubiquitination, leading to down-regulation of Wnt signaling activity. Based on these results, we suggest that E3 ligase Pja2 regulates stem cell differentiation by controlling the level of TCF/LEF1 by ubiquitination. PMID- 30021255 TI - Correction. PMID- 30021254 TI - Erratum. PMID- 30021256 TI - Corrigendum to "Environmental noise pollution and risk of preeclampsia" [Environ. Pollut. 239 (2018) 599-606]. PMID- 30021257 TI - Challenging Hofmann's negative thoughts: A rebuttal. AB - In his commentary on Longmore and Worrell [Longmore, R., & Worrell, M. (2007) Do we need to challenge thoughts in Cognitive Behavioural Therapy? Clinical Psychology review, 27, 173-187], Hofmann [Hofmann, S. G. (2008-this issue). Common misconceptions about cognitive mediation of treatment change: A commentary to Longmore and Worrell (2007). Clinical Psychology Review, doi:10.1016/j.cpr.2007.03.003] argues that the paper shows a range of errors, biases, and misconceptions that have led to incorrect interpretations of the literature and general conclusions. Hofmann discusses recent developments in the methodological criteria for mediation studies in support of his contentions. In this rebuttal it is demonstrated that Hofmann has in fact misrepresented the primary focus and arguments of Longmore and Worrell (2007). Additionally, it is shown that the arguments and research findings that Hofmann discusses do not constitute a significant challenge to the conclusions drawn as a result of the original review. PMID- 30021258 TI - A Rebuttal. PMID- 30021259 TI - Reply to "Effect of wrist position on sensorimotor processing in the grip-lift task". PMID- 30021260 TI - Answer to the letter entitled "Characterization of temporal evolution of metabolic acidosis in adult patients with severe diabetic ketoacidosis admitted to the intensive care unit: Not quite done". PMID- 30021261 TI - Response to Kang et al. PMID- 30021262 TI - Correction. PMID- 30021263 TI - Correction. PMID- 30021264 TI - Reply to Letter to the Editor. PMID- 30021265 TI - Reply to Letter to the Editor by Wang. PMID- 30021266 TI - Author reply. PMID- 30021267 TI - Microbial and geochemical controls on waste rock weathering and drainage quality. AB - Bacteria can adversely affect the quality of drainage released from mine waste by catalyzing the oxidation of sulfide minerals and thereby accelerating the release of acidity and metals. However, the microbiological and geochemical controls on drainage quality from unsaturated and geochemically heterogeneous waste rock remain poorly understood. Here, we identified coexisting neutrophilic and acidophilic bacteria in different types of waste rock, indicating that robust endemic consortia are sustained within pore-scale microenvironments. Subsequently, natural weathering was simulated in laboratory column experiments with waste rock that contained either in-situ microbial consortia or suppressed populations with up to 1000 times smaller abundance and reduced phenotypic diversity after heating and drying. Drainage from waste rock with in-situ populations was up to two pH units lower and contained up to 16 times more sulfate and heavy metals compared to drainage from waste rock bearing treated populations, indicating significantly higher sulfide-oxidation rates. The drainage chemistry was further affected by sorption and formation of secondary mineral phases (e.g., gypsum and hydroxy-carbonates). This study provides direct evidence for the existence of diverse microbial communities in waste rock and their important catalytic role on weathering rates, and illustrates the mutual controls of microbiology and geochemistry on waste-rock drainage quality. PMID- 30021268 TI - Occurrence and distribution of carbamazepine, nicotine, estrogenic compounds, and their transformation products in wastewater from various treatment plants and the aquatic environment. AB - The concentrations and fates of carbamazepine and metabolites (CBMs), nicotine and metabolites (NCTs), estrogenic compounds and metabolites (Es) in various water samples were investigated. Different concentrations were found for water from different sources. The concentrations of these pharmaceuticals and personal care products and their metabolites in human waste treatment plant (HTP) influents (0.08-173 MUg L-1) were higher than in the other influent samples and the lowest levels were observed in hospital wastewater treatment plant influents (0.03-7.33 MUg L-1). The concentrations were higher in HTP effluents (0.01-11.2 MUg L-1) than in the other effluent samples and lowest in sewage treatment plant effluents (0.003-1.26 MUg L-1). The NCTs were the most frequently detected pharmaceuticals and personal care products (concentration range 0.05-89.6 MUg L 1) in the wastewater treatment plant influents, but the CBMs were found at the highest concentrations (0.003-6.88 MUg L-1). 10, 11-Dihydro-10, 11 dihydroxycarbamazepine was the most abundant of the CBMs in the wastewater treatment plants and water samples. Trans-3'-hydroxycotinine was dominant in the HTP and hospital wastewater treatment plant influents, whereas the parent NCT was dominant in the sewage treatment plant influents and in all the effluent and other water samples. Estriol was the dominant estrogenic compound in the HTP and hospital wastewater treatment plant influents. Estriol and estrone were found in many of the HTP influents, but estrone was dominant in the effluent and other water samples. The total removal efficiencies for the CBMs, NCTs, and estrogenic compounds for the treatment plants were -101% to 56%, 2.9%-99%, and >98%, respectively. PMID- 30021269 TI - Zebrafish embryo bioassays for a comprehensive evaluation of microalgae efficiency in the removal of diclofenac from water. AB - This work deals with a preliminary study aimed at evaluating the efficiency of three different microalgae strains, namely Chlorella sorokiniana, Chlorella vulgaris and Scenedesmus obliquus in the bioremediation of diclofenac contaminated water. For this purpose, microalgae were cultured in bubbling column photobioreactors (PBRs) under batch operation until the end of the exponential growth phase. For the three strains, the concentration of diclofenac in the PBRs aquatic medium decreased along microalgae growing, which pointed to biodegradation as the main removal mechanism. Among the three strains, S. obliquus was the most capable to reduce diclofenac concentration (99% removal from an initial concentration of 25,000 MUg l-1). However, such a large removal does not guarantee an efficient treatment since transformation products (TPs) exceeding the concentration and/or toxicity of the parent compound may be generated during biodegradation of diclofenac. Thus, for a comprehensive evaluation of the microalgae treatments efficiency, the final effluents from the PBRs were tested for their effects on the embryonic development of zebrafish. Again, the S. obliquus treatment was the most efficient in the reduction of toxicity, with the corresponding effluents having no effects on the embryo's mortality or abnormalities incidence (at 80 h post fertilization). In any case, for the three strains, the toxicity effects of effluents were equal or lower than those determined for diclofenac solutions with the same concentration. Therefore, it may be stated that, at the end of the batch culture, the removal of diclofenac by the considered strains did not involve the generation of toxic TPs to zebrafish embryos. PMID- 30021270 TI - Effects of Pseudomonas chenduensis and biochar on cadmium availability and microbial community in the paddy soil. AB - The cadmium contamination in the paddy soil results in serious environmental pollutions. In situ soil remediation based on the applications of additives such as functional microorganisms and biochars has gradually attained more attentions. However, how these exogenous additives affect the local microbial communities is less discussed. In this study, a heavy metal resistant bacterium (Pseudomonas chenduensis, strain MBR) and biochar derived from oil palm fibers were separately added into the simulated Cd-contaminated paddy soil to investigate the roles of these additives in the soil remediation and regulating local microbial community. The results showed that compared with control, the addition of the strain MBR and biochar reduced the exchangeable/acid soluble cadmium fraction by 30% and 18%, respectively. Moreover, higher microbial diversity, more deterministic effects and less variation in microbial community were observed in the treatments supplemented with the strain MBR and biochar, and the increase of the deterministic effects on microbial interactions was demonstrated by network analysis further. Additionally, the abundance of the strain MBR in the paddy soil decreased as time passed, which maximally decreased the disturbance for the local micro-ecological niche and ensured ecological security. These results showed that two additives supplementation, in particular Pseudomonas chenduensis, can significantly decrease cadmium availability, contributing to the reduction of the disturbance on soil microbial community and maintaining microbial stability under cadmium pressure. It highlights a new criterion referred to micro-ecology for the evaluation of the roles of additives in local soil remediation. PMID- 30021271 TI - First multi-tool exploration of a gas-condensate-pyrolysate system from the environment of burning coal mine heaps: An in situ FTIR and laboratory GC and PXRD study based on Upper Silesian materials. AB - A methodological approach to the complex geochemical analysis of the coal fire in burning coal mine heaps (BCMH) of Upper Silesian Coal Basin has been developed. The other approach used is gas chromatography and indicatory tubes. Powder X-Ray Diffraction is applied for phase analysis to determine the species composition of mineral condensates present within and around gas flues. The gas compositions are proved to be extremely variable, when comparing both different BCMH and flues or flue zones of the same heaps. One outstanding determination concerns GeCl4, found in most samples often in large quantities. No evident dependence between the gas and mineral condensate compositions is found: N-rich condensates may but do not have to be associated with NH3-, pyridine-, or NOx-rich gases. This is also true for S-rich and Cl-rich mineralization in connection with gases of SO2, H2S, OCS, CS2, thiophene, dimethyl sulfide, dimethyl disulfide, HCl, and various halogenated hydrocarbons. Fluorine is rarely present as HF, whereas SiF4 occurs more frequently and in much larger quantities. AsH3 is mainly a trace gas but may locally be enriched. Besides the common gases, a number of trace gases is also determined based on residual FTIR spectra. Those with the highest presence chance include cyanogen isocyanate, cyanogen N-oxide, (iso)cyanic acid, c cyanomethanimine (ethylenediimine), isocyanatomethane, iodocyanoacetylene, acetonitrile, acetaldehyde, m-hydroxybenzonitrile (m-cyanophenol), isonitrosyl chloride, nitrosyl isocyanide, difluorosilane, pentacene, triphenylene, thiazolidine, cyclohexane, and a trinitrenetriazine. The occurrence of some metals and semimetals (e.g., Al, Mg, Ga) as neutral hydroxides, suggested by other authors to occur in natural gases, is possibly confirmed. The presence of trace metal carbonyls, nitrosyls and hydrides is also possible. PMID- 30021272 TI - Impacts of dam draining on the mobility of heavy metals and arsenic in water and basin bottom sediments of three studied dams in Germany. AB - The draining of a dam is a relatively rare event, however, it can have severe consequences for a watercourse connected to that reservoir. In order to understand the effects of the draining on the mobility of pollutants stored in the bottom sediments, the concentrations of heavy metals and arsenic were measured in pore water, river water, and sediments sampled from three emptied reservoirs in Germany. Two of these sites were analyzed immediately after the draining, while the third reservoir was studied one and a half years after the complete discharge of the stored water. Heavy metal and arsenic concentrations within the sediments varied among the studied dams as a result of different geological characteristics and the degree of anthropogenic impacts. Based on the analysis of pore water samples, the concentrations of heavy metals and arsenic were not significantly altered shortly after the draining. However, increased concentrations of As, Fe, Cd, Ni, and Zn were measured in pore water samples after a longer duration of sediment exposure, which altered the redox conditions and sediment properties. The changes in Cu, Cr, Mn, and Pb concentrations in pore water samples were less pronounced. As a result of the pore water drainage increased dissolved heavy metal concentrations were found in the discharge water immediately after draining. At the third site, which had been emptied for one and a half years, only for Mn, a concentration increase was detected in the reservoir discharge water, which emphasizes the strong temporal dynamic of the mobilization of the analyzed elements. PMID- 30021273 TI - Influence of different sludge compositions on understorey vegetation in an amended Pinus pinatser forest plantation. AB - The present study reports on the influence of sludge application on understory abundance and species richness in an eight year-old maritime pine forest. Four types of sludge (liquid, dewatered, limed and composted sludge) were applied at a rate equivalent to 3 tons dry weight per ha-1 per year-1. Understorey vegetation was monitored before treatment and for three successive years following initial sludge application. Species richness, the biodiversity index and naturally occurring plant community cover in maritime pine forests were measured. Results showed a significant increase in species richness two years following initial sludge application. In fact, compared to the unamended plot, eighteen additional species (Aira caryophyllea, Cerastium glomeratum, Conyza canadensis, Danthonia decumbens, Geranium robertianum, Gnaphalium sylvaticum, Hypericum humifusum, Hypericum perforatum ssp. perforatum, Jasione montana, Lonicera periclymenum ssp. periclymenum, Ornithopus compressus, Phytolacca americana, Rhamnus frangula, Teesdalia nudicaulis, Veronica arvensis, Vicia sativa angustifolia and Vulpia myuros) appeared after sludge application. Most of these species were observed with the solid limed or composted sludge treatments. The new species then declined the following year, highlighting the temporary effect of sludge treatment on species diversity. However, the cover by these eighteen new species was low and did not exceed 1%, except for Hypericum perforatum and Jasione montana for the limed sludge treatment and Vulpia myuros for the liquid sludge treatment. Additionally, sludge significantly reduces bare soil percentage, which ranged from 5 to 18% compared to the control (38%). According to sludge type, treatment also led to a significant change in species dominance of the understorey plant communities. Indeed, the cover of Molinia caerulea decreased in spite of an increase in Agrostis capillaris and/or Holcus lanatus following application of solid limed, liquid or composted sludge. PMID- 30021274 TI - Effects of secondary salinisation on macroinvertebrate functional traits in surface mining-contaminated streams, and recovery potential. AB - Secondary salinisation has become a hot spot internationally due to its adverse effects on freshwater ecosystems. Although its effects on ecosystem patterns has been broadly studied, its potential effect on ecosystem functions, in particular on the functional traits of freshwater organisms, and functional trait recovery are largely unknown. In this study, we conducted a field investigation at 405 sample sites from May 2009 to July 2016 in surface mining-contaminated streams, in order to evaluate the influence of secondary salinisation on macroinvertebrate functional traits and the recovery potential of dominant functional traits. Results of univariate models showed that sensitive, very tolerant, gill breathers, cutaneous-breathers, shredders, predators and gatherers were the most responsive indicators to enhanced specific conductivity and sulfate loadings with sensitive, gill-breathers, shredders and predators demonstrating a reduction in abundance, whereas cutaneous-breathers and gatherers exhibiting an increase. Complicated relationships among different species indicated that co-exclusions would not occur because all macroinvertebrate taxa exhibited positive correlations. Results of relative recovery potential showed that omnivores and gatherers recovered quickly following improvements in water quality, whereas gill breathers, pneumostome-breathers, filterers and scrapers would be expected to recover slowly due to their sensitivity to both specific conductivity and sulfate and low drift propensity. Overall, secondary salinisation has posed severely ecological risks to macroinvertebrate functional attributes in surface mining contaminated streams, and their effects should be considered in future conservation plans. PMID- 30021275 TI - Wind-driven rain and future risk to built heritage in the United Kingdom: Novel metrics for characterising rain spells. AB - Wind-driven rain (WDR) is rain given a horizontal velocity component by wind and falling obliquely. It is a prominent environmental risk to built heritage, as it contributes to the damage of porous building materials and building element failure. While predicted climate trends are well-established, how they will specifically manifest in future WDR is uncertain. This paper combines UKCP09 Weather Generator predictions with a probabilistic process to create hourly time series of climate parameters under a high-emissions scenario for 2070-2099 at eight UK sites. Exposure to WDR at these sites for baseline and future periods is calculated from semi-empirical models based on long-term hourly meteorological data using ISO 15927-3:2009. Towards the end of the twenty-first century, it is predicted that rain spells will have higher volumes, i.e. a higher quantity of water will impact facades, across all 8 sites. Although the average number of spells is predicted to remain constant, they will be shorter with longer of periods of time between them and more intense with wind-driven rain occurring for a greater proportion of hours within them. It is likely that in this scenario building element failure - such as moisture ingress through cracks and gutter over-spill - will occur more frequently. There will be higher rates of moisture cycling and enhanced deep-seated wetting. These predicted changes require new metrics for wind-driven rain to be developed, so that future impacts can be managed effectively and efficiently. PMID- 30021276 TI - The detrital input and removal treatment (DIRT) network: Insights into soil carbon stabilization. AB - Ecological research networks functioning across climatic and edaphic gradients are critical for improving predictive understanding of biogeochemical cycles at local through global scales. One international network, the Detrital Input and Removal Treatment (DIRT) Project, was established to assess how rates and sources of plant litter inputs influence accumulations or losses of organic matter in forest soils. DIRT employs chronic additions and exclusions of aboveground litter inputs and exclusion of root ingrowth to permanent plots at eight forested and two shrub/grass sites to investigate how soil organic matter (SOM) dynamics are influenced by plant detrital inputs across ecosystem and soil types. Across the DIRT network described here, SOM pools responded only slightly, or not at all, to chronic doubling of aboveground litter inputs. Explanations for the slow or even negative response of SOM to litter additions include increased decomposition of new inputs and priming of old SOM. Evidence of priming includes increased soil respiration in litter addition plots, decreased dissolved organic carbon (DOC) output from increased microbial activity, and biochemical markers in soil indicating enhanced SOM degradation. SOM pools decreased in response to chronic exclusion of aboveground litter, which had a greater effect on soil C than did excluding roots, providing evidence that root-derived C is not more critical than aboveground litter C to soil C sequestration. Partitioning of belowground contributions to total soil respiration were predictable based on site-level soil C and N as estimates of site fertility; contributions to soil respiration from root respiration were negatively related to soil fertility and inversely, contributions from decomposing aboveground litter in soil were positively related to site fertility. The commonality of approaches and manipulations across the DIRT network has provided greater insights into soil C cycling than could have been revealed at a single site. PMID- 30021277 TI - Biodegradation pathway of di-(2-ethylhexyl) phthalate by a novel Rhodococcus pyridinivorans XB and its bioaugmentation for remediation of DEHP contaminated soil. AB - A novel bacterial strain designated as Rhodococcus pyridinivorans XB, capable of utilizing various endocrine disruptor phthalates or phthalic acid (PA) as sole source of carbon and energy, was isolated from activated sludge. Under the optimal culture conditions (pH 7.08, 30.4 degrees C, inoculum size (OD600 nm) of 0.6) obtained by response surface methodology, di-(2-ethylhexyl) phthalate (DEHP, 200 mg/L) could be degraded by strain XB with a removal rate of 98% within 48 h. Under the observation of an atomic force microscope, it was confirmed that DEHP did not inhibit the growth of strain XB which might produce some extracellular polymeric substances as a response to DEHP stress, resulting in rapid degradation of DEHP. At initial concentrations of 50-800 mg/L DEHP, its degradation curves were well fitted with the first-order kinetic model, and the half-life of DEHP degradation varied from 5.44 to 23.5 h. The degradation intermediates of DEHP were identified by both GC-MS and high performance liquid chromatography-time of flight-mass spectrometry (HPLC-TOF-MS). Significant up-regulation was observed for the relative expression levels of genes (i.e., phthalate hydrolase, PA 3,4 dioxygenase, protocatechuate 3,4-alpha and 3,4-beta dioxygenase) involved in DEHP degradation determined by real-time quantitative PCR (RT-qPCR). A DEHP biodegradation pathway by strain XB was proposed based on the identified intermediates and the degrading genes. Bioaugmentation of DEHP-contaminated soils with strain XB could efficiently promote DEHP removal, offering great potential in bioremediation of DEHP-contaminated environment. PMID- 30021278 TI - Influence of environmental factors on tenuazonic acid production by Epicoccum sorghinum: An integrative approach of field and laboratory conditions. AB - Sorghum is the fifth most cultivated and consumed grain in the world. However, this grain is frequently contaminated with toxins from fungi. The present study evaluated the effects of environmental factors on tenuazonic acid (TeA) production by Epicoccum sorghinum in the field and in controlled laboratory conditions. In this study, 50 sorghum grain samples were collected from summer and autumn growing seasons and analyzed for TeA contamination using LC-MS/MS. To further understand the ecophysiology of this fungus, an isolated strain of E. sorghinum from the field was investigated for its development and TeA production under controlled environmental conditions in the laboratory. In the ecophysiological investigation, the effects of water activity (0.90, 0.95, 0.99) and temperature (18, 22, 26 and 30 degrees C) were evaluated on the radial growth, enzymatic production and expression of TAS1, which is the gene involved in TeA production. Results showed that in the field, the summer season presented the highest TeA average level in the grains (587.8 MUg/kg) compared to level found in the autumn (440.5 MUg/kg). The ecophysiological investigation confirmed that E. sorghinum produces more actively TeA under environmental conditions simulating the summer season. Optimum growth, maximum TAS1 gene expression, and higher extracellular enzymatic production were observed at 26 degrees C with a water activity of 0.99. Pearson correlation analyses showed that the production of TeA highly correlates with fungal growth. The present study demonstrates that abiotic factors in a combined approach of field and laboratory conditions will assist in predicting the driving environmental factors that could affect growth of E. sorghinum and TeA production in sorghum grains. PMID- 30021279 TI - An evaluation on the intra-day dynamics, seasonal variations and removal of selected pharmaceuticals and personal care products from urban wastewater treatment plants. AB - Pharmaceuticals and personal care products (PPCPs) in wastewater have become an emerging issue due to their negative effects on human health and aquatic ecosystems. Two full-scale municipal and industrial wastewater treatment plants (WWTPs) along the Songhua River were chosen to evaluate the intra-day dynamics, seasonal variations and removal of 12 selected PPCPs. Our results suggested that the selected PPCPs were frequently detected in the influent and effluent. Caffeine was the predominant compound in the influent; while the selected PPCPs was dominated by TCS in the effluent, suggesting the different fates of selected PPCPs in the WWTPs. The intra-day dynamics of PPCPs in the influent were evaluated, suggesting that the 12 PPCPs can be grouped into three categories because of their different use patterns. The analysis of seasonal changes of PPCPs concentrations in the WWTPs suggested that the concentrations of some PPCPs were influenced by the chemical usage, degradation and temperature. The removal efficiency for the PPCPs were very high with the values ranged from 70.0% to 99.7% for WWTP#1, and from 62.5% to 99.4% for WWTP#2. Significant seasonal variations of PPCPs removal efficiency were observed. Base on the mass loading of PPCPs in the two WWTPs, our results suggested that WWTP#1 in the urban core received much more PPCPs in comparison to WWTP#2 in the suburban regions, suggesting that influences of the service population. PMID- 30021280 TI - Transient coastal landscapes: Rising sea level threatens salt marshes. AB - Salt marshes are important coastal environments that provide key ecological services. As sea level rise has accelerated globally, concerns about the ability of salt marshes to survive submergence are increasing. Previous estimates of likely survival of salt marshes were based on ratios of sea level rise to marsh platform accretion. Here we took advantage of an unusual, long-term (1979-2015), spatially detailed comparison of changes in a representative New England salt marsh to provide an empirical estimate of habitat losses based on actual measurements. We show prominent changes in habitat mosaic within the marsh, consistent and coincident with increased submergence and coastal erosion. Model results suggest that at current rates of sea level rise, marsh platform accretion, habitat loss, and with the limitation of the widespread "coastal squeeze", the entire ecosystem might disappear by the beginning of the next century, a fate that might be likely for many salt marshes elsewhere. Meta analysis of available data suggests that 40 to 95% of the world's salt marshes will be submerged, depending on whether sea level rise remains at current or reaches anticipated rates for the end of this century. PMID- 30021281 TI - Organic UV filters in indoor dust and human urine: A study of characteristics, sources, associations and human exposure. AB - Organic ultraviolet (UV) filters are emerging contaminants that may pose health risks to humans. We measured the concentrations of four commonly used organic UV filters (2-hydroxy-4-methoxybenzophenone (BP-3), 4-methylbenzylidene camphor (4 MBC), homosalate (HMS), and octocrylene (OC)) in 203 indoor dust samples and 98 human urine samples from households in eastern China. The total concentrations of the four organic UV filters ranged from 66.6-56,123.0 ng g-1 in indoor dust and 1.17-52.15 MUg g-1 (creatinine-adjusted concentration (Cr)) in urine. BP-3 was the most abundant organic UV filter in the urine samples (median concentration: 1.89 MUg g-1 Cr), while OC was the most abundant in the indoor dust samples (median concentration: 325.7 ng g-1). No significant correlations were found between organic UV filter concentrations in paired urine and dust samples, but the concentrations of UV filters in the indoor dust samples were positively correlated with family income and sunscreen use. The sources of the organic UV filters in the indoor dust samples differed based on the geographical location of the tested household. The fraction of human exposure to organic UV filters that resulted from ingestion or dermal absorption of indoor dust was close to 8%. PMID- 30021282 TI - Improvement of a combination of TMPA (or IMERG) and ground-based precipitation and application to a typical region of the East China Plain. AB - Hydrological model and water resource assessment performance are highly dependent on the quality of the precipitation input, which can be improved by means of the optimal interpolation method for the merged precipitation. However, the traditional first-guess field of satellite precipitation often increases the merging error on account of its inherent bias. Some authors have suggested the need of generating a more accurate first-guess field for the merged precipitation, but the research in this improvement is rarely reported. Therefore, an improved merging method is proposed in this paper in which the precipitation from rain gauges is added to the first-guess field when combining the precipitation estimates of Tropical Rainfall Measuring Mission (TRMM) Multi Satellite Precipitation Analysis (TMPA) 3B42 with rain gauges in a typical region of the East China Plain, China. Furthermore, the influence of the gauge station densities on the merged accuracy of the precipitation is investigated based on the traditional and improved methods. The results show that the improved merging method has effectively reduced the influence of the uncertainty caused by the error of the first-guess field owing to the consideration of the spatial distribution of TMPA precipitation and the precision of the gauge precipitation. Compared with results of traditional interpolation methods using only gauge data, the precipitation-merging method in this study can obtain better performance results only when the observation density is lower than 6.0 * 103 km2 per gauge under average conditions of many years. The higher the observation density, the more notably the accuracy increases. In addition, the greater the precipitation, the more homogeneous the spatial and temporal distribution of the precipitation and the better the improved effect of the merging method. The Integrated Multi satellitE Retrievals for the Global Precipitation Measurement (GPM) mission (IMERG) data is also used to validate the conclusions here. PMID- 30021283 TI - Wave farm effects on the coast: The alongshore position. AB - For wave energy to become a fully-fledged renewable and thus contribute to the much-needed decarbonisation of the energy mix, the effects of wave farms (arrays of wave energy converters) on coastal systems must be addressed. The objective of this work is to investigate the effects of wave farms on the longshore sediment transport and shoreline evolution of a gravel-dominated beach and, in particular, its sensitivity to the longshore position of the farm based on eight scenarios. Nearshore wave propagation patterns are computed by means of a spectral wave propagation model (SWAN), variations in sediment transport rates induced by the farm are calculated, and a one-line model is applied to determine the shoreline position and dry beach area. The significant wave height at breaking is reduced in the lee of the wave farm, dampening sediment transport. We find that changes in the dry beach area induced by the wave farm are highly sensitive to its alongshore position, and may result in: (i) erosion relative to the baseline scenario (without wave farm) in three of the eight scenarios, (ii) accretion in three other scenarios, and (iii) negligible effects in the remaining two. These results prove that the alongshore position of the wave farm controls the response of the beach to the extent that it may shift from accretionary to erosionary, and provide evidence of its effectiveness in countering erosion if appropriately positioned. This effectiveness opens up the possibility of using wave farms not only to generate carbon-free energy but also to manage coastal erosion, thus strengthening the case for the development of wave energy. PMID- 30021284 TI - Implications of RCP emissions on future concentration and direct radiative forcing of secondary organic aerosol over China. AB - This study applies the nested-grid version of Goddard Earth Observing System (GEOS) chemical transport model (GEOS-Chem) to examine future changes (2000-2050) in SOA concentration and associated direct radiative forcing (DRF) over China under the Representative Concentration Pathways (RCPs). The projected changes in SOA concentrations over 2010-2050 generally follow future changes in emissions of toluene and xylene. On an annual mean basis, the largest increase in SOA over eastern China is simulated to be 25.1% in 2020 under RCP2.6, 20.4% in 2020 under RCP4.5, 56.3% in 2050 under RCP6.0, and 44.6% in 2030 under RCP8.5. The role of SOA in PM2.5 increases with each decade in 2010-2050 under RCP2.6, RCP4.5, and RCP8.5, with a maximum ratio of concentration of SOA to that of PM2.5 of 16.3% in 2050 under RCP4.5 as averaged over eastern China (20 degrees -45 degrees N, 100 degrees -125 degrees E). Concentrations of SOA are projected to be able to exceed those of sulfate, ammonium, and black carbon (BC) in the future. The future changes in SOA levels over eastern China are simulated to lead to domain-averaged (20 degrees -45 degrees N, 100 degrees -125 degrees E) DRFs of +0.19 W m-2, +0.12 W m-2, - 0.28 W m-2, and -0.17 W m-2 in 2050 relative to 2000 under RCP2.6, RCP4.5, RCP6.0, and RCP8.5, respectively. Model results indicate that future changes in SOA owing to future changes in anthropogenic precursor emissions are important for future air quality planning and climate mitigation measures. PMID- 30021285 TI - Electrochemical degradation of ibuprofen-contaminated soils over Fe/Al oxidation electrodes. AB - Ibuprofen (IBP) is one of the most known non-steroidal anti-inflammatory drugs. Due to the high consumption and the several ways of discharge, both the aquifer and soil matrix were contaminated by IBP. This study examined the degradation of the IBP in a soil matrix over Fe/Al oxidation electrodes in an electrokinetic system with processing fluids of sodium dodecylsulfate (SDS). The preparation of the Fe/Al oxidation electrode was carried out at a calcination temperature of 500, 550, and 600 degrees C, which accounted for Fe3+ coating rate of 3.89 +/- 0.03%, 4.62 +/- 0.04%, and 4.72 +/- 0.04%, respectively. Results indicated the generation of hydroxyl radical was proportional to the coating rate of Fe3+ on the electrode. A 200 mg kg-1 of IBP-spiked soil sample was conducted in an electrokinetic system under a potential gradient of 2 V cm-1. The experimental parameters included electrode area of 11-33 cm2 and treatment time of 5-9 days. The remediation efficiency of IBP in the EK systems coupled with Fe/Al oxidation electrode was 70.1-94.6%, which was highly dependent on H2O2 addition, electrode area, and treatment time. Both addition of H2O2 and prolonging treatment time significantly enhanced the degradation of IBP. Whereas increasing electrode area was only favorable for removal mechanism of IBP. Five reaction mechanisms were clearly provided in this study. The aluminum plays an electron donner to trigger Fenton-like reaction continuously to produce hydroxyl radicals. This study confirmed that the electrokinetic process coupled with Fe/Al oxidation electrodes is a viable technique for the remediation of IBP-contaminated soil. Make good use of redox characteristic of aluminum to trigger the Fenton-like reaction in Fe2+ rich environment is a great success in this study. The use of Fe/Al electrodes effectively expands the application of electrochemical degradation in soil remediation. PMID- 30021286 TI - Benzophenone-UV filters in personal care products and urine of schoolchildren from Shenzhen, China: Exposure assessment and possible source. AB - The use of benzophenone (BP)-type UV filters in personal care products (PCPs) has rapidly increased in China over the past decade, leading to growing concerns on the potential adverse effects associated with the usage. Urine analysis is an ideal non-invasive approach for human biomonitoring of xenobiotics that are excreted mainly through urinary system. To investigate human exposure of PCPs to children from South China, we determined BP-type UV filters in a total of 156 commercial PCP goods covering 11 categories, as well as 280 urine samples collected from elementary school students in Shenzhen, China. Five BP analogues (i.e., BP1, BP2, BP3, BP8, and 4HB) were frequently detected in both PCPs and urine, among which BP3 was the dominant analogue, accounting for 96.3% of the total BPs in PCPs and 53.2% in urine, respectively. Sunscreens contained the highest BP concentrations (mean: 2.15 * 104 ng g-1) among all PCP goods. Girls exhibited higher urinary BP concentrations than boys, and body mass index positively influenced BP concentrations. However, no regional difference in urinary BP concentration was observed. The estimated dermal uptake of BPs from PCPs after considering the percutaneous absorption rates was much lower than the estimated dermal intake. The total daily excretion doses estimated from urinary BPs were 74.4 and 47.4 ng.kg-1bw day-1 for girls and boys, respectively. The higher usage of body lotions, hand lotions, and sunscreens by girls than boys (1.49 vs. 1.03 times week-1) might play an important role. PMID- 30021287 TI - Combined application of biochar and nitrogen fertilizer benefits nitrogen retention in the rhizosphere of soybean by increasing microbial biomass but not altering microbial community structure. AB - The application of nitrogen fertilizer and biochar (N-biochar) is one of promising management practices recommended to improve soil fertility. A field trial based on seven treatments (control, urea, urea + biochar, KNO3, KNO3 + biochar, (NH4)2SO4, (NH4)2SO4 + biochar) were carried out in the field. Both rhizosphere and bulk soils were collected after harvest to investigate the response of microorganisms to N-biochar and the influence on N retention. The results showed that N-biochar increased total microbial biomass but did not change the relative proportions of microbial groups compared with the control. Principal component analysis suggested that microbial community structure in the rhizosphere differed from that in bulk soils, with lower ratios of G+/G- bacterial PLFAs, Saturated/Monounsaturated PLFAs and Cyclopropyl/Precursor PLFAs in the rhizosphere. More abundant biomass and better developed community structure in the rhizosphere could be ascribed to labile C from root exudates. The increased N content in soil-plant system as well as the relative high concentration of total N in the rhizosphere indicated that N-biochar benefited N retention towards near-root areas. Redundancy analysis and correlation analysis suggested that both fungi and bacteria were involved in promoting N retention, especially G- bacteria. Biochar-induced high soil pH favored G- bacteria development while the importance of labile C availability from biochar to G- bacterial activity. PMID- 30021288 TI - Spatio-temporal trends and source apportionment of fossil fuel and biomass burning black carbon (BC) in the Los Angeles Basin. AB - In this study, we evaluated the spatial and temporal trends of black carbon (BC) in the Los Angeles Basin between 2012-2013 and 2016-2017. BC concentrations were measured in seven wavelengths using Aethalometers (AE33) at four sites, including central Los Angeles (CELA), Anaheim, Fontana, and Riverside. Sources of BC were quantified using the equivalent black carbon (EBC) model. Results indicate that total BC concentrations nearly doubled in colder period compared to the warm period. Source apportionment results revealed that fossil fuel combustion has higher annual contributions (ranging from 82% in Riverside to 91% in CELA) than biomass burning (ranging from 9.3% in CELA to 18.7% in Riverside) to the total BC concentrations at all sites. This trend was more clearly observed at the sites closer to major freeways, such as CELA and Anaheim. The relative contribution of fossil fuel to total BC concentrations was higher in the warm period, whereas biomass burning had higher contributions in the colder period. The diurnal variation of fossil-fuel-originated BC (BCff) to the total BC concentrations revealed major rises during the traffic rush hours, especially in the warm period. In contrast, the fraction of BC originating from biomass burning (BCbb) peaked at nighttime, particularly in the cold period, reaching values as high as 25-30% of total BC concentration. Moreover, we observed a clear decrease in both absolute BC concentrations as well as relative contributions of BCff to total BC concentrations from 2012-2013 to 2016-2017, which can be attributed to the implementation of strict regulations in California to reduce transportation related PM emissions. Results from the present study suggest that as these regulations become increasingly stricter, the relative contributions of traffic sources to BC also decrease, thereby making the impact of non-fossil fuel combustion sources, such as biomass burning, to the overall BC levels more significant. PMID- 30021289 TI - Antagonistic, synergistic and non-interactive competitive sorption of sulfamethoxazole-trimethoprim and sulfamethoxazole-cadmium (ii) on a hybrid clay nanosorbent. AB - The competitive sorption of the antibiotics sulfamethoxazole (SMX) and trimethoprim (TMP) and SMX-Cd(II) on a hybrid clay nanosorbent (NanoSorb) was investigated in detail in this work. NanoSorb was synthesized by sorbing a surfactant on bentonite. Besides, the sorption of SMX on the NanoSorb was confirmed by FTIR analysis, and SMX was mainly sorbed on NanoSorb by a partition mechanism due to hydrophobic interactions. Otherwise, the single adsorption of Cd(II) and TMP onto NanoSorb were due to electrostatic interaction and hydrophobic partition, respectively. The capacity of NanoSorb for sorbing single SMX was very similar to that for single Cd(II), but more than 10 times higher than that for single TMP. The competitive sorption of SMX-TMP was antagonistic because the sorption of one antibiotic on NanoSorb was decreased by the presence of the other antibiotic. The uptake of SMX was reduced up to 43.4% by the presence of TMP, whereas the presence of SMX decreased the uptake of TMP up to 29.6%. The non-modified Langmuir multicomponent isotherm (NLMI) interpreted quite well the experimental competitive sorption data of SMX-TMP. On the other hand, the competitive sorption of SMX-Cd(II) on NanoSorb revealed that the sorption of SMX was non-interactive because it was not influenced by the presence of Cd(II). Whereas, the sorption of Cd(II) was synergistic or cooperative since the uptake of Cd(II) sorbed increased considerably with the uptake of SMX sorbed on NanoSorb. The two-site Langmuir model fitted the experimental competitive sorption data of Cd(II) on NanoSorb saturated with SMX. The application of this isotherm was based on the fact that Cd(II) sorbed on two types of sites: a) cationic sites of the NanoSorb and b) Pi-cation interactions between the aromatic ring of the SMX sorbed on NanoSorb and Cd2+. PMID- 30021290 TI - Adsorptive immobilization of agro-industrially produced crude laccase on various micro-biochars and degradation of diclofenac. AB - Although enzymes are gifted with unique and unprecedented catalytic activity and selectivity over a wide range of pollutants, still their stability related issues often hinder their application in real environmental conditions. In this study, agro-industrially produced crude laccase was concentrated using ultrafiltration. Crude laccase was immobilized on pine wood (BC-PW), pig manure (BC-PM) and almond shell (BC-AS) biochar microparticles. Immobilization of laccase was investigated at various laccase activities on micro-biochars and the release (desorption) of the enzyme has been studied. It was observed that for all the biochars, as the initial concentration of laccase increased in the crude solution, the binding capacity and as result immobilization efficiency also increased. BC-PM was found to be the most effective (31.4 +/- 3.1 U g-1) at 10 U mL-1 of enzyme activity followed by BC-AS (24.3 +/- 4.8 U g-1) and BC-PW (14.58 +/- 3.3 U g-1). In addition, the biochars were functionalized with citric acid for possible surface modifications and the effect of biochars for the adsorption of enzymes has been investigated. Isotherm studies of enzyme loading onto biochar established homogeneous monolayer adsorption as the major mechanism. The desorption of laccase from all biochars followed pseudo-second-order model. Immobilized laccase exhibited superior storage ability and shelf-life which were three times higher than free laccase. Finally, the immobilized laccase was used for the degradation of micropollutant, DCF and near 100% removal was obtained within 5 h at an environmentally relevant concentration (500 MUg L-1). PMID- 30021291 TI - Mapping magnesium sulfate salts from saline mine discharge with airborne hyperspectral data. AB - Managing saline water discharges from mining operations is a global environmental challenge. Measuring the location and extent of surface efflorescence can indicate solute movement before changes in electrical conductivity (EC) are detected in waterways. We hypothesised through the use of a case study that ground-based reflectance spectrometry and airborne hyperspectral (450-2500 nm) analysis of surface efflorescence could be a rapid method for monitoring large regions of the surrounding environment, including downstream of remote mines. X ray diffraction and X-ray fluorescence were used to determine mineralogy and elemental composition of surface salts around a uranium mine. Salt samples were found to be mixtures of magnesium sulfate. The reflectance of field spectra varied depending on the hydration of the mineral, mainly hexahydrite and starkeyite. A constrained energy minimisation technique was used to match the field reflectance spectra to the airborne data. Airborne matches were confirmed at the field sampling sites and surrounds. Salts were also detected at lower matches at mine water irrigation areas where excess mine water had previously been applied. Hence, hyperspectral remote sensing is a potentially rapid and sensitive method for mapping magnesium sulfates over large areas in operating and rehabilitated mines. It was successfully demonstrated as a tool for monitoring and assessment of efflorescence as a result of saline processes. PMID- 30021292 TI - Long-term photosynthetic CO2 removal from biogas and flue-gas: Exploring the potential of closed photobioreactors for high-value biomass production. AB - The long-term performance of a tubular photobioreactor interconnected to a gas absorption column for the abatement of CO2 from biogas and flue-gas was investigated. Additionally, a novel nitrogen feast-famine regime was implemented during the flue-gas feeding stage in order to promote the continuous storage of highly-energetic compounds. Results showed effective CO2 (~98%) and H2S (~99%) removals from synthetic biogas, supported by the high photosynthetic activity of microalgae which resulted in an alkaline pH (~10). In addition, CO2 removals of 99 and 91% were observed during the flue-gas operation depending on the nutrients source: mineral salt medium and digestate, respectively. A biomass productivity of ~8 g m-2 d-1 was obtained during both stages, with a complete nitrogen and carbon recovery from the cultivation broth. Moreover, the strategy of feeding nutrients during the dark period promoted the continuous accumulation of carbohydrates, their concentration increasing from 22% under normal nutrition up to 37% during the feast-famine cycle. This represents a productivity of ~3 g carbohydrates m-2 d-1, which can be further valorized to contribute to the economic sustainability of the photosynthetic CO2 removal process. PMID- 30021293 TI - Deriving aquatic life criteria for PBDEs in China and comparison of species sensitivity distribution with TBBPA and HBCD. AB - Polybrominated diphenyl ethers (PBDEs) are important industrial brominated flame retardants. PBDEs have raised great concerns for their persistence, bioaccumulation, and harm to aquatic life and human health. Pentabromodiphenyl ether (PeBDE), octabromodiphenyl ether (OcBDE), and decabromodiphenyl ether (DeBDE) are three main commercial PBDEs congeners. In this study, published ecotoxicity data of these three PBDEs congeners for Chinese freshwater species were collected, and several acute and chronic toxicity tests for the three PBDEs congeners were performed. Using the derivation method for aquatic life criteria developed by the United States Environmental Protection Agency (USEPA), we determined that the criterion maximum concentration (CMC) for PeBDE, OcBDE and DeBDE for protection of freshwater organisms were 0.0492 mg/L, 0.197 mg/L and 0.239 mg/L, respectively. The criterion continuous concentration (CCC) for PeBDE, OcBDE and DeBDE were 0.0103 mg/L, 0.0224 mg/L and 0.0267 mg/L, respectively. The results provided a good reference for the derivation of PBDEs' water quality criteria and a basis for ecological risk assessment of PBDEs. In addition, the results of species sensitivity distribution comparison showed that the toxicity rank of five brominated flame retardants was TBBPA > PeBDE > OcBDE > DeBDE > HBCD. PMID- 30021294 TI - Corrigendum to "Supplementary feeding stations for conservation of vultures could be an important source of monophasic Salmonella Typhimurium 1,4,[5],12:i:-" [Sci. Total Environ. 636 (2018) 449-455]. PMID- 30021295 TI - Short-term biochar manipulation of microbial nitrogen transformation in wheat rhizosphere of a metal contaminated Inceptisol from North China plain. AB - While metal immobilization had been increasingly reported with biochar soil amendment (BSA), changes in microbial activity and nitrogen (N) transformation in metal contaminated croplands following biochar addition had been insufficiently addressed. In a field experiment, a Pb/Cd contaminated Inceptisol from North China was amended to topsoil with wheat straw biochar at 0 (CK), 20 (C1) and 40 t ha-1 (C2). The changes within two years following BSA were tested in microbial biomass and respiration, and in abundance of N transforming microbial communities and their activities. Corresponding to the results of decreased soil extractable Cd and Pb, significant reductions in qCO2 were found in rhizosphere and bulk soil only under C2 in the first year. The potential nitrification activity was significantly increased by 20-71%, along with an increase in ammonium (by 7-21%) and nitrate (by 21%-70%) concentration, with BSA compared to CK. Meanwhile, N2O production activity was slightly increased (by up to 20%) but N2O reduction activity greatly enhanced (by up to 84%), with a higher ratio of nosZ/(nirS + nirK), under C2 in rhizosphere in both wheat seasons. Whereas, such changes were not remarkable in bulk soil. Moreover, microbial communities were less respondent to biochar in the second year following the addition. Therefore, microbial growth and functioning for N transforming and cycling in metal contaminated soils could be largely improved with BSA at 40 t ha-1. Of course, studies are still deserved to mimic the long term changes with biochar in N cycling of the metal contaminated dry croplands. PMID- 30021296 TI - Rhizosheaths stimulate short-term root decomposition in a semiarid grassland. AB - Rhizosheaths are frequently found in arid and semiarid ecosystems, but their impacts on root decomposition rates and associated carbon (C) and nutrient fluxes remain unclear. We investigated mass, C and nitrogen (N) loss for the roots of Stipa krylovii and Carex korshinskii; the roots were exposed to rhizosheaths, bulk soil, or no soil in litterbags during a 102-d short-term decomposition experiment. Compared with no soil addition, rhizosheath addition increased the mass loss by 39% for S. krylovii, a sheath-forming grass, and by 11% for C. korshinskii, a non-sheath-forming grass. Rhizosheath addition also increased root C loss by 39% and N loss by 41% for S. krylovii but did not significantly alter root C or N loss for C. korshinskii, which may be due to a "home-field advantage" effect. In contrast, bulk soil addition did not alter mass, C, or N loss for either plant species, possibly because bulk soils contained fewer nutrients (C, N, and phosphorus) than rhizosheaths. We demonstrate for the first time that conventional root decomposition studies that do not account for rhizosheaths will underestimate the root mass, C and N loss by >20% in semiarid grasslands. Future studies should emphasize the crucial yet unappreciated role of rhizosheaths in driving soil organic matter cycling. PMID- 30021297 TI - Labile and recalcitrant sediment organic carbon pools in the Pearl River Estuary, southern China. AB - Little is known about the labile and recalcitrant sediment organic carbon (SOC) in estuarine ecosystem, and the effects of human activities on SOC sequestration also remain poorly understood. In this study, sediment cores in the Pearl River Estuary (PRE) and adjacent coastal areas in the South China Sea were collected to analyse variations in the sources of SOC and its labile and recalcitrant pools. Concentrations of SOC, microbial biomass carbon (MBC), and recalcitrant organic carbon (ROC) ranged from 4.37 to 10.4 g/kg, 0.522 to 1.53 g/kg, and 1.59 to 5.42 g/kg, respectively, with their corresponding mean values as 7.20 +/- 1.43 g/kg, 0.896 +/- 0.228 g/kg, and 3.71 +/- 1.01 g/kg, respectively. ROC was the chief fraction of SOC, and SOC, MBC and ROC has a similar source. Higher SOC and MBC were observed in the upper sediments, which might be attributable to the enhancement of seawater nutrient and particulate organic carbon concentrations in recent decades. Higher concentrations of SOC, ROC, and SOC stock were found in the inner estuary relative to the outer estuary due to a higher terrigenous organic carbon contribution, while the ratio of water-soluble organic carbon, salt-extractable carbon, and MBC to SOC exhibited a contrasting trend caused by a higher autochthonous contribution. Sand excavation reduced SOC, ROC, ROC/SOC, and SOC stock. The estimated SOC stock of the top 75 cm of sediment in the PRE was 34.0 Mg C ha-1, and the reduction of SOC stock in the PRE due to sea reclamation from 1973 to 2015 was 1,171,159.6 Mg C. Therefore, measures should be taken to control sea reclamation and sand excavation activities in the PRE to enhance carbon sequestration capacity. PMID- 30021298 TI - Short- and medium-chain chlorinated paraffins in the Henan section of the Yellow River: Occurrences, fates, and fluxes. AB - Short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) were measured in sediment and suspended particulate matter (SPM) from the middle and lower reaches of the Yellow River in the three seasons to elucidate their environmental behavior. The mean concentrations of ?SCCPs and ?MCCPs were 262 and 97.1 ng g-1 dw (dry weight) in sediment and 17,055 and 2573 ng g-1 dw in SPM, respectively, and higher SCCP levels did not clearly reflect a shift to more MCCPs in this section of the Yellow River. The predominant homologue groups were C10-CP and C11 CP for SCCPs and C14-CP for MCCPs. The CPs possibly mainly derived from the use of CP commercial mixtures, mainly included CP-42 and CP-52. The spatial distributions and principal component analysis indicated that industrial inputs, dams, and topography played important roles in influencing the environmental behavior of CPs in both sediment and SPM. In addition, decreasing fluxes of CPs were observed in SPM from Tongguan to Aishan stations, particularly in reservoirs, which implies that CPs may have accumulated in the Henan section of the Yellow River. PMID- 30021299 TI - Structure and performance properties of environmentally-friendly biocomposites based on poly(E-caprolactone) modified with copper slag and shale drill cuttings wastes. AB - The potential application of two types of industrial wastes, drill cuttings (DC) and copper slag (CS), as silica-rich modifiers of poly(E-caprolactone) (PCL) was investigated. Chemical structure and physical properties of DC and CS fillers were characterized using X-ray diffractometer, X-ray fluorescence spectroscopy, particle size and density measurements. PCL/DC and PCL/CS composites with a variable content of filler (5 to 50 parts by weight) were prepared by melt compounding in an internal mixer. It was observed that lower particle size of DC filler enhanced processing of biocomposites comparing to CS filler. Smaller particles of DC filler and thus the higher specific surface area, enabled better encapsulation of filler by polymer chains, hence lower porosity and consequently higher tensile properties comparing to PCL/CS biocomposites. It was noticed, that the impact of waste filler characteristics on tensile properties became negligible at higher loadings. This indicates weak interactions between waste filler and PCL matrix, due to aggregation of filler particles and formulation of voids in phase boundary. This phenomenon was confirmed by scanning electron microscopy, headspace analysis and thermogravimetric analysis. Microbial tests revealed that prepared biocomposites show no toxic effect towards analyzed bacterial strains, therefore could be considered as environmentally-friendly. PMID- 30021300 TI - Assessing the effects of temperature and salinity oscillations on a key mesopredator fish from European coastal systems. AB - A population dynamics model was developed to assess the short and long-term effects of temperature and salinity variations in the common goby Pomatoschistus microps in a Portuguese estuary (Minho estuary, NW Portugal). The population was divided into juveniles, females and males, which constituted the model's state variables. Linear regressions between the observed and the predicted density of juveniles, females and the total population were significant. Parameter's sensitivity and uncertainty analysis were estimated. The model was able to satisfactory describe the P. microps population dynamics, and thus was used to simulate the effects of climatic changes on the fish population. Simulations indicated that the common goby population is sensitive to both temperature and salinity changes. Overall, scenarios of more than 3 degrees C increase caused significant population decreases. Similarly, increased salinities led to a population shrinkage, whereas scenarios of salinity decrease generated an opposite variation on the population. According to the IPCC predictions for climatic tendencies, the population of the common goby will tend to decrease in the near future, experiencing marked oscillations (decrease or increase) during climatic extremes, namely droughts and floods, respectively. These results may be a useful for future planning and management of estuarine systems given that the common goby is an important species of estuarine food webs in many temperate ecosystems. PMID- 30021301 TI - Occurrence of beta-lactam and polyether ionophore antibiotics in lagoon water and animal manure. AB - The occurrence of micropollutants in agricultural wastes is an emerging area of interest due to the potential impact of these compounds on the environment. A sensitive and reliable analytical method using liquid chromatography-electrospray tandem mass spectrometry has been developed and validated for the determination of three beta-lactam and three polyether ionophore antibiotics in lagoon water and animal manure matrices. The method was applied to evaluate the occurrence of these compounds from participating farms in northern Colorado. Seven of the 19 lagoon water samples and two of the six animal manures showed detectable. The three targeted beta-lactams (cephapirin, penicillin G, cloxacillin) were found at 0.97-43.31 MUg/L in the lagoon water samples. Of the three targeted polyether ionophores, only monensin (94 to 1077 MUg/L) was detected in the beef runoff pond water samples. Only cloxacillin was measured in the dairy animal manure samples at levels from 8.09 to 45.20 MUg/kg. No cephapirin, penicillin G, cloxacillin, salinomycin, or narasin A were detected in any solid animal manure sample. These results indicate that elevated concentrations of beta-lactam and ionophore compounds might be found in lagoon or runoff pond waters and solid animal manures compared to surface waters, which these compounds are used in veterinary applications. PMID- 30021302 TI - Soil erosion and transport of Imidacloprid and Clothianidin in the upland field under simulated rainfall condition. AB - Surface runoff has been recognized as an important medium of pesticides transport to surface water and groundwater causing critical risk to the aquatic ecosystem. Although total pesticide transport in surface runoff in most cases reported being below 1% of applied mass, much larger losses may occur in extreme cases. In this study, surface runoff potential of Imidacloprid and Clothianidin was investigated in an upland field with 5% slope under two simulated rainfall experiments of 70 mm/h intensity. Additionally, the downward movement of the pesticides was determined in soil (n = 87) taken at several depths on different time scales. The result showed that the second rainfall experiment caused more surface runoff than first rainfall experiment, and accounted 30.0 mm and 21.2 mm of applied rainfall, respectively. The cumulative surface runoff developed during first and second rainfall experiments was equal to 30% and 44% of the applied rainfall, respectively. The sediment transport in runoff was relatively higher in second rainfall than first rainfall, and was mostly stable after 30 min of rainfall. The chemical masses of Imidacloprid and Clothianidin were primarily transported in runoff sediments than runoff water and accounted for 10.8% and 7.93% of the applied mass, respectively. The transport of Imidacloprid both in runoff water and sediment was 1-2 times greater than that of Clothianidin. The concentrations of both pesticides were measured highest in the second fraction of runoff (10 min) collected during the first experiment. In soil, the transport of both pesticides prior to rainfall experiment was 1-2 times greater than post-rainfall experiments. The concentration of these pesticides decreased continuously with the time in the upper layer of soil; while a gradual increase of the pesticides mass was observed in the second soil layer. The cumulative mass transport of both pesticides was directly proportional to the cumulative runoff depth. PMID- 30021303 TI - Global distribution potential and regional environmental risk of F-53B. AB - Recent years have witnessed increases in emissions and environmental contamination by F-53B, a chlorinated polyfluorinated ether sulfonate used as a mist suppressant in the Chinese electroplating industry. In this study, based on a national industrial survey and statistics, we estimated the annual release of F 53B across China during the period 2006-2015. We evaluated the global transport and distribution of F-53B using the Globo-POP model, and assessed its environmental risk in regions of China using the EUSES model. Our calculations indicate that approximately 10-14 metric tons (t) of F-53B are released annually into the environment, mainly in East China. Our Globo-POP calculations demonstrate that a limited fraction (0.02-0.50%) of the cumulative F-53B emissions can reach the Arctic via oceanic advection. Despite its low long-range transport potential, F-53B can accumulate in Chinese local waters. Our EUSES calculations predict that the F-53B concentration in fresh water (South China) currently approaches 0.7 mg/L and will reach 2.3 mg/L by 2020 in the region surrounding chromium-plating plants if its use remains uncontrolled. Such an increase in concentration implies a potential risk to aquatic environments. This study highlights the risk if F-53B is proposed to be used as a substitute for perfluorooctanesulfonic salt-based mist suppressants. PMID- 30021304 TI - Physiological responses to cold stress in the gills of discus fish (Symphysodon aequifasciatus) revealed by conventional biochemical assays and GC-TOF-MS metabolomics. AB - Discus fish (Symphysodon aequifasciatus) is a cichlid that is among the most popular fish for warm-water aquaria and also frequently used as the model animal for environmental science. However, little is known about the responses of S. aequifasciatus to low temperatures caused by environmental variation. Here, by using conventional biochemical assays and gas chromatography time-of-flight mass spectrometry metabolomics, we investigated the physiological responses of S. aequifasciatus gills exposed for 30 days to two temperature regimes: 28 degrees C and 20 degrees C. Low temperature resulted in elevated production of reactive oxygen species but not increased malondialdehyde. This might be partially related to protective responses in the antioxidant system, revealed by increased activities of superoxide dismutase and glutathione peroxidase, and level of reduced glutathione (GSH), compensating for the depletion of catalase activity. A total of 35 metabolites were identified as potential biomarkers of cold stress, showing the most influenced pathways including starch and sucrose metabolism, pentose phosphate pathway, glycerolipid metabolism, sphingolipid metabolism, glutathione metabolism, and arginine and proline metabolism. Moreover, the activation of glutathione metabolism agreed with the increased GSH level detected by biochemical assays. Overall, the results of this study suggest that low temperature can activate a protective antioxidant defence response and modify the metabolic pathways in gills of S. aequifasciatus, providing insights into the physiological regulation in response to cold stress in this tropical fish. PMID- 30021305 TI - Long-term impact of conservation agriculture and diversified maize rotations on carbon pools and stocks, mineral nitrogen fractions and nitrous oxide fluxes in inceptisol of India. AB - Given the increasing scarcity of production resources such as water, energy and labour coupled with growing climatic risks, maize-based production systems could be potential alternatives to intensive rice-wheat (RW) rotation in western Indo Gangetic Plains (IGP). Conservation agriculture (CA) in maize systems has been widely promoted for minimizing soil degradation and ensuring sustainability under emerging climate change scenario. Such practices are also believed to provide mitigation co-benefits through reduced GHG emission and increased soil carbon sequestration. However, the combined effects of diversified crop rotations and CA based management on GHG mitigation potential and other co-benefits are generally over looked and hence warrant greater attention. A field trial was conducted for 5-years to assess the changes in soil organic carbon fractions, mineral-N, N2O emission and global warming potential (GWP) of maize-based production systems under different tillage & crop establishment methods. Four diversified cropping systems i.e. maize-wheat-mungbean (MWMb), maize-chickpea-Sesbania (MCS), maize mustard-mungbean (MMuMb) and maize-maize-Sesbania (MMS) were factorially combined with three tillage & crop establishment methods i.e. zero tilled permanent beds (PB), zero-tillage flat (ZT) and conventional tillage (CT) in a split-plot design. After 5-years of continued experimentation, we recorded that across the soil depths, SOC content, its pools and mineral-N fractions were greatly affected by tillage & crop establishment methods and cropping systems. ZT and PB increased SOC stock (0-30 cm depth) by 7.22-7.23 Mg C ha-1 whereas CT system increased it only by 0.88 Mg C ha-1as compared to initial value. Several researchers reported that SOC & mineral-N fraction contents in the top 30 cm soil depth are correlated with N2O-N emission. In our study, global warming potential (GWP) under CT system was higher by 18.1 and 17.4%, compared to CA-based ZT and PB, respectively. Among various maize systems, GWP of MMS were higher by 11.2, 6.7 and 6.6%, compared that of MWMb (1212 kg CO2-eq. ha-1), MCS (1274 kg CO2-eq. ha-1) and MMuMb (1275 kg CO2-eq. ha-1), respectively. The results of our study suggest that CA and diversified crop rotations should be promoted in north-western IGP and other similar agro-ecologies across the globe for ensuring food security, restoration of soil health and climate change mitigation, the key sustainable development goals (SDGs). PMID- 30021306 TI - Diclofenac, carbamazepine and triclocarban biodegradation in agricultural soils and the microorganisms and metabolic pathways affected. AB - The incomplete elimination of pharmaceuticals and personal care products (PPCPs) during wastewater treatment has resulted in their detection in the environment. PPCP biodegradation is a potential removal mechanism; however, the microorganisms and pathways involved in soils are generally unknown. Here, the biodegradation of diclofenac (DCF), carbamazepine (CBZ) and triclocarban (TCC) in four agricultural soils at concentrations typically detected in soils and biosolids (50 ng g-1) was examined. Rapid DCF removal (<7 days) was observed under aerobic conditions, but only limited biodegradation was noted under other redox conditions. CBZ and TCC degradation under aerobic conditions was slow (half-lives of 128-241 days and 165 190 days for CBZ and TCC). Phylotypes in the Proteobacteria, Gemmatimonadales and Actinobacteria were significantly more abundant during DCF biodegradation compared to the controls (no DCF). For CBZ, those in the Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia were enriched compared to the controls. Actinobacteria and Proteobacteria were also enriched during TCC biodegradation. Such differences could indicate these microorganisms are associated with the biodegradation of these compounds, as they appear to be benefiting from their removal. The impact of these PPCPs on the KEGG pathways associated with metabolism was also examined. Four pathways were positively impacted during DCF biodegradation (propanoate, lysine, fatty acid & benzoate metabolism). These pathways are likely common in soils, explaining the rapid removal of DCF. There was limited impact of CBZ on the metabolic pathways. TCC removal was linked to genes associated with the degradation of simple and complex substrates. The results indicate even low concentrations of PPCPs significantly affect soil communities. The recalcitrant nature of TCC and CBZ suggests soils receiving biosolids could accumulate these chemicals, representing risks concerning crop uptake. PMID- 30021307 TI - Metabolic routes involved in the removal of linear alkylbenzene sulfonate (LAS) employing linear alcohol ethoxylated and ethanol as co-substrates in enlarged scale fluidized bed reactor. AB - In this study, the microbial community characterization and metabolic pathway identification involved in the linear alkylbenzene sulfonated (LAS) degradation from commercial laundry wastewater in a fluidized bed reactor (FBR) on an increased scale were performed using the Illumina MiSeq platform. Ethanol and non ionic surfactant (LAE, Genapol C-100) were used as co-substrates. The FBR was operated in five operational phases: (I) synthetic substrate for inoculation; (II) 7.9 +/- 4.7 mg/L LAS and 11.7 +/- 6.9 mg/L LAE; (III) 19.4 +/- 12.9 mg/L LAS, 19.6 +/- 9.2 mg/L LAE and 205 mg/L ethanol; (IV) 25.9 +/- 11 mg/L LAS, 19.5 +/- 9.1 mg/L LAE and 205 mg/L ethanol and (V) 43.9 +/- 18 mg/L LAS, 25 +/- 9.8 mg/L LAE and 205 mg/L ethanol. At all operation phases, organic matter was removed from 40.4 to 85.1% and LAS removal was from 24.7 to 56%. Sulfate-reducing bacteria (SRB) were identified in the biofilm of FBR in all operational phases. Although the LAS promoted a toxic effect on the microbiota, this effect can be reduced when using biodegradable co-substrates, such as ethanol and LAE, which was observed in Phase IV. In this phase, there was a greater microbial diversity (Shannon index) and higher microorganism richness (Chao 1 index), both for the Domain Bacteria, and for the Domain Archaea. PMID- 30021308 TI - Chromium(VI) removal by siderite (FeCO3) in anoxic aqueous solutions: An X-ray absorption spectroscopy investigation. AB - Chromium(VI) is an environmental contaminant of priority concern, which can be treated by reduction of toxic Cr(VI) to non-toxic Cr(III). Siderite (FeCO3), an Fe(II)-containing mineral, occurs in many anaerobic sediments and groundwater systems and is extremely reactive, thus making it a potentially important host phase in governing the fate and transport of Cr(VI) in a range of anoxic aqueous environments. Here, we investigate the fate of Cr(VI) during sorption and reduction by siderite, as well as speciation of Cr(VI)-reacted siderite as a function of varying pH (4-10) and initial Cr(VI) concentrations (0.5-10 mM) under strictly oxygen-free conditions. Notably, up to 97% and 91% of initial added aqueous Cr(VI) (0.5-10 mM) was reduced to Cr(III) at pH 4 and 5, respectively. However, the reduction efficiency of Cr(VI) by siderite slightly decreased in the pH range from 6 to 10 (~90% Cr(III)), only at 0.5-1.5 mM initial Cr(VI) concentrations. Chromium K-edge XANES spectroscopy confirmed the complete reduction of sorbed Cr(VI) to Cr(III) after equilibration of siderite with low (2 mM) and high (10 mM) initial Cr(VI) concentrations at pH 5, 7 and 9. In addition, Fe K-edge XANES and EXAFS spectra of solid-phase samples showed that 74-78% and 78-89% of Fe remained as siderite, respectively, after equilibration with Cr(VI) at pH 7 and 9, whereas only 24% remained for the low Cr(VI) treatment at pH 5. The results imply that under anoxic aqueous conditions, siderite can help immobilize and detoxify Cr(VI) with the extent of these coupled sorption and redox reactions being controlled by initial Cr(VI) concentrations and pH. PMID- 30021309 TI - Variability and uncertainty of particle build-up on urban road surfaces. AB - Particle build-up is a key stormwater pollutant process that is typically replicated using a power function with increasing antecedent dry days. Though the use of a power function is recommended by a range of researchers, its applicability is demonstrated primarily for residential roads. Particle build-up process is also subjected to significant variability due to catchment heterogeneity and variability associated with source characteristics such as traffic and land use. Variability in the build-up process and use of stereotypical coefficients can lead to significant model uncertainty. This study evaluates particle build-up characteristics on urban road surfaces using an extensive field investigation program, giving specific priority to industrial and commercial roads. Based on the outcomes, particle build-up process characteristics and respective uncertainties were evaluated and compared for road surfaces in residential, industrial and commercial areas. The study primarily found that both, industrial and commercial land uses generally manifested greater particle build-up loads compared to residential land uses. The study provides estimates for build-up coefficients for a range of land uses, including industrial and commercial with their potential uncertainties in build-up predictions. This provides new knowledge to improve stormwater quality modelling. Aside from land use, the proximity of sites to major road networks was also identified as a critical factor influencing the variability and uncertainty in particle build-up. Variability of the fraction of particles in the <75 MUm size range with antecedent dry days exerts the most distinct influence on particle build-up variability across all land uses. The outcomes of this research study are expected to enhance stormwater quality monitoring, modelling and remediation, and thereby promoting greater protection of human and aquatic ecosystem health. PMID- 30021310 TI - Persistence of the antibiotic sulfamethoxazole in river water alone or in the co presence of ciprofloxacin. AB - Sulfamethoxazole and ciprofloxacin are among the most prescribed antibiotics and are frequently detected in surface water ecosystems. The aim of this study was to assess the role of a riverine natural microbial community in sulfamethoxazole (SMX) degradation in presence and absence of ciprofloxacin (CIP). River samples were collected from a stretch of the Tiber River highly impacted by human pressure. An experimental set up was performed varying some abiotic (dark/UV light) and biotic (presence/absence of microorganisms) conditions that can affect antibiotic degradation. The residual concentrations of SMX and CIP were measured (HPLC-MS or HPLC-UV/FLD) and the effects on the natural microbial community were assessed in terms of microbial number (N. live cells/mL) and structure (Fluorescence In Situ Hybridization - FISH). Finally, the occurrence of the antibiotic resistance sul1 gene was also verified using quantitative PCR (qPCR). In 28 days, in the presence of both UV-light and microorganisms SMX disappeared (75%) of 16 contaminants of emerging concern (CECs), which include a variety of pharmaceuticals (e.g., sulfamethoxazole and ibuprofen), X-ray contrast agent (i.e., iopromide), and pesticides (e.g., atrazine) that are prevalently found in municipal waste streams. Proteobacteria and Planctomycetes were the most abundant phyla in filter media, while the influent and effluent samples were dominated by Proteobacteria, Actinobacteria, and Chlamydiae. Factorial and principal component analysis revealed microbial structures in the media were significantly affected by the operation conditions, including media type (GAC versus dual media anthracite sand), EBCT (10 versus 18 min), and pre-ozonation. Detrended correspondence analysis demonstrated media materials predominantly governed the structures of the acclimated biofilm in BAFs as they provide direct attachment surface. This is in line with the higher microbial activity and better treatment performance exhibited by GAC BAFs compared to the dual media BAFs, corroborating the importance of filter media selection to promote the acclimation of active and robust biofilm for efficient CEC removal. Principal component analysis revealed the significant influence from ozonation, which does not only break down CECs, but also stimulates microbes that grow on the ozonation products. Partial canonical correlation analysis further proved the shaping of biofilm communities on the BAF media is more associated with media type and ozonation compared to EBCT. Putative CEC degraders are predicted based on their dominance in the media and degradation capabilities reported in previous literature. This is the first study to examine the relationship between the microbial community structure and the BAF operating parameters, which are both aligned with the treatment performance exhibited by the BAFs. PMID- 30021314 TI - Investigation of the potential risk of coal fire to local environment: A case study of Daquanhu coal fire, Xinjiang region, China. AB - Underground coal fires are disasters associated with coal mining activities. This study, attempts to investigate the impact of coal fires on the soil and atmosphere by measuring heavy metal concentration and borehole gas emissions for the Daquanhu coal fire zone. Different methods and equipment were used in this study, such as remote sensing, determination of the surface temperature and vegetation, field meteorological surveys, air/smoke analysis, flame photometry, atomic absorption spectrophotometry, atomic fluorescence spectrophotometry, and alkali diffusion. The results show that the surface temperature of the Daquanhu coal fire zone was reduced with a progress in coal fire extinction since 2015. Surface vegetation grew better in 2016 than in other years. The mercury (Hg) content in the western part of the fire zone is much higher than that in other parts of the fire zone. The arsenic (As) content in the eastern part is much higher than that of other parts. Data show that the estimated total amount of gas emissions during fire extinction is ~31,500 kg for CO, 489 kg for SO2, 12,885 kg for NO, 576 kg for NO2, and 20,295 kg for NOx. The intensity of the gas emissions during extinction is notably higher than that before extinction. The results also indicate coal fire's potential risk to adjacent communities, especially the risks associated with borehole injection of large amounts of possible harmful slurry, which needs to be taken seriously. PMID- 30021315 TI - Impact of industrial waste water treatment plants on Dutch surface waters and drinking water sources. AB - Direct industrial discharges of Chemicals of Emerging Concern (CEC) to surface water via industrial wastewater treatment plants (IWTP) gained relatively little attention compared to discharges via municipal sewage water treatment plants. IWTP effluents may however seriously affect surface water quality. Here we modelled direct industrial emissions of all 182 Dutch IWTP from 19 different industrial classes, and derived their impact on Dutch surface water quality and drinking water production. We selected industrial chemicals relevant for drinking water production, however a lack of systematic information on concentrations in IWTP effluents for many chemicals of interest was found. Therefore, we used data from the European Pollutant Release and Transfer Register and data on Dutch IWTP as surrogate. We coupled these to a detailed hydrological model under two extreme river discharge conditions, and compared the predicted and measured concentrations. We derived relative impact factors for the IWTP based on their contribution to concentrations at surface water locations with a drinking water function. In total, a third of the abstracted water for drinking water production is influenced by the IWTP. From all Dutch 182 IWTP, only a limited number has - based on the model approach using surrogate parameters - a high impact on surface waters with a drinking water function. Mitigation measures can be taken cost efficiently, by placing extra treatment technologies at the IWTP with high impact. Finally, we propose recommendations for licensing and controlling industrial aqueous emissions and give suggestions to fill the currently existing knowledge gaps and diminish uncertainties in the approach. PMID- 30021317 TI - Airborne particulate matter biotoxicity estimated by chemometric analysis on bacterial luminescence data. AB - In this work, PM10 samples previously subjected to thorough chemical speciation and receptor modelling, have been investigated for their bio-toxicity using an inhibition test based on bacterial luminescence modulation when in contact with airborne particulate samples. The variation of light emission intensity from a luminescent bacteria strain, the Photobacterium phosphoreum, is proposed as an efficient proxy for the quantification of bio-toxic effects induced by airborne particulate matter. PM10 samples characterized by definite levels of pollutants from the pertaining air shed were found to induce a decrease in the bacterial bioluminescence intensity, expressed as percentage of Inhibition Ratio (IR%). This behaviour suggests the decay of this energy-consuming activity because of a toxic effect. Cluster analysis on chemical composition and IR% data provides evidence of a statistically significant association between the adverse effects on living cells and the range of specific chemical species in PM10. PMID- 30021316 TI - First record of bioaccumulation and bioconcentration of metals in Scleractinian corals and their algal symbionts from Kharg and Lark coral reefs (Persian Gulf, Iran). AB - Metal pollution is nowadays a serious threat worldwide for ecosystem and human health. Despite that, there is still a paucity of data on metal impact on coral reef ecosystems. Herein, the levels of eleven metals (Mn, Zn, Cu, Cr, Co, Ni, V, As, Cd, Hg, Pb) were assessed in surface sediments, seawater samples, Scleractinian corals (tissue and skeleton) and their algal symbionts collected from Kharg and Lark coral reefs in the Persian Gulf, Iran. At Kharg, surface sediments and seawater showed higher concentrations of metals than Lark, attributable to the higher metal loads and petrochemical activities in the area. Sediment quality guidelines indicated Hg as a serious threat to biota both at Kharg and Lark. Accordingly, metals bioaccumulation and bioconcentration was higher in corals from Kharg relatively to Lark Island. Interestingly, as supported by values of BCFs and BSAFs, metal accumulation was higher in coral tissues in respect to skeletons, and in zooxanthellae relatively to coral tissues at both coral reefs. Differential metal bioaccumulation was found among Scleractinian species, indicating that corals have distinct selectivity for assimilating metals from ambient sediments and seawater. Overall, metal accumulation in corals and zooxanthellae is an appropriate tool for environmental monitoring studies in coral reefs. Noteworthy, the use of Porites lutea, among Scleractinian corals, seems to be as a good bioindicator in monitoring studies of metal pollution. PMID- 30021318 TI - Potamodromous brown trout movements in the North of the Iberian Peninsula: Modelling past, present and future based on continuous fishway monitoring. AB - Brown trout uses river flow and thermal regimens as main stimuli for initiating and maintaining behavioral reactions such as migration and spawning. Therefore, anthropogenic alterations on these factors may have strong impacts on its populations. The aim of this work is to understand these consequences by assessing potamodromous brown trout movements in the past and present, and to model future responses. For this, brown trout movements in a fishway in the Marin River (Bidasoa basin, Northern Iberian Peninsula) have been monitored from 2008 to 2017. Random forest regression has been used to assess the influence of environmental variables on brown trout movements and to model the response under hypothetical climatic and hydrological scenarios. Results show that brown trout uses the fishway during the whole year, with more upstream movements during the spawning season. The model is able to predict accurately the timing and number of migrants. Its use under hypothetical climate change and flow regulation scenarios shows a delay in the migration time. Therefore, modelling using large time series can be a powerful tool to define management and conservation strategies and prepare compensation measures for future scenarios. PMID- 30021319 TI - Sublethal and chronic effects of reclaimed water on aquatic organisms. Looking for relationships between physico-chemical characterisation and toxic effects. AB - The use of reclaimed water for irrigation and aquaculture purposes is generally considered a reliable alternative for sustainable water management in regions with water scarcity. Many organic compounds, generally called compounds of emerging concern (CECs), have been detected in reclaimed water, which implies continuous exposure for aquatic organisms. To date no quality criteria have been proposed for this group of compounds. This work aims to assess the acute, sublethal and chronic effects of reclaimed water using two representative organisms of the aquatic compartment; the green alga Chlorella vulgaris and the microcrustacean Daphnia magna. The study comprises the 72 h-algal growth inhibition test, the D. magna feeding bioassay and the D. magna reproduction test. The results highlighted, for the selected characterised compounds, no differences in the concentrations between the different tertiary WWTP treatments, except for the particular case of carbamazepine. Considering seasonality, no differences were observed between the two different sample collection campaigns. The sublethal and chronic effects observed for these samples could not be explained by the lower concentrations found in the chemical characterisation. However, in the majority of cases, dilution of raw reclaimed water reduced the toxic effects of these samples. Several interactions among compounds can affect the mixture's toxicity. Canonical correlation analyses (CCA) were included to explore the potential relationships between the physico-chemical characterisation of reclaimed water and effects on aquatic organisms. The results corroborated the toxic effect of some pharmaceuticals, in particular beta-blockers and antibiotics, on the growth and yield of green algae, as well as inhibition of daphnia reproduction. Thus the CCA methods could help to elucidate the potential relationships between the physico-chemical characterisation and toxic effects by considering all the potential interactions. PMID- 30021320 TI - Effect of climate change on humic substances and associated impacts on the quality of surface water and groundwater: A review. AB - Humic substances (HS), a highly transformed part of non-living natural organic matter (NOM), comprise up to 70% of the soil organic matter (SOM), 50-80% of dissolved organic matter (DOM) in surface water, and 25% of DOM in groundwater. They considerably contribute to climate change (CC) by generating greenhouse gases (GHG). On the other hand, CC affects HS, their structure and reactivity. HS important role in global warming has been recognized and extensively studied. However, much less attention has been paid so far to effects on the freshwater quality, which may result from the climate induced impact on HS, and HS interactions with contaminants in soil, surface water and groundwater. It is expected that an increased temperature and enhanced biodegradation of SOM will lead to an increase in the production of DOM, while the flooding and runoff will export it from soil to rivers, lakes, and groundwater. Microbial growth will be stimulated and biodegradation of pollutants in water can be enhanced. However, there may be also negative effects, including an inhibition of solar disinfection in brown lakes. The CC induced desorption from soil and sediments, as well as re mobilization of metals and organic pollutants are anticipated. In-situ treatment of surface water and groundwater may be affected. Quality of the source freshwater is expected to deteriorate and drinking water production may become more expensive. Many of the possible effects of CC described in this article have yet to be explored and understood. Enormous potential for interesting, multidisciplinary studies in the important research areas has been presented. PMID- 30021321 TI - Importance of fisheries for food security across three climate change vulnerable deltas. AB - Deltas are home to a large and growing proportion of the world's population, often living in conditions of extreme poverty. Deltaic ecosystems are ecologically significant as they support high biodiversity and a variety of fisheries, however these coastal environments are extremely vulnerable to climate change. The Ganges-Brahmaputra-Meghna (Bangladesh/India), the Mahanadi (India), and the Volta (Ghana) are among the most important and populous delta regions in the world and they are all considered at risk of food insecurity and climate change. The fisheries sector is vital for populations that live in the three deltas, as a source of animal protein (in Bangladesh and Ghana around 50-60% of animal protein is supplied by fish while in India this is about 12%) through subsistence fishing, as a source of employment and for the wider economy. The aquaculture sector shows a rapid growth in Bangladesh and India while in Ghana this is just starting to expand. The main exported species differ across countries with Ghana and India dominated by marine fish species, whereas Bangladesh exports shrimps and prawns. Fisheries play a more important part in the economy of Bangladesh and Ghana than for India, both men and women work in fisheries, with a higher proportion of women in the Volta then in the Asian deltas. Economic and integrated modelling using future scenarios suggest that changes in temperature and primary production could reduce fish productivity and fisheries income especially in the Volta and Bangladesh deltas, however these losses could be mitigated by reducing overfishing and improving management. The analysis provided in this paper highlights the importance of applying plans for fisheries management at regional level. Minimizing the impacts of climate change while increasing marine ecosystems resilience must be a priority for scientists and governments before these have dramatic impacts on millions of people's lives. PMID- 30021322 TI - A survey of multiple pesticide residues in pollen and beebread collected in China. AB - Honeybees, as major pollinators, make vital contributions to humans and ecosystems. Worryingly, a phenomenon known as honeybee colony losses has been reported in recent years. One of the factors underlying the occurrence of honeybee colony losses is exposure of honey bees to pesticide residues in their food, which cause detrimental sublethal effects and may lead to the collapse of their colonies. In this paper, 189 pollen samples and 226 beebread samples collected from five major beekeeping areas in China were analyzed from spring 2016 to autumn 2017. The most common active ingredient residues found include the insecticides (imidacloprid, thiamethoxam, fenpropathrin, bifenthrin and chlorpyrifos), the acaricides (coumaphos and fluvalinate) and the fungicides (carbendazim and triadimefon). Our data shows that the residual level of three chemicals (i.e. imidacloprid, thiamethoxam and chlorpyrifos) was higher in pollen than in beebread. Moreover, contamination of pollen and beebread was most serious in spring and in the middle and lower reaches of the Yellow River Area of China. Our data lay the foundation for the risk assessment of pesticides on honeybees in China. PMID- 30021323 TI - Comparative behavioral toxicology with two common larval fish models: Exploring relationships among modes of action and locomotor responses. AB - Behavioral responses inform toxicology studies by rapidly and sensitively detecting molecular initiation events that propagate to physiological changes in individuals. These behavioral responses can be unique to chemical specific mechanisms and modes of action (MOA) and thus present diagnostic utility. In an initial effort to explore the use of larval fish behavioral response patterns in screening environmental contaminants for toxicity and to identify behavioral responses associated with common chemical specific MOAs, we employed the two most common fish models, the zebrafish and the fathead minnow, to define toxicant induced swimming activity alterations during interchanging photoperiods. Though the fathead minnow (Pimephales promelas) is a common model for aquatic toxicology research and regulatory toxicology practice, this model has received little attention in behavioral studies compared to the zebrafish, a common biomedical model. We specifically compared behavioral responses among 7 different chemicals (1-heptanol, phenol, R-(-)-carvone, citalopram, diazinon, pentylenetetrazole (PTZ), and xylazine) that were selected and classified based on anticipated MOA (nonpolar narcosis, polar narcosis, electrophile, specific mechanism) according to traditional approaches to examine whether these comparative responses differ among chemicals with various structure-based predicted toxicity. Following standardized experimental guidelines, zebrafish embryos and fathead minnow larvae were exposed for 96 h to each compound then were observed using digital behavioral analysis. Behavioral observations included photomotor responses, distance traveled, and stimulatory, refractory and cruising locomotor activity. Though fathead minnow larvae displayed greater behavioral sensitivity to 1 heptanol, phenol and citalopram, zebrafish were more sensitive to diazinon and R (-)-carvone. Both fish models were equally sensitive to xylazine and PTZ. Further, the pharmaceuticals citalopram and xylazine significantly affected behavior at therapeutic hazard values, and each of the seven chemicals elicited unique behavioral response profiles. Larval fish behaviors appear useful as early tier diagnostics to identify mechanisms and pathways associated with diverse biological activities for chemicals lacking mechanistic data. PMID- 30021324 TI - Application of response surface methodology in physicochemical removal of dyes from wastewater: A critical review. AB - Response surface methodology (RSM) is a powerful tool in designing the experiments and optimizing different environmental processes. However, when it comes to wastewater treatment and specifically dye-containing wastewater, two questions arise; "Is RSM being used correctly?" and "Are all capabilities of RSM being exploited properly?". The current review paper aims to answer these questions by scrutinizing different physicochemical processes that utilized RSM in dye removal. The literature that applied RSM to adsorption, advanced oxidation processes, coagulation/flocculation and electrocoagulation processes were critically reviewed in this paper. The common errors in applying RSM to physicochemical removal of dyes are identified and some suggestions are made for future studies. PMID- 30021325 TI - CO2 oversaturation and degassing using chambers and a new gas transfer velocity model from the Three Gorges Reservoir surface. AB - Reservoirs are considered as important carbon source of the atmosphere, whilst, regional and global reservoir CO2 quantification is hampered by data limitation and bias in spatial and temporal sampling. By deploying chamber measurements and employing the newly developed model of gas transfer velocity, CO2 partial pressure (pCO2) and evasion in the main stem of the Three Gorges Reservoir (TGR) were investigated. The pCO2 ranged from 429 to 8668 MUatm with an average of 2511.6 +/- 1721.3 MUatm, 6.1-fold higher than the ambient air pCO2 (mean: 410 MUatm). All the samples were net CO2 sources via water-air interface, displaying pronounced spatial and monthly variability. The CO2 areal flux averaged 212.5 +/- 120.1 mmol/m2/d in June, 123.3 +/- 78.5 mmol/m2/d in July in the lotic TGR main stream, much higher than its lentic system, i.e., 79.6 +/- 41.3 mmol/m2/d in November, and 76.3 +/- 88.1 mmol/m2/d in March. Much lower k levels in the lentic reservoir surface resulted in lower CO2 evasion rates. Furthermore, dam impoundment considerably altered the riverine carbon cycle, as reflected by the changing magnitude of CO2 efflux and environmental controls of dissolved CO2. Precipitation and concurrent soil CO2 influx exhibited a central role in controlling riverine pCO2, and respiration of allochthonous organic carbon was a secondary factor in the TGR lotic system, whilst, both in-stream metabolism and terrestrial inputs played crucial roles in controlling aqueous CO2 in the TGR lentic system. In comparison, we provided key findings of k model and more reliable CO2 quantification with a consideration of water level shifts and a complete coverage of spatial sampling. Our higher CO2 emission (1.47 (1.16-2.13) Tg CO2/y) than previous studies called more field measurements to assess the resulting changes in CO2 flux owing to dam operation and changing environment, and their implications for regional carbon budgets should be warranted. PMID- 30021326 TI - Multiple environmental factors influence 238U, 232Th and 226Ra bioaccumulation in arbuscular mycorrhizal-associated plants. AB - Ecological consequences of low-dose radioactivity from natural sources or radioactive waste are important to understand but knowledge gaps still remain. In particular, the soil transfer and bioaccumulation of radionuclides into plant roots is poorly studied. Furthermore, better knowledge of arbuscular mycorrhizal (AM) fungi association may help understand the complexities of radionuclide bioaccumulation within the rhizosphere. Plant bioaccumulation of uranium, thorium and radium was demonstrated at two field sites, where plant tissue concentrations reached up to 46.93 MUg g-1 238U, 0.67 MUg g-1 232Th and 18.27 kBq kg-1 226Ra. High root retention of uranium was consistent in all plant species studied. In contrast, most plants showed greater bioaccumulation of thorium and radium into above-ground tissues. The influence of specific soil parameters on root radionuclide bioaccumulation was examined. Total organic carbon significantly explained the variation in root uranium concentration, while other soil factors including copper concentration, magnesium concentration and pH significantly correlated with root concentrations of uranium, radium and thorium, respectively. All four orders of Glomeromycota were associated with root samples from both sites and all plant species studied showed varying association with AM fungi, ranging from zero to >60% root colonisation by fungal arbuscules. Previous laboratory studies using single plant-fungal species association had found a positive role of AM fungi in root uranium transfer, but no significant correlation between the amount of fungal infection and root uranium content in the field samples was found here. However, there was a significant negative correlation between AM fungal infection and radium accumulation. This study is the first to examine the role of AM fungi in radionuclide soil-plant transfer at a community level within the natural environment. We conclude that biotic factors alongside various abiotic factors influence the soil-plant transfer of radionuclides and future mechanistic studies are needed to explain these interactions in more detail. PMID- 30021327 TI - Simultaneous nutrient removal and biomass/lipid production by Chlorella sp. in seafood processing wastewater. AB - Microalgae cultivation in wastewater has received increasing attention in recent years due to its many advantages. In this work, microalgae were cultured in seafood processing wastewater (SPW) for algal biomass and lipid production as well as nutrient removal. The biomass yield of Chlorella sp. achieved in the batch cultivation was 896 mg L-1, indicating that SPW contains a certain amount of nutrients which can be used for the growth of microalgae. However, the maximum specific growth rate of Chlorella sp. cultured in SPW throughout the whole cultivation period was only 0.040 d-1, suggesting that the growth of algal cells was inhibited during the culture process. High concentration of unionized ammonia in the SPW was found to be a factor inhibiting the growth of Chlorella sp. Aerated SPW (ASPW) and diluted SPW (DSPW) proved to be better culture media than SPW without pretreatment. The maximum specific growth rates of Chlorella sp. cultured in ASPW and DSPW during the culture interval were 0.156 and 0.091 d-1, respectively. Aeration pretreatment of SPW reduced the amount of toxic unionized ammonia, while most of the nutrients were retained in the wastewater. Therefore, higher biomass productivity (77.7 mg L-1 d-1) and higher lipid productivity (20.4 mg L-1 d-1) of microalgae were achieved in ASPW. Additionally, improved nutrient removal rates from ASPW were also achieved due to the faster growth of microalgae. The average nutrient removal rates in ASPW during the whole cultivation period were 4.98 and 1.91 mg L-1 d-1 for nitrogen and phosphorus, respectively. PMID- 30021328 TI - Natural forest remnants as refugia for bryophyte diversity in a transformed mountain river valley landscape. AB - Riparian forests are among the most threatened ecosystem types worldwide. Their exploitation and replacement by coniferous plantations affects species pools and contributes to loss of biodiversity. We aimed to investigate bryophyte species pools within different habitat types in a transformed mountain river valley. We especially focused on the contribution of habitat types (relative to their proportional cover) to the species pool of the whole area. The study was conducted along the Czerwona Woda river - a model stream in the Stolowe Mountains National Park (SW Poland, study area: 91.2 ha) - and an example of coniferous plantations replacing natural broadleaved forest vegetation. Our study revealed the presence of 147 bryophyte species. The most valuable habitats in terms of diversity of bryophyte assemblages were remnants of the natural vegetation - broadleaved forests and streams. These habitats, constituting <5% of the study area, hosted ca 40% of the total species pool (61 and 62 species, respectively), while the species pool of Picea abies forests (92 species) was proportional to cover of this habitat type (ca 60%). Remnants of natural vegetation were hotspots of bryophyte diversity within the heavily altered landscape, and may play a future role as sources of recolonization by forest specialists. Our study also confirmed the important role of riparian areas in maintaining bryophyte species diversity at the landscape scale. The river valley studied contributes >20-fold more to the bryophyte species pool of the whole national park than indicated by its size. Thus, river valleys require special treatment - conservation based on natural restoration, and should remain reserved from wood production, as areas providing a wide range of ecosystem services. PMID- 30021329 TI - Estimation of bus emission models for different fuel types of buses under real conditions. AB - Urban buses are heavy vehicles that move frequently throughout the day, and most of them are propelled by heavy-duty diesel engines. For these reasons, they have energy and environmental impacts that should not be ignored. Consequently, the primary objectives of this study were to compare the changes in bus speed, acceleration, and emissions between bus stops, intersections, and road sections by applying statistical methods; and to develop a vehicle specific power (VSP) based artificial neural network (ANN) model to estimate emissions of CO, HC, NOX, and CO2 for four different fuel types of buses including gas-electric hybrid electric buses (GEHE bus), compressed natural gas buses (CNG bus), EURO 4 heavy duty diesel engine buses (EURO 4 bus), and EURO 5 heavy-duty diesel engine buses (EURO 5 bus). The results of t-tests (with p-values varying between <0.001 and 0.026, which were not >0.050) showed that the differences in emissions between different locations and between different fuel types of buses were all statistically significant. In addition, to evaluate the performance of the proposed method, a polynomial regression model using linear, quadratic, and cubic terms of transient speed and acceleration was utilized for comparison. According to the results, the proposed method had more accurate and reliable estimation, which increased the lower 10% of absolute percentage error (Lower-10% APE) by 65.2%; reduced mean absolute percentage error (MAPE) by 41.4%, root mean squared error (RMSE) by 44.9%, and mean absolute error (MAE) by 43.5%; and increased R squared from 0.659 to 0.781. PMID- 30021330 TI - Elucidation of the oxidation mechanisms and pathways of sulfamethoxazole degradation under Fe(II) activated percarbonate treatment. AB - Fe(II) activated sodium percarbonate (SPC) process (SPC/Fe(II)) could efficiently remove sulfamethoxazole (SMX) in the aqueous phase, and has the potential in groundwater remediation. However, the degradation mechanisms, especially the degradation products and pathways till now have remained unclear. In the present study, intermediate products were identified using high resolution liquid chromatography coupled with ion trap and time-of-flight mass spectrometry (LCMS IT-TOF). Nine intermediate products were identified, six of which have not yet been reported during the oxidation of SMX. The oxidation mechanisms involved hydroxyl substitution, the cleavage of sulfonamide bond, isoxazole ring opening and a rearrangement following the loss of the SO2-group. Based on the identified intermediate products, the degradation pathways of SMX by SPC/Fe(II) process were illustrated. Fenton's reaction after the dissolution of SPC was proposed as the main reaction mechanisms, which was checked and confirmed by radical species detection tests and radical species scavenging studies. The results showed that although both O2- and HO were present in SPC/Fe(II) system, HO was dominant in the system while O2- was seldom involved in the degradation of SMX. These findings provided useful information and supported the application of this advanced oxidation process for antibiotics elimination in the groundwater. PMID- 30021331 TI - Degradation mechanisms of carbamazepine by delta-MnO2: Role of protonation of degradation intermediates. AB - Carbamazepine (CBZ), a widely used antiepileptic drug, is refractory to biological wastewater treatment. Rapid removal of CBZ is possible using synthetic manganese oxide (delta-MnO2) but the removal mechanisms require further investigation. In this study, CBZ degradation by delta-MnO2 was carried out at different pH to further explore the degradation mechanisms. Results show that CBZ degradation by delta-MnO2 was highly pH dependent, and rapid degradation occurred when pH <2.8. Based on the density functional theory calculations, increasing [H+] not only increased the reactivity of delta-MnO2, but also enhanced the secondary reactions of the intermediates. During the degradation process, protonation of CBZ degradation intermediates, instead of CBZ, played an important role. The overall kinetics of CBZ degradation was then described by the retarded first-order model. The initial rate (rinit) in the model between pH 2.0 and 6.2 was determined to be rinit = (2.41 +/- 0.51) * 10-3[CBZ]1.21[MnO2]1.07[H+]1.41. This is the first report revealing that protonation of intermediates from CBZ degradation can improve the CBZ oxidation by delta-MnO2. The pathways of CBZ degradation by delta-MnO2 were also proposed. The results of this study provide a new insight into the processing mechanism. PMID- 30021332 TI - Isotopic composition of atmospheric precipitation and its tracing significance in the Laohequ Basin, Loess plateau, China. AB - Based on the delta18O and deltaD values in precipitation and related meteorological parameters in the Chinese Loess Plateau (CLP) from June 2014 to April 2016, the effects of temperature and precipitation amount effect on stable isotopic compositions were analyzed, as well as the tracing significance of deuterium excess. The results show that the Local Meteoric Water Line (LMWL) was defined as deltaD = 7.08delta18O + 4.73(R2 = 0.99), with a slope of <8, indicating that a non-equilibrium evaporation process occurred when the drops fell below the cloud base in the arid and semi-arid environment. The temperature effect was defined as deltaD = 0.4536T-46.937.44 (r = 0.113, n = 150, p = 0.168), which shows a weak positive correlation between temperature and isotopic composition. Meanwhile, the precipitation amount effect was defined as deltaD = 0.7883P-34.152 (r = -0.223, n = 150, p = 0.011), which shows a weak negative correlation between temperature and isotope composition. The slopes in cross plotting deltaD - delta18O records were 8.3, 7.7, 7.4, and 6.3, displaying a decreasing trend in the temperature gradient of T <= 0 degrees C, 0 < T <= 10 degrees C, 10 < T <= 20 degrees C and T > 20 degrees C, respectively. The amount effect is significant (deltaD = -7.0946P + 48.686, r = -0.548, n = 20, p = 0.012) in the precipitation range from 10 to 20 mm. The average deuterium excess values in winter were 240/00 and 25.30/00 for 2015 and 2016, respectively; however, the low values of 3.10/00 and 5.50/00 occurred in the summers of 2014 and 2015, respectively. These results suggested that intense sub-cloud evaporation decreased the deuterium excess values in the Chinese Loess Plateau under the climate conditions of the rainy season with high temperatures. However, deuterium excess values of snow in wintertime (LT-1, LT-2) could be reflective of the reliable characteristics of atmospheric vapor for weak sub-cloud evaporation and surface evaporation. PMID- 30021333 TI - Pro-inflammatory responses to PM0.25 from airport and urban traffic emissions. AB - Air traffic is rapidly growing, raising concerns about the air pollution in the surroundings of airports and its impact on public health. However, little is known about the impact of air pollution sources on air quality and health in the vicinity of airports. In this study, the sources and adverse health effects of airport-related particulate matter (PM) were investigated and compared to those of urban traffic emissions. Ambient PM0.25 were collected at the Los Angeles International Airport (LAX) and at a central Los Angeles site (USC campus), along with PM2.5 collected directly from turbine and diesel engines. The particle chemical composition, oxidative potential (OP) (ascorbic acid (AA), and electron spin resonance (ESR) assay) as well as their reactive oxygen species (ROS) activity, inflammatory potential (interleukin (IL) 6 and 8 and tumor necrosis factor (TNF)-alpha) and cytotoxicity on human bronchial epithelial (16HBE) cells were assessed. Chemical composition measurements confirmed that aircraft emissions were the major source to LAX PM0.25, while the sources of the USC samples were more complex, including traffic emissions, suspended road and soil dust, and secondary aerosols. The traffic-related transition metals (Fe and Cu) in LAX and USC samples mainly affected OP values of particles, while multiple factors such as composition, size distribution and internalized amount of particles contributed to the promotion of ROS generation in 16HBE cells during 4 h exposure. Internalized particles in cells might also play an important role in activating inflammatory responses during cell recovery period, with LAX particles being more potent. Our results demonstrated considerable toxicity of airport related particles, even at low exposure concentrations, suggesting that airport emission as source of PM0.25 may also contribute to the adverse effects on public health attributable to PM. The potency of such particles is in the same range as those collected at a site in urban area impacted heavily by traffic emissions. PMID- 30021334 TI - Carolyn Elaine Reed, MD March 4, 1950-November 16, 2012. AB - Carolyn Reed, 48th President of The Society of Thoracic Surgeons, was an accomplished surgeon, an outstanding educator, a dedicated investigator, a role model for both women and men in surgery, and a national leader in our specialty of cardiothoracic surgery. She filled all of these roles extremely well, but most important to her was her role as a physician who truly cared about her patients, friends, and colleagues as was apparent in her 2007 Southern Thoracic Surgical Association Presidential Address, "Patient Versus Customer, Technology Versus Touch: Where Has Humanism Gone?" PMID- 30021335 TI - Current advances of pharmacological properties of 7-chloro-4-(phenylselanyl) quinoline: Prevention of cognitive deficit and anxiety in Alzheimer's disease model. AB - This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4 PSQ) at a dose of 1 mg/kg in memory impairment and anxiety in an Alzheimer's disease (AD) model induced by amyloid beta-peptide (Abeta) (fragment 25-35) in mice. The involvement of acetylcholinesterase (AChE) activity and lipid peroxidation in hippocampus and cerebral cortex was evaluated. Male Swiss mice were pretreated with 4-PSQ (1 mg/kg, intragastrically (i.g.), daily) for fourteen days. Thirty minutes after the first treatment with 4-PSQ, the animals received a single injection of Abeta (3 nmol/3 MUl/per site, intracerebroventricular (i.c.v.)). Mice were submitted to the behavioral tasks (open-field, elevated plus maze, Barnes maze, object recognition and location, and step-down inhibitory avoidance tests) from the fifth day onwards. On the fifteenth day, blood was removed for analysis of biochemical markers (glucose, triglycerides, urea, aspartate (AST) and alanine (ALT) aminotrasferases), and cerebral cortex and hippocampus for determination of AChE activity and thiobarbituric acid reactive species (TBARS) levels. Abeta caused memory impairment, anxiogenic behavior, increased AChE activity in the cerebral structures and TBARS levels in the cerebral cortex. 4-PSQ was effective to protect against behavioral changes, AChE activity and TBARS levels. In conclusion, 4-PSQ protected against learning and memory impairment and anxiety in a mouse model of AD induced by Abeta, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound. PMID- 30021336 TI - Protective effects of Spinacia oleracea seeds extract in an experimental model of schizophrenia: Possible behavior, biochemical, neurochemical and cellular alterations. AB - Schizophrenia is one of the psychotic mental disorders characterized by symptoms of thought, behavior, and social problems. Newer biomedicine and pharmacotherapy has been investigated for the treatment of various neuropsychiatric disorders in the past few decades. Spinacia oleracea is one of these, reported to have beneficial effect against several neurodegenerative disorders. The present study was carried to explore the protective effects of Spinacia oleracea seed extract (SOEE) in an experimental model of ketamine-induced schizophrenia in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioral studies (locomotor activity, stereotype behaviors, immobility duration and memory retention) were carried out to investigate the protective of SOEE on ketamine-induced psychotic symptoms, followed by biochemical, neurochemical and cellular alterations in the brain. Treatment with SOEE for 15 consecutive days significantly attenuated stereotyped behavioral symptoms in mice. Biochemical estimations revealed that SOEE reduced lipid peroxidation and restored total brain proteins. Furthermore, SOEE remarkably reduced dopamine levels, AChE activity & inflammatory surge (serum TNF-alpha) and increased the levels of GABA and reduced glutathione in mice. The outcomes of the study suggested that SOEE could ameliorate ketamine-induced psychotic symptoms in mice, indicating a protective effect in the treatment of schizophrenia. PMID- 30021337 TI - 17-DMAG-loaded nanofibrous scaffold for effective growth inhibition of lung cancer cells through targeting HSP90 gene expression. AB - Up-regulation of heat shock protein 90 (HSP90) gene takes place in lung cancer cells. Therefore, targeting HSP90 in lung cancer may be promising step in lung cancer therapy. The present study aimed to evaluate the efficiency of implantable 17-dimethylaminoethylamino-17-demethoxy geldanamycin (17-DMAG)-loaded Poly(caprolactone)-poly(ethylene glycol) (PCL/PEG) nanofibers to increase the anti-cancer effects via inhibition of HSP90 expression and telomerase activity. For this purpose, 17-DMAG-loaded PCL/PEG nanofibers were successfully fabricated via electrospinning and characterized using FE-SEM and FTIR. Colorimetric MTT assay was used to determine the drug cytotoxicity. Also, the expression levels of HSP90 mRNA in the A549 cells treated with the nanofibers were assessed using Quantitative Real-Time PCR. The effect of free 17-DMAG and 17-DMAG-loaded PCL/PEG nanofiber treatment on telomerase activity was monitored by TRAP assay. MTT assay confirmed that loading of 17-DMAG into PCL/PEG nanofiber enhanced dramatically cytotoxicity in the lung cancer cells. This finding was associated with reduction of HSP90 mRNA expression and telomerase activity in the cells seeded on 17-DMAG loaded PCL/PEG nanofibers in relative to free 17-DMAG. In conclusion, the findings demonstrated that 17-DMAG-loaded PCL/PEG nanofibers are more effectual than free 17-DMAG against A549 lung cancer cells via modulation of Hsp90 expression and inhibition of telomerase activity. Hence, the implantable 17-DMAG loaded nanofibrous scaffolds might be an excellent tool for efficiently killing of the lung residual cancer cells and avoid the local cancer recurrence. PMID- 30021338 TI - Effects of the SGLT2 inhibitor ipragliflozin on food intake, appetite-regulating hormones, and arteriovenous differences in postprandial glucose levels in type 2 diabetic rats. AB - AIMS: The sodium-glucose cotransporter (SGLT) 2 inhibitor, ipragliflozin, improves not only hyperglycemia but also obesity in type 2 diabetic animals and patients; however, there have been concerns that it may also cause an increase in compensatory food intake. Appetite is regulated by complex mechanisms involving the central nervous system, part of which involves appetite-related hormones and arteriovenous differences in postprandial glucose levels. We evaluated the effect of ipragliflozin in type 2 diabetic rats on food intake, appetite-related hormones and arteriovenous differences in postprandial glucose levels, and their correlation with food intake. MAIN METHODS: Ipragliflozin and several antidiabetic drugs were administered to type 2 diabetic rats and various parameters concerning food intake were measured. KEY FINDINGS: Ipragliflozin significantly increased urinary glucose excretion and reduced postprandial hyperglycemia. Compared to normal rats, diabetic rats exhibited hyperphagia and elevated plasma levels of the appetite-stimulating hormones neuropeptide Y and ghrelin. Ipragliflozin induced significant weight loss and reduced plasma levels of appetite-stimulating hormones without affecting food intake. Diabetic rats exhibited a significantly reduced arteriovenous difference in postprandial glucose levels due to insulin insufficiency; this was improved by ipragliflozin, which increased renal arteriovenous differences in glucose levels by increasing urinary glucose excretion. SIGNIFICANCE: These results indicate that the SGLT2 inhibitor, ipragliflozin, exerts antihyperglycemic actions by increasing urinary glucose excretion, and induces weight loss without a compensatory increase in food intake in type 2 diabetic mice. The mechanisms underlying these effects can be attributed, in part, to an increased arteriovenous difference in postprandial glucose levels and improved regulation of appetite-related hormones in the diabetic animal model. While this study was conducted in rodents and the results may be distinct from those in humans, it is possible that some of the pharmacological mechanisms, including the regulation of appetite-related hormones, can be extrapolated to clinical settings and may be valuable for further studies including clinical investigations. PMID- 30021339 TI - Tanshinones from Salvia miltiorrhiza Bunge revert chemotherapy-induced neuropathic pain and reduce glioblastoma cells malignancy. AB - Medicinal plants and herbal extracts from traditional Chinese medicine are used increasingly commonly worldwide for their benefits to health and quality of life as dietary supplements or as ingredients in functional foods. Among them, Salvia miltiorrhiza Bunge (a natural strong remedy for the treatment of a variety of conditions) is traditionally used for centuries in Asian countries as antioxidant, anticancer, and anti-inflammatory agent. In this context, several evidences support the hypothesis that some tanshinones (in particular tanshinone IIA and cryptotanshinone) extracted from the roots (Danshen) of Salvia miltiorrhiza exert neuroprotective and analgesic activities. Oxaliplatin (OXA), a platinum-based drug used for the treatment of solid tumors, induces neuropathic pain which hampers the chemotherapy success. While several attempts were made to prevent oxaliplatin-induced painful neuropathy, a growing number of evidences look to natural sources as an effective remedy to counterbalance the OXA-mediated side effects. The aim of the present study was to investigate the pain-relieving profile of Danshen and its active constituents tanshinone IIA (TIIA) and cryptotanshinone (CRY) in animal models of neuropathic pain induced by OXA, anticancer drug characterized by a dose-limiting neurotoxicity. Contextually, the neuroprotective and anticancer activities of the selected compounds were tested in different cells lines. A single administration per os of CRY (30 mg mg/kg) significantly, in a dose dependent manner, attenuated chemotherapy-induced pain. A 7 days repeated administrations highlighted the effectiveness and potency of both CRY and TIIA (10 mg/kg). On the other hand, Danshen showed a painkiller profile against oxaliplatin-induced neuropathy. Contextually, Danshen and its active constituents showed remarkable and selective inhibitory activities on glioblastoma cells lines LN-229 (IC50: 50.0 +/- 4.0, 48.2 +/- 4.9 and 51.9 +/- 2.3 MUM respectively for Danshen standardized extract, TIIA and CRY) next to healthy but high proliferative cell lines enterocytes (IC50:> 250 MUM for TIIA and CRY) and keratinocytes (IC50: >100 and 97 +/- 2 MUM respectively for TIIA and CRY). Taken together the results reported here demonstrated the long-lasting pain relieving effects of Danshen and its related bioactive constituents in animal models of neuropathic pain and their selective in vitro neuroprotective properties on certain central malignancy cells lines. Thus, suggest that S. miltiorrhiza roots could be considered as a new potential source of active diterpenoidic compounds useful for pharmaceutical or nutraceutical industries and beneficial as food complements. PMID- 30021340 TI - Berberine promoted myocardial protection of postoperative patients through regulating myocardial autophagy. AB - BACKGROUND: Berberine has been verified to protect the heart from ischemia/reperfusion injury through animal experiments. However, the cardioprotective properties of berberine have not been established fully. This study was aimed at investigating whether berberine is cardioprotective in vivo and in vitro. METHODS: In the cardiomyoblast cells, the autophagosomes were observed by immunostaining. The apoptosis was detected by a flow cytometry. Beclin-1, LC3-II/I, adenosine monophosphate-activated protein kinase (AMPK), and mTOR in cardiomyocytes were detected by Western blot. Next, one hundred patients, who were undergoing percutaneous coronary intervention (PCI), were randomly assigned to the berberine group (n = 52) or control group (n = 48). Berberine was administered on them postoperatively. Their plasma was then analyzed for CRP, TNF alpha and IL-6. RESULTS: In the cardiomyoblast cells, berberine reduced the autophagy and apoptosis induced by NaH2PO4. At the same time, berberine increased the activation of p-AMPK and inhibited the activation of p-mTOR induced by NaH2PO4. in vivo, berberine significantly reduced the levels of CRP, TNF-alpha and IL-6 in the patients' plasma. CONCLUSION: It was concluded that berberine therapy reduced myocardial injury partly by reducing myocardial autophagy and apoptosis through the AMPK/mTOR pathway. PMID- 30021341 TI - Effect of simvastatin and microRNA-21 inhibitor on metastasis and progression of human salivary adenoid cystic carcinoma. AB - Salivary adenoid cystic carcinoma (SACC) is a common malignancy of the salivary glands. Epithelial-mesenchymal transition (EMT) and P53 signaling pathway are associated with SACC metastasis and progression. Although simvastatin (SIM) is effective against the growth of many cancer types, its side effects limit its use. microRNA-21 (miR-21) is highly expressed in a variety of tumors and has a role in promoting tumor development. Therefore, the aim of the present study was to evaluate the effect of SIM in combination with miR-21 inhibitor (miR-21i) against lung metastatic SACC cells (SACC-LM). Our results showed that miR-21i was effective in reducing the resistance of SACC-LM to SIM, resulting in SACC-LM acquisition of epithelial traits, cell migration and invasion reduction, growth inhibition and induction of apoptosis. The expression of proteins associated to metastasis and tumor progression were regulated by the combined use of SIM and miR-21i. Thus, our findings demonstrated that such combination was effective in inhibiting SACC-LM progression, suggesting that multi-target therapy against SACC might represent a potentially successful approach in clinical treatment. PMID- 30021342 TI - Extract of Penicillium sclerotiorum an endophytic fungus isolated from Cassia fistula L. induces cell cycle arrest leading to apoptosis through mitochondrial membrane depolarization in human cervical cancer cells. AB - Seventeen endophytic fungi were isolated from various tissues of Cassia fistula and the ethyl acetate extracts obtained from 21-day cultures of all the endophytic fungal isolates were initially screened for their cytotoxicity against HeLa (human cervical carcinoma) cells using MTT assay. Of these, Penicillium sclerotiorum extract (PSE), significantly affected the viability of HeLa cells in a dose-dependent manner. The extract of P. Sclerotiorum was further analyzed by GC-MS, which showed three compounds, hexadecanoic acid, oleic acid and benzoic acid to be the major active principles in the extracts.The extract was further tested for invitro cytotoxicity against five cancer cell lines. Of the cell lines tested, HeLa cells showed maximum sensitivity followed by A549, while A431 and U251 were moderately sensitive and MCF-7 was insensitive to the treatment. In addition, normal human embryonic kidney cells, HEK293 remained insensitive to the treatment. Furthermore, the mechanism of cytotoxic activity exhibited by PSE was investigated by evaluating cell cycle progression and apoptotic induction in HeLa cells. Cell cycle analysis revealed that the PSE arrested cells at S and G2/M phase of the cell cycle in a dose-dependent manner. Annexin V- Propidium iodide double staining showed that, the extract potentiates apoptosis rather than necrosis in cells. This was supported by the down regulation in the proapoptotic protein BCL2 and up regulation of BAX (BCL2 Associated X), tumor suppressor protein, p53 and Apaf-1 [Apoptotic Peptidase Activating Factor 1]. Loss of mitochondrial membrane potential and a distinct DNA fragmentation pattern observed following the treatment, suggest that the PSE treatment leads to activation of mitochondrial pathway of apoptosis. Further, the extract also exhibited both antioxidant and anti-angiogenic properties. These results indicate that endophytic fungi isolated from medicinal plants may serve as potential sources of the anti-cancerous compounds. PMID- 30021343 TI - MiR-129 regulates growth and invasion by targeting MAL2 in papillary thyroid carcinoma. AB - MAL2, a member of the MAL proteolipid family, is essential for raft-mediated transport. In this study, we investigated the roles and underlying mechanism of MAL2 in the development of papillary thyroid carcinoma (PTC). Up-regulation of MAL2 was found in human PTC tissues and significantly correlated with poor overall survival (OS). Knockdown of MAL2 dramatically suppressed PTC cell proliferation and invasion in vitro and inhibited tumor growth in vivo. We further found that miR-129 suppressed the expression of MLA through directly binding to the 3' untranslated region (3' UTR). While forced miR-129 expression suppressed growth and invasion of PTC cells, re-expression of MAL2 rescued these effects. Taken together, our data indicated that MAL2 acted as an oncogene and was negatively regulated by miR-129, supporting the potential therapeutic strategy against PTC by targeting miR-129-MAL2 axis. PMID- 30021344 TI - Probable mechanisms involved in the antipsychotic-like activity of morin in mice. AB - Evidence derived from preliminary studies suggests that morin, a neuroactive flavonoid with proven antioxidant and antiinflammatory properties possess antipsychotic-like activity. The present study was designed to evaluate the probable mechanisms involve in the antipsychotic-like activity of morin in ketamine model of schizophrenia. The effects of morin, haloperidol and risperidone on neurobehavioral and anti-schizophrenia-like effects were evaluated in mice (n = 7) following intraperitoneal (i.p.) administration of morin (25-100 mg/kg), haloperidol (1 mg/kg) and risperidone (0.5 mg/kg) alone or in combination with ketamine (20 mg/kg, i.p.) for 10 days. Neurobehavioral and schizophrenia like activities consisting of open-field (positive symptoms), Y-maze, novel object recognition (cognitive symptoms), social interaction (negative symptoms) tests were assessed. Also, wood-block catalepsy and rota-rod tests were employed to evaluate extrapyramidal side effects of morin. Thereafter, brain levels of biomarkers of oxidative, nitrergic and acetylcholinesterase alterations as well as histomorphological changes in the striatum and prefrontal-cortex were determined. Administration of morin and risperidone alone but not haloperidol significantly (p > 0.05) prevented ketamine-induced hyperlocomotion, social withdrawal and cognitive impairments relative to controls, and were devoid of extrapyramidal side effects. Morin alone or in combination with ketamine significantly increased glutathione concentration, superoxide dismutase and catalase activities compared with saline- or ketamine-treated mice. Moreover, morin alone or in combination with ketamine also significantly decreased malondialdehyde, nitrite and acetylcholinesterase alterations in mice brains. Furthermore, morin prevented ketamine-induced brain neuronal alterations in the striatum and prefrontal-cortex. Together, our findings suggest that morin may demonstrate antipsychotic-like therapeutic effect via modulation of oxidative/nitrergic, cholinergic actions and neuroprotection. PMID- 30021345 TI - Modulation of hyperglycemia and dyslipidemia in experimental type 2 diabetes by gallic acid and p-coumaric acid: The role of adipocytokines and PPARgamma. AB - There are many indications that confirm the vital role of adipocytokines and PPARgamma in diabetics. Hence, the current investigation aimed to study the modulatory effects of gallic acid and p-coumaric acid on adipocytokines secretion and PPARgamma mRNA expression in type 2 diabetic rats. After induction of type 2 diabetes, diabetic rats were orally treated with 20 mg/kg body mass gallic acid and 40 mg/kg body mass p-coumaric acid for six weeks. Among treatment diabetic rats, glucose and glycosylated hemoglobin levels significantly declined in diabetic rats, while insulin level and body weight significantly increased as compared to control group. Gallic acid and p-coumaric acid markedly decreased the level of TNF-alpha and increased the levels of PPARgamma mRNA and adiponectin. In addition, the tested agents improved markedly lipid profile parameters, cardiovascular indices 1 and 2 and anti-atherogenic index. In conclusion, gallic acid and p-coumaric acid exhibited marked antidiabetic action that could be mediated via modulation of TNF-alpha and adipocytokines secretions as well as upregulation of PPARgamma mRNA expression. PMID- 30021346 TI - Morphometric changes and AQP2 expression in kidneys of young male rats exposed to chronic stress and a high-sucrose diet. AB - OBJECTIVE: Consumption of a cafeteria-like diet and chronic stress have a negative impact on kidney function and morphology in adult rats. However, the interaction between chronic restraint stress and high-sucrose diet on renal morphology in young rats is unknown. A high-sucrose diet does not modify serum glucose levels but reduces serum corticosterone levels in stressed young rats, in this way it is confusing a possible potentiate or protector effect of this diet on kidney damage induced by stress. METHODS: Wistar male rats at 4 weeks of age were randomly assigned into 4 groups: control (C), stressed (St), high-sucrose diet (S30), and chronic restraint stress plus a 30% sucrose diet (St + S30). Rats were fed with a standard chow and tap water (C group) or 30% sucrose diluted in water (S30 group). Chronic restraint stress consisted of 1-h daily placement into a plastic cylinder, 5 days per week, and for 4 weeks. RESULTS: Stressed rats exhibited a low number of corpuscles, glomeruli, high number of mesangial cells, major deposition of mesangial matrix and aquaporin-2 protein (AQP-2) expression, and low creatinine levels. Meanwhile, high-sucrose diet ameliorated AQP-2 expression and avoided the reduction of creatinine levels induced by chronic stress. The combination of stress and high-sucrose diet maintained similar effects on the kidney as stress alone, although it induced a greater reduction in the area of proximal tubules. CONCLUSIONS: Our results show that both chronic stress and a high-sucrose diet induce histological changes, but chronic stress may generate an accelerated glomerular hypertrophy associated with functional changes before puberty. PMID- 30021347 TI - miR-149 regulates the proliferation and apoptosis of cervical cancer cells by targeting GIT1. AB - MiRNAs are emerging as critical regulators in carcinogenesis and tumor progression. Recently, miR-149 has been demonstrated as a tumor suppressor in several cancers, but its functions in the context of cervical cancer remains unknown. The objective of this study is to investigate the clinicopathological and prognostic values of miR-149 expression and its roles in cervical cancer progression. In this study, miR-149 expression is decreased in CC tissues and cell lines compare with paired normal tissues and normal epithelial cell, respectively. Moreover, the restoration of miR-149 expression inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro. We further proved that miR-149 overexpression suppresse the growth of cervical cancer cells in vivo using a mouse xenograft model. Dual luciferase assays identified the GIT1 as a novel direct target of miR-149. To identify the mechanisms, we investigated the PI3K/AKT/mTOR pathway and found that the expression of PI3K, AKT and mTOR were suppressed in cells which were transfected with miR-149 mimics. Taken together, these results indicate that miR-149 is involved in the carcinogenesis and development of cervical cancer by targeting GIT1 via PI3K/AKT/mTOR pathway. Given these, our data suggest that miR-149 functions as a tumor suppressor and may serve as a biomarker or useful therapeutic target of cervical cancer. PMID- 30021348 TI - Protective aptitude of Periploca hydaspidis Falc against CCl4 induced hepatotoxicity in experimental rats. AB - In the present study the antioxidant capacity of Periploca hydaspidis was assessed through various in vitro assays and by the hepatoprotective potential on CCl4 induced toxicity in rat. Phytochemical analysis of different extracts of P. hydaspidis indicated existence of various phytochemical classes. HPLC-DAD analysis of methanol extract indicated the existence of rutin, gallic acid and caffeic acid. Total phenolic (TPC) and total flavonoid content (TFC) exhibited significant (p < 0.05) correlation with 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide, hydroxyl ion, inhibition of beta-carotene oxidation, iron chelation, reducing power and total antioxidant capacity. In hepatic sample of rat, CCl4 administration increased (p < 0.05) the level of nitrite, hydrogen peroxide (H2O2), thiobarbituric acid reactive substances (TBARS) whereas a decline was recorded in antioxidant enzymes; superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and in reduced glutathione (GSH). Concentration of alanine transaminase (ALT), alkaline phosphatase (ALP), aspartate transaminase (AST) and globulin increased (p < 0.05) whereas level of total protein and albumin decreased in serum of CCl4 treated rats. Level of pro-inflammatory cytokines; tumor necrosis factor-alpha (TNF-alpha), tumor growth factor-beta1 (TGF-beta1) and resistin was increased (p < 0.05) in serum whereby anti inflammatory markers; interleukin-10 (IL-10), adiponectin and nuclear factor erythroid 2- related factor 2 (Nrf-2) decreased (p < 0.05) in hepatic tissues of CCl4 treated rats. DNA damages and histopathological alterations were induced with administration of CCl4 to rat. The altered levels of various parameters provoked by CCl4 toxicity restored towards the control level by the methanol extract of P. hydaspidis in a dose dependent manner. These results suggested the presence of antioxidant and anti-inflammatory phyto-constituents in methanol extract of P. hydaspidis. PMID- 30021350 TI - Knockdown of CREB1 promotes apoptosis and decreases estradiol synthesis in mouse granulosa cells. AB - Cyclic AMP response element-binding protein 1 (CREB1), a member of the CREB family, is known to be involved in follicular growth, ovulation, and ovarian disease. However, the physiological function of CREB1 in mouse granulosa cells (mGCs) remains lagerly unknown. The aim of this study was to determine the role of CREB1 in mGCs by knocking down CREB1 expression. CREB1 knock-down in mGCs at the mRNA and protein levels, was confirmed by quantitative real-time polymerase chain reaction and western blot. Results of enzyme linked immunosorbent assay revealed that CREB1 knockdown significantly decreased the concentrations of estradiol (E2) and progesterone (P4) in mGCs. Furthermore, the CREB1 knockdown in mGCs promoted cell proliferation and apoptosis, and arrested the cell cycle in S phase. To elucidate the regulatory mechanism underlying the effects of CREB1 knockdown on steroid synthesis, cell cycle, and apoptosis, we measured the protein expression levels of several related genes in mGCs knocked down CREB1. When CREB1 was knocked down, the expression of Cyp1b1 and Cyp19a1, which encode steroidogenic enzymes, was down-regulated; the expression of the cell cycle factors CyclinA1, CyclinB1, and CyclinD2 were significantly decreased. Among apoptosis-related genes, Bcl-2 was down-regulated, whereas Bax and cleaved Caspase3 were upregulated. Moreover, CREB1 knockdown significantly decreased expression level of Has2, Ptgs2, and Igfbp4, which are essential genes for folliculogenesis in mGCs. Taken together, these findings suggested that CREB1 might be a key regulator of mGCs through regulating steroid synthesis, cell proliferation, cell cycle, apoptosis, and other regulators of folliculogenesis. PMID- 30021349 TI - Long non-coding RNA HOTTIP is upregulated in renal cell carcinoma and regulates cell growth and apoptosis by epigenetically silencing of LATS2. AB - Renal cell carcinoma (RCC) is one of the most aggressive malignancies with increasing incidence worldwide and is characterized by dismal prognosis owing to a lack of early detection and prognostic biomarkers for this fatal disease. Accumulating studies demonstrated that abnormally expressed long non-coding RNAs (lncRNAs) are involved in tumorigenesis and progression. Specifically, HOTTIP is upregulated and exerts oncogenic properties in some cancers. However, its clinical significance, biological functions and molecular mechanisms in RCC have not been studied. In the current study, RT-qPCR was performed to quantify the relative expression of HOTTIP in RCC tissues and cells. Additionally, we explored its clinical value using Fisher's exact test. Moreover, cell growth and apoptosis altered by HOTTIP was evaluated in vitro and in vivo. Mechanistically, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) analysis was used to determine its molecular mechanism in cell growth and apoptosis. As a result, upregulated HOTTIP is closely associated with unfavorable phenotypes in RCC patients. The mechanistic investigations showed that HOTTIP could bind to enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1), thereby repressing LATS2 expression. Collectively, our study illustrates how HOTTIP plays an oncogenic role in RCC and may offer a potential therapeutic target for treating this fatal disease. PMID- 30021351 TI - microRNA-19a-3p promotes tumor metastasis and chemoresistance through the PTEN/Akt pathway in hepatocellular carcinoma. AB - microRNA-19a-3p (miR-19a-3p) has been reported to regulate cell proliferation in hepatocellular carcinoma (HCC), but its role in HCC metastasis remains unknown. In this study, miR-19a-3p was noted to be upregulated in HCC specimens and cell lines. Aberrant expression of miR-19a-3p stimulated HCC cell metastasis, and phosphatase and tensin homolog (PTEN) was shown to be a direct target of miR-19a 3p. miR-19a-3p-mediated HCC metastasis was reversed by restoration of PTEN or could be imitated by silencing of PTEN. Modulation of miR-19a-3p also altered expression of phosphorylated Akt, a downstream mediator of PTEN. Moreover, aberrant expression of miR-19a-3p induced sorafenib resistance by regulating the PTEN/Akt pathway. In conclusion, ectopic expression of miR-19a-3p contributes to HCC metastasis and chemoresistance by modulating PTEN expression and the PTEN dependent pathways. PMID- 30021352 TI - Oncogenic miR-663a is associated with cellular function and poor prognosis in renal cell carcinoma. AB - BACKGROUND: MicroRNA(miRNA) plays a key regulatory role in various stages of tumorigenesis, including cell growth, cell cycle control, apoptosis avoidance, tissue invasion, and metastasis. Several microRNAs are involved in the development of renal cell carcinoma (RCC) and the malignant transformation process. However, the effects of miR-663a on RCC have rarely been reported. METHODS: In the present study, the expression of miR-663a was examined in RCC using matched normal kidney tissues and four cell lines (786-O, Caki-1, ACHN and HK-2). MicroRNA mimics were transiently transfected into RCC cells and the effects of over expression on proliferation, migration, invasion, and apoptosis was observed. In addition, the relationship between miR-663a expression in 42 formalin-fixed paraffin-embedded (FFPE) clear cell renal carcinoma (ccRCC) samples and clinical pathological variables and overall survival was investigated. We evaluated the prognostic value of miR-663a expression in ccRCC by experimental results. RESULTS: The results showed that the expression of miR 663a was up-regulated in RCC cells and tissues and miR-663a was associated with proliferation, migration, invasion, and apoptosis of RCC. Cox proportional hazard regression analysis showed that a high expression of miR-663a patients had a significantly shorter overall survival in univariate and multivariate analysis. Kaplan-Meier survival curves showed that a high expression of miR-663a patients had a significantly shorter overall survival. CONCLUSIONS: These results indicate that miR-663a can be used as an independent marker for the poor prognosis of ccRCC, and may also play an important role as a tumor oncogene in the occurrence and development of RCC. PMID- 30021353 TI - Role of high mobility group A1/nuclear factor-kappa B signaling in coronary microembolization-induced myocardial injury. AB - OBJECTIVE: Coronary microembolization (CME) is a common complication in percutaneous coronary intervention (PCI). Local myocardial inflammation caused by CME is the major cause of progressive cardiac dysfunction. High mobility group A1 (HMGA1)/nuclear factor-kappa B (NF-kappaB) signaling plays an important role in the development and progression of inflammation, but its role in CME remains unclear. This study evaluated the effect of HMGA1/NF-kappaB signaling on CME induced myocardial inflammation and cardiac dysfunction. METHODS: Forty Sprague Dawley rats were randomly divided into four groups: sham, CME, CME + HMGA1 small interfering RNA (HMGA1 siRNA), and CME + scrambled siRNA (control siRNA) groups, with 10 animals each. The CME model group was established by clamping the ascending aorta and injecting microspheres through the left ventricular apex for embolization, and the sham group was established by injecting the same amount of normal saline. The HMGA1 siRNA group was injected with HMGA1 siRNA transfection complexes into the tail vein 72 h before CME modeling, and the control siRNA group was caudally injected with the same amount of scrambled siRNA 72 h before CME modeling. Twelve hours after the operation, cardiac function, serum c troponin I level, and microinfarct size were examined. The levels of HMGA1, NF kappaB p65, TNF-alpha, and IL-1beta were detected. RESULTS: Myocardial dysfunction, enhanced serum c-troponin I, and microinfarct were induced following CME. Moreover, CME induced an increased expression of HMGA1, NF-kappaB p65, TNF alpha, and IL-1beta. The HMGA1 siRNA reversed these effects by CME, while the scrambled siRNA had no effect. CONCLUSIONS: HMGA1/NF-kappaB signaling is involved in CME-induced myocardial inflammation. Inhibition of HMGA1/NF-kappaB signaling attenuated the CME-induced myocardial injury and improved cardiac function, suggesting a new potential target for the prevention and treatment of CME-induced myocardial injury. PMID- 30021354 TI - Sirt3-mediated mitochondrial fission regulates the colorectal cancer stress response by modulating the Akt/PTEN signalling pathway. AB - Sirtuin-3 (Sirt3), a sub-family member of the nicotinamide adenine dinucleotide dependent histone deacetylases, has been reported to be involved in mitochondrial oxidative stress regulation, mitochondrial calcium management, mitophagy activation, and mitochondrial energy metabolism. The aim of our study was to explore the functional role of Sirt3 in colorectal cancer stress, focusing particularly on its effects on mitochondrial fission. Our study demonstrated that Sirt3 was highly upregulated in colorectal cancer cells compared to normal rectal mucosa cells. However, the genetic ablation of Sirt3 reduced colorectal cancer cell viability, mobility and proliferation. At the molecular level, we found that Sirt3 knockdown suppressed the expression of adhesive factors and cyclins. Furthermore, Sirt3 deletion was also associated with mitochondrial membrane potential reduction, ROS overproduction, mPTP opening, mitochondrial pro apoptotic upregulation, and caspase-9-related death programme activation. Furthermore, we determined that Sirt3 regulated the colorectal cancer stress response by modulating mitochondrial fission. The loss of Sirt3 triggered fatal mitochondrial fission by suppressing the Akt/PTEN pathway. Re-activation of the Akt/PTEN pathway combatted mitochondrial fission and promoted colorectal cancer mobility, survival, and growth. Altogether, these findings provide an additional rationale for the function of Sirt3 in supporting the growth and survival of colorectal cancer. PMID- 30021355 TI - LncRNA H19 functions as an Aquaporin 1 competitive endogenous RNA to regulate microRNA-874 expression in LPS sepsis. AB - OBJECTIVE: Sepsis is a whole-body inflammation disease after severe trauma, burn injury, infection and major surgeries, accompanied by multiple organs failure. We sought to investigate the potential mechanism of Aquaporin 1 (AQP1), miRNA-874, and lncRNA H19 in lipopolysaccharide (LPS) sepsis and the anti-inflammatory responses related to sepsis myocardial dysfunction. MATERIAL AND METHODS: Serum from peripheral blood samples of sepsis patients and in vivo mice model were collected for AQP1, H19, and miR-874 expression. In vitro model in cardiomyocytes was established using LPS. H19 and miR-874 expressions were interfered in LPS induced mice and cardiomyocytes to explore the association between them and its effect on anti-inflammatory responses. RESULTS: H19 and AQP1 decreased and accompanied with elevated miR-874 expression in sepsis samples, in vivo mice model and in vitro cells. There was negative relationship between expression of H19 and miR-874, and a positive correlation between H19 and AQP1 expression. However, H19 overexpression transfection significantly reversed LPS induced dysregulation in expression of miR-874 and AQP1, secretion of anti-inflammatory cytokines, and myocardial dysfunction in vivo and in vitro. CONCLUSION: We determined that H19 acted as AQP1 ceRNA in regulating miR-874. H19 acted as AQP1 ceRNA in regulating miR-874 and restoring LPS dysregulated inflammatory responses and myocardial dysfunction. H19 expression might be used as a potential therapeutic target for LPS induced sepsis and myocardial dysfunction. PMID- 30021357 TI - Neurobiology and consequences of social isolation stress in animal model-A comprehensive review. AB - The brain is a vital organ, susceptible to alterations under genetic influences and environmental experiences. Social isolation (SI) acts as a stressor which results in alterations in reactivity to stress, social behavior, function of neurochemical and neuroendocrine system, physiological, anatomical and behavioral changes in both animal and humans. During early stages of life, acute or chronic SIS has been proposed to show signs and symptoms of psychiatric and neurological disorders such as anxiety, depression, schizophrenia, epilepsy and memory loss. Exposure to social isolation stress induces a variety of endocrinological changes including the activation of hypothalamic-pituitary-adrenal (HPA) axis, culminating in the release of glucocorticoids (GCs), release of catecholamines, activation of the sympatho-adrenomedullary system, release of Oxytocin and vasopressin. In several regions of the central nervous system (CNS), SIS alters the level of neurotransmitter such as dopamine, serotonin, gamma aminobutyric acid (GABA), glutamate, nitrergic system and adrenaline as well as leads to alteration in receptor sensitivity of N-methyl-D-aspartate (NMDA) and opioid system. A change in the function of oxidative and nitrosative stress (O&NS) mediated mitochondrial dysfunction, inflammatory factors, neurotrophins and neurotrophicfactors (NTFs), early growth response transcription factor genes (Egr) and C-Fos expression are also involved as a pathophysiological consequences of SIS which induce neurological and psychiatric disorders. PMID- 30021356 TI - Umbilical cord blood-mesenchymal stem cells and carvedilol reduce doxorubicin- induced cardiotoxicity: Possible role of insulin-like growth factor-1. AB - In this study, we tried to demonstrate the effects of adding human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) to carvedilol in improving the doxorubicin- induced cardiotoxicity in rats. Rats were randomly divided into four groups: group 1: control group, group 2: doxorubicin untreated group, group 3: rats injected with doxorubicin and received carvedilol, and group 4: rats injected with doxorubicin and received carvedilol and stem cell-treated. Electrocardiography (ECG) was performed to assess cardiac function after animals were sacrificed. Cardiac muscle sections were examined histologically using H&E, Masson trichrome and immunohistochemically using caspase 3 immunostaining. The morphometric and statistical analysis was performed. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), insulin-like growth factor (IGF-1), and vascular endothelial growth factor (VEGF) were measured. We concluded that combination of hUCB-MSCs and carvedilol markedly improves histological and immunohistochemical structure of cardiac muscle fibers and restores cardiac function in doxorubicin- induced cardiotoxicity in rats. PMID- 30021358 TI - Therapeutic effect of vitamin B3 on hyperglycemia, oxidative stress and DNA damage in alloxan induced diabetic rat model. AB - Evidences in the form of experimental analysis and scientific investigations suggest that oxidative stress embody an imperative role in the onset and progression of type-2 diabetes mellitus (T2DM). Aberrant elevation in levels of free radicals, as observed upon disease onset, and the subsequent reduction in anti-oxidant defenses is pernicious to metabolic enzymes and cellular organelles. Niacin (Vitamin B3) is an essential nutrient for humans and is considered to be an important food additive for animals too. This research was conducted to examine the effect of nutraceutical antioxidant on diabetic environment. This important member of Vitamin B complex is a forerunner of nicotinamide adenine dinucleotide (NAD) and also nicotinamide adenine dinucleotide phosphate (NADP), both of them serving as coenzymes for several metabolic enzymes. This study reports the effects of niacin supplementation in alloxan induced diabetic rats divided into five groups. Diabetes induced rats were further treated with niacin at two doses (10 and 15 mg /kg body weight) and compared with a control set of diabetes without treatment. Niacin treatment showed recovery in almost all parameters in a dose reliant pattern. A notable decline in oxidative stress parameters with reductions in fasting blood glucose levels was observed. Histological studies reveal damage recovery in the liver as well as kidney tissues. A notable amount of recovery was observed in cellular DNA damage. As a deduction, it is advocated that dietary niacin supplementation might help in reducing problems associated with diabetes. A probable mechanism pertaining to the action of niacin is proposed as well. PMID- 30021359 TI - LncRNA MEG3 enhances 131I sensitivity in thyroid carcinoma via sponging miR-182. AB - BACKGROUND: Long non-coding RNA (LncRNA) MEG3 has been demonstrated as a tumor suppressor in various cancers, including thyroid carcinoma (TC). However, the detail functions and possible mechanisms of MEG3 in 131I resistance of TC remain to be uncovered. METHODS: qRT-PCR was performed for the detection of MEG3 and miR 182 levels. 131I-resistant TC cells were constructed by continuous exposure to stepwise increased concentrations of 131I. Western blot assay was used to measure the protein expressions of gamma-H2 AX and H2 AX. CCK-8 and flow cytometry assays were carried out for the evaluation of cell viability and apoptosis, respectively. Bioinformatics and dual-luciferse assays were conducted to prove the interaction of MEG3 and miR-182. RESULTS: MEG3 expression was down-regulated in TC tumor tissues, and the cumulative survival rate was decreased in low MEG3 expression group in TC patients under 131I treatment. MEG3 expression appeared a decline and miR-182 expression displayed an increase in 131I-resistant FTC-133 (res-FTC-133) and TPC-1 (res-TPC-1) cells. Moreover, MEG3 overexpression suppressed 131I-resistant cell viability, promoted apoptosis and induced DNA damage. MEG3 was verified as a molecular sponge for miR-182, and inhibition of miR-182 exerted similar functions as MEG3 overexpression. Furthermore, MEG3 knockdown substantially abrogated the anti-cancer functions of anti-miR-182. CONCLUSIONS: MEG3 enhanced the radiosensitivity of 131I in TC cells via sponging miR-182, indicating that MEG3 may act as a potential biomarker and therapeutic target for TC patients with 131I resistance. PMID- 30021360 TI - Protective effect of human umbilical cord mesenchymal stem cell exosomes on preserving the morphology and angiogenesis of placenta in rats with preeclampsia. AB - AIM: This study aims to investigate the effect of human umbilical cord mesenchymal stem cell exosomes (hucMSC-Ex) on placental tissue and angiogenesis in rats with preeclampsia (PE). METHOD: The expression of MSC surface markers were identified by flow cytometry. Alizarin red staining and oil red O staining were used to examine osteogenic and adipogenic differentiation of hucMSCs. Western blotting was used to determine expressions of CD63 and CD81 in hucMSC-Ex. PE rat models were established using endothelial nitric oxide synthase, eNOS)NG Nitro-l-arginine Methyl Ester, which were then treated with exosome (Exo) of low dosage (L-Exo), Exo of medium dosage (M-Exo) and Exo of high dosage (H-Exo). The blood pressure at the 15d, 17d and 19d of pregnancy and 24-h urinary protein were measured. TUNEL staining and immunohistochemistry were applied to detect the cell apoptosis and micro-vascular density (MVD) in placental tissues, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to examine serum levels of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase receptor-1 (sFlt1). RESULTS: In vitro cultured hucMSCs showed expression of MSC surface markers (CD29, CD90 and CD105), and no expression of CD34 and CD45. Besides, the isolated exosomes expressed the exosome markers (CD63 and CD81). In response to the treatment of L-Exo, M-Exo and H-Exo, the blood pressure of PE rat models on the 17 d and the 19 d as well as the 24-h urinary protein were substantially decreased. Moreover, at the 21 d, PE rat models treated with L-Exo, M-Exo and H-Exo exhibited an increase in the number and quality of fetuses, placenta quality, MVD and VEGF expression, but substantial decreased cell apoptosis and expression of sFlt1. The influence of Exos was exerted in a dosage dependent manner. CONCLUSION: hucMSC-Ex, in a dose-dependent manner, can improve the morphology of placental tissue in rats with PE, by inhibiting cell apoptosis and promoting angiogenesis in placental tissue. PMID- 30021361 TI - Thyme extract increases mucociliary-beating frequency in primary cell lines from chronic obstructive pulmonary disease patients. AB - Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterized by a progressive and irreversible airflow limitation. COPD is associated to a chronic inflammatory response with infiltration of inflammatory cells in the surface epithelium of large airways and abnormalities in structure and functions of cilia. Thyme (Thymus vulgaris L.) is a traditional medicinal plant of the Mediterranean area used to treat respiratory disorders. We previously evidenced that thyme extract reduce IL-1beta and IL-8, by downregulating the activated NF-kappaB levels, suggesting its potential therapeutically use in COPD. Cilia beating frequency (CBF) is dramatically impaired in COPD and different pharmacological agents can modulate cilia function. Herein we evaluated the effect of a commercial thyme extract in modulating CBF by measuring its activity in stimulating cAMP, Ca2+ levels and CBF in a MucilAir 3D human COPD airway epithelia reconstituted in vitro system using salmeterol, YM976, isoproterenol and GSK1016790 A as positive controls. Results showed that thyme extract increased cAMP levels starting from 12 h post treatment, decreased extracellular Ca2+ levels and increased the CBF in airway epithelia from COPD donors. Overall, this work demonstrated that thyme extract is effective in stimulating CBF by inducing an increase of cAMP and Ca2+ levels, thus supporting its therapeutical use in the treatment of COPD. PMID- 30021362 TI - Neuroprotective activity of tetramethylpyrazine against 3-nitropropionic acid induced Huntington's disease-like symptoms in rats. AB - Huntington's disease (HD) is an autosomal neurodegenerative disease characterized by chorea, dystonia, motor ataxia, cognitive decline and psychiatric disorders with gradual loss of nerve cells and has no existing cure for the disease. In the present study, a mitochondrial toxin, 3-nitropropionic acid (3-NP) is used to induce HD like symptoms in rats. Tetramethylpyrazine is one of the active ingredients of Chuan Xiong which was reported to have neurotrophic and neuroprotective activities. The present study was designed to evaluate the role of TMP on 3-NP induced behavioral, biochemical, neurochemical, and histological alterations in the different regions of the brain. Animals were pretreated with normal saline/TMP for 7 days. From 8th day, the treatment groups were co administered with 3-NP (10 mg/kg, i.p) and continued to the 21st day of the treatment protocol. At the end of the study, we found that the TMP improved all the behavioral performances of 3-NP induced neurotoxic rats, significantly. Further, oxidative stress parameters (lipid peroxidation, reduced glutathione, catalase, and superoxide dismutase), succinate dehydrogenase enzyme, and neurochemical (GABA and glutamate) estimations were done in the brain homogenate. In our study, the treatment with TMP ameliorated the 3-NP induced alterations, in the biochemical and neurochemical parameter in the brain homogenate, dose dependently. The protective role of TMP further confirmed by measuring the lesion area with the 2,3,5-triphenyltetrazolium chloride staining of the brain slices and histopathological alteration in the hippocampus (CA1 and CA3) and striatal regions of the brain. Hence, the present findings suggest that the protective role of TMP against 3-NP induced behavioral, biochemical, neurochemical, and histological alterations in rats. PMID- 30021363 TI - Yes-associated protein enhances proliferation and attenuates sensitivity to cisplatin in human gastric cancer cells. AB - BACKGROUND: Yes-associated protein (YAP) is upregulated in many cancer types, and its overexpression is involved in tumor cell proliferation, metastasis and resistance to chemotherapy. In the present study, we aimed to investigate the potential role of YAP in the development and progression of gastric cancer. METHODS: YAP levels were analyzed in human gastric cancer and adjacent normal tissues by Western blotting and immunohistochemistry. Potential roles of YAP in regulating gastric cancer cell proliferation and sensitivity to cisplatin were examined by genetic manipulation in vitro. The molecular signaling was determined to understand the mechanisms of observed YAP effects. RESULTS: YAP level was higher in gastric cancer tissues as compared to paired normal tissues. Knockdown of YAP attenuated gastric cancer cell proliferation and enhanced sensitivity to cisplatin in vitro while YAP overexpression possessed the opposite effects. YAP regulated Epidermal growth factor receptor (EGFR) expression and its downstream AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in gastric cancer cells. CONCLUSION: YAP enhances gastric cancer cell proliferation and attenuates sensitivity to cisplatin potentially through targeting the EGFR signaling, indicating that YAP/EGFR signaling axis may serve as a potential target for treatment of gastric cancer. PMID- 30021364 TI - MicroRNA-34a promotes iNOS secretion from pulmonary macrophages in septic suckling rats through activating STAT3 pathway. AB - Pediatric sepsis is frequently a fatal condition and a major cause of death globally. The mortality rate of sepsis remains high despite that the advanced therapeutic methods have been carried out. Our research aims to investigate the potentials of miR-34a in the treatment of pediatric sepsis. Results indicated that miR-34a was up-regulated in Lipopolysaccharide (LPS)-induced pulmonary macrophages and U937 cell lines. In addition, miR-34a silence reduced the production of iNOS through inactivating STAT3 pathway in U937 cell lines and cecal ligation and puncture (CLP)-induced lung tissues. Besides, high expression of iNOS and STAT3 in cells transfected with miR-34a mimic further validated it. Furthermore, in vivo experiment demonstrated that miR-34a silence protected CLP induced suckling rats from lung injury. All in all, our study demonstrated that miR-34a promoted iNOS secretion from pulmonary macrophages in LPS-induced sepsis suckling rats through activating STAT3 pathway. These results provided a possibility to convert miR-34a into clinical application. PMID- 30021365 TI - Apigenin prevents metabolic syndrome in high-fructose diet-fed mice by Keap1-Nrf2 pathway. AB - Chronic dietary high fructose leads to various kinds of undesirable metabolic effects. Apigenin, a naturally occurring plant flavone, is plentiful in fruits and vegetables. The aim of this study was to identify the protective effects of apigenin on metabolic syndrome and elucidate potential underlying mechanisms. The animal model was established by 4-weeks high fructose feeding. Insulin resistance was estimated by oral glucose tolerance test and homeostasis model assessment insulin resistance index. Liver function was evaluated by serum AST and ALT, hepatic histopathological alternation, and lipid accumulation in the liver. The alterations of lipid profile was evaluated by TG, TC, LDL-C and HDL-C levels in serum. Administration of apigenin exerted beneficial effects through improving insulin resistance, alleviating liver injury, and inhibiting the alterations of lipid profile in high fructose-fed mice. In addition, apigenin potently facilitated the accumulation of Nrf2 nuclear translocation and accompanied by increasing HO-1 and NQO1 protein expressions, which are responsible for attenuating oxidative stress. Molecular docking results demonstrated that potential interaction of apigenin with the Nrf2-binding site in the Keap1 protein. In summary, we demonstrated that apigenin prevented high fructose induced metabolic syndrome probably by inhibiting binding of Keap1 to Nrf2, and thus Nrf2 nuclear translocation, subsequently resulting in increased the expressions of anti-oxidative genes including HO-1 and NQO1. PMID- 30021366 TI - Naringin suppresses the growth and motility of hypertrophic scar fibroblasts by inhibiting the kinase activity of Akt. AB - Hypertrophy is a very common pathologic phenomenon of scar hyperplasia after human skin injury and wound healing. In this article, we first proved that naringin could inhibit the proliferation of fibroblasts by MTT experiments. Flow cytometry indicated that naringin could block the cell cycle and promote apoptosis. Transwell experiments showed that naringin could inhibit the motility activity of fibroblasts. We also found that naringin specifically inhibits the kinase activity of Akt and the phosphorylation of Akt in hypertrophic scar fibroblasts by Kinase-Glo, western blot and real-time PCR assays. Subsequently, western blots and real-time PCR indicated that naringin can inhibit phosphorylation of Akt and downstream proteins of Akt. Our data demonstrated that naringin inhibits the development of hypertrophic scars, at least to a certain extent, by its inhibition of Aktp-Ser473/Thr308. PMID- 30021367 TI - Scutellaria: Debates on the anticancer property. AB - The widespread use of plants as accessible anticancer agents leads to the identification of many natural source chemotherapeutic agents. Scutellaria one of the popular genus of flowering plants has been used for various human illnesses for thousands of years. Scutellaria has anti-metastatic, anti-proliferative, anti invasion, anti-angiogenic and apoptosis effects in vitro as well as in vivo. Despite numerous reports on the cytotoxic-antitumor activity of the plant, there are still some issues need further consideration. Issues such as unjustified interpretations, lack of attention to the pharmacokinetics profile and weak study design may affect the final decision about the use of plants as anticancer agents and possibly needs reconsideration. In this review, we have summarized the potential health benefits of Scutellaria and its active components also the underlying mechanism of cytotoxicity and antitumor activity. Meanwhile we have discussed concerns may interfere with the precise conclusion. PMID- 30021369 TI - KGF inhibits hypoxia-induced intestinal epithelial cell apoptosis by upregulating AKT/ERK pathway-dependent E-cadherin expression. AB - OBJECTIVE: Intestinal ischemia-reperfusion (I/R) causes direct cellular damage, and the potential injury to the mucosal structure and barrier function. Keratinocyte growth factor (KGF) is highly expressed in gastrointestinal tract and exerts beneficial effects for intestinal epithelial growth and maintenance. E cadherin plays an important role in intestinal epithelium renewal. However, the regulatory role of KGF on E-cadherin levels and I/R-induced apoptosis remain to be explored. The present study aimed to identify the effect of KGF on E-cadherin expression and I/R-induced intestinal epithelial cell apoptosis. METHODS: Caco2 cells were treated with KGF (100 ng/ml) for 0, 4, 8, 12, and 24 h under hypoxia or normoxia. An E-cadherin-knockdown model was successfully established by treatment with E-cadherin RNAi. Western blotting and immunofluorescence labeling were performed to assess E-cadherin expression. Levels of PI3K|[sol]|Akt/mitogen activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K|[sol]|Akt)/PI3K|[sol]|Akt pathway-related proteins, and apoptosis-related proteins were also detected by western blot. Finally, a rat model of acute intestinal I/R was established and treated with KGF. Hematoxylin-eosin (HE), terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), and immunofluorescence staining were performed to detect morphological changes in intestinal mucosal epithelium and Caco2 cell apoptosis. RESULTS: KGF enhanced E cadherin expression in differentiated intestinal epithelial cells under hypoxia via AKT/extracellular-regulated kinase (ERK) pathway regulation. In vitro, E cadherin downregulation aggravates hypoxia-induced intestinal epithelial cell apoptosis. In the rat model, KGF increased E-cadherin expression, which was associated with the reduced apoptosis. CONCLUSIONS: KGF exerts protective effects on intestinal epithelial cells under hypoxia by elevating E-cadherin levels or activating AKT/ERK signaling. PMID- 30021368 TI - The effect of Sebastiania hispida gel on wound model infected by methicillin resistant Staphylococcus aureus. AB - Medicinal plants are an alternative for the treatment of infected wounds. The objective of this study was to evaluate the efficacy of Sebastiania hispida in an animal model with a wound infected by Staphylococcus aureus. The crude ethanol extract (ExtEtOH) of S. hispida underwent phytochemical analysis, quantification of metabolites and antibacterial activity analysis performed using S. aureus. Wistar rats were used to test healing activity, and the groups evaluated comprised gels of ExtEtOH at the concentrations 0.2 and 2% compared with control groups. Animals were inoculated with the bacteria S. aureus resistant to methicillin. The treatment periods were of 3 and 21 days. Macroscopic and microscopic analysis were conducted and data were submitted to analysis of variance (p < 0.05). Phytochemical and quantification analysis indicated that phenolic compounds and flavonoids are the major constituents, followed by tyterpenes. ExtEtOH 0.2% was the most effective gel against the growth of strains of S. aureus. Histological wound and regression analysis showed that ExtEtOH gels (0.2% and 2%) were similar and effective in promoting wound healing. In the quantification of collagen fibers, the animals from all groups showed a high amount of thick collagen fibers. Thus, ExtEtOH gels based on the shoots of S. hispida can be used for the treatment of infected wounds as a complementary therapy for infected wound closure and further assays are required with other means. The healing effectiveness may be due to the high content of phenolics, flavonoids and triterpenes. PMID- 30021370 TI - Over-expression of miR-15a-3p enhances the radiosensitivity of cervical cancer by targeting tumor protein D52. AB - BACKGROUND: Radioresistance is a challenge in the treatment of cervical cancer. Recent studies have reported that microRNAs (miRNAs) mediate radiotherapy resistance and play a vital role in the occurrence and development of cancer. The aim of this study was to investigate whether the expression of miR-15a-3p was correlated with radiosensitivity in cervical cancer. METHODS: Quantitative real time PCR experiment was performed to detect the expression of miR-15a-3p in cervical cancer tissues and cells lines. Then, the effect of miR-15a-3p on proliferation in cervical cancer cells radiation-induced were determined by using CCK-8, clonogenic formation and EdU assays. In addition, the TUNEL, flow cytometry analysis and western blotting assays were conducted to evaluate radiation-induced cells apoptosis. A dual-luciferase reporter assay was used to test the target. In addition, tumor xenograft experiment was conducted to test tumor growth in vivo. RESULTS: In this study, miR-15a-3p was downregulated in cervical cancer tissues and cells lines, however, the expression of miR-15a-3p significantly increased exposed to radiation. Moreover, over-expression of miR 15a-3p inhibited cells proliferation and enhanced cells apoptosis radiation induced. Further, TPD52 was identified as a direct target of miR-15a-3p. Inhibition of TPD52 could suppress cells proliferation and induce cells apoptosis. Tumor xenograft experiments indicated that over-expression of miR-15a 3p could increase sensitivity to radiation therapy by targeting TPD52. CONCLUSION: In conclusion, our findings suggested that miR-15a-3p enhanced radiosensitivity in cervical cancer by targeting tumor protein D52, suggesting that miR-15a-3p may be a potential therapeutic target for cervical cancer patients. PMID- 30021371 TI - Hesperidin, piperine and bee venom synergistically potentiate the anticancer effect of tamoxifen against breast cancer cells. AB - Despite advances in cancer treatment, breast cancer remains one of the main life threatening diseases in women. Most anti-breast cancer drugs cause severe health complications and multidrug resistance. Although, some natural products, such as hesperidin (Hes), piperine (Pip) and bee venom (BV), showed anti-breast cancer effect when used separately, their combined effect together or with the anti cancer drug tamoxifen (Tam) has not yet been studied. Herein, we hypothesized that these three natural products could potentiate the therapeutic effect of Tam when used together. First, we studied the cytotoxic effect of Hes, Pip, and BV on MCF7 and T47D cells using MTT assay and found reasonable IC50 comparable to that of Tam. Second, we checked the effect of all combinations (n = 67 for each cell line, prepared as non-constant ratio from fractions of IC50 of the four compounds) and found enhanced anti-proliferative effects on MCF7 and T47D and synergistic effect, revealed by combination index (CI) values below one. Next, the best 5 combinations with lowest Tam doses and CI but with highest cell death were selected for further molecular analysis in comparison to single-drug treatment. All single- and combined-treated groups showed a significant increase in apoptosis (indicated by upregulated mRNA level of the pro-apoptotic marker Bax and downregulated mRNA level of the anti-apoptotic marker Bcl2) and a significant decrease in mRNA level of the two breast cancer related receptors EGFR and ERalpha, with the best effect in combined groups especially that contained the 4 compounds, as compared to vehicle-treated group. Moreover, Pip, BV and all combinations, except Tam + Hes group, arrested MCF7 and T47D in G2/M phase of cell cycle, while Tam and/or Hes caused G0/G1 phase arrest. These results indicate that Hes, Pip and BV synergistically enhance the anti-cancer effect of Tam and could be used as safe adjuvant/vehicle to Tam in treatment of breast cancer after further confirmatory in vivo investigations. PMID- 30021372 TI - Comparison of three different extracts of Centella asiatica for anti-amnesic, antioxidant and anticholinergic activities: in vitro and in vivo study. AB - Centella asiatica (CA) has been used by Ayurvedic medical practitioners in India for almost 3000 years. The neuropharmacological properties of CA and its constituents have been studied extensively. Anti-oxidant, free radical scavenging and cholinergic modulatory activities are the reported mechanisms of action for its efficacy in memory disorders. Its medicinal values are mainly attributed to the presence of several triterpenes, namely asiatic acid, madecassic acid, asiaticoside, and madecassoside. The present study was aimed to investigate the role of these triterpenes content in CA extract on the antioxidant, cholinesterase modulation and anti-amnesic properties. The fractions of CA extract enriched for (CAE-EF) and depleted/freed of (CAE-FF) triterpenes contents were compared with methanolic extract (CAE). Both in vitro and in vivo methods for evaluation of antioxidant and anticholinergic activities were used. In vitro, free radical scavenging assays (ABTS, DPPH, NO, NORAC, and ORAC) and cholinesterase (AChE and BuChE) inhibition assays were used. For evaluation of anti-amnesic effect, scopolamine induced amnesia in rats, as the acute model of memory loss was used. Following behavioural assessments (MWM, PA, EPM), biomarkers of oxidative stress (reduced GSH, MDA and SOD activity) and cholinesterase (AChE and BuChE) status were also estimated in cerebral cortex and hippocampus of rat brain. The methanolic extract (CAE) was found to perform best among all three fractions for in vitro free radical scavenging, cholinesterase inhibition, improvement of scopolamine-induced amnesia and also in vivo antioxidant effect and cholinesterase inhibitory activities. Interestingly triterpenes free fraction (CAE-FF) showed better antioxidant activity than triterpenes enriched fraction (CAE-EF) along with comparable anti-amnesic effect. This indicates that triterpenes are not solely responsible for antioxidant activity, cholinesterase inhibitory and anti-amnesic effect of CA. PMID- 30021373 TI - Clofazimine: A useful antibiotic for drug-resistant tuberculosis. AB - Drug resistance is still the major threat to global tuberculosis (TB) control, and drug-resistant (DR) Mycobacterium tuberculosis (M. tuberculosis) strains have become the main challenge worldwide. Currently used antibiotics for treatment of DR-TB are often poorly tolerated and not sufficiently effective. Since the therapeutic options are still limited, the main strategy for treatment of DR-TB is to repurpose existing anti-mycobacterial agents. Clofazimine (CFZ) is one such drug that has recently attracted interest against DR-TB. CFZ is a hydrophobic riminophenazine that was initially synthesized as an anti-TB antibiotic. Although the mechanisms of action of CFZ are not yet entirely understood, it has been suggested that outer membrane is its primary action site, and the respiratory chain and ion transporters are the putative targets. In this review, we will discuss the anti-mycobacterial properties of CFZ, and provide new insights into the clinical use of this drug. PMID- 30021374 TI - Potent tocolytic activity of ethyl acetate fraction of Ananas comosus on rat and human uteri. AB - The aim of this study was to investigate the tocolytic properties of Ananas comosus extract in rat and human uterine tissue in vitro and in the rat in vivo. Organ bath technique was employed to perform functional studies in vitro. The PhysioTel transmitter was implanted in SD rats to measure the changes in intrauterine pressure (IUP) in vivo. Analyses of F2 was performed using LC-HRMS. F2 produced a non-selective inhibitory response on oxytocin, prostaglandin F2alpha, acetylcholine and KCl. The inhibitory activity of F2 on oxytocin-induced contraction was not attenuated by propranolol, TEA, glibenclamide and indomethacin. Nomega-Nitro-L-arginine, a nitric oxide synthase inhibitor, suppressed the maximal tocolytic activity of F2 by 25%. DIDS, an inhibitor of chloride channels, appeared to suppress the relaxant effect of F2. F2 suppressed the oxytocin-induced contraction in Ca2+ free solution. The in vivo tocolytic activity of F2 and ritodrine were observed in non-pregnant rats during the estrous stage by suppressing the frequency and amplitude of IUP peaks following intrauterine administration. Chemical analysis confirmed the involvement of citric acid in the tocolytic activity of F2. However, another less polar fraction is essential to accompany citric acid to produce such potent inhibitory response of F2. It is likely that F2 exerted tocolytic activity by multiple mechanisms, including antagonizing L-type Ca2+ channels, interfering with the intracellular Ca2+ release mechanism and releasing nitric oxide. F2 would be a promising candidate to develop as a tocolytic agent. PMID- 30021375 TI - Synergistic effect of glucosamine and vitamin E against experimental rheumatoid arthritis in neonatal rats. AB - The effect of glucosamine and vitamin E against rheumatoid arthritis (RA) in a neonatal rat model was investigated. Lipid peroxidation, superoxide dismutase (SOD), catalase, reduced glutathione (GSH), glutathione peroxidase (Gpx), matrix metalloproteinase-3 (MMP-3), prostaglandin E2 (PGE2), ceruloplasmin, copper, zinc, nitric oxide (NO), uric acid, inducible nitric oxide synthase (iNOS), and nuclear factor-kappaB (NF-kappaB) levels were determined in control and rheumatoid arthritis neonatal rats. Glucosamine plus vitamin E supplementation reduced the MDA level by 61.9% and increased the SOD, catalase, GSH, Gpx, and zinc levels. MMP-3, PGE2, ceruloplasmin, copper, NO and uric acid levels were significantly reduced by supplementation of glucosamine plus vitamin E. NF kappaB, and iNOS protein levels were decreased by 47.7% and 39.5%, respectively, by glucosamine plus vitamin E supplementation. Thus, supplementation with glucosamine plus vitamin E exerted a synergistic effect against RA. PMID- 30021376 TI - Suppression of SMOC2 reduces bleomycin (BLM)-induced pulmonary fibrosis by inhibition of TGF-beta1/SMADs pathway. AB - Although the initiation and modulation of lung fibrosis has been widely investigated, the pathogenesis was not well understood. Secreted modular calcium binding protein 2 (SMOC2) as the secreted protein acidic is enriched in cysteine (SPARC) family of matricellular proteins, which are important in regulating cell matrix interactions. Here we aimed to calculate the effects and molecular mechanism of SMOC2 on the progression and severity of lung fibrosis in murine bleomycin (BLM)-induced mice. The pulmonary fibrosis was significantly induced by BLM in wild type (WT) C57BL6 mice, as evidenced by the lung sections histology and collagen accumulation using H&E and Masson Trichrome staining. Notably, SMOC2 knockout (SMOC2-/-) mice treated with BLM exhibited the decrease in inflammation accompanied by the reduction of neutrophils, macrophages and lymphocytes in bronchoalveolar lavage fluids (BALF). In addition, the levels of inflammation associated cytokines and chemokines induced by BLM were also decreased in BALF obtained from SMOC2-/- mice. Meanwhile, SMOC2-/- suppressed the progression of pulmonary fibrosis, as evidenced by the reduction in levels of transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin (alpha-SMA), p-SMAD2 and p-SMAD3 in lung tissue samples. Increasing expression of SMOC2 in TGF-beta1 treated cells were further observed in vitro. Of note, up regulation of SMOC2 activated-fibrosis development in MRC-5 cells, along with increase of alpha-SMA, p-SMAD2 and p-SMAD3 were determined. In contrast, SMOC2 knockdown reduced TGF beta1-stimulated expressions of alpha-SMA, p-SMAD2 and p-SMAD3 in cells. The findings above suggested that SMOC2 knockout contributes to inhibit BLM-induced pulmonary fibrosis. PMID- 30021378 TI - Immunomodulatory effects of Thymol through modulation of redox status and trace element content in experimental model of asthma. AB - Oxidative stress plays a key role in the immunopathogenesis of asthma. The objective of this study was to investigate the thymol effects on oxidative parameters along with trace elements in asthma experimental model. The Balb/c mice were sensitized by intraperitoneal injection of ovalbumin and thymol (8, 16 and 32 mg/kg) and dexamethasone (DEX) (2 mg/kg) were orally administered to sensitized mice. Oxidative stress parameters including protein carbonyl content, malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and total antioxidant capacity (TAC) besides trace element levels were evaluated. The protein carbonyl content, MDA and 8-OHdG in treated mice with 32 mg/kg of thymol significantly decreased compared to asthmatic mice (P < 0.01). Also, TAC significantly increased (P < 0.001) as well as zinc and selenium levels while copper level decreased. 16 mg/kg of thymol reduced the protein carbonyl content, MDA and 8 OHdG compared to asthmatic mice (P < 0.05). In addition, thymol improved the most prominent inflammation characteristics of asthma. The obtained results suggest that thymol has a protective effect against oxidative stress and it was also able to partially restore the defective trace element levels in asthma. Based on our observations, thymol may be used for alternative / complementary therapy in asthma. PMID- 30021377 TI - Heterogeneous nuclear ribonucleoprotein M promotes the progression of breast cancer by regulating the axin/beta-catenin signaling pathway. AB - Despite significant progress in the treatment of breast cancer due to advances in surgery, cytotoxic agents, and endocrine therapy, the prognosis for patients has not improved much. Accumulated evidence indicates that heterogeneous nuclear ribonucleoprotein M (hnRNPM) and Wnt/beta-catenin function as tumor oncogenes in the progression of many cancers. The present study aimed to explore whether HnRNPM/beta-catenin signaling molecules might serve as a genetic target for breast cancer treatment. To shed light on this issue, quantitative real-time polymerase chain reaction (qRT-PCR) detection, Western blotting, and immunohistochemical staining were performed. The hnRNPM is expressed at a much higher level in breast cancer tissues and cell lines than in noncancerous tissues and cell lines. In vitro studies revealed that overexpressed hnRNPM promoted cell proliferation and colony formation but inhibited cell apoptosis. In vivo results demonstrated that upregulation of hnRNPM dramatically increased breast cancer xenograft tumor growth. Western blotting and immunofluorescence studies revealed that hnRNPM markedly activated the Wnt/beta-catenin pathway and catalyzed its translocation from the cytoplasm to the nucleus by targeting axin, a negative regulator of Wnt/beta-catenin signaling in MCF-7 and KPL-4 cells. Elevated levels of c-Myc and cyclin D1 were observed when MCF-7 and KPL-4 cells were transfected with a hnRNPM vector. These findings indicate that the hnRNPM/axin/beta-catenin signaling pathway acts as an oncogenic promoter in the progression of breast cancer, suggesting that hnRNPM may be a potential target for the treatment of this disease. PMID- 30021379 TI - Peperomin E (PepE) protects against high fat diet-induced atherosclerosis in Apolipoprotein E deficient (ApoE-/-) mice through reducing inflammation via the suppression of NLRP3 signaling pathway. AB - Peperomin E (PepE) is a type of secolignan, a major component of the plant Peperomia dindygulensis. It has been shown to exert anti-inflammatory effects; however, the effects of PepE on human atherosclerosis remain unexplored. In the study, we investigated the role of PepE in high fat diet (HFD) induced atherosclerosis using apolipoprotein E defcient (ApoE-/-) mice. Elevated serum homocyteine, cholesterol, and triglyceride levels, accelerated progression of atherosclerosis and exacerbated macrophage infiltration into atherosclerotic lesions were observed in HFD-fed ApoE-/- mice, which were attenuated by PepE treatment. ApoE-/- mice fed with HFD exhibited significantly high levels of inflammation-associated regulators in artery tissues, accompanied with an increased expression of p-inhibitor of kappaBalpha (IkappaBalpha) and p-nuclear factor-kappa B (NF-kappaB), and the process was blocked by PepE administration. Further, we found NOD-like receptor pyrin 3 (NLRP3) inflammasome activation in artery tissues of HFD-fed ApoE-/- mice. In vitro, silencing NLRP3 using small interfering RNA efficiently inhibited oxidized-low-density lipoprotein (oxLDL) induced ASC and Caspase-1 expressions, interleukin (IL)-1beta and IL-18 production in human aortic endothelial cells (HAECs). Further experiments indicated that NLRP3-ASC pathway was activated by reactive oxygen species (ROS), since ROS scavenger of N-acetyl-cysteine (NAC) prevented, which was further reduced by PepE addition. However, the anti-inflammatory effects of PepE on oxLDL incubated HAECs were abolished by over-expression NLRP3. Together, our study revealed that PepE inhibited atherosclerosis development in HFD-fed ApoE-/- mice by suppressing NLRP3 inflammatory signaling pathway, and suggested that PepE might be a potential therapeutic strategy in the prevention of atherosclerosis. PMID- 30021380 TI - The effects of DMARDs on the expression and function of P-gp, MRPs, BCRP in the treatment of autoimmune diseases. AB - The ATP-binding cassette (ABC) transporter family is a large class of ATP energy dependent transmembrane proteins, and its primary function is to use the energy produced by ATP hydrolysis to transfer the substrate bound to the plasma membrane. This family is also closely related to multidrug resistance (MDR) in various diseases. Among the ABC transporter proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) are the main members associated with MDR. At present, the roles of these transporters in therapeutic failures have been extensively studied and reviewed in cancer; however, they have rarely been described in autoimmune diseases (AIDs). AID is a group of chronic inflammatory diseases of unknown aetiology. AID's basic feature is the production of a large number of autoantibodies, which leads to extensive damage to multiple systems and multiple organs. Disease-modifying anti-rheumatic drugs (DMARDs) are commonly used in the treatment of AID, but a considerable number of patients have no response or develop resistance to these drugs over time. This phenomenon may be related to the abnormal expression of the ABC transporter, which leads to a decrease in the amount of drug entering cells that produce MDR. This article reviews the effects of DMARDs on the expression and function of P-gp, MRPs, and BCRP and the related molecular mechanism in the treatment of AID. PMID- 30021381 TI - MicroRNA-519d-3p inhibits cell proliferation and migration by targeting TROAP in colorectal cancer. AB - Increasing evidence suggests that miR-519d-3p functions as tumor suppressor in several tumors, including breast cancer. However, its biological role in the development of colorectal cancer (CRC) still remains unclear. In this study, we found that miR-519d-3p expression level was remarkably down-regulated in CRC tissues samples and cell lines when compared to adjacent normal tissues and cell line by using qRT-PCR detection. Lower miR-519d-3p expression was significantly correlated with TNM stage, tumor size and lymph node metastasis. CRC patients with high level of miR-519d-3p had higher five-year survival rate than those with low expression of miR-519d-3p (p = 0.01178) using Kaplan-Meier analysis. Moreover, multivariate analysis suggested that miR-519d-3p expression might be an independent prognostic indicator for the survival of CRC patients. The in vitro functional analysis, including MTT, flow cytometry and transwell assays indicated that miR-519d-3p overexpression significantly suppressed cell proliferation, migration and invasion, induced cell cycle G0/G1 phase arrest and cell apoptosis of CRC cells. Furthermore, bioinformatics and luciferase reporter assays verified that trophinin associated protein (TROAP) was a direct target of miR-519d-3p in CRC cells. Using Oncomine database analysis, TROAP was confirmed to be upregulated in human CRC tissues. In addition, we found knockdown of TROAP presented similar inhibitory effects of miR-519d-3p overexpression in CRC cell function. In conclusion, miR-519d-3p might be a promising therapeutic strategy against human CRC by directly targeting TROAP. PMID- 30021383 TI - Chios mastic gum decreases renin levels and ameliorates vascular remodeling in renovascular hypertensive rats. AB - Chios mastic gum (CMG) exerts robust anti-inflammatory and antioxidant properties and it affects pathways that are implicated in the pathophysiology of endothelial and vascular inflammation. Aim of this study was to test the hypothesis that CMG administration lowers blood pressure (BP) and improves hypertension-induced target organ damage. 2-kidney, 1-clip (2K1C) hypertensive rats were treated with CMG (40 mg/kg body weight/day) for 2-weeks after the establishment of hypertension. Acute CMG administration lowered systolic, diastolic and mean arterial BP, while these hemodynamic effects were sustained throughout the 2-week administration period. CMG group also exhibited alleviated target organ damage as proposed by amelioration of biomechanical properties of the aorta -including cross-sectional area (CSA), aortic wall stiffness and thickness-, reversal of myocardial small vessel hypertrophy and maintenance of serum albumin levels. The anti-hypertensive effects of CMG are likely to be mediated by the decrease in renin serum levels. Regression analysis indicated that the effect of CMG on organ damage was BP-lowering dependent and was not associated with direct effects of renin or with its anti-inflammatory properties. We suggest a BP lowering effect of CMG via down-regulation of renin excretion associated with attenuation of target organ damage and inflammatory status. These observations provide profound evidence for the beneficial role of CMG in hypertension, which could possibly translate to further clinical research. PMID- 30021382 TI - MiR-373-3p enhances the chemosensitivity of gemcitabine through cell cycle pathway by targeting CCND2 in pancreatic carcinoma cells. AB - OBJECTIVE: This study aimed to detect the expression of miR-373-3p and CCND2 in gemcitabine-resistance pancreatic carcinoma (PC) cells, investigate the relationship between miR-373-3p and CCND2, and explore their effects on PC propagation, migration, invasion and apoptosis. METHODS: R software was applied for analyzing differentially expressed genes (DEGs) in cell samples. The potential biological pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, based on R software. The gemcitabine-resistance PC cells were screened out using MTT assay, and they were applied in the next experiments. MiR-373-3p and CCND2 expression in GEM-PANC-1 cells were measured by qRT-PCR. After transfection, the expression of CCND2 protein was examined via western blot assay. Cells viability and apoptosis were confirmed by MTT proliferation assay and Flow cytometry, whereas cells migration and invasion were analyzed by transwell assay. The targeting relationship between miR-373-3p and CCND2 was identified by dual-luciferase reporter assay. RESULTS: MiR-373-3p was found to be low expressed in GEM-PANC-1 cells while CCND2 was highly expressed in GEM-PANC-1 cells. MiR-373-3p negatively regulated CCND2 expression through KEGG_Cell_Cycle_Signaling_Pathway. The targeted relationship between miR-373-3p and CCND2 could be verified using dual luciferase reporter assay. MTT proliferation assay, transwell assay and Annexin V assay demonstrated that miR 373-3p suppressed GEM-PANC-1 cells propagation and invasion and promoted cell apoptosis, while CCND2 showed totally reverse effects compared with miR-373-3p. All the results suggested that miR-373-3p could enhance the chemosensitivity of GEM-PANC-1 cells by regulating CCND2. CONCLUSION: MiR-373-3p inhibited cell propagation, migration and invasion and boosted apoptosis in gemcitabine resistance pancreatic carcinoma cells by targeting CCND2. PMID- 30021384 TI - Trehalose prevents sciatic nerve damage to and apoptosis of Schwann cells of streptozotocin-induced diabetic C57BL/6J mice. AB - Type 1 diabetes (T1DM) affects approximately 1 in 500 children. Diabetic peripheral neuropathy (DPN) is the most common form of peripheral neuropathy in diabetes and is a significant risk factor for serious pathological change. It is difficult and costly to treat DPN and although there have been several pivotal trials. The development of new drugs to treat DPN remains a high priority. Trehalose is a naturally occurring disaccharide, which is indicated to prevent maternal type 1 diabetes-induced neural tube defects. Thus, the primary aim of this study is to determine whether trehalose ameliorates DPN-induced sciatic nerve injury in TIDM. To establish a T1DM mouse model, wild-type (WT) male C57BL/6 J mice were injected with streptozotocin (STZ). WT mice, T1DM mice, and mice fed with trehalose were assayed for myelin-related gene expression and with behavioral tests. To mimic high glucose in vivo, Schwann cells were cultured under high glucose conditions with or without trehalose. In addition, oxidative damage, apoptosis, and mitochondrial translocation of the pro-apoptotic B-cell lymphoma-2 (Bcl-2) family members were assessed in Schwann cells. Results showed that treatment by trehalose prevented DPN and preserved diabetes-decreased expression of myelin-related genes in T1DM mice. Furthermore, trehalose abolished diabetes-suppressed regeneration of the sciatic nerve. More importantly, trehalose suppressed high glucose-induced oxidative damage and apoptosis in Schwann cells. In summary, trehalose ameliorates DPN-induced sciatic nerve injury in T1DM by preventing apoptosis, which makes it a promising candidate for the treatment of DPN. PMID- 30021385 TI - Ursolic acid improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-induced rats. AB - Inflammation plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). Overexpression of inflammatory chemokine and cytokines is involved in the development of DN. Ursolic acid (UA), a common pentacyclic triterpenoid compound, has been reported to have myriad benefits and medicinal properties. However, its protective effects against renal injury in streptozotocin (STZ)-induced diabetic rats have not been firmly established. In the current report, we investigated whether UA inhibits oxidative stress and inflammation in the kidneys of STZ induced diabetic rats. Diabetes mellitus (DM) was induced by STZ (40 mg/ kg, i.v.). Animals were randomly divided into control group (normal saline, i.g.), DN group (normal saline, i.g.), DN + UA group (35 mg/kg UA + normal saline, i.g.) and DN + telmisartan group (12 mg/kg telmisartan + normal saline, i.g.). Fasting blood glucose (FBG) levels were monitored at regular intervals. The administration of compounds started at 5th week and lasted for 8 weeks. At the beginning of 13th week, rats were humanely euthanized, KW/BW, BUN, SCr, SOD and MDA were measured. Histopathological changes in renal tissue were observed after hematoxylin-eosin (HE) staining. Furthermore, the expressions of TNF-alpha, MCP-1 and IL-1beta in kidney were determined by immunohistochemistry and western blot. Our results showed that UA significantly lowered the levels of FBG, KW/BW, BUN, SCr and MDA in diabetic rats. Additionally, the SOD activity in UA treated group was higher than that in DN group. Furthermore, renal structural abnormalities and the elevation of TNF-alpha, MCP-1 and IL-1beta expression level were blocked by the administration of UA. In conclusion, our data demonstrate that UA could be well used as a protective agent to counter renal dysfunction - through antioxidant and anti-inflammatory effects. PMID- 30021387 TI - Angiopoietin 2 promotes angiogenesis in tissue-engineered bone and improves repair of bone defects by inducing autophagy. AB - Angiogenesis plays a key role in the repair of large segmental bone defects with tissue-engineered bones. However, there is no effective method of promoting angiogenesis in tissue-engineered bone. Both angiopoietin 2 (Ang2) and autophagy have been shown to be involved in angiogenesis, but their roles in angiogenesis of tissue-engineered bone remains unknown. In this in vivo study, a radius bone defect was created in New Zealand white rabbits, which were then treated by implantation of a hydroxyapatite/collagen scaffold followed by injection of different concentrations of Ang2. Expression of the autophagic modulators microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and SQSTM1/P62 were measured via western blotting, while the angiogenic modulators VEGF and CD31 were detected by western blotting and immunohistochemistry, respectively. X-ray imaging combined with general observation was used to evaluate bone defect healing. Expression of LC3 -I/LC3-II, Beclin-1, VEGF, and CD31 in the callus area increased and SQSTM1/p62 decreased in a dose-dependent manner with increasing Ang2 concentration. In the group treated with a high concentration of Ang2, the new callus grew well, accompanied by remarkable angiogenesis, leading to good repair of the bone defects. However, in the low concentration of Ang2 group, in spite of the existence of angiogenesis and new bone formation, the bone defects were not repaired. Furthermore, angiogenesis and osteogenesis were both obstructed in the control group. In conclusion, our study demonstrated that a high concentration of Ang2 promoted angiogenesis in tissue-engineered bone and improved repair of bone defects by inducing autophagy. PMID- 30021386 TI - MiR-363-3p suppresses tumor growth and metastasis of colorectal cancer via targeting SphK2. AB - Aberrant expression of miR-363-3p is seen in a wide array of cancers. The exact function of miR-363-3p in colorectal cancer (CRC), and the underlying mechanisms remain undefined. In the current study, we observed a down-regulation of miR-363 3p in CRC tissues, along with a strong correlation between low miR-363-3p levels and clinico-pathological parameters like tumor stage and lymph node metastasis. Ectopic overexpression of miR-363-3p in HT29 and HCT116 cell lines effectively inhibited cell proliferation and metastasis, and promoted apoptosis. Concurrently, miR-363-3p inhibition facilitated cell proliferation and suppressed apoptosis. Consistent with the in vitro findings, tumor growth and metastasis were also suppressed by the overexpression of miR-363-3p in vivo. Furthermore, miR-363-3p overexpression resulted in a significant decrease in SphK2 mRNA and protein levels, while miR-363-3p inhibition elevated SphK2 levels in CRC cell lines. Overexpression of SphK2 significantly abrogated the effects of miR-363-3p on cell growth, apoptosis, and metastasis. Taken together, our findings establish miR-363-3p as a potential tumor suppressor in CRC with SphK2 as its downstream target. PMID- 30021388 TI - MicroRNA-449a upregulation promotes chondrocyte extracellular matrix degradation in osteoarthritis. AB - Osteoarthritis (OA) is a highly prevalent chronic and degenerative joint disease characterized by the continuous destruction of the articular cartilage. MicroRNAs (miRNAs) have been reported to be strongly involved in the pathogenesis of OA. The aim of this study was to explore whether miR-449a regulates the expression of growth differentiation factor5 (GDF5), which promotes chondrocyte extracellular matrix (ECM) degradation. We found that miR-449a expression was upregulated in OA cartilage compared to that in normal cartilage. Overexpression of miR-449a increased the expression of chondrocyte ECM catabolic factors, such as matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motif, while inhibiting that of anabolic genes, such as type II collagen and aggrecan. In contrast, suppression of miR-449a exerted the opposite effects. Moreover, GDF5 was identified as a direct target of miR-449a, and its expression was significantly suppressed by miR-449a overexpression. In addition, the suppression of chondrocyte ECM degradation induced by miR-449a inhibitor was attenuated by small interfering RNA-mediated knockdown of GDF5. Overall, these results suggest that miR-449a contributes to chondrocyte ECM degradation in OA via directly targeting GDF5, thereby providing insights to a promising therapeutic target for the treatment of human OA. PMID- 30021389 TI - Role of an indole-thiazolidiene PPAR pan ligand on actions elicited by G-protein coupled receptor activated neutrophils. AB - Neutrophils are the first line of defence during inflammatory processes; nevertheless, exacerbated influx and actions of neutrophils in terms of uncontrolled inflammation are harmful to the host. Hence, neutrophil activity is the target of drugs seeking to address undesired inflammation. Here, we investigated the mechanisms of action of a ligand of the three isoforms of peroxisome proliferator-activated receptors (PPAR; (5Z)-5-[(5-bromo-1H-indole-3 yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione), dubbed LYSO-7, on neutrophils activated by N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), an agonist of G-protein coupled receptors (GPCRs) that binds to membrane-formylated peptide and activates intracellular inflammation pathways. Neutrophils were collected from the peritoneal cavity of male Wistar rats four hours after oyster glycogen injection. Afterwards, the neutrophils were incubated with saline or LYSO-7 (1 or 10 MUM, 30 min), washed and stimulated with fMLP (10-7 MUM, 1 h). LYSO-7 treatment inhibited gene and protein expression of adhesion molecules, CD62 L and CD18, abolished adhesion of neutrophils to endothelial cells, impaired chemotaxis, blocked the enhancement of intracellular calcium levels, induced the expression of PPARgamma as well as PPARbetadelta and reduced nuclear translocation of nuclear factor kappaB (NF-kappaB). Moreover, topical application of LYSO-7 (10 mM) prior to local application of fMLP (10-7 MUM) diminished the in vivo leukocyte-endothelial interactions in the mesentery microcirculation of rats. Together, our data highlight the effectiveness of anti-inflammatory actions of LYSO-7 on neutrophils activated by GPCRs, depending, at least in part, on impaired of NF-kappaB activation and induction of PPAR expression. PMID- 30021390 TI - Erythropoietin: A potential drug in the management of diabetic neuropathy. AB - Erythropoietin (EPO) is required for promoting the progress of erythroid differentiation. However, the discovery of EPO and the EPO receptor (EPOR) in the nervous system may contribute to new treatment strategies for the use of EPO in neurodegenerative disorders. Diabetic neuropathy is a neurodegenerative disease that affects a large proportion of diabetic patients and results in alterations in functionality, mood and sleep. The pathogenic mechanisms generating diabetic neuropathy involve: Schwannopathy, polyol pathway activity, advanced glycation end-products (AGEs) accumulation, protein kinase C (PKC) activity, increased hexosamine pathway flux, oxidative stress, nitric oxide and inflammation. In this sense, evidence from both clinical and experimental studies indicates that EPO may reverse diabetic neuropathy through an antioxidant action by decreasing pro inflammatory cytokines, restoring Na+/K+-ATPase activity, and blocking the generation of pro-apoptotic proteins. The aim of this review is to discuss the neuroprotector effect of EPO on pathogenic mechanisms of diabetic neuropathy. PMID- 30021391 TI - Comprehensive anti-tumor effect of Brusatol through inhibition of cell viability and promotion of apoptosis caused by autophagy via the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. AB - Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan. PMID- 30021392 TI - TGF-beta1 modulates podocyte migration by regulating the expression of integrin beta1 and -beta3 through different signaling pathways. AB - AIMS: Podocyte migration may lead foot process effacement and proteinuria. Transforming growth factor-beta1 (TGF-beta1) and integrins are involved in the adhesion and migration of cells. However, the crosstalk of TGF-beta1 and integrins is unclear. Here, we examined how TGF-beta1 regulates the expression of integrin-beta1 and -beta3 to modulate podocyte adhesion and migration. MAIN METHODS: Podocytes were exposed to TGF-beta1 and/or the inhibitors of Smad2/3, ERK and p38, then the expression of integrin-beta1 and -beta3 was assessed by Real-time PCR and western blot analyses. Podocyte adhesion and migration were measured under TGF-beta1 treatment and/or anti-integrin-beta3 antibody by cell adhesion assay and wound healing assay. KEY FINDINGS: TGF-beta1 had no effect on integrin-beta1 mRNA expression. In the analysis of protein expression, TGF-beta1 decreased the mature form of integrin-beta1, but increased both the precursor form and core peptide of integrin-beta1. The inhibitors of ERK and p38, but not Smad2/3, abrogated TGF-beta1-induced changes in integrin-beta1 protein expression. TGF-beta1 increased integrin-beta3 mRNA and protein levels. The inhibitors of Smad2/3, ERK and p38 attenuated the TGF-beta1-induced increase in integrin-beta3 mRNA and protein levels. Podocyte adhesion and migration were enhanced under the stimulation of TGF-beta1. The blockade of interactions between integrin-alphavbeta3 and the extracellular matrix by the anti-integrin-beta3 antibody abrogated the TGF-beta1-induced enhancement in podocyte adhesion and migration. SIGNIFICANCE: Our results demonstrate that TGF-beta1up-regulates integrin-beta3 expression and down-regulates integrin-beta1 expression through different pathways. The up-regulation of integrin-beta3 expression enhances podocyte migration. This study provides a novel mechanism for TGF-beta1 signaling in regulating podocyte migration. PMID- 30021393 TI - Therapeutic efficacy of zingerone against vancomycin-induced oxidative stress, inflammation, apoptosis and aquaporin 1 permeability in rat kidney. AB - Vancomycin (VCM) is a glycopeptidic broad-spectrum antibiotic against methicillin resistant Staphylococcus aureus, though it has some adverse effects, including nephrotoxicity, that limit its usefulness. Zingerone (ZO), a component of dry ginger root, has several pharmacological activities due to its antioxidant, anti inflammatory and antiapoptotic properties. The aim of this study was to determine the therapeutic efficacy of ZO against VCM-induced oxidative stress, inflammation, apoptosis and kidney aquaporin 1 (AQP1) levels in rats. Intraperitoneal administration of VCM (200 mg/kg body weight) for seven days increased kidney lipid peroxidation and decreased antioxidant enzyme activities, including kidney superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). VCM increased serum creatinine and urea levels and induced histopathological changes while causing a decrease in AQP1 protein level. VCM also increased the levels of the inflammatory markers nuclear factor kappa B (NF kappaB), B-cell lymphoma-3(Bcl-3), interleukin-1beta (IL-1beta), interleukin-33 (IL-33), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) and cyclooxygenase 2 (COX-2). Moreover, it activated the apoptotic pathway by increasing the expression levels of p53, Bcl-2 associated X protein (Bax), cysteine aspartate specific protease-3 (caspase-3) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is a marker of oxidative DNA damage. Treatment with ZO (25 and 50 mg/kg body weight) at both doses prevented nephrotoxicity by ameliorating the histopathological alterations, oxidative stress, inflammation, apoptosis, oxidative DNA damage and renal AQP1 levels. The findings of the present study suggested that ZO attenuates VCM-induced nephrotoxicity. PMID- 30021394 TI - Effect of Monacolin K and COQ10 supplementation in hypertensive and hypercholesterolemic subjects with metabolic syndrome. AB - INTRODUCTION: Metabolic syndrome (MetS) is a world-wide epidemic disease with an increased risk of morbidity and mortality. Treatment strategies of MetS include pharmacologic and non-pharmacologic interventions and in this respect a relevant role has been shown for nutraceutical compounds (NCs). The aim of this study was to investigate the efficacy and safety of NCs incorporated with diet and lifestyle management versus diet alone, in lowering blood pressure (BP) values and improving lipid and glucose profile, in a group of hypertensives and hyper cholesterolemic patients with MetS. METHODS: 104 subjects with MetS (mean age 57.4 +/- 8.8 years, 51% males) without history of cardio-vascular (CV) diseases were enrolled in the study. 52 subjects were treated with a once-daily oral formulation of a NCs containing red yeast rice and coenzyme Q10 added to their diet for 2 months and were compared with the 52 patients following a diet program. Differences in BP, serum total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDLC and HDLC), triglycerides (TG) and glucose values were compared by analysis of variance. RESULTS: A significant reduction of BP, TC, TG, LDLC and glucose levels was observed in both treatment groups. However, a greater reduction of systolic BP (-5.2 vs. -3.0 mmHg), diastolic BP (-4.9 vs. 2.9 mmHg), total cholesterol (-17.2%), LDLC (-21.8%), TG (-16.0%) and serum glucose ( 3.4%) was observed in the treatment group relative to the control (p < 0.001 for all); HDLC remained unchanged (p = N.S.). Gender difference was not found in either group (p = N.S.). CONCLUSIONS: In patients with MetS, NC supplementation was safe, well tolerated and effective in improving clinic BP, lipid and glucose profile. PMID- 30021395 TI - Neuroprotective effect of Decalepis hamiltonii aqueous root extract and purified 2-hydroxy-4-methoxy benzaldehyde on 6-OHDA induced neurotoxicity in Caenorhabditis elegans. AB - In this study, we investigated the possible neuroprotective efficacy of Decalepis hamiltonii tuber extract against 6-Hydroxy dopamine (6-OHDA) induced neurotoxicity and associated effects in Caenorhabditis elegans. The major component of flavour rich extract from D. hamiltonii is 2-hydroxy-4-methoxy benzaldehyde (2H4MB) which is an isomer of vanillin. We have conducted preliminary experiments with different types of extracts and subsequently DHFE (D. hamiltonii Fresh Tuber Extract) and DHPF (D. hamiltonii purified 2H4MB fraction) were used for further studies. Here we attempted to enumerate the neuroprotective efficacy of the above compounds in worms by evaluating behavioural and mitochondrial function, dopamine content and selective degeneration of dopaminergic neurons in BZ555 strains in comparison with control and 6-OHDA treated organisms. The relative expression levels of selected antioxidant genes involved in defence mechanism like SOD-3, GST-2 and GST-4 were evaluated along with those of CAT-2 and DOP-2 at mRNA level. We observed that both DHPF and DHFE exhibited significant levels of neuroprotective property against 6-OHDA induced neurotoxicity, which was evident in mitochondrial/dopaminergic function and antioxidant defence mechanism. PMID- 30021396 TI - Injectable polysaccharide hydrogel embedded with hydroxyapatite and calcium carbonate for drug delivery and bone tissue engineering. AB - To meet the progressive requirements for bone regeneration purpose, injectable hydrogels have attracted increasing attention in tissue regeneration and local drug delivery applications. In this study, we report a facile method to prepare injectable and degradable polysaccharide-based hydrogels doubly integrated with hydroxyapatite (HAp) nanoparticles and calcium carbonate microspheres (CMs) under physiological condition. The mechanism of cross-linking is attributed to the Schiff-base reaction between amino and aldehyde groups of carboxymethyl chitosan (CMCS) and oxidized alginate (OAlg), respectively. Synchronously, tetracycline hydrochloride (TH) loaded CMs were fabricated by the precipitation reaction with an average diameter of 6.62 MUm. To enhance bioactive and mechanical properties, nano-HAp and CMs containing TH were encapsulated into the polysaccharide-based hydrogel to form injectable gel scaffolds for imitation of bone niche. The gelation time, morphology, mechanical properties, swelling ratio and in vitro degradation of the gel scaffolds could be controlled by varying HAp and CMs contents. Moreover, the composite gel scaffolds had good sustained drug release and antibacterial properties, as confirmed by drugs release calculation and antibacterial evaluation. In addition, the gel scaffolds were found to be self healing due to dynamic equilibrium of the Schiff-base linkages. These results suggested that the prepared composite gel scaffolds hold great potential for drug delivery and regeneration of irregular bone defects. PMID- 30021398 TI - Histological and enzymatic studies on the renal tubules of some marine elasmobranchs. AB - Renal tubules in the dog shark, leopard shark, and red skate were examined histologically and analyzed histochemically for enzymes. Cells of the distal and collecting tubules exhibit extensive interdigitations and large intercellular spaces, suggesting that these tubules are sites of sodium reabsorption. Although Na-K-ATPase is very scarce to nonexistent in the distal and collecting tubules, very intense carbonic anhydrase activity in these segments indicates that they secrete large amounts of hyrogen ion and reabsorb sodium by H+ /Na+ exchange process. Epithelial cells of the necks are not interdigitated, tightly join adjacent cells, and have low enzyme activities. They seem to be passively permeable to the water. Necks are attached to the distal tubules with scant intervening stroma. It seems likely that the stroma has a high osmotic pressure resulting from absorption of solutes in the distal tubules. Water may be reabsorbed from necks to stroma because of a concentration gradient of the solutes distributed between these sites. PMID- 30021397 TI - Accelerated skin wound healing by soy protein isolate-modified hydroxypropyl chitosan composite films. AB - In this study, a series of hydroxypropyl chitosan (HPCS)/soy protein isolate (SPI) composite films (HCSFs) with different SPI contents were developed via crosslinking, solution casting, and evaporation process. Effects of the SPI content on the structure and physical properties of the HCSFs were characterized by Fourier transform infrared spectroscopy, X-ray diffraction patterns, scanning electron microscopy, swelling kinetics analysis, and mechanical testing. The HCSFs exhibited a lower swelling ratio with an increase in the SPI content. The tensile strength was in a tunable range from 7.88 +/- 3.08 to 40.44 +/- 2.31 MPa by adjusting the SPI content. Cytocompatibility and hemocompatibility of the HCSFs were evaluated by a series of in vitro assays, including MTT assay, live/dead assay, cell morphology observation, hemolysis ratio testing, and plasma recalcification time measurement. Results showed that the HCSFs support L929 cells attachment and proliferation without obvious hemolysis, indicating good cytocompatibility and hemocompatibility. The potential of resultant HCSFs as the wound dressings was investigated using a full-thickness skin wound model in rats. Results exhibited that the HCSFs with 50% SPI content had the fastest healing speed and the best skin regeneration efficiency and may be a potential candidate as the wound dressing. PMID- 30021399 TI - Functional adaptations of the digestive system of the carnivorous mollusc Pleurobranchaea californica MacFarland, 1966. AB - The opisthobranch mollusc Pleurobranchaea californica feeds on whole organisms and the functional morphology of the digestive system reflects this behavior. By a rhythmic behavior involving well-developed extrinsic buccal muscles and hemocoelic fluid, the buccal mass is protracted to the tip of the everted oral tube. Here a series of repeated protractions and retractions of the intrinsic buccal muscles associated with the flat radular ribbon and jaws draws the prey into the buccal cavity and conveys it to the dorsal esophagus, where by peristaltic action it is passed to the expansible crop for storage. Prey entering the buccal cavity is mixed with acid from a large single gland and secretion from the paired salivary glands. Prey is retained in the crop over long periods of time while it is slowly broken down and passed via the stomach into the digestive glands. Special modifications that allow flexibility of the digestive organs include elongated salivary gland ducts with propulsive bulbs, long flexible nerve cords connecting the ganglia, a long, large muscular duct for storage of the acid secretion, large jaws for muscle attachment and grasping the prey, and a broad radular ribbon with many teeth that acts as a conveyor belt to move food. Additional modifications for handling whole prey include a buccal membrane that aids in maintaining hemocoelic fluid pressure, the extensive acid gland for immobilization of prey, and the expansible crop for storage of food. PMID- 30021400 TI - Developmental stages of ovarian follicles of the silkworm, Bombyx mori L. AB - Oogenesis in the silkworm, Bombyx mori, was studied by light and electron microscopy of sections of resin-embedded follicles. The development of the follicles was divided into a series of 12 distinctive stages based on various morphological criteria. Structural changes in the oocyte, nurse cells, and follicle cells are described and illustrated. PMID- 30021401 TI - Histomorophological studies of the female reproductive system of Platynotus punctatipennis (Coleoptera: Tenebrionidae). AB - The internal reproductive apparatus of female Platynotus punctatipennis is composed of the paired ovaries, paired lateral oviducts, common oviduct, spermatheca associated with its accessory gland, and a bursa copulatrix. The accessory (colleterial) glands are absent. The ovary is made up of a large number of telotrophic ovarioles which are covered by a double-layered peritoneal sheath. The terminal filament is separated from the germarium by the basement membrane of the latter and consists of a syncytial core surrounded by the peritoneal sheath. Nutritive cords are absent. The pedicel shows highly eosinophilic and PAS positive secretion of obscure origin. The spermatheca reveals a number of interesting features. It is composed of a pair of sperm-storing tubules, enclosed in a very thin muscle layer. A winecup-like structure, provided with a thick coat of circular muscles, connects the spermathecal gland with thespermathecal duct. Four types of intimal linings occur in the spermatheca and its associated structures. The wine-cup-like connection and four types of intima are entirely new features observed. Histology of the various parts of the reproductive apparatus is described. PMID- 30021402 TI - Formation and ultrastructure of the micropylar apparatus in Bombyx mori ovarian follicles. AB - The formation of the micropylar apparatus during oogenesis in the silkworm, Bombyx mori, has been studied using light and transmission electron microscopy. The micropylar apparatus is formed by three types of cells: the micropylar channel-forming cells (MCFCs), the micropylar orifice-forming cells (MOFCs), and the micropylar rosette-forming cells (MRFCs). During the formation of the vitelline membrane and the chorion, each of the MCFCs extends a cytoplasmic projection serving as the mold of a micropylar-channel into the egg envelopes. The detachment and collapse of the projections takes place at the end of choriogenesis. The micropylar channels possess a common external orifice on the chorion and several internal orifices within the vitelline membrane. The MOFCs interact closely with the MCFCs and contribute to the formation of the external micropylar orifice. A petal-like rosette surrounding the orifice is imprinted on the outer chorionic surface by the MRFCs which enclose a group of the MCFCs and MOFCs. PMID- 30021403 TI - Fine structure of antennal mechanosensilla of adult Rhodnius prolixus stal (Hemiptera: Reduviidae). AB - Each antenna of both sexes of adult Rhodnius prolixus has approximately 570 mechanosensitive neurons that innervate five morphologic types of cuticular mechanosensilla: campaniform sensilla, tapered hairs, trichobothria, and type I and type II bristle sensilla. Each campaniform sensillum and tapered hair is presumably innervated by one mechanosensitive bipolar neuron and probably functions in proprioception. The campaniform sensilla being located at the base of the scape could monitor the position of the antenna. Tapered hairs are found at the distal margin of flagellar segment I and projecting laterally from the bases of the pedicel and scape. They probably provide information about the relative positions of the antennal segments. Seven trichobothrium are located on the pedicel and three on flagellar segment I. Each trichobothrium has a long filamentous hair inserted into the base of a socket that extends inwardly as a cuticular tube and is innervated by one bipolar neuron with a tublar body, a parallel arrangement of microtubules associated with electron-dense material. The trichobothria may respond to small variations in air currents. Type I bristles occur at the base of the antenna and are the most numerous type of mechanosensillum; an average of 452 occur on each antenna of females and 440 on males. The bristle is curved toward the antennal shaft and is serrated distally. Type II bristles are located distally and are the second most numerous type of mechanosensillum; an average of 88 were counted on each antenna of females and 94 on males. The type II bristle is straight with small, longitudinal, external grooves and projects laterally from the antennal shaft. Each type I and II bristle sensillum is innervated by a bipolar neuron whose dendrite is divided into an inner and outer segment. The outer segment is encased by a dendritic sheath which may be highly convoluted and distally contains a tubular body. Two sheath cells are associated with each sensillum. Both types of bristle sensilla have a tactile function. The tubular bodies of both types of bristle sensilla have a complex structure indicating that they are very sensitive. Variations in the amount and arrangement of the electron-dense material at the tip of the tubular bodies may reflect differences in viscoelastic properties that underlie functional characteristics. PMID- 30021404 TI - Freeze-fracture characteristics of insect gustatory and olfactory sensilla. II. Cuticular features. AB - The freeze-fracture technique has been used to obtain detailed information about cuticular constituents and outgrowths of the external skeleton of labella and antennae in the bluebottle fly Calliphora vicina and the antennae of the small moth (Yponomeuta spp.). The lamellated exoskeleton has a fibrous endocuticle and an exocuticle lacking fibers. Ductuli connecting the inside of the animal with the outside run perpendicularly through the endocutile and at angles of up to 45 degrees in the exocuticle. Skeletal outgrowths lack fibers and display fracture features similar to those of the exocuticle. Among those having neuronal endings, gustatory, olfactory, and tactile hairs can be recognized. Noninnervated outgrowths can be subdivided into scales and pseudotrichia. Criteria such as shape, length/width-ratio of hairs, texture, presence and place of pores, shape of pores, and form of the socket or base are presented for further classification. Cuticular features of single-walled olfactory hairs of Calliphora are compared with those of several other species. Based on the shape of the pores, five types of hairs can be distinguished using literature data. It is concluded that the freeze-fracture technique is a valuable tool with which to describe the microarchitecture of the insect exoskeleton and supplements scanning electron microscopy, which is useful for describing the overall skeletal features. PMID- 30021405 TI - Comparative study of the choanosome of Porifera: 1. The Homoscleromorpha. AB - The choanoderm and pinacoderm of representatives of the two families of Homoscleromorpha sponges, the Oscarellidae and Plakinidae, have been examined by transmission and scanning electron microscopy. Different fixative procedures have shown the dramatic influence of fixation conditions on the morphology of choanocytes. These two families of sponges have the following morphological features in common: flagellated endopinacocytes with short apical microvilli and basal pseudopods; the presence of a very thin and dense sheet of matrix material which limits the mesohyl. There are, however, only minor differences in the flagellar morphology, granule content, and anchoring system of their choanocytes. Two findings are of particular interest: (1) the presence of glycocalyx bridges between the microvilli of the choanocyte collar; and (2) the discovery of a new cell type, the apopylar cell, which has a morphology intermediate between that of pinacocytes and choanocytes. The apopylar cells limit the apopylar opening of the choanocyte chamber and indicate the transition between choanoderm and pinacoderm. PMID- 30021406 TI - Head skeleton of the marine catfish Arius tenuispinis day (Osteichthyes: Siluriformes, Ariidae). AB - The osteology of the head skeleton of marine catfish Arius tenuispinis is described in detail. The skeletal elements of the different regions are dealt with categorically. Bones of the ethmoidal, orbitotemporal, auditory, and occipital regions of the cranium; and the upper jaw, lower jaw, hyoid arch, hypobranchial, and opercular series of the visceral skeleton are described in detail. Identity of the ectopterygoid, mesopterygoid, and metapterygoid is established in accordance with the current nomenclature and accepted homologies. The shelving bone of the epiotic is found to be large, having articulation with the parapophyses of the complex vertebra. The head skeleton of A. tenuispinis conforms to the normal siluroid pattern. PMID- 30021407 TI - Fusion of ancestrulae germinated from statoblasts in plumatellid freshwater bryozoans. AB - Upon germination of a statoblast, the shell is split into two valves; a mucous pad which represents the basal portion of the body wall of the incipient zooid or ancestrula then appears from between the valves; lastly, a tiny polypide evaginates at the opposite site. When two or more contiguously located statoblasts (floatoblasts or sessoblasts) of the same species germinate simultaneously, their mucous pads often come into contact with each other. The walls of the mucous pads then disappear in the contact areas, thus uniting the coeloms of the ancestrulae. This type of fusion between mucous pads of statoblast derived ancestrulae was ascertained in Plumatella emarginata, P. repens, P. casmiana, and Hyalinella punctata. The fusion is clearly species specific, and shows no clone specificity or allogeneic recognition. The fusibility test reported here seems to be a useful method for the examination of conspecificity in plumatellid bryozoans. PMID- 30021408 TI - Pregabalin and dexmedetomidine conscious sedation for flexible bronchoscopy: a randomized double blind controlled study. AB - BACKGROUND: Conscious sedation is usually required during flexible bronchoscopy. Sedation should be achieved without respiratory depression or loss of consciousness. The present study was designed to evaluate the effect of pregabalin pre-medication on reducing the amount of sedatives and to show its advantages for patients undergoing flexible bronchoscopy with dexmedetomidine. METHODS: Seventy patients undergoing elective flexible bronchoscopy were randomly divided into two groups of 35 patients each. All patients received premedication one hour before the procedure. PG group received 150mg pregabalin and C group received placebo. All patients were sedated with dexmedetomidine infusion to achieve optimum sedation. During the procedure peripheral oxygen saturation, respiratory rate, haemodynamics, Ramsay sedation score, cough score, and total amount of dexmedetomidine used were recoded. After the procedure patients' and pulmonologists' satisfaction were compared. RESULTS: The total amount of dexmedetomidine used in PG was less compared to C group (P = 0.01). Sedation score was higher in PG group at the time of theatre admission (P < 0.0001). Cough score was higher, but insignificant in group C (P = 0.1). Patients' and pulmnologists' satisfaction scores were higher in group PG (P = 0.03 and 0.02 respectively). The heart rate and mean arterial pressure were lower in the C group (P = 0.02 and 0.03 respectively). Post-operative care unit stay was less in group PG with less analgesic requirements. CONCLUSIONS: Conscious sedation facilitates flexible bronchoscpy. Premedication with pregabalin can reduce the amount of sedatives. Dexmedetomidine with pregabalin premedication has many advantages over dexmedetomidine alone. PMID- 30021409 TI - Complicated appendicitis wrongly diagnosed as nonspecific diarrhea: ways to decrease this continuous threat. AB - BACKGROUND: The diagnostic assessment of right lower quadrant pain in children and adolescents is still a challenge. The aim of this study was to analyze the cases of complicated appendicitis wrongly diagnosed as nonspecific diarrhea, and based on the information obtained suggest a clear and simple policy in order to decrease misdiagnosis in the future. METHODS: Three groups of patients were analyzed: children who underwent appendectomy (group 1); those with gastroenteritis (group 2), and those who underwent appendectomy following hospitalization under the wrong diagnosis of gastroenteritis (group 3). RESULTS: Group 3 presented a more prolonged and complicated clinical course, higher fever, diffuse abdominal pain, repeat vomiting, higher C-reactive protein values, longer surgery duration and recovery. CONCLUSIONS: When the etiology of right lower quadrant abdominal pain is not immediately evident and associated with atypical diarrhea, high fever, repeat vomiting, and significantly increased CRP values, early surgical consultation is required. If the clinical findings are unclear, an abdominal US should be performed as soon as possible. A limited abdominal computed tomography scan CT should follow those cases not resolved by history, physical examination, blood tests, and abdominal ultrasound. PMID- 30021410 TI - What information does YouTube offer on laparoscopic pyloromyotomy? AB - BACKGROUND: YouTube is overloaded with various medical videos and has become a common source for surgeons and the general public alike to update on surgical procedures. This study determined the quality and benefits of information with regards to laparoscopic pyloromyotomy on YouTube. METHODS: A search was performed on YouTube using the key words "Laparoscopic pyloromyotomy". All of the videos were viewed and evaluated by 2 surgeons watching the first 20 seconds and selected segments of each video to determine the content of the videos. The exclusion criteria were videos not related to laparoscopic pyloromyotomy, Microsoft-PowerPoint slide presentations and repeated videos. RESULTS: The search revealed 471 videos and video playlists, and of the 350 watched videos only 34 were on the topic of laparoscopic pyloromyotomy. Eight videos had an institutional source and 26 were private uploads. Among the analyzed videos, n=11 were in High-Definition (HD) and n=23 non-HD. Regarding the country of origin, most of them were from India n=6 and the USA n=6, and regarding language, English was most common n=28. The videos were uploaded between the years 2007-2016.The number of views ranged from 21-14783 and mean duration of the videos was 2.55min. There was a noticeable paucity of information as the largest number of videos offered a brief text description below only. CONCLUSIONS: Social media exposure of laparoscopic pyloromyotomy on YouTube can be summarized as follows: one quarter of the videos are institutional uploads, English language videos top the list, mean video durations are 2.5 minutes with an average number of views >2500 and the majority of surgery videos focus on the main part of the procedure. PMID- 30021411 TI - Prevalence of human cosavirus and saffold virus in young children with gastroenteritis, Northern Italy. AB - BACKGROUND: Gastroenteritis is a common disease in children, characterized by diarrhea, vomiting, abdominal pain, and fever. Human Cosavirus (HCoSV) and Saffold virus (SAFV) both have a worldwide distribution. Both viruses have been detected in the stools of patients with acute gastroenteritis in several countries. METHODS: In order to provide more insights into the epidemiology of enteric viruses that are not included usually in routine diagnostic tests, cases of childhood sporadic gastroenteritis of unknown etiology requiring hospital admission in Turin, Italy, during December 2014 to November 2015, were screened for HCoSV and SAFV. RESULTS: A total of 1 out of 164 (0.6%) episodes of acute gastroenteritis were associated with SAFV genomic detection. Among the 1 SAFV positive cases, 1 were also positive for adenovirus. The patient positive for SAFV don't present diarrheal episodes but vomiting. HCoSV was not detected in any of the samples. CONCLUSIONS: In conclusion, this study presents the current epidemiological data regarding the two viruses, HCoSV and SAFV, circulating in pediatric patients admitted to hospital with acute gastroenteritis in Turin, Italy. PMID- 30021412 TI - Diagnosis and treatment of Helicobacter pylori in the pediatric population. AB - Although about 35 years have elapsed since the discovery of the Helicobacter pylori, its diagnosis and the choice of optimal eradication therapy are still to be defined. Over time, there has been an increase in interest, publications, recommendations and guidelines. Moreover, management of the disease in pediatric subjects differs somewhat to that of adults and requires a more delicate approach leading to alternative strategies for both diagnosis and treatment. Which patient should be investigated for H. pylori, when to perform noninvasive or invasive tests, what are the proper therapeutic options and best antibiotics regimen to eradicate the infection are practices changing with evidences through time. Therefore, an updated guideline was published by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) in 2017. The aim of this review is to highlight what is new and what differs between adult and pediatric population regarding the management of H. pylori infection after the ESPGHAN/NASPGHAN guidelines, enriched with updates from literature reviews published over the last two years. PMID- 30021413 TI - Celiac disease in children. AB - Celiac disease is a common immune-mediated disease, that may present, after gluten ingestion, with various and heterogeneous symptoms that can vary according to patients' age. The diagnostic screening test is serum anti tissue transglutaminase IgA level. In doubt cases, anti-endomysium IgA and the anti deamidated gliadin peptides IgG could be useful to confirm the suspicion, before a biopsy will be perform. Since 2012, guidelines have made it possible to avoid the biopsy in symptomatic pediatric patients with high levels of anti transglutaminase IgA, positivity to antiendomysium IgA, and with HLA DQ2 or DQ8. In all other cases duodenal biopsy is still mandatory to confirm the diagnosis. The therapy of celiac disease is a lifelong gluten free diet. In children prognosis of celiac disease is good, without complications. Here we review and discuss the present literature about celiac disease in childhood. PMID- 30021414 TI - Initial Nutritional Status and Clinical Outcomes in Patients with Deep Neck Infection. AB - OBJECTIVES: The current study aims to determine the correlation between nutritional status upon presentation and disease severity, as well as treatment and survival outcomes. METHODS: Patients who were diagnosed with deep neck infection, underwent at least one surgical drainage/debridement, and had more than 1 week of hospitalization at a tertiary medical center from 2007 to 2015 were retrospectively included. Thereafter, initial serum albumin, C-reactive protein (CRP), and body mass index (BMI) were reviewed. RESULTS: A total of 135 patients were included in the final analysis. Accordingly, the proportion of patients with simultaneous mediastinitis (21.0%), necrotizing fasciitis (12.9%), disease extent >1 cervical level (72.6%), mean CRP (22.4 mg/dL), mean length of hospitalization (25.0 days), and mean 1-week follow-up CRP (7.2 mg/dL) was significantly higher in the hypoalbuminemia group (initial serum albumin <3.0 g/dL) than in the normoalbuminemia group (all P<0.05). No significant correlations had been observed according to BMI status. After adjusting for age and Charlson comorbidity index, odds ratios for the following outcomes were calculated in patients initially presenting with hypoalbuminemia: simultaneous mediastinitis (3.07), necrotizing fasciitis (7.89), disease extent >1 cervical level (2.12), initial serum CRP over 20 mg/dL (3.79), hospitalization of more than 14 days (4.10), 1-week follow-up CRP over 5 mg/dL (3.78), and increased duration for an over 50% decrease in initial CRP (2.70) (all P<0.05). Although intravascular albumin replenishment decreased the proportion of patients with hypoalbuminemia after 2 weeks (P<0.05), it did not significantly predict better treatment outcomes. CONCLUSION: Among the markers reflecting an individual's nutritional state, an initial serum albumin of less than 3.0 g/dL was an independent serologic marker predicting increased disease severity and complications in patients with deep neck infection. PMID- 30021415 TI - Common Sites, Etiology, and Solutions of Persistent Septal Deviation in Revision Septoplasty. AB - OBJECTIVES: To investigate the common causes of persistent septal deviation in revision septoplasty and to report the surgical techniques and results to correct them. METHODS: A total of 100 consecutive patients (86 males) who had revision septoplasty due to persistent septal deviation from 2008 and 2014 were included in the study. Their mean age was 35.6 years and the mean follow-up duration was 9.1 months. Presenting symptoms, sites of persistent septal deviation, techniques used to correct the deviation, and surgical results were reviewed. RESULTS: The mean interval between primary and revision surgery was 6.2 years. Forty-eight patients received revision septoplasty and 52 received revision septoplasty combined with rhinoplasty. Nasal obstruction was the most presenting symptom in almost all patients. The most common site of persistent septal deviation was middle septum (58%) followed by caudal septum (31%). Correcting techniques included further chondrotomy and excision of deviated portion in 76% and caudal batten graft in 39%. Rhinoscopic and endoscopic exams showed straight septum in 97% and 92 patients had subjective symptom improvement postoperatively. CONCLUSION: Middle septum and caudal septum were common sites of persistent deviation. Proper chondrotomy with excision of deviated middle septum and correction of the caudal deviation with batten graft are key maneuvers to treat persistent deviation. PMID- 30021416 TI - Losartan Prevents Maladaptive Auditory-Somatosensory Plasticity After Hearing Loss via Transforming Growth Factor-beta Signaling Suppression. AB - Objectives: Hearing loss disrupts the balance of auditory-somatosensory inputs in the cochlear nucleus (CN) of the brainstem, which has been suggested to be a mechanism of tinnitus. This disruption. Results.: from maladaptive auditory somatosensory plasticity, which is a form of axonal sprouting. Axonal sprouting is promoted by transforming growth factor (TGF)-beta signaling, which can be inhibited by losartan. We investigated whether losartan prevents maladaptive auditory-somatosensory plasticity after hearing loss. Methods: The study consisted of two stages: determining the time course of auditory-somatosensory plasticity following hearing loss and preventing auditory-somatosensory plasticity using losartan. In the first stage, rats were randomly divided into two groups: a control group that underwent a sham operation and a deaf group that underwent cochlea ablation on the left side. CNs were harvested 1 and 2 weeks after surgery. In the second stage, rats were randomly divided into either a saline group that underwent cochlear ablation on the left side and received normal saline or a losartan group that underwent cochlear ablation on the left side and received losartan. CNs were harvested 2 weeks after surgery. Hearing was estimated with auditory brainstem responses (ABRs). Western blotting was performed for vesicular glutamate transporter 1 (VGLUT1), reflecting auditory input; vesicular glutamate transporter 2 (VGLUT2), reflecting somatosensory input; growth-associated protein 43 (GAP-43), reflecting axonal sprouting; and p Smad2/3. Results: Baseline ABR thresholds before surgery ranged from 20 to 35 dB sound pressure level. After cochlear ablation, ABR thresholds were higher than 80 dB. In the first experiment, VGLUT2/VGLUT1 ratios did not differ significantly between the control and deaf groups 1 week after surgery. At 2 weeks after surgery, the deaf group had a significantly higher VGLUT2/VGLUT1 ratio compared to the control group. In the second experiment, the losartan group had a significantly lower VGLUT2/VGLUT1 ratio along with significantly lower p-Smad3 and GAP-43 levels compared to the saline group. Conclusion: Losartan might prevent axonal sprouting after hearing loss by blocking TGF-beta signaling thereby preventing maladaptive auditory-somatosensory plasticity. PMID- 30021417 TI - The correlation of pharyngeal morphology and obstructive sleep apnea in patients with recent stroke. PMID- 30021418 TI - Novel approaches for diagnosis and management of low prognosis patients in ART: the POSEIDON concept. AB - The management of patients with a poor ovarian response (POR) to ovarian stimulation represents a challenging issue in reproductive medicine. Apart from economic burdens, the patient with POR has poor prognosis in assisted reproductive technology (ART), which represents a common cause of drop-out from treatment. To introduce a more nuanced picture of POR, the POSEIDON group developed novel criteria to identify and classify patients with low prognosis who undergo ART. The primary goal of POSEIDON criteria is to offer clinicians a pragmatic system to guide therapeutic management with the mindset to obtain the number of oocytes needed for improving ART success. A novel marker of ART success, namely, the ability to obtain the number of oocytes required for achieving at least one euploid embryo for transfer in each patient, is aligned with the POSEIDON criteria. A novel prediction model (ART Calculator) is developed to help clinicians estimate the POSEIDON marker of success. Furthermore, the POSEIDON criteria can also be used to identify more homogeneous populations to test in interventional trials. PMID- 30021419 TI - Paternal age and assisted reproductive technologies: problem solver or trouble maker? AB - In our society, the number of couples with advanced reproductive age seeking fertility treatment is increasing steadily. While the negative effect of female age on assisted reproductive technology (ART) outcomes is well established, the impact of paternal age needs to be clarified. We reviewed the current literature to determine whether advanced paternal age affects the results of ART and the health of resulting offspring. We found that the published literature is overall supportive of a positive association between advanced paternal age (>40 years) and semen quality deterioration. However, the existing evidence does not corroborate nor discard the influence of advanced paternal age on ART outcomes. Similarly, the effect of paternal age on the health of ART offspring remains equivocal, although data from naturallyconceived children clearly indicates that advanced paternal age increases the frequency of genetic, neurodevelopmental, and psychiatric diseases in the progeny. Noteworthy, the current literature is limited and subjected to bias due to the impact of maternal age as a critical confounder. Health care providers should discuss with concerned couples the available options to counteract the possible negative influence of advanced paternal age on ART outcomes and health of resulting offspring. These include identification and treatment of underlying conditions with potential negative long-term effects on fertility, sperm freezing at a young age, and use of antioxidant supplements for men at risk of excessive oxidative stress. Aged male partner from couples undergoing ART, in particular men of 50 years and older, should consider use of preimplantation genetic testing as a means to detect embryo abnormalities and select euploid embryos for transfer to the uterine cavity. PMID- 30021421 TI - Use of ratiometric probes with a spectrofluorometer for bacterial viability measurement. AB - Assessment of micro-organism viability is useful in many industrial fields. A large number of methods associated with the use of fluorescent probes have been developed including fluorimetry, fluorescence microscopy, and cytometry. In this study, a microvolume spectrofluorometer was used to measure the membrane potential variations of Escherichia coli. In order to estimate the sensitivity of the device, the membrane potential of E. coli was artificially disrupted using an ionophore agent: carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Membrane potential was evaluated using two ratiometric methods: a Rhodamine 123/4',6 diamidino-2-phenylindole (DAPI) combination and a JC-10 ratiometric probe. These methods were used to study the impact of freezing on E. coli, and were compared with the conventional enumeration method. The results showed that it is beneficial to use this compact, easy-to-use and inexpensive spectrofluorometer to assess the viability of bacterial cells via their membrane potential. PMID- 30021422 TI - Antimicrobial Activity of Antimicrobial Peptide LPcin-YK3 Derived from Bovine Lactophoricin. AB - We previously reported on lactophoricin (LPcin), a cationic alpha-helical antimicrobial peptide derived from bovine milk, which has antimicrobial effects on Candida albicans as well as Gram-positive and Gram-negative bacteria. In this study, we designed the LPcin-YK3 peptide, a shorter analog of LPcin, and investigated its antimicrobial activity. This peptide, consisting of 15 amino acids with + 3 net charges, was an effective antimicrobial agent against the on the Gram-positive strain, Staphylococcus aureus (MIC: 0.62 MUg/ml). In addition, the hemolytic activity assay revealed that the peptide was not toxic to mouse and human erythrocytes up to 40 MUg/ml. We also used circular dichroism spectroscopy to confirm that peptide in the presence of lipid has alpha-helical structures and later provide an overview of the relationship between each structure and antimicrobial activity. This peptide is a member of a new class of antimicrobial agents that could potentially overcome the problem of bacterial resistance caused by overuse of conventional antibiotics. Therefore, it could be used as a therapeutic or natural additive, particularly in the cosmetics industry. PMID- 30021423 TI - Production of Bioactive 3'-Hydroxystilbene Compounds Using the Flavin-Dependent Monooxygenase Sam5. AB - The flavin-dependent monooxygenase Sam5 was previously reported to be a bifunctional hydroxylase with a coumarte 3-hydroxylase and a resveratrol 3' hydroxylase activity. In this article, we showed the Sam5 enzyme has 3' hydroxylation activities for methylated resveratrol (pinostilbene and pterostilbene), hydroxylated resveratrol (oxyresveratrol) and glycosylated resveratrol (piceid) as substrates. However, the use of piceid, a glycone type stilbene, as a substrate for bioconversion experiments with the Sam5 enzyme expressed in, Escherichia coli does not convert to the hydroxylated compound astringin, but it has converted in vitro enzyme reactions. Finally, we report a novel catalytic activity of Sam5 monooxygenase for the synthesis of piceatannol derivatives, 3'-hydroxylated stilbene compounds. Development of this bioproduction method for the hydroxylation of stilbenes is challenging because of the difficulty in expressing P450-type hydroxylase in E. coli and regionspecific chemical synthesis. PMID- 30021424 TI - Enhancing Electricity Generation Using a Laccase-Based Microbial Fuel Cell with Yeast Galactomyces reessii on the Cathode. AB - The fungi associated with termites secrete enzymes such as laccase (multi-copper oxidase) that can degrade extracellular wood matrix. Laccase uses molecular oxygen as an electron acceptor to catalyze the degradation of organic compounds. Owing to its ability to transfer electrons from the cathodic electrode to molecular oxygen, laccase has the potential to be a biocatalyst on the surface of the cathodic electrode of a microbial fuel cell (MFC). In this study, a two chamber MFC using the laccase-producing fungus Galactomyces reessii was investigated. The fungus cultured on coconut coir was placed in the cathode chamber, while an anaerobic microbial community was maintained in the anode chamber fed by industrial rubber wastewater and supplemented by sulfate and a pH buffer. The laccase-based biocathode MFC (lbMFC) produced the maximum open circuit voltage of 250 mV, output voltage of 145 mV (with a 1,000 Omega resistor), power density of 59 mW/m2, and current density of 278 mA/m2, and a 70% increase in half-cell potential. This study demonstrated the capability of laccase-producing yeast Galactomyces reessii as a biocatalyst on the cathode of the two-chamber lbMFC. PMID- 30021425 TI - Extraperitoneal robot-assisted radical prostatectomy: a high-volume surgical center experience. AB - BACKGROUND: Herein we report our high-volume single center experience with extraperitoneal robot-assisted radical prostatectomy (eRARP) in patients with prostate cancer (PCa). METHODS: A retrospective chart review of our prospectively maintained institutional PCa database was performed to analyze eRARP cases done between April 2009 and March 2016. Nerve-sparing technique was applied in accordance with Tewari. Baseline characteristics, surgical outcomes, continence and erectile function were assessed by descriptive statistics. RESULTS: Of 1354 patients, 61% had intermediate-risk disease. Mean total operative duration was 146+/-44 min (median 140 minutes; interquartile range 120-160 minutes). In 91.7% of case no complication was recorded. Gleason Score on final pathology was mostly 6 (43.3%) or 7 (3+4) (32.3%). The pathological T stage was mostly pT2c (53.8%). Patients who had a bilateral nerve sparing procedure showed the best functional results, with 81.2% continence rate at 1 month, and 65% reported recovery of erectile function at 3 months postoperation. CONCLUSIONS: eRARP is a safe, reproducible, and effective procedure for the surgical treatment of prostate cancer. Superior functional outcome can be achieved when a bilateral intrafascial nerve-sparing approach can be performed. PMID- 30021426 TI - Immune check point inhibitors for metastatic urothelial carcinoma: current evidence-based approach for urology daily practice. AB - INTRODUCTION: Treatment strategy for inoperable and metastatic urothelial carcinoma (mUC) has been revolutionized by the introduction of programmed cell death protein 1 (PD-1) and programmed cell death protein ligand (PD-L1) antibodies. During the last 3 decades treatment options were limited to chemotherapy, making further treatment of patients whose disease progressed under ongoing therapy or who were ineligible to receive cytotoxic therapy in the first place, nearly impossible. EVIDENCE ACQUISITION: Five antibodies including pembrolizumab (PD-L1 antibody), atezolizumab (PD-1 antibody), nivolumab (PD-1 antibody), avelumab and durvalumab (PDL1 antibodies) have been approved in the treatment of advanced urothelial carcinoma in firstand second-line treatment setting. The objective of this review is to examine and compare the different cohorts and to discuss the quality of the respective studies in order to set up selection criteria for clinical decision making. EVIDENCE SYNTHESIS: So far pembrolizumab and atezolizumab have demonstrated overall survival (OS) benefit in phase II studies and have shown superiority over standard chemotherapy in phase III studies which has granted them approval in first and second-line treatment setting. Improved OS and durable responses were also seen in phase Ib/II nonrandomized, single-arm trials conducted with nivolumab, avelumab and durvalumab and granting accelerated approval for second-line treatment. The huge advantage of immunotherapy and one of the reasons for its overall recognition is its good tolerability profile especially in comparison to chemotherapy. CONCLUSIONS: Pembrolizumab has to be recommended in second-line therapy due to reporting in a phase III trial and OS survival benefit compared to chemotherapy control group. In cisplatin-eligible and treatment-naive patients with visceral or liver metastases data also slightly favors pembrolizumab rather than atezolizumab. PMID- 30021431 TI - Engineering a 3D DNA-Logic Gate Nanomachine for Bispecific Recognition and Computing on Target Cell Surfaces. AB - Among the vast number of recognition molecules, DNA aptamers generated from cell SELEX exhibit unique properties for identifying cell membrane biomarkers, in particular protein receptors on cancer cells. To integrate all recognition and computing modules within a single structure, a three-dimensional (3D) DNA-based logic gate nanomachine was constructed to target overexpressed cancer cell biomarkers with bispecific recognition. Thus, when the Boolean operator "AND" returns a true value, it is followed by an "ON" signal when the specific cell type is presented. Compared with freely dispersed double-stranded DNA (dsDNA) based molecular circuits, this 3D DNA nanostructure, termed DNA-logic gate triangular prism (TP), showed better identification performance, enabling, in turn, better molecular targeting and fabrication of recognition nanorobotics. PMID- 30021432 TI - Different Microtubule Structures Assembled by Kinesin Motors. AB - The microtubule-kinesin system is used to form microtubule-based structures via microtubule gliding motility. On the kinesin-coated surface, the microtubules can be easily assembled into stable micro- and nanostructures like circles and microtubule bundles using the streptavidin-biotin system. Furthermore, these microtubules structures can still retain performance with kinesin motor movement in spite of different velocities. Collisions bear responsibility for the majority of events leading to circle formation. By taking advantage of biological substances, some micro- or nanostructures, which are difficult to fabricate by artificial processes, can be easily obtained. PMID- 30021433 TI - Effects of Coadsorbed Water on the Heterogeneous Photochemistry of Nitrates Adsorbed on TiO2. AB - Nitric acid, a well-known sink of NO x gases in the atmosphere, has been found to be photoactive while adsorbed on tropospheric particles. When adsorbed onto semiconductive metal oxides, nitrate's photochemical degradation can be interpreted as a photocatalytic process. Yet, the photolysis of nitrate ions on the surface of aerosols can also be initiated by changes in the symmetry of the ion upon adsorption. In this study, we use quantum chemistry to model the vibrational spectra of adsorbed nitrate on TiO2, a semiconductor component of atmospheric aerosols, and determine the kinetics of the heterogeneous photochemical degradation of nitrate under simulated solar light. Frequencies and geometry calculations suggest that the symmetry of chemisorbed nitrate ion depends strongly on coadsorbed water, with water changing the reactive surface of TiO2. Upon irradiation, surface nitrate undergoes photolysis to yield nitrogen containing gaseous products including NO2, NO, HONO, and N2O, in proportions that depend on relative humidity (RH). In addition, the heterogeneous photochemistry rate constant decreases an order of magnitude, from (5.7 +/- 0.1) * 10-4 s-1 on a dry surface to (7.1 +/- 0.8) * 10-5 s-1 when nitrate is coadsorbed with water above monolayer coverage. Little is known about the roles of coadsorbed water on the heterogeneous photochemistry of nitrates on TiO2, along with its impact on the chemical balance of the atmosphere. This work discusses the roles of water in the photolysis of surface nitrates on TiO2 and the concomitant renoxification of the atmosphere. PMID- 30021434 TI - Crystallization of Femtoliter Surface Droplet Arrays Revealed by Synchrotron Small-Angle X-ray Scattering. AB - The crystallization of oil droplets is critical in the processing and storage of lipid-based food and pharmaceutical products. Arrays of femtoliter droplets on a surface offer a unique opportunity to study surfactant-free colloidlike systems. In this work, the crystal growth process in these confined droplets was followed by cooling a model lipid (trimyristin) from a liquid state utilizing synchrotron small-angle X-ray scattering (SAXS). The measurements by SAXS demonstrated a reduced crystallization rate and a greater degree of supercooling required to trigger lipid crystallization in droplets compared to those of bulk lipids. These results suggest that surface droplets crystallize in a stochastic manner. Interestingly, the crystallization rate is slower for larger femtoliter droplets, which may be explained by the onset of crystallization from the three-phase contact line. The larger surface nanodroplets exhibit a smaller ratio of droplet volume to the length of three-phase contact line and hence a slower crystallization rate. PMID- 30021435 TI - Metabolic Flux Enhancement and Transcriptomic Analysis Displayed the Changes of Catechins Following Long-Term Pruning in Tea Trees ( Camellia sinensis). AB - The tea tree is a perennial woody plant, and pruning is one of the most crucial cultivation measurements for tea plantation management. To date, the relationship between long-term pruning and metabolic flux enhancement in tea trees has not been studied. In this research, 11-year-old pruned tea trees from four different cultivars were randomly selected for transcriptome analysis and characteristic secondary metabolite analysis together with controls. The findings revealed that epigallocatechin gallate (EGCG) accumulation in pruned tea trees was significantly higher than that in unpruned tea trees. SCPL1A expression (encoding a class of serine carboxypeptidase), which has been reported to have a catalytic ability during EGCG biosynthesis, together with LAR, encoding leucoanthocyanidin reductase, was upregulated in the pruned tea trees. Moreover, metabolic flux enhancement and transcriptome analysis revealed low EGCG accumulation in the leaves of unpruned tea trees. Because of the bitter and astringent taste of EGCG, these results provide a certain understanding to the lower bitterness and astringency in teas from "ancient tea trees", growing in the wild with no trimming, than teas produced from pruned plantation trees. PMID- 30021436 TI - Quantification of Catalytic Activity for Electrostatically Enhanced Thioureas via Reaction Kinetics and UV-vis Spectroscopic Measurement. AB - Charged thiourea derivatives containing one and two methylated or octylated pyridinium ion centers and a tetraarylborate or triflate counteranion are reported. These novel catalysts are much more active in the Friedel-Crafts reactions of trans-beta-nitroalkenes with N-methylindoles than the privileged N, N'-bis(3,5-bis(trifluoromethyl)phenyl)thiourea (i.e., Schreiner's thiourea) by up to 2-3 orders of magnitude. A previously reported UV-vis spectroscopic method by Kozlowski et al. was exploited to rationalize their reactivity order along with noncharged analogues. These results offer a new design strategy for organocatalysts by introducing positively charged centers without adding additional N-H, O-H, or S-H hydrogen bond donor sites. PMID- 30021437 TI - Near-Road Air Pollutant Measurements: Accounting for Inter-Site Variability Using Emission Factors. AB - A daily integrated emission factor (EF) method was applied to data from three near-road monitoring sites to identify variables that impact traffic related pollutant concentrations in the near-road environment. The sites were operated for 20 months in 2015-2017, with each site differing in terms of design, local meteorology, and fleet compositions. Measurement distance from the roadway and local meteorology were found to affect pollutant concentrations irrespective of background subtraction. However, using emission factors mostly accounted for the effects of dilution and dispersion, allowing intersite differences in emissions to be resolved. A multiple linear regression model that included predictor variables such as fraction of larger vehicles (>7.6 m in length; i.e., heavy-duty vehicles), vehicle speed, and ambient temperature accounted for intersite variability of the fleet average NO, NO x, and particle number EFs (R2:0.50 0.75), with lower model performance for CO and black carbon (BC) EFs (R2:0.28 0.46). NO x and BC EFs were affected more than CO and particle number EFs by the fraction of larger vehicles, which also resulted in measurable weekday/weekend differences. Pollutant EFs also varied with ambient temperature and because there were little seasonal changes in fleet composition, this was attributed to changes in fuel composition and/or post-tailpipe transformation of pollutants. PMID- 30021438 TI - Bioinspired Peptide for Imaging Hg2+ Distribution in Living Cells and Zebrafish Based on Coordination-Mediated Supramolecular Assembling. AB - Peptides with modular structure provide a tailorable platform for constructing responsive supramolecular assemblies, which are attractive as functional biomaterials and smart sensors. In this work, the feasibility of regulating small peptides assembly with molecular design and metal ion recognition was demonstrated. Tripeptides were designed and found to have diverse response and self-assembly behavior to Hg2+. The incorporation of an aggregation-induced emission fluorophore TPE enabled the visualization of Hg2+ recognition and the assembly phenomenon. A structural analogue (Pep2) to gamma-glutathione was identified with high specificity and nanomolar response to Hg2+ both in buffer solution and living cells. Driven by the coordination force and noncovalent intramolecular stacking, assembling of twisted nanofibers from Pep2-TPE and Hg2+ were observed. Benefiting from its biocompatibility, fast and switchable fluorescence response, Pep2-TPE was applied for imaging and monitoring Hg2+ distribution in living cells and zebrafish. With good permeability to plasma membrane and tissues, Pep2-TPE indicated the preferential distribution of Hg2+ in cell nucleoli and brain of zebrafish, which is related with the deleterious effect of inorganic mercury in living biosystems. PMID- 30021439 TI - Synthesis of Au Nanoparticles Assisted by Linker-Modified TiO2 Nanoparticles. AB - Plasmonic nanoparticles, especially gold ones, have been widely employed as photosensitizers in photoelectrovoltaic or photocatalytic systems. To improve the system's performance, a greater interaction of the nanoparticles with the semiconductor, generally TiO2, is desired. Moreover, this performance is enhanced when an efficient covering of TiO2 surface by the sensitizer is achieved. The Brust-Schiffrin-like methods are of the most employed approaches for nanoparticles synthesis. In a traditional approach, the reduction of the gold precursor is performed in the presence of a stabilizer (typically a thiol molecule) free in solution. A second step in which the obtained nanoparticles are anchored to the semiconductor surface is necessary in the case of photosensitive applications. Drawbacks like steric hindrance turn more difficult the covering of the semiconductor's surface by nanoparticles. In this paper, we report a variation of this methodology, where the linker is previously anchored to the TiO2 nanoparticles surface. The resulting system is employed as the stabilizer in the gold reduction step. This strategy is carried out in aqueous media in two simple steps. A great covering of the titania surface by gold nanoparticles is achieved in all cases and the gold nanoparticles in the resulting nanoaggregate might be useful for photoelectrovoltaic or photocatalytic applications. PMID- 30021440 TI - Label-Free Sensitive Detection of Microcystin-LR via Aptamer-Conjugated Gold Nanoparticles Based on Solid-State Nanopores. AB - A versatile and highly sensitive strategy for nanopore detection of microcystin LR (MC-LR) is proposed herein based on the aptamer and host-guest interactions by employing a gold nanoparticle (AuNP) probe. The aptamer of MC-LR and its complementary DNA (cDNA) are respectively immobilized on AuNPs with distinct sizes (5 nm AuNPs for the aptamer and 20 nm for the cDNA), and the constructed polymeric AuNP network via the hybridization of the aptamer and cDNA was disintegrated upon the addition of MC-LR. The specific interactions between the aptamer and MC-LR disrupt and release the cDNA-AuNPs that were then removed by centrifugation, leaving the MC-LR-aptamer-AuNP species in the supernatant for subsequent nanopore determination. By monitoring the current blockade of released MC-LR-aptamer-AuNPs using a specific tailored nanopore (10 and 20 nm in diameter, generated by current dielectric breakdown), we could deduce the presence of MC LR, as the bulky NP network could not pass through a nanopore with a relatively smaller size. We realized the detection of MC-LR with a concentration as low as 0.1 nM; additionally, we have proved the specificity of the interaction between the aptamer and MC-LR by replacing MC-LR with other congener toxins (MC-RR and MC YR), chlorophyll (a component abundantly coexists in water), and the mixture of the four. PMID- 30021441 TI - Enhanced Light Emission from the Ridge of Two-Dimensional InSe Flakes. AB - InSe, a newly rediscovered two-dimensional (2D) semiconductor, possesses superior electrical and optical properties as a direct-band-gap semiconductor with high mobility from bulk to atomically thin layers and is drastically different from transition-metal dichalcogenides, in which the direct band gap only exists at the single-layer limit. However, absorption in InSe is mostly dominated by an out-of plane dipole contribution, which results in the limited absorption of normally incident light that can only excite the in-plane dipole at resonance. To address this challenge, we have explored a unique geometric ridge state of the 2D flake without compromising the sample quality. We observed the enhanced absorption at the ridge over a broad range of excitation frequencies from photocurrent and photoluminescence (PL) measurements. In addition, we have discovered new PL peaks at low temperatures due to defect states on the ridge, which can be as much as ~60 times stronger than the intrinsic PL peak of InSe. Interestingly, the PL of the defects is highly tunable through an external electrical field, which can be attributed to the Stark effect of the localized defects. InSe ridges thus provide new avenues for manipulating light-matter interactions and defect engineering that are vitally crucial for novel optoelectronic devices based on 2D semiconductors. PMID- 30021442 TI - Water-Assisted Transfer Patterning of Nanomaterials. AB - We introduce a straightforward and cost-effective water-assisted approach to transfer patterns of nanomaterials onto diverse substrates. The transfer method relies on the hydrophobic effect and utilizes a water-soluble polymer film as a carrier to transfer hydrophobic nanomaterials from a patterned source substrate onto a target substrate. Using this approach, nanomaterials are transferred readily from solutions onto surfaces of various shapes and compositions with high fidelity for feature sizes approaching 10 microns. PMID- 30021443 TI - Complex ZnO-TiO2 Core-Shell Flower-Like Architectures with Enhanced Photocatalytic Performance and Superhydrophilicity without UV Irradiation. AB - ZnO-TiO2 core-shell photocatalysts of a complex flower-like architecture were synthesized, using a well-controlled sol-gel coating reaction of presynthesized ZnO flower-like structures. The samples were characterized by X-ray diffraction, field emission scanning and transmission electron microscopy, energy-dispersive X ray spectroscopy, diffuse reflectance UV-vis and attenuated total reflectance Fourier transform infrared spectroscopy, nitrogen adsorption-desorption measurements, and photoluminescence measurements. Well-defined, core-shell flowers with a wurtzite ZnO core and anatase TiO2 shells, with variable shell thickness, were acquired by appropriately adjusting the ZnO/Ti precursor mass feed ratio in the reaction. Moreover, hollow TiO2 flowers were obtained, and they retained their morphology following the etching of the ZnO core in an acidic solution. The photocatalytic performance of the core-shell and hollow semiconductors was evaluated via the decoloration of a methylene blue dye solution under UV-vis irradiation. The core-shell flowers exhibited a higher decoloration rate, when compared with bare ZnO flowers, TiO2 particles, and hollow TiO2 flowers, and the photoactivity was dependent on the TiO2 shell thickness. This was attributed to the efficient separation of the photogenerated holes and electrons at the ZnO-TiO2 interface. Moreover, the most photoactive core-shell catalyst exhibited excellent reusability and stability for at least three photocatalytic cycles and excellent superhydrophilicity without UV irradiation, which is due to the increased roughness of the flower-like structures. PMID- 30021444 TI - Discovery and Evaluation of Biosynthetic Pathways for the Production of Five Methyl Ethyl Ketone Precursors. AB - The limited supply of fossil fuels and the establishment of new environmental policies shifted research in industry and academia toward sustainable production of the second generation of biofuels, with methyl ethyl ketone (MEK) being one promising fuel candidate. MEK is a commercially valuable petrochemical with an extensive application as a solvent. However, as of today, a sustainable and economically viable production of MEK has not yet been achieved despite several attempts of introducing biosynthetic pathways in industrial microorganisms. We used BNICE.ch as a retrobiosynthesis tool to discover all novel pathways around MEK. Out of 1325 identified compounds connecting to MEK with one reaction step, we selected 3-oxopentanoate, but-3-en-2-one, but-1-en-2-olate, butylamine, and 2 hydroxy-2-methylbutanenitrile for further study. We reconstructed 3 679 610 novel biosynthetic pathways toward these 5 compounds. We then embedded these pathways into the genome-scale model of E. coli, and a set of 18 622 were found to be the most biologically feasible ones on the basis of thermodynamics and their yields. For each novel reaction in the viable pathways, we proposed the most similar KEGG reactions, with their gene and protein sequences, as candidates for either a direct experimental implementation or as a basis for enzyme engineering. Through pathway similarity analysis we classified the pathways and identified the enzymes and precursors that were indispensable for the production of the target molecules. These retrobiosynthesis studies demonstrate the potential of BNICE.ch for discovery, systematic evaluation, and analysis of novel pathways in synthetic biology and metabolic engineering studies. PMID- 30021445 TI - Spotlights: Volume 9, Issue 14. PMID- 30021446 TI - Parallelized microfluidic diatom accumulation assay to test fouling-release coatings. AB - Assessing the efficiency of the next generation of protective marine coatings is highly relevant for their optimization. In this paper, a parallelized microfluidic testing device is presented to quantify the accumulation of a model organism (Navicula perminuta) under constant laminar flow. Using automated microscopy in conjunction with image analysis, the adhesion densities on the tested surfaces could be determined after exposure to a flow of suspended algae for 90 min. The optimized protocol for the assay is presented, and the reproducibility of the densities of attached diatoms was verified on four identical surfaces (self-assembled dodecanethiol monolayers). A set of well characterized self-assembled monolayers with different chemical terminations was used to validate the performance of the assay and its capability to discriminate diatom accumulation on different surface chemistries under dynamic conditions. The observed trends are in good agreement with previously published results obtained in single channel accumulation and detachment assays. To demonstrate the practical relevance of the dynamic experiment, diatom attachment on four technically relevant silicone coatings with different fouling-release properties could clearly be distinguished. PMID- 30021448 TI - Increasing partner HIV testing and linkage to care in TB settings: findings from an implementation study in Pwani, Tanzania. AB - Couples HIV testing for tuberculosis (TB) patients and their partners may be an effective means to identify HIV-positive persons and strengthen linkage to HIV care. We evaluated an intervention to increase HIV testing and linkage to care (LTC) of newly diagnosed persons and re-linkage for TB/HIV patients in Pwani, Tanzania. In 2014, 12 TB settings within two regional clusters participated; each cluster included >=1 referral hospital, health center, and directly observed therapy center. Three months after introducing tools to record HIV service delivery, TB clinic staff and peer education volunteers in Cluster 1 received training on HIV partner testing and linkage/re-linkage, and staff in the second cluster received training 3 months thereafter. Twelve months after tools were introduced, clinic records were abstracted to assess changes in couples HIV testing, LTC, and re-linkage. Staff interviews assessed the feasibility and acceptability of the service delivery model. HIV prevalence was high among TB patients during the study period (44.9%; 508/1132), as well as among others who received HIV testing (19.8%; 253/1288). Compared to pre-implementation, couples HIV testing increased in both clusters from 1.8% to 35.2%. Documented LTC increased (from 5.7% to 50.0%) following the introduction of the tools. Additional increases in LTC (from 57.9% to 79.3%) and re-linkage (from 32.9% to 53.7%) followed Cluster 1 training, but no additional increases after Cluster 2 training. Staff perceived little burden associated with service delivery. This study demonstrated a feasible, low-burden approach to expand couples HIV testing and linkage of HIV-positive persons to care. TB settings in sub-Saharan Africa serve populations at disproportionate risk for HIV infection and should be considered key venues to expand access to effective HIV prevention strategies for both patients and their partners. HIV services in TB settings should include HIV testing, condom distribution, and linkage to appropriate additional services. PMID- 30021447 TI - Biologics in Chronic Rhinosinusitis: An Update and Thoughts for Future Directions. AB - Background Potential biologic therapies for chronic rhinosinusitis (CRS) is a growing field of interest and research. Biologics target specific immune cells or inflammatory pathways within a disease process, increasing drug efficacy while reducing complications. The success of biologics in other inflammatory conditions such as asthma and atopic dermatitis has spurred much of the corresponding research in CRS. A rapid expansion in the volume of research concerning biologic therapies with potential crossover to treating CRS has made it difficult to stay current. Furthermore, much of the literature has been focused on allergy, asthma, and immunology subspecialties. As the role for biologic therapies in CRS continues to expand, it is increasingly important for otolaryngologists to remain up to date on their progression. Objective The objectives of this review are to provide an update on the growing field of biologics for otolaryngologists who treat CRS and discuss potential future areas of research. Methods A literature review of biologic therapies studied in CRS was performed. In addition, a detailed review of all biologic therapies targeting inflammatory markers involved in Th1-, Th2-, and Th17-mediated inflammation was performed to identify potential areas for future research. The role for biologic therapies in CRS, endotypes of CRS, current biologic therapies studies in CRS, and future areas for research were reviewed. Results Sixty-nine unique biologic therapies have been developed for Th1-, Th2-, and Th17-mediated inflammation. Five biologics are currently being investigated for use in patients with CRS with nasal polyposis. Conclusions As the field of biologics continues to expand, remaining up to date on the current literature may help clinicians identify patients who may benefit from biologic therapies. In addition, ongoing research in other inflammatory disorders with shared pathophysiology to CRS may reveal other potential therapies for CRS that have not previously been investigated. PMID- 30021449 TI - Medication costs associated with early initiation of antiretroviral therapy. AB - The START Study randomly assigned 4685 persons with CD4+ counts >500 to either immediate treatment (2326 persons) or a group (2359) that had treatment delayed until the CD4+ count was <350 or clinical judgment dictated treatment. The average time in the study was three years. The immediate group (IG) had 42 serious clinical events and the delayed group (DG) had 96. Policy considerations for adopting these results should consider the cost of medications for early treatment, which is the purpose of this article. Cost of early treatment was estimated by assuming the delayed treatment group had been treated for the three year average course of the study. However, 48% of the DG received ART before the study's end, so that portion of the group's time on ART was reduced to 1.5 years. Average wholesale prices in the United States of the five recommended ART regimens were discounted by 50% to reflect actual pricing. An average medication cost for the five regimens of $20,000 per person year was used. The three-year cost was $107,580,000 for the 52% who would have been treated for three years and for the 48% treated for an average of 1.5 years. The cost per clinical event avoided was $1,992,222. Formulae are provided that will allow the reader to adjust these results to reflect local prices and volumes. Additional factors to be considered should include the cost savings from avoiding serious clinical events, reduction in transmission of HIV for those being treated early in the infection and the issues associated with long-term adherence for those receiving ART at >500 CD4 counts. PMID- 30021451 TI - Effect of Process- and Outcome-Based Financial Incentives on Weight Loss Among Prediabetic New York Medicaid Patients: A Randomized Clinical Trial. AB - PURPOSE: To determine whether different financial incentives are effective in promoting weight loss among prediabetic Medicaid recipients. DESIGN: Four-group, multicenter, randomized clinical trial. SETTING AND PARTICIPANTS: Medicaid managed care enrollees residing in New York, aged 18 to 64 years, and diagnosed as prediabetic or high risk for diabetes (N = 703). INTERVENTION: In a 16-week program, participants were randomly assigned to one of 4 arms: (1) control (no incentives), (2) process incentives for attending weekly Diabetes Prevention Program sessions, (3) outcome incentives for achieving weekly weight loss goals, and (4) combined process and outcome incentives. MEASURES: Weight loss over a 16 week period; proportion who completed educational sessions; proportion who met weight loss goals. Analysis and Results: No intervention arm achieved greater reduction in weight than control (outcome incentive -6.6 lb [-9.1 to -4.1 lb], process incentive -7.3 lb [-9.5 to -5.1 lb], combined incentive -5.8 lb [-8.8 to 2.8 lb], control -7.9 lb [-11.1 to -4.7 lb]; all P > .29). Session attendance in the process incentive arm (50%) was significantly higher than control (31%; P < .0001) and combined incentive arms (28%; P < .0001), but not significantly higher than the outcome incentive arm (38%). CONCLUSION: Process incentives increased session attendance, but when combined at half strength with outcome incentives did not achieve that effect. There were no significant effects of either process or outcomes incentives on weight loss. PMID- 30021452 TI - Timing of treatment initiation of direct-acting antivirals for HIV/HCV coinfected and HCV monoinfected patients. AB - Direct-acting antiviral therapy is safe and cost-effective for the treatment of hepatitis C virus (HCV) infection. However, variability in drug payment rules represents a barrier to treatment that may disproportionately affect certain populations. We conducted a retrospective cohort study among HIV/HCV coinfected and HCV monoinfected patients using Kaplan-Meier and Fisher's exact test to analyze the time from the prescription of a direct-acting antiviral agent to delivery to the patient. Variables with significance p < .20 in univariate analysis were included in a Cox regression model. Factors associated with faster treatment were Infectious Diseases office setting (p = .01), public insurance payer (p = .01), and initial approval of requested regimen (p = .01). The presence of other liver disease was associated with delay in treatment (p = .05). Unrestrictive Medicare and Medicaid regulations resulted in more rapid delivery of medication compared to private payers. Fibrosis level, Child-Pugh class and HIV status did not significantly change time to treatment. PMID- 30021450 TI - Early suboptimal ART adherence was associated with missed clinical visits in HIV infected patients in Asia. AB - Missed clinic visits can lead to poorer treatment outcomes in HIV-infected patients. Suboptimal antiretroviral therapy (ART) adherence has been linked to subsequent missed visits. Knowing the determinants of missed visits in Asian patients will allow for appropriate counselling and intervention strategies to ensure continuous engagement in care. A missed visit was defined as having no assessments within six months. Repeated measures logistic regression was used to analyse factors associated with missed visits. A total of 7100 patients were included from 12 countries in Asia with 2676 (37.7%) having at least one missed visit. Patients with early suboptimal self-reported adherence <95% were more likely to have a missed visit compared to those with adherence >=95% (OR = 2.55, 95% CI(1.81-3.61)). Other factors associated with having a missed visit were homosexual (OR = 1.45, 95%CI(1.27-1.66)) and other modes of HIV exposure (OR = 1.48, 95%CI(1.27-1.74)) compared to heterosexual exposure; using PI-based (OR = 1.33, 95%CI(1.15-1.53) and other ART combinations (OR = 1.79, 95%CI(1.39-2.32)) compared to NRTI+NNRTI combinations; and being hepatitis C co-infected (OR = 1.27, 95%CI(1.06-1.52)). Patients aged >30 years (31-40 years OR = 0.81, 95%CI(0.73-0.89); 41-50 years OR = 0.73, 95%CI(0.64-0.83); and >50 years OR = 0.77, 95%CI(0.64-0.93)); female sex (OR = 0.81, 95%CI(0.72-0.90)); and being from upper middle (OR = 0.78, 95%CI(0.70-0.80)) or high-income countries (OR = 0.42, 95%CI(0.35-0.51)), were less likely to have missed visits. Almost 40% of our patients had a missed clinic visit. Early ART adherence was an indicator of subsequent clinic visits. Intensive counselling and adherence support should be provided at ART initiation in order to optimise long-term clinic attendance and maximise treatment outcomes. PMID- 30021453 TI - HIV information needs of transgender people and their healthcare providers. AB - Despite the disproportionate burden of HIV among transgender people in the United States, few HIV-related communication materials exist for transgender people or their healthcare providers. Our goal was to understand the barriers and facilitators transgender people face in accessing HIV prevention, testing, and care services and the potential implications for message development and dissemination. We reviewed the literature and interviewed nine key informants representing healthcare and service providers, researchers, and transgender advocates. Healthcare providers who care for transgender patients often demonstrate a lack of transgender competent care strategies. In addition, transgender people face many barriers to accessing HIV services. Although communication materials cannot address many of these barriers, materials specifically developed for transgender people and their healthcare providers would fill a gap and may increase uptake of HIV services. Materials for transgender people should include gender-affirming messaging and imagery, be framed in terms of resiliency, and present HIV information tailored to the needs of transgender people. Materials for healthcare providers should provide basic information to increase transgender competency and provision of comprehensive healthcare for transgender patients, inclusive of gender-affirming and HIV prevention, testing and care services. Channels for disseminating materials to transgender people and healthcare providers are described. PMID- 30021454 TI - Using the Theoretical Domains Framework to identify barriers and facilitators to exercise among older adults living with HIV. AB - People with HIV are living longer. However, co-morbidities are often more prevalent and severe than in the general population and have greater impacts on health status. Although compelling evidence exists about the health benefits of exercise in the HIV literature, many people living with HIV tend to be physically inactive. The purpose of this study was to use the Theoretical Domains Framework to investigate the barriers and facilitators to participation in exercise of older people living with HIV. This qualitative study involved in-depth, semi structured interviews with 12 adults aged 45 years and older recruited from HIV organizations and health centres. Data were analyzed thematically using the Theoretical Domains Framework, and two investigators independently coded transcripts. Six prominent domains were identified from the interviews: Social influences, environmental context and resources, reinforcement, intentions, social and professional role, and knowledge. Themes emerging from the interviews fit into all 14 domains of the Theoretical Domains Framework, and 67% of themes fit into the six most prominent domains. The participants had a working knowledge of exercise and its health benefits but were unfamiliar with specific exercise parameters. The majority identified environmental or resource constraints as salient barriers for participation in exercise programmes. Co-morbidities, injuries, and the side effects of HIV disease and medication were also acknowledged as barriers. Stigma and discrimination from friends, family, people within the LGBTQ community, and health care providers were commonly discussed. Participants spoke of the importance of social support to facilitate participation in exercise programmes. Other facilitators included using technology and incorporating exercise into day-to-day activities. People aging with HIV experience many barriers to exercise. Those designing exercise interventions for people aging with HIV should incorporate strategies to address these obstacles. PMID- 30021455 TI - Reply to the Letter to the Editor: "Accurate Patient Selection for Percutaneous Coronary Intervention for Coronary Chronic Total Occlusions". PMID- 30021456 TI - Persistent stigmatizing and negative perceptions of pre-exposure prophylaxis (PrEP) users: implications for PrEP adoption among Latino men who have sex with men. AB - The Centers for Disease Control and Prevention (CDC) estimates the lifetime HIV risk is one in four for Latino men who have sex with men (MSM). Pre-Exposure Prophylaxis (PrEP) is an efficacious biomedical prevention strategy to help prevent the acquisition of HIV. At present, there has been limited uptake of PrEP by Latino MSM. Unfortunately, the negative perceptions and social stigma surrounding PrEP and those who use it may deter uptake of this novel prevention strategy, particularly among high-risk Latino MSM. In this qualitative study, we explore the experiences of using PrEP among Latino MSM. Participants were recruited using gay-oriented social and sexual networking apps to complete an interviewer-administered, semi-structured qualitative interview. Thematic analysis was used to identify emerging themes relating to perceptions of PrEP users and PrEP as an HIV prevention strategy. Major themes included: feelings of protection and sexual freedom; negative and stigmatizing labels associated with PrEP use; assumptions about sexual behaviors and perceptions of sexual risk taking and irresponsibility; and attitudes related to PrEP use in relationships. A striking but not prevalent theme was the perception reported by participants that monolingual Spanish-speaking Latino MSM are skeptical about the effectiveness of PrEP. These findings suggest that efforts are needed to address the stigmatizing and negative perceptions of PrEP that persist in the gay community that may deter adoption among Latino MSM. PMID- 30021458 TI - The Genetic Epidemiology of Treated Major Depression in Sweden. AB - OBJECTIVE: The authors examined the heritability of treated major depression in a twin and full/half-sibling design, to describe key genetic epidemiological features of major depression and to determine which clinical indices of genetic liability optimally predict risk of depression in relatives. METHOD: The authors examined all treated cases of major depression in Sweden recorded in inpatient, specialist, and primary care registries and, using OpenMx, estimated the etiologic role of genetic and environmental factors from monozygotic and dizygotic twin pairs and full and half siblings reared together and apart (total N=1,718,863 pairs). Eight indices of genetic risk were examined in 875,010 proband-relative pairs. RESULTS: The heritability of major depression in men and women was estimated at 0.41 (95% CI=0.21, 0.49) and 0.49 (95% CI=0.31, 0.56), respectively, in the twin design and 0.36 (95% CI=0.31, 0.38) and 0.51 (95% CI=0.51, 0.53), respectively, in the independent full/half-sibling design. The best estimate of the correlation in genetic effects across sexes was 0.89 (95% CI=0.87, 0.91). The results also showed evidence of modest shared environmental effects (0.02-0.05). Seven of the eight indices predicted risk for major depression in relatives, with stronger effects in those more closely related. The strongest indices were early age at onset, recurrence, comorbid anxiety disorder, and measures of clinical severity. CONCLUSIONS: In a large national sample, the heritability of major depression was similar when estimated from twin and full/half-sibling designs. The heritability of major depression was greater in women than in men, with the two sexes sharing most but not all genetic risk factors. In affected individuals, genetic risk for major depression could be meaningfully assessed from commonly available clinical indices. PMID- 30021457 TI - As Safe as Possible (ASAP): A Brief App-Supported Inpatient Intervention to Prevent Postdischarge Suicidal Behavior in Hospitalized, Suicidal Adolescents. AB - OBJECTIVE: The authors report on a pilot study of an inpatient intervention for suicidal adolescents, As Safe as Possible (ASAP), supported by a smartphone app (BRITE) to reduce suicide attempts following hospital discharge. METHOD: Across two sites, 66 adolescents hospitalized for suicidal ideation (N=26) or a recent suicide attempt (N=40) were randomly assigned to the ASAP intervention program plus treatment as usual or to treatment as usual alone. ASAP, which focuses on emotion regulation and safety planning, is a 3-hour intervention delivered on the inpatient unit. The BRITE app prompted participants to rate their level of emotional distress on a daily basis and provided personalized strategies for emotion regulation and safety planning. A blind, independent evaluator assessed suicide attempts following hospital discharge and suicidal ideation at 4, 12, and 24 weeks after discharge. RESULTS: The ASAP intervention did not have a statistically significant effect on suicide attempt, although findings were in the hypothesized direction for occurrence of an attempt (16% compared with 31%; chi2=1.86, df=1, g=-0.36) and time to an attempt (hazard ratio=0.49, 95% CI=0.16, 1.47). Past history of a suicide attempt was a significant moderator of treatment outcome, with a stronger, albeit nonsignificant, effect of the ASAP intervention among participants with a history of suicide attempt (hazard ratio=0.23, 95% CI=0.05, 1.09). There were no treatment effects on suicidal ideation. The majority of participants (70%) used the BRITE app (median usage, 19 times). Participants reported high satisfaction with both the intervention and the app. CONCLUSIONS: The ASAP intervention program shows promise in reducing the incidence of postdischarge suicide attempts among adolescents hospitalized for suicidality and merits further study. PMID- 30021459 TI - Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer's Disease. AB - OBJECTIVE:: The presence of psychosis in Alzheimer's disease denotes a phenotype with more rapid cognitive deterioration than in Alzheimer's disease without psychosis. Discovery of novel pharmacotherapies that engage therapeutic targets for prevention or treatment of Alzheimer's disease with psychosis would benefit from identifying the neurobiology of resilience to psychosis in Alzheimer's disease. The primary objective of this study was to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms in Alzheimer's disease and, if present, were independent of neuropathologic burden. METHOD:: Quantitative immunohistochemistry was used to measure multiple neuropathologies in dorsolateral prefrontal cortex from subjects with early and middle-stage Alzheimer's disease who differed in psychosis status. Synaptic proteins were quantified by liquid chromatography-mass spectrometry in gray matter homogenates from these subjects and from neuropathologically unaffected subjects. The synaptic proteome was similarly evaluated in cortical gray matter homogenate and in postsynaptic density fractions from an APPswe/PSEN1dE9 mouse model of amyloidosis with germline reduction in Kalrn, which has been shown to confer resilience to progression of psychosis-associated behaviors relative to APPswe/PSEN1dE9 alone. RESULTS:: Subjects resilient to psychotic symptoms in Alzheimer's disease had higher levels of synaptic proteins compared with those with psychosis and unaffected control subjects. Neuropathologic burden predicted less than 20% of the variance in psychosis status and did not account for the synaptic protein level differences between groups. Reduction of Kalrn in APPswe/PSEN1dE9 mice resulted in higher levels of synaptic proteins in cortical homogenate and normalized protein levels in the postsynaptic density. CONCLUSIONS:: Accumulation of synaptic proteins, particularly those that are enriched in the postsynaptic density, is associated with resilience to psychosis in Alzheimer's disease. One candidate mechanism for this synaptic proteome compensation is alteration in levels of proteins that facilitate the transport of synaptic proteins to and from the postsynaptic density. PMID- 30021461 TI - Variation in treatment strategies for the eradication of Pseudomonas aeruginosa in primary ciliary dyskinesia across European centers. AB - Primary ciliary dyskinesia (PCD) is a rare disease causing motile cilia dysfunction, recurrent airway infection, and bronchiectasis. Airway infection management strategies are borrowed from cystic fibrosis. The aim of this study is to describe the management of airway infection with Pseudomonas aeruginosa ( PA) in children and adults with PCD across European centers. An online survey questionnaire was sent electronically using SurveyMonkey(r) to 55 PCD centers in 36 European countries. Fifty-two responded from 43 centers in 26 countries, a response rate of 70%. Most (89%) countries did not have written guidelines for PCD management. Airway sampling for infection detection at each clinic visit was more likely when follow-up was frequent. Eighty-seven percent of centers chose to treat the first PA isolate, most prescribing combined oral ciprofloxacin and inhaled colistimethate sodium (43%, n = 18). The preferred treatment for chronic infection with PA was nebulized colistimethate in 51% ( n = 22). In summary, considerable variation exists across European centers in the frequency of patient follow-up and airway sampling for infection, treatment goals, and the management of PA infection. Few centers had written guidelines for PCD management. Clinical trials to determine optimal treatment of PA in PCD patients are urgently needed. PMID- 30021460 TI - Meta-Analysis of 89 Structural MRI Studies in Posttraumatic Stress Disorder and Comparison With Major Depressive Disorder. AB - OBJECTIVE:: The authors conducted a comprehensive meta-analysis of MRI region-of interest and voxel-based morphometry (VBM) studies in posttraumatic stress disorder (PTSD). Because patients have high rates of comorbid depression, an additional objective was to compare the findings to a meta-analysis of MRI studies in depression. METHOD:: The MEDLINE database was searched for studies from 1985 through 2016. A total of 113 studies met inclusion criteria and were included in an online database. Of these, 66 were selected for the region-of interest meta-analysis and 13 for the VBM meta-analysis. The region-of-interest meta-analysis was conducted and compared with a meta-analysis of major depressive disorder. Within the region-of-interest meta-analysis, three subanalyses were conducted that included control groups with and without trauma. RESULTS:: In the region-of-interest meta-analysis, patients with PTSD compared with all control subjects were found to have reduced brain volume, intracranial volume, and volumes of the hippocampus, insula, and anterior cingulate. PTSD patients compared with nontraumatized or traumatized control subjects showed similar changes. Traumatized compared with nontraumatized control subjects showed smaller volumes of the hippocampus bilaterally. For all regions, pooled effect sizes (Hedges' g) varied from -0.84 to 0.43, and number of studies from three to 41. The VBM meta-analysis revealed prominent volumetric reductions in the medial prefrontal cortex, including the anterior cingulate. Compared with region-of interest data from patients with major depressive disorder, those with PTSD had reduced total brain volume, and both disorders were associated with reduced hippocampal volume. CONCLUSIONS:: The meta-analyses revealed structural brain abnormalities associated with PTSD and trauma and suggest that global brain volume reductions distinguish PTSD from major depression. PMID- 30021462 TI - Utility of the Beck Depression Inventory in measuring major depression among individuals seeking HIV testing in the Western Cape, South Africa. AB - The Beck Depression Inventory (BDI) is often used to screen individuals for symptoms of major depressive disorder (MDD). Yet, its effectiveness in correctly discriminating between MDD cases and non-cases among individuals seeking HIV testing has not been investigated. We report on the effectiveness of the BDI-I in predicting caseness for MDD with the Structured Clinical Interview for the DSM (SCID) as a gold standard. A total of 500 HIV test-seekers were recruited at five non-medical testing sites in the Western Cape, South Africa. Receiver operating characteristic curve analysis was used to determine the extent to which the screening instrument was able to discriminate between MDD caseness or non caseness. The SCID-based prevalence of MDD was 14.4%. The BDI-I predicted MDD with 67% sensitivity and 67% specificity, with an area under the curve (AUC) of 77%. The positive and negative predictive values were 0.25 and 0.92, respectively. Even though the BDI-I is often used to screen large numbers of people for depression, especially in psychiatric and medical settings, its ability to predict MDD is limited. Persons screening positive for MDD may still require evaluation with a clinical interview by a trained professional to be diagnosed with depression. PMID- 30021464 TI - How do parents perceive and utilize knowledge of their infant's mental health? A systematic review. AB - Infant mental health (IMH) is a growing area of practice for health, education and social care practitioners, as links are increasingly made between experiences in the early years and subsequent child development, mental health and well being. It is unclear how parents perceive IMH and use knowledge relating to IMH with their children. We conducted a systematic review, the aim of which was to determine parents' perceptions of IMH and how they utilize this knowledge with their infants. We undertook a search of relevant databases and journals and from an initial list of 4147 potential papers, identified 16 for the review. Original data were extracted and presented in a table, and the content of all papers was analysed thematically and presented in narrative form. Three main themes emerged from the available research: knowledge and understanding of child development, influences of society and culture, and interpretation of emotions and expressions. Our results indicate that research is limited in terms of parental perspectives of IMH and how they obtain and use this knowledge. Further research is needed to investigate this topic to maximize mental well-being in infancy and later life. PMID- 30021463 TI - Efficacy and Safety of a Biosimilar Versus Branded Enoxaparin in the Prevention of Venous Thromboembolism Following Major Abdominal Surgery: A Randomized, Prospective, Single-Blinded, Multicenter Clinical Trial. AB - Several biosimilar versions of enoxaparin are already approved and in use globally. Analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in clinical outcomes between biosimilar and branded enoxaparin. This study evaluated the efficacy and safety of biosimilar Cristalia versus branded Sanofi enoxaparin in venous thromboembolism (VTE) prevention in patients undergoing major abdominal surgery at risk for VTE. In this randomized, prospective single-blind study, we compared Cristalia enoxaparin (Ce), a biosimilar version, versus branded Sanofi enoxaparin (Se; at a dose of 40 mg subcutaneously per day postoperatively from 7 to 10 days) in 243 patients submitted to major abdominal surgery at risk for VTE for VTE prevention. The primary efficacy outcome was occurrence of VTE or death related to VTE. The principal safety outcomes were a combination of major bleeding and clinically relevant non-major bleeding. Bilateral duplex scanning of the legs was performed from days 10 to 14, and follow-ups were performed up to 60 days after surgery. The incidence of VTE was 4.9% in the Cristalia group and 1.1% in the Sanofi group (absolute risk difference = 3.80%, 95% confidence interval [CI]: 1.4%-9.0%) yielding noninferiority since the 95% CI does not reach the prespecified value Delta = 20%. Clinically significant bleeding occurred in 9.9% in the Cristalia group and in 5.5% in the Sanofi group (n.s. ). In conclusion, this study suggests that 40 mg once daily of Ce, a biosimilar enoxaparin, is as effective and safe as the branded Sanofi enoxaparin in the prophylaxis of VTE in patients submitted to major abdominal surgery at risk for VTE. PMID- 30021465 TI - Food security and dietary diversity are associated with health related quality of life after 6 months of follow up among people living with HIV in Accra, Ghana. AB - With the efficacy of antiretroviral therapy, people living with HIV (PLWH) are surviving longer and improving their health related quality of life (HRQol) has become an important long-term HIV treatment and management indicator. HRQol has been associated with various factors, including food insecurity (FI). The objective of this prospective study was to examine the association between FI and dietary diversity (HDDS) and HRQol among PLWH in Accra, Ghana. We recruited 152 PLWH from the HIV clinics of six district hospitals Accra, Ghana and utilized a prospective cohort study design with data collection at baseline, three and six months after recruitment for this study. Participants completed questionnaires measuring HRQol, FI and HDDS. Repeated measures ANOVA was used to analyze the associations between FI and HRQol as well as HDDS and HRQol separately and then together. Being food secure [0.035 (95% CI = 0.005, 0.065)] and having a high dietary diversity score [0.029 (95% CI = 0.004, 0.053)] were independently associated with an improvement in quality of life scores over time after adjusting for other covariates and each other. Interventions to improve dietary diversity and food security among PLWH have the potential to improve nutritional status as well as HRQol. PMID- 30021466 TI - Immortal Time Bias in Observational Studies of Time-to-Event Outcomes: Assessing Effects of Postmastectomy Radiation Therapy Using the National Cancer Database. AB - The objectives of this study are to illustrate the effects of immortal time bias (ITB) using an oncology outcomes database and quantify through simulations the magnitude and direction of ITB when different analytical techniques are used. A cohort of 11 626 women who received neoadjuvant chemotherapy and underwent mastectomy with pathologically positive lymph nodes were accrued from the National Cancer Database (2004-2008). Standard Cox regression, time-dependent (TD), and landmark models were used to compare overall survival in patients who did or did not receive postmastectomy radiation therapy (PMRT). Simulation studies showing ways to reduce the effect of ITB indicate that TD exposures should be included as variables in hazard-based analyses. Standard Cox regression models comparing overall survival in patients who did and did not receive PMRT showed a significant treatment effect (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.88-0.99). Time-dependent and landmark methods estimated no treatment effect with HR: 0.97, 95% CI: 0.92 to 1.03 and HR: 0.98, 95% CI, 0.92 to 1.04, respectively. In our simulation studies, the standard Cox regression model significantly overestimated treatment effects when no effect was present. Estimates of TD models were closest to the true treatment effect. Landmark model results were highly dependent on landmark timing. Appropriate statistical approaches that account for ITB are critical to minimize bias when examining relationships between receipt of PMRT and survival. PMID- 30021467 TI - Effect of Riboflavin/Rose Bengal-Mediated PACK-CXL on Acanthamoeba Trophozoites and Cysts in Vitro. AB - PURPOSE: To evaluate the antiamoebic properties of photo-activated chromophore for keratitis (PACK)-corneal cross-linking (CXL) (PACK-CXL), in combination with riboflavin (0.1 and 0.25%) or rose bengal (0.1 and 0.2%), for treatment of Acanthamoeba trophozoites and cysts. MATERIALS AND METHODS: Cultures of Acanthamoeba castellanii were grown in a fluid medium at a concentration of 2.7 * 105 cell/ml. PACK-CXL was used on A. castellani cells in combination with either riboflavin (0.1 and 0.25%) or rose bengal (0.1 and 0.2%). Riboflavin-containing wells were irradiated with ultraviolet-A (UVA) light (365-nm wavelength). Rose bengal-containing wells were irradiated with green light (523-nm wavelength). A power density of 9 mW/cm2 for 10 min and total irradiation dose of 5.4 J/cm2 was used for both riboflavin and rose bengal. After UVA and green light irradiation, cell viabilities were evaluated, and percentage of dead cells calculated. RESULTS: No significant amoebicidal activity was observed following PACK CXL/riboflavin at either concentration. PACK-CXL/rose bengal, however, was observed to be highly effective in eradicating Acanthamoeba cells at either concentration, with no significant difference observed between the two concentrations. The percentage of dead cells was 63% following treatment at either rose bengal concentration. CONCLUSION: PACK-CXL with rose bengal demonstrated pronounced antiamoebic activity against A.castellanii. Further in vitro and in vivo studies are needed to confirm this finding. PMID- 30021468 TI - Effect of maternal psychopathology on neurodevelopmental outcome and quality of the dyadic relationship in preterm infants: an explorative study. AB - BACKGROUND: The literature shows that parents of preterm infants are at risk of psychological distress and that this may impact on the quality of the parent child relationship and on the child's development. AIM: This longitudinal study was conducted to examine in preterm infants relationships between maternal psychological variables, parental protective factors, perinatal infant variables, and neurodevelopmental outcome. Furthermore, we explored the impact of these variables on the quality of the mother-infant relationship (dyadic synchrony). SUBJECTS AND METHODS: A total of 29 preterm infants (GA < 34 weeks) and their mothers were evaluated twice: at t0, during the infant's hospitalization in the neonatal intensive care unit (NICU), and at 12 months of infant corrected age (t2). RESULTS: With the exception of decreases in anxiety and perceived social support and an increase in the rate of severe depression at follow-up, there were no significant changes between t0 and t1 assessments. The infant's perinatal risk status was the variable that impacted most on maternal psychopathology. Furthermore, our data revealed that baseline maternal stress related to the appearance of the child and to the mother's perception of her parenting role represent a risk factor in relation to developmental outcome at 12 months of corrected age. Finally, no correlations emerged between dyadic synchrony and infant perinatal data, maternal psychological variables (at t0 and at t1), or child developmental outcome at t1. CONCLUSIONS: Our results underline the need to identify negative maternal affective states early in the mother-child relationship and to provide mothers with adequate support in the NICU, to enhance their parental role. PMID- 30021469 TI - On-Farm Evaluation of an Automatic Enrichment Device with Maize Silage for Laying Hens. AB - Challenges in alternative housing for laying hens are barren functional areas such as winter gardens and the occurrence of behavioral disorders. Environmental enrichment is a measure to deal with these problems. Therefore, an enrichment device offering maize silage automatically was tested in two winter gardens on farm. The use of the winter gardens and the times individual hens stayed there and occupied themselves with the maize silage were determined in a temporary preference test. The proportion of residing hens was significantly larger in the enriched winter garden. The mean time individual hens stayed in the enriched winter garden ranged from 02:16 +/- 02:22 (mm:ss) to 03:17 +/- 02:27, whereas the time ranged from 00:18 +/- 00:32 to 00:59 +/- 01:19 in the other winter garden (p < .05). Once the enrichment device ran in both winter gardens, no differences were found between the observed parameters. On average, the hens occupied themselves with the enrichment material for 03:50 +/- 02:12 to 05:01 +/- 03:06. Thus, based on its use and acceptance by the laying hens, the automatic device provided adequate environmental enrichment. PMID- 30021472 TI - Erratum. AB - International Journal of Immunopathology and Pharmacology 2018; 32, 1-15 Michal Ciebiera, Marta Wlodarczyk, Malgorzata Wrzosek, Cezary Wojtyla, Blazej Meczekalski, Grazyna Nowicka, Krzysztof Lukaszuk and Grzegorz Jakiel TNF-alpha serum levels are elevated in women with clinically symptomatic uterine fibroids 10.1177/2058738418779461 The original version of this article contained an error in the author name Blazej Meczekalski which was incorrectly given as Meczekalski Blazej. This has now been corrected. SAGE would like to apologise for this error. PMID- 30021471 TI - Recombinant human C1 esterase inhibitor (Conestat alfa) for prophylaxis to prevent attacks in adult and adolescent patients with hereditary angioedema. AB - INTRODUCTION: Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a debilitating and potentially lethal disease. Management includes on-demand treatment of angioedema and their prophylaxis. Plasma derived C1-INH is an established treatment for both on demand and prophylaxis of HAE. Conestat alfa is a recombinant form of human C1-INH (rhC1-INH) produced in transgenic rabbits. It has granted drug's registration as treatment option for acute HAE attacks in adults and adolescents in Europe, America, and other countries. Long-term prophylaxis with rhC1-INH received recent consideration in clinical trials. Areas covered: This review will critically appraise available information about rhC1 INH (conestat alfa) prophylactic treatment in adult and adolescent patients with congenital C1-INH deficiency. Results from a phase II randomized placebo controlled trial for prophylaxis of severe HAE evidenced positive treatment outcomes for its application, both twice or once weekly. Expert commentary: Phase II clinical studies suggest that rhC1-INH is a viable option for prophylaxis of HAE. Safety and tolerability data are comparable to other available HAE specific drugs, zeroing the possibility for blood-born viral transmission. Sustainability of modern technologies is granting a practically stable and continuous recombinant production process. With other available options, rhC1-INH facilitates tailoring HAE treatment to patients' needs. PMID- 30021470 TI - Adolescent female school dropouts who use drugs and engage in risky sex: effects of a brief pilot intervention in Cape Town, South Africa. AB - Female adolescents from socioeconomically underserved communities in Cape Town, South Africa, who have dropped out of school, use substances, and engage in risky sex behaviour are at risk of HIV. Tailored gender-focused HIV behavioural interventions for this key population are needed to mitigate these risk factors. A pilot trial of a woman-focused risk-reduction intervention for adolescents was conducted (N = 100), with a one-month follow-up appointment. Participants in the intervention group attended two group workshops. Data were examined for significant differences within and between the groups. At baseline, 94% of participants tested positive for cannabis, 17% were HIV-positive and 11% were pregnant. Ninety-two participants returned for 1-month follow-up. At follow-up, the proportion who tested positive for cannabis use decreased significantly in both the intervention (p = 0.07) and control groups (p = 0.04). Impaired sex with any partner (p = 0.02), or with main partner (p = 0.06) decreased among the intervention group. Impaired sex with a main partner was less likely in the intervention group (p = 0.07) in the regression model. In conclusion, findings indicate a need for HIV prevention interventions among out-of-school female adolescents. Intervention acceptability was high, and there were some decreases in sexual risk behaviour among intervention participants which is promising. Future intervention research with this key population involving larger sample sizes and longer follow-up periods will help to determine intervention efficacy. PMID- 30021473 TI - A Collaborative Model for Managing Animal Hoarding Cases. AB - Companion-animal hoarding is a significant problem in the United States and internationally. Hoarding situations can incubate for years before a case is reported to law enforcement or animal control agencies. According to a survey by Gary Patronek, animal control agencies have estimated there are approximately 3000 reportable cases of animal hoarding annually in the United States. Animal hoarding cases vary in size from fewer than 20 animals to hundreds of animals. Every case of animal hoarding results in suboptimal animal welfare. Wake County, North Carolina, developed a proactive plan for addressing companion-animal hoarding that implemented a team approach to assist animals at risk, hold people accountable, address the mental health component of this problem, and create a more humane community. The plan involved animal control officers, crisis intervention counselors, law enforcement officers, veterinarians, veterinary technicians, and animal rescue partners. This intervention strategy was implemented in 2015, and cases were tracked to document animal outcomes. The conclusion of this experience is that a diverse team approach can best address the animal and human welfare challenges and the environmental concerns associated with animal hoarding. PMID- 30021474 TI - Five New Species of the Tapeworm Genus Anthocephalum (Rhinebothriidea: Anthocephaliidae) Parasitizing A Single Species of Indo-Pacific Stingray and A Revised Diagnosis of the Genus. AB - Five new species of the elasmobranch tapeworm genus Anthocephalum Linton, 1890 (Rhinebothriidea: Anthocephaliidae Ruhnke, Caira and Cox, 2015 ) are described from the mangrove whipray, Urogymnus granulatus (Macleay) from the Solomon Islands and northern Australia. Anthocephalum blairi n. sp., Anthocephalum gravisi n. sp., Anthocephalum haroldsoni n. sp., Anthocephalum mounseyi n. sp., and Anthocephalum ruhnkei n. sp. differ from one another and their congeners based on quantitative and qualitative features of the scolex and proglottid anatomy. Species boundaries recognized by these distinguishing morphological features are supported by a maximum likelihood phylogenetic analysis based on combined 18S rDNA and 28S rDNA (D1-D3) sequence data showing the new species as independent lineages among 13 of the 18 species of Anthocephalum described to date. Several morphological features (the possession of columns of vitelline follicles that are interrupted by the ovary, a uterus that does not extend to the anterior margin of the proglottid but stops short in the anterior region of the field of testes, proximal surfaces of the marginal loculi covered with acicular filitriches only throughout, or with gladiate spinitriches and acicular filitriches throughout, and proximal bothridial surfaces with gladiate spinitriches and acicular filitriches) are collectively exhibited by the 5 new species and have not been documented previously in other species of Anthocephalum. The genus is herein amended to reflect these features. Additionally, the replacement name Anthocephalum centrurum ( Southwell, 1925 ) Ruhnke, 1994 is reinstated as the valid name for the type species of the genus, Anthocephalum gracile Linton, 1890 , with the latter being the junior secondary homonym of A. gracile ( Wedl, 1855 ) Ruhnke, 1994 . The description of these new species increases the number of valid species of Anthocephalum from 18 to 23. PMID- 30021475 TI - Peripheral neuroblastic tumor of the kidney: case report and review of literature. AB - INTRODUCTION: Peripheral neuroblastic tumors (PNTs) account for 8%-10% of all pediatric tumors. Adrenal glands and sympathetic ganglia are the commonest site of tumor growth. In the clinicopathologic spectrum of PNTs, neuroblastoma and ganglioneuroma are the most primitive and the most mature tumor form, while ganglioneuroblastoma represents an intermediate state of maturation. Surgical resection is the therapy of choice in localized disease, but can lead to serious complications when performed in the presence of certain imaging-defined risk factors. CASE PRESENTATION: We present a rare case of primary intrarenal ganglioneuroblastoma diagnosed in a teenager who underwent conservative surgery and, despite this, developed upper pole renal ischemia without loss of parenchymal function. CONCLUSION: We underline the complex management of these extremely rare cases of neuroblastic tumors, which require a dedicated multidisciplinary team. PMID- 30021476 TI - Quality of life evaluation in patients with mucopolysaccharidosis using PedsQL. AB - Mucopolysaccharidosis (MPS) is a rare and neglected disorder. Only a few studies to date have focused on humanistic impacts of the disease, particularly health related quality of life (HRQOL). The objective of our research is to (1) evaluate HRQOL in Brazilian patients with MPS and (2) assess the validity of the PedsQL 4.0 Generic Core Scales (PedsQL) in this specific disease. We performed an analytical cross-sectional study using the Brazilian Portuguese version of the PedsQL in 22 patients with MPS between the ages of 8 and 21. With regard to assessing the validity of the PedsQL for MPS, we evaluated internal consistency using Cronbach's alpha coefficient and reliability using the Spearman-Brown estimate of agreement. The mean HRQOL score in our sample was 63.6 points. The worst score was obtained in the Psychosocial domain (61.9) on account of interference with school (56.1), while the Physical Health domain had the highest score (67.6). The total PedsQL internal consistency was .764 points. The Physical Health domain obtained the highest internal consistency (.914), whereas the Psychosocial Health domain obtained the lowest one (.754). MPS was demonstrated to decrease HRQOL, and PedsQL seems to be a valid instrument to perform this kind of analysis. PMID- 30021477 TI - IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide and despite an initial response to therapeutic agents, the majority of patients have chemoresistant disease. There is no treatment strategy with proven efficacy against chemoresistant EOC and in this setting, overcoming therapy resistance is the key to successful treatment. METHODS: This study aimed to investigate expression of interleukin-6 (IL-6) (IL-6) and IL-6 receptor (IL 6R) in a panel of the EOC cell lines. To achieve this, the expression of IL-6 and its receptor were compared in the EOC cells using quantitative reverse transcription polymerase chain reaction. MTT assay was performed to obtain chemosensitivity of the EOC cells. RESULTS: In this report, we show that expressions of IL6 and IL6R are higher in therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6 and its receptor correlated with resistance to certain chemotherapeutic agents. Moreover, our findings showed that combination of tocilizumab (Actemra; Roche), an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited growth and proliferation of the EOC cells and the most direct axis for IL-6 gene expression was NF-kappaB pathway. CONCLUSION: Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics. PMID- 30021478 TI - A Simple Scoring System Using the Red Blood Cell Distribution Width, Delta Neutrophil Index, and Platelet Count to Predict Mortality in Patients With Severe Sepsis and Septic Shock. AB - PURPOSE: The purpose of our study was to investigate whether a simple scoring system based on the red blood cell distribution width (RDW), delta neutrophil index (DNI), and platelet count was associated with the prognosis of patients with sepsis, and whether this scoring system was more useful than each individual parameter. MATERIALS AND METHODS: We conducted a retrospective cohort study involving adult patients who received intensive therapy due to severe sepsis and septic shock from January 2010 to December 2015 at a tertiary teaching hospital in South Korea. RESULTS: A total of 730 patients were included in this study. Each patient was rated on a scale of 0 to 3 according to the new scoring system using the platelet count, RDW, and DNI. Point values were assigned based on the following definitions: RDW > 14.5%, DNI > 5.0%, and platelet count < 150 000/mm3. The 28-day mortality rate was 12.6% (92/730). The nonsurvivors had higher scores than the survivors (2.05 +/- 0.80 vs 1.06 +/- 0.87, P < .001). In the multivariate Cox proportional hazard analysis, the scoring system was an independent predictor of the 28-day mortality. The scoring system was well calibrated ( P = .81 for the goodness-of-fit test) and discriminated (area under the receiver operating characteristic curve = 0.785). CONCLUSION: Our new scoring system using the RDW, DNI, and platelet count was useful for predicting the mortality in patients with severe sepsis and septic shock. PMID- 30021479 TI - Development and validation of an observational measure of symptoms of Reactive Attachment Disorder. AB - Reactive Attachment Disorder (RAD) is presumed to be a consequence of social neglect and deprivation of the kind particularly associated with institutional care. Despite its clinical relevance there is a lack of assessment tools for RAD based on the direct observation of child-caregiver interaction. Here we describe the development and validation of such a tool for use with preschool children, the Rating of Inhibited Attachment Disordered Behavior (RInAB). The RInAB is composed of 17 ratings grouped in three subscales assessing (1) Attachment, (2) Exploratory, and (3) Socioemotional behavior. Participants were 134 institutionalized preschool children (M = 54.84 months; SD = 10.83; 60% boys) and their caregivers. Adequate reliability was found for RInAB subscales and total score. Confirmatory factor analyses documented the three aforementioned RInAB subscales. Correlational analyses documented: (i) construct validity via positive and significant associations with caregiver sensitivity and quality of child caregiver relationship; (ii) convergence validity via association evidence with some emotionally/withdrawn inhibited items of the Disturbed Attachment Interview (DAI), as well as, with Child Behavior Checklist (CBCL)'s somatic complaints and withdraw syndrome scales; and (iii) discriminant validity via nonsignificant or negative associations with DAI-indiscriminate subscale, Rating of Infant and Stranger Engagement (RISE) and CBCL-externalizing problems. Discussion highlights the contributions complementary roles of RInAB for a comprehensive assessment of child RAD-related functioning. PMID- 30021480 TI - Unusual Histopathological Findings in Appendectomy Specimens: A Retrospective Analysis of 2047 Cases. AB - BACKGROUND: In this study, we retrospectively evaluated cases of patients who had undergone appendectomy in our hospital and aimed to present the efficiency of diagnostic tests and demographic data of cases. Pathological reports were analyzed for the following parameters: age, gender, and pathological diagnosis. In addition, the demographic and clinicopathologic characteristics of patients with unusual histopathologic findings were evaluated in detail, and reanalysis of archived resected appendix specimens was carried out. METHODS: Files of 2047 patients (1329 males, 718 females, sex ratio: 1.85, age range: 1-87 years, mean age: 26, 50 years), who had been operated with a diagnosis of acute appendicitis in the emergency department of Bezmialem Vakif University Medical Faculty from November 2011 to June 2014, were retrospectively evaluated. RESULTS: Cases were separated into 2 groups. Cases with histopathologic examination reported as acute appendicitis constituted group 1 (n = 2013, 98.34%), and cases with pathologic findings other than acute appendicitis constituted group 2 (n = 34, 1.66%). The second group consisted of 8 low-grade mucinous neoplasms, 7 mucoceles, 6 carcinoid, 5 granulomatous inflammation, 4 intraluminal Enterobius vermicularis, 1 endometriosis externa, 1 adenocarcinoma infiltrated to serosa, 1 mesenteric cyst, and 1 low-grade adenocarcinoma formed in mucinous cystic neoplasm background. CONCLUSION: Acute appendicitis is the most common emergency surgical condition. Although most of the resected appendectomy specimens showed typical histopathologic findings, some (1.66%) showed unusual histopathologic findings. Even if the macroscopic appearance of the specimen is normal or acute appendicitis, we suggest routine histopathological examination. PMID- 30021481 TI - Chlorhexidine-alcohol versus povidone-iodine for skin preparation before elective cesarean section: a prospective observational study. AB - INTRODUCTION: The ideal antiseptic agent for skin preparation before elective cesarean section (CS) is not yet determined. The aim of the study was to assess the impact of skin preparation by chlorhexidine-alcohol compared with povidone iodine before elective CS on the rate of surgical site infection (SSI). MATERIALS AND METHODS: This prospective observational study included a total of 1424 pregnant women at term who were candidates for the elective CS and were divided into two equal groups of 712 patients in each, group 1 (chlorhexidine-alcohol group) and group 2 (povidone-iodine group). Patients were followed up at 1 week and 1 month postoperative to determine the rate of SSI. RESULTS: The rate of SSI was 3.7% (26 patients) in the chlorhexidine-alcohol group compared with 4.6% (33 patients) in the povidone-iodine group (odds ratio: 0.7798, 95% CI: 0.46-1.3, p = .35), nine patients in the chlorhexidine-alcohol group, and 10 patients in the povidone-iodine group required resuturing (odds ratio: 0.9, 95% CI: 0.36-2.2, p = .82). Four patients (0.56%) in the chlorhexidine-alcohol group and five patients (0.7%) in the povidone-iodine group developed endometritis (p = .74). The rate or readmission because of SSI was 2.7% (19 patients) in the chlorhexidine-alcohol group and 2.9% (21 patients) in the povidone-iodine group (p = .75). CONCLUSIONS: Skin preparation with either chlorhexidine-alcohol or povidone-iodine resulted in comparable rates of SSIs. Accordingly, both are suitable antiseptic agents for skin preparation before elective CS. PMID- 30021482 TI - The effect of delay in viral production in within-host models during early infection. AB - Delay in viral production may have a significant impact on the early stages of infection. During the eclipse phase, the time from viral entry until active production of viral particles, no viruses are produced. This delay affects the probability that a viral infection becomes established and timing of the peak viral load. Deterministic and stochastic models are formulated with either multiple latent stages or a fixed delay for the eclipse phase. The deterministic model with multiple latent stages approaches in the limit the model with a fixed delay as the number of stages approaches infinity. The deterministic model framework is used to formulate continuous-time Markov chain and stochastic differential equation models. The probability of a minor infection with rapid viral clearance as opposed to a major full-blown infection with a high viral load is estimated from a branching process approximation of the Markov chain model and the results are confirmed through numerical simulations. In addition, parameter values for influenza A are used to numerically estimate the time to peak viral infection and peak viral load for the deterministic and stochastic models. Although the average length of the eclipse phase is the same in each of the models, as the number of latent stages increases, the numerical results show that the time to viral peak and the peak viral load increase. PMID- 30021483 TI - Abuse of pregnant women in the healthcare system. AB - OBJECTIVE: The purpose of this study was to determine the incidence of abuse in healthcare system during pregnancy and its impact on pregnancy outcomes. MATERIALS AND METHODS: A validated screening Norvold Abuse Questionnaire for the identification of female victims of four kinds of abuse: emotional, physical, sexual, and the abuse in the healthcare system was anonymously offered to all women in the first 2 days postpartum. RESULTS: The study group consisted of 1018 women, 6.2% of which reported experiencing abuse in healthcare system during pregnancy. Affected women had a higher incidence of preterm delivery (OR 2.4; 95% CI 1.2-4.8) and cesarean section rate (OR 2.0; 95% CI 1.1-3.6). Sexual abuse and abuse in healthcare system during childhood were associated with abuse in healthcare system during pregnancy (OR 4.4; CI 95% 1.2-16.2 and OR 6.9; CI 95% 1.3-35.4, respectively). CONCLUSIONS: Our study indicates that as many as 6.2% of pregnant women experience abusive encounters with perinatal care providers. These pregnancies eventually end more often preterm and by cesarean section. This possibly causal relationship should be further explored. PMID- 30021484 TI - The Ability of Prostate Health Index (PHI) to Predict Gleason Score in Patients With Prostate Cancer and Discriminate Patients Between Gleason Score 6 and Gleason Score Higher Than 6-A Study on 320 Patients After Radical Prostatectomy. AB - AIM: The purpose of this study was to investigate the Prostate Health Index as a marker for tumor aggressiveness in prostate biopsy and the optimization of indication for treatment options. METHODS: Our cohort consisted of 320 patients indicated for radical prostatectomy with preoperative measurements of total prostate-specific antigen, free prostate-specific antigen, [-2]proPSA, calculated %freePSA, and Prostate Health Index. The Gleason score was determined during biopsy and after radical prostatectomy. Using the Gleason score, we divided the group of patients into the 2 subgroups: Gleason score <=6 and Gleason score >6. This division was performed according to the biopsy Gleason score and according to the postoperative Gleason score. We compared total prostate-specific antigen, [-2]proPSA, %freePSA, and Prostate Health Index in the subgroups Gleason score <=6 and Gleason score >6 after biopsy and the definitive score. RESULTS: On evaluation of the subgroups created by Gleason score <=6 and Gleason score >6, we observed agreement between biopsy Gleason score and definitive Gleason score in only 45.3% of cases. Of the calculated biopsy, Gleason score <=6 and Gleason score >6 subgroups, [-2]proPSA, and Prostate Health Index ( P = .0003 and P = .0005) were statistically significant. Of the definitive Gleason score <=6 and Gleason score >6 subgroups, Prostate Health Index, [-2]proPSA, %freePSA, and PSA ( P < .0001, P < .0001, P = .0003, and P = .0043) were statistically significant. The best area under the curve value (0.7496) was achieved by Prostate Health Index when the subgroups were established according to the postoperative Gleason score. CONCLUSION: Prostate Health Index is the best of the tested markers for the categorization of Gleason score 6 tumors and for facilitating the management of patients with prostate cancer. Prostate Health Index can be a helpful marker for indication of active surveillance or radical prostatectomy. Prostate health index can also simplify the decision of whether to perform nerve-sparing radical prostatectomy. PMID- 30021485 TI - Don't stare, unless you don't want to remember: Maintaining fixation compromises autobiographical memory retrieval. AB - This study has developed an original approach to the relationship between eye movements and autobiographical memory, by investigating how maintained fixation could influence the characteristics of retrieved memories. We invited participants to retrieve autobiographical memories in two conditions: while fixating a cross at the centre of a screen and while freely exploring the screen. Memories retrieved during the maintained fixation condition were less detailed and contained less visual imagery than those retrieved during the free-gaze condition. Memories retrieved during the maintained fixation condition were retrieved slower and took less time to describe than those retrieved during the free-gaze condition. As for the characteristics of eye movements, analysis showed fewer and longer fixations as well as fewer saccades in the maintained fixation than in the free-gaze condition. Maintaining fixation is likely to tax cognitive resources that are necessary for the reconstruction of autobiographical memory. Our findings demonstrate how maintained fixation may result in a more effortful construction of autobiographical memory and memories with lower spatiotemporal specificity and poorer mental images. PMID- 30021486 TI - Relational autonomy in action: Rethinking dementia and sexuality in care facilities. AB - BACKGROUND: Caregivers and administrators in long-term facilities have fragile moral work in caring for residents with dementia. Residents are susceptible to barriers and vulnerabilities associated with the most intimate aspects of their lives, including how they express themselves sexually. The conditions for sexual agency are directly affected by caregivers' perceptions and attitudes, as well as facility policies. OBJECTIVE: This article aims to clarify how to approach capacity determinations as it relates to sexual activity, propose how to theorize about patient autonomy in this context, and suggest some considerations for finding an ethically responsible and practically feasible way to respect the sexual rights of this population. RESEARCH DESIGN: The focus is on residents with early to moderate dementia in states of daily dependency on professional caregivers. The article critically examines existing empirical research on sexuality among persons with dementia, caregivers' attitudes, and institutional roadblocks to enabling residents' sexuality. A relational lens and insights from disability studies are used in the philosophical analysis. Participants and Research Context: No research participants were part of this analysis. Ethical Considerations: This article offers a conceptual analysis and normative framework only. FINDINGS: The analysis highlights the delicate balance that capacity assessments for sexual activity have to strike; while caregivers should protect those who cannot give adequate consent, the denial of sexuality among residents can cause deep, long-ranging harms. Sexual agency features into an ongoing sense of self for many individuals with dementia, and the imposition of inappropriate standards and expectations for sexual autonomy can lead to unwarranted obstacles to sexual activity. DISCUSSION: Recommendations include developing clear and inclusive institutional policies and practices of care, providing education for caregivers on how to discuss and document residents' sexual preferences over time, and taking advantage of ethics consultation services. CONCLUSION: This analysis establishes the need for more research and discussion on this sensitive topic. Future research should investigate the specific responsibilities of caregivers in furthering the sexual interests of residents, how exactly to modify existing capacity instruments, and how best to support historically marginalized patients in their sexual identities. PMID- 30021487 TI - 'We would have missed out so much had we terminated': What fathers of a child with Down syndrome think about current non-invasive prenatal testing for Down syndrome. AB - Non-invasive prenatal testing (NIPT) allows early, accurate diagnosis of Down syndrome that has resulted in increased terminations. This qualitative study involved in-depth interviews of fathers of children with Down syndrome about their views on the availability of NIPT. Thematic network analysis revealed that although fathers appreciated an early diagnosis with NIPT, they saw the test as being a predetermined pathway to termination. Fathers felt that expectation to terminate reflects negative societal attitudes towards those with Down syndrome and disability, fearing that NIPT may become a form of eugenics. Fathers retrospectively contrasted these attitudes with the actual reality of raising their children with Down syndrome, which they described as bringing joy to their lives. Findings suggest that although fathers valued NIPT as an information giving tool that allowed autonomous parental choices about the pregnancy, they believe that it should be accompanied by balanced information about the reality of raising a child with Down syndrome. PMID- 30021488 TI - Reactive Attachment Disorder in maltreated young children in foster care. AB - Reactive attachment disorder (RAD) is one of the least researched and most poorly understood psychiatric disorders. Very little is known about the prevalence and stability of RAD symptoms over time. Until recently it has been difficult to investigate RAD due to limited tools for informing a diagnosis. Utilising a newly developed observational tool along with the Disturbances of Attachment Interview. this short-term prospective longitudinal study explored RAD symptoms in maltreated young children in Scotland (n=100, age range =12-62 months) over 12 months. Children were recruited as part of The Best Services Trial (BeST?), in which all infants who came in to the care of the local authority in Glasgow due to child protection concerns were invited to participate. Prevalence of RAD was found to be 5.0% (n=5, 95% CI [0.7-9.3]) when children were first placed in to foster care. Following at least 1 year of improved care conditions, prevalence in the 76 children remaining in the study was 2.1% (n=2, 95% CI [below 0-4.7]). RAD was associated with some mental health and cognitive difficulties. While levels of carer-reported RAD symptoms decreased significantly over time, observed symptoms did not. Findings suggest that RAD resolved in a small majority of cases but further exploration in larger samples would be invaluable. PMID- 30021489 TI - A developmental model of addictions: integrating neurobiological and psychodynamic theories through the lens of attachment. AB - Although substance use and abuse may impact brain and behavior, it is still unclear why some people become addicted while others do not. Neuroscientific theories explain addiction as a series of between- and within-system neuroadaptations that lead to an increasingly dysregulating cycle, affecting reward, motivation, and executive control systems. In contrast, psychoanalysis understands addiction through a relational perspective wherein there is an underlying failure in affect regulation, a capacity shaped early developmentally. Considering recent findings suggesting the neurobiological overlap of addiction and attachment, it may be possible to integrate both perspectives into a developmental model through the lens of attachment. The goal of the present review is to evaluate the value of neurobiological and psychodynamic perspectives to inform our understanding of addiction, particularly substance-use disorders. PMID- 30021490 TI - Comparison of Lurasidone and Quetiapine in Critically Ill Patients. PMID- 30021492 TI - Association of Platelet to Lymphocyte Ratio and Risk of 30-Day Postoperative Complications in Patients Undergoing Abdominal Aortic Surgical Repair. AB - INTRODUCTION: The predictive value of the platelet to lymphocyte ratio (PLR) has been demonstrated in several cardiovascular diseases. The aim of this study was to investigate the interest of the preoperative PLR as a predictor of 30-day postoperative outcome in patients with abdominal aortic aneurysm (AAA) undergoing open or endovascular surgical repair. MATERIAL AND METHODS: Two hundred twenty four consecutive patients with infrarenal AAA were retrospectively included and divided into 4 quartiles according to the value of the preoperative PLR: PLR < 91.5 (group I), 91.5 < PLR < 120.8 (group II), 120.8 < PLR < 163.3 (group III), and PLR > 163.3 (group IV). RESULTS: The AAA diameter was similar among the groups (54.9 mm vs 58.6, 57.5, and 58.7 mm; P = .4655). The proportion of symptomatic AAA and the procedural characteristics did not differ. Patients from group I and IV had significantly higher rates of all-cause postoperative complications compared to group II and III (55.4% and 64.3% vs 39.3% and 46.4%, respectively; P = .0478). The all-cause mortality tended to be higher in group I and IV (7.1% and 8.9% vs 0% and 3.6%, respectively; P = .1305). CONCLUSION: Extreme values of PLR are associated with a higher risk of complications following AAA surgical repair, suggesting its interest as a biomarker to evaluate the surgical risk. PMID- 30021491 TI - Canadian Stroke Best Practice Consensus Statement: Acute Stroke Management during pregnancy. AB - The Canadian Stroke Best Practice Consensus Statement Acute Stroke Management during Pregnancy is the second of a two-part series devoted to stroke in pregnancy. The first part focused on the unique aspects of secondary stroke prevention in a woman with a prior history of stroke who is, or is planning to become, pregnant. This document focuses on the management of a woman who experiences an acute stroke during pregnancy. This consensus statement was developed in recognition of the need for a specifically tailored approach to the management of this group of patients in the absence of any broad-based, stroke specific guidelines or consensus statements, which do not exist currently. The foundation for the development of this document was the concept that maternal health is vital for fetal well-being; therefore, management decisions should be based first on the confluence of two clinical considerations: (a) decisions that would be made if the patient wasn't pregnant and (b) decisions that would be made if the patient hadn't had a stroke, then nuanced as needed. While empirical research in this area is limited, this consensus document is based on the best available literature and guided by expert consensus. Issues addressed in this document include initial emergency management, diagnostic imaging, acute stroke treatment, the management of hemorrhagic stroke, anesthetic management, post stroke management for women with a stroke in pregnancy, intrapartum considerations, and postpartum management. These statements are appropriate for healthcare professionals across all disciplines and system planners to ensure pregnant women who experience a stroke have timely access to both expert neurological and obstetric care. PMID- 30021493 TI - Open Versus Endovascular Revascularization of Below-Knee Arteries in Patients With End-Stage Renal Disease and Critical Limb Ischemia. AB - BACKGROUND:: Evaluation of below-the-knee open revascularization (OR) versus endovascular revascularization (EVT) in patients with end-stage renal disease and critical limb ischemia (CLI) was performed. PATIENTS AND METHODS:: Seventy-seven dialysis patients with CLI and infrapopliteal involvement from 2007 to 2017 were included. Thirty-five patients received OR and 42 patients were treated with EVT. Survival, amputation-free survival (AFS) and wound-healing were evaluated. Furthermore, both groups were analyzed for differences as to anatomic (lesion length, runoff, pedal arch classification) and clinical (VSG risk score, WIfI score) characteristics. RESULTS:: Amputation-free survival (1-year AFS: OR 54.5% vs 47.6% in EVT, 2-year AFS OR 38.3% vs 23.9% EVT, P = .201) did not significantly differ between OR and EVT nor did the wound healing rate (29% OR vs 31% EVT, P = .532). Overall survival was noticeably poor (1-year survival: 66.7% in OR and 49% in EVT, 2-year survival OR 47.4% vs EVT 27.7%; P = .088); evaluation of peripheral runoff (Rutherford score 6.9 OR vs 7.1 EVT, P = .499) and pedal arch classification as well as WIfI or VSG risk score (9.8 OR vs 9.6 EVT, P = .673) could not detect significant differences as to both the groups. Treated median lesion length was significantly increased in OR patients (OR 26 cm vs EVT 7 cm, P < .001), whereas the incidence of major adverse cardiac events was higher in EVT patients (67% in EVT vs 40% OR, P = .023). CONCLUSION:: OR and EVT showed comparable outcomes as to AFS and wound healing. Poor overall survival remains the determining factor in patients with ESRD having CLI. Both groups differ in terms of anatomic features as lesion length and severity of comorbidities; considering the comparable long-term outcomes, decision-making should be based on these premises; individually applied, each method can contribute to limb salvage, although the overall survival remains limited. PMID- 30021495 TI - University of Pennsylvania 10th annual conference on statistical issues in clinical trials: Current issues regarding data and safety monitoring committees in clinical trials (morning panel session). PMID- 30021494 TI - The relationship of maternal glycemia to childhood obesity and metabolic dysfunction?. AB - OBJECTIVE: To determine the association of maternal glycemia with childhood obesity and metabolic dysfunction. STUDY DESIGN: Secondary analysis of follow-up data 5-10 years after a mild gestational diabetes mellitus (GDM) treatment trial. The relationship between maternal oral glucose tolerance testing (OGTT) at 24-31 week gestation and body mass index (BMI), fasting glucose, insulin, and anthropometric measurements (sum of skinfolds, subscapular/triceps ratio, and waist circumference) in the offspring of untreated mild GDM and non-GDM (abnormal 50-g screen/normal OGTT) women was assessed. Multivariable regression modeling controlling for maternal and neonatal characteristics was employed. RESULTS: A cohort of 236 untreated mild GDM and 480 non-GDM offspring were analyzed. In the combined cohort, significant correlations existed between fasting, 1, 2, and 3 h maternal glucose and subscapular/triceps ratio (all p < .04) and in all OGTT values other than the 2-hour value for homeostatic model assessment-estimated insulin resistance (HOMA-IR) (all p < .04) and sum of skinfold measurements (all p < .03). No correlation was found between OGTT values and childhood BMI Z-score. Multivariable regression modeling showed that OGTT values were associated with only sum of skinfolds and subscapular/triceps ratio and not with childhood BMI Z score. Hispanic ethnicity and prepregnancy maternal BMI were most consistently related to childhood BMI Z-score and HOMA-IR, and Hispanic ethnicity with fasting glucose. CONCLUSIONS: Among women with untreated mild GDM and those without GDM, maternal glycemia is associated with childhood anthropometric measures of obesity but not childhood BMI, fasting glucose, or insulin resistance. Hispanic ethnicity, maternal BMI, and gestational weight gain were consistently related to childhood BMI. PMID- 30021496 TI - Use of composite outcomes to assess risk-benefit in clinical trials. AB - Before a novel treatment can be deemed a clinical success, an assessment of its risk-benefit profile must be made. One of the inherent challenges for this assessment comes from the multiplicity that arises from comparing treatment groups across multiple outcomes. Composite outcomes that summarize a patient's clinical status, or severity, across a prioritized list of safety and efficacy outcomes have become increasing popular. In this article, we review these approaches and illustrate through examples some of the challenges and complexities of a composite derived from prioritized outcomes, such as the win ratio. These challenges include the difficult tension between the analytical validity that comes from choosing a pre-specified outcome and an evaluation that is responsive to unexpected safety events that arise during the course of a trial. Other challenges include a sensitivity of the resulting test statistic to the underlying censoring distribution and other nuisance parameters. Approaches that resolve some of the difficulties of the analytical challenges associated with prioritized outcomes are then discussed. Ultimately, a composite outcome of net clinical benefit is another decision tool, but one to be used alongside more traditional analyses of efficacy and safety, and with the broader perspective that investigators, the data safety monitoring board, and regulators bring to an evaluation of risk-benefit. PMID- 30021497 TI - University of Pennsylvania 10th annual conference on statistical issues in clinical trials: Current issues regarding data and safety monitoring committees in clinical trials (afternoon panel session). PMID- 30021499 TI - Ubiquinol (Reduced Coenzyme Q10) and Cellular Oxygen Consumption in Patients Undergoing Coronary Artery Bypass Grafting. AB - Ubiquinol is a fundamental component of cellular metabolism. Low ubiquinol levels have been associated with mortality. This was a substudy of a randomized trial in patients undergoing coronary artery bypass grafting. We drew blood before and after surgery. Ubiquinol or placebo was added to peripheral blood mononuclear cells for oxygen consumption (OCR) measurements. In vivo ubiquinol levels were lower postsurgery compared to presurgery (0.16 MUmol/L [quartiles: 0.02-0.39], P = .01), although the difference disappeared when adjusting for hemoglobin levels ( P = .30). There was no difference in presurgical basal (1.0 mL/min/mg [95% confidence interval [CI]: -0.9 to 2.2], P = .08) and maximal (0.5 mL/min/mg [95% CI: -4.3 to 7.3], P = .56) OCR in cells receiving ubiquinol or placebo. There was a difference in postsurgical basal (1.1 mL/min/mg [95% CI: 0.9-1.6], P < .001) and maximal (4.2 mL/min/mg [95% CI: 0.3-7.0], P = .01) OCR between the groups. We found no association between ubiquinol and OCR levels (all P > .05). PMID- 30021498 TI - ESOPE-Equivalent Pulsing Protocols for Calcium Electroporation: An In Vitro Optimization Study on 2 Cancer Cell Models. AB - Reversible electroporation is used to increase the uptake of chemotherapeutic drugs in local tumor treatment (electrochemotherapy) by applying the pulsing protocol (8 rectangular pulses, 1000 V/cm, 100 us) standardized in the framework of the European Standard Operating Procedure on Electrochemotherapy multicenter trial. Currently, new electrochemotherapy strategies are under development to extend its applicability to tumors with different histology. Electrical parameters and drug type are critical factors. A possible approach is to test pulse parameters different from European Standard Operating Procedure on Electrochemotherapy but with comparable electroporation yield (European Standard Operating Procedure on Electrochemotherapy-equivalent protocols). Moreover, the use of non-toxic drugs combined with electroporation represents the new frontier for electrochemotherapy applications; calcium electroporation has been recently proposed as a simple tool for anticancer therapy. In vitro investigations facilitate the optimization of electrical parameters and drugs for in vivo and clinical testing. In this optimization study, new pulsing protocols have been tested by increasing the pulse number and reducing the electric field with respect to the standard. European Standard Operating Procedure on Electrochemotherapy-equivalent protocols have been identified in HL-60 and A431 cancer cell models, and a higher sensitivity in terms of electroporation yield has been recorded in HL-60 cells. Moreover, cell killing efficacy of European Standard Operating Procedure on Electrochemotherapy-equivalent protocols has been demonstrated in the presence of increasing calcium concentrations on both cell lines. Equivalent European Standard Operating Procedure on Electrochemotherapy protocols can be used to optimize the therapeutic effects in the clinic, where different regions of the same cancer tissue, with different electrical properties, might result in a differential electroporation yield of the standard protocol over the same tissue, or, eventually, in an override of the operational limits of the instrument. Moreover, using calcium can help overcome the drawbacks of standard drugs (side effects, high costs, difficult handling, preparation, and storage procedures). These results support the possibility of new treatment options in both standard electrochemotherapy and calcium electroporation, with clear advantages in the clinic. PMID- 30021501 TI - Choosing the harder road: Naming the challenges for families in person-centred planning. AB - Person-centred planning (PCP) has underpinned disability service provision in many Western countries for the past 30 years. For many people with an intellectual disability, family members are central to this process and are important allies in facilitating positive change. This article presents findings from an evaluation of a family resourcing and capacity building project in New South Wales (NSW), Australia. Accounts from families show the merits of such work, but family efforts can be undermined by apathy and discrimination to disability from extended family, community and service providers. Asking families to be the primary support in PCP initiatives may potentially ignore the impacts of structural and psycho-emotional disablism on all family members. For families to support people with intellectual disability in PCP, there is a need to acknowledge and respond to the material, cultural and personal challenges for all family members in planning processes. PMID- 30021502 TI - Hybrid model intermediate between a laboratory and field study: A humane paradigm shift in feline research. AB - OBJECTIVES: Non-surgical contraceptives are under development to provide accessible, affordable and humane alternatives for the management of free-roaming cat populations. The objective of this project was to develop a research approach for promising non-surgical contraceptives using outbred cats in a simulated free roaming setting, meeting high standards for both animal welfare and scientific rigor. METHODS: A facility, specially constructed with indoor and outdoor living areas, was approved and regulated as both an animal shelter and a United States Department of Agriculture research facility. Thirty female and five male cats, healthy but at high risk of euthanasia, were recruited from animal shelters and private homes. Guided by a detailed protocol, cats were housed in this facility for up to 18 months after acclimatization. Cats were administered the study product or a placebo, and then entered into a breeding trial. Cats were adopted at the end of the study. A range of methods was used to provide enrichment and balance a natural environment with the need for detailed daily monitoring. RESULTS: Primary study results related to contraceptive safety and efficacy are published separately. Achieving a research model that is an intermediate step between a laboratory and an uncontained free-roaming cat colony was complex. Significant learnings shared in this current publication span: the selection of cats; acclimatization to a simulated colony environment; cat behavioral training during the study and in preparation for adoption; disease management; contract staff and volunteer support; and cat behavior throughout a breeding study. CONCLUSIONS AND RELEVANCE: This model inspires continued movement away from the paradigm of breeding cats for research and instead sources existing cats at risk for euthanasia. The housing and management of the cats elevates research animals' quality of life and provides positive post-study outcomes. While not appropriate for every feline research scenario, this hybrid model (between a laboratory and field study) proved to be a practical, humane and reliable scenario for research requiring a simulated real-world environment. PMID- 30021505 TI - APA Annual Convention Division 40 (Society for Clinical Neuropsychology) Program Summary ? August 9-12, 2018; San Francisco, CA. PMID- 30021503 TI - Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018. AB - The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence based recommendations, appropriate for use by healthcare providers and system planners caring for persons with very recent symptoms of acute stroke or transient ischemic attack. The recommendations are intended for use by a interdisciplinary team of clinicians across a wide range of settings and highlight key elements involved in prehospital and Emergency Department care, acute treatments for ischemic stroke, and acute inpatient care. The most notable changes included in this 6th edition are the renaming of the module and its integration of the formerly separate modules on prehospital and emergency care and acute inpatient stroke care. The new module, Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care is now a single, comprehensive module addressing the most important aspects of acute stroke care delivery. Other notable changes include the removal of two sections related to the emergency management of intracerebral hemorrhage and subarachnoid hemorrhage. These topics are covered in a new, dedicated module, to be released later this year. The most significant recommendation updates are for neuroimaging; the extension of the time window for endovascular thrombectomy treatment out to 24 h; considerations for treating a highly selected group of people with stroke of unknown time of onset; and recommendations for dual antiplatelet therapy for a limited duration after acute minor ischemic stroke and transient ischemic attack. This module also emphasizes the need for increased public and healthcare provider's recognition of the signs of stroke and immediate actions to take; the important expanding role of paramedics and all emergency medical services personnel; arriving at a stroke-enabled Emergency Department without delay; and launching local healthcare institution code stroke protocols. Revisions have also been made to the recommendations for the triage and assessment of risk of recurrent stroke after transient ischemic attack/minor stroke and suggested urgency levels for investigations and initiation of management strategies. The goal of this updated guideline is to optimize stroke care across Canada, by reducing practice variations and reducing the gap between current knowledge and clinical practice. PMID- 30021504 TI - Updating the amniotic fluid index nomograms according to perinatal outcome. AB - BACKGROUND: The two most commonly used nomograms for amniotic fluid index (AFI) were developed by Moore and Cayle and Magann et al. However, there are several inconsistencies between the two methods. OBJECTIVE: The aim of the study was to determine whether these differences carry clinical significance. METHODS: A retrospective cohort of women with singleton pregnancies evaluated for AFI during pregnancy at a tertiary medical center in 2007-2014 were divided into five groups: group A, definite oligohydramnios-AFI below the fifth percentile according to the nomograms of both Moore and Cayle and Magann et al.; group B, intermediate oligohydramnios-AFI below the fifth percentile according to only one nomogram (Moore and Cayle); group C, euhydramnios-normal AFI according to both nomograms; group D, intermediate polyhydramnios-AFI above the 95th percentile according to one nomogram (Magann et al.); group E, definite polyhydramnios-above the 95th percentile according to both nomograms. The association of group by maternal and perinatal outcomes was analyzed. RESULTS: A total of 6987 women were included: group A, 996 (14%); group B, 1344 (19%); group C, 2561 (37%); group D, 1051 (15%); group E, 1034 (15%). Group B (intermediate oligohydramnios) was characterized by significantly lower rates of adverse perinatal outcomes than group A (definite oligohydramnios): small for gestational age neonate (12.3 versus 15.2%, p = .05), neonatal intensive care unit admission (11.1 versus 21.5%; p < .001), composite respiratory outcome (4.8 versus 9.8%; p < .001), and neonatal sepsis (6.4 versus 10.8%; p < .001). No such differences were found between groups B and C. Group D (intermediate polyhydramnios) differed from group E (definite polyhydramnios) by lower rates of 5 minutes Apgar score <7 (1.3 versus 3.2%; p = .003), neonatal intensive care unit admission (10.9 versus 14.4%; p = .02), and major congenital anomalies (1.7 versus 5.6%; p = .02). There was no difference in these parameters between groups D and C. CONCLUSION: This study suggests that intermediate oligohydramnios and intermediate polyhydramnios are not associated with adverse perinatal outcomes. Outcome in these pregnancies is similar to pregnancies with euhydramnios. Commonly used AFI nomograms should be updated. PMID- 30021506 TI - How should we implement collaborative care for older people with depression? A qualitative study using normalisation process theory within the CASPER plus trial. AB - BACKGROUND: Depression in older people may have a prevalence as high as 20%, and is associated with physical co-morbidities, loss, and loneliness. It is associated with poorer health outcomes and reduced quality of life, and is under diagnosed and under-treated. Older people may find it difficult to speak to their GPs about low mood, and GPs may avoid identifying depression due to limited consultation time and referral options for older patients. METHODS: A qualitative study nested within a randomised controlled trial for older people with moderate to severe depression: the CASPER plus Trial (Care for Screen Positive Elders). We interviewed patient participants, GPs, and case managers (CM) to explore patients' and professionals' views on collaborative care developed for older people, and how this model could be implemented at scale. Transcripts were analysed thematically using normalization process theory. RESULTS: Thirty-three interviews were conducted. Across the three data-sets, four main themes were identified based on the main principles of the Normalization Process Theory: understanding of collaborative care, interaction between patients and professionals, liaison between GPs and case managers, and the potential for implementation. CONCLUSIONS: A telephone-delivered intervention, incorporating behavioural activation, is acceptable to older people with depression, and is deliverable by case managers. The collaborative care framework makes sense to case managers and has the potential to optimize patient outcomes, but implementation requires integration in day to day general practice. Increasing GPs' understanding of collaborative care might improve liaison and collaboration with case managers, and facilitate the intervention through better support of patients. The CASPER plus model, delivering therapy to older adults with depression by telephone, offers the potential for implementation in a resource poor health service. PMID- 30021507 TI - Factors associated with intravenous lidocaine in pediatric patients undergoing laparoscopic appendectomy - a retrospective, single-centre experience. AB - BACKGROUND: Due to its potential beneficial effects, intra- and postoperative application of intravenous lidocaine has become increasingly accepted over the last couple of years, e.g. in patients undergoing laparoscopic surgical procedures. Based on its beneficial properties, lidocaine was introduced to the standard of care for all pediatric laparoscopic procedures in our institution in mid-2016. In contrast to adult care, scarce data is available regarding the use of perioperative intravenous lidocaine administration in children undergoing laparoscopic procedures, such as an appendectomy. METHODS: Retrospective analysis of all pediatric patients undergoing laparoscopic appendectomy at the University Children's Hospital Zurich in 2016. Perioperative data, as recorded in the electronic patient data management system, were evaluated for any signs of systemic lidocaine toxicity (neurological and cardiovascular), behavioral deterioration, as well as for hemodynamic instability. Additionally, the incidence of postoperative nausea and vomiting, administration of pain rescue medication, time to hospital discharge and to first bowel movement, as well as any postoperative complications were recorded. Starting on 01/07/2016, all patients undergoing laparoscopic surgery received intravenous lidocaine (1.5 mg/kg body weight (BW) bolus after induction of anesthesia followed by continuous infusion of 1.5 mg/kgBW/h). These patients were then compared to children without lidocaine administration who had undergone laparoscopic appendectomy between 01/01/2016 and 30/06/2016. RESULTS: Data of 116 patients was analyzed. Of these, 60 patients received lidocaine. No signs of systemic toxicity, neurologic impairment or circulatory disturbances were noted in any of these patients. A (non-significant) difference in the incidence of emergence delirium was observed (0 cases in the lidocaine group vs. 4 cases in the control group, p = 0.05). CONCLUSION: This retrospective analysis did not reveal any adverse effects in pediatric patients receiving intravenous lidocaine for laparoscopic appendectomy under general anesthesia. However, further trials investigating beneficial effects as well as pharmacokinetic properties of intravenous lidocaine in children are required. PMID- 30021508 TI - Using a modified nominal group technique to develop general practice. AB - BACKGROUND: There are few areas of health care where sufficient research-based evidence exists and primary health care is no exception. In the absence of such evidence, the development of assisted support must be based on the opinions and experience of professionals with knowledge of the relevant field. The purpose of this research project is to explore how the nominal group technique can be used to establish consensus by analysing how it supported the development of structured, knowledge-based, electronic health records for preventive child health examinations in Danish general practice. METHODS: We convened an expert panel of five general practitioners with a special interest in the preventive child health examinations. We introduced the panel to the nominal group technique, a well-established, structured, multistep, facilitated, group meeting technique used to generate consensus. The panel used the technique to agree on the key clinical and socioeconomic themes to include in new electronic records for the seven preventive child health examinations in Denmark. The panel met three times over a four-month period between 2013 and 2014 and their meetings lasted between two-and-a-half and five hours. RESULTS: 1) The structured and stepwise process of the nominal group technique supported our expert panel's focus as well as their equal opportunities to speak. 2) The method's flexibility enabled participants to work as a group and in pairs to discuss and refine thematic classifications. 3) Serial meetings supported continual evaluation, critical reflection, and knowledge searches, enabling our panel to produce a template that could be adapted for all seven preventive child health examinations. CONCLUSION: The nominal group technique proved to be a useful method for reaching consensus by identifying key quality markers for use in daily clinical practice. Our study focused on the development of content and a layout for systematic, knowledge-based, electronic health records. We recommend the method as a suitable working tool for dealing with complex questions in general practice or similar settings, and we present and discuss modifications to the original model. PMID- 30021509 TI - Novel oral anticoagulants in primary care in patients with atrial fibrillation: a cross-sectional comparison before and after their introduction. AB - BACKGROUND: Novel oral anticoagulation (NOAC) has been introduced in recent years, but data on use in atrial fibrillation (AF) in primary care setting is scarce. In Germany, General Practitioners are free to choose type of oral anticoagulation (OAC) in AF. Our aim was to explore changes in prescription-rates of OAC in German primary care before and after introduction of NOAC on the market. METHODS: Data of a representative morbidity registration project in primary care in Germany (CONTENT) were analysed. Patients with AF in 2011 or 2014 were included (before and after broad market authorization of NOAC, respectively). We defined three independent groups: patients from 2011 without follow-up (group A), patients from 2014 but without previous record in 2011 (group B) and patients with AF and records in 2011 and 2014 (group C). RESULTS: 2642 patients were included. Group A (n = 804) and B (n = 755) were comparable regarding patient characteristics. 87.3% of group A and 84.8% of group B had CHA2DS2-VASc-Score >= 2, indicating a need for oral anticoagulation (OAC). Prescription of OAC increased from 23.1% (n = 186) to 42.8% (n = 323, p < .01) with stable use of vitamin-k-antagonist (22.6-24.9%). NOAC increased from 0.6 to 19.2% (p < .01). Monotherapy with Acetylsalicylic acid (ASA) decreased from 15.3% (n = 123) to 8.2% (n = 62, p < .01). In group C (n = 1083), OAC increased from 35.3 to 55.4% (p < .01), with stable prescription rate of vitamin-k-antagonist (34.4-35.7%). NOAC increased from 0.9 to 21.5% (p < .01). CONCLUSIONS: In summary, our study showed a significant increase of OAC over time, which is fostered by the use of NOAC but with a stable rate of VKA and a sharp decrease of ASA. Patients on VKA are rarely switched to NOAC, but new patients with AF are more likely to receive NOAC. PMID- 30021510 TI - Challenges in providing maternity care in remote areas and islands for primary care physicians in Japan: a qualitative study. AB - BACKGROUND: Maintaining a maternity care system is one of the biggest issues in Japan due to the decreasing number of obstetricians, especially in remote areas and islands. The aim of this qualitative study was to explore the challenges in women's health and maternity care in remote areas and islands for primary care physicians and obstetricians in order to provide an insight necessary to develop a better health care system. METHODS: We conducted semi-structured interviews with 13 primary care physicians and 4 obstetricians practicing maternity care at clinics/hospitals in remote areas and islands across Japan. Interview data were analyzed, using the modified Grounded Theory Approach, to elucidate the challenges primary care physicians faced in their practice. RESULTS: Primary care physicians who engaged in maternity care recognized the following challenges: low awareness of primary care, lack of training opportunities, unclear goal of the training, lack of certification system, lack of consultation system, and lack of obstetricians to offer support. These six challenges along with the specialty's factors such as sudden changes of patients' condition were considered to result to the provider's hesitation and anxiety to engage in the practice. CONCLUSIONS: This study found six environmental/systemic factors and three specialty's factors as the main challenges for primary care physicians in providing maternity care in remote areas and islands for primary care physicians in Japan. Increasing the awareness of primary care and developing a maternity care training program to certify primary care physicians may enable more primary care physicians to engage in and provide women's health and maternity care in remote areas and islands. PMID- 30021511 TI - Association of prenatal and childhood environment smoking exposure with puberty timing: a systematic review and meta-analysis. AB - OBJECTIVES: Mothers who smoke during pregnancy or while their children are small were common in some populations. Epidemiological studies have tried to detect the effect of prenatal tobacco smoke (PTS), and childhood environmental tobacco smoke (ETS) on puberty timing have not shown a consensus results. We aimed to examine current evidence and estimate the associations between PTS or/and ETS and puberty timing. METHODS: Seven databases were searched from inception to May 2017. All the cohort studies examining the associations between PTS and/or ETS and puberty timing were identified. Two reviewers independently screened all studies, evaluated the quality of eligible studies, and extracted the data. The quality assessment of the eligible cohort studies was based on the Newcastle-Ottawa Scale. Risk ratio (RR), standard mean difference (SMD), and 95% confidence intervals (CIs) were calculated and pooled by CMA (Version 2.0, Biostat, Inc., USA). RESULTS: Compared with controls, girls with PTS and ETS exposure have an earlier age at menarche (SMD - 0.087, 95% CI 0.174 to - 0.000), and similar results were found in both PTS subgroup (SMD - 0.097, 95% CI - 0.192 to - 0.002) and prospective cohort subgroup (SMD - 0.171, 95% CI - 0.253 to - 0.090). And number of boys with early voice break in PTS group was significantly increasing than non-exposed boys (RR 1.34, 95% CI 1.29 to 1.40). CONCLUSIONS: PTS exposure possibly decrease age of menarche of girls, and studies on boys were urgent needed. Appropriate and comprehensive outcome measures using unified criteria to classify puberty should be reported in future studies. PMID- 30021513 TI - De novo assembly of bacterial genomes with repetitive DNA regions by dnaasm application. AB - BACKGROUND: Many organisms, in particular bacteria, contain repetitive DNA fragments called tandem repeats. These structures are restored by DNA assemblers by mapping paired-end tags to unitigs, estimating the distance between them and filling the gap with the specified DNA motif, which could be repeated many times. However, some of the tandem repeats are longer than the distance between the paired-end tags. RESULTS: We present a new algorithm for de novo DNA assembly, which uses the relative frequency of reads to properly restore tandem repeats. The main advantage of the presented algorithm is that long tandem repeats, which are much longer than maximum reads length and the insert size of paired-end tags can be properly restored. Moreover, repetitive DNA regions covered only by single read sequencing data could also be restored. Other existing de novo DNA assemblers fail in such cases. The presented application is composed of several steps, including: (i) building the de Bruijn graph, (ii) correcting the de Bruijn graph, (iii) normalizing edge weights, and (iv) generating the output set of DNA sequences. We tested our approach on real data sets of bacterial organisms. CONCLUSIONS: The software library, console application and web application were developed. Web application was developed in client-server architecture, where web browser is used to communicate with end-user and algorithms are implemented in C++ and Python. The presented approach enables proper reconstruction of tandem repeats, which are longer than the insert size of paired-end tags. The application is freely available to all users under GNU Library or Lesser General Public License version 3.0 (LGPLv3). PMID- 30021512 TI - Mesenchymal stromal cells attenuate sevoflurane-induced apoptosis in human neuroglioma H4 cells. AB - BACKGROUND: Inhalation of sevoflurane can induce neuronal apoptosis, cognitive impairment and abnormal behaviors. Bone marrow mesenchymal stem cells (MSCs) can secret neurotrophic factors and cytokines to protect from oxidative stress related neuronal apoptosis. However, whether MSCs can protect from sevoflurane induced neuronal apoptosis and the potential mechanisms are unclear. METHODS: A non-contact co-culture of MSCs with human neuroglioma H4 cells (H4 cells) was built. H4 cells were co-cultured with MSCs or without MSCs (control) for 24 h. The co-cultured H4 cells were exposed to 4% sevoflurane for 6 h. The levels of caspase-3, reactive oxygen species (ROS), adenosine triphosphate (ATP), and the release of cytochrome C were determined by Western blot and fluorescence assay. RESULTS: Sevoflurane exposure significantly elevated the levels of cleaved caspase 3 and Bax in H4 cells. However, these phenomena were significantly offset by the co-culture with MSCs in H4 cells. Co-culture with MSCs before, but not after, sevoflurane exposure, significantly attenuated sevoflurane-induced ROS production in H4 cells. MSCs prevented sevoflurane-mediated release of cytochrome C from the mitochondria and production of ATP in H4 cells. CONCLUSIONS: Our study indicated that soluble factors secreted by MSCs attenuated the sevoflurane induced oxidative stress and apoptosis of neuronal cells by preserving their mitochondrial function. PMID- 30021514 TI - The analgesic efficacy of intravenous regional anesthesia with a forearm versus conventional upper arm tourniquet: a systematic review. AB - BACKGROUND: The main objective of this review is to perform a systematic review and meta-analysis of the existing evidence related to the analgesic efficacy with the use of conventional, upper arm intravenous regional anesthesia (IVRA) as compared to a modified, forearm IVRA in adult patients undergoing procedures on the distal upper extremity. METHODS: MEDLINE, EMBASE and CENTRAL (Cochrane) databases were searched for randomized controlled trials published in English, French, Dutch, German or Spanish language. Primary outcomes of interest including description of quality level of anesthesia and onset of sensory block were assessed for this review. Dosage of the local anesthetic, local anesthetic toxicity and need for sedation due to tourniquet pain were considered as secondary outcomes. RESULTS: Our literature search yielded 3 papers for qualitative synthesis. Four other articles were added into a parallel analysis of 7 reports that provided data on the incidence of complications and success rate after forearm IVRA. Forearm IVRA was found to be as efficient as upper arm IVRA (RR = 0.98 [0.93, 1.05], P = 0.78), but comes with the advantage of a lower need for sedation due to less tourniquet pain. CONCLUSION: Our results demonstrate that forearm IVRA is as effective in providing a surgical block as compared to a conventional upper arm IVRA, even with a reduced, non-toxic dosage of local anesthetic. No severe complications were associated with the use of a forearm IVRA. Other benefits of the modified technique include a faster onset of sensory block, better tourniquet tolerance and a dryer surgical field. REGISTRATION OF THE SYSTEMATIC REVIEW: A review protocol was published in the PROSPERO register in November 2015 with registration number CRD42015029536 . PMID- 30021515 TI - Increased expression of the Cbl family of E3 ubiquitin ligases decreases Interleukin-2 production in a rat model of peripheral neuropathy. AB - BACKGROUND: Interleukin 2 (IL-2) influences the development and severity of pain due to its antinociceptive and immunomodulatory effects. Its production is influenced by the increased expression of c-Cbl (Casitas B-lineage lymphoma proto oncogene) and Cbl-b E3 ubiquitin ligases. We evaluated the effects on IL-2 mediated changes in c-Cbl and Cbl-b expression in a rat model of chronic neuropathic pain. METHODS: Peripheral neuropathy was induced in adult male Sprague-Dawley rats weighing 250-300 g by chronic spinal nerve ligation. Half of the spinal cord ipsilateral to the nerve injury was harvested at 1, 3, and 6 weeks, and the expression levels of IL-2, c-Cbl, Cbl-b, phospholipase C-gamma1 (PLC-gamma1), ZAP70, and protein kinase Ctheta (PKCtheta), as well as ubiquitin conjugation, were evaluated. RESULTS: Total IL-2 mRNA levels were significantly decreased at 3 and 6 weeks after nerve injury compared to those in sham-operated rats. The mRNA levels of c-Cbl and Cbl-b, as well as the level of ubiquitin conjugation, were significantly increased at 3 and 6 weeks. In contrast, the levels of phosphorylated ZAP70 and PLC-gamma1 were decreased at 3 and 6 weeks after spinal nerve ligation. Ubiquitination of PLC-gamma1 and PKCtheta was increased at 3 and 6 weeks. CONCLUSIONS: Our results suggest that ubiquitin and the E3 ubiquitin ligases c-Cbl and Cbl-b function as neuroimmune modulators in the subacute phase of neuropathic pain after nerve injury. PMID- 30021516 TI - Divergence times in demosponges (Porifera): first insights from new mitogenomes and the inclusion of fossils in a birth-death clock model. AB - BACKGROUND: Approximately 80% of all described extant sponge species belong to the class Demospongiae. Yet, despite their diversity and importance, accurate divergence times are still unknown for most demosponge clades. The estimation of demosponge divergence time is key to answering fundamental questions on the origin of Demospongiae, their diversification and historical biogeography. Molecular sequence data alone is not informative on an absolute time scale, and therefore needs to be "calibrated" with additional data such as fossils. Here, we calibrate the molecular data with the fossilized birth-death model, which compared to strict node dating, allows for the inclusion of young and old fossils in the analysis of divergence time. We use desma-bearing sponges, a diverse group of demosponges that form rigid skeletons and have a rich and continuous fossil record dating back to the Cambrian (~500 Ma), to date the demosponge radiation and constrain the timing of key evolutionary events, like the transition from marine to freshwater habitats. To infer a dated phylogeny of Demospongiae we assembled the mitochondrial genomes of six desma-bearing demosponges from reduced representation genomic libraries. The total dataset included 33 complete demosponge mitochondrial genomes and 30 fossils. RESULTS: Our study supports a Neoproterozoic origin of Demospongiae. Novel age estimates for the split of freshwater and marine sponges dating back to the Carboniferous and the previously assumed recent (~18 Ma) diversification of freshwater sponges is supported. Moreover, we provide detailed age estimates for a possible diversification of Tetractinellidae (~315 Ma), the Astrophorina (~240 Ma), the Spirophorina (~120 Ma) and the family Corallistidae (~188 Ma) all of which are considered as key groups for dating the Demospongiae due to their extraordinary rich and continuous fossil history. CONCLUSION: This study provides novel insights into the evolution of Demospongiae. Observed discrepancies of our dated phylogeny with their putative first fossil appearance dates are discussed for selected sponge groups. For instance, a Carboniferous origin of the order Tetractinellida seems to be too late, compared to their first appearance in the fossil record in the Middle Cambrian. This would imply that Paleozoic spicule forms are not homologous to post-Paleozoic forms. PMID- 30021517 TI - Shoelaces: an interactive tool for ribosome profiling processing and visualization. AB - BACKGROUND: The emergence of ribosome profiling to map actively translating ribosomes has laid the foundation for a diverse range of studies on translational regulation. The data obtained with different variations of this assay is typically manually processed, which has created a need for tools that would streamline and standardize processing steps. RESULTS: We present Shoelaces, a toolkit for ribosome profiling experiments automating read selection and filtering to obtain genuine translating footprints. Based on periodicity, favoring enrichment over the coding regions, it determines the read lengths corresponding to bona fide ribosome protected fragments. The specific codon under translation (P-site) is determined by automatic offset calculations resulting in sub-codon resolution. Shoelaces provides both a user-friendly graphical interface for interactive visualisation in a genome browser-like fashion and a command line interface for integration into automated pipelines. We process 79 libraries and show that studies typically discard excessive amounts of quality data in their manual analysis pipelines. CONCLUSIONS: Shoelaces streamlines ribosome profiling analysis offering automation of the processing, a range of interactive visualization features and export of the data into standard formats. Shoelaces stores all processing steps performed in an XML file that can be used by other groups to exactly reproduce the processing of a given study. We therefore anticipate that Shoelaces can aid researchers by automating what is typically performed manually and contribute to the overall reproducibility of studies. The tool is freely distributed as a Python package, with additional instructions, tutorial and demo datasets available at https://bitbucket.org/valenlab/shoelaces . PMID- 30021518 TI - Design of the Weight-loss Endoscopy Trial (WET): a multi-center, randomized, controlled trial comparing weight loss in endoscopically implanted duodenal jejunal bypass liners vs. intragastric balloons vs. a sham procedure. AB - BACKGROUND: Obesity is a global problem leading to reduced life expectancy, cardiovascular diseases, diabetes and many types of cancer. Even people willing to accept treatment only achieve a mean weight loss of about 5 kg using commercial weight loss programs. Surgical interventions, e.g. sleeve gastrectomy or gastric bypass are effective but accompanied by risk of serious complications and side effects. Less invasive endoscopic procedures mainly comprise the intragastric balloon (IB) and the duodenal-jejunal bypass liner (DJBL). To date, a randomized comparison between these devices has not been undertaken or shown to be superior to a sham procedure. METHODS: We designed a multi-center, randomized, patient and assessor-blinded, controlled trial comparing weight loss in endoscopically implanted IB vs. DJBL vs. a sham procedure. A total of 150 patients with a BMI > 35 kg/m2 or > 30 with obesity-related comorbidities and indication for proton pump inhibitors are randomized to receive either IB, DJBL or a sham gastroscopy (2:2:1 ratio). All participants undergo regular dietary consultation. The IB will be removed after 6 months, whereas the DJBL will be explanted after 12 months. All patients will receive gastroscopies at implantation and explantation of the devices or sedation without gastroscopy to maintain blinding. Main exclusion criteria are malignant diseases, peptic ulcer or previous bariatric intervention. Weight loss 12 months after explantation of the devices, changes in comorbidities, quality of life, complication rates and safety will be evaluated. DISCUSSION: This trial could help to identify the most effective and safest endoscopic device, thus determining the new standard procedure for endoscopic bariatric treatment. TRIAL REGISTRATION: 16th January 2017. DRKS00011036. Funded by the German Research Foundation (DFG). PMID- 30021520 TI - Survey of postoperative pain control in different types of hospitals: a multicenter observational study. AB - BACKGROUND: Current pain assessment and treatment does not address every patient's requirements. Although the Polish national guidelines for post operative pain management have been published, many patients experience severe pain in the postoperative period. The main goal of our study was to assess pain severity among patients from different types of hospitals (primary, secondary, and tertiary centers) after similar types of surgeries. We also aimed to determine if there were any differences in pain severity associated with anesthesia technique, type of surgery, and the patient's age and sex. METHODS: This was a prospective, observational study. A questionnaire form was used to collect demographic data, type of hospital, surgery, anesthesia, and patient satisfaction of pain control in the postoperative period. The visual analogue scale (VAS) was used to measure pain severity at four time points after surgery (4, 8, 12, and 24 h). RESULTS: The study was conducted from November 2015 to June 2016 in seven hospitals in Eastern Poland, and 269 women and 293 men participated. At the 4-h measurement, 39.32% of patients assessed the pain as moderate and 19.75% as severe. A difference was found in pain intensity between patients treated in primary and secondary hospitals. Vascular surgery patients had the lowest pain intensity (19 (13-26)), especially in comparison to those undergoing thoracic surgery (30 (27-33)). A sudden elevation in pain severity among patients anesthetized with single-shot spinal technique was observed. Only 4.9% of participants received strong opioids during the first 24 h after surgery. CONCLUSIONS: Postoperative pain control seems to be unexpectedly poor after single-shot subarachnoid anesthesia. Despite concerns, the use of analgesics may be insufficient in some groups of patients. Our study indicates new variables that influence the severity of pain, such as operated region, anesthetic technique, and type of surgical department. The results obtained in our study are in discrepancy with recommendations presented by the national guidelines for post operative pain management. PMID- 30021519 TI - Genome-wide analysis of genes encoding core components of the ubiquitin system in soybean (Glycine max) reveals a potential role for ubiquitination in host immunity against soybean cyst nematode. AB - BACKGROUND: Ubiquitination is a major post-translational protein modification that regulates essentially all cellular and physiological pathways in eukaryotes. The ubiquitination process typically involves three distinct classes of enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3). To date, a comprehensive identification and analysis of core components comprising of the whole soybean (Glycine max) ubiquitin system (UBS) has not been reported. RESULTS: We performed a systematic, genome-wide analysis of genes that encode core members of the soybean UBS in this study. A total of 1431 genes were identified with high confidence to encode putative soybean UBS components, including 4 genes encoding E1s, 71 genes that encode the E2s, and 1356 genes encoding the E3-related components. Among the E3-encoding genes, 760 encode RING-type E3s, 124 encode U-box domain-containing E3s, and 472 encode F box proteins. To find out whether the identified soybean UBS genes encode active enzymes, a set of genes were randomly selected and the enzymatic activities of their recombinant proteins were tested. Thioester assays indicated proteins encoded by the soybean E1 gene GmUBA1 and the majority of selected E2 genes are active E1 or E2 enzymes, respectively. Meanwhile, most of the purified RING and U box domain-containing proteins displayed E3 activity in the in vitro ubiquitination assay. In addition, 1034 of the identified soybean UBS genes were found to express in at least one of 14 soybean tissues examined and the transcript level of 338 soybean USB genes were significantly changed after abiotic or biotic (Fusarium oxysporum and Rhizobium strains) stress treatment. Finally, the expression level of a large number of the identified soybean UBS related genes was found significantly altered after soybean cyst nematode (SCN) treatment, suggesting the soybean UBS potentially plays an important role in soybean immunity against SCN. CONCLUSIONS: Our findings indicate the presence of a large and diverse number of core UBS proteins in the soybean genome, which suggests that target-specific modification by ubiquitin is a complex and important part of cellular and physiological regulation in soybean. We also revealed certain members of the soybean UBS may be involved in immunity against soybean cyst nematode (SCN). This study sets up an essential foundation for further functional characterization of the soybean UBS in various physiological processes, such as host immunity against SCN. PMID- 30021521 TI - Nutritional ketosis delays the onset of isoflurane induced anesthesia. AB - BACKGROUND: Ketogenic diet (KD) and exogenous ketone supplements can evoke sustained ketosis, which may modulate sleep and sleep-like effects. However, no studies have been published examining the effect of ketosis on the onset of general isoflurane induced anesthesia. Therefore, we investigated the effect of the KD and different exogenous ketogenic supplements on the onset of akinesia induced by inhalation of isoflurane. METHODS: We used a high fat, medium protein and low carbohydrate diet (KD) chronically (10 weeks) in the glucose transporter 1 (GLUT1) deficiency (G1D) syndrome mice model and sub-chronically (7 days) in Sprague-Dawley (SPD) rats. To investigate the effect of exogenous ketone supplements on anesthetic induction we also provided either 1) a standard rodent chow diet (SD) mixed with 20% ketone salt supplement (KS), or 2) SD mixed with 20% ketone ester supplement (KE; 1,3 butanediol-acetoacetate diester) to G1D mice for 10 weeks. Additionally, SPD rats and Wistar Albino Glaxo Rijswijk (WAG/Rij) rats were fed the SD, which was supplemented by oral gavage of KS or KE for 7 days (SPD rats: 5 g/kg body weight/day; WAG/Rij rats: 2.5 g/kg body weight/day). After these treatments (10 weeks for the mice, and 7 days for the rats) isoflurane (3%) was administered in an anesthesia chamber, and the time until anesthetic induction (time to immobility) was measured. Blood ketone levels were measured after anesthetic induction and correlation was calculated for blood beta hydroxybutyrate (betaHB) and anesthesia latency. RESULTS: Both KD and exogenous ketone supplementation increased blood ketone levels and delayed the onset of isoflurane-induced immobility in all investigated rodent models, showing positive correlation between the two measurements. These results demonstrate that elevated blood ketone levels by either KD or exogenous ketones delayed the onset of isoflurane-induced anesthesia in these animal models. CONCLUSIONS: These findings suggest that ketone levels might affect surgical anesthetic needs, or could potentially decrease or delay effects of other narcotic gases. PMID- 30021522 TI - Disentangling the drivers of diversification in an imperiled group of freshwater fishes (Cyprinodontiformes: Goodeidae). AB - BACKGROUND: One of the most perplexing questions in evolutionary biology is why some lineages diversify into many species, and others do not. In many cases, ecological opportunity has played an important role, leading to diversification along trophic or habitat-based axes. The Goodeidae (Teleostomi: Cyprinodontiformes) are a family of freshwater fishes with two subfamilies: Goodeinae (42 species, viviparous, heterogeneous habitats, Mesa Central of Mexico) and Empetrichthyinae (4 species, oviparous, homogeneous habitats, Great Basin of the United States). These discrepant sets of characteristics and their sister-group relationship make the goodeids amenable to a comparative study of diversification. We gathered lateral body images from more than 1600 specimens of all extant species in the family. Geometric morphometric, and phylogenetic comparative analyses were used to address whether higher species diversity correlates with higher rates of morphological shape evolution and whether there are differences in functional/habitat modules between the two subfamilies. RESULTS: This study recovered a higher rate of overall body shape evolution in the Goodeinae that is nearly double in magnitude compared to the Empetrichthyinae. A modularity test indicated that the Goodeinae displayed elevated rates of morphological evolution in comparison to the Empetrichthyinae when only trunk (locomotor) regions were compared between subfamilies. No significant differences in evolutionary shape rates were recovered when the trophic (head) regions were compared between subfamilies. DISCUSSION: These results support the hypothesis that Mexican goodeids radiated via an ecological opportunity scenario into a wide-array of novel habitats in the island-like Mesa Central as evidenced by their high rate of shape evolution, relative to the Empetrichthyinae. This study quantitatively unraveled the drivers of evolution and eliminated trophic specialization as a driving force within the Goodeidae. CONCLUSIONS: A combination of phylogenetic and morphometric data, and phylogenetic comparative analyses were used to examine body shape rate evolution within the Goodeidae. Results support the hypothesis that species in the subfamily Goodeinae on the central Mexican plateau had a higher rate of body shape evolution relative to its sister subfamily Empetrichthyinae in the Great Basin suggesting that the Goodeinae diversified via an ecological opportunity scenario along habitat, rather than trophic axes. PMID- 30021523 TI - Contemporary ancestor? Adaptive divergence from standing genetic variation in Pacific marine threespine stickleback. AB - BACKGROUND: Populations that have repeatedly colonized novel environments are useful for studying the role of ecology in adaptive divergence - particularly if some individuals persist in the ancestral habitat. Such "contemporary ancestors" can be used to demonstrate the effects of selection by comparing phenotypic and genetic divergence between the derived population and their extant ancestors. However, evolution and demography in these "contemporary ancestors" can complicate inferences about the source (standing genetic variation, de novo mutation) and pace of adaptive divergence. Marine threespine stickleback (Gasterosteus aculeatus) have colonized freshwater environments along the Pacific coast of North America, but have also persisted in the marine environment. To what extent are marine stickleback good proxies of the ancestral condition? RESULTS: We sequenced > 5800 variant loci in over 250 marine stickleback from eight locations extending from Alaska to California, and phenotyped them for platedness and body shape. Pairwise FST varied from 0.02 to 0.18. Stickleback were divided into five genetic clusters, with a single cluster comprising stickleback from Washington to Alaska. Plate number, Eda, body shape, and candidate loci showed evidence of being under selection in the marine environment. Comparisons to a freshwater population demonstrated that candidate loci for freshwater adaptation varied depending on the choice of marine populations. CONCLUSIONS: Marine stickleback are structured into phenotypically and genetically distinct populations that have been evolving as freshwater stickleback evolved. This variation complicates their usefulness as proxies of the ancestors of freshwater populations. Lessons from stickleback may be applied to other "contemporary ancestor"-derived population studies. PMID- 30021524 TI - Do older individuals who are diagnosed with cancer have worse physical performance prior to diagnosis compared to matched controls? A longitudinal cohort study. AB - BACKGROUND: Impaired physical performance is highly prevalent in older cancer patients and is associated with cancer-related outcomes such as mortality and chemotherapy-related toxicity. Physical performance might already decline prior to the cancer diagnosis due to undiagnosed disease. This study aimed to assess whether the physical performance of community-dwelling individuals prior to cancer diagnosis is worse compared to matched controls who are not diagnosed with cancer. METHODS: The study sample was selected from the Longitudinal Aging Study Amsterdam, a longitudinal study on a nationally representative sample of the Dutch older population. Physical performance of initially cancer-free individuals aged 55-84 years who were diagnosed with cancer during 10 or 20 years of follow up was compared to the physical performance of controls who were not diagnosed with cancer. For controls, the physical performance measurements of the cycle with a median age closest to the cancer group were used. The time interval between physical performance measurements and the report of cancer was 2 to 4 years. Groups were compared using logistic and linear regression analysis. RESULTS: The study sample included 1735 individuals with a median age of 68.7 [interquartile range 63.3-76.4] years. During follow-up, 414 (23.9%) individuals were diagnosed with cancer. Handgrip strength, gait speed, chair stand ability, chair stand test time and ability to put on and take off a cardigan did not differ between groups. Individuals prior to cancer diagnosis were more likely to complete the tandem balance test. CONCLUSIONS: Physical performance of individuals 2 to 4 years prior to report of cancer diagnosis is not lower compared to controls. This suggests that physical performance may not be influenced by cancer before diagnosis. PMID- 30021525 TI - A novel non sense mutation in WDR62 causes autosomal recessive primary microcephaly: a case report. AB - BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by a reduced head circumference at birth with no remarkable anomalies of brain architecture and variable degrees of intellectual impairment. Clinical and genetic heterogeneity in genetic disorders represent a major diagnostic challenge. CASE PRESENTATION: Two patients, 11 and 9 years old, born from consanguineous parents, were referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of MCPH was made, based on reduced head circumference without brain architecture abnormalities. The two patients were subject to the whole-exome sequencing, which allowed to diagnose a novel homozygous mutation c.1027C > T; p.Gln343* in exon 8 of WDR62, a gene already known to be related to MCPH. Sanger sequencing confirmed the segregation of the mutation in the family. CONCLUSION: Our data expends the spectrum of mutations in WDR62 gene, proves the efficiency and cost-effectiveness of whole exome sequencing for the molecular diagnosis of genetically heterogeneous disorders such MCPH. Exome sequencing led to the rapid and cost-effective identification of a novel homozygous mutation in WDR62 gene, thereby facilitating genetic counseling. PMID- 30021526 TI - Pulmonary blastomycosis presenting as primary lung cancer. AB - BACKGROUND: Blastomycosis is an endemic mycosis in North America that is caused by the dimorphic fungus Blastomyces dermatitidis. The illness is a systemic disease with a wide variety of pulmonary and extra-pulmonary manifestations. The initial presentation of blastomycosis may easily be mistaken for other infectious or non-infectious etiologies. CASE PRESENTATION: We present the case of a 52-year old African-American male and former smoker that presented to his primary care provider with a 2-week history of non-productive cough, night sweats and weight loss. Initially diagnosed with primary lung malignancy, the patient was subsequently found to have pulmonary blastomycosis mimicking lung cancer. The patient underwent a successful course of treatment with posaconazole. CONCLUSIONS: Chronic blastomycosis can present with clinical and radiographic features indistinguishable from thoracic malignancies. There is no clinical syndrome specific for blastomycosis, thus a high degree of suspicion is required for early diagnosis. In this case report, we review recent evidence in radiographic features, diagnostic considerations and treatment of the disease. PMID- 30021527 TI - Supporting shared decision making for older people with multiple health and social care needs: a realist synthesis. AB - BACKGROUND: Health care systems are increasingly moving towards more integrated approaches. Shared decision making (SDM) is central to these models but may be complicated by the need to negotiate and communicate decisions between multiple providers, as well as patients and their family carers; particularly for older people with complex needs. The aim of this review was to provide a context relevant understanding of how interventions to facilitate SDM might work for older people with multiple health and care needs, and how they might be applied in integrated care models. METHODS: Iterative, stakeholder driven, realist synthesis following RAMESES publication standards. It involved: 1) scoping literature and stakeholder interviews (n = 13) to develop initial programme theory/ies, 2) systematic searches for evidence to test and develop the theories, and 3) validation of programme theory/ies with stakeholders (n = 11). We searched PubMed, The Cochrane Library, Scopus, Google, Google Scholar, and undertook lateral searches. All types of evidence were included. RESULTS: We included 88 papers; 29 focused on older people or people with complex needs. We identified four context-mechanism-outcome configurations that together provide an account of what needs to be in place for SDM to work for older people with complex needs. This includes: understanding and assessing patient and carer values and capacity to access and use care, organising systems to support and prioritise SDM, supporting and preparing patients and family carers to engage in SDM and a person centred culture of which SDM is a part. Programmes likely to be successful in promoting SDM are those that allow older people to feel that they are respected and understood, and that engender confidence to engage in SDM. CONCLUSIONS: To embed SDM in practice requires a radical shift from a biomedical focus to a more person-centred ethos. Service providers will need support to change their professional behaviour and to better organise and deliver services. Face to face interactions, permission and space to discuss options, and continuity of patient professional relationships are key in supporting older people with complex needs to engage in SDM. Future research needs to focus on inter-professional approaches to SDM and how families and carers are involved. PMID- 30021528 TI - Polypharmacy in older patients with chronic diseases: a cross-sectional analysis of factors associated with excessive polypharmacy. AB - BACKGROUND: Polypharmacy is common in older people and associated with potential harms. The aim of this study was to analyse the characteristics of an older multimorbid population with polypharmacy and to identify factors contributing to excessive polypharmacy in these patients. METHODS: This cross-sectional analysis is based on the PRIMA-eDS trial, a large randomised controlled multicentre study of polypharmacy in primary care. Patients' baseline data were used for analysis. A number of socioeconomic and medical data as well as SF-12-scores were entered into a generalized linear mixed model to identify variables associated with excessive polypharmacy (taking >=10 substances daily). RESULTS: Three thousand nine hundred four participants were recruited. Risk factors significantly associated with excessive polypharmacy were frailty (OR 1.45; 95% CI 1.22-1.71), > 8 diagnoses (OR 2.64; 95% CI 2.24-3.11), BMI >=30 (OR 1.18; 95% CI 1.02-1.38), a lower SF-12 physical health composite score (OR 1.47; 95% CI 1.26-1.72), and a lower SF-12 mental health composite score (OR 1.33; 95% CI 1.17-1.59) than the median of the study population (<=36.6 and <= 48.7, respectively). Age >= 85 years (OR 0.83; 95% CI 0.70-0.99) led to a significantly lower risk for excessive polypharmacy. No association with excessive polypharmacy could be found for female sex, low educational level, and smoking. Regarding the study centres, being recruited in the UK led to a significantly higher risk for excessive polypharmacy compared to being recruited in Germany 1/Rostock (OR 1.71; 95% CI 1.27-2.30). Being recruited in Germany 2/Witten led to a slightly significant lower risk for excessive polypharmacy compared to Germany 1/Rostock (OR 0.74; 95% CI 0.56-0.97). CONCLUSIONS: Frailty, multimorbidity, obesity, and decreased physical as well as mental health status are risk factors for excessive polypharmacy. Sex, educational level, and smoking apparently do not seem to be related to excessive polypharmacy. Physicians should especially pay attention to their frail, obese patients who have multiple diagnoses and a decreased health related quality of life, to check carefully whether all the drugs prescribed are evidence-based, safe, and do not interact in an unfavourable way. TRIAL REGISTRATION: This trial has been registered with Current Controlled Trials Ltd. on 31 July 2014 (ISRCTN10137559). PMID- 30021529 TI - Association between tongue pressure and subclinical carotid atherosclerosis in relation to platelet levels in hypertensive elderly men: a cross-sectional study. AB - BACKGROUND: Age-related low-grade inflammation causing endothelial disruption influences sarcopenia, hypertension, and atherosclerosis. We reported previously that maintenance of muscle strength in elderly hypertensive men with high platelet levels is positively associated with subclinical atherosclerosis but not in those with low platelet levels. Since reduced tongue pressure is related to sarcopenia, tongue pressure may be associated with subclinical carotid atherosclerosis in hypertensive elderly subjects, and platelet levels may function as an indicator of the association between tongue pressure and subclinical carotid atherosclerosis. METHODS: We conducted a cross-sectional study of 342 hypertensive elderly Japanese men aged 60-89 who participated in an annual health check-up in 2015 and 2016. Subclinical carotid atherosclerosis was defined as a common carotid intima-media thickness (CIMT) of 1.1 mm or more. RESULTS: In the overall study population, 171 subjects demonstrated low platelets (< 21.4 * 104/MUL). Tongue pressure was significantly inversely associated with subclinical carotid atherosclerosis in these subjects, but not in subjects with high platelets. The known cardiovascular risk factor adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of subclinical carotid atherosclerosis for a 1 standard deviation (SD) increment in tongue pressure (10.4 kPa) were 0.54 (0.35, 0.85) and 1.31 (0.87, 1.96), respectively. CONCLUSION: Tongue pressure is inversely associated with subclinical carotid atherosclerosis in hypertensive elderly men with low platelet levels, but not in those with high levels. This finding may thus constitute an efficient tool for clarifying the background mechanism of age-related diseases such as sarcopenia, hypertension, and atherosclerosis. PMID- 30021530 TI - De novo profile generation based on sequence context specificity with the long short-term memory network. AB - BACKGROUND: Long short-term memory (LSTM) is one of the most attractive deep learning methods to learn time series or contexts of input data. Increasing studies, including biological sequence analyses in bioinformatics, utilize this architecture. Amino acid sequence profiles are widely used for bioinformatics studies, such as sequence similarity searches, multiple alignments, and evolutionary analyses. Currently, many biological sequences are becoming available, and the rapidly increasing amount of sequence data emphasizes the importance of scalable generators of amino acid sequence profiles. RESULTS: We employed the LSTM network and developed a novel profile generator to construct profiles without any assumptions, except for input sequence context. Our method could generate better profiles than existing de novo profile generators, including CSBuild and RPS-BLAST, on the basis of profile-sequence similarity search performance with linear calculation costs against input sequence size. In addition, we analyzed the effects of the memory power of LSTM and found that LSTM had high potential power to detect long-range interactions between amino acids, as in the case of beta-strand formation, which has been a difficult problem in protein bioinformatics using sequence information. CONCLUSION: We demonstrated the importance of sequence context and the feasibility of LSTM on biological sequence analyses. Our results demonstrated the effectiveness of memories in LSTM and showed that our de novo profile generator, SPBuild, achieved higher performance than that of existing methods for profile prediction of beta-strands, where long-range interactions of amino acids are important and are known to be difficult for the existing window-based prediction methods. Our findings will be useful for the development of other prediction methods related to biological sequences by machine learning methods. PMID- 30021531 TI - Enigmatic Diphyllatea eukaryotes: culturing and targeted PacBio RS amplicon sequencing reveals a higher order taxonomic diversity and global distribution. AB - BACKGROUND: The class Diphyllatea belongs to a group of enigmatic unicellular eukaryotes that play a key role in reconstructing the morphological innovation and diversification of early eukaryotic evolution. Despite its evolutionary significance, very little is known about the phylogeny and species diversity of Diphyllatea. Only three species have described morphology, being taxonomically divided by flagella number, two or four, and cell size. Currently, one 18S rRNA Diphyllatea sequence is available, with environmental sequencing surveys reporting only a single partial sequence from a Diphyllatea-like organism. Accordingly, geographical distribution of Diphyllatea based on molecular data is limited, despite morphological data suggesting the class has a global distribution. We here present a first attempt to understand species distribution, diversity and higher order structure of Diphyllatea. RESULTS: We cultured 11 new strains, characterised these morphologically and amplified their rRNA for a combined 18S-28S rRNA phylogeny. We sampled environmental DNA from multiple sites and designed new Diphyllatea-specific PCR primers for long-read PacBio RSII technology. Near full-length 18S rRNA sequences from environmental DNA, in addition to supplementary Diphyllatea sequence data mined from public databases, resolved the phylogeny into three deeply branching and distinct clades (Diphy I - III). Of these, the Diphy III clade is entirely novel, and in congruence with Diphy II, composed of species morphologically consistent with the earlier described Collodictyon triciliatum. The phylogenetic split between the Diphy I and Diphy II + III clades corresponds with a morphological division of Diphyllatea into bi- and quadriflagellate cell forms. CONCLUSIONS: This altered flagella composition must have occurred early in the diversification of Diphyllatea and may represent one of the earliest known morphological transitions among eukaryotes. Further, the substantial increase in molecular data presented here confirms Diphyllatea has a global distribution, seemingly restricted to freshwater habitats. Altogether, the results reveal the advantage of combining a group-specific PCR approach and long-read high-throughput amplicon sequencing in surveying enigmatic eukaryote lineages. Lastly, our study shows the capacity of PacBio RS when targeting a protist class for increasing phylogenetic resolution. PMID- 30021532 TI - Characteristics of facial expression recognition ability in patients with Lewy body disease. AB - BACKGROUND: The facial expression of medical staff has been known to greatly affect the psychological state of patients, making them feel uneasy or conversely, cheering them up. By clarifying the characteristics of facial expression recognition ability in patients with Lewy body disease, the aim of this study is to examine points to facilitate smooth communication between caregivers and patients with the disease whose cognitive function has deteriorated. METHODS: During the period from March 2016 to July 2017, we examined the characteristics of recognition of the six facial expressions of "happiness," "sadness," "fear," "anger," "surprise," and "disgust" for 107 people aged 60 years or more, both outpatient and inpatient, who hospital specialists had diagnosed with Lewy body diseases of Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies. Based on facial expression recognition test results, we classified them by cluster analysis and clarified features of each type. RESULTS: In patients with Lewy body disease, happiness was kept unaffected by aging, age of onset, duration of the disease, cognitive function, and apathy; however, recognizing the facial expression of fear was difficult. In addition, due to aging, cognitive decline, and apathy, the facial expression recognition ability for sadness and anger decreased. In particular, cognitive decline reduced recognition of all of the facial expressions except for happiness. The test accuracy rates were classified into three types using the cluster analysis: "stable type," "mixed type," and "reduced type". In the "reduced type", the overall facial recognition ability declined except happiness, and in the mixed type, recognition ability of anger particularly declined. CONCLUSION: There were several facial expressions that the Lewy body disease patients were unable to accurately identify. Caregivers are recommended to make an effort to compensate for such situations with language or body contact, etc., as a way to convey correct feeling to the patients of each type. PMID- 30021533 TI - Molecular characterization of invasive meningococcal isolates in Burkina Faso as the relative importance of serogroups X and W increases, 2008-2012. AB - BACKGROUND: Neisseria meningitidis serogroup A disease in Burkina Faso has greatly decreased following introduction of a meningococcal A conjugate vaccine in 2010, yet other serogroups continue to pose a risk of life-threatening disease. Capsule switching among epidemic-associated serogroup A N. meningitidis strains could allow these lineages to persist despite vaccination. The introduction of new strains at the national or sub-national levels could affect the epidemiology of disease. METHODS: Isolates collected from invasive meningococcal disease in Burkina Faso between 2008 and 2012 were characterized by serogrouping and molecular typing. Genome sequences from a subset of isolates were used to infer phylogenetic relationships. RESULTS: The ST-5 clonal complex (CC5) was identified only among serogroup A isolates, which were rare after 2010. CC181 and CC11 were the most common clonal complexes after 2010, having serogroup X and W isolates, respectively. Whole-genome phylogenetic analysis showed that the CC181 isolates collected during and after the epidemic of 2010 formed a single clade that was closely related to isolates collected in Niger during 2005 and Burkina Faso during 2007. Geographic population structure was identified among the CC181 isolates, where pairs of isolates collected from the same region of Burkina Faso within a single year had less phylogenetic diversity than the CC181 isolate collection as a whole. However, the reduction of phylogenetic diversity within a region did not extend across multiple years. Instead, CC181 isolates collected during the same year had lower than average diversity, even when collected from different regions, indicating geographic mixing of strains across years. The CC11 isolates were primarily collected during the epidemic of 2012, with sparse sampling during 2011. These isolates belong to a clade that includes previously described isolates collected in Burkina Faso, Mali, and Niger from 2011 to 2015. Similar to CC181, reduced phylogenetic diversity was observed among CC11 isolate pairs collected from the same regions during a single year. CONCLUSIONS: The population of disease-associated N. meningitidis strains within Burkina Faso was highly dynamic between 2008 and 2012, reflecting both vaccine imposed selection against serogroup A strains and potentially complex clonal waves of serogroup X and serogroup W strains. PMID- 30021534 TI - Benchmarking differential expression analysis tools for RNA-Seq: normalization based vs. log-ratio transformation-based methods. AB - BACKGROUND: Count data generated by next-generation sequencing assays do not measure absolute transcript abundances. Instead, the data are constrained to an arbitrary "library size" by the sequencing depth of the assay, and typically must be normalized prior to statistical analysis. The constrained nature of these data means one could alternatively use a log-ratio transformation in lieu of normalization, as often done when testing for differential abundance (DA) of operational taxonomic units (OTUs) in 16S rRNA data. Therefore, we benchmark how well the ALDEx2 package, a transformation-based DA tool, detects differential expression in high-throughput RNA-sequencing data (RNA-Seq), compared to conventional RNA-Seq methods such as edgeR and DESeq2. RESULTS: To evaluate the performance of log-ratio transformation-based tools, we apply the ALDEx2 package to two simulated, and two real, RNA-Seq data sets. One of the latter was previously used to benchmark dozens of conventional RNA-Seq differential expression methods, enabling us to directly compare transformation-based approaches. We show that ALDEx2, widely used in meta-genomics research, identifies differentially expressed genes (and transcripts) from RNA-Seq data with high precision and, given sufficient sample sizes, high recall too (regardless of the alignment and quantification procedure used). Although we show that the choice in log-ratio transformation can affect performance, ALDEx2 has high precision (i.e., few false positives) across all transformations. Finally, we present a novel, iterative log-ratio transformation (now implemented in ALDEx2) that further improves performance in simulations. CONCLUSIONS: Our results suggest that log-ratio transformation-based methods can work to measure differential expression from RNA-Seq data, provided that certain assumptions are met. Moreover, these methods have very high precision (i.e., few false positives) in simulations and perform well on real data too. With previously demonstrated applicability to 16S rRNA data, ALDEx2 can thus serve as a single tool for data from multiple sequencing modalities. PMID- 30021535 TI - Implementing telemonitoring in primary care: learning from a large qualitative dataset gathered during a series of studies. AB - BACKGROUND: Telemonitoring for long term conditions such as hypertension and diabetes has not been widely adopted despite evidence of efficacy in trials and policy support. The Telescot programme comprised a series of seven trials and observational studies of telemonitoring for long term conditions in primary care, all with an explanatory qualitative component which had been analysed and published separately. There were changes to the models of care within and between studies and combining datasets would provide a longitudinal view of the evolution of primary care based telemonitoring services that was not available in the individual studies, as well as allowing comparison across the different conditions monitored. We aimed to explore what drove changes to the way telemonitoring was implemented, compare experience of telemonitoring across the range of long term conditions, and identify what issues, in the experience of the participants, need to be considered in implementing new telemonitoring systems. METHOD: Synthesis and thematic reanalysis of transcribed qualitative interview and focus group data from the Telescot programme adopting an interpretive description approach. All transcribed and coded text was re-read and data relating to the experience of the telemonitoring services, perceptions of future use and strategies for implementation were recoded into one consistent system. This was analysed thematically. RESULTS: The combined dataset contained transcribed qualitative interview and focus group data from 181 patients and 109 professionals. Four major themes were identified, using data, empowering patients, adjusting the model of care and system design. CONCLUSION: Telemonitoring was valued by patients who found it empowering and convenient. This, combined with initial professional concern that increased surveillance may create dependency led to the development of a more patient led service. However, despite a number of initial concerns being addressed as the service evolved, primary care professionals identified a number of barriers to widespread routine adoption of telemonitoring, many of which could be addressed by improved system design. PMID- 30021536 TI - Non-response bias in estimates of prevalence of club-based sport participation from an Australian national physical activity, recreation and sport survey. AB - BACKGROUND: An estimate of the prevalence of an activity derived from a sample survey is potentially subject to non-response bias, whereby people not involved in the activity are less likely to respond than those involved. Quantifying the extent of non-response bias is generally difficult, since it involves estimating differences between respondents for whom data is directly available from the survey, and non-respondents, for whom data is generally not directly or readily available. However, in the case of the Australian Exercise Recreation and Sport Survey (ERASS), comparative "gold standard" benchmarks exist for some aspects of the survey, in the form of state sporting association (SSA) registration databases, each of which purports to constitute a complete enumeration of club based players of a particular sport. METHODS: ERASS estimates of the prevalence of participation in four major club-based team sports in the Australian state of Victoria in the year 2010 were compared with prevalences based on numbers of registered participants in the corresponding SSA databases. Comparisons were made for the adult population as a whole (ERASS scope being 15+ years of age), and for strata defined by age and geographical region. Because three of the four sports investigated are strongly sex-specific, no sex breakdowns were conducted. In each case the proportion of ERASS respondents reporting participation, with associated confidence limits, was compared with the corresponding SSA count expressed as a proportion of the population, to form an ERASS/SSA prevalence ratio with associated confidence limits. RESULTS: The 24 ERASS/SSA ratios ranged from 1.72 to 7.80. Most ratios lay in the range 2 to 3. The lower 95% confidence bound for the ratio was greater than 1.0 in 23 out of 24 cases. CONCLUSIONS: ERASS estimates of prevalence of these particular aspects of sport participation were higher than SSA estimates, to statistically significant degrees. The effect sizes (i.e. the discrepancies represented by the ratios) were large enough to be of great practical importance. It is conjectured that non-response bias is the most likely explanation for the discrepancies. PMID- 30021537 TI - Exacerbation of ichthyosis vulgaris phenotype by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis: a case report. AB - BACKGROUND: X-linked ichthyosis (XLI) is a recessive keratinization condition caused by deficient activity of steroid-sulfatase due to mutations in steroid sulfatase (STS) gene located on the X chromosome. In contrast, ichthyosis vulgaris (IV) is caused by filaggrin deficiency due to semi-dominant loss-of function mutations of filaggrin (FLG) gene. Filaggrin defects could synergize with XLI to exacerbate its phenotype. CASE PRESENTATION: We report a Chinese family with patients presenting diverse phenotype of Keratosis pilaris. A next generation sequencing panel interrogating 25 ichthyosis related genes with sequencing coverage of the coding regions and splice site junctions, was applied to screen genetic mutations. A gross deletion encompassing the STS gene ranging from exon 1-10 and the FLG c.3321delA mutation were identified in a 31-year old male proband, one of his sister, and his mother, and all the three patients showed obvious symptom. The deletion of STS gene was confirmed by real-time quantitative PCR. The proband's another sister and his two nephews carried only FLG c.3321delA mutation. Patients carried both mutations presented more severe symptom, while those only carried FLG c.3321delA mutation showed slight or normal phenotype. CONCLUSIONS: In conclusion, we found that the IV phenotype was exacerbated by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis. Other genomic regions no included in the study might be also involved in phenotypic modifications. PMID- 30021538 TI - The influence of education on the access to childhood immunization: the case of Spain. AB - BACKGROUND: In order to enhance childhood vaccination uptake and the health consequences for the whole society, there is a need to study predictors that might help in understanding parents' behaviour in relation to childhood vaccination schemes. The aim of this paper is to assess whether parental education has an influence on their children's public health-care use in terms of visits for vaccinations, and thus evaluate whether more educated parents use public health resources more frequently in childhood immunization schedules. METHODS: The setting was the region of Catalonia in the north-east of Spain. Three different databases, containing information about 11,415 individuals corresponding to 79,905 observations, were merged and linked: 1) observational and longitudinal administrative data for adults and children in Catalonia; 2) a database containing information on the vaccination of children in relation to the public health programme called the "Healthy Child Programme"; and 3) the governmental vaccination registration. The presence of an education gradient was explored using a logistic regression. Children's health-care use was modelled using a logistic procedure. RESULTS: The greater the mothers' educational attainment level, the higher the probability of being vaccinated in this immunization programme. The presence of an age profile for vaccinations showed that less educated parents visit their GPs more frequently for immunizations when their children are below the age of six, but that pattern is completely the opposite after that age. Hence, for children aged between six and 16, more educated parents are more likely to ensure their children are immunized. Likewise, systematic vaccinations are more likely for those parents with a lower educational attainment level. CONCLUSIONS: This paper evidenced the presence of an education gradient for specific preventive care through the public health system and visits to the GP without any particular disease or advice for specific vaccinations. PMID- 30021539 TI - Prevalence and risk factors of gestational diabetes mellitus: findings from a universal screening feasibility program in Lima, Peru. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a global public health concern with potential implications for the health of a mother and her offspring. However, data on the prevalence and risk factors of GDM in Latin America are scarce. The study was designed to estimate the prevalence of GDM and identify maternal risk factors among Peruvian women. METHODS: A cross-sectional study was conducted among 1300 pregnant women attending a prenatal clinic in Lima, Peru. GDM was diagnosed using an Oral Glucose Tolerance Test (OGTT) performed between 24 and 28 gestational weeks using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Depression status was assessed using the Patient Health Questionnaire-9. Multivariate logistic regression models were used to identify risk factors of GDM. RESULTS: Approximately 16% of pregnant women were diagnosed with GDM. The prevalence of obesity and depression were 24.4 and 10.6%, respectively. After adjusting for confounders, mid-pregnancy obesity was associated with a 1.64-fold increased odds of GDM (OR: 1.64; 95% CI: 1.03 2.61). Participants with a family history of diabetes had a 1.5-fold increased odds of developing GDM (OR: 1.51, 95% CI: 1.10-2.07) as compared to women without this family history. Depression was associated with a 1.54-fold increased odds of GDM (OR: 1.54; 95% CI:1.09-2.17). CONCLUSIONS: GDM is highly prevalent and was associated with maternal obesity, family history of diabetes and antepartum depression among Peruvian women. Intervention programs aimed at early diagnoses and management of GDM need to take maternal obesity, family history of diabetes and antepartum depression into account. PMID- 30021540 TI - Online cognitive-behavioral based group interventions for adolescents with chronic illness and parents: study protocol of two multicenter randomized controlled trials. AB - BACKGROUND: Adolescents with chronic illness (CI) and parents of a child with CI are at risk for psychosocial problems. Psychosocial group interventions may prevent these problems. With the use of cognitive-behavioral therapy, active coping strategies can be learned. Offering an intervention online eliminates logistic barriers (travel time and distance) and improves accessibility for participants. Aim of this study is to examine the effectiveness of two cognitive behavioral based online group interventions, one for adolescents and one for parents: Op Koers Online. The approach is generic, which makes it easier for patients with rare illnesses to participate. METHODS/DESIGN: This study conducts two separate multicenter randomized controlled trials. Participants are adolescents (12 to 18 years of age) with CI and parents of children (0 to 18 years of age) with CI. Participants are randomly allocated to the intervention group or the waitlist control group. Outcomes are measured with standardized questionnaires at baseline, after 8 (adolescents) or 6 (parents) weeks of treatment, and at 6- and 12-month follow-up period. Primary outcomes are psychosocial functioning (emotional and behavioral problems) and disease-related coping skills. Secondary outcomes for adolescents are self-esteem and quality of life. Secondary outcomes for parents are impact of the illness on family functioning, parental distress, social involvement and illness cognitions. The analyses will be performed according to the intention-to-treat principle. Primary and secondary outcomes will be assessed with linear mixed model analyses using SPSS. DISCUSSION: These randomized controlled trials evaluate the effectiveness of two online group interventions improving psychosocial functioning in adolescents with CI and parents of children with CI. If proven effective, the intervention will be optimized and implemented in clinical practice. TRIAL REGISTRATION: ISRCTN ISRCTN83623452 . Registered 30 November 2017. Retrospectively registered. PMID- 30021541 TI - Contribution of early nutrition on the development of malnutrition and allergic diseases in the first year of life: a study protocol for the Mother and Infant Cohort Study (MICOS). AB - BACKGROUND: Nutrition and environmental factors are essential for the education of the neonatal immune system. Epidemiological evidence has shown that malnutrition and allergic diseases that occur during early childhood share similar protective and risk factors. This paper describes the protocol of the Mother and Infant Cohort Study (MICOS), which aims to determine the contribution of early nutrition to the development of malnutrition and allergic diseases in infants' first year of life. METHODS: MICOS is a prospective cohort study conducted at selected government health clinics in two states, namely Selangor and Wilayah Persekutuan Kuala Lumpur, Malaysia. Women in their third trimester of pregnancy are recruited into the study and their infants will be followed-up at 3, 6, and 12 months of age. Information on prenatal factors including socio demographic characteristics, obstetric history, pre-pregnancy body mass index, gestational weight gain, smoking, family history of allergic diseases, maternal dietary intake and sunlight exposure during pregnancy are obtained through face to-face interviews. Postnatal factors including dietary intake, sun exposure, and anthropometric measurements of the mothers, as well as feeding practices, dietary intake, anthropometric measurements, and development of allergic diseases of the infants are assessed at each follow-up. Blood samples are collected from the mothers in the third trimester to determine 25-hydroxyvitamin D levels as well as from the infants at age 12 months to determine atopic sensitisation. DISCUSSION: The concept of developmental origins of health and disease (DOHaD) which emphasises on the role of early life environments in shaping future health and disease susceptibility in adulthood has gained a huge interest in recent years. The DOHaD paradigm has influenced many fields of research including malnutrition and allergic diseases. While findings from the developed countries remain controversial, such studies are scarce in developing countries including Malaysia. The present study will determine the cause and effect relationship between early nutrition and the development of malnutrition and allergic diseases in infants' first year of life. PMID- 30021542 TI - Cross-sectional and longitudinal analyses of the association between lung function and exercise capacity in healthy Norwegian men. AB - BACKGROUND: It is widely accepted that exercise capacity in healthy individuals is limited by the cardiac function, while the respiratory system is considered oversized. Although there is physiological, age-related decline in both lung function and physical capacity, the association between decline in lung function and decline in exercise capacity is little studied. Therefore, we examined the longitudinal association between lung function indices and exercise capacity, assessed by the total amount of work performed on a standardized incremental test, in a cohort of middle-aged men. METHODS: A total of 745 men between 40 and 59 years were examined using spirometry and standardized bicycle exercise ECG test within "The Oslo Ischemia Study," at two time points: once during 1972-1975, and again, approximately 16 years later, during 1989-1990. The subjects exercise capacity was assessed as physical fitness i.e. the total bicycle work (in Joules) at all workloads divided by bodyweight (in kg). RESULTS: Higher FEV1, FVC and PEF values related to higher physical fitness at both baseline and follow-up (all p values < 0.05). Higher explanatory values were found at follow-up than baseline for FEV1 (r2 = 0.16 vs. r2 = 0.03), FVC (r2 = 0.14 vs. r2 = 0.03) and PEF (r2 = 0.13 vs. r2 = 0.02). No significant correlations were found between decline in physical fitness and declines in FEV1, FVC or PEF. CONCLUSIONS: A weak association between lung function indices and exercise capacity, assessed through physical fitness, was found in middle-aged, healthy men. This association was strengthened with increasing age, suggesting a larger role for lung function in limiting exercise capacity among elderly subjects. However, decline in physical fitness over time was not related to decline in lung function. PMID- 30021543 TI - Evaluating the impact of screening plus eave tubes on malaria transmission compared to current best practice in central Cote d'Ivoire: a two armed cluster randomized controlled trial. AB - BACKGROUND: Access to long-lasting insecticidal nets (LLINs) has increased and malaria has decreased globally, but malaria transmission remains high in parts of sub-Saharan Africa and insecticide resistance threatens current progress. Eave tubes are a new tool for the targeted delivery of insecticides against mosquitoes attempting to enter houses. The primary objective of this trial is to test whether screening plus eave tubes (SET) provides protection against malaria, on top of universal coverage with LLINs in an area of intense pyrethroid resistance. The trial will also assess acceptability and cost-effectiveness of the intervention. METHODS/DESIGN: A two-armed, cluster randomized controlled trial will be conducted to evaluate the effect of SET on clinical malaria incidence in children living in central Cote d'Ivoire. Forty villages will be selected based on population size and the proportion of houses suitable for modification with SET. Using restricted randomization, half the villages will be assigned to the treatment arm (SET + LLINs) and the remainder will be assigned to the control arm (LLINs only). In both arms, LLINs will be distributed and in the treatment arm, householders will be offered SET. Fifty children aged six months to eight years old will be enrolled from randomly selected households in each of the 40 villages. Cohorts will be cleared of malaria parasites at the start of the study and one year after recruitment, and will be monitored for clinical malaria case incidence by active case detection over two years. Mosquito densities will be assessed using CDC light traps and human landing catches and a subset of Anopheles mosquitoes will be examined for parity status and tested for sporozoite infection. Acceptability of SET will be monitored using surveys and focus groups. Cost-effectiveness analysis will measure the incremental cost per case averted and per disability-adjusted life year (DALY) averted of adding SET to LLINs. Economic and financial costs will be estimated from societal and provider perspective using standard economic evaluation methods. DISCUSSION: This study will be the first evaluation of the epidemiological impact of SET. Trial findings will show whether SET is a viable, cost-effective technology for malaria control in Cote d'Ivoire and possibly elsewhere. TRIAL REGISTRATION: ISRCTN18145556 , registered on 01 February 2017 - retrospectively registered. PMID- 30021544 TI - Prevalence of insomnia symptoms and their associated factors in patients treated in outpatient clinics of four general hospitals in Guangzhou, China. AB - BACKGROUND: Data on the prevalence of insomnia symptoms in medical outpatient clinics in China are lacking. This study examined the prevalence of insomnia symptoms and their socio-demographic correlates in patients treated at medical outpatient clinics affiliated with four general hospitals in Guangzhou, a large metropolis in southern China. METHOD: A total of 4399 patients were consecutively invited to participate in the study. Data on insomnia and its socio-demographic correlates were collected with standardized questionnaires. RESULTS: The prevalence of any type of insomnia symptoms was 22.1% (95% confidence interval (CI): 20.9-23.3%); the prevalence of difficulty initiating sleep was 14.3%, difficulty maintaining sleep was 16.2%, and early morning awakening was 12.4%. Only 17.5% of the patients suffering from insomnia received sleeping pills. Multiple logistic regression analysis revealed that male gender, education level, rural residence, and being unemployed or retired were negatively associated with insomnia symptoms, while lacking health insurance, older age and more severe depressive symptoms were positively associated with insomnia symptoms. CONCLUSIONS: Insomnia symptoms are common in patients attending medical outpatient clinics in Guangzhou. Increasing awareness of sleep hygiene measures, regular screening and psychosocial and pharmacological interventions for insomnia are needed in China. TRIAL REGISTRATION: ChiCTR-INR-16008066 . Registered 8 March 2016. PMID- 30021545 TI - Increasing return-to-work among people on sick leave due to common mental disorders: design of a cluster-randomized controlled trial of a problem-solving intervention versus care-as-usual conducted in the Swedish primary health care system (PROSA). AB - BACKGROUND: Common mental disorders affect about one-third of the European working-age population and are one of the leading causes of sick leave in Sweden and other OECD countries. Besides the individual suffering, the costs for society are high. This paper describes the design of a study to evaluate a work-related, problem-solving intervention provided at primary health care centers for employees on sick leave due to common mental disorders. METHODS: The study has a two-armed cluster randomized design in which the participating rehabilitation coordinators are randomized into delivering the intervention or providing care-as usual. Employees on sick leave due to common mental disorders will be recruited by an independent research assistant. The intervention aims to improve the employee's return-to-work process by identifying problems perceived as hindering return-to-work and finding solutions. The rehabilitation coordinator facilitates a participatory approach, in which the employee and the employer together identify obstacles and solutions in relation to the work situation. The primary outcome is total number of sick leave days during the 18-month follow-up after inclusion. A long-term follow-up at 36 months is planned. Secondary outcomes are short-term sick leave (min. 2 weeks and max. 12 weeks), psychological symptoms, work ability, presenteeism and health related quality of life assessed at baseline, 6 and 12-month follow-up. Intervention fidelity, reach, dose delivered and dose received will be examined in a process evaluation. An economic evaluation will put health-related quality of life and sick leave in relation to costs from the perspectives of society and health care services. A parallel ethical evaluation will focus on the interventions consequences for patient autonomy, privacy, equality, fairness and professional ethos and integrity. DISCUSSION: The study is a pragmatic trial which will include analyses of the intervention's effectiveness, and a process evaluation in primary health care settings. Methodological strengths and challenges are discussed, such as the risk of selection bias, contamination and detection bias. If the intervention shows promising results for return-to-work, the prospects are good for implementing the intervention in routine primary health care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346395 Registered January, 12 2018. PMID- 30021546 TI - Anti-IL-5 therapy in patients with severe eosinophilic asthma - clinical efficacy and possible criteria for treatment response. AB - BACKGROUND: Interleukin-5 (IL-5) antibodies represent a promising therapeutic option for patients with severe eosinophilic asthma. To date, no official treatment response criteria exist. In this study, simple criteria for treatment response applicable to all asthma patients were used to evaluate clinical efficacy and predictors for treatment response in a real-life setting. METHODS: Data from 42 patients with severe eosinophilic asthma treated with mepolizumab for at least six months were analysed. Simple criteria to assess treatment response in clinical practice were used: increase of FEV1 >= 12% or >= 200 ml, reduction of blood eosinophils (< 150/MUl or < 80% from baseline) and improvement of subjective condition (patient-judged subjective improvement or worsening following therapy). Patients were considered treatment responders if two criteria were fulfilled. RESULTS: Thirty-two out of 42 patients (76% [61-87%]) were classified as responders. Within the groups (responder vs non-responder), treatment with mepolizumab led to significant increase in FEV1 (+ 600 ml vs -100 ml, p = 0.003), oxygenation (+ 8 mmHg vs -3 mmHg, p = 0.001), quality of life (visual analogue scale; + 28% vs - 5%, p = 0.004) and Asthma Control Test (+ 8 vs + 1 points, p = 0.002). In the responder group a significant decrease in the exacerbation rate over 12 months (1.45 vs 0.45, p = 0.002) was observed. Baseline characteristics (sex, BMI, smoking history, allergies, baseline level of eosinophils) did not predict treatment response. CONCLUSION: Using improvement of lung function, decrease of eosinophils and improvement of subjective condition as response criteria, 76% of treated patients could be classified as treatment responders, demonstrating the efficacy of anti-IL-5 therapy in clinical practice. PMID- 30021547 TI - Impact of the Safe Childbirth Checklist on health worker childbirth practices in Luapula province of Zambia: a pre-post study. AB - BACKGROUND: A strong evidence base exists regarding routine and emergency services that can effectively prevent or reduce maternal and new-born mortality. However, even when skilled providers care for women in labour, many of the recommended services are not provided, despite being available. Barriers to the provision of appropriate childbirth services may include lack of availability of supplies, limited health worker knowledge and confidence, or inadequate time. The WHO Safe Childbirth Checklist (SCC) includes reminders for evidenced-based practices at specific points in the childbirth process. Zambia is currently considering nation-wide adoption of the SCC, but there is a need for context specific evidence. Beginning in September 2017, a program is being implemented in Nchelenge District to pilot use of the SCC, along with coaching that focuses on strengthening the systems that allow the essential practices in childbirth to be performed. METHODS: This study will use a pre-post study design to measure health worker adherence to the essential practices for delivery care outlined in the SCC. Data will be collected through observations of health workers as they care for mothers during childbirth at four facilities. Data collection will take place before the start of the intervention, at 3 months, and at 6 months post intervention. The primary outcome interest is the change in the average proportion of essential childbirth practices completed. A health worker questionnaire will be administered at the time that the SCC is introduced and 6 months later to gather their perspectives on incorporating the SCC into clinical practice in Zambia. DISCUSSION: Findings are expected to inform plans for introducing the SCC in Zambia. This evaluation will aim to understand uptake and impact of the SCC and associated coaching in the context of a basic level of mentorship that the government could feasibly provide at a national scale. TRIAL REGISTRATION: Clinical Trials.gov ( NCT03263182 ) Registered August 28, 2017. PMID- 30021548 TI - A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/- nab-paclitaxel in elderly pancreatic cancer patients (GrantPax). AB - BACKGROUND: In the group of elderly patients (>=70 years) with metastatic pancreatic ductal adenocarcinoma (mPDAC), it is not known who benefits from intensive 1st line nab-paclitaxel/gemcitabine (nab-p/gem) combination chemotherapy or who would rather suffer from increased toxicity. We aim to determine whether treatment individualization by comprehensive geriatric assessments (CGAs) improves functional outcome of the patients. METHODS/DESIGN: GrantPax is a multicenter, open label phase 4 interventional trial. We use a CGA to stratify elderly patients into three parallel treatment groups (n = 45 per arm): 1) GOGO (nab-p/gem), 2) SLOWGO (gem mono) or 3) FRAIL (best supportive care). After the 1st cycle of chemotherapy (or 4 weeks in FRAIL group) another CGA and safety assessment is performed. CGA-stratified patients may not decline in their CGA performance in response to the first cycle of chemotherapy (primary objective), measured as a loss of 5 points or less in Barthels activities of daily living. Based on the second CGA, patients are re-assigned to their definite treatment arm and undergo further CGAs to monitor the course of treatment. Secondary endpoints include CGA scores during the course of therapy (CGA1-4), response rates, safety and survival rates. DISCUSSION: GrantPax is the first trial implementing a CGA-driven treatment to personalize therapy for elderly patients with pancreatic cancer. This may lead to standardization of therapy decisions for elderly patients and may optimize standard of care for this increasing group of patients. TRIAL REGISTRATION: NCT02812992 , registered 24.06.2016. PMID- 30021549 TI - Investigation into the biomechanics of lumbar spine micro-dynamic pedicle screw. AB - BACKGROUND: Numerous reports have shown that rigid spinal fixation contributes to a series of unwanted complications in lumbar fusion procedure. This innovative micro-dynamic pedicle screw study was designed to investigate the biomechanical performance of lumbar implants using numerical simulation technique and biomechanical experiment. METHODS: Instrumented finite element models of three configurations (dynamic fixation, rigid fixation and hybrid fixation) using a functional L3-L4 lumbar unit were developed, to compare the range of motion of the lumbar spine and stress values on the endplate and implants. An in vitro experiment was simultaneously conducted using 18 intact porcine lumbar spines and segmental motion analyses were performed as well. RESULTS: Simulation results indicated that the dynamic fixation and the hybrid fixation models respectively increased the range of motion of the lumbar spine by 95 and 60% in flexion and by 83 and 55% in extension, compared with the rigid fixation model. The use of micro dynamic pedicle screw led to higher stress on endplates and lower stress on pedicle screws. The outcome of the in vitro experiment demonstrated that the micro-dynamic pedicle screw could provide better range of motion at the instrumented segments than a rigid fixation. CONCLUSION: The micro-dynamic pedicle screw has the advantage of providing better range of motion than conventional pedicle screw in flexion-extension, without compromising stabilization, and has the potential of bringing the load transfer behavior of fusional segment closer to normal and also lowers the stress values of pedicle screws. PMID- 30021550 TI - Recombinant oncolytic Newcastle disease virus displays antitumor activities in anaplastic thyroid cancer cells. AB - BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors for which no effective therapies are currently available. Oncolytic Newcastle disease virus (NDV) has shown the potential to induce oncolytic cell death in a variety of cancer cells of diverse origins. However, whether oncolytic NDV displays antitumor effects in ATC remains to be investigated. We have previously shown that the oncolytic NDV strain FMW (NDV/FMW) induces oncolytic cell death in several cancer types. In the present study, we investigated the oncolytic effects of NDV/FMW in ATC. METHODS: In this study, a recombinant NDV expressing green fluorescent protein (GFP) was generated using an NDV reverse genetics system. The resulting virus was named after rFMW/GFP and the GFP expression in infected cells was demonstrated by direct fluorescence and immunoblotting. Viral replication was evaluated by end-point dilution assay in DF 1 cell lines. Oncolytic effects were examined by biochemical and morphological experiments in cultural ATC cells and in mouse models. RESULTS: rFMW/GFP replicated robustly in ATC cells as did its parent virus (NDV/FMW) while the expression of GFP protein was detected in lungs and spleen of mice intravenously injected with rFMW/GFP. We further showed that rFMW/GFP infection substantially increased early and late apoptosis in the ATC cell lines, THJ-16 T and THJ-29 T and increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage in ATC cells as assessed by immunoblotting. In addition, rFMW/GFP induced lyses of spheroids derived from ATC cells in three-dimensional (3D) cultures. We further demonstrated that rFMW/GFP infection resulted in the activation of p38 MAPK signaling, but not Erk1/2 or JNK, in THJ-16 T and THJ-29 T cells. Notably, inhibition of p38 MAPK activity by SB203580 decreased rFMW/GFP induced cleavage of caspase-3 and PARP in THJ-16 T and THJ-29 T cells. Finally, both rFMW/GFP and its parent virus inhibited tumor growth in mice bearing THJ-16 T derived tumors. CONCLUSION: Taken together, these data indicate that both the recombinant reporter virus rFMW/GFP and its parent virus NDV/FMW, display oncolytic activities in ATC cells in vitro and in vivo and suggest that oncolytic NDV may have potential as a novel therapeutic strategy for ATC. PMID- 30021551 TI - The BeHealthyR Study: a randomized trial of a multicomponent intervention to reduce stress, smoking and improve financial health of low-income residents in Rotterdam. AB - BACKGROUND: Compared to higher socioeconomic status (SES) groups, those in lower SES groups are financially strained, experience higher rates of smoking-related morbidity, are in poorer health and have reduced life expectancy. This is especially true for the city of Rotterdam, where a large inequality in health is observed between low and high SES groups. The BeHealthyR study (Dutch: Grip en Gezondheid) is a randomized controlled trial (RCT) which will evaluate the impact of a theory-based multicomponent behavior intervention aiming to reduce stress, smoking, and improve financial health by means of a group-based stress management program combining cognitive and behavioral techniques, and nudges in low-SES residents living in Rotterdam. METHODS: The BeHealthyR study is a three-arm RCT. Between February 2018 and July 2019, low-SES participants who perceive stress, smoke, are financially strained and reside in Rotterdam (one of the four largest cities in The Netherlands) are recruited. Subsequently, participants are randomly assigned to either a stress management condition (SM), stress management with a buddy condition (SM-B) or a control condition (CC). Participants in the SM and SM B conditions will attend four weekly group sessions (1.5 h/session) and a follow up session eight weeks later. The SM condition includes psychoeducation and exercises, and cognitive and behavioral intervention techniques. Demographic data and objective measures will be collected at baseline (T0), four weeks post baseline (T1), and twelve weeks post-baseline (T2). Primary outcome measures are to reduce stress, smoking and improve financial health. We hypothesize that low SES participants in the intervention conditions, compared with those in the control condition, will experience less stress, smoke less and have improved financial health. DISCUSSION: This study is a group-based intervention which aims to investigate the effects of a theory-based behavioral change intervention employing several components on reducing stress, smoking, and improving financial health in low-SES residents living in Rotterdam. If effective, the findings from the present study will serve to inform future directions of research and clinical practice with regard to behavioral change interventions for low-SES groups. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT03553979 ). Registered on January 1 2018. PMID- 30021552 TI - The effectiveness of inpatient rehabilitation after uncomplicated total hip arthroplasty: a propensity score matched cohort. AB - BACKGROUND: Inpatient rehabilitation is an expensive option following total hip arthroplasty (THA). We aimed to determine if THA patients who receive inpatient rehabilitation report better hip and quality of life scores post-surgery compared to those discharged directly home. METHODS: Prospective, propensity score matched cohort involving 12 private hospitals across five Australian States. Patients undergoing THA secondary to osteoarthritis were included. Those receiving inpatient rehabilitation for reasons other than choice or who experienced significant health events within 90-days post-surgery were excluded. Comparisons were made between those who did and did not receive inpatient rehabilitation for patient-reported hip pain and function (Oxford Hip Score, OHS) and 'today' health rating (EuroQol 0-100 scale). Rehabilitation provider charges were also estimated and compared. RESULTS: Two hundred forty-six patients (123 pairs, mean age 67 (10) yr., 66% female) were matched on 19 covariates for their propensity to receive inpatient rehabilitation. No statistically nor clinically significant between-group differences were observed [OHS median difference (IQR): 0 (- 3, 3), P = 0.60; 0 (- 1 to 1), P = 0.91, at 90 and 365-days, respectively; EuroQol scale median difference 0 (- 10, 12), P = 0.24; 0 (- 10, 10), P = 0.49; 5 (- 10, 15), P = 0.09, at 35-, 90- and 365-days, respectively]. Median rehabilitation provider charges were 10-fold higher for those who received inpatient rehabilitation [median difference $7582 (5649, 10,249), P < 0.001]. Sensitivity analyses corroborated the results of the primary analyses. CONCLUSION: Utilization of inpatient rehabilitation pathways following THA appears to be low value healthcare. Sustainability of inpatient rehabilitation models may be enhanced if inpatient rehabilitation is reserved for those most impaired or who have limited social supports. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01899443 . PMID- 30021553 TI - A risk assessment model for chronic ankle instability: indications for early surgical treatment? An observational prospective cohort - study protocol. AB - BACKGROUND: Chronic ankle instability (CAI) is a common result of an ankle sprain. Even though early surgical treatment yields the best results, overall only professional athletes are eligible for acute surgical stabilization. Treating all patients with early surgical stabilization leads to a high amount of unnecessary invasive interventions, as not all patients progress to CAI. If patients at risk of developing CAI can be identified, treatment policies may be applied more effectively and efficiently. The purpose of this study is to develop a risk assessment model to identify patients at risk for CAI that should receive early surgical treatment. METHODS: In this observational prospective cohort, all patients aged sixteen years and older, reporting at the emergency department of one of the participating hospitals after sustaining a lateral ankle sprain, and filled out 1 out of 3 follow-up questionnaires and the 1 year follow-up are included. A lateral and anteroposterior radiograph is made. Patients are excluded if a fracture or other pathology is present. The included patients receive four questionnaires, including questions focusing on the sprain, treatment and complaints, the Foot and Ankle Outcome Score and the Cumberland Ankle Instability Tool. A total of eleven radiographic variables are assessed for inter- and intra observer reliability. Additionally, four factors extracted from the questionnaires, will be evaluated for correlation with CAI. Significantly correlating factors (e.a. risk factors) will be implemented in a risk assessment model. For the final model, based on sixteen variables with a minimum of 20 events per variable and a prevalence of 30-40% after an initial sprain, a sample size of 2370 patients is needed to perform both internal and external model validation. DISCUSSION: This study will develop the first large scale model for the risk at CAI after an ankle sprain combining radiographic and patient characteristics. With this risk assessment model, patients at risk for CAI may be identified and properly informed on the treatment options. Patients identified as being at risk, may receive more adequate follow-up and become eligible for early surgical stabilization. This prevents patients from experiencing unnecessary long lasting complaints, increasing the success rate of conservative and surgical treatment. TRIAL REGISTRATION: Retrospectively registered: NCT02955485 [Registration date: 3-11-2016]. NTR6139 [Registration date: 3-1-2017]. PMID- 30021554 TI - The Promoting Activity in Cancer Survivors (PACES) trial: a multiphase optimization of strategy approach to increasing physical activity in breast cancer survivors. AB - BACKGROUND: Despite the significant, empirically supported benefits of physical activity, the majority of breast cancer survivors do not meet recommended guidelines for physical activity. A variety of effective strategies to increase physical activity in breast cancer survivors have been identified. However, it is unknown which of these strategies is most effective or how these strategies might be combined to optimize intervention effectiveness. METHODS: The proposed trial uses multiphase optimization strategy (MOST) to evaluate four evidence-based intervention strategies for increasing physical activity in breast cancer survivors. We will enroll 500 breast cancer survivors, age 18 and older, who are 3-months to 5 years post-treatment. Using a full-factorial design, participants will be randomized to receive a combination: 1) supervised exercise, 2) facility access, 3) self-monitoring, and 4) group-based active living counseling. The primary outcome, moderate-to-vigorous physical activity (MVPA) will be measured at baseline, 3 months, and 6 months using an Actigraph GT3X+. To evaluate intervention effects, a linear mixed-effects model will be conducted with MVPA as the outcome and with time (3 months and 6 months) as the within-subjects factor and intervention (i.e., supervised exercise, facility access, self-monitoring, and active living counseling) as the between subjects factor, along with all two way interactions. DISCUSSION: The purpose of the PACES study is to evaluate multiple strategies for increasing physical activity in breast cancer survivors. Results of this study will provide in an optimized intervention for increasing physical activity in breast cancer survivors. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03060941 . Registered February 23, 2017. PMID- 30021555 TI - Study protocol of the CORRECT multicenter trial: the efficacy of blended cognitive behavioral therapy for reducing psychological distress in colorectal cancer survivors. AB - BACKGROUND: Approximately one third of the colorectal cancer survivors (CRCS) experience high levels of psychological distress. Common concerns experienced by CRCS include distress related to physical problems, anxiety, fear of cancer recurrence (FCR) and depressive symptoms. However, psychological interventions for distressed CRCS are scarce. Therefore, a blended therapy was developed, combining face-to-face cognitive behavioral therapy (CBT) with online self management activities and telephone consultations. The aim of the study is to evaluate the efficacy and cost-effectiveness of this blended therapy in reducing psychological distress in CRCS. METHODS/DESIGN: The CORRECT study is a two-arm multicenter randomized controlled trial (RCT). A sample of 160 highly distressed CRCS (a score on the Distress Thermometer of 5 or higher) will be recruited from several hospitals in the Netherlands. CRCS will be randomized to either the intervention condition (blended CBT) or the control condition (care as usual). The blended therapy covers approximately 14 weeks and combines five face-to-face sessions and three telephone consultations with a psychologist, with access to an interactive self-management website. It includes three modules which are individually-tailored to patient concerns and aimed at decreasing: 1) distress caused by physical consequences of CRC, 2) anxiety and FCR, 3) depressive symptoms. Patients can choose between the optional modules. The primary outcome is general distress (Brief Symptom Inventory-18). Secondary outcomes are quality of life and general psychological wellbeing. Assessments will take place at baseline prior to randomization, after 4 and 7 months. DISCUSSION: Blended CBT is an innovative and promising approach for providing tailored supportive care to reduce high distress in CRCS. If the intervention proves to be effective, an evidence-based intervention will become available for implementation in clinical practice. TRIAL REGISTRATION: This trial is registered in the Netherlands Trial Register ( NTR6025 ) on August 3, 2016. PMID- 30021556 TI - Custom foot orthoses improve first-step pain in individuals with unilateral plantar fasciopathy: a pragmatic randomised controlled trial. AB - BACKGROUND: Foot orthoses are routinely used to treat plantar fasciopathy in clinical practice. However, minimal evidence exists as to the effect of both truly custom designed foot orthoses, as well as that of the shoe the foot orthoses are placed into. This study investigated the effect of wearing custom foot orthoses and new athletic footwear on first-step pain, average 24-h pain and plantar fascia thickness in people with unilateral plantar fasciopathy over 12 weeks. METHODS: A parallel, three-arm randomised controlled trial with blinding of participants and assessors. 60 participants diagnosed with unilateral plantar fasciopathy were randomised to either custom foot orthoses and new shoes (orthoses group), a sham insole with a new shoes (shoe group) or a sham insole placed in the participant's regular shoes (control group). Primary outcome was first-step pain. Secondary outcomes were average 24-h pain and plantar fascia thickness measured on ultrasound. Outcomes were assessed at baseline, 4 week and 12 week trial time-points. RESULTS: At 4 weeks, the orthoses group reported less first-step pain (p = 0.002) compared to the control group. At 12 weeks, the orthoses group reported less first-step pain compared to both the shoe (p = < 0.001) and sham (p = 0.01) groups. Both the orthoses (p = < 0.001) and shoe (p = 0.006) groups reported less average 24-h pain compared to the control group at 4 and 12 weeks. The orthoses group demonstrated reduced plantar fascia thickness on ultrasound compared to both the shoe (p = 0.032) and control groups (p = 0.011). CONCLUSIONS: Custom foot orthoses in new shoes improve first-step pain and reduce plantar fascia thickness over a period of 12 weeks compared to new shoes alone or a sham intervention. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN 12613000446763 ). Submitted on the 10th of April 2013 and registered on the 18th of April 2013. PMID- 30021557 TI - Determinants of perinatal mortality among cohorts of pregnant women in three districts of North Showa zone, Oromia Region, Ethiopia: Community based nested case control study. AB - BACKGROUND: Statistics indicate that Ethiopia has made remarkable progress in reducing child mortality. It is however estimated that there is high rate of perinatal mortality although there is scarcity of data due to a lack of vital registration in the country. This study was conducted with the purpose of assessing the determinants and causes of perinatal mortality among babies born from cohorts of pregnant women in three selected districts of North Showa Zone, Oromia Region, Ethiopia. The study used community based data, which is believed to provide more representative and reliable information and also aimed to narrow the data gap on perinatal mortality. METHODS: A community based nested case control study was conducted among 4438 (cohorts of) pregnant women. The cohort was followed up between March 2011 to December 2012 in three districts of Oromia region, Ethiopia, until delivery. The World Health Organization verbal autopsy questionnaire for neonatal death was used to collect data. A binary logistic regression model was used to identify determinants of perinatal mortality. Causes of deaths were assigned by a pediatrician and neonatologist. Cases are stillbirths and early neonatal death. Control are live births surviving of the perinatal period' RESULT: A total of 219 newborns (73 cases and 146 controls) were included in the analysis. Perinatal mortality rate was 16.5 per 1000 births. Mothers aged 35 years and above had a higher risk of losing their newborn babies to perinatal deaths than younger mothers [AOR 7.59, (95% CI, 1.91-30.10)]. Babies born to mothers who had a history of neonatal deaths were also more likely to die during the perinatal period than their counterparts [AOR 5.42, (95% CI, 2.27 12.96)]. Preterm births had a higher risk of perinatal death than term babies [AOR 8.58, (95% CI, 2.27-32.38)]. Similarly, male babies were at higher risk than female babies [AOR 5.47, (95% CI, 2.50-11.99)]. Multiple birth babies had a higher chance of dying within the perinatal period than single births [AOR 3.59, (95% CI, 1.20-10.79)]. Home delivery [AOR 0.23, (95% CI, 0.08-0.67)] was found to reduce perinatal deaths. Asphyxia, sepsis and chorioamnionitis were among the leading causes of perinatal deaths. CONCLUSION: This study reported a lower perinatal mortality rate. The main causes of perinatal death identified were often related to maternal factors. There is still a need for greater focus on these interrelated issues for further intervention. PMID- 30021558 TI - Can the health related quality of life measure QOLIBRI- overall scale (OS) be of use after stroke? A validation study. AB - BACKGROUND: Brief measures of health-related quality of life (HRQOL) that assess both patient-reported functioning and well-being after stroke are scarce. The objective of this study was to examine reliability and validity of one of these measures, the patient-reported Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS), in patients after stroke. METHODS: Stroke survivors were examined prospectively using survey methods. Core survey data (n = 125) and retest data (n = 36) were obtained at 3 and 12 months, respectively. Item properties (distribution, floor and ceiling effects), psychometric properties (reliability and model fit), and validity (correlations with established measures of anxiety, depression and HRQOL) of the QOLIBRI-OS were examined. RESULTS: Missing responses on the questionnaire were low (0.5%). All items were positively skewed. No floor effects were present, whereas five out of six items showed ceiling effects. The summary QOLIBRI-OS score exhibited no floor or ceiling effects, and had excellent internal consistency (Cronbach's alpha =0.93). All item-total correlations were high (0.73-0.88). The test-retest reliability of single items varied from 0.74 to 0.91 and was 0.93 for the overall score. The confirmatory factor analysis yielded an excellent fit for a five-item version and provided tentative support for the original six-item version. The convergent validity correlations were in the hypothesized directions, thus supporting the construct validity. CONCLUSIONS: The brief QOLIBRI-OS is a valid and reliable brief health-related outcome measure that is appropriate for screening HRQOL in patients after stroke. PMID- 30021559 TI - Impact and cultural acceptance of the Narrative Exposure Therapy in the aftermath of a natural disaster in Burundi. AB - BACKGROUND: In the aftermath of natural disasters, affected populations are at risk of suffering from trauma-related mental health disorders such as posttraumatic stress disorder (PTSD) or depression. Particularly in poor post conflict regions, these mental disorders have the potential to impair the ability of individuals to move on with their lives. We aimed to evaluate the feasibility, cultural acceptance, and effect of a trauma-focused psychotherapy, Narrative Exposure Therapy (NET), in the aftermath of a flood disaster in Burundi. METHODS: Fifty-one individuals who were living in emergency camps overseen by the Burundian Red Cross in the aftermath of a flood disaster, and who had lost homes and close relatives, were invited to participate in semi-structured diagnostic interviews. Trained Burundian psychology students conducted these interviews, and six sessions of NET were offered to the 15 individuals most affected by trauma related symptoms. An additional group of psychology students, blind to the treatment conditions, conducted three and 9 months follow-ups with them including also 25 participants who had reported significant but less severe trauma-related symptoms, assessing mental health symptoms, acceptance of NET, stigmatization due to trauma symptoms, and participants' economic well-being. RESULTS: Between baseline and 9-months post-intervention assessment, symptoms of PTSD (Hedges' g = 3.44) and depression (Hedges' g = 1.88) improved significantly within participants who received NET and within those who received no treatment (Hedges' gPTSD = 2.55; Hedges' gdepression = 0.72). Furthermore, those who received NET felt less stigmatized by their participation in the intervention than by the trauma-related mental health symptoms they experienced. Overall, participants reported that they would be willing to forego as much as 1 month's worth of income in exchange for receiving trauma-focused interventions in the months following the disaster. CONCLUSIONS: Individuals severely affected by trauma related mental health symptoms might benefit significantly from NET in the aftermath of natural disasters, while less affected individuals seem to recover spontaneously. Despite significant challenges conducting NET in emergency camps in the aftermath of natural disaster in a post-conflict country, such interventions are feasible, appreciated and might have long-lasting impacts on the lives of survivors if conducted with due respect to participants' privacy. TRIAL REGISTRATION: UKCR2014 , the 19.06.2014, retrospectively registered. PMID- 30021561 TI - Evaluation of a combination "lymphocyte apoptosis model" to predict survival of sepsis patients in an intensive care unit. AB - BACKGROUND: A major challenge in sepsis intervention is unclear risk stratification. We postulated that a panel of biomarkers of lymphocyte apoptosis and immune function, termed the "lymphocyte apoptosis model," would be an effective tool for predicting 28-day survival for sepsis patients. METHODS: A total of 52 consecutive sepsis patients were enrolled. Peripheral blood samples were collected on day 1 of admission for quantification of biomarkers of lymphocyte apoptosis and immune function, including lymphocyte count, lymphocyte apoptotic percentage, expression on monocyte HLA-DR, CD4+/CD8+ T cell ratio, T helper type 1 to type 2 ratio (Th1/Th2), cytochrome c levels, and various proinflammatory cytokine levels. Sepsis severity was classified using Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Survival was assessed at 28 days. RESULTS: Compared with survivors, non-survivors had significantly higher lymphocyte apoptotic percentages and plasma cytochrome c levels and significantly lower lymphocyte counts, Th1/Th2 ratios, and HLA-DR expression on day 1 of admission. Multivariate analysis identified cytochrome c levels (odds ratio [OR]1.829, p = 0.025), lymphocyte apoptotic percentage (OR 1.103, p = 0.028), lymphocyte count (OR 0.150, p = 0.047), and HLA-DR expression (OR 0.923, p = 0.021) as independent predictors of 28-day mortality. A logistic regression equation incorporating the independent risk factors predicted 28-day mortality with greater accuracy than did the APACHE II score or single components biomarkers. CONCLUSIONS: The "lymphocyte apoptosis model" may be useful for risk stratification and predicting prognosis of sepsis patients. PMID- 30021560 TI - Fc receptor-like 3 (-169T>C) polymorphism increases the risk of tendinopathy in volleyball athletes: a case control study. AB - BACKGROUND: Tendinopathy pathogenesis is associated with inflammation. Regulatory T (Treg) cells contribute to early tissue repair through an anti-inflammatory action, with the forkhead box P3 (FOXP3) transcription factor being essential for Treg function, and the FC-receptor-like 3 (FCRL3) possibly negatively regulating Treg function. FCRL3 -169T>C and FOXP3 -2383C>T polymorphisms are located near elements that regulate respective genes expression, thus it was deemed relevant to evaluate these polymorphisms as risk factors for tendinopathy development in athletes. METHODS: This case-control study included 271 volleyball athletes (146 tendinopathy cases and 125 controls) recruited from the Brazilian Volleyball Federation. Genotyping analyses were performed using TaqMan assays, and the association of the polymorphisms with tendinopathy evaluated by multivariate logistic regression. RESULTS: Tendinopathy frequency was 63% patellar, 22% rotator cuff and 15% Achilles tendons respectively. Tendinopathy was more common in men (OR = 2.87; 95% CI = 1.67-4.93). Higher age (OR = 8.75; 95% CI = 4.33 17.69) and more years of volleyball practice (OR = 8.38; 95% CI = 3.56-19.73) were risk factors for tendinopathy. The FCRL3 -169T>C frequency was significantly different between cases and controls. After adjustment for potential confounding factors, the FCRL3 -169C polymorphism was associated with increased tendinopathy risk (OR = 1.44; 95% CI = 1.02-2.04), either considering athletes playing with tendon pain (OR = 1.98; 95% CI = 1.30-3.01) or unable to train due to pain (OR = 1.89; 95% CI = 1.01-3.53). The combined variant genotypes, FCRL3 -169TC or -169CC and FOXP3 -2383CT or -2383TT, were associated with an increased risk of tendinopathy among athletes with tendon pain (OR = 2.24; 95% CI: 1.14-4.40 and OR = 2.60; 95% CI: 1.11-6.10). The combined analysis of FCRL3 -169T>C and FOXP3 2383C>T suggests a gene-gene interaction in the susceptibility to tendinopathy. CONCLUSIONS: FCRL3 -169C allele may increase the risk of developing tendinopathy, and together with knowledge of potential risk factors (age, gender and years playing) could be used to personalize elite athletes' training or treatment in combination with other approaches, with the aim of minimizing pathology development risk. PMID- 30021563 TI - Correction to: the impact of pharmacokinetic gene profiles across human cancers. AB - Correction to: BMC Cancer (2018) 18:577 DOI https://doi.org/10.1186/s12885-018 4345-2. PMID- 30021562 TI - An economical strategy for early medical education in ultrasound. AB - BACKGROUND: A movement to include ultrasound training in undergraduate medical education is slowly taking place. However, many educational institutions are hesitant to include formal ultrasound training as a part of their curricula due to curricular time constraints, high cost of ultrasound equipment, and a lack of sufficient faculty skilled with ultrasound. We suggest that an economical ultrasound training strategy is needed to resolve these obstacles and enable hesitant medical programs to include ultrasound training. METHODS: Twenty-eight first year medical students volunteered to attend extra-curricular ultrasound training sessions covering topics related to 11 commonly used sonographical imaging categories. Study assessments included subjective pre/post-training skill evaluation surveys, and objective numerical scores awarded by the session instructor during real-time evaluation of each participant's performance in obtaining each target ultrasound view. RESULTS: A Wilcoxon matched-pairs signed rank test was performed to evaluate the difference between pre-training and post training survey questions. P values < 0.05 were considered significant. Moreover, following analysis the p value for all test was found to be < 0.0001. Of the 308 total ultrasound-related tasks attempted collectively by all 28 participants, only 7 (2.3%) tasks were deemed unsuccessful by an instructor. CONCLUSIONS: The training program presented in this study requires one faculty member, a single ultrasound machine, and time to conduct six 30-min training sessions with small groups of students over 4 weeks. Many medical schools are concerned that they don't have adequate time or resources to include ultrasound training in their curricula. Our intention is to negate these concerns by providing a simple and practical training method that is both temporally and fiscally economical. PMID- 30021564 TI - Women's knowledge and attitudes related to cervical cancer and cervical cancer screening in Isiolo and Tharaka Nithi counties, Kenya: a cross-sectional study. AB - BACKGROUND: Cervical cancer is the most common cancer among women in Kenya. However, only 3% of women are routinely screened. This study aimed to assess women's knowledge and attitudes towards cervical cancer and cervical cancer screening in Kenya's Isiolo and Tharaka Nithi counties. METHODS: A cross sectional survey was conducted between January and March 2017. Using a multistage cluster sampling methodology, 451 women 18 years of age and older participated in the study. Interviewers administered a 35-item questionnaire collecting demographic information, knowledge of risk factors and attitudes towards cervical cancer and cervical cancer screening. Bivariate and multivariate analyses of cervical cancer knowledge and demographic characteristics were conducted. RESULTS: The response rate for the study was 98% (451/460). Two-thirds of the study participants originated from Tharaka Nithi county (n = 318). Respondents reported a median age of 32; 70.5% were married; and 35.0% had primary education. Eighty percent of the participants were aware of cervical cancer, 25.6% of whom had previously undergone a cervical screening examination, and 44.4% had above average knowledge of risk factors of cervical cancer. Knowledge of cervical cancer risk factors was significantly associated with employment status (adjusted odds ratio = 1.6; 95% CI: 1.0-2.6) and county of origin (adjusted odds ratio = 2.8; 95% CI: 1.6-5.0). Almost all (89.2%) of those who had heard of cervical cancer categorised it as "scary". There was a marginal significant difference in the overall attitude assessment score towards cervical cancer between participants from Isiolo and Tharaka Nithi counties; the mean (SD) score was 2.13 (0.34) and 2.20 (0.30) respectively. The score was comparatively higher among participants residing in Tharaka Nithi (95% CI: 0.002-0.146; p = 0.043). CONCLUSIONS: Interventions to increase cervical cancer knowledge are needed in Isiolo and Tharaka Nithi counties, Kenya. Additional research is needed to further understand and assess the effectiveness of different strategies to improve attitudes regarding cervical cancer in order to increase the uptake of screening services, particularly among less-educated women and those in hard-to reach areas. PMID- 30021565 TI - Impact of obesity and other risk factors on labor dystocia in term primiparous women: a case control study. AB - BACKGROUND: Purpose of this study was to investigate differences between primiparous term pregnancies, one leading to vaginal delivery (VD) and the other to acute cesarean section (CS) due to labor dystocia in the first stage of labor. We particularly wanted to assess the influence of body mass index (BMI) on CS risk. METHODS: A retrospective case-control study in a tertiary delivery unit with 5200 deliveries annually. Cases were 296 term primiparous women whose intended vaginal labor ended in acute CS because of dystocia. Controls were primiparas with successful vaginal delivery VD (n = 302). The data were retrieved from medical records. Multiple logistic regression analyses were used to assess the associations between BMI and covariates on labor dystocia. RESULTS: In the cases ending with acute CS, women were older (OR 1.06 [1.03-1.10]), shorter (OR 0.94 [0.91-0.96]) and more often had a chronic disease (OR 1.60 [1.1-2.29]). In this group fetal malposition (OR 42.0 [19.2-91.9]) and chorioamnionitis (OR 10.9 [5.01-23.6]) were more common, labor was less often in an active phase (OR 3.37 [2.38-4.76]) and the cervix was not as well ripened (1.5 vs. 2.5 cm, OR 0.57 [0.48-0.67] on arrival at the birth unit. BMI was higher in the dystocia group (24.1 vs. 22.6 kg/m2, p < 0.001), and rising maternal pre-pregnancy BMI had a strong association with dystocia risk. If BMI increased by 1 kg/m2, the risk of CS was 10% elevated. Among obese primiparas, premature rupture of membranes, chorioamnionitis and induction of labor were more common. Their labors were less often in an active phase at hospital admission. Severely obese primiparas (BMI >= 35 kg/m2) had 4 hours longer labor than normal-weight parturients. CONCLUSIONS: Labor dystocia is a multifactorial phenomenon in which the possibility to ameliorate the condition via medical treatment is limited. Hospital admission at an advanced stage of labor is recommended. Pre-pregnancy weight control in the population at reproductive age is essential, as a high BMI is strongly associated with labor dystocia. PMID- 30021566 TI - A randomized clinical efficacy trial of a psychosocial intervention to strengthen self-acceptance and reduce HIV risk for MSM in India: study protocol. AB - BACKGROUND: Men who have sex with men (MSM) in India are a key group at risk for HIV acquisition and transmission. They are also an extremely marginalized and stigmatized population, facing immense psychosocial stressors including, but not limited to, stigma, homophobia, discrimination, criminalization, low self-esteem, low self-acceptance, distress, and, as a result, high rates of mental health problems. Although these multi-level psychosocial problems may put MSM at high risk for HIV acquisition and transmission, currently HIV prevention interventions in India do not address them. This paper describes the design of a psychosocial intervention to reduce HIV risk for MSM in India. METHODS: Funded by the National Institute of Mental Health, this study is a two-arm randomized clinical efficacy trial of a self-acceptance based psychosocial HIV prevention intervention, informed by the minority stress model and syndemic theory, that was developed with extensive community-based formative work and input from the Indian MSM community and key informants who are knowledgeable about the experiences faced by MSM in India. Participants are MSM in Chennai and Mumbai who endorsed recent sexual behaviors placing them at high risk for HIV/sexually transmitted infection (STI) acquisition and transmission. Enrolled participants are equally randomized to either 1) the experimental condition, which consists of four group and six individual counseling sessions and includes standard of care HIV/STI testing and counseling, or 2) the standard of care condition, which includes HIV/STI testing and counseling alone. The primary outcomes are changes in the frequency of condomless anal sex acts and STI incidence (syphilis seropositivity and urethral, rectal, and pharyngeal gonorrhea and chlamydia infection. Major study assessment visits occur at baseline, 4-, 8-, and 12-months. DISCUSSION: HIV prevention interventions that address the psychosocial stressors faced by MSM in India are needed; this study will examine the efficacy of such an intervention. If the intervention is successful, it may be able to reduce the national HIV/AIDS burden in India while empowering a marginalized and highly stigmatized group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02556294 , registered 22 September 2015. PMID- 30021567 TI - The prevalence and under-diagnosis of vertebral fractures on chest radiograph. AB - BACKGROUND: Vertebral fracture is the most common fragility fracture but it remains frequently unrecognized and is underdiagnosed worldwide. In this retrospective study, we examined the prevalence of moderate and severe vertebral fractures on chest radiographs of hospitalized female patients aged 50 years and older and determined missed diagnosis of vertebral fractures in the original radiology reports. METHODS: 3216 female patients 50 years of age and older were enrolled in our study. The patients' medical records including their original radiology reports and lateral chest radiographs were retrospectively reviewed by the study radiologists who had training certificates from the International Society for Clinical Densitometry (ISCD). Vertebral fractures between thoracic spine T4 and lumbar spine L1 were identified and classified using Genant's semi quantitative scale. The definition of vertebral fractures used in this study was Genant grade 2 or higher. RESULTS: The study radiologists identified 295(9.2%) patients with grade 2 or 3 fractured vertebrae, total 444 vertebrae on 3216 chest radiographs. The prevalence of vertebral fracture was 2.4% in women aged 50-59 yrs., 8.9% in women aged 60-69 yrs., and 21.9% in women aged>=70 yrs. There were 213 patients with a single vertebral fracture, 49 patients with two vertebral fractures and 33 patients with >= three vertebral fractures. Fractured vertebrae were identified with greater frequency in thoracic spine T11,12 and lumbar spine L1. According to our statistics, 66.8% of patients with vertebral fractures found in this study were undiagnosed in the original radiology reports. CONCLUSIONS: Vertebral fracture is common on chest radiographs but it is often ignored by radiologists. Genant's semiquantitative assessment is a simple and effective method for detecting vertebral fracture. Because osteoporotic vertebral fracture increases the risk of new fractures, radiologists have an important role in accurately diagnosing vertebral fractures. PMID- 30021568 TI - Arthroscopic knotless anterior labral stabilization using labral tape and wide awake anaesthesia-short term results. AB - BACKGROUND: The shoulder is the least constrained of all joints of the body and is more susceptible to injury including dislocation. The rate of recurrent instability following primary stabilization procedure at 10 years of follow-up ranged from 3.4 to 20%. There is a lack of evidence in the literature regarding use of labral tape and anchors for anterior stabilization despite the growing market for this product. We describe the outcomes of 67 patients who underwent knotless arthroscopic anterior stabilisation under awake anaesthesia using 1.5 mm LabralTape with 2.9 mm Pushlock anchors for primary anterior instability by a single surgeon. METHODS: This was a retrospective analysis of prospectively collected outcome data for adult patients undergoing anterior stabilisation for primary traumatic anterior shoulder instability between 2013 and 2016 at two centres. Patients with > 25% glenoid bone loss, engaging Hill Sach's, and multidirectional instability were excluded. All cases underwent surgery using awake anaesthetic technique. The surgical technique and post-operative physiotherapy was standardized. Outcomes were measured at 6 months and 12 months. RESULTS: Of the 74 patients in our study, 7 were lost to follow up. Outcomes were measured using the Oxford Instability Shoulder Score (OISS) and clinical assessment including the range of motion. The OISS showed statistically significant improvement from a mean score and standard deviation (SD) of 24.72 +/ 2.8 pre-surgery to 43.09 +/- 3.5 after the procedure at 12 months with good to excellent outcomes in 66 cases (98.5%). The mean abduction was 134.2 +/- 6.32 and external rotation was 72.55 +/- 5.42 at 60-90 position at 12 months. We report no failures due to knot slippage or anchor pull-out. CONCLUSION: Our case series using the above technique has distinct advantages of combining a small non absorbable implant with flat, braided, and high-strength polyethylene tape. This technique demonstrates superior medium term results to conventional suture knot techniques for labral stabilization thereby validating its use. PMID- 30021569 TI - Leading top-down implementation processes: a qualitative study on the role of managers. AB - BACKGROUND: Leadership has been identified as an influential factor in implementation processes in healthcare organizations. However, the processes through which leaders affect implementation outcomes are largely unknown. The purpose of this study is to analyse how managers interpret and make sense of a large scale top-down implementation initiative and what implications this has for the implementation process. This was studied at the implementation of an academic primary healthcare initiative covering 210 primary healthcare centres in central Sweden. The aim of the initiative was to integrate research and education into regular primary healthcare services. METHODS: The study builds on 16 in-depth individual semi-structured interviews with all managers (n = 8) who had operative responsibility for the implementation. Each manager was interviewed twice during the initial phase of the implementation. Data were analysed using a thematic approach guided by theory on managerial role taking based on the Transforming Experience Framework. RESULTS: How the managers interpreted and made sense of the implementation task built on three factors: how they perceived the different parts of the initiative, how they perceived themselves in relation to these parts, and the resources available for the initiative. Based on how they combined these three factors the managers chose to integrate or separate the different parts of the initiative in their management of the implementation process. CONCLUSIONS: This research emphasizes that managers in healthcare seem to have a substantial impact on how and to what extent different tasks are addressed and prioritized in top-down implementation processes. This has policy implications. To achieve intended implementation outcomes, the authors recognize the necessity of an early and on-going dialogue about how the implementation is perceived by the managers responsible for the implementation. PMID- 30021570 TI - Protocol for a longitudinal mixed methods realist evaluation of holistic needs assessment and care planning for people affected by cancer. AB - BACKGROUND: In 2012, approximately 14 million new cases of cancer were diagnosed. As a result of advances in treatment, screening and prevention programmes the number of people surviving cancer globally is also increasing. The growing understanding of the diversity and scale of the need for support, compounded by the increasing prevalence of cancer survivors has fuelled the development and evaluation of a range of services and models to meet them. A key intervention is the holistic needs assessment and care planning, however there is little homogeneity in its actual delivery to cancer survivors. To fill this evidence gap there is a need to understand any effect implementation variables have on patient experiences, measurable outcomes and resource use. We are exploring this through a realist evaluation of holistic needs assessment and care planning. METHODS: This longitudinal, mixed method realist evaluation has been approached in 4 phases. Phases 1 and 2 have been completed (2014-2017) and a summary of this work is presented. We then provide a detailed protocol for Phases 3 and 4 (2017 onwards). Phase 1: Establishment of programme theory for HNA and care planning; Phase 2: Exploration and documentation of local programme theories; Phase 3: Theory testing and refinement and Phase 4 - Theory validation and dissemination. Phase 3 draws on a range of data derived from 6 study sites. Methods include analysis of patient characteristics and concerns identified, qualitative interviews /fieldwork with local project staff, national stakeholders, professionals using the needs assessment tool and patients, a three-year longitudinal online survey of wider programme stakeholders and a review and synthesis of local project evaluations and patient care plans. DISCUSSION: This intervention is a key component globally of cancer survivorship care. The results of this realist evaluation can be used to optimise the delivery and development of HNA and care planning for people affected by cancer. To our knowledge this is the first study of this type. By utilising the discipline of Realistic Evaluation this mixed methods study will elicit findings with greater potential for generalisability and transferability within Scotland, the UK and beyond. PMID- 30021571 TI - When, where and who? Accessing health facility delivery care from the perspective of women and men in Tanzania: a qualitative study. AB - BACKGROUND: Childbirth is a momentous event for women and their partners, yet women continue to die in childbirth worldwide, particularly in sub-Saharan Africa. To reduce maternal mortality and increase the number of women delivering at health facilities, it is important to understand reasons why women who do deliver at health facilities chose to do so. Therefore, the objective of this qualitative study was to explore the perceptions of women and men on (i) when women go to the hospital; (ii) where women deliver; and (iii) who is involved in the delivery process related to accessing health facilities for delivery care in Tanzania. METHODS: Using a qualitative design, four focus group discussions (n = 23) and semi-structured interviewers (n = 12) were held with postnatal women and men who were attending a postnatal clinic in the Lake Zone region of Tanzania. Data was analyzed using thematic coding. RESULTS: Women and men expressed factors that influenced when, where, and with whom they accessed health facilities for delivery care, with the quality of care received providing a significant influence. When decisions were made about going to the hospital, there were challenges that resulted in delayed treatment seeking; however, couples recognized the need to seek care earlier to prevent complications. Private hospitals were the preferred location for delivery with public hospitals and home deliveries with traditional birth attendants being less desirable. Both when and where delivery took place was influenced by the desire for better quality of care received as well as financial costs. Finally, there was mixed evidence on who was involved in decision making around delivery location from the perspective of women and men, but both groups expressed a preference for more male involvement during the delivery. CONCLUSION: Men and women show desire for women to delivery at health facilities; however, improvements are needed with respect to maternal care and humanizing the birth process in Tanzania. Greater emphasis needs to be placed on including men during the birth process, improving the quality of care received in public hospitals, and reducing the barriers to accessing health facilities for delivery care. PMID- 30021572 TI - Progress of children with severe acute malnutrition in the malnutrition treatment centre rehabilitation program: evidence from a prospective study in Jharkhand, India. AB - BACKGROUND: In Jharkhand, Malnutrition Treatment Centres (MTCs) have been established to provide care to children with severe acute malnutrition (SAM). The study examined the effects of facility- and community based care provided as part the MTC program on children with severe acute malnutrition. METHOD: A cohort of 150 children were enrolled and interviewed by trained investigators at admission, discharge, and after two months on the completion of the community-based phase of the MTC program. Trained investigators collected data on diet, morbidity, anthropometry, and utilization of health and nutrition services. RESULTS: We found no deaths among children attending the MTC program. Recovery was poor, and the majority of children demonstrated poor weight gain, with severe wasting and underweight reported in 52 and 83% of the children respectively at the completion of the community-based phase of the MTC program. The average weight gain in the MTC facility (3.8 +/- 5.9 g/kg body weight/d) and after discharge (0.6 +/- 2.1 g/kg body weight/d) was below recommended standards. 67% of the children consumed food that met less than 50% of the recommended energy and protein requirement. Children experienced high number of illness episodes after discharge: 68% children had coughs and cold, 40% had fever and 35% had diarrhoea. Multiple morbidities were common: 50% of children had two or more episodes of illness. Caregiver's exposure to MTC's health and nutrition education sessions and meetings with frontline workers did not improve feeding practices at home. The take-home ration amount distributed to children through the supplementary food program was inadequate to achieve growth benefits. CONCLUSIONS: Recovery of children during and after the MTC program was suboptimal. This highlights the need for additional support to strengthen MTC program so that effective care to children can be provided. PMID- 30021573 TI - Is unilateral lower leg orthosis with a circular foot unit in the treatment of idiopathic clubfeet a reasonable bracing alternative in the Ponseti method? Five year results of a supraregional paediatric-orthopaedic centre. AB - BACKGROUND: In the Ponseti treatment of idiopathic clubfoot, children are generally provided with a standard foot abduction orthosis (FAO). A significant proportion of these patients experience irresolvable problems with the FAO leading to therapeutic non-compliance and eventual relapse. Accordingly, these patients were equipped with a unilateral lower leg orthosis (LLO) developed in our institution. The goal of this retrospective study was to determine compliance with and the efficacy of the LLO as an alternative treatment measure. The minimum follow-up was 5 years. RESULTS: A total of 45 patients (75 ft) were retrospectively registered and included in the study. Compliance with the bracing protocol was 91% with the LLO and 46% with the FAO. The most common problems with the FAO were sleep disturbance (50%) and cutaneous problems (45%). Nine percent of patients experienced sleep disturbance, and no cutaneous problems occurred with the LLO. Thirteen percent of patients being treated with an FAO until the age of four (23 patients; 40 ft) underwent surgery because of relapse, defined by rigid recurrence of any of the components of a clubfoot. Fourteen percent of patients being treated with an LLO (22 patients; 35 ft), mostly following initial treatment with an FAO, experienced recurrence. CONCLUSION: Changing from FAO to LLO at any point during treatment did not result in an increased rate of surgery and caused few problems. PMID- 30021574 TI - Heterologous production of levopimaric acid in Saccharomyces cerevisiae. AB - BACKGROUND: Levopimaric acid (LA), a type of diterpene resin acid produced by plants, is a significant industrial intermediate that is mainly produced via phytoextraction. This work aimed to apply synthetic biology to produce LA in yeast strains from a simple carbon source. RESULTS: Levopimaradiene (LP), the precursor of LA, was produced via LP synthase (LPS) expression in yeast. LPS was then modified by N-terminal truncating and site-directed mutagenesis. The strain containing t79LPSMM (79 N-terminal amino acid truncating and M593I/Y700F mutation) produced 6.92 mg/L of LP, which were 23-fold higher than the strain containing LPS. Next, t79LPSMM was expressed in a new metabolically engineered chassis, and the final LP production increased 164-folds to 49.21 mg/L. Three cytochrome P450 reductases (CPRs) were co-expressed with CYP720B1 (the enzyme responsible for LA production from LP) in yeast to evaluate their LA producing abilities, and the CPR from Taxus cuspidata (TcCPR) was found to be the best (achieved 23.13 mg/L of LA production). CYP720B1 and TcCPR genes overexpression in the multi-copy site of the S.cerevisiae genome led to a 1.9-fold increase in LA production to 45.24 mg/L in a shake-flask culture. Finally, LA production was improved to 400.31 mg/L via fed-batch fermentation in a 5-L bioreactor. CONCLUSIONS: This is the first report to produce LA in a yeast cell factory and the highest titer of LA is achieved. PMID- 30021575 TI - Combined use of topical intraarticular tranexamic acid and rivaroxaban in total knee arthroplasty safely reduces blood loss, transfusion rates, and wound complications without increasing the risk of thrombosis. AB - BACKGROUND: Blood loss and deep vein thrombosis (DVT) are important complications after total knee arthroplasty (TKA). Topical tranexamic acid (TXA) effectively reduces wound bleeding but may elevate the risk of DVT. In contrast, rivaroxaban potently prevents DVT but has been associated with bleeding complications. The simultaneous use of topical TXA and rivaroxaban in TKA has not been much investigated. METHODS: A retrospective cohort study was conducted with two consecutive groups of patients who underwent TKA. Intraoperatively, one group (RVTX group) received topical, intraarticular TXA, while the other (RV group) did not. Both groups were administered rivaroxaban postoperatively for 14 days and underwent Doppler ultrasound for DVT screening. After propensity score matching, both groups consisted of 52 patients (104 patients in total) and were compared regarding total drain output, nadir haemoglobin (Hb), maximum Hb decrease, calculated total blood loss, transfusion rate, and incidence of DVT and wound complications. RESULTS: Both groups showed no significant differences in the propensity-matched variables of age, sex, body mass index, American Society of Anesthesiologists physical status score, and preoperative Hb. The RVTX group showed a significantly higher nadir Hb (p < 0.001), lower drain output (p < 0.001), Hb decrease (p = 0.015), total blood loss (p < 0.001), and rate of transfusion (p < 0.001) and fewer wound complications (p = 0.027). However, the incidence of DVT (p = 1.000) did not differ significantly between the two groups, and all cases were asymptomatic. CONCLUSIONS: The combined use of intraarticular topical TXA with rivaroxaban in patients undergoing TKA is a safe and effective method to reduce blood loss, the need for transfusion, and wound complications without elevating the risk of DVT. PMID- 30021576 TI - High rate of inappropriate blood transfusions in the management of children with severe anemia in Ugandan hospitals. AB - BACKGROUND: Severe anaemia (SA) is a common reason for hospitalisation of children in sub-Saharan Africa but the extent to which blood transfusion is used appropriately in the management of severe anemia has hitherto remained unknown. We report on the use of blood transfusion in the management of anemic children in two hospitals in Uganda. METHODS: Inpatient records of children 0-5 years of age admitted to Lira and Jinja regional referral hospitals in Uganda were reviewed for children admitted on selected days between June 2016 and May 2017. Data was extracted on the results, if any, of pre-transfusion hemoglobin (Hb) level, whether or not a blood transfusion was given and inpatient outcome for all children with a diagnosis of 'severe anemia'. Qualitative data was also collected from health workers to explain the reasons for the clinical practices at the two hospitals. RESULTS: Overall, 574/2275 (25.2%) of the children admitted in the two hospitals were assigned a diagnosis of SA. However 551 (95.9%) of children assigned a diagnosis of SA received a blood transfusion, accounting for 551/560 (98.4%) of the blood transfusions in the pediatric wards. Of the blood transfusions in SA children, only 245 (44.5%) was given appropriately per criteria (Pre-transfusion Hb <= 6 g/dL), while 306 (55.5%) was given inappropriately; (pre-transfusion Hb not done, n = 216, or when a transfusion is not indicated [Hb > 6.0 g/dl], n = 90). SA children transfused appropriately per Hb criteria had lower inpatient mortality compared to those transfused inappropriately, (7 (2.9%) vs. 22 (7.2%), [OR 0.4, 95% CI 0.16, 0.90]). Major issues identified by health workers as affecting use of blood transfusion included late presentation of SA children to hospital and unreliable availability of equipment for measurement of Hb. CONCLUSION: More than half the blood transfusions given in the management of anemic children admitted to Lira and Jinja hospitals was given inappropriately either without pre-transfusion Hb testing or when not indicated. Verification of Hb level by laboratory testing and training of health workers to adhere to transfusion guidelines could result in a substantial decrease in inappropriate blood transfusion in Ugandan hospitals. PMID- 30021577 TI - Poor reporting of multivariable prediction model studies: towards a targeted implementation strategy of the TRIPOD statement. AB - BACKGROUND: As complete reporting is essential to judge the validity and applicability of multivariable prediction models, a guideline for the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) was introduced. We assessed the completeness of reporting of prediction model studies published just before the introduction of the TRIPOD statement, to refine and tailor its implementation strategy. METHODS: Within each of 37 clinical domains, 10 journals with the highest journal impact factor were selected. A PubMed search was performed to identify prediction model studies published before the launch of TRIPOD in these journals (May 2014). Eligible publications reported on the development or external validation of a multivariable prediction model (either diagnostic or prognostic) or on the incremental value of adding a predictor to an existing model. RESULTS: We included 146 publications (84% prognostic), from which we assessed 170 models: 73 (43%) on model development, 43 (25%) on external validation, 33 (19%) on incremental value, and 21 (12%) on combined development and external validation of the same model. Overall, publications adhered to a median of 44% (25th-75th percentile 35-52%) of TRIPOD items, with 44% (35-53%) for prognostic and 41% (34 48%) for diagnostic models. TRIPOD items that were completely reported for less than 25% of the models concerned abstract (2%), title (5%), blinding of predictor assessment (6%), comparison of development and validation data (11%), model updating (14%), model performance (14%), model specification (17%), characteristics of participants (21%), model performance measures (methods) (21%), and model-building procedures (24%). Most often reported were TRIPOD items regarding overall interpretation (96%), source of data (95%), and risk groups (90%). CONCLUSIONS: More than half of the items considered essential for transparent reporting were not fully addressed in publications of multivariable prediction model studies. Essential information for using a model in individual risk prediction, i.e. model specifications and model performance, was incomplete for more than 80% of the models. Items that require improved reporting are title, abstract, and model-building procedures, as they are crucial for identification and external validation of prediction models. PMID- 30021578 TI - Facilitating physical activity and reducing symptoms in patients with knee osteoarthritis: study protocol of a randomized controlled trial to test a theory based PrevOP-psychological adherence program (PrevOP-PAP). AB - BACKGROUND: The present randomized controlled trial, which is crossed with the "PREVenting the impairment of primary Osteoarthritis by high impact long-term Physical exercise regimen" Main Medical Trial (PrevOP-MMT), aims to evaluate a psychological adherence program (PrevOP-PAP), and is designed to support persons with knee osteoarthritis (OAK) in the uptake and maintenance of regular physical activity to reduce OAK symptoms. The PrevOP-PAP is based on the Health Action Process Approach (HAPA), a social-cognitive theory predicting health behavior change in individuals, extended here by social network characteristics and social exchange processes. It is expected that participants with OAK receiving the PrevOP-PAP will maintain higher levels of regular physical activity throughout a 24-month period and consequently report lower levels of OAK symptoms than participants of an active control condition. METHODS: A total of N = 240 participants with medically verified moderate OAK will be randomly assigned to an intervention condition (PrevOP-PAP-I; 50%) or an active control condition (PrevOP PAP-CTRL). The PrevOP-PAP-I includes a motivational intervention, repeated self regulation interventions, and a network creation intervention delivered over 12 months. Modes of intervention delivery include a paper-pencil motivation leaflet with a quiz, a computer-assisted face-to-face intervention, four computer assisted phone-based interventions, and activity calendars. The PrevOP-PAP-CTRL includes the motivational intervention only. Primary outcome will be OAK symptoms. Secondary outcomes include objectively and subjectively measured physical activity and indicators of quality of life. Other outcomes are HAPA derived self-regulatory indicators as well as proposed social network and social exchange mechanisms of health behavior change. Assessments take place at baseline, 6 months, 12 months, 18 months, and 24 months following baseline. DISCUSSION: Based on the extended HAPA, this study seeks to reveal the self regulatory and social mechanisms of the uptake and maintenance of physical activity and their relation to disease symptoms in persons with OAK. The design and evaluation of this program are intended to become a yardstick for future development and implementation of digitalized psychological adherence programs in this population. TRIAL REGISTRATION: German Clinical Trials Register; also available at http://apps.who.int/trialsearch/ ; registration number: DRKS00009677 ; date of registration: 26 January 2016. PMID- 30021579 TI - Anti-cancer activity of Angelica gigas by increasing immune response and stimulating natural killer and natural killer T cells. AB - BACKGROUND: The polysaccharide component of Angelica gigas induces immuno stimulatory effects on innate immune cells. However, it is unclear whether A. gigas' adjuvant activity on the immune system can elicit anti-cancer responses. METHODS: A water-soluble immuno-stimulatory component of A. gigas was prepared. How this ISAg modulated the activation of innate immune cells such as dendritic cells (DCs) was examined. ISAg-induced cytotoxic activity via natural killer (NK) and NKT cells was also tested using a tumor-bearing mouse model. RESULTS: ISAg treatment induced nitric oxide (NO) production and cytokine gene expression involved in innate immune responses. ISAg activated macrophages and DCs to secrete cytokine IL-12, through the TLR4 signaling pathway. IL-12 plays a crucial role in ISAg-mediated NK and NKT cell activation. Thus, the anti-cancer activity of NK and NKT cells induced ISAg-mediated cytotoxicity of B16 melanoma cells in mice. CONCLUSIONS: These results indicated that the natural ingredient, ISAg, has adjuvant activity to induce strong anti-cancer activity of NK and NKT cells in vivo. PMID- 30021580 TI - Early versus delayed cord clamping in small for gestational age infants and iron stores at 3 months of age - a randomized controlled trial. AB - BACKGROUND: Delayed cord clamping is the standard of care in infants not requiring resuscitation; however effects of cord clamping strategies have not been evaluated systematically in small for gestational age (SGA) infants. The primary objective was to compare effects of delayed cord clamping (DCC) and early cord clamping (ECC) on serum ferritin at 3 months in SGA infants born at >=35 weeks. The secondary objectives were to compare hematological parameters, clinical outcomes in neonatal period and growth at 3 months of age. METHODS: All eligible infants with fetal growth restriction were randomized to two groups, DCC at 60 s or ECC group in which the cord was clamped immediately after birth. RESULTS: Total of 142 infants underwent randomization and subsequently 113 infants underwent definite inclusion. At 3 months, the median (IQR) serum ferritin levels were higher in DCC group, compared to ECC; 86 ng/ml (43.35 134.75) vs 50.5 ng/ml (29.5-83.5), p = 0.01. Fewer infants had iron deficiency in DCC group compared to ECC group; 9 (23.6%) vs 21 (47.7%), p = 0.03 [NNT being 4; 95% CI (2-25)].The proportion of infants with polycythemia was significantly higher in DCC group; 23 (41.81) % vs 12 (20.6%), p = 0.01. There was no difference in proportion of infants with symptomatic polycythemia or those who underwent partial exchange transfusions. Clinical outcomes and mortality were similar. CONCLUSIONS: DCC improves iron stores in SGA infants >=35 weeks at 3 months of age without increasing the risk of symptomatic polycythemia, need for partial exchange transfusions or morbidities associated with polycythemia. TRIAL REGISTRATION: Our trial was retrospectively registered on 29th May 2015 through Clinical trials registry India. Registration number: CTRI 2015/05/005828 . PMID- 30021581 TI - A comparative study of flat surface design and medial pivot design in posterior cruciate-retaining total knee arthroplasty: a matched pair cohort study of two years. AB - BACKGROUND: Component design is one of the contributory factors affecting the postoperative flexion angle. The purpose of this study was to compare short-term outcomes of flat surface and medial pivot designs in posterior cruciate-retaining (CR) total knee arthroplasty (TKA). METHODS: A retrospective, case-control, and observational cohort study consisted of matched-pairs of the flat surface design (Hi-Tech Knee II) and the medial pivot design (FINE Knee) in CR-TKA with a two year follow-up period. RESULTS: Hi-Tech Knee II and FINE knee groups each included 7 males and 38 females. Surgical time was significantly shorter in the FINE Knee group than in the Hi-Tech Knee II group (104.8 min versus 154.9 min, p = 0.001). Estimated total blood loss was significantly lower in the FINE Knee group than in the Hi-Tech Knee II group (654 ml versus 1158 ml, p = 0.001). The postoperative flexion angle was significantly better in the FINE Knee group than in the Hi-Tech Knee II group (119.3 degrees versus 112.5 degrees), and was positively correlated with the preoperative flexion angle. Postoperative Knee Society scores were significantly better in the FINE Knee group than in the Hi Tech Knee II group (93.0 points versus 85.0 points, p = 0.001), especially for postoperative pain relief (46.0 points versus 39.0 points out of 50, p = 0.001). Complications were not observed in either group over a two-year follow-up period. CONCLUSION: The short-term outcome of the medial pivot design used in CR-TKA was more favorable than the flat surface design, especially for surgical time, estimated total blood loss, postoperative flexion angle, and knee pain. PMID- 30021583 TI - Experiences and challenges of home care nurses and general practitioners in home based palliative care - a qualitative study. AB - BACKGROUND: Norway has one of the lowest home death rates in Europe. However, it is the health authorities' ambition to increase this by facilitating palliative care at home. The aim of this study was to achieve more insight, through home care nurses and general practitioners, of conditions that facilitate or hamper more time at home and more home deaths for patients with terminal disease and short life expectancy. METHODS: We used a qualitative research design with four focus groups with a total of 19 participants, of either home care nurses or general practitioners, using semi-structured question guides. The data were processed by systematic text condensation and encompassed thematic analysis of meaning and content of data across cases, which included four steps of analysis. RESULTS: Three main themes were identified: 1) The importance of a good start for the patient and family with five sub-themes, 2) 'Passing the baton' - the importance of collaboration across the health system with four sub-themes, and 3) Avoiding new hospitalization by establishing collaboration and competence within primary health care with four sub-themes. CONCLUSIONS: This study demonstrates that optimum palliative care at home depends on close collaboration and dialogue between the patient, family, home care nurses and general practitioner. It suggests the need for safer discharge routines and planning when hospitals transfer patients with terminal disease to their homes. A good start for the patient and family, where the initial interdisciplinary collaboration meeting takes place in the patient's home, is crucial for a good result. The general practitioners' perception of their 'disconnection' during hospitalization and prior to discharge has the potential to reduce patient safety. The family seems to be fundamental in gaining more time at home for the patient and supporting the patient to eventually die at home. Home-based palliative care demands experience and competence as well as regular supportive mentoring. PMID- 30021582 TI - Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology. AB - Cystic Fibrosis (CF) is a genetic disorder that arises due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene, which encodes for a protein responsible for ion transport out of epithelial cells. This leads to a disruption in transepithelial Cl-, Na + and HCO3- ion transport and the subsequent dehydration of the airway epithelium, resulting in infection, inflammation and development of fibrotic tissue. Unlike in CF, fibrosis in other lung diseases including asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis has been well characterised. One of the driving forces behind fibrosis is Epithelial Mesenchymal Transition (EMT), a process where epithelial cells lose epithelial proteins including E-Cadherin, which is responsible for tight junctions. The cell moves to a more mesenchymal phenotype as it gains mesenchymal markers such as N-Cadherin (providing the cells with migration potential), Vimentin and Fibronectin (proteins excreted to help form the extracellular matrix), and the fibroblast proliferation transcription factors Snail, Slug and Twist. This review paper explores the EMT process in a range of lung diseases, details the common links that these have to cystic fibrosis, and explores how understanding EMT in cystic fibrosis may open up novel methods of treating patients with cystic fibrosis. PMID- 30021584 TI - Footwear for self-managing knee osteoarthritis symptoms: protocol for the Footstep randomised controlled trial. AB - BACKGROUND: Knee osteoarthritis (OA) is a leading cause of musculoskeletal pain and disability globally, and abnormal knee loading is central to disease pathogenesis. Clinical guidelines recommend clinicians provide advice regarding appropriate footwear for people with knee OA, yet there is little research comparing the effects of different footwear on knee OA symptoms. Research suggests that wearing flat flexible shoes is associated with lower knee joint loads compared to stable supportive shoe styles. This two-arm pragmatic, comparative effectiveness randomised controlled trial will compare the effects of daily use of flat flexible shoes and stable supportive shoes on knee OA clinical outcomes, over 6 months. METHODS: 164 people with symptomatic medial tibiofemoral OA of moderate to severe radiographic severity (Kellgren and Lawrence Grade 3 & 4) will be recruited from the community. Following baseline assessment, participants will be randomly allocated to receive either i) flat flexible shoes or; ii) stable supportive shoes. Participants will choose two different pairs of shoes from a selection that fulfil the criteria in their allocated shoe class. Limited disclosure will blind participants to group allocation. Participants will be instructed to wear their allocated shoes daily for 6 months (minimum of 6 h/day), after which participants will be reassessed. The primary outcomes are knee pain severity on walking (measured by numerical rating scale) and self reported physical function (measured by the Western Ontario and McMaster Universities Osteoarthritis Index), assessed at baseline and 6 months. Secondary outcomes include additional measures of knee pain, function, sport and recreation participation and quality-of-life (measured using subscales of the Knee Osteoarthritis Outcome Score), as well as pain at other sites (measured by numerical rating scale), self-reported global ratings of change in pain and physical function (measured by 7-point rating scale), and physical activity levels (measured by Physical Activity Scale for the Elderly). DISCUSSION: This study will determine whether daily wear of flat flexible shoes improves clinical outcomes in the management of knee OA, compared to stable supportive shoes. Findings will assist clinicians in providing evidence-based advice regarding appropriate footwear for people with knee OA to self-manage symptoms. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry reference: ACTRN12617001098325 . Registered 28/07/2017. PMID- 30021585 TI - Age-dependent bone loss and recovery during hindlimb unloading and subsequent reloading in rats. AB - BACKGROUND: Bone structure and strength are rapidly lost during conditions of decreased mechanical loading, and aged bones have a diminished ability to adapt to increased mechanical loading. This is a concern for older patients that experience periods of limited mobility or bed rest, but the acute effects of disuse on the bones of aged patients have not been thoroughly described. Previous animal studies have primarily examined the effect of mechanical unloading on young animals. Those that have studied aged animals have exclusively focused on bone loss during unloading and not bone recovery during subsequent reloading. In this study, we investigated the effect of decreased mechanical loading and subsequent reloading on bone using a hindlimb unloading model in Adult (9 month old) and Aged (28 month old) male rats. METHODS: Animals from both age groups were subjected to 14 days of hindlimb unloading followed by up to 7 days of reloading. Additional Aged rats were subjected to 7 days of forced treadmill exercise during reloading or a total of 28 days of reloading. Trabecular and cortical bone structure of the femur were quantified using ex vivo micro-computed tomography (MUCT), and mechanical properties were quantified with mechanical testing. RESULTS: We found that Adult rats had substantially decreased trabecular bone volume fraction (BV/TV) following unloading (- 27%) while Aged animals did not exhibit significant bone loss following unloading. However, Aged animals had lower trabecular BV/TV after 3 days of reloading (- 20% compared to baseline), while trabecular BV/TV of Adult rats was not different from baseline values after 3 days of reloading. Trabecular BV/TV of Aged animals remained lower than control animals even with exercise during 7 days of reloading and after 28 days of reloading. CONCLUSIONS: These data suggest that aged bone is less responsive to both increased and decreased mechanical loading, and that acute periods of disuse may leave older subjects with a long-term deficit in trabecular bone mass. These finding indicate the need for therapeutic strategies to improve the skeletal health of elderly patients during periods of disuse. PMID- 30021586 TI - Does special education in palliative medicine make a difference in end-of-life decision-making? AB - BACKGROUND: Characteristics of the physician influence the essential decision making in end-of-life care. However, the effect of special education in palliative medicine on different aspects of decision-making in end-of-life care remains unknown. The aim of this study was to explore the decision-making in end of-life care among physicians with or without special competency in palliative medicine (cPM). METHODS: A questionnaire including an advanced lung cancer patient-scenario with multiple decision options in end-of-life care situation was sent to 1327 Finnish physicians. Decisions to withdraw or withhold ten life prolonging interventions were asked on a scale from 1 (definitely would not) to 5 (definitely would) - first, without additional information and then after the family's request for aggressive treatment and the availability of an advance directive. Values from chronological original scenario, family's appeal and advance directive were clustered by trajectory analysis. RESULTS: We received 699 (53%) responses. The mean values of the ten answers in the original scenario were 4.1 in physicians with cPM, 3.4 in general practitioners, 3.4 in surgeons, 3.5 in internists and 3.8 in oncologists (p < 0.05 for physicians with cPM vs. oncologists and p < 0.001 for physicians with cPM vs. others). Younger age and not being an oncologist or not having cPM increased aggressive treatment decisions in multivariable logistic regression analysis. The less aggressive approach of physicians with cPM differed between therapies, being most striking concerning intravenous hydration, nasogastric tube and blood transfusions. The aggressive approach increased by the family's request (p < 0.001) and decreased by an advance directive (p < 0.001) in all physicians, regardless of special education in palliative medicine. CONCLUSION: Physicians with special education in palliative medicine make less aggressive decisions in end-of-life care. The impact of specialty on decision-making varies among treatment options. Education in end-of-life care decision-making should be mandatory for young physicians and those in specialty training. PMID- 30021587 TI - Effect of local infiltration analgesia, peripheral nerve blocks, general and spinal anesthesia on early functional recovery and pain control in total knee arthroplasty. AB - BACKGROUND: Postoperative pain control and enhanced mobilization, muscle strength and range of motion following total knee arthroplasty (TKA) are pivotal requisites to optimize rehabilitation and early recovery. The aim of the study was to analyze the effect of local infiltration analgesia (LIA), peripheral nerve blocks, general and spinal anesthesia on early functional recovery and pain control in primary total knee arthroplasty. METHODS: Between January 2016 until August 2016, 280 patients underwent primary TKA and were subdivided into four groups according to their concomitant pain and anesthetic procedure with catheter based techniques of femoral and sciatic nerve block (group GA&FNB, n = 81) or epidural catheter (group SP&EPI, n = 51) in combination with general anesthesia or spinal anesthesia, respectively, and LIA combined with general anesthesia (group GA&LIA, n = 86) or spinal anesthesia (group SP&LIA, n = 61). Outcome parameters focused on the evaluation of pain (NRS scores), mobilization, muscle strength and range of motion up to 7 days postoperatively. The cumulative consumption of (rescue) pain medication was analyzed. RESULTS: Pain relief was similar in all groups, while the use of opioid medication was significantly lower (up to 58%) in combination with spinal anesthesia, especially in SP&EPI. The LIA groups, in contrast, revealed significant higher mobilization (up to 26%) and muscle strength (up to 20%) in the early postoperative period. No analgesic technique-related or surgery-related complications occurred within the first 7 days. Due to insufficient pain relief, 8.4% of the patients in the catheter-based groups and 12.2% in the LIA groups resulted in a change of the anesthetics pain management. CONCLUSIONS: The LIA technique offers a safe and effective treatment option concerning early functional recovery and pain control in TKA. Significant advantages were shown for mobilization and muscle strength in the early postoperative period while pain relief was comparable within the groups. PMID- 30021588 TI - A randomised controlled trial of the clinical and cost-effectiveness of ultrasound-guided intra-articular corticosteroid and local anaesthetic injections: the hip injection trial (HIT) protocol. AB - BACKGROUND: Evidence on the effectiveness of intra-articular corticosteroid injection for hip osteoarthritis is limited and conflicting. The primary objective of the Hip Injection Trial (HIT) is to compare pain intensity over 6 months, in people with hip OA between those receiving an ultrasound-guided intra articular hip injection of corticosteroid with 1% lidocaine hydrochloride plus best current treatment with those receiving best current treatment alone. Secondary objectives are to determine specified comparative clinical and cost effectiveness outcomes, and to explore, in a linked qualitative study, the lived experiences of patients with hip OA and experiences and impact of, ultrasound guided intra-articular hip injection. METHODS: The HIT trial is a pragmatic, three-parallel group, single-blind, superiority, randomised controlled trial in patients with painful hip OA with a linked qualitative study. The current protocol is described, in addition to details and rationale for amendments since trial registration. 204 patients with moderate-to-severe hip OA will be recruited. Participants are randomised on an equal basis (1:1:1 ratio) to one of three interventions: (1) best current treatment, (2) best current treatment plus ultrasound-guided intra-articular hip injection of corticosteroid (triamcinolone acetonide 40 mg) with 1% lidocaine hydrochloride, or (3) best current treatment plus an ultrasound-guided intra-articular hip injection of 1% lidocaine hydrochloride alone. The primary endpoint is patient-reported hip pain intensity across 2 weeks, 2 months, 4 months and 6 months post-randomisation. Recruitment is over 29 months with a 6-month follow-up period. To address the primary objective, the analysis will compare participants' 'average' follow-up pain NRS scores, based on a random effects linear repeated-measures model. Data on adverse events are collected and reported in accordance with national guidance and reviewed by external monitoring committees. Individual semi-structured interviews are being conducted with up to 30 trial participants across all three arms of the trial. DISCUSSION: To ensure healthcare services improve outcomes for patients, we need to ensure there is a robust and appropriate evidence-base to support clinical decision making. The HIT trial will answer important questions regarding the clinical and cost-effectiveness of intra-articular corticosteroid injections. TRIAL REGISTRATION: ISRCTN: 50550256 , 28th July 2015. PMID- 30021589 TI - In vitro antiviral activity of twenty-seven medicinal plant extracts from Southwest Nigeria against three serotypes of echoviruses. AB - BACKGROUND: Echoviruses, a serotype of enteroviruses, infect millions of people globally and there is no specific drug treatment or vaccine available for its management. The screening of medicinal plants used locally for the treatment of infectious diseases, can provide a reliable option in the discovery of potent therapeutic compounds. This study was carried out to investigate the antiviral activities of 27 medicinal plant extracts, belonging to 26 different plant species, selected from Nigerian ethnobotany, against echovirus 7, 13 and 19 serotypes (E7, E13 and E19, respectively). METHODS: The plants were macerated in methanol and the cytotoxicities of the crude extracts were evaluated on the rhabdomyosarcoma cell line using the MTT assay. The antiviral activity of the plant extracts and fractions against echoviruses (E7, E13, and E19) was determined using the neutralisation assay, an assay that measures the inhibition of cytopathic effect on cell culture. RESULTS: The crude extract of Macaranga barteri leaves had the highest cytotoxicity with CC50 value of 0.27 MUg/mL. This was followed by Crinum jagus (9.88 MUg/mL) and Terminalia ivorensis (12.14 MUg/mL). The antiviral screening showed that ten out of the 27 crude plant extracts tested were active on E7 and E19, inhibiting the cytopathic effect of the virus in tissue culture. None of the extracts inhibited the cytopathic effect caused by E13 serotype. Amongst the active plant extracts, the methanol extract of M. barteri leaves had the highest antiviral activity on both E7 and E9 with IC50 values of 0.028 and 0.0017 ng/mL, respectively, followed by the Ageratum conyzoides extract (0.208 MUg/mL, E7; 0.006 MUg/mL, E19) and Mondia whitei extract (0.038 MUg/mL, E7; 0.005 MUg/mL, E19). Amongst the fractions of M. barteri, the DCM fraction was most the active and selective on E7 (IC50 = 0.0075 ng/mL; SI = 19,896.54) and E19 (IC50 = 0.0175 ng/mL; SI = 8581.24). CONCLUSION: Our research has demonstrated that Macaranga barteri extracts has potent antiviral activity against echoviruses E7 and E19, and our findings suggest that this extract may have potential as a therapeutic agent in the treatment of enteroviral infections. PMID- 30021591 TI - Platelet storage induces accelerated desialylation of platelets and increases hepatic thrombopoietin production. AB - BACKGROUND: Stored platelets undergo deleterious changes, referred to as platelet storage lesions (PSLs), which accelerate the desialylation of platelets and result in their phagocytosis and clearance by hepatic macrophages. Recent studies have reported that Ashwell-Morell receptor binds to desialylated platelets, thereby inducing hepatic thrombopoietin (TPO) production in a mouse model. Therefore, this study aimed to demonstrate these relationships between PSL and hepatic TPO production in human study. METHODS: Platelet concentrates (PCs) were obtained from 5 healthy volunteers and the remaining were discarded samples from the blood bank. PCs were divided into two halves, and stored either at 22 or 4 degrees C. Experiments were conducted using serial samples. Desialylation was assessed using flow cytometry, and structural changes were visualized using electron microscopy. Following co-culture of HepG2 cells (HB-8065, ATCC) with isolated platelets, hepatic TPO production was determined using real-time quantitative polymerase chain reaction and the supernatant TPO level was measured using a Luminex kit. RESULTS: For 5 days of storage duration, platelet counts were not influenced by the storage conditions, but the degree of desialylation was proportional to the storage duration. Significant changes in the platelet surface and structure according to storage conditions were noted in electron microscopy. HepG2 cells incubated with aged platelets expressed more TPO mRNA, and supernatant TPO levels were proportional to the storage duration. Refrigeration also influenced on the results of this study, but they were not statistically significant. CONCLUSIONS: This is the first study to demonstrate that, in vitro, aging and refrigeration affect the integrity of human platelets, resulting in induction of hepatic TPO mRNA and protein expression. PMID- 30021590 TI - The association between body fat and musculoskeletal pain: a systematic review and meta-analysis. AB - BACKGROUND: Obesity and musculoskeletal pain are strongly related, but there is emerging evidence that body fat, not body weight, may be a better indicator of risk. There is, therefore, a need to determine if body fat is associated with musculoskeletal pain as it may improve management strategies. The aim of this systematic review was to investigate the association between body fat and musculoskeletal pain. METHODS: Seven electronic databases were searched from inception to 8th January 2018. Cross-sectional and longitudinal studies investigating the association between measures of body fat and musculoskeletal pain were included. All included articles were assessed for methodological rigour using the Epidemiology Appraisal Instrument. Standardised mean differences (SMDs) and effect estimates were pooled for meta-analysis. RESULTS: A total of 10,221 citations were identified through the database searching, which after abstract and full-text review, yielded 28 unique articles. Fourteen studies were included in the meta-analyses, which found significant cross-sectional associations between total body fat mass and widespread pain (SMD 0.49, 95% CI 0.37-0.61, p < 0.001). Individuals with low-back pain and knee pain had a higher body fat percentage than asymptomatic controls (SMD 0.34, 95% CI 0.17-0.52, p < 0.001 and SMD 0.18, 95% CI 0.05-0.32, p = 0.009, respectively). Fat mass index was significantly, albeit weakly, associated with foot pain (SMD 0.05, 95% CI 0.03 0.06, p < 0.001). Longitudinal studies (n = 8) were unsuitable for meta-analysis, but were largely indicative of elevated body fat increasing the risk of incident and worsening joint pain. There was conflicting evidence for an association between body fat percentage and incident low-back pain (3 studies, follow-up 4-20 years). Increasing knee pain (1 study) and incident foot pain (2 studies) were positively associated with body fat percentage and fat mass index. The percentage of items in the EAI graded as 'yes' for each study ranged from 23 to 85%, indicating variable methodological quality of the included studies. CONCLUSIONS: This systematic review and meta-analysis identified positive cross-sectional associations between increased body fat and widespread and single-site joint pain in the low-back, knee and foot. Longitudinal studies suggest elevated body fat may infer increased risk of incident and worsening joint pain, although further high-quality studies are required. PMID- 30021592 TI - A group-based lifestyle intervention for diabetes prevention in low- and middle income country: implementation evaluation of the Kerala Diabetes Prevention Program. AB - BACKGROUND: While several efficacy trials have demonstrated diabetes risk reduction through targeting key lifestyle behaviours, there is a significant evidence gap in relation to the successful implementation of such interventions in low- and middle-income countries (LMICs). This paper evaluates the implementation of a cluster randomised controlled trial of a group-based lifestyle intervention among individuals at high-risk of developing type 2 diabetes mellitus (T2DM) in the state of Kerala, India. Our aim is to uncover provider-, participant- and community-level factors salient to successful implementation and transferable to other LMICs. METHODS: The 12-month intervention program consisted of (1) a group-based peer-support program consisting of 15 sessions over a period of 12 months for high-risk individuals, (2) peer leader (PL) training and ongoing support for intervention delivery, (3) diabetes education resource materials and (4) strategies to stimulate broader community engagement. The evaluation was informed by the RE-AIM and PIPE frameworks. RESULTS: Provider-level factors: Twenty-nine (29/30, 97%) intervention groups organised all 15 sessions. A 2-day PL training was attended by 51(85%) of 60 PLs. The PL handbook was found to be 'very useful' by 78% of PLs. Participant-level factors: Of 1327 eligible individuals, 1007(76%) participants were enrolled. On average, participants attended eight sessions. Sixty-eight percent rated their interest in group sessions as 'very interested', and 55% found the group sessions 'very useful' in making lifestyle changes. Inconvenient time (43%) and location (21%) were found to be important barriers for participants who did not attend any sessions. Community-level factors: Community-based activities reached to 41% of the participants for walking groups, 40% for kitchen garden training, and 31% for yoga training. PLs were readily available for support outside the sessions, as 75% of participants reported extracurricular contacts with their PLs. The commitment from the local partner institute and political leaders facilitated the high uptake of the program. CONCLUSION: A comprehensive evaluation of program implementation from the provider-, participant- and community-level perspectives demonstrates that the K DPP program was feasible and acceptable in changing lifestyle behaviours in high risk individuals. The findings from this evaluation will guide the future delivery of structured lifestyle modification diabetes programs in LMICs. TRIAL REGISTRATION: Trial registration: Australia and New Zealand Clinical Trials Registry ACTRN12611000262909 . Registered 10 March 2011. PMID- 30021594 TI - Workplace wellness: industry associations are well placed and some are ready to take a more active role in workplace health. AB - BACKGROUND: Investments in settings-based health interventions can include workplaces, however, engaging with businesses and convincing them to take a role can be difficult. Our research investigated the potential for trade or industry associations (IAs) to have a role in promoting workplace health initiatives to their members. METHODS: Seventeen semi-structured interviews were undertaken with senior executives from IAs representing industries in the mining, transport, agriculture, manufacturing, farming, hospitality, and construction sectors. Analysis of interviews identified themes around attitudes to workplace health promotion programs and the perceived, actual and potential role/s of IAs in promoting workplace wellness. RESULTS: IA representatives believed workplaces had potential to be promoting the health and wellbeing of workers through their member organisations; however for some the extent of their role was unclear and for others there was confusion between government-mandated safety initiatives and non-mandated health and wellbeing initiatives. All reported that their IA could have a role in promoting worker health and wellbeing initiatives to member organisations. IAs with larger companies as members were more likely to recognise the importance of workplaces promoting workers' health; however, the degree of involvement considered appropriate varied. Most IAs had not discussed the topic with their member organisations although they identified resources and support that could assist them in encouraging members to undertake workplace health programs. Resources included industry-relevant business cases outlining the benefits of workplace health, and industry-appropriate worker health information. CONCLUSIONS: Our research suggests that across many industry sectors, larger IAs in particular are ready to take a more active role in workplace health initiatives and are well placed to promote these to member organisations. PMID- 30021595 TI - Kikuchi-Fujimoto disease in children: two case reports and a review of the literature. AB - BACKGROUND: Kikuchi-Fujimoto disease is a rare, idiopathic and generally self limiting cause of lymphadenitis of unknow etiology with a low recurrence rate. The typical clinical signs are cervical lymphadenopathy, fever, and symptoms of respiratory infection, and less frequently chills, night sweats, arthralgia, rash, and weight loss. CASE PRESENTATION: Here we describe two case reports of Kikuchi Fujimoto disease presenting in Milan within the space of a few months. The first involved the recurrence of KFD in a young boy from Sri Lanka; the second was a rare case of severe KFD complicated by HLH. CONCLUSIONS: Pediatricians must consider KFD in the differential diagnosis of fever of unknown origin in children, even in western countries. Although rare, recurrence and severe complications are possible. Where symptoms suggest KFD, a systematic diagnostic approach is key. Since no guidelines on the management of KFD are available, further studies should be conducted to investigate the therapeutic options and long term outcome in children. PMID- 30021593 TI - Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA. AB - BACKGROUND: Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. RESULTS: Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic. CONCLUSIONS: With dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information. PMID- 30021596 TI - Recovery of kinematic arm function in well-performing people with subacute stroke: a longitudinal cohort study. AB - BACKGROUND: Most motor function improvements in people who have experienced strokes occur within the first 3 months. However, individuals showing complete or nearly complete arm function recovery, as assessed using clinical scales, still show certain movement kinematic deficits at 3 months, post-stroke. This study evaluated the changes in upper extremity kinematics, in individuals demonstrating minor clinical motor impairments, 3-12 months post-stroke, and also examined the association between kinematics and the subjects's self-perceived hand abilities during the chronic stage, 12 months post-stroke. METHODS: Forty-two subjects recovering from strokes and having Fugl-Meyer upper extremity motor assessment scores >=60 were included from the Stroke Arm Longitudinal Study at the University of Gothenburg (SALGOT). Kinematic analyses of a drinking task, performed 3, 6, and 12 months post-stroke, were compared with kinematic analyses performed in 35 healthy controls. The Stroke Impact Scale-Hand domain was evaluated at the 12-month follow-up. RESULTS: There were no significant changes in kinematic performance between 3 and 12 months, post-stroke. The patients recovering from stroke showed lower peak elbow extension velocities, and increased shoulder abduction and trunk displacement during drinking than did healthy controls, at all time points. At 12 months, post-stroke, better self perceived arm functions correlated with improved trunk displacements, movement times, movement units, and time to peak velocity percentages. CONCLUSION: Kinematic movement deficits, observed at 3 months post-stroke, remained unchanged at 12 months. Movement kinematics were associated with the patient's self perceived ability to use their more affected hand. TRIAL REGISTRATION: ClinicalTrials: NCT01115348 . PMID- 30021597 TI - Lipid profiles in adolescents with and without asthma: Korea National Health and nutrition examination survey data. AB - BACKGROUND: Metabolic syndrome and dyslipidemia contribute to the development of a pro-inflammatory state in asthma. However, studies investigating the association between asthma and dyslipidemia have reported conflicting results. This study aimed to uncover the relationship between asthma and lipid profiles in adolescents using a national health and nutrition survey. METHODS: This cross sectional study analyzed the 2010-2012 Korea National Health and Nutrition Examination Survey data and included 2841 subjects aged 11-18 years with fasting blood sample data. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were analyzed. We compared asthma prevalence between high-risk and low risk lipid groups. RESULTS: There were 123 adolescents with asthma and 2718 without asthma (controls). The TC/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C levels were significantly higher in the asthma group than in the non-asthma group (P < 0.05). The high-risk groups displayed significantly higher asthma prevalence with higher TC, TG, LDL-C, and non-HDL-C levels and TG/HDL-C ratio than the low risk groups (P < 0.05). After adjusting for potential confounding factors, the high-risk groups were associated with asthma according to their higher TC levels (adjusted odds ratio, 1.69; 95% confidence interval, 1.012-2.822) and TG/HDL-C ratios (adjusted odds ratio, 1.665; 95% confidence interval, 1.006-2.756). CONCLUSIONS: Asthma prevalence was greater in adolescents with a high TC level and TG/HDL-C ratio. In addition to the standard lipid profile, elevated TG/HDL-C ratio can be used as a useful additional lipid measure to evaluate interactions between dyslipidemia and asthma. PMID- 30021598 TI - Evaluation of the correlation of MACC1, CD44, Twist1, and KiSS-1 in the metastasis and prognosis for colon carcinoma. AB - BACKGROUND: Metastasis-associated in colon cancer 1 (MACC1) has been reported to promote tumor cell invasion and metastasis. Cancer stem cells and epithelial mesenchymal transition (EMT) have also been reported to promote tumor cell proliferation, invasion, and metastasis. KiSS-1, a known suppressor of metastasis, has been reported to be down-regulated in various tumors. However, the associations of MACC1, CD44, Twist1, and KiSS-1 in colonic adenocarcinoma (CAC) invasion and metastasis remain unclear. The purpose of this study is to investigate the roles of MACC1, CD44, Twist1, and KiSS-1 in CAC invasion and metastasis and their associations with each other and with the clinicopathological characteristics of CAC patients. METHODS: Immunohistochemistry and multivariate analysis were carried out to explore the expression of MACC1, CD44, Twist1, and KiSS-1 in 212 whole-CAC-tissue specimens and the corresponding normal colon mucosa tissues. Demographic, clinicopathological, and follow-up data were also collected. RESULTS: The results of this study showed MACC1, CD44, and Twist1 expression to be up-regulated, and KiSS-1 expression was down-regulated in CAC tissues. Positive expression of MACC1, CD44, and Twist1 was found to be positively correlated with invasion, tumor grades, and lymph- node-metastasis (LNM) stages and tumor-node-metastasis (TNM) stages for patients with CAC. Positive expression of KiSS-1 was inversely associated with invasion, tumor size, LNM stage, and TNM stage. The KiSS-1 positive expression group had significantly more favorable OS than did the KiSS-1 negative group. Univariate analysis indicated that overexpression of MACC1, CD44, and Twists1 was negatively associated with longer overall survival (OS) time, and there was a positive relationship between KiSS-1-positive expression and OS time for patients with CAC. Multivariate Cox analysis demonstrated that overexpression of MACC1, CD44, Twist1, and low expression of KiSS-1 and LNM and TNM stages were independent predictors of prognosis in patients with CAC. CONCLUSIONS: The results in this study indicated that levels of expression of MACC1, CD44, Twist1, and KiSS-1 are related to the duration of OS in patients with CAC. MACC1, CD44, Twist1, and KiSS-1 may be suitable for use as biomarkers and therapeutic targets in CAC. PMID- 30021599 TI - Anatomy of the ventricular septal defect in congenital heart defects: a random association? AB - BACKGROUND: A ventricular septal defect (VSD) is an integral part of most congenital heart defects (CHD). To determine the prevalence of VSD in various types of CHD and the distribution of their anatomic types. METHODS: We reviewed 1178 heart specimens with CHD from the anatomic collection of the French Reference Centre for Complex Congenital Heart Defects. During the morphologic study a special attention was paid to the localisation of the VSD viewed from the right ventricular side. The VSDs were classified as muscular, central perimembranous, outlet located between the two limbs of the septal band, and inlet. The specimens were classified according to the 9 categories and 23 subcategories of the anatomic and clinical classification of CHD1 (ACC-CHD). RESULTS: Ventricular septum was almost always intact in anomalies of pulmonary veins (4/73, 5%), Ebstein anomaly (3/21, 14%), and double-inlet right ventricle (DIRV, 1/10, 10%). There was always a VSD in tetralogy of Fallot and variants (TOF, 123 cases) and common arterial trunk (CAT, 55 cases), always of the outlet type. There was almost always a VSD in double inlet left ventricle (33/34, 97%, always muscular), congenitally corrected transposition of great arteries (ccTGA, 23/24, 96%), interrupted aortic arch (IAA, 25/27, 93%), and double outlet right ventricle (DORV, 92/106, 87%). A VSD was found in 68% of aortic coarctation (CoA, 43/63), 62% of heterotaxy syndromes (21/34), 54% of transposition of the great arteries (TGA, 104/194). The VSD was located between the two limbs of the septal band in 100% of TOF and CAT, 80% of IAA, 77% of DORV, 82% of DD. The VSD was of the inlet type in 17% of cc TGA and in 71% of heterotaxy syndromes. In TGA, the VSD was outlet in 40%, central perimembranous in 25%, muscular in 25%, inlet in 10%. In CoA, the VSD was outlet in 44%, central perimembranous in 35%, muscular in 21%. In the 10% hearts with isolated VSD, the distribution was outlet in 44%, central perimembranous in 36%, muscular in 18%, and inlet in 2%. CONCLUSION: The anatomic distribution of VSD is similar in isolated VSD, CoA and TGA, while the VSD is predominantly outlet in outflow tract defects except TGA. This reinforces the allegedly different mechanisms in TGA and cardiac neural crest defects. This anatomic approach could provide new insights in the grouping and aetiology of CHD. PMID- 30021600 TI - Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K/AKT signaling. AB - BACKGROUND: Bone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological role of miR-133a-3p and its molecular mechanisms underlying bone metastasis of PCa remain unclear. METHODS: miR-133a-3p expression was evaluated in 245 clinical PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-133a-3p expression and clinicopathological features, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-133a-3p in the bone metastasis of PCa were investigated both in vitro and in vivo. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to demonstrate the relationship between miR-133a-3p and its potential targets. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the anti-tumor role of miR-133a-3p. Clinical correlation of miR-133a-3p with its targets was verified in human PCa tissues. RESULTS: miR-133a-3p expression is reduced in PCa tissues compared with the adjacent normal tissues and benign prostate lesion tissues, particularly in bone metastatic PCa tissues. Low expression of miR-133a-3p is significantly correlated with advanced clinicopathological characteristics and shorter bone metastasis-free survival in PCa patients by statistical analysis. Moreover, upregulating miR-133a-3p inhibits cancer stem cell-like phenotypes in vitro and in vivo, as well as attenuates anoikis resistance in vitro in PCa cells. Importantly, administration of agomir 133a-3p greatly suppresses the incidence of PCa bone metastasis in vivo. Our results further demonstrate that miR-133a-3p suppresses bone metastasis of PCa via inhibiting PI3K/AKT signaling by directly targeting multiple cytokine receptors, including EGFR, FGFR1, IGF1R and MET. The negative clinical correlation of miR-133a-3p with EGFR, FGFR1, IGF1R, MET and PI3K/AKT signaling activity is determined in clinical PCa tissues. CONCLUSION: Our results unveil a novel mechanism by which miR-133a-3p inhibits bone metastasis of PCa, providing the evidence that miR-133a-3p may serve as a potential bone metastasis marker in PCa, and delivery of agomir-133a-3p may be an effective anti-bone metastasis therapeutic strategy in PCa. PMID- 30021601 TI - Factors influencing on health-related quality of life in South Korean with chronic liver disease. AB - BACKGROUND: The objective of this study was to determine health-related quality of life (HRQoL) among chronic liver disease (CLD) subjects in South Korea using EuroQol five-dimension questionnaire (EQ-5D). METHOD: The sample consisted of 139 subjects with CLD from the sixth Korean National Health and Nutrition Examination Survey (KNHNES VI). Data were analyzed using SPSS program for descriptive statistics, t-test, ANOVA, Scheffe's test and hierarchical multiple regression. RESULTS: Results indicated that marital status (P < 0.01), occupation (P < 0.01), basic livelihood security recipient status (P < 0.05), hepatocellular carcinoma (P < 0.05), subjective health status (P < 0.01), and depression (P < 0.001) were significant predictors of HRQoL. Health behaviors (alcohol intake, sleep duration) variables were insignificant. CONCLUSION: In conclusion, marital status, occupation, basic livelihood security recipient status (BLSRS), hepatocellular carcinoma (HCC), subjective health status (SHS), and depression were confirmed to be factors affecting the HRQoL. We should be provide to continuous monitoring and education of adequate alcohol intake for patients with CLD. Findings of this study might be used to develop community based health programs and policies for CLD. PMID- 30021602 TI - MicroRNAs are appropriate in mitochondrial related hearing loss? Answer to the skepticism. AB - AIM: We aim to clarify some points that have been criticized about our previous paper "Hearing Impairment in MELAS: new prospective in clinical use of microRNA, a systematic review". MATERIAL AND METHOD: We answered to the criticism of Dr. Finsterer point by point, by citing all literature in support of our previous paper. CONCLUSION: The point by point answering allows us to clarify doubts and to support the proposal that we exposed in our review, the possibility to use microRNA for detecting the hearing damage in patients affected from mitochondrial disease. PMID- 30021603 TI - SR-FTIR as a tool for quantitative mapping of the content and distribution of extracellular matrix in decellularized book-shape bioscaffolds. AB - BACKGROUND: To evaluate synchrotron radiation-based Fourier transform infrared microspectroscopy (SR-FTIR) as a tool for quantitative mapping of the content and distribution of the extracellular matrix in decellularized fibrocartilage bioscaffolds, and to provide a new platform for quantitatively characterizing bioscaffolds for tissue engineering. METHODS: Fibrocartilage was harvested and cut into book-shape bioscaffolds (N = 54), which were then decellularized. The structures and distribution of collagen fibrous and intrinsic ultrastructure in decellularized fibrocartilage bioscaffolds were evaluated by histological staining and scanning electron microscopy (SEM), respectively. The content of collagen and proteoglycan in the cellularized or decellularized bioscaffolds were also measured by SR-FTIR and biochemical assay. RESULTS: Book-shape fibrocartilage decellularized bioscaffolds were successfully obtained. Histological examination revealed that the structure of extracellular matrix endured during decellularization. Histology and DNA quantification analysis confirmed substantial removal of cells during decellularization. SEM demonstrated that intrinsic ultrastructure of the fibrocartilage bioscaffold was also well preserved. SR-FTIR quantitative analysis confirmed that decellularization had a significant effect on the content and distribution of collagen and proteoglycan in fibrocartilage bioscaffolds, these results are confirmed with the biochemical assay results. CONCLUSION: SR-FTIR imaging can capture the histological morphology of decellularized bioscaffolds. Moreover, it can be used for quantitative mapping of the content and distribution of collagen in the bioscaffolds. PMID- 30021604 TI - Paired box 8 suppresses tumor angiogenesis and metastasis in gastric cancer through repression of FOXM1 via induction of microRNA-612. AB - BACKGROUND: Paired box 8 (PAX8) has been documented to be downregulated in gastric cancer. However, its biological function in this malignancy is poorly understood. METHODS: In the present work, we investigated the effects of PAX8 overexpression and knockdown on the aggressive phenotype of gastric cancer cells. We further checked the involvement of forkhead box M1 (FOXM1), a ubiquitously expressed oncogene that can facilitate gastric cancer progression, in the action of PAX8. RESULTS: Ectopic expression of PAX8 blocked the migration and invasion of both AGS and SGC-7901 cells, but had no effect on cell proliferation. Conversely, knockdown of PAX8 enhanced gastric cancer cell migration and invasion. PAX8 overexpression inhibited epithelial-mesenchymal transition (EMT) and pro-angiogenic activity of gastric cancer cells. Mechanistically, PAX8 overexpression downregulated FOXM1 by stimulating microRNA (miR)-612 expression. Ectopic expression of miR-612 recapitulated the effect of PAX8 overexpression on gastric cancer cells, causing an inhibition of migration, invasion, EMT, and angiogenesis. Knockdown of miR-612 or overexpression of FOXM1 significantly reversed the tumor-suppressive activity of PAX8. In vivo studies further demonstrated that PAX8 overexpression restrained tumor angiogenesis and metastasis in nude mice, which was accompanied by increased expression of miR-612 and decreased expression of FOXM1. CONCLUSIONS: PAX8 exerts a tumor-suppressive effect against gastric cancer cells, largely through induction of miR-612 and repression of FOXM1. Therefore, restoration of PAX8 expression may offer therapeutic benefits in the treatment of gastric cancer. PMID- 30021605 TI - Association between circulating full-length angiopoietin-like protein 8 and non high-density lipoprotein cholesterol levels in Chinese non-diabetic individuals: a cross-sectional study. AB - BACKGROUND: Angiopoietin-like protein 8 (ANGPTL8) is a novel hormone involved in the regulation of lipid metabolism and glucose homeostasis. There are inconsistent results regarding the association between ANGPTL8 and lipids in humans. We aimed to investigate the associations between ANGPTL8 and lipids in people without diabetes. METHODS: This was a cross-sectional study of 107 patients with dyslipidemia and 141 patients without. Dyslipidemia diagnosis was based on Chinese guidelines for the prevention and treatment of dyslipidemia in adults. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C) were examined. Non HDL-C was calculated by subtracting HDL-C from TC. Circulating full-length ANGPTL8 concentrations were measured using enzyme-linked immunosorbent assay. Associations between log-transformed circulating full-length ANGPTL8 and serum lipids were examined using multivariate linear regression analysis. RESULTS: Circulating ANGPTL8 concentrations were significantly elevated in patients with dyslipidemia compared with patients without dyslipidemia. Circulating full-length ANGPTL8 concentrations were positively associated with non-HDL-C, TG and TC levels after adjusting for age, gender, body mass index, high-sensitivity C reactive protein, alanine aminotransferase, and creatinine. CONCLUSION: In people without diabetes, circulating full-length ANGPTL8 concentrations in patients with dyslipidemia were significantly elevated compared with non-dyslipidemia, and ANGPTL8 was positively associated with serum non-HDL-C levels. PMID- 30021606 TI - Absorption rate of krill oil and fish oil in blood and brain of rats. AB - BACKGROUND: Krill (Euphausia superba) is a small marine crustacean with a lipid content. The mechanism of Krill oil function is not clear yet and research reports on the absorption rate of the phospholipids of krill oil in the blood and brain are very poor. METHODS: We studied the effect of oral short-term and long term administration of Krill oils (KOs) on bioavailability in the blood and brain of rats. For short-term testing of fish and KO bioavailability, rats were divided into four groups: normal, fish oil (FO), Krill oil 1 (KO), and Krill oil 2 (CKO). The blood and brain were collected at 2, 4, 8, 12, 24, and 48 h after oral administration (1000 mg/rat). Five hundred milligrams of FO, KO, and CKO were orally administered daily for 2 weeks for long-term administration, and then the brain and blood were collected. RESULTS: Two types of KOs showed high content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the PL. The EPA content of CKO and KO were 41.13 and 32.49%, respectively. After short-term KO administration, KO showed a higher EPA content than CKO in the blood after 2 h. KO showed higher content of DHA than CKO even after 2 h. FO increased until 8 h, but then decreased rapidly until 12 h. Although the total unsaturated fatty acid (UFA) content of KOs was lower than the total UFS content in FO, the remaining UFS content in the brain was higher than that in FO over time. Following oral administration of FO, KO, and CKO for 1 and 2 weeks, triglycerides (TG) and PL contents in the blood for KOs were slightly higher than for FO. EPA and DHA levels in the brain were slightly higher in KOs following long-term administration, but the difference was not significant. CONCLUSIONS: Base on these findings, KOs have functional potential for the brain and vascular diseases, and can be utilized as a multi-functional material composed mainly of functional ingredients. PMID- 30021607 TI - Apolipoprotein CIII may mediate the impacts of angiopoietin-like protein 8 on triglyceride metabolism. AB - BACKGROUND: Angiopoietin-like protein 8(ANGPTL8) and apolipoprotein CIII (apoCIII) were found to inhibit the activity of lipoprotein lipase (LPL) and disrupt the clearance of triglyceride-rich lipoproteins (TRLs), leading to hypertriglyceridemia. Whether any relationship exists between these two important modulators of triglyceride metabolism has not been reported. Besides, whether ANGPTL8 concentration is altered in the patients with coronary artery disease (CAD) is still unclear. METHODS: A hospital-based case-control study was conducted. Sixty-eight CAD subjects and fifty-two nonCAD controls were recruited. Plasma apoCIII, ANGPTL8 was measured. RESULTS: ANGPTL8 and apoCIII concentration exhibited no significant difference between CAD group and nonCAD group. Both ANGPTL8 and apoCIII were significantly correlated with triglyceride level(r = - 0.243, P = 0.008; r = 0.335, P < 0.001, respectively). Regression analysis revealed that apoCIII was an independent contributor to triglyceride level independent of ANGPTL8 concentration (standardized beta = 0.230, P < 0.01). CONCLUSION: ApoCIII may mediate the effects of ANGPTL8 on triglyceride metabolism. PMID- 30021608 TI - Effects of mesenchymal stromal cells versus serum on tendon healing in a controlled experimental trial in an equine model. AB - BACKGROUND: Mesenchymal stromal cells (MSC) have shown promising results in the treatment of tendinopathy in equine medicine, making this therapeutic approach seem favorable for translation to human medicine. Having demonstrated that MSC engraft within the tendon lesions after local injection in an equine model, we hypothesized that they would improve tendon healing superior to serum injection alone. METHODS: Quadrilateral tendon lesions were induced in six horses by mechanical tissue disruption combined with collagenase application 3 weeks before treatment. Adipose-derived MSC suspended in serum or serum alone were then injected intralesionally. Clinical examinations, ultrasound and magnetic resonance imaging were performed over 24 weeks. Tendon biopsies for histological assessment were taken from the hindlimbs 3 weeks after treatment. Horses were sacrificed after 24 weeks and forelimb tendons were subjected to macroscopic and histological examination as well as analysis of musculoskeletal marker expression. RESULTS: Tendons injected with MSC showed a transient increase in inflammation and lesion size, as indicated by clinical and imaging parameters between week 3 and 6 (p < 0.05). Thereafter, symptoms decreased in both groups and, except that in MSC-treated tendons, mean lesion signal intensity as seen in T2w magnetic resonance imaging and cellularity as seen in the histology (p < 0.05) were lower, no major differences could be found at week 24. CONCLUSIONS: These data suggest that MSC have influenced the inflammatory reaction in a way not described in tendinopathy studies before. However, at the endpoint of the current study, 24 weeks after treatment, no distinct improvement was observed in MSC-treated tendons compared to the serum-injected controls. Future studies are necessary to elucidate whether and under which conditions MSC are beneficial for tendon healing before translation into human medicine. PMID- 30021609 TI - Western diet feeding influences gut microbiota profiles in apoE knockout mice. AB - BACKGROUND: Gut microbiota plays an important role in many metabolic diseases such as diabetes and atherosclerosis. Apolipoprotein E (apoE) knock-out (KO) mice are frequently used for the study of hyperlipidemia and atherosclerosis. However, it is unknown whether apoE KO mice have altered gut microbiota when challenged with a Western diet. METHODS: In the current study, we assessed the gut microbiota profiling of apoE KO mice and compared with wild-type mice fed either a normal chow or Western diet for 12 weeks using 16S pyrosequencing. RESULTS: On a western diet, the gut microbiota diversity was significantly decreased in apoE KO mice compared with wild type (WT) mice. Firmicutes and Erysipelotrichaceae were significantly increased in WT mice but Erysipelotrichaceae was unchanged in apoE KO mice on a Western diet. The weighted UniFrac principal coordinate analysis exhibited clear separation between WT and apoE KO mice on the first vector (58.6%) with significant changes of two dominant phyla (Bacteroidetes and Firmicutes) and seven dominant families (Porphyromonadaceae, Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae, Helicobacteraceae, Erysipelotrichaceae and Veillonellaceae). Lachnospiraceae was significantly enriched in apoE KO mice on a Western diet. In addition, Lachnospiraceae and Ruminococcaceae were positively correlated with relative atherosclerosis lesion size in apoE KO. CONCLUSIONS: Collectively, our study showed that there are marked changes in the gut microbiota of apoE KO mice, particularly challenged with a Western diet and these alterations may be possibly associated with atherosclerosis. PMID- 30021610 TI - Kawasaki disease: abnormal initial echocardiogram is associated with resistance to IV Ig and development of coronary artery lesions. AB - BACKGROUND: Kawasaki disease (KD) is an acute febrile systemic vasculitis that affects small and medium blood vessels. Intensified treatments for the most severely affected patients have been proposed recently, and the early identification of KD patients at high risk for coronary artery aneurysms (CAA) is crucial. However, the risk scoring systems developed in Japan have not been validated in European populations, and little data is available concerning the link between initial echocardiogram findings other than high z-scores and cardiac prognosis. METHODS: In order to investigate whether the presence of any abnormalities, other than high z-scores in first echocardiogram, are associated with resistance to IV immunoglobulins and/or subsequent development of CAA, we retrospectively analyzed data from children diagnosed with KD between 2006 and 2016 at a tertiary Hospital in Paris, France. RESULTS: A total of 157 children were included. The initial echocardiogram was performed after a median of 7 days of fever and was abnormal in 48 cases (31%). The initial presence of any echocardiographic abnormality (coronary artery dilatation, CAA, pericardial effusion, perivascular brightness of the coronary arteries, left-ventricular dysfunction and mitral insufficiency) was strongly associated with resistance to intravenous immunoglobulin (p = 0.005) and development of coronary artery lesions within the first 6 weeks of disease (p = 0.01). All patients (n = 7) with persistent coronary abnormalities at 1 year already had an abnormal initial echocardiogram. Severity scoring systems from Japan had low sensitivity (0-33%) and low specificity (71-82%) for predicting immunoglobulin resistance or cardiac involvement. CONCLUSIONS: In European populations with mixed ethnic backgrounds, the presence of any abnormalities at the initial echocardiogram may contribute to early identification of patients with severe disease. PMID- 30021611 TI - Alzheimer disease pathology and the cerebrospinal fluid proteome. AB - BACKGROUND: Altered proteome profiles have been reported in both postmortem brain tissues and body fluids of subjects with Alzheimer disease (AD), but their broad relationships with AD pathology, amyloid pathology, and tau-related neurodegeneration have not yet been fully explored. Using a robust automated MS based proteomic biomarker discovery workflow, we measured cerebrospinal fluid (CSF) proteomes to explore their association with well-established markers of core AD pathology. METHODS: Cross-sectional analysis was performed on CSF collected from 120 older community-dwelling adults with normal (n = 48) or impaired cognition (n = 72). LC-MS quantified hundreds of proteins in the CSF. CSF concentrations of beta-amyloid 1-42 (Abeta1-42), tau, and tau phosphorylated at threonine 181 (P-tau181) were determined with immunoassays. First, we explored proteins relevant to biomarker-defined AD. Then, correlation analysis of CSF proteins with CSF markers of amyloid pathology, neuronal injury, and tau hyperphosphorylation (i.e., Abeta1-42, tau, P-tau181) was performed using Pearson's correlation coefficient and Bonferroni correction for multiple comparisons. RESULTS: We quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF Abeta1-42 levels (p value <= 0.05 with correlation coefficient (R) >= 0.38). We identified 50 additional CSF proteins associated with CSF tau and 46 proteins associated with CSF P-tau181 (p value <= 0.05 with R >= 0.37). The majority of those proteins that showed such associations were brain-enriched proteins. Gene Ontology annotation revealed an enrichment for synaptic proteins and proteins originating from reelin-producing cells and the myelin sheath. CONCLUSIONS: We used an MS-based proteomic workflow to profile the CSF proteome in relation to cerebral AD pathology. We report strong evidence of previously reported CSF proteins and several novel CSF proteins specifically associated with amyloid pathology or neuronal injury and tau hyperphosphorylation. PMID- 30021612 TI - Influence of the load exerted over a forearm crutch in spatiotemporal step parameters during assisted gait: pilot study. AB - BACKGROUND: Assisted gait with forearm crutches is frequently performed during the recovery of musculoskeletal injuries of the lower limb. The amount of body weight applied to the crutch or crutches depends on the pathology and the treatment phase. The transition from assisted gait with two crutches to a single crutch is usually recommended when the subject is able to load the 50% of the body weight upon the affected member. An altered assisted gait will cause biomechanic alterations and, therefore, longer treatments and relapses. The aim of this study was to analyze the influence of 10, 25 and 50% of body weight applied to a forearm crutch during a unilateral assisted gait in the spatial and temporal step parameters to determine the load that produces alterations in gait biomechanics and the load that does not. METHODS: Eleven healthy subjects performed normal gait (NG) and assisted gait with a forearm crutch, in which the applied loads were: comfortable (C), 25 and 50% of their body weight. Vicon System was employed for gait recording. GCH System 2.0 and GCH Control Software 1.0 controlled the loads. The variables were: step length, step period, velocity, step width and step angle. Friedman test compared all the gait modalities: NG and the different loads. Wilcoxon signed-rank test analyzed ipsilateral and contralateral step parameters to the crutch globally and for each subject. RESULTS: Friedman test showed significant differences between NG, C, 25 and 50%, especially for step period and velocity. Wilcoxon test had significant differences only in 4 of the 20 general comparisons between ipsilateral and contralateral steps to the crutch. In the analysis by subjects, step length, step period and velocity showed 79/132, 110/132 and 58/66 significant differences, respectively. CONCLUSIONS: The increase in the load exerted over a forearm crutch produced an increase in the step period, accompanied by a reduction of step length and gait velocity. Step width and step angle were not modified. The unloading of 25 and 50% of body weight on a single crutch is incorrect from the biomechanical point of view. Two crutches should be employed when the body weight to unload exceeds 10%. PMID- 30021613 TI - Single-word comprehension deficits in the nonfluent variant of primary progressive aphasia. AB - BACKGROUND: A subset of patients with the nonfluent variant of primary progressive aphasia (PPA) exhibit concomitant single-word comprehension problems, constituting a 'mixed variant' phenotype. This phenotype is rare and currently not fully characterized. The aim of this study was twofold: to assess the prevalence and nature of single-word comprehension problems in the nonfluent variant and to study multimodal imaging characteristics of atrophy, tau, and amyloid burden associated with this mixed phenotype. METHODS: A consecutive memory-clinic recruited series of 20 PPA patients (12 nonfluent, five semantic, and three logopenic variants) were studied on neurolinguistic and neuropsychological domains relative to 64 cognitively intact healthy older control subjects. The neuroimaging battery included high-resolution volumetric magnetic resonance imaging processed with voxel-based morphometry, and positron emission tomography with the tau-tracer [18F]-THK5351 and amyloid-tracer [11C] Pittsburgh Compound B. RESULTS: Seven out of 12 subjects who had been classified a priori with nonfluent variant PPA showed deficits on conventional single-word comprehension tasks along with speech apraxia and agrammatism, corresponding to a mixed variant phenotype. These mixed variant cases included three females and four males, with a mean age at onset of 65 years (range 44-77 years). Object knowledge and object recognition were additionally affected, although less severely compared with the semantic variant. The mixed variant was characterized by a distributed atrophy pattern in frontal and temporoparietal regions. A more focal pattern of elevated [18F]-THK5351 binding was present in the supplementary motor area, the left premotor cortex, midbrain, and basal ganglia. This pattern was closely similar to that seen in pure nonfluent variant PPA. At the individual patient level, elevated [18F]-THK5351 binding in the supplementary motor area and premotor cortex was present in six out of seven mixed variant cases and in five and four of these cases, respectively, in the thalamus and midbrain. Amyloid biomarker positivity was present in two out of seven mixed variant cases, compared with none of the five pure nonfluent cases. CONCLUSIONS: A substantial proportion of PPA patients with speech apraxia and agrammatism also have single word comprehension deficits. At the neurobiological level, the mixed variant shows a high degree of similarity with the pure nonfluent variant of PPA. TRIAL REGISTRATION: EudraCT, 2014-002976-10 . Registered on 13-01-2015. PMID- 30021614 TI - Co-circulation of Aedes flavivirus, Culex flavivirus, and Quang Binh virus in Shanghai, China. AB - BACKGROUND: With increases in global travel and trade, the spread of arboviruses is undoubtedly alarming. Pathogen detection in field-caught mosquitoes can provide the earliest possible warning of transmission. Insect-specific flavivirus (ISFV) has been first detected in 1991 and documented worldwide in the latest ten years. Although infection with ISFVs is apparently limited to insects, an increase in the infection rate of mosquito-borne flaviviruses may be able to induce cytopathic effects in vertebrate cells during co-infection with other human pathogens. However, little is known whether ISFVs persist in most regions of China. METHODS: During the mosquito activity season in 2016, a surveillance program was carried out to detect ISFVs in mosquitoes in metropolitan Shanghai, China. The presence of ISFVs was randomly tested in different species of mosquitoes using RT-PCR-based and hemi-nested PCR assays, following by the sequencing of PCR products. Sequences from positive pooled samples were compared with those deposited in GenBank. Thereafter, sequences of representative insect flaviviruses were used for further phylogenetic and molecular evolutionary analyses. RESULTS: Our investigations showed: (1) the presence of Aedes flavivirus (AEFV) in 11/161 pooled samples (nine pools in Songjiang District, one pool in Huangpu District, and one pool in Qingpu District) of Aedes albopictus, (2) the presence of Quang Binh virus (QBV) in 10/195 pooled samples (all in Chongming District) of Culex tritaeniorhynchus; and (3) the presence of Culex flavivirus (CxFV) in 9/228 pooled samples (six pools in Pudong New Area, two pools in Huangpu District, and one pool in Chongming District) of Cx. pipiens. Furthermore, phylogenetic analyses of the gene sequences of envelope proteins indicated that Shanghai CxFV strains belonged to the Asia/USA genotype. The overall maximum likelihood estimation values (and 95% confidence interval) for CxFV, QBV, and AEFV in mosquitoes collected in Shanghai in 2016 were 1.34 (0.66 2.45), 1.65 (0.87-2.85), and 1.51 (0.77-2.70) per 1000, respectively. CONCLUSIONS: This study reveals the presence and the geographical distribution of ISFVs, and determines the genetic variation and the infection rate of ISFVs in Shanghai, China. At least, three insect flaviviruses including ISFVs, AEFV, CxFV, and QBV, co-circulate in this area. To our knowledge, this is the first report of AEFV in China. PMID- 30021616 TI - Gray literature in systematic reviews on population health in the Middle East and North Africa: protocol of an overview of systematic reviews and evidence mapping. AB - BACKGROUND: Systematic review (SR) guidelines recommend extending literature search to gray literature in order to identify all available data related to the review topic. We aim to conduct an overview of SRs on population health in the Middle East and North Africa (MENA), to assess the methodology of these SRs, to produce an evidence map highlighting methodological gaps in SRs regarding gray literature searching, and to aid in developing future SRs by listing gray literature sources related to population health in MENA. METHODS/DESIGN: We will conduct an overview of SRs based on the Cochrane Handbook for Systematic Reviews of Interventions. This overview will be reported following PRISMA 2009 guidelines. Using comprehensive search criteria, we will search the PubMed database to identify relevant SRs published since 2008. Our primary outcomes are gray literature sources and study-level quality in the gray literature. We will include MENA countries with Arabic, English, French, and/or Urdu as primary official languages and/or media of instruction in universities. Two reviewers will independently conduct a multilevel screening on Rayyan software. Extraction of relevant data will be done on Statistical Package for the Social Sciences (SPSS) software. The methodological quality of included SRs will be assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Any disagreements will be resolved by discussion and consensus. We will estimate the overall proportion of SRs that used gray literature as one of their data sources. Subgroup analyses will be conducted to identify characteristics of these gray literature sources. Chi-squared and t tests will be used to determine whether the differences between subgroups are statistically significant. Additionally, an evidence gap map will be constructed to highlight characteristics and quality of the gray literature used in SRs on population health in MENA and emphasize existing gaps in gray literature searching. We will also list gray literature sources identified in the included SRs stratified by country and research topic. DISCUSSION: This overview will comprehensively assess the overall quality of the SRs on population health issues in MENA. Our findings will contribute to the improvement of population health research practices in MENA. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 26 October 2018 (registration number CRD42017076736 (Syst Rev 2:4, 2013). PMID- 30021615 TI - Lipid peroxidation diminishing perspective of isolated theaflavins and thearubigins from black tea in arginine induced renal malfunctional rats. AB - BACKGROUND: Recently oxidative stress induced maladies have amplified owing to sedentary lifestyle and monotonous diet. Introduction of plant based biomolecules may be a suitable strategy to cope with the lipid peroxidation. In this context, black tea polyphenols (theaflavin & thearubigins) are in fame among the scientific community as cost effective therapeutic agents owing to their safety, economics, structural diversity and ability to modulate various lipid peroxidation responses by halting the expression of different metabolic targets. METHODS: The mandate of present investigation was to first time check the synergism among the isolated theaflavins & thearubigins against lipid peroxidative indicators both in vitro and in vivo. Purposely, theaflavins and thearubigins were isolated from black tea through solvent partition methods by using different solvents (Aqueous ethanol, Aqueous methanol & Water) and time intervals (30, 60 & 90 min) and subjected to in vitro characterization through different antioxidant indices to access the in vitro lipid peroxidation shooting effect of these bioactive moieties. Moreover, individual theaflavins contents also estimate through HPLC. For evaluation of in vivo antioxidant effect, renal malfunction was induced through arginine and forty rats were divided in four groups (10 each after power analysis) and 04 types of diets were given i.e. T0 (control diet without supplementation), T1 (Basic experimental Diet+ theaflavins supplementation @ 1 g), T2 (Basic experimental Diet+ Thearubigins supplementation @ 1 g) & T3 (Basic experimental Diet+ Supplementation of theaflavins+ thearubigins @ 0.5 + 0.5 g, respectively) for the period of 56 days. Alongside, a control study was also carried out for comparison by involving normal rats fed on arginine free diet. The body weight, lipid profile, glycemic responses, Renal function test, liver function test, antioxidant indices and hematological parameters were estimated at the termination of study. RESULTS: The results indicated that theaflavins and thearubigins isolation was significantly affected by time of extraction and solvent. In this context, aqueous ethanol at 60 min extraction interval caused maximum extraction. Likewise, theaflavins isolate exhibited more antioxidant activity as compared to thearubigins. Moreover, the theaflavins and thearubigins based experimental diets imparted significant reduction in Lipid profile, glucose content, renal function tests and TBARS with enhancement in insulin, HDL and hematological parameters. In this context, theaflavin based diet caused maximum reduction in lipid profile and TBARS better as compared to thearubigins and theaflavins + thearubigins based. However, theaflavin+ thearubigins based diet caused highest glucose, urea & creatinine decline and maximum insulin increase & antioxidant indices as compared to other nutraceuticals. CONCLUSIONS: It was deduced that theaflavins & thearubigins have strong antioxidative potential both in in vitro as well as in vivo to tackle the menace associated with lipid peroxidation. PMID- 30021617 TI - Pericardial windows have limited diagnostic success. AB - BACKGROUND: Pericardial effusion (PE) is a common finding in patients who have chronic cardiac failure, who had undergone cardiac surgery, or who have certain other benign and malignant diseases. Pericardial drainage procedures are often requested for both diagnostic and therapeutic purposes. The perceived benefit is that it allows for diagnosis of malignancy or infection for patients with PEs of unclear etiology. The purpose of the study is to determine the diagnostic yield of surgical drainage procedures. METHODS: We conducted a retrospective chart review of patients who underwent surgical drainage procedures of PEs from July 1st, 2011 to January 1st, 2017 at a single institution. The variables included data on preoperative, intraoperative, and postoperative findings; morbidity; and survival. RESULTS: A total of 145 patients with an average age of 61 +/- 5 and primarily men (53%) were evaluated. All of the surgical drainage procedures were performed through the sub-xiphoid approach. Twenty-five of the 145 patients (17.2%) had diagnostic findings in either the pericardial tissue or fluid. The cytology alone was diagnostic in 4.8% (N = 7) of patients with mixed findings including adenocarcinoma of the lung and breast. The pathology was diagnostic for cancer in 1.4% (N = 2) of patients with Melanoma and Lung cancer identified. The cytology and pathology were concordant in 4.0% (N = 6) identifying cancers that included mesothelioma and adenocarcinoma. Infection was identified in the pericardial fluid in 6.9% (N = 10) of the patients. CONCLUSION: Surgical pericardial drainage procedures allow for removal of PE that may lead to tamponade physiology and potential mortality. Although there is therapeutic benefit from these procedures there is only a small diagnostic benefit. PMID- 30021618 TI - Cannabis for pediatric epilepsy: protocol for a living systematic review. AB - BACKGROUND: Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers. METHODS: We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings. DISCUSSION: Our review aims to provide a comprehensive and up-to date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084755. PMID- 30021619 TI - Endonuclease G takes part in AIF-mediated caspase-independent apoptosis in Mycobacterium bovis-infected bovine macrophages. AB - Mycobacterium bovis, the causative agent of bovine tuberculosis encodes different virulence mechanisms to survive inside of host cells. One of the possible outcomes in this host-pathogen interaction is cell death. Previous results from our group showed that M. bovis induces a caspase-independent apoptosis in bovine macrophages with the possible participation of apoptosis inducing factor mitochondria associated 1 (AIFM1/AIF), a flavoprotein that functions as a cell death regulator. However, contribution of other caspase-independent cell death mediators in M. bovis-infected macrophages is not known. In this study, we aimed to further characterize M. bovis-induced apoptosis, addressing Endonuclease G (Endo G) and Poly (ADP-ribose) polymerase 1 (PARP-1). In order to accomplish our objective, we infected bovine macrophages with M. bovis AN5 (MOI 10:1). Analysis of M. bovis-infected nuclear protein extracts by immunoblot, identified a 15- and 43-fold increase in concentration of mitochondrial proteins AIF and Endo G respectively. Interestingly, pretreatment of M. bovis-infected macrophages with cyclosporine A, a mitochondrial permeability transition pore inhibitor, abolished AIF and Endo G nuclear translocation. In addition, it also decreased macrophage DNA fragmentation to baseline and caused a 26.2% increase in bacterial viability. We also demonstrated that PARP-1 protein expression in macrophages did not change during M. bovis infection. Furthermore, pretreatment of M. bovis-infected bovine macrophages with 3-aminobenzamide, a PARP-1 inhibitor, did not change the proportion of macrophage DNA fragmentation. Our results suggest participation of Endo G, but not PARP-1, in M. bovis-induced macrophage apoptosis. To the best of our knowledge this is the first report associating Endo G with caspase independent apoptosis induced by a member of the Mycobacterium tuberculosis complex. PMID- 30021621 TI - In vitro activity of Morinda citrifolia Linn. fruit juice against the axenic amastigote form of Leishmania amazonensis and its hydrogen peroxide induction capacity in BALB/c peritoneal macrophages. AB - OBJECTIVE: The current treatment of leishmaniasis induces strong side effects and increasing numbers of cases of resistance to reference drugs have been reported. The discovery of the therapeutic properties of active substances in plant extracts represents an interesting field of research into a more efficient treatment against leishmaniasis. Morinda citrifolia, commonly known as noni, has demonstrated promising results as antileishmanial and immunomodulator. Thus, the aim of this work was to evaluate activity against axenic amastigote and hydrogen peroxide induction capacity by M. citrifolia fruit juice. RESULTS: Phytochemical screening identified anthraquinones, flavonoids, alkaloids, terpenoids, steroids, saponins, coumarins, phenolic compounds, tannins, anthocyanidins and chalcones. Noni juice exhibited dose-dependent activity and an IC50 of 240.1 ug/mL for axenic amastigotes. An absence of endotoxins was observed at the concentrations analyzed, while no cytotoxic effects were identified. Noni juice induced hydrogen peroxide production in BALB/c peritoneal macrophages but not in macrophages infected with Leishmania amazonensis. M. citrifolia fruit juice exhibited antileishmanial activity against L. amazonensis axenic amastigotes and activated macrophages by hydrogen peroxide induction, asserting its potential for further research into new forms of leishmaniasis treatment. PMID- 30021620 TI - Preferential use of Siglec-1 or Siglec-10 by type 1 and type 2 PRRSV strains to infect PK15S1-CD163 and PK15S10-CD163 cells. AB - Cellular entry mediators define whether the cell is permissive to PRRSV infection. Porcine sialoadhesin (pSn, Siglec-1) and CD163 are main entry mediators facilitating infection of porcine macrophages by PRRSV. Recently, Siglec-10 was demonstrated to be an alternative receptor for PRRSV. To examine if virulence and pathogenicity of PRRSV strains could be correlated with the use of different Siglecs, a PK15 cell line recombinantly expressing Siglec-1 and CD163 (PK15S1-CD163) and a PK15 cell line recombinantly expressing Siglec-10 and CD163 (PK15S10-CD163) were used to compare the virus replication of 7 genotype 1 subtype 1 strains (G1s1), 2 genotype 1 subtype 3 (G1s3) strains and 5 genotype 2 (G2) strains. Some strains (08VA (G1s1), 13V117 (G1s1), 17V035 (G1s1), VR2332 (G2)) were poor virus producers (<104 TCID50/mL), while other strains (07V063 (G1s1), 13V091 (G1s1), Su1-Bel (G1s3), MN-184 (G2), Korea17 (G2) and SDSU-73 (G2)) easily grew up to >=106 TCID50/mL. PK15S10-CD163 cells exhibited a higher efficiency in virus production per infected cell than the PK15S1-CD163 cells. The G1s1 strains LV and 07V063 infected more cells in the PK15S1-CD163, whereas the 94V360 and 08VA strains preferred PK15S10-CD163. The highly virulent G1s3 strains Lena and Su1-Bel showed a strong preference for PK15S1-CD163. The G2 strains MN 184, SDSU-73, Korea17 had a much higher infection rate in PK15S10-CD163, while the reference strain VR2332 and the NADC30 strain had a slight preference for PK15S1-CD163. Differences in receptor use may influence the outcome of a PRRSV infection in pigs and explain in part the virulence/pathogenicity of PRRSV strains. PMID- 30021622 TI - Protocol for a systematic review of autologous fat grafting for wound healing. AB - BACKGROUND: Autologous fat grafting is an emerging therapeutic option for cutaneous wounds. The regenerative potential of autologous fat relates to the presence of adipose-derived stem cells (ADSCs) within the stromal vascular fraction (SVF). ADSCs are capable of differentiating into fibroblasts and keratinocytes, as well as secreting soluble mediators with angiogenic and anti inflammatory properties. However, to date, there has been no comprehensive assessment of the wound healing literature in humans. This systematic review aims to critically evaluate the efficacy and safety of autologous fat grafting in acute and chronic cutaneous wounds with an appraisal of the quality of evidence available. METHODS: Following PRISMA guidelines, MEDLINE, Embase and Cochrane Library databases will be searched from inception to December 2017. All primary clinical studies in which wounds are treated with lipotransfer, cell-assisted lipotransfer (CAL), SVF products or isolated ADSCs will be eligible for inclusion. Study screening and data extraction will be conducted by two authors in duplicate. Our primary outcome measure will be the proportion of completely healed wounds at 12 weeks. Secondary outcome measures will include the proportion of partially healed wounds at 12 weeks; the mean wound surface area reduction at 12 weeks; the mean time to wound healing; and adverse event rates. The quality of evidence for each summary outcome measure will be assessed using the GRADE approach. DISCUSSION: In light of the growing popularity of autologous fat grafting for wound healing, a systematic appraisal of the available evidence is timely. If autologous fat grafting is associated with a positive treatment effect, we will compare these outcomes to those achieved using alternative wound management strategies. This review also aims to determine if one or more autologous fat grafting techniques are superior and whether this varies according to patient- and wound-specific factors. We anticipate that these results will guide future research and inform clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017081499. PMID- 30021623 TI - The epigenetic clock and pubertal, neuroendocrine, psychiatric, and cognitive outcomes in adolescents. AB - BACKGROUND: Molecular aging biomarkers, such as epigenetic age predictors, predict risk factors of premature aging, and morbidity/mortality more accurately than chronological age in middle-aged and elderly populations. Yet, it remains elusive if such biomarkers are associated with aging-related outcomes earlier in life when individuals begin to diverge in aging trajectories. We tested if the Horvath epigenetic age predictor is associated with pubertal, neuroendocrine, psychiatric, and cognitive aging-related outcomes in a sample of 239 adolescents, 11.0-13.2 years-old. RESULTS: Each year increase in epigenetic age acceleration (AA) was associated with 0.06 SD units higher weight-for-age, 0.08 SD units taller height-for-age, -0.09 SD units less missed from the expected adult height, 13 and 16% higher odds, respectively, for each stage increase in breast/genitals development on the Tanner Staging Questionnaire and pubertal stage on the Pubertal Development Scale, 4.2% higher salivary cortisol upon awakening, and 18 to 34% higher odds for internalizing and thought problems on the Child Behavior Checklist (p values < 0.045). AA was not significantly associated with cognition. CONCLUSIONS: Our findings suggest that already in adolescence, AA is associated with physiological age acceleration, which may index risk of earlier aging. AA may identify individuals for preventive interventions decades before aging-related diseases become manifest. PMID- 30021624 TI - Bone marrow derived mesenchymal stem cells ameliorate inflammatory response in an in vitro model of familial hemophagocytic lymphohistiocytosis 2. AB - BACKGROUND: Familial hemophagocytic lymphohistiocytosis 2 (FHL2) is the most common familial type of hemophagocytic lymphohistiocytosis with immune dysregulation. FHL2 patients have mutations in the perforin gene which cause overactivation and proliferation of cytotoxic T lymphocytes and natural killer cells. Perforin is the key component of the cytolytic granule response function of cytotoxic T lymphocytes and natural killer cells. Perforin dysfunction causes a cytotoxic immune deficiency with a clinical outcome of uncontrolled and continuous immune stimulation response. This excessive stimulation leads to continuous systemic inflammation and, ultimately, multiorgan failure. Radical therapy is hematopoietic stem cell transplantation which is limited by the availability of a donor. Exacerbations of inflammatory attacks require a palliative immunosuppressive regimen. There is a need for an alternative or adjuvant therapy to maintain these patients when immunosuppression is ineffective or a donor is not available. Beneficial actions of mesenchymal stem cells (MSCs) have been shown in autoimmune diseases in clinical trials and are attributed to their immune-modulatory properties. This study aimed to assess the immune modulatory effect of MSCs in an in-vitro model of FHL2. METHODS: We generated a targeted mutation in the perforin gene of NK92 cells to create an in-vitro FLH2 model using Crispr/Cas technology. A coculture setup was employed to assess the immunomodulatory efficacy of MSCs. RESULTS: Engineered NK92 clones did not show PRF1 mRNA expression and failed to secrete perforin upon phorbol myristate acetate-ionomycin stimulation, providing evidence for a valid FHL2 model. Coculture media of the engineered cells were investigated for the abundance of several cytokines. Coculture with MSCs revealed a reduction in major proinflammatory cytokines and an induction in anti-inflammatory and immunomodulatory cytokines compared to the parental NK92 cells. CONCLUSIONS: This study shows the ameliorating effect of MSCs as an adjuvant immune modulator toward the therapy of FHL2 patients. MSCs are supportive therapy candidates for FHL2 patients under circumstances where prolonged immunosuppression is required to gain time before allogeneic hematopoietic stem cell transplantation. PMID- 30021625 TI - Effects of small-dose remifentanil combined with index of consciousness monitoring on gastroscopic polypectomy: a prospective, randomized, single-blinded trial. AB - BACKGROUND: With the development of painless diagnosis and treatment, remifentanil, a synthetic opioid agonist, is increasingly used in gastroscopy for its rapid, short-term, and potent analgesic effect. However, the dosage of remifentanil used in endoscopy is unclear. Index of consciousness (IOC) is a new anesthesia depth-monitoring indicator that can be divided into index of consciousness 1 (IOC1) and index of consciousness 2 (IOC2); IOC1 is used for estimating a patient's sedation state, whereas IOC2 reflects analgesic depth. We hypothesized that combining with IOC1 and IOC2 monitoring may be helpful to identify an optimal remifentanil dosage in gastroscopic polypectomy. METHODS: One hundred twenty patients scheduled for gastroscopic polypectomy were enrolled and were randomly assigned to remifentanil 2 ng/mL (group R2), 4 ng/mL (group R4), or 6 ng/mL (group R6), and 40 cases were in each group. During the anesthesia period, remifentanil was kept at the initial given concentration but propofol was adjusted according to IOC1. The primary outcomes were the dosage of propofol and remifentanil. The secondary outcomes were the variety of IOC1 and IOC2, patients' awakening time, and peri-operative adverse reactions such as hypotension, hypertension, bradycardia, tachycardia, body movements, hypoxemia, therapy interruption, nausea, vomiting, aspiration, and intra-operative awareness. RESULTS: With the increasing dosage of remifentanil, the propofol dosage and patients' awakening time decreased significantly, the morbidity of hypertension and body movements also declined, but the incidence of hypotension, bradycardia, and hypoxemia rose. In group R2, the value of IOC2 remained above 50 during the treatment. However, IOC2 dropped to below 30 at the beginning of the gastroscopy in group R6, and there was statistical difference in hypoxemia between groups R2 and R6 (P <0.05). CONCLUSIONS: With the help of IOC monitoring, we found that a target concentration of remifentanil 4 ng/mL is comparatively ideal in patients under gastroscopic polypectomy. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR-OOD-16009489 , on October 19, 2016. PMID- 30021626 TI - Dietary intakes of flavan-3-ols and cardiovascular health: a field synopsis using evidence mapping of randomized trials and prospective cohort studies. AB - BACKGROUND: There is considerable interest in the impact of increased flavan-3-ol intake on cardiovascular disease (CVD) and diabetes outcomes. Through evidence mapping, we determined the extent of the evidence base to initiate a future systematic review investigating the impact of flavan-3-ol intake on CVD and diabetes outcomes. METHODS: We developed a research protocol, convened a technical expert panel (TEP) to refine the specific research questions, conducted a systematic search in multiple databases, double-screened abstracts and full text articles, performed data extractions, and synthesized the data. We focused on randomized controlled trials (RCTs) and prospective cohort studies which assessed intakes of flavan-3-ol from foods, beverages, and supplement/extract sources on biomarkers and clinical outcomes of CVD and diabetes. RESULTS: Of 257 eligible articles, 223 and 34 publications contributed to 226 RCTs and 39 prospective cohort studies, respectively. In RCTs, the most frequently studied interventions were cocoa-based products (23.2%); berries (16.1%); tea in the form of green tea (13.9%), black tea (7.2%), or unspecified tea (3.6%); and red wine (11.2%). Mean total flavan-3-ol intake was highest in the cocoa-based trials (618.7 mg/day) and lowest in the interventions feeding red wine (123.7 mg/day). The most frequently reported outcomes were intermediate biomarkers including serum lipid levels (63.4%), blood glucose (50.9%), blood pressure (50.8%), flow mediated dilation (21.9%), and high-sensitivity C-reactive protein (21.9%). The included 34 prospective cohort studies predominantly examined exposures to flavan 3-ols (26%), cocoa-based products (23.2%), berries (16.1%), and green tea (13.9%) and CVD incidence and mortality. CONCLUSION: Through a systematic, evidence-based approach, evidence mapping on flavan-3-ol intake and CVD outcomes demonstrated sufficient data relating to flavan-3ol intake and biomarkers and clinical outcomes of CVD and diabetes. The current evidence base highlights the distribution of available data which both support the development of a future systematic review and identified the research need for future long-term RCTs. SYSTEMATIC REVIEW REGISTRATION: At present, evidence mapping is not eligible for registration on the international prospective register of systematic reviews (i.e., PROSPERO). PMID- 30021627 TI - Knowledge, attitudes and practices of malaria transmission and preventive measures in Woreta town, Northwest Ethiopia. AB - OBJECTIVE: Despite a high public health burden of malaria in endemic regions of Ethiopia, there are limitations on the availability of data concerning public awareness about the disease and its preventive measures. The present study aimed in producing base line data on the community knowledge, attitudes and practices towards malaria transmission and its preventive measures in Woreta town, northwest Ethiopia. A community based two-stage random cluster study was conducted from May to July 2013. Household heads were interviewed to assess their awareness about malaria and its control measures. RESULTS: About 78.5% (113/144) of the respondents rated bite of infected mosquito as a way of malaria transmission. The majority of participants, 126 (87.5%) stated one or more symptoms of malaria. About 95.8% (138/144) of the respondents indicated that malaria is preventable and curable disease. Only about 25% (36/144) of the study participants practiced frequent and proper use of insecticide treated bed nets (ITNs). Draining logged water was a highly rated, 83 (57.6%), practice of environmental management of malaria. PMID- 30021628 TI - Previously claimed male germline stem cells from porcine testis are actually progenitor Leydig cells. AB - BACKGROUND: Male germline stem cells (mGSCs) offer great promise in regenerative medicine and animal breeding due to their capacity to maintain self-renewal and to transmit genetic information to the next generation following spermatogenesis. Human testis-derived embryonic stem cell-like cells have been shown to possess potential of mesenchymal progenitors, but there remains confusion about the characteristics and origin of porcine testis-derived stem cells. METHODS: Porcine testis-derived stem cells were obtained from primary testicular cultures of 5-day old piglets, and selectively expanded using culture conditions for long-term culture and induction differentiation. The stem cell properties of porcine testis derived stem cells were subsequently assessed by determining the expression of pluripotency-associated markers, alkaline phosphatase (AP) activity, and capacity for sperm and multilineage differentiation in vitro. The gene expression profile was compared via microarray analysis. RESULTS: We identified two different types of testis-derived stem cells (termed as C1 and C2 here) during porcine testicular cell culture. The gene expression microarray analysis showed that the transcriptome profile of C1 and C2 differed significantly from each other. The C1 appeared to be morphologically similar to the previously described mouse mGSCs, expressed pluripotency- and germ cell-associated markers, maintained the paternal imprinted pattern of H19, displayed alkaline phosphatase activity, and could differentiate into sperm. Together, these data suggest that C1 represent the porcine mGSC population. Conversely, the C2 appeared similar to the previously described porcine mGSCs with three-dimensional morphology, abundantly expressed Leydig cell lineage and mesenchymal cell-specific markers, and could differentiate into testosterone-producing Leydig cells, suggesting that they are progenitor Leydig cells (PLCs). CONCLUSION: Collectively, we have established the expected characteristics and markers of authentic porcine mGSCs (C1). We found for the first time that, the C2, equivalent to previously claimed porcine mGSCs, are actually progenitor Leydig cells (PLCs). These findings provide new insights into the discrepancies among previous reports and future identification and analyses of testis-derived stem cells. PMID- 30021629 TI - Use of a gene score of multiple low-modest effect size variants can predict the risk of obesity better than the individual SNPs. AB - BACKGROUND: Obesity is a complex disorder, the development of which is modulated by a multitude of environmental, behavioral and genetic factors. The common forms of obesity are polygenic in nature which means that many variants in the same or different genes act synergistically and affect the body weight quantitatively. The aim of the current study was to use information from many common variants previously identified to affect body weight to construct a gene score and observe whether it improves the associations observed. The SNPs selected were G2548A in leptin (LEP) gene, Gln223Arg in leptin receptor (LEPR) gene, Ala54Thr in fatty acid binding protein 2 (FABP2) gene, rs1121980 in fat mass and obesity associated (FTO) gene, rs3923113 in Growth Factor Receptor Bound Protein 14 (GRB14), rs16861329 in Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1), rs1802295 in Vacuolar protein sorting-associated protein 26A (VPS26A), rs7178572 in high mobility group 20A (HMG20A), rs2028299 in adaptor-related protein complex 3 (AP3S2), and rs4812829 in Hepatocyte Nuclear Factor 4 Alpha (HNF4A). METHODS: A total of 475 subjects were genotyped for the selected SNPs in different genes using different genotyping techniques. The study subjects' age, weight, height, BMI, waist and hip circumference, serum total cholesterol, triglycerides, LDL and HDL were measured. A summation term, genetic risk score (GRS), was calculated using SPSS. RESULTS: The results showed a significantly higher mean gene score in obese cases than in non-obese controls (9.1 +/- 2.26 vs 8.35 +/- 2.07, p = 2 * 10 4). Among the traits tested for association, gene score appeared to significantly affect BMI, waist circumference, and all lipid traits. CONCLUSION: In conclusion, the use of gene score is a better way to calculate the overall genetic risk from common variants rather than individual risk variants. PMID- 30021630 TI - Probabilistic cost-effectiveness analysis of controlled ovarian stimulation with recombinant FSH plus recombinant LH vs. human menopausal gonadotropin for women undergoing IVF. AB - BACKGROUND: The association of recombinant FSH plus recombinant LH in 2:1 ratio may be used not only to induce ovulation in anovulatory women with hypogonadotropic hypogonadism but also to achieve multiple follicular developments in human IVF. The aim of this analysis was to estimate the cost effectiveness of Controlled Ovarian Stimulation (COS) with recombinant FSH (rFSH) plus recombinant LH (rLH) in comparison with highly purified human menopausal gonadotropin (HP-hMG) in the woman undergoing in vitro fertilization (IVF) in Italy. METHODS: A probabilistic decision tree was developed to simulate patients undergoing IVF, either using r-FSH + r-LH or HP-hMG to obtain COS. The model considers the National Health System (NHS) perspective and a time horizon equal to two years. Simulations were reported considering the number of retrieved oocytes (5-9, 10-15 and > 15) and transition probabilities were estimated through specific analyses carried out on the population of 848 women enrolled in the real life. RESULTS: The model estimated that patients undertaking therapeutic protocol with r-FSH + r-LH increase the general success rate (+ 6.6% for pregnancy). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) of r-FSH + r-LH was below the willingness to pay set at ?20,000 for all the considered scenarios. CONCLUSIONS: The cost-utility analysis demonstrated that the r-FSH + r-LH is a cost-effective option for the Italian National Health System (NHS). PMID- 30021631 TI - Conceptions of sleep experience: a layman perspective. AB - OBJECTIVE: To date, there is little information on how lay people understand and discuss sleep in the context of daily life. Efforts to conceptualize sleep quality have been largely driven by clinical considerations of sleep disorders. As such, they are not necessarily of how normal sleepers without clinical expertise conceptualize sleep quality. A phenomenological approach was taken to understand the essence of the sleep experience and the concepts held by lay people without sleep disorders. A sentence completion questionnaire was developed and administered to a quota sample of 64 respondents who were selected aiming for sufficient representation of different gender, ages, and education levels. RESULTS: Significant sentences and meaningful units were derived inductively, resulting in a classification of nine categories. The major facets of sleep experience of lay people were 'daytime functioning', 'interruptions during the night' and 'before bed state'. This implies that the experienced sleep quality is not only depending on the progress of the night. These results can guide future research to provide suitable psychometric measures for normal sleepers, as well as the design of sleep data visualization applications in the context of health self-monitoring. PMID- 30021633 TI - Comparative evaluation of refractive outcomes after implantation of two types of intraocular lenses with different diopter intervals (0.25 diopter versus 0.50 diopter). AB - BACKGROUND: Intraocular lenses (IOLs) with different diopter (D) intervals may have different tolerance, and may provide different accuracy of refractive outcome after cataract surgery. The aim of the study is to compare the accuracy of refractive outcome after implantation of IOLs with different D intervals after cataract surgery. METHODS: A total of 80 eyes from 40 patients who underwent phacoemulsification with implantation of a 0.50 D interval Akreos AO IOL in one eye and a 0.25 D interval Softec HDTM IOL in the other eye were enrolled. The percentages of eyes with refractive prediction error within +/-0.50 D at one month after surgery were compared. To evaluate the effect of the dioptric errors of the IOL itself on refractive prediction error, the percentage of eyes with refractive prediction error within +/-0.25 D of the IOL with a standard deviation (SD) of +/-0.40 D was compared with that of the IOL with a SD of +/-0.11 D through Monte Carlo simulations. RESULTS: In this clinical study, the percentage of eyes with refractive prediction error within +/-0.50 D by the Haigis formula in the Softec HDTM group (85.0%) was significantly greater than that in the Akreos AO group (57.5%; P = 0.027). In Monte Carlo simulations, all percentages of eyes with refractive prediction error within +/-0.25 D by the Haigis and SRK/T formulas in the Softec HDTM group were significantly greater than those in the Akreos AO group. CONCLUSIONS: The IOL with a 0.25 D interval was more accurate than the IOL with a 0.50 D interval in predicting refractive outcome after cataract surgery. TRIAL REGISTRATION: Current Controlled Trials KCT0002192 , Retrospectively registered (Date of registration: 6 January 2017). PMID- 30021632 TI - Mechanical and aesthetics compatibility of Brazilian red propolis micellar nanocomposite as a cavity cleaning agent. AB - BACKGROUND: Propolis is a natural substance produced by bees and is known to have antimicrobial activity. Our aim was to evaluate the antimicrobial effect of micellar nanocomposites loaded with an ethyl acetate extract of Brazilian red propolis as a cavity cleaning agent and its influence on the color and microtensile bond strength (MUTBS) of the dentin/resin interface. METHODS: An ultra-performance liquid chromatography coupled with a diode array detector (UPLC DAD) assay was used to determine the flavonoids and isoflavones present in an ethyl acetate extract of Brazilian red propolis (EARP) and micellar nanocomposites loaded with EARP (MNRP). The antimicrobial activity of EARP and MNRP was tested against Streptococcus mutans, Lactobacillus acidophilus, and Candida albicans. One of the following experimental treatments was applied to etched dentin (phosphoric acid, 15 s): 5 MUL of MNRP (RP3, 0.3%; RP6, 0.6%; or RP1, 1.0% w/v), placebo, and 2% chlorhexidine digluconate. Single Bond adhesive (3 M/ESPE) was applied and a 4-mm-thick resin crown (Z350XT, 3 M/ESPE) was built up. After 24 h, the teeth were sectioned into sticks for the MUTBS test and scanning electron microscopy. Spectrophotometry according to the CIE L*a*b* chromatic space was used to evaluate the color. Data were analyzed using one-way ANOVA and the Tukey test or Kruskal-Wallis test and the same test for pairwise comparisons between the means (P < 0.05). RESULTS: The UPLC-DAD assay identified the flavonoids liquiritigenin, pinobanksin, pinocembrin, and isoliquiritigenin and the isoflavonoids daidzein, formononetin, and biochanin A in the EARP and micellar nanocomposites. EARP and MNRP presented antimicrobial activity against the cariogenic bacteria Streptococcus mutans and Lactobacillus acidophilus, and for Candida albicans. DeltaE values varied from 2.31 to 3.67 (P = 0.457). The mean MUTBS for RP1 was significantly lower than for the other groups (P < 0.001). Dentin treated with RP1 showed the shortest resin tags followed by RP6 and RP3. CONCLUSIONS: The EARP and (MNRP) showed antimicrobial activity for the main agents causing dental caries (Streptococcus mutans and Lactobacillus acidophilus) and for Candida albicans. MNRP at concentrations of 0.3 and 0.6% used as a cavity cleaner do not compromise the aesthetics or MUTBS of the dentin/resin interface. PMID- 30021634 TI - Effect of preconceptional orlistat treatment on in-vitro fertilization outcome in overweight/obese women: study protocol for a randomized controlled trial. AB - BACKGROUND: Obese women have fewer oocytes retrieved, an increased cancelation rate, a higher miscarriage rate, and a lower live birth rate after assisted reproductive technology (ART) treatment compared with women with normal weight. Weight loss before ART treatment can significantly improve pregnancy rates and/or live births. An orlistat plus diet intervention could promote weight loss, but there is no evidence from randomized clinical trials evaluating the effect of orlistat preconceptional treatment on pregnancy outcome in overweight and obese women. METHODS/DESIGN: We are conducting a multicenter, randomized placebo controlled, double-blind clinical trial in overweight and obese women aged 20-40 years undergoing in-vitro fertilization and embryo transfer (IVF-ET) with or without intracytoplasmic sperm injection, to evaluate whether orlistat treatment for 1-3 months before IVF-ET can improve the live birth rate. The primary outcome is live birth. DISCUSSION: The results of this study will provide evidence for the effect of preconceptional orlistat treatment on IVF outcome in overweight/obese women. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-17011629 . Registered on 11 June 2017. PMID- 30021635 TI - A systematic review of the literature on ethical aspects of transitional care between child- and adult-orientated health services. AB - BACKGROUND: Healthcare policy and academic literature have promoted improving the transitional care of young people leaving child and adolescent mental health services (CAMHS). Despite the availability of guidance on good practice, there seems to be no readily accessible, coherent ethical analysis of transition. The ethical principles of non-maleficence, beneficence, justice and respect for autonomy can be used to justify the need for further enquiry into the ethical pros and cons of this drive to improve transitional care. The objective of this systematic review was therefore to systematically search for existing ethical literature on child- to adult-orientated health service transitions and to critically appraise and collate the literature, whether empirical or normative. METHODS: A wide range of bioethics, biomedical and legal databases, grey literature and bioethics journals were searched. Ancestral and forward searches of identified papers were undertaken. Key words related to transition, adolescence and young adulthood, ethics, law and health. The timeframe was January 2000 to at least March 2016. Titles, abstracts and, where necessary, full articles were screened and duplicates removed. All included articles were critically appraised and a narrative synthesis produced. RESULTS: Eighty two thousand four hundred eighty one titles were screened, from which 96 abstracts were checked. Forty seven full documents were scrutinised, leading to inclusion of two papers. Ancestral and forward searches yielded four further articles. In total, one commentary, three qualitative empirical studies and two clinical ethics papers were found. All focused on young people with complex care needs and disabilities. The three empirical papers had methodological flaws. The two ethical papers were written from a clinical ethics context rather than using a bioethical format. No literature identified specifically addressed the ethical challenges of balancing the delivery of transitional care to those who need it and the risk of pathologizing transient and self-limited distress and dysfunction, which may be normal during adolescence. CONCLUSIONS: There is very little research on ethical aspects of transitional care. Most existing studies come from services for young people with complex care needs and disabilities. There is much scope for improvement in the amount and quality of empirical research and ethical analysis in this area. PMID- 30021636 TI - Dietary interventions for managing glucose abnormalities in cystic fibrosis: a systematic review protocol. AB - BACKGROUND: Glucose abnormalities in cystic fibrosis (CF) are common, but there is limited evidence to guide their dietary management. Progressive impaired glucose tolerance eventually leads to cystic fibrosis-related diabetes (CFRD), the most prevalent complication of CF, which is associated with increased morbidity and mortality. Optimising glycaemic control improves clinical status and reduces mortality; insulin therapy is the primary means of controlling glycaemia in CFRD, but its role in managing pre-diabetes is less clear. CF dietary therapy requires a high calorie diet due to increased energy expenditure and malabsorption, but this energy-dense diet is typically high in fat and sugar, and high sugar intakes often result in hyperglycaemia in individuals who have impaired glucose handling. Current guidelines for the dietary management of glucose abnormalities in CF are based on clinical consensus rather than empirical evidence. A systematic review conducted in 2012 on the effects of low glycaemic index dietary intervention in CF concluded that there is a dearth of evidence in this area. This review will update the systematic review by Balzer et al. in 2012 and will broaden the scope of their review to include any type of dietary intervention for managing glucose abnormalities in CF. METHODS: Quantitative studies of dietary interventions to manage glucose abnormalities in individuals aged over 5 years with CF and glucose abnormalities will be reviewed. No limits will be placed on language or study design. The comparator will be standard CF dietary therapy (energy dense, high-fat diet) in addition to insulin therapy for individuals with CFRD. Electronic databases will be searched for completed quantitative studies published in peer-review journals that focus on dietary interventions for managing glucose abnormalities in CF. Searches will be conducted from 2000 up to the present day to reflect the evolving improvements in CF management. No restrictions will be placed on study design or language. Duration of the dietary intervention must be a minimum of 2 months and only interventions in out-patient or community settings will be included. Studies must report on dietary intervention, glycaemic control, anthropometry and lung function. Evidence will be assessed for heterogeneity and a narrative review or meta-analysis conducted as appropriate. DISCUSSION: This systematic review will elucidate current knowledge of the effects of dietary interventions for managing glucose abnormalities in the vulnerable CF clinical population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42018085569 www.crd.york.ac.uk/prospero/. PMID- 30021638 TI - Role of imitation and limited rehabilitation capacity on the spread of drug abuse. AB - OBJECTIVES: We formulate a mathematical model for the spread of drug abuse using non linear ordinary differential equations. The model seeks to investigate both peer influence and limited rehabilitation effects on the dynamics of drug abuse. Peer-influence is modelled through the mechanism of imitation and limited rehabilitation is described using a special treatment function. Center manifold theory is used to show that the model exhibits the phenomenon of backward bifurcation. Matlab has been used to carry out numerical simulations to support theoretical findings. RESULTS: The model analysis shows that the model has multiple equilibria. It has been shown that the classical [Formula: see text] threshold is not the key to control drug abuse within a population. In fact drug abuse problems may persist in the population even with subthreshold values of [Formula: see text]. This was shown to result, in particular when, [Formula: see text], [Formula: see text] and [Formula: see text] are high enough such that [Formula: see text], [Formula: see text] and [Formula: see text]. The results suggest the need for comprehensive and accessible substance abuse treatment services to curtail drug abuse. PMID- 30021637 TI - Retrospective analysis of tacrolimus combined with Tripterygium wilfordii polyglycoside for treating idiopathic membranous nephropathy. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common adult nephrotic syndromes. Some patients with this disorder require immunosuppressive therapy. This retrospective case series was performed to assess the effects of tacrolimus (TAC) combined with Tripterygium wilfordii polyglycoside (TWG) in treating IMN. METHODS: From January 2015 to August 2016, kidney-biopsy-proven IMN patients treated with TAC in the Chinese PLA General Hospital were screened. Data were retrieved from the patients' medical records. The first efficacy evaluation index was remission rate (complete remission and partial remission), and the secondary efficacy evaluation indices included relapse rate, proteinuria, serum albumin and estimated glomerular filtration rate (eGFR). Adverse events were also assessed. RESULTS: The included patients' treatments were tacrolimus monotherapy (TAC group, n = 33), tacrolimus combined with methylprednisolone (MP) (TAC + MP group, n = 24) and tacrolimus combined with Tripterygium wilfordii polyglycoside (TAC + TWG group, n = 21). The remission rates of the TAC, TAC + MP, and TAC + TWG groups in the 10th month were 54.5, 62.5, and 85.7%, respectively (TAC + TWG group vs TAC group, P = 0.037, TAC + TWG group vs TAC + MP group, P = 0.125). Moreover, the complete remission rates of the TAC, TAC + MP, and TAC + TWG groups in the 10th month were 21.2, 20.8, and 57.1%, respectively (TAC + TWG group vs TAC group, P = 0.007, TAC + TWG group vs TAC + MP group, P = 0.012). Compared with the TAC group, the TAC + TWG group had a higher remission rate during these ten months (log-rank, P = 0.005). Compared with the TAC and TAC + MP groups, the TAC + TWG group had a higher complete remission rate (log-rank, P = 0.019 and log-rank, P = 0.005, respectively). CONCLUSION: This retrospective study showed that TAC combined with TWG may be effective for treating IMN. Further randomized controlled trials (RCTs) are needed to assess the efficacy and safety of TAC combined with TWG. PMID- 30021639 TI - Different reliability of instrumented gait analysis between patients with unilateral hip osteoarthritis, unilateral hip prosthesis and healthy controls. AB - BACKGROUND: The gait pattern varies within the population and between patient groups with different musculoskeletal diseases. It also varies over time due to various reasons. Three-dimensional gait analysis (3DGA) is frequently used to measure these changes, but the precision of this methodology may vary. METHODS: We primarily aimed to study the repeatability of hip motion measurements in patients with unilateral osteoarthritis (OA), patients with unilateral total hip arthroplasty (THA) and healthy controls. A secondary aim was to delineate any differences in hip motion during walking between these groups. Ten males and 10 females in each group were recruited. All patients underwent gait assessments using 3DGA recorded by 2 examiners. Data was analysed with comparison of variance and linear regression. RESULTS: The variability of the extension-flexion recordings was smallest in healthy controls (SD < 7.7 degrees ), increased in patients with THA (SD < 11.1 degrees ) and was most pronounced in the OA patients (SD < 12.2 degrees ). The degree of hip extension-flexion turned out to be the variable that most effectively could separate the controls from the 2 patient groups and the patient groups from each other. One to 2 years after THA the gait pattern was improved but still differed comparing a group of THA from a group of healthy controls. CONCLUSIONS: Patients with hip osteoarthritis showed the poorest repeatability between gait recordings collected by different examiners, as compared to patients operated with a THA and healthy controls. The walking pattern after THA still differed from healthy controls 1-2 years after the operation. PMID- 30021641 TI - Predictive value of the pendulum test for assessing knee extensor spasticity. AB - BACKGROUND: The pendulum test is commonly used to quantify knee extensor spasticity, but it is currently unknown to what extent common pendulum test metrics can detect spasticity in patients with neurological injury or disease, and if the presence of flexor spasticity influences the test outcomes. METHODS: A retrospective analysis was conducted on 131 knees, from 93 patients, across four different patient cohorts. Clinical data included Modified Ashworth Scale (MAS) scores for knee extensors and flexors, and years since diagnosis. BioToneTM measures included extensor strength, passive and active range of motion, and pendulum tests of most affected or both knees. Pendulum test metrics included the relaxation index (RI), 1st flexion amplitude (F1amp) and plateau angle (Plat), where RI=F1amp/Plat. Two-way ANOVA tests were used to determine if pendulum test metrics were influenced by the degree of knee flexor spasticity graded by the MAS, and ANCOVA was used to test for confounding effects of age, years since injury, strength and range of motion (ROM). In order to identify the best pendulum test metrics, Receiver Operator Characteristic analysis and logistic regression (LR) analysis were used to classify knees by spasticity status (none or any) and severity (low/moderate or high/severe). RESULTS: Pendulum test metrics for knee extensors were not influenced by degree of flexor spasticity, age, years since injury, strength or ROM of the limb. RI, F1amp and Plat were > 70% accurate in classifying knees by presence of clinical spasticity (from the MAS), but were less accurate (< 70%) for grading spasticity level. The best classification accuracy was obtained using F1amp and Plat independently in the model rather than using RI alone. CONCLUSIONS: We conclude that the pendulum test has good predictive value for detecting the presence of extensor spasticity, independent of the existence of flexor spasticity. However, the ability to grade spasticity level as measured by MAS using the RI and/or F1amp may be limited. Further study is warranted to explore if the pendulum test is suitable for quantifying more severe spasticity. PMID- 30021642 TI - Outcomes of simultaneous high tibial osteotomy and anterior cruciate ligament reconstruction in anterior cruciate ligament deficient knee with osteoarthritis. AB - BACKGROUND: We aimed to evaluate clinical and radiological results after simultaneous open-wedge high tibial osteotomy (HTO) and anterior cruciate ligament (ACL) reconstruction in patients with ACL deficiency combined with medial uni-compartmental osteoarthritis (OA) and varus deformity. METHODS: This retrospective study was performed using data collected from 2005 to 2011 on a total of 24 patients who were diagnosed with ACL injury and medial unicompartmental OA with varus deformity, and who subsequently underwent simultaneous open-wedge HTO and arthroscopic ACL reconstruction. The mean follow up duration was 5.2 years. For clinical outcomes, we evaluated Lysholm score, Tegner activity score, range of motion, Lachmann test, and pivot-shift test, and for radiological outcomes, we evaluated the degree of varus deformity, progression of medial OA, tibial posterior slope, anterior instability, and postoperative complication. RESULTS: There were no limitations in range of motion found in any cases. Three patients showed progressive osteoarthritis on the medial compartment. The mechanical femorotibial angle was significantly corrected from varus 7.0 degrees to valgus 1.2 degrees, and the tibial posterior slope was not significantly changed. The Lysholm and Tegner activity scores were significantly improved after surgery (from 58 to 94 points on the Lysholm scale and from 4.0 to 5.3 points on the Tegner activity scale). Although the Lachman test and the pivot-shift test showed significant improvements after surgery, instability greater than Gr II was observed in three patients on the Lachman test and in four patients on the pivot-shift test. The side-to-side difference improved from 9.6 mm to 4.2 mm postoperatively as assessed using a Telos(r) arthrometer. There were no cases of nonunion or fixation loss. CONCLUSIONS: Simultaneous open-wedge HTO and ACL reconstruction in patients with ACL injury with medial compartmental OA showed satisfactory functional outcomes and postoperative activity level scores. However, some patients showed residual instability and progression of OA. PMID- 30021640 TI - Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis. AB - BACKGROUND: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. METHODS: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI(r)) were recorded during 4 years of follow-up. RESULTS: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p < 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. CONCLUSIONS: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively. PMID- 30021643 TI - Discovery and validation of autosomal dominant Alzheimer's disease mutations. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. METHODS: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. RESULTS: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. CONCLUSIONS: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes. PMID- 30021644 TI - An inhibitor of 11-beta hydroxysteroid dehydrogenase type 1 (PF915275) alleviates nonylphenol-induced hyperadrenalism and adiposity in rat and human cells. AB - BACKGROUND: Nonylphenol (NP) is an environmental endocrine-disrupting chemical (EDC) detected in human cord blood and milk. NP exposure in developmental periods results in hyperadrenalism and increasing 11beta-hydroxysteroid dehydrogenase I (11beta-HSD1) activity in an adult rat model. Alleviating 11beta-HSD1 activity is therefore a logical and common way to treat hyperadrenalism. PF915275 (PF; 4' cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide) is a selective inhibitor for 11beta-HSD1. This study aimed to determine whether PF915275 could alleviate the hyperadrenalism induced by NP. In addition to a rat model, the effects of NP and PF915275 were measured in human preadipocytes. METHODS: For the in vivo rat model, female adult rats exposed to NP during the developmental period were divided into two treatment groups, with one receiving oral DMSO solution and the other receiving PF915275 once per day for 4 weeks. After the final treatment, the rats from each group were sacrificed for analysis. For the in vitro human model, human preadipocytes received 2 regimens of NP treatment. One treatment regimen occurred before differentiation (to mimic the sensitive developmental period; P exposure), and the other included continuous exposure from preadipocytes to fully differentiated adipocytes (to mimic the growing and adult periods, respectively; C exposure). Protein and RNA were extracted from rat tissues and the preadipocytes for western blot and real-time PCR analysis. RESULTS: In the rat model, PF915275 alleviated NP-induced effects by interfering with adipogenesis pathways, including enhancing PPARalpha expression, decreasing PPARgamma expression, and reducing both 11beta-HSD1 protein and mRNA expression levels. Additionally, PF915275 reduced the effects of the adrenal corticoid synthesis pathway by reducing StAR expression and 11beta-hydroxylase and aldosterone synthase activities. With short-term exposure, NP enhanced PPARgamma and FASN mRNA expression levels and reduced PPARalpha expression, whereas PF915275 alleviated these effects. With C exposure, the NP-induced accumulation of intracellular lipids was reduced by PF915275 treatment, which was mediated by decreased PPARgamma mRNA and protein expression levels and increased PPARalpha protein expression. CONCLUSIONS: The effects of NP and PF915275 treatment in both rat and human cell models are similar. Rats may be an appropriate model to study the effects of NP in humans, especially during the developmental period. PMID- 30021645 TI - No evidence for human papillomavirus having a causal role in salivary gland tumors. AB - BACKGROUND: Salivary gland malignancies are a very heterogeneous group of cancers, with histologically > 20 different subtypes, and prognosis varies greatly. Their etiology is unknown, however, a few small studies show presence of human papillomavirus (HPV) in some subtypes, although the evidence for HPV having a causal role is weak. The aim of this study was to investigate if HPV plays a causal role in the development of different parotid salivary gland tumor subtypes. METHODS: DNA was extracted from 107 parotid salivary gland formalin fixed paraffin embedded tumors and 10 corresponding metastases, and tested for 27 different HPV types using a multiplex bead based assay. HPV DNA positive tumors were stained for p16INK4a overexpression by immunohistochemistry. RESULTS: One of the 107 malignant parotid salivary gland tumors (0.93%) and its corresponding metastasis on the neck were positive for HPV16 DNA, and both also overexpressed p16INK4a. The HPV positive primary tumor was a squamous cell carcinoma; neither mucoepidermoid nor adenoid cystic tumors were found HPV positive. CONCLUSIONS: In conclusion, HPV DNA analysis in a large number of malignant parotid salivary gland tumors, including 12 different subtypes, did not show any strong indications that tested HPV types have a causal role in the studied salivary gland tumor types. PMID- 30021646 TI - A protocol for a multicentre, randomised, double-blind, placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients - ZAP2. AB - BACKGROUND: Bisphosphonates are a class of drugs that slow bone loss and are a promising candidate to treat knee osteoarthritis (OA) patients. In a pilot study, we demonstrated that zoledronic acid reduced knee pain and size of subchondral bone marrow lesions (BMLs) over 6 months in knee OA patients with significant knee pain and BMLs. A longer, larger study is required to assess whether decreases in BML size will translate to reductions in cartilage loss over time. We are currently conducting a multicentre, randomised, double-blind, placebo controlled trial over 24 months that aims to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change (assessed using magnetic resonance imaging (MRI)) and knee pain in knee OA patients. METHODS: Two hundred sixty-four patients with clinical knee OA, significant knee pain and subchondral BMLs present on MRI will be recruited in Hobart, Melbourne, Sydney and Adelaide. They will be randomly allocated to the two arms of the study, receiving an annual identical intravenous infusion of either 100 mL of fluid containing zoledronic acid (5 mg/100 mL) or placebo (0.9% NaCl 100 mL), at baseline and 1 year later. MRI of the study knee will be performed at screening, month 6 and 24. Knee structure, symptoms and function will be assessed using validated methods. The primary outcome is absolute change in tibiofemoral cartilage volume (mm3) over 24 months. Secondary outcomes include improvement in knee pain over 3, 6, 12, 18, and 24 months and reductions in BML size over 6 and 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to assess whether zoledronic acid has a novel disease modifying effect in OA by slowing cartilage loss and reducing pain. If zoledronic acid proves effective, it suggests great potential for cost savings through a delay or reduced need for joint replacement surgery, and potential for great improvements in quality of life for OA suffers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000039785 , registered on 14 January 2013. PMID- 30021647 TI - Relative frequency and risk factors for long-term opioid therapy following surgery and trauma among adults: a systematic review protocol. AB - BACKGROUND: When patients have been on opioid therapy for more than 90 days, more than half of them continue using opioids years later. Knowing that long-term opioid consumption could lead to harmful side effects including misuse, abuse, and addiction, it is important to understand the risks of transitioning to prolonged opioid therapy to reduce its occurrence. Perioperative and trauma contexts are ideal models commonly used to study such transition. Long-term use of opioids might be associated with transformation of acute pain to chronic, which might be an example of a risk factor. The objectives of this knowledge synthesis are to examine the relative frequency and the risk factors for transitioning to long-term opioid therapy among patients who have undergone a surgical procedure or experienced a trauma. METHODS: The proposed study methodology is based on Preferred ReportIng Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statements on the conduct of systematic review and meta analysis, the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies, and the Cochrane Handbook for Systematic Review of Interventions. A systematic literature search will include multiple databases: Cochrane Central, EMBASE, MEDLINE, PsycINFO, CINHAL, PubMed, and the grey literature. We will identify studies related to opioid use beyond acute/subacute pain control after surgery or trauma. Two of the reviewers will screen all retrieved articles for eligibility and data extraction then critically appraise all identified studies. We will compile a narrative synthesis of all results and conduct a meta-analysis when feasible. As available data permits, we will perform a subgroup analysis of vulnerable populations. DISCUSSION: This systematic review will contribute to the prevention and harm reduction strategies associated with prescription opioids by identifying risk factors leading to the unwarranted long term opioid therapy. The identification of common risk factors for long-term opioid therapy will help to orient further research on pain management as well as offer key therapeutic targets for the development of strategies to prevent prolonged opioid use. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered in PROSPERO on March 2, 2018; registration number CRD42012018089907 . PMID- 30021648 TI - Variability analysis and inter-genotype comparison of human respiratory syncytial virus small hydrophobic gene. AB - BACKGROUND: Small hydrophobic (SH) gene is one of the mostly diverse genomic regions of human respiratory syncytial virus (HRSV). Its coding region constitutes less than 50% of the complete gene length, enabling SH gene to be highly variable and the SH protein highly conserved. In standard HRSV molecular epidemiology studies, solely sequences of the second hypervariable region of the glycoprotein gene (HVR2) are analyzed. To what extent do the strains identical in HVR2 differ elsewhere in genomes is rarely investigated. Our goal was to investigate whether diversity and inter-genotype differences observed for HVR2 are also present in the SH gene. METHODS: We sequenced 198 clinical samples collected within a limited area and time frame. In this HRSV collection, rapid and significant changes in HVR2 occurred. RESULTS: Over 20% of strains from this pool (containing HRSV genotypes NA1, ON1, GA5, BA9 and BA10) would be incorrectly assumed to be identical to another strain if only the HVR2 region was analysed. The majority of differences found in SH gene were located in the 5' untranslated region (UTR). Seven indels were detected, one was genotype GA5 specific. An in frame deletion of 9 nucleotides (coding for amino acids 49-51) was observed in one of group A strains. Fifteen different SH protein sequences were detected; 68% of strains possessed the consensus sequence and most of others differed from the consensus in only one amino acid (only 4 strains differed in 2 amino acids). The majority of differing amino acids in group A viruses had the same identity as the corresponding amino acids in group B strains. When analysis was restricted to strains with identical HVR2 nucleotide sequences and differing SH protein sequences, 75% of differences observed in the SH ectodomain were located within region coding for amino acids 49-51. CONCLUSIONS: Basing HRSV molecular epidemiology studies solely on HVR2 largely underestimates the complexity of circulating virus populations. In strain identification, broadening of the genomic target sequence to SH gene would provide a more comprehensive insight into viral pool versatility and its evolutionary processes. PMID- 30021649 TI - Is exclusion of leukocytes from platelet-rich plasma (PRP) a better choice for early intervertebral disc regeneration? AB - BACKGROUND: Platelet-rich plasma (PRP) is becoming a promising strategy to treat early intervertebral disc degeneration (IDD) in clinics. Pure PRP without leukocytes (P-PRP) may decrease the catabolic and inflammatory changes in the early degenerated intervertebral discs. The aim of this study was to investigate the effects of P-PRP on nucleus pulposus-derived stem cells (NPSCs) isolated from early degenerated intervertebral discs in vitro. METHODS: NPSCs isolated from early degenerated discs of rabbits were treated with P-PRP or leukocyte-platelet rich PRP (L-PRP) in vitro, followed by measuring cell proliferation, stem cell marker expression, inflammatory gene expression, and anabolic and catabolic protein expression by immunostaining, quantitative real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. RESULTS: Cell proliferation was induced by P-PRP in a dose-dependent manner with maximum proliferation at 10% P-PRP dose. P-PRP induced differentiation of NPSCs into active nucleus pulposus cells. P-PRP mainly increased the expression of anabolic genes and relative proteins, aggrecan (AGC), collagen types II (Col II), while L PRP predominantly increased the expression of catabolic and inflammatory genes, matrix metalloproteinase-1 (MMP-1), MMP-13, interleukin-1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and protein production of IL-1beta and TNF-alpha. CONCLUSIONS: Leukocytes in PRP activate inflammatory and catabolic effects on NPSCs from early degenerated intervertebral discs. Hence, P-PRP may be a more suitable therapeutic strategy for early IDD. PMID- 30021650 TI - Role of Notch1 in the arterial specification and angiogenic potential of mouse embryonic stem cell-derived endothelial cells. AB - BACKGROUND: Endothelial cells have been shown to mediate angiogenesis in ischemic injury sites and contribute to the repair of damaged tissues. However, the treatment of ischemic disease requires a significant number of endothelial cells, which are difficult to isolate from patients. Embryonic stem cells have been considered a potential source of therapeutic cells due to their unlimited self renewal and pluripotent properties. With regard to vascular development, Notch1 has been established as a key regulator of the specification of arterial endothelial cells. METHODS: Using a doxycycline-induced expression system of the intracellular domain of Notch1, we explored the role of Notch1 in the differentiation of embryonic stem cells to arterial endothelial cells. The therapeutic effect of the arterial endothelial cells was investigated in a murine hindlimb ischemia model. The blood perfusion rate in the ischemic limb was determined by laser Doppler perfusion imaging, and vasculogenesis was quantified using immunocytochemistry. RESULTS: Induced expression of the intracellular domain of Notch1 increased the levels of endothelial markers, such as CD31 and VE cadherin, in differentiated endothelial cells. Induction of intracellular domain of Notch1 stimulated expression of the arterial-type endothelial cell markers (Nrp1 and Ephrin B2), but not the venous-type endothelial cell markers (Nrp2 and Coup-TFII). In addition, overexpression of intracellular domain of Notch1 resulted in increased expression of CXCR4, a chemokine receptor involved in vascular development. Induction of intracellular domain of Notch1 increased endothelial tube formation and migration of differentiated endothelial cells. Intramuscular administration of Notch1-induced arterial endothelial cells was more effective than administration of the control endothelial cells in restoring the blood flow in an ischemic hindlimb mouse model. Transplantation of Notch1 induced arterial endothelial cells augmented the number of blood vessels and incorporation of endothelial cells into newly formed blood vessels. CONCLUSIONS: These results suggest that Notch1 promotes endothelial maturation and arterial specification during the differentiation of embryonic stem cells to endothelial cells and increases the angiogenic potential of endothelial cells. PMID- 30021651 TI - Identification of a threshold to discriminate fasting hypertriglyceridemia with postprandial values. AB - BACKGROUND: Postprandial lipemia is an important cardiovascular risk factor. The assessment of postprandial lipid metabolism is a newly trend that several consortiums and countries have adopted. The aim of the study is to determine a postprandial triglyceride concentration cut-off point that accurately discriminate individuals with fasting normal triglyceride concentrations from those with fasting hypertriglyceridemia. METHODS: Cross sectional population based study. A total of 212 subjects underwent an eight hours' oral fat tolerance test. Samples were taken fasting, three, four, five, six and eight hours after the meal. The area under the receiver operating characteristic curve (c statistic) was computed using postprandial triglycerides concentrations as independent predictor, and fasting hypertriglyceridemia as dependent variable. RESULTS: The best threshold of postprandial lipemia to discriminate fasting hypertriglyceridemia was 280 mg/dL at any hour area under the curve 0.816 (95% confidence interval 0.753-0.866), bootstrap-corrected c-statistic = 0.733 (95% confidence interval 0.68-0.86). The same value was compared with apolipoprotein B concentrations (>90th percentile) having a good performance: area under the curve 0.687 95% confidence interval 0.624-0.751). Likewise, subjects with high postprandial lipemia have higher Globo risk scores. CONCLUSION: The 280 mg/dL cut off point value of postprandial triglycerides concentration any time after a test meal discriminate subjects with fasting hypertriglyceridemia. This threshold has a good performance in a heterogeneous population and has a good concordance with cardiovascular risk surrogates. PMID- 30021652 TI - The dynamic changes in the number of uterine natural killer cells are specific to the eutopic but not to the ectopic endometrium in women and in a baboon model of endometriosis. AB - BACKGROUND: Endometriosis is a common condition associated with growth of endometrial-like tissue beyond the uterine cavity. Previous reports have suggested a role for uNK cells in the pathogenesis of endometriosis postulating that survival and accumulation of menstrual endometrial tissue in the peritoneal cavity may relate to a reduction in the cytotoxic activity of peripheral blood NK cells. We aimed to assess the differences in percentage of uNK cells and their phenotypical characterization in eutopic and ectopic endometrial samples from women with and without endometriosis and baboons with induced endometriosis. METHODS: Eutopic and ectopic endometrial samples from 82 women across the menstrual cycle with/without endometriosis and from 8 baboons before and after induction of endometriosis were examined for CD56 and NKp30 expression with immunohistochemistry, quantified using computer assisted image analysis. Curated secretory phase endometrial microarray datasets were interrogated for NK cell receptors and their ligands. In silico data was validated by examining the secretory phase eutopic endometrium of women with and without endometriosis (n = 8/group) for the immuno-expression of BAG6 protein. RESULTS: The percentage of uNK cells increased progressively from the proliferative phase with the highest levels in the late secretory phase in the eutopic endometrium of women with and without endometriosis. The percentage of uNK cells in ectopic lesions remained significantly low throughout the cycle. In baboons, induction of endometriosis increased the percentage of uNK in the ectopic lesions but not NKp30. Published eutopic endometrial microarray datasets demonstrated significant upregulation of NKp30 and its ligand BAG6 in women with endometriosis compared with controls. Immunohistochemical staining scores for BAG6 was also significantly higher in secretory phase eutopic endometrium from women with endometriosis compared with the endometrium of healthy women (n = 8/group). CONCLUSIONS: The dynamic increase in the percentage of uNK cells in the secretory phase is preserved in the endometrium of women with endometriosis. The low number of uNK cells in human and baboon ectopic lesions may be due to their exaggerated reduction in hormonal responsiveness (progesterone resistance). PMID- 30021653 TI - Ciliostasis of airway epithelial cells facilitates influenza A virus infection. AB - Porcine precision-cut lung slices (PCLS) were used to analyze the effect of the ciliary activity on infection of airway epithelial cells by influenza viruses. Treatment of slices with 2% NaCl for 30 min resulted in reversible ciliostasis. When PCLS were infected by a swine influenza virus of the H3N2 subtype under ciliostatic conditions, the viral yield was about twofold or threefold higher at 24 or 48 h post-infection, respectively, as compared to slices with ciliary activity. Therefore, the cilia beating not only transports the mucus out of the airways, it also impedes virus infection. PMID- 30021654 TI - Prevalence of type 2 diabetes, prediabetes, and gestational diabetes mellitus in women of childbearing age in Middle East and North Africa, 2000-2017: protocol for two systematic reviews and meta-analyses. AB - BACKGROUND: Diabetes mellitus (DM) in women of childbearing age may affect the fetus, thereby accelerating the intergenerational risk of DM. The Middle East and North Africa (MENA) region is experiencing a growing epidemic of DM. We aim to conduct two systematic reviews to summarize the burden of DM in women of childbearing age in the MENA region. In the systematic review 1, we aim to (1) systematically aggregate the evidence on type 2 DM (T2DM) and prediabetes and (2) to synthesize overall estimate on the prevalence of T2DM and overall estimate on the prevalence of prediabetes, in women of childbearing age (15-49 years). In the systematic review 2, we aim to (1) systematically aggregate the evidence on gestational DM (GDM) and (2) to synthesize overall estimate on the prevalence of GDM in pregnant women. METHODS: For systematic reviews 1 and 2, we will conduct a comprehensive search of the literature published in six electronic databases (MEDLINE-PubMed, EMBASE, Web of Science, SCOPUS, Cochrane Library, and Academic Search Complete). Variant and broad search terms will be designed to identify epidemiologic studies on the prevalence of T2DM and prediabetes in women of childbearing age, and GDM in pregnant women, published between 2000 and 2017. The MENA region will be defined according to the World Bank Country and Lending Groups. Retrieved citations will be screened, and data from the eligible research reports against specific eligibility criteria will be extracted. The findings of each systematic review will be reported separately following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA). DISCUSSION: Published literature on the prevalence of different types of DM among different population groups has been recently increased in the MENA region. This is the first review to fill an evidence gap on the overall burden, in the form of prevalence, of T2DM, prediabetes, and GDM in women of childbearing age in the MENA region. The findings of the two reviews will help in understanding the regional burden of these three types of DM in specific population groups to identify priority areas for interventions. SYSTEMATIC REVIEW REGISTRATION: The PROSPERO registration number for the systematic review 1 is " CRD42017069231 " dated 12/06/2017 and for the systematic review 2 is " CRD42018100629 " dated 18/06/2018. PMID- 30021655 TI - Peripheral-blood gene expression profiling studies for coronary artery disease and its severity in Xinjiang population in China. AB - BACKGROUND: Alterations in gene expression in peripheral blood cells play a curtail role in the presence and extent of coronary artery disease (CAD), but its severity reflected by gene expression alterations in peripheral blood cells is still unknown in Xinjiang population in China. METHODS: Global gene expression profiling in peripheral blood was used to explore differentially expressed genes in coronary artery stenosis patients. RNA was extracted from peripheral blood of 9 controls without coronary stenosis and 21 cases with angiographically CAD. The extent of CAD severity was categorized angiographically as no CAD, mild CAD (20 to 50% luminal diameter stenosis [LDS]), moderate CAD (50 to 75% LDS) and severe CAD (>=75% LDS). Differentially expressed genes related with CAD severity from peripheral blood cells were screened by linear mixed effects analysis using the lme4 package in R. Then the differentially expressed genes that gradually up regulated or down-regulated were enriched by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: The most significantly enrichments were toll-like receptor signaling pathway, immune responses, translational processes, cellular growth, inflammation and metabolic processes. Combined with NCBI-GeneRIF and PubMed analysis, we focused on the 12 genes associated with toll-like receptor signaling pathway in the extent of coronary artery stenosis patients. Receiver operating characteristic (ROC) analysis of 12 genes associated with toll-receptor signaling pathway in the 236 CAD patients from GEO database demonstrated that 12 genes expression could predict severe CAD with an area under the curve of 0.67, sensitivity of 77.65% and specificity of 51.52%. CONCLUSION: These results suggest that 12 genes associated with toll-like receptor signaling pathway in peripheral-blood cells reflect the presence and extent of CAD severity in Xinjiang population in China. PMID- 30021656 TI - Diffusion-weighted imaging in monitoring the pathological response to neoadjuvant chemotherapy in patients with breast cancer: a meta-analysis. AB - BACKGROUND: Diffusion-weighted imaging (DWI) is suggested as an non-invasive and non-radioactive imaging modality in the identification of pathological complete response (pCR) in breast cancer patients receiving neoadjuvant chemotherapy (NACT). A growing number of trials have been investigating in this aspect and some studies found a superior performance of DWI compared with conventional imaging techniques. However, the efficiency of DWI is still in dispute. This meta analysis aims at evaluating the accuracy of DWI in the detection of pCR to NACT in patients with breast cancer. METHODS: Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were drawn to estimate the diagnostic effect of DWI to NACT. Summary receiver operating characteristic curve (SROC), the area under the SROC curve (AUC), and Youden index (*Q) were also calculated. The possible sources of heterogeneity among the included studies were explored using single factor meta-regression analyses. Publication bias and quality assessment were assessed using Deek's funnel plot and QUADAS-2 form respectively. RESULTS: Twenty studies incorporated 1490 participants were enrolled in our analysis. Pooled estimates revealed a sensitivity of 0.89 (95% CI, 0.86-0.91), a specificity of 0.72 (95% CI, 0.68-0.75), and a DOR of 27.00 (95% CI, 15.60-46.73). The AUC of SROC curve and *Q index were 0.9088 and 0.8408, respectively. The results of meta regression analyses showed that pCR rate, time duration of study population, and study design were not the sources of heterogeneity. CONCLUSION: A relatively high sensitivity and specificity of DWI in diagnosing pCP for patients with breast cancer underwent NACT treatment was found in our meta-analysis. This finding indicated that the use of DWI might provide an accurate and precise assessment of pCR to NACT. PMID- 30021657 TI - The role of mesenchymal stem cells in chemotherapy-induced gonadotoxicity. AB - BACKGROUND: The therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) against cisplatin-induced nephrotoxicity has been reported, however, its efficacy in gonadotoxicity still has not been addressed. Herein, we investigated the effect of BM-MSCs in cisplatin-induced testicular toxicity and its underlying mechanism of action. METHODS: Thirty male Sprague-Dawley rats were divided into a control group: injected with phosphate-buffered saline (PBS) intraperitoneal (ip), a cisplatin group: injected with a single dose of 7 mg/kg cisplatin ip to induce gonadotoxicity and a BM-MSCs group: received cisplatin ip followed by BM-MSCs injection 1 day after cisplatin. In testicular tissues, malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) levels were assessed. Additionally, gene expressions of inducible nitric oxide synthase (iNOS), caspase-3, and p38 mitogen-activated protein kinase (MAPK) were measured. The testicular tumor necrosis factor alpha (TNF-alpha) protein contents and Bcl-2 associated X protein (BAX) expression were determined. Histopathology of testicular tissues was examined. RESULTS: Cisplatin injection showed a significant decrease in GSH and SOD testicular levels besides a significant increase of MDA and TNF-alpha testicular levels and upregulation of testicular gene expressions of iNOS, caspase-3, and p38-MAPK in comparison to the control group. Moreover, a marked increase in BAX protein expression was observed in the cisplatin group when compared with the control one. Histopathological examination exhibited significant seminiferous tubules atrophy in cisplatin-treated rats. CONCLUSIONS: The BM-MSCs injection significantly repaired the testicular injury and improved both biochemical and histopathological changes. The MSCs mitigated the gonadotoxicity induced by cisplatin through antioxidative, anti-inflammatory, and antiapoptotic mechanisms. PMID- 30021658 TI - The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment. AB - BACKGROUND: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals. METHODS: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community. RESULTS: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent. CONCLUSIONS: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI. PMID- 30021661 TI - Delirium etiology subtypes and their effect on six-month function and cognition in older emergency department patients. AB - : ABSTRACTBackground:Delirium is heterogeneous and can vary by etiology. OBJECTIVES: We sought to determine how delirium subtyped by etiology affected six month function and cognition. DESIGN: Prospective cohort study. SETTING: Tertiary care, academic medical center. PARTICIPANTS: A total of 228 hospitalized patients > 65 years old were admitted from the emergency department (ED). MEASUREMENTS: The modified Brief Confusion Assessment Method was used to determine delirium in the ED. Delirium etiology was determined by three trained physician reviewers using a Delirium Etiology checklist. Pre-illness and six-month function and cognition were determined using the Older American Resources and Services Activities of Daily Living (OARS ADL) questionnaire and the short-form Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Multiple linear regression was performed to determine if delirium etiology subtypes were associated with six-month function and cognition adjusted for baseline OARS ADL and IQCODE. Two-factor interactions were incorporated to determine pre-illness function or cognition-modified relationships between delirium subtypes and six month function and cognition. RESULTS: In patients with poorer pre-illness function only, delirium secondary to metabolic disturbance (beta coefficient = 2.9 points, 95%CI: -0.3 to -5.6) and organ dysfunction (beta coefficient = -4.3 points, 95%CI: -7.2 to -1.4) was significantly associated with poorer six-month function. In patients with intact cognition only, delirium secondary to central nervous system insults was significantly associated with poorer cognition (beta coefficient = 0.69, 95%CI: 0.19 to 1.20). CONCLUSIONS: Delirium is heterogeneous and different etiologies may have different prognostic implications. Furthermore, the effect of these delirium etiologies on outcome may be dependent on the patient's pre-illness functional status and cognition. PMID- 30021660 TI - Genome-wide methylomic analysis in individuals with HNF1B intragenic mutation and 17q12 microdeletion. AB - Heterozygous mutation of the transcription factor HNF1B is the most common cause of monogenetic developmental renal disease. Disease-associated mutations fall into two categories: HNF1B intragenic mutations and a 1.3 Mb deletion at chromosome 17q12. An increase in neurodevelopmental disorders has been observed in individuals harbouring the 17q12 deletion but not in patients with HNF1B coding mutations.Previous investigations have concentrated on identifying a genetic cause for the increase in behavioural problems seen in 17q12 deletion carriers. We have taken the alternative approach of investigating the DNA methylation profile of these two HNF1B genotype groups along with controls matched for age, gender and diabetes status using the Illumina 450K DNA methylation array (total sample n = 60).We identified a number of differentially methylated probes (DMPs) that were associated with HNF1B-associated disease and passed our stringent experiment-wide significance threshold. These associations were largely driven by the deletion patients and the majority of the significant probes mapped to the 17q12 deletion locus. The observed changes in DNA methylation at this locus were not randomly dispersed and occurred in clusters, suggesting a regulatory mechanism reacting to haploinsufficiency across the entire deleted region.Along with these deletion-specific changes in DNA methylation, we also identified a shared DNA methylation signature in both mutation and deletion patient groups indicating that haploinsufficiency of HNF1B impacts on the methylome of a number of genes, giving further insight to the role of HNF1B. PMID- 30021662 TI - General practitioners' perceptions of their role and their collaboration with district nurses in wound care. AB - : AimTo explore the perceptions of general practitioners (GPs) regarding their role and their collaboration with district nurses (DNs) in the management of leg ulcers in primary healthcare. BACKGROUND: Earlier research regarding the treatment of leg ulcers in a primary care context has focussed primarily on wound healing. Less is known about GPs' understandings of their role and their collaboration with DNs in the management of leg ulcers. Since the structured care of patients with leg ulcers involving both GP and DN is currently rather uncommon in Swedish primary care, this study sets out to highlight these aspects from the GP's perspective. METHODS: Semi-structured individual interviews with 16 GPs including both private and county council run healthcare centres. Thematic analysis was used to analyse the data. RESULTS: Four themes were identified. The first theme: 'role as consultant and coordinator' shows how the GPs perceived their role in wound care. In the second theme: 'responsibility for diagnosis' the GPs' views on responsibility for wound diagnosis is presented. The third theme: 'desire for continuity' is based on the GPs' desire for continuity concerning various aspects. In the fourth theme: 'collaboration within the organisation' the importance of the organisation for collaboration between GPs and DNs is presented. CONCLUSIONS: The GP's often work on a consultation-like basis and feel that they become involved late in the patients' wound treatment. This can have negative consequences for the medical diagnosis and, thereby, lead to a prolonged healing time for the patient. Shortcomings regarding collaboration are mainly attributed to organisational factors. PMID- 30021659 TI - First evidence of Besnoitia bennetti infection (Protozoa: Apicomplexa) in donkeys (Equus asinus) in Belgium. AB - BACKGROUND: Besnoitiosis is caused by different species of intracellular protozoan parasites belonging to the family Sarcocystidae and affecting multiple host species worldwide. Including B. besnoiti, ten species are described infecting animals. Among ungulates, Besnoitia bennetti infects horses, donkeys and zebras and was described in Africa and in the USA where donkey besnoitiosis is considered as an emerging disease. CASE PRESENTATION: A two-year-old male donkey was purchased in May 2016 in poor body condition (cachexia, alopetic areas and pruritus mainly on neck and head) by the present owner in Le Roeulx (Belgium) from a milk producing donkey farm in Frasnes-lez-Buissenal (Belgium). Shortly after its purchase and shearing, the donkey presented with crusts, hyperkeratosis (both flanks and neck) anorexia and cachexia. A treatment with phoxim was given with no improvement. A cutaneous biopsy of hyperkeratotic skin was performed in July. It showed a perivascular eosinophilic infiltrate with a large thick walled cyst located in the dermis containing numerous bradyzoites. This was highly suggestive of besnoitiosis. Several skin biopsy samples were obtained for qPCR analysis and confirmed the presence of Besnoitia spp. DNA. Further laboratory diagnosis tests were performed (western blot and rDNA sequencing) confirming Besnoitia bennetti aetiology for the male. For the female, the punch-biopsy, haematology and qPCR were negatives but the western blot showed the presence of antibodies directed to Besnoitia spp. Further clinical examination performed in August highlighted scleral pinhead sized cysts (pearl) in the right eye and between nares. Another ten-year-old female donkey purchased in France and sharing the same accommodation showed a good clinical condition, but a thorough clinical examination showed the presence of numerous cysts on the inner face of upper labial mucosa. A daily treatment based on sulfamethaxzole and trimethoprim (Emdotrim 60% Mix(r), 30 mg/kg) was given orally and some improvement was noticed. CONCLUSION: This is the first evidence of Besnoitia bennetti infection (Protozoa: Apicomplexa) in donkeys (Equus asinus) in Belgium. PMID- 30021663 TI - IMPACT OF HEALTH TECHNOLOGY ASSESSMENT REPORTS ON HOSPITAL DECISION MAKERS - 10 YEAR INSIGHT FROM A HOSPITAL UNIT IN SHERBROOKE, CANADA: IMPACT OF HEALTH TECHNOLOGY ASSESSMENT ON HOSPITAL DECISIONS. AB - OBJECTIVES: The overarching goal of this research was to (i) evaluate the impact of reports with recommendations provided by a hospital-based health technology assessment (HB-HTA) unit on the local hospital decision-making processes and implementation activities and (ii) identify the underlying factors of the nonimplementation of recommendations. METHODS: All reports produced by the HB-HTA unit between December 2003 and March 2013 were retrieved, and hospital decision makers who requested these reports were solicited for enrolment. Participants were interviewed using a mixed design survey. RESULTS: Twenty reports, associated with fifteen decision makers, fulfilled the study criteria. Nine decision makers accepted to participate, corresponding to thirteen reports and twenty-three recommendations. Of the twenty-three recommendations issued, 65 percent were implemented, 9 percent were accepted for implementation but not implemented, and 26 percent were declined. In terms of the utility of each report to guide decision makers, 92 percent of the reports were considered in the decision-making process; 85 percent had one or more recommendations adopted; and 77 percent had recommendations implemented. The most frequently mentioned reasons for nonimplementation were related to contextual factors (64 percent), production/diffusion process factors (14 percent), content/format factors (14 percent), or other factors (9 percent). Among the contextual factors, the complexity of the changes (i.e., administrative reasons), budget and resources constraints, failure to identify administrative responsibility to carry out the recommendation, and nonpriority status of the HTA recommendation, were provided. CONCLUSIONS: This study highlights that although HB-HTA reports are useful to hospital managers in their decision-making processes, certain barriers such as contextual factors need to be better addressed to improve HB-HTA efficiency and usefulness. PMID- 30021664 TI - Mass vaccination response to a measles outbreak is not always possible. Lessons from a London prison. AB - In this study, we describe a contained measles outbreak in a London prison, the second such outbreak in a custodial setting. Once vaccination commenced, just under a third of eligible prisoners were immunised due to a low uptake of the vaccine. We conducted a root-cause analysis in order to identify factors which may have prevented or altered the course of the outbreak. Our analysis revealed that many of the factors identified are those that cannot be easily changed. It is unlikely that mass vaccination at the time, even in the absence of some of the more easily rectifiable issues, could have fully avoided further cases in the event of a mass outbreak. Both measles outbreaks in a custodial setting started with a member of staff and immunisation status of the staff were largely unknown. We argue that mass vaccination following an outbreak in a prison is unlikely to fully prevent a mass outbreak, and that implementing opt-out testing, empirical vaccination and insisting on full immunisation of staff are most likely to both prevent and contain outbreaks in the future. PMID- 30021665 TI - Food insecurity and anaemia risk: a systematic review and meta-analysis. AB - OBJECTIVE: Increasing evidence has suggested an association between food insecurity and the risk of anaemia. Therefore, a systematic review and meta analysis were performed to examine the associations between food insecurity and anaemia risk. SETTING: Pertinent studies were identified by searching PubMed and EMBASE databases up to August 2017. Data were available from nineteen studies; seventeen studies were cross-sectional and two studies were longitudinal. Risk ratios of 95993 individual participants from twelve different countries in these studies were pooled for the meta-analysis. RESULTS: The results showed that there was an overall positive relationship between food insecurity and anaemia risk (OR=1.27; 95 % CI 1.13, 1.40). Similar results were observed for Fe-deficiency anaemia (OR=1.45; 95 % CI 1.04, 1.86). These results revealed that food insecurity at two levels, including mild food insecurity (OR=1.15; 95 % CI 1.00, 1.31) and moderate food insecurity (OR=1.36; 95 % CI 1.23, 1.48), increased the risk of anaemia. In addition, it was found that age had an impact on the associations between food insecurity and anaemia risk (OR=1.22; 95 % CI 1.09, 1.36). Age subgroup analysis indicated that food insecurity significantly increased the risk of anaemia among infants/toddlers (OR=1.17; 95 % CI 1.05, 1.29) and adult women (OR=1.35; 95 % CI 1.16, 1.54). CONCLUSIONS: It seems that infants, toddlers and adult women in food-insecure households are at a higher risk of anaemia. To prevent anaemia in food-insecure households, these age groups may require more nutritional support. PMID- 30021666 TI - The importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring. AB - A 24-year-old woman with a history of idiopathic dilated cardiomyopathy status post heart transplant gave birth to a healthy term female infant. At 5 months of age, the infant was diagnosed with severe left ventricular dysfunction with an ejection fraction of 18% and moderate non-compaction of the left ventricle. She received a heart transplant at 7 months of age. Familial dilated cardiomyopathy was diagnosed. Genetic testing revealed a likely pathogenic variant in the TPM1 gene. Fetal cardiac screening is critical for offspring of heart transplant recipients, especially when the reason for transplant was cardiomyopathy. Early genetic consultation and counselling is necessary for all heart transplant recipients, preferably prenatally. Postnatal screening of offspring is essential at birth, at 3-month intervals until 1 year of age, and then annually until the risk for familial cardiomyopathy is assessed. PMID- 30021667 TI - Comparing the Mini-Mental State Examination and the modified Mini-Mental State Examination in the detection of mild cognitive impairment in older adults. AB - : ABSTRACTObjectives:To show enhanced psychometric properties and clinical utility of the modified Mini-Mental State Examination (3MS) compared to the Mini Mental State Examination (MMSE) in mild cognitive impairment (MCI). DESIGN: Psychometric and clinical comparison of the 3MS and MMSE. SETTING: Neuropsychological clinic in the northeastern USA. PARTICIPANTS: Older adults referred for cognitive concerns, 87 of whom were cognitively intact (CI) and 206 of whom were diagnosed with MCI. MEASUREMENTS: The MMSE, the 3MS, and comprehensive neuropsychological evaluations. RESULTS: Both instruments were significant predictors of diagnostic outcome (CI or MCI), with comparable odds ratios, but the 3MS explained more variance and showed improved classification accuracies relative to the MMSE. The 3MS also demonstrated greater receiver operating characteristic area under the curve values (0.85, SE = 0.02) compared to the MMSE (0.74, SE = 0.03). Scoring lower than 95/100 on the 3MS suggested MCI, while scoring lower than 28/30 on the MMSE suggested MCI. Additionally, compared to the MMSE, the 3MS shared more variance with neuropsychological composite scores in Language and Memory domains but not in Attention, Visuospatial, and Executive domains. Finally, 65.5% MCI patients were classified as impaired (scoring <=1 SD below the mean) using 3MS normative data, compared to only 11.7% of patients who were classified as impaired using MMSE normative data. CONCLUSIONS: Broadly speaking, our data strongly favor the widespread substitution of the MMSE with the 3MS in older adults with concerns for cognitive decline. PMID- 30021668 TI - Italian version and normative data of Addenbrooke's Cognitive Examination III. AB - : ABSTRACTObjectives:Addenbrooke's Cognitive Examination III (ACE-III) is a brief cognitive screening tool to assess five cognitive domains: attention/orientation, verbal fluency, memory, language, and visuospatial abilities. This study aimed to provide normative data (for total score and subscale scores) of the Italian version of ACE-III for gender, age, and education. METHODS: A total of 574 healthy Italian participants (mean age 68.70 +/- 9.65; mean education 9.15 +/- 4.04) were recruited from the community and included in the study. Linear regression analysis was performed to evaluate the effects of age, gender, and education on the ACE-III total performance score. RESULTS: Age and education exerted a significant effect on total and subscale ACE-III scores, whereas gender was on attention/orientation, language, and visuospatial subscale scores. From the derived linear equation, correction grids to adjust raw scores and equivalent scores (ESs) with cut-off values were provided. CONCLUSIONS: The present study provided normative data, correction grids, and ESs for ACE-III in an Italian population. PMID- 30021669 TI - It really does take a village: The role of neighbors in the etiology of nonaggressive rule-breaking behavior. AB - Although there is growing recognition that disadvantaged contexts attenuate genetic influences on youth misbehavior, it is not yet clear how this dampening occurs. The current study made use of a "geographic contagion" model to isolate specific contexts contributing to this effect, with a focus on nonaggressive rule breaking behaviors (RB) in the families' neighbors. Our sample included 847 families residing in or near modestly-to-severely disadvantaged neighborhoods who participated in the Michigan State University Twin Registry. Neighborhood sampling techniques were used to recruit neighbors residing within 5km of a given family (the mean number of neighbors assessed per family was 13.09; range, 1-47). Analyses revealed clear evidence of genotype-environment interactions by neighbor RB, such that sibling-level shared environmental influences on child RB increased with increasing neighbor self-reports of their own RB, whereas genetic influences decreased. Moreover, this moderation appeared to be driven by geographic proximity to neighbors. Sensitivity analyses further indicated that this effect was specifically accounted for by higher levels of neighbor joblessness, rather than elements of neighbor RB that would contribute to neighborhood blight or crime. Such findings provocatively suggest that future genotype-environment interactions studies should integrate the dynamic networks of social contagion theory. PMID- 30021670 TI - Online market research panel members as controls in case-control studies to investigate gastrointestinal disease outbreaks: early experiences and lessons learnt from the UK - ERRATUM. PMID- 30021673 TI - An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma. AB - Recent studies showed that the PD-1/PD-L1 checkpoint blockade is a dramatic therapy for melanoma by enhancing antitumor immune activity. Currently, major strategies for the PD-1/PD-L1 blockade have mainly focused on the use of antibodies and compounds. Seeking an alternative approach, others employ endogenous proteins as blocking agents. The extracellular domain of PD-1 (ePD1) includes the binding site with PD-L1. Accordingly, we constructed a PD-1-based recombinantly tailored fusion protein (dFv-ePD1) that consists of bivalent variable fragments (dFv) of an MMP-2/9-targeted antibody and ePD1. The melanoma binding intensity and antitumor activity were also investigated. We found the intense and selective binding capability of the protein dFv-ePD1 to human melanoma specimens was confirmed by a tissue microarray. In addition, dFv-ePD1 significantly suppressed the migration and invasion of mouse melanoma B16-F1 cells, and displayed cytotoxicity to cancer cells in vitro. Notably, dFv-ePD1 significantly inhibited the growth of mouse melanoma B16-F1 tumor cells in mice and in vivo fluorescence imaging showed that dFv-ePD was gradually accumulated into the B16-F1 tumor. Also the B16-F1 tumor fluorescence intensity at the tumor site was stronger than that of dFv. This study indicates that the recombinant protein dFv-ePD1 has an intensive melanoma-binding capability and exerts potent therapeutic efficacy against melanoma. The novel format of the PD-L1-blocked agent may play an active role in antitumor immunotherapy. [BMB Reports 2018; 51(11): 572-577]. PMID- 30021671 TI - Hepatic Vitamin A Concentrations in Vervets (Chlorocebus aethiops) Supplemented with Carotenoids Derived from Oil Palm. AB - Commonly used in biomedical research, vervets (Chlorocebus aethiops) are omnivorous but primarily meet their vitamin A requirements from provitamin A carotenoids. Hypervitaminosis A has occurred in vervets that consume feed high in preformed vitamin A. We investigated the vitamin A status of vervets supplemented daily with various antioxidants derived from palm oil. Male vervets (n = 40) were placed for 23 wk on a high-fat diet (34.9% energy) containing 645 MU g retinol activity equivalents (RAE), with 515 MU g RAE from preformed vitamin A. Vervets were randomized to 5 treatments (duration, 20 mo): control; 100 mg d-alpha tocopheryl acetate; 100 mg oil palm (Elaeis guineensis)-derived vitamin E; 50 mg oil palm-derived vitamin E + 50 mg carotenoid complex + unrestricted palm-derived water-soluble antioxidants; and 5) unrestricted water-soluble antioxidants. Livers (n = 38) were analyzed for vitamin A, alpha-retinol (alpha-vitamin A), and carotenoids. Median hepatic vitamin A and total carotenoid concentrations were 6.49 MU mol/g and 4.30 nmol/g, respectively. Compared with controls, vervets fed the carotenoid complex had higher hepatic vitamin A (11.9 +/- 5.1 MU mol/g), alpha -vitamin A (1.3 +/- 0.7 MU mol/g), alpha -carotene (11.5 +/- 5.3 nmol/g), beta-carotene (15.6 +/- 8.6 nmol/g), and total carotenoids (28.1 +/- 13.9 nmol/g) but lower lutein (0.66 +/- 0.28 nmol/g) and zeaxanthin (0.24 +/- 0.06 nmol). NHP may benefit from replacement of preformed vitamin A with carotenoids in feeds; however, bioconversion efficiency in these models should be investigated to determine optimal levels. PMID- 30021675 TI - Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation. AB - Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an NAD+ dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesis, as well as inflammatory pathways. We show that APAP decreases the expression of Sirt2. Moreover, the ablation of Sirtuin2 attenuates APAP-induced liver injuries, such as oxidative stress and mitochondrial damage in hepatocytes. We found that Sirt2 deficiency alleviates the APAP -mediated endoplasmic reticulum stress and phosphorylation of the p70 ribosomal S6 kinase 1 (S6K1). Moreover, Sirt2 interacts with and deacetylates S6K1, followed by S6K1 phosphorylation induction. This study elucidates the molecular mechanisms underlying the protective role of Sirt2 inactivation in APAP-induced liver injuries. PMID- 30021674 TI - Activation of formyl peptide receptor 2 by WKYMVm enhances emergency granulopoiesis through phospholipase C activity. AB - Emergency granulopoiesis is a very important strategy to supply efficient neutrophil number in response to infection. However, molecular mechanism involved in this process remains unclear. Here, we found that administration of WKYMVm, an immune modulating peptide, to septic mice strongly increased neutrophil number through augmented emergency granulopoiesis. WKYMVm-induced emergency granulopoiesis was blocked not only by a formyl peptide receptor 2 (FPR2) antagonist (WRW4), but also by FPR2 deficiency. As progenitors of neutrophils, Lin-c-kit+Sca-1- cells expressed FPR2. WKYMVm-induced emergency granulopoiesis was also blocked by a phospholipase C inhibitor (U-73122). These results suggest that WKYMVm can stimulate emergency granulopoiesis via FPR2 and phospholipase C enzymatic activity. [BMB Reports 2018; 51(8): 418-423]. PMID- 30021677 TI - Clinical engagement: a new concept or common sense all round? AB - Clinical engagement has supplemented clinical governance in healthcare to strengthen the contribution of medical professionals to the assessment of clinical outcomes for patients. Assessments of clinical engagement have, until now, been qualitative; this case study introduces the concept of quantitative assessment of clinical engagement by measuring the number of patients managed according to specialist society guidelines. Such an assessment engages all staff (medical, nursing, allied health and pharmacy) involved in patients receiving treatment according to such guidelines and provides an assessment of individual and organisational compliance with those guidelines. Clinical engagement is then quantified as the percentage of patients that have been documented to receive specialist society- or college-approved guideline-compliant treatment, relative to the total number who could receive such treatment, in any healthcare organisation.What is known about the topic? Clinical engagement has emerged in recent years as a virtue to be encouraged in healthcare organisations because of its association with improved patient outcomes and employee satisfaction. Assessments have relied on repeated staff surveys in order to gauge engagement.What does this paper add? This paper proposes a novel means of measuring clinical engagement in an organisational setting. The vision put forward is that adherence to clinical guidelines in an organisation measures clinician engagement across professional disciplines.What are the implications for practitioners? The implications are that organisations will contribute to measuring the adherence of specialty groups of clinicians to guidelines that the clinicians select and use the data for individual and organisational accreditation. PMID- 30021676 TI - Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation. AB - Homotypic cell-in-cell (CIC) structures forming between cancer cells were proposed to promote tumor evolution via entosis, a nonapoptotic cell death process. However, the mechanisms underlying their formation remained poorly understood. We performed a microarray analysis to identify genes associated with homotypic CIC formation. Cancer cells differing in their ability to form homotypic CIC structures were selected for the study. Association analysis identified 73 probe sets for 62 candidate genes potentially involved in CIC formation. Among them, twenty-one genes were downregulated while 41 genes were upregulated. Pathway analysis identified a gene interaction network centered on IL-8, which was upregulated in high CIC cells. Remarkably, CIC formation was significantly inhibited by IL-8 knockdown and enhanced upon recombinant IL-8 treatment, which correlated with altered cell-cell adhesion and expression of adhesive molecules such as P-cadherin and gamma-catenin. Together, our work identified IL-8 as a positive regulator of homotypic CIC formation via enhancing intercellular adhesion. [BMB Reports 2018; 51(8): 412-417]. PMID- 30021679 TI - Meet the Editors. PMID- 30021680 TI - The development of an online risk calculator for the prediction of future syphilis among a high-risk cohort of men who have sex with men and transgender women in Lima, Peru. AB - : Background Syphilis incidence worldwide has rebounded since 2000, particularly among men who have sex with men (MSM). A predictive model for syphilis infection may inform prevention counselling and use of chemoprophylaxis. METHODS: Data from a longitudinal cohort study of MSM and transgender women meeting high-risk criteria for syphilis who were followed quarterly for 2 years were analysed. Incidence was defined as a four-fold increase in rapid plasma reagin (RPR) titres or new RPR reactivity if two prior titres were non-reactive. Generalised estimating equations were used to calculate rate ratios (RR) and develop a predictive model for 70% of the dataset, which was then validated in the remaining 30%. An online risk calculator for the prediction of future syphilis was also developed. RESULTS: Among 361 participants, 22.0% were transgender women and 34.6% were HIV-infected at baseline. Syphilis incidence was 19.9 cases per 100-person years (95% confidence interval (CI) 16.3-24.3). HIV infection (RR 2.22; 95% CI 1.54-3.21) and history of syphilis infection (RR 2.23; 95% 1.62 3.64) were significantly associated with incident infection. The final predictive model for syphilis incidence in the next 3 months included HIV infection, history of syphilis, number of male sex partners and sex role for anal sex in the past 3 months, and had an area under the curve of 69%. The online syphilis risk calculator based on those results is available at: www.syphrisk.net. CONCLUSIONS: Using data from a longitudinal cohort study among a population at high risk for syphilis infection in Peru, we developed a predictive model and online risk calculator for future syphilis infection. The predictive model for future syphilis developed in this study has a moderate predictive accuracy and may serve as the foundation for future studies. PMID- 30021681 TI - How do health consumer organisations in Australia manage pharmaceutical industry sponsorship? A cross-sectional study. AB - Objective The aim of this study was to investigate how health consumer organisations manage their relationships with the pharmaceutical industry in Australia.Methods We identified 230 health consumer organisations that received pharmaceutical industry support from 2013 to 2016 according to reports published by Medicines Australia, the industry trade association. A random sample of 133 organisations was selected and their websites assessed for financial transparency, policies governing corporate sponsorship and evidence of potential industry influence.Results In all, 130 of the 133 organisations evaluated received industry funding. Of these 130, 68 (52.3%; 95% confidence interval (CI) 43.4-61.1%) disclosed this funding. Nearly all (67; 98.5%) reported the identity of their industry donors, followed by uses (52.9%), amount (13.2%) and proportion of income from industry (4.4%). Less than one-fifth (24/133; 18.0%; 95% CI 11.9 25.6%) had publicly available policies on corporate sponsorship. Six organisations (7.2%; 95% CI 2.7-15.1%) had board members that were currently or previously employed by pharmaceutical companies, and 49 (36.8%; 95% CI 28.6 45.6%) had company logos, web links or advertisements on their websites.Conclusion Industry-funded health consumer organisations in Australia have low transparency when reporting industry funding and few have policies governing corporate sponsorship. Relationships between health consumer organisations and the industry require effective actions to minimise the risks of undue influence.What is known about this topic? Pharmaceutical industry funding of health consumer organisations is common in the US and Europe, yet only a minority of such organisations publicly disclose this funding and have policies regulating their relationships with industry.What does this paper add? Industry funded health consumer organisations in Australia have inadequate financial transparency and rarely have policies addressing corporate funding. Organisations that have received more industry funding are more likely to report it publicly.What are the implications for practitioners? Robust policies addressing corporate sponsorship and increased transparency are needed to maintain the independence of health consumer organisations. Governments may also consider regulating non-profit organisations to ensure public reporting of funding sources. PMID- 30021684 TI - Increased allied health services to general and acute medical units decreases length of stay: comparison with a historical cohort. AB - Objective The present study evaluated the effect of an initiative to fund increased allied health (AH) services, enabling increased days and both volume and scope of AH services, for general medical in-patients in the Central Adelaide Local Health Network for a 6-month trial period. Methods A quasi-experimental mixed-methods study was undertaken involving general medical in-patients at two acute tertiary-referral public hospitals with a prospective (December 2015-May 2016) and historical comparison (December 2014-May 2015) cohort. Outcome measures compared between the two cohorts included hospital length of stay (LOS), occupied bed-days, adverse events and AH service data. Results After implementation of increased AH services, there were significant decreases in the median (interquartile range) of both hospital LOS (from 7.2 (7.0-8.0) to 6.5 (6.1-6.7) days; P=0.006) and occupied bed-days (from 5295.0 (5200.0-5622.3) to 4662.5 (4335.8-4744.3) bed-days per month; P=0.004). There was no significant change in weekend discharges or adverse events. AH services increased, with the median number of referrals seen by AH professionals per month, occasions of AH service and AH intervention time per month increasing by 17%, 45% and 43% respectively after implementation, along with a faster response time to referrals. Conclusions Increased levels of AH staffing to general medical in-patients were associated with a significant reduction in hospital LOS and occupied bed-days. What is known about the topic? AH services are an important component in the delivery of safe, effective and efficient health care to hospitalised patients. There is little evidence specifically investigating the effect of increased AH services for general medical patients in an acute hospital setting. What does this paper add? This study provides new evidence demonstrating that increasing AH services to general medical in-patients within two acute tertiary-referral public hospitals decreased hospital LOS and occupied bed-days, without an increase in adverse events. What are the implications for practitioners? A funding initiative to enable increased AH services to general medical in-patients significantly reduced hospital LOS and occupied bed-days. These findings will be of considerable interest to other healthcare centres, particularly those where AH levels are below benchmark figures. PMID- 30021683 TI - Informing best practice for conducting morbidity and mortality reviews: a literature review. AB - Objective Preventable hospital mortality is a critical public health issue, particularly when mortalities are associated with events that are preventable. Mortality and morbidity reviews (MMRs) provide a rigorous, systematic, open, collaborative and transparent review process for clinicians to examine areas of improvement. The aim of the present review was to explore the evidence for best practice when conducting MMRs. Methods Searches of published and grey literature from 2009 to February 2016 were conducted. This period was selected to update a previous review. Inclusion and exclusion criteria was established a priori and based on the Population-Intervention-Comparison-Outcome (PICO) framework. Specific search terms were generated and used to identify relevant articles, with reference lists and citing articles also screened for inclusions. Titles and abstracts were screened and duplicates removed. Study details regarding setting, study design, reported outcomes, tool type, clinicians present and the timing of MMRs were extracted and summarised. Results After screening, 31 documents were included in the present review: 20 peer-reviewed articles and 11 items from the grey literature. Specific outcomes reported included mortality rates, satisfaction, education, cost and quality of care. The most common features of MMRs included timing, leadership, attendees, case presentation format, terms of reference, agenda and governance. Conclusions MMRs decrease gross mortality rates and are effective in identifying and engaging clinicians in system improvements. MMRs should not focus on the actions of individuals, rather on education and/or quality improvement. MMRs should consist of a multidisciplinary team following a structured presentation format with an analysis of error process including actions to be followed-up. Further, it is possible for a single standardised MMR to be implemented hospital wide. What is known about the topic? MMRs are conducted in a variety of clinical settings to educate clinicians and improve patient care. What does this paper add? This review updates a previous review published in 2009 and summarises current evidence around morbidity and mortality reviews. This review also provides a framework for a standardised MMR to be implemented hospital wide. What are the implications for practitioners? This summary of the evidence can be used to guide the development, formation or conduct of MMRs in any healthcare setting. PMID- 30021685 TI - A 'scoping review' of qualitative literature about engagement with HIV care in Indonesia. AB - Background: The Indonesian response to HIV has been informed largely by quantitative evidence. This review examines what is known about the Indonesian HIV care cascade from published qualitative research. Methods: A 'scoping review' method was used to synthesise and interpret the findings of 17 eligible peer reviewed publications. Results: Qualitative findings are reported in relation to two themes. Factors influencing successful engagement include a lack of HIV related knowledge among clients, fear of stigma or lack of privacy/confidentiality at services, limited accessibility and affordability, and poor linkages between services. Factors affecting the broader response include a failure to adapt programs to specific socio-cultural settings, political issues in the distribution of donor funding, distrust and poor communication between service users and providers, the need for cultural privacy in particular community settings, and systemic experiences of gendered stigmatisation. Conclusions: Enhancing understanding of the Indonesian context would benefit from future qualitative research on HIV care in urban settings, describing the experiences of the most at-risk populations, and examining the role of clinics and providers in delivering HIV care in an increasingly decentralised health system. PMID- 30021688 TI - Patient satisfaction of telephone or video interpreter services compared with in person services: a systematic review. AB - Objective This review was conducted to identify and synthesise the evidence around the use of telephone and video interpreter services compared with in person services in healthcare. Methods A systematic search of articles published in the English language was conducted using PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, Database of Abstracts of Reviews of Effects (DARE), Joanna Briggs, Google Scholar and Google. Search terms included 'interpreter', 'patient satisfaction', 'consumer satisfaction' and 'client satisfaction'. Any study that did not compare in-person interpreter services with either telephone or video interpreter services was excluded from analysis. Studies were screened for inclusion or exclusion by two reviewers, using criteria established a priori. Data were extracted via a custom form and synthesised. Results The database search yielded 196 studies, eight of which were included in the present review. The search using an Internet search engine did not identify any relevant studies. Of the studies included, five used telephone and three used video interpreter services. All studies, except one, compared levels of satisfaction regarding in-person interpretation and telephone or video interpretation. One study compared satisfaction of two versions of video interpretation. There is evidence of higher satisfaction with hospital-trained interpreters compared with ad hoc (friend or family) or telephone interpreters. There is no difference in satisfaction between in-person interpreting, telephone interpreting or interpretation provided by the treating bilingual physician. Video interpreting has the same satisfaction as in-person interpreting, regardless of whether the patient and the physician are in the same room. Higher levels of satisfaction were reported for trained telephone interpreters than for in-person interpreters or an external telephone interpreter service. Conclusions Current evidence does not suggest there is one particular mode of interpreting that is superior to all others. This review is limited in its translational capacity given that most studies were from the US and in a Spanish-speaking cohort. What is known about the topic? Access to interpreters has been shown to positively affect patients who are not proficient in speaking the local language of the health service. What does this paper add? This paper adds to the literature by providing a comprehensive summary of patient satisfaction when engaging several different types of language interpreting services used in healthcare. What are the implications for practitioners? This review provides clear information for health services on the use of language interpreter services and patient satisfaction. The current body of evidence does not indicate a superior interpreting method when patient satisfaction is concerned. PMID- 30021689 TI - Corrigendum to: Supporting return to work through appropriate certification: a systematic approach for Australian primary care. AB - Primary care practitioners play a critical role in supporting return to work (RTW) and minimising the detrimental physical and psychosocial sequelae of unnecessary and prolonged work absence in injured and ill workers. Accurate and consistent certification of capacity is an essential component of this role that has been scrutinised recently given the identified variation in certification practices between and within professions. This Perspective outlines the importance of correct certification of capacity for injured workers and provides a RTW flowchart to support systematised and appropriate certification. The flowchart is aimed at primary care practitioners (e.g. general practitioners or physiotherapists). The flowchart was developed at the Transport Accident Commission and WorkSafe Victoria as a guide for Australian primary care practitioners when certifying capacity. A more systematised approach to certification coupled with professional education and support may reduce variations and inaccuracies in certification, improve RTW rates and reduce the increasing burden of disease related to workplace injuries. PMID- 30021691 TI - Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets. AB - OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.?. PMID- 30021690 TI - Dose-ranging study of an orlistat tablet formulation. AB - OBJECTIVE: Examine inhibition of dietary fat absorption with orlistat tablets (24, 36, 48, 72, and 144 mg) vs. 60-mg orlistat capsule. MATERIALS AND METHODS: 83 overweight/obese subjects randomized to 1 of 6 open-label treatments. Pre- vs. post-treatment fecal fat analysis was conducted. RESULTS: Mean percent fecal fat (60-mg capsule, 16.8%; 48-mg tablet, 16.5%) was similar (ratio of geometric mean and 90% CI: 60-mg capsule/48-mg tablet, 1.05 (0.79, 1.39)). Fecal fat excretion was ~2.5 times greater with 144-mg vs. 24-mg tablets. No new safety concerns emerged. CONCLUSION: Dietary fat excretion increases with increasing orlistat tablet dose.?. PMID- 30021692 TI - Comparison of four eGFR equations in assessing complications associated with chronic loss of kidney function: A cross-sectional study in a Chinese population?. AB - There are various equations for estimating glomerular filtration rate (eGFR), mainly including abbreviated Modification of Diet in Renal Disease Study Equations (aMDRD), c-aMDRD for the Chinese population, Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI 2009) and Creatinine-Cystatin C equation (CKD-EPI 2012). Currently, it is unclear which eGFR equation more realistically predicts and reflects the development of complications closely associated with chronic loss of kidney function. Our study selected a total of 1,012 nondialysis patients at stages 2 through 4 chronic kidney disease (CKD) to assess these complications using eGFR calculated by these four equations. Receiver operating characteristic (ROC) analysis was used to analyze various metabolic complications and compare the areas under the curve. The results showed that the most widely applied equation, eGFRcreat-cys, had equal or better sensitivity and specificity in assessing four complications (anemia, hyperphosphatemia, hyperparathyroidism, and metabolic acidosis) as compared to the other three equations. The eGFRcreat-cys thresholds for detecting complications with 90% sensitivity were 47.4, 37.5, 25.7, and 37.8 mL/min/1.73m2 for anemia, hyperphosphatemia, hyperparathyroidism, and acidosis, respectively. The results of net reclassification improvement (NRI) and integrated discrimination improvement (IDI) showed that the eGFRcreat-cys equation was better or not worse than the other three equations for screening the four complications. In summary, timing the onset of CKD-associated complications is an important step for delaying their progression. Our study showed that the CKD-EPI 2012 had an optimal correlation with complications associated with loss of kidney function. We suggest that CKD-EPI 2012 should be used for early detection of CKD associated complications to minimize the missed diagnosis rate in the Chinese population. PMID- 30021694 TI - Idiopathic immune complex-mediated tubulointerstitial nephritis with hypocomplementemia and neutrophil-rich interstitial infiltrates?. AB - A 69-year-old man presented with acute kidney injury, hypocomplementemia, antinuclear antibody, and anti-dsDNA antibody. He had no signs of systemic lupus erythematosus or Sjogren syndrome. He had not begun taking any new drugs in the preceding 6 months. Kidney biopsy revealed 13 glomeruli, 3 with global sclerosis. The remaining glomeruli showed slight mesangial proliferation. The interstitial inflammation was extensive, comprising mainly mature lymphocytes and plasma cells, neutrophils, and a few eosinophils. Remarkable granular and diffuse deposition of IgG and C1q was observed along the tubular basement membranes. Electron microscopy showed electron-dense deposits in the tubular basement membrane. Immunohistochemistry showed only 1 - 4 IgG4-positive plasma cells per high-power field and an IgG4/CD138 ratio of ~ 10%. He was treated with oral prednisolone 35 mg/day, and his kidney function gradually improved. This is a unique case that is not consistent with any known disease entities with immune complex-mediated tubulointerstitial nephritis.?. PMID- 30021693 TI - Clostridium difficile infection in patients with chronic kidney disease in Mexico?. AB - BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of healthcare-associated diarrhea worldwide. Patients with chronic kidney disease (CKD) are especially vulnerable, as they are exposed to CDI risk factors including frequent antibiotics. MATERIALS AND METHODS: In order to identify the risk factors for CDI in CKD patients, a 33-month long case-control study was carried out at a tertiary-care hospital in Mexico. CDI was confirmed at the genetic level, and univariate and multivariate analyses were performed to identify the association between risk factors, biomarkers, and outcome options (survival, relapse, death). RESULTS: Among the 1,198 patients with healthcare associated diarrhea, 354 (29.5%) were CDI cases. 105 (29.6%) CDI cases and 192 (22.7%) controls had CKD. 84 (80%) CKD+CDI cases had a favorable outcome, 10 (9.5%) relapsed, and the 3-month mortality rate included 11 (10.4%) patients. Compared with controls, CDI cases had more previous hospitalizations (63.8 vs. 46.9%, p = 0.005), abdominal distension (46.7 vs. 36.5%, p = 0.056), abdominal pain (60.0 vs. 41.1%, p = 0.002), and polymorphonuclear leukocyte in stools (71.4 vs. 40.5%, p = 0.001) as well as poorer outcomes at 3 months. The patients in the 027-strain group were older, and most of the patients had CKD stage 5 (88.5% vs. 71.1%, p = 0.007), while CKD stage-4 patients were more frequently infected with non-027 strains. In the multivariate analysis of risk factors for CDI, only previous antibiotic exposure (odds ratio = 2.01, 95% confidence interval: 1.05 - 3.84; p = 0.034) was independently associated with CDI in patients with CKD stage 5. CONCLUSION: Mexican patients with CKD are at risk for CDI. This susceptible group should be protected by promoting appropriate guidelines.?. PMID- 30021695 TI - Potential of serum microRNAs as biomarkers of radiation injury and tools for individualization of radiotherapy. AB - Due to tremendous technological advances, radiation oncologists are now capable of personalized treatment plans and deliver the dose in a highly precise manner. However, a crucial challenge is how to escalate radiation doses to cancer cells while reducing damage to surrounding healthy tissues. This determines the probability of achieving therapeutic success whilst safeguarding patients from complications. The current dose constraints rely on observational data. Therefore, incidental toxicity observed in a minority of patients limits the admissible dose thresholds for the whole population, theoretically narrowing down the curative potential of radiotherapy. Future tools for measurements of individual's radiosensitivity before and during treatment would allow proper treatment personalization. Variation in tissue tolerance is at least partially genetically-determined and recent progress in the field of molecular biology raises the possibility that novel assays will allow to predict the response to ionizing radiation. Recently, microRNAs have garnered interest as stable biomarkers of tumor radiation response and normal-tissue toxicity. Preclinical studies in mice and nonhuman primates have shown that serum circulating microRNAs can be used to accurately distinguish pre- and postirradiation states and predict the biological impact of high-dose irradiation. First reports from human studies are also encouraging, however biology-driven precision radiation oncology, which tailors treatment to individual patient's needs, still remains to be translated into clinical studies. In this review, we summarize current knowledge about the potential of serum microRNAs as biodosimeters and biomarkers for radiation injury to lung and hematopoietic cells. PMID- 30021696 TI - Responding to Veiga et al. 'Long term radiological features of radiation-induced lung damage'. PMID- 30021697 TI - Long term outcome of skull-base chondrosarcoma patients treated with high-dose proton therapy with or without conventional radiation therapy. AB - BACKGROUND AND PURPOSE: Skull-base chondrosarcoma (ChSa) is a rare bone tumor and the outcome of patients with this malignancy has been documented only in a limited number of series with a restricted number of patients. OBJECTIVE: This study was conducted to assess the outcome and prognostic factors of a large cohort of ChSa patients treated with radiotherapy in two proton therapy centers. MATERIALS AND METHODS: From 1996 to 2015, 251 (male, 43.4%) patients (mean age, 42.0 +/- 16.2 years) were treated with protons with (n = 135; 53.8%) or without photons (n = 116; 46.2%). Median delivered dose was 70.2 GyRBE. Failure-free survival (FFS), overall survival (OS) and CTCAE grade >=3 toxicity free survival (TFS) were calculated using the Kaplan-Meier method. RESULTS: After a median follow-up of 88.0 months for surviving patients, local and distant failures were observed in 12 (4.8%) and 4 (1.6%) patients, respectively. Late failures >6 years were observed in 4 (33.3%) patients. The estimated 7-year FFS was 93.1%. Twenty five (10%) patients died. The estimated 7-year OS was 93.6%. Tumor volume (p = 0.006) and optic pathway compression (p = 0.027) were significantly associated with the risk of treatment failure on univariate analysis. Treatment failure was significantly associated with a higher risk of death (hazard ratio = 126). The estimated 7-year TFS was 84.2%. CONCLUSIONS: The outcome of skull-base ChSa patients treated with high-dose protons with or without photons is excellent, particularly for patients with small tumors with no optic pathway compression. Treatment failure was however associated with a significantly increased risk of death. PMID- 30021698 TI - Fully automatic detection of strict left bundle branch block. PMID- 30021699 TI - Biomolecular Consequences of Platelet Pathogen Inactivation Methods. AB - Pathogen inactivation (PI) for platelet concentrates (PC) is a fairly recent development in transfusion medicine that is intended to decrease infectious disease transmission from the donor to the receiving patient. Effective inactivation of viruses, bacteria and eukaryotic parasites adds a layer of safety, protecting the blood supply against customary and emerging pathogens. Three PI methods have been described for platelets. These are based on photochemical damage of nucleic acids which prevents replication of most infectious pathogens and contaminating donor leukocytes. Because platelets do not replicate, the collateral damage to platelet function is considered low to non existing. This is disputable however because photochemistry is not specific for nucleic acids and significantly affects platelet biomolecules as well. The impact of these biomolecular changes on platelet function and hemostasis is not well understood, but is increasingly being studied. The results of these studies can help explain current and future clinical observations with PI platelets, including the impact on transfusion yield and bleeding. This review summarizes the biomolecular effects of PI treatment on platelets. We conclude that despite a comparable principle of photochemical inactivation, all three methods affect platelets in different ways. This knowledge can help blood banks and transfusion specialists to guide their choice when considering the implementation or clinical use of PI treated platelets. PMID- 30021701 TI - Many pathways to ending AIDS by 2030. PMID- 30021700 TI - Community-based HIV prevalence in KwaZulu-Natal, South Africa: results of a cross sectional household survey. AB - BACKGROUND: In high HIV burden settings, maximising the coverage of prevention strategies is crucial to achieving epidemic control. However, little is known about the reach and effect of these strategies in some communities. METHODS: We did a cross-sectional community survey in the adjacent Greater Edendale and Vulindlela areas in the uMgungundlovu district, KwaZulu-Natal, South Africa. Using a multistage cluster sampling method, we randomly selected enumeration areas, households, and individuals. One household member (aged 15-49 years) selected at random was invited for survey participation. After obtaining consent, questionnaires were administered to obtain sociodemographic, psychosocial, and behavioural information, and exposure to HIV prevention and treatment programmes. Clinical samples were collected for laboratory measurements. Statistical analyses were done accounting for multilevel sampling and weighted to represent the population. A multivariable logistic regression model assessed factors associated with HIV infection. FINDINGS: Between June 11, 2014, and June 22, 2015, we enrolled 9812 individuals. The population-weighted HIV prevalence was 36.3% (95% CI 34.8-37.8, 3969 of 9812); 44.1% (42.3-45.9, 2955 of 6265) in women and 28.0% (25.9-30.1, 1014 of 3547) in men (p<0.0001). HIV prevalence in women aged 15-24 years was 22.3% (20.2-24.4, 567 of 2224) compared with 7.6% (6.0-9.3, 124 of 1472; p<0.0001) in men of the same age. Prevalence peaked at 66.4% (61.7-71.2, 517 of 760) in women aged 35-39 years and 59.6% (53.0-66.3, 183 of 320) in men aged 40-44 years. Consistent condom use in the last 12 months was 26.5% (24.1 28.8, 593 of 2356) in men and 22.7% (20.9-24.4, 994 of 4350) in women (p=0.0033); 35.7% (33.4-37.9, 1695 of 5447) of women's male partners and 31.9% (29.5-34.3, 1102 of 3547) of men were medically circumcised (p<0.0001), and 45.6% (42.9-48.2, 1251 of 2955) of women and 36.7% (32.3-41.2, 341 of 1014) of men reported antiretroviral therapy (ART) use (p=0.0003). HIV viral suppression was achieved in 54.8% (52.0-57.5, 1574 of 2955) of women and 41.9% (37.1-46.7, 401 of 1014) of men (p<0.0001), and 87.2% (84.6-89.8, 1086 of 1251) of women and 83.9% (78.5 89.3, 284 of 341; p=0.3670) of men on ART. Age, incomplete secondary schooling, being single, having more than one lifetime sex partner (women), sexually transmitted infections, and not being medically circumcised were associated with HIV-positive status. INTERPRETATION: The HIV burden in specific age groups, the suboptimal differential coverage, and uptake of HIV prevention strategies justifies a location-based approach to surveillance with finer disaggregation by age and sex. Intensified and customised approaches to seek, identify, and link individuals to HIV services are crucial to achieving epidemic control in this community. FUNDING: The President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention. PMID- 30021702 TI - Sodium-glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice. AB - It is unclear whether long-term sodium-glucose cotransporter 2 (SGLT2) inhibition such as that during the treatment of diabetes has deleterious effects on the kidney. Therefore, we first sought to determine whether abnormal glucose metabolism occurs in the kidneys of 22-week-old BTBR ob/ob diabetic mice. Second, the cumulative effect of chronic SGLT2 inhibition by ipragliflozin and 30% calorie restriction, either of which lowered blood glucose to a similar extent, on renal glucose metabolism was evaluated. Mass spectrometry-based metabolomics demonstrated that these diabetic mice exhibited an abnormal elevation in the renal pools of tricarboxylic acid cycle metabolites. This was almost completely nullified by SGLT2 inhibition and calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the tricarboxylic acid cycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as calorie restriction almost completely eliminated citrate accumulation in the cortex. Furthermore, imaging mass spectrometry revealed that the accumulation of oxidized glutathione in the cortex of the kidneys, prominent in the glomeruli, was also canceled by SGLT2 inhibition and calorie restriction. Effects of these beneficial interventions were consistent with improvements in glomerular damage, such as albuminuria, glomerular hyperfiltration, and mesangial expansion. Tubulointerstitial macrophage infiltration and fibrosis were ameliorated only by calorie restriction, which may have been due to autophagy activation, which was observed only with calorie restriction. Thus, chronic SGLT2 inhibition is efficient in normalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stress in the kidneys of diabetic mice. PMID- 30021703 TI - Distinctive profiles of traits predisposing to violence in schizophrenia and in the general population. AB - OBJECTIVE: We delineated important trait predispositions to violence, including psychopathic and impulsive traits and trait aggression, in patients with schizophrenia and in the general population. METHOD: The study included 144 subjects: 40 violent (VS's) and 34 nonviolent (NV's) patients with schizophrenia, 35 healthy controls (HC's) and 35 non-psychotic violent subjects (NPV's). We used the Psychopathy Checklist, Buss-Perry Aggression Questionnaire, and Barratt Impulsiveness Scale (BIS-11). Life History of Aggression, psychiatric symptoms, drug/alcohol abuse and history of conduct problems were also assessed. RESULTS: The two violent groups presented with more severe psychopathy, trait aggressiveness and impulsivity than the non-violent subjects; some of these traits being more pronounced in NPV's than in VS's. We further divided the violent patients (VS's) into 2 subgroups, those with a history of conduct problems (VS-CD) and those without (VS-NCD). When we compared these 2 subgroups to each other and to NPV's, we obtained 3 distinct multivariate profiles of traits, consisting of psychopathic traits, anger, motor impulsiveness, and self control problems. NPV's have the profile with the most severe impairments, followed by VS-CD's and then VS-NCD's. Psychiatric symptoms were more strongly associated with violence in VS-NCD's than in VS-CD's. CONCLUSION: Our study provides new insights on trait predispositions to violence. Trait aggressiveness, psychopathic and impulsive traits form a distinctive profile which underlies a core predisposition to violence across populations, including patients with schizophrenia, but particularly in those with a history of early conduct problems. In those without such problems, the symptoms of the illness play a more important role for the violent behavior. PMID- 30021704 TI - Diazirine-containing tag-free RNA probes for efficient RISC-loading and photoaffinity labeling of microRNA targets. AB - We designed and synthesized a photo-reactive and tag-free RNA probe for the identification of microRNA (miRNA) targets. To synthesize the RNA probe, we designed a novel nucleoside analog 1-O-[3-ethynyl-5-(3-trifluoromethyl-3H diazirine-3-yl)]benzyl-beta-d-ribofuranose containing aryl trifluoromethyl diazirine and ethynyl moieties. The RNA probe containing this analog was observed to form crosslinks with complementary RNA by UV irradiation and was rapidly tagged by Cu-catalyzed azide alkyne cycloaddition (CuAAC). In addition, the tag free and photo-reactive miRNA-145 probe showed comparable gene silencing activity to that of unmodified miRNA-145. Therefore, miRNA probes containing the nucleoside analog are promising candidates for the identification of target mRNAs of miRNAs. PMID- 30021706 TI - Improving Linkage to HIV Care Through Mobile Phone Apps: Randomized Controlled Trial. AB - BACKGROUND: In HIV treatment program, gaps in the "cascade of care" where patients are lost between diagnosis, laboratory evaluation, treatment initiation, and retention in HIV care, is a well-described challenge. Growing access to internet-enabled mobile phones has led to an interest in using the technology to improve patient engagement with health care. OBJECTIVE: The objectives of this trial were: (1) to assess whether a mobile phone-enabled app could provide HIV patients with laboratory test results, (2) to better understand the implementation of such an intervention, and (3) to determine app effectiveness in improving linkage to HIV care after diagnosis. METHODS: We developed and tested an app through a randomized controlled trial carried out in several primary health care facilities in Johannesburg. Newly diagnosed HIV-positive patients were screened, recruited, and randomized into the trial as they were giving a blood sample for initial CD4 staging. Trial eligibility included ownership of a phone compatible with the app and access to the internet. Trial participants were followed for a minimum of eight months to determine linkage to HIV care indicated by an HIV-related laboratory test result. RESULTS: The trial outcome results are being prepared for publication, but here we describe the significant operational and technological lessons provided by the implementation. Android was identified as the most suitable operating system for the app, due to Android functionality and communication characteristics. Android also had the most significant market share of all smartphone operating systems in South Africa. The app was successfully developed with laboratory results sent to personal smartphones. However, given the trial requirements and the app itself, only 10% of screened HIV patients successfully enrolled. We report on issues such as patient eligibility, app testing in a dynamic phone market, software installation and compatibility, safe identification of patients, linkage of laboratory results to patients lacking unique identifiers, and present lessons and potential solutions. CONCLUSIONS: The implementation challenges and lessons of this trial may assist future similar mHealth interventions to avoid some of the pitfalls. Ensuring sufficient expertise and understanding of the programmatic needs by the software developer, as well as in the implementation team, with adequate and rapid piloting within the target groups, could have led to better trial recruitment. However, the majority of screened patients were interested in the study, and the app was installed successfully in patients with suitable smartphones, suggesting that this may be a way to engage patients with their health care data in future. TRIAL REGISTRATION: ClinicalTrials.gov NCT02756949; https://clinicaltrials.gov/ct2/show/NCT02756949 (Archived by WebCite at http://www.webcitation.org/6z1GTJCNW). PMID- 30021705 TI - Digital Food Records in Community-Based Interventions: Mixed-Methods Pilot Study. AB - BACKGROUND: A pressing need exists to understand and optimize the use of dietary assessment tools that can be used in community-based participatory research (CBPR) interventions. A digital food record, which uses a mobile device to capture the dietary intake through text and photography inputs, is a particularly promising mobile assessment method. However, little is understood about the acceptability and feasibility of digital food records in CBPR and how to best tailor dietary assessment tools to the needs of a community. OBJECTIVE: The objective of our study was to evaluate the acceptability and feasibility of digital food records among church-based populations in resource-limited wards of Washington, DC, USA, using a mixed-methods approach. METHODS: This community based pilot study was conducted as part of the Washington, DC Cardiovascular Health and Needs Assessment. Participants (n=17) received a mobile device (iPod Touch) to photodocument their dietary intake for a 3-day digital food record using a mobile app, FitNinja (Vibrent Health). The acceptability of the digital food record was explored through the thematic analysis of verbatim transcripts from a moderated focus group (n=8). In addition, the feasibility was evaluated by the percentage of participants complying with instructions (ie, capturing both before and after meal photos for at least 2 meals/day for 3 days). RESULTS: Qualitative themes identified were related to (1) the feasibility and acceptability of the mobile device and app, including issues in recording the dietary information and difficulty with photodocumentation; (2) suggestions for additional support and training experiences; and (3) comparisons with other mobile apps. Overall, the participants accepted the digital food record by demonstrating satisfaction with the tool and intent to continue the use (eg, participants recorded an average of 5.2, SD 7, consecutive days). Furthermore, of the 17 participants, 15 photodocumented at least 1 meal during the study period and 3 fully complied with the digital food record instructions. CONCLUSIONS: This study demonstrated digital food records as an acceptable tool in CBPR and identified contributors and barriers to the feasibility of digital food records for future research. Engaging community members in the implementation of novel assessment methods allows for the tailoring of technology to the needs of the community and optimizing community-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927783; https://www.clinicaltrials.gov/ct2/show/NCT01927783 (Archived by WebCite at http://www.webcitation.org/70WzaFWb6). PMID- 30021707 TI - Mobile-Based Nutrition Counseling and Unconditional Cash Transfers for Improving Maternal and Child Nutrition in Bangladesh: Pilot Study. AB - BACKGROUND: Inappropriate feeding practices, inadequate nutrition knowledge, and insufficient access to food are major risk factors for maternal and child undernutrition. There is evidence to suggest that the combination of cash transfer and nutrition education improves child growth. However, a cost-effective delivery platform is needed to achieve complete, population-wide coverage of these interventions. OBJECTIVE: This study aimed to assess the feasibility, acceptability, and perceived appropriateness of an intervention package consisting of voice messaging, direct counseling, and unconditional cash transfers all on a mobile platform for changing perceptions on nutrition during pregnancy and the first year of a child's life in a poor rural community in Bangladesh. METHODS: We conducted a mixed-methods pilot study. We recruited 340 pregnant or recently delivered, lactating women from rural Bangladesh. The intervention consisted of an unconditional cash transfer combined with nutrition counseling, both delivered on a mobile platform. The participants received a mobile phone and BDT 787 per month (US $10). We used a voice messaging service to deliver nutrition-related messages. We provided additional nutrition counseling through a nutrition counselor from a call center. We carried out cross-sectional surveys at baseline and at the end of the study, focus group discussions, and in depth interviews with participants and their family members. RESULTS: Approximately 89% (245/275) of participants reported that they were able to operate the mobile phones without much trouble. Charging of the mobile handsets posed some challenges since only approximately 45% (124/275) households in our study had electricity at home. Approximately 26% (72/275) women reported they had charged their mobile phones at their neighbor's house, while 34% (94/275) reported that they charged it at a marketplace. Less than 10% (22/275) of women reported difficulties understanding the voice messages or direct counseling through mobile phones, while only 3% (8/275) of women reported they had some problems withdrawing cash from the mobile bank agent. Approximately 87% (236/275) women reported spending the cash to purchase food for themselves and their children. CONCLUSIONS: The nature of our study precludes any conclusion about the effectiveness of the intervention package. However, the high coverage of our intervention and the positive feedback from the mothers were encouraging and support the feasibility, acceptability, and appropriateness of this program. Further research is needed to determine the efficacy and cost-effectiveness of mobile-based nutrition counseling and unconditional cash transfers in improving maternal and child nutrition in Bangladesh. PMID- 30021708 TI - Evaluating Doctor Performance: Ordinal Regression-Based Approach. AB - BACKGROUND: Doctor's performance evaluation is an important task in mobile health (mHealth), which aims to evaluate the overall quality of online diagnosis and patient outcomes so that customer satisfaction and loyalty can be attained. However, most patients tend not to rate doctors' performance, therefore, it is imperative to develop a model to make doctor's performance evaluation automatic. When evaluating doctors' performance, we rate it into a score label that is as close as possible to the true one. OBJECTIVE: This study aims to perform automatic doctor's performance evaluation from online textual consultations between doctors and patients by way of a novel machine learning method. METHODS: We propose a solution that models doctor's performance evaluation as an ordinal regression problem. In doing so, a support vector machine combined with an ordinal partitioning model (SVMOP), along with an innovative predictive function will be developed to capture the hidden preferences of the ordering labels over doctor's performance evaluation. When engineering the basic text features, eight customized features (extracted from over 70,000 medical entries) were added and further boosted by the Gradient Boosting Decision Tree algorithm. RESULTS: Real data sets from one of the largest mobile doctor/patient communication platforms in China are used in our study. Statistically, 64% of data on mHealth platforms lack the evaluation labels from patients. Experimental results reveal that our approach can support an automatic doctor performance evaluation. Compared with other auto-evaluation models, SVMOP improves mean absolute error (MAE) by 0.1, mean square error (MSE) by 0.5, pairwise accuracy (PAcc) by 5%; the suggested customized features improve MAE by 0.1, MSE by 0.2, PAcc by 3%. After boosting, performance is further improved. Based on SVMOP, predictive features like politeness and sentiment words can be mined, which can be further applied to guide the development of mHealth platforms. CONCLUSIONS: The initial modelling of doctor performance evaluation is an ordinal regression problem. Experiments show that the performance of our proposed model with revised prediction function is better than many other machine learning methods on MAE, MSE, as well as PAcc. With this model, the mHealth platform could not only make an online auto evaluation of physician performance, but also obtain the most effective features, thereby guiding physician performance and the development of mHealth platforms. PMID- 30021709 TI - Implementing a National Electronic Referral Program: Qualitative Study. AB - BACKGROUND: Electronic referrals or e-referrals can be defined as the electronic transmission of patient data and clinical requests between health service providers. National electronic referral systems have proved challenging to implement due to problems of fit between the technical systems proposed and the existing sociotechnical systems. In seeming contradiction to a sociotechnical approach, the Irish Health Service Executive initiated an incremental implementation of a National Electronic Referral Programme (NERP), with step 1 including only the technical capability for general practitioners to submit electronic referral requests to hospital outpatient departments. The technology component of the program was specified, but any changes required to embed that technology in the existing sociotechnical system were not specified. OBJECTIVE: This study aimed to theoretically frame the lessons learned from the NERP step 1 on the design and implementation of a national health information technology program. METHODS: A case study design was employed, using qualitative interviews with key stakeholders of the NERP step 1 (N=41). A theory-driven thematic analysis of the interview data was conducted, using Barker et al's Framework for Going to Full Scale. RESULTS: The NERP step 1 was broadly welcomed by key stakeholders as the first step in the implementation of electronic referrals delivering improvements in the speed, completeness of demographic information, and legibility and traceability of referral requests. National leadership and digitalized health records in general practice were critical enabling factors. Inhibiting factors included policy uncertainty about the future organizational structures within which electronic referrals would be implemented; the need to establish a central referral office consistent with these organizational structures; outstanding interoperability issues between the electronic referral solution and hospital patient administration systems; and an anticipated need to develop specialist referral templates for some specialties. A lack of specification of the sociotechnical elements of the NERP step 1 inhibited the necessary testing and refinement of the change package used to implement the program. CONCLUSIONS: The key strengths of the NERP step 1 are patient safety benefits. The NERP was progressed beyond the pilot stage despite limited resources and outstanding interoperability issues. In addition, a new electronic health unit in Ireland (eHealth Ireland) gained credibility in delivering national health information technology programs. Limitations of the program are its poor integration in the wider policy and quality improvement agenda of the Health Service Executive. The lack of specification of the sociotechnical elements of the program created challenges in communicating the program scope to key stakeholders and restricted the ability of program managers and implementers to test and refine the change package. This study concludes that while the sociotechnical elements of a national health information technology program do not need to be specified in tandem with technical elements, they do need to be specified early in the implementation process so that the change package used to implement the program can be tested and refined. PMID- 30021710 TI - Exploring User Needs for a Mobile Behavioral-Sensing Technology for Depression Management: Qualitative Study. AB - BACKGROUND: Today, college students are dealing with depression at some of the highest rates in decades. As the primary mental health service provider, university counseling centers are limited in their capacity and efficiency to provide mental health care due to time constraints and reliance on students' self reports. A mobile behavioral-sensing platform may serve as a solution to enhance the efficiency and accessibility of university counseling services. OBJECTIVE: The main objectives of this study are to (1) understand the usefulness of a mobile sensing platform (ie, iSee) in improving counseling services and assisting students' self-management of their depression conditions, and (2) explore what types of behavioral targets (ie, meaningful information extracted from raw sensor data) and feedback to deliver from both clinician and students' perspectives. METHODS: We conducted semistructured interviews with 9 clinicians and 12 students with depression recruited from a counseling center at a large Midwestern university. The interviews were 40-50 minutes long and were audio recorded and transcribed. The interview data were analyzed using thematic analysis with an inductive approach. Clinician and student interviews were analyzed separately for comparison. The process of extracting themes involved iterative coding, memo writing, theme revisits, and refinement. RESULTS: From the clinician perspective, the mobile sensing platform helps to improve counseling service by providing objective evidence for clinicians and filling gaps in clinician-patient communication. Clinicians suggested providing students with their sensed behavioral targets organized around personalized goals. Clinicians also recommended delivering therapeutic feedback to students based on their sensed behavioral targets, including positive reinforcement, reflection reminders, and challenging negative thoughts. From the student perspective, the mobile sensing platform helps to ease continued self-tracking practices. Students expressed their need for integrated behavioral targets to understand correlations between behaviors and depression. They also pointed out that they would prefer to avoid seeing negative feedback. CONCLUSIONS: Although clinician and student participants shared views on the advantages of iSee in supporting university counseling, they had divergent opinions on the types of behavioral targets and feedback to be provided via iSee. This exploratory work gained initial insights into the design of a mobile sensing platform for depression management and informed a more conclusive research project for the future. PMID- 30021711 TI - The Association Between Increased Levels of Patient Engagement With an Internet Support Group and Improved Mental Health Outcomes at 6-Month Follow-Up: Post-Hoc Analyses From a Randomized Controlled Trial. AB - BACKGROUND: We recently reported that depressed and anxious primary care patients randomized to a moderated internet support group (ISG) plus computerized cognitive behavioral therapy (cCBT) did not experience improvements in depression and anxiety over cCBT alone at 6-month follow-up. OBJECTIVE: The 1% rule posits that 1% of participants in online communities generate approximately 90% of new user-created content. The aims of this study were to apply the 1% rule to categorize patient engagement with the ISG and identify whether any patient subgroups benefitted from ISG use. METHODS: We categorized the 302 patients randomized to the ISG as: superusers (3/302, 1.0%), top contributors (30/302, 9.9%), contributors (108/302, 35.8%), observers (87/302, 28.8%) and those who never logged in (74/302, 24.5%). We then applied linear mixed models to examine associations between engagement and 6-month changes in health-related quality of life (HRQoL; Short Form Health Survey Mental Health Component, SF-12 MCS) and depression and anxiety symptoms (Patient-Reported Outcomes Measurement Information System, PROMIS). RESULTS: At baseline, participant mean age was 42.6 years, 81.1% (245/302) were female, and mean Patient Health Questionnaire (PHQ 9), Generalized Anxiety Disorder scale (GAD-7), and SF-12 MCS scores were 13.4, 12.6, and 31.7, respectively. Of the 75.5% (228/302) who logged in, 61.8 % (141/228) created >=1 post (median 1, interquartile range, IQR 0-5); superusers created 42.3 % (630/1488) of posts (median 246, IQR 78-306), top contributors created 34.6% (515/1488; median 11, IQR 10-18), and contributors created 23.1 % (343/1488; median 3, IQR 1-5). Compared to participants who never logged in, the combined superuser + top contributor subgroup (n=33) reported 6-month improvements in anxiety (PROMIS: -11.6 vs -7.8; P=.04) and HRQoL (SF-12 MCS: 16.1 vs 10.1; P=.01) but not in depression. No other subgroup reported significant symptom improvements. CONCLUSIONS: Patient engagement with the ISG was more broadly distributed than predicted by the 1% rule. The 11% of participants with the highest engagement levels reported significant improvements in anxiety and HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01482806; https://clinicaltrials.gov/ct2/show/NCT01482806 (Archived by WebCite at http://www.webcitation.org/708Bjlge9). PMID- 30021712 TI - The Family Check-Up Online Program for Parents of Middle School Students: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Research has established that skillful family management during adolescence protects youth from a variety of mental health and behavioral problems. Interventions associated with this research have focused on parenting skills as the mediator that links early risk factors with a profile of later behavioral risk, including problem behavior, substance use, and school failure. Fortunately, positive changes in family management skills have been linked to meaningful improvements in adolescent behavior, and these improvements have been significant across a variety of cultural groups. OBJECTIVE: We describe the background, research design, and intervention components of an electronic health version of the Family Check-Up program that is targeting middle school children and is being evaluated in a randomized controlled trial for its usability, feasibility, and efficacy. METHODS: We used an iterative formative research process to develop an electronic health version of the Family Check-Up program. In our ongoing randomized controlled trial, eligible families are randomly assigned to 1 of 3 conditions: Family Check-Up Online-only (n~100), Family Check Up Online + Coach (n~100), and a waitlist control condition (middle school as usual; n~100). We are conducting assessments at baseline, 3 months following randomization (posttest), and at follow-ups scheduled for 6 months and 12 months. RESULTS: This randomized controlled trial project was funded in 2015. Participant recruitment was completed in spring 2018 and enrollment is ongoing. Follow-up assessments will be completed in 2019. CONCLUSIONS: The innovative Family Check Up Online program has the potential to help address many of the barriers that more traditional school-based behavioral mental health implementation strategies have yet to solve, including staffing and resources to implement family-centered support within schools. TRIAL REGISTRATION: ClinicalTrials.gov NCT03060291; https://clinicaltrials.gov/ct2/show/NCT03060291 (Archived by WebCite at http://www.webcitation.org/70f8keeN4). TRIAL REGISTRATION: RR1-10.2196/11106. PMID- 30021715 TI - [Roles of the FGF signaling pathway in regulating inner ear development and hair cell regeneration]. AB - The inner ear is a complex sensory organ that detects sound and mediates balance. During inner ear development, fibroblast growth factor (FGF) signaling pathway is involved in the induction of otic placode, cell fate determination of statoacoustic ganglion (SAG) neurons, and epithelial differentiation of the Corti organ. FGF signaling initiates the regulatory network of otic genes in the early development of inner ear, and induces the formation of pre-placodal region and the otic placode. The specification of the neuroblast ventral to the otic vesicle could be promoted by the normally-expressed FGF, and inhibited by excessive FGF5 secreted by mature SAG neurons, which could form a negative feedback loop and stabilize the SAG cell identity. The expression of FGF20 is regulated by the Notch signaling pathway and implicated in the differentiation of hair cells and supporting cells in the prosensory epithelium. FGF8 secreted by hair cells could regulate the differentiation of partial supporting cells into pillar cells. Abnormal FGF signaling in humans could lead to different kinds of deafness related genetic diseases. In addition, it is noteworthy that FGF signaling pathway plays an important role in hair cell regeneration and induction from stem cells in lower vertebrates. In this review, we summarize recent advancements on roles of the FGF signaling pathway in inner ear development and hair cell regeneration, and lay a theoretical foundation for elucidating the regulatory mechanisms of FGF signal pathway in hair cell regeneration. PMID- 30021713 TI - Facial-Aging Mobile Apps for Smoking Prevention in Secondary Schools in Brazil: Appearance-Focused Interventional Study. AB - BACKGROUND: Most smokers start smoking during their early adolescence, often with the idea that smoking is glamorous. Interventions that harness the broad availability of mobile phones as well as adolescents' interest in their appearance may be a novel way to improve school-based prevention. A recent study conducted in Germany showed promising results. However, the transfer to other cultural contexts, effects on different genders, and implementability remains unknown. OBJECTIVE: In this observational study, we aimed to test the perception and implementability of facial-aging apps to prevent smoking in secondary schools in Brazil in accordance with the theory of planned behavior and with respect to different genders. METHODS: We used a free facial-aging mobile phone app ("Smokerface") in three Brazilian secondary schools via a novel method called mirroring. The students' altered three-dimensional selfies on mobile phones or tablets and images were "mirrored" via a projector in front of their whole grade. Using an anonymous questionnaire, we then measured on a 5-point Likert scale the perceptions of the intervention among 306 Brazilian secondary school students of both genders in the seventh grade (average age 12.97 years). A second questionnaire captured perceptions of medical students who conducted the intervention and its conduction per protocol. RESULTS: The majority of students perceived the intervention as fun (304/306, 99.3%), claimed the intervention motivated them not to smoke (289/306, 94.4%), and stated that they learned new benefits of not smoking (300/306, 98.0%). Only a minority of students disagreed or fully disagreed that they learned new benefits of nonsmoking (4/306, 1.3%) or that they themselves were motivated not to smoke (5/306, 1.6%). All of the protocol was delivered by volunteer medical students. CONCLUSIONS: Our data indicate the potential for facial-aging interventions to reduce smoking prevalence in Brazilian secondary schools in accordance with the theory of planned behavior. Volunteer medical students enjoyed the intervention and are capable of complete implementation per protocol. PMID- 30021716 TI - [Long non-coding RNAs: Emerging regulators of antiviral innate immune responses]. AB - Long non-coding RNAs (lncRNAs) are designated as the transcripts longer than 200 nucleotides without protein-coding capacity. As a category of important gene regulatory factors, lncRNAs regulate the expression of target genes at epigenetic, transcription and post-transcriptional levels by various mechanisms, such as chromatin remodeling, DNA modification, transcription inhibition and RNA RNA interactions, etc. In recent years, studies have shown that many lncRNAs can be induced by viruses or interferon (IFN) and to regulate the expression of related antiviral genes in IFN-mediated antiviral innate immune responses. In this review, we focus on the regulation of lncRNAs in IFN-mediated antiviral innate immune responses, especially in the transcription of IFN-stimulated genes (ISGs). In addition, we summarize the regulatory network of lncRNAs, IFN and ISGs. This review will provide a valuable reference for the researchers working in this field. PMID- 30021717 TI - [Comparation and utilization of crop-omics databases]. AB - Omics plays an important role in life sciences, which studies all the components and their interrelations as a whole. The omics databases collected and sorted out the relevant information to support omics research. The crop-omics database, based on the major food crop information, especially on the sequencing information and data mining, is set up to improve the basic research level of crop sciences and production, which potentially benefit our grain stock. Here, we summarize crop genomics, transcriptomics, proteomics, metabolomics and phenomics, explore the development and utilization status of crop-omics, and reveal that the comprehensive utilization of multiple omics databases has become an important research method for crop sciences in the era of high throughput information. PMID- 30021714 TI - Toward Increasing Engagement in Substance Use Data Collection: Development of the Substance Abuse Research Assistant App and Protocol for a Microrandomized Trial Using Adolescents and Emerging Adults. AB - BACKGROUND: Substance use is an alarming public health issue associated with significant morbidity and mortality. Adolescents and emerging adults are at particularly high risk because substance use typically initiates and peaks during this developmental period. Mobile health apps are a promising data collection and intervention delivery tool for substance-using youth as most teens and young adults own a mobile phone. However, engagement with data collection for most mobile health applications is low, and often, large fractions of users stop providing data after a week of use. OBJECTIVE: Substance Abuse Research Assistant (SARA) is a mobile application to increase or sustain engagement of substance data collection overtime. SARA provides a variety of engagement strategies to incentivize data collection: a virtual aquarium in the app grows with fish and aquatic resources; occasionally, funny or inspirational contents (eg, memes or text messages) are provided to generate positive emotions. We plan to assess the efficacy of SARA's engagement strategies over time by conducting a micro randomized trial, where the engagement strategies will be sequentially manipulated. METHODS: We aim to recruit participants (aged 14-24 years), who report any binge drinking or marijuana use in the past month. Participants are instructed to use SARA for 1 month. During this period, participants are asked to complete one survey and two active tasks every day between 6 pm and midnight. Through the survey, we assess participants' daily mood, stress levels, loneliness, and hopefulness, while through the active tasks, we measure reaction time and spatial memory. To incentivize and support the data collection, a variety of engagement strategies are used. First, predata collection strategies include the following: (1) at 4 pm, a push notification may be issued with an inspirational message from a contemporary celebrity; or (2) at 6 pm, a push notification may be issued reminding about data collection and incentives. Second, postdata collection strategies include various rewards such as points which can be used to grow a virtual aquarium with fishes and other treasures and modest monetary rewards (up to US $12; US $1 for each 3-day streak); also, participants may receive funny or inspirational content as memes or gifs or visualizations of prior data. During the study, the participants will be randomized every day to receive different engagement strategies. In the primary analysis, we will assess whether issuing 4 pm push-notifications or memes or gifs, respectively, increases self-reporting on the current or the following day. RESULTS: The microrandomized trial started on August 21, 2017 and the trial ended on February 28, 2018. Seventy-three participants were recruited. Data analysis is currently underway. CONCLUSIONS: To the best of our knowledge, SARA is the first mobile phone app that systematically manipulates engagement strategies in order to identify the best sequence of strategies that keep participants engaged in data collection. Once the optimal strategies to collect data are identified, future versions of SARA will use this data to provide just-in-time adaptive interventions to reduce substance use among youth. TRIAL REGISTRATION: ClinicalTrials.gov NCT03255317; https://clinicaltrials.gov/show/NCT03255317 (Archived by WebCite at http://www.webcitation.org/70raGWV0e). REGISTERED REPORT IDENTIFIER: RR1-10.2196/9850. PMID- 30021719 TI - [Assessing abundance and specificity of different types of sgRNA targeting miRNA precursors]. AB - CRISPR/Cas technology enables efficient and specific editing the genome. Since different bacterial sources or artificially modified Cas9, as well as Cpf1 and other nucleases, recognize different PAMs (protospacer adjacent motifs), different gene editing nucleases may use different types of sgRNAs (small guide RNA). MicroRNAs (miRNAs) are a class of regulatory small non-coding RNAs. To determine whether specific targets for sgRNAs in miRNA precursor exit, the abundance and specificity of 11 different types of sgRNA targeting 28 645 miRNA precursors were analyzed in the present study using the CRISPR-offinder, a bioinformatics software developed in our own laboratory. The CRISPR/Cas9 lentivirus technology was used to target the miR-302/367 cluster in a porcine cell line, and its knockout efficiency for the miRNA target was evaluated. The results show that there are about 8 different types of sgRNAs that can target individual miRNA precursors. By assessing the off-target effect, only 18.2% of the sgRNAs showed high specificity for targeting the porcine miRNA precursors. Lastly, using the miR-302/367 cluster target as an example, we showed that the CRISPR/Cas9 lentivirus technology was 40% efficient in successfully establishing correct knockout of the target miRNA in the porcine cell line. This present study provides an important resource for the use of CRISPR/Cas technology to target miRNAs for knockout studies. PMID- 30021718 TI - [Acid-resistant genes in Mycobacterium tuberculosis and the underlying regulatory network]. AB - The molecular mechanisms of pathogen persistence within host cells are emerging hotspots, and one of the causes of its persistence is the acid resistance of bacteria. Currently, tuberculosis remains a serious threat to global public health and it is caused by Mycobacterium tuberculosis. In particular, acid resistance of M. tuberculosis and its persistence within macrophages contribute significantly to tuberculosis. Investigations have uncovered three major mechanisms underlying its acid resistance: the control of proton entry, metabolic regulation of intracellular acid-base balance and regulation of the two-component signaling system. In this review, we summarize the overall regulation network of M. tuberculosis in the acidic environment, aiming at providing a new overall idea for treating M. tuberculosis persistence and exploring new targets for tuberculosis control. PMID- 30021720 TI - [miR-362 regulates the proliferation and apoptosis of porcine immature Sertoli cells through targeting the ZNF644 gene]. AB - In testicular tissue, immature Sertoli cell proliferation ability determines the size of mature Sertoli cell populations, which further regulates the spermatogenesis in the adult male animals. Studies have demonstrated that microRNAs (miRNAs) participate in the regulation of the immature Sertoli cell proliferation and apoptosis, but the functions of most identified miRNAs remain unclear. In this study, based on previous RNA-seq results, we analyzed the regulatory role (s) of miR-362 in proliferation and apoptosis of porcine immature Sertoli cells. The ZFN644 gene was predicted to be a target gene of miR-362 using bioinformatics methods. The expression levels of miR-362 and ZNF644 gene were measured using qRT-PCR assay in developing porcine testicular tissues and in immature Sertoli cells transfected with either miR-362 mimic or miR-362 inhibitor. The dual luciferase reporter assay was used to determine the regulatory relationship between miR-362 and ZNF644. The results showed that a putative target site of miR-362 was located in the 3'UTR of ZNF644. The expression of miR-362 was significantly and negatively correlated with ZNF644 expression in the developing porcine testicular tissues. Co-transfection of miR 362 and psiCHECK2-ZNF644-WT 3'UTR luciferase vector significantly suppressed luciferase activity. The ZNF644 gene expression level was significantly regulated by miR-362, demonstrating that miR-362 targets ZNF644 gene and inhibits its expression in porcine immature Sertoli cells. Flow cytometry, CCK8, and EdU assays were used to measure the effects of over-expression of miR-362 or knockdown of ZNF644 on porcine immature Sertoli cell proliferation; Annexin V FITC/PI staining assays and qRT-PCR technology were used to test the apoptosis and the expression levels of cell survival-related genes, respectively. Over expression of miR-362 and knockdown of ZNF644 arrested the porcine immature Sertoli cells in G1 and G2 phases of the cell cycle, respectively, and inhibited proliferation, enhanced apoptosis in the porcine immature Sertoli cells, and significantly regulated the expression levels of cell survival-related genes. Taken together, these data indicate that miR-362 inhibits proliferation and promotes apoptosis in porcine immature Sertoli cells by targeting the ZNF644 gene, thereby providing the scientific basis for further study on the function(s) of miR-362 in the porcine spermatogenesis. PMID- 30021721 TI - [Evolution and the flanking sequences of Beta-lactamase resistance gene blaOKP]. AB - blaOKP genes are chromosomally encoded beta-lactamases that mediate several classes of antibiotics resistance. To investigate the evolution and flanking sequences of OKP beta-lactamase gene, the gene blaOKP and its flanking sequences from a newly isolated Klebsiella pneumoniae were studied using whole genome sequencing. The flanking sequences of different variant blaOKP genes and blaSHV, another plasmid-encoded beta-lactamase gene, were then compared. These studies show that the blaOKP and blaSHV genes evolve differently and belong to two different evolution branches. The blaOKP gene variants can be divided into subgroups: blaOKP-A and blaOKP-B. Although both blaOKP and blaSHV genes have no mobile genetic elements in their flanking sequences, their genetic environments are quite different. The blaOKP gene is adjacent to KdpC while blaSHV gene is flanked by RecF and ygbN-ygbM-ygbK. Furthermore, there are a variety of mobile genetic elements in the neighboring sequence plasmid-encoded blaSHV genes that are absent in blaOKP genes. These structural differences may slow the evolution of blaOKP gene. Collectively, we demonstrate that the evolution and flanking sequence of blaOKP gene are different from those of the blaSHV gene, which could be an important reason for its relatively slow evolution. PMID- 30021722 TI - [Analyses on distribution and structure of blaCARB-2 in Klebsiella pneumoniae]. AB - In order to characterize the structure of the beta-lactamase gene and its corresponding mobile genetic elements in Klebsiella pneumoniae, the beta lactamase genes from 240 clinical Klebsiella pneumoniae isolates were studied. blaCARB-2, a newly characterized gene, was extensively investigated utilizing next-generation sequencing, PCR, molecular cloning, conjugation, and comparative genomics analysis. We identified 11 beta-lactamase genes among the 240 clinical Klebsiella pneumoniae isolates; the blaCARB-2 gene exists only in one specific isolate (Klebsiella pneumoniae KP1276) (1/240, 0.42%). The blaCARB-2 gene lies on a conjugative plasmid pKP1276-82, a 182,450-bp plasmid, which encodes 222 open reading frames. The plasmid has seven resistance genes, termed blaCARB-2, blaKLUC, aadA1, aadA2, cmlA1, dfrA1, and sul2. Among these genes, blaCARB-2 was identified for the first time in Klebsiella pneumoniae. Four of these resistance genes and an int gene form a class 1 integron (int-blaCARB-2-aadA2-cmlA1-aadA1). Further studies show that the blaCARB-2, aadA2, and cmlA1 genes are resistant to their corresponding antibiotics and the blaCARB-2 exhibits higher resistance activities to penicillin beta-lactams. These results reveal the possibility of horizontal transfer of the resistance genes and dissemination of resistance among bacteria of different genera or species of Enterobacteriaceae. PMID- 30021723 TI - [Research on the blended learning mode of "Microbial Breeding Experiments" based on WeChat]. AB - With the rapid development of the internet technology, the blended learning mode plays a more and more important role in education reforms by integrating traditional classroom teaching and online learning. WeChat is the most popular Chinese social software, and its public platform is also suitable for mobile learning. Here, we report an application of the blended learning method based on WeChat public platforms in microbiology breeding experiment courses, using the site-directed mutagenesis of the green fluorescent protein (GFP) as an example. The learning process was divided into five modules: teaching design, learning resource preparation, pre-class learning, classroom learning, post-class review and evaluation. By introducing one mutation (Y66H) in mutagenic primers, the mutated GFP gene was amplified by PCR using pGFPuv as templates, followed by removal of the original plasmid template by Dpn1 digestion. Students can monitor the color changes from green to blue in the fluorescence emission of the mutated proteins. As a useful addition to classroom teaching, WeChat is suitable for students to use fragmented time to learn and improve teaching interaction. Learning assessment results revealed the blended learning environment improves students' study interests and self-learning abilities, thus achieving a fruitful teaching result. PMID- 30021724 TI - CRISPR-Cas13 Precision Transcriptome Engineering in Cancer. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated genes (Cas) system has been rapidly harnessed to perform various genomic engineering tasks. Recently, it has been demonstrated that a novel RNA targeting CRISPR effector protein, called Cas13, binds and cleaves RNA rather than DNA substrates analogously to the eukaryotic RNA interference system. The known Cas13a-Cas13d effectors are able to efficiently cleave complementary target single-stranded RNAs, which represent a potentially safer alternative to deoxyribonuclease Cas9, because it induces loss-of-function phenotypes without genomic loss of the targeted gene. Furthermore, through the improvement in Cas13 effector functionalities, a system called REPAIR has been developed to edit full length transcripts containing pathogenic mutations, thus providing a promising opportunity for precise base editing. Moreover, advanced engineering of this CRISPR effector also permits nucleic acid detection, allowing the identification of mutations in cell-free tumor DNA through a platform termed Specific High Sensitivity Enzymatic Reporter Unlocking. All of these properties give us a glimpse about the potential of the CRISPR toolkit for precise transcriptome engineering, possibly leading to an expansion of CRISPR technologies for cancer therapeutics and diagnostics. Here, we examine previously unaddressed aspects of the CRISPR-based RNA-targeting approach as a feasible strategy for globally interrogating gene function in cancer in a programmable manner. Cancer Res; 78(15); 4107-13. (c)2018 AACR. PMID- 30021725 TI - Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment. AB - Stimulation of Toll-like receptor 7 (TLR7) activates myeloid cells and boosts the immune response. Previously, we have shown that stimulation of the inhibitory CD200 receptor (CD200R) suppresses TLR7 signaling and that the absence of CD200R signaling leads to a decreased number of papillomas in mice. Here, we investigated the effects of agonistic anti-CD200R on the antitumor activity of a TLR7 agonist (R848) in a syngeneic mouse tumor model. Intratumoral administration of R848 inhibited the growth of the CT26 colon carcinoma and simultaneously decreased CD200R expression in tumor-infiltrating immune cells. The antitumor effects of R848 were potentiated by anti-CD200R. Successfully treated mice were resistant to rechallenge with the same tumor cells. However, the immediate antitumor effects were independent of lymphocytes, because treatment efficacy was similar in wild-type and Rag1tm1Mom mice. Administration of R848, particularly in combination with anti-CD200R, changed the phenotype of intratumoral myeloid cells. The infiltration with immature MHC-II+ macrophages decreased and in parallel monocytes and immature MHC-II- macrophages increased. Combined treatment decreased the expression of the macrophage markers F4/80, CD206, CD86, CD115, and the ability to produce IL1beta, suggesting a shift in the composition of intratumor myeloid cells. Adoptively transferred CD11b+ myeloid cells, isolated from the tumors of mice treated with R848 and anti-CD200R, inhibited tumor outgrowth in recipient mice. We conclude that administration of agonistic anti CD200R improves the antitumor effects of TLR7 signaling and changes the local tumor microenvironment, which becomes less supportive of tumor progression. Cancer Immunol Res; 6(8); 930-40. (c)2018 AACR. PMID- 30021727 TI - Correction: Hypoparathyroidism in pregnancy. PMID- 30021726 TI - Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo. AB - There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5'-adenosine monophosphate-activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 MUmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629-42. (c)2018 AACR. PMID- 30021728 TI - Case of lower limb revascularisation using composite sequential bypass graft with a 'diamond' intermediate anastomosis. AB - In patients with critical infracrural disease, autologous saphenous vein grafting offers the best reported conduit patency and limb salvage rates but is only feasible in approximately 30% of patients due to the lack of available or suitable vein. In the absence of a suitable length of available vein, various composite grafting techniques have been explored with the aim to improve graft longevity, maximise native vein use and improve overall clinical outcomes, including limb salvage rates. We report a case of a 66-year-old man with critical limb ischaemia and a history of venous disease, where a complex composite sequential bypass graft combining both native vein and synthetic graft, incorporated into a novel intermediate anastomotic technique in a 'diamond' configuration, offered promising results in limb salvage. This case highlights the key steps and advantages in this novel technique. PMID- 30021729 TI - Severe herpes simplex virus pneumonia in an elderly, immunocompetent patient. AB - Although not common, herpes simplex virus (HSV) pneumonia can occur in immunocompromised patients. However, HSV pneumonia in immunocompetent hosts is very rare. The authors encountered a very rare case of severe HSV pneumonia in an immunocompetent host. The patient was an 85-year-old Japanese woman who presented with severe intractable pneumonia refractory to empirical antimicrobial therapy. Furthermore, the causative microorganisms remained unknown. Therefore, cytological examination of bronchoalveolar lavage fluid and protected brush biopsy of the lower respiratory tract were performed, which indicated herpes virus-infected cells with nuclear inclusions; PCR assay was positive for HSV DNA. Accordingly, the patient was diagnosed with HSV pneumonia. Her respiratory condition improved immediately after initiation of acyclovir monotherapy. In selected cases of intractable pneumonia refractory to standard antimicrobial therapy, the possibility of HSV pneumonia should be pursued. PMID- 30021730 TI - Aggressive myxoinflammatory fibroblastic sarcoma with multiple site metastases. AB - Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare soft tissue sarcoma which was initially observed in acral sites and characterised by spindle cells, pleomorphic bizarre cells and distinctive large Reed-Sternberg-like cells admixed with an intense inflammatory cell infiltrates. MIFS manifests as a slow growing often superficial lesion which can be mistaken as infectious or chronic inflammatory process or benign tumours such as nodular fasciitis, giant cell tumour of tendon sheath or synovial pseudocyst. We report a rare presentation of a MIFS in a 38-year-old man with extensive local spread from subcutaneous tissue to the ankle joint and bones as well as multiple synchronous metastases to lung, sixth rib and vertebra. Our case is peculiar for its aggressive clinical behaviour with short duration, fast growth and extensive metastases, a feature infrequent in MIFS. PMID- 30021731 TI - Metastasis of malignant myoepithelial carcinoma to the brain. AB - Myoepithelial tumours are a rare form of salivary gland neoplasm and intracranial metastases have rarely been described. The authors present the case of a 61-year old patient with a history of primary myoepithelial carcinoma of the right foot. Metastases were found in the third ventricle, left temporal lobe and right frontal lobe. The third ventricular and left temporal lobe tumours were resected in a two-stage operation. Pathology of the third ventricular lesion was most consistent with metastasis. MRI of the spine 2 weeks after his operation revealed an intradural mass with several lesions in the lumbar thecal space suggesting further metastases. The patient succumbed to his disease 2 months after his two stage operation and 5 years after his initial diagnosis. This appears to be the first case in the literature of multiple primary myoepithelial carcinoma metastases to the brain. Further information is needed to provide diagnostic and therapeutic recommendations. PMID- 30021732 TI - Caseous calcification of the mitral valve annulus: a rare cause of bilateral cerebral and ocular embolisation. AB - A 65-year-old woman presented with sudden bilateral visual loss of recent onset. She was recently diagnosed with multiple acute stroke syndrome for which she was commenced on antiplatelet therapy. Funduscopic examination revealed bilateral inferotemporal retinal artery occlusions. The recent history of multiple cerebral infarcts combined with the current ocular findings prompted a transoesophageal echocardiogram which successfully revealed caseous calcification of the mitral valve annulus as the source of the numerous sequential emboli, a finding which the conventional transthoracic echocardiogram had failed to disclose as a result of suboptimal image quality. Transoesophageal echocardiography should always be considered as part of the diagnostic workup of retinal arterial occlusive disease, particularly in bilateral lesions, due to its higher yield in identifying posteriorly located cardiac valvular and aortic lesions. PMID- 30021733 TI - Transformation of jejunoileal follicular lymphoma into diffuse large B-cell lymphoma detected using double-balloon enteroscopy. AB - Jejunoileal follicular lymphomas (FLs) are rare and have been reported to undergo histological transformation (HT). We report a case of jejunoileal FL transformation into diffuse large B-cell lymphoma (DLBCL). An 82-year-old woman presented with a 5.5 cm ulcerated jejunal mass, identified through double-balloon enteroscopy. The histopathology report revealed diffuse atypical lymphoid cells, which confirmed the presence of DLBCL. Neoplastic follicles confirmed the presence of FL. Genetic analysis revealed a match between the FL and DLBCL. Following a segmentectomy and chemotherapy, the patient is in remission. Based on this case, we should consider the possibility of jejunoileal FLs transforming into DLBCL. PMID- 30021734 TI - Rare cause for a common presentation: isolated pulmonary valve endocarditis yet another mimicker. AB - Isolated pulmonary valve endocarditis (PVE) is a rare condition. Known risk factors in previous case reports were intravenous drug abuse and congenital heart disease. Epidemiology of PVE has been changing. It is now being reported specially following invasive healthcare-related procedures even in patients with structurally normal heart. Vast majority of patients present with respiratory symptoms and diagnosis of endocarditis may be challenging unless there is high index of suspicion. Various microorganisms had been isolated as aetiological agents; however, Enterococcus faecalis is being increasingly isolated. PVE mostly managed conservatively with intravenous antibiotics with option for surgical intervention in specific situations. We present a patient with isolated PVE due to E. faecalis following colonoscopy and polypectomy with predisposing risk factor of alcohol excess, mimicking clinically as pneumonia and radiologically as a neoplastic lesion. PMID- 30021735 TI - Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature. AB - We report a case of Cryptococcus neoformans pulmonary infection complicated by empyema in a 79-year-old man with diffuse large B-cell lymphoma treated with R CHOP and ibrutinib. A literature review identified 25 cases of cryptococcal pleural disease published since 1980. Most cases were caused by the C. neoformans species in immunocompromised hosts with an exudative pleural effusion and lymphocyte-predominant infiltrate. The cryptococcal antigen test was often positive when pleural fluid and serum were tested. The outcome was favourable in most cases with antifungal therapy and either thoracocentesis or surgical resection. We also identified 40 cases of opportunistic infections, most commonly aspergillosis, cryptococcosis and Pneumocystis jirovecii pneumonia, in patients treated with ibrutinib. In vitro studies indicate Bruton tyrosine kinase inhibition impairs phagocyte function and offer a mechanism for the apparent association between ibrutinib and invasive fungal infections. PMID- 30021736 TI - Splenic torsion: a rare cause of abdominal pain. AB - Splenic torsion is an exceedingly rare but clinically important disease process that should be recognised promptly by the treating physician. In this condition, there is twisting of the spleen along its vascular pedicle, subsequently leading to abdominal pain in the setting of organ ischaemia. Vascular thrombosis and splenic infarction may ensue. Torsion has been described in cases of a known wandering spleen. Abnormal development of the splenic suspensory ligaments may predispose a patient to a wandering spleen. Treatment of splenic torsion is typically surgical, with goals of preservation of the spleen if possible.We present a case of a young woman who presented with left-sided chest and abdominal pain and was found to have splenic torsion with complete splenic infarction. Surgical intervention was required, and splenectomy was performed. In this case presentation, we outline the multidisciplinary approach needed to care for the patient with this rare condition. PMID- 30021737 TI - Aortocaval fistula: an unusual complication of ruptured abdominal aortic aneurysm. AB - Aortocaval fistula (ACF) is a rare complication of abdominal aortic aneurysm, which erodes into the wall of the inferior vena cava, resulting in the formation of a fistula. ACF presents with various inconsistent symptoms and signs. ACF can be a diagnostic dilemma if not suspected and it is lethal if left untreated.A 60 year-old man presented with abdominal and lower back pain of sudden onset. Renal and liver functions were impaired, without signs of cardiac failure. CT angiography revealed an abdominal aneurysm rupture into the inferior vena cava. Patient underwent a successful open repair: ACF ligation from within the aneurysmal sac and an aorto-bi-iliac bypass using a Dacron graft. Renal and liver functions improved and the patient was discharged on the eighth postoperative day. A month later, the patient was fit and well with normal liver and renal functions.Despite progress made in the endovascular treatment of ACF, complications still persist with a reported endoleak rate of 50%. Open repair is still a valid method for ACF repair in patients fit to undergo laparotomy and general anaesthesia. In this case, the patient was fit and along the lack of a suitable stent graft, the vascular team performed an open repair with good results.Open repair of an ACF is a valid treatment method for patients who are fit enough to undergo laparotomy and general anaesthesia, and avoids complications related to endovascular repair, such as endoleaks. PMID- 30021739 TI - Laryngoceles with airway compromise complicating mucous membrane pemphigoid. AB - Mucous membrane pemphigoid (MMP) encompasses a group of autoantibody-mediated, subepithelial blistering diseases, which primarily affect mucosal surfaces including oral, ocular, skin, genital, nasopharyngeal and oesophageal sites. We present a first description of laryngoceles as a manifestation of mucous membrane pemphigoid resulting in dynamic airway closure. Mucosal injury at other sites had previously resulted in pathergy and localised cicatrisation. We discuss successful combined medical and transcutaneous surgical intervention designed to avoid tracheostomy and minimise iatrogenic laryngeal cicatrisation. PMID- 30021738 TI - The successful treatment of a multidrug-resistant Achromobacter xylosoxidans corneal ulcer with topical meropenem. AB - Microbial keratitis is a common corneal condition, with many known risk factors. We present a case of an 88-year-old female patient with a multidrug-resistant Achromobacter xylosoxidans corneal ulcer in a previously failed second penetrating keratoplasty, successfully managed with topical meropenem drops administered hourly around the clock, for five days preceding and then hourly day only, for five days following a repeat third penetrating keratoplasty. Topical meropenem 50 mg/mL was prepared by mixing a 500 mg vial of meropenem with 10 mL of sterile water with pharmacy advice that administration should be within an hour. To the best of our knowledge, this is the first report of the use of topical meropenem in the management of A.xylosoxidans keratitis. This case highlights the importance of the mean inhibitory concentrations for antibiotics when considering sensitivities. Topical meropenem may be a useful treatment option for multidrug-resistant bacterial corneal ulcers that are resistant to conventional therapy. PMID- 30021740 TI - Acute infection-related glomerulonephritis with disseminated gonococcal infection in a 13-year-old girl. AB - Infection-related glomerulonephritis results from glomerular immune complex deposition due to a variety of potential pathogens. Poststreptococcal glomerulonephritis is the best known example. We present a case of acute infection-related glomerulonephritis associated with disseminated gonococcal infection in a sexually active 13-year-old girl, the first report of such an association in the absence of endocarditis. The patient presented with features of acute disseminated gonococcal infection including fever, hypotension, tenosynovitis, polyarthralgias and petechiae. She developed hypocomplementemic glomerulonephritis synchronous with the acute infection. The renal biopsy revealed a diffuse endocapillary proliferative and exudative glomerulonephritis with subepithelial electron-dense humps and granular glomerular capillary wall staining for C3 and IgG, typical of acute postinfectious glomerulonephritis. After treatment and resolution of the gonococcal infection, the serum creatinine, complement levels and urine sediment normalised. The only residual renal damage 16 months later was low-grade proteinuria. PMID- 30021741 TI - Primary bladder amyloidosis as a cause of haematuria. AB - We report the case of a 46-year-old man who initially presented with macroscopic haematuria. Although initially concerning for a malignancy in the bladder, histology demonstrated a primary bladder amyloidosis that has remained stable for 6 years since the initial diagnosis. Primary bladder amyloidosis is an important clinical entity that can mimic bladder malignancy on clinical history, radiological investigation and cystoscopic evaluation. Although uncommon, it should not be neglected as a possible diagnosis in patients presenting with haematuria. PMID- 30021742 TI - Two for the price of one: emerging carbapenemases in a returning traveller to New York City. AB - We report a case of a complex orthopaedic infection in a patient returning to New York City from Bangladesh where he was involved in a serious motor vehicle accident. He developed extensive osteomyelitis with a carbapenem-resistant Klebsiella pneumoniae The isolate was unique due to the coexistence of New Delhi metallo-beta-lactamase-1 and Oxacillinase type-181 carbapenemases, which are relatively uncommon in North America and were presumably acquired in Bangladesh. Herein, we explore challenges associated with management of carbapenem-resistant Enterobacteriaceae infections, including limited available data on effective antimicrobial therapy. We also highlight the added value of rapid diagnostic technology in guiding clinical management. Ultimately, the patient required both aggressive surgical management and combination therapy with aztreonam and ceftazidime-avibactam for true source control and favourable clinical outcome. PMID- 30021743 TI - Polypoidal lesions associated to choroidal naevus: spectrum of pachychoroid disease? AB - A 78-year-old woman was referred by an optician for an incidental finding of peripapillary naevus in the absence of visual symptoms. On examination, the right eye showed a choroidal naevus of around 1.5 disc diameter, adjacent to the optic disc. Optical coherence tomography detected the presence of pigment epithelium detachment and subretinal fluid within the context of the naevus. Fundus fluorescein angiography and indocyanine green showed multiple polypoidal lesions (Polypoidal Choroidal Vasculopathy, PCV) in the choroid within the spectrum of a pachychoroid, without any sign of malignancy related to neovascularisation. The patient underwent a follow-up of 6 months, showing stability of the lesions over this timeframe. No treatment has been required since the polypoidal lesions were outside the fovea and visual acuity remained stable. The association between choroidal naevi and polypoidal lesions is rare1; however, this seems to confirm that these findings are part of the spectrum of pachychoroid disease. PMID- 30021745 TI - Unruptured giant left ventricular pseudoaneurysm after silent myocardial infarction. PMID- 30021744 TI - Efficacy of 4-year treatment of icon infiltration resin on postorthodontic white spot lesions. AB - White spot lesions are defined as enamel surface and sub surface demineralisation, although these lesions can be reversed and do not form cavities. Infiltration using fluid resin proved to be a valid micro-invasive alternative compared with traditional conservative therapy. This has allowed treatment without any trauma (no use of local anaesthesia and cavity preparation) of numerous lesions in only one session with stable clinical (mechanical stability, enamel hardness, conservation of sound tissue) and aesthetic results (disappearance of lesions) over the time. The present report evaluates the effectiveness of Icon infiltration resin on postorthodontic white spots at 6 months, 1 and 4 years. PMID- 30021746 TI - Hypophosphataemia: an important cause of collapse. AB - We present a case of a 44-year-old man, civil servant, who presented to the emergency department (ED) following an episode of collapse. He was usually fit and well and while at work he had developed a headache with pins and needles over his face and subsequently collapsed. On arrival to ED, he had a Glasgow Coma Scale (GCS) of 4/15. There was no history of note apart from being prescribed citalopram for depression. Laboratory investigations revealed severe hypophosphataemia (phosphate 0.19 mmol/L) and no other electrolyte abnormality. He was commenced on intravenous phosphate and his GCS improved to 15 within 4 hours. Further investigations revealed no cause for his severe hypophosphataemia and repeat bloods in clinic follow-up showed a normal phosphate level. PMID- 30021747 TI - Extravasation of contrast beneath the preputial skin due to improper technique of retrograde urethrogram. PMID- 30021748 TI - Purple urinary bag syndrome: what every primary healthcare provider should know. PMID- 30021749 TI - Venous air embolism in a patient with a massive upper gastrointestinal bleeding. PMID- 30021750 TI - Upping Enrollment of Veterans in Trials. AB - The NCI and Department of Veterans Affairs (VA) are collaborating on the NCI and VA Interagency Group to Accelerate Trials Enrollment, or NAVIGATE, which will launch at 12 VA facilities across the country. The program aims to increase participation of veterans with cancer in NCI-sponsored clinical trials. PMID- 30021751 TI - Patient-tailored triage decisions by anaesthesiologist-staffed prehospital critical care teams: a retrospective descriptive study. AB - OBJECTIVES: The primary objective was to estimate the incidence of patients in the Central Denmark Region triaged to bypass the local emergency department without being part of a predefined fast-track protocol. The secondary objective was to describe these triage decisions in more detail with regard to the most common diagnoses, incidence of direct referral sorted by the prehospital critical care team (PHCCT) and the destination hospital. DESIGN: Retrospective descriptive study. SETTING AND PARTICIPANTS: The emergency medical service in the Central Denmark Region primarily consists of emergency medical technician (EMT)-staffed ambulances and anaesthesiologist-EMT-staffed PHCCTs. Patients treated by the nine ground-based PHCCTs in the region constituted the study population. The inclusion criteria were all patients treated by the PHCCTs during 2013 and 2014. The exclusion criteria were interhospital transfers, and patients with ST-segment elevation myocardial infarction, stroke or were in active labour. ENDPOINTS: Incidence of prehospital critical care anaesthesiologist-initiated direct referral, prehospital tentative diagnoses and transport destination. RESULTS: During the study period, the PHCCTs treated 39 396 patients and diverted 989 (2.5%) patients not covered by a predefined fast-track protocol to a specialised hospital department. 'Resuscitated from cardiac arrest' (n=143), 'treatment and observations following road traffic accident' (n=105) and 'observation and treatment for an unspecified disease/condition' (n=78) were the most common prehospital tentative diagnoses, accounting for 33.0% of all diverted patients. In total, 943 (95.3%) of the PHCCT-diverted patients were diverted to a department at Aarhus University Hospital. CONCLUSION: Our results demonstrate that in 1 out of 40 patient contacts, the anaesthesiologist-staffed PHCCTs in the Central Denmark Region divert critically ill and injured patients directly to a specialised hospital department, bypassing local emergency departments and potentially reducing time to definitive care for these patients. There may be a potential for increased referral of patients with no predefined fast-track directly to specialised departments in the Central Denmark Region. PMID- 30021752 TI - Gender, stressful life events and interactions with sleep: a systematic review of determinants of adiposity in young people. AB - OBJECTIVES: Overweight and obesity among young people are high and rising. Social stressors and sleep are independently associated with obesity, but are rarely studied together or examined for gender-specific effects. The literature regarding adolescent populations is especially lacking. This review assesses whether experiencing stressful life events results in greater adiposity in young women and young men compared with those who do not experience stressful life events, and whether the relationship is modified by sleep problems. DESIGN: We systematically searched six bibliometric databases (Web of Science, Embase Ovid, PsycINFO, CINHAL, PubMed, ProQuest Dissertations) supplemented by hand searches. Longitudinal prospective studies or reviews were eligible for inclusion when they examined gender-specific changes in adiposity in young adults (age 13-18 years) as a function of stressful life event alone or in combination with sleep problems. RESULTS: We found one study eligible for inclusion reporting mixed impact of stressful life events on body mass index (BMI) between genders. The study assessed specific life events and showed significantly lower BMI at follow up among young men who experienced a residence change, but significantly higher BMI among young women who experienced setting up a family and who reported internal locus of control. CONCLUSIONS: Despite ample research on social stressors or sleep problems and weight, we still know little about the role of stressful life events, or combined effects with sleep, on obesity risk in adolescents from a gender perspective. Existing evidence suggests specific life events affect weight differently between the genders. Robust, high-quality longitudinal studies to decipher this dual burden on obesity during adolescence should be prioritised, as firm conclusions remain elusive. PMID- 30021754 TI - Attitudes towards a programme of risk assessment and stratified management for ovarian cancer: a focus group study of UK South Asians' perspectives. AB - OBJECTIVE: Population-based risk assessment, using genetic testing and the provision of appropriate risk management, could lead to prevention, early detection and improved clinical management of ovarian cancer (OC). Previous research with mostly white British participants found positive attitudes towards such a programme. The current study aimed to explore the attitudes of South Asian (SA) women and men in the UK with the aim of identifying how best to implement such a programme to minimise distress and maximise uptake. DESIGN: Semistructured qualitative focus group discussions. SETTING: Community centres across North London and Luton. PARTICIPANTS: 49 women and 13 men who identified as SA (Indian, Pakistani or Bangladeshi), which constitutes the largest non-European ethnic minority group in the UK. METHODS: Seven community-based focus groups were held. Group discussions were transcribed verbatim, coded and analysed thematically. RESULTS: Awareness and knowledge of OC symptoms and specific risk factors was low. The programme was acceptable to most participants and attitudes to it were generally positive. Participants' main concerns related to receiving a high-risk result following the genetic test. Younger women may be more cautious of genetic testing, screening or risk-reducing surgery due to the importance of marriage and childbearing in their SA cultures. CONCLUSIONS: A crucial first step to enable implementation of population-based genetic risk assessment and management in OC is to raise awareness of OC within SA communities. It will be important to engage with the SA community early on in programme implementation to address their specific concerns and to ensure culturally tailored decision support. PMID- 30021753 TI - Causes of premature death and their associated risk factors in the Golestan Cohort Study, Iran. AB - OBJECTIVES: To examine the causes of premature mortality (<70 years) and associated risk factors in the Golestan Cohort Study. DESIGN: Prospective. SETTING: The Golestan Cohort Study in northeastern Iran. PARTICIPANTS: 50 045 people aged 40 or more participated in this population-based study from baseline (2004-2008) to August 2017, with over 99% success follow-up rate. MAIN OUTCOME MEASURES: The top causes of premature death, HR and their 95% CI and population attributable fraction (PAF) for risk factors. RESULTS: After 444 168 person-years of follow-up (median of 10 years), 6347 deaths were reported, of which 4018 (63.3%) occurred prematurely. Ischaemic heart disease (IHD) accounted for 33.9% of premature death, followed by stroke (14.0%), road injuries (4.7%), stomach cancer (4.6%) and oesophageal cancer (4.6%). Significant risk/protective factors were: wealth score (HR for highest vs lowest quintile: 0.57, PAF for lowest four quintiles vs top quintile: 28%), physical activity (highest vs lowest tertile: 0.67, lowest two tertiles vs top tertile: 22%), hypertension (1.50, 19%), opium use (1.69, 14%), education (middle school or higher vs illiterate: 0.84, illiterate or primary vs middle school or higher: 13%), tobacco use (1.38, 11%), diabetes (2.39, 8%) and vegetable/fruit consumption (highest vs lowest tertile: 0.87, lowest two tertiles vs top tertile: 8%). Collectively, these factors accounted for 76% of PAF in men and 69% in women. CONCLUSION: IHD and stroke are the leading causes of premature mortality in the Golestan Cohort Study. Enhancing socioeconomic status and physical activity, reducing opium and tobacco use, increasing vegetable/fruit consumption and controlling hypertension and diabetes are recommended to reduce premature deaths. PMID- 30021756 TI - Effectiveness of natural S-equol supplement for premenstrual symptoms: protocol of a randomised, double-blind, placebo-controlled trial. AB - INTRODUCTION: Premenstrual syndrome (PMS) comprises a range of mood, behavioural and physical symptoms, and impairs many women's quality of life. Isoflavones are expected to stabilise the natural fluctuation of the oestrogen cycle through their selective oestrogen receptor modulator-like activities that alleviate PMS symptoms. Equol, a metabolite of a soy isoflavone converted from daidzein by specific gut bacteria, has a greater bioavailability compared with other soy isoflavones. We aim to examine the effect of natural S-equol supplements on premenstrual symptoms. METHODS AND ANALYSIS: This study will enrol 124 women (aged 20-45 years) who have PMS symptoms and are non-equol producers in a double blind, parallel, randomised, placebo-controlled trial, in which they will receive natural S-equol supplement (equol 10 mg a day) or placebo, orally, twice daily, for three menstrual cycles. The primary outcome measure (Daily Record of Severity of Problems total score) will be assessed during intervention cycles. To compare the primary outcomes between the S-equol group and the placebo group, the mean differences in the Daily Record of Severity of Problems total score between the two groups will be determined. The p values will be determined using Student's t test, where the significance level is 5% (two-sided). ETHICS AND DISSEMINATION: The institutional review board at Kindai University approved the study. The findings of this trial will be submitted to an international peer-reviewed journal. Abstracts will be submitted to national and international conferences. TRIAL REGISTRATION NUMBER: UMIN000031815. PMID- 30021758 TI - Mechanisms of beneficial effects of metformin on fatty acid-treated human islets. AB - Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, ER stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2-day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2alpha and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2-day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p-AMPK was reduced, and p-EIF2alpha, CHOP and cleaved caspase 3 were strongly up-regulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2alpha, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms. PMID- 30021755 TI - Keloid risk in patients with atopic dermatitis: a nationwide retrospective cohort study in Taiwan. AB - OBJECTIVE: The pathogenesis of keloid is largely unknown. Because keloid and atopic dermatitis have overlapping pathophysiological mechanisms, we aimed to evaluate keloid risk in patients with atopic dermatitis. STUDY DESIGN: Population based retrospective cohort study. SETTING: The Taiwan National Health Insurance Research Database was used to analyse data for people who had been diagnosed with atopic dermatitis. PARTICIPANTS: We identified 8371 patients with newly diagnosed atopic dermatitis during 1996-2010. An additional 33 484 controls without atopic dermatitis were randomly identified and frequency matched at a one-to-four ratio. PRIMARY AND SECONDARY OUTCOME MEASURE: The association between atopic dermatitis and keloid risk was estimated using Cox proportional hazard regression models. RESULTS: After adjustment for covariates, the atopic dermatitis patients have a 3.19-fold greater risk of developing keloid compared with the non-atopic dermatitis group (3.19vs1.07 per 1000 person-years, respectively). During the study period, 163 patients with atopic dermatitis and 532 patients without atopic dermatitis developed keloid. Notably, keloid risk increased with severity of atopic dermatitis, particularly in patients with moderate to severe atopic dermatitis. CONCLUSIONS: Our results indicate that patients with atopic dermatitis had a higher than normal risk of developing keloid and suggest that atopic dermatitis may be an independent risk factor for keloid. PMID- 30021757 TI - TNF Signaling Impacts Glucagon-Like Peptide-1 Expression and Secretion. AB - Numerous studies have implicated tumor necrosis factor alpha (TNFalpha) in the pathogenesis of type 2 diabetes. However, the role of its primary receptor, TNF receptor 1 (TNFR1), in homeostatic regulation of glucose metabolism is still controversial. In addition to TNFalpha, lymphotoxin alpha (LTalpha) binds to and activates TNFR1. Thus, TNFalpha and LTalpha together are known as TNF. To delineate the role of TNF signaling in glucose homeostasis, the present study ascertained how TNF signaling deficiency affects major regulatory components of glucose homeostasis. To this end, normal diet-fed male TNFR1 deficient mice (TNFR1-/-), TNFalpha/LTalpha/LTbeta triple deficient mice (TNF/LT?3), and their littermate controls were subjected to intraperitoneal glucose tolerance test, insulin tolerance test, and oral glucose tolerance test. The present results showed that TNFR1-/- and TNF/LT?3 mice versus their controls had comparable body weight, tolerance to intraperitoneal glucose, and sensitivity to insulin. However, their tolerance to oral glucose was significantly increased. Additionally, glucose-induced insulin secretion assessments revealed that TNFR1 or TNF/LT deficiency significantly increased oral but not intraperitoneal glucose induced insulin secretion. Consistently, qPCR and immunohistochemistry analyses showed that TNFR1-/- and TNF/LT?3 mice versus their controls had significantly increased ileal expression of glucagon-like peptide-1 (GLP-1), one of the primary incretins. Their oral glucose-induced secretion of GLP-1 was also significantly increased. These data collectively suggest that physiological TNF signaling regulates glucose metabolism primarily through effects on GLP-1 expression and secretion and subsequently insulin secretion. PMID- 30021759 TI - A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects. AB - Background Despite epidemiologic evidence for increased cardiovascular morbidity and mortality associated with both high dietary and serum phosphate in humans with normal renal function, no controlled phosphate intervention studies of systemic hemodynamics have been reported. Higher serum 25(OH) vitamin D levels are associated with better cardiovascular outcomes, but vitamin D increases intestinal phosphate absorption.Methods We conducted a prospective outpatient study with blinded assessment in 20 young adults with normal renal function randomized to high phosphate (regular diet plus 1 mmol/kg body wt per day of Na as neutral sodium phosphate) or low phosphate (regular diet plus lanthanum, 750 mg thrice/day, plus 0.7 mmol/kg body wt per day of Na as NaCl) for 11 weeks. After 6 weeks, all subjects received vitamin D3 (600,000 U) by intramuscular injection. Outcome parameters were 24-hour ambulatory systolic and diastolic BP (SBP and DBP), pulse rate (PR), biomarkers, and measures of endothelial and arterial function.Results Compared with the low-phosphate diet group, the high phosphate diet group had a significant increase in mean+/-SEM fasting plasma phosphate concentration (0.23+/-0.11 mmol/L); 24-hour SBP and DBP (+4.1; 95% confidence interval [95% CI], 2.1 to 6.1; and +3.2; 95% CI, 1.2 to 5.2 mm Hg, respectively); mean 24-hour PR (+4.0; 95% CI, 2.0 to 6.0 beats/min); and urinary metanephrine and normetanephrine excretion (54; 95% CI, 50 to 70; and 122; 95% CI, 85 to 159 ug/24 hr, respectively). Vitamin D had no effect on any of these parameters. Neither high- nor low-phosphate diet nor vitamin D affected endothelial function or arterial elasticity.Conclusions Increased phosphate intake (controlled for sodium) significantly increases SBP, DBP, and PR in humans with normal renal function, in part, by increasing sympathoadrenergic activity. PMID- 30021761 TI - Thermal spikes from the urban heat island increase mortality and alter physiology of lizard embryos. AB - Effects of global change (i.e. urbanization, climate change) on adult organisms are readily used to predict the persistence of populations. However, effects on embryo survival and patterns of development are less studied, even though embryos are particularly sensitive to abiotic conditions that are altered by global change (e.g. temperature). In reptiles, relatively warm incubation temperatures increase developmental rate and often enhance fitness-relevant phenotypes, but extremely high temperatures cause death. Due to the urban heat island effect, human-altered habitats (i.e. cities) potentially create unusually warm nest conditions that differ from adjacent natural areas in both mean and extreme temperatures. Such variation may exert selection pressures on embryos. To address this, we measured soil temperatures in places where the Puerto Rican crested anole lizard (Anolis cristatellus) nests in both city and forest habitats. We bred anoles in the laboratory and subjected their eggs to five incubation treatments that mimicked temperature regimes from the field, three of which included brief exposure to extremely high temperatures (i.e. thermal spikes) measured in the city. We monitored growth and survival of hatchlings in the laboratory for 3 months and found that warmer, city temperatures increase developmental rate, but brief, thermal spikes reduce survival. Hatchling growth and survival were unaffected by incubation treatment. The urban landscape can potentially create selection pressures that influence organisms at early (e.g. embryo) and late life stages. Thus, research aimed at quantifying the impacts of urbanization on wildlife populations must include multiple life stages to gain a comprehensive understanding of this important aspect of global change. PMID- 30021762 TI - Early-career researchers: an interview with Erika Eliason. AB - Erika Eliason is an Assistant Professor at University of California, Santa Barbara, USA, where she studies ecological and evolutionary physiology. She received her Bachelor's degree at Simon Fraser University, Canada, in 2003 before completing her MSc and PhD with Tony Farrell at the University of British Columbia, Canada. She then completed postdocs with Frank Seebacher at the University of Sydney, Steve Cooke at Carleton University, Canada, and Scott Hinch at the University of British Columbia, Canada. Erika gave the Cameron Award Lecture at the annual Canadian Society of Zoologists meeting in 2013. PMID- 30021760 TI - Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease. AB - Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency. Vitamin E is often supplemented in the form of fat-soluble vitamin E acetate, but fat malabsorption considerably limits correction of the deficiency. In this crossover study, we administered two different forms of vitamin E, tocofersolan (a water-soluble derivative of RRR alpha-tocopherol) and alpha-tocopherol acetate, to three patients with ABL and four patients with CMRD. The aims of this study were to evaluate the intestinal absorption characteristics of tocofersolan versus alpha-tocopherol acetate by measuring the plasma concentrations of alpha-tocopherol over time after a single oral load and to compare efficacy by evaluating the ability of each formulation to restore vitamin E storage after 4 months of treatment. In patients with ABL, tocofersolan and alpha-tocopherol acetate bioavailabilities were extremely low (2.8% and 3.1%, respectively). In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; alpha-tocopherol acetate, 11.4%). Plasma concentrations of alpha-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD. This study provides new insights about vitamin E status in ABL and CMRD and suggests the potential of different formulations as treatment options. PMID- 30021763 TI - The Critical Role of the Hippocampus in Mind Wandering. PMID- 30021764 TI - Delving Deep into Crossmodal Integration. PMID- 30021765 TI - Cutting Edge: Deletion of Ezrin in B Cells of Lyn-Deficient Mice Downregulates Lupus Pathology. AB - Genetic deletion of the Src family tyrosine kinase Lyn in mice recapitulates human systemic lupus erythematosus, characterized by hyperactive BCR signaling, splenomegaly, autoantibody generation, and glomerulonephritis. However, the molecular regulators of autoimmunity in Lyn-deficient mice and in human lupus remain poorly characterized. In this study, we report that conditional deletion of the membrane-cytoskeleton linker protein ezrin in B cells of Lyn-deficient mice (double knockout [DKO] mice) ameliorates B cell activation and lupus pathogenesis. B cells from DKO mice respond poorly to BCR stimulation, with severe downregulation of major signaling pathways. DKO mice exhibit reduced splenomegaly as well as significantly lower levels of autoantibodies against a variety of autoantigens, including dsDNA, histone, and chromatin. Leukocyte infiltration and deposition of IgG and complement component C3 in the kidney glomeruli of DKO mice are markedly reduced. Our data demonstrate that ezrin is a novel molecular regulator of B cell-associated lupus pathology. PMID- 30021766 TI - A Pilot Study To Investigate the Immune-Modulatory Effects of Fasting in Steroid Naive Mild Asthmatics. AB - A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. PFTs were not changed by a prolonged fast. However, steroid-naive mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics cocultured with human epithelial cells resulted in blunting of house dust mite-induced epithelial cell cytokine production and reduced CD4+ T cell Th2 activation compared with refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level-dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma. PMID- 30021767 TI - Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells. AB - Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell-targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3zeta transmembrane and signaling domains. We termed these "BAR" for B cell-targeting Ab receptors. CD4+CD25hiCD127low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 or A2 domains (C2- and A2-BAR). Such BAR-Tregs specifically suppressed the recall Ab response of spleen cultures from FVIII-immunized mice in vitro and completely prevented anti-FVIII Ab development in response to FVIII immunization. Mechanistic studies with purified B cells and T cells from tolerized or control recipients demonstrated that the FVIII-specific B cells were directly suppressed or anergized, whereas the T cell response remained intact. Taken together, we report in this study a successful proof-of-principle strategy using Ag-expressing Tregs to directly target specific B cells, an approach which could be adapted to address other adverse immune responses as well. PMID- 30021768 TI - Membrane-Associated Proteinase 3 on Granulocytes and Acute Myeloid Leukemia Inhibits T Cell Proliferation. AB - Proteinase 3 (P3), a serine protease expressed by myeloid cells, localized within azurophil granules, and also expressed on the cellular membrane of polymorphonuclear neutrophils (PMN), is the target of autoimmunity in granulomatosis with polyangiitis. PR1, an HLA-A2 restricted nonameric peptide derived from P3, has been targeted effectively in myeloid leukemia. We previously showed (Molldrem et al. 2003. JClinInvest 111: 639-647) that overexpression of P3 in chronic myeloid leukemia induces apoptosis of high-affinity PR1-specific T cells, leading to deletional tolerance and leukemia outgrowth. In this study, we investigated the effect of membrane P3 (mP3)-expressing PMN and acute myeloid leukemia (AML) blasts on the proliferation of CD4 and CD8 T cells in vitro. We demonstrate that mP3-expressing PMN significantly inhibits autologous healthy donor T cell proliferation but does not affect cytokine production in activated T cells and that this effect requires cell proximity and was abrogated by P3 blockade. This inhibition required P3 enzyme activity. However, suppression was not reversed by either the addition of catalase or the inhibition of arginase I. In addition to P3 blockade, anti-low density lipoprotein receptor-related protein 1 (LRP1) Ab also restored T cells' capacity to proliferate. Last, we show dose dependent inhibition of T cell proliferation by mP3-expressing AML blasts. Together, our findings demonstrate a novel mechanism whereby PMN- and AML associated mP3 inhibits T cell proliferation via direct LRP1 and mP3 interaction, and we identify P3 as a novel target to modulate immunity in myeloid leukemia and autoimmune disease. PMID- 30021771 TI - Massive fall in teenage pregnancy down to sensible drinking and more time spent online. PMID- 30021772 TI - Devalue existing model of general practice and lose its benefits for patients. PMID- 30021769 TI - Functional Interrogation of Primary Human T Cells via CRISPR Genetic Editing. AB - Developing precise and efficient gene editing approaches using CRISPR in primary human T cell subsets would provide an effective tool in decoding their functions. Toward this goal, we used lentiviral CRISPR/Cas9 systems to transduce primary human T cells to stably express the Cas9 gene and guide RNAs that targeted either coding or noncoding regions of genes of interest. We showed that multiple genes (CD4, CD45, CD95) could be simultaneously and stably deleted in naive, memory, effector, or regulatory T cell (Treg) subsets at very high efficiency. Additionally, nuclease-deficient Cas9, associated with a transcriptional activator or repressor, can downregulate or increase expression of genes in T cells. For example, expression of glycoprotein A repetitions predominant (GARP), a gene that is normally and exclusively expressed on activated Tregs, could be induced on non-Treg effector T cells by nuclease-deficient Cas9 fused to transcriptional activators. Further analysis determined that this approach could be used in mapping promoter sequences involved in gene transcription. Through this CRISPR/Cas9-mediated genetic editing we also demonstrated the feasibility of human T cell functional analysis in several examples: 1) CD95 deletion inhibited T cell apoptosis upon reactivation; 2) deletion of ORAI1, a Ca2+ release activated channel, abolished Ca2+ influx and cytokine secretion, mimicking natural genetic mutations in immune-deficient patients; and 3) transcriptional activation of CD25 or CD127 expression enhanced cytokine signaling by IL-2 or IL 7, respectively. Taken together, application of the CRISPR toolbox to human T cell subsets has important implications for decoding the mechanisms of their functional outputs. PMID- 30021770 TI - Pre-Existing Maternal Antibodies Cause Rapid Prenatal Rejection of Allotransplants in the Mouse Model of In Utero Hematopoietic Cell Transplantation. AB - In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative nonimmunosuppressive alternative to postnatal hematopoietic stem cell transplantation for the treatment of congenital hemoglobinopathies. Anti-HLA donor-specific Abs (DSA) are associated with a high incidence of graft rejection following postnatal hematopoietic stem cell transplantation. We determine if DSA present in the mother can similarly cause graft rejection in the fetus following IUHCT. Ten million C57BL/6 (B6, H2kb) bone marrow cells were transplanted in utero into gestational day 14 BALB/c (H2kd) fetuses. The pregnant BALB/c dams carrying these fetuses either had been previously sensitized to B6 Ag or were injected on gestational days 13-15 with serum from B6-sensitized BALB/c females. Maternal-fetal Ab transmission, Ab opsonization of donor cells, chimerism, and frequency of macrochimeric engraftment (chimerism >1%) were assessed by flow cytometry. Maternal IgG was transmitted to the fetus and rapidly opsonized donor cells following IUHCT. Donor cell rejection was observed as early as 4 h after IUHCT in B6-sensitized dams and 24 h after IUHCT in dams injected with B6 sensitized serum. Efficient opsonization was strongly correlated with decreased chimerism. No IUHCT recipients born to B6-sensitized dams or dams injected with B6-sensitized serum demonstrated macrochimeric engraftment at birth compared with 100% of IUHCT recipients born to naive dams or dams injected with naive serum (p < 0.001). In summary, maternal donor-specific IgG causes rapid, complete graft rejection in the fetus following IUHCT. When a third-party donor must be used for clinical IUHCT, the maternal serum should be screened for DSA to optimize the chance for successful engraftment. PMID- 30021773 TI - Safe staffing: this is how many doctors we really need. PMID- 30021774 TI - Remembering the person. PMID- 30021775 TI - Boys should be given HPV vaccine, says joint committee. PMID- 30021776 TI - Damon Francis: Making the road by walking. PMID- 30021777 TI - Medical students' GP training: five minutes with . . . Robert McKinley. PMID- 30021778 TI - Are doctors wrong for stating the elephant in the room? PMID- 30021779 TI - A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML. PMID- 30021780 TI - TCF1 expression marks self-renewing human CD8+ T cells. AB - Expression of the transcription factor T-cell factor 1 (TCF1) identifies antigen experienced murine CD8+ T cells that retain potential for lymphoid recirculation and the ability to self-renew while producing more differentiated effector cells. We found that CD8+ T cells in the blood of both healthy and chronically infected humans expressed TCF1 at 3 distinct levels: high (TCF1-hi), intermediate (TCF1 int), and low (TCF1-lo). TCF1-hi cells could be found within both the naive and memory compartments and were characterized by relative quiescence and lack of immediate effector function. A substantial fraction of TCF1-int cells were found among memory cells, and TCF1-int cells exhibited robust immediate effector functions. TCF1-lo cells were most enriched in effector memory cells that expressed the senescence marker CD57. Following reactivation, TCF1-hi cells gave rise to TCF1-lo descendants while self-renewing the TCF1-hi progenitor. By contrast, reactivation of TCF1-lo cells produced more TCF1-lo cells without evidence of de-differentiating into TCF1-hi cells. Flow cytometric analyses of TCF1 expression from patient specimens may become a useful biomarker for adaptive immune function in response to vaccination, infection, autoimmunity, and cancer. PMID- 30021782 TI - Nearly 1700 requests for knee and hip surgery were rejected in England last year. PMID- 30021781 TI - Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. AB - OBJECTIVE: To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes. DESIGN: Population based cohort study. SETTING: General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS: Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013. MAIN OUTCOME MEASURES: Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes. RESULTS: Among 77 138 metformin initiators, 25 699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia. CONCLUSIONS: Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching. PMID- 30021783 TI - Health and wellbeing is the most common reason for doctors to take a break from training. PMID- 30021784 TI - Ibrutinib blocks Btk-dependent NF-KB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. PMID- 30021786 TI - Putting prevention into practice for the benefit of children and young people with cerebral palsy. PMID- 30021785 TI - Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study. AB - OBJECTIVE: To describe liver disease related mortality in the United States during 1999-2016 by age group, sex, race, cause of liver disease, and geographic region. DESIGN: Observational cohort study. SETTING: Death certificate data from the Vital Statistics Cooperative, and population data from the US Census Bureau compiled by the Center for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (1999-2016). PARTICIPANTS: US residents. MAIN OUTCOME MEASURE: Deaths from cirrhosis and hepatocellular carcinoma, with trends evaluated using joinpoint regression. RESULTS: From 1999 to 2016 in the US annual deaths from cirrhosis increased by 65%, to 34 174, while annual deaths from hepatocellular carcinoma doubled to 11 073. Only one subgroup-Asians and Pacific Islanders-experienced an improvement in mortality from hepatocellular carcinoma: the death rate decreased by 2.7% (95% confidence interval 2.2% to 3.3%, P<0.001) per year. Annual increases in cirrhosis related mortality were most pronounced for Native Americans (designated as "American Indians" in the census database) (4.0%, 2.2% to 5.7%, P=0.002). The age adjusted death rate due to hepatocellular carcinoma increased annually by 2.1% (1.9% to 2.3%, P<0.001); deaths due to cirrhosis began increasing in 2009 through 2016 by 3.4% (3.1% to 3.8%, P<0.001). During 2009-16 people aged 25-34 years experienced the highest average annual increase in cirrhosis related mortality (10.5%, 8.9% to 12.2%, P<0.001), driven entirely by alcohol related liver disease. During this period, mortality due to peritonitis and sepsis in the setting of cirrhosis increased substantially, with respective annual increases of 6.1% (3.9% to 8.2%) and 7.1% (6.1% to 8.4%). Only one state, Maryland, showed improvements in mortality (-1.2%, -1.7% to -0.7% per year), while many, concentrated in the south and west, observed disproportionate annual increases: Kentucky 6.8% (5.1% to 8.5%), New Mexico 6.0% (4.1% to 7.9%), Arkansas 5.7% (3.9% to 7.6%), Indiana 5.0% (3.8% to 6.1%), and Alabama 5.0% (3.2% to 6.8%). No state showed improvements in hepatocellular carcinoma related mortality, while Arizona (5.1%, 3.7% to 6.5%) and Kansas (4.3%, 2.8% to 5.8%) experienced the most severe annual increases. CONCLUSIONS: Mortality due to cirrhosis has been increasing in the US since 2009. Driven by deaths due to alcoholic cirrhosis, people aged 25-34 have experienced the greatest relative increase in mortality. White Americans, Native Americans, and Hispanic Americans experienced the greatest increase in deaths from cirrhosis. Mortality due to cirrhosis is improving in Maryland but worst in Kentucky, New Mexico, and Arkansas. The rapid increase in death rates among young people due to alcohol highlight new challenges for optimal care of patients with preventable liver disease. PMID- 30021787 TI - Building UK infrastructure for research that benefits infants, children and young people. PMID- 30021789 TI - Latest guidance on the management of gout. PMID- 30021788 TI - Medicine's generation gap: let's stop comparing. PMID- 30021790 TI - Sulfonylureas as second line treatment for type 2 diabetes. PMID- 30021791 TI - Association between inflammatory bowel disease and Parkinson's disease: seek and you shall find? PMID- 30021792 TI - The Insulator Protein CTCF Is Required for Correct Hox Gene Expression, but Not for Embryonic Development in Drosophila. AB - Insulator binding proteins (IBPs) play an important role in regulating gene expression by binding to specific DNA sites to facilitate appropriate gene regulation. There are several IBPs in Drosophila, each defined by their ability to insulate target gene promoters in transgenic assays from the activating or silencing effects of neighboring regulatory elements. Of these, only CCCTC binding factor (CTCF) has an obvious ortholog in mammals. CTCF is essential for mammalian cell viability and is an important regulator of genome architecture. In flies, CTCF is both maternally deposited and zygotically expressed. Flies lacking zygotic CTCF die as young adults with homeotic defects, suggesting that specific Hox genes are misexpressed in inappropriate body segments. The lack of any major embryonic defects was assumed to be due to the maternal supply of CTCF protein, as maternally contributed factors are often sufficient to progress through much of embryogenesis. Here, we definitively determined the requirement of CTCF for developmental progression in Drosophila We generated animals that completely lack both maternal and zygotic CTCF and found that, contrary to expectation, these mutants progress through embryogenesis and larval life. They develop to pharate adults, which fail to eclose from their pupal case. These mutants show exacerbated homeotic defects compared to zygotic mutants, misexpressing the Hox gene Abdominal-B outside of its normal expression domain early in development. Our results indicate that loss of Drosophila CTCF is not accompanied by widespread effects on gene expression, which may be due to redundant functions with other IBPs. Rather, CTCF is required for correct Hox gene expression patterns and for the viability of adult Drosophila. PMID- 30021793 TI - Genomic Prediction Using Individual-Level Data and Summary Statistics from Multiple Populations. AB - This study presents a method for genomic prediction that uses individual-level data and summary statistics from multiple populations. Genome-wide markers are nowadays widely used to predict complex traits, and genomic prediction using multi-population data are an appealing approach to achieve higher prediction accuracies. However, sharing of individual-level data across populations is not always possible. We present a method that enables integration of summary statistics from separate analyses with the available individual-level data. The data can either consist of individuals with single or multiple (weighted) phenotype records per individual. We developed a method based on a hypothetical joint analysis model and absorption of population-specific information. We show that population-specific information is fully captured by estimated allele substitution effects and the accuracy of those estimates, i.e., the summary statistics. The method gives identical result as the joint analysis of all individual-level data when complete summary statistics are available. We provide a series of easy-to-use approximations that can be used when complete summary statistics are not available or impractical to share. Simulations show that approximations enable integration of different sources of information across a wide range of settings, yielding accurate predictions. The method can be readily extended to multiple-traits. In summary, the developed method enables integration of genome-wide data in the individual-level or summary statistics from multiple populations to obtain more accurate estimates of allele substitution effects and genomic predictions. PMID- 30021794 TI - Second-trimester medication abortion outside the clinic setting: an analysis of electronic client records from a safe abortion hotline in Indonesia. AB - INTRODUCTION: Unsafe abortion past the first trimester disproportionately accounts for the majority of global abortion-related morbidity and mortality; research that documents the safety, feasibility and acceptability of existing models for providing information and support to women who self-manage outside of formal clinic settings is needed. METHODS: This study is a retrospective analysis of anonymised electronic client records from callers to a safe abortion hotline in Indonesia. Between July 2012 and October 2016, a total of 96 women contacted the hotline for information on medication abortion beyond 12 weeks' gestation and are included in this study. Descriptive statistics were calculated regarding pregnancy termination status, client experience with warning signs of potential complications, and medical care seeking and treatment. RESULTS: Ninety-six women with pregnancies beyond the first trimester called the hotline for information on medication abortion; 91 women received counselling support from the hotline. Eighty-three women (91.2%) successfully terminated their pregnancies using medication and did not seek medical care. Five women exhibited warning signs of potential complications and sought medical care; one woman sought care after a failed abortion. Two women were lost to follow-up and the outcomes of their pregnancies are unknown. CONCLUSIONS: Evidence from our analysis suggests that a model of remote provision of support for abortions later in pregnancy by non medically trained, skilled abortion counsellors could be a safe alternative for women in need of abortions beyond 12 weeks' gestation in a legally restrictive context. Further examination and documentation of the model is warranted. PMID- 30021795 TI - Increasing income-based inequality in suicide mortality among working-age women and men, Sweden, 1990-2007: is there a point of trend change? AB - BACKGROUND: Income inequalities have risen from the 1990s to 2000s, following the economic recession in 1994, but little research has investigated socioeconomic inequalities in suicide mortality for working-age men and women (aged between 30 and 64 years) over the time using longitudinal data in Sweden. METHODS: Using Swedish national register data between 1990 and 2007 as a series of repeated cohort studies with a 3-year follow-up (sample sizes were approximately 3.7 to 4.0 million in each year), relative and slope indices of inequality (RII and SII respectively) based on quintiles of individual disposable income were calculated and tested for temporal trends. RESULTS: SII for the risk of suicide mortality ranged from 27.6 (95% CI 19.5 to 35.8) to 44.5 (36.3 to 52.6) in men and 5.2 (0.2 to 10.4) to 16.6 (10.7 to 22.4) in women (per 100 000 population). In men, temporal trends in suicide inequalities were stable in SII but increasing in RII by 3% each year (p=0.002). In women, inequalities tended to increase in both RII and SII, especially after the late-1990s, with 10% increment in RII per year (p<0.001). CONCLUSIONS: Despite universal social security and generous welfare provision, income inequalities in suicide were considerable and have widened, especially in women. The steeper rise in women may be partially related to higher job insecurity and poorer working conditions in the female dominated public sector after the recession. To reduce health consequences following an economic crisis and widened income inequalities, additional measures may be necessary in proportion to the levels of financial vulnerability. PMID- 30021796 TI - Temporal Trends in Contemporary Use of Ventricular Assist Devices by Race and Ethnicity. AB - BACKGROUND: The proportion of racial/ethnic minorities receiving ventricular assist devices (VADs) has previously been less than expected. It is unclear if trends have changed since the broadening of access to insurance in 2014 and the rapid adoption of VAD technology. METHODS AND RESULTS: Using the Interagency Registry of Mechanically Assisted Circulatory Support, we analyzed time trends by race/ethnicity for 10 795 patients (white, 67.4%; African-American, 24.8%; Hispanic, 6.3%; Asian, 1.5%) who had a VAD implanted between 2012 and 2015. Linear models were fit to the annual census-adjusted rate of VAD implantation for each racial/ethnic group, stratified by sex and age group. From 2012 to 2015, African-Americans had an increase in the census-adjusted annual rate of VAD implantation per 100 000 (0.26 [95% confidence interval, 0.17-0.34]) while other ethnic groups exhibited no significant changes (white: 0.06 [-0.03 to 0.14]; Hispanic: 0.04 [-0.05 to 0.12]; Asian: 0.04 [-0.04 to 0.13]). Stratified by sex, rates increased in both African-American men and women (P<0.05), but the change in rate was highest among African-American men (men 0.37 [0.28-0.46]; women 0.16 [0.07-0.25]; interaction with sex P=0.004). Stratified by age group, rates increased in African-Americans aged 40 to 69 years and Asians aged 50 to 59 years (P<0.05). The observed differential change in VAD implantation rate by age group was significant among African-Americans (interaction with age, P<0.01) and Asians (interaction with age, P=0.02). CONCLUSIONS: From 2012 to 2015, VAD implantation rates increased among African-Americans but not other racial/ethnic groups. The greatest increase in rate was observed among middle-aged African-American men, suggesting a decline in racial disparities. Further investigation is warranted to reduce disparities among women and older racial/ethnic minorities. PMID- 30021799 TI - AAV-mediated gene therapy as a strategy to fight obesity and metabolic diseases. PMID- 30021797 TI - LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma. AB - Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Numerous studies have suggested that early life exposure to lipopolysaccharide (LPS) is negatively associated with allergic asthma. One proposed mechanism invokes desensitization of lung epithelial cells by LPS. We report here that acyloxyacyl hydrolase (AOAH), a host lipase that degrades and inactivates LPS, renders mice more susceptible to house dust mite (HDM)-induced allergic asthma. Lung epithelial cells from Aoah-/- mice are refractory to HDM stimulation, decreasing dendritic cell activation and Th2 responses. Antibiotic treatment that diminished commensal LPS-producing bacteria normalized Aoah-/- responses to HDM, while giving LPS intrarectally ameliorated asthma. Aoah-/- mouse feces, plasma, and lungs contained more bioactive LPS than did those of Aoah+/+ mice. By inactivating commensal LPS, AOAH thus prevents desensitization of lung epithelial cells. An enzyme that prevents severe lung inflammation/injury in Gram-negative bacterial pneumonia has the seemingly paradoxical effect of predisposing to a Th2-mediated airway disease. PMID- 30021798 TI - miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling. AB - The onset of secondary resistance represents a major limitation to long-term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is the key to the rational design of therapeutic strategies for resistant patients. MiRNA profiling combined with RNA Seq in MET-addicted cancer cell lines led us to identify the miR-205/ERRFI1 (ERBB receptor feedback inhibitor-1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET-TKIs, epigenetically induced miR-205 expression determined the downregulation of ERRFI1 which, in turn, caused EGFR activation, sustaining resistance to MET-TKIs. Anti-miR-205 transduction reverted crizotinib resistance in vivo, while miR-205 over expression rendered wt cells refractory to TKI treatment. Importantly, in the absence of EGFR genetic alterations, miR-205/ERRFI1-driven EGFR activation rendered MET-TKI-resistant cells sensitive to combined MET/EGFR inhibition. As a proof of concept of the clinical relevance of this new mechanism of adaptive resistance, we report that a patient with a MET-amplified lung adenocarcinoma displayed deregulation of the miR-205/ERRFI1 axis in concomitance with onset of clinical resistance to anti-MET therapy. PMID- 30021800 TI - Cerebral catheter angiography and its complications. AB - Catheter-based angiography is an important but invasive procedure in vascular neurology. It is used mainly for diagnosis and for planning treatment in patients with a suspected underlying vascular abnormality. It is often performed as a semiurgent, planned investigation or linked to an interventional procedure. Cerebral angiography provides high-resolution, three-dimensional, pathoanatomical data about the cerebral vasculature and also allows real-time analysis of blood flow. Contrast injections can be repeated to identify subtleties. A physical intervention may also follow angiography. For these reasons, angiography remains the gold standard for delineating vascular lesions of the brain (and spine). Permanent neurological complications are rare, approximately 1%, but become increasingly common in patients aged over 55 years. The main complications are embolic stroke, groin haematoma and contrast-induced nephropathy. In the new era of thrombectomy, it may transpire that other specialists including neurologists may learn to perform the procedure and to manage its complications. PMID- 30021801 TI - What I learned from my illness. Listen to what a patient tells you about changes in their experience and function, not about their current state. AB - I only realised how much my osteoarthritic hip had altered my life after the operation enabled me to return to activities I did not know I had stopped. Identifying need for and benefit from treatments should focus on relative changes in experience and function, not on a person's absolute state at a particular time. PMID- 30021802 TI - Implementing electronic patient-reported outcomes measurements: challenges and success factors. PMID- 30021803 TI - Slit2/Robo4 axis may contribute to endothelial cell dysfunction and angiogenesis disturbance in systemic sclerosis. AB - OBJECTIVE: In systemic sclerosis (SSc), early microvascular injury is followed by impaired angiogenesis and peripheral capillary loss. Here, we investigated the possible contribution of the neurovascular guidance molecule Slit2 and its Roundabout (Robo) receptors to SSc-related endothelial cell dysfunction. METHODS: Circulating Slit2 levels were measured in patients with SSc and healthy controls. Slit2, Robo1 and Robo4 expression was investigated in SSc and healthy skin biopsies and explanted dermal microvascular endothelial cells (MVECs). Slit2/Robo4 function in MVEC angiogenesis was studied by cell viability, wound healing and capillary-like tube formation assays. RESULTS: Circulating Slit2 was significantly increased in either SSc or patients with a very early diagnosis of SSc (VEDOSS) compared with controls. Interestingly, serum Slit2 levels were raised in patients with VEDOSS with nailfold videocapillaroscopy (NVC) abnormalities, while they were similar in VEDOSS with normal NVC and controls. In SSc, Slit2 and Robo4 expression was upregulated in clinically affected skin and explanted MVECs in respect to controls. The angiogenic performance of healthy MVECs was significantly reduced after challenge with recombinant human Slit2 or SSc sera. These inhibitory effects were significantly attenuated when SSc sera were preincubated with an anti-Slit2 blocking antibody. In vitro angiogenesis was severely compromised in SSc-MVECs and could be significantly ameliorated by Slit2 neutralisation or ROBO4 gene silencing. Slit2/Robo4 axis interfered with angiogenesis through the inhibition of Src kinase phosphorylation. CONCLUSIONS: In SSc, increased circulating levels of Slit2 and activation of the Slit2/Robo4 antiangiogenic axis may contribute to peripheral microangiopathy since the very early phase of the disease. PMID- 30021804 TI - Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. AB - OBJECTIVE: Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-kappa) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. METHODS: mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-kappa were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. RESULTS: IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8*10-04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-kappa is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-kappa, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-alpha and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-kappa or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. CONCLUSION: Collectively, our data identify IFN kappa as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-kappa is a potential novel target for UVB prophylaxis and CLE-directed therapy. PMID- 30021805 TI - Effects of Leisure-Time and Transport-Related Physical Activities on the Risk of Incident and Recurrent Myocardial Infarction and Interaction With Traffic-Related Air Pollution: A Cohort Study. AB - BACKGROUND: Physical activity enhances the uptake of air pollutants, possibly reducing its beneficial effects. We examined the effects of leisure-time and transport-related physical activities on the risk of myocardial infarction (MI), and whether potential benefits on MI are reduced by exposure to traffic-related air pollution. METHODS AND RESULTS: A group of 57 053 participants (50-65 years of age) from the Danish Diet, Cancer, and Health cohort reported physical activity at baseline (1993-1997) and were linked to registry data on hospital contacts and out-of-hospital deaths caused by MI, until December 2015. Nitrogen dioxide levels were estimated at participants' baseline residences. We used Cox regressions to associate participation in sports, cycling, walking, and gardening with incident and recurrent MI, and tested for interaction by nitrogen dioxide. Of 50 635 participants without MI at baseline, 2936 developed incident MI, and of 1233 participants with MI before baseline, 324 had recurring MI during follow-up. Mean nitrogen dioxide concentration was 18.7 MUg/m3 at baseline (1993-1997). We found inverse statistically significant associations between participation in sports (hazard ratio; 95% confidence interval: 0.85; 0.79-0.92), cycling (0.91; 0.84-0.98), gardening (0.87; 0.80-0.95), and incident MI, while the association with walking was statistically nonsignificant (0.95; 0.83-1.08). Recurrent MI was statistically nonsignificantly inversely associated with cycling (0.80; 0.63 1.02), walking (0.82, 0.57-1.16), and gardening (0.91; 0.71-1.18), and positively with sports (1.06; 0.83-1.35). There was no effect modification of the associations between physical activity and MI by nitrogen dioxide. CONCLUSIONS: Benefits of physical activity on both the incidence and the recurrence of MI are not reduced by exposure to high levels of air pollution. PMID- 30021808 TI - Recanalization in Cerebral Venous Thrombosis. AB - Background and Purpose- The role of recanalization of the occluded dural sinus or vein in the outcome of patients with cerebral venous thrombosis (CVT) is not established. We aimed to systematically review, in patients with CVT, (1) the recanalization rate and its association with (2) clinical outcome and (3) CVT recurrence. Methods- Systematic search in MEDLINE (Medical Literature Analysis and Retrieval System Online), Cochrane Library, and clinicaltrials.gov (inception to September 2017). We considered cohort studies reporting the recanalization rate in adult patients with CVT treated with anticoagulation. Reported rates of venous recanalization at the last follow-up, functional outcome defined using the modified Rankin scale at last follow-up dichotomized for favorable (0-1) and unfavorable (2-6) outcome, and recurrence rate of CVT according to recanalization status were extracted independently by 2 authors. Meta-analyses of proportions were performed using Freeman-Tukey double arcsine transformation. Functional outcomes according to the recanalization status were compared using meta-analysis and ordinal logistic regression. We conducted sensitivity analyses for time to assessment of recanalization and study quality. Results- Four hundred sixty-eight studies were identified, and 19 studies were included. (1) We found report of 694 patients with recanalization in the follow-up among 818 cases of CVT. The overall pooled proportion of patients achieving recanalization was 85% (95% confidence interval, 80-89; I2=58%). In studies with higher methodological quality, the recanalization rate was 77% (95% confidence interval, 70-82; I2=0%). (2) There was a significant increase in the chance of favorable outcome (modified Rankin scale, 0-1) in patients with recanalization with a pooled odds ratio of 3.3 (95% confidence interval, 1.2-8.9; I2=32%) in the random effects meta-analysis and a common odds ratio of 3.3 (95% confidence interval, 1.7-6.3) in the ordinal logistic regression. (3) Data on CVT recurrence according to recanalization was scarce. Conclusions- The overall rate of recanalization in patients receiving anticoagulation was 85%, but exclusion of severe patients from follow-up imaging is a plausible source of bias. Lack of venous recanalization was associated with worse clinical outcome. PMID- 30021806 TI - Short-Term E-Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice. AB - BACKGROUND: Cardiovascular disease is the main cause of death in the United States, with smoking being the primary preventable cause of premature death, and thrombosis being the main mechanism of cardiovascular mortality in smokers. Due to the perception that electronic/e-cigarettes are "safer/less harmful" than conventional cigarettes, their usage-among a variety of ages-has increased tremendously during the past decade. Notably, there are limited studies regarding the negative effects of e-cigarettes on the cardiovascular system, which is also the subject of significant debate. METHODS AND RESULTS: We employed a passive e VapeTM vapor inhalation system and developed an in vivo whole-body e-cigarette mouse exposure protocol that mimics real-life human exposure scenarios/conditions and investigated the effects of e-cigarettes and clean air on platelet function and thrombogenesis. Our results show that platelets from e-cigarette-exposed mice are hyperactive, with enhanced aggregation, dense and alpha granule secretion, activation of the alphaIIbbeta3 integrin, phosphatidylserine expression, and Akt and ERK activation, when compared with clean air-exposed platelets. E-cigarette exposed platelets were also found to be resistant to inhibition by prostacyclin, relative to clean air. Furthermore, the e-cigarette-exposed mice exhibited a shortened thrombosis occlusion and bleeding times. CONCLUSIONS: Taken together, our data demonstrate for the first time that e-cigarettes alter physiological hemostasis and increase the risk of thrombogenic events. This is attributable, at least in part, to the hyperactive state of platelets. Thus, the negative health consequences of e-cigarette exposure should not be underestimated and warrant further investigation. PMID- 30021809 TI - Thyroid hormones stimulate L-arginine transport in human endothelial cells. AB - Thyroid hormone activity is associated with L-arginine metabolism and nitric oxide (NO) production, which participate in the cardiovascular manifestations of thyroid disorders. L-arginine transporters play an important role in activating L arginine uptake and NO production. However, the effects of thyroid hormones on L arginine transporters in endothelial cells have not yet been evaluated. We measured L-arginine uptake, mRNA expression of L-arginine transporters, endothelial nitric oxide synthase (eNOS) mRNA and NO generation after the administration of T3, T4, and the T3 analog, 3,3',5-triiodothyroacetic acid TRIAC in human umbilical vein endothelial cells (HUVECs). We also analyzed the role of alphavbeta3 integrin and of phosphatidyl-inositol-3 kinase (PI3K), mitogen activated protein kinases (MAPKs: ERK1/2, p38 and SAPK-JNK) and intracellular calcium signaling pathways as underlying mechanisms. To this end, alphavbeta3 integrin was pharmacologically inhibited by tetraiodothyroacetic acid (TETRAC) or genetically blocked by silencing alphav mRNA, and PI3K, MAPKs and intracellular calcium by selective inhibitors. We found that thyroid hormones and the T3 analog TRIAC increased L-arginine uptake in HUVECs, the sodium-independent y+/CAT isoforms, except CAT2b, sodium-dependent y+L system and sodium-independent system b0,+L-arginine transporters, eNOS mRNA; and NO production. These effects were suppressed by alphavbeta3 integrin inhibition with TETRAC or alphav integrin downregulation or by PI3K, MAPK or intracellular Ca2+ signaling inhibitors. We report for the first time that activation of L-arginine uptake by thyroid hormones is related to an up-regulation of L-arginine transporters. This effect seems to be mediated by activation of alphavbeta3 integrin receptor and subsequent PI3K, MAPK and intracellular Ca2+ signaling pathways. PMID- 30021810 TI - Change in biomarkers of type-2 inflammation following severe exacerbations of asthma. AB - : We investigated the time course of change of type-2 asthma biomarkers after a severe asthma exacerbation. Blood eosinophils were lowest immediately after treatment was initiated (0.07 vs 0.33*109/L, p<0.001) while serum IgE levels were at their highest (339 vs 249 U/L, p<0.001). Fractional exhaled Nitric Oxide levels were lowest 2 weeks after treatment (23 vs 33 ppb, p=0.06) and serum periostin levels were lowest 1 week after treatment (45.9 vs 50.9 ng/mL, p<0.001). A delay of 4-8 weeks following a severe exacerbation is required if these biomarkers are used to guide the ongoing management of patients with asthma. TRIAL REGISTRATION NUMBER: Post-results; The Australia New Zealand Trial Registry, >ACTRN12614000443695. PMID- 30021807 TI - Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces. AB - BACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening. METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP (WASL) locus is associated with carotid-femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness. CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness. PMID- 30021811 TI - Expression network analysis reveals cord blood vitamin D-associated genes affecting risk of early life wheeze. AB - Cord blood 25-hydroxyvitamin D (25OHD) has been reported in association with risk of early life recurrent wheeze. In a subset of infants who participated in the Vitamin D Antenatal Asthma Reduction Trial, we demonstrated that higher cord blood 25OHD at birth (>31 ng/mL) was associated with a reduced risk of recurrent wheeze in the first year of life. We then identified a module of co-expressed genes associated with cord blood 25OHD levels >31 ng/mL. Genes in this module are involved in biological and immune pathways related to development and progression of asthma pathogenesis including the Notch1 and transforming growth factor-beta signalling pathways. PMID- 30021812 TI - Targeted therapy for the post-operative conjunctiva: SPARC silencing reduces collagen deposition. AB - BACKGROUND: To develop targeted antifibrotic therapy for glaucoma filtration surgery; this study determines the effectiveness of small interfering RNA (siRNA) to reduce in vivo secreted protein acidic and rich in cysteine (SPARC) expression using the mouse model of conjunctival scarring. METHODS: Experimental surgery was performed as described for the mouse model of conjunctival scarring. Scrambled (siScram) or Sparc (siSparc) siRNAs, loaded on layer-by-layer (LbL) nanoparticles, were injected into the conjunctiva immediately after surgery. Expression of Sparc, Col1a1, Fn1 and Mmp14 was measured by real-time PCR and immunoblotting on days 7 and 14 postsurgery. Live imaging of the operated eyes was performed using slit lamp, anterior segment-optical coherence tomography and confocal microscopy. Tissue pathology was evaluated by histochemical and immunofluorescent analyses of operated conjunctival cryosections. Tissue apoptosis was quantitated by annexin V assay. RESULTS : siSparc, delivered via expanded LbL nanoparticles, significantly inhibited Sparc transcription in both day 7 (2.04-fold) and day 14 (1.39-fold) treated tissues. Sparc suppression on day 7 was associated with a significant reduction of Col1a1 (2.52-fold), Fn1 (2.89-fold) and Mmp14 (2.23-fold) mRNAs. At the protein level, both SPARC and collagen 1A1 (COL1A1) were significantly reduced at both time points with siSparc treatment. Nanoparticles were visualised within cell-like structures by confocal microscopy, while overt tissue response or apoptosis was not observed. CONCLUSIONS : SPARC targeted therapy effectively reduced both SPARC and collagen production in the operated mouse conjunctiva. This proof-of-concept study suggests that targeted treatment of fibrosis in glaucoma surgery is safe and feasible, with the potential to extend to a range of potential genes associated with fibrosis. PMID- 30021814 TI - Ocular preservation with neoadjuvant vismodegib in patients with locally advanced periocular basal cell carcinoma. AB - BACKGROUND/AIMS: Locally advanced (T4 per American Joint Committee on Cancer (AJCC) 8th edition) periocular basal cell carcinoma (BCC) can lead to loss of the eye. We report the neoadjuvant use of vismodegib followed by surgery in patients with such lesions with eye preservation as primary goal. METHODS: This retrospective interventional study includes all patients with a T4 periocular BCC (per 8th edition AJCC for eyelid carcinoma) treated by the senior author between 2013 and 2017 with neoadjuvant vismodegib prior to definitive surgery. RESULTS: Eight patients had a T4 tumour. Six patients presented with recurrent disease. Indications for neoadjuvant treatment were an unresectable tumour in one patient, an attempt to avoid an orbital exenteration in six patients and an attempt to avoid disfiguring facial surgery in one patient. Patients were treated for a median of 14 months (range: 4-36 months). All patients underwent an eye-sparing surgery following neoadjuvant vismodegib and all final surgical margins were negative for tumour. Five patients had a complete response to vismodegib with no microscopic residual BCC found during surgery; three patients had a significant partial response with residual tumour found on pathology. At last follow-up, a mean of 18 (range: 6-43) months after surgery, all patients were off-vismodegib and alive without evidence of disease. CONCLUSIONS: Neoadjuvant vismodegib for locally advanced (T4) periocular BCC enabled an eye-sparing surgery in all patients in our cohort. Prolonged treatment was well tolerated by most patients. Over half of patients achieved a complete response with no residual microscopic disease. Careful long-term follow-up is needed to confirm long-term disease-free survival. PMID- 30021813 TI - Distinct clinical characteristics of paraneoplastic optic neuropathy. AB - OBJECTIVE: Paraneoplastic optic neuropathy (PON) is relatively uncommon, and the visual outcomes and prognosis of this disease have not been well documented. The aim of this study was to investigate the clinical features and prognosis of antibody-mediated PON. METHODS: Clinical data were retrospectively collected from hospitalised patients diagnosed with PON at the Neuro-Ophthalmology Department at the Chinese People's Liberation Army General Hospital from January 2015 to June 2017. RESULTS: A total of seven patients (four females and three males, 13 involved eyes) were included with a mean age of 56.28+/-11.32 years (36-70 years). Simultaneous or early sequential bilateral eye involvement (5/7, 71.4%) was common in the patients with PON. Severe vision loss (<=0.1) was seen in 76.9% (10/13) of the eyes. There were 13 eyes in the acute phase of the disease, and six eyes presented with optic disc oedema. All patients had definite evidence of paraneoplastic-associated antibodies (three with serum positive for antiamphilphysin, one for anti-PNMA2 (Ma2/Ta), one for anti-Yo, one for anti-Ma2 and one for anti-CV2). All of the serum samples were negative for myelin oligodendrocyte glycoprotein antibody and two patients companied with seropositive for the aquaporin-4 antibody. Five patients had history of primary malignancy, including thyroid cancer, type B thymoma, testicular seminoma, cervical cancer and lung carcinoma. Two patients had positive paraneoplastic syndrome antibodies (anti-Yo and antiamphiphysin), but the solid tumour had not been found through a PET scan. Visual acuity in 9/13 (69.2%) eyes was below 0.1, and all of the patients survived to the follow-up with no metastatic lesions. CONCLUSIONS: PON is relative rare, with a predominance of bilateral involvement and more with a poor visual prognosis. Paraneoplastic antibody testing can contribute to the diagnosis of PON, distinct from other types of optic neuropathies, which can help doctors to find the primary cancer earlier to guide further treatment. PMID- 30021815 TI - Incidence, management and outcome of raised intraocular pressure in childhood onset uveitis at a tertiary referral centre. AB - BACKGROUND/AIMS: To investigate the incidence, management and outcome of uveitis and raised intraocular pressure (IOP) in children treated at the Manchester Uveitis Clinic (MUC). METHODS: This was a retrospective, observational study of patients who presented with uveitis under the age of 16 to the MUC from July 2002 to June 2016. RESULTS: A total of 320 children were included in the study. Out of these, 55 (17.2%) patients (75 eyes) were found to have raised IOP requiring treatment. The mean age at diagnosis of uveitis and at first recorded raised IOP was 8.2+/-4.3 and 10.8+/-3.6 years, respectively. The pre-treatment IOP was 32.3+/-6.6 mm Hg and the IOP at the final visit was 15.5+/-3.7 mm Hg (median follow-up period, 43.7 months) on a median number of 0 medications. Twenty-eight eyes (37.3%) required glaucoma drainage surgery, and eight eyes (12.5%) had cyclodiode laser before this. Kaplan-Meier analysis showed that 11.5% of eyes required glaucoma surgery at 1 year after diagnosis of raised IOP, increasing to 50.0% by 5 years. The best-corrected visual acuity at diagnosis of uveitis was 0.26+/-0.42 logMAR, which remained stable at 0.28+/-0.65 logMAR at final follow up visit. Four eyes (5.3%) from four patients fulfilled the definition of blindness by the WHO criteria. The mean cup:disc ratio at final follow-up was 0.4. CONCLUSION: Our cohort of children with raised IOP appeared to have a good outcome overall through aggressive medical and surgical management. Regular long term follow-up is recommended, and early surgical intervention in eyes with uncontrolled IOP can prevent loss of vision. PMID- 30021816 TI - Peripapillary and parafoveal vascular network assessment by optical coherence tomography angiography in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders. AB - BACKGROUND/AIMS: Current understanding of the alterations in the retinal vascular network in neuromyelitis optica spectrum disorders (NMOSDs) is limited. We aim to assess the peripapillary and parafoveal vessel density in aquaporin-4 antibody positive NMOSD patients by optical coherence tomography (OCT) angiography. METHODS: A total of 55 aquaporin-4 antibody-positive NMOSD patients with or without a history of optic neuritis (ON) and 33 healthy controls underwent spectral domain OCT and OCT angiography. Clinical histories, Expanded Disability Status Scale score, visual functional system score (VFSS) and disease duration were collected. RESULTS: Peripapillary and parafoveal vessel density was significantly decreased in NMOSD eyes with or without a history of ON. The decrease in retinal vessel density could occur before ON and retinal nerve fibre layer (RNFL) atrophy. Peripapillary vessel density correlated well with the spectral domain OCT measurements and VFSS in NMOSD eyes with a history of ON. CONCLUSION: Subclinical primary retinal vasculopathy may occur in NMOSD prior to ON and RNFL atrophy. Peripapillary vessel density might be a sensitive predictor of visual outcomes in NMOSD patients with ON. PMID- 30021817 TI - Keratoprostheses in silicone oil-filled eyes: long-term outcomes. AB - PURPOSE: To analyse the functional and anatomical outcomes of different types of keratoprostheses in eyes with retained silicone oil following vitreoretinal surgery. METHODS: Retrospective chart review of patients operated with any type of permanent keratoprosthesis (Kpro) in silicone oil-filled eyes between March 2003 and June 2017 were analysed.. RESULTS: 40 silicone oil-filled eyes underwent keratoprostheses, of which 22 were type 1 and 18 were type 2 Kpros (Lucia variant nine, modified osteo odonto kerato prosthesis (MOOKP)-four, Boston type 2-three and osteoKpro-two) with a mean follow-up of 61.54 , 42.77, 45.25 , 25 and 37 months, respectively. Anatomic retention of the primary Kpro was noted in 33 eyes (82.5%). A best-corrected visual acuity of better than 20/200 and 20/400 was achieved in 26 (65%)+32 (80%) eyes. Retroprosthetic membrane (RPM) was the most common complication noted in 17 eyes ( 42.5% ). Perioptic graft melt was noted in 4 of 22 eyes of the type 1 Kpro ( 2 (10.5%) without associated ocular surface disorder (OSD)) and in 1 eye each of Boston and Lucia type 2 Kpro. Laminar resorption occurred in one eye each of the MOOKP and OKP groups. Endophthalmitis and glaucoma did not occur in any eye. CONCLUSION: Appropriately chosen keratoprosthesis is a viable option for visual rehabilitation in eyes post vitreoretinal surgery with retained silicone oil-induced keratopathy not amenable to conventional penetrating keratoplasty. Kpro melt among type 1 Kpro did not occur in 89.5% eyes without associated OSD (19 of 22 eyes), despite the lack of aqueous humour and presence of RPM (4 eyes), two factors considered to play a significant role in the causation of sterile melts. Of interest to note was the absence of infection in any of these eyes. The possible protective role of oil from endophthalmitis is interesting, though yet to be ascertained. PMID- 30021820 TI - Proof of Concept for MBT ASTRA, a Rapid Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS)-Based Method To Detect Caspofungin Resistance in Candida albicans and Candida glabrata. AB - The incidence of candidemia caused by Candida albicans and Candida glabrata is constantly increasing and is accompanied by the rising use of the few available antifungals. The widespread use of echinocandins and azoles for the treatment of invasive candidemia has enhanced the development of antifungal resistance, resulting in an increasing health care problem. Hence, the rapid detection of resistant strains is required. This study aimed to evaluate the detection of C. albicans and C. glabrata strains resistant to caspofungin by the matrix-assisted laser desorption ionization Biotyper antibiotic susceptibility test rapid assay (MBT ASTRA). This novel semiquantitative technique facilitates the detection of caspofungin-resistant strains within 6 h. MBT ASTRA results were compared to the data obtained by the use of Clinical and Laboratory Standards Institute (CLSI) guidelines. Clinical isolates of C. albicans (n = 58) and C. glabrata (n = 57) were analyzed by MBT ASTRA and the CLSI microdilution method. Antifungal susceptibility testing against caspofungin by the CLSI microdilution method classified the C. albicans isolates into 36 susceptible and 22 resistant strains and the C. glabrata isolates into 5 susceptible, 33 resistant, and 19 intermediate strains. For C. albicans, the comparison of MBT ASTRA and the CLSI method revealed an excellent categorical agreement of 100%. A sensitivity and a specificity between MBT ASTRA and the CLSI microdilution method of 94% and 80%, respectively, were detected for C. glabrata strains, based on categorical agreement. In conclusion, the results obtained by MBT ASTRA indicate that this is a very promising approach for the rapid detection of Candida isolates resistant to caspofungin. PMID- 30021819 TI - Cost of Dialysis Therapy by Modality in Manitoba. AB - BACKGROUND AND OBJECTIVES: The prevalence of ESKD is increasing worldwide. Treating ESKD is disproportionately costly in comparison with its prevalence, mostly due to the direct cost of dialysis therapy. Here, we aim to provide a contemporary cost description of dialysis modalities, including facility-based hemodialysis, peritoneal dialysis, and home hemodialysis, provided with conventional dialysis machines and the NxStage System One. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We constructed a cost-minimization model from the perspective of the Canadian single-payer health care system including all costs related to dialysis care. The labor component of costs consisted of a breakdown of activity-based per patient direct labor requirements. Other costs were taken from statements of operations for the kidney program at Seven Oaks General Hospital (Winnipeg, Canada). All costs are reported in Canadian dollars. RESULTS: Annual maintenance expenses were estimated as $64,214 for in-center facility hemodialysis, $43,816 for home hemodialysis with the NxStage System One, $39,236 for home hemodialysis with conventional dialysis machines, and $38,658 for peritoneal dialysis. Training costs for in-center facility hemodialysis, home hemodialysis with the NxStage System One, home hemodialysis with conventional dialysis machines, and peritoneal dialysis are estimated as $0, $16,143, $24,379, and $7157, respectively. The threshold point to achieve cost neutrality was determined to be 9.7 months from in-center hemodialysis to home hemodialysis with the NxStage System One, 12.6 months from in-center hemodialysis to home hemodialysis with conventional dialysis machines, and 3.2 months from in-center hemodialysis to peritoneal dialysis. CONCLUSIONS: Home modalities have lower maintenance costs, and beyond a short time horizon, they are most cost efficient when considering their incremental training expenses. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2018_07_18_CJASNPodcast_18_8_F.mp3. PMID- 30021821 TI - Subpopulation Primers Essential for Exhaustive Detection of Diverse Hemagglutinin Genes of H5 Subtype Avian Influenza Viruses by Loop-Mediated Isothermal Amplification Method. AB - Loop-mediated isothermal amplification (LAMP) is a potential screening test for avian influenza (AI), but its narrow detection spectrum limits its applications. To improve this narrow detection spectrum, 3 types of primers were compared for detection of diverse H5 subtype hemagglutinin (HA) genes. Four and 6 genes, of 10 genetically different H5 HA genes tested, were detected with S primers specific for A/duck/Tsukuba/9/2005 (H5N2) and with M primers (which contained mixed bases), respectively. In contrast, all 10 HA genes became positive with population primers (P primers) (a mixture of primers designed for each subpopulation of 2,202 HA genes). Our study indicated that the P primers for the forward inner primer (FIP) and backward inner primer (BIP) sites were essential for exhaustive detection, whereas those for the F3, forward loop (FL), backward loop (BL), and B3 sites were exchangeable with M primers. A base mismatch experiment demonstrated that HA genes with <=2 base mismatches per primer site and <=10 base mismatches per HA gene were amplifiable. Reverse transcription-LAMP was broadly reactive, specific for H5 subtype HA genes, and applicable to field samples, with the sensitivity of real-time PCR. The in silico analysis suggested that most H5 HA genes (2,586 positive genes/2,588 genes tested) registered in the GenBank database might be amplifiable. These results indicate that the use of subpopulation primers in LAMP allows exhaustive detection of diverse HA genes and H5 LAMP can be used as a reliable AI screening test in general diagnostic laboratories. PMID- 30021823 TI - Bronchoalveolar Lavage Fluid Cytology in Culture-Documented Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases: Analysis of 67 Episodes. AB - There is a paucity of studies on the yield of Gomori-methenamine-silver (GMS) staining in bronchoalveolar lavage (BAL) fluid cytology and its comparison with fluorescent dye staining for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with hematologic malignancies. To that end, we analyzed the yield of direct fungal visualization in BAL fluid cytology with GMS staining, in a series of culture-positive IPA cases in 67 patients with hematologic malignancies, and we compared the results with those of direct examination with calcofluor white staining and BAL fluid galactomannan assays, when available. GMS staining in BAL fluid cytology was positive in 42% of the 67 cases and revealed coinfections in 7 cases. In contrast, only 2/67 (3.6%) BAL fluid samples were positive in direct smears stained with the fluorescent dye calcofluor white. Positive GMS staining results were significantly more frequent in IPA cases with cavitary lesions and IPA cases caused by >1 Aspergillus species, but the proportions of positive cytology results among Aspergillus species were not different. PMID- 30021822 TI - Yellow Fever Virus: Diagnostics for a Persistent Arboviral Threat. AB - Yellow fever (YF) is the prototypical hemorrhagic fever and results from infection with yellow fever virus (YFV), which is endemic to regions of Africa and South America. Despite the availability of an effective vaccine, YFV continues to cause disease throughout regions where it is endemic, including intermittent large outbreaks among undervaccinated populations. A number of diagnostic methods and assays have been described for the detection of YFV infection, including viral culture, molecular testing, serology, and antigen detection. Commercial diagnostics are not widely available, and testing is generally performed at a small number of reference laboratories. The goal of this article, therefore, is to review available clinical diagnostics for YFV, which may not be familiar to many practitioners outside areas where it is endemic. Additionally, we identify gaps in our current knowledge about YF that pertain to diagnosis and describe interventions that may improve YFV detection. PMID- 30021818 TI - Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. AB - SUMMARYTuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium. PMID- 30021825 TI - Laboratory Evaluation of a Commercially Available Rapid Syphilis Test. AB - Serological diagnosis of syphilis depends on assays that detect treponemal and nontreponemal antibodies. Laboratory certification and trained personnel are needed to perform most of these tests, while high costs and long turnaround time can hinder treatment initiation or linkage to care. A rapid treponemal syphilis test (RST) that is simple to perform, accessible, and inexpensive would be ideal. The Syphilis Health Check (SHC) assay is the only Food and Drug Administration (FDA)-cleared and Clinical Laboratory Improvement Amendments (CLIA)-waived RST in the United States. In this study, 1,406 archived human serum samples were tested using SHC and traditional treponemal and nontreponemal assays. Rapid test results were compared with treponemal data alone and with a laboratory test panel consensus defined as being reactive by both treponemal and nontreponemal assays for a given specimen, or nonreactive by both types of assays. The sensitivity and specificity of the SHC assay compared with treponemal tests alone were 88.7% (95% confidence interval [CI], 86.2 to 90.0%) and 93.1% (95% CI, 90.0 to 94.9%), respectively, while comparison with the laboratory test panel consensus showed 95.7% (95% CI, 93.6 to 97.2%) sensitivity and 93.2% (95% CI, 91.0 to 95.1%) specificity. The data were further stratified based on age, sex, pregnancy, and HIV status. The sensitivity and specificity of the SHC assay ranged from 66.7% (95% CI, 46.0 to 83.5%) to 91.7% (95% CI, 87.7 to 94.7%) and 88% (95% CI, 68.8 to 97.5%) to 100% (95% CI, 47.8 to 100%), respectively, across groups compared to traditional treponemal assays, generally increasing for all groups except the HIV positive (HIV+) population when factoring in the laboratory test panel consensus. These data contribute to current knowledge of the SHC assay performance for distinct populations and may guide use in various settings. PMID- 30021824 TI - Evaluation of a Culture-Dependent Algorithm and a Molecular Algorithm for Identification of Shigella spp., Escherichia coli, and Enteroinvasive E. coli. AB - Identification of Shigella spp., Escherichia coli, and enteroinvasive E. coli (EIEC) is challenging because of their close relatedness. Distinction is vital, as infections with Shigella spp. are under surveillance of health authorities, in contrast to EIEC infections. In this study, a culture-dependent identification algorithm and a molecular identification algorithm were evaluated. Discrepancies between the two algorithms and original identification were assessed using whole genome sequencing (WGS). After discrepancy analysis with the molecular algorithm, 100% of the evaluated isolates were identified in concordance with the original identification. However, the resolution for certain serotypes was lower than that of previously described methods and lower than that of the culture-dependent algorithm. Although the resolution of the culture-dependent algorithm is high, 100% of noninvasive E. coli, Shigella sonnei, and Shigella dysenteriae, 93% of Shigella boydii and EIEC, and 85% of Shigella flexneri isolates were identified in concordance with the original identification. Discrepancy analysis using WGS was able to confirm one of the used algorithms in four discrepant results. However, it failed to clarify three other discrepant results, as it added yet another identification. Both proposed algorithms performed well for the identification of Shigella spp. and EIEC isolates and are applicable in low resource settings, in contrast to previously described methods that require WGS for daily diagnostics. Evaluation of the algorithms showed that both algorithms are capable of identifying Shigella species and EIEC isolates. The molecular algorithm is more applicable in clinical diagnostics for fast and accurate screening, while the culture-dependent algorithm is more suitable for reference laboratories to identify Shigella spp. and EIEC up to the serotype level. PMID- 30021826 TI - Monitoring Viral Genetic Variation as a Tool To Improve Molecular Diagnostics for Mumps Virus. AB - Here, we report how the analysis of viral genetic variation using next-generation sequencing (NGS) can be used as a tool to improve mumps virus diagnostics. Analysis of NGS data from recently circulating mumps virus isolates allowed optimization of the current mumps virus real-time reverse transcription-PCR (RT PCR) by primer and probe modifications due to nucleotide variations. The modified assay showed a higher efficiency and sensitivity than the previously used CDC protocol for the detection of currently circulating mumps virus strains and could therefore offer better support for outbreak control. The NGS sequence data were also used to make predictions of changes in the hemagglutinin-neuraminidase protein structure that could explain possible immune escape mechanisms. PMID- 30021827 TI - The Tail Wagging the Dog (or the Challenges Faced When the Financing of Medicine Gets Ahead of the Science of Medicine). AB - In their article in this issue of the Journal of Clinical Microbiology, S. R. Dominguez et al. (J Clin Microbiol 56:e00632-18, 2018, https://doi.org/10.1128/JCM.00632-18) describe the performance of PCR detection of herpes simplex virus (HSV) DNA versus viral culture in skin and mucosal samples from 7 neonates with HSV disease. This is a significant contribution to our understanding of the optimal diagnostic approach in babies being evaluated for neonatal HSV disease. Many diagnostic laboratories already have made the change to molecular diagnostics for skin and mucosal swab testing, however, in large part due to the labor costs associated with viral cultures. Thus, important studies such as this one are being conducted to support a decision that has already been made in many locations on mostly economic grounds. This small case series supports the decision to use molecular testing for samples from skin and mucosal sites, but larger studies are needed to more fully define the performance characteristics of PCR in this population. Since a false-positive result would commit a baby to months of management that would be unnecessary and have potential harm, it is critical to base diagnostic decision making on data that support the use of a specific test. PMID- 30021828 TI - Detection of (1,3)-beta-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis. AB - The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-beta-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of >=80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis. PMID- 30021830 TI - A Bayesian Decision Theory Approach for Genomic Selection. AB - Plant and animal breeders are interested in selecting the best individuals from a candidate set for the next breeding cycle. In this paper, we propose a formal method under the Bayesian decision theory framework to tackle the selection problem based on genomic selection (GS) in single- and multi-trait settings. We proposed and tested three univariate loss functions (Kullback-Leibler, KL; Continuous Ranked Probability Score, CRPS; Linear-Linear loss, LinLin) and their corresponding multivariate generalizations (Kullback-Leibler, KL; Energy Score, EnergyS; and the Multivariate Asymmetric Loss Function, MALF). We derived and expressed all the loss functions in terms of heritability and tested them on a real wheat dataset for one cycle of selection and in a simulated selection program. The performance of each univariate loss function was compared with the standard method of selection (Std) that does not use loss functions. We compared the performance in terms of the selection response and the decrease in the population's genetic variance during recurrent breeding cycles. Results suggest that it is possible to obtain better performance in a long-term breeding program using the single-trait scheme by selecting 30% of the best individuals in each cycle but not by selecting 10% of the best individuals. For the multi-trait approach, results show that the population mean for all traits under consideration had positive gains, even though two of the traits were negatively correlated. The corresponding population variances were not statistically different from the different loss function during the 10th selection cycle. Using the loss function should be a useful criterion when selecting the candidates for selection for the next breeding cycle. PMID- 30021829 TI - Event Analysis: Using Transcript Events To Improve Estimates of Abundance in RNA seq Data. AB - Alternative splicing leverages genomic content by allowing the synthesis of multiple transcripts and, by implication, protein isoforms, from a single gene. However, estimating the abundance of transcripts produced in a given tissue from short sequencing reads is difficult and can result in both the construction of transcripts that do not exist, and the failure to identify true transcripts. An alternative approach is to catalog the events that make up isoforms (splice junctions and exons). We present here the Event Analysis (EA) approach, where we project transcripts onto the genome and identify overlapping/unique regions and junctions. In addition, all possible logical junctions are assembled into a catalog. Transcripts are filtered before quantitation based on simple measures: the proportion of the events detected, and the coverage. We find that mapping to a junction catalog is more efficient at detecting novel junctions than mapping in a splice aware manner. We identify 99.8% of true transcripts while iReckon identifies 82% of the true transcripts and creates more transcripts not included in the simulation than were initially used in the simulation. Using PacBio Iso seq data from a mouse neural progenitor cell model, EA detects 60% of the novel junctions that are combinations of existing exons while only 43% are detected by STAR. EA further detects ~5,000 annotated junctions missed by STAR. Filtering transcripts based on the proportion of the transcript detected and the number of reads on average supporting that transcript captures 95% of the PacBio transcriptome. Filtering the reference transcriptome before quantitation, results in is a more stable estimate of isoform abundance, with improved correlation between replicates. This was particularly evident when EA is applied to an RNA seq study of type 1 diabetes (T1D), where the coefficient of variation among subjects (n = 81) in the transcript abundance estimates was substantially reduced compared to the estimation using the full reference. EA focuses on individual transcriptional events. These events can be quantitate and analyzed directly or used to identify the probable set of expressed transcripts. Simple rules based on detected events and coverage used in filtering result in a dramatic improvement in isoform estimation without the use of ancillary data (e.g., ChIP, long reads) that may not be available for many studies. PMID- 30021832 TI - Bilateral blood pressure differential as a clinical marker for acute aortic dissection in the emergency department. AB - INTRODUCTION: Interarm systolic BP differential is a classic sign of acute aortic dissection (AAD). All previous studies looking at the association of BP differential with AAD combine systolic BP differential >20 mm Hg with pulse deficit. Our aim was to assess the association of systolic BP differential with AAD, and its role in predicting AAD in the context of other signs and symptoms. METHODS: Historical matched case-control study using patient data collected between 2002 and 2014: participants were adults >18 years old with a bilateral BP measurement presenting to two tertiary care EDs or one regional cardiac referral centre in Canada. Cases were patients with diagnosed AAD; controls were those with a triage diagnosis of truncal pain (<14 days) and an absence of a clear diagnosis on basic investigation. Cases and controls were matched in a 1:1 ratio by sex and age. Bilateral BP differential and pulse deficit were compared between groups. RESULTS: A total of 222 patients (111 cases and 111 controls) were analysed. On univariate analysis systolic BP differential >20 mm Hg (OR 2.7, 95% CI 1.39 to 5.25) was significantly associated with AAD. Pulse deficit (diagnostic OR (DOR) 28.9) in isolation had better diagnostic accuracy than systolic BP differential >20 mm Hg in isolation (DOR 2.71) or combined with systolic BP differential >20 mm Hg (DOR 4.2). CONCLUSION: Bilateral systolic BP differentials >20 mm Hg are associated with non-traumatic AAD. However, the poor diagnostic accuracy and potential variability in measurement limits its clinical usefulness. PMID- 30021833 TI - Ultrasound-guided intravenous catheter survival impacted by amount of catheter residing in the vein. AB - OBJECTIVE: Ultrasound (US)-guided peripheral IVs have a high failure rate. We explore the relationship between the quantity of catheter residing within the vein and the functionality of the catheter over time. METHODS: This was a prospective, observational single-site study. Adult ED patients with US-guided IVs had the catheter visualised under ultrasound post-placement. IV placement time and catheter length residing in the vein was obtained. Exclusions included catheter not visualised, patient discharged from ED unless IV failed, <24 hour hospitalisation unless IV failed or patient self-removed IV.Inpatient follow-up occurred within 24, 48 and 72 hours from the IV placement time. Catheter functionality was noted. If the catheter failed, the time and reason for failure was documented. RESULTS: 113 patients were enrolled; 27 were excluded. Of the 86 study subjects, 29 (33.7%) patients' IVs failed and 57 (66.3%) remained functional. Median time to IV failure was 15.6 hours. 100% of IVs failed when <30% of the catheter was in the vein; 32.4% of IVs failed when 30%-64% of the catheter was in the vein; no IVs failed when >=65% of the catheter was in the vein (p<0.0002). The HR was 0.71 (95% CI 0.60 to 0.83), and for every 5% increase of catheter in vein, the hazard of the IV failing decreases by 29% (p<0.0001). CONCLUSION: The quantity of catheter residing in the vein is a key predictor of long-term functionality of US-guided IVs and is strongly associated with the hazard of failure within 72 hours. Catheter failure is high when <30% of the catheter resided in the vein. Optimum catheter survival occurs when >=65% of the catheter is placed in the vein. PMID- 30021831 TI - Identification of the Novel Nup188-brr7 Allele in a Screen for Cold-Sensitive mRNA Export Mutants in Saccharomyces cerevisiae. AB - The maturation and export of mRNA from the nucleus through the nuclear pore complex is critical for maintaining an appropriate proteome in all eukaryotic cells. Here we summarize a previously unpublished screen in S. cerevisiae that utilized an established dT50 in situ hybridization assay to identify cold sensitive mutants that accumulated bulk poly A RNA in the nucleus. The screen identified seven mutants in six complementation groups, including the brr6-1 strain that we described previously. In addition to brr6-1, we identified novel alleles of the key transport gene GLE1 and NUP188, a component of the Nic96 nucleoporin complex. Notably, we show that the nup188-brr7 allele causes defects in select protein import pathways as well as mRNA export. Given recent structural and functional evidence linking the Nic96 complex to transport components, this mutant may be particularly useful to the transport community. PMID- 30021834 TI - Structural basis for specific inhibition of the highly sensitive ShHTL7 receptor. AB - Striga hermonthica is a root parasitic plant that infests cereals, decimating yields, particularly in sub-Saharan Africa. For germination, Striga seeds require host-released strigolactones that are perceived by the family of HYPOSENSITIVE to LIGHT (ShHTL) receptors. Inhibiting seed germination would thus be a promising approach for combating Striga However, there are currently no strigolactone antagonists that specifically block ShHTLs and do not bind to DWARF14, the homologous strigolactone receptor of the host. Here, we show that the octyl phenol ethoxylate Triton X-100 inhibits S. hermonthica seed germination without affecting host plants. High-resolution X-ray structures reveal that Triton X-100 specifically plugs the catalytic pocket of ShHTL7. ShHTL7-specific inhibition by Triton X-100 demonstrates the dominant role of this particular ShHTL receptor for Striga germination. Our structural analysis provides a rationale for the broad specificity and high sensitivity of ShHTL7, and reveals that strigolactones trigger structural changes in ShHTL7 that are required for downstream signaling. Our findings identify Triton and the related 2-[4-(2,4,4-trimethylpentan-2 yl)phenoxy]acetic acid as promising lead compounds for the rational design of efficient Striga-specific herbicides. PMID- 30021835 TI - Chemical and genetic control of IFNgamma-induced MHCII expression. AB - The cytokine interferon-gamma (IFNgamma) can induce expression of MHC class II (MHCII) on many different cell types, leading to antigen presentation to CD4+ T cells and immune activation. This has also been linked to anti-tumour immunity and graft-versus-host disease. The extent of MHCII upregulation by IFNgamma is cell type-dependent and under extensive control of epigenetic regulators and signalling pathways. Here, we identify novel genetic and chemical factors that control this form of MHCII expression. Loss of the oxidative stress sensor Keap1, autophagy adaptor p62/SQSTM1, ubiquitin E3-ligase Cullin-3 and chromatin remodeller BPTF impair IFNgamma-mediated MHCII expression. A similar phenotype is observed for arsenite, an oxidative stressor. Effects of the latter can be reversed by the inhibition of HDAC1/2, linking oxidative stress conditions to epigenetic control of MHCII expression. Furthermore, dimethyl fumarate, an antioxidant used for the treatment of several autoimmune diseases, impairs the IFNgamma response by manipulating transcriptional control of MHCII We describe novel pathways and drugs related to oxidative conditions in cells impacting on IFNgamma-mediated MHCII expression, which provide a molecular basis for the understanding of MHCII-associated diseases. PMID- 30021837 TI - A variable undecad repeat domain in cavin1 regulates caveola formation and stability. AB - Caveolae are plasma membrane invaginations involved in transport, signalling and mechanical membrane sensing in metazoans. Their formation depends upon multiple interactions between membrane-embedded caveolins, lipids and cytosolic cavin proteins. Of the four cavin family members, only cavin1 is strictly required for caveola formation. Here, we demonstrate that an eleven residue (undecad) repeat sequence (UC1) exclusive to cavin1 is essential for caveolar localization and promotes membrane remodelling through binding to phosphatidylserine. In the notochord of mechanically stimulated zebrafish embryos, the UC1 domain is required for caveolar stability and resistance to membrane stress. The number of undecad repeats in the cavin1 UC1 domain varies throughout evolution, and we find that an increased number also correlates with increased caveolar stability. Lastly, we show that the cavin1 UC1 domain induces dramatic remodelling of the plasma membrane when grafted into cavin2 suggesting an important role in membrane sculpting. Overall, our work defines a novel conserved cavin1 modular domain that controls caveolar assembly and stability. PMID- 30021836 TI - Sirt1 protects from K-Ras-driven lung carcinogenesis. AB - The NAD+-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-RasG12V driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs. PMID- 30021838 TI - Regulation of monoamine oxidase A (MAO-A) expression, activity, and function in IL-13-stimulated monocytes and A549 lung carcinoma cells. AB - Monoamine oxidase A (MAO-A) is a mitochondrial flavoenzyme implicated in the pathogenesis of atherosclerosis and inflammation and also in many neurological disorders. MAO-A also has been reported as a potential therapeutic target in prostate cancer. However, the regulatory mechanisms controlling cytokine-induced MAO-A expression in immune or cancer cells remain to be identified. Here, we show that MAO-A expression is co-induced with 15-lipoxygenase (15-LO) in interleukin 13 (IL-13)-activated primary human monocytes and A549 non-small cell lung carcinoma cells. We present evidence that MAO-A gene expression and activity are regulated by signal transducer and activator of transcription 1, 3, and 6 (STAT1, STAT3, and STAT6), early growth response 1 (EGR1), and cAMP-responsive element binding protein (CREB), the same transcription factors that control IL-13 dependent 15-LO expression. We further established that in both primary monocytes and in A549 cells, IL-13-stimulated MAO-A expression, activity, and function are directly governed by 15-LO. In contrast, IL-13-driven expression and activity of MAO-A was 15-LO-independent in U937 promonocytic cells. Furthermore, we demonstrate that the 15-LO-dependent transcriptional regulation of MAO-A in response to IL-13 stimulation in monocytes and in A549 cells is mediated by peroxisome proliferator-activated receptor gamma (PPARgamma) and that signal transducer and activator of transcription 6 (STAT6) plays a crucial role in facilitating the transcriptional activity of PPARgamma. We further report that the IL-13-STAT6-15-LO-PPARgamma axis is critical for MAO-A expression, activity, and function, including migration and reactive oxygen species generation. Altogether, these results have major implications for the resolution of inflammation and indicate that MAO-A may promote metastatic potential in lung cancer cells. PMID- 30021839 TI - EDEM1's mannosidase-like domain binds ERAD client proteins in a redox-sensitive manner and possesses catalytic activity. AB - Endoplasmic reticulum (ER) degradation-enhancing alpha-mannosidase-like 1 protein (EDEM1) is a protein quality control factor that was initially proposed to recognize N-linked glycans on misfolded proteins through its mannosidase-like domain (MLD). However, recent studies have demonstrated that EDEM1 binds to some misfolded proteins in a glycan-independent manner, suggesting a more complex binding landscape for EDEM1. In this study, we have identified a thiol-dependent substrate interaction between EDEM1 and the alpha1-antitrypsin ER-associated protein degradation (ERAD) clients Z and NHK, specifically through the single Cys residue on Z/NHK (Cys256), required for binding under stringent detergent conditions. In addition to the thiol-dependent interaction, the presence of weaker protein-protein interactions was confirmed, suggestive of bipartite client binding properties. About four reactive thiols on EDEM1 were identified and were not directly responsible for the observed redox-sensitive binding by EDEM1. Moreover, a protein construct comprising the EDEM1 MLD had thiol-dependent binding properties along with its active glycan-trimming activities. Lastly, we identified an additional intrinsically disordered region (IDR) located at the C terminus of EDEM1 in addition to its previously identified N-terminal IDR. We also determined that both IDRs are required for binding to the ERAD component ERdj5 as an interaction with ERdj5 was not observed with the MLD alone. Together, our findings indicate that EDEM1 employs different binding modalities to interact with ERAD clients and ER quality control (ERQC) machinery partners and that some of these properties are shared with its homologues EDEM2 and EDEM3. PMID- 30021840 TI - Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae. AB - Stress-induced strand breaks in rRNA have been observed in many organisms, but the mechanisms by which they originate are not well-understood. Here we show that a chemical rather than an enzymatic mechanism initiates rRNA cleavages during oxidative stress in yeast (Saccharomyces cerevisiae). We used cells lacking the mitochondrial glutaredoxin Grx5 to demonstrate that oxidant-induced cleavage formation in 25S rRNA correlates with intracellular iron levels. Sequestering free iron by chemical or genetic means decreased the extent of rRNA degradation and relieved the hypersensitivity of grx5Delta cells to the oxidants. Importantly, subjecting purified ribosomes to an in vitro iron/ascorbate reaction precisely recapitulated the 25S rRNA cleavage pattern observed in cells, indicating that redox activity of the ribosome-bound iron is responsible for the strand breaks in the rRNA. In summary, our findings provide evidence that oxidative stress-associated rRNA cleavages can occur through rRNA strand scission by redox-active, ribosome-bound iron that potentially promotes Fenton reaction induced hydroxyl radical production, implicating intracellular iron as a key determinant of the effects of oxidative stress on ribosomes. We propose that iron binding to specific ribosome elements primes rRNA for cleavages that may play a role in redox-sensitive tuning of the ribosome function in stressed cells. PMID- 30021841 TI - Angiopoietin-like 4 promotes the intracellular cleavage of lipoprotein lipase by PCSK3/furin in adipocytes. AB - Lipoprotein lipase (LPL) catalyzes the breakdown of circulating triglycerides in muscle and fat. LPL is inhibited by several proteins, including angiopoietin-like 4 (ANGPTL4), and may be cleaved by members of the proprotein convertase subtilisin/kexin (PCSK) family. Here, we aimed to investigate the cleavage of LPL in adipocytes by PCSKs and study the potential involvement of ANGPTL4. A substantial portion of LPL in mouse and human adipose tissue was cleaved into N- and C-terminal fragments. Treatment of different adipocytes with the PCSK inhibitor decanoyl-RVKR-chloromethyl ketone markedly decreased LPL cleavage, indicating that LPL is cleaved by PCSKs. Silencing of Pcsk3/furin significantly decreased LPL cleavage in cell culture medium and lysates of 3T3-L1 adipocytes. Remarkably, PCSK-mediated cleavage of LPL in adipocytes was diminished by Angptl4 silencing and was decreased in adipocytes and adipose tissue of Angptl4-/- mice. Differences in LPL cleavage between Angptl4-/- and WT mice were abrogated by treatment with decanoyl-RVKR-chloromethyl ketone. Induction of ANGPTL4 in adipose tissue during fasting enhanced PCSK-mediated LPL cleavage, concurrent with decreased LPL activity, in WT but not Angptl4-/- mice. In adipocytes, after removal of cell surface LPL by heparin, levels of N-terminal LPL were still markedly higher in WT compared with Angptl4-/- adipocytes, suggesting that stimulation of PCSK-mediated LPL cleavage by ANGPTL4 occurs intracellularly. Finally, treating adipocytes with insulin increased full-length LPL and decreased N-terminal LPL in an ANGPTL4-dependent manner. In conclusion, ANGPTL4 promotes PCSK-mediated intracellular cleavage of LPL in adipocytes, likely contributing to regulation of LPL in adipose tissue. Our data provide further support for an intracellular action of ANGPTL4 in adipocytes. PMID- 30021843 TI - Polyploidy in tissue homeostasis and regeneration. AB - Polyploid cells, which contain multiple copies of the typically diploid genome, are widespread in plants and animals. Polyploidization can be developmentally programmed or stress induced, and arises from either cell-cell fusion or a process known as endoreplication, in which cells replicate their DNA but either fail to complete cytokinesis or to progress through M phase entirely. Polyploidization offers cells several potential fitness benefits, including the ability to increase cell size and biomass production without disrupting cell and tissue structure, and allowing improved cell longevity through higher tolerance to genomic stress and apoptotic signals. Accordingly, recent studies have uncovered crucial roles for polyploidization in compensatory cell growth during tissue regeneration in the heart, liver, epidermis and intestine. Here, we review current knowledge of the molecular pathways that generate polyploidy and discuss how polyploidization is used in tissue repair and regeneration. PMID- 30021844 TI - Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk? AB - In vitro assays are commonly used during drug discovery to try to decrease the risk of idiosyncratic drug-induced liver injury (iDILI). But how effective are they at predicting risk? One of the most widely used methods evaluates cell cytotoxicity. Cytotoxicity assays that used cell lines that are very different from normal hepatocytes, and high concentrations of drug, were not very accurate at predicting idiosyncratic drug reaction risk. Even cytotoxicity assays that use more biologically normal cells resulted in many false-positive and false-negative results. Assays that quantify reactive metabolite formation, mitochondrial injury, and bile salt export pump (BSEP) inhibition have also been described. Although evidence suggests that reactive metabolite formation and BSEP inhibition can play a role in the mechanism of iDILI, these assays are not very accurate at predicting risk. In contrast, inhibition of the mitochondrial electron transport chain appears not to play an important role in the mechanism of iDILI, although other types of mitochondrial injury may do so. It is likely that there are many additional mechanisms by which drugs can cause iDILI. However, simply measuring more parameters is unlikely to provide better predictive assays unless those parameters are actually involved in the mechanism of iDILI. Hence, a better mechanistic understanding of iDILI is required; however, mechanistic studies of iDILI are very difficult. There is substantive evidence that most iDILI is immune mediated; therefore, the most accurate assays may involve those that determine immune responses to drugs. New methods to manipulate immune tolerance may greatly facilitate development of more suitable methods. PMID- 30021845 TI - Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence - Prospective Data from the Women's Health Study. AB - Background -Despite strong and consistent prospective associations of elevated low-density lipoprotein-cholesterol (LDL-C) concentration with incident coronary and cerebrovascular disease (CCVD), data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle concentration (LDL-P), rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein-cholesterol (HDL-C) may be the primary lipid driver of PAD risk. Methods -The study population was a prospective cohort study of 27,888 women >=45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations as well as nuclear magnetic resonance (NMR) spectroscopy-derived lipoprotein measures were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization. Results -In age-adjusted analyses, while LDL-C was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very low-density lipoprotein particle subclasses (VLDL-P), increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle concentration (HDL-P) (all P for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (HRadj 2.03; 95% CI, 1.14 to 3.59), small LDL-P [HRadj 2.17 (1.10 to 4.27)], very large VLDL-P (HRadj 1.68 (1.06 to 2.66)], medium VLDL-P (HRadj 1.98 (1.15 to 3.41)], and TC:HDL-C [HRadj, 3.11 (1.67 to 5.81)]. HDL was inversely associated with risk; HRadj for extreme tertiles of HDL-C and HDL-P were 0.30 (P-trend <0.0001) and 0.29 (P-trend <0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident CCVD. Finally, the addition of LDL-P and HDL-P to TC:HDL-C measures identified women at heightened PAD risk. Conclusions -In this prospective study, NMR-derived measures of LDL particle concentration, but not LDL-C, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and NMR-derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to CCVD. Clinical Trial Registration -URL: http://clinicaltrials.gov Unique Identifier: NCT00000479. PMID- 30021842 TI - SOX9 is dispensable for the initiation of epigenetic remodeling and the activation of marker genes at the onset of chondrogenesis. AB - SOX9 controls cell lineage fate and differentiation in major biological processes. It is known as a potent transcriptional activator of differentiation specific genes, but its earliest targets and its contribution to priming chromatin for gene activation remain unknown. Here, we address this knowledge gap using chondrogenesis as a model system. By profiling the whole transcriptome and the whole epigenome of wild-type and Sox9-deficient mouse embryo limb buds, we uncover multiple structural and regulatory genes, including Fam101a, Myh14, Sema3c and Sema3d, as specific markers of precartilaginous condensation, and we provide evidence of their direct transactivation by SOX9. Intriguingly, we find that SOX9 helps remove epigenetic signatures of transcriptional repression and establish active-promoter and active-enhancer marks at precartilage- and cartilage-specific loci, but is not absolutely required to initiate these changes and activate transcription. Altogether, these findings widen our current knowledge of SOX9 targets in early chondrogenesis and call for new studies to identify the pioneer and transactivating factors that act upstream of or along with SOX9 to prompt chromatin remodeling and specific gene activation at the onset of chondrogenesis and other processes. PMID- 30021846 TI - Cardiomyopathy and Preeclampsia: Shared Genetics? AB - Background -Preeclampsia (PE), is associated with diastolic dysfunction, peripartum cardiomyopathy (CM), and both preexisting and subsequent maternal cardiovascular disease (CVD). Gene mutations causing idiopathic CM were recently implicated in peripartum CM. We sought to determine whether CM gene mutations are also a contributory factor in PE. Methods -Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of PE completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing (WES) was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with CM. Missense variants were deemed "damaging missense" if so classified by any of 7 standard function prediction algorithms. Variants were defined as "loss-of-function" if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from two control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium (ExAC). PE was not excluded in control groups. Results -Of 181 subjects with confirmed PE, 96% were Caucasian. 72% had >=1 preterm PE delivery <37 weeks. Among PE subjects, WES demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 CM genes considered. The prevalence of these loss-of-function variants was significantly higher in PE subjects (5.5%) compared to the local control (2.5%) population (p=0.014). 68% of women with PE carried >=1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum CM, most mutations (55%) were found in the TTN gene. 73% of PE subjects had TTN mutations in PE cohort versus 48% in local controls (p=1.36E-11). Conclusions -Women who develop PE are more likely to carry protein-altering mutations in genes associated with CM, particularly in TTN. Mutations promoting CM are prevalent in PE, idiopathic CM, and peripartum CM, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk. PMID- 30021847 TI - Two protein/protein interaction assays in one go. PMID- 30021848 TI - AMPK blunts chronic heart failure by inhibiting autophagy. AB - AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, has been shown to exert a protective effect against cardiac hypertrophy and heart failure. Our previous reports have demonstrated that AMPK can inhibit cardiac hypertrophy and block the development of heart failure by promoting autophagy. However, other investigators have demonstrated that overactive and dysregulated autophagy may also contribute to the onset and exacerbation of heart failure. Thus, a major goal of the present investigation is to explore how AMPK regulates autophagy in heart failure. First, heart failure was induced in mice by 4 weeks of pressure overload; AMPK activation was subsequently induced by injecting 5-aminoimidazole 4-carboxamide 1-beta-d-ribonucleotide (AICAR) after the establishment of chronic heart failure. We showed that AMPK activation significantly attenuated the progression of heart failure and improved cardiac function, which was accompanied by decreased autophagy levels in the failing hearts. Additionally, we demonstrated that the treatment with AICAR inhibited phosphorylation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) downstream effectors 4E binding protein1 (4EBP1), and ribosomal protein S6 kinase (p70S6K). A major action of AICAR was significantly to activate AKT (Ser473), the downstream substrate of mTOR complex 2 (mTORC2). In conclusion, the data suggest that AMPK improved cardiac function during the development of chronic heart failure by attenuating autophagy, potentially via mTORC2 activation and the downstream effects. PMID- 30021849 TI - Role of carbon allocation efficiency in the temperature dependence of autotroph growth rates. AB - Relating the temperature dependence of photosynthetic biomass production to underlying metabolic rates in autotrophs is crucial for predicting the effects of climatic temperature fluctuations on the carbon balance of ecosystems. We present a mathematical model that links thermal performance curves (TPCs) of photosynthesis, respiration, and carbon allocation efficiency to the exponential growth rate of a population of photosynthetic autotroph cells. Using experiments with the green alga, Chlorella vulgaris, we apply the model to show that the temperature dependence of carbon allocation efficiency is key to understanding responses of growth rates to warming at both ecological and longer-term evolutionary timescales. Finally, we assemble a dataset of multiple terrestrial and aquatic autotroph species to show that the effects of temperature-dependent carbon allocation efficiency on potential growth rate TPCs are expected to be consistent across taxa. In particular, both the thermal sensitivity and the optimal temperature of growth rates are expected to change significantly due to temperature dependence of carbon allocation efficiency alone. Our study provides a foundation for understanding how the temperature dependence of carbon allocation determines how population growth rates respond to temperature. PMID- 30021850 TI - Exopolysaccharide protects Vibrio cholerae from exogenous attacks by the type 6 secretion system. AB - The type 6 secretion system (T6SS) is a nanomachine used by many Gram-negative bacteria, including Vibrio cholerae, to deliver toxic effector proteins into adjacent eukaryotic and bacterial cells. Because the activity of the T6SS is dependent on direct contact between cells, its activity is limited to bacteria growing on solid surfaces or in biofilms. V. cholerae can produce an exopolysaccharide (EPS) matrix that plays a role in adhesion and biofilm formation. In this work, we investigated the effect of EPS production on T6SS activity between cells. We found that EPS produced by V. cholerae cells functions as a unidirectional protective armor that blocks exogenous T6SS attacks without interfering with its own T6SS functionality. This EPS armor is effective against both same-species and heterologous attackers. Mutations modulating the level of EPS biosynthesis gene expression result in corresponding modulation in V. cholerae resistance to exogenous T6SS attack. These results provide insight into the potential role of extracellular biopolymers, including polysaccharides, capsules, and S-layers in protecting bacterial cells from attacks involving cell associated macromolecular protein machines that cannot readily diffuse through these mechanical defenses. PMID- 30021851 TI - Efficient compression in color naming and its evolution. AB - We derive a principled information-theoretic account of cross-language semantic variation. Specifically, we argue that languages efficiently compress ideas into words by optimizing the information bottleneck (IB) trade-off between the complexity and accuracy of the lexicon. We test this proposal in the domain of color naming and show that (i) color-naming systems across languages achieve near optimal compression; (ii) small changes in a single trade-off parameter account to a large extent for observed cross-language variation; (iii) efficient IB color naming systems exhibit soft rather than hard category boundaries and often leave large regions of color space inconsistently named, both of which phenomena are found empirically; and (iv) these IB systems evolve through a sequence of structural phase transitions, in a single process that captures key ideas associated with different accounts of color category evolution. These results suggest that a drive for information-theoretic efficiency may shape color-naming systems across languages. This principle is not specific to color, and so it may also apply to cross-language variation in other semantic domains. PMID- 30021853 TI - Inner Workings: After years of listening with detectors buried in Antarctic ice, IceCube researchers trace neutrino source. PMID- 30021852 TI - Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro. AB - T cell receptors (TCRs) bind to peptide-major histocompatibility complex (pMHC) with low affinity (Kd ~ MUM), which is generally assumed to facilitate cross reactive TCR "scanning" of ligands. To understand the relationship between TCR/pMHC affinity and cross-reactivity, we sought to engineer an additional weak interaction, termed "velcro," between the TCR and pMHC to probe the specificities of TCRs at relatively low and high affinities. This additional interaction was generated through an eight-amino acid peptide library covalently linked to the N terminus of the MHC-bound peptide. Velcro was selected through an affinity-based isolation and was subsequently shown to enhance the cognate TCR/pMHC affinity in a peptide-dependent manner by ~10-fold. This was sufficient to convert a nonstimulatory ultra-low-affinity ligand into a stimulatory ligand. An X-ray crystallographic structure revealed how velcro interacts with the TCR. To probe TCR cross-reactivity, we screened TCRs against yeast-displayed pMHC libraries with and without velcro, and found that the peptide cross-reactivity profiles of low-affinity (Kd > 100 MUM) and high-affinity (Kd ~ MUM) TCR/pMHC interactions are remarkably similar. The conservation of recognition of the TCR for pMHC across affinities reveals the nature of low-affinity ligands for which there are important biological functions and has implications for understanding the specificities of affinity-matured TCRs. PMID- 30021856 TI - Out-of-Home Care and Subsequent Preterm Delivery: An Intergenerational Cohort Study. AB - OBJECTIVES: Adverse early-life experience may affect preterm delivery later in life through priming of stress response. We aim to investigate the links between out-of-home care (OHC) experience in childhood, as a proxy of severe adversities, on subsequent risk of preterm delivery. METHODS: A register-based national cohort of all women born in Sweden between 1973 and 1977 (N = 175 821) was crosslinked with information on these women's subsequent deliveries as recorded in the Swedish medical birth register. During 1986-2012, 343 828 livebirths of these women were identified. The associations between women's OHC experience and her risk of preterm delivery were analyzed through logistic regression models, adjusting for women's own preterm birth, intrauterine growth, and childhood socioeconomic situation. RESULTS: Compared with women that never entered OHC, women with OHC experience up to and after age 10 were both associated with increased risks of preterm delivery (adjusted odds ratio [aOR] = 1.23 [95% confidence interval 1.08-1.40] and aOR = 1.29 [1.13-1.48], respectively). Women who experienced OHC before or at 10 years of age had increased risk of both spontaneous and medically indicated preterm delivery (aOR = 1.19 [1.03-1.38] and aOR = 1.27 [1.02-1.59], respectively). Women who experienced OHC after age 10 had a more pronounced risk of medically indicated preterm delivery (aOR = 1.76 [1.44 2.16]) than for spontaneous preterm delivery (aOR = 1.08 [0.92-1.27]). CONCLUSIONS: Women who were placed in OHC in childhood had increased risk of preterm delivery independent from their own perinatal history. Stress response, as 1 consequence of early life adversities, may take its toll on women's reproductive health and their offspring, calling for integrative efforts in preventing early life adversity. PMID- 30021857 TI - Stress As a Link Between Childhood Trauma and Preterm Delivery. PMID- 30021854 TI - Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell like fate: Implications for priming of neuroblastoma. AB - Neuroblastoma is a neural crest-derived childhood tumor of the peripheral nervous system in which MycN amplification is a hallmark of poor prognosis. Here we show that MycN is expressed together with phosphorylation-stabilizing factor CIP2A in regions of the neural plate destined to form the CNS, but MycN is excluded from the neighboring neural crest stem cell domain. Interestingly, ectopic expression of MycN or CIP2A in the neural crest domain biases cells toward CNS-like neural stem cells that express Sox2. Consistent with this, some forms of neuroblastoma have been shown to share transcriptional resemblance with CNS neural stem cells. As high MycN/CIP2A levels correlate with poor prognosis, we posit that a MycN/CIP2A-mediated cell-fate bias may reflect a possible mechanism underlying early priming of some aggressive forms of neuroblastoma. In contrast to MycN, its paralogue cMyc is normally expressed in the neural crest stem cell domain and typically is associated with better overall survival in clinical neuroblastoma, perhaps reflecting a more "normal" neural crest-like state. These data suggest that priming for some forms of aggressive neuroblastoma may occur before neural crest emigration from the CNS and well before sympathoadrenal specification. PMID- 30021855 TI - Environmental limits of Rift Valley fever revealed using ecoepidemiological mechanistic models. AB - Vector-borne diseases (VBDs) of humans and domestic animals are a significant component of the global burden of disease and a key driver of poverty. The transmission cycles of VBDs are often strongly mediated by the ecological requirements of the vectors, resulting in complex transmission dynamics, including intermittent epidemics and an unclear link between environmental conditions and disease persistence. An important broader concern is the extent to which theoretical models are reliable at forecasting VBDs; infection dynamics can be complex, and the resulting systems are highly unstable. Here, we examine these problems in detail using a case study of Rift Valley fever (RVF), a high-burden disease endemic to Africa. We develop an ecoepidemiological, compartmental, mathematical model coupled to the dynamics of ambient temperature and water availability and apply it to a realistic setting using empirical environmental data from Kenya. Importantly, we identify the range of seasonally varying ambient temperatures and water-body availability that leads to either the extinction of mosquito populations and/or RVF (nonpersistent regimens) or the establishment of long-term mosquito populations and consequently, the endemicity of the RVF infection (persistent regimens). Instabilities arise when the range of the environmental variables overlaps with the threshold of persistence. The model captures the intermittent nature of RVF occurrence, which is explained as low level circulation under the threshold of detection, with intermittent emergence sometimes after long periods. Using the approach developed here opens up the ability to improve predictions of the emergence and behaviors of epidemics of many other important VBDs. PMID- 30021858 TI - Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels. AB - Synthetic gabapentinoids, exemplified by gapapentin and pregabalin, are in extensive clinical use for indications including epilepsy, neuropathic pain, anxiety, and alcohol withdrawal. Their mechanisms of action are incompletely understood, but are thought to involve inhibition of alpha2delta subunit containing voltage-gated calcium channels. Here, we report that gabapentin is a potent activator of the heteromeric KCNQ2/3 voltage-gated potassium channel, the primary molecular correlate of the neuronal M-current, and also homomeric KCNQ3 and KCNQ5 channels. In contrast, the structurally related gabapentinoid, pregabalin, does not activate KCNQ2/3, and at higher concentrations (>=10 uM) is inhibitory. Gabapentin activation of KCNQ2/3 (EC50 = 4.2 nM) or homomeric KCNQ3* (EC50 = 5.3 nM) channels requires KCNQ3-W265, a conserved tryptophan in KCNQ3 transmembrane segment 5. Homomeric KCNQ2 or KCNQ4 channels are insensitive to gabapentin, whereas KCNQ5 is highly sensitive (EC50 = 1.9 nM). Given the potent effects and the known anticonvulsant, antinociceptive, and anxiolytic effects of M-channel activation, our findings suggest the possibility of an unexpected role for M-channel activation in the mechanism of action of gabapentin. PMID- 30021859 TI - Efficacy of negative feedback in the HPA axis predicts recovery from acute challenges. AB - The glucocorticoid stress response mediates a suite of physiological and behavioural changes that allow vertebrates to cope with transient stressors. Chronically elevated glucocorticoid levels are known to result in a variety of organismal costs, but relatively little is known about the downstream effects of mounting a series of brief, acute spikes in circulating glucocorticoids. Conceptual models of stress suggest that repeated acute stressors might produce 'wear-and-tear' on the stress-response system when encountered in sequence. We used a novel technique to experimentally induce acute corticosterone spikes on either three or six consecutive days in incubating tree swallows. Consistent with the 'wear-and-tear' hypothesis, we found that (i) a sequence of corticosterone spikes produced cumulative effects on corticosterone regulation, (ii) treatment frequency predicted the severity of consequences, and (iii) individual variation in the ability to terminate the stress response through negative feedback predicted the duration of physiological disruption in the group that experienced the most frequent challenges. Our results illustrate the importance of assessing multiple aspects of the hormonal stress response and have implications for understanding both individual and population resilience to repeated transient stressors. PMID- 30021860 TI - Effect of genetic drift on determinants of protein evolution. AB - A number of previous studies reported that gene expression, tissue specificity, gene essentiality and the number of protein-protein interactions influence the rate of protein evolution. Here we investigated the influence of effective population size (Ne) on these determinants of protein evolution. For this purpose, we compared the ratio of non-synonymous-to-synonymous diversities (piN/piS) estimated for protein-coding genes of Mus musculus castaneus and Mus musculus musculus: populations with high and low Ne respectively. Our results revealed that the difference between piN/piS estimated for genes with high and low expression levels was significantly smaller for M. m. musculus compared to that observed for M. m. castaneus The difference between the piN/piS of broadly expressed and tissue specific genes was much higher for M. m. castaneus compared to that of M. m. musculus. Furthermore, the difference between the piN/piS computed for essential and non-essential genes was much smaller for M. m. musculus than M. m. castaneus A similar pattern was observed for genes involved in many protein-protein interactions versus those involved in one. These results suggest that the effects of the determinants on protein evolution were much reduced for the population with small Ne due to increased genetic drift. PMID- 30021861 TI - Beyond burial: lateral exchange is a significant atmospheric carbon sink in mangrove forests. AB - The blue carbon paradigm has evolved in recognition of the high carbon storage and sequestration potential of mangrove, saltmarsh and seagrass ecosystems. However, fluxes of the potent greenhouse gases CH4 and N2O, and lateral export of carbon are often overlooked within the blue carbon framework. Here, we show that the export of dissolved inorganic carbon (DIC) and alkalinity is approximately 1.7 times higher than burial as a long-term carbon sink in a subtropical mangrove system. Fluxes of methane offset burial by approximately 6%, while the nitrous oxide sink was approximately 0.5% of burial. Export of dissolved organic carbon and particulate organic carbon to the coastal zone is also significant and combined may account for an atmospheric carbon sink similar to burial. Our results indicate that the export of DIC and alkalinity results in a long-term atmospheric carbon sink and should be incorporated into the blue carbon paradigm when assessing the role of these habitats in sequestering carbon and mitigating climate change. PMID- 30021863 TI - Plumage coloration and social context influence male investment in song. AB - Animals use multiple signals to attract mates, including elaborate song, brightly coloured ornaments and physical displays. Female birds often prefer both elaborate male song and intense carotenoid-based plumage coloration. This could lead less visually ornamented males to increase song production to maximize their attractiveness to females. We tested this possibility in the highly social and non-territorial house finch (Haemorhous mexicanus), in which females discriminate among males based on both song and on the intensity of red carotenoid-based plumage coloration. We manipulated male plumage coloration through carotenoid supplementation during moult, so that males were either red or yellow. Males were then housed under three social environments: (i) all red birds, (ii) all yellow birds or (iii) a mixture of red/yellow birds. We recorded song after presentation of a female. Red males produced more song than yellow males. But when yellow males were housed with red conspecifics, they produced more song relative to yellow males housed with equally unattractive yellow males. This study provides novel evidence that a male's plumage coloration and the plumage colour of his social competitors influence investment in song. PMID- 30021862 TI - In ovo microbial communities: a potential mechanism for the initial acquisition of gut microbiota among oviparous birds and lizards. AB - Vertebrate gut microbiota mediate critical physiological processes known to affect host fitness, but the mechanisms that expose wildlife to pioneer members of this important microbial community are not well understood. For example, oviparous vertebrates are thought to acquire gut microbiota through post-natal exposure to the external environment, but recent evidence from placental mammals suggests that the vertebrate reproductive tract harbours microbiota that may inoculate offspring in utero These findings suggest that oviparous vertebrates may be capable of acquiring pioneer microbiota in ovo, but this phenomenon remains unexplored. To fill this knowledge gap, we used culture-independent inventories to determine if the eggs of wild birds and lizards harboured in ovo microbial communities. Our approach revealed distinct in ovo bacterial communities, but fungal communities were indistinguishable from controls. Further, lizard eggs from the same clutch had bacterial community structures that were more similar to each other than to unrelated individuals. These results suggest that oviparous vertebrates may acquire maternal microbiota in ovo, possibly through the inoculation of egg yolk prior to shelling. Therefore, this study may provide a first glimpse of a phenomenon with substantial implications for our understanding of the ecological and evolutionary factors shaping gut microbial communities. PMID- 30021864 TI - The IGF pathway is activated in insulinomas but downregulated in metastatic disease. AB - Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p 4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas. PMID- 30021865 TI - Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. AB - Mutations in DAXX/ATRX, MEN1 and genes involved in the phosphoinositide-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway have been implicated in pancreatic neuroendocrine neoplasms (pNENs). However, mainly mutations present in the majority of tumor cells have been identified, while proliferation-driving mutations could be present only in small fractions of the tumor. This study aims to identify high- and low-abundance mutations in pNENs using ultra-deep targeted resequencing. Formalin-fixed paraffin-embedded matched tumor-normal tissue of 38 well-differentiated pNENs was sequenced using a HaloPlex targeted resequencing panel. Novel amplicon-based algorithms were used to identify both single nucleotide variants (SNVs) and insertion-deletions (indels) present in >10% of reads (high abundance) and in <10% of reads (low abundance). Found variants were validated by Sanger sequencing. Sequencing resulted in 416,711,794 reads with an average target base coverage of 2663 +/- 1476. Across all samples, 32 high-abundance somatic, 3 germline and 30 low abundance mutations were withheld after filtering and validation. Overall, 92% of high-abundance and 84% of low-abundance mutations were predicted to be protein damaging. Frequently, mutated genes were MEN1, DAXX, ATRX, TSC2, PI3K/Akt/mTOR and MAPK-ERK pathway-related genes. Additionally, recurrent alterations on the same genomic position, so-called hotspot mutations, were found in DAXX, PTCH2 and CYFIP2. This first ultra-deep sequencing study highlighted genetic intra-tumor heterogeneity in pNEN, by the presence of low-abundance mutations. The importance of the ATRX/DAXX pathway was confirmed by the first-ever pNEN-specific protein damaging hotspot mutation in DAXX. In this study, both novel genes, including the pro-apoptotic CYFIP2 gene and hedgehog signaling PTCH2, and novel pathways, such as the MAPK-ERK pathway, were implicated in pNEN. PMID- 30021867 TI - Correction: T cell clonality assessment: past, present and future. PMID- 30021866 TI - Evaluating gastroenteropancreatic neuroendocrine tumors through microRNA sequencing. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be challenging to evaluate histologically. MicroRNAs (miRNAs) are small RNA molecules that often are excellent biomarkers due to their abundance, cell-type and disease stage specificity and stability. To evaluate miRNAs as adjunct tissue markers for classifying and grading well-differentiated GEP-NETs, we generated and compared miRNA expression profiles from four pathological types of GEP-NETs. Using quantitative barcoded small RNA sequencing and state-of-the-art sequence annotation, we generated comprehensive miRNA expression profiles from archived pancreatic, ileal, appendiceal and rectal NETs. Following data preprocessing, we randomly assigned sample profiles to discovery (80%) and validation (20%) sets prior to data mining using machine-learning techniques. High expression analyses indicated that miR-375 was the most abundant individual miRNA and miRNA cistron in all samples. Leveraging prior knowledge that GEP-NET behavior is influenced by embryonic derivation, we developed a dual-layer hierarchical classifier for differentiating GEP-NET types. In the first layer, our classifier discriminated midgut (ileum, appendix) from non-midgut (rectum, pancreas) NETs based on miR-615 and -92b expression. In the second layer, our classifier discriminated ileal from appendiceal NETs based on miR-125b, -192 and -149 expression, and rectal from pancreatic NETs based on miR-429 and -487b expression. Our classifier achieved overall accuracies of 98.5% and 94.4% in discovery and validation sets, respectively. We also found provisional evidence that low- and intermediate-grade pancreatic NETs can be discriminated based on miR-328 expression. GEP-NETs can be reliably classified and potentially graded using a limited panel of miRNA markers, complementing morphological and immunohistochemistry-based approaches to histologic evaluation. PMID- 30021868 TI - Distinct Roles of Small GTPases Rac1 and Rac2 in Histamine H4 Receptor-Mediated Chemotaxis of Mast Cells. AB - Histamine induces chemotaxis of mast cells through the H4 receptor. However, little is known about the precise intracellular signaling pathway that mediates this process. In this study, we identified small GTPases Rac1 and Rac2 as intracellular binding partners of the H4 receptor and characterized their roles in H4 receptor signaling. We showed that histamine induced Rac GTPase activation via the H4 receptor. A Rac inhibitor NSC23766 attenuated chemotaxis of mast cells toward histamine, as well as histamine-induced calcium mobilization and extracellular signal-regulated kinase (ERK) activation. Histamine-induced migration of mast cells was also sensitive to PD98059, an inhibitor of the mitogen-activated protein kinase kinase, indicating that the Rac-ERK pathway was involved in chemotaxis through the H4 receptor. Inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) by LY294002 suppressed the histamine-induced chemotaxis and activation of Rac GTPases, suggesting that PI3K regulates chemotaxis upstream of Rac activation. Specific knockdown of Rac1 and Rac2 by short-hairpin RNA revealed that both Rac GTPases are necessary for histamine-induced migration. Downregulation of Rac1 and Rac2 led to attenuated response in calcium mobilization and ERK activation, respectively. These observations suggested that Rac1 and Rac2 have distinct and essential roles in intracellular signaling downstream of H4 receptor-PI3K in histamine-induced chemotaxis of mast cells. PMID- 30021869 TI - Little filtered cigars: US sales, flavours, package sizes and prices. AB - OBJECTIVE: At least four varieties of little filtered cigars (LFCs) violate the US prohibition on flavoured cigarettes other than menthol. This study characterises the sales of prohibited products and other LFCs by flavour category and pack size, as well as the price of LFCs relative to cigarettes. METHODS: Using retail sales data for 2016, we computed the sales volume in dollars and equivalent units and the percentage of total sales by flavour and pack size for the USA by region and state. Paired t-tests compared the prices for LFCs and cigarettes sold in same-sized packs and cartons. RESULTS: LFC sales totalled 24 033 equivalent units per 100 000 persons in 2016. Flavoured LFC varieties accounted for almost half (47.5%) of the total sales. LFCs were sold in 12 different pack sizes, but 79.7% of sales were packs of 20. The price of 20-packs averaged $2.41 (SD=$1.49), which was significantly less than cigarettes (M=$5.90, SD=$0.85). Regional differences suggest a greater proportion of menthol/mint LFCs and lower prices in the South than in other regions. CONCLUSION: Classifying all LFCs as cigarettes would require that they be offered in a minimum package of 20, eliminate flavoured varieties other than menthol and increase prices through applicable state and local cigarette taxes. PMID- 30021870 TI - Prevalence and characteristics of secondhand smoke and secondhand vapour exposure among youth. AB - BACKGROUND: It is well established that secondhand smoke (SHS) is harmful, and concern about the potential dangers associated with secondhand vapour (SHV) (ie, vapour from electronic vapour products, EVP) is growing. The present study examines the prevalence and characteristics associated with SHS and SHV exposure. METHODS: Data from youth aged 11-17 who completed the 2016 Florida Youth Tobacco Survey (n=58 616) were analysed. Demographics, past 30 day SHS and SHV exposure, environmental factors, cigarette and EVP use status, SHS and SHV harm perceptions, and tobacco susceptibility were assessed. Weighted multivariable logistic regressions were performed to examine characteristics associated with SHS and SHV exposure, and SHS and SHV exposure with tobacco susceptibility. RESULTS: Overall, 42% of Florida youth reported SHS exposure and 29% reported SHV exposure during the past 30 days. Living in a home where tobacco use was permitted (vs not permitted) was positively associated with SHS (adjusted OR (AOR) 2.57) and SHV exposure (AOR 1.56). Perceived SHS as harmful (vs not harmful) was positively associated with SHS (AOR 1.73) and SHV exposure (AOR 1.97), while perceived SHV as harmful was negatively associated with SHS (AOR 0.86) and SHV exposure (AOR 0.56). SHS and SHV exposure was significantly associated with susceptibility to cigarette and EVP use (AOR 1.40 and 2.08, respectively). CONCLUSIONS: Almost one-third of Florida youth reported SHV exposure. Factors associated with SHS and SHV exposure are somewhat similar, and exposure to SHS and SHV is associated with tobacco susceptibility in youth. Promoting tobacco-free homes is needed to protect youth from SHS and SHV exposure. PMID- 30021871 TI - Little and filtered cigars meet the legal definition of cigarettes and should be included in nicotine reduction regulation. PMID- 30021872 TI - The Dynamic Transcriptome: Using Clustered Time Points to Tease Apart Rice Tiller Angle Control. PMID- 30021873 TI - Evolution and Comparative Genomics of F33:A-:B- Plasmids Carrying blaCTX-M-55 or blaCTX-M-65 in Escherichia coli and Klebsiella pneumoniae Isolated from Animals, Food Products, and Humans in China. AB - To understand the underlying evolution process of F33:A-:B- plasmids among Enterobacteriaceae isolates of various origins in China, the complete sequences of 17 blaCTX-M-harboring F33:A-:B- plasmids obtained from Escherichia coli and Klebsiella pneumoniae isolates from different sources (animals, animal-derived food, and human clinics) in China were determined. F33:A-:B- plasmids shared similar plasmid backbones comprising replication, leading, and conjugative transfer regions and differed by the numbers of repeats in yddA and traD and by the presence of group II intron, except that pHNAH9 lacked a large segment of the leading and transfer regions. The variable regions of F33:A-B- plasmids were distinct and were inserted downstream of the addiction system pemI/pemK, identified as the integration hot spot among F33:A-B- plasmids. The variable region contained resistance genes and mobile elements or contained segments from other types of plasmids, such as IncI1, IncN1, and IncX1. Three plasmids encoding CTX-M-65 were very similar to our previously described pHN7A8 plasmid. Four CTX-M 55-producing plasmids contained multidrug resistance regions related to that of F2:A-B- plasmid pHK23a from Hong Kong. Five plasmids with IncN and/or IncX replication regions and IncI1-backbone fragments had variable regions related to those of pE80 and p42-2. The remaining five plasmids with IncN replicons and an IncI1 segment also possessed closely related variable regions. The diversity in variable regions was presumably associated with rearrangements, insertions, and/or deletions mediated by mobile elements, such as IS26 and IS1294IMPORTANCE Worldwide spread of antibiotic resistance genes among Enterobacteriaceae isolates is of great concern. F33:A-:B- plasmids are important vectors of resistance genes, such as blaCTX-M-55/-65, blaNDM-1, fosA3, and rmtB, among E. coli isolates from various sources in China. We determined and compared the complete sequences of 17 F33:A-:B- plasmids from various sources. These plasmids appear to have evolved from the same ancestor by mobile element-mediated rearrangement, acquisition, and/or loss of resistance modules and similar IncN1, IncI1, and/or IncX1 plasmid backbone segments. Our findings highlight the evolutionary potential of F33:A-:B- plasmids as efficient vectors to capture and diffuse clinically relevant resistance genes. PMID- 30021874 TI - Broadscale Ecological Patterns Are Robust to Use of Exact Sequence Variants versus Operational Taxonomic Units. AB - Recent discussion focuses on the best method for delineating microbial taxa, based on either exact sequence variants (ESVs) or traditional operational taxonomic units (OTUs) of marker gene sequences. We sought to test if the binning approach (ESVs versus 97% OTUs) affected the ecological conclusions of a large field study. The data set included sequences targeting all bacteria (16S rRNA) and fungi (internal transcribed spacer [ITS]), across multiple environments diverging markedly in abiotic conditions, over three collection times. Despite quantitative differences in microbial richness, we found that all alpha and beta diversity metrics were highly positively correlated (r > 0.90) between samples analyzed with both approaches. Moreover, the community composition of the dominant taxa did not vary between approaches. Consequently, statistical inferences were nearly indistinguishable. Furthermore, ESVs only moderately increased the genetic resolution of fungal and bacterial diversity (1.3 and 2.1 times OTU richness, respectively). We conclude that for broadscale (e.g., all bacteria or all fungi) alpha and beta diversity analyses, ESV or OTU methods will often reveal similar ecological results. Thus, while there are good reasons to employ ESVs, we need not question the validity of results based on OTUs.IMPORTANCE Microbial ecologists have made exceptional improvements in our understanding of microbiomes in the last decade due to breakthroughs in sequencing technologies. These advances have wide-ranging implications for fields ranging from agriculture to human health. Due to limitations in databases, the majority of microbial ecology studies use a binning approach to approximate taxonomy based on DNA sequence similarity. There remains extensive debate on the best way to bin and approximate this taxonomy. Here we examine two popular approaches using a large field-based data set examining both bacteria and fungi and conclude that there are not major differences in the ecological outcomes. Thus, it appears that standard microbial community analyses are not overly sensitive to the particulars of binning approaches. PMID- 30021875 TI - Air-Liquid Interface Method To Study Epstein-Barr Virus Pathogenesis in Nasopharyngeal Epithelial Cells. AB - : Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that establishes a latent reservoir in peripheral B-lymphocytes with sporadic reactivation. EBV also infects epithelial cells, predominantly resulting in a lytic infection, which may contribute to EBV transmission from saliva. In the nasopharynx, EBV infection can lead to the clonal expansion of a latently infected cell and the development of nasopharyngeal carcinoma (NPC). The mechanisms governing EBV pathogenesis in nasopharyngeal epithelium are largely unknown. An advanced understanding would depend on a physiologically relevant culture model of polarized airway epithelium. The recent application of the organotypic raft culture in keratinocytes has demonstrated great promise for the use of polarized cultures in the study of EBV permissive replication. In this study, the adaptation of an air liquid interface (ALI) culture method using transwell membranes was explored in an EBV-infected NPC cell line. In the EBV-infected NPC HK1 cell line, ALI culture resulted in the completion of EBV reactivation, with global induction of the lytic cascade, replication of EBV genomes, and production of infectious progeny virus. We propose that the ALI culture method can be widely adopted as a physiologically relevant model to study EBV pathogenesis in polarized nasal epithelial cells. IMPORTANCE: Lifting adherent cells to the air-liquid interface (ALI) is a method conventionally used to culture airway epithelial cells into polarized apical and basolateral surfaces. Reactivation of Epstein-Barr virus (EBV) from monolayer epithelial cultures is sometimes abortive, which may be attributed to the lack of authentic reactivation triggers that occur in stratified epithelium in vivo In the present work, the ALI culture method was applied to study EBV reactivation in nasopharyngeal epithelial cells. The ALI culture of an EBV-infected cell line yielded high titers and can be dissected by a variety of molecular virology assays that measure induction of the EBV lytic cascade and EBV genome replication and assembly. EBV infection of polarized cultures of primary epithelial cells can be challenging and can have variable efficiencies. However, the use of the ALI method with established EBV-infected cell lines offers a readily available and reproducible approach for the study of EBV permissive replication in polarized epithelia. PMID- 30021876 TI - Rifampin- or Capreomycin-Induced Remodeling of the Mycobacterium smegmatis Mycolic Acid Layer Is Mitigated in Synergistic Combinations with Cationic Antimicrobial Peptides. AB - The mycobacterial cell wall affords natural resistance to antibiotics. Antimicrobial peptides (AMPs) modify the surface properties of mycobacteria and can act synergistically with antibiotics from differing classes. Here, we investigate the response of Mycobacterium smegmatis to the presence of rifampin or capreomycin, either alone or in combination with two synthetic, cationic, alpha-helical AMPs that are distinguished by the presence (D-LAK120-HP13) or absence (D-LAK120-A) of a kink-inducing proline. Using a combination of high resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) metabolomics, diphenylhexatriene (DPH) fluorescence anisotropy measurements, and laurdan emission spectroscopy, we show that M. smegmatis responds to challenge with rifampin or capreomycin by substantially altering its metabolism and, in particular, by remodeling the cell envelope. Overall, the changes are consistent with a reduction of trehalose dimycolate and an increase of trehalose monomycolate and are associated with increased rigidity of the mycolic acid layer observed following challenge by capreomycin but not rifampin. Challenge with D LAK120-A or D-LAK120-HP13 induced no or modest changes, respectively, in mycomembrane metabolites and did not induce a significant increase in the rigidity of the mycolic acid layer. Furthermore, the response to rifampin or capreomycin was significantly reduced when these were combined with D-LAK120-HP13 and D-LAK120-A, respectively, suggesting a possible mechanism for the synergy of these combinations. The remodeling of the mycomembrane in M. smegmatis is therefore identified as an important countermeasure deployed against rifampin or capreomycin, but this can be mitigated and the efficacy of rifampin or capreomycin potentiated by combining the drug with AMPs.IMPORTANCE We have used a combined NMR metabolomics/biophysical approach to better understand differences in the mechanisms of two closely related antimicrobial peptides, as well as the response of the model organism Mycobacterium smegmatis to challenge with first- or second-line antibiotics used against mycobacterial pathogens. We show that, in addition to membrane damage, the triggering of oxidative stress may be an important part of the mechanism of action of one AMP. The metabolic shift that accompanied rifampin and, particularly, capreomycin challenge was associated with modest and more dramatic changes, respectively, in the mycomembrane, providing a rationale for how the response to one antibiotic may affect bacterial penetration and, hence, the action of another. This study presents the first insights into how antimicrobial peptides may operate synergistically with existing antibiotics whose efficacy is waning or sensitize MDR mycobacteria and/or latent mycobacterial infections to them, prolonging the useful life of these drugs. PMID- 30021877 TI - Phosphorylation of FtsZ and FtsA by a DNA Damage-Responsive Ser/Thr Protein Kinase Affects Their Functional Interactions in Deinococcus radiodurans. AB - Deinococcus radiodurans, a highly radioresistant bacterium, does not show LexA dependent regulation of recA expression in response to DNA damage. On the other hand, phosphorylation of DNA repair proteins such as PprA and RecA by a DNA damage-responsive Ser/Thr protein kinase (STPK) (RqkA) could improve their DNA metabolic activities as well as their roles in the radioresistance of D. radiodurans Here we report RqkA-mediated phosphorylation of cell division proteins FtsZ and FtsA in vitro and in surrogate Escherichia coli bacteria expressing RqkA. Mass spectrometric analysis mapped serine 235 and serine 335 in FtsZ and threonine 272, serine 370, and serine 386 in FtsA as potential phosphorylation sites. Although the levels of FtsZ did not change during postirradiation recovery (PIR), phosphorylation of both FtsZ and FtsA showed a kinetic change during PIR. However, in an rqkA mutant of D. radiodurans, though FtsZ underwent phosphorylation, no kinetic change in phosphorylation was observed. Further, RqkA adversely affected FtsA interaction with FtsZ, and phosphorylated FtsZ showed higher GTPase activity than unphosphorylated FtsZ. These results suggest that both FtsZ and FtsA are phosphoproteins in D. radiodurans The increased phosphorylation of FtsZ in response to radiation damage in the wild-type strain but not in an rqkA mutant seems to be regulating the functional interaction of FtsZ with FtsA. For the first time, we demonstrate the role of a DNA damage-responsive STPK (RqkA) in the regulation of functional interaction of cell division proteins in this bacterium.IMPORTANCE The LexA/RecA type SOS response is the only characterized mechanism of DNA damage response in bacteria. It regulates cell cycle by attenuating the functions of cell division protein FtsZ and inducing the expression of DNA repair proteins. There are bacteria, including Deinococcus radiodurans, that do not show this classical SOS response. D. radiodurans is known for its extraordinary resistance to gamma radiation, and a DNA damage-responsive Ser/Thr protein kinase (RqkA) has been characterized for its role in radioresistance. RqkA phosphorylates a large number of proteins in solution. The phosphorylation of RecA and PprA by RqkA enhanced their activities. FtsZ phosphorylation is inducible by gamma radiation in wild type D. radiodurans but not in an rqkA mutant. Phosphorylation affected the interaction of FtsZ and FtsA in this bacterium. This study, therefore, brought forth some findings that might lead to the discovery of a new mechanism regulating the bacterial cell cycle in response to DNA damage. PMID- 30021878 TI - MntC-Dependent Manganese Transport Is Essential for Staphylococcus aureus Oxidative Stress Resistance and Virulence. AB - Staphylococcus aureus is a human pathogen that has developed several approaches to evade the immune system, including a strategy to resist oxidative killing by phagocytes. This resistance is mediated by production of superoxide dismutase (SOD) enzymes which use manganese as a cofactor. S. aureus encodes two manganese ion transporters, MntABC and MntH, and a possible Nramp family manganese transporter, exemplified by S. aureus N315 SA1432. Their relative contributions to manganese transport have not been well defined in clinically relevant isolates. For this purpose, insertional inactivation mutations were introduced into mntC, mntH, and SA1432 individually and in combination. mntC was necessary for full resistance to methyl viologen, a compound that generates intracellular free radicals. In contrast, strains with an intact mntH gene had a minimal increase in resistance that was revealed only in mntC strains, and no change was observed upon mutation of SA1432 in strains lacking both mntC and mntH Similarly, MntC alone was required for high cellular SOD activity. In addition, mntC strains were attenuated in a murine sepsis model. To further link these observations to manganese transport, an S. aureus MntC protein lacking manganese binding activity was designed, expressed, and purified. While circular dichroism experiments demonstrated that the secondary and tertiary structures of this protein were unaltered, a defect in manganese binding was confirmed by isothermal titration calorimetry. Unlike complementation with wild-type mntC, introduction of the manganese-binding defective allele into the chromosome of an mntC strain did not restore resistance to oxidative stress or virulence. Collectively, these results underscore the importance of MntC-dependent manganese transport in S. aureus oxidative stress resistance and virulence.IMPORTANCE Work outlined in this report demonstrated that MntC-dependent manganese transport is required for S. aureus virulence. These study results support the model that MntC-specific antibodies elicited by a vaccine have the potential to disrupt S. aureus manganese transport and thus abrogate to its virulence. PMID- 30021879 TI - Escherichia coli Sequence Type 410 Is Causing New International High-Risk Clones. AB - Escherichia coli sequence type 410 (ST410) has been reported worldwide as an extraintestinal pathogen associated with resistance to fluoroquinolones, third generation cephalosporins, and carbapenems. In the present study, we investigated national epidemiology of ST410 E. coli isolates from Danish patients. Furthermore, E. coli ST410 was investigated in a global context to provide further insight into the acquisition of the carbapenemase genes blaOXA-181 and blaNDM-5 of this successful lineage. From 127 whole-genome-sequenced isolates, we reconstructed an evolutionary framework of E. coli ST410 which portrays the antimicrobial-resistant clades B2/H24R, B3/H24Rx, and B4/H24RxC. The B2/H24R and B3/H24Rx clades emerged around 1987, concurrently with the C1/H30R and C2/H30Rx clades in E. coli ST131. B3/H24Rx appears to have evolved by the acquisition of the extended-spectrum beta-lactamase (ESBL)-encoding gene blaCTX-M-15 and an IncFII plasmid, encoding IncFIA and IncFIB. Around 2003, the carbapenem-resistant clade B4/H24RxC emerged when ST410 acquired an IncX3 plasmid carrying a blaOXA 181 carbapenemase gene. Around 2014, the clade B4/H24RxC acquired a second carbapenemase gene, blaNDM-5, on a conserved IncFII plasmid. From an epidemiological investigation of 49 E. coli ST410 isolates from Danish patients, we identified five possible regional outbreaks, of which one outbreak involved nine patients with blaOXA-181- and blaNDM-5-carrying B4/H24RxC isolates. The accumulated multidrug resistance in E. coli ST410 over the past two decades, together with its proven potential of transmission between patients, poses a high risk in clinical settings, and thus, E. coli ST410 should be considered a lineage with emerging "high-risk" clones, which should be monitored closely in the future.IMPORTANCE Extraintestinal pathogenic Escherichia coli (ExPEC) is the main cause of urinary tract infections and septicemia. Significant attention has been given to the ExPEC sequence type ST131, which has been categorized as a "high risk" clone. High-risk clones are globally distributed clones associated with various antimicrobial resistance determinants, ease of transmission, persistence in hosts, and effective transmission between hosts. The high-risk clones have enhanced pathogenicity and cause severe and/or recurrent infections. We show that clones of the E. coli ST410 lineage persist and/or cause recurrent infections in humans, including bloodstream infections. We found evidence of ST410 being a highly resistant globally distributed lineage, capable of patient-to-patient transmission causing hospital outbreaks. Our analysis suggests that the ST410 lineage should be classified with the potential to cause new high-risk clones. Thus, with the clonal expansion over the past decades and increased antimicrobial resistance to last-resort treatment options, ST410 needs to be monitored prospectively. PMID- 30021881 TI - Air-Liquid Interface System To Understand Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma. AB - Epstein-Barr virus (EBV) infects epithelial cells and is associated with epithelial malignancies. Although EBV reactivation is induced by epithelial differentiation, the available methods for differentiation are not widely used. In a recent study, Caves et al. (mSphere 3:e00152-18, 2018, https://doi.org/10.1128/mSphere.00152-18) explored the use of a new transwell based air-liquid interface (ALI) system to differentiate EBV-infected nasopharyngeal carcinoma cells. They found that cells cultured in the ALI system expressed markers of differentiation and supported complete EBV reactivation. This system offers an easy method for differentiation that could be widely adopted. This system could be extended to other epithelial cell types. PMID- 30021880 TI - Uptake of l-Alanine and Its Distinct Roles in the Bioenergetics of Trypanosoma cruzi. AB - Amino acids participate in several critical processes in the biology of trypanosomatids, such as osmoregulation, cell differentiation, and host cell invasion. Some of them provide reducing power for mitochondrial ATP synthesis. It was previously shown that alanine, which is formed mainly by the amination of pyruvate, is a metabolic end product formed when parasites are replicating in a medium rich in glucose and amino acids. It was shown as well that this amino acid can also be used for the regulation of cell volume and resistance to osmotic stress. In this work, we demonstrate that, despite it being an end product of its metabolism, Trypanosoma cruzi can take up and metabolize l-Ala through a low specificity nonstereoselective active transport system. The uptake was dependent on the temperature in the range between 10 and 40 degrees C, which allowed us to calculate an activation energy of 66.4 kJ/mol and estimate the number of transporters per cell at ~436,000. We show as well that, once taken up by the cells, l-Ala can be completely oxidized to CO2, supplying electrons to the electron transport chain, maintaining the electrochemical proton gradient across the mitochondrial inner membrane, and supporting ATP synthesis in T. cruzi epimastigotes. Our data demonstrate a dual role for Ala in the parasite's bioenergetics, by being a secreted end product of glucose catabolism and taken up as nutrient for oxidative mitochondrial metabolism.IMPORTANCE It is well known that trypanosomatids such as the etiological agent of Chagas' disease, Trypanosoma cruzi, produce alanine as a main end product of their energy metabolism when they grow in a medium containing glucose and amino acids. In this work, we investigated if under starvation conditions (which happen during the parasite life cycle) the secreted alanine could be recovered from the extracellular medium and used as an energy source. Herein we show that indeed, in parasites submitted to metabolic stress, this metabolite can be taken up and used as an energy source for ATP synthesis, allowing the parasite to extend its survival under starvation conditions. The obtained results point to a dual role for Ala in the parasite's bioenergetics, by being a secreted end product of glucose catabolism and taken up as nutrient for oxidative mitochondrial metabolism. PMID- 30021885 TI - PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. AB - Kinase inhibitor resistance constitutes a major unresolved clinical challenge in cancer. Furthermore, the role of serine/threonine phosphatase deregulation as a potential cause for resistance to kinase inhibitors has not been thoroughly addressed. We characterize protein phosphatase 2A (PP2A) activity as a global determinant of KRAS-mutant lung cancer cell resistance across a library of >200 kinase inhibitors. The results show that PP2A activity modulation alters cancer cell sensitivities to a large number of kinase inhibitors. Specifically, PP2A inhibition ablated mitogen-activated protein kinase kinase (MEK) inhibitor response through the collateral activation of AKT/mammalian target of rapamycin (mTOR) signaling. Combination of mTOR and MEK inhibitors induced cytotoxicity in PP2A-inhibited cells, but even this drug combination could not abrogate MYC up regulation in PP2A-inhibited cells. Treatment with an orally bioavailable small molecule activator of PP2A DT-061, in combination with the MEK inhibitor AZD6244, resulted in suppression of both p-AKT and MYC, as well as tumor regression in two KRAS-driven lung cancer mouse models. DT-061 therapy also abrogated MYC-driven tumorigenesis. These data demonstrate that PP2A deregulation drives MEK inhibitor resistance in KRAS-mutant cells. These results emphasize the need for better understanding of phosphatases as key modulators of cancer therapy responses. PMID- 30021886 TI - MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. AB - Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti-CTLA-4, anti-PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti-CTLA-4, but not anti-PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-gamma (IFN-gamma) and IFN-gamma-mediated gene signatures, and predicted response to anti-PD-1, but not anti-CTLA-4, therapy. We conclude that primary response to anti-CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti-PD-1 is associated with preexisting IFN-gamma-mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity. PMID- 30021887 TI - Erratum for the Research Article: "Durability and correlates of vaccine protection against Zika virus in rhesus monkeys" by P. Abbink, R. A. Larocca, K. Visitsunthorn, M. Boyd, R. A. De La Barrera, G. D. Gromowski, M. Kirilova, R. Peterson, Z. Li, O. Nanayakkara, R. Nityanandam, N. B. Mercado, E. N. Borducchi, A. Chandrashekar, D. Jetton, S. Mojta, P. Gandhi, J. LeSuer, S. Khatiwada, M. G. Lewis, K. Modjarrad, R. G. Jarman, K. H. Eckels, S. J. Thomas, N. L. Michael, D. H. Barouch. PMID- 30021883 TI - Global Involvement of Lysine Crotonylation in Protein Modification and Transcription Regulation in Rice. AB - Lysine crotonylation (Kcr) is a newly discovered posttranslational modification (PTM) existing in mammals. A global crotonylome analysis was undertaken in rice (Oryza sativa L. japonica) using high accuracy nano-LC-MS/MS in combination with crotonylated peptide enrichment. A total of 1,265 lysine crotonylation sites were identified on 690 proteins in rice seedlings. Subcellular localization analysis revealed that 51% of the crotonylated proteins identified were localized in chloroplasts. The photosynthesis-associated proteins were also mostly enriched in total crotonylated proteins. In addition, a genomic localization analysis of histone Kcr by ChIP-seq was performed to assess the relevance between histone Kcr and the genome. Of the 10,923 identified peak regions, the majority (86.7%) of the enriched peaks were located in gene body, especially exons. Furthermore, the degree of histone Kcr modification was positively correlated with gene expression in genic regions. Compared with other published histone modification data, the Kcr was co-located with the active histone modifications. Interestingly, histone Kcr-facilitated expression of genes with existing active histone modifications. In addition, 77% of histone Kcr modifications overlapped with DNase hypersensitive sites (DHSs) in intergenic regions of the rice genome and might mark other cis-regulatory DNA elements that are different from IPA1, a transcription activator in rice seedlings. Overall, our results provide a comprehensive understanding of the biological functions of the crotonylome and new active histone modification in transcriptional regulation in plants. PMID- 30021882 TI - Retrotransposon-induced mosaicism in the neural genome. AB - Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions. PMID- 30021884 TI - Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. AB - Cells organize their actions partly through tightly controlled protein-protein interactions-collectively termed the interactome. Here we use crosslinking mass spectrometry (XL-MS) to chart the protein-protein interactions in intact human nuclei. Overall, we identified ~8,700 crosslinks, of which 2/3 represent links connecting distinct proteins. From these data, we gain insights on interactions involving histone proteins. We observed that core histones on the nucleosomes expose well-defined interaction hot spots. For several nucleosome-interacting proteins, such as USF3 and Ran GTPase, the data allowed us to build low resolution models of their binding mode to the nucleosome. For HMGN2, the data guided the construction of a refined model of the interaction with the nucleosome, based on complementary NMR, XL-MS, and modeling. Excitingly, the analysis of crosslinks carrying posttranslational modifications allowed us to extract how specific modifications influence nucleosome interactions. Overall, our data depository will support future structural and functional analysis of cell nuclei, including the nucleoprotein assemblies they harbor. PMID- 30021888 TI - Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice. AB - Chronic pain is a widespread debilitating condition affecting millions of people worldwide. Although several pharmacological treatments for relieving chronic pain have been developed, they require frequent chronic administration and are often associated with severe adverse events, including overdose and addiction. Persistent increased sensitization of neuronal subpopulations of the peripheral and central nervous system has been recognized as a central mechanism mediating chronic pain, suggesting that inhibition of specific neuronal subpopulations might produce antinociceptive effects. We leveraged the neurotoxic properties of the botulinum toxin to specifically silence key pain-processing neurons in the spinal cords of mice. We show that a single intrathecal injection of botulinum toxin conjugates produced long-lasting pain relief in mouse models of inflammatory and neuropathic pain without toxic side effects. Our results suggest that this strategy might be a safe and effective approach for relieving chronic pain while avoiding the adverse events associated with repeated chronic drug administration. PMID- 30021889 TI - Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. AB - Vitiligo is an autoimmune disease of the skin mediated by CD8+ T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (TRM) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired TRM formation, and IL-15 promotes TRM function ex vivo. We found that both human and mouse TRM express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short term treatment with anti-CD122 inhibits TRM production of interferon-gamma (IFNgamma), and long-term treatment depletes TRM from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving TRM. PMID- 30021890 TI - Growth-Adaptive Mutations in the Ebola Virus Makona Glycoprotein Alter Different Steps in the Virus Entry Pathway. AB - The Zaire ebolavirus (EBOV) glycoprotein (GP) is cleaved into two subunits (GP1 and GP2) that are both required for virus attachment and entry into cells. Sequence changes in the GP have been proposed to increase pathogenesis and to alter virus growth properties. Mutations in GP acquired during EBOV tissue culture passage have also been reported to change virus growth properties. Here, we report the isolation of six amino acid mutations in EBOV GP that spontaneously appeared during recovery and passage of an EBOV-Makona GP-pseudotyped vesicular stomatitis virus (VSV), two of which also occur during passage of EBOV clinical isolates in tissue culture. Each of the six mutations resulted in increased virus growth in monkey and human cell lines. All mutations are located in the GP2 fusion subunit and increase entry kinetics of EBOV virus-like particles (VLPs). The gain-of-entry function mapped to two mechanistic phenotypes. Mutations in heptad repeat 1 (HR1) decreased the requirement for cathepsin B activity for viral infection. Mutations directly within the fusion loop increased entry kinetics without altering the cathepsin B dependence. Several mutations in the fusion loop were substitutions of residues present in other ebolavirus glycoproteins, illustrating the evolutionary paths for maintaining an optimally functioning fusion loop under selection pressure.IMPORTANCEZaire ebolavirus (EBOV) is the causative agent of the highly lethal Ebola virus disease and poses a significant threat to the global health community. Approved antivirals against EBOV are lacking; however, promising therapies targeting the EBOV glycoprotein are being developed. Efficacy testing of these candidate therapeutics relies on EBOV laboratory stocks, which when grown in tissue culture may acquire mutations in the glycoprotein. These mutations can produce inaccurate results in therapeutic testing. Until recently, distinguishing between tissue culture mutations and naturally occurring polymorphisms in EBOV GP was difficult in the absence of consensus clinical GP sequences. Here, we utilize recombinant VSV (rVSV) pseudotyped with the consensus clinical EBOV Makona GP to identify several mutations that have emerged or have potential to emerge in EBOV GP during tissue culture passage. Identifying these mutations informs the EBOV research community as to which mutations may arise during preparation of laboratory virus stocks. PMID- 30021891 TI - Oral Prion Neuroinvasion Occurs Independently of PrPC Expression in the Gut Epithelium. AB - The early replication of certain prion strains within Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain after oral exposure. Our data show that orally acquired prions utilize specialized gut epithelial cells known as M cells to enter Peyer's patches. M cells express the cellular isoform of the prion protein, PrPC, and this may be exploited by some pathogens as an uptake receptor to enter Peyer's patches. This suggested that PrPC might also mediate the uptake and transfer of prions across the gut epithelium into Peyer's patches in order to establish infection. Furthermore, the expression level of PrPC in the gut epithelium could influence the uptake of prions from the lumen of the small intestine. To test this hypothesis, transgenic mice were created in which deficiency in PrPC was specifically restricted to epithelial cells throughout the lining of the small intestine. Our data clearly show that efficient prion neuroinvasion after oral exposure occurred independently of PrPC expression in small intestinal epithelial cells. The specific absence of PrPC in the gut epithelium did not influence the early replication of prions in Peyer's patches or disease susceptibility. Acute mucosal inflammation can enhance PrPC expression in the intestine, implying the potential to enhance oral prion disease pathogenesis and susceptibility. However, our data suggest that the magnitude of PrPC expression in the epithelium lining the small intestine is unlikely to be an important factor which influences the risk of oral prion disease susceptibility.IMPORTANCE The accumulation of orally acquired prions within Peyer's patches in the small intestine is essential for the efficient spread of disease to the brain. Little is known of how the prions initially establish infection within Peyer's patches. Some gastrointestinal pathogens utilize molecules, such as the cellular prion protein PrPC, expressed on gut epithelial cells to enter Peyer's patches. Acute mucosal inflammation can enhance PrPC expression in the intestine, implying the potential to enhance oral prion disease susceptibility. We used transgenic mice to determine whether the uptake of prions into Peyer's patches was dependent upon PrPC expression in the gut epithelium. We show that orally acquired prions can establish infection in Peyer's patches independently of PrPC expression in gut epithelial cells. Our data suggest that the magnitude of PrPC expression in the epithelium lining the small intestine is unlikely to be an important factor which influences oral prion disease susceptibility. PMID- 30021892 TI - Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans. AB - In 2009, a pandemic H1N1 influenza A virus (IAV) (pH1N1) emerged in the human population from swine causing a pandemic. Importantly, this virus is still circulating in humans seasonally. To analyze the evolution of pH1N1 in humans, we sequenced viral genes encoding proteins inhibiting general gene expression (nonstructural protein 1 [NS1] and PA-X) from circulating seasonal viruses and compared them to the viruses isolated at the origin of the pandemic. Recent pH1N1 viruses contain amino acid changes in the NS1 protein (E55K, L90I, I123V, E125D, K131E, and N205S), as previously described (A. M. Clark, A. Nogales, L. Martinez Sobrido, D. J. Topham, and M. L. DeDiego, J Virol 91:e00721-17, 2017, https://doi.org/10.1128/JVI.00721-17), and amino acid changes in the PA-X protein (V100I, N204S, R221Q, and L229S). These amino acid differences between early and more recent pH1N1 isolates are responsible for increased NS1-mediated inhibition of host gene expression and decreased PA-X-mediated shutoff, including innate immune response genes. In addition, currently circulating pH1N1 viruses have acquired amino acid changes in the PA protein (V100I, P224S, N321K, I330V, and R362K). A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from currently circulating viruses is fitter in replication in cultured cells and in mice and is slightly more pathogenic than the original ancestor pH1N1 virus. These results demonstrate the need to monitor the evolution of pH1N1 in humans for mutations in the viral genome that could result in enhanced virulence. Importantly, these results further support our previous findings suggesting that inhibition of global gene expression mediated by NS1 and PA-X proteins is subject to a balance which can determine virus pathogenesis and fitness.IMPORTANCE IAVs emerge in humans from animal reservoirs, causing unpredictable pandemics. One of these pandemics was caused by an H1N1 virus in 2009, and this virus is still circulating seasonally. To analyze host-virus adaptations likely affecting influenza virus pathogenesis, protein amino acid sequences from viruses circulating at the beginning of the pandemic and those circulating currently were compared. Currently circulating viruses have incorporated amino acid changes in two viral proteins (NS1 and PA-X), affecting innate immune responses, and in the PA gene. These amino acid differences led to increased NS1-mediated and decreased PA-X-mediated inhibition of host gene expression. A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from recently circulating viruses is fitter in replication in tissue culture cells and in mice, and the virus is more pathogenic in vivo Importantly, these results suggest that a balance in the abilities of NS1 and PA-X to induce host shutoff is beneficial for IAVs. PMID- 30021893 TI - The RNA-binding protein of a double-stranded RNA virus acts like a scaffold protein. AB - Infectious bursal disease virus (IBDV), a non-enveloped, double-stranded (ds)RNA virus with a T=13 icosahedral capsid, has a virion assembly strategy that initiates with a precursor particle based on an internal scaffold shell similar to that of tailed dsDNA viruses. In IBDV-infected cells, the assembly pathway results mainly in mature virions that package four dsRNA segments, although minor viral populations ranging from zero to three dsRNA segments also form. We used cryo-electron microscopy, cryo-electron tomography and atomic force microscopy to characterize these IBDV populations. The VP3 protein was found to act as a scaffold protein by building an irregular, ~40 A-thick internal shell without icosahedral symmetry, which facilitates formation of a precursor particle, the procapsid. Analysis of IBDV procapsid mechanical properties indicated a VP3 layer beneath the icosahedral shell, which increased effective capsid thickness. Whereas scaffolding proteins are discharged in tailed dsDNA viruses, VP3 is a multifunctional protein. In mature virions, VP3 is bound to the dsRNA genome, which is organized as ribonucleoprotein complexes. IBDV is an amalgam of dsRNA viral ancestors and traits from dsDNA and single-stranded (ss)RNA viruses.IMPORTANCE Structural analyses highlight the constraint of virus evolution to a limited number of capsid protein folds and assembly strategies that result in a functional virion. We report cryo-EM and cryo-electron tomography structures and atomic force microscopy studies of the infectious bursal disease virus (IBDV), a double-stranded RNA virus with an icosahedral capsid. We found evidence of a new inner shell that might act as an internal scaffold during IBDV assembly. The use of an internal scaffold is reminiscent of tailed dsDNA viruses, which constitute the most successful self-replicating system on Earth. The IBDV scaffold protein is multifunctional and, after capsid maturation, is genome-bound to form ribonucleoprotein complexes. IBDV encompasses numerous functional and structural characteristics of RNA and DNA viruses; we suggest that IBDV is a modern descendent of ancestral viruses, and comprises different features of current viral lineages. PMID- 30021894 TI - The S2 Subunit of Infectious Bronchitis Virus Beaudette Is a Determinant of Cellular Tropism. AB - The spike (S) glycoprotein of the avian gammacoronavirus infectious bronchitis virus (IBV) is comprised of two subunits (S1 and S2), has a role in virulence in vivo, and is responsible for cellular tropism in vitro We have previously demonstrated that replacement of the S glycoprotein ectodomain from the avirulent Beaudette strain of IBV with the corresponding region from the virulent M41-CK strain resulted in a recombinant virus, BeauR-M41(S), with the in vitro cell tropism of M41-CK. The IBV Beaudette strain is able to replicate in both primary chick kidney cells and Vero cells, whereas the IBV M41-CK strain replicates in primary cells only. In order to investigate the region of the IBV S responsible for growth in Vero cells, we generated a series of recombinant IBVs expressing chimeric S glycoproteins, consisting of regions from the Beaudette and M41-CK S gene sequences, within the genomic background of Beaudette. The S2, but not the S1, subunit of the Beaudette S was found to confer the ability to grow in Vero cells. Various combinations of Beaudette-specific amino acids were introduced into the S2 subunit of M41 to determine the minimum requirement to confer tropism for growth in Vero cells. The ability of IBV to grow and produce infectious progeny virus in Vero cells was subsequently narrowed down to just 3 amino acids surrounding the S2' cleavage site. Conversely, swapping of the 3 Beaudette associated amino acids with the corresponding ones from M41 was sufficient to abolish Beaudette growth in Vero cells.IMPORTANCE Infectious bronchitis remains a major problem in the global poultry industry, despite the existence of many different vaccines. IBV vaccines, both live attenuated and inactivated, are currently grown on embryonated hen's eggs, a cumbersome and expensive process due to the fact that most IBV strains do not grow in cultured cells. The reverse genetics system for IBV creates the opportunity for generating rationally designed and more effective vaccines. The observation that IBV Beaudette has the additional tropism for growth on Vero cells also invokes the possibility of generating IBV vaccines produced from cultured cells rather than by the use of embryonated eggs. The regions of the IBV Beaudette S glycoprotein involved in the determination of extended cellular tropism were identified in this study. This information will enable the rational design of a future generation of IBV vaccines that may be grown on Vero cells. PMID- 30021895 TI - Mutant Cellular AP-1 Proteins Promote Expression of a Subset of Epstein-Barr Virus Late Genes in the Absence of Lytic Viral DNA Replication. AB - Epstein-Barr virus (EBV) ZEBRA protein activates the EBV lytic cycle. Cellular AP 1 proteins with alanine-to-serine [AP-1(A/S)] substitutions homologous to ZEBRA(S186) assume some functions of EBV ZEBRA. These AP-1(A/S) mutants bind methylated EBV DNA and activate expression of some EBV genes. Here, we compare expression of 67 viral genes induced by ZEBRA versus expression induced by AP 1(A/S) proteins. AP-1(A/S) activated 24 genes to high levels and 15 genes to intermediate levels; activation of 28 genes by AP-1(A/S) was severely impaired. We show that AP-1(A/S) proteins are defective at stimulating viral lytic DNA replication. The impairment of expression of many late genes compared to that of ZEBRA is likely due to the inability of AP-1(A/S) proteins to promote viral DNA replication. However, even in the absence of detectable viral DNA replication, AP 1(A/S) proteins stimulated expression of a subgroup of late genes that encode viral structural proteins and immune modulators. In response to ZEBRA, expression of this subgroup of late genes was inhibited by phosphonoacetic acid (PAA), which is a potent viral replication inhibitor. However, when the lytic cycle was activated by AP-1(A/S), PAA did not reduce expression of this subgroup of late genes. We also provide genetic evidence, using the BMRF1 knockout bacmid, that these genes are true late genes in response to ZEBRA. AP-1(A/S) binds to the promoter region of at least one of these late genes, BDLF3, encoding an immune modulator.IMPORTANCE Mutant c-Jun and c-Fos proteins selectively activate expression of EBV lytic genes, including a subgroup of viral late genes, in the absence of viral DNA replication. These findings indicate that newly synthesized viral DNA is not invariably required for viral late gene expression. While viral DNA replication may be obligatory for late gene expression driven by viral transcription factors, it does not limit the ability of cellular transcription factors to activate expression of some viral late genes. Our results show that expression of all late genes may not be strictly dependent on viral lytic DNA replication. The c-Fos A151S mutation has been identified in a human cancer. c Fos A151S in combination with wild-type c-Jun activates the EBV lytic cycle. Our data provide proof of principle that mutant cellular transcription factors could cause aberrant regulation of viral lytic cycle gene expression and play important roles in EBV-associated diseases. PMID- 30021898 TI - SOSIP changes affect human immunodeficiency virus (HIV-1) envelope glycoprotein conformation and CD4 engagement. AB - The entry of human immunodeficiency virus into the host cells is mediated by the envelope glycoprotein (Env) trimeric spike, which consists of three exterior gp120 and three transmembrane gp41 subunits. The trimeric Env undergoes extensive conformational rearrangement upon interaction with the CD4 receptor, transitioning from the unliganded, "closed" State 1 to more open downstream State 2 and State-3 conformations. Changes in "restraining" amino acid residues such as leucine 193 and isoleucine 423 destabilize State-1 Env, which then assumes entry competent, downstream conformations. The introduction of an artificial disulfide bond linking the gp120 and gp41 subunits (SOS) in combination with the I559P (IP) change has allowed structural characterization of soluble gp140 trimers. The conformation of these SOSIP-stabilized sgp140 trimers has been suggested to represent the closed native State-1 conformation. Here we compare the impact on the membrane Env conformation of the SOSIP changes and well-characterized changes (L193R and I423A) that shift Env to downstream States 2 and 3. The results presented herein suggest that the SOSIP changes stabilize Env in a conformation that differs from State 1 but also from the downstream Env conformations stabilized by L193R or I423A.IMPORTANCEThe human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer is triggered by receptor binding to mediate the entry of the virus into cells. Most structural studies of Env trimers utilized truncated soluble gp140 Envs stabilized with the I559P and SOS changes. Here we present evidence indicating that these stabilizing changes have a profound impact on Env conformation, moving Env away from the native pre triggered Env conformation. Our studies underscore the need to acquire structural information on the pre-triggered Env conformation, which is recognized by most broadly reactive neutralizing antibodies. PMID- 30021896 TI - Emerging Proviral Roles of Caspases during Lytic Replication of Gammaherpesviruses. AB - Due to their roles in the regulation of programmed cell death and inflammation, the cellular caspase proteases are considered antiviral factors. However, recent studies have revealed examples of proviral functions for caspases. Here, we review a growing body of literature on the role of caspases in promoting the replication of human gammaherpesviruses. We propose that gammaherpesviruses have evolved ways to redirect these enzymes and to use their activation to support viral replication and immune evasion. PMID- 30021897 TI - Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype. AB - Hepatitis B virus (HBV) infection is a major health problem worldwide, and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. Using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and signaling pathways of infected hepatocytes and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of the transforming growth factor beta (TGF-beta) family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 genes associated with the cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase compared to the predominantly G0/G1 phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA, and CEBPB, were upregulated upon HBV infection and particularly enriched in cells in the G2/M phase. Together, these results support the notion that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation.IMPORTANCE Hepatitis B virus (HBV) infection is a major health problem with high risk of developing hepatocellular carcinoma (HCC). By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and whether these effects are relevant to HBV-associated HCC. HBV induced a distinct profile of growth factor production, marked particularly by significantly lower levels of the transforming growth factor beta (TGF-beta) family of proteins. Transcriptome profiling revealed multiple changes in cell proliferation and cell cycle control pathways. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase. HBV proviral host factors were upregulated upon infection and particularly enriched in cells in the G2/M phase. Together, these results support the notion that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive infection. This may coincidently induce a premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation. PMID- 30021899 TI - Analysis of Complement-Mediated Lysis of Simian Immunodeficiency Virus (SIV) and SIV-Infected Cells Reveals Sex Differences in Vaccine-Induced Immune Responses in Rhesus Macaques. AB - An effective human immunodeficiency virus (HIV) vaccine has yet to be developed, and defining immune correlates of protection against HIV infection is of paramount importance to inform future vaccine design. The complement system is a component of innate immunity that can directly lyse pathogens and shape adaptive immunity. To determine if complement lysis of simian immunodeficiency virus (SIV) and/or SIV-infected cells represents a protective immune correlate against SIV infection, sera from previously vaccinated and challenged rhesus macaques were analyzed for the induction of antibody-dependent complement-mediated lysis (ADCML). Importantly, the vaccine regimen, consisting of a replication-competent adenovirus type 5 host-range mutant SIV recombinant prime followed by a monomeric gp120 or oligomeric gp140 boost, resulted in overall delayed SIV acquisition only in females. Here, sera from all vaccinated animals induced ADCML of SIV and SIV infected cells efficiently, regardless of sex. A modest correlation of SIV lysis with a reduced infection rate in males but not females, together with a reduced peak viremia in all animals boosted with gp140, suggested a potential for influencing protective efficacy. Gag-specific IgG and gp120-specific IgG and IgM correlated with SIV lysis in females, while Env-specific IgM correlated with SIV infected cell lysis in males, indicating sex differences in vaccine-induced antibody characteristics and function. In fact, gp120/gp140-specific antibody functional correlates between antibody-dependent cellular cytotoxicity, antibody dependent phagocytosis, and ADCML as well as the gp120-specific IgG glycan profiles and the corresponding ADCML correlations varied depending on the sex of the vaccinees. Overall, these data suggest that sex influences vaccine-induced antibody function, which should be considered in the design of globally effective HIV vaccines in the future.IMPORTANCE An HIV vaccine would thwart the spread of HIV infection and save millions of lives. Unfortunately, the immune responses conferring universal protection from HIV infection are poorly defined. The innate immune system, including the complement system, is an evolutionarily conserved, basic means of protection from infection. Complement can prevent infection by directly lysing incoming pathogens. We found that vaccination against SIV in rhesus macaques induces antibodies that are capable of directing complement lysis of SIV and SIV-infected cells in both sexes. We also found sex differences in vaccine-induced antibody species and their functions. Overall, our data suggest that sex affects vaccine-induced antibody characteristics and function and that males and females might require different immune responses to protect against HIV infection. This information could be used to generate highly effective HIV vaccines for both sexes in the future. PMID- 30021900 TI - Two Conserved Amino Acids within the NSs of Severe Fever with Thrombocytopenia Syndrome Phlebovirus Are Essential for Anti-interferon Activity. AB - The nonstructural protein (NSs) of severe fever with thrombocytopenia syndrome phlebovirus (SFTSV) sequesters TANK-binding kinase 1 (TBK1) into NSs-induced cytoplasmic structures to inhibit the phosphorylation and nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3) and subsequent interferon beta (IFN-beta) production. Although the C-terminal region of SFTSV NSs (NSs66-249) has been linked to the formation of NSs-induced cytoplasmic structures and inhibition of host IFN-beta responses, the role of the N-terminal region in antagonizing host antiviral responses remains to be defined. Here, we demonstrate that two conserved amino acids at positions 21 and 23 in the SFTSV and heartland virus (HRTV) NSs are essential for suppression of IRF3 phosphorylation and IFN beta mRNA expression following infection with SFTSV or recombinant influenza virus lacking the NS1 gene. Surprisingly, formation of SFTSV/HRTV NSs-induced cytoplasmic structures is not essential for inhibition of host antiviral responses. Rather, an association between SFTSV/HRTV NSs and TBK1 is required for suppression of mitochondrial antiviral signaling protein (MAVS)-mediated activation of IFN-beta promoter activity. Although SFTSV NSs did not prevent the ubiquitination of TBK1, it associates with TBK1 through its N-terminal kinase domain (residues 1 to 307) to block the autophosphorylation of TBK1. Furthermore, we found that both wild-type NSs and the 21/23A mutant (NSs in which residues at positions 21 and 23 were replaced with alanine) of SFTSV suppressed NLRP3 inflammasome-dependent interleukin-1beta (IL-1beta) secretion, suggesting that the importance of these residues is restricted to TBK1-dependent IFN signaling. Together, our findings strongly implicate the two conserved amino acids at positions 21 and 23 of SFTSV/HRTV NSs in the inhibition of host interferon responses.IMPORTANCE Recognition of viruses by host innate immune systems plays a critical role not only in providing resistance to viral infection but also in the initiation of antigen-specific adaptive immune responses against viruses. Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease caused by the SFTS phlebovirus (SFTSV), a highly pathogenic tick-borne phlebovirus. The 294-amino-acid nonstructural protein (NSs) of SFTSV associates with TANK-binding kinase 1 (TBK1), a key regulator of host innate antiviral immunity, to inhibit interferon beta (IFN-beta) production and enhance viral replication. Here, we demonstrate that two conserved amino acids at positions 21 and 23 in the NSs of SFTSV and heartland virus, another tick-borne phlebovirus, are essential for association with TBK1 and suppression of IFN-beta production. Our results provide important insight into the molecular mechanisms by which SFTSV NSs helps to counteract host antiviral strategies. PMID- 30021901 TI - Testicular degeneration and infertility following arbovirus infection. AB - Arboviruses can cause a variety of clinical signs including febrile illness, arthritis, encephalitis and hemorrhagic fever. The recent Zika epidemic highlighted the possibility that arboviruses may also negatively affect the male reproductive tract. In this study, we focused on bluetongue virus (BTV), the causative agent of bluetongue and one of the major arboviruses of ruminants. We show that rams that recovered from bluetongue displayed signs of testicular degeneration and azoospermia up to 100 days after the initial infection. Importantly, testicular degeneration was induced in rams experimentally infected with either a high (BTV-1IT2006) or low (BTV-1IT2013) virulence strain of BTV. Rams infected with the low virulent BTV strain displayed testicular lesions in the absence of other major clinical signs. Testicular lesions in BTV-infected rams were due to viral replication in the endothelial cells of the peritubular areas of the testes, resulting in stimulation of a type-I IFN response, reduction of testosterone biosynthesis by Leydig cells, and destruction of Sertoli cells and the blood-testis barrier in more severe cases. Hence, BTV induces testicular degeneration and disruption of spermatogenesis by replicating solely in the endothelial cells of the peritubular areas unlike other gonadotropic viruses. This study shows that a naturally occurring arboviral disease can cause testicular degeneration and affect male fertility at least temporarily.ImportanceDuring the recent Zika epidemic, it has become apparent that arboviruses could potentially cause reproductive health problems in male patients. Little is known regarding the effects that arboviruses have on the male reproductive tract. Here, we studied bluetongue virus (BTV), an arbovirus of ruminants, and its effects on the testes of rams. We show that BTV was able to induce testicular degeneration in naturally and experimentally infected rams. Testicular degeneration was caused by BTV replication in the endothelial cells of the peritubular area surrounding the seminiferous tubules (the functional unit of the testes) and was associated with a localized type-I interferon response, destruction of the cells supporting the developing germinal cells (Sertoli cells), and reduction of testosterone synthesis. As a result of BTV infection, rams became azoospermic. This study highlights that problems in the male reproductive tract caused by arboviruses could be more common than previously thought. PMID- 30021904 TI - Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells. AB - The oncogenic microRNA miR-155 is the most frequently upregulated miRNA in Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates IRF4 transcription indicating that EBV may upregulate miR-155 through direct and indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can activate IRF4 and miR-155HG expression through specific upstream enhancers that are dependent on the Notch signaling transcription factor RBPJ, a known binding partner of EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 can also activate miR 155HG via the upstream enhancer also targeted by EBNA2. Gene editing to remove the EBNA2- and IRF4-responsive miR-155HG enhancer located 60 kb upstream of miR 155HG led to reduced miR155HG expression in EBV-infected cells. Our data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4 miR-155 expression network and play a key role in the maintenance of miR-155 expression in EBV-infected B cells. These findings provide important insights that will improve our understanding of miR-155 control in B cell malignancies.IMPORTANCE MicroRNA-155 (miR-155) is expressed at high level in many human cancers particularly lymphomas. Epstein-Barr virus (EBV) infects human B cells and drives the development of numerous lymphomas. Two EBV-encoded genes (LMP1 and EBNA2) upregulate miR-155 expression and miR-155 expression is required for the growth of EBV-infected B cells. We show that the EBV transcription factor EBNA2 upregulates miR-155 expression by activating an enhancer upstream from the miR-155 host gene (miR-155HG) from which miR-155 is derived. We show that EBNA2 also indirectly activates miR-155 expression through enhancer-mediated activation of IRF4 IRF4 then activates both the miR-155HG promoter and the upstream enhancer, independently of EBNA2. Gene editing to remove the miR-155HG enhancer leads to a reduction in miR-155HG expression. We therefore identify enhancer mediated activation of miR-155HG as a critical step in promoting B cell growth and a likely contributor to lymphoma development. PMID- 30021902 TI - Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity. AB - The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-beta) induced by Sendai virus and poly(I.C), while knockdown of Cdc25A enhances the transcription of IFN-beta stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-beta. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1 transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-beta reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-beta. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity.IMPORTANCE The RLR mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-beta transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-beta. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection. PMID- 30021903 TI - Sendai Virus V Protein Inhibits the Secretion of Interleukin-1beta by Preventing NLRP3 Inflammasome Assembly. AB - Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1beta (IL-1beta) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro Casp-1 cleavage, leading to IL-1beta maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V( )] induced markedly greater amounts of IL-1beta than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(-)-induced IL 1beta secretion, indicating an essential role for NLRP3 in SeV V(-)-induced IL 1beta activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1beta secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1beta activation.IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases. PMID- 30021905 TI - Middle East Respiratory Syndrome Coronavirus Spike Protein Is Not Activated Directly by Cellular Furin during Viral Entry into Target Cells. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes host cellular proteases to enter cells. A previous report shows that furin, which is distributed mainly in the Golgi apparatus and cycled to the cell surface and endosomes, proteolytically activates the MERS-CoV spike (S) protein following receptor binding to mediate fusion between the viral and cellular membranes. In this study, we reexamined furin usage by MERS-CoV using a real-time PCR-based virus cell entry assay after inhibition of cellular proteases. We found that the furin inhibitor dec-RVKR-CMK blocked entry of MERS-CoV harboring an S protein lacking furin cleavage sites; it even blocked entry into furin-deficient LoVo cells. In addition, dec-RVKR-CMK inhibited not only the enzymatic activity of furin but also those of cathepsin L, cathepsin B, trypsin, papain, and TMPRSS2. Furthermore, a virus cell entry assay and a cell-cell fusion assay provided no evidence that the S protein was activated by exogenous furin. Therefore, we conclude that furin does not play a role in entry of MERS-CoV into cells and that the inhibitory effect of dec-RVKR-CMK is specific for TMPRSS2 and cathepsin L rather than furin.IMPORTANCE Previous studies using the furin inhibitor dec-RVKR CMK suggest that MERS-CoV utilizes a cellular protease, furin, to activate viral glycoproteins during cell entry. However, we found that dec-RVKR-CMK inhibits not only furin but also other proteases. Furthermore, we found no evidence that MERS CoV uses furin. These findings suggest that previous studies in the virology field based on dec-RVKR-CMK should be reexamined carefully. Here we describe appropriate experiments that can be used to assess the effect of protease inhibitors on virus cell entry. PMID- 30021906 TI - Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming in vivo, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcgammaRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection. PMID- 30021907 TI - Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection. AB - While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I-restricted epitopes. The CE were evaluated for CD8 T cell responses for patients with chronic and acute HIV infections. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic and acute infections, respectively. The immunogenic CE were all derived from a single antisense reading frame within pol However, when these CE were tested using longitudinal study samples, CE-specific T cell responses were detected but did not consistently select for viral escape mutations. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. The latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, or the magnitude of CE responses during acute infections.IMPORTANCE Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence that targeting these epitopes drives HIV escape mutations has been substantially limited, and no studies have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I-associated viral escape. Our data show that cryptic epitopes are immunogenic during acute infection and that many of the responses they elicit are toward translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8 mediated immune escape. Nevertheless, improving cryptic epitope-specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines. PMID- 30021908 TI - Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma. AB - Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. (c)2018 AACR. PMID- 30021910 TI - A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer. AB - Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno oncology. This study was undertaken to evaluate the preclinical efficacy of BMS 986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.Results: BMS-986012 showed a high binding affinity for FcgammaRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS 986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178-89. (c)2018 AACR. PMID- 30021909 TI - Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. AB - Purpose: Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematologic malignancies, but have limited efficacy in solid tumors. This study aimed to identify combination therapies that exploit clinical BH3 mimetics for prostate cancer.Experimental Design: Prostate cancer cells or xenografts were treated with BH3 mimetics as single agents or in combination with other agents, and effects on MCL1 and apoptosis were assessed. MCL1 was also targeted directly using RNAi, CRISPR, or an MCL1-specific BH3 mimetic, S63845.Results: We initially found that MCL1 depletion or inhibition markedly sensitized prostate cancer cells to apoptosis mediated by navitoclax, but not venetoclax, in vitro and in vivo, indicating that they are primed to undergo apoptosis and protected by MCL1 and BCLXL. Small-molecule EGFR kinase inhibitors (erlotinib, lapatinib) also dramatically sensitized to navitoclax-mediated apoptosis, and this was associated with markedly increased proteasome-dependent degradation of MCL1. This increased MCL1 degradation appeared to be through a novel mechanism, as it was not dependent upon GSK3beta-mediated phosphorylation and subsequent ubiquitylation by the ubiquitin ligases betaTRCP and FBW7, or through other previously identified MCL1 ubiquitin ligases or deubiquitinases. Inhibitors targeting additional kinases (cabozantinib and sorafenib) similarly caused GSK3beta-independent MCL1 degradation, and in combination with navitoclax drove apoptosis in vitro and in vivo Conclusions: These results show that prostate cancer cells are primed to undergo apoptosis and that cotargeting BCLXL and MCL1, directly or indirectly through agents that increase MCL1 degradation, can induce dramatic apoptotic responses. Clin Cancer Res; 24(21); 5458-70. (c)2018 AACR. PMID- 30021911 TI - Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A Post Hoc Analysis of the PR.7 Trial. AB - Purpose: Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer.Experimental Design: Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence postradiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable Cox regression analyses adjusted for baseline prognostic factors assessed time to castration-resistant prostate cancer (CRPC), prostate cancer survival, and overall survival according to tertile of sex steroid measured by mass spectrometry.Results: Post-ADT initiation, we measured samples in 219 patients as well as two subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and DHT, while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA), and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone (E1) and estradiol (E2) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups.Conclusions: Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E1 and E2 and rising DHEA and AST levels, which predict a shorter time to CRPC. Clin Cancer Res; 24(21); 5305-12. (c)2018 AACR. PMID- 30021912 TI - Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis. AB - Sepsis is a profoundly morbid and life-threatening condition, and an increasingly alarming burden on modern healthcare economies. Patients with septic shock exhibit persistent hypotension despite adequate volume resuscitation requiring pharmacological vasoconstrictors, but the molecular mechanisms of this phenomenon remain unclear. The accumulation of misfolded proteins is linked to numerous diseases, and it has been observed that soluble oligomeric protein intermediates are the primary cytotoxic species in these conditions. Oligomeric protein assemblies have been shown to bind and activate a variety of pattern recognition receptors (PRRs) including formyl peptide receptor (FPR). While inhibition of endoplasmic reticulum (ER) stress and stabilization of protein homeostasis have been promising lines of inquiry regarding sepsis therapy, little attention has been given to the potential effects that the accumulation of misfolded proteins may have in driving sepsis pathogenesis. Here we propose that in sepsis, there is an accumulation of toxic misfolded proteins in the form of soluble protein oligomers (SPOs) that contribute to the inflammation and vascular dysfunction observed in sepsis via the activation of one or more PRRs including FPR. Our laboratory has shown increased levels of SPOs in the heart and intrarenal arteries of septic mice. We have also observed that exposure of resistance arteries and vascular smooth muscle cells to SPOs is associated with increased mitogen-activated protein kinase (MAPK) signaling including phosphorylated extracellular signal-regulated kinase (p-ERK) and p-P38 MAPK pathways, and that this response is abolished with the knockout of FPR. This hypothesis has promising clinical implications as it proposes a novel mechanism that can be exploited as a therapeutic target in sepsis. PMID- 30021914 TI - Valsalva-triggered pseudotumor cerebri syndrome: Case series and pathogenetic implications. AB - OBJECTIVE: To report the clinical and radiologic features of 3 patients in whom prolonged vigorous coughing/Valsalva triggered the development of pseudotumor cerebri syndrome (PTCS) that persisted even after the coughing attacks had stopped and to discuss how this novel proximate trigger supports a "hydraulic model" of PTCS pathogenesis. METHODS: This was a retrospective case series of 3 patients seen between January 2011 and July 2017 in a tertiary care neuro ophthalmology clinic. RESULTS: Three female patients (ages 13, 28, and 21 years) were asymptomatic until developing prolonged fits of profuse coughing. Two patients had upper respiratory tract infections, and 1 patient had a prolonged asthma exacerbation. Symptoms typical of PTCS began 2 weeks into the coughing attacks, and patients were examined 1 to 2 weeks after coughing had ceased. One patient was overweight and 2 were obese. All 3 patients had papilledema, and 1 of 3 patients had lateral rectus palsy. Two of 3 patients had visual field defects, and all 3 patients had dural venous sinus stenoses (DVSS) on venous imaging. Lumbar puncture (LP) confirmed elevated opening pressures in 2 of 3 patients and brought immediate and sustained relief of symptoms; LP attempts failed in the third patient because of body habitus (body mass index 68 kg/m2). All patients were given acetazolamide and advised to work on weight loss. At follow-up 3 to 6 months later, all 3 patients had complete remission of their clinical syndromes and resolution of their DVSS on neuroimaging. CONCLUSIONS: In susceptible individuals, prolonged coughing/Valsalva can trigger PTCS in the setting of collapsible (nonfixed) DVSS. This new observation supports a hydraulic model of PTCS pathogenesis. PMID- 30021913 TI - Blastocyst-induced changes in the bovine endometrial transcriptome. AB - The objectives of this study were (i) to determine whether blastocyst-induced responses in endometrial explants were detectable after 6- or 24-h co-culture in vitro; (ii) to test if direct contact is required between embryos and the endometrial surface in order to stimulate endometrial gene expression; (iii) to establish the number of blastocysts required to elicit a detectable endometrial response; (iv) to investigate if upregulation of five interferon-stimulated genes (ISGs) in the endometrium was specific to the blastocyst stage and (v) to test if alterations in endometrial gene expression can be induced by blastocyst conditioned medium. Exposure of endometrial explants to Day 8 blastocysts in vitro for 6 or 24 h induced the expression of ISGs (MX1, MX2, OAS1, ISG15, RSAD2); expression of IFNAR1, IFNAR2, NFKB1, IL1B, STAT1, LGALS3BP, LGALS9, HPGD, PTGES, ITGB1, AKR1C4, AMD1 and AQP4 was not affected. Culture of explants in the presence of more than five blastocysts was sufficient to induce the effect, with maximum expression of ISGs occurring in the presence of 20 blastocysts. This effect was exclusive to blastocyst stage embryos; oocytes, 2-cell embryos or Day 5 morulae did not alter the relative abundance of any of the transcripts examined. Direct contact between blastocysts and the endometrial surface was not required in order to alter the abundance of these transcripts and blastocyst conditioned medium alone was sufficient to stimulate a response. Results support the notion that local embryo-maternal interaction may occur as early as Day 8 of pregnancy in cattle. PMID- 30021915 TI - Severe hyperhomocysteinemia manifesting as moyamoya vasculopathy and Henoch Schonlein purpura. PMID- 30021916 TI - Hypoglossal nerve stimulation on sleep and level of alertness in OSA: A preliminary study. AB - OBJECTIVES: To quantify the effect of hypoglossal nerve stimulation (HNS), a novel therapy for patients with obstructive sleep apnea, on objective level of alertness (measured with Maintenance of Wakefulness Test [MWT] values) and nocturnal sleep architecture. METHODS: Ten male patients (mean age 52.0 +/- 9.4 years; mean body mass index 28.8 +/- 3.3 kg/m2) noncompliant to continuous positive airway pressure received HNS (Inspire therapy) and were prospectively evaluated at baseline and 6 months after HNS therapy. Polysomnographic parameters (sleep breathing and sleep architecture) and objective level of alertness (MWT) were measured. RESULTS: The mean preimplantation apnea-hypopnea index of 46.7/h +/- 12.2/h was reduced to 14.5/h +/- 8.9/h at 6 months postimplantation (p < 0.001). The mean MWT latency improved from 25.0 +/- 12.8 minutes at baseline to 36.8 +/- 7.0 minutes after 6 months of treatment (p = 0.004). A reduction of N1% (11.8 +/- 10.6 vs 4.2 +/- 1.9, p = 0.04) was observed. The reduction in the duration of wake after sleep onset (WASO) was 71.4 +/- 32.4 minutes vs 53.4 +/- 13.5 minutes (p = 0.06) but was not significant. MWT latencies at 6 months were negatively correlated with the intensity of stimulation (r = -0.63, p = 0.05). Intensity of stimulation was positively correlated with WASO (r = 0.76, p = 0.01). CONCLUSION: HNS improved the objective level of alertness and changed nocturnal sleep architecture. The level of neural stimulation determines the amount of nocturnal WASO and the level of objective level of alertness. PMID- 30021917 TI - Neuroimaging and neuropathology indices of cerebrovascular disease burden: A systematic review. AB - OBJECTIVE: To systematically review the literature on the use of both neuroimaging and neuropathologic indices of cerebrovascular disease (CVD) burden, as estimation of this burden could have multiple benefits in the diagnosis and prognosis of cognitive impairment and dementia. METHODS: MEDLINE and EMBASE databases were searched (inception to June 2017) to obtain and then systematically review all pertinent neuroimaging and neuropathology studies, where an index of CVD was developed or tested. RESULTS: Twenty-five neuroimaging articles were obtained, which included 4 unique indices. These utilized a limited range of CVD markers from mainly structural MRI, most commonly white matter hyperintensities (WMH), cerebral microbleeds, and dilated perivascular spaces. Weighting of the constituent markers was often coarse. There were 7 unique neuropathology indices, which were heterogeneous in their regions sampled and lesions examined. CONCLUSION: There is increasing interest in indices of total CVD burden that incorporate multiple lesions, as traditional individual markers of CVD such as WMH only provide limited information. Neuropathologic indices are needed to validate neuroimaging findings. The studies clearly demonstrated proof of concept that information from multiple imaging measures of CVD provide more information, including a stronger association with cognitive impairment and dementia, than that provided by a single measure. There has been limited exploration of the psychometric properties of published indices and no comparison between indices. Further development of indices is recommended, including the use of data from diffusion tensor and perfusion imaging. PMID- 30021918 TI - GABA and hallucinations in Parkinson disease: Who is that sitting on my chair? PMID- 30021919 TI - Differential effects of completed and incomplete pregnancies on the risk of Alzheimer disease. AB - OBJECTIVE: To investigate the effects of completed pregnancy with childbirth and incomplete pregnancy without childbirth on the late-life cognition and the risk of Alzheimer disease (AD) in women. METHODS: Using the pooled data of 3,549 women provided by 2 population-based cohort studies, we conducted logistic regression analyses to examine retrospectively the associations of completed and incomplete pregnancy with the risks of mild cognitive impairment and AD. For women without dementia, we also conducted analyses of covariance to examine the associations of completed and incomplete pregnancy with Mini-Mental State Examination (MMSE) score. RESULTS: Grand multiparous women who experienced >=5 completed pregnancies showed an ~1.7-fold higher risk of AD than those who experienced 1 to 4 completed pregnancies (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.04-2.72), while those who had incomplete pregnancies showed half the level of AD risk compared with those who never experienced an incomplete pregnancy (OR 0.43, 95% CI 0.24 0.76 for 1 incomplete pregnancy; OR 0.56, 95% CI 0.34-0.92 for >=2 incomplete pregnancies). In women without dementia, the grand multiparous had worse MMSE scores than those with 1 to 4 completed pregnancies (p < 0.001), while those who experienced >=1 incomplete pregnancies had better MMSE scores than those who never experienced an incomplete pregnancy (p = 0.008). CONCLUSIONS: Grand multiparity was associated with high risk of AD, while incomplete pregnancy was associated with low risk of AD in late life. PMID- 30021921 TI - The cerebellar histiocytosis: Progressive ataxia is not always a genetic disease. PMID- 30021920 TI - Reduced occipital GABA in Parkinson disease with visual hallucinations. AB - OBJECTIVE: To investigate the relationship between visual hallucinations in Parkinson disease (PD) and levels of gamma-aminobutyric acid (GABA) in the primary visual cortex. METHODS: We utilized magnetic resonance spectroscopy to investigate occipital GABA levels in 36 participants with PD, 19 with and 17 without complex visual hallucinations, together with 20 healthy controls without hallucinations. In addition, we acquired T1-weighted MRI, whole-brain fMRI during a visual task, and diffusion tensor imaging. RESULTS: We found lower GABA+/creatine in PD with visual hallucinations (0.091 +/- 0.010) vs those without (0.101 +/- 0.010) and controls (0.099 +/- 0.010) (F2,49 = 4.5; p = 0.016). Reduced gray matter in the hallucinations group was also observed in the anterior temporal lobe. Although there were widespread reductions in white matter integrity in the visual hallucinations group, this was no longer significant after controlling for cognitive function. CONCLUSIONS: The data suggest that reduced levels of GABA are associated with visual hallucinations in PD and implicate changes to the ventral visual stream in the genesis of visual hallucinations. Modulation of visual cortical excitability through, for example, pharmacologic intervention, may be a promising treatment avenue to explore. PMID- 30021922 TI - Development of a Highly Sensitive Device for Counting the Number of Disease Specific Exosomes in Human Sera. AB - BACKGROUND: Although circulating exosomes in blood play crucial roles in cancer development and progression, difficulties in quantifying exosomes hamper their application for reliable clinical testing. By combining the properties of nanobeads with optical disc technology, we have developed a novel device named the ExoCounter to determine the exact number of exosomes in the sera of patients with various types of cancer. METHOD: In this system, individual exosomes were captured in the groove of an optical disc coated with antibodies against exosome surface antigens. The captured exosomes were labeled with antibody-conjugated magnetic nanobeads, and the number of the labeled exosomes was counted with an optical disc drive. RESULTS: We showed that the ExoCounter could detect specific exosomes derived from cells or human serum without any enrichment procedures. The detection sensitivity and linearity with this system were higher than those with conventional detection methods such as ELISA or flow cytometry. In addition to the ubiquitous exosome markers CD9 and CD63, the cancer-related antigens CD147, carcinoembryonic antigen, and human epidermal growth factor receptor 2 (HER2) were also used to quantify cancer cell line-derived exosomes. Furthermore, analyses of a cross-sectional cohort of sera samples revealed that HER2-positive exosomes were significantly increased in patients with breast cancer or ovarian cancer compared with healthy individuals and those with noncancer diseases. CONCLUSIONS: The ExoCounter system exhibits high performance in the direct detection of exosomes in cell culture and human sera. This method may enable reliable analysis of liquid biopsies. PMID- 30021923 TI - Circulating Adipocyte Fatty Acid-Binding Protein Concentrations Predict Multiple Mortality Outcomes among Men and Women with Diabetes. AB - INTRODUCTION: Raised circulating adipocyte fatty acid-binding protein (AFABP) concentrations are associated with various adverse health conditions. However, their relationship with mortality remains to be defined, especially in view of the sexual dimorphism of circulating AFABP concentrations. Here we investigated prospectively whether serum AFABP concentrations predict multiple mortality outcomes in men and women alike, using a large clinic-based cohort of individuals with type 2 diabetes, a condition with raised AFABP concentrations. METHODS: Baseline serum AFABP concentrations were measured in 5305 research participants with a monoclonal antibody-based sandwich immunoassay. The role of circulating AFABP concentrations in predicting mortality outcomes was evaluated by multivariable Cox regression analysis. RESULTS: Among the 5305 participants (59% men) in this study, over a median follow-up of 5 years, there were 512 deaths (19.3 deaths per 1000 person-years). Circulating AFABP concentrations, with higher levels in women at baseline, predicted all-cause mortality (P < 0.001), cardiovascular mortality (P = 0.037), and infection-related deaths (P < 0.002) among all participants. In sex-specific analyses, circulating AFABP concentration was an independent predictor of all-cause mortality in both men and women and a predictor of cancer-related deaths and infection-related deaths in men only. Furthermore, the addition of serum AFABP concentrations improved the time dependent c statistics in predicting all-cause mortality in participants with type 2 diabetes (P = 0.008). CONCLUSIONS: Circulating AFABP concentration was an independent predictor of various mortality outcomes in type 2 diabetes over and above known risk factors of reduced survival in men and women. The role of AFABP as a prognostic biomarker and therapeutic target warrants further investigation. PMID- 30021925 TI - Optimal experimental design for predator-prey functional response experiments. AB - Functional response models are important in understanding predator-prey interactions. The development of functional response methodology has progressed from mechanistic models to more statistically motivated models that can account for variance and the over-dispersion commonly seen in the datasets collected from functional response experiments. However, little information seems to be available for those wishing to prepare optimal parameter estimation designs for functional response experiments. It is worth noting that optimally designed experiments may require smaller sample sizes to achieve the same statistical outcomes as non-optimally designed experiments. In this paper, we develop a model based approach to optimal experimental design for functional response experiments in the presence of parameter uncertainty (also known as a robust optimal design approach). Further, we develop and compare new utility functions which better focus on the statistical efficiency of the designs; these utilities are generally applicable for robust optimal design in other applications (not just in functional response). The methods are illustrated using a beta-binomial functional response model for two published datasets: an experiment involving the freshwater predator Notonecta glauca (an aquatic insect) preying on Asellus aquaticus (a small crustacean), and another experiment involving a ladybird beetle (Propylea quatuordecimpunctata L.) preying on the black bean aphid (Aphis fabae Scopoli). As a by-product, we also derive necessary quantities to perform optimal design for beta-binomial regression models, which may be useful in other applications. PMID- 30021926 TI - Mechanically inferior constituents in spider silk result in mechanically superior fibres by adaptation to harsh hydration conditions: a molecular dynamics study. AB - Spider silk exhibits mechanical properties such as high strength and toughness that are superior to those of any man-made fibre (Bourzac 2015 Nature519, S4-S6 (doi:10.1038/519S4a)). This high strength and toughness originates from a combination of the crystalline (exhibiting robust strength) and amorphous (exhibiting superb extensibility) regions present in the silk (Asakura et al 2015 Macromolecules48, 2345-2357 (doi:10.1021/acs.macromol.5b00160)). The crystalline regions comprise a mixture of poly-alanine and poly-glycine-alanine. Poly-alanine is expected to be stronger than poly-glycine-alanine, because alanine exhibits greater interactions between the strands than glycine (Tokareva et al 2014 Acta Biomater.10, 1612-1626 (doi:10.1016/j.actbio.2013.08.020)). We connect this characteristic sequence to the interactions observed upon the hydration of spider silk. Like most proteinaceous materials, spider silks become highly brittle upon dehydration, and thus water collection is crucial to maintaining its toughness (Gosline et al 1986 Endeavour10, 37-43 (doi:10.1016/0160-9327(86)90049-9)). We report on the molecular dynamic simulations of spider silk structures with different sequences for the crystalline region of the silk structures, of wild type (WT), poly-alanine, and poly-glycine-alanine. We reveal that the characteristic sequence of spider silk results in the beta-sheets being maintained as the degree of hydration changes and that the high water collection capabilities of WT spider silk sequence prevent the silk from becoming brittle and weak in dry conditions. The characteristic crystalline sequence of spider dragline silk is therefore relevant not for maximizing the interactions between the strands but for adaption to changing hydration conditions to maintain an optimal performance even in harsh conditions. PMID- 30021924 TI - Greater wealth inequality, less polygyny: rethinking the polygyny threshold model. AB - Monogamy appears to have become the predominant human mating system with the emergence of highly unequal agricultural populations that replaced relatively egalitarian horticultural populations, challenging the conventional idea-based on the polygyny threshold model-that polygyny should be positively associated with wealth inequality. To address this polygyny paradox, we generalize the standard polygyny threshold model to a mutual mate choice model predicting the fraction of women married polygynously. We then demonstrate two conditions that are jointly sufficient to make monogamy the predominant marriage form, even in highly unequal societies. We assess if these conditions are satisfied using individual-level data from 29 human populations. Our analysis shows that with the shift to stratified agricultural economies: (i) the population frequency of relatively poor individuals increased, increasing wealth inequality, but decreasing the frequency of individuals with sufficient wealth to secure polygynous marriage, and (ii) diminishing marginal fitness returns to additional wives prevent extremely wealthy men from obtaining as many wives as their relative wealth would otherwise predict. These conditions jointly lead to a high population-level frequency of monogamy. PMID- 30021927 TI - A reversible fluorescent probe for monitoring Ag(I) ions. AB - Silver-containing nanomaterials are of interest for their antibiotic properties, for a wide range of applications from medicine to consumer products. However, much remains to be learnt about the degradation of such materials and their effects on human health. While most analyses involve measurement of total silver levels, it is important also to be able to measure concentrations of active free Ag(I) ions. We report here the preparation of a coumarin-based probe, thiocoumarin silver sensor 1 (TcAg1), that responds reversibly to the addition of silver ions through the appearance of a new fluorescence emission peak at 565 nm. Importantly, this peak is not observed in the presence of Hg(II), a common interferent in Ag(I) sensing. To establish the utility of this sensor, we prepared silver-doped phosphate glasses with demonstrated bactericidal properties, and observed the Ag(I) release from these glasses in solutions of different ionic strength. TcAg1 is therefore a useful tool for the study of the environmental and medical effects of silver-containing materials. PMID- 30021928 TI - Inference-based assessment of parameter identifiability in nonlinear biological models. AB - As systems approaches to the development of biological models become more mature, attention is increasingly focusing on the problem of inferring parameter values within those models from experimental data. However, particularly for nonlinear models, it is not obvious, either from inspection of the model or from the experimental data, that the inverse problem of parameter fitting will have a unique solution, or even a non-unique solution that constrains the parameters to lie within a plausible physiological range. Where parameters cannot be constrained they are termed 'unidentifiable'. We focus on gaining insight into the causes of unidentifiability using inference-based methods, and compare a recently developed measure-theoretic approach to inverse sensitivity analysis to the popular Markov chain Monte Carlo and approximate Bayesian computation techniques for Bayesian inference. All three approaches map the uncertainty in quantities of interest in the output space to the probability of sets of parameters in the input space. The geometry of these sets demonstrates how unidentifiability can be caused by parameter compensation and provides an intuitive approach to inference-based experimental design. PMID- 30021931 TI - Towards optimal visual presentation design for hybrid EEG-fTCD brain-computer interfaces. AB - OBJECTIVE: In this paper, we introduce a novel hybrid brain-computer interface (BCI) system that measures electrical brain activity as well as cerebral blood velocity using electroencephalography (EEG) and functional transcranial Doppler ultrasound (fTCD) respectively in response to flickering mental rotation (MR) and flickering word generation (WG) cognitive tasks as well as a fixation cross that represents the baseline. This work extends our previous approach, in which we showed that motor imagery induces simultaneous changes in EEG and fTCD to enable task discrimination; and hence, provides a design approach for a hybrid BCI. Here, we show that instead of using motor imagery, the proposed visual stimulation technique enables the design of an EEG-fTCD based BCI with higher accuracy. APPROACH: Features based on the power spectrum of EEG and fTCD signals were calculated. Mutual information and support vector machines were used for feature selection and classification purposes. MAIN RESULTS: EEG-fTCD combination outperformed EEG by 4.05% accuracy for MR versus baseline problem and by 5.81% accuracy for WG versus baseline problem. An average accuracy of 92.38% was achieved for MR versus WG problem using the hybrid combination. Average transmission rates of 4.39, 3.92, and 5.60 bits min-1 were obtained for MR versus baseline, WG versus baseline, and MR versus WG problems respectively. SIGNIFICANCE: In terms of accuracy, the current visual presentation outperforms the motor imagery visual presentation we designed before for the EEG-fTCD system by 10% accuracy for task versus task problem. Moreover, the proposed system outperforms the state of the art hybrid EEG-fNIRS BCIs in terms of accuracy and/or information transfer rate. Even though there are still limitations of the proposed system, such promising results show that the proposed hybrid system is a feasible candidate for real-time BCIs. PMID- 30021932 TI - Irregularly timed electrical pulses reduce adaptation of retinal ganglion cells. AB - OBJECTIVE: Retinal prostheses aim to provide visual percepts to blind people affected by diseases caused by photoreceptor degeneration. One of the main challenges presented by current devices is neural adaptation in the retina, which is believed to be the cause of fading-an effect where artificially produced percepts disappear over a short period of time, despite continuous stimulation of the retina. We aim to understand the neural adaptation generated in retinal ganglion cells (RGCs) during electrical stimulation. APPROACH: Current visual prostheses use electrical pulses with fixed frequencies and amplitudes modulated over hundreds of milliseconds to stimulate the retina. However, in nature, neuronal spiking occurs with stochastic timing, hence the information received naturally from other neurons by RGCs is irregularly timed. We used a single epiretinal electrode to stimulate and compare rat RGC responses to stimulus trains of biphasic pulses delivered at regular and random inter-pulse intervals (IPI), the latter taken from an exponential distribution. MAIN RESULTS: Our observations suggest that stimulation with random IPIs result in lower adaptation rates than stimulation with constant IPIs at frequencies of 50 Hz and 200 Hz. We also found a high proportion of lower amplitude action potentials, or spikelets. The spikelets were more prominent at high stimulation frequencies (50 Hz and 200 Hz) and were less susceptible to adaptation, but it was not clear if they propagated along the axon. SIGNIFICANCE: Using random IPI stimulation in retinal prostheses reduces the decay of RGCs and this could potentially reduce fading of electrically induced visual perception. PMID- 30021930 TI - Signatures of photo-aging and intrinsic aging in skin were revealed by transcriptome network analysis. AB - There are various factors that alter physiological characteristics in skin. Elucidating the underlying mechanism of transcriptional alterations by intrinsic and extrinsic factors may lead us to understand the aging process of skin. To identify the transcriptomic changes of the aging skin, we analyzed publicly available RNA sequencing data from Genotype-Tissue Expression (GTEx) project. GTEx provided RNA sequencing data of suprapubic (n=228) and lower leg (n=349) skins, which are photo-protected and photo-damaged. Using differentially expressed gene analysis and weighted gene co-expression network analysis, we characterized transcriptomic changes due to UV exposure and aging. Genes involved in skin development such as epidermal differentiation complex component (SPRR and LCE families), vasculature development (TGFBR1, TGFBR2, TGFBR3, KDR, FGF2, and VEGFC), and matrix metalloproteinase (MMP2, MMP3, MMP8, MMP10, and MMP13) were up regulated by UV exposure. Also, down-regulated lipid metabolism and mitochondrial biogenesis were observed in photo-damaged skin. Moreover, wound healing process was universally down-regulated in suprapubic and lower leg with aging and further down-regulation of lipid metabolism and up-regulation of vasculature development were found as photo-aging signatures. In this study, dynamic transcriptomic alterations were observed in aged skin. Hence, our findings may help to discover a potential therapeutic target for skin rejuvenation. PMID- 30021929 TI - Conformational dynamics and enzyme evolution. AB - Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-of-the-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutations. PMID- 30021933 TI - Overexpression of the Rybp Gene Inhibits Differentiation of Bovine Myoblasts into Myotubes. AB - RING1 and YY1 binding protein (Rybp) genes inhibit myogenesis in mice, but there are no reports on the effects of these genes in cattle. The aim of this study is to investigate the roles of the Rybp gene on bovine skeletal muscle development and myoblast differentiation. In the present study, the Rybp gene was overexpressed in bovine myoblasts via adenovirus. RNA-seq was performed to screen differentially expressed genes (DEGs). The results showed that overexpressing the Rybp gene inhibits the formation of myotubes. The morphological differences in myoblasts began on the second day and were very significant 6 days after adenovirus induction. A total of 1311 (707 upregulated and 604 downregulated) DEGs were screened using RNA-seq between myoblasts with added negative control adenoviruses (AD-NC) and Rybp adenoviruses (AD-Rybp) after 6 days of induction. Gene ontology (GO) and KEGG analysis revealed that the downregulated DEGs were mainly involved in biological functions related to muscle, and, of the 32 pathways, those associated with muscle development were significantly enriched for the identified DEGs. This study can not only provide a theoretical basis for the regulation of skeletal muscle development in cattle by exploring the roles of the Rybp gene in myoblast differentiation, but it can also lay a theoretical foundation for molecular breeding of beef cattle. PMID- 30021934 TI - In the Digital Era, Is Community Outrage a Feasible Proxy Indicator of Emotional Epidemiology? The Case of Meningococcal Disease in Sardinia, Italy. AB - The aims of this study were (i) to evaluate the relationship between official data on invasive meningococcal disease cases in Sardinia and the reporting of the cases by a regional online newspaper and (ii) to identify indicators useful for understanding the community outrage related to health events. Cases of meningococcal disease, selected from articles published between 1999 and 2016 on a regional newspaper database, were compared to those reported to the Infectious Disease Information Service. In order to evaluate the equality of the two distribution records, the Kolgomorov Smirnov test for two samples was applied. A community outrage indicator was obtained by calculating the number of published articles for each case of meningococcal disease identified. The outrage indicator was evaluated in comparison with other phenomena: drinking water supply limitation and domestic accidents. Overall, 2724 articles on meningitis/sepsis referring to 89 cases related to meningococcal disease were considered. Significant differences between the distribution of cases officially reported and those found in the newspaper (combined K-S = 0.39; p = 0.08) were not observed. The meningococcal disease outrage indicator showed an average of seven items per case. Comparing the meningococcal disease outrage indicator with those regarding the limitation of drinking water supplies and domestic accidents, a different risk perception by the reference media was found, with the highest outrage for meningococcal disease. The present study supports the role played by emotional factors as behavioral determinants in emerging threats to public health. The analysis of the data allowed us to highlight that the proposed outrage indicator could be a feasible proxy of emotional epidemiology. Finally, data confirm that meningitis is perceived as a highly outrageous health threat. PMID- 30021935 TI - In Vitro Cytotoxicity and Morphological Assessments of GO-ZnO against the MCF-7 Cells: Determination of Singlet Oxygen by Chemical Trapping. AB - Graphene-based materials have attracted considerable interest owing to their distinctive characteristics, such as their biocompatibility in terms of both their physical and intrinsic chemical properties. The use of nanomaterials with graphene as a biocompatible agent has increased due to an uptick in dedication from biomedical investigators. Here, GO-ZnO was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), ultraviolet-visible (UV-Vis) spectroscopy, energy dispersive X-ray analysis (EDAX), and Raman spectroscopy for structural, morphological, and elemental analysis. The toxic extent of GO-ZnO was noted by a methyl-thiazole-tetrazolium (MTT), while cellular morphology was observed towards the MCF-7 cells using an inverted microscope at magnification 40*. The cytotoxic effect of GO-ZnO investigated the cell viability reduction in a dose-dependent manner, as well as prompted the cell demise/destruction in an apoptotic way. Moreover, statistical analysis was performed on the experimental outcomes, with p-values < 0.05 kept as significant to elucidate the results. The generation of reactive oxygen species (ROS) demonstrated the potential applicability of graphene in tumor treatment. These key results attest to the efficacy of GO-ZnO nanocomposites as a substantial candidate for breast malignancy treatment. PMID- 30021936 TI - Interference with Processing Negative Stimuli in Problematic Internet Users: Preliminary Evidence from an Emotional Stroop Task. AB - Although it has been proposed that problematic Internet use (PIU) may represent a dysfunctional coping strategy in response to negative emotional states, there is a lack of experimental studies that directly test how individuals with PIU process emotional stimuli. In this study, we used an emotional Stroop task to examine the implicit bias toward positive and negative words in a sample of 100 individuals (54 females) who also completed questionnaires assessing PIU and current affect states. A significant interaction was observed between PIU and emotional Stroop effects (ESEs), with participants who displayed prominent PIU symptoms showing higher ESEs for negative words compared to other participants. No significant differences were found on the ESEs for positive words among participants. These findings suggest that PIU may be linked to a specific emotional interference with processing negative stimuli, thus supporting the view that PIU is a dysfunctional strategy to cope with negative affect. A potential treatment implication for individuals with PIU includes a need to enhance the capacity to process and regulate negative feelings. PMID- 30021937 TI - Ginsenoside Drug Nanocomposites Prepared by the Aerosol Solvent Extraction System for Enhancing Drug Solubility and Stability. AB - Ginsenosides are the pharmacologically active constituents of ginseng. So far, more than 30 ginsenosides have been identified and widely used in pharmaceutical formulations. However, the therapeutic applications of ginsenosides are hampered by their poor solubility and low bioavailability. In this study, we selected two of the most important ginsenosides-Re and Rh2 as model drugs to prepare ginsenoside drug nanocomposites (NanoGS) using the simple aerosol solvent extraction system (ASES) technique to address the poor solubility and bioavailability of these compounds. Compared with raw ginsenosides, NanoGS exhibited significantly enhanced dissolution rate owing to their low crystallinity and high surface area. Furthermore, in vitro cellular investigations showed that NanoGS-Rh2 exhibited outstanding anticancer activity against MCF-7 cancer cells. Therefore, this study is expected to provide a promising strategy that could optimize and broaden the applications of ginsenosides, as well as other water-insoluble drugs in pharmaceutical formulations. PMID- 30021938 TI - Project SoL-A Community-Based, Multi-Component Health Promotion Intervention to Improve Healthy Eating and Physical Activity Practices among Danish Families with Young Children Part 2: Evaluation. AB - Project SoL is implemented over a period of four years with the aim to promote healthy eating and physical activity among children aged 3-8 years by targeting the families in a Danish municipality based on the multi-component, supersetting strategy. Interventions are implemented in childcare centres, schools and supermarkets in three local communities as well as in local mass media and social media during a 19 months period in the Municipality of Bornholm. The matching Municipality of Odsherred serves as a control site based on its similarity to Bornholm regarding several socio-demographic and health indicators. The present paper gives an account of the design used for the summative and formative evaluation based on a realistic evaluation and a mixed methods approach combining qualitative and quantitative methods. Summative studies are conducted on changes of health behaviours among the involved families and within the municipalities in general, changes in community awareness of the project, changes in purchase patterns, changes in overweight and obesity among the targeted children and changes in knowledge and preferences among children due to sensory education workshops. The formative research comprises studies on children's perceptions of health, perceptions of staff at supermarkets and media professionals on their roles in supporting the health promotion agenda, and motivations and barriers of community stakeholders to engage in health promotion at community level. The paper discusses operational issues and lessons learnt related to studying complex community interventions, cross-disciplinarily, interfaces between practice and research and research capacity strengthening; and suggests areas for future research. The development and implementation of the intervention and its theoretical foundation is described in a separate paper. PMID- 30021939 TI - A Novel Squirrel Respirovirus with Putative Zoonotic Potential. AB - In a globalized world, the threat of emerging pathogens plays an increasing role, especially if their zoonotic potential is unknown. In this study, a novel respirovirus, family Paramyxoviridae, was isolated from a Sri Lankan Giant squirrel (Ratufa macroura), which originated in Sri Lanka and deceased with severe pneumonia in a German zoo. The full-genome characterization of this novel virus, tentatively named Giant squirrel respirovirus (GSqRV), revealed similarities to murine (71%), as well as human respiroviruses (68%) with unique features, for example, a different genome length and a putative additional accessory protein. Congruently, phylogenetic analyses showed a solitary position of GSqRV between known murine and human respiroviruses, implicating a putative zoonotic potential. A tailored real-time reverse transcription-polymerase chain reaction (RT-qPCR) for specific detection of GSqRV confirmed a very high viral load in the lung, and, to a lesser extent, in the brain of the deceased animal. A pilot study on indigenous and exotic squirrels did not reveal additional cases in Germany. Therefore, further research is essential to assess the geographic distribution, host range, and zoonotic potential of this novel viral pathogen. PMID- 30021940 TI - A Prosthodontic Treatment Plan for a Saxophone Player: A Conceptual Approach. AB - INTRODUCTION: A wind instrumentalist was diagnosed with a periapical lesion on tooth 21. The prosthetic rehabilitation options were considered with respect to the embouchure mechanism of the saxophonist. The underlying mechanism associated with the embouchure of the saxophone player was observed in this particular case in order to understand if asymmetrical forces were transmitted to the upper central incisors. Periapical lesions can be harmful to the oral health of musicians. The treatment options thus have to be taken into consideration with special focus on the need for oral rehabilitation on the anterior maxilla. MATERIAL AND METHODS: The patient underwent a radiographic examination with a panoramic X-ray. Subsequently, two piezoresistive sensors (FlexiForceTM) were placed on the upper surface of the mouthpiece in order to quantify the pressure applied to the central incisors during the embouchure. In order to understand the values involved during this procedure, the saxophone player was required to play three different notes at different pitches: high, medium, and low. This procedure was repeated three times for each pitch in order to obtain a medium value for each note. Signal acquisition was obtained within software developed for this purpose, with the voltage output observed in LabView 2011(r). RESULTS: The panoramic X-ray showed a periapical lesion with the characteristics of a radicular cyst on tooth 21. The FlexiForceTM piezoresistive sensors allowed us to find that greater force (kg) was being applied to tooth 11 in comparison to tooth 21 during the embouchure mechanism. CONCLUSIONS: The sensors used in this research are acceptable for identifying the tooth where the greatest pressure is applied during the mouthpiece stabilization. In the case of executing an oral rehabilitation procedure for wind instrumentalists, a clinical examination can be complemented with the aid of bioengineering and the inherent development of sensor technology in order to better understand the embouchure mechanism. Likewise, the prosthetic rehabilitation should be taken into consideration in order to provide minimal changes to the musician's performance. PMID- 30021942 TI - Effects of Solidification Cooling Rate on the Microstructure and Mechanical Properties of a Cast Al-Si-Cu-Mg-Ni Piston Alloy. AB - The effects of cooling rate 0.15, 1.5, 15, 150, and 1.5 * 105 degrees C/s on the microstructures and mechanical properties of Al-13Si-4Cu-1Mg-2Ni cast piston alloy were investigated. The results show that with an increase of solidification cooling rate, the secondary dendrite arm spacing (SDAS) of this model alloy can be calculated using the formula D = 47.126v - 1/3. The phases formed during the solidification with lower cooling rates primarily consist of eutectic silicon, M Mg2Si phase, gamma-Al7Cu4Ni phase, delta-Al3CuNi phase, epsilon-Al3Ni phase, and Q-Al5Cu2Mg8Si6 phase. With the increase in the solidification cooling rate from 0.15 to 15 degrees C/s, the hardness increased from 80.9 to 125.7 HB, the room temperature tensile strength enhanced from 189.3 to 282.5 MPa, and the elongation at break increased from 1.6% to 2.8%. The epsilon -Al3Ni phase disappears in the alloy and the Q phase emerges. The delta phase and the gamma phase change from large-sized meshes and clusters to smaller meshes and Chinese script patterns. Further increase in the cooling rate leads to the micro hardness increasing gradually from 131.2 to 195.6 HV and the alloy solidifying into a uniform structure and forming nanocrystals. PMID- 30021941 TI - Protective Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate on Abeta1-42-Induced Cognitive Deficit, Oxidative Stress, Inflammation, and Apoptosis in Mice. AB - Alzheimer's disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of beta-amyloid oligomers (Abeta1-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated Abeta1-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following Abeta1-42O injection were reduced by 6 MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy. PMID- 30021944 TI - Behavior of an Inductive Loop Sensor in the Measurement of Partial Discharge Pulses with Variations in Its Separation from the Primary Conductor. AB - Ideally, an insulation system must be capable of electrically insulating the active components of a machine or device subjected to high voltages. However, due to the presence of polluting agents or imperfections inside or on the surface of the insulation, small current pulses called partial discharges (PDs) are common, which partially short-circuit the insulation and cause it to lose its insulating properties, and thus its insulation capacity, over time. In some cases, measurements of this phenomenon are limited by the type of sensor used; if it is not adequate, it can distort the obtained results, which can lead to a misdiagnosis of the state of the device. The inductive loop sensor has experimentally been demonstrated to be capable of properly measuring different types of PDs. However, because of its current design, there are several practical limitations on its use in real devices or environments. An example is the presence of a primary conductor located at a fixed distance from the sensor, through which PD pulses must flow for the sensor to capture them. In this article, the sensor's behavior is studied at different separation distances from the line through which the PD pulses flow. In addition, the measuring capacity of the sensor is tested by removing the presence of the primary conductor and placing the sensor directly over the line through which the PD pulses of a real device flow. PMID- 30021945 TI - Trivariate Empirical Mode Decomposition via Convex Optimization for Rolling Bearing Condition Identification. AB - As a multichannel signal processing method based on data-driven, multivariate empirical mode decomposition (MEMD) has attracted much attention due to its potential ability in self-adaption and multi-scale decomposition for multivariate data. Commonly, the uniform projection scheme on a hypersphere is used to estimate the local mean. However, the unbalanced data distribution in high dimensional space often conflicts with the uniform samples and its performance is sensitive to the noise components. Considering the common fact that the vibration signal is generated by three sensors located in different measuring positions in the domain of the structural health monitoring for the key equipment, thus a novel trivariate empirical mode decomposition via convex optimization was proposed for rolling bearing condition identification in this paper. For the trivariate data matrix, the low-rank matrix approximation via convex optimization was firstly conducted to achieve the denoising. It is worthy to note that the non convex penalty function as a regularization term is introduced to enhance the performance. Moreover, the non-uniform sample scheme was determined by applying singular value decomposition (SVD) to the obtained low-rank trivariate data and then the approach used in conventional MEMD algorithm was employed to estimate the local mean. Numerical examples of synthetic defined by the fault model and real data generated by the fault rolling bearing on the experimental bench are provided to demonstrate the fruitful applications of the proposed method. PMID- 30021943 TI - Beneficial Impact and Molecular Mechanism of Bacillus coagulans on Piglets' Intestine. AB - The aim of this research was to investigate the beneficial impact and molecular mechanism of B. coagulans on piglets' intestine. Twenty-four 21 days old weaned piglets were allotted to three treatments: Control group (basal diet), B6 group (basal diet + 2 * 106 CFU/g B. coagulans), and the B7 group (basal diet + 2 * 107 CFU/g B. coagulans). The results showed that, compared with the control group, the B7 group had a reduced cholesterol content and gamma glutamyl transpeptidase (GGT) in plasma (p < 0.05); the B6 and B7 groups had a significantly decreased diarrhea rate and diamine oxidase (DAO) activity in plasma (p < 0.05), increased villus height in ileum and decreased crypt depth in the jejunum (p < 0.05); increased activities of superoxide dismutase (SOD) and catalase (CAT), and decreased the content of malondialdehyde (MDA) and H2O2 in the intestine (p < 0.05). These data suggested that supplementing B. coagulans had beneficial impacts on promoting nutrients' metabolism, maintaining intestinal integrity, and alleviating oxidative stress and diarrhea. Further research of molecular mechanisms showed changing expression levels of related proteins and genes, suggesting that these could be involved in the regulation of the impact. The community composition of the gut microbiota was also found to be altered in several operational taxonomic units within the genus, Prevotella (order Bacteroidales), and the order, Clostridiales. PMID- 30021948 TI - Effects of Cold Rolling and Annealing Prior to Dealloying on the Microstructure of Nanoporous Gold. AB - The properties of nanoporous gold (NPG) were known to be dependent on the microstructure of NPG. In this study, the effects of cold rolling and annealing of the original Ag0.7Au0.3 alloy on the microstructure of NPG produced by dealloying under free corrosion condition were investigated. Ag0.7Au0.3 alloy samples were cold-rolled to different strain levels/thickness reductions up to 98% and annealed at 900 degrees C for 3 h before dealloying. It was found that cold rolling and annealing of the original alloy can lead to reduced ligament and pore sizes of NPG. Moreover, post-deformation annealing of the original alloy was found to facilitate the formation of a homogeneous and continuous NPG structure. The minima of pore and ligament sizes (both being ~8 nm) with uniform distribution were obtained in the annealed sample with a thickness reduction of 60% for a dealloying time of 7 h. The present study indicated the significant effect of a pre-dealloying treatment of the original alloy (by plastic deformation and annealing) on the formation and optimization of the NPG microstructure produced by dealloying. PMID- 30021949 TI - Systematic Development of Self-Nanoemulsifying Liquisolid Tablets to Improve the Dissolution and Oral Bioavailability of an Oily Drug, Vitamin K1. AB - The purpose of this study is to improve the dissolution and oral bioavailability of an oily drug, vitamin K1 (VK1) by combination of self-nanoemulsifying and liquisolid technologies. The optimal liquid self-nanoemulsifying drug delivery systems (SNEDDS) formulation including VK1 (oil), mixture of soybean lecithin and glycocholic acid (surfactant) and Transcutol HP (cosurfactant) was obtained according to ternary phase diagrams and a central composite design. Based on compatibility, adsorption capacity and dissolution profile, liquid SNEDDS was then solidified on Fujicalin(r) to form solid SNEDDS by liquisolid technology and compressed directly with excipients into self-nanoemulsifying liquisolid (SNE-L) tablets. Uniform nano-emulsion suspension was formed rapidly when the SNE-L tablets disintegrated in dissolution media and higher drug dissolution was observed compared with the conventional tablets. The results of pharmacokinetic study in beagle dogs showed that the mean Cmax and the area under the curve of SNE-L tablets were remarkably higher than those of conventional tablets, which were consistent with the results of the in vitro dissolution. The relative bioavailability of SNE-L tablets and conventional tablets was approximately 200%. In conclusion, this combination method showed promise to improve the dissolution and oral bioavailability of oily drug vitamin K1. PMID- 30021946 TI - Constitutive Expression of Aechmea fasciata SPL14 (AfSPL14) Accelerates Flowering and Changes the Plant Architecture in Arabidopsis. AB - Variations in flowering time and plant architecture have a crucial impact on crop biomass and yield, as well as the aesthetic value of ornamental plants. Aechmea fasciata, a member of the Bromeliaceae family, is a bromeliad variety that is commonly cultivated worldwide. Here, we report the characterization of AfSPL14, a squamosa promoter binding protein-like gene in A. fasciata. AfSPL14 was predominantly expressed in the young vegetative organs of adult plants. The expression of AfSPL14 could be upregulated within 1 h by exogenous ethephon treatment. The constitutive expression of AfSPL14 in Arabidopsis thaliana caused early flowering and variations in plant architecture, including smaller rosette leaves and thicker and increased numbers of main inflorescences. Our findings suggest that AfSPL14 may help facilitate the molecular breeding of A. fasciata, other ornamental and edible bromeliads (e.g., pineapple), and even cereal crops. PMID- 30021950 TI - Clutter and Range Ambiguity Suppression Using Diverse Pulse Train in Pulse Doppler System. AB - Pulse Doppler (PD) systems are widely used for moving target detection, especially in scenarios with clutter. Range ambiguity, which arises from fixed parameters in waveforms, is an inherent drawback in conventional systems. By using a diverse pulse train such as a train of coherent diverse phase coded pulses, these ambiguous peaks can be suppressed effectively but at the cost of sidelobe dispersions. In this work, a novel efficient PD process is proposed to suppress range ambiguity and detect moving targets under strong clutter. Poly phase coded pulses are employed along with optimal receiving filters, by which the dispersed sidelobes are mitigated to a great extent. Moreover, a novel clutter suppression procedure is included in the PD process, by which strong clutter can be greatly suppressed. Well-designed receiving and inverse filters are employed. Simulation examples are presented to verify the theories. Compared with conventional methods, much better detection results are obtained for both near and remote targets, especially in scenarios with strong clutter. PMID- 30021947 TI - Gene Level Regulation of Na,K-ATPase in the Renal Proximal Tubule Is Controlled by Two Independent but Interacting Regulatory Mechanisms Involving Salt Inducible Kinase 1 and CREB-Regulated Transcriptional Coactivators. AB - For many years, studies concerning the regulation of Na,K-ATPase were restricted to acute regulatory mechanisms, which affected the phosphorylation of Na,K ATPase, and thus its retention on the plasma membrane. However, in recent years, this focus has changed. Na,K-ATPase has been established as a signal transducer, which becomes part of a signaling complex as a consequence of ouabain binding. Na,K-ATPase within this signaling complex is localized in caveolae, where Na,K ATPase has also been observed to regulate Inositol 1,4,5-Trisphosphate Receptor (IP3R)-mediated calcium release. This latter association has been implicated as playing a role in signaling by G Protein Coupled Receptors (GPCRs). Here, the consequences of signaling by renal effectors that act via such GPCRs are reviewed, including their regulatory effects on Na,K-ATPase gene expression in the renal proximal tubule (RPT). Two major types of gene regulation entail signaling by Salt Inducible Kinase 1 (SIK1). On one hand, SIK1 acts so as to block signaling via cAMP Response Element (CRE) Binding Protein (CREB) Regulated Transcriptional Coactivators (CRTCs) and on the other hand, SIK1 acts so as to stimulate signaling via the Myocyte Enhancer Factor 2 (MEF2)/nuclear factor of activated T cell (NFAT) regulated genes. Ultimate consequences of these pathways include regulatory effects which alter the rate of transcription of the Na,K ATPase beta1 subunit gene atp1b1 by CREB, as well as by MEF2/NFAT. PMID- 30021951 TI - Pharmacokinetics of Salicylic Acid Following Intravenous and Oral Administration of Sodium Salicylate in Sheep. AB - The pharmacokinetics of salicylic acid (SA) in sheep was evaluated following intravenous (IV) and oral administration of sodium salicylate (sodium salt of salicylic acid) at different doses. Six healthy sheep were administered sodium salicylate (SS) IV at doses of 10, 50, 100 and 200 mg/kg body weight and another six sheep were drenched with 100 and 200 mg/kg of SS orally. Both studies were randomised crossover trials. A one-week washout period between each treatment was allowed in both studies. Blood samples were collected at 0, 15, 30 min and 1, 2, 4 and 6 h after IV and oral SS administrations. Plasma SA concentrations were determined using high-performance liquid chromatography (HPLC) with diode array detection method. Pharmacokinetic variables were calculated in a non compartmental model. The elimination half-life (T1/2 el) of SA after IV administration of 200 mg/kg SS was 1.16 +/- 0.32 h. Mean bioavailability of SA was 64%, and mean T1/2 el was 1.90 +/- 0.35 h, after 200 mg/kg of oral SS. The minimum plasma SA concentration (16.8 ug/mL) reported to produce analgesia in humans was achieved after IV administration of 100 and 200 mg/kg SS in sheep for about 0.17 h in this study. Experiments on pharmacokinetic-pharmacodynamics modelling are required to determine the actual effective plasma concentration range of SA in sheep. PMID- 30021952 TI - Pancreatic Cancer Related Health Disparities: A Commentary. AB - We summarize the risk factors that may significantly contribute to racial disparities in pancreatic cancer, which is now the third leading cause of cancer deaths and projected to be second around 2030 in 12 years. For decades, the incidence rate of pancreatic cancer among Blacks has been 30% to 70% higher than other racial groups in the United States and the 5-year survival rate is approximately 5%. Diabetes and obesity have been identified as potentially predisposing factors to pancreatic cancer and both are more common among Blacks. Smoking continues to be one of the most important risk factors for pancreatic cancer and smoking rates are higher among Blacks compared to other racial groups. The overall risk of pancreatic cancer due to changes in DNA is thought to be the same for most racial groups; however, DNA methylation levels have been observed to be significantly different between Blacks and Whites. This finding may underlie the racial disparities in pancreatic cancer. Identification and prevention of these factors may be effective strategies to reduce the high incidence and mortality rates for pancreatic cancer among Blacks. PMID- 30021954 TI - Terahertz Image Detection with the Improved Faster Region-Based Convolutional Neural Network. AB - In recent years, terahertz imaging systems and techniques have been developed and have gradually become a leading frontier field. With the advantages of low radiation and clothing-penetrable, terahertz imaging technology has been widely used for the detection of concealed weapons or other contraband carried on personnel at airports and other secure locations. This paper aims to detect these concealed items with deep learning method for its well detection performance and real-time detection speed. Based on the analysis of the characteristics of terahertz images, an effective detection system is proposed in this paper. First, a lots of terahertz images are collected and labeled as the standard data format. Secondly, this paper establishes the terahertz classification dataset and proposes a classification method based on transfer learning. Then considering the special distribution of terahertz image, an improved faster region-based convolutional neural network (Faster R-CNN) method based on threshold segmentation is proposed for detecting human body and other objects independently. Finally, experimental results demonstrate the effectiveness and efficiency of the proposed method for terahertz image detection. PMID- 30021953 TI - "In Their Own Voice"-Incorporating Underlying Social Determinants into Aboriginal Health Promotion Programs. AB - Despite growing acknowledgement of the socially determined nature of health disparities among Aboriginal people, how to respond to this within health promotion programs can be challenging. The legacy of Australia's assimilation policies have left profound consequences, including social marginalisation, limited educational opportunities, normalisation of premature death, and entrenched trauma. These social determinants, in conjunction with a reluctance to trust authorities, create barriers to accessing healthcare services for the prevention, treatment, and rehabilitation of chronic disease. The Heart Health program is a culturally sensitive cardiac rehabilitation program run at the local Aboriginal Medical Service in Perth, Western Australia that has since moved beyond cardiac education to provide a holistic approach to chronic disease management. A participatory action research framework was used to explore Heart Health participant and service provider perspectives on the barriers, enablers, and critical success factors to program participation and behaviour change. Thematic analysis of interview transcripts was undertaken, and through yarning (Aboriginal storytelling) sessions, many participants made unprompted reference to the impacts of white settlement, discrimination, and the forced fracturing of Aboriginal families, which have been explored in this paper reiterating the need for a social determinants lens to be taken when planning and implementing Aboriginal health promotion programs. PMID- 30021957 TI - Differential Toxicity of Cyanobacteria Isolated from Marine Sponges towards Echinoderms and Crustaceans. AB - Marine sponges and cyanobacteria have a long history of co-evolution, with documented genome adaptations in cyanobionts. Both organisms are known to produce a wide variety of natural compounds, with only scarce information about novel natural compounds produced by cyanobionts. In the present study, we aimed to address their toxicological potential, isolating cyanobacteria (n = 12) from different sponge species from the coast of Portugal (mainland, Azores, and Madeira Islands). After large-scale growth, we obtained both organic and aqueous extracts to perform a series of ecologically-relevant bioassays. In the acute toxicity assay, using nauplii of Artemia salina, only organic extracts showed lethality, especially in picocyanobacterial strains. In the bioassay with Paracentrotus lividus, both organic and aqueous extracts produced embryogenic toxicity (respectively 58% and 36%), pointing to the presence of compounds that interfere with growth factors on cells. No development of pluteus larvae was observed for the organic extract of the strain Chroococcales 6MA13ti, indicating the presence of compounds that affect skeleton formation. In the hemolytic assay, none of the extracts induced red blood cells lysis. Organic extracts, especially from picoplanktonic strains, proved to be the most promising for future bioassay guided fractionation and compounds isolation. This approach allows us to classify the compounds extracted from the cyanobacteria into effect categories and bioactivity profiles. PMID- 30021955 TI - Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies. AB - Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients' survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author's own experiences/views. PMID- 30021956 TI - Possible Biological Mechanisms Linking Mental Health and Heat-A Contemplative Review. AB - This review provides examples of possible biological mechanisms that could, at least partly, explain the existing epidemiological evidence of heatwave-related exacerbation of mental disease morbidity. The author reviews the complicated central processes involved in the challenge of maintaining a stable body temperature in hot environments, and the maladaptive effects of certain psychiatric medicines on thermoregulation. In addition, the author discusses some alternative mechanisms, such as interrupted functional brain connectivity and the effect of disrupted sleep, which may further increase the vulnerability of mental health patients during heatwaves. PMID- 30021958 TI - Low-Molecular-Weight Heparins: Reduced Size Particulate Systems for Improved Therapeutic Outcomes. AB - A wide range of diseases have been treated using low-molecular-weight heparins (LMWHs), the drug of choice for anticoagulation. Owing to their better pharmacokinetic features compared to those of unfractionated heparin (uFH), several systems incorporating LMWHs have been investigated to deliver and improve their therapeutic outcomes, especially through development of their micro- and nano-particles. This review article describes current perspectives on the fabrication, characterization, and application of LMWHs-loaded micro- and nano particles to achieve ameliorated bioavailability. The valuable applications of LMWH will continue to encourage researchers to identify efficient delivery systems that have specific release characteristics and ameliorated bioavailability, overcoming the challenges presented by biological obstructions and the physicochemical properties of LMWHs. PMID- 30021960 TI - Verdazyls as Possible Building Blocks for Multifunctional Molecular Materials: A Case Study on 1,5-Diphenyl-3-(p-iodophenyl)-verdazyl Focusing on Magnetism, Electron Transfer and the Applicability of the Sonogashira-Hagihara Reaction. AB - This work explores the use of Kuhn verdazyl radicals as building blocks in multifunctional molecular materials in an exemplary study, focusing on the magnetic and the electron transfer (ET) characteristics, but also addressing the question whether chemical modification by cross-coupling is possible. The ET in solution is studied spectroscopically, whereas solid state measurements afford information about the magnetic susceptibility or the conductivity of the given samples. The observed results are rationalized based on the chemical structures of the molecules, which have been obtained by X-ray crystallography. The crystallographically observed molecular structures as well as the interpretation based on the spectroscopic and physical measurements are backed up by DFT calculations. The measurements indicate that only weak, antiferromagnetic (AF) coupling is observed in Kuhn verdazyls owed to the low tendency to form face-to face stacks, but also that steric reasons alone are not sufficient to explain this behavior. Furthermore, it is also demonstrated that ET reactions proceed rapidly in verdazyl/verdazylium redox couples and that Kuhn verdazyls are suited as donor molecules in ET reactions. PMID- 30021959 TI - Bacteriophages of Myxococcus xanthus, a Social Bacterium. AB - Bacteriophages have been used as molecular tools in fundamental biology investigations for decades. Beyond this, however, they play a crucial role in the eco-evolutionary dynamics of bacterial communities through their demographic impact and the source of genetic information they represent. The increasing interest in describing ecological and evolutionary aspects of bacteria-phage interactions has led to major insights into their fundamental characteristics, including arms race dynamics and acquired bacterial immunity. Here, we review knowledge on the phages of the myxobacteria with a major focus on phages infecting Myxococcus xanthus, a bacterial model system widely used to study developmental biology and social evolution. In particular, we focus upon the isolation of myxophages from natural sources and describe the morphology and life cycle parameters, as well as the molecular genetics and genomics of the major groups of myxophages. Finally, we propose several interesting research directions which focus on the interplay between myxobacterial host sociality and bacteria phage interactions. PMID- 30021963 TI - Stretchable Supercapacitors Based on Carbon Nanotubes-Deposited Rubber Polymer Nanofibers Electrodes with High Tolerance against Strain. AB - We report a new fabrication method for a fully stretchable supercapacitor based on single wall carbon nanotube (SWCNT)-coated electrospun rubber nanofibers as stretchable supercapacitor electrodes. The deposition conditions of SWCNT on hydrophobic rubber nanofibers are experimentally optimized to induce a uniform coating of SWCNT. For surfactant-assisted coating of SWCNT, both water contact angle and sheet resistance were lower compared to the cases with other surface treatment methods, indicating a more effective coating approach. The excellent electromechanical properties of this electrode under stretching conditions are demonstrated by the measurement of Young's modulus and normalized sheet resistance. The superb tolerance of the electrode with respect to stretching is the result of (i) high aspect ratios of both nanofiber templates and the SWCNT conductors, (ii) the highly elastic nature of rubbery nanofibers, and (iii) the strong adherence of SWCNT-coated nanofibers on the elastic ecoflex substrate. Electrochemical and electromechanical measurements on stretchable supercapacitor devices reveal that the volumetric capacitance (15.2 F cm-3 at 0.021 A cm-3) of the unstretched state is maintained for strains of up to 40%. At this level of strain, the capacitance after 1,000 charge/discharge cycles was not significantly reduced. The high stability of our stretchable device suggests potential future applications in various types of wearable energy storage devices. PMID- 30021961 TI - Transcriptome Analyses from Mutant Salvia miltiorrhiza Reveals Important Roles for SmGASA4 during Plant Development. AB - Salvia miltiorrhiza (S. miltiorrhiza) is an important Chinese herb that is derived from the perennial plant of Lamiaceae, which has been used to treat neurasthenic insomnia and cardiovascular disease. We produced a mutant S. miltiorrhiza (MT), from breeding experiments, that possessed a large taproot, reduced lateral roots, and defective flowering. We performed transcriptome profiling of wild type (WT) and MT S. miltiorrhiza using second-generation Illumina sequencing to identify differentially expressed genes (DEGs) that could account for these phenotypical differences. Of the DEGs identified, we investigated the role of SmGASA4, the expression of which was down-regulated in MT plants. SmGASA4 was introduced into Arobidopsis and S. militiorrhiza under the control of a CaMV35S promoter to verify its influence on abiotic stress and S. miltiorrhiza secondary metabolism biosynthesis. SmGASA4 was found to promote flower and root development in Arobidopsis. SmGASA4 was also found to be positively regulated by Gibberellin (GA) and significantly enhanced plant resistance to salt, drought, and paclobutrazol (PBZ) stress. SmGASA4 also led to the up-regulation of the genes involved in salvianolic acid biosynthesis, but inhibited the expression of the genes involved in tanshinone biosynthesis. Taken together, our results reveal SmGASA4 as a promising candidate gene to promote S. miltiorrhiza development. PMID- 30021962 TI - Long-Term Effects of Dietary Protein and Branched-Chain Amino Acids on Metabolism and Inflammation in Mice. AB - Aging is the main factor involved in the onset of degenerative diseases. Dietary protein restriction has been shown to increase the lifespan of rodents and improve metabolic phenotype. Branched-chain amino acids (BCAA) can act as nutrient signals that increase the lifespan of mice after prolonged supplementation. It remains unclear whether the combination of protein restriction and BCAA supplementation improves metabolic and immunological profiles during aging. Here, we investigated how dietary protein levels and BCAA supplementation impact metabolism and immune profile during a 12-month intervention in adult male C57BL/6J mice. We found that protein restriction improved insulin tolerance and increased hepatic fibroblast growth factor 21 mRNA, circulating interleukin (IL)-5 concentration, and thermogenic uncoupling protein 1 in subcutaneous white fat. Surprisingly, BCAA supplementation conditionally increased body weight, lean mass, and fat mass, and deteriorated insulin intolerance during protein restriction, but not during protein sufficiency. BCAA also induced pro-inflammatory gene expression in visceral adipose tissue under both normal and low protein conditions. These results suggest that dietary protein levels and BCAA supplementation coordinate a complex regulation of metabolism and tissue inflammation during prolonged feeding. PMID- 30021965 TI - Continuous or Batch Solid-Liquid Extraction of Antioxidant Compounds from Seeds of Sterculia apetala Plant and Kinetic Release Study. AB - This work has been intended to investigate the antioxidant properties of compounds extracted from seeds of Sterculia apetala (a plant from Central America) in order to add further results to the relatively poor existing literature on the beneficial properties of this plant. Different extraction methodologies were used such as batch or continuous extraction conditions using water or ethanol 50% as solvents. The kinetic study has allowed estimation of the effective diffusion coefficients in a continuous solid-liquid extraction, highlighting the strict dependence of the diffusion rate and temperature and kind of solvent, showing the highest diffusion rate with ethanol 50% at 60 degrees C. The comparison between different techniques and two solvents led to the selection of water as the best extraction solvent while batch mechanically-agitated extraction was the most efficient mode, with the benefits of use of an environmental-friendly solvent and reduction in process time to achieve a high amount of extracted phenolic compounds. The analysis techniques used were ABTS and Folin-Ciocalteau methods to investigate the antioxidant activity and quantify the Total Phenolic Content (TPC) respectively. Also, different fatty acids were extracted from Sterculia apetala seeds and analysed by Gas Chromatography in order to quantify other interesting chemical species besides antioxidants. PMID- 30021966 TI - Efficient Node and Sensed Module Management for Multisensory Wireless Sensor Networks. AB - In target tracking wireless sensor networks, choosing a part of sensor nodes to execute tracking tasks and letting the other nodes sleep to save energy are efficient node management strategies. However, at present more and more sensor nodes carry many different types of sensed modules, and the existing researches on node selection are mainly focused on sensor nodes with a single sensed module. Few works involved the management and selection of the sensed modules for sensor nodes which have several multi-mode sensed modules. This work proposes an efficient node and sensed module management strategy, called ENSMM, for multisensory WSNs (wireless sensor networks). ENSMM considers not only node selection, but also the selection of the sensed modules for each node, and then the power management of sensor nodes is performed according to the selection results. Moreover, a joint weighted information utility measurement is proposed to estimate the information utility of the multiple sensed modules in the different nodes. Through extensive and realistic experiments, the results show that, ENSMM outperforms the state-of-the-art approaches by decreasing the energy consumption and prolonging the network lifetime. Meanwhile, it reduces the computational complexity with guaranteeing the tracking accuracy. PMID- 30021964 TI - Detection of Legionella Anisa in Water from Hospital Dental Chair Units and Molecular Characterization by Whole-Genome Sequencing. AB - This study aims to assess contamination with Legionella spp. in water from dental chair units (DCUs) of a hospital dental ward and to perform its molecular characterization by whole-genome sequencing (WGS). We collect eight water samples (250 mL) from four DCUs (sink and water-syringe). Samples are tested for the presence of Legionella spp. (CFUs/mL) by culturing according to the Nederland Norm (NEN) 6265. Three DCUs are found positive for Legionella anisa, and four isolates are cultured (sink n = 2, water-syringe n = 1; two isolates from the same chair) with 1 * 102 CFU/mL. Whole-genome multi-locus sequence typing (wgMLST) results indicate that all strains belong to the same cluster with two to four allele differences. Classical culture combined with WGS allows the identification of a unique clone of L. anisa in several DCUs in the same hospital dental ward. This may indicate a common contamination source in the dental unit waterlines, which was fixed by replacing the chairs and main pipeline of the unit. Our results reveal tap water contamination in direct contact with patients and the usefulness of WGS to investigate bacterial molecular epidemiology. PMID- 30021967 TI - Using Spectral Representation to Classify Proteins' Conformational States. AB - Numerous proteins are molecular targets for drug action and hence are important in drug discovery. Structure-based computational drug discovery relies on detailed information regarding protein conformations for subsequent drug screening in silico. There are two key issues in analyzing protein conformations in virtual screening. The first considers the protein's conformational change in response to physical and chemical conditions. The second is the protein's atomic resolution reconstruction from X-ray crystallography or nuclear magnetic resonance (NMR) data. In this latter problem, information is needed regarding the sample's position relative to the source of X-rays. Here, we introduce a new measure for classifying protein conformational states using spectral representation and Wigner's D-functions. Predictions based on the new measure are in good agreement with conformational states of proteins. These results could also be applied to improve conformational alignment of the snapshots given by protein crystallography. PMID- 30021968 TI - The Odor Characterizations and Reproductions in Machine Olfactions: A Review. AB - Machine olfaction is a novel technology and has been developed for many years. The electronic nose with an array of gas sensors, a crucial application form of the machine olfaction, is capable of sensing not only odorous compounds, but also odorless chemicals. Because of its fast response, mobility and easy of use, the electronic nose has been applied to scientific and commercial uses such as environment monitoring and food processing inspection. Additionally, odor characterization and reproduction are the two novel parts of machine olfaction, which extend the field of machine olfaction. Odor characterization is the technique that characterizes odorants as some form of general odor information. At present, there have already been odor characterizations by means of the electronic nose. Odor reproduction is the technique that re-produces an odor by some form of general odor information and displays the odor by the olfactory display. It enhances the human ability of controlling odors just as the control of light and voice. In analogy to visual and auditory display technologies, is it possible that the olfactory display will be used in our daily life? There have already been some efforts toward odor reproduction and olfactory displays. PMID- 30021969 TI - Analytical Solutions for Stochastic Vibration of Orthotropic Membrane under Random Impact Load. AB - Orthotropic membrane materials have been applied in the numerous fields, such as civil engineering, space and aeronautics, and mechanical engineering, among others. During their serving lifespan, these membranes are always facing strong stochastic vibrations induced by the random impact load such as hail, heavy rain, and noise, among others. In this paper, the stochastic vibration problem of orthotropic membrane subjected to random impact load is investigated. The statistical characteristics of random impact load are initially obtained based on the stochastic pulse theory. Then, the Von Karman theory is applied to model the nonlinear vibration of membrane with geometric nonlinearity, which is then used to derive and solve the corresponding fokker-plank-kolmogorov (FPK). The theoretical model developed is validated by means of experiment study and monte carlo simulation (MCS) analysis. The effects of variables like pretension force, velocity of impact load, and material features on stochastic dynamic behavior of membranes are discussed in detail. This exposition provides theoretical framework for stochastic vibration control and design of membranes subjected to random dynamic load. PMID- 30021970 TI - A Brief Introduction to the Multidimensional Intercultural Training Acculturation Model (MITA) for Middle Eastern Adolescent Refugees. AB - The large number of adolescent refugees around the world constitutes a great challenge for societies. However, current models of acculturation have been developed for migrants, but not specifically for adolescent refugees. Crucial factors to describe adolescent refugee acculturation, such as intentions to return to their homeland, especially with respect to adolescent refugees with temporary residency and experiences of potentially traumatic events, are missing. Hence, the Multidimensional Intercultural Training Acculturation (MITA) model is introduced. The model proposes that two major concerns for adolescent refugees, which are socio-cultural adjustment and mental health, are predicted by intercultural and social-emotional competence, intentions to return to their homeland, and experiences of traumatic events. Moreover, the effects of three modes of acculturation are also proposed in the model. It is expected that these variables mediate the effects of intercultural competence, social-emotional competence, intentions to return to the homeland, and experiences of traumatic events on socio-cultural adjustment as well as mental health. Finally, it is also expected that in-group social support and out-group social support moderate the direct connection between the experiences of traumatic events and mental health. PMID- 30021971 TI - Microstructure and Corrosion Behavior of Composite Coating on Pure Mg Acquired by Sliding Friction Treatment and Micro-Arc Oxidation. AB - For the purpose of detecting the influence of grain structure of a Mg matrix on the microstructure and corrosion resistance of micro-arc oxidation (MAO) coating, prior to MAO processing, sliding friction treatment (SFT) was adopted to generate a fine-grained (FG) layer on coarse-grained (CG) pure Mg surface. It showed that the FG layer had superior corrosion resistance, as compared to the CG matrix, owing to the grain refinement; furthermore, it successfully survived after MAO treatment. Thus, an excellent FG-MAO coating was gained by combining SFT and MAO. The surface morphology and element composition of FG-MAO and CG-MAO samples did not show significant changes. However, the FG layer favorably facilitated the formation of an excellent MAO coating, which possessed a superior bonding property and greater thickness. Consequently, the modified FG-MAO sample possessed enhanced corrosion resistance, since a lower hydrogen evolution rate, a larger impedance modulus and a lower corrosion current were observed on the FG MAO sample. PMID- 30021972 TI - Platinum Nanoparticle Inclusion into a Carbonized Polymer of Intrinsic Microporosity: Electrochemical Characteristics of a Catalyst for Electroless Hydrogen Peroxide Production. AB - The one-step vacuum carbonization synthesis of a platinum nano-catalyst embedded in a microporous heterocarbon (Pt@cPIM) is demonstrated. A nitrogen-rich polymer of an intrinsic microporosity (PIM) precursor is impregnated with PtCl62- to give (after vacuum carbonization at 700 degrees C) a nitrogen-containing heterocarbon with embedded Pt nanoparticles of typically 1-4 nm diameter (with some particles up to 20 nm diameter). The Brunauer-Emmett-Teller (BET) surface area of this hybrid material is 518 m2 g-1 (with a cumulative pore volume of 1.1 cm3 g-1) consistent with the surface area of the corresponding platinum-free heterocarbon. In electrochemical experiments, the heterocarbon-embedded nano-platinum is observed as reactive towards hydrogen oxidation, but essentially non-reactive towards bigger molecules during methanol oxidation or during oxygen reduction. Therefore, oxygen reduction under electrochemical conditions is suggested to occur mainly via a 2-electron pathway on the outer carbon shell to give H2O2. Kinetic selectivity is confirmed in exploratory catalysis experiments in the presence of H2 gas (which is oxidized on Pt) and O2 gas (which is reduced on the heterocarbon surface) to result in the direct formation of H2O2. PMID- 30021973 TI - Stampede Prevention Design of Primary School Buildings in China: A Sustainable Built Environment Perspective. AB - In China, crowd stampede accidents usually take place within crowded areas in middle and primary schools. The crowd stampede risk is particularly related to the architectural design such as the staircase design, the layout of crowded places, obstacles, etc. Through the investigation of building design in several primary schools, the relationship between the sustainable layout of crowded places (e.g., toilets, canteens, playgrounds, staircases) and the crowd stampede risk of students are introduced via agent-based simulations. In particular, different experimental scenarios are conducted on stairs in the primary buildings. The evacuation processes are recorded by video camera and spatial stepping characteristics (e.g., foot clearance, step length, mass center, the distance between the mass center and ankle, and etc.) are extracted from the video. Dynamic steady ability is investigated by adopting the margin of stability, quantified by the instantaneous difference between the edge of the base of support and extrapolated vertical projection of the mass center. Based on the sustainable built environment principles and historical data of students, this paper focuses on an in-depth analysis of the staircase design aiming at preventing the crowd stampede risk. PMID- 30021975 TI - Towards a Scalable Software Defined Network-on-Chip for Next Generation Cloud. AB - The rapid evolution of Cloud-based services and the growing interest in deep learning (DL)-based applications is putting increasing pressure on hyperscalers and general purpose hardware designers to provide more efficient and scalable systems. Cloud-based infrastructures must consist of more energy efficient components. The evolution must take place from the core of the infrastructure (i.e., data centers (DCs)) to the edges (Edge computing) to adequately support new/future applications. Adaptability/elasticity is one of the features required to increase the performance-to-power ratios. Hardware-based mechanisms have been proposed to support system reconfiguration mostly at the processing elements level, while fewer studies have been carried out regarding scalable, modular interconnected sub-systems. In this paper, we propose a scalable Software Defined Network-on-Chip (SDNoC)-based architecture. Our solution can easily be adapted to support devices ranging from low-power computing nodes placed at the edge of the Cloud to high-performance many-core processors in the Cloud DCs, by leveraging on a modular design approach. The proposed design merges the benefits of hierarchical network-on-chip (NoC) topologies (via fusing the ring and the 2D mesh topology), with those brought by dynamic reconfiguration (i.e., adaptation). Our proposed interconnect allows for creating different types of virtualised topologies aiming at serving different communication requirements and thus providing better resource partitioning (virtual tiles) for concurrent tasks. To further allow the software layer controlling and monitoring of the NoC subsystem, a few customised instructions supporting a data-driven program execution model (PXM) are added to the processing element's instruction set architecture (ISA). In general, the data-driven programming and execution models are suitable for supporting the DL applications. We also introduce a mechanism to map a high-level programming language embedding concurrent execution models into the basic functionalities offered by our SDNoC for easing the programming of the proposed system. In the reported experiments, we compared our lightweight reconfigurable architecture to a conventional flattened 2D-mesh interconnection subsystem. Results show that our design provides an increment of the data traffic throughput of 9.5% and a reduction of 2.2* of the average packet latency, compared to the flattened 2D-mesh topology connecting the same number of processing elements (PEs) (up to 1024 cores). Similarly, power and resource (on FPGA devices) consumption is also low, confirming good scalability of the proposed architecture. PMID- 30021974 TI - Nanotechnology for Environmental Remediation: Materials and Applications. AB - Environmental remediation relies mainly on using various technologies (e.g., adsorption, absorption, chemical reactions, photocatalysis, and filtration) for the removal of contaminants from different environmental media (e.g., soil, water, and air). The enhanced properties and effectiveness of nanotechnology based materials makes them particularly suitable for such processes given that they have a high surface area-to-volume ratio, which often results in higher reactivity. This review provides an overview of three main categories of nanomaterials (inorganic, carbon-based, and polymeric-based materials) used for environmental remediation. The use of these nanomaterials for the remediation of different environmental contaminants-such as heavy metals, dyes, chlorinated organic compounds, organophosphorus compounds, volatile organic compounds, and halogenated herbicides-is reviewed. Various recent examples are extensively highlighted focusing on the materials and their applications. PMID- 30021976 TI - Heterometallic ZnII-LnIII-ZnII Schiff Base Complexes with Linear or Bent Conformation-Synthesis, Crystal Structures, Luminescent and Magnetic Characterization. AB - A series of racemic, heteronuclear complexes [Zn2Nd(ac)2(HL)2]NO3.3H2O (1), [Zn2Sm(ac)2(HL)2]NO3.3CH3OH.0.3H2O (2), [Zn2Ln(ac)2(HL)2]NO3.5.33H2O (3-5) (where HL is the dideprotonated form of N,N'-bis(5-bromo-3-methoxysalicylidene)-1,3 diamino-2-propanol, ac = acetate ion, and Ln = Eu (3), Tb (4), Dy (5), respectively) with an achiral multisite coordination Schiff base ligand (H3L) were synthesized and characterized. The X-ray crystallography revealed that the chirality in complexes is centered at lanthanide(III) ions due to two vicinally located MU-acetato-bridging ligands. The presented crystals have isoskeletal coordination units but they crystallize in monoclinic (1, 2) or trigonal crystal systems (3-5) with slightly different conformation. In 1 and 2 the ZnII-LnIII ZnII coordination core is linear, whereas in isostructural crystals 3-5 the chiral coordination cores are bent and lie on a two-fold axis. The complexes 1, 3 5 show a blue emission attributed to the emission of the ligand. For ZnII2SmIII complex (2) the characteristic emission bands of f-f* transitions were observed. The magnetic properties for compounds 1, 4 and 5 are characteristic for the paramagnetism of the corresponding lanthanide(III) ions. PMID- 30021977 TI - A Better Understanding of Bee Nutritional Ecology Is Needed to Optimize Conservation Strategies for Wild Bees-The Application of Ecological Stoichiometry. AB - The observed decline in wild bees may be connected to the decreasing diversity of flowering plants. Changes in floral composition shape nutrient availability in inhabited areas, and bee larvae need food rich in body-building nutrients to develop into adults. Adult food, mainly composed of energy-rich nectar, differs from larval food, mainly composed of pollen, and adult bees forage on different plant species for nectar and pollen. Defining bee-friendly plants based on the quantities of food produced, and on the visitation rates of adult pollinating insects leads to the planting of bee habitats with poor-quality food for larvae, which limits their growth and development, and negatively affects the population. Consequently, failing to understand the nutritional needs of wild bees may lead to unintended negative effects of conservation efforts. Ecological stoichiometry was developed to elucidate the nutritional constraints of organisms and their colonies, populations, and communities. Here, I discuss how applying ecological stoichiometry to the study of the nutritional ecology of wild bees would help fill the gaps in our understanding of bee biology. I present questions that should be answered in future studies to improve our knowledge of the nutritional ecology of wild bees, which could result in better conservation strategies. PMID- 30021978 TI - Effects of Temperature and Strain Rate on the Fracture Behaviors of an Al-Zn-Mg Cu Alloy. AB - Effects of temperature and strain rate on the fracture behaviors of an Al-Zn-Mg Cu alloy are investigated by isothermal uniaxial tensile experiments at a wide range of temperatures and strain rates, from room temperature (RT) to 400 degrees C and from 10-4 s-1 to 10-1 s-1, respectively. Generally, the elevation of temperature leads to the increasing of elongation to fracture and the reduction of peak stress, while higher strain rate results in the decreasing of elongation to fracture and the increasing of peak stress. Interestingly, we found that the coefficient of strain rate sensitivity (m-value) considerably rises at 200 degrees C and work of fracture (Wf) fluctuates drastically with the increase of strain rate at RT and 100 degrees C, both of which signify a non-uniform and unstable deformation state below 200 degrees C. A competition of work hardening (WH) and dynamic recrystallization (DRX) exists at 200 degrees C, making it serve as a transitional temperature. Below 200 degrees C, WH is the main deformation mechanism of flow stress, and DRX dominates the flow stress above 200 degrees C. It has been found that from RT to 200 degrees C, the main feature of microstructure is the generation of dimples and microvoids. Above 200 degrees C, the coalescence of dimples and microvoids mainly leads to the failure of specimen, while the phenomenon of typically equiaxed dimples and nucleation appear at 400 degrees C. The observations of microstructure are perfectly consistent with the related macroscopic results. The present work is able to provide a comprehensive understanding of flow stress of an Al-Zn-Mg-Cu alloy at a wide range of temperatures and strain rates, which will offer valuable information to the optimization of the hot forming process and structural design of the studied alloy. PMID- 30021981 TI - Analysis of the Evolution Game of Construction and Demolition Waste Recycling Behavior Based on Prospect Theory under Environmental Regulation. AB - With the development of the construction industry, increasing concern over construction and demolition waste (CDW) has initiated a wave of environmental regulation by the government in order to reduce the environmental impact and ensure sustainable development. Research on behavioral decision-making can offer a theoretical basis for the government and individuals. This paper aims to study the behavioral decision-making of stakeholders in CDW recycling under environmental regulation. Considering the limited rationality of stakeholders and the difference in reference points, an evolutionary game model including contractors and manufacturers of construction materials is proposed based on the prospect theory of behavioral economics. The results indicate that, only when the perceived benefits of one or both stakeholders for participation under the environmental regulation exceed those for non-participation, can the CDW recycling system eventually evolve to a stable state in which both stakeholders choose to participate. In addition, factors such as the initial strategy, production cost, technology, subsidies, recycling benefits, and the degree of perception of the stakeholders, exert certain influences on the stable state. To attain the required stable state, the government should increase the subsidies for the stakeholders and strengthen the publicity regarding recycling effects to improve the perceived benefits. PMID- 30021980 TI - Coalition Formation Based Compressive Sensing in Wireless Sensor Networks. AB - Compressive sensing originates in the field of signal processing and has recently become a topic of energy-efficient data gathering in wireless sensor networks. In this paper, we propose an energy efficient distributed compressive sensing solution for sensor networks. The proposed solution utilizes sparsity distribution of signals to group sensor nodes into several coalitions and then implements localized compressive sensing inside coalitions. This solution improves data-gathering performance in terms of both data accuracy and energy consumption. The approach curbs both data-transmission costs and number of measurements. Coalition-based data gathering cuts transmission costs, and the number of measurements is reduced by scheduling sensor nodes and adjusting their sampling frequency. Our simulation showed that our approach enhances network performance by minimizing energy cost and improving data accuracy. PMID- 30021979 TI - Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations. AB - The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step. PMID- 30021982 TI - Investigation of Forward Tunneling Characteristics of InGaN/GaN Blue Light Emitting Diodes on Freestanding GaN Detached from a Si Substrate. AB - We report forward tunneling characteristics of InGaN/GaN blue light emitting diodes (LEDs) on freestanding GaN detached from a Si substrate using temperature dependent current-voltage (T-I-V) measurements. T-I-V analysis revealed that the conduction mechanism of InGaN/GaN LEDs using the homoepitaxial substrate can be distinguished by tunneling, diffusion and recombination current, and series resistance regimes. Their improved crystal quality, inherited from the nature of homoepitaxy, resulted in suppression of forward leakage current. It was also found that the tunneling via heavy holes in InGaN/GaN LEDs using the homoepitaxial substrate can be the main transport mechanism under low forward bias, consequentially leading to the improved forward leakage current characteristics. PMID- 30021983 TI - Prevalence of All-Cause Mortality and Suicide among Bariatric Surgery Cohorts: A Meta-Analysis. AB - INTRODUCTION: Prior meta-analysis has reported mortality rates among post operative bariatric patients, but they have not considered psychiatric factors like suicide contributing to mortality. OBJECTIVES: The current meta-analysis aims to determine the pooled prevalence for mortality and suicide amongst cohorts using reported suicides post bariatric surgery. It is also the aim of the current meta-analytical study to determine moderators that could account for the heterogeneity found. RESULTS: In our study, the pooled prevalence of mortality in the studies which reported suicidal mortality was 1.8% and the prevalence of suicide was 0.3%. Mean body mass index (BMI) and the duration of follow-up appear to be significant moderators. CONCLUSIONS: Given the prevalence of suicide post bariatric surgery, it is highly important for bariatric teams to consider both the medical and psychiatric well-being of individuals pre- and post-operatively. PMID- 30021984 TI - Genome Identification of B-BOX Gene Family Members in Seven Rosaceae Species and Their Expression Analysis in Response to Flower Induction in Malus domestica. AB - BBX proteins play important roles in regulating plant growth and development including photomorphogenesis, photoperiodic regulation of flowering, and responses to biotic and abiotic stresses. At present, the genomes of seven Rosaceae fruit species have been fully sequenced. However, little is known about the BBX gene family and their evolutionary history in these Rosaceae species. Therefore, in this study total, 212 BBX genes were investigated from seven Rosaceae species (67 from Malus * domestica, 40 from Pyruscommunis, 22 from Rosa Chinesis, 20 from Prunuspersica, 21 from Fragariavesca, 22 from Prunusavium, and 20 from Rubusoccidentalis). The chemical properties, gene structures, and evolutionary relationships of the BBX genes were also studied. All the BBX genes were grouped into six subfamilies on the basis of their phylogenetic relationships and structural features. Analysis of gene structure, segmental and tandem duplication, gene phylogeny, and tissue-specific expression with the ArrayExpress database showed their diversification in function, quantity, and structure. The expression profiles of 19 MdBBX genes in different tissues were evaluated through qRT-PCR. These genes showed distinct transcription level among the tested tissues (bud, flower, fruit, stem, and leaf). Moreover, expression patterns of 19 MdBBX genes were examined during flowering induction time under flowering-related hormones and treatments (GA3, 6-BA, and sucrose). The expressions of the candidates BBX genes were affected and showed diverse expression profile. Furthermore, changes in response to these flowering-related hormones and treatment specifying their potential involvement in flowering induction. Based on these findings, BBX genes could be used as potential genetic markers for the growth and development of plants particularly in the area of functional analysis, and their involvement in flower induction in fruit plants. PMID- 30021986 TI - Fault Detection and Isolation via the Interacting Multiple Model Approach Applied to Drive-By-Wire Vehicles. AB - The place of driving assistance systems is currently increasing drastically for road vehicles. Paving the road to the fully autonomous vehicle, the drive-by-wire technology could improve the potential of the vehicle control. The implementation of these new embedded systems is still limited, mainly for reliability reasons, thus requiring the development of diagnostic mechanisms. In this paper, we investigate the detection and the identification of sensor and actuator faults for a drive-by-wire road vehicle. An Interacting Multiple Model approach is proposed, based on a non-linear vehicle dynamics observer. The adequacy of different probabilistic observers is discussed. The results, based on experimental vehicle signals, show a fast and robust identification of sensor faults while the actuator faults are more challenging. PMID- 30021987 TI - The Local Atomic Structure of Colloidal Superparamagnetic Iron Oxide Nanoparticles for Theranostics in Oncology. AB - The paper contains an overview of modern spectroscopic methods for studying the local atomic structure of superparamagnetic nanoparticles based on iron oxide (SPIONs), which are an important class of materials promising for theranostics in oncology. Practically important properties of small and ultra small nanoparticles are determined primarily by their shape, size, and features of the local atomic, electronic, and magnetic structures, for the study of which the standard characterization methods developed for macroscopic materials are not optimal. The paper analyzes results of the studies of SPIONs local atomic structure carried out by X-ray absorption spectroscopy at synchrotron radiation sources and Mossbauer spectroscopy during the last decade. PMID- 30021988 TI - Biotoxicity of Water-Soluble UV Photodegradation Products for 10 Typical Gaseous VOCs. AB - Ultraviolet (UV) photodegradation is increasingly applied to control volatile organic compounds (VOCs) due to its degradation capabilities for recalcitrant compounds. However, sometimes the UV photodegradation products are also toxic and can affect human health. Here, 10 VOCs at 150~200 ppm in air were treated using a laboratory-scale UV reactor with 185/254 nm irradiation, and the biotoxicity of their off-gas was studied by investigating their off-gas absorption solutions. The CO2 increase and VOC decrease were 39~128 ppm and 0~42 ppm, respectively, indicating that the VOCs and their products were mineralized in off-gas absorption solutions. The total organic carbon (TOC) of the absorption solutions are 4~20 mg?L-1. Luminescent bacteria and Daphnia magna were used to detect the acute toxicity, and an umu assay was used to determine the genotoxic potential. Trichloroethylene showed a highest toxicity to luminescent bacteria, while chlorobenzene had the lowest toxicity. Water-soluble UV photodegradation products for styrene are very toxic to Daphnia magna. In the umu assay, the genotoxicities of off-gas absorption solutions of trichloroethylene, methylbenzene, ethyl acetate, butyl alcohol, and styrene were 51.26, 77.80, 86.89, 97.20, and 273.62 mg (4-NQO).L-1 respectively. In addition, the analysis of the genotoxicity/TOC and intermediates products indicated that the off-gas absorption solutions of styrene, trichloroethylene, and butyl alcohol contain many highly toxic substances. PMID- 30021989 TI - Geo-Positioning Accuracy Improvement of Multi-Mode GF-3 Satellite SAR Imagery Based on Error Sources Analysis. AB - The GaoFen-3 (GF-3) satellite is the only synthetic aperture radar (SAR) satellite in the High-Resolution Earth Observation System Project, which is the first C-band full-polarization SAR satellite in China. In this paper, we proposed some error sources-based weight strategies to improve the geometric performance of multi-mode GF-3 satellite SAR images without using ground control points (GCPs). To get enough tie points, a robust SAR image registration method and the SAR-features from accelerated segment test (SAR-FAST) method is used to achieve the image registration and tie point extraction. Then, the original position of these tie points in object-space is calculated with the help of the space intersection method. With the dataset clustered by the density-based spatial clustering of applications with noise (DBSCAN) algorithm, we undertake the block adjustment with a bias-compensated rational function model (RFM) aided to improve the geometric performance of these multi-mode GF-3 satellite SAR images. Different weight strategies are proposed to develop the normal equation matrix according to the error sources analysis of GF-3 satellite SAR images, and the preconditioned conjugate gradient (PCG) method is utilized to solve the normal equation. The experimental results indicate that our proposed method can improve the geometric positioning accuracy of GF-3 satellite SAR images within 2 pixels. PMID- 30021990 TI - Evaluation of Antimicrobial, Enzyme Inhibitory, Antioxidant and Cytotoxic Activities of Partially Purified Volatile Metabolites of Marine Streptomyces sp.S2A. AB - In the present study, marine actinobacteria Streptomyces sp.S2A was isolated from the Gulf of Mannar, India. Identification was carried out by 16S rRNA analysis. Bioactive metabolites were extracted by solvent extraction method. The metabolites were assayed for antagonistic activity against bacterial and fungal pathogens, inhibition of alpha-glucosidase and alpha-amylase enzymes, antioxidant activity and cytotoxic activity against various cell lines. The actinobacterial extract showed significant antagonistic activity against four gram-positive and two gram-negative pathogens. Excellent reduction in the growth of fungal pathogens was also observed. The minimum inhibitory concentration of the partially purified extract (PPE) was determined as 31.25 MUg/mL against Klebsiella pneumoniae, 15.62 MUg/mL against Staphylococcus epidermidis, Staphylococcus aureus and Bacillus cereus. The lowest MIC was observed against Micrococcus luteus as 7.8 MUg/mL. MIC against fungal pathogens was determined as 62.5 MUg/mL against Bipolaris maydis and 15.62 MUg/mL against Fusarium moniliforme. The alpha-glucosidase and alpha-amylase inhibitory potential of the fractions were carried out by microtiter plate method. IC50 value of active fraction for alpha-glucosidase and alpha-amylase inhibition was found to be 21.17 MUg/mL and 20.46 MUg/mL respectively. The antioxidant activity of partially purified extract (PPE) (DPPH, ABTS, FRAP and Metal chelating activity) were observed and were also found to have significant cytotoxic activity against HT 29, MDA and U-87MG cell lines. The compound analysis was performed using gas chromatography-mass spectrometry (GC-MS) and resulted in three constituents; pyrrolo[1-a]pyrazine-1,4-dione,hexahydro-3-(2-methylpropyl)-, being the main component (80%). Overall, the strain possesses a wide spectrum of antimicrobial, enzyme inhibitory, antioxidant and cytotoxic activities which affords the production of significant bioactive metabolites as potential pharmacological agents. PMID- 30021991 TI - Influence of Acid, Ethanol, and Anthocyanin Pigment on the Optical and Mechanical Properties of a Nanohybrid Dental Composite Resin. AB - This study investigated the influences of acidity, ethanol, and pigment on the optical properties, microhardness, and surface roughness (Ra) of a nanohybrid dental composite resin. A total of 108 disc-shaped specimens were fabricated using a nanohybrid dental composite and allocated into 36 different storage solutions according to the levels of pH (2.0, 3.0, 4.0, and 5.5), ethanol (0%, 20%, and 40%), and anthocyanin pigment (0%, 2.5%, and 12.5%). Measurements of the colorimetric parameter and the amount of color change (DeltaE), translucency parameter (TP), microhardness, and surface roughness (Ra) were performed at 24 h (baseline), 1-, 2-, 3-, and 4-weeks. Repeated measures of analysis of variance (ANOVA) with a Tukey honestly significant difference test and Pearson correlation analysis were carried out (alpha = 0.05). Pigment of 12.5% or 40% ethanol significantly increased the DeltaE (P < 0.001, P = 0.048, respectively). Pigment of 2.5% or 12.5% significantly decreased the TP (P = 0.001, P < 0.001, respectively). Microhardness of composite resin stored in pH 2.0, 3.0, 4.0 solution was lower than that for pH 5.5 (P < 0.001). Pigment, ethanol, and pH did not influence the Ra. TP change and DeltaE, and Ra and DeltaE had a significant positive correlation (P < 0.05). In conclusion, pigment and ethanol levels influenced the optical properties and acidity affected the microhardness of composite resin. PMID- 30021992 TI - Beckmann Rearrangement of Ketoxime Catalyzed by N-methyl-imidazolium Hydrosulfate. AB - Beckmann rearrangement of ketoxime catalyzed by acidic ionic liquid-N-methyl imidazolium hydrosulfate was studied. Rearrangement of benzophenone oxime gave the desirable product with 45% yield at 90 degrees C. When co-catalyst P2O5 was added, the yield could be improved to 91%. The catalyst could be reused three cycles with the same efficiency. Finally, reactions of other ketoximes were also investigated. PMID- 30021994 TI - Synthesis and Physical Property Characterisation of Spheroidal and Cuboidal Nuclear Waste Simulant Dispersions. AB - This study investigated dispersions analogous to highly active nuclear waste, formed from the reprocessing of Spent Nuclear Fuel (SNF). Non-radioactive simulants of spheroidal caesium phosphomolybdate (CPM) and cuboidal zirconium molybdate (ZM-a) were successfully synthesised; confirmed via Scanning Electron Microscopy (SEM), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) spectroscopy. In addition, a supplied ZM (ZM-b) with a rod-like/wheatsheaf morphology was also analysed along with titanium dioxide (TiO2). The simulants underwent thermal gravimetric analysis (TGA) and size analysis, where CPM was found to have a D50 value of 300 nm and a chemical formula of Cs3PMo12O40.13H2O, ZM-a a D50 value of 10 MUm and a chemical formula of ZrMo2O7(OH)2.3H2O and ZM-b to have a D50 value of 14 MUm and a chemical formula of ZrMo2O7(OH)2.4H2O. The synthesis of CPM was tracked via Ultraviolet-visible (UV-Vis) spectroscopy at both 25 degrees C and 50 degrees C, where the reaction was found to be first order with the rate constant highly temperature dependent. The morphology change from spheroidal CPM to cuboidal ZM-a was tracked via SEM, reporting to take 10 days. For the onward processing and immobilisation of these waste dispersions, centrifugal analysis was utilised to understand their settling behaviours, in both aqueous and 2 M nitric acid environments (mimicking current storage conditions). Spheroidal CPM was present in both conditions as agglomerated clusters, with relatively high settling rates. Conversely, the ZM were found to be stable in water, where their settling rate exponents were related to the morphology. In acid, the high effective electrolyte resulted in agglomeration and faster sedimentation. PMID- 30021993 TI - A Review of Recent Advances in the Treatment of Elderly and Poor Performance NSCLC. AB - Until recently, chemotherapy has remained the mainstay of treatment for the majority of patients with advanced non-small cell lung cancer (NSCLC). Excellent responses have been observed with immune-checkpoint inhibitors, and targeted treatments for those tumours with actionable mutations, resulting in a paradigm shift in the treatment approach for these patients. Elderly patients and those with poor performance status (PS), such as Eastern Cooperative Oncology Group (ECOG) 2, have historically been excluded from clinical trials due to poor outcomes. There is therefore a lack of data to define the optimal treatment strategy for these patients. Due to improved tolerability of novel therapies, inclusion of these patients in clinical trials has increased, and sub-group analyses have identified many treatments demonstrating potential activity. Here, we summarise key recent advances in the treatment of NSCLC, specifically evaluating their efficacy and tolerability in these patient cohorts. PMID- 30021995 TI - Peptide-Cellulose Conjugates on Cotton-Based Materials Have Protease Sensor/Sequestrant Activity. AB - The growing incidence of chronic wounds in the world population has prompted increased interest in chronic wound dressings with protease-modulating activity and protease point of care sensors to treat and enable monitoring of elevated protease-based wound pathology. However, the overall design features needed for the combination of a chronic wound dressing that lowers protease activity along with protease detection capability as a single platform for semi-occlusive dressings has scarcely been addressed. The interface of dressing and sensor specific properties (porosity, permeability, moisture uptake properties, specific surface area, surface charge, and detection) relative to sensor bioactivity and protease sequestrant performance is explored here. Measurement of the material's zeta potential demonstrated a correlation between negative charge and the ability of materials to bind positively charged Human Neutrophil Elastase. Peptide cellulose conjugates as protease substrates prepared on a nanocellulosic aerogel were assessed for their compatibility with chronic wound dressing design. The porosity, wettability and absorption capacity of the nanocellulosic aerogel were consistent with values observed for semi-occlusive chronic wound dressing designs. The relationship of properties that effect dressing functionality and performance as well as impact sensor sensitivity are discussed in the context of the enzyme kinetics. The sensor sensitivity of the aerogel-based sensor is contrasted with current clinical studies on elastase. Taken together, comparative analysis of the influence of molecular features on the physical properties of three forms of cellulosic transducer surfaces provides a meaningful assessment of the interface compatibility of cellulose-based sensors and corresponding protease sequestrant materials for potential use in chronic wound sensor/dressing design platforms. PMID- 30021996 TI - Rapid Airplane Detection in Remote Sensing Images Based on Multilayer Feature Fusion in Fully Convolutional Neural Networks. AB - To address the issues encountered when using traditional airplane detection methods, including the low accuracy rate, high false alarm rate, and low detection speed due to small object sizes in aerial remote sensing images, we propose a remote sensing image airplane detection method that uses multilayer feature fusion in fully convolutional neural networks. The shallow layer and deep layer features are fused at the same scale after sampling to overcome the problems of low dimensionality in the deep layer and the inadequate expression of small objects. The sizes of candidate regions are modified to fit the size of the actual airplanes in the remote sensing images. The fully connected layers are replaced with convolutional layers to reduce the network parameters and adapt to different input image sizes. The region proposal network shares convolutional layers with the detection network, which ensures high detection efficiency. The simulation results indicate that, when compared to typical airplane detection methods, the proposed method is more accurate and has a lower false alarm rate. Additionally, the detection speed is considerably faster and the method can accurately and rapidly complete airplane detection tasks in aerial remote sensing images. PMID- 30021985 TI - Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues. AB - Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N acylethanolamines showed to protect cell damage and death from reactive aldehydes induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts. PMID- 30021998 TI - Ionic Liquid Solutions as a Green Tool for the Extraction and Isolation of Natural Products. AB - In the past few years, the application of ionic liquids (ILs) had attracted more attention of the researchers. Many studies focused on extracting active components from traditional herbals using ILs as alternative solvents so as to address the issue caused by the traditional methods for extraction of natural products (NPs) with organic chemical reagents. Through the summary of reported research work, an overview was presented for the application of ILs or IL-based materials in the extraction of NPs, including flavonoids, alkaloids, terpenoids, phenylpropanoids and so on. Here, we mainly describe the application of ILs to rich the extraction of critical bioactive constituents that were reported possessing multiple therapeutic effects or pharmacological activities, from medicinal plants. This review could shed some light on the wide use of ILs in the field of natural products chemistry to further reduce the environmental damage caused by large quantity of organic chemical reagents. PMID- 30021999 TI - Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton. AB - BACKGROUND: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for clinical use. We anticipated that efficient lead finding and enhancement of activity toward nuclear receptors recognizing endogenous steroidal ligands might be achieved by exhaustive evaluation of a steroid surrogate library coupled with examination of structure-activity relationships (SAR). METHOD: We evaluated our library of RORs (retinoic acid receptor-related orphan receptors) inverse agonists and/or PR (progesterone receptor) antagonists based on the phenanthridinone skeleton for antagonistic activities toward liver X receptors (LXRs), androgen receptor (AR) and glucocorticoid receptor (GR) and examined their SAR. RESULTS: Potent LXRbeta, AR, and GR antagonists were identified. SAR studies led to a potent AR antagonist (IC50: 0.059 MUM). CONCLUSIONS: Our approach proved effective for efficient lead finding, activity enhancement and preliminary control of selectivity over other receptors. The phenanthridinone skeleton appears to be a promising steroid surrogate. PMID- 30022000 TI - Gelatin-Methacryloyl (GelMA) Hydrogels with Defined Degree of Functionalization as a Versatile Toolkit for 3D Cell Culture and Extrusion Bioprinting. AB - Gelatin-methacryloyl (GelMA) is a semi-synthetic hydrogel which consists of gelatin derivatized with methacrylamide and methacrylate groups. These hydrogels provide cells with an optimal biological environment (e.g., RGD motifs for adhesion) and can be quickly photo-crosslinked, which provides shape fidelity and stability at physiological temperature. In the present work, we demonstrated how GelMA hydrogels can be synthesized with a specific degree of functionalization (DoF) and adjusted to the intended application as a three-dimensional (3D) cell culture platform. The focus of this work lays on producing hydrogel scaffolds which provide a cell promoting microenvironment for human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) and are conductive to their adhesion, spreading, and proliferation. The control of mechanical GelMA properties by variation of concentration, DoF, and ultraviolet (UV) polymerization conditions is described. Moreover, hAD-MSC cell viability and morphology in GelMA of different stiffness was evaluated and compared. Polymerized hydrogels with and without cells could be digested in order to release encapsulated cells without loss of viability. We also demonstrated how hydrogel viscosity can be increased by the use of biocompatible additives, in order to enable the extrusion bioprinting of these materials. Taken together, we demonstrated how GelMA hydrogels can be used as a versatile tool for 3D cell cultivation. PMID- 30022001 TI - Application of Pin-On-Disc Techniques for the Study of Tribological Interferences in the Dry Machining of A92024-T3 (Al-Cu) Alloys. AB - One of the main criteria for the establishment of the performance of a forming process by material removal is based on cutting tool wear. Wear is usually caused by different mechanisms, however, only one is usually considered as predominant or the controller of the process. This experimental research is focused on the application of Pin-on-Disc wear tests, in which the tribological interference between UNS A92024-T3 Aluminum-Copper alloy and tungsten carbide (WC-Co) has been studied. The main objective of this study is focused on the determination of the predominant wear mechanisms involved in the process, as well as the characterization of the sliding and friction effects by using SEM and Energy Dispersion Spectroscopy (EDS) techniques, as applied to WC-Co (cutting tool material)/Al (workpiece material) which are widely used in the aerospace industry. Performed analysis prove the appearance of abrasive wear mechanisms prior to adhesion. This fact promotes adhesion mechanisms in several stages because of the surface quality deterioration, presenting different alloy composition in the form of a Built-Up Layer (BUL)/Built-Up Edge (BUE). PMID- 30022002 TI - Beam Diameter Dependence of Performance in Thick-Layer and High-Power Selective Laser Melting of Ti-6Al-4V. AB - A 400 W high-power laser was used to fabricate 200-um-thick Ti-6Al-4V samples to evaluate the effects of small (50 MUm) and large (200 MUm) beam diameter on density, microstructure and mechanical properties. A series of single-track experiments demonstrated that it was challenging for the small-beam laser to fabricate smooth and defect-free scan tracks. A larger beam diameter efficiently avoided process instability and provided a more stable and uniform melt pool. By increasing the beam diameter, the density of multilayer samples reached 99.95% of the theoretical value, which is much higher than that achieved with the small beam diameter. However, it was difficult to completely eliminate defects due to serious spatter and evaporation. Moreover, all of the generated samples had relatively coarse surfaces. For the large beam diameter of 200 um, the optimal yield strength, ultimate tensile strength and elongation were 1150 MPa, 1200 MPa and 8.02%, respectively. In comparison, the small beam diameter of 50 um resulted in values of 1035 MPa, 1100 MPa and 5.91%, respectively. Overall, the large diameter laser is more suitable for high-power selective laser melting (SLM) technology, especially for thick layers. PMID- 30022003 TI - Visible Light Driven Photoanodes for Water Oxidation Based on Novel r-GO/beta Cu2V2O7/TiO2 Nanorods Composites. AB - This paper describes the preparation and the photoelectrochemical performances of visible light driven photoanodes based on novel r-GO/beta-Cu2V2O7/TiO2 nanorods/composites. beta-Cu2V2O7 was deposited on both fluorine doped tin oxide (FTO) and TiO2 nanorods (NRs)/FTO by a fast and convenient Aerosol Assisted Spray Pyrolysis (AASP) procedure. Ethylenediamine (EN), ammonia and citric acid (CA) were tested as ligands for Cu2+ ions in the aerosol precursors solution. The best performing deposits, in terms of photocurrent density, were obtained when NH3 was used as ligand. When beta-Cu2V2O7 was deposited on the TiO2 NRs a good improvement in the durability of the photoanode was obtained, compared with pure beta-Cu2V2O7 on FTO. A further remarkable improvement in durability and photocurrent density was obtained upon addition, by electrophoretic deposition, of reduced graphene oxide (r-GO) flakes on the beta-Cu2V2O7/TiO2 composite material. The samples were characterized by X-ray Photoelectron Spectroscopy (XPS), Raman, High Resolution Transmission Electron Microscopy (HR-TEM), Scanning Electron Microscopy (SEM), Wide Angle X-ray Diffraction (WAXD) and UV-Vis spectroscopies. The photoelectrochemical (PEC) performances of beta-Cu2V2O7 on FTO, beta-Cu2V2O7/TiO2 and r-GO/beta-Cu2V2O7/TiO2 were tested in visible light by linear voltammetry and Electrochemical Impedance Spectroscopy (EIS) measurements. PMID- 30021997 TI - Nutrition and Lung Growth. AB - Experimental evidence from animal models and epidemiology studies has demonstrated that nutrition affects lung development and may have a lifelong impact on respiratory health. Chronic restriction of nutrients and/or oxygen during pregnancy causes structural changes in the airways and parenchyma that may result in abnormal lung function, which is tracked throughout life. Inadequate nutritional management in very premature infants hampers lung growth and may be a contributing factor in the pathogenesis of bronchopulmonary dysplasia. Recent evidence seems to indicate that infant and childhood malnutrition does not determine lung function impairment even in the presence of reduced lung size due to delayed body growth. This review will focus on the effects of malnutrition occurring at critical time periods such as pregnancy, early life, and childhood, on lung growth and long-term lung function. PMID- 30022004 TI - Calmodulin: A Multitasking Protein in Kv7.2 Potassium Channel Functions. AB - The ubiquitous calcium transducer calmodulin (CaM) plays a pivotal role in many cellular processes, regulating a myriad of structurally different target proteins. Indeed, it is unquestionable that CaM is the most relevant transductor of calcium signals in eukaryotic cells. During the last two decades, different studies have demonstrated that CaM mediates the modulation of several ion channels. Among others, it has been indicated that Kv7.2 channels, one of the members of the voltage gated potassium channel family that plays a critical role in brain excitability, requires CaM binding to regulate the different mechanisms that govern its functions. The purpose of this review is to provide an overview of the most recent advances in structure-function studies on the role of CaM regulation of Kv7.2 and the other members of the Kv7 family. PMID- 30022007 TI - Evaluation of Atmospheric Effects on Interferograms Using DEM Errors of Fixed Ground Points. AB - High-resolution synthetic aperture radar (SAR) data are widely used for disaster monitoring. To extract damaged areas automatically, it is essential to understand the relationships among the sensor specifications, acquisition conditions, and land cover. Our previous studies developed a method for estimating the phase noise of interferograms using several pairs of TerraSAR-X series (TerraSAR-X and TanDEM-X) datasets. Atmospheric disturbance data are also necessary to interpret the interferograms; therefore, the purpose of this study is to estimate the atmospheric effects by focusing on the difference in digital elevation model (DEM) errors between repeat-pass (two interferometric SAR images acquired at different times) and single-pass (two interferometric SAR images acquired simultaneously) interferometry. Single-pass DEM errors are reduced due to the lack of temporal decorrelation and atmospheric disturbances. At a study site in the city of Tsukuba, a quantitative analysis of DEM errors at fixed ground objects shows that the atmospheric effects are estimated to contribute 75% to 80% of the total phase noise in interferograms. PMID- 30022005 TI - Improved Induction of Anti-Melanoma T Cells by Adenovirus-5/3 Fiber Modification to Target Human DCs. AB - To mount a strong anti-tumor immune response, non T cell inflamed (cold) tumors may require combination treatment encompassing vaccine strategies preceding checkpoint inhibition. In vivo targeted delivery of tumor-associated antigens (TAA) to dendritic cells (DCs), relying on the natural functions of primary DCs in situ, represents an attractive vaccination strategy. In this study we made use of a full-length MART-1 expressing C/B-chimeric adenoviral vector, consisting of the Ad5 capsid and the Ad3 knob (Ad5/3), which we previously showed to selectively transduce DCs in human skin and lymph nodes. Our data demonstrate that chimeric Ad5/3 vectors encoding TAA, and able to target human DCs in situ, can be used to efficiently induce expansion of functional tumor-specific CD8+ effector T cells, either from a naive T cell pool or from previously primed T cells residing in the melanoma-draining sentinel lymph nodes (SLN). These data support the use of Ad3-knob containing viruses as vaccine vehicles for in vivo delivery. "Off-the-shelf" DC-targeted Ad vaccines encoding TAA could clearly benefit future immunotherapeutic approaches. PMID- 30022006 TI - Epstein-Barr Virus-Induced Epigenetic Pathogenesis of Viral-Associated Lymphoepithelioma-Like Carcinomas and Natural Killer/T-Cell Lymphomas. AB - : Cancer genome studies of Epstein-Barr virus (EBV)-associated tumors, including lymphoepithelioma-like carcinomas (LELC) of nasopharyngeal (NPC), gastric (EBVaGC) and lung tissues, and natural killer (NK)/T-cell lymphoma (NKTCL), reveal a unique feature of genomic alterations with fewer gene mutations detected than other common cancers. It is known now that epigenetic alterations play a critical role in the pathogenesis of EBV-associated tumors. As an oncogenic virus, EBV establishes its latent and lytic infections in B-lymphoid and epithelial cells, utilizing hijacked cellular epigenetic machinery. EBV-encoded oncoproteins modulate cellular epigenetic machinery to reprogram viral and host epigenomes, especially in the early stage of infection, using host epigenetic regulators. The genome-wide epigenetic alterations further inactivate a series of tumor suppressor genes (TSG) and disrupt key cellular signaling pathways, contributing to EBV-associated cancer initiation and progression. Profiling of genome-wide CpG methylation changes (CpG methylome) have revealed a unique epigenotype of global high-grade methylation of TSGs in EBV-associated tumors. Here, we have summarized recent advances of epigenetic alterations in EBV associated tumors (LELCs and NKTCL), highlighting the importance of epigenetic etiology in EBV-associated tumorigenesis. Epigenetic study of these EBV associated tumors will discover valuable biomarkers for their early detection and prognosis prediction, and also develop effective epigenetic therapeutics for these cancers. PMID- 30022009 TI - Adaptive Square-Root Unscented Particle Filtering Algorithm for Dynamic Navigation. AB - This paper presents a new adaptive square-root unscented particle filtering algorithm by combining the adaptive filtering and square-root filtering into the unscented particle filter to inhibit the disturbance of kinematic model noise and the instability of filtering data in the process of nonlinear filtering. To prevent particles from degeneracy, the proposed algorithm adaptively adjusts the adaptive factor, which is constructed from predicted residuals, to refrain from the disturbance of abnormal observation and the kinematic model noise. Cholesky factorization is also applied to suppress the negative definiteness of the covariance matrices of the predicted state vector and observation vector. Experiments and comparison analysis were conducted to comprehensively evaluate the performance of the proposed algorithm. The results demonstrate that the proposed algorithm exhibits a strong overall performance for integrated navigation systems. PMID- 30022010 TI - Different Myosin Head Conformations in Bony Fish Muscles Put into Rigor at Different Sarcomere Lengths. AB - At a resting sarcomere length of approximately 2.2 um bony fish muscles put into rigor in the presence of BDM (2,3-butanedione monoxime) to reduce rigor tension generation show the normal arrangement of myosin head interactions with actin filaments as monitored by low-angle X-ray diffraction. However, if the muscles are put into rigor using the same protocol but stretched to 2.5 um sarcomere length, a markedly different structure is observed. The X-ray diffraction pattern is not just a weaker version of the pattern at full overlap, as might be expected, but it is quite different. It is compatible with the actin-attached myosin heads being in a different conformation on actin, with the average centre of cross-bridge mass at a higher radius than in normal rigor and the myosin lever arms conforming less to the actin filament geometry, probably pointing back to their origins on their parent myosin filaments. The possible nature of this new rigor cross-bridge conformation is discussed in terms of other well-known states such as the weak binding state and the 'roll and lock' mechanism; we speculate that we may have trapped most myosin heads in an early attached strong actin binding state in the cross-bridge cycle on actin. PMID- 30022012 TI - Update of Single Event Effects Radiation Hardness Assurance of Readout Integrated Circuit of Infrared Image Sensors at Cryogenic Temperature. AB - This paper review presents Single Event Effects (SEE) irradiation tests under heavy ions of the test-chip of D-Flip-Flop (DFF) cells and complete readout integrated circuits (ROIC) as a function of temperature, down to 50 K. The analyses of the experimental data are completed using the SEE prediction tool MUSCA SEP3. The conclusions derived from the experimental measurements and related analyses allow to update the current SEE radiation hardness assurance (RHA) for readout integrated circuits of infrared image sensors used at cryogenic temperatures. The current RHA update is performed on SEE irradiation tests at room temperature, as opposed to the operational cryogenic temperature. These tests include SET (Single Event Transient), SEU (Single Event Upset) and SEFI (Single Event Functional Interrupt) irradiation tests. This update allows for reducing the cost of ROIC qualifications and the test setup complexity for each space mission. PMID- 30022011 TI - DNA Origami Nanomachines. AB - DNA can assemble various molecules and nanomaterials in a programmed fashion and is a powerful tool in the nanotechnology and biology research fields. DNA also allows the construction of desired nanoscale structures via the design of DNA sequences. Structural nanotechnology, especially DNA origami, is widely used to design and create functionalized nanostructures and devices. In addition, DNA molecular machines have been created and are operated by specific DNA strands and external stimuli to perform linear, rotational, and reciprocating movements. Furthermore, complicated molecular systems have been created on DNA nanostructures by arranging multiple molecules and molecular machines precisely to mimic biological systems. Currently, DNA nanomachines, such as molecular motors, are operated on DNA nanostructures. Dynamic DNA nanostructures that have a mechanically controllable system have also been developed. In this review, we describe recent research on new DNA nanomachines and nanosystems that were built on designed DNA nanostructures. PMID- 30022014 TI - Extending QGroundControl for Automated Mission Planning of UAVs. AB - Unmanned Aerial Vehicles (UAVs) have become very popular in the last decade due to some advantages such as strong terrain adaptation, low cost, zero casualties, and so on. One of the most interesting advances in this field is the automation of mission planning (task allocation) and real-time replanning, which are highly useful to increase the autonomy of the vehicle and reduce the operator workload. These automated mission planning and replanning systems require a Human Computer Interface (HCI) that facilitates the visualization and selection of plans that will be executed by the vehicles. In addition, most missions should be assessed before their real-life execution. This paper extends QGroundControl, an open source simulation environment for flight control of multiple vehicles, by adding a mission designer that permits the operator to build complex missions with tasks and other scenario items; an interface for automated mission planning and replanning, which works as a test bed for different algorithms, and a Decision Support System (DSS) that helps the operator in the selection of the plan. In this work, a complete guide of these systems and some practical use cases are provided. PMID- 30022013 TI - Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes. AB - The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Current non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease. PMID- 30022008 TI - Acyltransferases as Tools for Polyketide Synthase Engineering. AB - Polyketides belong to the most valuable natural products, including diverse bioactive compounds, such as antibiotics, anticancer drugs, antifungal agents, immunosuppressants and others. Their structures are assembled by polyketide synthases (PKSs). Modular PKSs are composed of modules, which involve sets of domains catalysing the stepwise polyketide biosynthesis. The acyltransferase (AT) domains and their "partners", the acyl carrier proteins (ACPs), thereby play an essential role. The AT loads the building blocks onto the "substrate acceptor", the ACP. Thus, the AT dictates which building blocks are incorporated into the polyketide structure. The precursor- and occasionally the ACP-specificity of the ATs differ across the polyketide pathways and therefore, the ATs contribute to the structural diversity within this group of complex natural products. Those features make the AT enzymes one of the most promising tools for manipulation of polyketide assembly lines and generation of new polyketide compounds. However, the AT-based PKS engineering is still not straightforward and thus, rational design of functional PKSs requires detailed understanding of the complex machineries. This review summarizes the attempts of PKS engineering by exploiting the AT attributes for the modification of polyketide structures. The article includes 253 references and covers the most relevant literature published until May 2018. PMID- 30022017 TI - Partial Inductance Model of Induction Machines for Fault Diagnosis. AB - The development of advanced fault diagnostic systems for induction machines through the stator current requires accurate and fast models that can simulate the machine under faulty conditions, both in steady-state and in transient regime. These models are far more complex than the models used for healthy machines, because one of the effect of the faults is to change the winding configurations (broken bar faults, rotor asymmetries, and inter-turn short circuits) or the magnetic circuit (eccentricity and bearing faults). This produces a change of the self and mutual phase inductances, which induces in the stator currents the characteristic fault harmonics used to detect and to quantify the fault. The development of a machine model that can reflect these changes is a challenging task, which is addressed in this work with a novel approach, based on the concept of partial inductances. Instead of developing the machine model based on the phases' coils, it is developed using the partial inductance of a single conductor, obtained through the magnetic vector potential, and combining the partial inductances of all the conductors with a fast Fourier transform for obtaining the phases' inductances. The proposed method is validated using a commercial induction motor with forced broken bars. PMID- 30022015 TI - Antioxidant and Antibacterial Activity of Roseroot (Rhodiola rosea L.) Dry Extracts. AB - Roseroot (Rhodiola rosea L.) belongs to plants revealing adaptogenic properties, which are attributed to the presence of specific phenolic compounds and are reflected mainly as antioxidant activity. The aim of the present study was to determine the antioxidant and antibacterial activity of various products obtained from R. rosea (underground organs as well as their aqueous and ethanolic dry extracts) in relation to the chemical profiles of phenolic and essential oil compounds. The chemical profiles were determined by High-performance Liquid Chromatography with a diode-array detector (HPLC-DAD) and Gas chromatography-mass spectrometry (GC-MS), antioxidant activity by (1,1-Diphenyl-2-picrylhydrazyl) Scavenging Capacity Assay (DPPH), (2,2'-Azino-bis(3-ethylbenzothiazoline-6 sulphonic acid)) Scavenging Capacity Assay (ABTS) and Ferric Reducing Antioxidant Power Assay (FRAP) and antimicrobial properties were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) values following the broth microdilutions method. The results show that the investigated samples differed in terms of their chemical compositions and biological activities. The extracts were more abundant in phenolic compounds (salidroside, tyrosol, and rosavin derivatives) in comparison to dried underground organs. The content of the determined phenolics in the analyzed extracts was affected by the solvent used for extraction. The ethanolic extract was characterized by the highest content of these substances in comparison to the aqueous one and the dried raw material, especially with regard to rosavin (969.71 mg/100 g). In parallel, this extract showed the strongest antioxidant and antibacterial activity. However, dried R. rosea underground organs also revealed strong antibacterial effects against, for example, Staphylococcus strains. PMID- 30022018 TI - Impact of Farmland Change on Soybean Production Potential in Recent 40 Years: A Case Study in Western Jilin, China. AB - During the last 40 years, the quantity and spatial patterns of farmland in Western Jilin have changed dramatically, which has had a great impact on soybean production potential. This study used one of the most advanced crop production potential models, the Global Agro-Ecological Zones model, to calculate the soybean production potential in Western Jilin based on meteorological, topography, soil and land use data, and analyzed the impact of farmland change on soybean production potential during 1975-2013. The main conclusions were the following: first, the total soybean production potential in Western Jilin in 2013 was 8.92 million tonnes, and the average soybean production potential was 1612 kg/ha. The production potential of eastern area was higher than the other areas of Western Jilin. Second, farmland change led to a growth of 3.30 million tonnes in soybean production potential between 1975 and 2000, and a decrease of 1.03 million tonnes between 2000 and 2013. Third, taking account of two situations of farmland change, the conversion between dryland and other categories, and the change of irrigation percentage led to the total soybean production potential in Western Jilin increased by 2.31 and only 0.28 million tonnes respectively between 1975 and 2000, and increased by 0.12 and 0.29 million tonnes respectively between 2000 and 2013. In general, the increase of soybean potential production was mainly due to grassland and woodland reclamation. The results of this study would be a good guideline for protecting safe baseline of farmland, managing land resources, and ensuring continuity and stability of soybean supply and food security. PMID- 30022016 TI - Differences of Four Work-Related Behavior and Experience Patterns in Work Ability and Other Work-Related Perceptions in a Finance Company. AB - The present study applies a salutogenetic approach to psycho-social stress and wellbeing at work and for the first time analyzes the relation of an extended model of four work-related behavior and experience patterns to work related perceptions, like work ability, job satisfaction and turnover intention, or engagement. Employees of an international financial services company (N = 182) completed the questionnaire Work-related behavior and experience pattern (Arbeitsbezogenes Verhaltens- und Erlebensmuster; AVEM). The AVEM has oftentimes been used for research in helping professions, but research in non-helping professions is scarce. In addition to the AVEM, measures of job satisfaction, work ability, work engagement, presenteeism, and turnover intention were included in this study. Almost half (46.2%) of the sample showed a rather unambitious attitude towards work, followed by a burnout-related risk pattern (22.0%), a healthy pattern (19.8%), and a pattern at risk for overexertion (12.1%). Significantly more favorable scores were found for all work-related perceptions in participants with the healthy pattern compared to those with the burnout related risk pattern, except for turnover intention where no significant differences were found. For work ability and vigor, those with a healthy pattern also had significantly higher scores than those with an unambitious pattern and a pattern at risk for overexertion. Being at risk for burnout not only affects job related wellbeing and coping resources, but also work ability and work engagement. A need for personnel and organizational development and health promotion is indicated by a high number of individuals with reduced working motivation and risk patterns for overexertion or burnout. PMID- 30022019 TI - A Parameter Self-Calibration Method for GNSS/INS Deeply Coupled Navigation Systems in Highly Dynamic Environments. AB - The GNSS/INS (Global Navigation Satellite System/Inertial Navigation System) navigation system has been widely discussed in recent years. Because of the unique INS-aided loop structure, the deeply coupled system performs very well in highly dynamic environments. In practice, vehicle maneuvering has a big influence on the performance of IMUs (Inertial Measurement Unit), and determining whether the selected IMUs and receiver parameters satisfy the loop dynamic requirement is still a critical problem for deeply coupled systems. Aiming at this, a new parameter self-calibration method based on the norm principle is proposed which explains the relationship between IMU precision and the velocity error of the system; the method will also provide a detailed solution to calculate the loop steady-state tracking error, so it will eventually make a judgment about the stability of the tracking loop under present system parameter settings. Lastly, a full digital simulation platform is set up, and the results of simulations show good agreement with the proposed method. PMID- 30022020 TI - Effects of Pinocembrin Pretreatment on Connexin 43 (Cx43) Protein Expression After Rat Myocardial Ischemia-Reperfusion and Cardiac Arrhythmia. AB - BACKGROUND Cardiac infarction frequently leads to arrhythmia and ischemia/reperfusion (I/R) aggravates cardiac injury. Pinocembrin can resist cerebral ischemia and decrease cardiac infarction area. This study thus generated a rat myocardial I/R model to assess the effect on ventricular rhythm and expression of gap junction connexin (Cx43). MATERIAL AND METHODS Male SD rats were randomly assigned into sham, model, and pinocembrin (30 mg/kg) pretreatment groups (N=15 each). The I/R model was generated by ligation of the left anterior descending coronary artery for 30 min. The pinocembrin group received intravenous injection 10 min before surgery. Heart rate (HR), mean artery pressure (MAP), rate pressure product (RPP), and arrhythmia were observed at 10 min before ischemia, 30 min after ischemia, and at 30, 60, and 120 min after reperfusion. ELISA was used to assess serum CK-MB and cTnI levels. Na+-K+ATPase and Ca+ Mg2+ATPase levels were quantified by spectrometry, followed by HE staining, IHC approach for Cx43 expression, and Western blot for Kir2.1 protein expression. RESULTS Model rats had significantly lower HR, MAP, and RPP than in the sham group, and the pinocembrin pretreatment group had higher serum indexes. Arrhythmia index, CK-MB, and cTnI were higher in the model and pinocembrin groups, while Na+-K+ATPase, Ca+-Mg2+ATPase, Cx43, and Kir2.1 proteins were lower (p<0.05). CONCLUSIONS Pinocembrin alleviated ventricular arrhythmia in I/R rats via enhancing Na+-K+ATPase and Ca+-Mg2+ATPase activity and upregulating Cx43 and Kir2.1 protein expression. PMID- 30022021 TI - Improvement of Ulcerations in Treatment-Resistant Chronic Scarring in a Patient with Pyoderma Gangrenosum After Improving Vascular Insufficiency, Gently Removing Necrotic Debris, and Decreasing Wound Fluid. AB - BACKGROUND Classical pyoderma gangrenosum is a rare, inflammatory, neutrophilic dermatosis that commonly presents with severe ulcerations on the lower extremities and is often misdiagnosed and mistreated. Delay in treatments can lead to worsening of the ulcerations and allows for multiple comorbid factors. Pyoderma gangrenosum is most commonly treated with immunosuppressants or anti inflammatory agents and is often worsened by surgical procedures due to the presence of pathergy. In acute cases, a course of anti-inflammatory treatments works well in alleviating symptoms and reducing ulcerations and residual scarring. However, in chronic cases with the presence of severe scarring and necrotic ulcerations, the simple implementation of systemic immunosuppressants is frequently ineffective alone. Although not mentioned in most case reports on pyoderma gangrenosum, the chronicity of its inflammatory component can lead to necrosis and scarring and subsequent vascular insufficiency. CASE REPORT We present a severe case of chronic ulcerative pyoderma gangrenosum in a patient who had treatment-resistant ulcerations and cribriform edematous scarring with subsequent vascular insufficiency of the right lower extremity. This patient, while receiving topical clobetasol, had marked improvement in the healing of his ulcerations only after starting a novel course of cadexomer iodine, compression stockings, and pentoxifylline. CONCLUSIONS The efficacy of non-anti-inflammatory treatments indicates that chronic pyoderma gangrenosum with extensive scarring is commonly associated with the comorbid factors of vascular insufficiency, necrotic debris, and extensive wound fluid. In cases of ulcerations in chronic pyoderma gangrenosum that are resistant to anti-inflammatory treatments alone, one should identify and address other compounding factors that may inhibit wound healing. PMID- 30022022 TI - Slow thermal equilibration in methylammonium lead iodide revealed by transient mid-infrared spectroscopy. AB - Hybrid organic-inorganic perovskites are emerging semiconductors for cheap and efficient photovoltaics and light-emitting devices. Different from conventional inorganic semiconductors, hybrid perovskites consist of coexisting organic and inorganic sub-lattices, which present disparate atomic masses and bond strengths. The nanoscopic interpenetration of these disparate components, which lack strong electronic and vibrational coupling, presents fundamental challenges to the understanding of charge and heat dissipation. Here we study phonon population and equilibration processes in methylammonium lead iodide (MAPbI3) by transiently probing the vibrational modes of the organic sub-lattice following above-bandgap optical excitation. We observe inter-sub-lattice thermal equilibration on timescales ranging from hundreds of picoseconds to a couple of nanoseconds. As supported by a two-temperature model based on first-principles calculations, the slow thermal equilibration is attributable to the sequential phonon populations of the inorganic and organic sub-lattices, respectively. The observed long lasting thermal non-equilibrium offers insights into thermal transport and heat management of the emergent hybrid material class. PMID- 30022025 TI - Thermal sensitivity of CO2 and CH4 emissions varies with streambed sediment properties. AB - Globally, rivers and streams are important sources of carbon dioxide and methane, with small rivers contributing disproportionately relative to their size. Previous research on greenhouse gas (GHG) emissions from surface water lacks mechanistic understanding of contributions from streambed sediments. We hypothesise that streambeds, as known biogeochemical hotspots, significantly contribute to the production of GHGs. With global climate change, there is a pressing need to understand how increasing streambed temperatures will affect current and future GHG production. Current global estimates assume linear relationships between temperature and GHG emissions from surface water. Here we show non-linearity and threshold responses of streambed GHG production to warming. We reveal that temperature sensitivity varies with substrate (of variable grain size), organic matter (OM) content and geological origin. Our results confirm that streambeds, with their non-linear response to projected warming, are integral to estimating freshwater ecosystem contributions to current and future global GHG emissions. PMID- 30022024 TI - The concerted roles of FANCM and Rad52 in the protection of common fragile sites. AB - Common fragile sites (CFSs) are prone to chromosomal breakage and are hotspots for chromosomal rearrangements in cancer cells. We uncovered a novel function of Fanconi anemia (FA) protein FANCM in the protection of CFSs that is independent of the FA core complex and the FANCI-FANCD2 complex. FANCM, along with its binding partners FAAP24 and MHF1/2, is recruited to CFS-derived structure-prone AT-rich sequences, where it suppresses DNA double-strand break (DSB) formation and mitotic recombination in a manner dependent on FANCM translocase activity. Interestingly, we also identified an indispensable function of Rad52 in the repair of DSBs at CFS-derived AT-rich sequences, despite its nonessential function in general homologous recombination (HR) in mammalian cells. Suppression of Rad52 expression in combination with FANCM knockout drastically reduces cell and tumor growth, suggesting a synthetic lethality interaction between these two genes, which offers a potential targeted treatment strategy for FANCM-deficient tumors with Rad52 inhibition. PMID- 30022023 TI - The potassium channel KCNJ13 is essential for smooth muscle cytoskeletal organization during mouse tracheal tubulogenesis. AB - Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13-mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis. PMID- 30022026 TI - Task-induced brain state manipulation improves prediction of individual traits. AB - Recent work has begun to relate individual differences in brain functional organization to human behaviors and cognition, but the best brain state to reveal such relationships remains an open question. In two large, independent data sets, we here show that cognitive tasks amplify trait-relevant individual differences in patterns of functional connectivity, such that predictive models built from task fMRI data outperform models built from resting-state fMRI data. Further, certain tasks consistently yield better predictions of fluid intelligence than others, and the task that generates the best-performing models varies by sex. By considering task-induced brain state and sex, the best-performing model explains over 20% of the variance in fluid intelligence scores, as compared to <6% of variance explained by rest-based models. This suggests that identifying and inducing the right brain state in a given group can better reveal brain-behavior relationships, motivating a paradigm shift from rest- to task-based functional connectivity analyses. PMID- 30022027 TI - Manipulation of facet orientation in hybrid perovskite polycrystalline films by cation cascade. AB - Crystal orientations in multiple orders correlate to the properties of polycrystalline materials, and it is critical to manipulate these microstructural arrangements to enhance device performance. Herein, we report a controllable approach to manipulate the facet orientation within the ABX3 hybrid perovskites polycrystalline films by cation cascade doping at A-site. Two-dimensional synchrotron radiation grazing incidence wide-angle X-ray scattering is employed to probe the crystal orientations in multiple orders in mixed perovskites thin films, revealing a general pattern to guide crystal planes stacking upon extrinsic doping during crystallization. Different from previous studies, this method enables to adjust the crystal stacking mode of certain crystallographic planes in polycrystalline perovskites. Moreover, the preferred facet orientation is found to facilitate photocarrier transport across the absorber and pertaining interface in the resultant PV device, which provides an exemplary paradigm for further explorations that relate to the microstructures of hybrid perovskite materials and relevant optoelectronics. PMID- 30022028 TI - Paeonin extracted from potatoes protects gastric epithelial cells from H2O2 induced oxidative damage in vitro by PI3K/Akt-mediated Nrf2 signaling pathway. AB - In this study, it is aimed to investigate the antioxidant mechanism of new extracts from potatoes. Four pigments, namely, Petunin, Paeonin, Malvidin and Pelargonidin, were extracted from potatoes by high performance liquid chromatography (HPLC). Our results showed that the cellular morphology and cell viability were significantly altered in gastric mucosal epithelial cells (GES-1) treated with different hydrogen peroxide (H2O2) concentrations over time (P < 0.05). Paeonin presented the strongest anti-oxidative effects on H2O2-treated cells, in both a dose- and time-dependent manner, determined by ARE-luciferase activity and HO-1 mRNA expression. After pre-treatment with Paeonin in H2O2 exposed cells, Keap1, Nrf2, HO-1 and NQO1 protein expressions were remarkably up regulated. Furthermore, immunostaining of Nrf2 expression was obviously elevated in the H2O2 + Paeonin group over time. The GSH content in the H2O2 + Paeonin group was notably lower than that in the H2O2 + Paeonin + GSK690693 group. Paeonin promoted cell cycle with augmented Cyclin D1 and p27 protein expressions. Moreover, Paeonin suppressed apoptosis with increased Bcl2, total Caspase3 and total Caspase8 protein expressions and decreased Bax, p-Caspase3 and p-Caspase8 protein expression in H2O2-treated cells. These results suggested that Paeonin might exert an anti-oxidative role by activating Nrf2 signaling pathway with the changes of cell cycle and apoptosis. PMID- 30022029 TI - Familial Associations in Testicular Cancer with Other Cancers. AB - Familial risks for testicular cancer (TC) are among the highest of all cancers. However, data are limited for histological types of TC and for possible familial associations of TC with other cancers. We used the nationwide Swedish Family Cancer Database for years 1958 to 2015 to analyse familial relative risks (RR) for 11,138 TC patients when first-degree relatives were diagnosed with TC or other cancer in reference to those without a family history. A total of 191 familial TCs were found, which accounted for 2.0% of all TC. The RR was 5.06 when one family member was diagnosed with TC with no significant difference between seminoma and nonseminoma. However, the risk for nonseminoma was 33.59 when two family members were affected. Internally consistent familial associations of TC, particularly of seminoma, were found with breast and nervous system cancers and melanoma. Individual significant associations were found for a number of sites, including ovarian, endometrial and prostate cancers. Our results suggest that nonseminoma may have a stronger genetic background than seminoma but seminoma shares more familial associations with discordant cancers. Clustering of TC with hormone-dependent cancers of the breast, ovary, endometrium and prostate may suggest mechanistic links and possibly gene-environment interactions. PMID- 30022030 TI - Magnetoelectric Spin Wave Modulator Based On Synthetic Multiferroic Structure. AB - We describe a spin wave modulator - spintronic device aimed to control spin wave propagation by an electric field. The modulator consists of a ferromagnetic film serving as a spin wave bus combined with a synthetic multiferroic comprising piezoelectric and magnetostrictive materials. Its operation is based on the stress-mediated coupling between the piezoelectric and magnetostrictive materials. By applying an electric field to the piezoelectric layer, the stress is produced. In turn, the stress changes the direction of the easy axis in the magnetostrictive layer and affects spin wave transport. We present experimental data on a prototype consisting of a piezoelectric [Pb(Mg1/3Nb2/3)O3](1-x) [PbTiO3]x substrate, and 30 nm layer of magnetostrictive Ni film, where the film is attached to a 30 nm thick Ni81Fe19 spin wave bus. We report spin wave signal modulation in Ni81Fe19 layer by an electric field applied across the piezoelectric layer. The switching between the spin wave conducting and non conducting states is achieved by applying +/-0.3 MV/m electric field. We report over 300% modulation depth detected 80 MUm away from the excitation port at room temperature. The demonstration of the spin wave modulator provides a new direction for spin-based device development by utilizing an electric field for spin current control. PMID- 30022031 TI - Crystal structure and substrate binding mode of ectonucleotide phosphodiesterase/pyrophosphatase-3 (NPP3). AB - Ectonucleotide phosphodiesterase/pyrophosphatase-3 (NPP3) is a membrane-bound glycoprotein that regulates extracellular levels of nucleotides. NPP3 is known to contribute to the immune response on basophils by hydrolyzing ATP and to regulate the glycosyltransferase activity in Neuro2a cells. Here, we report on crystal structures of the nuclease and phosphodiesterase domains of rat NPP3 in complex with different substrates, products and substrate analogs giving insight into details of the catalytic mechanism. Complex structures with a phosphate ion, the product AMP and the substrate analog AMPNPP provide a consistent picture of the coordination of the substrate in which one zinc ion activates the threonine nucleophile whereas the other zinc ion binds the phosphate group. Co-crystal structures with the dinucleotide substrates Ap4A and UDPGlcNAc reveal a binding pocket for the larger leaving groups of these substrates. The crystal structures as well as mutational and kinetic analysis demonstrate that the larger leaving groups interact only weakly with the enzyme such that the substrate affinity is dominated by the interactions of the first nucleoside group. For this moiety, the nucleobase is stacked between Y290 and F207 and polar interactions with the protein are only formed via water molecules thus explaining the limited nucleobase selectivity. PMID- 30022032 TI - Biotic and abiotic drivers of tree seedling recruitment across an alpine treeline ecotone. AB - Treeline responses to climate change ultimately depend on successful seedling recruitment, which requires dispersal of viable seeds and establishment of individual propagules in novel environments. In this study, we evaluated the effects of several abiotic and biotic drivers of early tree seedling recruitment across an alpine treeline ecotone. In two consecutive years, we sowed seeds of low- and high-elevation provenances of Larix decidua (European larch) and Picea abies (Norway spruce) below, at, and above the current treeline into intact vegetation and into open microsites with artificially removed surface vegetation, as well as into plots protected from seed predators and herbivores. Seedling emergence and early establishment in treatment and in control plots were monitored over two years. Tree seedling emergence occurred at and several hundred metres above the current treeline when viable seeds and suitable microsites for germination were available. However, dense vegetation cover at lower elevations and winter mortality at higher elevations particularly limited early recruitment. Post-dispersal predation, species, and provenance also affected emergence and early establishment. This study demonstrates the importance of understanding multiple abiotic and biotic drivers of early seedling recruitment that should be incorporated into predictions of treeline dynamics under climate change. PMID- 30022034 TI - Carbon dioxide stimulates lake primary production. AB - Gross primary production (GPP) is a fundamental ecosystem process that sequesters carbon dioxide (CO2) and forms the resource base for higher trophic levels. Still, the relative contribution of different controls on GPP at the whole ecosystem scale is far from resolved. Here we show, by manipulating CO2 concentrations in large-scale experimental pond ecosystems, that CO2 availability is a key driver of whole-ecosystem GPP. This result suggests we need to reformulate past conceptual models describing controls of lake ecosystem productivity and include our findings when developing models used to predict future lake ecosystem responses to environmental change. PMID- 30022033 TI - Prior object-knowledge sharpens properties of early visual feature-detectors. AB - Early stages of visual processing are carried out by neural circuits activated by simple and specific features, such as the orientation of an edge. A fundamental question in human vision is how the brain organises such intrinsically local information into meaningful properties of objects. Classic models of visual processing emphasise a one-directional flow of information from early feature detectors to higher-level information-processing. By contrast to this view, and in line with predictive-coding models of perception, here, we provide evidence from human vision that high-level object representations dynamically interact with the earliest stages of cortical visual processing. In two experiments, we used ambiguous stimuli that, depending on the observer's prior object-knowledge, can be perceived as either coherent objects or as a collection of meaningless patches. By manipulating object knowledge we were able to determine its impact on processing of low-level features while keeping sensory stimulation identical. Both studies demonstrate that perception of local features is facilitated in a manner consistent with an observer's high-level object representation (i.e., with no effect on object-inconsistent features). Our results cannot be ascribed to attentional influences. Rather, they suggest that high-level object representations interact with and sharpen early feature-detectors, optimising their performance for the current perceptual context. PMID- 30022035 TI - Compressing Networks with Super Nodes. AB - Community detection is a commonly used technique for identifying groups in a network based on similarities in connectivity patterns. To facilitate community detection in large networks, we recast the network as a smaller network of 'super nodes', where each super node comprises one or more nodes of the original network. We can then use this super node representation as the input into standard community detection algorithms. To define the seeds, or centers, of our super nodes, we apply the 'CoreHD' ranking, a technique applied in network dismantling and decycling problems. We test our approach through the analysis of two common methods for community detection: modularity maximization with the Louvain algorithm and maximum likelihood optimization for fitting a stochastic block model. Our results highlight that applying community detection to the compressed network of super nodes is significantly faster while successfully producing partitions that are more aligned with the local network connectivity and more stable across multiple (stochastic) runs within and between community detection algorithms, yet still overlap well with the results obtained using the full network. PMID- 30022037 TI - A micron-scale surface topography design reducing cell adhesion to implanted materials. AB - The micron-scale surface topography of implanted materials represents a complementary pathway, independent of the material biochemical properties, regulating the process of biological recognition by cells which mediate the inflammatory response to foreign bodies. Here we explore a rational design of surface modifications in micron range to optimize a topography comprised of a symmetrical array of hexagonal pits interfering with focal adhesion establishment and maturation. When implemented on silicones and hydrogels in vitro, the anti adhesive topography significantly reduces the adhesion of macrophages and fibroblasts and their activation toward effectors of fibrosis. In addition, long term interaction of the cells with anti-adhesive topographies markedly hampers cell proliferation, correlating the physical inhibition of adhesion and complete spreading with the natural progress of the cell cycle. This solution for reduction in cell adhesion can be directly integrated on the outer surface of silicone implants, as well as an additive protective conformal microstructured biocellulose layer for materials that cannot be directly microstructured. Moreover, the original geometry imposed during manufacturing of the microstructured biocellulose membranes are fully retained upon in vivo exposure, suggesting a long lasting performance of these topographical features after implantation. PMID- 30022036 TI - Quantitative muscle MRI to follow up late onset Pompe patients: a prospective study. AB - Late onset Pompe disease (LOPD) is a slow, progressive disorder characterized by skeletal and respiratory muscle weakness. Enzyme replacement therapy (ERT) slows down the progression of muscle symptoms. Reliable biomarkers are needed to follow up ERT-treated and asymptomatic LOPD patients in clinical practice. In this study, 32 LOPD patients (22 symptomatic and 10 asymptomatic) underwent muscle MRI using 3-point Dixon and were evaluated at the time of the MRI with several motor function tests and patient-reported outcome measures, and again after one year. Muscle MRI showed a significant increase of 1.7% in the fat content of the thigh muscles in symptomatic LOPD patients. In contrast, there were no noteworthy differences between muscle function tests in the same period of time. We did not observe any significant changes either in muscle MRI or in muscle function tests in asymptomatic patients over the year. We conclude that 3-point Dixon muscle MRI is a useful tool for detecting changes in muscle structure in symptomatic LOPD patients and could become part of the current follow-up protocol in daily clinics. PMID- 30022038 TI - Cord Blood IL-12 Confers Protection to Clinical Malaria in Early Childhood Life. AB - Using a well-designed longitudinal cohort, we aimed to identify cytokines that were protective against malaria and to explore how they were influenced by genetic and immunological factors. 349 Mozambican pregnant women and their newborn babies were recruited and followed up for malaria outcomes until 24 months of age. Six Th1 cytokines in cord blood were screened for correlation with malaria incidence, of which IL-12 was selected for further analyses. We genotyped IL-12 polymorphisms in children/mothers and evaluated the genotype-phenotype associations and genetic effects on IL-12 levels. Maternal IL-12 concentrations were also investigated in relation to Plasmodium infections and cord blood IL-12 levels. Our data showed that high background IL-12 levels were prospectively associated with a low incidence of clinical malaria, while IL-12 production after parasite stimulation had the opposite effect on malaria incidence. IL-12 genotypes (IL-12b rs2288831/rs17860508) and the haplotype CGTTAGAG distribution were related to malaria susceptibility and background IL-12 levels. Maternal genotypes also exhibited an evident impact on host genotype-phenotype associations. Finally, a positive correlation in background IL-12 levels between maternal and cord blood was identified. Thus, cord blood background IL-12 concentrations are important for protecting children from clinical malaria, likely mediated by both genotypes (children&mothers) and maternal immunity. PMID- 30022039 TI - Electrostatic Tuning of the Ligand Binding Mechanism by Glu27 in Nitrophorin 7. AB - Nitrophorins (NP) 1-7 are NO-carrying heme proteins found in the saliva of the blood-sucking insect Rhodnius prolixus. The isoform NP7 displays peculiar properties, such as an abnormally high isoelectric point, the ability to bind negatively charged membranes, and a strong pH sensitivity of NO affinity. A unique trait of NP7 is the presence of Glu in position 27, which is occupied by Val in other NPs. Glu27 appears to be important for tuning the heme properties, but its influence on the pH-dependent NO release mechanism, which is assisted by a conformational change in the AB loop, remains unexplored. Here, in order to gain insight into the functional role of Glu27, we examine the effect of Glu27 -> Val and Glu27 -> Gln mutations on the ligand binding kinetics using CO as a model. The results reveal that annihilation of the negative charge of Glu27 upon mutation reduces the pH sensitivity of the ligand binding rate, a process that in turn depends on the ionization of Asp32. We propose that Glu27 exerts a through space electrostatic action on Asp32, which shifts the pKa of the latter amino acid towards more acidic values thus reducing the pH sensitivity of the transition between open and closed states. PMID- 30022041 TI - Author Correction: Mutant p53 stimulates cell invasion through an interaction with Rad21 in human ovarian cancer cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30022040 TI - An integrative approach to discovering cryptic species within the Bemisia tabaci whitefly species complex. AB - Bemisia tabaci is a cryptic whitefly-species complex that includes some of the most damaging pests and plant-virus vectors of a diverse range of food and fibre crops worldwide. We combine experimental evidence of: (i) differences in reproductive compatibility, (ii) hybrid verification using a specific nuclear DNA marker and hybrid fertility confirmation and (iii) high-throughput sequencing derived mitogenomes, to show that the "Mediterranean" (MED) B. tabaci comprises at least two distinct biological species; the globally invasive MED from the Mediterranean Basin and the "African silver-leafing" (ASL) from sub-Saharan Africa, which has no associated invasion records. We demonstrate that, contrary to its common name, the "ASL" does not induce squash silver-leafing symptoms and show that species delimitation based on the widely applied 3.5% partial mtCOI gene sequence divergence threshold produces discordant results, depending on the mtCOI region selected. Of the 292 published mtCOI sequences from MED/ASL groups, 158 (54%) are low quality and/or potential pseudogenes. We demonstrate fundamental deficiencies in delimiting cryptic B. tabaci species, based solely on partial sequences of a mitochondrial barcoding gene. We advocate an integrative approach to reveal the true species richness within cryptic species complexes, which is integral to the deployment of effective pest and disease management strategies. PMID- 30022042 TI - Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats. AB - Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p < 8.97 * 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions. PMID- 30022043 TI - Reading and Myopia: Contrast Polarity Matters. AB - In myopia the eye grows too long, generating poorly focused retinal images when people try to look at a distance. Myopia is tightly linked to the educational status and is on the rise worldwide. It is still not clear which kind of visual experience stimulates eye growth in children and students when they study. We propose a new and perhaps unexpected reason. Work in animal models has shown that selective activation of ON or OFF pathways has also selective effects on eye growth. This is likely to be true also in humans. Using custom-developed software to process video frames of the visual environment in realtime we quantified relative ON and OFF stimulus strengths. We found that ON and OFF inputs were largely balanced in natural environments. However, black text on white paper heavily overstimulated retinal OFF pathways. Conversely, white text on black paper overstimulated ON pathways. Using optical coherence tomography (OCT) in young human subjects, we found that the choroid, the heavily perfused layer behind the retina in the eye, becomes about 16 um thinner in only one hour when subjects read black text on white background but about 10 um thicker when they read white text from black background. Studies both in animal models and in humans have shown that thinner choroids are associated with myopia development and thicker choroids with myopia inhibition. Therefore, reading white text from a black screen or tablet may be a way to inhibit myopia, while conventional black text on white background may stimulate myopia. PMID- 30022045 TI - Extract from Aphloia theiformis, an edible indigenous plant from Reunion Island, impairs Zika virus attachment to the host cell surface. AB - The mosquito-borne Zika virus (ZIKV) belongs to the flavivirus genus of the Flaviviridae family. Contemporary epidemic strains of ZIKV are associated with congenital malformations in infants, including microcephaly, as well as Guillain Barre syndrome in adults. A risk of human-to-human transmission of ZIKV is also well documented. A worldwide research effort has been undertaken to identify safe and effective strategies to prevent or treat ZIKV infection. We show here that extract from Aphloia theiformis, an edible endemic plant from Indian Ocean islands, exerts a potent antiviral effect against ZIKV strains of African and Asian lineages, including epidemic strains. The antiviral effect of A. theiformis extract was extended to clinical isolates of dengue virus (DENV) of the four serotypes in human hepatocytes. A. theiformis inhibited virus entry in host cells by acting directly on viral particles, thus impairing their attachment to the cell surface. Electron microscopic observations revealed that organization of ZIKV particles was severely affected by A. theiformis. We propose a model of antiviral action for A. theiformis against flaviviruses that highlights the potential of medicinal plants as promising sources of naturally-derived antiviral compounds to prevent ZIKV and DENV infections. PMID- 30022044 TI - p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis. AB - Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function. PMID- 30022046 TI - Osterix regulates corticalization for longitudinal bone growth via integrin beta3 expression. AB - Corticalization, coalescence of trabecular bone into the metaphyseal cortex, is important for the longitudinal growth of long bones. However, little is known about the molecular mechanisms controlling corticalization. To understand the molecular mechanisms underlying corticalization, we analyzed osteoblast-specific Osterix-knockout mice (Col-OMT). In control mice, corticalization was initiated after 7 postnatal days, and the number of osteoblasts in the peripheral spongiosa was increased compared to the number in the central spongiosa. In contrast, in Col-OMT mice, corticalization was delayed, and the number of osteoblasts in peripheral zones was unchanged compared to the central zone. Furthermore, femoral length was decreased in Col-OMT mice at 1 month. Because Col-OMT mice exhibited impaired matrix coalescence and osteoblast migration, we evaluated integrin signaling in Col-OMT mice. Osterix bound to the Itgb3 promoter and increased transcription of the Itgb3 gene in osteoblast cells. Interestingly, the inner and outer cortical bones were separated in Itgb3-null mice at postnatal day 7. In Itgb3-null mice, the number of osteoblasts in peripheral zones was not changed, and the femoral length was decreased. Taken together, these results indicate that Osterix regulates corticalization for longitudinal bone growth via the control of integrin beta3 expression in osteoblasts. Our findings imply that the ability to control osteoblast function during corticalization may help in the treatment of short stature. PMID- 30022047 TI - Potent effect of the MDM2 inhibitor AMG232 on suppression of glioblastoma stem cells. AB - Testing new ways to identify untapped opportunities for glioblastoma therapies remains highly significant. Amplification and overexpression of MDM2 gene is frequent in glioblastoma and disrupting the MDM2-p53 interaction is a promising strategy to treat the cancer. RG7112 is the first-in class inhibitor and recently discovered AMG232 is the most potent MDM2 inhibitor known to date. Here, we compared the effects of these two clinical MDM2 inhibitors in six glioblastoma cell lines and ten patient-derived glioblastoma stem cells. Targeted sequencing of the TP53, MDM2 genes and whole transcriptome analysis were conducted to verify genetic status associated with sensitivity and resistance to the drugs. Although TP53 wild-type glioblastoma cell lines are similarly sensitive to AMG232 and RG7112, we found that four TP53 wild-type out of ten patient-derived glioblastoma cells are much more sensitive to AMG232 than RG7112 (average IC50 of 76 nM vs. 720 nM). Among these, 464T stem cells containing MDM2 gene amplification were most sensitive to AMG232 with IC50 of 5.3 nM. Moreover, AMG232 exhibited higher selectivity against p53 wild-type cells over p53 mutant stem cells compared to RG7112 (average selectivity of 512-fold vs. 16.5-fold). Importantly, we also found that AMG232 is highly efficacious in three-dimensional (3D) tumor spheroids growth and effectively inhibits the stemness-related factors, Nestin and ZEB1. Our data provide new evidence that glioblastoma stem cells have high susceptibility to AMG232 suggesting the potential clinical implications of MDM2 inhibition for glioblastoma treatment. These will facilitate additional preclinical and clinical studies evaluating MDM2 inhibitors in glioblastoma and direct further efforts towards developing better MDM2-targeted therapeutics. PMID- 30022048 TI - Crosstalk between hepatic tumor cells and macrophages via Wnt/beta-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. AB - Tumor-associated macrophages (TAMs) are a major component of tumor microenvironment (TME) and play pivotal roles in the progression of hepatocellular carcinoma (HCC). Wnt signaling is evolutionarily conserved and participates in liver tumorigenesis. Several studies have shown that macrophage derived Wnt ligands can activate Wnt signaling in tumor cells. However, whether Wnt ligands secreted by tumor cells can trigger Wnt signaling in macrophages is still elusive. In this study, we first verified that canonical Wnt/beta-catenin signaling was activated during monocyte-to-macrophage differentiation and in M2 polarized macrophages. Knockdown of beta-catenin in M2 macrophages exhibited stronger antitumor characteristics when cocultured with Hepa1-6 HCC cells in a series of experiments. Activation of Wnt signaling promoted M2 macrophage polarization through c-Myc. Moreover, co-culturing naive macrophages with Hepa1-6 HCC cells in which Wnt ligands secretion was blocked by knockdown of Wntless inhibited M2 polarization in vitro. Consistently, the growth of HCC tumor orthotopically inoculated with Wntless-silenced Hepa1-6 cells was impeded, and the phenotype of M2-like TAMs was abrogated due to attenuated Wnt/beta-catenin signaling in TAMs, leading to subverted immunosuppressive TME. Finally, we confirmed the correlation between M2 macrophage polarization and nuclear beta catenin accumulation in CD68+ macrophages in human HCC biopsies. Taken together, our study indicates that tumor cells-derived Wnt ligands stimulate M2-like polarization of TAMs via canonical Wnt/beta-catenin signaling, which results in tumor growth, migration, metastasis, and immunosuppression in HCC. To block Wnts secretion from tumor cells and/or Wnt/beta-catenin signal activation in TAMs may be potential strategy for HCC therapy in future. PMID- 30022051 TI - The emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016. PMID- 30022050 TI - Nucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells. AB - Genomic imprinting is a phenomenon that restricts transcription to predominantly one parental allele. How this transcriptional duality is regulated is poorly understood. Here we perform an RNA interference screen for epigenetic factors involved in paternal allelic silencing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells. Multiple factors are identified, including nucleoporin 107 (NUP107). To determine NUP107's role and specificity in Kcnq1ot1 imprinted domain regulation, we deplete Nup107, as well as Nup62, Nup98/96 and Nup153. Nup107, Nup62 and Nup153, but not Nup98/96 depletion, reduce Kcnq1ot1 noncoding RNA volume, displace the Kcnq1ot1 domain from the nuclear periphery, reactivate a subset of normally silent paternal alleles in the domain, alter histone modifications with concomitant changes in KMT2A, EZH2 and EHMT2 occupancy, as well as reduce cohesin interactions at the Kcnq1ot1 imprinting control region. Our results establish an important role for specific nucleoporins in mediating Kcnq1ot1 imprinted domain regulation. PMID- 30022049 TI - Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice. AB - Dietary lipids favor the growth of the pathobiont Bilophila wadsworthia, but the relevance of this expansion in metabolic syndrome pathogenesis is poorly understood. Here, we showed that B. wadsworthia synergizes with high fat diet (HFD) to promote higher inflammation, intestinal barrier dysfunction and bile acid dysmetabolism, leading to higher glucose dysmetabolism and hepatic steatosis. Host-microbiota transcriptomics analysis reveal pathways, particularly butanoate metabolism, which may underlie the metabolic effects mediated by B. wadsworthia. Pharmacological suppression of B. wadsworthia-associated inflammation demonstrate the bacterium's intrinsic capacity to induce a negative impact on glycemic control and hepatic function. Administration of the probiotic Lactobacillus rhamnosus CNCM I-3690 limits B. wadsworthia-induced immune and metabolic impairment by limiting its expansion, reducing inflammation and reinforcing intestinal barrier. Our results suggest a new avenue for interventions against western diet-driven inflammatory and metabolic diseases. PMID- 30022054 TI - Ovarian estradiol supports sexual behavior but not energy homeostasis in female marmoset monkeys. AB - OBJECTIVE: In adult female rodents, ovarian estradiol (E2) regulates body weight, adiposity, energy balance, physical activity, glucose-insulin homeodynamics, and lipid metabolism, while protecting against diet-induced obesity. The same E2 actions are presumed to occur in primates, but confirmatory studies have been lacking. METHODS: We investigated the consequences of ovariectomy (OVX) and E2 replacement in female marmoset monkeys on major metabolic and morphometric endpoints. Sexual behavior and uterine diameters were assessed as positive controls for E2 treatment efficacy. Metabolic parameters were measured 1 mo prior to OVX, and 3 and 6 mo thereafter. During OVX, animals received empty or E2 containing silastic s.c. implants. To test the interaction between E2 and diet, both treatment groups were assigned to either a higher fat diet (HFD) or a low fat diet (LFD). RESULTS: As anticipated, OVX animals exhibited diminished frequency (p = 0.04) of sexually receptive behavior and increased rejection behavior (p = 0.04) toward their male partners compared with E2-treated OVX females. OVX also decreased (p = 0.01) uterine diameter. There were no treatment effects on total caloric intake. There were no significant effects of OVX, E2 treatment, or diet on body weight, body composition, energy expenditure, physical activity, fasting glucose, or glucose tolerance. Regardless of E2 treatment, serum triglycerides were higher (p = 0.05) in HFD than LFD females. Postmortem qPCR analysis of hypothalamic tissues revealed higher mRNA expression (p < 0.001) for PGR in E2-treated monkeys versus OVX controls regardless of diet, but no differences between groups in other selected metabolic genes. In contrast, regardless of E2 treatment, there was a decreased mRNA expression of PGC1alpha (PPARGC1A), HTR1A, and HTR5A in HFD compared with LFD females. CONCLUSIONS: Our findings, overall, document a greatly diminished role for ovarian E2 in the metabolic physiology of a female primate, and encourage consideration that primates, including humans, evolved metabolic control systems regulated by extra ovarian E2 or are generally less subject to E2 regulation. PMID- 30022053 TI - Bistable and photoswitchable states of matter. AB - Classical materials readily switch phases (solid to fluid or fluid to gas) upon changes in pressure or heat; however, subsequent reversion of the stimulus returns the material to their original phase. Covalently cross-linked polymer networks, which are solids that do not flow when strained, do not change phase even upon changes in temperature and pressure. However, upon the addition of dynamic cross-links, they become stimuli responsive, capable of switching phase from solid to fluid, but quickly returning to the solid state once the stimulus is removed. Reported here is the first material capable of a bistable switching of phase. A permanent solid to fluid transition or vice versa is demonstrated at room temperature, with inherent, spatiotemporal control over this switch in either direction triggered by exposure to light. PMID- 30022055 TI - Serum vascular adhesion protein-1 is up-regulated in hyperglycemia and is associated with incident diabetes negatively. AB - BACKGROUND/OBJECTIVES: Vascular adhesion protein-1 (VAP-1) can enhance tissue glucose uptake in cell studies and normalize hyperglycemia in animal studies. However, serum VAP-1 concentration (sVAP-1) is higher in subjects with diabetes in cross-sectional studies. In this cohort study, we test our hypothesis that sVAP-1 is increased in prediabetes to counteract hyperglycemia and is associated with incident diabetes negatively. SUBJECTS/METHODS: From 2006 to 2012, 600 subjects without diabetes from Taiwan Lifestyle Study were included and followed regularly. Diabetes was diagnosed if FPG >= 126 mg/dL (7 mmol/L), 2-h plasma glucose (2hPG) during an oral glucose tolerance test (OGTT) >= 200 mg/dL (11.1 mmol/L), or hemoglobin A1c (HbA1c) >= 6.5%, or if the subject received anti diabetic medications. Abdominal fat areas were measured by abdominal computed tomography and sVAP-1 was analyzed by ELISA. RESULTS: sVAP-1 was higher in subjects with prediabetes (p < 0.05) and increased during an OGTT (p < 0.001). Fasting sVAP-1 was associated with the response of sVAP-1 during an OGTT (p < 0.001). Besides, sVAP-1 was associated negatively with body mass index (BMI, r = 0.1449, p = 0.003), waist circumference (r = -0.1425, p = 0.004), abdominal visceral (r = -0.1457, p = 0.003), and subcutaneous (r = -0.1025, p = 0.035) fat areas, and serum high-sensitivity C-reactive protein (hsCRP) concentration (r = 0.2035, p < 0.0001), and positively with plasma adiponectin concentration (r = 0.2086, p < 0.0001), adjusted for age and gender. After 4.7 +/- 2.6 years, 73 subjects (12.2%) developed incident diabetes. High sVAP-1 predicted a lower incidence of diabetes, adjusted for age, gender, BMI, family history of diabetes, HbA1c, HOMA2-%B and HOMA2-IR (HR = 0.66, 95% CI = 0.50-0.88, p < 0.01). CONCLUSIONS: sVAP-1 is increased in response to hyperglycemia. It is associated with obesity and serum hsCRP concentration negatively, and plasma adiponectin concentration positively. Besides, a high sVAP-1 is associated with a lower incidence of diabetes in human. PMID- 30022056 TI - How has big data contributed to obesity research? A review of the literature. AB - There has been growing interest in the potential of 'big data' to enhance our understanding in medicine and public health. Although there is no agreed definition of big data, accepted critical components include greater volume, complexity, coverage and speed of availability. Much of these data are 'found' (as opposed to 'made'), in that they have been collected for non-research purposes, but could include valuable information for research. The aim of this paper is to review the contribution of 'found' data to obesity research to date, and describe the benefits and challenges encountered. A narrative review was conducted to identify and collate peer-reviewed research studies. Database searches conducted up to September 2017 found original studies using a variety of data types and sources. These included: retail sales, transport, geospatial, commercial weight management data, social media, and smartphones and wearable technologies. The narrative review highlights the variety of data uses in the literature: describing the built environment, exploring social networks, estimating nutrient purchases or assessing the impact of interventions. The examples demonstrate four significant ways in which 'found' data can complement conventional 'made' data: firstly, in moving beyond constraints in scope (coverage, size and temporality); secondly, in providing objective, quantitative measures; thirdly, in reaching hard-to-access population groups; and lastly in the potential for evaluating real-world interventions. Alongside these opportunities, 'found' data come with distinct challenges, such as: ethical and legal questions around access and ownership; commercial sensitivities; costs; lack of control over data acquisition; validity; representativeness; finding appropriate comparators; and complexities of data processing, management and linkage. Despite widespread recognition of the opportunities, the impact of 'found' data on academic obesity research has been limited. The merit of such data lies not in their novelty, but in the benefits they could add over and above, or in combination with, conventionally collected data. PMID- 30022052 TI - The solute carrier SLC9C1 is a Na+/H+-exchanger gated by an S4-type voltage sensor and cyclic-nucleotide binding. AB - Voltage-sensing (VSD) and cyclic nucleotide-binding domains (CNBD) gate ion channels for rapid electrical signaling. By contrast, solute carriers (SLCs) that passively redistribute substrates are gated by their substrates themselves. Here, we study the orphan sperm-specific solute carriers SLC9C1 that feature a unique tripartite structure: an exchanger domain, a VSD, and a CNBD. Voltage-clamp fluorimetry shows that SLC9C1 is a genuine Na+/H+ exchanger gated by voltage. The cellular messenger cAMP shifts the voltage range of activation. Mutations in the transport domain, the VSD, or the CNBD strongly affect Na+/H+ exchange, voltage gating, or cAMP sensitivity, respectively. Our results establish SLC9C1 as a phylogenetic chimaera that combines the ion-exchange mechanism of solute carriers with the gating mechanism of ion channels. Classic SLCs slowly readjust changes in the intra- and extracellular milieu, whereas voltage gating endows the Na+/H+ exchanger with the ability to produce a rapid pH response that enables downstream signaling events. PMID- 30022057 TI - Neuroanatomical differences in obesity: meta-analytic findings and their validation in an independent dataset. AB - BACKGROUND: Obesity has been linked with subtle differences in brain structure. These differences tend to be especially relevant in prefrontal cortex regions, areas which play an important role in executive control. However, results in this field are often contradictory: although studies tend to report lower gray matter volume in relation to obesity, some have also observed null or positive associations. To overcome this issue, we conducted a meta-analysis on voxel-based morphometry (VBM) differences associated with obesity-related variables and validated the findings with an independent dataset. METHODS: The literature search included combinations of the following key words: (i) neuroimaging terms: MRI, gray matter, brain, magnetic resonance; (ii) obesity-related terms: obesity, obese, body mass, waist circumference, adiposity. We conducted the meta-analysis using Anisotropic Effect-Size Seed-Based d Mapping (AES-SDM) software. Twenty-one studies on obesity and VBM fulfilled our inclusion criteria, representing 5882 participants (54% females) aged 18-92 years. To examine the validity of our meta analytic results, we additionally tested on an independent dataset (Human Connectome Project, n = 378 participants) whether mean VBM values obtained for each cluster showed correlations with body mass index (BMI). RESULTS: We found that obesity-related variables were consistently associated with lower gray matter volume in areas including the medial prefrontal cortex, bilateral cerebellum, and left temporal pole. The clusters showed negative associations between gray matter volume and BMI in the independent dataset, with the exception of one cluster in the cerebellum. CONCLUSIONS: Our findings provide robust evidence that obesity and body mass are related to significantly lower gray matter volume in brain areas with a key role in executive control. These findings might suggest a neurobiological link between obesity and self-regulatory deficits. PMID- 30022058 TI - Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. AB - Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration. PMID- 30022059 TI - "Tossing a coin:" defining the excessive use of short-acting beta2-agonists in asthma-the views of general practitioners and asthma experts in primary and secondary care. AB - The National Review of Asthma Deaths (NRAD) identified high prescribing of short acting beta2-agonists (SABAs) as a key factor in over 40% of deaths. We interviewed asthma experts from both a hospital background (n = 5) and a primary care background (n = 8), and general practitioners delivering asthma care (n = 8), to identify how SABA use is defined and perceived. We identified disparity in how acceptable SABA use is defined, ranging from 0.5 (100 doses/year) to 12 SABA inhalers (2400 doses/year), and complacency in the perception that over-use did not represent a marker for risk of asthma death. Despite current evidence, these findings suggest clinicians of various backgrounds are complacent about excessive SABA use. PMID- 30022060 TI - Nano-photosensitizer based on layered double hydroxide and isophthalic acid for singlet oxygenation and photodynamic therapy. AB - Singlet oxygen has won a great deal of attention to catalysis and biological studies due to its strong oxidizing properties. However, the photosensitizers which require for the generation of singlet oxygen remain inadequate because of their lack of long-wavelength absorption, weak hydrophilicity, and poor biocompatibility. Here, we develop near-infrared laser activated supramolecular photosensitizers (isophthalic acid/layered double hydroxide nanohybrids) for efficient two-photon photodynamic therapy. The singlet oxygen quantum yield of nanohybrid is up to 0.74. Critically, in vitro tests verify the superior anti cancer properties of nanohybrid with an IC50 determine to be 0.153 MUg mL-1. The nanohybrids take advantage of the superior tissue penetration of 808 nm laser irradiation and exhibit a dramatically strong ability to ablate tumors in vivo, with extremely low toxicity. This work provides the proof of concept that ultralong-lived triplet excitons can function as two-photon-activated photosensitizers for an effective singlet oxygen generation. PMID- 30022061 TI - Attosecond time-resolved photoelectron holography. AB - Ultrafast strong-field physics provides insight into quantum phenomena that evolve on an attosecond time scale, the most fundamental of which is quantum tunneling. The tunneling process initiates a range of strong field phenomena such as high harmonic generation (HHG), laser-induced electron diffraction, double ionization and photoelectron holography-all evolving during a fraction of the optical cycle. Here we apply attosecond photoelectron holography as a method to resolve the temporal properties of the tunneling process. Adding a weak second harmonic (SH) field to a strong fundamental laser field enables us to reconstruct the ionization times of photoelectrons that play a role in the formation of a photoelectron hologram with attosecond precision. We decouple the contributions of the two arms of the hologram and resolve the subtle differences in their ionization times, separated by only a few tens of attoseconds. PMID- 30022064 TI - TBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival. AB - The cytokine IL-15 mediates development and survival of immune cells, including natural killer T (NKT) cells, but the underlying mechanism of IL-15 function is incompletely understood. Here we show that IL-15 induces autophagy in NKT cells with a mechanism that involves a crucial signaling component, TBK-binding protein 1 (Tbkbp1). Tbkbp1 facilitates activation of the autophagy-initiating kinase Ulk1 through antagonizing the inhibitory action of mTORC1. This antagonization involves the recruitment of an mTORC1-opposing phosphatase to Ulk1. Tbkbp1 deficiency attenuates IL-15-stimulated NKT cell autophagy, and is associated with mitochondrial dysfunction, aberrant ROS production, defective Bcl2 expression and reduced NKT cell survival. Consequently, Tbkbp1-deficient mice have profound deficiency in NKT cells, especially IFN-gamma-producing NKT1. We further show that Tbkbp1 regulates IL-15-stimulated autophagy and survival of NK cells. These findings suggest a mechanism of autophagy induction by IL-15, and establish Tbkbp1 as a regulator of NKT cell development and survival. PMID- 30022062 TI - Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression. AB - Lipid microdomains ("rafts") are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin 1A, 2A, 3A, and 7A receptors; and dopamine D1 and beta2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to beta1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting. PMID- 30022065 TI - Caspases maintain tissue integrity by an apoptosis-independent inhibition of cell migration and invasion. AB - Maintenance of tissue integrity during development and homeostasis requires the precise coordination of several cell-based processes, including cell death. In animals, the majority of such cell death occurs by apoptosis, a process mediated by caspase proteases. To elucidate the role of caspases in tissue integrity, we investigated the behavior of Drosophila epithelial cells that are severely compromised for caspase activity. We show that these cells acquire migratory and invasive capacities, either within 1-2 days following irradiation or spontaneously during development. Importantly, low levels of effector caspase activity, which are far below the threshold required to induce apoptosis, can potently inhibit this process, as well as a distinct, developmental paradigm of primordial germ cell migration. These findings may have implications for radiation therapy in cancer treatment. Furthermore, given the presence of caspases throughout metazoa, our results could imply that preventing unwanted cell migration constitutes an ancient non-apoptotic function of these proteases. PMID- 30022063 TI - Sex differences in stress reactivity in arousal and attention systems. AB - Women are more likely than men to suffer from psychiatric disorders with hyperarousal symptoms, including posttraumatic stress disorder (PTSD) and major depression. In contrast, women are less likely than men to be diagnosed with schizophrenia and attention deficit hyperactivity disorder (ADHD), which share attentional impairments as a feature. Stressful events exacerbate symptoms of the aforementioned disorders. Thus, researchers are examining whether sex differences in stress responses bias women and men towards different psychopathology. Here we review the preclinical literature suggesting that, compared to males, females are more vulnerable to stress-induced hyperarousal, while they are more resilient to stress-induced attention deficits. Specifically described are sex differences in receptors for the stress neuropeptide, corticotropin-releasing factor (CRF), that render the locus coeruleus arousal system of females more vulnerable to stress and less adaptable to CRF hypersecretion, a condition found in patients with PTSD and depression. Studies on the protective effects of ovarian hormones against CRF induced deficits in sustained attention are also detailed. Importantly, we highlight how comparing males and females in preclinical studies can lead to the development of novel therapeutics to improve treatments for psychiatric disorders in both women and men. PMID- 30022066 TI - Developmental arrest in Drosophila melanogaster caused by mitochondrial DNA replication defects cannot be rescued by the alternative oxidase. AB - The xenotopic expression of the alternative oxidase AOX from the tunicate Ciona intestinalis in diverse models of human disease partially alleviates the phenotypic effects of mitochondrial respiratory chain defects. AOX is a non proton pumping, mitochondrial inner membrane-bound, single-subunit enzyme that can bypass electron transport through the cytochrome segment, providing an additional site for ubiquinone reoxidation and oxygen reduction upon respiratory chain overload. We set out to investigate whether AOX expression in Drosophila could counteract the effects of mitochondrial DNA (mtDNA) replication defects caused by disturbances in the mtDNA helicase or DNA polymerase gamma. We observed that the developmental arrest imposed by either the expression of mutant forms of these enzymes or their knockdown was not rescued by AOX. Considering also the inability of AOX to ameliorate the phenotype of tko25t, a fly mutant with mitochondrial translation deficiency, we infer that this alternative enzyme may not be applicable to cases of mitochondrial gene expression defects. Finding the limitations of AOX applicability will help establish the parameters for the future putative use of this enzyme in gene therapies for human mitochondrial diseases. PMID- 30022067 TI - Unveiling the bosonic nature of an ultrashort few-electron pulse. AB - Quantum dynamics is very sensitive to dimensionality. While two-dimensional electronic systems form Fermi liquids, one-dimensional systems-Tomonaga-Luttinger liquids-are described by purely bosonic excitations, even though they are initially made of fermions. With the advent of coherent single-electron sources, the quantum dynamics of such a liquid is now accessible at the single-electron level. Here, we report on time-of-flight measurements of ultrashort few-electron charge pulses injected into a quasi one-dimensional quantum conductor. By changing the confinement potential we can tune the system from the one dimensional Tomonaga-Luttinger liquid limit to the multi-channel Fermi liquid and show that the plasmon velocity can be varied over almost an order of magnitude. These results are in quantitative agreement with a parameter-free theory and demonstrate a powerful probe for directly investigating real-time dynamics of fractionalisation phenomena in low-dimensional conductors. PMID- 30022068 TI - BAP31, a newly defined cancer/testis antigen, regulates proliferation, migration, and invasion to promote cervical cancer progression. AB - Malignant tumors typically undergo an atavistic regression characterized by the overexpression of embryonic genes and proto-oncogenes, including a variety of cancer/testis antigens (CTAs) that are testis-derived and are not expressed or expressed in trace amounts in somatic tissues. Based on this theory, we established a new method to identify unknown CTAs, the spermatogenic cells specific monoclonal antibody-defined cancer/testis antigen (SADA) method. Using the SADA method, we identified BAP31 as a novel CTA and confirmed that BAP31 expression is associated with progression and metastasis of several cancers, particularly in cervical cancer. We found that BAP31 was significantly upregulated in stage I, II, and III cervical cancer patients and highly correlated with poor clinic outcomes. We further demonstrated that BAP31 regulates cervical cancer cell proliferation by arresting the cell cycle at the G0/G1 stage and that depletion of BAP31 inhibits hyper-proliferation. Moreover, depletion of BAP31 inhibits cervical cancer cell invasion and migration by regulating the expression and subcellular localization of Drebrin, M-RIP, SPECC1L, and Nexilin, and then affect the cytoskeleton assemblage. Finally, the depletion of BAP31 prevents cervical cancer progression and metastasis in vivo. These findings provide a new method for identifying novel CTAs as well as mechanistic insights into how BAP31 regulates cervical cancer hyper-proliferation and metastasis. PMID- 30022070 TI - MreB polymers and curvature localization are enhanced by RodZ and predict E. coli's cylindrical uniformity. AB - The actin-like protein MreB has been proposed to coordinate the synthesis of the cell wall to determine cell shape in bacteria. MreB is preferentially localized to areas of the cell with specific curved geometries, avoiding the cell poles. It remains unclear whether MreB's curvature preference is regulated by additional factors, and which specific features of MreB promote specific features of rod shape growth. Here, we show that the transmembrane protein RodZ modulates MreB curvature preference and polymer number in E. coli, properties which are regulated independently. An unbiased machine learning analysis shows that MreB polymer number, the total length of MreB polymers, and MreB curvature preference are key correlates of cylindrical uniformity, the variability in radius within a single cell. Changes in the values of these parameters are highly predictive of the resulting changes in cell shape (r2 = 0.93). Our data thus suggest RodZ promotes the assembly of geometrically-localized MreB polymers that lead to the growth of uniform cylinders. PMID- 30022071 TI - Mechanical interactions between bacteria and hydrogels. AB - Mechanical interactions between bacterial cells and extracellular polymeric substance are essential in determining biofilm assembly and disassembly as well the mechanical characteristics of biofilms. However, the physics of these mechanical interactions in different cell culture conditions are poorly understood. We created typical artificial biofilm consisting of planktonic bacteria and hydrogel, in the absence of metabolic or regulatory effect. We have demonstrated that the cell culture medium can significantly affect the mechanical interactions between bacterial cells and hydrogels. The stiffness of the bacteria hydrogel artificial biofilm cannot be simply attributed by the summation of the contribution from the bacteria and hydrogel based on the mathematical models and computational models. We have revealed that the tryptone component of Luria Bertani broth medium plays an important role in stiffening effect of bacteria hydrogel construct. Such significant stiffening effect can be explained by the following mechanism: the presence of tryptone in cell culture medium may enable the bacteria itself to crosslink the hydrogel polymer chains. Our findings have also demonstrated the synergy of modelling and innovative experiments which would potentially impact the biofilm control strategies. PMID- 30022069 TI - Crystal structure of an L chain optimised 14F7 anti-ganglioside Fv suggests a unique tumour-specificity through an unusual H-chain CDR3 architecture. AB - Targeted cancer immunotherapy offers increased efficacy concomitantly with reduced side effects. One antibody with promising clinical potential is 14F7, which specifically recognises the NeuGc GM3 ganglioside. This antigen is found in the plasma membrane of a range of tumours, but is essentially absent from healthy human cells. 14F7 can discriminate NeuGc GM3 from the very similar NeuAc GM3, a common component of cell membranes. The molecular basis for this unique specificity is poorly understood. Here we designed and expressed 14F7-derived single-chain Fvs (scFvs), which retained the specificity of the parent antibody. Detailed expression and purification protocols are described as well as the synthesis of the NeuGc GM3 trisaccharide. The most successful scFv construct, which comprises an alternative variable light chain (VLA), allowed structure determination to 2.2 A resolution. The structure gives insights into the conformation of the important CDR H3 loop and the suspected antigen binding site. Furthermore, the presence of VLA instead of the original VL elucidates how this subdomain indirectly stabilises the CDR H3 loop. The current work may serve as a guideline for the efficient production of scFvs for structure determination. PMID- 30022072 TI - Remote C-H functionalization using radical translocating arylating groups. AB - Site selective chemical functionalization at unactivated C(sp3)-H bonds is highly challenging and recent successful studies mostly focus on the use of transition metal catalysis in combination with directing groups. Radical chemistry offers a complementary approach with the Barton and the Hofmann-Loffler-Freytag reactions being landmark contributions in the area of remote C-H functionalization at unactivated aliphatic sites. Herein we introduce the concept of radical translocation arylation at unactivated secondary and tertiary C(sp3)-H bonds in various alcohols. The straightforward two-step sequence comprises an ionic alcohol sulfonylation with especially designed ortho-iodoaryl sulfonyl chlorides followed by a radical cascade reaction including aryl radical generation, remote radical translocation, aryl migration, reduction, and SO2 extrusion to give the corresponding gamma-arylated alcohols. Moderate to good yields are obtained, remote C-H arylation occurs with excellent regioselectivity and for secondary C(sp3)-H bonds good to excellent stereoselectivity is achieved. PMID- 30022073 TI - Automatic multiple zebrafish tracking based on improved HOG features. AB - As an excellent model organism, zebrafish have been widely applied in many fields. The accurate identification and tracking of individuals are crucial for zebrafish shoaling behaviour analysis. However, multi-zebrafish tracking still faces many challenges. It is difficult to keep identified for a long time due to fish overlapping caused by the crossings. Here we proposed an improved Histogram of Oriented Gradient (HOG) algorithm to calculate the stable back texture feature map of zebrafish, then tracked multi-zebrafish in a fully automated fashion with low sample size, high tracking accuracy and wide applicability. The performance of the tracking algorithm was evaluated in 11 videos with different numbers and different sizes of zebrafish. In the Right-tailed hypothesis test of Wilcoxon, our method performed better than idTracker, with significant higher tracking accuracy. Throughout the video of 16 zebrafish, the training sample of each fish had only 200-500 image samples, one-fifth of the idTracker's sample size. Furthermore, we applied the tracking algorithm to analyse the depression and hypoactivity behaviour of zebrafish shoaling. We achieved correct identification of depressed zebrafish among the fish shoal based on the accurate tracking results that could not be identified by a human. PMID- 30022074 TI - A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. AB - Mutations in proteins like FUS which cause Amyotrophic Lateral Sclerosis (ALS) result in the aberrant formation of stress granules while ALS-linked mutations in other proteins impede elimination of stress granules. Repeat expansions in C9ORF72, the major cause of ALS, reduce C9ORF72 levels but how this impacts stress granules is uncertain. Here, we demonstrate that C9ORF72 associates with the autophagy receptor p62 and controls elimination of stress granules by autophagy. This requires p62 to associate via the Tudor protein SMN with proteins, including FUS, that are symmetrically methylated on arginines. Mice lacking p62 accumulate arginine-methylated proteins and alterations in FUS dependent splicing. Patients with C9ORF72 repeat expansions accumulate symmetric arginine dimethylated proteins which co-localize with p62. This suggests that C9ORF72 initiates a cascade of ALS-linked proteins (C9ORF72, p62, SMN, FUS) to recognize stress granules for degradation by autophagy and hallmarks of a defect in this process are observable in ALS patients. PMID- 30022075 TI - Ranking genome-wide correlation measurements improves microarray and RNA-seq based global and targeted co-expression networks. AB - Co-expression networks are essential tools to infer biological associations between gene products and predict gene annotation. Global networks can be analyzed at the transcriptome-wide scale or after querying them with a set of guide genes to capture the transcriptional landscape of a given pathway in a process named Pathway Level Coexpression (PLC). A critical step in network construction remains the definition of gene co-expression. In the present work, we compared how Pearson Correlation Coefficient (PCC), Spearman Correlation Coefficient (SCC), their respective ranked values (Highest Reciprocal Rank (HRR)), Mutual Information (MI) and Partial Correlations (PC) performed on global networks and PLCs. This evaluation was conducted on the model plant Arabidopsis thaliana using microarray and differently pre-processed RNA-seq datasets. We particularly evaluated how dataset * distance measurement combinations performed in 5 PLCs corresponding to 4 well described plant metabolic pathways (phenylpropanoid, carbohydrate, fatty acid and terpene metabolisms) and the cytokinin signaling pathway. Our present work highlights how PCC ranked with HRR is better suited for global network construction and PLC with microarray and RNA seq data than other distance methods, especially to cluster genes in partitions similar to biological subpathways. PMID- 30022077 TI - High climate model dependency of Pliocene Antarctic ice-sheet predictions. AB - The mid-Pliocene warm period provides a natural laboratory to investigate the long-term response of the Earth's ice-sheets and sea level in a warmer-than present-day world. Proxy data suggest that during the warm Pliocene, portions of the Antarctic ice-sheets, including West Antarctica could have been lost. Ice sheet modelling forced by Pliocene climate model outputs is an essential way to improve our understanding of ice-sheets during the Pliocene. However, uncertainty exists regarding the degree to which results are model-dependent. Using climatological forcing from an international climate modelling intercomparison project, we demonstrate the high dependency of Antarctic ice-sheet volume predictions on the climate model-based forcing used. In addition, the collapse of the vulnerable marine basins of Antarctica is dependent on the ice-sheet model used. These results demonstrate that great caution is required in order to avoid making unsound statements about the nature of the Pliocene Antarctic ice-sheet based on model results that do not account for structural uncertainty in both the climate and ice sheet models. PMID- 30022078 TI - Magnetic resonance as a local probe for kagome magnetism in Barlowite Cu4(OH)6FBr. AB - Temperature- and field-dependent 1H-, 19F-, and 79,81Br-NMR measurements together with zero - field 79,81Br-NQR measurements on polycrystalline samples of barlowite, Cu4(OH)6FBr are conducted to study the magnetism and possible structural distortions on a microscopic level. The temperature dependence of the 79,81Br-NMR spin-lattice relaxation rates 1/T1 indicate a phase transition at TN [Formula: see text] 15 K which is of magnetic origin, but with an unusually weak slowing down of fluctuations below TN. Moreover, 1/T1T scales linear with the bulk susceptibility which indicates persisting spin fluctuations down to 2 K. Quadupolare resonance (NQR) studies reveal a pair of zero-field NQR- lines associated with the two isotopes of Br with the nuclear spins of I = 3/2. Quadrupole coupling constants of vQ ? 28.5 MHz and 24.7 MHz for 79Br- and 81Br nuclei are determined from Br-NMR and the asymmetry parameter of the electric field gradient was estimated to eta ? 0.2. The Br-NQR lines are consistent with our findings from Br-NMR and they are relatively broad, even above TN. This broadening and the relative large eta value suggests a symmetry reduction at the Br- site reflecting the presence of a local distortion in the lattice. Our density-functional calculations show that the displacements of Cu2 atoms located between the kagome planes do not account for this relatively large eta. On the other hand, full structural relaxation, including the deformation of kagome planes, leads to a better agreement with the experiment. PMID- 30022076 TI - Dynamic Loading and Tendon Healing Affect Multiscale Tendon Properties and ECM Stress Transmission. AB - The extracellular matrix (ECM) is the primary biomechanical environment that interacts with tendon cells (tenocytes). Stresses applied via muscle contraction during skeletal movement transfer across structural hierarchies to the tenocyte nucleus in native uninjured tendons. Alterations to ECM structural and mechanical properties due to mechanical loading and tissue healing may affect this multiscale strain transfer and stress transmission through the ECM. This study explores the interface between dynamic loading and tendon healing across multiple length scales using living tendon explants. Results show that macroscale mechanical and structural properties are inferior following high magnitude dynamic loading (fatigue) in uninjured living tendon and that these effects propagate to the microscale. Although similar macroscale mechanical effects of dynamic loading are present in healing tendon compared to uninjured tendon, the microscale properties differed greatly during early healing. Regression analysis identified several variables (collagen and nuclear disorganization, cellularity, and F-actin) that directly predict nuclear deformation under loading. Finite element modeling predicted deficits in ECM stress transmission following fatigue loading and during healing. Together, this work identifies the multiscale response of tendon to dynamic loading and healing, and provides new insight into microenvironmental features that tenocytes may experience following injury and after cell delivery therapies. PMID- 30022080 TI - Cherishing family values: let us not let immigration policy harm children. PMID- 30022079 TI - Weighted Betweenness Preferential Attachment: A New Mechanism Explaining Social Network Formation and Evolution. AB - The dynamics of social networks is a complex process, as there are many factors which contribute to the formation and evolution of social links. While certain real-world properties are captured by the degree-driven preferential attachment model, it still cannot fully explain social network dynamics. Indeed, important properties such as dynamic community formation, link weight evolution, or degree saturation cannot be completely and simultaneously described by state of the art models. In this paper, we explore the distribution of social network parameters and centralities and argue that node degree is not the main attractor of new social links. Consequently, as node betweenness proves to be paramount to attracting new links - as well as strengthening existing links -, we propose the new Weighted Betweenness Preferential Attachment (WBPA) model, which renders quantitatively robust results on realistic network metrics. Moreover, we support our WBPA model with a socio-psychological interpretation, that offers a deeper understanding of the mechanics behind social network dynamics. PMID- 30022081 TI - Natural menstrual rhythm and oral contraception diversely affect exhaled breath compositions. AB - Natural menstrual cycle and/or oral contraception diversely affect women metabolites. Longitudinal metabolic profiling under constant experimental conditions is thereby realistic to understand such effects. Thus, we investigated volatile organic compounds (VOCs) exhalation throughout menstrual cycles in 24 young and healthy women with- and without oral contraception. Exhaled VOCs were identified and quantified in trace concentrations via high-resolution real-time mass-spectrometry, starting from a menstruation and then repeated follow-up with six intervals including the next bleeding. Repeated measurements within biologically comparable groups were employed under optimized measurement setup. We observed pronounced and substance specific changes in exhaled VOC concentrations throughout all cycles with low intra-individual variations. Certain blood-borne volatiles changed significantly during follicular and luteal phases. Most prominent changes in endogenous VOCs were observed at the ovulation phase with respect to initial menstruation. Here, the absolute median abundances of alveolar ammonia, acetone, isoprene and dimethyl sulphide changed significantly (P-value <= 0.005) by 18.22?, 13.41?, 18.02? and 9.40?%, respectively. These VOCs behaved in contrast under the presence of combined oral contraception; e.g. isoprene decreased significantly by 30.25?%. All changes returned to initial range once the second bleeding phase was repeated. Changes in exogenous benzene, isopropanol, limonene etc. and smoking related furan, acetonitrile and orally originated hydrogen sulphide were rather nonspecific and mainly exposure dependent. Our observations could apprehend a number of known/pre investigated metabolic effects induced by monthly endocrine regulations. Potential in vivo origins (e.g. metabolic processes) of VOCs are crucial to realize such effects. Despite ubiquitous confounders, we demonstrated the true strength of volatolomics for metabolic monitoring of menstrual cycle and contraceptives. These outcomes may warrant further studies in this direction to enhance our fundamental and clinical understanding on menstrual metabolomics and endocrinology. Counter-effects of contraception can be deployed for future noninvasive assessment of birth control pills. Our findings could be translated toward metabolomics of pregnancy, menopause and post-menopausal complications via breath analysis. PMID- 30022082 TI - Propagation topography of redox phase transformations in heterogeneous layered oxide cathode materials. AB - Redox phase transformations are relevant to a number of metrics pertaining to the electrochemical performance of batteries. These phase transformations deviate from and are more complicated than the conventional theory of phase nucleation and propagation, owing to simultaneous changes of cationic and anionic valence states as well as the polycrystalline nature of battery materials. Herein, we propose an integrative approach of mapping valence states and constructing chemical topographies to investigate the redox phase transformation in polycrystalline layered oxide cathode materials under thermal abuse conditions. We discover that, in addition to the three-dimensional heterogeneous phase transformation, there is a mesoscale evolution of local valence curvatures in valence state topographies. The relative probability of negative and positive local valence curvatures alternates during the layered-to-spinel/rocksalt phase transformation. The implementation of our method can potentially provide a universal approach to study phase transformation behaviors in battery materials and beyond. PMID- 30022084 TI - Author Correction: Evolution of extrema features reveals optimal stimuli for biological state transitions. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30022083 TI - Evaluating the potential of residual Pap test fluid as a resource for the metaproteomic analysis of the cervical-vaginal microbiome. AB - The human cervical-vaginal area contains proteins derived from microorganisms that may prevent or predispose women to gynecological conditions. The liquid Pap test fixative is an unexplored resource for analysis of microbial communities and the microbe-host interaction. Previously, we showed that the residual cell-free fixative from discarded Pap tests of healthy women could be used for mass spectrometry (MS) based proteomic identification of cervical-vaginal proteins. In this study, we reprocessed these MS raw data files for metaproteomic analysis to characterize the microbial community composition and function of microbial proteins in the cervical-vaginal region. This was accomplished by developing a customized protein sequence database encompassing microbes likely present in the vagina. High-mass accuracy data were searched against the protein FASTA database using a two-step search method within the Galaxy for proteomics platform. Data was analyzed by MEGAN6 (MetaGenomeAnalyzer) for phylogenetic and functional characterization. We identified over 300 unique peptides from a variety of bacterial phyla and Candida. Peptides corresponding to proteins involved in carbohydrate metabolism, oxidation-reduction, and transport were identified. By identifying microbial peptides in Pap test supernatants it may be possible to acquire a functional signature of these microbes, as well as detect specific proteins associated with cervical health and disease. PMID- 30022085 TI - Scalable photonic reinforcement learning by time-division multiplexing of laser chaos. AB - Reinforcement learning involves decision-making in dynamic and uncertain environments and constitutes a crucial element of artificial intelligence. In our previous work, we experimentally demonstrated that the ultrafast chaotic oscillatory dynamics of lasers can be used to efficiently solve the two-armed bandit problem, which requires decision-making concerning a class of difficult trade-offs called the exploration-exploitation dilemma. However, only two selections were employed in that research; hence, the scalability of the laser chaos-based reinforcement learning should be clarified. In this study, we demonstrated a scalable, pipelined principle of resolving the multi-armed bandit problem by introducing time-division multiplexing of chaotically oscillated ultrafast time series. The experimental demonstrations in which bandit problems with up to 64 arms were successfully solved are presented where laser chaos time series significantly outperforms quasiperiodic signals, computer-generated pseudorandom numbers, and coloured noise. Detailed analyses are also provided that include performance comparisons among laser chaos signals generated in different physical conditions, which coincide with the diffusivity inherent in the time series. This study paves the way for ultrafast reinforcement learning by taking advantage of the ultrahigh bandwidths of light wave and practical enabling technologies. PMID- 30022086 TI - Non-canonicaly recruited TCRalphabetaCD8alphaalpha IELs recognize microbial antigens. AB - In the gut, various subsets of intraepithelial T cells (IELs) respond to self or non-self-antigens derived from the body, diet, commensal and pathogenic microbiota. Dominant subset of IELs in the small intestine are TCRalphabetaCD8alphaalpha+ cells, which are derived from immature thymocytes that express self-reactive TCRs. Although most of TCRalphabetaCD8alphaalpha+ IELs are thymus-derived, their repertoire adapts to microbial flora. Here, using high throughput TCR sequencing we examined how clonal diversity of TCRalphabetaCD8alphaalpha+ IELs changes upon exposure to commensal-derived antigens. We found that fraction of CD8alphaalpha+ IELs and CD4+ T cells express identical alphabetaTCRs and this overlap raised parallel to a surge in the diversity of microbial flora. We also found that an opportunistic pathogen (Staphylococcus aureus) isolated from mouse small intestine specifically activated CD8alphaalpha+ IELs and CD4+ derived T cell hybridomas suggesting that some of TCRalphabetaCD8alphaalpha+ clones with microbial specificities have extrathymic origin. We also report that CD8alphaalphaCD4+ IELs and Foxp3CD4+ T cells from the small intestine shared many alphabetaTCRs, regardless whether the later subset was isolated from Foxp3CNS1 sufficient or Foxp3CNS1 deficient mice that lacks peripherally-derived Tregs. Overall, our results imply that repertoire of TCRalphabetaCD8alphaalpha+ in small intestine expends in situ in response to changes in microbial flora. PMID- 30022087 TI - A dual-fMRI investigation of the iterated Ultimatum Game reveals that reciprocal behaviour is associated with neural alignment. AB - Dyadic interactions often involve a dynamic process of mutual reciprocity; to steer a series of exchanges towards a desired outcome, both interactants must adapt their own behaviour according to that of their interaction partner. Understanding the brain processes behind such bidirectional reciprocity is therefore central to social neuroscience, but this requires measurement of both individuals' brains during real-world exchanges. We achieved this by performing functional magnetic resonance imaging (fMRI) on pairs of male individuals simultaneously while they interacted in a modified iterated Ultimatum Game (iUG). In this modification, both players could express their intent and maximise their own monetary gain by reciprocating their partner's behaviour - they could promote generosity through cooperation and/or discourage unfair play with retaliation. By developing a novel model of reciprocity adapted from behavioural economics, we then show that each player's choices can be predicted accurately by estimating expected utility (EU) not only in terms of immediate payoff, but also as a reaction to their opponent's prior behaviour. Finally, for the first time we reveal that brain signals implicated in social decision making are modulated by these estimates of EU, and become correlated more strongly between interacting players who reciprocate one another. PMID- 30022088 TI - Determination of risk factors for herpesvirus outbreak in oysters using a broad scale spatial epidemiology framework. AB - Marine diseases have major impacts on ecosystems and economic consequences for aquaculture and fisheries. Understanding origin, spread and risk factors of disease is crucial for management, but data in the ocean are limited compared to the terrestrial environment. Here we investigated how the marine environment drives the spread of viral disease outbreak affecting The Pacific oyster worldwide by using a spatial epidemiology framework. We collected environmental and oyster health data at 46 sites spread over an area of 300 km2 along an inshore-offshore gradient during an epizootic event and conducted risk analysis. We found that disease broke out in the intertidal farming area and spread seaward. Mortalities and virus detection were observed in oysters placed 2 km from the farming areas, but oysters of almost all sites were subclinically infected. Increasing food quantity and quality, growth rate and energy reserves of oyster were associated with a lower risk of mortality offshore whereas increasing turbidity, a proxy of the concentration of suspended particulate matter, and terrestrial inputs, inferred from fatty acid composition of oysters, were associated with a higher risk of mortality. Offshore farming and maintenance of good ecological status of coastal waters are options to limit disease risk in oysters. PMID- 30022090 TI - Advances in single-scan time-encoding magnetic resonance imaging. AB - Time-encoding MRI is a single-scan method that uses traditional k-encoding only in one direction. In the orthogonal "time-encoding" direction, a string of echoes appears in an order that depends on the position of the corresponding spin packets. In one variant of time-encoding, this is achieved by using a series of selective pulses and appropriate gradients in both k-encoding and time-encoding directions. Although time-encoding offers some advantages over traditional single scan Fourier methods such as echo planar imaging (EPI), the original time encoding sequence also has some drawbacks that limit its applications. In this work, we show how one can improve several aspects of the original time-encoding sequence. By using an additional gradient pulse one can change the order in which the echoes appear, leading to identical echo times for all echoes, and hence to a uniform signal attenuation due to transverse relaxation and a reduction in average signal attenuation due to diffusion. By rearranging positive and negative gradients one can reduce the switching rate of the gradients. Furthermore, we show how one can implement time-encoding sequences in an interleaved fashion in order to reduce signal attenuation due to transverse relaxation and diffusion, while increasing the spatial resolution. PMID- 30022091 TI - MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites. AB - Chromatin dynamics mediated by post-translational modifications play a crucial role in cellular response to genotoxic stress for the maintenance of genome integrity. MDC1 is a pivotal chromatin adaptor in DNA damage response (DDR) and its methylation is essential to recruit repair factors at DNA double-strand break (DSB) sites, yet their precise molecular mechanisms remain elusive. Here we identified euchromatic histone-lysine N-methyltransferase 1 (EHMT1) and EHMT2 as novel regulators of MDC1, which is required for the accumulation of DDR factors e.g. 53BP1 and RAP80, at the DSB sites. MDC1 interacts mainly with EHMT1, which is facilitated by DNA damage-initiated ATM signalling, and EHMT2 dominantly modulates methylation of MDC1 lysine 45. This regulatory modification promotes the interaction between MDC1 and ATM to expand activated ATM on damaged chromatin and dysfunctional telomere. These findings identify EHMT1 and EHMT2 as DDR components, with implications for genome-integrity maintenance through proper dynamic methylation of MDC1. PMID- 30022089 TI - Inactivation of TCA cycle enhances Staphylococcus aureus persister cell formation in stationary phase. AB - Persister cells constitute a small subpopulation of bacteria that display remarkably high antibiotic tolerance and for pathogens such as Staphylococcus aureus are suspected as culprits of chronic and recurrent infections. Persisters formed during exponential growth are characterized by low ATP levels but less is known of cells in stationary phase. By enrichment from a transposon mutant library in S. aureus we identified mutants that in this growth phase displayed enhanced persister cell formation. We found that inactivation of either sucA or sucB, encoding the subunits of the alpha-ketoglutarate dehydrogenase of the tricarboxylic acid cycle (TCA cycle), increased survival to lethal concentrations of ciprofloxacin by 10-100 fold as did inactivation of other TCA cycle genes or atpA encoding a subunit of the F1F0 ATPase. In S. aureus, TCA cycle activity and gene expression are de-repressed in stationary phase but single cells with low expression may be prone to form persisters. While ATP levels were not consistently affected in high persister mutants they commonly displayed reduced membrane potential, and persistence was enhanced by a protein motive force inhibitor. Our results show that persister cell formation in stationary phase does not correlate with ATP levels but is associated with low membrane potential. PMID- 30022092 TI - Association between Height and Actinic Keratosis: A Nationwide Population-based Study in South Korea. AB - The association between actinic keratosis (AK) and anthropometric measures has not been investigated. This study aims to evaluate the associations between anthropometric measures and the incidence of AK in South Korea. We analyzed clinical data from individuals aged over 20 years who received a health examination arranged by the national insurance program between 2005 and 2008. Newly diagnosed AK was identified using claims data from baseline to the date of diagnosis or until December 31, 2015. The incidence of AK was highest among the elderly (aged over 60 years) and showed a male bias. The risk of AK increased with greater height. The quintile with the greatest height had an increased risk of AK compared with the quintile with the lowest height (hazard ratio = 1.28, 95% confidence interval: 1.24-1.33) after adjustment for age, sex, income, smoking status, alcohol consumption, hypertension, dyslipidemia, myocardial infarction, congestive heart failure, and chronic obstructive pulmonary disease. This study showed a positive association between the incidence of AK and human height. However, it is unclear whether these findings can be generalized to Koreans who have not received an examination or to populations in other countries. PMID- 30022093 TI - Nuclear Norm Clustering: a promising alternative method for clustering tasks. AB - Clustering techniques are widely used in many applications. The goal of clustering is to identify patterns or groups of similar objects within a dataset of interest. However, many cluster methods are neither robust nor sensitive to noises and outliers in real data. In this paper, we present Nuclear Norm Clustering (NNC, available at https://sourceforge.net/projects/nnc/), an algorithm that can be used in various fields as a promising alternative to the k means clustering method. The NNC algorithm requires users to provide a data matrix M and a desired number of cluster K. We employed simulated annealing techniques to choose an optimal label vector that minimizes nuclear norm of the pooled within cluster residual matrix. To evaluate the performance of the NNC algorithm, we compared the performance of both 15 public datasets and 2 genome wide association studies (GWAS) on psoriasis, comparing our method with other classic methods. The results indicate that NNC method has a competitive performance in terms of F-score on 15 benchmarked public datasets and 2 psoriasis GWAS datasets. So NNC is a promising alternative method for clustering tasks. PMID- 30022094 TI - How different sterols contribute to saponin tolerant plasma membranes in sea cucumbers. AB - Sea cucumbers produce saponins as a chemical defense mechanism, however their cells can tolerate the cytotoxic nature of these chemicals. To elucidate the molecular mechanisms behind this tolerance a suite of complementary biophysical tools was used, firstly using liposomes for in vitro techniques then using in silico approaches for a molecular-level insight. The holothuroid saponin Frondoside A, caused significantly less permeabilization in liposomes containing a Delta7 holothuroid sterol than those containing cholesterol and resulted in endothermic interactions versus exothermic interactions with cholesterol containing liposomes. Lipid phases simulations revealed that Frondoside A has an agglomerating effect on cholesterol domains, however, induced small irregular Delta7 sterol clusters. Our results suggest that the structural peculiarities of holothuroid sterols provide sea cucumbers with a mechanism to mitigate the sterol agglomerating effect of saponins, and therefore to protect their cells from the cytotoxicity of the saponins they produce. PMID- 30022095 TI - Potent Attractant for Root-Knot Nematodes in Exudates from Seedling Root Tips of Two Host Species. AB - Root-knot nematodes (RKN; Meloidogyne spp.) can parasitize over 2,000 plant species and are generally considered to be the most agriculturally damaging group of plant-parasitic nematodes worldwide. Infective juveniles (J2) are non-feeding and must locate and invade a host before their reserves are depleted. However, what attracts J2 to appropriate root entry sites is not known. An aim of this research is to identify semiochemicals that attract RKN to roots. J2 of the three RKN species tested are highly attracted to root tips of both tomato and Medicago truncatula. For both hosts, mutants defective in ethylene signaling were found to be more attractive than those of wild type. We determined that cell-free exudates collected from tomato and M. truncatula seedling root tips were highly attractive to M. javanica J2. Using a pluronic gel-based microassay to monitor chemical fractionation, we determined that for both plant species the active component fractionated similarly and had a mass of ~400 based on size-exclusion chromatography. This characterization is a first step toward identification of a potent and specific attractant from host roots that attracts RKN. Such a compound is potentially a valuable tool for developing novel and safe control strategies. PMID- 30022096 TI - Trichromatic perception of flower colour improves resource detection among New World monkeys. AB - Many plants use colour to attract pollinators, which often possess colour vision systems well-suited for detecting flowers. Yet, to isolate the role of colour is difficult, as flowers also produce other cues. The study of florivory by Neotropical primates possessing polymorphic colour vision provides an opportunity to investigate the importance of colour directly. Here we determine whether differences in colour vision within a mixed population of wild dichromatic and trichromatic white-faced capuchins (Cebus capucinus imitator) affect flower foraging behaviours. We collected reflectance data for flower foods and modelled their chromatic properties to capuchin colour vision phenotypes. We collected behavioural data over 22 months spanning four years, determined the colour vision phenotype of each monkey based on amino acid variation of the L/M opsin gene from fecal DNA, and compared foraging behaviours of dichromats and trichromats. Most flowers were more conspicuous to trichromats, and trichromats foraged in small flower patches significantly more often. These data demonstrate a difference in wild primate foraging patterns based on colour vision differences, supporting the hypothesis that trichromacy enhances detection of small, ephemeral resources. This advantage, which may also extend to other foods, likely contributes to the maintenance of colour vision polymorphism in Neotropical monkeys. PMID- 30022097 TI - Coverage and diagnostic yield of Whole Exome Sequencing for the Evaluation of Cases with Dilated and Hypertrophic Cardiomyopathy. AB - Targeted next generation sequencing of gene panels has become a popular tool for the genetic diagnosis of hypertrophic (HCM) and dilated cardiomyopathy (DCM). However, it is uncertain whether the use of Whole Exome Sequencing (WES) represents a more effective approach for diagnosis of cases with HCM and DCM. In this study, we performed indirect comparisons of the coverage and diagnostic yield of WES on genes and variants related to HCM and DCM versus 4 different commercial gene panels using 40 HCM and DCM patients, assuming perfect coverage in those panels. We identified 6 pathogenic or likely pathogenic among 14 HCM patients (diagnostic yield 43%). 3 pathogenic or likely pathogenic were found among the 26 DCM patients (diagnostic yield 12%). The coverage was similar to that of four existing commercial gene panels due to the clustering of mutation within MYH7, MYBPC3, TPM1, TNT2, and TTN. Moreover, the coverage of WES appeared inadequate for TNNI3 and PLN. We conclude that most of the pathogenic variants for HCM and DCM can be found within a small number of genes which were covered by all the commercial gene panels, and the application of WES did not increase diagnostic yield. PMID- 30022099 TI - Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. AB - Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts. PMID- 30022098 TI - GOATOOLS: A Python library for Gene Ontology analyses. AB - The biological interpretation of gene lists with interesting shared properties, such as up- or down-regulation in a particular experiment, is typically accomplished using gene ontology enrichment analysis tools. Given a list of genes, a gene ontology (GO) enrichment analysis may return hundreds of statistically significant GO results in a "flat" list, which can be challenging to summarize. It can also be difficult to keep pace with rapidly expanding biological knowledge, which often results in daily changes to any of the over 47,000 gene ontologies that describe biological knowledge. GOATOOLS, a Python based library, makes it more efficient to stay current with the latest ontologies and annotations, perform gene ontology enrichment analyses to determine over- and under-represented terms, and organize results for greater clarity and easier interpretation using a novel GOATOOLS GO grouping method. We performed functional analyses on both stochastic simulation data and real data from a published RNA seq study to compare the enrichment results from GOATOOLS to two other popular tools: DAVID and GOstats. GOATOOLS is freely available through GitHub: https://github.com/tanghaibao/goatools . PMID- 30022100 TI - Breast milk, formula, the microbiome and overweight. PMID- 30022101 TI - Exercise as medicine for survivors of paediatric cancer. PMID- 30022103 TI - Feast and famine: the keys to gut engraftment. PMID- 30022102 TI - Segmental Additive Tissue Engineering. AB - Segmental bone defects caused by trauma and disease represent a major clinical problem worldwide. Current treatment options are limited and often associated with poor outcomes and severe complications. Bone engineering is a promising alternative solution, but a number of technical challenges must be addressed to allow for effective and reproducible construction of segmental grafts that meet the size and geometrical requirements needed for individual patients and routine clinical applications. It is important to devise engineering strategies and standard operating procedures that make it possible to scale up the size of bone engineered grafts, minimize process and product variability, and facilitate technology transfer and implementation. To address these issues, we have combined traditional and modular tissue engineering approaches in a strategy referred to as Segmental Additive Tissue Engineering (SATE). To demonstrate this approach, a digital reconstruction of a rabbit femoral defect was partitioned transversally to the longitudinal axis into segments (modules) with discoidal geometry and defined thickness to enable protocol standardization and effective tissue formation in vitro. Bone grafts corresponding to each segment were then engineered using biomimetic scaffolds seeded with human induced pluripotent stem cell-derived mesodermal progenitors (iPSC-MPs) and a novel perfusion bioreactor with universal design. The SATE strategy enables the effective and reproducible engineering of segmental bone grafts for personalized skeletal reconstruction, and will facilitate technology transfer and implementation of a tissue engineering approach to segmental bone defect therapy. PMID- 30022104 TI - Provoking your enemies to kill each other. PMID- 30022105 TI - Author Correction: Multidrug efflux pumps: structure, function and regulation. AB - In the version of this Review originally published, the author contributions of co-author Arthur Neuberger were incorrectly listed. The author contributions should have appeared as 'D.D., X.W.-K., A.N., H.W.v.V., K.M.P., L.J.V.P. and B.F.L. researched data for the article, made substantial contributions to discussions of the content, wrote the article, and reviewed and edited the manuscript before submission'. This has now been corrected in all versions of the Review. The authors apologize to readers for this error. PMID- 30022106 TI - Gold rush to gene-editing in the brain. PMID- 30022107 TI - MMP12 makes the cut. PMID- 30022108 TI - Assembly and Analysis of Unmapped Genome Sequence Reads Reveal Novel Sequence and Variation in Dogs. AB - Dogs are excellent animal models for human disease. They have extensive veterinary histories, pedigrees, and a unique genetic system due to breeding practices. Despite these advantages, one factor limiting their usefulness is the canine genome reference (CGR) which was assembled using a single purebred Boxer. Although a common practice, this results in many high-quality reads remaining unmapped. To address this whole-genome sequence data from three breeds, Border Collie (n = 26), Bearded Collie (n = 7), and Entlebucher Sennenhund (n = 8), were analyzed to identify novel, non-CGR genomic contigs using the previously validated pseudo-de novo assembly pipeline. We identified 256,957 novel contigs and paired-end relationships together with BLAT scores provided 126,555 (49%) high-quality contigs with genomic coordinates containing 4.6 Mb of novel sequence absent from the CGR. These contigs close 12,503 known gaps, including 2.4 Mb containing partially missing sequences for 11.5% of Ensembl, 16.4% of RefSeq and 12.2% of canFam3.1+ CGR annotated genes and 1,748 unmapped contigs containing 2,366 novel gene variants. Examples for six disease-associated genes (SCARF2, RD3, COL9A3, FAM161A, RASGRP1 and DLX6) containing gaps or alternate splice variants missing from the CGR are also presented. These findings from non reference breeds support the need for improvement of the current Boxer-only CGR to avoid missing important biological information. The inclusion of the missing gene sequences into the CGR will facilitate identification of putative disease mutations across diverse breeds and phenotypes. PMID- 30022109 TI - U6 can be used as a housekeeping gene for urinary sediment miRNA studies of IgA nephropathy. AB - Recent studies have indicated that urinary sediment miRNAs not only are able to serve as non-invasive diagnostic biomarkers for IgA nephropathy (IgAN) but may also be closely related to several clinical and pathological indicators. However, the lack of a suitable internal reference miRNA has hampered research into urinary sediment miRNAs. To date, U6 has been used as a reference gene in urinary sediment miRNA studies mostly based on the results from studies using tissue samples and cell lines. In a total of 330 IgAN patients, 164 disease control patients and 130 normal control patients, there was no significant difference in U6 levels. We also compared the U6 levels in different types of primary glomerular disease groups (IgA nephropathy, membranous nephropathy, minimal change nephrosis and focal segmental glomerular sclerosis). The results confirmed that there was no significant difference in the expression of U6 in different primary glomerular disease groups. Moreover, treatment had no significant effect on the expression levels of U6 in IgA nephropathy. Therefore, U6 is an excellent housekeeping gene for urinary sediment miRNA studies of IgA nephropathy. PMID- 30022110 TI - Using controlled disorder to probe the interplay between charge order and superconductivity in NbSe2. AB - The interplay between superconductivity and charge-density wave (CDW) in 2H-NbSe2 is not fully understood despite decades of study. Artificially introduced disorder can tip the delicate balance between two competing long-range orders, and reveal the underlying interactions that give rise to them. Here we introduce disorder by electron irradiation and measure in-plane resistivity, Hall resistivity, X-ray scattering, and London penetration depth. With increasing disorder, the superconducting transition temperature, Tc, varies non monotonically, whereas the CDW transition temperature, TCDW, monotonically decreases and becomes unresolvable above a critical irradiation dose where Tc drops sharply. Our results imply that the CDW order initially competes with superconductivity, but eventually assists it. We argue that at the transition where the long-range CDW order disappears, the cooperation with superconductivity is dramatically suppressed. X-ray scattering and Hall resistivity measurements reveal that the short-range CDW survives above the transition. Superconductivity persists to much higher dose levels, consistent with fully gapped superconductivity and moderate interband pairing. PMID- 30022111 TI - Natural Course of Clinically Isolated Syndrome: A Longitudinal Analysis Using a Markov Model. AB - Clinically isolated syndrome (CIS) refers to the initial clinical episode with symptoms suggestive of multiple sclerosis (MS). Due to limited number of long term follow-up studies, progression pattern from CIS to more advanced stages remains unclear. In the current study, we constructed a Markov model to simulate the natural course of CIS. The model estimated the probabilities of transition from CIS to more advanced disease stages and the duration needed for the progression. The analysis showed: (1) CIS is a solid disease identity: more than 85% of the subjects with a diagnosis of CIS progress to RRMS or more advanced stages within 20 years; (2) the reduction of life expectancy in subjects with CIS is marginal. PMID- 30022113 TI - Pregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report. AB - OBJECTIVES: We described pregnancy outcomes in Crohn's disease (CD) patients enrolled in the TREAT Registry who received infliximab before, or during pregnancy and those not treated with infliximab or any biologic agent. METHODS: In the TREAT Registry (1999-2012), pregnancy outcomes were analyzed from maternal and paternal patients exposed to infliximab <=365 days (gestational exposure), >365 days (pre-gestational exposure) of pregnancy outcome or without infliximab exposure (non-biologic exposed). "Healthy infants" were defined as those with no congenital abnormalities, neonatal complications (e.g., jaundice, prematurity, heart murmur, cortical vision/fine motor delay, cardiac failure, hemophilia, or torticollis), prolonged hospitalization, or those who received no special treatment. Disease activity and concomitant medications were also evaluated. RESULTS: Overall, 92.3% (324/351) of pregnancies had known outcomes. The majority of both maternal pregnancies (92.6, 91.2, and 87.8%) and partner outcomes (92.7, 93.8, and 91.7%) resulted in live births of healthy infants across gestational, pre-gestational, and non-biologic exposure groups, respectively. Among these, rates of neonatal complications were low for both maternal (6.2, 7.0, and 8.5%), and partner outcomes (4.9, 0, and 0%) in gestational, pre-gestational, and non biologic exposure groups, respectively. Among maternal pregnancies, numerically higher rates of spontaneous abortions were observed for the gestational exposure group than for the pre-gestational or non-biologic exposed groups. CONCLUSIONS: The clinical condition of infants born to women with gestational infliximab exposure was similar to those without exposure. Although a lower live birth rate was reported among infliximab-exposed women, these patients had more severe CD and were more likely to have been exposed to immunosuppressives. PMID- 30022114 TI - Author Correction: Quantification of subclonal selection in cancer from bulk sequencing data. AB - In the version of this article originally published, in the "Theoretical framework of subclonal selection" section of the main text, ref. 11 instead of ref. 19 should have been cited at the end of the phrase "Our previously presented frequentist approach to detect subclonal selection from bulk sequencing data involves an R2 test statistic." The error has been corrected in the HTML and PDF versions of the article. PMID- 30022112 TI - Steric interference from intrinsically disordered regions controls dynamin related protein 1 self-assembly during mitochondrial fission. AB - The self-assembling, mechanoenzymatic dynamin superfamily GTPase, dynamin-related protein 1 (Drp1), catalyzes mitochondrial and peroxisomal fission. Distinct intrinsically disordered regions (IDRs) in Drp1 substitute for the canonical pleckstrin homology (PH) domain and proline-rich domain (PRD) of prototypical dynamin, which cooperatively regulate endocytic vesicle scission. Whether the Drp1 IDRs function analogously to the corresponding dynamin domains however remains unknown. We show that an IDR unique to the Drp1 GTPase (G) domain, the 'extended 80-loop', albeit dissimilar in location, structure, and mechanism, functions akin to the dynamin PRD by enabling stable Drp1 mitochondrial recruitment and by suppressing Drp1 cooperative GTPase activity in the absence of specific partner-protein interactions. Correspondingly, we find that another IDR, the Drp1 variable domain (VD), in conjunction with the conserved stalk L1N loop, functions akin to the dynamin PH domain; first, in an 'auto-inhibitory' capacity that restricts Drp1 activity through a long-range steric inhibition of helical inter-rung G-domain dimerization, and second, as a 'fulcrum' for Drp1 self assembly in the proper helical register. We show that the Drp1 VD is necessary and sufficient for specific Drp1-phospholipid interactions. We further demonstrate that the membrane-dependent VD conformational rearrangement essential for the alleviation of Drp1 auto-inhibition is contingent upon the basal GTP hydrolysis-dependent generation of Drp1 dimers from oligomers in solution. IDRs thus conformationally couple the enzymatic and membrane activities of Drp1 toward membrane fission. PMID- 30022116 TI - Spatiotemporal epidemiology of rabies at an interface between domestic dogs and wildlife in South Africa. AB - We characterized the spatiotemporal epidemiology of rabies from January 2009 through March 2014 across the interface between a wildlife reserve and communal livestock farming area in South Africa. Brain tissue from 344 animals of 28 different species were tested for lyssavirus antigen. Of these, 146 (42.4%) samples tested positive, of which 141 (96.6%) came from dogs. Brain samples of dogs were more likely to test positive for lyssavirus antigen if they were found and destroyed in the reserve, compared to samples originating from dogs outside the reserve (65.3% vs. 45.5%; odds ratio (OR) = 2.26, 95% confidence interval (CI) = 1.27-4.03), despite rabies surveillance outside the reserve being targeted to dogs that have a higher index of suspicion due to clinical or epidemiological evidence of infection. In the reserve, dogs were more likely to test positive for rabies if they were shot further from villages (OR = 1.42, 95% CI 1.18-1.71) and closer to water points (OR = 0.41, 95% CI 0.21-0.81). Our results provide a basis for refinement of existing surveillance and control programs to mitigate the threat of spillover of rabies to wildlife populations. PMID- 30022115 TI - Label-free multiphoton microscopy reveals relevant tissue changes induced by alginate hydrogel implantation in rat spinal cord injury. AB - The development of therapies promoting recovery after spinal cord injury is a challenge. Alginate hydrogels offer the possibility to develop biocompatible implants with mechanical properties tailored to the nervous tissue, which could provide a permissive environment for tissue repair. Here, the effects of non functionalized soft calcium alginate hydrogel were investigated in a rat model of thoracic spinal cord hemisection and compared to lesioned untreated controls. Open field locomotion tests were employed to evaluate functional recovery. Tissue analysis was performed with label-free multiphoton microscopy using a multimodal approach that combines coherent anti-Stokes Raman scattering to visualize axonal structures, two-photon fluorescence to visualize inflammation, second harmonic generation to visualize collagenous scarring. Treated animals recovered hindlimb function significantly better than controls. Multiphoton microscopy revealed that the implant influenced the injury-induced tissue response, leading to decreased inflammation, reduced scarring with different morphology and increased presence of axons. Demyelination of contralateral white matter near the lesion was prevented. Reduced chronic inflammation and increased amount of axons in the lesion correlated with improved hindlimb functions, being thus relevant for locomotion recovery. In conclusion, non-functionalized hydrogel improved functional outcome after spinal cord injury in rats. Furthermore, label-free multiphoton microscopy qualified as suitable technique for regeneration studies. PMID- 30022117 TI - Histamine-reduced diet and increase of serum diamine oxidase correlating to diet compliance in histamine intolerance. AB - Diagnosis of histamine intolerance (HIT) has been based on low serum diamine oxidase (DAO) values, functional gastrointestinal disorders and improvement of symptoms with a histamine-reduced diet (HRD). In a retrospective analysis of outpatients' charts we identified 101 patients with HIT. After a median of 13 months, a questionnaire was distributed to the patients so that they could be classified into four diet-compliance groups. Calculated with all 101 patients we found an increase of serum DAO values due to a HRD. In the 63 patients that completed the questionnaire, we found that 50 patients had improvement of symptoms or no continuing symptoms. A significant increase of serum DAO levels was found in the patients with strict and occasional diet compliance. Therefore, we demonstrate that a HRD is not only improving symptoms in HIT, but is causing an increase in serum DAO values that correlates with the degree of diet compliance. PMID- 30022118 TI - Control energy of complex networks towards distinct mixture states. AB - Controlling complex networked systems is a real-world puzzle that remains largely unsolved. Despite recent progress in understanding the structural characteristics of network control energy, target state and system dynamics have not been explored. We examine how varying the final state mixture affects the control energy of canonical and conformity-incorporated dynamical systems. We find that the control energy required to drive a network to an identical final state is lower than that required to arrive a non-identical final state. We also demonstrate that it is easier to achieve full control in a conformity-based dynamical network. Finally we determine the optimal control strategy in terms of the network hierarchical structure. Our work offers a realistic understanding of the control energy within the final state mixture and sheds light on controlling complex systems. PMID- 30022120 TI - Publisher Correction: Single-cell multi-omics sequencing of human early embryos. AB - In the version of this Resource originally published, owing to a technical error an incorrect file was used for Supplementary Table 2; this has now been replaced with the correct file. PMID- 30022119 TI - Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. AB - BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1 deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1 deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1 deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP inhibitor resistance. PMID- 30022121 TI - Motion cues modulate responses to emotion in movies. AB - Film theorists and practitioners suggest that motion can be manipulated in movie scenes to elicit emotional responses in viewers. However, our understanding of the role of motion in emotion perception remains limited. On the one hand, movies continuously depict local motion- movements of objects and humans, which are crucial for generating emotional responses. Movie scenes also frequently portray global motion, mainly induced by large camera movements, global motion being yet another source of information used by the brain during natural vision. Here we used functional MRI to elucidate the contributions of local and global motion to emotion perception during movie viewing. Subjects observed long (1 min) movie segments depicting emotional or neutral content. Brain activity in areas that showed preferential responses to emotional content was strongly linked over time with frame-wide variations in global motion, and to a lesser extent with local motion information. Similarly, stronger responses to emotional content were recorded within regions of interest whose activity was attuned to global and local motion over time. Since global motion fields are experienced during self motion, we suggest that camera movements may induce illusory self-motion cues in viewers that interact with the movie's narrative and with other emotional cues in generating affective responses. PMID- 30022123 TI - Author Correction: Depth related adaptations in symbiont bearing benthic foraminifera: New insights from a field experiment on Operculina ammonoides. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30022122 TI - Rapid oral bacteria detection based on real-time PCR for the forensic identification of saliva. AB - This study developed a new method for forensic saliva identification using three oral bacteria, Streptococcus salivarius, Streptococcus sanguinis, and Neisseria subflava, combined with a real-time polymerase chain reaction (RT-PCR) system we called OB mRT-PCR. Analytical sensitivity results showed that the target bacteria were amplified at 102-107 copies/reaction, and analytical specificity was assessed using 24 other viruses, bacteria, and protozoa. To evaluate the OB mRT PCR kit for forensic applications, saliva from 140 Korean individuals was tested, and at least two target bacteria were detected in all the samples. Additional studies on non-saliva samples demonstrated the specificity of the kit. Comparison of the kit with two conventional saliva test methods, the SALIgAE and RSID-Saliva assays, indicated that it was more sensitive and applicable to saliva samples in long-term storage (up to 14 weeks). Additionally, through amplification of mock forensic items and old DNA samples (isolated without lysis of the bacterial cells, regardless of their Gram-positivity), we found that the kit was applicable to not only saliva swabs, but also DNA samples. We suggest that this simple RT PCR-based experimental method is feasible for rapid on-site analysis, and we expect this kit to be useful for saliva detection in old forensic DNA samples. PMID- 30022124 TI - Menthol, a unique urinary volatile compound, is associated with chronic inflammation in interstitial cystitis. AB - Chronic inflammation is a potential systemic risk factor for many bladder dysfunctions, including interstitial cystitis (IC). However, the underlying mechanism through which a healthy bladder protects itself from inflammatory triggers remains unknown. In this study, we identified odor compounds in urine obtained from IC patients and healthy controls. Using comprehensive solid-phase microextraction-gas chromatography-time-of-flight-mass spectrometry (SPME-GC-TOF MS) profiling and bioinformatics, we found that levels of urinary volatile metabolites, such as menthol, were significantly reduced in IC patients, compared to healthy controls. In an attempt to understand the mechanistic meaning of our volatile metabolites data and the role of menthol in the immune system, we performed two independent experiments: (a) cytokine profiling, and (b) DNA microarray. Our findings suggest that lipopolysaccharide (LPS)-stimulated inflammatory events, such as the production and secretion of inflammatory cytokines (e.g., TNF-alpha, IL-6, and IL-1beta) and the activation of NF-kappaB and associated proteins within a large signaling network (e.g., Akt, TLR1, TNFAIP3, and NF-kappaB), are suppressed by the presence of menthol. These findings broaden our knowledge on the role of urinary menthol in suppressing inflammatory events and provide potential new strategies for alleviating both the odor and inflammation associated with IC. PMID- 30022125 TI - Publisher Correction: Community Detection in Complex Networks via Clique Conductance. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30022126 TI - Endocrine cell type sorting and mature architecture in the islets of Langerhans require expression of Roundabout receptors in beta cells. AB - Pancreatic islets of Langerhans display characteristic spatial architecture of their endocrine cell types. This architecture is critical for cell-cell communication and coordinated hormone secretion. Islet architecture is disrupted in type-2 diabetes. Moreover, the generation of architecturally correct islets in vitro remains a challenge in regenerative approaches to type-1 diabetes. Although the characteristic islet architecture is well documented, the mechanisms controlling its formation remain obscure. Here, we report that correct endocrine cell type sorting and the formation of mature islet architecture require the expression of Roundabout (Robo) receptors in beta cells. Mice with whole-body deletion of Robo1 and conditional deletion of Robo2 either in all endocrine cells or selectively in beta cells show complete loss of endocrine cell type sorting, highlighting the importance of beta cells as the primary organizer of islet architecture. Conditional deletion of Robo in mature beta cells subsequent to islet formation results in a similar phenotype. Finally, we provide evidence to suggest that the loss of islet architecture in Robo KO mice is not due to beta cell transdifferentiation, cell death or loss of beta cell differentiation or maturation. PMID- 30022127 TI - The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins. AB - We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using human alpha1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV.F/HN carrying either the secreted reporter gene Gaussia luciferase or the hAAT or hFVIII cDNAs by nasal sniffing. rSIV.F/HN-hAAT transduction lead to therapeutically relevant hAAT levels (70 MUg/ml) in epithelial lining fluid, with stable expression persisting for at least 19 months from a single application. Secreted proteins produced in the lung were released into the circulation and stable expression was detectable in blood. The levels of hFVIII in murine blood approached therapeutically relevant targets. rSIV.F/HN was also able to produce secreted hAAT and hFVIII in transduced human primary airway cells. rSIV.F/HN transduction of the murine lungs leads to long-lasting and therapeutically relevant levels of secreted proteins in the lung and systemic circulation. These data broaden the use of this vector platform for a large range of disease indications. PMID- 30022128 TI - Point-driven modern Chladni figures with symmetry breaking. AB - Point-driven modern Chladni figures subject to the symmetry breaking are systematically unveiled by developing a theoretical model and making experimental confirmation in the orthotropic brass. The plates with square shape are employed in the exploration based on the property that the orientation-dependent elastic anisotropy can be controlled by cutting the sides with a rotation angle with respect to the characteristic axes of the brass. Experimental results reveal that the orientation symmetry breaking not only causes the redistribution of resonant frequencies but also induces more resonant modes. More intriguingly, the driving position in some of new resonant modes can turn into the nodal point, whereas this position is always the anti-node in the isotropic case. The theoretical model is analytically developed by including a dimensionless parameter to consider the orientation symmetry-breaking effect in a generalized way. It is numerically verified that all experimental resonant frequencies and Chladni patterns can be well reconstructed with the developed model. The good agreement between theoretical calculations and experimental observations confirms the feasibility of using the developed model to analyze the modern Chladni experiment with orientation symmetry breaking. The developed model is believed to offer a powerful tool to build important database of plate resonant modes for the applications of controlling collective motions of micro objects. PMID- 30022129 TI - Reduction of the forming voltage through tailored oxygen non-stoichiometry in tantalum oxide ReRAM devices. AB - In this study, we investigated the influence of oxygen non-stoichiometry on the resistive switching performance of tantalum oxide based memristive devices. Thin films of tantalum oxide were deposited with varying sputter power and oxygen partial pressure. The electroforming voltage was found to decrease with increasing power density or decreased oxygen partial pressure, while the endurance remained stable and the resistance window ROFF/RON was found to increase. In-depth XPS analysis connects these observations to a controllable oxygen sub-stoichiometry in the sputter-deposited films. Our analysis shows that the decrease of the forming voltage results from an increase in carrier density in the as-prepared thin-films, which is induced by the presence of oxygen vacancies. PMID- 30022130 TI - Immature particles and capsid-free viral RNA produced by Yellow fever virus infected cells stimulate plasmacytoid dendritic cells to secrete interferons. AB - Plasmacytoid dendritic cells (pDCs) are specialized in the production of interferons (IFNs) in response to viral infections. The Flaviviridae family comprises enveloped RNA viruses such as Hepatitis C virus (HCV) and Dengue virus (DENV). Cell-free flaviviridae virions poorly stimulate pDCs to produce IFN. By contrast, cells infected with HCV and DENV potently stimulate pDCs via short range delivery of viral RNAs, which are either packaged within immature virions or secreted exosomes. We report that cells infected with Yellow fever virus (YFV), the prototypical flavivirus, stimulated pDCs to produce IFNs in a TLR7- and cell contact- dependent manner. Such stimulation was unaffected by the presence of YFV neutralizing antibodies. As reported for DENV, cells producing immature YFV particles were more potent at stimulating pDCs than cells releasing mature virions. Additionally, cells replicating a release-deficient YFV mutant or a YFV subgenomic RNA lacking structural protein-coding sequences participated in pDC stimulation. Thus, viral RNAs produced by YFV-infected cells reach pDCs via at least two mechanisms: within immature particles and as capsid-free RNAs. Our work highlights the ability of pDCs to respond to a variety of viral RNA-laden carriers generated from infected cells. PMID- 30022131 TI - Electron ptychography of 2D materials to deep sub-angstrom resolution. AB - Aberration-corrected optics have made electron microscopy at atomic resolution a widespread and often essential tool for characterizing nanoscale structures. Image resolution has traditionally been improved by increasing the numerical aperture of the lens (alpha) and the beam energy, with the state-of-the-art at 300 kiloelectronvolts just entering the deep sub-angstrom (that is, less than 0.5 angstrom) regime. Two-dimensional (2D) materials are imaged at lower beam energies to avoid displacement damage from large momenta transfers, limiting spatial resolution to about 1 angstrom. Here, by combining an electron microscope pixel-array detector with the dynamic range necessary to record the complete distribution of transmitted electrons and full-field ptychography to recover phase information from the full phase space, we increase the spatial resolution well beyond the traditional numerical-aperture-limited resolution. At a beam energy of 80 kiloelectronvolts, our ptychographic reconstruction improves the image contrast of single-atom defects in MoS2 substantially, reaching an information limit close to 5alpha, which corresponds to an Abbe diffraction limited resolution of 0.39 angstrom, at the electron dose and imaging conditions for which conventional imaging methods reach only 0.98 angstrom. PMID- 30022132 TI - Global surface warming enhanced by weak Atlantic overturning circulation. AB - Evidence from palaeoclimatology suggests that abrupt Northern Hemisphere cold events are linked to weakening of the Atlantic Meridional Overturning Circulation (AMOC)1, potentially by excess inputs of fresh water2. But these insights-often derived from model runs under preindustrial conditions-may not apply to the modern era with our rapid emissions of greenhouse gases. If they do, then a weakened AMOC, as in 1975-1998, should have led to Northern Hemisphere cooling. Here we show that, instead, the AMOC minimum was a period of rapid surface warming. More generally, in the presence of greenhouse-gas heating, the AMOC's dominant role changed from transporting surface heat northwards, warming Europe and North America, to storing heat in the deeper Atlantic, buffering surface warming for the planet as a whole. During an accelerating phase from the mid 1990s to the early 2000s, the AMOC stored about half of excess heat globally, contributing to the global-warming slowdown. By contrast, since mooring observations began3-5 in 2004, the AMOC and oceanic heat uptake have weakened. Our results, based on several independent indices, show that AMOC changes since the 1940s are best explained by multidecadal variability6, rather than an anthropogenically forced trend. Leading indicators in the subpolar North Atlantic today suggest that the current AMOC decline is ending. We expect a prolonged AMOC minimum, probably lasting about two decades. If prior patterns hold, the resulting low levels of oceanic heat uptake will manifest as a period of rapid global surface warming. PMID- 30022133 TI - Controlling an organic synthesis robot with machine learning to search for new reactivity. AB - The discovery of chemical reactions is an inherently unpredictable and time consuming process1. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy2. Reaction prediction based on high-level quantum chemical methods is complex3, even for simple molecules. Although machine learning is powerful for data analysis4,5, its applications in chemistry are still being developed6. Inspired by strategies based on chemists' intuition7, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert8. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions. PMID- 30022134 TI - A record-breaking microscope. PMID- 30022135 TI - Evaluation woes: professors should have fought harder. PMID- 30022136 TI - Why organizing a scientific conference can produce huge benefits. PMID- 30022137 TI - Evaluation woes: define metrics from the off. PMID- 30022138 TI - Iran's scientists uncrushed by decades of sanctions. PMID- 30022139 TI - Evaluation woes: Metrics can help beat bias. PMID- 30022141 TI - Track the fate of postdocs to help the next generation of scientists. PMID- 30022140 TI - Learn from industry to build a healthy lab. PMID- 30022142 TI - Officials and scientists need help to track down rogue source of CFCs. PMID- 30022143 TI - Turtle trouble, fund fraud and India's escape module. PMID- 30022144 TI - Potential of a polyherbal drug to prevent antimicrobial resistance in bacteria to antibiotics. AB - Persistence of antibacterial drugs for prolonged period in milk increases the probability of antimicrobial resistance progress. Ceftizoxime was found to be excreted in milk for a prolonged period in goats, cows and buffaloes following intravenous injection of ceftriaxone and ceftizoxime. A single dose of ceftriaxone was administered intravenously in healthy control goats (group I) and a single oral dose of the commercial mammary protective polyherbal drug (1.9 gm) was given one hour prior to intravenous ceftriaxone injection in healthy (group II) and induced mastitic (group III) goats to evaluate milk disposition of ceftizoxime following single intravenous dosing of ceftriaxone at 42.25 mg kg 1.Ceftriaxone/ceftizoxime was analyzed by HPLC. The t1/2alpha and t1/2beta values were 14.755 +/- 2.733 and 149.079 +/- 18.565 hour, respectively indicating prolonged persistence of ceftizoxime in milk. The polyherbal drug increased the milk concentration at later hours and hastened the excretion of ceftizoxime from milk compared to control group. Ceftriaxone could not be detected in milk. The study suggested that adjunct single or repeated therapy of the polyherbal drug may cause non persistence of ceftriaxone and shorter persistence of ceftizoxime in milk. PMID- 30022145 TI - Second chances. PMID- 30022146 TI - Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis. AB - Renal tubulointerstitial injury, an inflammation-associated condition, is a major cause of chronic kidney disease (CKD). Levels of activated factor X (FXa), a blood coagulation factor, are increased in various inflammatory diseases. Therefore, we investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor (PAR)-1 and PAR-2 were significantly higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis and extracellular matrix expression were suppressed in UUO mice treated with the FXa inhibitor edoxaban. Additionally, edoxaban attenuated UUO-induced macrophage infiltration and inflammatory molecule upregulation. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against CKD by inhibiting tubulointerstitial fibrosis. PMID- 30022147 TI - Nano@lignocellulose intercalated montmorillonite as adsorbent for effective Mn(II) removal from aqueous solution. AB - This paper describes the preparation of nano@lignocellulose (nano@LC) and a nano@lignocellulose/montmorillonite (nano@LC/MT) nanocomposite, as well as the capacity of the nano@LC/MT for adsorbing manganese ions from aqueous solution. The structure of nano@LC and nano@LC/MT was characterised by Fourier-transform infrared spectroscopy, X-ray diffraction, Scanning electron microscopy, and Transmission electron microscopy, which revealed that the diffraction peak of montmorillonite almost disappeared, infrared bands of the functional groups shifted, and morphology of the material changed after the formation of the composite. The optimum conditions for the adsorption of Mn(II) on the nano@LC/MT nanocomposite were investigated in detail by changing the initial Mn(II) concentration, pH, adsorption temperature, and time. The results revealed that the adsorption capacity of the nano@LC/MT nanocomposite for Mn(II) reached 628.0503 mg/g at a Mn(II) initial concentration of 900 mg/L, solution pH 5.8, adsorption temperature 55 degrees C, and adsorption time 160 min. Adsorption kinetics experiments revealed good agreement between the experimental data and the pseudo-second order kinetic model. The experimental data was satisfactorily fitted to the Langmuir isotherm. Adsorption-desorption results showed that nano@LC/MT exhibited excellent reusability. The adsorption mechanism was investigated through FT-IR and EDX spectroscopic analyses. The results suggested that nano@LC/MT have great potential in removing Mn(II) from water. PMID- 30022148 TI - Triptolide attenuates proteinuria and podocyte apoptosis via inhibition of NF kappaB/GADD45B. AB - Podocyte injury is a primary contributor to proteinuria. Triptolide is a major active component of Tripterygium wilfordii Hook F that exhibits potent antiproteinuric effects. We used our previously developed in vivo zebrafish model of inducible podocyte-target injury and found that triptolide treatment effectively alleviated oedema, proteinuria and foot process effacement. Triptolide also inhibited podocyte apoptosis in our zebrafish model and in vitro. We also examined the mechanism of triptolide protection of podocyte. Whole-genome expression profiles of cultured podocytes demonstrated that triptolide treatment downregulated apoptosis pathway-related GADD45B expression. Specific overexpression of gadd45b in zebrafish podocytes abolished the protective effects of triptolide. GADD45B is a mediator of podocyte apoptosis that contains typical NF-kappaB binding sites in the promoter region, and NF-kappaB p65 primarily transactivates this gene. Triptolide inhibited NF-kappaB signalling activation and binding of NF-kappaB to the GADD45B promoter. Taken together, our findings demonstrated that triptolide attenuated proteinuria and podocyte apoptosis via inhibition of NF-kappaB/GADD45B signalling, which provides a new understanding of the antiproteinuric effects of triptolide in glomerular diseases. PMID- 30022149 TI - Histone deacetylase function in CD4+ T cells. AB - The differentiation of T helper cell subsets and their acquisition of effector functions are accompanied by changes in gene expression programmes, which in part are regulated and maintained by epigenetic processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators that function by mediating dynamic changes in the acetylation of histones at lysine residues. In addition, many non-histone proteins are also acetylated, and reversible acetylation affects their functional properties, demonstrating that HDACs mediate effects beyond the epigenetic regulation of gene expression. In this Review, we discuss studies revealing that HDACs are key regulators of CD4+ T cell-mediated immunity in mice and humans and that HDACs are promising targets in T cell-mediated immune diseases. Finally, we discuss unanswered questions and future research directions to promote the concept that isoform-selective HDAC inhibitors might broaden the clinical application of HDAC inhibitors beyond their current use in certain types of cancer. PMID- 30022150 TI - Evolution of rough-surface geometry and crystalline structures of aligned TiO2 nanotubes for photoelectrochemical water splitting. AB - Nowadays, increasing awareness of environment and fossil fuels protection stimulates intensive research on clean and renewable sources of energy. Production of hydrogen from water through solar-driven splitting reactions is one of the most promising approaches in the field of photoelectrochemistry (PEC). In this work we have fabricated well-aligned, highly-ordered, smooth-mouth TiO2 nanotube arrays (TNAs) in a two-step anodization process of titanium foil, which were then used as photoelectrodes for PEC water splitting. It demonstrates for the first time correspondence between non-linear component characteristics of multiscale rough surface and crystalline structure of annealed TNAs measured at various fabrication stages and their photoelectrochemical response. The as anodized TNAs with isotropic surface (deduced from AFM and SEM images) and largest figure of merit (according to their PEC performance) were annealed at 450 degrees C in air. Scale-invariant descriptors of the surface structure of the deposits involved: fractal dimension, corner frequency, roughness, size of nanostructures and their dominant habits. Moreover, X-ray diffraction data processed using the Rietveld method confirmed co-existence of various oxides, for example: TiO2 in the form of anatase, TiO and Ti3O5 phases in the TNAs under study pointing that previous well-established mechanisms of the TNA growth were to certain degree incomplete. PMID- 30022152 TI - The trends of aquacultural nitrogen budget and its environmental implications in China. AB - The rapid development of aquaculture has sustained aquatic food production but has also led to a host of environmental problems, ranging from eutrophication of aquatic ecosystems to global acidification. China has become the world's largest producer and consumer of aquaculture products. Nitrogen is an essential nutrient in aquaculture ecosystems, and the quantitative environmental fate and impact of nitrogen during aquaculture processes have notable environmental consequences but have received little attention. Here, we established a nitrogen cycling model for China's aquaculture ecosystem to investigate the creation and fate of reactive nitrogen over a decadal time scale. A nitrogen balance analysis showed that reactive nitrogen input in the aquaculture ecosystem increased from 9.43 Tg N yr 1 in 1978 to 18.54 Tg N yr-1 in 2015, while aquaculture production increased from 0.034 to 1.33 Tg N yr-1 during the same period. The environmental fate analysis showed that nitrogen emissions, accumulation, sediment deposition, and export into the oceans increased by 9.05-fold, 0.24-fold, 9.04-fold, and 2.56-fold, respectively. Finally, we investigated four scenarios representing different consumption levels of aquatic products and provided policy recommendations (larger aquaculture size, standardized aquaculture production model, nutritional element management and balanced dietary structure, etc.) on improved management practices in aquaculture ecosystems. PMID- 30022153 TI - Cannabidiol does not display drug abuse potential in mice behavior. AB - Recent evidence suggests that cannabidiol (CBD) may be useful for the treatment of different neuropsychiatric disorders. However, some controversy regarding its profile as a drug of abuse hampers the further development of basic and clinical studies. In this study, the behavioral profile of CBD as a potential drug of abuse was evaluated in C57BL/6J mice. Reinforcing properties of CBD (15, 30, and 60 mg/kg; i.p.) were assessed using the conditioned place preference (CPP) paradigm. Spontaneous withdrawal symptoms and motor activity in the open field were examined 12 h after the last CBD administration (30 mg/kg/12 h, i.p., 6 days). CBD plasma concentrations were measured at 2, 4, 8, 12, and 24 h after the administration of CBD (30 mg/kg, i.p.). Furthermore, an oral CBD self administration paradigm (50 mg/kg; CBD water-soluble 1.2 mg/mL) was performed to evaluate whether this drug produced any effects on motivation compared with a non reinforcing substance (water). We found that CBD failed to induce CPP, withdrawal symptoms, or altered motor behavior 12 h after its administration. At that time, only traces of CBD were detected, ensuring that the lack of alterations in somatic signs and locomotor activity was not due to residual drug in plasma. Interestingly, mice displayed similar motivation and consumption of CBD and water. Taken together, these results show that CBD lacks activity as a drug of abuse and should stimulate the development of the basic and clinical studies needed to elucidate its potential therapeutic use for the treatment of neuropsychiatric and drug use disorders. PMID- 30022151 TI - Electrical Transport and Power Dissipation in Aerosol-Jet-Printed Graphene Interconnects. AB - This paper reports the first known investigation of power dissipation and electrical breakdown in aerosol-jet-printed (AJP) graphene interconnects. The electrical performance of aerosol-jet printed (AJP) graphene was characterized using the Transmission Line Method (TLM). The electrical resistance decreased with increasing printing pass number (n); the lowest sheet resistance measured was 1.5 kOmega/sq. for n = 50. The role of thermal resistance (RTH) in power dissipation was studied using a combination of electrical breakdown thermometry and infrared (IR) imaging. A simple lumped thermal model ([Formula: see text]) and COMSOL Multiphysics was used to extract the total RTH, including interfaces. The RTH of AJP graphene on Kapton is ~27 times greater than that of AJP graphene on Al2O3 with a corresponding breakdown current density 10 times less on Kapton versus Al2O3. PMID- 30022154 TI - Activation of SIRT1 ameliorates LPS-induced lung injury in mice via decreasing endothelial tight junction permeability. AB - The integrity of the endothelial barrier is a determinant of the prognosis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, we investigated whether and how Sirtuin 1 (SIRT1) maintained the vascular integrity during ALI. An experimental model of ALI was established in mice through intratracheal administration of LPS (10 mg/kg). LPS stimulation significantly increased the pulmonary permeability and decreased the expression of SIRT1 and tight junction proteins (TJs), including occludin, claudin-5, tight junction protein 1 and tight junction protein 2. Morphological studies showed that LPS induced obvious lung injury with inflammatory cell infiltration in the interstitial and alveolar space, hemorrhage, edema, and the thickened alveolar wall compared to the control mice. Intratracheal administration of the selective SIRT1 activator SRT1720 (6.25 mg/kg) significantly attenuated LPS-induced lung injury, lung hyper-permeability and increased TJs expression, whereas intratracheal administration of the selective SIRT1 inhibitor EX527 (6.25 mg/kg) aggravated LPS-induced ALI. Similar protective effects of SIRT1 on pulmonary cellular permeability were observed in primary human pulmonary microvascular endothelial cells treated with LPS (2 mg/mL) in vitro. We further demonstrated that the RhoA/ROCK signaling pathway was activated in SIRT1 regulation of tight junction permeability. The RhoA/ROCK inhibitor Y-27632 (10 MUM) increased the expression of TJs and reversed LPS- or EX527-induced hyper-permeability. In conclusion, SIRT1 ameliorates LPS-induced lung injury via decreasing endothelial tight junction permeability, possibly via RhoA/ROCK signaling pathway. This finding may contribute to the development of new therapeutic approaches for lung injury. PMID- 30022155 TI - Response to Mendelsohn and Sabbadini. PMID- 30022156 TI - Multiple stable states in microbial communities explained by the stable marriage problem. AB - Experimental studies of microbial communities routinely reveal that they have multiple stable states. While each of these states is generally resilient, certain perturbations such as antibiotics, probiotics, and diet shifts, result in transitions to other states. Can we reliably both predict such stable states as well as direct and control transitions between them? Here we present a new conceptual model-inspired by the stable marriage problem in game theory and economics-in which microbial communities naturally exhibit multiple stable states, each state with a different species' abundance profile. Our model's core ingredient is that microbes utilize nutrients one at a time while competing with each other. Using only two ranked tables, one with microbes' nutrient preferences and one with their competitive abilities, we can determine all possible stable states as well as predict inter-state transitions, triggered by the removal or addition of a specific nutrient or microbe. Further, using an example of seven Bacteroides species common to the human gut utilizing nine polysaccharides, we predict that mutual complementarity in nutrient preferences enables these species to coexist at high abundances. PMID- 30022157 TI - Endosymbiont genomes yield clues of tubeworm success. AB - Forty years after discovery of chemosynthetic symbiosis in the tubeworm Riftia pachyptila, how organisms maintain their unique host-symbiont associations at the cellular level is still largely unknown. Previous studies primarily focus on symbionts associated with host lineages living in hydrothermal vents. To understand physiological adaptations and evolution in these holobiont systems in markedly different habitats, we characterized four novel siboglinid-symbiont genomes spanning deep-sea seep and sedimented environments. Our comparative analyses suggest that all sampled siboglinid chemoautotrophic symbionts, except for frenulate symbionts, can use both rTCA and Calvin cycle for carbon fixation. We hypothesize that over evolutionary time siboglinids have been able to utilize different bacterial lineages allowing greater metabolic flexibility of carbon fixation (e.g., rTCA) enabling tubeworms to thrive in more reducing habitats, such as vents and seeps. Moreover, we show that sulfur metabolism and molecular mechanisms related to initial infection are remarkably conserved across chemoautotrophic symbionts in different habitats. Unexpectedly, we find that the ability to use hydrogen, as an additional energy source, is potentially more widespread than previously recognized. Our comparative genomic results help elucidate potential mechanisms used to allow chemosynthetically dependent holobionts adapt to, and evolve in, different environments. PMID- 30022158 TI - 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polalpha-dependent fill-in. AB - In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair-which requires a 3' overhang-and classical non homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3-8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7-SHLD1-SHLD2-SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6-9. Here we address the mechanism by which 53BP1-RIF1-shieldin regulates the generation of recombinogenic 3' overhangs. We report that CTC1-STN1 TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-alpha (Polalpha)-primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polalpha to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polalpha inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST-Polalpha-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin. PMID- 30022159 TI - Accumulation of succinate controls activation of adipose tissue thermogenesis. AB - Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease1. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP-protein kinase A signalling; this pathway has been subject to longstanding clinical investigation2-4. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule. PMID- 30022160 TI - The outer membrane is an essential load-bearing element in Gram-negative bacteria. AB - Gram-negative bacteria possess a complex cell envelope that consists of a plasma membrane, a peptidoglycan cell wall and an outer membrane. The envelope is a selective chemical barrier1 that defines cell shape2 and allows the cell to sustain large mechanical loads such as turgor pressure3. It is widely believed that the covalently cross-linked cell wall underpins the mechanical properties of the envelope4,5. Here we show that the stiffness and strength of Escherichia coli cells are largely due to the outer membrane. Compromising the outer membrane, either chemically or genetically, greatly increased deformation of the cell envelope in response to stretching, bending and indentation forces, and induced increased levels of cell lysis upon mechanical perturbation and during L-form proliferation. Both lipopolysaccharides and proteins contributed to the stiffness of the outer membrane. These findings overturn the prevailing dogma that the cell wall is the dominant mechanical element within Gram-negative bacteria, instead demonstrating that the outer membrane can be stiffer than the cell wall, and that mechanical loads are often balanced between these structures. PMID- 30022161 TI - Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. AB - Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3-5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5 hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment. PMID- 30022162 TI - Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. AB - T cell development and selection are coordinated in the thymus by a specialized niche of diverse stromal populations1-3. Although much progress has been made over the years in identifying the functions of the different cell types of the thymic stromal compartment, there is no comprehensive characterization of their diversity and heterogeneity. Here we combined massively parallel single-cell RNA sequencing4,5, spatial mapping, chromatin profiling and gene targeting to characterize de novo the entire stromal compartment of the mouse thymus. We identified dozens of cell states, with thymic epithelial cells (TECs) showing the highest degree of heterogeneity. Our analysis highlights four major medullary TEC (mTEC I-IV) populations, with distinct molecular functions, epigenetic landscapes and lineage regulators. Specifically, mTEC IV constitutes a new and highly divergent TEC lineage with molecular characteristics of the gut chemosensory epithelial tuft cells. Mice deficient in Pou2f3, a master regulator of tuft cells, have complete and specific depletion of mTEC IV cells, which results in increased levels of thymus-resident type-2 innate lymphoid cells. Overall, our study provides a comprehensive characterization of the thymic stroma and identifies a new tuft-like TEC population, which is critical for shaping the immune niche in the thymus. PMID- 30022163 TI - Triple oxygen isotope evidence for limited mid-Proterozoic primary productivity. AB - The global biosphere is commonly assumed to have been less productive before the rise of complex eukaryotic ecosystems than it is today1. However, direct evidence for this assertion is lacking. Here we present triple oxygen isotope measurements (?17O) from sedimentary sulfates from the Sibley basin (Ontario, Canada) dated to about 1.4 billion years ago, which provide evidence for a less productive biosphere in the middle of the Proterozoic eon. We report what are, to our knowledge, the most-negative ?17O values (down to -0.880/00) observed in sulfates, except for those from the terminal Cryogenian period2. This observation demonstrates that the mid-Proterozoic atmosphere was distinct from what persisted over approximately the past 0.5 billion years, directly reflecting a unique interplay among the atmospheric partial pressures of CO2 and O2 and the photosynthetic O2 flux at this time3. Oxygenic gross primary productivity is stoichiometrically related to the photosynthetic O2 flux to the atmosphere. Under current estimates of mid-Proterozoic atmospheric partial pressure of CO2 (2-30 times that of pre-anthropogenic levels), our modelling indicates that gross primary productivity was between about 6% and 41% of pre-anthropogenic levels if atmospheric O2 was between 0.1-1% or 1-10% of pre-anthropogenic levels, respectively. When compared to estimates of Archaean4-6 and Phanerozoic primary production7, these model solutions show that an increasingly more productive biosphere accompanied the broad secular pattern of increasing atmospheric O2 over geologic time8. PMID- 30022164 TI - Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. AB - The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function. PMID- 30022165 TI - Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. AB - Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice1,2. A major set of pathogenic CD4 T cells specifically recognizes the 12-20 segment of the insulin B-chain (B:12-20), an epitope that is generated from direct presentation of insulin peptides by antigen presenting cells3,4. These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13-214. CD4 T cells that recognize B:12-20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13-21 have only a minor role in autoimmunity3-5. Although presentation of B:12-20 is evident in the islets3,6, insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread7,8. Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in beta-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues. PMID- 30022166 TI - Leukaemia hijacks a neural mechanism to invade the central nervous system. AB - Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor alpha6 integrin is expressed in most cases of ALL. We found that alpha6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kdelta inhibitor, which decreased alpha6 integrin expression on ALL cells, or specific alpha6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that alpha6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS. PMID- 30022167 TI - Photoswitching topology in polymer networks with metal-organic cages as crosslinks. AB - Polymer networks can have a range of desirable properties such as mechanical strength, wide compositional diversity between different materials, permanent porosity, convenient processability and broad solvent compatibility1,2. Designing polymer networks from the bottom up with new structural motifs and chemical compositions can be used to impart dynamic features such as malleability or self healing, or to allow the material to respond to environmental stimuli3-8. However, many existing systems exhibit only one operational state that is defined by the material's composition and topology3-6; or their responsiveness may be irreversible7,9,10 and limited to a single network property11,12 (such as stiffness). Here we use cooperative self-assembly as a design principle to prepare a material that can be switched between two topological states. By using networks of polymer-linked metal-organic cages in which the cages change shape and size on irradiation, we can reversibly switch the network topology with ultraviolet or green light. This photoswitching produces coherent changes in several network properties at once, including branch functionality, junction fluctuations, defect tolerance, shear modulus, stress-relaxation behaviour and self-healing. Topology-switching materials could prove useful in fields such as soft robotics and photo-actuators as well as providing model systems for fundamental polymer physics studies. PMID- 30022170 TI - How driving rates determine the statistics of driven non-equilibrium systems with stationary distributions. AB - Sample space reducing (SSR) processes offer a simple analytical way to understand the origin and ubiquity of power-laws in many path-dependent complex systems. SRR processes show a wide range of applications that range from fragmentation processes, language formation to search and cascading processes. Here we argue that they also offer a natural framework to understand stationary distributions of generic driven non-equilibrium systems that are composed of a driving- and a relaxing process. We show that the statistics of driven non-equilibrium systems can be derived from the understanding of the nature of the underlying driving process. For constant driving rates exact power-laws emerge with exponents that are related to the driving rate. If driving rates become state-dependent, or if they vary across the life-span of the process, the functional form of the state dependence determines the statistics. Constant driving rates lead to exact power laws, a linear state-dependence function yields exponential or Gamma distributions, a quadratic function produces the normal distribution. Logarithmic and power-law state dependence leads to log-normal and stretched exponential distribution functions, respectively. Also Weibull, Gompertz and Tsallis-Pareto distributions arise naturally from simple state-dependent driving rates. We discuss a simple physical example of consecutive elastic collisions that exactly represents a SSR process. PMID- 30022169 TI - Consequences of diverse evolutionary processes on american genetic gradients of modern humans. AB - European genetic gradients of modern humans were initially interpreted as a consequence of the demic diffusion of expanding Neolithic farmers. However, recent studies showed that these gradients may also be influenced by other evolutionary processes such as population admixture or range contractions. Genetic gradients were observed in the Americas, although their specific evolutionary causes were not investigated. Here we extended the approach used to study genetic gradients in Europe to analyze the influence of diverse evolutionary scenarios on American genetic gradients. Using extensive computer simulations, we evaluated the impact of (i) admixture between expansion waves of modern humans, (ii) the presence of ice-sheets during the last glacial maximum (LGM) and (iii) long-distance dispersal (LDD) events, on the genetic gradients (detected by principal component analysis) of the entire continent, North America and South America. The specific simulation of North and South America showed that genetic gradients are usually orthogonal to the direction of range expansions either expansions from Bering or posterior re-expansions to recolonize northern regions after ice sheets melting-and we suggest that they result from allele surfing processes. Conversely, our results on the entire continent show a northwest-southeast gradient obtained with any scenario, which we interpreted as a consequence of isolation by distance along the long length of the continent. These findings suggest that distinct genetic gradients can be detected at different regions of the Americas and that subcontinent regions present gradients more sensible to evolutionary and environmental factors (such as LDD and the LGM) than the whole continent. PMID- 30022168 TI - The shieldin complex mediates 53BP1-dependent DNA repair. AB - 53BP1 is a chromatin-binding protein that regulates the repair of DNA double strand breaks by suppressing the nucleolytic resection of DNA termini1,2. This function of 53BP1 requires interactions with PTIP3 and RIF14-9, the latter of which recruits REV7 (also known as MAD2L2) to break sites10,11. How 53BP1-pathway proteins shield DNA ends is currently unknown, but there are two models that provide the best potential explanation of their action. In one model the 53BP1 complex strengthens the nucleosomal barrier to end-resection nucleases12,13, and in the other 53BP1 recruits effector proteins with end-protection activity. Here we identify a 53BP1 effector complex, shieldin, that includes C20orf196 (also known as SHLD1), FAM35A (SHLD2), CTC-534A2.2 (SHLD3) and REV7. Shieldin localizes to double-strand-break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 and POT1. Loss of shieldin impairs non-homologous end-joining, leads to defective immunoglobulin class switching and causes hyper-resection. Mutations in genes that encode shieldin subunits also cause resistance to poly(ADP-ribose) polymerase inhibition in BRCA1-deficient cells and tumours, owing to restoration of homologous recombination. Finally, we show that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair. PMID- 30022171 TI - Engineering the oleaginous red yeast Rhodotorula glutinis for simultaneous beta carotene and cellulase production. AB - Rhodotorula glutinis, an oleaginous red yeast, intrinsically produces several bio products (i.e., lipids, carotenoids and enzymes) and is regarded as a potential host for biorefinery. In view of the limited available genetic engineering tools for this yeast, we have developed a useful genetic transformation method and transformed the beta-carotene biosynthesis genes (crtI, crtE, crtYB and tHMG1) and cellulase genes (CBHI, CBHII, EgI, EgIII, EglA and BGS) into R. glutinis genome. The transformant P4-10-9-63Y-14B produced significantly higher beta carotene (27.13 +/- 0.66 mg/g) than the wild type and also exhibited cellulase activity. Furthermore, the lipid production and salt tolerance ability of the transformants were unaffected. This is the first study to engineer the R. glutinis for simultaneous beta-carotene and cellulase production. As R. glutinis can grow in sea water and can be engineered to utilize the cheaper substrates (i.e. biomass) for the production of biofuels or valuable compounds, it is a promising host for biorefinery. PMID- 30022173 TI - Aluminum dihydride complexes and their unexpected application in atomic layer deposition of titanium carbonitride films. AB - Aluminum dihydride complexes containing amido-amine ligands were synthesized and evaluated as potential reducing precursors for thermal atomic layer deposition (ALD). Highly volatile monomeric complexes AlH2(tBuNCH2CH2NMe2) and AlH2(tBuNCH2CH2NC4H8) are more thermally stable than common Al hydride thin film precursors such as AlH3(NMe3). ALD film growth experiments using TiCl4 and AlH2(tBuNCH2CH2NMe2) produced titanium carbonitride films with a high growth rate of 1.6-2.0 A per cycle and resistivities around 600 MUOmega cm within a very wide ALD window of 220-400 degrees C. Importantly, film growth proceeded via self limited surface reactions, which is the hallmark of an ALD process. Root mean square surface roughness was only 1.3% of the film thickness at 300 degrees C by atomic force microscopy. The films were polycrystalline with low intensity, broad reflections corresponding to the cubic TiN/TiC phase according to grazing incidence X-ray diffraction. Film composition by X-ray photoelectron spectroscopy was approximately TiC0.8N0.5 at 300 degrees C with small amounts of Al (6 at%), Cl (4 at%) and O (4 at%) impurities. Remarkably, self-limited growth and low Al content was observed in films deposited well above the solid-state thermal decomposition point of AlH2(tBuNCH2CH2NMe2), which is ca. 185 degrees C. Similar growth rates, resistivities, and film compositions were observed in ALD film growth trials using AlH2(tBuNCH2CH2NC4H8). PMID- 30022172 TI - Storage conditions modulate the metabolomic profile of a black raspberry nectar with minimal impact on bioactivity. AB - Pre-clinical and clinical studies suggest black raspberries (BRBs) may inhibit the development of oral cancer. Lyophilized BRB powder is commonly used in these studies, but processed BRB products are more often consumed. The objective of this work was to understand how storage conditions influence the phytochemical profile and anti-proliferative activity of a BRB nectar beverage. Untargeted UHPLC-Q-TOF-MS based metabolomics analyses demonstrated that large chemical variation was introduced by storage above -20 degrees C over 60 days. However, minimal change in anti-proliferative activity was observed when stored nectar extracts were applied to SCC-83-01-82 premalignant oral epithelial cells. As proof of concept, cyanidin-3-O-rutinoside and its degradation product, protocatechuic acid, were administered in different ratios maintaining an equimolar dose, and anti-proliferative activity was maintained. This study shows the utility of metabolomics to profile global chemical changes in foods, while demonstrating that isolated phytochemicals do not explain the complete bioactivity of a complex food product. PMID- 30022174 TI - High sensitive and broad-range detection of cortisol in human saliva using a trap lateral flow immunoassay (trapLFI) sensor. AB - Cortisol, a steroid hormone, is a main biomarker of psychological stress. Early diagnosis and proper treatment of such stress is crucial to prevent the excessive secretion of cortisol. However, cortisol has a low molecular weight and cannot provide sufficient recognition sites for sandwich immunoreaction; it has previously been measured using a competitive immunoassay instead of a general sandwich immunoassay. The disadvantage of this approach is that quantitative measurements are limited because of the narrow measurable range that is key for biosensors. To overcome this limitation, we propose a new detection platform that enables small molecules such as cortisol to be quantified with high detection sensitivity. A trap lateral flow immunoassay (trapLFI) sensor has deletion and detection zones instead of the test and control zones in general lateral flow immunoassay (LFI) sensors. The conjugates used to minimize possible detection targets at low concentration are gold nanoparticles that include an antibody against cortisol and an enzyme for signal generation. Target-bound conjugates are captured in the detection zone, whereas conjugates not binding with targets are trapped in the deletion zone. Using this platform, enzyme-catalyzed color signals increase in the detection zone and decrease in the deletion zone with the concentration of cortisol. The ratio of signal from deletion zone and detection zone supplied a wide analytical range (0.01-100 ng mL-1) with high detection sensitivity (9.9 pg mL-1). Analysis of 15 human saliva samples showed a good correlation with conventional ELISA results (R2 = 0.9432). PMID- 30022175 TI - The effects of lanthanide-doped upconverting nanoparticles on cancer cell biomarkers. AB - Lanthanide-doped upconverting nanoparticles (Ln-UCNPs) possess optical and physicochemical properties that are promising for the design of new theranostic platforms. This applies in particular to the treatment of cancer. Towards this goal, oleate-capped-NaLuF4:Tm3+(0.5%)/Yb3+(20%)/Gd3+(30%) with an average size of 35 nm +/- 2 nm were synthesized by co-precipitation. Due to their hydrophobic surface, these Ln-UCNPs produced agglomerates under cell culture conditions. To assess the cellular response to Ln-UCNPs at the molecular level, we evaluated several key aspects of tumor cell physiology. Using cancer lines of different origins, we demonstrated Ln-UCNP dependent changes of cancer cell biomarkers. Multiple cellular components that regulate tumorigenesis and cancer cell homeostasis were affected. In particular, Ln-UCNPs reduced the abundance of hsp70s, elevated DNA damage, and diminished nucleolin and B23/nucleophosmin, proteins required for the assembly of ribosomes. Treatment with Ln-UCNPs also decreased the concentration of paxillin, a focal adhesion protein that is involved in directed cell migration. Furthermore, epidermal growth factor (EGFR) levels were decreased by Ln-UCNPs for most cancer cell lines examined. Taken together, we identified several potential cancer cell targets that were affected by Ln-UCNPs. Our work thereby provides the foundation to optimize Ln-UCNPs for the targeted killing of tumor cells. PMID- 30022176 TI - Cyclotrimerization of phenylacetylene catalyzed by a cobalt half-sandwich complex embedded in an engineered variant of transmembrane protein FhuA. AB - An (eta5-cyclopentadienyl)cobalt(i) complex was covalently incorporated into an engineered variant of the transmembrane protein ferric hydroxamate uptake protein component: A, FhuA DeltaCVFtev, using a thiol-ene reaction. A CD spectrum shows the structural integrity of the biohybrid catalyst. MALDI-TOF of the segment containing the anchoring site for the cobalt complex Cys545 confirmed successful conjugation. This biohybrid catalyst catalyzed the cyclotrimerization of phenylacetylene to give a mixture of regioisomeric 1,2,4- and 1,3,5 triphenylbenzene in aqueous medium. PMID- 30022177 TI - Base controlled diverse reactivity of allyl cyanide for synthesis of multi substituted benzenes. AB - A base controlled regioselective 1,6-cyanoallylation of suitably functionalized 2H-pyran-2-ones has been demonstrated for the synthesis of various multi substituted benzenes through a tandem process. We observed that lithium hydroxide provides a major product from alpha-attack and a minor product from gamma-attack of allyl cyanide, while the use of sodium hydride as a base exclusively provides the product by gamma-attack of allyl cyanide. We have also performed NMR experiments to understand the mechanistic pathway. The structure of the compound was confirmed by single crystal X-ray analysis. PMID- 30022178 TI - A theoretical study on NHC-catalysed enantioselective cycloaddition of ketenes and 3-aroylcoumarins: mechanism and enantioselectivity. AB - NHC-catalysed enantioselective cycloaddition of ketenes to 3-aroylcoumarins to yield dihydrocoumarin-fused dihydropyranones has been investigated using DFT methods at the B3LYP/6-31G* and MPWB1K/6-311G** computational levels. Two plausible mechanisms have been studied: the "ketene-first" mechanism A and the "coumarin-first" mechanism B. An analysis of the activation Gibbs free energies involved in the two competitive pathways makes it possible to rule out the pathway associated with the "coumarin-first" mechanism B. The first step of the "ketene-first" mechanism A is the formation of zwitterionic intermediate IN1-Zvia a nucleophilic attack of NHC 1 on ketene 2. A [4 + 2] cycloaddition through the nucleophilic attack of enolate IN1-Z on the conjugated double bond of the benzoyl group of coumarin 3, viaTS3-SS-a2 or TS3-RR-a2, yields IN3. Finally, the extrusion of the catalyst through TS5 leads to the final products, either 4-SS or 4-RR. Enantioselectivity observed in the experimental results is determined in the transition states TS3-SS-a2/TS3-RR-a2. In this pathway, the intramolecular hydrogen-bonding between the hydroxyl group of the IN1-Z adduct and the carbonyl oxygen of the original ketene group directs the final stereochemistry throughout the entire process. PMID- 30022180 TI - Mesoporous silica nanoparticles in recent photodynamic therapy applications. AB - In this review, the use of mesoporous silica nanoparticles for photodynamic therapy (PDT) applications is described for the year 2017. Since the pioneering work in 2009, nanosystems involving mesoporous silica nanoparticles have gained in complexity with a sophisticated core-shell system able to perform multi imaging and multi-therapies, not only for cancer diseases but also for anti microbial therapy, atherosclerosis, or Alzheimer disease. Near-infrared, excitation light based on up-converting systems, X-rays or persistent luminescent systems are described for deeper tissue treatments. PMID- 30022181 TI - A catalytic asymmetric interrupted Nazarov-type cyclization of 2-indolylmethanols with cyclic enaminones. AB - A chiral phosphoric acid-catalyzed asymmetric interrupted Nazarov-type cyclization of C3-alkenyl-substituted 2-indolylmethanols has been established by using cyclic enaminones as nucleophiles, which afforded chiral cyclopenta[b]indole derivatives with excellent diastereoselectivities and moderate to good enantioselectivities. This reaction will not only enrich the research contents of indolylmethanol-involved catalytic asymmetric transformations, but also advance the chemistry of catalytic asymmetric interrupted Nazarov-type cyclizations. In addition, this reaction will also provide a useful method for synthesizing chiral cyclopenta[b]indole derivatives. PMID- 30022182 TI - Auxetic multiphase soft composite material design through instabilities with application for acoustic metamaterials. AB - We investigate the instability-induced pattern transformations in 3D-printed soft composites consisting of stiff inclusions and voids periodically distributed in a soft matrix. These soft auxetic composites are prone to elastic instabilities giving rise to negative Poisson's ratio (NPR) behavior. Upon reaching the instability point, the composite microstructure rearranges into a new morphology attaining an NPR regime. Remarkably, identical composites can morph into distinct patterns depending on the loading direction. These fully determined instability induced distinct patterns are characterized by significantly different NPR behaviors, thus, giving rise to enhanced tunability of the composite properties. Finally, we illustrate a potential application of these reversible pattern transformations as tunable acoustic-elastic metamaterials capable of selectively filtering low frequency ranges controlled by deformation. PMID- 30022183 TI - An exosomal- and interfacial-biosensing based strategy for remote monitoring of aberrantly phosphorylated proteins in lung cancer cells. AB - It is a well-known phenomenon that cancer cells release key biological information such as DNA, RNA or proteins into body fluids (e.g., blood, urine or saliva). The analysis of these molecules-often encapsulated within nanovesicules called exosomes-is highly attractive, because it could replace current surgical biopsies, which are painful, costly and potentially risky for patients. For example, current strategies in lung cancer diagnosis involve genetic analyses from tumour tissues to detect the presence of underlying DNA mutations, known to alter the phosphorylation status and function of proteins. This information is used to direct therapy, as aberrantly phosphorylated proteins are the main targets of current drugs such as Tyrosine Kinase Inhibitors (TKIs). An alternative and less invasive strategy would be the remote analysis of these phospho-proteins by isolating them from cancer-derived exosomes. This would allow evaluating not only their phosphorylation status at diagnosis, but also the timely restoration of protein phosphorylation levels during therapy with TKIs. Yet, this proteomic approach remains vastly unexplored. Herein, we demonstrate that key lung cancer phosphoproteins, such as EGFR and ERK, are expressed in lung cancer exosomes and we outline a new exosomal proteomic-based approach for their fast and convenient detection. This approach, which could complement current genetic analysis for lung cancer detection, easily detects the phosphorylation status of lung cancer exosomal proteins within minutes after their extraction, bringing hope of circumventing the need for tissue biopsy and costly and cumbersome DNA sequencing techniques. It exploits the fact that phosphorylation induces protein conformational changes, which in turn alter protein's ability to effectively interact with bare gold surfaces. This leads to phosphorylated and non-phosphorylated protein isoforms displaying different gold-adsorption profiles. Using single-use and inexpensive, gold (Au) screen-printed electrodes (SPEs), we demonstrate the successful detection of aberrantly phosphorylated EGFR and ERK protein isoforms derived from lung cancer cell exosomes with a sensitivity down to 15 ng MUL-1 in samples with up to 90% excess of their non phosphorylated (wild-type) forms. We further show the applicability of this strategy for monitoring the action of Tyrosine Kinase Inhibitors over time. We believe that this non-invasive technique will open up new avenues for facilitating cancer diagnosis and time-point monitoring of therapeutic responses. PMID- 30022184 TI - Reduction of C[double bond, length as m-dash]O functional groups through H addition reactions: a comparative study between H2CO + H, CH3CH2CHO + H and CH3OCHO + H under interstellar conditions. AB - H-addition reactions on the icy interstellar grains may play an important role in the formation of complex organic molecules. In the present work we propose a comparative study of H2CO + H, CH3CH2CHO + H and CH3OCHO + H solid state reactions at 10 K under interstellar conditions in order to characterize the main reaction pathways involved in the hydrogenation of a CHO functional group. We show that the most probable mechanism for the formation of alcohols under non energetic conditions through the saturation of the CHO group corresponds to the attachment of the H atom to the CH group with noticeable variations of the energy barriers for each studied reaction. These energy barriers have been calculated to be 8.3, 14.6 and 32.7 kJ mol-1 for H2CO + H, CH3CH2CHO + H and CH3OCHO + H, respectively. The coupling of the experimental and theoretical analysis proves that while the simplest aldehyde, formaldehyde, is easily reduced to methanol, methylformate and propanal behave differently under H-bombardments but they cannot be a source of alcohol formation through H-addition reactions. Consequently, for the formation of alcohols larger than CH3OH, other chemical pathways should be taken into account, probably energetic processing such as the photolysis of interstellar ice analogues containing C-, H- and O-bearing compounds or the coupling of the H-addition reaction and photon-irradiation on species with a CHO functional group. PMID- 30022185 TI - Observation of an electric field-induced interface redox reaction and magnetic modification in GdOx/Co thin film by means of depth-resolved X-ray absorption spectroscopy. AB - We study an electric field-induced redox reaction at the interface of GdOx/Co thin film, by means of soft X-ray absorption spectroscopy (XAS). The fluorescence yield depth-resolved XAS analysis reveals that the interfacial Co layer at GdOx/Co is composed of ~50% Co oxide when the negative field is applied, while metallic Co is dominant in the case of the positive field. We suppose that the interfacial layer is oxidized by oxygen migration from the GdOx layer with the negative field while the interfacial layer shows the metallic state with the positive field, which means that the redox reaction is induced by the electric field. In addition, it is found from the X-ray magnetic circular dichroism (XMCD) measurement that the orbital magnetic moment of Co is larger when the negative electric field is applied to the film, as compared to the positive field. Moreover, the depth-resolved XMCD analysis reveals that the interfacial Co layer shows no or little magnetization regardless of the electric field, while for the inner layer, an increase of the orbital magnetic moment is suggested with the negative field. The field-induced magnetic modification could be attributed to the change of the orbital moment in the inner Co layer due to interfacial modifications. We thus succeed in the direct observation of the redox reaction induced change in the interface magnetic state. PMID- 30022186 TI - Ab initio study of methanol and ethanol adsorption on Bronsted sites in zeolite H MFI. AB - We examine the interaction of methanol and ethanol with a bridging OH group of H MFI (Al12-O20(H)-Si3 site). The computational standard approach for molecule surface interaction uses density functional theory with inclusion of dispersion for energies and harmonic vibrational frequencies for entropies and finite temperature effects for enthalpies. At 300 K, this yields -117 and -135 kJ mol-1 for adsorption enthalpies of methanol and ethanol, respectively, and 59 and 61 kJ mol-1, respectively for their entropy terms -T.DeltaS. To reach chemical accuracy (+/-4 kJ mol-1) we go beyond this approach. The energies are calculated using a hybrid QM:QM scheme (QM - quantum mechanics) which combines plane-wave density functional theory accounting for the periodicity of the system with wave function based methods (Moller-Plesset perturbation and Coupled Cluster theories). Finite temperature and entropy contributions are calculated from anharmonic vibrational partition functions. This yields as final predictions for methanol and ethanol 84 and -104 kJ mol-1, respectively, for the enthalpies of adsorption, 56 and 48 kJ mol-1, respectively, for the -T.DeltaS term, and -28 and -56 kJ mol-1, respectively, for the Gibbs free energies at 300 K. PMID- 30022187 TI - Exploring the scope of capacitance-assisted electrochemical carbon dioxide capture. AB - Optimisation of a capacitance-assisted electrochemical carbon-capture process is facilitated by the physical separation of the graphite and aluminium anode electrodes. This facilitates graphite electrode recycling and enables high current and increased aluminium surface area experiments which fix carbon at a higher rate and the same cell-voltage. Quantification of the H2 cathode byproduct shows that this process could be a net energy producer if recycled aluminium is used as the sacrificial anode. PMID- 30022188 TI - Influence of interface inhomogeneity on the electrical transport mechanism of CdSe nanowire/Au Schottky junctions. AB - Schottky junctions based on one-dimensional semiconductor nanomaterials, such as nanowires (NWs) and nanobelts (NBs), have been widely used in building high performance nano-electric and nano-optoelectric devices during the past 15 years. Meanwhile, with considerable development in diverse application fields, more and more interests are turning to the investigation of the fundamental physics inside the junctions. The inhomogeneity of the interface between semiconductor NWs/NBs and metal electrodes has significant influence on the electrical transport mechanism of Schottky junctions. However, few researchers are involved in such studies and the physical mechanism here is far from fully understood. In this work, we fabricated Schottky junctions based on single CdSe NWs, in which Au was used as a Schottky contact with CdSe NW. The temperature dependence of the electrical transport characteristics of typical CdSe NW/Au Schottky junctions were characterized. The ideality factor was found to decrease and the zero-bias Schottky barrier height (SBH) increased monotonously as the temperature was increased from 140 to 320 K, and this relationship was ascribed to SBH inhomogeneity. The electrical transport mechanism was analyzed quantitatively with a spatial potential fluctuation model, in which SBHs obey the Gaussian distribution. The standard deviation of the SBH distribution was determined to be as high as 13.54% and 13.94% of the zero-bias mean SBH in the temperature ranges 140-200 K and 200-320 K, respectively. Our work revealed the barrier inhomogeneity at CdSe NW/Au interfaces and its influence on the electrical transport mechanism of NW-based Schottky junctions. PMID- 30022189 TI - Emerging photonic architectures in two-dimensional opto-electronics. AB - The isolation of thermodynamically stable, free standing materials with single to few atom thicknesses has brought about a revolution in materials science, condensed matter physics and device engineering for opto-electronic applications. These two dimensional (2D) materials cover a broad range of electronic properties ranging from zero-band gap, semi-metallic graphene to wide band gap semiconductors in sulfides and selenides of Mo and W to metallic behavior in Ti, Nb and Ta sulfides and selenides. This permits their potential application in opto-electronic devices from terahertz frequencies up to the ultraviolet portion of the spectrum. However, their atomically thin nature poses fundamental challenges in driving efficient light-matter interactions. A range of strategies have been explored from the area of photonics and resonant optics that enhance the coupling and interaction of light with atomically thin layers to overcome this challenge. By comparing and contrasting critical advantages of integrating nanophotonic elements with 2D materials, this review highlights the challenges and advantages of such opto-electronic devices. PMID- 30022190 TI - Molecular simulations of the piezoionic effect. AB - We present a molecular dynamics study of two polyelectrolyte gels with different degrees of ionization coupled in a slab geometry. Our simulations show that a pressure gradient emerges between the two gels that results in the buildup of a Nernst-Donnan potential. This methodology is reverse to experiments of the piezoionic or mechanoelectric effect, in which an electric potential gradient appears upon application of a pressure gradient to a hydrogel. The Nernst-Donnan potential at the interface is found to scale linearly with temperature with the coefficient of proportionality given by the fraction of concentrations of the uncondensed counterions. We show that the potential difference can also be expressed as a linear function of the lateral pressure, thus providing a molecular interpretation of the piezoionic effect. PMID- 30022191 TI - The effect of preparation methods on the thermal and chemical reducibility of Cu in Cu-Al oxides. AB - The influence of the preparation methods on the physicochemical properties of Cu and Al oxides was studied. Four different preparation methods were used to synthesize the oxides (catalysts): co-precipitation by the hydrotalcite precursor route (CuAl-HT-c), the solid-state reaction route (CuAl-s), the physical mixing of the oxides (CuAl-o), and individual oxide precipitation followed by physical mixing (CuAl-p). Chemical analysis, X-ray diffraction and textural analysis results of the precursor CuAl-HT-c showed that the respective preparation method is efficient to obtain the hydrotalcite phase with high purity as well as generating a mixed oxide with the greatest surface area among all of the catalysts in this study. The efficacy of this method should be highlighted as it is very difficult to obtain high purity hydrotalcites with copper and aluminum. Furthermore, through the evolution of the FWHM with temperature, this method provided a structurally and texturally more stable mixed oxide. The thermal reducibility of the CuAl-HT-c catalyst was also much higher than that observed in the Cu and Al oxides prepared by other methods. Under an He flow, the CuAl-HT-c catalyst showed a significant reduction of CuO starting at 440 degrees C, with the formation of Cu2O and metallic Cu, confirmed by XRD and XANES, both in situ. When investigating the effect of the pretreatment gas for this catalyst, H2 reduction occurs faster than with CO, and with less Cu+ formation. Thus, Cu and Al mixed oxides obtained from a precursor with the hydrotalcite structure showed advantages over other methods, presenting unique textural and reducibility properties. PMID- 30022192 TI - Di- and tetranuclear transition metal complexes of a tetrakisguanidino substituted phenazine dye by stepwise coordination. AB - 2,3-Bis- and 2,3,7,8-tetrakisguanidino-substituted phenazines are intensely coloured dyes that offer two different sites for metal coordination or benzylation, namely the imino nitrogen atoms of the guanidino groups and the phenazine nitrogen atoms. In this work, sequential coordination at both sites is studied, and the effects on the electronic structure and optical properties are analyzed. The step-wise coordination is used to synthesize tetranuclear mixed valence (CuI)2(CuII)2 and heterobimetallic Cu2Ni2 complexes. Coordination at the guanidino groups switches on a ligand-metal charge-transfer character of electronic transitions in the visible region, leading to a massive intensity gain in the case of copper coordination. The second coordination step with CuI takes place at the phenazine nitrogen atoms and further decreases the ligand frontier orbitals. In the case of two tricoordinated CuI atoms in the product complex, the charge-transfer character of the electronic excitation vanishes, while their energies are very similar. On the other hand, for CuI atoms with a coordination number of only 2, the stronger Cu-N bond leads to a red-shift of the electronic transitions. PMID- 30022194 TI - Short-range ion dynamics in methylammonium lead iodide by multinuclear solid state NMR and 127I NQR. AB - We explore the short-range ion dynamics in methylammonium lead iodide (MAPbI3, the archetypal halide perovskite) by means of solid-state NMR (1H, 13C, 14N, 15N and 207Pb) and Nuclear Quadrupolar Resonance (127I NQR), in combination with molecular dynamics simulations. We focus on the rotational motion of the methylammonium (MA) cation, and on the interaction between MA and the inorganic lattice, since these processes are linked to electronic carrier lifetimes, optical and electronic properties and even structural stability of this promising solar cell material. We show that the motion of the MA cation can be described by a bi-axial rotation, with similar interactions of CH3 and NH3+ groups with the inorganic framework. This motion becomes nearly isotropic above the cubic phase transition, dominating the spin-lattice relaxation of 1H, 13C and 15N through spin-rotational interactions. In addition, we observe strong cross-relaxation between 207Pb and 127I, which fully controls spin-spin and spin-lattice relaxation in 207Pb. PMID- 30022195 TI - Ruthenium-catalyzed selective alpha-deuteration of aliphatic nitriles using D2O. AB - Selective catalytic alpha-deuteration of aliphatic nitriles using deuterium oxide as a deuterium source is reported. A PNP-ruthenium pincer complex catalyzed the alpha-deuteration of aliphatic nitriles including acetonitrile. Efficient deuteration occurred with a low catalyst load (0.2 to 0.5 mol%) and under mild conditions. A [2+2] cycloadduct formation from nitrile functionality and a deprotonated catalytic intermediate, followed by an imine-enamine tautomerization and a H/D exchange between the enamine intermediate and deuterium oxide leading to the selective deuteration at the alpha-position of the nitrile, is proposed as a plausible reaction mechanism. PMID- 30022196 TI - Biocompatible protamine sulfate@silicon nanoparticle-based gene nanocarriers featuring strong and stable fluorescence. AB - The development of biocompatible and fluorescent gene carriers is of particular importance in the gene-delivery field. Taking advantage of the unique optical properties (e.g., strong and robust fluorescence) of silicon nanoparticles (SiNPs), as well as the excellent biocompatibility of silicon and protamine sulfate (PS, approved by the U.S. Food and Drug Administration (FDA) for clinical use), we herein present a type of PS-modified SiNP (PS@SiNP)-based gene carrier. Plasmid DNA (pDNA) with negative charges can be effectively bound onto the surface of the as-prepared fluorescent PS@SiNP-based gene carriers via electrostatic interactions. In particular, such resultant gene carriers possess stable and high fluorescence (photoluminescent quantum yield (PLQY): ~25%). In addition, the PS@SiNP-based gene carriers show minimal toxic effects on normal mitochondrial metabolic activity (e.g., human retinal pigment epithelial (ARPE 19) cells preserve ~90% of their cell viability after a 48 h incubation with the resultant carriers). Based on tracking the strong and stable fluorescence signals of SiNPs, the dynamic behavior of the PS@SiNP-based gene carriers in live cells (e.g., clathrin-mediated endocytosis, lysosomal escape, pDNA release, etc.) is investigated in a long-term manner, providing valuable information for understanding the intracellular behavior of gene vectors and designing high efficacy gene carriers. PMID- 30022197 TI - Brightly luminescent and color-tunable green-violet-emitting halide perovskite CH3NH3PbBr3 colloidal quantum dots: an alternative to lighting and display technology. AB - Organic-inorganic hybrid perovskite (CH3NH3PbX3, X = Cl, Br, or I) quantum dots have become one of the most promising materials for optoelectronic applications. We controllably synthesized CH3NH3PbBr3 quantum dots with a tunable spectrum with the emission peaks covering the range from green (523.6 nm), blue and eventually to deep violet (409.4 nm), which is wider than that of quantum dots obtained without changing the halide component. The mechanism of the blueshift was investigated. The purified quantum dots have allowed the fabrication of efficient electroluminescence devices having a simple glass/ITO/PEDOT:PSS/TFB/CH3NH3PbBr3 quantum dot/TPBi/LiF/Al structure. CH3NH3PbBr3 quantum dots with 5-30 MUL n octylamine showed an ideal color-saturated green emission with Commission Internationale de l'Eclairage color coordinates of (0.123, 0.744) and a narrow full width at half-maximum of 19-24 nm. The photoluminescence quantum yield was up to 90.2%. In addition, it is also worth noting that the chromaticity coordinates (x, y) of CH3NH3PbBr3 quantum dots with 50-100 MUL n-octylamine are (0.300, 0.344), (0.305, 0.314) and (0.323, 0.318) in the white region. All these properties indicate that these MAPbBr3 quantum dots can provide effective data support for the application of white LEDs, and may potentially be used as single component multicolor-emitting materials, which can be applied to lighting and display technology. PMID- 30022198 TI - Inducing regioselective chemical reactivity in graphene with alkali metal intercalation. AB - First principles calculations demonstrate that alkali metal atoms, intercalated between metal substrates and adsorbed graphene monolayers, induce localised regions of increased reactivity. The extent of this localisation is proportional to the size of the alkali atom and the strength of the graphene-substrate interaction. Thus, larger alkali atoms are more effective (e.g. K > Na > Li), as are stronger-interacting substrates (e.g. Ni > Cu). Despite the electropositivity of these alkali metal adsorbates, analysis of charge transfer between the alkali metal, the substrate and the adsorbed graphene layer indicates that charge transfer does not give rise to the observed regioselective reactivity. Instead, the increased reactivity induced in the graphene structure is shown to arise from the geometrical distortion of the graphene layer imposed by the intercalated adsorbed atom. We show that this strategy can be used with arbitrary adsorbates and substrate defects, provided such structures are stable, towards controlling the mesoscale patterning and chemical functionalisation of graphene structures. PMID- 30022200 TI - Entropic effects make a more tightly folded conformer of a beta-amino acid less stable: UV-UV hole burning and IR dip spectroscopy of l-beta3-homotryptophan using a laser desorption supersonic jet technique. AB - UV-UV hole burning and IR dip spectra of l-beta3-homotryptophan were measured by a laser desorption supersonic jet technique as a bottom-up approach to understand the secondary structures of beta-peptides. 14 conformers were found by UV-UV hole burning spectroscopy. The conformers were classified into three groups depending on their hydrogen bonding patterns observed in their conformer-specific IR spectra, and tentatively assigned by comparing with quantum chemical calculations. Group 1 had free OH stretch but no NH2 anti-symmetric stretch vibrational transition and was assigned to NH-pi hydrogen bonded structures. Group 2, including the most abundant conformer, showed both free OH and NH2 anti symmetric stretch vibrations, and belonged to NH-O hydrogen bonded conformations. Group 3 of conformers had hydrogen-bonded OH stretch IR transition and had OH-N hydrogen bonds. The internal hydrogen bond of group 3 is a C6 hydrogen bond due to the additional carbon atom at the beta position and shows a shorter bond length than that of a C5 hydrogen bond. While the OH-N C6 hydrogen bond is stronger than NH-O, the entropic effect prefers the more flexible NH-O hydrogen bonded structure. It is expected that the unnatural C6 hydrogen bond influences the conformations of beta-peptides and builds totally different secondary structures than those of alpha-peptides. PMID- 30022201 TI - Retention and multiphase transformation of selenium oxyanions during the formation of magnetite via iron(ii) hydroxide and green rust. AB - Environmental and health hazards associated with the trace element selenium are mainly related to the presence of the highly mobile selenium oxyanions selenite and selenate (oxidation states IV and VI). In this study, we investigated the immobilization of dissolved selenite and selenate during the formation of magnetite in coprecipitation experiments based on the progressive oxidation of an alkaline, anoxic Fe2+ system (pH 9.2). Up to initial selenium concentrations of 10-3 mol L-1 (mass/volume ratio = 3.4 g L-1), distribution coefficient values (log Kd) of 3.7 to 5.1 L kg-1 demonstrate high retention of selenium oxyanions during the mineral formation process. This immobilization is due to the reduction of selenite or selenate, resulting in the precipitation of sparingly soluble selenium compounds. By X-ray diffraction analysis, these selenium compounds were identified as trigonal elemental selenium that formed in all coprecipitation products following magnetite formation. Time-resolved analysis of selenium speciation during magnetite formation and detailed spectroscopic analyses of the solid phases showed that selenium reduction occurred under anoxic conditions during the early phase of the coprecipitation process via interaction with iron(ii) hydroxide and green rust. Both minerals are the initial Fe(ii)-bearing precipitation products and represent the precursor phases of the later formed magnetite. Spectroscopic and electron microscopic analysis showed that this early selenium interaction leads to the formation of a nanoparticulate iron selenide phase [FeSe], which is oxidized and transformed into gray trigonal elemental selenium during the progressive oxidation of the aquatic system. Selenium is retained regardless of whether the oxidation of the unstable iron oxides leads to the formation of pure magnetite or other iron oxide phases, e.g. goethite. This reductive precipitation of selenium induced by interaction with metastable Fe(ii) containing iron oxide minerals has the potential to influence the mobility of selenium oxyanions in contaminated environments, including the behavior of 79Se in the near-field of nuclear waste repositories. PMID- 30022202 TI - Epitaxial 8YSZ/Y2Zr2O7 multilayers: a conductivity and strain study. AB - Thin films of Y2Zr2O7 were grown via pulsed laser deposition (PLD) on substrates of MgO(110), Al2O3(0001) and Al2O3(11[combining macron]02). Electrical properties were investigated via electrical impedance spectroscopy. Unexpectedly, the ionic conductivity is not affected by the microstructure; only minor differences in conductivities and activation energies were measured between epitaxial thin films (on MgO) and textured thin films (on Al2O3, both orientations). This indicates the grain boundaries of such a material to only marginally block the oxygen vacancy transport. Starting from these results, epitaxial multilayers of Y2Zr2O7 and 8 mol% yttria-stabilized zirconia with same overall thickness (between 60 and 70 nm) and different number of interfaces (from 1 up to 9) have been deposited on MgO(110) and the role of the residual compressive strain on the electrical properties has been investigated by means of XRD analysis and impedance spectroscopy. The results, showing no effect of the strain field on the ionic conductivity, indicate the negligible effect of the compressive strain on the ionic transport properties of the material. PMID- 30022203 TI - An extended excited-state intramolecular proton transfer (ESIPT) emitter for random lasing applications. AB - An original molecular fluorophore displaying single keto (K*) excited-state intramolecular proton transfer (ESIPT) emission is presented in this article. Substitution at the 3 and 5 positions of the phenol ring of a 2-(2' hydroxyphenylbenzoxazole) (HBO) dye by triethylsilyl-ethynyl fragments leads to a drastic enhancement of fluorescence in the solution-state as compared to unsubstituted analogues. This intense fluorescence emission is also retained in a protic solvent like ethanol and in the solid-state as embedded in a potassium bromide pellet or as 1% doped in a poly(methyl methacrylate) (PMMA) film. The experimental optical properties were confirmed by ab initio calculations. Random lasing (RL) studies performed on this ESIPT emitter show the presence of stimulated emission occurring above the threshold level of pumping energy density (rhoth ~ 300 MUJ cm-2) in the PMMA matrix. To the best of our knowledge, this study constitutes the first observation of RL based on ESIPT fluorescence. PMID- 30022204 TI - Enabling the synthesis of homogeneous or Janus hairy nanoparticles through surface photoactivation. AB - Nanoparticles (NPs) homogeneously covered with polymer chains or with chains of two different polymers segregated in distinct domains ("Janus" particles) possess remarkable features. Their unique colloidal properties can be finely tuned by the grafted polymers while the characteristics of the nano-core remain unaffected. Herein, a simple and robust photochemical approach is reported to synthesize, from 50 nm cores, homogeneous and Janus "hairy" nanoparticles with hydrophilic and amphiphilic properties, respectively. This is achieved by using a surface anchored bis(acyl)phosphane oxide photoinitiator which allows a spatially controlled surface-initiated photopolymerization at room temperature. Homogeneous and Janus hairy nanoparticles dispersed in water have very different interaction behaviours which are directly visualized by in situ liquid cell transmission electron microscopy and confirmed by small angle X-ray scattering from a statistically relevant number of particles. PMID- 30022205 TI - Extracting the surface tension of soft gels from elastocapillary wave behavior. AB - Mechanically-excited waves appear as surface patterns on soft agarose gels. We experimentally quantify the dispersion relationship for these waves over a range of shear modulus in the transition zone where the surface energy (capillarity) is comparable to the elastic energy of the solid. Rayleigh waves and capillary gravity waves are recovered as limiting cases. Gravitational forces appear as a pre-stress through the self-weight of the gel and are important. We show the experimental data fits well to a proposed dispersion relationship which differs from that typically used in studies of capillary to elastic wave crossover. We use this combined theoretical and experimental analysis to develop a new technique for measuring the surface tension of soft materials, which has been historically difficult to measure directly. PMID- 30022206 TI - Micellar and bicontinuous microemulsion structures show different solute-solvent interactions: a case study using ultrafast nonlinear infrared spectroscopy. AB - Microemulsions are transparent, thermodynamically stable liquid mixtures of oil, water and surfactant. They typically exist in the form of micellar and bicontinuous structures, which appear to be equilibrium systems but are actually complex in structure and are difficult to characterize at the molecular level. In this work, potassium ferrocyanide [K4Fe(CN)6] and tungsten hexacarbonyl [W(CO)6] were chosen as two probe molecules for water and organic phases respectively to simultaneously explore the structures and dynamics of commonly prepared reverse micellar and bicontinuous microemulsion structures using aerosol OT (AOT) as the surfactant and isooctane as the oil phase. Even though these two structures have quite different solvent environments due to the varying geometry and boundary conditions, the steady-state infrared spectra of the C[triple bond, length as m dash]N- stretching mode in the water phase are quite similar, and so are those of the C[triple bond, length as m-dash]O stretching mode in the oil phase. However, vibrational and anisotropic relaxation dynamics obtained from infrared pump-probe spectroscopy and spectral diffusion dynamics extracted from two-dimensional infrared spectroscopy of the two infrared chromophores in the two probe molecules are found to be quite sensitive to whether the probe molecules are in pure solvent or in a restricted microemulsion environment. The results in the water phase and oil phase are discussed separately. Our work demonstrated that ultrafast nonlinear infrared spectroscopy can be used to differentiate the structural details at the molecular level for different microemulsion systems. PMID- 30022207 TI - Exploring the electrochemical performance of graphite and graphene paste electrodes composed of varying lateral flake sizes. AB - We report the fabrication, characterisation (SEM/EDX, TEM, XRD, XPS and Raman spectroscopy) and electrochemical properties of graphite and graphene paste electrodes with varying lateral flake sizes. The fabricated paste electrodes are electrochemically analysed using both outer-sphere and inner-sphere redox probes, namely; hexaammineruthenium(iii) chloride, N,N,N',N'-tetramethyl-p phenylenediamine (TMPD), potassium ferrocyanide(ii) and ammonium ferrous(ii) sulphate. Upon comparison of different graphite paste electrodes, a clear correlation between the lateral flake sizes (La), ranging from 1.5 mm-0.5 MUm, and electrochemical activity (heterogeneous electron transfer (HET) kinetics) is evident, where an improvement in the HET is observed at smaller lateral flake sizes. We infer that the beneficial response evident when employing laterally smaller flakes is due to an increased number of edge plane like-sites/defects available upon the electrode surface, facilitating electron transfer. Interestingly, given that the overall lateral flake sizes of the graphenes utilised (10.0-1.3 MUm) were significantly smaller than those studied previously, an improvement in HET kinetics was also evident with the reduction of lateral flake size; the extent to which is redox-probe dependent. Improvements are observed up to a distinct point, termed the 'lateral size threshold' (ca. <=2 MUm) where the electrochemical reversible limit is approached. Further support is provided from density functional theory (DFT), exploring the electronic structure (i.e. HOMO-LUMO) as a function of flake size, which demonstrates that the coverage of edge plane like-sites/defects comprising the geometric structure of the relatively small graphene flakes is such that effectively the entire flake has become electrochemically active. In this study, the importance of lateral flake size with respect to electrochemical reactivity at carbon-based electrodes has been demonstrated alongside a structural relationship upon HET performance, a phenomenon that has not previously been described in the literature. Such work is both highly important and informative for the field of electrochemistry and electrode performance, with potential implications in a plethora of areas, ranging from novel renewable energy sources to electroanalytical sensing platforms. PMID- 30022209 TI - A neptunium(v)-mediated interwoven transuranium-rotaxane network incorporating a mechanically interlocked [c2]daisy chain unit. AB - As an extension of actinide-rotaxane complexes from uranium to transuranium, we report the first crystal structure of a neptunium-rotaxane complex, NRCP-1, in which an interwoven neptunium(v)-rotaxane coordination network incorporating a mechanically-interlocked [c2]daisy chain unit is promoted via the simultaneous coordination of cucurbituril (CB6) and axle molecules in [2]pseudorotaxane to NpV. PMID- 30022210 TI - pH dependent binding in de novo hetero bimetallic coiled coils. AB - Herein the first example of a bimetallic coiled coil featuring a lanthanide binding site is reported, opening opportunities to exploit the attractive NMR and photophysical properties of the lanthanides in multi metallo protein design. In our efforts to fully characterise the system we identified for the first time that lanthanide binding to such sites is pH dependent, with optimal binding at neutral pH, and that the double AsnAsp site is more versatile in this regard than the single Asp site. Our second site featured the structural HgCys3 site, the chemistry of which was essentially unaltered by the presence of the lanthanide site. In fact, both metal binding sites within the hetero bimetallic coiled coil displayed the same properties as their mononuclear single binding site controls, and operated independently of each other. Finally, pH can be used as an external trigger to control the binding of Hg(ii) and Tb(iii) to the two distinct sites within this coiled coil, and offers the opportunity to "activate" metal binding sites within complex multi metallo and multi-functional designs. PMID- 30022211 TI - Efficient intersystem crossing in 2-aminopurine riboside probed by femtosecond time-resolved transient vibrational absorption spectroscopy. AB - The photophysical dynamics of 2-aminopurine riboside (2APr) in CHCl3 have been studied following excitation at lambdapump = 310 nm by means of femtosecond transient vibrational absorption spectroscopy (TVAS) aided by quantum chemical density functional theory (DFT) and ab initio calculations. The experiments identified numerous vibrational marker bands in the regions of the NH2 stretch and the 2AP ring vibrations which could be assigned to the bleach of the S0 electronic ground state (GS) and to transient populations in the 1pipi* and 3pipi* excited electronic states. The temporal evolution of the transient vibrational bands shows that the decay of the 1pipi* population is accompanied by a partial recovery of the GS and a concurrent population of the 3pipi* state with a time constant of tau2 = 740 +/- 15 ps. The ensuing electronic relaxation is concluded to proceed via the 1npi* state as intermediate state. The absence of observable transient vibrational bands of this state hints at an upper limit for its lifetime of tau < 100 ps. The triplet quantum yield is found to be phiT = 0.42 +/- 0.07. PMID- 30022212 TI - Charge transfer through a fragment of the respiratory complex I and its regulation: an atomistic simulation approach. AB - We simulate electron transfer within a fragment of the NADH:ubiquinone oxidoreductase (respiratory complex I) of the hyperthermophilic bacterium Aquifex aeolicus. We apply molecular dynamics simulations, thermodynamic integration, and a thermodynamic network least squares analysis to compute two key parameters of Marcus' theory of charge transfer, the thermodynamic driving force and the reorganization energy. Intramolecular contributions to the Gibbs free energy differences of electron and hydrogen transfer processes, DeltaG, are accessed by calibrating against experimental redox titration data. This approach permits the computation of the interactions between the species NAD+, FMNH2, N1a-, and N3-, and the construction of a free energy surface for the flow of electrons within the fragment. We find NAD+ to be a strong candidate for the regulation of charge transfer. PMID- 30022213 TI - Tunable WSe2-CdS mixed-dimensional van der Waals heterojunction with a piezo phototronic effect for an enhanced flexible photodetector. AB - Due to the absence of bond fracture and atomic reconstruction under strain, vdWs structures hold great promise in flexible electronic/optoelectronic applications. Besides all-2D heterojunctions, the dangling-bond-free surfaces of 2D materials also enable vdWs interaction with other materials of different dimensionalities, forming mixed-dimensional vdWs heterostructures. Such structures allow a much broader selection of materials and may provide a promising approach to compensate for the intrinsic weakness of 2D crystals before realizing their full potential. In this study, we present the fabrication of a WSe2-CdS mixed-dimensional vdWs p n heterojunction for flexible photodetection. A strain-tunable vdWs interface was demonstrated and the photoresponse was dramatically enhanced with the piezo phototronic effect. The photocurrent can be increased by ~110% under a compressive strain of -0.73% and the corresponding photoresponsivity reaches up to 33.4 A W-1. The enhancement originates from realigned local energy-band tilting at the WSe2-CdS interface by strain-induced piezopolarization, which promotes the transport process of photoexcited carriers. Our work provides a new route to a tunable vdWs interface other than with electrostatic gating, which may inspire the development of novel flexible vdWs optoelectronics. PMID- 30022215 TI - Synthesis, properties, and optoelectronic applications of two-dimensional MoS2 and MoS2-based heterostructures. AB - As a two-dimensional (2D) material, molybdenum disulfide (MoS2) exhibits unique electronic and optical properties useful for a variety of optoelectronic applications including light harvesting. In this article, we review recent progress in the synthesis, properties and applications of MoS2 and related heterostructures. Heterostructured materials are developed to add more functionality or flexibility compared to single component materials. Our focus is on their novel properties and functionalities as well as emerging applications, especially in the areas of light energy harvesting or conversion. We highlight the correlation between structural properties and other properties including electronic, optical, and dynamic. Whenever appropriate, we also try to provide fundamental insight gained from experimental as well as theoretical studies. Finally, we discuss some current challenges and opportunities in technological applications of MoS2. PMID- 30022216 TI - Discrete evolution of the crystal structure during the growth of Ba-hexaferrite nanoplatelets. AB - An understanding of the adaptation of the crystal structure of materials confined at the nanoscale, the influences of their specific structures on the evolution of their morphologies and, finally, their functional properties is essential not only for expanding fundamental knowledge, but also for facilitating the designs of novel nanostructures for diverse technological and medical applications. Here we describe how the distinct structure of barium-hexaferrite nanoplatelets evolves in a stepwise manner in parallel with the development of their size and morphology during hydrothermal synthesis. The nanoplatelets are formed by reactions between Ba- and Fe-hydroxides in an aqueous suspension at temperatures below 80 degrees C. Scanning-transmission electron microscopy showed that the structure of the as-synthesized, discoid nanoplatelets (~2.3 nm thick, ~10 nm wide) terminates at the basal surfaces with Ba-containing planes. However, after subsequent washing of the nanoplatelets with water the top two atomic layers dissolve from the surfaces. The final structure can be represented by a SRS* sequence of the barium-hexaferrite SRS*R* unit cell, where S and R represent a hexagonal (BaFe6O11)2- and a cubic (Fe6O8)2+ structural block, respectively. Due to the stable SRS* structure, the thickness of the primary nanoplatelets remains unchanged up to approximately 150 degrees C, when some of the primary nanoplatelets start to grow exaggeratedly and their thicknesses increase discretely with the addition of the RS segments to their structure. The SRS* structure of the primary nanoplatelets is too thin for the complete development of magnetic ordering. However, the addition of just one RS segment (SRS*R*S structure) gives the nanoplatelets hard magnetic properties. PMID- 30022217 TI - Maltodextrin recognition by a macrocyclic synthetic lectin. AB - A monocyclic "temple" synthetic lectin, with extended electron-rich aromatic surfaces, shows enhanced affinities for carbohydrates in water. The methoxy substituents favour binding to alpha-linked maltodextrins, against the all equatorial substrates normally favoured by this family of receptors. PMID- 30022218 TI - True compression of pelvic fractures under lateral impact. AB - PURPOSE: To promote the understanding of pelvic fracture mechanism and make more accurate evaluation of maximal deformity at the moment of fracture, kinematic response of pelvis to lateral impact and the difference between peak and final displacement were investigated. METHODS: A total of three human cadaver pelves were seated uprightly on a sled test table, explored to horizontal lateral impact by a 22.1-kg impactor at a speed of 5.2, 4.0, and 4.8 m/s. Kinematic data of pelvic osseous interesting points (POIP) were measured by the motion capture system. Trajectories of POIP, duration of impact, and deflection of pelvis were calculated as well as rotational movement of pelvis was evaluated. After impact, autopsy and CT scan were made to validate the motion capture data. RESULTS: The peak deflection of pelvis under lateral impact was 31.9, 30.1, and 18.5%, while final deflection was 19.6, 13.8, and 13.8%. The final deflection was only 61.5, 45.9, and 74.46% of the peak deflection. CONCLUSIONS: In clinical practice, pelvic fracture displacement tends to be underestimated. The peak compression can be 1.3-2.2 times of final compression appearing on images in hospital. Clinicians shall give adequate estimation of displacement and related injuries. PMID- 30022219 TI - "Pseudoprogression": more than semantics. PMID- 30022220 TI - Computed tomography-based texture analysis of bladder cancer: differentiating urothelial carcinoma from micropapillary carcinoma. AB - PURPOSE: The purpose of the study is to determine the feasibility of using computed tomography-based texture analysis (CTTA) in differentiating between urothelial carcinomas (UC) of the bladder from micropapillary carcinomas (MPC) of the bladder. METHODS: Regions of interests (ROIs) of computerized tomography (CT) images of 33 MPCs and 33 UCs were manually segmented and saved. Custom MATLAB code was used to extract voxel information corresponding to the ROI. The segmented tumors were input to a pre-existing radiomics platform with a CTTA panel. A total of 58 texture metrics were extracted using four different texture extraction techniques and statistically analyzed using a Wilcoxon rank-sum test to determine the differences between UCs and MPCs. RESULTS: Of the 58 texture metrics extracted using the gray level co-occurrence matrix (GLCM) and gray level difference matrix (GLDM), 28 texture metrics were statistically significant (p < 0.05) for differences in tumor textures and 27 texture metrics were statistically significant (p < 0.05) for peritumoral fat textures. The remaining nine metrics extracted using histogram and fast Fourier transform analyses did not show significant differences between the textures of the tumors and their peritumoral fat. CONCLUSIONS: CTTA shows that MPC have a more heterogeneous texture compared to UC. As visual discrimination of MPC from UC from clinical CT scans are difficult, results from this study suggest that tumor heterogeneity extracted using GLCM and GLDM may be a good imaging aid in segregating MPC from UC. This tool can aid clinicians in further sub-classifying bladder cancers on routine imaging, a process which has potential to alter treatment and patient care. PMID- 30022221 TI - High ETS2 expression predicts poor prognosis in acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation. PMID- 30022223 TI - Morphological variability of the palmaris longus muscle in human fetuses. AB - PURPOSE: The palmaris longus (PL) muscle is characterized by high-morphological variability. It is clinically important as it is routinely harvested for the reconstruction of other tendons. The study characterizes the morphology of the PL in human fetuses and creates a new classification based on its variations that would relate to the spectrum of morphological variability in adults. METHODS: Eighty spontaneously aborted human foetuses (44 male, 36 female, 160 upper limbs), aged 18-38 weeks of gestation, were examined. RESULTS: The palmaris longus muscle was present in 62.5% of fetuses. The absence was bilateral in 26.25%, and unilateral in 22.5%. Nine types of palmaris longus muscles were identified based on the morphology of its insertion (Types I-IX). All types originated on the medial epicondyle of the humerus. The most common type was Type I, which was characterized by insertion to the palmar aponeurosis (52%). The rarest types were Type VII and Type IX (1% each). Type VII was characterized by partial doubling of the muscle belly, which then turned into two separate tendons that inserted together into the palmar aponeurosis. Type IX was characterized by fusion with the flexor carpi ulnaris muscle. CONCLUSION: Our findings concerning morphological variability of the PL in fetuses present a new perspective on the understanding nature of the morphological variation of the PL muscle in adults. LIST OF EVIDENCE: Basic Science Study. PMID- 30022222 TI - Vasa vasorum: an old term with new problems. AB - PURPOSE: The aim of the study was to describe the origin of the Latin anatomical term vasa vasorum and its role in current medical research and to present examples of grammatical errors in its use. METHODS: Literary searches oriented on the term vasa vasorum were used to identify publications using it in the medical literature from the seventeenth century up to the present. RESULTS: The Latin term vasa vasorum was introduced by Ludwig in 1739. The vasa vasorum became an important topic in clinical research around the middle of the twentieth century, with implications in angiology, cardiology and cardiosurgery. We report 18 grammatical errors concerning the use of the term vasa vasorum, starting from the year 1959. A similar decline in the correct use of Latin terminology is also evident in other medical research disciplines. CONCLUSIONS: The numerous errors found in the use of Latin terminology in recent medical literature have occurred as a consequence of decreased use of Latin in the medical community. The only way to improve this situation is by improving awareness of international standard anatomical terminology, which is available worldwide in both Latin and English. PMID- 30022224 TI - A phase I pharmacokinetic and pharmacodynamic study of GTI-2040 in combination with gemcitabine in patients with solid tumors. AB - PURPOSE: GTI-2040 is a novel antisense oligonucleotide inhibitor of the R2 subunit of ribonucleotide reductase. This phase I study assessed safety and maximum tolerated dose (MTD) of GTI-2040 in combination with weekly gemcitabine in patients with advanced solid tumors. METHODS: GTI-2040 was given as a 14-day continuous intravenous infusion, while gemcitabine was administered on days 1, 8, and 15. This combination was repeated every 4 weeks and study followed a modified 3 + 3 Fibonacci schema. Incidence, severity of adverse events, pharmacokinetics (PK), and pharmacodynamics (PD) was assessed. Responses were assessed using RECIST criteria version 1.0 with CT scans performed after every other cycle. RESULTS: A total of 16 patients received at least one dose of GTI 2040/gemcitabine and were included in the safety analysis. The MTD of this regimen is 100 mg/m2/day of GTI-2040 over 14 days combined with 400 mg/m2/day of gemcitabine administered weekly on days 1, 8, and 15. The dose-limiting toxicities (DLTs) included grade 3 fatigue and thrombocytopenia with hematemesis (both at 100/600 mg/m2/day). The most common adverse events were grade 1/2 fatigue, nausea, vomiting, diarrhea, and anorexia. There was no evidence of alteration in gemcitabine PKs. PD modulation of R2mRNA expression in peripheral blood mononuclear cells was observed. No objective tumor response was observed although stable disease was seen in 25% patients. CONCLUSIONS: The combination of GTI-2040 and gemcitabine has an acceptable safety profile in a heavily pre treated patient population with advanced solid tumors. No clear signal of anti tumor activity was observed; however, several patients had prolonged stable disease. PMID- 30022225 TI - [Prognostic relevance of TIM3 in renal cell carcinoma]. PMID- 30022226 TI - Influence of Road Paving on Particulate Matter Emission and Fingerprinting of Elements of Road Dust. AB - Most assessments of road dust have focused largely on the resuspension of materials from the paved road while the contribution from unpaved shoulder to particulate matter is poorly understood. We evaluated the role of unpaved road shoulders in the contribution of particulate matter emitted by analyzing elements in the road dust. We collected road dust samples and employed US-EPA empirical equations. The results of TSP emission reveal that unpaved shoulder adjacent to paved roads (43.1-29.9%) is a potential emitter than that at roundabouts (27%). In paved road environment, the contribution of TSP emission was 54.9-25.6% from unpaved shoulders based on driving share of vehicles. TSP emission results suggest that waste material is frequently exchanged from paved to unpaved shoulder, which leads to seasonal variations in paved road. The observed particle size of paved surface waste material shows that about 36% particles were less than 2.5 MUm and 52% were greater than 10 MUm, suggesting that dust is resuspendable and presents a health risk due to being respirable. Elemental analysis confirmed the presence of the toxic elements Cr, Ni, Cu, Zn, Pb, Sn, Sb, and Ba in waste material. Moreover, receptor models indicate that the waste material comprised of elements from tire wear (31%), mineral dust (27%), brake wear (17%), vehicle exhaust (14%), and coal (7%). The elemental contribution of coal is a location-specific source identified from principal component analysis and hierarchical cluster analysis, which originated spillage during transportation. The study illustrates the contributions of PM emission from the different road networks and the mechanism of exchange of waste materials. Microscopic observation of resuspension and transportation of road dust due to vehicular movement leads to advection mechanism at the roundabout and the paved road having unpaved shoulders. PMID- 30022227 TI - Spatial Distribution of Microcracks in Osteoarthritic Femoral Neck: Influence of Osteophytes on Microcrack Formation. AB - Osteophytes have been suggested to influence the bone mechanical properties. The aim of this study was to compare the microcrack density in osteophytes with that in the other parts of the osteoarthritic femoral neck (FN). The presence of microcracks was investigated in the ultra-distal FN and in the osteophytes in samples obtained during hip arthroplasty in 24 postmenopausal women aged 67 +/- 10 years. Furthermore, the 3D microarchitecture and the collagen crosslinks contents were assessed by high-resolution peripheral quantitative computed tomography and high-performance liquid chromatography, respectively. Osteophytes were present in the 24 FN, mainly at the level of the inferior quadrant. Microcracks were present in all FN with an average of 2.8 per sample. All observed microcracks were linear. The microcrack density (Cr.N/BV; #/mm2) was significantly higher in cancellous than in cortical bone (p = 0.004), whereas the microcrack length (Cr.Le, um) was significantly greater in cortical bone (p = 0.04). The collagen crosslinks ratio pyridinoline/deoxypyridinoline was significantly and negatively correlated with Cr.N/BV in the posterior (r' = - 0.68, p = 0.01) and inferior (r' = - 0.53, p = 0.05) quadrants. Microcracks were observed in seven osteophytes in seven patients. When microcracks were present in the osteophyte area, Cr.N/BV was also significantly higher in the whole FN and in the quadrant of the osteophyte compared to the cases without microcrack in the osteophyte (p < 0.03). In conclusion, in FN from hip osteoarthritis microcracks are present in all FNs but in only 23% of the osteophytes. The microcrack formation was greater and their progression was smaller in the cancellous bone than in the cortex. The spatial distribution of microcracks varied according to the proximity of the osteophyte, and suggests that osteophyte may influence microcrack formation related to changes in local bone quality. PMID- 30022228 TI - Deproteinization of Cortical Bone: Effects of Different Treatments. AB - Bone is a biological composite material having collagen and mineral as its main constituents. In order to better understand the arrangement of the mineral phase in bone, porcine cortical bone was deproteinized using different chemical treatments. This study aims to determine the best method to remove the protein constituent while preserving the mineral component. Chemicals used were H2O2, NaOCl, NaOH, and KOH, and the efficacy of deproteinization treatments was determined by thermogravimetric analysis and Raman spectroscopy. The structure of the residual mineral parts was examined using scanning electron microscopy. X-ray diffraction was used to confirm that the mineral component was not altered by the chemical treatments. NaOCl was found to be the most effective method for deproteinization and the mineral phase was self-standing, supporting the hypothesis that bone is an interpenetrating composite. Thermogravimetric analyses and Raman spectroscopy results showed the preservation of mineral crystallinity and presence of residual organic material after all chemical treatments. A defatting step, which has not previously been used in conjunction with deproteinization to isolate the mineral phase, was also used. Finally, Raman spectroscopy demonstrated that the inclusion of a defatting procedure resulted in the removal of some but not all residual protein in the bone. PMID- 30022229 TI - Identification of proteins regulated by acid adaptation related two component system HPK1/RR1 in Lactobacillus delbrueckii subsp. bulgaricus. AB - Lactobacillus delbrueckii subsp. bulgaricus is currently one of the most valuable lactic acid bacteria (LAB) and widely used in global dairy industry. The acid tolerance and adaptation ability of LAB is the key point of their survival and proliferation during fermentation process and in gastrointestinal tract of human body. Two component system (TCS) is one of the most important mechanisms to allow bacteria to sense and respond to changes of environmental conditions. TCS typically consists of a histidine protein kinase (HPK) and a corresponding response regulator (RR). Our previous study indicated a TCS (JN675228/JN675229) was involved in acid adaptation in L. bulgaricus. To reveal the role of JN675228 (HPK1)/JN675229 (RR1) in acid adaptation, the target genes of JN675228 (HPK1)/JN675229 (RR1) were identified by means of a proteomic approach complemented with transcription data in the present study. The results indicated that HPK1/RR1 regulated the acid adaptation ability of bacteria by means of many pathways, including the proton pump related protein, classical stress shock proteins, carbohydrate metabolism, nucleotide biosynthesis, DNA repair, transcription and translation, peptide transport and degradation, and cell wall biosynthesis, etc. To our knowledge, this is the first report with the effect of acid adaptation-related TCS HPK1/RR1 on its target genes. This study will offer experimental basis for clarifying the acid adaptation regulation mechanism of L. bulgaricus, and provide a theoretical basis for this bacterium in industry application. PMID- 30022230 TI - Higher failure rate of two-stage revision for infected knee arthroplasties in significantly compromised (host-C) patients. AB - PURPOSE: To evaluate clinical outcomes of two-stage revision arthroplasty for managing infected knee arthroplasties in significantly compromised patients (host C). METHODS: This was a prospective consecutive series of two-stage revisions of infected total knee arthroplasties in host-C-type patients with a minimum 2-year follow-up using objective and patient-reported outcome measures. Thirteen consecutive patients were included and prospectively followed with a median 5 year follow-up (range 2-10). Median age was 68 years (range 59-73) at time of initial presentation. All patients were type-C host using McPherson classification system. All patients had primary arthroplasties in situ with confirmed chronic infections; the infecting pathogens were Staphylococcus aureus in 5/13 patients, coagulase-negative Staphylococci in 5/13, and the remaining three patients had mixed growth. All patients underwent two-stage revision protocol. RESULTS: At the final follow-up, 9/13 patients were infection free achieving satisfactory outcomes. Two patients had recurrent infections with different organisms and treated with suppressive antibiotics and salvage knee arthrodesis, respectively. Furthermore, two patients had chronic pain and poor functional outcomes with deficient extensor mechanism and significant bone loss; later underwent salvage knee arthrodesis. The preoperative knee society score (median 35.5; range 22-51; n = 10) showed a statistically significant improvement at the final follow-up (median 79.5; range 49-87; n = 10) p < 0.05. Patients reported outcome scores at the final follow-up were WOMAC-knee (median 59.1; range 47.7-94.7; n = 13) and Oxford knee score (median 26; range 11 to 43; n = 13). CONCLUSION: This study highlights the challenge of treating infected knee arthroplasties in physiologically compromised patients with 9/13 (69%) having satisfactory clinical outcomes. LEVEL OF EVIDENCE: Case series, level IV. PMID- 30022231 TI - Comparison of field-of-view optimized and constrained undistorted single-shot diffusion-weighted imaging and conventional diffusion-weighted imaging of optic nerve and chiasma at 3T. AB - PURPOSE: Single-shot echo-planar imaging is the conventional diffusion-weighted imaging (C-DWI) sequence for evaluating orbital disease. However, its utility is restricted in small organs like the chiasma and optic nerve. This study was conducted to investigate the utility of field-of-view optimized and constrained undistorted single-shot diffusion-weighted imaging (FOCUS-DWI) for evaluating the chiasma and optic nerve in acute optic neuritis, making comparisons with C-DWI. METHODS: FOCUS-DWI and C-DWI were performed on 36 acute optic neuritis patients and 16 normal controls. Two readers assessed image quality using 5-point Likert scales. Differences in the visual assessments and apparent diffusion coefficient (ADC) values between C-DWI and FOCUS-DWI were evaluated. Inter-observer agreement in the qualitative data was assessed using Cohen's kappa coefficients. Inter- and intra-observer agreements in the ADC values were evaluated using intraclass correlation coefficients. RESULTS: FOCUS-DWI was superior to C-DWI in all aspects of the image evaluations. The Cohen's kappa coefficients for FOCUS-DWI were almost perfect (0.81-1) or substantial (0.61-0.80) for all the image quality categories. In the FOCUS-DWI images, the structural conspicuity of the chiasma and canalicular and cisternal segments was significantly superior on coronal views than on axial views (P < 0.0001). ROC analysis showed that in optic neuritis patients, the diagnostic value of ADC measurements on FOCUS-DWI was higher than ADC values measured on C-DWI. CONCLUSION: The FOCUS-DWI technique can provide substantial improvements over C-DWI for imaging different aspects of the optic nerve and chiasma. The coronal scan direction is more suitable than the axial scan direction for FOCUS-DWI. PMID- 30022233 TI - Aromatic formulas in ambient PM2.5 samples from Hong Kong determined using FT-ICR ultrahigh-resolution mass spectrometry. AB - Many aromatic compounds (e.g., polycyclic aromatic hydrocarbons (PAHs)) found in atmospheric aerosols are toxic and exist in both unsubstituted and substituted forms. Previous studies have mainly concentrated on investigating unsubstituted PAHs, leaving the substituted compounds largely uncharacterized. This study focuses on detection of both unsubstituted and substituted aromatics in ambient aerosol samples using ultrahigh-resolution mass spectrometry. Aerosol samples collected from roadside, urban, and suburban sites in Hong Kong were characterized by Fourier-transform ion cyclotron resonance mass spectrometry (FT ICR-MS) coupled with atmospheric pressure photoionization (APPI) or electrospray ionization (ESI). In the APPI+ mode, 166 aromatic CH formulas (i.e., formulas containing C and H only and with a double bond equivalent (DBE) of 4 or higher) were determined through molecular formula calculations based on an accurate m/z determination. Among the determined aromatic CH formulas, 141 are possible alkylated monocyclic aromatic hydrocarbon (MAH) or PAH formulas, and account for >= 45% of the total intensity by aromatic CH+ formulas. Both APPI+ and ESI+ are effective in detecting nitroaromatics (i.e., CHO2N1 formulas and DBE >= 5). The two ionization modes provide complementary formula coverage, with formulas determined by APPI+ extending to higher DBE and those by ESI+ covering higher carbon numbers. Alkylated nitrobenzene compounds are the most abundant among nitroaromatics, and they, together with alkylated nitro-PAHs, account for > 80% of the total intensity of aromatic CHO2N+ formulas, indicating the importance of these compounds in real aerosol samples. Aromatic CHN+ and CHO+ formulas are also determined, confirming the atmospheric presence of some previously reported O- and N-containing aromatic compounds and revealing new possible formulas. The determination of aromatic organic formulas in this study provides useful guidance for future quantitative analysis of hazardous aromatic compounds. Future work is needed to determine the abundance and to study the toxicity of alkylated MAHs and PAHs outside the 16 US EPA priority PAH compounds. Graphical abstract. PMID- 30022232 TI - Neuroprotective effect of vildagliptin against cerebral ischemia in rats. AB - Stroke is the leading cause of death worldwide. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of anti-diabetic drugs for treatment of type-2 diabetes mellitus. The aim of this study is to evaluate the possible neuroprotective effect of a dipeptidyl peptidase-4 inhibitor, vildagliptin, independent of its anti-diabetic properties in non-diabetic rats subjected to cerebral ischemia. Anesthetized Wistar rats were subjected to either left middle cerebral artery occlusion (MCAO) or sham operation followed by reperfusion after 30 min of MCAO. The other three groups were orally administered vildagliptin at 3 dose levels (2.5, 5, 10 mg/kg) for 3 successive weeks before subjected to left focal cerebral ischemia/reperfusion and till the end of the study. Neurological deficit scores and motor activity were assessed 24 h following reperfusion. Forty-eight hours following reperfusion, rats were euthanized and their left brain hemispheres were harvested and used in biochemical, histopathological, and immunohistochemical investigations. Vildagliptin pretreatment improved neurological deficit score, locomotor activity, and motor coordination in MCAO rats. Moreover, vildagliptin reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), phosphotylinosital 3 kinase (PI3K), phosphoryated of protein kinase B (p-AKT), and mechanistic target of rapamycin (mTOR) brain contents in addition to reducing protein expression of caspase-3. Also, vildagliptin showed a dose-dependent attenuation in neuronal cell loss and histopathological alterations in MCAO rats. This study proves that vildagliptin exerted a neuroprotective effect in a dose dependent manner as shown in the attenuation of the infarct area, neuronal cell loss, and histopathological damage in MCAO rats, which may be mediated by attenuating neuronal and motor deficits, its antioxidant property, activation of the PI3K/AKT/mTOR pathway, and its anti-apoptotic effect. PMID- 30022234 TI - Spectrofluorometric determination of berberine using a novel Au nanocluster with large Stokes shift. AB - Berberine hydrochloride (BHC), a natural isoquinoline alkaloid, is widely applied as a an agent in traditional Chinese medicine. Almost all the traditional methods for BHC detection require complicated preprocessing steps or expensive instruments. In this article, we report a simple, rapid, sensitive, and selective method for BHC detection using fluorescent gold nanoclusters (F-AuNCs) as the fluorescent probe with a large Stokes shift of 237 nm. The F-AuNCs prepared with citrate-stabilized stannous chloride and hydrogen tetrachloroaurate(III) as raw materials in an aqueous medium display strong and stable fluorescence at 566 nm. When F-AuNCs are mixed with BHC, the fluorescence of F-AuNCs is effectively quenched. Under optimized conditions, this method allows sensitive and selective measurements of BHC in a concentration ranging from 1.0 * 10-6 to 1.0 * 10-4 mol L-1 with a detection limit of 7.5 * 10-8 mol L-1, which is relatively low among reported spectral methods. This method provides excellent selectivity for the detection of BHC against inorganic anions and natural amino acids. In addition, the BHC content in two different types of berberine tablets was successfully determined by this method and the results showed high accuracy. Graphical Abstract ?. PMID- 30022235 TI - The long road home: are outcomes different for patients with sepsis? PMID- 30022236 TI - [Recording and assessment of medication errors : Experience of the Drug Commission of the German Medical Association]. AB - Adverse drug reactions (ADRs) are a common problem in daily clinical practice and they may in part result from medication errors. According to the extended interpretation in the new European pharmacovigilance guideline, medication error related reactions are classified as ADRs. Therefore, the pharmacovigilance system needs to be adjusted to record medication errors. As a partner in the German pharmacovigilance system, the Drug Commission of the German Medical Association (DCGMA) has set up a project for developing a subsystem for the recording and assessment of medication errors within the existing spontaneous reporting system for ADRs. The aim of the project was to evaluate the feasibility of recording and assessing medication errors within the existing structures and to investigate whether it is possible to deduce risk-reducing strategies from the information obtained by the case reports. In the present narrative review, the experience of the DCGMA with the recording and assessment of medication errors is described. The conclusions and recommendations from the analysis of the reports of medication errors show how they can be used to improve medication safety. The project has closed a gap in pharmacovigilance. PMID- 30022237 TI - [Medication safety in hospitals : Integration of clinical pharmacists to reduce drug-related problems in the inpatient setting]. AB - Drug-related problems (DRPs) are a significant and often preventable cause for morbidity and mortality. Hospitalization is associated with a high risk for DRPs, especially due to a lack of information transfer at transitions of care. At the same time, interventions during inpatient treatment usually require a change in drug therapy and additionally increase the risk of DRPs. Thereby, DRPs can occur at all levels of the medication process and can be caused by different groups of professionals. One way to improve medication safety in hospitals is to integrate clinical pharmacists into the medication process.According to available data, the integration of a clinical pharmacist in multi-professional teams during admission, hospitalization and discharge can significantly reduce DRPs, costs and increases efficacy of drug therapy. In addition, drug supply with unit-dose systems in combination with digitalization of the medication process can achieve an improvement in medication safety. Improvement in continuity of medical care through a structured medication review and seamless transmission of medically relevant information upon discharge contribute to a significant reduction of hospital readmissions and emergency admissions due to ABPs, as well as health costs. With a university education, the hospital pharmacist specialized in clinical pharmacy is the only professional group that can comprehensively support the physician in the field of drug therapy. PMID- 30022238 TI - First evidence of the presence of adenovirus type 8 in myocardium of patients with severe idiopathic dilated cardiomyopathy. AB - Previous studies have detected adenovirus and cytomegalovirus (CMV) in cardiac tissue of patients with myocarditis. Therefore, in this study, we investigated the frequency of these viruses, which may be involved in the development of severe dilated cardiomyopathy (DCM). Myocardial tissue from of 23 cardiac transplant candidates with acute idiopathic DCM below the age of 40 years were analyzed by amplification of adenovirus and CMV DNA and subsequent sequencing. Adenovirus was detected in four (17.4%) and CMV in one (4.3%) of the patients. All controls were negative for the presence of both viruses. Our study shows that myocardial infection with adenovirus may play an important role in the pathogenesis of severe DCM and suggests that vaccination against adenovirus might be helpful in decreasing the prevalence of severe idiopathic DCM. This is the first study in which adenovirus type 8 has been detected in the hearts of patients with DCM. PMID- 30022240 TI - Revision ACL reconstruction with autograft: long-term functional outcomes and influencing factors. AB - PURPOSE: To present the long-term functional outcomes of revision anterior cruciate ligament (ACL) reconstruction with autograft and factors that influence the outcomes. METHODS: Retrospective study of 51 consecutive revision ACL reconstructions performed using autograft under the care of a single surgeon with interference screw fixation. Bone-patellar tendon-bone graft was used in 35 (69%) and hamstring tendons in 16 (31%). The subjective IKDC activity level and Lysholm Knee functional scores were collected at mean follow-up of 9.0 years (range 5.17 14.75 years). RESULTS: Five (9.8%) had re-ruptured and one patient had a total knee replacement. Functional scores were available for 43 patients (84.3%). Twenty-eight had IKDC activity level I or II (65%), level III in 12 (28%) and level IV in 3 (7%). The average Lysholm score was 86.2 +/- 12.88, and there is a statistically significant relationship with age (95% CI: - 0.88, - 0.60) (P < 0.05). For each additional 10 years of age, there is a reduction of 5.18 points. No statistically significant effect of sex has been detected. The mean Lysholm score was lower in patients who had partial medial meniscectomy (77.33), although this was not statistically significant (P = 0.06). Regression analysis of the Lysholm score means by chondral damage category adjusted for age, showed that the Grade 3 or 4 group shows a reduction of about 25 points for every 10 years increase in age (95% CI; P = 0.05). CONCLUSION: Revision ACL reconstruction with autograft affords satisfactory long-term outcomes. Expectations should be carefully managed in patients with increasing age associated with severe chondral damage and previous medial meniscectomy. PMID- 30022239 TI - Genome characterization of the newly identified maize-associated totivirus Anhui. AB - Maize-associated totivirus Anhui (MATV-Ah) is a novel totivirus with a 5536-nt genome and two large ORFs that encode a putative coat protein (CP) and an RNA dependent RNA polymerase (RdRP). The two ORFs share amino acid identities of 32 and 56% when compared to other plant-associated totiviruses, respectively. Based on genome sequence similarity and phylogenetic analysis, MATV-Ah is proposed to be a member of the family Totiviridae genus Totivirus. PMID- 30022241 TI - Platelet-rich plasma injections for carpal tunnel syndrome: a systematic and comprehensive review. AB - A series of clinical trials focused on the use of ultrasound-guided platelet-rich plasma (PRP) infusions for the treatment of patients with carpal tunnel syndrome (CTS) were published over the last few years. However, the role of PRP for CTS remains unclear. We performed a systematic review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Two reviewers independently conducted the search using multiple databases: MEDLINE/PubMed, SCOPUS, Cochrane Database, and Web of Science. These databases were searched using terms "platelet" AND "rich" AND "plasma" AND "carpal" AND "tunnel". To maximize the search, backward chaining of references from retrieved papers was also undertaken. From the initial 19 studies, only five met our eligibility criteria. These articles included one randomized controlled double blind study, one randomized controlled single-blind study, one randomized controlled non-blind study, one case-control study, and one case report. The vast majority of the included studies supported that PRP infusion improved the clinical condition of the patients and that PRP infusion was beneficial for patients with mild-to-moderate CTS. Therefore, PRP seems to be an interesting alternative for the treatment of mild-to-moderate CTS which, still, has not been thoroughly investigated. However, despite the promising results of the present studies, PRP has to be further tested before we reach to a definite conclusion regarding its therapeutic value. PMID- 30022242 TI - Spatial grounding of symbolic arithmetic: an investigation with optokinetic stimulation. AB - Growing evidence suggests that mental calculation might involve movements of attention along a spatial representation of numerical magnitude. Addition and subtraction on nonsymbolic numbers (numerosities) seem to induce a "momentum" effect, and have been linked to distinct patterns of neural activity in cortical regions subserving attention and eye movements. We investigated whether mental arithmetic on symbolic numbers, a cornerstone of abstract mathematical reasoning, can be affected by the manipulation of overt spatial attention induced by optokinetic stimulation (OKS). Participants performed additions or subtractions of auditory two-digit numbers during horizontal (experiment 1) or vertical OKS (experiment 2), and eye movements were concurrently recorded. In both experiments, the results of addition problems were underestimated, whereas results of subtractions were overestimated (a pattern that is opposite to the classic Operational Momentum effect). While this tendency was unaffected by OKS, vertical OKS modulated the occurrence of decade errors during subtractions (i.e., fewer during downward OKS and more frequent during upward OKS). Eye movements, on top of the classic effect induced by OKS, were affected by the type of operation during the calculation phase, with subtraction consistently leading to a downward shift of gaze position and addition leading to an upward shift. These results highlight the pervasive nature of spatial processing in mental arithmetic. Furthermore, the preeminent effect of vertical OKS is in line with the hypothesis that the vertical dimension of space-number associations is grounded in universal (physical) constraints and, thereby, more robust than situated and culture dependent associations with the horizontal dimension. PMID- 30022243 TI - We do as we construe: extended behavior construed as one task is executed as one cognitive entity. AB - We select and execute extended task episodes ('make tea') as one entity and not individually execute their very many components (find kettle, boil water, etc.). Such hierarchical execution is thought to occur in familiar task situations with pre-existing task episode-related scripts that once selected, control the identity and sequence of component steps. Here, in contrast, we show hierarchical execution of extended behavior in situations, where the identity and sequence of component steps were unknown and a predetermined script could not have existed. Participants performed a rule-switching task in which the rule to be applied on each trial could not be predicted. Crucially, they were biased into construing a recurring instance of three or five trials as a single task episode. Behavioral signs of hierarchical execution, identical to those seen during memorized task sequence executions, were present. These included longer reaction time on the first trial of each episode that was proportionate to the length of that episode, and absence of rule switch costs only between those consecutive trials that crossed episode boundaries. Hierarchical execution thus occurs every time the to be-executed behavior is construed as one task episode, and is not limited to predictable sequences. We suggest that hierarchical execution occurs because task episodes are controlled and executed through goal-related entities assembled at the beginning of execution that subsume the execution and instantiate purposive control across time until the goal is complete. PMID- 30022244 TI - The effects of inpatient versus outpatient spa therapy on pain, anxiety, and quality of life in elderly patients with generalized osteoarthritis: a pilot study. AB - This study aimed to investigate the effect of inpatient vs outpatient spa therapy on pain, quality of life, and anxiety in elderly patients with generalized osteoarthritis. A total of 150 patients were randomized into three groups. Group I was given medical treatment, group II was treated as outpatients, and group III was treated as inpatient spa therapy. Assessments were made using the Pain (VAS), EQ-5D-3L Scale, and State and Trait Anxiety Inventory (STAI) at the beginning of treatment (W0), at the end of treatment (W2), and at the fourth week after treatment (W6). The comparison of outpatient spa group and etodolac treatment group showed that outpatient spa group was superior to etodolac treatment group in all evaluated parameters at W2 vs W0 and W6 vs W0. The comparison of inpatient spa group and etodolac treatment group showed that inpatient spa group was superior to etodolac treatment group in all evaluated parameters at W2 vs W0 and W6 vs W0. The comparison of inpatient spa group and outpatient spa group showed that inpatient spa group was superior to outpatient spa group in all evaluated parameters except STAI-TXII at W2 vs W0 and in all evaluated parameters W6 vs W0. Spa therapy, either as an outpatient or inpatient basis, may have a positive effect on pain, anxiety, and quality of life in geriatric patients with generalized osteoarthritis. The inpatient spa therapy may be more beneficial than outpatient spa therapy. When the side effects of drug treatments are emphasized, spa therapy may be considered as an interesting option for elderly with osteoarthritis. PMID- 30022246 TI - FGF-2 combined with bilayer artificial dermis composed of collagen matrix prompts generation of fat pad in subcutis of mice. AB - Fibroblast growth factor (FGF)-2 induces mitogenesis, angiogenesis and adipogenesis. In this study, the adipogenesis-inducing effects of FGF-2 combined with bilayer artificial dermis in mice were evaluated. FGF-2-impregnated bilayer artificial dermis composed of collagen matrix, PELNAC (Gunze Corp., Osaka, Japan) was implanted subcutaneously into the thoracic region of mice. At 1, 2, 3, and 4 weeks, samples were collected for H&E staining, von Willebrand factor immunostaining, and perilipin immunostaining to examine adipose tissue localization and angiogenesis. The collagen matrix-implanted group without the addition of FGF-2 was prepared as a control. At 2 weeks after the implantation of FGF-2 combined with dermal substitutes, adipocytes appeared in the collagen fibers. At 3-4 weeks, a fat pad was generated with neovascularization. The thickness of the fat pad had significantly increased at 2, 3, and 4 weeks. The remaining collagen was decreased by absorption over time. In the control group, no fat pad was newly formed. This study has identified a promising method to enhance adipogenic effects in the murine subcutis, representing a potential technique for soft tissue reconstruction. PMID- 30022245 TI - The complete genome sequence of Rhodobaca barguzinensis alga05 (DSM 19920) documents its adaptation for life in soda lakes. AB - Soda lakes, with their high salinity and high pH, pose a very challenging environment for life. Microorganisms living in these harsh conditions have had to adapt their physiology and gene inventory. Therefore, we analyzed the complete genome of the haloalkaliphilic photoheterotrophic bacterium Rhodobaca barguzinensis strain alga05. It consists of a 3,899,419 bp circular chromosome with 3624 predicted coding sequences. In contrast to most of Rhodobacterales, this strain lacks any extrachromosomal elements. To identify the genes responsible for adaptation to high pH, we compared the gene inventory in the alga05 genome with genomes of 17 reference strains belonging to order Rhodobacterales. We found that all haloalkaliphilic strains contain the mrpB gene coding for the B subunit of the MRP Na+/H+ antiporter, while this gene is absent in all non-alkaliphilic strains, which indicates its importance for adaptation to high pH. Further analysis showed that alga05 requires organic carbon sources for growth, but it also contains genes encoding the ethylmalonyl-CoA pathway for CO2 fixation. Remarkable is the genetic potential to utilize organophosphorus compounds as a source of phosphorus. In summary, its genetic inventory indicates a large flexibility of the alga05 metabolism, which is advantageous in rapidly changing environmental conditions in soda lakes. PMID- 30022247 TI - Letter to the Editor concerning "Minimally invasive surgery procedure in isthmic spondylolisthesis" by F.C. Tamburrelli et al. (Eur Spine J; 2018: doi:10.1007/s00586-018-5627-8). PMID- 30022249 TI - NaPi-IIa interacting partners and their (un)known functional roles. AB - The sorting and stabilization of proteins at specific subcellular domains depend upon the formation of networks build up by specific protein-protein interactions. In addition, protein networks also ensure the specificity of many regulatory processes by bringing together regulatory molecules with their targets. Whereas the success on the identification of protein-protein interactions is (up to a point) technology-driven, the assignment of functional roles to specific partners remains a major challenge. This review summarizes the work that led to the identification of partners of the Na+/phosphate cotransporter NaPi-IIa as well as the effects of the interactions in the expression and/or regulation of the cotransporter. PMID- 30022248 TI - SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. AB - PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI. PMID- 30022250 TI - White matter tract anatomy in the rhesus monkey: a fiber dissection study. AB - Brain connectivity in non-human primates (NHPs) has been mainly investigated using tracer techniques and functional connectivity studies. Data on structural connections are scarce and come from diffusion tensor imaging (DTI), since gross anatomical white matter dissection studies in the NHP are lacking. The current study aims to illustrate the course and topography of the major white matter tracts in the macaque using Klingler's fiber dissection. 10 hemispheres obtained from 5 primate brains (Macaca mulatta) were studied according to Klingler's fiber dissection technique. Dissection was performed in a stepwise mesial and lateral fashion exposing the course and topography of the major white matter bundles. Major white matter tracts in the NHP include the corona radiata, tracts of the sagittal stratum, the uncinate fasciculus, the cingulum and the fornix. Callosal fiber topography was homologous to the human brain with leg motor fibers running in the posterior half of the corpus callosum. The relative size of the anterior commissure was larger in the NHP. NHPs and humans share striking homologies with regard to the course and topography of the major white matter tracts. PMID- 30022251 TI - Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons. AB - Brain-derived neurotrophin factor (BDNF) has been implicated in neuronal survival, differentiation and activity-dependent synaptic plasticity in the central nervous system. It was suggested that during postnatal development BDNF regulates neuronal architecture and spine morphology of neurons within certain brain areas but not others. Particularly striking are the differences between striatum, cortex and hippocampus. Whether this is due to region- or cell type specific effects is so far not known. We address this question using conditional bdnf knock-out mice to analyze neuronal architecture and spine morphology of pyramidal cortical and hippocampal neurons as well as inhibitory neurons from these brain areas and excitatory granule neurons from the dentate gyrus. While hippocampal and cortical inhibitory neurons and granule cells of the dentate gyrus are strongly impaired in their architecture, pyramidal neurons within the same brain regions only show a mild phenotype. We found a reduced TrkB phosphorylation within hippocampal interneurons and granule cells of the dentate gyrus, accompanied by a significant decrease in dendritic complexity. In contrast, in pyramidal neurons both TrkB phosphorylation and neuronal architecture are not altered. The results suggest diverse levels of responsiveness to BDNF for different hippocampal and cortical neuronal populations within the same brain area. Among the possible mechanisms mediating these differences in BDNF function, we tested whether zinc might be involved in TrkB transactivation specifically in pyramidal neurons. We propose that a BDNF independent transactivation of TrkB receptor may be able to compensate the lack of BDNF signaling to modulate neuronal morphology in a cell type-specific manner. PMID- 30022252 TI - Application of autologous serum eye drops after pterygium surgery: a prospective study. AB - PURPOSE: The study aims to determine the effect of 50% autologous serum drops (ASD) on corneal healing and patient comfort following pterygium surgery. METHODS: Fifty eyes of 50 patients who underwent pterygium excision combined with autologous conjunctival graft were included in this prospective randomized study: in 25 eyes, 50% ASD. In the remaining 25 eyes, conventional artificial tears (CAT) were applied postoperatively until corneal epithelium had completely epithelialized. Corneal epithelium healing speed, visual analog scale (VAS) for postoperative pain assessment, conjunctival inflammation, and recurrences were evaluated. Patients were followed up for 6 months. RESULTS: Mean corneal epithelium closure time was 3.16 +/- 0.37 days (range 3 and 4 days) in ASD group and 4.96 +/- 0.84 days in CAT group (range 4 and 6 days), and the difference was statistically significant (p < 0.001). VAS scores were significantly lower in ASD group than CAT group in the first 5 days after surgery. In 9 of 50 eyes, moderate conjunctival inflammation continued 1 month: 4 (16%) in ASD group and 5 (20%) in CAT group (p = 0.713). In total, pterygium recurrence was seen in 5 (10%) eyes: 2 eyes (8%) in ASD group and 3 eyes (12%) in CAT group (p = 0.637). CONCLUSION: ASD accelerated corneal epithelial healing following pterygium surgery. ASD group had lesser pain that was seem to be related with accelerated corneal epithelial healing. PMID- 30022254 TI - Medication persistence and risk of fracture among female Medicare beneficiaries diagnosed with osteoporosis. AB - : We examined the relationship between persistent osteoporosis medication use and fracture risk among female Medicare beneficiaries diagnosed with osteoporosis using Medicare claims, 2009-2012. Persistent use was associated with reduced risk of fracture and significantly lower total health care costs in the follow-up period. Results were consistent using different analytical methods. INTRODUCTION: This study aimed to examine the relationship between medication persistence and fracture risk among female Medicare beneficiaries diagnosed with osteoporosis. METHODS: Elderly female Medicare beneficiaries diagnosed with osteoporosis and initiated on osteoporosis medication January 1, 2009-June 30, 2011, were included. Persistent medication use was defined as continuous use (no gap >= 60 days) for 1 year or longer. The key outcome was fragility fracture. A difference in-difference analysis was performed at the log scale of fracture rate using a Poisson regression model with months 1-6 before medication initiation as the pre initiation period and up to 18 months after as the post-initiation period. Total health care costs were compared using a similar approach. Sensitivity analyses were conducted using different pre- and post-initiation periods. RESULTS: The study included 294,369 patients; 32.9% were persistent osteoporosis medication users and 67.1% non-persistent (< 12 months continuous use). Fracture incidence rates were 16.2 per 100 patient-years pre-initiation and 4.1 post-initiation for persistent users; corresponding rates for non-persistent users were 19.0 and 7.3 per 100 patient-years. The adjusted post-/pre-initiation fracture rate ratios were 0.284 for persistent and 0.411 for non-persistent users. The ratio of the two rate ratios was 0.692 (persistent vs. non-persistent, p < 0.0001), suggesting a significantly greater fracture rate reduction for persistent users. Adjusted cost ratios were significantly lower for persistent users. Sensitivity analyses results were similar. CONCLUSIONS: Persistent use of osteoporosis medications was associated with reduced risk of fracture and significantly lower total health care costs. Payers and patients would benefit from interventions aimed at improving medication persistence. PMID- 30022253 TI - VITamin D and OmegA-3 TriaL (VITAL) bone health ancillary study: clinical factors associated with trabecular bone score in women and men. AB - : We investigated the association of clinical variables with TBS at baseline in the bone health sub-cohort of the VITamin D and OmegA-3 TriaL (VITAL). Lower TBS was associated with female sex, aging, BMI >= 25 kg/m2, SSRI use, high alcohol intake, and presence of diabetes; there was a trend towards significance between lower TBS and history of fragility fractures. INTRODUCTION: We investigated whether TBS differs by sex, race, body mass index (BMI), and other clinical variables. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is determining effects of vitamin D3 and/or omega-3 fatty acid (FA) supplements in reducing risks of cancer and cardiovascular disease. In the VITAL: Effects on Bone Structure/Architecture ancillary study, effects of these interventions on bone will be investigated. Here, we examine the associations of clinical risk factors with TBS assessments at baseline in the bone health sub-cohort, comprised of 672 participants (369 men and 303 women), mean (+/- SD) age 63.5 +/- 6.0 years; BMI <= 37 kg/m2, no bisphosphonates within 2 years or other bone active medications within 1 year. RESULTS: TBS was greater in men than women (1.311 vs. 1.278, P < 0.001) and lower with elevated BMIs (P < 0.001), higher age (P = 0.004), diabetes (P = 0.008), SSRI use (P = 0.044), and high alcohol intake (P = 0.009). There was a trend for history of fragility fractures (P = 0.072), and lower TBS. TBS did not vary when analyzed by race, smoking, history of falls, and multivitamin or caffeine use. CONCLUSIONS: Lower TBS was associated with female sex, aging, BMI >= 25 kg/m2, SSRI use, alcohol use, and presence of diabetes; there was a trend between lower TBS and history of fragility fractures. TBS may be useful clinically to assess structural changes that may be associated with fractures among patients who are overweight or obese, those on SSRIs, or with diabetes. Ongoing follow-up studies will clarify the effects of supplemental vitamin D3 and/or FA's on TBS and other bone health measures. TRIAL REGISTRATION: NCT01747447. PMID- 30022255 TI - Effort-reward imbalance among students at German universities: associations with self-rated health and mental health. AB - PURPOSE: Although psychosocial stress has been associated with adverse health parameters, little is known about this topic among the variety of university students. We thus examined associations of psychosocial stress due to academic education with self-rated health, and symptoms of depression and anxiety among students from various study disciplines. METHODS: We used data from the Nutrition and Physical Activity (NuPhA) Study, a cross-sectional online survey among students enrolled across German universities (n = 698). Academic stress was assessed by a newly developed and validated student version of the Effort-Reward Imbalance (ERI-Student) Questionnaire. Depressive and anxiety symptoms were measured by applying the Patient Health Questionnaire-4 (PHQ-4) and using validated cut-offs. RESULTS: Separate multivariate logistic regression analyses run for the different ERI components, the ERI-ratio revealed that high effort, low reward, high over-commitment, and a high ERI-ratio were associated with poor self-rated health, and depressive and anxiety symptoms (odds ratios >= 2.43). Separate analyses for medical students and non-medical students largely confirmed these findings for both groups. Associations between all ERI components, the ERI ratio, and both mental health measures were, however, more pronounced among medical students. CONCLUSIONS: We were able to show consistent associations between the ERI-Student Questionnaire and self-rated health and mental health across students from different study disciplines. Further research on associations between academic stress and health parameters is necessary to develop effective strategies that prevent students from adverse health outcomes during their academic education. PMID- 30022256 TI - [Pilot study: Determination of the subjective trunk vertical in upright head position]. AB - BACKGROUND: Consensus has been established that the subjective vertical (SV) is a result of multimodal sensory integration. In order to be able to calculate the vestibulocervical sensory competence for the SV, the isolated subjective trunk vertical axis (STV) was measured under conditions of vertical head fixation. MATERIALS AND METHODS: Young, healthy volunteers (n = 49) were compared to older, healthy volunteers (n = 50) on a three-dimensionally deflectable (tilt, torsion, pitch) trunk excursion chair in which the volunteer's head remains in an upright position. Another young, healthy group was divided into a placebo (n = 27) and a monophasic cervical transcutaneous electrical nerve stimulation (C-TENS; n = 22) group to examine verticality perception. RESULTS: In the STV after trunk pitch, age was a significant variable (p = 0.021). The older, healthy group of subjects missed the physical vertical by an average of 1.8 degrees more than the younger group. Only the placebo group showed an average improvement in STV of 4.3 degrees after torsion. CONCLUSION: Apart from the macular organs the vestibulocervical sensory afference is involved in finding the trunk vertical. A difference in age to the disadvantage of the older healthy subjects was observed, as well as a lack of learning success after applied C-TENS. The presented pilot study was able to confirm that a correct vertical trunk sensation is caused by vestibulocervical sensory afference in upright head position. PMID- 30022257 TI - Influence of hearing on vestibulospinal control in healthy subjects. AB - BACKGROUND: Balance control is based on multisensory interaction. In addition to vestibular, proprioceptive and visual information, it seems that auditory input also plays an important role. OBJECTIVES: The aim of the study was to investigate the effect of hearing on vestibulospinal coordination and to obtain deeper knowledge about mechanisms of audiovestibular interaction. MATERIALS AND METHODS: In normal hearing, healthy subjects who performed the Unterberger (Fukuda) stepping test with and without frontal presentation of noise, the distance of displacement, the angle of displacement and the angle of rotation were measured by means of ultrasound based cranio-corpo-graphy (CCG). Additionally, subjective estimation of the effect of auditory input was compared to objective test results. RESULTS: In the noise condition, there was a significant improvement in the distance of displacement (mean with noise 66.9 cm+/- 33.5 standard deviation, SD, mean without noise 77.0 cm+/-32.7 SD, p< 0.001) and in the angle of rotation (mean with noise 14.2 degrees +/- 10.1 SD, mean without noise 28.3 degrees +/- 20.2 SD, p< 0.001), while no difference was found within the conditions regarding the angle of displacement (mean with noise 29.1 degrees +/- 33.5 SD, mean without noise 30.0 degrees +/- 34.0 SD, p= 0.641). Side-specific analysis revealed a positive correlation between angle of displacement and angle of rotation in the condition without noise (Spearman r = 0.441, p< 0.001). The rate of agreement between subjective estimation of noise influence and objective test results ranged between only 43% and 63%, depending on the question and endpoint. CONCLUSION: Hearing had a clearly beneficial effect of auditory inputs on vestibulospinal coordination, especially for distance of displacement and angle of rotation. PMID- 30022258 TI - A comprehensive institutional overview of intrathecal nusinersen injections for spinal muscular atrophy. AB - BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder resulting in progressive muscle weakness. In December 2016, the U.S. Food and Drug Administration approved the first treatment for SMA, a drug named nusinersen (Spinraza) that is administered intrathecally. However many children with SMA have neuromuscular scoliosis or spinal instrumentation resulting in challenging intrathecal access. Therefore alternative routes must be considered in these complex patients. OBJECTIVE: To investigate routes of drug access, we reviewed our institutional experience of administering intrathecal nusinersen in all children with spinal muscular atrophy regardless of spinal anatomy or instrumentation. MATERIALS AND METHODS: We reviewed children with SMA who were referred for intrathecal nusinersen injections from March to December 2017 at our institution. In select children with spinal hardware, spinal imaging was requested to facilitate pre-procedure planning. Standard equipment for intrathecal injections was utilized. All children were followed up by their referring neurologist. RESULTS: A total of 104 intrathecal nusinersen injections were performed in 26 children with 100% technical success. Sixty procedures were performed without pre-procedural imaging and via standard interspinous technique. The remaining 44 procedures were performed in 11 complex (i.e. neuromuscular scoliosis or spinal instrumentation) patients requiring pre-procedural imaging for planning purposes. Nineteen of the 44 complex procedures were performed via standard interspinous technique from L2 to S1. Twenty-two of the 44 complex procedures were performed using a neural-foraminal approach from L3 to L5. Three of the 44 complex procedures were performed via cervical puncture technique. There were no immediate or long-term complications but there was one child with short-term complications of meningismus and back pain at the injection site. CONCLUSION: Although we achieved 100% technical success in intrathecal nusinersen administration, our practices evolved during the course of this study. As a result of our early experience we developed an algorithm to assist in promoting safe and effective nusinersen administration in children with spinal muscular atrophy regardless of SMA type, abnormal spinal anatomy and complex spinal instrumentation. PMID- 30022259 TI - Ultrasound diagnosis of tracheal cartilaginous sleeve in a patient with Pfeiffer syndrome. AB - There is an association between tracheal cartilaginous sleeve and syndromic craniosynostosis. We present a case of tracheal cartilaginous sleeve diagnosed by ultrasound (US) in a patient with Pfeiffer syndrome. The patient developed respiratory failure and was suspected at bronchoscopy to have tracheal cartilaginous sleeve. US performed before tracheostomy placement demonstrated continuous hypoechoic cartilage along the anterior surface of the trachea, confirming the diagnosis. Our report shows that US can make a definitive diagnosis of tracheal cartilaginous sleeve and raises the possibility of using US to screen for the condition in patients with syndromic craniosynostosis without the need for anesthesia or ionizing radiation. PMID- 30022260 TI - Expectation of movement generates contrasting changes in multifinger synergies in young and older adults. AB - Anticipatory synergy adjustment (ASA) is a feed-forward control mechanism that describes a continuous decrease in the stability of the current motor state beginning about 150 ms prior to a state transition. Recently, we described an associated phenomenon in which the system stability was reduced solely in response to a cue that generates an expectation of a state change, independent of whether the state change actually occurs. Both phenomena are of the same kind (stability reduction), but evoked by distinct antecedent conditions. Since, logically, cuing for movement must occur before the initiation of that movement, we named this new phenomenon 'Stage-1 ASA' and rechristened the well-established version 'Stage-2 ASA'. Here, we used a four-finger, isometric force production task to explore (1) the effect of healthy aging on Stage-1 ASA, and (2) if Stage 1 ASA resulted in a more rapid state change. Young and older adult participants produced 10% of their maximal force when they did not expect to produce any change in the force, and when they expected to change their force in an unknown direction and at an unknown time. In the latter condition, the 10% constant-force phase was followed by a choice reaction time task, in which the participants rapidly changed their force to follow a moving target presented on a computer monitor. Both young and older adults displayed equivalent amount of Stage-1 ASA. This was driven by a 42% reduction in finger-force variability in young adults. In contrast, it was driven by a 38% increase in finger-force variability in older adults. We speculate that the reduction in finger force variability assists the young adults in rapid state changes via two mechanisms: (1) the finger forces occupy a restricted set of states that are optimal for quick state transitions, and (2) lower variability during steady state translates into lower self-motion during state transition. Self-motion is the covariation between finger forces that fails to change the total force. The older adults are unable to adopt this strategy, and the increase in finger-force variability arises from (1) the adoption of an alternative strategy of destabilizing the attractor associated with the current state to facilitate state transitions and (2) the inability to coordinate multiple finger forces. Finally, older adults displayed longer reaction times than young adults, but a clear relation between Stage-1 ASA and consequent behavioral benefit in terms of reduced reaction time remained elusive. PMID- 30022261 TI - Anticancer potential of rosmarinic acid and its improved production through biotechnological interventions and functional genomics. AB - Rosmarinic acid (RA) is a highly valued natural phenolic compound that is very commonly found in plants of the families Lamiaceae and Boraginaceae, including Coleus blumei, Heliotropium foertherianum, Rosmarinus officinalis, Perilla frutescens, and Salvia officinalis. RA is also found in other members of higher plant families and in some fern and horned liverwort species. The biosynthesis of RA is catalyzed by the enzymes phenylalanine ammonia lyase and cytochrome P450 dependent hydroxylase using the amino acids tyrosine and phenylalanine. Chemically, RA can be produced via methods involving the esterification of 3,4 dihydroxyphenyllactic acid and caffeic acid. Some of the derivatives of RA include melitric acid, salvianolic acid, lithospermic acid, and yunnaneic acid. In plants, RA is known to have growth-promoting and defensive roles. Studies have elucidated the varied pharmacological potential of RA and its derived molecules, including anticancer, antiangiogenic, anti-inflammatory, antioxidant, and antimicrobial activities. The demand for RA is therefore, very high in the pharmaceutical industry, but this demand cannot be met by plants alone because RA content in plant organs is very low. Further, many plants that synthesize RA are under threat and near extinction owing to biodiversity loss caused by unscientific harvesting, over-collection, environmental changes, and other inherent features. Moreover, the chemical synthesis of RA is complicated and expensive. Alternative approaches using biotechnological methodologies could overcome these problems. This review provides the state of the art information on the chemistry, sources, and biosynthetic pathways of RA, as well as its anticancer properties against different cancer types. Biotechnological methods are also discussed for producing RA using plant cell, tissue, and organ cultures and hairy-root cultures using flasks and bioreactors. The recent developments and applications of the functional genomics approach and heterologous production of RA in microbes are also highlighted. This chapter will be of benefit to readers aiming to design studies on RA and its applicability as an anticancer agent. PMID- 30022262 TI - Comprehensive analyses of functional bacteria and genes in a denitrifying EGSB reactor under Cd(II) stress. AB - A bench-scale expanded granular sludge bioreactor (EGSB) was continuously operated to treat synthesized high-nitrate industrial wastewater with increasing bivalent cadmium (Cd(II)) stress. The bioreactor showed nearly complete nitrate removal regardless of Cd(II) loadings, while nitrite accumulated in the effluent when influent Cd(II) loading was over 64 mg/L. Mi-seq sequencing of 16S rRNA gene amplicons elucidated that denitrifiers had decreasing abundances while biodiversity showed increasing trend as the Cd(II) loading increased. In the bioreactor, genera Halomonas, Thauera, Pseudomonas, and Zoogloea played major roles in the denitrification under lower Cd(II) loadings (< 32 mg/L), while Halomonas sp. KM-1 and Halomonas sp. BC04 acted as the crucial Cd-resistant denitrifiers under 128 mg/L Cd(II) loading. Metagenomic analyses and real-time quantitative PCR consistently indicated that napA encoding nitrate reductase was the predominant denitrifying gene, that could be mainly functioning on the efficient nitrate removal. Statistical analyses revealed the significantly positive correlation between Halomonas and nirS gene, both of which were functionally responsible for nitrite reduction. The obtained results may be practically useful for regulation and optimization of the biological processes to treat industrial wastewater containing high levels of nitrate and Cd(II). PMID- 30022263 TI - Immune responses induced by recombinant Lactobacillus plantarum expressing the spike protein derived from transmissible gastroenteritis virus in piglets. AB - Transmissible gastroenteritis coronavirus (TGEV) is one of the most severe threats to the swine industry. In this study, we constructed a suite of recombinant Lactobacillus plantarum with surface displaying the spike (S) protein coming from TGEV and fused with DC cells targeting peptides (DCpep) to develop an effective, safe, and convenient vaccine against transmissible gastroenteritis. Our research results found that the recombinant Lactobacillus plantarum (NC8 pSIP409-pgsA-S-DCpep) group expressing S fused with DCpep could not only significantly increase the percentages of MHC-II+CD80+ B cells and CD3+CD4+ T cells but also the number of IgA+ B cells and CD3+CD4+ T cells of ileum lamina propria, which elevated the specific secretory immunoglobulin A (SIgA) titers in feces and IgG titers in serum. Taken together, these results suggest that NC8 pSIP409-pgsA-S-DCpep expressing the S of TGEV fused with DCpep could effectively induce immune responses and provide a feasible original strategy and approach for the design of TGEV vaccines. PMID- 30022264 TI - Perfluoroalkyl acid exposure induces protective mitochondrial and endoplasmic reticulum autophagy in lung cells. AB - Wide application of perfluoroalkyl acids (PFAAs) has raised great concerns on their side-effects on human health. PFAAs have been shown to accumulate mainly in the liver and cause hepatotoxicity. However, PFAAs can also deposit in lung tissues through air-borne particles and cause serious pulmonary toxicity. But the underlying mechanisms are still largely unknown. Autophagy is a type of programmed cell death parallel to necrosis and apoptosis, and may be involved in the lung toxicity of PFAAs. In this study, lung cancer cells, A549, were employed as the model to investigate the effects of three PFAAs with different carbon chain lengths on cell autophagy. Through Western blot analysis on LC3-I/II ratio of cells exposed to non-cytotoxic concentration (200 uM) and cytotoxic concentration (350 uM), we found concentration-dependent increase of autophagosomes in cells, which was further confirmed by TEM examination on ultra thin section of cells and fluorescence imaging on autophagosomes in live cells. The abundance of p62 increased with the PFAAs concentration indicating the blockage of autophagy flux. Furthermore, we identified the mitochondrial autophagy (mitophagy) and endoplasmic reticulum autophagy (ER-phagy) morphologically as the major types of autophagy, suggesting the disruption on mitochondria and ERs. These organelle damages were confirmed by the overgeneration of ROS, hyperpolarization of mitochondrial membrane potential, as well as the up-regulation of ER-stress-related proteins, ATF4 and p-IRE1. Further analysis on the signaling pathways showed that PFAAs activated the MAPK pathways and inhibited the PI3K/Akt pathway, with potencies following the order of PFDA > PFNA > PFOA. Anti-oxidant (NAC) treatment did not rescue cells from death, indicating that oxidative stress is not the reason of cytotoxicity. Inhibition of autophagy by Atg5 siRNA and chloroquine even increased the toxicity of PFAAs, suggesting that PFAAs-autophagy was induced as the secondary effects of organelle damages and played a protective role during cell death. PMID- 30022265 TI - Flavobacterium knui sp. nov., a novel member of the family Flavobacteriaceae. AB - A Gram-stain negative, non-motile, rod-shaped bacterial strain, designated 2-56T, was isolated from water and characterized taxonomically using a polyphasic approach. Comparative 16S rRNA gene sequence analysis showed that strain 2-56T belongs to the family Flavobacteriaceae in the phylum Bacteroidetes and is closely related to Flavobacterium paronense KNUS1T (98.4%) and Flavobacterium collinsense 4-T-2T (96.7%). The G + C content of the genomic DNA of strain 2-56T was 33.4 mol%. The isolate contained MK-6 as the predominant respiratory quinone, and iso-C15:1 G (15.9%), iso-C15:0 (15.8%), iso-C17:0 3-OH (10.7%), and iso-C15:0 3-OH (9.6%) were the major fatty acids. The major polar lipids were phosphatidylethanolamine and an unidentified lipid. The phenotypic and chemotaxonomic data support the affiliation of strain 2-56T with the genus Flavobacterium. However, the DNA-DNA relatedness between the isolate and F. paronense and F. collinsense were 35.7 and 21.5%, respectively, clearly showing that strain 2-56T is not related to them at the species level. Strain 2-56T could be clearly differentiated from its close neighbours on the basis of its phenotypic, genotypic and chemotaxonomic features. Therefore, strain 2-56T represents a novel species of the genus Flavobacterium, for which the name Flavobacterium knui sp. nov. is proposed. The type strain is 2-56T (= KCTC 62061T = JCM 32247T). PMID- 30022266 TI - To guide or to follow? Teaching visual problem solving at the workplace. AB - Visual problem solving is essential to highly visual and knowledge-intensive professional domains such as clinical pathology, which trainees learn by participating in relevant tasks at the workplace (apprenticeship). Proper guidance of the visual problem solving of apprentices by the master is necessary. Interaction and adaptation to the expertise level of the learner are identified as key ingredients of this guidance. This study focuses on the effect of increased participation of the learner in the task on the interaction and adaptation of the guidance by masters. Thirteen unique dyads consisting of a clinical pathologist (master) and a resident (apprentice) discussed and diagnosed six microscope images. Their dialogues were analysed on their content. The dyads were divided in two groups according to the experience of the apprentice. For each dyad, master and apprentice both operated the microscope for half of the cases. Interaction was operationalised as the equal contribution of both master and apprentice to the dialogue. Adaptation was operationalised as the extent to which the content of the dialogues was adapted to the apprentice's level. The main hypothesis stated that the interaction and adaptation increase when apprentices operate the microscope. Most results confirmed this hypothesis: apprentices contributed more content when participating more and the content of these dialogues better reflected expertise differences of apprentices. Based on these results, it is argued that, for learning visual problem solving in a visual and knowledge-intensive domain, it is not only important to externalise master performance, but also that of the apprentice. PMID- 30022267 TI - Correction to: A hypergravity environment increases chloroplast size, photosynthesis, and plant growth in the moss Physcomitrella patens. AB - The original article can be found online. PMID- 30022268 TI - Correction to: Space-time analysis of gravitropism in etiolated Arabidopsis hypocotyls using bioluminescence imaging of the IAA19 promoter fusion with a destabilized luciferase reporter. AB - The article Space-time analysis of gravitropism in etiolated Arabidopsis hypocotyls using bioluminescence imaging of the IAA19 promoter fusion with a destabilized luciferase reporter, written by Kotaro T. Yamamoto, Masaaki K. Watahiki, Jun Matsuzaki, Soichirou Satoh and Hisayo Shimizu, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 10 April 2017 without open access. PMID- 30022269 TI - Antimicrobial effect of bioceramic cements on multispecies microcosm biofilm: a confocal laser microscopy study. AB - OBJECTIVES: To assess the viability of multispecies microcosm biofilm after contact with NeoMTA Plus, Biodentine, and MTA Angelus. MATERIALS AND METHODS: Fifty-four human dentin blocks (4 * 5 * 4 mm) were allocated to Hawley retainers, worn by six volunteers for 72 h. The blocks were then individually incubated in BHI broth for 21 days at 37 degrees C. At the end of experimental time for biofilm growth, the samples were randomly divided into four groups (n = 12): NeoMTA Plus, Biodentine, MTA Angelus, and negative control. The materials were placed in contact with the blocks. All samples were placed in cell-culture plate wells and incubated in BHI broth for 7 days at 37 degrees C. One sample from each volunteer (n = 6) was analyzed by SEM to describe the biofilm morphology. CLSM was performed to determine the percentage of viable biofilm biovolume. The data were statistically analyzed by one-way ANOVA and Tukey's multiple comparison test (alpha = 5%). RESULTS: SEM showed biofilm formed by spherical and rod-shaped bacteria surrounded by an extracellular matrix. No material was able to kill all biofilm cells, and all groups had more than 50% of viable bacteria. NeoMTA Plus was significantly different from the negative control group (P < .05). CONCLUSIONS: All tested materials were not effective against multispecies microcosm biofilm. CLINICAL RELEVANCE: NeoMTA Plus, Biodentine, and MTA Angelus were not effective against multispecies microcosm biofilm. It is essential to understand that these bioceramic cements are indicated for infected clinical situations. Thus, complementary disinfection procedures should be conducted prior to filling with these materials. PMID- 30022270 TI - Changes in periapical status, quality of root fillings and estimated endodontic treatment need in a similar urban German population 20 years later. AB - OBJECTIVES: The study aimed at assessing, as primary objective, the periapical status and quality of root fillings, and, as secondary objective, the endodontic treatment need of a German urban population in a cross-sectional study 20 years after the first one. MATERIALS AND METHODS: Clinical and radiographic data of 353 patients were evaluated. Descriptive and regression analyses were performed and the endodontic treatment need was calculated. Results were compared with data from the year 1993. RESULTS: A total of 9269 teeth were examined (26.2 teeth per patient; 1993, 24.4), of which 337 teeth were root filled (3.6%; 1993, 2.7%). Prevalence of apical periodontitis in root-filled teeth was 34% (1993, 61%). Quality of root fillings was adequate in 117 cases (35%; 1993, 14%). Minimum endodontic treatment need was estimated with 1.6% (1993, 2.3%), including teeth with clinical symptoms. Considering symptomless teeth with apical periodontitis and poor quality of root filling, the treatment need was 2.9% (1993, 3.7%). Regression analysis identified quality of root filling as a significant factor for periapical health (p = 0.01, odds ratio 3.4*, 95% CI 1.9-6.3*), likewise the type of instrumentation. Teeth treated with rotary files had a significantly better outcome (p = 0.02, odds ratio 2.0*, 95% CI 1.1-3.7*). CONCLUSIONS: Quality of root fillings and the periapical status have improved over the last 20 years in Germany. However, there is still a need for an increase in quality of root canal treatment. PMID- 30022271 TI - Bone tissue reaction, setting time, solubility, and pH of root repair materials. AB - OBJECTIVES: This study aims to compare the bone tissue reaction, setting time, solubility, and pH of NeoMTA Plus, Biodentine (BD), and MTA Angelus (MTA-A). MATERIALS AND METHODS: Initial and final setting times (n = 7) and solubility up to 7 days (n = 11) were evaluated in accordance with ASTM C266-15 and ANSI/ADA Specification No. 57, respectively. pH (n = 10) was measured up to 28 days. Bone tissue reactions in 48 rats' femur were histologically analyzed after 7, 30, and 90 days. ANOVA and Tukey's tests compared setting time, solubility, and pH data; bone reactions data were compared by Kruskal-Wallis and Dunn's tests. RESULTS: NeoMTA Plus had longer initial and final setting times than MTA-A and BD (P < 0.05). At 7 days, BD showed the highest solubility, similar to NeoMTA Plus (P > 0.05) and different from MTA-A (P < 0.05). NeoMTA Plus had a progressive mass loss over time; at 7 days, it was significantly different from the initial mass (P < 0.05). BD showed higher pH in the periods assessed when compared to the other materials (P < 0.05). Bone tissue repair had no differences between groups in each experimental period (P > 0.05). All groups presented no difference from 30 to 90 days (P > 0.05) and had better bone repair at 90 days than at 7 days (P < 0.05). CONCLUSIONS: NeoMTA Plus, BD, and MTA-A showed satisfactory setting time, high mass loss, alkaline pH, and allowed bone repair. CLINICAL RELEVANCE: Calcium silicate-based cements are indicated for multiple clinical situations. NeoMTA Plus and BD showed satisfactory physical-chemical and biological properties, being considered as alternatives to MTA-A, as root repair materials for clinical use. PMID- 30022272 TI - Effects of non-thermal atmospheric plasma treatment on dentin wetting and surface free energy for application of universal adhesives. AB - OBJECTIVES: The study aims to evaluate the effects of non-thermal atmospheric plasma (NTAP) treatments on dentin wetting and surface free energy (SFE) and compare the effects of NTAP treatment, etch-and-rinse, and self-etch protocols for application of universal adhesives. MATERIALS AND METHODS: Mid-coronal dentin of intact third molars was used to measure contact angles of distilled water, ethylene-glycol, and diiodomethane and calculate SFE following different NTAP preset treatments (feeding gas consisting of pure He, He + 1% O2, He + 1.5% O2), power input (1 or 3 W), and tip-to-surface distance (2, 4, or 8 mm). Contact angles of reference liquids and SFE of dentin following He + 1.5% O2 at 3-W and 4 mm treatment was compared to phosphoric acid etching. Contact angles of Single Bond Universal (SBU; 3M ESPE) and Clearfil Universal Bond (CUB; Kuraray Noritake) were measured following NTAP, etch-and-rinse, and self-etch protocols. RESULTS: NTAP significantly reduced contact angles of reference liquids and increased dentin SFE compared to untreated dentin (p < 0.05). O2 intensified the effect of He NTAP (p < 0.05). NTAP and phosphoric acid increased dentin polarity and Lewis base surface characteristics. Phosphoric acid increased contact angles of adhesives compared to the self-etch protocol (p < 0.05). NTAP resulted in lower adhesive contact angles than phosphoric acid, the difference being statistically significant for CUB (p < 0.05). Compared to the self-etch protocol, NTAP slightly reduced CUB contact angle but not that of SBU (p > 0.05). CONCLUSIONS: He NTAP with and without O2 increased dentin wetting and SFE, surpassing the effect of phosphoric acid and lowering adhesive contact angles. NTAP produced no apparent micro-morphological changes on dentin surface comparable to acid etching. CLINICAL SIGNIFICANCE: NTAP treatment of dentin prior to adhesive application increases dentin wetting and surface free energy facilitating better adhesive distribution on dentin surface compared to phosphoric acid etching and similar to the "self-etch" application protocol. PMID- 30022273 TI - Declining Use of Orthotopic Reconstruction for Bladder Cancer. PMID- 30022274 TI - Extrathyroidal Extension: Does Strap Muscle Invasion Alone Influence Recurrence and Survival in Patients with Differentiated Thyroid Cancer? AB - BACKGROUND: According to the 8th edition American Joint Committee on Cancer staging system, extrathyroidal extension (ETE) and primary tumor size remain the principle determinants of T stage. However, impact of gross ETE into strap muscles on survival remains controversial. PATIENTS AND METHODS: A retrospective review of 2084 patients with <= 4 cm nonmetastatic differentiated thyroid cancer who underwent surgery between 2000 and 2015 was conducted. Patients were divided into three groups according to degree of ETE: no ETE (group 1), ETE into perithyroidal soft tissue (group 2), and gross ETE into strap muscle (group 3). Survivals were analyzed using Kaplan-Meier method and compared using log-rank test. Factors predictive of survival were analyzed using Cox proportional hazard model. RESULTS: Ten-year disease-free survival (DFS) of patients in groups 1-3 was 90, 82, and 83%, respectively (p = 0.003). On multivariate analysis, age >= 55 years, male sex, and pathologic N1b category predicted significantly worse DFS, while ETE into perithyroidal soft tissue or gross strap muscle invasion did not predict worse DFS. Overall survival (p = 0.957) and disease-specific survival (p =0.910) were not significantly different between the three groups. There was a statistically significant difference in locoregional recurrence-free survival between groups 1 and 2 [HR 2.02, 95% CI 1.06-3.94]. CONCLUSION: Gross strap muscle invasion may not be an important survival prognostic factor for staging purposes. Although both gross strap muscle invasion and perithyroidal soft tissue extension may be predictive for locoregional recurrence, the distinction between them may not be as important for postoperative risk stratification. PMID- 30022275 TI - Laparoscopic resection of idiopathic jejunal arteriovenous malformation after metallic coil embolization. AB - BACKGROUND: Arteriovenous malformations (AVM) developed in the small intestine are rare, and it is sometimes difficult to identify and treat bleeding from small intestinal AVMs endoscopically because of their localization. We present a case of a jejunal AVM successfully treated with the combination of metallic coil embolization and laparoscopic surgery. CASE PRESENTATION: A 50-year-old woman with a history of repetitive gastrointestinal bleeding was admitted to the hospital. Selective angiography revealed a jejunal AVM that was treated with metallic coil embolization. However, the lesion rebled 3 months later, and it was embolized again with metallic coils. Considering the risk of rebleeding, we performed laparoscopic resection of the jejunal AVM. Under laparoscopy alone, it was impossible to detect the lesion of the AVM. We used X-ray fluoroscopy intraoperatively to detect the metallic coils at the AVM. Partial resection of the jejunum with the AVM was performed followed by functional end-to-end anastomosis. The patient was discharged from the hospital without any complications after the surgery. CONCLUSIONS: The combination of metallic coil embolization by angiography and laparoscopic surgery with X-ray fluoroscopy can be effective for patients with repetitive bleeding from jejunal AVM. PMID- 30022276 TI - Genetics of coronary artery disease in the light of genome-wide association studies. AB - As clinicians, we understand the development of atherosclerosis as a consequence of cholesterol deposition and inflammation in the arterial wall, both being triggered by traditional risk factors such as hypertension, hyperlipidaemia or diabetes mellitus. Another risk factor is genetic predisposition, as indicated by the predictive value of a positive family history. However, we had to wait until recently to appreciate the abundant contribution of genetic variation to the manifestation of atherosclerosis. Indeed, by now 164 chromosomal loci have been identified by genome-wide association studies (GWAS) to affect the risk of coronary artery disease. By design, practically all risk variants discovered by GWAS are frequently found in our population, resulting in the fact that principally every Western European individual carries between 130 and 190 risk alleles at the known, genome-wide significant loci (there are 0, 1, or 2 risk alleles per locus). One can assume that it is this widespread disposition that makes mankind susceptible to the detrimental effects of lifestyle factors, which likewise increase the risk of atherosclerosis. In this review, we summarize the recent genetic discoveries and attempt to group the multiple genetic risk variants in functional groups that may become actionable from a preventive or therapeutic perspective. PMID- 30022277 TI - Accuracy assessment of a potential clinical use of navigation-guided intra operative liver metastasis brachytherapy-a planning study. AB - For patients with inoperable liver metastases, intra-operative liver high dose rate brachytherapy (HDR-BT) is a promising technology enabling delivery of a high radiation dose to the tumor, while sparing healthy tissue. Liver brachytherapy has been described in the literature as safe and effective for the treatment of primary or secondary hepatic malignancies. It is preferred over other ablative techniques for lesions that are either larger than 4 cm or located in close proximity to large vessels or the common bile duct. In contrast to external beam radiation techniques, organ movements do not affect the size of the irradiated volume in intra-operative HDR-BT and new technical solutions exist to support image guidance for intra-operative HDR-BT. We have retrospectively analyzed anonymized CT datasets of 5 patients who underwent open liver surgery (resection and/or ablation) in order to test whether the accuracy of a new image-guidance method specifically adapted for intra-operative HDR-BT is high enough to use it in similar situations and whether patients could potentially benefit from navigation-guided intra-operative needle placement for liver HDR-BT. PMID- 30022278 TI - A molecular perspective on starch metabolism in woody tissues. AB - MAIN CONCLUSION: The elucidation of the molecular mechanisms of starch synthesis and mobilization in perennial woody tissues is of the utmost scientific and agricultural importance. Starch is the main carbohydrate reserve in plants and is fundamental in human nutrition and several industrial processes. In leaves, starch accumulated during the day is degraded throughout the night and the resulting sugars, glucose and maltose, are exported to the cytosol by the specialized transmembrane translocators pGT and MEX, respectively. Nevertheless, the degradation of the starch granule is a complex process not completely elucidated. While the mechanisms of starch mobilization during germination in the dead endosperm of cereal seeds are well described, the molecular and biochemical mechanisms involved in starch storage in the heterotrophic tissues of woody plants and its utilization in spring and winter are still puzzling. It is known that some biochemical steps of starch synthesis are conserved in heterotrophic tissues and in the leaves, but some aspects are particular to sink organs. From an agronomic standpoint, the knowledge on starch storage and mobilization in woody tissues is pivotal to understand (and to optimize) some common practices in the field that modify source-sink relationships, such as pruning and defoliation. Soluble sugars resulting from starch are also pivotal to cold adaptation, and in several fruits, such as banana and kiwifruit, starch may provide soluble sugars during ripening. In this review, we explore the recent advances on the molecular mechanisms and regulations involved in starch synthesis and mobilization, with a focus on perennial woody tissues. PMID- 30022279 TI - Outcome of routine cerebrospinal fluid screening for enterovirus and human parechovirus infection among infants with sepsis-like illness or meningitis in Cornwall, UK. AB - : Enteroviruses (EV) and human parechoviruses (HPeV) are known and emerging cause of sepsis-like illnesses in infants; however, testing is not yet routine. We retrospectively evaluated the number of diagnosed EV/HPeV infections in children under the age of 5 years who presented with sepsis-like illness or meningitis in Cornwall, UK, before and after routine implementation of viral screening of cerebrospinal fluid samples. During the 4-year period prior to routine testing, we identified 20 cases of EV meningitis and no cases of HPeV. In the year after introduction of routine screening, 27 cases of EV and 14 cases of HPeV were identified in 1 year. The majority of EV/HPeV infections occurred among children under 3 months old between May and August. Clinical and laboratory characteristics of EV and HPeV infections were mostly indistinguishable. We found that CSF pleocytosis and biochemistry-based testing strategy could miss 48.1 and 78.5% of EV and HPeV cases, respectively. With routine viral screening, the mean length of hospital stay (3.8 vs 5.9 days, P < 0.001) and antibiotic days (2.8 vs 4.7 days, P < 0.001) were significantly reduced in EV/HPeV-positive cases compared to a similar cohort without any detectable microbial aetiology. CONCLUSION: Routine EV and HPeV testing of CSF samples in children has the potential to reduce length of stay and antibiotic use. What is Known: * EV and HPeV are frequent cause of meningitis and sepsis-like illness among young children. * There is increasing evidence supporting routine EV and HPeV testing of paediatric CSF. What is New: * Outcome of routine EV and HPeV testing in Cornwall, UK. * The value of testing all paediatric CSF without any screening criteria. * A rapid diagnosis of EV/HPeV can significantly reduce length of hospital stay and unnecessary antibiotics. PMID- 30022280 TI - Comparisons of percutaneous versus retroperitoneoscopic cryoablation for renal masses. AB - PURPOSE: Preserving renal function and controlling oncological outcomes are pertinent while managing renal tumours. We compared outcomes of percutaneous cryoablation (PCA) and retroperitoneoscopic cryoablation (RCA) in patients with renal neoplasms. METHODS: We identified 108 patients with renal tumours at two medical centres, where 63 patients received PCA and 45 patients underwent RCA from August 2009 to July 2015, and they were followed up until February 2017. We compared preoperative and postoperative parameters, namely gender, systemic diseases, age, American Society of Anesthesiologists score, body mass index (BMI), haemoglobin, the estimated glomerular filtration rate, tumour size, operative time, tumour type, Clavien-Dindo classification of surgical complications, and tumour recurrence, by using an independent sample t test, Pearson's Chi-square test, Fisher's exact test, a Mann-Whitney test, and a generalised linear model. RESULTS: Based on baseline characteristics, we found that the patients in the PCA group were older and had higher BMI than those in the RCA group, whereas the patients in the RCA group had more comorbidities than those in the PCA group. Retroperitoneoscopic and percutaneous methods had similar operative times, blood transfusion rates, postoperative fever episodes, and complication rates for either minor or major complications. However, the percutaneous method was associated with a shorter length of stay. No patient experienced deterioration in renal function until 2 years after both procedures. Impaired renal function was found in both groups in the 3-year follow-up. In both groups, tumour recurrence was significant for tumours > 4 cm. CONCLUSIONS: Our results confirm that both cryoablation methods (PCA and RCA) are safe and effective for renal cell carcinoma. Favourable oncological control was achieved in both groups if the renal tumour size was <= 4 cm. PMID- 30022281 TI - Autophagy blockade sensitizes human head and neck squamous cell carcinoma towards CYT997 through enhancing excessively high reactive oxygen species-induced apoptosis. AB - : The functional relationship between apoptosis and autophagy in anticancer drug treatment is extremely complex, and the molecular machinery is obscure. This study aims to investigate the efficacy of CYT997, a novel microtubule-disrupting agent, in head and neck squamous cell carcinomas (HNSCCs) and complete the autophagy-apoptosis puzzle involved in drug action. We report here that CYT997 exhibits anticancer activity by triggering oxidative stress-associated apoptosis in HNSCC cells. Interestingly, upregulation of autophagy by mTOR-dependent pathways appears to have a cytoprotective role in preventing apoptosis by inhibiting CYT997-induced excessively high levels of reactive oxygen species (ROS). Blockade of autophagy by ATG7 depletion or addition of autophagy inhibitor hydroxychloroquine (HCQ) sensitizes HNSCC cells to CYT997 as evidenced by enhanced ROS-associated apoptosis. Moreover, HCQ exhibits a good synergism with CYT997 on induction of apoptosis in HNSCC xenografts without cytotoxicity, suggesting combined treatment of CYT997 with autophagy inhibitors would increase the anticancer efficacy of CYT997. These findings unveil the importance of ROS in crosstalk between autophagy and apoptosis in CYT997 treatment, raising concerns that genetic or pharmacologic blockade of autophagy should be considered in the design of new therapeutics for HNSCC. KEY MESSAGES: * CYT997 exhibits anticancer activity by induction of ROS-associated apoptosis. * mTOR-dependent cytoprotective autophagy prevents CYT997-induced apoptosis. * Blockade of autophagy augments CYT997 efficacy by enhanced ROS-associated apoptosis. * Combination of autophagy inhibitors with CYT997 is more effective against HNSCC. PMID- 30022282 TI - iBTA-induced bovine Biosheet for repair of abdominal wall defects in a beagle model: proof of concept. AB - INTRODUCTION: We evaluated the usefulness of xeno-Biosheets, an in-body tissue architecture-induced bovine collagenous sheet, as repair materials for abdominal wall defects in a beagle model. MATERIALS AND METHODS: Biosheets were prepared by embedding cylindrical molds into subcutaneous pouches of three Holstein cows for 2-3 months and stored in 70% ethanol. The Biosheets were 0.5 mm thick, cut into 2 cm * 2 cm, and implanted to replace defects of the same size in the abdominal wall of nine beagles. The abdominal wall and Biosheets were harvested and subjected to histological evaluation at 1, 3, and 5 months after implantation (n = 3 each). RESULTS: The Biosheet and bovine pericardiac patch (control) were not stressed during the suture operation and did not split, and patches were easily implanted on defective wounds. After implantation, the patch did not fall off and was not perforated, and healing was observed nacroscopically in all cases. During the first month of implantation, accumulation of inflammatory cells was observed along with decomposition around the Biosheet. Decomposition was almost complete after 3 months, and the Biosheet was replaced by autologous collagenous connective tissue without rejection. After 5 months, the abdominal wall muscle elongated from the periphery of the newly formed collagen layer and the peritoneum was formed on the peritoneal cavity surface. Regeneration of almost all layers of the abdominal wall was observed. However, almost all pericardium patches were remained even at 5 months with inflammation. CONCLUSION: Bovine Biosheets requiring no special post-treatment can be useful as off-the-shelf materials for abdominal wall repair. PMID- 30022283 TI - Management of hydrocephalus in patients with leptomeningeal metastases: an ethical approach to decision-making. AB - PURPOSE: Leptomeningeal metastases (LM) are a rare, but often debilitating complication of advanced cancer that can severely impact a patient's quality-of life. LM can result in hydrocephalus (HC) and lead to a range of neurologic sequelae, including weakness, headaches, and altered mental status. Given that patients with LM generally have quite poor prognoses, the decision of how to manage this HC remains unclear and is not only a medical, but also an ethical one. METHODS: We first provide a brief overview of management options for hydrocephalus secondary to LM. We then apply general ethical principles to decision making in LM-associated hydrocephalus that can help guide physicians and patients. RESULTS: Management options for LM-associated hydrocephalus include shunt placement, repeated lumbar punctures, intraventricular reservoir placement, endoscopic third ventriculostomy, or pain management alone without intervention. While these options may offer symptomatic relief in the short-term, each is also associated with risks to the patient. Moreover, data on survival and quality-of life following intervention is sparse. We propose that the pros and cons of each option should be evaluated not only from a clinical standpoint, but also within a larger framework that incorporates ethical principles and individual patient values. CONCLUSIONS: The decision of how to manage LM-associated hydrocephalus is complex and requires close collaboration amongst the physician, patient, and/or patient's family/friends/community leaders. Ultimately, the decision should be rooted in the patients' values and should aim to optimize a patient's quality-of life. PMID- 30022285 TI - The Relation Between Vocal Pitch and Vocal Emotion Recognition Abilities in People with Autism Spectrum Disorder and Typical Development. AB - We tested the relation between vocal emotion and vocal pitch perception abilities in adults with high-functioning autism spectrum disorder (ASD) and pairwise matched adults with typical development. The ASD group had impaired vocal but typical non-vocal pitch and vocal timbre perception abilities. The ASD group showed less accurate vocal emotion perception than the comparison group and vocal emotion perception abilities were correlated with traits and symptoms associated with ASD. Vocal pitch and vocal emotion perception abilities were significantly correlated in the comparison group only. Our results suggest that vocal emotion recognition difficulties in ASD might not only be based on difficulties with complex social tasks, but also on difficulties with processing of basic sensory features, such as vocal pitch. PMID- 30022284 TI - Superior sealing effect of a three-dimensional printed modified supraglottic airway compared with the i-gel in a three-dimensional printed airway model. AB - PURPOSE: The aim of this study was to compare the force exerted by a three dimensional (3D) printed modified supraglottic airway (mSGA) vs. that exerted by the i-gel on a 3D printed airway model. METHODS: After a preliminary experiment in Thiel embalmed cadavers, we created a 3D printed mSGA and five 3D printed airway models based on computed tomography data from five female Japanese patients. We compared the force exerted by the i-gel and mSGA on the larynx of the 3D printed airway models. In addition, tidal volumes with insertion of the airway devices into the 3D printed airway model and administration of different levels of pressure-controlled ventilation (PCV) were compared. RESULTS: The values below indicate mean values +/- SD (p value, 95% confidence interval) for the mSGA and i-gel, respectively. The forces exerted by the cuff parts were as follows: ventral: 12.5 +/- 5.4 vs. 20.7 +/- 3.7 N (p = 0.0001, - 10.0 to - 6.5), proximal: 1.9 +/- 1.4 vs. 1.7 +/- 1.3 N (p = 0.322, - 0.26 to 0.74), and dorsal parts: 6.9 +/- 2.2 vs. 12.5 +/- 4.8 N (p = 0.0001, - 7.9 to - 3.4), respectively. We also found significantly higher tidal volumes with the mSGA under PCV of 10, 15, and 20 cmH2O. CONCLUSIONS: The method of creating the mSGA that we proposed in this study can be applied to development of novel SGAs that is anatomically more suitable for pharyngolaryngeal structure. PMID- 30022286 TI - Analyzing urban landscape with City Biodiversity Index for sustainable urban growth. AB - Urbanization process converts natural landscape into an anthropogenic urban landscape. The present paper attempts to understand spatiotemporal urban dynamics of a mid-sized Indian town-Khammam in Telangana-by carrying out Land Use Land Cover Change Analysis for assessing urban growth pattern. A set of metrics of Landscape Analysis available to analyze growth pattern and broadly categorized into two sets-composition and configuration. Principal Component Analysis was used to identify three critical metrics from Landscape Analysis, viz., Number of Patches and Edge Length and Splitting Indexes while two additional metrics of the composition set, viz., Shannon Diversity and Shannon Evenness Indexes, based on expert opinion were added to make the study amenable. Twenty-three indicators of City Biodiversity Index broadly grouped into three core components, viz., Native Biodiversity in City, Ecosystem Services provided, and governance and management of CBI, were analyzed, and five indicators that were amenable to digital interpretation of satellite data pertaining to proportion of park and natural area within city, availability of water or quantum of water for urbanization, extent of natural protected area, extent of parks and natural area, and impact of vegetated area on ambient cooling were studied. Study indicated that in Khammam score of 8 out of a total score of 20 in CBI analysis indicated unsustainable growths, although trends among individual LULC components varied making it essential to study individual patterns. Study highlights need to use such indicators to guide urban development in mid-sized urban towns and cities that could substitute for large metropolitan cities as the growth engine in future. PMID- 30022287 TI - Peritoneal perforation during transanal endoscopic microsurgery is not associated with significant short-term complications. AB - BACKGROUND: In patients treated by transanal endoscopic microsurgery (TEM), breach of the peritoneal cavity is a feared intraoperative challenge. Our aim is to analyze predictors and short-term outcomes of patients with peritoneal perforation (TEM-P) when compared to similar patients with no peritoneal compromise (TEM-N). METHODS: At St. Paul's Hospital, demographic, surgical, pathologic, and follow-up data for all patients treated by TEM is maintained in a prospectively populated database. A retrospective review was performed and two groups were established for comparison: TEM-P and TEM-N. Statistical analysis was performed using student's t or chi-squared test, where appropriate. RESULTS: Of 619 patients treated by TEM between 2007 and 2016, 39 (6%) patients were in the TEM-P group and 580 (94%) in the TEM-N group. There were no differences between the groups in patient age, gender, histology, or tumor size. Patients who had peritoneal perforations had more proximal lesions (11 vs. 7 cm, p < 0.0001), anterior lesions (56 vs. 43%, p < 0.05), and longer operations (80 vs. 51 min, p < 0.005). While most defects were closed endoluminally, 2 patients with perforation were converted to transabdominal surgery. There was a difference in overall hospital stay with TEM-P patients staying on average 2 days in hospital with fewer patients managed as day surgery (31 vs. 73%, p < 0.0001). There were no mortalities or significant 30-day complications in the TEM-P group and only one patient required readmission. CONCLUSIONS: The St. Paul's Hospital TEM experience suggests patients with peritoneal breach during TEM can be safely managed with outcomes similar to patients without peritoneal entry. Proximal, anterior lesions are at highest risk of peritoneal perforation. PMID- 30022288 TI - A novel percutaneous magnetically guided gastrostomy technique without endoscopy or imaging guidance: a feasibility study in a porcine model. AB - BACKGROUND: In order to simplify a percutaneous gastrostomy procedure and avoid the need of endoscopy or imaging methods, a novel percutaneous magnetically guided gastrostomy (PMG) technique was conceived. The aim of the present study is to evaluate the feasibility of a novel PMG technique with no endoscopy or any imaging guidance in a porcine model. METHODS: Fourteen crossbred domestic pigs were used for prototype development (cadaveric experiments) and proof-of concept, survival study. The magnetic device was conceived using commercially available rare-earth neodymium-based magnets. The experimental design consisted of developing an internal magnetic gastric tube prototype to be orally inserted and coupled to an external magnet placed on the skin, which facilitated stomach and abdominal wall apposition for blind percutaneous gastrostomy tube placement. Then, a gastrostomy tube was percutaneously and blindly placed. RESULTS: Twelve procedures were undertaken in animal cadavers and two in live models. The technique chosen consisted of using a magnetic gastric tube prototype using six 1 * 1-cm-ring magnets attached to its end. This device enabled successful magnetic coupling with a large (5 cm in diameter) magnet disc placed on the skin. For gastric tube placement, a direct trocar insertion allowed easier and safer placement of a gastric tube as compared to a needle-guide-wire dilation (Seldinger-based) technique. Gastropexy was added to avoid early gastric tube displacement. This novel PMG technique was feasible in a live model experiment. CONCLUSIONS: A novel magnetically guided percutaneous gastrostomy tube insertion technique without the use of endoscopy or image-guidance was successful in a porcine model. A non-inferiority experimental controlled study comparing this technique to percutaneous endoscopic gastrostomy is needed to confirm its efficacy and safety. PMID- 30022289 TI - Preliminary report of occurrence of Corynosoma spp. (Acanthocephala: Polymorphidae) in Southern Caspian sprat (Clupeonella grimmi). AB - In recent years, there has been a steady decline in the populations of clupeid fish in the Caspian Sea which has been attributed to factors such as overfishing and introduced invasive species of jellyfish. Very little is known about the diseases and possible health impacts of infectious agents such as parasites on the population of these important fish in the Caspian Sea. The aim of this study was to determine if infection with parasites can have adverse impacts on fish health and population. Sixty fish were collected, measured for weight and length, aged, and then examined for presence of Acanthocephala. Ages were recorded, as well as length and weight data for each age category and the number of acanthocephalan parasites. The internal organs, including the liver, ovary, and testis, were subjected to histopathological examination. Ninety percent of fish were found to be infected with acanthocephalan parasites, identified as Corynosoma strumosum. Fish data including the number of parasites, age, length, and weight showed that there was no significant difference in length and weight between different age groups, e.g., between 2 and 6 years old, suggesting that those fish may not grow fully as they age. There were several granuloma of different sizes in the liver and gonads, indicating the occurrence of a chronic inflammation. It is known that large numbers of granuloma may disturb the normal function of the liver and gonads and if associated with long term infection this may cause sterility, affecting the population numbers. Further research, with targeted aims, is needed to understand the impact of infection with acanthocephala on this fish and to determine the causative agents of the histopathological changes observed in the present study. PMID- 30022290 TI - Molecular characterisation of Hepatozoon aegypti Bashtar, Boulos & Mehlhorn, 1984 parasitising the blood of Spalerosophis diadema (Serpentes: Colubridae). AB - Hepatozoon aegypti Bashtar, Boulos & Mehlhorn, 1984 was first described from the blood of the diadem snake (Spalerosophis diadema) in Egypt. During an investigation of the diversity of reptilian haemogregarines in Saudi Arabia, seven diadem snakes (100% of the sample) were found to be highly parasitised by H. aegypti, with an average parasitaemia of 37% per 500 counted erythrocytes. A complete characterisation of this species with morphometrics and 18S rDNA sequence data is therefore presented here. The infection was found to be restricted to the erythrocytes with, frequently, single and, sometimes, double infections. Mature gamonts were sausage-shaped with round posterior and anterior extremities and measured 14 (13-17) * 3.5 (3-5) MUm. The infected erythrocytes were hypertrophied with a faintly stained cytoplasm and longitudinally stretched nuclei. The merogonic stages occurred only in the endothelial cells of the snakes' lungs, and no stages were found in other organs. Mature meronts were round in shape, measured 18 (17-21) MUm in diameter and were estimated to produce between 9 and 15 merozoites. Phylogenetic analysis based on the partial 18S small subunit ribosomal DNA sequences indicates that Hepatozoon aegypti cluster within a mixed clade of Hepatozoon species parasitising snakes, geckos and rodents from various geographic areas. Our results might reinforce the theory of prey-predator transmission in respect to the relationships of snake-host Hepatozoon species. PMID- 30022291 TI - Ultrastructural, cytochemistry and electron tomography analysis of Caryophyllaeides fennica (Schneider, 1902) (Cestoda: Lytocestidae) reveals novel spermatology characteristics in the Eucestoda. AB - Spermatozoon formation in Caryophyllaeides fennica (Schneider, 1902) is characterised by the following: (1) apical electron-dense material in the zone of differentiation, (2) typical striated roots situated unconventionally in opposite directions in early stages of spermiogenesis, (3) intercentriolar body composed of three electron-dense and two electron-lucent plates, (4) free flagellum and a flagellar bud that correspond to a greatly reduced flagellum and (5) rotation of free flagellum and a flagellar bud to the median cytoplasmic process at 90 degrees . The development of two flagella of significantly unequal length clearly supports a derived form of spermiogenesis in the Caryophyllidea. New for cestodes is a finding of two additional striated roots situated opposite each other, in conjunction with both the flagellar bud and free flagellum. Mutual position of additional striated roots and typical striated roots is parallel in early stages and perpendicular in advanced stages of spermiogenesis. A complete proximodistal fusion gives rise to a mature spermatozoon consisting of one axoneme, parallel cortical microtubules, a nucleus and a moderately electron-dense cytoplasm with glycogen particles, detected by a technique of Thiery (J Microsc 6:987-1018, 1967), in the principal regions (II, III, IV). Electron tomography analysis of the free flagellum and one axoneme of a mature spermatozoon of C. fennica provides clear evidence, for the first time, that two tubular structures are present in the central axonemal electron-dense core. Phylogenetically important aspects of spermiogenesis of the Caryophyllidea with one axoneme, and other cestodes with one or two axonemes, are briefly reviewed and discussed. PMID- 30022293 TI - "In front of patients, I will always be a pupil." Dr. Xiaoqian Zhang: the founder of the modern Chinese gastroenterology. PMID- 30022292 TI - Genetic variant strains of Leishmania (Viannia) braziliensis exhibit distinct biological behaviors. AB - A variety of clinical forms of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis, as well as differing immune responses of patients, have been reported for an ACL focus in the state of Minas Gerais, Brazil. In addition, two genetic profiles of L. braziliensis have been described, of which one variant profile (hsp70-variant) has been associated with atypical lesions. We investigated the biological behavior of genetic variant strains of L. braziliensis isolated from patients with different clinical manifestations of ACL. Experimental infections were performed with golden hamsters for five L. braziliensis strains in standardized doses of 1 * 106 parasites per inocula. The characteristics of skin lesions, histopathological features, and parasite burden were independently analyzed at 30 and 60 days post-infection. The data revealed distinct patterns in the onset time of visible skin lesions as well as in lesion size and parasite burden among the strains. The extent and density of the inflammatory infiltrate differed among strains, although cellular composition of granulomas appeared similar. Multivariate analysis indicated the occurrence of two clusters: one comprising native strains (cluster 1) and one comprising the reference strain (cluster 2). Within cluster 1, the genetic variants of L. braziliensis did not group with the non-variant strain suggesting that the distinct patterns of biological behavior of these strains could be associated with the known genetic diversity previously described for them. PMID- 30022294 TI - Screening Tools as a Predictor of Injury in Dance: Systematic Literature Review and Meta-analysis. AB - BACKGROUND: Dance involves movements of complexity and physical intensity which result in stress on the body. As a consequence, dancers are at risk of injury which can impact on their well-being. Screening tools are used for injury prevention to identify those dancers at risk of injury. The aim of this study was to investigate which screening tools can predict injury in dancers, encompassing all dance genres, levels and ages. METHODS: An electronic search of seven databases from their inception to December 2017 was conducted. The databases were the Allied and Complementary Medicine Database (AMED), CINAHL, eBOOK Collection (EBSCOhost), MEDLINE, Cochrane Database of Systematic Reviews, SPORTDiscus and PEDro: the Physiotherapy Evidence Base. The following search terms were used: (i) Dance AND injury AND Screening, (ii) Screening AND dance and (iii) Musculoskeletal AND Screening AND Dance. Studies were assessed using a 20-point scoring tool, and eligible studies were included in a meta-analysis. RESULTS: The mean methodological quality score was 12.2 points. Injured dancers had a significantly higher compensated turnout range of motion than non-injured dancers: pooled mean difference of compensated turnout (23.29 degrees ; 95% CI 14.85-31.73; P < 0.00001; I2 = 0%). Injured dancers had significantly greater functional turnout range of motion when compared to non-injured dancers: pooled mean difference of functional turnout (14.08 degrees ; 95% CI 7.09-21.07; P < 0.0001; I2 = 0%). There also some evidence for use of hip range of motion as a predictor of dance injury. CONCLUSIONS: Some evidence exists for the potential use of dance-specific positions as a predictor of injury. A number of studies were limited by a lack of prospective injury design, injury definition and self reporting of injury. PMID- 30022295 TI - Evolutionary Perspectives of Genotype-Phenotype Factors in Leishmania Metabolism. AB - The sandfly midgut and the human macrophage phagolysosome provide antagonistic metabolic niches for the endoparasite Leishmania to survive and populate. Although these environments fluctuate across developmental stages, the relative changes in both these environments across parasite generations might remain gradual. Such environmental restrictions might endow parasite metabolism with a choice of specific genotypic and phenotypic factors that can constrain enzyme evolution for successful adaptation to the host. With respect to the available cellular information for Leishmania species, for the first time, we measure the relative contribution of eight inter-correlated predictors related to codon usage, GC content, gene expression, gene length, multi-functionality, and flux coupling potential of an enzyme on the evolutionary rates of singleton metabolic genes and further compare their effects across three Leishmania species. Our analysis reveals that codon adaptation, multi-functionality, and flux-coupling potential of an enzyme are independent contributors of enzyme evolutionary rates, which can together explain a large variation in enzyme evolutionary rates across species. We also hypothesize that a species-specific occurrence of duplicated genes in novel subcellular locations can create new flux routes through certain singleton flux-coupled enzymes, thereby constraining their evolution. A cross species comparison revealed both common and species-specific genes whose evolutionary divergence was constrained by multiple independent factors. Out of these, previously known pharmacological targets and virulence factors in Leishmania were identified, suggesting their evolutionary reasons for being important survival factors to the parasite. All these results provide a fundamental understanding of the factors underlying adaptive strategies of the parasite, which can be further targeted. PMID- 30022296 TI - Differences in the dietary requirement for vitamin D among Caucasian and East African women at Northern latitude. AB - CONTEXT: Current vitamin D recommendations have been established based on an assumption that there are no differences between Caucasian and other ethnic/racial groups in terms of vitamin D requirements. This assumption, largely made due to the absence of data, is a key knowledge gap identified by a number of authorities. OBJECTIVE: To test whether the distribution of dietary requirements for maintaining winter serum 25-hydroxyvitamin D [25(OH)D] concentrations >= 30 nmol/L (a priority threshold linked to vitamin D deficiency prevention) differ between Caucasian and Somali women living at northerly latitude. METHODS: We used data from a 5-month, winter-based, vitamin D3 dose-related randomized, placebo controlled trial in Somali (n 47) and Causcian women (n 69), aged 21-64-year old, living in Southern Finland (60 degrees N), to model the vitamin D intake-serum 25(OH)D dose-response relationship. Regression analyses were used to predict the vitamin D intake required to maintain 97.5% (as well as 50, 90, and 95%) of women in both ethnic groups above serum 25(OH)D thresholds of 30, 40 and 50 nmol/L. RESULTS: Using a model which adjusted for baseline 25(OH)D, age, and BMI, the estimated vitamin D intake that maintained serum 25(OH)D >= 30 nmol/L in 97.5% of Caucasian and Somali women was 8 and 18 ug/day, respectively. Ethnic differences were also evident at 40 and 50 nmol/L serum 25(OH)D thresholds. CONCLUSION: The present study adds further evidence that ethnic differences in the dietary requirement for vitamin D do exist and that dose-response vitamin D intervention studies are required in at-risk target populations specified by ethnicity. PMID- 30022297 TI - Gastric adenocarcinoma coexisting with a reddish semipedunculated polyp arising from Helicobacter pylori-negative normal gastric mucosa: a report of two cases. AB - We experienced two cases of adenocarcinoma coexisting with a hyperplastic polyp arising from Helicobacter pylori-negative normal gastric mucosa. The first case was of a 59-year-old man. Esophagogastroduodenoscopy revealed a protruding lesion measuring 4 mm in diameter on the greater curvature of the middle gastric body. The second case was of a 47-year-old man. Esophagogastroduodenoscopy showed a protruding lesion measuring 5 mm located at the greater curvature of the upper gastric body. The absence of atrophic changes in the entire gastric mucosa was confirmed endoscopically in both cases. Multiple H. pylori tests were all negative. Endoscopically, these protruding lesions appeared as reddish, semipedunculated polyps. Hyperplastic polyps were suspected based on white light endoscopic findings. Magnified endoscopy with narrow band imaging could not predict the coexistence of cancer. However, histopathological examination of the resected specimen revealed focal cancer at the surface of the gastric hyperplastic polyps. Considering the possibility that cancer may be coexisting in polyps, when reddish polyps are detected in H. pylori-negative normal gastric mucosa, it is important to perform a biopsy, or a careful follow-up endoscopy. PMID- 30022298 TI - Associative Learning of Food Odor by Social Wasps in a Natural Ecosystem. AB - The ability of insects to associate olfactory cues with food from their environment has been well documented with various insect orders. However, these studies were based on prior training of insects to associate odors with food sources in the laboratory or in the field with almost no evidence for the development of this phenomenon in natural ecosystems. In New Zealand's ancient Fuscospora spp. or beech forests, invasive Vespula social wasps were attracted to odor from honeydew (benzaldehyde and n-octanol) but did not respond to a known wasp attractant (isobutanol and acetic acid). On the other hand, wasps in a rural/suburban area in New Zealand did not respond to honeydew odor but responded instead to the known wasp attractant. Similarly, social wasps in Hungary did not respond to honeydew odor, but responded to the known wasp attractant. DNA sequences of Vespula vulgaris from the two locations in New Zealand were 100% identical. Similarly, DNA sequences of V. germanica from the two locations in New Zealand were 100% identical, indicating little or no intra-specific variation. On the other hand, DNA sequences of V. vulgaris and V. germanica from New Zealand were 99.56 and 99.78% matches with V. vulgaris and V. germanica samples from Hungary, respectively. Electroantennogram (EAG) response profiles of wasps from the three locations to benzaldehyde, isobutanol, acetic acid, n-octanol and heptyl butyrate were similar. The high similarity in DNA sequences and EAG profiles, with only a behavioral difference in the response to odor sources, suggests that social wasps in New Zealand's beech forest have naturally developed associative learning for the odor of the carbohydrate-rich honeydew. This is the first study to provide conclusive evidence of the occurrence and the development of associative learning of food odor by social insects in a natural ecosystem free of human interference. The ability of social wasps to naturally develop associative learning of food odor might in part explain why they are extremely successful invaders of new ecosystems, especially those with rich honeydew resources. The finding of our study will have significant implications for the use of attractants in wasp monitoring and control in different habitats. PMID- 30022299 TI - Hematological malignancies mimicking rheumatic syndromes: case series and review of the literature. AB - It is well established that some rheumatic syndromes (RS) are associated with several hematological malignancies. We aimed to describe the clinical course of patients with hematological malignancies mimicking RS. We studied a series of four patients presenting with apparent RS who were eventually diagnosed with hematological malignancies, and reviewed the relevant literature. Our series consisted of 4 patients, with a mean age of 62.8 +/- 20.3 years, who presented to our rheumatology unit between December 2012 and March 2018. Two patients were initially diagnosed with polyarthritis. One of these patients was eventually diagnosed with multiple myeloma and amyloidosis and the other was diagnosed with angioimmunoblastic T-cell lymphoma. The third patient was initially diagnosed with migratory arthritis and was eventually diagnosed with acute myeloid leukemia. The fourth patient was initially diagnosed with giant cell arteritis and eventually diagnosed with anaplastic large T-cell lymphoma. All the patients displayed a very good response to corticosteroid treatment. Vigilance for occult malignancy is essential in the diagnostic workup of RS. A good response to corticosteroids may constitute a major diagnostic pitfall in patients with hematological malignancies presenting with an apparent RS. In these cases, subtle clinical and laboratory features should elicit the clinician to seek for an occult malignancy. PMID- 30022300 TI - Development and validation of SCAISS, a tool for semi-automated quantification of sacroilitis by magnetic resonance in spondyloarthritis. AB - To develop a semi-automated method to quantify inflammation in sacroiliac (SI) joints by measuring bone marrow edema (BME) on MRI. The SCAISS was designed as an image-processing software. Validation followed: (1) three readers evaluated SI images of 23 patients with axial SpA and various levels of BME severity with the SCAISS, and two non-automated methods, SPARCC and Berlin; (2) 20 readers evaluated 12 patients images, also with the three methods; (3) 203 readers evaluated 12 patient images with the Berlin and the SCAISS. Convergent validity, reliability and feasibility were estimated in the first two steps and reliability was confirmed with the third. The interobserver reliability (ICC and 95% CI) in the three observers' study was similar across methods: SCAISS = 0.770 (0.580 0.889); Berlin = 0.725 (0.537-0.860); and SPARCC = 0.824 (0.671-0.916). In the 20 observers' study, ICC was: SCAISS = 0.801 (0.653-0.927); Berlin = 0.702 (0.518 0.882); and SPARCC = 0.790 (0.623-0.923). In the 203 observers' study, ICC were: SCAISS = 0.810 (0.675-0.930), and Berlin = 0.636 (0.458-0.843). SCAISS showed good convergent validity (r with SPARCC = 0.760). Median time (interquartile range) employed in the reading procedure was 28 (27) seconds for the SCAISS, 14 (9) for the Berlin score, and 94 (68) for the SPARCC. The SCAISS permits a valid, reliable, and fast calculation of overall BME lesion at the SI joint on MRI images not dependent on readers' experience. PMID- 30022301 TI - Rheumatology science and practice in India. AB - The practice of rheumatology in a country like India presents its own unique challenges, including the need to manage patients in a cost-constrained setting, where the lack of uniform government funding for healthcare merits the need to optimize the use of cheaper medicines, as well as devise innovative strategies to minimize the use of costlier drugs such as biologic disease-modifying agents. Use of immunosuppressive agents is also associated with increased risks of infectious complications, such as the reactivation of tuberculosis. In this narrative review, we provide a flavor of such challenges unique to Rheumatology practice in India, and review the published literature on the management of common rheumatic diseases from India. In addition, we critically review existing guidelines for the management of rheumatic diseases from this part of the world. We also discuss infectious etiologies of rheumatic complaints, such as leprosy, tuberculosis, and Chikungunya arthritis, which are often encountered here, and pose a diagnostic as well as therapeutic challenge for clinicians. There remains a need to identify and test more cost-effective strategies for Indian patients with rheumatic diseases, as well as the requirement for more government participation to enhance scant facilities for the treatment of such diseases as well as foster the development of healthcare services such as specialist nurses, occupational therapists and physiotherapists to enable better management of these conditions. PMID- 30022302 TI - Environmental proteomic studies: closer step to understand bacterial biofilms. AB - Advancement in proteome analytical techniques and the development of protein databases have been helping to understand the physiology and subtle molecular mechanisms behind biofilm formation in bacteria. This review is to highlight how the evolving proteomic approaches have revealed fundamental molecular processes underlying the formation and regulation of bacterial biofilms. Based on the survey of research reports available on differential expression of proteins in biofilms of bacterial from wide range of environments, four important cellular processes viz. metabolism, motility, transport and stress response that contribute to formation of bacterial biofilms are discussed. This review might answer how proteins related to these cellular processes contribute significantly in stabilizing biofilms of different bacteria in diverse environmental conditions. PMID- 30022303 TI - [Acute and chronic instability of the elbow joint]. AB - Elbow dislocations are frequent and present with a broad spectrum of subsequent ligamentous and soft tissue injuries. Beside clinical examination, fluoroscopy, ultrasound and magnetic resonance imaging (MRI) can specify the extent of the injuries and provide a foundation for decision-making between conservative and operative treatment. This article highlights the basic underlying biomechanics and anatomy, discusses the trauma mechanisms and presents clinical and imaging diagnostic procedures. Treatment algorithms for conservative and surgical treatment are presented in detail. In addition to acute instability, chronic instability of the elbow has recently been recognized as the cause of a large variety of symptoms, often resulting in significant functional impairment. The most commonly used techniques for reconstruction of the medial and lateral collateral ligaments and the rehabilitation protocols are described in detail. PMID- 30022305 TI - Presynaptic disorders: a clinical and pathophysiological approach focused on the synaptic vesicle. AB - The aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis-endocytosis cycle, with the main purpose of neurotransmitter release). Given that SVs have been defined as individual organelles, we highlight the link between the biological processes disturbed by genetic mutations and the clinical presentation of these disorders. The great majority of diseases may present as epileptic encephalopathies, intellectual disability (syndromic or nonsyndromic) with/without autism spectrum disorder (and other neuropsychiatric symptoms), and movement disorders. These symptoms may overlap and present in patients as a combination of clinical signs that results in the spectrum of the synaptopathies. A small number of diseases may also exhibit neuromuscular signs. In general, SV disorders tend to be severe, early encephalopathies that interfere with neurodevelopment. As a consequence, developmental delay and intellectual disability are constant in almost all the defects described. Considering that some of these diseases might mimic other neurometabolic conditions (and in particular treatable disorders), an initial extensive metabolic workup should always be considered. Further knowledge into pathophysiological mechanisms and biomarkers, as well as descriptions of new presynaptic disorders, will probably take place in the near future. PMID- 30022304 TI - Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons. AB - The astrocyte-neuron lactate shunt (ANLS) hypothesis is the most widely accepted model of brain glucose metabolism. However, over the past decades, research has shown that neuronal and astrocyte plasma membrane receptors, in particular, GLUT2, Kir6.2 subunit of the potassium ATP-channel, SGLT-3 acting as glucosensors, play a pivotal role in brain glucose metabolism. Although both ANLS hypothesis and glucosensor model substantially improved our understanding of brain glucose metabolism, the latter appears to be gaining more attention in the scientific community as the former could not account for new research data indicating that hypothalamic and brainstem neurons may not require astrocyte derived lactate for energy. More recently, emerging evidences suggest a crucial role of sweet taste receptors in brain glucose metabolism. Furthermore, a couple of intracellular molecules acting as glucosensors have been identified in central astrocytes and neurons. This review integrates new data on the mechanisms of brain glucose sensing and metabolism. The role of the glucosensors including the sweet taste T1R2 + T1R3-mediated brain glucose-sensing and metabolism in brain glucose metabolic disorders is discussed. Possible role of glucose sensors (GLUT2, K-ATPKir6.2, SGLT3, T1R2 + T1R3) in brain diseases involving metabolic dysfunctions and the therapeutic significance in targeting central glucosensors for the treatment of these brain diseases are also discussed. PMID- 30022307 TI - Costs of Managing Benign Prostatic Hyperplasia in the Office and Operating Room. AB - PURPOSE OF REVIEW: To review the costs associated with benign prostatic hyperplasia (BPH) management. Specifically, to compare the costs of medical therapy, office-based procedures, and surgical management from a payer perspective. RECENT FINDINGS: The American Urological Association released updated guidelines in 2018 for the surgical management of BPH. Over recent years, analyses investigating the cost-effectiveness of the modalities included in these guidelines have been completed. These show relatively newer, minimally-invasive office-based therapies can provide cost-effective alternatives to medical therapy. Likewise, surgical therapies provide a cost-effective means of BPH management, if performed well with low complication rates. However, comparisons of these studies are limited by the biases they contain. Minimally-invasive office-based therapies and well performed surgical therapies for BPH can achieve cost equivalence to combination medical therapy within a few years. Factors such as age, gland size, patient compliance, and surgeon skill should be considered when personalizing treatment recommendations for each patient. PMID- 30022308 TI - Brodifacoum-contaminated synthetic marijuana: clinical and radiologic manifestations of a public health outbreak causing life-threatening coagulopathy. AB - Synthetic marijuana is a dangerous substance due to its potency, ever-changing composition, and unpredictable side effects. Recently, brodifacoum-contaminated synthetic marijuana has led to multiple deaths and morbidity throughout the USA from severe coagulopathy associated with use of this strain of the drug (brodifacoum is a rodenticide and potent Vitamin K antagonist/anticoagulant). We describe the clinical and radiologic findings in two patients who were diagnosed with, and treated for, ingestion of this new strain of synthetic marijuana. The radiologic manifestations were most notable for hemorrhagic pyelitis/ureteritis. Both patients required hospitalization with Vitamin K supplementation. The radiologic and clinical pictures in these patients are important for radiologists to recognize in order to help guide appropriate patient management. PMID- 30022306 TI - Disease outbreak accompanies the dispersive structure of shrimp gut bacterial community with a simple core microbiota. AB - Increasing evidence has emerged supporting a tight link between gut bacterial community and shrimp health. However, the knowledge about the variation of gut bacterial community, especially with different disease onset time, remains elusive. Here, healthy and diseased shrimps were collected at 3 disease-outbreak times (day 70, 80 and 85) to investigate the variation of gut bacterial community and its underlying ecological process with 16S rRNA gene amplicon sequencing. The gut bacterial community of diseased shrimp was distinct from the healthy one and temporally less stable, characterized by decreased alpha-diversity and dispersive structure. And its dominant ecological process experienced a transition with disease onset time, although deterministic process mainly governed the healthy gut bacterial assembly. In addition, the core microbiota of healthy shrimp gut harbored more diverse bacterial taxa with more cooperative interactions, while the diseased core microbiota showed opposite pattern with significantly higher abundance of opportunistic pathogens as well. These findings indicate that shrimp heath is highly relevant to the homeostasis of its gut bacterial community. Preservation and restoration of the bacterial community equilibrium could represent an effective strategy for shrimp disease prevention. PMID- 30022309 TI - Nonoperative management of blunt liver injury in hemodynamically stable versus unstable patients: a retrospective study. AB - PURPOSE: The success rate of nonoperative management (NOM) of traumatic liver injury is approximately 90%. Although NOM has become the standard treatment when patients' vital signs are stable, open surgical hemostasis is often selected when these signs are unstable. At our hospital, we extensively use NOM along with transcatheter arterial embolization (TAE) to treat patients with severe abdominal trauma, as per our original protocol. We also apply NOM for severe liver injury with unstable hemodynamics. This retrospective study aimed to investigate the efficacy of NOM for blunt liver injury in hemodynamically stable and unstable patients. METHODS: We retrospectively examined 23 patients with severe liver injuries who underwent NOM after visiting our emergency outpatient department between 2007 and 2017. Patients were assigned to either the stable group with stable hemodynamics or the unstable group with unstable hemodynamics. RESULTS: The stable group comprised 13 patients, and the unstable group comprised 10 patients. All patients underwent TAE. While all patients in the stable group were discharged alive, one patient in the unstable group died during the hospital stay. The response rate to NOM was 90%, and no patient switched from NOM to open surgery. A higher rate of complications with a significantly longer average stay in the intensive care unit was observed in the unstable group. CONCLUSIONS: Even in the unstable group, NOM with TAE performed under careful general management facilitated avoidance of open surgery and provided high survival rates. PMID- 30022310 TI - Groundwater quality in open-defecation-free villages (NIRMAL grams) of Kurukshetra district, Haryana, India. AB - Groundwater is an indispensable natural resource for drinking water, generally in rural areas due to unavailability of treated water. The study was designed to investigate the groundwater quality in nine open-defecation-free (ODF) villages (Nirmal Grams) of Kurukshetra district, Haryana, India. For the research, 81 groundwater samples were collected from different borewells of Nirmal Grams during pre-monsoon (PRM), monsoon (MON), and post-monsoon (POM) seasons and were analyzed for 13 water quality parameters, i.e., pH, EC, TDS, Cl-, TH, Ca2+, Mg2+, Na+, K+, HCO3-, F-, SO42-, and PO42-, using standard methods. The Water Quality Index (WQI) was calculated from the analyzed parameters and the results were compared with the World Health Organization (WHO 2011) and the Bureau of Indian Standards (BIS 2012) in order to have an overview of the groundwater quality. The concentration of major anions and cations was found to be in the order of HCO3- > Cl- > SO42- > F- > PO42- and Ca2+ > Na+ > K+ > Mg2+, respectively. Statistical Package of Social Sciences (SPSS) version 23 was used for statistical analysis, Aquachem 2014 software (trial version) was used for Piper diagram, Box-Whisker plot, Schoeller, and Gibbs diagram, whereas WQI was calculated manually. The values of WQI in the study area were ranged between 32.08 and 88.38 in PRM, 46.62 and 102.33 in MON, and 34.99 and 79.81 in POM seasons, respectively. Groundwater quality index reveals that the majority of the samples fall under 'good' to 'excellent' water category. It indicates that the groundwater is suitable for drinking and other domestic uses. PMID- 30022311 TI - Comparative study of persistent organic pollutant (POP) (chlorinated pesticides, PCBs, and dioxins/furans) concentrations in cancer-affected human organs with those of healthy organs. AB - The concentrations of POPs (persistent organic pollutants) including 16 compounds of OCPs, 12 dioxin-like PCBs congeners, and 17 PCDDs/Fs congeners were determined in 46 human adipose tissue samples gathered from Jordanian citizens. Thirteen adipose tissue samples of healthy people were collected from Jordan University Hospital and 33 adipose tissue samples of cancer-affected patients were collected from King Hussein Cancer Center. All samples were extracted, cleaned-up, and analyzed using GC/MS. In the healthy person's samples, among the OCP compounds, the highest concentration was found for heptachlor-oxo-epoxide (5696.71 MUg/kg), while among the PCB congeners, the non-ortho PCB 126 shows the highest TEQ concentrations (5554.5 MUg TEQ/kg) and among the PCDDs/Fs congeners, the highest TEQ value was found for the congener 2,3,4,7,8-PeCDFs (5.93 MUg TEQ/kg). For the cancer-affected patient's samples, the highest concentration among the OCP compounds was found for o,p-DDT (638.7 MUg/kg), while among the PCBs congeners, the highest TEQ value was found for the non-ortho-PCB 126 (3366.24 MUg TEQ/kg) and among the PCDDs/Fs congeners, the highest TEQ value was found for the congener 1,2,3,7,8-PeCDDs (20.64 MUg TEQ/kg). OCP concentration level in adipose tissue samples for healthy people was 32 times higher than for cancer patient persons, while the TEQ values for dioxin-like PCB concentrations in adipose tissue samples of healthy people was 2.2 times higher than in the samples of cancer-affected patient and the TEQ values for PCDDs/Fs in adipose tissue samples of cancer-affected patient was 3 times higher than in the samples of healthy people. PMID- 30022312 TI - Pre-operative level of FGF23 predicts severe acute kidney injury after heart surgery in children. AB - BACKGROUND: Early detection of acute kidney injury (AKI) after cardiac surgery has improved recently with the discovery and validation of novel urinary biomarkers. However, objective tools to predict the risk of AKI before the insult are still missing. We tested the hypothesis that pre-operative serum fibroblast growth factor 23 (FGF23) concentrations would be elevated in children who develop AKI after heart surgery with cardiopulmonary bypass (CPB). We also compared post operative FGF23 concentrations to other biomarkers for early detection of AKI. METHODS: Blood and urine samples were collected in a prospective observational study from 83 children with congenital heart disease. Severe AKI (sAKI) development (KDIGO stages II-III) in the first seven days after surgery was the primary outcome. RESULTS: Thirty of 76 (39.5%) and 11/76 (14.5%) of patients developed AKI and sAKI, respectively. Pre-operative serum creatinine, cystatin C, and urine biomarker concentrations did not differ between sAKI patients and controls. Pre-operative serum FGF23 levels were higher in patients who developed sAKI (median [IQR] value of 819 RU/ml [397.7, 1196.8] vs. 324.3 RU/ml [124.6, 679.8] (p = 0.02). FGF23 12-24 h after the termination of CPB was also associated with sAKI in the first week after surgery (498 RU/ml [226, 928] vs. 1435 RU/ml [831, 12,996]). CONCLUSIONS: Pre- and post-operative FGF23 levels are higher in children who develop sAKI after cardiac surgery. We suggest FGF23 may be able to detect sub-clinical kidney injury and can be used with demographic AKI risk factors to enhance post-operative sAKI risk prediction. PMID- 30022314 TI - Special Issue on High Performance Computing in Bio-medical Informatics. PMID- 30022313 TI - Genome-Wide Association Studies of Coronary Artery Disease: Recent Progress and Challenges Ahead. AB - PURPOSE OF REVIEW: Genome-wide association studies (GWAS) have been the primary tool for unbiased assessment of the genetic basis of coronary artery disease (CAD) for more than a decade. We summarize successes as well as shortcomings of recent studies in this context. RECENT FINDINGS: The number of CAD-associated loci has more than doubled in the past year to 161. This rapid progress has been in large part due to the release of genome-wide genotyping data for the largely European participants of the UK Biobank study which has been combined with existing GWAS from the CARDIoGRAMplusC4D consortium. Additional discoveries have been achieved through large-scale genotyping of participants using custom high yield genotyping arrays including the Metabochip and the Exome chip. As a consequence, the ability of genetic risk scores in predicting incident CAD events has improved but that improvement has only been shown in European populations. GWAS have proven to be a fruitful approach for uncovering the genetic drivers of CAD. However, determining the mechanisms of association of GWAS findings remains a challenging endeavor requiring long-term investment. Genetic risk scores offer an opportunity for recent findings to have an immediate clinical impact. Going forward, CAD genetics will benefit greatly from the release of more genetic data produced by mega-biobanks. These new data will allow for the more comprehensive examination of underrepresented populations. PMID- 30022315 TI - Elucidation of the molecular and electronic structures of some magic silver clusters Agn (n = 8, 18, 20). AB - Density functional theory (DFT) calculations were carried out to explore the geometric, spectroscopic, and electronic properties of three magic silver clusters Agn (n = 8, 18, and 20) in detail. The computed results show that the global minima of these clusters are compact, near-spherical structures, while other low-lying isomers exhibit oblate or prolate shapes. Vertical ionization energies for the low-lying isomers were also computed and assigned with respect to available experimental values. Although several isomers were predicted to have similar energies, their electronic and vibrational signatures were quite distinctive, meaning that they could be used as fingerprint signals to distinguish between isomers. In addition, the electronic structures of these systems were explored using the phenomenological shell model. Calculations for the coinage metal clusters M20 (M = Cu, Ag, Au) indicated that the structures and properties of the Ag cluster are similar to those of the Cu cluster in that both Cu20 and Ag20 prefer a compact structure whereas Au20 prefers to adopt a tetrahedral form. Graphical abstract Shell Orbitals of Ag8 Cluster. PMID- 30022316 TI - Passive therapeutic hypothermia during ambulance and helicopter secondary neonatal transport in neonates with hypoxic brain injury: a 10-year retrospective survey. AB - BACKGROUND: Therapeutic hypothermia is a method of treatment in newborns with hypoxic ischemic encephalopathy. Hypothermia should be initiated no later than 6 h after birth. The purpose of this study was to evaluate the quality of the passive therapeutic cooling during neonatal transport. PURPOSE: The study aims to evaluate the efficiency of our transport in maintenance of target body temperature during transport. METHODS: We conducted a 10-year retrospective study in neonates, transported by helicopter or ambulance, who received therapeutic passive-induced hypothermia during transport to the Department of Pediatric Surgery and Intensive Therapy at the University Medical Centre Ljubljana between September 1, 2006, and December 31, 2016. RESULTS: Out of 68 transported newborns, 57 met the criteria for therapeutic induced hypothermia. Eight out of 51 (15.7%) were within therapeutic temperature zone before start of transport while 30 out of 57 (52.6%) were within therapeutic temperature zone at the end of transport. There was a negative correlation between the duration of transport and temperature at the admission (rho = - 0.306; p = 0.026). A positive correlation was found between the body temperature before and at the end of transport (rho = 0.410; p = 0,003). A positive correlation between axillary and rectal temperature on admission was found (rho = 0,832; p < 0,0005). The type of transport, meteorological season, or gender differences did not affect any of measured parameters. Newborns who received chest compression had lower temperature. CONCLUSION: Therapeutic temperature zone during transport was achieved in 52.6% of transported neonates. Axillary temperature positively correlated with rectal temperature on admission. PMID- 30022317 TI - Thought Chart: tracking the thought with manifold learning during emotion regulation. AB - The Nash embedding theorem demonstrates that any compact manifold can be isometrically embedded in a Euclidean space. Assuming the complex brain states form a high-dimensional manifold in a topological space, we propose a manifold learning framework, termed Thought Chart, to reconstruct and visualize the manifold in a low-dimensional space. Furthermore, it serves as a data-driven approach to discover the underlying dynamics when the brain is engaged in a series of emotion and cognitive regulation tasks. EEG-based temporal dynamic functional connectomes are created based on 20 psychiatrically healthy participants' EEG recordings during resting state and an emotion regulation task. Graph dissimilarity space embedding was applied to all the dynamic EEG connectomes. In order to visualize the learned manifold in a lower dimensional space, local neighborhood information is reconstructed via k-nearest neighbor based nonlinear dimensionality reduction (NDR) and epsilon distance-based NDR. We showed that two neighborhood constructing approaches of NDR embed the manifold in a two-dimensional space, which we named Thought Chart. In Thought Chart, different task conditions represent distinct trajectories. Properties such as the distribution or average length in the 2-D space may serve as useful parameters to explore the underlying cognitive load and emotion processing during the complex task. In sum, this framework is a novel data-driven approach to the learning and visualization of underlying neurophysiological dynamics of complex functional brain data. PMID- 30022318 TI - Brief vs. ultrabrief pulse ECT: focus on seizure quality. AB - The effect of electroconvulsive therapy (ECT) performed with ultrabrief pulse (UBP) stimulation has been found inferior to brief pulse (BP) ECT in various studies. We reinvestigated this issue using a new dosing strategy that is based on seizure quality instead of seizure threshold. There is a long history of studies associating ictal characteristics of ECT with the clinical outcome. Accordingly, we used the clinical status of the patient and the quality of the prior seizure to determine the dosage for the upcoming treatment-referred to as Clinical and Seizure Based Stimulation (CASBAS). This approach aims at continuously providing high-quality seizures to optimize the outcome. While this dosing strategy was applied in our department, the pulse width was changed for a period of time from BP to UBP. It was hypothesized that the procedure would: (1) maintain seizure quality and clinical outcome under both conditions and would; and (2) compensate the lesser clinical efficacy of UBP by an increase in stimulus intensity. 245 patients received an ECT course according to the dosing strategy described, 162 with brief pulse (BP) and 83 with ultrabrief pulse ECT (UBP). In a retrospective evaluation, seizure quality and clinical outcome (available in a 20% subgroup of patients) did not differ between both groups in most of the examined parameters, while stimulus intensity was found to be significantly higher in the UBP group. As hypothesized, UBP was less efficient than BP in providing comparable ictal quality and clinical outcome. In a first test of concept the dosing strategy CASBAS seemed suitable to continuously adjust the stimulus intensity in ECT and maintain the seizure quality. PMID- 30022319 TI - Prevalence of seasonal depression in a prospective cohort study. AB - The prevalence of autumn/winter seasonality in depression has been documented in the longitudinal Zurich cohort study by five comprehensive diagnostic interviews at intervals over more than 20 years (N = 499). Repeated winter major depressive episodes (MDE-unipolar + bipolar) showed a prevalence of 3.44% (5* more women than men), whereas MDE with a single winter episode was much higher (9.96%). A total of 7.52% suffered from autumn/winter seasonality in major and minor depressive mood states. The clinical interviews revealed novel findings: high comorbidity of Social Anxiety Disorder and Agoraphobia within the repeated seasonal MDE group, high incidence of classic diurnal variation of mood (with evening improvement), as well as a high rate of oversensitivity to light, noise, or smell. Nearly twice as many of these individuals as in the other MDE groups manifested the syndrome of atypical depression (DSM-V), which supports the prior description of seasonal affective disorder (SAD) as presenting primarily atypical symptoms (which include hypersomnia and increase in appetite and weight). This long-term database of regular structured interviews provides important confirmation of SAD as a valid diagnosis, predominantly found in women, and with atypical vegetative symptoms. PMID- 30022320 TI - The association of endothelin-1 levels with renal survival in polycystic kidney disease patients. AB - BACKGROUND: The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival. METHODS: In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis. RESULTS: Endothelin levels and height adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1-4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension. CONCLUSIONS: Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD. PMID- 30022321 TI - Autonomic dysfunction in the neurological intensive care unit. AB - Autonomic dysfunction is common in neuro-critical care patients and may compromise the function of various organs. Among the many diseases causing or being associated with autonomic dysfunction are traumatic brain injury, cerebrovascular diseases, epilepsy, Guillain-Barre syndrome (GBS), alcohol withdrawal syndrome, botulism and tetanus, among many others. Autonomic dysfunction may afflict various organs and may involve hyper- or hypo-activity of the sympathetic or parasympathetic system. In this short overview, we address only a small number of neuro-intensive care diseases with autonomic dysfunction. In GBS, autonomic dysfunction is frequent and may account for increased mortality rates; rapid changes between sympathetic and parasympathetic hypo- or hyper activity may cause life-threatening cardiovascular complications. Paroxysmal sympathetic hyperactivity occurs after brain injury, hypoxia and cerebrovascular and other events, causes paroxysmal tachycardia, hypertension, tachypnoea and hyperthermia and is associated with a poorer prognosis and prolonged intensive care treatment. Other, at times life-threatening autonomic complications with exaggerated sympathetic activity and compromised baroreflex sensitivity arise during the alcohol withdrawal syndrome triggered by abrupt cessation of alcohol consumption. Botulism and tetanus are examples of life-threatening autonomic dysfunction caused by bacterial neurotoxins. Common neurological diseases, such as epilepsy, stroke or subarachnoid haemorrhage, are also associated with autonomic dysfunction that can on occasion cause critical deterioration of disease severity and prognosis. PMID- 30022322 TI - Commentary to the paper by Walter Dempsey and Peter McCullagh. PMID- 30022323 TI - Contribution to the discussion of 'Survival models and health sequences' by W. Dempsey and P. McCullagh. PMID- 30022324 TI - Obstructive sleep apnea negatively impacts objectively measured physical activity. AB - PURPOSE: Obesity and obstructive sleep apnea (OSA) are frequent comorbid conditions. The impact of OSA on objectively measured physical activity (PA), independent of obesity, is not clear. The purpose of this study is to examine the effect of OSA on PA measured via accelerometer. METHODS: Overweight-to-obese individuals were recruited and screened for the presence of OSA via portable diagnostic device and divided into an OSA (n = 35) and control group (n = 24). Daytime sleepiness was assessed with the Epworth Sleepiness Scale. Body composition was assessed with dual-energy X-ray absorptiometry. Subjects wore an accelerometer (Actigraph GT3X+, Actigraph Corp., Pensacola, FL) for a minimum of 4 and maximum of 7 days, including at least one weekend day. RESULTS: There were no group differences in body mass index (BMI) or daytime sleepiness. Waist and neck circumference were higher in the OSA group. The OSA group was significantly older than the control group. The OSA group had fewer steps, moderate intensity minutes, moderate-to-vigorous minutes, number of PA bouts per day (>= moderate intensity PA for >= 10 consecutive minutes), and total number of PA bouts. When adjusted for age, the PA bout data was no longer significant. CONCLUSION: Individuals screened as likely possessing OSA were less physically active than individuals without OSA when measured through objective means. We found no group differences in daytime sleepiness, BMI, or percent fat, suggesting other mechanisms than obesity and sleepiness for this difference. PMID- 30022325 TI - Noncontact identification of sleep-disturbed breathing from smartphone-recorded sounds validated by polysomnography. AB - PURPOSE: Diagnosis of obstructive sleep apnea by the gold-standard of polysomnography (PSG), or by home sleep testing (HST), requires numerous physical connections to the patient which may restrict use of these tools for early screening. We hypothesized that normal and disturbed breathing may be detected by a consumer smartphone without physical connections to the patient using novel algorithms to analyze ambient sound. METHODS: We studied 91 patients undergoing clinically indicated PSG. Phase I: In a derivation cohort (n = 32), we placed an unmodified Samsung Galaxy S5 without external microphone near the bed to record ambient sounds. We analyzed 12,352 discrete breath/non-breath sounds (386/patient), from which we developed algorithms to remove noise, and detect breaths as envelopes of spectral peaks. Phase II: In a distinct validation cohort (n = 59), we tested the ability of acoustic algorithms to detect AHI < 15 vs AHI > 15 on PSG. RESULTS: Smartphone-recorded sound analyses detected the presence, absence, and types of breath sound. Phase I: In the derivation cohort, spectral analysis identified breaths and apneas with a c-statistic of 0.91, and loud obstruction sounds with c-statistic of 0.95 on receiver operating characteristic analyses, relative to adjudicated events. Phase II: In the validation cohort, automated acoustic analysis provided a c-statistic of 0.87 compared to whole night PSG. CONCLUSIONS: Ambient sounds recorded from a smartphone during sleep can identify apnea and abnormal breathing verified on PSG. Future studies should determine if this approach may facilitate early screening of SDB to identify at risk patients for definitive diagnosis and therapy. CLINICAL TRIALS: NCT03288376; clinicaltrials.org. PMID- 30022327 TI - Recommendations for clear aligner therapy using digital or plaster study casts. AB - BACKGROUND: Clear aligner therapy has evolved considerably since its introduction 20 years ago. Clinicians have become more experienced with aligner therapy, but little is known about the types of malocclusions that clinicians currently treat with aligners. Similarly, it is not known if viewing digital vs plaster models has any impact on the treatment planning process for aligners. The aim of this study was to assess which types of malocclusions are recommended for treatment with clear aligners, and also to determine if recommendations for aligner treatment differed when using digital versus plaster models. METHODS: Sixteen orthodontists treatment planned 20 cases at two time points with either the same or different model formats (digital versus plaster). As part of the treatment planning process, they were asked whether each patient was a good candidate for Invisalign(r) treatment, and if not, why. Generalized estimating equations regression (GEE), the permutation test, and a logistic regression model with GEE were used to analyze the data. RESULTS: No significant difference was found between the Invisalign(r) choices in the digital model group and those in the plaster model group at T1 (p = 0.59). There was no significant difference between the agreement rate of the different formats group and that of the same format group (p = 0.97). Cases with extractions had less Invisalign(r) recommendations (15%) compared to cases with no extractions (55%) (p = 0.0015). Cases with surgery had less Invisalign(r) recommendations (29%) compared to cases with no surgery (57%) (p = 0.035). CONCLUSIONS: In this study, viewing orthodontic records with digital versus plaster models did not influence decisions about Invisalign(r) recommendations. Additionally, the orthodontists in this study tended to not recommend Invisalign(r) for extraction cases, surgical cases, or difficult cases. PMID- 30022326 TI - Bifurcations of Limit Cycles in a Reduced Model of the Xenopus Tadpole Central Pattern Generator. AB - We present the study of a minimal microcircuit controlling locomotion in two-day old Xenopus tadpoles. During swimming, neurons in the spinal central pattern generator (CPG) generate anti-phase oscillations between left and right half centres. Experimental recordings show that the same CPG neurons can also generate transient bouts of long-lasting in-phase oscillations between left-right centres. These synchronous episodes are rarely recorded and have no identified behavioural purpose. However, metamorphosing tadpoles require both anti-phase and in-phase oscillations for swimming locomotion. Previous models have shown the ability to generate biologically realistic patterns of synchrony and swimming oscillations in tadpoles, but a mathematical description of how these oscillations appear is still missing. We define a simplified model that incorporates the key operating principles of tadpole locomotion. The model generates the various outputs seen in experimental recordings, including swimming and synchrony. To study the model, we perform detailed one- and two-parameter bifurcation analysis. This reveals the critical boundaries that separate different dynamical regimes and demonstrates the existence of parameter regions of bi-stable swimming and synchrony. We show that swimming is stable in a significantly larger range of parameters, and can be initiated more robustly, than synchrony. Our results can explain the appearance of long-lasting synchrony bouts seen in experiments at the start of a swimming episode. PMID- 30022328 TI - Onco-metabolism: defining the prognostic significance of obesity and diabetes in women with brain metastases from breast cancer. AB - PURPOSE: Metabolic dysregulation has been implicated as a molecular driver of breast cancer in preclinical studies, especially with respect to metastases. We hypothesized that abnormalities in patient metabolism, such as obesity and diabetes, may drive outcomes in breast cancer patients with brain metastases. METHODS: We retrospectively identified 84 consecutive patients with brain metastases from breast cancer treated with intracranial radiation therapy. Radiation was delivered as whole-brain radiation to a median dose of 3000 cGy or stereotactic radiosurgery to a median dose of 2100 cGy. Kaplan Meier curves were generated for overall survival (OS) data and Mantel-Cox regression was performed to detect differences in groups. RESULTS: At analysis, 81 survival events had occurred and the median OS for the entire cohort was 21.7 months. Despite similar modified graded prognostic assessments, resection rates, and receptor status, BMI >= 25 kg/m2 (n = 45) was associated with decreased median OS (13.7 vs. 30.6 months; p < 0.001) and median intracranial progression-free survival (PFS) (7.4 vs. 10.9 months; p = 0.04) compared to patients with BMI < 25 kg/m2 (n = 39). Similar trends were observed among all three types of breast cancer. Patients with diabetes (n = 17) had decreased median OS (11.8 vs. 26.2 months; p < 0.001) and median intracranial PFS (4.5 vs. 10.3 months; p = 0.001) compared to non diabetics (n = 67). On multivariate analysis, both BMI >= 25 kg/m2 [HR 2.35 (1.39 3.98); p = 0.002] and diabetes [HR 2.77 (1.454-5.274); p = 0.002] were associated with increased mortality. CONCLUSIONS: Elevated BMI or diabetes may negatively impact both overall survival and local control in patients with brain metastases from breast cancer, highlighting the importance of the translational development of therapeutic metabolic interventions. Given its prognostic significance, BMI should be used as a stratification in future clinical trial design in this patient population. PMID- 30022329 TI - Population-based validation of the National Cancer Comprehensive Network recommendations for breast cancer staging. AB - OBJECTIVE: The aim of the current study is to evaluate the performance characteristics of the National Comprehensive Cancer Network (NCCN) staging recommendations for breast cancer with regard to the detection of lung, bone, and liver metastases. METHODS: Surveillance, epidemiology, and end points (SEER) database (2010-2015) was accessed, and patients with breast cancer and complete information about T stage and clinical N stage, ER status, Her2 status, and metastatic sites were extracted. Performance characteristics evaluated for the current study included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), number needed to investigate (NNI), and accuracy. RESULTS: A total of 239,196 patients were included in the analysis. For the overall cohort, the required PPV (for the recognition of lung metastases) is 10.6% and NNI to detect one case of lung metastasis is 9.4. Likewise, PPV (for the recognition of bone metastases) is 18.6% and NNI to detect one case of bone metastasis is 5.3. Moreover, PPV (for the recognition of liver metastases) is 7.6% and NNI to detect one case of liver metastasis is 13.1. When changing the threshold for baseline imaging to includeT2N1 patients, a better balance between sensitivity and specificity among ER+/Her2- patients (> 92% for both sensitivity and specificity for the three metastatic sites) was observed. On the other hand, the proposed change improved sensitivity while it lowers significantly the specificity among Her2+ and triple negative subtypes (specificity < 84% for Her2+ disease for the three metastatic sites; specificity < 87% for triple negative disease for the three metastatic sites). CONCLUSION: The current NCCN recommendations for breast cancer staging have an excellent NPV and miss only few patients with lung, liver, or bone metastases. Future studies incorporating the subtype of breast cancer as a determinant of staging pathway is needed. PMID- 30022330 TI - Systematic review of blood diagnostic markers in colorectal cancer. AB - The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples. PMID- 30022331 TI - Bilateral versus unilateral botulinum toxin injections for chronic anal fissure: a randomised trial. AB - BACKGROUND: Botulinum toxin injected into the internal anal sphincter is used in the treatment of chronic anal fissure but there is no standardised technique for its administration. This randomised single centre trial compares bilateral (either side of fissure) to unilateral injection. METHODS: Participants were randomised to receive bilateral (50 + 50 units) or unilateral (100 units) Dysport(r) injections into the internal anal sphincter in an outpatient setting. Injection-related pain assessed by visual analogue scale was the primary outcome measure. Secondary outcomes were healing rate, fissure pain, incontinence, and global health scores. RESULTS: Between October 2008 and April 2012, 100 patients with chronic anal fissure were randomised to receive bilateral or unilateral injections. Injection-related pain was comparable in both groups. There was no difference in healing rate. Initially, there was greater improvement in fissure pain in the bilateral group but at 1 year the unilateral group showed greater improvement. Cleveland Clinic Incontinence score was lower in the unilateral group in the early post-treatment period and global health assessment (EuroQol EQ VAS) was higher in the unilateral group at 1 year. CONCLUSIONS: Injection-related pain was similar in bilateral and unilateral injection groups. Unilateral injection was as effective as bilateral injections in healing and improving fissure pain without any deterioration in continence. PMID- 30022332 TI - Patterns of uveitis in patients with proven systemic (pulmonary and extrapulmonary) tuberculosis. AB - PURPOSE: To report patterns of uveitis in patients with systemic tuberculosis. METHODS: Records of patients presenting at uvea clinic of a tertiary eye care centre were evaluated retrospectively, and 47 cases with proven systemic tuberculosis were analyzed for patterns of uveitis. Tuberculosis had been proven with a combination of radio imaging and detection of acid fast bacilli in body fluids. All patients had been reviewed by a specialist as applicable before diagnosing tuberculosis. These patients had undergone a thorough ocular workup. Pattern of uveitis was the primary outcome measure. RESULTS: Mean age was 35.34 +/- 15.56 years. Lung was the commonest systemic focus, seen in nearly 75% of the cases. Anterior uveitis was the most common presentation (48.9%), followed by posterior (25.5%), panuveitis (10.6%) and intermediate uveitis (10.6%). Multifocal serpiginoid choroidopathy (MSC) was seen in only one patient, while granulomatous choroiditis was the commonest type of posterior uveitis. CONCLUSIONS: Anterior uveitis is the most frequent type of uveitis seen in patients with proven systemic tuberculosis. Rarity of MSC in such patients indicates possibility of etiologies other than tuberculosis in causing MSC. PMID- 30022333 TI - Discontinuation of non-anti-TNF drugs for rheumatoid arthritis in interventional versus observational studies: a systematic review and meta-analysis. AB - PURPOSE: Although randomized controlled trials (RCTs) are the gold standard for the assessment of clinical outcomes, long-term extension trials (LTEs) and observational cohorts may help generate evidence. Our goal was to compare the discontinuation rates of abatacept, rituximab, and tocilizumab in rheumatoid arthritis (RA) reported in different study designs. METHODS: A systematic review was conducted with searches in PubMed, Scopus, and the Cochrane Library, plus a manual search, for RCTs, LTEs, and observational cohorts reporting discontinuation rates by any of three causes (all-cause, inefficacy, adverse events). Meta-analyses with sensitivity analyses and meta-regressions were conducted. RESULTS: Of the 111 studies included, 74 were RCTs (n = 55) or LTEs (n = 17) reporting data on abatacept (n = 33), rituximab (n = 10), and tocilizumab (n = 31) and 37 were observational cohort studies (abatacept = 11, rituximab = 8, tocilizumab = 18). The follow-up duration did not differ among the study designs. Discontinuation rates were similar among the drugs but varied among the study designs. Discontinuation rates were significantly higher in cohort studies than those in interventional studies for the three drugs. Sensitivity analyses could not identify patient characteristics associated with these differences. Meta regression analyses demonstrated no correlation between study follow-up duration and discontinuation rates. CONCLUSIONS: The discontinuation rates reported for non-anti-TNF drugs varied relative to the study design in which they were investigated. Regulatory agencies, price-setting entities, and evidence-gathering researchers should consider the effect of the real-life environment in their decisions and conclusions. PMID- 30022334 TI - A randomised controlled trial of the impact of structured written and verbal advice by community pharmacists on improving hypertension education and control in patients with high blood pressure. AB - PURPOSE: This study was aimed to determine whether structured written and verbal education provided to patients by community pharmacists about high blood pressure (BP) and its treatment would be (a) better retained and (b) be associated with improved BP control as compared to patients receiving verbal advice only. METHODS: The study was designed as a randomised controlled trial and was conducted in the West Midlands, UK, between January 2014 and June 2014. The primary outcome measures were differences in systolic and diastolic BP from baseline and retention of information about high BP assessed with a questionnaire at 2-, 4- and 26-week follow-up points. RESULTS: A total of 64 adults were included in the study. At the week 26 follow-up, compared to participants in the control group, there was a significant improvement in the knowledge of intervention participants about the risks associated with high BP (p < 0.001) and awareness about potential adverse effects of the new BP medicine (p < 0.001). Similarly, there was a greater and more significant reduction in systolic BP in favour of the intervention group 8 mmHg (95% CI 2.1-13.3 p = 0.009) compared to 6 mmHg (95% CI 0.6-11.7 p = 0.02) in the control group at the week 4 follow-up. However, this greater effect of an intervention on BP was not sustained at the 26 week follow-up. For diastolic BP, there was no added effect of the intervention. CONCLUSION: This randomised controlled trial suggests that although written advice provided by community pharmacists in comparison to verbal advice was more effective in improving knowledge and understanding of patients about hypertension and its treatment, it did not lead to better blood pressure control. PMID- 30022335 TI - Using hospital medical record data to assess the accuracy of the SEER Los Angeles Cancer Surveillance Program for initial treatment of prostate cancer: a small pilot study. AB - PURPOSE: Treatment information from the Surveillance, Epidemiology, and End Result Program (SEER) cancer registries is increasingly being used for population based cancer research; however, it may be incomplete for outpatient procedures and is not quality controlled. We sought to validate SEER information on initial treatment of prostate cancer by comparison to electronic medical record (EMR) review. METHODS: Patients diagnosed with prostate cancer between 1 January 2010 and 31 December 2014 in Los Angeles County who received treatment at our institution within 6 months of diagnosis were identified from the SEER registry. We reviewed the hospital EMR for these patients and identified initial treatment received within 6 months of diagnosis. We compared data reported to SEER data to our re-abstracted hospital EMR data (defined as the gold standard) to identify the completeness of SEER treatment data (sensitivity) and the accuracy of the SEER information (positive predictive value). RESULTS: Based on 266 eligible patients, SEER's sensitivity in capturing initial treatment was 95.9% (118/123) for prostatectomy, 95.8% (69/72) for no treatment, 87.5% (21/24) for radiation therapy, 68.3% (28/41) for active surveillance or watchful waiting, and 50.0% (2/4) for cryosurgery. The SEER positive predictive value was 100% for radiation therapy and cryosurgery, 97.5% (118/121) for radical prostatectomy, 82.3% (28/34) for active surveillance or watchful waiting, and 78.4% (69/88) for no treatment. CONCLUSION: The SEER data were highly sensitive and has a high positive predictive value for surgery and radiation therapy but underreported use of active surveillance. These results may assist researchers in understanding the strengths and weaknesses of using SEER prostate cancer treatment data. PMID- 30022337 TI - Investigating toxic metal levels in popular edible fishes from the South Durban basin: implications for public health and food security. AB - Contamination of the ocean by heavy metals may have ecosystem-wide implications because they are toxic even if present in trace levels, and the relative ease of their bioaccumulation by marine organisms may affect human health, primarily through consumption of contaminated fish. We evaluated metal concentrations in six different popular edible fish species and estimated the potential health risks from consumption of contaminated fish. There was no correlation between fish length and average metal accumulation although the fish species tended to accumulate significantly more Al and Zn (P < 0.05) than any of the other metals. Significantly higher Mn concentrations were found in fish gills compared to other body parts in all fish species. Bronze seabream, Catface rockcod, and Slinger seabream had significantly higher mean Cr concentration in the liver than in either the tissues or gills. The highest concentration of Zn in fleshy tissue was in Horse mackerel (56.71 MUg g-1) followed by Bronze seabream (31.07 MUg g-1). Al levels ranged from 5.6 MUg g-1 in Atlantic mackerel to 35.04 MUg g-1 in Horse mackerel tissue while Cu and Cr concentrations were highest in the tissues of Horse mackerel (6.83 and 1.81 MUg g-1, respectively) followed by Santer seabream (3.15; 1.09 MUg g-1) and Bronze seabream (3.09; 1.30 MUg g-1), respectively. The highest tissue concentration of Mn was detected in Bronze seabream (8.23 MUg g-1) followed by Catface rockcod (6.05 MUg g-1) and Slinger seabream (5.21 MUg g-1) while Pb concentrations ranged from a high of 8.44 MUg g-1 in Horse mackerel to 1.09 MUg g-1 in Catface rockcod. However, the estimated potential health risks from fish consumption as determined by the target hazard quotient (THQ) and hazard index (HI) were significantly lower than 1, implying that metals were not present in sufficiently high quantities to be of any health and/or food and security concern in the studied fishes. PMID- 30022336 TI - Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer. AB - PURPOSE: Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes. METHODS: We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes. RESULTS: Among 42,217 new metformin users and 42,217 matched new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use. CONCLUSIONS: In this large cohort study that accounted for time related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations. PMID- 30022339 TI - Reorganization energies of the electron transfer reactions involving quinones in the reaction center of Rhodobacter sphaeroides. AB - In framework of the continuum electrostatics theory, the reorganization energies of the electron transfers QA--QB (fast phase), Bph--QA, P+-QA-, and P+-QB- in the photosynthetic bacterial reaction center have been calculated. The calculations were based on the static dielectric permittivity spatial distribution derived from the data on the electrogenesis, with the corresponding characteristic times relatively close to the reaction times of QA--QB (fast phase) and Bph--QA but much shorter than those times of the latter two recombination reactions. The calculated reorganization energies were reasonably close to the experimental estimates for QA--QB (fast phase) and Bph--QA but substantially lower than those of P+-QA- and P+-QB-. A higher effective dielectric permittivity contributes to this effect, but the dominant contribution is most probably made by a non dielectric relaxation, especially for the P+-QB- recombination influenced by the proton transfer. This situation calls for reconsidering of the current electron transfer rate estimates. PMID- 30022338 TI - Validation of a robust LLE-GC-MS method for determination of trihalomethanes in environmental samples. AB - An analytical liquid-liquid extraction-gas chromatography-mass spectrometry (LLE GC-MS) method was developed and validated for the determination of trihalomethanes (THMs) in environmental samples. The compounds studied were trichloromethane (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and tribromomethane (TBM). The calibration curves for the THMs showed high linearity in the range of 1-1000 MUg L-1. Studies of intra-day and inter-day precision, limit of detection (LOD), limit of quantification (LOQ), accuracy, and recovery were performed with low (10 MUg L-1), medium (40 MUg L-1), and high (200 MUg L-1) concentrations of THMs. The intra-day and inter-day precision RSD varied in the ranges of 0.17-6.95% and 0.26-15.70%, respectively. No statistical differences were observed between the analysis of the concentration of certified reference materials (CRM 4M8140-U) and the values reported by CRM, indicating the good accuracy of the proposed method. The recovery was 88.75-119.21%. The LOD and LOQ were smaller than 0.13 and 0.40 MUg L-1. Compared with reported LLE-GC-MS methods, the validated method had similar LOD and enhanced LOQ, precision, accuracy, and recovery. Also, the method is robust, selective to THMs, and the total time for the extraction and GC separation of THMs is about 18 min. The method was useful for detecting and quantifying low concentrations of TCM (40-80 MUg L-1) formed by water chlorination in the presence of Microcystis aeruginosa cyanobacteria, thus demonstrating its applicability for monitoring THMs in real samples. PMID- 30022340 TI - Reference Parameters for Protein Hydrogen Exchange Rates. AB - The analysis of many hydrogen exchange (HX) experiments depends on knowledge of exchange rates expected for the unstructured protein under the same conditions. We present here some minor adjustments to previously calibrated values and a stringent test of their accuracy. Graphical Abstract ?. PMID- 30022341 TI - Protective role of antifreeze proteins on sterlet (Acipenser ruthenus) sperm during cryopreservation. AB - The loss of sperm quality in sterlet (Acipenser ruthenus) due to freeze-thaw process in cryopreservation was investigated in the present study. Two antifreeze proteins (AFPI or AFPIII) were used at different concentrations of 0.1, 1, 10, and 100 MUg/mL. We compared motility, curvilinear velocity, and plasma membrane integrity of fresh, cryopreserved sperm, and sperm cryopreserved in the presence of antifreeze proteins. Fresh sperm (control) had 85 +/- 4% motility and 160 +/- 2 MUm/s curvilinear velocity, respectively. After cryopreservation, the motility of frozen-thawed sperm without addition of antifreeze proteins significantly decreased (44 +/- 9%), compared to the control. The highest motility of frozen thawed sperm was obtained in cryopreserved sperm with addition of 1 MUg/mL of AFPIII (58 +/- 14%). No significant differences were observed in curvilinear velocity between fresh sperm and cryopreserved sperm with/without addition of AFPI or AFPIII. The flow cytometry analysis revealed that fresh sperm contained 94.5 +/- 6% live cells, while the cryopreserved sperm only contained 26.6 +/- 14% live cells. Supplementation of antifreeze proteins has significantly improved the percentage of live cells in frozen-thawed sperm, except 0.1 MUg/ml of AFPI group. No significant difference in percentage of live cells was detected in the sperm cryopreserved with 10 MUg/mL of AFPI or AFPIII, compared to fresh sperm. Thus, addition of antifreeze proteins to cryopreservation medium could be considered to improve the post-thawed sperm quality of sterlet. PMID- 30022342 TI - Risk assessment and copper geochemistry of an orchard irrigated with mine water: a case study in the semiarid region of Brazil. AB - This study aimed to evaluate mine water reuse, elucidating the potential problems related to trace metal biogeochemistry focusing on Cu dynamics in water, soil, and plants. Water samples were collected from a Cu mine and a reservoir used to store mine water. Additional samples were taken from soils from an uncultivated area and a banana orchard (irrigated with mine water for at least 10 years) and plant from the irrigated area. The following parameters were analyzed: pH, redox potential, dissolved ions in water samples (e.g., Ca2+, Mg2+, Na+, K+, Cu2+, SO 42- , and Cl-), bioavailable Cu and Cu solid-phase fractionation (in soils and reservoir sediments samples), as well as Cu content in banana plants. Mine water presents high dissolved Cu concentration (mean 2.3 +/- 0.0 mg L-1), limiting its use for irrigation. Water storage at the reservoir increased water quality, reducing dissolved Cu concentration (mean 0.2 +/- 0.0 mg L-1), due to adsorption/precipitation as carbonates (mean 131.8 +/- 24.6 mg kg-1), organic matter (mean 1526.2 +/- 4.7 mg kg-1) and sulfides (mean 158.4 +/- 56.9 mg kg-1). Despite higher water quality at the reservoir, the use of mine water increased the amount of bioavailable Cu in soils, which was primarily associated with organic matter. Increased bioavailable Cu in the soil did not increase the Cu content of banana leaves but resulted in high Cu content of roots and fruit, increasing the risk of toxicity for the population. PMID- 30022343 TI - Comparative genetic variability in HIV-1 subtype C p24 Gene in early age groups of infants. AB - It is important to study the molecular properties of vertically transmitted viruses in early infancy to understand disease progression. P24 having an important role in virus assembly and maturation was selected to explore the genotypic characteristics. Blood samples, obtained from 82 HIV-1 positive infants, were categorized into acute (<= 6 months) and early (> 6-18 months) age groups. Of the 82 samples, 79 gave amplification results for p24, which were then sequenced and analysed. Amino acid heterogeneity analysis showed that substitutions were more frequent. Several substitution mutations were present in some of the sequences of both the age groups in the functional motifs of the gene namely Beta hairpin, CyPA binding loop, residues L136 and L190, linker region and major homology region. In the acute age group, an insertion of Asparagine residue (N5NL6) was observed in the beta hairpin region in one of the sequences. This insertion was accompanied with analogous substitutions of N5Q, Q7L and G8R. In the early age group, a deletion of two residues; VK181-182, was observed at the C terminal end in one of the sequences. These mutations may impair the structure of the protein leading to defective virus assembly. Protein variation effect analyzer software showed that deleterious mutations were more in the acute than the early age group. Variability analysis revealed that the amino acid heterogeneity was comparatively higher in the acute than the early age group. Variability in the virus was decreasing with the increasing age of the infants indicating that the virus is gradually evolving under positive selection pressure. HLA class 1 binding peptide analysis showed that the epitopes TPQDLNTML and RMYSPVSIL may be helpful in designing epitope based vaccine. PMID- 30022344 TI - Ecotoxicological Test Assay Using OECD TG 212 in Marine Java Medaka (Oryzias javanicus) and Freshwater Japanese Medaka (Oryzias latipes). AB - The lethal effects of chemicals is a serious concern to the protection of ecosystems, and the OECD TG 212 was established to estimate the lethal and sublethal effects on embryo and sac-fry stages of fish. It is still unclear, however, whether this test can effectively estimate the impacts of chemicals using marine fish. Therefore, this study aimed to use a recognized testing method on the marine fish Oryzias javanicus, and to assess differences in response to organotin compounds between a freshwater congener (Oryzias latipes) and O. javanicus. The lowest observed effect concentration (LOEC) of triphenyltin for lethal effect was the same in both species. The LOEC of tributyltin for lethal and sublethal effects were the same in both species. Our results provide the first evidence that O. javanicus and O. latipes are similarly affected by organotin compounds, suggesting that O. javanicus is a good model marine fish for the ecotoxicological assessment of chemicals. PMID- 30022345 TI - Chromium Speciation in the Size-Fractions of a Soil Polluted by Weathered Chromate Ore Process Residue Using Synchrotron X-ray Analysis. AB - The chromate ore process residues (COPR) polluted soil was physically separated into coarse sand (2.000-0.425 mm), fine sand (0.425-0.053 mm) and silt to clay (< 0.053 mm) fractions. The Cr speciation was characterized by synchrotron based micro X-ray fluorescence (u-XRF) and micro X-ray absorption near-edge spectra (u XANES). The results indicated that Cr was bearing both in COPR parent minerals and hydrated products and was dominated by Cr(III) in three size-fractions. The synchrotron results indicated that Cr(III) was dominated by chromite, organic matter bound Cr(III) and particle adsorbed Cr3+ in the selected hotspots from the coarse sand, fine sand and silt to clay sized fraction, respectively. While Cr(VI) occurred in the form of CrO42- in the selected hotspots from three size fractions. The difference of Cr(III) species in the size-fractions suggested that higher edaphic effects occurred in the fine size-fractions than in the coarse size-fraction for the weathered COPR. PMID- 30022347 TI - Preference of cancer patients and family members regarding delivery of bad news and differences in clinical practice among medical staff. AB - OBJECTIVES: To study the preferences of cancer patients and their families in way of being informed of their condition and, by comparing their preferences with the medical staff's clinical practices, explore the factors underlying the latter's preferences. METHODS: A survey was conducted with 216 cancer patients, 242 families, and 176 clinical staff members with the Medical Status Communication questionnaire (Simplified Chinese edition). RESULTS: The clinical staff scored lower than the cancer patients and their families in terms of the total score, way of communication, emotional support, and additional information (F = 16.134, p < .001; F = 28.604, p < .001; F = 13.839, p < .001; F = 16.745, p < .001). Factors underlying the medical staff's clinical practices included, as revealed by the multiple linear regression analysis, gender (p = .03), and willingness to improve the way of communication about cancer (p = .006). CONCLUSIONS: A gap existed between the medical staff's clinical practice and the preferences of the cancer patients and their families. The medical staff should receive adequate training in cancer communication skills and techniques for improvement in this respect. When designing training for skills in delivering bad news to cancer patients, the well-being of cancer patients and their families must be thoroughly considered, and patient demands for information should be satisfied in the context of the information explosion of the current age. PMID- 30022346 TI - The efficacy and prescription of neuromuscular electrical stimulation (NMES) in adult cancer survivors: a systematic review and meta-analysis. AB - PURPOSE: This study aims to (1) summarise and critically evaluate the effects of neuromuscular electrical stimulation (NMES) on indices of health and quality of life (QoL) in adult cancer survivors, (2) assess the safety of NMES as a rehabilitation method in this population, and (3) identify commonly used NMES treatment parameters and describe treatment progression. METHODS: A systematic search of four electronic databases targeted studies evaluating the effects of NMES on physical function, aerobic fitness, muscle strength, body composition, and health-related quality of life (HR-QoL) in adult cancer survivors, published through March 2018. Two reviewers independently reviewed and appraised the risk of bias of each study. RESULTS: Nine studies were included. Meta-analyses found that the overall pooled effect favoured NMES for improving muscle strength, but the standardised mean difference was not significant (0.36; 95% CI - 0.25, 0.96). Further meta-analyses indicated that NMES significantly improved HR-QoL (0.36; 95% CI 0.10, 0.62), with notable gains identified under the subcategories QoL Function (0.87; 95% CI 0.32, 1.42). Current NMES prescription is not standardised and NMES is prescribed to target secondary complications of treatment. Risk of bias was high for most studies. CONCLUSIONS: NMES use in adult cancer survivors is an emerging field and current literature is limited by studies of poor quality and a lack of adequately powered RCTs. Existing evidence suggests that NMES is safe and may be more effective than usual care for improving HR-QoL. Prescription and progression should be tailored for the individual based on functional deficits. PMID- 30022348 TI - Correlates of anxiety and depression symptoms among patients and their family caregivers prior to allogeneic hematopoietic cell transplant for hematological malignancies. AB - PURPOSE: Given the complexities and risks of allogeneic HCT, patients and their family caregivers may experience elevated psychological distress, including symptoms of anxiety and depression, in anticipation of the procedure. Patients and caregivers also bring with them their pre-HCT experiences of diagnosis, prior treatment, and associated burdens, thus potentially compounding their acute distress. Identification of clinical, psychosocial, and sociodemographic factors related to pre-HCT distress would allow targeting of patients and caregivers who may require assistance during the HCT process. METHODS: Consecutive patients (n = 111) and their caregivers (n = 110) completed measures of anxiety, depression, cancer distress, perceived threat, perceived control, self-efficacy, relationship quality, and physical quality of life in the week before HCT. Multivariate linear regression analysis was used to identify factors associated with patient and caregiver anxiety or depression, including disease type, donor type, and patient and caregiver sociodemographic, health-related, and psychosocial factors. RESULTS: Family caregivers had higher levels of anxiety and depression symptoms than patients. Thirty percent of caregivers vs. 17% of patients met criteria for clinically significant anxiety and a lesser amount (5% for both) met criteria for clinically significant depression. Patient anxiety was related to younger age (b = - 0.22, p = 0.005) and greater cancer-related distress (b = 0.59, p < 0.001), while caregiver anxiety was related to lower self-efficacy (b = - 0.19, p = 0.011) and greater cancer-related distress (b = 0.58, p < 0.001). Similarly, patient depression was related to lower perceived control (b = - 0.17, p = 0.050), greater cancer-related distress (b = 0.34, p = 0.005), and lower physical functioning (b = - 0.26, p = 0.008), while caregiver depression was related to greater cancer-related distress (b = 0.46, p < 0.001). CONCLUSIONS: Family caregivers may be more emotionally vulnerable than patients before HCT and in need of additional assistance. Cancer-related distress was the strongest correlate of anxiety and depression in both patients and caregivers, suggesting that distress related to their cancer experience and its consequences plays a major role in their emotional functioning prior to HCT. PMID- 30022349 TI - Perceptions of Dutch health care professionals on weight gain during chemotherapy in women with breast cancer. AB - PURPOSE: Dutch Health care professionals (HCPs) provide little information concerning health risks associated with weight gain during chemotherapy for breast cancer. Women with breast cancer have specified the need for more information on nutrition and physical activity to deal with weight gain. The aims of this study were to assess the perceptions of Dutch HCPs on weight gain during chemotherapy and in addition evaluate whether and what kind of information on dietary intake and physical activity HCPs provide to prevent/treat weight gain during (neo)adjuvant chemotherapy. METHODS: A qualitative study was conducted using semi-structured interviews with 34 HCPs involved in breast cancer care: general practitioners, oncologists, specialized nurses, and dieticians. RESULTS: To date, little information about nutrition, physical activity, and weight gain is given during chemotherapy because it is not part of most HCPs' training, it is not included in the guidelines and it is not the best time to bring up information in the opinion of HCPs. Weight gain was perceived as just a matter of a few kilos and not an important health issue during treatment. All HCPs felt it is better that women themselves addressed their weight gain after chemotherapy. CONCLUSION: More knowledge about health risks associated with chemotherapy induced weight gain and how to combat these issues needs to be made readily available to the HCPs and should become part of their training. Existing patient guidelines should include information on how to prevent and/or reduce weight gain through self-management of nutrition intake and physical activity during and post chemotherapy. PMID- 30022350 TI - Meta-analysis of randomized controlled trials of the efficacy of propolis mouthwash in cancer therapy-induced oral mucositis. AB - PURPOSE: This meta-analysis aimed to evaluate the efficacy and safety of propolis mouthwash in cancer patients with therapy-induced oral mucositis. METHODS: This was a systematic review of randomized control trails (RCTs). We searched ten electronic databases for studies published prior to April 06, 2017. The included RCTs were published in English and Chinese. The Jadad score was used to evaluate the quality of the articles identified. Two reviewers independently evaluated each of the studies. The data were entered into Review Manager (RevMan) 5.3 software and checked for accuracy. Outcome incidence analysis was performed using odds ratios (ORs). RESULTS: Of the 352 articles identified, five potentially relevant articles met our inclusion criteria. These 5 RCTs included a total of 209 participants. The Jadad score for methodological quality was 3.60 +/- 0.55. No obvious publication bias was noted. The incidence of severe oral mucositis was significantly lower in the propolis group than in the control group (OR = 0.35, p = 0. 003). The corresponding 95% confidence interval (CI) was 0.18 to 0.70. Between-study heterogeneity was low (I2 = 0.000, p = 0.45). No side effects were reported. CONCLUSIONS: Propolis mouthwash is effective and safe in the treatment of severe oral mucositis. To maintain propolis safety, propolis usage should occur under the supervision of medical staff and health professionals. Future multi-center studies and a clinical protocol are needed to confirm the current findings regarding the efficacy and safety of propolis mouthwash. PMID- 30022351 TI - Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy. AB - IgA nephropathy (IgAN) is recognized as most frequent form of primary glomerulonephritis worldwide. IgAN is associated with renal degradation occurring due to irreversible pathological changes leading to glomerulosclerosis and interstitial fibrosis. It remains poorly understood whether and to what extent these changes are followed by the activation of regenerative mechanisms. Therefore, in this study we aimed to evaluate regenerative potential of IgAN patients by quantitating the frequencies of several stem cell types, namely circulating very small embryonic-like stem cells (VSELs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) as well as different monocyte subsets with varying maturation and angiopoietic potential. Moreover, we analyzed whether changes in stem cell and monocyte frequencies were related to alterations of several chemotactic factors (stromal derived-factor (SDF-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)) and a marker of monocyte/macrophage activation, namely soluble form of CD163 receptor (sCD163). We showed that IgAN patients presented with enhanced levels of VSELs, but not other stem cell types. We also demonstrated significantly elevated numbers of intermediate monocytes known for their M2-like properties as well as high angiopoietic potential and CD163 expression. This finding was accompanied by detection of elevated sCD163 plasma levels in IgAN patients. Taking together, we demonstrated here that IgAN is associated with selective mobilization of VSELs and increased maturation of monocytes towards M2-like and angiopoietic phenotype. These findings contribute to better understanding of the role of regenerative mechanisms in the pathogenesis of chronic inflammation in the course of IgAN. PMID- 30022352 TI - Characterization of a large sex determination region in Salix purpurea L. (Salicaceae). AB - Dioecy has evolved numerous times in plants, but heteromorphic sex chromosomes are apparently rare. Sex determination has been studied in multiple Salix and Populus (Salicaceae) species, and P. trichocarpa has an XY sex determination system on chromosome 19, while S. suchowensis and S. viminalis have a ZW system on chromosome 15. Here we use whole genome sequencing coupled with quantitative trait locus mapping and a genome-wide association study to characterize the genomic composition of the non-recombining portion of the sex determination region. We demonstrate that Salix purpurea also has a ZW system on chromosome 15. The sex determination region has reduced recombination, high structural polymorphism, an abundance of transposable elements, and contains genes that are involved in sex expression in other plants. We also show that chromosome 19 contains sex-associated markers in this S. purpurea assembly, along with other autosomes. This raises the intriguing possibility of a translocation of the sex determination region within the Salicaceae lineage, suggesting a common evolutionary origin of the Populus and Salix sex determination loci. PMID- 30022353 TI - Quantitative performance of 124I PET/MR of neck lesions in thyroid cancer patients using 124I PET/CT as reference. AB - BACKGROUND: In patients with differentiated thyroid cancer (DTC), serial 124I PET/CT imaging is, for instance, used to assess the absorbed (radiation) dose to lesions. Frequently, the lesions are located in the neck and they are close to or surrounded by different tissue types. In contrast to PET/CT, MR-based attenuation correction in PET/MR may be therefore challenging in the neck region. The aim of this retrospective study was to assess the quantitative performance of 124I PET/MRI of neck lesions by comparing the MR-based and CT-based 124I activity concentrations (ACs). Sixteen DTC patients underwent PET/CT scans at 24 and 120 h after administration of about 25 MBq 124I. Approximately 1 h before or after PET/CT examination, each patient additionally received a 24-h PET/MR scan and sometimes a 120-h PET/MR scan. PET images were reconstructed using the respective attenuation correction approach. Appropriate reconstruction parameters and corrections were used to harmonize the reconstructed PET images to provide, for instance, similar spatial resolution. For each lesion, two types of ACs were ascertained: the maximum AC (max-AC) and an average AC (avg-AC). The avg-AC is the average activity concentration obtained within a spherical volume of interest with a diameter of 7 mm, equaling the PET scanner resolution. For each type of AC, the percentage AC difference between MR-based and CT-based ACs was determined and Lin's concordance correlation analysis was applied. Quantitative performance was considered acceptable if the standard deviation was +/- 25% (precision), and the mean value was within +/- 10% (accuracy). RESULTS: The avg-ACs (max-ACs within parentheses) of 74 lesions ranged from 0.20 (0.33) to 657 (733) kBq/mL. Excluding two lesions with ACs of approximately 1 kBq/mL, the mean (median) +/- standard deviation (range) was - 4% (- 5%) +/- 14% (- 28 to 29%) for the avg-AC and - 9% (- 11%) +/- 14% (- 33 to 33%) for the max-AC. Lin's concordance correlation coefficients were >= 0.97, indicating substantial AC agreement. CONCLUSIONS: Quantification of lesions in the neck region using 124I PET/MR showed acceptable quantitation performance to 124I PET/CT for AC above 1 kBq/mL. The PET/MRI-based 124I ACs in the neck region can be therefore reliably used in pre-therapy dosimetry planning. PMID- 30022354 TI - MitoNEET in Perivascular Adipose Tissue Prevents Arterial Stiffness in Aging Mice. AB - PURPOSE: Arterial stiffness is an inevitable consequence of the aging process and is considered an early stage in the development of cardiovascular diseases. The perivascular adipose tissue (PVAT) is a distinct functional integral layer of the vasculature actively involved in blood pressure regulation and atherosclerosis development via PVAT-derived paracrine/autocrine factors. However, there is little knowledge regarding the relationship between PVAT and arterial stiffness. METHODS: Using unique mice lacking PVAT, high-fat diet-induced obesity, and in mice overexpressing brown adipocyte selective mitoNEET, we investigated the relationship between PVAT and arterial stiffness in mice. RESULTS: We found that lack of PVAT enhanced arterial stiffness in aging mice. High-fat diet feeding of aging C57BL/6J wild-type mice significantly induced hypertrophic PVAT and enhanced arterial stiffness. Furthermore, the expression of mitoNEET, a mitochondrial membrane protein related to energy expenditure, was significantly increased by pioglitazone treatment, while reduced in the hypertrophic PVAT induced by high-fat diet. Overexpression of mitoNEET in PVAT reduced the expression of inflammatory genes and was associated with lower pulse wave velocity in aging mice. CONCLUSIONS: These data indicate that local PVAT homeostasis especially inflammation in PVAT is associated with arterial stiffness development. Pioglitazone-induced mitoNEET in PVAT prevents PVAT inflammation and is negatively associated with arterial stiffness. These findings provide new experimental insight into the roles of pioglitazone on PVAT in arterial stiffness and indicate that PVAT might be a target to treat or prevent cardiovascular disease. PMID- 30022355 TI - Thiamine Therapy for Heart Failure: a Promise or Fiction? PMID- 30022357 TI - The Incredible Years Teacher Classroom Management Program: Outcomes from a Group Randomized Trial. AB - This group randomized controlled trial (RCT) evaluated the efficacy of the Incredible Years Teacher Classroom Management Program (IY TCM) on student social behavioral and academic outcomes among a large diverse sample of students within an urban context. Participants included 105 teachers and 1817 students in kindergarten to third grade. Three-level hierarchical linear models (HLM) were conducted to examine the overall treatment effects on teacher-reported student behavior and academic outcomes. In addition, multi-level moderation analyses were conducted to examine whether the treatment effects on student outcomes differed by demographic variables and pretest measures of social emotional and disruptive behavior and academics. Findings indicate that IY TCM reduced student emotional dysregulation (d = - 0.14) and increased prosocial behavior (d = 0.13) and social competence (d = 0.13). In addition, students initially lower on measures of social and academic competence demonstrated significant improvements on the same measure at outcome in comparison to similar peers in control classrooms. Practical significance of the findings and implications for schools and policy makers are discussed. PMID- 30022356 TI - Can Teenage Men Be Targeted to Prevent Teenage Pregnancy? A Feasibility Cluster Randomised Controlled Intervention Trial in Schools. AB - The World Health Organisation advocates a direct focus on adolescent men in reducing adolescent pregnancy; however, no trials have been conducted. This trial (ISRCTN11632300; NCT02092480) determines whether a novel Relationship and Sexuality Educational intervention, If I Were Jack, is acceptable and feasible to implement in mixed sex UK classrooms. The intervention is a teacher-delivered intervention that emphasises male alongside female responsibility in preventing unintended pregnancies and is designed to prevent unprotected sex. The trial was a parallel-group cluster randomised controlled feasibility trial with embedded process and cost evaluation in eight secondary schools (unit of randomisation) among 831 pupils (mean age 14) in Northern Ireland, alongside a qualitative evaluation of transferability in ten schools in Scotland, Wales and England. The sampling strategy was a maximum variation quota sample designed to capture a range of school management types. Four schools were randomised to each arm and the control arm continued with usual practice. Study duration was 12 months (from November 2014), with follow-up 9 months post-baseline. Results demonstrated that the intervention was acceptable to schools, pupils and teachers, and could be feasibly implemented, cost-effectively, with minor enhancements. The between group difference in incidence of unprotected sex (primary outcome at pupil level) of 1.3% (95% CI 0.5-2.2) by 9 months demonstrated a potential effect size consistent with those reported to have had meaningful impact on teenage pregnancy. The study responds to global health policy for a paradigm shift towards inclusion of men in the achievement of sexual and reproductive health goals in a practical way by demonstrating that a gender-sensitive as well as a gender transformative intervention targeting males to prevent teenage pregnancy is acceptable to adolescent men and women and implementable in formal education structures. If I Were Jack now merits further effectiveness testing. PMID- 30022358 TI - Non-sarcomeric causes of heart failure: a Sydney Heart Bank perspective. PMID- 30022359 TI - Implementing efficient concerted rotations using Mathematica and C code?. AB - In this article we demonstrate a general and efficient metaprogramming implementation of concerted rotations using Mathematica. Concerted rotations allow the movement of a fixed portion of a polymer backbone with fixed bending angles, like a protein, while maintaining the correct geometry of the backbone and the initial and final points of the portion fixed. Our implementation uses Mathematica to generate a C code which is then wrapped in a library by a Python script. The user can modify the Mathematica notebook to generate a set of concerted rotations suited for a particular backbone geometry, without having to write the C code himself. The resulting code is highly optimized, performing on the order of thousands of operations per second. PMID- 30022360 TI - Prof Ronan O'Connell Festschrift: Stricture pathogenesis in Crohn's disease-the role of intestinal fibroblasts. AB - Approximately one-third of patients with Crohn's disease have a distinct fibrostenosing phenotype predisposing them to recurrent intestinal stricture formation. The intestinal fibroblast was thought to play a critical role in the abnormal wound healing which ends in stricture formation. Recognising this, a laboratory-based research study was initiated at the Mater Misericordiae Hospital and University College Dublin with the aim of investigating the key steps in intestinal fibroblast-mediated stricture pathogenesis. An in vitro model was developed using cultured fibroblasts taken from sites of stricture in patients undergoing surgery. In summary, these fibroblasts were shown to carry multiple distinct pro-fibrotic phenotypic changes which may explain the abnormal wound healing and scar formation found at their sites of origin. This paper reviews that body of work, undertaken by series of surgical researchers and scientists, and driven by the insight, guidance and mentorship of Professor Ronan O'Connell. PMID- 30022361 TI - Magnetic sphincter augmentation for gastroesophageal reflux disease: review of clinical studies. AB - Use of the magnetic sphincter augmentation (MSA) device for the laparoscopic treatment of gastroesophageal reflux disease is increasing since the first clinical implant performed a decade ago. The MSA procedure is a minimally invasive and highly standardized surgical option for patients who are partially responders to proton-pump inhibitors, which have troublesome regurgitation or develop progressive symptoms despite continuous medical therapy. The procedure has proven to be highly effective in improving typical reflux symptoms, reducing the use of proton-pump inhibitors, and decreasing esophageal acid exposure. Observational cohort studies have shown that MSA compares well with fundoplication in selected patients and has an acceptable safety profile. The device can be easily removed if necessary, thereby preserving the option of fundoplication in the future. The majority of the removals have occurred within 2 years after implant and have been managed non-emergently, with no complications or long-term consequences. "Expanded" indications to MSA (large hiatal hernia and Barrett's esophagus) need to be tested in further comparative studies with classic fundoplication procedures. PMID- 30022362 TI - The comparison of single-dose preemptive intravenous ibuprofen and paracetamol on postoperative pain scores and opioid consumption after open septorhinoplasty: a randomized controlled study. AB - PURPOSE: Septorhinoplasty is performed in combination with septoplasty and rhinoplasty operations and is characterized by severe postoperative pain. The aim of this study is to evaluate preemptive effects of intravenous (IV) ibuprofen and IV paracetamol on opioid consumption and pain scores after open septorhinoplasty. METHODS: The study included 150 patients who had undergone elective open septorhinoplasty. Patients were randomly assigned into three groups; Group Control (Group C, n = 50) received 100 ml saline solution, Group Paracetamol (Group P, n = 50) received 1000 mg IV paracetamol in 100 ml solution, and Group Ibuprofen (Group I, n = 50) received 800 mg IV ibuprofen in 100 ml saline before surgery. Postoperative analgesia was achieved by opioid administration via patient-controlled analgesia. Visual analog scores (VASs), postoperative opioid consumption, additional analgesic requirements, and side effects were recorded. RESULTS: Compared with Group C, VASs in Group P and Group I were statistically lower at all time points (p < 0.05). VAS was lower in Group I than in Group P at postoperative, 1st and 6th hours (p < 0.05). Opioid consumption in Group C was highest in all groups at all time periods (p < 0.05). At the 0-6 and 6-12 time intervals, total opioid consumption was significantly lower in Group I compared to Group P (p < 0.05). Total opioid consumption was highest in Group C (p < 0.05). CONCLUSIONS: This study has indicated that ibuprofen has more analgesic effect than paracetamol during first 12 h, but there is a non-inferiority between ibuprofen and paracetamol after first 12 h. PMID- 30022363 TI - PPARgamma Agonist PGZ Attenuates OVA-Induced Airway Inflammation and Airway Remodeling via RGS4 Signaling in Mouse Model. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone (PGZ) exhibits potential protective effects in asthma. Recently, regulator of G protein 4 (RGS4) has been reported to be associated with immunological and inflammatory responses. However, no evidence has shown the influence of PPARgamma on RGS4 expression in airway disorders. In this study, BALB/c mice received ovalbumin (OVA) sensitization followed by OVA intranasal challenge for 90 days to establish a chronic asthma mouse model. Accompanied with OVA challenge, the mice received administration of PPARgamma agonist PGZ (10 mg/kg) intragastrically or RGS4 inhibitor CCG 63802 (0.5 mg/kg) intratracheally. Invasive pulmonary function tests were performed 24 h after last challenge. Serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for further analyses after the mice were sacrificed. We found that PPARgamma agonist PGZ administration significantly attenuated the pathophysiological features of OVA-induced asthma and increased the expression of RGS4. In addition, the attenuating effect of PGZ on airway inflammation, hyperresponsiveness (AHR), and remodeling was partially abrogated by administration of RGS4 inhibitor CCG 63802. We also found that the downregulation of RGS4 by CCG 63802 also significantly increased inflammatory cell accumulation and AHR, and increased levels of IL-4, IL-13, eotaxin, IFN gamma, and IL-17A in BALF, and total and OV-specific IgE in serum. Furthermore, the inhibitory effects of PGZ on the activations of ERK and Akt/mTOR signaling, and MMPs were apparently reversed by CCG 63802 administration. In conclusion, the protective effect of PGZ on OVA-induced airway inflammation and remodeling might be partly regulated by RGS4 expression through ERK and Akt/mTOR signaling. PMID- 30022364 TI - Inpatient Expenditures Attributable to Hospital-Onset Clostridium difficile Infection: A Nationwide Case-Control Study in Japan. AB - BACKGROUND: Hospital-onset Clostridium difficile infections (CDIs) have a considerable clinical and economic impact on patients and payers. Quantifying the economic impact of CDIs can guide treatment strategies. However, previous studies have generally focused on acute care hospitals, and few have included cost estimates from non-acute care hospitals such as long-term care facilities. AIM: This study aimed to quantify the hospital-onset CDI-attributable inpatient expenditures and length-of-stay durations in all healthcare institutions that provide inpatient care (including acute and non-acute care) in Japan. METHODS: Using national-level insurance claims data, we analyzed patients who had been hospitalized between April 2010 and December 2016. CDI cases were identified and matched with non-CDI controls using hospitalization year, treating hospital, age, sex, surgical procedure, comorbidities, and main diagnoses. Through multivariable regression analyses, we estimated the CDI-attributable inpatient expenditures (2016 US dollars) and length-of-stay durations (days) while adjusting for variations in factors such as patient characteristics, comorbidities, surgery, prescribed antibiotic, geographic region, and hospitalization year. We also analyzed the CDI-attributable inpatient expenditures and length-of-stay durations according to hospital type (acute care and rehabilitation/long-term care). RESULTS: The analysis was conducted using 3768 matched pairs. Overall, CDI attributable inpatient expenditures and length-of-stay durations were US$3213 and 11.96 days, respectively. Rehabilitation/long-term care hospitals had substantially higher inpatient expenditures and longer hospitalizations than acute care hospitals. CONCLUSION: This study quantified the hospital-onset CDI attributable inpatient expenditures and hospitalizations in both acute and non acute care hospitals. The inclusion of non-acute care hospitals provides a more accurate representation of the economic burden of CDIs. PMID- 30022365 TI - Novel frontiers in detecting cancer metastasis. AB - Cancer microenvironment is the critical battle ground between the cancer cells and host response. Thus, more emphasis is directed to study the relationship between cancer cells and the stromal cells. Multiplex microscopy is an emerging technique in which multiple cell populations within the cancer microenvironment may be stained so that spatial relationship between cancer cells and, in particular, the immune cells may be studied during different stages of cancer development. Recent discovery of mutational burden and neoantigens in cancer has opened new landscapes in the interaction of host immune cells and cancer neoantigens. The emerging role of miRNAs may become an added dimension to study cancer beyond traditional pathway of DNA directed RNA being associated with the malignant behavior of cancer. Circulating tumor cells, cancer markers and ctDNA can be used as markers for circulating cancer cells in the blood. Further studies are needed to validate if liquid biopsy of cancer may become a routine clinical tool to screen cancer or follow patients for recurrence or responses to treatment. PMID- 30022366 TI - Resynchronization Therapy for Patients with Congenital Heart Disease: Are We Ready for Prime Time? AB - PURPOSE OF REVIEW: This review aims to summarize and provide an update of evidence for cardiac resynchronization therapy (CRT) in pediatric and adult congenital heart disease (CHD). RECENT FINDINGS: CRT is a valuable tool in the treatment of heart failure in the setting of CHD. Current evidence points toward the ability of this therapy to increase hemodynamic parameters and reduce heart failure-related symptoms. Within the CHD population, patients with systemic left ventricles appear to benefit the most from CRT. Utilization of CRT in CHD has been technically difficult due to the complexity and variety of anatomic substrates. However, lateral thoracotomies and other advances have made implantation more feasible. The most up-to-date evidence continues to support the use of CRT in the heterogeneous population of CHD with careful and individualized patient selection. Further studies are needed to evaluate the utility of CRT for specific anatomic substrates within this population. PMID- 30022367 TI - Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia. AB - BACKGROUND AND OBJECTIVE: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged <= 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study. METHODS: The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two compartment model with two clearance components: a linear clearance (CL1) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL1 and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL1 and central volume. RESULTS AND CONCLUSIONS: PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m2 on days 1 and 15 versus, 3 mg/m2 fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen. STUDY IDENTIFIER: 0903A1-102 US. PMID- 30022368 TI - Do SNPs in folate pharmacokinetic pathway alter levels of intracellular methotrexate polyglutamates and affect response? A prospective study in Indian patients. AB - This study investigated the impact of seven polymorphisms in genes of folate transport and (de)glutamation pathway on methotrexate polyglutamate levels and response in patients with rheumatoid arthritis. This prospective study included patients with rheumatoid arthritis. They were treated with methotrexate (up to 25 mg per week) for 24 weeks and categorized by EULAR response criteria into responders (good and moderate) and non-responders. Using real-time Taqman discrimination assay, SNPs were genotyped-rs1045642 (ABCB1 3435C>T), rs1128503 (ABCB1 1236C>T), rs10106 (FPGS 1994A>G), rs1544105 (FPGS G>A), rs11545078 (GGH 452C>T), rs3758149 (GGH -401C>T), and rs1051266 (RFC1 80G>A). RBC methotrexate polyglutamate1-5(MTX-glu1-5) levels were determined at 4, 8, 16, and 24 weeks using by reverse phase HPLC using C-18 column followed by post column photo oxidation. This study included 117 patients with rheumatoid arthritis (M:F = 14:103). The mean dose of methotrexate at 24 weeks was 22.0 +/- 4.0 mg, with data on DAS28(3) at 24 weeks available in 96 patients-61 responders and 35 non responders. Minor allele of GGH 452C>T had an association with non-response (odds ratio 2.9, 95% CI 1.4-5.6) and assuming the dominance of C, the recessive genetic model found GGH 452C>T CC genotype (odds ratio 9.5, 95% CI 1.2 to 76.0) was significantly associated with response. However, there was no difference in MTX glu1-5 levels among the various genotypes of this SNP (p = 0.9). Other SNPs were neither associated with response nor with alteration in methotrexate polyglutamate levels. On logistic regression, GGH 452C>T CC genotype and DAS28(3) at baseline were independent predictors of response. GGH 452C>T CC genotype was associated with response to methotrexate. None of the SNPs affected MTX-glu1 5levels. PMID- 30022369 TI - Exercise habits and C-reactive protein may predict development of spinal immobility in patients with ankylosing spondylitis. AB - To assess predictors for spinal immobility in a long-term clinical study of patients with AS, data from annual clinical measurements of spinal mobility in 54 patients (41 men, mean of age at end of follow-up 54.7 years) with ankylosing spondylitis were co-analysed with data regarding lifestyle factors as well as laboratory measurements from a previous cross-sectional study. Spinal immobility was graded on the basis of recently published age-, sex- and length-specific reference intervals. Exercise habits and high-sensitivity C-reactive protein (hsCRP) were independently associated with the development of subnormal spinal immobility (p = 0.019 and p = 0.021). In multiple regression models, approximately 25% of the spinal immobility could be attributed to disease duration (p <= 0.011), levels of hsCRP (p <= 0.004) and exercise in leisure time (p <= 0.019). The mean concentration of hsCRP was 4.2 mg/L (range 0.2-8.4 mg/L) in the study cohort. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR) and physical activity at work were not associated with spinal immobility. The results indicate that exercise habits may have an impact in preventing the development of spinal immobility in AS independently of disease duration and inflammation. This corresponds well with the accumulated knowledge from long-term clinical experience among rheumatologists, health professionals and patients. Consequently, exercise should remain an important part of the non-pharmacological treatment and self-care for patients with AS. Furthermore, modest inflammatory activity, measured as a slightly elevated hsCRP concentration, appears to affect subsequent spinal immobility in AS. PMID- 30022370 TI - Serum-soluble folate receptor beta as a biomarker for the activity of rheumatoid arthritis synovitis and the response to anti-TNF agents. AB - This study aims to develop a sandwich ELISA system for the measurement of soluble folate receptor beta (sFRbeta) and evaluate whether base line levels of serum sFRbeta are a biomarker for the activity of RA synovitis and the response to anti TNF agents. Serum sFRbeta from normal controls (41 samples), patients with OA (29 samples), and patients with RA (27 samples) and synovial fluid sFRbeta from patients with RA (17 samples) were measured by sandwich ELISA, using anti FRalphabeta and anti-FRbeta antibodies as capture and detection antibodies, respectively. Baseline levels of serum sFRbeta before therapy were evaluated in relation with DAS28-CRP or CRP and response to anti-TNF agents at 3-month follow up. sFRbeta levels in RA synovial fluids were higher than those in RA sera, and sFRbeta levels in RA sera were higher than those in osteoarthritis and normal control sera. A significant relationship was observed between serum sFRbeta levels and the DAS28-CRP scores or CRP values. The area under curve (AUC) values for receiver-operating characteristic curves defined using the serum sFRbeta levels of RA patients before therapy had a higher predictive capacity than DAS28 CRP and CRP for the effective response of anti-TNF agents. The high serum sFRbeta levels with a cutoff value of 8 ng/mL were 100% specificity for the effective response of anti-TNF agents. The findings support that the serum sFRbeta levels in patients with RA act as a disease activation biomarker and that high serum sFRbeta levels act as a predictive biomarker for the response to anti-TNF agents. PMID- 30022371 TI - Generation and histomorphometric evaluation of a novel fluvastatin-containing poly(lactic-co-glycolic acid) membrane for guided bone regeneration. AB - The purpose of this study was to evaluate the effects of a poly(lactic-co glycolic acid) (PLGA) membrane containing fluvastatin on bone regeneration at bone defects in rat calvaria and tibia for possible use as a guided bone regeneration (GBR) membrane. PLGA and fluvastatin-containing PLGA (PLGA fluvastatin) membranes were prepared and mechanical properties were evaluated. Standardized bony defects were created in rat calvaria and the right tibia, and covered with a PLGA or PLGA-fluvastatin membrane. Bone regeneration was evaluated using image analysis based on histologic examination. At 4 and 8 weeks after membrane implantation, the PLGA-fluvastatin group displayed enhanced new bone formation around the edge of the defect compared with the PLGA membrane group in the calvarial model. Thick bone regeneration was observed in tibia-defect sites in the PLGA-fluvastatin membrane group. These results suggest that the PLGA containing fluvastatin membrane prepared in this study may potentially be used as a GBR membrane. PMID- 30022372 TI - Serum Uric Acid Is Highly Associated with Epilepsy Secondary to Cerebral Infarction. AB - In this study, we examined the association between serum uric acid levels and epilepsy secondary to cerebral infarction. Clinical data including age, gender, epileptic seizure type, imaging, and serum uric acid levels before and after seizures in patients with cerebral infarction that were collected and analyzed. One hundred patients with cerebral infarction but without epilepsy, 147 patients with epilepsy secondary to cerebral infarction, and 55 patients with status epilepticus secondary to cerebral infarction were recruited. Interestingly, epilepsy secondary to cerebral infarction was associated with both reduced uric acid (adjusted OR 2.09; 95% CI 1.07-4.08) and increased uric acid (adjusted OR 4.05; 95% CI 1.99-8.25); however, status epilepsy secondary to cerebral infarction was only associated with increased uric acid (adjusted OR 2.60; 95% CI 1.05-6.45). A U-shaped association between uric acid levels and seizures was observed by using a multivariable logistic regression model with restricted cubic spline. Serum uric acid levels are associated with both epilepsy secondary to cerebral infarction and status epilepticus secondary to cerebral infarction in patients with cerebral infarction. The appropriate intervention of serum uric acid level might be a therapeutic strategy to reduce epileptic seizures or inhibit the development of status epilepticus. PMID- 30022373 TI - Spatial distribution pattern of degree-day factors of glaciers on the Qinghai Tibetan Plateau. AB - Glaciers have a very obvious feedback effect on the global water cycle and environmental change. The Qinghai-Tibetan Plateau, also known as the "Water Towers of Asia," provides an important source of freshwater resources derived from glacial meltwater. Changes in glaciers on the Qinghai-Tibetan Plateau are the most important aspect of the research related to global climate change. Because only a few input parameters are available, the degree-day factor model of glacier mass balance has been widely used on the Qinghai-Tibetan Plateau. Study of the spatial distribution pattern of degree-day factors for glaciers on the Qinghai-Tibetan Plateau and the factors that influence glaciers is important scientifically. The study of degree-day factors is important to the calculation of the glacial grid mass balance on the Qinghai-Tibetan Plateau, and this data can be used in the analysis of the response of glaciers experiencing climate change and for predicting future glacial trends. Through an analysis of the degree-day factors related to 24 glaciers on the Qinghai-Tibetan Plateau, one can conclude that the mean value of glacial degree-day factors on the Qinghai-Tibetan Plateau is 8.14 mm day-1 degrees C-1. The glacial degree-day factor shows a longitudinal zonality with values ranging from high to low from east to west, a latitudinal zonality with values ranging from high to low from south to north, and a vertical zonal regularity along with the change of elevation. The spatial distribution pattern of glacial degree-day factors in the Tibetan Plateau is related to the fact that the climate environment across the Qinghai-Tibetan Plateau is mainly affected by the Indian monsoon, the eastern monsoon, and the westerly winds. The climate gradually changes from cold-humid to warm-humid from northwest to southeast. The single-unit glacier of Qinghai-Tibetan Plateau-the Renlongba Glacier-is located in the southeastern portion of the Qinghai-Tibetan Plateau in a warm and humid climate; its degree-day factor is slightly large, averaging at 6.12 mm day-1 degrees C-1. Mountainous barriers exist in the eastern and western parts of the Renlongba Glacier. On the east side, the degree day factor is small (5.63 mm day-1 degrees C-1) because of large mountains block weather systems. The glacial tongue is affected by valley wind, contributing to glacial ablation, so the degree-day factor is large on the tongue, averaging at 6.56 mm day-1 degrees C-1. The degree-day factor on the west side of the Renlongba Glacier increases gradually increasing radiation and elevation, presenting a vertical zonal feature. In general, the climate of the Qinghai Tibetan Plateau is mainly affected by the Indian and eastern monsoons and by westerly winds. In dry and cold climatic conditions, the glacial degree-day factor in the Tibetan Plateau is small, while at warm and humid climate conditions, it is large, with latitudinal, longitudinal, and vertical zonality. In addition, the degree-day factor is also affected by blocking, topography, and other local microclimatic conditions. PMID- 30022374 TI - Endocytosis of G Protein-Coupled Receptors and Their Ligands: Is There a Role in Metal Trafficking? AB - The prevalence of metal dysregulation in many neurodegenerative and neurocognitive disorders has compelled many studying such diseases to investigate the mechanisms underlying metal regulation in the central nervous system. Metal homoeostasis is often complex, with sophisticated, multilayered pathways in operation. G protein-coupled receptors are omnipresent on cell membranes and have intriguing mechanisms of endocytosis and trafficking that may be useful in metal homoeostasis. Indeed, many receptors and/or their cognate ligands are able to bind metals, and in many cases metals are considered to have neuromodulatory roles as a result of receptor binding. In this mini-review, we outline the structural and functional aspects of G protein-coupled receptors with a focus on the mechanisms leading to endocytosis and cellular trafficking. We further highlight how this may help in the trafficking of metal ions, notably copper. PMID- 30022377 TI - How Does Health Education Given to Lung Cancer Patients Before Thoracotomy Affect Pain, Anxiety, and Respiratory Functions? AB - In this study, it was aimed to determine how the postoperative pain level, state trait anxiety level, and respiratory function were affected by the health education given through a patient education booklet to patients with lung cancer, in comparison with control group, before pulmonary resection through thoracotomy. The 60 patients (n = 60) having pulmonary resection indication because of lung cancer were recruited in the present study. The patients were separated as control (n = 30) and experimental groups (n = 30). The patient education was applied to patients in the experimental groups via the education booklet 24 h before the surgery. Patients in the control groups received only usual clinical nursing information. The pain was evaluated via visual analog scale (VAS). The State-Trait Anxiety Scale (STAS) was used for evaluating the anxiety level. The evaluated pulmonary functions were peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and forced expiratory flow 25-75 (FEF25-75). The pain level of the experimental group was statistically lower than control group (p < 0.05). The state anxiety level of experimental group received education was statistically lower than control group (p < 0.05). There was no any statistical difference in trait anxiety levels between control and experimental groups (p > 0.05). The FEV1 and FEF25-75 values in experimental group were statistically higher than control group. A planned health education applied via the thoracotomy patient education booklet has a positive effect on clinical recovery process by affecting postoperative pain, state anxiety, and FEV1 and FEF25-75 values. PMID- 30022376 TI - Thiol-Capped Gold Nanoparticle Biosensors for Rapid and Sensitive Visual Colorimetric Detection of Klebsiella pneumoniae. AB - In the last few years, gold nanoparticle biosensors have been developed for rapid, precise, easy and inexpensive with high specificity and sensitivity detection of human, plant and animal pathogens. Klebsiella pneumoniae serotype K2 is one of the common gram-negative pathogens with high prevalence. Therefore, it is essential to provide the effective and exclusive method to detect the bacteria. Klebsiella pneumoniae serotype K2 strain ATCC9997 genomic DNA was applied to establish the detection protocol either with thiol-capped oligonucleotide probes and gold nanoparticles or polymerase chain reaction based on K2A gene sequence. In the presence of the genomic DNA and oligonucleotide probes, a change in the color of gold nanoparticles and maximum changes in wavelength at 550-650 nm was achieved. In addition, the result showed specificity of 15 * 105 CFU/mL and 9 pg/MUL by gold nanoparticles probes. The lower limit of detection obtained by PCR method was 1 pg/MUL. Moreover, results demonstrated a great specificity of the designed primers and probes for colorimetric detection assay and PCR. Colorimetric detection using gold nanoparticle probe with advantages such as the lower time required for detection and no need for expensive detection instrumentation compared to the biochemical and molecular methods could be introduced for rapid, accurate detection of the bacteria. PMID- 30022375 TI - Dipeptidyl peptidase-4(DPP-4) inhibitors: promising new agents for autoimmune diabetes. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors constitute a novel class of anti diabetic agents confirmed to improve glycemic control and preserve beta-cell function in type 2 diabetes. Three major large-scale studies, EXAMINE, SAVOR-TIMI 53, and TECOS, have confirmed the cardiovascular safety profile of DPP-4 inhibitors. Based on these results, DPP-4 inhibitors have gained widespread use in type 2 diabetes treatment. It is currently unknown, however, whether DPP-4 inhibitors have similar therapeutic efficacy against autoimmune diabetes. Several in vitro and in vivo studies have addressed this issue, but the results remain controversial. In this review, we summarize experimental findings and preliminary clinical trial results, and identify potentially effective immune modulation targets of DPP-4 inhibitors for autoimmune diabetes. PMID- 30022378 TI - The Relationship Between Health Literacy, Cancer Prevention Beliefs, and Cancer Prevention Behaviors. AB - While cancer prevention behaviors have been clearly defined, many people do not engage in these risk-reduction behaviors. Factors such as cancer prevention beliefs and limited health literacy may undermine cancer prevention behavior recommendations. This study explored the relationships between cancer prevention beliefs, health literacy, and cancer prevention behaviors. Data were analyzed from the 2013 Health Information National Trends Survey (n = 1675). Regression analyses for four cancer prevention belief (prevention is not possible, cancer is fatal, there are too many recommendations for prevention, everything causes cancer) statements were modeled, including health literacy and sociodemographic variables as predictors. In addition, separate regression analyses predicted four cancer prevention behaviors (fruit and vegetable consumption, physical activity, cigarette smoking) from cancer prevention beliefs, health literacy, and sociodemographic variables. Participants with low health literacy were more likely to hold fatalistic cancer prevention beliefs than those with higher health literacy. Cancer prevention beliefs were related to less fruit and vegetable consumption, fewer days of physical activity, and with being a nonsmoker after controlling for sociodemographic variables. Health literacy was not a significant predictor of cancer prevention behaviors. Given the relationship between health literacy and cancer prevention beliefs, research is needed to ascertain how to empower patients with low health literacy to have a more realistic understanding of cancer. PMID- 30022379 TI - Scenario modeling for spatial-temporal change detection of carbon storage and sequestration in a forested landscape in Northern Iran. AB - The present study was conducted, based on scenario modeling approach, in the Do hezar and Se-hezar forested landscape in the Mazandaran Province in Northern Iran in order to detect spatial-temporal changes of carbon storage and sequestration in four different carbon pools, i.e., aboveground and belowground biomasses, dead organic matter, and organic soils. For this purpose, firstly, the changing trend of land use/land cover (LULC) was detected by analyzing and comparing remotely sensed data of the landscape during the period of 1984-2016. Then, the impacts of future LULC changes on carbon storage and sequestration were predicted and valued using the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) model under two future plausible scenarios of business as usual (BAU) and balanced development (BD). According to the results of BAU scenario, continuation of the current trend will lead to a significant reduction in the carbon sequestration and a huge amount of social cost due to the loss of carbon stored in the landscape and its release to the atmosphere. The BD scenario which refers to the principled and under control development of human settlements simultaneously with forest conservational and restoration activities, could potentially reverse the downtrend of carbon sequestration service and avoid future socioeconomic costs, hence add to the economic value of the forest landscape in terms of providing a better sink for carbon storage. The results of this research can facilitate the quantitative and accurate assessment of carbon storage and sequestration relying on more precise biophysical and economic data as well as provide insight for effective land-use planning. PMID- 30022380 TI - All Trans Retinoic Acid Attenuates Markers of Neuroinflammation in Rat Brain by Modulation of SIRT1 and NFkappaB. AB - Alcohol abuse affects several neurological pathways and causes significant alterations in the brain. Abstention from alcohol causes only a marginal decrease in oxidative stress and neuro inflammation. Our previous studies had shown that an active metabolite of vitamin A, all trans retinoic acid (ATRA), ameliorates alcohol induced toxicity. Hence in the present study we investigated whether ATRA regressed alcohol induced neuroinflammation. We focused on the role of silent mating type information regulation 2 homolog 1(SIRT1) and nuclear factor kappa-B (NFkappaB). Animals were administered with ethanol at a daily dose of (4 g/kg body weight) for 90 days. On the 91st day ethanol administration was stopped and animals were divided into ethanol abstention (A) and ATRA supplementation group (ATRA + A) (100 ug/kg body weight) and maintained for 30 days. Ethanol exposure increased markers of oxidative stress, inflammation and the activities of alcohol and acetaldehyde dehydrogenases and reduced the expression of SIRT1 in the whole brain.The ethanol induced altered expressions of NFkappaB and SIRT1 were modulated by supplementation of ATRA. Abstention also reduced toxicity, but to a lower extent in comparison with supplementation of ATRA. Our results seemed to suggest that ATRA regressed the mediators of ethanol induced neuroinflammation by reducing oxidative stress and by regulating the expression of NFkappaB and SIRT1. The ameliorative potential of ATRA was much higher than abstention. PMID- 30022381 TI - The spread of Injectate after ultrasound-guided lateral elbow injection - a cadaveric study. AB - BACKGROUND: Injections into the tendinous portion of the common extensor origin are a common intervention in the treatment of Lateral Elbow Tendinopathy (LET). Clinical trials report a heterogeneous selection of injectate volumes and delivery techniques, with systematic reviews finding no clear consensus. The aim of this study was to assess the intratendinous distribution and surrounding tissue contamination of ultrasound-guided injections into the Common Extensor Tendon (CET) of the elbow. METHODS: Twenty cadaveric elbows were injected by a Consultant Radiologist under Ultrasound guidance. Elbows were randomised to equal groups of 1 or 3 mls of methylene blue injection, delivered using single shot or fenestrated techniques. Following injection, each cadaver underwent a dry arthroscopy and dissection of superficial tissues. The CET was excised, set and divided into 1 mm sections using microtome. Each slice was photographed and analysed to assess spread and pixel density of injectate in four colour graduations. The cross-sectional area of distribution was calculated and compared between groups. RESULTS: In all 20 cadaveric samples, contamination of the joint was noted on arthroscopy and dissection. Injectate spread through over 97% of the cross-sectional area. No differences were found in intratendinous spread of injectate between differing volumes or techniques. CONCLUSION: This study found that commonly used injection volumes and techniques distribute widely throughout cadaveric CETs. There was no improvement when the volume was increased from 1 to 3 mls or between single shot of fenestrated injection techniques. It should be noted that joint contamination using these techniques and volumes may be inevitable. PMID- 30022382 TI - Pulmonary metastases in children and adolescents with papillary thyroid cancer in China: prognostic factors and outcomes from treatment with 131I. AB - PURPOSE: Papillary thyroid carcinoma (PTC) with pulmonary metastases is rare in children and adolescents. Unlike adults, limited data are available on children with this disease. Thus, this study evaluated the therapeutic efficacy and prognostic factors of individuals less than 21 years of age with pulmonary metastases from PTC. METHODS: Seventy-six children and adolescents with pulmonary metastases from PTC treated with 131I were retrospectively analyzed. Therapeutic efficacy was evaluated by changes in serum thyroglobulin (Tg) and chest computed tomography (CT). Factors predictive of progression-free survival and overall survival were measured by the Kaplan-Meier method. RESULTS: Among the 76 patients included in this study, 22.4% (17 of 76) were less than 15 years old and 65.8% (50 of 76) were female. Under the evaluation of stimulated serum Tg levels, RAI treatment were effective in 55.9% (38 of 68), stable in 26.5% (18 of 68) and ineffectvie in 17.6% (12 of 68) of patients. Changes on anatomical imaging suggested complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) in 8.5, 62.0, 15.5, and 14.1% of individuals, respectively. Univariate analysis showed that size and tumor doubling time of pulmonary metastases were independent factors affecting therapeutic efficacy. Extra-thyroidal extension, tumor diameter of pulmonary metastases and tumor doubling time were significant independent factors regarding progression-free survival rates, while only tumor doubling time and tumor diameter were significant risk factors associated with overall survival rate. CONCLUSIONS: Radioactive iodine therapy is an effective treatment for children and adolescents with pulmonary metastases from PTC. Extra-thyroid extension was associated with disease progression while did not show significant influence on overall survival. Tumor doubling time and tumor diameter were the main factors influencing both progression-free survival and overall survival. PMID- 30022384 TI - Differences on metabolic behavior between intra and extrahepatic cholangiocarcinomas at 18F-FDG-PET/CT: prognostic implication of metabolic parameters and tumor markers. AB - BACKGROUND AND PURPOSE: Cholangiocarcinoma is an infrequent neoplasm barely studied with 18F-FDG-PET/CT. We evaluated the metabolic behavior of cholangiocarcinoma in PET/CT according to its location (intra or extrahepatic) and analyzed the relationship between metabolic parameters of the primary tumor and tumor markers (CA19-9 and CEA), determining their prognostic significance. METHODS: Retrospective study of PET/CT of 60 patients with untreated cholangiocarcinoma, divided into two groups according to tumor location. FDG uptake was evaluated visually and semiquantitatively [SUVmax and tumor-to-liver ratio (TLR)], and differences between intra and extrahepatic cholangiocarcinomas were tested, both for FDG uptake in the primary tumor and for the presence of regional or distant disease (per-patient), as well as regarding tumor marker levels. A correlation between metabolic parameters and tumor markers was performed, and prognostic value of these factors was determined (univariate and multivariate analyses). RESULTS: Intrahepatic cholangiocarcinomas were significantly more FDG-avid than extrahepatic ones (p = 0.006 for SUVmax; p = 0.002 for TLR). There were differences neither between both groups considering the capacity of PET/CT to detect regional (p = 0.261) and distant involvement (p = 0.876), nor regarding the levels of tumor markers (p = 0.160 for CA19-9; p = 0.708 for CEA). Metabolic parameters and tumor markers showed a weak positive correlation (R2 0.22-0.27). At the multivariate analysis, advanced stage (p = 0.024), increased CEA (p = 0.022), and higher TLR (p = 0.003) were significantly related with shorter overall survival. CONCLUSIONS: Intra and extrahepatic cholangiocarcinomas behave differently on PET/CT, though no differences between both groups exist in its capacity to detect regional or distant disease. Metabolic parameters and levels of tumor markers seem to relate with tumor burden, impacting in prognosis. PMID- 30022385 TI - Prognostic implication of EGFR mutation status and subtype in resected lung adenocarcinoma patients irrespective of therapy. AB - OBJECTIVE: This study aimed to investigate the pure prognostic role of epidermal growth factor receptor (EGFR) mutation status and subtype in lung adenocarcinoma patients irrespective of therapy. MATERIALS AND METHODS: We retrospectively enrolled 119 cases of completely resected pathological stage I lung adenocarcinoma patients who received no postoperative chemotherapy or tyrosine kinase inhibitors. EGFR gene mutations from 18 to 21 exons were tested for all the patients. Disease-free survival (DFS) and overall survival (OS) were compared between patients with different EGFR mutation status and subtype using Kaplan Meier methods. RESULTS: EGFR mutations were detected in 54 (45.4%) patients including two common mutation subtypes: 32 in-frame deletion within exon 19 (19del) and 19 point mutation within exon 21 (L858R). The frequency of EGFR mutations was much greater for patients of non-smokers versus current or ever smokers (58.1 versus 24.4%, P = 0.000), and a little greater for females versus males (53.8 versus 35.2%, P = 0.042). The median follow-up duration was 43.5 months, and there were no differences on DFS (P = 0.461) and OS (P = 0.989) between patients with EGFR mutations and those without in univariate analysis. The patients harboring 19del mutation had a better DFS (P = 0.028) and OS (P = 0.001) than the patients harboring L858R mutation with significant statistical difference. CONCLUSIONS: This study suggests that there is no difference on survival between patients with EGFR mutations and those without, but the patients harboring EGFR 19del mutation have survival advantage compared to those harboring EGFR L858R mutation. PMID- 30022383 TI - Targeting Gastrointestinal Transport Proteins to Control Hyperphosphatemia in Chronic Kidney Disease. AB - Management of hyperphosphatemia in patients with dialysis-dependent chronic kidney disease remains a major challenge, requiring a multifaceted approach that includes dietary phosphate restriction, dialysis, and phosphate binders. However, these treatments fail to meet serum phosphate targets in many patients, potentially further exacerbating the significant morbidity and mortality burden associated with the disease. Recent advances in our understanding of the mechanisms underlying phosphate homeostasis have shed new light on the issue and suggest that gastrointestinal transport proteins may be promising targets for new hyperphosphatemia treatments. Drugs that inhibit or downregulate these transport proteins, and thus reduce phosphate uptake from the gut, may overcome some of the limitations of existing phosphate-lowering strategies, such as interdialytic rises in serum phosphate levels, poor adherence to dietary and phosphate-binder regimens, and maladaptive responses that can increase gastrointestinal phosphate absorption. Here, we review the latest preclinical and clinical data for two candidates in this novel drug class: tenapanor, a small-molecule inhibitor of the sodium/hydrogen ion-exchanger isoform 3, and nicotinamide, an inhibitor of sodium phosphate-2b cotransporters. We also discuss how potential synergies in their mechanisms of action suggest that coadministering phosphate binders with sodium phosphate-2b cotransporter inhibitors may yield additive benefits over traditional phosphate-binder therapy. PMID- 30022386 TI - Effectiveness, safety and cost of abiraterone acetate in patients with metastatic castration-resistant prostate cancer: a real-world data analysis. AB - PURPOSE: New therapies with diverse mechanisms of action are available for metastatic castration-resistant prostate cancer (mCRPC). This study aims to evaluate the effectiveness, safety and cost of abiraterone acetate (AA) in patients with mCRPC. MATERIALS AND METHODS: Observational retrospective cohort study in which mCRPC patients who initiated AA between January 1, 2012 and December 31, 2017, were included. The patients were followed-up until death or March 31, 2018. Demographic, clinical and economic data were collected from the corporate electronic information systems. Survival distributions were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 69 mCRPC patients were started on AA, of whom 18 (26.1%) received prior chemotherapy (post-CT) and 51 (73.9%) did not receive it (CT-naive). A PSA decline of >= 50% was achieved in five (27.8%) post-CT and 32 (62.7%) CT-naive patients (p = 0.011). Median time to PSA progression, progression-free survival (PFS) and overall survival (OS) were 4.4/7.9 months (p = 0.003), 5.1/7.5 months (p = 0.034) and 12.1/21.3 months (p = 0.119), respectively, for post-CT/CT-naive patients. Treatment-related adverse events (AEs) occurred in 10 (55.6%) post-CT and 11 (21.6%) CT-naive patients (p = 0.007). The most common AEs were hypokalaemia (11.6%), hypertension (8.7%) and fatigue (5.8%). The cost per median PFS month and per median OS month was ?2818.4/?2784.3 and ?1187.9/?980.4 for post CT/CT-naive patients, respectively. CONCLUSIONS: CT-naive patients treated with AA obtained a better clinical benefit in terms of effectiveness, safety and cost effectiveness ratio than post-CT patients. The effectiveness outcomes were poorer than those reported previously in the clinical trial setting. PMID- 30022388 TI - Study on the removal effect and influencing factors of nitrobenzene reduction by iron carbonate precipitates. AB - To investigate the activity of iron carbonate precipitates produced by long-term operation of Fe0 permeable reactive barriers, three kinds of precipitates, namely Fe6(OH)12CO3, Fe2(OH)2CO3, and FeCO3, were prepared to reduce the pollutant nitrobenzene. We studied the reduction effects of these iron carbonate precipitates on nitrobenzene by considering three factors, namely the initial nitrobenzene concentration, initial pH, and precipitate dosage, and established the kinetic degradation using pseudo-first-order kinetics model. The results showed that all three precipitates can reduce nitrobenzene, and the order of reducing capability is Fe6(OH)12CO3 > Fe2(OH)2CO3 > FeCO3; moreover, the removal efficiency values of nitrobenzene are 68.08, 53.00, and 50.29%. A high initial nitrobenzene concentration and high pH value are beneficial to nitrobenzene reduction, and removal efficiency was increased when pH was increased from 4 to 9. In addition, the increased precipitate addition in the Fe6(OH)12CO3 and Fe2(OH)2CO3 systems increased removal efficiency. Furthermore, the dosage did not significantly influence the removal rate in the FeCO3 system. Fe6(OH)12CO3 and Fe2(OH)2CO3 mainly relied on the precipitate itself with the structural Fe(II) to reduce nitrobenzene, and FeCO3 mainly relied on the dissolved Fe2+. The reaction of all three precipitates in reducing nitrobenzene followed the first-order reaction kinetics. PMID- 30022387 TI - Leaching of metals from asphalt pavement incorporating municipal solid waste incineration fly ash. AB - Rising municipal solid waste incineration (MSWI) makes it imperative to recycle the fly ash (FA). FA can be solidified by asphalt and then applied in the asphalt road. However, little information on the metal leaching and associated with risks from asphalt solidified forms for FA is available. In the present study, metal leaching characteristics and long-term leaching potential from the asphalt-based FA matrices was determined based on the national standard method and simulating the actual using of the solidified forms in highways, respectively. The immobilization effect of asphalt on MSWI FA is well. Leaching velocity was in the order of magnitude of 10~10-6 cm h-1 during the entire leaching period. At the early age, leaching velocity of metals is high, especially Zn, Cd, and Ba. Cumulative leaching concentration of metals and leaching time has positive correlation. Only considering the leaching of simulating acid, leaching of metals in asphalt-based matrices is very slow, and the leaching toxicity of metals is lower than the Chinese National Standard. PMID- 30022389 TI - Novel magnetic graphene oxide functionalized cyanopropyl nanocomposite as an adsorbent for the removal of Pb(II) ions from aqueous media: equilibrium and kinetic studies. AB - This work presents the synthesis of the novel silica-cyanopropyl functionalized magnetic graphene oxide (MGO/SiO2-CN) hybrid nanomaterial derived by sol-gel method as a cheap efficient magnetic sorbent for the removal of extremely hazardous lead ions from aqueous media. The integration of the magnetic property, the carbon substrate, and the nitrile (-C = N) containing organic grafted silica matrix promoted the adsorption capability against lead ions along with its simple synthesis recovery and low cost. The prepared nanocomposite was comprehensively characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. Adsorption of lead was found to be pH dependent because of the charged nature of both analyte and adsorbent surface. Adsorption experiments were conducted under the optimum conditions, and the obtained experimental data from atomic absorption spectroscopy were analyzed using the popular isothermal models namely Langmuir, Freundlich, and Dubinin-Radushkevich isotherms as well as kinetically studied and evaluated for adsorption standard free energy (E). The experimental results have demonstrated the enhanced adsorption capability of the proposed sorbent nanocomposite for lead ion removal with the maximum adsorption capacity of 111.11 mg/g at pH 5.0. The proposed mechanism of lead adsorption was mainly attributed to the complexation of lead positive ions with the grafted -C = N bond. The synergistic effect of the combination of three components (i.e., the magnetic graphene oxide matrix, the triple bond containing organic moiety, and the inorganic porous silica framework) excelled the adsorption capability and proved to be a good candidate as adsorbent for the removal of lead ions. PMID- 30022390 TI - RECOTOX, a French initiative in ecotoxicology-toxicology to monitor, understand and mitigate the ecotoxicological impacts of pollutants in socioagroecosystems. AB - RECOTOX is a cross-cutting initiative promoting an integrated research to respond to the challenges of monitoring, understanding, and mitigating environmental and health impacts of pesticides in agroecosystems. The added value of RECOTOX is to develop a common culture around spatial ecotoxicology including the whole chain of pressure-exposure-impact, while strengthening an integrated network of in natura specifically equipped sites. In particular, it promotes transversal approaches at relevant socioecological system scales, to capitalize knowledge, expertise, and ongoing research in ecotoxicology and, to a lesser extent, environmental toxicology. Thus, it will open existing research infrastructures in environmental sciences to research programs in ecotoxicology of pesticides. PMID- 30022391 TI - Hair mercury concentrations in the spotted seal (Phoca largha) pups from the Sea of Japan. AB - This publication presents the results of a study of the total mercury (THg) concentration in the fetal hair (lanugo) of the young spotted seals inhabiting the Peter the Great Bay, Sea of Japan. We analyzed samples from pups that were collected in 2014-2017 at the seal breeding grounds. The concentration of total mercury was determined by atomic absorption spectrometry. The concentration of THg ranged from 1.52 to 6.68 MUg/g dry weight. Mercury concentration in the lanugo exceeds that found in the environment (bottom sediments, sea water) and in other animals inhabiting the Bay. At the same time, the level was generally lower than that found in young seals of most other pinniped species (Steller sea lion Eumetopias jubatus, Northern fur seal Callorhinus ursinus, Harbor seal Phoca vitulina richardsi, Northern elephant seal Mirounga angustirostris, California sea lion Zalophus californianus) from the North Pacific. PMID- 30022392 TI - Microscale dispersion behaviors of dust particles during coal cutting at large height mining face. AB - In order to ensure safe production and occupational health at a large-mining height fully mechanized mining face in a coal mine, the present study firstly establishes an airflow-dust coupled model based on gas/solid two-phase flow equations and combines numerical simulation and field measurement for analyzing the dispersion pattern of dust particles with various sizes for different coal cutter locations. Results show that, due to the existence of drums, airflow deviates from the original direction and enters the footway. Driven by the airflow, dust particles enter the footway at different locations depending on coal cutter locations. The coal-cutting location (denoted as Prl) and the location where dust particles enter the footway (denoted as Pdt) are correlated as follows: Pdt(Prl) = - 0.0007Prl2 + 1.0343Prl - 3.3536. When Prl < 55 m, dust particles produced by the rear drum during coal cutting enter the footway earlier than those produced by the front drum, leading to the first and second dust concentration peaks in respiratory zones of footway. Dust suppression effects are assessed in these regions based on the first and second dust concentration peaks. Due to the superposition of the concentration fields associated with dust particles 2.5, 7, and 20 MUm in diameter, dust concentration 25 m down the leeward side of the coal cutter can reach 1440 mg/m3. The concentration of dust particles with a diameter of 40 MUm drops steadily and approaches 0 at the return corner. The dust particles 80 MUm in diameter are fully settled within 22 m down the leeward side of the coal cutter. A comparison with the field measurement indicates that the present simulation results are highly accurate. Graphical abstract. PMID- 30022393 TI - Spatial and temporal variations in the geochemistry of shallow groundwater contaminated with nitrate at a residential site. AB - The concentrations of nitrate (NO3-), major ions, and dissolved inorganic carbon (DIC) and the stable carbon isotopes of DIC (delta13CDIC) in shallow groundwater below a 45 * 60 m residential property was investigated over a period of 38 months. Our aim was to identify the processes which control the spatial and temporal distribution of NO3- in the shallow groundwater and assess water-rock interactions linked to denitrification. Groundwater sampled quarterly from eight locations showed an average NO3- concentration of 36.8 mg/L and a range between 0.1 and 214.9 mg/L compared to the US EPA maximum contaminant level of 10 mg/L. Heterogeneity in nitrate distribution was from residential application of N-based fertilizers offsite and from onsite application on flower beds and for lawn care. The temporal behavior of nitrate at all eight groundwater locations was markedly different and independent of seasonal hydrologic variations. Nitrate attenuation was spatially controlled by heterogeneous denitrification and rain dilution near roof drains. Groundwater locations with active denitrification were characterized by higher DIC concentrations and lower delta13CDIC from organic carbon mineralization and by higher ionic concentrations from weathering of aquifer minerals. The variation in the relative standard deviations (RSD) of the measured parameters over space (RSD-s) and time (RSD-t) was highest for NO3- associated with variable spatiotemporal input and lowest for pH, pCO2, and delta13CDIC indirectly controlled by denitrification. Denitrification induced mineral weathering products such as DIC, Ca2+, Mg2+, and HCO3- showed medium to high RSD s and RSD-t. The RSD-s and RSD-t were positively correlated (R2 = 0.85) with the RSD-s showing approximately twofold higher magnitude than RSD-t due to greater variability between monitoring wells locations than variability at each groundwater location over time. Nitrate contamination and denitrification represent important long-term driver of aquifer weathering and changes in groundwater geochemistry below residential communities. PMID- 30022394 TI - A qualitative study of the determinants of adherence to NICE falls guideline in managing older fallers attending an emergency department. AB - BACKGROUND: The National Institute for Health and Care Excellence (NICE) 2004 Falls guideline was developed to improve the assessment and management of falls and prevention of future falls. However, adherence to the guideline can be poor. As emergency departments (EDs) are usually consulted by older adults (aged 65 and over) who experience a fall, they provide a setting in which assessments can be conducted or referrals made to more appropriate settings. The objective of this study was to investigate how falls are managed in EDs, reasons why guideline recommendations are not always followed, and what happens instead. METHODS: The study involved two EDs. We undertook 27 episodes of observation of healthcare professional interactions with patients aged 65 or over presenting with a fall, supported by review of the clinical records of these interactions, and subsequently, 30 interviews with healthcare professionals. The qualitative analysis used the framework approach. RESULTS: Various barriers and enablers (i.e. determinants of practice) influenced adherence at both EDs, including the following: support from senior staff; education; cross-boundary care; definition of falls; communication; organisational factors; and staffing. CONCLUSIONS: A variety of factors influence adherence to the Falls guideline within an ED, and it may be difficult to address all of them simultaneously. Simple interventions such as education and pro-formas are unlikely to have substantial effects alone. However, taking advantage of the influence of senior staff on juniors could enhance adherence. In addition, collaborative care with other NHS services offers a potential approach for emergency practitioners to play a part in managing and preventing falls. PMID- 30022395 TI - Epidemiology of Colorectal Cancer and the Risk Factors in Kermanshah Province Iran 2009-2014. AB - INTRODUCTION AND OBJECTIVE: Colorectal cancer is the fourth prevalent cancer in the world and there are several factors effective on development of the disease. These factors vary based on geographical distribution. The present study is aimed at surveying epidemiology of colorectal cancer and its risk factors in Kermanshah Iran between 2009 and 2014. METHODOLOGY: A descriptive cross-sectional study was carried out on all colorectal cancer cases in two Kermanshah-based hospitals Imam Reza and Taleghani between 2009 and 2014. Demographic and epidemiological information was collected from the medical files and interviewing the patients. The collected data was analyzed in SPSS. FINDINGS: Totally, 336 patients had been registered from 2009 to 2014. Mean and standard deviation of age was 59.98 +/- 15.26. Fifty-four subjects (16.05%) had a history of colorectal cancer among their relatives and 253 (62.5) had no history of physical activity. In addition, 81 subjects (24.1%) had a history of digestive diseases. In terms of diet, 205 subjects (61%) used less than 6 unit/day of grains and bread, and meat consumption in 150 subjects (44.6%) was less than 2 unit/day. CONCLUSION: The results showed that the prevalence of colorectal cancers was growing in Kermanshah. To change the rate, changes in lifestyle and screening tests for more susceptible age groups are recommended. PMID- 30022396 TI - An unusual cause of acute thoracic pain: left ventricular pseudoaneurysm. PMID- 30022397 TI - The diagnostic challenge: are we missing pulmonary embolism diagnosis in patients with syncope? PMID- 30022398 TI - Bertolotti's syndrome: a transitional anatomic cause of low back pain. PMID- 30022399 TI - Recurrent pericarditis: still idiopathic? The pros and cons of a well-honoured term. AB - In developed countries, more than 80% of cases of acute pericarditis remain without an established diagnosis after a conventional and standard diagnostic approach. These cases are generally labelled as 'idiopathic', i.e. without a known cause. This lack of information is a matter of concern for both patients and clinicians. Some years ago, this term reflected the state of the art of scientific knowledge on the topic. Advances have changed this point of view, in light of available molecular techniques like polymerase chain reaction able to identify viral cardiotropic agents in pericardial fluid and biopsies. Furthermore, the remarkable efficacy of interleukin-1 antagonists, a therapy targeting the innate immune response, suggests clinical and pathogenic similarity between a proportion of patients with idiopathic recurrent pericarditis and classical autoinflammatory diseases. So, it seems useful to discuss the pros and cons of using the term "idiopathic" in light of the new knowledge. PMID- 30022401 TI - Maternal Decision-Making and Uptake of Health Services for the Prevention of Mother-to-Child HIV Transmission: A Secondary Analysis. AB - Objectives We investigated whether a woman's role in household decision-making was associated with receipt of services to prevent mother-to-child HIV transmission (PMTCT). Methods We conducted a secondary analysis of the PEARL study, an evaluation of PMTCT effectiveness in Cameroon, Cote d'Ivoire, South Africa, and Zambia. Our exposure of interest was the women's role (active vs. not active) in decision-making about her healthcare, large household purchases, children's schooling, and children's healthcare (i.e., four domains). Our primary outcomes were self-reported engagement at three steps in PMTCT: maternal antiretroviral use, infant antiretroviral prophylaxis, and infant HIV testing. Associations found to be significant in univariable logistic regression were included in separate multivariable models. Results From 2008 to 2009, 613 HIV infected women were surveyed and provided information about their decision-making roles. Of these, 272 (44.4%) women reported antiretroviral use; 281 (45.9%) reported infant antiretroviral prophylaxis; and 194 (31.7%) reported infant HIV testing. Women who reported an active role were more likely to utilize infant HIV testing services, across all four measured domains of decision-making (adjusted odds ratios [AORs] 2.00-2.89 all p < .05). However, associations between decision making and antiretroviral use-for both mother and infant-were generally not significant. An exception was active decision-making in a woman's own healthcare and reported maternal antiretroviral use (AOR 1.69, p < 0.05). Conclusions for Practice Associations between decision-making and PMTCT engagement were inconsistent and may be related to specific characteristics of individual health seeking behaviors. Interventions seeking to improve PMTCT uptake should consider the type of health-seeking behavior to better optimize health services. PMID- 30022400 TI - Can a Call Make a Difference? Measured Change in Women's Breastfeeding Self efficacy Across Call Interactions on a Telephone Helpline. AB - Background Telephone helplines providing 24-h specialist-nurse contact present a source of immediate support for women encountering challenges with breastfeeding and may serve to prolong breastfeeding duration by building self-efficacy. To date there is little evidence on interaction effectiveness and still less on the relative effectiveness for women from different socio-economic backgrounds. Research Aim To establish the effect on maternal breastfeeding self-efficacy of calls made to a nurse-led parenting helpline. Methods From a corpus of calls made to the Australian Child Health Line (N = 723), those made by women presenting a breastfeeding concern as a prime issue (n = 60) were scored for breastfeeding self-efficacy at commencement and completion of recorded interactions. Analyses examined the significance and direction of change from beginning to end of calls and compared difference in change across calls originating from high and low social advantage locations. Results A significant increase in self-efficacy was found, but with low effect size. There was considerable variation among calls; 53% showed improvement, 25% showed no change and 22% showed reduction in breastfeeding self-efficacy. While most calls were made by women from socially advantaged locations, change was more positive for the small number of callers from disadvantaged locations. Conclusion The potential of nurse-led reactive telephone support is evident, but dependent on qualities of the interaction. For women living in disadvantaged locations telephone support may be of particular significance given the greater social barriers to breastfeeding they are likely to encounter. PMID- 30022402 TI - Preliminary results of the placental decorin profile in bovine pregnancy and parturition. AB - Decorin is a small leucine-rich proteoglycan which is involved in multiple biological functions mainly as a structural and signaling molecule. Due to its biological properties in connective tissue, decorin may participate in remodeling of ECM during attachment and detachment of placenta within the course of pregnancy and at parturition in cows. The aim of the study was to detect the presence of decorin protein in bovine placental tissues and to evaluate its profile during pregnancy and at parturition. Placental tissues from healthy pregnant cows (2-5 month) were collected in abattoir (n = 10), while parturient tissues were obtained during caesarian section at physiological term (n = 6). Maternal and fetal parts were separated manually and subjected to homogenization and to quantitative ELISA and verification by Western blotting with anti-decorin antibodies. ELISA test showed that the concentration of decorin during pregnancy was higher in the fetal part of placenta compared with the maternal part (p < 0.001). Similar pattern was noted regarding to maternal and fetal samples derived from parturient cows. Our preliminary results demonstrate that the concentration of decorin is gestation time-dependent in healthy bovine placenta. Possible confirmation of the involvement of decorin in early pregnancy attachment and detachment of the placenta during parturition requires further research. PMID- 30022403 TI - Beyond the grey tsunami: a cross-sectional population-based study of multimorbidity in Ontario. AB - OBJECTIVES: To determine volumes and rates of multimorbidity in Ontario by age group, sex, material deprivation, and geography. METHODS: A cross-sectional population-based study was completed using linked provincial health administrative databases. Ontario residents were classified as having multimorbidity (3+ chronic conditions) or not, based on the presence of 17 chronic conditions. The volumes (number of residents) of multimorbidity were determined by age categories in addition to crude and age-sex standardized rates. RESULTS: Among the 2013 Ontario population, 15.2% had multimorbidity. Multimorbidity rates increased across successively older age groups with lowest rates observed in youngest (0-17 years, 0.2%) and highest rates in the oldest (80+ years, 73.5%). The rate of multimorbidity increased gradually from ages 0 to 44 years, with a substantial and graded increase in the rates as the population aged. The top five chronic conditions, of the 17 examined, among those with multimorbidity were mood disorders, hypertensive disorders, asthma, arthritis, and diabetes. CONCLUSION: Much of the common rhetoric around multimorbidity concerns the aging 'grey tsunami'. This study demonstrated that the volume of multimorbidity is derived from adults beginning as young as age 35 years old. A focus only on the old underestimates the absolute burden of multimorbidity on the health care system. It can mask the association of material deprivation and geography with multimorbidity which can turn our attention away from two critical issues: (1) potential inequality in health and health care in Ontario and (2) preventing younger and middle-aged people from moving into the multimorbidity category. PMID- 30022404 TI - Chagas heart disease: A contemporary review. AB - Chagas disease is caused by a parasite infection endemic of the Americas. Traditionally observed in rural areas of Latin America, current migration trends have turned Chagas disease into a global epidemic. Acute infection is rarely severe and once it resolves, some patients can develop cardiomyopathy as part of the chronic form many years later. Multiple factors related with both the host and the parasite determine the susceptibility and progression to cardiomyopathy. Current imaging techniques are able to identify cardiac autonomic denervation, perfusion abnormalities, and myocardial fibrosis at an early of stage before the development of symptoms. The prognosis of patients with Chagasic cardiomyopathy remains poor and life-threatening ventricular arrhythmias can occur at an early stage. Treatment of chronic Chagas cardiomyopathy is challenging with a great need for more studies in the field. PMID- 30022405 TI - Cardiac amyloidosis imaging with amyloid positron emission tomography: A systematic review and meta-analysis. AB - BACKGROUND: Recent progress in amyloid positron emission tomography (PET) has enabled the targeted imaging of cardiac amyloidosis with accuracy. We performed a systematic review and meta-analysis on the diagnostic performance of cardiac amyloidosis using amyloid PET. METHODS: A systematic search was performed using key words: cardiac amyloidosis, amyloid, and PET. We estimated the pooled sensitivity, specificity, positive and negative likelihood ratio (LR), and diagnostic odds ratio (DOR). Furthermore, the semiquantitative parameters of PET were evaluated to diagnose cardiac amyloidosis and discern its type [systemic light chain amyloidosis (AL) vs transthyretin amyloidosis (ATTR)] using the pooled standardized mean difference (SMD). RESULTS: In total, six eligible studies with a total of 98 subjects were included in this meta-analysis. The pooled sensitivity was 0.95, the specificity was 0.98, positive LR was 10.130, negative LR was 0.1, and DOR was 148.83. The semiquantitative parameters of amyloid PET showed significantly higher values for cardiac amyloidosis patients than those for controls (pooled SMD = 1.42; P < .001), and in AL than ATTR (pooled SMD = 0.96; P < .001). CONCLUSION: Amyloid PET imaging can be a useful method for diagnosing cardiac amyloidosis. The semiquantitative parameters of amyloid PET can help diagnose cardiac amyloidosis and discern its type. PMID- 30022406 TI - Renal tumor biopsy: indicators, technique, safety, accuracy results, and impact on treatment decision management. AB - CONTEXT: Renal tumor biopsy (RTB), as distinct from the more common renal biopsy for medical renal disease, is an option for patients with renal masses. It is mainly used for small renal masses (SRM) but it may also be indicated for larger masses and even in the presence of metastatic disease. Its main indication in SRM is to avoid intervention for benign kidney tumors but increasingly enables more personalized treatment for kidney cancer patients. OBJECTIVE: The objective of this paper is to provide a comprehensive review of the most recent literature available for RTB including the indications, the technique and also the possible complications. RESULTS: The urological community continues to optimize the indications for RTB. Non-operative treatment modalities, such as active surveillance, ablative modalities, and immunotherapy, may have different results influenced by tumor histology. Continuing concern regarding complications and accuracy and, therefore, the utility of RTB has been addressed. Recent reports support the potential benefit of RTB, safely avoiding a significant number of interventions with good results and minimal complications. CONCLUSION: Urologists should be aware of the benefits of RTB and develop experience with this technique to optimize the results. This diagnostic strategy should be discussed with patients and adopted as it has been with other solid tumors. PMID- 30022407 TI - Answer to comment on manuscript "Prognostic significance of Fuhrman grade and age for cancer-specific and overall survival in patients with papillary renal cell carcinoma: results of an international multi-institutional study on 2189 patients". PMID- 30022408 TI - Do Patients with Cellulitis Need to be Hospitalized? A Systematic Review and Meta analysis of Mortality Rates of Inpatients with Cellulitis. AB - BACKGROUND: Cellulitis is a common cause of hospitalization. In the USA, the International Classification of Diseases (ICD) code "other cellulitis and abscess" accounts for 1.4% of all admissions and $5.5 billion in annual costs. The Infectious Disease Society of America recommends hospitalization for patients with cellulitis under certain circumstances but there is little actual clinical evidence to guide the decision to admit. The purpose of this study is to determine the mortality rate of patients hospitalized with cellulitis and to ascertain if the rate is comparable to the rate for low risk patients with community acquired pneumonia that are currently recommended for outpatient management. METHODS: A systematic literature search was conducted for studies of consecutive patients hospitalized with cellulitis or erysipelas that reported inpatient mortality. Study quality was assessed using a modified Newcastle-Ottawa Quality Assessment Scale. The mortality rates from the included studies were pooled using a random effects model. Heterogeneity was estimated using the I2 statistic. RESULTS: Eighteen studies met inclusion criteria. The overall worldwide mortality rate was 1.1% (95% confidence interval (CI), 0.7-1.8). For studies from the USA, the rate was 0.5% (95% CI 0.3-0.9). The actual cause of death was generally poorly described, and only one third of deaths appeared to be due to infection. DISCUSSION: The estimated mortality rate for patients currently being hospitalized for cellulitis is comparable to the mortality rate of patients with community-acquired pneumonia that are recommended for outpatient management by the Pneumonia Severity Index and CURB65 prediction models and strongly endorsed by major infectious disease societies. Outpatient management of these patients could result in large cost savings and may be much preferred by patients. PMID- 30022410 TI - Ward Capacity Strain: A Novel Predictor of 30-Day Hospital Readmissions. PMID- 30022409 TI - Patient-Family Agenda Setting for Primary Care Patients with Cognitive Impairment: the SAME Page Trial. AB - BACKGROUND: Establishing priorities for discussion during time-limited primary care visits is challenging in the care of patients with cognitive impairment. These patients commonly attend primary care visits with a family companion. OBJECTIVE: To examine whether a patient-family agenda setting intervention improves primary care visit communication for patients with cognitive impairment DESIGN: Two-group pilot randomized controlled study PARTICIPANTS: Patients aged 65 + with cognitive impairment and family companions (n = 93 dyads) and clinicians (n = 14) from two general and one geriatrics primary care clinic INTERVENTION: A self-administered paper-pencil checklist to clarify the role of the companion and establish a shared visit agenda MEASUREMENTS: Patient-centered communication (primary); verbal activity, information disclosure including discussion of memory, and visit duration (secondary), from audio recordings of visit discussion RESULTS: Dyads were randomized to usual care (n = 44) or intervention (n = 49). Intervention participants endorsed an active communication role for companions to help patients understand what the clinician says or means (90% of dyads), remind patients to ask questions or ask clinicians questions directly (84% of dyads), or listen and take notes (82% of dyads). Intervention dyads identified 4.4 health issues for the agenda on average: patients more often identified memory (59.2 versus 38.8%; p = 0.012) and mood (42.9 versus 24.5%; p = 0.013) whereas companions more often identified safety (36.7 versus 18.4%; p = 0.039) and personality/behavior change (32.7 versus 16.3%; p = 0.011). Communication was significantly more patient-centered in intervention than in control visits at general clinics (p < 0.001) and in pooled analyses (ratio of 0.86 versus 0.68; p = 0.046). At general clinics, intervention (versus control) dyads contributed more lifestyle and psychosocial talk (p < 0.001) and less biomedical talk (p < 0.001) and companions were more verbally active (p < 0.005). No intervention effects were found at the geriatrics clinic. No effect on memory discussions or visit duration was observed. CONCLUSION: Patient-family agenda setting may improve primary care visit communication for patients with cognitive impairment. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02986958. PMID- 30022411 TI - The Value of Outpatient Imaging-Based Cancer Screening Episodes. AB - In order to shift US health care towards greater value, the Centers for Medicare & Medicaid Services (CMS) is exploring outpatient episode-based cost measures under the new Quality Payment Program and planning a bundled payment program that will introduce the first ever outpatient episodes of care. One novel approach to capitalize on this paradigm shift and extend bundled payment policies is to engage primary care physicians and specialists by bundling outpatient imaging studies and associated procedures-central tools in disease screening and diagnosis, but also tools that are expensive and susceptible to increasing health care costs and patient harm. For example, both breast and lung cancer screening represent target areas ripe for bundled payment given high associated costs and variation in management strategies and suboptimal care coordination between responsible clinicians. Benefits to imaging-based screening episodes include stronger alignment between providers (primary care physicians, radiologists, and other clinicians), reduction in unwarranted variation, creation of appropriateness standards, and ability to overcome barriers to cancer screening adherence. Implementation considerations include safeguarding against providers inappropriately withholding care as well as ensuring that accountability and financial risk are distributed appropriately among responsible clinicians. PMID- 30022412 TI - Are Primary Care Residents Trained to Perform Skin Cancer Examinations? PMID- 30022414 TI - Gender Pay Gaps in Medicine: Moving from Explanations to Action. PMID- 30022413 TI - Effects of Ivabradine on Hemodynamic and Functional Parameters in Left Ventricular Systolic Dysfunction: a Systematic Review and Meta-analysis. AB - BACKGROUND: Ivabradine is licensed as add-on therapy in patients with severe left ventricular systolic dysfunction (LVSD), normal sinus rhythm, and suboptimal heart rate (HR) control, but effects are not fully established. This study sought to assess the impact of ivabradine therapy on hemodynamic and functional outcome measures in all patients with LVSD. METHODS: MEDLINE (1996-2017), Embase (1996 2017), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, ClinicalTrials.gov , and ISI Web of Science were searched for randomized clinical trials (RCTs) comparing standard medical therapy (SMT) plus ivabradine to SMT alone for patients with LVSD of any severity. Each trial was assessed using the Cochrane Collaborations Risk of Bias tool. RESULTS: Eight RCTs with 17,823 patients were included. Add-on use of ivabradine reduced resting HR (mean difference [MD] 10.3 bpm; p < 0.001), improved ejection fraction (EF) (MD 3.6%, p < 0.001), and preserved systolic blood pressure (MD 3.4 mmHg; p = 0.09). Stratified analyses according to severity of LVSD did not influence conferred benefits on HR and EF. Small improvements were noted in exercise tolerance (standardized MD 5.9 s; p = 0.004) and peak oxygen consumption (MD 2.9 ml/kg/min; p = 0.02). DISCUSSION: Adjunct therapy with ivabradine in patients with LVSD results in a favorable hemodynamic profile and correlates with improved functional capacity. Benefits appear to be broadly preserved irrespective of baseline EF. This was a meta-analysis of RCTs, though limited by exclusion of post hoc analyses, lack of access to patient level data, and inter-study variability in some baseline characteristics. Further, large-scale RCTs are warranted to evaluate effectiveness of ivabradine in cohorts with non-severe LVSD. PMID- 30022415 TI - Primary Care Confusion-Public Knowledge of NP and PA Duties and Their Information Gathering Behaviors. PMID- 30022416 TI - Childbearing Motivations and Desires, Fertility Beliefs, and Contraceptive Use among Urban African-American Adolescents and Young Adults with STI Histories. AB - This study explored the influence of STI history on childbearing motivations, fertility beliefs, current childbearing desires, and contraception use among urban African-American adolescents and young adults (AYA). Secondary data were from the Neighborhood Influences on Adolescent and Young Adult Health (NIAAH) study, conducted from 2004 to 2007. Sample included 517 AYA ages 15-24 years (male: n = 199, female: n = 318). Linear and logistic regression models examined gender differences in childbearing motivations (CBM) and desires, fertility beliefs, condom, and contraception use. Logistic regression models were constructed to examine age, pregnancy history, and STI fertility knowledge as potential confounders. AYA men (3.29) and AYA women (3.23) had similar CBM mean scores. AYA women had more positive CBM and used condoms less. Condom use was not associated with CBM among AYA men (OR = 0.71, p = 0.069). Low beliefs about fertility (OR = 0.52, p = 0.003) and prior pregnancy (OR = 5.27, p = 0.002) were associated with current childbearing desires among AYA women. AYA men's low fertility beliefs were only associated with current childbearing desires (OR = 0.56, p = 0.044). AYA men reported more contraception use (67.46 vs. 55.04%), especially with no partner pregnancy history (OR = 0.26, p = 0.017). Younger men (15 to 18 years old) reported more contraception or condom use compared to older AYA men (19-25 years old) (OR = 0.40, p = 0.016). Young men reporting a partner's prior pregnancy used fewer condoms or contraception (OR = 0.23, p = 0.028). STI history did not influence CBM in this sample of urban youth. Prior pregnancy experiences and chronological age, however, were important milestones shaping proximal motivations and desires to bear children, beliefs about fertility, and contraception behaviors. PMID- 30022417 TI - Correction to: Is the Urban Child Health Advantage Declining in Malawi?: Evidence from Demographic and Health Surveys and Multiple Indicator Cluster Surveys. AB - The third from last sentence of the abstract, which reads: "However, U-5MR shows reversal to a significant urban advantage in 2015/2016, and slight increases in urban advantage are noted for infant mortality rate, underweight, full childhood immunization, and stunting rate in 2015/2016". PMID- 30022418 TI - Variable Uptake of Medicaid-Covered Prenatal Care Coordination: The Relevance of Treatment Level and Service Context. AB - Prenatal care coordination programs direct pregnant Medicaid beneficiaries to medical, social, and educational services to improve birth outcomes. Despite the relevance of service context and treatment level to investigations of program implementation and estimates of program effect, prior investigations have not consistently attended to these factors. This study examines the reach and uptake of Wisconsin's Prenatal Care Coordination (PNCC) program among Medicaid-covered, residence occurrence live births between 2008 and 2012. Data come from the Big Data for Little Kids project, which harmonizes birth records with multiple state administrative sources. Logistic regression analyses measured the association between county- and maternal-level factors and the odds of any PNCC use and the odds of PNCC uptake (> 2 PNCC services among those assessed). Among identified Medicaid-covered births (n = 136,057), approximately 24% (n = 33,249) received any PNCC and 17% (n = 22,680) took up PNCC services. Any PNCC receipt and PNCC uptake varied substantially across counties. A higher county assessment rate was associated with a higher odds of individual PNCC assessment but negatively associated with uptake. Mothers reporting clinical risk factors such as chronic hypertension and previous preterm birth were more likely to be assessed for PNCC and, once assessed, more likely to received continued PNCC services. However, most mothers reporting clinical risk factors were not assessed for services. Estimates of care coordination's effects on birth outcomes should account for service context and the treatment level into which participants select. PMID- 30022419 TI - Correction to: Examining the Associations Between Immigration Status and Perceived Stress Among HIV-Infected and Uninfected Women. AB - The original version of this article unfortunately published with the incorrect article title. PMID- 30022420 TI - Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort. AB - Isolated Methylmalonic acidemia/aciduria (MMA) is a group of inborn errors of metabolism disease which is caused by defect in methylmalonyl-CoA mutase (MCM) enzyme. The enzyme has a key function in the catabolism of branched chain amino acids (BCAA, isoleucine, and valine), methionine, and threonine. MCM is encoded by a single gene named "MUT". Other subtypes of MMA are caused by mutations in cblA (encoded by MMAA) and cblB (encoded by MMAB), which is involved in the synthesis of methylmalonyl-coenzyme A cofactor. Different types of mutations have been identified as the cause of MMA. However, the mutation spectrum of MMA in Iran has not been studied so far. Here, we aimed to investigate the MMA causative mutations in the Iranian population. Using STR (Short Tandem Repeat) markers, we performed autozygosity mapping to identify the potential pathogenic variants in 11 patients with clinical diagnosis of MMA. Nineteen STR markers which are linked to the MUT, MMAA and MMAB genes (the genes with known causative mutations in MMA) were selected for PCR-amplification using two recently designed multiplex PCR panels. Next, the families that were diagnosed with homozygous haplotypes for the candidate genes were directly sequenced. Five novel mutations (c.805delG, c.693delC, c.223A > T, c.668A > G and c.976A > G in MUT) were identified beside other 4 recurrent mutations (c.361insT in MUT, c.571C > T and c.197-1 G > T in MMAB and c.1075C > T in MMAA). In silico analyses were also performed to predict the pathogenicity of the identified variants. The mutation c.571C > T in MMAB was the most common mutation in our study. PMID- 30022421 TI - Early Onset of Obesity and Adult Onset of Obesity as Factors Affecting Patient Characteristics Prior to Bariatric Surgery. AB - BACKGROUND: Patients who are slated for bariatric surgery vary in terms of their age at onset of obesity, duration of obesity, and their health complications. Therefore, we aimed to explore a relationship between the age at onset of obesity, metabolic parameters, and health problems in bariatric surgery candidates. METHODS: A total of 469 unrelated adults with obesity prior to bariatric surgery were included in this study. The study group consisted of 246 individuals who became obese < 20 years of age, and 223 individuals who became obese >= 20 years. Clinical, biochemical, anthropometric assessments, and DXA derived measures were taken. RESULTS: Patients with early onset of obesity had a higher total body fat mass, and higher body fat percentage, and a 1.84 times higher risk of BMI above 40 kg/m2 than patients with adult onset of obesity (>= 20 years). Multivariable logistic regression demonstrated that, among bariatric surgery candidates with early onset of obesity, the frequency of hypertension and type 2 diabetes was significantly lower than that in cases with an adult onset of obesity, despite a longer duration of obesity and higher BMI. CONCLUSIONS: The age at which an individual reaches obesity has a significant impact on patient characteristics on the day he or she is evaluated for bariatric surgery. A younger age at obesity onset is a predicting factor for a higher BMI in patients, but they are less likely to clinically manifest well-established consequences of obesity, such as diabetes or hypertension, compared to patients with adult onset of obesity. PMID- 30022422 TI - Predicting Symptom Relief After Reoperation for Suspected Internal Herniation After Laparoscopic Roux-en-Y Gastric Bypass. AB - BACKGROUND: Internal herniation (IH) is one of the most common long-term complications after laparoscopic Roux-en-Y gastric bypass (LRYGB). Diagnosis of IH may be difficult, and not all patients with suspected IH will have full relief of symptoms after closure of both mesenteric defects. OBJECTIVES: To investigate possible predictive factors for relief of symptoms in patients with suspected IH. METHODS: All patients that underwent reoperation for (suspected) IH after LRYGB from June 2009 to December 2016 were retrospectively evaluated in this multicentre cohort study. Logistic regression analysis was used to identify predictive factors for pain relief after closure of the mesenteric defects. RESULTS: A total of 193 patients underwent laparoscopy for (suspected) IH during the study period. The median interval between LRYGB and reoperation was 18.3 +/- 19.0 months. In 40.2% of cases, IH was identified on computed tomography (CT), and IH was objectified during surgery in 61.1%. Postoperative symptom relief was observed in 146 patients (77.2%). For patients in which IH was present during surgery, 82.8% had relief of pain postoperatively, as compared to 68.5% for those procedures in which no IH was found. The only significant predictor for postoperative pain relief was a swirl sign on CT (OR 4.24, 95%CI 1.63-11.05). CONCLUSIONS: Pain relief after closure of the mesenteric defects for IH remains unpredictable. A positive CT for IH was a predictive factor for symptom relief after reoperation for (suspected) IH after LRYGB. However, many patients benefit from closure of the mesenteric defects, irrespective of perioperative presence of IH. PMID- 30022423 TI - Conversion Surgery for Failed Adjustable Gastric Banding: Outcomes with Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass. AB - OBJECTIVES: Laparoscopic adjustable gastric banding (LAGB) was once a preferred method of obesity treatment featuring a straightforward technique, removability, and good early results. In a significant proportion of patients, however, it was not a durable weight-loss procedure and has been associated with a high longer term complication rate. The purpose of this study was to directly compare the results of conversion to laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) after failed LAGB. METHODS: Post-LAGB complications and weight outcomes of conversion (absolute weight, excess weight loss [%EWL], total weight loss [%TWL]) to LSG vs LRYGB were retrospectively reviewed and statistically compared using Fisher's exact test and the independent samples t test. RESULTS: Over a 6-year period, 74/272 (27.2%) morbidly obese LAGB patients experienced marked complications requiring band removal. Forty-nine of these patients underwent conversion by LRYGB (n = 29) or LSG (n = 20). There was no statistically significant difference in complication rates between converted procedures and no significant difference in respective EWL and TWL (6-month EWL: LRYGB, 53.6% vs LSG, 51.3% and respective TWL, 22.8 vs 21.3%; 12-month EWL, 70.1 vs 56.1%; and TWL, 30.7 vs 23.2%; p > 0.05). All conversion patients were present at each time point. CONCLUSIONS: Outcomes for LSG vs LRYGB following failed LAGB were equally safe and effective. PMID- 30022424 TI - Efficacy of High-Dose Liraglutide as an Adjunct for Weight Loss in Patients with Prior Bariatric Surgery. AB - BACKGROUND: Bariatric surgery is the most effective long-term treatment of severe obesity. Unfortunately, many patients experience inadequate weight loss, weight plateau, or weight recidivism. We sought to determine the efficacy of high-dose liraglutide (3.0 mg once daily) in patients with prior bariatric surgery. METHODS: We performed a retrospective chart review of 33 consecutive patients, aged 18-65, who received liraglutide for weight loss in the setting of any previous bariatric surgery. Indications were weight recidivism (> 10% weight regain from lowest post-surgical weight), inadequate weight loss (< 20% weight loss from initial clinic assessment, or pre-surgical weight if unavailable), and plateau (patient desires further weight loss but does not fit into either other category). Our primary outcomes were median percentage weight loss and median BMI change at 16 and 28 weeks, inclusive of time taken to titrate the medication to target dose. Secondary outcomes were the presence of adverse effects and the need to discontinue the medication. RESULTS: Of a total of 33 patients identified, 20 met inclusion criteria and had adequate data to be included in our analysis. At 16 weeks median percentage weight loss was 7.1% (IQR 5.1-12.2%), and at 28 weeks 9.7% (IQR 7.8-13.9%). Median BMI change was 3.5 kg/m2 (16 weeks, IQR 2.2-4.6 kg/m2) and 4.7 kg/m2 (28 weeks, IQR 3.7-5.6 kg/m2). There were no major adverse events. CONCLUSIONS: High-dose liraglutide is an effective adjunct treatment for weight loss in patients with prior bariatric surgery. PMID- 30022425 TI - Not All Leaks Are Created Equal: a Comparison Between Leaks After Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. AB - INTRODUCTION: It is commonly stated in bariatric surgical forums that leaks following laparoscopic sleeve gastrectomy (LSG) are more difficult to manage than those following laparoscopic roux-en-Y gastric bypass (LRYGB). However, no previous study has provided a thorough comparison of leak management following these two operations. METHODS: Our database was retrospectively reviewed to identify patients with leak following LSG and LRYGB performed between January 2007 and December 2017. RESULTS: Postoperative leak was diagnosed in 16/2132 (0.75%) LSG and 9/595 (1.5%) LRYGB patients. More of the LRYGB leaks had undergone revisional surgeries (66.7 vs. 6.3%, p < 0.001), and were diagnosed in the index admission (77.8 vs. 18.7%, p = 0.002). The mean time between the bariatric operation and the diagnosis of leak was 6.0 days in LRYGB and 26.2 days in LSG patients (p = 0.097). Approximately two thirds of each group were initially treated with laparoscopic exploration and drainage. Subsequent endoscopy was utilized more commonly in LSG patients (87.5 vs. 22.2%, p < 0.001). Drainage alone (laparoscopic or percutaneous) eventually led to leak resolution in more LRYGB patients (66.7 vs. 18.8%, p = 0.02), while endoscopic intervention led to resolution in more LSG patients (37.5 vs. 0%, p = 0.04). The mean time between leak diagnosis and its resolution was 57.8 and 44.2 days, for LSG and LRYGB patients, respectively. CONCLUSION: The diagnosis of leak tends to be earlier in LRYGB patients. Endoscopic therapies are more frequently required in the management of leaks following LSG, while in those following LRYGB, drainage alone leads to resolution of leak in the majority of cases. PMID- 30022426 TI - Effective Implementation of Peri-operative Local Guidelines for Metabolic Surgery in Patients with Diabetes Mellitus in a Tier 4 Setting Demonstrate Improved Work Efficiency and Resource Allocation. AB - BACKGROUND: Dynamic changes in glycaemia predominate peri-operatively in patients with type 2 diabetes mellitus (T2DM) undergoing metabolic surgery. There is a lack of consensus and clear guidance on effective glycaemic management of such patients. The aim of this study was to design, pilot, and implement a proforma to improve consistency of glycaemic management and clarity of communication with healthcare professionals following metabolic surgery in patients with T2DM, thereby reducing unnecessary diabetes specialist nurse (DSN) referrals. METHODS: A proforma was designed and piloted for 12 months to guide healthcare professionals on managing glycaemic therapies for T2DM patients undergoing metabolic surgery. Glycaemic control (HbA1c) and glycaemic therapies were reviewed 3 weeks pre-operatively and a proforma was completed accordingly. RESULTS: Of the patients with T2DM (n = 34) who underwent metabolic surgery prior to the new proforma being implemented, 71% (n = 24) had a DSN referral. Half of these referrals were deemed unnecessary by the DSNs. Of the patients with T2DM (n = 33) who underwent metabolic surgery following implementation of the proforma, 21% (n = 7) had a DSN referral. Only 10% of these were deemed unnecessary. Despite the reduced DSN input, no diabetes-related complications were reported. CONCLUSION: Implementation of our proforma effectively halved the proportion of patients with T2DM requiring a DSN referral. Additionally, there was a 40% absolute reduction in the proportion of unnecessary DSN referrals. The proforma improved clarity of communication and guidance for healthcare professionals in the glycaemic management of patients. This also facilitated improved work efficiency and resource allocation. PMID- 30022428 TI - Iron Deficiency Reduces Synapse Formation in the Drosophila Clock Circuit. AB - Iron serves as a critical cofactor for proteins involved in a host of biological processes. In most animals, dietary iron is absorbed in enterocytes and then disseminated for use in other tissues in the body. The brain is particularly dependent on iron. Altered iron status correlates with disorders ranging from cognitive dysfunction to disruptions in circadian activity. The exact role iron plays in producing these neurological defects, however, remains unclear. Invertebrates provide an attractive model to study the effects of iron on neuronal development since many of the genes involved in iron metabolism are conserved, and the organisms are amenable to genetic and cytological techniques. We have examined synapse growth specifically under conditions of iron deficiency in the Drosophila circadian clock circuit. We show that projections of the small ventrolateral clock neurons to the protocerebrum of the adult Drosophila brain are significantly reduced upon chelation of iron from the diet. This growth defect persists even when iron is restored to the diet. Genetic neuronal knockdown of ferritin 1 or ferritin 2, critical components of iron storage and transport, does not affect synapse growth in these cells. Together, these data indicate that dietary iron is necessary for central brain synapse formation in the fly and further validate the use of this model to study the function of iron homeostasis on brain development. PMID- 30022429 TI - Comparison of Diagnostic Accuracy of Different Sites for Transcutaneous Bilirubin Measurement in Early Preterm Infants. AB - OBJECTIVE: To evaluate correlation of transcutaneous bilirubin (TcB) measured at different body sites with serum total bilirubin (TSB) in early preterm infants. METHODS: This hospital based prospective comparative study was carried out in the Department of Pediatrics, SMS Medical College, Jaipur between April 2015 to March 2016. Early preterm infants with gestational age <= 34 weeks in whom clinical jaundice was significant mandating TSB measurement were included in the study. Study subjects who met the inclusion criteria were chosen consecutively. Neonates in whom phototherapy was already initiated and those with poor perfusion (capillary refill time > 3 s) were excluded from the study. All the measurements were carried out within first postnatal week. Transcutaneous bilirubin was measured from three sites: forehead, sternum and interscapular region and within 15 min of TcB measurement, blood samples were taken and serum bilirubin level was calculated. RESULTS: Correlation coefficients of transcutaneous bilirubin measured from forehead, sternum and interscapular sites were 0.82, 0.84 and 0.86 respectively. TcB measured from all the three sites correlated significantly with serum bilirubin (p < 0.001), but the correlation was best at interscapular site. Sensitivity, specificity and false negative rates were calculated with respect to starting phototherapy. Interscapular site had the highest sensitivity and lowest false negative rate (87.6 and 12.4% respectively) as compared to forehead (79.2 and 20.8% respectively) and sternum (87.1 and 12.9% respectively). CONCLUSIONS: Transcutaneous bilirubin measurement is an acceptable method for identification of hyperbilirubinemia requiring treatment in early preterm newborns. The authors recommend interscapular region as a reliable site in infants of gestational age <=34 wk for measuring transcutaneous bilirubin. PMID- 30022427 TI - Resting-state connectivity and spontaneous activity of ventromedial prefrontal cortex predict depressive symptomology and peripheral inflammation in HIV. AB - Depression and chronic inflammation are common in persons infected with the human immunodeficiency virus (HIV+). Although depression and response to inflammatory challenge are shown to reflect activity in common neural networks, little is known regarding sub-clinical presentation in persons chronically infected with HIV. The relationship of resting-state functional connectivity (rsFC) between the subgenual anterior cingulate cortex (sgACC) and bilateral amygdala to Beck Depression Inventory-1 (BDI) scores were compared within a group of 23 HIV+ and 23 HIV-negative comparison adults. An interaction was found wherein lower rsFC between the sgACC and both right and left amygdala was associated with higher BDI scores in HIV+ individuals. Total BDI scores and plasma levels of IL-6, IL-8, TNF alpha, and IL-10 made available from 10 of the HIV+ patients were regressed upon an index of spontaneous whole-brain activity at rest; i.e., the amplitude of low frequency fluctuations (ALFFs). Elevated levels of depression and IL-6 were associated with increased ALFF in a cluster of voxels on the medial portion of the ventral surface of the frontal lobe (Brodmann Area 11). Within this sample of HIV+ individuals lower rsFC of the sgACC with subcortical limbic regions predicts greater burden of depressive symptomology whereas elevated activity in the adjacent BA 11 may reflect sickness, indexed by elevated IL-6, and associated depressive behaviors. PMID- 30022431 TI - Dehydroepiandrosterone Induces Temozolomide Resistance Through Modulating Phosphorylation and Acetylation of Sp1 in Glioblastoma. AB - Glioblastoma is the most malignant type of brain tumor for which there are currently no effective treatments. Patient prognosis is improved by radiation combined with temozolomide (TMZ) therapy but only for a short period of time due to the high prevalence of recurrence. Although O6-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair is a well-defined characteristic of TMZ resistance, the mechanism by which MGMT-deficient glioblastoma counteracts TMZ-induced DNA damage, leading to apoptosis, still remains unclear. Previously, we determined that aberrantly activated cytochrome P450 17A1 causes TMZ resistance in MGMT-deficient glioblastoma by increasing the secretion of dehydroepiandrosterone (DHEA), a neurosteroid that maintains the health of neurons and astrocytes. However, the precise mechanism by which DHEA alters the response of glioblastoma to TMZ has not been studied. In the present study, we found that DHEA prevents TMZ-induced apoptosis by attenuating DNA damage in MGMT deficient glioblastoma. In addition, DHEA activated the LYN-AKT cascade to induce Sp1 phosphorylation. Phospho-Sp1 localized in TMZ-damaged DNA, prevented further DNA damage, and was deacetylated through the recruitment of HDAC1/2. Deacetylated Sp1 recruited proliferating cell nuclear antigen (PCNA) to attenuate DNA damage. To confirm whether the DHEA-induced cellular process contributes to TMZ resistance, we established a TMZ-resistant glioblastoma cell line, A172R, and isolated primary resistant tumor cells, PtR#1, from a glioblastoma patient exhibiting chemotherapeutic resistance. Sp1 exhibited phosphorylated and deacetylated status, and associated with HDAC1/2 and PCNA in TMZ-resistant cells. Based on these findings, we conclude that DHEA induces TMZ resistance in glioblastoma via the induction of phospho-Sp1-mediated DNA repair. PMID- 30022430 TI - Electrophysiological markers of working memory usage as an index for truth-based lies. AB - People prefer to lie using altered truthful events from memory, perhaps because doing so can increase their credibility while reducing cognitive and working memory (WM) load. One possible way to counter such deceptive behavior is to track WM usage, since fabricating coherent lies or managing between truth and lies is likely to involve heavy WM load. In this study, participants memorized a list of words in the study session and used these old words to provide deceptive answers when cued later, in the testing session. Our behavioral results showed that people needed more time to make a deceptive response during the execution stage, and this prolonged deceptive reaction time (RT) was negatively correlated with each participant's WM capacity. Event-related potential findings showed a more negative-going frontal amplitude between the lie and truth conditions during the preparation stage, suggesting that WM preparatory processes can be detected long before a deceptive response is verbalized. Furthermore, we observed a larger positive frontal-central amplitude during the execution stage, which was negatively correlated with participants' lie-truth RT differences, suggesting that participants' efficiency in producing deceptive responses can be readily traced electrophysiologically. Together, these findings suggest that WM capacity and preparation are crucial to efficient lying and that their related electrophysiological signatures can potentially be used to uncover deceptive behaviors. PMID- 30022432 TI - Recombinant FGF21 Protects Against Blood-Brain Barrier Leakage Through Nrf2 Upregulation in Type 2 Diabetes Mice. AB - Blood-brain barrier (BBB) damage is a characteristic feature of diabetes mellitus pathology and plays significant roles in diabetes-associated neurological disorders. However, effective treatments for diabetes targeting BBB damage are yet to be developed. Fibroblast growth factor 21 (FGF21) is a potent regulator of lipid and glucose metabolism. In this study, we tested the hypothesis that recombinant FGF21 (rFGF21) administration may reduce type 2 diabetes (T2D) induced BBB disruption via NF-E2-related factor-2 (Nrf2) upregulation. Our experimental results show that rFGF21 treatment significantly ameliorated BBB permeability and preserved junction protein expression in db/db mice in vivo. This protective effect was further confirmed by ameliorated transendothelial permeability and junction protein loss by rFGF21 under hyperglycemia and IL1beta (HG-IL1beta) condition in cultured human brain microvascular endothelial cells (HBMEC) in vitro. We further reveal that rFGF21 can activate FGF receptor 1 (FGFR1) that increases its binding with Kelch ECH-associating protein 1 (Keap1), a repressor of Nrf2, thereby reducing Keap1-Nrf2 interaction leading to Nrf2 release. These data suggest that rFGF21 administration may decrease T2D-induced BBB permeability, at least in part via FGFR1-Keap1-Nrf2 activation pathway. This study may provide an impetus for development of therapeutics targeting BBB damage in diabetes. PMID- 30022433 TI - Pegvaliase: First Global Approval. AB - BioMarin Pharmaceutical is developing pegvaliase (PALYNZIQTM) as a treatment for phenylketonuria, a genetic disorder caused by deficiency of phenylalanine hydroxylase which leads to neurotoxic accumulation of phenylalanine. Data from the phase III PRISM clinical trial program indicate treatment with pegvaliase is associated with sustained reductions in blood phenylalanine levels and sustained improvements in neurological sequelae in patients with phenylketonuria. Based on these positive results pegvaliase was recently approved in the US for adults with phenylketonuria who have uncontrolled blood phenylalanine concentrations on current treatment. This article summarizes the milestones in the development of pegvaliase leading to this first approval. PMID- 30022434 TI - Computational study of the NO, SO2, and NH3 adsorptions on fragments of 3N graphene and Al/3N graphene. AB - The adsorption properties of common gas molecules (NO, NH3, and SO2) on the surface of 3N-graphene and Al/3N graphene fragments are investigated using density functional theory. The adsorption energies have been calculated for the most stable configurations of the molecules on the surface of 3N-graphene and Al/3N graphene fragments. The adsorption energies of Al/3N graphene-gas systems are -220.5 kJ mol-1 for Al/3NG-NO, -111.9 kJ mol-1 for Al/3NG-NH3, and -347.7 kJ mol-1 for Al/3NG-SO2, respectively. Compared with the 3N-graphene fragment, the Al/3N graphene fragment has significant adsorption energy. Furthermore, the molecular orbital, density of states, and electron densities distribution were used to explore the interaction between these molecules and the surface. We found that orbital hybridization exists between these molecules and the Al/3N graphene surface, which indicates that doping Al significantly increases the interaction between the gas molecules and Al/3N graphene. In addition, compared with Li, Al can more powerfully enhance adsorption of the 3N-graphene fragment. The results indicate that Al/3N graphene can be viewed as a new nanomaterial adsorbent for NO, NH3, and SO2. PMID- 30022435 TI - Quantitative proteome and lysine succinylome analyses provide insights into metabolic regulation in breast cancer. AB - BACKGROUND: Breast cancer, the most common invasive cancer and cause of cancer related death in women worldwide, is a multifactorial, complex disease, and many molecular players and mechanisms underlying the complexity of its clinical behavior remain unknown. METHODS: To explore the molecular features of breast cancer, quantitative proteome and succinylome analyses in breast cancer were extensively studied using quantitative proteomics techniques, anti-succinyl lysine antibody-based affinity enrichment, and high-resolution LC-MS/MS analysis. RESULTS: Our study is the first to detect the regulation of lysine succinylation in breast cancer progression. We identified a novel mechanism by which the pentose phosphate pathway and the endoplasmic reticulum protein processing pathway might be regulated via lysine succinylation in their core enzymes. CONCLUSIONS: These results expand our understanding of tumorigenesis mechanisms and provide a basis for further characterization of the pathophysiological roles in breast cancer progression, laying a foundation for innovative and novel breast cancer drugs and therapies. PMID- 30022436 TI - Analysis of the Promoter Region of Human Dopamine Receptor D1. AB - Dysregulation of dopamine receptor D1 (DRD1) is involved in multiple neuropsychiatric disorders. The 5' regulatory region of DRD1 has not been characterized fully. We applied the luciferase assay and the electrophoretic mobility shift assay to explore the activity of the 5' regulatory region of DRD1 in SH-SY5Y and 293T cells. We found that the promoter region of DRD1 corresponded to positions - 1250 to + 250 in the DNA sequence, and the putative core promoter region was from - 113 to + 250 (transcriptional start site of exon, +1). The sequence 5'-gggacgcgcgggcggggtgggctgtgccccgcgggaaccccgccggcctgtgcgcttgctg-3' was identified as a possible transcription factor-binding domain. Further research is warranted to explore the function of the 5' regulatory region of DRD1. PMID- 30022437 TI - Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy. AB - Members of the neurotrophin family and in particular brain-derived neurotrophic factor (BDNF) regulate the response to rapid- and slow-acting chemical antidepressants and voluntary exercise. Recent work suggests that rapid-acting antidepressants that modulate N-methyl-D-aspartate receptor (NMDA-R) signaling (e.g., ketamine and GLYX-13) require expression of VGF (non-acronymic), the BDNF inducible secreted neuronal protein and peptide precursor, for efficacy. In addition, the VGF-derived C-terminal peptide TLQP-62 (named by its 4 N-terminal amino acids and length) has antidepressant efficacy following icv or intra hippocampal administration, in the forced swim test (FST). Similar to ketamine, the rapid antidepressant actions of TLQP-62 require BDNF expression, mTOR activation (rapamycin-sensitive), and alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor activation (NBQX-sensitive) and are associated with GluR1 insertion. We review recent findings that identify a rapidly induced autoregulatory feedback loop, which likely plays a critical role in sustained efficacy of rapid-acting antidepressants, depression-like behavior, and cognition, and requires VGF, its C-terminal peptide TLQP-62, BDNF/TrkB signaling, the mTOR pathway, and AMPA receptor activation and insertion. PMID- 30022439 TI - Integrating Qualitative Techniques in Model Development: A Case Study Using the Framework Approach. AB - BACKGROUND: Despite their potential, there is limited uptake of formal qualitative methods in model development by modellers and health economists. The aim of this case study was to highlight in a real-world context how a qualitative approach has been applied to gain insight into current practice (delineating existing care pathways) for typhoid fever in Ghana, which can then assist in model structure conceptualisation in a model-based cost-effectiveness analysis. METHODS: The perspectives of a range of healthcare professionals working in different settings and across different practices in the Eastern region of Ghana were captured with a self-administered survey using open-ended questions and analysed using the framework method. RESULTS: A total of 51 completed questionnaires were retrieved representing a 73% response rate. It was found that two main care pathways for typhoid fever exist in Ghana and there was no consensus on how a new test might be applied to the existing pathways. CONCLUSION: The two settings in Ghana have different care pathways and any cost effectiveness analysis should consider the alternative pathways separately. This study demonstrated that framework analysis is a qualitative methodology that is likely to be accessible and feasible across a wide range of health economic settings. PMID- 30022438 TI - PACAP38-Mediated Bladder Afferent Nerve Activity Hyperexcitability and Ca2+ Activity in Urothelial Cells from Mice. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate PAC1 receptor (Adcyap1r1) have tissue-specific distributions in the lower urinary tract (LUT). The afferent limb of the micturition reflex is often compromised following bladder injury, disease, and inflammatory conditions. We have previously demonstrated that PACAP signaling contributes to increased voiding frequency and decreased bladder capacity with cystitis. Thus, the present studies investigated the sensory components (e.g., urothelial cells, bladder afferent nerves) of the urinary bladder that may underlie the pathophysiology of aberrant PACAP activation. We utilized bladder-pelvic nerve preparations and urothelial sheet preparations to characterize PACAP-induced bladder afferent nerve discharge with distention and PACAP-induced Ca2+ activity, respectively. We determined that PACAP38 (100 nM) significantly (p <= 0.01) increased bladder afferent nerve activity with distention that was blocked with a PAC1/VPAC2 receptor antagonist PACAP6-38 (300 nM). PACAP38 (100 nM) also increased Ca2+ activity in urothelial cells over that observed in control preparations. Taken together, these results establish a role for PACAP signaling in bladder sensory components (e.g., urothelial cells, bladder afferent nerves) that may ultimately facilitate increased voiding frequency. PMID- 30022440 TI - Opportunities for Use of Blockchain Technology in Medicine. AB - Blockchain technology is a decentralized database that stores a registry of assets and transactions across a peer-to-peer computer network, which is secured through cryptography, and over time, its history gets locked in blocks of data that are cryptographically linked together and secured. So far, there have been use cases of this technology for cryptocurrencies, digital contracts, financial and public records, and property ownership. It is expected that future uses will expand into medicine, science, education, intellectual property, and supply chain management. Likely applications in the field of medicine could include electronic health records, health insurance, biomedical research, drug supply and procurement processes, and medical education. Utilization of blockchain is not without its weaknesses and currently, this technology is extremely immature and lacks public or even expert knowledge, making it hard to have a clear strategic vision of its true future potential. Presently, there are issues with scalability, security of smart contracts, and user adoption. Nevertheless, with capital investments into blockchain technology projected to reach US$400 million in 2019, health professionals and decision makers should be aware of the transformative potential that blockchain technology offers for healthcare organizations and medical practice. PMID- 30022441 TI - Platelet-Albumin Score as a Sensitive Measure for Surgical Risk Prediction and Survival Outcomes of Patients with Hepatocellular Carcinoma. AB - BACKGROUND: Given that patients with hepatocellular carcinoma (HCC) usually suffer from dual diseases (i.e., HCC and underlying liver disease), a complete survival estimation model is difficult to establish because both the oncological stage and the underlying liver function affect the survival outcome. METHODS: A new surgical risk model for estimating the survival of patients undergoing resection for HCC was created using a cohort treated between 1995 and 2013 (training set, n = 889), and its efficacy was then validated using a cohort treated between 2014 and 2017 (validation set, n = 310). RESULTS: The following statistical model was developed based on the results of multivariate analysis: albumin-platelet (PAL) score = - 0.777 * albumin (g/dL) - 0.575 * log10 (platelet count [104/MUL]) (cut-off value, - 3.77 and - 3.04 for grading). A time-dependent receiver-operating curve analysis revealed that the area under the curve for 3 year survival was 0.644 in the training set and 0.666 in the validation set. The incidences of postoperative morbidity were 14.0% for PAL grade 1, 18.7% for PAL grade 2, and 26.1% for PAL grade 3 (P = 0.039), while the incidences of refractory ascites were 2.2, 7.1, and 12.5% (P = 0.005), respectively, in the training set. The reproducibility of these results was confirmed in the validation set with morbidity rates of 13.5, 23.3, and 40.7% (P = 0.003), respectively, and the incidences of refractory ascites were 0.7, 10.7, and 22.2% (P < 0.0001), respectively. CONCLUSIONS: The PAL score can be used as a grading system for the stratification of survival outcomes and surgical risks of patients undergoing HCC resection. PMID- 30022442 TI - An Interview with Dr. John L. Cameron, the Hall of Famer of Pancreatic Cancer. AB - The Society of Surgical Alimentary Tract (SSAT) Resident Education Committee aim is to facilitate resident participation in the annual meeting and foster the education of the next generation of gastrointestinal. The SSAT "Residents Corner" was developed as a video-blog highlighting areas of interest for surgical trainees looking to focus on a career in gastrointestinal surgery. The topics covered are to make surgical education more accessible, one way is to highlight leaders in the field who discuss their journey. A 10-min video of a surgical mentor is recorded and archived on the SSAT site under a video series called "Mentor of the Month." A synopsis of a video published online February 2018 featuring Dr. John Cameron interviewed by one of his trainee, Dr. Vanita Ahuja. Dr. Cameron shares his thoughts on his accomplishments, challenges, and advice for young surgeons and the future of pancreatic surgery. The interview offers an insight into the mind of one of the greatest leaders of surgery of our time. PMID- 30022444 TI - Evolution of MRI characteristics of heatstroke in a patient with schizophrenia maintained with antipsychotic drugs. AB - Although heatstroke commonly occurs in summer, herein, we present a case of heatstroke that occurred in March. The patient has been schizophrenic for over 20 years and has been receiving long-term medications, such as lithium carbonate, clozapine, and lorazepam. We analyzed the evolution of her cerebellar magnetic resonance imaging characteristics to determine the association of heatstroke in schizophrenia. Patients with schizophrenia are at high risk for developing heatstroke, possibly due to the use of antipsychotic drugs. PMID- 30022445 TI - PEX10-related autosomal recessive cerebellar ataxia with hearing loss. PMID- 30022443 TI - Association Between Juxtapapillary Duodenal Diverticula and Risk of Choledocholithiasis: a Systematic Review and Meta-analysis. AB - BACKGROUND/OBJECTIVES: Studies have suggested that the presence of juxtapapillary duodenal diverticula (JDD) could be a predisposing factor for choledocholithiasis. This systematic review and meta-analysis was conducted with the aims to summarize all available evidence to better characterize the risk. METHODS: A literature search was performed using MEDLINE and EMBASE database from inception to January 2018. Cross-sectional studies that reported odd ratios (OR) comparing the risk of choledocholithiasis among individuals with JDD versus individuals without JDD were included. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Of 527 retrieved articles, 11 studies met our eligibility criteria and were included in analysis. We found a significant association between the presence of JDD and choledocholithiasis with the pooled OR of 2.30 (95% CI, 1.84-2.86). The statistical heterogeneity was moderate with an I2 of 60%. CONCLUSIONS: A significantly increased risk of choledocholithiasis among individuals with JDD was observed in this study. PMID- 30022446 TI - Similarity between an unfamiliar human and the owner affects dogs' preference for human partner when responding to an unsolvable problem. AB - This study investigates whether dogs are able to differentiate between people according to whether or not they show similarities to their owners. We hypothesized that dogs would show a preference for the "similar" partner when interacting with unfamiliar humans. After having familiarized with two experimenters displaying different degrees of similarity to their owners, dogs (N = 36) participated in a situation where the desired toy object was made inaccessible in order to find out whether they initiate interaction with the two partners differently. Two different types of "similarity cues" were used (either alone or combined with each other): (1) persistent behavioral characteristics (i.e., familiar vs. strange motion pattern and language usage) and (2) an unfamiliar arbitrary group marker (i.e., one of the potential helpers was wearing clothing similar to that worn by the owner). Results show that although dogs payed equal attention to the human partners displaying various types of similarity to their owners during familiarization, they exhibited a visual attention preference for the human whose motion pattern and language usage were similar to their owner's in the inaccessible-toy task. However, there was weak evidence of discrimination based on the arbitrary group marker (clothing). Although dogs' different tendencies to interact with the potential helpers do not necessarily imply an underlying ability to create social categories based on the degree of similarity between the owner and unfamiliar people, these results suggest that functionally human infant-analogue forms of social categorization may have emerged in dogs. PMID- 30022447 TI - CD147 (EMMPRIN) controls malignant properties of breast cancer cells by interdependent signaling of Wnt and JAK/STAT pathways. AB - EMMPRIN (extracellular matrix metalloproteinase inducer, EMN, CD147) is a member of the immunoglobulin superfamily expressed in numerous cell types both as a soluble and a membrane-spanning glycoprotein. It is involved in many physiological processes, as well as in cancer. This study addresses mechanisms of crosstalk between EMN-driven cancer-related cellular responses and the canonical Wnt-pathway in MCF-7 breast carcinoma cells. Genetic knockdown of EMN in MCF-7 resulted in characteristic changes in cellular shape, organization of the actin cytoskeleton and malignancy profile, indicating that EMN expression represses cell motility, but, in contrast, exerts a stimulatory effect on cell proliferation and invasive properties. Increased invasiveness coincided with elevated expression of Wnt-target genes and established invasion driver matrix metalloproteinase MMP14. Activation of the downstream Wnt-pathway by means of heterologous beta-catenin and/or TCF-4 expression, through inhibition of GSK 3beta by LiCl treatment, or by cell stimulation with insulin-like growth factor-1 (IGF-1) resulted in increased EMN expression. EMN over-expression raised the ratio of the two opposing Wnt pathway-driven transcription factors Sp1 and Sp5, leading to stimulation of the EMN promoter. Furthermore, the EMN promoter was activated by a feed-forward circuit involving an EMN-dependent drop in expression of the repressive signal transducer and activator of transcription 1 (STAT1). Taken together, we show that the influence of EMMPRIN on malignancy-related properties of breast cancer cells is functionally connected to both Wnt- and JAK/STAT pathways. PMID- 30022448 TI - Silibinin ameliorates amylin-induced pancreatic beta-cell apoptosis partly via upregulation of GLP-1R/PKA pathway. AB - The objective was to investigate the mechanism of the protective effect of silibinin on amylin/Abeta1-42-induced INS-1 cell apoptosis, with special reference to the roles of glucagon-like peptide-1 receptor (GLP-1R) and protein kinase A (PKA). The effects of silibinin on apoptosis, insulin secretion, GLP-1R, and PKA expression in the INS-1 cells treated with amylin/Abeta1-42 were examined. INS-1 cells exposed to amylin showed increased TUNEL-positive ratio, reduced expression of GLP-1R and PKA. GLP-1R antagonists or PKA inhibitor enhanced the expression of apoptosis-associated proteins and TUNEL-positive ratio. Silibinin exerted antiapoptotic effect on and upregulation of GLP-1R and PKA. However, Abeta1-42-induced INS-1 cell apoptosis, GLP-1R, and PKA expressions were not changed. Our results indicate that down-regulation of GLP-1R and PKA contributes to INS-1 cell apoptosis induced with amylin. Silibinin protects INS-1 cells from amylin-induced apoptosis through activation of GLP-1R/PKA signaling. Silibinin's inhibition of the toxic effects of Abeta1-42 is independent of GLP 1R/PKA pathway. PMID- 30022449 TI - High-glucose-induced changes in macrophage secretome: regulation of immune response. AB - Secretory products from infiltrating macrophages have been thought to play crucial roles in development and progression of diabetic complications in various tissues/organs. Nevertheless, diabetes-induced changes in macrophage secretory products remained largely unknown. We thus analyzed high-glucose (HG)-induced changes in secretome of human macrophages derived from U937 human monocytic cell line after phorbol 12-myristate 13-acetate (PMA) activation. Serum-free culture supernatants were collected from macrophages exposed to 5.5 mM glucose (NG-M-sup) (normal control), 25 mM glucose (HG-M-sup), or 5.5 mM glucose + 19.5 mM mannitol (MN-M-sup) (osmotic control) for 16 h. After dialysis and lyophilization, secreted proteins were subjected to 2-DE analysis (n = 5 gels derived from 5 independent cultures per group). Quantitative analysis and statistics revealed 23 protein spots whose secretory levels significantly differed among the three conditions. These proteins were successfully identified by nanoLC-ESI-MS/MS analyses and changes in levels of heat shock protein 90 (HSP90), HSP70, HSP60, and beta-actin were confirmed by Western blotting. Global protein network and functional enrichment analyses revealed that the altered proteins in HG-M-sup were involved mainly in regulation of immune response that might communicate with other bystander cells through the release of extracellular vesicles. These data may lead to a wider view of pathogenic mechanisms of diabetic complications. PMID- 30022450 TI - The endocrine disruptor bisphenol A promotes nuclear ERRgamma translocation, facilitating cell proliferation of Grade I endometrial cancer cells via EGF dependent and EGF-independent pathways. AB - Endocrine disruptors have become a global social and public health problem since the late 1980s. Bisphenol A (BPA) has a steroid-like skeleton similar to estrogen and progesterone, and is an endocrine disruptor that disturbs the physiological hormone balance. The potential involvement of BPA in malignancy of endometrial cancer cells caused by overexposure of steroid hormones remains incompletely understood. The present study aimed at understanding the regulatory mechanism underlying BPA-induced cell proliferation in hormone-sensitive endometrial cancer cells. BPA selectively and significantly induced cell proliferation of Grade I endometrial cancer cells such as HEC265 and Ishikawa cells. In HEC265 and Ishikawa cells, BPA induced nuclear translocation of estrogen-related receptor gamma (ERRgamma) in a time-dependent manner and increased expression of BPA/ERRgamma-target genes. In Ishikawa cells, BPA promoted the influx of Ca2+ followed by epidermal growth factor (EGF) secretion to the extracellular space. Furthermore, EGF secreted from Ishikawa had an autocrine effect, leading to activation of the EGFR/ERK pathway. Contrastingly, in HEC265 cells, BPA increased the expression of BPA/ERRgamma-target genes but did not affect Ca2+ mobilization EGF secretion. In conclusion, BPA induced cell proliferation via the BPA/ERRgamma/EGF/EGFR/ERK signaling pathway in Ishikawa cells and contrastingly, in HEC265 cells, induced cell proliferation through the BPA/ERRgamma signaling pathway. PMID- 30022451 TI - Recirculating Immunocompetent Cells in Colitic Mice Intensify Their Lung Response to Bacterial Endotoxin. AB - BACKGROUND: Patients with inflammatory bowel disease have higher incidence of airway hyperresponsiveness compared to the general population. Lung inflammation leading to airway hyperresponsiveness causes illnesses for more than ten percent of the population in USA. AIMS: We investigated the lung response to bacterial endotoxin in colitic mice. METHODS: Rag-1 mice were transplanted with negatively selected splenic T cells. Some mice groups were treated with NSAID to develop colitis. All mice were treated with bacterial endotoxin and necropsied 3 weeks later. RESULTS: Colitic mice developed intensified lung inflammation on day 21 of treatment with bacterial endotoxin. Pulmonary lymphocytes from colitic mice displayed a proinflammatory cytokine profile, expressed high ICAM1 and low FoxP3. CD11c+, CD8+ cells bound and responded to non-systemic antigens from gut localized microbiota and had higher expression of TLR4. CONCLUSIONS: Colitic mice developed exacerbated lung inflammation in response to bacterial endotoxin compared to non-colitic mice. Proinflammatory cytokines from pulmonary lymphocytes induced high expression of ICAM1 and suppressed FoxP3 on CD4+ cells. CD11c+, CD8+ cells binding and responding to gut-localized antigens as well as high expression of TLR4 indicate innate and adaptive lung response to bacterial endotoxin. Inflammatory cells from colons of colitic mice homed in the lungs as well as the intestine suggesting recirculation of sensitized immunocompetent cells. These data support our hypothesis that colitis intensifies lung inflammation. PMID- 30022452 TI - Both Full Glasgow-Blatchford Score and Modified Glasgow-Blatchford Score Predict the Need for Intervention and Mortality in Patients with Acute Lower Gastrointestinal Bleeding. AB - BACKGROUND: Glasgow-Blatchford score (GBS) has been developed for risk stratification in management of acute upper gastrointestinal (GI) bleeding. However, the performance of GBS in patients with lower GI bleeding is unknown. AIM: To evaluate the performance of full or modified GBS and modified GBS in prediction of major clinical outcomes in patients with lower GI bleeding. METHODS: A retrospective study of patients admitted to a tertiary care center with either non-variceal upper GI bleeding or lower GI bleeding was conducted. The full and modified GBS were calculated for all patients. The primary outcome was a combined outcome of inpatient mortality, need for endoscopic, surgical, or radiologic procedure to control the bleed or treat the underlying source, and need for blood transfusion. RESULTS: A total of 1026 patients (562 cases for upper GI and 464 cases for lower GI) were included in the study. Hospital-based interventions and mortality were significantly higher in upper GI bleeding group. The performance of the full GBS in lower GI bleeding (area under the receiver operating curve (AUROC) 0.78, 95% CI 0.74-0.82) was comparable to full GBS in upper GI bleeding (AUROC 0.77, 95% CI 0.73-0.81) in predicting the primary outcome. Similarly, the performance of modified GBS in lower GI bleeding was shown to be comparable to modified GBS in upper GI bleeding (AUROC 0.78, 95% CI 0.74-0.83 vs. AUROC 0.76 95% CI 0.72-0.80). CONCLUSION: In patients with lower GI bleeding, both full GBS and modified GBS can predict the need for hospital-based interventions and mortality. PMID- 30022453 TI - The Use of Higher Dose Steroids Increases the Risk of Rebleeding After Endoscopic Hemostasis for Peptic Ulcer Bleeding. AB - BACKGROUND: Previous studies have shown that several factors such as hemodynamic instability at admission are risk factors for rebleeding of peptic ulcer bleeding. However, whether steroid use increases the risk of rebleeding remains elusive. AIMS: This study aimed to clarify the risk factors for rebleeding after endoscopic hemostasis for peptic ulcer bleeding. METHODS: A total of 185 patients who underwent endoscopic hemostasis for peptic ulcer bleeding at our institution between 2005 and 2017 were retrospectively analyzed. We evaluated factors, including comorbid conditions, in-hospital onset, and steroid use, associated with rebleeding by logistic regression analysis. In addition, we investigated the association between the dose of steroids and rebleeding. RESULTS: The rebleeding rate after endoscopic hemostasis for peptic ulcer bleeding was 14.6%. In the multivariate analysis, the independent risk factors for rebleeding were steroid use (odds ratio 4.56, p = 0.015), multiple ulcers (4.43, p = 0.005), number of comorbidities >= 3 3.18, p = 0.026), hemodynamic instability (3.06, p = 0.039), and number of comorbidities >= 3 (2.93, p = 0.047). Furthermore, the use of higher dose steroids (>= 20 mg per day in prednisolone; 10.55, p = 0.002), but not lower dose (< 20 mg per day in prednisolone), was an independent risk factor for rebleeding in the multivariate analysis. The relationship between steroid use and rebleeding was observed in a dose-dependent manner (p for trend = 0.002). CONCLUSIONS: This study first revealed that using higher dose steroids was an independent risk factor for rebleeding after endoscopic hemostasis for peptic ulcer bleeding, with a dose-response relation. PMID- 30022454 TI - Depressive Symptoms Predict Anti-tumor Necrosis Factor Therapy Noncompliance and Healthcare Utilization in Patients with Inflammatory Bowel Disease. PMID- 30022455 TI - Different Prognostic Implications of Aquaporin-1 and Aquaporin-5 Expression among Different Histological Types of Ovarian Carcinoma. AB - The aquaporins (AQPs) are a family of transmembrane water channel proteins that are distributed in various human tissues. Recent studies have suggested that AQP expression correlates with various aspects of cancer biology that determine the aggressiveness of different cancers. Ovarian carcinoma is one of the most lethal gynecological cancers. Some studies have suggested that AQPs are expressed in ovarian carcinoma, and are associated with cancer cell growth and migration. In this study, we immunohistochemically evaluated the expression of AQP1, 3, 5, and 9 in a total of 300 ovarian carcinomas using tissue microarrays. In our analyses of correlations between aquaporin expression and overall survival, high AQP5 expression was significantly associated with poorer prognosis (P = 0.029). For AQP1, the low expression group trended towards poorer prognosis than the high expression group, but the difference was not statistically significant. When ovarian carcinomas were divided by histological types, high AQP5 expression correlated with poorer prognosis in serous carcinoma (P = 0.015), and low AQP1 expression correlated with poorer prognosis in clear cell carcinomas (P = 0.0055). By contrast, high AQP1 expression correlated with poorer prognosis in mucinous carcinoma (P = 0.0001) and endometrioid carcinoma (P = 0.021). Our studies suggest that AQPs can be useful prognostic markers in ovarian carcinoma, but their correlation with prognosis depends on the histological type of ovarian carcinoma. PMID- 30022456 TI - Historical evolution of concrete and abstract language revisited. AB - This paper investigates the historical (1850s-2000s) evolution of semantics in the English language using contemporaneous, decade-specific computational estimates of word concreteness. Study 1 describes the computational method of generating time-locked estimates of concreteness based on the Corpus of Historic American English, and makes available the computed scores for 25,000 English words over 15 decades. We also report several tests of reliability and validity, demonstrating that our historical concreteness scores have high levels of both. Study 2 uses concreteness scores to revisit findings of studies that use a static set of contemporary human concreteness norms to examine historical trends of semantic change. Specifically, we observed (contra Hills & Adelman, (Cognition, 143, 87-92 2015)) that distinct word types of the English language become increasingly more concrete over time and (in line with Hills & Adelman, (Cognition, 143, 87-92 2015) & Hills, Adelman & Noguchi, (The Quarterly Journal of Experimental Psychology, 70(8), 1603-1619 2016)) that relatively concrete words tend to be used more often than abstract ones. We discuss both contrastive and corroborative claims in light of recent work on semantic evolution and argue for the use of time-locked computed estimates over static human norms when examining diachronic linguistic phenomena. PMID- 30022457 TI - Randomized single-case AB phase designs: Prospects and pitfalls. AB - Single-case experimental designs (SCEDs) are increasingly used in fields such as clinical psychology and educational psychology for the evaluation of treatments and interventions in individual participants. The AB phase design, also known as the interrupted time series design, is one of the most basic SCEDs used in practice. Randomization can be included in this design by randomly determining the start point of the intervention. In this article, we first introduce this randomized AB phase design and review its advantages and disadvantages. Second, we present some data-analytical possibilities and pitfalls related to this design and show how the use of randomization tests can mitigate or remedy some of these pitfalls. Third, we demonstrate that the Type I error of randomization tests in randomized AB phase designs is under control in the presence of unexpected linear trends in the data. Fourth, we report the results of a simulation study investigating the effect of unexpected linear trends on the power of the randomization test in randomized AB phase designs. The implications of these results for the analysis of randomized AB phase designs are discussed. We conclude that randomized AB phase designs are experimentally valid, but that the power of these designs is sufficient only for large treatment effects and large sample sizes. For small treatment effects and small sample sizes, researchers should turn to more complex phase designs, such as randomized ABAB phase designs or randomized multiple-baseline designs. PMID- 30022458 TI - Interaction effects on common measures of sensitivity: choice of measure, type I error, and power. AB - Here we use simulation to assess previously unaddressed problems in the assessment of statistical interactions in detection and recognition tasks. The proportion of hits and false-alarms made by an observer on such tasks is affected by both their sensitivity and bias, and numerous measures have been developed to separate out these two factors. Each of these measures makes different assumptions regarding the underlying process and different predictions as to how false-alarm and hit rates should covary. Previous simulations have shown that choice of an inappropriate measure can lead to inflated type I error rates, or reduced power, for main effects, provided there are differences in response bias between the conditions being compared. Interaction effects pose a particular problem in this context. We show that spurious interaction effects in analysis of variance can be produced, or true interactions missed, even in the absence of variation in bias. Additional simulations show that variation in bias complicates patterns of type I error and power further. This under-appreciated fact has the potential to greatly distort the assessment of interactions in detection and recognition experiments. We discuss steps researchers can take to mitigate their chances of making an error. PMID- 30022459 TI - Combining speed and accuracy to control for speed-accuracy trade-offs(?). AB - In psychological experiments, participants are typically instructed to respond as fast as possible without sacrificing accuracy. How they interpret this instruction and, consequently, which speed-accuracy trade-off they choose might vary between experiments, between participants, and between conditions. Consequently, experimental effects can appear unpredictably in either RTs or error rates (i.e., accuracy). Even more problematic, spurious effects might emerge that are actually due only to differential speed-accuracy trade-offs. An often-suggested solution is the inverse efficiency score (IES; Townsend & Ashby, 1983), which combines speed and accuracy into a single score. Alternatives are the rate-correct score (RCS; Woltz & Was, 2006) and the linear-integrated speed accuracy score (LISAS; Vandierendonck, 2017, 2018). We report analyses on simulated data generated with the standard diffusion model (Ratcliff, 1978) showing that IES, RCS, and LISAS put unequal weights on speed and accuracy, depending on the accuracy level, and that these measures are actually very sensitive to speed-accuracy trade-offs. These findings stand in contrast to a fourth alternative, the balanced integration score (BIS; Liesefeld, Fu, & Zimmer, 2015), which was devised to integrate speed and accuracy with equal weights. Although all of the measures maintain "real" effects, only BIS is relatively insensitive to speed-accuracy trade-offs. PMID- 30022460 TI - Taking advantage of drug resistance, a new approach in the war on cancer. AB - Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit.We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy. PMID- 30022461 TI - High-level expression, purification and properties of an Endochitinase gene without signal peptide from Lecanicillium lecanii 43H in Pichia pastoris. AB - Chitinases play the key role in hydrolysis of chitin, a huge organic carbon reservoir on earth, into monomeric sugars and their eventual conversion into valuable chemicals and energy sources. The Lecanicillium lecanii strain 43H was used as the source for the Endochitinase gene without signal peptide (mchit1). This mchit1 gene was cloned and sequenced. The recombinant Endochitinase non signal peptide was overexpressed in Pichia pastoris X33 with a level of 2.048 U mL-1 culture supernatant. The molecular mass of the purified recombinant Endochitinase (rmchit1) without signal peptide was 43 kDa. Metal ions, detergents, and organic solvents tested indicated a significantly influence on rmchit1 activity. The obtained results demonstrated that signal peptides affect the yield expression, purification methods, recovery as well as the physicochemical properties of the enzyme. PMID- 30022462 TI - Genetic variations and forensic characteristics of Han Chinese population residing in the Pearl River Delta revealed by 23 autosomal STRs. AB - Pearl River Delta, known as the Chinese "South Gate", locates adjacent to Hong Kong and Macao, and across the sea from the Southeast Asian region. Herein, 4325 unrelated Han Chinese individuals residing in the Pearl River Delta region were recruited and genotyped with 23 autosomal STRs (the expanded CODIS core loci plus D6S1043, Penta D and Penta E). No evidence of deviation from Hardy-Weinberg equilibrium after Bonferroni correction was observed. The combined match probability and combined power of exclusion were 1.7829 * 10-28 and 0.9999999996, respectively. Next, population comparisons among ethnically, linguistically, and geographically diverse populations (11 Chinese populations based on genotypes of same 23 autosomal STRs, 46 Chinese nationwide populations based on allele frequency distributions of 19 autosomal STRs and 51 worldwide populations on the basis of 20 autosomal STRs) were performed via Structure, MDS, PCA and neighbor joining tree. Genetic heterogeneities among Chinese nationalities along ethno linguistic boundaries (Turkic-speaking, Tibeto-Burman-speaking, and Chinese speaking populations) and geographic divisions (North-Han and South-Han) have been illustrated by first two autosomal microsatellite datasets. The results from worldwide population genetic relationship exploration based on 20 autosomal STRs demonstrated that genetic affinity has existed within ethnical and geographical close populations. PMID- 30022463 TI - An overview of apoptosis assays detecting DNA fragmentation. AB - Apoptosis has been recognized as a type of programmed cell death connected with characteristic morphological and biochemical changes in cells. This programmed cell death plays an important role in the genesis of a number of physiological and pathological processes. Thus, it can be very important to detect the signs of apoptosis in a study of cellular metabolism. The present paper provides an overview of methods often being used for detecting DNA fragmentation as one of the most specific findings in apoptosis. To date, three routine assays have been developed for detecting DNA fragmentation: DNA ladder assay, TUNEL assay, and comet assay. All these methods differ in their principles for detecting DNA fragmentation. DNA ladder assay detects the characteristic "DNA ladder" pattern formed during internucleosomal cleavage of DNA. Terminal deoxynUcleotidyl transferase Nick-End Labeling (TUNEL) assay detects DNA strand breaks using terminal deoxynucleotidyl transferase catalyzing attachment of modified deoxynucleotides on the DNA strand breaks. Comet assay can be used for detecting nucleus breakdown producing single/double-strand DNA breaks. The aim of this review is to describe the present knowledge on these three methods, including optimized approaches, techniques, and limitations. PMID- 30022464 TI - Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study. AB - BACKGROUND: Two phase III trials have demonstrated the clinical and radiological efficacy of delayed-release dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS). However, data on its safety and effectiveness in real world practice are still limited. OBJECTIVES: The aim of our study was to explore the safety and tolerability profile of DMF in RRMS. We also tried to identify individual variables associated with better clinical and radiological outcomes. METHODS: We collected the clinical and magnetic resonance imaging (MRI) data of patients with RRMS who started DMF between 2012 and 2017 in seven MS clinics in central Italy. We first evaluated DMF discontinuation rates and the incidence of adverse events and side effects. We then assessed the annualized relapse rate (ARR), the number of patients with clinical relapses or disability worsening and the presence of radiological activity. Third, we investigated which baseline variables were associated with clinical and radiological outcomes. RESULTS: We collected data for 1089 patients with a mean on-treatment follow-up of 17 +/- 8 months; 331 (30.4%) of these patients were treatment naive. In total, 210 (19.5%) patients discontinued DMF mainly because of poor tolerability (n = 103) and disease activity (n = 63), and 166 (16.5%) patients presented with lymphopenia. The ARR reduced from 0.55 to 0.13. Mean change in Expanded Disability Status Scale (EDSS) score was 0.08 +/- 0.44 per year. The occurrence of clinical and/or radiological activity during follow-up was associated with younger age [hazard ratio (HR) 0.97; p < 0.001], higher EDSS score (HR 1.18; p < 0.001), greater number of Gd-enhancing lesions at baseline scan (HR 1.14; p = 0.003) and prior exposure to MS treatments (HR 1.43; p = 0.02). CONCLUSION: This post-marketing data confirms the short-term safety, tolerability and effectiveness of DMF, supporting its use as an early treatment in MS. PMID- 30022466 TI - Cerebellar Structural Variations in Subjects with Different Hypnotizability. AB - Hypnotizability-the proneness to accept suggestions and behave accordingly-has a number of physiological and behavioral correlates (postural, visuomotor, and pain control) which suggest a possible involvement of cerebellar function and/or structure. The present study was aimed at investigating the association between cerebellar macro- or micro-structural variations (analyzed through a voxel-based morphometry and a diffusion tensor imaging approach) and hypnotic susceptibility. We also estimated morphometric variations of cerebral gray matter structures, to support current evidence of hypnotizability-related differences in some cerebral areas. High (highs, N = 12), and low (lows, N = 37) hypnotizable healthy participants (according to the Stanford Hypnotic Susceptibility Scale, form A) were submitted to a high field (3 T) magnetic resonance imaging protocol. In comparison to lows, highs showed smaller gray matter volumes in left cerebellar lobules IV/V and VI at uncorrected level, with the results in left lobule IV/V maintained also at corrected level. Highs showed also gray matter volumes smaller than lows in right inferior temporal gyrus, middle and superior orbitofrontal cortex, parahippocampal gyrus, and supramarginal parietal gyrus, as well as in left gyrus rectus, insula, and middle temporal cortex at uncorrected level. Results of right inferior temporal gyrus survived also at corrected level. Analyses on micro-structural data failed to reveal any significant association. The here found morphological variations allow to extend the traditional cortico centric view of hypnotizability to the cerebellar regions, suggesting that cerebellar peculiarities may sustain hypnotizability-related differences in sensorimotor integration and emotional control. PMID- 30022468 TI - Acupuncture Treatment for Post-Stroke Dysphagia: An Update Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To explore the effectiveness and safety of acupuncture in patients with post-stroke dysphagia by an update meta-analysis. METHODS: Potentially eligible RCTs aimed to evaluate the effects of acupuncture vs. non-acupuncture treatments, such as rehabilitation training or routine medication on the swallowing difficulty after stroke were searched from PubMed, Cochrane Library, China National Knowledge Infrastructure, and other database from the earliest record to June 2016. Patient demographics, regimens for acupuncture, type of controls, methods of randomization, and measurements of the clinical symptoms of dysphagia were retrieved. The relative risk (RR) and 95% confidence interval (CI) of effective rate of dysphagia was calculated after intervention performed following admission. Subgroup analyses and a metaregression analysis were performed to describe the heterogeneity. RESULTS: Twenty-nine RCTs comprising 2,190 patients were included. The included studies had a medium quality grade based on the Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) checklist. Acupuncture therapy provided a higher effective rate compared with nonacupuncture treatments [RR=1.33, 95% confidence interval (CI), 1.25 to 1.43]. Subgroup and meta-regression analyses suggested that acupuncture intensity and measurement method were main sources of heterogeneity and resulted in a significant difference for pooled effect size. No severe adverse events were documented in these RCTs. CONCLUSIONS: Our meta-analysis provides a new evidence supporting the efficacy and safety of acupuncture in treatment to post-stroke dysphagia in short-term compared with rehabilitation or medication. More high quality and large-scale research studies are needed. PMID- 30022467 TI - Chitosan/polyethylene glycol fumarate blend films for wound dressing application: in vitro biocompatibility and biodegradability assays. AB - Blending is one of the effective approaches in preparing tailored materials with a wide range of properties. Thus, chitosan-based polymers have been fabricated and used as wound dressings since they possess better properties than those of the constituent materials. The objective of this work was to evaluate the biocompatibility and biodegradability of biodegradable blend films based on polyethylene glycol-co-fumarate (PEGF) and chitosan (Ch). The blend films of Ch/PEGF were prepared by solution casting/solvent evaporation method. Degradation behavior of these blend films was evaluated in a simulated fluid at physiological pH supplemented with lysozyme at a concentration similar to that in human serum by weight loss of the films and changes in the pH of media. When the pH of incubation media was analyzed, with an increase of PEGF content in the blend films, the degradation rate increased accordingly. The pH of the media of samples was not significantly changed at any measured time point and all films kept their integrities during 28 days. The biocompatibility of the films and cell behavior on the surface of these films were investigated by in vitro tests. Biological assessment using mouse fibroblast cell line L929 on the blend films of Ch/PEGF indicated that films supported the attachment, spreading and proliferation of cells. Since the Ch/PEGF films are biocompatible with the tailored biodegradation rate, they might have a great prospective position in the application of wound dressings. PMID- 30022469 TI - Investing for Health: Potential Mechanisms for the Investment Community to Contribute to Obesity Prevention and Improved Nutrition. AB - PURPOSE OF REVIEW: There is a critical need for corporations to be part of the solutions to major societal issues, such as obesity. Investment decisions can have a substantial impact on both corporate practices and population health. This paper aimed to explore potential mechanisms for incorporating obesity and related nutrition considerations into responsible investment (RI) approaches. RECENT FINDINGS: We found that there are a number of available strategies for the investment community to incorporate obesity considerations into their decisions. However, despite some recent efforts to improve company disclosure in the area and the emergence of new tools for assessing food company nutrition policies, the inclusion of obesity and related nutrition considerations as part of RI is currently extremely limited. There appears to be substantial scope to apply approaches already in widespread use for other RI considerations to the area of obesity. Ways in which to apply measurement frameworks across different markets and sectors need to be explored. PMID- 30022470 TI - The role of functional thyroid capacity in pituitary thyroid feedback regulation. AB - BACKGROUND: Thyroid feedback regulation and equilibria between thyroid hormones differ in the presence or absence of a functioning thyroid remnant. MATERIALS AND METHODS: This study examines the relationship between the sensitivity of TSH feedback and thyroid capacity in untreated patients with thyroid autoimmune disease (n = 86) and healthy controls (n = 271). Functional capacity was estimated at maximum TSH stimulation, and pituitary TSH response was FT4 standardised with two established indices, the TSH index and the thyrotroph thyroid hormone resistance index. RESULTS: The two indices correlated inversely with thyroid volume and functional thyroid capacity. Relationships were shifted upwards in patients with thyroid autoimmune disease. This positioned patients with thyroid autoimmune disease predominantly at the lower capacity range and upper part of TSH index. The relationship was modulated by serum FT3 concentrations, shifting 0.19 [95%CI: 0.12, 0.26] mIU/L per pmol FT3 increase. FT3 correlated with TSH index in total group ( CONCLUSION: Functional thyroid capacity and preferential T3 generation are essential elements in adjusting the sensitivity of hypothalamic-pituitary-thyroid feedback control and balancing system equilibria. This suggests that the indirect regulatory role of glandular T3 co-secretion exceeds its quantitative contribution to the thyroid hormone pool. Implications for clinical practice extend to the diagnostic use of TSH in patients with impaired thyroid reserve. PMID- 30022465 TI - Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention. AB - The term schizophrenia describes a group of multifaceted psychiatric conditions causing significant impairment of the quality of life of affected patients. Although multiple pharmacological treatment options exist, e.g. first- or second generation antipsychotics, these therapeutics often cause disturbing side effects, such as extrapyramidal symptoms, prolactin increase, sexual dysfunction and/or metabolic syndrome. Furthermore, cognitive impairments and negative symptoms, two factors significantly influencing the course and outcome, are not sufficiently addressed by the available antipsychotics. Since its discovery, multiple clinical and preclinical studies have linked the endocannabinoid system to schizophrenia. Both the endocannabinoid anandamide and the cannabinoid CB1 receptor are deeply linked to underlying disease processes. Based hereon, clinical trials in schizophrenia have explored cannabidiol, a primary component of Cannabis sativa, and rimonabant, a partial antagonist to the CB1 receptor. While the latter did not reveal positive results, cannabidiol significantly ameliorated psychotic symptoms, which was associated with an increase in anandamide serum levels. However, the exact mechanisms of the antipsychotic effects of cannabidiol are not fully understood, and, furthermore, only a limited number of clinical trials in humans have been concluded to date. Thus, the level of proof of safety and efficacy required to approve the therapeutic use of cannabidiol in schizophrenia is currently lacking. However, cannabidiol is a promising candidate as an effective and mechanistically different antipsychotic treatment with a favourable side-effect profile. We therefore conclude that further studies are urgently needed to clarify the antipsychotic effects and safety profile of cannabidiol, and to fully explore its potential antipsychotic mechanism. PMID- 30022472 TI - Carnauba wax as a wall material for urea microencapsulation. AB - BACKGROUND: The high ureolytic activity of rumen microbiota is a concern when urea is used in ruminant feed, because it leads to fast urea conversion, resulting in possible intoxication and lower nitrogen utilization. This study intended to microencapsulate urea using carnauba wax to obtain slow-release systems in the rumen. The experiment was conducted in a randomized block design, arranged in a 3 * 2 factorial, with the urea encapsulated with carnauba wax in ratios of 1 : 2; 1 : 3, and 1 : 4 (UME 2; UME 3, and UME 4) and two particles sizes (small, PS ; and large, PL ). RESULTS: All formulations showed excellent properties, including inhibition of urea hygroscopicity. The formulation UME 2 exhibited the greatest yield (91.6%) and microencapsulation efficiency (99.6%) values, whereas the formulation UME 4 presented the greatest thermal stability (259.5 degrees C) and lowest moisture content (1.81%). The UME 2 formulation presented a slower release than the other UME formulations studied. CONCLUSION: The production of urea microspheres using carnauba wax was successful for all microencapsulated systems developed, evidencing the promising potential for use in ruminant animal diets. The UME 2 formulation with large particles is the most recommended because it permitted greater resistance to microbial attack, allowing a slower release of urea into the rumen, reducing the risk of intoxication or ruminal alkalosis. (c) 2018 Society of Chemical Industry. PMID- 30022471 TI - Functional status of immune cells in patients with long-lasting type 2 diabetes mellitus. AB - Although patients with diabetes contract infectious diseases at higher frequencies, and in more severe forms, compared to non-diabetics, the underlying defects of the immune function have not been defined clearly. To address this, we designed an immune monitoring protocol and analysed the functional status of various immune cells. Peripheral blood mononuclear cells (PBMCs) were stimulated with the proper ligands and the functional reactivity of each lineage of cells was subsequently measured. Patients with type 2 diabetes mellitus (T2DM) had PBMC composition ratios comparable to healthy controls, except for a higher frequency of B cell and effector T cell fractions. The capacity of myeloid cells to secrete proinflammatory cytokines was not diminished in terms of the sensitivity and magnitude of the response. Furthermore, cytolytic activity and interferon (IFN) gamma production of natural killer (NK) cells and CD8+ T cells were not decreased in T2DM patients. Phenotypical maturation of dendritic cells, indicated by the up regulation of major histocompatibility complex (MHC) proteins and co-stimulatory molecules in response to lipopolysaccharide (LPS), was slightly enhanced in T2DM patients. Finally, the functional differentiation profiles of CD4+ T cells did not differ between T2DM patients and the control group. These data indicate that patients with long-lasting T2DM do not have any gross functional defects in immune cells, at least in circulating monocytes, dendritic cells, NK cells and T lymphocytes. PMID- 30022473 TI - CLC-Nt1 affects Potato Virus Y infection via regulation of endoplasmic reticulum luminal Ph. AB - Chloride channel (CLC) proteins are important anion transporters conserved in organisms ranging from bacteria and yeast to plants and animals. According to sequence comparison, some plant CLCs are predicted to function as Cl- /H+ antiporters, but not Cl- channels. However, no direct evidence was provided to verify the role of these plant CLCs in regulating the pH of the intracellular compartment. We identified tobacco CLC-Nt1 interacting with the Potato virus Y (PVY) 6K2 protein. To investigate its physiological function, homologous genes of CLC-Nt1 in Nicotiana benthamiana were knocked out using the CRISPR/Cas9 system. Complementation experiments were subsequently performed by expression of wild type or point-mutated CLC-Nt1 in knockout mutants. The data presented herein demonstrate that CLC-Nt1 is localized at endoplasmic reticulum (ER). Using a pH sensitive fluorescent protein (pHluorin), we found that loss of CLC-Nt1 function resulted in a decreased ER luminal pH. Secreted GFP (secGFP) was retained mostly in ER in knockout mutants, indicating that CLC-Nt1 is also involved in protein secretion. PVY infection induced a rise in ER luminal pH, which was dependent on functional CLC-Nt1. By contrast, loss of CLC-Nt1 function inhibited PVY intracellular replication and systemic infection. We propose that PVY alters ER luminal pH for infection in a CLC-Nt1-dependent manner. PMID- 30022474 TI - Peripheral lymphocytes analyses in children with chronic hepatitis C virus infection. AB - BACKGROUND: Hepatitis C virus (HCV)-specific immune response is believed to play a crucial role in viral clearance. There is, nevertheless, no reliable parameter to monitor this immune response or predict chronic HCV infection development. METHOD: An observational case-control study was performed to identify such parameters, peripheral blood mononuclear cells from 57 children with chronic HCV were systemically phenotyped, and the serum level of Interferon gamma and interleukin (IL) -17 was measured. The data were compared with 37 age-matched healthy volunteers (controls). RESULTS: Children with chronic HCV infection had a lower frequency of natural killer cells (NK) cells, CD56Dim NK cells and expansion of CD56Bright NK cells compared with controls (P = 0.001, P < 0.0001 and P < 0.0001 respectively). Increased CD56Dim NK cells were negatively correlated with the higher viral load, R2 = 0.29, P = 0.05, while, increased NK T cells were positively correlated with high viral load, R2 = 0.17, P = 0.011. T helper cells, naive T cells, CD127 negative T cells, and HLA-DR-positive T cells significantly increased in patients than in controls. The frequency of CD4+CD25high+ T regulatory (Treg) cells increased in HCV-infected patients, compared with those in control, and FOXP3 was upregulated within them. Treg cells' increase was positively correlated with high viral load, R2 = 0.45, P = 0.004. The level of IL-17 was higher in HCV patients than that in control, P < 0.0001. CONCLUSION: Although the contribution of those markers to the chronic HCV establishment in children remains elusive, the results may provide important clues for reliable indicators of HCV infection. PMID- 30022475 TI - Central nervous system lymphoma in 18 dogs (2001 to 2015). AB - OBJECTIVES: To investigate the outcome of dogs with central nervous system lymphoma. MATERIALS AND METHODS: A multi-center, retrospective, observational study was conducted by reviewing medical records of 18 cases of central nervous system lymphoma from seven institutions. RESULTS: Diagnosis of lymphoma was made through cerebrospinal fluid analysis, histopathology, flow cytometry of the cerebrospinal fluid, and cytology of cerebrospinal fluid, lymph node or spleen with correlated imaging. A total of 15 of 18 dogs received specific treatment other than prednisone. Three dogs underwent chemotherapy and radiation therapy after surgical decompression, five dogs underwent chemotherapy, two dogs underwent radiation therapy after surgical decompression, three dogs underwent chemotherapy after surgical decompression and two dogs underwent radiation therapy and chemotherapy. Only one dog received prednisone, and two dogs did not receive any treatment. Overall, the median survival time was 171 days (range 1 to 1942 days). CLINICAL SIGNIFICANCE: Dogs receiving any type of treatment for central nervous system lymphoma lived longer than cases described in previous historical reports. Further studies are needed to elucidate the importance of specific treatment modalities. PMID- 30022477 TI - The fruit of competition: seed dispersal by Magellanic Woodpeckers in the threatened Valdivian Rainforest. PMID- 30022476 TI - Measures used to quantify participation in childhood disability and their alignment with the family of participation-related constructs: a systematic review. AB - AIM: We aimed to identify measures used to assess the participation of disabled children and to map the measures' content to the family of participation-related constructs (fPRC) to inform future research and practice. METHOD: Six databases were searched to identify measures used to assess participation in health, psychology, and education research. Included studies involved children aged 0 to 18 years with a permanent impairment or developmental disability and reported use of a quantitative measure of participation. A second search sought relevant literature about each identified measure (including published manuals) to allow a comprehensive understanding of the measure. Measurement constructs of frequently reported measures were then mapped to the fPRC. RESULTS: From an initial yield of 32 767 articles, 578 reported one or more of 118 participation measures. Of these, 51 measures were reported in more than one article (our criterion) and were therefore eligible for mapping to the fPRC. Twenty-one measures quantified aspects of participation attendance, 10 quantified aspects of involvement as discrete scales, and four quantified attendance and involvement in a manner that could not be separated. INTERPRETATION: Improved understanding of participation and its related constructs is developing rapidly; thoughtful selection of measures in research is critical to further our knowledge base. WHAT THIS PAPER ADDS: The fPRC can support our rapidly evolving and expanding understanding of participation. Instruments selected to measure participation do not always align with emerging concepts. Matching research aims to a chosen measure's content will improve understanding of participation. Opportunities exist to develop validated participation measures, especially self-reported measures of involvement. PMID- 30022478 TI - Diffuse erythema with 'angel wings' sign in Japanese patients with anti-small ubiquitin-like modifier activating enzyme antibody-associated dermatomyositis. PMID- 30022479 TI - Angiogenesis in the lung. AB - Both systemic (tracheal and bronchial) and pulmonary circulations perfuse the lung. However, documentation of angiogenesis of either is complicated by the presence of the other. Well-documented angiogenesis of the systemic circulations have been identified in asthma, cystic fibrosis, chronic thromboembolism and primary carcinomas. Angiogenesis of the vasa vasorum, which are branches of bronchial arteries, is seen in the walls of large pulmonary vessels after a period of chronic hypoxia. Documentation of increased pulmonary capillaries has been shown in models of chronic hypoxia, after pneumonectomy and in some carcinomas. Although endothelial cell proliferation may occur as part of the repair process in several pulmonary diseases, it is separate from the unique establishment of new functional perfusing networks defined as angiogenesis. Identification of the mechanisms driving the expansion of new vascular beds in the adult needs further investigation. Yet the growth factors and molecular mechanisms of lung angiogenesis remain difficult to separate from underlying disease sequelae. PMID- 30022481 TI - Response of pomegranate arils (cv. Wonderful) to low oxygen stress under active modified atmosphere condition. AB - BACKGROUND: Successful characterization of the relationship between respiration rate (RR) and low oxygen (O2 ) limit is critical for optimizing the modified atmosphere condition. It is well documented that a low O2 atmosphere reduces the RR of fresh produce, but could also lead to abiotic stress due to the accumulation of glycolysis end products. Therefore, this study investigated the response of pomegranate arils exposed to low O2 atmosphere (composed of 2 kPa O2 , 18 kPa carbon dioxide, and 80 kPa nitrogen) and identified the low O2 limit at 5 degrees C and 10 degrees C. The study aim was achieved by using real-time RR and respiration quotient (RQ) data, microbial growth, identifying changes in the fermentative volatile organic compounds profile, and the consumption of respiratory metabolites (organic acids and individual sugars). RESULTS: The gas concentrations changed significantly respective to the storage temperature and resulted in a significant change in the parameters studied. The response of pomegranate arils to low O2 stress involves making alterations to the metabolic composition, especially those involved in anaerobiosis, such as the accumulation of ethanol, and an immediate increase on RQ. CONCLUSION: Pomegranate arils (cv. Wonderful) can tolerate down to 1.9 kPa O2 and 2.3 kPa O2 concentrations at 5 degrees C and 10 degrees C respectively. (c) 2018 Society of Chemical Industry. PMID- 30022483 TI - Mepacrine-induced interstitial lung disease in discoid lupus erythematosus? PMID- 30022482 TI - Impact of Medicare's Nonpayment Program on Venous Thromboembolism Following Hip and Knee Replacements. AB - OBJECTIVE: To determine whether Medicare's Nonpayment Program was associated with decline in venous thromboembolism (VTE) following hip and knee replacements; and whether the decline was greater among hospitals at risk of larger financial losses from the Program. DATA SOURCES: State Inpatient Database for New York (NY) from 2005 to 2013. STUDY DESIGN: The primary outcome was an occurrence of VTE. Medicare Utilization Ratio (MUR), which is the proportion of inpatient days in a hospital that is financed by Medicare, represented a hospital's financial sensitivity. We used hierarchical logistic regressions with difference-in differences estimation to study the Program effects. PRINCIPAL FINDINGS: A total of 98,729 hip replacement and 111,361 knee replacement stays were identified. For hip replacement, the Program was associated with significant reduction (Range: 44% to 53%) in VTE incidence among hospitals in MUR quartiles 2 to 4. For knee replacement, the Program was associated with significant reduction (47%) in VTE incidence only among quartile 2 hospitals. CONCLUSION: Implementation of the Program was associated with a reduction in VTE, especially for hip replacements, in higher MUR hospitals. Payment reforms such as Medicare's Nonpayment Program that withhold payments for complications are effective and should be continued. PMID- 30022480 TI - Immune-bone interplay in the structural damage in rheumatoid arthritis. AB - The immune and bone systems maintain homeostasis by interacting closely with each other. Rheumatoid arthritis is a pathological consequence of their interplay, as activated T cell immune responses result in osteoclast-mediated bone erosion. An imbalance between forkhead box protein 3 (Foxp3)+ regulatory T (Treg ) cells and T helper type 17 (Th17) cells is often linked with autoimmune diseases, including arthritis. Th17 cells contribute to the bone destruction in arthritis by up regulating receptor activator of nuclear factor kappa-Beta ligand (RANKL) on synovial fibroblasts as well as inducing local inflammation. Studies on the origin of Th17 cells in inflammation have shed light on the pathogenic conversion of Foxp3+ T cells. Th17 cells converted from Foxp3+ T cells (exFoxp3 Th17 cells) comprise the most potent osteoclastogenic T cell subset in inflammatory bone loss. It has been suggested that osteoclastogenic T cells may have developed originally to stop local infection in periodontitis by inducing tooth loss. In addition, Th17 cells also contribute to the pathogenesis of arthritis by modulating antibody function. Antibodies and immune complexes have attracted considerable attention for their direct role in osteoclastogenesis, and a specific T cell subset in joints was shown to be involved in B cell antibody production. Here we summarize the recent advances in our understanding of the immune-bone interplay in the context of the bone destruction in arthritis. PMID- 30022484 TI - A neutrophil "Ugly Duckling". PMID- 30022485 TI - Curcumin sensitized the antitumour effects of irradiation in promoting apoptosis of oesophageal squamous-cell carcinoma through NF-kappaB signalling pathway. AB - OBJECTIVES: To investigate the potential synergistic effect of curcumin with irradiation (IR) in oesophageal squamous-cell carcinoma (ESCC) and elucidate the underlying molecular mechanisms. METHODS: The ESCC cell lines were established from clinical samples. Cell apoptosis post-treatment was stained by Annexin V/PI staining and analysed by flow cytometry. Cells survived IR was evaluated with clonogenic assay. Xenograft tumour model was established by subcutaneous inoculation, and tumour progression was monitored. The NF-kappaB pathway was characterized by immunoblotting. KEY FINDINGS: Curcumin enhanced the pro apoptotic effect of IR in ESCC cells. Pretreatment with curcumin significantly sensitized ESCC cells to IR in a dose-dependent manner. Coadministration with curcumin remarkably extended the median survival time of ESCC xenograft mice while exposed to IR therapy. The xenograft tumour progression was significantly suppressed as well. Mechanistically, curcumin treatment was demonstrated to efficiently inhibited NF-kappaB signalling. CONCLUSIONS: We have well recapitulated the pathological properties and therapeutic response of ESCC with established cell lines derived from clinical samples. We further demonstrated the significantly synergistic effect of curcumin on IR-elicited cell apoptosis in ESCC both in vitro and in vivo. Our data suggested the potential therapeutic values of curcumin for future clinical investigations. PMID- 30022486 TI - Transepidermal water loss in healthy adults: a systematic review and meta analysis update. AB - BACKGROUND: Transepidermal water loss (TEWL) is one of the most important skin barrier characteristics. Higher TEWL is usually associated with skin barrier impairments, and lower TEWL with healthy skin. OBJECTIVES: To update an existing systematic review and meta-analysis to provide TEWL reference values for healthy skin in adults. METHODS: The databases MEDLINE and Embase and other sources were searched. This update includes studies identified by two combined searches that cover the period from 1947 to 13 April 2017. Primary empirical observational and interventional studies in healthy adults providing quantitative estimates of TEWL measurements including measures of spread, such as SDs, with clear reporting of skin areas and age were included. Data were extracted per skin area and statistically pooled. RESULTS: After full-text assessment, the results of 45 studies were included additionally to the existing meta-analysis. TEWL estimates were identified for 86 skin areas in 212 studies. The lowest TEWL of 2.3 g m-2 h 1 (95% confidence interval 1.9-2.7) was reported for breast skin and the highest TEWL of 44.0 g m-2 h-1 (95% confidence interval 39.8-48.2) for the axilla. Sample sizes ranged from four (forehead middle left middle) to 4013 (mid volar right forearm). The clinical relevance of the difference between TEWL estimates for different measurement devices seems to be minimal. TEWL in elderly patients was either similar to or lower than values in the younger group. CONCLUSIONS: Reference estimates are useful for clinical study planning and interpretation of results. TEWL is highly dependent on skin area, and our results further support the symmetry between right and left measuring sites. TEWL in elderly people seems to be generally similar or decreased compared with younger individuals, but available evidence is limited. Reporting of TEWL should be improved: mean and spread parameters should always be reported in future studies. PMID- 30022487 TI - Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia. AB - Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low-level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice-site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads. PMID- 30022488 TI - RS1 (Rsc1A1) deficiency limits cerebral SGLT1 expression and delays brain damage after experimental traumatic brain injury. AB - Acute cerebral lesions are associated with dysregulation of brain glucose homeostasis. Previous studies showed that knockdown of Na+ -D-glucose cotransporter SGLT1 impaired outcome after middle cerebral artery occlusion and that widely expressed intracellular RS1 (RSC1A1) is involved in transcriptional and post-translational down-regulation of SGLT1. In the present study, we investigated whether SGLT1 is up-regulated during traumatic brain injury (TBI) and whether removal of RS1 in mice (RS1-KO) influences SGLT1 expression and outcome. Unexpectedly, brain SGLT1 mRNA in RS1-KO was similar to wild-type whereas it was increased in small intestine and decreased in kidney. One day after TBI, SGLT1 mRNA in the ipsilateral cortex was increased 160% in wild-type and 40% in RS1-KO. After RS1 removal lesion volume 1 day after TBI was reduced by 12%, brain edema was reduced by 28%, and motoric disability determined by a beam walking test was improved. In contrast, RS1 removal did neither influence glucose and glycogen accumulation 1 day after TBI nor up-regulation of inflammatory cytokines TNF-alpha, IL-1beta and IL-6 or microglia activation 1 or 5 days after TBI. The data provide proof of principle that inhibition or down-regulation of SGLT1 by targeting RS1 in brain could be beneficial for early treatment of TBI. PMID- 30022489 TI - Intraganglionic macrophages: a new population of cells in the enteric ganglia. AB - The enteric nervous system shares embryological, morphological, neurochemical, and functional features with the central nervous system. In addition to neurons and glia, the CNS includes a third component, microglia, which are functionally and immunophenotypically similar to macrophages, but a similar cell type has not previously been identified in enteric ganglia. In this study we identify a population of macrophages in the enteric ganglia, intermingling with the neurons and glia. These intraganglionic macrophages (IMs) are highly ramified and express the hematopoietic marker CD45, major histocompatibility complex (MHC) class II antigen, and chB6, a marker specific for B cells and microglia in avians. These IMs do not express antigens typically associated with T cells or dendritic cells. The CD45+ /ChB6+ /MHCII+ signature supports a hematopoietic origin and this was confirmed using intestinal chimeras in GFP-transgenic chick embryos. The presence of green fluorescent protein positive (GFP+) /CD45+ cells in the intestinal graft ENS confirms that IMs residing within enteric ganglia have a hematopoietic origin. IMs are also found in the ganglia of CSF1RGFP chicken and CX3CR1GFP mice. Based on the expression pattern and location of IMs in avians and rodents, we conclude that they represent a novel non-neural crest-derived microglia-like cell population within the enteric ganglia. PMID- 30022490 TI - Similarity to imagined interlocutor and integration of viewpoints in internal dialogues. AB - Numerous positive functions are ascribed to integrative internal dialogues (IDs). Additionally, IDs simulating social relationships are thought to serve as "prototypes" for interpersonal communication. Therefore, it would be useful to know how to increase the frequency of integrative IDs. Previous studies exploring the relationship between similarity to an imagined interlocutor and the integration in ID have produced inconsistent results. The aim of the present study was to examine the moderating and mediating factors in this relationship. Data from 119 people (mostly students) were analysed. Before the participants conducted IDs, they had written down 3 characteristics common to them and to their interlocutor. Finally, the Integration-Confrontation questionnaire was completed. Plausibility of ID was a moderator of the relationship between similarity to imagined interlocutor and integration in IDs; this relationship was significantly positive at lower plausibility, but non-significant at high plausibility. Perceived similarity in ID exerted an indirect effect on ID's integration in 2 ways. The first pathway was through identifying with the interlocutor and the author's integrative attitude, suggesting a mechanism in line with social identity theory. The second potential mechanism, which seems to be consistent with similarity-attraction theory, was connected with the wishfulness of IDs and the interlocutor's integrative attitude. PMID- 30022491 TI - Identification of prognostic parameters in CLL with no abnormalities detected by chromosome banding and FISH analyses. AB - Chronic Lymphocytic Leukaemia (CLL) is a heterogeneous disease with a clinical course dependent on cytogenetic features. However, in 15-20% of cases both chromosome banding and fluorescence in situ hybridisation analyses do not show any kind of abnormality. With the aim to identify dependable molecular prognostic factors in this subgroup, we performed a comprehensive analysis on 171 patients including genomic arrays (comparative genomic hybridisation and single nucleotide polymorphism), immunoglobulin heavy chain variable region genes (IGHV) status, flow cytometry and targeted sequencing. Genomic arrays detected 73 aberrations in 39 patients (23%). Most frequently, patients had 1 aberration (25/171; 15%), while 14 patients (8%) had at least 2 aberrations. IGHV status was unmutated in 53/171 (31%) patients. SF3B1 was the most frequently mutated gene (26/171 patients; 15%), followed by NOTCH1 (15/171; 9%). At univariate analysis, an adverse impact on time to treatment (TTT) was evident for SF3B1 mutations, higher white blood cell count, higher CLL cells percentage by flow cytometry, CD38 positivity, IGHV unmutated status and at least 2 genomic array abnormalities. Of these, SF3B1 mutations, CLL cells percentage, IGHV unmutated status and number of genomic array aberrations maintained their impact in multivariate analysis. In conclusion, by integrating genomic and molecular data, we identified patients at higher risk for treatment need. PMID- 30022492 TI - Perceived competence and impression management: Testing the mediating and moderating mechanisms. AB - Using a diverse and unique sample of triads (N = 191 self, peer, and supervisor reports) from a field survey of two service sector organisations, this study examined the effects of perceived competence (self-reported) and supervisor-rated performance ratings on peer-rated impression management. The study also tested the mediating role of performance in competence-impression management relationships and the moderating role of job satisfaction (self-reported) in performance-impression management relationships using bootstrapping techniques. The study further examined the conditional indirect effects (i.e., moderated mediation) of perceived competence on impression management. The sample consisted of white collar employees from a government organisation and a leading cellular company in a developing country (i.e., Pakistan). Employees with low perceived competence were more likely to use impression management tactics than were those with high perceived competence. Similarly, poor performance ratings produced high impression management. Moreover, performance mediated the relationship between competence and impression management. The findings also suggest that perceived competence has a negative indirect effect on impression management for those with high levels of job satisfaction. Finally, impression management was highest when performance and satisfaction were low. PMID- 30022494 TI - Exposure to suicide and suicide bereavement among women firefighters: Associated suicidality and psychiatric symptoms. AB - OBJECTIVE: To examine experiences with suicide exposure and bereavement among women firefighters. METHODS: Women firefighters (N = 266, Mage = 37.64y) completed self-report measures assessing their experiences with suicide exposure, history of suicidality, current psychiatric symptoms, and suicide risk. RESULTS: Three-fourths (74.4%) of participants reported knowing someone who had died by suicide; of these participants, 31.3% reported losing a fellow firefighter to suicide. Exposure to suicide during one's firefighting career was associated with more severe psychiatric symptoms and suicide risk. Greater impact of a suicide death was significantly associated with more severe current suicide risk, even after controlling for prior suicidality and other psychiatric symptoms. CONCLUSIONS: Women firefighters exposed to suicide during their careers may experience more severe psychiatric symptoms and increased suicide risk as compared to their counterparts without this exposure. In particular, women firefighters who are more severely impacted by a suicide loss may be at increased suicide risk. PMID- 30022493 TI - Neural memory of the genioglossus muscle during sleep is stage-dependent in healthy subjects and obstructive sleep apnoea patients. AB - KEY POINTS: In most patients with obstructive sleep apnoea (OSA), there is a spontaneous resolution of the breathing disorders during slow wave sleep (SWS) for yet unknown reasons related to non-anatomical factors. Some recently identified forms of neural memory specific of upper airway muscles may play a role in this phenomenon. In the present study, we show for the first time that a form of memory of the genioglossus (tongue) muscle is greatly enhanced during SWS compared to non-rapid eye movement stage 2 sleep. The present study represents a step forward in understanding the mechanisms responsible for the spontaneous development of stable breathing during SWS in OSA patients and may help the discovery of novel therapeutic strategies for this disease. ABSTRACT: Several studies have shown that obstructive sleep apnoea (OSA) improves during slow wave sleep (SWS) for reasons that remain unclear. Recent studies have identified forms of neural memory such as short-term potentiation or after-discharge that can occur in response to upper airway obstruction. Neural memory may play a role in the development of stable breathing during SWS by increasing upper airway muscles activity in this sleep stage. We hypothesize that the after-discharge of the genioglossus muscle following upper airway obstruction is enhanced during SWS compared to non-rapid eye movement stage 2 (N2). During sleep, we performed five breath drops in continuous positive airway pressure (CPAP-drop) to simulate obstructive events and reflexively activate the genioglossus. Immediately afterwards, CPAP was returned to an optimal level. Once the post-drop ventilation returned to eupnoea, the genioglossus after-discharge was measured as the time it took for genioglossus activity to return to baseline levels. In total, 171 CPAP drops were analysed from a group of 16 healthy subjects and 19 OSA patients. A mixed-model analysis showed that after-discharge duration during SWS was 208% (95% confidence interval = 112% to 387%, P = 0.022) greater than during N2 after adjusting for covariates (ventilatory drive, CPAP levels). There was also a non significant trend for a -35% reduction in after-discharge duration following an arousal vs. no-arousal from sleep (95% confidence interval = -59.5% to 5%, P = 0.08). Genioglossus after-discharge is two-fold greater in SWS vs. N2, which could partly explain the breathing stabilization described in OSA patients during this sleep stage. PMID- 30022495 TI - Bone marrow erythrocyte and neutrophil phagocytosis and cannibalism by neuroendocrine carcinoma. PMID- 30022496 TI - The effect of growth rate on the three-dimensional orientation of vascular canals in the cortical bone of broiler chickens. AB - Vascular canals in cortical bone during growth and development typically show an anisotropic pattern with canals falling into three main categories: circumferential, radial, and longitudinal. Two major hypotheses attempt to explain the preferred orientations in bone: that vascular canal orientation is optimized to resist a predominant strain direction from functional loading, or that it reflects growth requirements and velocity. We use a controlled growth experiment in broiler chickens to investigate the effect of growth rate on vascular canal orientation. Using feed restriction we set up a fast growing control group and a slow growing restricted group. We compared the microstructure in the humerus and the femur at 42 days of age using synchrotron micro-computed tomography (micro-CT), a three-dimensional (3D) method that visualizes the full canal network. We measured the 3D orientation of each canal in the whole cross section of the bone cortex using a set of custom ImageJ scripts. Using these orientations we compute laminar, radial, and longitudinal indices that measure the proportion of circumferential, radial, and longitudinal canals, by unit of length, in the cortex. Following previous studies we hypothesized that vascular canal orientation is related to growth, with radial canals linked to a faster growth rate and related to functional loading through a high laminar index in flight bones which reflects torsional loading resulting from active flight. The control group had final body weights that were nearly twice the final weights of the restricted group and higher absolute growth rates. We found consistent patterns in the comparison between the humerus and the femur in both groups, with the humerus having higher laminar and longitudinal indices, and a lower radial index than the femur. The control group had higher radial indices and lower laminar and longitudinal indices in both the humerus and the femur than the restricted group. The higher radial indices in our control group point to a link between radial canals and faster growth, and between laminar canals and slower growth, while the higher laminar indices in the humerus point to a link between circumferential canals and torsional loading. Overall, our results indicate that the orientation of the cortical canal network in a bone is the consequence of a complex interaction between the growth rate of that bone and functional loading environment. PMID- 30022498 TI - Oral health in end-of-life patients: A rapid review. AB - INTRODUCTION: Maintaining oral health is vital for every individual's quality of life. Little consideration, however, has been given to the oral health of patients approaching end-of-life, perhaps due to sensitivities over research ethics. The aim of this rapid review is to synthesize existing evidence on oral health in this population. METHODS AND RESULTS: A rapid review of the literature was conducted using the key words: "Oral/Dental Health" in "End-of-life" or "Palliative care" patients. Nineteen articles met the inclusion criteria: five retrospective cohort studies, ten cross sectional studies, two experimental studies, one systematic review, and one audit. Quality was medium to low. The prevalence of oral/dental conditions was high in the end-of-life population, as were self-reported symptoms, and poor OHRQOL. Staff placed value on oral health but identified several barriers to providing both routine daily and professional dental care. Professional oral care was beneficial in relieving palliative specific conditions and providing guidance/training for daily care. CONCLUSION: There is a paucity of high quality research in relation to oral health at end-of life. The existing literature suggests that oral health and oral health related quality of life are poor and professional support and care for this population is needed. PMID- 30022497 TI - Logistic regression with a continuous exposure measured in pools and subject to errors. AB - In a multivariable logistic regression setting where measuring a continuous exposure requires an expensive assay, a design in which the biomarker is measured in pooled samples from multiple subjects can be very cost effective. A logistic regression model for poolwise data is available, but validity requires that the assay yields the precise mean exposure for members of each pool. To account for errors, we assume the assay returns the true mean exposure plus a measurement error (ME) and/or a processing error (PE). We pursue likelihood-based inference for a binary health-related outcome modeled by logistic regression coupled with a normal linear model relating individual-level exposure to covariates and assuming that the ME and PE components are independent and normally distributed regardless of pool size. We compare this approach with a discriminant function-based alternative, and we demonstrate the potential value of incorporating replicates into the study design. Applied to a reproductive health dataset with pools of size 2 along with individual samples and replicates, the model fit with both ME and PE had a lower AIC than a model accounting for ME only. Relative to ignoring errors, this model suggested a somewhat higher (though still nonsignificant) adjusted log-odds ratio associating the cytokine MCP-1 with risk of spontaneous abortion. Simulations modeled after these data confirm validity of the methods, demonstrate how ME and particularly PE can reduce the efficiency advantage of a pooling design, and highlight the value of replicates in improving stability when both errors are present. PMID- 30022499 TI - Optimization of chitosanase production by Bacillus mojavensis EGE-B-5.2i. AB - Maximum production of industrially important enzymes such as chitosanases through media optimization still holds foremost interest. The present study was conducted to improve chitosanase activity of an indigenous strain identified as Bacillus mojavensis. Initially, carbon and nitrogen sources were optimized by one-variable at-a-time approach. Further, fermentation medium was optimized using Plackett Burman (PB) and central composite designs (CCD). PB verified soluble starch (SS), colloidal chitosan (CC) peptone, and NaCl as most significant variables affecting chitosanase production. CCD results predicted the optimum concentrations of SS, CC, peptone, and NaCl as 7.8, 7.0, 6.5, and 2.7 g L-1 , respectively to achieve maximum chitosanase activity (21.1 U ml-1 ). Discovery of the novel optimal medium has improved chitosanase production by B. mojavensis up-to 9.5 folds. Lastly, 18.6 U ml-1 chitosanase activity was achieved in stirred tank bioreactor using optimal medium, which is quite satisfactory to proclaim this strain as a potential candidate to provide commercial chitosanase. PMID- 30022500 TI - Metagenomics analysis of the virome of 300 concentrates from a Swiss platelet bank. AB - BACKGROUND AND OBJECTIVES: Platelet concentrates are frequently transfused to patients with reduced immunity. An exhaustive description of their viral content is needed to prevent unwanted infection. MATERIAL AND METHODS: To track viral sequences, a shotgun metagenomics approach was used on a bank of 300 platelets concentrates. Sequences were analysed through the diagnostics-oriented pipeline ezVIR. RESULTS: We only observed viruses commonly described in healthy individuals. CONCLUSION: Herein is reported the first viral landscape of a platelet concentrates bank. PMID- 30022501 TI - Amelioration of diabetes-induced testicular and sperm damage in rats by cerium oxide nanoparticle treatment. AB - Cerium oxide nanoparticles (CNPs) as an antioxidant have been used frequently to attenuate hyperglycaemia oxidative damage in different organs. We investigated the impact CNPs on the qualitative and quantitative sperm parameters, spermatogenesis and NFE2-related factor 2 (Nrf2) expression as a major contributor of antioxidant defence in the male diabetic rats. Twenty-four male rats were divided into four groups. Controls received only mouse food and water. Second group were treated with CNPs (30 mg kg-1 day-1 ) for 2 weeks. Rats in third group received streptozotocin (STZ) (60 mg/kg). In fourth group, animals became diabetic and received CNPs (30 mg kg-1 day-1 ) for 2 weeks. The results showed a significant abnormality in the sperm parameters and histopathological patterns of testes in the diabetic group compared to the control group and CNPs treatment significantly improved all testicular parameters. Following CNPs administration, sperm DNA fragmentation significantly reduced in the STZ-treated rats. Moreover, after CNPs intake in the STZ-treated rats, Nfr2 expression levels increased significantly. Overall, CNPs administration on the diabetic rates can attenuate detrimental effects of diabetes on the sperm potential fertility, sperm parameters, DNA integrity and Nrf2 expression levels. This study gives a future prospect to determine the role of CNPs in the context of diabetes. PMID- 30022502 TI - Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Post-Hepatectomy Liver Failure. AB - BACKGROUND: Acute Liver Failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry and liver regeneration in post-hepatectomy ALF pigs. METHODS: Wild-type large white swine (20-30kg) underwent ICP probe placement followed by 85% hepatectomy. CT volumetrics were performed to measure the extent of resection, and at 48 hours post-hepatectomy to assess regeneration of the remnant liver. Animals were randomized into three groups based on treatment delivered 24 to 48 hour post-hepatectomy: Group1 - Standard medical therapy (SMT, n=6); Group2 - SMT plus BAL treatment using no hepatocytes (0g, n=6); Group3 - ST plus SRBAL treatment using 200 grams of primary porcine hepatocyte spheroids (200g, n=6). Primary end point was survival to 90 hours post-hepatectomy. Death equivalent was defined as unresponsive grade 4 hepatic encephalopathy or ICP >20 mmHg with clinical evidence of brain herniation. RESULTS: All animals in both (SMT and 0g) control groups met death equivalent prior to 51 hours post-hepatectomy. Five out of 6 animals in 200g group survived to 90 hours (p< 0.01). Mean ammonia, ICP, and INR values were significantly lower in 200g group. CT volumetrics demonstrated increased volume regeneration at 48 hours post-hepatectomy in 200g group compared to SMT (p<0.01) and 0g (p<0.01) groups. Ki-67 staining showed increased positive staining at 48 hours post-hepatectomy (p<0.01). CONCLUSION: The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in post-hepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL. This article is protected by copyright. All rights reserved. PMID- 30022503 TI - STAYGREEN, STAY HEALTHY: a loss-of-susceptibility mutation in the STAYGREEN gene provides durable, broad-spectrum disease resistances for over 50 years of US cucumber production. AB - The Gy14 cucumber (Cucumis sativus) is resistant to oomyceteous downy mildew (DM), bacterial angular leaf spot (ALS) and fungal anthracnose (AR) pathogens, but the underlying molecular mechanisms are unknown. Quantitative trait locus (QTL) mapping for the disease resistances in Gy14 and further map-based cloning identified a candidate gene for the resistant loci, which was validated and functionally characterized by spatial-temporal gene expression profiling, allelic diversity and phylogenetic analysis, as well as local association studies. We showed that the triple-disease resistances in Gy14 were controlled by the cucumber STAYGREEN (CsSGR) gene. A single nucleotide polymorphism (SNP) in the coding region resulted in a nonsynonymous amino acid substitution in the CsSGR protein, and thus disease resistance. Genes in the chlorophyll degradation pathway showed differential expression between resistant and susceptible lines in response to pathogen inoculation. The causal SNP was significantly associated with disease resistances in natural and breeding populations. The resistance allele has undergone selection in cucumber breeding. The durable, broad-spectrum disease resistance is caused by a loss-of-susceptibility mutation of CsSGR. Probably, this is achieved through the inhibition of reactive oxygen species over accumulation and phytotoxic catabolite over-buildup in the chlorophyll degradation pathway. The CsSGR-mediated host resistance represents a novel function of this highly conserved gene in plants. PMID- 30022504 TI - Clinical associations between acetylcholine levels and cholinesterase activity in saliva and gingival crevicular fluid and periodontal diseases. AB - AIM: The oral mucosa possesses a non-neuronal cholinergic system. This study aimed to determine clinical evidence for a role of cholinergic mechanisms in the pathogenesis of periodontal diseases. MATERIALS AND METHODS: Fifty healthy participants, 52 patients with gingivitis and 49 with periodontitis were recruited. Full periodontal parameters were recorded and saliva and gingival crevicular fluid (GCF) collected. Levels of acetylcholine and inflammatory mediators were quantified using commercially available assay kits. Acetylcholinesterase and butyrylcholinesterase activities were measured using a published biochemical assay. RESULTS: Acetylcholine levels are significantly elevated in saliva and GCF, whereas GCF levels of butyrylcholinesterase activity are significantly decreased, in patients with periodontal diseases. Acetylcholine levels in saliva and GCF correlated positively with clinical markers of disease severity and with increased levels of IL-17A and IL-17F. In contrast, butyrylcholinesterase activity levels in GCF showed significant negative correlations with clinical markers of disease severity and IL-17A and IL-17F levels. None of the findings were due to smoking. CONCLUSIONS: Elevated acetylcholine levels and reduced butyrylcholinesterase activity are clinically associated with periodontal diseases and elevated levels of IL-17A and IL-17F. Therefore, non-neuronal cholinergic mechanisms may influence IL-17 biology and the aetiopathogenesis of periodontal diseases and therefore are possible therapeutic targets. PMID- 30022506 TI - Evidence for the positive association of physical activity and healthy ageing in longitudinal observational studies. PMID- 30022505 TI - Screening of antifungal activity of 12 essential oils against eight pathogenic fungi of vegetables and mushroom. AB - : The antifungal properties of 12 Eos, that is, Syzygium aromaticum, Pelargonium graveolens, Lavandula angustifolia, Cupresus sempervirens, Mentha piperita, Santolina chamaecyparissus, Citrus sinensis, Pogostemon patchouli, Thymus mastichina, Thymus vulgaris, Eucalyptus globulus and Rosmarinus officinalis, were screened. The influence of five doses of each EOs was tested against Botrytis cinerea, Sclerotinia sclerotiorum, Fusarium oxysporum, Phytophthora parasitica, Pythium aphanidermatum, Alternaria brassicae, Cladobotryum mycophilum and Trichoderma aggressivum f.sp. europaeum using disc-diffusion method. The mycelial growth inhibition and ED50 were calculated. The chemical analysis of the EOs was analysed using gas chromatography-mass spectroscopy. A total of 58 compounds were identified in the 12 EOs. All essential oils (EOs) analysed showed antifungal activity against the test pathogens in the range of 5.32-100%. The inhibitory effect of oils showed dose-dependent activity on the tested fungus. Based on the ED50 values, clove, rose geranium, peppermint and patchouli were the most effective. This study warrants further research into the practical use of EOs for the control of important myco- and phytopathogens in intensive horticulture. SIGNIFICANCE AND IMPACT OF THE STUDY: Due to the serious damage caused by fungal pathogens of vegetables and mushrooms, it is necessary to search for integrated strategies of disease control. This study provides relevant information about the effects of 12 essential oils (EOs) against eight pathogens of agricultural interest, included mycopathogens with emphasis on the possible future application of the EOs as alternative antifungal agents. PMID- 30022508 TI - Linearized solar elastosis of the legs: A novel presentation and review of the literature. AB - There exists a spectrum of solar elastotic variants based on the clinical and histopathologic findings. We present here a peculiar case of solar elastosis that is unusual in its anatomic location, relative lack of background actinic damage, and pattern of linearization. Its presentation suggests that other factors in addition to ultraviolet radiation may play a role in the pathogenesis of solar elastosis. PMID- 30022509 TI - Astrocytes and Glutamine Synthetase in Epileptogenesis. AB - The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood. Here we review the role of astrocytes in epilepsy development (a.k.a. epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir4.1, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase. We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy. We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions. Currently, no antiepileptogenic therapies are available for human use. The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain. PMID- 30022507 TI - Interatrial block as a predictor of atrial fibrillation in patients with ST segment elevation myocardial infarction. AB - INTRODUCTION: Interatrial block (IAB) is strongly associated with recurrence of atrial fibrillation (AF) in different clinical scenarios. Atrial fibrosis is considered the responsible mechanism underlying the pathogenesis of IAB. The aim of this study was to investigate whether IAB predicted AF at 12 months follow-up in a population of patients with ST segment elevation myocardial infarction (STEMI). HYPOTHESIS: We aimed to investigate whether IAB predicted AF at 12 months follow up in a population of patients with STEMI. METHODS: Prospective, single center, observational study of patients presenting with ST-segment elevation myocardial infarction (STEMI) and referred to primary percutaneous coronary intervention (P-PCI). Surface electrocardiograms (ECG) were recorded on admission and at 6th hour post P-PCI. Patients were screened for the occurrence of AF at a 12-months visit. RESULTS: A total of 198 patients were included between September 2015 and September 2016. IAB (partial and advanced) was detected in 102 (51.5%) patients on admission. Remodeling of the P-wave and subsequent normalization reduced the prevalence of IAB to 47 (23.7%) patients at 6th hour. AF was detected in 17.7% of study patients at 12 months. Partial IAB (p IAB) on admission (OR 5.10; 95% CI, 1.46-17.8; P = 0.011) and on 6th hour (OR 4.15; 95% CI, 1.29-13.4; P = 0.017), presence of a lesion in more than one coronary artery (OR 3.29; 95% CI, 1.32-8.16; P = 0.010) found to be independent predictors of AF at 12 months. CONCLUSION: IAB is common in patients with STEMI and along with the presence of diffuse coronary artery disease is associated with new onset of AF. PMID- 30022510 TI - The 12-year prevalence and trends of childhood disabilities in Australia: Findings from the Survey of Disability, Aging and Carers. AB - AIM: This paper contributes to knowledge on the prevalence and nature of disabilities in Australian children over a 12-year period (2003-2015). Understanding the current state of childhood disability is imperative for predicting future needs for long-term care and early intervention services for this population. METHODS: We used data on children 0-14 years from the 2003, 2009, 2012, and 2015 survey of Disability, Aging and Carers, which is an ongoing national survey covering both rural and urban areas of all States and Territories of Australia. RESULTS: Using the test for trends in population, no significant increases were noted in the prevalence of childhood disabilities over the last 12 years, although the prevalence of any developmental disability increased from 6.9% to 7.42% between 2009 and 2015. The rate and severity of disability was higher among boys compared with girls of the same age for a number of selected disabilities and higher for children aged 5-14 years. CONCLUSIONS: With the anticipated rise in psychological related disability among Australian children, there is a need to ensure availability of a flexible and responsive model of service delivery for this population. This also implies that respite service coverage may need to be substantially increased to meet children and caregivers' needs. PMID- 30022512 TI - Histological characteristics of ovarian follicle atresia in dairy cows with different milk production. AB - Follicle atresia in mammals is a universal phenomenon characteristic by degenerative morphological changes in granulosa and theca cells. The unfavourable effect of milk production in relation to fertility has been studied starting from the 70s of the last century; however, there is no unambiguous and persuasive data on association of ovarian atresia with milk yield of dairy cows. The aim of this study was to define histological signs of ovarian follicle atresia in dairy cows in relation to their milk production. The ovaries were recovered from slaughtered Holstein dairy cows assigned into two groups according to average level of annual milk production: Group 1 (n = 25)-low (<=8,000 kg/year) and Group 2 (n = 23)-high (>=8,000 kg/year). Atresia of antral follicles was evaluated on the basis of histopathological image (staining with basic fuchsine and toluidine blue) of nonovulated follicles, classified into five categories: an initial atresia, cystic atresia, obliterated atresia, atresia with luteinization of the granulosa and follicle structures of the fibrous body-corpus fibrosum. We found that the histopathological image of follicle atresia in groups of low-milk- or high-milk producing cows is essentially similar. Prevalent form of atresia in follicles of all experimental cows was the formation of fibrous bodies and obliterated atresia. The occurrence of fibrous bodies was significantly higher (55.44%) in low-milk-producing cows compared with high-milk-producing cows (34.61%). In the same way, the higher incidence of obliterated atresia was recorded in ovarian follicles from cows with the lower milk production (36.96%) compared to the cows with the higher milk production (25.48%). In contrast, ovaries from lower milk producing cows showed lower (p < 0.05) incidence of initial (p < 0.001) and cystic (p < 0.05) follicle atresia than ovaries from the higher milk-producing cows. Our results show that cows in the higher lactation group showed more initial and cystic atresia, what may adversely affect the fertility of dairy cows. PMID- 30022511 TI - QRS voltage is a predictor of in-hospital mortality of acutely ill medical patients. AB - BACKGROUND: Low QRS voltage has been shown to be associated with increased mortality in the general population and in a small pilot study the combined QRS voltage of ECG leads I and II was found to be associated with in-hospital mortality. HYPOTHESIS: Confirm that low QRS voltage predicts the in-hospital mortality of acutely ill patients, and compare QRS voltage with other predictors of mortality that can be easily, quickly and cheaply obtained at the bedside. METHODS: Prospective observational study of vital signs, QRS voltage and simple tools used to assess mental, functional and nutritional status at the bedside in unselected acutely ill patients admitted to a resource-poor hospital in sub Saharan Africa. RESULTS: Out of 1486 patients, 77 died (5.2%) in hospital. A combined lead I + II voltage <1.8 mV was present in 789 (53.1%) of patients, and significantly associated with in-hospital mortality (odds ratio 3.6, 95% CI 2.0 6.5, chi2 21.2, P < 0.00001). On logistic regression impaired mobility, the National Early Warning Score, male gender and lead I + II voltage were the only independent predictors of mortality. None of the 445 patients who were mobile on admission with a lead I + II voltage >= 1.8 mV died in hospital. CONCLUSIONS: Low QRS voltage, male gender, NEWS, and impaired mobility were independent predictors of in-hospital mortality in the study population. These four variables, which are easily obtained at the bedside, could potentially provide a rapid, easy, and cheap risk stratification system. PMID- 30022513 TI - Allergic contact dermatitis caused by "Rosa mosqueta" oil. PMID- 30022514 TI - Clinical practice guidelines for peroral endoscopic myotomy. AB - Peroral endoscopic myotomy (POEM) is a novel clinical technique developed in Japan used to treat esophageal achalasia and esophageal motility disorders. This technique has been rapidly accepted and widely disseminated throughout our clinical practice because of its low invasiveness, technical novelty, and high efficacy. Since the advent of POEM, there have been no clinical guidelines that clearly indicated its standard of care, and these guidelines have been anticipated both nationally and internationally by clinicians who engage in POEM practice. In 2017, to meet these needs, the Japan Gastroenterological Endoscopy Society (JGES) launched the guideline committee for POEM. Based on the guideline development process proposed by the Medical Information Network Distribution Service (MINDS), the guideline committee initially created research questions on POEM and conducted a systematic review and meta-analysis on each topic. The clinical research extracted from databases for these clinical questions and the systematic review mainly comprised a few retrospective studies with a small number of participants and short trial periods; hence, the strength of the evidence and recommendations derived from these results was low. Throughout this process, the guideline committee met thrice: once on May 13, 2017, and again on September 17, 2017, to formulate the draft. A consensus meeting was then held on January 14, 2018, in Tokyo to establish the guideline statements and finalize the recommendations using the modified Delphi method. This manuscript presents clinical guidelines regarding current standards of practice and recommendations in terms of the nine chief topics in POEM. PMID- 30022515 TI - The immune system and stroke: from current targets to future therapy. AB - Stroke is a major cause of morbidity and mortality worldwide. Despite the intensive search for new therapies, hundreds of agents targeting various pathophysiological mechanisms have failed clinical trials, and the thrombolytic agent tissue plasminogen activator is currently the only FDA-approved medication for the treatment of acute ischemic stroke. The immune system is involved in all stages of stroke, from the pathogenesis of risk factors to neurotoxicity, to tissue remodeling and repair. There is a bidirectional interaction between the brain and the immune system, with stroke-induced immunosuppression and subsequent infection a principal source of patient mortality. Newer work also points to a role for the gut microbiota in the immune response to stroke, while clinical sequelae such as dementia might now also be explained in immune terms. However, the exact roles of innate and adaptive components have not been fully elucidated, with studies reporting both detrimental and beneficial functions. Time is a key determinant in defining whether immunity and inflammation are neuroprotective or neurotoxic. The local inflammatory milieu also has a clear influence on many proposed treatments. This review examines the individual components of the immune response to stroke, highlighting the most promising future stroke immunotherapies. PMID- 30022516 TI - Gastrointestinal: "Ghost gland" in probe-based confocal laser endomicroscopy for diagnosing ischemic colitis: A novel approach. PMID- 30022517 TI - Severity and threshold of peanut reactivity during hospital-based open oral food challenges: An international multicenter survey. AB - BACKGROUND: Peanut allergy is classically managed by food avoidance. Immunotherapy programs are available at some academic centers for selected patients reacting to small amounts of peanut during food challenge. We aimed to determine and compare reaction thresholds and prevalence of anaphylaxis during peanut oral challenges at multiple specialist allergy centers. METHODS: A retrospective, international survey of anonymized case records from seven specialist pediatric allergy centers from the UK and Ireland, as well as the Australian HealthNuts study. Demographic information, allergy test results, reaction severity and threshold during open oral peanut challenges were collated and analyzed. RESULTS: Of the 1634 children aged 1-18 years old included, 525 (32%) failed their peanut challenge. Twenty-eight percent reacted to 25 mg, while 38% only reacted after consuming 1 g or more of whole peanut. Anaphylaxis (55 [11%]) was 3 times more common in teenagers than younger children and the likelihood increased at all ages as children consuming more peanut at the challenge. Children who developed anaphylaxis to 25-200 mg of whole peanut were significantly older. Previous history of reaction did not predict reaction threshold or severity. CONCLUSIONS: More than a third of the children in this large international cohort tolerated the equivalent of one peanut in an oral challenge. Anaphylaxis, particularly to small amounts of peanut, was more common in older children. Tailored immunotherapy programs might be considered not only for children with low, but also higher reaction thresholds. Whether these programs could prevent heightened sensitivity and anaphylaxis to peanut with age also deserves further study. PMID- 30022518 TI - A diagnostic test can prove anything if you use incorrect assumptions and circular reasoning. PMID- 30022520 TI - Statins and cognition in late-life bipolar disorder. AB - OBJECTIVES: Recent data suggests that statins have positive effects on cognition in older adults. Studies in patients with mood disorders have found contradicting positive and negative effects of statins on mood and cognition, with limited data in bipolar disorder (BD). The objective of this study was to assess the association between statin use and cognition in older adults with BD. METHODS: In a cross-sectional sample of 143 euthymic older adults with BD (age >= 50), statin users (n = 48) and nonusers (n = 95) were compared for cognitive outcomes: Global and cognitive domain z-scores were calculated from detailed neuropsychological batteries using normative data from healthy comparators (n = 87). RESULTS: The sample had a mean age of 64.3 (+/-8.9) years, 65.0% were female, with an average of 15.1 (+/-2.79) years of education. Statin users did not differ from nonusers on global (-0.60 [+/-0.69] vs -0.49 [+/-0.68], t[127] = 0.80, P = .42) or individual cognitive domains z-score. CONCLUSIONS: In older patients with BD, statin use is not independently associated with cognitive impairment. This suggests that in older BD patients, the cognitive dysfunction associated with BD trumps the potential cognitive benefit that is associated with statins in older adults without a psychiatric disorder. Further, statins do not seem to exacerbate this cognitive dysfunction. Future longitudinal studies are needed to confirm these findings. PMID- 30022521 TI - How to master endoscopic submucosal dissection in the USA. AB - Endoscopic submucosal dissection (ESD) is an established technique for the endoscopic therapy of dysplastic and early cancerous lesions throughout the gastrointestinal tract. The procedure requires both a sophisticated knowledge for lesion characterization and high-level endoscopic skills. As a result, the learning curve is very steep and, in Japan, it takes years to gain proficiency under the traditional Master-Apprentice teaching model. At present, as a result of multiple limitations, this training model is not applicable to the USA. Nevertheless, a unique, multipronged, stepwise approach has emerged as a viable pathway to train US endoscopists in ESD. Although this approach deserves refinement, it has already led to the expansion of ESD in the USA, has contributed to the widening of the indications for ESD, and has further developed ESD techniques. Multiple challenges remain, but they can be overcome by active collaboration between Japanese and US endoscopists and professional societies. The robust interest in ESD in the USA has drawn industry attention with a few innovations already coming to fruition and many more in development. PMID- 30022519 TI - Surgical resection of ripple onset predicts outcome in pediatric epilepsy. AB - OBJECTIVE: In patients with medically refractory epilepsy (MRE), interictal ripples (80-250Hz) are observed in large brain areas whose resection may be unnecessary for seizure freedom. This limits their utility as epilepsy biomarkers for surgery. We assessed the spatiotemporal propagation of interictal ripples on intracranial electroencephalography (iEEG) in children with MRE, compared it with the propagation of spikes, identified ripples that initiated propagation (onset ripples), and evaluated their clinical value as epilepsy biomarkers. METHODS: Twenty-seven children who underwent epilepsy surgery were studied. We identified propagation sequences of ripples and spikes across multiple iEEG contacts and calculated each ripple or spike latency from the propagation onset. We classified ripples and spikes into categories (ie, onset, spread, and isolated) based on their spatiotemporal characteristics and correlated their mean rate inside and outside resection with outcome (good outcome, Engel 1 versus poor outcome, Engel>=2). We determined, as onset-zone, spread-zone, and isolated-zone, the areas generating the corresponding ripple or spike category and evaluated the predictive value of their resection. RESULTS: We observed ripple propagation in all patients and spike propagation in 25 patients. Mean rate of onset-ripples inside resection predicted the outcome (odds ratio = 5.37; p = 0.02) and correlated with Engel class (rho = -0.55; p = 0.003). Resection of the onset ripple-zone was associated with good outcome (p = 0.047). No association was found for the spread-ripple-zone, isolated-ripple-zone, or any spike-zone. INTERPRETATION: Interictal ripples propagate across iEEG contacts in children with MRE. The association between the onset-ripple-zone resection and good outcome indicates that onset-ripples are promising epilepsy biomarkers, which estimate the epileptogenic tissue better than spread-ripples or onset-spikes. Ann Neurol 2018;84:331-346. PMID- 30022522 TI - Elevated obstructive sleep apnoea risk score is associated with poor healing of diabetic foot ulcers: a prospective cohort study. AB - AIMS: To assess the prevalence of risk factors for obstructive sleep apnoea in people with diabetic foot ulcers and to determine whether this risk predicts diabetic foot ulcer healing. METHODS: We studied 94 consecutive people (69% men) with diabetic foot ulcers (Type 2 diabetes, n=66, Type 1 diabetes, n=28) attending a university hospital foot unit. All participants were screened for obstructive sleep apnoea using the STOP-BANG questionnaire, with a score >=4 identifying high risk of obstructive sleep apnoea. The primary outcome was poor diabetic foot ulcer healing, defined as diabetic foot ulcer recurrence (diabetic foot ulcers which healed and re-ulcerated in same anatomical position) and/or diabetic foot ulcer persistence (no evidence of healing on clinical examination). All participants were evaluated at 12 months. RESULTS: Of the 94 participants, 60 (64%) had a STOP-BANG score >=4. Over 12 months, 27 participants with a score >=4 had poor diabetic foot ulcer healing as compared to seven with a score <4 (45% vs 20.5%; P=0.025). A STOP-BANG score >=4 significantly increased the relative risk of poor healing more than twofold, independently of other risk factors in multivariable analyses. CONCLUSIONS: There is a high prevalence of features and risk of obstructive sleep apnoea in people with diabetic foot ulcers. A STOP-BANG score >=4 predicts poor diabetic foot ulcer healing. Obstructive sleep apnoea may be a potential, modifiable risk factor/treatment target to improve diabetic foot ulcer outcomes. PMID- 30022523 TI - Presynaptic cannabinoid CB2 receptors modulate [3 H]-Glutamate release at subthalamo-nigral terminals of the rat. AB - Recent studies suggested the expression of CB2 receptors in neurons of the CNS, however, most of these studies have only explored one aspect of the receptors, i.e., expression of protein, messenger RNA, or functional response, and more complete studies appear to be needed to establish adequately their role in the neuronal function. Electron microscopy studies showed the presence of CB2r in asymmetric terminals of the substantia nigra pars reticulata (SNr), and its mRNA appeared is expressed in the subthalamic nucleus. Here, we explore the expression, source, and functional effects of such receptors by different experimental approaches. Through PCR and immunochemistry, we showed mRNA and protein for CB2rs in slices and primary neuronal cultures from subthalamus. GW833972A, GW405833, and JHW 133, three CB2r agonists dose-dependent inhibited K+ -induced [3 H]-Glutamate release in slices of SNr, and the two antagonist/inverse agonists, JTE-907 and AM630, but not AM281, a CB1r antagonist, prevented GW833972A effect. Subthalamus lesions with kainic acid prevented GW833972A inhibition on release and decreased CB2r protein in nigral synaptosomes, thus nigral CB2rs originate in subthalamus. Inhibition of [3 H]-Glutamate release was PTX- and gallein-sensitive, suggesting a Gibetagamma -mediated effect. P/Q Ca2+ type channel blocker, omega-Agatoxin-TK, also inhibited the [3 H]-Glutamate release, this effect was occluded with GW833972A inhibition, indicating that the betagamma subunit effect is exerted on Ca2+ channel activity. Finally, microinjections of GW833972A in SNr induced contralateral turning. Our data showed that presynaptic CB2rs inhibit [3 H]-Glutamate release in subthalamo nigral terminals by P/Q-channels modulation through the Gibetagamma subunit and suggested their participation in motor behavior. PMID- 30022525 TI - Correcting common misconceptions to inspire conservation action in urban environments. AB - Despite repeated calls to action, proposals for urban conservation are often met with surprise or scepticism. There remains a pervasive narrative in policy, practice, and the public psyche that urban environments, although useful for engaging people with nature or providing ecosystem services, are of little conservation value. We argue that the tendency to overlook the conservation value of urban environments stems from misconceptions about the ability of native species to persist within cities and towns and that this, in turn, hinders effective conservation action. However, recent scientific evidence shows that these assumptions do not always hold. Although it is generally true that increasing the size, quality, and connectivity of habitat patches will improve the probability that a species can persist, the inverse is not that small, degraded, or fragmented habitats found in urban environments are worthless. In light of these findings we propose updated messages that guide and inspire researchers, practitioners, and decision makers to undertake conservation action in urban environments: consider small spaces, recognize unconventional habitats, test creative solutions, and use science to minimize the impacts of future urban development. PMID- 30022526 TI - Successful antiviral therapy in patients with chronic hepatitis C virus infection and severe associated disease. PMID- 30022524 TI - Diabetes transition care and adverse events: a population-based cohort study in Ontario, Canada. AB - AIMS: To describe patterns of primary and diabetes care during transition age (17 to < 19 years) into early adulthood (age 19 to 26 years), and to evaluate the association of primary and diabetes care patterns during transition age with the risk of adverse events in early adulthood. METHODS: We conducted a population based cohort study of individuals in Ontario, Canada who were diagnosed with diabetes aged < 15 years and who turned 17 between November 2006 and March 2011, followed until March 2015 (n = 2525). Using linked administrative databases, we examined healthcare use during: 'pre-transition-age' (15 to < 17 years), 'transition-age' (17 to < 19 years), and 'early adulthood' (19 to 26 years). The main outcomes were time to death or ketoacidosis and rate of diabetes-related admissions. The main exposures were the gap in diabetes care and primary care visits during transition age. RESULTS: There were < 6 deaths and 446 individuals (17.7%) had at least one admission for ketoacidosis during early adulthood. In all, 1188 individuals (47.0%) had a > 12-month gap in diabetes care and 241 (9.5%) had no primary care visits during transition age. A gap in diabetes care of > 12 months and no primary care visits during transition age were associated with an increased risk of ketoacidosis or death (adjusted hazard ratio 1.31, 95% CI 1.04-1.66 and adjusted hazard ratio 1.42, 95% CI 1.02-1.97, respectively). CONCLUSIONS: In Ontario, Canada, where physician and hospital-based services are universally covered, a high proportion of young adults with diabetes have insufficient care during transition age and this is associated with a higher risk of important adverse outcomes in early adulthood. Ensuring primary care involvement during transition may be a strategy to reduce morbidity. PMID- 30022527 TI - Report from the American Society of Transplantation Psychosocial Community of Practice Adherence Task Force: Real-world options for promoting adherence in adult recipients. AB - Starting in 2015, the American Society of Transplantation Psychosocial Community of Practice, with representatives of the Transplant Pharmacy Community of Practice, convened a taskforce to develop a white paper that focused on clinically practical, evidenced-based interventions that transplant centers could implement to increase adherence to medication and behavioral recommendations in adult solid organ transplant recipients. The group focused on what centers could do in their daily routines to implement best practices to increase adherence in adult transplant recipients. We developed a list of strategies using available resources, clinically feasible methods of screening and tracking adherence, and activities that ultimately empower patients to improve their own self-management. We limited the target population to adults because they predominate the research, and because adherence issues differ in pediatric patients, given the necessary involvement of parents/guardians. We also examined broader multilevel areas for intervention including provider and transplant program practices. Ultimately, the task force aims to foster greater recognition, discussion, and solutions required for implementing practical interventions targeted at improving adherence. PMID- 30022529 TI - Intracoronary focal nitroglycerin injection through drilled balloon is very effective in the resolution of coronary spasm versus into proximal coronary artery: A prospective randomized comparison study. AB - BACKGROUND: In this study, we aimed to compare the effectiveness and safety of NTG administration via catheter and local NTG infusion through a perforated balloon in order to prevent coronary spasm from developing during percutaneous intervention. METHOD: The study began with 1:1 randomization into two groups of a total of 1688 patients scheduled for PCT. A total of 91 patients in the proximal group who developed lesions received 500 mcg NTG through a catheter, while 85 patients in the local group with lesions developed during the procedure received 500 mcg local NTG through a perforated balloon. After excluding patients who did not develop lesions during the procedure, and those without any change in the lesion with NTG application, the study was completed with 74 patients in the local group, and 70 patients in the proximal group. RESULTS: Both groups were similar in terms of basic characteristics. Incidences of procedure-related hypotension (10% vs 52%, P < 0.001) and tachycardia (20% vs 57%, P < 0.001) were significantly lower in the local NTG group. Success in addressing spasm was significantly higher in the local NTG than in the proximal NTG group (91.66 +/- 14.09% vs 75.99 +/- 16.86%, P < 0.001). DISCUSSION: Intracoronary injection with a perforated balloon, a simple technique introduced worldwide with our publication, can be used for administration of local NTG. Using this method, NTG can be better delivered with the perforated balloon to the vascular epithelium because of lower output, higher eruption rate, and perpendicularity to the endothelium. In this application, the balloon can better deliver drugs to the desired area via back-and-forth movements using a 0.014 guidewire. CONCLUSION: The local administration of NTG to a spasming area through a perforated balloon is more effective and safer than the proximal administration of NTG. PMID- 30022528 TI - Impact of material emissions and sorption of volatile organic compounds on indoor air quality in a low energy building: Field measurements and modeling. AB - The assessment of VOC emission rates and sorption coefficients was performed for ten surfaces present within a classroom, using field and laboratory emission cells (FLEC) coupled to online and off-line VOC quantification techniques. A total of 21 identified VOCs were emitted by the different surfaces. VOC emission rates measured using PTR-ToF-MS were compared to gas chromatographic measurements. The results showed that the two methods are complementary to one another. Sorption parameters were also successfully measured for a mixture of 14 VOCs within a few hours (<17 hours per surface). A study of the spatial and temporal variability of the measured parameters was also carried out on the two surfaces that presented the most potential for interaction with VOCs, accounting for the largest surface areas within the room. The dataset of emission rates and sorption parameters was used in the INCA-Indoor model to predict indoor air concentrations of VOCs that are compared to experimental values measured in the room. Modeling results showed that sorption processes had a limited effect on indoor concentrations of VOCs for these field campaigns. Modeled daily profiles show good agreement with the experimental observations for VOCs such as toluene (indoor source) and xylenes (outdoor source) but underestimate concentrations of methanol (both indoor and outdoor sources). PMID- 30022530 TI - Impact of donor coronary angiography on kidney transplantation outcomes. AB - Coronary angiography (CA) is the gold standard evaluation of coronary artery disease in potential multi-organ donors. This use of iodinated contrast media could lead to contrast-induced acute kidney injury and consequently to delayed graft function (DGF). All patients in France who received a kidney from a 45-70 year-old donor without medical contraindication for cardiac donation and with at least one cardiovascular risk factor were included. Recipients of preemptive kidney transplant or multi-organ transplant, or who died within the first 8 days post-transplantation were excluded. Data were obtained from CRISTAL database. From March 2012 to June 2014, 892 kidneys from 483 donors were transplanted. DGF was reported in 38.9% of the 375 kidney recipients grafted with a kidney from the 217 donors who had CA and in 45.5% of the 440 kidney recipients who received a kidney from the 257 donors without CA. Multivariate analysis showed that CA or repeated injection of iodinated contrast media did not influence the risk of DGF. CA did not increase the risk of primary non-function, the duration of DGF or post transplantation hospital stay and did not affect the graft function at 1 year. Evaluation of potential multi-organ donors with CA does not affect kidney graft outcomes. PMID- 30022531 TI - Empirical selection between least-cost and current-flow designs for establishing wildlife corridors in Gabon. AB - Corridors are intended to increase species survival by abating landscape fragmentation resulting from the conversion of natural habitats into human dominated matrices. Conservation scientists often rely on 1 type of corridor model, typically the least-cost model or current-flow model, to construct a linkage design, and their choice is not usually based on theory or empirical evidence. We developed a method to empirically confirm whether corridors produced by these 2 models are used by target species under current landscape conditions. We applied this method in the Gamba landscape between 2 national parks in southwestern Gabon. We collected signs of presence of African forest elephant (Loxodonta cyclotis), forest buffalo (Syncerus caffer nanus), and 2 apes, western lowland gorilla (Gorilla gorilla gorilla) and central chimpanzee (Pan troglodytes troglodytes), on transects. We used patch-occupancy models to identify least-cost and current-flow corridors for these 4 species. On average, 28.7% of current-flow corridors overlapped with least-cost corridors, confirming that the choice of corridor model can affect the location of the resulting linkage design. We validated these corridors by monitoring signs and examining camera detections on new transects within and outside modeled corridors. Current-flow corridors performed better than least-cost corridors for elephants, whereas the opposite was found for buffalo and apes. Locations of the highest priority corridors for the 3 taxa did not overlap, and only 18.3% of their combined surface was common among 2 species. We used centrality metrics to calculate the average contribution of corridor pixels to landscape connectivity and derived an index that can be used to prioritize corridors. As a result, we recommend protecting at least 17.4% of the land surface area around Gamba town to preserve the preferred travel routes of the target species. PMID- 30022532 TI - Lung transplant patients with coronary artery disease rarely die of cardiac causes. AB - BACKGROUND: A relative contraindication for lung transplant (LT) is coronary disease burden sufficient to cause risk of myocardial infarction after LT. We analyzed cause of death and outcomes of our LT patients with coronary artery disease (CAD). METHODS: Inpatient records from March 1, 2004, to January 31, 2015, were retrospectively examined and data of 306 LTs extracted. Twenty-five patients without coronary angiography (CA) and 7 with redo LTs were excluded. The other 274 patients were divided into 2 groups: CAD (n = 116) and no CAD (n = 158). Patients with prior revascularization or coronary stenosis >10% were placed into the CAD group. RESULTS: The CAD group was older and had more male patients, greater history of smoking and hypertension, and greater proportion of patients with interstitial lung disease than the no-CAD group. CAD patients were more likely to receive a single-lung transplant. Death of cardiac causes occurred for 2 patients (1.7%) in the CAD group and for 1 patient (0.6%) in the no-CAD group (P = 0.39). CONCLUSIONS: This analysis shows that compared with patients who have no CAD, patients with CAD have different demographic characteristics and receive more single-lung transplants. Incidence of death of cardiac causes is rare. PMID- 30022533 TI - Association between cytomegalovirus seropositivity and Type 2 diabetes is explained by age and other demographic characteristics: the National Health and Nutrition Examination Survey. AB - AIMS: To assess the association between cytomegalovirus and Type 2 diabetes among 6664 participants from the National Health and Nutrition Examination Survey. METHODS: We used existing data from adults aged 20-49 years who participated in the National Health and Nutrition Examination Survey from 1999 to 2004. Cytomegalovirus status was determined using cytomegalovirus-specific immunoglobulin G antibodies. Prevalent Type 2 diabetes was assessed through self report or a plasma fasting glucose of >=7 mmol/l. Logistic regression models were used to evaluate the association between Type 2 diabetes and cytomegalovirus seropositivity after adjustment for age, gender, race/ethnicity, smoking status, education, BMI and physical activity. RESULTS: In a univariate model, the crude odds of Type 2 diabetes were 47% higher in those who were cytomegalovirus seropositive vs cytomegalovirus-seronegative. The association was attenuated and no longer significant after adjustment for age and other covariates: the odds ratio for diabetes was 1.09 (95% CI 0.71 to 1.66) for cytomegalovirus seropositive vs -seronegative individuals. CONCLUSIONS: Our study suggests that the association between cytomegalovirus and Type 2 diabetes is explained by age and other risk factors for diabetes. PMID- 30022534 TI - High-Mobility Helical Tellurium Field-Effect Transistors Enabled by Transfer Free, Low-Temperature Direct Growth. AB - The transfer-free direct growth of high-performance materials and devices can enable transformative new technologies. Here, room-temperature field-effect hole mobilities as high as 707 cm2 V-1 s-1 are reported, achieved using transfer-free, low-temperature (<=120 degrees C) direct growth of helical tellurium (Te) nanostructure devices on SiO2 /Si. The Te nanostructures exhibit significantly higher device performance than other low-temperature grown semiconductors, and it is demonstrated that through careful control of the growth process, high performance Te can be grown on other technologically relevant substrates including flexible plastics like polyethylene terephthalate and graphene in addition to amorphous oxides like SiO2 /Si and HfO2 . The morphology of the Te films can be tailored by the growth temperature, and different carrier scattering mechanisms are identified for films with different morphologies. The transfer free direct growth of high-mobility Te devices can enable major technological breakthroughs, as the low-temperature growth and fabrication is compatible with the severe thermal budget constraints of emerging applications. For example, vertical integration of novel devices atop a silicon complementary metal oxide semiconductor platform (thermal budget <450 degrees C) has been theoretically shown to provide a 10* systems level performance improvement, while flexible and wearable electronics (thermal budget <200 degrees C) can revolutionize defense and medical applications. PMID- 30022535 TI - Mechanically Robust Atomic Oxygen-Resistant Coatings Capable of Autonomously Healing Damage in Low Earth Orbit Space Environment. AB - Polymeric materials used in spacecraft require to be protected with an atomic oxygen (AO)-resistant layer because AO can degrade these polymers when spacecraft serves in low earth orbit (LEO) environment. However, mechanical damage on AO resistant coatings can expose the underlying polymers to AO erosion, shortening their service life. In this study, the fabrication of durable AO-resistant coatings that are capable of autonomously healing mechanical damage under LEO environment is presented. The self-healing AO-resistant coatings are comprised of 2-ureido-4[1H]-pyrimidinone (UPy)-functionalized polyhedral oligomeric silsesquioxane (POSS) (denoted as UPy-POSS) that forms hydrogen-bonded three dimensional supramolecular polymers. The UPy-POSS supramolecular polymers can be conveniently deposited on polyimides by a hot pressing process. The UPy-POSS polymeric coatings are mechanically robust, thermally stable, and transparent and have a strong adhesion toward polyimides to endure repeated bending/unbending treatments and thermal cycling. The UPy-POSS polymeric coatings exhibit excellent AO attack resistance because of the formation of epidermal SiO2 layer after AO exposure. Due to the reversibility of the quadruple hydrogen bonds between UPy motifs, the UPy-POSS polymeric coatings can rapidly heal mechanical damage such as cracks at 80 degrees C or under LEO environment to restore their original AO resistant function. PMID- 30022536 TI - Recent Progress in High-Mobility Organic Transistors: A Reality Check. AB - Over the past three decades, significant research efforts have focused on improving the charge carrier mobility of organic thin-film transistors (OTFTs). In recent years, a commonly observed nonlinearity in OTFT current-voltage characteristics, known as the "kink" or "double slope," has led to widespread mobility overestimations, contaminating the relevant literature. Here, published data from the past 30 years is reviewed to uncover the extent of the field-effect mobility hype and identify the progress that has actually been achieved in the field of OTFTs. Present carrier-mobility-related challenges are identified, finding that reliable hole and electron mobility values of 20 and 10 cm2 V-1 s-1 , respectively, have yet to be achieved. Based on the analysis, the literature is then reviewed to summarize the concepts behind the success of high-performance p type polymers, along with the latest understanding of the design criteria that will enable further mobility enhancement in n-type polymers and small molecules, and the reasons why high carrier mobility values have been consistently produced from small molecule/polymer blend semiconductors. Overall, this review brings together important information that aids reliable OTFT data analysis, while providing guidelines for the development of next-generation organic semiconductors. PMID- 30022537 TI - FENS-Kavli winter symposium: Review and perspectives on neurological diseases. AB - The FENS-Kavli winter symposium was held in December, 2017 at the Institute of Science and Technology, Austria. This short report reviews the session on neurological disorders, which included presentations on recent research into chronic pain, demyelinating disease, Alzheimer's disease and autism spectrum disorder. Key advances, emerging themes and major challenges remaining in the field are discussed. PMID- 30022538 TI - First homozygous large deletion in EDARADD gene associated with a severe form of anhidrotic ectodermal dysplasia. PMID- 30022539 TI - Hierarchically Porous Fe2 CoSe4 Binary-Metal Selenide for Extraordinary Rate Performance and Durable Anode of Sodium-Ion Batteries. AB - Owing to high energy capacities, transition metal chalcogenides have drawn significant research attention as the promising electrode materials for sodium ion batteries (SIBs). However, limited cycle life and inferior rate capabilities still hinder their practical application. Improvement of the intrinsic conductivity by smart choice of elemental combination along with carbon coupling of the nanostructures may result in excellence of rate capability and prolonged cycling stability. Herein, a hierarchically porous binary transition metal selenide (Fe2 CoSe4 , termed as FCSe) nanomaterial with improved intrinsic conductivity was prepared through an exclusive methodology. The hierarchically porous structure, intimate nanoparticle-carbon matrix contact, and better intrinsic conductivity result in extraordinary electrochemical performance through their synergistic effect. The synthesized FCSe exhibits excellent rate capability (816.3 mA h g-1 at 0.5 A g-1 and 400.2 mA h g-1 at 32 A g-1 ), extended cycle life (350 mA h g-1 even after 5000 cycles at 4 A g-1 ), and adequately high energy capacity (614.5 mA h g-1 at 1 A g-1 after 100 cycles) as anode material for SIBs. When further combined with lab-made Na3 V2 (PO4 )3 /C cathode in Na-ion full cells, FCSe presents reasonably high and stable specific capacity. PMID- 30022540 TI - Macaque parvocellular mediodorsal thalamus: dissociable contributions to learning and adaptive decision-making. AB - Distributed brain networks govern adaptive decision-making, new learning and rapid updating of information. However, the functional contribution of the rhesus macaque monkey parvocellular nucleus of the mediodorsal thalamus (MDpc) in these key higher cognitive processes remains unknown. This study investigated the impact of MDpc damage in cognition. Preoperatively, animals were trained on an object-in-place scene discrimination task that assesses rapid learning of novel information within each session. Bilateral neurotoxic (NMDA and ibotenic acid) MDpc lesions did not impair new learning unless the monkey had also sustained damage to the magnocellular division of the MD (MDmc). Contralateral unilateral MDpc and MDmc damage also impaired new learning, while selective unilateral MDmc damage produced new learning deficits that eventually resolved with repeated testing. In contrast, during food reward (satiety) devaluation, monkeys with either bilateral MDpc damage or combined MDpc and MDmc damage showed attenuated food reward preferences compared to unoperated control monkeys; the selective unilateral MDmc damage left performance intact. Our preliminary results demonstrate selective dissociable roles for the two adjacent nuclei of the primate MD, namely, MDpc, as part of a frontal cortical network, and the MDmc, as part of a frontal-temporal cortical network, in learning, memory and the cognitive control of behavioural choices after changes in reward value. Moreover, the functional cognitive deficits produced after differing MD damage show that the different subdivisions of the MD thalamus support distributed neural networks to rapidly and fluidly incorporate task-relevant information, in order to optimise the animals' ability to receive rewards. PMID- 30022541 TI - Performance Improvements in Conjugated Polymer Devices by Removal of Water Induced Traps. AB - The exploration of a wide range of molecular structures has led to the development of high-performance conjugated polymer semiconductors for flexible electronic applications including displays, sensors, and logic circuits. Nevertheless, many conjugated polymer field-effect transistors (OFETs) exhibit nonideal device characteristics and device instabilities rendering them unfit for industrial applications. These often do not originate in the material's intrinsic molecular structure, but rather in external trap states caused by chemical impurities or environmental species such as water. Here, a highly efficient mechanism is demonstrated for the removal of water-induced traps that are omnipresent in conjugated polymer devices even when processed in inert environments; the underlying mechanism is shown, by which small-molecular additives with water-binding nitrile groups or alternatively water-solvent azeotropes are capable of removing water-induced traps leading to a significant improvement in OFET performance. It is also shown how certain polymer structures containing strong hydrogen accepting groups will suffer from poor performances due to their high susceptibility to interact with water molecules; this allows the design guidelines for a next generation of stable, high-performing conjugated polymers to be set forth. PMID- 30022542 TI - Biofilm production and antibiotic susceptibility of Staphylococcus epidermidis strains from Hidradenitis Suppurativa lesions. AB - BACKGROUND: An aberrant interaction between commensal skin bacteria and the host skin immune system is considered important in the pathogenesis of hidradenitis suppurativa (HS). OBJECTIVE: In this study, we investigated the antibiotic susceptibility and biofilm-forming capabilities of S. epidermidis strains isolated from HS patients. METHODS: Skin biopsies were taken from active HS lesions such as inflammatory nodules and/or sinuses and non-involved skin from 26 patients and cultured under optimal microbiological conditions for 24 h. Planktonic growth, biofilm production, antibiotic susceptibility and biofilm eradication by clindamycin, doxycycline, rifampicin and tetracycline were tested including a laboratory control strain of S. epidermidis for reference. RESULTS: Staphylococcus epidermidis was cultured in 16 of 26 HS patients (62%). In total 27 different S. epidermidis isolates were identified; 16 (59%) from non-involved skin and 11 (41%) from HS lesions. All bacterial strains showed planktonic growth. Twenty-four of 27 (89%) isolates were strong biofilm producers in vitro. The biofilm-forming capability varied amongst the strains from non-involved skin and lesional skin. Twenty-four strains had an intermediate to resistant antibiotic susceptibility to clindamycin (89%). Rifampicin was the most effective antibiotic at inhibiting planktonic growth and at eradication of biofilm (P < 0.05). CONCLUSION: We observed a slight increase in S. epidermidis virulence, characterized by resistance to commonly used antibiotics, increased biofilm production and resistance to biofilm eradication. In particular, the reduced sensitivity to tetracycline and clindamycin, two standard antibiotics in the treatment of HS, is alarming. Rifampicin, also important in HS treatment, showed the greatest efficacy at eradicating the biofilm at low MIC concentrations. PMID- 30022544 TI - A randomized, intraindividual, non-inferiority, Phase III study comparing daylight photodynamic therapy with BF-200 ALA gel and MAL cream for the treatment of actinic keratosis. AB - BACKGROUND: The most effective treatment modality for actinic keratosis (AK) is photodynamic therapy (PDT). Major obstacles of PDT are the need of a special illumination device and pain accompanying the illumination. These issues may be overcome by replacing an artificial high-power light source with natural daylight for more extended illumination at lower light doses. OBJECTIVE: To determine whether BF-200 ALA (a nanoemulsion gel containing 7.8% 5-aminolaevulinic acid) is non-inferior to MAL (a cream containing 16% methyl-aminolaevulinate) in the treatment of mild-to-moderate AK with daylight PDT (dPDT). Non-inferiority of the primary efficacy variable (total lesion clearance rate per patient's side 12 weeks after PDT) is established if the mean response for BF-200 ALA is no worse than for MAL, within a statistical margin of Delta = -12.5%. METHODS: The study was performed as an intraindividual comparison with 52 patients in seven centres in Germany and Spain. Each patient received one dPDT. Results include clinical endpoints as well as 1-year follow-up results. RESULTS: Twelve weeks after a single dPDT, 79.8% of the AK lesions treated with BF-200 ALA gel and 76.5% of the lesions treated with MAL cream were completely cleared. The median of differences was 0.0 with a one-sided 97.5% CI of 0.0, establishing non-inferiority (P < 0.0001). Results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 1 year after the treatment were 19.9% for lesions treated with BF-200 ALA and 31.6% for lesions treated with MAL. Adverse reactions including pain were mostly mild and transient and identical to those previously described for dPDT. CONCLUSION: Daylight PDT of AK with BF-200 ALA is well tolerated and non-inferior to MAL/dPDT. The study demonstrates a trend towards higher efficacies after 3 months and significantly lower recurrence rates after 1 year follow-up. PMID- 30022545 TI - Active Materials for Organic Electrochemical Transistors. AB - The organic electrochemical transistor (OECT) is a device capable of simultaneously controlling the flow of electronic and ionic currents. This unique feature renders the OECT the perfect technology to interface man-made electronics, where signals are conveyed by electrons, with the world of the living, where information exchange relies on chemical signals. The function of the OECT is controlled by the properties of its core component, an organic conductor. Its chemical structure and interactions with electrolyte molecules at the nanoscale play a key role in regulating OECT operation and performance. Herein, the latest research progress in the design of active materials for OECTs is reviewed. Particular focus is given on the conducting polymers whose properties lead to advances in understanding the OECT working mechanism and improving the interface with biological systems for bioelectronics. The methods and device models that are developed to elucidate key relations between the structure of conducting polymer films and OECT function are discussed. Finally, the requirements of OECT design for in vivo applications are briefly outlined. The outcomes represent an important step toward the integration of organic electronic components with biological systems to record and modulate their functions. PMID- 30022543 TI - Design of a forward view antenna for prostate imaging at 7 T. AB - PURPOSE: To design a forward view antenna for prostate imaging at 7 T, which is placed between the legs of the subject in addition to a dipole array. MATERIALS AND METHODS: The forward view antenna is realized by placing a cross-dipole antenna at the end of a small rectangular waveguide. Quadrature drive of the cross-dipole can excite a circularly polarized wave propagating along the axial direction to and from the prostate region. Functioning of the forward view antenna is validated by comparing measurements and simulations. Antenna performance is evaluated by numerical simulations and measurements at 7 T. RESULTS: Simulations of B1+ on a phantom are in good correspondence with measurements. Simulations on a human model indicate that the signal-to-noise ratio (SNR), specific absorption rate (SAR) efficiency and SAR increase when adding the forward view antenna to a previously published dipole array. The SNR increases by up to 18% when adding the forward view antenna as a receive antenna to an eight-channel dipole array in vivo. CONCLUSIONS: A design for a forward view antenna is presented and evaluated. SNR improvements up to 18% are demonstrated when adding the forward view antenna to a dipole array. PMID- 30022546 TI - Development and validation of a new tool to assess the Burden of Sensitive Skin (BoSS). AB - BACKGROUND: Sensitive skin usually manifests itself as unpleasant sensations and sometimes erythema. There are various triggering factors for this condition. Although sensitive skin may alter quality of life, its burden has not yet been explored. OBJECTIVE: The aim of this study was to develop and validate a specific sensitive skin burden questionnaire called the BoSS (Burden of Sensitive Skin). METHODS: A conceptual phase was developed, followed by a development phase, external validation, psychometric analysis, test-retest analysis and, finally, a translation, cross-cultural adaptation and cognitive debriefing. RESULTS: A total of 6471 individuals participated in the study (4614 people in the validation study). The dimensionality of items was evaluated using factor analyses, suggesting three dimensions (self-care, daily life and appearance). Unidimensionality was confirmed by higher order factor analysis. The overall Cronbach's alpha coefficient was high, and intradimensional coherences all demonstrated good reliability. The final instrument consisted of 14 items. The test-retest reliability demonstrated very good reproducibility. The intraclass correlation of each dimension was high. External validity was confirmed by the correlation coefficients of the BoSS vs. those of the SF-12 and the DLQI assessment tools. CONCLUSION: BoSS is the first reliable tool to assess the burden of sensitive skin. PMID- 30022547 TI - Repurposing an established drug: an emerging role for methylene blue in L-DOPA induced dyskinesia. AB - The nitric oxide (NO) system has been proven to be a valuable modulator of L-DOPA induced dyskinesia in Parkinsonian rodents. NO activates the enzyme soluble guanylyl cyclase and elicits the synthesis of the second-messenger cGMP. Although we have previously described the anti-dyskinetic potential of NO synthase inhibitors on L-DOPA-induced dyskinesia, the effect of soluble guanylyl cyclase inhibitors remains to be evaluated. The aim of this study was to analyze whether the clinically available non-selective inhibitor methylene blue, or the selective soluble guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1 one), could mitigate L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Here, we demonstrated that methylene blue was able to reduce L-DOPA-induced dyskinesia incidence when chronically co-administered with L-DOPA during 3 weeks. Methylene blue chronic (but not acute) administration (2 weeks) was effective in attenuating L-DOPA-induced dyskinesia in rats rendered dyskinetic by a previous course of L-DOPA chronic treatment. Furthermore, discontinuous methylene blue treatment (e.g., co-administration of methylene blue and L-DOPA for 2 consecutive days followed by vehicle and L-DOPA co-administration for 5 days) was effective in attenuating dyskinesia. Finally, we demonstrated that microinjection of methylene blue or ODQ into the lateral ventricle effectively attenuated L-DOPA induced dyskinesia. Taken together, these results demonstrate an important role of NO-soluble guanylyl cyclase-cGMP signaling on L-DOPA-induced dyskinesia. The clinical implications of this discovery are expected to advance the treatment options for patients with Parkinson's disease. PMID- 30022548 TI - Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5-day repeated sessions study. AB - Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a "build-up" effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30 min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5 days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day to-day was low in both groups, implying high within-subject variability of both active and sham iTBS after-effects. In contrast, we found a high within-subject repeatability of resting and active motor threshold, and baseline motor-evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5 days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols. PMID- 30022549 TI - Normal-phase versus reversed-phase thin-layer chromatography (TLC) to monitor oxidized phosphatidylcholines by TLC/mass spectrometry. AB - RATIONALE: Normal-phase thin-layer chromatography (NP-TLC) is an established method for the separation of all major phospholipid classes according to the different polarities of the head groups. In contrast, reversed-phase (RP)-TLC is much less frequently used for this purpose. This study aimed to compare the NP and the RP approach regarding their separation potential of phospholipid oxidation products. METHODS: Commercially available 1-palmitoyl-2-oleoyl-sn phosphatidylcholine (POPC) (PC 16:0/18:1) and 1-palmitoyl-2-linoleoyl-sn phosphatidylcholine (PLPC) (PC 16:0/18:2) were oxidized by NaMnO4 . Oxidation products were subsequently separated by NP- and RP-TLC and analyzed by electrospray ionization mass spectrometry. RESULTS: In comparison with NP-TLC, RP TLC was clearly superior regarding the separation of oxidation products of phospholipids. RP-TLC enabled the separation not only of primary oxidation products of POPC such as alcohols and ketones but also of secondary oxidation products. Furthermore some oxidation products, such as aldehydes, were only detectable by ESI after RP-TLC but not after NP-TLC. CONCLUSIONS: RP-TLC is the method of choice to characterize oxidized PL such as oxidized phosphatidylcholines. PMID- 30022551 TI - Enigma portal case: Thyroid FNA. PMID- 30022550 TI - Assessing high-intensity focused ultrasound treatment of prostate cancer with hyperpolarized 13 C dual-agent imaging of metabolism and perfusion. AB - The goal of the study was to establish early hyperpolarized (HP) 13 C MRI metabolic and perfusion changes that predict effective high-intensity focused ultrasound (HIFU) ablation and lead to improved adjuvant treatment of partially treated regions. To accomplish this a combined HP dual-agent (13 C pyruvate and 13 C urea) 13 C MRI/multiparametric 1 H MRI approach was used to measure prostate cancer metabolism and perfusion 3-4 h, 1 d, and 5 d after exposure to ablative and sub-lethal doses of HIFU within adenocarcinoma of mouse prostate tumors using a focused ultrasound applicator designed for murine studies. Pathologic and immunohistochemical analysis of the ablated tumor demonstrated fragmented, non viable cells and vasculature consistent with coagulative necrosis, and a mixture of destroyed tissue and highly proliferative, poorly differentiated tumor cells in tumor tissues exposed to sub-lethal heat doses in the ablative margin. In ablated regions, the intensity of HP 13 C lactate or HP 13 C urea and dynamic contrast-enhanced (DCE) MRI area under the curve images were reduced to the level of background noise by 3-4 h after treatment with no recovery by the 5 d time point in either case. In the tissues that received sub-lethal heat dose, there was a significant 60% +/- 12.4% drop in HP 13 C lactate production and a significant 30 +/- 13.7% drop in urea perfusion 3-4 h after treatment, followed by recovery to baseline by 5 d after treatment. DCE MRI Ktrans showed a similar trend to HP 13 C urea, demonstrating a complete loss of perfusion with no recovery in the ablated region, while having a 40%-50% decrease 3-4 h after treatment followed by recovery to baseline values by 5 d in the margin region. The utility of the HP 13 C MR measures of perfusion and metabolism in optimizing focal HIFU, either alone or in combination with adjuvant therapy, deserves further testing in future studies. PMID- 30022552 TI - Non-Covalently Pre-Assembled High-Performance Near-Infrared Fluorescent Molecular Probes for Cancer Imaging. AB - New fluorescent molecular probes, which can selectively target specific cell surface receptors, are needed for microscopy, in vivo imaging, and image guided surgery. The preparation of multivalent probes using standard synthetic chemistry can be a laborious process due to low reaction yields caused by steric effects. In this study, fluorescent molecular probes were prepared by a programmed non covalent pre-assembly process that used a near-infrared fluorescent squaraine dye to thread a macrocycle bearing a cyclic arginine-glycine-aspartate peptide antagonist (cRGDfK) as a cancer targeting unit. Cell microscopy studies using OVCAR-4 (ovarian cancer) and A549 (lung cancer) cells that express high levels of the integrin alphavbeta3 or alphavbeta5 receptors, respectively, revealed a multivalent cell targeting effect. That is, there was comparatively more cell uptake of a pre-assembled probe equipped with two copies of the cRGDfK antagonist than a pre-assembled probe with only one appended cRGDfK antagonist. The remarkably high photostability and low phototoxicity of these near-infrared probes allowed for acquisition of long-term fluorescence movies showing endosome trafficking in living cells. In vivo near-infrared fluorescence imaging experiments compared the biodistribution of a targeted and untargeted probe in a xenograft mouse tumor model. The average tumor-to-muscle ratio for the pre assembled targeted probe was 3.6 which matches the tumor targeting performance reported for analogous cRGDfK-based probes that were prepared entirely by covalent synthesis. The capability to excite these pre-assembled near-infrared fluorescent probes with blue or deep-red excitation light makes it possible to determine if a target site is located superficially or buried in tissue, a probe performance feature that is likely to be very helpful for eventual applications such as fluorescence guided surgery. PMID- 30022553 TI - Bifunctional Separator Coated with Hexachlorocyclotriphosphazene/Reduced Graphene Oxide for Enhanced Performance of Lithium-Sulfur Batteries. AB - Although extensive research has been performed in the field of Li-S rechargeable batteries, commercial applications are still hindered by the dissolution of the reaction intermediates of lithium polysulfides (LiPSs). Through the combination of experimental and theoretical results, a bifunctional separator has been designed by coating hexachlorocyclotriphosphazene (HCCP)-decorated reduced graphene oxide (rGO), which provides effective anchor sites for immobilizing the LiPSs. LiPSs can be adsorbed on the HCCP/rGO surface with moderate binding strength, and their structures and the electrical conductivity of HCCP/rGO are well maintained. The synergetic effect of the effective barrier and good electrical conductivity within the HCCP/rGO sheets efficiently anchors LiPSs and achieves enhanced electrochemical performance. More importantly, different substituents can be used to tune the immobilization of LiPSs by HCCP derivatives. Therefore, it is expected that HCCP and its derivatives can be utilized as a promising anchoring material for high-performance Li-S batteries. PMID- 30022554 TI - Revealing the potential of capillary electrophoresis/mass spectrometry: the tipping point. AB - The hyphenation of capillary electrophoresis and mass spectrometry (CE/MS) remains a minor technique compared with liquid chromatography/mass spectrometry (LC/MS), which represents nowadays the standard instrumentation, regardless of its introduction thirty years ago. However, from a theoretical point of view, CE coupling should be quite favorable especially with electrospray ionization mass spectrometry (ESI-MS). At the time, the sensitivity provided by CE/MS was often limited, due to hyphenation requirements, which at some point appeared to disqualify CE/MS from benefiting from the performance gain driving the evolution of MS instruments. However, this context has been significantly modified in a matter of a few years. The development of innovative CE/MS interfacing systems has enabled an important improvement regarding sensitivity and reinforced robustness in order to provide an instrumentation accessible to the largest scientific community. Because of the unique selectivity delivered by the electrophoretic separation, CE/MS has proved to be particularly relevant for the analysis of biological molecules. The conjunction of these aspects is motivating the interest in CE/MS analysis and shows that CE/MS is mature enough to enrich the toolbox of analytical techniques for the analysis of complex biological samples. Here we discuss the characteristics of the major types of high sensitivity CE/ESI-MS instrumentation and emphasize the late evolution and future positioning of CE/MS analysis for the characterization of biological molecules like peptides and proteins, through some pertinent applications. PMID- 30022555 TI - Favre-Racouchot disease: systematic review and possible therapeutic strategies. AB - Favre-Racouchot disease (FRD) is a relatively common dermatosis induced by chronic sun exposure. FRD is clinically and histologically characterized by the presence of both comedones and cysts in the context of an elastotic degeneration of the dermis. Those lesions are mainly located in the face, especially in the malar and periorbital areas. Smoking and radiotherapy seem to play a role in the pathogenesis together with UV exposure. The disease affects predominantly the aged population and seems to be a problem of mainly aesthetic concern. No official guidelines are available for the treatment of FRD; most common therapeutic strategies are represented by topical retinoids and laser treatments. The goal of our review was to identify the principal clinical and epidemiological characteristics of FRD and to analyse all the therapeutic strategies available. We also focused our attention on the follow-up of this particular dermatosis. Our aim was therefore to suggest alternative possible strategies for both the treatment and the follow-up of these patients. Our data support the efficacy of carbon dioxide laser and topical retinoids in the setting of FRD, but we also suggest considering alternative treatments, such as plasma exeresis. We also recommend planning both a short-term and a long-term follow-up visit, as the majority of relapses is observed after 10-12 months. PMID- 30022556 TI - The health effects of smoking bans: Evidence from German hospitalization data. AB - This paper studies the short-term impact of public smoking bans on hospitalizations in Germany. It exploits the staggered implementation of smoking bans over time and across the 16 federal states along with the universe of hospitalizations from 2000 to 2008 and daily county-level weather and pollution data. Smoking bans in bars and restaurants have been effective in preventing 1.9 hospital admissions (-2.1%) due to cardiovascular diseases per day, per 1 million population. We also find a decrease by 0.5 admissions (-6.5%) due to asthma per day, per 1 million population. The health prevention effects are more pronounced on sunny days and days with higher ambient pollution levels. PMID- 30022557 TI - Optimizing an algorithm for the identification and classification of pregnancy outcomes in German claims data. AB - PURPOSE: For studying drug utilization and safety in pregnancy based on administrative health care data, the reliable identification and classification of pregnancy outcomes in the data is essential. We aimed to optimize an existing algorithm for the identification and classification of pregnancy outcomes in the German Pharmacoepidemiological Research Database (GePaRD) with a particular focus on births. METHODS: We reconsidered all codes used by the original algorithm and applied it to data of GePaRD from 2006 to 2014. Longitudinal records of pregnancies were used to identify targets for enhancing the algorithm's specificity. We checked the plausibility of the results, eg, regarding the age distribution of persons with pregnancy outcomes. Based on 20 longitudinal records of pregnancies, we compared the outcome classification by clinical experts with the results of the modified algorithm. RESULTS: Our algorithm identified 1 235 261 pregnancy outcomes in the database, with the majority (94%) being live births, classified as preterm (10%), term (78%), and (12%) births after the expected delivery date. The median age of pregnant women was 32 years (Q1 28; Q3 35). Implausible sequence of outcomes (for example, an induced abortion within a pregnancy categorized as ending in a live birth) were rare (0.03%). The case profile review by clinical experts resulted in the same outcome type and date as the algorithm in 95%. CONCLUSIONS: Our algorithm led to plausible results regarding the identification and classification of pregnancy outcomes. It will be an important foundation for studies on drug utilization and drug safety during pregnancy based on GePaRD. PMID- 30022559 TI - Fetal blood gases at fetoscopic myelomeningocele repair. PMID- 30022560 TI - Validation studies of claims data in the Asia-Pacific region: A comprehensive review. AB - PURPOSE: To describe published validation studies of administrative health care claims data in the Asia-Pacific region. METHODS: A comprehensive literature search was conducted in PubMed for English language articles published through 31 Oct-2017 in humans from 10 Asian-Pacific countries or regions (Japan, Australia, New Zealand, China, Hong Kong, India, Singapore, South Korea, Taiwan, and Thailand) that validated claims-based diagnoses with a gold standard data source. Search terms included the: validation, validity, accuracy, sensitivity, agreement, specificity, positive predictive value, kappa, kappa coefficient, and Cohen's kappa. RESULTS: Forty-three studies across six countries were identified: Australia (21); Japan (6); South Korea (6); Taiwan (7); Singapore (2); and New Zealand (1). Gold standard diagnoses were obtained from: medical records (18); registry data (11); self-reported questionnaires (5); and other data sources (9). Validity measures used included sensitivity, specificity, positive and negative predictive values (12); sensitivity, specificity, and positive predictive value (4); sensitivity and specificity (4); sensitivity and positive predictive value (4); and combinations of other measures (19). Validated outcomes included medical conditions (28); disease-specific comorbidities (8); death, smoking, and other (ie, injury, hospital outcome measures) (5); medication/transfusion (2). Approximately 72% of the studies were published within the last 5 years. CONCLUSIONS: Validation studies of claims data published in the English language in the Asia-Pacific region are very limited. Given the increased reliance on administrative health care databases for pharmacoepidemiology and the need for ensuring the credibility of results from such data, additional support for the conduct of validation research of claims data in the Asia-Pacific region is needed. PMID- 30022562 TI - Reply. PMID- 30022558 TI - Long noncoding RNA n339260 promotes vasculogenic mimicry and cancer stem cell development in hepatocellular carcinoma. AB - Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. Cancer stem cells (CSC) represent a subpopulation of tumor cells endowed with the capacity for self renewal and multilineage differentiation. Previous studies have indicated that CSC may participate in the formation of VM. With the advance of high-resolution microarrays and massively parallel sequencing technology, long noncoding RNAs (lncRNAs) are suggested to play a critical role in tumorigenesis and, in particular, the development of human hepatocellular carcinoma (HCC). Currently, no definitive relationship between lncRNA and VM formation has been described. In the current study, we demonstrated that expression of the lncRNA, n339260, is associated with CSC phenotype in HCC, and n339260 level correlated with VM, metastasis, and shorter survival time in an animal model. Overexpression of n339260 in HepG2 cells was associated with a significant increase in CSC. Additionally, the appearance of VM and vascular endothelial (VE)-cadherin, a molecular marker of VM, was also induced by n339260 overexpression. Using a short hairpin RNA approach, n339260 was silenced in tumor cells, and knockdown of n339260 was associated with reduced VM and CSC. The results of this study indicate that n339260 promotes VM, possibly by the development of CSC. The related molecular pathways may be used as novel therapeutic targets for the inhibition of HCC angiogenesis and metastasis. PMID- 30022563 TI - New challenges in psycho-oncology: Neural regulation of the cancer genome. PMID- 30022561 TI - Comparison of privacy-protecting analytic and data-sharing methods: A simulation study. AB - PURPOSE: Privacy-protecting analytic and data-sharing methods that minimize the disclosure risk of sensitive information are increasingly important due to the growing interest in utilizing data across multiple sources. We conducted a simulation study to examine how avoiding sharing individual-level data in a distributed data network can affect analytic results. METHODS: The base scenario had four sites of varying sizes with 5% outcome incidence, 50% treatment prevalence, and seven confounders. We varied treatment prevalence, outcome incidence, treatment effect, site size, number of sites, and covariate distribution. Confounding adjustment was conducted using propensity score or disease risk score. We compared analyses of three types of aggregate-level data requested from sites: risk-set, summary-table, or effect-estimate data (meta analysis) with benchmark results of analysis of pooled individual-level data. We assessed bias and precision of hazard ratio estimates as well as the accuracy of standard error estimates. RESULTS: All the aggregate-level data-sharing approaches, regardless of confounding adjustment methods, successfully approximated pooled individual-level data analysis in most simulation scenarios. Meta-analysis showed minor bias when using inverse probability of treatment weights (IPTW) in infrequent exposure (5%), rare outcome (0.01%), and small site (5,000 patients) settings. SE estimates became less accurate for IPTW risk-set approach with less frequent exposure and for propensity score-matching meta analysis approach with rare outcomes. CONCLUSIONS: Overall, we found that we can avoid sharing individual-level data and obtain valid results in many settings, although care must be taken with meta-analysis approach in infrequent exposure and rare outcome scenarios, particularly when confounding adjustment is performed with IPTW. PMID- 30022564 TI - Reliability of parent report measures of behaviour in children with Down syndrome. AB - BACKGROUND: Behavioural problems are common among children with Down syndrome (DS). Tools to detect and evaluate maladaptive behaviours have been developed for typically developing children and have been evaluated for use among children with intellectual and developmental disabilities. However, these measures have not been evaluated for use specifically in children with DS. This psychometric evaluation is important given that some clinically observed behaviours are not addressed in currently available rating scales. The current study evaluates the psychometric properties of the Child Behavior Checklist (CBCL), a commonly used screening tool developed for typically developing children and commonly used with children with intellectual and developmental disabilities. METHODS: The study investigated the psychometric properties of the CBCL among school-aged children with DS, including an assessment of the rate of detecting behaviour problems, concerns with distribution, internal consistency, inter-rater reliability and convergent and discriminant validity with the Aberrant Behavior Checklist and Nisonger Child Behavior Rating Form. Caregivers of 88 children with DS aged 6-18 years rated their child's behaviour with the CBCL, Aberrant Behavior Checklist and Nisonger Child Behavior Rating Form. Teachers completed the Teacher Report Form. RESULTS: About one-third of children with DS were reported to exhibit behaviours of clinical concern on the total score of the CBCL. Internal consistency for CBCL sub-scales was poor to excellent, and inter-rater reliability was generally acceptable. The sub-scales of the CBCL performed best when evaluating convergent validity, with variable discriminant validity. Normative data conversions controlled for age and gender differences in this sample. CONCLUSIONS: The study findings suggest that, among children with DS, some CBCL sub-scales generally performed in a psychometrically sound and theoretically appropriate manner in relation to other measures of behaviour. Caution is warranted when interpreting specific sub-scales (Anxious/Depressed, Somatic Complaints and Thought Problems). The CBCL can continue to be used as a screening measure when evaluating behavioural concerns among children with DS, acknowledging poor discriminant validity and the possibility that key behaviour concerns in DS may not be captured by the CBCL screen. PMID- 30022566 TI - Glycine receptors are involved in hippocampal neuronal damage caused by oxygen glucose deficiency. AB - Glycine receptors (GlyRs) belong to the family of ligand-gated cys-loop receptors and effectuate fast inhibitory neurotransmission in central nervous system (CNS). They are involved in numerous physiological processes, such as movement, respiration, and processing of sensory information, as well as in regulation of neuronal excitability in different brain regions. GlyRs play important role in the maintenance of excitatory/inhibitory balance in the hippocampus and participate in the development of various brain pathologies. In the present study, we have examined a surface expression of GlyRs by pyramidal neurons and astrocytes in control and after 30 min of oxygen-glucose deprivation (OGD) in the organotypic culture of hippocampal slices. Our investigation has demonstrated a decrease in GlyR-positive staining associated with pyramidal neurons and relative stability of GlyRs expression at the surface of astrocytes 4 hs after OGD. These data indicate that GlyRs dysfunction may represent a significant additional factor leading to enhanced neuronal damage induced by OGD. Pharmacological modulation of GlyRs is a promising venue of research for the correction of negative consequences of oxygen-glucose deficiency. PMID- 30022565 TI - Altered editing level of microRNAs is a potential biomarker in lung adenocarcinoma. AB - Adenosine-to-inosine (A-to-I) microRNA editing is associated with tumor phenotypes in various cancer types. Recent analyses of The Cancer Genome Atlas (TCGA) dataset have shown several microRNAs that undergo A-to-I editing in human cancers, some of which have been reported to be associated with prognosis. Herein, we examined published small RNA deep sequencing data of 74 cases of lung adenocarcinoma (AD) and the corresponding normal counterpart (NC) specimen in silico in order to identify A-to-I microRNA editing events. Editing levels of miR 379-5p, miR-99a-5p, and miR-497-5p were lower in AD than in NC and, in a large number of cases, the editing level of miR-200b-3p was higher in AD than in NC. Difference in the editing level between AD and NC was largest for miR-99a-5p. Then, we examined the editing level of miR-99a-5p in 50 surgically resected lung adenocarcinoma cases at our institution by a conventional sequence-based method, and its association with clinical outcomes. The editing level of miR-99a-5p was significantly lower in 19 cases of AD (38%) than in corresponding NC. These cases showed a shorter overall survival as assessed using the log-rank test (P = .047). This trend was consistent with previous analyses of TCGA dataset. The altered editing level of microRNAs in lung adenocarcinoma could serve as a potential biomarker. PMID- 30022567 TI - Emotionally aligned: Preliminary results on the effects of a mindfulness-based intervention for depression on congruence between implicit and explicit mood. AB - BACKGROUND: Mindfulness-based interventions (MBIs) are effective in treating major depression. Because mindfulness involves monitoring and accepting current experiences, it may lead people resolve incongruencies between emotional responses that would otherwise remain unnoticed. Mindfulness may thus foster congruence between implicit and explicit emotions. The current randomized controlled trial tested this notion. METHODS: N = 39 patients with an acute depressive episode were randomly assigned to an 8-week MBI (n = 24) or a psychopharmacological consultation condition (n = 15). Explicit and implicit mood and depressive symptoms were assessed before treatment and at the end of treatment. RESULTS: Compared with the control condition, patients receiving MBI demonstrated higher congruence between implicit and explicit negative mood after treatment. There was no such difference in congruence of implicit and explicit positive mood. Additional analyses showed that only within the MBI group, individual differences in explicit mood became less stable. In contrast, individual differences in implicit mood remained stable in both groups. LIMITATIONS: There was no control group including an active psychological intervention, the sample was small, and emotional congruence was not assessed within persons. CONCLUSIONS: These findings correspond with the idea that mindfulness reduces incongruencies between implicit and explicit emotional responses. We found preliminary evidence for this effect for negative emotional responses. There was suggestive evidence that congruence arose from the alignment of explicit responses (which became less stable) to implicit responses (which remained stable). Studying the interplay between implicit and explicit processes may shed light on the working mechanisms of clinical-psychological interventions. PMID- 30022569 TI - Extracellular calcium regulates the adhesion and migration of osteoclast via integrin alphav beta3 / Rho A/Cytoskeleton signaling. AB - Integrin alphav beta3 is a transmembrane integrin which can initiate osteoclasts' attachment on bone, leading to downward signaling pathways and subsequent bone resorption. Different calcium concentrations have reported to have influence on the activation of integrin alphav beta3 . To elucidate the regulatory mechanism of extracellular calcium concentrations on osteoclasts, a controlled micro flow plate (M04S) was utilized in the ONIX flow control system to observe osteoclasts' adhesion and migration in different calcium concentration medium. Fluorescent staining is conducted to show the distribution of integrin alphav beta3 and cytoskeleton reorganization. In addition, western blots were performed to detect the expression of integrin alphav beta3 and its downstream signaling pathways related to bone resorption. Also, real-time RT-PCR data of transcription co activator (YAP/TAZ) and hydrolytic enzymes (the matrix metalloproteinase 9 and cathepsin K) is evaluated. Our findings suggest that osteoclasts' migration and adhesion is better promoted at 0.5 mM than 1.2 mM, which can be partly explained by the induced cytoskeleton organization via integrin alphav beta3 /Rho GTPase. But the activation and nuclear localization of YAP/TAZ, and the secretion of hydrolytic enzymes were upregulated when calcium concentration is at a higher level (1.2 mM). According to our study, there is a highly possibility that the migration and attachment of osteoclasts and subsequent osteoclastic bone resorption are regulated by a specific range of extracellular calcium concentration. PMID- 30022568 TI - Fluid shear stress improves morphology, cytoskeleton architecture, viability, and regulates cytokine expression in a time-dependent manner in MLO-Y4 cells. AB - The effects of load-induced interstitial fluid shear stress (FSS) on instantaneous signaling response of osteocytes (e.g., calcium signaling) have been well documented. FSS can also initiate the release of many important messenger molecules of osteocytes (e.g., ATP and PGE2 ). However, the effects of FSS on cellular function and bone metabolism-modulating cytokine expression of osteocytes have not been fully identified (some inconsistent/conflicting results have been documented). Herein, osteocyte-like MLO-Y4 cells were stimulated with 1 Pa, 2-h FSS, and the effects of FSS on cellular morphology, cytoskeletal microstructure, biological activity, and gene and protein expression of important cytokines were investigated. SEM and cytoskeleton staining revealed that FSS induced well-organized cytoskeleton and increased filopodia processes. The osteocytic viability was sustained and apoptosis was inhibited via flow cytometry. FSS promoted Wnt3a and beta-catenin gene and protein expression in 0-, 3-, and 6-h (sample collection time post FSS) groups. The FSS-stimulated cells in the 3-h group exhibited more significant effects on the promotion of OCN and Cx43 and inhibition of DKK1 and SOST expression than the 0- and 6-h groups. The 3-h group with FSS stimulation also showed the most prominent effects on suppressing RANKL and RANKL/OPG gene and protein expression. This study revealed a direct regulatory effect of FSS on osteocytic morphology and apoptotic characteristics, and showed that osteocyte-secreted bone metabolism-modulating molecule expression was regulated by FSS in a time-dependent manner. This study not only enriches our basic knowledge for understanding osteocytic mechanotransduction, but also provides important evidence for more scientific experimental design. PMID- 30022570 TI - Personal characteristics and outcomes of individuals with developmental disabilities who need support for self-injurious behaviour. AB - BACKGROUND: For people with intellectual and developmental disabilities, self injurious behaviour (SIB) can have serious negative effects on both health and quality of life. This descriptive analysis will provide information on the characteristics and outcomes of a subsample of individuals who are identified as needing some or extensive support for SIB in the National Core Indicators Adult Consumer Survey sample. METHODS: The data for this analysis come from states that participated in the 2015-2016 data collection cycle of National Core Indicators Adult Consumer Survey which is a face-to-face survey of adults receiving services through state developmental disability agencies. RESULTS: The characteristics and outcomes of individuals who need at least some support for SIB differ from those of individuals with intellectual and developmental disabilities who do not need support for SIB. Individuals with SIB support needs, for example, tend to live in more structured settings, have fewer relationships, less inclusion in their communities and poorer employment outcomes. CONCLUSIONS: The exploratory descriptive analysis concludes with suggested recommendations for more standardised definitions of SIB in public systems, enhanced behaviour plan protocols and the need for additional research. PMID- 30022571 TI - Non-adjunctive flash glucose monitoring system use during summer-camp in children with type 1 diabetes: The free-summer study. AB - BACKGROUND: A factory-calibrated sensor for intermittently scanned continuous glucose monitoring (isCGM) is accurate and safe in children with type 1 diabetes (T1D). Data on isCGM effectiveness as a replacement for self-monitoring of blood glucose (SMBG) in this population is scarce. OBJECTIVE: The aim of this study was to evaluate the non-adjunctive use of isCGM in children with T1D during 2 weeks in a challenging summer-camp setting. METHODS: In this two-arm, parallel, randomized, outpatient clinical trial we enrolled 46 children (25 females, mean +/- SD: age 11.1 +/- 2.6 years, glycated hemoglobin (HbA1c) 7.4% +/- 0.7%): 26 in the isCGM group were blinded for the SMBG and insulin dosing was isCGM-based, whereas 20 in the control group were blinded for isCGM and performed SMBG-based insulin dosing. The primary outcome of intention-to-treat analysis was between group difference in the proportion of time within range 3.9 to 10 mmol/L (TIR). RESULTS: There was no significant difference in TIR (3.9-10 mmol/L) between the two groups. In participants with suboptimal metabolic control (HbA1c > 7%) we observed a significant reduction in time spent above 10 mmol/L (P < 0.05) and an improvement in TIR (P = 0.05) in the isCGM group. No severe hypoglycemic events or serious adverse events occurred. Overall mean absolute relative difference (MARD) between isCGM and SMBG was 18.3%, with median absolute relative difference (ARD) of 8%. Consensus error grid analysis demonstrated 82.2% and 95.2% of results in zone A, and zone A + B, respectively. CONCLUSION: The non-adjunctive use of isCGM was as safe and effective as SMBG, and reduced time spent in hyperglycemia in a sub-population of children with T1D with suboptimal glycemic control. TRIAL REGISTRATION: NCT03182842. PMID- 30022572 TI - Reduced insulin sensitivity is correlated with impaired sleep in adolescents with cystic fibrosis. AB - BACKGROUND: Prevalence of cystic fibrosis-related diabetes (CFRD) rises sharply in adolescence/young-adulthood and is associated with increased morbidity/mortality. Sleep may be a modifiable risk factor for diabetes but its relationship with metabolic function has not been fully examined in youth with CF. The aim of the study was to examine the relationship between objectively measured sleep and glucose metabolism in youth with CF. METHODS: Adolescents (43 with CF and 11 healthy controls) completed 1-week of concurrent home continuous glucose monitoring (CGM) and actigraphy. Fasting labs and an oral glucose tolerance test were obtained. T-tests and analysis of variance (ANOVA) were used to test differences between actigraphy outcomes in CF participants and controls. Spearman's rank correlation coefficients were used to test for correlations between actigraphy, CGM, and insulin sensitivity (IS) measures. RESULTS: All participants averaged insufficient sleep (mean = 7.5 hours per night) compared to the 8 to 10 hours recommended for this age group. CF participants had poorer sleep by actigraphy measures than healthy controls. Higher minimum daytime glucoses on CGM correlated with shorter total sleep time (TST) and worse sleep efficiency (SE). Reduced IS in CF participants with dysglycemia was correlated with shorter TST, longer sleep latency, more wake after sleep onset, and poorer SE. CONCLUSIONS: Poor sleep appears to correlate with higher blood glucose and lower IS in CF adolescents with dysglycemia. Further research is needed to better understand the mechanisms and directionality behind this relationship. PMID- 30022574 TI - A Randomised controlled trial of patient information leaflets as a medication counselling aid. AB - INTRODUCTION: Medication counselling improves patient safety, adherence and satisfaction but is poorly done in clinical practice. Written aids further improve outcomes when used with verbal counselling. No studies have previously compared two types of written counselling aid. AIM: To compare the utility of a patient information leaflet (PIL) with a drug monograph as a medication counselling tool for patients starting a new medicine. METHODS: A single-blinded randomised controlled trial of medical students counselling simulated patients during a clinical examination. The PILs were compared with the drug monographs as counselling aids by assessing information transfer and aid usage. RESULTS: 96 students were recruited. The PIL was superior to the drug monograph for counselling relating to missed doses (p = 0.02), and non-inferior for other domains of information transfer. The aid was used more frequently in the PIL arm (91% vs 77%, p = 0.09) and for longer (4.6 minutes vs 2.9 minutes, p < 0.01). CONCLUSIONS: The PIL was non-inferior to the drug monograph for overall information transfer, but superior for contingency planning. Aid usage was greater in the PIL arm which may reflect greater student satisfaction with the tool. This article is protected by copyright. All rights reserved. PMID- 30022573 TI - Alteration to hippocampal volume and shape confined to cannabis dependence: a multi-site study. AB - Cannabis use is highly prevalent and often considered to be relatively harmless. Nonetheless, a subset of regular cannabis users may develop dependence, experiencing poorer quality of life and greater mental health problems relative to non-dependent users. The neuroanatomy characterizing cannabis use versus dependence is poorly understood. We aimed to delineate the contributing role of cannabis use and dependence on morphology of the hippocampus, one of the most consistently altered brain regions in cannabis users, in a large multi-site dataset aggregated across four research sites. We compared hippocampal volume and vertex-level hippocampal shape differences (1) between 121 non-using controls and 140 cannabis users; (2) between 106 controls, 50 non-dependent users and 70 dependent users; and (3) between a subset of 41 controls, 41 non-dependent users and 41 dependent users, matched on sample characteristics and cannabis use pattern (onset age and dosage). Cannabis users did not differ from controls in hippocampal volume or shape. However, cannabis-dependent users had significantly smaller right and left hippocampi relative to controls and non-dependent users, irrespective of cannabis dosage. Shape analysis indicated localized deflations in the superior-medial body of the hippocampus. Our findings support neuroscientific theories postulating dependence-specific neuroadaptations in cannabis users. Future efforts should uncover the neurobiological risk and liabilities separating dependent and non-dependent use of cannabis. PMID- 30022575 TI - Ion Hydration and Ion Pairing as Probed by THz Spectroscopy. AB - Ion hydration is of pivotal importance for many fundamental processes. Various spectroscopic methods are used to study the retardation of the hydration bond dynamics in the vicinity of anions and cations. Here we introduce THz-FTIR spectroscopy as a powerful method to answer the open questions. We show through dissection of THz spectra that we can pinpoint characteristic absorption features that can be attributed to the rattling modes of strongly hydrating ions within their hydration cages as well as vibrationally induced charge fluctuations in the case of weakly hydrating ions. Further analysis yields information on anion cation cooperativity, the size of the dynamic hydration shell, as well as the lifetimes of these collective ion-hydration water modes and their connecting thermal bath states. Our study provides evidence for a non-additive behavior, thus questioning the simplified Hofmeister model. THz spectroscopy enables ion pairing to be observed and quantified at a high salt concentration. PMID- 30022576 TI - Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein-2 drive reinstatement of alcohol reward seeking. AB - Alcohol use disorder is a chronic relapsing disease. Maintaining abstinence represents a major challenge for alcohol-dependent patients. Yet the molecular underpinnings of alcohol relapse remain poorly understood. In the present study, we investigated the potential role of the mammalian target of rapamycin complex 1 (mTORC1) in relapse to alcohol-seeking behavior by using the reinstatement of a previously extinguished alcohol conditioned place preference (CPP) response as a surrogate relapse paradigm. We found that mTORC1 is activated in the nucleus accumbens shell following alcohol priming-induced reinstatement of alcohol place preference. We further report that the selective mTORC1 inhibitor, rapamycin, abolishes reinstatement of alcohol place preference. Activation of mTORC1 initiates the translation of synaptic proteins, and we observed that reinstatement of alcohol CPP is associated with increased protein levels of one of mTORC1's downstream targets, collapsin response mediator protein-2 (CRMP2), in the nucleus accumbens. Importantly, the level of mTORC1 activation and CRMP2 expression positively correlate with the CPP score during reinstatement. Finally, we found that systemic administration of the CRMP2 inhibitor, lacosamide, attenuates alcohol priming-induced reinstatement of CPP. Together, our results reveal that mTORC1 and its downstream target, CRMP2, contribute to mechanisms underlying reinstatement of alcohol reward seeking. Our results could have important implications for the treatment of relapse to alcohol use and position the Food and Drug Administration approved drugs, rapamycin and lacosamide, for the treatment of alcohol use disorder. PMID- 30022579 TI - Agitation and CANMAT and ISBD 2018 Bipolar Guidelines. PMID- 30022578 TI - Comprehensive assessment of T-cell repertoire following autologous hematopoietic stem cell transplantation for treatment of type 1 diabetes using high-throughput sequencing. AB - OBJECTIVE: We aimed to investigate T-cell receptor (TCR) repertoires in type 1 diabetes (T1D) patients receiving autologous hematopoietic stem cell transplantation (AHSCT) treatment. METHODS: High-throughput deep TCR beta (TCRB) chain sequencing was performed to assess millions of individual TCRs in five T1D patients receiving AHSCT treatment and another five patients receiving insulin treatment during 12 months of follow-up. RESULTS: No significant changes in TCRB sequence reads, complementarity-determining region 3 (CDR3) sequences, or the usage of TCRB VJ gene-segments were observed at 12 months after AHSCT. Compared with the baseline, the usage of TCRB VJ gene-segments at 12 months decreased in the insulin treatment group (1836.4 +/- 437.7 vs 2763.6 +/- 390.6, P = 0.015), and the change rates were larger than those undergoing AHSCT (-0.62 +/- 0.16 vs 0.06 +/- 0.45, P = 0.002). Changes in the TCR repertoire were smaller after AHSCT than those with insulin treatment (P = 2.2*10-32 ). TCRBV 7-7/TCRBJ 2-5 was depleted after AHSCT while expanded with insulin treatment. TCRBV 12-4, TCRBV 10 3, TCRBV 12-3/TCRBJ 1-2 were expanded after AHSCT while ablated with insulin treatment. CONCLUSIONS: We found that AHSCT is safe without reduction in the diversity of TCR repertoires and TCR repertoires tend to be more stable after AHSCT. Furthermore, these four candidate TCRBV/TCRBJ gene usages on CDR3 regions may act as therapeutic targets and biomarkers. PMID- 30022577 TI - Pressure-Tuneable Visible-Range Band Gap in the Ionic Spinel Tin Nitride. AB - The application of pressure allows systematic tuning of the charge density of a material cleanly, that is, without changes to the chemical composition via dopants, and exploratory high-pressure experiments can inform the design of bulk syntheses of materials that benefit from their properties under compression. The electronic and structural response of semiconducting tin nitride Sn3 N4 under compression is now reported. A continuous opening of the optical band gap was observed from 1.3 eV to 3.0 eV over a range of 100 GPa, a 540 nm blue-shift spanning the entire visible spectrum. The pressure-mediated band gap opening is general to this material across numerous high-density polymorphs, implicating the predominant ionic bonding in the material as the cause. The rate of decompression to ambient conditions permits access to recoverable metastable states with varying band gaps energies, opening the possibility of pressure-tuneable electronic properties for future applications. PMID- 30022580 TI - Attachment between heterotrophic bacteria and microalgae influences symbiotic microscale interactions. AB - The surface and surroundings of microalgal cells (phycosphere) are critical interaction zones but have been difficult to functionally interrogate due to methodological limitations. We examined effects of phycosphere-associated bacteria for two biofuel-relevant microalgal species (Phaeodactylum tricornutum and Nannochloropsis salina) using stable isotope tracing and high spatial resolution mass spectrometry imaging (NanoSIMS) to quantify elemental exchanges at the single-cell level. Each algal species responded differently to bacterial attachment. In P. tricornutum, a high percentage of cells had attached bacteria (92%-98%, up to eight bacteria per alga) and fixed 64% more carbon with attached bacteria compared to axenic cells. In contrast, N. salina cells were less commonly associated with bacteria (42%-63%), harboured fewer bacteria per alga, and fixed 10% more carbon without attached bacteria compared to axenic cells. An uncultivated bacterium related to Haliscomenobacter sp. was identified as an effective mutualist; it increased carbon fixation when attached to P. tricornutum and incorporated 71% more algal-fixed carbon relative to other bacteria. Our results illustrate how phylogenetic identity and physical location of bacteria and algae facilitate diverse metabolic responses. Phycosphere-mediated, mutualistic chemical exchanges between autotrophs and heterotrophs may be a fruitful means to increase microalgal productivity for applied engineering efforts. PMID- 30022582 TI - Modulation of serotonin and noradrenaline in the BLA by pindolol reduces long term ethanol intake. AB - Repeated cycles of binge-like alcohol consumption and abstinence change the activity of several neurotransmitter systems. Some of these changes are consolidated following prolonged alcohol use and are thought to play an important role in the development of dependence. We have previously shown that systemic administration of the dual beta-adrenergic antagonist and 5-HT1A/1B partial agonist pindolol selectively reduces long-term but not short-term binge-like consumption of ethanol and alters excitatory postsynaptic currents in basolateral amygdala (BLA) principal neurons. The aim of this study was to investigate the effects of pindolol microinfusions in the BLA on long-term ethanol intake using the drinking-in-the-dark paradigm in mice. We also microinfused RU24969 (5 HT1A/1B receptor partial agonist) and CGP12177 (beta1/2 adrenergic antagonist) following long-term ethanol intake and determined the densities of 5-HT1A/1B receptors and beta1/2 adrenergic in the BLA following short-term (4 weeks) and long-term ethanol (12 weeks) consumption. We show that intra-BLA infusion of pindolol (1000 pmol/0.5 MUl), RU24969 (0.3 and 3 pmol/0.5 MUl) and CGP12177 (500 pmol/0.5 MUl) produce robust decreases in long-term ethanol consumption. Additionally, we identified reduced beta1/2 adrenergic receptor expression and no change in 5-HT1A/1B receptor density in the BLA of long-term ethanol-consuming mice. Collectively, our data highlight the effects of pindolol on voluntary, binge-like ethanol consumption behavior following long-term intake. PMID- 30022581 TI - Rational Design of MOF/COF Hybrid Materials for Photocatalytic H2 Evolution in the Presence of Sacrificial Electron Donors. AB - Crystalline and porous covalent organic frameworks (COFs) and metal-organic frameworks (MOFs) materials have attracted enormous attention in the field of photocatalytic H2 evolution due to their long-range order structures, large surface areas, outstanding visible light absorbance, and tunable band gaps. In this work, we successfully integrated two-dimensional (2D) COF with stable MOF. By covalently anchoring NH2 -UiO-66 onto the surface of TpPa-1-COF, a new type of MOF/COF hybrid materials with high surface area, porous framework, and high crystallinity was synthesized. The resulting hierarchical porous hybrid materials show efficient photocatalytic H2 evolution under visible light irradiation. Especially, NH2 -UiO-66/TpPa-1-COF (4:6) exhibits the maximum photocatalytic H2 evolution rate of 23.41 mmol g-1 h-1 (with the TOF of 402.36 h-1 ), which is approximately 20 times higher than that of the parent TpPa-1-COF and the best performance photocatalyst for H2 evolution among various MOF- and COF-based photocatalysts. PMID- 30022584 TI - Nickel-Catalyzed Stereospecific C-H Coupling of Benzamides with Epoxides. AB - A Ni(OAc)2 -catalyzed C-H coupling of 8-aminoquinoline-derived benzamides with epoxides has been developed. The reaction proceeds with concomitant removal of the 8-aminoquinoline auxiliary to form the corresponding 3,4-dihydroisocoumarins directly. Additionally, the nickel catalysis is stereospecific, and the cis- and trans-epoxides are converted into the corresponding cis- and trans dihydroisocoumarins with retention of configuration, which is complementary to previously reported palladium catalysis. Moreover, while still preliminary, the Csp3 -H functionalization is also achieved in the presence of modified NiCl2 catalysts. PMID- 30022583 TI - Combatting social isolation and increasing social participation of older adults through the use of technology: A systematic review of existing evidence. AB - OBJECTIVES: There are growing concerns that social isolation presents risks to older people's health and well-being. Thus, the objective of the review was to explore how technology is currently being utilised to combat social isolation and increase social participation, hence improving social outcomes for older people. METHODS: A systematic review of the literature was conducted across the social science and human-computer interaction databases. RESULTS: A total of 36 papers met the inclusion criteria and were analysed using a four-step process. Findings were threefold, suggesting that: (i) technologies principally utilised social network services and touch-screen technologies; (ii) social outcomes are often ill-defined or not defined at all; and (iii) methodologies used to evaluate interventions were often limited and small-scale. CONCLUSION: Results suggest a need for studies that examine new and innovative forms of technology, evaluated with rigorous methodologies, and drawing on clear definitions about how these technologies address social isolation/participation. PMID- 30022585 TI - DREEM-ing of dentistry: Students' perception of the academic learning environment in Australia. AB - INTRODUCTION: Continuous evaluation and improvement of the learning environment are required to respond to the changing nature of dental practice and dental education. This study aimed to describe a cohort of undergraduate dentistry students' perceptions of their learning environment. METHODS: Students enrolled in years 1-4 of the Bachelor of Dental Science (Honours) programme at The University of Queensland were invited to complete an online survey which included demographics and the Dundee Ready Education Environment Measure (DREEM). This scale measures students' perception of the educational environment overall, and for five domains: Learning, Teaching, Academic self-perception, Atmosphere and Social self-perception. Data analysis was mostly descriptive, t tests and univariate statistics compared groups. RESULTS: Participants (N = 192; females = 57%) were generally positive about their learning environment, with a total DREEM score of 127 of 200. Overall, Academic and Social self-perception domain scores were ranked lower than others. Students in preclinical years of study and/or had dentistry as a first career preference were more positive across all domains, except Social self-perception. CONCLUSIONS: Differences between the preclinical and clinical phases of the curriculum point to the structure of teaching and learning in health professional degrees. Further research should investigate how each environmental domain more specifically correlates with other aspects of the curriculum and student progression, including well-being. This could include logistical factors such as timetabling and its effect on physical well-being, to less tangible factors that may impact on mental well-being. PMID- 30022586 TI - Burden of Anemia in Chronic Kidney Disease Patients in Japan: A Literature Review. AB - Anemia is a common complication for patients with chronic kidney disease (CKD) and is associated with cardiovascular comorbidities and reduced quality of life. The incidence of anemia increases as kidney function declines and affects approximately 32% of Japanese patients with stage 3-5 CKD. This review examined the current literature on anemia in CKD patients in Japan to provide an overview of the burden of anemia in CKD. Medline, Embase, and Igaku Chuo Zasshi databases were searched to identify relevant manuscripts and abstracts published from 2004 onward. The population included CKD patients with anemia, and the outcomes of interest were epidemiology, economic, humanistic, and treatment patterns. Observational studies, database analysis, and economic evaluation studies were included in the analysis. A total of 1151 references were identified, and 50 were eligible for final review. Economic burden was reported in most studies (n = 37) followed by treatment patterns (n = 26), and epidemiological (n = 25) and humanistic (n = 1) burdens. Prevalence of anemia varied largely (0-95%) based on the different definitions of anemia, and increased with CKD severity. Higher mortality was associated with erythropoiesis-stimulating agent (ESA) resistance and lower hemoglobin levels among patients treated with ESA. Drug dosage was the most reported economic burden (n = 33), followed by medical, and non-medical outcomes. Costs associated with anemia were considerable and depended on dialysis status and ESA treatment. Only one study reported data on quality of life, suggesting that further investigation on the humanistic burden of anemia in CKD is needed. PMID- 30022587 TI - Ligulate inflorescence of Helianthus * multiflorus, cv. Soleil d'Or, correlates with a mis-regulation of a CYCLOIDEA gene characterised by insertion of a transposable element. AB - Members of CYCLOIDEA (CYC)/TEOSINTE BRANCHED1 (TB1) transcription factor family are essential to control flower symmetry and inflorescence architecture. In the Helianthus annuus genome, ten CYC/TB1 genes have been identified. Studies performed on mutants recognised HaCYC2c as one of the key players controlling zygomorphism in sunflower. We identified CYC2c genes in the diploid Helianthus decapetalus (HdCYC2c) and in the interspecific hybrid Helianthus * multiflorus (H * mCYC2cA and H * mCYC2cB), a triploid (2n = 3* = 51), originated from unreduced eggs of H. decapetalus fertilised by reduced H. annuus male gametes. Phylogenetic analysis showed that HdCYC2c and H * mCYC2c were placed within a CYC2 subclade together with HaCYC2c but distinct from it. The present data showed that in H. * multiflorus the allele derived from H. annuus is deleted or highly modified. The H. * multiflorus taxon exists as radiate and ligulate inflorescence types. We analysed CYC2c expression in H. decapetalus and in the cultivar 'Soleil d'Or' of H. * multiflorus, a ligulate inflorescence type with actinomorphic corolla of disk flowers transformed into a zygomorphic ray-like corolla. In H. decapetalus, the HdCYC2c gene showed differential expression between developing flower types, being up-regulated in the corolla of ray flowers in comparison to the disk flower corolla. In H. * multiflorus, an insertion of 865 bp, which is part of a CACTA transposable element, was found in the 5'-untranslated region (5'-UTR) of H * mCYC2cB. This insertion could promote, even with epigenetic mechanisms, ectopic expression of the gene throughout the inflorescence, resulting in the observed loss of actinomorphy and originating a ligulate head. PMID- 30022588 TI - Dispersive liquid-liquid microextraction with in situ derivatization coupled with gas chromatography and mass spectrometry for the determination of 4 methylimidazole in red ginseng products containing caramel colors. AB - A rapid analytical method was developed for the determination of 4 methylimidazole from red ginseng products containing caramel colors by using dispersive liquid-liquid microextraction with in situ derivatization followed by gas chromatography with mass spectrometry. Chloroform and acetonitrile were selected as the extraction and dispersive solvents, and based on the extraction efficiency, their optimum volumes were 200 and 100 MUL, respectively. The optimum volumes of the derivatizing agent (isobutyl chloroformate) and catalyst (pyridine), pH, and concentration of NaCl in the sample solution were determined to be 25 and 100 MUL, pH 7.6, and 0% w/v, respectively. Validation of the optimized method showed good linearity (R2 > 0.999), accuracy (>=89.86%), intra- (<=6.70%) and interday (<=4.17%) repeatability, limit of detection (0.96 MUg/L), and limit of quantification (5.79 MUg/L). The validated method was applied to quantify 4-methylimidazole in red ginseng juices and concentrates, 4 methylimidazole was only found in red ginseng juices containing caramel colorant (42.91-2863.4 MUg/L) and detected in red ginseng concentrates containing >1% caramel colorant. PMID- 30022589 TI - Chiral ligand-induced photoluminescence intermittence difference of CdTe quantum dots. AB - Semiconductor quantum dots (QDs) are a new nano-material, and their unique optical properties have become a focal point of research in both academia and industry. In this study, we studied photoluminescence (PL) intermittence (or 'blinking') behaviors of individual QDs prepared with different chiral ligands by using single molecule microscopy and single molecule fluorescence correlation spectroscopy (FCS). We found that the chirality of N-isobutyryl-d/l-cysteine (D/L NIC) as surface stabilizers significantly influences PL blinking behaviors of cadmium telluride (CdTe) QDs synthesized in aqueous solution. The 'on time' distribution and the power-law exponent analyses show that the D-NIC more efficiently suppresses the blinking of QDs over L-NIC. Ensemble spectroscopies verfied that the remarkably-different blinking behaviors of QDs induced by ligand chirality were attributed to the different number of chiral ligands bound in the surface of QDs. PMID- 30022591 TI - Re: Cervical dilatation over time is a poor predictor of severe adverse birth outcomes: a diagnostic accuracy study. PMID- 30022590 TI - Clinical significance of detectable and quantifiable HCV RNA at the end of treatment with ledipasvir/sofosbuvir in GT1 patients. AB - BACKGROUND & AIMS: AASLD/IDSA treatment guidelines for hepatitis C virus (HCV) infection state that testing for quantitative HCV RNA can be considered at the end of antiviral treatment (EOT) with interferon-free regimens. However, it remains unclear how to respond to a detectable or even quantifiable HCV RNA result. The aim of this study was to analyse the frequency and predictive value of detectable and quantifiable HCV RNA results at the EOT in patients with HCV genotype 1 infection treated with ledipasvir (LDV) and sofosbuvir (SOF) +/- ribavirin (RBV) in a large real-world cohort. METHODS: A retrospective analysis of the DHC-R (Deutsches Hepatitis C-Register, German Hepatitis C-Registry) cohort was performed including all patients who were treated with LDV/SOF +/- RBV and in whom HCV RNA testing was done with either the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) or the Abbott RealTime HCV assay (ART). RESULTS: The frequency of detectable HCV RNA at the EOT was 7% in this real-world study involving 471 patients. Furthermore, 3% of the patients (n = 14/471) even had quantifiable viral load at the EOT. Detectable and quantifiable results were more frequent if the ART was used for testing. However, SVR was achieved by 32/33 patients (97%) with detectable and even by all 14 patients (100%) with quantifiable HCV RNA results at the EOT. CONCLUSION: Detectable and even quantifiable HCV RNA results are quite frequent if highly sensitive HCV RNA assays are used. However, treatment prolongation is not indicated, as SVR rates remain high in these patients. PMID- 30022592 TI - 5-hydroxymethylfurfural- and fluorescein-fused fluorescence probe of mast cells (RBL-2H3): Synthesis, photophysical properties, and bioimaging. AB - A fluorescent probe (Fluo-HMF) was developed via introduction of a furfural moiety into the fluorescein molecular skeleton, aiming at specially labeling cell membrane of mast cells. To illustrate its specificity, we designed and synthesized a series of fluorescent compounds based on fluorescein molecular skeleton. The fluorescent properties of Fluo-HMF were investigated, which were in accordance with theoretical calculations. Compared with other fluorescein derivatives, Fluo-HMF could specially label RBL-2H3 cells. The results suggested that Fluo-HMF could be used as a fluorescent probe for bioimaging on some related research of allergic mechanism. PMID- 30022593 TI - Clinical features and outcomes of Merkel cell carcinoma in 20 cats. AB - The biological behaviour and prognostic factors of Merkel cell carcinoma (MCC) in 20 cats were studied. The tumours were surgically removed and histopathologically examined. The animals were 8 to 20 years old (median age: 14 years), and the tumours were predominantly located in the neck and head. Follow-up data were available in 17 cases, and 12 cats died within a year of surgery. The overall median survival time after resection was 243 days (range 16-360 days). Recurrence occurred in 11 cases, although 6 of them (55%) were found to be margin-negative. Possible metastasis occurred after the surgery in 10 cases, although 6 of them (60%) were found to be margin-negative. The histopathological features of MCC included tumour necrosis in 16 cases (80%), vascular invasion in 6 cases (38%) and high mitotic counts (median: 28.5 per high-power field). Irregular acanthosis was noted adjacent to the tumours in 9 cases (60%). Immunohistochemically, the tumour cells were positive for cytokeratin (CK) 20 and p63 in all cases, synaptophysin in 19 (95%) cases, and CK18 in 16 cases (80%). The study shows that feline MCC is associated with a poor prognosis and exhibited a strong tendency towards local recurrence, regional lymph node metastasis and distant spread. PMID- 30022594 TI - Potential investment tradeoff between offspring production and functional recovery promoted by larval cannibalism in Coccinella septempunctata (Coleoptera: coccinellidae). AB - BACKGROUND: Since larval cannibalism is frequently observed in intensive rearing systems, the regeneration of lost legs is common for the beneficial species Coccinella septempunctata (Coccinella: Coccinellidae) to adapt to the competitive environment, but whether functional recovery occurs in the leg-regenerated coccinellids remains unknown. To evaluate the functional recovery of regenerated right foreleg after being damaged, the behaviors of leg-regenerated ladybugs containing predation, attachment, intraspecific competition, prey preference and fecundity were studied in the laboratory. RESULTS: The prey consumption and searching rate of leg-regenerated ladybugs decreased, and their handling time extended. A significantly reduced attachment coefficient was detected in leg regenerated coccinellids. Because of the competitive inferiority, leg-regenerated ladybugs were greatly hampered in competition with normal opponents, and this inferiority led to a switch of prey preference from big-sized adults to small sized first-second instar nymphs of Paratrioza sinica. However, although reduced functional abilities were examined, the leg-regenerated paternity had a higher reproductive output compared to the normal paternity. CONCLUSION: Leg-regenerated ladybugs caused by cannibalism may make an investment tradeoff between egg fecundity and functional recovery. Thus, larval cannibalism potentially improves the offspring production of the biological control agent in complex environments. (c) 2018 Society of Chemical Industry. PMID- 30022595 TI - Effect of a botanical cleansing lotion on skin sebum and erythema of the face: A randomized controlled blinded half-side comparison. AB - BACKGROUND: Elevated levels of skin sebum are associated with the growth of Propionibacterium acnes. Intensive degreasing of the skin reduces Propionibacterium acnes but also may cause skin irritation. AIMS: We assessed the degreasing effect and skin tolerability of a botanical face cleanser with hops and willow bark extract and disodium cocoyl glutamate as mild cleansing agent compared to a standard face cleanser with sodium laureth sulfate (SLES). MATERIALS AND METHODS: A total of 21 healthy volunteers with normal to oily skin were enrolled in this study. Both cleansers were applied twice a day on the left or right side of the forehead for 15 days in a standardized manner. Bioengineering measurements were performed on day 8 and 15 and on day 17 after an application break of 48 hours. The sebum level was determined using a Sebumeter(r) , and skin redness was measured using a Mexameter(r) . RESULTS: The botanical face cleanser significantly reduced the sebum level (P < .01) in the test area on day 17. The SLES containing cleanser showed a statistically relevant degreasing effect already on day 15, but after the application break the sebum level increased again on day 17. None of the cleansers caused skin irritation as determined by skin redness measurements. CONCLUSIONS: In contrast to the SLES containing cleanser, the botanical skin cleanser with hops and willow bark extract had a continuous degreasing effect without reactive seborrhoe after the treatment break. Skin cleansing without SLES might be advantageous for sensitive skin. PMID- 30022596 TI - Preparation and biological evaluation of metronidazole derivatives with monoterpenes and eugenol. AB - Two series of metronidazole derivatives (ester derivatives and ether derivatives) were prepared reacting metronidazole and its acetic acid oxidized form with menthol, thymol, carvacrol, and eugenol. Both series of compounds were tested in vitro against two strains of Helicobacter pylori (the ATCC 26695 and P12), and one strain of Clostridium (Clostridium perfringens). Most of the prepared compounds showed biological activity against the targeted bacteria. Compound 11 was highly active against all tested bacterial strains, especially against P12 with IC50 0.0011 MUM/ml. Compound 6 was highly active against C. perfringens with MIC 0.0094 nM/ml. Viability test was conducted for compound 11 to test its selectivity for normal human fetal lung fibroblasts (MRC5), and it was found to be non-toxic with IC50 more than 50 MUM/ml. PMID- 30022597 TI - Liver Grafts From Donors After Circulatory Death on Regional Perfusion With Extended Warm Ischemia Compared With Donors After Brain Death. AB - Donation after circulatory death (DCD) in Italy constitutes a relatively unique population because of the requirement of a no-touch period of 20 minutes. The first aim of this study was to compare liver transplantations from donors who were maintained on normothermic regional perfusion after circulatory death and suffered extended warm ischemia (DCD group, n = 20) with those from donors who were maintained on extracorporeal membrane oxygenation (ECMO) and succumbed to brain death (ECMO group, n = 17) and those from standard donors after brain death (donation after brain death [DBD] group, n = 52). Second, we conducted an explorative analysis on the DCD group to identify relationships between the donor characteristics and the transplant outcomes. The 1-year patient survival for the DCD group (95%) was not significantly different from that of the ECMO group (87%; P = 0.47) or the DBD group (94%; P = 0.94). Graft survival was slightly inferior in the DCD group (85%) because of a high rate of primary nonfunction (10%) and retransplantation (15%) but was not significantly different from the ECMO group (87%; P = 0.76) or the DBD group (91%; P = 0.20). Although ischemic cholangiopathy was more frequent in the DCD group (10%), this issue did not adversely impact graft survival because none of the recipients underwent retransplantation due to biliary complications. Moreover, the DCD recipients were more likely to develop posttransplant renal dysfunction with the need for renal replacement therapy. Further analysis of the DCD group showed that warm ischemia >125 minutes and an Ishak fibrosis score of 1 at liver biopsy negatively impacted serum creatinine and alanine transaminase levels in the first posttransplant week, respectively. In conclusion, our findings encourage the use of liver grafts from DCD donors maintained by regional perfusion after proper selection. PMID- 30022599 TI - What The Neighbor Says. PMID- 30022598 TI - Preliminary study of outcome-based clinical practicum for undergraduate nursing students. AB - AIM: A growing trend in South Korean nursing education is toward outcome-based education. In response, there is now a greater emphasis on achieving the learning outcomes that are outlined in the curricula of outcome-based education. This study aimed to describe the effectiveness of outcome-based clinical practicum for nursing students. METHODS: In this preliminary longitudinal study, 62 third-year nursing students were enrolled from a university in Seoul, Korea. Three parameters of proficiency were measured three times in the students for 1 year including: achievement of expected learning outcomes, nurses' core competence, and critical thinking. For the data analysis, a descriptive analysis and repeated measures ANOVA were used with the IBM SPSS v. 23.0 software program. RESULTS: Completing the outcome-based clinical practicum was associated with a significantly enhanced achievement of expected learning outcomes, nurses' core competency, and critical thinking. All of the six expected learning outcomes significantly improved across the pre-, mid-, and postpracticum time points. CONCLUSIONS: The outcome-based clinical practicum improved the achievement of the expected learning outcomes, nurses' core competency, and critical thinking of the nursing students. Further study is recommended to investigate students' and educators' qualitative experiences of outcome-based clinical practicum. PMID- 30022600 TI - Renewable Time-Responsive DNA Circuits. AB - DNA devices have been shown to be capable of evaluating Boolean logic. Several robust designs for DNA circuits have been demonstrated. Some prior DNA-based circuits are use-once circuits since the gate motifs of the DNA circuits get permanently destroyed as a side effect of the computation, and hence cannot respond correctly to subsequent changes in inputs. Other DNA-based circuits use a large reservoir of buffered gates to replace the working gates of the circuit and can be used to drive a finite number of computation cycles. In many applications of DNA circuits, the inputs are inherently asynchronous, and this necessitates that the DNA circuits be asynchronous: the output must always be correct regardless of differences in the arrival time of inputs. This paper demonstrates: 1) renewable DNA circuits, which can be manually reverted to their original state by addition of DNA strands, and 2) time-responsive DNA circuits, where if the inputs change over time, the DNA circuit can recompute the output correctly based on the new inputs, that are manually added after the system has been reset. The properties of renewable, asynchronous, and time-responsiveness appear to be central to molecular-scale systems; for example, self-regulation in cellular organisms. PMID- 30022601 TI - Process Evaluation of a Participatory, Multimodal Intervention to Improve Evidence-Based Care in Long-Term Care Settings. AB - BACKGROUND: Evidence-based improvements in long-term care (LTC) are challenging due to human resource constraints. AIMS: To evaluate implementation of a multimodal, participatory intervention aimed at improving evidence-based care. METHODS: Using a qualitative descriptive design, we conducted and inductively analyzed individual interviews with staff at midpoint and end-point to identify action plan implementation processes and challenges. The 9-month intervention engaged professional and unregulated staff in an on-site workshop and provided support for their development and implementation of site-specific action plans. RESULTS: Ten of 12 enrolled sites participated for the full study period. Interviews were conducted with 44 and 69 participants at midpoint and end-point, respectively. Seven of 10 sites focused their action plan on team functioning and communication. Main achievements described at end-point were improved team communication, better staff engagement, and improved teamwork. Internal and external supports for action plan implementation were described as critical for success. DISCUSSION: Three factors influenced change: vertically and horizontally linked teams, external facilitator support for action plan implementation, and coaching by Best Practice Coordinators that emphasized organizational change and normalization of evidence-based practice. IMPLICATIONS: Team functioning and communication are forerunners of clinical practice changes in LTC. An off-site model of facilitation is promising and may provide a more efficient means to reach a wider array of LTC settings. LINKING EVIDENCE TO ACTION: Practice changes need engagement of all staff. PMID- 30022602 TI - A call to action-The transplant recipient's expectation of precision in transplant medicine. PMID- 30022603 TI - Prenatal detection of critical cardiac outflow tract anomalies remains suboptimal despite revised obstetrical imaging guidelines. AB - BACKGROUND: Fetal echocardiography can accurately diagnose critical congenital heart disease prenatally, but relies on referrals from abnormalities identified on routine obstetrical ultrasounds. Critical congenital heart disease that is frequently missed due to inadequate outflow tract imaging includes anomalies such as truncus arteriosus, double outlet right ventricle, transposition of the great arteries, tetralogy of Fallot, pulmonary stenosis, and aortic stenosis. OBJECTIVE: This study evaluated the prenatal detection rate of critical outflow tract anomalies in a single urban pediatric hospital before and after "AIUM Practice Guideline for the Performance of Obstetric Ultrasound Examinations," which incorporated outflow tract imaging. DESIGN: Infants with outflow tract anomalies who required cardiac catheterization and/or surgical procedure(s) in the first 3 months of life were retrospectively identified. This study evaluated two time periods; pre-guidelines from June 2010 to May 2013 and post-guidelines from January 2015 to June 2016. June 2013-December 2014 was excluded as a theoretical period necessary for obstetrical practices to implement the revised guidelines. RESULTS: Overall, prenatal diagnosis occurred in 55% of infants with critical outflow tract anomalies; of the three most common defects, prenatal diagnosis occurred in 53% of D-transposition of the great arteries, 63% of tetralogy of Fallot, and 80% of double outlet right ventricle patients. Pre guidelines, prenatal diagnosis occurred in 52% (52 of 102) infants with critical outflow tract anomalies requiring early cardiac intervention. Post-guidelines, prenatal diagnosis occurred in 61% (33 of 54) infants, not significantly different than the prenatal detection rate pre-guidelines (P = .31). CONCLUSIONS: Despite revised obstetrical guidelines highlighting the importance of outflow tract imaging, referrals and prenatal diagnosis of these types of critical congenital heart disease remain low. Education of obstetrical sonographers and practitioners who perform fetal anatomic screening is vital to increase referrals and prenatal detection of critical outflow tract anomalies. PMID- 30022604 TI - GOSPEL 4 - Patients with early onset gout develop earlier severe joint involvement and metabolic comorbid conditions. AB - OBJECTIVE: Little is known of the clinical features and comorbidity profile of patients presenting with early onset gout (EOG) although international guidelines recommend their treatment rapidly after diagnosis. The objective of this study was to assess specific characteristics and comorbidities of patients suffering from gout having had an early onset. METHODS: Patients from a cross-sectional French national cohort ('GOSPEL'), having suffered their first gout flare before the age of 40 were included in the EOG group and compared to those with an onset after 40, the common gout group. RESULTS: A total of 120 patients, were included in the EOG group (aged 49.5 (+/-11.9) years) and 865 patients in the common gout group (aged 64.4 (+/-10.1) years). Patients with EOGmore often presented with a history of polyarticular flares (p<0.01), but had similar frequency of flares (p=0.16), gout arthropathy (p=0.79) and tophi (p=0.53). Prevalence of each item composing the metabolic syndrome did not differ between groups. In early onset patients, all cardiovascular comorbidities were diagnosed after gout onset. Greater age, low HDL and excessive alcohol intake were associated in multivariate analysis to the common gout group, while familial history of gout, longer urate lowering treatment, higher serum urate levels and the metabolic syndrome were associated to the early onset gout group. CONCLUSION: Herein early onset gout patients developed slightly more severe joint involvement and earlier metabolic disorders than common gout patients. This article is protected by copyright. All rights reserved. PMID- 30022605 TI - The Molecular Interplay between Axon Degeneration and Regeneration. AB - Neurons face a series of morphological and molecular changes following trauma and in the progression of neurodegenerative disease. In neurons capable of mounting a spontaneous regenerative response, including invertebrate neurons and mammalian neurons of the peripheral nervous system (PNS), axons regenerate from the proximal side of the injury and degenerate on the distal side. Studies of Wallerian degeneration slow (WldS /Ola) mice have revealed that a level of coordination between the processes of axon regeneration and degeneration occurs during successful repair. Here, we explore how shared cellular and molecular pathways that regulate both axon regeneration and degeneration coordinate the two distinct outcomes in the proximal and distal axon segments. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018. PMID- 30022606 TI - Validation of formula-predicted glaucomatous optic disc appearances: the Glaucoma Stereo Analysis Study. AB - AIMS: The Glaucoma Stereo Analysis Study (GSAS) is a multicentre collaborative study of the characteristics of glaucomatous optic disc morphology using a stereo fundus camera. Using the GSAS dataset, we previously established a formula for predicting different appearances of glaucomatous optic discs, although the formula lacked validation in an independent dataset. In this study, the formula was validated in another testing dataset. SUBJECTS AND METHODS: Testing dataset contained three-dimensionally analysed optic disc topographic parameters from 93 eyes with primary open-angle glaucoma; six topographic parameters (temporal and nasal rim-disc ratios, mean cup depth, height variation contour, disc tilt angle and rim decentring absolute value) were used for predicting different appearances of glaucomatous optic discs. The agreement between grader-classified optic disc types, that is, focal ischemic (FI), generalized enlargement, myopic glaucomatous (MY), and senile sclerotic (SS) and formula-predicted optic disc types, that is, pFI, pGE, pMY and pSS, were assessed. RESULTS: Based on this formula, the eyes were classified with pFI (21 eyes, 22.6%), pGE (27 eyes, 29.0%), pMY (26 eyes, 28.0%) and pSS (19 eyes, 20.4%) when the top predictive element based on the formula was considered as the optic disc appearance in each eye. The six topographic parameters used in the formula differed significantly among the four predicted optic disc types. Substantial agreement (kappa = 0.7496) was seen for the top two predictive elements based on the formula that agreed with the graders' classification in 76 (81.7%) eyes. Among the four optic disc types, the levels of agreement were relatively lower in the SS type (kappa = 0.3863-0.5729) compared with the other three optic disc types (kappa = 0.7898-0.8956) even though the unclassifiable and mixed optic disc types were excluded from the testing dataset. CONCLUSION: The GSAS classification formula can predict and quantify each component of different optic disc appearances in each eye and provide a novel parameter to describe glaucomatous optic disc characteristics. PMID- 30022608 TI - Cyanobacterial blooms in oil-contaminated subtidal sediments revealed by integrated approaches. AB - Cyanobacteria are important primary producers on the surface of oceans and are susceptible to oil spills. However, their tolerance to oil and their roles in the bioremediation of crude oil remain elusive. We analysed the response of microbial communities to a simulated oil spill in estuarine sediment microcosms under a series of oil concentrations (0, 25, 125, and 250 g kg-1 dry wt.). Cyanobacterial blooms only occurred on the sediment surface in the low oil (LO, 25 g kg-1 dry wt.) group, and cyanobacteria grew from very small amounts to enriched levels according to an internal mechanism. The dominant phylotypes enriched in the oil contaminated sediments on day 35 were Leptolyngbya, Oscillatoria, Arthrospira (Spirulina), Geitlerinema and Cyanothece, and the majority were capable of fixing nitrogen. Gammaproteobacterial blooms occurred during the early stage, and Oceanospirillales dominated the sediment surface. The annotation of unassembled metatranscriptomic data revealed an increase in nitrogen metabolism, particularly photosynthesis (antenna proteins) during the later stage, together with depletion of fatty acid metabolism. In summary, high concentrations of crude oil are toxic to cyanobacteria but can facilitate the emergence of cyanobacterial aggregation at low concentrations (crude oil concentration < 25 g kg-1 dry wt.). PMID- 30022607 TI - Predicting sequential bilateral cochlear implantation performance in postlingually deafened adults; A retrospective cohort study. AB - OBJECTIVE: To identify which preoperative patient characteristics influence sequential bilateral cochlear implantation performance and to create a statistical model that predicts benefit. DESIGN: Multicentre retrospective cohort study. SETTING: All patients were operated in four academic teaching hospitals in Perth, Australia, and followed up by audiologists of the Ear Science Institute Australia. PARTICIPANTS: A total of 92 postlingually deafened adult patients who had undergone sequential cochlear implantations between 19 June 1990 and 14 March 2016 were included. Patients were excluded if the 12-month follow-up consonant nucleus-consonant (CNC) phoneme score was missing. MAIN OUTCOME MEASURE: The effect of 18 preoperative factors on the CNC phoneme score in quiet (at 65 dB SPL) with the second cochlear implant (CI2) one year after implantation. RESULTS: Two factors were positively correlated to speech understanding with CI2: Wearing a hearing aid (HA) before receiving CI2 (r = 0.46, P = 0.00) and the maximum CNC phoneme score with the first CI (CI1) (r = 0.21, P = 0.05). Two factors were negatively correlated: the length of hearing loss before CI2 in the second implanted ear (r = -0.25, P = 0.02) and preoperative pure tone average (PTA) (0.5, 1, 2 kHz) before CI2 in the second implanted ear (r = -0.27, P = 0.01). The following model could be created: predicted CNC phoneme score with CI2 (%) = 16 + (44 * HA use before CI2 (yes)) - (0.22 * length of hearing loss before CI2 (years)) + (0.23 * CNC phoneme score with CI1 (%)). Because the effect of HA use before implantation played such a major role, we also created a model after exclusion of the HA factor: Predicted CNC phoneme score with CI2 (%) = 82 - (0.17 * length of hearing loss before CI2 (years)) - (0.27 * PTA in second implanted ear before CI2 (0.5, 1, 2 kHz)) + (0.20 * CNC phoneme score with CI1 (%)). CONCLUSION: Advanced age or a long interval between implantations does not necessarily lead to poor CI2 results. Patients who are successful HA users before CI2, who have a low PTA before CI2, a high CNC phoneme score with CI1 and a limited length of hearing loss before CI2, are likely to be successful CI2 recipients. PMID- 30022609 TI - Return to work after specialized rehabilitation-An explorative longitudinal study in a cohort of severely disabled persons with stroke in seven countries: The Sunnaas International Network stroke study. AB - INTRODUCTION: Stroke may impose disabilities with severe consequences for the individual, with physical, psychological, social, and work-related consequences. The objective with the current study was to investigate to what extent persons with stroke were able to return to work, to maintain their financial situation, and to describe the follow-up services and participation in social networks and recreational activities. METHODS: The design was a prospective, descriptive study of specialized stroke rehabilitation in nine rehabilitation centers in seven countries. Semistructured interviews, which focused on the return to work, the financial situation, follow-up services, the maintenance of recreational activities, and networks, were performed 6 and 12 months post discharge from rehabilitation. RESULTS: The working rate before the onset of stroke ranged from 27% to 86%. At 12 months post stroke, the return to work varied from 11% to 43%. Consequently, many reported a reduced financial situation from 10% to 70% at 6 months and from 10% to 80% at 12 months. Access to postrehabilitation follow-up services varied in the different countries from 24% to 100% at 6 months and from 21% to 100% at 12 months. Physical therapy was the most common follow-up services reported. Persons with stroke were less active in recreational activities and experienced reduced social networks. Associations between results from the semistructured interviews and related themes in LiSat-11 were small to moderate. The study shows that education, age, and disability are predictors for return to work. Differences between countries were observed in the extent of unemployment. CONCLUSIONS: In this international multicentre study, return to work after severe stroke and specialized/comprehensive rehabilitation was possible, depending on the extent of the disability, age, and education. Altered financial situation, reduced social networks, and reduced satisfaction with life were common psychosocial situations for these patients. PMID- 30022610 TI - ddPCR applied on archived Continuous Plankton Recorder samples reveals long-term occurrence of class 1 integrons and a sulphonamide resistance gene in marine plankton communities. AB - Antibiotic resistance is a rising threat for human health. Although in clinical settings and terrestrial environments the rise of antibiotic resistant bacteria is well documented, their dissemination and spread in the marine environment, covering almost two-thirds of the Earth's surface, is still poorly understood. In this study, the presence and abundance of sulphonamide resistance gene (sul2) and class 1 integron-integrase gene (intI1), used as markers for the occurrence and spread of antibiotic resistance genes since the beginning of the antibiotic era, were investigated. Twenty-nine archived formalin-fixed samples, collected by the Continuous Plankton Recorder (CPR) survey in the Atlantic Ocean and North Sea from 1970 to 2011, were analysed using Droplet Digital PCR (ddPCR) applied for the first time on CPR samples. The two marker genes were present in a large fraction of the samples (48% for sul2 and 76% for intI1). In contrast, results from Real-Time PCR performed on the same samples greatly underestimate their occurrence (21% for sul2 and 52% for intI1). Overall, besides providing successful use of ddPCR for the molecular analysis of CPR samples, this study reveals long-term occurrence and spread of sul2 gene and class 1 integrons in the plankton-associated bacterial communities in the ocean. PMID- 30022612 TI - Accumulation of NO2 -cobalamin in nutrient-stressed ammonia-oxidizing archaea and in the oxygen deficient zone of the eastern tropical North Pacific. AB - Cobalamin (vitamin B12 ) is a precious resource in natural systems that is produced by select prokaryotes and required by a broad range of organisms. In this way, the production of cobalamin reinforces numerous microbial interdependencies. Here we report the accumulation of an unusual form of cobalamin, nitrocobalamin (NO2 -cobalamin), in a marine oxygen deficient zone (ODZ), isolates of ammonia-oxidizing archaea (AOA), and an anaerobic ammonium oxidizing (anammox) bacteria enriched bioreactor. Low oxygen waters were enriched in NO2 -cobalamin, and AOA isolates experiencing ammonia or copper stress produced more NO2 -cobalamin, though there is wide strain-to-strain and batch-to batch variability. NO2 -cobalamin has no known biochemical role. We hypothesize that AOA and anammox bacteria are a source of marine NO2 -cobalamin in the environment via a reactive nitrogen intermediate. These findings suggest connections between cobalamin forms and nitrogen transformations, physiological stress and ocean deoxygenation. PMID- 30022613 TI - Building Molecular Complexity from Quinizarin: Conjoined Coumarins and Coronene Analogs. AB - The double Knoevenagel condensation of 1,4-dibenzoyloxyanthraquinone with methyl esters of arylacetic acids affords a series of compounds based upon a previously unknown 1,8-dioxa-benzo[e]pyrene-2,7-dione heterocyclic core. The aryl groups incorporated in the 3- and 6-positions can be oxidatively coupled to the pi expanded backbone to produce a further new heterocyclic core: 1,10-dioxa dibenzo[dj]coronene-2,9-dione. The intriguing optical properties of these pi expanded coumarin derivatives are discussed and rationalized through quantum chemical calculations. The broad absorption bands of 1,8-dioxa-benzo[e]pyrene-2,7 dione-based dyes are attributed to both HOMO-1->LUMO and HOMO->LUMO transitions, which have a similar energy. Weakly coupled electron-donating aryl substituents result in a moderate bathochromic shift of both the absorption and emission by 30 60 nm in toluene. The emissive properties of these compounds are in part determined by the oscillator strength of the main transition, lifetimes of the excited state, and by the energy match of the excited state with a triplet state of a similar energy. The 1,10-dioxa-dibenzo[dj]coronene-2,9-dione displays a much smaller Stokes shift, yet a markedly increased fluorescence quantum yield of 90 % owing to the increased rigidity compared with the 1,8-dioxa-benzo[e]pyrene-2,7 dione core. PMID- 30022611 TI - The Phosphodiesterase 9 Inhibitor PF-04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning. AB - The cyclic nucleotide cGMP is an intracellular second messenger with important roles in neuronal functions and animals' behaviors. The phosphodiesterases (PDEs) are a family of enzymes that hydrolyze the second messengers cGMP and cAMP. Inhibition of phosphodiesterase 9 (PDE9), a main isoform of PDEs hydrolyzing cGMP, has been shown to improve learning and memory as well as cognitive function in rodents. However, the role of PDE9 in regulating neuronal structure and function in vivo remains unclear. Here we used in vivo two-photon microscopy to investigate the effect of a selective PDE9 inhibitor PF-04449613 on the activity and plasticity of dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex. We found that administration of PF-04449613 increased calcium activity of dendrites and dendritic spines of layer V pyramidal neurons in mice under resting and running conditions. Chronic treatment of PF-04449613 over weeks increased dendritic spine formation and elimination under basal conditions. Furthermore, PF-04449613 treatment over 1-7 days increased the formation and survival of new spines as well as performance improvement after rotarod motor training. Taken together, our studies suggest that elevating the level of cGMP with the PDE9 inhibitor PF-04449613 increases synaptic calcium activity and learning-dependent synaptic plasticity, thereby contributing to performance improvement after learning. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018. PMID- 30022614 TI - Desymmetrization of Achiral Heterobicyclic Alkenes through Catalytic Asymmetric Hydrophosphination. AB - Asymmetric addition of diarylphosphines to oxa- and azabicyclic alkenes proceeded in the presence of a chiral phosphapalladacycle catalyst and a mild acid at room temperature to give exclusively the enantioenriched addition products in excellent yields and good selectivities. Three new chiral carbon centers were generated stereoselectively by the catalytic hydrophosphination reaction. PMID- 30022615 TI - Professions and the Social Order: Some Lessons from Burkina Faso? AB - The study of professions has been dominated by Anglo-American models, with their focus on a small group of legally licensed occupations. The field has recently shifted, mainly through studies of European experience, to a wider examination of the social management of expert workers. Very little has been written about developments in Africa and their implications for the way in which we might think about professions. This paper presents a case study of the role and practices of the medical profession in Burkina Faso, which has a relatively open market for the supply of healing services and limited regulation of the suppliers, whether physicians or traditional practitioners. The study returns to classic questions about the extent to which practice is shaped by the nature of occupational niches within the division of labor or to the development of a distinctive moral character among the workers within that niche. PMID- 30022616 TI - Daily pain measurements and retrospective pain measurements in hip osteoarthritis patients with intermittent pain. AB - OBJECTIVE: To examine the value of daily pain measurements in hip osteoarthritis patients, and if the reliability of retrospective measurements was lower in patients with intermittent pain than in patients with a more constant pain. METHODS: We used data from a randomised controlled trial that investigated the effectiveness of general practitioner care plus exercise therapy in 203 patients with hip osteoarthritis. During the first 6 weeks, patients scored their pain each day. These daily measurements were available for 185 patients. At 6-weeks follow-up, patients filled in a retrospective measurement rating their pain during the previous week. We examined if the daily measurements provided other results of pain than the retrospective measurements, using a linear mixed model. We also explored differences between subgroups, based on frequency and severity of intermittent pain, in the course of pain and in the reliability between the retrospective measurements and the daily measurements. RESULTS: Daily measurements showed no different effect of exercise therapy on pain than the retrospective measurements. We found statistical differences (ANOVA) in the course of pain between the subgroups based on intensity of intermittent pain. The reliability between retrospective and daily measurements was lower in the subgroup with severe intermittent pain (Cronbach's alpha=0.642) than in other subgroups (Cronbach's alpha >0.843). CONCLUSION: In this specific trial, the daily measurements did not yield more precise or additional information than the retrospective measurements at 6-weeks follow-up. However, the reliability of retrospective measurements may be lower in patients with a higher intensity of intermittent pain. This article is protected by copyright. All rights reserved. PMID- 30022617 TI - Computational methods for analyzing and modeling genome structure and organization. AB - Recent advances in chromosome conformation capture technologies have led to the discovery of previously unappreciated structural features of chromatin. Computational analysis has been critical in detecting these features and thereby helping to uncover the building blocks of genome architecture. Algorithms are being developed to integrate these architectural features to construct better three-dimensional (3D) models of the genome. These computational methods have revealed the importance of 3D genome organization to essential biological processes. In this article, we review the state of the art in analytic and modeling techniques with a focus on their application to answering various biological questions related to chromatin structure. We summarize the limitations of these computational techniques and suggest future directions, including the importance of incorporating multiple sources of experimental data in building a more comprehensive model of the genome. This article is categorized under: Analytical and Computational Methods > Computational Methods Laboratory Methods and Technologies > Genetic/Genomic Methods Models of Systems Properties and Processes > Mechanistic Models. PMID- 30022618 TI - Primary Baerveldt versus trabeculectomy study after one-year follow-up. AB - PURPOSE: To compare a Baerveldt implant and trabeculectomy with respect to intraocular pressure (IOP) and failure rate at 1 year of follow-up. Secondary outcomes are pharmacological therapy and complications at 1 year of follow-up. METHODS: This was a randomized, comparative study. A total of 119 glaucoma patients without previous ocular surgery were included at the Rotterdam Eye Hospital, the Netherlands. One eye of each subject was randomized to either a Baerveldt glaucoma drainage device (BGI) or trabeculectomy (TE). Follow-up visits were conducted at 1 day, 2 weeks, 6 weeks, 3 months, 6 months and 1 year after surgery. RESULTS: After one year, the final IOP was equivalent for both treatment groups: 14 +/- 4 mmHg (mean +/- SD) for the Baerveldt group versus 13 +/- 4 mmHg for the trabeculectomy group. Statistically, we found no significant difference in failure rate between the two groups. However, the Baerveldt group needed significantly more medication to decrease IOP. Overall, self-limiting complication rate was similar in both groups. Diplopia, a serious complication, was significantly more present in the BGI group. CONCLUSION: One year after surgery, TE shows better results than the BGI. The final IOP, IOP reduction and failure rate are similar, but the need for additional IOP lowering medication in the BGI group is higher as well as the complication rate. The increased risk of developing diplopia after placement of a BGI must be taken into consideration. PMID- 30022619 TI - PV Analyzer: A Decision Support System for Photovoltaic Solar Cells Libraries. AB - This work describes the integration of several data mining and machine learning tools for researching Photovoltaic (PV) solar cells libraries into a unified workflow embedded within a GUI-supported Decision Support System (DSS), named PV Analyzer. The analyzer's workflow is composed of several data analysis components including basic statistical and visualization methods as well as an algorithm for building predictive machine learning models. The analyzer allows for the identification of interesting trends within the libraries, not easily observable using simple bi-parametric correlations. This may lead to new insights into factor affecting solar cells performances with the ultimate goal of designing better solar cells. The analyzer was developed using MATLAB version R2014a and consequently could be easily extended by adding additional tools and algorithms. Furthermore, while in our hands, the analyzer has been primarily used in the area of PV cells, is it equally applicable to the analysis of any other dataset composed of activities as dependent variables and descriptors as independent variables. PMID- 30022620 TI - Effect of a new self-care guide package on maternal and neonatal outcomes in gestational diabetes: A randomized control trial. AB - BACKGROUND: The aim of this study was to determine the effect of a new self-care guide package on gestational diabetes mellitus (GDM). METHODS: This randomized clinical trial was conducted on 152 women with GDM. The intervention group was provided with the self-care guide package and three face-to-face educational sessions. The control group received routine clinical services, including physician visits and short training regarding nutrition, blood glucose control, and insulin injections. The primary outcomes were fasting and 2-h postprandial blood glucose and self-efficacy measured at the beginning of the study and 1 month after the end of the intervention. Secondary outcomes included Apgar scores, birth weight, type of delivery, and newborn hospitalization. Data were analyzed using t-tests, as well as Mann-Whitney, Chi-squared, and linear and logistic regression tests. RESULTS: The mean (+/-SD) self-efficacy score was higher in the intervention than control group (74.4 +/- 7.0 vs 36.4 +/- 5.2, respectively; P < 0.001). There was no significant difference in mean fasting plasma glucose between the two groups (P = 0.163), but mean 2-h postprandial plasma glucose was lower in the intervention than control group (105.1 +/- 17.6 vs 127.2 +/- 20.4 mg/dL, respectively; P < 0.001). There were no significant differences in the weight and age of the neonate at delivery or in the type of delivery between the two groups. However, the newborn hospitalization rate was higher in the control group (P < 0.001). CONCLUSION: The use of a self-care package had a positive effect on maternal self-efficacy and 2-h postprandial plasma glucose, Apgar scores, and neonatal hospitalization. PMID- 30022621 TI - BeSMART2: What is the Best Supportive Management for Adults Referred with Tonsillopharyngitis? Our experience surveying the attitudes of 80 patients and professionals. PMID- 30022622 TI - Interstage outcomes in single ventricle patients undergoing hybrid stage 1 palliation. AB - OBJECTIVE: Interstage readmissions are common in infants with single ventricle congenital heart disease undergoing staged surgical palliation. We retrospectively examined readmissions during the interstage period. DESIGN: Retrospective analysis. SETTING: The Heart Center at Nationwide Children's Hospital, Columbus, Ohio. PATIENTS: Newborns undergoing hybrid stage 1 palliation from January 2012 to December 2016 who survived to hospital discharge and were followed at our institution. INTERVENTIONS: All patients underwent hybrid stage 1 palliation. OUTCOME MEASURES: Outcomes included (1) reason for interstage readmission; (2) feeding modality during interstage period; (3) major interstage adverse events; and (4) interstage mortality. RESULTS: Study group comprised 57 patients. Five patients only admitted once during the interstage period for scheduled cardiac catheterization were included in the no readmission group. Therefore, 43 patients (75%) had a total of 87 interstage readmissions. Fourteen patients had 15 major interstage adverse events accounting for 17% of total readmissions. Stroke (n = 1); sepsis (n = 1); pericardial effusion requiring drainage (n = 1); mesenteric ischemia (n = 1); shock (n = 1); and cardiac catheterization requiring intervention (n = 11)-ductal stent balloon angioplasty (n = 3), enlargement of atrial septal defect/stent placement (n = 3), retrograde aortic arch stenosis (n = 4). Thirty-three readmissions were secondary to gastrointestinal/feeding issues; 15 cyanosis; 15 work of breathing; and 9 asymptomatic patients. Four patients suffered interstage deaths (7%). Five patients (9%) spent >30 days in the hospital during the interstage period. Of the 47 newborns (82%) discharged exclusively orally feeding, 74% remained all orally feeding throughout interstage period. No patient discharged with tube feedings learned to eat during the interstage period. CONCLUSION: Interstage readmissions are common in the hybrid patient population. Seventeen percent were secondary to major adverse events. Interstage mortality was 7%. Future studies to identify interventions aimed at decreasing feeding issues and viral bronchiolitis in this tenuous patient population will hopefully improve quality outcomes, reduce readmissions, and lessen health care costs. PMID- 30022624 TI - Insights into Carbon Dioxide Electroreduction in Ionic Liquids: Carbon Dioxide Activation and Selectivity Tailored by Ionic Microhabitat. AB - Electroreduction of carbon dioxide (CO2 ) into high value-added products is a potential solution to a reduction in CO2 levels and its utilization. One major challenge is the lack of an efficient system that can highly selectively reduce CO2 into desirable products with low energy consumption. Ionic liquids (ILs) have been used as electrolytes for the electroreduction of CO2 , and it has been proven that the CO2 -cation complex results in a low-energy pathway. In this work, an ionic microhabitat (IMH) has been built for CO2 electroreduction, and a novel anion-functionalized IL, 1-butyl-3-methylimidazolium 1,2,4triazolide ([Bmim][124Triz]), has been designed as the reaction medium. The results showed that the IMH played a key role in enhancing the performance of CO2 electroreduction, especially in dominating the product selectivity, which is recognized to be a great challenge in an electroreduction process. New insights into the role of the IMH in higher CO2 solubility, bending linear CO2 by forming the [124Triz]-CO2- adduct, and transferring activated CO2 into the cathode surface easily were revealed. The Faradaic efficiency for formic acid is as high as 95.2 %, with a current density reaching 24.5 mA cm-2 . This work provides a promising way for the design of robust and highly efficient ILs for CO2 electroreduction. PMID- 30022623 TI - CD164 promotes tumor progression and predicts the poor prognosis of bladder cancer. AB - CD164 was found to play a role in many malignant diseases. But the roles of CD164 in human bladder cancer have not yet been studied. The object of our study was to investigate the functions of CD164 in urothelial bladder carcinoma. The immunohistochemistry (IHC) was performed to evaluate the associations between the expression level of CD164 and clinical-pathological features of patients, and IHC was used to analyze the relationship between CD164 and CXCR4 in tumor tissues. Real-time qPCR and Western blot were used to measure the expression of relevant genes. The roles of CD164 in tumor cells and tissues were investigated by in vitro and in vivo experiments. The results of immunohistochemistry found that CD164 was associated with clinical and pathological features of patients. High level of CD164 was related to the distant metastasis and vascular invasion of bladder cancer patients. In vitro, by silencing of CD164, the proliferation, migration, and invasion of tumor cells were inhibited significantly by regulating related proteins such as Ki67, proliferating cell nuclear antigen, matrix metalloproteinases-2, and matrix metalloproteinases-9. In vivo, knocking-down of CD164 could reduce the growth and metastasis of tumors in mice. In addition, a co expression was found between CD164 and CXCR4 in tumor tissues. In conclusion, our study demonstrated that CD164 was associated with the poor clinical outcomes of BC patients. Silencing of CD164 could inhibit the progression of tumors in vivo and in vitro, which may become an effective target in the treatment of bladder cancer. PMID- 30022626 TI - Sequential Preparation of Dual-Layer Fluorine-Doped Tin Oxide Films for Highly Efficient Perovskite Solar Cells. AB - A dual-layer fluorine-doped tin oxide (FTO) film has been fabricated by means of sequential spray pyrolysis for high-efficiency perovskite solar cells (PSCs). The H-FTO/L-FTO dual layer film consists of a H-FTO layer prepared at high deposition temperature (~450 degrees C) and a L-FTO layer, fabricated at low deposition temperature (~150 degrees C), which is used to replace the traditional compact TiO2 /FTO layer. The effects of F/Sn molar ratio, precursor solution concentration, and deposition temperature on the electrical, optical, surface morphological, and grain structural characteristics of H-FTO layers have been studied systematically. With an increase in precursor solution concentration, the mobility and carrier concentration of H-FTO increases; however, the grain size and sheet resistance decreases as the precursor solution concentration increases. A high deposition temperature results in a large grain size and enhanced haze value. The L-FTO layer expresses compact layer growth, inconsistent with the H FTO surface structure, and possesses excellent electron collection and transport efficiency. The effect of the hole-blocking characteristics of L-FTO on the PSC performance is studied. This study provides a novel dual-layer FTO film to replace the traditional compact TiO2 /FTO layer, which is usually prepared by coating TiO2 precursor on FTO following calcination at 450 degrees C. The H FTO/L-FTO dual-layer film can simplify the fabrication process and maintain a high power conversion efficiency (PCE); this results in more efficient electron transportation and blocking of holes. The champion device of PSCs with H-FTO/L FTO shows the highest PCE of 17.37 % under the illumination of 100 mW cm-2 (AM1.5G). PMID- 30022625 TI - A novel microbial technique for producing high-quality sophorolipids from horse oil suitable for cosmetic applications. AB - Horse oil contains linoleic, palmitoleic and unsaturated fatty acids that are similar to those in human skin, and may therefore be an ideal substance from which to isolate biosurfactants for cosmetic products to improve human skin quality. Herein, an innovative approach was developed to synthesise sophorolipids from horse oil by hydrolysis, followed by fermentation using the yeast Candida bombicola. The yield of sophorolipids from direct fermentation of horse oil and hydrolysed horse oil was 40.6 +/- 1.3 g l-1 and 58.4 +/- 1.8 g l-1 respectively. To further increase the yield, 30-40 g l-1 glucose was added in a fed-batch fermentation process to maintain the pH between 4.0 and 4.5, resulting in a conversion yield of 71.7 +/- 0.8 g l-1 . The purity and structure of the synthesised sophorolipids were analysed by ultra-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. An in vitro human dermal fibroblast model was used as a surrogate for human skin to measure elastase inhibition activity. Antiwrinkle properties of isolated sophorolipids were better than those of horse oil or hydrolysed horse oil in several in vitro assays. Furthermore, no cytotoxicity was observed at a concentration of 50 MUg ml 1 , and wound-healing capacity was evident in a cell culture model. Additionally, the synthesised sophorolipids attenuated lipopolysaccharide-induced expression of inflammatory cytokines in macrophages, and efficiently inhibited several strains of bacteria and yeast. In conclusion, fed-batch fermentation of hydrolysed horse oil is a novel and efficient approach for producing high-quality and high-yield sophorolipids that exhibit great potential as cosmetic ingredients. PMID- 30022628 TI - Burden of cervical neoplasia in mid-western rural Nepal: a population-based study. AB - OBJECTIVE: To assess the burden of cervical neoplasia in mid-western rural, Nepal using cytology, visual inspection with acetic acid (VIA) and visual inspection with Lugol's iodine (VILI). METHOD: A cross-sectional, population-based study was conducted. Total of 2,279 married, non-pregnant women aged 20-65 years participated in a screening clinic from May 2016 to January 2017. All eligible women completed self-report of socio-demographic and reproductive health data followed by screening tests. Biopsies were obtained from areas on the cervix assessed by VIA and or VILI to be abnormal. Final disease was confirmed by biopsy report. RESULTS: A total of 96.09% (n=2,190) women were eligible for this study with mean age 32.78+/-9.33 years. The overall rate of positive cytology, VIA, and VILI were 3.69%, 12.45%, and 16.89%, respectively. Sixty-two cases were biopsy proven cervical neoplasia. Altogether 78 (3.69%) cases were cytologically abnormal: 25 (1.18%) were atypical squamous cells of undetermined significance, 33 (1.56%) were low-grade squamous intraepithelial lesion, 11 (0.52%) were high grade squamous intraepithelial lesion, and 9 (0.42%) were squamous cell carcinoma. Illiterate women appeared to be at higher risk for cervical neoplasia (p<0.001). Similarly, age >=46 years (p<0.013), participant's multiple marriages or sexual partners (p<0.005), and positive human immunodeficiency virus status (p<0.001) were significantly associated with abnormal cytology. CONCLUSION: Based on cytology report, there is 3.69% prevalence of cervical neoplasia among women in a rural region of mid-western, Nepal. A "screen and treat" approach would be more attractive in low resource settings. PMID- 30022627 TI - Prognostic impact of reduced tumor-free margin distance on long-term survival in FIGO stage IB/II vulvar squamous cell carcinoma. AB - OBJECTIVE: We aimed to identify the minimum tumor-free margin distance conferring long-term oncological safety in patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB/II vulvar squamous cell carcinoma (VSCC). METHODS: This was a retrospective cohort study in patients with stage IB/II VSCC treated at a single institution in Turin, Italy. The main aim was to identify the minimum tumor-free margin distance that confers oncological safety in early-stage VSCC. Patients were divided in groups according to tumor-free histological margin distance to compare survival outcomes. Overall survival (OS), disease-specific survival (DSS), and recurrence rate (RR) were estimated by the Kaplan-Meier method for the newly proposed and the currently recommended 8 mm margin cut-off. Log-rank test was used to compare survival between groups. RESULTS: One hundred and fourteen patients met the study criteria. Median age was 68 years and median follow-up was 80 months. The minimum margin distance that conferred long-term oncological safety was 5 mm. OS, DSS were significantly lower in the <5 mm group when compared with the >=5 mm group (p=0.002 and p=0.033, respectively) although no difference in RR was observed between groups. Analysis at the 8-mm cut-off indicated there is no difference in OS, DSS, or RR between groups. CONCLUSION: FIGO stage IB/II VSCC patients' prognosis is affected by margin distance. Long-term survival is significantly reduced in patients with tumor-free margins <5 mm, even in the absence of lymph node metastasis. Thus, these patients should be offered further surgical or adjuvant treatment. PMID- 30022630 TI - Artificial intelligence weights the importance of factors predicting complete cytoreduction at secondary cytoreductive surgery for recurrent ovarian cancer. AB - OBJECTIVE: Accumulating evidence support that complete cytoreduction (CC) at the time of secondary cytoreductive surgery (SCS) improves survival in patients affected by recurrent ovarian cancer (ROC). Here, we aimed to determine whether artificial intelligence (AI) might be useful in weighting the importance of clinical variables predicting CC and survival. METHODS: This is a retrospective study evaluating 194 patients having SCS for ROC. Using artificial neuronal network (ANN) analysis was estimated the importance of different variables, used in predicting CC and survival. ANN simulates a biological neuronal system. Like neurons, ANN acquires knowledge through a learning-phase process and allows weighting the importance of covariates, thus establishing how much a variable influences a multifactor phenomenon. RESULTS: Overall, 82.9% of patients had CC at the time of SCS. Using ANN, we observed that the 3 main factors driving the ability of achieve CC included: disease-free interval (DFI) (importance: 0.231), retroperitoneal recurrence (importance: 0.178), residual disease at primary surgical treatment (importance: 0.138), and International Federation of Gynecology and Obstetrics (FIGO) stage at presentation (importance: 0.088). Looking at connections between different covariates and overall survival (OS), we observed that DFI is the most important variable influencing OS (importance: 0.306). Other important variables included: CC (importance: 0.217), and FIGO stage at presentation (importance: 0.100). CONCLUSION: According to our results, DFI should be considered as the most important factor predicting both CC and OS. Further studies are needed to estimate the clinical utility of AI in providing help in decision making process. PMID- 30022629 TI - A triage strategy in advanced ovarian cancer management based on multiple predictive models for R0 resection: a prospective cohort study. AB - OBJECTIVE: To present the surgical outcomes of advanced epithelial ovarian cancer (AEOC) since the implementation of a personalized approach and to validate multiple predictive models for R0 resection. METHODS: Personalized strategies included: 1) Non-invasive model: preoperative clinico-radiological assessment according to Suidan criteria with a predictive score for all individuals. Patients with a score 0-2 were recommended for primary debulking surgery (PDS, group A), or otherwise were counseled on the choices of PDS, neoadjuvant chemotherapy (NAC, group B) or staging laparoscopy (S-LPS). 2) Minimally invasive model: S-LPS with a predictive index value (PIV) according to Fagotti. Individuals with a PIV <8 underwent PDS (group C) or otherwise received NAC (group D). Intraoperative assessment (with Eisenkop, peritoneal cancer index [PCI], and Aletti scores) and surgical results were prospectively collected. RESULTS: Between September 2015 and August 2017, 161 pathologically confirmed epithelial ovarian cancer patients were included. A total of 52 (32.3%) patients had a predictive score of 0-2, and 109 (67.7%) patients had a score >=3. Among these individuals, 41 (25.5%) patients received S-LPS. Finally, 110 (68.3%) patients underwent PDS (A+C), and 51 (31.7%) patients received NAC (B+D). The R0 resection rates in PDS and NAC patients were 56.4% and 60.8%, respectively. The area under the curve (AUC) of Suidan criteria was 0.548 for group (A+C). The AUC of Fagotti score was 0.702 for group C. The AUC of Eisenkop, PCI, and Aletti scores were 0.808, 0.797, and 0.524, respectively. CONCLUSION: The Suidan criteria were not effective in these AEOC patients. S-LPS was helpful in decision making for PDS and should be endorsed in the future. PMID- 30022631 TI - Clinical associations of Trousseau's syndrome associated with cerebral infarction and ovarian cancer. AB - OBJECTIVE: Since there have been few large series studies to date, we investigated the relationship between Trousseau's syndrome associated with cerebral infarction and its clinical associations with ovarian cancer. METHODS: In this study, we investigated the association between cerebral infarction onset and ovarian cancer. Eight-hundred twenty-seven consecutive ovarian cancer patients from 4 affiliated academic institutions were included in the study over a 12 years period. All patients were histopathologically diagnosed as epithelial ovarian cancer and were analyzed retrospectively. RESULTS: The 27 patients (3.2%) presented with cerebral infarction during the study period, 14 patients onset prior to treatment (1.7%), and 13 patients onset after start of initial treatment (1.5%). Univariate analysis and multivariate analysis was performed for onset of Trousseau's syndrome and various clinical and pathological parameters. There was no statistical significance between the occurrence of Trousseau's syndrome with age or International Federation of Gynecology and Obstetrics (FIGO) stage; however, univariate analysis and multivariate analysis demonstrated a statistically significant association between clear cell carcinoma (CCC) and non CCC histology. CONCLUSION: Thus, our results demonstrate that Trousseau's syndrome with cerebral infarction occurred with greater incidence among CCC cases compared to non-CCC cases. PMID- 30022632 TI - The influence of surgeon volume on outcomes after pelvic exenteration for a gynecologic cancer. AB - OBJECTIVE: To determine the effect of surgeon experience on intraoperative, postoperative and long-term outcomes among patients undergoing pelvic exenteration for gynecologic cancer. METHODS: This was a retrospective analysis of all women who underwent exenteration for a gynecologic malignancy at MD Anderson Cancer Center, between January 1993 and June 2013. A logistic regression was used to model the relationship between surgeon experience (measured as the number of exenteration cases performed by the surgeon prior to a given exenteration) and operative outcomes and postoperative complications. Cox proportional hazards regression was used to model survival outcomes. RESULTS: A total of 167 exenterations were performed by 19 surgeons for cervix (78, 46.7%), vaginal (43, 25.8%), uterine (24, 14.4%), vulvar (14, 8.4%) and other cancer (8, 4.7%). The most common procedure was total pelvic exenteration (69.4%), incontinent urinary diversion (63.5%) and vertical rectus abdominis musculocutaneous reconstruction (42.5%). Surgical experience was associated with decreased estimated blood loss (p<0.001), intraoperative transfusion (p=0.009) and a shorter length of stay (p=0.03). No difference was noted in the postoperative complication rate (p=0.12-0.95). More surgeon experience was not associated with overall or disease specific survival: OS (hazard ratio [HR]=1.02; 95% confidence interval [CI]=0.97-1.06; p=0.46) and DSS (HR=1.01; 95% CI=0.97 1.04; p=0.66), respectively. CONCLUSION: Patients undergoing exenteration by more experienced surgeons had improvement in intraoperative factors such as estimated blood loss, transfusion rates and length of stay. No difference was seen in postoperative complication rates, overall or disease specific survival. PMID- 30022633 TI - Adequate pelvic lymphadenectomy and survival of women with early-stage epithelial ovarian cancer. AB - OBJECTIVE: To examine the trends and survival for women with early-stage epithelial ovarian cancer who underwent adequate lymphadenectomy during surgical treatment. METHODS: This is a retrospective observational study examining the Surveillance, Epidemiology, End Results program between 1988 and 2013. We evaluated 21,537 cases of stage I-II epithelial ovarian cancer including serous (n=7,466), clear cell (n=6,903), mucinous (n=4,066), and endometrioid (n=3,102) histology. A time-trend analysis of the proportion of patients who underwent adequate pelvic lymphadenectomy (>=8 per Gynecologic Oncology Group [GOG] criteria, >=12 per Collaborative Group Report [CGR] criteria for bladder cancer, and >22 per Mayo criteria for endometrial cancer) and a survival analysis associated with adequate pelvic lymphadenectomy were performed. RESULTS: There were significant increases in the proportion of women who underwent adequate lymphadenectomy: GOG criteria 3.6% to 28.6% (1988-2010); CGR criteria 2.4% to 22.4% (1988-2013); and Mayo criteria 0.7% to 9.5% (1988-2013) (all, p<0.05). On multivariable analysis, adequate lymphadenectomy was independently associated with improved cause-specific survival compared to inadequate lymphadenectomy: GOG criteria, adjusted-hazard ratio (HR)=0.75, CGR criteria, adjusted-HR=0.77, and Mayo criteria, adjusted-HR=0.85 (all, p<0.05). Compared to inadequate lymphadenectomy, adequate lymphadenectomy was significantly associated with improved cause-specific survival for serous (HR range=0.67-0.73), endometrioid (HR range=0.59-0.61), and clear cell types (HR range=0.66-0.73) (all, p<0.05) but not in mucinous type (HR range=0.80-0.91; p>0.05). CONCLUSION: Quality of lymphadenectomy during the surgical treatment for early-stage epithelial ovarian cancer has significantly improved. Adequate lymphadenectomy is associated with a 15%-25% reduction in ovarian cancer mortality compared to inadequate lymphadenectomy. PMID- 30022634 TI - Negative peritoneal washing cytology during interval debulking surgery predicts overall survival after neoadjuvant chemotherapy for ovarian cancer. AB - OBJECTIVE: Optimal debulking in interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) has been reported as a prognostic factor for patients with ovarian cancer. However, the identification of microscopic residual disease (MRD) using visualization and palpation is subjective. Peritoneal washing cytology (PWC) during IDS is an easy-to-implement, objective approach for assessing disease status, although its clinical relevance and association with MRD is not known. The aim of this study was to evaluate the efficacy of PWC during IDS. METHODS: In total, 164 patients diagnosed with ovarian cancer at our institution were retrospectively evaluated, including 64 who had received NAC. Seventeen patients had undergone an exploratory laparotomy followed by NAC, while the remaining patients were diagnosed based on imaging, peritoneal cytology, and tumor markers. The PWC was performed before intraperitoneal observation at laparotomy during IDS. RESULTS: NAC-treated patients had stage III-IV disease. IDS was performed in 78.1% of NAC-treated patients. Seventeen patients (26.6%) were PWC-negative and 33 patients (51.6%) were PWC-positive. Fourteen patients (21.9%) had progressive disease and were ineligible for IDS. The median overall survival of the PWC-negative, PWC-positive, and non-IDS groups was 47, 18, and 5 months, respectively. The differences were significant (p<0.01). PWC was an independent prognostic factor in the multivariate Cox regression analysis (p<0.001). CONCLUSION: PWC during IDS may be a prognostic factor for NAC-treated patients with ovarian cancer. PWC may be more useful than visualization and palpation in IDS for determining the presence of MRD. PMID- 30022635 TI - The influence of hormone therapy with drospirenone-estradiol on endometrioid type endometrial cancer patients. AB - OBJECTIVE: To determine whether drospirenone/estradiol (DRSP/E2) has an adverse effect on clinical outcomes in surgically staged International Federation of Gynecology and Obstetrics (FIGO) stage I/II endometrial cancer (EC) patients. METHODS: In a retrospective case-controlled study, 58 women with EC who had received DRSP/E2 postoperatively were compared with 116 women who had not. And, oncologic safety of postoperative hormone therapy with DRSP/E2 in EC survivors were compared between the 2 groups after propensity score matching using a logistic regression model. RESULTS: The median ages were 47.7 years and 53.6 years for the study and the control groups, respectively (p<0.001). The study group had similar parity (p=0.71), lower body mass index (p=0.03) and more premenopausal women (p<0.001) than the control group. The stages were completely matched. The grades (p=0.42), lymphovascular space invasion (p=0.23), preoperative cancer antigen 125 (CA 125) level (p=0.89), and hormone receptor status (p=0.07) were similar in both groups. The median tumor diameter was statistically larger in the study group than in the control group (p<0.001). Both group received similar adjuvant therapy (p=0.80). In the propensity matching, only hormone receptor status was significantly different (p=0.03). In the univariate analysis, only stage was significantly associated with disease-free survival (DFS) and there was no variable associated with overall survival (OS). And, there was no significant factor identified in multivariate analysis. The difference in the DFS (p=0.63) and in the OS (p=0.32) was not significant. The same results were obtained after propensity score matching. CONCLUSION: Postoperative hormone therapy with DRSP/E2 in EC survivors did not increase recurrence or the death rate. PMID- 30022636 TI - Treatment outcomes of patients with stage II pure endometrioid-type endometrial cancer: a Taiwanese Gynecologic Oncology Group (TGOG-2006) retrospective cohort study. AB - OBJECTIVE: Choice of hysterectomy and adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) 2009 stage II endometrioid endometrial cancer (EEC) is still controversial. Aims of this study were to evaluate survival benefits and adverse effects of different hysterectomies with or without adjuvant radiotherapy (RT), and to identify prognostic factors. METHODS: The patients at 14 member hospitals of the Taiwanese Gynecologic Oncology Group from 1992 to 2013 were retrospectively investigated. Patients were divided into simple hysterectomy (SH) alone, SH with RT, radical hysterectomy (RH) alone, and RH with RT groups. Endpoints were recurrence-free survival (RFS), overall survival (OS), disease-specific survival (DSS), adverse effects and prognostic factors for survival. RESULTS: Total of 246 patients were enrolled. The 5-year RFS, OS, DSS and recurrence rates for the entire cohort were 89.5%, 94.3%, 96.2% and 10.2%, respectively. Patients receiving RH had more adverse effects including blood loss (p<0.001), recurrent urinary tract infections (p=0.013), and leg lymphedema (p=0.038). Age over 50-year (HR=9.2; 95% confidence interval [CI]=1.2-70.9) and grade 3 histology (HR=7.28; 95% CI=1.45-36.6) were independent predictors of OS. Grade 3 histology was an independent predictor of RFS (HR=5.13; 95% CI=1.38-19.1) and DSS (HR=5.97; 95% CI=1.06-58.7). Patients receiving adjuvant RT had lower locoregional recurrence (p=0.046), but no impact on survival. CONCLUSION: Different treatment modalities yield similar survival outcomes. Patients receiving SH with RT had lower locoregional recurrent with acceptable morbidity. Age and tumor grading remained significant predictors for survival among patients with FIGO 2009 stage II EEC. PMID- 30022637 TI - Efficacy of palonosetron plus dexamethasone in preventing chemotherapy-induced nausea and emesis in patients receiving carboplatin-based chemotherapy for gynecologic cancers: a phase II study by the West Japan Gynecologic Oncology Group (WJGOG 131). AB - OBJECTIVE: Palonosetron is effective for the management of acute and delayed chemotherapy-induced nausea and vomiting (CINV). While emetogenic carboplatin based chemotherapy is widely used to treat gynecologic cancers, few studies have evaluated the antiemetic effectiveness of palonosetron in this setting. METHODS: A multicenter, single-arm, open-label phase II trial was conducted to evaluate the safety and effectiveness of palonosetron in controlling CINV in patients with gynecologic cancer. Chemotherapy-naive patients received intravenous palonosetron (0.75 mg/body) and dexamethasone before the infusion of carboplatin-based chemotherapy on day 1. Dexamethasone was administered (orally or intravenously) on days 2-3. The incidence and severity of CINV were evaluated using the patient completed Multinational Association of Supportive Care in Cancer Antiemesis Tool and treatment diaries. The primary endpoint was the proportion of patients experiencing complete control (CC) of vomiting, with "no rescue antiemetic medication" and "no clinically significant nausea" or "only mild nausea" in the delayed phase (24-120 hours post-chemotherapy). Secondary endpoints were the proportion of patients with a complete response (CR: "no vomiting" and "no rescue antiemetic medication") in the acute (0-24 hours), delayed (24-120 hours), and overall (0-120 hours) phases, and CC in the acute and overall phases. RESULTS: Efficacy was assessable in 77 of 80 patients recruited. In the acute and delayed phases, the CR rates the primary endpoint, were 71.4% and 59.7% and the CC rates, the secondary endpoint, were 97.4% and 96.1%, respectively. CONCLUSION: While palonosetron effectively controls acute CINV, additional antiemetic management is warranted in the delayed phase after carboplatin-based chemotherapy in gynecologic cancer patients (Trial registry at UMIN Clinical Trials Registry, UMIN000012806). PMID- 30022638 TI - Using low-coverage whole genome sequencing technique to analyze the chromosomal copy number alterations in the exfoliative cells of cervical cancer. AB - OBJECTIVES: We analyzed the chromosomal-arm-level copy number alterations (CNAs) in the cervical exfoliative cell and tissue samples by using the low-coverage whole genomic sequencing technique. METHODS: In this study, we retrospectively collected 55 archived exfoliated cervical cell suspension samples and the corresponding formalin-fixed and paraffin-embedded tissue section samples including 27 invasive cervical cancer and 28 control cases. We also collected 19 samples of the cervical exfoliative cells randomly from women to verify the new algorithm model. We analyzed the CNAs in cervical exfoliated cell and tissue samples by using the low-coverage next generation of sequencing. RESULTS: In the model-building study, multiple chromosomal-arm-level CNAs were detected in both cervical exfoliated cell and tissue samples of all cervical cancer cases. By analyzing the consistency of CNAs between exfoliated cells and cervical tissue samples, as well as the heterogeneity in individual patient, we also established a C-score algorithm model according to the chromosomal-arm-level changes of 1q, 2q, 3p, 7q. The C-score model was then validated by the pathological diagnosis of all 74 exfoliated cell samples (including 55 cases in model-building group and 19 cases in verification group). In our result, a cutoff value of C-score >6 showed 100% sensitivity and 100% specificity in the diagnosis of cervical cancer. CONCLUSION: In this study, we found that CNAs of cervical exfoliated cell samples could robustly distinguish invasive cervical cancer from cancer-free tissues. And we have also developed a C-score algorithm model to process the sequencing data in a more standardized and automated way. PMID- 30022639 TI - Teenage pregnancy complicated by primary invasive ovarian cancer: association for oncologic outcome. AB - OBJECTIVE: To examine survival of teenage women with pregnancies complicated by primary ovarian cancer. METHODS: This is a secondary analysis of a previously organized systematic literature review of primary ovarian cancer diagnosed during pregnancy. Cases eligible for analysis were patients whose age at cancer diagnosis and survival outcome were known (n=201). Pregnancy and oncologic outcome were then examined based on patient age. RESULTS: These were comprised of 95 (47.3%) epithelial ovarian cancers (EOCs), 82 (40.8%) malignant germ cell tumors (MGCTs), and 24 (11.9%) sex-cord stromal tumors (SCSTs). Teenage pregnancy was seen in 21 (10%) cases, and was highest among the SCST group compared to the other cancer types (EOC, 1.1%; MGCT, 14.6%; and SCST, 29.2%, p<0.001). Live birth rates, neonatal weight, full term delivery rates, and Cesarean section rates were similar between the teenage group and the non-teenage group (all, p>0.05); however, teenage pregnancy was significantly associated with an increased risk of serious maternal/neonatal adverse events (50% vs. 22.7%, p=0.013). On univariable analysis, teenage pregnancy was significantly associated with decreased ovarian cancer-specific survival (5-year rate: age >=30, 79.6%; age 20-29, 87.2%; and age <20, 41.6%; p<0.001). On multivariable analysis controlling for calendar year, cancer type, cancer stage, and gestational age at ovarian cancer diagnosis, teenage pregnancy remained an independent prognostic factor for decreased ovarian cancer-specific survival compared to women aged >=30 (adjusted-hazard ratio=4.71; 95% confidence interval=1.17-18.9; p=0.029). CONCLUSION: Teenage women with pregnancies complicated by primary ovarian cancer may be at increased risk of poor survival from ovarian cancer. PMID- 30022640 TI - Erratum: Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube. AB - This corrects the article on p. e43 in vol. 29, PMID: 29770616. PMID- 30022642 TI - Enhancing in vivo renal ischemia assessment by high-dynamic-range fluorescence molecular imaging. AB - Fluorescence imaging has been used to evaluate the physiological features of renal ischemia in animal model. However, the fluorophore distribution details of the ischemia model could not be fully represented due to the limited dynamic range of the charged-couple device. A high-dynamic-range (HDR) strategy was adopted in renal ischemia fluorescence imaging, both ex vivo and in vivo. The HDR strategy successfully combined ischemia relevant biological features that could only be captured with different exposure times, and then presented these features in the HDR results. The HDR results effectively highlighted the renal ischemic areas with relatively better perfusion and diminished the saturation that resulted from long exposure time. The relative fluorescence intensities of the ischemic kidneys and the image entropy values were significantly higher in the HDR images than in the original images, therefore enhancing the visualization of the renal ischemia model. The results suggest that HDR could serve as a postprocessing strategy to enhance the assessment of in vivo renal ischemia, and HDR fluorescence molecular imaging could be a valuable imaging tool for future studies of clinical ischemia detection and evaluation. PMID- 30022641 TI - A practical guide to understanding, using and including patient reported outcomes in clinical trials in ovarian cancer. AB - Health related quality of life (HRQOL) is a key priority for patients with ovarian cancer as there is significant morbidity associated with the disease and the treatment. It is therefore essential to include measures of HRQOL and patient reported outcomes (PROs) in all clinical trials and ideally report them in the initial manuscript. The results of these analyses help interpret the primary trial endpoints which are typically progression free survival and overall survival from the perspective of the patients, but can also assist with regulatory approval of new drugs and inform future patients regarding the potential benefits and downsides of the treatment as well as help support clinical recommendations. Including PROs in clinical trials allows patient defined clinical benefits to be assessed in parallel to traditional survival outcomes to provide a more holistic overview and aid in the interpretation of the trial results. Given the importance of these instruments in clinical trials, greater effort is required to improve the appropriate inclusion, quality of analyses and reporting of PROs. It is also essential that all clinicians understand the intricacies of the selection, implementation and interpretation of these measures of HRQOL and PRO's and how important their contribution is to clinical trials as well as clinical practice. This review is a practical guide for clinicians to gain a better understanding of PROs and how they can be incorporated into ovarian cancer trials. PMID- 30022643 TI - Light-assisted drying for protein stabilization. AB - A light-based processing method to create an amorphous trehalose matrix for the stabilization of proteins is discussed. This method has potential applications in the stabilization of protein-based therapeutics and diagnostics. During light assisted drying (LAD), proteins suspended in a trehalose solution are dehydrated using near-infrared (NIR) laser light. The goal of this study was to determine processing parameters that resulted in fast processing times and low end moisture contents (EMC), while maintaining the functionality of embedded proteins. We compared the effect of changing processing wavelength, power and resulting sample temperature, and substrate material on the EMC for two NIR laser sources (1064 and 1850 nm). The 1850-nm laser resulted in the lowest EMC (0.03 +/- 0.01 gH2O / gDryWeight) after 20 min of processing on glass microfiber paper. This suggests a storage temperature of 68.3 degrees C. We also tested the functionality of a model protein, lysozyme, after LAD processing using a standard assay. LAD showed no significant effect on the functionality of lysozyme when processed at a maximum temperature of ~44 degrees C to an EMC of 0.17 +/- 0.06 gH2O / gDryWeight. LAD is a promising technique for forming amorphous trehalose solids that could stabilize proteins at ambient temperatures. PMID- 30022644 TI - A complex nursing intervention of CAM increase quality of life and satisfaction in lung cancer patients. PMID- 30022645 TI - Management of primary biliary cholangitis prior to obeticholic acid availability. A study from Turin, Italy. AB - BACKGROUND: Primary Biliary Cholangitis (PBC) is an autoimmune cholestatic liver disease with unknown etiology. The prognosis of patients affected by PBC is heterogeneous, with a relevant improvement achieved after the introduction of ursodeoxycolic acid (UDCA). Since in the last years obeticholic acid (OCA) has been approved for the combined treatment of PBC, in patient nonresponders to UDCA or as monotherapy in those intolerant to UDCA, we evaluated the response to UDCA in a cohort of patients with PBC managed in a specialistic setting. METHODS: We included 38 UCDA-treated non-cirrhotic, early-PBC patients. Data were retrieved from documents compiled during the annual follow-up. The response to therapy was assessed comparing the parameters of our cohort with the inclusion criteria of the POISE trial and the Paris I and Paris II criteria. RESULTS: The cohort included 34/38 female patients and the average age was 65.34+/-10.69 years. Over 50% of the patients were affected by at least one disease associated to PBC. Using the POISE criteria and the Paris I and Paris II criteria, we identified 5, 2 and 5 non-responders, respectively. All patients with severe fibrosis had a biochemical response to UDCA according to the three different criteria applied. No side effect was reported. CONCLUSIONS: We confirm that UDCA is a safe and effective treatment in patients with PBC. Non-responder patients represent 13% of our population, with high risk of disease progression and complications. In this context, further therapy using OCA should be considered. PMID- 30022652 TI - Design, synthesis and evaluation of pentacyclic triterpenoids similar to glycyrrhetinic acid via combination of chemical and microbial modification as glycogen phosphorylases inhibitor. AB - A series of pentacyclic triterpenoids similar to glycyrrhetinic acid were designed and synthesized via the combination of chemical modification and microbial catalysis. All products were screened for the glycogen phosphorylases inhibitory activities in vitro. Within this series of derivatives, compound 5 displayed good inhibitory activities with IC50 value of 27.7 MUM, which is better than that of the other derivatives and glycyrrhetinic acid. Structure-activity relationship (SAR) analysis of these inhibitors was also discussed. PMID- 30022654 TI - Duty-Hour Flexibility Trial in Internal Medicine. PMID- 30022655 TI - Duty-Hour Flexibility Trial in Internal Medicine. PMID- 30022656 TI - Duty-Hour Flexibility Trial in Internal Medicine. PMID- 30022657 TI - Graphene Oxide Signal Reporter Based Multifunctional Immunosensing Platform for Amperometric Profiling of Multiple Cytokines in Serum. AB - Cytokines are small proteins and form complicated cytokine networks to report the status of our health. Thus, accurate profiling and sensitive quantification of multiple cytokines is essential to have a comprehensive and accurate understanding of the complex physiological and pathological conditions in the body. In this study, we demonstrated a robust electrochemical immunosensor for the simultaneous detection of three cytokines IL-6, IL-1beta, and TNF-alpha. First, graphene oxides (GO) were loaded with redox probes nile blue (NB), methyl blue (MB), and ferrocene (Fc), followed by covalent attachment of anti-cytokine antibodies for IL-6, IL-1beta, and TNF-alpha, respectively, to obtain Ab2-GO-NB, Ab2-GO-MB, and Ab2-GO-Fc, acting as the signal reporters. The sensing interface was fabricated by attachment of mixed layers of 4-carboxylic phenyl and 4 aminophenyl phosphorylcholine (PPC) to glassy carbon surfaces. After that, the capture monoclonal antibody for IL-6, IL-1beta, and TNF-alpha was modified to the carboxylic acid terminated sensing interface. And finally a sandwich assay was developed. The quantitative detection of three cytokines was achieved by observing the change in electrochemical signal from signal reporters Ab2-GO-NB, Ab2-GO-MB, and Ab2-GO-Fc. The designed system has been successfully used for detection of three cytokines (IL-6, IL-1beta, and TNF-alpha) simultaneously with desirable performance in sensitivity, selectivity, and stability, and recovery of 93.6%-105.5% was achieved for determining cytokines spiked in the whole mouse serum. PMID- 30022658 TI - Tunable Out-of-Plane Piezoelectricity in Thin-Layered MoTe2 by Surface Corrugation-Mediated Flexoelectricity. AB - Piezoelectricity crystallographically exists only in the in-plane direction in two-dimensional transition metal dichalcogenides. Here, we demonstrated flexoelectricity-tunable out-of-plane piezoelectricity in semiconducting 2H-MoTe2 flakes by creating surface corrugation. In particular, the strong out-of-plane piezoelectricity and its spatial variation depending on local flexoelectricity was observed even though crystallographically there exists only in-plane piezoelectricity. Surface corrugation-mediated flexoelectricity tuning can be applied to other two-dimensional or thin-layered materials and, furthermore, the results could provide useful information on the interweaving nature between mechanical stimulus and electric dipole in low-dimensional materials. PMID- 30022659 TI - Extremely Fast Hydrogen Atom Transfer between Nitroxides and HOO. Radicals and Implication for Catalytic Coantioxidant Systems. AB - We report a novel coantioxidant system based on TEMPO (2,2,6,6 tetramethylpiperidine-1-oxyl radical) that, in biologically relevant model systems, rapidly converts chain-carrying alkylperoxyl radicals to HOO.. Extremely efficient quenching of HOO. by TEMPO blocks the oxidative chain. Rate constants in chlorobenzene were measured to be 1.1 * 109 M-1 s-1 for the reductive reaction TEMPO + HOO. -> TEMPOH + O2 and 5.0 * 107 M-1 s-1 for the oxidative reaction TEMPOH + HOO. -> TEMPO + H2O2. These rate constants are significantly higher than that associated with the reaction of HOO. with alpha-tocopherol, Nature's best lipid soluble antioxidant ( k = 1.6 * 106 M-1 s-1). These data show that in the presence of ROO.-to-HOO. chain-transfer agents, which are common in lipophilic environments, the TEMPO/TEMPOH couple protects organic molecules from oxidation by establishing an efficient reductive catalytic cycle. This catalytic cycle provides a new understanding of the efficacy of the antioxidant capability of TEMPO in nonaqueous systems and its potential to act as a chemoprotective against radical damage. PMID- 30022660 TI - Receptor-Free Detection of Picric Acid: A New Structural Approach for Designing Aggregation-Induced Emission Probes. AB - A pristine aggregation-induced enhanced emission (AIEE) active monomer 2,5-bis(( E)-4-bromostyryl)-3,4-diphenylthiophene (TPBZ) and its copolymer (PFTPBZ) with 9,9-dioctylfluorene-2,7-diboronic acid bis(1,3-propandiol) ester have been synthesized via Suzuki coupling polymerization. PFTPBZ that is devoid of any receptor showed AIEE property and demonstrated excellent and selective fluorometric recognition of 2,4,6-trinitrotoluene (TNT) in aggregated state (aqueous medium) and picric acid (PA) in aggregated state and solution state (organic solvent) as well as in vapor phase via PFTPBZ dip-coated Whatman filter paper on a solid-phase platform in 1.86 ng level (naked eye). Limit of detection (LOD) for TNT in 95% water fraction ( fw) was 53.74 * 10-6 M, and at 40% fw, it was 14.26 * 10-7 M. PA detection in tetrahydrofuran solution was possible with a LOD of 28.16 * 10-7 M, 95% fw with LOD of 10.47 * 10-6 M, and in 40% fw with LOD of 47.39 * 10-8 M. As a unique example of structural design, the probe PFTPBZ surprisingly possesses no receptor, yet remarkably high selectivity was achieved via Forster resonance energy transfer (FRET) and photoinduced electron transfer from the copolymer PFTPBZ to PA and TNT. Detection of PA in the presence of various metal analytes and inorganic acids in real water samples (lakes, rivers, and sea water) was also demonstrated using this concept of receptor-free conjugated polymer probe. PMID- 30022661 TI - A Bridging Peroxide Complex of Platinum(IV). AB - The photolysis of the allylplatinum(IV) complex [PtBr(C3H5)(4-MeC6H4)2(bipy)], 1, bipy = 2,2'-bipyridine, in air yielded [{PtBr(4-MeC6H4)2(bipy)}2(MU-O2)], 2, the first diplatinum(IV) complex containing a single bridging peroxide ligand. The PtO-OPt bond distance in 2 is 1.481(3) A. Complex 2 is thought to be formed by homolysis of the allyl-platinum bond of 1, followed by reaction of the platinum(III) intermediate [PtBr(4-MeC6H4)2(bipy)] with oxygen. PMID- 30022662 TI - Direct Catalytic Enantioselective Vinylogous Aldol Reaction of Allyl Ketones to Pyrazole-4,5-diones. AB - The first catalytic enantioselective vinylogous nucleophilic addition to pyrazole 4,5-diones is reported. Using quinine-derived bifunctional tertiary amino-amide as the catalyst, this direct aldol reaction of allyl ketones is shown to proceed exclusively in gamma- and E-selective manner to generate pyrazolone derivatives, bearing an oxygen-containing quaternary stereogenic center, in good yields with moderate to high enantioselectivities (up to 97:3 er). PMID- 30022663 TI - Mesoscale Complexations in Lithium Electrodeposition. AB - Mechanistic understanding of lithium electrodeposition and morphology evolution is critical for lithium metal anodes. In this study, we deduce that Li deposition morphology evolution is determined by the mesoscale complexations that underlie due to local electrochemical reaction, Li surface self-diffusion, and Li-ion transport in the electrolyte. Li-ion depletion at the reaction front for higher reaction rates primarily accounts for dendritic growth with needlelike or fractal morphology. Large Li self-diffusion barrier, on the other hand, may lead to the formation of porous Li film for lower reaction rates. Enhanced ion transport in the electrolyte contributes to homogeneous deposition, thereby avoiding nucleation for Li dendrite formation. This study also demonstrates that the substrate surface roughness strongly affects dendritic growth localization over the protrusive surface features. A nondimensional electrochemical Damkohler number is further proposed, which correlates surface diffusion rate and reaction rate and allows constructing a comprehensive phase map for lithium electrodeposition morphology evolution. PMID- 30022664 TI - Interaction of Positively Charged Gold Nanoparticles with Cancer Cells Monitored by an in Situ Label-Free Optical Biosensor and Transmission Electron Microscopy. AB - Functionalized nanoparticles (NPs) can penetrate into living cells and vesicles, opening up an extensive range of novel directions. For example, NPs are intensively employed in targeted drug delivery and biomedical imaging. However, the real-time kinetics and dynamics of NP-living cell interactions remained uncovered. In this study, we in situ monitored the cellular uptake of gold NPs functionalized with positively charged alkaline thiol-into surface-adhered cancer cells, by using a high-throughput label-free optical biosensor employing resonant waveguide gratings. The characteristic kinetic curves upon NP exposure of cell coated biosensor surfaces were recorded and compared to the kinetics of NP adsorption onto bare sensor surfaces. We demonstrated that from the above kinetic information, one can conclude about the interactions between the living cells and the NPs. Real-time biosensor data suggested the cellular uptake of the functionalized NPs by an active process. It was found that positively charged particles penetrate into the cells more effectively than negatively charged control particles, and the optimal size for the cellular uptake of the positively charged particles is around 5 nm. These conclusions were obtained in a cost effective, fast, and high-throughput manner. The fate of the NPs was further revealed by electron microscopy on NP-exposed and subsequently fixed cells, well confirming the results obtained by the biosensor. Moreover, an ultrastructural study demonstrated the involvement of the endosomal-lysosomal system in the uptake of functionalized NPs and suggested the type of the internalization pathway. PMID- 30022665 TI - Thermodynamic Scale of beta-Amino Acid Residue Propensities for an alpha-Helix like Conformation. AB - A thiol-thioester exchange system has been used to measure the propensities of diverse beta-amino acid residues to participate in an alpha-helix-like conformation. These measurements depend on formation of a parallel coiled-coil tertiary structure when two peptide segments become linked by thioester formation. One peptide segment contains a "guest" site that accommodates diverse beta residues and is distal to the coiled-coil interface. We find that helix propensity is influenced by side chain placement within the beta residue [beta3 (side chain adjacent to nitrogen) slightly favored relative to beta2 (side chain adjacent to carbonyl)]. The previously recognized helix stabilization resulting from five-membered ring incorporation is quantified. These results are significant because so few quantitative thermodynamic measurements have been reported for alpha/beta-peptide folding. PMID- 30022666 TI - Probing Multiphoton Photophysics Using Two-Beam Action Spectroscopy. AB - Multiphoton absorption (MPA) is an enabling technology for many applications. However, due to the low probability of MPA processes, their accurate characterization remains a challenge. Here we introduce a new technique, two-beam constant emission intensity (2-BCEIn) spectroscopy, that offers substantial advantages over other existing methods that use the generation of optical emission for the characterization of absorptive nonlinearities. We use 2-BCEIn to study nonlinear absorption in solutions of crystal violet lactone (CVL) over a range of excitation wavelengths in which the dominant nonlinear absorption process transitions from two-photon absorption (750 nm) to three-photon absorption (830 nm). At an excitation wavelength of 800 nm, both two-photon absorption and three-photon absorption contribute substantially to the nonlinear fluorescence excitation (NFE) signal, although the dynamic range of the NFE data is not sufficient to quantify the contributions of each process. 2-BCEIn spectroscopy enables the direct measurement of the local exponent at each emission intensity. 2-BCEIn measurements made at several different emission intensities demonstrate unambiguously that the nonlinear excitation of CVL at 800 nm cannot be described solely as the sum of a two-photon process and a three photon process. A kinetic model that includes intrapulse excited-state absorption reproduces the features of the 2-BCEIn measurements and enables the determination of the ratio of the three-photon absorption cross section to the two-photon absorption cross section. Such information cannot easily be extracted from conventional NFE measurements. These results demonstrate the power and versatility of two-beam action spectroscopies for elucidating the complex photophysics of multiphoton absorption processes. PMID- 30022667 TI - Visible-Light-Induced C (sp3)-H Functionalization of Tosylhydrazones: Synthesis of Polysubstituted Pyrroles under Metal-Free Conditions. AB - Iodine catalyzed C (sp3)-H functionalization of tosylhydrazones with beta-enamino esters under visible light irradiation for the synthesis of trisubstituted pyrroles has been described. The present method is also applicable to alpha- substituted tosylhydrazones to yield the tetra-substituted pyrroles. PMID- 30022668 TI - Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-beta lactamase Inhibitors. AB - The rise of antimicrobial resistance (AMR) worldwide and the increasing spread of multi-drug-resistant organisms expressing metallo-beta-lactamases (MBL) require the development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against Pseudomonas aeruginosa and Klebsiella pneumoniae expressing carbapenemases Verona integron encoded metallo-beta-lactamase (VIM-2) and New Delhi metallo-beta-lactamase 1 (NDM-1), respectively. These adjuvants were prepared via standard chemical methods and evaluated in biological assays for potentiation of MEM against bacteria and toxicity (IC50) against HepG2 human liver carcinoma cells. One of the best compounds, 15, lowered the minimum inhibitory concentration (MIC) of MEM by a factor of 32-256 at 50 MUM within all tested MBL-expressing clinical isolates and showed no activity toward serine carbapenemase expressing isolates. Biochemical assays with purified VIM-2 and NDM-1 and 15 resulted in inhibition kinetics with kinact/ KI of 12.5 min-1 mM-1 and 0.500 min-1 mM-1, respectively. The resistance frequency of 15 at 50 MUM was in the range of 10-7 to 10-9. 15 showed good tolerance in HepG2 cells with an IC50 well above 100 MUM, and an in vivo study in mice showed no acute toxic effects even at a dose of 128 mg/kg. PMID- 30022669 TI - Selective Long-Distance Isomerization of Terminal Alkenes via Nondissociative Chain Walking. AB - Selective long-distance isomerization of terminal alkenes to silyl enol ethers proceeded via nondissociative chain walking using phenanthroline palladium catalysts. Notable features achieved taking advantage of the nondissociative chain walking mechanism include high efficiency obtained regardless of the chain length, high chemoselectivity toward terminal alkenes over internal ones, and retention of the stereoconfiguration of the stereocenter on the alkyl chain. PMID- 30022670 TI - Diastereo- and Enantioselective Construction of Dihydrobenzo[ e]indole Scaffolds via Catalytic Asymmetric [3 + 2] Cycloannulations. AB - The first catalytic asymmetric construction of chiral dihydrobenzo[ e]indole scaffolds has been established in a highly diastereo- and enantioselective mode (30 examples, up to 99% yield, >95:5 dr, >99% ee), which makes use of chiral phosphoric acid-catalyzed [3 + 2] cycloannulations of azonaphthalene derivatives with 3-vinylindoles. This reaction also represents the first catalytic asymmetric cycloannulation of azonaphthalene derivatives with alkenes, which will not only provide a useful method for constructing enantioenriched dihydrobenzo[ e]indole scaffolds but also advance the chemistry of catalytic asymmetric reactions of azonaphthalene derivatives. PMID- 30022671 TI - Ultralow Thermal Conductivity and Mechanical Resilience of Architected Nanolattices. AB - Creating materials that simultaneously possess ultralow thermal conductivity, high stiffness, and damage tolerance is challenging because thermal and mechanical properties are coupled in most fully dense and porous solids. Nanolattices can fill this void in the property space because of their hierarchical design and nanoscale features. We report that nanolattices composed of 24- to 182-nm-thick hollow alumina beams in the octet-truss architecture achieved thermal conductivities as low as 2 mW m-1 K-1 at room temperature while maintaining specific stiffnesses of 0.3 to 3 MPa kg-1 m3 and the ability to recover from large deformations. These nanoarchitected materials possess the same ultralow thermal conductivities as aerogels while attaining specific elastic moduli that are nearly 2 orders of magnitude higher. Our work demonstrates a general route to realizing multifunctional materials that occupy previously unreachable regions within the material property space. PMID- 30022672 TI - Replacing animal use in education and training. AB - In the USA, the general public want the use of animals in medical training to cease, but, at least in Australia, some teachers want it to continue, even when effective non-animal alternatives are available. PMID- 30022673 TI - Characterisation of a canine epithelial cell line for modelling the intestinal barrier. AB - Little is known about how food interacts with the intestinal epithelium during the digestion process. However, it is known that ingredients in food can modulate the intestinal barrier, and have the potential to disrupt homeostasis of the gut. Here, we characterise a conditionally immortalised canine intestinal epithelial cell (cIEC) line for use in in vitro assays, to assess the effect of food ingredients on intestinal barrier function, permeability, cell health, and inflammation. Microscopy and flow cytometry confirmed that cIECs had a phenotype consistent with those of epithelial origin, and were able to differentiate to mature enterocytes. The cIECs also formed a monolayer when grown on Transwell(r) inserts, producing functional tight junctions between the cells. In contrast to the human-derived Caco-2 cell line, transepithelial electrical resistance (TEER) was increased in cIECs in response to two different raw ingredients. The exposure of cIECs to known inflammatory stimuli and raw ingredients induced the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-?B). This work demonstrates the value of a unique cIEC in vitro model to study the effects of food ingredients on canine intestinal function and health, and supports continued efforts to reduce and refine the use of animals in scientific research. PMID- 30022674 TI - A survey to understand public opinion regarding animal use in medical training. AB - A random survey was performed by ORC International Telephone CARAVAN(r), on 24-27 March 2016, by trained interviewers. The aim of this survey was to gain further understanding of public perceptions in the United States of laboratory animal use, specifically for the purposes of medical training. Five statements were read in random order to the participants, who were then asked whether they agreed or disagreed with the statement. Survey responses were obtained from 1011 participants. For the combined statements: "If effective non-animal methods are available to train a) medical students and physicians, b) emergency physicians and paramedics, and c) paediatricians, those methods should be used instead of live animals", most respondents (82-83%) agreed. For the statement: "You want your doctor to be trained by using methods that replicate human anatomy instead of live animals", most respondents (84%) agreed. For the statement: "If effective non-animal methods are available, it is morally wrong or unethical to use live animals to train medical students, physicians and paramedics", 67% of respondents agreed. Responses were similar among the 15 pre-specified demographic subgroups. Given that effective non-animal training methods are readily available, the survey suggests that a substantial majority of the public wants the use of animals in medical training to cease. PMID- 30022675 TI - Exploring the use of alternatives to animals in undergraduate education in Australia. AB - The replacement, reduction and refinement of animal use in education is part of the regulatory legislation in Australia, and requires the use of alternatives to animals where appropriate. The aims of this study were: a) to explore the extent of the replacement of animals when teaching life sciences to Australian undergraduate students; b) to understand which alternative models were being used, and the learning objectives covered; and c) to gain some insight into the circumstances facilitating the use of alternatives to animals in education. An anonymous online survey, consisting of open and closed questions, was conducted among faculty members that used either animal or alternative models in their teaching. A total of 27 faculty members participated, from eight universities. Human anatomy and physiology had the highest number of survey participants who had replaced animals entirely with alternative models. These subjects also had the highest number of participants that were using animal models. According to the participants, most learning objectives were met effectively by both types of model. Participants who only used alternatives were influenced by ethical considerations significantly more than those who used animal models and alternatives. We concluded that, while some participants have replaced animals successfully, others in the same field are still employing them, and that there appears to be a range of barriers to the wider adoption of alternatives to animal use. PMID- 30022676 TI - The development of a clinical skills laboratory at Ross University School of Medicine. AB - Dedicated clinical skills laboratories (CSLs) that make use of models, mannequins and simulators, are being increasingly established in medical and veterinary schools. These have been commonplace in medical schools for more than two decades, but their incorporation within the teaching of veterinary curricula has occurred much more recently. In 2007, a decision was taken to establish a CSL at Ross University School of Veterinary Medicine. We considered the range of skills that we wished to teach, the physical space and equipment needed, the storage and air conditioning requirements, the facilities needed to deliver PowerPoint lectures and case study presentations, and other essentials necessary to handle cadaver specimens. We converted an appropriate campus building to our needs, hired teaching staff, and started to source models and mannequins for the teaching of veterinary clinical skills. In 2010, 177 senior students completed a survey evaluating their experiences within our CSL. Student satisfaction was generally high, with 95% of respondents feeling that the CSL had improved their psychomotor skills. However, 15% of them felt that the models were insufficiently realistic. Our clinical skills programme has since developed considerably, and it currently offers instruction in a diverse array of surgical, medical and other clinical skills. We hope that this description of our experiences may assist others embarking on similar projects elsewhere. PMID- 30022677 TI - Ambiguities in existing Iranian national policies addressing excessive gaming. AB - Considering the scarcity of available science and controversies around effective policies addressing gaming disorder and its health-related consequences, Kiraly et al. have conducted a systematic review on current evidence regarding this issue. We, a group of researchers in this field, would like to express our perspective from Iran. With rapid growth of gaming, Iran seems to be facing some specific policy issues and challenges, which are going to be reviewed in this short commentary. PMID- 30022678 TI - Prognostic and predictive signatures for treatment decisions. AB - AIM: We develop a subgroup selection procedure using both prognostic and predictive biomarkers to identify four patient subpopulations: low- and high-risk responders, and low- and high-risk nonresponders. METHODS: We utilize three regression models to identify three sets of biomarkers: S, prognostic biomarkers; T, predictive biomarkers; and U, prognostic and predictive biomarkers. The prognostic signature C(S) combines with a predictive signature, either C(T) or C(U), to develop two procedures C(S,T) and C(S,U) for identification of four subgroups. RESULTS: Simulation experiment showed that proposed models for identifying the biomarker sets S and U performed well, as did the procedure C(S,U) for subgroup identification. CONCLUSION: The proposed model provides more comprehensive characterization of patient subpopulations, and better accuracy in patient treatment assignment. PMID- 30022679 TI - 14-3-3eta protein: a promising biomarker for rheumatoid arthritis. AB - Effective management of rheumatoid arthritis (RA) depends on early identification followed by timely invention and proper monitoring of treatment responses which remain challenges facing rheumatologists for lacking biomarkers of high sensitivity and specificity. 14-3-3eta has been reported to be a novel RA-related biomarker inducing the expression of multiple factors mediating the pathogenesis of RA, and increasing the diagnostic capture when combined with rheumatoid factor and anticyclic citrullinated peptide antibody. Besides, elevated serum 14-3-3eta was relevant to more serious joint erosion and worse therapy outcomes. Here, we summarized the emerging knowledge regarding the roles 14-3-3eta plays in RA and its clinical implications as diagnostic, prognostic and therapeutic response surrogate as well as potential drug target for RA. PMID- 30022680 TI - Physiological adaptations to specific endurance training in professional female handball players. AB - Several Hungarian and foreign researchers have already studied the cardiorespiratory parameters of elite handball players. There are only a few studies though, which would separately review the changes in the functions of different organ systems. The aim of this study is to investigate the effect of an intervention (physical activity) on the cardiorespiratory system. In this study, 16 elite female handball players participated, whose body compositions were measured and took two vita maxima tests. During the analysis, each cardiorespiratory parameter was monitored for every 20 s. Between the two examinations, 6 weeks passed and an intervention took place. There was a significant decrease in relative body fat and a significant increase in relative muscle mass. Remarkable positive changes occurred in the values of ventilation, oxygen pulse, and in both absolute and relative aerobic capacities as well. The mean values of the team developed as expected, but the individual changes in body composition and cardiorespiratory parameters are just as important. First, we chose four players, who had the most outstanding changes. Second, we analyzed such parameters, which were expected to show adequate results in terms of the apparatus(es) functioning. PMID- 30022681 TI - Hazardous alcohol consumption and alcohol-related problems are associated with unknown and HIV-positive status in fishing communities in Uganda. AB - In Uganda, alcohol consumption is associated with higher HIV prevalence. However, research is needed to better understand how different patterns of alcohol consumption and alcohol-related problems may drive this association. In this cross-sectional study, we examined how hazardous alcohol use and alcohol-related problems such as psychological, physical, and social harms are associated with HIV status in fishing communities in Uganda. 300 (132 male, 168 female) residents of fishing communities in Uganda (75 participants from each of the following occupational groups: fishmongers, alcohol sellers, commercial sex workers (CSW), and fishermen) completed an interviewer-assisted computerized interview. We captured information on sociodemographics and HIV testing history. Prior 12-month hazardous alcohol consumption patterns and alcohol-related problems were assessed with the AUDIT and AUDADIS. 19.7%, 58.0%, and 23.3% of the sample reported being HIV positive, being HIV negative from a test within the prior 12 months, and not knowing their HIV status respectively. 18.7% reported the co-occurrence of hazardous alcohol consumption patterns and alcohol-related problems. 7.7% reported either hazardous alcohol consumption patterns or alcohol-related problems. Compared to non-drinkers, those with co-occurring hazardous consumption and alcohol-related problems had greater odds of being HIV positive (adjOR 2.75, 95% CI 1.17-6.43) and of unknown HIV status (adjOR 3.35, 95% CI 1.52-7.42). Reporting only hazardous consumption levels, only alcohol-related problems, or low-risk drinking, did not increase the odds of being HIV positive or of unknown status. Among those not HIV positive, those with co-occurring hazardous consumption and alcohol-related problems had greater odds of never having had an HIV test (adjOR 3.78, 95% CI 1.63-8.68). The co-occurrence of hazardous alcohol use and alcohol related problems appears to be a prominent risk factor for HIV infection, not knowing one's HIV status, and never testing for HIV in this setting. PMID- 30022682 TI - Effect of CYP2C19 and CYP2D6 genotype on tamoxifen treatment outcome indicates endogenous and exogenous interplay. AB - AIM: We investigated the interaction of CYP2C19 and CYP2D6 genotype on clinical outcome in tamoxifen-treated breast cancer patients. MATERIALS & METHODS: A cohort of 306 patients on tamoxifen treatment for a minimum of 1 year were employed to analyze the effect of genotype-predicted phenotype on relapse-free survival. RESULTS & CONCLUSION: We show that the group with worst outcome and highest risk of relapse is that of 2C19?-2D6? (hazard ratio: 2.94), when adjusting for age, Nottingham prognostic index and adjuvant chemotherapy. Furthermore, the effect of 2C19?-2D6?genotype-predicted phenotype is greatly enhanced in premenopausal patients (hazard ratio: 21.08). We hypothesize that poor bioactivation of tamoxifen in patients with low CYP2D6 activity and high CYP2C19 metabolism represents a tamoxifen-treated patient group that has the worst clinical outcome. PMID- 30022683 TI - Addressing smoking among people living with HIV: a cross-sectional survey of Australian HIV health practitioners' practices and attitudes. AB - People living with HIV (PLHIV) have high rates of tobacco smoking, and smoking is a leading cause of premature mortality and morbidity. It is important to understand HIV healthcare providers' practices and attitudes towards addressing smoking with their patients. An online survey that measured: (i) use of the 5A framework for addressing smoking (Ask, Assess, Advise, Assist, Arrange) and (ii) attitudes and barriers to addressing smoking cessation was distributed by relevant professional bodies. Eligible participants were Australian health practitioners providing healthcare to PLHIV. Of the 179 respondents, most reported practising at least one of the 5As: Ask (94%); Assess (78%); Advise (82%); Assist (89%); and Arrange (73%). Practising the full 5A framework (completing at least one activity from each A) was less common (62%) and associated with having undertaken smoking cessation training (OR 2.1, CI 1.1 3.9), being a medical practitioner (OR 6.0, CI 3.1-11.6), having greater perceived knowledge and resources (OR 1.7, CI 1.3-2.4) and more positive attitudes (OR 1.5, CI 1.1-2.0). Common barriers to delivering cessation assistance related to knowledge and availability of resources. Development and greater dissemination of effective smoking cessation training and resources may be required to ensure healthcare practitioners have the capacity to complete all aspects of the 5A framework for smoking cessation and support their patients with HIV who smoke. PMID- 30022685 TI - Editorial. PMID- 30022684 TI - Hydrogen Sulfide Protects Human Cardiac Fibroblasts Against H2O2-induced Injury Through Regulating Autophagy-Related Proteins. AB - Autophagy, an intracellular bulk degradation process of proteins and organelles, can be induced by myocardial ischemia in the heart. However, the causative role of autophagy in the survival of human cardiac fibroblasts and the underlying mechanisms are incompletely understood. Oxidative stress can induce autophagy in cultured cells upon hydrogen peroxide (H2O2) exposure. Because hydrogen sulfide (H2S) regulates reactive oxygen species (ROS) and apoptosis, we hypothesize that H2S may have a cardioprotective function. To examine our hypothesis, we investigated the regulation of autophagy by the H2S donor sodium hydrosulfide (NaHS), using a cell model of human cardiac fibroblasts from adult ventricles (HCF-av) that suffered from endoplasmic reticulum (ER) stress by H2O2. In the present study, we found that the apoptosis and autophagy were induced along with ER stress by H2O2 in the primary cultured HCF-av cells. In contrast, H2S suppressed HCF-av cell apoptosis and autophagic flux, in part directly by inhibiting ROS production and preserving mitochondrial functions. PMID- 30022687 TI - Mental health care utilization and stigma in the military: comparison of Asian Americans to other racial groups. AB - OBJECTIVE: To investigate race disparities in the US Military among Asian, White, Black, Native American and Other, seeking mental health care in the context of stigma defined by perceived damage to career. DESIGN: Using 2008 survey data taken from US military personnel, mental disorders including depression, generalized anxiety disorder, suicidal ideation, suicidal attempt and post traumatic stress disorder serious psychological distress (as defined in Kessler - 6), as well as seeking mental health care in past 12 months and stigma were dichotomized and weighted logistic regression models were used. RESULTS: A significant race disparity existed in seeking mental health care when data were stratified by stigma and depression adjusted for demographic variables. Compared to Asians with depression that perceived stigma, Blacks were more likely to seek mental health care (OR with 95% confidence interval for Asians: 3.97[2.21, 7.15], Black: 9.25[6.02, 14.20], p < .005) adjusting for demographic variables. Similar results held for other mental disorders with the exception of suicide attempts and serious psychological distress. Compared to Asians with serious psychological distress who did not perceive stigma, only Whites were more likely to seek mental health care (OR for Asians: 3.27[2.15, 4.97], White: 6.47[4.60, 9.11], p < .005). Among those without a mental health disorder, regardless of the presence or absence of perceived stigma, there was no disparity between any two race groups in seeking mental health care. CONCLUSION: Among individuals having perceived stigma with mental health disorders, Asian American active-duty personnel may be less likely to use mental health care when compared to non-Asian peers. PMID- 30022688 TI - Oestrogen receptor beta5 and epidermal growth factor receptor synergistically promote lung cancer progression. AB - Oestrogen receptor beta (ERbeta) and epidermal growth factor receptor (EGFR) pathway can synergistically promote the proliferation, invasion, and metastasis of non-small-cell lung cancer (NSCLC) cells. ERbeta has five subtypes, and the selective splicing of exon 8 in ERbeta5 transcription translational phase makes its biological function different from other subtypes. The following study investigates whether ERbeta5 interacts with EGFR pathway in lung cancer. Briefly, we found that the overexpression of ERbeta5 and EGFR is associated with poor prognosis and decreased overall survival in NSCLC patients. Furthermore, the effects of ERbeta5 and EGFR on cell biological behaviour were investigated in vitro. These results indicated that the combination of ERbeta5 and EGF induces cell proliferation and invasion, while the combination of ERbeta5 and Gefitinib (EGFR inhibitors, Gef) induces cell apoptosis and promotes cell mitosis in A549 cell line. In addition, the combination of ERbeta5 and EGF increases the expression of ERbeta5, EGFR, and p-ERK1/2 in lung cancer cells. To sum up, the obtained results suggest that ERbeta5 and EGFR synergistically promote the progression of lung cancer by activating MEK/ERK signalling pathway, which provides a theoretical basis for more accurate combined targeted therapy. PMID- 30022689 TI - Functional Status in Older Intensive Care Unit Survivors. AB - Older ICU survivors are often challenged with clusters of geriatric syndromes and functional decline. The purpose of this study was (a) to assess patterns of geriatric syndromes and functional status from admission to 6 months post discharge and (b) to examine the predictors of longitudinal functional status. This is a prospective cohort study. Demographic information, clinical variables, geriatric syndromes, and functional status were collected longitudinally. A total of 192 medical ICU older adult survivors were included in the analysis. Factors associated with reductions in functional status over 6 months were (a) institutionalized prior to hospitalization, (b) pressure sore before admission, (c) existing delirium, (d) impaired mobility at baseline, (e) increased APACHE II score upon ICU admission, and (f) use of mechanical ventilation during the ICU stay. Importantly, overweight was the only factor that was associated with increased functional level over 6 months. PMID- 30022690 TI - Chinese Herbal Medicine Versus Other Interventions in the Treatment of Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. AB - Diabetes affects 422 million people and directly caused 4.9 million deaths according to the global report on diabetes in 2014. Type 2 diabetes accounts for 90% of people with diabetes around the world. Chinese herbal medicine treatment for diabetes has more than 2000-year history in China. An increasing number of people around the world are trying to manage type 2 diabetes with Chinese herbal medicine. However, there is a lack of evidence to decide if Chinese herbal medicine is effective and safe when compared with other interventions for the treatment of type 2 diabetes We identified 58 randomized controlled trials involving 6637 participants with type 2 diabetes with trial periods lasting from 8 weeks to 1 year (average 12 weeks). We extracted data following a predefined hierarchy. A total of 132 different Chinese herbal medicines were examined. We included studies comparing Chinese herbal medicine with other interventions and excluded trials that did not satisfy the inclusion criteria. We evaluated primary outcomes of trials in accordance with the Cochrane Handbook for Systematic Reviews of Intervention. Fifty-six out of 58 studies reported evidence that Chinese herbal medicines were effective at controlling blood sugar, insulin resistance, and traditional Chinese medicine clinical symptoms for patients with type 2 diabetes. And outcome variables are summarized. However, the evidence is limited because of the quality of the studies. Well-designed long-term studies with large samples and multiple centers as well as standardization and quality control will be required to determine if Chinese herbal medicine treatment is effective and safe for type 2 diabetes. PMID- 30022691 TI - Reproducibility between oral radiologists and general dentists with regards to radiographic diagnosis of caries: methodological issue. PMID- 30022686 TI - Windows of sensitivity to toxic chemicals in the development of reproductive effects: an analysis of ATSDR's toxicological profile database. AB - Development of the fetus is a complex process influenced by many factors including genetics, maternal health, and environmental exposures to toxic chemicals. Adverse developmental effects on the reproductive system have the potential to harm generations beyond those directly exposed. Here, we review the available literature in Agency for Toxic Substances and Disease Registry toxicological profiles related to reproductive-developmental effects in animals following in utero exposure to chemicals. We attempt to identify windows of sensitivity. In the discussion, we correlate the findings with human development. The endpoints noted are fertility, estrus, anogenital distance, sex ratio, spermatogenesis, and mammary gland development. We identified some windows of sensitivity; however, the results were hampered by chronic-exposure studies designed to detect effects occurring throughout developmental, including multi generational studies. This paper demonstrates the need for more acute studies in animals aimed at understanding time periods of development that are more susceptible to chemically induced adverse effects. PMID- 30022693 TI - Systematic review and meta-analysis of the negative outcomes of retinopathy of prematurity treated with laser photocoagulation. AB - INTRODUCTION: Retinopathy of prematurity is a leading cause of potentially avertable childhood blindness around the world. And laser photocoagulation is currently performed as a gold standard for retinopathy of prematurity treatment, but it may contribute to elevated myopia and decreased visual field. Therefore, the objective of this meta-analysis is to explore the negative impact of laser photocoagulation for retinopathy of prematurity in terms of anatomic outcomes and structural outcomes. METHODS: Studies were retrieved through literature searches in PubMed and EMBASE from 1990 to 2017 in English. Case-control studies that reported anatomic and structural changes or significant complications after laser coagulation or cryotherapy for retinopathy of prematurity were eligible. RESULTS: This meta-analysis included eight original studies related to laser treatment for retinopathy of prematurity at any stages. A total of 1422 infants were participated, of which 1156 documented subthreshold or threshold retinopathy of prematurity without laser treatment were selected as comparison group and the rest treated with diode or argon laser coagulation were chosen for experiment group. Taking all included studies into account, spherical equivalent (mean difference -2.53, 95% confidence interval: -5.23 to 0.18, I2 = 96%, P < 0.00001), anterior chamber depth (mean difference -0.52, 95% confidence interval: -0.76 to 0.28, I2 = 55%, P = 0.11), astigmatism (odds ratio 3.19, 95% confidence interval: 1.61 to 6.32, I2 = 0%, P = 0.54), and myopia (odds ratio 8.08, 95% confidence interval: 3.79 to 17.23, I2 = 37%, P = 0.21) were associated with laser treatment for retinopathy of prematurity. Axial length (mean difference -0.01, 95% confidence interval: -0.28 to 0.27, I2 = 0%, P = 0.62) and anisometropia (odds ratio 4.21, 95% confidence interval: 0.54 to 33.17, I2 = 1%, P = 0.31) had no statistical significance on laser coagulation for retinopathy of prematurity. CONCLUSION: This meta-analysis showed that spherical equivalent, anterior chamber depth, astigmatism, and myopia were associated with the negative outcomes of laser coagulation, while axial length and anisometropia had no statistical importance on the defects of laser coagulation. Therefore, patients treated with laser coagulation should follow periodic cycloplegic refraction and receive early optical correction. PMID- 30022692 TI - Optimization on conditions of podophyllotoxin-loaded liposomes using response surface methodology and its activity on PC3 cells. AB - The purpose of this study was to optimize the preparation conditions of podophyllotoxin liposomes (PPT-Lips), and to investigate their effects on PC3 cells. PPT-Lips were prepared by using a thin-film dispersion method. In order to achieve maximum drug encapsulation efficiency (EE), the process and formulation variables were optimized by response surface methodology (RSM). The optimum preparation conditions were cholesterol to lecithin ratio of 3.6:40 (w/w), lipid to drug ratio of 15.8:1 (w/w), and the ultrasonic intensity of 35% (total power of 400 W). The experimental EE of PPT-Lips was 90.425%, which was consistent with the theoretically predicted value. The characterization studies showed that PPT Lips were well-dispersible spherical particles with an average size of 106 nm and a zeta potential of -10.1 mV. A gradual and time-dependent pattern of PPT from liposomes was found in in vitro drug release, with a cumulative release amount up to 70.3% in 24 h. Results of cell viability experiments on PC3 cells demonstrated that PPT-Lips exhibited more effective anticancer activity in comparison with free PTT. Therefore, PPT-Lips represent an efficient and promising drug delivery system for PPT. PMID- 30022694 TI - Circulating miRNA-33: a potential biomarker in patients with Coronary Artery Disease (CAD). AB - BACKGROUND: Circulating microRNAs (miRNA) are present in body fluids in stable, cell free form. Likewise, these miRNAs can be identified in various stages of coronary artery disease (CAD) such as inflammation, endothelial dysfunction, proliferation and atherosclerosis among others. miRNA expression levels can be identified. AIMS AND OBJECTIVES: To determine the expression of circulating miRNAs (miR-126, miR-92, miR-33, miR-145 and miR-155) in CAD patients of Indian origin. MATERIALS AND METHODS: miRNA profiling analysis in blood plasma was performed by quantitative real-time-PCR (qRT-PCR) in 60 angiographically verified subjects including 30 CAD patients and 30 age and gender matched controls. Association between the expression of all 5 circulating miRNAs and clinical characteristics of patients with CAD were analysed using Medcalc statistics. The severity of CAD was assessed using SYNTAX score (SS). RESULTS: Expression of plasma miR-33 increased by 2.9 folds in CAD patients than in control group (p value >= 0.002) also it was found that miR-33 expression levels in mild cases (SS:<=22) were significantly higher than CAD controls. There was a modest negative correlation between miR-33 and total cholesterol/high density lipoprotein ratio, triglycerides and very low density lipoprotein. CONCLUSION: The study reports a significant association between increased levels of plasma miR-33 and CAD. Thus, plasma miR-33 appears to be a promising non-invasive biomarker, but requires further validation in a large cohort. PMID- 30022696 TI - Systematic review and network meta-analysis of clinical outcomes associated with isavuconazole versus relevant comparators for patients with invasive aspergillosis. AB - OBJECTIVES: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA. METHODS: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model. RESULTS: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3-5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (-1.39 [-2.21, 0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L AmB and voriconazole were not statistically significant for either ACM (0.18 [ 1.17, 1.53], 0.50 [-1.11, 2.13] and 0.32 [-0.19, 0.84], respectively) or overall response (-0.99 [-2.21, 0.29], -0.89 [-2.41, 0.65] and 0.06 [-0.43, 0.57], respectively). CONCLUSIONS: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole. PMID- 30022695 TI - Superior anti-neoplastic activities of triacontanol-PEG conjugate: synthesis, characterization and biological evaluations. AB - Triacontanol (TA, C30H62O), abundantly present in plant cuticle waxes and bee waxes, has been found to display promising anti-neoplastic potentials. As a long chain fatty alcohol, TA possesses limited aqueous solubility, which hinders its medicinal application. To overcome its solubility barrier, a polymer prodrug was synthesized through attaching TA to poly ethylene glycol (PEG), using succinic acid as a linker with bifunctional amide and ester bonds. Anti-neoplastic effects of PEG-TA were assessed in LoVo and MCF7 cells, anti-proliferative and apoptosis inducing activities were subsequently confirmed in mouse xenograft model. Encouragingly, PEG-TA possessed selective anti-cancer ability. It did not exhibit significant cytotoxicity on normal cells. Mechanistic examination revealed inhibition of NF-kappaB nuclear translocation, suppression on matrix degradation enzyme and down-regulation of angiogenic signaling might contribute to its anti malignant effects. Pharmacokinetics clearly indicated PEGylated TA (named as mPEG2K-SA-TA) substantially enhanced TA delivery with increased plasma exposure (19,791 vs. 336.25 ng.mL-1.h-1, p < .001), mean residence time (8.46 vs. 2.95 h, p < .001) and elimination half-life (7.78 vs. 2.57 h, p < .001) compared to those of original TA. Moreover, mPEG2K-SA-TA appeared to be safe in preliminary toxicological assessment. PEGylated TA also emerged as a functional carrier to deliver hydrophobic chemotherapeutic agents, since it readily self-assembled to micelles in aqueous solution with a low critical micelle concentration (CMC, 19.1 ug.mL-1). Conclusively, PEG-TA conjugate displayed superior anti-neoplastic activities and low toxicity, as well as facilitated the delivery of other hydrophobic agents, which appeared to be an innovative strategy for cancer therapy. PMID- 30022697 TI - Predictive Value of Epileptiform Discharges for Subsequent Epilepsy After Febrile Seizures. AB - The predictive value of epileptiform discharges for subsequent epilepsy after febrile seizures was studied in 140 children: 72 children (51%) had simple febrile seizures and 68 children (49%) had complex febrile seizures. Electroencephalography (EEG) was performed in 103 children (74%), it was normal in 66 (47%) and with epileptiform patterns in 37 patients (26%). At follow-up in 2017, 10 children developed epilepsy, 1 had a single epileptic seizure, 9 of them had epileptiform EEGs. Of the patients with normal EEGs after complex febrile seizures, none developed epilepsy, and 92% of patients with normal EEGs after recurrent febrile seizures did not develop epilepsy. Therefore, patients with normal EEGs were unlikely to develop epilepsy. Fifteen percent of patients with complex and 31% of patients with recurrent febrile seizures and epileptiform EEGs developed epileptic seizures. The positive predictive value of epileptiform discharges was low in complex and twice as high in recurrent febrile seizures. PMID- 30022698 TI - Defining the seed sequence of the Cas12b CRISPR-Cas effector complex. AB - Target binding by CRISPR-Cas ribonucleoprotein effectors is initiated by the recognition of double-stranded PAM motifs by the Cas protein moiety followed by destabilization, localized melting, and interrogation of the target by the guide part of CRISPR RNA moiety. The latter process depends on seed sequences, parts of the target that must be strictly complementary to CRISPR RNA guide. Mismatches between the target and CRISPR RNA guide outside the seed have minor effects on target binding, thus contributing to off-target activity of CRISPR-Cas effectors. Here, we define the seed sequence of the Type V Cas12b effector from Bacillus thermoamylovorans. While the Cas12b seed is just five bases long, in contrast to all other effectors characterized to date, the nucleotide base at the site of target cleavage makes a very strong contribution to target binding. The generality of this additional requirement was confirmed during analysis of target recognition by Cas12b effector from Alicyclobacillus acidoterrestris. Thus, while the short seed may contribute to Cas12b promiscuity, the additional specificity determinant at the site of cleavage may have a compensatory effect making Cas12b suitable for specialized genome editing applications. PMID- 30022700 TI - Temperature-sensitive liposomes for co-delivery of tamoxifen and imatinib for synergistic breast cancer treatment. AB - Co-delivery of chemotherapeutic agents using nanocarriers is a promising strategy for enhancing therapeutic efficacy of anticancer agents. The aim of this work was to develop tamoxifen and imatinib dual drug loaded temperature-sensitive liposomes to treat breast cancer. Liposomes were prepared using 1, 2-dipalmitoyl sn-glycero-3-phosphocholine (DPPC), monopalmitoyl-2-hydroxy-sn-glycero-3 phosphocholine (MPPC), and different surface active agents. The liposomes were characterized for the average particle size, zeta potential, transition temperature, and drug release below and above liposomal transition temperature. The temperature-sensitive liposomes co-encapsulated with tamoxifen and imatinib were investigated for their synergistic activity against MCF-7 and MDA-MB-231 breast cancer cells. The liposomal nanoparticles showed a transition temperature of 39.4 degrees C and >70% encapsulation efficiency for tamoxifen and imatinib. The temperature-responsive liposomes showed more than 80% drug released within 30 min above transition temperature. Dual drug loaded liposomes showed synergistic growth inhibition against MCF-7 and MDA-MB-231 breast cancer cells. Co-delivery of tamoxifen and imatinib using temperature-sensitive liposomes can be developed as a potential targeting strategy against breast cancer. PMID- 30022699 TI - Inhibitor selectivity of CNTs and ENTs. AB - The concentrative nucleoside transporters (CNT; solute carrier family 28 (SLC28)) and the equilibrative nucleoside transporters (ENT; solute carrier family 29 (SLC29)) are important therapeutic targets but may also mediate toxicity or adverse events. To explore the relative role of the base and the monosaccharide moiety in inhibitor selectivity we selected compounds that either harbor an arabinose moiety or a cytosine moiety, as these groups had several commercially available drug members. The screening data showed that more compounds harboring a cytosine moiety displayed potent interactions with the CNTs than compounds harboring the arabinose moiety. In contrast, ENTs showed a preference for compounds with an arabinose moiety. The correlation between CNT1 and CNT3 was good as five of six compounds displayed IC50 values within the threefold threshold and one displayed a borderline 4-fold difference. For CNT1 and CNT2 as well as for CNT2 and CNT3 only two of six IC50 values correlated and one displayed a borderline 4-fold difference. Interestingly, of the six compounds that potently interacted with both ENT1 and ENT2 only nelarabine displayed selectivity. Our data show differences between inhibitor selectivities of CNTs and ENTs as well as differences within the CNT family members. PMID- 30022701 TI - Dental avoidance among adolescents - a retrospective case -control study based on dental records in the public dental service in a Swedish county. AB - OBJECTIVE: This study aimed to investigate the occurrence of missed dental appointments among 16-19-year-old adolescents in a Swedish county. A second aim was to explore associations between background and concomitant factors and missed appointments and to investigate if these associations differed between areas with different sociodemographic profiles. MATERIALS AND METHODS: A list of booked, and missed, appointments for 10,158 individuals during 2012 was used for assessments. Based on the total sample, 522 cases with, and 522 matched controls without, dental avoidance behavior in 2012 were identified. Data on previous missed and cancelled appointments, oral health status, dental treatment, fear or behavior problems, and medical, and, where available, psychosocial or lifestyle factors were extracted from the dental records using a preset protocol covering the period 2009-2012. RESULTS: In 2012, 13.1% of 23,522 booked appointments were missed, with a higher proportion of missed appointments among boys than girls. Cases with avoidance behavior more often had a record of sociodemographic load and dental fear or behavior management problems. They also had more oral health problems, more invasive dental treatments, and, in the past, more missed and canceled appointments. CONCLUSION: To enable good oral health and continued regular dental care, we need to pay more attention to adolescents' individual situation and be observant of early signs of avoidance. PMID- 30022702 TI - Disruptive Behaviors across Different Disorders: Evaluation of a Clinical Sample Using the Eyberg Child Behavior Inventory. AB - OBJECTIVE: The study reports the prevalence of disruptive behaviors in a help seeking sample of young children across a diverse range of clinical diagnoses (based on ICD-10). METHOD: The Eyberg Child Behavior Inventory (ECBI), a parent rating scale of disruptive behaviors, was completed on 310 children (2-11 years) at three child and adolescent psychiatry clinics in three German states (Bavaria, Hesse, Lower Saxony); the majority of children were outpatients. RESULTS: Mean intensity scores of disruptive behaviors differed significantly by diagnostic group, with the lowest ratings within a community sample, and increasingly higher scores in children with a diagnosis from the internalizing spectrum, those with pervasive developmental disorders, and finally, those with externalizing disorders (e. g. hyperkinetic disorder, conduct disorders). Seventy percent of the clinical sample, compared to only 17 % of the community sample, exceeded the normative cut-off score of 111, indicating that disruptive behaviors are common in young German children seeking help for different mental health problems. CONCLUSIONS: These findings support the Research Domain Criteria approach by showing that disruptive behaviors cross our current diagnostic labels and may need to be assessed and conceptualized in treatment planning, even in children without a primary diagnosis from the externalizing spectrum. PMID- 30022703 TI - Successful list-method directed forgetting without retroactive interference of post-instruction learning. AB - The focus of the study is the role of interference in list-method directed forgetting. More specifically, our question was whether retroactive interference of the to-be-remembered information is a necessary prerequisite for the directed forgetting effect. In Experiment 1 we used a directed forgetting procedure with one learning list without the interference of any to-be-remembered information. In line with previous results, we did not find a significant directed forgetting effect. Experiment 2 applied a directed forgetting procedure with two study lists, however, the forget instruction was given following the second list. So, List 2 items were designated as to-be-forgotten items, without further learning, whereas List 1 items were to-be-remembered items. The forget instruction selectively decreased the recall of List 2 items, without decreasing the recall performance for List 1. In Experiment 3, using the same procedure with different items, smaller learning lists and reversed output order, we replicated the results of Experiment 2. Altogether, these results point to a flexible, goal related nature of the directed forgetting phenomenon, showing that some form of interference is a necessary requirement for successful directed forgetting. However, proactive interference of to-be-remembered information in interaction with a forget instruction is suitable for forgetting of subsequently encoded information. PMID- 30022704 TI - Loving the Group That Denies You First: Social Identity Effects of Ostracism Before Inclusion. AB - Ostracism is an aversive situation that occurs frequently in everyday life; however, few empirical studies have investigated multiple experiences of inclusion or ostracism from the same group. The prior work in this area has also not evaluated the influence of subsequent inclusion and ostracism on identification with the group, perceptions of the group, or group member behaviors. Across three experiments, the current study investigated the impact of subsequent inclusion and ostracism on an individual's fundamental needs, identification with the group, perceptions of the group, and risk taking to benefit the group. It was hypothesized that participants who were ostracized and then included would show significant increases in group identification, positive group perceptions, and risk taking to benefit the group. Support for these hypotheses was found. Results are discussed regarding the impact of subsequent experiences of ostracism and inclusion on the individual and his or her relationship with the group. PMID- 30022705 TI - Animacy effects in episodic memory: do imagery processes really play a role? AB - Animates are remembered better than inanimates because the former are ultimately more important for fitness than the latter. What, however, are the proximate mechanisms underpinning this effect? We focused on imagery processes as one proximate explanation. We tested whether animacy effects are related to the vividness of mental images (Study 1), or to the dynamic/motoric nature of mental images corresponding to animate words (Study 2). The findings showed that: (1) Animates are not estimated to be more vivid than inanimates; (2) The potentially more dynamic nature of the representations of animates does not seem to be a factor making animates more memorable than inanimates. We compared (Study 3) a condition in which participants had to categorise animate and inanimate words with a condition in which they had to form mental images from them. The animacy effect was significant after categorising but not after forming mental imagery. In Study 4, we compared the recall rates of animates and inanimates after these words had been encoded with or without a concurrent visual-spatial memory load. Again, animates were better remembered than inanimates. Taken overall, the findings do not fit well with the hypothesis that imagery processes support animacy effects in memory. PMID- 30022706 TI - Darling, Get Closer to Me: Spatial Proximity Amplifies Interpersonal Liking. AB - Does close distance increase liking for a social object? In a preliminary sociogram task, an association between proximity and intimacy was found in drawings of self and others. In three experimental studies, male participants consistently preferred female targets who were (actually or appeared to be) close than far from them. Distance was manipulated through various means-sitting distance (Study 2), presenting two facial images separately to each eye by a stereoscopic device (Study 3), or a video clip (Study 4). This effect was stronger among those with deprived social needs and occurred in part because close (vs. far) targets seemed psychologically more accessible to the perceiver. Our findings offer rare experimental evidence for the empirically challenged propinquity effect and provide new insights on how distance shapes inner experience. PMID- 30022707 TI - SOBIR1 and AGB1 independently contribute to nonhost resistance to Pyricularia oryzae (syn. Magnaporthe oryzae) in Arabidopsis thaliana. AB - Rice blast caused by Pyricularia oryzae (syn. Magnaporthe oryzae) is a disease devastating to rice. We have studied the Arabidopsis-P. oryzae pathosystem as a model system for nonhost resistance (NHR) and found that SOBIR1, but not BAK1, is a positive regulator of NHR to P. oryzae in Arabidopsis. AGB1 is also involved in NHR. However, the genetic interactions between SOBIR1, BAK1, and AGB1 are uncharacterized. In this study, we delineated the genetic interactions between SOBIR1, BAK1, and AGB1 in NHR to P. oryzae in Arabidopsis and found SOBIR1 and AGB1 independently control NHR to P. oryzae in Arabidopsis pen2-1 mutant plants. Furthermore, XLG2, but not TMM, has a positive role in penetration resistance to P. oryzae in Arabidopsis pen2-1 mutant plants. Our study characterized genetic interactions in Arabidopsis NHR. Abbreviations: PRR: pattern recognition receptor, RLK: receptor-like kinase, RLP: receptor-like protein, BAK1: BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1, BIR1: BAK1 INTERACTING RECEPTOR-LIKE KINASE 1, SOBIR1: SUPPRESSOR OF BIR1-1-1, AGB1: ARABIDOPSIS G PROTEIN beta-SUBUNIT 1, XLG2: EXTRA-LARGE G PROTEIN 2. PMID- 30022708 TI - A Method of Applying Flight Data to Evaluate Landing Operation Performance. AB - : Pilots' operation has an important effect on flight safety and performance, particularly in the final landing stage when pilots need to deal with complicated operations. This study aims to determine the potential value of flight data and develop a method of evaluating a pilot's performance during landing phase based on flight quick access recorder (QAR) data from the perspective of risk assessment. First, a Landing Operation Performance Evaluation Model was developed based on risk evaluation principles. Three landing parameters, which are touchdown distance, touchdown vertical acceleration and touchdown pitch angle, were selected as indicators to evaluate the pilots' landing operation performance in this model. Second, the flight landing operation performance evaluation system (FLOPES) was set up based on the evaluation model. Test results showed that FLOPES can accomplish all calculation flow of operation performance evaluation. Finally, it concluded that this method is a more accurate and effective way for evaluating the landing operation performance of a flight. It could be as a practical tool for airlines to manage landing risk quantitatively and to provide a more practical support for improving training and design in aviation.Practitioner summary: This study aims to determine the potential value of flight data and to develop a method of evaluating pilot's landing operation performance from the risk evaluation perspective. Test results showed that this method is effective and could be as a practical tool for airlines to manage landing risk and improve training. ABBREVIATIONS: QAR: Quick Access Recorder; FLOPES: Flight Landing Operation Performance Evaluation System; ICAO: International Civil Aviation Organization; IATA: International Air Transport Association; SMS: Safety Management System; CAAC: Civil Aviation Administration of China; FOQA: Flight Operations Quality Assurance; VBA: Visual Basic for Applications. PMID- 30022709 TI - The proliferation of colorectal cancer cells is suppressed by silencing of EIF3H. AB - Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Eukaryotic translation initiation factor 3, subunit H (EIF3H) is a subunit of EIF3, which is involved in mRNA recruitment and ribosomal complex disassembly and is known to be a driver of cell proliferation and survival in cancer. To investigate its function in colorectal cancer, the Oncomine database was used to evaluate the expression of EIF3H in human colorectal cancer and normal tissues. Then, we constructed a Lentivirus shorthair EIF3H vector (Lv shEIF3H) to silence EIF3H expression in the colorectal cancer cell lines HCT116 and SW1116. We observed impaired cell growth and colony formation in these silenced cell lines. In addition, we showed that EIF3H knock-down led to cell apoptosis. In conclusion, EIF3H plays key roles in the apoptosis in colorectal cancer cells, which suggests EIF3H as a potential diagnostic biomarker in colorectal cancer. PMID- 30022710 TI - Joint modelling for organ transplantation outcomes for patients with diabetes and the end-stage renal disease. AB - This article is motivated by jointly modelling longitudinal and time-to-event clinical data of patients with diabetes and end-stage renal disease. All patients are on the waiting list for the pancreas transplant after kidney transplant, and some of them have a pancreas transplant before kidney transplant failure or death. Scant literature has studied the dynamical joint relationship of the estimated glomerular filtration rates trajectory, the effect of pancreas transplant, and time-to-event outcomes, although it remains an important clinical question. In an attempt to describe the association in the multiple outcomes, we propose a new joint model with a longitudinal submodel and an accelerated failure time submodel, which are linked by some latent variables. The accelerated failure time submodel is used to determine the relationship of the time-to-event outcome with all predictors. In addition, the piecewise linear function in the survival submodel is used to calculate the dynamic hazard ratio curve of a time-dependent side event, because the effect of the side event on the time-to-event outcome is non-proportional. The model parameters are estimated with a Monte Carlo EM algorithm. The finite sample performance of the proposed method is investigated in simulation studies. Our method is demonstrated by fitting the joint model for the clinical data of 13,635 patients with diabetes and the end-stage renal disease. PMID- 30022711 TI - Right ventricular function in elite male athletes meeting the structural echocardiographic task force criteria for arrhythmogenic right ventricular cardiomyopathy. AB - Athlete pre-participation screening is focused on detecting pathological conditions like arrhythmogenic right ventricular cardiomyopathy (ARVC). The diagnosis of ARVC is established by applying the revised 2010 ARVC Task Force Criteria (TFC) that assesses RV structure and function. Some athletes may meet structural TFC without having ARVC but we do not know the consequences for RV function. This study compared RV structural and functional indices in male athletes that meet the structural TFC (MTFC) for ARVC and those that do not (NMTFC). We recruited 214 male elite athletes. All participants underwent 2D, Doppler, tissue Doppler and strain (epsilon) echocardiography with a focused and comprehensive assessment of the right heart. Athletes were grouped on RV structural data: MTFC n = 34; NMTFC n = 180. Functional data were compared between groups. By selection, MTFC had larger absolute and scaled RV outflow tract (RVOT) diameter compared to NMTFC (P ?0.05) but these athletes did not develop a proportional increase in the RV inflow dimensions. There was no difference in global conventional RV systolic function between both groups however, there was significantly lower global RV epsilon in athletes that MTFC which can be explained, in part, by the RVOT dimension. PMID- 30022712 TI - How I Do It: New Dissector Device Allows for Effective Operative Field in Transoral Endoscopic Thyroid Surgery Using Vestibular Approach. AB - BACKGROUND: Minimally invasive thyroid and parathyroid resections are rarely performed. Promising new endoscopic transoral approaches to the anterior neck (transoral endoscopic thyroidectomy vestibular approach [TOETVA]) have been described with good results and few complications. This study evaluates a new device to allow the safe entrance of trocars in the subplatysmal space for TOETVA in a cadaver model. METHODS: The technique was performed in 4 unilateral thyroidectomies in female cadavers. The technical steps consisted of a 10-mm incision made at the center of the oral vestibule followed by subplatysmal hydrodissection. The blunt dissector is a metallic stick with an olive at the end and promotes progressive gain in subplatysmal space enlarging the operative field. The instrument was inserted creating a space below the platysma to the anterior neck and the strap muscles. Three trocars were inserted in the vestibular area. The dissection begins by cutting the linea alba cervicalis. The isthmus was dissected and transected. Anatomical structures as the superior thyroid artery, parathyroid glands, and the recurrent laryngeal nerve could be safely identified with magnified vision. RESULTS: Optimal operative field due to subplatysmal dissection by the device allowed for exposition of thyroid and parathyroid glands in all cases. Unilateral thyroidectomy was performed in a mean of 54 minutes with excellent aesthetic results. CONCLUSIONS: The new device is a promising feature to allow safe transoral thyroid surgery in a cadaver model. Further studies in clinical series are needed to evaluate the broad application of the device. PMID- 30022713 TI - Orthodontic management of a non-vital immature tooth treated with regenerative endodontics: a case report. AB - Management of non-vital immature permanent teeth in children remains a challenge in paediatric dentistry. The resulting short roots, thin root dentinal walls, and compromised crown root ratios, not only affect the long-term survival of these teeth but also complicate any intended orthodontic treatment. This case report shows a successful orthodontic movement of a traumatised non-vital immature tooth treated using regenerative endodontics. PMID- 30022714 TI - Resurrecting Maunder's ghost: John 'Jack' Eddy, the Maunder Minimum, and the rise of a dilettante astrophysicist. AB - During the 1970s, widespread scientific interest in the risks of climate change prompted John A. Eddy (1931-2009), an astrophysicist with the National Center for Atmospheric Research in Boulder, CO, to investigate whether sunspots could be used to predict future climate changes. Methodologically, Eddy's investigations were uniquely historical in nature. By interrogating old manuscripts of solar observations since the early seventeenth century, he identified what appeared to be a correlation between the so-called Maunder Minimum - a virtual cessation of sunspots between 1645 and 1715 - and severely cold temperatures during the Little Ice Age. While he could not identify the physical mechanisms that governed solar climate relationships, this historical episode fostered his curiosity. Fortuitously, Eddy's solar-climate research coincided with efforts to use satellites to monitor and record variations in solar energy output, which in context constituted a significant development in managing environmental and technological risk. But using the Maunder Minimum to advance the frontiers of knowledge about solar-terrestrial relationships was not Eddy's only - or even primary - motivation. In the mid-1840s, German astronomer Heinrich Schwabe (1789 1875) discovered what appeared to be a decadal sunspot cycle, the existence of which inspired generations of astrophysicists to more precisely estimate its length as well as determine its underlying causes. Eddy, however, came to believe that the astronomical community failed to consider the implications of subsequent evidence suggesting that Schwabe's solar cycle was not an enduring characteristic of the sun. Instead, he reasoned that evidence offered by nineteenth-century European astronomers Gustav Sporer and Edward Maunder in the 1880s and 1890s had been entirely overlooked. But rather than arguing that their evidence was overlooked in error, Eddy identified what he cast as a conspiracy of wilful ignorance on the part of a staid and conservative astronomical community. By utilizing Eddy's private hand-written notes as they appeared in undergraduate lectures, public speeches and academic talks, as well as his appreciation for the seminal views of sociologist of science Thomas Kuhn, I show that Eddy sought to rectify this injustice by proposing a contrasting vision of science as an interdisciplinary, collaborative and creative process of exploring the ignored areas between scientific disciplines. PMID- 30022715 TI - Dynamics of malaria transmission model with sterile mosquitoes. AB - In this paper, a malaria transmission model with sterile mosquitoes is considered. We first formulate a simple SEIR malaria transmission model as our baseline model. Then sterile mosquitoes are introduced into the baseline model. We consider the case that the release rate of sterile mosquitoes is proportional to the wild mosquito population size. To investigate the impact of releasing sterile mosquitoes on the malaria transmission, the dynamics of the baseline model and the models with the sterile mosquitoes are discussed. We derive formulas of the reproductive numbers and explore the existence of endemic equilibrium as the reproductive number is more than unity for these models. It is shown that both the baseline model and the models with the sterile mosquitoes undergo backward bifurcations. Based on theoretical analysis and numerical simulation, we investigate the impact of releasing sterile mosquitoes on malaria transmission. PMID- 30022716 TI - Introducing quality improvement teaching into general practice undergraduate placements. AB - Quality Improvement skills are deemed essential for future clinical practice of doctors by professional regulatory bodies. This paper presents the challenges of a curriculum development initiative to ensure that all medical students have involvement with a quality improvement project during a general practice placement in their fourth year. The curriculum development is described within a 'Plan-Do-Study-Act' framework. The learning is presented as a reflective discussion with conclusions and recommendations on how potential current barriers to implementing authentic participation in quality improvement projects for undergraduate medical students might be met. The key barriers include lack of opportunities within the curriculum structure to allow sufficient time for authentic quality improvement projects and a lack of confidence amongst placement tutors to support medical students with quality improvement projects. PMID- 30022717 TI - A review of the methodology and applications of anthropometry in ergonomics and product design. AB - Anthropometry is a key element of ergonomic studies for addressing the problem of fitting the tasks/products to user characteristics, but there is a gap between anthropometric data and their application for designing ergonomic products and environments. This research was conducted to review the literature on the methodology and applications of anthropometry for the ergonomic design of products and environments, and to identify where further research is needed to improve its application and evaluation protocols. One hundred and sixteen papers meeting the inclusion criteria were reviewed. Although a number of anthropometric investigations have been conducted to improve the design of products/environments for different users, further research seems to be necessary, particularly for special groups, such as children, the elderly and people with disabilities. Different anthropometric measurement methods/techniques and fitting criteria are discussed regarding their applicability for various design applications. This review also highlights methodological issues (sampling considerations and prototype evaluation and testing) that should be considered in future research to ensure a user-centred approach of the design process. Practitioner Summary: A literature review was conducted on the methodology and applications of anthropometry for the ergonomic design of products/environments. This review emphasises the need for anthropometric research to design for special groups, such as children, the elderly and people with disabilities, and methodological issues that should be considered in future research. Abbreviations: 1D: one dimensional; 2D: two-dimensional; 3D: three-dimensional; HF/E: Human Factors/Ergonomics; PCA: Principal Components Analysis; CA: Cluster Analysis; DHM: Digital Human Modelling. PMID- 30022718 TI - Staged ultrasound-guided liposuction for hidden arteriovenous fistulas in obese patients. AB - BACKGROUND: In obese patients with end stage renal disease, puncturing matured arteriovenous fistulas (AVF) that run deep under the skin surface may prove difficult. To achieve reliable puncturability, there are several surgical solutions. Superficialization with mobilization is common. With some newer options (lipectomy and liposuction) subcutaneous adipose tissue is surgically reduced. There are only a few authors who have published their experience with liposuction and we want to add our own results. PATIENTS AND METHODS: We report our experience with ultrasound-guided liposuction (USGL). We introduce liposuction cannulas via small incisions to reduce the subcutaneous adipose tissue overlying the planned cannulation zones under ultrasound control using tumescent anaesthesia till the prospective needle access segments become easily palpable. So far, we have used this technique for cephalic forearm and upper arm fistulas only. Furthermore, we review the relevant literature. RESULTS: From February 2014 through November 2016, six patients were treated using USGL. Their body mass indices ranged from 30.8 to 53.8 kg/m2 (mean 37.6). The mean depths of the AVFs beneath the skin surface were 13.3 (8-20) mm before and 5.1 (3.5-6) mm after surgery. The mean time of the procedure was 15 minutes. There were no postoperative complications. In five patients, the AVFs could reliably be punctured after three weeks. One patient is not yet on dialysis. During the follow-up period of 24 (11-43) months, all six AVFs remained primarily patent. In the literature, we found nine reports on altogether 81 patients undergoing USGL. Almost all noteworthy complications occurred only after ultrasound-powered liquefaction of adipose tissue, which was only used by a single investigator. CONCLUSIONS: USGL is a method that can be learned easily, is minimally invasive, seems to be safe, and requires only short operation times. PMID- 30022719 TI - [Anticipation at the end of life - a critical appraisal for the clinical practice]. AB - Anticipation at the end of life - a critical appraisal for the clinical practice Abstract. Advance planning or anticipation in health care is based on prognosis, and that is no more (and no less) than dealing with probabilities. Knowledge about prognostic factors in medicine is needed here, and competencies how to communicate it. In medicine, advance planning is currently more and more regarded as an elementary right as an expression of the implementation of patient autonomy - but what content can or must be discussed and defined? The terminology on the subject of "advance planning" is inconsistent both nationally and internationally. In Switzerland, therefore, an attempt was made to contribute to a more uniform understanding in this respect with the new "framework concept for advance planning in health care". For clinical practice it can be summarized as follows: Advance planning requires the following attributes: Trust, shared experience of health crises and how to deal with them, communicative abilities of all those involved (not only on the part of medicine!), an understanding of the role of medicine between coach and mountain guide, a systemic approach with the involvement of relatives in important decisions, an established regional health network that functions perfectly up to the electronic documentation, full cost reimbursement of the sometimes very demanding decision-making processes, documentation and revision - and of all the awareness and self-reflection that advance planning is not about certainties but about probabilities. PMID- 30022720 TI - [Role of the influence of cultural and religious beliefs on medical end-of-life decision-making]. AB - Role of the influence of cultural and religious beliefs on medical end-of-life decision-making Abstract. Decision-making at the end of life must encompass medical indication, therapeutic offer, patient autonomy and consent. Furthermore, physicians must reflect on whether their own cultural and religious beliefs have an influence on their decision-making process. Basic knowledge in palliative care or integration of experts in palliative care may be useful when dealing with patients at the end of life, particularly when shifting treatment goals to palliative or comfort care measures is considered or necessary. Expertise in palliative care may also be useful in the care for patients well before the end of life, for example in symptom management, wound care, communication with family or psycho-social care. Ideally, goals of care should be discussed with the patient. Decision-making includes judging, respecting individual values, caring and taking on responsibility - including responsibility for potentially wrong choices. It is imperative that respect for patient autonomy and increasingly strengthened patient competence must be reflected in physicians' reasoning about medical and ethical end-of-life decisions, as well as about empirical and normative aspects of medical indication. PMID- 30022721 TI - [Give the due value to the end of life: the systematic underfunding of specialised palliative care in the Swiss DRG system]. AB - Give the due value to the end of life: the systematic underfunding of specialised palliative care in the Swiss DRG system Abstract. Palliative care is an integral part of modern medicine, improving quality of life, treatment satisfaction, and reducing the costs of care in severe disease. Patients' access should be early, regardless of age, diagnosis and setting, when incurable or advanced disease has been diagnosed. The public expenditure for specialised palliative care units in hospitals can be seen as yardstick for an appropriate palliative care supply, but in Switzerland only a mere fraction of revenues is dedicated to the palliative care units. Every year, 66'000 patients die in Switzerland, 38 % of them in a hospital. Health care costs for the last year of life account for 1.9 billion Swiss francs, but palliative care units receive only estimated 51 million Swiss francs per year. Reasons are a too little number of palliative care units, a systemic underfunding of their services and a fragmentary supply chain for severely ill or dying patients. This leads to ethically conflicting situations for clinicians. They have to deal with shortage of supply and, due to economic reasons, are forced to transfer severely ill or dying patients into inadequate settings. Based on international recommendations, Switzerland is in need of further 500 beds for specialised palliative care (actually 335), and at least 11'000 patients per year need access to a specialised palliative care service (actually about 3'500). Under the actual tariffing system, units for palliative care in hospitals are endangered in their existence. Corrections of the remuneration system are urgently warranted. On the long run, a national legal basis should be elaborated to safeguard adequate palliative care supply for all patients in need and as a base for monitoring, formation and research in palliative care. PMID- 30022722 TI - [Palliative Care - not just for the final phase. A rewiev of evidence]. AB - Palliative Care - not just for the final phase. A rewiev of evidence Abstract. Already in early stages of their disease, patients with incurable, advanced cancer and non-cancer disease suffer from a range of limitations of their quality of life due to symptoms (i. e. pain, dyspnoea) or psychical, social or spiritual problems. Palliative Care aims to maintain the patients' quality of life and is applicable already early in the disease trajectory and not only at the end of life. As providers of general (basic) palliative care, all health care providers from all disciplines should therefore hold basic expertise in symptom control and communication. Also, they should be aware of psychical, social and spiritual dimensions of suffering. The integration and cooperation of health care services should be driven by the actual needs and demands of the individual patient. In addition to general palliative care, specialist palliative care is provided by multi-professional teams, for example, as specialist palliative home care teams or palliative care services in hospitals. In the future, it will be paramount to routinely identify patients with complex needs and severe (symptom) burden who will benefit most from early integration of specialist palliative care. PMID- 30022723 TI - [Delirium in Palliative Care: Evidence and Practice]. AB - Delirium in Palliative Care: Evidence and Practice Abstract. Delirium is a frequent condition in Palliative Care. For patients, their families and the formal caregivers it is associated with substantial burden, fears and challenges. It is also associated with increased morbidity and mortality and often irreversible. Of utmost importance is the identification of patients and threat for delirium and prophylactic measures to avoid delirium whenever possible. For this, risk factors should be identified and eliminated whenever possible. The correct identification of delirium is challenging and especially the hypoactive form of delirium is often unrecognised. When delirium is diagnosed, the etiology must be explored thoroughly and potentially reversible causes should be treated and eliminated whenever feasible and appropriate. The pharmacologic therapy is based on benzodiazepines and neuroleptics. Yet, the use of the substances should be restricted to severe psychotic episodes of the hyperactive form of delirium. It is of utmost importance to know that "disorientation", "restlessness" or delirium alone are no indication for pharmacotherapy. Recently two landmark randomized controlled clinical trials concerning pharmacotherapy for delirium in palliative care have been published. This review presents a practical overview of the prevention, diagnosis and therapy of delirium in palliative care alongside the presentation and discussion of the recently published trials. PMID- 30022724 TI - [Palliative Sedation: Comments on a controversial topic]. AB - Palliative Sedation: Comments on a controversial topic Abstract. Palliative sedation (PS) is an accepted medical practice for terminally ill patients. It intends the alleviation of unbearable suffering by intentionally lowering the level of consciousness. In contrast to physician assisted suicide and euthanasia, palliative sedation aims to relieve burdensome symptoms with no intention of hastening death. PC can be applied as "intermittent palliative sedation" or "continuous (deep) sedation until death". Most ethical controversies are related to the latter form of PS: 1: Is existential or psychosocial suffering a possible indication for PS? 2: What is the earliest possible time point to start PS? 3: The withdrawal or withholding of artificial nutrition and hydration during PS. A critical reflection of these ethical controversial aspects within the treatment team is highly desirable. However, the patient's well-being and the respect for the patient's decisions that are based on experiences which are made only by him or her, must remain the guiding principle for medical actions. PMID- 30022725 TI - [Dementia from a palliative care perspective: why a disease-specific advance care planning is necessary]. AB - Dementia from a palliative care perspective: why a disease-specific advance care planning is necessary Abstract. Palliative Care has to transform profoundly in the context of population aging in many countries around the globe. It has to collaborate increasingly with geriatric medicine and incorporate geriatric expertise. One of the pivotal challenges of geriatric palliative care is ethically appropriate decision making for patients who have lost decision-making capacity. While the traditional approach to advance directives (living wills) has demonstrably proven ineffective, the new approach that is currently being embraced, including in German-speaking countries, is the systemic process of advance care planning (ACP). In this article, ACP is first presented with its general aims, elements and effects. Second, it is shown why we need an adapted ACP program for people with dementia and what such a dementia-specific ACP must entail. PMID- 30022726 TI - [Paediatric Palliative Care: What is different in children compared to adults?] AB - Paediatric Palliative Care: What is different in children compared to adults? Abstract. The number of children and adolescents (0 - 18 years) with life limiting conditions and needs for paediatric palliative care (PPC) is rising. In Switzerland, the awareness for these needs lags largely behind other developed countries. In the United Kingdom, the prevalence for children with life-limiting conditions and PPC needs was estimated at 32 children per 10'000 population (0 - 19 years). In Switzerland, this would correspond to an absolute number of 5'000 children living with a life-limiting condition and potentially in need of PPC. In contrast, the number of deaths accounts for around 500 children (0 - 18 years) every year. Most common causes of death are perinatal conditions, contributing to nearly 50 % of all deaths in childhood, followed by accidents and complex chronic conditions such as genetic / congenital disorders, neurological and cardiac conditions and cancer. Compared to adults with palliative care needs, the group of children is significantly smaller but at the same time highly heterogenic. Heterogeneity relates to: the whole age continuum from neonates, infants and children to adolescents; a broad spectrum of diseases including rare diseases; a variety of needs due to age, development and the illness, e. g. needs for specialist care or technical support; various in- and outpatient settings. Paediatric care always encompasses the whole family and their particular needs. Internationally, hospital-based programmes have been developed and implemented to meet these particular needs of children and their families. PMID- 30022727 TI - ? PMID- 30022728 TI - [Caring for patients at the end of life: Experiences and needs of physicians]. AB - Caring for patients at the end of life: Experiences and needs of physicians Abstract. In the context of death and dying, physicians are challenged in many different ways, not only professionally but also personally. Physicians are described as having a hard time accepting the finality of life. Medical practitioners find difficulties balancing their emotional involvement and their anxiety in facing death. Many specialists focus their treatment on pressing physiological problems at the time of acute crises, and have difficulty accepting that the limits of treatment effectiveness have been reached. This manuscript provides an overview of the aspects that characterise physicians' attitudes, experiences and needs when dealing with dying patients, with a view to provide information on useful approaches to communication at the end of life, as well as to encourage the development of strategies to better integrate end of life conversations and self-care practices into everyday practice. Medical training has favoured overtime a detached approach to emotions and death and dying as an isolating experience. While some patient deaths may be more confronting than others, and some conversations more difficult to start than others, turning the view to oneself can help to not only understand where the discomfort comes from, but also to improve communication patterns, stay healthy, and derive job satisfaction. By sharing perspectives and learning how other colleagues deal with similar issues, there is an opportunity for medical practitioners to develop a well-rounded approach to dealing with death and dying, which may enhance personal and professional relationships and may ultimately influence future generations of medical practitioners, as well as societal expectations. PMID- 30022730 TI - Speech Understanding With Various Maskers in Cochlear-Implant and Simulated Cochlear-Implant Hearing: Effects of Spectral Resolution and Implications for Masking Release. AB - The purpose of this study was to investigate the relationship between psychophysical spectral resolution and sentence reception in various types of interfering backgrounds for listeners with cochlear implants and normal-hearing subjects listening to vocoded speech. Spectral resolution was measured with a spectral modulation detection (SMD) task. For speech testing, maskers included stationary speech-shaped noise (SSN), four-talker babble, multitone noise, and a competing talker. To explore the possible trade-offs between spectral resolution and susceptibility to different types of maskers, the degree of simulated current spread was varied within the vocoder group, achieving a range of performance for SMD and speech tasks. Greater simulated current spread was detrimental to both spectral resolution and speech recognition, suggesting that interventions that decrease current spread may improve performance for both tasks. Better SMD sensitivity was significantly correlated with improved sentence reception. In addition, differences in sentence reception across the four maskers were significantly associated with SMD across the combined group of cochlear-implant and vocoder subjects. Masking release (MR) was quantified as the signal-to-noise ratio difference in speech reception threshold between the SSN and competing talker. Several individual cochlear-implant subjects demonstrated substantial MR, in contrast to previous studies, and the degree of MR increased with better SMD thresholds across subjects. The results of this study suggest that alternative masker types, particularly competing talkers, are more sensitive than stationary SSN to differences in spectral resolution in the cochlear-implant population. PMID- 30022731 TI - Adjusting Expectations: Hearing Abilities in a Population-Based Sample Using an SSQ Short Form. AB - The German short form of the Speech, Spatial, and Qualities of Hearing Scale (SSQ) was administered in a cross-sectional study based on stratified random samples complemented by audiometric tests and a general interview. Data from 1,711 unaided adults aged 18 to 97 years were analyzed in order to determine a distribution of hearing abilities considered as normal and the main factors that impact self-assessments. An innovative mathematical approach was used to overcome the constraints of statistics based on the mean. Quantile regression analysis yielded a benchmark distribution of SSQ scores that might support audiologists in setting realistic SSQ score targets and estimated how the effect of auditory and nonauditory factors changes across the distribution of SSQ scores. Regression models showed significant effects for nonauditory factors on SSQ ratings when controlled for pure-tone hearing and interaural asymmetry. Self-reporting of hearing difficulties, when asked in general terms, was substantially related to SSQ ratings. This effect was observed in both high and low scoring participants and led to a considerable score decrease in all SSQ subscales. Gender, educational level, and self-reporting of health issues also were significantly related to SSQ ratings, but the corresponding effects were regularly unbalanced across the score distribution and particularly large at lower quantiles. The estimated effects of age, however, were mostly small in size, inconsistent regarding the direction, and failed significance for all SSQ items. Overall, the results suggest that nonauditory factors and cumulative effects must be considered when evaluating rehabilitative interventions against an ideal outcome. PMID- 30022729 TI - The Neuronal Basis of Predictive Coding Along the Auditory Pathway: From the Subcortical Roots to Cortical Deviance Detection. AB - In this review, we attempt to integrate the empirical evidence regarding stimulus specific adaptation (SSA) and mismatch negativity (MMN) under a predictive coding perspective (also known as Bayesian or hierarchical-inference model). We propose a renewed methodology for SSA study, which enables a further decomposition of deviance detection into repetition suppression and prediction error, thanks to the use of two controls previously introduced in MMN research: the many-standards and the cascade sequences. Focusing on data obtained with cellular recordings, we explain how deviance detection and prediction error are generated throughout hierarchical levels of processing, following two vectors of increasing computational complexity and abstraction along the auditory neuraxis: from subcortical toward cortical stations and from lemniscal toward nonlemniscal divisions. Then, we delve into the particular characteristics and contributions of subcortical and cortical structures to this generative mechanism of hierarchical inference, analyzing what is known about the role of neuromodulation and local microcircuitry in the emergence of mismatch signals. Finally, we describe how SSA and MMN are occurring at similar time frame and cortical locations, and both are affected by the manipulation of N-methyl- D-aspartate receptors. We conclude that there is enough empirical evidence to consider SSA and MMN, respectively, as the microscopic and macroscopic manifestations of the same physiological mechanism of deviance detection in the auditory cortex. Hence, the development of a common theoretical framework for SSA and MMN is all the more recommendable for future studies. In this regard, we suggest a shared nomenclature based on the predictive coding interpretation of deviance detection. PMID- 30022733 TI - Event-Related Potentials Measured From In and Around the Ear Electrodes Integrated in a Live Hearing Device for Monitoring Sound Perception. AB - Future hearing devices could exploit brain signals of the user derived from electroencephalography (EEG) measurements, for example, for fitting the device or steering signal enhancement algorithms. While previous studies have shown that meaningful brain signals can be obtained from ear-centered EEG electrodes, we here present a feasibility study where ear-EEG is integrated with a live hearing device. Seventeen normal-hearing participants were equipped with an individualized in-the-ear hearing device and an ear-EEG system that included 10 electrodes placed around the ear (cEEGrid) and 3 electrodes spread out in the concha. They performed an auditory discrimination experiment, where they had to detect an audible switch in the signal processing settings of the hearing device between repeated presentations of otherwise identical stimuli. We studied two aspects of the ear-EEG data: First, whether the switches in the hearing device settings can be identified in the brain signals, specifically event-related potentials. Second, we evaluated the signal quality for the individual electrode positions. The EEG analysis revealed significant differences between trials with and without a switch in the device settings in the N100 and P300 range of the event-related potential. The comparison of electrode positions showed that the signal quality is better for around-the-ear electrodes than for in-concha electrodes. These results confirm that meaningful brain signals related to the settings of a hearing device can be acquired from ear-EEG during real-time audio processing, particularly if electrodes around the ear are available. PMID- 30022732 TI - Cortical Speech Processing in Postlingually Deaf Adult Cochlear Implant Users, as Revealed by Functional Near-Infrared Spectroscopy. AB - An experiment was conducted to investigate the feasibility of using functional near-infrared spectroscopy (fNIRS) to image cortical activity in the language areas of cochlear implant (CI) users and to explore the association between the activity and their speech understanding ability. Using fNIRS, 15 experienced CI users and 14 normal-hearing participants were imaged while presented with either visual speech or auditory speech. Brain activation was measured from the prefrontal, temporal, and parietal lobe in both hemispheres, including the language-associated regions. In response to visual speech, the activation levels of CI users in an a priori region of interest (ROI)-the left superior temporal gyrus or sulcus-were negatively correlated with auditory speech understanding. This result suggests that increased cross-modal activity in the auditory cortex is predictive of poor auditory speech understanding. In another two ROIs, in which CI users showed significantly different mean activation levels in response to auditory speech compared with normal-hearing listeners, activation levels were significantly negatively correlated with CI users' auditory speech understanding. These ROIs were located in the right anterior temporal lobe (including a portion of prefrontal lobe) and the left middle superior temporal lobe. In conclusion, fNIRS successfully revealed activation patterns in CI users associated with their auditory speech understanding. PMID- 30022736 TI - Current Advances in Pharmacotherapy and Drug Design against Inflammatory-related Pathologies. PMID- 30022735 TI - A Hearing-Model-Based Active-Learning Test for the Determination of Dead Regions. AB - This article describes a Bayesian active-learning procedure for estimating the edge frequency, fe, of a dead region, that is, a region in the cochlea with no or very few functioning inner hair cells or neurons. The method is based on the psychophysical tuning curve (PTC) but estimates the shape of the PTC from the parameters of a hearing model, namely fe, and degree of outer hair cell loss. It chooses the masker frequency and level for each trial to be highly informative about the model parameters in the context of previous data. The procedure was tested using 14 ears from eight subjects previously diagnosed with high-frequency dead regions. The estimates of fe agreed well with estimates obtained using "Fast PTCs" or more extensive measurements from an earlier study. On average, 33 trials were needed for the estimate of fe to fall and stay within 0.3 Cams of the final "true" value on the equivalent rectangular bandwidth-number scale. The time needed to obtain a reliable estimate was 5 to 8 min. This is comparable to the time required for Fast PTCs and short enough to be used when fitting a hearing aid. Compared with Fast PTCs, the new method has the advantage of using yes-no judgments rather than continuous Bekesy tracking. This allows the slope of a subject's psychometric function and thus the reliability of his or her responses to be estimated, which in turn allows the test duration to be adjusted so as to achieve a given accuracy. PMID- 30022734 TI - Electrophysiological and Behavioral Evidence of Reduced Binaural Temporal Processing in the Aging and Hearing Impaired Human Auditory System. AB - A person's ability to process temporal fine structure information is indispensable for speech understanding. As speech understanding typically deteriorates throughout adult life, this study aimed to disentangle age and hearing impairment (HI)-related changes in binaural temporal processing. This was achieved by examining neural and behavioral processing of interaural phase differences (IPDs). Neural IPD processing was studied electrophysiologically through steady-state activity in the electroencephalogram evoked by periodic changes in IPDs over time, embedded in the temporal fine structure of acoustic stimulation. In addition, behavioral IPD discrimination thresholds were determined for the same stimuli. To disentangle potential effects of age from those of HI, both measures were applied to six participant groups: young, middle aged, and older persons, with either normal hearing or sensorineural HI. All participants passed a cognitive screening, and stimulus audibility was controlled for in participants with HI. The results demonstrated that HI changes neural processing of binaural temporal information for all age-groups included in this study. These outcomes were revealed, superimposed on age-related changes that emerge between young adulthood and middle age. Poorer neural outcomes were also associated with poorer behavioral performance, even though the behavioral IPD discrimination thresholds were affected by age rather than by HI. The neural outcomes of this study are the first to evidence and disentangle the dual load of age and HI on binaural temporal processing. These results could be a valuable first step toward future research on rehabilitation. PMID- 30022737 TI - Serum magnesium and cardiovascular mortality in peritoneal dialysis patients: a 5 year prospective cohort study. AB - The aim of this study was to explore the association between serum Mg and cardiovascular mortality in the peritoneal dialysis (PD) population. This prospective cohort study included prevalent PD patients from a single centre. The primary outcome of this study was cardiovascular mortality. Serum Mg was assessed at baseline. A total of 402 patients (57 % male; mean age 49.3+/-14.9 years) were included. After a median of 49.9 months (interquartile range: 25.9-68.3) of follow-up, sixty-two patients (25.4 %) died of CVD. After adjustment for conventional confounders in multivariate Cox regression models, being in the lower quartile for serum Mg level was independently associated with a higher risk of cardiovascular mortality, with hazards ratios of 2.28 (95 % CI 1.04, 5.01), 1.41 (95 % CI 0.63, 3.16) and 1.62 (95 % CI 0.75, 3.51) for the lowest, second and third quartiles, respectively. A similar trend was observed when all-cause mortality was used as the study endpoint. Further analysis showed that the relationships between lower serum Mg and higher risk of cardiovascular and all cause mortality were present only in the female subgroup, and not among male patients. The test for interaction indicated that the associations between lower serum Mg and cardiovascular and all-cause mortality differed by sex (P=0.008 and P=0.011, respectively). In conclusion, lower serum Mg was associated with a higher risk of cardiovascular and all-cause mortality in the PD population, especially among female patients. PMID- 30022738 TI - Active screening and interfacility communication of carbapenem-resistant Enterobacteriaceae (CRE) in a tertiary-care hospital. AB - BACKGROUND: Hospitals may implement admission screening cultures and may review transfer documentation to identify patients colonized with carbapenem-resistant Enterobacteriaceae (CRE) to implement isolation precautions; however, outcomes and logistical considerations have not been well described. METHODS: At an academic hospital in Chicago, we retrospectively studied the implementation and outcomes of CRE admission screening from 2013 to 2016 during 2 periods. During period 1, we implemented active CRE rectal culture screening for all adults patients admitted to intensive care units (ICUs) and for those transferred from outside facilities to general wards. During period 2, screening was restricted only to adults transferred from outside facilities. For a subset of transferred patients who were previously reported to the health department as CRE positive, we reviewed transfer paperwork for appropriate documentation of CRE. RESULTS: Overall, 11,757 patients qualified for screening; rectal cultures were performed for 8,569 patients (73%). Rates of CRE screen positivity differed by period, previous facility type (if transferred), and current inpatient location. A higher combined CRE positivity rate was detected in the medical and surgical ICUs among period 2 patients (3.3%) versus all other ward-period comparisons (P<.001). Among 13 transferred patients previously known to be CRE colonized, appropriate CRE transfer documentation was available for only 4 patients (31%). CONCLUSIONS: Active screening for CRE is feasible, and screening patients transferred from outside facilities to the medical or surgical ICU resulted in the highest screen positivity rate. Furthermore, CRE carriage was inconsistently documented in transfer paperwork, suggesting that admission screening or enhanced inter facility communication are needed to improve the identification of CRE-colonized patients. PMID- 30022739 TI - Depletion and repletion of fruit and vegetable intake alters serum bone turnover markers: a 28-week single-arm experimental feeding intervention. AB - This study was designed to evaluate the effects of elevated fruit and vegetable intake on bone turnover markers. In all, twenty-nine subjects (nine male and twenty female, with a mean age of 32.1 (sem 2.5) years) participated in a 28-week single-arm experimental feeding intervention trial and consumed a prescribed low fruit and vegetable diet for 6 weeks (depletion-1), a provided high-fruit and vegetable diet for 8 weeks (fruit: 360-560 g; vegetables: 450-705 g), another prescribed low-fruit and vegetable diet for 6 weeks (depletion-2) and then their usual diets for 8 weeks (repletion). Serum bone-related biomarkers were analysed with commercial ELISA kits. Plasma carotenoid levels decreased as a result of the depletion phase and increased with the high-fruit and vegetable diet. Compared with the baseline, depletion-1 resulted in higher serum bone resorption marker C terminal telopeptide of type 1 collagen (CTX) and lower bone formation marker alkaline phosphatase (BAP) (CTX, 0.68 (sem 0.05) v. 0.97 (sem 0.08) ng/ml and BAP, 10.7 (sem 0.7) v. 9.5 (sem 0.8) ug/l for the baseline and the depletion-1, respectively, P<0.05). High intake of fruit and vegetables decreased serum CTX (P<0.05) to 0.60 (sem 0.04) ng/ml and increased serum BAP to 11.3 (sem 0.7) ug/l (P<0.05), compared with the depletion-1 phase. Serum concentrations of CTX were inversely correlated and those of BAP were positively correlated with blood lycopene. These data show that increased fruit and vegetable consumption at or above federal dietary guidance may be beneficial to bone health. PMID- 30022740 TI - Basic Seismic Response Capability of Hospitals in Lima, Peru. AB - OBJECTIVE: The objective of the study was to research the basic seismic response capability (BSRC) of hospitals in Lima Metropolitana. A large number of wounded could be registered in case of an earthquake; therefore, operational hospitals are necessary to cure the injured. The study focused on the operational performance of the hospitals, autonomies of essential resources such as power, water, medical gases, and medicine, in addition to the availability of emergency communication system and ambulances. METHODS: Data by a probabilistic seismic risk analysis have been used to assess the operational level of the hospitals. Subsequently, availability of an essential resource has been combined with the immediately operational hospitals to evaluate the BSRC of the health facilities. RESULTS: Forty-one of Lima's hospitals have been analyzed for a seismic event with 72-100 years of a return period. Three hospitals (7.3%) were capable to work in a self-sufficient manner for 72 hours, another three (7.3%) for 24 hours, and one (2.4%) for 12 hours. CONCLUSION: Results showed a low performance of the hospitals in case of an earthquake. The issue is due to the high seismic vulnerability of the existing structures. Given the importance of Lima city in Peru, structural and nonstructural retrofitting plans should be implemented to improve the preparedness of the health system in case of an emergency. (Disaster Med Public Health Preparedness. 2018;page 1 of 6). PMID- 30022741 TI - Katakam and co-workers have not shown SSRIs to be harmful and ineffective and should stop claiming that they have. AB - Funded by the Danish state to provide guidance in health-related matters, the Copenhagen Trial Unit (CTU) at Rigshospitalet may cause considerable societal harm if allowing their analyses to be influenced by bias and prejudice rather than rigor and impartiality. This is why we found it worthwhile to comment on a report from the CTU in which the authors invoked analyses marred by numerous errors and methodological mistakes to claim that selective serotonin reuptake inhibitors (SSRIs) are harmful and ineffective. The CTU group has now produced a response to our comment which is on par with their original contribution in terms of bias, misconceptions and mistakes. Our conclusion is that the reputation of the CTU would be best served by the authors asking for retraction of their SSRI paper. PMID- 30022742 TI - Trends in "usual care" for septic shock. PMID- 30022743 TI - Silicon-mediated and constitutive resistance to Rhopalosiphum maidis (Hemiptera: Aphididae) in corn hybrids. AB - The corn leaf aphid, Rhopalosiphum maidis (Fitch) (Hemiptera: Aphididae), is an important pest of corn, but no corn genotypes resistant to R. maidis are commercially available. Although the ability of silicon to induce plant resistance against some insects is known, the effect of silicon on R. maidis and in corn hybrids with different levels of constitutive resistance is still unknown. This study sought to determine the constitutive resistance of corn hybrids to R. maidis and silicon resistance induction in hybrids with different degrees of constitutive resistance. Field experiments with natural infestations of aphids were conducted in three locations in Brazil (Patos de Minas, Araguari, and Tupaciguara). Greenhouse trials were also used to evaluate the effect of varietal resistance on aphid population growth and identify resistant and susceptible genotypes. Aphid resistance induced by silicon was determined with resistant and susceptible corn hybrids. In the field, the corn hybrids BM8850, AS1625PRO, and DKB310PRO had the greatest proportion of plants infested by R. maidis in all three localities. The hybrids P30F53H, STATUS VIP, BM9288, DAS2B587HX, DKB175PRO, AS1633PRO, and DKB390PRO2 were the least infested in Patos de Minas and Araguari, and P30F53H was the least infested in Tupaciguara. When antibiosis effects were evaluated by aphid population growth, the hybrids AG7088PRO3 and DKB310PRO2 were susceptible, while P30F53YH was resistant. When natural aphid infestation was evaluated, wherein the effects of antibiosis and non-preference could not be discriminated, soil applications of silicon-induced resistance to R. maidis in both susceptible and constitutively resistant corn hybrids. PMID- 30022744 TI - Hearing healthcare in remote or resource-constrained environments. AB - BACKGROUND: Hearing loss is a leading contributor to the global burden of disease, with more than 80 per cent of affected persons residing in low- and middle-income countries, typically where hearing health services are unavailable. OBJECTIVES: This article discusses the challenges to hearing care in remote and resource-limited settings, and describes recommended service delivery models, taking personnel and equipment requirements into consideration. The paper also considers the novel roles of telemedicine approaches in these contexts for improving access to preventative care. Finally, two case studies illustrate the challenges and strategies for service provision in remote and underserved settings. PMID- 30022745 TI - Co-existence of social isolation and homebound status increase the risk of all cause mortality. AB - : ABSTRACTBackground:Social isolation and homebound statuses are possible risk factors for increased mortality among older adults. However, no study has addressed the impact of accumulation of these two factors on mortality. The aim of this study was to examine whether such accumulation increased the risk of all cause mortality. METHODS: The analyzed sample was drawn from a mail survey of 1,023 older adults without instrumental activities of daily living disability. Participants were classified into four groups according to the frequency of both face-to-face and non-face-to-face interactions with others (social isolation and non-social isolation) and the frequency of going outdoors (homebound and non homebound). Social isolation and homebound statuses were defined as having a social interaction less than once a week and going outdoors either every few days or less, respectively. All-cause mortality information during a six-year follow up was obtained. RESULTS: In total, 78 (7.6%) participants were both socially isolated and homebound. During the follow-up period, 65 participants died, with an overall mortality rate of 10.6 per 1000 person-years. Cox proportional hazards regression analyses demonstrated that older adults who were socially isolated and homebound showed a significantly higher risk of subsequent all-cause mortality compared with healthy adults who were neither socially isolated nor homebound, independent of potential covariates (aHR, 2.19; 95% CI: 1.04-4.63). CONCLUSION: Our results suggest that the co-existence of social isolation and homebound statuses may synergistically increase risk of mortality. Both active and socially integrated lifestyle in later life might play a major role in maintaining a healthy status. PMID- 30022746 TI - Synchronizing developmental stages in Neotropical catfishes for application in germ cell transplantation - CORRIGENDUM. PMID- 30022747 TI - The use of visual distraction to improve the tolerability of flexible laryngoscopy. AB - BACKGROUND: Flexible laryngoscopy is a commonly performed procedure in otolaryngology. Although this procedure is not considered painful, many patients describe it as uncomfortable. This study investigated the role of visual distraction as a form of pain relief during flexible laryngoscopy. METHODS: The study included patients undergoing flexible laryngoscopy at the University Hospital Southampton. Patients were self-allocated to one of four groups: with or without co-phenylcaine anaesthetic spray; and with and without visual distraction. Visual distraction involved the patient watching the procedure concurrently with the clinician, via a video monitor. Pre- and post-procedural discomfort was assessed using a visual analogue scale. RESULTS: The use of topical anaesthetic spray was not associated with significantly reduced discomfort scores (p > 0.05). Discomfort scores were significantly reduced in the visual distraction groups (p = 0.04), irrespective of the use of topical anaesthetic spray. CONCLUSION: This small study showed that visual distraction should be considered as a simple and cost-effective alternative to local anaesthetic for flexible laryngoscopy. PMID- 30022748 TI - Integrating primary and community care: an international perspective. PMID- 30022749 TI - Spread and Persistence of Virulence and Antibiotic Resistance Genes: A Ride on the F Plasmid Conjugation Module. AB - The F plasmid or F-factor is a large, 100-kbp, circular conjugative plasmid of Escherichia coli and was originally described as a vector for horizontal gene transfer and gene recombination in the late 1940s. Since then, F and related F like plasmids have served as role models for bacterial conjugation. At present, more than 200 different F-like plasmids with highly related DNA transfer genes, including those for the assembly of a type IV secretion apparatus, are completely sequenced. They belong to the phylogenetically related MOBF12A group. F-like plasmids are present in enterobacterial hosts isolated from clinical as well as environmental samples all over the world. As conjugative plasmids, F-like plasmids carry genetic modules enabling plasmid replication, stable maintenance, and DNA transfer. In this plasmid backbone of approximately 60 kbp, the DNA transfer genes occupy the largest and mostly conserved part. Subgroups of MOBF12A plasmids can be defined based on the similarity of TraJ, a protein required for DNA transfer gene expression. In addition, F-like plasmids harbor accessory cargo genes, frequently embedded within transposons and/or integrons, which harness their host bacteria with antibiotic resistance and virulence genes, causing increasingly severe problems for the treatment of infectious diseases. Here, I focus on key genetic elements and their encoded proteins present on the F-factor and other typical F-like plasmids belonging to the MOBF12A group of conjugative plasmids. PMID- 30022750 TI - [Changes in T helper lymphocytes and their subsets in children with tic disorders]. AB - OBJECTIVE: To explore the changes in T helper lymphocytes and their subsets in children with tic disorders (TD) and their clinical significance. METHODS: Flow cytometry was used to measure the percentages of T helper lymphocytes and their subsets in the peripheral blood of children with TD and healthy children (controls). RESULTS: The percentage of T helper lymphocytes was significantly lower in the TD group than in the control group (P<0.001). The abnormal rate of T helper lymphocytes in the TD group was significantly higher than that in the control group (68.7% vs 18.8%; P<0.001). The percentage of T helper lymphocytes was negatively correlated with Yale Global Tic Severity Scale score (r=-0.3945, P<0.001). As for the subsets of T helper lymphocytes, the TD group had a significantly higher percentage of Th1 cells and a significantly lower percentage of Th2 cells compared with the control group (P<0.001). CONCLUSIONS: The abnormality of T helper lymphocytes and the imbalance of their subsets may be associated with the pathogenesis of TD in children. The percentage of T helper lymphocytes can be used as an indicator for assessing the severity of TD. PMID- 30022751 TI - [Clinical and genetic features of early-onset progressive encephalopathy associated with NAXE gene mutations]. AB - Early-onset progressive encephalopathy is a lethal encephalopathy caused by NAXE gene mutations. This paper reports the clinical and genetic features of a patient with early-onset progressive encephalopathy. A 4-year-old boy admitted to the hospital had repeated walking instability and limb weakness for 2 years. The patient and his elder brother (already dead) had clinical onset at 2 years of age. Both of them showed symptoms such as strabismus, ataxia, reduced muscle tone, delayed development, and repeated respiratory failure after infection. The NAXE gene of the patient showed new compound heterozygous mutations, i.e., c.255 (exon 2) A>T from his mother and c.361 (exon 3) G>A from his father. The NAXE gene encodes an epimerase that is essential for the repair of cellular metabolites of NADHX and NADPHX. This disease is associated with a deficiency of the mitochondrial NAD(P)HX repair system. Patients usually have rapid disease progression. They are also quite likely to have respiratory failure immediately after infection. PMID- 30022752 TI - [A novel mutation in the ETFDH gene of an infant with multiple acyl-CoA dehydrogenase deficiency]. AB - This article reports the results of tandem mass spectrometry and the mutation features of the ETFDH gene for an infant with multiple acyl-CoA dehydrogenase deficiency. The results of tandem mass spectrometry showed that C14 : 1, C8, C6, C10, and C12 increased. Exon sequencing was performed on this infant and his parents and revealed double heterozygous mutations in the ETFDH gene of the infant: c.992A>T and c.1450T>C. The former was inherited from his mother, and the latter was inherited from his father. c.1450T>C was shown to be the pathogenic mutation in the HGMD database. PolyPhen2, SIFT, and PROVEAN all predicted that the novel mutation c.992A>T might be pathogenic, and the mutant amino acids were highly conserved across various species. The findings expand the mutation spectrum of the ETFDH gene, and provide molecular evidence for the etiological diagnosis of the patient with multiple acyl-CoA dehydrogenase deficiency as well as for the genetic counseling and prenatal diagnosis in the family. PMID- 30022753 TI - [Efficacy of recombinant human thrombopoietin combined with high-dose dexamethasone in the treatment of refractory immune thrombocytopenia in children]. AB - OBJECTIVE: To explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with high-dose dexamethasone (DXM) in the treatment of children with refractory immune thrombocytopenic purpura (ITP). METHODS: Fifty-eight ITP children who had failed first-line therapy were randomly divided into two groups: DXM treatment (n=27) and rhTPO + DXM treatment (n=31). The DXM treatment group received two continuous cycles of DXM treatment; in each cycle, patients received high-dose DXM (0.6 mg/kg daily) by intravenous drip for 4 days every 28 days. The rhTPO group received subcutaneous injection of rhTPO (300 U/kg daily) for 14 days additional to DXM treatment. The overall response rate (marked response rate + slight response rate) and adverse reactions were evaluated after 3, 7, and 14 days and 1, 2, and 3 months of treatment. RESULTS: After 7 and 14 days and 1 month of treatment, the rhTPO + DXM treatment group had a significantly higher marked response rate and a significantly higher overall response rate than the DXM treatment group (P<0.05). After 2 months of treatment, the rhTPO + DXM treatment group had a significantly higher overall response rate than the DXM group (P<0.05). One patient in the DXM treatment group had liver damage during the first week of treatment. There was no hypertension, fever, rash, allergy, or weakness in the two groups. CONCLUSIONS: rhTPO combined with high-dose DXM is an effective and safe approach for treating refractory ITP. PMID- 30022754 TI - [Effects of minimal residual disease level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia]. AB - OBJECTIVE: To study the effects of minimal residual disease (MRD) level on day 33 of remission induction and IKZF1 genotype on the survival of children with B lineage acute lymphoblastic leukemia (B-ALL). METHODS: A total of 152 children with newly-diagnosed B-ALL who had complete remission after the first cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups: standard-risk (SR) group (MRD <10 4; n=60), intermediate-risk (IR) group (10-4<= MRD <10-2; n=55), and high-risk (HR) group (MRD >=10-2; n=37). Nested RT-PCR was used to determine the IKZF1 genotype of all children before chemotherapy. The effects of MRD level on day 33 of remission induction and IKZF1 genotype on the recurrence-free survival (RFS) of children with B-ALL were analyzed. RESULTS: There were 7 common IKZF1 subtypes in all the 152 children with B-ALL: IK1, IK2/3, IK4, IK6, IK8, IK9, and IK10. Of the 152 children, 130 had functional subtypes of IKZF1 and 22 had non-functional subtypes of IKZF1. During the follow-up period, relapse occurred in 26 (17%) children, and the recurrence rate was highest in the HR group (P<0.05). However, there was no significant difference in the recurrence rate between the SR group and the IR group (P>0.05). The cumulative recurrence rate of the children with non-functional subtypes of IKZF1 was significantly higher than that of those with functional types of IKZF1 (P<0.01). The predicted 5-year RFS rates in the SR, IR, and HR groups were (94.2+/-2.9)%, (86.7+/-3.8)%, and (56.2+/-4.5)% respectively (P<0.05). The 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1 (P<0.01). There was no significant difference in the predicted 5-year RFS rate between the children with functional subtypes of IKZF1 and those with non functional subtypes of IKZF1 in the SR group (P>0.05). However, the predicted 5 year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1 in the IR group and the HR group (P<0.05). CONCLUSIONS: B-ALL children with non-functional subtypes of IKZF1 have a high recurrence rate, and the recurrence rate will be even higher in B-ALL children with non-functional subtypes of IKZF1 and MRD >=10 4 on day 33 of chemotherapy. PMID- 30022755 TI - [Serum levels of interleukin-38 and interleukin-1beta in the acute phase of Kawasaki disease in children]. AB - OBJECTIVE: To study the expression of serum cytokines, interleukin-38 (IL-38) and interleukin-1beta (IL-1beta) in the acute phase of Kawasaki disease (KD) in children and the association of IL-38 and IL-1beta with inflammatory response in the acute phase and the development of coronary artery lesion (CAL). METHODS: A total of 40 children with KD who were hospitalized in the hospital between July 2015 and June 2016 were enrolled, with 21 children in the CAL group and 19 in the non-CAL (NCAL) group. Thirty healthy children and 19 children with infection and pyrexia, who were matched for sex and age, were enrolled as healthy control group and pyrexia control group respectively. ELISA was used to measure the serum levels of IL-38 and IL-1beta in the 40 children in the acute phase of KD. Spearman's rank correlation analysis was used to investigate the correlations of IL-1beta and IL-38 with interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), N-terminal pro-brain natriuretic peptide (NT-proBNP), triglyceride (TG), and total cholesterol (TC). RESULTS: The serum level of IL-38 in the children in the acute phase of KD was significantly lower than that in the healthy control group (P<0.05), but significantly higher than that in the pyrexia control group (P<0.05). There was no significant difference in the level of IL-38 between the CAL and NCAL groups (P>0.05). The children in the acute phase of KD had a significantly higher level of IL-1beta than the healthy control group (P<0.05), while there was no significant difference between this group and the pyrexia control group (P>0.05). There was also no significant difference in the level of IL-1beta between the CAL and NCAL groups (P>0.05). Serum IL-1beta and IL-38 levels were not correlated with serum levels of CRP, ESR, PCT, IL-6, and NT-ProBNP or blood lipids (TG and TC) (P>0.05). CONCLUSIONS: IL-38 is involved in an inflammatory response in the acute phase of KD and may exert an anti-inflammatory effect, which is opposite to the effect of IL-1beta to promote inflammatory response. However, there is no significant correlation between these two cytokines and the development of CAL in KD. PMID- 30022756 TI - [Association of +45 and +276 polymorphisms in the adiponectin gene with the development of Kawasaki disease]. AB - OBJECTIVE: To investigate the distribution of adiponectin +45T/G and +276G/T polymorphisms and its association with the development of Kawasaki disease and coronary artery lesion (CAL). METHODS: A total of 81 children with Kawasaki disease (among whom 11 had CAL) and 100 normal children who underwent physical examination (control group) were enrolled in a case-control study. Sequencing was performed to investigate the distribution of adiponectin +45T/G and +276G/T polymorphisms. RESULTS: There were no significant differences between the Kawasaki disease and control groups in the frequencies of TT, TG, and GG genotypes and T/G alleles of +45T/G polymorphism in the adiponectin gene (P>0.05). In the Kawasaki disease group, there were also no significant differences in the genotype and allele frequencies of the +45T/G polymorphism between the children with CAL and those without (P>0.05). There were significant differences between the Kawasaki disease and control groups in the frequencies of GG, GT, and TT genotypes and G/T alleles of +276G/T polymorphism in the adiponectin gene (P<0.05). GG genotype was a risk factor for the development of Kawasaki disease (OR=2.313, P=0.006). In the Kawasaki disease group, there was no significant difference in the genotype distribution of the +276G/T polymorphism between the children with CAL and those without (P>0.05). CONCLUSIONS: The adiponectin +276G/T polymorphism may be associated with the development of Kawasaki disease, but not associated with CAL. The adiponectin +45T/G polymorphism may not be associated with Kawasaki disease or CAL. PMID- 30022757 TI - [Relationship between expression of peripheral blood HLA-DR, CD4+CD25+ regulatory T cells, IL-17 and IL-27 with liver damage in children with human cytomegalovrius infection]. AB - OBJECTIVE: To study the relationship between the expression of peripheral blood HLA-DR, CD4+CD25+ regulatory T cells, IL-17 and IL-27 with liver damage in children with human cytomegalovirus (HCMV) infection. METHODS: Twenty-one HCMV children with liver damage and twenty-one HCMV children without liver damage were enrolled in this study. The expression of peripheral blood HLA-DR and CD4+CD25+ regulatory T cells was detected by flow cytometry. Plasma levels of IL-17 and IL 27 were measured using ELISA. RESULTS: The plasma levels of IL-17 and IL-27 in children with liver damage were significantly higher than in those without liver damage, while the expression of peripheral blood CD4+CD25+ regulatory T cells was lower than in those without liver damage (P<0.05). Plasma IL-17 and IL-27 levels were negatively correlated with the expression of peripheral blood CD4+CD25+ regulatory T cells (P<0.01). CONCLUSIONS: Immune imbalance mediated by CD4+CD25+ regulatory T cells and over-expression of IL-17 and IL-27 may be involved in the pathogenesis of liver damage in children with HCMV infection. PMID- 30022758 TI - [Predictive value of red blood cell distribution width for acute kidney injury in children with sepsis]. AB - OBJECTIVE: To study the clinical value of red blood cell distribution width (RDW) in the early prediction of acute kidney injury (AKI) in children with sepsis. METHODS: A total of 126 children with sepsis were divided into an AKI group (n=66) and a non-AKI group (n=60) according to the presence or absence of AKI. These patients were also classified into high-RDW and low-RDW groups according to the mean RDW. The groups were compared in terms of age, male-to-female ratio, body mass index (BMI), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, serum blood urea nitrogen (BUN), creatinine (Cr), uric acid (UA), serum C-reactive protein (CRP), and routine blood test results. Independent factors associated with RDW were analyzed by multiple linear regression. RESULTS: Age, male-to-female ratio, BMI, CRP, SOFA score, and APACHE II score did not differ significantly between the AKI and non-AKI groups (P>0.05), but the AKI group had significantly higher BUN, Cr, UA, and RDW levels than the non-AKI group (P<0.05). Age, male-to-female ratio, and BMI did not differ significantly between the high-RDW and low-RDW groups (P>0.05), but the high-RDW group had significantly higher BUN, Cr, UA, CRP, SOFA score, APACHE II score, Hb, and mean corpuscular volume (MCV) than the low-RDW group (P<0.05). The multiple linear regression analysis showed that age, sex, APACHE II score, Cr, Hb, and MCV were independent factors associated with RDW. CONCLUSIONS: RDW has a certain clinical value in the early prediction of AKI in children with sepsis. PMID- 30022759 TI - [Clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis]. AB - OBJECTIVE: To study the clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis and its effect on T lymphocyte subsets. METHODS: A total of 76 children with infectious mononucleosis, who were admitted to the hospital between July 2016 and June 2017, were enrolled and randomly divided into two groups: conventional treatment and pidotimod treatment (n=38 each). The children in the conventional treatment group were given antiviral therapy with ganciclovir for injection and symptomatic treatment. Those in the pidotimod treatment group were given pidotimod oral liquid in addition to the treatment in the conventional treatment group. The course of treatment was two weeks for both groups. The two groups were compared in terms of the recovery of clinical indices and the changes in peripheral blood T lymphocyte subsets. RESULTS: Compared with the conventional treatment group, the pidotimod treatment group had significantly shorter fever clearance time, time to the disappearance of isthmopyra, time to the relief of lymph node enlargement, time to the relief of hepatosplenomegaly, and length of hospital stay (P<0.05). After treatment, the pidotimod treatment group had significant reductions in the percentages of CD3+ and CD8+ T cells and had significantly lower percentages of CD3+ and CD8+ T cells than the conventional treatment group (P<0.001). The pidotimod treatment group had significant increases in the percentage of CD4+ T cells and CD4+/CD8+ ratio after treatment, which was significantly higher than those in the conventional treatment group (P<0.001). The conventional treatment group had no significant changes in T lymphocyte subsets after treatment (P>0.05). CONCLUSIONS: Pidotimod oral liquid has a good clinical effect as the adjuvant therapy for infectious mononucleosis and can improve cellular immune function, so it holds promise for clinical application. PMID- 30022760 TI - [Clinical features and prognosis of gastrointestinal injury due to foreign bodies in the upper gastrointestinal tract in children: a retrospective analysis of 217 cases]. AB - OBJECTIVE: To study the clinical features and prognosis of gastrointestinal injury caused by foreign bodies in the upper gastrointestinal tract in children. METHODS: A retrospective analysis was performed for the clinical data of 217 children who were diagnosed with foreign bodies in the upper gastrointestinal tract complicated by gastrointestinal injury by gastroscopy from January 2011 to December 2016, including clinical features, gastroscopic findings, complications, and prognosis. RESULTS: Among the 217 children, 114 (52.5%) were aged 1-3 years. The most common foreign body was coin (99/217, 45.6%), followed by hard/sharp edged food (45/217, 20.7%) and metal (35/217, 16.1%). The most common gastrointestinal mucosal injury was ulceration (43.8%), followed by erosion (33.2%). Compared with other foreign bodies, button cells were significantly more likely to cause esophageal perforation (P<0.01). The esophagus was the most commonly injured organ (207/217, 95.4%). Of all the 217 children, 24 (11.1%) experienced infection. The children with perforation caused by foreign bodies had a significantly higher incidence rate of infection than those with ulceration caused by foreign bodies (P=0.003). Of all the 217 children, 204 (94.0%) underwent successful endoscopic removal of foreign bodies. Among these children, 98 were hospitalized due to severe mucosal injury and were given anti-infective therapy, antacids, and supportive care including enteral nutrition through a nasogastric tube and/or parenteral nutrition. Of all the children, 10 left the hospital and were lost to follow-up, and all the other children were improved and discharged. CONCLUSIONS: Most cases of foreign bodies in the upper gastrointestinal tract occur at 1-3 years of age. Coin, hard/sharp-edged food, and metal are the most common foreign bodies. Button cells are more likely to cause esophageal perforation. The incidence rate of secondary infection increases with the increasing severity of gastrointestinal mucosal injury. Children undergoing endoscopic removal of foreign bodies and enteral nutrition through a nasogastric tube tend to have a good prognosis. PMID- 30022761 TI - [Effects of different feeding patterns on the growth and development of infants with very/extremely low birth weight]. AB - OBJECTIVE: To investigate the growth and development of very low birth weight (VLBW)/extremely low birth weight (ELBW) preterm infants within the corrected age of 6 months and the effect of different feeding patterns on growth and development. METHODS: A total of 109 VLBW/ELBW preterm infants who were discharged from January 2016 to April 2017 and who had completed regular follow up were enrolled, and their growth and development within the corrected age of 6 months were monitored. The Z-score method was used to evaluate physical indices and analyze the effect of different feeding patterns (breastfeeding group: breast milk + human milk fortifier; mixed feeding group: breast milk + preterm formula milk; artificial feeding: preterm formula milk) on growth and development. RESULTS: The peaks of weight-for-age Z-score, height-for-age Z-score, weight-for height Z-score, and BMI-for-age Z-score occurred within the corrected age of 3 months, and the peak of head circumference-for-age Z-score occurred at the corrected age of 5 months. Growth deviation of the infants often occurred within the corrected age of 1-3 months. At the corrected age of 3 months, the breastfeeding group had significantly better body weight, height and head circumference growth than the mixed feeding group and/or the artificial feeding group (P<0.05). At the corrected age of 6 months, the breastfeeding group had significantly better head circumference and body length growth than the mixed feeding group and/or the artificial feeding group (P<0.05). CONCLUSIONS: Growth deviation of VLBW/ELBW preterm infants often occurs within the corrected age of 1 3 months, suggesting that early individualized follow-up and nutritional guidance should be strengthened to reduce growth deviation. Maternal breastfeeding with the addition of human milk fortifier is the best feeding pattern for VLBW/ELBW preterm infants. PMID- 30022762 TI - [Effect of lipoxin A4 on the expression of Toll-like receptor 4 and TNF receptor associated factor 6 in the liver of obese rats with sepsis]. AB - OBJECTIVE: To study the protective effect of lipoxin A4 (LXA4) against sepsis induced by lipopolysaccharide (LPS) in rats with obesity and its effect on the expression of Toll-like receptor 4 (TLR4) and TNF receptor-associated factor 6 (TRAF6) in the liver. METHODS: A total of 60 male Sprague-Dawley rats aged three weeks were randomly divided into a normal group and an obesity group, with 30 rats in each group. A rat model of obesity was established by high-fat diet. Each of the two groups was further randomly divided into control group, sepsis group, and LXA4 group, and 8 rats were selected from each group. The rats in the control, sepsis, and LXA4 groups were treated with intraperitoneal injection of normal saline, LPS, and LXA4+LPS respectively. Twelve hours later, blood samples were collected from the heart and liver tissue samples were also collected. ELISA was used to measure the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Western blot was used to measure the protein expression of TLR4 and TRAF6 in liver tissue. Quantitative real-time PCR was used to measure the mRNA expression of TLR4 and TRAF6. RESULTS: After being fed with high-fat diet for 6 weeks, the obesity group had significantly higher average weight and Lee's index than the normal group (P<0.05). Compared with the normal group, the obesity group had significant increases in the serum levels of IL-6 and TNF-alpha (P<0.05). In the normal group or the obesity group, the sepsis subgroup had significant increases in the serum levels of IL-6 and TNF-alpha compared with the control subgroup (P<0.05), while the LXA4 subgroup had significant reductions in the two indices compared with the sepsis subgroup (P<0.05). Compared with the normal group, the obesity group had significant increases in the protein and mRNA expression of TLR4 and TRAF6 (P<0.05). In the normal group or the obesity group, the sepsis subgroup had significant increases in the protein and mRNA expression of TLR4 and TRAF6 compared with the control subgroup (P<0.05). Compared with the sepsis subgroup, the LXA4 subgroup had significant reductions in the protein and mRNA expression of TLR4 and TRAF6 (P<0.05). CONCLUSIONS: LXA4 can reduce the serum levels of IL-6 and TNF-alpha and alleviate inflammatory response. LXA4 can inhibit the expression of TLR4 and TRAF6 in the liver of septic rats, possibly by inhibiting the TLR4 signaling pathway. PMID- 30022763 TI - [Warburg-Micro syndrome caused by 1q43-q44 deletion: genotypic and phenotypic analysis in a child]. PMID- 30022764 TI - [Research advances in the diagnosis and treatment of Pompe disease]. AB - Pompe disease, also called type II glycogen storage disease, is a rare autosomal recessive inherited disease caused by the storage of glycogen in lysosome due to acid alpha-glucosidase (GAA) deficiency, with the most severe conditions in the skeletal muscle, the myocardium, and the smooth muscle. Patients may have the manifestations of dyspnea and dyskinesia, with or without hypertrophic cardiomyopathy. GAA gene mutation has ethnic and regional differences, and new mutation sites are found with the advances in research. Gene analysis is the gold standard for the diagnosis of Pompe disease. Conventional methods, such as skin and muscle biopsies and dried blood spot test, have certain limitations for the diagnosis of this disease. In recent years, prenatal diagnosis and newborn screening play an important role in early diagnosis of this disease. Enzyme replacement therapy (ERT) has a satisfactory effect in the treatment of this disease, but it may lead to immune intolerance. New targeted gene therapy and modified ERT will be put into practice in the future. This article reviews the research advances in the diagnosis and treatment of Pompe disease. PMID- 30022765 TI - [Research advances in the pathogenesis of familial Kawasaki disease]. AB - Kawasaki disease has become the leading cause of acquired heart disease in children in North America and Japan. The incidence rate of Kawasaki disease varies significantly across regions and races. The first-degree relatives of patients with Kawasaki disease have a significantly higher risk of this disease than the general population. This article reviews the onset of familial Kawasaki disease and possible pathogenesis. PMID- 30022766 TI - [Preventive effect of caffeine on bronchopulmonary dysplasia in preterm infants]. AB - With the increase in the rescue success rate of critically ill preterm infants and extremely preterm infants, the incidence rate of bronchopulmonary dysplasia (BPD) is increasing year by year. BPD has a high mortality rate and high possibility of sequelae, which greatly affects the quality of life of preterm infants and brings a heavy burden to their families, and so the treatment of BPD is of vital importance. At present, no consensus has been reached on the treatment measures for BPD. However, recent studies have shown that early application of caffeine can prevent BPD. With reference to the latest studies on the effect of caffeine in the prevention of BPD, this article reviews the mechanism of action of caffeine in reducing pulmonary inflammation, improving morphological abnormalities of lung injury, reducing oxidative stress injury, and improving pulmonary function. PMID- 30022767 TI - Singular value-guided similarity filter improves detection of vessels in low-dose dynamic CT angiography: application to DIEP flap studies. AB - Dynamic CT angiography provides much more information compared to static 3D CT angiography, in several clinical applications. The prolonged exposure, on the other hand, results in higher radiation dose for to the patient. Care should be taken when designing noise reduction algorithms so that temporal profiles and spatial resolution is not significantly compromised. In particular, in deep inferior epigastric perforators (DIEP) flap studies, the temporal enhancement of small abdominal subcutaneous and intramuscular vessels needs to be evaluated from the surgeons to plan breast reconstruction. We propose a new approach to exploit the data redundancy in the temporal direction and successfully reduce noise via singular value decomposition. The similarity of voxels temporal profiles is then measured on the noise-reduced dataset and a spatial smoothing is performed with an additional edge-preserving weight coming from the noise-reduced tMIP. We named our filter the singular value decomposition guided similarity (SVGS) filter, and compared it to the TIPS (time-intensity profile similarity) filtered data and to the highly constrained filtered backprojection (HYPR) processed data. This institutional review board-approved study included 17 DIEP flap clinical cases, that were retrospectively processed with HYPR, TIPS and SVGS and then compared both qualitatively and quantitatively. Contrast-to-noise ratio (CNR) was used for quantitative evaluation, while a blinded subjective evaluation was performed by an experienced radiologist. We reported significantly improved results with the SVGS filter when compared to the other approaches, both in terms of CNR, as well as with the subjective clinical evaluation. The results over 17 clinical cases suggest that a potential dose reduction of a factor of 9 could be achieved, while preserving the same image quality. In conclusion, we developed an efficient algorithm for dynamic CT angiographic data processing, which successfully enables a reduction of spatial and temporal noise, while preserving and enhancing the visualization of small vessels. We demonstrated the clinical usefulness of the SVGS for the DIEP flap application. The proposed algorithm can be employed to significantly improve image quality and diagnostic acceptability at same dose level or alternatively to reduce radiation dose, to which extent needs to be evaluated in future studies. PMID- 30022768 TI - Re-evaluation of pediatric 18F-FDG dosimetry: Cristy-Eckerman versus UF/NCI hybrid computational phantoms. AB - Because of the concerns associated with radiation exposure at a young age, there is an increased interest in pediatric absorbed dose estimates for imaging agents. Almost all reported pediatric absorbed dose estimates, however, have been determined using adult pharmacokinetic data with radionuclide S values that take into account the anatomical differences between adults and children based upon the older Cristy-Eckerman (C-E) stylized phantoms. In this work, we use pediatric model-derived pharmacokinetics to compare absorbed dose and effective dose estimates for 18F-FDG in pediatric patients using S values generated from two different geometries of computational phantoms. Time-integrated activity coefficients of 18F-FDG in brain, lungs, heart wall, kidneys and liver, retrospectively, calculated from 35 pediatric patients at the Boston's Children Hospital were used. The absorbed dose calculation was performed in accordance with the Medical Internal Radiation Dose method using S values generated from the University of Florida/National Cancer Institute (UF/NCI) hybrid phantoms, as well as those from C-E stylized computational phantoms. The effective dose was computed using tissue-weighting factors from ICRP Publication 60 and ICRP Publication 103 for the C-E and UF/NCI, respectively. Substantial differences in the absorbed dose estimates between UF/NCI hybrid pediatric phantoms and the C-E stylized phantoms were found for the lungs, ovaries, red bone marrow and urinary bladder wall. Large discrepancies in the calculated dose values were observed in the bone marrow; ranging between -26% to +199%. The effective doses computed by the UF/NCI hybrid phantom S values were slightly different than those seen using the C-E stylized phantoms with percent differences of -0.7%, 2.9% and 2.5% for a newborn, 1 year old and 5 year old, respectively. Differences in anatomical modeling features among computational phantoms used to perform Monte Carlo-based photon and electron transport simulations for 18F, and very likely for other radionuclides, impact internal organ dosimetry computations for pediatric nuclear medicine studies. PMID- 30022769 TI - Correlates and Prognostic Values of Appearance of L Wave in Heart Failure Patients With Preserved vs. Reduced Ejection Fraction. AB - BACKGROUND: Mid-diastolic mitral forward flow (L wave) is occasionally detected in heart failure (HF), but its correlates and prognostic value are still unknown, particularly in light of the type of HF, that is, HF with preserved or with reduced ejection fraction (HFpEF, HFrEF). Methods and Results: Of 151 patients with HF, L wave was observed in 23 of 82 HFrEF patients and in 25 of 69 HFpEF patients. Mitral early diastolic velocity (E), the ratio of E to mitral annulus velocity, and left atrial volume index were greater in the patients with L wave than in those without L wave in both subsets. Left ventricular (LV) mass index and relative wall thickness were greater in the patients with L wave than in those without L wave in the HFpEF group, but there was no difference in either parameter in the HFrEF group. Prognosis was poorer in those with L wave than in those without L wave both in the HFrEF and HFpEF groups. CONCLUSIONS: Appearance of L wave is associated with the degree of LV diastolic dysfunction, but there was a difference in LV geometrical correlates of the appearance of L wave between the HFpEF and HFrEF groups. Detection of L wave is suggestive of poor prognosis independent of LVEF in HF. PMID- 30022770 TI - Interleukin-18. AB - A prospective observational study was conducted to evaluate the predictive value of interleukin-18 (IL-18) for major adverse cardiovascular events (MACEs) in hemodialysis patients. A total of 85 participants (45 hemodialysis patients and 40 healthy volunteers) with a mean age of 56.3 years were enrolled in this study. Demographic and clinical data were collected. MACE was used as the primary endpoint. Results showed that the hemodialysis patients had higher levels of IL 18 (701.6 +/- 88.52 versus 152.0 +/- 55.31 pg/mL, P < 0.01) and a high rate of MACE (15.6% versus 2.5%, P < 0.01) compared with healthy controls. Multiple linear regression analysis showed that the serum creatinine and left ventricular ejection fraction were significantly effective factors influencing IL-18 (P < 0.01). Receiver-operating characteristic curve analysis showed that IL-18 levels were better predictors for MACE. The area under the curve of IL-18 was 0.81 (0.70 0.92) (P = 0.004). IL-18 levels provided 87.5% sensitivity and 26% specificity with a threshold value of 534.5 pg/mL. Our findings indicated that hemodialysis patients with high levels of IL-18 had a high incidence rate of MACE. IL-18 is a good predictive marker of MACE in hemodialysis patients. PMID- 30022772 TI - TRPV4 Channel-Regulated ATP Release Contributes to gamma-Irradiation-Induced Production of IL-6 and IL-8 in Epidermal Keratinocytes. AB - External stimuli, such as radiation, induce inflammatory cytokine and chemokine production in skin, but the mechanisms involved are not completely understood. We previously showed that the P2Y11 nucleotide receptor, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) all participate in interleukin (IL)-6 production induced by gamma-irradiation. Here, we focused on the transient receptor potential vanilloid 4 (TRPV4) channel, which is expressed in skin keratinocytes and has been reported to play a role in inflammation. We found that irradiation of human epidermal keratinocytes HaCaT cells with 5 Gy of gamma-rays (137Cs: 0.75 Gy/min) induced IL-6 and IL-8 production. HaCaT cells treated with TRPV4 channel agonist GSK1016790A also showed increased IL-6 and IL 8 production. In both cases, IL-6/IL-8 production was not increased at 24 h after stimulation, but was increased at 48 h. ATP was released from cells exposed to gamma-irradiation or TRPV4 channel agonist, and the release was suppressed by TRPV4 channel inhibitors. The gamma-irradiation-induced increase in IL-6 and IL-8 production was suppressed by apyrase (ecto-nucleotidase), NF157 (selective P2Y11 receptor antagonist) and SB203580 (p38 MAPK inhibitor). GSK1016790A-induced inhibitor of kappa B-alpha (IkappaBalpha) decomposition, which causes NF-kappaB activation was suppressed by NF157 and SB203580, and gamma-irradiation-induced IkappaBalpha decomposition was suppressed by TRPV4 channel inhibitors. Our results suggest that gamma-irradiation of keratinocytes induces ATP release via activation of the TRPV4 channel, and then ATP activates P2Y11 receptor and p38 MAPK-NF-kappaB signaling, resulting in IL-6/IL-8 production. PMID- 30022771 TI - Prognostic Value of a Simple Echocardiographic Parameter, the Right Ventricular Systolic to Diastolic Duration Ratio, in Patients with Advanced Heart Failure with Non-Ischemic Dilated Cardiomyopathy. AB - The prognostic value of the right ventricular (RV) systolic to diastolic duration ratio (S/D ratio) in patients with advanced heart failure is not clear.We enrolled 45 patients with DCM (40 +/- 13 years, 33 male) who were admitted to our hospital for evaluation or treatment of heart failure. The RV systolic and diastolic durations were measured using continuous Doppler imaging of tricuspid regurgitation, and the RV S/D ratio was calculated. Cardiac events were defined as cardiac death or left ventricular assist device implantation within the first year. Twenty-eight cardiac events occurred. The RV S/D ratio was significantly higher in the event group than in the event-free group (1.8 +/- 0.8 versus 1.2 +/ 0.5, P = 0.008). Univariate analysis showed that the RV S/D ratio, plasma brain natriuretic peptide concentration, left atrial volume index, and mitral deceleration time were associated with these events. Receiver operating characteristic curve analysis revealed that the optimal RV S/D cutoff value to predict events was 1.2 (sensitivity 79%, specificity 65%, area under the curve 0.745). Kaplan-Meier analysis indicated a significantly higher event rate in patients with an RV S/D ratio > 1.2 (log-rank test, P = 0.003). The addition of an RV S/D ratio > 1.2 improved the prognostic utility of a model that included conventional variables (P = 0.014).In patients with advanced heart failure with DCM, the RV S/D ratio was higher in patients with events than in those without events. The addition of the RV S/D ratio to conventional parameters may provide better prognostic information. PMID- 30022773 TI - Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism. AB - To identify the spectrum and prevalence of thirteen causative genes mutations in congenital hypothyroidism (CH) patients, we collected blood samples and extracted genomic DNA of 106 CH patients, and designed a customized targeted next generation sequencing panel containing 13 CH-causing genes to detect mutations. A total of 132 mutations were identified in 65.09% of patients (69/106) on the following nine genes: DUOX2, TG, TPO, TSHR, TTF1, TTF2, NKX2-5, PAX8 and GNAS. 69.70% (92/132) mutations related to thyroid dyshormonogenesis genes, including DUOX2 (n = 49), TG (n = 35), and TPO (n = 8). 21.21% (28/132) mutations related to thyroid dysgenesis genes, including TSHR (n = 19), TTF1 (n = 5), TTF2 (n = 1), PAX8 (n = 2), and NKX2-5 (n = 1). 9.09% (12/132) mutations related to GNAS, which was associated with thyrotropin resistance. No mutation of THRA, TSHB, IYD or SLC5A5 was detected. Among 69 mutations detected patients, 41 (59.42%) patients were two or more mutations detected, and mutations of 30 (43.48%) patients related to two or three genes. According to the pathomechanism of the mutant genes, 57.97% CH patients were classified as thyroid dyshormonogenesis. Overall, DUOX2, TG and TSHR mutations were the most common genetic defects in Chinese CH patients, and thyroid dyshormonogenesis could be the first genetic etiology of CH in Chinese. Besides, multiple mutations accounts for a part of genetic pathogenesis. PMID- 30022774 TI - Association Between Aplastic Anemia and Atrial Fibrillation: Is Inflammation the Only Underlying Mechanism? PMID- 30022775 TI - Association Between Aplastic Anemia and Atrial Fibrillation: Is Inflammation the Only Underlying Mechanism? - Reply. PMID- 30022776 TI - Comparative evaluation of the efficacy of commercial and prototype PRRS subunit vaccines against an HP-PRRSV challenge. AB - The objective of this study was to compare the efficacy of a commercial porcine reproductive and respiratory syndrome (PRRS) subunit vaccine and a prototype PRRS II subunit vaccine against a highly pathogenic PRRS virus (HP-PRRSV) in pigs. Both vaccines were administered intramuscularly in 2 doses at 21 and 42 days of age, and the pigs were challenged intranasally with HP-PRRSV at 63 days of age. Pigs vaccinated with the prototype PRRS II subunit vaccine had significantly higher anti-PRRSV antibody titers, a greater number of interferon-gamma-secreting cells, and a greater reduction in lung lesion scores compared to pigs vaccinated with the commercial PRRS subunit vaccine. Therefore, the commercial PRRS subunit and prototype PRRS II subunit vaccines are efficacious against HP-PRRSV. PMID- 30022777 TI - A retrospective study of surgical affections of mammary glands in cattle and buffaloes and their management in the field. AB - The present retrospective study was conducted from 2003 to 2015 in Egypt to document common surgical affections of the udder and teat in cattle and buffaloes, and determine medical and surgical treatment options that are feasible in a field setting. We diagnosed 19 different surgical affections and classified them into 4 groups according to their location. Teat orifice affections (12.41%) included imperforate teat, contracted teat orifice, enlarged teat orifice, and black spot. Teat cistern affections (23.76%) included teat fistula, dilated teat cistern, teat polypi, and webbed teat. Teat surface affections (50.35%) included sore teat, supernumerary teat, sloughed teat, teat papilloma and fibropapilloma, teat wounds, and teat viral lesions. Udder affections (13.48%) included hypermastia, udder wounds, and suppurative and gangrenous mastitis. In cattle, the number of surgical affections located on the teat surface (20 +/- 5.4) was significantly higher compared with other locations as well as compared with buffaloes (P<0.05). No treatment was indicated in 24% of recorded cases. Medical and surgical treatment was indicated in 73.75% of affected animals. Favorable results were achieved with the recommended treatments when applied in the field. PMID- 30022778 TI - Long-term monitoring of circulating progesterone and its relationship to peripheral white blood cells in female false killer whales Pseudorca crassidens. AB - Long-term monitoring of circulating progesterone levels in three captive female false killer whales, Pseudorca crassidens, was conducted to characterize their reproductive events and to reveal the relationship between their estrous cycles or pregnancies and peripheral white blood cell (WBC) counts. Blood samples were collected at 2-3-day intervals or on a weekly-to-monthly basis for up to 10 years, from 2006 to 2017. In two mature females (initial body lengths of 4.22 and 4.07 m), some cyclic progesterone elevations were detected during the study period; the estimated mean (+/- SE) estrous cycle length was 40.5 +/- 0.7 days (n=12). The seasonality of ovulation, estimated from the elevation of progesterone levels, varied among individuals or years, and ovulation did not occur every year. The third female (3.26 m) showed progesterone elevations, despite irregular cycles after sexual maturity, and became pregnant. The progesterone levels during pregnancy ranged from 7.3 to 42.2 ng/ml, and the gestation period lasted for 14 months until parturition. The mean WBC counts during estrous cycles were the lowest before the progesterone levels began to increase and then gradually increased toward the luteal phase. The WBC counts were significantly higher during pregnancy than before and were particularly high in early pregnancy. To the best of our knowledge, this is the first report of the relationship between the estrous cycle or pregnancy and WBC counts in cetaceans. PMID- 30022780 TI - [NASAL MUCOSAL BARRIER FUNCTIONS]. PMID- 30022779 TI - Immune protection conferred by three commonly used commercial live attenuated vaccines against the prevalent local strains of avian infectious bronchitis virus in southern China. AB - Live attenuated vaccines are critical in the control of avian infectious bronchitis. It is necessary to know the protection conferred by commonly used commercial live vaccines. In this study, specific pathogen-free chicks were vaccinated with the commercial live vaccines H120, 4/91 and LDT3-A. Blood samples were collected at weekly intervals for the detection of IBV-specific antibodies and quantification of CD4+ and CD8+ T lymphocytes. At 21 days post-inoculation the vaccinated birds were challenged with the IBV prevalent local strains GX-YL5, GX-GL11079 and GX-NN09032, respectively. Trachea and kidney samples were collected at 5 days post-challenge for the detection of the virus. The results showed that the H120 group exhibited medium antibody levels, the lowest percentages of CD4+, CD8+ T lymphocytes and the highest viral loads. The 4/91 group showed the lowest antibody levels, but the highest percentages of CD4+, CD8+ T lymphocytes and the lowest viral loads. The LDT3-A group showed the highest antibody levels, the medium percentages of CD4+, CD8+ T lymphocytes and the medium viral loads. The protection rates of H120, 4/91 and LDT3-A groups were 41.7-58.3%, 75.0-83.7% and 66.7-75.0%, respectively. The present study demonstrated that the vaccines H120, 4/91 and LDT3-A could stimulate the immunized chicks to produce different levels of humoral and cellular immunity to resist the infection of IBV, but couldn't provide complete protection against the prevalent local strains of IBV in southern China. Also, the vaccine 4/91 offered the best immune protection among the three vaccines. PMID- 30022781 TI - [DIETARY GUIDANCE TO PATIENTS WITH FOOD ALLERGY IN INFANCY]. PMID- 30022782 TI - [THE EFFECT OF OCCUPATION AND ENVIRONMENT ON ASTHMA-WHAT WE HAVE CLARIFIED, WHAT WE NEED TO CLARIFY]. PMID- 30022783 TI - [SWEAT PLAYS A ROLE IN IMMUNE PROTECTION]. PMID- 30022784 TI - [USE OF MULTIPLE DOSES OF ADRENALINE FOR FOOD-INDUCED ANAPHYLAXIS]. AB - BACKGROUND: The aim of this study was to determine the rate, characteristics, and risk factors in patients who required multiple doses of adrenaline for treatment of anaphylaxis. METHODS: We retrospectively reviewed the positive oral food challenges (OFCs) with anaphylaxis in pediatric patients at Saitama City Hospital between January 2013 and November 2014, analyzing age, sex, comorbid allergic disease, specific IgE level, food, symptoms, and treatment. RESULT: There were 42 positive challenges with anaphylaxis, and the median age of the patients was 4 years old. Eighteen patients were treated with adrenaline, 5 of whom (11.9% of anaphylaxis cases) were administered multiple doses of adrenaline. Among the 5 patients, 3 were treated with infusion. We compared patients who were not administered adrenaline or were administered a single dose of adrenaline with those who were administered multiple doses of adrenaline. No significant differences were found among the groups in relation to age, sex, comorbid allergic disease, and the aim of OFCs. The number of patients who received multiple doses of adrenaline treatment was more in the milk OFCs than the other foods OFCs. Cardiovascular and neurological symptoms were more severe in patients who received multiple doses of adrenaline. CONCLUSION: Information that multiple doses of adrenaline may be required at the time of anaphylaxis should be widely disseminated. PMID- 30022785 TI - [USEFULNESS OF THE FORCED OSCILLATION TECHNIQUE IN THE DIAGNOSIS OF COUGH VARIANT ASTHMA WITH PROLONGED OR CHRONIC COUGH]. AB - BACKGROUND: Usefulness of carrying out the reversibility test after inhaling bronchodilator by forced oscillation technique (FOT) in addition to spirometry was investigated in the diagnosis of bronchial asthma (BA), cough variant asthma (CVA) and allergic rhinitis (AR) with prolonged or chronic cough. METHODS: The subjects were the 622 patients at Idaimaeminamiyojo Clinic in Sapporo who complained cough over three weeks, and underwent bronchial reversibility test with salbutamol by using spirometry and FOT. We divided them into 5 groups; BA, BA+AR, CVA, CVA+AR, AR, and examined their lung functions. RESULTS: The mean of improvement of FEV1 after inhalation of salbutamol was significantly different (p<0.001); 465ml (26%) of BA, 136ml (5.5%) of CVA, and 44ml (1.6%) of AR. However, in CVA, the mean reversibility value was not over the diagnostic criteria of BA; 200ml (12%). Improvement of respiratory resistant at 5Hz (R5) using FOT in BA/CVA were 25.7%/24.1%, and significantly higher (p<0.001) than that in AR, and these results were alike even in cases accompanied by AR; BA+AR, CVA+AR, and AR. AUC value in the ROC curve for diagnosis of CVA from AR with R5 was 0.870, and highest among with R5, R20, R35 and Fres. When the cut off value of R5 improvement was 15%, sensitivity was 74% and specificity was 81%. CONCLUSION: It was suggested that the additional bronchial reversibility test using FOT may be useful especially in the diagnosis of cough variant asthma where the reversibility in spirometry alone is not sufficient. PMID- 30022786 TI - [ESTIMATED NUMBER OF PATIENTS WITH FOOD ALLERGY IN JAPAN: THE PRESENT STATUS AND ISSUES REGARDING EPIDEMIOLOGICAL INVESTIGATION]. AB - BACKGROUND: The number of patients with food allergy in Japan is increasing year by year, although the precise prevalence of them is not clear. We aimed to determine the estimated number of people with food allergies in Japan and produce new methods of the investigation of them. METHODS: We determined the number of people with food allergies using government data and statistics such as demographic statistic and the number of students. RESULTS: In infants, the number of patients with a food allergy was 800000 as per the self-reported prevalence; however, as per the physician's diagnoses, 300000-500000 of them had a food allergy. In students, the selfreported number was 600000, while 350000 cases were diagnosed by physicians. In adults, the consumer agency investigated the patients who visited the hospital with the immediate hypersensitivity. In this study, the participants were limited to patients who visited the hospital. This made the estimation of the overall prevalence of food allergy in Japan. CONCLUSION: For children, if we add the questionnaire to the existing study, which questions them regarding the symptoms of food allergy, the diagnosis by the physician, and the blood test, we can better investigate the prevalence of food allergies and changing pattern by the year. In adults, we propose that future investigations consisting of the National Health and Nutrition Survey and a comprehensive survey of living conditions should be conducted, because few studies have reported on food allergies. PMID- 30022788 TI - ? PMID- 30022787 TI - [SENSITIVITY OF FRUIT-SPECIFIC IgE SCREENING IN MULTI-PANEL ANTIBODY TESTING]. AB - BACKGROUND: One of the strengths of multi-panel IgE testing is that it facilitates screening for IgE antibodies (Abs) in allergic patients by providing data on levels of IgE Abs to multiple allergens at the same time. Nonetheless, its diagnostic sensitivity for clinical use has not been well-studied. METHODS: We tested sera from 33 fruit-allergic patients. The sensitivity of determining IgE Abs to fruit allergens using the MAST Immunosystems (MAST) system and the View Allergy 39 (VA) system was calculated separately in patients sensitized to PR-10 or to profilin, and compared with that of single-panel IgE testing (ImmunoCAP system). RESULTS: In both the PR-10 sensitized and 31 profilin sensitized groups, the sensitivity of the IgE Abs to apple measured by VA (87%, and 83%, respectively) was almost identical to that of ImmunoCAP. On the other hand, the sensitivity of IgE Abs to peach measured by MAST (23% and 25%, respectively) was markedly lower than that of ImmunoCAP. CONCLUSIONS: The sensitivity of fruit IgE Abs in the MAST system was remarkably lower than that of the ImmunoCAP system. Caution is necessary in clinical practice when interpreting of the results of some multipanel IgE testing. PMID- 30022789 TI - ? PMID- 30022790 TI - ? PMID- 30022791 TI - ? PMID- 30022793 TI - The Flood-Related Behaviour of River Users in Australia. AB - Introduction: Flooding is a common natural disaster affecting 77.8 million people and claiming the lives of 4,731 people globally in 2016. During times of flood, drowning is a leading cause of death. Flooding is a known risk factor for river drowning in Australia. With little known about river usage in Australia, this study aimed to examine the links between person demographics and self-reported participation in two flood-related behaviours, driving through floodwaters and swimming in a flooded river. Methods: A self-reported questionnaire was administered to adult river users at four high-risk river drowning locations; Alligator Creek, Townsville, Queensland; Murrumbidgee River, Wagga Wagga, New South Wales; Murray River, Albury, New South Wales; and Hawkesbury River, Windsor, New South Wales. Univariate and chi square analysis was undertaken with a 95% confidence interval (p<0.05). All river users surveyed, were also breathalysed to record an estimate of their blood alcohol content (BAC) on their expired breath. Results: 688 river users responded to the questionnaire; 676 (98.3%) answered the driving question and 674 (98.0%) answered the swimming in floodwaters questions. Of the respondents, 35.7% stated they had driven through floodwater and 18.7% had swum in a flooded river. Males were more likely (p<0.001) to report having undertaken both activities. Australian-born respondents were more likely to report having driven through floodwaters (p=0.006). Those aged 18-24 years old and those residing in outer regional areas were more likely (p<0.001) to have swum in a flooded river. Those who self reported participating in both driving through floodwaters (p=0.001) and swimming in a flooded river (p<0.001) were significantly more likely to record contributory levels of alcohol (i.e. a BAC >=0.05%) when breathalysed at the river. Discussion: Ensuring the safe movement of people during floods is difficult, particularly for those living in regional Australia, due in part to long distances travelled and reduced investment in infrastructure such as bridges. With males and females equally exposed, more effective prevention strategies must target both sexes and may include improved education on when it is safe to drive through (low depth, still water, stable road base) and when it is not (e.g. deep water, moving water and unstable road base). This study identified one in five respondents had swum in a flooded river, most commonly young people aged 18-24 years, with participants signficantly more likely to have recorded contributory levels of alcohol when breathalysed. Further research should examine the reasons behind participation in this behaviour, including the role of alcohol. Conclusion: Preventing drowning in floodwaters is an international challenge, made more difficult by people driving through or swimming in floodwaters. Strategies for driving through floodwaters should educate both males and females on when it is safe to drive through floodwaters and when it is not. Further research is required to improve knowledge of the poorly understood behaviour of swimming in flooded rivers. PMID- 30022794 TI - B vitamins for stroke prevention. AB - Supplementation with B vitamins (vitamin B9(folic acid), vitamin B12 and vitamin B6) lowers blood total homocysteine (tHcy) concentrations by about 25% and reduces the relative risk of stroke overall by about 10% (risk ratio (RR) 0.90, 95% CI 0.82 to 0.99) compared with placebo. Homocysteine-lowering interventions have no significant effect on myocardial infarction, death from any cause or adverse outcomes. Factors that appear to modify the effect of B vitamins on stroke risk include low folic acid status, high tHcy, high cyanocobalamin dose in patients with impaired renal function and concurrent antiplatelet therapy. In regions with increasing levels or established policies of population folate supplementation, evidence from observational genetic epidemiological studies and randomised controlled clinical trials is concordant in suggesting an absence of benefit from lowering of homocysteine with folic acid for prevention of stroke. Clinical trials indicate that in countries which mandate folic acid fortification of food, folic acid supplementation has no significant effect on reducing stroke risk (RR 1.05, 95% CI 0.90 to 1.23). However, in countries without mandatory folic acid food fortification, folic acid supplementation reduces the risk of stroke by about 15% (RR 0.85, 95% CI 0.77 to 0.94). Folic acid alone or in combination with minimal cyanocobalamin (<=0.05 mg/day) is associated with an even greater reduction in risk of future stroke by 25% (RR 0.75, 95% CI 0.66 to 0.86), whereas the combination of folic acid and a higher dose of cyanocobalamin (>=0.4 mg/day) is not associated with a reduced risk of future stroke (RR 0.95, 95% CI 0.86 to 1.05). The lack of benefit of folic acid plus higher doses of cyanocobalamin (>=0.4 mg/day) was observed in trials which all included participants with chronic kidney disease. Because metabolic B12 deficiency is very common and usually not diagnosed, future randomised trials of homocysteine lowering interventions for stroke prevention should probably test a combination of folic acid and methylcobalamin or hydroxocobalamin instead of cyanocobalamin, and perhaps vitamin B6. PMID- 30022792 TI - Polymorphism rs1052536 in Base Excision Repair Gene Is a Risk Factor in a High Risk Area of Neural Tube Defects in China. AB - BACKGROUND DNA Base Excision Repair Gene-DNA LigaseIII (LIG3) is an important repair gene in the repair pathway and plays an important role in maintaining the integrity of mitochondria. Rs1052536 and rs3135967 polymorphisms of the gene are associated with lung cancer, keratoconus, and Fuchs endothelial corneal dystrophy. There is no previously published report on the relationship between the polymorphisms and neural tube defects (NTDs). MATERIAL AND METHODS Mass ARRAY iPLEX was used to determine the distribution of the polymorphisms in the case group of 108 NTD pregnant women and a control group of 233 normal healthy pregnant women to examine the relevance of their polymorphisms and NTD occurrence. RESULTS The homozygotes of rs1052536 TT were associated with an increased risk for NTDs than CC (P=0.014, OR=2.31, 95%CI [1.17-4.54]), and variants of rs1052536 T were associated with an increased risk of NTDs (P=0.024, OR=1.50, 95%CI [1.06-2.13]). The stratified analysis showed that TT genotype of rs1052536 increased the risk of anencephaly (P=0.016, OR=2.69, 95%CI [1.18-6.10]) and the T allele significantly increased the risk of cranial NTDs (P=0.033, OR=1.56, 95%CI [1.04-2.35]). CONCLUSIONS Rs1052536 in LIG3 gene might be a potential genetic risk factor in a high-risk area of NTDs in China. PMID- 30022796 TI - Stroke Prevention: Editorial to accompany June issue of SVN. PMID- 30022795 TI - How to identify which patients with asymptomatic carotid stenosis could benefit from endarterectomy or stenting. AB - Offering routine carotid endarterectomy (CEA) or carotid artery stenting (CAS) to patients with asymptomatic carotid artery stenosis (ACS) is no longer considered as the optimal management of these patients. Equally suboptimal, however, is the policy of offering only best medical treatment (BMT) to all patients with ACS and not considering any of them for prophylactic CEA. In the last few years, there have been many studies aiming to identify reliable predictors of future cerebrovascular events that would allow the identification of patients with high risk ACS and offer a prophylactic carotid intervention only to these patients to prevent them from becoming symptomatic. All patients with ACS should receive BMT. The present article will summarise the evidence suggesting ways to identify these high-risk asymptomatic individuals, namely: (1) microemboli detection on transcranial Doppler, (2) plaque echolucency on Duplex ultrasound, (3) progression in the severity of ACS, (4) silent embolic infarcts on brain CT/MRI, (5) reduced cerebrovascular reserve, (6) increased size of juxtaluminal hypoechoic area, (7) identification of intraplaque haemorrhage using MRI and (8) carotid ulceration. The evidence suggests that approximately 10%-15% of patents with asymptomatic stenosis might benefit from intervention; this will become more clear after publication of ongoing studies comparing stenting or endarterectomy with best medical therapy. In the meantime, no patient should be offered intervention unless there is evidence of high risk of ipsilateral stroke, from modalities such as those discussed here. PMID- 30022797 TI - Endarterectomy versus stenting for stroke prevention. AB - The European Society for Vascular Surgery (ESVS) has recently prepared updated guidelines for the management of patients with symptomatic and asymptomatic atherosclerotic carotid artery disease, with specific reference to the roles of best medical therapy, carotid endarterectomy (CEA) and carotid artery stenting (CAS). In symptomatic patients, there is a drive towards performing carotid interventions as soon as possible after onset of symptoms. This is because it is now recognised that the highest risk period for recurrent stroke is the first 7 14 days after onset of symptoms. The guidelines advise that there is a role for both CEA and CAS, but the levels of evidence are slightly lower for CAS than for CEA. This is because 30-day risks of death/stroke in the randomised controlled trials (RCTs) were significantly higher than after CEA (especially in the first 7 14 days after onset of symptoms) and there are concerns that the results obtained in the RCTs may not be generalisable into routine clinical practice. In asymptomatic patients, the 2018 ESVS guidelines were the first to recommend that CEA/CAS should be targeted into a smaller cohort of patients who may be 'higher risk for stroke' on medical therapy. As with symptomatic patients, the ESVS guidelines advise that there is a potential role for both CEA and CAS, but the levels of evidence are again slightly lower for CAS than for CEA. This is because 30-day risks of death/stroke in the two largest RCTs, which used credentialed (experienced CAS practitioners), were only just within the accepted 3% risk threshold and there remain concerns that the results obtained in RCTs may not be generalisable into routine clinical practice. PMID- 30022798 TI - Dual versus mono antiplatelet therapy for acute non-cardioembolic ischaemic stroke or transient ischaemic attack: a systematic review and meta-analysis. AB - Objective: Recent years have seen new evidence on the efficacy and safety of dual antiplatelet therapy for secondary stroke prevention. We updated a meta-analysis of randomised controlled trials evaluating dual antiplatelet versus monotherapy for patients with acute non-cardioembolic ischaemic stroke (IS) or transient ischaemic attack (TIA). Methods: We searched PubMed and identified randomised controlled trials evaluating dual antiplatelet versus monotherapy for acute non cardioembolic IS or TIA within 3 days of ictus up to May 2018. Risk ratio (RR) with 95% CI were calculated using random effects models. Clinical endpoints included stroke recurrence, composite vascular events and major bleeding. Results: 18 randomised controlled trials including 15 515 patients were pooled in the meta-analysis. When compared with monotherapy among patients with acute IS or TIA, dual antiplatelet therapy reduced the risk of stroke recurrence (RR 0.69; 95% CI 0.61 to 0.78; p<0.001) and composite vascular events (RR 0.72; 95% CI 0.64 to 0.80; p<0.001). Dual therapy was associated with a significant increase in the risk of major bleeding (RR 1.77; 95% CI 1.09 to 2.87; p=0.02) when all trial data were combined. However, when all previous trials before the completion of the POINT trial were analysed, dual antiplatelet versus monotherapy was not associated with a significant increase in the risk of major bleeding (RR 1.46; 95% CI 0.77 to 2.75; p=0.25). Conclusions: Among patients with acute non cardioembolic IS or TIA within 3 days of ictus, dual antiplatelet therapy was associated with a reduction in stroke recurrence, and composite vascular events, when compared with monotherapy. However, a significant increase in the risk of major bleeding was observed. PMID- 30022799 TI - Controlling resistant hypertension. AB - Resistant hypertension (failure to achieve target blood pressures with three or more antihypertensive drugs including a diuretic) is an important and preventable cause of stroke. Hypertension is highly prevalent in China (>60% of persons above age 65), and only ~6% of hypertensives in China are controlled to target levels. Most strokes occur among persons with resistant hypertension; approximately half of strokes could be prevented by blood pressure control. Reasons for uncontrolled hypertension include (1) non-compliance; (2) consumption of substances that aggravated hypertension, such as excess salt, alcohol, licorice, decongestants and oral contraceptives; (3) therapeutic inertia (failure to intensify therapy when target blood pressures are not achieved); and (4) diagnostic inertia (failure to investigate the cause of resistant hypertension). In China, an additional factor is lack of availability of appropriate antihypertensive therapy in many healthcare settings. Sodium restriction in combination with a diet similar to the Cretan Mediterranean or the DASH (Dietary Approaches to Stop Hypertension) diet can lower blood pressure in proportion to the severity of hypertension. Physiologically individualised therapy for hypertension based on phenotyping by plasma renin activity and aldosterone can markedly improve blood pressure control. Renal hypertension (high renin/high aldosterone) is best treated with angiotensin receptor antagonists; primary aldosteronism (low renin/high aldosterone) is best treated with aldosterone antagonists (spironolactone or eplerenone); and hypertension due to overactivity of the renal epithelial sodium channel (low renin/low aldosterone; Liddle phenotype) is best treated with amiloride. The latter is far more common than most physicians suppose. PMID- 30022800 TI - Diet for stroke prevention. AB - Lifestyle is far more important than most physicians suppose. Dietary changes in China that have resulted from increased prosperity are probably responsible for a marked rise in coronary risk in the past several decades, accelerating in recent years. Intake of meat and eggs has increased, while intake of fruits, vegetables and whole grains has decreased. Between 2003 and 2013, coronary mortality in China increased 213%, while stroke mortality increased by 26.6%. Besides a high content of cholesterol, meat (particularly red meat) contains carnitine, while egg yolks contain phosphatidylcholine. Both are converted by the intestinal microbiome to trimethylamine, in turn oxidised in the liver to trimethylamine n oxide (TMAO). TMAO causes atherosclerosis in animal models, and in patients referred for coronary angiography high levels after a test dose of two hard boiled eggs predicted increased cardiovascular risk. The strongest evidence for dietary prevention of stroke and myocardial infarction is with the Mediterranean diet from Crete, a nearly vegetarian diet that is high in beneficial oils, whole grains, fruits, vegetables and legumes. Persons at risk of stroke should avoid egg yolk, limit intake of red meat and consume a diet similar to the Mediterranean diet. A crucial issue for stroke prevention in China is reduction of sodium intake. Dietary changes, although difficult to implement, represent an important opportunity to prevent stroke and have the potential to reverse the trend of increased cardiovascular risk in China. PMID- 30022801 TI - Cardioembolic stroke: everything has changed. AB - Historically, because of the difficulty of using warfarin safely and effectively, many patients with cardioembolic stroke who should have been anticoagulated were instead given ineffective antiplatelet therapy (or no antithrombotic therapy). With the arrival of new oral anticoagulants that are not significantly more likely than aspirin to cause severe haemorrhage, everything has changed. Because antiplatelet agents are much less effective in preventing cardioembolic stroke, it is now more prudent to anticoagulate patients in whom cardioembolic stroke is strongly suspected. Recent advances include the recognition that intermittent atrial fibrillation is better detected with more prolonged monitoring of the cardiac rhythm, and that percutaneous closure of patent foramen ovale (PFO) may reduce the risk of stroke. However, because in most patients with stroke and PFO the PFO is incidental, this should be reserved for patients in whom paradoxical embolism is likely. A high shunt grade on transcranial Doppler saline studies, and clinical clues to paradoxical embolism, can help in appropriate selection of patients for percutaneous closure. For patients with atrial fibrillation who cannot be anticoagulated, ablation of the left atrial appendage is an emerging option. It is also increasingly recognised that high levels of homocysteine, often due to undiagnosed metabolic deficiency of vitamin B12, markedly increase the risk of stroke in atrial fibrillation, and that B vitamins (folic acid and B12) do prevent stroke by lowering homocysteine. However, with regard to B12, methylcobalamin should probably be used instead of cyanocobalamin. Many important considerations for judicious application of therapies to prevent cardioembolic stroke are discussed. PMID- 30022802 TI - Patent foramen ovale and cryptogenic stroke: diagnosis and updates in secondary stroke prevention. AB - The patent foramen ovale (PFO), given its high prevalence in the general population and especially in patients with cryptogenic stroke, has long generated investigation and debate on its propensity for stroke by paradoxical embolism and its management for stroke prevention. The pendulum has swung for percutaneous PFO closure for secondary stroke prevention in cryptogenic stroke. Based on a review of current evidence, the benefit from PFO closure relies on careful patient selection: those under the age of 60 years with few to no vascular risk factors and embolic-appearing stroke deemed cryptogenic after thorough evaluation. As these data look towards influencing guideline statements and device approvals in the future, patient selection remains the crucial ingredient for clinical decision making and future trials. PMID- 30022804 TI - Parametrical Study on CO2 Capture from Ambient Air Using Hydrated K2CO3 Supported on an Activated Carbon Honeycomb. AB - Potassium carbonate is a highly hygroscopic salt, and this aspect becomes important for CO2 capture from ambient air. Moreover, CO2 capture from ambient air requires adsorbents with a very low pressure drop. In the present work an activated carbon honeycomb monolith was coated with K2CO3, and it was treated with moist N2 to hydrate it. Its CO2 capture capacity was studied as a function of the temperature, the water content of the air, and the air flow rate, following a factorial design of experiments. It was found that the water vapor content in the air had the largest influence on the CO2 adsorption capacity. Moreover, the deliquescent character of K2CO3 led to the formation of an aqueous solution in the pores of the carrier, which regulated the temperature of the CO2 adsorption. The transition between the anhydrous and the hydrated forms of potassium carbonate was studied by means of FT-IR spectroscopy. It can be concluded that hydrated potassium carbonate is a promising and cheap alternative for CO2 capture from ambient air for the production of CO2-enriched air or for the synthesis of solar fuels, such as methanol. PMID- 30022803 TI - Sluggish Cognitive Tempo Symptoms Contribute to Heterogeneity in Adult Attention Deficit Hyperactivity Disorder. AB - Attention-deficit hyperactivity disorder (ADHD) persists into adulthood in over 50% of cases, although its associated symptom profiles, comorbid problems, and neuropsychological deficits change substantially across development. Sluggish cognitive tempo (SCT) symptoms may contribute to associations between ADHD and comorbid problems and may partially explain the substantial heterogeneity observed in its correlates. 349 adults aged 18-38 years (M = 23.2, SD = 4.5, 54.7% male, 61.03% with ADHD) completed a multi-informant diagnostic procedure and a comprehensive neuropsychological battery. Adults with ADHD (n = 213) were retained for analyses. Latent class analyses (LCA) revealed three profiles of SCT symptoms among those with ADHD, which we classified as minimal, moderate, or severe SCT. Multiple analysis of covariance (MANCOVA) revealed significant differences among these profiles, which remained when controlling for persistence of ADHD symptoms and sex. In general, adults with ADHD combined with SCT symptoms (moderate and severe) had significantly more symptoms of anxiety, depression, and persistent inattention, and had more severe professional and relational impairment compared to ADHD adults without SCT. Compared to those with moderate or minimal SCT symptoms, the severe SCT group had the most symptoms of depression and internalizing disorders, and the most impairment in the domain of daily responsibility. No significant differences based on externalizing symptoms emerged when controlling for sex and persistence of inattention symptoms, suggesting the moderate and severe SCT groups do not simply reflect more symptoms. Moreover, follow-up mediation analyses revealed that SCT might at least partially explain the heterogeneity in ADHD. Findings have implications for refinement of etiological conceptualization, assessment methods, and intervention strategies. PMID- 30022805 TI - Quantitative Study on Dissolution Behavior of Nd2O3 in Fluoride Melts. AB - The dissolution of rare earth oxides in molten fluorides is a critical step in the preparation of the corresponding rare earth metals by oxide-fluoride electrolysis. However, quantitatively understanding the nature of dissolution, especially in the case of molten salts, is usually difficult to be achieved by postmortem characterization. In this paper, the dissolution behavior of Nd2O3 particles in molten fluorides was studied via in situ observation with confocal scanning laser microscopy. Combining direct observation with thermodynamic analyses on the oxide dissolution, the rate-limiting step(s) and the effects of parameters like temperature, salt type, and composition on the dissolution rate are identified. This study provides a methodology to estimate the dissolution kinetics of rare earth oxides in molten fluorides during their primary and secondary processing. PMID- 30022806 TI - Electrodeposition of Hole-Transport Layer on Methylammonium Lead Iodide Film: A Strategy To Assemble Perovskite Solar Cells. PMID- 30022808 TI - Atypical Evolution of the F1Fo Adenosine Triphosphate Synthase Regulatory ATP6 subunit in Glacier Ice Worms (Annelida: Clitellata: Mesenchytraeus). AB - The glacier ice worm, Mesenchytraeus solifugus, is among a few animals that reside permanently in glacier ice. Their adaptation to cold temperature has been linked to relatively high intracellular adenosine triphosphate (ATP) levels, which compensate for reductions in molecular motion at low physiological temperatures. Here, we show that ATP6-the critical regulatory subunit of the F1Fo ATP synthase and primary target of mitochondrial disease-acquired an unprecedented histidine-rich, 18-amino acid carboxy-terminal extension, which counters the strong evolutionary trend of mitochondrial genome compaction. Furthermore, sequence analysis suggests that this insertion is not of metazoan origin, but rather is a product of horizontal gene transfer from a microbial dietary source, and may act as a proton shuttle to accelerate the rate of ATP synthesis. PMID- 30022807 TI - Laparoscopic Surgery for Epiphrenic Esophageal Diverticulum. AB - Background and Objectives: We wanted to assess our surgical results focusing on the patients' quality of life. We present our experience with laparoscopic surgery for epiphrenic esophageal diverticulum. Short- and long-term results of surgical therapy were analyzed. Methods: Eight patients were examined with a symptom-causing epiphrenic diverticulum. Patients underwent complex gastroenterologic examinations before and after surgery. Laparoscopic transhiatal epiphrenic diverticulectomy, Heller cardiomyotomy, and Dor anterior partial fundoplication were performed on 7 patients. One patient underwent only diverticulectomy, where no motility disorder was present. Results from surgical treatments and changes in patients' pre- and postoperative complaints were evaluated. Results: In all cases except 1, the preoperative examination showed dysmotility of the esophagus. The average duration of the surgeries was 165 (130 195) minutes; blood loss was minimal. One patient developed bleeding in the early postoperative period, and a second laparoscopy was required. No other intraoperative complication was detected, and no mortality occurred. In one case, a staple line leak developed (1/8 [12.5%]), which was resolved with conservative therapy. Functional check-ups confirmed adequate esophageal function. The total symptom score for the patients was 6.3 points before surgery, and it decreased to 1.6 (P < .001) after surgery, an average of 74% subjective improvement. During the follow-up period (mean, 60 months; 10-138 months), proton pump inhibitor therapy was started in 4 patients to treat gastroesophageal reflux. In 3 cases, drug therapy was successful; in one case, Nissen antireflux surgery was performed. Conclusion: Laparoscopic transhiatal diverticulectomy and Heller-Dor surgery are effective interventions with low morbidity. Patient quality of life significantly improves in the long term, but gastroesophageal reflux disease may occur. PMID- 30022809 TI - Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors. AB - Background: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth. Methods: For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-beta carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P selectin receptors. Results: The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 MUmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver. Conclusion: Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth. PMID- 30022810 TI - Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer's disease model. AB - Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment. Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Abeta), tau phosphorylation, oxidative stress, and neuroinflammation. To enable its oral use, novel edaravone formulation (NEF) was previously developed. The aim of the present investigation was to evaluate safety and efficacy of NEF by using in vitro/in vivo disease model. Materials and methods: In vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Abeta42 oligomer, and cellular uptake on SH-SY5Y695 amyloid beta precursor protein (APP) human neuroblastoma cell line. For in vivo safety and efficacy assessment, totally seven groups of APP/PS1 (five treatment groups, one each as a basal and sham control) and one group of C57BL/6 mice as a positive control for behavior tests were used. Three groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 umol/kg, whereas one group was supplied with each Donepezil (5.27 uM/kg) and Soluplus (amount present in NEF of 414 umol/kg dose of EDR). Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze). For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period. Moreover, biochemical, hematological, and morphological parameters were determined. Results: Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line. Furthermore, it showed nontoxicity of NEF up to 414 uM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner. Conclusion: Our results indicate that oral delivery of NEF holds a promise as a safe and effective therapeutic agent for AD. PMID- 30022811 TI - Development of a tin oxide carrier with mesoporous structure for improving the dissolution rate and oral relative bioavailability of fenofibrate. AB - Background: Biopharmaceutics classification system class II drugs have low solubility, which limits their extent and speed of absorption after oral administration. Over the years, mesoporous materials have been widely used to increase the dissolution rate and oral relative bioavailability of poorly water soluble drugs. Objectives: In order to improve the dissolution rate and increase oral relative bioavailability of the poorly water-soluble drugs, a tin oxide carrier (MSn) with a mesoporous structure was successfully synthesized. Methods: In this study, MSn was synthesized using mesoporous silica material (SBA-15) as the template. Fenofibrate (FNB) was adsorbed into the channels of MSn by an adsorption method. Characterizations of the pure FNB, MSn, physical mixture of the drug and MSn (PM; 1:1) and FNB-loaded MSn (FNB-MSn) samples were carried out by the scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption/desorption, powder X-ray diffractometer (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. Cytotoxicity assay (MTT) was used to evaluate the cytotoxicity of MSn. In vitro dissolution studies were performed to investigate the dissolution rate of FNB MSn. In vivo pharmacokinetic studies were used to investigate the changes of plasma drug concentrations of FNB-MSn tablets and commercial FNB tablets in rabbits. Results: Detailed characterization showed that FNB in the channels of MSn was present in an amorphous state. The in vitro release tests demonstrated that MSn with a good biocompatibility could effectively enhance the dissolution rate of FNB. Pharmacokinetic results indicated that MSn significantly increased the oral relative bioavailability of FNB. Conclusion: MSn can be regarded as a promising carrier for an oral drug delivery system. PMID- 30022812 TI - Effect of green tea catechins on the pharmacokinetics of digoxin in humans. AB - Background: Previous in vitro studies have reported the inhibitory effect of green tea on p-glycoprotein (p-gp) encoded by ABCB1. This study aimed to investigate the effect of green tea on the pharmacokinetics of digoxin, a typical probe drug of p-gp. Methods: Sixteen healthy volunteers participated in this study. At Day 1, 0.5 mg of digoxin was administered via oral route. After a 14 day washout period, 630 mg of green tea catechins (GTC) was administered via oral route, followed by 0.5 mg of digoxin 1 hour later. From Day 16 through Day 28, 630 mg of GTC was administered alone. At Day 29, 630 mg of GTC and 0.5 mg of digoxin were administered in the same way as Day 15. Blood samples for the pharmacokinetic assessments of digoxin were collected up to 8 hours after each dose. Pharmacokinetic parameters were estimated by noncompartmental analysis. Area under the curve (AUC) and peak plasma concentration (Cmax) were compared using mixed effect model between digoxin alone and digoxin with GTC. ABCB1 was genotyped to determine whether its polymorphism affects digoxin-GTC interaction. Results: Fifteen subjects completed the study. Compared to digoxin alone, the concomitant administration of digoxin and GTC significantly reduced the systemic exposure of digoxin: geometric mean ratios (GMR) and 90% confidence intervals (CI) of area under the concentration-time curve from time 0 to the last measurable time (AUClast) and Cmax were 0.69 (0.62-0.75) and 0.72 (0.61-0.85), respectively. The concomitant administration of digoxin and GTC following pretreatment of GTC (Day 29) similarly reduced the AUClast (GMR [90% CI]: 0.67 [0.61-0.74]) and Cmax (GMR [90% CI]: 0.74 [0.63-0.87]). In the comparison of the percentage changes from Day 1 (digoxin single administration) of AUClast between genotypes, C1236T variant type showed a significant difference to wild-type on Day 15 (concomitant administration of digoxin and GTC) (P=0.005). Conclusion: This study demonstrates that the coadministration of GTC reduces the systemic exposure of digoxin regardless of pretreatment of GTC. PMID- 30022813 TI - Heroin-dependent patient satisfaction with methadone as a medication influences satisfaction with basic interventions delivered by staff to implement methadone maintenance treatment. AB - Purpose: The aim of the present study was to test a structural equation model of patient satisfaction with different key facets of methadone maintenance treatment (MMT). In this model, the three dimensions of patient satisfaction with methadone as a medication (ie, personal functioning and well-being, anti-addictive effect on heroin, and anti-addictive effect on non-opioid substances) were expected to predict satisfaction with the basic interventions delivered by the staff of treatment centers to implement MMT. Patients and methods: A sample of 210 heroin dependent patients, resistant to MMT treatment (mean age =41.66 years, SD =6.50; 75.7% male), participated voluntarily in this study. Preliminary analysis based on exploratory structural equation modeling supported the expected three-factor measurement model of the scale to assess satisfaction with medications for addiction treatment - methadone for heroin addiction. Moreover, the 15 items measuring staff's basic interventions were shown to be compatible with the expected single-factor measurement model. Then, both measurement models were included in a structural model. Results: Results of this model show that patient satisfaction with the compatibility of methadone with personal functioning and well-being, as well as with the anti-addictive effects of methadone on non-opioid substances, predicts satisfaction with basic interventions conducted at methadone treatment centers (beta=0.191 and beta=0.152, respectively). Conclusion: Our results provide further understanding regarding patient satisfaction with MMT, which could help professionals to better understand patient perspective and experience during MMT. PMID- 30022814 TI - Identification of the drug-use behaviors of the elderly living in nursing homes. AB - Objective: As our society ages, the incidence of acute and chronic diseases increases, and so does chronic drug use and polypharmacy. This study was intended to examine the medication behaviors of the elderly who lived in the nursing homes in the Elazig and Malatya provinces, located in eastern Turkey, and in the Kayseri province located in Central Anatolia. Materials and methods: The population of this cross-sectional study included people over the age of 60 years (n=310) who lived in the nursing homes in the Elazig, Malatya, and Kayseri provinces. The entire population was included in the research without sampling, of which 255 (82.2%) people participated. Data were collected using a survey form, and the survey was conducted through face-to-face interviews. The data were reported in numbers, percentages, and averages. Results: Of the studied population, 87.8% were treated through polypharmacy, using various drugs. The most commonly used drugs were antihypertensives (52.2%). Females over 60 years used more polypharmacy than men (p<0.05). Of the elderly studied, 97.3% used drugs as recommended, 95.3% did not know about the side effects of the drugs they used, and 93.7% did not read the prospectuses of the drugs. Also, 82.7% stated that their drugs did not have any side effects and 70.2% said that the health care personnel did not educate them about their drugs. Of the elderly who were informed about their drugs, 55.3% obtained the information from the nurse and 44.7% from the physician. Of the elderly, 51.3% received education on the duration they would need to take the drug, 30.3% were educated on the intended use of the drugs, 7.9% received education on their drug dose, and 6.6% were educated on the side effects of the drugs. Conclusion: The results of this study showed that the majority of the elderly studied used more than one drug (polypharmacy) and the most used drug group was antihypertensives. PMID- 30022815 TI - Some aspects need to be considered in assessment and treatment of sarcopenia. PMID- 30022816 TI - The impact of atrial fibrillation in patients with COPD during hospitalization. AB - Background: Atrial fibrillation (AF) occurs frequently in patients with COPD. There are limited data about the impact of AF in hospitalized COPD patients on other serious health outcomes, such as acute organ dysfunction, severe sepsis, and respiratory failure. The aim of our study was to delineate the impact of AF in hospitalized COPD patients. Methods: We defined COPD populations with and without AF from the National Health Insurance database in Taiwan. The control subjects (patients with COPD without AF) were selected from the population of COPD patients who had no history of AF and were matched to the COPD patients with AF by age (+/-1 year), gender, and the year of COPD diagnosis (+/-1 year). The primary outcome was the time to any first event, which included acute organ dysfunction, severe sepsis, respiratory failure, and death during the hospitalization period. Secondary outcomes, which also included acute organ dysfunction, severe sepsis, respiratory failure, and death, were estimated separately over time. Results: The primary outcome probability was higher in COPD patients with AF than in COPD patients without AF, with an adjusted HR (aHR) of 1.169 (95% confidence interval [CI]: 1.034-1.320), and higher risks of acute organ dysfunction and respiratory failure were also observed in the former group, with aHRs of 1.179 (95% CI: 1.0370-1.339) and 1.176 (95% CI: 1.006-1.374), respectively. Conclusion: Compared with COPD patients without AF, those with AF had a higher risk of hepatic dysfunction and respiratory failure. PMID- 30022817 TI - Feasibility and challenges of using multiple breath washout in COPD. AB - Background: Lung clearance index (LCI), derived from multiple-breath washout (MBW), is a well-established assessment of ventilation inhomogeneity in cystic fibrosis but has not been widely applied in other conditions characterized by heterogeneous airways disease, such as COPD. The aim of this study was to evaluate the sensitivity, repeatability, and practicality of LCI in patients with COPD. Methods: Fifty-four COPD patients completed MBW using nitrogen as the washout tracer gas (MBWN2, measured using an ExhalyzerTM device), spirometry, and plethysmography. Twenty patients repeated MBWN2, MBWSF6 (using a separate InnocorTM gas analyzer to measure washout of the exogenous trace sulphur hexafluoride), and spirometry at a second visit >=24 hours later. Results: Mean (SD) COPD LCI measured by nitrogen washout (LCIN2) was 12.1 (2.2); mean (SD) LCI Z-score 5.8 (2.0). LCIN2 increased across Global Initiative for Obstructive Lung Disease stages 1 to 3 and was abnormal (Z-score >1.65) in all COPD patients, including those with forced expiratory volume in 1 second (FEV1) >=80% predicted. LCI was repeatable (median intra-test coefficient of variation 4.1%) and reproducible (limits of agreement -1.8 to 1.6) after mean of 16 days. Functional residual capacity (FRC) measurements were significantly greater using nitrogen than SF6 or plethysmography: mean FRC measured by nitrogen washout (FRCN2) 139% predicted versus FRC measured by plethysmography 125% predicted, p<0.0001. Conclusion: LCI is most suitable as a measure of early airways disease in COPD in those with well-preserved FEV1, with similar repeatability and limitations to that observed in cystic fibrosis. Using the Exhalyzer system to perform MBWN2, however, appeared to substantially over-read FRC. This discrepancy needs addressing before FRCN2 measurements made using this device can be reliably deployed. PMID- 30022818 TI - Development and validation of a predictive model to identify patients at risk of severe COPD exacerbations using administrative claims data. AB - Background: Patients with COPD often experience severe exacerbations involving hospitalization, which accelerate lung function decline and reduce quality of life. This study aimed to develop and validate a predictive model to identify patients at risk of developing severe COPD exacerbations using administrative claims data, to facilitate appropriate disease management programs. Methods: A predictive model was developed using a retrospective cohort of COPD patients aged 55-89 years identified between July 1, 2010 and June 30, 2013 using Humana's claims data. The baseline period was 12 months postdiagnosis, and the prediction period covered months 12-24. Patients with and without severe exacerbations in the prediction period were compared to identify characteristics associated with severe COPD exacerbations. Models were developed using stepwise logistic regression, and a final model was chosen to optimize sensitivity, specificity, positive predictive value (PPV), and negative PV (NPV). Results: Of 45,722 patients, 5,317 had severe exacerbations in the prediction period. Patients with severe exacerbations had significantly higher comorbidity burden, use of respiratory medications, and tobacco-cessation counseling compared to those without severe exacerbations in the baseline period. The predictive model included 29 variables that were significantly associated with severe exacerbations. The strongest predictors were prior severe exacerbations and higher Deyo-Charlson comorbidity score (OR 1.50 and 1.47, respectively). The best performing predictive model had an area under the curve of 0.77. A receiver operating characteristic cutoff of 0.4 was chosen to optimize PPV, and the model had sensitivity of 17%, specificity of 98%, PPV of 48%, and NPV of 90%. Conclusion: This study found that of every two patients identified by the predictive model to be at risk of severe exacerbation, one patient may have a severe exacerbation. Once at-risk patients are identified, appropriate maintenance medication, implementation of disease-management programs, and education may prevent future exacerbations. PMID- 30022820 TI - Modified magnetic nanoparticles by PEG-400-immobilized Ag nanoparticles (Fe3O4@PEG-Ag) as a core/shell nanocomposite and evaluation of its antimicrobial activity. AB - Background: Noble metal nanoparticles, due to their good physicochemical properties, have been exploited in biological applications. Among these metals, nanosilver has attracted great attention because of its optical properties and broad-spectrum antimicrobial activities with no drug tolerance. Purpose: The present study has attempted to conduct chemical synthesis of Fe3O4@PEG-Ag core/shell nanocomposites in aqueous solutions through co-precipitation of Fe3+ and Fe2+ ions, encapsulating the iron oxide core by poly (ethylene-glycol) (PEG) improve its hydrophilicity and biocompatibility, and immobilizing silver ions by application of NaBH4 as a reducing agent. Patients and methods: The synthesized structures were characterized by Fourier-transform infrared (FT-IR), field emission scanning electron microscopy, energy-dispersive X-ray spectrum, wavelength-dispersive X-ray, vibrating sample magnetometer, inductively coupled plasma-mass spectrometry and transmission electron microscopy methods. Antimicrobial activity of the nanostructures against Staphylococcus aureus, Escherichia coli and Candida albicans was evaluated by broth microdilution based on the methods suggested by Clinical Laboratory Standard Institute. Furthermore, the nanocomposite was tested for possible anti-parasitic effects against Leishmania major promastigotes by MTT assay. Also, its impacts on bacterial cell morphology were defined using atomic force microscopy. Moreover, toxicity of the nanostructure related to animal cell line was determined based on MTT assay. Results: In general, the synthesized core/shell nanostructure can demonstrate noticeable activity against the evaluated representative microorganisms while its toxicity against animal cell line is not considerable. Conclusion: This nanostructure can be applied as a smart drug delivery system with the help of an external magnetic field or it can be used as a powerful antibiotic agent along with other antibiotics that can form a shell on its structure. PMID- 30022819 TI - Nanostructured Ti surfaces and retinoic acid/dexamethasone present a spatial framework for the maturation and amelogenesis of LS-8 cells. AB - Purpose: To investigate the amelogenesis-inductive effects of surface structures at the nanoscale. For this purpose, variable nanostructured titanium dioxide (TiO2) surfaces were used as a framework to regulate the amelogenic behaviors of ameloblasts with the administration of retinoic acid (RA)/dexamethasone (DEX). Materials and methods: TiO2 nanotubular (NT) surfaces were fabricated via anodization. Mouse ameloblast-like LS-8 cells were seeded and cultured on NT surfaces in the presence or absence of RA/DEX for 48 h. The amelogenic behaviors and extracellular matrix (ECM) mineralization of LS-8 cells on nanostructured Ti surfaces were characterized using field emission scanning electron microscope, laser scanning confocal microscope, quantitative polymerase chain reaction, MTT assay, and flow cytometry. Results: TiO2 NT surfaces (tube size ~30 and ~80 nm) were constructed via anodization at 5 or 20 V and denoted as NT5 and NT20, respectively. LS-8 cells exhibited significantly increased spread and proliferation, and lower rates of apoptosis and necrosis on NT surfaces. The amelogenic gene expression and ECM mineralization differed significantly on the NT20 and the NT5 and polished Ti sample surfaces in standard medium. The amelogenic behaviors of LS-8 cells were further changed by RA/DEX pretreatment, which directly drove maturation of LS-8 cells. Conclusion: Controlling the amelogenic behaviors of ameloblast-like LS-8 cells by manipulating the nanostructure of biomaterials surfaces represents an effective tool for the establishment of a systemic framework for supporting enamel regeneration. The administration of RA/DEX is an effective approach for driving the amelogenesis and maturation of ameloblasts. PMID- 30022821 TI - Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma. AB - Background: To date, the rapid clearance from ocular surface has been a huge obstacle for using eye drops to treat glaucoma, since it has led to the short preocular residence time and low bioavailability. Methods: The novel nanoparticles (NPs) were designed for topical ophthalmic controlled drug delivery system through intercalating the BH into the interlayer gallery of Na montmorillonite (Na+Mt) and then further enchasing chitosan nanoparticles. The resulting nanoparticles had a positive charge (+29+/-0.18 mV) with an average diameter of 460+/-0.6 nm. Results: In vitro study of drug release profiles suggested controlled release pattern. The irritation experiment analysis on both human immortalized cornea epithelial cell (iHCEC) and chorioallantoic membrane trypan blue staining (CAM-TBS) showed good tolerance for ocular tissues. It was interestingly found that the nanoparticles could enter into iHCEC from the result of cellular uptake experiment measured by confocal layer scan microscopy (CLSM). Meanwhile, multilayered iHCEC was used to simulate the barrier of corneal epithelial cells for in vivo preocular retention capacity study, which suggested that BH-Mt/CS NPs could prolong the retention time in comparison with BH solution. The ocular pharmacokinetics studied by microdialysis sampling technique showed that AUC0-t and MRT0-t of BH-Mt/CS NPs were 1.99-fold and 1.75-fold higher than those of BH solution, indicating higher bioavailability. Moreover, the study of blood drug concentration, few researchers have reported, showed that low level drug could enter into blood, suggesting lower systematic side effect. Importantly, pharmacodynamics studies suggested that BH-Mt/CS NPs could make a significant decreased intraocular pressure on glaucomatous rabbits. Conclusion: Inspired by these advance of montmorillonite/chitosan nanoparticles, we envision that the BH-Mt/CS NPs will be a potential carrier for BH, opening up the possible applications in glaucoma therapy. PMID- 30022822 TI - Polysaccharide-modified nanoparticles with intelligent CD44 receptor targeting ability for gene delivery. AB - Background: Hyaluronic acid (HA) and chondroitin sulfate (CD) are endogenous polysaccharides. In recent years, they have aroused the interest of scientists because of specific binding to CD44 receptors, which are overexpressed in several types of tumors. Methods: In this study, HA- and CD-modified poly(D,L-lactide-co glycolide)-poly(ethylene glycol) (PLGA-PEG) copolymers were synthesized and applied to encapsulate 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP)/pDNA (D/P) lipoplex as CD44 receptor targeting gene delivery nanoparticles (NPs). Results: The particle size of CD-PEG-PLGA-D/P (186.8 +/- 21.7 nm) was smaller than that of HA-PEG-PLGA-D/P (270.2 +/- 13.8 nm), with narrow size distribution, and both HA-PEG-PLGA-D/P NPs and CD-PEG-PLGA NPs possessed negative zeta potentials (-39.63 +/- 5.44 mV and -38.9 +/- 2.0 mV, respectively), which prevent erythrocytes from agglutination. Both NPs exhibited pH-dependent release and had faster release in pH 4.0 than in pH 7.4. Generally, the CD-PEG-PLGA-D/P NPs possessed less cytotoxicity than HA-PEG-PLGA-D/P NPs. The D/P-loaded HA-PEG-PLGA and CD-PEG-PLGA NPs expressed significantly higher transfection in CD44 high expressed U87 (30.1% +/- 2.1% and 40.7% +/- 4.3%, respectively) than in CD44 negative HepG2 (3.3% +/- 1.5% and 1.4% +/- 1.0%, respectively) (p < 0.001). It was revealed that the endocytosis of HA-PEG-PLGA-D/P NPs was majorly dominated by macropinocytosis and the endocytosis of CD-PEG-PLGA-D/P NPs was dominated by clathrin-mediated endocytosis pathway (p < 0.001). Conclusion: The high selectivity to CD44-positive U87 cancer cells and low cytotoxicity in L929 normal cells assured the promising potential of CD-PEG-PLGA NPs as gene delivery nano carriers. PMID- 30022823 TI - Non-ionic thiolated cyclodextrins - the next generation. AB - Introduction: The current study was aimed at developing a novel mucoadhesive thiolated cyclodextrin (CD) without ionizable groups and an intact ring backbone for drug delivery. Materials and methods: Thiolated beta CD (beta-CD) was prepared through bromine substitution of its hydroxyl groups followed by replacement to thiol groups using thiourea. The thiolated beta-CD was characterized in vitro via dissolution studies, cytotoxicity studies, mucoadhesion studies on freshly excised porcine intestinal mucosa, and inclusion complex formation with miconazole nitrate. Results: Thiolated beta-CDs namely beta-CD-SH600 and beta-CD-SH1200 displayed 558.66 +/- 78 and 1,163.45 +/- 96 umol thiol groups per gram of polymer, respectively. Stability constant (Kc) of 190 M 1 confirmed the inclusion complex formation of miconazole nitrate with beta-CD SH. Inclusion complexes of beta-CD-SH600 and beta-CD-SH1200 resulted in 157- and 257-fold increased solubility of miconazole nitrate, respectively. In addition, more than 80% of thiol groups were stable even after 6 hours at pH 5. Both beta CD-SH compounds showed at least 1.3-fold improved solubility in water. In contrast to cationic thiolated CDs of the first generation, both thiomers showed no significant cytotoxicity. The mucoadhesive properties of the new thiolated CDs were 39.73- and 46.37-fold improved, respectively. Conclusion: These results indicate that beta-CD-SH might provide a new favorable tool for delivery of poorly soluble drugs providing a prolonged residence time on mucosal surfaces. PMID- 30022824 TI - Lyophilization and stability of antibody-conjugated mesoporous silica nanoparticle with cationic polymer and PEG for siRNA delivery. AB - Introduction: Long-term stability of therapeutic candidates is necessary toward their clinical applications. For most nanoparticle systems formulated in aqueous solutions, lyophilization or freeze-drying is a common method to ensure long-term stability. While lyophilization of lipid, polymeric, or inorganic nanoparticles have been studied, little has been reported on lyophilization and stability of hybrid nanoparticle systems, consisting of polymers, inorganic particles, and antibody. Lyophilization of complex nanoparticle systems can be challenging with respect to preserving physicochemical properties and the biological activities of the materials. We recently reported an effective small-interfering RNA (siRNA) nanoparticle carrier consisting of 50-nm mesoporous silica nanoparticles decorated with a copolymer of polyethylenimine and polyethyleneglycol, and antibody. Materials and methods: Toward future personalized medicine, the nanoparticle carriers were lyophilized alone and loaded with siRNA upon reconstitution by a few minutes of simple mixing in phosphate-buffered saline. Herein, we optimize the lyophilization of the nanoparticles in terms of buffers, lyoprotectants, reconstitution, and time and temperature of freezing and drying steps, and monitor the physical and chemical properties (reconstitution, hydrodynamic size, charge, and siRNA loading) and biological activities (gene silencing, cancer cell killing) of the materials after storing at various temperatures and times. Results: The material was best formulated in Tris-HCl buffer with 5% w/w trehalose. Freezing step was performed at -55 degrees C for 3 h, followed by a primary drying step at -40 degrees C (100 uBar) for 24 h and a secondary drying step at 20 degrees C (20 uBar) for 12 h. The lyophilized material can be stored stably for 2 months at 4 degrees C and at least 6 months at -20 degrees C. Conclusion: We successfully developed the lyophilization process that should be applicable to other similar nanoparticle systems consisting of inorganic nanoparticle cores modified with cationic polymers, PEG, and antibodies. PMID- 30022827 TI - Relation of high neuroticism with increased methylation of the BDNF gene. AB - Background: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has an important function in neuroplasticity and neuronal development. It is suggested that increased methylation of the BDNF gene resulting in decreased BDNF activity is associated with depression. Meanwhile, neuroticism is a well-known risk factor for developing depression. In the present study, the relationship between methylation of the BDNF gene and personality traits including neuroticism was examined. Subjects and methods: The subjects were 98 healthy Japanese. Methylation levels of the BDNF gene were determined by the bisulfite pyrosequencing method. Personality traits including neuroticism were assessed by the NEO Personality Inventory-Revised. Results: There was a positive correlation between neuroticism scores and methylation levels of the BDNF gene. The subjects with higher neuroticism scores had higher levels of BDNF gene methylation compared with those with lower neuroticism scores. Meanwhile, other personality traits were not associated with BDNF gene methylation. Conclusion: The present study suggests that high neuroticism is related to increased methylation of the BDNF gene. PMID- 30022825 TI - Nanostructured titanium regulates osseointegration via influencing macrophage polarization in the osteogenic environment. AB - Introduction: Fabricating nanostructured surface topography represents the mainstream approach to induce osteogenesis for the next-generation bone implant. In the past, the bone implant was designed to minimize host repulsive reactions in order to acquire biocompatibility. However, increasing reports indicate that the absence of an appropriate immune response cannot acquire adequate osseointegration after implantation in vivo. Materials and methods: We prepared different topographies on the surface of titanium (Ti) specimens by grinding, etching and anodizing, and they were marked as polished specimen (P), specimen with nanotubes (NTs) in small diameters (NT-30) and specimen with NTs in large diameters (NT-100). We evaluated the ability of different topographies of the specimen to induce osteogenic differentiation of mice bone marrow mesenchymal stem cells (BMSCs) in vitro and to induce osseointegration in vivo. Furthermore, we investigated the effect of different topographies on the polarization and secretion of macrophages, and the effect of macrophage polarization on topography induced osteogenic differentiation of mice BMSCs. Finally, we verified the effect of macrophage polarization on topography-induced osseointegration in vivo by using Cre*RBP-Jfl/fl mice in which classically activated macrophage was restrained. Results: The osteogenic differentiation of mice BMSCs induced by specimen with different topographies was NT-100>NT-30>P, while the osseointegration induced by specimen with different topographies in vivo was NT 30>NT-100>P. In addition, specimen of NT-30 could induce more macrophages to M2 polarization, while specimen of P and NT-100 could induce more macrophages to M1 polarization. When co-culture mice BMSCs and macrophages on specimen with different topographies, the osteogenic differentiation of mice BMSCs was NT-30>NT 100>=P. The osseointegration induced by NT-100 in Cre*RBP-Jfl/fl mice was much better than that of wild type mice. Conclusion: It is suggested that the intrinsic immunomodulatory effects of nanomaterials are not only crucial to evaluate the in vivo biocompatibility but also required to determine the final osseointegration. To clarify the immune response and osseointegration may be beneficial for the designation and optimization of the bone implant. PMID- 30022826 TI - Triphenylphosphonium and D-alpha-tocopheryl polyethylene glycol 1000 succinate modified, tanshinone IIA-loaded lipid-polymeric nanocarriers for the targeted therapy of myocardial infarction. AB - Background: Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide. Currently, the best treatment options for myocardial infarction focus on the restoration of blood flow as soon as possible, which include reperfusion therapy, percutaneous coronary intervention, and therapeutic thrombolytic drugs. Materials and methods: In the present study, we report the development of lipid polymeric nanocarriers (LPNs) for mitochondria-targeted delivery of tanshinone IIA (TN). D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was linked to the triphenylphosphonium (TPP) cation. The LPNs were fabricated by nanoprecipitation method. LPNs were evaluated in vitro and in vivo in comparison with free drugs and other similar nanocarriers. Results: The mean diameter of TN/nanoparticles (NPs) was 89.6 nm, while that of TN/LPNs was 121.3 nm. The zeta potential of TN/NPs and TN/LPNs was -33.6 and -22.3 mV, respectively. Compared with free TN and TN/NPs, TN/LPNs exhibited significantly improved compatibility and therapeutic efficiency. In addition, the in vivo pharmacokinetics, biodistribution, and infarct therapy studies in Sprague Dawley rats showed that TPP-TPGS/TN/LPNs had better efficiency than their nonmodified TN/LPNs counterparts in all respects. Conclusion: These results indicated that the TPP TPGS/TN/LPNs were promising nanocarriers for efficient delivery of cardiovascular drugs and other therapeutic agents for the treatment of CVDs. PMID- 30022828 TI - Gender differences in the protective effects of green tea against amnestic mild cognitive impairment in the elderly Han population. AB - Background: Gender differences may contribute to variances in the potential protective effects of tea against cognitive impairment in the elderly. Objective: To examine the association between different types of tea consumption and the risk of amnestic mild cognitive impairment (aMCI) along gender lines. Methods: A cross-sectional study was conducted with reference to 20 communities in China. The sample population included elderly participants aged 60 years or older. A standardized questionnaire was used to collect each participant's general demographic information. Trained psychologists administrated the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess participants' cognitive function. An attending psychiatrist evaluated each participant's cognitive function. Finally, data from 2,131 participants were analyzed to assess the association. Results: With regard to male participants, the percentage of green tea consumption was higher in the normal control group than in the aMCI group (X2=4.64, P=0.031). Logistic regression analysis showed that green tea consumption reduced the risk of aMCI in male participants (OR=0.657, P=0.019), and this finding was highly significant in males aged under 70 years (OR=0.376, P=0.002). Regarding female participants across every age group, the results indicated that tea consumption failed to significantly decrease the risk of aMCI (P>0.05). Unlike green tea, black tea and oolong tea were not correlated with a reduced risk of aMCI in terms of gender or age group. Multiple linear regression analysis also revealed that age, years of education, and green tea consumption (B=0.996, P=0.000) were associated with MoCA and MMSE scores, though only in male participants. Conclusion: Green tea consumption showed a protective effect against aMCI in males but not in females, particularly in males aged <70 years. However, black tea and oolong tea failed to show any protective effect in either males or females. PMID- 30022829 TI - Association between insomnia and coping style in Japanese patients with type 2 diabetes mellitus. AB - Purpose: Insomnia, which is associated with type 2 diabetes mellitus (DM), results in a low quality of life, and several relationships exist between insomnia and coping style. Thus, we clarified the association between some coping styles and insomnia among Japanese type 2 DM patients. Subjects and methods: The subjects included 503 type 2 DM patients (mean age 63.9+/-12.5 years). Sleep disturbance and personality traits were evaluated using the Japanese version of the Pittsburgh Sleep Quality Index and the Brief Scale for Coping Profile, respectively. Lifestyle factors, glycated hemoglobin A1c (HbA1c) levels, and the depression statuses of the patients were also included in the analyses. Results: Among the 503 subjects with type 2 DM, 141 (28.0%) subjects exhibited probable insomnia. After adjusting for confounders, being female, living alone, and using "avoidance and suppression" were significantly correlated with current insomnia. No other relationships were found between insomnia and HbA1c or lifestyle factors, such as smoking, drinking alcohol, and exercise frequency. Conclusion: The prevalence of insomnia in individuals with type 2 DM was high, and the protective factors included some emotion-focused coping styles. Future prospective studies are required to confirm the therapeutic effects of behavioral interventions on insomnia in patients with type 2 DM. PMID- 30022830 TI - Risperidone for children and adolescents with autism spectrum disorder: a systematic review. AB - Background: Various clinical trials suggested that risperidone was beneficial in the treatment of autism spectrum disorder (ASD) in children and adolescents. Objective: The aim of this systematic review was to determine the efficacy, acceptability and tolerability of risperidone in the treatment of children and adolescents with ASD. Data sources: The databases of Scopus, PubMed, CINAHL and Cochrane Controlled Trials Register were searched in February 2017. Study eligibility criteria participants and interventions: Eligible RCTs of risperidone in the treatment of child and adolescent patients with ASD. Languages were not restricted. Study appraisal and synthesis methods: The full-text versions of relevant studies were thoroughly assessed and extracted. The primary efficacy of outcome was the pooled response rate and the pooled mean changed scores of the standardized rating scales for ASD. Results: A total of 372 randomized subjects from seven RCTs were included in this review. In acute treatment, the pooled mean change score of the Aberrant Behavior Checklist for irritability subscale (ABC-I) and response rate for the risperidone-treated group had a greater significance than that of the placebo-treated group. In the long-term treatment, the pooled mean change score of the CARS in the risperidone-treated group was significantly greater than that in the placebo-treated group. According to the discontinuation phase, the overall pooled relapse rate of the risperidone-treated group was significantly less than that of the placebo-treated group. The rates of pooled overall discontinuation and discontinuation due to adverse events rates were not different between the two groups in acute and long-term treatments. Limitations: A small study was included in the current review. Conclusion: In relation to the current systematic review, risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD. Although its acceptability is comparable to placebo, treatment with risperidone is well tolerated in children and adolescents with ASD. PMID- 30022831 TI - Efficacy of zofenopril in combination with thiazide diuretics in patients with acute myocardial infarction: a pooled individual data analysis of four randomized, double-blind, controlled, prospective studies. AB - Background: In the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) studies, early administration of zofenopril after acute myocardial infarction (AMI) was prognostically beneficial as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs), such as lisinopril and ramipril. Here, we investigated whether zofenopril efficacy could be affected by a concomitant use of thiazide diuretics (TDs). Methods: This was a post hoc analysis of pooled individual patient data from the SMILE studies. Patients treated with other diuretics than TDs were excluded. The primary study endpoint was the 1-year combined occurrence of death or hospitalization for CV causes, with or without TD. Results: Among 2,995 patients, 263 (8.8%) were treated with a combination including a TD (TD+), whereas 2,732 (91.2%) were not treated with any diuretic (TD-). Proportions of subjects who were treated with TD were equally distributed (p=0.774) within the placebo, zofenopril, and other ACEIs groups. The 1-year risk of major cardiovascular events was similar in TD+ (18.3%) and TD- (16.8%) patients (hazard ratio [HR] 1.04; 95% CI 0.74-1.45; p=0.838). After stratifying per concomitant treatment and TD, the 1-year risk of CV events was significantly lower with zofenopril than with placebo (HR 0.70; 95% CI 0.55-0.88; p=0.002) and other ACEIs (HR 0.58; 95% CI 0.46-0.74; p=0.0001). Treatment with ACEIs and TD as concomitant therapy was associated with a larger blood pressure (BP) reduction (p=0.0001 for systolic BP and p=0.045 for diastolic BP). Conclusion: In post AMI patients, zofenopril maintained its positive impact on prognosis compared to placebo or other ACEIs, regardless concomitant TD administration. In this setting, TD shows advantages in managing the most difficult hypertensive patients. PMID- 30022832 TI - A meta-analysis and systematic review evaluating the use of erythropoietin in total hip and knee arthroplasty. AB - Purpose: The debate is still ongoing on the effectiveness and safety of erythropoietin (EPO) treatment in orthopedic surgeries. Specifically, previous studies have not compared the dynamic change of hemoglobin (Hb) levels between different transfusion methods. Besides, complications or side effects of this alternative have not been quantitatively analyzed. We conducted a meta-analysis and systemic review to evaluate the efficacy of EPO on Hb levels observed during the whole perioperative period as well as the volume of allogeneic blood transfusion (ABT), the risk of venous thromboembolism, and application frequency of ABT in hip and knee surgery. Materials and methods: PubMed, Embase, Web of Science, and the Cochrane library were systematically searched from inception to November 2017. The data from randomized controlled trials were extracted and the risk of bias assessed using Cochrane's Collaboration's tool. Results: Twenty-five randomized controlled trials involving 4,159 patients were included in this meta analysis. EPO could reduce exposure to allogeneic blood transfused (odds ratio [OR] =0.42, P=0.001) and reduce the average volume of allogeneic blood transfused (OR = -0.28, P=0.002). When EPO and preoperative autologous blood donation (PABD) were compared, the use of EPO was associated with lower exposure to ABT (OR =0.48, P=0.03), but no significant decrease in the average volume of allogeneic blood transfused (OR = -0.23, P=0.32). The use of EPO was associated with a higher level of Hb with or without use of PABD at all the 4 time points (preoperation, 24-48 hours postoperation, 3-5 days postoperation, discharge of last observation) (P<0.0001), which means EPO could increase the level of Hb significantly during the perioperative period. The results also indicated EPO does not increase the risk of a venous thromboembolism event. Conclusion: Preoperative administration of EPO was shown to generally increase Hb levels during the whole perioperative period; however, the extent of the positive effects varies with time points. Additionally, EPO minimizes the need for transfusion significantly in patients undergoing hip or knee surgery without increasing the chance of developing thrombotic complications. Therefore, EPO offers an alternative blood management strategy in total hip arthroplasty and total knee arthroplasty. PMID- 30022833 TI - Delayed surgical and non-surgical treatment of placental remnants: no difference was found in the clinical efficacy and long-term pregnancy outcomes. AB - Purpose: In a tertiary hospital, patients facing delayed treatment with placental remnants were common. The aim of this study was to assess the clinical efficacy and long-term pregnancy outcomes of the delayed surgical/non-surgical treatment for placental remnants. Patients and methods: The records of referral patients with placental remnants after second/third-trimester delivery/termination of pregnancy were retrospectively analyzed. A long-term follow-up was made by phone to inquire about the future pregnancy outcomes. The measurements of clinical efficacy included the postpartum intervals for Doppler ultrasound to become normal and for menstrual cycle to return to normal. Conception rate, interval for future pregnancy and obstetric outcomes were used to assess future pregnancies. Results: A total of 65 patients, who were clinically diagnosed with placental remnants after termination of pregnancy at the second or third trimester from 2000 to 2016, were included in this study. Delayed surgical treatments employed at a median interval (MI) of 2.7 months after termination of pregnancy had a similar interval for ultrasound (P=0.353) and menstrual cycle (P=0.751) to return to normal compared with non-surgical treatments. For non-lactating patients who accepted expectant treatments, the postpartum interval for ultrasound to return to normal was significantly longer than that for menstrual cycle to become normal (MI=3.6, 1.5 months, respectively, P=0.000). For all of the patients successfully treated, the conception rate (P=1.00), the interval for a second pregnancy (P=0.771), ongoing-pregnancy/live birth rate (P=0.419) and the recurrence rate of placenta accrete (P=1.00) there was no significant difference between non surgical and surgical treatments. Assisted selective uterine artery embolization at an MI of 23 days after the termination of pregnancy had a longer interval for ultrasound to become normal than single expectant treatment (P=0.017). For all patients after expectant treatments, 94.1% of patients conceived after an MI of 12.5 months with the ongoing-pregnancy/live birth rate of 66.7% and a 33.3% recurrence rate of placenta accreta. Conclusion: According to our experience, delayed surgeries at a postpartum interval of 2.7 months might have similar clinical efficacy and long-term pregnancy outcomes with expectant treatment in treating placental remnants. PMID- 30022834 TI - Effect of denosumab on bone mineral density in Japanese women with osteopenia treated with aromatase inhibitors for breast cancer: subgroup analyses of a Phase II study. AB - Background: The aim of the study was to conduct subgroup analyses of therapeutic effects of 12-month denosumab therapy on the percentage change in bone mineral density (BMD) from baseline in the lumber spine and femoral neck. Materials and methods: We prospectively evaluated the BMD of the lumbar spine and femoral neck of 100 hormone receptor-positive, clinical stage I-IIIA postoperative postmenopausal breast cancer patients, for whom treatment with aromatase inhibitors (AIs) as adjuvant endocrine therapy was scheduled. The primary endpoint was the percent change in lumbar spine BMD from baseline to 12 months. Patient subgroups were analyzed according to baseline variables that are known risk factors for bone loss, including previous AI therapy, age, time since menopause, baseline body mass index (BMI), and baseline BMD T-score. Results: At 12 months, lumbar spine BMD increased by 4.7%; the patients who were administered AI therapy prior to denosumab (n=70) demonstrated a 4.7% increase in BMD, and the patients who received denosumab at the start of AI therapy (n=30) demonstrated a 4.5% increase in BMD (p=0.8385). Additionally, 2.4% and 1.4% increases in BMD of the right and left femoral neck, respectively, were observed. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, >=65 years), time since menopause (<=5, >5 years), BMI (<25, >=25 kg/m2), and T-score (<=-1.0, >-1.0) of the right femoral neck were as follows: (2.2%, 2.5%, p=0.7773), (2.6%, 0.9%, p=0.1726), (2.5%, 2.3%, p=0.7594), (2.1%, 2.4%, p=0.2034), (2.1%, 2.9%, p=0.2034), and (2.3%, 2.7%, p=0.6823), respectively. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, >=65 years), time since menopause (<=5, >5 years), BMI (<25, >=25 kg/m2), and T-score (<=-1.0, >-1.0) of the left femoral neck were as follows: (1.0%, 1.5%, p=0.1972), (1.2%, 2.7%, p=0.2931), (1.4%, 1.3%, p=0.8817), (-0.1%, 1.6%, p=0.1766), (1.3%, 1.9%, p=0.6465), and (1.5%, 1.1%, p=0.6573), respectively. Conclusion: Twice-yearly treatment with denosumab was associated with increased BMD among Japanese women receiving adjuvant AI therapy, regardless of the baseline characteristics or skeletal site. PMID- 30022836 TI - Overexpression of DJ-1 correlates with aggressive clinicopathological characteristics and poor prognosis in malignant tumors: a meta-analysis. AB - Purpose: A number of studies have investigated the role of DJ-1 in the development and progression of malignant tumors. This meta-analysis aims to systematically estimate the rela-tionship between the expression level of DJ-1 and the malignant biological behaviors of tumors and to assess the clinical significances of DJ-1 in the prognosis and diagnosis of cancer. Materials and methods: We searched PubMed, Web of Science, China National Knowledge Infrastructure and Wanfang databases from inception to December 1, 2017. Pooled odds ratio (OR) and hazard ratio (HR) with their 95% confidence interval and the diagnostic value of DJ-1 were calculated. Results: Fourteen eligible studies with a total of 1,947 subjects were enrolled in our meta-analysis. The results showed that DJ-1 was overexpressed in cancer patients compared with noncancer patients (OR = 30.72), and elevated expression of DJ-1 was demonstrated to be closely associated with high tumor-node-metastasis stage (OR = 5.52), poor differentiated degree (OR = 2.46), positive lymph node metastasis (OR = 4.12) and worse overall survival (HR = 2.23). In addition, the combined sensitivity and specificity for DJ-1 to discern malignant tumors were 0.73 and 0.93, respectively. The diagnostic OR was 34.87, and the area under the summary receiver operating characteristic curve was 0.88. Conclusion: This meta-analysis demonstrated that DJ-1 was an important biomarker in tumor assessment and prognosis prediction. PMID- 30022835 TI - Serum markers for asymptomatic atherosclerosis in Egyptian psoriatic patients: study controlled by Doppler estimation of carotid intima-media thickness. AB - Background: The aim of the study was to measure serum levels of endocan, myeloperoxidase (MPO), pentraxin 3 (PTX3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in psoriatic patients and to study their correlations with carotid intima-media thickness (CIMT) in trial to evaluate predictability of these parameters in diagnosing asymptomatic atherosclerosis (AAS). Patients and methods: Seventy-five psoriasis patients and 75 control subjects underwent complete clinical examination and Doppler estimation of CIMT using thickness of 0.9 mm as cutoff point for diagnosis of AAS. Blood samples were collected for determination of fasting blood glucose, lipid profile and serum C-reactive protein (CRP), endocan, MPO, PTX3 and 1,25(OH)2D3. Results: Estimated blood low density lipoprotein cholesterol (LDL-c) and serum CRP, PTX3, MPO and endocan levels were significantly higher, while blood high-density lipoprotein cholesterol (HDL-c) and serum 1,25(OH)2D3 levels were significantly lower in patients than in controls. CIMT showed significant positive correlation with disease severity and duration; patients' age; and endocan, MPO, LDL-c, PTX3 and CRP levels, and significant negative correlation with HDL-c and 1,25(OH)2D3 levels. Regression analysis defined high serum endocan and MPO, low serum 1,25(OH)2D3 and increased disease severity as significant predictors of high CIMT. Conclusion: Elevated serum levels of endocan and MPO and low 1,25(OH)2D3 levels may underlie the development of psoriasis-related cardiac manifestations. Elevated serum endocan and low 1,25(OH)2D3 levels could be used as early predictors of increased CIMT, which is a pathognomonic feature of AAS. PMID- 30022837 TI - Role of chemotherapy with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) rechallenge in small cell transformation after EGFR-TKI failure: a case report. AB - Background: Small cell lung cancer (SCLC) transformation is one of the resistance mechanisms associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Rechallenge with the first-line TKI after the second line chemotherapy is suggested as a salvage treatment despite modest efficacy. Case presentation: Here, we report the case of a 72-year-old, never-smoker female diagnosed with multiple metastatic lung adenocarcinoma (cT2aN2M1) harboring EGFR mutations in exon 21 (L858R) of the primary lesion. Despite subsequent treatment with gefitinib for more than a year, the patient developed resistance to the drug. Histological analysis based on rebiopsy at subphrenic mass revealed small cell transformation. After a partial response to irinotecan and carboplatin, the metastatic subphrenic and liver masses presented dramatic progression despite another round of cytotoxic chemotherapy. Rechallenge with erlotinib based on the original EGFR mutation (L858R) without small cell transformation confirmed by re biopsy of hepatic mass lesions elicited only mixed response. Therefore, cytotoxic chemotherapy comprising irinotecan and carboplatin combined with erlotinib was effective against all the metastatic lesions. Conclusion: To the best of our knowledge, this is the first case of concurrent retreatments with TKIs and chemotherapy previously effective in SCLC transformation. PMID- 30022839 TI - SIRT4 acts as a tumor suppressor in gastric cancer by inhibiting cell proliferation, migration, and invasion. AB - Background: Previous study has proven that SIRT4 is downregulated in gastric cancer (GC), but the role of SIRT4 has not been clearly understood. The aim of our work was to explore in detail the function and mechanism of SIRT4 in GC. Methods: A total of 86 pairs of GC tumor tissues and adjacent normal tissues were collected, and quantitative real-time polymerase chain reaction and Western blotting analyses were used to determine the expression of SIRT4. Results: Our study revealed that the expression of SIRT4 was downregulated in GC tissues and cells. In addition, the low expression of SIRT4 was negatively correlated with tumor size, pathological grade, and lymph node metastasis, which predicted a poor prognosis. Multiple functional experiments, including Cell Counting Kit-8 assay as well as colony formation assay, demonstrated SIRT4 suppressed cell proliferation. Moreover, we found epithelial-mesenchymal transition was regulated by SIRT4, thereby regulating cell migration and invasion. Conclusion: Overall, our findings show that SIRT4 serves as a tumor suppressor in GC and might act as a novel biomarker and a therapeutic target of GC. PMID- 30022838 TI - Immunohistochemical expression of hormone receptors, Ki-67, endoglin (CD105), claudins 3 and 4, MMP-2 and -9 in endometrial polyps and endometrial cancer type I. AB - Objective: The aim of this study was to investigate the malignant potential of endometrial polyps (EP) by assessing the immunoexpressions of both estrogen receptor (ER) and progesterone receptor (PR), Ki-67 cell proliferation index, neovascularization network (endoglin - CD105), cellular adhesion molecules (claudins 3 and 4), and extracellular matrix proteins (MMP-2 and -9) in both EP and endometrioid adenocarcinoma (type I) in comparison with the normal endometrium. Study design: This is a cross-sectional comparative study. Patients were identified from the database of Botucatu Medical School, Sao Paulo State University (BMS-UNESP) Clinical Pathology Laboratory. Setting: The study was conducted using a convenience sample of patients attending the Sectors of Gynecologic Endoscopy and Family Planning and Gynecologic Oncology of the Department of Gynecology and Obstetrics of BMS-UNESP, Brazil. Patients: A total of 90 women were allocated into the following three groups: EP without atypia (EP, n=30), endometrioid endometrial cancer (EC, n=30), and normal endometrium (control, n=30). Methods: Epidemiological and clinical data were obtained by reviewing medical records. Adenocarcinoma and control cases were assessed using the tissue microarray technique. The immunoexpressions of ER, PR, Ki-67, CD105, claudins 3 and 4, and MMP-2 and -9 were assessed in paraffin blocks containing sections of the largest polyploid lesion fragment and tissue microarray recipient blocks. Major results: Compared to the control group, significant differences in the expression of ER (P<0.001), PR (P<0.05), Ki-67 (P<0.001), CD105 (P<0.001), and claudin 3 (P<0.001) were observed in EP and EC. No significant differences were found between EP and EC (P>=0.05). MMP-2 and -9 expression were nearly absent in all groups. Conclusion: The malignant potential of EP could not be determined through the immunohistochemical parameters used in this study. No MMP 2 or -9 expression was observed in any endometrial tissue sample. Further studies are necessary for a better understanding of the biomolecular mechanisms underlying endometrial carcinogenesis. PMID- 30022840 TI - Increased expression of antisense lncRNA SPINT1-AS1 predicts a poor prognosis in colorectal cancer and is negatively correlated with its sense transcript. AB - Purpose: Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Natural antisense transcripts (NATs) are pervasively expressed in human genome and have been confirmed to contribute to cancer progression. In our study, we aimed to investigate the expression and clinical pertinence of serine peptidase inhibitor, Kunitz type 1 antisense RNA1 (SPINT1 AS1) in CRC. Materials and methods: The expression levels of SPINT1-AS1 and the corresponding sense transcript SPINT1 mRNA were analyzed in 150 pairs of CRC tissues and adjacent normal (AN) tissues, along with 45 pairs of preoperative and postoperative serum exosome samples by the strand-specific real-time quantitative polymerase chain reaction. Results: Compared with AN tissues, the expression of SPINT1-AS1 was increased (P<0.001, 3.771 vs 0.980) in CRC tissues, while SPINT1 mRNA expression was decreased in CRC (P<0.001, 0.927 vs 1.165), and there was an obviously negative correlation between SPINT1-AS1 expression and its sense transcript (r=-0.701, P<0.001). SPINT1-AS1 yielded an area under the receiver operating characteristic curve value of 0.865 (95% confidence interval, 0.821 0.902) for discriminating CRC tissues from AN tissues. Moreover, high SPINT1-AS1 expression was correlated with regional lymph node metastasis (P<0.001), distant metastasis (P<0.001), and shorter relapse-free survival (RFS) time (P<0.001), and Cox regression analysis indicated that SPINT1-AS1 was an independent prognostic factor for RFS. Meanwhile, significant reduction of SPINT1-AS1 expression level (P=0.001) was observed in CRC serum exosomes after surgical resection. Conclusion: SPINT1-AS1 is upregulated in CRC tissues and plays an essential role in CRC progression and prognosis. Thereby, SPINT1-AS1 may serve as a candidate prognostic biomarker and molecular therapy target for CRC. PMID- 30022841 TI - Overexpressed CDR1as functions as an oncogene to promote the tumor progression via miR-7 in non-small-cell lung cancer. AB - Background: Circular RNA (circRNA) is a novel member of the noncoding RNA and function as efficient microRNA sponges with gene-regulatory potential, especially the circular RNA ciRS-7 (CDR1as)/tumor suppressor miRNA-7 (miR-7) signals. However, the function of CDR1as/miR-7 in non-small cell lung cancer (NSCLC) is unknown. Methods: Normal lung tissues (n=20), adjacent non-tumor tissues (n=60), and NSCLC tissues (n=60) were collected to determine the expression and significance of CDR1as/miR-7. Lung cancer cell lines A549 and H460 were overexpressed or knocked down of CDR1as, miR-7 to determine the tumor growth etc. The CDR1as/miR-7-related pathway were analyzed. Results: CDR1as levels was robustly increased with the development of NSCLC (P<0.001) and the NSCLC tissues harbored highest expression of CDR1as, which negatively correlated to the expression of miR-7. Patients with high expression of CDR1as had high TNM stage (P=0.004), more lymph nodes metastasis (LNM) (P=0.021) and shorted overall survival time (OS) (P=0.0135). The CDR1as level was an independent prognostic factor for the patients with NSCLC. Overexpression of CDR1as induced increased cell vitalities and growth, which could be abrogated by knockdown of CDR1as or overexpressed miR-7 to induce apoptosis and G1/S arrest. Mechanistically, CDR1as functioned as miR-7 sponges to up-regulate the key target genes of miR-7 including EGFR, CCNE1 and PIK3CD. The results in vivo further confirmed that CDR1as functioned as oncogene to inhibit the anti-tumor effects of tumor suppressor miR-7 by up-regulation of proliferation index Ki-67, EGFR, CCNE1 and PIK3CD levels. Conclusion: Overexpressed CDR1as in NSCLC functions promotes the tumor progression via miR-7 signals. PMID- 30022842 TI - The effect of tubeimoside-1 on the proliferation, metastasis and apoptosis of oral squamous cell carcinoma in vitro. AB - Background: Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from traditional Chinese medicine tubeimoside, exerts a cytotoxic effect on several human cancer cell lines. However, no study has focused on whether TBMS1 works on oral squamous cell carcinoma (OSCC). Materials and methods: We treated OSCC cells with TBMS1 to detect the effect and relevant molecular basis of TBMS1 for the first time. We chose two oral cancer cell lines, CAL27 and SCC15, for this study. First, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide assay and cell proliferation 5'-bromo-2'-deoxyuridine assay were carried out to detect cell growth. Second, colony formation assay was performed to assess clonogenesis capacity. Next apoptosis was analyzed by flow cytometry. Subsequently, wound healing and transwell assays were applied to explore cell migration. Finally, Western blot was further performed to examine corresponding proteins' expression change. Results: Our data showed that TBMS1 significantly suppressed proliferation of OSCC cells in a dose- and time-dependent manner and it inhibited migration of OSCC cells as well. After treatment with TBMS1, OSCC cells underwent cell apoptosis. Furthermore, Western blot demonstrated that TBMS1 downregulated apoptosis-associated proteins such as PARP, p-ERK1/2, Bcl-2, caspase-3, caspase-7 and caspase-8 and upregulated cleaved PARP, cleaved caspase-3 and cleaved caspase 9. It could also reduce expression of c-Myc and MMP-7. Meanwhile, TBMS1 did not change the total ERK1/2 expression. Conclusion: These results revealed that TBMS1 might be a potential chemotherapeutic drug for the management of OSCC. PMID- 30022844 TI - Idiopathic scrotal calcinosis: report of 2 cases, and review of pathogenesis and factors that determine patients' acceptance of surgical treatment. AB - Introduction: Idiopathic scrotal calcinosis is a benign and rare disease of the scrotal skin that presents as solitary or multiple asymptomatic calcified nodules in the absence of systemic disorders of calcium/phosphorus balance. Case reports: We report the management of 2 cases and review the literature with comments on factors that determine acceptance or otherwise of surgical treatment. Our patients were 29 and 33 years old and presented with nodular scrotal lesions. Through multiple elliptical incisions, all nodules were excised from patient 1, but patient 2 refused surgery. Reasons for rejection included fear of future reproductive performances. Histology shows calcium deposition in basophilic globules of varying sizes and shapes within the reticular dermis, multinucleated giant cells, dense collagenous stroma, areas of fibrosis, and sparse lymphocytic infiltrate. Conclusion: In the management of idiopathic scrotal calcinosis, factors that determine acceptance of surgical treatment could include impaired quality of life, reduced self-esteem, fear of future sexual dysfunction, and development of complications. PMID- 30022845 TI - A novel animal model for residence time evaluation of injectable hyaluronic acid based fillers using high-frequency ultrasound-based approach. AB - Background: Hyaluronic acid (HA)-based devices are among the most popular filler agents for skin rejuvenation. One of the principal goals is the improvement in residence time of HA-based products, to increase their performance and reduce frequency of the treatment. So, understanding fillers, behavior after subcutaneous injection is a fundamental aspect for discovery and optimization of new products. Current in vivo approaches to detect/quantify injected HA fillers are not always well optimized or easy to apply. Objective: To develop more efficacious and noninvasive diagnostic tools to make a quantitative evaluation of the degradation of fillers in a small animal model. Materials and methods: We evaluated the residence time of different HA-based fillers, fluorescein-labeled and not, injected subcutaneously in mice. Volumes of fillers were monitored through high-frequency ultrasound (HF-US) method while fluorescence intensity through the well-established fluorescence living imaging method. To confirm the effectiveness of HF-US, obtained volumetric measurements were compared with fluorescence intensity values. Results: Both the presented methods revealed the same degradation kinetics for the tested products. Conclusion: The two used methods are fully comparable and quantitatively accurate. The presented approach has been proved to be noninvasive, sensitive, and reproducible. PMID- 30022846 TI - Refeeding syndrome in the frail elderly population: prevention, diagnosis and management. AB - Aging is linked to physiological and pathophysiological changes. In this context, elderly patients often are frail, which strongly correlates with negative health outcomes and disability. Elderly patients are often malnourished, which again is an independent risk factor for both frailty and adverse clinical outcomes. Malnutrition and resulting frailty can be prevented by adequate nutritional interventions. Yet, use of nutritional therapy can also have negative consequences, including a potentially life-threatening metabolic alteration called refeeding syndrome (RFS) in high-risk patients. RFS is characterized by severe electrolyte shifts (mainly hypophosphatemia, hypomagnesemia and hypokalemia), vitamin deficiency (mainly thiamine), fluid overload and salt retention leading to organ dysfunction and cardiac arrhythmias. Although the awareness of malnutrition among elderly people is well established, the risk of RFS is often neglected, especially in the frail elderly population. This partly relates to the unspecific clinical presentation and laboratory changes in the geriatric population. The aim of this review is to summarize recently published recommendations for the management of RFS based on current evidence from clinical studies adapted with a focus on elderly patients. PMID- 30022843 TI - Depression in people with type 2 diabetes: current perspectives. AB - Type 2 diabetes mellitus (T2DM) is associated with depressive symptoms, and comorbid depression in those with T2DM has been associated with adverse clinical profiles. Recognizing and addressing psychological symptoms remain significant clinical challenges in T2DM. Possible mediators of the reciprocal relationship between T2DM and depression may include physical activity levels, effectiveness of self-management, distress associated with a new T2DM diagnosis, and frailty associated with advanced diabetes duration. The latter considerations contribute to a "J-shaped" trajectory from the time of diagnosis. There remain significant challenges to screening for clinical risks associated with psychological symptoms in T2DM; poorer outcomes may be associated with major depressive episodes, isolated (eg, anhedonic), or subsyndromal depressive symptoms, depressive-like symptoms more specific to T2DM (eg, diabetes-related distress), apathy or fatigue. In this review, we discuss current perspectives on depression in the context of T2DM with implications for screening and management of these highly comorbid conditions. PMID- 30022847 TI - IL-1alpha correlates with severity of hepatitis C virus-related liver diseases. AB - Background and aims: Immunoregulatory cytokines influence the persistence of hepatitis C virus (HCV) chronic infection and the extent of liver damage. Interleukin-1 (IL-1) plays an important role in the inflammatory process. Some studies have demonstrated that IL-1alpha production was impaired in patients with chronic infections of HCV, implying that IL-1alpha may play a role in viral clearance. The aim of this study was to evaluate the serum level of proinflammatory cytokine IL-1alpha in patients with chronic hepatitis C (CHC). Methods: This study was performed on 20 CHC patients with cirrhosis in (Group I), 20 CHC patients without cirrhosis in (Group II), 20 hepatocellular carcinoma (HCC) patients with positive anti-HCV in (Group III), and 10 healthy subjects as a control group. Serum levels of IL-1alpha were measured by enzyme-linked immunoassay technique. Results: IL-1alpha had the highest mean concentration in the HCC group and then in the group of CHC with cirrhosis compared to the group of CHC without cirrhosis. Also, it was higher in all studied groups than in the control group (P<0.001). Statistical analysis showed that IL-1alpha was positively correlated with bilirubin (P<=0.001), alanine aminotransferase (P=0.006), aspartate aminotransferase (P=0.001), and viral load (P=0.001) but it was negatively correlated with albumin (P<=0.001) and Hb (P<=0.001), and was not significantly correlated with other parameters (age, international normalized ratio, urea, creatinine, white blood cells, and platelet count). Conclusion: Serum level of IL-1alpha was elevated in patients with CHC and its related liver diseases (liver cirrhosis and HCC) and can be used as an important parameter of inflammatory activity and for fibrosis evaluation in patients with chronic liver disease. PMID- 30022848 TI - Immune function after major surgical interventions: the effect of postoperative pain treatment. AB - Introduction: Impaired immune function during the perioperative period may be associated with worse short- and long-term outcomes. Morphine is considered a major contributor to immune modulation. Patients and methods: We performed a pilot study to investigate postoperative immune function by analyzing peripheral blood mononuclear cells' functionality and cytokine production in 16 patients undergoing major abdominal surgery. All patients were treated with intravenous (i.v.) patient-controlled analgesia with morphine and continuous wound infusion with ropivacaine+methylprednisolone for 24 hours. After 24 hours, patients were randomized into two groups, one continuing intrawound infusion and the other receiving only i.v. analgesia. We evaluated lymphoproliferation and cytokine production by peripheral blood mononuclear cells at the end of surgery and at 24 and 48 hours postoperatively. Results: A significant reduction in TNF-alpha, IL 2, IFN-gamma and lymphoproliferation was observed immediately after surgery, indicating impaired cell-mediated immunity. TNF-alpha and IFN-gamma remained suppressed up to 48 hours after surgery, while a trend to normalization was observed for IL-2 and lymphoproliferation, irrespective of the treatment group. A significant inverse correlation was present between age and morphine and between age and lymphoproliferation. No negative correlation was present between morphine and cytokine production. We did not find any differences within the two groups between 24 and 48 hours in terms of morphine consumption and immune responses. Conclusion: A relevant depression of cell-mediated immunity is associated with major surgery and persists despite optimal analgesia. Even though morphine may participate in immunosuppression, we did not retrieve any dose-related effect. PMID- 30022849 TI - The added value of bedside examination and screening QST to improve neuropathic pain identification in patients with chronic pain. AB - Background: The assessment of a neuropathic pain component (NePC) to establish the neurological criteria required to comply with the clinical description is based on history taking, clinical examination, and quantitative sensory testing (QST) and includes bedside examination (BSE). The objective of this study was to assess the potential association between the clinically diagnosed presence or absence of an NePC, BSE, and the Nijmegen-Aalborg screening QST (NASQ) paradigm in patients with chronic (>=3 months) low back and leg pain or with neck shoulder arm pain or in patients with chronic pain due to suspected peripheral nerve damage. Methods: A total of 291 patients participated in the study. Pain (absence or presence of neuro-pathic pain) was assessed independently by two physicians and compared with BSE (measurements of touch [finger, brush], heat, cold, pricking [safety pin, von Frey hair], and vibration). The NASQ paradigm (pressure algometry, electrical pain thresholds, and conditioned pain modulation) was assessed in 58 patients to generate new insights. Results: BSE revealed a low association of differences between patients with either absent or present NePC: heat, cold, and pricking sensations with a von Frey hair were statistically significantly less common in patients with present NePC. NASQ did not reveal any differences between patients with and without an NePC. Conclusion: Currently, a standardized BSE appears to be more useful than the NASQ paradigm when distinguishing between patients with and without an NePC. PMID- 30022850 TI - Sensitivity of high-resolution ultrasonography in clinically diagnosed carpal tunnel syndrome patients with hand pain and normal nerve conduction studies. AB - Background: Suspecting carpal tunnel syndrome (CTS) in patients with hand pain is usual. Considering the variable rate of false-negative results in nerve conduction study (NCS), as a frequent reference confirmatory standard test, we aimed to evaluate the diagnostic accuracy of neuromuscular ultrasound in patients with clinical evidence of CTS and normal NCS. Methods: It was a diagnostic accuracy study conducted in the outpatient clinic of Rofaydeh Hospital, Tehran, Iran, between July 2012 and December 2016; it recruited clinically diagnosed CTS patients and a control group. All participants underwent comprehensive clinical examination, NCS, and high-resolution ultrasonography of the median nerve. Results: Two hundred and fifty patients with clinical evidence of CTS met the inclusion criteria, of whom 103 (27.1%) had normal NCS and underwent an ultrasound examination. A cutoff point of 9.4 mm2 (mean + 2 standard deviation) for median nerve cross-sectional area at the carpal tunnel inlet from the control group was set to detect 73% abnormality in the case group. Conclusion: Ultrasonography had a sensitivity rate of 73% in patients with clinical CTS and negative NCS, increasing the overall diagnostic sensitivity for clinically suspected CTS in the electrodiagnostic lab setting to 92%. The study highlights the complementary role of ultraso-nography in diagnosing CTS in conjunction with NCS. PMID- 30022851 TI - Dynamic Interaction Between Microtubules and the Nucleus Regulates Nuclear Movement During Neuronal Migration. AB - Fine structures of the mammalian brain are formed by neuronal migration during development. Newborn neurons migrate long distances from the germinal zone to individual sites of function by squeezing their largest cargo, the nucleus, through the crowded neural tissue. Nuclear translocation is thought to be orchestrated by microtubules, actin, and their associated motor proteins, dynein and myosin. However, where and how the cytoskeletal forces are converted to actual nuclear movement remains unclear. Using high-resolution confocal imaging of live migrating neurons, we demonstrated that microtubule-dependent forces are directly applied to the nucleus via the linker of nucleoskeleton and cytoskeleton complex, and that they induce dynamic nuclear movement, including translocation, rotation, and local peaking. Microtubules bind to small points on the nuclear envelope via the minus- and plus-oriented motor proteins, dynein and kinesin-1, and generate a point force independent of the actin-dependent force. Dynamic binding of microtubule motors might cause a continuously changing net force vector acting on the nucleus and results in a stochastic and inconsistent movement of the nucleus, which are seen in crowded neural tissues. PMID- 30022852 TI - The prognostic significance of carcinoma-associated fibroblasts and tumor associated macrophages in nasopharyngeal carcinoma. AB - Purpose: Tumor stroma cells play an important role in the carcinogenesis and progression of cancer. The aim of the present investigation was to explore the predictive role of carcinoma-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in nasopharyngeal carcinoma (NPC). Patients and methods: The densities of CAFs and TAMs were measured by immunohistochemistry staining for alpha-smooth muscle actin (alpha-SMA), CD68, and CD163 in two sets of tissue microarrays including 260 pretreatment NPC tissues, that is, a training test comprising of 152 patients and a validation set comprising of 108 patients. Chi square tests were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. Cox proportional hazards models were used to identify significant independent variables. Results: Patients older than 50 years showed a lower expression of CD68, and there was a positive relationship between the densities of CAFs and CD163+ TAMs (p=0.001). In the multivariate analysis of the training test, both alpha-SMA and CD163 were independent prognostic factors for overall survival and progression-free survival (all p<0.05). Based on the expression levels of alpha SMA and CD163, patients were categorized into three groups: high-risk, intermediate-risk, and low-risk groups according to both high, either high, and both low, respectively. Survival analysis and Cox multivariate analysis showed that the risk groups based on alpha-SMA and CD163 expression were independent predictors for the survival of patients with NPC in the training test, which was also confirmed by the validation test. Conclusion: A patient's risk group based on the level of CD163+ TAMs and CAFs was an independent predictor of survival, which may facilitate patient counseling and individualized treatment. PMID- 30022854 TI - Prognostic significance of lymph node metastasis and lymphadenectomy in early stage ovarian carcinosarcoma. AB - Background: The role that lymph node dissection (LND) plays in the management of ovarian carcinosarcoma (OCS) is unclear due to its rarity. This study investigated lymph node metastasis (LNM) prevalence in women with early OCS and effects of LND and LNM on survival. Methods: Data of women diagnosed with OCS, whose primary tumor was confined to ovaries (American Joint Committee on Cancer [AJCC] T1) or pelvic cavity (AJCC T2), between 1988 and 2010 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified into lymphadenectomy (LND [+]) and no lymphadenectomy (LND [-]) groups. Results: A total of 363 women were included. The prevalence of LNM was 9.6% in AJCC T1 and 16.3% in AJCC T2. Multivariate analysis showed that LND and AJCC T categories were independent prognostic variables, irrespective of cancer specific survival (CSS) or overall survival (OS). Subgroup analysis by AJCC T categories revealed that LND (+) group in AJCC T2 had a better survival outcome compared to LND (-) group (CSS, HR [95% CI] = 0.61 [0.43-0.87]; OS, HR [95% CI] = 0.59 [0.42-0.83]). There was no survival difference between groups in AJCC T1 (CSS, HR [95% CI] = 0.96 [0.56-1.65]; OS, HR [95% CI] = 0.88 [0.56-1.38]). Multivariate analysis was further carried out in LND (+) group and demonstrated that LNM and AJCC T2 had poor CSS and OS. Subgroup analysis by AJCC T categories showed that worse survival was observed in LNM (+) group compared to LNM (-) group in AJCC T2 (CSS, HR [95% CI] = 3.62 [1.50-8.73]; OS, HR [95% CI] = 3.71 [1.59-8.68]) but not in AJCC T1 (CSS, HR [95% CI] = 1.78 [0.50-6.37]; OS, HR [95% CI] = 1.97 [0.61-6.39]). Conclusion: Regional lymphadenectomy should be performed in patients with AJCC T2 OCS. LND and LNM were not significantly associated with prognosis in AJCC T1 while LNM had a trend toward worse survival. PMID- 30022855 TI - Neuropilin-1 expression is associated with lymph node metastasis in breast cancer tissues. AB - Purpose: Neuropilin-1 (NRP1) as an isoform-specific receptor for vascular endothelial growth factor and placenta growth factor in endothelial cells has been demonstrated to be expressed in breast cancer cells where it plays functional roles in cell survival, invasion, and migration. We hypothesized that an expression of NRP1 in breast cancer tissues is associated with clinicopathological data of patients and expression of the tumor suppressor miR 206. Patients and methods: We evaluated the expression of NRP1 in 48 invasive ductal carcinomas of the breast and their corresponding adjacent noncancerous tissues (ANCTs) by means of real-time polymerase chain reaction. We also extracted data on miR-206 gene expression from the same cohort of patients to evaluate the correlation between expression levels of miR-206 and NRP1. In addition, we quantified NRP1 protein levels using the enzyme-linked immunosorbent assay technique. Results: No significant difference was found in NRP1 expression between tumoral tissues and ANCTs. We also assessed the associations between expression levels of NRP1 and clinicopathological data of patients and found no significant associations between NRP1 transcript levels and any characteristic. However, NRP1 protein concentrations were significantly higher in patients with lymph node involvement compared with those without lymph node involvement. No correlation was found between NRP1 and miR-206 expression levels. Conclusion: NRP1 protein levels might be an indicator of metastasis potential in breast cancer. Future studies are needed to confirm these results in larger cohorts of patients. PMID- 30022853 TI - Direct comparison of five serum biomarkers in early diagnosis of hepatocellular carcinoma. AB - Background: Although a number of serum biomarkers for detection of hepatocellular carcinoma (HCC) have been explored, their exact diagnostic value remains unclear. We aimed to conduct a direct comparison of five representative serum biomarkers for detecting HCC and to derive multi-marker prediction algorithms. Patients and methods: In total, 846 patients were recruited from three hospitals in China, including 202 HCC patients, 226 liver cirrhosis patients, 215 chronic hepatitis B virus-infected patients, and 203 healthy volunteers. Serum levels of alpha fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), des-gamma carboxyprothrombin (DCP), squamous cell carcinoma antigen, and centromere protein F autoantibody were measured by ELISA. The diagnostic performances of individual biomarkers and multi-marker combinations were evaluated by receiver operating characteristics analysis. The bootstrapping method was adopted to adjust for potential overfitting of all diagnostic indicators. Results: DCP exhibited the best diagnostic performance, with areas under the curve (AUC) for detecting HCC of 0.82 (95% CI 0.64-0.80) and sensitivity of 65.2% (95% CI 63.3-82.1%) at 90% specificity. Of note, DCP showed similar diagnostic efficacy for detecting AFP positive and AFP-negative HCC. After a comprehensive search for multi-marker combinations, a two-marker prediction algorithm including AFP and DCP was constructed and yielded an AUC of 0.87 (95% CI 0.68-0.84) for detecting HCC. In addition, the combination showed good ability in discriminating early-stage HCC and decompensated liver cirrhosis, with an AUC of 0.81 (95% CI 0.75-0.86). Conclusion: DCP could be a complementary biomarker in the early diagnosis of HCC. The constructed multi-marker prediction algorithms could contribute toward distinguishing HCC from non-malignant chronic liver diseases. PMID- 30022856 TI - Rising trends in pancreatic cancer incidence and mortality in 2000-2014. AB - Background: The morbidity and mortality of pancreatic cancer vary considerably around the world. The aim of this study was to characterize and evaluate recent changes in incidence and incidence-based mortality in the USA. Methods: Incidence and incidence-based mortality data were based on the 18 Surveillance, Epidemiology, and End Results (SEER) registries through SEER*Stat software. We adopted joinpoint regression to analyze the temporal trends stratified by age, gender, ethnicity, stage, tumor site, and size. Results: Based on 18 SEER data sets, the age-adjusted incidence of pancreatic cancer increased from 11.85/100,000 in 2000 to 14.70/100,000 in 2014, increasing by an average annual percentage change (AAPC) of 1.6 (95% CI 1.5-1.8, p<0.05). The incidence-based mortality also increased, from 9.96/100,000 in 2001 to 12.96/100,000 in 2014, increasing by an AAPC of 1.9 (95% CI 1.3-2.5, p<0.05). However, we observed a deceleration in mortality since 2005, with the annual percentage change decreasing from 4.1 (2001-2005) to 1.0 (2005-2014). These increasing trends in pancreatic cancer were observed in most subgroups (stratified by age, gender, ethnicity, stage, tumor site, and size). Conclusion: The incidence and mortality rates of pancreatic cancer in the USA have increased significantly since 2000, highlighting the need for increased preventive, screening, and surveillance efforts. PMID- 30022857 TI - Influence of socioeconomic factors and region of residence on cancer stage of malignant melanoma: a Danish nationwide population-based study. AB - Background: Socioeconomic differences in survival after melanoma may be due to late diagnosis of the disadvantaged patients. The aim of the study was to examine the association between educational level, disposable income, cohabitating status and region of residence with stage at diagnosis of melanoma, including adjustment for comorbidity and tumor type. Methods: From The Danish Melanoma Database, we identified 10,158 patients diagnosed with their first invasive melanoma during 2008-2014 and obtained information on stage, localization, histology, thickness and ulceration. Sociodemographic information was retrieved from registers of Statistics Denmark and data on comorbidity from the Danish National Patient Registry. We used logistic regression to analyze the associations between sociodemographic factors and cancer stage. Results: Shorter education, lower income, living without partner, older age and being male were associated with increased odds ratios for advanced stage of melanoma at time of diagnosis even after adjustment for comorbidity and tumor type. Residence in the Zealand, Central and Northern region was also associated with advanced cancer stage. Conclusion: Socioeconomically disadvantaged patients and patients with residence in three of five health care regions were more often diagnosed with advanced melanoma. Initiatives to increase early detection should be directed at disadvantaged groups, and efforts to improve early diagnosis of nodular melanomas during increased awareness of the Elevated, Firm and Growing nodule rule and "when in doubt, cut it out" should be implemented. Further studies should investigate regional differences in delay, effects of number of specialized doctors per inhabitant as well as differences in referral patterns from primary to secondary health care across health care regions. PMID- 30022859 TI - Miswak users' behavior model based on the theory of planned behavior in the country with the largest Muslim population. AB - Background: Maintaining proper oral hygiene has an influence on oral health. Religious obedience may influence individual behavior. According to Islamic religious guidance, as recommended by an Islamic role model, it is obligated to maintain oral health and the recommended tool to use is miswak. Purpose: To describe miswak users' behavior based on the theory of planned behavior. Subjects and methods: The population of this study was the students of As-Salafi Al-Fitrah Islamic Boarding School who used miswak regularly and were healthy physically and mentally. One hundred and nine samples were chosen randomly and asked to complete a semi-open and a closed-ended questionnaire. Results: Perceived behavioral control had the most dominant influence toward improving intention with beta=0.211 and p<0.05. In contrast, attitude and subjective norms had less influence toward improving intention with beta=0.190 and p>0.05, and beta=0.164 and p<0.0001, respectively. Meanwhile, perceived behavioral control showed direct correlation toward action in model parameter with beta=0.445 and p<0.0001. Conclusion: Perceived behavioral control is the most dominant predisposing factor in increasing intention and attitude of miswak use. PMID- 30022858 TI - Internal accuracy of digitally fabricated cross-arch yttria-stabilized tetragonal zirconia polycrystalline prosthesis. AB - Objective: This investigation determined the internal precision of one-piece cross-arch yttria partially stabilized tetragonal zirconia polycrystalline (Y TZP) ceramic fabricated from two digital systems (Trios-3 and CS-3500) compared to traditional metal alloy casting. Materials and methods: A metal model consisting of four abutments (two canine and two molar) was used for one-piece cross-arch reconstruction. The metal abutments were computerized, prepared in a cylinder form possessing 5 degrees taper and chamfer margin. Two digital approaches of computer-aided design and computer-aided manufacturing were used to fabricate one-piece cross-arch Y-TZP prostheses. The traditional lost wax technique was used to fabricate conventional cast prostheses with nonnoble metal alloys. Ten prostheses were constructed from each system. The preciseness of the prosthesis was evaluated at 22 positions for each abutment using a digital stereomicroscope. Analysis of variance (ANOVA) and Tukey's method were determined for all pairwise differences at the 95% CI. Results: The means and SDs of internal accuracy of prostheses constructed from the traditional cast technique, Trios-3, and CS-3500 were 75.15+/-13.46 MUm, 78.55+/-14.30 MUm, and 82.43+/-16.32 MUm, respectively. ANOVA revealed statistical significance for the internal accuracy of prostheses between the different techniques at different positions of each abutment. Preciseness of the Y-TZP prosthesis constructed from Trios-3 illustrated significantly better internal fit than that constructed from CS-3500 (p<0.05). Tukey multiple comparisons revealed that the Y-TZP prosthesis constructed from both digital systems displayed significantly less internal fit than the traditionally fabricated prosthesis (p<0.05). Conclusion: The one-piece cross-arch Y-TZP prosthesis constructed from Trios-3 demonstrated superior internal accuracy than that from CS-3500, but both slightly lower in accuracy than the traditional cast metal prosthesis. Nevertheless, the internal discrepancies of the Y-TZP prosthesis fabricated by both digital techniques were not beyond the range of clinical prestige and were convincingly precise to be recommended for one-piece cross-arch extensive reconstruction. PMID- 30022860 TI - Risky sexual behavior and associated factors among antiretroviral therapy attendees in Nekemte Referral Hospital, Western Ethiopia: a cross-sectional study. AB - Background: HIV/AIDS remains a major public health problem. Practice of risky sexual behaviors is the major effective driver of the HIV epidemic among HIV positive individuals. This behavior exposes their partners to HIV, and for those that are already positive it exposes them to a risk of suprainfection by other strains. Objective: The aim of this study was to assess the prevalence of risky sexual behavior and associated factors among people living with HIV attending antiretroviral therapy (ART) clinic at Nekemte Referral Hospital. Methods: An institution-based based cross-sectional study was conducted at the ART clinic of Nekemte Referral Hospital from March to April 2016. A total of 337 people living with HIV on ART for at least 3 months were selected by consecutive sampling technique. Data were collected through face-to-face interview. Data were entered into Epi-data Version 3.1 and analyzed using SPSS version 20. Variables significant on bivariate logistic regression analysis at p<0.25 were considered as candidates for the multivariable logistic regression analysis, and statistical significance was set at p<0.05. Results: Approximately one third (32.9%) of the study participants were engaged in risky sexual behavior in the past 3 months prior to the study. Having multiple sexual partners (adjusted odds ratio [AOR] =6.38, 95% CI: 1.65, 24.74), being with a positive sero-status partner (AOR =2.68, 95% CI: 1.31, 5.5), not disclosing sero-status (AOR =5.99, 95% CI: 1.36, 26.35), having a desire for a child (AOR =2.6, 95% CI: 1.5, 4.51), having experience of perceived stigma (AOR =2.63, 95% CI: 1.5, 4.62), and lack of education on importance of protecting self from strain (AOR =5.64, 95% CI: 3.19, 9.96) were significantly associated with risky sexual behavior. Conclusion and recommendation: The prevalence of risky sexual behavior was high, and approximately one third of study participants were engaged in risky sexual behavior. Efforts to increase awareness through health education and counseling are highly recommended. PMID- 30022861 TI - Intrapartum fetal heart rate monitoring using a handheld Doppler versus Pinard stethoscope: a randomized controlled study in Dar es Salaam. AB - Background: Fetal stethoscopes are mainly used for intermittent monitoring of fetal heart rate (FHR) during labor in low-income countries, where perinatal mortality is still high. Handheld Dopplers are rarely available and are dependent on batteries or electricity. The objective was to compare the Pinard stethoscope versus a new wind-up handheld Doppler in the detection of abnormal FHR. Materials and methods: We conducted a randomized controlled study at Muhimbili National Hospital, Tanzania, from April 2013 to September 2015. Women with gestational age >=37 weeks, cephalic presentation, normal FHR on admission, and cervical dilatation <7 cm were included. Primary outcome was abnormal FHR detection (<120 or >160 beats/min). Secondary endpoints were time to delivery, mode of delivery, and perinatal outcomes. chi2, Fisher's exact test, Mann-Whitney test, and logistic regression were conducted. Unadjusted and adjusted odds ratios were calculated with respective 95% confidence interval. Results: In total, 2,844 eligible women were assigned to FHR monitoring with Pinard (n=1,423) or Doppler (n=1,421). Abnormal FHRs were more often detected in the Doppler (6.0%) versus the Pinard (3.9%) arm (adjusted odds ratio =1.59, 95% confidence interval: 1.13 2.26, p=0.008). Median (interquartile range) time from abnormal FHR detection to delivery was comparable between Doppler and Pinard, ie, 80 (60,161) and 89 (52,165) minutes, respectively, as was the incidence of cesarean delivery (12.0% versus 12.2%). The incidence of adverse perinatal outcomes (fresh stillbirths, 24 hour neonatal admissions, and deaths) was similar overall; however, among newborns with abnormal FHR delivered vaginally, adverse outcomes were less incident in Doppler (7 of 43 births, 16.3%) than in the Pinard arm (10 of 23 births, 43.5%), p=0.021. Conclusion: Intermittent FHR monitoring using Doppler was associated with an increased detection of abnormal FHR compared to Pinard in a low-risk population. Time intervals from abnormal FHR detection to delivery were longer than recommended in both arms. Perinatal outcomes were better among vaginally delivered newborns with detected abnormal FHR in the Doppler arm. PMID- 30022862 TI - Intestinal tuberculosis in a 55-year-old woman with a 30-year history of rheumatoid arthritis. AB - Introduction: Tuberculosis (TB) is one of the endemic diseases with a challenging diagnosis in the absence of pulmonary disease. On the other hand, rheumatoid arthritis (RA) is a systemic autoimmune disease with extra-articular manifestations that occur at any age after onset, such as nodules, Sjogren's syndrome, anemia of chronic disease, and pulmonary manifestations, which are more frequently seen in patients with severe, active disease. Here we present a case of RA with intestinal TB. Case report: A 55-year-old woman with a 30-year history of RA using prednisolone and hydroxychloroquine presented with a nonpositional hypogastric pain and a weight loss of 20 kg over 7 months. No history of biological therapy was recorded. Colonoscopy revealed an ulcerated mass that was suspicious for malignancy. The pathobiological assessments confirmed ulceration and granulation tissue formation, foci of necrotizing granulomatous inflammation in lamina propria with adjacent mild crypt regenerative changes. Also, Ziehl Neelsen staining for acid-fast bacilli in the granulomas was positive though the polymerase chain reaction assay did not detect the Mycobacterium tuberculosis. Anti-TB medication for 2 weeks eliminated the symptoms. Conclusions: Intestinal TB in patients with vague abdominal symptoms and relevant physical findings such as pain and palpable mass should be considered to prevent late or misdiagnosis. PMID- 30022863 TI - Understanding health care avoidance and initial help-seeking behavior in German veterans: a theory of planned behavior. AB - Objective: To gain initial insights into salient beliefs of former German soldiers (veterans) about the use of mental health services. Data source: Narrative interviews with former German soldiers (veterans) were conducted in 2016. Data collection/extraction method: Forty-three interviews were transcribed and analyzed thematically based on the theoretical framework of the theory of planned behavior. From within the behavorial, normative, and control beliefs, the salient beliefs were identified. Principal findings: Four groups of salient beliefs were identified, described, and named: "Autarky", "Ineffectiveness", "Heteronomy", and "Incapacity". Conclusion: Interventions and campaigns addressing these four specific groups of beliefs may lead to higher health service use rates. However, as a result of methodological limitations of the study design, the conclusion remains tentative. PMID- 30022864 TI - Factors associated with early cardiac complications following transcatheter aortic valve implantation with transapical approach. AB - Purpose: To estimate the incidence of postprocedural early cardiac complications among patients undergoing transcatheter aortic valve implantation, through transapical approach (TA-TAVI), and to identify factors independently associated with the occurrence of them. Patients and methods: A retrospective cohort study of 90 patients, who had undergone TA-TAVI in a tertiary hospital of Liverpool, UK, during a 5-year period (September 2008-October 2013), was conducted. Data on patient demographics, periprocedural characteristics and cardiac complications presented within 30-day post TA-TAVI were collected, retrospectively, using the hospital's electronic database. Results: The overall 30-day incidence of cardiac complications was estimated at 18.9% (n=17/90). The rate of new onset of atrial fibrillation (AF), atrioventricular block requiring permanent pacemaker implantation, shockable cardiac arrest rhythm and cardiac tamponade was 11.1%, 3.3%, 2.2% and 2.2%, respectively. Bivariate analysis found that absence of preoperative AF (p=0.01), receiving of oral inotropes preprocedurally (p=0.01), intravenous inotropic support postprocedurally (p=0.01) and requirement for postprocedural tracheal intubation (p=0.001) were the main factors associated with increased probability for patient cardiac morbidity. Conclusion: It seems that patients with absence of AF and oral inotropic support preprocedurally and those with post TA-TAVI mechanical ventilatory and intravenous inotropic support have greater probability to develop cardiac complications. This knowledge allows the early identification of high-risk patients and supports clinicians to apply both preventive and therapeutic interventions for the optimum patient management and care. In addition, administrators could allocate the health care system resources effectively. PMID- 30022865 TI - In vivo assessment of time dependent changes of T2* in medial meniscus under loading at 3T: A preliminary study. AB - Due to the internal structure of the knee joint, the ability to characterize and quantify the dynamic response of the meniscal tissue directly in vivo is highly problematic. The main purpose of this study was to investigate the behaviour of the meniscus under loading conditions. Four healthy young females were included. To obtain T2* values in the meniscus, the vTE sequence was used with 10 echoes ranging from 0.8 to 10.1 ms. Submilisecond first echo time is a great advantage of vTE sequence allowing for precise mapping of relatively short T2*. The two parametric least squares fitting procedure was used to calculate T2* pixel-wise. A custom-made diamagnetic apparatus was developed to simulate stress conditions on the lower limb in a conventional MR scanner. vTE T2* was performed in five consecutive scans, 6:10 min apart. Three different compartments of the medial and lateral meniscus were segmented. The differences at the different time-points were calculated. A constant increase of T2* times after compression was statistically significant in the anterior horn of the medial meniscus. T2* mapping with variable echo time sequence might be a satisfactorily sensitive technique to detect the changes of meniscus physiology under loading conditions in vivo. PMID- 30022867 TI - Astrocytic proBDNF and Tonic GABA Distinguish Active versus Reactive Astrocytes in Hippocampus. AB - Astrocytes are the most abundant cell type in the brain and they make close contacts with neurons and blood vessels. They respond dynamically to various environmental stimuli and change their morphological and functional properties. Both physiological and pathological stimuli can induce versatile changes in astrocytes, as this phenomenon is referred to as 'astrocytic plasticity'. However, the molecular and cellular mechanisms of astrocytic plasticity in response to various stimuli remain elusive, except for the presence of hypertrophy, a conspicuous structural change which is frequently observed in activated or reactive astrocytes. Here, we investigated differential characteristics of astrocytic plasticity in a stimulus-dependent manner. Strikingly, a stab wound brain injury lead to hypertrophy of astrocytes accompanied by increased GABA expression and tonic GABA release in mouse CA1 hippocampus. In contrast, the mice experiencing enriched environment exhibited astrocytic hypertrophy with enhanced proBDNF immunoreactivity but without GABA signal. Based on the results, we define proBDNF-positive/GABA-negative hypertrophic astrocytes as 'active' astrocytes and GABA-positive hypertrophic astrocytes as 'reactive' astrocytes, respectively. We propose for the first time that astrocytic proBDNF can be a bona fide molecular marker of the active astrocytes, which are distinct from the reactive astrocytes which show hypertrophy but with aberrant GABA. PMID- 30022869 TI - Desynchronization of Theta Oscillations in Prefrontal Cortex during Self stimulation of the Medial Forebrain Bundles in Mice. AB - Stimulation of the medial forebrain bundle (MFB) can reinforce intracranial self stimulation (ICSS) in rodents (i.e., reward-seeking behavior). The MFB stimulation produces a highly reliable behavioral output that enabled a clear distinction of the animal behavioral states between the non-ICSS and ICSS periods. However, the cortical states during these reward-seeking behaviors are not fully characterized in comparison to those during volitional behavior. This study was designed to characterize the cortical rhythms of and coherence between prefrontal cortex and hippocampus during the wheel-turning behavior reinforced by the ICSS in comparison to the wheel-turning without ICSS. We used a wheel for freely moving mice, which was programmed to deliver cathode currents through an electrode in the MFB at each one-quarter turn of the wheel to induce ICSS. The wheel-turning epochs were extracted from the pre-ICSS, ICSS and post-ICSS sessions and the prefrontal EEGs and the hippocampal LFPs in the epochs were analyzed with power and synchronization analyses. During the ICSS, the EEG power decreased at 6~10 Hz in the prefrontal cortex, while was not significantly altered in the hippocampus. Furthermore, we found that the phase synchrony between the prefrontal cortex and the hippocampus corresponding to information transmission between the two regions during reward-seeking motion decreased preceding MFB stimulation reinforced by ICSS. Our findings suggest that theta activity can be reliably dissociated from active behavior if the animal is involved in self-stimulation. PMID- 30022868 TI - LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation. AB - Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD). LRRK2 contains a functional kinase domain and G2019S, the most prevalent LRRK2 pathogenic mutation, increases its kinase activity. LRRK2 regulates mitochondria morphology and autophagy in neurons. LPS treatment increases LRRK2 protein level and mitochondrial fission in microglia, and down-regulation of LRRK2 expression or inhibition of its kinase activity attenuates microglia activation. Here, we evaluated the direct role of LRRK2 G2019S in mitochondrial dynamics in microglia. Initial observation of microglia in G2019S transgenic mice revealed a decrease in mitochondrial area and shortage of microglial processes compared with their littermates. Next, we elucidated the molecular mechanisms of these phenotypes. Treatment of BV2 cells and primary microglia with LPS enhanced mitochondrial fission and increased Drp1, a mitochondrial fission marker, as previously reported. Importantly, both phenotypes were rescued by treatment with GSK2578215A, a LRRK2 kinase inhibitor. Finally, the protein levels of CD68, an active microglia marker, Drp1 and TNF alpha were significantly higher in brain lysates of G2019S transgenic mice compared with the levels in their littermates. Taken together, our data suggest that LRRK2 could promote microglial mitochondrial alteration via Drp1 in a kinase dependent manner, resulting in stimulation of pro-inflammatory responses. This mechanism in microglia might be a potential target to develop PD therapy since neuroinflammation by active microglia is a major symptom of PD. PMID- 30022866 TI - The Emerging Concept of Intrinsic Plasticity: Activity-dependent Modulation of Intrinsic Excitability in Cerebellar Purkinje Cells and Motor Learning. AB - What is memory? How does the brain process the sensory information and modify an organism's behavior? Many neuroscientists have focused on the activity- and experience-dependent modifications of synaptic functions in order to solve these fundamental questions in neuroscience. Recently, the plasticity of intrinsic excitability (called intrinsic plasticity) has emerged as an important element for information processing and storage in the brain. As the cerebellar Purkinje cells are the sole output neurons in the cerebellar cortex and the information is conveyed from a neuron to its relay neurons by forms of action potential firing, the modulation of the intrinsic firing activity may play a critical role in the cerebellar learning. Many voltage-gated and/or Ca2+-activated ion channels are involved in shaping the spiking output as well as integrating synaptic inputs to finely tune the cerebellar output. Recent studies suggested that the modulation of the intrinsic excitability and its plasticity in the cerebellar Purkinje cells might function as an integrator for information processing and memory formation. Moreover, the intrinsic plasticity might also determine the strength of connectivity to the sub-cortical areas such as deep cerebellar nuclei and vestibular nuclei to trigger the consolidation of the cerebellar-dependent memory by transferring the information. PMID- 30022870 TI - Antidepressant-like Effects of p-Coumaric Acid on LPS-induced Depressive and Inflammatory Changes in Rats. AB - Depression causes mental and physical changes which affect quality of life. It is estimated to become the second most prevalent disease, but despite its commonness, the pathophysiology of depression remains unclear and medicine is not sufficiently protective. p-Coumaric acid (p-CA) is a dietary phenolic acid which has been proven to have antifungal, anti-HIV, anti-melanogenic, antioxidant and anti-inflammatory effects. Considering these effects, we investigated whether p CA can prevent depressive symptoms by reducing inflammatory cytokines in animals injected with lipopolysaccharide (LPS). Changes in despair-related behaviors, inflammatory cytokines, neurotrophic factors and synaptic activity were measured. In these animals, p-CA improved despair-related behavioral symptoms induced by LPS in the forced swim test (FST), tail suspension test (TST) and sucrose splash test (SST). p-CA also prevented the increase of inflammatory cytokines in the hippocampus such as cycloxigenase-2 and tumor necrosis factor-alpha due to LPS. Similarly, it prevented the reduction of brain-derived neurotrophic factor (BDNF) by LPS. Electrophysiologically, p-CA blocked the reduction of long-term depression in LPS-treated organotypic tissue slices. In conclusion, p-CA prevented LPS-induced depressive symptoms in animals, as determined by behavioral, biochemical and electrophysiological measures. These findings suggest the potential use of p-CA as a preventive and therapeutic medicine for depression. PMID- 30022871 TI - Radix Polygalae Extract Attenuates PTSD-like Symptoms in a Mouse Model of Single Prolonged Stress and Conditioned Fear Possibly by Reversing BAG1. AB - Radix Polygalae (RP) has been used to relieve psychological stress in traditional oriental medicine. Recently, cell protective, antiamnestic and antidepressant like effects were disclosed but the possible application of RP to post-traumatic stress disorder, in which exaggerated fear memory persists, has not yet been explored. For this purpose, the effects of RP on fear behavior was examined in a mouse model of single prolonged stress and conditioned fear (SPS-CF), previously shown to mimic key symptoms of post-traumatic stress disorder. Male mice received daily oral dose of RP extract or vehicle during the SPS-CF procedure. Then fear related memory (cohort 1, n=25), non-fear-related memory (cohort 2, n=38) and concentration-dependent effects of RP on fear memory (cohort 3, n=41) were measured in 3 separate cohort of animals. Also working memory and anxiety-like behaviors were measured in cohort 1. RP-treated SPS-CF mice exhibited attenuated contextual but not cued freezing and no impairments in the working memory and spatial reference memory performances relative to vehicle-treated SPS-CF controls. RP-treated SPS-CF and naive mice also demonstrated no difference in anxiety-like behavior levels relative to vehicle-treated SPS-CF and naive controls, respectively. In the hippocampus of SPS-CF mice, expression of BAG1, which regulates the activity of GR, was decreased, whereas RP increased expression of BAG1 in naive and SPS-CF mice. These results suggest that RP exerts some symptomatic relief in a mouse with exaggerated fear response. RP and its molecular components may thus constitute valuable research targets in the development of novel therapeutics for stress-related psychological disorders. PMID- 30022872 TI - Blue-on-Green Flash Induces Maximal Photopic Negative Response and Oscillatory Potential and Serves as a Diagnostic Marker for Glaucoma in Rat Retina. AB - The purpose of this study was to investigate the application of various electroretinography (ERG) to the diagnosis of inner retinal dysfunction induced by mild intraocular pressure (IOP) elevation in a rat glaucoma model. For inner retinal function measurements, available photopic ERG protocols were applied under various light conditions including monochromatic combinations, which complement conventional scotopic ERG. Three episcleral veins in the right eyes of Sprague-Dawley rats were cauterized to induce an experimental model of glaucoma, leading to mild IOP elevation. ERG responses were measured before surgery and at 1, 2, 4, and 8 weeks after cauterization. We first confirmed that the amplitude reduction in the standard photopic b-wave was almost comparable to the amplitudes of scotopic a- and b-waves in glaucomatous eyes over time. We have implemented additional photopic ERG protocols under different stimulus conditions, which consisted of a longer duration and different monochromatic combinations. Such a change in the stimulations resulted in more pronounced differences in response between the two groups. Especially in normal animals, blue stimulation on a green background produced the largest b-wave and photopic negative response (PhNR) amplitudes and caused more pronounced oscillatory potential (OP) wavelets (individual components). In glaucomatous eyes, blue stimulation on a green background significantly reduced PhNR amplitudes and abolished the robust OP components. These results, by providing the usefulness of blue on green combination, suggest the applicable photopic ERG protocol that complements the conventional ERG methods of accessing the progression of glaucomatous damage in the rat retina. PMID- 30022873 TI - Cortical Axonal Secretion of BDNF in the Striatum Is Disrupted in the Mutant huntingtin Knock-in Mouse Model of Huntington's Disease. AB - Deficient BDNF signaling is known to be involved in neurodegenerative diseases such as Huntington's disease (HD). Mutant huntingtin (mhtt)-mediated disruption of either BDNF transcription or transport is thought to be a factor contributing to striatal atrophy in the HD brain. Whether and how activity-dependent BDNF secretion is affected by the mhtt remains unclear. In the present study, I provide evidence for differential effects of the mhtt on cortical BDNF secretion in the striatum during HD progression. By two-photon imaging of fluorescent BDNF sensor (BDNF-pHluorin and -EGFP) in acute striatal slices of HD knock-in model mice, I found deficient cortical BDNF secretion regardless of the HD onset, but antisense oligonucleotide (ASO)-mediated reduction of htts only rescues BDNF secretion in the early HD brain before the disease onset. Although secretion modes of individual BDNF-containing vesicle were not altered in the pre symptomatic brain, the full-fusion and partial-fusion modes of BDNF-containing vesicles were significantly altered after the onset of HD symptoms. Thus, besides abnormal BDNF transcription and transport, our results suggest that mhtt-mediated alteration in activity-dependent BDNF secretion at corticostriatal synapses also contributes to the development of HD. PMID- 30022874 TI - Morin Prevents Granule Cell Dispersion and Neurotoxicity via Suppression of mTORC1 in a Kainic Acid-induced Seizure Model. AB - An abnormal reorganization of the dentate gyrus and neurotoxic events are important phenotypes in the hippocampus of patients with temporal lobe epilepsy (TLE). The effects of morin, a bioflavonoid constituent of many herbs and fruits, on epileptic seizures have not yet been elucidated, though its beneficial effects, such as its anti-inflammatory and neuroprotective properties, are well described in various neurodegenerative diseases. In the present study, we investigated whether treatment with morin hydrate (MH) can reduce the susceptibility to seizures, granule cell dispersion (GCD), mammalian target of rapamycin complex 1 (mTORC1) activity, and the increases in the levels of apoptotic molecules and inflammatory cytokines in the kainic acid (KA)-induced seizure mouse model. Our results showed that oral administration of MH could reduce susceptibility to seizures and lead to the inhibition of GCD and mTORC1 activity in the KA-treated hippocampus. Moreover, treatment with MH significantly reduced the increased levels of apoptotic signaling molecules and pro inflammatory mediators in the KA-treated hippocampus compared with control mice, suggesting a neuroprotective role. Therefore, these results suggest that morin has a therapeutic potential against epilepsy through its abilities to inhibit GCD and neurotoxic events in the in vivo hippocampus. PMID- 30022875 TI - Leucine-rich G Protein-coupled Receptor-5 Is Significantly Increased in the Aqueous Humor of Human Eye with Proliferative Diabetic Retinopathy. AB - Leucine-rich G protein-coupled receptor-5 (LGR5) is known to be a stem cell marker in many organs. LGR5 may have important roles in proliferative diabetic retinopathy (PDR) because LGR5 potentiate the Wnt/beta-catenin pathway, which plays crucial roles in pathologic neovascularization in the retina. The association between LGR5 and retinal pathologic neovascularization has not yet been reported. In the present study, LGR5 was compared in human aqueous humor (AH) between normal control and patients with PDR to confirm the relationship between LGR5 and PDR. AH was collected from 7 naive PDR patients and 3 control subjects before intravitreal injection and cataract surgery, respectively. LGR5 and key members of Wnt/beta-catenin were assessed by western blotting. In the present study, it was confirmed for the first time that LGR5 is detected in AH and it increases in PDR patients. Key members of Wnt/beta-catenin pathway were also increased in AH of PDR patients compared to control. These findings might support the hypothesis that LGR5 has important roles in PDR especially considering the roles of the Wnt/beta-catenin pathway, which is activated by LGR5, contributing to retinal pathologic neovascularization. PMID- 30022877 TI - Expected long-term defect rate of analytical performance in the medical laboratory: Assured Sigma versus observed Sigma. AB - Reliability of laboratory results is determined by the ratio of incorrect results expected in long-term. Sigma is a measure of defect ratio, therefore long-term Sigma is a measure of the reliability of laboratory results. Commonly, long-term Sigma is estimated based on the short-term Sigma. The Six Sigma methodology assumes that in long-term performances will shift up to 1.5 Sigma, and therefore the long-term Sigma is considered 1.5 Sigma less than short-term Sigma. Analytical performance in the medical laboratory is prone to shifts larger than 1.5 Sigma. Thus, the 1.5 Sigma shift assumed in the Six Sigma is not a correct estimate in the medical laboratory. On the other hand, in the medical laboratory statistical quality control procedure (SQC) is applied to detect and correct shifts. Since SQC can be planned to trap shifts of different sizes, the threshold set for SQC determines the defect rate expected for long-term. PMID- 30022878 TI - Special issue on Six Sigma metrics - experiences and recommendations. PMID- 30022876 TI - Fractionated Gamma Knife Radiosurgery as Initial Treatment for Large Skull Base Meningioma. AB - We present our experience on the hypofractionated Gamma Knife radiosurgery (FGKS) for large skull base meningioma as an initial treatment. We retrospectively reviewed 23 patients with large skull base meningioma >=10 cm3 who underwent FGKS as the initial treatment option. The mean volume of tumors prior to radiosurgery was 21.2+/-15.63 cm3 (range, 10.09~71.42). The median total margin dose and marginal dose per fraction were 18 Gy (range, 15~20) and 6 Gy (range, 5~6), respectively. Patients underwent three or four fractionations in consecutive days with the same Leksell(r) frame. The mean follow-up duration was 38 months (range, 17~78). There was no mortality. At the last follow-up, the tumor volume was stationary in 15 patients (65.2%) and had decreased in 8 patients (34.8%). Six patients who had cranial neuropathy at the time of FGKS showed improvement at the last clinical follow-up. Following FGKS, 4 patients (17%) had new cranial neuropathy. The trigeminal neuropathy was the most common and all were transient. The mean Karnofsky Performance Status score at pre-FGKS and the last clinical follow-up was 97.0+/-10.4 points (median, 100) and 98.6+/-6.9 (median, 100) points, respectively. FGKS has showed satisfactory tumor control with functional preservation for large skull base meningiomas. Further prospective studies of large cohorts with long term follow-up are required to clarify the efficacy in the tumor control and functional outcome as well as radiation toxicity. PMID- 30022879 TI - Analytical Sigma metrics: A review of Six Sigma implementation tools for medical laboratories. AB - Sigma metrics have become a useful tool for all parts of the quality control (QC) design process. Through the allowable total error model of laboratory testing, analytical assay performance can be judged on the Six Sigma scale. This not only allows benchmarking the performance of methods and instruments on a universal scale, it allows laboratories to easily visualize performance, optimize the QC rules and numbers of control measurements they implement, and now even schedule the frequency of running those controls. PMID- 30022880 TI - Sigma metrics in laboratory medicine revisited: We are on the right road with the wrong map. AB - Reliable procedures are needed to quantify the performance of instruments and methods in order to increase the quality in clinical laboratories. The Sigma metrics serves that purpose, and in the present study, the current methods for the calculation of the Sigma metrics are critically evaluated. Although the conventional model based on permissible (or allowable) total error is widely used, it has been shown to be flawed. An alternative method is proposed based on the within-subject biological variation. This model is conceptually similar to the model used in industry to quantify measurement performance, based on the concept of the number of distinct categories and consistent with the Six Sigma methodology. The quality of data produced in clinical laboratories is expected, however, to be higher than the quality of industrial products. It is concluded that this model is consistent with Six Sigma theory, original Sigma metrics equation and with the nature of patients' samples. Therefore, it can be used easily to calculate the performance of measurement methods and instruments used in clinical laboratories. PMID- 30022881 TI - Corrigendum to: The potential of component-resolved diagnosis in laboratory diagnostics of allergy. AB - [This corrects the article DOI: 10.11613/BM.2018.020501.]. PMID- 30022882 TI - Risk analysis and assessment based on Sigma metrics and intended use. AB - Introduction: In order to ensure the quality in clinical laboratories and meet the low risk requirements of patients and clinicians, a risk analysis and assessment model based on Sigma metrics and intended use was constructed, based on which differential sigma performance (sigma) expectations of 42 analytes were developed. Materials and methods: Failure mode and effects analysis was applied to produce an analytic risk rating based on three factors, each test of which was graded as follows: 1) Sigma metrics; 2) the severity of harm; 3) intended use. By multiplying the score of Sigma metrics by the score of severity of harm by the score of intended use, each was assigned a typical risk priority number (RPN), with RPN <= 25 rated as low risk. Low risk was defined as acceptable standards; the sigma performance expectations were calculated. Results: Among the 42 analytes, tests with sigma >= 6, 5 <= sigma < 6, 4 <= sigma < 5, 3 <= sigma < 4, sigma < 3 were 21, 5, 5, 6, and 5, respectively; there were 7 high-risk tests, 8 of them medium risk tests. According to the risk assessment conclusion, 13 tests had sigma performance expectations >= 6; 15 test items had sigma performance expectations >= 5, while 3 test items had sigma performance expectations >= 4; 11 test items had sigma performance expectations >= 3. Conclusions: Constructing the risk analysis and assessment model based on Sigma metrics and intended use will help clinical laboratories to identify the high-risk tests more objectively and comprehensively. Such model can also be used to establish the sigma performance expectations and meet the low risk requirements of patients and clinicians. PMID- 30022883 TI - Sigma metrics for assessing the analytical quality of clinical chemistry assays: a comparison of two approaches: Electronic supplementary material available online for this article. AB - Introduction: Two approaches were compared for the calculation of coefficient of variation (CV) and bias, and their effect on sigma calculation, when different allowable total error (TEa) values were used to determine the optimal method for Six Sigma quality management in the clinical laboratory. Materials and methods: Sigma metrics for routine clinical chemistry tests using three systems (Beckman AU5800, Roche C8000, Siemens Dimension) were determined in June 2017 in the laboratory of Peking Union Medical College Hospital. Imprecision (CV%) and bias (bias%) were calculated for ten routine clinical chemistry tests using a proficiency testing (PT)- or an internal quality control (IQC)-based approach. Allowable total error from the Clinical Laboratory Improvement Amendments of 1988 and the Chinese Ministry of Health Clinical Laboratory Center Industry Standard (WS/T403-2012) were used with the formula: Sigma = (TEa - bias) / CV to calculate the Sigma metrics (sigmaCLIA, sigmaWS/T) for each assay for comparative analysis. Results: For the PT-based approach, eight assays on the Beckman AU5800 system, seven assays on the Roche C8000 system and six assays on the Siemens Dimension system showed sigmaCLIA > 3. For the IQC-based approach, ten, nine and seven assays, respectively, showed sigmaCLIA > 3. Some differences in sigma were therefore observed between the two calculation methods and the different TEa values. Conclusions: Both methods of calculating sigma can be used for Six Sigma quality management. In practice, laboratories should evaluate Sigma multiple times when optimizing a quality control schedule. PMID- 30022884 TI - Application of Sigma metrics in assessing the clinical performance of verified versus non-verified reagents for routine biochemical analytes. AB - Introduction: Sigma metrics analysis is considered an objective method to evaluate the performance of a new measurement system. This study was designed to assess the analytical performance of verified versus non-verified reagents for routine biochemical analytes in terms of Sigma metrics. Materials and methods: The coefficient of variation (CV) was calculated according to the mean and standard deviation (SD) derived from the internal quality control for 20 consecutive days. The data were measured on an Architect c16000 analyser with reagents from four manufacturers. Commercial reference materials were used to estimate the bias. Total allowable error (TEa) was based on the CLIA 1988 guidelines. Sigma metrics were calculated in terms of CV, percent bias and TEa. Normalized method decisions charts were built by plotting the normalized bias (biasa: bias%/TEa) on the Y-axis and the normalized imprecision (CVa: mean CV%/TEa) on the X-axis. Results: The reagents were compared between different manufacturers in terms of the Sigma metrics for relevant analytes. Abbott and Leadman's verified reagents provided better Sigma metrics for the alanine aminotransferase assay than non-verified reagents (Mindray and Zybio). All reagents performed well for the aspartate aminotransferase and uric acid assays with a sigma of 5 or higher. Abbott achieved the best performance for the urea assay, evidenced by the sigma of 2.83 higher than all reagents, which were below 1-sigma. Conclusion: Sigma metrics analysis system is helpful for clarifying the performance of candidate non-verified reagents in clinical laboratory. Our study suggests that the quality of non-verified reagents should be assessed strictly. PMID- 30022885 TI - Comprehensive evaluation of the internal and external quality control to redefine analytical quality goals. AB - Introduction: The aim of this work is to design a selection algorithm for total allowable error (TEa) source using a graphic tool that, by integrating internal (IQC) and external (EQC) quality control performances, enables the laboratory to evaluate which TEa source better fits the test analytical performance. Materials and methods: Two analytical performance indicators (bias and Sigma metrics) were estimated for 23 biochemistry tests during 2016. Bias was estimated on the EQC, and Sigma metrics was calculated through the results obtained in the IQC. The Sigma metrics was charted as a function of the bias (TEa%). Following the proposed algorithm (considering the hierarchy in the Milan 2014 consensus), the TEa was evaluated depending on two areas. One area in the chart was defined as the objective area in which the used TEa is the appropriate one for the analytical performance of the test under evaluation. For any test located outside this area, a performance re-evaluation was required using another source of TEa. Results: In 19 out of 23 evaluated tests, the resulting analytical performance allowed for the selection of biologic variability as TEa source. In the four remaining cases, TEa sources of lesser hierarchy were selected. Conclusion: The graphic tool designed together with the proposed algorithm enabled the laboratory to standardize the selection procedure of the most appropriate TEa for the test analytical performance. PMID- 30022886 TI - Comparison between Sigma metrics in four accredited Egyptian medical laboratories in some biochemical tests: an initiative towards sigma calculation harmonization. AB - Introduction: Analytical quality is an essential requirement for best practice in any medical laboratory. Lack of a harmonized approach for sigma calculation is considered an obstacle in the objective comparability of analytical performance among laboratories adopting sigma metrics. It is urgently needed that all laboratory professionals interested in the analytical quality to work hard towards harmonization protocol for sigma calculation in order to properly select their analytical goals. This study aims at harmonization of Sigma metrics calculation in four accredited Egyptian laboratories. Materials and methods: This observational cross sectional study compared the sigma levels for certain biochemical parameters in the four participating laboratories. Results: Coefficient of variation (CV) and bias were determined for some biochemical analytes, data assayed by different automated analysers in the four different accredited laboratories. The sigma level for the four medical laboratories was calculated for each biomedical parameter with changed sigma level after total allowable error (Tea) unification among participating laboratories. Conclusion: Each laboratory should select the TEa goal based on clear standardized criteria of selection without any subjective preferences as either under or over estimation of Sigma metrics will affect the patient centred care negatively if laboratories use quality control procedures wrongly based on incorrect Sigma metrics calculation with subsequent misleading medical decisions. PMID- 30022887 TI - Evaluation of the analytical performances of Cobas 6500 and Sysmex UN series automated urinalysis systems with manual microscopic particle counting. AB - Introduction: Automated urinalysis systems are valuable tools in clinical laboratories, especially those with a high work load. The objective of this study was to compare the analytical performance of Sysmex UN series urine analyser, which may become a new one in our laboratory, with the Cobas 6500 automated urine analyser, which is used in our laboratory for a long time. For comparisons, manual microscopical examination was accepted as reference method. Materials and methods: A total of 470 urine samples were tested in the two automated urinalysis systems, and urine sediment testing with manual microscopy was applied to a 100 pathological samples of the total 470. The diagnostic performance of the two automated urine analysers was compared with each other and manual microscopy. Results: Differences were determined between automated and manual microscopy in some pathological samples. The resultant regression equations were as follows. Comparison of Cobas U701 with Sysmex UF-5000: y = - 0.57 (- 0.85 to - 0.29) + 0.95 (0.92 to 0.99) x for RBC, and y = - 0.11 (- 0.54 to 0.29) + 0.89 (0.84 to 0.98) x for WBC; comparison of Cobas U701 with manual microscopy: y = - 0.45 (- 0.85 to 0.21) + 1.00 (0.92 to 1.07) x for WBC; and comparison of Sysmex UF-5000 with manual microscopy: y = - 0.74 (- 1.09 to - 0.57) + 0.87 (0.85 to 0.91) x for WBC. Conclusions: We can conclude that the new Sysmex UN series urine analyser can be safely used in our laboratory. Although the results showed good to moderate concordance, the microscopy results of the automated platforms should be confirmed by manual microscopy, particularly in pathological samples. PMID- 30022888 TI - Utilization of a healthcare failure mode and effects analysis to identify error sources in the preanalytical phase in two tertiary hospital laboratories. AB - Introduction: The presence of errors in the preanalytical phase is a thoroughly studied problem. A strategy to increase their source detection might be the use of the Healthcare Failure Mode and Effects Analysis (HFMEA). The aim of this study is improving the capacity of identifying sources of error during the preanalytical period in samples provided by primary care clinics (PCC) with the use of the HFMEA as a tool in the laboratories of two tertiary hospitals. Materials and methods: A HFMEA was carried out in each laboratory, by means of the creation of groups of experts with similar characteristics (doctors and nurses from PCC and laboratory, support staff, and laboratory technicians). The Risk Priority Number (RPN) was calculated. Results: Items with elevated RPN were presented in both centers. The highest RPN were in LAB1: "two request notes for a patient" and "the segregation of oncology urgent samples" (both with 384), while in LAB2 was "the lack of information in patients with oral glucose overload test" (RPN 576). Considering the different steps in the preanalytical phase, LAB1 paid attention in sampling, samples reception and the programming in the Laboratory Information System, while LAB2 paid attention in the request form, the appointment system, sampling procedures, transport and reception. Conclusion: The laboratories prioritized the problems differently. However, both centers offer solutions to these possible sources of error. We proposed improvement actions that can be resolved easily, with a low cost for the system, mainly to schedule a specific formative programme and a deep revision of the existing protocols. PMID- 30022889 TI - Using Sigma metrics to establish analytical product performance requirements and optimize analytical performance of an in vitro diagnostic assay using a theoretical total PSA assay as an example. AB - Introduction: Establishing analytical performance requirements for in vitro diagnostic (IVD) assays is a challenging process. Manufacturers try to optimize analytical performance by choosing amongst many combinations of different product performance characteristics. Sigma metrics and method decision charts can be helpful aids in choosing appropriate analytical performance requirements. The objective of this research was to demonstrate the use of Sigma metrics and method decision charts to help establish analytical performance requirements and to optimize analytical performance at medical decision concentrations for an IVD assay. Materials and methods: A range of possible Sigma metrics were determined using three sources for total allowable error (TEa) and hypothetical total PSA assay results. Method decision charts were created for each TEa source and used to identify the maximum precision and bias that the assay could have to maintain sigma level performance of at least 3. Results: To achieve a sigma performance level of at least 3 for a hypothetical total PSA assay, the maximum allowable coefficient of variation ranged from 5.0% to 11.2% depending on the TEa source. To achieve a sigma performance level of at least 6, the maximum allowable coefficient of variation ranged from 2.5% to 5.6% depending on the TEa source. Conclusions: Using Sigma metrics and method decision charts when establishing analytical performance requirements can help manufacturers choose product requirements that will optimize IVD assay product performance. PMID- 30022890 TI - Evaluating analytical quality in clinical biochemistry laboratory using Six Sigma. AB - Introduction: In recent years, Six Sigma metrics has became the hotspot in all trades and professions, which contributes a general procedure to explain the performance on sigma scale. Nowadays, many large companies, such as General Healthcare, Siemens, etc., have applied Six Sigma to clinical medicine and achieved satisfactory results. In this paper, we aim to evaluate the process performance of our laboratory by using Sigma metrics, thereby choosing the correct analytical quality control approach for each parameter. Materials and methods: This study was conducted in the clinical chemistry laboratory of Shandong Provincial Hospital. The five-months data of internal quality control were harvested for the parameters: amylase (AMY), lactate dehydrogenase (LD), potassium, total bilirubin (TBIL), triglyceride, aspartate aminotransferase (AST), uric acid, high density lipoprotein-cholesterol (HDL-C), alanine aminotransferase (ALT), urea, sodium, chlorine, magnesium, alkaline phosphatase (ALP), creatinine (CRE), total protein, creatine kinase (CK), total cholesterol, glucose (GLU), albumin (ALB). Sigma metrics were calculated using total allowable error, precision and percent bias for the above-mentioned parameters. Results: Sigma values of urea and sodium were below 3. Sigma values of total protein, CK, total cholesterol, GLU and ALB were in the range of 3 to 6. Sigma values of AMY, uric acid, HDL-C, TBIL, ALT, triglyceride, AST, ALP and CRE were more than 6. Conclusion: Amylase was the best performer with a Sigma metrics value of 19.93, while sodium had the least average sigma values of 2.23. Actions should be taken to improve method performance for these parameters with sigma below 3. PMID- 30022891 TI - What do we mean by school entry age? Conceptual ambiguity and its implications: the example of Indonesia. AB - The age pattern of school entry reflects a complex social and empirical reality that is inadequately captured by a single number. Recognising these complexities in national and international research and policy discourse raises important but neglected questions around the identification of vulnerable groups, the relative value of pre-primary and primary education, as well as the normative powers and responsibilities of governments vis-a-vis parents, and the international educational community vis-a-vis both. This is illustrated by the example of Indonesia, where the official age norm for primary school entry is widely disregarded in practice, with a majority of children starting school one or even two years earlier. Crucially, it is the compliant children entering at the statutory age who tend to be from more disadvantaged households, and enjoy no benefit in educational outcomes from their greater maturity. PMID- 30022892 TI - Calibration to American options: numerical investigation of the de Americanization method. AB - American options are the reference instruments for the model calibration of a large and important class of single stocks. For this task, a fast and accurate pricing algorithm is indispensable. The literature mainly discusses pricing methods for American options that are based on Monte Carlo, tree and partial differential equation methods. We present an alternative approach that has become popular under the name de-Americanization in the financial industry. The method is easy to implement and enjoys fast run-times (compared to a direct calibration to American options). Since it is based on ad hoc simplifications, however, theoretical results guaranteeing reliability are not available. To quantify the resulting methodological risk, we empirically test the performance of the de Americanization method for calibration. We classify the scenarios in which de Americanization performs very well. However, we also identify the cases where de Americanization oversimplifies and can result in large errors. PMID- 30022893 TI - A characterization of finite abelian groups via sets of lengths in transfer Krull monoids. AB - Let H be a transfer Krull monoid over a finite abelian group G (for example, rings of integers, holomorphy rings in algebraic function fields, and regular congruence monoids in these domains). Then each nonunit a?H can be written as a product of irreducible elements, say a=u1...uk , and the number of factors k is called the length of the factorization. The set L(a) of all possible factorization lengths is the set of lengths of a. It is classical that the system L(H) = {L(a)?a?H} of all sets of lengths depends only on the group G, and a standing conjecture states that conversely the system L(H) is characteristic for the group G. Let H' be a further transfer Krull monoid over a finite abelian group G' and suppose that L(H) = L(H' ). We prove that, if G?Cnr with r<=n-3 or (r>=n-1>=2 and n is a prime power), then G and G' are isomorphic. PMID- 30022894 TI - Transcriptional Changes in Cancer Cells Induced by Exposure to a Healing Method. AB - Energy healing, or healing with intent, is a complementary and alternative medicine therapy reported to be beneficial with a wide variety of conditions. We are developing a delivery technology for a method previously tested in mouse models with solid tumors (the Bengston method) independent of the presence of a healer. The goal of this study was to assess whether stored or recorded energy has an impact on breast cancer cells in vitro, using energy-charged cotton and electromagnetic recording of healers practicing the method. Expression of genes involved in cancer and inflammation pathways was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Treatment of cells using energy-charged cotton resulted in statistically significant changes <1.5-fold. In cells exposed to an electromagnetic recording, 37 genes of 167 tested showed a >1.5-fold change when compared to the control, and 68 genes showing statistically significant fold changes. Two genes, ATP citrate lyase (ACLY) and interleukin 1beta (IL-1beta), were consistently downregulated at 4 and 24 hours of exposure to the recording, respectively, in 3 independent experiments. Both ACLY and IL 1beta were also downregulated in cells exposed to a hands-on delivery of the method, suggesting these 2 genes as potential markers of the healing method. PMID- 30022895 TI - Treatment of ambulant patients by a general practitioner within a university hospital's emergency department - follow-up study of patients' behaviour shortly afterwards. AB - Aims: Hospital emergency departments (ED) face an increasing number of outpatient cases. Therefore, Hannover Medical School employs general practitioners for the treatment of walk-in patients within the ED. Up to now, little has been reported on how these patients behave after treatment in the ED. This study aims to assess these patients' behaviour after attending the ED, to find out how many patients consult a physician subsequently, and to explore patients' utilisation of health care in case of similar health problems. Methods: For this follow-up study, patients treated at Hannover Medical School's ED during daytime (Monday - Friday) by a general practitioner (GP) within a period of six weeks in 2016 were subsequently followed up by phone interviews 10-15 days after their consultation. Main topics in the semi-structured interview guide were patients' behaviour after leaving the ED, subsequent contacts with medical care, and how patients would behave in the future given similar symptoms. Data were transferred to a SPSS database, and descriptive data analyses were performed. Results: In total, 171 patients were screened for inclusion, and 91 participated in the study. About half (n=48; 53%) of them were male, and the mean age was 46.6 years. After visiting the GP in the ED, 62 patients (68%) went directly home. Another 14 (15%) took up regular activities (e.g. work, university), while eight patients visited their usual GP practice. Within 10-15 days, 52 patients (57%) had had an appointment with a physician. In most cases this was a GP (n=34; 37%); 12 patients visited a specialist and six patients visited both a GP and a specialist. Physician appointments took place within an average of 3.4 days after treatment in the ED. In case of similar complaints, 37 patients (41%) would visit the ED again rather than visiting the GP, whereas 36% would consult the GP first, and 11% would visit a specialist first. Conclusion: A noteworthy number of patients considered visiting the ED again with similar symptoms instead of visiting a GP in ambulatory care. Consequently our findings suggest that the ED itself plays a minor role in navigating patients' utilisation of medical treatment. PMID- 30022896 TI - A call to action to improve research quality in Saudi Arabia. PMID- 30022897 TI - Complete blood picture with skeletal and visceral changes in patients with thalassemia major. AB - Objective: The objective of this to find the prevalence of skeletal and visceral changes in thalassemics and its relationship with variation in blood components. Methodology: This is a cross-sectional study conducted in tertiary care hospital in Karachi among patients diagnosed with thalassemia major who require regular blood transfusions. Result: Among 200 individuals, 95 were females, whereas 105 were males. 96.5% of the study sample showed normocytic normochromic blood picture. Mean pre-transfusion hemoglobin (Hb) for 200 patients was 8.91 g/dl, while the mean post-transfusion Hb was 12.07 g/dl. Among all the variables, some strong predictors of change were age and HbA which were found associated with the development of cardiac change in transfusion-dependent thalassemia patients. Hepatomegaly was observed in 66.5% of the patients while normal liver span was observed in 33.5%. 6% of patients showed evidence of skeletal changes on X-ray. Splenomegaly was observed in 26.5%, while in 4.5% of the patients, spleen was not visualized due to splenectomy. Cardiac involvement was observed in 8% of the patients on T2*magnetic resonance imaging. Conclusion: Visceral changes particularly hepatomegaly is very common among transfusion-dependent thalassemia patients. Blood studies for Hb and ferritin levels help to detect these changes when conventional investigations are not possible. PMID- 30022898 TI - Evaluation of the extent and reasons for increased non-prescription antibiotics use in a University town, Nsukka Nigeria. AB - Objectives: The use of non-prescribed antibiotics has become a public health concern, and this behavior continues to thrive in many countries of the world including Nigeria. Evidence from previous studies suggests that increased antibiotic prescriptions and patients' past experiences are some of the factors contributing to the use of non-prescribed antibiotics. The present investigation was aimed at determining the factors driving this behavior and the extent of usage among people living in a sub-urban Nigerian community. Methods: A community based, cross-sectional study was conducted in Nsukka, South-East Nigeria using a semi-structured and self-administered questionnaire. An estimated sample size of approximately 400 respondents, with ages ranging from 18 to 60 years participated in the study. A number of males were 233 and 197 were females. Results: Demographics showed that the majority of respondents were well educated. The behavior appeared to be common regardless of gender, age, and educational level. Results showed that more than 86% of the respondents use non-prescribed antibiotics for treatment or prevention or both. A significant percentage uses it to treat cold and cough. The most frequently used antibiotics where the penicillins (58%) followed by quinolones (22%). Tetracycline, aminoglycosides, and cephalosporin represented 20.75%, 14.75%, and 11% usage, respectively. Conclusion: This study revealed a substantial use of over-the-counter antibiotics, with this behavior cutting across gender, age and levels of education. However, participants' knowledge and awareness of the hazards associated with this behavior were lacking. PMID- 30022899 TI - Work-related musculoskeletal disorders among faculty members of college of Applied Medical Sciences, Majmaah University, Saudi Arabia: A cross-sectional study. PMID- 30022900 TI - Effects of pre-operative individualized education on anxiety and pain severity in patients following open-heart surgery. AB - Objectives: Individualized education is important for preparing patients for the operation both physically and psychologically. This study investigated the effects of pre-operative individualized education for open-heart surgery patients on post-operative anxiety and pain severity. Methods: This quasi-experimental study was conducted in a university hospital between January and October 2014 and involved 109 patients. Data were collected through a form developed by the authors, the State-Trait Anxiety Inventory (STAI), and the visual analog scale (VAS). Patients underwent STAI 1 day before the operation to identify their sources of anxiety and educational needs, and then individualized education was given accordingly. 1 day after the operation, STAI was used to measure patients' state anxiety level, and VAS was used to measure their pain level. The effect of demographic variables on differences in anxiety and pain was investigated. Results: The average age of the participants was 59.62; 69.7% were male, 92.7% were married, 49.5% graduated from primary school, and the majority (71.6%) had coronary heart disease. The most common sources of anxiety reported the participants included lack of knowledge, being away from family, risk of death, and pain. An analysis of the participants' pre-operative mean scores for state anxiety displayed statistically significant differences (P < 0.05) according to age groups and gender. No significant difference was detected between mean pre- and post-operative state anxiety scores. There was a statistically significant relationship between mean pre- and post-operative state anxiety scores and mean pain scores. Conclusions: The individualized education is given to patients before surgery was found to have potential effects on their post-operative pain levels. PMID- 30022901 TI - Deep breathing exercise education receiving and performing status of patients undergoing abdominal surgery. AB - Objectives: This study aimed to explore deep breathing exercise education receiving and performing status of patients undergoing abdominal surgery and the relation between them. Methodology: This descriptive and cross-sectional study was conducted at the surgical ward of a university hospital with 130 patients between August 17 and October 15, 2015. A patient information form and a deep breathing exercise questionnaire were used for data collection. The patients were visited in their rooms after their surgeries and were asked to answer these questions through face-to-face interviews. Descriptive statistics, the Mann Whitney U test, Spearman's correlation, and Pearson's Chi-squared test were used for analyzing the data. Results: Of the patients, 56.2% of the patients received education about deep breathing exercises, and 51.5% of them performed it. A total of 60.3% of the patients received their education from nursing students. Furthermore, 54.8% of them received this education after surgery. A strong correlation was found between the status of receiving education and performing statuses of patients (P < 0.001). Conclusion: The study results indicated that the surgical patients did not receive adequate education about deep breathing exercises and most of them received this education after their surgeries. As a good finding, receiving education affected patients' exercise performing statuses positively. It is advised from this study that clinical nurses should receive in service education on the importance of pre-operative deep breathing exercise education to improve the exercise application rate among surgical patients. PMID- 30022902 TI - Pattern of refractive errors in Buraydah. How serious is the problem? AB - Objective: The incidence of refractive errors is on the rise globally. This study was done to assess the pattern and prevalence of various errors of refraction including myopia, hypermetropia, and astigmatism in Qassim region of Saudi Arabia. Methods: This is a cross-sectional study conducted in Buraydah city during January 2015. The participants consisted of 188 subjects of both sexes ranging from 2 to 75 years in a shopping mall picked randomly regardless of age and gender. The study subjects were picked up from a temporary eye clinic established for 2 days in a busy shopping mall in Qassim. The refraction was performed on those patients who were willing for the examination and gave consent to be inducted in the study. Those who had any sort of refractive disorders were assessed and classified by the kind of refractive error. Results: The incidence of refractive errors was found to be reasonably high among general population regardless of gender; however, increasing age was found to be associated with increasing incidence. We found myopia as the most common error of refraction found in 91 (48.40%) study subjects, while astigmatism and hypermetropia were other errors detected. Conclusions: Refractive errors are one of the main reasons of treatable visual impairment in youth. There is a need of standard vision testing in young population to diagnose any such problem at an early stage. PMID- 30022904 TI - Effect of sampling procedure on the quality control metrics of cytoscan HD array for studying cytogenetic aspects of colorectal cancer. AB - Objectives: The method of colorectal cancer (CRC) tissue sampling would affect its molecular profile and the downstream processing. In this study, we described the impact of CRC tissue sampling procedures on the quality control (QC) metrics of cytoscan HD array. Methods: We employed a high-resolution cytoscan HD microarray platform to investigate the chromosomal aberrations that could be associated with CRC. We compared the tissue extraction procedures and their impact on the QC parameters from the cytoscan HD array determined by chromosome analysis software (Suite3.1). Median of absolute values of all pairwise differences (MAPD), waviness-standard deviation (Waviness-SD), and single nucleotide polymorphism QC (SNPQC) were the QC parameters that were analyzed. Results: From 67 patients, we collected 843 colorectal tissues. Of these, 65.7% were obtained through endoscopic procedures, and the rest was after surgical resections. The mean transit time between tissue excision and preservation was 26 +/- 15.5 and 74.6 +/- 24.8 min, respectively. The tissues extracted from the surgical procedure showed mean MAPD of 0.28 +/- 0.06 compared to 0.24 +/- 0.06, for endoscopy, P = 0.005, degree of waviness-SD of 0.20 +/- 0.1 compared to 0.2 +/- 0.1, P = 0.64, and SNPQC of 9.6 +/- 4.2 compared to 11.1 +/- 4.6, P = 0.23. Conclusions: This report provides objective results that can help in tissue sampling intended to be used for DNA based molecular studies. Tissue collection protocol should be optimized to support microarray-analysis methods. Tissue extraction from endoscopic procedures had faster transit time and relatively better quality metrics outcome than surgical procedures. However, surgical procedures have less refusal rate, higher tissue quantity, and less negative results for malignancy. PMID- 30022903 TI - Awareness of cervical cancer among women in Malaysia. AB - Objectives: The purpose of this study is to evaluate and ascertain the current knowledge, perception, level of awareness, and attitudes toward cervical cancer (CC) among women in Malaysia. Methods: A cross-sectional study was conducted which involved 210 women aged between 21 and 60 years old at the public in Malaysia, a subsequent statistical analysis was performed by SPSS version 22. Results: In comparison with other studies, there is still lacking of awareness on CC and these induced informal cluelessness and poor attitudes toward it. In terms of risk factors, there are two factors with some degree of awareness among women in Malaysia, i.e., multiple sexual partners and sexually transmitted diseases. Women in Malaysia have less awareness on the causes and clinical manifestations of the disease (P < 0.05). They are aware that regular papanicolaou (Pap) smear would screen CC and surgery could be a treatment of choice. In addition, women in Malaysia also have moderate awareness about Pap smear as prevention to detect and prevent CC at the early stage. Conclusions: Women in Malaysia only has a good awareness about multiple sex partner and sexually transmitted disease as a risk factor for CC, they also have good knowledge on regular Pap smear as a tool to diagnose and surgery as a treatment. Future, further effort is required to promote awareness of women's perception and attitudes toward CC. PMID- 30022905 TI - An intervention significantly improve medical waste handling and management: A consequence of raising knowledge and practical skills of health care workers. AB - Objective: Health-care waste has not attended much attention in developing countries. Staff is involved in cleaning and collect waste may often be at greater risk due to their less education and training. The current intervention study was conducted to improve knowledge and practice skills for medical waste handlers in some selected hospitals of Alexandria, Egypt. Methods: An intervention study was conducted on medical waste handlers from some selected hospitals who accepted to participate in the study in the period of May 2015 to June 2016. A predesigned questionnaire was developed to measure knowledge, skills, and practice on medical waste management pre- and post-intervention. Results: Analysis of pre-intervention data revealed that 9.6%, 80.8%, and 9.6% of participants had high, moderate, and low knowledge levels, respectively. Whereas post-intervention, data revealed that 97.3%, 2.2%, and 0.5% of workers had high, moderate, and low knowledge levels, respectively. A significant increase in knowledge after the intervention was detected among all knowledge items except in four items which were related to the necessity to segregate medical waste, knowledge of color coding system for segregation, disposal of general waste in black bags and disposal of infectious waste in red bags. Regarding practice of waste handlers, 80% were in poor practice category pre-training and changed to 0.8% post-training; 1.1% were in good practice category and increased to 92.1% post-training. Conclusion: The current findings emphasize the role of educative skill-raising training in enhancing knowledge and practice skills of medical waste handlers. PMID- 30022906 TI - A retrospective cross-sectional study of antibiotics prescribing patterns in admitted patients at a tertiary care setting in the KSA. AB - Objective: Little is known about the pattern of antibiotics' prescribing for hospitalized adult patients in the Kingdom of Saudi Arabia. This study explored the prescribing practices of antibiotics in a large tertiary care setting serving diverse population. Methods: This retrospective cross-sectional study included 1.666 antibiotic prescriptions prescribed over a period of 3 months (January 2016 March 2016) in an adult inpatient department of King Saud Medical City (KSMC). Data were collected from pharmacy electronic database. The World Health Organization (WHO) prescribing indicators were also used. Results: Of the 13.414 prescriptions in pharmacy database, percentage share of antibiotic prescriptions was 12.41. The average number of drugs per encounter was 1.2. 61% of the prescriptions contained parenteral antibiotics. The percentage of drugs prescribed from essential drug list and by generic name was 100% in each indicator. The most frequently prescribed antibiotics were cefuroxime (19.44%), piperacillin/tazobactam (16.30%), and cefazolin (13.85%). Ciprofloxacin and ceftriaxone were prescribed without stated indications in 62 prescriptions. Restricted antibiotic such as meropenem was prescribed without a diagnosis in 52 prescriptions. Conclusion: This study gathered baseline data pertinent to the prudent use of antibiotics in KSMC. The diagnosis was not documented in more than one-third of the admission episodes. Majority of the antibiotics were broad spectrum. Three prescribing indicators shows deviation from the WHO's standard values while prescribing from essential drug list and by generic name was not a problem in this setting. There is a need to explore the impact of prescriptions lacked indication on patient's safety. PMID- 30022907 TI - Does health financing in Saudi Arabia need a national health accounts framework? AB - National health account (NHA) is considered as an effective tool to support policymakers in capturing financial flows within the health system and providing information required to develop effective health policies. Global experiences on NHAs have demonstrated a significant impact on health policy development for better health care. Many countries in the Arab region have already made efforts to institutionalize the NHA in their health systems. Based on extensive review of different reports, documents, and empirical studies in the field of NHA, the paper gives the concept and evolution of NHA and discusses the Saudi health system perspectives and the way forward for institutionalizing a NHA system. The findings indicate the significance of implementing the NHA framework for evidence based decision-making as well as an aid to the development of a robust and effective policy for the health sector to achieve Saudi Arabia's "Vision 2030." The paper also offers a plan of action to be followed to institutionalize a NHA system in the Ministry of Health. PMID- 30022909 TI - Giant-cell tumors of soft tissue in the head and neck: A review article. AB - Giant-cell tumor of soft tissue (GCT-ST) is a rare neoplasm that was first described in 1972. Due to its histological and immune-histochemical similarities with GCT of bones, GCT-ST is thought to be its counterpart. This review article aims to recognize the characteristics of this rare tumor along with a favorable way to diagnose and treat. We reviewed 12 cases of GCT-ST in the head and neck. This tumor involves both sexes at any age. Histopathology in many cases revealed the presence of mononuclear cells and spindle cells. Immunohistochemistry was positive in many cases for CD68. Complete excision was the most accepted management technique; however, few cases reported recurrence and metastasis. Post operative radiology is suggested to prevent local recurrence and in case of incomplete excision of the tumor. PMID- 30022910 TI - Giant epidermoid cyst of the occipital area with bone invasion: A case report. AB - Epidermoid cysts are slowly growing pseudotumors usually measuring <2 cm in diameter. Large epidermoid cysts invading bones have been rarely reported in the literature. They may be a source of diagnostic difficulties before pathological analyses, and radiological examinations are essential to determine the extension of the cyst and to guide the surgical technique. We report, herein, on a patient having an unusually large epidermoid cyst located in the left occipital area invading the occipital bone. PMID- 30022908 TI - The impact of immunosuppressant therapy on the recurrence of hepatitis C post liver transplantation. AB - The use of immunosuppressants to reduce the likelihood of acute graft rejections is a cornerstone in the post-transplantation management of recipients. However, these agents were always associated with increased risk of deleterious effects such as infections vulnerability and comorbidities. The objective of this review is to discuss the impact of different immunosuppression strategies used in liver transplant recipients (LTRs) on the recurrence of hepatitis C virus (HCV) infections after transplantation. Traditionally, corticosteroids were a mainstay in immunosuppressive regimens in LTRs. Several trials have suggested early tapering of corticosteroids or steroid-free immunosuppression protocols to minimize metabolic complications and other accompanied adverse events. However, there is no consistent agreement on the apparent benefit of steroid-avoidance regimens on HCV recurrence. At present, calcineurin inhibitors alone or in combination with other immunosuppressants are the standard regimen for immunosuppression in LTRs. Although the use of mycophenolate mofetil and sirolimus were sometimes associated with a significantly lower risk of liver injury as a result of HCV recurrence, they were associated with an increased risk of acute graft rejection compared to calcineurin inhibitors. Consequently, reducing the incidence of HCV recurrence in LTRs could be at the expense of other potential complications. The appropriate selection of adequate immunosuppression could diminish the associated increased risk of HCV recurrence after liver transplantation. However, further clinical studies are still pivotal to establish the appropriate/optimal immunosuppressive therapies for HCV-positive LTRs. PMID- 30022911 TI - Mixed Neuroendocrine Carcinoma and Squamous Cell Carcinoma of the Colon: Case Report and Literature Review. AB - Neuroendocrine carcinoma (NEC) of the colon is very rare, and squamous cell carcinoma (SCC) of colon cancer is rare. We recently treated a patient with both NEC and SCC that initially presented as multiple unresectable liver and lung metastases. A 68-year-old Japanese man was referred to our hospital because of diarrhea with descending colon cancer obstruction. He underwent a left colectomy. Based on immunohistochemistry results, we diagnosed mixed NEC and SCC, the primary lesion location of which was probably the lung in the final pathologic examination. He began systemic palliative chemotherapy with CDDP and CPT-11. After 3 months of treatment, shown the progressive disease, we started CDDP and VP-16. The patient was not eligible for additional chemotherapy after 2 months. PMID- 30022912 TI - Pancreatic Duct Stricture That Rapidly Progressed to Pancreatic Ductal Adenocarcinoma and Formed a Mass within 3 Months: A Case Report. AB - The natural growth rate of pancreatic carcinoma in situ with pancreatic duct stricture remains unclear. Herein, we present a case with pancreatic duct stricture that rapidly grew to form a mass lesion within 3 months. A 74-year-old woman was referred to us for the investigation of a pancreatic duct dilatation. Initial images did not reveal any clear mass lesions near the pancreatic duct stricture. Pancreatic juice cytology showed suspicious findings. Distal pancreatectomy was recommended; however, the patient refused to undergo surgical treatment at that time. Images taken 3 months later demonstrated a nodular pancreatic body mass which was identified as a moderately to poorly differentiated tubular adenocarcinoma. Previous reports have suggested that pancreatic carcinoma in situ and small pancreatic ductal adenocarcinoma require at least 1-2 years to progress to an advanced mass. This case suggests that pancreatic carcinoma in situ may grow rapidly and indicates a need for close follow-up in patients with pancreatic duct strictures, even if the pathological evidence is not confirmed. PMID- 30022913 TI - Phlegmonous Proctitis: A Rare Entity of the Presentation of Proctitis. AB - Phlegmonous proctitis is a rare condition; it was first described in 1940. We report the case of an elderly woman who presented with acute severe lower abdominal pain, tenesmus, and fever. A computed tomography of the whole abdomen revealed a long segment of circumferential wall thickening of the rectum and rectosigmoid colon. Colonoscopy was done subsequently and showed marked edematous and erythematous rectal mucosa. When rectal tissue biopsy was performed, a large amount of pus came out at the biopsy site, which led to the diagnosis of phlegmonous proctitis. PMID- 30022914 TI - Pemphigus Vulgaris in the Mouth and Esophageal Mucosa. AB - Pemphigus vulgaris (PV) is a chronic autoimmune mucocutaneous disease. In most cases, the initial manifestation occurs in the mouth as multiple ulcerations preceded by blisters that rupture and later spread to other mucous membranes and the skin. Esophageal impairment is rare. We report a case of PV with esophageal involvement in a 53-year-old woman who sought medical care, complaining of diffuse painful lesions in the oral cavity for approximately 1 month, with no improvement with nystatin. Upper digestive endoscopy (UDE) was performed with findings of vesiculobullous lesions in the proximal and middle esophagus, which were biopsied and for which histopathology confirmed PV in the esophageal mucosa. We draw attention to UDE as important for the diagnosis, and it should be indicated in patients with vesiculobullous lesions of the mouth, especially if there are esophageal complaints. PMID- 30022915 TI - Usefulness of Plain Computed Tomography with Swallowing of GastrografinTM for the Diagnosis of a Late-Onset Iatrogenic Diaphragmatic Hernia following Biopsy of a Diaphragmatic Tumor: Report of a Case. AB - Although diaphragmatic hernia (DH) may be congenital, posttraumatic, or iatrogenic, DHs after diaphragmatic surgery are rarely reported in the literature. This report describes the rare case of a 14-year-old girl complicated by iatrogenic DH following the biopsy of granulomatous lesions of the left diaphragm, when a mediastinal mixed germ cell tumor was extirpated. Plain computed tomography (CT) with swallowing of GastrografinTM was useful for the diagnosis of this disorder. The patient presented to our hospital with frequent epigastric pain and vomiting 11 months after the original surgery. Chest X-ray, a gastrointestinal contrast study, and plain CT with swallowing of GastrografinTM revealed the left DH with gastric content. At laparotomy, the diaphragmatic defect, 3 * 3 cm in diameter, was repaired using nonabsorbable sutures after hernia reduction. The patient showed a rapid recovery with complete resolution of symptoms. We should consider the presence of iatrogenic DH in patients who develop epigastralgia after procedures involving the diaphragm, even at 11 months after the original surgery. Furthermore, plain CT with swallowing of GastrografinTM is useful for the diagnosis of this disorder. PMID- 30022916 TI - Signet Ring Carcinoma of the Appendix Presenting as Crohn's Disease in a Young Male. AB - Primary signet ring cell carcinoma is a rare event in surgery. It looks like acute appendicitis and it is difficult to diagnose it on clinical grounds alone. The diagnosis is always confirmed by histopathology of a surgically removed appendix. A young man, 22 years old, presented with vomiting, diarrhea, and cramps in his abdomen without abdominal tenderness (mild abdominal discomfort in the right lower abdominal quadrant without signs of peritoneal irritation) during the previous month. The first endoscopic results showed only changes of mucosa that could be attributed to endoscopic and clinical representation of Crohn's disease. A few days after the initiation of the therapy with aminosalicylates and corticosteroids, the patient went into ileus and was transferred to the Department of Surgery, where he underwent an emergency right-sided hemicolectomy with resection of the transversal colon and forming of an ileostoma. The first pathohistological diagnosis was pseudomembranous colitis. Because the patient's condition was deteriorating, a revision of the pathohistological diagnosis was done. After careful revision and extensive sampling, a signet ring cell carcinoma arising in the appendix with infiltration of the ileocecal region was found. Immunohistochemically, tumor cells were positive for CDX-2 CK7, CK20, CK19, and carcinoembryonic antigen and negative for chromogranin A. Sixteen isolated lymph nodes were negative. Although the patient had a disease that was localized to the appendix and ileocecal region with no apparent distal metastasis, his clinical condition was worsening rapidly and he died after 2 months. This case shows the aggressive biological behavior of the appendix signet ring cell carcinoma. Scrupulous histopathological examination of the appendix is an obligatory procedure. Elimination of the signet ring cell carcinoma from other carcinoma subtypes is of special importance as it has an exceptionally poor prognosis and is generally diagnosed in its advanced stages. PMID- 30022917 TI - Hepatic Failure by Spontaneous Reactivation of Hepatitis B Virus without a Trigger Factor in a Patient with Anti-HBs. AB - A patient who has achieved resolution of acute hepatitis B and acquired anti-HBs would get protective immunity against hepatitis B virus (HBV). However, reactivation of HBV could happen if the patient was exposed to an immunocompromised state by using immunosuppressive drugs or chemotherapeutic agents. That is because cccDNA could reside within hepatocytes after recovery of acute hepatitis B. Therefore, guidelines for hepatitis B recommend the use of prophylactic antiviral agents such as entecavir or tenofovir in patients with anti-HBc IgG. The reactivation of hepatitis B without exposure to an immunocompromised state is very rare and only 1 case has been reported in the world to date. An 82-year-old male patient visited Dankook University Hospital because of high aspartate transaminase, alanine aminotransferase, and total bilirubin. He had shown HBsAg negative/anti-HBs positive when he had blood test examinations 1 year previously. However, the present blood test revealed HBsAg positive/anti-HBs negative and a high titer of HBV DNA (814,815 copies/mL). He had undergone vertebroplasty 5 years previously and had no other medical history. Other blood and radiological examinations failed to show other diseases that could affect host immunity. He started antiviral treatment with entecavir. However, he passed away because of deteriorated hepatic function and hepatorenal syndrome 20 days after admission. It is very rare that a patient with anti-HBs would develop hepatic failure and pass away without trigger factors. Here, we report the case with a literature review. PMID- 30022918 TI - Unusual Cause of Gastrointestinal Bleeding in a Patient with Turner Syndrome. AB - Turner syndrome is an exclusively female genetic disease caused by complete or partial absence of the second X chromosome. It is classically characterized by congenital lymphedema, short stature, and gonadal dysgenesis. In addition, the syndrome is associated with several other abnormalities. One of them is gastrointestinal bleeding, which is frequently associated with inflammatory bowel disease, but it can also be caused by vascular lesions such as hemangioma, vascular ectasia, and telangiectasia. We report the case of a patient with Turner syndrome with an episode of gastrointestinal bleeding, outlining our pathway for the investigation and treatment of this condition. PMID- 30022919 TI - Abdominoperineal Resection for Unexpected Distal Intramural Spreading of Rectal Cancer. AB - Introduction: In rectal cancer, distal intramural spread may sometimes occur, but a maximum extent of distal spread of > 6 cm is very rare. Case Presentation: A 65 year-old Japanese male with an advanced rectal cancer tumor with para-aortic lymph node metastasis was admitted. We performed a low anterior resection with lymphadenectomy, but the intraoperative frozen-section analysis of margins revealed malignant cell positivity; we, therefore, performed an abdominoperineal resection. Pathological findings showed that the maximum extent of distal spread was 6 cm. After 12 courses of FOLFOX4 as adjuvant chemotherapy, abdominal computed tomography revealed whole lymph node metastases, including Virchow's node. Though FOLFIRI + panitumumab was started, he was not eligible for additional chemotherapy after 10 cycles. Conclusion: An intraoperative frozen pathology examination was helpful for the additional resection, when unexpected distal spreading had occurred in rectal cancer. The evidence of a distal negative margin should not be underestimated. PMID- 30022921 TI - Spontaneous Resolution of IgG4-Related Hepatic Inflammatory Pseudotumor Mimicking Malignancy. AB - Hepatic inflammatory pseudotumor (IPT) is characterized by a well-circumscribed benign tumor mimicking or often mistaken for a malignant lesion. A 48-year-old male presented to the hospital with complaints of epigastric pain, with initial laboratory findings showing mildly elevated alkaline phosphatase (140 U/L) with normal AST, ALT, bilirubin, and lipase, a CD4 count of 384, and an HIV viral load of > 10 million copies. The total IgG level was elevated to 2,228 mg/dL (normal IgG4 level 114 mg/dL). Contrast-enhanced MRI of the abdomen showed heterogeneous mass-like infiltration in the right lobe of the liver measuring 9.6 cm. The liver mass was biopsied which showed dense collagenous fibrosis with abundant lymphoplasmacytic infiltrates with 18 IgG4-positive plasma cells per high-power field. The patient was not given any treatment for this IPT. For more than 1 year of follow-up triple-phase CT scan of the liver was repeated, which showed no liver mass. As radiological images of hepatic IPTs, including IgG4-related hepatic IPT, mimic liver malignancy, histological analysis of the biopsy remains the cornerstone for the diagnosis. Symptomatic patients with IgG4-related hepatic IPT have shown improvement with corticosteroid use; however, spontaneous resolution has also been reported like in the present case. PMID- 30022920 TI - A Small Bowel Ulcer due to Clopidogrel with Cytomegalovirus Enteritis Diagnosed by Capsule and Double-Balloon Endoscopy. AB - We report the first case of small bowel ulcers due to clopidogrel in a 74-year old man. He presented with diarrhea and melena after having been taking low-dose aspirin (LDA) and clopidogrel. There was no evidence of bleeding in the stomach, duodenum, or colon. Capsule endoscopy showed multiple ulcers and erosions in the small intestine. Double-balloon endoscopy revealed multiple ulcers throughout the ileum. Examination of the biopsy specimen showed cytomegalovirus infection. His LDA was discontinued and he was prescribed ganciclovir. However, the small bowel ulcers were aggravated. Therefore, clopidogrel was discontinued. The small bowel ulcers subsequently healed completely, forming scars. PMID- 30022922 TI - Gastroparesis in a Patient with Gastric AL Amyloidosis. AB - Systemic amyloidosis is a group of complex disorders characterized by the extracellular deposition of nonbranching fibrils in various tissues, ultimately leading to a variety of clinical presentations including isolated or multiorgan dysfunction. Amyloid involvement of the gastrointestinal tract is common depending on the subtype of this disease; light chain primary amyloidosis (AL) and secondary amyloidosis (AA) affect the gastrointestinal tract in unique ways due to differing pathophysiology. A case is reported of gastroparesis associated with AL amyloidosis diagnosed by esophagogastroduodenoscopy and study of gastric emptying, then subsequently confirmed by Congo red staining performed on endoscopic biopsies. PMID- 30022923 TI - A Patient with Ulcerative Colitis Complicated by Systemic Vein Thrombosis. AB - Crohn's disease and ulcerative colitis (UC) patients have an increased risk for thromboembolic complications, the most common of them are deep venous thrombosis and pulmonary embolism. Other locations and genetic mutations of coagulation factors are not so common in these patients. Here we present a case of a young woman with exacerbation of previously diagnosed mild UC complicated by multiple thrombotic incidents due to MTHFR gene mutation. PMID- 30022924 TI - Diaphragm Disease: NSAID-Induced Small Bowel Stricture. AB - The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is ubiquitous. However, it remains an oftentimes under-recognized risk factor for the development of strictures and small bowel obstruction. Herein we describe the case of a 63-year old female with a prolonged course of abdominal pain and occult anemia found to have a diaphragmatic stricture in the small bowel related to chronic NSAID use. PMID- 30022925 TI - Metabolic Pancreatitis: Pancreatic Steatosis, Hypertriglyceridemia, and Associated Chronic Pancreatitis in 3 Patients with Metabolic Syndrome. AB - Obesity, insulin resistance, and metabolic syndrome continue to increase in prevalence. Hypertriglyceridemia is commonly associated and represents a valuable marker of metabolic syndrome. An increase in subcutaneous fat deposition places patients at risk for visceral adipose deposition in sites such as the liver, heart, and pancreas. Pancreatic steatosis in the setting of metabolic syndrome is a rapidly emerging entity whose clinical spectrum remains to be defined. Hypertriglyceridemia is an accepted cause of acute pancreatitis but its role in chronic pancreatic injury remains to be explored. We present 3 patients with chronic abdominal pain and pancreatic steatosis in the setting of underlying metabolic syndrome with hypertriglyceridemia. These cases were identified in one endoscopic ultrasonographer's practice over a 12-month period. Each patient had documented hypertriglyceridemia but no history of acute hypertriglyceride-induced pancreatitis. A history of significant alcohol exposure was carefully excluded. Each patient underwent endoscopic ultrasonography (EUS) which proved critical in delineating the spectrum of chronic pancreatic injury. Each of our patients had EUS documentation of pancreatic steatosis and sufficient criteria to establish a diagnosis of chronic pancreatitis. Intraductal pancreatic calculi were identified in all 3 patients. Our series suggests that in the setting of metabolic syndrome, chronic hypertriglyceridemia and pancreatic steatosis may be associated with chronic pancreatitis. We hypothesize that hypertriglyceridemia may provide a pathogenic role in the development of chronic pancreatic microinjury. In addition, each of our patients had EUS-documented pancreatic ductal lithiasis. To our review, these are novel findings which have yet to be reported. We believe that with an enhanced awareness, it is likely that the entity of metabolic syndrome with features of pancreatic steatosis and hypertriglyceridemia with their associated manifestations of chronic pancreatitis, including ductal lithiasis, will be widely appreciated. PMID- 30022926 TI - Acute Small Bowel Perforation Caused by Obstruction of a Novel Tag-Less AgileTM Patency Capsule. AB - A 74-year-old man visited our hospital complaining of abdominal pain. An abdominal computed tomography scan showed multiple wall thickness of the small bowel. Capsule endoscopy was recommended for further evaluation, and patency capsule examination was performed. Eighteen hours after patency capsule ingestion, he experienced small bowel perforation with severe peritonitis caused by intestinal pressure rising because of the patency capsule trapped in his terminal ileum. An ileocolic resection was performed, including the removal of the sclerotic ileum as an emergency surgery. A pathological examination showed transmural inflammation and multiple ulcers with perforation of the small intestine, consistent with Crohn's disease. Here, we report a rare and valuable case of novel tag-less AgileTM patency capsule (Given Imaging Ltd., Yoqneam, Israel) retention leading to small bowel perforation. PMID- 30022927 TI - En Bloc Endoscopic Resection of Large Pedunculated Brunner's Gland Hamartoma: A Case Report. AB - Brunner's gland hamartoma (BGH) is an uncommon benign tumor arising from alkaline based mucin-secreting glands of the duodenum. These lesions are typically discovered incidentally during upper gastrointestinal endoscopy or radiological diagnostics, even though they can eventually lead (in the case of increasing size) to obstructive or hemorrhagic symptoms. We report the case of a 67-year-old Caucasian man with two episodes of melena and epigastric pain during the last month. Esophagogastroduodenoscopy revealed a large pedunculated and eroded polyp inside the antrum with a 2-cm-long stalk arising from the anterior wall of the duodenal bulb. Endoscopic ultrasonography showed a submucosal lesion with homogeneous hyperechoic parietal thickening and some central gaps. The muscularis was undamaged. No lymphadenopathy was observed. We performed an en bloc endoscopic resection of the polyp. The size of the whole piece was approximately 6 * 3 * 2 cm, pseudocapsulated and tough in consistency. In the case presented, the en bloc endoscopic removal was successful despite the size of the tumor. PMID- 30022928 TI - Effects of Cathode Location and the Size of Anode on Anodal Transcranial Direct Current Stimulation Over the Leg Motor Area in Healthy Humans. AB - Objective: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) involves passing low currents through the brain and is a promising tool for the modulation of cortical excitability. In this study, we investigated the effects of cathode location and the size of anode for anodal tDCS of the right-leg area of the motor cortex, which is challenging due to its depth and orientation in the inter-hemispheric fissure. Methods: We first computationally investigated the effects of cathode location and the size of the anode to find the best montage for specificity of stimulation effects for the targeted leg motor area using finite element analysis (FEA). We then compared the best electrode montage found from FEA with the conventional montage (contralateral supraorbital cathode) via neurophysiological testing of both, the targeted as well as the contralateral leg motor area. Results: The conventional anodal tDCS electrode montage for leg motor cortex stimulation using a large anode (5 cm * 7 cm, current strength 2 mA) affected the contralateral side more strongly in both the FEA and the neurophysiological testing when compared to other electrode montages. A small-anode (3.5 cm * 1 cm at 0.2 mA) with the same current density at the electrode surface and identical contralateral supraorbital cathode placement improved specificity. The best cathode location for the small anode in terms of specificity for anodal tDCS of the right-leg motor area was T7 (10-10 EEG system). Conclusion: A small-anode (3.5 cm * 1 cm) with the same current density at the electrode surface as a large-anode (5 cm * 7 cm) resulted in similar cortical excitability alterations of the targeted leg motor cortex respresentation. In relation to the other stimulation conditions, the small-anode montage with the cathode positioned at T7 resulted in the best specificity. PMID- 30022929 TI - Region-Specific Effects of Immunotherapy With Antibodies Targeting alpha synuclein in a Transgenic Model of Synucleinopathy. AB - Synucleinopathies represent a group of neurodegenerative disorders which are characterized by intracellular accumulation of aggregated alpha-synuclein. alpha synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting alpha-synuclein species represents an important candidate therapeutic approach. Our aim was to analyze the biological effects of passive immunization targeting alpha-synuclein and to identify the possible underlying mechanisms in a transgenic mouse model of oligodendroglial alpha-synucleinopathy. We used PLP-alpha-synuclein mice overexpressing human alpha-synuclein in oligodendrocytes. The animals received either antibodies that recognize alpha-synuclein or vehicle. Passive immunization mitigated alpha-synuclein pathology and resulted in reduction of total alpha synuclein in the hippocampus, reduction of intracellular accumulation of aggregated alpha-synuclein, particularly significant in the spinal cord. Lowering of the extracellular oligomeric alpha-synuclein was associated with reduction of the density of activated iba1-positive microglia profiles. However, a shift toward phagocytic microglia was seen after passive immunization of PLP-alpha synuclein mice. Lowering of intracellular alpha-synuclein was mediated by autophagy degradation triggered after passive immunization in PLP-alpha-synuclein mice. In summary, the study provides evidence for the biological efficacy of immunotherapy in a transgenic mouse model of oligodendroglial synucleinopathy. The different availability of the therapeutic antibodies and the variable load of alpha-synuclein pathology in selected brain regions resulted in differential effects of the immunotherapy that allowed us to propose a model of the underlying mechanisms of antibody-aided alpha-synuclein clearance. PMID- 30022930 TI - Functional Identification and Characterization of the Diuretic Hormone 31 (DH31) Signaling System in the Green Shore Crab, Carcinus maenas. AB - The functional characterization of crustacean neuropeptides and their cognate receptors has not kept pace with the recent advances in sequence determination and, therefore, our understanding of the physiological roles of neuropeptides in this important arthropod sub-phylum is rather limited. We identified a candidate receptor-ligand pairing for diuretic hormone 31 (DH31) in a neural transcriptome of the crab, Carcinus maenas. In insects, DH31 plays species -specific but central roles in many facets of physiology, including fluid secretion, myoactivity, and gut peristalsis but little is known concerning its functions in crustaceans. The C. maenas DH31 transcript codes for a 147 amino acid prepropeptide, and a single receptor transcript translates to a secretin-like (Class B1) G protein-coupled receptor (GPCR). We used an in vitro aequorin luminescence Ca2+ mobilization assay to demonstrate that this candidate DH31R is activated byCarcinus and insect DH31s in a dose-dependent manner (EC50 15-30 nM). Whole mount immunohistochemical and in situ hybridization localization revealed extensive DH31 expressing neurons throughout the central nervous system, most notably in the abdominal ganglion where large, unpaired cells give rise to medial nerves, which terminate in extensive DH31 immunopositive dendritic fields intimately associated with oesophageal musculature. This system constitutes a large and hitherto undescribed neurohemal area adjacent to key muscle groups associated with the gastric system. DH31 expressing neurons were also seen in the cardiac, commissural, oesophageal, and stomatogastric ganglia and intense labeling was seen in dendrites innervating fore- and hindgut musculature but not with limb muscles. These labeling patterns, together with measurement of DH31R mRNA in the heart and hindgut, prompted us test the effects of DH31 on semi isolated heart preparations. Cardiac superfusion with peptide evoked increased heart rates (10-100 nM). The neuroanatomical distribution of DH31 and its receptor transcripts, particularly that associated with gastric and cardiac musculature, coupled with the cardio- acceleratory effects of the peptide implicate this peptide in key myoactive roles, likely related to rhythmic coordination. PMID- 30022933 TI - Preferred Interaction Styles for Human-Robot Collaboration Vary Over Tasks With Different Action Types. AB - How do humans want to interact with collaborative robots? As robots become more common and useful not only in industry but also in the home, they will need to interact with humans to complete many varied tasks. Previous studies have demonstrated that autonomous robots are often more efficient and preferred over those that need to be commanded, or those that give instructions to humans. We believe that the types of actions that make up a task affect the preference of participants for different interaction styles. In this work, our goal is to explore tasks with different action types together with different interaction styles to find the specific situations in which different interaction styles are preferred. We have identified several classifications for table-top tasks and have developed a set of tasks that vary along two of these dimensions together with a set of different interaction styles that the robot can use to choose actions. We report on results from a series of human-robot interaction studies involving a PR2 completing table-top tasks with a human. The results suggest that people prefer robot-led interactions for tasks with a higher cognitive load and human-led interactions for joint actions. PMID- 30022931 TI - A Translational Framework of Educational Neuroscience in Learning Disorders. AB - Neuroimaging has undergone enormous progress during the last two and a half decades. The combination of neuroscientific methods and educational practice has become a focus of interdisciplinary research in order to answer more applied questions. In this realm, conditions that hamper learning success and have deleterious effects in the population - such as learning disorders (LD) - could especially profit from neuroimaging findings. At the moment, however, there is an ongoing debate about how far neuroscientific research can go to inform the practical work in educational settings. Here, we put forward a theoretical translational framework as a method of conducting neuroimaging and bridging it to education, with a main focus on dyscalculia and dyslexia. Our work seeks to represent a theoretical but mainly empirical guide on the benefits of neuroimaging, which can help people working with different aspects of LD, who need to act collaboratively to reach the full potential of neuroimaging. We provide possible ideas regarding how neuroimaging can inform LD at different levels within our multidirectional framework, i.e., mechanisms, diagnosis/prognosis, training/intervention, and community/education. In addition, we discuss methodological, conceptual, and structural limitations that need to be addressed by future research. PMID- 30022934 TI - Bullous Pemphigoid as an Adverse Reaction to Pembrolizumab: Two Case Reports. AB - Checkpoint inhibitors are novel and promising treatment options for different types of cancer. Programmed cell death 1 (PD-1) inhibitors, such as pembrolizumab, have been shown to significantly raise the survival rates of disseminated malignant melanoma (MM). Autoimmune adverse reactions are very common in checkpoint inhibitors. We present 2 cases of bullous pemphigoid, as adverse reactions to pembrolizumab-treated MM. PMID- 30022932 TI - Reasons, Years and Frequency of Yoga Practice: Effect on Emotion Response Reactivity. AB - Yoga practice, even in the short term, is supposed to enhance wellbeing and counteract psychopathology through modification of emotion reactivity. Yoga teaches that emotional responses may be less pronounced with longer and more frequent practice, and potentially when people perform yoga for mental rather than physical reasons. We tested 36 yoga practitioners of varying experience (between 6 months and 11 years of practice). We assessed participants' self reported emotional experience and peripheral physiological reactions (heart rate, skin conductance, respiration) when seeing positive and negative pictures. Results were analyzed as a function of the years of, frequency of, and reasons for yoga practice. We found a heart rate increase with the degree participants performed yoga for mental reasons. In addition, years of yoga practice were significantly associated with reduced abdominal respiratory rate when facing negative pictures, speaking in favor of reduced arousal with yoga experience. Finally, regarding frequency of practice, a higher frequency in the last month was linked to less negative and positive experiences as well as a reduced abdominal respiratory amplitude when viewing positive pictures. Altogether, these results demonstrate that intense short-term yoga practice might relate to a (i) decrease in the intensity of self-reported emotional experiences and (ii) deepened respiration. Short-term effects might be shaped by what participants expect as practice benefits. However, several years of practice might be needed to decrease respiratory arousal in the face of negative situations, which likely is a manifestation of an evolution in the emotion regulation process. PMID- 30022935 TI - A Case of Annular Elastolytic Giant Cell Granuloma Associated with Syphilis. AB - Annular elastolytic giant cell granuloma (AEGCG) is a rare granulomatous skin disease characterized by annular patches with slightly raised borders, hypopigmented and/or atrophic centers found mainly on sun-exposed skin. Histologically, it is characterized by phagocytosis of elastic fibers by multinucleated giant cells. The pathogenesis of the disease is unclear. We report a case of 55-year-old man with AEGCG in association with syphilis, whose condition improved when hydroxychloroquine sulfate and topical tacrolimus were administered over a 2-month period. PMID- 30022936 TI - Pseudolymphomatous Reaction to Red Tattoo Pigment. AB - Decorative tattooing is a procedure in which exogenous pigment and/or dye is introduced into the dermis with the aim of creating a permanent skin decoration. The increasing prevalence of tattooed individuals leads to more reported tattoo related complications. Pseudolymphomatous reaction is a benign reactive proliferation of lymphocytes that may uncommonly occur secondary to tattooing. We describe the clinical, histological, and molecular aspects of a pseudolymphomatous reaction to red tattoo pigment. PMID- 30022938 TI - Paraneoplastic Seronegative Pauci-Immune Glomerulonephritis Associated with Lung Adenocarcinoma Responds to Rituximab: A Case Report. AB - Anti-neutrophil cytoplasmic antibodies (ANCA) play an important role in the pathogenesis of pauci-immune renal vasculitis. However, in 10% of the cases, ANCA are absent. We present a case of a 64-year-old man with a chronic untreated hepatitis C virus infection and Middle Eastern thalassemia who was ANCA-negative when he was hospitalized due to acute kidney injury and accounts for an uncommon presentation of renal vasculitis. The patient had earlier reported to have undergone local lobectomy and adjuvant chemotherapy (carboplatin/pemetrexed) for lung adenocarcinoma a month prior. IL-6 has been reported to be involved in the pathophysiological cascade causing pauci-immune glomerulonephritis amongst non small cell lung cancer patients. Previous studies with subgroup analysis have demonstrated that ANCA negativity has been associated with more chronic glomerular lesions and less crescent formation, which tends to have a critical outcome in the renal system. However, our patient underwent kidney biopsy exhibiting active crescentic glomerulonephritis, pauci-immune type with 5 cellular crescents amongst 15 glomeruli. To our knowledge, this is the third reported case of ANCA-negative vasculitis with typical presentation on biopsy in non-small cell lung cancer patients. PMID- 30022937 TI - Widely Spread Unilateral Inflammatory Linear Verrucous Epidermal Nevus (ILVEN). AB - Inflammatory linear verrucous epidermal nevus (ILVEN) is an epidermal nevus that clinically and histologically mimics linear psoriasis. The pathogenesis of psoriasis has been widely investigated, with recent studies focusing especially on targeting proinflammatory cytokines such as IL-17A, TNFalpha, IL-23, and IL 12, while little is known about ILVEN. Since the treatment for ILVEN varies widely from the administration of topical ointment for psoriasis to invasive methods such as carbon dioxide gas laser, the differential diagnosis between ILVEN and psoriasis is necessary. In this report, we describe a case of widely spread unilateral ILVEN that clinically and histologically mimicked psoriasis vulgaris and could be diagnosed by immunohistochemical staining focused on the IL 36gamma/IL-17A axis. PMID- 30022939 TI - Pigmented Epithelioid Melanocytoma (Animal Types of Melanoma) on the Nose. AB - Pigmented epithelioid melanocytoma (PEM), also known as an animal-type melanoma, is a distinctive group of melanocytic tumors with a more favorable prognosis than conventional melanoma. Since tumor-associated macrophages (TAMs) extend in the premetastatic lymph nodes in several cancers, we hypothesized that the lower rate of lymph node metastasis in PEM might be correlated with the phenotypes of TAMs. Therefore, in this report, we further investigate the subpopulation of TAMs in PEM, revealing that the main population of TAMs in histiocytic lesion is CD163+CD206+PD-L1+ M2-polarized macrophages. In addition, since the PD-L1 expressing CD205+ dendritic cells are also detected in histiocytic lesions, the PD-L1-expressing TAMs and dendritic cells might suggest favorable prognostic factors in patients with PEM. PMID- 30022940 TI - Successful Treatment of a Large Superficial Bladder Cancer with Neoadjuvant Arterial Infusion Chemotherapy: A Case Report. AB - We present a case in which neoadjuvant arterial infusion chemotherapy was effective in treating a large superficial bladder cancer. A 50-year-old male was admitted to the Kanazawa Medical Center with the complaint of dizziness. The patient exhibited severe anemia, and his computer tomography showed a large bladder tumor. Cystoscopy revealed a large papillary tumor. Magnetic resonance imaging showed no muscle invasion and no metastasis. To avoid a prolonged operation time and excessive blood loss, we performed neoadjuvant arterial infusion chemotherapy for tumor volume reduction before transurethral resection of the bladder tumor (TUR-BT). The arterial infusion chemotherapy was performed twice, and the tumor size gradually reduced from 275 to 28 cm3. After neoadjuvant chemotherapy, TUR-BT was safely performed without blood transfusion. The tumor was staged as T1 with G1. This is the first report demonstrating that neoadjuvant arterial infusion chemotherapy is effective in treating large superficial bladder cancer and is a possible strategy for bladder preservation. PMID- 30022941 TI - An Enlarging Metastatic Calcified Liver Lesion of an Occult Melanoma. AB - Calcified liver lesions are caused by a wide variety of factors. The most common lesions are inflammatory liver lesions followed by benign and malignant neoplasms. Hemangioma, one of the most common benign hepatic neoplasm in adults, often contains calcifications, in up to 20% of cases secondary to fibrosis and thrombosis of blood vessels. These calcifications are typically large, coarse, and located in the center of the lesions. Liver metastases, the most common malignant lesions found in the noncirrhotic liver, may contain areas of calcification. Radiologists should be aware of morphologic imaging features of calcified liver lesions to help differentiate benign from malignant lesions. Liver biopsy should be offered when the diagnosis is doubtful. PMID- 30022942 TI - Long-Term Disease-Free Survival of a Patient with Oligometastatic Nasopharyngeal Carcinoma Treated with Radiotherapy Alone. AB - Distant metastases in nasopharyngeal carcinoma are fairly common. While the mainstay of treatment for metastatic nasopharyngeal carcinoma remains chemotherapy, it is now increasingly recognised that metastatic cases are a heterogenous group and can be stratified into oligometastatic cases versus those with widespread metastases, the former potentially benefiting more from local therapy. In this report, we describe a case of nasopharyngeal carcinoma with a solitary vertebral metastasis successfully treated with high-dose palliative radiotherapy alone, resulting in a long-term disease-free interval of more than 8 years at the time of writing. To our knowledge, this is the first report of a long-term survivor of metastatic nasopharyngeal carcinoma with oligometastatic bone disease who had received no chemotherapy. In view of this case, there may be potential for other patients with oligometastases from nasopharyngeal carcinoma to be treated solely with local therapy, thereby sparing them the toxicities of chemotherapy. PMID- 30022943 TI - Genomic Profiling Reveals Medullary Thyroid Cancer Misdiagnosed as Lung Cancer. AB - Mutations or other alterations in the RET gene have been implicated in a variety of malignancies - most commonly thyroid, but also chronic myelomonocytic leukemia, acute myeloid leukemia, and lung, breast, pancreatic, and colon cancers. Here we present a case of a gentlemen initially diagnosed with and treated for non-small cell lung adenocarcinoma. Genomic profiling of his tumor specimen revealed a RET point mutation with a known association with medullary thyroid cancer (MTC). Further pathological and molecular diagnostic evaluation confirmed a diagnosis of MTC, leading to a change in treatment from standard chemotherapy for non-small cell lung cancer to targeted therapy against RET and potential implications regarding inherited cancer risk for his offspring. The patient experienced a clinical response to treatment and several months of improved quality of life. This case illustrates the capacity of genomic profiling to uncover molecular drivers of disease and help ensure proper diagnosis and management of cancer. PMID- 30022944 TI - Refractory Septic Shock due to Underlying Immunocompromised Disease: A Case of Fatal Peripheral T-Cell Lymphoma Not Otherwise Specified in a Young Hispanic Woman. AB - Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is known as an unclassified group of non-Hodgkin lymphomas. PTCL-NOS is a subtype of peripheral T-cell lymphoma that accounts for 3% of all lymphomas in the United States. PTCL NOS commonly presents as a disseminated disease, B symptoms (fever, night sweats, and weight loss), generalized lymphadenopathy, bone marrow infiltration, and extranodal involvement. Other rare and possible manifestations include peripheral eosinophilia, pruritus, or hemophagocytic syndrome. This type of lymphoma is aggressive in nature and carries a high mortality rate. There is no established standard-of-care treatment protocol for PTCL-NOS, several chemotherapy drug combinations are frequently used as a frontline treatment with an overall 5-year survival rate of 25%. We present a case of a 35-year old Hispanic woman who initially presented with a chief complaint of bilateral lower extremity swelling due to hypoalbuminemia and new-onset hyperkeratotic skin of the palms and soles. PMID- 30022945 TI - Unruptured Saccular Aneurysm Arising from the Fenestrated A1 Segment of the Anterior Cerebral Artery: Report of 2 Cases. AB - Some cases of aneurysms originating from the fenestrated A1 segment of the anterior cerebral artery (ACA) have been reported, but the pitfalls of the surgical procedure have not been well determined. We herein report 2 cases of a saccular aneurysm arising from the fenestrated A1 segment. Case 1 was a 72-year old man incidentally diagnosed with an unruptured left ACA aneurysm on magnetic resonance imaging (MRI). Cerebral angiography revealed a saccular aneurysm arising from the proximal end of the left A1 segment. He underwent surgical clipping via the left pterional approach. The aneurysm originated from the proximal bifurcation of the fenestrated left A1 segment. A fenestrated ring clip was applied to obliterate the aneurysmal neck and one small fenestrated trunk, preserving the other fenestrated trunk and perforators around the fenestration. Case 2 was a 73-year-old man incidentally diagnosed with an unruptured ACA aneurysm on MRI. Cerebral angiography revealed a saccular aneurysm arising from the proximal end of the fenestrated left A1 segment. He underwent surgical clipping via the interhemispheric approach. The aneurysm originated from the proximal bifurcation of the fenestrated left A1 segment. A fenestrated ring clip was applied to obliterate the aneurysmal neck and one hypoplastic fenestrated trunk, preserving the other fenestrated trunk and perforators around the aneurysm. Detailed intraoperative evaluations of the anatomical structure and hemodynamics around the fenestration are important. The intentional obliteration of a fenestrated trunk and application of fenestrated clips need to be considered in difficult cases in order to expose the aneurysmal neck. PMID- 30022946 TI - Ocular Basidiobolomycosis: A Case Report. AB - Background: Ocular basidiobolomycosis is an unusual infection caused by fungus of the order Entomophthorales. This fungus has been previously reported as a common cause of skin, subcutaneous, and gastrointestinal tract infection. The fungus isolation and its typical characteristics are clues for diagnosis of this uncommon pathogen. Case Report: A 47-year-old male patient with nodular scleritis in the left eye after an eye injury from sawdust was treated as bacterial scleritis. The lesion improved with early surgical drainage and antibacterial therapy; then, he was discharged from the hospital. Thereafter, the patient was re-admitted due to progression of infectious scleritis with keratitis and orbital cellulitis. Surgical abscess drainage was performed again. The microbiological study demonstrated Basidiobolus ranarum. The patient was treated with topical ketoconazole, subconjunctival fluconazole injection, and oral itraconazole with partial response to the treatment. However, the patient eventually denied any further treatment and did not return for follow-up. Conclusions: B. ranarum is a rare pathogen of ocular infection in which a definite diagnosis requires isolation of the causative organism. Delay in diagnosis and appropriate treatment can lead to extension of the infection and poor outcomes. PMID- 30022947 TI - Acute Macular Neuroretinopathy following Oral Intake of Adrenergic Flu Treatments. AB - Purpose: The purpose of this study was to report a case series of patients with acute macular neureretinopathy in which patients concomitantly used ephedrine or pseudo-ephedrine. Methods: This is a retrospective case review. Results: Two patients with retinal findings consistent with acute macular neuroretinopathy are presented. Conclusion: Acute macular neuroretinopathy should be considered in any young patient with unexplained loss of vision and exposed to direct or indirect adrenergic stimulation. PMID- 30022948 TI - Retinal Endovascular Surgery with Tissue Plasminogen Activator Injection for Central Retinal Artery Occlusion. AB - Purpose: To report 2 cases of central retinal artery occlusion (CRAO) who underwent retinal endovascular surgery with injection of tissue plasminogen activator (tPA) into the retinal artery and showed a remarkable improvement in visual acuity and retinal circulation. Methods: Standard 25-G vitrectomy was performed under local anesthesia. Simultaneously, tPA (80,000 units/mL) solution was injected into the retinal artery of the optic disc for 2-3 min using a microneedle. Changes in visual acuity, fundus photography, optical coherence tomography (OCT), fluorescein angiography, and laser speckle flowgraphy (LSFG) results were examined. Results: Both cases could be treated within 12 h after the onset of CRAO. Case 1 was a 47-year-old woman. Her visual acuity improved from counting fingers before operation to 0.08 logMAR 1 month after the surgery. However, thinning of the retina at the macula was observed by OCT. Case 2 was a 70-year-old man. His visual acuity improved from counting fingers to 0.1 logMAR 2 months after the surgery. Both fluorescein angiography and LSFG showed improvement in retinal circulation after the surgery in case 2. Conclusions: Retinal endovascular surgery with injection of tPA into the retinal artery was feasible and may be a way to improve visual acuity and retinal circulation when performed in the acute phase of CRAO. PMID- 30022949 TI - Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac. AB - Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity, and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2,700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers. Data are available via ProteomeXchange with identifier PXD008918. PMID- 30022950 TI - Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators. AB - The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4. PMID- 30022951 TI - Visualizing Mitochondrial FoF1-ATP Synthase as the Target of the Immunomodulatory Drug Bz-423. AB - Targeting the mitochondrial enzyme FoF1-ATP synthase and modulating its catalytic activities with small molecules is a promising new approach for treatment of autoimmune diseases. The immunomodulatory compound Bz-423 is such a drug that binds to subunit OSCP of the mitochondrial FoF1-ATP synthase and induces apoptosis via increased reactive oxygen production in coupled, actively respiring mitochondria. Here, we review the experimental progress to reveal the binding of Bz-423 to the mitochondrial target and discuss how subunit rotation of FoF1-ATP synthase is affected by Bz-423. Briefly, we report how Forster resonance energy transfer can be employed to colocalize the enzyme and the fluorescently tagged Bz 423 within the mitochondria of living cells with nanometer resolution. PMID- 30022952 TI - Role of Vitamin C in Skin Diseases. AB - Vitamin C (ascorbic acid) plays an important role in maintaining skin health and can promote the differentiation of keratinocytes and decrease melanin synthesis, leading to antioxidant protection against UV-induced photodamage. Normal skin needs high concentrations of vitamin C, which plays many roles in the skin, including the formation of the skin barrier and collagen in the dermis, the ability to counteract skin oxidation, and the modulation of cell signal pathways of cell growth and differentiation. However, vitamin C deficiency can cause or aggravate the occurrence and development of some skin diseases, such as atopic dermatitis (AD) and porphyria cutanea tarda (PCT). Levels of vitamin C in plasma are decreased in AD, and vitamin C deficiency may be one of the factors that contributes to the pathogenesis of PCT. On the other hand, high doses of vitamin C have significantly reduced cancer cell viability, as well as invasiveness, and induced apoptosis in human malignant melanoma. In this review, we will summarize the effects of vitamin C on four skin diseases (porphyria cutanea tarda, atopic dermatitis, malignant melanoma, and herpes zoster and postherpetic neuralgia) and highlight the potential of vitamin C as a therapeutic strategy to treat these diseases, emphasizing the clinical application of vitamin C as an adjuvant for drugs or physical therapy in other skin diseases. PMID- 30022955 TI - Cortical Gray Matter Loss, Augmented Vulnerability to Speech-on-Speech Masking, and Delusion in People With Schizophrenia. AB - People with schizophrenia exhibit impairments in target-speech recognition (TSR) against multiple-talker-induced informational speech masking. Up to date, the underlying neural mechanisms and its relationships with psychotic symptoms remain largely unknown. This study aimed to investigate whether the schizophrenia associated TSR impairment contribute to certain psychotic symptoms by sharing underlying alternations in cortical gray-matter volume (GMV) with the psychotic symptoms. Participants with schizophrenia (N = 34) and their matched healthy controls (N = 29) were tested for TSR against a two-talker-speech masker. Psychotic symptoms of participants with schizophrenia were evaluated using the Positive and Negative Syndrome Scale. The regional GMV across various cortical regions was assessed using the voxel-based morphometry. The results of partial correlation and mediation analyses showed that in participants with schizophrenia, the TSR was negatively correlated with the delusion severity, but positively with the GMV in the bilateral superior/middle temporal cortex, bilateral insular, left medial orbital frontal gyrus, left Rolandic operculum, left mid-cingulate cortex, left posterior fusiform, and left cerebellum. Moreover, the association between GMV and delusion was based on the mediating role played by the TSR performance. Thus, in people with schizophrenia, both delusions and the augmented vulnerability of TSR to informational masking are associated with each other and share the underlying cortical GMV reduction, suggesting that the origin of delusion in schizophrenia may be related to disorganized or limited informational processing (e.g., the incapability of adequately filtering information from multiple sources at the perceptual level). The TSR impairment can be a potential marker for predicting delusion severity. PMID- 30022953 TI - Physiological Differences Between Low Versus High Skeletal Muscle Hypertrophic Responders to Resistance Exercise Training: Current Perspectives and Future Research Directions. AB - Numerous reports suggest there are low and high skeletal muscle hypertrophic responders following weeks to months of structured resistance exercise training (referred to as low and high responders herein). Specifically, divergent alterations in muscle fiber cross sectional area (fCSA), vastus lateralis thickness, and whole body lean tissue mass have been shown to occur in high versus low responders. Differential responses in ribosome biogenesis and subsequent protein synthetic rates during training seemingly explain some of this individual variation in humans, and mechanistic in vitro and rodent studies provide further evidence that ribosome biogenesis is critical for muscle hypertrophy. High responders may experience a greater increase in satellite cell proliferation during training versus low responders. This phenomenon could serve to maintain an adequate myonuclear domain size or assist in extracellular remodeling to support myofiber growth. High responders may also express a muscle microRNA profile during training that enhances insulin-like growth factor-1 (IGF 1) mRNA expression, although more studies are needed to better validate this mechanism. Higher intramuscular androgen receptor protein content has been reported in high versus low responders following training, and this mechanism may enhance the hypertrophic effects of testosterone during training. While high responders likely possess "good genetics," such evidence has been confined to single gene candidates which typically share marginal variance with hypertrophic outcomes following training (e.g., different myostatin and IGF-1 alleles). Limited evidence also suggests pre-training muscle fiber type composition and self-reported dietary habits (e.g., calorie and protein intake) do not differ between high versus low responders. Only a handful of studies have examined muscle biomarkers that are differentially expressed between low versus high responders. Thus, other molecular and physiological variables which could potentially affect the skeletal muscle hypertrophic response to resistance exercise training are also discussed including rDNA copy number, extracellular matrix and connective tissue properties, the inflammatory response to training, and mitochondrial as well as vascular characteristics. PMID- 30022954 TI - Transdiagnostic Tailored Internet- and Mobile-Based Guided Treatment for Major Depressive Disorder and Comorbid Anxiety: Study Protocol of a Randomized Controlled Trial. AB - : Introduction: Depression is highly prevalent and often accompanied by comorbid anxiety disorder. Internet-based interventions have shown to be one effective treatment modality; however, comorbidities are often not targeted. Transdiagnostic tailored internet-and mobile-based interventions (IMIs) might be promising to overcome such issues. Aim: This study aims to evaluate the efficacy, moderators, and cost-effectiveness of a transdiagnostic tailored internet- and mobile-based guided intervention for depression and comorbid anxiety in individuals with major depressive disorder (MDD). Method: Two-hundred participants with MDD will be randomly assigned to an 8-week guided self-help internet intervention (IC) or a 6-month wait-list control group (WLC). Participants of the IC will receive weekly content-focused feedback on module completion as well as monitored adherence reminders from an eCoach. The primary outcome is clinician-rated depression severity (QIDS-C) at post-assessment assessed by diagnostic raters blind to study condition. Secondary outcomes include, e.g., change in diagnostic status (MDD and anxiety disorders), remission and response rates, disorder symptom severity, health related quality of life, incongruence related to needs and values, and behavioral activation. Assessments will take place at baseline (T1), post-assessment (T2), 6-month follow-up (T3), and 12-month follow-up in the IC. Data will be analyzed on an intention-to-treat basis and per protocol. A large number of a priori defined moderators of treatment outcome will be assessed at baseline and tested in predicting treatment outcome. Cost-effectiveness will be evaluated from a societal perspective. Discussion: The present study will provide evidence on the efficacy, potential cost-effectiveness, and moderators of a transdiagnostic tailored guided internet- and mobile-based treatment protocol. TRIAL REGISTRATION: German Register of Clinical Studies DRKS00011690 (https://www.drks.de/drks_web/). PMID- 30022956 TI - Cannabis, a Significant Risk Factor for Violent Behavior in the Early Phase Psychosis. Two Patterns of Interaction of Factors Increase the Risk of Violent Behavior: Cannabis Use Disorder and Impulsivity; Cannabis Use Disorder, Lack of Insight and Treatment Adherence. AB - Background: Previous literature suggests that prevalence of cannabis use in the early phase of psychosis is high, and that early psychosis patients are at high risk for violent behavior. However, the link between cannabis use and violent behavior in early psychosis patients is unclear. We carried out a study on a sample of early psychosis patients, in order to explore the impact of cannabis use on the risk of violent behavior (VB), while taking into account (1) potential confounding factors and, (2) interactions with other dynamic risk factors of VB. Method: In a sample of 265 early psychosis patients, treated at the Treatment and Early Intervention in Psychosis Program (TIPP) in Lausanne, we used logistic regression models to explore the link between various dynamic risk factors of VB [positive symptoms, substance use disorder (drugs including cannabis, alcohol and others drugs), insight, impulsivity, affective instability, and treatment adherence], and VB occurring during treatment. In order to understand hierarchical effects attributable to the combinations of risk factors on VB we conducted a Classification and Regression Tree (CART). Results: Our results show that cannabis use disorder is a risk factor for VB. The associations among risk factors suggest the presence of two patient profiles with an increased rate of VB: the first is composed of patients with cannabis use disorder and impulsivity, and the second of patients combining cannabis use disorder, absence of insight and non-adherence to treatment. The results also show the moderating role of insight and adherence to treatment on the rate of VB in patients with cannabis use disorder. Conclusion: This study suggests that cannabis use disorder is a significant risk factor for VB amongst early psychosis patients, particularly when combined with either impulsivity, lack of insight and non-adherence to treatment. These results suggest that preventive strategies could be developed on the basis of such patient profiles. PMID- 30022957 TI - Psychological Profiling of Triathlon and Road Cycling Athletes. AB - Psychological characteristics of athletes play a key role in sport performance and may moderate and mediate the influence of technical, tactical, and physical abilities athletes show. Different authors have emphasized the special attention such psychological characteristics should receive considering the extent they can influence athletes' behavior either in training or in competition. This paper is aimed at describing the psychological profiles of two cycling sports: triathlon and road cycling. One hundred and twenty-nine male and female professional and amateur cycling athletes (35.74 years old average age +/-12.79; 14.94 average number of years practicing cycling +/-11.20) were assessed on different psychological characteristics. For that purpose, the Psychological Characteristics related to the Sport Performance (CPRD) Questionnaire and the Psychological Skills Inventory for Sports (PSIS) was used. Results showed significant differences among triathlon and road cyclists (Stress control = t116 =-3.711, p = 0.000, d = 0.48 ; Influence of Performance Evaluation = t115 =-3 115, p = 0.002, d = 0.49; Motivation = t124 =-5.520, p = 0.000, d = 0.82; Mental Skills = t119 =-4.985, p = 0.000, d = 1.02). There were no significant differences between men and women though there were differences among pros and amateur athletes. Triathlon professional, compared to amateurs, showed higher scores in all the psychological dimensions assessed (Stress control = t85 = 3.005, p = 0.003, d = 1.07; Influence of Performance Evaluation = t83 = 2.858, p = 0.005, 0.77; Motivation = t91 = 2.721, p = 0.008, d = 0.26; Mental Skills = t87 = 2.556, p = 0.012, d = 0.77). The results of this descriptive study contribute to establishing a model of optimal psychological profiling applied to the different cycling groups that can be used by sport psychologist, trainers, and coaches in order to promote peak performance of these athletes. PMID- 30022958 TI - Why the Conjunction Effect Is Rarely a Fallacy: How Learning Influences Uncertainty and the Conjunction Rule. AB - In this article we explore the relationship between learning and the conjunction fallacy. The interpretation of the conjunction effect as a fallacy assumes that all observers share the same knowledge, and that nobody has access to privileged information. Such situations are actually quite rare in everyday life. Building on an existing model of surprise, we prove formally that in the more typical scenarios, where observers are alert to the possibility of learning from event outcomes, the conjunction rule does not apply. Scenarios which have been engineered to produce the so-called conjunction "fallacy" (e.g., Tverksy and Kahneman, 1983) often imply subjective uncertainty and hence the possibility of learning. In Experiment 1 we demonstrate that when these scenarios are rephrased so as to eliminate subjective uncertainty, the effect is mitigated. In Experiment 2 we demonstrate that when subjective uncertainty is reduced by allowing participants to learn about the mechanism behind a conjunction-inducing scenario, the conjunction effect again diminishes. We conclude that the conjunction effect arises due to the unnaturalness of interpreting verbal descriptions in terms of a situation in which all observers share the same knowledge. Instead, when people hear descriptions of real world situations, they are likely to assume that learning is possible, and that subjective rather than objective uncertainty applies. PMID- 30022959 TI - Counterfinality: On the Increased Perceived Instrumentality of Means to a Goal. AB - The present research investigates the counterfinality effect, whereby the more a means is perceived as detrimental to an alternative goal, the more it is perceived as instrumental to its focal goal. The results from five studies supported this hypothesis. Study 1 demonstrated the counterfinality effect in an applied context: The more pain people experienced when getting tattooed, the more they perceived getting tattooed as instrumental to attaining their idiosyncratic goals (being unique, showing off, etc.). Study 2 experimentally replicated and extended the results of Study 1: A counterfinal (vs. non-counterfinal) consumer product was perceived as more detrimental, which in turn predicted the perceived effectiveness of the product. In Studies 3 and 5, we showed that increased perceived instrumentality due to counterfinality led to more positive attitudes toward a means. Finally, Studies 4 and 5 indicated that simultaneous commitment to both the focal and the alternative goal moderated the counterfinality effect. We discuss how various psychological phenomena can be subsumed under the general framework of counterfinality, which has broad practical implications extending to consumer behavior, health psychology, and terrorism. PMID- 30022960 TI - Parental Warmth and Hostility and Child Executive Function Problems: A Longitudinal Study of Chinese Families. AB - This study examined the longitudinal associations of maternal and paternal warmth and hostility with child executive function problems. Data were collected for two consecutive years from 333 kindergarten children who resided in Hong Kong, China, as well as their mothers, fathers, and class teachers. At Time 1, the average age of children was 57.73 months, and 56% of them were girls. At Time 1, mothers and fathers rated their own parenting practices with their children. At Times 1 and 2, class teachers rated children's problems in three aspects of executive functions, including updating/working memory, inhibition, and shifting/cognitive flexibility. As control variables, at Time 1, parents provided information on child and family demographic factors, and children completed verbal ability tasks. Multilevel modeling revealed that controlling for child and family demographic factors, child verbal abilities, and paternal parenting practices, maternal hostility, but not maternal warmth, was linked to increases in child inhibition and shifting/cognitive flexibility problems. Moreover, paternal hostility, but not paternal warmth, was linked to increases in updating/working memory problems. Theoretically, this study highlighted the importance of considering the contributions of both mothers and fathers, and differentiating between positive and negative aspects of parenting, when examining the development of child executive functions. Practically, this study pointed to the utility of targeting maternal and paternal hostility in family intervention and community education in order to reduce child executive function problems. PMID- 30022961 TI - Anorexia Nervosa, Anxiety, and the Clinical Implications of Rapid Refeeding. AB - The current study aimed to examine the temporal relationship between anxiety symptoms and weight gain for adolescents with anorexia nervosa over the course of an inpatient admission targeting weight restoration through rapid refeeding. Participants were 31 females presenting to a specialist inpatient unit. Psychometric assessments using standardized procedures were conducted to assess co-morbid anxiety diagnoses, and eating disorder symptom severity at admission and discharge. Study protocols were completed on a weekly basis over the course of their admission and were compared with weekly BMI change. Multiple mixed effects linear models with random intercepts were used to assess change in weight status and psychological variables. Results indicated a reduction in anxiety over the course of hospitalization; however, there was no evidence to support a relationship between anxiety change and weight restoration. The clinical implications of these results are discussed and directions for future research recommended. PMID- 30022962 TI - Precious Property or Magnificent Money? How Money Salience but Not Temperature Priming Affects First-Offer Anchors in Economic Transactions. AB - The present study aims for a better understanding of how individuals' behavior in monetary price negotiations differs from their behavior in bartering situations. Two contrasting hypotheses were derived from endowment theory and current negotiation research to examine whether negotiators are more susceptible to anchoring in price negotiations versus in bartering transactions. In addition, past research found that cues of coldness enhance cognitive control and reduce anchoring effects. We attempted to replicate these coldness findings for price anchors in a distributive negotiations scenario and to illuminate the potential interplay of coldness priming with a price versus bartering manipulation. Participants (N = 219) were recruited for a 2 * 2 between-subjects negotiation experiment manipulating (1) monetary focus and (2) temperature priming. Our data show a higher anchoring susceptibility in price negotiations than in bartering transactions. Despite a successful priming manipulation check, coldness priming did not affect participants' anchoring susceptibility (nor interact with the price/bartering manipulation). Our findings improve our theoretical understanding of how the focus on negotiation resources frames economic transactions as either unidirectional or bidirectional, and how this focus shapes parties' susceptibility to the anchoring bias and negotiation behavior. Implications for theory and practice are discussed. PMID- 30022963 TI - Effects of Directed Attention on Subsequent Processing of Emotions: Increased Attention to Unpleasant Pictures Occurs in the Late Positive Potential. AB - Directed attention is a fundamental mental resource for voluntarily managing the focus and direction of cognitive resources. The present study investigated how processing of unpleasant and neutral images is affected by emotion and previous directed attention. The results showed that there was enhanced early posterior negativity, anterior N2, and parietal late positive potential (LPP) in response to unpleasant pictures compared to neutral pictures. Furthermore, attention history (i.e., whether stimuli were previously attended to) modulated the amplitudes of the anterior N2 and parietal LPP. Most notably, an interaction between attention history and emotion was found in the LPP: pictures with an 'attended history' evoked larger LPP amplitudes than pictures with an 'unattended history,' but this effect was only significant for unpleasant pictures (not for neutral pictures). These results suggest that directed attention to affective pictures facilitates subsequent neural processing of these pictures, and that this effect was amplified by unpleasant emotions experienced in the LPP. The current findings provide further empirical evidence of a two-stage model of emotion-attention interaction. PMID- 30022964 TI - Do Implicit Motives Influence Perceived Chronic Stress and Vital Exhaustion? AB - Vital exhaustion (VE) results from the experience of chronic stress. However, research on stress types and their relation to VE is rare. Moreover, the role of implicit motives in these processes has not yet been investigated. Analysis included 101 vitally exhausted men aged 40-65 years. Participants provided self report data on their experience of chronic stress and social support. Subtypes of work-related and social stress were positively associated with VE. Implicit affiliation and achievement motives were linked to social support and chronic stress, and indirectly to VE. Moreover, they moderated the relationship between stress and exhaustion. In conclusion, implicit motives are key factors in the stress process: They are involved in an individual's experience of stress and stress-related consequences for mental health. PMID- 30022965 TI - General and Life-Domain Procrastination in Highly Educated Adults in Israel. AB - Procrastination is usually perceived as a general behavioral tendency, and was studied mostly in college students in academic settings. Recently there is a growing body of literature to support the study of procrastination in older adults and in different life-domains. Based on these advances in the literature, the present study examined procrastination in 430 highly educated adults in Israel. Findings showed that respondents reported significantly higher procrastination in maintaining health behaviors and spending leisure time rather in other life-domains. Forty percent of participants reported high procrastination in health behaviors, while only 9.5% reported this level of procrastination in parenting and 1% in the general tendency to procrastinate. Further findings suggested that 25% of respondents reported high procrastination in four or more life-domains, and 40%-in one to three life-domains. The general tendency to procrastinate was moderately associated with procrastination in finance, education, and career life-domains and weekly with other life-domains. Fourteen percent of participants reported that procrastination influenced their life the most in health behaviors, 12% in career and education and 11% in romance and family life. These initial findings contribute to the overall perspective of life-domain specificity of procrastination in adults, and emphasize the importance to further study and develop a life-span perspective. PMID- 30022966 TI - The Effect of Environmental Enrichment on Glutathione-Mediated Xenobiotic Metabolism and Antioxidation in Normal Adult Mice. AB - Olfactory bulb (OB) plays an important role in protecting against harmful substances via the secretion of antioxidant and detoxifying enzymes. Environmental enrichment (EE) is a common rehabilitation method and known to have beneficial effects in the central nervous system. However, the effects of EE in the OB still remain unclear. At 6 weeks of age, CD-1(r) (ICR) mice were assigned to standard cages or EE cages. After 2 months, we performed proteomic analysis. Forty-four up-regulated proteins were identified in EE mice compared to the control mice. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes Pathway demonstrated that the upregulated proteins were mainly involved in metabolic pathways against xenobiotics. Among those upregulated proteins, 9 proteins, which participate in phase I or II of the xenobiotic metabolizing process and are known to be responsible for ROS detoxification, were validated by qRT-PCR. To explore the effect of ROS detoxification mediated by EE, glutathione activity was measured by an ELISA assay. The ratio of reduced glutathione to oxidized glutathione was significantly increased in EE mice. Based on a linear regression analysis, GSTM2 and UGT2A1 were found to be the most influential genes in ROS detoxification. For further analysis of neuroprotection, the level of iNOS and the ratio of Bax to Bcl-2 were significantly decreased in EE mice. While TUNEL+ cells were significantly decreased, Ki67+ cells were significantly increased in EE mice, implicating that EE creates an optimal state for xenobiotic metabolism and antioxidant activity. Taken together, our results suggested that EE protects olfactory layers via the upregulation of glutathione-related antioxidant and xenobiotic metabolizing enzymes, eventually lowering ROS-mediated inflammation and apoptosis and increasing neurogenesis. This study may provide an opportunity for a better understanding of the beneficial effects of EE in the OB. PMID- 30022967 TI - Cerebrospinal Fluid Biomarkers Are Associated With Glial Fibrillary Acidic Protein and alphaII-spectrin Breakdown Products in Brain Tissues Following Penetrating Ballistic-Like Brain Injury in Rats. AB - Treatments to improve outcomes following severe traumatic brain injury (TBI) are limited but may benefit from understanding subacute-chronic brain protein profiles and identifying biomarkers suitable for use in this time. Acute alterations in the well-known TBI biomarkers glial fibrillary acidic protein (GFAP), alphaII-spectrin, and their breakdown products (BDPs) have been well established, but little is known about the subacute-chronic post-injury profiles of these biomarkers. Thus, the current study was designed to determine the extended profile of these TBI-specific biomarkers both in brain tissue and cerebral spinal fluid (CSF). Protein abundance was evaluated in brain tissue samples taken from regions of interest and in CSF at 24 h, 3 days, 7 days, 1 month, and 3 months following severe TBI in rats. Results showed increased full length GFAP (GFAP-FL) and GFAP-BDPs starting at 24 h that remained significantly elevated in most brain regions out to 3 months post-injury. However, in CSF, neither GFAP-FL nor GFAP-BDPs were elevated as a consequence of injury. Regional specific reduction in alphaII-spectrin was evident in brain tissue samples from 24 h through 3 months. In contrast, SBDP-145/150 was robustly elevated in most brain regions and in CSF from 24 h through 7 days. Correlation analyses revealed numerous significant relationships between proteins in CSF and brain tissue or neurological deficits. This work indicates that TBI results in chronic changes in brain protein levels of well-known TBI biomarkers GFAP, alphaII-spectrin, and their BDPs and that SBDP-145/150 may have utility as an acute-chronic biomarker. PMID- 30022968 TI - Evolution of Traumatic Parenchymal Intracranial Hematomas (ICHs): Comparison of Hematoma and Edema Components. AB - This study seeks to quantitatively assess evolution of traumatic ICHs over the first 24 h and investigate its relationship with functional outcome. Early expansion of traumatic intracranial hematoma (ICH) is common, but previous studies have focused on the high density (blood) component. Hemostatic therapies may increase the risk of peri-hematoma infarction and associated increased cytotoxic edema. Assessing the magnitude and evolution of ICH and edema represented by high and low density components on computerized tomography (CT) may be informative for designing therapies targeted at traumatic ICH. CT scans from participants in the COBRIT (Citicoline Brain Injury Trial) study were analyzed using MIPAV software. CT scans from patients with non-surgical intraparenchymal ICHs at presentation and approximately 24 h later (+/-12 h) were selected. Regions of high density and low density were quantitatively measured. The relationship between volumes of high and low density were compared to several outcome measures, including Glasgow Outcome Score-Extended (GOSE) and Disability Rating Score (DRS). Paired scans from 84 patients were analyzed. The median time between the first and second scan was 22.79 h (25%ile 20.11 h; 75%ile 27.49 h). Over this time frame, hematoma and edema volumes increased >50% in 34 (40%) and 46 (55%) respectively. The correlation between the two components was low (r = 0.39, p = 0.002). There was a weak correlation between change in edema volume and GOSE at 6 months (r = 0.268, p = 0.037), change in edema volume and DRS at 3 and 6 months (r = -0.248, p = 0.037 and r = 0.358, p = 0.005, respectively), change in edema volume and COWA at 6 months (r = 0.272, p = 0.049), and between final edema volume and COWA at 6 months (r = 0.302, p = 0.028). To conclude, both high density and low density components of traumatic ICHs expand significantly in the first 2 days after TBI. In our study, there does not appear to be a relationship between hematoma volume or hematoma expansion and functional outcome, while there is a weak relationship between edema expansion and functional outcome. PMID- 30022969 TI - Index Finger Pointing (Likely a Subtle Form of Hand Dystonia): Prevalence Across Movement Disorders. AB - Objective: To investigate the prevalence of index finger pointing (IFP) while walking, which is likely a subtle form of hand dystonia, in cranio-cervical focal dystonia syndromes, Parkinson's disease (PD), essential tremor (ET), and controls. Methods: We recruited patients with an established diagnosis of PD, dystonia, or ET and healthy controls. All participants were videotaped while walking. Videotapes were evaluated by the authors, blinded to diagnosis, to assess the presence or absence of IFP. Results: Two-hundred-fifty participants included 50 dystonia, 50 PD, 80 ET and 70 controls. IFP was present in 29/250 (11.6%) participants: 10 dystonia (20.0%), 8 PD (16.0%), 8 ET (10.0%), and 3 controls (3.8%) (p = 0.03). There was a significant evidence of a trend in the odds of having this sign among disorders with higher risk of dystonic features (dystonia>PD>ET>control; test for trend = 0.004). Among the 180 patients (dystonia, PD, and ET, i.e., excluding the 70 controls), IFP was present in 26 (14.4% prevalence). Conclusion: IFP during gait, likely a subtle form of hand dystonia, was observed in 14.4% of movement disorder patients. The highest prevalence was in dystonia, the second highest in a disease that is often accompanied by dystonia (PD), a lower prevalence among individuals with a disease that is rarely accompanied by dystonia (ET), and the lowest in controls. PMID- 30022971 TI - GlnR Activation Induces Peroxide Resistance in Mycobacterial Biofilms. AB - Mycobacteria spontaneously form surface-associated multicellular communities, called biofilms, which display resistance to a wide range of exogenous stresses. A causal relationship between biofilm formation and emergence of stress resistance is not known. Here, we report that activation of a nitrogen starvation response regulator, GlnR, during the development of Mycobacterium smegmatis biofilms leads to peroxide resistance. The resistance arises from induction of a GlnR-dependent peroxide resistance (gpr) gene cluster comprising of 8 ORFs (MSMEG_0565-0572). Expression of gpr increases the NADPH to NADP ratio, suggesting that a reduced cytosolic environment of nitrogen-starved cells in biofilms contributes to peroxide resistance. Increased NADPH levels from gpr activity likely support the activity of enzymes involved in nitrogen assimilation, as suggested by a higher threshold of nitrogen supplement required by a gpr mutant to form biofilms. Together, our study uniquely interlinks a nutrient sensing mechanism with emergence of stress resistance during mycobacterial biofilm development. The gpr gene cluster is conserved in several mycobacteria that can cause nosocomial infections, offering a possible explanation for their resistance to peroxide-based sterilization of medical equipment. PMID- 30022970 TI - Decontamination of Minimally-Processed Fresh Lettuce Using Reuterin Produced by Lactobacillus reuteri. AB - Over the last years the demand for pre-washed, fresh-cut, and minimally-processed (MP) produce has increased. MP fresh vegetable are rapidly spoiled, whereas there is consumers' concern about chemical disinfection treatments such as with chlorine. A promising antimicrobial is reuterin, a broad-spectrum-antimicrobial compound produced by food-grade Lactobacillus reuteri from glycerol. In aqueous solution, reuterin is a dynamic system consisting of 3-hydroxypropionaldehyde (3 HPA), its hydrate, its dimer as well as acrolein, which was recently identified as the main antimicrobial component of the system. Here, we tested the use of reuterin containing similar 3-HPA levels but different acrolein concentrations for decontaminating and preserving fresh-cut lettuce. Crude reuterin (CR) was produced by biotransformation of 600 mM glycerol using L. reuteri DSM 20016T. CR preparations were further incubated for 16 h at 50 degrees C to produce enhanced reuterin (ER) with raised concentration of acrolein. Fresh-cut iceberg lettuce (Lactuca sativa) was washed using CR (1.5-1.9 mM acrolein) and ER (7.2-21.9 mM acrolein) solutions at 4 degrees C, or sodium hypochloride (250 mg/L) and tap water, and compared with unwashed lettuce. Washed lettuce samples were packed under modified atmosphere (2% O2, 5% CO2, and 93% N2) and stored for 13 days at 4 degrees C. Application of ER containing 12.1, 20.9, or 21.9 mM acrolein reduced the initial viable plate counts of Enterobacteriaceae (by 2.1-2.8 log CFU/g), and yeasts and molds (by 1.3-2.0 log CFU/g) when compared with unwashed samples. In contrast, reuterin solutions containing 7.2 mM acrolein, sodium hypochlorite and tap water only showed very limited and transient, or no effects on the cell loads of lettuce after washing and during storage. Visual assessment of leaves washed with ER showed acrolein concentration-dependent discoloration noticeable already after 3 days of storage for the highest acrolein concentrations. Discoloration became severe for all ER treatments after 7 days, while the other treatments preserved the aspect of washed lettuce. Our data show the predominant role of acrolein as the main antimicrobial component of the reuterin system for food biopreservation. Reuterin preparations with enhanced acrolein concentration of 12.1 mM and higher were effective to reduce plate counts of Enterobacteriaceae and yeasts and molds washed lettuce until day 7 but induced pronounced discoloration of lettuce. PMID- 30022972 TI - Comparative Genomic Analysis of 130 Bacteriophages Infecting Bacteria in the Genus Pseudomonas. AB - Bacteria of the genus Pseudomonas are genetically diverse and ubiquitous in the environment. Like other bacteria, those of the genus Pseudomonas are susceptible to bacteriophages which can significantly affect their host in many ways, ranging from cell lysis to major changes in morphology and virulence. Insights into phage genomes, evolution, and functional relationships with their hosts have the potential to contribute to a broader understanding of Pseudomonas biology, and the development of novel phage therapy strategies. Here we provide a broad-based comparative and evolutionary analysis of 130 complete Pseudomonas phage genome sequences available in online databases. We discovered extensive variation in genome size (ranging from 3 to 316 kb), G + C percentage (ranging from 37 to 66%), and overall gene content (ranging from 81-96% of genome space). Based on overall nucleotide similarity and the numbers of shared gene products, 100 out of 130 genome sequences were grouped into 12 different clusters; 30 were characterized as singletons, which do not have close relationships with other phage genomes. For 5/12 clusters, constituent phage members originated from two or more different Pseudomonas host species, suggesting that phage in these clusters can traverse bacterial species boundaries. An analysis of CRISPR spacers in Pseudomonas bacterial genome sequences supported this finding. Substantial diversity was revealed in analyses of phage gene families; out of 4,462 total families, the largest had only 39 members and there were 2,992 families with only one member. An evolutionary analysis of 72 phage gene families, based on patterns of nucleotide diversity at non-synonymous and synonymous sites, revealed strong and consistent signals for purifying selection. Our study revealed highly diverse and dynamic Pseudomonas phage genomes, and evidence for a dominant role of purifying selection in shaping the evolution of genes encoded in them. PMID- 30022973 TI - Antibiotic Resistance Acquisition in the First Week of Life. AB - Objectives: The fetus is considered sterile but recent studies have suggested that gut colonization could start before birth. Scarce data are available for the acquisition of resistant Gram-negative bacteria (GNB) during the first days of life. Several studies have shown that integrons play a major role in antibiotic resistance acquisition. In this work, we studied the dynamics of human intestinal acquisition of GNB and integrons during the first days of life. Methods: Meconium was collected at birth and a stool sample before hospital discharge (days 2 or 3) on 185 term neonates. GNB were searched by culture on each sample and class 1, 2, and 3 integrons from each GNB or directly from samples. Eight risk factors for integron and GNB acquisition were studied. Results: We isolated 228 GNB, 46 from meconium and the remainder from stools. No link was found between GNB isolation and antibiotic exposure during delivery, but antibiotic exposure during labor significantly selected blaTEM-positive amoxicillin-resistant Enterobacteria. Two thirds of GNB were antibiotic-susceptible and most of the resistant isolates were acquired after birth. Integrons were detected in 18 of the 228 GNB isolates from 3 meconium and 20 stools. Antibiotic administration during delivery and vaginal carriage of Streptococcus agalactiae appeared as risk factors for integron acquisition. Conclusion: Gram-negative bacteria and integrons are mostly acquired after birth during the first days of life even if for some term neonates, meconium was not sterile. Antibiotic administration during delivery is a major risk for integron acquisition and for selection of amoxicillin-resistant Enterobacteria. PMID- 30022974 TI - Transgenerational Epigenetic Inheritance Under Environmental Stress by Genome Wide DNA Methylation Profiling in Cyanobacterium. AB - Epigenetic modifications such as DNA methylation are well known as connected with many important biological processes. Rapid accumulating evidence shows environmental stress can generate particular defense epigenetic changes across generations in eukaryotes. This transgenerational epigenetic inheritance in animals and plants has gained interest over the last years. Cyanobacteria play very crucial role in the earth, and as the primary producer they can adapt to nearly all diverse environments. However, few knowledge about the genome wide epigenetic information such as methylome information in cyanobacteria, especially under any environment stress, was reported so far. In this study we profiled the genome-wide cytosine methylation from a model cyanobacterium Synechocystis sp. PCC 6803, and explored the possibility of transgenerational epigenetic process in this ancient single-celled prokaryote by comparing the DNA methylomes among normal nitrogen medium cultivation, nitrogen starvation for 72 h and nitrogen recovery for about 12 generations. Our results shows that DNA methylation patterns in nitrogen starvation and nitrogen recovery are much more similar with each other, significantly different from that of the normal nitrogen. This study reveals the difference in global DNA methylation pattern of cyanobacteria between normal and nutrient stress conditions and reports the evidence of transgenerational epigenetic process in cyanobacteria. The results of this study may contribute to a better understanding of epigenetic regulation in prokaryotic adaptation to and survive in the ever changing environment. PMID- 30022975 TI - Expression and (Lacking) Internalization of the Cell Surface Receptors of Clostridioides difficile Toxin B. AB - Toxin-producing strains of Clostridioides difficile and Clostridium perfringens cause infections of the gastrointestinal tract in humans and ruminants, with the toxins being major virulence factors, essential for the infection, and responsible for the onset of severe symptoms. C. difficile toxin A (TcdA) and toxin B (TcdB), and the large cytotoxin (TpeL) from C. perfringens are single chain bacterial protein toxins with an AB-like toxin structure. The C-terminal delivery domain mediates cell entry of the N-terminal glycosyltransferase domain by receptor-mediated endocytosis. Several cell surface proteins have been proposed to serve as toxin receptors, including chondroitin-sulfate proteoglycan 4 (CSPG4), poliovirus receptor-like 3 (PVRL3), and frizzled-1/2/7 (FZD1/2/7) for TcdB and LDL-receptor-related protein-1 (LRP1) for TpeL. The expression of the TcdB receptors was investigated in human intestinal organoids (HIOs) and in cultured cell lines. HIOs from four human donors exhibited a comparable profile of receptor expression, with PVRL3, LRP1, and FZD7 being expressed and CSPG4 and FZD2 not being expressed. In human epithelial Caco-2 cells and HT29 cells as well as in immortalized murine fibroblasts, either receptor FZD2/7, CSPG4, PVRL3, and LRP1 was expressed. The question whether the toxins take advantage of the normal turnover of their receptors (i.e., constitutive endocytosis and recycling) from the cell surface or whether the toxins activity induce the internalization of their receptors has not yet been addressed. For the analysis of receptor internalization, temperature-induced uptake of biotinylated toxin receptors into immortalized mouse embryonic fibroblasts (MEFs) and Caco-2 cells was exploited. Solely LRP1 exhibited constitutive endocytosis from the plasma membrane to the endosome, which might be abused by TpeL (and possibly TcdB as well) for cell entry. Furthermore, internalization of CSPG4, PVRL3, FZD2, and FZD7 was observed neither in MEFs nor in Caco-2 cells. FZD2/7, CSPG4, and PVRL3 did thus exhibit no constitutive recycling. The presence of TcdB and the p38 activation induced by anisomycin were not able to induce or enhance CSPG4 or PVRL3 uptake in MEFs. In conclusion, FZD2/7, CSPG4, and PVRL3 seem to serve as cell surface binding receptors rather than internalizing receptors of TcdB. PMID- 30022976 TI - Intra-Hospital, Inter-Hospital and Intercontinental Spread of ST78 MRSA From Two Neonatal Intensive Care Unit Outbreaks Established Using Whole-Genome Sequencing. AB - From 2009 to 2011 [transmission period (TP) 1] and 2014 to 2017 (TP2), two outbreaks involving community-associated clonal complex (CC) 88-MRSA spa types t186 and t786, respectively, occurred in the Neonatal Intensive Care Unit (NICU) of an Irish hospital (H1). This study investigated the relatedness of these isolates, their relationship to other CC88 MRSA from Ireland and their likely geographic origin, using whole-genome sequencing (WGS). All 28 CC88-MRSA isolates identified at the Irish National MRSA Reference Laboratory between 2009 and 2017 were investigated including 20 H1 patient isolates, two H1 isolates recovered from a single healthcare worker (HCW) 2 years apart, three patient isolates from a second hospital (H2) and one patient isolate from each of three different hospitals (H3, H4, and H5). All isolates underwent DNA microarray profiling. Thirteen international isolates with similar microarray profiles to at least one Irish isolate were selected from an extensive global database. All isolates underwent Illumina MiSeq WGS. The majority of Irish isolates (25/28; all H1 isolates, two H2 isolates and the H3 isolate) were identified as ST78-MRSA-IVa and formed a large cluster, exhibiting 1-71 pairwise allelic differences, in a whole-genome MLST-based minimum spanning tree (MST) involving all Irish isolates. A H1/H2, H1/H3, and H1 HCW/patient isolate pair each exhibited one allelic difference. The TP2 isolates were characterised by a different spa type and the loss of hsdS. The three remaining Irish isolates (from H2, H4, and H5) were identified as ST88-MRSA-IVa and dispersed at the opposite end of the MST, exhibiting 81-211 pairwise allelic differences. Core-genome MLST and sequence based plasmid analysis revealed the recent shared ancestry of Irish and Australian ST78-MRSA-IVa, and of Irish and French/Egyptian ST88-MRSA-IVa. This study revealed the homogeneity of isolates recovered during two NICU outbreaks (despite spa type and hsdS carriage variances), HCW involvement in the outbreak transmission chain and the strain's spread to two other Irish hospitals. The outbreak strain, CC88/ST78-MRSA-IVa, was likely imported from Australia, where it is prevalent. CC88/ST88-MRSA-IVa was also identified in Irish hospitals and was likely imported from Africa, where it is predominant, and/or a country with a large population of African descent. PMID- 30022977 TI - Antimicrobial Resistance and Virulence-Associated Traits of Campylobacter jejuni Isolated From Poultry Food Chain and Humans With Diarrhea. AB - The objective of this study was to test the prevalence of virulence-associated markers and antimicrobial resistance in 624 C. jejuni isolated from poultry food chain, i. e., chicken feces (n = 160), poultry carcasses (n = 157), poultry meat (n = 152) and from humans (n = 155). All human strains were positive for 9 out of 13 putative virulence genes responsible for expression of pathogenic factors involved in different stages of the infection. The presence of all markers was also high in strains from chicken feces, carcasses and meat although not all of them were identified in 100% of the isolates. On the other hand, the virB11, wlaN, and iam putative pathogenic genes were detected in only 1.9, 15.2, and 20.5% of strains, respectively. C. jejuni isolates, irrespective of the origin, were highly resistant to ciprofloxacin (92.5% isolates), followed by nalidixic acid (88.9%) and tetracycline (68.4%). In case of ciprofloxacin, significantly more isolates from poultry feces, carcasses and meat were resistant than those obtained from humans and the same relationship was observed for tetracycline where the isolates from chicken feces were more often resistant than C. jejuni of carcasses and meat origin. A low number of strains was resistant to streptomycin (18.4% isolates) and only 5 strains (0.8%) displayed resistance to erythromycin. A relationship between resistance to fluoroquinolones and presence of selected pathogenic markers was observed, e.g., from 83.3% strains with the virB11 to 93.4% with the docA genes were resistant to ciprofloxacin. The isolates that did not possess any of the pathogenic traits were also mainly resistant to this antimicrobial, although the number of such strains was usually low, except virB11 (612 isolates), wlaN (529 strains), and iam (496 isolates). Furthermore, resistance to tetracycline was somehow associated with the presence of the virulence associated genes wlaN and virB11 (56.8 and 75.0% isolates, respectively). The present study shows a high antimicrobial resistance to quinolones and tetracycline of C. jejuni isolated along poultry food chain and from patients with diarrhea, which was closely correlated with the presence of several virulence genes playing a role in the pathogenesis of Campylobacter infection. PMID- 30022978 TI - Mouse Model Established by Early Renal Transplantation After Skin Allograft Sensitization Mimics Clinical Antibody-Mediated Rejection. AB - Antibody-mediated rejection (AMR) is the main barrier to renal graft survival, and mouse renal AMR models are important to study this process. Current mouse models are established by priming the recipient to donor skin for over 7 days before kidney transplantation. The robustness of AMR in these cases is too strong to mimic clinical AMR and it is unclear why altering the priming times ranging from 7 to 91 days fails to reduce the AMR potency in these models. In the present study, we found that the donor-recipient combination and skin graft size were determinants of donor-specific antibody (DSA) development patterns after skin transplantation. DSA-IgG was sustained for over 100 days after skin challenge, accounting for an identical AMR robustness upon different skin priming times over 7 days. However, decreasing the skin priming time within 7 days attenuated the robustness of subsequent renal allograft AMR in C3H to Balb/c mice. Four-day skin priming guaranteed that recipients develop acute renal AMR mixed with a high ratio of graft-infiltrating macrophages, renal grafts survived for a mean of 6.4 +/- 2.1 days, characterized by typical AMR histological changes, such as glomerulitis, peritubular capillary (PTC) dilation, and capillaritis, deposition of IgG and C3d in PTCs, but less prevalence of microthrombus, whereas the cellular rejection histological change of tubulitis was absent to mild. With this scheme, we also found that the renal AMR model can be developed using common mouse strains such as C57BL/6 and Balb/c, with mean prolonged renal graft survival times of 14.4 +/- 5.0 days. Finally, we proved that donor-matched skin challenge after kidney transplantation did not strongly affect DSA development and kidney graft outcome. These findings may facilitate an understanding and establishment of mouse renal allograft AMR models and promote AMR-associated studies. PMID- 30022979 TI - The Transcription Factor Zfx Regulates Peripheral T Cell Self-Renewal and Proliferation. AB - Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC have long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of Zfx, a transcription factor specifically required for HSC maintenance. We report that T cell-specific deletion of Zfx caused age-dependent depletion of naive peripheral T cells. Zfx deficient T cells also failed to undergo homeostatic proliferation in a lymphopenic environment, and showed impaired antigen-specific expansion and memory response. In addition, the invariant natural killer T cell compartment was severely reduced. RNA-Seq analysis revealed that the most dysregulated genes in Zfx-deficient T cells were similar to those observed in Zfx-deficient HSC and B cells. These studies identify Zfx as an important regulator of peripheral T cell maintenance and expansion and highlight the common molecular basis of HSC and lymphocyte homeostasis. PMID- 30022980 TI - A Case of Adult-Onset Still's Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab. AB - TNFAIP3 encodes the NF-kappaB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-kappaB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-kappaB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients' sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20. PMID- 30022981 TI - Protective Effects of Lactic Acid Bacteria Against TLR4 Induced Inflammatory Response in Hepatoma HepG2 Cells Through Modulation of Toll-Like Receptor Negative Regulators of Mitogen-Activated Protein Kinase and NF-kappaB Signaling. AB - The beneficial effects of probiotics in several liver diseases have been investigated in both animal and clinical models; however, the precise mechanisms responsible for their effects have not yet been elucidated. Gut transmitted endotoxins such as LPS have been shown to play critical roles in hepatic inflammation and injury. Therefore, in this study, we investigated the beneficial role of selected lactic acid bacteria (LABs) on reduction of hepatic steatosis (HS) and attenuation of LPS induced inflammatory response in vitro. Total cellular fluid (TCF) of LABs treatment reduced HS by decreasing the amount of lipid accumulation in vitro. Additionally, HepG2 cells exposed to LPS showed increased expression of exacerbated inflammatory cytokines, such as IL-6, CXCL8, CCL2, and TNF-alpha, but these effects were counteracted when cells were treated with TCF of LABs prior to LPS challenge. Moreover, TCF of LABs was able to modulate mRNA levels of TLR negative regulators and protein levels of p38 MAPK and p65 NF-kappaB transcription factors. However, these modulations were differed remarkably between both free fatty acid treated and untreated HepG2 cells. Heat killed LABs were also indirectly suppressed THP-1 cells to produce higher level of IL-10, TLR4, and lower at genes level of TGF-beta, IL-1beta, and IL-6, and at protein level of TNF-alpha in response to LPS. Taken together, our findings indicate that selected LABs exhibit profound immunoregulatory effects on liver cells via modulation of TLR negative regulators of the MAPK and NF-kappaB pathways. PMID- 30022982 TI - BCL10 - Bridging CARDs to Immune Activation. AB - Since the B-cell lymphoma/leukemia 10 (BCL10) protein was first described in 1999, numerous studies have elucidated its key functions in channeling adaptive and innate immune signaling downstream of CARMA/caspase-recruitment domain (CARD) scaffold proteins. While T and B cell antigen receptor (TCR/BCR) signaling induces the recruitment of BCL10 bound to mucosa-associated lymphoid tissue (MALT)1 to the lymphocyte-specific CARMA1/CARD11-BCL10-MALT1 (CBM-1) signalosome, alternative CBM complexes utilize different CARMA/CARD scaffolds in distinct innate or inflammatory pathways. BCL10 constitutes the smallest subunit in all CBM signalosomes, containing a 233 amino acid coding for N-terminal CARD as well as a C-terminal Ser/Thr-rich region. BCL10 forms filaments, thereby aggregating into higher-order clusters that mediate and amplify stimulation-induced signals, ultimately leading to MALT1 protease activation and canonical NF-kappaB and JNK signaling. BCL10 additionally undergoes extensive post-translational regulation involving phosphorylation, ubiquitination, MALT1-catalyzed cleavage, and degradation. Through these feedback and feed-forward events, BCL10 integrates positive and negative regulatory processes that govern the function as well as the dynamic assembly, disassembly, and destruction of CBM complexes. Thus, BCL10 is a critical regulator for activation as well as termination of immune cell signaling, revealing that its role extends far beyond that of a mere linking factor in CBM complexes. PMID- 30022984 TI - Single Cell RNA Sequencing of Rare Immune Cell Populations. AB - Single-cell RNA sequencing (scRNA-Seq) is transforming our ability to characterize cells, particularly rare cells that are often overlooked in bulk population analytical approaches. This has lead to the discovery of new cell types and cellular states that echo the underlying heterogeneity and plasticity in the immune system. Technologies for the capture, sequencing, and bioinformatic analysis of single cells are rapidly improving, and scRNA-Seq is now becoming much more accessible to non-specialized laboratories. Here, we describe our experiences in adopting scRNA-Seq to the study of rare immune cells in their microanatomical niches. PMID- 30022983 TI - Potential Role of MicroRNAs in the Regulation of Antiviral Responses to Influenza Infection. AB - Influenza is a major health burden worldwide and is caused by influenza viruses that are enveloped and negative stranded RNA viruses. Little progress has been achieved in targeted intervention, either at a population level or at an individual level (to treat the cause), due to the toxicity of drugs and ineffective vaccines against influenza viruses. MicroRNAs (miRNAs) are small non coding RNAs that play critical roles in gene expression, cell differentiation, and tissue development and have been shown to silence viral replication in a sequence-specific manner. Investigation of these small endogenous nucleotides may lead to new therapeutics against influenza virus infection. Here, we describe our current understanding of the role of miRNAs in host defense response against influenza virus, as well as their potential and limitation as new therapeutic approaches. PMID- 30022985 TI - Assessing European Wheat Sensitivities to Parastagonospora nodorum Necrotrophic Effectors and Fine-Mapping the Snn3-B1 Locus Conferring Sensitivity to the Effector SnTox3. AB - Parastagonospora nodorum is a necrotrophic fungal pathogen of wheat (Triticum aestivum L.), one of the world's most important crops. P. nodorum mediates host cell death using proteinaceous necrotrophic effectors, presumably liberating nutrients that allow the infection process to continue. The identification of pathogen effectors has allowed host genetic resistance mechanisms to be separated into their constituent parts. In P. nodorum, three proteinaceous effectors have been cloned: SnToxA, SnTox1, and SnTox3. Here, we survey sensitivity to all three effectors in a panel of 480 European wheat varieties, and fine-map the wheat SnTox3 sensitivity locus Snn3-B1 using genome-wide association scans (GWAS) and an eight-founder wheat multi-parent advanced generation inter-cross (MAGIC) population. Using a Bonferroni corrected P <= 0.05 significance threshold, GWAS identified 10 significant markers defining a single locus, Snn3-B1, located on the short arm of chromosome 5B explaining 32% of the phenotypic variation [peak single nucleotide polymorphisms (SNPs), Excalibur_c47452_183 and GENE-3324_338, log10P = 20.44]. Single marker analysis of SnTox3 sensitivity in the MAGIC population located Snn3-B1 via five significant SNPs, defining a 6.2-kb region that included the two peak SNPs identified in the association mapping panel. Accordingly, SNP Excalibur_c47452_183 was converted to the KASP genotyping system, and validated by screening a subset of 95 wheat varieties, providing a valuable resource for marker assisted breeding and for further genetic investigation. In addition, composite interval mapping in the MAGIC population identified six minor SnTox3 sensitivity quantitative trait loci, on chromosomes 2A (QTox3.niab-2A.1, P-value = 9.17-7), 2B (QTox3.niab-2B.1, P = 0.018), 3B (QTox3.niab-3B.1, P = 48.51-4), 4D (QTox3.niab-4D.1, P = 0.028), 6A (QTox3.niab 6A.1, P = 8.51-4), and 7B (QTox3.niab-7B.1, P = 0.020), each accounting for between 3.1 and 6.0 % of the phenotypic variance. Collectively, the outcomes of this study provides breeders with knowledge and resources regarding the sensitivity of European wheat germplasm to P. nodorum effectors, as well as simple diagnostic markers for determining allelic state at Snn3-B1. PMID- 30022986 TI - Evolutionary History of Plant LysM Receptor Proteins Related to Root Endosymbiosis. AB - LysM receptor-like kinases (LysM-RLKs), which are specific to plants, can control establishment of both the arbuscular mycorrhizal (AM) and the rhizobium-legume (RL) symbioses in response to signal molecules produced, respectively, by the fungal and bacterial symbiotic partners. While most studies on these proteins have been performed in legume species, there are also important findings that demonstrate the roles of LysM-RLKs in controlling symbiosis in non-legume plants. Phylogenomic studies, which have revealed the presence or absence of certain LysM RLKs among different plant species, have provided insight into the evolutionary mechanisms underlying both the acquisition and the loss of symbiotic properties. The role of a key nodulation LysM-RLK, NFP/NFR5, in legume plants has thus probably been co-opted from an ancestral role in the AM symbiosis, and has been lost in most plant species that have lost the ability to establish the AM or the RL symbiosis. Another LysM-RLK, LYK3/NFR1, that controls the RL symbiosis probably became neo-functionalised following two rounds of gene duplication. Evidence suggests that a third LysM-RLK, LYR3/LYS12, is also implicated in perceiving microbial symbiotic signals, and this protein could have roles in symbiosis and/or plant immunity in different plant species. By focusing on these three LysM-RLKs that are widespread in plants we review their evolutionary history and what this can tell us about the evolution of both the RL and the AM symbioses. PMID- 30022987 TI - Glycans as Modulators of Plant Defense Against Filamentous Pathogens. AB - Plants and microbes utilize glycoconjugates as structural entities, energy reserves for cellular processes, and components of cellular recognition or binding events. The structural heterogeneity of carbohydrates in such systems is a result of the ability of the carbohydrate biosynthetic enzymes to reorient sugar monomers in a variety of forms, generating highly complex, linear, branched, or hierarchical structures. During the interaction between plants and their microbial pathogens, the microbial cell surface glycans, cell wall derived glycans, and glycoproteins stimulate the signaling cascades of plant immune responses, through a series of specific or broad spectrum recognition events. The microbial glycan-induced plant immune responses and the downstream modifications observed in host-plant glycan structures that combat the microbial attack have garnered immense interest among scientists in recent times. This has been enabled by technological advancements in the field of glycobiology, making it possible to study the ongoing co-evolution of the microbial and the corresponding host glycan structures, in greater detail. The new glycan analogs emerging in this evolutionary arms race brings about a fresh perspective to our understanding of plant-pathogen interactions. This review discusses the role of diverse classes of glycans and their derivatives including simple sugars, oligosaccharides, glycoproteins, and glycolipids in relation to the activation of classical Pattern Triggered Immunity (PTI) and Effector-Triggered Immunity (ETI) defense responses in plants. While primarily encompassing the biological roles of glycans in modulating plant defense responses, this review categorizes glycans based on their structure, thereby enabling parallels to be drawn to other areas of glycobiology. Further, we examine how these molecules are currently being used to develop new bio-active molecules, potent as priming agents to stimulate plant defense response and as templates for designing environmentally friendly foliar sprays for plant protection. PMID- 30022988 TI - Cold Tolerance of Photosynthetic Electron Transport System Is Enhanced in Wheat Plants Grown Under Elevated CO2. AB - The effects of CO2 elevation on sensitivity of photosynthetic electron transport system of wheat in relation to low temperature stress are unclear. The performance of photosynthetic electron transport system and antioxidant system in chloroplasts was investigated in a temperature sensitive wheat cultivar Lianmai6 grown under the combination of low temperature (2 days at 2/-1 degrees C in the day/night) and CO2 elevation (800 MUmol l-1). It was found that CO2 elevation increased the efficiency of photosynthetic electron transport in wheat exposed to low temperature stress, which was related to the enhanced maximum quantum yield for electron transport beyond QA and the increased quantum yield for reduction of end electron acceptors at the PSI acceptor side in plants under elevated CO2. Also, under low temperature, the activities of ATPases, ascorbate peroxidase, and catalase in chloroplasts were enhanced in wheat under elevated CO2. It suggested that the cold tolerance of photosynthetic electron transport system is enhanced by CO2 elevation. PMID- 30022989 TI - Dissecting Key Adaptation Traits in the Polyploid Perennial Medicago sativa Using GBS-SNP Mapping. AB - Understanding key adaptation traits is crucial to developing new cultivars with broad adaptations. The main objective of this research is to understand the genetic basis of winter hardiness (WH) and fall dormancy (FD) in alfalfa and the association between the two traits. QTL analysis was conducted in a pseudo testcross F1 population developed from two cultivars contrasting in FD (3010 with FD = 2 and CW 1010 with FD = 10). The mapping population was evaluated in three replications at two locations (Watkinsville and Blairsville, GA). FD levels showed low to moderate correlations with WH (0.22-0.57). Assessing dormancy in winter is more reliable than in the fall in southern regions with warm winters. The mapping population was genotyped using Genotyping-by-sequencing (GBS). Single dose allele SNPs (SDA) were used for constructing linkage maps. The parental map (CW 1010) consisted of 32 linkage groups spanning 2127.5 cM with 1377 markers and an average marker density of 1.5 cM/SNP. The maternal map (3010) had 32 linkage groups spanning 2788.4 cM with 1837 SDA SNPs with an average marker density of 1.5 cM/SNP. Forty-five significant (P < 0.05) QTLs for FD and 35 QTLs for WH were detected on both male and female linkage maps. More than 75% (22/28) of the dormancy QTL detected from the 3010 parent did not share genomic regions with WH QTLs and more than 70% (12/17) dormancy QTLs detected from CW 1010 parent were localized in different genomic regions than WH QTLs. These results suggest that the two traits have independent inheritance and therefore can be improved separately in breeding programs. PMID- 30022990 TI - Suppression of SlMBP15 Inhibits Plant Vegetative Growth and Delays Fruit Ripening in Tomato. AB - MADS-box genes have been demonstrated to participate in a number of processes in tomato development, especially fruit ripening. In this study, we reported a novel MADS-box gene, SlMBP15, which is implicated in fruit ripening. Based on statistical analysis, the ripening time of SlMBP15-silenced tomato was delayed by 2-4 days compared with that of the wild-type (WT). The accumulation of carotenoids and biosynthesis of ethylene in fruits were decreased in SlMBP15 silenced tomato. Genes related to carotenoid and ethylene biosynthesis were greatly repressed. SlMBP15 can interact with RIN, a MADS-box regulator affecting the carotenoid accumulation and ethylene biosynthesis in tomato. In addition, SlMBP15-silenced tomato produced dark green leaves, and its plant height was reduced. The gibberellin (GA) content of transgenic plants was lower than that of the WT and GA biosynthesis genes were repressed. These results demonstrated that SlMBP15 not only positively regulated tomato fruit ripening but also affected the morphogenesis of the vegetative organs. PMID- 30022991 TI - Overexpression of a SDD1-Like Gene From Wild Tomato Decreases Stomatal Density and Enhances Dehydration Avoidance in Arabidopsis and Cultivated Tomato. AB - Stomata are microscopic valves formed by two guard cells flanking a pore, which are located on the epidermis of most aerial plant organs and are used for water and gas exchange between the plant and the atmosphere. The number, size and distribution of stomata are set during development in response to changing environmental conditions, allowing plants to minimize the impact of a stressful environment. In Arabidopsis, STOMATAL DENSITY AND DISTRIBUTION 1 (AtSDD1) negatively regulates stomatal density and optimizes transpiration and water use efficiency (WUE). Despite this, little is known about the function of AtSDD1 orthologs in crop species and their wild stress-tolerant relatives. In this study, SDD1-like from the stress-tolerant wild tomato Solanum chilense (SchSDD1 like) was identified through its close sequence relationship with SDD1-like from Solanum lycopersicum and AtSDD1. Both Solanum SDD1-like transcripts accumulated in high levels in young leaves, suggesting that they play a role in early leaf development. Arabidopsis sdd1-3 plants transformed with SchSDD1-like under a constitutive promoter showed a significant reduction in stomatal leaf density compared with untransformed sdd1-3 plants. Additionally, a leaf dehydration shock test demonstrated that the reduction in stomatal abundance of transgenic plants was sufficient to slow down dehydration. Overexpression of SchSDD1-like in cultivated tomato plants decreased the stomatal index and density of the cotyledons and leaves, and resulted in higher dehydration avoidance. Taken together, these results indicate that SchSDD1-like functions in a similar manner to AtSDD1 and suggest that Arabidopsis and tomatoes share this component of the stomatal development pathway that impinges on water status. PMID- 30022992 TI - Melatonin Induces Parthenocarpy by Regulating Genes in Gibberellin Pathways of 'Starkrimson' Pear (Pyrus communis L.). AB - Parthenocarpy, the production of seedless fruit without fertilization, has a variety of valuable qualities, especially for self-incompatible species, such as pear. To explore whether melatonin (MT) induces parthenocarpy, we used 'Starkrimson' pear as a material for morphological observations. According to our results, exogenous MT promoted the expansion and division of the mesocarp cells in a manner similar to hand pollination. However, the seeds of exogenous MT treated fruit were undeveloped and aborted later in the fruit-setting stage. To further investigate how MT induced parthenocarpy, we studied changes of related hormones in the ovaries and found that MT significantly increased the contents of the gibberellins (GAs) GA3 and GA4. Thus, paclobutrazol (PAC), a GA-biosynthesis inhibitor, was used to study the relationship between GAs and MT. In addition, spraying MT after treatment with PAC did not increase GA content nor lead to parthenocarpy. Through a transcriptome analysis, we discovered that MT can cause significant upregulation of PbGA20ox and downregulation of PbGA2ox. However, no significant difference was observed in PbGA2ox compared with the control after PAC and MT applications. Thus, MT induces parthenocarpy by promoting GA biosynthesis along with cell division and mesocarp expansion in pear. PMID- 30022993 TI - The Tropical Invasive Seagrass, Halophila stipulacea, Has a Superior Ability to Tolerate Dynamic Changes in Salinity Levels Compared to Its Freshwater Relative, Vallisneria americana. AB - The tropical seagrass species, Halophila stipulacea, originated from the Indian Ocean and the Red Sea, subsequently invading the Mediterranean and has recently established itself in the Caribbean Sea. Due to its invasive nature, there is growing interest in understanding this species' capacity to adapt to new conditions. One approach to understanding the natural tolerance of a plant is to compare the tolerant species with a closely related non-tolerant species. We compared the physiological responses of H. stipulacea exposed to different salinities, with that of its nearest freshwater relative, Vallisneria americana. To achieve this goal, H. stipulacea and V. americana plants were grown in dedicated microcosms, and exposed to the following salt regimes: (i) H. stipulacea: control (40 PSU, practical salinity units), hyposalinity (25 PSU) and hypersalinity (60 PSU) for 3 weeks followed by a 4-week recovery phase (back to 40 PSU); (ii) V. americana: control (1 PSU), and hypersalinity (12 PSU) for 3 weeks, followed by a 4-week recovery phase (back to 1 PSU). In H. stipulacea, leaf number and chlorophyll content showed no significant differences between control plants and plants under hypo and hypersalinities, but a significant decrease in leaf area under hypersalinity was observed. In addition, compared with control plants, H. stipulacea plants exposed to hypo and hypersalinity were found to have reduced below-ground biomass and C/N ratios, suggesting changes in the allocation of resources in response to both stresses. There was no significant effect of hypo/hypersalinity on dark-adapted quantum yield of photosystem II (Fv/Fm) suggesting that H. stipulacea photochemistry is resilient to hypo/hypersalinity stress. In contrast to the seagrass, V. americana exposed to hypersalinity displayed significant decreases in above-ground biomass, shoot number, leaf number, blade length and Fv/Fm, followed by significant recoveries of all these parameters upon return of the plants to non-saline control conditions. These data suggest that H. stipulacea shows remarkable tolerance to both hypo and hypersalinity. Resilience to a relatively wide range of salinities may be one of the traits explaining the invasive nature of this species in the Mediterranean and Caribbean Seas. PMID- 30022994 TI - UV RESISTANCE LOCUS 8 From Chrysanthemum morifolium Ramat (CmUVR8) Plays Important Roles in UV-B Signal Transduction and UV-B-Induced Accumulation of Flavonoids. AB - UV Resistance Locus 8 (UVR8), an ultraviolet-B (UV-B; 280-315 nm) photoreceptor, participates in the regulation of various plant growth and developmental processes. UV-B radiation is an important factor enhancing the production of active components in medicinal plants. To-date, however, studies on UV-B photoreceptors have largely focused on Arabidopsis, and the functions of UVR8 in medicinal plants are still largely unknown. In the present study, a homolog of Arabidopsis UVR8, CmUVR8, was isolated from Chrysanthemum morifolium Ramat, and its structure and function were analyzed in detail. Protein sequence analysis showed that CmUVR8 contained nine conserved regulators of chromosome condensation 1 repeats, seven conserved bladed propellers, one C27 region, three "GWRHT" motifs and several crucial amino acid residues (such as 14 Trps and 2 Args), similar to AtUVR8. 3-D structural analysis of CmUVR8 indicated that its structure was similar to AtUVR8. Heterologous expression of CmUVR8 could rescued the deficient phenotype of uvr8-6, a mutant of UVR8 in Arabidopsis, indicating the role of CmUVR8 in the regulation of hypocotyl elongation and HY5 gene expression under UV-B irradiation. Moreover, CmUVR8 regulates UV-B-induced expression of four flavonoids biosynthesis-related genes and the UV-B-induced accumulation of flavonoids. Furthermore, the interaction between CmUVR8 and CmCOP1 were confirmed using a yeast two-hybrid assay. These results indicated that CmUVR8 plays important roles in UV-B signal transduction and the UV-B-induced accumulation of flavonoids, as a counterpart of AtUVR8. PMID- 30022995 TI - Functional Dissection of Auxin Response Factors in Regulating Tomato Leaf Shape Development. AB - The phytohormone auxin is involved in many aspects of plant growth and developmental processes. The tomato Aux/IAA transcription factor SlIAA9/ENTIRE/E plays an important role in leaf morphogenesis and fruit development, and the E gene encodes a protein from the Aux/IAA family of auxin response repressors. Both SlIAA9-RNAi transgenic and entire (e) mutant plants reduce the leaf complexity in tomato, but the underlying mechanism is not yet completely resolved. Auxin signaling is known to regulate target genes expression via Aux/IAA and ARFs (auxin response factors) transcriptional regulators. ARFs mediate a wide range of developmental processes. Through an Y2H (yeast two-hybrid) assay coupled with expression profiling of the SlARF genes family, we identified a group of ARFs: SlARF6A, SlARF8A, SlARF8B, and SlARF24. Pull-down and BiFC (Bimolecular Fluorescence Complementation) results demonstrated that these SlARFs interact with SlIAA9 in vitro and in vivo, and the e mutation altered the expression patterns of multiple SlARFs. The simple leaves of the e mutant were partially converted to wild-type compound leaves by VIGS (virus-induced gene silencing) of these four SlARFs. Furthermore, IAA content in these samples was significantly increased compared to the e mutant. In addition, SlARF6A and SlARF24 bound to the SlPIN1 promoter and act as transcriptional activators to regulate genes expression involved in leaflet initiation. It may also suggest that SlARFs regulate leaf morphology through direct binding to auxin-responsive genes in the absence of SlIAA9, providing an insight for the role of SlARFs in leaf shape development. PMID- 30022997 TI - Impact of the Sonas Programme on Communication over a Period of 24 Weeks in People with Moderate-to-Severe Dementia. AB - Objectives: The primary aim was to examine how communication abilities changed over time among nursing home residents with moderate-to-severe dementia who were attending the Sonas programme and to explore whether changes in communication abilities were related to cognitive ability. Method: A longitudinal secondary descriptive study method was employed, where 56 people with moderate-to-severe dementia attended a 45-min Sonas group session twice a week for 24 weeks. The Threadgold Communication Tool (TCT) was completed every 4 weeks. Results: The impact of the Sonas programme on communication showed a significant non-linear trend in the TCT, with an increase in communication abilities during the first 16 weeks, regardless of the level of the residents' cognitive abilities. Thereafter it levelled out. No interaction was found between time and the frequency of attendances at Sonas sessions. Both verbal and non-verbal communication increased from the baseline, with non-verbal communication increasing quickly and verbal communication increasing marginally. Conclusion: Communication abilities increased with the time of the intervention, but the peak was achieved after 16 weeks, after which the effect levelled out. This suggest that the Sonas programme should be used for a period of at least 16 weeks before evaluating its effect. PMID- 30022996 TI - Mild Cognitive Impairment Reversion and Progression: Rates and Predictors in Community-Living Older Persons in the Singapore Longitudinal Ageing Studies Cohort. AB - Background: Studies report varying rates and predictors of mild cognitive impairment (MCI) progression and reversion. Methods: We determined MCI reversion and progression among 473 community-living adults aged >=55 years in the Singapore Longitudinal Ageing Study with an average of 6 years of follow-up and estimated association with baseline variables. Results: A total of 208 MCI participants reverted to normal cognition (44.0%) and 19 progressed to dementia (4.0%). In a model adjusted for age, gender, education, ethnicity, cardiovascular risk factors/diseases, APOE epsilon4 status, depressive symptoms, leisure-time activities (LTA), and baseline Mini-Mental State Examination (MMSE), we found that LTA score (OR = 1.07, 95% CI 1.02-1.13), MMSE score (OR = 1.21, 95% CI 1.11 1.31), and subjective memory complaint (OR = 1.83, 95% CI 1.16-2.90) significantly predicted MCI reversion. Controlling for all variables, age (OR = 1.09, 95% CI 1.02-1.17), lower education (OR = 3.26, 95% CI 1.01-10.49), and the metabolic syndrome (OR = 3.13, 95% CI 1.12-8.77) significantly predicted MCI progression. Controlling for age, sex, ethnicity, and education, diabetes significantly predicted MCI progression (OR = 3.19, 95% CI 1.23-8.26), but the presence of other cardiometabolic factors reduced this association to an OR of 2.18 (95% CI 0.72-6.60). Conclusion: In this relatively younger population, there were higher rates of MCI reversion and lower rates of MCI progression which were predicted by the positive effects of LTA and a higher MMSE score as well as by the deleterious effect of the metabolic syndrome and diabetes. PMID- 30022998 TI - Pre-clinical Models for Malignant Mesothelioma Research: From Chemical-Induced to Patient-Derived Cancer Xenografts. AB - Malignant mesothelioma (MM) is a rare disease often associated with environmental exposure to asbestos and other erionite fibers. MM has a long latency period prior to manifestation and a poor prognosis. The survival post-diagnosis is often less than a year. Although use of asbestos has been banned in the United States and many European countries, asbestos is still being used and extracted in many developing countries. Occupational exposure to asbestos, mining, and migration are reasons that we expect to continue to see growing incidence of mesothelioma in the coming decades. Despite improvements in survival achieved with multimodal therapies and cytoreductive surgeries, less morbid, more effective interventions are needed. Thus, identifying prognostic and predictive biomarkers for MM, and developing novel agents for targeted therapy, are key unmet needs in mesothelioma research and treatment. In this review, we discuss the evolution of pre-clinical model systems developed to study MM and emphasize the remarkable capability of patient-derived xenograft (PDX) MM models in expediting the pre-clinical development of novel therapeutic approaches. PDX disease model systems retain major characteristics of original malignancies with high fidelity, including molecular, histopathological and functional heterogeneities, and as such play major roles in translational research, drug development, and precision medicine. PMID- 30022999 TI - RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models? AB - Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling. Furthermore, we and other investigators have used these models to generate new insights into the causes and progression of TOC, including findings suggesting a tissue-specific role of the RHBDF2-EGFR pathway, rather than a role of the immune system, in mediating TOC; and indicating that amphiregulin, an EGFR ligand, is a functional driver of the disease. This review highlights the mouse models of TOC available to researchers for use in investigating the disease mechanisms and possible therapies, and the significance of genetic modifiers of the disease identified in these models in delineating the underlying molecular mechanisms. PMID- 30023000 TI - Association of Transfer RNA Fragments in White Blood Cells With Antibody Response to Bovine Leukemia Virus in Holstein Cattle. AB - Bovine leukemia virus (BLV) affects cattle health and productivity worldwide, causing abnormal immune function and immunosuppression. Transfer RNA fragments (tRFs) are known to be involved in inhibition of gene expression and have been associated with stress and immune response, tumor growth, and viral infection. The objective of this study was to identify tRFs associated with antibody response to BLV in Holstein cattle. Sera from 14 animals were collected to establish IgG reactivity to BLV by ELISA. Seven animals were seropositive (positive group) and seven were seronegative (negative group) for BLV exposure. Leukocytes from each animal were collected and tRFs were extracted for sequencing. tRF5GlnCTG, tRF5GlnTTG, and tRF5HisGTG, were significantly different between seropositive and seronegative groups (P < 0.0067). In all cases the positive group had a lower number of normalized sequences for tRFs when compared to the negative group. Result suggests that tRF5s could potentially be used as biomarkers to establish exposure of cattle to BLV. PMID- 30023001 TI - Genomic Prediction of Breeding Values Using a Subset of SNPs Identified by Three Machine Learning Methods. AB - The analysis of large genomic data is hampered by issues such as a small number of observations and a large number of predictive variables (commonly known as "large P small N"), high dimensionality or highly correlated data structures. Machine learning methods are renowned for dealing with these problems. To date machine learning methods have been applied in Genome-Wide Association Studies for identification of candidate genes, epistasis detection, gene network pathway analyses and genomic prediction of phenotypic values. However, the utility of two machine learning methods, Gradient Boosting Machine (GBM) and Extreme Gradient Boosting Method (XgBoost), in identifying a subset of SNP makers for genomic prediction of breeding values has never been explored before. In this study, using 38,082 SNP markers and body weight phenotypes from 2,093 Brahman cattle (1,097 bulls as a discovery population and 996 cows as a validation population), we examined the efficiency of three machine learning methods, namely Random Forests (RF), GBM and XgBoost, in (a) the identification of top 400, 1,000, and 3,000 ranked SNPs; (b) using the subsets of SNPs to construct genomic relationship matrices (GRMs) for the estimation of genomic breeding values (GEBVs). For comparison purposes, we also calculated the GEBVs from (1) 400, 1,000, and 3,000 SNPs that were randomly selected and evenly spaced across the genome, and (2) from all the SNPs. We found that RF and especially GBM are efficient methods in identifying a subset of SNPs with direct links to candidate genes affecting the growth trait. In comparison to the estimate of prediction accuracy of GEBVs from using all SNPs (0.43), the 3,000 top SNPs identified by RF (0.42) and GBM (0.46) had similar values to those of the whole SNP panel. The performance of the subsets of SNPs from RF and GBM was substantially better than that of evenly spaced subsets across the genome (0.18-0.29). Of the three methods, RF and GBM consistently outperformed the XgBoost in genomic prediction accuracy. PMID- 30023002 TI - IRWNRLPI: Integrating Random Walk and Neighborhood Regularized Logistic Matrix Factorization for lncRNA-Protein Interaction Prediction. AB - Long non-coding RNA (lncRNA) plays an important role in many important biological processes and has attracted widespread attention. Although the precise functions and mechanisms for most lncRNAs are still unknown, we are certain that lncRNAs usually perform their functions by interacting with the corresponding RNA- binding proteins. For example, lncRNA-protein interactions play an important role in post transcriptional gene regulation, such as splicing, translation, signaling, and advances in complex diseases. However, experimental verification of lncRNA-protein interactions prediction is time-consuming and laborious. In this work, we propose a computational method, named IRWNRLPI, to find the potential associations between lncRNAs and proteins. IRWNRLPI integrates two algorithms, random walk and neighborhood regularized logistic matrix factorization, which can optimize a lot more than using an algorithm alone. Moreover, the method is semi-supervised and does not require negative samples. Based on the leave-one-out cross validation, we obtain the AUC of 0.9150 and the AUPR of 0.7138, demonstrating its reliable performance. In addition, by means of case study in the "Mus musculus," many lncRNA-protein interactions which are predicted by our method can be successfully confirmed by experiments. This suggests that IRWNRLPI will be a useful bioinformatics resource in biomedical research. PMID- 30023003 TI - Adding ezetimibe to statin therapy: latest evidence and clinical implications. AB - Background: Statins are the hypolipemic treatment of choice for hyperlipidemia with confirmed atherosclerotic cardiovascular disease (ASCVD) protective effect, proven even in normolipemic patients. But in rare situations, even with a high dose treatment regimen, or maximally tolerated statin dose treatment, treatment targets of low-density lipoprotein cholesterol (LDL-C), according to the risk profile of the patient, cannot be achieved. Combination therapy with ezetimibe is an effective treatment choice, as it is one of the few hypolipemic drugs with proven ASCVD protective effect. Aim: In this review, we address the question of therapeutic efficacy and safety of ezetimibe in combination therapy with statins, as expressed through its hypolipemic and vasoprotective effects and its potential side effects. Methods: We conducted a literature review of English articles through PubMed, PubMed Central, and Cochrane for randomized clinical trials, retrospective analyses, meta-analyses, and review articles by using key words: ezetimibe, statins, combination therapy, adverse effects. We analyzed data on ezetimibe-statin combination therapy in terms of hypolipemic efficacy, ASCVD risk reduction, and adverse effects. Results: Statins have been proven to be very effective in reducing ASCVD risk, with no apparent threshold at which LDL-C lowering is not associated with reduced risk. Yet, a significant on-treatment residual risk of major cardiovascular (CV) events still exists according to meta analyses of statin trials. Findings like this point to the unmet needs of the patients on statin treatment. The unmet needs in terms of LDL-C targets and ASCVD risk reduction raise the question of statin combination therapy. Ezetimibe is a cholesterol-lowering drug from the class of cholesterol absorption inhibitors, with the potency to decrease LDL-C by about 10-18% and Apo B by 11-16%, while in combination therapy with statins, an additional LDL-C lowering of 25% or total LDL-C lowering of 34-61% is observed. The effects on LDL-C and other lipoprotein (LP) fractions are translated by ASCVD risk reduction. Ezetimibe is one of the few hypolipemic medications that leads to additional ASCVD risk reduction when added to statin therapy. Present data on ezetimibe support the existence of pleotropic anti-inflammatory and antioxidative effects, in addition to its hypolipemic effect, which are responsible for this added ASCVD risk reduction on top of statin monotherapy. Ezetimibe, in combination therapy with a maximal or maximally tolerated statin therapy, is used in patients who fail to achieve target LDL-C levels with statin monotherapy. In combination with low-to-moderate statin dose treatment, or with second- or third-line statins, ezetimibe is used in situations of statin-associated muscle symptoms. The combination therapy is relatively safe. Conclusion: Ezetimibe add-on to statin combination therapy is an effective treatment option that leads to additional LDL-C lowering - recommended in situations where, with a maximal or maximally tolerated statin monotherapy treatment regimen, LDL-C targets cannot be achieved. It leads to additional ASCVD risk reduction, without raising significant safety concerns. PMID- 30023004 TI - First-line alectinib for ALK-positive lung cancer: is there room for further improvement? AB - In the present editorial we describe the therapeutic achievements in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive advanced non small cell lung cancer (NSCLC). We focus on the major breakthroughs we have been witnessing in this context, from the introduction of crizotinib as the first approved targeted drug, to the meaningful improvement in terms of clinical benefit that alectinib, a second generation ALK-inhibitor, has recently provided over crizotinib. Finally, we address major trends of clinical research in this setting, and whether this might translate into further clinical improvement in the near future. PMID- 30023005 TI - Intestinal ultrasound in assessment of suspected Crohn's disease in patients with negative ileocolonoscopy: a paradigm shift? PMID- 30023006 TI - Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer. AB - Background: Somatic mutations in the ERBB genes (epidermal growth factor receptor: EGFR, ERBB2, ERBB3, ERBB4) promote oncogenesis and lapatinib resistance in metastatic HER2+ (human epidermal growth factor-like receptor 2) breast cancer in vitro. Our study aimed to determine the frequency of mutations in four genes: EGFR, ERBB2, ERBB3 and ERBB4 and to investigate whether these mutations affect cellular behaviour and therapy response in vitro and outcomes after adjuvant trastuzumab-based therapy in clinical samples. Methods: We performed Agena MassArray analysis of 227 HER2+ breast cancer samples to identify the type and frequency of ERBB family mutations. Of these, two mutations, the somatic mutations ERBB4-V721I and ERBB4-S303F, were stably transfected into HCC1954 (PIK3CA mutant), HCC1569 (PIK3CA wildtype) and BT474 (PIK3CA mutant, ER positive) HER2+ breast cancer cell lines for functional in vitro experiments. Results: A total of 12 somatic, likely deleterious mutations in the kinase and furin-like domains of the ERBB genes (3 EGFR, 1 ERBB2, 3 ERBB3, 5 ERBB4) were identified in 7% of HER2+ breast cancers, with ERBB4 the most frequently mutated gene. The ERBB4-V721I kinase domain mutation significantly increased 3D-colony formation in 3/3 cell lines, whereas ERBB4-S303F did not increase growth rate or 3D colony formation in vitro. ERBB4-V721I sensitized HCC1569 cells (PIK3CA wildtype) to the pan class I PI3K inhibitor copanlisib but increased resistance to the pan-HER family inhibitor afatinib. The combinations of copanlisib with trastuzumab, lapatinib, or afatinib remained synergistic regardless of ERBB4-V721I or ERBB4 S303F mutation status. Conclusions: ERBB gene family mutations, which are present in 7% of our HER2+ breast cancer cohort, may have the potential to alter cellular behaviour and the efficacy of HER- and PI3K-inhibition. PMID- 30023008 TI - Salvage surgery for local recurrence after stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review. AB - Introduction: Stereotactic body (or ablative) radiotherapy (SBRT/SABR) is now a guideline-recommended treatment for medically inoperable patients with peripherally-located, stage I non-small cell lung cancer (NSCLC), and for medically operable patients who decline surgery. The 5-year local failure rate after SBRT is about 10% and in highly selected patients, surgery has been used as a salvage therapy. We performed a systematic review to address the feasibility, safety, and outcome of salvage surgery for locally recurrent early stage NSCLC after SBRT. Methods: A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed, Embase and Cochrane databases were searched and two authors independently assessed the articles. A total of seven eligible articles were identified. Results: All seven articles were retrospective case series, representing a total of 47 patients. Surgery was completed in all patients. Where reported in sufficient detail, morbidity (four studies) was between 29 and 50% (series of two patients) and 90-day mortality (six studies) was between 0% (four studies) and 11% (n = 1, disease progression). Median (n = 5)/mean (n = 1) reported or calculated follow ups were 7-54.5/17.3 months. Median overall survival was reported in three studies and ranged between 13.6-82.7 months. Crude survival in three others was 2-35 months. Conclusion: Limited, low-level evidence prevents firm conclusions, but based on the existing data, salvage surgery after local recurrence of NSCLC following SBRT appears technically feasible, with acceptable morbidity and mortality in appropriately selected and counselled patients who are fit enough and who accept the risks (level of evidence 4, strength of recommendation C). PMID- 30023009 TI - Improving drug adherence in osteoporosis: an update on more recent studies. AB - Similar to other chronic diseases such as diabetes and hypertension, osteoporosis has struggled with suboptimal medication adherence, resulting in an increased risk of fractures and all-cause mortality. The goal of this narrative review was to summarize interventions to improve medication adherence in osteoporosis. Because past reviews of this topic covered published literature through 2013, we conducted our literature search to include the period between January 2012 and November 2017. We identified 10 studies evaluating healthcare system and patient interventions aimed at improving osteoporosis treatment adherence, including three fracture liaison service (FLS) programs, one pharmacist-delivered counseling program, and six patient-directed interventions consisting of three coaching or counseling programs and three interventions using reminder prompts. Four out of the six patient-directed interventions did not lead to significant improvements in outcomes, suggesting that patient-directed interventions may have limited success in this setting. The healthcare system interventions that evaluated FLS programs and pharmacist-directed tailored counseling were effective at improving medication adherence; however, the studies were not randomized, they were costly, resource intensive and effective in countries with more centralized healthcare, possibly limiting their generalizability. In conclusion, while healthcare system interventions such as FLS, and pharmacist-delivered counseling appeared to be successful in improving osteoporosis medication adherence in some settings, behavioral interventions including patient counseling and reminder prompts for medication utilization were not, perhaps due to patient perceptions regarding osteoporosis consequences and need for treatment. Thus, these patient attributes may define patients 'at high risk' for poor adherence and developing intervention approaches to enhance patient knowledge and understanding of osteoporosis and its consequences may improve the perception of the need for treatment, optimize osteoporosis care and thereby improve overall outcomes of patients with osteoporosis. We hope that the knowledge gained through our review will help inform the design of further programs aimed at optimizing osteoporosis care. PMID- 30023007 TI - Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies. AB - Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit - for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities. PMID- 30023010 TI - Hypophosphatemia in the setting of metabolic bone disease: case reports and diagnostic algorithm. AB - Osteoporosis is the most commonly encountered metabolic bone disease, and metabolic bone-disease clinics have been established to assist in the diagnosis and treatment of uncommon causes of low bone-mineral density. Hypophosphatemia leading to metabolic bone disease may be encountered, and an understanding of phosphate homeostasis can aid in the diagnosis. Two cases of hypophosphatemia leading to low bone-mineral densities were seen at the University of Alabama at Birmingham Osteoporosis Clinic. We developed a diagnostic algorithm, and the laboratory values of each patient were tested with the algorithm. The algorithm, incorporating the use of a spot urine phosphate and spot urine creatinine level at the time of initial serum metabolic profile evaluation, accurately determined the cause of hypophosphatemia in each case. PMID- 30023012 TI - Editorial. PMID- 30023011 TI - Placental protein 13: An important biological protein in preeclampsia. AB - Placental protein 13 (PP13), a glycan binding protein predominantly expressed in syncytiotrophoblast, dimeric in nature, lacks N-terminal signal peptide, bypasses the endoplasmic reticulum, and secretes into maternal circulation as exosomes or microvesicles. PP13 has jelly roll fold conformation with conserved carbohydrate recognition domain which specifically binds to beta-galactosides of the glycan receptors during placentation. PP13 binds to glycosylated receptors on human erythrocytes and brings about hemagglutination by the property of lectin activity; other functions are immunoregulation and vasodilation during placentation and vascularization. The gene LGALS13 located on 19q13.2 comprising four exons expresses a 32-kDa protein with 139 amino acid residues, PP13. Impaired expression due to mutation in the gene leads to a nonfunctional truncated PP13. The low serum levels predict high risk for the onset of preeclampsia or obstetric complications. Hence, PP13 turned to be an early marker for risk assessment of preeclampsia. The recombinant PP13 and monoclonal antibodies availability help for replenishing PP13 in conditions with low serum levels and for detection and prevention of preeclampsia, respectively. PMID- 30023014 TI - Protein-Polymer Matrix Mediated Synthesis of Silver Nanoparticles. AB - Silver nanoparticles were synthesized in the protein-polymer matrices of two different ratios to obtain a stringent control over the morphology. UV-visible spectrophotometry showed a single plasmon resonance peak at 416nm and 418nm respectively, confirming the formation of silver nanoparticles. X-ray diffractometry confirmed that the peaks matched with that of the reference silver. Both confocal microscopy and FEG-SEM confirmed the uniform morphology of the synthesized particles dependent on the template ratio. Doubling the protein polymer concentration results in greater stability, more nucleation sites and hence restricted growth. Photoluminescence of the sample in the doubled matrix was found to be much greater at any given wavelength, meaning the flexibility and rigidity of interacting molecules affects the luminescence signal. The interaction in turn is dependent on the proximity of the proteins and polymer in the dispersion that forms a template and dictates the synthesis. PMID- 30023013 TI - Engineering Iron Oxide Nanoparticles for Clinical Settings. AB - Iron oxide nanoparticles (IONPs) occupy a privileged position among magnetic nanomaterials with potential applications in medicine and biology. They have been widely used in preclinical experiments for imaging contrast enhancement, magnetic resonance, immunoassays, cell tracking, tissue repair, magnetic hyperthermia and drug delivery. Despite these promising results, their successful translation into a clinical setting is strongly dependent upon their physicochemical properties, toxicity and functionalization possibilities. Currently, IONPs-based medical applications are limited to the use of non-functionalized IONPs smaller than 100 nm, with overall narrow particle size distribution, so that the particles have uniform physical and chemical properties. However, the main entry of IONPs into the scene of medical application will surely arise from their functionalization possibilities that will provide them with the capacity to target specific cells within the body, and hence to play a role in the development of specific therapies. In this review, we offer an overview of their basic physicochemical design parameters, giving an account of the progress made in their functionalization and current clinical applications. We place special emphasis on past and present clinical trials. PMID- 30023015 TI - Impact of Silver Nanoparticles on Haemolysis, Platelet Function and Coagulation. AB - Silver nanoparticles (Ag NPs) are increasingly used in biomedical applications because of their large antimicrobial spectrum. Data in the literature on the ability of Ag NPs to perform their desired function without eliciting undesirable effects on blood elements are very limited and contradictory. We studied the impact of Ag NPs on erythrocyte integrity, platelet function and blood coagulation. Erythrocyte integrity was assessed by spectrophotometric measurement of haemoglobin release. Platelet adhesion and aggregation was determined by light transmission aggregometry and scanning electron microscopy. The calibrated thrombin generation test was used to study the impact on coagulation cascade. We demonstrated that Ag NPs induced haemolysis. They also increase platelet adhesion without having any impact on platelet aggregation. Finally, they also had procoagulant potential. Bringing all data from these tests together, the no observed effect concentration is 5 MUg/mL. PMID- 30023017 TI - Tryptophan-Assisted Synthesis Reduces Bimetallic Gold/Silver Nanoparticle Cytotoxicity and Improves Biological Activity. AB - Aiming to reduce the potential in vivo hepato-and nephrotoxicity of Ag/Au bimetallic nanoparticles (NPs) stabilized by sodium dodecyl sulphate (SDS), an approach involving a simultaneous reduction of silver nitrate and tetrachlorauratic acid using tryptophan (Trp) as a reducing/stabilizing agent was applied during NP synthesis. The obtained Ag/Au/Trp NPs (5-15 nm sized) were able to form stable aggregates with an average size of 370-450 nm and were potentially less toxic than Ag/Au/SDS in relation to a mouse model system based on clinical biochemical parameters and oxidative damage product estimation. Ag/Au/Trp NPs were shown to exhibit anticancer activity in relation to a Lewis lung carcinoma model. The data generated from the present study support the fact that the use of tryptophan in NP synthesis is effective in attenuating the potential hepatotoxicity and nephrotoxicity of NPs during their in vivo application. PMID- 30023018 TI - Noncovalent Functionalization of Boron Nitride Nanotubes in Aqueous Media Opens Application Roads in Nanobiomedicine. AB - Boron nitride nanotubes (BNNTs) are of intense scientific interest due to their unique physiochemical properties and prospective applications in various nanotechnologies, particularly nanobiomedicine. A critical problem hampering the application processing of BNNTs is the outer sidewall functionalization, which is primarily acquired to lead BNNTs dispersible in various solvents. Furthermore, the surface of BNNTs should be intelligently designed and precisely controlled to satisfy the specific demands of different applications. For these purposes, covalent and noncovalent approaches have been factually developed to help to extend the full potential of applications. Importantly, wrapping the outermost sidewall of BNNTs with either water-soluble polymers or biomolecules through weak noncovalent interactions has been proved to be efficient for giving BNNTs considerable dispersity in aqueous media, and endowing novel chemical functions to BNNTs with almost no change in their pristine physiochemical properties. This article summarizes recent progress in this field and addresses future perspectives on the noncovalent functionalization of BNNTs for promoting their application processing in various bio-related nanotechnologies. PMID- 30023019 TI - Emerging Strategies and Applications of Layer-by-Layer Self-Assembly. AB - Layer-by-layer self-assembly is an approach to develop an ultrathin film on solid support by alternate exposure to positive and negative species with spontaneous deposition of the oppositely charged ions. This paper summarizes various approaches used for fabrication of layer-by-layer self-assembly as well as their utility to produce various devices. The layer-by-layer technique is basically used for formation of multilayer films. A variety of nanomaterials use it for the modification of films to enhance their resultant durability as well as strength. Studies have shown that many different types of materials can be used for fabrication of multilayers. Recently the layer-by-layer self-assembly technique has also been used for fabrication of gas sensors, hydrogen sensors and solar based cells. Various methods, such as spin deposition, calcinations, and dry transfer printing are being used for fabrication of thin films. In this review, the author summarizes the various interesting properties as well as fabrication strategies of layer-by-layer self-assembly. PMID- 30023016 TI - Micro and Nano-Scale Technologies for Cell Mechanics. AB - Cell mechanics is a multidisciplinary field that bridges cell biology, fundamental mechanics, and micro and nanotechnology, which synergize to help us better understand the intricacies and the complex nature of cells in their native environment. With recent advances in nanotechnology, microfabrication methods and micro-electro-mechanical-systems (MEMS), we are now well situated to tap into the complex micro world of cells. The field that brings biology and MEMS together is known as Biological MEMS (BioMEMS). BioMEMS take advantage of systematic design and fabrication methods to create platforms that allow us to study cells like never before. These new technologies have been rapidly advancing the study of cell mechanics. This review article provides a succinct overview of cell mechanics and comprehensively surveys micro and nano-scale technologies that have been specifically developed for and are relevant to the mechanics of cells. Here we focus on micro and nano-scale technologies, and their applications in biology and medicine, including imaging, single cell analysis, cancer cell mechanics, organ-on-a-chip systems, pathogen detection, implantable devices, neuroscience and neurophysiology. We also provide a perspective on the future directions and challenges of technologies that relate to the mechanics of cells. PMID- 30023020 TI - Modified Seed Growth of Iron Oxide Nanoparticles in Benzyl Alcohol - Optimization for Heating and Broad Stability in Biomedical Applications. AB - Iron oxide nanoparticles have received sustained interest for biomedical applications as synthetic approaches are continually developed for control of nanoparticle properties. However, many approaches focus solely on the material, rather than the complete optimization of synthesis and functionalization together to enhance translation into biological systems. Presented herein is a modified seed growth method designed for obtaining optimal nanoparticle properties and ease of surface functionalization for long term stability. With a one or two addition process, iron oxide nanoparticles were produced in crystallite sizes ranging from 5-15 nm using only benzyl alcohol and an iron precursor. In the functionalization process, concentration variations were required for stabilizing different nanoparticle sizes. Radio frequency induction heating experiments of various crystallite and hydrodynamic sizes verified that the heating efficiency greatly increased while approaching the 15 nm crystallite, and suggested an important role of the overall particle size on heating efficiency. Initial in vitro experiments with the functionalized nanoparticles showed success in providing hyperthermia-induced tumour cell killing without an increase in the temperature of the cell suspension medium. This demonstrates the potential for nanoparticle-based hyperthermia to provide a therapeutic effect while limiting normal tissue damage. PMID- 30023021 TI - Impact of printed antimicrobial stewardship recommendations on early intravenous to oral antibiotics switch practice in district hospitals. AB - Background: Early intravenous to oral (IV-PO) antibiotics switch, which is one of the important elements in antimicrobial stewardship (AMS) is not well implemented in Malaysian district hospitals. A systematic interventional strategy is required to facilitate IV-PO antibiotic switch. Objective: This study aimed to evaluate the impact of printed AMS recommendations on early IV-PO antibiotics switch practice in district hospitals. Methods: This study was an interventional study conducted in medical wards of eight Sarawak district hospitals from May to August 2015. In pre-intervention phase, pharmacists performed the conventional practice of reviewing medication charts and verbally informed the prescribers on eligible IV-PO switches. In post-intervention phase, pharmacists attached printed checklist which contained IV-PO switch criteria to patients' medical notes on the day patients were eligible for the switch. Stickers of IV-PO switch were applied to the antibiotic prescription to serve as reminders. Results: 79 and 77 courses of antibiotics were studied in the pre-intervention phase and post-intervention phase respectively. Timeliness of switch was improved by 1.63 days in the post intervention phase (95%CI 1.26:2.00 days, p<0.001). Mean duration of IV antibiotics in the post-intervention phase was shorter than pre-intervention phase (2.81 days (SD=1.77) vs 4.05 days (SD=2.81), p<0.001). The proportion of IV PO switches that were only performed upon discharge reduced significantly in the post-intervention phase (31.2% vs 82.3%, p<0.001). Length of hospital stay in the post-intervention phase was shortened by 1.44 days (p<0.001). Median antibiotic cost savings increased significantly in the post-intervention phase compared to the pre-intervention phase [MYR21.96 (IQR=23.23) vs MYR13.10 (IQR=53.76); p=0.025)]. Conclusions: Pharmacist initiated printed AMS recommendations are successful in improving the timeliness of IV-PO switch, reducing the duration of IV, reducing the length of hospitalisation, and increasing antibiotic cost savings. PMID- 30023022 TI - Pharmaceutical care in community pharmacies in Jordan: a public survey. AB - Objective: This study aims to assess the views and attitudes of the general public towards the current role of pharmacists in Jordan. Methods: This study is a cross-sectional quantitative questionnaire-based study. After a thorough literature review on public perspectives of pharmaceutical care services, a draft questionnaire was designed. This questionnaire was examined and discussed in a focus group of invited public members and was amended accordingly to reach the final draft. The questionnaire was administered using a structured interview technique in which members of the public were asked a series of questions by a trained pharmacist. The study took a place over a period of six months, from January to June 2013. Individuals were recruited from urban and rural areas of Jordan. Results: A total of 1214 respondents were interviewed during the study. Of the respondents, 67.8% were female. Most of the respondent were married (64%) and had a university degree (88.5%). Approximately half of the respondents (55.1%) had no previous knowledge of pharmaceutical care. A relative majority of respondents considered the most important activity performed by pharmacists to be dispensing medications (46.2%), followed by patient counseling (34.6%). The majority of respondents (86.4%) believed that pharmacists have a role in providing healthcare services, and 68% of respondents reported that in order to serve their needs, a pharmacist must consider the patient's needs and engage patients in determining medication timing and options. Conclusions: The plurality of respondents believed in the importance of pharmacists in providing pharmaceutical care services. However, respondents expected much from pharmacists and felt that their current role was unsatisfying. PMID- 30023023 TI - Assessing the perceptions of pharmacists working in Lebanese hospitals on the continuing education preferences. AB - Background: Continuing education (CE) is an international tool that requires lifelong active participation in learning activities allowing the pharmacist to stay a major player among others. In 2014 the CE program was introduced to the pharmacists licensed in Lebanon as a mandatory requirement for re-licensure. In the absence of guidelines regarding the quality and quantity of CE programs, behavioral resistance to precipitate in the CE programs might be encountered among the pharmacists. Objective: The objective of this study is to assess the perceptions of pharmacists working in Lebanese hospitals on the continuing education preferences. The advantage of this program is to collect information that would help the Order of Pharmacy in Lebanon to upgrade the CE program in a way that is more acceptable and convenient for the pharmacists. Methods: A cross sectional study was carried out in 2016, using a proportionate random sample of Lebanese hospital pharmacies from all governorates in Lebanon. A structured questionnaire was distributed to all hospital pharmacies in Lebanon. Descriptive statistics were calculated for all study variables. This includes the mean and standard deviation for continuous measures, counts and percentages for categorical variables. Results: A total of 107 (53.5%) participants completed the questionnaires. The majority of participants were from Beirut and Mount Lebanon. The percentage of participants working at private hospitals was (68.2%).The majority of participants who completed the questionnaire (86.2%) agreed that continuing education programs affects their way of practice and increases their knowledge. Their preferred CE types to be used in the future were the computer based ones (60.6%), interactive workshops (45.5%) and printed materials (44.9%). Their considerations for selecting the CE type is based on their interest in the topic (80.6%), the ease of access to print or online material (77.2%), or the convenience of being offered during an event (67.1%). Participants noted that barriers to attend live CEs were mainly work responsibilities (76%), travel distance (65.6%), family commitments (48.4%) and scheduling (40.6%). Conclusions: Lebanese hospital pharmacists are highly committed to CE. They consider it a practical tool for career development and advancement. PMID- 30023024 TI - Evaluating glycemic control for patient-aligned care team clinical pharmacy specialists at a large Veterans Affairs medical center. AB - Background: Management of diabetes mellitus (DM) remains a challenge in the US, as almost half of patients with diabetes are uncontrolled with a hemoglobin A1c (HbA1c) >7%. Over the last decade there has been increasing evidence supporting the integration of Clinical Pharmacy Specialists (CPSs) to multidisciplinary medical teams which have demonstrated improved glycemic control and better clinical outcomes in the primary care setting. Objectives: The primary objective of this study was to evaluate the change in HbA1c levels in patients with diabetes followed by a CPS. The secondary objectives of this study were to evaluate the percent of patients who reached American Diabetes Association (ADA) goal HbA1c (<7%) by study conclusion and evaluate documentation of hypoglycemic events in progress notes. Methods: A retrospective chart review evaluating glycemic control was conducted on patients with DM managed by a CPS at a large Veterans Affairs Medical Center. Patients with a diagnosis of Type 1 or Type 2 DM with a baseline HbA1c >=9% and at least three CPS visits over twelve months were included in this study. Patients with cognitive impairment as documented by ICD-9 codes or with less than three CPS visits over twelve months were excluded. Results: A sample of 79 patients was identified. The mean HbA1c declined by 1.5 percentage points (from 10.6%, SD=1.4 to 9.1%, SD=1.5) after one year. No patients reached ADA goal of HbA1c <7% at study conclusion, however 23% of patients reached a less stringent goal of <8%. All CPS progress notes assessed episodes of hypoglycemia and provided education, and no hospitalizations were related to hypoglycemic events. Conclusions: Integration of a CPS into a veteran's diabetes care was associated with improved outcomes and enhanced hypoglycemic education. Our results advance the existing literature by demonstrating a positive association between CPS intervention and improved glycemic control in a complex veteran population. PMID- 30023025 TI - Community pharmacists' perceptions towards online health information in Kuala Lumpur, Malaysia. AB - Objective: The current study was carried out to assess community pharmacists' perceptions towards online health information, to examine the type of information seek from Internet and to identify the barriers when they retrieved online health information. Methods: The study was designed as a cross-sectional questionnaire based survey whereby all (300) community pharmacists practicing in Federal Territory of Kuala Lumpur, Malaysia were targeted for data collection. A 35 itemed questionnaire was posted out along with a stamped addressed envelope, invitation letter and support letter. Responses were also accepted via online response. Both descriptive and inferential statistics were used for data analysis. All statistical analysis was performed using SPSS v. 20.0. Results: A total of 67 responses were received with a response rate of 22.3%. The top three frequently health information searched by respondents were medicine information, general healthcare information and disease-related information. High number of respondents agreed that Internet had too much health information to scan through. Gender (p=0.018) showed significant association with visiting established health websites. Meanwhile, statistical significant was observed between age and searching medicine information (p=0.037), undertaking online continuing professional development (p=0.023), as well as searching clinical guidelines (p=0.047). Respondents' education level showed significant association with uncertainty about the reliability of online health information (p=0.023) and unsure about filtering the information (p=0.007). Conclusions: Majority of the respondents expressed positive perception with the use of Internet for health information. The findings of the current study showed the widely use of Internet for health information among community pharmacists. Hence, this study provides opportunity for future works to further examine community pharmacist's retrieval and appraisal skills for online health information, as well as application of this information into their daily pharmacy practice. PMID- 30023026 TI - A cross-sectional survey on cold chain management of vaccines in Cebu, Philippines. AB - Background: Appropriate cold chain management is the foundation of safety and quality of vaccines. Objectives: This cross-sectional study was conducted to assess the cold chain management of the rural health units of Consolacion and Liloan, Cebu, Philippines on August to September 2017. Methods: Data was collected using a structured questionnaire, which was developed based on previous studies of cold chain survey. The questionnaire was administered to one personnel who is responsible for the storage and maintenance of vaccines in each public health center (PHC). Results: Of 42 targeted PHCs, only 52.4% (n=22) agreed to join in the study. The results of the study indicated that storage units and equipments were available in all 22 PHCs, even though only five of them (22.7%) stored vaccines. The majority of PHCs (90.9%, n=20) did not have access to a generator and only 9% (n=2) had a voltage stabilizer connected to the refrigerator. Refrigerators that were equipped with thermometer were only found in 68.2% (n=15) PHCs. No statistically significant relationship was found (p=0.159) between the statuses of PHCs to store vaccine and the level of knowledge of health professionals assigned to manage the vaccine. Conclusions: Primary health centers that store vaccines have at least one functional refrigerator and freezer and alternative power sources. Contingency plans in the event of mechanical and power failure as well as proper temperature monitoring are needed. Personnel handling vaccines must be updated on proper storage and transport of such like the use of cold boxes and ice packs to maintain cold chain. Improvement of cold-chain management for vaccines in Cebu City's PHCs was necessary. PMID- 30023027 TI - What drives using antibiotic without prescriptions? A qualitative interview study of university students in United Arab Emirates. AB - Background: Bacterial resistance to antibiotics is considered as natural phenomenon that occurs over the time due to genetic changes. Bacterial resistance to antibiotics is significantly increasing in the UAE. Self-medication with antibiotics has been identified as a major factor for the development of antibiotic resistance, which is significantly increasing in the UAE. Objectives: The purpose of this study was to explore the factors that contribute to the use of antibiotics without prescriptions among first year healthcare university students in UAE. Methods: Based on the findings of an earlier survey study, a qualitative interview study was designed to explore common themes related to student's knowledge, awareness, attitude, views, and perceptions. Data were analyzed thematically for the identification of themes and subthemes within the data through the use of coding. Results: The interview study identified four main themes with multiple subthemes related to the use of antibiotics without a physician's prescription by first-year healthcare students. The thematic analysis of the interviews revealed four main themes; medication habits and practices; reasons for self-medication; access to antibiotics without a prescription and gaps in students' knowledge regarding antibiotic resistance. Conclusions: Healthcare students in UAE are influenced by several factors including parents and friends influence, successful previous experience and investment of time and money to visit a physician. Our sample of healthcare students has a misconception about the use of antibiotics. The current interview study identified six new reasons for using antibiotics without prescriptions as compared to our earlier survey study. There is a need of multifaceted strategies to decrease unnecessary antibiotic use in our population sample. PMID- 30023028 TI - Magnitude and determinants of uncontrolled blood pressure among hypertensive patients in Ethiopia: hospital-based observational study. AB - Background: Hypertension is an important public health problem worldwide. There is lack of data on uncontrolled blood pressure in developing countries. Objectives: To determine the magnitude and predicting factors of uncontrolled blood pressure in hypertensive patients attending Gondar university hospital, Ethiopia. Methods: A hospital-based cross-sectional survey was conducted from July 2015 to March 2016. All hypertensive patients were followed and the blood pressure levels were measured. Binary logistic regression analysis was done to determine the predictors of uncontrolled blood pressure. A p-value of <0.05 was set at priori with 95% confidence interval to test the level of significance. Results: Of the total 578 hypertension patients, 543 (93.9%) fulfilled the study criteria and were included in the final analysis. The mean age of the participants was 55.96+/-14.6 years. Nearly two-third (58.2%) of the participants were females. More than one-tenth (11.4%) of the respondents had uncontrolled blood pressure. High salt intake carried six times more risk of uncontrolled blood pressure. Elderly individuals had lower risk as compared to young age group. However, comorbidities were not related with uncontrolled blood pressure. Conclusions: Blood pressure control was relatively high in the hospital studied. High salt intake was strongly linked with uncontrolled blood pressure. Individuals with high salt intake should be followed for their medication experience and disease knowledge. PMID- 30023030 TI - Assessing adherence to current national guidelines for appropriate albumin use at an academic medical center. AB - Objective: To assess adherence to current national guidelines for appropriate albumin use at an academic medical center. Methods: This retrospective chart review of 150 randomly selected patients prescribed and administered at least one dose of albumin was conducted in an urban academic medical center to evaluate the adherence of albumin orders to current national guidelines. Inclusion criteria consisted of discharged patients at least 18-years-old admitted to the intensive care unit or medical/surgical unit from September 1, 2015 to August 31, 2016. The primary outcome was the number of patients who inappropriately received albumin based on national guidelines and FDA approved indications. Secondary outcomes included the number of patients who received the incorrect concentration or dose of albumin based on indication, as well as the cost associated with inappropriate albumin prescribing. Descriptive statistics were used to report outcomes. Results: There were 68 instances (45%) where albumin was prescribed inappropriately according to guideline recommendations. Of the 82 instances where albumin was used appropriately, 18 patients received an incorrect dose (22%), and 6 received the inappropriate concentration of albumin (7%). The cost for the 150 patients included in the study associated with inappropriate albumin prescribing was approximately $13,000. Conclusions: This study identified areas for pharmacist intervention to ensure appropriate albumin utilization, as well as proper dosing for the most frequently incorrectly dosed indications, including hepato-renal syndrome, spontaneous bacterial peritonitis, and paracentesis. This study also identified an unexpected indication with significant inappropriate albumin utilization, perioperative hypotension, which is an area for further intervention to monitor and decrease use. PMID- 30023029 TI - Communicating risk of medication side-effects: role of communication format on risk perception. AB - Background: Medication side-effects often arouse fear in the minds of consumers and therefore need to be communicated in a manner such that the intended message is clearly understood, without causing undue fear. Objectives: Considering the message format and contextual factors that influence perceptions of risk, this study aimed at assessing the interaction effects of message format and contextual factors (rate of occurrence and severity) on risk perception of medication side effects. Methods: Using Rhormann's risk communication process model, a 2 (message format: words-only vs. words + numeric) X 2 (rate of occurrence: high vs low) X 2 (severity: mild vs severe) experimental factorial study was designed. Participants were presented with four of eight possible combinations of the three factors and were asked to indicate the risk perception with the associated side effects. Repeated measures analysis was conducted while adjusting for control variables. Results: A total of 196 completed surveys were collected. Communication format did not have significant main effect on risk perception (P=0.4237) but demonstrated a significant interaction with rate of occurrence (P=0.0001). As compared to words-only format, least square means for words + numeric format were lower among low-rate side-effects but were higher among high rate side-effects. Rate of occurrence (P<0.0001) and severity (P<0.0001) had significant main effects on risk perception as well as interaction effect with each other (P<0.0001). Conclusions: The results indicated that effect of communication format on risk perception of side-effect is dependent on the underlying rate of occurrence of side-effect. Healthcare providers should therefore carefully construct risk communication messages for effective communication with patients. PMID- 30023031 TI - An initial exploration of the perceptions of preparedness to practise among Saudi Arabian trained hospital pharmacists. AB - Background: There is a dearth of literature on perceptions of preparedness to practise, which explores the extent to which educational institutions prepare their students to fulfil their professional role. Objective: The aim of this study was to explore perceptions of preparedness to practise among Saudi Arabian pharmacy graduates working in hospital. Method: Face-to-face, semi-structured interviews were conducted with ten hospital pharmacists based in four hospitals in the Eastern Province of Saudi Arabia who had qualified within the last five years from a Saudi Arabian School of Pharmacy. Interviews focused on expectations of hospital practise, perceptions of preparedness and challenges encountered, and reflections on how to better prepare students. Interviews were audio-recorded, transcribed and analysed thematically by two independent researchers using the Framework Approach. Results: Five key themes were identified: expectations versus reality of practise; issues relating to university course; practice related training; adapting to the work environment; and proposed improvements to undergraduate education. Participants were generally disappointed to find practise was not as expected. University training was largely didactic, with skills such as critical thinking not being sufficiently developed. Where practice related training was provided, it was variable in length and content. Cultural issues, most notably working in a mixed sex environment, were also considered to impact preparedness. Suggested improvements included greater focus on skills development and structured training placements. Conclusions: Participants experiences in university, and experiential placements varied greatly and were perceived to impact greatly on preparedness to practise. Further multiple perspective exploration of perceptions of preparedness to practise is warranted. PMID- 30023032 TI - Paediatric antimicrobial stewardship and safe prescribing: an assessment of medical staff knowledge and behaviour. AB - Objective: Determine baseline knowledge of antimicrobial stewardship, and safe prescribing among junior medical officers, monitor their level of participation in interactive education during protected teaching time and assess day-to-day prescribing behaviours over the subsequent 3-month period. Methods: A voluntary and anonymous survey of all non-consultant level medical officers was conducted with the use of an audience response system during mandatory face-to-face orientation sessions at a tertiary paediatric hospital. Routine prescribing audits monitored compliance with national and locally derived quality use of medicines indicators. Results: Eighty-six percent of medical officers participated by responding to at least one question (171/200). Response rate for individual questions ranged between 31% and 78%. Questions that addressed adverse drug reactions, documentation and monitoring for empiric antibiotics and the error-prone abbreviations IU and U were correctly answered by over 90% of participants. Other non-standard and error-prone abbreviations were less consistently identified. In practice, 68% of patients had complete adverse drug reaction documentation (113/166). Error-prone abbreviations were identified on 5% of audited medication orders (47/976), approximately half included a documented indication and intended dose. Conclusions: Participants demonstrated a good understanding of safe prescribing and antimicrobial stewardship. Audits of prescribing identified potential discrepancies between prescribing knowledge and behaviours. PMID- 30023034 TI - Contrast enhanced genitosonography (CEGS) of urogenital sinus: A case of improved conspicuity with image inversion. AB - Imaging plays a pivotal role in evaluating the urogenital anatomy in children with ambiguous genitalia. Contrast enhanced genitosonography (CEGS) represents a low-cost and radiation-free alternative to the traditional techniques of fluoroscopic genitography and magnetic resonance imaging. We report a case of a child with ambiguous genitalia whose urogenital sinus anomaly is clearly demonstrated using CEGS and the postprocessing technique of image inversion. This case report shows the utility of CEGS in this patient population and the enhanced conspicuity with image inversion. PMID- 30023033 TI - Differences and similarities between Journal Impact Factor and CiteScore. AB - Two major journal-based metrics are in competition: the Journal Impact Factor and CiteScore. Although these two metrics are based on similar principles of measuring the impact by citations, some differences between them exist. Years used to calculate the metric, access to computing data, and number of journals covered are some of these differences. One of the most relevant differences for pharmacy journals is the recognition in CiteScore of Pharmacy as an independent Subject Area, whereas it appears to have merged with pharmacology in the Journal Citation Reports. The immediate consequence of this differentiation is that pharmacy journals remain in the third and fourth quartiles in the Journal Impact Factor distribution, while a true quartile distribution exists in CiteScore. PMID- 30023035 TI - Concurrent acute appendicitis and ileocolic intussusception in a 1-year-old child. AB - Intussusception and acute appendicitis are part of a differential diagnosis for acute abdominal pain and vomiting in the pediatric population. We describe a unique case combining appendiceal intussusception with concurrent acute appendicitis, or "appendi-sception." A 1-year-old boy presented with 1 day of fussiness, vomiting, and red, gelatinous stool. Initial diagnosis on ultrasound was a routine ileocolic intussusception with nonvisualization of the appendix. However, after a failed air enema decompression, the patient was taken to the operating room where the appendix was discovered to be inflamed within the intussusceptum. This case is unique as few cases of both conditions occurring simultaneously have been previously described. It is important for radiologists to be aware of this combination of diagnoses as both require urgent evaluation and prompt treatment. PMID- 30023036 TI - A case of Caplan syndrome in a recently diagnosed patient with silicosis: A case report. AB - Rheumatoid pneumoconiosis, also known as Caplan's syndrome is defined as the association between silicosis and rheumatoid arthritis (RA). It is a rare and usually diagnosed in an advanced stage of RA course. It affects generally patients with long exposure to silica. In this article, we report a case of Caplan's syndrome. PMID- 30023037 TI - Acute traumatic superficial femoral arterial laceration findings on computed tomographic angiography: A case report. AB - We present a case of superficial femoral artery laceration that was identified on computed tomographic angiography. The patient was a 25-year-old man who injured his right proximal thigh while using a wood sanding machine and was transferred to our emergency department in a state of hemorrhagic shock. Following resuscitation, preoperative computed tomographic angiography helped predict the arterial injury and aided us in prompt diagnosis and decisive management. PMID- 30023038 TI - Meshed Split-Thickness Autograft With a Viable Cryopreserved Placental Membrane Overlay for Lower-Extremity Recipient Sites With Increased Risk of Graft Failure. AB - Introduction: Meshed split-thickness skin grafting represents a rapid and effective technique for surgical wound closure. Factors such as ongoing inflammation, microbial colonization, and a poorly vascularized wound bed increase the rate of skin autograft failure up to 33%. Because of the inherent angiogenic, anti-inflammatory, antimicrobial, and antifibrotic properties of human placental membranes, the complementary use of human placental membranes may promote graft survival and improve success rate for complete ulcer resolution. Methods: In this case series, a viable cryopreserved placental membrane was used as a meshed split-thickness skin grafting overlay in 6 high-risk patients with various comorbidities and recalcitrant nonhealing lower-extremity wounds. Results: The mean size of grafted wounds was 130.3 cm2. The average graft take rate by postoperative days 10 to 14 was 92.5%, with complete epithelialization of all skin graft interstices observed between days 10 and 21. Transplanted autograft tissues did not lyse or dissolve, and sites remained free of infection and maceration throughout postoperative follow-up. Complete wound closures remained intact at the 12-month follow-up visit. Discussion: Thus far, our clinical experience has warranted the complementary use of viable cryopreserved placental membrane and meshed split-thickness skin grafting to reduce the need for repeat surgical interventions or prolonged local wound care due to graft loss or failure in high-risk patients. PMID- 30023039 TI - Unilateral Cleft Lip Repair With a Simple Assymetric Z-plasty. AB - Objective: The objective of this case report is to provide an example of the repair of a complete unilateral cleft lip using a modification of the classic Z plasty. Methods: A Z-plasty for cleft lip is described that does not depend on measurements and formulas. The tissue available on the lateral lip "unit" determines the limb length of the Z: from cupid's bow to the highest point of "good" lip skin. This length is then transposed to the medial side, scribing an arc from both cupid's bows. Where the arcs intersect determines length and direction of the releasing incision. The angles are not predetermined as in a classic Z. The incisions are made "on block" through skin, muscle, and mucosa. Flap transposition uprights the isosceles triangle-shaped philtrum, aligning the cupid's bows. Results: All degrees of unilateral cleft lips have been successfully repaired using this technique. The operation is simple, rapid, and dependable. There is minimal bleeding, as there is no muscle dissection. On both medial and lateral sides, the muscle is transposed toward the free border, that is, downward. Achieving downward rotation of cupid's bows along with the philtrum dimple provides attractive fullness and pout to the lower part of the upper lip. Fullness and length are permanently maintained by the medially based flap under the nose. Conclusions: The Z-plasty is well suited for unilateral cleft lip repair. It is especially useful for wide, complete cases but is applicable to all types of unilateral cleft lips. It is a simple, fast, and stable repair. PMID- 30023040 TI - MULTI-TASK SPARSE SCREENING FOR PREDICTING FUTURE CLINICAL SCORES USING LONGITUDINAL CORTICAL THICKNESS MEASURES. AB - Cortical thickness estimation performed in-vivo via magnetic resonance imaging (MRI) is an effective measure of brain atrophy in preclinical individuals at high risk for Alzheimer's disease (AD). However, the high dimensionality of individual cortical thickness data coupled with small population samples make it challenging to perform cortical thickness feature selection for AD diagnosis and prognosis. Thus far, there are very few methods that can accurately predict future clinical scores using longitudinal cortical thickness measures. In this paper, we propose an unsupervised dictionary learning algorithm, termed Multi-task Sparse Screening (MSS) that produces improved results over previous methods within this problem domain. Specifically, we formulate and solve a multi-task problem using extracted top-p significant features from the Alzheimer's Disease Neuroimaging Initiative (ADNI) longitudinal data. Empirical studies on publicly available longitudinal data from ADNI dataset (N = 2797) demonstrate improved correlation coefficients and root mean square errors, when compared to other algorithms. PMID- 30023041 TI - Rapid Facial Reactions in Response to Facial Expressions of Emotion Displayed by Real Versus Virtual Faces. AB - Facial expressions of emotion provide relevant cues for understanding social interactions and the affective processes involved in emotion perception. Virtual human faces are useful for conducting controlled experiments. However, little is known regarding the possible differences between physiological responses elicited by virtual versus real human facial expressions. The aim of the current study was to determine if virtual and real emotional faces elicit the same rapid facial reactions for the perception of facial expressions of joy, anger, and sadness. Facial electromyography (corrugator supercilii, zygomaticus major, and depressor anguli) was recorded in 30 participants during the presentation of dynamic or static and virtual or real faces. For the perception of dynamic facial expressions of joy and anger, analyses of electromyography data revealed that rapid facial reactions were stronger when participants were presented with real faces compared with virtual faces. These results suggest that the processes underlying the perception of virtual versus real emotional faces might differ. PMID- 30023044 TI - Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies. AB - Polymorphisms in the T cell (or transmembrane) immunoglobulin and mucin domain 1 ( TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1 Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation. PMID- 30023042 TI - The role of acid inhibition in Helicobacter pylori eradication. AB - Infection of the stomach by the gastric pathogen Helicobacter pylori results in chronic active gastritis and leads to the development of gastric and duodenal ulcer disease and gastric adenocarcinoma. Eradication of H. pylori infection improves or resolves the associated pathology. Current treatments of H. pylori infection rely on acid suppression in combination with at least two antibiotics. The role of acid suppression in eradication therapy has been variously attributed to antibacterial activity of proton pump inhibitors directly or through inhibition of urease activity or increased stability and activity of antibiotics. Here we discuss the effect of acid suppression on enhanced replicative capacity of H. pylori to permit the bactericidal activity of growth-dependent antibiotics. The future of eradication therapy will rely on improvement of acid inhibition along with current antibiotics or the development of novel compounds targeting the organism's ability to survive in acid. PMID- 30023043 TI - Developing new therapeutic approaches for rheumatoid arthritis: the continuing challenges of clinical assessments. AB - The management of rheumatoid arthritis has changed dramatically over the last three decades. Improvements in clinical assessment have been a key driver of these changes. However, in the last five years, three areas of unresolved uncertainty have dominated specialist thinking in the field. These challenges comprise identifying the optimal management target, determining how best to reach this target by using intensive treatments, and individualising management because not all patients need or respond to identical treatments. The key problem that links each of these areas is balancing different types of evidence and is most readily appreciated in relation to treatment intensity. Giving more intensive therapy improves outcomes but also increases risks and, with biologic treatments, substantially increases drug costs. Specialists and healthcare funders need to agree on how best to rationalise optimal care for patients with what is most effective and safe and what is affordable. PMID- 29333257 TI - Recent advances on gradient hydrogels in biomimetic cartilage tissue engineering. AB - Articular cartilage (AC) is a seemingly simple tissue that has only one type of constituting cell and no blood vessels and nerves. In the early days of tissue engineering, cartilage appeared to be an easy and promising target for reconstruction and this was especially motivating because of widespread AC pathologies such as osteoarthritis and frequent sports-induced injuries. However, AC has proven to be anything but simple. Recreating the varying properties of its zonal structure is a challenge that has not yet been fully answered. This caused the shift in tissue engineering strategies toward bioinspired or biomimetic approaches that attempt to mimic and simulate as much as possible the structure and function of the native tissues. Hydrogels, particularly gradient hydrogels, have shown great potential as components of the biomimetic engineering of the cartilaginous tissue. PMID- 29333235 TI - Case Report: Synchronous primary malignancy including the breast and endometrium. AB - Breast and endometrial cancer are the most common types of female cancers, but the incidence of both of these malignancies in a single patient is a rare event. Multiple primary malignancy has been increasingly reported over the past decade, and double primary cancer is considered as the most common type. In this study, we present a 53-year-old woman with synchronous primary malignancy of breast and endometrium. This patient had a history of breast and endometrial cancer in her family. Mammography and chest CT of the patient revealed a mass in the right breast and left supraclavicular region. However, the patient did not want to initiate treatment. Subsequently, the patient returned with a chief complaint of persistent abnormal vaginal bleeding. Abdominopelvic CT scan of the patient revealed a huge soft tissue mass in the pelvic cavity. She underwent hysterectomy, and pathology revealed endometrioid carcinoma, which had invaded the full thickness of uterine wall. Since this type of malignancy is rare and several risk factors are associated with it, it is worth being considered by clinicians when making decisions about screening or strategy for prevention. PMID- 29511531 TI - netSmooth: Network-smoothing based imputation for single cell RNA-seq. AB - Single cell RNA-seq (scRNA-seq) experiments suffer from a range of characteristic technical biases, such as dropouts (zero or near zero counts) and high variance. Current analysis methods rely on imputing missing values by various means of local averaging or regression, often amplifying biases inherent in the data. We present netSmooth, a network-diffusion based method that uses priors for the covariance structure of gene expression profiles on scRNA-seq experiments in order to smooth expression values. We demonstrate that netSmooth improves clustering results of scRNA-seq experiments from distinct cell populations, time course experiments, and cancer genomics. We provide an R package for our method, available at: https://github.com/BIMSBbioinfo/netSmooth. PMID- 29904596 TI - Scepticaemia: The impact on the health system and patients of delaying new treatments with uncertain evidence; a case study of the sepsis bundle. AB - BACKGROUND: A sepsis care bundle of intravenous vitamin C, thiamine, and hydrocortisone was reported to improve treatment outcomes. The data to support it are uncertain and decision makers are likely to be cautious about adopting it. The objective of this study was to model the opportunity costs in dollars and lives of waiting for better information before adopting the bundle. METHODS: A decision tree was built using information from the literature. We modelled the impact of bundle adoption under three scenarios using a simulation in which the bundle was effective as reported in the primary trial, less effective based on other information, and ineffective. The measurements were health services costs, quality-adjusted life years, and transition probabilities. RESULTS: If the bundle proves to be effective under either scenario, it will save billions of dollars and millions of life-years in the United States. This is the opportunity cost of delaying an adoption decision and waiting for better quality evidence. We suggest that hospital decision-makers consider implementing the bundle on a trial basis while monitoring costs and outcomes data even while the evidence base is uncertain. CONCLUSIONS: If the decision maker is unwilling to use the best available evidence now, but rather wishes to wait for definitive evidence they are risking incurring large costs for health care systems and for the patients they serve. An explicit analysis of uncertain clinical outcomes is a useful adjunct to guide decision making where there is clinical ambiguity. This approach offers a valid alternative to the default of clinical inactivity when faced with uncertainty. PMID- 30023051 TI - Definition and use of "valid" district level vaccination coverage to monitor Global Vaccine Action Plan (GVAP) achievement: evidence for revisiting the district indicator. AB - Background: The Global Vaccine Action Plan (GVAP) Monitoring and Accountability Framework includes an indicator to reach 90% national vaccination coverage and 80% vaccination coverage in every district or equivalent administrative unit with three doses of diphtheria-tetanus-pertussis containing vaccines (DTP) across all 194 country signatories to GVAP by 2020. Assessment of progress against the district indicator component requires GVAP defined "valid" coverage. GVAP defines district coverage "valid" if the WHO and UNICEF estimate of national immunization coverage for DTP3 in the most recent year is 1) >=90%, or 2) is identical to the reported national administrative coverage for DTP3 (regardless of coverage level). We draw attention to the potential disconnect that currently exists between GVAP vaccination coverage indicators and the practical capacity to monitor progress against those indicators. Methods: We obtained national and aggregated district coverage data for the third dose of DTP containing vaccine (DTP3) for 194 countries for 2016 from publicly available databases maintained by the World Health Organization (WHO). We reviewed district line lists of coverage data for 96 countries for which district line lists of DTP3 coverage were available and categorized the district coverage values using the same groupings used by the GVAP Monitoring Framework. In doing so, we also tracked the number of districts with reported coverage >100%. Results: In 2016, at least one district with DTP3 coverage value >100% was reported in the line lists of 76 of the 96 countries. Agreement in district coverage categories across each of five coverage groupings (<50%, 50-79%, 80-89%, 90-94%, >=95%) was observed in 43 of the 96 countries. In 2016, 46 of 194 countries were classified as achieving both national DTP3 coverage >=90% and DTP3 coverage >=80% in every district, thereby achieving the GVAP target. Among these 46 countries, 22 countries reported district line-listing coverage data. We identified 10 of the 22 countries that reported at least one district with DTP3 coverage >100% ranging from 8% of districts in Sri Lanka to 97% of districts in Bangladesh. Seven countries reported at least 25% of the total districts had DTP3 coverage >100%. Conclusions: The observations of disparate district coverage from a subset of countries reporting district line lists of coverage data are a concern for the current GVAP approach ascribing the achievement of "valid" district coverage data. Our review of district line lists of coverage data does not support a current GVAP assumption that the district coverage values >=80% fall between 80% and 100% (inclusive). We hope these results spur a review of the current approach to assess the GVAP coverage target of >=90% national DTP3 coverage and >=80% DTP3 coverage in all districts. PMID- 30023050 TI - Service readiness for inpatient care of small and sick newborns: what do we need and what can we measure now? AB - Background: Each year an estimated 2.6 million newborns die, mainly from complications of prematurity, neonatal infections, and intrapartum events. Reducing these deaths requires high coverage of good quality care at birth, and inpatient care for small and sick newborns. In low- and middle-income countries, standardised measurement of the readiness of facilities to provide emergency obstetric care has improved tracking of readiness to provide care at birth in recent years. However, the focus has been mainly on obstetric care; service readiness for providing inpatient care of small and sick newborns is still not consistently measured or tracked. Methods: We reviewed existing international guidelines and resources to create a matrix of the structural characteristics (infrastructure, equipment, drugs, providers and guidelines) for service readiness to deliver a package of inpatient care interventions for small and sick newborns. To identify gaps in existing measurement systems, we reviewed three multi-country health facility survey tools (the Service Availability and Readiness Assessment, the Service Provision Assessment and the Emergency Obstetric and Newborn Care Assessment) against our service readiness matrix. Findings: For service readiness to provide inpatient care for small and sick newborns, our matrix detailed over 600 structural characteristics. Our review of the SPA, the SARA and the EmONC assessment tools identified several measurement omissions to capture information on key intervention areas, such as thermoregulation, feeding and respiratory support, treatment of specific complications (seizures, jaundice), and screening and follow up services, as well as specialised staff and service infrastructure. Conclusions: Our review delineates the required inputs to ensure readiness to provide inpatient care for small and sick newborns. Based on these findings, we detail where questions need to be added to existing tools and describe how measurement systems can be adapted to reflect small and sick newborns interventions. Such work can inform investments in health systems to end preventable newborn death and disability as part of the Every Newborn Action Plan. PMID- 29904599 TI - Preparation of organotypic brain slice cultures for the study of Alzheimer's disease. AB - Alzheimer's disease, the most common cause of dementia, is a progressive neurodegenerative disorder characterised by amyloid-beta deposits in extracellular plaques, intracellular neurofibrillary tangles of aggregated tau, synaptic dysfunction and neuronal death. Transgenic rodent models to study Alzheimer's mimic features of human disease such as age-dependent accumulation of abnormal beta-amyloid and tau, synaptic dysfunction, cognitive deficits and neurodegeneration. These models have proven vital for improving our understanding of the molecular mechanisms underlying AD and for identifying promising therapeutic approaches. However, modelling neurodegenerative disease in animals commonly involves aging animals until they develop harmful phenotypes, often coupled with invasive procedures. We have developed a novel organotypic brain slice culture model to study Alzheimer's disease using 3xTg-AD mice which brings the potential of substantially reducing the number of rodents used in dementia research from an estimated 20,000 per year. Using a McIllwain tissue chopper, we obtain 36 x 350 micron slices from each P8-P9 mouse pup for culture between 2 weeks and 6 months on semi-permeable 0.4 micron pore membranes, considerably reducing the numbers of animals required to investigate multiple stages of disease. This tractable model also allows the opportunity to modulate multiple pathways in tissues from a single animal. We believe that this model will most benefit dementia researchers in the academic and drug discovery sectors. We validated the slice culture model against aged mice, showing that the molecular phenotype closely mimics that displayed in vivo, albeit in an accelerated timescale. We showed beneficial outcomes following treatment of slices with agents previously shown to have therapeutic effects in vivo, and we also identified new mechanisms of action of other compounds. Thus, organotypic brain slice cultures from transgenic mouse models expressing Alzheimer's disease related genes may provide a valid and sensitive replacement for in vivo studies that do not involve behavioural analysis. PMID- 30023052 TI - Association between life-course socio-economic status and prevalence of cardio metabolic risk ractors in five middle-income countries. AB - Background: The burden of non-communicable diseases has increased rapidly in low- and middle-income countries. Past studies have reported an association between socioeconomic status (SES) and cardio-metabolic risk factors, but most have focused on upper income countries. The purpose of this study is to examine the association between SES over the life-course and the burden of cardio-metabolic risk factors in middle-income countries. Methods: A total of 38 297 adults from China, Mexico, India, South Africa and Russia were included in this cross sectional study. Life-course SES was defined based on maternal and participant education, and data on blood pressure, body mass index (BMI), self-reported diabetes and hypertension were obtained by trained interviewers. Descriptive, age standardized and multivariable adjusted analyses were conducted using survey weighted statistical procedures in SAS 9.4 (SAS Institute, Cary, NC, USA). Results: Although 14% of men and 12% of women had current hypertension based on blood pressure measurements, only 2% of men and 4% of women were aware of their hypertensive status. Men with stable high life-course SES had higher odds of being overweight/obese (odds ratio OR = 2.01, 95% confidence interval (CI) = 1.30 3.10), diabetic (OR = 4.82, 95% CI = 2.07-11.2) and hypertensive based on self report (OR = 3.42, 95% CI = 1.85-6.32) compared to men of low life-course SES. Among women, the odds of being overweight/obese were significantly higher among women with high life-course SES (OR = 1.50, 95% CI = 1.08-2.08). Conclusions: Higher life-course SES for both men and women was associated with increased odds of overweight/ obesity, and additionally diabetes and hypertension for men in middle income countries. PMID- 30023053 TI - Impact of integrating a postpartum family planning program into a community-based maternal and newborn health program on birth spacing and preterm birth in rural Bangladesh. AB - Background: Short birth intervals are associated with an increased risk of adverse perinatal outcomes. However, reduction of rates of short birth intervals is challenging in low-resource settings where majority of the women deliver at home with limited access to family planning services immediately after delivery. This study examines the feasibility of integrating a post-partum family planning intervention package within a community-based maternal and newborn health intervention package, and evaluates the impact of integration on reduction of rates of short birth intervals and preterm births. Methods: In a quasi experimental trial design, unions with an average population of about 25 000 and a first level health facility were allocated to an intervention arm (n = 4) to receive integrated post-partum family planning and maternal and newborn health (PPFP-MNH) interventions, or to a control arm (n = 4) to receive the MNH interventions only. Trained community health workers were the primary outreach service providers in both study arms. The primary outcomes of interest were birth spacing and preterm births. We also examined if there were any unintended consequences of integration. Results: At baseline, short birth intervals of less than 24 months and preterm birth rates were similar among women in the intervention and control arms. Integrating PPFP into the MNH intervention package did not negatively influence maternal and neonatal outcomes; during the intervention period, there was no difference in community health workers' home visit coverage or neonatal care practices between the two study arms. Compared to the control arm, women in the intervention arm had a 19% lower risk of short birth interval (adjusted relative risk (RR) = 0.81, 95% confidence interval (CI) = 0.69-0.95) and 21% lower risk of preterm birth (adjusted RR = 0.79; 95% CI = 0.63-0.99). Conclusions: Study findings demonstrate the feasibility and effectiveness of integrating PPFP interventions into a community based MNH intervention package. Thus, MNH programs should consider systematically integrating PPFP as a service component to improve pregnancy spacing and reduce the risk of preterm birth. PMID- 30023054 TI - Community health workers during the Ebola outbreak in Guinea, Liberia, and Sierra Leone. AB - Background: The role of community health workers (CHWs) in the West Africa Ebola outbreak has been highlighted to advocate for increasing numbers of CHWs globally to build resilience, strengthen health systems, and provide emergency response capacity. However, the roles CHWs played, the challenges they faced, and their effectiveness during the outbreak are not well documented. This study assessed the impact of Ebola on community-based maternal, newborn, and child health (MNCH) services, documented the contribution of CHWs and other community-based actors to the Ebola response, and identified lessons learned to strengthen resilience in future emergencies. Methods: This mixed methods study was conducted in Guinea, Liberia, and Sierra Leone, with data collected in four Ebola-affected districts of each country. Qualitative data were collected through in-depth interviews and focus group discussions with stakeholders at national, district, and community levels. Quantitative program data were used to assess trends in delivery of community-based MNCH services. Results: There was a sharp decline in MNCH service provision due to weak service delivery, confusion over policy, and the overwhelming nature of the outbreak. However, many CHWs remained active in their communities and were willing to continue providing services. When CHWs received clear directives and were supported, service provision rebounded. Although CHWs faced mistrust and hostility from community members because of their linkages to health facilities, the relationship between CHWs and communities proved resilient over time, and CHWs were more effectively able to carry out Ebola-related activities than outsiders. Traditional birth attendants, community health committees, community leaders, and traditional healers also played important roles, despite a lack of formal engagement or support. Service delivery weaknesses, especially related to supply chain and supervision, limited the effectiveness of community health services before, during, and after the outbreak. Conclusions: CHWs and other community-level actors played important roles during the Ebola outbreak. However, maintenance of primary care services and the Ebola response were hampered because community actors were engaged late in the response and did not receive sufficient support. In the future, communities should be placed at the forefront of emergency preparedness and response plans and they must be adequately supported to strengthen service delivery. PMID- 30023055 TI - Sudden sensorineural hearing loss in atypical Cogan's syndrome: A case report. AB - The Cogan's syndrome (CS) is a very uncommon inflammatory condition that appears in young adults without a gender predisposition. It can be presented as typical, with interstitial non-syphilitic keratitis and Meniere-like audiovestibular manifestations. An atypical form of CS involves uveitis, scleritis, episcleritis, and systemic vascuitis symptoms. This is a case of a 41-year old male who reported eye redness, photophobia, and gait instability. His condition progressed to a sudden sensorineural hearing loss, tinnitus, and constant vertigo accompanied by cephalea. He was evaluated by the Otolaryngology, Ophthalmology, and Neurology departments giving rise to CS, Meniere's syndrome, acoustic neuroma, glaucoma, multiple sclerosis, and meningioma as differential diagnoses. The patient was prescribed with oral and intravenous steroids, ophthalmic antibiotics and steroids, as well as oral omeprazole. The patient was discharged, without his eye manifestations, and for his clinical progress and underwent conventional and speech audiometry, otoacoustic emissions, nystagmography, tympanometry, and auditory steady-state response, that showed a vestibular disfunction and a severe sensorineural hearing loss. His follow-up, six months later resulted with a normal vestibular function and an improvement from severe to mild sensorineural hearing loss. The Cogan's syndrome is a rare condition which can leave the patient with permanent incapacitating secuelae including profound hearing loss. Effective treatment is necessary to avoid complications and improve the patient's condition and life quality. PMID- 30023056 TI - Cardiogenic and septic shock associated with aortic and mitral valve infective endocarditis caused by Abiotrophia Defectiva from a urinary tract infection. AB - Abiotrophia defectiva, also known as nutritionally variant streptococcus, is part of the normal flora of the oral cavity and urogenital and intestinal tracts and is a rare cause of infective endocarditis. It is fastidious or difficult to culture and associated with high rates of septic embolization, treatment failure and mortality. We describe an unusual presentation of infective endocarditis with severe mitral valve regurgitation due to Abiotrophia defectiva in an immunocompetent patient. After a complicated hospital course, surgical replacement of both the mitral and aortic valves was performed. We suggest that this patient likely had subacute infective endocarditis before diagnosis and treatment of her urinary tract infection, and following treatment failure, she developed life-threatening infective endocarditis. This case report highlights that patients with Abiotrophia defectiva infections are at high risk for infective endocarditis and that the clinical progression from this infection can be slow, with difficulty isolating the pathogen, which can significantly impact patient outcome. PMID- 30023057 TI - Propofol for gastrointestinal endoscopy. AB - Most gastrointestinal endoscopic procedures are now performed with sedation. Moderate sedation using benzodiazepines and opioids continues to be widely used, but propofol sedation is becoming more popular because its unique pharmacokinetic properties make endoscopy almost painless, with a very predictable and rapid recovery process. There is controversy as to whether propofol should be administered only by anesthesia professionals. According to published values, endoscopist-directed propofol has a lower mortality rate than endoscopist delivered benzodiazepines and opioids, and a comparable rate to general anesthesia by anesthesiologists. Rapid recovery has a major impact on patient satisfaction, post-procedure education and the general flow of the endoscopy unit. According to estimates, the absolute economic benefit of endoscopist directed propofol implementation in a screening setting is probably substantial, with 10-year savings of $3.2 billion in the USA. Guidelines concerning the use of propofol emphasize the need for adequate training and certification in sedation by non-anesthetists. PMID- 30023058 TI - Non-invasive tests for the detection of oesophageal varices in compensated cirrhosis: systematic review and meta-analysis. AB - Introduction: Conclusive data on the accuracy and clinical applicability of non invasive screening tests for oesophageal varices (OV) in patients with compensated cirrhosis remain lacking. We conducted this study to identify currently available tests, estimate their diagnostic performance and then exemplify how these could be utilized in clinical practice. Materials and methods: A systematic literature search was performed to identify all primary studies that reported accuracy using oesophagogastroduodenoscopy (OGD) as the gold standard. Sources searched included Ovid MEDLINE, Ovid EMBASE and The Cochrane Library databases. Results: Twenty-one studies with a total of 2471 patients were identified. Several tests were evaluated in more than three studies. Platelet count/spleen diameter ratio (PSR) had the highest summary area under the curve for detection of any size OV of 0.85 (95% confidence interval 0.78-0.92). At a cut-off of 909 (n = 4 studies) and prevalence rates of 10, 20, 30, 40 and 50% for OV, PSR screening correctly avoided the need for OGD in 70, 62, 55, 47 and 39% of patients, respectively. Conclusions: PSR appears to be the most accurate and validated non-invasive screening test for OV in patients with compensated cirrhosis. At a cut-off of 909, PSR could be clinically useful to avoid OGDs in a significant proportion of patients. PMID- 30023059 TI - A study of dysphagia symptoms and esophageal body function in children undergoing anti-reflux surgery. AB - Background: The role of high-resolution esophageal impedance manometry (HRIM) for establishing risk for dysphagia after anti-reflux surgery is unclear. We conducted a prospective study of children with primary gastroesophageal reflux (GER) disease, for whom symptoms of dysphagia were determined pre-operatively and then post-operatively and we examined for features that may predict post operative dysphagia. Methods: Thirteen children (aged 6.8-15.5 years) undergoing work-up prior to 360o Nissen fundoplication were included in the study. A dysphagia score assessed symptoms at pre-operative study and post-operatively (mean 1.4 years). A HRIM procedure recorded 5-ml liquid, 5-ml viscous and 2-cm solid boluses. We assessed esophageal motility, esophago-gastric junction (EGJ) morphology, EGJ contractility and pressure-flow variables indicative of bolus distension pressures and bolus clearance pressures. A composite pressure-flow index score was also derived. Results: Pre-operative pressure-flow index was positively correlated with post-operative dysphagia score (viscous bolus r = 0.771, p < 0.005). Of three variables that comprise the pressure-flow index, the ramp pressure measured during bolus clearance was the main driver of the effect seen (viscous bolus r = 0.819, p < 0.005). Conclusions: In order to mitigate symptoms in relation to anti-reflux surgery, dysphagia symptoms and esophageal function need to be pre-operatively assessed. In patients with normal motility, an elevated pressure-flow index may predict post-operative dysphagia. PMID- 30023061 TI - Use of volumetric laser endomicroscopy for determining candidates for endoscopic therapy in superficial esophageal squamous cell carcinoma. AB - Background: Accurate staging of superficial esophageal squamous cell cancer (ESCC) for endoscopic therapy is challenging. Optical coherence tomography (OCT) has been shown to be superior to high-resolution endoscopic ultrasound (EUS). Volumetric Laser Endomicroscopy (VLE), a second-generation OCT, has recently become commercially available. Objective: To assess if VLE can determine which patients with superficial ESSC can undergo endoscopic therapy. Methods: This is a multi-center retrospective study. Patients were included if (a) they had visible ESCC, (b) they underwent VLE and EUS for staging, and c) if superficial disease was suspected then endoscopic resection had to be performed to have accurate histology to compare the VLE scan to. VLE scans were then compared to the gold standard: histology for superficial disease and EUS for disease T1b and greater. Results: Seventeen patients were included with the following disease: squamous intraepithelial neoplasia (4 patients), T1a disease (6 patients), T1b (2 patients), T2 disease (2 patients) and T3 disease (3 patients). VLE was able to distinguish superficial disease, defined as disease limited up to the lamina propria, from non-superficial disease in all cases. Conclusions: VLE may be able to determine which ESCC patients are candidates for endoscopic therapy. Prospective studies are needed to confirm this. PMID- 30023060 TI - Development of benchmark quality criteria for assessing whole-endoscopy Barrett's esophagus biopsy cases. AB - Background: Dysplasia in Barrett's esophagus (BE) biopsies is associated with low observer agreement among general pathologists. Therefore, expert review is advised. We are developing a web-based, national expert review panel for histological review of BE biopsies. Objective: The aim of this study was to create benchmark quality criteria for future members. Methods: Five expert BE pathologists, with 10-30 years of BE experience, weekly handling 5-10 cases (25% dysplastic), assessed a case set of 60 digitalized cases, enriched for dysplasia. Each case contained all slides from one endoscopy (non-dysplastic BE (NDBE), n = 21; low-grade dysplasia (LGD), n = 20; high-grade dysplasia (HGD), n = 19). All cases were randomized and assessed twice followed by group discussions to create a consensus diagnosis. Outcome measures: percentage of 'indefinite for dysplasia' (IND) diagnoses, intra-observer agreement, and agreement with the consensus 'gold standard' diagnosis. Results: Mean percentage of IND diagnoses was 8% (3-14%) and mean intra-observer agreement was 0.84 (0.66-1.02). Mean agreement with the consensus diagnosis was 90% (95% prediction interval (PI) 82-98%). Conclusion: Expert pathology review of BE requires the scoring of a limited number of IND cases, consistency of assessment and a high agreement with a consensus gold standard diagnosis. These benchmark quality criteria will be used to assess the performance of other pathologists joining our panel. PMID- 30023062 TI - The effect of sildenafil on gastric motility and satiation in healthy controls. AB - : Sildenafil induces relaxation of smooth muscle cells by blocking PDE5. Dyspepsia is one of sildenafil's most frequently reported adverse events, suggesting its effect on gastric motility. Our aim was to study the effect of sildenafil on gastric accommodation (GA) and gastric emptying (GE) in healthy volunteers (HVs). Methods: Sildenafil (50 mg) or placebo was randomly administered to 16 blinded HVs. After a manometry probe and an infusion catheter were positioned in the proximal stomach, the intragastric pressure (IGP) was measured before and during nutrient drink infusion (ND, 60 ml/min). HVs were asked to score their hunger, satiation and six epigastric symptoms at five-minute intervals. The experiment ended when the HVs scored maximal satiation during ND infusion at one-minute intervals. To assess GE, breath samples were collected every 15 minutes for six hours after the meal (244 kcal). Results: ND infusion induced a drop in proximal stomach IGP, which was suppressed by sildenafil (average area under the curve for sildenafil: -33.6 +/- 8.8 mmHg; placebo: -60.8 +/- 11.3 mmHg, p = 0.005). Sildenafil-treated volunteers reached earlier maximal satiation compared to placebo (678 +/- 70 ml vs. 836 +/- 82.6 ml, p = 0.019). Finally, GE was significantly slower after sildenafil (90.6 +/- 5.9 min vs. 76.6 +/- 7.1 min, p = 0.04). Conclusion: Sildenafil inhibits GA, leading to significantly decreased nutrient tolerance, and slightly delays the GE rate in humans. PMID- 30023063 TI - Case-finding in primary care for coeliac disease: Accuracy and cost-effectiveness of a rapid point-of-care test. AB - Background: An on-site, rapid, fingertip, whole-blood point-of-care test (POCT) is attractive for active case-finding of coeliac disease (CD) in primary care because of its simplicity. Aim: The aim of this article is to assess the usefulness and cost-effectiveness of adult case-finding using a POCT based on deamidated gliadin peptide antibodies (IgA/IgG-DGP) in primary care for CD diagnosis. Methods: A case-finding study for CD was conducted by using an easy-to use, on-site, whole-blood for IgA/IgG-DGP-based fingertip POCT compared with tTG2 in 350 individuals. Sample size was calculated based on 0.28% prevalence in the reference population. Duodenal biopsies for histology, intraepithelial lymphocytes and in situ deposition of tTG2 were obtained if tTG2 and/or POCT were positive. Accuracy and cost-effectiveness of strategies using serology or POCT were calculated. Results: Prevalence of CD was 1.14% (95% CI, 0.3-3.4), almost double what was previously observed. Four patients were diagnosed with CD. tTG2 was positive in three (0.85%) and POCT in 29 (8.2%). Sensitivity of POCT for CD was 100%, specificity 93%, PPV 14%, and NPV 100%. POCT followed by duodenal biopsy was the most cost-effective approach in our setting (standard diagnosis: ?13,033/case; POCT + duodenal biopsy: ?7360/case). Conclusions: A negative POCT allows ruling out CD in primary care, making it suitable for case-finding. POCT strategy was the most cost effective. PMID- 30023064 TI - The distribution of HLA DQ2 and DQ8 haplotypes and their association with health indicators in a general Danish population. AB - Background: Human leukocyte antigen (HLA) DQ2 and DQ8 are important risk factors for some autoimmune diseases such as celiac disease (CD), but their possible role in other diseases and health conditions is not fully explored. Objectives: The objective of this article is to examine the distribution of HLA DQ2 and HLA DQ8 in an adult general population, and their association with health indicators (diseases, symptoms and biomarkers). Methods: In this cross-sectional, population based study, 2293 individuals were screened for HLA DQ2 and DQ8; CD-associated alleles (DQA*0201*03*05/DQB*02*0301/0304*0302/0305) and DQB1*02 homozygosity were determined for screen-positive participants. The National Patient Registry provided diagnosis information. Results: A total of 47.7% (1093/2293) individuals were positive for DQ2 and/or DQ8: 31.2% (716/2293) only DQ2, 11.9% (273/2293) only DQ8, 4.1% (93/2293) both DQ2 and DQ8. Among nine individuals diagnosed with CD, 89.9% (8/9) had DQ2.5cis, 22.2% (2/9) DQ8 and 22.2% (2/9) DQ2.2 (two both DQ2 and DQ8). HLA DQ2.5 was associated with higher thyroid-stimulating hormone levels, while DQ2/DQ8-positive participants had significantly lower prevalence of irritable bowel syndrome (IBS). DQ2/DQ8 were strongly associated with CD, but no other registry-based diagnoses. Conclusion: In this general Danish population, 47.7% were HLA DQ2/DQ8 positive and thus potentially at risk for CD. All individuals with CD were DQ2/DQ8 positive; the majority DQ2.5. Surprisingly, DQ2/DQ8-positivity was associated with lower IBS prevalence. PMID- 30023065 TI - Usefulness of small bowel reexamination in obscure gastrointestinal bleeding patients with negative capsule endoscopy findings: Comparison of repeat capsule endoscopy and double-balloon enteroscopy. AB - Background: Although capsule endoscopy (CE) is a noninvasive diagnostic tool for patients with obscure gastrointestinal bleeding (OGIB), bleeding lesions are often not detected. No strategies have been established to determine whether CE or double-balloon enteroscopy (DBE) should be performed after negative CE. Methods: Among 652 patients who underwent CE for OGIB, a total of 359 patients had negative findings. Of these, 41 and 48 patients underwent repeat CE and DBE for small bowel reexamination, respectively. We compared the rate of positive findings between the two groups. The findings were considered positive if mucosal break, vascular lesion, tumor, or active bleeding was observed. Results: The rate of positive findings in the repeat CE group was significantly higher than that in the DBE group (73.2% vs. 39.6%; p = 0.001). Logistic regression analysis showed that the repeat CE group was significantly associated with positive findings (odds ratio (OR), 4.2; 95% confidence interval (CI), 1.7-10.2; p = 0.002). Inverse probability of treatment-weighted analysis revealed that repeat CE was significantly associated with positive findings (OR, 4.4; 95% CI, 1.6-12.2; p = 0.004). Conclusions: Reexamination via CE appears to have more diagnostic value than DBE for OGIB patients with negative CE findings. PMID- 30023067 TI - Utility of serum phosphate as a marker for predicting the severity of post endoscopic retrograde cholangiopancreatography pancreatitis. AB - Background: To date, no reliable marker for predicting the severity of post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis exists. A previous animal study reported a correlation between serum phosphate level and the severity of acute pancreatitis. Objective: The purpose of this study was to evaluate the feasibility of serum phosphate as a marker for predicting the severity of post-ERCP pancreatitis in humans. Methods: A cohort of patients that were diagnosed with post-ERCP pancreatitis between January 2005 and December 2016 was queried. In addition to serum phosphate levels measured between 12 and 24 hours after ERCP, several candidates deemed suitable for accurately predicting the severity of post-ERCP pancreatitis were also explored. Results: A total of 191 patients with severe (n = 42, 22.0%) and mild-to-moderate (n = 149, 78.0%) post-ERCP pancreatitis were included. Several factors for predicting severe post ERCP pancreatitis were identified in the multivariate analysis: malignancy as the primary indication for ERCP (odds ratio (OR) 2.65, P = 0.038), systemic inflammatory response syndrome (OR 4.49, P = 0.016) and serum phosphate level (OR 1.97, P = 0.040). In the receiver operating characteristic analysis, the area under the curve of serum phosphate level for severe post-ERCP pancreatitis was 0.65 (95% confidence interval, 0.56-0.75). The optimal cut-off value of serum phosphate level for prediction of severe post-ERCP pancreatitis was 3.35 mg/dL (sensitivity, 0.62; specificity, 0.73). Conclusions: Serum phosphate level after ERCP can be used as a reliable prognostic marker in predicting the severity of post-ERCP pancreatitis. Future prospective studies would be the cogent next step in validating its value. PMID- 30023066 TI - The impact of a history of cancer on pancreatic ductal adenocarcinoma survival. AB - Background and objective: Previous studies indicated cancer survivors had a higher risk of developing subsequent pancreatic ductal adenocarcinoma. However, the influence of prior cancer on survival outcomes of current pancreatic cancer remains unclear. Methods: Eligible populations were selected from the Surveillance, Epidemiology, and End Results programs from 2000 to 2012. We adopted Kaplan-Meier curves and Cox analysis to compare survival differences between patients with and without prior cancer. Results: Overall, 67,555 pancreatic cancer patients, including 5582 (8.26%) with and 61,973 (91.74%) without prior cancer, were included. The most common types of prior cancers were prostate, breast, and colorectal cancers. The median time from diagnosis of an initial malignancy to subsequent pancreatic cancer was 59.8 months. Patients with a prior cancer had higher overall one-year and three-year survival rates compared with those without a prior cancer. Multivariable Cox analysis demonstrated that a history of prior malignancy could independently predict the better overall survival outcome of pancreatic cancer (HR = 0.92, 95% CI, 0.89-0.94, p < 0.001), especially for colorectal, breast, corpus uteri and prostate cancer survivors. Conclusions: A history of cancer did not contribute to a poor survival outcome for patients with pancreatic cancer. More prospective trials might be warranted to validate our findings. PMID- 30023068 TI - Safety, diagnostic accuracy and therapeutic efficacy of digital single-operator cholangioscopy. AB - Background: Digital single-operator cholangioscopes (digital SOCs), equipped with an improved image quality, have been recently introduced. Objective: The aim of this study is to evaluate the safety and diagnostic and therapeutic efficacy of digital SOCs (SpyglassTM DS). Methods: Sixty-seven digital SOC procedures performed between 2015 and 2017 were retrospectively analyzed. Results: The most frequent indications for examination were indeterminate biliary strictures (61.2%) and biliary stone disease (23.9%). In 25 patients (37.3), visual findings predicted malignancy with a sensitivity of 88.9%, a specificity of 97.6%, a positive predictive value (PPV) of 96.0% and a negative predictive value (NPV) of 92.9%. For histological analysis, forceps biopsies were performed in 29 patients (43.2%). Compared with visual findings, forceps biopsies yield a lower diagnostic efficacy in diagnosing malignancy (sensitivity 62.5%, specificity 90.0%, PPV 90.9%, NPV 60.0%). Therapeutic interventions were performed in 19 patients with a technical success rate of 89.4%. Adverse events were observed in 17 patients (25.4%). Of these, 11 patients (16.4%) suffered from severe adverse events (pancreatitis, cholangitis or major bleeding), which led to a prolonged hospital stay. Conclusion: Digital SOCs have excellent diagnostic and therapeutic efficacies, but are accompanied by high rates of adverse events; therefore, physicians should use digital SOCs in carefully selected cases. PMID- 30023069 TI - Risk factors and outcomes of infected pancreatic necrosis: Retrospective cohort of 148 patients admitted to the ICU for acute pancreatitis. AB - Objective: The primary objective of this article is to identify risk factors for infected pancreatic necrosis (IPN) in patients admitted to the intensive care unit (ICU) for severe acute pancreatitis. We also described outcomes of IPN. Background: Acute pancreatitis is common and associated with multiple, potentially life-threatening complications. Over the last decade, minimally invasive procedures have been developed to treat IPN. Methods: We retrospectively studied consecutive patients admitted for severe acute pancreatitis to the ICUs of the Nantes University Hospital in France, between 2012 and 2015. Logistic regression was used to evaluate potential associations linking IPN to baseline patient characteristics and outcomes. Results: Of the 148 included patients, 26 (17.6%) died. IPN developed in 62 (43%) patients and consistently required radiological, endoscopic, and/or surgical intervention. By multivariate analysis, factors associated with IPN were number of organ failure (OF) (for >= 3: OR, 28.67 (6.23-131.96), p < 0.001) and portosplenomesenteric venous thrombosis (OR, 8.16 (3.06-21.76)). Conclusion: IPN occurred in nearly half our ICU patients with acute pancreatitis and consistently required interventional therapy. Number of OFs and portosplenomesenteric venous thrombosis were significantly associated with IPN. Early management of OF may reduce IPN incidence, and management of portosplenomesenteric venous thrombosis should be investigated. PMID- 30023070 TI - Ethanol sclerotherapy or polidocanol sclerotherapy for symptomatic hepatic cysts. AB - Background: Over the past decades, multiple approaches to aspiration sclerotherapy of large symptomatic hepatic cysts have been investigated. However, comparative data are scarce. Objective: The objective of this article is to compare cyst reduction, symptomatic relief, and adverse events between ethanol sclerotherapy and polidocanol sclerotherapy. Methods: This retrospective study included adults having a symptomatic hepatic cyst treated at a European tertiary referral center with ethanol sclerotherapy (Center 1) or polidocanol sclerotherapy (Center 2). We compared cyst diameter reduction (%) and symptom improvement (yes/no) within 12 months' post-treatment between centers using multivariate regression analyses adjusted for confounding factors. Finally, we compared adverse events using Fisher's exact test. Results: We included 71 patients from Center 1 and 66 patients from Center 2 (median age 57 years; 126/137 (92%) female). Cyst reduction was comparable between Centers 1 and 2: 37.5% (IQR 15.7-61.0%) versus 44.2% (IQR 24.6-60.5%), respectively (p = 0.35). Correspondingly, symptomatic relief was comparable: 30/53 (56.6%) versus 43/66 (65.2%), respectively (p = 0.88). Center 1 reported significantly more (11 versus 3; p = 0.047) adverse events than Center 2. Conclusion: We found comparable cyst reduction and symptomatic relief rates between ethanol- and polidocanol sclerotherapy, while adverse events occurred more often in the ethanol group. Prospective studies focused on clinical response are needed to further explore differences between approaches. PMID- 30023071 TI - Demographic and clinical features distinguish subgroups of diverticular disease patients: Results from an Italian nationwide registry. AB - Background: Clinical features and lifestyle factors associated with diverticulosis compared to diverticular disease (DD), either symptomatic uncomplicated diverticular disease (SUDD) or in patients who have had previous diverticulitis (PD), are unclear. Objective: The objective of this article is to compare cross-sectionally demographic and clinical features and quality of life (QoL) in diverticulosis, SUDD and PD patients. Methods: The REMAD Registry is a prospective, observational, multicentre, cohort study. Patients were categorised according to: diverticulosis; SUDD (recurrent abdominal symptoms attributed to diverticula in absence of overt inflammation) and PD (>=1 previous diverticulitis). Results: A total of 1217 patients (57.9% diverticulosis, 24.7% SUDD and 17.4% PD) were included. Compared to diverticulosis, female gender was associated to SUDD (OR 1.94; 95% CI: 1.43-2.62) and PD (OR 1.79; 95% CI: 1.24 2.56); age <= 60 years was associated to PD (OR 2.10; 95% CI: 1.42-3.08 vs diverticulosis, OR 1.57; 95% CI: 1.01-2.45 vs SUDD). PD patients showed an association with past bleeding (OR 29.29; 95% CI: 8.17-104.98 vs diverticulosis, OR 16.84; 95% CI: 3.77-75.25 vs SUDD). Compared to diverticulosis, family history for diverticula was associated to PD (OR 1.88; 95% CI: 1.27-2.78). Patients with diverticulosis showed higher QoL scores, both physical (p = 0.0001 and 0.0257) and mental (p < 0.0001 and 0.0038), in comparison to SUDD and PD. Conclusion: Family history for diverticula and history of bleeding distinguish diverticulosis from DD. These clinical features should be kept in mind in the management of DD. PMID- 30023072 TI - Lifestyle factors and risk for colorectal polyps and cancer at index colonoscopy in a FIT-positive screening population. AB - Background: Many countries have adopted the fecal immunochemical test (FIT) as the primary colorectal cancer (CRC) screening tool; however, its accuracy is limited. Epidemiological studies have shown that obesity and type 2 diabetes increase risk for the disease. Objective: The objective of this article is to evaluate the association of colorectal polyps and cancer with comorbidities and lifestyle factors in a population that is part of a FIT-based CRC screening program. Methods: Between 2005 and 2013, we analyzed 3894 FIT + patients who underwent total colonoscopy. The impact of lifestyle factors on polyps and cancer was assessed using individuals with a negative colonoscopy as the control group. A multivariate logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: We collected data from 3894 FIT + patients. Obesity (OR 1.29; 95% CI 1.05-1.60) and smoking (OR 1.45; 95% CI 1.24-1.71) were significantly associated with high-risk adenomas. Smoking and heavy alcohol drinking were both independently associated with high risk of CRC (OR 1.50; 95% CI 1.10-2.04 and OR 2.29; 95% CI 1.15-4.58) and colon cancer alone (OR 1.43; 95% CI 1.01-2.02 and OR 3.09; 95% CI 1.53-6.23). Positivity to first round of FIT was associated with high-risk adenomas (OR 1.47; CI 95% 1.26-1.71) and CRC (OR 1.74; 95% CI 1.29-2.36). No associations were found for diabetes. Conclusion: In our FIT + population, lifestyle factors are significantly associated with the risk of carrying high-risk adenomas and CRC. In the future, studies could be aimed at finding better screening strategies through the development of clinical algorithms based on lifestyle changes/comorbidities. PMID- 30023074 TI - Young GI angle: Tips and tricks for an academic career. PMID- 30023073 TI - Years of life lost due to malignant neoplasms of the digestive system in Poland in the years 2000-2014. AB - Background: Every fourth death that occurs in Poland is caused by a malignant neoplasm. A particularly negative epidemiological situation relates to colorectal cancers; in 2015 they constituted the fifth most important cause of years of life lost (YLL) in Poland. Objective: We aimed to analyse YLL due to malignant neoplasms of the digestive system in Poland in between 2000 and 2014. Methods: The study material included a database containing information gathered from 5,601,568 death certificates of Poles who died in 2000-2014. YLLs were calculated with the use of the standard expected years of life lost index (SEYLL). Results: In the 15-year study period, malignant neoplasms of the digestive system contributed to 213,041 deaths in males and 177,644 deaths in females, which corresponded to a loss of 158.6 years per 10,000 men and 105.3 years per 10,000 women. Neoplasms of the large intestine (23.6%), stomach (22.0%) and pancreas (17.4%) contributed the most. A time trend analysis revealed (p < 0.05) a growing tendency of YLLs due to neoplasms of the large intestine and pancreas, and a decreasing trend due to neoplasms of the stomach. Conclusion: Malignant neoplasms of the digestive system, especially of the large intestine, are becoming a more common cause of premature mortality in Poland. PMID- 30023075 TI - GOAL study: clinical and non-clinical predictive factors for achieving glycemic control in people with type 2 diabetes in real clinical practice. AB - Objective: The American Diabetes Association and the European Association for the Study of Diabetes guidelines recommend to individualize treatment targets/strategies in inadequately controlled patients by lifestyle management and glucose-lowering drugs to decrease the burden of diabetes-related complications. This real-world practice study aimed to assess predictive factors for achieving the glycemic hemoglobin A1c (HbA1c) at 6 months as targeted by the treating physician in adults with type 2 diabetes who required initiation of basal insulin, initiation of bolus insulin, or modification from basal or premixed insulin to new insulin regimen containing insulin glargine and/or insulin glulisine. Research design and methods: This was an international, multicenter, observational survey with 12-month follow-up time in adults with type 2 diabetes inadequately controlled conducted in 10 developing countries. Results: Overall, 2704 patients (mean age: 54.6 years, body mass index: 28.7 kg/m2; Caucasian: 46.1%, type 2 diabetes duration: 10.1 years) with poor glycemic control (mean HbA1c: 9.7% (83 mmol/mol), fasting blood glucose: 196.8 mg/dL) were eligible. At 6 months, advanced age, Caucasian ethnicity, shorter type 2 diabetes duration (>10 vs 1 year, p<0.0001), lower baseline HbA1c (>= 8.5% vs <7%, p<0.0001) and no intake of oral antidiabetic drug (OAD) (none vs 2, p=0.02) were predictive factors for achieving glycemic goal as targeted by the treating physician. Absolute changes in the mean HbA1c of -1.7% and -2% were observed from baseline to 6 and 12 months, respectively. Conclusions: Along with some well known predictive factors, this study suggested that early insulin regimen treatment initiation and/or intensification allowed patients to promote glycemic control. PMID- 30023077 TI - Ideology over evidence? PMID- 30023078 TI - Rational antidepressant use. PMID- 30023079 TI - Author's reply. PMID- 30023076 TI - Obesity, mental health, and sexual dysfunction: A critical review. AB - Obesity has profound medical, psychological, and emotional consequences and is associated with sexual difficulties. Little is known regarding the interrelationship between obesity and sexual functioning from a psychological perspective, and less is known regarding treatment options. This review examines these issues and considers various treatments. Literature searches were conducted to locate original research, reviews, systematic reviews, and meta-analyses of obesity, overweight, sexual function, sexual dysfunction, psychological health, mental health, and weight loss. Research demonstrates an association between obesity, mental health, and sexual functioning, but has failed to identify casual pathways between these conditions. Clarifying such pathways is necessary to inform treatment guidelines for clinical practice. PMID- 30023080 TI - Unlocking an acute psychiatric ward: open doors, absent patients? PMID- 30023081 TI - Lung cancer surgery for octogenarians: an option for select patients only? PMID- 30023082 TI - The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants. PMID- 30023083 TI - Pulmonary metastasectomy and laser-assisted resection. PMID- 30023084 TI - The burden of heart failure in the general population: a clearer and more concerning picture. PMID- 30023085 TI - Are predictive models useful in clinical medicine? PMID- 30023086 TI - Cetuximab in the treatment of advanced non-small cell lung cancer: FISHing for a miraculous catch. PMID- 30023087 TI - Efficacy and immune activation of ipilimumab in early-stage lung cancer patients. PMID- 30023088 TI - Transcatheter Mitral Valve Replacement: slow and steady progress. PMID- 30023089 TI - The more and the heavier may not always be an answer. PMID- 30023090 TI - Mesothelioma diagnosis and prognosis, are we moving beyond histology and performance status towards circulating biomarkers? PMID- 30023091 TI - Hydrocortisone in septic shock: all the questions answered? PMID- 30023092 TI - Malignant pleural mesothelioma: main topics of American Society of Clinical Oncology clinical practice guidelines for diagnosis and treatment. PMID- 30023093 TI - The optimal sequencing of postoperative chemotherapy and radiation therapy in patients with locally advanced or incompletely resected non-small cell lung cancer. PMID- 30023094 TI - Comparing apples to oranges: short-term mortality after surgery versus stereotactic body radiotherapy for early-stage non-small cell lung cancer. PMID- 30023095 TI - Application of bronchoscope for the placement of nasoenteric feeding tube: new ideas from old ways. PMID- 30023096 TI - Patient selection for VV ECMO: have we found the crystal ball? PMID- 30023097 TI - Targeting minimal residual disease after surgery with molecular targeted therapy: the real path to a cure? PMID- 30023098 TI - Can molecularly targeted therapy cure patients with resected EGFR mutant NSCLC? PMID- 30023100 TI - Elective ICU admission after major surgery: can too much support be futile? PMID- 30023099 TI - EML4-ALK V3, treatment resistance, and survival: refining the diagnosis of ALK+ NSCLC. PMID- 30023101 TI - Lung cancer resection in octogenarian patients. PMID- 30023102 TI - Minimally invasive surgery is best treatment for early lung cancer. PMID- 30023103 TI - Stereotactic body radiotherapy for operable, early stage non-small cell lung cancer-let's all take a deep breath. PMID- 30023104 TI - Stereotactic body radiotherapy for early-stage non-small cell lung cancer has low post-treatment mortality. PMID- 30023105 TI - Surgery vs. SBRT in retrospective analyses: confounding by operability is the elephant in the room. PMID- 30023106 TI - The immune system as a victim and aggressor in chronic obstructive pulmonary disease. PMID- 30023107 TI - Strategy of intentional limited resection for lung adenocarcinoma in situ. PMID- 30023108 TI - Weighing the relative importance of short-term versus long-term outcomes when comparing surgery versus stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer. PMID- 30023109 TI - Developing competency in video-assisted thoracic surgery (VATS) lobectomy. PMID- 30023110 TI - Reperfusion injury to ischemic medullary brain nuclei after stopping continuous positive airway pressure-induced CO2-reduced vasoconstriction in sleep apnea. PMID- 30023111 TI - SECURE PCI: how important can a subgroup analysis be? PMID- 30023112 TI - In acute respiratory distress syndrome, is extracorporeal membrane oxygenation an adjuvant for "everyone"? PMID- 30023113 TI - The PRESET-Score: the extrapulmonary predictive survival model for extracorporeal membrane oxygenation in severe acute respiratory distress syndrome. PMID- 30023114 TI - Infection and colonisation in V-V ECMO-not a predictor of poor outcome. PMID- 30023115 TI - Editorial based on: "Risk of dementia in adults with congenital heart disease: population-based cohort study". PMID- 30023116 TI - Between hypoxia or hyperoxia: not perfect but more physiologic. PMID- 30023117 TI - Who benefits from postoperative ICU admissions?-more research is needed. PMID- 30023119 TI - Early treatment with high-potency statins in patients with acute coronary syndrome-an example of personalized medicine. PMID- 30023118 TI - What about prognostic outcome parameters in patients with acute respiratory distress syndrome (ARDS) treated with veno-venous extracorporeal membrane oxygenation (VV-ECMO)? PMID- 30023120 TI - Fat but fit for the improved survival in lung cancer surgery. PMID- 30023121 TI - Early oral intake through meticulous chewing after esophagectomy. PMID- 30023122 TI - Who really benefits from surgical tray reduction? PMID- 30023123 TI - MetaLanc9 as a novel biomarker for non-small cell lung cancer: promising treatments via a PGK1-activated AKT/mTOR pathway. PMID- 30023124 TI - Prone Positioning for ARDS: still misunderstood and misused. PMID- 30023125 TI - Invited letter to the editor on the editorial on "Clinical staging of NSCLC: current evidence and implications for adjuvant chemotherapy". PMID- 30023127 TI - Using the scoring schemes in the right way: the dynamic assessment of stroke and bleeding risk in patients with atrial fibrillation. PMID- 30023126 TI - Need for prospective collection of experience and repeated samples in esophageal squamous cell carcinoma. PMID- 30023128 TI - Prone positioning acute respiratory distress syndrome patients. PMID- 30023129 TI - Primary malignant melanoma of esophagus shared similar genetic characters with both cutaneous and oral mucosal melanoma. PMID- 30023130 TI - Adjuvant therapy for resected pN2 non-small cell lung cancer: sequence is not all that matters. PMID- 30023131 TI - Pulmonary nodules measurements in CT lung cancer screening. PMID- 30023132 TI - Parametric optimization of delignification of rice straw through central composite design approach towards application in grafting. AB - The present investigation deals with process optimisation of delignification of rice straw towards its micro-porous structural enhancement for its utilization in polymer grafting. The individual effect of influential parameters viz. sodium hydroxide concentration (1-12%, w/v), reaction time (30-126 min), and temperature (20-150 degrees C) on delignification were studied in a single mode batch process. The process parameters were further optimized with Central composite design (CCD) approach of response surface methodology in Design expert software. Delignification of rice straws was observed to follow quadratic equation. Analysis of variance (ANOVA) study suggested the equation to be significant for the process with major impact of sodium hydroxide concentration on the delignification process than reaction time and temperature. The optimized parametric conditions of delignification are: alkali concentration 7.59%, reaction time 75.11 min, and reaction temperature 40 degrees C. The software predicted lignin extraction concentration to be 72.4 mg/g, which upon experimentation was found to be 70.03 mg/g. Instrumental analysis of the delignified rice straw demonstrated porous structure and change in surface chemistry due to lignin removal. Therefore, the delignified rice straw obtained under optimized conditions were found to be appropriate for grafting of polymers which improved its resilience for variable usages. PMID- 30023133 TI - Functional transformation of Fourier-transform mid-infrared spectrum for improving spectral specificity by simple algorithm based on wavelet-like functions. AB - Herein a simple algorithm for the mathematical transformation of FTIR spectrum was developed, evaluated, and applied for description of different systems. Water, ethanol, n-butanol, n-hexanol, formic acid, acetic acid, citric acid, and water-acetic acid mixtures at different concentrations were used as model systems. We found that functional transformation of FTIR spectrum can be performed by functionally-enhanced derivative spectroscopy approach using the Function P, which is defined as P = (1 + aj )(s)-0.5 where aj and s are the absorbance and the scale factor, respectively. It is also demonstrated that Function P can be used for qualitative and quantitative analysis of pure substances and mixtures. It is concluded that Function P can be understood as a wavelet transformation, which is evaluated at small times and displacements, with scaling factor given by the change of absorbance inverse. PMID- 30023135 TI - Highly Active and Stable CH4 Oxidation by Substitution of Ce4+ by Two Pd2+ Ions in CeO2(111). AB - Methane (CH4) combustion is an increasingly important reaction for environmental protection, for which Pd/CeO2 has emerged as the preferred catalyst. There is a lack of understanding of the nature of the active site in these catalysts. Here, we use density functional theory to understand the role of doping of Pd in the ceria surface for generating sites highly active toward the C-H bonds in CH4. Specifically, we demonstrate that two Pd2+ ions can substitute one Ce4+ ion, resulting in a very stable structure containing a highly coordinated unsaturated Pd cation that can strongly adsorb CH4 and dissociate the first C-H bond with a low energy barrier. An important aspect of the high activity of the stabilized isolated Pd cation is its ability to form a strong sigma-complex with CH4, which leads to effective activation of CH4. We show that also other transition metals like Pt, Rh, and Ni can give rise to similar structures with high activity toward C-H bond dissociation. These insights provide us with a novel structural view of solid solutions of transition metals such as Pt, Pd, Ni, and Rh in CeO2, known to exhibit high activity in CH4 combustion. PMID- 30023136 TI - MARIJUANA ON THE BRAIN- A CONCERN. PMID- 30023134 TI - Two faces of the coin: Minireview for dissecting the role of reactive oxygen species in stem cell potency and lineage commitment. AB - Reactive oxygen species (ROS) are produced as by-products of several intracellular metabolic pathways and are reduced to more stable molecules by several protective pathways. The presence of high levels of ROS can be associated with disturbance of cell function and could lead to apoptosis. The presence of ROS within the physiological range has many effects on several signalling pathways. In stem cells, this role can range between keeping the potency of the naive stem cells to differentiation towards a certain lineage. In addition, the level of certain ROS would change according to the differentiation stage. For example, the presence of ROS can be associated with increasing the proliferation of mesenchymal stem cells, decreasing the potency of embryonic stem cells and adding to the genomic stability of induced pluripotent stem cells. ROS can enhance the differentiation of stem cells into cardiomyocytes, adipocytes, endothelial cells, keratinocytes and neurons. In the meantime, ROS inhibits osteogenesis and enhances the differentiation of cartilage to the hypertrophic stage, which is associated with chondrocyte death. Thus, ROS may form a link between naive stem cells in the body and the environment. In addition, monitoring of ROS levels in vitro may help in tissue regeneration studies. PMID- 30023137 TI - ACUTE SCHIZOPHRENIA-LIKE PSYCHOTIC DISORDER: A CRITICAL APPRAISAL OF ITS DIAGNOSTIC VALIDITY THROUGH A CASE SERIES. PMID- 30023138 TI - PNEUMOCEPHALUS: IS THE NEEDLE SIZE SIGNIFICANT? PMID- 30023140 TI - SECAPR-a bioinformatics pipeline for the rapid and user-friendly processing of targeted enriched Illumina sequences, from raw reads to alignments. AB - Evolutionary biology has entered an era of unprecedented amounts of DNA sequence data, as new sequencing technologies such as Massive Parallel Sequencing (MPS) can generate billions of nucleotides within less than a day. The current bottleneck is how to efficiently handle, process, and analyze such large amounts of data in an automated and reproducible way. To tackle these challenges we introduce the Sequence Capture Processor (SECAPR) pipeline for processing raw sequencing data into multiple sequence alignments for downstream phylogenetic and phylogeographic analyses. SECAPR is user-friendly and we provide an exhaustive empirical data tutorial intended for users with no prior experience with analyzing MPS output. SECAPR is particularly useful for the processing of sequence capture (synonyms: target or hybrid enrichment) datasets for non-model organisms, as we demonstrate using an empirical sequence capture dataset of the palm genus Geonoma (Arecaceae). Various quality control and plotting functions help the user to decide on the most suitable settings for even challenging datasets. SECAPR is an easy-to-use, free, and versatile pipeline, aimed to enable efficient and reproducible processing of MPS data for many samples in parallel. PMID- 30023139 TI - Evaluation of antioxidant and neuroprotective activities of Cassia fistula (L.) using the Caenorhabditis elegans model. AB - Background: Cassia fistula (L.) (Fabaceae) is a medicinal plant from tropical Asia. It is known for its marked antioxidant activity, which is attributed to its high phenolic content. The present study aims at testing both the antioxidant and neuroprotective effects of a hydroalcoholic extract from the aerial parts of Cassia fistula using the Caenorhabditis elegans model, which is widely used in this context. Methods: Chemical profiling of secondary metabolites that seem to be responsible for both antioxidant and neuroprotective capacities was carried out by HPLC/PDA/ESI-MSn. Antioxidant activity was tested in vitro by CUPRAC and DPPH assays. In vivo antioxidant and neuroprotective activities were investigated using the C. elegans model. Results: The Cassia extract improved the survival rate of the nematodes and protected them against oxidative stress. In addition, a decrease in the accumulation of reactive oxygen species (ROS) was observed. The important role of DAF-16/FOXO pathway was confirmed through an increased nuclear localization of the DAF-16 transcription factor, increased expression of SOD-3 stress response gene and decreased expression of HSP-16.2. Furthermore, the putative involvement of SKN-1/NRF2 pathway was demonstrated by a decrease in GST 4 levels. A neuroprotective activity of the Cassia extract was shown by a decline in polyglutamine (polyQ40) aggregate formation and a delay in paralysis caused by amyloid beta (Abeta1-42) accumulation. Discussion: The Cassia extract exhibits substantial antioxidant and neuroprotective activities in vivo, which might provide a rich and novel source of natural antioxidants and neuroprotective compounds to be further studied for the use in various food and cosmetic industrial fields. PMID- 30023141 TI - Synthesis and Characterization of Lignin Hydrogels for Potential Applications as Drug Eluting Antimicrobial Coatings for Medical Materials. AB - Lignin is the second most abundant biopolymer on the planet. It is a biocompatible, cheap, environmentally friendly and readily accessible material. It has been reported that these biomacromolecules have antimicrobial activities. Consequently, lignin (LIG) has the potential to be used for biomedical applications. In the present work, a simple method to prepare lignin-based hydrogels is described. The hydrogels were prepared by combining LIG with poly(ethylene glycol) and poly(methyl vinyl ether-co-maleic acid) through an esterification reaction. The synthesis took place in the solid state and can be accelerated significantly (24 vs 1 h) by the use of microwave (MW) radiation. The prepared hydrogels were characterized by evaluation of their swelling capacities and with the use of infrared spectroscopy/solid-state nuclear magnetic resonance. The prepared hydrogels showed LIG contents ranging between 40% and 24% and water uptake capabilities up to 500%. Furthermore, the hydrophobic nature of LIG facilitated loading of a model hydrophobic drug (curcumin). The hydrogels were capable of sustaining the delivery of this compound for up to 4 days. Finally, the materials demonstrated logarithmic reductions in adherence of Staphylococcus aureus and Proteus mirabilis of up to 5.0 relative to the commonly employed medical material poly(vinyl chloride) (PVC). PMID- 30023142 TI - Pregnancy and Breastfeeding during Intrathecal Baclofen Therapy - A Case Study and Review. AB - We report the case of a young woman who received intrathecal baclofen therapy (ITB) and subsequently became pregnant and had a normal delivery. A 28-year-old woman with flexion myelopathy had anterior decompression with fusion at C4/5 and C5/6 levels. Clinical symptoms improved after surgery. However, when she was 29 years old, her symptoms steadily advanced to Modified Ashworth Scale 3 spasticity level in the lower legs, with pain in both of them and urinary retention tendency. Since a 25 MUg intrathecal baclofen injection improved her symptoms, an ITB pump system was implanted. After surgery, lower limb spasticity and urinary retention improved. Two years after ITB pump implantation, the patient married and became pregnant. The patient intended to have normal delivery but the induction of labor was ineffective and childbirth was completed by Cesarean section with lumbar anesthesia. The infant's Apgar score was 8 at 1 min and 9 at 5 min, and birth-weight was 2,704 g. We measured the baclofen concentration in the patient's breast milk using high-performance liquid chromatography/tandem mass spectrometry. The level of baclofen in the breast milk was very low (0.617 ng/ml) and the predicted pharmacological effect on the infant was judged to be negligible. No withdrawal symptoms or muscle tone abnormalities were found after birth. Our findings indicate that ITB therapy could be considered for young women with severe spasticity, even if they plan to have children. PMID- 30023143 TI - Non-contiguous Meningeal Recurrence of Olfactory Neuroblastoma: A Case Report and Literature Review. AB - Olfactory neuroblastoma is an uncommon malignant tumor of neural crest origin arising from the olfactory epithelium of the superior nasal cavity. There are some reports of local recurrence or continuous extension along the olfactory epithelium to the central nervous system, but non-contiguous distant meningeal metastasis without local recurrence at the primary site is rare. We report a case of non-contiguous meningeal recurrence of olfactory neuroblastoma presenting as a giant frontal mass. A 66-year-old woman was admitted with a left nasal intranasal localized tumor without cranial extension and gross total removal was achieved. Pathological examination showed olfactory neuroblastoma and radiation therapy was added in a limited region of the removal cavity. Radiological follow-up continued for 10 years and there was no local recurrence. Sixteen years after radiation therapy, the patient found a slight frontal mass gradually growing. Magnetic resonance imaging revealed an enhanced mass lesion of 7 cm in thickness and 9 cm in diameter associated with marked thickness of the frontal bone, intradural cystic mass compressing the bilateral frontal lobe, and no local recurrence. A second operation was performed followed by radiotherapy and we diagnosed no contiguous meningeal recurrence of metastatic olfactory neuroblastoma. Olfactory neuroblastoma is a locally aggressive tumor. Although metastasis of this tumor has been reported, non-contiguous spread to the dura is rare. Understanding the route of remote metastasis and careful evaluation after primary treatment are needed to avoid misdiagnosis and treatment delays. PMID- 30023144 TI - Production of ethanol fuel from enzyme-treated sugarcane bagasse hydrolysate using d-xylose-fermenting wild yeast isolated from Brazilian biomes. AB - In this study, we evaluated the potential of yeasts isolated from Amazon to produce second-generation ethanol from sugarcane bagasse delignified with alkaline hydrogen peroxide and hydrolysed with commercial enzyme preparation. The best efficiency savings in glucose and release of xylose were determined by considering the solids and enzyme loads. Furthermore, we selected Spathaspora passalidarum UFMG-CM-Y473 strain with the best fermentative parameters. Fermentations used bagasse hydrolysate without any nutritional supplementation, a significant difference from previous studies, which is closer to industrial conditions. Ethanol yield of 0.32 g/g and ethanol productivity of 0.34 g/L h were achieved after the consumption of 78% of the sugar. This hydrolysis/fermentation technology package could represent the input of an additional 3180 L of ethanol per hectare in areas of average sugarcane productivity such as 60 ton/ha. Thus, we concluded that Sp. passalidarum UFMG-CM-Y473 has a clear potential for the production of second-generation ethanol from delignified and enzyme-hydrolysed bagasse. PMID- 30023145 TI - Efficient phosphate accumulation in the newly isolated Acinetobacter junii strain LH4. AB - Phosphate (PO43-) accumulation associated with bacteria contributes to efficient remediation of eutrophic waters and has attracted attention due to its low cost, high removal efficiency and environmental friendliness. In the present study, we isolated six strains from sludge with high concentrations of chemical oxygen demand, total nitrogen and total phosphorus levels. Among them, strain LH4 exhibited the greatest PO43- removal ability. Strain LH4 is typical of Acinetobacter junii based on physiological, biochemical, and molecular analyses and is a PO43--accumulating organism (PAO) based on toluidine blue staining. The strain grew quickly when subjected to aerobic medium after pre-incubation under anaerobic condition, with a maximum OD600 of 1.429 after 8 h and PO43- removal efficiency of 99%. Our data also indicated that this strain preferred utilizing the carbon (C) sources sodium formate and sodium acetate and the nitrogen (N) sources NH4Cl and (NH4)2SO4 over other compounds. To achieve optimal PO43- removal efficiency, a C:N ratio of 5:1, inoculation concentration of 3%, solution pH of 6, incubation temperature of 30 degrees C, and shaking speed of 100 rpm were recommended for A. junii strain LH4. By incubating this strain with different concentrations of PO43-, we calculated that its relative PO43- removal capacity ranged from 0.67 to 3.84 mg L-1 h-1, ranking in the top three among reported PAOs. Our study provided a new PO43--accumulating bacterial strain that holds promise for remediating eutrophic waters, and its potential for large-scale use warrants further investigation. PMID- 30023146 TI - In silico design of potentially functional artificial metallo-haloalkane dehalogenase containing catalytic zinc. AB - Artificial metalloenzymes are unique as they combine the good features of homogeneous and enzymatic catalysts, and they can potentially improve some difficult catalytic assays. This study reports a method that can be used to create an artificial metal-binding site prior to proving it to be functional in a wet lab. Haloalkane dehalogenase was grafted into a metal-binding site to form an artificial metallo-haloalkane dehalogenase and was studied for its potential functionalities in silico. Computational protocols regarding dynamic metal docking were studied using native metalloenzymes and functional artificial metalloenzymes. Using YASARA Structure, a simulation box covering template structure was created to be filled with water molecules followed by one mutated water molecule closest to the metal-binding site to metal ion. A simple energy minimization step was subsequently run using an AMBER force field to allow the metal ion to interact with the metal-binding residues. Long molecular dynamic simulation using YASARA Structure was performed to analyze the stability of the metal-binding site and the distance between metal-binding residues. Metal ions fluctuating around 2.0 A across a 20 ns simulation indicated a stable metal binding site. Metal-binding energies were predicted using FoldX, with a native metalloenzyme (carbonic anhydrase) scoring 18.0 kcal/mol and the best mutant model (C1a) scoring 16.4 kcal/mol. Analysis of the metal-binding site geometry was performed using CheckMyMetal, and all scores for the metalloenzymes and mutant models were in an acceptable range. Like native metalloenzymes, the metal binding site of C1a was supported by residues in the second coordination shell to maintain a more coordinated metal-binding site. Short-chain multihalogenated alkanes (1,2-dibromoethane and 1,2,3-trichloropropane) were able to dock in the active site of C1a. The halides of the substrate were in contact with both the metal and halide-stabilizing residues, thus indicating a better stabilization of the substrate. The simple catalytic mechanism proposed is that the metal ion interacted with halogen and polarized the carbon-halogen bond, thus making the alpha carbon susceptible to attack by nucleophilic hydroxide. The interaction between halogen in the metal ion and halide-stabilizing residues may help to improve the stabilization of the substrate-enzyme complex and reduce the activation energy. This study reports a modified dynamic metal-docking protocol and validation tests to verify the metal-binding site. These approaches can be applied to design different kinds of artificial metalloenzymes or metal-binding sites. PMID- 30023148 TI - Correction to: The production of UL16-binding protein 1 targeted pigs using CRISPR technology. AB - [This corrects the article DOI: 10.1007/s13205-018-1107-4.]. PMID- 30023147 TI - Co-expression network of transcription factors reveal ethylene-responsive element binding factor as key regulator of wood phenotype in Eucalyptus tereticornis. AB - Suitability of wood biomass for pulp production is dependent on the cellular architecture and composition of secondary cell wall. Presently, systems genetics approach is being employed to understand the molecular basis of trait variation and co-expression network analysis has enabled holistic understanding of complex trait such as secondary development. Transcription factors (TFs) are reported as key regulators of meristematic growth and wood formation. The hierarchical TF network is a multi-layered system which interacts with downstream structural genes involved in biosynthesis of cellulose, hemicelluloses and lignin. Several TFs have been associated with wood formation in tree species such as Populus, Eucalyptus, Picea and Pinus. However, TF-specific co-expression networks to understand the interaction between these regulators are not reported. In the present study, co-expression network was developed for TFs expressed during wood formation in Eucalyptus tereticornis and ethylene-responsive element-binding factor, EtERF2, was identified as the major hub transcript which co-expressed with other secondary cell wall biogenesis-specific TFs such as EtSND2, EtVND1, EtVND4, EtVND6, EtMYB70, EtGRAS and EtSCL8. This study reveals a probable role of ethylene in determining natural variation in wood properties in Eucalyptus species. Understanding this transcriptional regulation underpinning the complex bio-processing trait of wood biomass will complement the Eucalyptus breeding program through selection of industrially suitable phenotypes by marker-assisted selection. PMID- 30023149 TI - In vitro multiplication and growth improvement of Olea europaea L. cv Canino with temporary immersion system (PlantformTM). AB - Olea europaea L. cv Canino shoots were micropropagated to test two different culture systems: (1) on conventional semi-solid medium in glass jars and (2) in liquid culture in a PlantformTM bioreactor. The temporary immersion system, PlantformTM, is a new propagation approach that uses liquid culture, where shoots undergo periodic immersion in liquid medium alternated with dry periods, avoiding gas accumulation through forced ventilation. This study proposes a protocol to improve in vitro propagation of olive reducing production costs. Our findings revealed that olive shoots propagated in PlantformTM, with an immersion frequency of 8 min every 16 h and additional ventilation, showed good adaptability and better growth rates than those cultured in conventional system. Overall, the PlantformTM improves in vitro culture of 'Canino', showing higher proliferation, shoot length and better vigour of shoots. Moreover, the study found no significant differences in shoot length when 5 or 10 uM zeatin was applied in PlantformTM (3.04 and 3.13 cm, respectively); it is, therefore, possible to achieve efficient olive proliferation also with half hormone concentration. The positive performance of the bioreactor approach was also confirmed by Relative Growth Rate index. This is the first documented study of the PlantformTM technique for olive propagation. PMID- 30023150 TI - Chikungunya virus: genomic microevolution in Eastern India and its in-silico epitope prediction. AB - This is the first study reporting whole genome sequences of two CHIKV strains (KJ679577 and KJ679578) isolated from Eastern Indian patients sera during 2010 2011 outbreak, both of which were of ECSA genotype, but from different subgroups: Indian Ocean outbreak and ECSA subtypes. Furthermore, viral sequences were analyzed using different in-silico approaches to identify potential genetic variations that might have functional implications on various aspects of virus replication, viral protein functionality, immunogenicity and transmission. Epitope prediction analysis revealed 70.9% increase in number of MHC Class-II interacting epitopes of KJ679578 and 25-28% increase in Class-I interacting epitopes of KJ679577 and KJ679578 compared to that of EF027141 (CHIKV of Asian genotype circulating in India during 1973, after which CHIKV infection disappeared from India for three decades). CHIKV peptides DLAKLAFKRSSKYDLECAQIPVHMKSDA and KVVLCGDPKQCGFFNMMQMKYNYNHNI were predicted to interact with maximum number of HLA Class-I (68 and 76.5%, respectively) and Class-II (47 and 100%, respectively) alleles present within Indian population with allele frequency of > 0.1 and were also recognized as predicted B-cell epitopes with BCPred score between 0.766 and 0.961 and with antigenicity ranging from 0.52 to 1.69; thus these peptides might be used to induce T- and B-cell mediated immunity against CHIKV. Thus, the present study might help to bridge the gap between virus microevolution and its implication in host immunity by taking into account viral genetic and conformational changes. Predicted epitopes might be used as promising targets for peptide-based vaccine development and rapid diagnostics against CHIKV infection. PMID- 30023151 TI - Paradigm Shift in Life Sciences. PMID- 30023152 TI - Study on Cardiopulmonary Function, Maximal Oxygen Uptake, and Obesity Index according to Smoking Status in Middle-Aged and Older Office Workers. AB - Objectives: To investigate the effect of smoking upon cardiopulmonary function, maximal oxygen uptake, and obesity index, in middle-aged and older workers to propose guidelines on healthcare for these age groups. Methods: This study analyzed medical data from 2,753 white-collar workers aged 50 years or older from workplaces located in Seoul, South Korea. Blood pressure (BP), resting heart rate, maximal oxygen uptake (VO2max), and body mass index (BMI) of each subject were measured. The collected data were analyzed using SPSS 21.0. Results: In the smoking group BP and resting heart rate were significantly higher than in the non smoking and smoking-cessation groups (p < 0.05). In addition, VO2max was lower in the smoking group compared to the other 2 groups. BP closely correlated with resting heart rate, abdominal fat ratio, and BMI. BMI was the highest in the group that stopped smoking and, BMI and abdominal fat ratio negatively correlated with VO2max. Conclusion: Smoking increases the risk of cardiopulmonary disease but obesity may be caused by stopping smoking. Therefore, healthcare guidelines on smoking cessation should also include nutritional advice. PMID- 30023153 TI - Seroprevalence of Toxocara in Children from Urban and Rural Areas of Ilam Province, West Iran. AB - Objectives: The present study was performed to determine the seroprevalence of Toxocara in children <= 10 years old, from rural and urban areas of Ilam. Methods: Serum samples from 383 children <= 10 years old, were selected randomly from rural and urban areas of Ilam province and surveyed using enzyme-linked immunosorbent assays. Results: The total rate of infection with Toxocara was 22% (31% with a history of contact with dogs and cats, and 14% without a history of contact). Of those infected, 23% were male and 18% were female, 36% lived a rural life and 20% had an urban life. A significant correlation was found between the incidence of disease, and urban and rural life, as well as exposure to dogs and cats. There was no correlation between prevalence and gender or age. Conclusion: Given the high prevalence of infection with Toxocara amongst children in Ilam province, preventive work in the community such as education in risk management and periodic treatment with anti-parasitic drugs and elimination of stray dogs and cats is an appropriate measure. PMID- 30023154 TI - How Should Biobanks Collect Biosamples for Clinical Application? A 20-year Biomarker-related Publication and Patent Trend Analysis. AB - Objectives: This study was designed to analyze biomarker-related publications and patent trends which biobanks could consider in planning biosample collections for biomarker research. Methods: Publications and patents containing the term "biomarker" in the title published between 1998 to 2017 were retrieved using Scopus database and Google Patents search engine. Results: Over the last 20 years there has been a steady increase in biomarker-related publications and patents; however this has slowed for patents over the last few years. Publications in 2017 that contained blood, serum, and plasma search terms in the abstract accounted for 50%, and serum as a search term in the title and abstract was more numerous than those containing blood, plasma, tissue, or urine. Blood-related patents were the most common patent in the last 10 years, and accounted for 110 patents in 2017. Biomarker-related publications since 2010 containing RNA and protein search terms in the title and abstract, were more numerous than those containing DNA and metabolite search terms. More than 27% of biomarker-related publications in 2017 and 21% of biomarker-related patents were associated with cancer. Conclusion: The results of this study will help biobanks establish a biosample collection strategy for clinical application. PMID- 30023155 TI - Estimating the Incidence of Cases and Deaths Resulting from Hand, Foot and Mouth Disease and Its Related Socioeconomic Disease Burden in Republic of Korea (2010 - 2014). AB - Objectives: Hand, Foot and Mouth disease (HFMD) is a highly contagious viral disease that affects young children and frequently causes epidemics. A vaccine is available in China (enterovirus 71) and, the Republic of Korea took the first step to develop a new vaccine. New vaccine development requires that disease burden is calculated in advance so the financial cost, morbidity and mortality can be measured. Methods: Data from National Sentinel Surveillance and health insurance systems of 1 million claimants were used. Direct medical and non medical costs, indirect (caregiving and premature death) costs, cases and related deaths were summarized. Results: From 2010 to 2014, there were an estimated 3,605 to 9,271 cases of HFMD, with 1 to 3 deaths. The estimated socioeconomic disease burden ranged from 80.5 to 164.2 million USD and was similar to that of hepatitis A (93.6-103.8 million USD). Among each costs, costs of caregiving consisted of highest proportion mainly due to hiring caregivers (50% - 60%) or opportunity costs from day off (62% - 69%). Conclusion: Considering the social impact of HFMD, the estimated socioeconomic disease burden is not high and government policies need to focus on reducing the loss of work in caregivers. PMID- 30023156 TI - Assessment of Weight Shift Direction in Chronic Stroke Patients. AB - Background: In patients who have suffered a stroke, the measurement of center of pressure excursion in all directions including oblique direction, anterior medial, anterior-lateral, posterior-medial, and posterior-lateral side is important for determining balance instability but no research has been reported. Objectives: This study investigated weight shift in all directions to determine balance instability in stroke patients, including the oblique direction, using the multi-directional functional reach test. Methods: Eleven subjects participated. Multi-directional functional reach test consisted of moving the unaffected arm as far as possible in 8 directions. The directions were as follows; anterior, middle of anterior and lateral in unaffected side, lateral in unaffected side, and middle of the posterior and lateral in unaffected side, posterior, middle of posterior and lateral in affected side, lateral in affected side, middle of anterior and lateral in affected side. Results: Movement was the lowest in the affected posterior-lateral side, followed by affected posterior, affected anterior-lateral, non-affected posterior lateral, affected lateral, non affected lateral, non-affected anterior-lateral and anterior side (p < 0.05). Conclusion: Center of pressure excursion of the affected posterior-lateral side was the most challenging for stroke patients and their reach was lowest from posterior, to lateral, and anterior directions, whilst patients could move less on the affected side compared with the non-affected side. PMID- 30023157 TI - Case of Rickettsia typhi-induced Brain Abscess Mimicking Brain Tumor. AB - Murine typhus is one of the most prevalent rickettsial infections in the world, caused by the bacterial genus Rickettsia. Though the disease manifests a relatively benign clinical course with fever, rash, and headache being the 3 classic symptoms, neurological complications may arise in patients that could become permanent. In this case study, a patient with a brain abscess caused by R typhi infection is described. Based upon the recent reemergence of arthropod borne disease, the findings in this case are significant; R typhi can cause a brain abscess that mimics a brain tumor, which delays the diagnosis and appropriate management of the disease. Murine typhus should always be considered when performing the differential diagnosis of brain abscesses in South Korea. PMID- 30023158 TI - Review of the Incidence of Japanese Encephalitis in Foreign-Born and Korean Nationals Living in the Republic of Korea, 2007-2016. AB - The Japanese encephalitis (JE) vaccine was introduced to the national immunization program in 1985, which has led to a dramatic decrease in the number of reported cases, but JE continues to occur in foreign nationals residing in or traveling to Korea. Although the incidence is low, this study demonstrated that more Koreans were infected with JE than foreign-born expatriates. The incidence rates of Korean-born nationals were between 0.01 and 0.08 cases per 100,000. In contrast, the incidence rates of foreign-born nationals ranged between 0 and 0.26 cases per 100,000. The incidence rates clearly showed that foreign-born expatriates were more at risk, which underscores the importance of vaccination. We recommend heightened surveillance among JE-susceptible individuals and promote vaccination among foreign-born nationals living in Korea. PMID- 30023159 TI - Impact of Time Delay in Processing Blood Sample on Next Generation Sequencing for Transcriptome Analysis. PMID- 30023160 TI - When food isn't medicine - A challenge for physicians and health systems. AB - Food can be powerful medicine. Good nutrition helps promote health and prevent and treat disease. Yet nutrition is not often part of a physician's training or clinical practice. Food might not be medicine when it's importance is under recognized and healthful eating is under-prescribed. Moreover, food cannot be medicine when it is not available to patients (or when available only in the form of unhealthful fare). This paper considers evolving thinking about when food isn't medicine by chronicling the experience of one physician-from college coursework to providing patient care and conducting research. The paper is framed around the experience of a representative patient struggling with diet-related chronic conditions, and describes some community-focused initiatives to help address issues related to food access in challenged communities. A principal focus is the over-abundance of foods from 'plants' (the industrial processing kind) and the low availability of food from 'plants' (the living botanical kind). Physicians and health systems can support access to healthier food and healthier eating, and the idea of food as medicine, through a variety of approaches that extend beyond hospital and clinic walls. Examples of such physician and health system approaches are provided. PMID- 30023161 TI - School socioeconomic disparities in e-cigarette susceptibility and use among central Texas middle school students. AB - Social-ecological theory posits that health-related behavior is shaped by the environments and settings that surround us. We examined e-cigarette susceptibility and ever use prevalence among central Texas middle school students by the level of economic disadvantage (ED) of their school. As a secondary aim, we explored gender and ethnic differences (Hispanic vs. White) in e-cigarette susceptibility across school ED levels. A cross-sectional analysis was conducted of baseline data collected in 2017 as part of the CATCH My Breath study. Participants (n = 5278) were 6th grade students from 23 central Texas public middle schools. E-cigarette susceptibility/use and demographics were self reported; school ED was determined by Texas Education Agency. Analyses included chi-square tests and multi-level logistic regression. E-cigarette susceptibility and use varied by school ED for total sample (p < .0001) and by ethnicity (p <= .003). While e-cigarette susceptibility was higher in boys (p < .001), no gender differences were found for e-cigarette use. Students in the highest school ED quartile (Q4) (lowest SES) had significantly higher odds of e-cigarette susceptibility (AOR = 2.01; 95% CI: 1.49-2.71) and use (AOR = 8.12, 95% CI: 2.58 26.30) compared with Q1 students. Significant gender differences in e-cigarette susceptibility persisted within school ED quartiles 1-3 (p <= .001); no gender differences were found for Q4 (p = .537). Despite overall higher e-cigarette susceptibility for Hispanic students, they had similar prevalence as White students within three school ED quartiles. Findings underscore a higher risk for e-cigarette susceptibility/use among central Texas sixth graders attending high ED schools and provide foundation for further exploration of the school socioeconomic context in adolescent e-cigarette use. PMID- 30023163 TI - Blastomycosis in a renal transplant recipient: Case of immune reconstitution inflammatory syndrome. AB - There are limited data on blastomycosis in solid organ transplant recipients with the subsequent development of the immune reconstitution inflammatory syndrome (IRIS). Herein we describe a case of pulmonary blastomycosis in a renal transplant recipient with the development of concomitant IRIS. PMID- 30023162 TI - Protocol and pilot study of a short message service-guided training after acute stroke/transient ischemic attack to increase walking capacity and physical activity. AB - Physical activity in community-living individuals after a stroke is usually scarce. This protocol describes a study that will evaluate a method to increase physical activity by performing a 3-month outdoor walking and muscle strengthening program and will examine the 3-month and 1-year effects of this program on individuals with acute stroke (AS) or transient ischemic attack (TIA). In a prospective randomized controlled trial in Uppsala, Sweden, 80 individuals with AS or TIA who maintained cognitive and motor function will be randomized into groups for continuous training for three months or for regular standard care. The training will be supervised by daily cellphone-delivered messages (short message services; SMS), and the intensity, duration and workload will be gradually increased. The primary outcome is a change in walking capacity according to the 6-Minute Walk Test and chair-rising at three months. Secondary outcomes include mobility, gait speed, handgrip strength, body composition (fat mass and muscle mass), biochemical risk-markers, health-related quality of life, and cardiovascular events. Adherence to the training program will be documented with a self-reported diary and step counts over two weeks. The major study started in November 2016, and results are expected in 2019. In a pilot study of 15 subjects post-stroke (mean-age 65 years), we observed improved walking capacity (increasing from 23 to 255 m) and chair-rising (decreasing 2.42 s) from baseline to three months. SMS-guided outdoor training will be tested as a potential therapeutic strategy to increase physical activity and thereby improve walking capacity and physical function following a stroke. PMID- 30023164 TI - Near-fatal mucormycosis post-double lung transplant presenting as uncontrolled upper gastrointestinal haemorrhage. AB - Invasive fungal infections in immunosuppressed transplant patients are associated with significant morbidity and mortality. We present a case of splenic mucormycosis post-double lung transplant, presenting as uncontrolled near-fatal upper gastrointestinal haemorrhage, to remind clinicians of the need to consider pre-transplant invasive fungal infection risk factors if an unexpected fungal infection arises in the post-transplant period. This case also highlights the valuable contribution of molecular technology for fungal identification but also the need for clinical correlation. PMID- 30023165 TI - Multiple Organ Dysfunction Syndrome (MODS) induced by Candida krusei in an Aldabra giant tortoise (Aldabrachelys gigantea) and confirmed by electron microscopy analysis. AB - A young female Aldabra giant tortoise (Adabrachelys gigantea) was presented with anorexia, ataxia, severe constipation and bloating. Analysis revealed liver disease and collected biopsy diagnosed Candida krusei infection. Despite Itraconazole treatment, the tortoise got worse and died. Full necropsy was performed; microbiology showed Candida krusei presence in liver, but histopathology didn't confirm fungal presence with special stains, so scanning electron microscopy was essential to prove a detailed diagnosis of extensive mycosis. PMID- 30023167 TI - Quantitative analysis of neurite orientation dispersion and density imaging in grading gliomas and detecting IDH-1 gene mutation status. AB - Background and purpose: Neurite orientation dispersion and density imaging (NODDI) is a new diffusion MRI technique that has rarely been applied for glioma grading. The purpose of this study was to quantitatively evaluate the diagnostic efficiency of NODDI in tumour parenchyma (TP) and peritumoural area (PT) for grading gliomas and detecting isocitrate dehydrogenase-1 (IDH-1) mutation status. Methods: Forty-two patients (male: 23, female: 19, mean age: 44.5 y) were recruited and underwent whole brain NODDI examination. Intracellular volume fraction (icvf) and orientation dispersion index (ODI) maps were derived. Three ROIs were manually placed on TP and PT regions for each case. The corresponding average values of icvf and ODI were calculated, and their diagnostic efficiency was assessed. Results: Tumours with high icvfTP (>=0.306) and low icvfPT (<=0.331) were more likely to be high-grade gliomas (HGGs), while lesions with low icvfTP (<0.306) and high icvfPT (>0.331) were prone to be low-grade gliomas (LGGs) (P < 0.001). A multivariate logistic regression model including patient age and icvf values in TP and PT regions most accurately predicted glioma grade (AUC = 0.92, P < 0.001), with a sensitivity and specificity of 92% and 89%, respectively. However, no significant differences were found in NODDI metrics for differentiating IDH-1 mutation status. Conclusions: The quantitative NODDI metrics in the TP and PT regions are highly valuable for glioma grading. A multivariate logistic regression model using the patient age and the icvf values in TP and PT regions showed very high predictive power. However, the utility of NODDI metrics for detecting IDH-1 mutation status has not been fully explored, as a larger sample size may be necessary to uncover benefits. PMID- 30023168 TI - Impact of partial volume correction on the regional correspondence between in vivo [C-11]PiB PET and postmortem measures of Abeta load. AB - The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C 11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Abeta) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Abeta pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques - the Meltzer, the modified Muller-Gartner, and the Region-Based Voxel-Wise - on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Abeta pathology in a unique cohort of nine subjects. Postmortem Abeta pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Abeta immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p < 0.01, suggesting that PVC is of minimal importance in understanding the relationship between Abeta PET and neuropathologically assessed Abeta. Thus, the utility of PVC in Abeta PET imaging should continue to be examined on an application-specific basis. PMID- 30023166 TI - How do morphological alterations caused by chronic pain distribute across the brain? A meta-analytic co-alteration study. AB - *In chronic pain, gray matter (GM) alterations are not distributed randomly across the brain.*The pattern of co-alterations resembles that of brain connectivity.*The alterations' distribution partly rely on the pathways of functional connectivity.*This method allows us to identify tendencies in the distribution of GM co-alteration related to chronic pain. PMID- 30023170 TI - Neural correlates of attention bias to masked facial threat cues: Examining children at-risk for social anxiety disorder. AB - Background: Behavioral inhibition (BI) is an early-appearing temperament trait and a robust predictor of social anxiety disorder (SAD). Both BI and anxiety may have distinct patterns of emotion processing marked by heightened neural responses to threat cues. BI and anxious children display similar frontolimbic patterns when completing an emotion-face attention bias task with supraliminal presentation. Anxious children also show a distinct neural response to the same task with subliminal face presentations, probing stimulus-driven attention networks. We do not have parallel data available for BI children, limiting our understanding of underlying affective mechanisms potentially linking early BI to the later emergence of anxiety. Method: We examined the neural response to subliminal threat presentation during an emotion-face masked dot-probe task in children oversampled for BI (N = 67; 30 BI, 9-12 yrs). Results: Non-BI children displayed greater activation versus BI children in several regions in response to threat faces versus neutral faces, including striatum, prefrontal and temporal lobes. When comparing congruent and incongruent trials, which require attention disengagement, BI children showed greater activation than non-BI children in the cerebellum, which is implicated in rapidly coordinating information processing, aversive conditioning, and learning the precise timing of anticipatory responses. Conclusions: Non-BI children may more readily engage rapid coordinated frontolimbic circuitry to salient stimuli, whereas BI children may preferentially engage subcortical circuitry, in response to limbic "alarms" triggered by subliminal threat cues. These data help reveal the extent to which temperamental risk shares similar neurocircuitry previously documented in anxious adolescents and young adults in response to masked threat. PMID- 30023169 TI - Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets. AB - Alzheimer's disease (AD) is characterized by an accumulation of beta-amyloid (Abeta42) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that Abeta42 accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the so-called preclinical stage of the AD (pre-AD). It also has been proved that the GM atrophy profile is not linear, both in normal ageing but, especially, on AD. However, several other factors may influence this association and may have an impact on the generalization of results from different samples. In this work, we estimate differences in rates of GM volume change in cognitively healthy elders in association with baseline core cerebrospinal fluid (CSF) AD biomarkers, and assess to what these differences are sample dependent. We report the dependence of atrophy rates, measured in a two-year interval, on Abeta42, computed both over continuous and categorical values of Abeta42, at voxel-level (p < 0.001; k < 100) and corrected for sex, age and education. Analyses were performed jointly and separately, on two samples. The first sample was formed of 31 individuals (22 Ctrl and 9 pre-AD), aged 60-80 and recruited at the Hospital Clinic of Barcelona. The second sample was a replica of the first one with subjects selected from the ADNI dataset. We also investigated the dependence of the GM atrophy rate on the basal levels of continuous p-tau and on the p-tau/Abeta42 ratio. Correlation analyses on the whole sample showed a dependence of GM atrophy rates on Abeta42 in medial and orbital frontal, precuneus, cingulate, medial temporal regions and cerebellum. Correlations with p-tau were located in the left hippocampus, parahippocampus and striatal nuclei whereas correlation with p-tau/Abeta42 was mainly found in ventral and medial temporal areas. Regarding analyses performed separately, we found a substantial discrepancy of results between samples, illustrating the complexities of comparing two independent datasets even when using the same inclusion criteria. Such discrepancies may lead to significant differences in the sample size needed to detect a particular reduction on cerebral atrophy rates in prevention trials. Higher cognitive reserve and more advanced pathological progression in the ADNI sample could partially account for the observed discrepancies. Taken together, our findings in these two samples highlight the importance of comparing and merging independent datasets to draw more robust and generalizable conclusions on the structural changes in the preclinical stages of AD. PMID- 30023171 TI - Neural correlates of exercise training in individuals with schizophrenia and in healthy individuals: A systematic review. AB - A body of evidence has revealed positive effects of physical exercise on behavioral, cognitive and physical outcomes in patients with schizophrenia. Notably, the effect of exercise at the neural level may be particularly relevant as well as it is hypothesized that exercise may stimulate the brain in a way that might normalize neural alterations related to the disorder. The aim of the current systematic review was to provide an up to date overview of studies investigating the neural effects of exercise in individuals with a schizophrenia spectrum disorder and healthy individuals. The majority of included studies focused on hippocampal effects, reporting beneficial effects of exercise. In addition, in schizophrenia increased extrastriate body area (EBA) activation and increased white matter fiber integrity in tracts relevant to the disorder were found and in healthy individuals decreased connectivity of the dorsolateral prefrontal cortex (DLPFC) indicating greater cognitive efficiency was reported. Comparing individuals with a schizophrenia spectrum disorder and healthy individuals within a similar age range, most studies found similar effects on hippocampal volume and white matter tracts for both groups, although the effect in schizophrenia spectrum disorders may be attenuated which is in line with previous literature on brain plasticity. The current review indicates a lack of studies investigating neural correlates other than the hippocampus. Although those studies that did focus on other neural correlates revealed promising results, these have not been replicated in other studies and call for replication. Furthermore, future studies should expand their focus, by investigating neural mechanisms underlying positive effects of physical exercise on positive symptoms, negative symptoms and symptoms such as depression, social withdrawal and social cognition. PMID- 30023174 TI - Neurosurgical treatment of nonconvulsive status epilepticus due to focal cortical dysplasia. AB - We present a rare case of focal cortical dysplasia (FCD) and nonconvulsive status epilepticus (NCSE) treated successfully with early surgical intervention. Our case is a 9-year-old boy whose seizures, characterized by short episodes of loss of consciousness, appeared at the age of 7, and he showed progressive cognitive decline in the following years. NCSE was diagnosed, and his MRI revealed FCD in the left frontal region which was the same side as his EEG abnormality. Following lesionectomy, his NCSE disappeared and cognitive functions improved. Histopathologic analysis of the resected tissue revealed type-IIB FCD. This case illustrates the importance of early surgery to help restore cognitive functions by eliminating the clinical and electrophysiological features of NCSE. PMID- 30023173 TI - Cortical markers of cognitive syndromes in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) can be associated with a spectrum of cognitive and behavioural symptoms, but the related patterns of focal cortical atrophy in non-demented ALS patients remain largely unknown. We enrolled 48 non demented ALS patients and 26 healthy controls for a comprehensive neuropsychological assessment and a magnetic resonance exam. Behavioural and cognitive impairment was defined on the basis of a data-driven multi-domain approach in 21 ALS patients. Averaged cortical thickness of 74 bilateral brain regions was used as a measure of cortical atrophy. Cortical thinning in a fronto parietal network, suggesting a disease-specific pattern of neurodegeneration, was present in all patients, independent of cognitive and behavioural status. Between group and correlational analyses revealed that inferior frontal, temporal, cingular and insular thinning are markers for cognitive and behavioural deficits, with language impairment mainly related to left temporal pole and insular involvement. These specific correlates support the concept of a spectrum of deficits, with an overlap between the ALS cognitive phenotypes and the syndromes of frontotemporal dementia. PMID- 30023172 TI - Transcranial magnetic stimulation in obsessive-compulsive disorder: A focus on network mechanisms and state dependence. AB - Background: Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that has shown promise as an adjunct treatment for the symptoms of Obsessive-Compulsive Disorder (OCD). Establishing a clear clinical role for TMS in the treatment of OCD is contingent upon evidence of significant efficacy and reliability in reducing symptoms. Objectives: We present the basic principles supporting the effects of TMS on brain activity with a focus on network-based theories of brain function. We discuss the promises and pitfalls of this technique as a means of modulating brain activity and reducing OCD symptoms. Methods: Synthesis of trends and critical perspective on the potential benefits and limitations of TMS interventions in OCD. Findings: Our critical synthesis suggests the need to better quantify the role of TMS in a clinical setting. The context in which the stimulation is performed, the neural principles supporting the effects of local stimulation on brain networks, and the heterogeneity of neuroanatomy are often overlooked in the clinical application of TMS. The lack of consideration of these factors may partly explain the variable efficacy of TMS interventions for OCD symptoms. Conclusions: Results from existing clinical studies and emerging knowledge about the effects of TMS on brain networks are encouraging but also highlight the need for further research into the use of TMS as a means of selectively normalising OCD brain network dynamics and reducing related symptoms. The combination of neuroimaging, computational modelling, and behavioural protocols known to engage brain networks affected by OCD has the potential to improve the precision and therapeutic efficacy of TMS interventions. The efficacy of this multimodal approach remains, however, to be established and its effective translation in clinical contexts presents technical and implementation challenges. Addressing these practical, scientific and technical issues is required to assess whether OCD can take its place alongside major depressive disorder as an indication for the use of TMS. PMID- 30023175 TI - A quick method to investigate the Drosophila Johnston's organ by confocal microscopy. AB - Drosophila antennae is gaining attention to study the hearing molecules and its mechanism in last few decades. Various molecules required for the formation of hearing organ is conserved between Drosophila and human being. This suggests Drosophila can be used as a model organism to decipher the vertebrate hearing mechanism. In this context a protocol describing the fixation, sectioning and staining of antennae is lacking from the literature. The current paper describes various commercially available markers of the antennae to visualise it under confocal microscope. PMID- 30023177 TI - Bcl-2 may play a role in the progression of endometrial hyperplasia and early carcinogenesis, but not linked to further tumorigenesis?. AB - The role of Bcl-2 in initiation and progression of endometrial carcinoma is still with inconsistent results. The aim of this study is to determine the role of Bcl 2 in endometrial tumorigenesis. It is a retrospective cross sectional study. We used 100 endometrial paraffin embedded specimens for Bcl-2 oncoprotein immunohistochemical staining; 20 samples of normal endometrium, 40 specimens of endometrial hyperplasia (simple, complex and atypical) and 40 specimens of endometrioid adenocarcinoma. The results were statistically analyzed. There was a significant increase in Bcl-2 staining from normal through complex and atypical hyperplasia into well differentiated adenocarcinoma (P =0.002, P =0.0008 and P =0.0001, respectively). There was a significant difference between the staining of different types of endometrial hyperplasia; as it up streamed from the simple through the complex up to the atypical types (P <0.05). Bcl-2 staining showed no significant correlation with the moderately, poorly differentiated and the different stages of adenocarcinoma (P =0.6, P =0.29 and P =0.1 respectively). These results might indicate a substantial role for Bcl-2 as one of the initiating drives for endometrial tumorigenesis, but not in further tumor progression. PMID- 30023178 TI - The prevalence of iron deficiency anemia in a Saudi University female students. AB - The study aims to determine the prevalence of anemia in apparently healthy university female students. This study was conducted in 2007-2008 at Taibah University and a total of 268 female students participated in this research. In order to assess iron deficiency and iron deficiency anemia, the venous blood samples were collected from consecutive female students at the medical center of Taibah University excluding those already on iron supplementation for iron deficiency anemia. One hundred and seventy-one (64%) students were found to be anemic. The overall prevalence of mild (10-11 g/dL), moderate (7-10 g/dL), and severe (Hb <7 g/dL) anemia was 45%, 49%, and 6%, respectively. Out of the anemic students, 81% showed microcytic (MCV <80 fL) and 1.6% had macrocytic (MCV >96 fL) variety. The results of this study warrant further evidence-based surveys on a larger scale to validate these findings and eventually set a stage to develop well-organized educational and nutritional programs to safeguard and improve the nation's health. The high prevalence of iron deficiency anemia in the present study might be related to life style of female students as well as to their dietary habits. It is recommended that female students never skip breakfast as it is essential for their cognitive functions and physical activities. PMID- 30023176 TI - The effect of manganese on the olfactory bulb of adult male albino rat and the role of meloxicam: A histological and immunohistochemical study. AB - Manganese (Mn) is an essential metal commonly found in the environment and is used for industrial purposes. Exposure to excessively high Mn levels may induce neurotoxicity referred to as manganism. This work was conducted to study the effect of manganese on the olfactory bulb of adult male albino rat and the possible protective role of meloxicam. Forty adult male albino rats were equally divided into four groups: control group, meloxicam-treated group (5 mg/kg/day orally for 4 weeks), MnCl2-treated group (10 mg/kg/day orally for 4 weeks), and the fourth group received both meloxicam and MnCl2 at the same doses and duration. Specimens of the olfactory bulbs were prepared for light and electron microscopy. An immunohistochemical study with a quantitative morphometry was performed using antibodies against glial fibrillary acidic protein (GFAP). The control group and meloxicam-treated group showed the same normal structure. MnCl2 treated group showed shrinkage of mitral nerve cells with dark peripheral nuclei as well as disorganization of mitral and granule nerve cells. The surrounding neuropil showed vacuolar spaces. Ultrastructurally, the mitral cells showed accumulation of lysosomes, swelling of mitochondria and irregularity of the nuclei. The nerve fibers contained swollen mitochondria with splitting and irregularity of the surrounding myelin sheaths. GFAP immunoreaction showed a highly significant increase compared to control group. On the other hand, the group that received both meloxicam and MnCl2 showed less marked histological changes. It was concluded that manganese induced structural changes in the olfactory bulb of albino rat that were ameliorated by concomitant use of meloxicam. PMID- 30023179 TI - Ultrastructures of silver nanoparticles biosynthesized using endophytic fungi. AB - Three endophytic fungi Aspergillus tamarii PFL2, Aspergillus niger PFR6 and Penicllium ochrochloron PFR8 isolated from an ethno-medicinal plant Potentilla fulgens L. were used for the biosynthesis of silver nanoparticles. Scanning and transmission electron microscopic analysis were performed to study the structural morphology of the biosynthesized silver nanoparticles. The electron microscopy study revealed the formation of spherical nanosized silver particles with different sizes. The nanoparticles synthesized using the fungus A. tamarii PFL2 was found to have the smallest average particle size (3.5 +/-3 nm) as compared to the nanoparticles biosynthesized using other two fungi A. niger PFR6 and P. ochrochloron PFR8 which produced average particle sizes of 8.7 +/-6 nm and 7.7 +/ 4.3 nm, respectively. The energy dispersive X-ray spectroscopy (EDS) technique in conjunction with scanning electron microscopy was used for the elemental analysis of the nanoparticles. The selected area diffraction pattern recorded from single particle in the aggregates of nanoparticles revealed that the silver particles are crystalline in nature. PMID- 30023180 TI - Ultrastructural effect on mastitis pathogens by extract of endophytic fungi associated with ethnoveterinary plant, Hibiscus sabdariffa L. AB - Three endophytic fungi isolated from different parts of Hibiscus sabdariffa L. were identified using morphological and molecular approaches. Ethanolic extract of endophytic fungi as well as plant extracts were evaluated for in vitro antibacterial activity by using well diffusion method and their minimum inhibitory concentration estimated. The culture extract of one endophytic fungus Glomerella acutata EF15 was found to be potent antibacterial agent against pathogenic coliform bacteria Klebsiella pneumoniae and Escherichia coli responsible for causing clinical mastitis. Scanning electron microscopy (SEM) revealed the ultrastructural alteration in the cells of K. pneumoniae and E. coli when treated with crude ethanolic extract of G. acutata. The ethanolic extract of the endophytic fungus revealed potential to be bioprospected as antibacterial agent against pathogens causing coliform mastitis, the existing havoc of dairy industries. PMID- 30023181 TI - Microscopic and histochemical characterization of the bovine uterine tube during the follicular and luteal phases of estrous cycle. AB - The morphometrical and morphological features of the infundibulum and ampulla of the uterine tubes of adult cattle were studied. The materials used in this study were consisted of 12 pairs of uterine tube of healthy cows at age of 16-36 months, collected from Assiut slaughterhouses. Through observations of the ovaries, follicular and luteal phases of estrous cycle of each cattle were specified. Semithin sections of ampulla and infundibulum at follicular and luteal phases were made and histochemical analysis of the ampulla by use of PAS, Alcian Blue, Sudan Black B was also done. In addition, acid phosphatase activity of the ampullar epithelium was demonstrated. Histological analysis of the epithelium of bovine oviduct revealed that it was consisted of non-ciliated secretory cells, two populations of ciliated cells (CC), basal cells and Peg cells. At the luteal phase, the secretory cells possessed many cytoplasmic protrusions that extended beyond the luminal borders of the ciliated cells and exocytosis of secretory materials was observed. While at the follicular phase, the ciliated cells were predominated. The histochemistry of the ampullar epithelium revealed increase in secretions of neutral, acidic mucopolysaccarides and lipid from the secretory cells at the luteal phase with moderate acid phosphatase activity. Histomorphometric examinations of infundibulum and ampulla indicated that the mean number and height of primary folds as well as the thickness of the epithelium were increased significantly at the follicular phase. PMID- 30023183 TI - Immunoexpression of cyclin D1 in colorectal carcinomas is not correlated with survival outcome. AB - Background: Colon and colorectal cancer (CRC) research has entered a new era with recent updates of molecular events and prognostic markers. Among other prognostic markers, exaggerated expression of nuclear CCND1 has key role in tumour pathogenesis and metastases of CRC and has also been claimed to predict response to treatment. Objectives: This study was designed to evaluate the prognostic and predictive value of CCND1 in CRC and the correlation of CCND1 expression with the different clinicopathological parameters. Methods: Paraffin blocks from 117 primary CRC were retrieved from the archives of the Department of Pathology at King Abdulaziz University. Tissue microarrays were designed and constructed. The immunostaining of CCND1 was performed and analysed. Results: There were more cases with low nuclear immunoexpression of CCND1 in both primary tumours and nodal metastasis (p <0.001). Cyclin D1 did not show association with clinicopathological features except with lymphovascular invasion. Low nuclear immunoexpression of CCND1 was associated with negative lymphovascular invasion (p = 0.046). There was no statistically significant correlation between CCND1 immunoexpression and survival probability (Log Rank = 2.474, p = 0.116). Conclusion: Our study indicates that CCND1 immunoexpression cannot be used as a predictor of survival in CRC. It also shows no significant correlation with clinicopathological features except with lymphovascular invasion. PMID- 30023184 TI - Immunohistochemical panel for differentiating renal cell carcinoma with clear and papillary features. AB - Objectives: Renal cell carcinoma (RCC) in which clear cells with papillary architecture are present is a difficult diagnostic challenge. Clear cell RCC, rarely has papillary architecture. Papillary RCC rarely contains clear cells. However, two recently described types; clear cell papillary and Xp11 translocation RCC characteristically feature both papillary and clear cells. Accurate diagnosis has both prognostic and therapeutic implications. This study aims to highlight the helpful features of each of these entities to enable reproducible classification. Methods: Sixty RCC cases with clear cells and papillary architecture were selected and classified according to The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia and graded according to The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma then stained for CK7, carbonic anhydrase IX (CA IX), alpha-methylacyl-CoA-racemase (AMACR) and TFE-3. Results: The characteristic immunoprofile of Clear RCC is CK7-, AMACR-, CA IX+ and TFE3-, papillary RCC is CK7+, AMACR+, CAIX- and TFE3-, while for clear cell papillary RCC it is CK7+, AMACR-, CAIX+ and TFE3- and lastly Xp11 translocation RCC is CK7-, AMACR+, CAIX- and TFE3+. Conclusions: Staining for CA IX, CK7, AMACR and TFE3 comprises a concise panel for distinguishing RCC with papillary and clear pattern. PMID- 30023186 TI - A new focus of autochthonous transmission of Cordylobia anthropophaga in Saudi Arabia. AB - Background: Cordylobia anthropophaga, is responsible for nodular cutaneous myiasis in sub-Saharan Africa. The fly has long been limited to tropical Africa except for Asir Province, Saudi Arabia. Al Baha Province; north of Asir has an ecological pattern close to that dominant in subtropical Africa. The Southern parts of Saudi Arabia, including Al Baha, are considered part of the Afro tropical zoogeographical belt where C. anthropophaga is dominant. A case, with cutaneous nodular lesions, was presented to us, where comprehensive investigations were done to establish the diagnosis and to relate it to the known epidemiological background. Materials and methods: A thorough history taking, comprehensive clinical examination and an intensive parasitological examination on a viable larva recovered from the cutaneous lesions, were performed. Taxonomic identification of the larva was done based on various criteria including shape, size, cuticle spine pattern and the posterior spiracles of the recovered larva. Results: We report a case of cutaneous myiasis, caused by Cordylobia anthropophaga, indigenously acquired in Al-Baha. The recovered larva was identified as the third instar of C. anthropophaga. With no history of travel to Africa or to Asir, along with a comprehensive epidemiological assessment, an autochthonous pattern of transmission was confirmed. Conclusion: We present a new focus of autochthonous transmission of C. anthropophaga in Saudi Arabia suggesting a need for an epidemiological reassessment. We also propose considering Cordylobia myiasis as a differential diagnosis in furuncular skin lesions, even in individuals with no history of traveling to Africa. PMID- 30023182 TI - Parasites-allergy paradox: Disease mediators or therapeutic modulators. AB - The noticeable phenomenon of an increased frequency of immune-inflammatory disorders, in the industrialized world, has led to the implication of parasitic infections in the pathophysiology of these diseases. Most of the studies investigated the infection connection to allergy have centered on helminthes. Parasitic helminthes are a group of metazoans that are evolutionary diverse, yet converge to evolve common modes of immunomodulation. Helminth immunoregulation is mainly mediated by a regulatory response including Treg and Breg cells with alternatively-activated macrophages. There is increasing evidence for a causal relationship between helminth infection and allergic hyporesponsiveness, however, conflicting data are still generating. The helminth immunoregulation seems to be species-specific and phase-specific. It depends on the stage of the clinical disease which correlates with a corresponding parasitic stage (egg, larva or mature adult). Here, we review the cellular and molecular mechanisms utilized by helminthes to manipulate the immune system and the consequent bystander immunomodulatory responses toward environmental allergens. We especially focus on parasitic species and molecules involved in the modulation of allergic disorders and summarize the experimental and clinical trials using them as therapeutic agents. We also discuss the potentials and obstacles, for helminthes and/or their derived molecules, to emerge as novel therapeutic modalities. PMID- 30023185 TI - Immunoelectron microscope localization of androgen receptors and proliferating cell nuclear antigen in the epithelial cells of albino rat ventral prostate. AB - Androgen receptor (AR) and proliferating cell nuclear antigen (PCNA) play a crucial role in development and progression of various prostatic diseases including prostatic carcinoma that is a leading cause of death in males. Previous studies have evaluated the expression pattern of AR and PCNA in prostate epithelial cells using immunohistochemistry (IHC). However, this technique has limited ability to identify their precise subcellular localization. Therefore, the aim of this study was to localize, subcellularly, AR and PCNA in the secretory epithelial cells of rat ventral prostate using post embedding immunogold-electron microscopy. The ventral lobes were dissected from six adult male albino rats after being perfused with paraformaldehyde. Some specimens were immuno-labeled with AR or PCNA and others were processed for immuno-electron microscope of AR and PCNA using 15-nm gold conjugated secondary antibodies. The results showed that, by immunoperoxidase reaction, AR and PCNA were localized diffusely throughout the nuclei of the epithelial cells of prostatic acini without visible cytoplasmic expression. However, the higher resolution immuno electron microscopy was able to detect AR and PCNA in the nucleus and some cytoplasmic organelles. In conclusion, this study emphasizes the importance of immuno-electron microscopy in precise localization of AR and PCNA at the subcelullar levels in the secretory epithelial cells of the rat prostatic acini. These findings will help to further understand the mechanism of action of these receptors under normal and pathological conditions that could have future clinical application after careful human investigation. PMID- 30023187 TI - The immunomodulatory effects of rolipram abolish drug-resistant latent phase of Toxoplasma gondii infection in a murine model. AB - Background: Latent toxoplasmosis always has the risk of reactivation leading to significant sequelae. The available medications, for chronic toxoplasmosis, are awfully limited by resistance of Toxoplasma cysts. Therefore, there is a growing necessity for novel therapeutic approaches. Agents increasing cAMP levels and downregulating proinflammatory cytokine could inhibit Toxoplasma conversion to the bradyzoite stage. This study explores a potential immunomodulatory effect of rolipram, a PDE4 inhibitor, on the course of experimental toxoplasmosis and links this role to deterrence of the resistant chronic phase of the disease. Materials and methods: Mice infected with low pathogenic strain of Toxoplasma gondii were treated with rolipram for three weeks. The effect of rolipram was evaluated through tissue injury scoring, brain cyst count, specific IgG titers as well as TNF-alpha, IFN-gamma and IL-12 assays. Results: Rolipram was partially able to prevent the progression to chronic toxoplasmosis. Toxoplasma brain cyst burden showed a 74% reduction while Toxoplasma-induced inflammatory foci per liver area and nucleated cells per inflammatory focus were significantly reduced: 57.14% and 61.3% respectively. Significant reduction of TNF-alpha (84.6%), IFN-gamma (76.7%) and IL-12 (71%) levels was demonstrated along with significant inhibition of anti Toxoplasma antibody response. Conclusion: Rolipram efficiently modulated the Toxoplasma-induced immunological changes with a consequent remission of chronic toxoplasmosis. This study is the first to report the utilization of PDE4 inhibitors as possible immune modulators of chronic phase of Toxoplasma infection. PMID- 30023188 TI - Morpho-histochemical characterization of the salivary glands of semi-engorged Amblyomma triste (Koch, 1844) (Acari: Ixodidae) female ticks. AB - This study presents the morphological and physiological characterization of the salivary glands of semi-engorged Amblyomma triste females. Unfed individuals were placed on New Zealand White rabbits for feeding and the females, after 4 days, were collected, dissected and the salivary glands were submitted to the application of histological (hematoxylin-eosin technique) and histochemical tests for the detection of protein (bromophenol blue technique, polysaccharides (periodic acid-Schiff technique), lipid (Nile blue technique) and calcium (von Kossa technique). The histological results show that the glandular tissue is composed by a system of ducts and three types of acini (I, II and III). The acini I are formed by a large central cell surrounded by several smaller agranular peripheral cells. Acini II are formed by cells a, c1, c2, c3 and c5, which are full of secretion granules. Acini III are constituted by cells d, e and f; the former two contain secretion granules, the latter is agranular. The glandular histochemical composition was also verified. Data obtained here will certainly help in the understanding of the cellular morphology and of the general physiology of these organs in this specie, providing important information for the creation of scientific bases which will contribute for the development of more specific and efficient methods of control. PMID- 30023189 TI - Regenerative medicine: Historical roots and potential strategies in modern medicine. AB - Regenerative medicine is a distinct major advancement in medical treatment which is based on the principles of stem cell technology and tissue engineering in order to replace or regenerate human tissues and organs and restore their functions. After many years of basic research, this approach is beginning to represent a valuable treatment option for acute injuries, chronic diseases and congenital malformations. Nevertheless, it is a little known field of research. The purpose of this review is to convey the state of the art in regenerative medicine in terms of historical steps, used strategies and pressing problems to solve in the future. This review represents a good starting point for more in depth studies and personal research projects. PMID- 30023191 TI - Can vitamin C affect the KBrO3 induced oxidative stress on left ventricular myocardium of adult male albino rats? A histological and immunohistochemical study. AB - Potassium bromate (KBrO3) cardiotoxicity is not widely recognized, in spite of its well known oxidative cell and tissue damage. The wide exposure to KBrO3 in food and water necessitates finding of a simple and available antidote for its hazards like vitamin C. There are growing evidences that the regulation of redox reactions in cells is intimately tied to the levels of antioxidants. As the heart is highly vulnerable for oxidative damage, left ventricle muscle was the spotlight of our study. For this purpose 20 adult male albino rats were categorized into four groups (five rats each). Group 1 served as control; group 2 received 30 mg/kg/day vitamin C for 4 weeks. Group 3 was injected intraperitoneally with KBrO3 20 mg/kg/dose twice weekly for 4 weeks, and group 4 received both vitamin C and KBrO3 in the same scheme. Heart specimens were processed for various histological examinations. Sections from KBrO3 treated animals showed focal disruption of cardiac myocytes, deeply stained nuclei and dilated congested blood vessels. Ultrastructurally, irregular indented nuclei, focal lysis of the myofibrils and swelling of mitochondria were also observed. In contrast, minimal changes were observed in rats treated concomitantly with both vitamin C and KBrO3. Caspase 3 immunohistochemical reaction was nonsignificantly increased in group 3 cardiomyocytes. Semiquantitative morphological mitochondrial scoring and statistical analyses revealed significant changes between the studied groups. Finally, KBrO3 induced structural changes in rat cardiac muscle could be ameliorated by concomitant treatment with vitamin C. PMID- 30023190 TI - Effect of genistein, a natural soy isoflavone, on pancreatic beta-cells of streptozotocin-induced diabetic rats: Histological and immunohistochemical study. AB - Diabetes mellitus is one of the oldest disorders that is rapidly emerging as a global health problem. Soy genistein is a legume that has numerous health benefits. This work aimed to study the effect of different doses of genistein on histological, immunohistochemical and morphometrical changes in beta-cells of streptozotocin (STZ)-induced diabetic rats and to correlate these effects with plasma glucose and insulin levels. Fifty adult male rats were divided into five equal groups. Group I served as a control. Group II received genistein. Group III comprised STZ-induced diabetic rats. Group IV diabetic animals treated with low dosage genistein. Group V diabetic animals treated with high dosage genistein. Genistein was given for 4 weeks after STZ injection. Rats were sacrificed and pancreatic specimens were taken for light and electron microscopic examination. Blood samples were collected for detection of serum glucose and insulin levels. After diabetic induction, the islets appeared shrunken with cytoplasmic vacuolation of their cells and negative insulin immunoreaction. Ultrastructurally, beta-cells showed darkly stained nuclei with marked loss of granules. Morphometrically, significant loss of beta-cells was detected. The serum insulin level was decreased with elevation in the serum glucose. High-dose but not low-dose genistein improved the morphology of islets with increased insulin immunoreaction. Genistein also significantly decreased beta-cells loss and improved glucose and insulin levels. In conclusion, genistein has a protective effect on pancreatic beta-cells damage, possesses the ability to regenerate beta-cells and improves serum levels of insulin and glucose in STZ induced diabetic rats in a dosage-dependent manner. PMID- 30023192 TI - The impact of vitamin E against acrylamide induced toxicity on skeletal muscles of adult male albino rat tongue: Light and electron microscopic study. AB - Acrylamide, one of the major environmental public health problems, results from its increased accumulation in the process of cooking food materials. This study aimed to demonstrate the light and electron microscopic structural effects of acrylamide on the skeletal muscle fibers of adult male albino rat tongue and to investigate the possible protective effect of vitamin E co-administration. Thirty adult male albino Sprague-Dawley rats were divided into 3 groups, each group included 10 rats. Group I (control), group II which was subdivided into two equal subgroups: subgroup IIa: included 5 rats that received acrylamide orally once daily for 20 days. Subgroup IIb: included 5 rats that received acrylamide orally once daily for 40 days. Group III was also subdivided into two equal subgroups: subgroup IIIa: included 5 rats that received acrylamide and vitamin E orally once daily for 20 days. Subgroup IIIb: included 5 rats that received acrylamide and vitamin E orally once daily for 40 days. At the end of the experiment the tongue was dissected out for histological and electron microscopic studies, another muscle sample was homogenized and processed for biochemical estimation of malondialdehyde (MDA) and total antioxidant capacity (TAC). Light microscopic study of tongue skeletal muscles in acrylamide exposed animals revealed abnormal wavy course and splitting of the muscle fibers with fatty infiltration in between. Moreover, pyknosis and remnants of nuclei were detected. EM revealed marked aggregation of mitochondria of different size and shape with giant cells formation, and partial loss of myofilaments. There were statistically significant increase in MDA and decrease in TAC indicating oxidative stress in acrylamide administrated groups (group II) than the control group which increased by prolonged duration (subgroup IIb versus subgroup IIa, p < 0.0001). This oxidative stress could explain the histological changes in tongue muscles of acrylamide exposed rats. Co-administration of vitamin E with acrylamide ameliorated most of the above mentioned histological changes in the animals used and signs of improvement that became better with prolonged administration of it (subgroup IIIb versus subgroup IIIa, p < 0.0001) were detected. It could be concluded that, chronic exposure to acrylamide might lead to skeletal muscle damage in rat tongue which becomes worth with prolonged duration of exposure. Acrylamide induced oxidative stress is the implicated mechanism of such histological changes. This toxic effect of acrylamide could be minimized when vitamin E is given concomitantly with it by its antioxidant effect. PMID- 30023193 TI - Serological evidences link toxoplasmosis with schizophrenia and major depression disorder. AB - The etiology of psychiatric disorders is largely unknown. A role of environmental insults during early neurodevelopment have been suggested. Infections are possible risk factors for psychiatric disorders especially Toxoplasma gondii, a neurotropic parasite with a lifelong residence in brain. This study has investigated a possible role of toxoplasmosis in the development of schizophrenia and major depression disorder (MDD). The influence of other covariates; age, gender and family history was also studied. A cross-sectional study on a total of 177 individuals, where anti-Toxoplasma IgG and IgM in sera of schizophrenia (n = 63) and MDD (n = 39) patients, all fulfilling DSM-5 diagnostic criteria, were compared to healthy volunteers (n = 55). Toxoplasma positivity was highest (31.75%) among schizophrenics followed by MDD (25.64%) and controls (14.55%). IgG levels were significantly higher in toxo-positive schizophrenics (230.1 +/- 22.9) and MDD (220.56 +/- 24.8) compared to controls (9.98 +/-1.78). Three patients only, all schizophrenic, have positive IgM antibodies. Age and male gender appear to have positive associations to toxoplasmosis and psychiatric disorders while family history has no obvious additive role. This report is one of few linking Toxoplasma infection to MDD and adds to many suggesting a link between latent toxoplasmosis and schizophrenia. PMID- 30023194 TI - Optimisation of proteomic approaches to study the maternal interaction with gametes in sow's reproductive tract. AB - The applications of 2DE and MS have been successfully used in many studies utilising different biological samples. The complex nature of cellular proteomes is a big challenge for proteomic technologies. Much effort has been applied to develop and improve the preparation techniques for proteomic samples to be able to detect the low abundant proteins. This is one of the major and unsolved challenges facing the proteomic analysis of biological samples. One partial remedy is to deplete the proteomic samples. In this study, we compared two techniques (acetone precipitation and commercial kit) for the cleaning and purification of oviductal and uterine horn secretory proteomes in primary cell culture system. The samples prepared from acetone precipitation and commercial kit 2-D clean up kit were compared by 2-dimentioanl electrophoresis. We found that no significant difference was observed in number of spots detected between the samples prepared by acetone precipitation technique to those prepared by commercial kit. Protein samples were run through strong cation exchange (SCX) liquid chromatography in order to fractionate samples of major proteins. Protein identification by mass spectrometry revealed a significant detection of low abundant proteins in comparing to high abundant proteins. In conclusion, acetone precipitation was found to be more efficient and cost effect technique. Depletion of proteomic samples from the most abundant protein species is strongly recommended to allow the mid and low abundant protein to be detected. A better resolution of the gels will be achieved by removing the major proteins such as albumin and immunoglobulin. PMID- 30023195 TI - Light and electron microscopic studies on the Y organ of the freshwater crab Travancoriana schirnerae. AB - The fine structure of the premoult Y organ in the freshwater crab Travancoriana schirnerae revealed elliptical epithelial gland cells with large, eccentric, multinucleolated nuclei and ample cytoplasm. The cytoplasm showed numerous polymorphic mitochondria with tubular cristae, highly anastomosed tubules and vesicles of smooth endoplasmic reticulum (SER), rich free ribosomes, small amounts of cisternae of rough endoplasmic reticulum (RER), microtubules and was devoid of Golgi complexes. Mitochondria were of two types the more abundant micromitochondria with electron dense matrix and the less abundant macromitochondria with moderately dense matrix. The tubular SER was particularly concentrated towards the basal region of the cell, intermingled with mitochondria and dense patches of free ribosomes while the vesicular SER lie close to the lateral plasma membrane. Large vesicles with flocculent substances, a few electron dense granules and multivesicular bodies could also be noticed in the gland cell cytoplasm. Aggregations of microvesicles which appeared close to the lateral plasma membrane, in association with dilated SER cisternae and microtubules, possibly suggest the intercellular exchange of substances. The plasma membrane beneath the basal lamina was composed of invaginations and the apical surface possessed numerous microvilli which serve to increase the surface area for metabolic exchange. Towards the apical region, the lateral plasma membrane of adjacent cells was linked by tight junctions. The presence of extraordinarily abundant tubular SER, high proportion of mitochondria with tubular cristae and rich free ribosomes could well be elucidated in favour of steroid production by the gland cells. PMID- 30023196 TI - The significance of sonic hedgehog immunohistochemical expression in colorectal carcinoma. AB - Colorectal carcinoma is a significant source of major morbidity and mortality. Sonic hedgehog (Shh) is expressed in normal gastrointestinal tract mucosa and in many malignancies. The purpose of the present study is to investigate the relationship between Shh immunoexpression in CRC and clinicopathological characteristics. Paraffin blocks of 155 primary CRCs and 37 nodal metastases were retrieved and tissue microarrays were constructed. Immunohistochemistry was performed using anti-Shh antibody. Immunostaining was scored and results were analysed in relation to the clinicopathological parameters. Shh was overexpressed in primary CRC (p = 0.02) and in nodal metastasis (p = 0.004). There was no difference between Shh immunoexpression in primary CRC and in nodal metastasis (p = 0.941). High Shh immunoexpression was associated with well differentiated tumours (p = 0.004). However, there was no association with other clinicopathological parameters. Shh overexpression was not associated disease free survival (log-rank = 0.079, p = 0.778). Shh is overexpressed in well differentiated CRC. However, Shh is not associated with other clinicopathological and prognostic factors. Loss of Shh may be associated with proliferation and loss of differentiation in CRC. Further molecular studies are required to address the potential importance of Shh signalling in CRC and to test Shh inhibitors and activators as potential therapeutic targets in CRC. PMID- 30023197 TI - Comparison between phenol red chromo-endoscopy and a stool rapid immunoassay for the diagnosis of Helicobacter pylori in patients with gastritis. AB - Helicobacter pylori infection is a widespread problem all over the world. Non invasive techniques are demanded for rapid diagnosis and treatment follow up. The aim of this study was to compare the diagnostic value of phenol red chromo endoscopy and stool (Rapid Strip HpSA) for H. pylori detection with reference to histopathology as the gold standard. A total of 80 adult patients with dyspepsia were enrolled on this study. Patients underwent phenol red chromo-endoscopy. Multiple Gastric biopsies were taken and examined for H. pylori detection. Stool sample was collected from every patient for Rapid Strip HpSA test. The study included 38 males (47.5%) and 42 females (52.5%) with their ages ranged between 19 and 56 years. According to histopathology, 71 patients (88.8%) were H. pylori positive and 9 (11.2%) were negative, most of biopsies showed inflammation with variable degree of activity, which showed significant statistical correlation with the density of H. pylori (P < 0.05). Phenol red chromo-endoscopy had 90.1% sensitivity, 88.9% specificity, 98.5% positive predictive value (PPV), 53.3% negative predictive value (NPV) and 90% accuracy. Rapid Strip HpSA had a sensitivity 93%, 77.8% Specificity, 97.1% PPV, 58% NPV and 91.3% accuracy. In conclusion; Phenol red chromo endoscopy was more specific and less sensitive than the rapid stool Rapid Strip HpSA(r) test regarding the detection of H. pylori infection with reference to histopathology as a gold standard, yet both showed high diagnostic accuracy; thus they can be used as reliable diagnostic tools for H. pylori infection in cases contraindicated for gastric biopsy. PMID- 30023198 TI - Histological and immunohistochemical study of the effect of gold nanoparticles on the brain of adult male albino rat. AB - Gold nanoparticles (GNPs) have numerous medical applications as in biological imaging, cancer treatment and in implants (pacemakers and stents). Many conflicting results about GNPs safety and its accumulation in liver, kidney and brain were recorded. This work was carried out to study the histological effect of long period exposure to gold nanoparticle on the brain of adult male albino rat. Twenty adult male albino rats were divided into two equal groups: The first one served as a control group and the second one received 400 MUg/kg/day GNPs by gastric tube once daily for eight weeks. Brain specimens were collected at the end of the experiment for histological and immunohistochemical studies using caspase-3 and glial fibrillary acidic protein (GFAP). GNPs treated group revealed wide spread histological alterations and deposition of gold nanoparticle aggregates in the neurons of cerebral cortex and hippocampus and also in the epithelium of choroid plexus with hyalinization of the wall of some blood vessels and disruption of the capillaries. All these changes were associated with localized positive caspase 3 reaction. Various degrees of astrogliosis were evidenced by astrocytic proliferation and increase size of their cell body with increase number and length of their processes. It could be concluded that repeated exposure of adult male albino rats to gold nanoparticles induced its deposition in the brain in association with histological alterations and various degrees of astrogliosis. PMID- 30023199 TI - Fine structure of thyroid gland in wild caught female bat Taphozous kachhensis (Dobson) during reproductive cycle. AB - The thyroid gland has long been recognized as an important modulator of reproductive function. Both hyper- and hypo-thyroidism are associated with reproductive dysfunction and infertility. In addition, thyroid hormones appear to play a key role in the expression of events that underlie seasonal reproductive cycles. Despite the considerable information is available on the histology of thyroid gland in some of the bats, literature related to study is very few, and further information available on the ultrastructure is also scanty. The specimen of Taphozous kachhensis was collected from Ambai Nimbi. Many collections were made during the breeding season so as to coincide with the time of reproductive cycle and to get an accurate pregnancy record. Thyroid is removed from the bat and cut into 1-2 mm piece and immersed in fresh ice-cold 3% gluteraldehyde solution for 2-4 h and send for further process. The thyroid gland is more active during estrus than the pregnancy and lactation. The cell organelles observed in follicular cell of thyroid gland indicate more synthetic activity. While during pregnancy and lactation the thyroid gland is not synthetically active but the appearance of more lysosomal bodies during pregnancy indicate the utilization of stored colloid and release of thyroid hormone in blood stream. The parafollicular cells are more developed during pregnancy and lactation than estrus as indicated by ultrastructural characteristics. These cells may secrete calcitonin, serotonin, and somatostatin and may be responsible for controlling the seasonal changes in plasma calcium concentration in this bat. PMID- 30023200 TI - Histodifferentiation and ultrastructure of nodular cultures from seeds of Vriesea friburgensis Mez var. paludosa (L.B. Smith) L.B. Smith and leaf explants of Vriesea reitzii Leme & A. Costa (Bromeliaceae). AB - Micropropagation via induction, multiplication and development of nodular cultures (NCs) is an efficient regeneration system for Bromeliaceae, a family of endangered monocot plants with ornamental value. Therefore, the present work aimed to induce NCs from seeds and leaf explants of Vriesea in order to characterize the morphological and histochemical aspects of induction and formation of these cultures. Seeds of Vriesea friburgensis var. paludosa were sterilized and inoculated into liquid culture media supplemented with different concentrations and combinations of growth regulators. Leaf explants of Vriesea reitzii were inoculated into medium supplemented with 4 MUM alpha-naphthalene acetic acid (NAA) and 2 MUM 6-benzylaminopurine (BAP). The addition of NAA (4 MUM) in the culture medium used for seeds led to an induction rate of 72% in NCs. First, the embryo began to germinate, and afterwards, nodular structures started to form. While NCs formed from seeds is associated with root and shoot meristems, the formation of NCs from leaf explants involves the intercalary meristem. Meristematic cells generate an appropriate response in the induction medium, producing NCs by the proliferation of small cells with meristematic characteristics and large vacuolated cells. These results provide a better understanding of morphogenetic responses in bromeliads and, hence, the opportunity to develop optimized micropropagation protocols. Abbreviations: BAP, 6-benzylaminopurine; 2-iP, N6 (2-isopentyl) adenine; CBB, Coomassie Brilliant Blue; CLSM, confocal laser scanning microscopy; MSB, MS basal medium; NAA, alpha Naphthalene acetic acid; NCs, nodular cultures; PAS, Periodic Acid-Schiff; SEM, scanning electron microscopy; TDZ, N-phenyl-N'-1,2,3-thidiazol-5-ylurea; TB-O, Toluidine Blue O; TEM, Transmission electron microscopy. PMID- 30023202 TI - Corrigendum to "The impact of vitamin E against acrylamide induced toxicity on skeletal muscles of adult male albino rat tongue: Light and electron microscopic study" [J. Microsc. Ultrastruct. 3 (2015) 137-147]. AB - [This corrects the article on p. 137 in vol. 3.]. PMID- 30023201 TI - Understanding the ultrastructural aspects of berberine-induced skin-darkening activity in the toad, Bufo melanostictus, melanophores. AB - Berberine is an active compound of Berberis vulgaris (Daruhaldi) with known multiple pharmacological activities, including antimicrobial, antiviral, anti inflammatory, cholesterol-lowering, and anticancer effects. The present work aimed to study the ultrastructural effects of berberine to determine its skin darkening potential using Bufo melanostictus melanophores, which has not been done to date. Light and electron microscopic analysis of isolated dorsal skin melanophores of B. melanostictus has been done after treatment with various concentrations of berberine, along with specific antagonists and agonists of beta adrenoceptors in order to explore the mechanism of action of berberine-induced skin darkening. The results showed that the number of melanophores with melanin loaded dendrites increased in the subepidermal layer significantly in berberine treated skin pieces in a dose-dependent manner leading to skin darkening. Highly electron-dense melanosomes of Stage IV increased considerably due to the enhanced process of melanization. These effects were found to be antagonized by propranolol, and were also found to be highly potentiated by isoprenaline, which is a specific beta-adrenoceptor agonist. The findings show that berberine possesses a skin-darkening potential and could be used as a safe melanogenic agent for the treatment of hypopigmentation disorders or vitiligo. PMID- 30023203 TI - Ultrastructural characterizations of DNA nanotubes using scanning tunneling and atomic force microscopes. AB - The potential applications of scanning tunneling microscopy and atomic force microscopy for the characterizations of DNA nanotubes in nanoscale have been described here. The nanotubes were designed using the Cadnano software according to M13 mp18 DNA as a scaffold. DNA nanotubes were fabricated using the origami technique assisted with ligase treatment subsequently. Transmission electron microscopy confirmed the morphology of DNA nanotubes. For the topographic characterization of DNA nanotubes, an atomic force microscope was used in comparison to a scanning tunneling microscope. The scanning tunneling microscopy results revealed a high-resolution topography of DNA nanotubes in the constant current mode; however, more details of the self-assembly in DNA strands in nanotubes were explored by atomic force microscopy with contact mode (or constant height). Our findings suggested that those two microscopes could be candidates for ultrastructural characterizations of DNA nanotubes for obtaining two- and three-dimensional micrographs. PMID- 30023204 TI - Pseudomyxoma peritonei with endometrial mucinous carcinoma and appendicular mucinous tumor: An unusual association. AB - The association between pseudomyxoma peritonei and appendicular or ovarian mucinous tumors is usually reported in the literature, while the association with endometrial carcinoma is exceptional. Although there has been always a continuous debate regarding its primary origin, tumors of the appendix and ovary remain the most common primary sites for this disease. The association of pseudomyxoma peritonei with two primaries from endometrial mucinous adenocarcinoma and appendicular mucinous tumor is very rare. So, we report this case to raise awareness among clinicians about this rare tumor association. PMID- 30023205 TI - Deep inside the ceramic texture: A microscopic-chemical approach to the phase transition via partial-sintering processes in ancient ceramic matrices. AB - High-resolution microscopy investigations on ancient ceramics recommend the complex progression of crystalline phases in an antique object via the sintering process. Based on materials-science point of view, sintering is not a routinely reaction in all crystalline phases with the same crystallographic pattern, but also is a transition pathway. Sintering depends on the processing of raw materials via the manufacturing process. Five samples are chosen for this analytical approach from two different periods from Tappeh Zaghe, Iran (5100 millennium BC). A multimicroscopical approach was carried out by means of polarized light microscopy, environmental scanning electron microscopy, and atomic force microscopy. Crystalline phases were determined by X-ray diffraction and refined after Rietveld method. The observation of the behavior of phase interphase boundaries of a crystalline part in the nano area suggests that the partial sintering is the point at which the mineral began to be decomposed, and the conditions of the occurrences of this phenomenon depend on crystallographic properties. PMID- 30023206 TI - Ultrastructural Features of Eutopic Endometrium in a Rat Model of Endometriosis. AB - Endometriosis is a chronic recurrent disease that is relatively common. Diagnosis is difficult and often delayed. Current treatments are inadequate with unacceptable side effects and multiple surgeries may be needed. Abnormal eutopic endometrium may play important role in endometriosis-associated infertility. This study aimed to examine the ultrastructural changes in eutopic endometrium in a rat model of surgically induced endometriosis. Endometrial tissue was removed from rats in surgical endometriosis induction group (n = 10), sham operated (n = 10) and non-operated control (n = 10) groups in the diestrus phase of the estrus cycle. They were studied with light, transmission and scanning electron microscope as well as morphometric analysis. Eutopic endometrium in surgically induced endometriosis showed pseudostratified epithelium, vacuolated columnar cells alternated with dark cells. The stroma was edematous exhibiting dilated, congested blood vessels. The mean endometrial mucosal depth and surface epithelial height significantly increased. Ultrastructurally, most luminal epithelial cells showed vacuolation. Mucous secretory granules were surrounded by dilated rough endoplasmic reticulum cisternae. Mitochondria, glycogen deposits and vesicles with electron dense cores were observed. The nuclei were highly euchromatic. Well defined microvilli were noticed with evident apical tight junctions. Scanning electron microscope revealed flattened and structurless surface epithelium with apparent decrease in the number of pinopodes. A different response to sex hormones in different parts of eutopic endometrium was observed. Ultrastructural features of estrogen dominance or progesterone resistance in the eutopic endometrium might account for inappropriate cyclic changes occurring in the disease. PMID- 30023207 TI - Microscopic study of the morphology and metabolic activity of Fusarium oxysporum f. sp. gladioli treated with Jatropha curcas oil and derivatives. AB - The fungus Fusarium oxysporum f. sp. gladioli is one of the main pathogenic microorganisms of the ornamental genus Gladiolus. The attack of this microorganism includes corms and different plant phenological stages. In this study, different microscopic techniques and fluorochromes were used to evaluate the effect of J. curcas oil and acylglycerides, namely trilinolein, triolein, monomyristin and dimyristin, on the morphology, membrane integrity (%), viability (%) and germination (%) of F. oxsporum f sp. gladioli. Phase-contrast optical photomicrographs and scanning microscopy showed that J. curcas oil and the triglycerides triolein and trilinolein caused the formation of numerous vacuoles, alterations in the morphology of the outer covering of the mycelium and conidia, and inhibition of membrane activity in the fungus during 24 h of incubation. The fluorochromes used detected no permanent damage to the viability of the conidia. The high germination percentage of the conidia of Fusarium oxysporum f. sp. gladioli indicates that the damage caused by the application of the treatments was fungistatic rather than fungicidal and did not cause cell death. PMID- 30023208 TI - Histological Study on the Protective Role of Ascorbic Acid on Cadmium Induced Cerebral Cortical Neurotoxicity in Adult Male Albino Rats. AB - Cadmium (Cd) toxicity represents a worldwide problem in environmental contamination and a common cause of occupational and non-occupational neurological diseases. So, this study aimed to evaluate the histological changes induced by Cd on the cerebral cortex of adult rats and evaluating the possible ameliorating role of ascorbic acid (AA). Twenty adult male rats were divided into; control group, AA group (each rat was received a daily oral dose of 200 mg AA/kg body weight (b.w) and Cd group (each rat was received 5 mg Cd/kg b.w orally) and protective group (each rat was given AA concomitantly with Cd at the same dose, route and period of administration of the previous groups. After two months the cerebral cortexes were processed for histological examination. The cerebral cortex of Cd treated animals exhibited severe degenerative changes especially in pyramidal and granule cells. Structural changes in these cells were in the form of dilated rER and Golgi complex, swollen mitochondria and marginated nuclear chromatin. Myelinated nerve fibers displayed myelination disruption and irregular neurofilaments. The neuropil appeared vacuolated with accumulation of neuroglial cells. On the other hand, these changes were ameliorated in rats which received AA concomitantly with Cd. So, it could be concluded that AA can ameliorate the histological changes induced by Cd and this direct the attention to the antioxidants as protective measures for the neurotoxicity. PMID- 30023209 TI - Morphometric and Ultrastructure studies of Primordial Follicles and Expression of Estrogen-dependent Genes in the Ovaries of Domestic Cats. AB - The aim of this study was to compare and estimate the population of the primordial follicle morphometrically and ultrastructurally in the left and right side ovaries of 10 ovariohysterectomied healthy domestic shorthair cats. The ovaries were processed for light microscopy, electron microscopy, and estrogen dependent gene expression for assessments. A total of 15,092 primordial follicles with and without a nucleus were examined and counted. A total of 6842 primordial follicles with a nucleus were examined and counted. The light-microscopy numerical data were collected from two histological sections per ovary for a total of 20 sections from the left ovary and 20 sections from the right ovary. The average surface area of the histological sections was 645.99 mm2. The number of tertiary follicles was found to be higher in the left ovaries than in the right ovaries. The primordial follicles are under the tunica albuginea at various levels. Some are crowded or scattered in one or two rows, although at times, there were areas without any primordial follicles. The primordial follicles varied in size, and were surrounded by 4-10 squamous granulosa cells. Some primordial follicles shared their ooplasm with one or two neighboring primordial follicles, forming a giant primordial follicle with two or three nuclei. The ultrastructure of the primordial follicles showed rounded nuclei with distinct nucleoli, rounded and elongated mitochondria, and a considerably thick basement membrane under the granulosa cells. The squamous granulosa cells showed well developed microvilli intermingled with the microvilli of the oocyte oolemma. Elongated mitochondria, coated pits, multicytoplasmic vesicles, ribosomes, and Golgi apparatuses were obvious in the oocyte ooplasm. Large vesicles contain small multivesicles and some scattered lipid globules in the ooplasm. There were estrogen-dependent gene-expression differences between the right and left ovaries. Further gene research is in the plan, using a larger pool of cats, with a focus on age differences. PMID- 30023211 TI - Sildenafil citrate (Viagra) reduces surface roughness of human erythrocytes: Atomic-force-microscopic study. AB - Sildenafil citrate (Viagra) is used to treat erectile dysfunction and pulmonary arterial hypertension. The objective of this study was to analyze the action of sildenafil citrate on normal human erythrocytes in vitro at a concentration (2.5 mg/mL) higher than the prescribed for clinical conditions. Imaging of drug treated erythrocytes was done using an atomic-force microscope in contact mode in air. Data analysis was performed using the scanning probe-microscopy software WSxM. The study revealed that the drug causes hemolysis of erythrocytes at high concentration in vitro at room temperature. The ghosts (membranes) of erythrocytes with reduced cell size and deformed shape were observed using atomic force-microscope imaging at low magnification. In addition, the high magnification images revealed alterations in the nanostructural features of the erythrocyte membrane. There was a complete loss of characteristic membrane architecture pattern. The root-mean-square surface roughness of the cell membrane after drug treatment was measured and found to be significantly less than that of erythrocytes in the native state. Sildenafil citrate causes hemolysis of erythrocytes in vitro at high concentration with significant alterations in morphometric properties, like change in cell shape, reduction in cell dimension, and disruption of membrane cytoarchitecture, along with a severe drop in membrane root-mean-square surface roughness. PMID- 30023212 TI - Food-induced immunoglobulin E-mediated allergic rhinitis. AB - Food allergies are estimated about 1-2% in adults and 8% in children younger than 6 years. Allergic rhinitis is a common disease with a prevalence of 40% among different societies. Although, some foods play a role on exacerbation of allergic rhinitis symptoms, but still there are controversies about the role of diet on incidence or worsening the symptoms. The ongoing research demonstrates a possible relationship between certain foods and their induction of allergic reactions by modulating immunoglobulin E. A total of 100 patients (including both children and adults), between the ages 10 to 60 years, diagnosed with allergic rhinitis were selected for the study. Pregnant females and treated patients with antihistamine were excluded from the study. In vitro serum immunoglobulin E (IgE) levels mediated by a combination of food and inhalant allergens were detected by RIDA(r) Allergy Screen in blood samples. Data were presented as mean, standard deviation and standard error. A statistical analysis was performed by one-way analysis of variance (ANOVA). A p value < 0.05 was considered statistically significant. We reported that 63% of patients with allergic rhinitis were sensitized to common food allergens whereas the rest 37% of patients were not sensitive to any of the food allergens. Similarly, a correlation between the age groups of patients with allergic rhinitis and food allergy were also accomplished. We found the highest response rate for allergic rhinitis and food allergy (53.2%) for the people between aged between 21 years and 40 years. We also demonstrated that females are more prone to mediate allergic rhinitis as induced by food allergies as compare to males (i.e., 66.2% vs. 33.3%). Food allergy is estimated to be 4.5% in adolescents and adults with asthma, rhinitis or both. Rice, citrus fruits, black grams and banana are identified as major allergens for inducing allergic-rhinitis symptoms. PMID- 30023210 TI - Modulation of dendritic cell immune functions by plant components. AB - Dendritic cells (DCs) are the key linkage between innate and adoptive immune response. DCs are classified as specialized antigen-presenting cells that initiate T-cell immune responses during infection and hypersensitivity, and maintain immune tolerance to self-antigens. Initiating T-cell immune responses may be beneficial in infectious diseases or cancer management, while, immunosuppressant or tolerogenic responses could be useful in controlling autoimmunity, allergy or inflammatory diseases. Several types of plant-derived components show promising properties in influencing DC functions. Various types of these components have been proven useful in clinical application and immune based therapy. Therefore, focusing on the benefits of plant-based medicine regulating DC functions may be useful, low-cost, and accessible strategies for human health. This review illustrates recent studies, investigating the role of plant components in manipulating DC phenotype and function towards immunostimulating or immunosuppressing effects either in vitro or in vivo. PMID- 30023213 TI - Nigella sativa oil alleviates ultrastructural alterations induced by tramadol in rat motor cerebral cortex. AB - Tramadol is an opioid analgesic used to alleviate acute and chronic pain. Nigella sativa oil is one of the traditional remedies with antioxidant activity. This study was designed in order to investigate the ultrastructural alterations induced by tramadol in the rat cerebral cortex and to find out any possible protective effect of N. sativa oil against these alterations. Twenty-four male albino rats were assigned to three groups. Group I received intraperitoneal and oral normal saline for 30 days. Group II received intraperitoneal injections of tramadol 20 mg/kg/day, 40 mg/kg/day and 80 mg/kg/day on the first, second and third 10 days of the study, respectively. Group III received intraperitoneal tramadol similar to Group II and oral N. sativa oil at a dose of 4 ml/kg/day for 30 days. Specimens from the motor area were obtained and processed for transmission electron microscopy. In the tramadol-treated group, pyramidal and granular cells appeared shrunken and showed ultrastructural features of apoptosis such as nuclear membrane invaginations, chromatin margination, dilated rough endoplasmic reticulum, dilated Golgi saccules, and mitochondria with disintegrated cristae. The myelinated axons showed disorganization and splitting of the myelin sheath and contained vacuoles and abnormal mitochondria. Administration of N. sativa oil partially protected the cortical neurons and myelinated axons against tramadol-induced changes. In conclusion, N. sativa oil alleviates ultrastructural apoptotic changes induced by tramadol in the rat motor cerebral cortex. PMID- 30023214 TI - Effects of UV-B radiation on germlings of the red macroalga Nemalion helminthoides (Rhodophyta). AB - Studies have clearly demonstrated the damaging effects of UV-B exposure on macroalgae, but few have reported the impact of UV-B on spore germination and development at juvenile stages. Therefore, this work aimed to analyze the effects of UV-B radiation on germlings of Nemalion helminthoides at the tetrasporophytic phase. To accomplish this, germlings of N. helminthoides were cultivated in the laboratory and separated into two groups. The control group was exposed onlyto photosynthetic radiation, while the treatment group was exposed to photosynthetic radiation + UV-B for 2 hours during a period of 12 days. Control germlings showed increasing cellular proliferation and accumulation of reserve substances, as well as intense ramification in the last observed stages between 9 days and 12 days of development. Moreover, the chloroplasts presented a typical globular pyrenoid, profusely traversed by thylakoid membranes. Treated germlings, by contrast, showed intracellular damage, such as cell wall thickness, loss of chloroplast organization, changes in mitochondrial cristae, and increasing atrophy of the Golgi bodies. Additionally, changes in developmental patterns were observed, including loss of polarity in the first divisions of carpospores and abnormal stem ramification. The quantification of autofluorescence data coincided with the ultrastructural changes observed in the chloroplasts of cells exposed to UV-B. It can be concluded that exposure to radiation changed the developmental pattern and morphology of the germlings of N. helminthoides. PMID- 30023215 TI - Comparative morphology of the reproductive system and germ cells of Amblyomma ticks (Acari: Ixodidae): A contribution to Ixodidae systematics. AB - Among arthropods, ticks of the genus Amblyomma are of great medical and veterinary importance and present phylogenetic and taxonomic divergences given polymorphisms and phenotypic plasticity between subpopulations. Generally, the male reproductive system and spermatozoon exhibit diversified morphology and ultrastructure species-specific, bringing new possibilities for phylogenetic and taxonomic issues. Therefore, the present study aimed to describe and compare the morphology of the male reproductive system and its germ cells of Amblyomma aureolatum, A. sculptum, and A. triste, intending to identify possible diagnostic features. Couples of the three tick's species were kept in colony, infested on rabbits and collected over 12 days of feeding. The males had their reproductive systems dissected, fixed and processed for histology and scanning electron microscopy. The results obtained here allowed the description of spermiogenesis stages and the comparison of spermatids morphology in the last stage of development. Furthermore, the testis of A. triste present an isthmus connecting the distal region of both, while in the other two species this structure could not be observed. Some anatomical features were identified which can be used for taxonomic and phylogenetic studies, like the presence or absence of the isthmus connecting testis, spV cell shape, the shape of the operculum and the presence or absence of the rim on its base. PMID- 30023216 TI - Ultrastructural characterization of Gonadotrophs in the Wild caught female bat Taphozous nudiventris kachhensis (Dobson). AB - Present study has been design to observe the ultramicroscopic structure of Gonadotrophs in the female bat Taphozous nudiventris kachhensis during the various phases of reproductive cycle. During the present study specimen were collected during Estrous and pregnancy to know the probable role of Gonadotrophs (FSH, LH) in respective stage of reproductive cycle. After collecting female specimen they were weight and dissect out for the pituitary gland and then those were fixed in ice cold gluteraldehyde. Gonadotrophs (FSH and LH) are mostly frequently observed cell types after Somatotrophs cells in the pars distalis of the female bat Taphozous nudiventris kachhensis. FSH cell during estrus is large, ovoid to polyhedral in shape with irregular shaped nucleus. Cell cytoplasm shows well developed Golgi apparatus, rough endoplasmic reticulum and mitochondria this indicating active state. During early pregnancy cytoplasm of FSH cell appears vacuolated because of dilation of rough endoplasmic reticulum. Mitochondria are spherical to rod shaped with lamellar cristae. During late pregnancy rough endoplasmic reticulum shows dilation. Golgi complex is juxtanuclear in position and mitochondria are numerous. LH cells during early part of gestation are large with bilobed nucleus. Cell cytoplasm shows well developed rough endoplasmic reticulum heavily dotted with ribosomes and contains large number of secretory granules. Hypertrophied LH cell in pars distalis of bat during late pregnancy shows well developed rough endoplasmic reticulum occupies major part of cytoplasm. Golgi zone is well developed with dilated saccules. Secretory granules are very few. PMID- 30023217 TI - The role of nutrition related genes and nutrigenetics in understanding the pathogenesis of cancer. AB - Nutrition has a predominant and recognizable role in health management. Nutrigenetics is the science that identifies and characterizes gene variants associated with differential response to nutrients and relating this variation to variable disease states especially cancer. This arises from the epidemiological fact that cancer accounts for a high proportion of total morbidity and mortality in adults throughout the world. There is much evidence to support that genetic factors play a key role in the development of cancer; these genetic factors such as DNA instability and gene alterations are affected by nutrition. Nutrition may also lead to aberrant DNA methylation, which in turn contributes to carcinogenesis. The aim of this work is to clarify the basic knowledge about the vital role of nutrition-related genes in various disease states, especially cancer, and to identify nutrigenetics as a new concept that could highlight the relation between nutrition and gene expression. This may help to understand the mechanism and pathogenesis of cancer. The cause of cancer is a complex interplay mechanism of genetic and environmental factors. Dietary nutrient intake is an essential environmental factor and there is a marked variation in cancer development with the same dietary intake between individuals. This could be explained by the variation in their genetic polymorphisms, which leads to emergence of the concept of nutrigenomics and nutrigenetics. PMID- 30023219 TI - Histological study on the protective effect of endogenous stem-cell mobilization in Adriamycin-induced chronic nephropathy in rats. AB - Chronic kidney disease is a global health problem with increasing morbidity and mortality. Therefore, this study was planned to test the protective effect of hematopoietic-stem-cell mobilization by granulocyte colony-stimulating factor (G CSF) on Adriamycin (ADR)-induced chronic renal disease in rats. Thirty albino rats were equally divided into three groups: control, ADR group [rats received a single intravenous injection of ADR (5 mg/kg)], and G-CSF group [rats received ADR by the same route and the same dose as the previous group, and then G-CSF (70 MUg/kg/d) 2 hours after ADR injection then daily for five consecutive days]. At the time of sacrifice (after 6 weeks), blood samples were taken to estimate the blood urea nitrogen and serum creatinine. Kidney sections were stained with hematoxylin and eosin, toluidine blue, Masson's trichrome, periodic acid-Schiff stains, and immunohistochemical staining against CD34 and caspase-3. The G-CSF group exhibited protection against renal injury manifested by reducing blood urea nitrogen and serum-creatinine levels, improving histological architecture, and increasing the proliferative capacity of renal tubules. PMID- 30023218 TI - Histopathological and immunohistochemical study of the protective effect of triptorelin on the neurocytes of the hippocampus and the cerebral cortex of male albino rats after short-term exposure to cyclophosphamide. AB - Chemotherapy treats many types of cancer effectively but it often causes side effects. Chemotherapy works on active cells, such as cancer cells, and some healthy cells. Side effects happen when chemotherapy damages these healthy cells. Today, many more drugs are available to treat side effects than in the past. Triptorelin (Decapeptyl) is a gonadotropin-releasing hormone agonist that is reported to have many therapeutic effects besides being an anti-cancer agent. In the current study, intraperitoneal cyclophosphamide (65 mg/kg/day) was administered for 4 weeks to induce marked dystrophic changes in the cerebral cortex and hippocampus of male albino rats. After 4 weeks, we observed significant degeneration of neurocytes with dystrophic changes. Subcutaneous triptorelin (0.05 mg/kg/day) for 4 weeks significantly improved histological signs of degeneration and apoptosis. Anti-Bcl2 staining of sections of the cerebral cortex and hippocampus showed that the apoptotic index was increased. This finding was confirmed by the anti-p53 staining, which showed a significant decrease in the apoptotic index. Ultimately, such improvements were accompanied by significant restoration of normal brain histology, as revealed by hematoxylin and eosin. In conclusion, triptorelin can reverse the apoptotic changes induced by cyclophosphamide therapy, which is more marked in the hippocampus than cerebral cortex. PMID- 30023220 TI - Bacterial contamination of cell phones of medical students at King Abdulaziz University, Jeddah, Saudi Arabia. AB - Cell phones are commonly used in healthcare settings for rapid communication within hospitals. Concerns have been increased about the use of these devices in hospitals, as they can be used everywhere, even in toilets. Therefore, they can be vehicles for transmitting pathogens to patients. This study aimed to examine the presence of pathogenic bacteria on the surfaces of cell phones that are used frequently by preclinical medical students. This cross-sectional study identified both pathogenic and nonpathogenic bacteria on cell phones of 105 medical students at King Abdulaziz University, Jeddah, Saudi Arabia, using standard microbiological methods. Out of 105 cell phones screened, 101 (96.2%) were contaminated with bacteria. Coagulase-negative staphylococci were the most abundant isolates (68%). Seventeen (16.2%) cell phones were found to harbor Staphylococcus aureus. Gram-positive bacilli were isolated from 20 (19%) samples. Viridans streptococci and Pantoea species were also isolated but at lower levels. Our findings indicate that cell phones can act as reservoirs of both pathogenic and nonpathogenic organisms. Therefore, full guidelines about restricting the use of cell phones in clinical environments, hand hygiene, and frequent decontamination of mobile devices are recommended at an early stage in medical schools, to limit the risk of cross-contamination and healthcare-associated infections caused by cell phones. PMID- 30023221 TI - Toxic effects of glyphosate-based herbicide, Excel Mera 71 on gill, liver, and kidney of Heteropneustes fossilis under laboratory and field conditions. AB - The effects of glyphosate-based herbicide Excel Mera 71 under field and laboratory conditions were investigated to evaluate the pathological symptoms through light and electron microscopic study in the gill, liver, and kidney of Heteropneustes fossilis (Bloch) for a period of 30 days. Histological alterations like hypertrophy and fusion in secondary lamellae, damage in chloride cells were more prominent in laboratory conditions under light microscopy. Topological changes such as complete loss of microridges, swelling, and irregular arrangement of microridges in the gills were prominent under scanning electron microscopic study under laboratory conditions. Transmission electron microscopy (TEM) study depicted vacuolation and degeneration in chloride cells, dilation in rough endoplasmic reticulum (RER), and mitochondria in gill epithelium. The liver showed enlarged and pyknotic hepatocytes, vacuolation, excess fat deposition, and necrosis under laboratory conditions, while enlarged acentric nuclei, increased sinusoidal space, and less vacuolation in cytoplasm were observed under field conditions. TEM displayed cytoplasmic vacuolation and a reduced number of endoplasmic reticulum and glycogen droplets in the laboratory, but this was less pronounced under field conditions. In the kidneys, loss of hematopoietic tissue, degenerative changes in glomeruli, proximal and distal convoluted tubule, and epithelial cell lining of the renal tubules were comparatively less prominent under field conditions. Under TEM, epithelial cell necrosis, endoplasmic reticulum fragmentation, and mitochondrial degeneration were more prominent under laboratory conditions. The present study evaluated the comparative toxicity under field and laboratory conditions under long-term exposure to glyphosate herbicide and identified pathological responses as indicators in monitoring the herbicidal contamination in aquatic ecosystems. PMID- 30023223 TI - Endogenic mediated synthesis of gold nanoparticles bearing bactericidal activity. AB - The present investigation aimed to synthesize gold nanoparticles using Pseudomonas fluorescens 417 inhabiting Coffea arabica L. Biologically synthesized gold nanoparticles were polydispersed in nature and characterized using hyphenated techniques such as UV-visible spectrophotometry, which ascertained characteristic peaks between 450 nm and 650 nm. Fourier transform infrared analysis predicted the functional groups present in the cell-free supernatant that mediated the synthesis and stabilization of gold nanoparticles. The crystalline nature of the gold nanoparticles was analyzed with X-ray diffraction techniques that displayed the Bragg's diffraction intensity. Transmission electron microscopy revealed the size of nanoparticles ranging from 5 nm to 50 nm, with most of them bearing a spherical shape. The study also revealed the bactericidal activity of synthesized nanoparticles against a panel of clinically significant pathogens. Maximum activity was observed against Pseudomonas aeroginosa followed by Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Klebsiella pneumoniae. The results obtained in the present investigation are promising for ecofriendly approaches for synthesis of gold nanoparticles bearing bactericidal activity that can act as an alternative to combat drug-resistant pathogens. PMID- 30023222 TI - Ultrastructure of the secretory epithelial cells of the Cowper's gland in the Indian fruit bat, Rousettus leschenaulti (Desmarest) during the reproductive cycle. AB - The present paper describes the ultrastructural characteristics of the Cowper' glands of the Indian fruit bat, Rousettus leschenaulti during its sexually inactive-breeding cycle. The functional significance of the secretions of the Cowper's gland in reproduction is discussed. In Rousettus, Cowper's glands are small, pear-shaped, bilaterally symmetrical and are situated on either side of the base of the penis. Each lobule is made up of secretory acini lined by columnar or pyramidal cells. Ultrastructurally, the secretory epithelial cells are characterized by well-developed rough endoplasmic reticulum, extensively developed Golgi complex, and mitochondria. Three different types of secretory granules can be identified on the basis of electron density. These granules represent the different stages of granule maturation. The secretory products are released into the lumen both by apocrine and merocrine modes. The secretory material synthesized by the Cowper' gland may be involved in various male reproductive processes of this species of bat. PMID- 30023225 TI - Effect of long term-administration of aspartame on the ultrastructure of sciatic nerve. AB - Aspartame is the most widely used artificial sweetener worldwide. There is much controversy about the effect of aspartame on different cells in the body. The aim of this study was to evaluate the effect of aspartame on the structure of the sciatic nerve. Thirty adult male albino rats were divided into three groups. Group I served as control; Group II received aspartame orally in a dose of 250 mg/kg/d for 3 months; Group III received aspartame at the same dose and for the same period, and was allowed to recover for 1 month. Specimens of sciatic nerve were processed, and semithin and ultrathin sections were examined by light and electron microscopy. A morphometric study was done to evaluate the g-ratio, which is the ratio between the axon diameter and total fiber diameter. Long-term aspartame administration resulted in many degenerative changes affecting mainly the myelin sheath, in the form of focal and extensive demyelination; disruption and splitting of myelin lamellae with loss of compact lamellar structure; and excessive enfolding with irregular thickening of myelin sheaths. Less frequent than those observed in the myelin sheath, some axonal changes were detected, such as compression and distortion. Dilated rough endoplasmic reticulum and vacuolation of the cytoplasm of Schwann cells were also detected. Partial improvement was observed in the recovery group. It was concluded that long-term administration of aspartame had a harmful effect on the structure of sciatic nerve and 1 month stoppage of aspartame was not enough to achieve complete recovery. PMID- 30023224 TI - Helicobacter pylori chronic gastritis updated Sydney grading in relation to endoscopic findings and H. pylori IgG antibody: diagnostic methods. AB - Helicobacter pylori (Hp) inhabits the stomach of > 50% of humans and has been established as a major etiological factor in the pathogenesis of chronic gastritis, gastric atrophy, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. The aim of this study was to provide unequivocal information about Hp-associated gastritis grading according to the Sydney grading system and to compare the histopathological features with the endoscopic findings and anti-Hp immunoglobulin (Ig)G serological status. This analytical study was conducted on 157 patients with dyspeptic gastritis. All patients underwent esophagogastroduodenoscopy, and antrum and corpus biopsies were taken. Blood samples were obtained from all participants. Different stains were performed on formalin-fixed, paraffin-embedded tissue blocks that included hematoxylin and eosin and Giemsa stain for histopathological interpretation. The endoscopic findings of gastritis were observed in 120 patients and most of them showed hyperemia (80 patients), whereas seven patients had normal appearing gastric mucosa. Histologically variable numbers of mononuclear inflammatory cellular infiltrates were seen in 150 cases (95.5%). Most of them showed Grade 1 gastritis (80 patients), whereas Grades 2 and 3 were found in 43 and 27 biopsies, respectively. Hp colonization was observed in most of the examined biopsies (93.7%). Hp-IgG seropositivity was found in 80.9% of cases and 19.1% were seronegative. The relationship between endoscopic and histological findings was significant (p < 0.001). PMID- 30023226 TI - Ultrastructure of ovotestis of young and adult pulmonate mollusk, Macrochlamys indica Benson, 1832. AB - Macrochlamys indica is a hermaphrodite terrestrial pulmonate mollusk. Transmission electron microscope studies were done on the ovotestis of young and adult (older) M. indica which are elaborated in this paper. The ovotestis contains numerous lobes each of which contains many ovoid shaped acini which are occupied by stages of spermatogenesis and a single oocyte. In younger snails, the acini contain stages of developing spermatogenesis, whereas each acinus of older snails is composed of single large oocyte and few stags of spermatogenesis. The number of Sertoli cells is high in the acini of younger snails than in older snails. Details of the cellular organization of the Sertoli cell are described. Some long thin threads extend from the acinar boundary to acinar lumen. The anterior end of these threads is either free or directly connected to the developing cells of spermatogenesis. There are two types of cells in the interacinar space of the ovotestis in both younger and older snails. One cell is small oval interstitial cell and other is thin elongated periacinar cell. The acinar boundary contains secretory cells with deeply stained nucleus. In the acinus of older snails, the Sertoli cells do not form any barrier between oocyte and spermatogenic cells. Functions of the periacinar cell and interacinar cell are discussed. It is found that the spermatogenesis is highly active in younger snails with single dormant oocyte while process of oogenesis predominates in the older snails. The reproductive strategy of this pulmonate species thus depends on the individual's body size and their maturity. PMID- 30023228 TI - Micrographical analysis of growth deformities in common pathogens induced by voucher fungi from India. AB - A vast diversity of microbes including macrofungi remain untapped for valuable bioactivities including antimicrobial activity. Searching wild sources may bring novel natural products with antimicrobial properties that can provide protection against infectious diseases. The present study was designed to identify the diverse forms of mushrooms being used as an ethnomycological source of food and medicine by the tribes of Meghalaya, India, and microscopically study the structures of mushrooms along with observing their antimicrobial effects on pathogens. Fruiting bodies of mushrooms were viewed morphologically and microscopically, and were identified using molecular markers. The dried aerial parts of the fruiting bodies were extracted with methanol and screened for their antimicrobial activity using 2,3,-triphenyl tetrazolium chloride against two Gram negative and two Gram-positive bacteria. The average diameter of the inhibitory zone induced by fungal extracts ranged from 9 mm to 22 mm for Gram-negative and from 16 mm to 24 mm for Gram-positive bacteria, indicating that this dietary source is a good antimicrobial agent. Mushroom structures were examined using optical microscopy, while the deformities on the pathogens inflicted by mushroom extracts were visualized using scanning electron microscopy, which showed accumulation and formation of biofilm in Gram-positive and shrinkage with cavity formation in Gram-negative bacteria. PMID- 30023227 TI - Immunohistochemical expression of proinflammatory enzyme COX-2 and p53 in ulcerative colitis and its associated dysplasia and colorectal carcinoma. AB - Background/aim: Ulcerative colitis (UC) patients are at increased risk for colorectal carcinoma (CRC). It is suggested that cyclooxygenase-2 (COX-2) plays a role in sporadic CRC. The p53 gene is a tumor-suppressor gene and the most frequent site of genetic alteration found in human cancer. The aim of this study was to analyze the immunoexpression of proinflammatory enzyme COX-2 and p53 in UC, UC-associated dysplasia, and CRC, in comparison with each other and with different clinical and histopathological parameters, to clarify if they have a possible role in the pathogenesis of CRC in UC patients. Materials and methods: In this cross-sectional study, 98 patients were divided into three groups: 39 patients with UC without dysplasia, 32 patients with UC with dysplasia, and 27 patients with colorectal cancer on top of UC, in addition to 10 healthy controls. All patients underwent colonoscopy, and multiple biopsies were taken for histopathological and COX-2 and p53 immunohistochemical studies. Results: There was significant difference in the expression of COX-2 and p53 in UC-related dysplasia either without or with CRC, compared with their expression in the UC group without dysplasia. Conclusion: Adding immunohistochemical analysis of COX-2 enzyme and p53 gene to routine histological assessment may improve the accuracy of early detection of dysplasia and colorectal cancer. COX-2 and p53 can be promising chemotherapeutic/chemopreventive targets in UC patients. PMID- 30023229 TI - Electron microscope based X-ray microanalysis on bioaccumulation of heavy metals and neural degeneration in mudskipper [Pseudapocryptes lanceolatus]. AB - The bioaccumulation of heavy metals and its probable cytological consequences in ciliated olfactory sensory receptor neuron (OSN) of two different groups of Pseudapocryptes lanceolatus has been studied using X-ray microanalysis in transmission electron microscopy (TEM-EDX) [i.e., Group I, collected near Kanchrapara (22.56 degrees N 88.26 degrees E) and Group II, collected near Tribeni (22.99 degrees N 88.40 degrees E) of West Bengal, India]. The ciliated OSN is a bipolar neuron and possesses a prolonged dendron with four to six cilia at the olfactory knob, perikaryon, and axon. Excess accumulation of copper (94.50%) and iron (83.81%) was noted under TEM-EDX in the cytoplasm of the olfactory knob as well as nucleoplasm of ciliated OSNs in P. lanceolatus (Group II). The degenerating ciliated OSNs show distinct features of lysis of the plasma membrane at the olfactory knob, disintegration of cytoskeletal structures in perinuclear cytoplasm and axoplasm, and fragmented chromatin fibers with granules (diameter, 20-30 nm) in the nucleoplasm. Crowding of acetylcholinesterase positive vesicles (diameter:, 30-40 nm) at the terminal part of the axoplasm was related to accumulation of heavy metals in degenerating ciliated OSNs of P. lanceolatus (Group II). The recorded concentrations of heavy metals in the same organ among different groups of P. lanceolatus in varying geographical areas indicates the stress of concerned environmental health. This ultrastructural interpretation on the fish ciliated OSN is a prerequisite for monitoring environmental health as well as metallobiology of several neurodegenerative disorders in fish caused by bioaccumulation of heavy metals. PMID- 30023230 TI - Genetic diversity among natural populations of Schistosoma haematobium might contribute to inconsistent virulence and diverse clinical outcomes. AB - There is an evident difference in the intensity of morbidity caused by Schistosoma haematobium in North-African zones compared to Sub-Saharan ones. Clinical outcome dichotomy corresponds to two geographically distinct intermediate host snail species that are only infected by the related strain of the parasite. In concert, there is a manifest hybridization of the parasite with other Schistosoma species confined to certain regions of Africa. This raises a reasonable suggestion that S. haematobium has no less than two phylogenetic clusters that have different virulence. The aim of the study was to examine the possible diversity among S. haematobium using simultaneous amplification of genomic DNA of selected isolates. Random amplified polymorphic DNA-polymerase chain reaction markers were used to study the genetic diversity among S. haematobium natural isolates from selected regions of Africa (Egypt, Zimbabwe, and South Africa) that represent different ecological conditions, different species of intermediate host, and different possibilities of field hybridization with other schistosomes. A moderate to high level of genetic diversity was evident among the three isolates. More bands were shared by the isolates from Zimbabwe and South Africa (similarity index = 0.721) than those shared by each with the Egyptian isolate (similarity index = 0.551 and 0.566, respectively), suggesting that at least two phylogenetic groups of S. haematobium do exist in distinct geographic regions of Africa. The elucidation of the possible genetic diversity among S. haematobium parasites may explain many ambiguous aspects of the biology of the parasite-like virulence, immune evasion and drug resistance. PMID- 30023231 TI - Regenerative medicine: Clinical applications and future perspectives. AB - After many years of basic research, regenerative medicine (RM) is now beginning to represent a valuable tool to cure several clinical conditions in both acute injuries and chronic diseases. The aim of this study is to update readers on current clinical applications of some selected organs and pathologies which may benefit from RM. An extensive literature research was performed using PubMed, Google and specialized journals. RM has achieved great successes, but there are still several challenges to tackle before it could be used on a daily basis in clinical practice. The crucial point of this revolution is represented by the appropriate and valid translation from bench to bedside. PMID- 30023232 TI - Ultrastructure of the salivary glands, alimentary canal and bacteria-like organisms in the Asian citrus psyllid, vector of citrus huanglongbing disease bacteria. AB - The Asian citrus psyllid (ACP, Diaphorina citri, Hemiptera: Liviidae) is the principal vector of Candidatus Liberibacter asiaticus (Las), the putative bacterial agent of citrus greening/huanglongbing (HLB); currently the most serious citrus disease worldwide. Las is transmitted in a persistent-propagative manner by ACP, and the salivary glands and midgut have been suggested as transmission barriers that can impede translocation of Las within the vector. However, no detailed ultrastructural studies have been reported on these organs in this or other psyllid species, although some bacterium-like structures have been described in them and assumed to be the causal agents of HLB. In this study, we describe the ultrastructure of the salivary glands, filter chamber, other parts of the alimentary canal, and other organs and tissues of ACP including the compound ganglionic mass (in the thorax) and the bacteriome (in the abdomen). Furthermore, in addition to two ultrastructurally apparently different symbiotic bacteria found in the bacteriome, other morphological types of bacteria were found in the gut epithelial cells and salivary glands of both Las-infected (quantitative polymerase chain reaction positive) and noninfected (quantitative polymerase chain reaction negative) ACP. These results show the importance of immunolabeling, fluorescence in situ hybridization, or other labeling techniques that must be used before identifying any bacterium-like structures in ACP or other vectors as Las or other possible agents of HLB. This ultrastructural investigation should help future work on the cellular and subcellular aspects of pathogen-psyllid relationships, including the study of receptors, binding sites, and transmission barriers of Las and other pathogens within their psyllid vectors. PMID- 30023233 TI - Scanning and transmission electron microscopy of the cells forming the hepatic sinusoidal wall of rat in acetaminophen and Escherichia coli endotoxin-induced hepatotoxicity. AB - Drugs and xenobiotics as well as bacterial endotoxins may reach the liver either systematically or after intestinal absorption. Therefore, cells lining the sinusoidal wall form the last barrier before blood constituents get in contact with the parenchymal cells. In this work, the ultrastructure of the cells forming the sinusoidal wall was studied after acetaminophen and Escherichia coli endotoxin treatments. Rats received acetaminophen at a dose of 1000 mg/kg body weight by intraperitoneal injection once in acute and four times with a 1-week interval in chronic treatments, and E. coli endotoxin at a dose of 5 mg/kg of body weight by intraperitoneal injection once in acute and four times with a 1 week interval in chronic treatments. Tissue samples were collected for scanning and transmission electron microscopy. Swelling of sinusoidal endothelial cells was noticed in both acute intoxicated groups with narrowing of the fenestrae, whereas large gaps were formed in chronic toxicity. Activation of Kupffer cells was a prominent common feature between the four toxicity groups. Interestingly, hepatic stellate cell activation was evident in both chronic acetaminophen and chronic endotoxin groups. Large amounts of collagen fibers were seen surrounding the hepatic stellate cells and in Disse space. PMID- 30023234 TI - The Pattern of Causes of Pneumoperitoneum-induced Peritonitis: Results of an Empirical Study. AB - Pneumoperitoneum refers to presence of free air within the peritoneal cavity, "Pneumoperitoneum induced Peritonitis" is synonymous of surgical pneumoperitoneum, as the leak of air and visceral contents contaminates the peritoneal cavity, producing peritonitis which mandates surgery. This entire pneumoperitoneum may result from inflammatory conditions, traumatic injury, neoplasia, anastomotic leak and vascular causes. The objectives of this study is to determine the incidence of Pneumoperitoneum-induced Peritonitis (surgical pneumoperitoneum) in emergency exploratory laparotomies, to identify the common anatomical sites of perforations and to review the pathological etiology of these cases. Review of 450 cases of emergency exploratory laparotomy cases performed in King Abdulaziz University Hospital from January 2011 to December 2015, among them 131 cases with radiologically documented pneumoperitoneum were selected to be involved in the study of surgical pneumoperitoneum, the anatomical site of perforation and the exact underlying pathology were documented. 29% of exploratory laparotomy cases were found to have pneumoperitoneum, mainly in the in the gastroduodenal region, inflammatory conditions as peptic ulcer disease or diverticulitis were the underlying cause of most of perforations. Pneumoperitoneum frequently indicates bowel injury or disease, hence it is called surgical pneumoperitoneum, Perforations are commonly found in gastro-duodenal area, the inflammatory conditions are responsible for the vast majority of cases, however presence of air with intact bowel, is called Non-Surgical or spontaneous Pneumoperitoneum, which has to be approached conservatively. PMID- 30023235 TI - Effect of pore size and morphology of activated charcoal prepared from midribs of Elaeis guineensis on adsorption of poisons using metronidazole and Escherichia coli O157:H7 as a case study. AB - Agricultural waste obtained from Elaeis guineensis mid ribs can provide a veritable source of materials which can be used as precursor materials for the production of pharmaceutical grade activated charcoal. The pore size and surface morphology of activated charcoal defines the types of molecules that could be adsorbed unto it, as surface morphology plays a significant role in determining the surface availability and areas of adsorption. The activated charcoal samples prepared from Elaeis guineensis via either physical or chemical activation was characterized via surface area using the BET method and subsequently pore structure and size analyzed by scanning electron microscopy (SEM). Physically activated Elaeis guineensis fronds activated with nitrogen gas had wide spread microporosity with micropore volume of 0.232 cc/g compared to the chemically activated with 1M and 3M phosphoric acid respectively. The commercial activated charcoal/metronidazole combination in the in vitro-pharmacodynamic model reflected no re-growth after 4 hours, however for charcoal formulated from Elaeis guineensis via chemical activation with 3M phosphoric acid and metronidazole no regrowth was seen at the second hour and this was maintained throughout the duration of the experiment. Increased macroporosity enhanced bacterial adsorption and this was further facilitated by the presence of antibacterial metronidazole in the in vitro pharmacodynamic model. Activated charcoal produced from agricultural waste obtained from Elaeis guineensis dried mid ribs consisting of increased macroporosity with mixed meso/micro porosity and antibacterial metronidazole form the best model for bacterial adsorption and will be useful in the treatment of diarrhea caused by E. coli O157:H7. PMID- 30023236 TI - HAART induces cell death in a cervical cancer cell line, HCS-2: A Scanning Electron Microscopy study. AB - Apoptosis is a tightly programmed cell suicide which occurs in multiple physiologic and pathological conditions where it plays an important role in tissue development and homeostasis by eliminating unwanted and damaged cells. Appropriate apoptosis signalling is crucial in maintaining the fine balance between cell death and cell survival in cancer. In response to death stimuli the morphology of the cell undergoes unique changes. The aim of this study was to examine and compare the changes in the cell surface morphology using scanning electron microscopy in HCS-2 cells, following 24 hour treatment with components of highly active antiretroviral therapy (HAART) at their clinical plasma concentrations. The cells were fixed in 2.5% Glutaraldehyde and post-fixed in 1% osmium tetroxide. The cells were then dehydrated through a graded series of alcohol and treated with hexamethyl-disilazane, then coated with a double layer of carbon. The cells were viewed under a Zeiss Ultra FEG Scanning Electron Microscope and a one way ANOVA and Tukey Kramer Post Hoc test was conducted based on the scoring of surface morphology of the cells using JMP 11 statistical software. The drugs used in this study induced morphological features which are known to be characteristic of apoptotic cell death. The drug combinations (ATP and LPV/r) were seemingly more effective than individual treatments in inducing cell death because morphological features observed were more advanced than those observed in individual treatments. However, LPV/r was more potent than ATP. In conclusion, HAART showed anticancer properties by inducing cell death through apoptosis. PMID- 30023237 TI - C-Kit, CD34 & alpha-SMA Immunohistochemical Features in Classic Kaposi Sarcoma and Kaposiform Hemangioendothelioma. AB - Purpose & Methods: The aim of this work was to study the clinicopathological features of Kaposi sarcoma (KS) & kaposiform hemangioendothelioma (KHE) and analyze their immunohistochemical expression of c-Kit, CD34, alpha-SMA. The study was performed on cutaneous 10 classic KS & 8 KHE. Results: KHE shows several dilated lymphatic channels, focal capillary formation, lack of nuclear atypia and mitosis within tumor cells. These features help to exclude Kaposi sarcoma in spite of the kaposiform pattern of tumor cells. C-Kit was expressed by tumor cells in all KHE cases and in 60% only of KS. All elements within both tumor groups expressed CD34 antibody. alpha-SMA was expressed by tumor cells in 70% of KS cases and none of KHE. Conclusion: C-Kit and CD34 seem to be reliable at labeling KS and KHE as they can help in diagnosis of these tumors in routinely processed tissue but they don't differentiate between them. If alpha-SMA also labeled the tumor, then KHE diagnosis can be ruled out. KS & KHE exemplify stem cell tumors that could give smooth muscle cell-like phenotype in KS. Anti C-kit therapy should be tested in KS & KHE to prevent recurrence. PMID- 30023238 TI - Breast cancer screening programs: Review of merits, demerits, and recent recommendations practiced across the world. AB - Breast cancer screening is defined as the evaluation of symptom free, otherwise healthy looking females of child bearing age or postmenopausal women for early detection of breast cancer. Screening mammography is the most common and widely practiced breast cancer screening modality across the world. The other modes of breast cancer screening being practiced across the world are: breast self examination (BSE), clinical breast examination (CBE), digital breast tomosynthesis (DBT), ultrasonography (USG), magnetic resonance imaging (MRI), and identification of certain genetic oncogenes. The major merits of breast cancer screening programs are: early diagnosis, sorting out and prevention of risk factors, and timely treatment to lessen the morbidity (5 years localized stage survival rate is 99%, regional disease 84% while metastatic breast cancer 5 year survival rate is 23%); it also reduces overall 20% mortality rate. The major demerits of breast cancer screening are: overdiagnosis (19% from the perspective of a woman invited to screening), high cost, ionizing radiation (lifetime attributable risk to develop breast cancer is 3/10,000), false positive biopsy recommendation (about 8/1000), false negative results 11/10,000), and their consequences. Worldwide, most of the countries recommend biennial screening for breast cancer at 50-74 years of age. However, some countries recommend screening mammography earlier, starting at the age of 40 years until 70-74 years based on higher breast cancer incidence rate in those countries. This article provides a detailed review of merits, demerits, and recent recommendations for screening programs being practiced across the world. PMID- 30023239 TI - Changes in rats' breast tumor ultrastructure and immune and messenger RNA responses caused by dietary Seaweed (Kappaphycus alvarezii) extract. AB - The edible red seaweed Kappaphycus alvarezii or Eucheuma cottonii is commercially cultivated in the pristine tropical seas for carrageenan production. The systemic, cellular, and molecular effects of E. cottonii 50% alcohol extract [seaweed E. cottonii ethanol extract (SECE)] on breast cancer were investigated in a rat model. Mammary tumor was induced by subcutaneously injecting LA7 cells in female rat mammary pads. After 2 weeks of cancer growth, the rats received oral administration of either SECE [150 mg/kg body weight (BW) and 300 mg/kg BW] or tamoxifen. Electron microscopy imaging results confirmed macrophage activity and hematoxylin and eosin staining indicated that tumor histopathological alterations were restored toward normal structures by the seaweed extract. The extract suppressed tumor development and modulated the immune responses. This was evidenced by the microscopic observations, the increased spleen weight, size, spleen CD19 B cells, and blood immunoglobulin G (IgG) levels. The extract also increased the circulating total white blood cells, lymphocytes, segmented neutrophils count, T cells (CD3), T-helper cells (CD4), cytotoxic T cell (CD8), and nuclear factor-kappa beta expressions. The extract enhanced cancer cell death, by upregulating the Birc5, Chk1, and p53 levels and downregulating the tumor growth cellular Mdm2 (transformed mouse 3T3 cell double minute 2) messenger RNA (mRNA) expression. The extract showed no toxicity at 150 mg/kg BW in rats. The lectin-rich SECE showed tumor suppression by enhancing immune responses and upregulating the cancer cell apoptosis mRNA expressions. PMID- 30023240 TI - Melanogenic effect of purified mushroom tyrosinase on B16F10 Melanocytes: A Phase Contrast and Immunofluorescence Microscopic Study. AB - Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. It has been proven that tyrosinase plays a pivotal role in melanocytes dendrite formation; however, the molecular mechanism underlying this process has not been fully elucidated. The morphological changes were observed under a phase contrast microscope. These changes were evident, with globular cell bodies and increased numbers of tree branch-like dendrites. The present work aimed to study the morphoanatomic effects of purified tyrosinase to determine its skin-darkening potential using B16F10 melanocyte, which has not been done to date. Phase contrast and immunofluorescence microscopic analysis of B16F10 melanocytes has been done after treatment with various concentrations of purified tyrosinase along with standard tyrosinase (Sigma) in order to explore the mechanism of action of purified tyrosinase induced skin darkening. The phase contrast microscopic results showed that the number of melanocytes with melanin-loaded dendrites has increased significantly in purified tyrosinase treated cells in a dose dependent manner leading to skin darkening. In addition, immunofluorescence microscopic analysis revealed purified tyrosinase increase cellular tyrosinase expression in doze dependent manner due to tyrosinase absorption in B16F10 melanocyte. Present findings proved that purified tyrosinase possesses a skin darkening potential and could be used as a safe melanogenic agent for the treatment of hypopigmentation disorders or vitiligo. PMID- 30023241 TI - Diagnostic utility of vimentin, CD117, cytokeratin-7 and caveolin-1 in differentiation between clear cell renal cell carcinoma, chromophobe renal cell carcinoma and oncocytoma. AB - Overlapping morphological characteristics pose some difficulties in making a proper diagnosis of clear cell renal cell carcinoma (CCRCC), chromophobe renal cell carcinoma (ChRCC), and oncocytoma, on the basis of hematoxylin-eosin-stained tissue sections. Our objective was to find out a fast, reliable panel of immunohistochemical markers for differentiation between them. The study was carried out on 55 selected renal tumor specimens: 36 cases of CCRCC, seven cases of ChRCC, and 12 cases of oncocytoma. The specimens were stained immunohistochemically for vimentin, CD117, cytokeratin (CK)7, and caveolin (Cav) 1. Sensitivity and specificity for each marker were calculated. Vimentin expression was exclusively observed in CCRCC (100%) and negative in ChRCC and oncocytoma. CD117 was absent in CCRCC, but it was strongly expressed in ChRCC (85.5%) and oncocytoma (91.7%), with high sensitivity and specificity. Most CCRCCs and oncocytomas were negative for CK7 (91.7% and 83.3%, respectively), in contrast to ChRCCs, which showed positivity in nearly 86% of the cases. Good sensitivity and specificity were calculated for CK7 in differentiating studied oncocytic tumors. Cav-1 was positive in ~78% of the CCRCCs and in all ChRCCs, whereas the vast majority of oncocytomas were negative. So the immunoprofile of CCRCC was vimentin+/CD117-/CK7-/Cav-1+/-, ChRCC was vimentin-/CD117+/CK7+/Cav-1+, and oncocytoma was vimentin-/CD117+/CK7+/-/Cav-1-. So, by using combination of four markers (vimentin, CD117, CK7, and Cav-1), we achieved excellent sensitivity and specificity for differential diagnosis of CCRCC, ChRCC and oncocytoma. PMID- 30023242 TI - Melanomacrophage centers in Clarias gariepinus as an immunological biomarker for toxicity of silver nanoparticles. AB - Although there are many applications of silver nanoparticles (Ag-NPs) in human activities, there is still little known about their potential environmental toxicity, particularly to fish. In the present study, the effects of Ag-NPs on African catfish (Clarias gariepinus) were studied using melanomacrophage centers as immunohistological biomarkers. Fish were exposed to 25 mg/L, 50 mg/L and 75 mg/L 100-nm Ag-NPs. We studied the effects on the size and number of melanomacrophage centers in all target tissues. Many histopathological alterations in those tissues were observed. The histological changes were represented as dislocation of the epithelium, dilatation of central veins associated with inflammatory leukocytic infiltration, necrosis, and pyknotic nuclei of hepatocytes. There was shrinkage of Malpighian corpuscles, dislocation of nuclei of convoluted tubules, cellular degeneration, and dispersed infiltration of leukocytes in kidney tissue. Examination of spleen sections after exposure to Ag-NPs showed rupture within the red pulp and hemorrhage, dislocation of nuclei, accumulation of inflammatory leukocytes, and congestion in blood vessels. In conclusion, exposure to Ag-NPs induced alterations in tissues, suggesting a possible increase in oxidative stress in those tissues. PMID- 30023243 TI - Establishment and characterization of female reproductive tract epithelial cell culture. AB - The oviductal and uterine epithelial cells have a crucial role, but are still poorly understood. Numerous studies have tried to isolate the epithelial cells from different organs in various models. The current study aimed to establish and characterize an in vitro monolayer culture of the oviduct and uterine horn epithelial cells by using two different techniques. Female reproductive epithelial cells from sows were cultured in follicular phase. Combined protocols to isolate the epithelial cells were performed. The viability and cell number were determined. Monolayers of epithelial cells from each group were cultured in four-well plates and were subjected to immunostaining using a Vector ABC Elite Kit. The immunohistochemical staining step was performed to evaluate the quality of the epithelial cells. Oviductal cells reached confluence faster than uterine horn cells. Cilia were seen in oviduct and uterine horn tissue culture. All the isolated cells reached confluence prior to harvesting. The number of cells was increased over the time of incubation. Monolayer culture using the trypsin/EDTA method took longer than culture with the collagenase method. Immunohistochemistry of epithelial cells showed strong staining for cytokeratin. Oviductal and uterus epithelial cells were cultured and established. Both techniques used in this experiment were useful and showed no significant differences. This cell culture model has the potential to study the secretory interactions of the female reproductive tract with spermatozoa, oocytesor embryos. PMID- 30023244 TI - Ultrastructure of the male accessory glands of sesarmid crab, Parasesarma plicatum (Latreille, 1803). AB - The structure of accessory glands (AGs) in the male sesarmid crab, Parasesarma plicatum, is described by light and transmission electron microscopy. Adult males of carapace of width 1.6-2.2 cm were collected from along the estuarine regions of Kanyakumari District, India. Posteriorly, the male reproductive system receives several sac-like structures, referred to as AGs. Histologically, the AG is internally lined by cuboidal epithelium and the lumen encloses eosinophilic vesicular secretions, apparently glycopreoteinaceous in nature. Ultrastructurally, the epithelium shows the signs of typical infrastructure for synthetic activity, as demonstrated by the prolific presence of rough endoplasmic reticulum, free ribosomes, and Golgi complex. The cytoplasm is manifested with electron-dense, electron-lucent, and medium-density secretory vesicles, and the mode of release into the lumen is both merocrine and apocrine. Within the lumen, these secretory vesicles coalesce and aggregate into large heterogeneous masses of varying sizes, which may play an important role post-copulation within the female duct. PMID- 30023245 TI - Literature review on imperfection of composite laminated plates. AB - A composite material can be defined as a combination of two or more materials that gives better properties than those of the individual components used alone. In contrast to metallic alloys, each material retains its separate chemical, physical, and mechanical properties. The two constituents are reinforcement and a matrix. The main advantages of composite materials are their high strength and stiffness combined with low density when compared to classical materials. Micromechanical approach is found to be more suitable for the analysis of composite materials because it studies the volume proportions of the constituents for the desired lamina stiffness and strength. It is found that the manufacturing processes are responsible of many defects which may arise in fibers, matrix and lamina. These defects, if they exist include misalignment of fibers, cracks in matrix, non uniform distribution of the fibers in the matrix, voids in fibers and matrix, delaminated regions, and initial stress in the lamina as a result of its manufacture and further treatment. The above mentioned defects tend to propagate as the lamina is loaded causing an accelerated rate of failure. The experimental and theoretical results in this case tend to differ. Hence, due to the limitations necessary in the idealization of the lamina components, the properties estimated should be proved experimentally. PMID- 30023246 TI - Histological effect of nicotine on adrenal zona fasciculata and the effect of grape seed extract with or without withdrawal of nicotine. AB - Cigarette smoking is harmful to the health of both smokers and nonsmokers. It is a major cause of death. This study aimed to investigate the structural changes in the zona fasciculata of albino rats caused by nicotine and the protective effect of grape seeds with or without the stoppage of nicotine administration. Thirty five adult male rats were used and equally divided into five groups: negative and positive control groups (Groups I and II), nicotine-treated group (Group III), nicotine- and grape seed extract-treated group (Group IV), and nicotine withdrawal and grape seed extract-treated group (Group V). Adrenal glands were dissected and prepared for histological studies. The majority of zona fasciculata cells of Group III showed striking changes in terms of swelling of the cells with marked cytoplasmic vacuolation, many pyknotic nuclei, and increased immunoexpression to caspase 3 antibodies. By electron microscopy, a marked increase in lipid deposition with its appearance in the capillary between zona fasciculata cells was noticed. Heterochromatic nuclei and dilated smooth endoplasmic reticulum were noted. Degenerated mitochondria and some mitochondria that had cavitation with a progressive loss of their cristae were seen. The zona fasciculata cells of Group IV were partially improved, while in Group V, those cells showed complete improvement. We can conclude that nicotine causes severe histological changes in zona fasciculata cells. Grape seed extract can partially ameliorate these changes, and complete recovery is achieved with grape seed extract after the stoppage of nicotine administration. PMID- 30023247 TI - Microscopic study on colonization and antimicrobial property of endophytic bacteria associated with ethnomedicinal plants of Meghalaya. AB - Microscopic visualization using transmission electron microscopy (TEM) can provide a better understanding of endophytic colonization within ethnomedicinal plants. Bacterial endophytes were found attached to the host cell wall colonizing the aerenchyma and intercellular spaces of the epidermis and outer cortex except the vascular system. Colonization was non-uniform as single cells, doublets or in the form of microcolonies. Analysis of in vivo antibacterial action of the methanolic extracts of the isolated endophytic bacteria against Gram-positive, Streptococcus pyogenes MTCC 1925 and Gram-negative, Salmonella enterica ser. paratyphi MTCC735 pathogens has revealed the morphological damages in the tested pathogens respectively, under scanning electron microscopy (SEM). Detached cell wall and cell burst were observed in Streptococcus pyogenes where as, cell blisters were shown in Salmonella enterica ser. paratyphi. The study on bacterial endophyte colonization process is important to better predict how endophytes interact with their host and establish themselves in the plant environment by procuring biocontrol activity. PMID- 30023248 TI - Histophysiological and surface ultrastructural studies of the saccus vasculosus of Notopterus chitala (Hamilton). AB - We investigated the cytoarchitecture and surface ultrastructural characteristics of different cells lining the epithelium of the saccus vasculosus of Notopterus chitala (Hamilton, 1822). The saccus vasculosus, the richly vascularized reddish, sac like organ is situated on the ventral aspect of the diencephalon just behind the pituitary gland. Histologically, the saccus vasculosus consisted of several loculi lined with a heterogeneous population of a large number of specialized coronet cells and a smaller number of alternately arranged supporting cells. The loculi were densely surrounded by blood sinusoids. The loculi opened into several collecting channels that united and ultimately drained into the third ventricle of the brain. The coronet cells possessed central or basal nuclei and an apical globular protrusion. Under scanning electron microscopy, the coronet cells were variable in shape with prominent nuclei. The supporting cells were triangular in shape and placed in between the coronet cells. The apical parts of the coronet cells had different shapes of globular protrusions with distinct stalks. Intense silver stain was noted in the terminal end of the coronet cells and nerves were attached with blood vessels. Under scanning electron microscopy observation, nerve fibers of different caliber were attached to the coronet cells and blood vessels. The various cells of the saccus vasculosus in N. chitala were correlated with their functional significance. PMID- 30023249 TI - Bio-tea prevents membrane destabilization during Isoproterenol-induced myocardial injury. AB - The present study was undertaken to determine the membrane-stabilizing effect of Bio-tea in the prevention of myocardial injury caused by isoproterenol in rats. The efficiency of Bio-tea pretreatment was compared against black tea pretreatment and the positive control (rats with isoproterenol-induced myocardial infarction) and negative control (normal control rats). For this purpose, biochemical analysis of the in vivo antioxidants (superoxide dismutase, catalase, and reduced glutathione), glycoprotein components (hexose, hexosamine, sialic acid, and fucose), lipids (total, ester and free cholesterol, triglycerides, free fatty acids, and phospholipids), and transmembrane protein activities (Na+/K+ ATPase, Ca2+ ATPase, and Mg2+ ATPase) was carried out along with the histological and ultrastructural study of the myocardial tissue. Induction of myocardial infarction using isoproterenol resulted in a significant decrease in tissue antioxidants and an increase in the levels of total, ester and free cholesterol, triglycerides, free fatty acids, and glycoprotein components in plasma and heart. The phospholipid content showed an increase in plasma and a simultaneous decrease in the heart tissue, while the Na+/K+ ATPase activity decreased and Ca2+ ATPase and Mg2+ ATPase activities increased, resulting in destabilization of the membranes. Pretreatment with Bio-tea was able to bring these components to near normal, indicating its reactive-oxygen-species-scavenging, lipid-lowering, membrane-stabilizing and glycoprotein-modulating effects and lending credibility to the regular use of Bio-tea. PMID- 30023250 TI - Histomorphological, histochemical, and ultrastructural studies on the stomach of the adult African catfish (Clarias gariepinus). AB - This study investigated the morphology, histochemistry, and ultrastructure of the adult African catfish (Clarias gariepinus) stomach in order to detect the functional aspects involved in gross and histological studies to get detailed information about the precise cellular structures of different cells lining the stomach. Forty fishes were used in this study. The stomach is a J-shaped sac divided into three regions: (1) cardiac; (2) fundic; and (3) pyloric. Histologically, its wall is composed of four tunics: (1) mucosa; (2) submucosa; (3) muscularis externa; and (4) serosa. The mucosa of the three portions showed thick longitudinal folds lined with simple high columnar cells containing oval basally located nuclei. These cells contained apically located mucosubstances that reacted positively with Periodic-acid Schiff and negatively with Alcian blue stains. Many gastric pits were formed by invaginations of the mucosal layer into the underlying lamina propria and continuous with the openings of the gastric glands. Only the cardiac and fundic regions contained mucosal glands. The fundic glands were lined with oxynticopeptic cells. Enteroendocrine cells were distributed in the gastric wall within the epithelial cells of the gastric mucosa and gland. The lamina propria composed of extensive collagen fibers, many blood vessels, and nerves. Strands of smooth muscle fibers situated between the lamina propria and the submucosa forming lamina muscularis mucosa. Loose connective tissue was the main component of the tunica submucosa. The pyloric portion had the thickest musclosa and the serosal coat of the stomach was formed of loose connective tissue containing blood vessels. PMID- 30023252 TI - Skeptical approaches concerning the effect of exposure to electromagnetic fields on brain hormones and enzyme activities. AB - This review discusses the effects of various frequencies of electromagnetic fields (EMF) on brain hormones and enzyme activity. In this context, the mechanism underlying the effects of EMF exposure on tissues generally and cellular pathway specifically has been discussed. The cell membrane plays important roles in mediating enzymatic activities as to response and reacts with extracellular environment. Alterations in the calcium signaling pathways in the cell membrane are activated in response to the effects of EMF exposure. Experimental and epidemiological studies have demonstrated that no changes occur in serum prolactin levels in humans following short-term exposure to 900 Mega Hertz (MHz) EMF emitted by mobile phones. The effects of EMF on melatonin and its metabolite, 6-sulfatoxymelatonin, in humans have also been investigated in the clinical studies to show a disturbance in metabolic activity of melatonin. In addition, although 900 MHz EMF effects on NF-kappaB inflammation, its effects on NF-kappaB are not clear. Abbreviations: ELF-EMF, extremely low frequency electromagnetic fields; EMF, electromagnetic fields; RF, Radiofrequency; ROS, reactive oxygen species; VGCCs, voltage-gated calcium channels; MAPK, mitogen activated phosphokinase; NF-kappaB, nuclear factor kappa B; ERK-1/2, extracellular signal-regulated kinase; GSH-Px, glutathione peroxidase; JNK, Jun N terminal kinases; SOD, superoxide dismutase; MnSOD, manganese-dependent superoxide dismutase; GLUT1, glucose transporter 1; GSSG-Rd, glutathione reductase MDA malondialdehyde; NO, nitric oxide; LH, luteinizing hormone; FSH, follicle-stimulating hormone. PMID- 30023253 TI - Does omega-3 have a protective effect on the rat adrenal gland exposed to 900 MHz electromagnetic fields? AB - The aim of this study was to investigate the harmful effects of exposure to 900 megahertz (MHz) electromagnetic fields (EMF) and the protective effects of omega 3 (Omg-3) against EMF in the rat adrenal gland. Eighteen Wistar albino rats were randomly assigned into three groups, control (Cont), EMF, and EMF + Omg-3. The EMF and EMF + Omg-3 groups both consisted of six rats exposed to an EMF of 900 MHz for 60 min/day for 15 days. No procedure was applied to the six rats in the Cont group. At the end of the experiment, all rats were sacrificed, and the mean volumes of the cortex and medulla of the adrenal gland were estimated using a stereological counting technique. The stereological results showed that the mean volume of the adrenal gland increased significantly in the EMF-exposed groups compared to the Cont group. Additionally, the mean volume of the adrenal gland was significantly lower in the EMF + Omg-3 group compared to the EMF group. We suggest that Omg-3 therapy aimed at suppressing the effects of EMF may prove a safe alternative for animals, whether or not they are exposed to EMF. PMID- 30023251 TI - Effects of electromagnetic fields exposure on the antioxidant defense system. AB - Technological devices have become essential components of daily life. However, their deleterious effects on the body, particularly on the nervous system, are well known. Electromagnetic fields (EMF) have various chemical effects, including causing deterioration in large molecules in cells and imbalance in ionic equilibrium. Despite being essential for life, oxygen molecules can lead to the generation of hazardous by-products, known as reactive oxygen species (ROS), during biological reactions. These reactive oxygen species can damage cellular components such as proteins, lipids and DNA. Antioxidant defense systems exist in order to keep free radical formation under control and to prevent their harmful effects on the biological system. Free radical formation can take place in various ways, including ultraviolet light, drugs, lipid oxidation, immunological reactions, radiation, stress, smoking, alcohol and biochemical redox reactions. Oxidative stress occurs if the antioxidant defense system is unable to prevent the harmful effects of free radicals. Several studies have reported that exposure to EMF results in oxidative stress in many tissues of the body. Exposure to EMF is known to increase free radical concentrations and traceability and can affect the radical couple recombination. The purpose of this review was to highlight the impact of oxidative stress on antioxidant systems. Abbreviations: EMF, electromagnetic fields; RF, radiofrequency; ROS, reactive oxygen species; GSH, glutathione; GPx, glutathione peroxidase; GR, glutathione reductase; GST, glutathione S-transferase; CAT, catalase; SOD, superoxide dismutase; HSP, heat shock protein; EMF/RFR, electromagnetic frequency and radiofrequency exposures; ELF-EMFs, exposure to extremely low frequency; MEL, melatonin; FA, folic acid; MDA, malondialdehyde. PMID- 30023254 TI - Effects of short and long term electromagnetic fields exposure on the human hippocampus. AB - The increasing use of mobile phones may have a number of physiological and psychological effects on human health. Many animal and human studies have reported various effects on the central nervous system and cognitive performance from of exposure to electromagnetic fields (EMF) emitted by mobile phones. The aim of the present study was to evaluate the effects of mobile phones on the morphology of the human brain and on cognitive performance using stereological and spectroscopic methods and neurocognitive tests. Sixty healthy female medical school students aged 18-25 years were divided into a low exposure group (30 subjects, <30 min daily use by the head) and high exposure group (30 subjects, >90 min daily use by the head). Magnetic resonance images (MRI) of the brain analysed on OsiriX 3.2.1 workstation. Neuropsychological tests were performed for each subject. In addition, three dominant specific metabolites were analysed, choline at 3.21 ppm, creatine at 3.04 ppm and N-acetyl aspartate at 2.02 ppm. Analysis of the spectroscopic results revealed no significant difference in specific metabolites between the groups (p > 0.05). There was also no significant difference in terms of hippocampal volume between the groups (p > 0.05). In contrast, the results of the stroop and digit span (backward) neurocognitive tests of high exposure group for evaluating attention were significantly poorer from low exposure group (p < 0.05). Based on these results, we conclude that a lack of attention and concentration may occur in subjects who talk on mobile phones for longer times, compared to those who use phones relatively less. PMID- 30023256 TI - Evaluation of the safety of conventional lighting replacement by artificial daylight. AB - Background: Short morning exposure to high illuminance visible electromagnetic radiations termed as artificial daylight is beneficial for the mental health of people living in geographical areas with important seasonal changes in daylight illuminance. However, the commercial success of high illuminance light sources has raised the question of the safety of long hour exposure. Methods: We have investigated the effect of the replacement of natural daylight by artificial daylight in Swiss mice raised under natural lighting conditions. Mice were monitored for neurotoxicity and general health changes. They were submitted to a battery of conventional tests for mood, motor and cognitive functions' assessment on exposure day (ED) 14 and ED20. Following sacrifice on ED21 due to marked signs of neurotoxicity, the expression of markers of inflammation and apoptosis was assessed in the entorhinal cortex and neurons were estimated in the hippocampal formation. Results: Signs of severe cognitive and motor impairments, mood disorders, and hepatotoxicity were observed in animals exposed to artificial daylight on ED20, unlike on ED14 and unlike groups exposed to natural daylight or conventional lighting. Activated microglia and astrocytes were observed in the entorhinal cortex, as well as dead and dying neurons. Neuronal counts revealed massive neuronal loss in the hippocampal formation. Conclusions: These results suggest that long hour exposure to high illuminance visible electromagnetic radiations induced severe alterations in brain function and general health in mice partly mediated by damages to the neocortex-entorhinal cortex-hippocampus axis. These findings raise caution over long hour use of high illuminance artificial light. PMID- 30023255 TI - Effects of folic acid on rat kidney exposed to 900 MHz electromagnetic radiation. AB - Because of increased use of cell phones, the purpose of this study was to investigation of the oxidative damage caused by electromagnetic radiation (EMR) emitted by cell phones and histological and morphometrical determination of the possible protective role of folic acid (FA) in preventing the detrimental effects of EMR on the kidney. Twenty-four adult male Wistar albino rats were divided into control (Cont), EMR, EMR + FA and FA groups, each containing six rats. The EMR and EMR + FA groups were exposed to EMR for 60 min a day over a period of 21 days, while no EMR exposure was applied to the Cont and FA groups. The source of the EMR was an EMR device which emits a digital signal producing 900-MHz frequency radiation. The generator connected to a one-monopole antenna was used in this study and the rats were placed in the plexiglass restrainer at an equal distance from the monopole antenna. Following the experimental period, and after tissue processing, a physical disector-Cavalieri method combination was applied to the sections. The mean volume of the cortex, medulla, proximal and distal tubules increased significantly in the EMR groups compared to the Cont group (p < 0.01). Contrarily, the total number of glomeruli in the EMR group decreased compared to the Cont group (p < 0.01). The protective effects of FA was observed in the kidney (p < 0.05). In conclusion, the 900-MHz EMR leads to kidney damage. FA may exhibit a protective effect against the adverse effects of EMR exposure in terms of the total number of glomeruli. PMID- 30023257 TI - Effects of 900-MHz radiation on the hippocampus and cerebellum of adult rats and attenuation of such effects by folic acid and Boswellia sacra. AB - The radiation emitted from mobile phones has various deleterious effects on human health. This study was conducted to evaluate the effects of exposure to the 900 MHz radiation electromagnetic fields (EMF) emitted by mobile phones on Ammon's horn and the dentate gyrus (DG) in the hippocampus and cerebellum of male Wistar albino rats. We also investigated the neuroprotective effects of the antioxidants Boswellia sacra (BS) and folic acid (FA) against exposure to EMF. Twenty-four adult male rats were randomly divided into four groups of six animals each, an EMF group, an EMF + FA exposure group (EFA), an EMF + BS exposure group (EBS) and a control group (Cont). The EMF, EFA and EBS groups were exposed to 900-MHz EMF radiation inside a tube once daily over 21 days (60 min/day). The Cont group was not exposed to 900-MHz EMF. The results showed that EMF caused a significant decrease in total pyramidal and granular cell numbers in the hippocampus, and DG and in Purkinje cell numbers in the cerebellum in the EMF group compared to the other groups (p < 0.05). BS and FA attenuated the neurodegenerative effects of EMF in the hippocampus and cerebellum. Significant differences were also determined between the numbers of neurons in the EFA and EMF groups, and between the EBS and EMF groups (p < 0.05). However, there were no significant differences among Cont, EFA and EBS (p > 0.05). Our results may contribute to ongoing research into the effects of 900-MHz EMF exposure. Abbreviations: BS, Boswellia sacra; CA, cornu ammonis; CAT, catalase; CE, coefficient of error; CV, coefficient of variation; DG, dentate gyrus; DNA, deoxyribonucleic acid; EMF, electromagnetic field; EBS, the group that is exposed to EMF and received a single daily gavage of BS (500 mg/kg/day) during 21 days; EEG, electroencephalogram; EFA, the group that is exposed to EMF and received a single daily gavage of folic acid (50 mg/kg/day) during 21 days; FA, folic acid; gr, granular layer; H2O2, hydrogen peroxide; MHz, Megahertz; ml, molecular layer; RF, radiofrequency; ROS, reactive oxygen specimens; SEM, standard error of the mean. PMID- 30023258 TI - Exposure to 2100 MHz electromagnetic field radiations induces reactive oxygen species generation in Allium cepa roots. AB - During the last few decades there has been an enormous increase in the usage of cell phones as these are one of the most convenient gadgets and provide excellent mode of communication without evoking any hindrance to movement. However, these are significantly adding to the electromagnetic field radiations (EMF-r) in the environment and thus, are required to be analysed for their impacts on living beings. The present study investigated the role of cell phone EMF-r in inciting oxidative damage in onion (Allium cepa) roots at a frequency of 2100 MHz. Onion roots were exposed to continuous wave homogenous EMF-r for 1, 2 and 4 h for single day and generation of reactive oxygen species (ROS) in terms of malondialdehyde (MDA), hydrogen peroxide (H2O2) and superoxide anion (O2*-) content and changes in the activities of antioxidant enzymes- superoxide dismutases (SOD) and catalases (CAT) were measured. The results showed that EMF-r exposure enhanced the content of MDA, H2O2 and O2*-. Also, there was an upregulation in the activity of antioxidant enzymes- SOD and CAT- in onion roots. The study concluded that 2100 MHz cell phone EMF-r incite oxidative damage in onion roots by altering the oxidative metabolism. PMID- 30023260 TI - Electromagnetic field exposure and health: Microscopic, radiological and stereological studies. PMID- 30023259 TI - Protective effects of melatonin and omega-3 on the hippocampus and the cerebellum of adult Wistar albino rats exposed to electromagnetic fields. AB - The purpose of the study was to investigate the effects of pulsed digital electromagnetic radiation emitted by mobile phones on the central nervous system of the adult Wistar albino rats. The study evaluated structural and functional impacts of four treatment arms: electromagnetic field (EMF) exposed; EMF exposed + melatonin treated group (EMF + Mel); EMF exposed + omega-3 (omega3) treated group (EMF + omega3); and control group (Cont). The 12-weeks-old rats were exposed to 900 MHz EMF for 60 min/day (4:00-5:00 p.m.) for 15 days. Stereological, biochemical and electrophysiological techniques were applied to evaluate protective effects of Mel and omega3. Significant cell loss in the CA1 and CA2 regions of hippocampus were observed in the EMF compared to other groups (p < 0.01). In the CA3 region of the EMF + omega3, a significant cell increase was found compared to other groups (p < 0.01). Granular cell loss was observed in the dentate gyrus of the EMF compared to the Cont (p < 0.01). EMF + omega3 has more granular cells in the cerebellum than the Cont, EMF + Mel (p < 0.01). Significant Purkinje cell loss was found in the cerebellum of EMF group compared to the other (p < 0.01). EMF + Mel and EMF + omega3 showed the same protection compared to the Cont (p > 0.05). The passive avoidance test showed that entrance latency into the dark compartment was significantly shorter in the EMF (p < 0.05). Additionally, EMF had a higher serum enzyme activity than the other groups (p < 0.01). In conclusion, our analyses confirm that EMF may lead to cellular damage in the hippocampus and the cerebellum, and that Mel and omega3 may have neuroprotective effects. PMID- 30023261 TI - Anti-Quorum Sensing Natural Compounds. AB - Increasing extent of pathogenic resistance to drugs has encouraged the seeking for new anti-virulence drugs. Many pharmacological and pharmacognostical researches are performed to identify new drugs or discover new structures for the development of novel therapeutic agents in the antibiotic treatments. Although many phytochemicals show prominent antimicrobial activity, their power lies in their anti-virulence properties. Quorum sensing (QS) is a bacterial intercellular communication mechanism, which depends on bacterial cell population density and controls the pathogenesis of many organisms by regulating gene expression, including virulence determinants. QS has become an attractive target for the development of novel anti-infective agents that do not rely on the use of antibiotics. Anti-QS compounds are known to have the ability to prohibit bacterial pathogenicity. Medicinal plants offer an attractive repertoire of phytochemicals with novel microbial disease-controlling potential, due to the spectrum of secondary metabolites present in extracts, which include phenolics, quinones, flavonoids, alkaloids, terpenoids, and polyacetylenes. They have recently received considerable attention as a new source of safe and effective QS inhibitory substances. The objective of this review is to give a brief account of the research reports on the plants and natural compounds with anti-QS potential. PMID- 30023262 TI - Prostatic Carcinogenesis: More Insights. AB - Background: Prostatic carcinoma ranks as the second most common malignant tumor and the fifth cause of cancer-related deaths in men. Many studies now focus on the different molecules involved in prostatic carcinogenesis. Maspin and prohibitin (PHB) are suggested to play crucial roles in the development and progression of many cancers; however, their roles in prostatic carcinogenesis have not been fully elucidated. Aim: This work was designed to study the immunohistochemical expression of maspin and PHB in prostatic carcinoma in comparison to their expression in benign prostatic hyperplasia (BPH) to give more insights about their roles in prostatic carcinogenesis. Materials and Methods: Archival blocks of 30 cases of prostatic adenocarcinomas and 15 cases of BPH were subjected to histopathological examination and immunohistochemical evaluation of maspin and PHB expression. Results: Maspin showed higher expression in prostatic carcinoma (88.9% of cases) compared to BPH (20% of cases). PHB expression was detected only in prostatic carcinoma (84.4% of cases), while all cases of BPH were negative. The expression of both maspin and PHB showed statistically significant increase with increasing Gleason score (P = 0.0125 and 0.0065 respectively). Conclusions: Overexpression of maspin and PHB in prostatic carcinoma reflects their vital roles in prostatic carcinogenesis. Their upregulation with increasing Gleason score indicates their prognostic significance. Moreover, PHB may differentiate between prostatic carcinoma and BPH being expressed only by malignant cells. PMID- 30023263 TI - Ultrastructure of the Parotid Salivary Gland in the Greater Cane Rats (Thryonomys Swinderianus). AB - The parotid glands of adult male African greater cane rat (Thryonomys swinderianus) were examined by light microscopy (semi-thin sections) and transmission electron microscopy. Histologically, it consisted of acinar cells with vacuoles which corresponded to large oval electron-dense granules, intercalated, striated ducts, and myoepithelial cells which contacted the cells and intercalated ducts (IDs). The cytoplasmic organizations of acinar cells represented the features of serous secreting cells. Ultrastructurally, the acinar cells contained granules of low and moderately electron densities without substructures in their matrix. Lipid droplets were interspersed with the granules. Several coalesced low electron-dense granules were common in some of the acinar cells. The acinar cells also contained few dilated (vesicular) and abundant parallel arrays of tubular rough endoplasmic reticulum and extensive Golgi complex. IDs were lined by tall cuboidal cells interconnected by tight junctions. Secretory granules were absent in their cytoplasm. Striated ducts were composed of columnar cells with few basal cells, and secretory granules were absent as well. Apical blebbing was observed in these ducts. Myoepithelial cells were limited to the acinar-intercalated ductal system. Nerve terminals were observed among the adjacent acinar cells and the underlying basement lamina. The functional significance of these structures is discussed. PMID- 30023264 TI - Histological and Ultrastructure Study of the Testes of Acrylamide Exposed Adult Male Albino Rat and Evaluation of the Possible Protective Effect of Vitamin E Intake. AB - Acrylamide (AA) is a hazardous unavoidable gonadal toxin. Hence, the aim of this study is to clarify its harmful effects on the testis of adult albino rat by light and electron microscope and to evaluate the possible role of Vitamin E (Vit E) in the prevention of such effects. Thirty-five adult male albino rats were enrolled in this study. They were divided into three groups: Group I (control); Group II (AA exposed), and Group III (AA and concomitant Vit E treated group). Animals of Groups II and III were further subdivided into two equal subgroups (each subgroup included five rats): (a) rats were sacrificed after 4 weeks and (b) rats were sacrificed after 6 weeks. The testes of each rat were dissected out, processed, and examined by Hematoxylin and Eosin, Periodic acid-Schiff and Mallory's trichrome stains as well as electron microscopic study. The study revealed that AA induces testicular damage at the histological and ultrastructural level in the form of degeneration and arrested spermatogenesis. Moreover, decreased seminiferous tubules diameters and epithelial height were detected. These changes are maximally improved in Vit E treated group. Hence, we could conclude that AA causes degenerative changes of the testes of albino rats and arrest of spermatogenesis. The AA-induced histological and ultrastructural changes of the testes could be explained by oxidative stress. These effects changes are proportional to the duration of exposure. Moreover, it could be concluded that Vitamin E has a protective role against AA-induced testicular damage by its antioxidant and anti-apoptotic effects. PMID- 30023266 TI - Histological, Immunohistochemical, and Biochemical Study of Experimentally Induced Fatty Liver in Adult Male Albino Rat and the Possible Protective Role of Pomegranate. AB - Nonalcoholic fatty liver disease is a major health problem and is considered the most common worldwide liver disease. Pomegranate has many biological activities and could modify the risk of hypercholesterolemia. The objective of the current research was to study the histological changes of experimentally induced fatty liver and possible protection by pomegranate. For this purpose, 50 adult male albino rats were divided into four groups, control group, pomegranate treated group that were given pomegranate juice for six weeks, fatty liver induced group that were fed on high fat diet for six weeks and protective group that were fed on high fat diet and received pomegranate juice for six weeks. Histological changes were detected in the fatty liver induced group in the form of disturbed hepatic architecture, dilatation and congestion of central veins, blood sinusoids and portal veins. Most of hepatocytes showed variable degrees of cytoplasmic vacuolation, mitochondrial structural changes, dilatation of endoplasmic reticulum in addition to nuclear structural changes like condensed chromatin, irregular shrunken nuclei and vacuolated nuclei. All these changes were associated with inflammatory cellular infiltrations, deposition of collagen fibers around the central vein, blood sinusoids, portal areas and in between the hepatocytes in addition to significant increase in number of hepatic stellate cells that was proved by electron microscope and confirmed by immunohistochemical study. Moreover, these structural changes were much less pronounced in animals treated with pomegranate either with or before receiving high fat diet. These findings suggested that pomegranate has a protective effect against experimentally induced fatty liver. PMID- 30023265 TI - Histopathological and Ultrastructural Alterations in Some Organs of Oreochromis niloticus Exposed to Glyphosate-based Herbicide, Excel Mera 71. AB - Oreochromis niloticus was exposed to glyphosate-based herbicide Excel Mera 71 for 30 days under field and laboratory conditions to investigate the histopathological and ultrastructural responses in gill, liver, and kidney. Gill displayed degenerative changes in the pillar cells of gill epithelium, curling of secondary lamella, and appearance of globular structure in laboratory condition under light microscopy. Scanning electron microscopic (SEM) observations revealed loss of microridges, disappearance of normal array of microridges, and damage in stratified epithelial cells under both the conditions, while severe vacuolation and necrosis were prominent under transmission electron microscopic (TEM) study in the laboratory condition. In liver, excess fat deposition and acentric nuclei in the laboratory condition were prominent under light microscopic and SEM study. TEM study showed necrosis in mitochondria, cytoplasmic vacuolation, degeneration in endoplasmic reticulum (ER), and reduced amount of glycogen droplets, but under field condition, lesions were less. Kidney showed fragmented glomerulus, excessive fat deposition, and hypertrophied nuclei under light microscope, while topological study showed shrinkage of glomerulus and degenerative changes under laboratory condition. TEM study also confirmed necrosis in mitochondria, dilation and fragmentation of ER, and appearance of severe vacuolation in the laboratory study, but no significant alterations were observed in field under SEM and TEM study. Therefore, the present study depicts that Excel Mera 71 caused comparatively less pathological lesions under field than laboratory condition, and finally, these responses could be considered as bioindicators for toxicity study in aquatic ecosystem. PMID- 30023267 TI - Epifluorescence and Stereomicroscopy of Trichomes Associated with Resistant and Susceptible Host Plant Genotypes of the Asian Citrus Psyllid (Hemiptera: Liviidae), Vector of Citrus Greening Disease Bacterium. AB - Background and Significance: Foliar trichomes (tiny hair-like structures) are part of the plant defense mechanisms that may confer resistance to some herbivore pests. Trifoliate orange, Poncirus trifoliata, is a genotype resistant to infestations by the Asian citrus psyllid, Diaphorina citri (Hemiptera: Liviidae), vector of the economically important citrus greening (huanglongbing) disease bacterium. We discovered that dense trichomes are associated with young leaves of trifoliate orange plants and hypothesized that these might be responsible for reduced infestation by this psyllid. Materials and Methods: Epifluorescence and stereomicroscopy were used to study the density and structure of trichomes associated with young flush leaves and stems of trifoliate orange and of five other plant genotypes that are highly susceptible to colonization by the psyllid: lemon, grapefruit, sweet orange, curry leaf, and orange jasmine. Results: Simple unicellular trichomes were observed at moderate-to-large densities on young leaves and stems of each genotype except lemon and sweet orange, which had considerably fewer trichomes. Trichomes were generally abundant on young leaves of curry leaf and orange jasmine, two genotypes that are often heavily colonized by the psyllid. Although we did not quantify oviposition rates on these genotypes, we observed that psyllid females deposited eggs on young leaves, buds, and stems regardless of the density of trichomes present, sometimes directly within or close to a dense bed of trichomes. Conclusions: While trichomes were moderately abundant on young leaves of trifoliate orange, our results strongly suggest that these trichomes may play little or no role in reduced colonization by the psyllid on this genotype. PMID- 30023268 TI - Inappropriate defibrillator shock during gynecologic electrosurgery. PMID- 30023269 TI - Quinidine effective for the management of ventricular and atrial arrhythmias associated with Brugada syndrome. PMID- 30023270 TI - A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects. PMID- 30023271 TI - Double devices: Dysfunction or not? PMID- 30023272 TI - Nonreentrant proximal fascicular ventricular tachycardia, with normal QRS duration and normal axis, originating from a region remote from the His bundle. PMID- 30023273 TI - Intramyocardial radiofrequency ablation of ventricular arrhythmias using intracoronary wire mapping and a coronary reentry system: Description of a novel technique. PMID- 30023274 TI - Bundle branch reentry: A novel mechanism for sustained ventricular tachycardia in Chagas heart disease. PMID- 30023275 TI - Right ventricularly paced right bundle-type pattern on ECG: Does this preclude upgrading to biventricular pacing? PMID- 30023276 TI - Arrhythmias and myocardial fragility in Ehlers-Danlos syndrome: Complications after routine ICD placement. PMID- 30023277 TI - Video-assisted thoracoscopic surgery to displace the phrenic nerve during endocardial ablation of right atrial tachycardia. PMID- 30023278 TI - Malignant transformation of a chronically infected implantable cardioverter defibrillator pocket. PMID- 30023279 TI - Successful ethanol injection into the anterior interventricular cardiac vein for ventricular premature contractions arising from the left ventricular summit. PMID- 30023280 TI - Late-onset asystolic episodes in a patient with a vagal nerve stimulator. PMID- 30023281 TI - Rare desmin variant causing penetrant life-threatening arrhythmic cardiomyopathy. PMID- 30023282 TI - Syncope on exertion in a young male. PMID- 30023283 TI - Type 1 sialidosis presenting with ataxia, seizures and myoclonus with no visual involvement. AB - Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in NEU1 which encodes lysosomal sialidase (neuraminidase 1). Lysosomal neuraminidase catalyzes the removal of terminal sialic acid molecules from glycolipids, glycoproteins and oligosaccharides. Sialidosis is classified into two types, based on phenotype and age of onset. Patients with the milder type 1 typically present late, usually in the second or third decade, with myoclonus, ataxia and visual defects. Type 2 is more severe and presents earlier with coarse facial features, developmental delay, hepatosplenomegaly and dysostosis multiplex. Presentation and severity of the disease are related to whether lysosomal sialidase is inactive or there is some residual activity. Diagnosis is suspected based on clinical features and increased urinary bound sialic acid excretion and confirmed by genetic testing showing pathogenic variants in NEU1. We report a patient with type 1 sialidosis who presented mainly with ataxia and both generalized and myoclonic seizures but no visual involvement. Whole exome sequencing of the proband detected compound heterozygous likely pathogenic variants (S182G and G227R) in NEU1. PMID- 30023284 TI - S-adenosylhomocysteine hydrolase over-expression does not alter S adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice. AB - Elevated plasma total homocysteine (tHcy) is associated with a number of human diseases including coronary artery disease, stroke, osteoporosis and dementia. It is highly correlated with intracellular S-adenosylhomocysteine (SAH). Since SAH is a strong inhibitor of methyl-transfer reactions involving the methyl-donor S adenosylmethionine (SAM), elevation in SAH could be an explanation for the wide association of tHcy and human disease. Here, we have created a transgenic mouse (Tg-hAHCY) that expresses human S-adenosylhomocysteine hydrolase (AHCY) from a zinc-inducible promoter in the liver and kidney. Protein analysis shows that human AHCY is expressed well in both liver and kidney, but elevated AHCY enzyme activity (131% increase) is only detected in the kidney due to the high levels of endogenous mouse AHCY expression in liver. Tg-hAHCY mice were crossed with mice lacking cystathionine beta-synthase activity (Tg-I278T Cbs-/- ) to explore the effect to AHCY overexpression in the context of elevated serum tHcy and elevated tissue SAM and SAH. Overexpression of AHCY had no significant effect on the phenotypes of Tg-I278T Cbs-/- mice or any effect on the steady state concentrations of methionine, total homocysteine, SAM, SAH, and SAM/SAH ratio in the liver and kidney. Furthermore, enhanced AHCY activity did not lower serum and tissue tHcy or methionine levels. Our data suggests that enhancing AHCY activity does not alter the distribution of methionine recycling metabolites, even when they are greatly elevated by Cbs mutations. PMID- 30023285 TI - Natural history of children and adults with maple syrup urine disease in the NBS MSUD Connect registry. PMID- 30023286 TI - Phenotypic variability of MTO1-deficiency. PMID- 30023287 TI - Sex differences in body composition and bone mineral density in phenylketonuria: A cross-sectional study. AB - Background: Low bone mineral density (BMD) and subsequent skeletal fragility have emerged as a long-term complication of phenylketonuria (PKU). Objective: To determine if there are differences in BMD and body composition between male and female participants with PKU. Methods: From our randomized, crossover trial [1] of participants with early-treated PKU who consumed a low-phenylalanine (Phe) diet combined with amino acid medical foods (AA-MF) or glycomacropeptide medical foods (GMP-MF), a subset of 15 participants (6 males, 9 females, aged 15-50 y, 8 classical and 7 variant PKU) completed one dual energy X-ray absorptiometry (DXA) scan and 3-day food records after each dietary treatment. Participants reported lifelong compliance with AA-MF. In a crossover design, 8 participants (4 males, 4 females, aged 16-35 y) provided a 24-h urine collection after consuming AA-MF or GMP-MF for 1-3 weeks each. Results: Male participants had significantly lower mean total body BMD Z-scores (means +/- SE, males = - 0.9 +/- 0.4; females, 0.2 +/- 0.3; p = 0.01) and tended to have lower mean L1-4 spine and total femur BMD Z scores compared to female participants. Only 50% percent of male participants had total body BMD Z-scores above - 1.0 compared to 100% of females (p = 0.06). Total femur Z-scores were negatively correlated with intake of AA-MF (r = - 0.58; p = 0.048). Males tended to consume more grams of protein equivalents per day from AA MF (means +/- SE, males: 67 +/- 6 g, females: 52 +/- 4 g; p = 0.057). Males and females demonstrated similar urinary excretion of renal net acid, magnesium and sulfate; males showed a trend for higher urinary calcium excretion compared to females (means +/- SE, males: 339 +/- 75 mg/d, females: 228 +/- 69 mg/d; p = 0.13). Females had a greater percentage of total fat mass compared to males (means +/- SE, males: 24.5 +/- 4.8%, females: 36.5 +/- 2.5%; p = 0.047). Mean appendicular lean mass index was similar between males and females. Male participants had low-normal lean mass based on the appendicular lean mass index. Conclusions: Males with PKU have lower BMD compared with females with PKU that may be related to higher intake of AA-MF and greater calcium excretion. The trial was registered at www.clinicaltrials.gov as NCT01428258. PMID- 30023289 TI - An atypical p.N215S variant of Fabry disease with end-stage renal failure. AB - Fabry disease is an X-linked metabolic disorder resulting in widespread deposition of Globotriaosylceramide within a variety of human tissues. The classical Fabry phenotype is one of early onset disease, with extensive tissue involvement resulting in acroparaesthesia, gastrointestinal disturbances, angiokeratoma, cornea verticillata renal failure, and cardiovascular disease. We describe two brothers exhibiting the GLA p.N215S mutation, a variant most often conferring a late-onset disease confined to the myocardium. The proband was diagnosed aged 34, following investigation into proteinuria. Despite Enzyme Replacement Therapy, he progressed to end-stage renal failure, and subsequently received a renal transplant. He also developed hypertrophic cardiomyopathy. His sibling however, whose disease was detected aged 32 following screening, exhibits mild left ventricular hypertrophy, and no evidence of renal disease. He remains clinically asymptomatic. This case report details a discordant phenotype in brothers with Fabry disease and p.N215S mutation. Despite the fact that in the majority of patients this mutation is associated with a late onset presentation with hypertrophic cardiomyopathy, we have clearly demonstrated that patients with GLA p.N215S mutation can present with the classical phenotype. Further studies are required to elucidate the underlying modifying factors that influence clinical presentation with a more severe phenotype. PMID- 30023288 TI - Effects of cold exposure on metabolites in brown adipose tissue of rats. AB - Brown adipose tissue (BAT) plays an important role in regulation of energy expenditure while adapting to a cold environment. BAT thermogenesis depends on uncoupling protein 1 (UCP1), which is expressed in the inner mitochondrial membranes of BAT. Gene expression profiles induced by cold exposure in BAT have been studied, but the metabolomic biological pathway that contributes to the activation of thermogenesis in BAT remains unclear. In this study, we comprehensively compared the relative levels of metabolites between the BAT of rats kept at room temperature (22 degrees C) and of those exposed to a cold temperature (4 degrees C) for 48 h using capillary electrophoresis (CE) time-of flight mass spectrometry (TOFMS) and liquid chromatography (LC)-TOFMS. We identified 218 metabolites (137 cations and 81 anions) by CE-TOFMS and detected 81 metabolites (47 positive and 34 negative) by LC-TOFMS in BAT. We found that cold exposure highly influenced the BAT metabolome. We showed that the cold environment lead to lower levels of glycolysis and gluconeogenesis intermediates and higher levels of the tricarboxylic acid (TCA) cycle metabolites, fatty acids, and acyl-carnitine metabolites than control conditions in the BAT of rats. These results indicate that glycolysis and beta-oxidation of fatty acids in BAT are positive biological pathways that contribute to the activation of thermogenesis by cold exposure, thereby facilitating the generation of heat by UCP1. These data provide useful information for understanding the basal metabolic functions of BAT thermogenesis in rats in response to cold exposure. PMID- 30023290 TI - Hyperphosphatasia with mental retardation syndrome, expanded phenotype of PIGL related disorders. AB - Hypomorphic mutations in six different genes involved in the glycosylphosphatidylinositol (GPI) biogenesis pathway are linked to Mabry syndrome (hyperphosphatasia with mental retardation syndrome, HPMRS). This report on the third affected family with a HPMRS phenotype caused by mutations in PIGL, confirming the seventh GPI biogenesis gene linked to HPMRS. Two siblings presented with the main features of HPMRS; developmental delay, cognitive impairment, seizure disorder, skeletal deformities, and high alkaline phosphatase. We identified two heterozygous mutations in the PIGL gene (P.Trp20Ter and p.Arg88Cys). PIGL mutations have been linked to another distinctive neuroectodermal disorder: CHIME syndrome. The clinical picture of our patients expands the spectrum of PIGL-related phenotypes. PMID- 30023292 TI - BAG3-related myofibrillar myopathy requiring heart transplantation for restrictive cardiomyopathy. PMID- 30023291 TI - The phenotype, genotype, and outcome of infantile-onset Pompe disease in 18 Saudi patients. AB - Infantile-Onset Pompe Disease (IOPD) is an autosomal recessive disorder of glycogen metabolism resulting from deficiency of the lysosomal hydrolase acid alpha-glucosidase encoded by GAA gene. Affected infants present before the age of 12 months with hypotonia, muscle weakness, and hypertrophic cardiomyopathy. Enzyme replacement therapy (ERT) has been shown to improve survival, cardiac mass, and motor skills. In this work, we aim to illustrate the genotypes of IOPD and the outcome of ERT in our population. The medical records of infants with confirmed diagnosis of IOPD who received ERT were reviewed. Eighteen infants (7 males, 11 females) were included in the study. The median age at presentation was 2 months and the median age at the start of ERT was 4.5 months. Fifteen (83.3%) infants died with a median age at death of 12 months. The 3 alive infants (whose current ages are 61/2 years, 6 years, and 10 years), who were initiated on ERT at the age of 3 weeks, 5 months, and 8 months respectively, has had variable response with requirement of assisted ventilation in one child and tracheostomy in another child. All infants were homozygous for GAA mutations except one infant who was compound heterozygous. All infants (n = 8) with truncating mutations died. Our work provides insight into the correlation of genotypes and outcome of ERT in IOPD in Saudi Arabia. Our data suggest that early detection of cases, through newborn screening, and immunomodulation before the initiation of ERT may improve the outcome of ERT in Saudi infants with IOPD. PMID- 30023293 TI - A beneficial effect of l-arginine for stroke-like episodes is currently unsupported. PMID- 30023294 TI - Elevation of plasma lysosphingomyelin-509 and urinary bile acid metabolite in Niemann-Pick disease type C-affected individuals. AB - Niemann-Pick disease type C (NPC) is a neurovisceral disorder associated with the accumulation of lipids such as cholesterol and sphingolipids. NPC is caused by either NPC1 or NPC2, which encode lysosomal proteins located at membraneous and soluble fractions, respectively. For the past decade, the oxidation products of cholesterol, such as cholestane-3beta,5alpha,6beta-triol and 7-ketocholesterol, have been considered selective biomarkers for NPC. However, recent evidence has indicated numerous novel biomarkers for NPC, which raises the possibility that the diagnosis of NPC might be associated with the elevation of multiple lipid biomarkers, rather than a single biomarker. Sphingosylphosphorylcholine (SPC) has been suggested to be one such biomarker for NPC, in which elevated sphingomyelin is a potential precursor. Thus, we first performed a validation study of plasma SPC using LC-MS/MS. The results showed the following plasma concentrations in the NPC-affected and control individuals, respectively: 8.2 +/- 2.8 nM (mean +/- SD; median, 7.0 nM; max, 11.7 nM; min, 5.1 nM; n = 5) and 3.1 +/- 1.4 nM (median, 2.9 nM; max, 4.8 nM; min, 1.5 nM; n = 7). We further extended the study to plasma lysophingomyelin-509 for NPC, a newly reported biomarker with uncharacterized chemical nature. Based on these result with plasma SPC as a surrogate marker, the value of mean of median of plasma lysophingomyelin-509 in NPC-affected individuals elevated at 65.2 (max, 73.2; min, 26.7; n = 5). Furthermore, the efficacy of plasma SPC and lysosphingomyelin-509 as promising biomarkers for this disorder was supported by the finding that the urinary concentration of 3beta sulfooxy-7beta-N-acetylglucosaminyl-5-cholen-24-oic acid, an established biomarker for NPC, was also elevated in the NPC-affected individuals. These results suggest that a novel combination of plasma biomarkers, such as SPC and/or lysophingomyelin-509, and urinary bile acid metabolite could offer a promising platform for the diagnosis of NPC. PMID- 30023295 TI - Causes of low muscle coenzyme-Q levels beyond primary coenzyme-Q-deficiency. PMID- 30023296 TI - Serendipitous effects of beta-cyclodextrin on murine model of Krabbe disease. PMID- 30023297 TI - Salivary serotonin does not correlate with central serotonin turnover in adult phenylketonuria (PKU) patients. AB - Introduction: Phenylketonuria (PKU) is an inborn error of metabolism associated with an increased risk of behavioural and mood disorders. There are currently no reliable markers for monitoring mood in PKU. The purpose of this study was to evaluate salivary serotonin as a possible non-invasive marker of long-term mood symptoms and central serotonin activity in patients with PKU. Methods: 20 patients were recruited from our Adult Metabolic Diseases Clinic. Age, sex, plasma phenylalanine (Phe) level, DASS (Depression Anxiety Stress Scales) depression score, DASS anxiety score, BMI, salivary serotonin, salivary cortisol, 2-year average Phe, 2-year average tyrosine (Tyr), and 2-year average Phe:Tyr ratio were collected for each patient. Spearman's rho correlation analysis was used to determine if there was any relationship between any of the parameters. Results: There were positive correlations between DASS anxiety and DASS depression scores (Spearman's rho = 0.8708, p-value < 0.0001), BMI and plasma Phe level (Spearman's rho = 0.6228, p-value = .0034), and 2-year average Phe and BMI (Spearman's rho = 0.5448, p-value = .0130). There was also a negative correlation between salivary cortisol and plasma Phe level (Spearman's rho = -0.5018, p-value = .0338). All other correlations were not statistically significant. Conclusion: Salivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, implying that salivary serotonin does not reflect central serotonin turnover. Additionally, this study suggests that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU. Synopsis: Salivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, suggesting that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU. PMID- 30023298 TI - Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data. AB - Incidence for the branched-chain intoxication-type disorders, maple syrup urine disease, propionic acidemia and methlymalonic aciduria is dependent on the population screened. Here newborn screening results from three world regions, state screening laboratories in the United States, a region in Germany and Kuwait provides new incidence numbers. Maple syrup urine disease incidence in the United States was calculated to be 1: 220219, in South-West Germany 1: 119573 (Germany nationwide 1:177978), and in Kuwait 1: 59426. Incidence of propionic acidemia alone is calculated to be 1: 242741 in the United States, 1: 284450 in South-West Germany (Germany nationwide 1:202617) and 1:59426 in Kuwait. Incidence of isolated methylmalonic aciduria alone is 1:69354 in the United States, 1:568901 in South-West Germany (Germany nationwide 1:159199) and 1: 19809 in Kuwait. In the United States several newborn screening laboratories combine their results for propionic acidemia and methylmalonic aciduria, and also include combined remethylation disorders in the respective category, resulting in an incidence of 1:50709. Combined evaluation of methylmalonic aciduria, propionic aciduria and combined remethylation disorders results in a similar incidence for Germany of 1:67539. This evaluation of newborn screening incidences reflects some population differences for three intoxication-type metabolic disorders. However, different sample sizes of the populations screened over different time periods, and differences in case definitions for methylmalonic acidurias have to be considered when interpreting these data. PMID- 30023299 TI - Genetic and clinical characteristics of Filipino patients with Gaucher disease. AB - Gaucher disease (GD) is a lysosomal storage disorder caused by the deficiency of the beta-glucocerebrosidase enzyme due to disease causing mutations in the GBA1 (glucosidase beta acid) gene, leading to the abnormal accumulation of the lipid glucocerebroside in lysosomal macrophages. This is a review of the clinical features and molecular profiles of 14 Filipino patients with GD. Five patients presented with type 1 disease, two had type 2 GD and seven had type 3 GD. The age of onset for all types was between 1 and 2 years of age but there was a delay of 2.2 years from the time of symptom onset to confirmation of diagnosis. Hepatosplenomegaly, anemia and thrombocytopenia were present in most of the patients. Stunting was seen in 64.3% and bone abnormalities were present in 63.6%. The most common mutant allele detected in this cohort was L483P (previously L444P), followed by F252I, P358A and G241R. IVS2+1 G>A, N409S and G416S mutations were reported singularly. There were 3 patients who were found to have N131S mutations and one patient with D257V mutation, mutant alleles that have only been reported among the Filipinos to date. Except for N409S, the mutations found in this cohort were generally severe and were congruent with the severe phenotypes found in most patients. Of the 14 patients, only 6 were able to undergo enzyme replacement therapy which significantly improved the hematologic parameters and decreased the sizes of the liver and spleen but did not consistently improve the growth and skeletal abnormalities nor alleviate the neurological manifestations of our patients with GD. Improved monitoring through recommended modalities for assessments and tools for evaluation should be implemented in order to fully appreciate the severity of the disease and accuracy of the response to treatment. PMID- 30023300 TI - Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program. AB - There is a growing interest in evaluating the effectiveness of enzyme replacement therapy (ERT) with elosulfase alfa in patients with mucopolysaccharidosis type IVA (MPS-IVA) under real-world conditions. We present the experience of seven pediatric MPS-IVA patients from the Spanish Morquio-A Early Access Program. Efficacy was evaluated based on the distance walked in the 6-min walking test (6 MWT) and the 3-min-stair-climb-test (3-MSCT) at baseline and after 8 months of ERT treatment. Additionally, urinary glycosaminoglycans were measured, and a molecular analysis of a GALNS mutation was performed. The health-related quality of life was evaluated using the EuroQoL (EQ)-5D-5 L. The distance walked according to the 6-MWT ranged from 0 to 325 m at baseline and increased to 12-300 m after 8 months with elosulfase alfa (the walked distance improved in all patients except one). An increase was observed for the two patients who had to use a wheelchair. Improvements were also observed for the 3-MSCT in four patients, whereas two patients showed no changes. Three patients showed an improvement in the EQ-VAS score, whereas the scores of three patients remained stable. Regarding urinary glycosaminoglycans measurements, an irregular response was observed. Our results showed overall improvement in endurance and functionality after 8 months of elosulfase alfa treatment in a heterogeneous subset of MPS IVA patients with severe clinical manifestations managed in a real world setting. PMID- 30023301 TI - Two siblings with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency suffered from rhabdomyolysis after l-carnitine supplementation. AB - Introduction: Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive mitochondrial fatty acid oxidation disorder and presents as hypoketotic hypoglycemia or rhabdomyolysis during childhood. l-Carnitine supplementation for patients with VLCAD deficiency is controversial. Herein, we describe two siblings with VLCAD deficiency who experienced more frequent episodes of rhabdomyolysis after l-carnitine supplementation. Case presentation: Case 1 involved a 6-year-old boy who was diagnosed with VLCAD deficiency after repeated episodes of hypoketotic hypoglycemia at 3 years of age. He developed rhabdomyolysis more frequently after starting l-carnitine supplementation. Case 2 involved an 8-year-old boy, the elder brother of case 1, who was also diagnosed with VLCAD deficiency by sibling screening at the age of 5 years. He first developed rhabdomyolysis during a common cold after treatment with l-carnitine. Both patients had fewer rhabdomyolysis episodes after the cessation of l carnitine supplementation. Conclusion: Our cases suggest that l-carnitine supplementation can increase rhabdomyolysis attacks in patients with VLCAD deficiency. PMID- 30023302 TI - A novel mutation in SGSH causing Sanfillipo type 3A Mucopolysaccharidoses in an Indian family. AB - Mucopolysaccharidoses (MPS) type III also termed as Sanfillipo syndrome, involves defect in enzymes required for degradation of heparan sulphate. We report a clinical case of MPS-III later followed by genetic investigation for MPS-III genes SGSH, NAGLU, HGSNAT and GNS. It allowed us to identify a novel and likely pathogenic variant p. G205R in SGSH. Protein based Inslico prediction and protein modelling suggests aberration of helical structure of SGSH protein and reduced binding affinity for its substrate. PMID- 30023303 TI - Vaccination triggering onset of m.8993T > G associated Leigh syndrome. PMID- 30023304 TI - Retrospective analysis of small cohorts does not support therapeutic efficacy of l-arginine. PMID- 30023306 TI - Phenotypic spectrum of maternally inherited Leigh Syndrome associated with the m.8993T>G variant. PMID- 30023305 TI - Marked elevation in plasma trimethylamine-N-oxide (TMAO) in patients with mitochondrial disorders treated with oral l-carnitine. AB - Oral supplementation with l-carnitine is a common therapeutic modality for mitochondrial disorders despite limited evidence of efficacy. Recently, a number of studies have demonstrated that a gut microbiota-dependent metabolite of l carnitine, trimethylamine oxide (TMAO), is an independent and dose-dependent risk factor for cardiovascular disease (CVD). Given the limited data demonstrating efficacy with oral l-carnitine therapy and the newly raised questions of potential harm, we assessed plasma TMAO levels in patients with mitochondrial disease with and without oral l-carnitine supplementation. Nine subjects were recruited and completed the study. Eight out of 9 subjects at baseline had plasma TMAO concentrations <97.5th percentile (<15.5 MUM). One subject with stage 3 renal disease, had marked elevation in plasma TMAO (pre 33.98 MUm versus post 101.6 MUm). Following at least 3 months of l-carnitine supplementation (1000 mg per day), plasma TMAO levels were markedly increased in 7out of 9 subjects; overall, plasma TMAO significantly increased 11.8-fold (p < 0.001) from a baseline median level of 3.54 MUm (interquartile range (IQR) 2.55-8.72) to 43.26 (IQR 23.99-56.04) post supplementation. The results of this study demonstrate that chronic oral l-carnitine supplementation markedly increases plasma TMAO levels in subjects with mitochondrial disorders. Further studies to evaluate both the efficacy and long term safety of oral l-carnitine supplementation for the treatment of mitochondrial disorders are warranted. PMID- 30023307 TI - Controversies on the potential therapeutic use of rapamycin for treating a lysosomal cholesterol storage disease. PMID- 30023308 TI - High retrocaval ureter: An unexpected intraoperative finding during robotic redo pyeloplasty. PMID- 30023309 TI - Incidence of hypocalcemia and hypercalcemia in hospitalized patients: Is it changing? AB - Disorders of calcium metabolism are frequently encountered in routine clinical practice. However limited data are available on the epidemiology of hypocalcemia and hypercalcemia in hospitalized patients. Our aim was to evaluate the frequency of hypocalcemia and hypercalcemia in hospitalized patients. This is a retrospective study based on the laboratory results of all hospitalized subjects (n = 12,334) whose calcemia was determined between January 1st, 2011 and December 31st, 2014. Measurements of serum calcium were carried out by a single centralized laboratory. Hypocalcemia was defined as serum calcium levels <8.2 mg/dl and hypercalcemia as serum calcium levels >10.4 mg/dl. Albumin correction was applied to adjust serum calcium values. Overall, hypocalcemia accounted for 27.72% (n = 3420) and hypercalcemia for 4.74% (n = 585) of the 12,334 inpatients. The highest prevalence of hypocalcemia was found in patients over 65 yr. (n = 2097, 61.31%) vs. younger subjects, while the highest prevalence of hypercalcemia was observed in patients aged 0-18 yr. (n = 380, 64.95%). Hypocalcemia was more often encountered in males (n = 1952, 57.07%) while no gender differences were found regarding hypercalcemia. Incidence of hypocalcemia changed over time varying from 35.42% (n = 1061) in 2011 to 21.93% (n = 672) in 2014 (r = -0.98; p = 0.01). Differently, incidence of hypercalcemia did not significantly increase significantly from 3.47% (n = 104) in 2011 to 6.92% (n = 211) in 2014 (r = 0.94; p = 0.052). Despite increased awareness about electrolytes disturbance, physicians should consider calcium levels because of life-threatening consequences associated to hypo- and hypercalcemia. Patient's gender and age could be associated to a different risk of calcium disturbance in hospitalized patients. PMID- 30023312 TI - Updating the ELISA standard curve fitting process to reduce uncertainty in estimated microcystin concentrations. AB - This study is aimed at exploring the optimal ELISA standard curve fitting process for reducing measurement uncertainty. Using an ELISA kit for measuring cyanobacterial toxin (microcystin), we show that uncertainty associated with the estimated microcystin concentrations can be reduced by defining the standard curve as a four-parameter logistic function on the natural log concentration scale, instead of the current approach of defining the curve on the concentration scale. The model comparison method is outlined in this paper, allowing it to be transferable to test different statistical models for other ELISA test kits. PMID- 30023310 TI - Serum omentin-1 levels in type 2 diabetic obese women in relation to glycemic control, insulin resistance and metabolic parameters. AB - Background: Omentin-1 a new anti-inflammatory adipokine has been identified as a major visceral (omental) secretory adipokine which plays important roles in glucose homeostasis, lipid metabolism, insulin resistance and diabetes. The aim of our study was to evaluate serum omentin-1 levels in type 2 diabetic obese females and assess its relation with glycemic control, insulin resistance and metabolic parameters. Methods: The study included 60 obese type 2 diabetic females and 30 healthy female subjects formed the control group. They subjected to full clinical examination, weight, height, waist and hip circumference. Fasting (blood glucose, insulin, lipid profile, omentin-1) and HbA1c were measured. BMI and HOMA-IR were calculated. Our data analyzed and expressed in terms of mean +/- SD. Pearson correlation performed to study the correlation of serum omentin-1 in relation to glycemic control, insulin resistance and metabolic parameters in the studied groups. Results: We found significant decrease in serum omentin-1 levels in cases with mean +/- SD (16.5 +/- 2.6 pg/ml) compared to controls (25.3 +/- 1.0 pg/ml) (P < 0.001). We also found strong significant negative correlations between serum omentin-1 and (BMI, fasting insulin, HOMA-IR) (r = -0.909, -0.853, -0.511) respectively (P < 0.001) and systolic blood pressure (r = -0.274, p = 0.031). The best cut off point of serum omentin-1 was 22.2 pg/ml to differentiate cases from controls using ROC curve analysis. Conclusion: Our study has shown significant low levels of serum omentin-1 in obese type 2 diabetic females in comparison to healthy subjects. Omentin-1 inversely related to obesity, insulin resistance and SBP. No significant associations with glycemic control and fasting lipids. Serum omentin-1 can be used as a biomarker for obesity related metabolic disorders. PMID- 30023313 TI - Atomic force microscopy nano-characterization of 3D collagen gels with tunable stiffness. AB - As extracellular matrix (ECM) nano-characteristics play a crucial role in cell behavior, including cancer development and metastasis, several ECM in vitro models have been used in order to study cells behavior under different biochemical and mechanical conditions. Among the ECM constituents, collagen (especially collagen type I) has been extensively used as an essential component of ECM models, since it is one of the most abundant ECM protein. Use of three dimensional (3D) collagen gels provides the advantage of allowing the cells to grow in a 3D environment that bears strong similarities to their natural, in vivo setting. Thus, the ability to form collagen gels with tunable stiffness and well defined naturally occurring nano-characteristics is crucial for these studies. Atomic Force Microscopy (AFM) is a unique tool that is ideal for the complete characterization of such models, in terms of morphology and mechanical properties without destroying the collagen fiber structure. In this protocol, the development and the AFM nano-scale characterization of 3D collagen type I gels is presented. The protocol includes: *The formation of 3D collagen type I gels with tunable stiffness*The preparation of histological sections from collagen gels*The AFM-based morphological and mechanical nano-characterization of the gels. PMID- 30023311 TI - Kobophenol A Isolated from Roots of Caragana sinica (Buc'hoz) Rehder Exhibits Anti-inflammatory Activity by Regulating NF-kappaB Nuclear Translocation in J774A.1 Cells. AB - Kobophenol A (KPA) is a biologically active natural compound isolated from the roots of Caragana sinica (Buc'hoz) Rehder (C. sinica). However, the anti inflammatory effects of KPA have not been reported. This study aims to find out whether KPA isolated from roots of C. sinica can act as a potential substance on inflammation and analyze the molecular mechanism using the lipopolysaccharide (LPS)-stimulated J774 A.1 macrophage cell line. We showed that KPA treatment significantly suppressed the production of nitric oxide (NO) by inhibiting inducible nitric oxide synthase (iNOS) expression in a dose-dependent manner without cytotoxicity. In the KPA also inhibited pro-inflammatory cytokine gene expression and production, such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in LPS-stimulated J774 A.1 cells. As continuing study on the mechanisms involved, we confirmed that these effects of KPA were related to the inhibition of nuclear factor-kappaB (NF-kappaB) pathway including the suppression of IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation and translocation of NF-kappaB into the nucleus. Taken together, the present study is the first to demonstrate that KPA isolated from C. sinica suppresses the expression of inflammatory mediators and cytokines by inhibiting NF-kappaB nuclear translocation in LPS stimulated J774 A.1 macrophages. KPA may be a potential candidate for the treatment of inflammatory diseases in the future. PMID- 30023314 TI - A GIS-based method for revealing the transversal continuum of natural landscapes in the coastal zone. AB - The method presented in this article is helpful for analyzing the landscape properties and unfolding the transversal continuity of natural landscapes in the coastal zone. The novel conceptual approach to analyze the landscape structure in the transversal direction with reference to coastline is different from others focusing on the longitudinal analysis of landscape properties in the coastal areas. The procedure is relying on the fundamental questioning of the spatial relation of each landscape patch with the coastline. The raw material is Land Use/ Land-Cover (LULC) data. At this stage the method is tested successfully utilizing CORINE Land Cover (CLC) data. The method is structured in four sequential stages, and formalized via ModelBuilder/ ArcGIS software into a model applicable to any coastal zone. The output of each phase is used as the raw material of the following stage. The presented method is useful in identifying a set of endangered natural landscape patches located as a hinge in between two transversally connected natural landscape mosaics (TCNLM). A second set is highlighted as potential artificial surfaces located as barriers between the coastline and TCNLM. The presented method is useful in the analysis stages of Integrated Coastal Zone Management (ICZM) and Sustainable Coastal Tourism (SCT). *The presented procedure focuses on the transversal landscape structure in the coastal zone rather that the classical longitudinal analysis of coastal landscapes.*The procedure brings a new way of CORINE Land Cover data utilization beyond its basic monitoring objective, useful for a variety of decision making and management processes such as; Integrated Coastal Zone Management (ICZM), Sustainable Coastal Tourism (SCT), Environmental protection, Landscape connectivity, etc.*The method builds a novel tool set customized via ModelBuilder in ArcGIS, being applicable to any coastal zone. PMID- 30023315 TI - Detection of plasmid-mediated colistin-resistant and carbapenem-resistant genes by multiplex PCR. AB - A multiplex PCR was described to simultaneously detect mcr-1 and frequently occurring carbapenem-resistant genes including blaKPC, blaNDM, blaIMP, and blaOXA 48-like in a single reaction. The PCR product sizes of these 4 carbapenem resistant genes were 232 bp, 438 bp, 621 bp, and 798 bp for blaIMP, blaOXA-48 like, blaNDM, and blaKPC, respectively, whereas mcr-1 revealed 1126 bp of PCR product. This protocol accurately detected those resistant genes in agreement with the reference strains, 127 local carbapenem-resistant Enterobacteriaceae, 8 mcr-1 carrying Enterobacteriaceae, and 62 carbapenem-susceptible Enterobacteriaceae. This method will be useful for laboratory application and surveillance of carbapenem and/or colistin-resistant bacteria. PMID- 30023316 TI - Quantification of sugars and organic acids in tomato fruits. AB - Sugar and organic acid contents are major factors for tomato fruit flavour and are important breeding traits. Here we provide an improved protocol for accurate quantification of the main sugars, glucose and fructose, and the organic acids, citric acid and malic acid, present in tomato. The tomato extract is spiked with lactose and tricarballylic acid as internal standards and loaded onto a NH2 solid phase extraction (SPE) column. The sugars appear in the flow-through and are subsequently analysed by HPLC using a Nucleodur NH2 column and a refractive index detector. The organic acids bind to the SPE column and are eluted with 400 mM phosphoric acid. For analysis, the organic acids are separated by HPLC using a Nucleodur C18ec column and detected by UV absorption at 210 nm. The method shows excellent inter-day and intra-day reproducibility for glucose, fructose and citric acid with standard deviations of 1-5%. Quantification of citric acid by HPLC and GC-MS showed perfect agreement with a deviation of less than 3%. *Simple method for quantification of glucose, fructose, citric acid and malic acid in tomato.*Efficient removal of interfering compounds by solid phase extraction.*High intra and inter-day reproducibility. PMID- 30023317 TI - Structural characterization of recombinant streptokinase following recovery from inclusion bodies using different chemical solubilization treatments. AB - Circular dichroism (CD) in far-UV region was employed to study the extent of changes occurred in the secondary structures of recombinant streptokinase (rSK), solubilized from inclusion bodies (IBs) by different chemicals and refolded/purified by chromatographic techniques. The secondary structure distribution of rSK, obtained following different chemical solubilization systems, was varied and values in the range of 12.4-14.5% alpha-helices, 40-51% beta-sheets and 35.5-48.3% turns plus residual structures were found. With reducing the concentration of chemicals during IB solubilization, the content of turns plus random coils was diminished and simultaneously the amounts of alpha- and beta-sheets were increased. These changes in the secondary structures would lower the hydrophobicity along with the chance of protein aggregation and expose the hydrophilic regions of the protein. Therefore, these alterations in the secondary structures, occurred following efficient IBs solubilization by low concentration of chemicals, could be related to enhancement in rSK biological potency previously observed. PMID- 30023318 TI - Chemical Enhancer: A Simplistic Way to Modulate Barrier Function of the Stratum Corneum. AB - Human skin could be a prime target to deliver drugs into the human body as it is the largest organ of human body. However, the main challenge of delivering drug into the skin is the stratum corneum (SC), the outer layer of epidermis, which performs the main barrier function of the skin. Scientists have developed several techniques to overcome the barrier properties of the skin, which include other physical and chemical techniques. The most common and convenient technique is to use special formulation additives (chemical enhancers, CEs) which either drags the drug molecule along with it or make changes in the SC structure, thereby allowing the drug molecule to penetrate in to the SC. The main focus is to deliver drugs in the certain layers of the skin (for topical delivery) or ensuring proper percutaneous absorption (for transdermal delivery). However, skin drug delivery is still very challenging as different CEs act in different ways on the skin and they have different types of interaction with different drugs. Therefore, proper understanding on the mechanism of action of CE is mandatory. In this article, the effect of several CEs on skin has been reviewed based on the published articles. The main aim is to compile the recent knowledge on skin-CE interaction in order to design a topical and transdermal formulation efficiently. A properly designed formulation would help the drug either to deposit into the target layer or to cross the barrier membrane to reach the systemic circulation. PMID- 30023319 TI - Essential Guide of Analysis Methods Applied to Silver Complexes with Antibacterial Quinolones. AB - To describe the chemical structure and characterize physico-chemical properties of organometallic complexes it is necessary to use a complex set of analysis methods. Thus, this review has been compiled as a relevant guide which includes the most commonly used methods of analysis in the study of silver complexes with antibacterial quinolones, compounds with promising biological potential. This selection of analysis methods puts on balance the obtained data and the accessibility of the experimental approach. The steps to follow in order to obtain reliable structural information about organometallic complexes of silver, particularly the silver complexes of antibacterial quinolones, are established and presented in the review. PMID- 30023320 TI - Bioemulsifiers Derived from Microorganisms: Applications in the Drug and Food Industry. AB - Emulsifiers are a large category of compounds considered as surface active agents or surfactants. An emulsifier acts by reducing the speed of chemical reactions, and enhancing its stability. Bioemulsifiers are known as surface active biomolecule materials, due to their unique features over chemical surfactants, such as non-toxicity, biodegradability, foaming, biocompatibility, efficiency at low concentrations, high selectivity in different pH, temperatures and salinities. Emulsifiers are found in various natural resources and are synthesized by Bacteria, Fungi and Yeast. Bioemulsifier's molecular weight is higher than that of biosurfactants. Emulsion's function is closely related to their chemical structure. Therefore, the aim of this paper was to study the various bioemulsifiers derived from microorganisms used in the drug and food industry. In this manuscript, we studied organisms with biosurfactant producing abilities. These inexpensive substrates could be used in environmental remediation and in the petroleum industry. PMID- 30023322 TI - The Effects of Natural Clinoptilolite and Nano-Sized Clinoptilolite Supplementation on Lipid Profile, Food Intakes and Body Weight in Rats with Streptozotocin-Induced Diabetes. AB - Purpose: To determine the effect of natural clinoptilolite (CLN) and nano-sized clinoptilolite (NCLN) on lipid profile, food intakes (FI) and weight changes in streptozotocin (STZ) induced diabetic rats. Methods: In this experimental study, 36 rats were randomly divided into two groups: diabetic group which was injected STZ (60 mg/kg BW), and a non-diabetic group. Three days after diabetes induction, each of these groups was randomly divided into 3 subgroups of 6 animals ((1) control, (2) 1%/food CLN, (3) 1%/food NCLN). The animals were supplemented for 28 days, starting three days after STZ administration. At the end of the study, blood was drawn for biochemical assays. The weights and FIs of the rats were measured at the beginning and end of each week. Results: Our findings revealed that there was no significant change in lipid profile, 28 days after administration of STZ in diabetic rats. Low density lipoprotein (LDL) was increased slightly in diabetic rats treated with NCLN without any significant changes in other lipid profile parameters in the other groups. Weight was reduced significantly in diabetic rats. Administration of CLN and NCLN prevented further weight loss in diabetic rats. All groups treated with STZ had higher food intake during the study. Conclusion: Lack of beneficial changes in lipid profile may be attributed to short study duration, insufficient for appearance of lipid abnormalities. Given the partial improvement in weight status and lack of undesirable effects of clinoptilolite supplementation, further research is recommended in subjects with typ1 diabetes mellitus. PMID- 30023323 TI - Porous Microparticles Containing Raloxifene Hydrochloride Tailored by Spray Freeze Drying for Solubility Enhancement. AB - Purpose: The goal of this study was to improve the solubility and dissolution behavior of Raloxifene Hydrochloride (RH) using Spray Freeze Drying (SFD) technique. Methods: For achieving this goal, series of samples containing RH with polyvinylpyrrolidone (PVP) or hydroxypropyl beta cyclodextrin (HPbetaCD) used as solubility enhancers were prepared and microparticles were formed via SFD. The resultant microparticles were physicochemically characterized. Morphology of the microparticles were observed using Scanning Electron Microscopy (SEM). High Performance Liquid Chromatography (HPLC) was used for analyzing the solubility and dissolution profile of the samples. Results: Fourier Transmission Infrared (FTIR) spectra showed that SFD processed compositions did not affect chemical structure of RH. SEM and Thermal Gravimetric Analysis (TGA) revealed that the fabricated spherical and highly porous microparticles were in amorphous state. SFD processed powders showed superior solubility and dissolution behavior; where, 80% of the drug was dissolved within 5 minutes. Conclusion: SFD method can be a promising alternative for enhancing the solubility of poorly water soluble compounds. PMID- 30023321 TI - Gold Coated Superparamagnetic Iron Oxide Nanoparticles as Effective Nanoparticles to Eradicate Breast Cancer Cells via Photothermal Therapy. AB - Purpose: Unique physiochemical properties of Fe2O3 nanoparticles make them great agents to serve as therapeutic and diagnostic nanoparticles (NPs). In this study, we developed gold coated Fe2O3 nanoparticles for photothermal therapy of breast cancer cells. Methods: Fe2O3 nanoparticles was prepared via microemulsion method and their surface was modified via gold. Differential light scattering (DLS) and transmission electron microscopy (TEM) methods were applied to evaluate physicochemical properties of NPs. Gold coated NP was further modified with MUC-1 aptamer as a targeting agent to increase drug delivery into the desired tissue. To evaluate cytotoxicity of prepared cells, MTT assay was employed. Targeting ability of aptamer modified NPs was assessed through confocal microscopy and flow cytometry method. Subsequently, MCF-7 and CHO cells were treated with aptamer modified NPs and were then irradiated via near infrared light (NIR) to produce heat. Results: The morphology of NPs was spherical and monodisperse with the size of 16 nm, which was confirmed via DLS and TEM. Confocal microscopy and flow cytometry results indicated that aptamer modified NPs had higher uptake compared to bare NPs. Finally, NIR exposure results revealed that higher uptake of NPs and application of NIR led to significant death of MCF-7 cells compared to CHO cells. Conclusion: To sum up, aptamer modified Fe2O3 nanoparticles showed higher uptake by cancerous cells and led to eradication of cancerous cells after exposure to NIR light. PMID- 30023324 TI - Preparation and Statistical Modeling of Solid Lipid Nanoparticles of Dimethyl Fumarate for Better Management of Multiple Sclerosis. AB - Purpose: The objective of this study was to synthesize and statistically optimize dimethyl fumarate (DMF) loaded solid lipid nanoparticles (SLNs) for better management of multiple sclerosis (MS). Methods: SLNs were formulated by hot emulsion, ultrasonication method and optimized with response surface methodology (RSM). A three factor and three level box-behnken design was used to demonstrate the role of polynomial quadratic equation and contour plots in predicting the effect of independent variables on dependent responses that were particle size and % entrapment efficiency (%EE). Results: The results were analyzed by analysis of variance (ANOVA) to evaluate the significant differences between the independent variables. The optimized SLNs were characterized and found to have an average particle size of 300 nm, zeta potential value of -34.89 mv and polydispersity index value < 0.3. Entrapment efficiency was found to be 59% and drug loading was 15%. TEM microphotograph revealed spherical shape and no aggregation of nanoparticles. In-vitro drug release profile was an indicative of prolonged therapy. In-vivo pharmacokinetic data revealed that the relative bioavailability was enhanced in DMF loaded SLNs in Wistar rats. Conclusion: This study showed that the present formulation with improved characteristics can be a promising formulation with a longer half-life for the better management of MS. PMID- 30023325 TI - Phytochemical Synthesis of Silver Nanoparticles by Two Techniques Using Saturaja rechengri Jamzad Extract: Identifying and Comparing in Vitro Anti-Proliferative Activities. AB - Purpose: A lot of plants are available which can produce nanoparticles used in medicine, life sciences, and the pharmaceutical industry. The present study aims to introduce safe biological and eco-friendly methods for synthesizing silver nanoparticles (AgNPs) by using Saturaja rechengri Jamzad extract, which can replace traditional chemical methods. In addition, the chemical nature and antimicrobial activities were identified and accordingly the anticancer effects of AgNPs was successfully reported on colon cancer cells (HT-29). Methods: Light and ultrasound, as two green chemistry techniques were first used for AgNPs synthesis. Then, morphological and crystalline structure of AgNPs was evaluated by scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis, respectively. In addition, functional groups were determined by using the Fourier transform infrared spectroscopy (FTIR) spectrum. Further, a maximum adsorption of AgNPs was observed in UV-visible spectrum. In the next stage, antibacterial activity of green synthesized AgNPs was evaluated against two pathogenic bacteria including Escherichia coli and Staphylococcus aureus. Finally, the cytotoxicity of AgNPs on HT-29 at different concentrations and times of AgNPs was determined by MTT assay. Results: The findings indicated that the synthesis of AgNPs by ultrasonic technique leads to smaller particle size and more distribution. Based on the results of MTT test for calculating the IC50%, the anti-proliferative effects of the light and ultrasound AgNPs were observed on HT-29 cell lines depending on the dose and time. Finally, the AgNPs had the most cytotoxicity HT 29 cell lines at 100 MUg/ml concentration although the lowest toxicity effect was reported on HEK-293 cell lines at the same conditions. Conclusion: The change in the concentration, physical and chemical properties of AgNPs including the form and size of particles, and their type of covering and fields can influence the induction of cytotoxicity and morphological change in the treated cells. The present research opens a new horizon on the development of new biological and cytotoxicity agents. PMID- 30023326 TI - Application of Response Surface Method for Preparation, Optimization, and Characterization of Nicotinamide Loaded Solid Lipid Nanoparticles. AB - Purpose: Solid lipid nanoparticles (SLNs) have been proven to possess pharmaceutical advantages. They have the ability to deliver hydrophilic drugs through lipid membranes of the body. However, the loading of such drugs into SLNs is challenging. Hydrophilic nicotinamide, a histone deacetylase inhibitor, is used to establish SLNs with enhanced encapsulation efficiency by using statistical design. Methods: The possible effective parameters of these particles' characteristics were determined using pre-formulation studies and preliminary tests. Afterwards, the Response Surface Method (RSM) was utilized to optimize the preparation condition of SLNs. The effect of the amount of lipid, drug, surfactant, and the mixing apparatus were studied on particle size, zeta potential, and encapsulation efficiency of the obtained particles. The acquired particles were characterized in respect of their morphology, in vitro release profile, and cytotoxicity. Results: According to this study, all the dependant variables could be fitted into quadratic models. Particles of 107 nm with zeta potential of about -40.9 and encapsulation efficiency of about 36% were obtained under optimized preparation conditions; i.e. with stearic acid to phospholipon(r) 90G ratio of 7.5 and nicotinamide to sodium taurocholate ratio of 14.74 using probe sonication. The validation test confirmed the model's suitability. The release profile demonstrated the controlled release profile following the initial burst release. Neither the nicotinamide nor the SLNs showed toxicity under the evaluated concentrations. Conclusion: The acquired results suggested the suitability of the model for designing the delivery system with a highly encapsulated water soluble drug for controlling its delivery. PMID- 30023328 TI - Synthesis of Bis(Isoxazol-4-Ylmethylsulfanyl)Alkanes and Some Metal Complexes as a Hepatoprotective Agents. AB - Purpose: This research is devoted to designing the synthesis of sulfanyl substituted 3,5-dimethylisoxazoles, which contain structural analogues of the SAM drug in the molecule. SAM (S-adenosyl-L-methionine), formed in the biosynthetic process, is used as an effective hepatoprotective drug. Complexation and hepatoprotective properties of the combinatorial series of bis(isoxazolylsulfanyl)ethane have been studied. Methods: Bis(isoxazol-4 ylmethylsulfanyl)alkanes were synthesized using the one-pot method. The structures of compounds were established by one-dimensional (1H,13C) and two dimensional (COSY, HCQS, HMBC) NMR spectroscopy, mass-spectrometry and X-ray diffraction. The biological activity of the combinatorial series of sulfanyl derivatives of diketones, azoles and their metal complexes has been studied by in vivo method. Simulation of the animal associated processes was carried out in accordance with the principles of bioethics. Screening studies of hepatoprotective activity were carried out in a model of acute CC14 intoxication after a single injection intraperitoneally as a 50% solution in olive oil. The pharmacologically known hepatoprotective drug SAM served as a control. Results: Two-step synthesis of novel alpha,omega-bis(isoxazol-4-ylmethylsulfanyl)alkanes was carried out via the multicomponent reaction between 2,4-pentandione, CH2O and alpha,omega-dithiols, then the resulting alpha,omega-bis(1,3-diketone-2 ylmethylsulfanyl)alkanes were transformed by hydroxyl amine to obtain bis isoxasole derivatives. Promising precursor 1,2-bis(isoxazol-4 ylmethylsulfanyl)ethane was converted to metal complexes by interaction with PdCl2 or CuCl. The obtained compounds were found to be practically non-toxic compounds (1001 - 3000 mg/kg) according to the classification of K.K. Sidorov, but copper complex refers to low-toxic compounds substances (165 mg/kg). Compounds of sulfanyl ethane series demonstrate hepatoprotective activity. Conclusion: Palladium(II) complex being almost non-toxic possesses hepatoprotective activity comparable to the drug like SAM. PMID- 30023327 TI - Enhanced Lymphatic Uptake of Leflunomide Loaded Nanolipid Carrier via Chylomicron Formation for the Treatment of Rheumatoid Arthritis. AB - Purpose: The current study aims the lymphatic delivery of leflunomide loaded nanostructured lipid carriers (LNLC) for the treatment of rheumatoid arthritis, mainly focussed to enhance the lymphatic delivery via chylomicron formation, improved bioavailability and reduced systemic toxicity. Methods: Melt emulsification ultra-sonication method was used to formulate the nanostructured lipid carrier (NLC) containing leflunomide. Four batches were prepared by using various concentration of surfactants (tween 80 and poloxmer 188) and lipid mixtures (stearic acid and oleic acid). All the formulations were studied for various physiochemical properties Results: The formulation with increased concentration of lipid and surfactants showed highest entrapment efficiency (93.96 +/- 0.47%) and better drug release (90.35%) at the end of 48 hrs. In vivo tests were carried out to determine the antiarthritic potential of the formulation in Sprague-dawley rats for a duration of 30d. The effect was evaluated by measuring the reduction in knee thickness. LNLC showed a marked reduction in inflammation compared to standard drug. Intestinal lymphatic uptake studies of LNLC were performed by intraduodenal administration and compared with leflunomide drug solution. The mesenteric lymph node was analysed by HPLC method and the concentration of drug was estimated. It showed that LNLC having highest uptake (40.34MUg/ml) when compared with leflunomide drug solution (10.04MUg/ml). Radiographic analysis and histopathological studies showed the formation of healthy cartilage after treatment period. Conclusion: The results suggested that LNLC has the potential to reduce the systemic toxicities associated with conventional therapy along with improved efficacy in the treatment of rheumatoid arthritis. PMID- 30023329 TI - PTPN22 Silencing in Human Acute T-Cell Leukemia Cell Line (Jurkat Cell) and its Effect on the Expression of miR-181a and miR-181b. AB - Purpose: T-cell acute lymphoblastic leukemia (T-ALL) is one of the most common malignancies associated with T-lymphocytes, accounting for 10 to 15 percent of ALL cases in children and 25 percent in adults. Innovative therapeutic approaches that overcome ineffective treatments on tumor cells may be a potential source of improvement in therapeutic approaches. Suppression of gene expression at transfusion level is one of the important strategies in gene therapy. The expression of PTPN22 and miR-181 genes in all types of hematologic malignancies increases and is likely to contribute to the survival and death of cells by affecting a variety of signaling pathways. The purpose of this study was to determine the role of PTPN22 inhibition by siRNA, and alteration in miR-181a and miR-181b in Jurkat cell line. Methods: Jurkat cells were transfected with 80 pmol of siRNA to inhibit PTPN22. After that, expression of PTPN22 mRNA and transcript levels of miR-181a and miR-181b were measured with Real-time PCR after 48hrs. Results: Experiments demonstrated that siRNA transfection resulted in significant downregulation of PTPN22 mRNA after 48 hrs in 80 pmol dose of siRNA. Moreover, transcript levels of both miR-181a and miR-181b was decreased after transfection. Conclusion: PTPN22, miR-181a and miR-181b might be involved in progression of Jurkat cells and targeting these molecules by RNAi might confer promising tool in treatment of T-ALL. PMID- 30023330 TI - Mummy Prevents IL-1beta-Induced Inflammatory Responses and Cartilage Matrix Degradation via Inhibition of NF-?B Subunits Gene Expression in Pellet Culture System. AB - Purpose: In Persian traditional medicine, application of Mummy material has been advised since hundred years ago for treatment of different diseases as bone fracture, cutaneous wounds and joint inflammation. Regarding to the claim of indigenous people for application of this material in the treatment of joint inflammation, the present study was designed to evaluate whether Mummy can revoke the inflammatory responses in chondrocytes stimulated with interleukin 1-beta (IL 1beta). Methods: Isolated chondrocytes at the second passage were plated in 50 ml conical tubes at density of 1x106 for pellet culture or were plated in T75 culture flasks as monolayer. Cells in both groups were treated as control (receiving serum free culture medium), negative control (receiving IL-1beta (10ng/ml for 24 hr)) and IL-1beta pre-stimulated cells which treated with Mummy at concentrations of 500 and 1000ug/ml for 72hrs. After 72 hrs, to evaluate whether Mummy can revoke the inflammatory response in chondrocytes, cell in different groups were prepared for investigation of gene expression profile of collagen II, Cox-2, MMP-13, C-Rel and P65 using real-time RT-PCR. Results: Treatment of chondrocytes with IL-1beta (10ng/ml) resulted in a significant increase in expression level of Cox-2, MMP-13, C-Rel and P65 in pellet culture system, while treatment of IL-1beta-stimulated choncrocytes with Mummy at both concentrations of 500 and 1000ug/ml inhibited the expression level of above mentioned genes. Compared to the pellet culture, Mummy did not affect expression level of genes in monolayer condition. Conclusion: The obtained data from this investigation revealed that Mummy can be used as a potent factor for inhibiting the inflammatory responses induced by IL-1beta in chondrocytes probably through inhibition of NF-?B subunits activation. PMID- 30023331 TI - The Effect of Mesenchymal Stem Cell-Derived Microvesicles on Erythroid Differentiation of Umbilical Cord Blood-Derived CD34+ Cells. AB - Purpose: Mesenchymal stem cells (MSCs) play an important role in the proliferation and differentiation of hematopoietic stem cells (HSCs) in the bone marrow via cell-to-cell contact, as well as secretion of cytokines and microvesicles (MVs). In this study, we investigated the effect of mesenchymal stem cell-derived microvesicles (MSC-MVs) on erythroid differentiation of umbilical cord blood-derived CD34+ cells. Methods: In this descriptive study, CD34+ cells were cultured with mixture of SCF (10 ng/ml) and rhEPO (5 U/ml) cytokines in complete IMDM medium as positive control group. Then, in MV1- and MV2-groups, microvesicles at 10 and 20 ug/ml concentration were added. After 72 hours, erythroid specific markers (CD71 and CD235a) and genes (HBG1, GATA1, FOG1 and NFE2) were assessed by flow cytometry and qRT-PCR, respectively. Results: The expression of specific markers of the erythroid lineages (CD71 and GPA) in the presence of different concentration of microvesicles were lower than that of the control group (P<0.001). Also, the expression of specific genes of the erythroid lineages (NFE2, FOG1, GATA1, and HBG1) was investigated in comparison to the internal control (GAPDH). Among all of them, HBG1 and FOG1 genes were significantly decreased to the control group (P<0.0001) but GATA1 and NFE2 gene expressions was not significant. Conclusion: The results of this study showed that MSC-MVs decrease the erythroid differentiation of umbilical cord blood derived CD34+ cells. Therefore, MSC-MVs play a key role in the regulation of normal erythropoiesis. PMID- 30023332 TI - An Investigation on the Regenerative Effects of Intra Articular Injection of Co Cultured Adipose Derived Stem Cells with Chondron for Treatment of Induced Osteoarthritis. AB - Purpose: Adipose tissue derived stem cells (ASCs) and chondrocytes are best cells for articular cartilage regeneration. Chondrocyte with peri-cellular matrix (PCM) is called chondron provides ideal microenviroment than chondrocytes. We aimed to evaluate the regenerative effects of intra-articular injection of ASCs co cultures with chondron in induced osteoarthritis (OA). Methods: ASC, from the peri-renal fat of male rat and chondron from primary newborn rat hyaline cartilage were isolated. ASCs were cultured for at least three passages in vitro. Six weeks after OA induction, rats were randomly distributed in five groups of control, osteoarthritic, ASC, chondron and co-cultured. ASCs (107), chondrons (107) and combination of chondrons and ASCs (107) were injected into intra articular space of the rat knee. The effect of treatments was evaluated by macroscopic and microscopic examinations. The expression levels of collagen type IotaIota was studied by immunohistochemistry. Results: Macroscopic appearance of the co-cultured group, showed much enhanced articular cartilage regeneration compared to ASC and chondron groups. H&E showed evidence of repair site of articular surface without erosion and fibrillation versus OA group which showed thin layer of hyaline cartilage over tidemark and spontaneous fibrocartilage formation. Metachromatic regions stained with toluidine blue were larger in treatment groups versus OA group. Strong intensity of type IotaIota collagen staining was observed in co-culture group compared to other groups. Conclusion: Co-culture of chondrons and ASCs increased articular hyaline cartilage formation and provides a useful tool to improve limitations of each of applied cells in this model. PMID- 30023333 TI - Effects of Pharmacologic Dose of Resveratrol Supplementation on Oxidative/Antioxidative Status Biomarkers in Nonalcoholic Fatty Liver Disease Patients: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Purpose: Despite a proposed role for oxidative stress in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), antioxidant approaches have not been sufficiently investigated in human NAFLD management. Resveratrol has been reported to possess a wide range of biological functions, including antioxidant activities. This study aimed to evaluate the effects of resveratrol supplementation on oxidative/anti-oxidative status in patients with NAFLD. Methods: This randomized, double-blind, placebo-controlled clinical trial was conducted on 60 patients with NAFLD (males and females) aged 20 to 60 years, and body mass index (BMI) of 25-35 kg/m2. Subjects were randomly assigned to receive a daily dose of 600 mg resveratrol (2*300 mg pure trans-resveratrol capsules; n=30) or placebo capsules (n=30) for 12 wk. Fasting blood samples, anthropometric measurements, and dietary intakes were collected for all patients at baseline and at the end of the trial. Oxidative stress was evaluated by measurement of serum malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), total antioxidant capacity (TAC), and erythrocyte superoxide dismutase (SOD) as well as glutathione peroxidase (GSH-Px) activities. Changes in the outcomes were analyzed using analysis of covariance (ANCOVA). Results: Resveratrol supplementation did not significantly affect neither serum MDA, ox-LDL, and TAC levels, nor erythrocyte SOD and GSH-Px activities, compared to placebo group (All P>0.05). Moreover, changes in serum levels of liver enzymes (ALT, AST, GGT, and ALP) were not significant in neither of the study groups (All P>0.05). Conclusion: Resveratrol supplementation did not modify oxidative/anti-oxidative status in patients with NAFLD. PMID- 30023334 TI - Combination of Vildagliptin and Ischemic Postconditioning in Diabetic Hearts as a Working Strategy to Reduce Myocardial Reperfusion Injury by Restoring Mitochondrial Function and Autophagic Activity. AB - Purpose: Diabetic hearts are resistant to cardioprotection by ischemic postconditioning (IPostC). Protection of diabetic hearts and finding related interfering mechanisms would have clinical benefits. This study investigated the combination effects of vildagliptin (Vilda) and IPostC on cardioprotection and the levels of autophagy and mitochondrial function following myocardial ischemia/reperfusion (I/R) injury in type-II diabetic rats. Methods: Diabetes was established by high fat diet/low dose of streptozotocin and lasted for 12 weeks. The diabetic rats received Vilda (6 mg/kg/day, orally) for one month before I/R. Myocardial regional ischemia was induced through the ligation of left coronary artery, and IPostC was applied immediately at the onset of reperfusion. The infarct size was assessed by a computerised planimetry and left ventricles samples were harvested for cardiac mitochondrial function studies (ROS production, membrane potential and staining) and western blotting was used for determination of autophagy markers. Results: None of Vilda or IPostC but combination of them could significantly reduce the infarct size of diabetic hearts, comparing to control (P<0.001). IPostC could not significantly affect p62 expression level in diabetic hearts, but pre-treatment with Vilda alone (p<0.05) and in combination with IPostC (p<0.01) more significantly decreased p62 expression in comparison with corresponding control group. The expression of LC3B II and LC3BII/LC3BI as well as mitochondrial ROS production were decreased significantly in treatment groups (p<0.001). Mitochondrial membrane depolarization was significantly higher and mitochondrial density was lower in untreated diabetic I/R hearts than treated groups (p<0.001). IPostC in combination with vildagliptin prevented the mitochondrial membrane depolarization and increased the mitochondrial content more potent than IPostC alone in diabetic hearts. Conclusion: Combination of vildagliptin and IPostC in diabetic hearts was a well-working strategy to reduce myocardial I/R damages by restoring mitochondrial membrane potential and ROS production and modulating the autophagic activity in I/R hearts. PMID- 30023336 TI - Cytotoxicity and Genotoxicity Assessment of Ascorbyl Palmitate (AP) Food Additive. AB - Purpose: Ascorbyl palmitate (AP) is a widely used food additive in food industry. In this study, AP was evaluated for potential cyto-genotoxicity on Human Umbilical Vein Endothelial Cells (HUVECs). Methods: MTT assay and flow cytometry analysis was used for cytotoxicity evaluation, while genotoxicity was carried out using DAPI staining assays and real time PCR. Results: The growth of HUVECs was decreased upon treatment with AP in dose-and time-dependent manner. Early/late apoptosis percentage in HUVECs treated with this additive was detected using flow cytometry analysis. Also morphology of DAPI stained HUVECs clearly showed chromatin fragmentation. Furthermore, real time PCR results showed that AP induces apoptosis by up-regulation of caspase-3, 9 and down-regulation of Bcl-2 ratio. Conclusion: The present results indicated that AP has capability to induce apoptosis in HUVECs and its better to make a thorough analysis about its extensive application in food industry. PMID- 30023335 TI - Protective Effect of Gemfibrozil on Hepatotoxicity Induced by Acetaminophen in Mice: the Importance of Oxidative Stress Suppression. AB - Purpose: Gemfibrozil (GEM) apart from agonist activity at peroxisome proliferator activated receptor-alpha (PPAR-alpha) has antioxidant and anti-inflammatory properties. Accordingly, the present study was designed to investigate the protective effect of GEM on acute liver toxicity induced by acetaminophen (APAP) in mice. Methods: In this study, mice divided in seven groups include, control group, APAP group, GEM group, three APAP groups pretreated with GEM at the doses of 25, 50 and 100 mg/kg respectively and APAP group pretreated with N-Acetyl cysteine. GEM, NAC or vehicle were administered for 10 days. In last day, GEM and NAC were gavaged 1 h before and 1 h after APAP injection. Twenty four hours after APAP, mice were sacrificed. Serum parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver tissue markers including catalase enzyme activity, reactive oxygen species (ROS), malondialdehyde and reduced glutathione (GSH) levels determined and histopathological parameters measured. Results: GEM led to significant decrease in serum ALT and AST activities and increase in catalase activity and hepatic GSH level and reduces malondialdehyde and ROS levels in the liver tissue. In confirmation, histopathological findings revealed that GEM decrease degeneration, vacuolation and necrosis of hepatocytes and infiltration of inflammatory cells. Conclusion: Present data demonstrated that GEM has antioxidant properties and can protect the liver from APAP toxicity, just in the same pathway that toxicity occurs by toxic ROS and that GEM may be an alternative therapeutic agent to NAC in APAP toxicity. PMID- 30023337 TI - Effect of Cucurbita Maxima on Control of Blood Glucose in Diabetic Critically Ill Patients. AB - Purpose: Cucurbita maxima Duchense (C. maxima) has been widely used in China and Mexico as a hypoglycemic plant for controlling blood glucose in diabetic patients. Furthermore, in northwest of Iran, this plant is used traditionally for controlling of diabetes. We examined the effect of C. maxima pulp besides insulin on control of hyperglycemia in diabetic patients admitted to Intensive care unit (ICU). Methods: Twenty critically ill patients who were admitted to the ICU were enrolled in this study. 5g lyophilized powder of C. maxima was administrated every 12 hours for 3 days. Moreover, blood glucose level and insulin dose were measured every 1-4 hours during 3 days before administration and 3days at the time of C. maxima administration. Results: The average of glucose level in 3 days before C. maxima administration was 214.9 +/- 55.7 mg/dl, while in 3 days during C. maxima administration it was decreased to 178.4 +/- 36.1 mg/dl (P<0.001). Additionally, the average insulin dose during 3 days before intervention was 48.05 +/- 36.5 IU and during the 3 days of C. maxima administration was decreased to 39.5 +/- 27.8 IU (P=0.06). Conclusion: It seems that C. maxima may decrease high blood glucose level fast and effective in diabetic critically ill patients. PMID- 30023338 TI - Erratum to: Chirality of Modern Antidepressants: An Overview. AB - [This corrects the article DOI: 10.15171/apb.2017.061.]. PMID- 30023339 TI - Community pharmacy Medicines Use Review: current challenges. AB - With a growing aging population, the appropriate, effective, and safe use of medicines is a global health policy priority. One concern is patients' non adherence to medicines, which is estimated to be up to 50%. Policymakers seek to reconfigure medicine management services and consider community pharmacy as especially well-placed to improve medicine use. In England and Wales, a commissioned medication review service called "Medicines Use Reviews (MURs)" was made available in through the National Health Service (NHS) in 2005. This involves a patient-pharmacist consultation to improve patients' knowledge and the use of medicines and to help reduce avoidable waste. However, over a decade since their introduction, questions remain over the extent to which the MUR policy has successfully been embedded in practice and translated into more effective use of medicines. The MUR intervention continues to hold many challenges ranging from poor public awareness and acceptance of MURs, organizational constraints, and issues over interprofessional collaboration. Many of these challenges are not exclusive to the MUR service, or even to the community pharmacy setting. Nevertheless, by identifying and exposing such challenges, an opportunity exists for policymakers and commissioners to seek to improve this service to patients. This narrative review explores the current challenges that face MURs. Damschroder et al's consolidated framework for implementation research is employed to help organize these challenges from patient and professional perspectives across multiple contexts. Over the past decade, MUR policy and practice has continued to evolve, being shaped by research, organizational and professional influences, and policy. Reforms to the service suggest that the MURs are becoming more responsive to patients' need and preferences. It is intended that this review will create impetus and scope for further debate, service reconfiguration, and ultimately service improvement. PMID- 30023340 TI - Analysis of Hierarchical Organization in Gene Expression Networks Reveals Underlying Principles of Collective Tumor Cell Dissemination and Metastatic Aggressiveness of Inflammatory Breast Cancer. AB - Clusters of circulating tumor cells (CTCs), despite being rare, may account for more than 90% of metastases. Cells in these clusters do not undergo a complete epithelial-to-mesenchymal transition (EMT), but retain some epithelial traits as compared to individually disseminating tumor cells. Determinants of single cell dissemination versus collective dissemination remain elusive. Inflammatory breast cancer (IBC), a highly aggressive breast cancer subtype that chiefly metastasizes via CTC clusters, is a promising model for studying mechanisms of collective tumor cell dissemination. Previous studies, motivated by a theory that suggests physical systems with hierarchical organization tend to be more adaptable, have found that the expression of metastasis-associated genes is more hierarchically organized in cases of successful metastases. Here, we used the cophenetic correlation coefficient (CCC) to quantify the hierarchical organization in the expression of two distinct gene sets, collective dissemination-associated genes and IBC-associated genes, in cancer cell lines and in tumor samples from breast cancer patients. Hypothesizing that a higher CCC for collective dissemination associated genes and for IBC-associated genes would be associated with retention of epithelial traits enabling collective dissemination and with worse disease progression in breast cancer patients, we evaluated the correlation of CCC with different phenotypic groups. The CCC of both the abovementioned gene sets, the collective dissemination-associated genes and the IBC-associated genes, was higher in (a) epithelial cell lines as compared to mesenchymal cell lines and (b) tumor samples from IBC patients as compared to samples from non-IBC breast cancer patients. A higher CCC of both gene sets was also correlated with a higher rate of metastatic relapse in breast cancer patients. In contrast, neither the levels of CDH1 gene expression nor gene set enrichment analysis (GSEA) of the abovementioned gene sets could provide similar insights. These results suggest that retention of some epithelial traits in disseminating tumor cells as IBC progresses promotes successful breast cancer metastasis. The CCC provides additional information regarding the organizational complexity of gene expression in comparison to GSEA. We have shown that the CCC may be a useful metric for investigating the collective dissemination phenotype and a prognostic factor for IBC. PMID- 30023341 TI - Single-Cell Tracking of A549 Lung Cancer Cells Exposed to a Marine Toxin Reveals Correlations in Pedigree Tree Profiles. AB - Long-term video-based tracking of single A549 lung cancer cells exposed to three different concentrations of the marine toxin yessotoxin (YTX) reveals significant variation in cytotoxicity, and it confirms the potential genotoxic effects of this toxin. Tracking of single cells subject to various toxic exposure, constitutes a conceptually simple approach to elucidate lineage correlations and sub-populations which are masked in cell bulk analyses. The toxic exposure can here be considered as probing a cell population for properties and change which may include long-term adaptation to treatments. Ranking of pedigree trees according to a measure of "size," provides definition of sub-populations. Following single cells through generations indicates that signaling cascades and experience of mother cells can pass to their descendants. Epigenetic factors and signaling downstream lineages may enhance differences between cells and partly explain observed heterogeneity in a population. Signaling downstream lineages can potentially link a variety of observations of cells making resulting data more suitable for computerized treatment. YTX exposure of A549 cells tends to cause two main visually distinguishable classes of cell death modalities ("apoptotic like" and "necrotic-like") with approximately equal frequency. This special property of YTX enables estimation of correlation between cell death modalities for sister cells indicating impact downstream lineages. Hence, cellular responses and adaptation to treatments might be better described in terms of effects on pedigree trees rather than considering cells as independent entities. PMID- 30023342 TI - Noninflammatory Diffuse Follicular Hypertrophy/Hyperplasia of Graves Disease: Morphometric Evaluation in an Experimental Mouse Model. AB - Objectives: Experimental models of Graves hyperthyroid disease accompanied by Graves orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. The interrelated pathological findings in the thyroid glands of Graves disease (GD) that explain the core changes classically include diffuse follicular hyperplasia and multifocal mild lymphocytic infiltrate. However, the relative contributions of different thyroid tissue components (colloid, follicular cells, and stroma) have not been previously evaluated. In this study, we characterize the thyroid gland of an experimental mouse model of autoimmune GD. Our objective was to define the relative contribution of the different thyroid tissue components to the pathology of glands in the experimental model. Methods: Mice were immunized with human TSHR A-subunit plasmid. Antibodies induced to human TSHR were pathogenic in vivo due to their cross-reactivity to mouse TSHR. Results: Autoimmune thyroid disease in the model was characterized by histopathology of hyperplastic glands with large follicular cells. Further examination of thyroid glands of immunized animals revealed a significantly increased follicular area and follicle/stroma ratio, morphometrically correlated with a noninflammatory follicular hyperplasia/hypertrophy. The increased follicle/stroma ratio was the most relevant morphometrically variable summarizing the pathological changes for screening purposes. Conclusion: GD thyroid glands are enlarged and characterized by a noninflammatory diffuse follicular cell hyperplasia/hypertrophy and a significant increase in the follicles with an increased follicle/stroma ratio. Overall, this mouse model is a faithful model of an early hyperthyroid status of GD (diffuse glandular involvement and follicular expansion). PMID- 30023344 TI - Aspirin Increases the Risk of Nondiagnostic Yield of Fine-Needle Aspiration and Biopsy of Thyroid Nodules. AB - Background: The link between the diagnostic yield of thyroid fine-needle aspiration and biopsy (FNAB) in patients taking antithrombotic or anticoagulant medications (AT/AC) remains poorly characterized. Objectives: We studied the risk of obtaining a nondiagnostic sample with ultrasound-guided thyroid FNAB in patients taking AT/AC medications. Methods: This is a retrospective cohort study using medical rec-ords of 556 patients who underwent thyroid FNAB. All cytology samples were reported using the Bethesda classification. For patients with a nondiagnostic cytology, logistic regression was used to calculate OR for patients taking AT/AC medications. Multivariate regression was used to adjust for potential confounding variables including age, cystic ultrasound features, presence of eggshell calcifications, number of passes performed, cystic aspirate on FNAB, and position of the nodule. Results: Out of 556 patients, cytology results were available for 547 patients. Of these, 46 subjects were taking aspirin and 1 was on warfarin. Among the entire cohort, 17.5% of the subjects had a nondiagnostic cytology. Among the patients on AT/AC medications, 34% had a nondiagnostic result compared to 16% for those not taking them (OR = 2.70, p = 0.003). The subgroup of patients taking aspirin had similarly higher odds of a nondiagnostic cytology (OR = 2.78, p = 0.002). These differences remained statistically significant after multivariate adjustment. Conclusions: This is the first study to demonstrate a 3-fold independently greater risk of a nondiagnostic FNAB cytology in patients taking aspirin. Our results highlight the importance of evaluating the need for continuation of aspirin in patients undergoing thyroid FNAB as this may impact the diagnostic yield of the procedure. PMID- 30023343 TI - Variables Contributing to Thyroid (Dys)Function in Pregnant Women: More than Thyroid Antibodies? AB - Variability in thyroid function in pregnant women is the result of 2 main determinants, each accounting for approximately half of it. The first is the genetically determined part of which the knowledge increases fast, but most remains to be discovered. The second determinant is caused by an ensemble of variables of which thyroid autoimmunity is the best known, but also by others such as parity, smoking, age, and BMI. More recently, new candidate variables have been proposed, such as iron, endocrine disruptors, and the ethnicity of the pregnant women. In the future, the diagnosis and treatment of thyroid (dys)function may be optimized by the use of each individual's pituitary-thyroid set point, corrected with a factor taking into account the impact of nongenetically determined variables. PMID- 30023345 TI - Bethesda Classification and Cytohistological Correlation of Thyroid Nodules in a Brazilian Thyroid Disease Center. AB - Background: The Bethesda System has been used to classify thyroid cytology in 6 categories besides presenting malignancy rates and respective approaches. Reference centers have validated its use by comparing its proposed malignancy rates with those in in their populations. However, to the best of our knowledge, there has been no corresponding study in Brazil. Objectives: To evaluate the performance of the Bethesda classification in a Brazilian thyroid reference center and correlate the results with cytohistological reports in patients referred to surgery. Methods: Data records from 980 fine-needle aspiration (FNA) results were retrospectively analyzed, and, in patients who underwent surgery, the results were correlated with the cytohistological findings. Results: 980 FNAs and 585 patients were evaluated. The incidence of each cytological category was: 11% nondiagnostic (ND), 59.6% benign, 7.1% (atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), 8.5% follicular neoplasm or suspicious for follicular neoplasm (FN/SFN), 5.1% suspicious for malignancy (SM), and 8.3% malignant. The surgery rate was 41.8% (245/585). The malignancy rate in each category was: 6% benign, 12% AUS/FLUS, 20.8% FN/SFN, 72.5% SM, and 97.3% malignant. For ND nodules, the malignancy rate was 25.7% (66.6% multifocal and papillary microcarcinomas), a higher rate than in the literature. In this category, surgery was performed in multinodular goiters presenting with another nodule > 3.0 cm and/or with an FN/SFN, SM, or malignant cytological result. Conclusion: The Bethesda System can be applied to the Brazilian population, since the frequency and malignancy rates of each category were similar to those described by its classification. It is noteworthy that a higher risk of malignancy was observed in the ND cytological category. PMID- 30023346 TI - Lenvatinib for Anaplastic Thyroid Cancer and Lenvatinib-Induced Thyroid Dysfunction. AB - Background: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has an anticancer action in patients with differentiated thyroid cancer that is refractory to radioiodine. Knowledge of the efficacy and safety of lenvatinib in patients with anaplastic thyroid cancer (ATC) is limited. Tyrosine kinase inhibitors frequently cause hypothyroidism, but the incidence of hypothyroidism with lenvatinib is unclear. Objectives: We conducted a retrospective study to investigate the efficacy and safety of lenvatinib in ATC. Methods: Five patients with unresectable ATC were enrolled. Lenvatinib 24 mg once daily was administered until disease progression, unmanageable toxicity, withdrawal, or death occurred. We retrospectively analyzed the objective response rate (ORR), time to progression (TTP), overall survival, and safety. Results: Three of the 5 patients (60%) had a partial response, and 5 (40%) had stable disease. The ORR was 60%. Median TTP was 88 days, and overall survival was 165 days. Hypothyroidism was a common treatment-related adverse effect; 4 patients (80%) had hypothyroidism of any grade. These 4 patients had not undergone total thyroidectomy prior to lenvatinib administration, and the other patient had undergone total thyroidectomy. Treatment-related adverse effects of any grade were hypertension in 80% of patients, diarrhea in 40%, fatigue in 80%, and decreased appetite in 80%. Conclusions: Lenvatinib is an effective treatment and may improve the prognosis of unresectable ATC. Four of the 5 patients had hypothyroidism, which may have been associated with treatment-induced injury of the thyroid gland. There were many treatment-related adverse effects, most of which were manageable by dose modification and medical therapy. PMID- 30023347 TI - Sorafenib-Induced Acute Pancreatitis in a Patient with Differentiated Thyroid Cancer. AB - Background: Sorafenib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma, and recently for radioactive iodine (RAI)-refractory metastatic differentiated thyroid carcinoma (DTC). Several side effects have been described including alterations in amylase and lipase levels. Nonetheless, only a few cases of pancreatitis during renal carcinoma and hepatocellular carcinoma treatment have been described. Objective: To describe the first case report of sorafenib-induced acute pancreatitis during the treatment of thyroid carcinoma. Methods and Results: In a 60-year-old Latin woman with RAI-refractory papillary thyroid carcinoma, T4bN1bM1, sorafenib was indicated due to locally recurrent, metastatic, and progressive lung involvement without iodine uptake. Therapy was initiated (200 mg) every 8 h. Three days after starting the medication, abdominal pain, nausea, and emesis appeared. A blood test revealed elevated amylase (343 U/L RV: 28-100) and lipase (1,969 U/L RV: 23 300) levels, but no other findings, confirming acute mild pancreatitis. Hypertriglyceridemia, hypercalcemia, and alcohol and biliary etiologies were ruled out and sorafenib-acute pancreatitis was concluded. Two weeks later, sorafenib was resumed without recurrence. To date, this is the tenth sorafenib related pancreatitis report and the first in a patient with RAI-refractory metastatic DTC. Conclusions: Sorafenib-acute pancreatitis may develop in patients with RAI-refractory thyroid cancer. This adverse event seems to be inde-pendent of the treatment duration and administered dose. Resuming the medication with an adjusted dose after pancreatitis resolution may be safe. PMID- 30023348 TI - Successful Treatment of Differentiated Thyroid Carcinoma with Transaxillary Robotic Surgery and Radioiodine: The First European Experience. AB - Objectives: Transaxillary robotic thyroidectomy surgery (TARS) has been reported to be a safe approach in patients with differentiated thyroid carcinoma, and oncological responses are promising. Study Design: This study aimed to evaluate the oncological outcomes of TARS followed by radioiodine (RAI) therapy in patients with differentiated thyroid carcinoma. Between 2011 and 2016, patients treated for differentiated thyroid carcinoma by TARS in a single institution, followed by RAI, were retrospectively included. The oncological response was performed according to the 2015 American Thyroid Association (ATA) guidelines 6 12 months later and at the last available visit. Results: A total of 42 patients (30 females) were included, with a median tumor size of 20 mm (12 cases of N1a and 5 cases of N1b on initial pathology report). According to ATA classification of recurrence risk after surgery, 17 and 25 patients were classified as low and intermediate risk, respectively. After RAI, all patients had a normal posttherapeutic whole body scan (except 1 patient, who had pathological lymph node uptake), but no unusual uptake was seen. At the 6- to 12-month evaluation (n = 37), 24 patients had excellent response, 8 had indeterminate response, and 5 had incomplete response (2 biological and 3 structural); no distant metastasis was found. At the last evaluation (median follow-up 15.9 months), 35 patients had no evidence of disease and 1 patient had a structural incomplete response. In total, a second open surgery was necessary for 3 patients to treat persistent lymph nodes (all intermediate risk). Conclusion: In this study, TARS followed by RAI therapy seems to be curative, even for patients with lymph node metastases, after good preoperative staging. More studies are required to confirm the findings. PMID- 30023350 TI - Nodules <=1 cm with Highly Suspicious Ultrasound Features and Papillary Microcarcinoma of the Thyroid: Is Fine-Needle Aspiration Cytology Necessary before Deciding on Active Surveillance? PMID- 30023349 TI - Thyroid Gland 18F-FDG Uptake in Neurofibromatosis Type 1. AB - Purpose: To investigate thyroid gland characteristics on 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging in patients with neurofibromatosis type 1 (NF1). Subjects and Methods: Thyroid gland characteristics of patients with a clinical diagnosis of NF1 who underwent 18F FDG PET/CT imaging for the first time to distinguish benign neurofibroma from malignant peripheral nerve sheath tumor (MPNST) at our institution (n = 69) were compared to PET/CT imaging of sarcoidosis (n = 25) and early stage lung cancer (T1N0M0 tumors, n = 15) patients. Results: Two NF1 patients (3%) showed a diffuse 18F-FDG uptake in the thyroid gland, 2 patients (3%) had an irregular uptake, and 7 patients (10%) had a focal uptake. Among the sarcoidosis patients, 1 showed a diffuse uptake (4%) and 1 had an irregular uptake (4%). In the early stage lung cancer group, 1 patient showed a diffuse uptake (7%) and 1 had a focal uptake (7%). NF1 patients had larger mean thyroid volume and mean SUVmax compared to sarcoidosis patients but not compared to early stage lung cancer patients. Four NF1 patients were diagnosed with multinodular goiter, 2 patients were diagnosed with benign chronic lymphocytic thyroiditis, 1 patient had metastasis to the thyroid, and 1 patient had medullary thyroid cancer. Conclusion: Even though NF1 patients did not show an increased risk of thyroid incidentaloma on PET/CT compared to previous studies on non-thyroid cancer patients, the incidence shows that awareness of possible thyroid disease is important. PMID- 30023351 TI - Epidemiological Characterization of the 2017 Dengue Outbreak in Zhejiang, China and Molecular Characterization of the Viruses. AB - Dengue, a mosquito-borne disease caused by the dengue virus (DV), has been recognized as a global public health threat. In 2017, an unexpected dengue outbreak occurred in Zhejiang, China. To clarify and characterize the causative agent of this outbreak, data on dengue fever cases were collected from the China Information System for Disease Control and Prevention in Zhejiang province for subsequent epidemiological analysis. A total of 1,229 cases were reported, including 1,149 indigenous and 80 imported cases. Most indigenous cases (1,128 cases) were in Hangzhou. The epidemic peak occurred in late August and early September, and the incidence rate of elderly people (4.34 per 100,000) was relatively high. Imported cases were reported all year round, and most were from South-East Asia and Western Pacific regions. Young people and men accounted for a large fraction of the cases. Acute phase serums of patients were collected for virus isolation. And 35 isolates (including 25 DV-2, 8 DV-1, 1 DV-3, and 1 DV-4) were obtained after inoculation and culture in mosquito C6/36 cells. The E genes of the 35 new DV isolates and the complete genome of a DV-2 isolate (Zhejiang/HZ33/2017), and the E gene of a DV-2 isolate from Ae. albopictus (Zhejiang/Aedes-1/2017) were determined. Phylogenetic analyses were performed using the neighbor-joining method with the Tajima-Nei model. Phylogenetically, DVs of all four serotypes with multiple genotypes (mainly including 21 Cosmopolitan genotype DV-2, 4 Asian I genotype DV-2, 6 genotype I DV-1, and 2 genotype V DV-1) were present in the indigenous and imported cases in Zhejiang during the same period. Most of the isolates probably originated from South-East Asia and Western Pacific countries. The imported cases, high density of mosquito vector, and missed diagnosis might contribute to the 2017 outbreak in Zhejiang. PMID- 30023353 TI - Unexplored Molecular Features of the Entamoeba histolytica RNA Lariat Debranching Enzyme Dbr1 Expression Profile. AB - The RNA lariat debranching enzyme (Dbr1) has different functions in RNA metabolism, such as hydrolyzing the 2'-5' linkage in intron lariats, positively influencing Ty1 and HIV-1 retrotransposition, and modulating snRNP recycling during splicing reactions. It seems that Dbr1 is one of the major players in RNA turnover. It is remarkable that of all the studies carried out to date with Dbr1, to our knowledge, none of them have evaluated the expression profile of the endogenous Dbr1 gene. In this work, we describe, for the first time, that Entamoeba histolytica EhDbr1 mRNA has a very short half-life (less than 30 min) and encodes a very stable protein that is present until trophozoite cultures die. We also show that the EhDbr1 protein is present in the nuclear periphery on the cytoplasmic basal side, contrary to the localization of human Dbr1. Comparing these results with previous hypotheses and with results from different organisms suggests that Dbr1 gene expression is finely tuned and conserved across eukaryotes. Experiments describing the aspects of Dbr1 gene expression and Dbr1 mRNA turnover as well as other functions of the protein need to be performed. Particularly, a special emphasis is needed on the protozoan parasite E. histolytica, the causative agent of amoebiasis, since even though it is a unicellular organism, it is an intron-rich eukaryote whose intron lariats seem to be open to avoid intron lariat accumulation and to process them in non-coding RNAs that might be involved in its virulence. PMID- 30023352 TI - Entamoeba histolytica Induce Signaling via Raf/MEK/ERK for Neutrophil Extracellular Trap (NET) Formation. AB - Amoebiasis, the disease caused by Entamoeba histolytica is the third leading cause of human deaths among parasite infections. E. histolytica was reported associated with around 100 million cases of amoebic dysentery, colitis and amoebic liver abscess that lead to almost 50,000 fatalities worldwide in 2010. E. histolytica infection is associated with the induction of inflammation characterized by a large number of infiltrating neutrophils. These neutrophils have been implicated in defense against this parasite, by mechanisms not completely described. The neutrophil antimicrobial mechanisms include phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs). Recently, our group reported that NETs are also produced in response to E. histolytica trophozoites. But, the mechanism for NETs induction remains unknown. In this report we explored the possibility that E. histolytica leads to NETs formation via a signaling pathway similar to the pathways activated by PMA or the Fc receptor FcgammaRIIIb. Neutrophils were stimulated by E. histolytica trophozoites and the effect of various pharmacological inhibitors on amoeba induced NETs formation was assessed. Selective inhibitors of Raf, MEK, and NF kappaB prevented E. histolytica-induced NET formation. In contrast, inhibitors of PKC, TAK1, and NADPH-oxidase did not block E. histolytica-induced NETs formation. E. histolytica induced phosphorylation of ERK in a Raf and MEK dependent manner. These data show that E. histolytica activates a signaling pathway to induce NETs formation, that involves Raf/MEK/ERK, but it is independent of PKC, TAK1, and reactive oxygen species (ROS). Thus, amoebas activate neutrophils via a different pathway from the pathways activated by PMA or the IgG receptor FcgammaRIIIb. PMID- 30023355 TI - Growth Mindset Moderates the Effect of the Neonatal Resuscitation Program on Performance in a Computer-Based Game Training Simulation. AB - This study examines for the first time the moderating role of growth mindset on the association between the time elapsed since participants' last refresher neonatal resuscitation program (NRP) course and their performance on neonatal resuscitation tasks in the RETAIN computer game training simulation. Participants were n = 50 health-care providers affiliated with a large university hospital. Results revealed that growth mindset moderated the relation between participants' task performance in the game and the time since their latest refresher NRP course. Specifically, participants who completed the course more recently (i.e., between 8 and 9 months before the current study) made significantly more mistakes in the game than the rest of the participants but only when they endorsed lower levels of growth mindset. Implications of this research include growth mindset interventions and increased screen time in simulation sessions that have the potential to help health-care providers achieve better performance on neonatal resuscitation clinical tasks. PMID- 30023354 TI - The Pseudomonas Quinolone Signal (PQS): Not Just for Quorum Sensing Anymore. AB - The Pseudomonas quinolone signal (PQS) has been studied primarily in the context of its role as a quorum-sensing signaling molecule. Recent data suggest, however, that this molecule may also function to mediate iron acquisition, cytotoxicity, outer-membrane vesicle biogenesis, or to exert host immune modulatory activities. PMID- 30023357 TI - Calcined Corncob-Kaolinite Combo as New Sorbent for Sequestration of Toxic Metal Ions From Polluted Aqua Media and Desorption. AB - This study investigated a new area of improving the adsorption capacity of clay using corn cob as an alternative means of clay modification to the more expensive and complicated chemical treatment techniques. Kaolinite Clay (KC), Calcined corncob-kaolinite Combo (CCKC), and Corncob (CC) adsorbents were utilized. The adsorbents were characterized by Fourier Transform-Infrared (FT-IR) Spectroscopy, Scanning Electron Microscopy (SEM), X-ray fluorescence spectroscopy, and Brunauer Emmett-Teller (BET) surface area analyzer. Batch adsorption methodology was used to investigate the effect of pH, initial metal concentration, adsorbent dose, and contact time on adsorption of Pb (II) and Cd (II). A slight increase in BET surface area of 29.31 m2/g for CCKC from 14.12 m2/g for raw KC was achieved. The trend of metal adsorption on the adsorbents was in the order CC>CCKC>KC. The Langmuir isotherm was found to present the best fit for the unmodified adsorbents while the Freundlich was applicable for CCKC indicating multilayer heterogeneous surface. The pseudo second order kinetic model was found to be suitable in the kinetic analysis. Thermodynamic studies revealed a spontaneous physical adsorption process of metal ions on CCKC. The combo adsorbent showed highest percentage desorption (>70%) of Cd and Pb ions in both acid and basic media compared to the other adsorbents. The results of the study established the efficiency of calcined corn cob kaolinite combo as suitable adsorbent for metal ions. PMID- 30023356 TI - The Sodium Sialic Acid Symporter From Staphylococcus aureus Has Altered Substrate Specificity. AB - Mammalian cell surfaces are decorated with complex glycoconjugates that terminate with negatively charged sialic acids. Commensal and pathogenic bacteria can use host-derived sialic acids for a competitive advantage, but require a functional sialic acid transporter to import the sugar into the cell. This work investigates the sodium sialic acid symporter (SiaT) from Staphylococcus aureus (SaSiaT). We demonstrate that SaSiaT rescues an Escherichia coli strain lacking its endogenous sialic acid transporter when grown on the sialic acids N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). We then develop an expression, purification and detergent solubilization system for SaSiaT and demonstrate that the protein is largely monodisperse in solution with a stable monomeric oligomeric state. Binding studies reveal that SaSiaT has a higher affinity for Neu5Gc over Neu5Ac, which was unexpected and is not seen in another SiaT homolog. We develop a homology model and use comparative sequence analyses to identify substitutions in the substrate-binding site of SaSiaT that may explain the altered specificity. SaSiaT is shown to be electrogenic, and transport is dependent upon more than one Na+ ion for every sialic acid molecule. A functional sialic acid transporter is essential for the uptake and utilization of sialic acid in a range of pathogenic bacteria, and developing new inhibitors that target these transporters is a valid mechanism for inhibiting bacterial growth. By demonstrating a route to functional recombinant SaSiaT, and developing the in vivo and in vitro assay systems, our work underpins the design of inhibitors to this transporter. PMID- 30023359 TI - FoodRepo: An Open Food Repository of Barcoded Food Products. PMID- 30023360 TI - Kisspeptin Modulates Luteinizing Hormone Release and Ovarian Follicular Dynamics in Pre-pubertal and Adult Murrah Buffaloes. AB - Kisspeptin is a neuropeptide that governs the reproductive axis upstream to GnRH. We wanted to study whether kisspeptin modulates plasma LH and FSH levels and ovarian follicular dynamics in buffaloes and whether kisspeptin can be used for fixed time artificial insemination (FTAI). We carried out these studies in comparison with buserelin, a potent GnRH agonist. Kisspeptin dose-dependently increased plasma LH levels. However, the kisspeptin-induced increase in LH was short-lived as the peak reached in 15-30 min returned to basal values by 1-2 h. The kisspeptin-induced increase in LH level was less compared to buserelin induced increase in LH level which sustained over time. Kisspeptin did not enhance FSH release while buserelin resulted in a gradual increase over time. LH response to repeated injections of kisspeptin was greater than that induced by buserelin. While buserelin induced an increase in the number of follicles, kisspeptin induced an increase in the growth rate of the follicle. In adult cycling animals, while both the drugs increased plasma LH levels, the increase was greater in buserelin group compared to kisspeptin group. In contrast to the findings in pre-pubertal animals, kisspeptin induced an increase in both the number as well as the size of follicles compared to buserelin. Our studies on oestrus synchronization, using either kisspeptin-PGF2alpha-kisspeptin protocol or buserelin-PGF2alpha-buserelin Ovsynch protocol on day 0, 7, and 9, respectively, revealed that kisspeptin increased the number of follicles at wave emergence and the diameter of dominant follicle after 2nd dose of drug, the oestrus response rate and duration of oestrus, compared to buserelin. However, conception rate was not significantly different among the groups. From our studies, it appears that Kp and Buserelin differentially modulate follicular dynamics depending on the reproductive age of the animals.However, studies in a larger herd are required to confirm whether kisspeptin can be used for oestrous synchronization in buffaloes. PMID- 30023358 TI - Calcium Signaling in Liver Injury and Regeneration. AB - The liver fulfills central roles in metabolic control and detoxification and, as such, is continuously exposed to a plethora of insults. Importantly, the liver has a unique ability to regenerate and can completely recoup from most acute, non iterative insults. However, multiple conditions, including viral hepatitis, non alcoholic fatty liver disease (NAFLD), long-term alcohol abuse and chronic use of certain medications, can cause persistent injury in which the regenerative capacity eventually becomes dysfunctional, resulting in hepatic scaring and cirrhosis. Calcium is a versatile secondary messenger that regulates multiple hepatic functions, including lipid and carbohydrate metabolism, as well as bile secretion and choleresis. Accordingly, dysregulation of calcium signaling is a hallmark of both acute and chronic liver diseases. In addition, recent research implicates calcium transients as essential components of liver regeneration. In this review, we provide a comprehensive overview of the role of calcium signaling in liver health and disease and discuss the importance of calcium in the orchestration of the ensuing regenerative response. Furthermore, we highlight similarities and differences in spatiotemporal calcium regulation between liver insults of different etiologies. Finally, we discuss intracellular calcium control as an emerging therapeutic target for liver injury and summarize recent clinical findings of calcium modulation for the treatment of ischemic-reperfusion injury, cholestasis and NAFLD. PMID- 30023361 TI - Pooled Platelet-Rich Plasma Lysate Therapy Increases Synoviocyte Proliferation and Hyaluronic Acid Production While Protecting Chondrocytes From Synoviocyte Derived Inflammatory Mediators. AB - Platelet-rich plasma (PRP) preparations are being used with moderate success to treat osteoarthritis (OA) in humans and in veterinary species. Such preparations are hindered, however, by being autologous in nature and subject to tremendous patient and processing variability. For this reason, there has been increasing interest in the use of platelet lysate preparations instead of traditional PRP. Platelet lysate preparations are acellular, thereby reducing concerns over immunogenicity, and contain high concentrations of growth factors and cytokines. In addition, platelet lysate preparations can be stored frozen for readily available use. The purpose of this study was to evaluate the effects of a pooled allogeneic platelet-rich plasma lysate (PRP-L) preparation on equine synoviocytes and chondrocytes challenged with inflammatory mediators in-vitro to mimic the OA joint environment. Our hypothesis was that PRP-L treatment of inflamed synoviocytes would protect chondrocytes challenged with synoviocyte conditioned media by reducing synoviocyte pro-inflammatory cytokine production while increasing synoviocyte anti-inflammatory cytokine production. Synoviocytes were stimulated with either interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS) for 24 h followed by no treatment or treatment with platelet-poor plasma lysate (PPP-L) or PRP-L for 48 h. Synoviocyte growth was evaluated at the end of the treatment period and synoviocyte conditioned media was assessed for concentrations of hyaluronic acid (HA), IL-1beta, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6). Chondrocytes were then challenged for 48 h with synoviocyte conditioned media from each stimulation and treatment group and examined for gene expression of collagen types I (COL1A1), II (COL2A1), and III (COL3A1), aggrecan (ACAN), lubricin (PRG4), and matrix metallopeptidase 3 (MMP-3) and 13 (MMP-13). Treatment of inflamed synoviocytes with PRP-L resulted in increased synoviocyte growth and increased synoviocyte HA and IL-6 production. Challenge of chondrocytes with conditioned media from PRP-L treated synoviocytes resulted in increased collagen type II and aggrecan gene expression as well as decreased MMP-13 gene expression. The results of this study support continued investigation into the use of pooled PRP-L for the treatment of osteoarthritis and warrant further in-vitro studies to discern the mechanisms of action of PRP L. PMID- 30023363 TI - Trends of snowboarding-related fractures that presented to emergency departments in the United States, 2010 to 2016. AB - Background: Since it was introduced as an Olympic sport in 1998, snowboarding has drawn the participation of individuals of all ages. Despite the growing popularity of this sport, individuals can suffer from a number of musculoskeletal injuries. The specific goals of the study were to: (I) compare the number of injuries and trends of snowboarding injuries; (II) identify the injury occurrences, trends, and incidence of snowboarding-related fractures; and (III) identify the injury occurrences and trends of snowboarding-related fractures by body part. Methods: The National Electronic Injury Surveillance System (NEISS) database was queried for snowboarding injuries and snowboarding-related fractures treated in US emergency departments (EDs) from 2010-2016. The weighted estimate of the number of injuries were obtained by using the NEISS statistical weight calculations that were provided in the data. An estimated total of 248,388 patients (mean age =20 years) experienced a snowboarding-related injury. Linear regression analysis was used to analyze annual trends of snowboarding-related fractures and the snowboarding-related fractures by body part; reported as the correlation coefficient (r) and the coefficient of determination (R2). Results: The estimated annual number of injuries decreased from 56,223 injuries in 2010 to 17,667 injuries in 2016 (r=-0.967, R2=0.936, P<0.001). The most common types of injuries were fractures (31.7%), strains/sprains (25.2%), contusions (10.9%), concussions (10.0%), internal injuries (7.2%), and dislocations (4.0%). From 2010 to 2016, the estimated annual number of fractures decreased from 18,757 in 2010 to 4,539 in 2016 (r=-0.978, R2=0.957, P<0.001), and the annual incidence of snowboarding-related fractures decreased by 23.1%. The most common location of snowboarding-related fractures was the upper extremity, more specifically the wrist (32.3%). There was a decrease in the estimated annual number of fractures of the wrist (r=-0.965, R2=0.932, P<0.001), forearm (r=-0.821, R2=0.861, P=0.023), shoulder (r=-0.872, R2=0.760, P=0.011), elbow (r=-0.901, R2=0.813, P=0.006), and lower leg (r=-0.929, R2=0.864, P=0.002). Conclusions: With the growing popularity of snowboarding in the US, it is important to know the common types of injuries that occur. This study found that fractures were the most common injuries, especially of the upper extremity. PMID- 30023364 TI - The efficacy of first-line chemotherapy in recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis. AB - Background: The standard first-line chemotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) has not been well established. We conducted a pooled meta-analysis to evaluate the efficacy of commonly used first line chemotherapy in this disease. Methods: Electronic databases including PubMed, Embase, and Corchrane library were searched for eligible literatures. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS) were pooled with the 95% confidence interval (CI) using R software. Results: Totally 973 patients were available for analysis from 14 phase II single arm clinical trials and 2 phase III randomized clinical trials. Four regimens were identified including 5-fluorouracil plus platinum (FP), gemcitabine plus platinum (GP), taxanes plus platinum (TP), and triplet combination regimen. Of these four regimens, triplet combination regimen demonstrated best short-term efficacy with a highest ORR (0.74; 95% CI, 0.62 0.87), DCR (0.91; 95% CI, 0.87-0.95), and 6-month PFS rate (0.83; 95% CI, 0.75 0.91), while 1-year OS rate (0.74; 95% CI, 0.61-0.87) was a little lower than TP regimen. Meanwhile, TP regimen showed best prognosis with a highest 1-year OS rate of 0.79 (95% CI, 0.65-0.92) and pretty good short-term efficacy with an ORR of 0.60 (95% CI, 0.48-0.72) and a DCR of 0.92 (95% CI, 0.86-0.98) comparable with triplet combination therapy. FP regimen had the lowest ORR (0.52; 95% CI, 0.38 0.65) and 1-year OS rate (0.63; 95% CI, 0.57-0.69). Efficacy of GP regimen fell between FP and TP regimens with an ORR of 0.54 (95% CI, 0.38-0.65), a DCR of 0.85 (95% CI, 0.71-0.93), a 6-month PFS rate of 0.69 (95% CI, 0.60-0.78) and a 1-year OS rate of 0.71 (95% CI, 0.61-0.80). Conclusions: Among four commonly used first line chemotherapy regimens for R/M NPC, triplet combination regimen showed best short-term efficacy but failed to improve prognosis. TP regimen demonstrated fairly good short-term efficacy and best long-term efficacy, followed by GP regimen, while FP regimen was the lowest. PMID- 30023365 TI - Cervical or thoracic anastomosis for patients with cervicothoracic esophageal squamous cell carcinoma. AB - Background: For cervical and higher-level esophageal tumors, the choice of cervical anastomosis or thoracic anastomosis is still controversial. The goal of this study was to explore the optimal surgical approach for cervicothoracic esophageal squamous tumors. Methods: We retrospectively analyzed 3,802 consecutive patients with esophageal squamous cell tumors in Nanjing Drum Tower Hospital from Jan 2001 to Jan 2017. Twenty-six patients with cervical anastomosis and twenty-eight patients with thoracic anastomosis were evaluated. Results: The cervical anastomosis group exhibited a greater number of resected lymph nodes (36.5+/-7.3 vs. 19.9+/-5.7, P<0.001). In addition, the cervical anastomosis group exhibited a higher recurrence rate (71.4% vs. 41.7%, P=0.047) and increased locoregional recurrence (P=0.040). Overall survival was not significantly different between groups (P=0.331). Moreover, multivariate Cox regression analysis revealed that postoperative locoregional recurrence is an independent risk factor for survival (P=0.031, 95% CI: 1.114-8.952). Conclusions: Thoracic anastomosis led to satisfactory results in patients with cervicothoracic esophageal squamous tumors. PMID- 30023362 TI - Blood pressure targets for hypertension in patients with type 2 diabetes. AB - Background: Clinical guidelines vary in determining optimal blood pressure targets in adults with diabetes mellitus. Methods: We systematically searched PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov in March 2018; conducted random effects frequentist meta-analyses of direct aggregate data; and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: From eligible 14 meta analyses and 95 publications of randomized controlled trials (RCT), only 6 RCTs directly compared lower versus higher blood pressure targets; remaining RCTs aimed at comparative effectiveness of hypotensive drugs. In adults with diabetes mellitus and elevated systolic blood pressure (SBP), direct evidence (2 RCTs) suggests that intensive target SBP <120-140 mmHg decreases the risk of diabetes related mortality [relative risk (RR) =0.68; 95% confidence interval (CI), 0.50 0.92], fatal (RR =0.41; 95% CI, 0.20-0.84) or nonfatal stroke (RR =0.60; 95% CI, 0.43-0.83), prevalence of left ventricular hypertrophy and electrocardiogram (ECG) abnormalities, macroalbuminuria, and non-spine bone fractures, with no differences in all-cause or cardiovascular mortality or falls. In adults with diabetes mellitus and elevated diastolic blood pressure (DBP) >=90 mmHg, direct evidence (2 RCTs) suggests that intensive DBP target <=80 versus 80-90 mmHg decreases the risk of major cardiovascular events. Published meta-analyses of aggregate data suggested a significant association between lower baseline and attained blood pressure and increased cardiovascular mortality. Conclusions: We concluded that in adults with diabetes mellitus and arterial hypertension, in order to reduce the risk of stroke, clinicians should target blood pressure at 120-130/80 mmHg, with close monitoring for all drug-related harms. PMID- 30023366 TI - Compensatory hyperhidrosis after different surgeries at the same sympathetic levels: a meta-analysis. AB - Background: Different techniques of video-assisted thoracoscopic sympathetic surgery have become the radical treatments for palmar and axillary hyperhidrosis (AH). However, there is no consensus over which technique can make a minimal incidence of compensatory hyperhidrosis (CH). This study was designed to compare the incidence of CH after different techniques at the same sympathetic levels in the treatment of upper limb and facial hyperhidrosis (FH). Methods: The databases of PubMed, Web of Science, ScienceDirect, Ovid Medline, Embase, and Cochrane Library were searched to identify studies comparing different surgical techniques at the same sympathetic levels for upper limb and FH. The data was analyzed by Revman 5.3 software. Results: A total of ten studies involving 896 patients were included, of whom 149 underwent sympathectomy, 435 underwent sympathicotomy, and 312 under endoscopic sympathetic clip (ESC). Meta-analysis showed that the difference of incidence of CH and patients' satisfaction was not significant between sympathectomy and sympathicotomy (P=0.05, 0.19, respectively). But, the incidence of CH is significant lower after ESC than after sympathicotomy (OR: 1.58, 95% CI: 1.04-2.38, P=0.03). However, the incidence of moderate/severe CH between these two groups is not significant different (OR: 1.49, 95% CI: 0.93 2.39, P=0.10). Conclusions: If only CH and the same sympathetic levels concerned, sympathectomy and sympathicotomy is equal for upper limb hyperhidrosis and FH. And, ESC should be recommended for a lower incidence of CH, comparing with sympathicotomy. PMID- 30023367 TI - Short-term outcomes for total knee arthroplasty patients with active extension lag. AB - Background: Despite the success of total knee arthroplasty (TKA), quadriceps strength can fail to recover. Active extension lag [quadriceps lag (Q-lag)] is a function of quadriceps weakness. Q-lag presents itself in patients who maintain a full passive range of motion (ROM), but are limited in active extension ROM. Few studies have evaluated the outcomes of post-TKA patients in the presence of post operative Q-lag. Thus, this study aims to compare: (I) pain scores; and (II) rates of readmission to physical therapy (PT) in TKA patients with Q-lag of >=15 degrees to patients without Q-lag. Methods: A retrospective review of primary TKA patients between 2013 and 2015 was performed. A total of 150 patients (mean age 63.0 years) with a mean follow-up of 30.7 months were analyzed. All patients received an evidence-based protocol for PT at our institution. Patient readmission to PT was recorded if the orthopedic surgeon wrote an additional prescription for PT intervention following the standard of care following TKA. An independent samples t-test and chi-square analysis was conducted to assess the continuous and categorical variables, respectively. Results: Fifty-one patients had Q-lag >=15 degrees and 97 patients had Q-lag <15 degrees. Analysis of mean pain scores between the groups demonstrated a significant difference in mean pain scores (1.9 vs. 3.9; P=0.043). Chi-square analysis demonstrated no significant difference in rates of PT readmission between patients who presented with Q-lag, and patients without Q-lag (23.5% vs. 13.4%; P=0.118). Conclusions: There was no significant difference in readmission rates; however, patients with Q-lag experienced a clinically significant higher pain level. Since this is the first study of its kind, we suggest further investigations on the effect of Q-lag on patient outcomes following primary TKA. PMID- 30023368 TI - Physical activity levels are low in patients with pulmonary hypertension. AB - Background: Pulmonary hypertension (PH) leads to exercise capacity impairment, but limited data are available on the objective evaluation of physical activity (PA) levels in these patients. Methods: We assessed PA levels using triaxial accelerometry in Spanish PH patients (n=75, 48+/-14 years, 65% female) and gender/age matched controls (n=107), and examined potential associations of meeting minimum international recommendations [moderate-vigorous PA (MVPA) >=150 min/week] with survival predictors. Results: With the exception of vigorous PA (with very low values in both groups), all accelerometry data showed significant differences between patients and controls, with lower PA levels and proportion of individuals meeting minimum PA guidelines, but higher inactivity time, in the former. Notably, the odds ratio (OR) of having a "low-risk" value of 6-minute walking distance (>=464 m) or ventilatory equivalent for carbon dioxide (<=39) was higher in patients following MVPA guidelines than in their less active peers [OR =4.3, 95% confidence interval (CI), 1.6-11.6, P=0.005, and OR =4.5, 95% CI, 0.9-21.1, P=0.054]. Conclusions: Daily PA is reduced in patients with PH, often to a level that may decrease their odds of survival. Efforts should be made to promote the implementation of healthy PA habits in this patient population. PMID- 30023369 TI - Impact of polymyxin B hemoperfusion in the treatment of patients with sepsis and septic shock: a meta-analysis of randomized controlled trials. AB - Background: Polymyxin B hemoperfusion is a strategy to remove circulating endotoxin in patients with sepsis. Previous systematic reviews derived from randomized and non-randomized studies suggested that use of polymyxin B hemoperfusion reduced mortality, based on the pooled data from various time points in the clinical course of sepsis. We conducted a meta-analysis of randomized controlled trials to assess the impact of polymyxin B hemoperfusion specifically on 28-day mortality in patients with sepsis and septic shock. Methods: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for eligible trials from inception through July 30, 2017. All randomized controlled trials were eligible if they examined the impact of polymyxin B hemoperfusion on 28-day mortality in patients with sepsis and septic shock. Risk of bias was evaluated with the Cochrane risk of bias assessment tool. Data were pooled using the DerSimonian and Laird random-effects model. Results: Seven trials involving 586 participants were identified for the analysis. Use of polymyxin B hemoperfusion was not associated with a reduced risk of 28-day mortality [risk ratio (RR), 0.76; 95% CI, 0.54-1.07] compared with usual care. One unpublished trial also showed no significant 28-day survival benefit. Conclusions: There is no evidence to support the use of polymyxin B hemoperfusion for patients with sepsis and septic shock with respect to 28-day mortality. PMID- 30023370 TI - Increasing clinical resistance rate of Shigella sonnei to cefotaxime in Jiangsu Province, China, between 2012 and 2015. AB - Background: The objective of this study is to evaluate the prevalence of Shigella sonnei (S. sonnei) and characterize the mechanism of its increasing resistance to cefotaxime, a third-generation cephalosporin agent between 2012 and 2015. Methods: We investigated the drug resistance in 95 isolates of S. sonnei by K-B dilution method and isolates with the extended-spectrum beta-lactamases (ESBLs) producing genes were detected by polymerase chain reaction (PCR) and sequencing. Results: Over a 4-year period, the resistance rate of S. sonnei to cefotaxime increased from 31.6% to 64.3%, between 2012 and 2015. Molecular characterization of the ESBL genes, comprising 28 strains of CTX-M-1 group: blaCTX-M-55 (n=22), blaCTX-M-3 (n=3) and blaCTX-M-15 (n=3); 11 strains of CTX-M-9 group: blaCTX-M-14 (n=9) and blaCTX-M-65 (n=2), and 36 strains with blaTEM-1 gene. None of S. sonnei isolates carried blaCTX-M-2 group and SHV-type. Conclusions: The antimicrobial resistance rate of S. sonnei to cefotaxime significantly increased. Accordingly, regular surveillance of the cephalosporin-resistant S. sonnei should be emphasized. Moreover, exploration of the mechanism underlying the resistance of S. sonnei to cefotaxime contributes to the prophylaxis of further emergence of drug resistance. PMID- 30023371 TI - Study on factors affecting local peak strain results in automatic functional imaging of transthoracic echocardiography. AB - Background: To investigate the important impacting factors on the accuracy of local peak strain (RLS) in transthoracic echocardiography real-time tri-axial automatic functional imaging (AFI), to evaluate the clinical efficacy of AFI and to improve the accuracy of the results. Methods: From May 2016 to May 2017, 82 healthy volunteers were enrolled in the AFI examination, of which 22 were excluded and 60 were eligible. The excluded 22 patients were analyzed for exclusion reasons, and the results of the 60 eligible AFI results were studied focusing on the longitudinal left ventricular regional longitudinal peak systolic strain (RLS) in different methods of operation, to compare the results and accuracies of AFI by different influencing factors, and to find the most important ones. Results: The success rate of AFI for this group of subjects is 74%, and the exclusion reason is that the left ventricular segments cannot be fully displayed. Among eligible subjects, the main influencing factors on RLS were region of interest (ROI), aortic valve closure time adjustment and image frame rate selection. The differences of results obtained by different operations were statistically significant (P<0.05). Conclusions: The success rate of AFI for this group of subjects is 74%. The RLS results were influenced by multiple factors, which can be effectively avoided. PMID- 30023372 TI - miR-486 inhibits PM2.5-induced apoptosis and oxidative stress in human lung alveolar epithelial A549 cells. AB - Background: Environmental exposure to particulate matter 2.5 (PM2.5) threatens public health, which has caused worldwide concerns. MicroRNAs (miRNAs, miRs) participate in multiple biological regulation. Among them, miR-486 has been reported to be a beneficial molecule for cell survival in various cell types. However, the potential function of miR-486 in PM2.5-induced cytotoxic is still uncertain. Methods: The expression of miR-486 was detected by quantitative real time polymerase chain reaction (qRT-PCR) after A549 cells incubated with PM2.5. Then TUNEL staining and DCFH-DA fluorescence were used to test the apoptosis and ROS generation of A549 cells after exposed to PM2.5 with miR-486 mimic. Western blot was performed to determine the expression of Bax/Bcl2 ratio. In addition, western blot and rescue experiments were conducted to determine the target gene of miR-486. Results: After treated with PM2.5, the expression of miR-486 was decreased. And miR-486 mimic treatment reduced cell apoptosis and reactive oxygen species (ROS) generation induced by PM2.5 exposure. Further studies showed that miR-486 negatively regulated the protein levels of PTEN and FOXO1. Rescue experiments demonstrated that PTEN and FOXO1 mediated the protective effects of miR-486 in PM2.5-treated human lung alveolar epithelial A549 cells. Conclusions: Collectively, our findings identify that miR-486 relieves PM2.5-induced cell injury by targeting PTEN and FOXO1 in human lung alveolar epithelial A549 cells. PMID- 30023373 TI - Surgery for intrathoracic tracheoesophageal and bronchoesophageal fistula. AB - Benign tracheoesophageal fistula (TEF) results from an abnormal communication between the posterior wall of the trachea or bronchi and the adjacent anterior wall of the esophagus. It can be acquired or congenital. The onset of the TEF has a negative impact on the patient's health status and quality of life because of swallowing difficulties, recurrent aspiration pneumonia, and severe weight loss. Several acquired conditions may cause TEF. The most frequent is prolonged orotracheal intubation (75% of the cases). Usually, there is an erosion of the tracheal and esophageal wall by the continuous pressure between the endotracheal tube and the esophageal wall; particularly in the presence of a nasogastric or feeding tube within the esophageal lumen. Furthermore, tracheal stenosis is often associated, and adds complexity to the disease. Preparation for the surgical procedure may take weeks or even months. It includes definitive weaning from mechanical ventilation, treatment of respiratory infection, physiotherapy, and correction of malnutrition through enteral feeding. Surgical repair of a TEF is an elective procedure. It consists of division of the fistula, suture of the esophagus and trachea and protection of the suture lines with a buttressed muscle flap. TEF repair is a complex and challenging procedure, thus, high morbidity and mortality are expected. Nonetheless, surgical management yields excellent long term results, and it should be considered the first-line treatment for this condition. Definitive fistula closure occurs in about 90-95% of the cases. PMID- 30023374 TI - Laparoscopic Roux-en-Y duodenojejunostomy for annular pancreas in adults: case report and literature review. AB - Annular pancreas is in adults is a rare congenital anomaly which incidence varied from 0.005% to 0.015%. Although 33% of the cases are symptomatic, the symptoms are most commonly associated with gastric outlet obstruction. Here we presented an adult diagnosed with annular pancreas treated by laparoscopic Roux-en-Y side to side duodenojejunostomy. PMID- 30023375 TI - Pulmonary sequestration associated with a synchronous elevation of carbohydrate antigen 50 and 19-9: a case report. AB - This report describes a 37-year-old woman who experienced elevated serum carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 50 (CA50). Intralobar pulmonary sequestration was confirmed via enhanced chest computed tomography (CT) scanning and positron emission tomography/computed tomography (PET/CT), which indicated two abnormal vessels arising from the descending thoracic aorta. Lobectomy of the left inferior lobe was performed as the optimal surgical approach and the pathological analysis met the diagnosis of intralobar pulmonary sequestration. Review of the patient's serum levels of CA50 and CA19-9 showed that these two tumor markers significantly decreased after surgery and finally went down to normal values. Therefore, the synchronically significant elevation of serum CA50 and CA19-9 was due to intralobar pulmonary sequestration. PMID- 30023376 TI - Laparoscopic pancreaticoduodenectomy with major venous resection and reconstruction with repassed round ligament: a case report. AB - It is technical challenging to perform laparoscopic pancreaticoduodenectomy (LPD) with major venous resection. Herein, we reported the first case of LPD with major venous resection and reconstruction with repassed round ligament. Between November 2015 and January 2018, a total of 35 LPD with major venous resection were performed in our department; however, only one patient underwent LPD with major venous resection and reconstruction with repassed round ligament. The patient suffered from pancreatic ductal adenocarcinoma with superior mesenteric vein and portal vein (SMV/PV) involvement. The operative time was 450 min and intra-operative blood loss was 200 mL. The duration of blood occlusion time was 48 min. No blood transfusion was required. The post-operative pathological examination showed that the pancreatic mass was pancreatic duct adenocarcinoma, and all the margins were negative. The post-operative period was uneventful. The patient was discharged on postoperative day 15. It is safe and feasible to perform LPD with major venous resection and reconstruction with repassed round ligament. However, long-term patency of repassed round ligament for venous reconstruction required further investigation. PMID- 30023377 TI - Development and clinical applications of glasses-free three-dimensional (3D) display technology for thoracoscopic surgery. AB - The conventional two-dimensional (2D) and glasses-assisted three-dimensional (3D) display systems can no longer meet the clinical requirements with the development of minimally invasive video-assisted thoracoscopic surgery (VATS). The glasses free 3D display technology adopts both lenticular lens technology and face tracking and -positioning systems and offers high brightness, large viewing area, and strong anti-interference capability, which significantly improve the operator's experience. When applied in VATS, it has many advantages including good display depth, convenience for performing complex and fine operations, and short learning curve. This novel display technology will greatly promote the development of minimally invasive surgery. PMID- 30023378 TI - Laparoscopic suture training curricula and techniques. AB - With the development and ubiquitous use of minimally invasive surgery, the advanced laparoscopic skills such as suture is essential for performing gastrointestinal procedures. However, the steep learning curve and lack of standardized training make most residents underprepared for laparoscopic suture. Moreover, the current simulation-based training is inadequate for trainees to master these advanced skills. Thus, there is a need for laparoscopic suture training modeled with cognitive knowledge, approachable techniques and standardized steps. Here, we present a suture training curriculum with video demonstration. In this study, we developed a suture training curriculum, which are divided into two categories depending on its difficulty and application. Basic techniques are designed for novice to master the basic suture skills, and it also shortens the learning curve of advanced suture techniques. Advanced techniques focused on the application of suture in specific circumstances. Also, it could prepare residents for more complex procedures. In order to increase the efficacy of suture training, we recommend a learning method similar to Peyton's four-step approach, personalized video feedback and spaced learning in our curricula. This article demonstrates the various laparoscopic techniques and their applications from simple to complex, with a view to help residents in training. Also, the training curricula and recommendations will further help residents to improve efficiently. Thus, we recommend to incorporate the curricula into suture training courses and surgical programs. PMID- 30023379 TI - Opening the black box of neural networks: methods for interpreting neural network models in clinical applications. AB - Artificial neural networks (ANNs) are powerful tools for data analysis and are particularly suitable for modeling relationships between variables for best prediction of an outcome. While these models can be used to answer many important research questions, their utility has been critically limited because the interpretation of the "black box" model is difficult. Clinical investigators usually employ ANN models to predict the clinical outcomes or to make a diagnosis; the model however is difficult to interpret for clinicians. To address this important shortcoming of neural network modeling methods, we describe several methods to help subject-matter audiences (e.g., clinicians, medical policy makers) understand neural network models. Garson's algorithm describes the relative magnitude of the importance of a descriptor (predictor) in its connection with outcome variables by dissecting the model weights. The Lek's profile method explores the relationship of the outcome variable and a predictor of interest, while holding other predictors at constant values (e.g., minimum, 20th quartile, maximum). While Lek's profile was developed specifically for neural networks, partial dependence plot is a more generic version that visualize the relationship between an outcome and one or two predictors. Finally, the local interpretable model-agnostic explanations (LIME) method can show the predictions of any classification or regression, by approximating it locally with an interpretable model. R code for the implementations of these methods is shown by using example data fitted with a standard, feed-forward neural network model. We offer codes and step-by-step description on how to use these tools to facilitate better understanding of ANN. PMID- 30023380 TI - James Neil Gilliam, MD-the career arc of a patient-oriented translational clinical investigation changemaker in rheumatologic skin disease. AB - James Neil Gilliam, MD, was an American academic physician who was trained in internal medicine, dermatology, dermatopathology and rheumatology. This "quadruple-threat" profile of postgraduate medical training provided him with a rather unique perspective on genetically-complex, environmentally-impacted human autoimmune disorders such as lupus erythematosus (LE). Both the skin and vital internal organs can be damaged by LE autoimmunity. And, LE is clinically expressed quite variably from one individual to another making prognosis difficult. As such it can be very challenging to know what the optimal treatment approach might be for new patients presenting with this potentially-fatal disorder. Dr. Gilliam's major career focus was to better understand the complex relationships that exist between the clinical expression of LE in the skin and vital internal organs. In the late 1970s, Dr. Gilliam first described a new clinical form of LE skin disease that he designated as "subacute cutaneous LE." Subacute cutaneous LE would subsequently serve as the linchpin for a new classification scheme for LE skin disease that would later become known as the "Gilliam classification" of LE skin disease. In addition, he was among the first to apply modern immunologic insight to the classification of cutaneous LE. This work was carried out in the Divisions of Dermatology and Rheumatology and the Department of Dermatology at the University of Texas Southwestern Medical School in Dallas, Texas (UT Southwestern) starting in 1972. Dr. Gilliam served as the Founding Chairman of the Department of Dermatology at UT Southwestern in 1982, 2 years before his untimely death. Dr. Gilliam's clinical research accomplishments were matched by his ability to identify and encourage like-minded young people. A high percentage of his trainees went on to successful academic research careers and leadership positions in American Dermatology. Dr. Gilliam's untimely death from cancer deprived several generations of dermatologists and rheumatologists the benefit of his warm support and insightful guidance. In addition, American Dermatology and Rheumatology leadership organizations were deprived of his strong leadership skills. PMID- 30023381 TI - Aspirin and diabetes mellitus in primary prevention: the Endless Conundrum. PMID- 30023382 TI - Low-dose aspirin for primary cardiovascular prevention in diabetic patients: the issue to believe it or not. PMID- 30023383 TI - Quality of life and treatment satisfaction are highly relevant patient-reported outcomes in type 2 diabetes mellitus. PMID- 30023384 TI - Multi-drug therapy in breast cancer: are there any alternatives? PMID- 30023385 TI - Which criteria should we use to evaluate the efficacy of immune-checkpoint inhibitors? PMID- 30023386 TI - An important piece of the puzzle for understanding the benefits of concomitant ablation of atrial fibrillation in cardiac surgery. PMID- 30023387 TI - Policy and governance solutions for ensuring equitable access to cancer medicines in low- and middle-income countries. PMID- 30023388 TI - The uremic solute-AHR-tissue factor axis in vascular cells, mouse models and thrombosis in chronic kidney disease patients. PMID- 30023389 TI - Is effective the hyperbaric oxygen therapy for the treatment of ischemic lower extremity ulcers?-new insights from a multicenter study. PMID- 30023390 TI - Building a cultural alliance for the prevention of fragility fractures among high risk older adults. PMID- 30023391 TI - Hyperbaric oxygen for treatment of diabetic foot ulcers: love you more than I can say. PMID- 30023392 TI - Optimal regimen of cisplatin in squamous cell carcinoma of head and neck yet to be determined. PMID- 30023393 TI - Gene-expression signature may be useful for the prediction of lymph node metastasis in esophageal cancer. PMID- 30023394 TI - The search for surrogate endpoints for immunotherapy trials. PMID- 30023395 TI - BLU-285-the breakthrough in treatment of patients with aggressive systemic mastocytosis and gastrointestinal stromal tumor. PMID- 30023396 TI - Noninvasive cancer biomarkers in solid malignancies: circulating tumor DNA clinical utility, current limitations and future perspectives. PMID- 30023397 TI - Unmask the genetic backbone of ibrutinib-relapsed chronic lymphocytic leukemia progression and Richter transformation. PMID- 30023398 TI - The promise and challenges of chimeric antigen receptor T cells in relapsed B cell acute lymphoblastic leukemia. PMID- 30023399 TI - Different prevalence and clinical outcome of Epstein-Barr virus positive diffuse large B-cell lymphoma between North American and non-Western populations. PMID- 30023401 TI - Is there a place for the combination of brentuximab vedotin and bendamustine in treatment of patients with relapsed/refractory Hodgkin lymphoma? PMID- 30023400 TI - Revolutionary changes in salvage treatment for Hodgkin lymphoma: toward a chemotherapy-free future. PMID- 30023402 TI - Comparison of different analysis algorithms to calculate multiple-breath washout outcomes. AB - Lung clearance index (LCI) is the main outcome of the multiple-breath washout (MBW) test. Current recommendations for LCI acquisition are based on low-grade evidence. The aim of this study was to challenge those recommendations using alternative methods for LCI analysis. Nitrogen MBW measurements from school-aged children, 20 healthy controls, 20 with cystic fibrosis (CF) and 17 with primary ciliary dyskinesia (PCD), were analysed using 1) current algorithms (standard), 2) three alternative algorithms to detect with higher precision the end of MBW testing and 3) two alternative algorithms to determine exhaled tracer gas concentrations. LCI values, intra-test repeatability, and ability to discriminate between health and lung disease were compared between these methods. The analysis methods strongly influenced LCI (mean+/-sd overall differences (%) between standard and alternative analysis methods: -4.9+/-5.7%; range: -66-19%), but did not improve intra-test variability. Discrimination between health and disease was comparable as areas under the receiver operator curves were not greater than that from standard analysis. This study supports current recommendations for LCI calculation in children. Alternative methods influence LCI estimates and hamper comparability between MBW setups. Alternative algorithms, whenever used, should be carefully reported. PMID- 30023403 TI - A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome. AB - Background. Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a recently recognized genetic disorder comprised of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy. It is caused by an autosomal dominant mutation in the POLD1 gene, with <20 genetically confirmed cases to date. Clinical overlap with other progeroid syndromes including Werner syndrome (WS) can present diagnostic challenges. Case. The proband is a 36-year-old male of Sicilian ancestry who was phenotypically normal at birth. Onset of lipodystrophic and progeroid features began at 18 months, with progressive loss of subcutaneous fat, prominent eyes, and pinched nose. Over the next 2 decades, he developed hearing loss, small fingers, joint contractures, hypogonadism, osteoporosis, and hypertriglyceridemia. Three of his 4 siblings had premature hair graying and loss, severe bilateral cataracts, skin changes, and varying degrees of age-related metabolic conditions, raising suspicion for a genetic progeroid syndrome. Genetic Analysis. A targeted sequencing panel identified a heterozygous WRN mutation in the proband's genomic DNA. Sanger sequencing further revealed his parents and an asymptomatic brother to be carriers of this mutation, and in his 3 brothers affected with classic WS the mutation was identified in the homozygous state. Whole exome sequencing ultimately revealed the proband harbored the causative de novo in-frame deletion in POLD1 (p.Ser605del), which is the most common mutation in MDPL patients. Conclusion. We report the unusual convergence of 2 rare progeroid disorders in the same family: the proband displayed sporadic MDPL syndrome, while 3 brothers had classical autosomal recessive WS. Whole exome sequencing was invaluable in clarifying the molecular diagnoses in this family. PMID- 30023404 TI - In Vivo Assessment of Exercise-Induced Glenohumeral Cartilage Strain. AB - Background: The human shoulder joint is the most mobile joint in the body. While in vivo shoulder kinematics under minimally loaded conditions have been studied, it is unclear how glenohumeral cartilage responds to high-demand loaded exercise. Hypothesis: A high-demand upper extremity exercise, push-ups, will induce compressive strain in the glenohumeral articular cartilage, which can be measured with validated magnetic resonance imaging (MRI)-based techniques. Study Design: Descriptive laboratory study. Methods: High-resolution MRI was used to measure in vivo glenohumeral cartilage thickness before and after exercise among 8 study participants with no history of upper extremity injury or disease. Manual MRI segmentation and 3-dimensional modeling techniques were used to generate pre- and postexercise thickness maps of the humeral head and glenoid cartilage. Strain was calculated as the difference between pre- and postexercise cartilage thickness, normalized to the pre-exercise cartilage thickness. Results: Significant compressive cartilage strains of 17% +/- 6% and 15% +/- 7% (mean +/- 95% CI) were detected in the humeral head and glenoid cartilage, respectively. The anterior region of the glenoid cartilage experienced a significantly higher mean strain (19% +/- 6%) than the posterior region of the glenoid cartilage (12% +/- 8%). No significant regional differences in postexercise humeral head cartilage strain were observed. Conclusion: Push-ups induce compressive strain on the glenohumeral joint articular cartilage, particularly at the anterior glenoid. This MRI-based methodology can be applied to further the understanding of chondral changes in the shoulder under high-demand loading conditions. Clinical Relevance: These results improve the understanding of healthy glenohumeral cartilage mechanics in response to loaded upper extremity exercise. In the future, these methods can be applied to identify which activities induce high glenohumeral cartilage strains and deviations from normal shoulder function. PMID- 30023405 TI - Relationship of Glove Arm Kinematics With Established Pitching Kinematic and Kinetic Variables Among Youth Baseball Pitchers. AB - Background: While the kinematics of the pitching arm, trunk, and pelvis have been described and studied, glove arm kinematics remain an understudied portion of the pitching motion. Baseball pitchers seek to achieve maximum ball velocity in a fashion that does not place the arm at risk of injury. Purpose: To assess the relationship between glove arm shoulder horizontal abduction and elbow flexion and pitching arm kinematics and kinetics among youth pitchers to determine whether recommendations can be made toward a safer pitching motion. Study Design: Descriptive laboratory study. Methods: Thirty-three right-handed youth male baseball pitchers (mean +/- SD: age, 13.6 +/- 2.0 years; height, 169.4 +/- 14.3 cm; weight, 63.5 +/- 13.0 kg; experience, 7.3 +/- 3.0 years) threw 3 fastballs to a catcher while kinematic data were collected with an electromagnetic tracking system. The Spearman rank-order test was used to identify relationships between glove arm horizontal abduction and glove arm elbow flexion and various kinematics and kinetics found at maximum shoulder external rotation (MER) and ball release for the fastest fastball delivered by each participant. Results: At MER, there were significant relationships found between a more flexed glove arm elbow and increased pitching arm elbow valgus force (rs [31] = -0.52, P = .002), increased pitching arm shoulder anterior force (rs = -0.39, P = .024), and decreased hip velocity (rs [31] = -0.45, P = .009). Additionally, there were significant relationships between greater glove arm horizontal abduction at MER and increased pitching arm humeral velocity (rs [31] = 0.52, P = .002) and increased trunk rotational velocity (rs [31] = 0.40, P = .022) at MER. Conclusion: A more extended glove arm elbow and more horizontally abducted glove arm shoulder at MER could prove to be more advantageous for performance and possibly be a safer motion for the baseball thrower. Clinical Relevance: The orthopaedic community can dictate safer biomechanics when communicating with pitchers, trainers, and pitching coaches. PMID- 30023406 TI - Outcomes From Conservative Treatment of Shoulder Idiopathic Adhesive Capsulitis and Factors Associated With Developing Contralateral Disease. AB - Background: Idiopathic adhesive capsulitis is a common condition resulting in painful multidirectional restriction of motion without other identifiable shoulder abnormality. First-line therapies for this condition are nonoperative, but limited data are available regarding which treatments are most effective. Factors associated with contralateral disease are not well established. Hypothesis: Younger patients will have a better response to treatments, and older patients and patients with diabetes will be more likely to develop contralateral disease. Study Design: Cohort study; Level of evidence, 3. Methods: Patients diagnosed with idiopathic adhesive capsulitis were treated with a single intra articular glenohumeral injection of local anesthetic and corticosteroid as well as 4 weeks of supervised physical therapy (PT). Patients were re-evaluated monthly and received additional conservative treatment based on failure to restore normal motion. Patient-reported outcome scores and range of motion were used to assess treatment efficacy. Results: Minimum 2-year follow-up data (mean, 3.4 years) were available for 60 of 75 eligible patients (80%). Patients who did not attend supervised PT as prescribed were more likely to undergo repeat injection due to a lack of adequate range of motion at follow-up (P = .003). Conservative therapy failed in 2 patients (3.3%), and they underwent arthroscopic release and manipulation under anesthesia. Twenty-two patients (36.7%) were subsequently diagnosed with contralateral idiopathic adhesive capsulitis, with a higher incidence in patients with diabetes (P = .009) and patients younger than 50 years (P = .005). American Shoulder and Elbow Surgeons score improved from 41.2 (95% CI, 33.0-49.4) at baseline to 92.0 (95% CI, 88.4-95.6) at final follow up (P < .0001). Patients with diabetes had a decrease in Shoulder Activity Scale score at final follow-up (P = .049). Conclusion: Conservative treatment for idiopathic adhesive capsulitis resulted in good clinical outcomes with a low incidence of surgical intervention. Physical therapy reduced the use of a second injection as part of treatment in this treatment algorithm. Young patients and patients with diabetes may be more likely to develop contralateral disease. PMID- 30023407 TI - A Gut Feeling: A Hypothesis of the Role of the Microbiome in Attention Deficit/Hyperactivity Disorders. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurologic disorder characterized by hyperactivity/impulsivity and/or inattentiveness, with genetic and environmental factors contributing to the disorder. With the growing recognition of the microbiome's role in many neurological disorders, the authors propose that it may also be implicated in ADHD. Here, we describe several evolving areas of research to support this hypothesis. First, a unique composition of gut bacteria has been identified and linked to behaviors in ADHD. Second, our research found an increased incidence of 2 gastrointestinal symptoms (constipation and flatulence) in children with ADHD, as compared to controls. Finally, emerging data may be interpreted to suggest that immune dysregulation in ADHD be associated with an altered microbiome, low-grade inflammation, and gastrointestinal dysfunction. Although more studies are needed to elucidate exact mechanisms and causality, we propose that an altered microbiome, gastrointestinal symptoms, and immune dysregulation may be associated with the ADHD phenotypes. PMID- 30023408 TI - Can different seating aids influence a sitting posture in healthy individuals and does gender matter? AB - This study determined differences in spinal-pelvic kinematics sitting on (i) mat (ii) block and (iii) novel 10o forward inclined wedge (ButtaflyTM) in a same subject repeated measures cross-over design in 60 healthy individuals (34 females). Repeated measures ANOVA revealed statistically significant differences between sitting conditions and lumbar and pelvic sagittal angles. Both, the inclined wedge and the block seating aids reduced overall flexion, but the inclined wedge had a greater influence in the lumbar region whilst the block induced the greatest change in the pelvis. This may be relevant for seating aid design personalised to posture type. Statistically significant gender differences were identified in all 3 seating conditions with males adopting more flexed lumbar spine and posteriorly tilted pelvis. Females flexed less in thoracic spine when sitting on an inclined wedge and a block. These statistically significant differences between males and females may provide first explorative direction for bespoke seating aids design. PMID- 30023409 TI - Bacterial Microcolonies in Gel Beads for High-throughput Screening. AB - High-throughput screening of a DNA library expressed in a bacterial population for identifying potentially rare members displaying a property of interest is a crucial step for success in many experiments such as directed evolution of proteins and synthetic circuits and deep mutational scanning to identify gain- or loss-of-function mutants. Here, I describe a protocol for high-throughput screening of bacterial (E. coli) microcolonies in gel beads. Single cells are encapsulated into monodisperse water-in-oil emulsion droplets produced with a microfluidic device. The aqueous solution also contains agarose that gelates upon cooling on ice, so that solid gel beads form inside the droplets. During incubation of the emulsion, the cells grow into monoclonal microcolonies inside the beads. After isolation of the gel beads from the emulsion and their sorting by fluorescence activated cell sorting (FACS), the bacteria are recovered from the gel beads and are then ready for a further round of sorting, mutagenesis or analysis. In order to sort by FACS, this protocol requires a fluorescent readout, such as the expression of a fluorescent reporter protein. Measuring the average fluorescent signals of microcolonies reduces the influence of high phenotypic cell-to-cell variability and increases the sensitivity compared to the sorting of single cells. We applied this method to sort a pBAD promoter library at ON and OFF states (Duarte et al., 2017). PMID- 30023412 TI - An enlarging subcutaneous nodule on the hand. PMID- 30023413 TI - Reticular rash on the lower extremities. PMID- 30023410 TI - The Brain-Gut-Microbiome Axis. AB - Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases. PMID- 30023414 TI - Flesh-colored papules and nodules on the face. PMID- 30023411 TI - Host-Gut Microbiota Crosstalk in Intestinal Adaptation. AB - Short-bowel syndrome represents the most common cause of intestinal failure and occurs when the remaining intestine cannot support fluid and nutrient needs to sustain adequate physiology and development without the use of supplemental parenteral nutrition. After intestinal loss or damage, the remnant bowel undergoes multifactorial compensatory processes, termed adaptation, which are largely driven by intraluminal nutrient exposure. Previous studies have provided insight into the biological processes and mediators after resection, however, there still remains a gap in the knowledge of more comprehensive mechanisms that drive the adaptive responses in these patients. Recent data support the microbiota as a key mediator of gut homeostasis and a potential driver of metabolism and immunomodulation after intestinal loss. In this review, we summarize the emerging ideas related to host-microbiota interactions in the intestinal adaptation processes. PMID- 30023415 TI - Simultaneous improvement of alopecia universalis and atopic dermatitis in a patient treated with a JAK inhibitor. PMID- 30023416 TI - Pustular tinea manuum from Trichophyton erinacei infection. PMID- 30023417 TI - Oral lichenoid reaction in a psoriatic patient treated with secukinumab: A drug related rather than a class-related adverse event? PMID- 30023418 TI - Ivermectin-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. PMID- 30023419 TI - Pancreatic panniculitis as the initial presentation of intrahepatic cholangiocarcinoma. PMID- 30023420 TI - Serous borderline tumor with micropapillary pattern of the right ovary that developed 6 recurrences over 30 years after primary surgery. AB - Serous borderline tumors (SBTs) are nonaggressive and have excellent prognosis. Furthermore, SBTs with micropapillary pattern (SBT-MP) are known to be associated with a higher recurrence rate, microinvasions and invasive implants compared to typical SBTs, and these characteristics have adverse effects on prognosis. Here, we report a case of SBT with micropapillary pattern (SBT-MP) that developed 6 recurrences over 30 years after primary surgery. The patient was a 70 year-old woman. At 41 years of the age she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy and pelvic lymphadenectomy and was found to have an SBT-MP involving the right ovary (International Federation of Gynecology and Obstetrics 2014, stage IC2). She was administered chemotherapy (cyclophosphamide, adriamicin, and cisplatin). She repeatedly developed recurrences 6 times after primary surgery. A left inguinal recurrence at age 55, a right inguinal recurrence at age 56, a right inguinal recurrence at age 64, an umbilical recurrence at age 65, a right inguinal recurrence at age 68 and left axillary recurrence at age 70. Histopathological examinations revealed that all recurrences were SBT-MP with noninvasive implants. Our case strongly justifies the belief that recurrent SBTs carry an excellent prognosis unless they develop significant malignant transformation. PMID- 30023421 TI - Cervical cancer in women over 65: An analysis of screening. AB - Objective: Evaluate the characteristics and screening history of patients diagnosed with cervical cancer over age 65. Methods: A retrospective review of 34 patients who were diagnosed with cervical cancer after the age of 65 at a single community cancer center between 2006 and 2016 was performed. Data collected included screening history, method of detection, stage, and survival. Results: Between 2006 and 2016, 346 women were diagnosed with cervical cancer at a single community cancer center, 34 (9.8%) of them were over 65 years old. 30 had known screening histories and could be evaluated. 15 women had adequate screening prior to being diagnosed with cervical cancer, indicating that 50% of women who developed cervical cancer after age 65 in this population followed screening guidelines and still developed disease. Conclusions: Women over 65 make up a significant portion of women diagnosed with cervical cancer. As many as half of all cervical cancers over age 65 occur in women who get recommended screening, and some of these may be prevented or detected early if screening was extended beyond age 65. PMID- 30023422 TI - How Acne Bumps Cause the Blues: The Influence of Acne Vulgaris on Self-Esteem. AB - Acne vulgaris is one of the most common dermatologic complaints. Although dermatologists are skilled at treating acne, invisible psychological scars can be left by the disease. We review 13 articles that examined the effect of acne vulgaris on patients' self-esteem. Overall, these studies demonstrated that acne has a negative effect on self-esteem among patients of all age groups. These effects most strongly affect women and those with severe acne (both subjectively and objectively). Despite the impact on self-esteem, only a minority of patients seek medical treatment, and even fewer seek treatment from a dermatologist. As dermatologists, we are trained in managing acne. We can provide early and effective treatment that improves both the physical and psychological effects. It is up to us to bridge the gap between those suffering from acne and their access to medical treatment. PMID- 30023423 TI - Quality of life and sexual health in patients with hidradenitis suppurativa. AB - Background: Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating follicular disease. The effect of HS on physical and psychological aspects of sexual function is not well understood. Objective: The objective of this study is to investigate the contribution of sexual dysfunction to the quality of life (QoL) of patients with HS and to investigate the extent to which sexual health predicts the QoL in these patients. Methods: This is an observational cross sectional study of 50 patients with HS and 50 healthy volunteers who completed questionnaires to measure QoL and sexual functioning using four validated tools. Results: Male patients experienced higher sexual dysfunction and a reduced quality of sexual life, while female patients reported higher sexual distress, compared with control groups. In male patients, sexual QoL and erectile dysfunction predicted a 72% decline in QoL. In female patients, sexual distress and sexual dysfunction predicted 46% variability in QoL index scores, beyond the effects of disease severity. Conclusion: Disruptions to sexual functioning greatly contribute to QoL impairments in patients with HS regardless of genital lesions. Health care professionals should inquire about and pay close attention to sexual health concerns in patients with HS. PMID- 30023424 TI - Video education to improve recognition of common benign and malignant cutaneous lesions and skin cancer prevention in the public. AB - Objective: Although dermatologists strive to provide patient education on sun protection and skin cancer, approximately 90% of Americans have limited health literacy skills. Little has been written about the means to best teach all levels of learners to recognize common benign and malignant skin lesions. Earlier work found that with advancing age, adults were less able to identify concerning lesions, thus underscoring the need for accessible education. Methods: We showed subjects a brief video (7th grade level) about common cutaneous growths, reducing the risk of skin cancer, and the importance of early detection. Subjects were asked about their skin cancer history, educational format preference, and the perceived impact of the video. Comprehension of symptoms of skin cancer and the benefits of sunscreen use and the ability to identify a melanoma, nevus, angioma, and seborrheic keratosis were also assessed. Results: Of the 156 subjects, mean age 52.7 years (range, 18-88 years), 31% had a history of skin cancer. A total of 98.7% found the video to be helpful; 92% preferred having a video as part of their teaching versus 9% who preferred written materials alone, 99% knew that a new or changing lesion could signal skin cancer, and 100% correctly answered that wearing sunscreen is protective. Subjects correctly identified lesions as melanoma (99%), benign mole (97%), angiomas (96%), and seborrheic keratosis (91%). There was a nominal trend toward higher scores in people who preferred video learning, had no history of skin cancer, and were older than 60 years of age. Conclusion: In this study, we found that a brief, plain-language video was effective at conveying understandable content to help subjects learn to identify common cancerous and benign skin growths while also teaching them strategies to protect against skin cancer. PMID- 30023425 TI - "I wanted a skeleton ... they brought a prince": A qualitative investigation of factors mediating the implementation of a Performance Based Incentive program in Malawi. AB - While several evaluations have examined the extent to which performance based financing (PBF) programs induce changes in the quantity and quality of health services provided, less is known about the process of implementing PBF. We conducted a process evaluation of a PBF intervention in Malawi that focused on understanding moderators of program implementation. Informed by a seminal theory of implementation, we first created a timeline and taxonomy of key events in the program lifeline and then undertook 25 in-depth interviews with stakeholders including implementers, central-level ministry officials and district-level health staff. While seven "moderator categories" emerged in this study, two categories (program complexity and quality of delivery) proved especially crucial in terms of moderating implementation and sparking adaptations. Complexity refers primarily to the manner in which PBF requires that those implementing the program have business acumen and forecasting skills, which are often beyond the purview of a clinician's training and thus proved challenging. Regarding quality of delivery, the program struggled to issue rewards in a timely and adequate manner, which proved highly problematic as it undermined a bedrock feature of PBF. Adaptations and adaptability refers here to a program's ability to make changes; the program proved rigid in several respects although nimble in terms of adjusting the verification process (upon noticing revengeful behaviors in peer verification). This PBF program is unique in several respects and findings cannot be generalized to all PBF programs. Nevertheless, process evaluations that draw from or expand upon existing implementation theories can allow researchers to better disentangle complex programming. We hope that more process evaluations, which track both core elements and necessary adaptations of PBF implementation, can further advance understandings of why PBF implementation functions or fails within a given setting, thereby enhancing implementers' abilities to replicate facilitators and bypass barriers. PMID- 30023426 TI - Spatial Sufficiency of 5% Medicare Standard Analytic Files. AB - The 5% Medicare Standard Analytic Files (SAF) are random samples used to analyze national trends in medical treatments, expenditures, and outcomes. Their utility in small-area or multilevel analyses is unknown. To demonstrate possible limitations of the 5% SAF for analysis of health behaviors in small areas. We use descriptive Chi-square goodness-of-fit tests and mapping to explore consistency in the 5% representation of the 100% population in states and counties. We conduct multilevel modeling of individual utilization of mammography or endoscopy services for cancer screening and contrast findings across the 5% and 100% files. Subjects are enrolled in both parts A and B Medicare coverage and ages 65-104, alive and residing in the same state, with no gaps in coverage during the study period. Identically defined groups are drawn from the 5% SAF and 100% population claims and denominator files. The Chi-square tests of homogeneous population subgroups in 5% and 100% files exhibit significant differences in 7 of 8 states. Maps confirm this among states' counties and find that one state is generally under-represented by the 5% SAF, while others show areas with variable representation. Multilevel modeling results are largely consistent across the partitions of the data, but 5% sample models have much lower statistical power. Area-level covariate effect estimates show some differences across the two datasets. Multilevel modeling with contextual variables may be misleading in small area analyses conducted using 5% Medicare SAFs. Provider supply and market characteristics show inconsistent results. Disparities research may benefit from 100% files to provide statistical power needed to detect meaningful differences. This is significant because the Centers for Medicare and Medicaid Services have recently curtailed permissions to use the 100% files. These 100% files are one of few sources of population data available in the U.S. that are representative of small areas in the U.S.. In times of constrained budgets, using population data files is essential so that resources can be targeted to areas robustly identified as having greatest need or gaps in outcomes. PMID- 30023427 TI - Human Motor Thalamus Reconstructed in 3D from Continuous Sagittal Sections with Identified Subcortical Afferent Territories. AB - Classification and delineation of the motor-related nuclei in the human thalamus have been the focus of numerous discussions for a long time. Difficulties in finding consensus have for the most part been caused by paucity of direct experimental data on connections of individual nuclear entities. Kultas-Ilinsky et al. (2011) showed that distribution of glutamic acid decarboxylase isoform 65 (GAD65), the enzyme that synthesizes inhibitory neurotransmitter gamma aminobutyric acid, is a reliable marker that allows to delineate connectionally distinct nuclei in the human motor thalamus, namely the territories innervated by nigral, pallidal, and cerebellar afferents. We compared those immunocytochemical staining patterns with underlying cytoarchitecture and used the latter to outline the three afferent territories in a continuous series of sagittal Nissl-stained sections of the human thalamus. The 3D volume reconstructed from the outlines was placed in the Talairach stereotactic coordinate system relative to the intercommissural line and sectioned in three stereotactic planes to produce color coded nuclear maps. This 3D coordinate-based atlas was coregistered to the Montreal Neurological Institute (MNI-152) space. The current report proposes a simplified nomenclature of the motor-related thalamic nuclei, presents images of selected histological sections and stereotactic maps illustrating topographic relationships of these nuclei as well as their relationship with adjacent somatosensory afferent region. The data are useful in different applications such as functional MRI and diffusion tractography. The 3D dataset is publicly available under an open license and can also be applicable in clinical interventions in the thalamus. PMID- 30023428 TI - Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Deltaex7 /- Mice. AB - Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Deltaex7-/- mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Deltaex6-7-/- mice. Minimal stimulation experiments reveal that Shank2 Deltaex7-/ mice possess an excessive fraction of silent (i.e., alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Deltaex6-7-/- mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs. PMID- 30023430 TI - Correction to: Case Report: Laparoscopic Approach for Orchiopexy in a 26-Year-Old Man with Accidently Discovered Persistent Mullerian Duct Syndrome and Bilateral Undescended Testis by Noureldin ME, Tawfeek AM, and Shaker HS. J Endourol Case Rep 2018;4:75-77. DOI: 10.1089/cren.2018.0035. AB - [This corrects the article DOI: 10.1089/cren.2018.0035.]. PMID- 30023429 TI - Impact of Daylight Saving Time on the Clinical Laboratory. AB - Daylight saving time is a practice in some countries and local regions to set clocks forward (typically 1 hour) during the longer days of summer and back again in autumn. Time changes resulting from daylight saving time have the potential to impact clinical laboratory instruments, computer interfaces, and information systems. We analyzed turnaround time data for an academic medical center clinical laboratories (chemistry, hematology, blood gas analyzer, and transfusion medicine), examining how turnaround time was impacted by the daylight saving time shifts in 2017. We also determined whether the daylight saving time shift on November 5, 2017 ("fall back" by 1 hour) resulted in any "absurd" time combinations such as a receipt time occurring "before" a normally later time such as final result. We also describe challenges resulting from daylight saving time changes over a 5-year period. The only significant impact on turnaround time was for clinical chemistry samples during the autumn daylight saving time change, but the overall impact was low. Four instances of absurd time combinations occurred in the autumn time change with only a transfusion medicine example resulting in an interface error (a Type and Screen resulted "before" receipt in laboratory). Over a 5-year period, other daylight saving time impacts included problems of reestablishing interface to instruments, inadvertent discrepancies in manual time changes at different points of the core laboratory automation line, and time change errors in instruments with older operating systems lacking patches that updated daylight saving time rules after 2007. Clinical laboratories should be aware that rare problems may occur due to issues with daylight saving time changes. PMID- 30023431 TI - Developing Trans-Affirming Health Services in an Underserved Area: An Intersectional Approach. AB - Purpose: Gender-nonconforming patients are at higher risk for medical problems that require prompt medical and mental health intervention. Barriers to healthcare for transgender individuals have been well characterized in the literature, but not in low resource settings. The purpose of this paper is to present the barriers encountered when bringing healthcare to transgender children, adolescents, and adults in a medically underserved, predominantly Hispanic area of the United States. Methods: In this medically underserved area on the U.S.-Mexico border, there is a severe shortage of medical expertise for transgender individuals at both the primary- and specialty-care levels. Further, given the mainly Hispanic population, there is an additional culturally based barrier to obtaining medical care for transgender patients. Results: It is important for academic centers in these regions to collaborate to overcome these barriers through a multidisciplinary approach that includes providing education for medical students and physicians in training and identifying medical providers who are able and willing to provide transgender-competent care adapted to local culture and gender norms. Conclusion: In this manuscript, we will describe the efforts of various groups to address the needs of the transgender community in the region. PMID- 30023432 TI - Alternative payment models: can (should) trauma care be bundled? AB - Background: Recent legislation repealing the Sustainable Growth Rate mandates gradual replacement of fee for service with alternative payment models (APMs), which will include service bundling. We analyzed the 2 years' experience at our state-designated level I trauma center to determine the feasibility of such an approach for trauma care. Methods: De-identified data from all injured patients treated by the trauma service during 2014 and 2015 were reviewed to determine individual patient injury profiles. Using these injury profiles we created the 'trauma bundle' by concatenating the highest Abbreviated Injury Scale score for each of the six body regions to produce a single 'signature' of injury by region for every patient. These trauma bundles were analyzed by frequency over 2 years and by each year. The impacts of physiology and resource consumption were evaluated by determination of the correlation of the mean and SD of calculated survival probability (Ps) and intensive care unit length of stay (ICU LOS) for each profile group occurring more than 12 times in 2 years. Results: The 5813 patients treated over 2 years produced 858 distinct injury profiles, only 8% (71) of which occurred more than 12 times in 2 years. Comparison of 2014 and 2015 profiles demonstrated high frequency variation among profiles between the 2 years. Analysis of injury patterns occurring >12 times in 2 years demonstrated an inverse correlation between the mean and SD for Ps (R2=0.68) and a direct correlation for ICU LOS (R2=0.84). Discussion: These data indicate that the disease of injury is too inconsistent a mix of injury pattern and physiologic response to be predictably bundled for an APM. The inverse correlation of increasing SD with increasing ICU LOS and decreasing Ps suggests an opportunity for measurable process improvement. Level of evidence: Economic and value-based evaluations, level IV. Study type: Economic/decision. PMID- 30023434 TI - Elevated plasma levels of TIMP-3 are associated with a higher risk of acute respiratory distress syndrome and death following severe isolated traumatic brain injury. AB - Background: Complications after injury, such as acute respiratory distress syndrome (ARDS), are common after traumatic brain injury (TBI) and associated with poor clinical outcomes. The mechanisms driving non-neurologic organ dysfunction after TBI are not well understood. Tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) is a regulator of matrix metalloproteinase activity, inflammation, and vascular permeability, and hence has plausibility as a biomarker for the systemic response to TBI. Methods: In a retrospective study of 182 patients with severe isolated TBI, we measured TIMP-3 in plasma obtained on emergency department arrival. We used non-parametric tests and logistic regression analyses to test the association of TIMP-3 with the incidence of ARDS within 8 days of admission and in-hospital mortality. Results: TIMP-3 was significantly higher among subjects who developed ARDS compared with those who did not (median 2810 pg/mL vs. 2260 pg/mL, p=0.008), and significantly higher among subjects who died than among those who survived to discharge (median 2960 pg/mL vs. 2080 pg/mL, p<0.001). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of ARDS increased significantly, OR 1.5 (95% CI 1.1 to 2.1). This association was only attenuated in multivariate models, OR 1.4 (95% CI 1.0 to 2.0). In an unadjusted logistic regression model, for each SD increase in plasma TIMP-3, the odds of death increased significantly, OR 1.7 (95% CI 1.2 to 2.3). The magnitude of this association was greater in a multivariate model adjusted for markers of injury severity, OR 1.9 (95% CI 1.2 to 2.8). Discussion: TIMP-3 may play an important role in the biology of the systemic response to brain injury in humans. Along with clinical and demographic data, early measurements of plasma biomarkers such as TIMP-3 may help identify patients at higher risk of ARDS and death after severe isolated TBI. Level of evidence: III. PMID- 30023433 TI - Primary prevention of contact sports-related concussions in amateur athletes: a systematic review from the Eastern Association for the Surgery of Trauma. AB - Background: Awareness of the magnitude of contact sports-related concussions has risen exponentially in recent years. Our objective is to conduct a prospectively registered systematic review of the scientific evidence regarding interventions to prevent contact sports-related concussions. Methods: Using the Grading of Recommendations Assessment, Development, and Evaluation methodology, we performed a systematic review of the literature to answer seven population, intervention, comparator, and outcomes (PICO) questions regarding concussion education, head protective equipment, rules prohibiting high-risk activity and neck strengthening exercise for prevention of contact sports-related concussion in pediatric and adult amateur athletes. A query of MEDLINE, PubMed, Scopus, Cumulative Index of Nursing and Allied Health Literature, and Embase was performed. Letters to the editor, case reports, book chapters, and review articles were excluded, and all articles reviewed were written in English. Results: Thirty-one studies met the inclusion criteria and were applicable to our PICO questions. Conditional recommendations are made supporting preventive interventions concussion education and rules prohibiting high-risk activity for both pediatric and adult amateur athletes and neck strengthening exercise in adult amateur athletes. Strong recommendations are supported for head protective equipment in both pediatric and adult amateur athletes. Strong recommendations regarding newer football helmet technology in adult amateur athletes and rules governing the implementation of body-checking in youth ice hockey are supported. Conclusion: Despite increasing scientific attention to sports-related concussion, studies evaluating preventive interventions remain relatively sparse. This systematic review serves as a call to focus research on primary prevention strategies for sports-related concussion. Level of evidence: IV. PROSPERO registration number: #42016043019. PMID- 30023435 TI - Bilateral distal ureteral transection in the setting of blunt trauma. AB - : A 69-year-old obese man was involved in a high-speed head-on motor vehicle collision. He was tachycardic and normotensive on arrival. He subsequently developed hemodynamic instability requiring blood transfusion. On examination he had bilateral pneumothoraces, an anterior-posterior compression (APC) pelvic fracture, an open wound at the left groin, and gross hematuria after Foley catheter placement.CT imaging revealed hemoperitoneum, right hepatic lobe grade II lacerations, splenic laceration, mesenteric root injury with extravasated contrast, intraperitoneal and extraperitoneal bladder rupture, bilateral ureteral injuries at the level of the pelvic inlet (see figure 1), APC pelvic fracture, bilateral rib fractures, pneumothoraces, and pulmonary contusions.Figure 1CT of the abdomen and pelvis with cystogram. Delayed images demonstrating accumulation of contrast in the retroperitoneum arising from the right and left ureter at the level of the pelvic brim. Extraluminal contrast from the intraperitoneal bladder injury is also identified.He underwent emergent exploratory laparotomy. Exploration confirmed the injuries noted on the CT scan. Hepatorrhaphy with abdominal and preperitoneal pelvic packing was performed. A large anterior bladder wall injury was visualized. Neither ureteral orifice was seen. The right ureter was completely transected at the level of the pelvic brim. The left ureter was decompressed and the full extent of its injury was not determined; however, the bladder injury left concern for a distal avulsion. The patient continued to be in shock. What would you do?: Reconstruct the urinary bladder and reimplant bilateral ureters.Ligate the ureter and prepare for pelvic embolization and nephrostomy tubes.Continue to explore looking for the full extent of the left ureter.Externalize the ureters to the abdominal wall with the open abdomen. PMID- 30023436 TI - Blunt rupture of the thoracic duct after severe thoracic trauma. AB - : A 53-year-old man was admitted to our trauma center after sustaining thoracoabdominal injuries, secondary to a rear-end motor vehicle collision. As he stepped out of his vehicle, he was struck by a tractor trailer at 55 mph. The following were the initial vital signs on his arrival: heart rate 140 beats/min, blood pressure 142/80 mm Hg, respiratory rate 28 breaths/min, temperature 36.8 degrees C, and oxygen saturation 93%. The Glasgow Coma Scale score was 15 and the Injury Severity Score was 59. He was evaluated and resuscitated per the advanced trauma life support protocols. The focused assessment with sonography for trauma examination was negative. Initial findings included bilateral chest wall and thoracic spine tenderness, subcutaneous emphysema in the chest and neck, and an unstable pelvis. He required bilateral chest tubes and a pelvic binder. CT imaging revealed a left temporal epidural hematoma, multiple facial fractures, a sternal fracture, a left scapula fracture, acromioclavicular fractures, bilateral hemopneumothoraces, pulmonary contusions, extensive pneumomediastinum compressing the right atrium, multiple rib fractures (2-10 on the left with a flail segment and 2-8 on the right) (figure 1), an unstable open-book pelvic fracture which included bilateral superior and inferior pubic rami fractures, sacral and left iliac wing fractures, and symphysis pubis diastasis.Figure 1Three-dimensional CT scan reconstruction demonstrating left-sided flail chest.The patient developed hypotension and severe respiratory distress, and was intubated. ECG revealed no dysrhythmias. Echocardiogram revealed significant left ventricular wall dysfunction consistent with myocardial contusion and right atrial compression. His troponins were also significantly elevated. He required significant resuscitation with crystalloids, blood products and vasopressors. He underwent bronchoscopy, esophagram and upper endoscopy to exclude tracheoesophageal injury, and these were negative. On hospital day 2, the patient was hemodynamically stable, and pressors were discontinued. His pelvic fractures were repaired using external fixation and sacral screws. Given his extensive left flail chest, he underwent reconstruction of his left chest wall on hospital day 5. Open reduction and internal fixation of his left ribs, 3 to 6 anteriorly and 4 to 7 posteriorly, with titanium plates was performed (figure 2). He had an epidural catheter inserted for analgesia. On postoperative day 2 after chest wall reconstruction, the patient was extubated and resumed enteral feeds. Overnight, the output from the left-sided chest tube changed from serosanguinous to milky. A sample was sent for triglycerides and lymphocyte counts confirming the diagnosis of chylothorax. His chest tube output increased to approximately 2000 mL/day. A lymphangiogram was performed with Lipiodol to diagnose the location of the chylous leak. It revealed contrast extravasation at the level of T3 to T4. An MRI was also performed to better define the anatomic course of the thoracic duct.Figure 2Postoperative chest X-ray demonstrating left chest wall reconstruction. What would you do?: Conservative management: placing the patient nulla per os (NPO), and starting total parenteral nutrition (TPN), octreotide and midodrine.Thoracic duct embolization by interventional radiology.CT-guided thoracic duct disruption.Thoracotomy with thoracic duct ligation. PMID- 30023437 TI - Launch of the National Trauma Research Repository coincides with new data sharing requirements. PMID- 30023439 TI - In vitro interactions of histones and alpha-crystallin. AB - The aggregation of crystallins in lenses is associated with cataract formation. We previously reported that mutant crystallins are associated with an increased abundance of histones in knock-in and knockout mouse models. However, very little is known about the specific interactions between lens crystallins and histones. Here, we performed in vitro analyses to determine whether alpha-crystallin interacts with histones directly. Isothermal titration calorimetry revealed a strong histone-alpha-crystallin binding with a Kd of 4 * 10-7 M, and the thermodynamic parameters suggested that the interaction was both entropy and enthalpy driven. Size-exclusion chromatography further showed that histone-alpha crystallin complexes are water soluble but become water insoluble as the concentration of histones is increased. Right-angle light scattering measurements of the water-soluble fractions of histone-alpha-crystallin mixtures showed a decrease in the oligomeric molecular weight of alpha-crystallin, indicating that histones alter the oligomerization of alpha-crystallin. Taken together, these findings reveal for the first time that histones interact with and affect the solubility and aggregation of alpha-crystallin, indicating that the interaction between alpha-crystallin and histones in the lens is functionally important. PMID- 30023438 TI - Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251. AB - The chemically synthesized endoperoxide compound N-89 and its derivative N-251 were shown to have potent antimalarial activity. We previously demonstrated that N-89 and N-251 potently inhibited the RNA replication of hepatitis C virus (HCV), which belongs to the Flaviviridae family. Since antimalarial and anti-HCV mechanisms have not been clarified, we were interested whether N-89 and N-251 possessed the activity against viruses other than HCV. In this study, we examined the effects of N-89 and N-251 on other flaviviruses (dengue virus and Japanese encephalitis virus) and hepatitis viruses (hepatitis B virus and hepatitis E virus). Our findings revealed that N-89 and N-251 moderately inhibited the RNA replication of Japanese encephalitis virus and hepatitis E virus, although we could not detect those anti-dengue virus activities. We also observed that N-89 and N-251 moderately inhibited the replication of hepatitis B virus at the step after viral translation. These results suggest the possibility that N-89 and N 251 act on some common host factor(s) that are necessary for viral replications, rather than the possibility that N-89 and N-251 directly act on the viral proteins except for HCV. We describe a new type of antiviral reagents, N-89 and N 251, which are applicable to multiple different viruses. PMID- 30023441 TI - StaySafe: A self-administered android tablet application for helping individuals on probation make better decisions pertaining to health risk behaviors. AB - This paper describes the development and protocol for feasibility and efficacy testing of a risk reduction intervention designed to improve behavioral health outcomes among drug offenders on probation under community supervision or in residential substance abuse treatment centers. StaySafe is a self-administered tablet-based intervention for teaching better decision-making skills regarding health risk behaviors, especially those involving HIV risks. We are using pre/post, experimental/control group randomized clinical trial (RCT) in both community and residential probation settings with goals to 1) assess the feasibility and acceptance of StaySafe by examining participation rates and satisfaction measures, and 2) examine the impact of StaySafe on decision-making skills, confidence and motivation to avoid sex and drug risks, willingness to discuss health risks and concerns with helpful others, and engagement in health risk behaviors. StaySafe consists of 12 brief sessions and utilizes an evidence based decision-making schema, called WORKIT, which guides participants through steps for identifying the problem and options, evaluating the options and making a decision about which option to carry out. Multiple sessions of StaySafe provide a practice effect so that the WORKIT steps become easily accessible to participants when making decisions. Three of the sessions provide participants a choice of activities designed to provide additional information about HIV and reinforce lessons learned during the WORKIT sessions. Preliminary data demonstrate feasibility and high levels of satisfaction with StaySafe. PMID- 30023440 TI - Herbal fertility treatments used in North America from colonial times to 1900, and their potential for improving the success rate of assisted reproductive technology. AB - This paper serves to fill a gap in the literature regarding evidence for the use of botanical remedies in the promotion of fertility. It examines the botanical remedies that were used in North America (1492-1900) for all stages of reproduction from preconception to birth, and discusses their potential for future use with present-day infertility treatments. Each medicinal plant discussed in this paper is assessed using an ethnomedicinal methodology that entails examining the published ethnobotanical, phytochemical and pharmacological data. A few clinical trials have shown that there is potential for medicinal plants to improve the success rate of assisted reproductive technology (ART) treatment if used in an integrated manner, similar to the integrated use of traditional Chinese medicine with ART treatment. For example, research has shown that older women who become pregnant have a high miscarriage rate, and this is one area that complementary and alternative medicines can address. PMID- 30023442 TI - Outpatient versus inpatient mixed meal tolerance and arginine stimulation testing yields comparable measures of variability for assessment of beta cell function. AB - : Standard practice to minimize variability in beta cell function (BCF) measurement is to test in inpatient (IP) settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP) testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in two separate type 2 diabetes (T2DM) cohorts (OP, n = 20; IP n = 22) in test-retest design. MMTT variables included: insulin sensitivity (Si); beta cell responsivity (Phitot); and disposition index (DItot = Si* Phitot) following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg) and during hyperglycemia (AIRargMAX). Results: Baseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility) across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort. [Table: see text] In conclusion, the variability (reproducibility) of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies. PMID- 30023443 TI - Recruitment practices for U.S. minority and underserved populations in NRG oncology: Results of an online survey. AB - Introduction: Cancer clinical trials (CCT) provide much of the evidence for clinical guidelines and standards of care. But low levels of CCT participation are well documented, especially for minorities. Methods and materials: We conducted an online survey of 556 recruitment practices across the NRG Oncology network. Survey aims were 1) to learn how sites recruit minority/underserved populations; 2) to better understand the catchment areas of the NRG institutions; and 3) to aid in planning education programs for accrual of minority/underserved populations. Results: The survey response rate was 34.9%. The most effective methods reported for recruiting minority/underserved participants were patient navigators (44.4%) and translators (38.9%). All institutions reported using a mechanism for eligibility screening and 71% of institutions reported using a screening/enrollment tracking system. CCT training was required at 78.1% and cultural competency training was required at 47.5% of responding institutions. Only 19.9% of sites used community partners to assist with minority recruitment and just 37.1% of respondents reported a defined catchment area. Sites reported very little race and ethnicity data. Conclusion: This NRG Oncology online survey provides useful data for improvements in trial enrollment and training to recruit minority/underserved populations to CCT. Areas for further investigation include web-based methods for recruitment and tracking, cultural competency training, definition of catchment areas, use of patient navigators, and community partnerships. The survey results will guide recruitment training programs. PMID- 30023444 TI - Implementing a STEMI system of care in urban Bangalore: Rationale and Study Design for heart rescue India. AB - Background: A system of care designed to measure and improve process measures such as symptom recognition, emergency response, and hospital care has the potential to reduce mortality and improve quality of life for patients with ST elevation myocardial infarction (STEMI). Objective: To document the methodology and rationale for the implementation and impact measurement of the Heart Rescue India project on STEMI morbidity and mortality in Bangalore, India. Study Design: A hub and spoke STEMI system of care comprised of two interventional, hub hospitals and five spoke hospitals will build and deploy a dedicated emergency response and transport system covering a 10 Km. radius area of Bangalore, India. High risk patients will receive a dedicated emergency response number to call for symptoms of heart attack. A dedicated operations center will use geo-tracking strategies to optimize response times including first responder motor scooter transport, equipped with ECG machines to transmit ECG's for immediate interpretation and optimal triage. At the same time, a dedicated ambulance will be deployed for transport of appropriate STEMI patients to a hub hospital while non-STEMI patients will be transported to spoke hospitals. To enhance patient recognition and initiation of therapy, school children will be trained in basic CPR and signs and symptom of chest pain. Hub hospitals will refine their emergency department and cardiac catheterization laboratory protocols using continuous quality improvement techniques to minimize treatment delays. Prior to hospital discharge, secondary prevention measures will be initiated to enhance long-term patient outcomes. PMID- 30023445 TI - Comparative effectiveness of family problem-solving therapy (F-PST) for adolescents after traumatic brain injury: Protocol for a randomized, multicenter, clinical trial. AB - Introduction: The objective of this manuscript is to describe the methodology that will be used to test the comparative effectiveness, feasibility, and acceptability of three formats of family problem solving therapy (F-PST) for improving functional outcomes of complicated mild to severe adolescent TBI. Methods: Three-arm comparative effectiveness, randomized clinical trial (RCT) design. We describe the protocol of a three-arm RCT comparing the effectiveness of three modalities of F-PST to reduce executive dysfunction and behavior problems following TBI in adolescence. The RCT will compare the relative effectiveness among face-to-face; online and self-directed; and therapist supported online modes of treatment. Ethics and dissemination: It is anticipated that findings from this work will inform future clinical care practices, with implications for treatment of other patient populations of youth with psychological symptoms arising from neurological conditions. Institutional review board approval will be obtained from all sites prior to commencement of the study. PMID- 30023447 TI - Evaluating the effectiveness and reliability of the Vibrant Soundbridge and Bonebridge auditory implants in clinical practice: Study design and methods for a multi-centre longitudinal observational study. AB - Background: The Vibrant Soundbridge middle ear implant and the Bonebridge bone conducting hearing device are hearing implants that use radio frequency transmission to send information from the sound processor to the internal transducer. This reduces the risk of skin problems and infection but requires a more involved surgical procedure than competitor skin penetrating devices. It is not known whether more complex surgery will lead to additional complications. There is little information available on the reliability of these systems and adverse medical or surgical events. The primary research question is to determine the reliability and complication rate for the Vibrant Soundbridge and Bonebridge. The secondary research question explores changes in quality of life following implantation of the devices. The tertiary research question looks at effectiveness via changes in auditory performance. Method: The study was designed based on a combination of a literature search, two clinician focus groups and expert review.A multi-centre longitudinal observational study was designed. There are three study groups, two will have been implanted prior to the start of the study and one group, the prospective group, will be implanted after initiation of the study. Outcomes are surgical questionnaires, measures of quality of life, user satisfaction and speech perception tests in quiet and in noise. Conclusion: This is the first multi-centre study to look at these interventions and includes follow up over time to understand effectiveness, reliability, quality of life and complications. PMID- 30023446 TI - Patient profiling for success after weight loss surgery (GO Bypass study): An interdisciplinary study protocol. AB - : Despite substantial research efforts, the mechanisms proposed to explain weight loss after gastric bypass (RYGB) and sleeve gastrectomy (SL) do not explain the large individual variation seen after these treatments. A complex set of factors are involved in the onset and development of obesity and these may also be relevant for the understanding of why success with treatments vary considerably between individuals. This calls for explanatory models that take into account not only biological determinants but also behavioral, affective and contextual factors. In this prospective study, we recruited 47 women and 8 men, aged 25-56 years old, with a BMI of 45.8 +/- 7.1 kg/m2 from the waiting list for RYGB and SL at Koge hospital, Denmark. Pre-surgery and 1.5, 6 and 18 months after surgery we assessed various endpoints spanning multiple domains. Endpoints were selected on basis of previous studies and include: physiological measures: anthropometrics, vital signs, biochemical measures and appetite hormones, genetics, gut microbiota, appetite sensation, food and taste preferences, neural sensitivity, sensory perception and movement behaviors; psychological measures: general psychiatric symptom-load, depression, eating disorders, ADHD, personality disorder, impulsivity, emotion regulation, attachment pattern, general self efficacy, alexithymia, internalization of weight bias, addiction, quality of life and trauma; and sociological and anthropological measures: sociodemographic measures, eating behavior, weight control practices and psycho-social factors.Joining these many endpoints and methodologies from different scientific disciplines and creating a multi-dimensional predictive model has not previously been attempted. Data on the primary endpoint are expected to be published in 2018. Trial registration: Clinicaltrials. gov ID NCT02070081. PMID- 30023448 TI - An integrative shrinkage estimator for random-effects meta-analysis of rare binary events. AB - Meta-analysis has been a powerful tool for inferring the treatment effect between two experimental conditions from multiple studies of rare binary events. Recently, under a random-effects (RE) model, Bhaumik et al. developed a simple average (SA) estimator and showed that with the continuity correction factor 0.5, the SA estimator was the least biased among a set of commonly used estimators. In this paper, under various RE models that allow for treatment groups with equal and unequal variability (in either direction), we develop an integrative shrinkage (iSHRI) estimator based on the SA estimator, which aims to improve estimation efficiency in terms of mean squared error (MSE) that accounts for the bias-variance tradeoff. Through simulation, we find that iSHRI has better performance in general when compared with existing methods, in terms of bias, MSE, type I error and confidence interval coverage. Data examples of rosiglitazone meta-analysis are provided as well, where iSHRI yields competitive results. PMID- 30023449 TI - Metabolic and functional changes in transgender individuals following cross-sex hormone treatment: Design and methods of the GEnder Dysphoria Treatment in Sweden (GETS) study. AB - Background: Although the divergent male and female differentiation depends on key genes, many biological differences seen in men and women are driven by relative differences in estrogen and testosterone levels. Gender dysphoria denotes the distress that gender incongruence with the assigned sex at birth may cause. Gender-affirming treatment includes medical intervention such as inhibition of endogenous sex hormones and subsequent replacement with cross-sex hormones. The aim of this study is to investigate consequences of an altered sex hormone profile on different tissues and metabolic risk factors. By studying subjects undergoing gender-affirming medical intervention with sex hormones, we have the unique opportunity to distinguish between genetic and hormonal effects. Methods: The study is a single center observational cohort study conducted in Stockholm, Sweden. The subjects are examined at four time points; before initiation of treatment, after endogenous sex hormone inhibition, and three and eleven months following sex hormone treatment. Examinations include blood samples, skeletal muscle-, adipose- and skin tissue biopsies, arteriography, echocardiography, carotid Doppler examination, whole body MRI, CT of muscle and measurements of muscle strength. Results: The primary outcome measure is transcriptomic and epigenomic changes in skeletal muscle. Secondary outcome measures include transcriptomic and epigenomic changes associated with metabolism in adipose and skin, muscle strength, fat cell size and ability to release fatty acids from adipose tissue, cardiovascular function, and body composition. Conclusions: This study will provide novel information on the role of sex hormone treatment in skeletal muscle, adipose and skin, and its relation to cardiovascular and metabolic disease. PMID- 30023450 TI - Study design for a clinical trial to examine food price elasticity among participants in federal food assistance programs: A laboratory-based grocery store study. AB - We present a protocol for a study investigating the effect of food price changes on purchasing decisions among individuals participating in federal food assistance programs and among those not participating in these programs. We use a laboratory-based grocery store design, which provides greater control over factors influencing food purchasing than in situ experiments in actual grocery stores. We focus primarily, but not exclusively, on eggs because they are highly nutritious, easy to prepare, can be included in many different dishes, and are a part of a wide range of cultural food menus. The primary aim of this study is to compare the own-and cross-price elasticity of eggs between individuals participating in federal food assistance programs and those not participating in these programs. Our secondary aims are to 1) compare the own- and cross-price elasticity of eggs between overweight/obese individuals and non-overweight/obese individuals, 2) examine whether delay discounting moderates the effect of income on own- and cross-price elasticity, 3) examine whether subjective social status moderates the effect of participation in federal food assistance programs on the purchase of high nutrient-dense foods, and 4) examine whether usual psychological stress level moderates the effect of subjective social status on the purchase of high-nutrient dense foods. The results of this study will provide information about the drivers of food demand among low-income adults. A better understanding of these drivers is needed to develop effective nutrition interventions for this large population. PMID- 30023451 TI - Integrated psychological therapy for people with bipolar disorder and co-morbid alcohol use: A feasibility and acceptability randomised controlled trial. AB - Background: Co-morbid substance misuse, particularly alcohol, is common in bipolar disorder (BD) and associated with worse treatment outcomes. Research into psychological interventions for substance misuse in BD is at an early stage and no studies have specifically targeted problematic alcohol use. This paper describes the context and protocol for a feasibility and acceptability randomised controlled trial (RCT) evaluating a novel intervention combining motivational interviewing and cognitive behavioural therapy (MI-CBT) for participants with BD and problematic alcohol use, developed in collaboration with people with lived experience of both issues. Methods and design: An RCT will assess the feasibility and acceptability of MI-CBT in addition to treatment as usual (TAU) compared with TAU alone. Participants will be recruited from across the North West of England through NHS services and self-referral. The primary outcomes will be the feasibility and acceptability of the intervention assessed by recruitment to target, adherence to intervention, retention rate at follow-up, absence of adverse events and qualitative analysis of participants' reported experiences of intervention. The effect size of the impact of the intervention on alcohol use and mood outcomes will also be estimated. In addition, we will explore a number of potential process variables in therapy. Discussion: This is the first RCT evaluating MI-CBT for BD and problematic alcohol use. Given the prevalence and impact of alcohol problems in BD this novel integrated intervention may have potential to offer important improvements in clinical and functional outcomes. PMID- 30023452 TI - Does the Alexis wound retractor increase the risk of blood splashes to the eyes? Early closure of a double blinded randomised controlled trial. PMID- 30023453 TI - Is it time for the weighted log-rank test to play a more important role in confirmatory trials? PMID- 30023454 TI - Presenting information on dental risk: PREFER study protocol for a randomised controlled trial involving patients receiving a dental check-up. AB - Introduction: A new dental contract being tested in England places patients into traffic light categories according to risk (Red = High risk). This reflects health policy which emphasises patients' shared responsibility for their health, and a growing expectation that clinicians discuss health risk in consultations. Alongside this, there are technological developments such as scans and photographs which have generated new, vivid imagery which may be used to communicate risk information to patients. However, there is little evidence as to whether the form in which risk information is given is important. Methods: The PREFER study is a pragmatic, multi-centre, three-arm, patient-level randomised controlled trial, based in four NHS dental practices, from which 400 high/medium risk patients will be recruited. The study compares three ways of communicating risk information at dental check-ups: 1) verbal only (usual care); 2) a Traffic Light graphic with verbal explanation; 3) a Quantitative Light-Induced Fluorescence (QLF) photograph showing, for example, patches of red fluorescence where dental plaque has been present for two days or more (with a verbal explanation). The study assesses patient preferences using the economic preference-based valuation methodology Willingness-to-Pay (WTP). Any changes in oral self-care (for example in tooth-brushing), will be measured by self-report, and clinical outcome data collected by clinicians and extracted from QLF photographs. Predictors and moderators of any behaviour change will be explored using demographic characteristics and psychological variables from the Extended Parallel Process Model. A cost-benefit framework will explore the financial implications for NHS dentistry of the three risk presentation methods. PMID- 30023456 TI - Comparison of intent-to-treat analysis strategies for pre-post studies with loss to follow-up. AB - In pre-post studies when all outcomes are completely observed, previous studies have shown that analysis of covariance (ANCOVA) is more powerful than a change score analysis in testing the treatment effect. However, there have been few studies comparing power under missing post-test values. This paper was motivated by the Behavior and Exercise for Physical Health Intervention (BePHIT) Study, a pre-post study designed to compare two interventions on postmenopausal women's walk time. The goal of this study was to compare the power of two methods which adhere to the intent-to-treat (ITT) principle when post-test data are missing: ANCOVA after multiple imputation (MI) and the mixed model applied to all available data (AA). We also compared the two ITT analysis strategies to two methods which do not adhere to ITT principles: complete-case (CC) ANCOVA and the CC mixed model. Comparisons were made through analyses of the BePHIT data and simulation studies conducted under various sample sizes, missingness rates, and missingness scenarios. In the analysis of the BePHIT data, ANCOVA after MI had the smallest p-value for the test of the treatment effect of the four methods. Simulation results demonstrated that the AA mixed model was usually more powerful than ANCOVA after MI. The power of ANCOVA after MI dropped the fastest as the missingness rate increased; in most simulated scenarios, ANCOVA after MI had the smallest power when 50% of the post-test outcomes were missing. PMID- 30023455 TI - Exercise training as S-Klotho protein stimulator in sedentary healthy adults: Rationale, design, and methodology. AB - Aims: The secreted form of the alpha-Klotho gene (S-Klotho), which is considered a powerful biomarker of longevity, makes it an attractive target as an anti ageing therapy against functional decline, sarcopenic obesity, metabolic and cardiovascular diseases, osteoporosis, and neurodegenerative disorders. The S Klotho plasma levels could be related to physical exercise inasmuch physical exercise is involved in physiological pathways that regulate the S-Klotho plasma levels. FIT-AGEING will determine the effect of different training modalities on the S-Klotho plasma levels (primary outcome) in sedentary healthy adults. FIT AGEING will also investigate the physiological consequences of activating the klotho gene (secondary outcomes). Methods: FIT-AGEING will recruit 80 sedentary, healthy adults (50% women) aged 45-65 years old. Eligible participants will be randomly assigned to a non-exercise group, i.e. the control group, (n = 20), a physical activity recommendation from World Health Organization group (n = 20), a high intensity interval training group (n = 20), and a whole-body electromyostimulation group (n = 20). The laboratory measurements will be taken at the baseline and 12 weeks later including the S-Klotho plasma levels, physical fitness (cardiorespiratory fitness, muscular strength), body composition, basal metabolic rate, heart rate variability, maximal fat oxidation, health blood biomarkers, free-living physical activity, sleep habits, reaction time, cognitive variables, and health-related questionnaires. We will also obtain dietary habits data and cardiovascular disease risk factors. PMID- 30023457 TI - Development of a standardized definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. AB - Background: Bleeding is the major risk of aspirin treatment, especially in the elderly. A consensus definition for clinically significant bleeding (CSB) in aspirin primary prevention trials is lacking in the literature. Methods: This paper details the development, modification, application, and quality control of a definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial, a primary prevention trial of aspirin in 19,114 community-dwelling elderly men and women. In ASPREE a confirmed bleeding event needed to meet criteria both for substantiated bleeding and clinical significance. Substantiated bleeding was defined as: 1) observed bleeding, 2) a reasonable report of symptoms of bleeding, 3) medical, nursing or paramedical report, or 4) imaging evidence. Bleeding was defined as clinically significant if it: 1) required transfusion of red blood cells, 2) required admission to the hospital for >24 h, or prolonged a hospitalization, with bleeding as the principal reason, 3) required surgery to stop the bleeding, or 4) resulted in death. Bleeding sites were subclassified as upper gastrointestinal, lower gastrointestinal, intracranial (hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, extradural hematoma, or other), or other sites. Potential events were retrieved from medical records, self-report or notification from treating doctors. Two reviewers adjudicated each event using electronic adjudication software, and discordant cases were reviewed by a third reviewer. Adjudication rules evolved to become more strictly defined as the trial progressed and decision rules were added to assist with frequent scenarios such as post-operative bleeding. Conclusions: This paper provides a detailed methodologic description of the development of a standardized definition for clinically significant bleeding and provides a benchmark for development of a consensus definition for future aspirin primary prevention trials. Trial registration: ASPREE is registered on the International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and on clinicaltrials.gov (NCT01038583). PMID- 30023459 TI - Maternal body weight and diet management system. AB - Background: Body weight control is a significant issue to pregnant women. Overweight or underweight not only affects the normal growth of the fetus but also results in health impacts for pregnant women. Currently, some mobile applications which have released to stress how to achieve the purpose of weight control are not suitable for pregnant women. To design an appropriate mobile application of body weight control for pregnant women, a multidiscipline team collaborated. Objective: This study proposed a mobile application approach to assist women to maintain an ideal weight control during their pregnancy. In addition, the usefulness of the application was evaluated among pregnancy women. Methods: Firstly, the guidance of weight and diet management for pregnant women were obtained from textbooks and professional healthcare providers including nurses and nutritionists. Secondly, the researcher considered aspects of Human Computer Interaction and theories of information technology behavior to design the mobile application. Finally, 52 pregnant women were recruited to test the prototype, which is a mobile application available on different devices with browsers. Conclusions: Compared with other similar types of body weight and diet management mobile applications, the proposed application offers several characteristics to increase pregnant women's willingness to use it. PMID- 30023458 TI - Exercise therapy in medical rehabilitation: Study protocol of a national survey at facility and practitioner level with a mixed method design. AB - Background: The importance of physical activity and the orientation of exercise therapy in rehabilitation has changed for many chronic health conditions. Exercise therapy is the most applied therapy form within multidisciplinary rehabilitation programs for almost all chronic health conditions. Despite the scientifically discussed need to refine exercise therapy, there is relatively little knowledge of how exercise therapy is actually conducted. This study protocol describes the methodological procedure used in the project "Exercise therapy in medical rehabilitation: a survey at facility and practitioner level", which aims to take a national survey of exercise therapy in rehabilitation practice in Germany. Methods: The project was implemented using an explanatory sequential mixed method design. Quantitative and qualitative methods were integrated in two consecutive project phases. Phase 1 used a standardized, quantitative written survey of the heads of exercise therapy departments to compile a national overview of concepts and process features of exercise therapy of individual rehabilitation facilities. Phase 2 recorded individual perspectives and opinions concerning exercise therapy goals, content and methods and current developments in the rehabilitation context (e.g., physical activity promotion, interdisciplinarity, standardization) of exercise therapy practitioners. Over the course of two one-and-a-half day workshops, central themes were introduced and prepared with standardized written individual surveys from Phase 1 and combined with qualitative surveys using facilitated group discussions (focus groups in mixed methods design). Discussion: The project generates a comprehensive picture of exercise therapy in medical rehabilitation at facility level and inserts further information at the practitioner level into this context. The chosen methodology of a mixed method design combines the perspective of the facility with that of the practitioner, thus allowing for a complex and multifaceted description of the status quo in exercise therapy practice and makes it possible to identify facilitators and barriers for the refinement of exercise therapy in specific everyday rehabilitation. These findings form the basis for the systematic development of quality exercise therapy in rehabilitation, in particular in terms of the refinement, implementation and dissemination of biopsychosocial concepts of exercise therapy. PMID- 30023460 TI - Cigarette Management System: An operating procedures guide to obtaining and managing investigational tobacco products for regulatory science research. AB - Investigational tobacco products, specifically variable nicotine content research cigarettes (SPECTRUM), are available through the National Institute of Drug Abuse Drug Supply Program. Randomized controlled trials using research cigarettes are intended to support tobacco regulatory science research. The current paper provides an in-depth look into managing research cigarettes for two multi-site clinical trials and the design of a computer-based Cigarette Management System (CMS). The paper provides guidance intended for any investigator using similar products on the operating procedures under Good Clinical Practice standards and describes features of the CMS. The CMS and procedures described have been field tested for the past three years and have dispensed over 160,000 cigarette packs to participants. The CMS can accommodate a range of practical issues with real world study implementation making it a robust application that is scalable to any study. PMID- 30023461 TI - Iris melanoma presenting as childhood glaucoma. AB - Purpose: To describe the natural history and management of a rare case of iris melanoma in a pediatric patient. Observations: A Caucasian female presented with left pupillary abnormalities at age 7, progressive iris changes at age 9, and markedly elevated intraocular pressure with advanced optic nerve cupping at 11 years of age. She was found to have a pigmented lesion overlying her iris and invading her angle. Trans-corneal fine needle aspirate biopsy demonstrated malignant melanoma of the iris. The patient subsequently underwent Iodine-125 plaque brachytherapy for the tumor. Conclusions: and Importance: Early identification and treatment of iris melanoma may be associated with decreased risk of local progression and metastatic disease. Treatment of glaucoma in conjunction with uveal melanoma is complicated by tumor specific considerations, including treatment of the tumor and prevention of metastasis. PMID- 30023462 TI - Evolutionary Viewpoint on GnRH (gonadotropin-releasing hormone) in Chordata - Amino Acid and Nucleic Acid Sequences. AB - GnRH (gonadotropin-releasing hormone) is a supreme hormone regulating reproductive activity in most animals. The sequences of amino acid and nucleic acid of GnRH reported up to now are examined from the evolutionary framework of Chordata. All identified GnRH are classified into GnRH1, GnRH2, or GnRH3. In all three forms of GnRH both N-terminal and C-terminal are conserved, which allows for effective binding to their receptors. The three amino acids in the middle of GnRH1 sequence have altered diversely from the primitive Chordata, which is indicative of the adaptation process to the ambient environment. GnRH2 and GnRH3 sequences are well conserved. There are more diverse modifications in the nucleic acids than in amino acid sequence of GnRH1. These variations can result from meiosis, mutation, or epigenetics and indicate that GnRH is the product of natural selection. PMID- 30023463 TI - Combination of BEZ235 and Metformin Has Synergistic Effect on Cell Viability in Colorectal Cancer Cells. AB - Patients with type II diabetes mellitus are more susceptible to colorectal cancer (CRC) incidence than non-diabetics. The anti-diabetic drug metformin is most commonly prescribed for the treatment of this disease and has recently shown antitumor effect in preclinical studies. The aberrant mutational activation in the components of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathway is very frequently observed in CRC. We previously reported that metformin inhibits the phosphorylation of ERK and BEZ235, a dual inhibitor of PI3K and mTOR, has anti tumor activity against HCT15 CRC cells harboring mutations of KRAS and PIK3CA. Therefore, we hypothesized that simultaneous inhibition of two pathways by combining metformin with BEZ235 could be more effective in the suppression of proliferation than single agent treatment in HCT15 CRC cells. Here, we investigated the combinatory effect of metformin and BEZ235 on the cell survival in HCT15 CRC cells. Our study shows that both of the two signaling pathways can be blocked by this combinational strategy: metformin suppressed both pathways by inhibiting the phosphorylation of ERK, 4E-BP1 and S6, and BEZ235 suppressed PI3K/AKT/ mTOR pathway by reducing the phosphorylation of 4E-BP1 and S6. This combination treatment synergistically reduced cell viability. The combination index (CI) values ranged from 0.44 to 0.88, indicating synergism for the combination. These results offer a preclinical rationale for the potential therapeutic option for the treatment of CRC. PMID- 30023464 TI - The C-terminal Phosphorylation Sites of eel Follicle-Stimulating Hormone Receptor are Important Role in the Signal Transduction. AB - The large extracellular domain of glycoprotein hormone receptors is a unique feature within the G protein-coupled receptors (GPCRs) family. After interaction with the hormone, the receptor becomes coupled to Gs, which, in turn stimulates adenylyl cyclase and the production of cAMP. Potential phosphorylation sites exist in the C-terminal region of GPCRs. The experiments described herein represent attempts to determine the functions of the eel follicle-stimulating hormone receptor (eelFSHR). We constructed a mutant of eelFSHR, in which the C terminal cytoplasmic tail was truncated at residue 614 (eelFSHR-t614). The eelFSHR-t614 lacked all potential phosphorylation sites present in the C-terminal region of eelFSHR. In order to obtain the eelFSHR ligand, we produced recombinant follicle-stimulating hormone (rec-eelFSHbeta/alpha) in the CHO-suspension cells. The expression level was 2-3 times higher than that of the transient expression of eelFSH in attached CHO-K1 cells. The molecular weight of the rec eelFSHbeta/alpha protein was identified to be approximately 34 kDa. The cells expressing eelFSHR-t614 showed an increase in agonist-induced cAMP responsiveness. The maximal cAMP responses of cells expressing eelFSHR-t614 were lower than those of cells expressing eelFSHR-wild type (eelFSHR-WT). The EC50 following C-terminal deletion in CHO-K1 cells was approximately 60.4% of that of eelFSHR-WT. The maximal response in eelFSHR-t614 cells was also drastically lower than that of eelFSHR-WT. We also found similar results in PathHunter Parental cells expressing beta-arrestin. Thus, these data provide evidence that the truncation of the C-terminal cytoplasmic tail phosphorylation sites in the eelFSHR greatly decreased cAMP responsiveness and maximal response in both CHO-K1 cells and PathHunter Parental cells expressing beta-arrestin. PMID- 30023465 TI - Effects of 17beta-estradiol, Interleukin-1beta, and Human Chorionic Gonadotropin on Activity and mRNA Expression of Plasminogen Activators in Porcine Endometrial Cells. AB - This study aimed to investigate changes in the activity and mRNA expression of plasminogen activators (PAs) induced by 17beta-estradiol (E2), human chorionic gonadotropin (hCG), and interleukin-1beta (IL-1beta) in porcine endometrial cells. Endometrial cells were isolated from the epithelium and cultured to 80% confluence. They were then treated for 24 h with E2 (0.2, 2, 20, and 200 ng/mL), IL-1beta (0.1, 1, 10, and 100 ng/mL), and hCG (0.5, 1, 1.5 and 2 IU/mL). mRNA expressions of urokinase-type (uPA) and tissue-type (tPA) PAs were analyzed using reverse transcription PCR, and activities were measured using a PA activity assay. mRNA expressions of uPA and tPA increased with E2 treatment; however, this was not significant. Similarly, treatment with hCG did not influence the mRNA expressions of PAs. Interestingly, treatment with 0.1 ng/mL IL-1beta significantly reduced the mRNA expression of uPA, but did not affect that of tPA. Treatment with 2, 20, and 200 ng/mL E2 increased PA activity compared with the control group; treatment with 0.1 and 1 ng/mL IL-1beta significantly increased PA activity compared with the other IL-1beta treatment groups, whereas treatment with 10 and 100 ng/mL IL-1beta decreased. Treatment with 2 IU/mL hCG increased PA activity compared with the other treatment groups, although there were no significant differences between the hCG and control groups. In conclusion, the activity and mRNA expression of PAs were differently regulated by the hormone/cytokine and its concentration in porcine endometrial cells. Therefore, understanding PA regulatory mechanisms may help to improve the reproductive potential of domestic animals. PMID- 30023466 TI - Pysiological Responses of Diploid and Triploid Far Eastern Catfish, Silurus asotus to Water Temperature Stress. AB - The aim of study is to contribute to this knowledge-base by investigating the respiratory function, the metabolic rate and the difference of physiological responses un-der low water temperature (20C->15C) stress be-tween diploid and triploid far eastern catfish, Silurus asotus. During the 48 hrs of water temperature stress exposure time, the respiratory frequencies, CO2 and NH4+ concentrations of diploid had higher values than those of triploid (p<0.05). However, pH of triploid was higher than those of diploid (p<0.05), and oxygen consumption rate was not different between diploid and triploid (p>0.05). The level of plasma cortisol and plasma glucose of triploid was lower than those of the diploid (p<0.05). However, in case of lactic acid, there were not significant between triploid and diploid (p>0.05). These results suggest that diploid was more sensitive for low water temperature stress response than triploid in this species. PMID- 30023467 TI - Effects of Different Light Spectra on the Oocyte Maturation in Grass Puffer Takifugu niphobles. AB - In order to examine the effects of four different light spectra (white, red, green, and blue) on the oocyte maturation, the change of reproductive parameters, via brain-pituitary-gonad (BPG) axis in grass puffer, were investigated. After exposure four different light spectra for 7 weeks, the abundance of gonadotropin releasing hormone (GnRH) mRNA which is a type of seabream (sbGnRH) and two different subunit of gonadotropin hormones mRNAs, follicle-stimulating hormone (fshbeta) mRNA and luteinizing hormone (lhbeta) mRNA, were analyzed in the brain and pituitary. Histological analysis showed that the mature oocyte ratio in the green spectrum was higher than other light spectra-exposed groups. Gonadosomatic index (GSI) and oocyte developmental stage were also investigated in the gonad based on histological observations. GSI value with the presence of yolk stage oocytes was significantly increased in the green spectrum-exposed group when compared to that of the other light-exposed groups (white, red, and blue) (p?0.05). The abundances of sbGnRH mRNA and fshbeta mRNA in the green spectrum exposed group were also significant higher than those of the other light spectra exposed groups (p?0.05). These results indicate that the maturation of oocyte in grass puffer can be accelerated by exposure to the spectrum of green. To better understand the molecular mechanism for the maturation of oocyte in grass puffer, further study examining the relationship between oocyte development and its related genes is required. PMID- 30023468 TI - Morphometric Characteristics of Diploid and Triploid Marine Medaka, Oryzias dancena. AB - The morphometric truss characteristics and classical dimensions of the marine medaka, Oryzias dancena, that might distinguish diploid and triploid fish were examined. Significant differences in all the classical and truss dimensions of the diploid and triploid fish were observed in both sexes (p<0.01). All the dimensions of the triploid fish were greater than those of the diploid fish. The triploid marine medaka shows sexual dimorphism in these characters, and the sexual dimorphism of the triploid marine medaka is similar to that of the diploid marine medaka. Thus, when their classical dimension and truss dimension was measured, the growth of triploid marine medaka is faster than that of the diploid fish, and it displays clear sexual dimorphism, with male fish having longer dorsal and anal fins than female fish. PMID- 30023469 TI - Genetic Variations of Intra- and between-razor Clam Solen corneus Population Identified by PCR Analysis. AB - The author undertook PCR-founded genetic platform to investigate the hierarchical dendrogram of Euclidean genetic distances of one razor clam population, particularly for Solen corneus, which was further associated with those of the other clam population, by engaging with the precisely designed oligonucleotide primer sets. Seven oligonucleotides primers were used producing a total of 639 counted bands in population A and 595 in population B, respectively, ranging in size of DNA fragments from larger than approximately 50 bp to less than 1,100 bp. Their primers generated 39 specific fragments (6.10%) in population A and 47 (7.90%) in population B, respectively Comparatively, individuals of one razor clam population were fairly related to that of the other clam population, as shown in the hierarchical dendrogram of Euclidean genetic distances. The analysis of genetic variation between razor clam populations could offer important statistics for fisheries and mariculture. Generally the results showed specific and/or conserved genetic loci between razor clam populations. Specific markers established by the author will be valuable for the genetic analysis, species protection and increase of razor clam individuals in coastal region of the Korean Peninsula. PMID- 30023470 TI - Prenatally Diagnosed Rare Trisomy 16 Mosaicism in Human Amniotic Fluid Cells in the Second Trimester: A Case Report. AB - Although trisomy 16 is commonly detected in spontaneous abortions and accounts for over 30% of cases of autosomal trisomy detected after spontaneous abortion, trisomy 16 mosaicism is rarely detected by amniocentesis in the second trimester. Here, we report a case of level III trisomy 16 mosaicism (47,XX,+16[8]/46,XX[31]) diagnosed by cytogenetic analysis of independently cultured amniotic fluid cells. The female baby was delivered at full term with low birth weight and intrauterine growth retardation, and interestingly, her karyotype was normal (46,XX). Given the difficulty in predicting the outcomes of fetuses with this mosaicism, it is recommended to inform the possibility of mosaicisms including this trisomy 16 mosaicism during prenatal genetic diagnosis and genetic counseling for parents. PMID- 30023471 TI - An RNA Binding Peptide Consisting of Four Types of Amino Acid by in Vitro Selection Using cDNA Display. AB - RNA-protein interactions have a central role in the living world. In this article, we examined whether primitive peptides (30 residues) consisting of four types of amino acid (Gly, Ala, Asp, and Val) could interact with tRNA as a model of primitive RNAs in the RNA world. By in vitro selection of binding peptides using the cDNA display method, a characteristic peptide was selected from a random peptide library and assayed by electrophoretic mobility shift and pull down assays. Interestingly, the selected peptide bound to a single-stranded region including a loop structure of an RNA molecule with some sequence specificity. PMID- 30023472 TI - Synthesis of Nanovesicular Glutathione Peroxidase Mimics with a Selenenylsulfide Bearing Lipid. AB - In this article, we describe the development of a nanosized-glutathione peroxidase (GPx) mimic based on liposomes of which the amphiphilic selenenylsulfide derivative (R-Se-S-R') was incorporated into a lipid membrane. A lipid membrane-compatible selenenylsulfide derivative, 1-oxo-headecyl-seleno-l cysteine-methyl-Se-yl-S-l-penicillamine methyl ester (OHSeP), was synthesized. X ray photoelectron spectroscopy revealed that the sulfur and selenium atoms of the OHSeP molecule formed a selenenylsulfide linkage. The use of OHSeP easily allowed the introduction of the seleno-l-cysteine (SeCys) moiety into the liposomal membranes by mixing with the phosphatidylcholines (PCs), which gave rise to the GPx-like catalytic activity because of the selenium atom in the SeCys moiety. The penicillamine moiety of the OHSeP molecule incorporated into the OHSeP/PC liposomes was thought to orient toward the outer water phase. The OHSeP/PC liposomes generated the GPx-like catalytic activity, which was ascribed to the SeCys moiety that was introduced into the PC-based liposomes. Consequently, the lipid/water interface of the liposomal membranes could possibly provide an effective colloidal platform for the development of water-soluble nanosized GPx mimics. PMID- 30023473 TI - On the Use of Scalable NanoISFET Arrays of Silicon with Highly Reproducible Sensor Performance for Biosensor Applications. AB - As a prerequisite to the development of real label-free bioassay applications, a high-throughput top-down nanofabrication process is carried out with a combination of nanoimprint lithography, anisotropic wet-etching, and photolithography methods realizing nanoISFET arrays that are then analyzed for identical sensor characteristics. Here, a newly designed array-based sensor chip exhibits 32 high aspect ratio silicon nanowires (SiNWs) laid out in parallel with 8 unit groups that are connected to a very highly doped, Pi-shaped common source and individual drain contacts. Intricately designed contact lines exert equal feed-line resistances and capacitances to homogenize the sensor response as well as to minimize parasitic transport effects and to render easy integration of a fluidic layer on top. The scalable nanofabrication process as outlined in this article casts out a total of 2496 nanowires (NWs) on a 4 inch p-type silicon-on insulator (SOI) wafer, yielding 78 sensor chips based on nanoISFET arrays. The sensor platform exhibiting high-performance transistor characteristics in buffer solutions is thoroughly characterized using state-of-the-art surface and electrical measurement techniques. Deploying a pH sensor in liquid buffers after high-quality gas-phase silanization, nanoISEFT arrays demonstrate typical pH sensor behavior with sensitivity as high as 43 +/- 3 mV.pH-1 and a device-to device variation of 7% at the wafer scale. Demonstration of a high-density sensor platform with uniform characteristics such as nanoISFET arrays of silicon (Si) in a routine and refined nanofabrication process may serve as an ideal solution deployable for real assay-based applications. PMID- 30023474 TI - Functionalization of Cellulose Nanocrystals with PEG-Metal-Chelating Block Copolymers via Controlled Conjugation in Aqueous Media. AB - Elongated nanoparticles have recently been shown to have distinct advantages over their spherical counterparts in drug delivery applications. Cellulose nanocrystals (CNCs) have rodlike shapes in nature and have demonstrated biocompatibility in a variety of mammalian cell lines. In this report, CNCs are put forward as a modular platform for the production of multifunctional rod shaped nanoparticles for cancer imaging and therapy. For the first time, PEGylated metal-chelating polymers containing diethylenetriaminepentaacetic acid (DTPA) (i.e., mPEG-PGlu(DPTA)18-HyNic and PEG-PGlu(DPTA)25-HyNic) are conjugated to CNCs to enable the chelation of radionuclides for diagnostic and therapeutic applications. The entire conjugation is based on UV/vis-quantifiable bis-aryl hydrazone-bond formation, which allows direct quantification of the polymers grafted onto the CNCs. Moreover, it has been shown that the mean number of polymers grafted per CNC could be controlled. The CNCs are also fluorescently labeled with rhodamine and Alexa Fluor 488 by embedding the probes in the polymer corona. Preliminary evaluation in a human ovarian cancer cell line (HEYA8) demonstrated that these CNCs are nontoxic and their penetration properties can be readily assessed in multicellular tumor spheroids (MCTSs) by optical imaging. These findings provide support for biomedical applications of CNCs, and further in vitro and in vivo studies are warranted to evaluate their potential as imaging and therapeutic agents for cancer treatment. PMID- 30023476 TI - Nanoprobes for Multimodal Visualization of Bone Mineral Phase in Magnetic Resonance and Near-Infrared Optical Imaging. AB - Imaging agents with affinity for bone can enable early detection of changes to bone mineral density, which is a hallmark of many bone-associated pathologies such as Paget's disease and osteoporosis. Here, we report the development of a polymer nanoparticle (NP)-based multimodal imaging probe that enables visualization of bone mineral phase in near-infrared (NIR) optical tomography and detection in T2-weighted magnetic resonance imaging (MRI). Ultrasmall superparamagnetic iron oxide was first encapsulated in NPs derived by blending poly(dl-lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) with N hydroxysuccinimide functionalized-PLGA (NHS-PLGA). Postmodification of NHS surface functionality on the NPs with alendronic acid (Aln), a bone-targeting ligand, yielded stable ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) containing NPs that exhibit good serum stability and favorable cytocompatibility. These post-Aln-modified NPs exhibit 8- to 10-fold higher affinity for synthetic and biogenic hydroxyapatite in comparison to NPs where Aln was introduced before NP formation and shorten the T2 relaxation times in both agarose phantoms and fresh spongy bone, thus enabling the interrogation of bone mineral phase in T2-MRI. Finally, by introducing an NIR-dye-modified PLGA during the NP formation step, NP probes that enable the visualization of bone mineral phase in both NIR optical tomography and MRI have been realized. The system presented herein meets many of the criteria for clinical translation and therefore opens new opportunities for bone imaging and targeted therapeutics. PMID- 30023475 TI - Biodegradable Copolymer for Stimuli-Responsive Sustained Release of Doxorubicin. AB - Pendent functionalization of biodegradable polymers provides unique importance in biological applications. In this work, we have synthesized a polymeric nanocarrier for the controlled release of the anticancer drug doxorubicin (DOXI). Inspired by the pH responsiveness of acylhydrazine bonds along with the interesting self-assembly behavior of amphiphilic copolymers, this report delineates the development of a PEG-SS-PCL-DOXI copolymer consisting of DOXI, PEG, and a caprolactone backbone. First, the inclusion of a PEG moiety in the copolymer helps to achieve biocompatibility and aqueous solubility as well as a prolonged circulation time of the nanocarrier. Second, an acid-sensitive acylhydrazine-based linkage is chosen to attach DOXI to trigger sustained drug release, whereas the inclusion of an enzymatically cleavable disulfide linkage in the backbone adds to the advantage of backbone biodegradability at the intracellular level. PMID- 30023477 TI - Folding Kinetics of Single Human Telomeric G-Quadruplex Affected by Cisplatin. AB - G-Quadruplex DNA structure has been proven to be a binding target for small molecular organic compounds and hence regarded as a promising pharmacological target. Cisplatin is a widely used chemotherapy drug that targets duplex DNA and was recently shown to react also with G-quadruplex, implying that cisplatin actually may also target G-quadruplex. In this work, we employed magnetic tweezers to investigate the influence of cisplatin on the folding kinetics of single human telomeric G-quadruplex. It was revealed that cisplatin and G quadruplex interact in two different and competitive ways that depend on cisplatin concentration. PMID- 30023480 TI - Simple Optical Imaging of Nanoscale Features in Free-Standing Films. AB - Measuring thicknesses in thin films with high spatial and temporal resolution is of prime importance for understanding the structure and dynamics in thin films and membranes. In the present work, we introduce fluorescence-interferometry, a method that combines standard reflected light thin film interferometry with simultaneous fluorescence measurements. We apply this method to the thinning dynamics and phase separation in free-standing inverse phospholipid bilayer films. The measurements were carried out using a standard fluorescence microscope using multichannel imaging and yielded subnanometer resolution, which is applied to optically measure the discrete thickness variations across phase-separated membranes. PMID- 30023478 TI - Predicting Binding Affinities for GPCR Ligands Using Free-Energy Perturbation. AB - The rapid growth of structural information for G-protein-coupled receptors (GPCRs) has led to a greater understanding of their structure, function, selectivity, and ligand binding. Although novel ligands have been identified using methods such as virtual screening, computationally driven lead optimization has been possible only in isolated cases because of challenges associated with predicting binding free energies for related compounds. Here, we provide a systematic characterization of the performance of free-energy perturbation (FEP) calculations to predict relative binding free energies of congeneric ligands binding to GPCR targets using a consistent protocol and no adjustable parameters. Using the FEP+ package, first we validated the protocol, which includes a full lipid bilayer and explicit solvent, by predicting the binding affinity for a total of 45 different ligands across four different GPCRs (adenosine A2AAR, beta1 adrenergic, CXCR4 chemokine, and delta opioid receptors). Comparison with experimental binding affinity measurements revealed a highly predictive ranking correlation (average spearman rho = 0.55) and low root-mean-square error (0.80 kcal/mol). Next, we applied FEP+ in a prospective project, where we predicted the affinity of novel, potent adenosine A2A receptor (A2AR) antagonists. Four novel compounds were synthesized and tested in a radioligand displacement assay, yielding affinity values in the nanomolar range. The affinity of two out of the four novel ligands (plus three previously reported compounds) was correctly predicted (within 1 kcal/mol), including one compound with approximately a tenfold increase in affinity compared to the starting compound. Detailed analyses of the simulations underlying the predictions provided insights into the structural basis for the two cases where the affinity was overpredicted. Taken together, these results establish a protocol for systematically applying FEP+ to GPCRs and provide guidelines for identifying potent molecules in drug discovery lead optimization projects. PMID- 30023481 TI - Selective Sensing of Metal Ions and Nitro Explosives by Efficient Switching of Excimer-to-Monomer Emission of an Amphiphilic Pyrene Derivative. AB - An amphiphilic pyrene derivative exhibiting unusually stable excimer emission due to strong aggregation is presented. The aggregated system served as an intelligent sensor for metal ions and nitro explosives in aqueous media. The excimer displayed excellent selectivity toward Cu2+ among the tested cations. The observation was interpreted on the basis of chelation of metal ions involving the hydroxyl and amino groups of two molecules, leading to the ligand-to-metal charge transfer (CT) process. The excimer was further applied for the cell imaging of Cu2+ ions. Also, while treating the excimer with various nitro explosives, it displayed efficient 2,4,6-trinitrophenol sensing, corroborating mainly the CT process from pyrene to the analyte due to intercalation of the analyte within pyrene. PMID- 30023482 TI - Effects of Nanosecond Pulsed Electric Fields on the Intracellular Function of HeLa Cells As Revealed by NADH Autofluorescence Microscopy. AB - The fluorescence lifetime of the endogenous fluorophore of reduced nicotinamide adenine dinucleotide (NADH) in HeLa cells is affected by the application of nanosecond pulsed electric fields (nsPEFs). In this study, we found that after nsPEF application, the fluorescence lifetime became longer and then decreased in a stepwise manner upon further application, irrespective of the pulse width in the range of 10-50 ns. This application time dependence of the NADH fluorescence lifetime is very similar to the time-lapse dependence of the NADH fluorescence lifetime following the addition of an apoptosis inducer, staurosporine. These results, as well as the membrane swelling and blebbing after the application of nsPEFs, indicate that apoptosis is also induced by the application of nsPEFs in HeLa cells. In contrast to the lifetime, the fluorescence intensity remarkably depended on the pulse width of the applied nsPEF. When the pulse width was as large as 50 ns, the intensity monotonically increased and was distributed over the entire cell as the application duration became longer. As the pulse width of the applied electric field became smaller, the magnitude of the field-induced increase in NADH fluorescence intensity decreased; the intensity was reduced by the electric field when the pulse width was as small as 10 ns. These results suggest that the mechanism of electric-field-induced apoptosis depends on the pulse width of the applied nsPEF. PMID- 30023479 TI - Design, Synthesis and Evaluation of Bifunctional Acridinine-Naphthalenediimide Redox-Active Conjugates as Antimalarials. AB - A novel class of bifunctional molecules was synthesized integrating acridine (Ac) and redox-active naphthalenediimide (NDI) scaffolds directly and through a flexible linker (en). We evaluated in vitro antiplasmodial activity, physicochemical properties, and a possible mode of action. Theoretical studies suggested electronic segmentation between the electron-rich Ac and electron deficient NDI scaffolds. Orthogonal Ac-NDI molecules showed activities in the micromolar to submicromolar range against a chloroquine (CQ)-sensitive strain of human malaria pathogen Plasmodium falciparum (maximum activity, IC50: 0.419 MUM). The flexible Ac-en-NDI molecules were most potent and showed activity in the nanomolar range against both CQ-sensitive (with most effective compounds, IC50: 3.65 and 4.33 nM) as well as CQ-resistant (with most effective compounds, IC50: 52.20 and 28.53 nM) strains of P. falciparum. Significantly, with CQ-resistant strains, the activity of the most effective compounds was 1 order of magnitude better than that of standard drug CQ. Ac-en-NDI-conjugated molecules were significantly more potent than the individual NDI and Ac-based molecules. The structure-activity relationship (SAR) suggests that the flexible spacer (en) linking the Ac and NDI scaffolds plays a vital role in exhibiting improved potency. None of the molecules triggered hemolysis in culture, and the most potent compounds did not show cytotoxicity in vitro against mammalian fibroblast NIH3T3 cells at their respective IC50 values. The other significant outcome of this work is that some of the investigated molecules have the potential to affect multiple processes in the parasite including the hemozoin formation in digestive vacuoles (DVs), mitochondrial membrane potential, and the redox homeostasis of the parasite. PMID- 30023483 TI - Improving the Sunscreen Properties of TiO2 through an Understanding of Its Catalytic Properties. AB - The use of particulate titanium dioxide (TiO2) as an active sunscreen ingredient has raised concerns about potential risks from TiO2-mediated free radical formation. To date, remediation attempts have concentrated on reducing the yield of free radical generation by TiO2 upon sunlight exposure. The problem with this approach is that given the band gap in TiO2, production of radical and the ensuing reactive oxygen species (ROS) is completely normal. Our strategy is based on a nontoxic, biocompatible shell that neutralizes the free radicals by scavenging them with natural antioxidants before they exit the particle. The new lignin@TiO2 composites preserve the scattering and absorption properties of TiO2 because the particles retain their nanoscale dimensions as preferred by the cosmetic industry. Although the target properties for photocatalysis and sun protection applications are opposite, we argue that exactly the same knowledge is required to optimize either one. PMID- 30023484 TI - Preparation and Binding Evaluation of Histamine-Imprinted Microspheres via Conventional Thermal and RAFT-Mediated Free-Radical Polymerization. AB - Elevated histamine (HTM) levels are closely linked to food poisoning as well as to pathophysiological allergic diseases. In this study, HTM-imprinted, solution processable microspheres were prepared via high-dilution conventional thermal polymerization (CTP) and controlled radical polymerization (CRP) using ethylene glycol dimethacrylate (80 or 90 wt %) and methacrylic acid at 60 degrees C in acetonitrile and evaluated as recognition materials for sensing applications. The polymers were selective to HTM in binding studies, cross-rebinding, and competitive binding assays against the HTM analogues histidine, imidazole, and tryptamine. The selective binding capacity was significantly higher with CTP-80 (on the basis of mass: 21.0 MUmol/g and surface area: 8.08 * 10-2 MUmol/m2) than that with both CTP-90 (8.47 MUmol/g, 4.49 * 10-2 MUmol/m2) and CRP-80 (9.00 MUmol/g, 1.19 * 10-2 MUmol/m2). PMID- 30023485 TI - Structure-Activity Relationships of Cbx7 Inhibitors, Including Selectivity Studies against Other Cbx Proteins. AB - The five human polycomb (Pc) paralog proteins, chromobox homolog (Cbx) 2/4/6/7/8, are a family of chromodomain containing methyllysine reader proteins that are canonical readers of trimethyllysine 27 on histone 3 (H3K27me3). The aberrant expression of the Cbx7 gene is implicated in several cancers including prostate, gastric, thyroid, pancreas, and colon cancer. Previous reports on antagonizing the molecular recognition of Cbx7-H3K27me3 with chemical inhibitors showed an impact on prostate cancer cell lines. We report here on the design, synthesis, and structure-activity relationships of a series of potent peptidomimetic antagonists that were optimized on a trimethyllysine-containing scaffold to target Cbx7. The ligands were characterized using fluorescence polarization (FP) for their binding efficiency and selectivity against the Pc paralog Cbx proteins. The most selective ligand 9, as indicated by the FP data analysis, was further characterized using the isothermal titration calorimetry (ITC). Compound 9 exhibits a 220 nM potency for Cbx7 and exhibits 3.3, 1.8, 7.3 times selective for Cbx7 over Cbx2/4/8 and 28-fold selective over the HP1 family member Cbx1. Our research provides several potent and partially selective inhibitors for Cbx2/4/7 that do not contain trimethyllysine. Our models and binding data suggest that the aromatic cages of Cbx7/Cbx4 can accommodate larger alkyl groups such as diisobutyl substitution on the lysine nitrogen. PMID- 30023486 TI - O-Aryl-Glycoside Ice Recrystallization Inhibitors as Novel Cryoprotectants: A Structure-Function Study. AB - Low-molecular-weight ice recrystallization inhibitors (IRIs) are ideal cryoprotectants that control the growth of ice and mitigate cell damage during freezing. Herein, we describe a detailed study correlating the ice recrystallization inhibition activity and the cryopreservation ability with the structure of O-aryl-glycosides. Many effective IRIs are efficient cryoadditives for the freezing of red blood cells (RBCs). One effective cryoadditive did not inhibit ice recrystallization but instead inhibited ice nucleation, demonstrating the significance of inhibiting both processes and illustrating the importance of this emerging class of cryoprotectants. PMID- 30023487 TI - Evaluation of Biocompatibility and Release of Reactive Oxygen Species of Aluminum Oxide-Coated Materials. AB - Surface properties of biomaterials can strongly influence biomaterial-host interactions. For this reason, coating processes open a wide range of possibilities to modulate the fate of a biomaterial in the body. This study evaluates the effect of a coating material intended for drug delivery capsules on biocompatibility and the release of reactive oxygen species (ROS), that is, respiratory burst in macrophages that indicates acute inflammation. In parallel with a new approach to develop drug-delivery capsules by directly coating solid state drug particles, in this study, glass slides and silicon nanoparticles (NPs) were coated with aluminum oxide (Al2O3) using atomic layer deposition. Different sizes of NPs (20 and 310 nm) were suspended at different concentrations (10, 100, and 1000 MUg/mL) and were evaluated. The homogeneous coating of slides was proved using X-ray photoelectron spectroscopy, and the coating on NP was observed using transmission electron microscopy. Human dermal fibroblasts and human osteoblasts were able to proliferate on the coated slides and in the presence of a suspension of coated NPs (20 and 310 nm) at a low concentration (10 MUg/mL). The macrophages released ROS only when in contact with NPs at a concentration of 1000 MUg/mL, where the 20 nm NPs caused a higher release of ROS than the 310 nm NPs. This study shows that Al2O3 coatings do not affect the cells negatively and that the cell viability was compromised only when in contact with a high concentration (1000 MUg/mL) of smaller (20 nm) NPs. PMID- 30023488 TI - Folate Receptor-Targeted Theranostic Nanoconstruct for Surface-Enhanced Raman Scattering Imaging and Photodynamic Therapy. AB - We report the synthesis of a folate receptor (FR)-targeted theranostic nanocomposite for surface-enhanced Raman scattering (SERS) imaging and photodynamic therapy (PDT). FR-specific SERS detection and PDT are demonstrated in vitro using two FR-positive cancer cell lines and one FR-negative cancer cell lines. PMID- 30023489 TI - Macrophage-Mediated Effects of Airborne Fine Particulate Matter (PM2.5) on Hepatocyte Insulin Resistance in Vitro. AB - Fine particulate matter (PM2.5) pollution poses significant health risks worldwide, including metabolic syndrome-related diseases with the characteristic feature of insulin resistance. However, the mechanism and influencing factors of this effect are poorly understood. In this serial in vitro study, we aimed at testing the hypothesis that macrophage-mediated effects of PM2.5 on hepatic insulin resistance depend on its chemical composition. Mouse macrophages were exposed to PM2.5 that had been collected during summer or winter in Beijing, which represented different compositions of PM2.5. Thereafter, hepatocytes were treated with macrophage-conditioned medium (CM). PM2.5 induced interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 expression and secretion in macrophages, particularly after winter PM2.5 exposure. Correspondingly, winter CM weakened hepatocellular insulin-stimulated glucose consumption. Further investigation revealed that the normal insulin pathway was suppressed in winter CM-treated hepatocytes, with increased phosphorylation of insulin receptor substrate 1 at serine residue 307 (Ser307) and decreased phosphorylation of protein kinase B (PKB/AKT) and forkhead box transcription factor O1 (FoxO1). Moreover, c-Jun N-terminal kinase, a key moderator of the sensitivity response to insulin stimulation, was activated in hepatocytes treated with winter CM. Although further studies are warranted, this preliminary study suggested an association between PM composition and insulin resistance, thus contributing to our understanding of the systemic toxicity of PM2.5. PMID- 30023490 TI - pH-Sensitive Nanoaggregates for Site-Specific Drug-Delivery as Well as Cancer Cell Imaging. AB - Multifunctional polymeric nanoaggregates could enable targeted cancer therapy and imaging, which eventually facilitate monitoring of the therapeutic effect. A fluorescent nanoaggregate is constructed for theranostic application. Chlorambucil (Chl), a fluorescent inactive chemotherapeutic agent, is covalently attached to the nanoaggregate for therapeutic action. The pyrene (Py) motif is also covalently attached to the nanoaggregates, with the motivation of cancer cell imaging. This nanoaggregate is further functionalized with biotin (Btn) for receptor-mediated drug delivery. The efficiency of this system is evaluated by in vitro cell studies to prove its receptor-mediated internalization as well as theranostic capabilities. This newly designed nanocarrier, Nor-Chl-Py-Btn (Nor, norbornene), has the ability to combine both therapeutic and diagnostic capabilities into a single polymer that offers existing prospects for the development of nanomedicine. PMID- 30023491 TI - Preparation of Aluminum Oxide-Coated Glass Slides for Glycan Microarrays. AB - In this study, we report the fabrication of aluminum oxide-coated glass (ACG) slides for the preparation of glycan microarrays. Pure aluminum (Al, 300 nm) was coated on glass slides via electron-beam vapor deposition polymerization (VDP), followed by anodization to form a thin layer (50-65 nm) of aluminum oxide (Al oxide) on the surface. The ACG slides prepared this way provide a smooth surface for arraying sugars covalently via phosphonate formation with controlled density and spatial distance. To evaluate this array system, a mannose derivative of alpha-5-pentylphosphonic acid was used as a model for the optimization of covalent arraying based on the fluorescence response of the surface mannose interacting with concanavalin A (ConA) tagged with the fluorescence probe A488. The ACG slide was characterized using scanning electron microscopy, atomic force microscopy (AFM), and ellipsometry, and the sugar loading capacity, uniformity, and structural conformation were also characterized using AFM, a GenePix scanner, and a confocal microscope. This study has demonstrated that the glycan array prepared from the ACG slide is more homogeneous with better spatial control compared with the commonly used glycan array prepared from the N hydroxysuccinimide-activated glass slide. PMID- 30023492 TI - Responsive Contrast Agents: Synthesis and Characterization of a Tunable Series of pH-Sensitive Near-Infrared Pentamethines. AB - The demand for responsive dyes in optical imaging is high to achieve a better signal-to-noise ratio and, more specifically, to visualize acidic compartments of the endocytic pathway. Herein, we present a new synthetic route, with a step-by step synthesis of water-soluble pH-sensitive cyanine dyes exhibiting pKa values in the region of physiological pH, as confirmed by absorption and fluorescence spectra. Moreover, modification of pKa values was achieved by two different substitution patterns, creating tunable pH-sensitive dyes. We demonstrated the functionality of the pH-sensitive dyes and their suitability as contrast agents for cellular uptake studies by preparing dye-labeled cetuximab and transferrin conjugates. Sulfonated head chains increased water solubility and prevented the formation of dimers, even in the context of dye-labeled bioconjugates. Confocal microscopy images of living cells revealed their pH-responsiveness, as specific fluorescence signal enhancements were observed in acidic compartments of the endocytic pathway (endosomes and lysosomes), although the background signal was low in a pH-neutral environment. Using mixtures of conjugates labeled with either a pH-sensitive or non-pH-sensitive dye for the uptake studies, we could follow the receptor binding and distinguish it from the endocytic uptake process of the conjugates in a simultaneous manner. Moreover, we used flow cytometry to quantify the fluorescence and observed a 3-fold signal enhancement for the pH-sensitive dye conjugates over a period of 3 h. PMID- 30023493 TI - Aragonite-Associated Mollusk Shell Protein Aggregates To Form Mesoscale "Smart" Hydrogels. AB - In the mollusk shell there exists a framework silk fibroin-polysaccharide hydrogel coating around nacre aragonite tablets, and this coating facilitates the synthesis and organization of mineral nanoparticles into mesocrystals. In this report, we identify that a protein component of this coating, n16.3, is a hydrogelator. Due to the presence of intrinsic disorder, aggregation-prone regions, and nearly equal balance of anionic and cationic side chains, this protein assembles to form porous mesoscale hydrogel particles in solution and on mica surfaces. These hydrogel particles change their dimensionality, organization, and internal structure in response to pH and ions, particularly Ca(II), which indicates that these behave as ion-responsive or "smart" hydrogels. Thus, in addition to silk fibroins, the gel phase of the mollusk shell nacre framework layer may actually consist of several framework hydrogelator proteins, such as n16.3, which can promote mineral nanoparticle organization and assembly during the nacre biomineralization process and also serve as a model system for designing ion-responsive, composite, and smart hydrogels. PMID- 30023494 TI - Immobilization of As(V) in Rhizopus oryzae Investigated by Batch and XAFS Techniques. AB - Arsenic (As) contamination in aqueous solutions has become an increasing public concern due to the immense harm to human health. Herein, bioaccumulation of arsenate (As(V)) by Rhizopus oryzae in aqueous systems was investigated under different environmental conditions, such as different pH's, ionic strengths, mycelia dosages, mycelia growths, and temperatures. The results showed that As(V) could be bioaccumulated efficiently by R. oryzae, and the maximum bioaccumulation capacity of As(V) in R. oryzae was 52.4 mg/g at T = 299 K, which was much higher than that for other biomaterials under similar conditions. R. oryzae generated a higher content of thiol compounds under As(V) stress to immobilize As(V) from aqueous solutions. X-ray absorption near-edge spectroscopy analysis indicated that As(V) was partly reduced to As(III) with increasing contact time, which increased As(V) bioaccumulation in mycelia. In addition, extended X-ray absorption fine structure analysis showed that the As-S complex played an important role in As(V) immobilization by mycelia. This study provided an in depth investigation of intracellular As speciation and coordination in R. oryzae on the molecular scale, which was crucial to understand the interaction mechanisms of As(V) with fungi during environmental cleanup. PMID- 30023495 TI - Investigation of the Antibacterial Effect of Mesoporous Magnesium Carbonate. AB - Mesoporous magnesium carbonate (MMC) was first presented in 2013, and this material is currently under consideration for use in a number of biotechnological applications including topical formulations. This study presents the first evaluation of the antibacterial properties of the material with mesoporous silica and two other magnesium-containing powder materials used as references. All powder materials in this study are sieved to achieve a particle size distribution between 25 and 75 MUm. The Gram-positive bacterium Staphylococcus epidermidis is used as the model bacterium due to its prevalence on human skin, its likelihood of developing resistance to antibiotics, for example, from routine exposure to antibiotics secreted in sweat, and because it is found inside affected acne vulgaris pores. Quantification of bacterial viability using a metabolic activity assay with resazurin as the fluorescent indicator shows that MMC exerts a strong antibacterial effect on the bacteria and that alkalinity accounts for the major part of this effect. The results open up for further development of MMC in on skin applications where bacterial growth inhibition without using antibiotics is deemed favorable. PMID- 30023496 TI - Using the Variable-Nearest Neighbor Method To Identify P-Glycoprotein Substrates and Inhibitors. AB - Permeability glycoprotein (Pgp) is an essential membrane-bound transporter that efficiently extracts compounds from a cell. As such, it is a critical determinant of the pharmacokinetic properties of drugs. Multidrug resistance in cancer is often associated with overexpression of Pgp, which increases the efflux of chemotherapeutic agents from the cell. This, in turn, may prevent an effective treatment by reducing the effective intracellular concentrations of such agents. Consequently, identifying compounds that can either be transported out of the cell by Pgp (substrates) or impair Pgp function (inhibitors) is of great interest. Herein, using publically available data, we developed quantitative structure-activity relationship (QSAR) models of Pgp substrates and inhibitors. These models employed a variable-nearest neighbor (v-NN) method that calculated the structural similarity between molecules and hence possessed an applicability domain, that is, they used all nearest neighbors that met a minimum similarity constraint. The performance characteristics of these v-NN-based models were comparable or at times superior to those of other model constructs. The best v-NN models for identifying either Pgp substrates or inhibitors showed overall accuracies of >80% and kappa values of >0.60 when tested on external data sets with candidate Pgp substrates and inhibitors. The v-NN prediction model with a well-defined applicability domain gave accurate and reliable results. The v-NN method is computationally efficient and requires no retraining of the prediction model when new assay information becomes available-an important feature when keeping QSAR models up-to-date and maintaining their performance at high levels. PMID- 30023497 TI - PdII-Catalyzed Oxidative Aldehyde-sp2C-H Functionalization and Cyclization Using NHC with Mild Oxidant DMSO for the Selective Synthesis of Esters, Sugar-Based Analogues, and beta-Hydroxy Chromanones: An 18O-Labeling Study. AB - We assume formation of acyl-PdII-N-heterocyclic-carbene (NHC) organometalics for diverse C-O/O-C and C-C/C-O coupling catalysis of direct functionalization and cyclization reactions. We report the first use of dimethyl sulfoxide (DMSO) as an oxidant under an inert atmosphere to O2-sensitive NHC for oxidative transformations. In situ generated imidazolium halides are utilized as a precursor of NHC and as a source of alkyl group for the sp2C-H functionalization of aldehydes to esters under mild conditions. In contrast to the reported NHC catalyzed esterification strategies, the outstanding substrate scope of this mild catalysis approach is established through synthesis of thermally labile sugar based chiral esters. Our competition experiments using various unsymmetrical imidazolium halides revealed an ascending rate of migratory aptitude among methyl ? allyl < crotyl < cinnamyl < benzyl moiety. DMSO is used as an oxidant for both esterification and cyclization reactions, and the transfer of the DMSO-oxygen to ester is confirmed using an 18O-labeling experiment. The diverse activity using DMSO-oxygen to acyl-PdII-NHC is verified by developing a unique C-C-coupled cyclization with side-chain hydroxylation of olefin to achieve valuable beta hydroxy chromanones. PMID- 30023498 TI - Small-Molecule Ice Recrystallization Inhibitors Improve the Post-Thaw Function of Hematopoietic Stem and Progenitor Cells. AB - The success of hematopoietic stem cell transplantation depends in part on the number and the quality of cells transplanted. Cryoinjuries during freezing and thawing reduce the ability of hematopoietic stem and progenitor cells (HSPCs) to proliferate and differentiate after thawing. Up to 20% of the patients undergoing umbilical cord blood (UCB) transplant experience delayed or failed engraftment, likely because of the inadequate hematopoietic potency of the unit. Therefore, the optimization of cryopreservation protocols, with an emphasis on the preservation of HSPCs, is an important issue. Current protocols typically utilize a 10% dimethyl sulfoxide cryoprotectant solution. This solution ensures 70-80% post-thaw cell viability by diluting intracellular solutes and maintaining the cell volume during cryopreservation. However, this solution fails to fully protect HSPCs, resulting in the loss of potency. Therefore, a new class of cryoprotectants (N-aryl-d-aldonamides) was designed and assessed for the ability to inhibit ice recrystallization and to protect HSPCs against cryoinjury. Several highly active ice recrystallization inhibitors were discovered. When used as additives to the conventional cryoprotectant solution, these nontoxic small molecules improved the preservation of functionally divergent hematopoietic progenitors in the colony-forming unit and long-term culture-initiating cell assays. By contrast, structurally similar compounds that did not inhibit ice recrystallization failed to improve the post-thaw recovery of myeloid progenitors. Together, these results demonstrate that the supplementation of cryopreservation solution with compounds capable of controlling ice recrystallization increases the post-thaw function and potency of HSPCs in UCB. This increase may translate into reduced risk of engraftment failure and allow for greater use of cryopreserved cord blood units. PMID- 30023499 TI - Suitable Fundamental Properties of Ta0.75V0.25ON Material for Visible-Light Driven Photocatalysis: A DFT Study. AB - By applying calculations based on density functional theory, and on density functional perturbation theory, together with generalized gradient approximation Perdew-Burke-Emzerho and screened Coulomb hybrid HSE06 functionals, we predict novel and suitable fundamental parameters of the stable monoclinic Ta0.75V0.25ON semiconductor for solar water splitting. In addition to its predicted bandgap of 2.0 eV in the required zone for solar-driven water splitting, this material reveals a high visible-light absorption coefficient, high static dielectric constant, high hole and electron mobilities along the [001] and [010] crystallographic directions, relatively low exciton binding energy, and suitable band edge energy levels for oxidizing water and reducing protons. The optical, charge-carrier transport, and redox features predicted for this material are found to be considerably better than those obtained for Ta3N5, which is the most common semiconductor photocatalyst used in visible-light-driven water splitting. PMID- 30023500 TI - Insights into Interprotein Electron Transfer of Human Cytochrome c Variants Arranged in Multilayer Architectures by Means of an Artificial Silica Nanoparticle Matrix. AB - The redox behavior of proteins plays a crucial part in the design of bioelectronic systems. We have demonstrated several functional systems exploiting the electron exchange properties of the redox protein cytochrome c (cyt c) in combination with enzymes and photoactive proteins. The operation is based on an effective reaction at modified electrodes but also to a large extent on the capability of self-exchange between cyt c molecules in a surface-fixed state. In this context, different variants of human cyt c have been examined here with respect to an altered heterogeneous electron transfer (ET) rate in a monolayer on electrodes as well as an enhanced self-exchange rate while being incorporated in multilayer architectures. For this purpose, mutants of the wild-type (WT) protein have been prepared to change the chemical nature of the surface contact area near the heme edge. The structural integrity of the variants has been verified by NMR and UV-vis measurements. It is shown that the single-point mutations can significantly influence the heterogeneous ET rate at thiol-modified gold electrodes and that electroactive protein/silica nanoparticle multilayers can be constructed with all forms of human cyt c prepared. The kinetic behavior of electron exchange for the mutant proteins in comparison with that of the WT has been found altered in some multilayer arrangements. Higher self-exchange rates have been found for K79A. The results demonstrate that the position of the introduced change in the charge situation of cyt c has a profound influence on the exchange behavior. In addition, the behavior of the cyt c variants in assembled multilayers is found to be rather similar to the situation of cyt c self-exchange in solution verified by NMR. PMID- 30023501 TI - Fingerprints of Conformational States of Human Hsp70 at Sub-THz Frequencies. AB - Large multidomain proteins occur in different conformational states to function. Detection and monitoring of these different structural states are of crucial interest for understanding the mechanics of proteins. Using computational methods, we show that different protein conformational states of the two-domain 70 kDa human Heat-shock protein (hHsp70), with similar vibrational density of states, lead to remarkably different far-IR spectra at acoustical frequencies (nu < 300 GHz). We found that the slow damped motions of the positively charged residues of hHsp70 contribute the most to collective IR active modes at low frequencies (nu < 300 GHz). We predicted that different structural states and functional modes of large proteins, such as hHsp70, might be detected in the sub THz frequency range by single-molecule spectroscopy similar to the recent extraordinary acoustic Raman spectroscopy (Wheaton S.; Nat. Photonics2015, 9, 68 72). PMID- 30023502 TI - In Silico Designing of an Industrially Sustainable Carbonic Anhydrase Using Molecular Dynamics Simulation. AB - Carbonic anhydrase (CA) is a family of metalloenzymes that has the potential to sequestrate carbon dioxide (CO2) from the environment and reduce pollution. The goal of this study is to apply protein engineering to develop a modified CA enzyme that has both higher stability and activity and hence could be used for industrial purposes. In the current study, we have developed an in silico method to understand the molecular basis behind the stability of CA. We have performed comparative molecular dynamics simulation of two homologous alpha-CA, one of thermophilic origin (Sulfurihydrogenibium sp.) and its mesophilic counterpart (Neisseria gonorrhoeae), for 100 ns each at 300, 350, 400, and 500 K. Comparing the trajectories of two proteins using different stability-determining factors, we have designed a highly thermostable version of mesophilic alpha-CA by introducing three mutations (S44R, S139E, and K168R). The designed mutant alpha CA maintains conformational stability at high temperatures. This study shows the potential to develop industrially stable variants of enzymes while maintaining high activity. PMID- 30023503 TI - Colloidal Polymeric Platform for Facile Click-Assisted Ligand Functionalization and Receptor Targeting. AB - Colloidal poly(glycidyl methacrylate) nanoparticles (NPs) are demonstrated to be platforms facilitating the "click" chemistry approach of surface functionalization for receptor targeting. Folate receptor-targeted NPs were synthesized, physicochemically characterized, confirmed for their biocompatibility, and validated for their selective targeting capabilities for ovarian cancer cells in vitro. PMID- 30023504 TI - Inhibition of DNA Methylation at the MLH1 Promoter Region Using Pyrrole-Imidazole Polyamide. AB - Aberrant DNA methylation causes major epigenetic changes and has been implicated in cancer following the inactivation of tumor suppressor genes by hypermethylation of promoter CpG islands. Although methylated DNA regions can be randomly demethylated by 5-azacytidine and 5-aza-2'-deoxycytidine, site-specific inhibition of DNA methylation, for example, in the promoter region of a specific gene, has yet to be technically achieved. Hairpin pyrrole (Py)-imidazole (Im) polyamides are small molecules that can be designed to recognize and bind to particular DNA sequences. In this study, we synthesized the hairpin polyamide MLH1_-16 (Py-Im-beta-Im-Im-Py-gamma-Im-Py-beta-Im-Py-Py) to target a CpG site 16 bp upstream of the transcription start site of the human MLH1 gene. MLH1 is known to be frequently silenced by promoter hypermethylation, causing microsatellite instability and a hypermutation phenotype in cancer. We show that MLH1_-16 binds to the target site and that CpG methylation around the binding site is selectively inhibited in vitro. MLH1_non, which does not have a recognition site in the MLH1 promoter, neither binds to the sequence nor inhibits DNA methylation in the region. When MLH1_-16 was used to treat RKO human colorectal cancer cells in a remethylating system involving the MLH1 promoter under hypoxic conditions (1% O2), methylation of the MLH1 promoter was inhibited in the region surrounding the compound binding site. Silencing of the MLH1 expression was also inhibited. Promoter methylation and silencing of MLH1 were not inhibited when MLH1_non was added. These results indicate that Py-Im polyamides can act as sequence-specific antagonists of CpG methylation in living cells. PMID- 30023506 TI - Lysine Scanning of Arg10-Teixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues. AB - Teixobactin is a recently discovered antimicrobial cyclodepsipeptide with good activity against Gram positive bacteria. Taking Arg10-teixobactin as a reference, where the nonproteinogenic residue l-allo-enduracididine was substituted by arginine, a lysine scan was performed to identify the importance of keeping the balance between hydrophilic and hydrophobic amino acids for the antimicrobial activities of this peptide family. Thus, the substitution of four isoleucine residues present in the natural sequence by lysine led to a total loss of activity. On the other hand, the substitution of the polar noncharged residues and alanine by lysine allowed us to keep and in some cases to improve the antimicrobial activity. PMID- 30023505 TI - Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells. AB - A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure-activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents. PMID- 30023507 TI - Cryptotanshinone-Loaded Cerasomes Formulation: In Vitro Drug Release, in Vivo Pharmacokinetics, and in Vivo Efficacy for Topical Therapy of Acne. AB - Cerasomes (CS), evolved from liposomes, are novel drug-delivery systems that have potential medical application as carriers for drugs or active ingredients. Although many studies have been conducted on the pharmaceutical and physicochemical properties of CS, the role of CS in influencing the in vivo plasma and topical pharmacokinetics and efficacy of topical drug delivery remain unclear. In this context, we chose cryptotanshinone (CTS) as a model drug for the preparation of CTS-CS by means of the ethanol injection method to investigate their in vitro/in vivo drug-release behavior and in vivo efficacy. (1) In in vitro studies, CTS-CS gel was proven to be capable of achieving a higher permeation rate and significant accumulation in the dermis of isolated rat skin using Franz diffusion cells. (2) In in vivo studies, microdialysis experiments used to measure the plasma and topical pharmacokinetics demonstrated that the CS had a high drug concentration, short peak time, and slow elimination. Meanwhile, the plasma area under the concentration-time curve of CTS-CS gel was less than half that for the CTS gel in 12 h, which indicates that the drug bioavailability dramatically increased in the experiments. (3) In in vivo efficacy studies, we duplicated a rat acne model and performed antiacne efficacy experiments. The CTS CS gel improved the antiacne efficacy compared to that of ordinary CTS gel. Moreover, it inhibited the expression of interleukin-1alpha and androgen receptors effectively. All of these results show that CTS-CS gel has significant potential for the treatment of acne induced by inflammation and excessive secretion of androgen, suggesting that CS formulations were designed as a good therapeutic option for skin disease. PMID- 30023508 TI - Field-Controlled Charge Separation in a Conductive Matrix at the Single-Molecule Level: Toward Controlling Single-Molecule Fluorescence Intermittency. AB - The fluorescence intermittency or "blinking" of single molecules of ATTO647N (ATTO) in the conductive matrix polyvinylcarbazole (PVK) is described in the presence of an external applied electric field. It is shown that due to the energy distribution of the highest occupied molecular orbital (HOMO) level of PVK, which is energetically close to the HOMO of ATTO, sporadic electron transfer occurs. As a result, the on/off dynamics of blinking can be influenced by the electric field. This field will, depending on the respective position and orientation of the dye/polymer system with respect to those of the electrodes, either enhance or suppress electron transfer from PVK to ATTO as well as the back electron transfer from reduced ATTO to PVK. After the charge-transfer step, the applied field will pull the hole in PVK away from the dye, increasing the overall time the dye resides in a dark state. PMID- 30023509 TI - Novel Adamantanyl-Based Thiadiazolyl Pyrazoles Targeting EGFR in Triple-Negative Breast Cancer. AB - The epidermal growth factor receptor (EGFR) is a validated therapeutic target for triple-negative breast cancer (TNBC). In the present study, we synthesize novel adamantanyl-based thiadiazolyl pyrazoles by introducing the adamantane ring to thiazolopyrazoline. On the basis of loss of cell viability in TNBC cells, 4 (adamantan-1-yl)-2-(3-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1 yl)thiazole (APP) was identified as a lead compound. Using a Parzen-Rosenblatt Window classifier, APP was predicted to target the EGFR protein, and the same was confirmed by surface plasmon resonance. Further analysis revealed that APP suppressed the phosphorylation of EGFR at Y992, Y1045, Y1068, Y1086, Y1148, and Y1173 in TNBC cells. APP also inhibited the phosphorylation of ERK at Y204 and of STAT3 at Y705, implying that APP downregulates the activity of EGFR downstream effectors. Small interfering RNA mediated depletion of EGFR expression prevented the effect of APP in BT549 and MDA-MB-231 cells, indicating that APP specifically targets the EGFR. Furthermore, APP modulated the expression of the proteins involved in cell proliferation and survival. In addition, APP altered the expression of epithelial-mesenchymal transition related proteins and suppressed the invasion of TNBC cells. Hence, we report a novel and specific inhibitor of the EGFR signaling cascade. PMID- 30023510 TI - Selective Bactericidal Activity of Divalent Metal Salts of Lauric Acid. AB - Bacteria play a crucial role in skin health. For example, Staphylococcus aureus and Propionibacterium acnes cause skin roughness and acne, whereas Staphylococcus epidermidis enhances innate barrier immunity. Therefore, controlling the bacterial flora is important in dermatology and cosmetic chemistry. In this study, the bactericidal activities of different metal salts of lauric acid were evaluated. The bactericidal behavior of the salts changed according to the type of metal ion. Specifically, the Mg-, Ca-, and Mn-containing salts effectively sterilized only S. aureus and P. acnes. Their Co, Ni, and Cu salts sterilized all bacteria, including S. epidermidis, whereas the Zn salt proved ineffective. The Cu salt displayed the strongest bactericidal activity. Spin-trapping, detected using electron spin resonance, showed that this salt catalyzed the generation of hydroxyl radicals, which can destroy bacterial cell membranes. These findings demonstrate that metal-ion selection is an important factor in the design of bactericidal agents for healthcare products. PMID- 30023511 TI - Mechanistic Modeling of Reversed-Phase Chromatography of Insulins with Potassium Chloride and Ethanol as Mobile-Phase Modulators. AB - The purpose of this study was to investigate the adsorption mechanism in reversed phase chromatography (RPC) of proteins and to develop a model for the effect of dual mobile phase modulators-a salt and an organic solvent-on this process. Two different adsorption mechanisms were considered: (1) pure association of a protein molecule and one or more ligands and (2) displacement of the organic modulator, with which the adsorbent is saturated, by the protein upon association with one or more ligands. One model was then derived from each of the two considered mechanisms, combining thermodynamic theories on salting-in, RPC, and the solubility of proteins. The model was then applied to chromatographic data from an earlier report as well as supplementary data for solubility and vapor liquid equilibria, and case-specific simplifications were made. We found that an adaptation of Kirkwood's electrostatic theories to hydrophobic interaction chromatography describes the observed effect of KCl well. Combining chromatographic and solubility data for one of the insulins, we concluded that the variation in the activity coefficient of the insulin with respect to the concentration of ethanol alone cannot describe its effect on retention. Consequently, one or more other phenomena must affect the adsorption process. Our second model fits the retention data well, supporting the hypothesis that ethanol is directly involved in the adsorption mechanism in this case. Using additional experiments at a high-protein load, we extended the linear-range equilibrium model into a dynamic model for preparative conditions. This model shows good agreement with the high-load data for one of the insulin variants, without any additional effects of the modulator concentrations on the adsorption capacity. PMID- 30023512 TI - Real-Time Observation of Enzymatic Polyhydroxyalkanoate Polymerization Using High Speed Scanning Atomic Force Microscopy. AB - The initial stage of in vitro polyhydroxyalkanoate (PHA) polymerization by PHA synthase from Ralstonia eutropha (PhaCRe) on a mica substrate in water was observed using high-speed scanning atomic force microscopy (HS-AFM). Before PHA polymerization, the adsorption-desorption cycle of the PhaCRe molecule on mica was observed in real time. For approximately 30 s after the addition of the PHA monomer, no significant change was observed on the mica substrate, but PhaCRe could be transformed into an active enzyme in water upon contact with the monomer during this period. Subsequently, linearly elongating rod-shaped objects were observed on the mica substrate, plausibly as a result of the polymerization reaction. The height of these elongating objects was considerably larger than the expected height for a single PHA chain. This observation suggests that PHA chains generated during the reported experiments might form some kind of a semiregular structure. PMID- 30023513 TI - Comparative Study of 5'- and 3'-Linked CpG-Antigen Conjugates for the Induction of Cellular Immune Responses. AB - Conjugation of CpG to an antigen induces a stronger immune response compared to that of the mixture. This study compares the in vitro immunostimulatory activity of CpG conjugated via either its 5' or 3' end to the model antigen ovalbumin (OVA). CpG modified with an amine at either the 5' or 3' end was conjugated to OVA via a stable bis-aryl hydrazone bond. Similar levels of CpG conjugation to OVA were observed for both conjugates on the basis of the absorbance at 360 nm for the formation of the bis-aryl hydrazone bond, which determined 2.8 +/- 0.3 CpGs linked per OVA. Both the 5' and 3' CpG-OVA conjugates had similar size exclusion chromatography elution profiles. The immunostimulatory properties of the conjugates were determined by dendritic cells (DCs) and T-cells isolated from mice. The activation of DCs was determined by the upregulation of activation markers CD86 and CD40. T-cells were co-cultured with stimulated DCs, and the immunogenicity was determined by measuring T-cell proliferation and interferon gamma production. Both the CpG 5'- and 3'-linked conjugates induced the same level (p > 0.5) of DC activation markers, which were significantly higher than those of the untreated control. Similarly, T-cell assays showed no significant difference (p > 0.5) between the 5' and 3' conjugates with respect to T-cell proliferation and interferon gamma production. The 5' and 3' conjugates induced T cell activation significantly higher than the mixture of CpG and OVA. This study showed that the end at which CpG is conjugated to an antigen has no influence on the generation of a T-cell-based immune response in vitro. PMID- 30023514 TI - Identification of a New Function of Cardiovascular Disease Drug 3 Morpholinosydnonimine Hydrochloride as an Amyloid-beta Aggregation Inhibitor. AB - Cardiovascular disease (CVD) and Alzheimer's disease (AD) have a mutual cause-and effect relationship, and they share some common risk factors. Although numerous Food and Drug Administration (FDA)-approved drugs have been developed for CVD treatment, no drugs are clinically available for AD treatment. Given the common disease-causing factors and links between the two diseases and the well demonstrated drugs for CVD, we propose to re-examine the new potential of the existing CVD drugs as amyloid-beta (Abeta) inhibitors. 3-Morpholinosydnonimine hydrochloride (SIN-1) is an FDA-approved drug for inhibiting platelet aggregation in CVD. Herein, we examine the inhibition activity of SIN-1 on the aggregation and toxicity of Abeta1-42 using combined experimental and computational approaches. Collective experimental data from ThT, circular dichroism, and atomic force microscopy demonstrate that SIN-1 can effectively inhibit amyloid formation at every stage of Abeta aggregation by prolonging lag phase, slowing down aggregation rate, and reducing final fibril formation. The cell viability assay also shows that SIN-1 enables the protection of SH-SY5Y cells from Abeta-induced cell toxicity. Such an inhibition effect is attributed to interference with the structural transition of Abeta toward a beta-sheet structure by SIN-1. Furthermore, molecular dynamic simulations confirm that SIN-1 preferentially binds to the C-terminal beta-sheet grooves of an Abeta oligomer and consequently disrupts the beta-sheet structure of Abeta and Abeta-Abeta association, explaining experimental observations. This work discovers a new function of SIN 1, making it a promising compound with dual protective roles in inhibiting both platelet and Abeta aggregations against CVD and AD. PMID- 30023515 TI - Peptide-Au Cluster Probe: Precisely Detecting Epidermal Growth Factor Receptor of Three Tumor Cell Lines at a Single-Cell Level. AB - Alterations in protein (e.g., biomarkers) expression levels have a significant correlation with tumor development and prognosis; therefore, it is desired to develop precise methods to differentiate the expression level of proteins in tumor cell lines, especially at the single-cell level. Here, we report a precise and versatile approach of quantifying the protein expression levels of three tumor cell lines in situ using a peptide-Au cluster probe. The probe (Au5Peptide3) consists of a peptide with a specific cell membrane epidermal growth factor receptor (EGFR) targeting ability and an Au cluster for both cell membrane EGFR imaging using confocal microscopy and cell membrane EGFR counting by laser ablation inductively coupled plasma mass spectrometry. Utilizing the peptide-Au cluster probe, we successfully quantify the EGFR expression levels of SMMC-7721, KB, and HeLa cells at a single-cell level and differentiate the EGFR expression levels among these cell lines. The peptide-Au cluster probe, with the ability to differentiate the protein expression level of different cell lines, shows exceptional promise for providing reliable predictive and prognostic information of tumors at a single-cell level. PMID- 30023516 TI - Biodegradable and Bioactive PCL-PGS Core-Shell Fibers for Tissue Engineering. AB - Poly(glycerol sebacate) (PGS) has increasingly become a desirable biomaterial due to its elastic mechanical properties, biodegradability, and biocompatibility. Here, we report microfibrous core-shell mats of polycaprolactone (PCL)-PGS prepared using wet-wet coaxial electrospinning. The anticoagulant heparin was immobilized onto the surface of these electrospun fiber mats, and they were evaluated for their chemical, mechanical, and biological properties. The core shell structure of PCL-PGS provided tunable degradation and mechanical properties. The slowly degrading PCL provided structural integrity, and the fast degrading PGS component increased fiber elasticity. Young's modulus of PCL-PGS ranged from 5.6 to 15.7 MPa. The ultimate tensile stress ranged from 2.0 to 2.9 MPa, and these fibers showed elongation from 290 to 900%. The addition of PGS and grafting of heparin improved the attachment and proliferation of human umbilical vein endothelial cells. Core-shell PCL-PGS fibers demonstrate improved performance as three-dimensional fibrous mats for potential tissue-engineering applications. PMID- 30023518 TI - Support Vector Machine Classification and Regression Prioritize Different Structural Features for Binary Compound Activity and Potency Value Prediction. AB - In computational chemistry and chemoinformatics, the support vector machine (SVM) algorithm is among the most widely used machine learning methods for the identification of new active compounds. In addition, support vector regression (SVR) has become a preferred approach for modeling nonlinear structure-activity relationships and predicting compound potency values. For the closely related SVM and SVR methods, fingerprints (i.e., bit string or feature set representations of chemical structure and properties) are generally preferred descriptors. Herein, we have compared SVM and SVR calculations for the same compound data sets to evaluate which features are responsible for predictions. On the basis of systematic feature weight analysis, rather surprising results were obtained. Fingerprint features were frequently identified that contributed differently to the corresponding SVM and SVR models. The overlap between feature sets determining the predictive performance of SVM and SVR was only very small. Furthermore, features were identified that had opposite effects on SVM and SVR predictions. Feature weight analysis in combination with feature mapping made it also possible to interpret individual predictions, thus balancing the black box character of SVM/SVR modeling. PMID- 30023519 TI - Miscibility and Performance Evaluation of Biocomposites Made from Polypropylene/Poly(lactic acid)/Poly(hydroxybutyrate-co-hydroxyvalerate) with a Sustainable Biocarbon Filler. AB - The incorporation of poly(lactic acid) (PLA) and poly(hydroxybutyrate-co hydroxyvalerate) (PHBV) as a partial biobased polymer substitute for polypropylene (PP) was investigated. The ternary blends were prepared through melt compounding extrusion followed by injection molding techniques with a constant biopolymer ratio of 30 wt %. Further addition of pyrolyzed miscanthus based carbon was carried out to establish a contrast between talc-filled PP. When the morphology of the biopolymer minor phase was analyzed theoretically using contact angle for interfacial tension and spreading coefficient values along with solubility parameter calculations and via scanning electron microscopy imaging, the core-shell architecture was found with the PHBV encasing the PLA phase. Mechanical testing of the materials showed that only the tensile properties were reduced for all samples, whereas the impact strength was increased above the neat PP. With inclusion of the biobased carbon filler into the blend system, the thermomechanical properties were elevated above that of the PP matrix. The final properties of the multiphase polymeric composites are found to be related to the morphology obtained and inherent properties of the individual constituents. PMID- 30023517 TI - Singular Interaction between an Antimetastatic Agent and the Lipid Bilayer: The Ohmline Case. AB - SK3 channels are abnormaly expressed in metastatic cells, and Ohmline (OHM), an ether lipid, has been shown to reduce the activity of SK3 channels and the migration capacity of cancer cells. OHM incorporation into the plasma membrane is proposed to dissociate the protein complex formed between SK3 and Orai1, a potassium and a calcium channel, respectively, and would lead to a modification in the lipid environment of both the proteins. Here, we report the synthesis of deuterated OHM that affords the determination, through solid-state NMR, of its entire partitioning into membranes mimicking the SK3 environment. Use of deuterated lipids affords the demonstration of an OHM-induced membrane disordering, which is dose-dependent and increases with increasing amounts of cholesterol (CHOL). Molecular dynamics simulations comfort the disordering action and show that OHM interacts with the carbonyl and phosphate groups of stearoylphosphatidylcholine and sphingomyelin and to a minor extent with CHOL. OHM is thus proposed to remove the CHOL OH moieties away from their main binding sites, forcing a new rearrangement with other lipid groups. Such an interaction takes its origin at the lipid-water interface, but it propagates toward the entire lipid molecules and leads to a cooperative destabilization of the lipid acyl chains, that is, membrane disordering. The consequences of this reorganization of the lipid phases are discussed in the context of the OHM induced inhibition of SK3 channels. PMID- 30023520 TI - Core-Shell Nanoparticles as an Efficient, Sustained, and Triggered Drug-Delivery System. AB - One of the challenges in designing a successful drug-delivery vehicle is the control over drug release. Toward this, a number of multifunctional nanoparticles with multiple triggers and complex chemistries have been developed. To achieve an efficient and maximum therapeutic effect, a trigger dependent drug-delivery system with sustained release is desirable. In this paper, we report the use of a combination of thermoresponsive gold core and polymeric shell nanoparticles that can provide a sustained, triggered release of doxorubicin, making the system more efficient compared to individual nanoparticles. The selection of the system was dependent on the best trigger applicable in biological systems and a component responsive to that trigger. Because of the best tissue penetration depth observed for radiofrequency (rf), we chose rf as a trigger. Whereas the gold nanoparticles (AuNPs) provided hyperthermia trigger on exposure to rf fields, the thermoresponsiveness was endowed by poly(N-isopropylacrylamide) (pNIPAm)-based polymer shells. AuNPs with three different compositions of shells, only pNIPAm and p(NIPAm-co-NIPMAm) with the ratio of NIPAm/N-(isopropylmethacrylamide) (NIPMAm) 1:1 (pNIPMAm50) and 1:3 (pNIPMAm75), were synthesized. We observed that the polymer coating on the AuNPs did not affect the heating efficiency of AuNPs by rf and exhibited a temperature-dependent release of the chemotherapeutic drug, doxorubicin. The nanoparticles were biocompatible, stable in biologically relevant media, and were able to show a burst as well as a sustained release, which was rf-dependent. Interestingly, we observed that when HeLa cells were treated with doxorubicin-loaded gold core-polymeric shell NPs and exposed to rf for varying times, the mixture of the two polymeric shell nanoparticles induced more cell death as compared to the cells treated with single nanoparticles, suggesting that such multi-nanoparticle systems can be more efficacious delivery systems instead of a single multicomponent system. PMID- 30023521 TI - Unraveling the Stability of Plasma Proteins upon Interaction of Synthesized Androstenedione and Its Derivatives-A Biophysical and Computational Approach. AB - 4-Androstene-3-17-dione (4A), also known as androstenedione, is the key intermediate of steroid metabolism. 5beta-Androstane-3-17-dione (5A) and (+)-6 methyl-5beta-androstane-3-17-dione (6M) are the steroid derivatives of androstenedione. The interactions of androstenedione and its derivatives with plasma proteins are important in understanding the distribution and bioavailability of these molecules. In our present study, we have studied the binding affinity of androstenedione and its derivatives with plasma proteins such as human serum albumin (HSA) and alpha1-acid glycoprotein (AGP). Our results showed that the 4A, 5A, and 6M steroid molecules can form stable complexes with HSA and AGP. The affinity of the studied steroid molecules with HSA is high compared to that with AGP, and the binding constants obtained for 4A, 5A, and 6M with HSA are 5.3 +/- 2 * 104, 5.3 +/- 1 * 104, and 9.5 +/- 0.2 * 104 M-1, respectively. Further, binding sites of these steroid molecules in HSA are identified using molecular displacement and docking studies: it is found that 4A and 5A bind to domain III while 6M binds to domain II of HSA. Furthermore, the circular dichroism data revealed that there is a partial unfolding of the protein while interacting with androstenedione and its derivatives. Also, molecular dynamics simulations were carried out for HSA-androstenedione and its derivative complexes to understand their stability; hence, these results yielded that HSA androstenedione and its derivative complexes were stabilized after 15 ns and maintained their stable structures. PMID- 30023522 TI - Biological Thiols and Carbon Disulfide: The Formation and Decay of Trithiocarbonates under Physiologically Relevant Conditions. AB - Carbon disulfide is an environmental toxin, but there are suggestions in the literature that it may also have regulatory and/or therapeutic roles in mammalian physiology. Thiols or thiolates would be likely biological targets for an electrophile, such as CS2, and in this context, the present study examines the dynamics of CS2 reactions with various thiols (RSH) in physiologically relevant near-neutral aqueous media to form the respective trithiocarbonate anions (TTC-, also known as "thioxanthate anions"). The rates of TTC- formation are markedly pH dependent, indicating that the reactive form of RSH is the conjugate base RS-. The rates of the reverse reaction, that is, decay of TTC- anions to release CS2, is pH-independent, with rates roughly antiparallel to the basicities of the RS- conjugate base. These observations indicate that the rate-limiting step of decay is simple CS2 dissociation from RS-, and according to microscopic reversibility, the transition state of TTC- formation would be simple addition of the RS- nucleophile to the CS2 electrophile. At pH 7.4 and 37 degrees C, cysteine and glutathione react with CS2 at a similar rate but the trithiocarbonate product undergoes a slow cyclization to give 2-thiothiazolidine-4-carboxylic acid. The potential biological relevance of these observations is briefly discussed. PMID- 30023523 TI - Effect of PEGylation on Ligand-Targeted Magnetoliposomes: A Missed Goal. AB - We tested the targeting efficiency of magnetoliposomes (MLPs) labeled with tripeptide arginine-glycine-aspartic acid (RGD) on two types of cells: HeLa cells expressing RGD receptors and 3T3 cells lacking RGD receptors. The targeting ability of RGD-MLPs was compared to that of bare MLPs and MLPs stabilized with poly(ethylene glycol) (PEG). Cellular internalization of these liposomes was determined by flow cytometry and confocal microscopy, which showed that both types of cells took up more nontargeting MLPs than targeting RGD-MLPs or PEG MLPs, with PEG-MLPs showing the lowest degree of internalization. The presence of specific receptors on HeLa cells did not facilitate the binding of RGD-MLPs, probably due to the presence of PEG chains on the liposomal surface. The polymer increases the circulation time of the liposomes in the organism but reduces their interactions with cells. Despite the localization of the RGD peptide on the tip of PEG in RGD-MLPs, the interaction between the liposome and cell was still limited. To avoid this drawback, targeting drug delivery systems can be prepared with two types of PEG: one of a short length to enable biocompatibility and the other of a longer chain to carry the ligand. PMID- 30023524 TI - Electrospun Polyacrylonitrile (PAN) Templated 2D Nanofibrous Mats: A Platform toward Practical Applications for Dye Removal and Bacterial Disinfection. AB - The fabrication of polymeric nanofibers and its potential versatility instigated to foster smart hybrid nanomaterials for the removal of environmental pollutants. In this pursuit, in this research work, polyacrylonitrile (PAN)-based two dimensional (2D) nanofibrous mats with polyethyleneimine (PEI)/Fe and quaternary ammonium (QA)/Fe as hybrid fillers were prepared by the electrospinning process for the effective dye removal and bacterial disinfection. The characteristics of the fabricated nanomaterials were extensively explored by several analytical techniques such as field emission-scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and Brunauer-Emmett-Teller analysis. Magnetic and thermal properties were investigated by superconducting quantum interference device and thermogravimetric measurements. The kinetic and isothermal models affirmed the adsorption behavior of the PAN-PEI/Fe nanofibers, and further regenerative studies substantiated the sustainability of the mats for the removal of industrial dye effluents. Subsequently, the magnetic-QA-loaded PAN nanofiber mats exhibited bactericidal killing efficacy of 99 and 89.5% in both Staphylococcus aureus and green fluorescence protein expressing Escherichia coli bacterial models evaluated from the conventional quantitative bacterial colony-counting assay. Disk diffusion method and microscopic investigations corroborated the disinfection efficacy with zone of inhibitions of ~23 and 33 mm, respectively. Interestingly, in vitro cell culture studies conducted in BHK-21 and NIH 3T3 cell lines demonstrated the cytocompatibility, and the in vivo toxicity investigations using the zebrafish models necessitated the real-time application of these nanofibrous mats. Therefore, the comprehensive study of the fabricated PAN-templated functionalized 2D nanofibrous mats affirmed to be competent for the remediation of industrial dye effluents and bacteria in water bodies. PMID- 30023525 TI - FIKK Kinase, a Ser/Thr Kinase Important to Malaria Parasites, Is Inhibited by Tyrosine Kinase Inhibitors. AB - A relatively high-affinity inhibitor of FIKK kinase from the malaria parasite Plasmodium vivax was identified by in vitro assay of recombinant kinase. The FIKK kinase family is unique to parasitic organisms of the Apicomplexan order and has been shown to be critical in malaria parasites. The recombinant kinase domain was expressed and screened against a small molecule library, revealing a number of tyrosine kinase inhibitors that block FIKK kinase activity. A family of tyrphostins was further investigated, to begin exploring the FIKK kinase pharmacophore. Finally, emodin was identified as a relatively high-affinity FIKK kinase inhibitor, identifying this family of anthraquinones as potential lead compounds for the development of antimalarials targeting the FIKK kinase. PMID- 30023526 TI - Electrochemical Determination of the Serotonin Reuptake Inhibitor, Dapoxetine, Using Cesium-Gold Nanoparticles. AB - Cesium-gold (Cs-Au) nanoparticles are shown to be analytically advantageous for the electroanalytical sensing of dapoxetine (DPX), a serotonin reuptake inhibitor used for the treatment of premature ejaculation. The Cs-Au nanoparticles are electrically wired and supported upon mass producible, economical screen-printed electrochemical sensing platforms and are characterized electrochemically (cyclic voltammetry and electrochemical impedance spectroscopy) and physiochemically (field emission scanning electron microscopy and energy dispersive X-ray analysis). The face-centered design was applied to optimize the significant experimental factors by using square wave voltammetry. The Cs-Au-based sensor is found to exhibit a large linear range (10-7 to 10-4 M) with a good analytical linearity with the limits of detection and quantification corresponding to 2.50 * 10-10 and 8.33 * 10-8 M, respectively. The developed sensor was successfully applied in the quantification of DPX in the presence of sildenafil, both of which are commonly found within combined dose tablet pharmaceutical formulations. The proposed DPX electrochemical Cs-Au-based sensor has the advantages of being single-shot and disposable and is shown to be successful in determining DPX in pharmaceutical formulations, human urine, and serum samples with acceptable recoveries. PMID- 30023527 TI - Tannic Acid-Based Multifunctional Hydrogels with Facile Adjustable Adhesion and Cohesion Contributed by Polyphenol Supramolecular Chemistry. AB - Adhesiveness of hydrogels depends on the balance and synergy of their cohesion and adhesion. However, it is a challenge to fabricate catechol-based hydrogels with high adhesiveness because the required condition for cohesion and adhesion of these hydrogels is in conflict with each other: strong cohesion (gelation) requires a weak basic condition, whereas strong adhesion requires an acidic condition. Here, we demonstrated that by utilizing polyphenol supramolecular chemistry, the coexistence of strong cohesion and adhesion can be achieved in a hydrogel via the one-pot method. Poly(dimethyl diallyl ammonium chloride)/tannic acid (PDDA/TA) hydrogel has been studied as a proof of concept. Compared with catechol moieties that covalently grafted on polymer chains, TA can bring high density of pyrogallol/catechol functional groups for polymers via a noncovalent pathway, as well as high acidity in the system. As a result, the cohesion of the hydrogel is enhanced significantly, the highest storage moduli can reach up to ca. 0.15 MPa; besides, the high acidity of the hydrogel prevents pyrogallol/catechol groups from oxidation and guarantees strong adhesion; thus, the hydrogel can adhere to diverse substrates steadily, including tissues, glass, metals, and plastic. Moreover, because of the adjustable adhesiveness via changing the pH, the PDDA/TA hydrogel becomes a unique system with patternable adhesiveness. In addition, the hydrogel has rapid self-healing and high ionic conductivity (~4.3 S m-1). This study demonstrates that utilizing polyphenol chemistry in the construction of hydrogels opens a new path toward multifunctional hydrogels with improved properties. PMID- 30023528 TI - Photoresponsive Block Copolymer Prodrug Nanoparticles as Delivery Vehicle for Single and Dual Anticancer Drugs. AB - In recent decades, drug delivery systems (DDSs) based on polymer nanoparticles have been explored due to their potential to deliver drugs with poor water solubility. Some of the limitations of nanoparticle-based DDSs can be overcome by developing an appropriate polymer prodrug. In this work, poly(NIPA)-b poly(HMNPPA)-b-poly(PEGMA-stat-BA) was synthesized using reversible addition fragmentation chain transfer polymerization and Chlorambucil (Cbl), an anticancer drug, was conjugated to the copolymer via 3-(3-(hydroxymethyl)-4 nitrophenoxy)propyl acrylate (HMNPPA) units to prepare the prodrug. A few biotin acrylate (BA) units were also incorporated to bring potential targeting capability to the prodrug in the copolymer. This polymer prodrug formed spherical micellar nanoparticles in physiological conditions, which were characterized by dynamic light scattering and transmission electron microscopy measurements. The very low critical aggregation concentration (cac) (0.011 mg/mL) of the prodrug, as measured from Nile Red fluorescence, makes it stable against dilution. The polymer prodrug was shown to release Cbl on photoirradiation by soft UV (lambda >= 365 nm) and laser (lambda = 405 nm) light. The prodrug micellar nanoparticles were capable of encapsulating a second drug (doxorubicin, DOX) in their hydrophobic core. On photoirradiation with UV and laser light of the DOX-loaded nanoparticles, both Cbl and DOX were released. Light-induced breaking of photolabile ester bond resulted in the release of Cbl and caused disruption of the nanoparticles facilitating release of DOX. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay confirmed the nontoxicity of the polymers and effectiveness of the dual drug-loaded micellar nanoparticles toward cancer cells. Confocal microscopy results showed a better cellular internalization capability of the DOX-loaded nanoparticles in cancer cells, possibly due to the presence of cancer cell targeting biotin molecules in the polymer. This new photoresponsive potentially biocompatible and cancer cell-targeted polymer prodrug may be useful for delivery of single and/or multiple hydrophobic drugs. PMID- 30023529 TI - Rapid and Easy Extracellular Vesicle Detection on a Surface-Functionalized Power Free Microchip toward Point-of-Care Diagnostics. AB - Extracellular vesicles (EVs) are promising novel cancer biomarkers. However, rapid and easy analysis of EVs is challenging because conventional detection methods require large sample volumes and long detection times. Microchip-based analytical systems have particularly attracted attention for development of point of-care (POC) diagnostics. Previously, various biomarker detection methods on a portable power-free poly(dimethylsiloxane) (PDMS) microchip using laminar flow assisted dendritic amplification have been developed. Recently, for easy functionalization, we proposed a microchannel inner surface-functionalized power free PDMS microchip (SF-PF microchip) utilizing electron beam-induced graft polymerization. In this study, we apply the technique and prepare a novel SF-PF microchip. On the microchip, EVs were successfully detected. The required sample volume was 1.0 MUL, and the total analysis time was 20 min. The microchip can contribute to EV-based POC cancer diagnosis. PMID- 30023530 TI - Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2R Affinity and Selectivity. AB - In search for selective ligands for the muscarinic acetylcholine receptor (MR) subtype M2, the dimeric ligand approach, that is combining two pharmacophores in one and the same molecule, was pursued. Different types (agonists, antagonists, orthosteric, and allosteric) of monomeric MR ligands were combined by various linkers with a dibenzodiazepinone-type MR antagonist, affording five types of heterodimeric compounds ("DIBA-xanomeline," "DIBA-TBPB," "DIBA-77-LH-28-1," "DIBA propantheline," and "DIBA-4-DAMP"), which showed high M2R affinities (pKi > 8.3). The heterodimeric ligand UR-SK75 (46) exhibited the highest M2R affinity and selectivity [pKi (M1R-M5R): 8.84, 10.14, 7.88, 8.59, and 7.47]. Two tritium labeled dimeric derivatives ("DIBA-xanomeline"-type: [3H]UR-SK71 ([3H]44) and "DIBA-TBPB"-type: [3H]UR-SK59 ([3H]64)) were prepared to investigate their binding modes at hM2R. Saturation-binding experiments showed that these compounds address the orthosteric binding site of the M2R. The investigation of the effect of various allosteric MR modulators [gallamine (13), W84 (14), and LY2119620 (15)] on the equilibrium (13-15) or saturation (14) binding of [3H]64 suggested a competitive mechanism between [3H]64 and the investigated allosteric ligands, and consequently a dualsteric binding mode of 64 at the M2R. PMID- 30023531 TI - Optical Spectroscopic and Morphological Characterizations of Curcuminized Silk Biomaterials: A Perspective from Drug Stabilization. AB - Silk protein fibroins have gained remarkable attention in recent years as a potential drug carrier in the developing medicinal field of research. In this work, the stability of anticancer agent curcumin in the presence of two different silk protein fibroins from nonmulberry Antheraea mylitta (Am) and mulberry Bombyx mori (Bm) has been examined, and the possible mechanism of stabilization in a physiologically relevant medium has also been explored. In solution phase, upon treatment with curcumin, the predominated beta-sheet structure of Am is marginally altered, whereas in the case of Bm, a substantial structural changeover has been observed (from coil to beta-sheet) to accommodate the hydrophobic drug. Also, the morphological assessments suggest that curcumin is nicely housed in the nanoscaffold of silk fibroin (SF). Consequently, the extent of degradation of curcumin is remarkably suppressed upon encapsulation with the SF. The dissimilarity in the binding patterns of curcumin with these silk proteins could be responsible for the observed difference in the stability orders. Curcumin binds the surface of Bm, whereas in Am, the drug is incorporated in the hydrophobic cavity, and as a consequence, the drug is effectively sequestered out of the aqueous medium. The increase in the fluorescence quantum yield upon interaction with the protein greatly modulates the excited-state intermolecular hydrogen atom transfer (ESIPT) process, which is in tune with a substantial increase in the lifetime of the excited-state of curcumin. The ESIPT is known to play a crucial role in the degradation of curcumin under physiological pH conditions, which perhaps implies its potential therapeutic activity in the presence of silk. The in-depth spectroscopic analyses of curcumin SF complexes in aqueous medium can provide useful insights for further applicative developments in bioengineering. PMID- 30023532 TI - ZnO-ZnS Heterojunctions: A Potential Candidate for Optoelectronics Applications and Mineralization of Endocrine Disruptors in Direct Sunlight. AB - Simple solution combustion synthesis was adopted to synthesize ZnO-ZnS (ZSx) nanocomposites using zinc nitrate as an oxidant and a mixture of urea and thiourea as a fuel. A large thiourea/urea ratio leads to more ZnS in ZSx with heterojunctions between ZnS and ZnO and throughout the bulk; tunable ZnS crystallite size and textural properties are an added advantage. The amount of ZnS in ZSx can be varied by simply changing the thiourea content. Although ZnO and ZnS are wide band gap semiconductors, ZSx exhibits visible light absorption, at least up to 525 nm. This demonstrates an effective reduction of the optical band gap and substantial changes in its electronic structure. Raman spectroscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and secondary ion mass spectrometry results show features due to ZnO and ZnS and confirm the composite nature with heterojunctions. The above mentioned observations demonstrate the multifunctional nature of ZSx. Bare ZSx exhibits a promising sunlight-driven photocatalytic activity for complete mineralization of endocrine disruptors such as 2,4-dichlorophenol and endosulphan. ZSx also exhibits photocurrent generation at no applied bias. Dye-sensitized solar cell performance evaluation with ZSx shows up to 4% efficiency and 48% incident photon conversion efficiency. Heterojunctions observed between ZnO and ZnS nanocrystallites in high resolution transmission electron microscopy suggest the reason for effective separation of electron-hole pairs and their utilization. PMID- 30023534 TI - The Chemical Sciences and Health: Strengthening Synergies at a Vital Interface. AB - The indispensable contributions to health made by the chemical sciences have become increasingly constrained by three systemic factors. These involve fragmentations: in the way that the chemicals sciences are structured, practiced, and inter-related to aspects of health; in the combination of public and private efforts delivering medicinal products; and in the regulatory systems which oversee health-related issues across health, food, and the environment. Interlinked systemic reforms are advocated, involving (1) recontextualization of the chemistry/health interface through creating a recognized field of "the chemical sciences and health"; (2) determined and comprehensive efforts, by countries wishing to retain or strengthen their pharmaceutical development capacities, to reinforce their education, research, and innovation eco-systems; and (3) adoption of an integrated approach to the regulation of pharmaceuticals, food, and the environment. PMID- 30023533 TI - Aptasensor Based on Hierarchical Core-Shell Nanocomposites of Zirconium Hexacyanoferrate Nanoparticles and Mesoporous mFe3O4@mC: Electrochemical Quantitation of Epithelial Tumor Marker Mucin-1. AB - A novel nanostructured hierarchical core-shell nanocomposite of zirconium hexacyanoferrate (ZrHCF) and a mesoporous nanomaterial composed of Fe3O4 and carbon nanospheres (denoted as ZrHCF@mFe3O4@mC) was prepared and used as a novel platform for an aptasensor to detect the epithelial tumor marker mucin-1 (MUC1) sensitively and selectively. The prepared ZrHCF@mFe3O4@mC nanocomposite exhibited good chemical functionality, water stability, and high specific surface area. Therefore, large amounts of aptamer molecules resulted in high sensitivity of the developed electrochemical aptasensor toward traces of MUC1. The constructed sensor also showed a good linear relationship with the logarithm of MUC1 concentration in the broad range of 0.01 ng.mL-1 to 1.0 MUg.mL-1, with a low detection limit of 0.90 pg.mL-1. The fabricated ZrHCF@mFe3O4@mC-based aptasensor exhibited not only high selectivity because of the formation of aptamer-MUC1 complex but also good stability, acceptable reproducibility, and applicability. The proposed novel strategy based on a newly prepared hierarchical core-shell nanocomposite demonstrated outstanding biosensing performance and presents potential applications in biomedical fields. PMID- 30023535 TI - Difatty Acyl-Conjugated Linear and Cyclic Peptides for siRNA Delivery. AB - A number of amphiphilic difatty acyl linear and cyclic R5K2 peptide conjugates were synthesized by solid-phase peptide methods to enhance the interaction with the hydrophobic cellular phospholipid bilayer and to improve siRNA delivery and silencing. Binding to siRNA molecules was significantly less for the cyclic peptide conjugates. A gradual decrease was observed in the particle size of the complexes with increasing peptide/siRNA ratio for most of the synthesized peptides, suggesting the complex formation. Most of the complexes showed a particle size of less than 200 nm, which is considered an appropriate size for in vitro siRNA delivery. A number of fatty acyl-conjugated peptides, such as LP-C16 and LP-C18, displayed near complete protection against serum degradation. Flow cytometry studies demonstrated significantly higher internalization of fluorescence-labeled siRNA (FAM-siRNA) in the presence of LP-C16, LP-C18, and CP C16 with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) addition. Confocal microscopy confirmed the cellular internalization of fluorescence-labeled siRNA in the presence of LP-C16 and LP-C18 with DOPE when compared with cells exposed to DOPE/FAM-siRNA. While C16- and C18-conjugated peptides (especially linear peptides) showed silencing against kinesin spindle protein (KSP) and janus kinase 2 (JAK2) proteins, the addition of DOPE enhanced the silencing efficiency significantly for all selected peptides, except for CP-C16. In conclusion, C16 and C18 difatty acyl peptide conjugates were found to enhance siRNA delivery and generate silencing of targeted proteins in the presence of DOPE. This study provides insights for the design and potential application of optimized difatty acyl peptide/lipid nanoparticles for effective siRNA delivery. PMID- 30023536 TI - Immunosensor for Pancreatic Cancer Based on Electrospun Nanofibers Coated with Carbon Nanotubes or Gold Nanoparticles. AB - We report the fabrication of immunosensors based on nanostructured mats of electrospun nanofibers of polyamide 6 and poly(allylamine hydrochloride) coated either with multiwalled carbon nanotubes (MWCNTs) or gold nanoparticles (AuNPs), whose three-dimensional structure was suitable for the immobilization of anti CA19-9 antibodies to detect the pancreatic cancer biomarker CA19-9. Using impedance spectroscopy, the sensing platform was able to detect CA19-9 with a detection limit of 1.84 and 1.57 U mL-1 for the nanostructured architectures containing MWCNTs and AuNPs, respectively. The high sensitivity achieved can be attributed to the irreversible adsorption between antibodies and antigens, as confirmed with polarization-modulated infrared reflection absorption spectroscopy. The adsorption mechanism was typical Langmuir-Freundlich processes. The high sensitivity and selectivity of the immunosensors were also explored in tests with blood serum from patients with distinct concentrations of CA19-9, for which the impedance spectra data were processed with a multidimensional projection technique. The robustness of the immunosensors in dealing with patient samples without suffering interference from analytes present in biological fluids is promising for a simple, effective diagnosis of pancreatic cancer at early stages. PMID- 30023537 TI - Tuning Cross-Coupling Approaches to C3 Modification of 3-Deazapurines. AB - A general approach to C3 modification of purine scaffold through various types of cross-coupling reactions has been established. Tuning substrate electronics and reaction conditions resulted in the development of highly efficient sp2-sp, sp2 sp2, and sp2-sp3 cross-coupling conditions for modification of 3-deazaadenine to access C3-modified adenine and hypoxanthine scaffolds. The optimized methodologies to access the corresponding 3-deazaadenosine phosphoramidites for solid-phase DNA synthesis have been demonstrated. PMID- 30023538 TI - Nanosilk-Grafted Poly(lactic acid) Films: Influence of Cross-Linking on Rheology and Thermal Stability. AB - This article reports a novel fabrication of branched cum cross-linked poly(lactic acid) (PLA) with nanosilk fibroin with graft chain topology by reactive extrusion process. It could be possible by the addition of a small amount of radical initiator (dicumyl peroxide (DCP)). Grafting of silk nanocrystals (SNCs) on PLA macromolecules that provides remarkable improvement in the rheological and thermal properties of the latter are confirmed by 1H NMR and Fourier transform infrared investigation. Significant improvement is observed in zero shear viscosities, and the crossover point shifts to lower frequencies as compared to the branched and cross-linked PLA system. Along with SNC grafting, the crystallization process is also enhanced and stable crystals appeared during cooling, which results in a single melting peak. The rate of crystallization of PLA has been improved although the percentage crystallinity reduces with DCP content, as higher grafting and cross-linking restricts the chain segmental motion, which is critical for crystallization process. Furthermore, SNC grafting increases the reprocessability performance of PLA and provides higher rheological properties as compared to the branched and cross-linked PLA at all reprocessing cycles. PMID- 30023539 TI - Planar and Cell Aggregate-Like Assemblies Consisting of Microreactors and HepG2 Cells. AB - The assembly of microreactors has made considerable progress toward the fabrication of artificial cells. However, their characterization remains largely limited to buffer solution-based assays in the absence of their natural role model-the biological cells. Herein, the combination of microreactors with HepG2 cells either in planar cell cultures or in the form of cell aggregates is reported. Alginate (Alg)-based microreactors loaded with catalase are assembled by droplet microfluidics, and their activity is confirmed. The acceptance of polymer-coated ~40 MUm Alg particles by proliferating HepG2 cells is depending on the terminating polymer layer. When these functional microreactors are cocultured with HepG2 cells, they can be employed for detoxification, that is, hydrogen peroxide removal, and by doing so, they assist the cells to survive. This report is among the first successful combination of microreactors with biological cells, that is, HepG2 cells, contributing to the fundamental understanding of integrating synthetic and biological partners toward the maturation of this semisynthetic concept for biomedical applications. PMID- 30023540 TI - Highly Efficient Visible Blue-Emitting Black Phosphorus Quantum Dot: Mussel Inspired Surface Functionalization for Bioapplications. AB - The preparation of blue-emitting black phosphorus quantum dots (BPQDs) is based on the liquid-phase exfoliation of bulk BP. We report the synthesis of soluble BPQDs showing a strong visible blue-light emission. Highly fluorescent (photoluminescence quantum yield of ~5% with the maximum emission (lambdamax) at ~437 nm) and dispersible BPQDs in various organic solvents are first prepared by simple ultrasonication of BP crystals in chloroform in the ambient atmosphere. Furthermore, simple mussel-inspired surface functionalization of BPQDs with catechol-grafted poly(ethylene glycol) in basic buffer afforded water-soluble blue-emitting BPQDs showing long-term fluorescence stability, very low cytotoxicity, and excellent fluorescence live cell imaging capability. PMID- 30023541 TI - Iminosugars Spiro-Linked with Morpholine-Fused 1,2,3-Triazole: Synthesis, Conformational Analysis, Glycosidase Inhibitory Activity, Antifungal Assay, and Docking Studies. AB - Synthesis of iminosugars 1, 2, 3a, and 4a and N-alkyl (ethyl, butyl, hexyl, octyl, decyl, and dodecyl) derivatives 3b-g and 4b-g spiro-linked with morpholine fused 1,2,3-triazole is described. Conformation of the piperidine ring in each spiro-iminosugar was evaluated by 1H NMR spectroscopy, and conformational change in N-alkylated compounds 4b-g with respect to parent spiro-iminosugar 4a is supported by density functional theory calculations. Out of 16 new spiro iminosugars, the spiro-iminosugars 3a (IC50 = 0.075 MUM) and 4a (IC50 = 0.036 MUM) were found to be more potent inhibitors of alpha-glucosidase than the marketed drug miglitol (IC50 = 0.100 MUM). In addition, 3a (minimum inhibition concentration (MIC) = 0.85 MUM) and 4a (MIC = 0.025 MUM) showed more potent antifungal activity against Candida albicans than antifungal drug amphotericin b (MIC = 1.25 MUM). In few cases, the N-alkyl derivatives showed increase of alpha glucosidase inhibition and enhancement of antifungal activity compare to the respective parent iminosugar. The biological activities were further substantiated by molecular docking studies. PMID- 30023542 TI - Two-Dimensional Bi2WO6 Nanosheets as a Robust Catalyst toward Photocyclization. AB - The present work describes the improved photocatalytic activity of cetyl trimethylammonium bromide (CTAB)-assisted Bi2WO6 (CBTH) toward the synthesis of bioactive benzazoles. X-ray diffraction analysis of CBTH suggests that crystal growth has occurred along the (200) plane, whereas field-emission scanning electron microscopy images confirm two-dimensional rose bud morphology and high resolution transmission electron microscopy analysis suggests the formation of thin nanosheets possessing an orthorhombic structure. Temperature-programmed desorption of ammonia and Py-IR measurements indicate substantial acidity with the generation of Bronsted acid sites on the surface of CBTH. Raman spectra of CBTH also corroborate these observations with the formation of defects within [Bi2O2]2+ layers, resulting in decreased thickness and shapes of nanoplates. These beneficial properties are explored toward the photochemical synthesis of benzazoles using a 35 W tungsten lamp and a CBTH photocatalyst, resulting in better yields at lesser exposure time. It is observed that the catalytic activity is retained up to five consecutive cycles with marginal decrease in % yield. Such a feature can be ascribed to the photostability of the photocatalyst even after continuous exposure to light, implying that the surface active sites remained unaltered as evident from the X-ray photoelectron spectroscopy analysis of pre- and post-characterization of CBTH. Moreover, decrease in the surface hydroxyl groups after five catalytic cycles also accounts for the generation of enhanced Bronsted sites owing to the presence of Bi-O on the surface of CBTH. It exhibits better catalytic activity as compared to other photocatalysts employed for the synthesis of benzazoles. Thus, CBTH serves as a robust photocatalyst for the facile synthesis of these heterocycles in a sustainable manner. PMID- 30023543 TI - Hsp72 Is an Intracellular Target of the alpha,beta-Unsaturated Sesquiterpene Lactone, Parthenolide. AB - The electrophilic natural product parthenolide has generated significant interest as a model for potential chemotherapeutics. Similar to other alpha,beta unsaturated carbonyl electrophiles, parthenolide induces the heat shock response in leukemia cells, potentially through covalent adduction of heat shock proteins. Other thiol-reactive electrophiles have also been shown to induce the heat shock response as well as to covalently adduct members of the heat shock protein family, such as heat shock protein 72 (Hsp72). To identify sites of modification of Hsp72 by parthenolide, we used high-resolution tandem mass spectrometry to detect 10 lysine, histidine, and cysteine residues of recombinant Hsp72 as modified in vitro by 10 and 100 MUM parthenolide. To further ascertain that modification of Hsp72 by parthenolide occurs inside cells and not simply as an in vitro artifact, an alkyne-labeled derivative of parthenolide was synthesized to enable enrichment and detection of protein targets of parthenolide using copper catalyzed [3 + 2] azide-alkyne cycloaddition. The alkyne-labeled parthenolide derivative displays an half maximal inhibitory concentration (IC50) in undifferentiated acute monocytic leukemia cells (THP-1) of 13.1 +/- 1.1 MUM, whereas parthenolide has an IC50 of 4.7 +/- 1.1 MUM. Concentration dependence of protein modification by the alkyne-parthenolide derivative was demonstrated, as well as in vitro adduction of Hsp72. Following treatment of THP-1 cells in culture by the alkyne-parthenolide, adducted proteins were isolated with neutravidin resin and detected by immunoblotting in the enriched protein fraction. Hsp70 proteins were detected in the enriched proteins, indicating that Hsp70 proteins were adducted intracellularly by the alkyne-parthenolide derivative. PMID- 30023544 TI - Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors. AB - We have recently identified a new class of filamenting temperature-sensitive mutant Z (FtsZ)-interacting compounds that possess a 2,4,6-trisubstituted pyrimidine-quinuclidine scaffold with moderate antibacterial activity. Employing this scaffold as a molecular template, a compound library of amine-linked 2,4,6 trisubstituted pyrimidines with 99 candidates was successfully established by employing an efficient convergent synthesis designed to explore their structure activity relationship. The results of minimum inhibitory concentration (MIC) assay against Staphylococcus aureus strains and cytotoxicity assay against the mouse L929 cell line identified those compounds with potent antistaphylococcal properties (MIC ranges from 3 to 8 MUg/mL) and some extent of cytotoxicity against normal cells (IC50 ranges from 6 to 27 MUM). Importantly, three compounds also exhibited potent antibacterial activities against nine clinically isolated methicillin-resistant S. aureus (MRSA) strains. One of the compounds, 14av_amine16, exhibited low spontaneous frequency of resistance, low toxicity against Galleria mellonella larvae, and the ability to rescue G. mellonella larvae (20% survival rate at a dosage of 100 mg/kg) infected with a lethal dose of MRSA ATCC 43300 strain. Biological characterization of compound 14av_amine16 by saturation transfer difference NMR, light scattering assay, and guanosine triphosphatase hydrolysis assay with purified S. aureus FtsZ protein verified that it interacted with the FtsZ protein. Such a property of FtsZ inhibitors was further confirmed by observing iconic filamentous cell phenotype and mislocalization of the Z-ring formation of Bacillus subtilis. Taken together, these 2,4,6-trisubstituted pyrimidine derivatives represent a novel scaffold of S. aureus FtsZ inhibitors. PMID- 30023545 TI - Enzymatic Catalysis at Nanoscale: Enzyme-Coated Nanoparticles as Colloidal Biocatalysts for Polymerization Reactions. AB - Enzyme-catalyzed controlled radical polymerization represents a powerful approach for the polymerization of a wide variety of water-soluble monomers. However, in such an enzyme-based polymerization system, the macromolecular catalyst (i.e., enzyme) has to be separated from the polymer product. Here, we present a compelling approach for the separation of the two macromolecular species, by taking the catalyst out of the molecular domain and locating it in the colloidal domain, ensuring quasi-homogeneous catalysis as well as easy separation of precious biocatalysts. We report on gold nanoparticles coated with horseradish peroxidase that can catalyze the polymerization of various monomers (e.g., N isopropylacrylamide), yielding thermoresponsive polymers. Strikingly, these biocatalyst-coated nanoparticles can be recovered completely and reused in more than three independent polymerization cycles, without significant loss of their catalytic activity. PMID- 30023546 TI - Surface Modification of Silicon Pillar Arrays To Enhance Fluorescence Detection of Uranium and DNA. AB - There is an ever-growing need for detection methods that are both sensitive and efficient, such that reagent and sample consumption is minimized. Nanopillar arrays offer an attractive option to fill this need by virtue of their small scale in conjunction with their field enhancement intensity gains. This work investigates the use of nanopillar substrates for the detection of the uranyl ion and DNA, two analytes unalike but for their low quantum efficiencies combined with the need for high-throughput analyses. Herein, the adaptability of these platforms was explored, as methods for the successful surface immobilization of both analytes were developed and compared, resulting in a limit of detection for the uranyl ion of less than 1 ppm with a 0.2 MUL sample volume. Moreover, differentiation between single-stranded and double-stranded DNA was possible, including qualitative identification between double-stranded DNA and DNA of the same sequence, but with a 10-base-pair mismatch. PMID- 30023547 TI - Polydiacetylene Nanofiber Composites as a Colorimetric Sensor Responding To Escherichia coli and pH. AB - Polydiacetylenes (PDAs) are conjugative polymers that demonstrate color changes as a response to an external stimulus. In this study, 10,12-pentacosadiynoic acid (PCDA) was mixed with a supporting polymer including poly(ethylene oxide) (PEO) and polyurethane (PU), and the mixture solution was electrospun to construct fiber composites. The electrospun fibers were then photopolymerized using UV irradiation to produce PEO-PDA and PU-PDA nanofiber mats with a fiber diameter ranging from 130 nm to 2.5 MUm. The morphologies of both PEO-PDA and PU-PDA nanofibers were dependent on electrospinning parameters such as the ratio of PCDA to PEO or PCDA to PU and the total polymer concentrations. Scanning electron microscopy images showed beaded fibers of PEO-PDA and PU-PDA at 2 and 18 w/v % concentrations, respectively. Smooth fibers were found when the solvent concentration was increased to 3.75 w/v % in PEO-PDA and 25 w/v % in PU-PDA fibers. Both PEO-PDA and PU-PDA nanofiber composites demonstrated excellent colorimetric responses to the presence of Escherichia coli ATCC25922 bacterial cells and the changes in pH as external stimuli. The nanofibers underwent a rapid colorimetric response when exposed directly to E. coli ATCC25922 grown on Luria Bertani agar. The comparison between the PEO-PDA and PU-PDA suggested that the combination of PEO and PDA is favorable because it provides a sensitive response to the presence of E. coli. The results were compared with samples of a PDA polymer in the absence of a matrix polymer. The colorimetric response was similar when the PDA polymer and the PDA nanofiber composites were exposed to pH changes, and the color change was found to occur at pH 10 and enhanced at pH 11-13. The PDA-containing nanofiber composites showed stronger colorimetric responses than those of the PDA polymer only, suggesting their potential as biosensors and chemosensors. PMID- 30023548 TI - Silver-Mediated Double Helix: Structural Parameters for a Robust DNA Building Block. AB - The DNA double helix is a versatile building block used in DNA nanotechnology. To potentiate the discovery of new DNA nanoscale assemblies, recently, silver cations have been introduced to pair DNA strands by base-Ag+-base bonding rather than by Watson-Crick pairing. In this work, we study the classical dynamics of a parallel silver-mediated homobase double helix and compare it to the dynamics of the antiparallel double helix. Our classical simulations show that only the parallel double helix is highly stable through the 100 ns simulation time. A new type of H-bond previously proposed by our collaboration and recently observed in crystal-determined helices drives the physicochemical stabilization. Compared to the natural B-DNA form, the metal-mediated helix has a contracted axial base pair rise and smaller numbers of base pairs per turn. These results open the path for the inclusion of this robust metal-mediated building block into new nanoscale DNA assemblies. PMID- 30023549 TI - Immunocontrolling Graphene Oxide Catalytic Nanogold Reaction and Its Application to SERS Quantitative Analysis. AB - The gold nanoreaction between HAuCl4 and H2O2 is very slow at 50 degrees C, and the nanoenzyme of graphene oxide (GO) greatly catalyzes the nanoreaction to form gold nanoparticles (AuNPs) with high SERS activity in the presence of Vitoria blue 4R (VB4r) molecular probes, strong resonance Rayleigh scattering (RRS), and surface plasmon resonance (SPR) absorption effect. With the increase of GO, the SERS, RRS, and SPR absorptions were enhanced linearly due to the formation of more AuNPs. The rabit antibody of human chorionic gonadotropin (RHCG) strongly adsorbed on the GO surface to inhibit its catalysis. Upon addition of human chorionic gonadotropin (HCG), the RHCG is separated from the GO surface due to the formation of HCG-RHCG specific immunocomplexes, which led to the recovery of GO catalysis. Using the new strategy of immunocontrolling GO catalysis, three types of resonance methods including SERS, RRS, and surface plasmon resonance (SPR) absorption have been developed for detection of HCG. PMID- 30023550 TI - Site-Specific Fluorescence Dynamics To Probe Polar Arrest by Fob1 in Replication Fork Barrier Sequences. AB - Fob1 protein plays an important role in aging and maintains genomic stability by avoiding clashes between the replication and transcription machinery. It facilitates polar arrest by binding to replication fork barrier (RFB) sites, present within the nontranscribed spacer region of the ribosomal DNA. Here, we investigate the mechanism of unidirectional arrest by creating multiple prosthetic forks within the RFB, with fluorescent adenine analogue 2-aminopurine incorporated site-specifically in both the "permissible" and "nonpermissible" directions. The motional dynamics of the RFB-Fob1 complexes analyzed by fluorescence lifetime and fluorescence anisotropy decay kinetics shows that Fob1 adopts a clamp-lock model of arrest and causes stronger perturbation with the bases in the double-stranded region of the nonpermissible-directed forks over those of the permissible directed ones, thereby creating a polar barrier. Corroborative thermal melting studies reveal a skewed distribution of GC content within the RFB sequence that potentially assists in Fob1-mediated arrest. PMID- 30023551 TI - Antibiotic Resistance: Current Perspectives. AB - Antibiotic resistance is one of the most serious challenges that the world is currently facing. The number of people succumbing to drug-resistant infections is increasing every day, but the rate of drug discovery has failed to match the requisite demands. Most of the currently known antibiotics target the three essential pathways of central dogma. However, bacteria have evolved multiple mechanisms to survive these antibiotics. Consequently, there is an urgent necessity to target auxiliary pathways for the discovery of new drugs. Metabolism related and stress-associated pathways are ideal in this regard. The stringent response pathway regulated by the signaling nucleotides (p)ppGpp is an attractive target as inhibition of the pathway would in turn decrease the persistence and long-term survival of pathogenic bacteria. In this perspective, we focus on the recent design of small molecule analogues of (p)ppGpp that have yielded promising results in terms of growth and biofilm inhibition. Additionally, we discuss how targeting small RNAs and riboswitches, as well as antimicrobial peptides, would help combat drug-resistant infections in the near future. PMID- 30023552 TI - Capillary-Driven Sensor Fabrication of Polydiacetylene-on-Silica Plate in 30 Seconds: Facile Utilization of pi-Monomers with C18- to C25-Long Alkyl Chain. AB - By utilizing the capillary-force-driven action, a novel polydiacetylene-based sensor on the porous silica plate was developed within 30 s for pi-diacetylene monomers with variable chain lengths. This method enables one to utilize diacetylene monomers even with the shorter alkyl chain length of C18-C21, which has not been possible with conventional methods. The invented sensor platform employing shorter monomers was found to perform better, as was demonstrated for gaseous and aqueous analytes, i.e., ammonia gas and nucleic acids in aqueous phase. This new polydiacetylene platform opens up the development of quick and easy fabrication and the use of chemical and biochemical chips. PMID- 30023553 TI - Enhancing Surface Sensitivity of Nanostructure-Based Aluminum Sensors Using Capped Dielectric Layers. AB - The studies of nanostructure-based aluminum sensors have attracted huge attention because aluminum is a more cost-effective plasmonic material. However, the intrinsic properties of the aluminum metal, having a large imaginary part of the dielectric function and a longer electromagnetic field decay length and problems of poor long-term chemical stability, limit the surface-sensing capability and applicability of nanostructures. We propose the combination of capped aluminum nanoslits and a thin-capped dielectric layer to overcome these limitations. We show that the dielectric layer can positively enhance the wavelength sensitivities of the Wood's anomaly-dominant resonance and asymmetric Fano resonance in capped aluminum nanoslits. The maximum improvement can be reached by a factor of 3.5. Besides, there is an optimal layer thickness for the surface sensitivity because of the trade-off relationship between the refractive index sensitivity and decay length. We attribute the enhanced surface sensitivity to a reduced evanescent length, which is confirmed by the finite difference time domain calculations. The protein-protein interaction experiments verify the high surface sensitivity of the structures, and a limit of quantification (LOQ) of 1 pg/mL anti-bovine serum albumin is achieved. Such low-cost, highly sensitive aluminum-based nanostructures can benefit various sensing applications. PMID- 30023554 TI - Enhanced Peripheral Nerve Regeneration by a High Surface Area to Volume Ratio of Nerve Conduits Fabricated from Hydroxyethyl Cellulose/Soy Protein Composite Sponges. AB - Multichannel nerve guide conduits (MCNGCs) have been widely studied and exhibited outstanding nerve repair function. However, the effect of the geometric structure of MCNGCs on the nerve repair function was still not clear. Herein, we postulated that MCNGCs with different inner surface area-to-volume ratios (ISA/V) of the channels inside the nerve guide conduits (NGCs) would show different nerve repair functions. Therefore, in current work, we constructed a series of hydroxyethyl cellulose/soy protein sponge-based nerve conduit (HSSN) with low, medium, and high ISA/V from hydroxyethyl cellulose (HEC)/soy protein isolate (SPI) composite sponges, which were abbreviated as HSSN-L, HSSN-M and HSSN-H, respectively. These NGCs were applied to bridge and repair a 10 mm long sciatic nerve defect in a rat model. Finally, the influence of ISA/V on nerve repair function was evaluated by electrophysiological assessment, histological investigation, and in vivo biodegradability testing. The results of electrophysiological assessment and histological investigation showed that the regenerative nerve tissues bridged with HSSN-H and HSSN-M had higher compound muscle action potential amplitude ratio, higher percentage of positive NF200 and S100 staining, larger axon diameter, lower G-ratio, and greater myelination thickness. Furthermore, the regenerative nerve tissues bridged with HSSN-H also showed higher density of regenerated myelinated nerve fibers and more number of myelin sheath layers. On the whole, the repair efficiency of the peripheral nerve in HSSN-H and HSSN-M groups might be better than that in HSSN-L. These results indicated that higher ISA/V based on HEC/SPI composite sponge may result in greater nerve repair functions. The conclusion provided a probable guiding principle for the structural designs of NGCs in the future. PMID- 30023555 TI - Influence of Acyl Chain Saturation on the Membrane-Binding Activity of a Short Antimicrobial Peptide. AB - Different bacterial types and their living environments can lead to different saturations in the chains of their membrane lipids. Such structural differences may influence the efficacy of antibiotics that target bacterial membranes. In this work, the effects of acyl chain saturation on the binding of an antimicrobial peptide G4 have been examined as a function of the packing density of lipid monolayers by combining external reflection Fourier transform infrared (ER-FTIR) spectroscopy and neutron reflection (NR) measurements. Langmuir monolayers were formed from 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac glycerol) (DPPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG), respectively, with the initial surface pressures controlled at 8 and 28 mN/m. A reduction in the order of the acyl chains associated with the increase in the layer thickness upon G4 binding was revealed from ER-FTIR spectroscopy, with peptide binding reaching equilibration faster in POPG than in DPPG monolayers. Whereas the dynamic DPPG-binding process displayed a steady increase in the amide I band area, the POPG-binding process showed little change in the amide area after the initial period. The peptide amide I area from ER-FTIR spectroscopy could be linearly correlated with the adsorbed G4 amount from NR, irrespective of time, initial pressure, or chain saturation, with clearly more peptide incorporated into the DPPG monolayer. Furthermore, NR revealed that although the peptide was associated with both POPG and DPPG lipid monolayers, it was more extensively distributed in the latter, showing that acyl chain saturation clearly promoted peptide binding and structural disruption. PMID- 30023556 TI - Generation of Novel Anti-MUC1 Monoclonal Antibodies with Designed Carbohydrate Specificities Using MUC1 Glycopeptide Library. AB - Numerous anti-mucin 1 (anti-MUC1) antibodies that recognize O-glycan core structures have already been developed. However, most of them show low specificities toward O-glycan structures and/or low affinity toward a monovalent epitope. In this study, using an MUC1 glycopeptide library, we established two novel anti-MUC1 monoclonal antibodies (1B2 and 12D10) with designed carbohydrate specificities. Compared with previously reported anti-MUC1 antibodies, 1B2 and 12D10 showed quite different features regarding their specificities, affinities, and reactivity profiles to various cell lines. Both antibodies recognized specific O-glycan structures at the PDT*R motif (the asterisk represents an O glycosylation site). 1B2 recognized O-glycans with an unsubstituted O-6 position of the GalNAc residue (Tn, T, and 23ST), whereas 12D10 recognized Neu5Ac at the same position (STn, 26ST, and dST). Neither of them bound to glycopeptides with core 2 O-glycans that have GlcNAc at the O-6 position of the GalNAc residue. Furthermore, 1B2 and 12D10 showed a strong binding to not only native MUC1 but also 20-mer glycopeptide with a monovalent epitope. These anti-MUC1 antibodies should thus become powerful tools for biological studies on MUC1 O-glycan structures. Furthermore, the strategy of using glycopeptide libraries should enable the development of novel antibodies with predesigned O-glycan specificities. PMID- 30023557 TI - Antifouling and Photocatalytic Antibacterial Activity of the AquaSun Coating in Seawater and Related Media. AB - Prolonged testing of the new xerogel photocatalytic coating AquaSun applied to a surface probe immersed in ocean water irradiated with simulated solar radiation shows excellent action against biofouling. Activated by moderate solar radiation, the organosilica film has also good antimicrobial properties. Considering the high stability, the environmental footprint, and the low cost of this sol-gel marine coating, the technology has significant potential toward replacing conventional antifouling and foul-release coatings with a single product of broad applicability. PMID- 30023558 TI - Dual Probe Sensors Using Atomically Precise Noble Metal Clusters. AB - This article adds a new direction to the functional capability of protein protected atomically precise gold clusters as sensors. Counting on the extensively researched intense luminescence of these clusters and considering the electron donating nature of select amino acids, we introduce a dual probe sensor capable of sensing changes in luminescence and conductivity, utilizing bovine serum albumin-protected atomically precise gold clusters hosted on nanofibers. To this end, we have also developed a hybrid nanofiber with a conducting core with a porous dielectric shell. We show that clusters in combination with nanofibers offer a highly selective and sensitive platform for the detection of trace quantities of trinitrotoluene, both in solution and in the vapor phase. In the solution phase, trinitrotoluene (TNT) can be detected down to 1 ppt at room temperature, whereas in vapor phase, 4.8 * 109 molecules of TNT can be sensed using a 1 mm fiber. Although the development in electrospinning techniques for fabricating nanofibers as sensors is quite substantial, a hybrid fiber with the dual properties of conductivity and luminescence has not been reported yet. PMID- 30023559 TI - Effect of Vitamin E and a Long-Chain Alcohol n-Octanol on the Carbohydrate-Based Nonionic Amphiphile Sucrose Monolaurate-Formulation of Newly Developed Niosomes and Application in Cell Imaging. AB - We have introduced new niosome formulations using sucrose monolaurate, vitamin E and n-octanol as independent additives. Detailed characterization techniques including turbidity, dynamic light scattering, transmission electron microscopy, xi potential, and proton nuclear magnetic resonance measurements have been introduced to monitor the morphological transition of the carbohydrate-based micellar assembly into niosomal aggregates. Moreover, microheterogeneity of these niosomal aggregates has been investigated through different fluorescence spectroscopic techniques using a hydrophobic probe molecule coumarin 153 (C153). Further, it has been observed that vitamin E and octanol have an opposing effect on the rotational motion of C153 in the respective niosome assemblies. The time resolved anisotropy studies suggest that incorporation of vitamin E and octanol into the surfactant aggregates results in slower and faster rotational motion of C153, respectively, compared to the micellar assemblies. Moreover, the ability to entrap a probe molecule by these niosomes is utilized to encapsulate and deliver the anticancer drug doxorubicin inside the mammalian cells which is monitored through fluorescence microscopic images. Interestingly, the niosome composed of vitamin E demonstrated better cytocompatibility toward primary chondrocyte cell lines compared to the octanol-forming niosome. PMID- 30023560 TI - Enhanced Transverse Magneto-Optical Kerr Effect in Magnetoplasmonic Crystals for the Design of Highly Sensitive Plasmonic (Bio)sensing Platforms. AB - We propose a highly sensitive sensor based on enhancing the transversal magneto optical Kerr effect (TMOKE) through excitation of surface plasmon resonances in a novel and simple architecture, which consists of a metal grating on a metal magneto-optical layer. Detection of the change in the refractive index of the analyte medium is made by monitoring the angular shift of the Fano-like resonances associated with TMOKE. A higher resolution is obtained with this technique than with reflectance curves. The key aspect of the novel architecture is to achieve excitation of surface plasmon resonances mainly localized at the sensing layer, where interaction with the analyte occurs. This led to a high sensitivity, S = 190 degrees RIU-1, and high performance with a figure of merit of the order of 103, which can be exploited in sensors and biosensors. PMID- 30023561 TI - Five-Part Pentameric Nanocomplex Shows Improved Efficacy of Doxorubicin in CD44+ Cancer Cells. AB - The CD44 receptor is common among many cancer types where overexpression is synonymous with poor prognosis in prostate, glioma, and breast cancer. More notably CD44 overexpression has been shown in a number of different cancer stem cells (CSC) which are present in many solid tumors and drive growth, recurrence, and resistance to conventional therapies. Triple negative breast cancer CSCs correlate to worse prognosis and early relapse due to higher drug resistance and increased tumor heterogeneity and thus are prime targets for anticancer therapy. To specifically target cells overexpressing CD44 receptors, including CSCs, we synthesized a pentameric nanocomplex (PNC) containing gold nanoparticles, doxorubicin (Dox) conjugated to thiolated hyaluronic acid via an acid-labile hydrazone bond, and thiolated poly(ethylene glycol) DNA CD44 aptamer. In vitro drug release was highest at 8 h time point at acidic pH (pH 4.7) and in 10 mM glutathione. The PNC is almost an order of magnitude more effective than Dox alone in CD44+ cells versus CD44 low cells. Functionally, the PNC reduced CSC self-renewal. The PNC provides a therapeutic strategy that can improve the efficiency of Dox and decrease nontargeted toxicity thereby prolonging its use to individual patients. PMID- 30023562 TI - Multifunctional Biochar for Highly Efficient Capture, Identification, and Removal of Toxic Metals and Superbugs from Water Samples. AB - According to the World Health Organization, more than two billion people in our world use drinking water sources which are not free from pathogens and heavy metal contamination. Unsafe drinking water is responsible for the death of several millions in the 21st century. To find facile and cost-effective routes for developing multifunctional materials, which has the capability to resolve many of the challenges associated with drinking water problem, here, we report the novel design of multifunctional fluorescence-magnetic biochar with the capability for highly efficient separation, identification, and removal of pathogenic superbugs and toxic metals from environmental water samples. Details of synthesis and characterization of multifunctional biochar that exhibits very good magnetic properties and emits bright blue light owing to the quantum confinement effect are reported. In our design, biochar, a carbon-rich low-cost byproduct of naturally abundant biomass, which exhibits heterogeneous surface chemistry and strong binding affinity via oxygen-containing group on the surface, has been used to capture pathogens and toxic metals. Biochar dots (BCDs) of an average of 4 nm size with very bright photoluminescence have been developed for the identification of pathogens and toxic metals. In the current design, magnetic nanoparticles have been incorporated with BCDs which allow pathogens and toxic metals to be completely removed from water after separation by an external magnetic field. Reported results show that owing to the formation of strong complex between multifunctional biochar and cobalt(II), multifunctional biochar can be used for the selective capture and removal of Co(II) from environmental samples. Experimental data demonstrate that multifunctional biochar can be used for the highly efficient removal of methicillin-resistant Staphylococcus aureus (MRSA) from environmental samples. Reported results also show that melittin, an antimicrobial peptide-attached multifunctional biochar, has the capability to completely disinfect MRSA superbugs after magnetic separation. A possible mechanism for the selective separation of Co(II), as well as separation and killing of MRSA, has been discussed. PMID- 30023563 TI - Exploring Structural Relationships between Bioactive and Commercial Chemical Space and Developing Target Hypotheses for Compound Acquisition. AB - Analog series were systematically extracted from more than 650 000 bioactive compounds originating from medicinal chemistry and screening sources and more than 3.6 million commercial compounds that were not biologically annotated. Then, analog series-based (ASB) scaffolds were generated. For each scaffold from a bioactive series, a target profile was derived and ASB scaffolds shared by bioactive and commercial compounds were determined. On the basis of our analysis, large segments of commercial chemical space were not yet explored biologically. Shared ASB scaffolds established structural relationships between bioactive and commercial chemical space, and the target profiles of these scaffolds were transferred to commercially available analogs of active compounds. This made it possible to derive target hypotheses for more than 37 000 compounds without biological annotations covering more than 1000 different targets. For many molecules, alternative target assignments were available. Target hypotheses for these compounds should be of interest, for example, for hit expansion, acquisition of compounds to design or further extend focused libraries for drug discovery, or testing of expanded analog series on different targets. They can also be used to search for analogs and complement compound series during target directed optimization. Therefore, all of the commercial molecules with new target hypotheses as well as key scaffolds identified in our analysis and their target profiles are made freely available. PMID- 30023564 TI - Hyaluronic Acid Layered Chimeric Nanoparticles: Targeting MAPK-PI3K Signaling Hub in Colon Cancer Cells. AB - Colon cancer has emerged as one of the most devastating diseases in the whole world. Mitogen-activated protein kinase (MAPK)-phosphatidylinsitol-3-kinase (PI3K) signaling hub has gained lots of attention due to its deregulation in colon cancer cells. However, selective targeting of oncogenic MAPK-PI3K hub in colon cancer has remained highly challenging, hence it has mostly been unexplored. To address this, we have engineered a hyaluronic acid layered lipid based chimeric nanoparticle (HA-CNP) consisting of AZD6244 (MAPK inhibitor), PI103 (PI3K inhibitor), and cisplatin (DNA impairing drug) ratiometrically in a single particle. Electron microscopy (field emission scanning electron microscopy and atomic force microscopy) and dynamic light scattering were utilized to characterize the size, shape, morphology, and surface charge of the HA-CNPs. Fluorescent confocal laser scanning microscopy and flow cytometry analysis confirmed that HA-CNPs were taken up by HCT-116 colon cancer cells by merging of clathrin and CD44 receptor-mediated endocytosis along with macropinocytosis to home into acidic organelles (lysosomes) within 1 h. A gel electrophoresis study evidently established that HA-CNPs simultaneously inhibited MAPK-PI3K signaling hub with DNA damage in HCT-116 cells. These HA-CNPs stalled the cell cycle into G0/G1 phase, leading to induction of apoptosis (early and late) in colon cancer cells. Finally, these HA-CNPs exerted remarkable cytotoxicity in HCT-116 colon cancer cells at 24 h compared to that of the free triple drug cocktail as well as HA-coated dual drug-loaded nanoparticles without showing any cell death in healthy L929 fibroblast cells. These HA-coated CNPs have potential to be translated into clinics as a novel platform to perturb various oncogenic signaling hubs concomitantly toward next-generation targeted colon cancer therapy. PMID- 30023565 TI - Small Molecules Targeting the Inactive Form of the Mnk1/2 Kinases. AB - Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogen-activated protein kinases-interacting kinases 1 and 2 (Mnk1/2) activate the oncogene eIF4E through posttranslational modification (phosphorylating it at the conserved Ser209). Inhibition of Mnk prevents eIF4E phosphorylation, making the Mnk-eIF4E axis a potential therapeutic target for oncology. Recently, the design and synthesis of a series of novel potent compounds inhibiting the Mnk1/2 kinases were carried out in-house. Here, we describe computational models of the interactions between Mnk1/2 kinases and these inhibitors. Molecular modeling combined with free energy calculations show that these compounds bind to the inactive forms of the kinases. All compounds adopt similar conformations in the catalytic sites of both kinases, stabilized by hydrogen bonds with the hinge regions and with the catalytic Lys78 (Mnk1) and Lys113 (Mnk2). These hydrogen bond interactions clearly play a critical role in determining the conformational stability and potency of the compounds. We also find that van der Waals interactions with an allosteric pocket are key to their binding and potency. Two distinct hydration sites that appear to further stabilize the ligand binding/interactions were observed. Critically, the inclusion of explicit water molecules in the calculations results in improving the agreement between calculated and experimental binding free energies. PMID- 30023566 TI - Green Transfection: Cationic Lipid Nanocarrier System Derivatized from Vegetable Fat, Palmstearin Enhances Nucleic Acid Transfections. AB - Cationic lipid-guided nucleic acid delivery holds great promise in gene therapy and genome-editing applications for treating genetic diseases. However, the major challenge lies in achieving therapeutically relevant efficiencies. Prior findings, including our own, demonstrated that asymmetry in the hydrophobic core of cationic lipids imparted superior transfection efficiencies. To this end, we have developed a lipid nanocarrier system with an asymmetric hydrophobic core (PS Lips) derived from a mixture of fatty acids of food-grade palmstearin and compared its efficiency with symmetric palmitic acid-based nanocarrier system (P Lip). PS-Lips exhibited superior transfection efficiencies with both plasmid DNA (pDNA) and mRNA in multiple cultured cells than the control P-Lip. More importantly, PS-Lips exhibited 2-fold superior transfections with linear nucleic acid, green fluorescent protein (GFP) mRNA in hematopoietic cells, when compared with the commercial control lipofectamine RNAiMAX. PS-Lips was also found to be effective in delivering genome-editing tools (CRISPR/Cas9, sgRNA encoded pDNA with a reporter GFP construct) than P-Lip in HEK-293 cells. In the present study, we report that cationic liposomes derivatized from natural food-grade fat palmstearin with a natural hydrophobic core asymmetry are efficient in delivering both linear and circular nucleic acids. In particular, PS-Lips is efficient in delivering mRNA to hematopoietic cells. These findings can be further exploited in the genome-editing approach for treating beta-globinopathies. PMID- 30023567 TI - Poly(l-lysine)-Coated Liquid Crystal Droplets for Sensitive Detection of DNA and Their Applications in Controlled Release of Drug Molecules. AB - Interactions between DNA and adsorbed poly(l-lysine) (PLL) on liquid crystal (LC) droplets were investigated using polarizing optical microcopy and epi fluorescence microscopy. Earlier, we demonstrated that adsorption of PLL to the LC/aqueous interface resulted in homeotropic orientation of the LC and thus exhibited a radial configuration of the LC confined within the droplets. Subsequent adsorption of DNA (single-stranded DNA/double-stranded DNA) at PLL coated LC droplets was found to trigger an LC reorientation within the droplets, leading to preradial/bipolar configuration of those droplets. To our surprise, subsequent exposure of complementary ssDNA to ssDNA/adsorbed PLL-modified LC droplets did not cause the LC reorientation. This is likely due to the formation of polyplexes (DNA-PLL complex) as confirmed by fluorescence microscopy and atomic force microscopy. In addition, dsDNA-adsorbed PLL droplets have been found to be effectively useful to displace (controlled release) propidium iodide (a model drug) encapsulated within dsDNA over time. These observations suggest the potential for a label-free droplet-based LC detection system that can respond to DNA and may provide a simple method to develop DNA-based drug nanocarriers. PMID- 30023568 TI - Temperature- and Composition-Dependent DNA Condensation by Thermosensitive Block Copolymers. AB - Successful intracellular delivery of genes requires an efficient carrier, as genes by themselves cannot diffuse across cell membranes. Because of the toxicity and immunogenicity of viral vectors, nonviral vectors are gaining tremendous interest in research. In this work, we have investigated the temperature dependent DNA condensation efficiency of various compositions of a thermosensitive block copolymer viz., poly(N-isopropylacrylamide)-b-poly(2 (diethylamino)ethyl methacrylate) (PNIPA-b-PDMAEMA). Three different copolymer compositions of varying molecular weights were successfully synthesized via the RAFT polymerization technique. Steady-state fluorescence and circular dichroism (CD) spectroscopies, dynamic light scattering (DLS) and zeta potential measurements, agarose gel electrophoresis, and atomic force microscopy techniques were utilized to study the interaction of the copolymers with DNA at temperatures above and below the critical aggregation temperature (CAT). All these experiments revealed that, above the CAT, there was formation of highly stable and tight polymer-DNA complexes (polyplexes). The size of polyplexes was dependent on the temperature up to a certain charge ratio, as determined by the DLS results. The results obtained from temperature-dependent fluorescence spectroscopy, CD, and gel electrophoresis indicated that the DNA molecules were shielded more from aqueous exposure above the CAT because of the formation of relatively more compact complexes. The polyplexes also exhibited changes in the particle morphology below and above the CAT, with particles generated above CAT being more spherical in morphology. These results suggested at the possibility of modulating the complex formation by temperature modification. The present biophysical studies would provide new physical insight into the design of novel gene carriers. PMID- 30023569 TI - Cancer Therapeutic Proficiency of Dual-Targeted Mesoporous Silica Nanocomposite Endorses Combination Drug Delivery. AB - The cargo-loaded mesoporous silica nanoparticles (MSNs) with convenient surface modification can facilitate the development of the innovative nanodrug system. Herein, the present investigation described the electrostatically self-assembled MSNs as a nanosized drug carrier to realize potent synergistic chemotherapy based on the specificity in targeting cytoplasm and nucleus of tumor cells. In this context, the primarily constructed MSNs were subjected with anticancer drug topotecan (TPT) into its large pores. Then, the selective TAT peptide (a nuclear localization signal peptide) was anchored onto TPT-loaded MSNs (TPT-MSN). Subsequently, the positive surface of TPT-MSN-TAT was capped with negatively charged components, poly(acrylic acid) (PAA)-cRGD peptide and citraconic anhydride (CAH)-metformin (MT), and acted as a smart gatekeeper. Comparatively, PAA-cRGD attached onto MSNs serving as the targeted molecules could upsurge by invasion into cancer cells. Interestingly, the acidic pH of the lysosomal compartment in tumor cells triggers the conjugated CAH from the polymer decorated mesoporous silica (PMS) nanocomposite and could efficiently release MT into the cytoplasm. Consequently, the remaining TPT-MSN-TAT efficiently targets the nucleus and delivers the TPT to improve synergistic chemotherapeutic effects. The precisely released drugs were individually enhanced in the in vitro and in vivo cell killing efficiencies. Thus, the study provides a potential drug delivery podium through combined drugs to realize cancer cell targeting approach. PMID- 30023570 TI - Controlling the Degree of Esterification of Citrus Pectin for Demanding Applications by Selection of the Source. AB - Analyzed by a quantitative method based on diffuse reflectance infrared Fourier transform spectroscopy, pectins extracted from different regions (outer skin, peel, and waste) of citrus fruits (red orange, lemon, and grapefruit) via microwave-assisted hydrodiffusion show significant variations. All polymers obtained are low-methoxyl pectins, with high contents in galacturonic acid regions. The degree of esterification (DE) of pectin extracted from different regions increases in the order waste < peel < outer skin for red orange, inverting for lemon. Thus, the pectins with the lowest DE are those extracted from red orange waste and lemon outer skin (~25%). These findings open the route to nutraceutical- and pharmaceutical-grade pectins from citrus, in which the source fruit and its regions may be chosen, according to the desired DE. PMID- 30023571 TI - Rapid, Acid-Free Synthesis of High-Quality Graphene Quantum Dots for Aggregation Induced Sensing of Metal Ions and Bioimaging. AB - Graphene quantum dots (GQDs) are zero-dimensional materials that exhibit characteristics of both graphene and quantum dots. Herein, we report a rapid, relatively green, one-pot synthesis of size-tunable GQDs from graphene oxide (GO) by a sonochemical method with intermittent microwave heating, keeping the reaction temperature constant at 90 degrees C. The GQDs were synthesized by oxidative cutting of GO using KMnO4 as an oxidizing agent within a short span of time (30 min) in an acid-free condition. The synthesized GQDs were of high quality and exhibited good quantum yield (23.8%), high product yield (>75%), and lower cytotoxicity (tested up to 1000 MUg/mL). Furthermore, the as-synthesized GQDs were demonstrated as excellent fluorescent probes for bioimaging and label free sensing of Fe(III) ions, with a detection limit as low as 10 * 10-6 M. PMID- 30023572 TI - Synthesis of Isomaltooligosaccharides by Saccharomyces cerevisiae Cells Expressing Aspergillus niger alpha-Glucosidase. AB - The alpha-glucosidase encoded by the aglA gene of Aspergillus niger is a secreted enzyme belonging to family 31 of glycoside hydrolases. This enzyme has a retaining mechanism of action and displays transglycosylating activity that makes it amenable to be used for the synthesis of isomaltooligosaccharides (IMOs). We have expressed the aglA gene in Saccharomyces cerevisiae under control of a galactose-inducible promoter. Recombinant yeast cells expressing the aglA gene produced extracellular alpha-glucosidase activity about half of which appeared cell bound whereas the other half was released into the culture medium. With maltose as the substrate, panose is the main transglycosylation product after 8 h of incubation, whereas isomaltose is predominant after 24 h. Isomaltose also becomes predominant at shorter times if a mixture of maltose and glucose is used instead of maltose. To facilitate IMO production, we have designed a procedure by which yeast cells can be used directly as the catalytic agent. For this purpose, we expressed in S. cerevisiae gene constructs in which the aglA gene is fused to glycosylphosphatidylinositol anchor sequences, from the yeast SED1 gene, that determine the covalent binding of the hybrid protein to the cell membrane. The resulting hybrid enzymes were stably attached to the cell surface. The cells from cultures of recombinant yeast strains expressing aglA-SED1 constructions can be used to produce IMOs in successive batches. PMID- 30023573 TI - Three-Dimensional Organization of Self-Encapsulating Gluconobacter oxydans Bacterial Cells. AB - Self-organized bacteria have been the subject of interest for a number of applications, including the construction of microbial fuel cells. In this paper, we describe the formation of a self-organized, three-dimensional network that is constructed using Gluconobacter oxydans B-1280 cells in a hydrogel consisting of poly(vinyl alcohol) (PVA) with N-vinyl pyrrolidone (VP) as a cross-linker, in which the bacterial cells are organized in a particular side-by-side alignment. We demonstrated that nonmotile G. oxydans cells are able to reorganize themselves, transforming and utilizing PVA-VP polymeric networks through the molecular interactions of bacterial extracellular polysaccharide (EPS) components such as acetan, cellulose, dextran, and levan. Molecular dynamics simulations of the G. oxydans EPS components interacting with the hydrogel polymeric network showed that the solvent-exposed loops of PVA-VP extended and engaged in bacterial self-encapsulation. PMID- 30023574 TI - Agro Waste Utilization for Cost-Effective Production of l-Asparaginase by Pseudomonas plecoglossicida RS1 with Anticancer and Acrylamide Mitigation Potential. AB - Agricultural wastes such as the peels of onion and garlic were used as a supplement along with l-asparagine for the very first time to produce increased yield of l-asparaginase by Pseudomonas plecoglossicida RS1. Statistical optimization strategies such as response surface methodology were used to generate a medium composition containing extracts of 0.9 (v/v) of garlic peel waste and 0.5% (v/v) onion peel waste along with 0.2% (w/w) l-asparagine, which yielded a twofold increase in the enzyme activity compared to the unsupplemented minimal (M-9) medium. The presence of l-asparagine content in the peel extract was confirmed by high-performance liquid chromatography. Further, l-asparaginase was purified to homogeneity, and identity was confirmed by matrix-assisted laser desorption ionization time-of-flight analysis. The application of the purified l asparaginase as a therapeutic was studied in HeLa cells which showed a p53 mediated G2 cell cycle arrest. Moreover, the purified l-asparaginase showed effective acrylamide mitigation in vitro, at 6 IU, and its effective degradation was also demonstrated by the effect on chemotactic index of Caenorhabditis elegans and the restoration of the cognitive abilities of C. elegans which was coexposed to acrylamide and l-asparaginase compared to that exposed to acrylamide alone. Thus, l-asparaginase, with multipotent applications, was produced by effective waste utilization for economical commercial production. PMID- 30023575 TI - Recognition Site Generated by Natural Changes in Erm Proteins Leads to Unexpectedly High Susceptibility to Chymotrypsin. AB - Erms are proteins that methylate the adenine (A2058) in Escherichia coli 23S rRNA, which results in resistance to macrolide, lincosamide, and streptogramin B antibiotics. In a previous report, ErmN appeared to be more susceptible to contaminating proteases in DNase I. To determine the underlying mechanism, cleavage with chymotrypsin over time was investigated. ErmN possesses unusually high-susceptibility recognition site (F45) as evidenced by a band (band 1) that represented greater than 80% of the total band intensity at 30 s. The exposure rate of the hydrophobic core was more than 67-fold and 104-fold faster in ErmN than those in ErmS and ErmE, respectively. After cleavage at F45, some of the hydrophobic interactions were disrupted. Further digestion of band 1 occurred through the exposed F163 with a half-life of 3.18 min. After 30 min, less than 1% of ErmN remained. On the basis of the structure of ErmC', the location of F45 was presumed to be in an alpha helix at the bottom of a cavity. Both substitution of most common amino acids such as isoleucine, valine, or leucine with phenylalanine (ErmH, ErmI, ErmN, and ErmZ out of the 37 known Erms) and the apparent added flexibility, which could result from the additional loop region attached to phenylalanine that is four to nine amino acids longer (ErmI, ErmN, and ErmZ, which form one cluster in the phylogenetic tree), could cause unusually high susceptibility. The unexpectedly high susceptibility among the homologous proteins could indicate that caution should be taken not to misinterpret the observations when conducting any procedure in which protease or protease contamination is involved. PMID- 30023576 TI - Fluorescent and Photosensitizing Conjugates of Cell-Penetrating Peptide TAT(47 57): Design, Microwave-Assisted Synthesis at 60 degrees C, and Properties. AB - Conjugates based on cell-penetrating peptides (CPPs) are scientifically relevant owing to their structural complexity; their ability to enter cells and deliver drugs, labels, antioxidants, bioactive compounds, or DNA fragments; and, consequently, their potential for application in research and biomedicine. In this study, carboxyamidated fluorescently labeled conjugates FAM-GG-TAT(47-57) NH2 and FAM-PEG6-TAT(47-57)-NH2 and photosensitizer-labeled conjugate Chk-PEG6 TAT(47-57)-NH2 [where TAT(47-57) is the CPP, 5(6)-carboxyfluorescein is the (FAM) fluorophore, chlorin k (Chk) is the photosensitizer, and the dipeptide glycyl glycine (GG) or hexaethylene glycol (PEG6) is the spacer] were originally designed, prepared, and fully characterized. Practically, all chemical reactions of the synthetic steps (peptide synthesis, spacer incorporation, and conjugation) were microwave-assisted at 60 degrees C using optimized protocols to give satisfying yields and high-quality products. Detailed analyses of the conjugates using spectrofluorimetry and singlet oxygen detection showed that they display photophysical properties typical of FAM or Chk. Anticandidal activity assays showed that not only this basic property of TAT(47-57) was preserved in the conjugates but also that the minimal inhibitory concentration was slightly reduced for cells incubated with PS-bearing conjugate Chk-PEG6-TAT(47-57)-NH2. Overall, these results indicated that the synthetic approach on-resin assisted by microwaves at 60 degrees C is simple, straightforward, selective, metal-free, sufficiently fast, cleaner, and more cost-effective than those previously used for preparing this type of macromolecule. Furthermore, such new data show that microwaves at 60 degrees C and/or conjugation did not harm the integrity of the conjugates' constituents. Therefore, FAM-GG-TAT(47-57)-NH2, FAM-PEG6-TAT(47-57) NH2, and Chk-PEG6-TAT(47-57)-NH2 have high potential for practical applications in biochemistry, biophysics, and therapeutics. PMID- 30023577 TI - New Six-Membered pH-Insensitive Rhodamine Spirocycle in Selective Sensing of Cu2+ through C-C Bond Cleavage and Its Application in Cell Imaging. AB - A new rhodamine-based chemosensor 1 with a six-membered spirocyclic ring has been synthesized, which exhibits excellent pH stability and shows selective "turn-on" fluorescent detection of Cu2+ ions over a series of other metal ions including Cu+ ions. The expansion of spirocycle improves the stability and selectivity of the chemosensors in sensing of metal ions. Till today only few rhodamine structures R1-R5 with thiourea-, hydrazine amide-, or pyrrole-decorated six membered spirocyclic rings are known that exhibit metal-ion sensing via C-N bond cleavage of the spiro ring. In this context, rhodamine compound that responds to the metal ion through C-C bond cleavage of the six-membered spiro ring is completely unknown. The present example is a first-time report that demonstrates selective sensing of Cu2+ ions through C-C bond cleavage over the conventional existing systems in the literature. The chemosensor 1 is cell permeable and can detect Cu2+ in live cells using confocal microscopy in the biologically relevant pH range with high photostability. PMID- 30023578 TI - Favorable Biological Responses of Neural Cells and Tissue Interacting with Graphene Oxide Microfibers. AB - Neural tissue engineering approaches show increasing promise for the treatment of neural diseases including spinal cord injury, for which an efficient therapy is still missing. Encouraged by both positive findings on the interaction of carbon nanomaterials such as graphene with neural components and the necessity of more efficient guidance structures for neural repair, we herein study the potential of reduced graphene oxide (rGO) microfibers as substrates for neural growth in the injured central neural tissue. Compact, bendable, and conductive fibers are obtained. When coated with neural adhesive molecules (poly-l-lysine and N cadherin), these microfibers behave as supportive substrates of highly interconnected cultures composed of neurons and glial cells for up to 21 days. Synaptic contacts close to rGO are identified. Interestingly, the colonization by meningeal fibroblasts is dramatically hindered by N-cadherin coating. Finally, in vivo studies reveal the feasible implantation of these rGO microfibers as a guidance platform in the injured rat spinal cord, without evident signs of subacute local toxicity. These positive findings boost further investigation at longer implantation times to prove the utility of these substrates as components of advanced therapies for enhancing repair in the damaged central neural tissue including the injured spinal cord. PMID- 30023579 TI - Target-Guided Synthesis and Antiplasmodial Evaluation of a New Fluorinated 3 Alkylpyridine Marine Alkaloid Analog. AB - The need to develop new alternatives for antimalarial treatment is urgent. Herein, we report the synthesis and antimalarial evaluation of a small library of synthetic 3-alkylpyridine marine alkaloid (3-APA) analogs. First, the compounds were evaluated in vitro against Plasmodium falciparum. The most active compound 5c was selected for optimization of its antimalarial properties. An in silico approach was used based on pure ab initio electronic structure prediction, and the results indicated that a substitution of the hydroxyl group by a fluorine atom could favor a more stable complex with heme at a molecular ratio of 2:1 (heme/3-APA halogenated). A new fluorinated 3-APA analog was synthesized (compound 7), and its antimalarial activity was re-evaluated. Compound 7 exhibited optimized antimalarial properties (P. falciparum IC50 = 2.5 MUM), low genotoxicity, capacity to form a more stable heme/3-APA complex at a molecular ratio of 2:1, and conformity to RO5. The new compound, therefore, has great potential as a new lead antimalarial agent. PMID- 30023580 TI - Multiple Techniques for Size Determination of Generalized Modules for Membrane Antigens from Salmonella typhimurium and Salmonella enteritidis. AB - In the last years, outer membrane vesicles have attracted a lot of attention for the development of vaccines against bacterial pathogens. Extracellular vesicles can be obtained in high yields by genetic mutations, resulting in generalized modules for membrane antigens (GMMA). Methods to check the quality, consistency of production, and stability of GMMA vaccines are of fundamental importance. In this context, analytical methods for size distribution determination and verifying the integrity and possible aggregation of GMMA particles are strongly needed. Herein, GMMA particle size distribution has been evaluated by means of three different techniques. Dynamic light scattering (DLS), multiangle light scattering (MALS) coupled with high-performance liquid chromatography-size exclusion chromatography (SEC), and nanoparticle tracking analysis (NTA) have been compared to characterize GMMA from different mutants of Salmonella typhimurium and Salmonella enteritidis strains. We found that the presence of O antigen chains on GMMA determined higher Z-average diameters by DLS compared to size estimation by MALS and that the hydrodynamic diameter increased with the number of O-antigen chains per GMMA particle. In the case of SEC-MALS, the size of the whole population better reflects the size of the most abundant particles, whereas DLS diameter is more influenced by the presence of larger particles in the sample. SEC-MALS and NTA are preferable to DLS for the analysis of bimodal samples, as they better distinguish populations of different size. MALS coupled to a size exclusion chromatography module also allows checking the purity of GMMA preparations, allowing determination of generally occurring contaminants such as soluble proteins and DNA. NTA permits real-time visualization with simultaneous tracking and counting of individual particles, but it is deeply dependent on the choice of data analysis parameters. All of the three techniques have provided complementary information leading to a more complete characterization of GMMA particles. PMID- 30023581 TI - Sensing Chemical Warfare Agent Simulants via Photonic Crystals of the Morpho didius Butterfly. AB - The rapid and portable detection of trace chemical warfare agents (CWAs) remains a challenge for the international security and monitoring community. This work reports the first use of natural photonic crystals (PhCs) as vapor sensors for CWA simulants. Dimethyl methylphosphonate, a nerve agent simulant, and dichloropentane, a mustard gas simulant, were successfully detected at the parts per million level by processing visible light reflected from the PhC inherent to the wing scales of the Morpho didius butterfly. Additionally, modeling of this natural system suggested several parameters for enhancing the sensitivity of a synthetic PhC toward CWA simulants, including materials selection, structure, and spacing of the PhC, and partial functionalization of the PhC toward the analyte of interest. Collectively, this study provides strategies for designing a sensitive, selective, rapid, and affordable means for CWA detection. PMID- 30023582 TI - Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme. AB - Human carbonic anhydrase II (HCA II) is an enzyme that catalyzes the reversible hydration of CO2 into bicarbonate (HCO3-) and a proton (H+) as well as other reactions at an extremely high rate. This enzyme plays fundamental roles in human physiology/pathology, such as controlling the pH level in cells and so on. However, the binding mechanism between apo-HCA II and CO2 or other ligands as well as related conformational changes remains poorly understood, and atomic investigation into it could promote our understanding of related internal physiological/pathological mechanisms. In this study, long-time atomic molecular dynamics simulations as well as the clustering and free-energy analysis were performed to reveal the dynamics of apo-HCA II as well as the mechanism upon ligand binding. Our simulations indicate that the crystallographic B-factors considerably underestimate the loop dynamics: multiple conformations can be adopted by loops 1 and 2, especially for loop 1 because loop 1 is one side of the binding pocket, and its left-to-right movement can compress or extend the binding pocket, leading to one inactive (closed) state, three intermediate (semiopen) states, and one active (open) state; CO2 cannot get into the binding pocket of the inactive state but can get into those of intermediate and active states. The coexistence of multiple conformational states proposes a possible conformational selection model for the binding mechanism between apo-HCA II and CO2 or other ligands, revising our previous view of its functional mechanism of conformational change upon ligand binding and offering valuable structural insights into the workings of HCA II. PMID- 30023584 TI - Denaturation of dsDNA Induced by Specific Major Groove Binding of Cadmium Ion to Thymine. AB - The toxicity of cadmium causes varying degrees of risk to organisms. The underlying mechanism has been conventionally attributed to Cd2+-ion-induced oxidative stress. Here, we propose that the Cd2+ ion directly and stably binds with the thymine specifically in the major groove and causes denaturation of dsDNA. Using molecular dynamics simulations, it was found that the Cd2+ ion preferred to bind to the thymine exposed in the major groove. This then destroyed the hydrogen bonds between adenine and thymine, resulting in a mismatched structure of dsDNA. Our findings are expected to promote the understanding of cadmium-induced direct destruction of genomic stability and may also be helpful for the facilitation of the experimental detection of the binding sites. PMID- 30023583 TI - S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope. AB - A synthetic molecule S006-830, belonging to the class of thiophene-containing trisubstituted methanes, had shown good in vitro and in vivo bactericidal activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). The molecule had also shown good druglike pharmacokinetic properties. However, S006-830 is a racemic mixture of two enantiomers, one of which could possess a better pharmacological profile than the other. We purified both the enantiomers on a chiral column and observed that S-enantiomer has a significantly higher inhibitory and cidal activity against Mtb than the R-enantiomer. Action of S-S006-830 was "synergistic" for rifampicin and "additive" for isoniazid and ethambutol. The combination of S-S006-830 and rifampicin produced 100% kill of Mtb within 8 days. In a chemical proteomics approach using matrix-bound compound to pull down its target protein(s) from Mtb membrane, FabG4 (beta-ketoacyl CoA reductase, EC 1.1.1.100) emerged as the most likely target for S-S006-830. In target validation assays, the compound exhibited 2-fold higher inhibitory concentration for an Mtb construct overexpressing FabG4. In addition, it inhibited mycolic acid biosynthesis and formation of biofilms by Mtb. Molecular docking of S-S006-830 with FabG4 was consistent with the experimental data. These results support the development of S-S006-830 as a novel lead against tuberculosis. PMID- 30023585 TI - Sensing Cellular Metabolic Activity via a Molecular-Controlled Semiconductor Resistor. AB - Over the last decade, we have developed a molecular-controlled semiconductor resistor (MOCSER) device that is highly sensitive to variations in its surface potentials. This device was applied as a molecular sensor both in the gas phase and in solutions. The device is based on an AlGaAs/GaAs structure. In the current work, we developed an electronic biosensor for real-time, label-free monitoring of cellular metabolic activity by culturing HeLa cells directly on top of the device's conductive channel. Several properties of GaAs make it attractive for developing biosensors, among others its high electron mobility and ability to control the device's properties by proper epitaxial growing. However, GaAs is very reactive and sensitive to oxidation in aqueous solutions, and its arsenic residues are highly toxic. Nevertheless, we have managed to overcome this inherent chemical instability by developing a surface-protecting layer using polymerized (3-mercaptopropyl)-trimethoxysilane (MPTMS). To improve cell adhesion and biocompatibility, the MPTMS-coated devices were further modified with an additional layer of (3-aminopropyl)-trimethoxysilane (APTMS). HeLa cells were found to grow successfully on these devices, and MOCSER devices cultured with these cells were stable and sensitive to cellular metabolic activity. The sensitivity of the MOCSER device results from the sensing of extracellular acidification in the microenvironment of the cell-MOCSER interspace. We have found that this sensitivity is maintained only when the device is partially covered with the cellular layer, whereas at full coverage the sensitivity is lost. This phenomenon is related to the negatively charged cellular membrane potentials that lead to a reduction in the channel's conductivity. We propose that the coated MOCSER device can be applied for real-time and continuous monitoring of cellular viability and activity. PMID- 30023586 TI - Structural Features and Ligand Selectivity for 10 Intermediates in the Activation Process of beta2-Adrenergic Receptor. AB - It has already been suggested by researchers that there should be multiple intermediate states in the activation process for G-protein-coupled receptors (GPCRs). However, the intermediate states are very short-lived and hardly captured by the experiments, leading to very limited understanding of their structural features and drug efficacies. In this work, a novel joint strategy of targeted molecular dynamics simulation, conventional molecular dynamics simulation, and virtual screening is developed to address the problems. The results from 10 intermediate conformations obtained from the work reveal that the ligand pocket is very unstable and fluctuates between the inactive state and the active one in the case of ligand-free, in particular for ECL2 as a gate-keeper of the ligand-binding. The ligand-binding site could be stable in the active state with a small volume and a completely closed ECL2, only when the G-protein-binding region is fully activated. In addition, the activations of the ligand-binding pocket and G-protein-binding site are relatively independent and exhibit a loose allosteric coupling, which contributes to the existence of multiple intermediate conformations. Interestingly, the screening performance of the agonists does not increase on increasing the overall activity of the intermediate state, but is dependent on the activated extent of the ligand pocket. The receptor is prone to bind the agonist when closing ECL2 and reducing the ligand-binding pocket volume, whereas it is more favorable for binding the antagonist when opening ECL2 and increasing the pocket volume. These observations added to previous studies could help us better understand the activation mechanism of GPCRs and provide valuable information for drug design. PMID- 30023587 TI - Detection of Organochlorine Pesticides in Contaminated Marine Environments via Cyclodextrin-Promoted Fluorescence Modulation. AB - The development of practical and robust detection methods for pesticides is an important research objective owing to the known toxicity, carcinogenicity, and environmental persistence of these compounds. Pesticides have been found in bodies of water that are located near areas where pesticides are commonly used and easily spread to beaches, lakes, and rivers; affect the species living in those waterways; and harm humans who come into contact with or eat fish from such water. Reported herein is the rapid, sensitive, and selective detection of four organochlorine pesticides in a variety of water sources across the state of Rhode Island using cyclodextrin-promoted fluorescence detection. This method relies on the ability of cyclodextrin to promote analyte-specific fluorescence modulation of a high quantum yield fluorophore when a pesticide is in close proximity, combined with subsequent array-based statistical analyses of the measurable changes in the emission signals. This system operates with high sensitivity (low micromolar detection limits), selectivity (100% differentiation between structurally similar analytes), and general applicability (for different water samples with varying salinity and pH as well as for different water temperatures). PMID- 30023588 TI - Detection of HSO3-: A Rapid Colorimetric and Fluorimetric Selective Sensor for Detecting Biological SO2 in Food and Living Cells. AB - A rapid fluorescent probe based on the conjugate of chromone and benzothiazole moiety was presented, which could selectively respond to HSO3- over other common anions and thiols. The function of the probe relies on nucleophilic addition to break down the pi-conjugation. The probe can be used as a signal tool to determine HSO3- levels in sugar-based food and living cells. PMID- 30023589 TI - Streamlined Preparation of Immobilized Candida antarctica Lipase B. AB - Candida antarctica lipase B (CalB) was efficiently expressed (6.2 g L-1) in Escherichia coli by utilizing an N-terminal tag cassette and the XylS/Pm expression system in a fed-batch bioreactor; subsequent direct binding to EziG from crude extracts resulted in an immobilized catalyst with superior activity to Novozym 435. PMID- 30023590 TI - Drug-Triggered Self-Assembly of Linear Polymer into Nanoparticles for Simultaneous Delivery of Hydrophobic and Hydrophilic Drugs in Breast Cancer Cells. AB - Breast cancer is the most devastating disease among females globally. Conventional chemotherapeutic regimen relies on the use of highly cytotoxic drugs as monotherapy and combination therapy leading to severe side effects to the patients as collateral damage. Moreover, combining hydrophobic and hydrophilic drugs create erratic biodistribution and suboptimal medicinal outcome. Hence, packaging multiple drugs of diverse mechanisms of action and biodistribution for safe delivery into tumor tissues with optimal dosages is indispensable for next generation breast cancer therapy. To address these, in this report, we describe a unique cisplatin-triggered self-assembly of linear polymer into 3D-spherical sub 200 nm particles. These nanoparticles comprise a hydrophobic (paclitaxel) and hydrophilic drug (cisplatin) simultaneously in a single particle. Molecular dynamics simulation revealed hydrophilic-hydrophilic interaction and interchain H bonding as underlying mechanisms of self-assembly. Confocal microscopy studies evidently demonstrated that these novel nanoparticles can home into lysosomes in breast cancer cells, fragment subcellular nuclei, and prevent cell division, leading to improved breast cancer cell death compared to free drug combination. Moreover, 3D-breast tumor spheroids were reduced remarkably by the treatment of these nanoparticles within 24 h. These dual-drug-loaded self-assembled polymeric nanoparticles have prospective to be translated into a clinical strategy for breast cancer patients. PMID- 30023591 TI - Supramolecular Dye Aggregate Assembly Enables Ratiometric Detection and Discrimination of Lysine and Arginine in Aqueous Solution. AB - Constructing sensor systems for rapid and selective detection of small biomolecules such as amino acids is a major area of focus in bioanalytical chemistry. Considering the biological relevance of arginine and lysine, significant efforts have been directed to develop fluorescent sensors for their detection. However, these developed sensors suffer from certain disadvantages such as poor aqueous solubility, technically demanding and time-consuming synthetic protocols, and more importantly, most of them operate through single wavelength measurements, making their performance prone to small variations in experimental conditions. Herein, we report a ratiometric sensor that operates through lysine- and arginine-induced dissociation of a supramolecular assembly consisting of emissive H-aggregates of a molecular rotor dye, thioflavin-T (ThT), on the surface of a polyanionic supramolecular host, sulfated beta-cyclodextrin. This disassembly brings out the modulation of monomer-aggregate equilibrium in the system which acts as an ideal scheme for the ratiometric detection of lysine and arginine in the aqueous solution. Besides facile framework of our sensor system, it employs a commercially available inexpensive probe molecule, ThT, which provides an added advantage over other sensor systems that employ synthetically demanding probe molecules. Importantly, the distinctive feature of the ratiometric detection of arginine and lysine provides an inherent advantage of increased accuracy in quantitative analysis. Interestingly, we have also demonstrated that arginine displays a multiwavelength distinctive recognition pattern which distinguishes it from lysine, using a single supramolecular ensemble. Furthermore, our sensor system also shows response in heterogeneous, biologically complex media of serum samples, thus extending its possible use in real-life applications. PMID- 30023592 TI - Studying DNA G-Quadruplex Aptamer by 19F NMR. AB - In this study, we demonstrated that 19F NMR can be used to study the thrombin binding aptamer (TBA) DNA G-quadruplex, widely used as a model structure for studying G-quadruplex aptamers. We systematically examined the structural feature of the TBA G-quadruplex aptamer with fluorine-19 (19F) labels at all of the thymidine positions. We successfully observed the structural change between the G quadruplex and the unstructured single strand by 19F NMR spectroscopy. The thermodynamic parameters of these DNA G-quadruplex aptamers were also determined from the 19F NMR signals. We further showed that the 19F NMR method can be used to observe the complex formed by TBA G-quadruplex and thrombin. Our results suggest that 19F NMR spectroscopy is a useful approach to study the aptamer G quadruplex structure. PMID- 30023593 TI - Drug-Loaded Supramolecular Gels Prepared in a Microfluidic Platform: Distinctive Rheology and Delivery through Controlled Far-from-Equilibrium Mixing. AB - It is shown here that controlled mixing of a gelator, drug, solvent, and antisolvent in a microfluidic channel leads to faster setting gels and more robust materials with longer release profiles than the physical gels of the same composition obtained using random mixing in solution. The system is similar to a related gelator system we had studied previously, but we were unable to apply the same gelling procedure because of the instability of the colloid caused by the small structural modification (length of the alkyl chain in the bis-imidazolium head group). This situation holds true for the gels formed with varying compositions and under different conditions (gelator/drug ratio, solvent proportion, and flow rates), with the most significant differences being the improved gel rheology and slower drug release rates. Very importantly, the gels (based on a previously unexplored system) have a higher water content ratio (water/EtOH 4:1) than others in the family, making their medicinal application more attractive. The gels were characterized by a variety of microscopy techniques, X-ray diffraction and infrared spectroscopy, and rheology. Salts of the antiinflammatory drugs ibuprofen and indomethacin were successfully incorporated into the gels. The diffraction experiments indicate that these composite gels with relatively short alkyl chains in the gelator component contrast to previous systems, in that they exhibit structural order and the presence of crystalline areas of the drug molecule implying partial phase separation (even though these drug crystallites are not discernible by microscopy). Furthermore, the release study with the gel incorporating ibuprofenate showed promising results that indicate a possible drug delivery vehicle application for this and related systems. PMID- 30023594 TI - Charge-Driven Interaction of Antimicrobial Peptide NK-2 with Phospholipid Membranes. AB - NK-2, derived from a cationic core region of NK-lysin, displays antimicrobial activity toward negatively charged bacterial membranes. We have studied the interaction of NK-2 with various phospholipid membranes, using a variety of experimental techniques, such as, isothermal titration calorimetry (ITC), zeta potential, and dynamic light scattering. As bacteria mimicking membranes, we have chosen large unilamellar vesicles (LUVs) composed of negatively charged phospholipid and neutral phospholipids. ITC and zeta potential results show the stronger binding affinity of NK-2 to negatively charged membranes than to neutral membranes. Saturation of the isotherm, obtained from ITC, at a given lipid to NK 2 ratio, was found to be consistent with the charge compensation, determined from zeta potential. A surface partition model with electrostatic contribution was used to estimate the intrinsic binding constant and other thermodynamical parameters of binding kinetics of NK-2. The size distribution of negatively charged LUV in the presence of NK-2 was found to increase drastically, indicating the presence of large aggregates. Such a large aggregate has not been observed in neutral membranes, which supports the ITC and zeta potential results. PMID- 30023595 TI - Supramolecular Host-Guest Chemistry-Based Folate/Riboflavin Functionalization and Cancer Cell Labeling of Nanoparticles. AB - Nanoparticle-based cellular probes are commonly designed via covalent conjugation with affinity biomolecules. Those nanobioconjugates selectively interact with cell surface receptors and induce endocytosis followed by intracellular trafficking. However, this approach requires functional modification of biomolecules that may alter their biochemical activity. Here, we show that supramolecular host-guest chemistry can be utilized as an alternative approach in nanoparticle functionalization and selective cell labeling. We have used cyclodextrin-conjugated quantum dots (QDs) for supramolecular host-guest interaction-based functionalization with folate (QD-folate) and riboflavin (QD riboflavin), where cyclodextrin acts as a host for the folate/riboflavin guest. We demonstrate that QD-folate and QD-riboflavin selectively label cells that have over-expressed folate/riboflavin receptors and induce the endocytosis pathway similar to covalently conjugated folate-/riboflavin-based nanoprobes. However, labeling is highly sensitive to the molar ratio of folate/riboflavin to cyclodextrin and incubation time. The presented functionalization/labeling approach is unique as it does not require covalent conjugation and may be extended for in vivo targeting application via simultaneous delivery of host and guest molecules. PMID- 30023596 TI - Electrospun Pectin-Polyhydroxybutyrate Nanofibers for Retinal Tissue Engineering. AB - Natural polysaccharide pectin has for the first time been grafted with polyhydroxybutyrate (PHB) via ring-opening polymerization of beta-butyrolactone. This copolymer, pectin-polyhydroxybutyrate (pec-PHB), was blended with PHB in various proportions and electrospun to produce nanofibers that exhibited uniform and bead-free nanostructures, suggesting the miscibility of PHB and pec-PHB. These nanofiber blends exhibited reduced fiber diameters from 499 to 336-426 nm and water contact angles from 123.8 to 88.2 degrees on incorporation of pec-PHB. They also displayed 39-335% enhancement of elongation at break relative to pristine PHB nanofibers. pec-PHB nanofibers were found to be noncytotoxic and biocompatible. Human retinal pigmented epithelium (ARPE-19) cells were seeded onto pristine PHB and pec-PHB nanofibers as scaffold and showed good proliferation. Higher proportions of pec-PHB (pec-PHB10 and pec-PHB20) yielded higher densities of cells with similar characteristics to normal RPE cells. We propose, therefore, that nanofibers of pec-PHB have significant potential as retinal tissue engineering scaffold materials. PMID- 30023597 TI - Role of Biorelevant Dissolution Media in the Selection of Optimal Salt Forms of Oral Drugs: Maximizing the Gastrointestinal Solubility and in Vitro Activity of the Antimicrobial Molecule, Clofazimine. AB - Clofazimine is an antimycobacterial agent that is routinely used for the treatment of leprosy. Clofazimine has also been shown to have high clinical potential for the treatment of many Gram-positive pathogens, including those that exhibit high levels of antibiotic resistance in the medical community. The use of clofazimine against these pathogens has largely been limited by the inherently poor water solubility of the drug substance. In this work, the possibility of repurposing and reformulating clofazimine to maximize its clinical potential is investigated. To achieve this, the potential of novel salt forms of clofazimine as supersaturating drug-delivery vehicles to enhance the aqueous solubility and gastrointestinal solubility of the drug substance was explored. The solution properties of seven novel salt forms, identified during an initial screening process, were examined in water and in a gastrointestinal-like media and were compared and contrasted with those of the free base, clofazimine, and the commercial formulation of the drug, Lamprene. The stability of the most promising solid forms was tested, and their bioactivity against Staphylococcus aureus was also compared with that of the clofazimine free base and Lamprene. Salts forms which showed superior stability as well as solubility and activity to the commercial drug formulation were fully characterized using a combination of spectroscopic techniques, including X-ray diffraction, solid-state NMR, and Fourier transform infrared spectroscopy. PMID- 30023598 TI - Intracellular Delivery of beta-Galactosidase Enzyme Using Arginase-Responsive Dextran Sulfate/Poly-l-arginine Capsule for Lysosomal Storage Disorder. AB - beta-Galactosidase (beta-gal) is one of the important lysosomal enzymes that is involved in the breakdown of glycosphingolipids (e.g., GM1 ganglioside), and its deficiency leads to GM1 Gangliosidosis, a lysosomal storage disorder (LSD). Intracellular delivery of beta-gal is one of the preferable methods to treat this kind of LSDs. However, it cannot permeate the cell membrane due to its intricate macromolecular nature, low stability, and degradation by endogenous proteases. To this end, we report efficient intracellular delivery of beta-gal via arginase responsive dextran sulfate/poly-l-arginine polymer capsules (DS/PA capsules). The therapeutic activity of beta-gal enzyme has been assessed in two gene-deficient diseased cell lines, SV (beta-galactosidase gene-deficient mouse fibroblast) and R201C (deficient human beta-galactosidase gene-introduced mouse fibroblast), and in wild-type mouse fibroblast immortalized cell lines. The activity of beta-gal enzyme has been estimated within cells by using fluorescein isothiocyanate cholera toxin B as a florescent probe that illustrates the level of GM1 ganglioside, the beta-gal substrate. We found 1.8-, 3.4-, and 2.8-fold reduction in the substrate level in R201C, SV, and wild-type mouse fibroblast, respectively, which confirms the release and therapeutic activity of beta-gal enzyme inside the cells. Moreover, enzyme delivery in gene-deficient diseased cell lines (SV and R201C) via DS/PA capsules reduced the level of enzyme substrate to a normal endogenous level, which is present in untreated wild-type mouse fibroblast cells. We note that loading of beta-gal enzyme within DS/PA capsules was estimated to be 3 mU per hundred capsules and more than 77% of beta gal is released within 12 h. Overall, these results highlight the potential of DS/PA capsules as an efficient delivery carrier for therapeutic enzyme. PMID- 30023599 TI - Anion Complexation Studies of 3-Nitrophenyl-Substituted Tripodal Thiourea Receptor: A Naked-Eye Detection of Sulfate via Fluoride Displacement Assay. AB - A thiourea-based tripodal receptor L substituted with 3-nitrophenyl groups has been synthesized, and the binding affinity for a variety of anions has been studied by 1H NMR titrations and nuclear Overhauser enhancement spectroscopy experiments in dimethyl sulfoxide-d6. As investigated by 1H NMR titrations, the receptor binds an anion in a 1:1 binding mode, showing the highest binding and strong selectivity for sulfate anion. A competitive colorimetric assay in the presence of fluoride suggests that the sulfate is capable of displacing the bound fluoride, showing a sharp visible color change. The strong affinity of L for sulfate was further supported by UV-vis titrations and density functional theory (DFT) calculations. Time-dependent DFT calculations indicate that the fluoride complex possesses a different optical absorption spectrum (due to charge transfer between the fluoride and the surrounding ligand) than the sulfate complex, reflecting the observed colorimetric change in these two complexes. The receptor was further tested for its biocompatibility on primary human foreskin fibroblasts and HeLa cells, exhibiting an excellent cell viability up to 100 MUM concentration. PMID- 30023600 TI - Methyl-beta-cyclodextrin Inclusion Complex with beta-Caryophyllene: Preparation, Characterization, and Improvement of Pharmacological Activities. AB - beta-Caryophyllene (BCP) is a sesquiterpene that shows high potential in pharmacological applications. However, these have been drastically limited by the respective volatility and poor water solubility. The present study investigates the formation of inclusion complexes between BCP and methyl-beta-cyclodextrin (MbetaCD) and shows that these complexes promote a significant improvement of the anti-inflammatory, gastric protection, and antioxidant activities relative to neat BCP. It is shown that the solubility of BCP is significantly increased through complexation in phase solubility studies. Inclusion complexes with MbetaCD in solid state were prepared by three different methods, kneading, rotary evaporation, and lyophilization, with the latter confirmed by differential scanning calorimetry, Fourier transformed infrared spectroscopy, scanning electron microscopy, 1H NMR spectroscopy, and molecular dynamics studies. This study provides for the first time a full characterization of inclusion complexes between BCP and MbetaCD and highlights the impact of complex formation upon pharmacological activity. PMID- 30023601 TI - pH-Regulated Synthesis of Trypsin-Templated Copper Nanoclusters with Blue and Yellow Fluorescent Emission. AB - In this article, a simple protocol to prepare water-soluble fluorescent copper nanoclusters (CuNCs) using trypsin as a stabilizer and hydrazine hydrate as a reducing agent was reported. It was found that the pH of the reaction solution was critical in determining the fluorescence of CuNCs. CuNCs with blue and yellow fluorescent emission were obtained under basic and acidic conditions, respectively. Although the detailed formation mechanisms of these CuNCs required further analysis, the synthetic route was promising for preparing different fluorescent metal NCs for applications. With good water solubility and excellent photostability, the yellow-emitting CuNCs could serve as a fluorescence probe for detection of Hg2+ based on the aggregation-induced quenching mechanism. The fluorescence quenching efficiency had fantastic linearity to Hg2+ concentrations in the range of 0.1-100 MUM, with a limit of detection of 30 nM. Additionally, the yellow-emitting CuNCs exhibited negligible cytotoxicity and were successfully applied to bioimaging of HeLa cells. PMID- 30023602 TI - Production and Characterization of Polyhydroxyalkanoate from Lignin Derivatives by Pandoraea sp. ISTKB. AB - The present study investigates polyhydroxyalkanoate (PHA) production from lignin and its derivatives by a previously reported lignin-degrading bacterial strain Pandoraea sp. ISTKB. PHA production was screened by fluorescence microscopy and flow cytometry using a Nile red stain. PHA and biomass accumulation, while screening, was found to be maximum on 4-hydroxybenzoic acid followed by p coumaric acid, vanillic acid, 2,6-dimethoxyphenol, and kraft lignin after 96 h. Monomer composition was analyzed by gas chromatography-mass spectrometry (GC-MS) and was followed by Fourier transform infrared and 1H NMR analysis, indicating PHA to be a copolymer of P(hydroxybutyrate-co-hydroxyvalerate). Genomic analysis of Pandoraea sp. ISTKB also complemented the results of GC-MS and NMR, and the relevant genes responsible for the synthesis of small chain length PHA were discovered in the genome. Process parameters were optimized by response surface methodology for enhanced production of PHA and biomass on 4-hydroxybenzoate. Optimization results showed 30 and 66% increase in the biomass and PHA production, respectively. The results obtained were promising and indicated that if lignin is depolymerized into low-molecular-weight intermediates, then it can easily be utilized and converted into value-added products like PHA by microbes. PMID- 30023603 TI - Mutational Analysis of a Conserved Glutamate Reveals Unique Mechanistic and Structural Features of the Phosphatase PRL-3. AB - Phosphatase of regenerating liver (PRL)-3 (PTP4A3) has gained much attention in cancer research due to its involvement in tumor promoting and metastatic processes. It belongs to the protein tyrosine phosphatase (PTP) superfamily and is thought to follow the catalytic mechanism shared by this family, which aside from the conserved active-site amino acids includes a conserved glutamic acid residue that is usually required for the integrity of the active site in PTPs. We noted that in structures of PRL-3, PRL-1, and PTEN these residues do not clearly align and therefore we sought to investigate if the glutamic acid residue fulfills its usual function in these proteins. Although this residue was essential for PTEN's catalytic activity, it was nonessential for PRL-1 and PRL-3. Surprisingly, the mutation E50R increased PRL-3 activity against all tested in vitro substrates and also enhanced PRL-3-promoted cell adhesion and migration. We show that the introduction of Arg50 leads to an enhancement of substrate turnover for both PRL-3 and, to a lesser extent, PRL-1, and that the stronger gain in activity correlates with a higher structural flexibility of PRL-3, likely allowing for conformational adaptation during catalysis. Thus, in contrast to its crucial functions in other PTPs, this conserved glutamic acid can be replaced in PRL-3 without impairing the structural integrity. The variant with enhanced activity might serve as a tool to study PRL-3 in the future. PMID- 30023604 TI - Indolizine-Based Scaffolds as Efficient and Versatile Tools: Application to the Synthesis of Biotin-Tagged Antiangiogenic Drugs. AB - We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug-biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug-protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223 interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheses on the mode of action of this antiangiogenic drug. PMID- 30023606 TI - Gram-Scale Synthesis of a beta-Secretase 1 (BACE 1) Inhibitor. AB - Development of a scalable synthesis of an oxazine class of beta-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields. PMID- 30023605 TI - Stern-Layer Adsorption of Oligonucleotides on Lamellar Cationic Lipid Bilayer Investigated by Polarization-Resolved SFG-VS. AB - The molecular interaction between the oligonucleotides and lipid membranes is the key to the functions of virus, aptamer, and various oligonucleotide-based materials. In this study, the conformational changes of oligonucleotides (dT25) on lamellar cationic 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP) bilayer were investigated by polarization-resolved sum frequency generation vibrational spectroscopy (SFG-VS) in situ. The SFG-VS spectra within different wavenumber ranges were analyzed to give conformation details of thymine groups, phosphate groups, and OD/OH groups and to provide a comprehensive and fundamental understanding of the oligonucleotide adsorption on a model bilayer. It is shown that the adsorption of dT25 on DMTAP bilayer reaches maximum at CdT ~ 500 nM. And the conformation of dT25 molecules change significantly when surface charge of DMTAP bilayer reaches the point of zero charge (PZC) at CdT ~ 100 nM. Combined spectroscopic evidences also indicate that the formation of electric double layer at the DMTAP/dT25 surface follows the Gouy-Chapman-Stern model. The analysis results also show that the symmetric PO2- stretching mode of oligonucleotide molecules can serve as a sensitive vibration molecular probe for quantifying the oligonucleotide/lipid charge ratio and determine the point of zero charge (PZC) of lipid bilayer surface, which may help researchers to control the layer-by layer assembly of oligonucleotide-lipid complexes and to improve the efficiency genetic therapy against cancer and viral infections. PMID- 30023607 TI - Injectable Alginate Hydrogel Cross-Linked by Calcium Gluconate-Loaded Porous Microspheres for Cartilage Tissue Engineering. AB - A great interest has been shown in the injectable scaffolds for cartilage tissue regeneration because it can fill irregularly shaped defects easily through minimally invasive surgical treatments. Herein, we developed a new injectable three-dimensional (3D) alginate hydrogel loaded with biodegradable porous poly(epsilon-caprolactone)-b-poly(ethylene glycol)-b-poly(epsilon-caprolactone) microspheres (MPs/Alg) as the calcium gluconate container to cross-link alginate. Suspensions of chondrocytes/alginate and porous microspheres turned into a gel because of the release of calcium gluconate; thus, the injectable composite hydrogels give a 3D scaffold to fit the defects perfectly and integrate the extracellular-matrix-mimicking architecture to efficiently accommodate cartilage cells in situ. Tissue repair in a full-thickness cartilage defect model was controlled at 6, 12, and 18 weeks after the implant by micro-CT and immunohistochemistry to evaluate the healing status. The defect in the MPs/Alg+ cells group achieved an almost complete repair at 18 weeks, and the repaired chondrocytes regained a normal tissue structure. Moreover, the MPs/Alg+ cells treated group increased the quality of tissue formed, including the accumulated glycosaminoglycan and the uniformly deposited type II collagen. The results point out the promising application of the injectable MPs/Alg-chondrocytes system for cartilage tissue engineering. PMID- 30023608 TI - Evaluation of Silk Inverse Opals for "Smart" Tissue Culture. AB - Visually tracking the subtle aspects of biological systems in real time during tissue culture remains challenging. Herein, we demonstrate the use of bioactive, cytocompatible, and biodegradable inverse opals from silk as a multifunctional substrate to transduce both the optical information and cells during tissue culture. We show that these substrates can visually track substrate degradation in various proteases during tissue digestion and protein deposition during the growth of mesenchymal stem cells. Uniquely, these substrates can be integrated in multiple steps of tissue culture for simple-to-use, visual, and quantitative detectors of bioactivity. These substrates can also be doped, demonstrated here with gold nanoparticles, to allow additional control of cell functions. PMID- 30023609 TI - Application-Specific Catalyst Layers: Pt-Containing Carbon Nanofibers for Hydrogen Peroxide Detection. AB - Complete removal of metal catalyst particles from carbon nanofibers (CNFs) and other carbon nanostructures is extremely difficult, and the envisioned applications may be compromised by the left-over impurities. To circumvent these problems, one should use, wherever possible, such catalyst materials that are meant to remain in the structure and have some application-specific role, making any removal steps unnecessary. Thus, as a proof-of-concept, we present here a nanocarbon-based material platform for electrochemical hydrogen peroxide measurement utilizing a Pt catalyst layer to grow CNFs with intact Pt particles at the tips of the CNFs. Backed by careful scanning transmission electron microscopy analysis, we show that this material can be readily realized with the Pt catalyst layer thickness impacting the resulting structure and also present a growth model to explain the evolution of the different types of structures. In addition, we show by electrochemical analysis that the material exhibits characteristic features of Pt in cyclic voltammetry and it can detect very small amounts of hydrogen peroxide with very fast response times. Thus, the present sensor platform provides an interesting electrode material with potential for biomolecule detection and in fuel cells and batteries. In the wider range, we propose a new approach where the selection of catalytic particles used for carbon nanostructure growth is made so that (i) they do not need to be removed and (ii) they will have essential role in the final application. PMID- 30023610 TI - Dual-Functional-Tag-Facilitated Protein Labeling and Immobilization. AB - An important strategy in the construction of biomimetic membranes and devices is to use natural proteins as the functional components for incorporation in a polymeric or nanocomposite matrix. Toward this goal, an important step is to immobilize proteins with high efficiency and precision without disrupting the protein function. Here, we developed a dual-functional tag containing histidine and the non-natural amino acid azidohomoalanine (AHA). AHA is metabolically incorporated into the protein, taking advantage of the Met-tRNA and Met-tRNA synthetase. Histidine in the tag can facilitate metal-affinity purification, whereas AHA can react with an alkyne-functionalized probe or surface via well established click chemistry. We tested the performance of the tag using two model proteins, green fluorescence protein and an enzyme pyrophosphatase. We found that the addition of the tag and the incorporation of AHA did not significantly impair the properties of these proteins, and the histidine-AHA tag can facilitate protein purification, immobilization, and labeling. PMID- 30023611 TI - Zinc(II)-Tetradentate-Coordinated Probe with Aggregation-Induced Emission Characteristics for Selective Imaging and Photoinactivation of Bacteria. AB - The emergence of drug-resistant bacterial pathogens highlights an urgent need for new therapeutic options. Photodynamic therapy (PDT) has emerged as a potential alternative to antibiotics to kill bacteria, which has been used in clinical settings. PDT employs photosensitizers (PSs), light, and oxygen to kill bacteria by generating highly reactive oxygen species (ROS). PDT can target both external and internal structures of bacteria, which does not really require the PSs to enter bacteria. Therefore, bacteria can hardly develop resistance to PDT. However, most of the PSs reported so far are hydrophobic and tend to form aggregates when they interact with bacteria. The aggregation could cause fluorescence quenching and reduce ROS generation, which generally compromises the effects of both imaging and therapy. In this contribution, we report on a Zn(II) tetradentate-coordinated red-emissive probe with aggregation-induced emission characterization. The probe could selectively image bacteria over mammalian cells. Moreover, the probe shows potent phototoxicity to both Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Bacillus subtilis). PMID- 30023612 TI - Impact of Environmental Pollutant Cadmium on the Establishment of a Cancer Stem Cell Population in Breast and Hepatic Cancer. AB - Cadmium, a heavy metal pollutant, causes cancer. The existence of cancer stem cells (CSCs) in tumors is widely considered to be the reason for the recurrence and treatment failure of cancer. Increasing evidence has confirmed that under certain conditions non-CSCs could be converted into CSCs. The impact of cadmium on the development of CSC lineage in the bulk tumor cell population is not yet studied. The aim of this study was to evaluate the effect of cadmium on the conversion of non-CSCs to CSCs and the identification of CSCs based on the concurrent monitoring of multiple CSC markers. High-content monitoring of molecular markers was performed using quantum dot (QD) nanoprobes and an acousto optical tunable filter (AOTF)-based imaging device. Cadmium treatment significantly increased the CSC population in MCF-7 and HepG2 cell lines. The cadmium-induced CSCs were identified by a concurrent analysis of stem-cell markers, namely, CD44, CD24, CD133, and ALDH1. Moreover, increased m-RNA expression of CD44, ALDH1, and CD133 and protein expression of p-Ras, p-Raf-1, p MEK-1, and p-ERK-1 were observed in the cadmium-treated MCF-7 and HepG2 cells. This study demonstrates that cadmium induces the gene expression of CSC markers in the breast and liver cancer cell lineage and promotes the conversion of non CSCs to CSCs. PMID- 30023613 TI - Polymer Nanoparticle Engineering for Podocyte Repair: From in Vitro Models to New Nanotherapeutics in Kidney Diseases. AB - Specific therapeutic targeting of kidney podocytes, the highly differentiated ramified glomerular cells involved in the onset and/or progression of proteinuric diseases, could become the optimal strategy for preventing chronic kidney disease. With this aim, we developed a library of engineered polymeric nanoparticles (NPs) of tuneable size and surface properties and evaluated their interaction with podocytes. NP cytotoxicity, uptake, and cytoskeletal effects on podocytes were first assessed. On the basis of these data, nanodelivery of dexamethasone loaded into selected biocompatible NPs was successful in repairing damaged podocytes. Finally, a three-dimensional in vitro system of co-culture of endothelial cells and podocytes was exploited as a new tool for mimicking the mechanisms of NP interaction with glomerular cells and the repair of the kidney filtration barrier. PMID- 30023614 TI - Diverse Synaptic Plasticity Induced by the Interplay of Ionic Polarization and Doping at Salt-Doped Electrolyte/Semiconducting Polymer Interface. AB - Pt/Ca2+-polyethylene oxide/polymer poly[3-hexylthiophene-2,5-diyl]/Pt devices were fabricated, and their pulse responses were studied. The discharging peak, represented by the postsynaptic current (PSC), first increases and then decreases with increasing input number in a pulse train. The weight of the PSC decreased for low-frequency stimulations but increased for high-frequency stimulations. However, the peak of the negative differential resistance during the charging process varied following the opposite trend. These behaviors suggested the ability for transferring the signal bidirectionally, confirming the equivalence between the ionic kinetics of our device and the transmitter kinetics of one kind of synapse. A facilitation (F)-depression (D) interplay model corresponding to the ionic polarization and doping interplay at the electrolyte/semiconducting polymer interface was adopted to successfully mimic the weight modification of the PSC. The simulation results showed that the observed synaptic plasticity was caused by the great disparity between the recovery time constants of F and D (tau F and tau D ). Moreover, such an interplay could inspire the features of responses to post-tetanic stimulations. Our study suggested a means to realize synaptic computation. PMID- 30023615 TI - Radiopaque Hemocompatible Ruminant-Sourced Gut Material with Antimicrobial Physiognomies for Biomedical Applications in Diabetics. AB - This study comprises the fabrication of a radiopaque gut material with its mechanical properties conforming to the US Pharmacopeia guidelines giving an antimicrobial advantage for suture application, especially in conditions such as diabetes mellitus, which has a high wound infection rate. Schiff base cross linking iodination of the material is evinced by the spectroscopic studies, and antimicrobial properties owing to released iodine are evinced through in vitro studies. Modified gut sutures demonstrated favorable physicomechanical features such as appropriate tensile strength (440 +/- 20 MPa) and knot strength (270 +/- 20) alongside a mean radiopacity value of 139.0 +/- 10 in comparison with that of the femoral shaft with 160 +/- 10. The diabetic model showed absence of clinical signs of infection, supported by wound swab culture and the absence of necrosis in histology. Hemocompatibility studies evinced the absence of contact platelet activation and hemolysis alongside the customary coagulation response. These promising results highlight the stimulating potential of the process in the development of biomedical applications, necessitating persistent studies for its evidence-based applicability, particularly in diabetic patients. PMID- 30023616 TI - Seed-Induced Heterogeneous Cross-Seeding Self-Assembly of Human and Rat Islet Polypeptides. AB - Amyloid peptides can misfold and aggregate into amyloid oligomers and fibrils containing conformationally similar beta-sheet structures, which are linked to the pathological hallmark of many neurodegenerative diseases. These beta-sheet rich amyloid aggregates provide common structural motifs to accelerate amyloid formation by acting as seeds. However, little is known about how one amyloid peptide aggregation will affect another one (namely, cross-seeding). In this work, we studied the cross-seeding possibility and efficiency between rat islet amyloid polypeptide (rIAPP) and human islet amyloid polypeptide (hIAPP) solution with preformed aggregates at different aggregation phases, using a combination of different biophysical techniques. hIAPP is a well-known peptide hormone that forms amyloid fibrils and induces cytotoxicity to beta-cells in type 2 diabetes, whereas rIAPP is a nonaggregating and nontoxic peptide. Experimental results showed that all different preformed hIAPP aggregates can cross-seed rIAPP to promote the final fibril formation but exhibit different cross-seeding efficiencies. Evidently, hIAPP seeds preformed at a growth phase show the strongest cross-seeding potential to rIAPP, which accelerates the conformational transition from random structures to beta-sheet and the aggregation process at the fibrillization stage. Homoseeding of hIAPP is more efficient in initiating and promoting aggregation than cross-seeding of hIAPP and rIAPP. Moreover, the cross-seeding of rIAPP with hIAPP at the lag phase also reduced cell viability, probably because of the formation of more toxic hybrid oligomers at the prolonged lag phase. The cross-seeding effects in this work may add new insights into the mechanistic understanding of the aggregation and coaggregation of amyloid peptides linked to different neurodegenerative diseases. PMID- 30023617 TI - Beyond the Antagonism: Self-Labeled Xanthone Inhibitors as Modeled "Two-in-One" Drugs in Cancer Therapy. AB - Self-labeled inhibitors (SLIs) are promising for creating links, ranging from cancer therapy and metastatic pathways to mechanistic elucidation. In this study, a new category of "two-in-one" fluorescent xanthone inhibitors was developed for the systematic evaluation of anticancer activity and the selective imaging of cytoplasm in vitro. These xanthone inhibitors presented high fluorescent brightness, working over a wide pH range enabled by a "switchable reaction" of the heterocyclic backbone. The strength and nature of fluorescence were probed via spectroscopic methods and density functional theory calculations on the molecular level, respectively. Along with the potent anticancer activity, which was demonstrated using MTT and clonogenic assays with high fluorescent brightness in the cytoplasm, SLI 3fd could be established as a modeled self-monitoring drug in cancer therapy. PMID- 30023618 TI - Quantum Chemical Study of Dual-Substrate Recognition in omega-Transaminase. AB - omega-Transaminases are attractive biocatalysts for the production of chiral amines. These enzymes usually have a broad substrate range. Their substrates include hydrophobic amines as well as amino acids, a feature referred to as dual substrate recognition. In the present study, the reaction mechanism for the half transamination of l-alanine to pyruvate in (S)-selective Chromobacterium violaceum omega-transaminase is investigated using density functional theory calculations. The role of a flexible arginine residue, Arg416, in the dual substrate recognition is investigated by employing two active-site models, one including this residue and one lacking it. The results of this study are compared to those of the mechanism of the conversion of (S)-1-phenylethylamine to acetophenone. The calculations suggest that the deaminations of amino acids and hydrophobic amines follow essentially the same mechanism, but the energetics of the reactions differ significantly. It is shown that the amine is kinetically favored in the half-transamination of l-alanine/pyruvate, whereas the ketone is kinetically favored in the half-transamination of (S)-1 phenylethylamine/acetophenone. The calculations further support the proposal that the arginine residue facilitates the dual-substrate recognition by functioning as an arginine switch, where the side chain is positioned inside or outside of the active site depending on the substrate. Arg416 participates in the binding of l alanine by forming a salt bridge to the carboxylate moiety, whereas the conversion of (S)-1-phenylethylamine is feasible in the absence of Arg416, which here represents the case in which the side chain of Arg416 is positioned outside of the active site. PMID- 30023619 TI - Multifunctional Nanocomposite Films for Synergistic Delivery of bFGF and BMP-2. AB - The development of novel materials capable of delivering multiple growth factors is urgent and essential for rapid and effective tissue regeneration. In this study, a kind of composite film composed of poly-l-lysine (PLL), heparin (Hep), and Au nanoparitcles (Au nps) has been fabricated to deliver the basic fibroblast growth factor (bFGF) and bone morphogenetic protein-2 (BMP-2) simultaneously. The films have been found to show enhanced mechanical property due to the incorporation of Au nps. They have also shown good anticoagulation activity with long activated partial thromboplastin time because of the contribution of Hep molecules. Moreover, the osteogenesis studies reveal that the loaded bFGF and BMP 2 in the composite films have a synergistic differentiation effect on mesenchymal stem cells, as indicated by alkaline phosphatase (ALP) activity assay and collagen type I (Col-I) gene expression. In contrast to the (PLL/Hep)6/BMP 2/(PLL/Au nps)6/(PLL/Hep)6 and (PLL/Hep)6/(PLL/Au nps)6/(PLL/Hep)6/bFGF films, the (PLL/Hep)6/BMP-2/(PLL/Au nps)6/(PLL/Hep)6/bFGF films have shown higher ALP activity and higher Col-I expression level. Therefore, the developed multifunctional films could be potentially used as osteoinductive coatings of biomaterials. Particularly, this simple and convenient strategy provides an effective approach for the immobilization of multiple growth factors, which may be extended to other bioactive systems for the development of novel multifunctional bioactive surfaces. PMID- 30023620 TI - Auxiliary Biomembranes as a Directional Delivery System To Control Biological Events in Cell-Laden Tissue-Engineering Scaffolds. AB - Delivery of growth factors is an indispensable part of tissue engineering. Here, we describe a detachable membrane-based release system composed of extracellular matrix components that can be attached to hydrogels to achieve directional release of bioactive molecules. This way, the release of cytokines/growth factors can be started at a desired point of tissue maturation or directly in vivo. As a model, we develop thin films of an interpenetrating network of double-cross linked gelatin and hyaluronic acid derivatives. The use of the auxiliary release system with vascular endothelial growth factor results in extensive sprouting by encapsulated vascular endothelial cells. The presence of the release system with interleukin-4 results in clustering of encapsulated macrophages with a significant decrease in M1 macrophages (proinflammatory). This system can be used in conjunction with three-dimensional structures as an auxiliary system to control artificial tissue maturation and growth. PMID- 30023621 TI - Crystal Structure and Potential Head-to-Middle Condensation Function of a Z,Z Farnesyl Diphosphate Synthase. AB - Plants produce a wide variety of secondary metabolites in response to adverse environmental factors. Z,Z-Farnesyl diphosphate (Z,Z-FPP), synthesized by Z,Z farnesyl diphosphate synthase (zFPS), supports the formation of phytochemicals in wild tomatoes. Here, the crystal structure of N-terminal truncated zFPS (DeltazFPS) was determined. Irregular products including lavandulyl diphosphate and an unknown compound were surprisingly found. Apart from the truncated N terminus as a functional regulator, structure-based analysis and mutagenesis assays revealed a residue H103 in DeltazFPS as one of the key elements to this irregular function. A series of substrate-enzyme complex structures were obtained from DeltazFPS-H103Y by co-crystallizing with isopentenyl diphosphate, dimethylallyl thiolodiphosphate, or both. Various substrate-binding modes were revealed. The catalytic mechanisms of both the head-to-tail and head-to-middle reactions in DeltazFPS were proposed. Functional switch between the two mechanisms in this enzyme and the essential role played by the flexible C terminus were elucidated as well. PMID- 30023622 TI - Facile Generation of A2B Corrole Radical Using Fe(III) Salts and Its Spectroscopic Properties. AB - A carboxyphenyl-substituted corrole, 5,15-dimesityl-10-(4'-carboxyphenyl)corrole (1), has been synthesized and characterized by UV-vis, fluorescence, 1H NMR spectroscopy, and electrospray ionization (ESI)-mass spectrometry (MS) techniques. An air-stable corrole radical (1*) was obtained with the addition of the Fe(III) salt to 1 in dimethyl sulfoxide (DMSO) and characterized by UV-vis, fluorescence, electron paramagnetic resonance (EPR), ESI-MS techniques, and density functional theory studies. The neutral corrole radical (1*) exhibited a sharp EPR signal at g = 2.006 in DMSO. The reduced bipyrrolic (N-C-C-N) dihedral angle (chi) of 1 from 19.11 to 7.07 degrees leads to the release of angle strain, which is the driving force for the generation of 1*. Notably, trans dimesityl groups prevent the dimerization or aggregation of the corrole radical. Further, 1* was converted to 1 by excess addition of Fe(II) salts in DMSO at 298 K. PMID- 30023624 TI - Biomimetic Coating of Hydroxyapatite on Glycerol Phosphate-Conjugated Polyurethane via Mineralization. AB - In this study, glycerol phosphate was introduced into polyurethane (PU) to promote the coating stability of hydroxyapatite (HA) during its mineralization on the PU surface. Glycerol phosphate was successfully conjugated with the PU chain during polymerization. Phosphate groups in glycerol phosphate accelerated the nucleation of HA under calcium phosphate ion-rich conditions (concentrated simulated body fluid), resulting in the enhancement of structural stability. The robust interface between HA and PU also improved mechanical properties. Hydrophilic phosphate groups and bioactive HA improved in vitro cellular responses in terms of the attachment and proliferation of L929 fibroblasts and MC3T3-E1 preosteoblasts. Thus, the highly elastic and bioactive PU-gp-HA could be a promising candidate for tissue engineering applications that experience frequent deformation, including diverse cartilage replacements. PMID- 30023623 TI - Naphthalenediimide-Linked Bisbenzimidazole Derivatives as Telomeric G-Quadruplex Stabilizing Ligands with Improved Anticancer Activity. AB - Human telomeric G-quadruplex DNA stabilization has emerged as an exciting novel approach for anticancer drug development. In the present study, we have designed and synthesized three C2-symmetric bisubstituted bisbenzimidazole naphthalenediimide (NDI) ligands, ALI-C3 , BBZ-ARO, and BBZ-AROCH2 , which stabilize human telomeric G-quadruplex DNA with high affinity. Herein, we have studied the binding affinities and thermodynamic contributions of each of these molecules with G-quadruplex DNA and compared the same to those of the parent NDI analogue, BMSG-SH-3. Results of fluorescence resonance energy transfer and surface plasmon resonance demonstrate that these ligands have a higher affinity for G4-DNA over duplex DNA and induce the formation of a G-quadruplex. The binding equilibrium constants obtained from the microcalorimetry studies of BBZ ARO, ALI-C3 , and BBZ-AROCH2 were 8.47, 6.35, and 3.41 MUM, respectively, with h telo 22-mer quadruplex. These showed 10 and 100 times lower binding affinity with h-telo 12-mer and duplex DNA quadruplexes, respectively. Analysis of the thermodynamic parameters obtained from the microcalorimetry study suggests that interactions were most favorable for BBZ-ARO among all of the synthesized compounds. The DeltaGfree obtained from molecular mechanics Poisson-Boltzmann surface area calculations of molecular dynamics (MD) simulation studies suggest that BBZ-ARO interacted strongly with G4-DNA. MD simulation results showed the highest hydrogen bond occupancy and van der Waals interactions were between the side chains of BBZ-ARO and the DNA grooves. A significant inhibition of telomerase activity (IC50 = 4.56 MUM) and induced apoptosis in cancer cell lines by BBZ-ARO suggest that this molecule has the potential to be developed as an anticancer agent. PMID- 30023625 TI - Diketopiperazines as Cross-Communication Quorum-Sensing Signals between Cronobacter sakazakii and Bacillus cereus. AB - Herein, we reveal a second quorum-sensing system produced by Cronobacter sakazakii. A cyclo(l-Pro-l-Leu) diketopiperazine, detected in pure and mixed cultures of C. sakazakii and Bacillus cereus explains the coexistence of both in the same industrial environments. The molecule was identified by gas chromatography-mass spectrometry (GC-MS), 1H, and 13C NMR, including 2D NMR (correlation spectroscopy, heteronuclear multiple bond correlation, and heteronuclear single quantum correlation), and the absolute configuration was compared with that of four synthetic standards produced by solid phase peptide synthesis using a chiral column on a GC-flame ionization detection. This article provides a new method to determine the absolute configuration of cyclo(Pro-Leu) diketopiperazine replacing the joint use of 1H NMR and Marfey's method. PMID- 30023626 TI - Template-Free Assembly in Living Bacterial Suspension under an External Electric Field. AB - Although template-assisted self-assembly methods are very popular in materials and biological systems, they have certain limitations such as lack of tunability and switchable functionality because of the irreversible association of cells and their matrix components. With an aim to achieve more tunability, we have made an attempt to investigate the self-assembly behavior of rod-shaped living bacteria subjected to an external alternating electric field using confocal microscopy. We demonstrate that rod-shaped living bacteria dispersed in a low salinity aqueous medium form different types of reversible freely suspended structures when subjected to an external alternating electric field. At low field strength, an oriented phase is observed where individual bacterium orients with its major axis aligned along the field direction. At intermediate field strength, bacteria align in the form of one-dimensional (1D) chains that lie along the field direction. Further, at high field strength, more bacteria associate with these 1D chains laterally to form a two-dimensional (2D) array. At higher bacterial concentration, these field-induced 2D arrays extend to form three-dimensional columnar structures. These results are discussed in the context of previously reported studies on bacterial self-assembly. PMID- 30023627 TI - N-Methyl-beta-carbolinium Salts and an N-Methylated 8-Oxoisoguanine as Acetylcholinesterase Inhibitors from a Solitary Ascidian, Cnemidocarpa irene. AB - New brominated beta-carbolines irenecarbolines A (1) and B (4) along with known beta-carbolines 2 and 3 and a new 8-oxoisoguanine derivative, 5, were isolated from a solitary ascidian, Cnemidocarpa irene. The structures of these compounds were determined on the basis of their spectral data. All, except for 3, inhibited the action of acetylcholinesterase (AchE). The activities of 1 and 5 were comparable to those of galantamine, a clinically used AchE inhibitor. Compounds 1 and 2 were found to be present in high concentrations in blood, and fluorescence was observed in certain types of cells found in the blood of the tunicate. PMID- 30023628 TI - Investigation of Core Structure and Stability of Human Pyruvate Dehydrogenase Complex: A Coarse-Grained Approach. AB - The human pyruvate dehydrogenase complex (hPDC) is a large macromolecular machine, and its unique structural and functional properties make it a versatile target for manipulation aiming for the design of new types of artificial multienzyme cascades. However, model-based and hence systematic understanding of the structure-function relationship of this kind of complexes is yet poor. However, with new structure data, modeling techniques, and increasing computation power available, this shortfall is about to cease. Recently, we have built new atomistic models of E2/E3BP, the two subunits of the massive hPDC core. Here, we present developed coarse-grained models of the same, on the basis of which we built and simulated the full core of hPDC, which is so far the first simulation of the catalytic core of any member in the branched-chain alpha-keto acid dehydrogenase complex family. We explored the stability of two previously proposed substitutional models of hPDC core: 40E2+20E3BP and 48E2+12E3BP. Our molecular dynamics simulations showed a higher stability and sphericity for the second model. Our core's radius of gyration was found to be in strong agreement with previously published experimental dynamic light scattering (DLS) data. Finally, in the direction of our experimental effort to design active minimized complexes, we simulated C-terminal truncated E2/E3BP cores of different lengths, which clearly showed the instability of the core assembly and symmetry due to subunit separations. This correlated very well with the findings of our experimental investigations by analysis of DLS data for variable truncation lengths. The use of polarizable water and an increased total ion concentration did not lead to a substantially different initial stability of the truncated mutants compared to that of standard MARTINI water; however, a different rearrangement behavior of the fragments was observed. The obtained structure models will serve as a basis for full complex simulations in the future, providing the possibility for the model-assisted targeted manipulation of such a complex enzymatic system. PMID- 30023629 TI - Spiral Countercurrent Chromatography Enrichment, Characterization, and Assays of Carbon Nanotube Chiralities for Use in Biosensors. AB - Single-walled carbon nanotubes (SWCNTs) are synthetic materials that hold great promise for electronics that are smaller and more versatile than the current silica-based technologies. But as-produced SWCNTs are generally a mixture of nanotubes with different structures that have vastly different properties. Separating these SWCNTs from multiwalled and metallic carbon nanotubes is vital to explore their individual properties and commercial utility ranging from optics to semiconductors. Compounding the problem of commercial investigation is that the semiconducting SWCNTs are also a mixture of different diameters and/or chiralities with different properties. Analyzing properties of enriched semiconducting SWCNT chiralities has only recently been possible through separation techniques such as aqueous two-phase solvent systems. Our study illustrates a semipreparative spiral countercurrent chromatography (CCC) separation of a commercial mixture of SWCNTs into distinct enriched fractions. A new mixer-settler spiral disk rotor was applied in this study, in which we compare the enriched SWCNTs for their effectiveness in biosensors with a high throughput model assay, followed by antibody-mediated detection of Escherichia coli. Our results demonstrate that CCC-enriched responsive SWCNTs for biosensors can be used in our model assay, as well as for the detection of E. coli. To date, we believe that this is the first study along with Liu et al. [Chirality controlled synthesis of single-wall carbon nanotubes using vapour-phase epitaxy. Nat. Commun.2012, 3, 1199] to demonstrate a specific utility of separated SWCNT species. PMID- 30023630 TI - Metal-Organic Framework/Graphene Quantum Dot Nanoparticles Used for Synergistic Chemo- and Photothermal Therapy. AB - In this study, a simple one-pot method was used to prepare a multifunctional platform for synergistic chemo- and photothermal therapy,, which is composed of zeolitic imidazolate framework-8 (ZIF-8) as drug nanocarriers and the embedded graphene quantum dots (GQDs) as local photothermal seeds. The structure, drug release behavior, photothermal effect, and synergistic therapeutic efficiency of the ZIF-8/GQD nanoparticles were systematically investigated. Using doxorubicin (DOX) as a model anticancer drug, the results showed that monodisperse ZIF-8/GQD nanoparticles with a particle size of 50-100 nm could encapsulate DOX during the synthesis procedure and trigger DOX release under acidic conditions. The DOX loaded ZIF-8/GQD nanoparticles could efficiently convert near-infrared (NIR) irradiation into heat and thereby increase the temperature. More importantly, with breast cancer 4T1 cells as a model cellular system, the results indicated that the combined chemo- and photothermal therapy with DOX-ZIF-8/GQD nanoparticles exhibited a significant synergistic effect, resulting in a higher efficacy to kill cancer cells compared with chemotherapy and photothermal therapy alone. Hence, ZIF-8/GQD nanoparticles would be promising as versatile nanocarriers for synergistic cancer therapy. PMID- 30023631 TI - Zein Microneedles for Transcutaneous Vaccine Delivery: Fabrication, Characterization, and in Vivo Evaluation Using Ovalbumin as the Model Antigen. AB - Transcutaneous antigen administration provides an alternative to invasive syringe injections. The objective of this study was to investigate the feasibility of fabrication and antigen delivery using microneedles made from corn protein, zein. Micromolding technique was used to cast cone-shaped zein microneedles (ZMNs). The insertion of ZMNs and the delivery of the model antigen, ovalbumin (OVA), into the skin was confirmed by histological examination and confocal microscopy. In addition, a significantly (p < 0.05) lower bacterial skin penetration was observed after ZMN application compared with hypodermic syringe application. OVA coated on ZMNs was stable after storage under ambient and refrigerator conditions. Transcutaneous immunization studies showed significantly (p < 0.001) greater antibody titers (total IgG, IgG1, and IgG2a) after the application of OVA coated ZMNs and OVA intradermal injection compared with the control group. Taken together, antigen-coated ZMNs can be developed for transcutaneous vaccine delivery. PMID- 30023632 TI - Singlet Oxygen Generation with Chemical Excitation of an Erythrosine-Luminol Conjugate. AB - Chemical generation of singlet oxygen under biologically relevant conditions is very important, considering the role played by singlet oxygen in cancer therapeutics. We now demonstrate that a luminol derivative can be chemically excited and transfer the excitation energy to the covalently attached photosensitizer derived from erythrosin. A photosensitizer module, when excited in this manner, can generate singlet oxygen in solution. As hydrogen peroxide is present in a relatively high concentration in cancer cells, singlet oxygen generation through chemical excitation may evolve into an important therapeutic approach. PMID- 30023634 TI - In Situ Monitoring of Nanostructure Formation during the Digestion of Mayonnaise. AB - Triglycerides in food products such as mayonnaise are a vital source of energy and essential for a complete and healthy diet. Their molecular structures consist of a glycerol backbone esterified with fatty acids on the two outer and the middle positions. During the digestion of triglycerides by pancreatic lipase in the small intestine, the ester bonds on the outer positions are hydrolyzed, leading to amphiphilic monoglycerides and free fatty acids as products. Depending on their chain length and degree of saturation, these products can self-assemble into a variety of structures in excess water. In this study, we report the discovery of highly ordered nanostructures inside of the mayonnaise emulsion droplets during in vitro digestion of mayonnaise under simulated in vivo conditions using time-resolved synchrotron small-angle X-ray scattering. The formation of these structures is most likely linked to their function as a carrier and controlled release system for food nutrients, especially poorly water soluble components, in the aqueous milieu of the digestive tract. This detailed understanding of nanostructure formation during the digestion of triglyceride containing food products such as mayonnaise may have fundamental implications for the development of foods with improved nutritional and functional properties. PMID- 30023633 TI - Development of a 68Ge/68Ga Generator System Using Polysaccharide Polymers and Its Application in PET Imaging of Tropical Infectious Diseases. AB - Gallium-68 (68Ga) is a positron emitter for clinical positron emission tomography (PET) applications that can be produced by a 68Ge/68Ga generator without cyclotron. However, commercially available 68Ge/68Ga generator systems require multiple steps for the preparation of 68Ga radiopharmaceuticals and are sometimes plagued by metallic impurities in the 68Ga eluent. We developed a 68Ge/68Ga generator system using polysaccharide-based adsorbents and direct application of the generator-eluted 68Ga-citrate to PET imaging of tropical infectious diseases. N-Methylglucamine (MG) as a 68Ge-adsorbing unit (Sepha-MGs) was introduced to a series of Sephadex G-10, G-15, G-25, G-50, and G-75. In the batch method, over 97% of the 68Ge in the solution was adsorbed onto the Sepha-MG series within 15 min. In particular, 68Ge was effectively adsorbed on the Sepha(15)-MG packed columns and 70-80% of the 68Ga was eluted by 1 mL of 0.1 M trisodium citrate with low 68Ge contamination (<0.001%). The chemical form of the generator-eluted 68Ga solution was identified as 68Ga-citrate. In PET studies, affected regions in mice infected with Leishmania and severe fever with thrombocytopenia syndrome virus were clearly visualized using the 68Ga-citrate. Sepha-MGs are useful adsorbents for 68Ge/68Ga generator systems with high 68Ga elution efficiency and minimal 68Ge breakthrough. These results indicated that eluted 68Ga-citrate can be directly used for PET imaging of infectious sites in mice. This novel generator system may be useful for straightforward PET imaging of infection in clinical practice. PMID- 30023635 TI - Application of a New Scaffold Concept for Computational Target Deconvolution of Chemical Cancer Cell Line Screens. AB - Target deconvolution of phenotypic assays is a hot topic in chemical biology and drug discovery. The ultimate goal is the identification of targets for compounds that produce interesting phenotypic readouts. A variety of experimental and computational strategies have been devised to aid this process. A widely applied computational approach infers putative targets of new active molecules on the basis of their chemical similarity to compounds with activity against known targets. Herein, we introduce a molecular scaffold-based variant for similarity based target deconvolution from chemical cancer cell line screens that were used as a model system for phenotypic assays. A new scaffold type was used for substructure-based similarity assessment, termed analog series-based (ASB) scaffold. Compared with conventional scaffolds and compound-based similarity calculations, target assignment centered on ASB scaffolds resulting from screening hits and bioactive reference compounds restricted the number of target hypotheses in a meaningful way and lead to a significant enrichment of known cancer targets among candidates. PMID- 30023636 TI - Studies toward the Synthesis of Smenamide A, an Antiproliferative Metabolite from Smenospongia aurea: Total Synthesis of ent-Smenamide A and 16-epi-Smenamide A. AB - A chiral pool protocol toward the synthesis of the smenamide family of natural products is described. Two stereoisomers of smenamide A, namely, ent-smenamide A and 16-epi-smenamide A were synthesized with a 2.6 and 2.5% overall yield, respectively. Their carboxylic acid moieties were assembled starting from S citronellene via two Wittig reactions and a Grignard process. Its coupling with either (S)- or (R)-dolapyrrolidinone, synthesized from Boc-l-Phe and Boc-d-Phe, respectively, was accomplished by using the Andrus protocol. This work also established the previously unknown relative and absolute configurations of smenamide A. PMID- 30023637 TI - Biosynthesized Protein-Capped Silver Nanoparticles Induce ROS-Dependent Proapoptotic Signals and Prosurvival Autophagy in Cancer Cells. AB - In recent years, the use of silver nanoparticles (AgNPs) in biomedical applications has shown an unprecedented boost along with simultaneous expansion of rapid, high-yielding, and sustainable AgNP synthesis methods that can deliver particles with well-defined characteristics. The present study demonstrates the potential of metal-tolerant soil fungal isolate Penicillium shearii AJP05 for the synthesis of protein-capped AgNPs. The particles were characterized using standard techniques, namely, UV-visible spectroscopy, transmission electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The anticancer activity of the biosynthesized AgNPs was analyzed in two different cell types with varied origin, for example, epithelial (hepatoma) and mesenchymal (osteosarcoma). The biological NPs (bAgNPs) with fungal-derived outer protein coat were found to be more cytotoxic than bare bAgNPs or chemically synthesized AgNPs (cAgNPs). Elucidation of the molecular mechanism revealed that bAgNPs induce cytotoxicity through elevation of reactive oxygen species (ROS) levels and induction of apoptosis. Upregulation of autophagy and activation of JNK signaling were found to act as a prosurvival strategy upon bAgNP treatment, whereas ERK signaling served as a prodeath signal. Interestingly, inhibition of autophagy increased the production of ROS, resulting in enhanced cell death. Finally, bAgNPs were also found to sensitize cells with acquired resistance to cisplatin, providing valuable insights into the therapeutic potential of bAgNPs. To the best of our knowledge, this is the first study that provides a holistic idea about the molecular mechanisms behind the cytotoxic activity of protein-capped AgNPs synthesized using a metal-tolerant soil fungus. PMID- 30023638 TI - Fe3O4@Resorcinol-Formaldehyde Resin/Cu2O Composite Microstructures: Solution Phase Construction, Magnetic Performance, and Applications in Antibacterial and Catalytic Fields. AB - Multifunctional Fe3O4@resorcinol-formaldehyde resin/Cu2O composite microstructures (denoted as Fe3O4@RF/Cu2O microstructures) were successfully constructed via a simple wet chemical route that has not been reported so far in the literature. The as-obtained Fe3O4@RF/Cu2O microstructures were characterized using field-emission scanning electron microscopy, (high-resolution) transmission electron microscopy, selected-area electron diffraction, X-ray diffraction, and X ray energy dispersive spectroscopy. The investigations showed that the as obtained microstructures presented not only excellent antibacterial activity to Staphylococcus aureus (Gram-positive bacteria) and Escherichia coli (Gram negative bacteria) but also highly efficient catalytic ability for the reduction of 4-nitrophenol (4-NP) in a solution with excess NaBH4. Owing to the presence of Fe3O4, the antibacterial reagent and the catalyst could be readily collected from the mixed systems under the assistance of an external magnetic field. It was found that the as-obtained microstructures displayed good cycling stability in antibacterial and catalytic applications. Fe3O4@RF/Cu2O microstructures still retained more than 87% of the antibacterial efficiency after 5 cycles and 89% of the catalytic efficiency after 10 cycles. PMID- 30023639 TI - Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6. AB - Little is known about the biological and structural features that govern the isoform selectivity for class I histone deacetylases (HDACs) over HDAC6. In addition to that for known inhibitors, like benzamides, psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was also observed for naturally occurring cyclopeptide HDAC inhibitors with an aliphatic flexible linker and ketonelike zinc-binding group (ZBG). The present study reports that this isoform selectivity is mainly due to the linker and ZBG, as replacement of the cyclopeptide cap region by a simple aniline retained class I HDAC isoform selectivity toward HDAC6 in enzymatic assays. The best cyclopeptide-free analogues preserved efficacy against Plasmodium falciparum and cancer cell lines. Molecular modeling provided hypotheses to explain this selectivity and suggests different behaviors of the flexible linker on HDAC1 and HDAC6 pockets, which may influence, on the basis of the strength of the ZBG, its coordination with the zinc ion. PMID- 30023640 TI - Side-Chain Amino Acid-Based Cationic Antibacterial Polymers: Investigating the Morphological Switching of a Polymer-Treated Bacterial Cell. AB - Synthetic polymer-based antimicrobial materials destroy conventional antibiotic resistant microorganisms. Although these antibacterial polymers imitate the properties of antimicrobial peptides (AMPs), their effect on bacterial cell morphology has not been studied in detail. To investigate the morphology change of a bacterial cell in the presence of antimicrobial polymer, herein we have designed and synthesized side-chain amino acid-based cationic polymers, which showed efficient antibacterial activity against Gram-negative (Escherichia coli), as well as Gram-positive (Bacillus subtilis) bacteria. Morphological switching from a rod shape to a spherical shape of E. coli cells was observed by field emission-scanning electron microscopy analysis due to cell wall disruption, whereas the B. subtilis cell structure and size remained intact, but stacks of the cells formed after polymer treatment. The zone of inhibition experiment on an agar plate for E. coli cells exhibited drastic morphological changes at the vicinity of the polymer-treated portion and somewhat less of an effect at the periphery of the plate. PMID- 30023641 TI - Thermophilic Talaromyces emersonii Flavin Adenine Dinucleotide-Dependent Glucose Dehydrogenase Bioanode for Biosensor and Biofuel Cell Applications. AB - Flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase (GDH) was identified and cloned from thermophilic filamentous fungi Talaromyces emersonii using the homology cloning method. A direct electron transfer bioanode composed of T. emersonii FAD-GDH and a single-walled carbon nanotube was produced. Enzymes from thermophilic microorganisms generally have low activity at ambient temperature; however, the T. emersonii FAD-GDH bioanode exhibits a large anodic current due to the enzymatic reaction (1 mA cm-2) at ambient temperature. Furthermore, the T. emersonii FAD-GDH bioanode worked at 70 degrees C for 12 h. This is the first report of a bioanode with a glucose-catalyzing enzyme from a thermophilic microorganism that has potential for biosensor and biofuel cell applications. In addition, we demonstrate how the glycoforms of T. emersonii FAD GDHs expressed by various hosts influence the electrochemical properties of the bioanode. PMID- 30023643 TI - Improved Performance of Recombinant Protein A Immobilized on Agarose Beads by Site-Specific Conjugation. AB - Protein A affinity adsorbent with high antibody-binding capacity plays a prominent part in the purification of biopharmaceuticals to decrease the manufacturing costs. We describe a site-specific covalent conjugation strategy for protein A to immobilize on agarose beads. Recombinant protein A, which has one cysteine introduced at the C terminus through genetic engineering technology, was immobilized site-specifically on maleimide-functionalized agarose beads by the thiol-maleimide reaction. As a comparison, the recombinant protein A was randomly immobilized on the aldehyde-functionalized agarose beads via free amino groups on the protein surface. The site-specific conjugation of recombinant protein A on the agarose beads was validated through the assay of free SH groups on the adsorbents using the Ellman's reagent. Adsorbents containing various amounts of protein A were used to adsorb antibody from human plasma. Analysis of immunoturbidimetry showed that the adsorbed fractions contained the 90.1% IgG, 4.2% IgA, and 5.7% IgM. The maximal antibodies-binding capacities with static adsorption and dynamic adsorption were approximately 64 and 50 mg, respectively, per swollen gram for site-specifically conjugated adsorbent and 31 and 26 mg for randomly conjugated adsorbent. Remarkably, the high antibody-binding capacity for site-specifically conjugated adsorbent outperformed the existing commercial protein A Sepharose (approximately 30 mg/g). The orientation of a protein is crucial for its activity after immobilization, and these results demonstrate that the site-specifically conjugated protein molecule is in a functionally active form to interact with the antibody with weak steric hindrance. The proposed approach may be an attractive strategy to synthesize affinity adsorbents with high-binding capacity. PMID- 30023642 TI - Ligand Selectivity between the ADP-Ribosylating Toxins: An Inverse-Docking Study for Multitarget Drug Discovery. AB - Bacterial adenosine 5'-diphosphate-ribosylating toxins are encoded by several human pathogens, such as Pseudomonas aeruginosa (exotoxin A (ETA)), Corynebacterium diphtheriae (diphtheria toxin (DT)), and Vibrio cholerae (cholix toxin (CT)). The toxins modify eukaryotic elongation factor 2, an essential human enzyme in protein synthesis, thereby causing cell death. Targeting external virulence factors, such as the above toxins, is a promising alternative for developing new antibiotics, while at the same time avoiding drug resistance. This study aims to establish a reliable computational methodology to find a "silver bullet" able to target all three toxins. Herein, we have undertaken a detailed analysis of the active sites of ETA, DT, and CT, followed by the determination of the most appropriate selection of the size of the docking sphere. Thereafter, we tested two different approaches for normalizing the docking scores and used these to verify the best target (toxin) for each ligand. The results indicate that the methodology is suitable for identifying selective as well as multitoxin inhibitors, further validating the robustness of inverse docking for target fishing experiments. PMID- 30023644 TI - Green and Sustainable Technology for High-Efficiency and Low-Damage Manipulation of Densely Crosslinked Proteins. AB - A two-step technology using nontoxic and eco-friendly chemicals is developed for the durable setting of densely/highly crosslinked proteins, such as wool and hair. Currently, most technologies for morphological modification are effective only for materials from non-highly-crosslinked proteins and cellulose. Before their morphological change, only water is needed to interrupt hydrogen bonds and ionic linkages, which stabilize the relative positions of molecules in non-highly crosslinked proteins and cellulose. However, highly crosslinked proteins contain disulfide crosslinks, which are insusceptible to water. Thus, the controlled cleavage of disulfide bonds is required for creating new morphologies of highly crosslinked protein materials, such as hair and wool. Herein, cysteine and citric acid (CA) were used for the two-step setting of highly crosslinked proteins. This recipe showed better morphological change and less mechanical loss than commercial hair styling products. A reaction between CA and keratin was proposed, and verified via NMR and Raman spectra and titration. This technology could be a prospective alternative to achieve durable hair setting, anticrease finishing of wool textiles, and other durable morphological changes needed for highly crosslinked proteins. PMID- 30023645 TI - Two-Photon Fluorescent Molybdenum Disulfide Dots for Targeted Prostate Cancer Imaging in the Biological II Window. AB - Molybdenum disulfide (MoS2) quantum dots (QDs) derived from this two-dimensional (2D) transition metal dichalcogenide are emerging zero-dimensional materials that possess very good optical properties. Bioimaging using light in the biological II window (950-1350 nm) is a next-generation approach that will allow clinicians to achieve deeper tissue imaging with better image contrast and reduced phototoxicity and photobleaching. This article reports the development of a water soluble, zero-dimensional antibody-conjugated transition metal dichalcogenide MoS2 QD-based two-photon luminescence (TPL) probe for the targeted bioimaging of cancer cells in the biological II window. The data indicates that MoS2 QDs exhibit an extremely high two-photon absorption cross-section (sigma = 58960 GM) and two-photon brightness (4.7 * 103 GM) because of the quantum confinement and edge effects. Experimental data show that anti-PSMA antibody-attached MoS2 QDs can be used for selective two-photon imaging of live prostate cancer cells using 1064 nm light because of the high two-photon brightness, very good photostability, and very good biocompatibility of these MoS2 QDs. The data demonstrate that the bioconjugated MoS2 QDs can distinguish targeted and nontargeted cells. This study illuminates the high two-photon brightness mechanism of MoS2 QDs and provides a zero-dimensional transition metal dichalcogenide-based selective TPL agent for high-efficiency live cell imaging. PMID- 30023646 TI - Analysis of Biphenyl-Type Inhibitors Targeting the Eg5 alpha4/alpha6 Allosteric Pocket. AB - Eg5 is a mitotic kinesin protein that plays an important role in the formation and maintenance of the bipolar spindle during the mitotic phase. Due to its potentially reduced side effects in cancer therapy, Eg5 is considered to be an attractive target for developing anticancer inhibitors. Herein, we report a computational modeling study involving biphenyl-type inhibitors known to interact with the alpha4/alpha6 allosteric pocket of Eg5. Compared to the well-known alpha2/L5/alpha3 allosteric inhibitors, biphenyl-type inhibitors show a unique activity profile. In the Eg5-PVZB1194 (a biphenyl-type inhibitor) crystal structure, loop L11, which is located in the entrance of the alpha4/alpha6 allosteric-binding pocket, is missing due to crystal-packing effects. To better understand the role of this flexible loop upon biphenyl-type inhibitor-binding, MD simulations were performed to observe the L11 conformations from different states. It was demonstrated that L11 was more stabilized and showed less fluctuation when PVZB1194 was bound to Eg5. Residue Asn287 from L11 forms hydrogen bonding to the sulfone group of PVZB1194, whereby L11 moves inward to the alpha4/alpha6 allosteric pocket and moves away from the pocket in absence of the inhibitor. Pharmacophore, three-dimensional (3D)-QSAR, and ADME studies of biphenyl-type inhibitors of Eg5 were also performed. A best pharmacophore model, DDRRH.6, was generated, having correlation coefficients in the 3D-QSAR study of R2 = 0.81 and Q2 = 0.64. Furthermore, docking studies were carried out to observe the interaction between the remaining biphenyl-type inhibitors with Eg5. In addition, on the basis of fragment docking, a structure-based pharmacophore was generated, which shares good overlap of the DHRR features of the pharmacophore model DDHRR.6. The structure-based pharmacophore also contains extra hydrogen bond acceptors and hydrophobic groups, features which provide possibilities in developing new or improved series of compounds. PMID- 30023647 TI - Essential Dynamics of an Effective Phototherapeutic Drug in a Nanoscopic Delivery Vehicle: Psoralen in Ethosomes for Biofilm Treatment. AB - Appropriate localization of a drug and its structure/functional integrity in a delivery agent essentially dictates the efficacy of the vehicle and the medicinal activity of the drug. In the case of a phototherapeutic drug, its photoinduced dynamics becomes an added parameter. Here, we have explored the photoinduced dynamical events of a model phototherapeutic drug psoralen (PSO) in a potential delivery vehicle called an ethosome. Dynamic light scattering confirms the structural integrity of the ethosome vehicle after the encapsulation of PSO. Steady state and picosecond resolved polarization gated spectroscopy, including the well-known strategy of solvation and Forster resonance energy transfer, reveal the localization of the drug in the vehicle and the environment in the proximity of PSO. We have also investigated the efficacy of drug delivery to various individual bacteria (Gram-negative: Escherichia coli; Gram-positive: Staphylococcus aureus) and bacterial biofilms. Our optical and electron microscopic studies reveal a significant reduction in bacterial survival (~70%) and the destruction of bacterial adherence following a change in the morphology of the biofilms after phototherapy. Our studies are expected to find relevance in the formulation of drug delivery agents in several skin diseases and biofilm formation in artificial implants. PMID- 30023648 TI - Sequential Synthesis, Olfactory Properties, and Biological Activity of Quinoxaline Derivatives. AB - A simple, practical, and rapid access to quinoxalin-2-ones 1, 1,2,3,4 tetrahydroquinoxalines 2, quinoxalines 3, and quinoxalin-2(1H)-ones 4 has been achieved, based on the copper-catalyzed quinoxalinone formation of 2-haloanilines and amino acids followed by their reduction and oxidation. The olfactory properties and lipid accumulation inhibitory activity in cultured hepatocytes of the quinoxaline derivatives were also evaluated. PMID- 30023649 TI - Chitosan-Covered Pd@Pt Core-Shell Nanocubes for Direct Electron Transfer in Electrochemical Enzymatic Glucose Biosensor. AB - Development of biosensors with high sensitivity, high spatial resolution, and low cost has received significant attention for their applications in medical diagnosis, diabetes management, and environment-monitoring. However, achieving a direct electrical contact between redox enzymes and electrode surfaces and enhancing the operational stability still remain as challenges. Inorganic metal nanocrystals (NCs) with precisely controlled shape and surface structure engineered with an appropriate organic coating can help overcome the challenges associated with their stability and aggregation for practical biosensor applications. Herein, we describe a facile, room-temperature, seed-mediated solution-phase route to synthesize monodisperse Pd@Pt core-shell nanocubes with subnanometer-thick platinum (Pt) shells. The enzyme electrode consisting of Pd@Pt core-shell NCs was first covered with a chitosan (CS) polymer and then glucose oxidase (GOx) immobilized by a covalent linkage to the CS. This polymer permits covalent immobilization through active amino (-NH) side groups to improve the stability and preserve the biocatalytic functions while the Pd@Pt NCs facilitate enhanced direct electron transfer (DET) in the biosensor. The resultant biosensor promotes DET and exhibits excellent performance for the detection of glucose, with a sensitivity of 6.82 MUA cm-2 mM-1 and a wide linear range of 1-6 mM. Our results demonstrate that sensitive electrochemical glucose detection based on Pd@Pt core-shell NCs provides remarkable opportunities for designing low-cost and sensitive biosensors. PMID- 30023650 TI - Structural Characterization of Bubbles Formed in DNA Melting: A Monte Carlo Simulation Study. AB - Bubbles in DNA are involved in many important biological processes. In this work, a coarse-grained model is used for characterizing bubbles formed in DNA melting. The model resorts only to electrostatic interactions at the Debye-Huckel level, in combination with a short-ranged attractive interaction within a base pair. In spite of also omitting atomistic details, the model is able to capture experimentally established trends in persistence length and radius of gyration. By applying it on different systems, it is possible to conclude that there is a minimum size for stable bubbles, in the interval between 12 and 20 bp, which agrees well with previously published experimental findings. Simulated scattering data distinguishes between different bubbles and detects conformational changes in the melting process. Therefore, SAXS is regarded as useful for bubble formation studies, while simulations provide a molecular understanding. PMID- 30023651 TI - POSS-Appended Diphenylalanine: Self-Cleaning, Pollution-Protective, and Fire Retardant Hybrid Molecular Material. AB - Ordered self-assemblies of hybrid molecules have potential as protective umbrellas against environmental pollution and corrosion. This article describes the design and fabrication of a new self-cleaning hybrid molecular material containing polyhedral oligomeric silsesquioxane (POSS) and diphenylalanine as hydrophobic and pollution-protective coating. The colorless organic-inorganic hybrid materials, in which the diphenylalanine motif controls the self-assembly, exhibit unique water resistance property and enhance mechanical strength of paper 1.5-fold. The hybrid building blocks self-assemble in antiparallel sheet manner through noncovalent interactions to form a supramolecular layerlike surface with enhanced roughness. The hybrid material is soluble in organic solvents at room temperature that makes it easy to coat on paper, wood, or metal surfaces. The coating is effective against rusting, corrosion, environmental pollution, and bacterial attack. The coating has been used as fire retardant and enhances fire safety. The sustainable molecular material is promising for the packaging industry and metal industry and artifact preservation. PMID- 30023652 TI - Synthesis of Calcium Bisphosphonate/Calcium Polyacrylate Spheres for Gene Delivery. AB - Calcium bisphosphonate/calcium polyacrylate spheres were synthesized by a facile method and applied for the first time as gene vectors for transfection. The colloidal spheres of the PAA-Ca2+-H2O complex, formed by sodium polyacrylate and calcium ions in the solution, were used as template to synthesize a spherical PAA Ca2+-BPMP composite (CaBPMP/CaPAA) in the presence of 1,4 bis(phosphomethyl)piperazine (BPMP). The CaBPMP/CaPAA composite exhibits uniform and well-dispersed spheres with a particle size of about 200 nm as expected. The cytotoxicity assays confirm that CaBPMP/CaPAA spheres are quite safe for different cells even at a high concentration of 500 MUg/mL. In vitro transfection results show that CaBPMP/CaPAA spheres serving as gene vectors are capable of transferring exogenous genes into different cells with about 25% of transfection efficiency and good reproducibility. The transfection capacity of CaBPMP/CaPAA spheres may be attributed to the controllable sphere morphology, low cytotoxicity, moderate DNA loading capacity, and bioresorbable property. The application of calcium phosphonates with adjustable surface properties derived from the different organic groups of phosphonic acid in gene delivery provides a new design idea for gene vectors. PMID- 30023653 TI - Highly Selective and Tunable Protein Hydrolysis by a Polyoxometalate Complex in Surfactant Solutions: A Step toward the Development of Artificial Metalloproteases for Membrane Proteins. AB - This study represents the first example of protein hydrolysis at pH = 7.4 and 60 degrees C by a metal-substituted polyoxometalate (POM) in the presence of a zwitterionic surfactant. Edman degradation results show that in the presence of 0.5% w/v 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) detergent, a Zr(IV)-substituted Wells-Dawson-type POM, K15H[Zr(alpha2 P2W17O61)2].25H2O (Zr1-WD2), selectively hydrolyzes human serum albumin exclusively at peptide bonds involving Asp or Glu residues, which contain carboxyl groups in their side chains. The selectivity and extent of protein cleavage are tuned by the CHAPS surfactant by an unfolding mechanism that provides POM access to the hydrolyzed peptide bonds. PMID- 30023654 TI - Development of Escherichia coli Asparaginase II for Immunosensing: A Trade-Off between Receptor Density and Sensing Efficiency. AB - The clinical success of Escherichia colil-asparaginase II (EcAII) as a front line chemotherapeutic agent for acute lymphoblastic leukemia (ALL) is often compromised because of its silent inactivation by neutralizing antibodies. Timely detection of silent immune response can rely on immobilizing EcAII, to capture and detect anti-EcAII antibodies. Having recently reported the use of a portable surface plasmon resonance (SPR) sensing device to detect anti-EcAII antibodies in undiluted serum from children undergoing therapy for ALL (Aube et al., ACS Sensors2016, 1 (11), 1358-1365), here we investigate the impact of the quaternary structure and the mode of immobilization of EcAII onto low-fouling SPR sensor chips on the sensitivity and reproducibility of immunosensing. We show that the native tetrameric structure of EcAII, while being essential for activity, is not required for antibody recognition because monomeric EcAII is equally antigenic. By modulating the mode of immobilization, we observed that low-density surface coverage obtained upon covalent immobilization allowed each tetrameric EcAII to bind up to two antibody molecules, whereas high-density surface coverage arising from metal chelation by N- or C-terminal histidine-tag reduced the sensing efficiency to less than one antibody molecule per tetramer. Nonetheless, immobilization of EcAII by metal chelation procured up to 10-fold greater surface coverage, thus resulting in increased SPR sensitivity and allowing reliable detection of lower analyte concentrations. Importantly, only metal chelation achieved highly reproducible immobilization of EcAII, providing the sensing reproducibility that is required for plasmonic sensing in clinical samples. This report sheds light on the impact of multiple factors that need to be considered to optimize the practical applications of plasmonic sensors. PMID- 30023655 TI - Influence of Hyperglycemic Conditions on Self-Association of the Alzheimer's Amyloid beta (Abeta1-42) Peptide. AB - Clinical studies have identified a correlation between type-2 diabetes mellitus and cognitive decrements en route to the onset of Alzheimer's disease (AD). Recent studies have established that post-translational modifications of the amyloid beta (Abeta) peptide occur under hyperglycemic conditions; particularly, the process of glycation exacerbates its neurotoxicity and accelerates AD progression. In view of the assertion that macromolecular crowding has an altering effect on protein self-assembly, it is crucial to characterize the effects of hyperglycemic conditions via crowding on Abeta self-assembly. Toward this purpose, fully atomistic molecular dynamics simulations were performed to study the effects of glucose crowding on Abeta dimerization, which is the smallest known neurotoxic species. The dimers formed in the glucose-crowded environment were found to have weaker associations as compared to that of those formed in water. Binding free energy calculations show that the reduced binding strength of the dimers can be mainly attributed to the overall weakening of the dispersion interactions correlated with substantial loss of interpeptide contacts in the hydrophobic patches of the Abeta units. Analysis to discern the differential solvation pattern in the glucose-crowded and pure water systems revealed that glucose molecules cluster around the protein, at a distance of 5-7 A, which traps the water molecules in close association with the protein surface. This preferential exclusion of glucose molecules and resulting hydration of the Abeta peptides has a screening effect on the hydrophobic interactions, which in turn diminishes the binding strength of the resulting dimers. Our results imply that physical effects attributed to crowded hyperglycemic environments are incapable of solely promoting Abeta self-assembly, indicating that further mechanistic studies are required to provide insights into the self-assembly of post-translationally modified Abeta peptides, known to possess aggravated toxicity, under these conditions. PMID- 30023656 TI - Role of Pseudoisocytidine Tautomerization in Triplex-Forming Oligonucleotides: In Silico and in Vitro Studies. AB - Pseudoisocytidine (PsiC) is a synthetic cytidine analogue that can target DNA duplex to form parallel triplex at neutral pH. Pseudoisocytidine has mainly two tautomers, of which only one is favorable for triplex formation. In this study, we investigated the effect of sequence on PsiC tautomerization using lambda dynamics simulation, which takes into account transitions between states. We also performed in vitro binding experiments with sequences containing PsiC and furthermore characterized the structure of the formed triplex using molecular dynamics simulation. We found that the neighboring methylated or protonated cytidine promotes the formation of the favorable tautomer, whereas the neighboring thymine or locked nucleic acid has a poor effect, and consecutive PsiC has a negative influence. The deleterious effect of consecutive PsiC in a triplex formation was confirmed using in vitro binding experiments. Our findings contribute to improving the design of PsiC-containing triplex-forming oligonucleotides directed to target G-rich DNA sequences. PMID- 30023657 TI - Selagintamarlin A: A Selaginellin Analogue Possessing a 1H-2-Benzopyran Core from Selaginella tamariscina. AB - Selagintamarlin A (1), a novel selaginellin analogue featuring the unique motif of 1H-2-benzopyran, a new selaginpulvilin E (2), together with eight known analogues were isolated from Selaginella tamariscina. Their structures were elucidated by extensive spectroscopic analyses. A plausible biosynthetic pathway of 1 was also postulated. Compound 1 showed remarkable inhibitory activity against phosphodiesterase-4 (PDE4D2), with an IC50 value of 40 nM, which is 20 fold higher than that of the positive control (rolipram). Furthermore, compound 1 significantly inhibited tubulin polymerization. PMID- 30023658 TI - A Short-Length Peptide YY Analogue with Anorectic Effect in Mice. AB - Peripheral administration of PYY3-36, a fragment of peptide YY (PYY), has been reported to reduce food intake by activating the neuropeptide Y2 receptor (Y2R). An N-terminally truncated PYY analogue, benzoyl-[Ala26,Ile28,31]PYY(25-36) (1), showed a relatively potent agonist activity for Y2R but a weak anorectic activity by intraperitoneal administration (2000 nmol/kg) in lean mice because of its markedly poor biological stability in the mouse serum. Notably, two cyclohexylalanine (Cha) substitutions for Tyr residues at positions 27 and 36 (4) improved the stability in the mouse serum concomitant with enhanced anorectic activity. Further optimization at positions 27, 28, 30, and 31 revealed that 21, containing Cha28 and Aib31 residues, showed a more potent anorectic activity than PYY3-36 at a low dose of 300 nmol/kg. The minimum effective dose by intraperitoneal administration of 21 was 30 nmol/kg (ca. 52 MUg/kg) in mice, suggesting the biologic potential of short-length PYY3-36 analogues with a potent anorectic effect. PMID- 30023660 TI - Drug-Loaded PLGA Electrospraying Porous Microspheres for the Local Therapy of Primary Lung Cancer via Pulmonary Delivery. AB - Nonsmall-cell lung cancer is a severe disease with high morbidity and mortality. However, the systemic administration of anticancer drugs generally leads to serious toxicity and low anti-lung cancer efficiency because of very limited drug distribution in the lung. In our previous research, we have confirmed the high anti-lung cancer effect of inhalable oridonin microparticles in spite of their long and complicated preparation process. Here, we develop a novel, simple, and quick method for preparing inhalable oridonin-loaded poly(d,l-lactic-co glycolic)acid (PLGA) porous microspheres using the electrospraying technique. The formulation and preparation processes were screened. The electrospraying porous microspheres (EPMs) were rough, porous, and suitable for pulmonary delivery. Most of the oridonin was released from the EPMs within 20 h based on drug diffusion and via PLGA erosion. The EPMs exhibited efficient lung deposition in vitro and in vivo because of their ideal aerodynamic diameters. Chemical carcinogens were used to prepare primary lung cancer rat models by direct pulmonary delivery. The EPMs showed high anti-lung cancer effect after pulmonary delivery according to CT images and pathology. Inhibition of angiogenesis and enhancement of lung cancer cell apoptosis could be the major anticancer mechanism. Electrospraying is an efficient method for the preparation of inhalable drug-loaded porous microspheres. The oridonin-loaded EPMs are promising dry powder inhalers for the local therapy of primary lung cancer. PMID- 30023659 TI - Disparate Antibiotic Resistance Gene Quantities Revealed across 4 Major Cities in California: A Survey in Drinking Water, Air, and Soil at 24 Public Parks. AB - Widespread prevalence of multidrug and pandrug-resistant bacteria has prompted substantial concern over the global dissemination of antibiotic resistance genes (ARGs). Environmental compartments can behave as genetic reservoirs and hotspots, wherein resistance genes can accumulate and be laterally transferred to clinically relevant pathogens. In this work, we explore the ARG copy quantities in three environmental media distributed across four cities in California and demonstrate that there exist city-to-city disparities in soil and drinking water ARGs. Statistically significant differences in ARGs were identified in soil, where differences in blaSHV gene copies were the most striking; the highest copy numbers were observed in Bakersfield (6.0 * 10-2 copies/16S-rRNA gene copies and 2.6 * 106 copies/g of soil), followed by San Diego (1.8 * 10-3 copies/16S-rRNA gene copies and 3.0 * 104 copies/g of soil), Fresno (1.8 * 10-5 copies/16S-rRNA gene copies and 8.5 * 102 copies/g of soil), and Los Angeles (5.8 * 10-6 copies/16S-rRNA gene copies and 5.6 * 102 copies/g of soil). In addition, ARG copy numbers in the air, water, and soil of each city are contextualized in relation to globally reported quantities and illustrate that individual genes are not necessarily predictors for the environmental resistome as a whole. PMID- 30023661 TI - Quantitative Photodeprotection Assessment of Caged Resveratrol by Fluorescence Measurement. AB - For monitoring the regenerated bioactivity of a masked bioactive compound, resveratrol (a luciferase inhibitor) was selected to target such a compound. Caged resveratrol, masked by thiochromone-type photolabile-protecting groups was synthesized in the study. Each caged resveratrol showed lower bioactivity when compared to that shown by the original molecule. After photoirradiation, the original bioactivity was found to be regenerated. Furthermore, the fluorescent compound derived from the thiochromone-type photolabile-protecting groups was generated simultaneously. A linear correlation was observed between the regenerated bioactivity and generated fluorescence intensity. Thus, we quantitatively monitored the recovered bioactivity successfully by measuring the fluorescence. PMID- 30023662 TI - Thixotropic Peptide-Based Physical Hydrogels Applied to Three-Dimensional Cell Culture. AB - Pseudopeptides containing the d-Oxd or the d-pGlu [Oxd = (4R,5S)-4-methyl-5 carboxyl-oxazolidin-2-one, pGlu = pyroglutamic acid] moiety and selected amino acids were used as low-molecular-weight gelators to prepare strong and thixotropic hydrogels at physiological pH. The addition of calcium chloride to the gelator solutions induces the formation of insoluble salts that get organized in fibers at a pH close to the physiological one. Physical characterization of hydrogels was carried out by morphologic evaluation and rheological measurements and demonstrated that the analyzed hydrogels are thixotropic, as they have the capability to recover their gel-like behavior. As these hydrogels are easily injectable and may be used for regenerative medicine, they were biologically assessed by cell seeding and viability tests. Human gingival fibroblasts were embedded in 2% hydrogels; all of the hydrogels allow the growth of encapsulated cells with a very good viability. The gelator toxicity may be correlated with their tendency to self-assemble and is totally absent when the hydrogel is formed. PMID- 30023663 TI - Optimizing the Performance of Supported Lipid Bilayers as Cell Culture Platforms Based on Extracellular Matrix Functionalization. AB - Strategies to fabricate biofunctionalized surfaces are essential for many biotechnological applications. Zwitterionic lipid bilayer coatings doped with lipids with chemically selective headgroups provide a robust platform for immobilization of biomolecules in an antifouling, protein resistant background. Herein, we assess the biological activity of two important components of the extracellular matrix (ECM), collagen type I (Col I) and fibronectin (FN), which are covalently attached to a supported lipid bilayer (SLB), and compare their activity with the same proteins, nonspecifically adsorbed onto a SiO2 surface. The characterization of protein coatings by quartz crystal microbalance with dissipation revealed that Col I and FN attached to SLB are less dense and have higher structural flexibility than when adsorbed onto SiO2. Cell adhesion, proliferation, and function, as well as Col I-FN interactions, were more efficient on the ECM-functionalized SLB, making it a promising platform for cell based diagnostics, tissue engineering, medical implants, and biosensor development. PMID- 30023664 TI - Synthesis of Novel Hybrids of Quinazoline and Artemisinin with High Activities against Plasmodium falciparum, Human Cytomegalovirus, and Leukemia Cells. AB - Many quinazoline derivatives have been synthesized over the last few decades with great pharmacological potential, such as antimalarial, anti-inflammatory, antimicrobial, anticancer, and antiviral. But so far, no quinazoline-artemisinin hybrids have been reported in the literature. In the present study, five novel quinazoline-artemisinin hybrids were synthesized and evaluated for their in vitro biological activity against malarial parasites (Plasmodium falciparum 3D7), leukemia cells (CCRF-CEM and CEM/ADR5000), and human cytomegalovirus. Remarkably, hybrid 9 (EC50 = 1.4 nM), the most active antimalarial compound of this study, was not only more potent than artesunic acid (EC50 = 9.7 nM) but at the same time more active than the clinically used drugs dihydroartemisinin (EC50 = 2.4 nM) and chloroquine (EC50 = 9.8 nM). Furthermore, hybrids 9 and 10 were the most potent compounds with regard to anticytomegaloviral activity (EC50 = 0.15-0.21 MUM). They were able to outperform ganciclovir (EC50 = 2.6 MUM), which is the relevant standard drug of antiviral therapy, by a factor of 12-17. Moreover, we identified a new highly active quinazoline derivative, compound 14, that is most effective in suppressing cytomegalovirus replication with an EC50 value in the nanomolar range (EC50 = 50 nM). In addition, hybrid 9 exhibited an antileukemia effect similar to that of artesunic acid, with EC50 values in the low micromolar range, and was 45 times more active toward the multidrug-resistant CEM/ADR5000 cells (EC50 = 0.5 MUM) than the standard drug doxorubicin. PMID- 30023666 TI - Preparation of a Peptide-Modified Electrode for Capture and Voltammetric Determination of Endotoxin. AB - Endotoxin is the major structural constituent of the outer membrane of Gram negative bacteria, which is a great threat to human health. Herein, a sensitive electrochemical biosensor for the detection of endotoxin is established by recording the voltammetric responses of the peptide-modified electrode. The utilized peptide has a high affinity for the target endotoxin, which ensures the high selectivity of this method. After the capture of endotoxin on the electrode surface, a negatively charged layer is formed, and the electron-transfer process is significantly hindered because of the increased steric hindrance and the electrostatic repulsion. The declined electrochemical signal could be used to indicate the concentration of endotoxin. This method is simple but effective, which requires limited reagents. Another highlight of this method is its user friendly operation. Moreover, its applicability in human blood plasma promises its great potential utility in the near future. PMID- 30023665 TI - EDB Fibronectin-Specific SPECT Probe 99mTc-HYNIC-ZD2 for Breast Cancer Detection. AB - Extradomain-B fibronectin (EDB-FN), an oncofetal isoform of FN, is a promising diagnostic and therapeutic target of tumors, including breast cancer. Many EDB-FN targeted drugs have been developed and have shown therapeutic effects in clinical trials. Molecular imaging to visualize EDB-FN-positive cancers may help select the right patients who will be benefit from EDB-FN-targeted therapy. Although a few EDB-FN-targeted imaging probes have been developed, the complicated manufacturing procedure and expensive material and equipment required limit their application for large-scale screening of EDB-FN-positive cancer patients. Thus, more simple and economic EDB-FN-targeted imaging probes are still urgently needed. Previously, we have identified a breast cancer-targeted peptide, CTVRTSADC. Coincidently, it was later identified as an EDB-FN-targeted peptide and named ZD2. In this study, we found a positive correlation between the binding activity of the ZD2 phage and the expression level of EDB-FN in breast cancer cells. Moreover, we observed the colocalization of the ZD2 peptide with EDB-FN in breast cancer cells. Furthermore, in vivo tumor targeting of the ZD2 phage, near infrared fluorescence imaging, and flow cytometry showed tumor-specific homing of the ZD2 peptide in mice bearing EDB-FN-positive breast cancers. Importantly, on the basis of this EDB-FN-targeted ZD2 peptide, we developed a kit-formulated probe, 99mTc-HYNIC-ZD2, for single-photon-emission computed tomography (SPECT) imaging of breast cancer. The high tumor uptake of 99mTc-HYNIC-ZD2 demonstrated its feasibility for use in visualizing EDB-FN-positive breast cancers in vivo. This kit-formulated EDB-FN-targeted SPECT probe has potential clinical applications for precision screening of EDB-FN-positive cancer patients who may benefit from EDB-FN-targeted therapy. PMID- 30023667 TI - Gold Nanocluster Containing Polymeric Microcapsules for Intracellular Ratiometric Fluorescence Biosensing. AB - A new approach to sensing and imaging hydrogen peroxide (H2O2) was developed using microcapsule-based dual-emission ratiometric luminescent biosensors. Bovine serum albumin-capped gold nanoclusters (BSA-AuNCs) sensitive to H2O2 were coencapsulated with insensitive FluoSpheres (FSs) within polymeric capsules fabricated via the layer-by-layer method. Under single-wavelength excitation, the microcapsule-based biosensors exhibited emission bands at ~516 and ~682 nm resulting from the FSs and BSA-AuNCs, respectively. The polyelectrolyte multilayers lining the microcapsules were effective in protecting BSA-AuNCs from the degradation catalyzed by proteases (chymotrypsin, trypsin, papain, and proteinase K) and subsequent luminescent quenching, overcoming a key limitation of prior BSA-AuNC-based sensing systems. The luminescent response of the sensors was also found to be independent of local changes in pH (5-9). Quenching of the AuNCs in the presence of H2O2 enabled the spectroscopic quantification and imaging of changes in H2O2 concentration from 0 to 1 mM. The microcapsule sensors were easily phagocytized by murine macrophage cells (RAW 264.7), were effective as intracellular H2O2 imaging probes, and were successfully used to detect local release of H2O2 in response to an external chemical stimulus. PMID- 30023669 TI - Zinc Oxide-Supported Copper Clusters with High Biocidal Efficacy for Escherichia coli and Bacillus cereus. AB - Cu clusters on ZnO have been prepared by a simple low-temperature solid-state reaction from their respective acetate precursors. The formation of metallic Cu along with a small quantity of CuO was influenced by the presence of the zinc acetate precursor. Although there is a lack of formation of any metallic Cu in the absence of zinc acetate, increase in the heating duration helps in the formation of increased metallic Cu. A mechanism for formation of the Cu@ZnO nanocomposite has been suggested. The prepared Cu@ZnO nanocomposite, with metallic Cu, was identified by X-ray diffraction studies followed by confirmation of clusters of the kind Cu9 and Cu18 by transmission electron microscopy and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The photoelectron spectroscopy is able to clearly distinguish the Cu from CuO, which is very well complimented by electron spin resonance analysis. The morphological feature of ZnO changes from flakes to rods on increasing the duration of heating, as shown by scanning electron microscopy (SEM) analysis. The observed Cu plasmonic band in UV-vis diffuse reflectance gets blue-shifted to 463 nm from its normally observed position of 550-580 nm possibly due to cluster formation and interaction with ZnO, the band gap of the latter getting red-shifted to 3.2-3.0 eV. The antibacterial activity of the synthesized Cu cluster-ZnO nanocomposites was investigated against Escherichia coli ATCC-25922 for Gram-negative and Bacillus cereus ATCC-10876 for Gram-positive bacteria. Tests were performed on a nutrient agar medium and liquid broth supplemented with different concentrations of nanoparticles. SEM analysis of the native and treated Gram-positive and Gram negative bacteria established a high efficacy of biocide activity in 24 h, with 200 MUg/mL of Cu@ZnO nanocomposites. PMID- 30023668 TI - Laccase-Mediated Enhancement of the Antioxidant Activity of Propolis and Poplar Bud Exudates. AB - The treatment of propolis and poplar bud exudates with laccase from Trametes versicolor and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical increased the antioxidant activity, as evaluated by the 2,2'-diphenyl picrylhydrazyl (DPPH)- and t-butyl-OOH-induced DNA breakage comet assay analyses. The effect was highest for shorter reaction times. Propolis showed the highest antioxidant activity in the DPPH test, whereas poplar bud exudates were more active in reducing the t butyl-OOH-induced lesions in the Chinese hamster ovary cell line. Even if the concentration of polyphenols decreased during the oxidation, the formation of low molecular-weight phenols phloroglucinol 4 (1,3,5-trihydroxy benzene), hydroquinone 5 (1,4-dihydroxy benzene), and catechol 6 (1,2-dihydroxy benzene), characterized by the radical-scavenging activity, can account for the observed increase in the antioxidant activity. PMID- 30023670 TI - Compound Ranking Based on Fuzzy Three-Dimensional Similarity Improves the Performance of Docking into Homology Models of G-Protein-Coupled Receptors. AB - Ligand docking into homology models of G-protein-coupled receptors (GPCRs) is a widely used approach in computational compound screening. The generation of "double-hypothetical" models of ligand-target complexes has intrinsic accuracy limitations that further complicate compound ranking and selection compared to those of X-ray structures. Given these uncertainties, we have explored "fuzzy 3D similarity" between hypothetical binding modes of known ligands in homology models and docking poses of database compounds as an alternative to conventional scoring schemes. Therefore, GPCR homology models at varying accuracy levels were generated and used for docking. Increases in recall performance were observed for fuzzy 3D similarity ranking using single or multiple ligand poses compared to that of conventional scoring functions and interaction fingerprints. Fuzzy similarity ranking was also successfully applied to docking into an external model of a GPCR for which no experimental structure is currently available. Taken together, our results indicate that the use of putative ligand poses, albeit approximate at best, increases the odds of identifying active compounds in docking screens of GPCR homology models. PMID- 30023671 TI - Quantification of Circulating Cancer Biomarkers via Sensitive Topographic Measurements on Single Binder Nanoarrays. AB - Early detection of cancer plays a crucial role in disease prognosis. It requires the recognition and quantification of low amounts of specific molecular biomarkers, either free or transported inside nanovesicles, through the development of novel sensitive diagnostic technologies. In this context, we have developed a nanoarray platform for the noninvasive quantification of cancer biomarkers circulating in the bloodstream. The assay is based on molecular manipulation to create functional spots of surface-immobilized binders and differential topography measurements. It is label-free and requires just a single binder per antigen, and when it is implemented with fluorescence labeling/readout, it can be used for epitope mapping. As a benchmark, we focused on the plasma release of Her2 extracellular domain (ECD), a proposed biomarker for the progression of Her2-positive tumors and response to anticancer therapies. By employing robust, easily engineered camelid nanobodies as binders, we measured ECD-Her2 concentrations in the range of the actual clinical cutoff value for Her2 positive breast cancer. The specificity for Her2 detection was preserved when it was measured in parallel with other potential biomarkers, demonstrating a forthcoming implementation of this approach for multiplexing analysis. Prospectively, this nanorarray platform may be customized to allow for the detection of promising new classes of circulating biomarkers, such as exosomes and microvesicles. PMID- 30023672 TI - Cytotoxic Spiroepoxide Lactone and Its Putative Biosynthetic Precursor from Goniobranchus Splendidus. AB - Epoxygoniolide-1 (1), possessing spiroepoxide lactone, enal, and masked dialdehyde functionalities, has been characterized from the conspicuously patterned mollusc Goniobranchus splendidus. Its relative configuration was investigated by spectroscopic analyses, molecular modeling, and density functional theory calculations. The biosynthesis of 1 may involve rearrangement of a diterpene framework, providing a precursor to cometabolite gonioline (2), followed by C-C bond cleavage (via Grob or P450 mechanism). Moderate cytotoxicity to NCIH-460, SW60, or HepG2 cancer cells was observed for norditerpene 1. PMID- 30023673 TI - Intracellular Trafficking of Fluorescent Nanodiamonds and Regulation of Their Cellular Toxicity. AB - In this paper, cellular management of fluorescent nanodiamonds (FNDs) has been studied for better understanding in the design for potential applications of FNDs in biomedicine. The FNDs have shown to be photostable probes for bioimaging and thus are well-suited, for example, long-term tracking purposes. The FNDs also exhibit good biocompatibility and, in general, low toxicity for cell labeling. To demonstrate the underlying mechanism of cells coping the low but potentially toxic effects by nondegradable FNDs, we have studied their temporal intracellular trafficking. The FNDs were observed to be localized as distinct populations inside cells in early endosomes, lysosomes, and in proximity to the plasma membrane. The localization of FNDs in early endosomes suggests the internalization of FNDs, and lysosomal localization, in turn, can be interpreted as a prestate for exocytosis via lysosomal degradation pathway. The endocytosis and exocytosis appear to be occurring simultaneously in our observations. The mechanism of continuous endocytosis and exocytosis of FNDs could be necessary for cells to maintain normal proliferation. Furthermore, 120 h cell growth assay was performed to verify the long-term biocompatibility of FNDs for cellular studies. PMID- 30023674 TI - Ru(II)-Catalyzed Regiospecific C-H/O-H Oxidative Annulation to Access Isochromeno[8,1-ab]phenazines: Far-Red Fluorescence and Live Cancer Cell Imaging. AB - A facile ruthenium(II)-catalyzed regiospecific C-H/O-H oxidative annulation methodology was developed to construct isochromeno[8,1-ab]phenazines. This methodology delivers various advantages, such as scope for diverse substrates, tolerance to a range of functional groups, stability under air, and yields regioselective products. This methodology was successfully applied to synthesize far red (FR) fluorescent probes for live cancer cell imaging. The synthesized compounds displayed notable fluorescence properties in solution and thin-film. Their application in live cancer cell imaging was investigated using various cancer cell lines. The synthesized compound showed prominent FR fluorescence, with high quantum yield, and exhibited better cell-imaging properties, with excellent biocompatibility. PMID- 30023675 TI - Characterizing Slow Photochemical Reaction Kinetics by Enhanced Sampling of Rare Events with Capillary Optical Fibers and Kramers' Theory. AB - Characterization of slow chemical reactions is essential for assessing catalytic efficiency in chemistry and biology. Traditionally, chemical reaction rates are obtained from population relaxation kinetics measurements and the Arrhenius equation. Unfortunately, it is difficult to use this approach to characterize reactions wherein concentrations change slowly. Thus, it is interesting to see whether a dynamical view of chemical reactions may be used to obtain the reaction rates of slow processes. In the present work, we perform Brownian dynamics simulations of an asymmetric double-well potential to investigate how enhanced sampling of barrier crossing at transition states improves the characterization of reaction rate constants. We then present the design of a liquid-filled capillary optical fiber-based fluorescence spectrometer, which, like rare events, is also based on Poissonian statistics. We use the instrument to characterize the slow photochemical degradation kinetics of poly[2-methoxy-5-(2-ethylhexyloxy)-1,4 phenylenevinylene] (MEH-PPV) in o-dichlorobenzene. We have employed in situ optical microscopy measurements and electrodynamics simulations to characterize the excitation beam profile inside a liquid-filled capillary fiber. We compare the cuvette and capillary fiber sample holders and show that the MEH-PPV fluorescence line shape is independent of the sample holder, as expected. We characterize the photochemical degradation kinetics of MEH-PPV in o dichlorobenzene solutions placed in the cuvette versus that in the capillary fiber. We observe small and slow changes in the time-dependent fluorescence spectra when the degradation reaction is performed in the cuvette. On the other hand, we are able to characterize reactant-concentration decay and product concentration buildup from the time-dependent fluorescence spectra recorded during photochemical degradation of MEH-PPV performed inside the capillary optical fiber. Ultrafast optically heterodyne-detected optical Kerr effect spectroscopy and multimode Brownian oscillator analysis provide further insights into the role of bath oscillator modes of friction in the mechanism of MEH-PPV photochemical degradation. Overall, the work presented herein shows that slow photochemical degradation kinetics of MEH-PPV can be successfully and efficiently assessed in the capillary fiber fluorescence spectrometer. PMID- 30023676 TI - Synthesis of a Biologically Important Adenosine Triphosphate Analogue, ApppD. AB - The chemical synthesis of a adenosine triphosphate analogue, 1-adenosin-5'-yl 3 (3-methylbut-2-enyl) triphosphoric acid diester (ApppD), is described. ApppD is known to be an active metabolite of the mevalonate pathway in the human body like its structural isomer isopentenyl ester of ATP (ApppI). Very recently, ApppI has been found to possess novel function(s); now it will also be possible to examine the effects of ApppD more precisely because it can be synthesized in reasonable amounts. 1-Adenosin-5'-yl 3-(3-methylbut-2-enyl) diphosphoric acid diester (AppD; a adenosine diphosphate analogue) was also isolated from the synthesis mixture. Both ApppD and AppD were characterized by 1H, 13C, 31P NMR and mass spectrometry methods. PMID- 30023677 TI - Microencapsulation of Live Cells in Synthetic Polymer Capsules. AB - In cell therapies, it is advantageous to encapsulate live cells in protective, semipermeable microparticles for controlled release of cytokines, growth factors, monoclonal antibodies, or insulin. Here, a modified electrospraying approach with an organic solution of poly(lactide-co-glycolide) (PLGA) polymer is used to create synthetic PLGA capsules that effectively protect live cells. Using a design of experiment (DOE) methodology, the effect of governing jetting parameters on encapsulation efficiency, yield, and size is systematically evaluated. On the basis of this analysis, the interaction between bovine serum albumin concentration and core flow rate is the most dominant factor determining core encapsulation efficiency as well as the microcapsule size. However, the interaction between shell solvent ratio and shell flow rate predominantly defines the particle yield. To validate these findings, live cells have been successfully encapsulated in microcapsules using optimized parameters from the DOE analysis and have survived the electrohydrodynamic jetting process. Extending the currently available toolkit for cell microencapsulation, these biodegradable, semi-impermeable cell-laden microcapsules may find a range of applications in areas such as tissue engineering, regenerative medicine, and drug delivery. PMID- 30023678 TI - Engineering Camptothecin-Derived Norbornene Polymers for Theranostic Application. AB - A multifunctional stimuli-responsive nanotheranostic agent provides huge benefits in nanomedicine by combining both the diagnostic agent and the drug molecule in a single system. This nanosystem is capable of doing multiple tasks, for example, diagnosis, drug delivery, and monitoring the therapeutic response. Hence, theranostic agents are expected to play a significant role in personalized medicine. Herein, a new class of nanotheranostic agents, Pnr-Cbt-Cpt-Pg-Bn, is proposed for the effective delivery of camptothecin. This new class of polymer has been functionalized with a superparamagnetic norbornene cobalt unit for its use in magnetic resonance imaging (MRI). The NMR one-dimensional image confirms the MRI capability of this nanotheranostic agent. This is further modified with the poly(ethylene glycol)-biotin moiety for biocompatibility and site specificity. The uniqueness of the design is confirmed by an in vitro study where a greater uptake of the nanotheranostic agent is observed when compared with free drugs. Hence, this new class of copolymer shows improved potential as nanotheranostic agents in drug delivery. PMID- 30023679 TI - Biophysical Viscosity: Thermodynamic Principles of Per Capita Chemical Potentials in Human Populations. AB - Dynamic viscosity has been used to describe molecular resistance to flow under an applied force. This study introduces the theory of biophysical viscosity, the resistance of a region to molecular flow under environmental force to define the rates of per capita anthropogenic chemical efflux into the environment. Biophysical viscosity is an important intermediate quantity, in that it can be used to calculate the chemical potentials of single molecules for individuals in a population. Nonhypothetical emission data was combined with chemical potentials of anthropogenic tracers, to demonstrate that thermodynamic quantities can be used as parameters to directly compare energies associated with individual chemical emissions across geographic regions. These results indicate that population density is not the only factor in the determination of population level chemical efflux and that biophysical viscosity is a useful tool in determining the per capita chemical potentials of anthropogenic chemicals for environmental risk assessment. PMID- 30023680 TI - Effects of Nanosecond Pulsed Electric Field on Intracellular NADH Autofluorescence: A Comparison between Normal and Cancer Cells. AB - Intracellular fluorescence lifetime and intensity images of the endogenous fluorophore of nicotinamide adenine dinucleotide (NADH) have been observed before and after application of nanosecond pulsed electric field (nsPEF) in normal and cancer cells, that is, in Wistar-King-Aptekman rat fetus fibroblast (WFB) cells and W31 cells, which are the malignant transformed cells from WFB. The application of nsPEF induces a change both in intensity and lifetime of NADH, indicating that the intracellular function is affected by application of nsPEF in both normal and cancer cells. The application of nsPEF induces an increase in the fluorescence lifetime of NADH and a morphological change, which is attributed to the induction of apoptosis by nsPEF. The field effect on the intensity and lifetime clearly depends on the pulse width, and magnitude of the field-induced increase in the fluorescence lifetime of NADH has a tendency to increase with a decreasing pulse width. It is also found that apoptosis can be induced only in cancer cells using a suitable nsPEF, showing a possibility that ultrashort pulsed electric field is applicable for drug-free cancer therapy. PMID- 30023682 TI - Post-Translational Sortase-Mediated Attachment of High-Strength Force Spectroscopy Handles. AB - Single-molecule force spectroscopy greatly benefits from site-specific surface immobilization and specific probing with a functionalized cantilever. Here, we describe a streamlined approach to such experiments by covalently attaching mechanically stable receptors onto proteins of interest (POI) to improve pickup efficiency and specificity. This platform provides improved throughput, allows precise control over the pulling geometry, and allows for multiple constructs to be probed with the same ligand-modified cantilever. We employ two orthogonal enzymatic ligation reactions [sortase and phosphopantetheinyl transferase (Sfp)] to covalently immobilize POI to a pegylated surface and to subsequently ligate the POI to a mechanically stable dockerin domain at the protein's C-terminus for use as a high-strength pulling handle. Our configuration permits expression and folding of the POI to proceed independently from the mechanically stable receptor used for specific probing and requires only two short terminal peptide sequences (i.e., ybbR-tag and sortase C-tag). We applied this system successfully to proteins expressed using in vitro transcription and translation reactions without a protein purification step and to purified proteins expressed in Escherichia coli. PMID- 30023681 TI - Computational Study Reveals the Molecular Mechanism of the Interaction between the Efflux Inhibitor PAbetaN and the AdeB Transporter from Acinetobacter baumannii. AB - Phenylalanine-arginine beta-naphthylamide (PAbetaN) is a broad-spectrum efflux pump inhibitor that has shown to potentiate the activity of antibiotics in Gram negative bacteria. AdeB is a part of the AdeABC tripartite pump that plays a pivotal role in conferring efflux-mediated resistance in Acinetobacter baumannii. To understand the molecular mechanism of efflux pump inhibition by PAbetaN, we investigated the interaction of PAbetaN with AdeB using different computational methods. We observed that PAbetaN does not have specific binding interactions with the proximal binding site and interacts strongly with the distal binding pocket. The Phe loop located between the proximal and distal binding pockets plays a key role in the PAbetaN-mediated inhibition and acts as a gate between the binding pockets. Molecular dynamics simulations suggested that PAbetaN behaved like a climber as we observed switching of the interaction energies between the ligand and the key Phe residues of the binding site during the course of the simulation. PAbetaN uses the hydrophobic microenvironment formed by Phe residues in the distal binding pocket to keep the binding monomer in the binding conformation. The simulation data suggests that this binding event should result in the inhibition of the peristaltic mechanism and prevent the exporter from extruding any other substrates leading to the inhibition of the tripartite pump. PMID- 30023683 TI - Graphene Oxide-Coated Surface: Inhibition of Bacterial Biofilm Formation due to Specific Surface-Interface Interactions. AB - Graphene oxide (GO) is a promising and remarkable nanomaterial that exhibits antimicrobial activity due to its specific surface-interface interactions. In the present work, for the first time, we have reported the antibacterial activity of GO-coated surfaces prepared by two different methods (Hummers' and improved, i.e., GOH and GOI) against bacterial biofilm formation. The bacterial toxicity of the deposited GO-coated surfaces was investigated for both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) models of bacteria. The mechanism of inhibition is different on the coated surface than that in suspension, as determined by measurement of the percentage inhibition of biofilm formation, Ellman's assay, and colony forming unit (CFU) studies. The difference in the nature, degree of oxidative functionalities, and size of the synthesized GO nanoparticles mitigates biofilm formation. To better understand the antimicrobial mechanism of GO when coated on surfaces, we were able to demonstrate that beside reactive oxygen species-mediated oxidative stress, the physical properties of the GO-coated substrate effectively inactivate bacterial cell proliferation, which forms biofilms. Light and atomic force microscopy (AFM) images display a higher inhibition in the proliferation of planktonic cells in Gram-negative bacteria as compared to that in Gram-positive bacteria. The existence of a smooth surface with fewer porous domains in GOI inhibits biofilm formation, as demonstrated by optical microscopy and AFM images. The oxidative stress was found to be lower in the coated surface as compared to that in the suspensions as the latter enables exposure of both a large fraction of the active edges and functionalities of the GO sheets. In suspension, GOH is selective against S. aureus whereas GOI showed inhibition toward E. coli. This study provides new insights to better understand the bactericidal activity of GO-coated surfaces and contributes to the design of graphene-based antimicrobial surface coatings, which will be valuable in biomedical applications. PMID- 30023684 TI - Saccharide Primers Comprising Xylosyl-Serine Primed Phosphorylated Oligosaccharides Act as Intermediates in Glycosaminoglycan Biosynthesis. AB - beta-Xylosides have been used as an artificial initiator of glycosaminoglycan (GAG) biosynthesis to investigate its mechanism and to obtain these oligosaccharides. In GAG biosynthesis, phosphorylation on the xylose residue is a crucial step. However, little attention has been paid to phosphorylated oligosaccharides obtained from beta-xylosides. In a previous study, we demonstrated that a novel beta-xyloside, N-lauryl-O-beta-xyloyranosyl-serinamide (Xyl-Ser-C12), had excellent GAG-type oligosaccharide priming ability, whereas phosphorylated oligosaccharides were not found in the primed oligosaccharides. This study examines the potential of Xyl-Ser-C12 and three of its derivatives for use as a probe to investigate the GAG biosynthesis mechanism. Glycosylated products were obtained by incubation of the beta-xylosides in normal human dermal fibroblast cells and compared by liquid chromatography-electrospray ionization mass spectrometry. By the optimized method to detect phosphorylated products, Xyl Ser-C12 was demonstrated to prime not only GAG-type oligosaccharides but also a variety of xylose-phosphorylated products. Among the synthesized beta-xylosides, those consisting of xylosyl-serine primed large amounts of phosphorylated and GAG type oligosaccharides, whereas the others primed sialyloligosaccharides mainly. The majority of the phosphorylated products were considered to be GAG intermediates, which are less observed in nature. To our best knowledge, this is the first report showing that the amino acid residues around the Xyl attachment position strongly affect the phosphorylation efficiency and GAG chain-priming ability of beta-xylosides. This study leads to the possibility of the use of beta xyloside as a probe to observe the Xyl phosphorylation process during GAG biosynthesis and investigate comparative glycosaminoglycomics between different cells. PMID- 30023685 TI - Tautomeric-Dependent Lactam Cycloaddition with Nitrile Oxide: Facile Synthesis of 1,2,4-Oxadiazole[4,5-a]indolone Derivatives. AB - A concise, metal-free, and gram-scale strategy to convert indoline-2,3-diones to 1,2,4-oxadiazole[4,5-a]indolones through an improved [3 + 2] cycloaddition of alpha-ketone-lactam with nitrile oxides has been developed. The lactim form of the resonance structure of isatin in protic solvents is the key active dipolarophile that shows chemo- and regioselectivity under experimental and theoretical conditions. This strategy conveniently enabled the assembly of several 1,2,4-oxadiazole[4,5-a]indolines with a broad range of functional groups. Compounds 3a and 4b exhibit cytotoxicity in the NCI/ADR-RES, SKOV3, and OVCAR8 cell lines. PMID- 30023686 TI - Antimicrobial Activity Enhancement of Poly(ether sulfone) Membranes by in Situ Growth of ZnO Nanorods. AB - Composite poly(ether sulfone) membranes integrated with ZnO nanostructures either directly blended or grown in situ have enhanced antibacterial activity with improved functionality in reducing the biofouling in water treatment applications. The pore structure and surface properties of the composite were studied to investigate the effect of the addition of ZnO nanostructures. The hydrophilicity of the blended membranes increased with a higher content of ZnO nanoparticles in the membrane (2-6%), which could be further controlled by varying the growth conditions of ZnO nanorods on the polymer surface. Improved water flux, bovine serum albumin rejection, and inhibition of Escherichia coli bacterial growth under visible light irradiation was observed for the membranes decorated with ZnO nanorods compared to those in the membranes simply blended with ZnO nanoparticles. No regrowth of E. coli was recorded even 2 days after the incubation. PMID- 30023687 TI - Leaching of Metals and Metalloids from Hydrothermal Ore Particulates and Their Effects on Marine Phytoplankton. AB - Seafloor massive sulfide deposits have attracted much interest as mineral resources. Therefore, the potential environmental impacts of full-scale mining should be considered. In this study, we focused on metal and metalloid contamination that could be triggered by accidental leakage and dispersion of hydrothermal ore particulates from mining vessels into surface seawater. We determined the leaching potential of metals and metalloids from four hydrothermal ores collected from the Okinawa Trough into aerobic seawater and then evaluated the toxic effects of ore leachates on a phytoplankton species, Skeletonema marinoi-dohrnii complex, which is present ubiquitously in the ocean. Large amounts of metals and metalloids were released from the ground hydrothermal ores into seawater within 5 min under aerobic conditions. The main components of leachates were Zn + Pb, As + Sb, and Zn + Cu, which were obtained from the Fe-Zn Pb-rich and Zn-Pb-rich zero-age, Ba-rich, and Fe-rich ores, respectively. The leachates had different chemical compositions from those of the ore. The rapid release and difference in chemical compositions between the leachates and the ores indicated that substances were not directly dissolved from the sulfide binding mineral phase but from labile phases mainly on the adsorption-desorption interface of the ores under these conditions. All ore leachates inhibited the growth of S. marinoi-dohrnii complex but with different magnitudes of toxic effects. These results indicate that the fine particulate matter of hydrothermal ores is a potential source of toxic contamination that may damage primary production in the ocean. Therefore, we insist on the necessity for the prior evaluation of toxic element leachability from mineral ores into seawater to minimize mining impacts on the surface environment. PMID- 30023688 TI - Spiked Genes: A Method to Introduce Random Point Nucleotide Mutations Evenly throughout an Entire Gene Using a Complete Set of Spiked Oligonucleotides for the Assembly. AB - In vitro mutagenesis methods have revolutionized biological research and the biotechnology industry. In this study, we describe a mutagenesis method based on synthesizing a gene using a complete set of forward and reverse spiked oligonucleotides that have been modified to introduce a low ratio of mutant nucleotides at each position. This novel mutagenesis scheme named "Spiked Genes" yields a library of clones with an enhanced mutation distribution due to its unbiased nucleotide incorporation. Using the far-red fluorescent protein emKate as a model, we demonstrated that Spiked Genes yields richer libraries than those obtained via enzymatic methods. We obtained a library without bias toward any nucleotide or base pair and with even mutations, transitions, and transversion frequencies. Compared with enzymatic methods, the proposed synthetic approach for the creation of gene libraries represents an improved strategy for screening protein variants and does not require a starting template. PMID- 30023689 TI - Substituent, Charge, and Size Effects on the Fluorogenic Performance of Amyloid Ligands: A Small-Library Screening Study. AB - Developing new molecular ligands for the direct detection and tracking of amyloid protein aggregates is key to understanding and defeating myriad neurodegenerative and other disorders including Alzheimer's and Parkinson's diseases. A crucial factor in the performance of an amyloid dye is its ability to detect the amyloid structural motif independent of the sequence of the amyloid-forming protomer. The current study investigates structure-function relationships of a class of novel phenyleneethynylene (PPE)-based dyes and fluorescent polymers using amyloid fibrils formed by two model proteins: lysozyme and insulin. A small library of 18 PPE compounds that vary in molecular weights, charge densities, water solubilities, and types and geometries of functional groups was tested. One compound, the small anionic oligo(p-phenylene ethynylene) electrolyte OPE1, was identified as a selective sensor for the amyloid conformation of both lysozyme and insulin. On the basis of protein binding and photophysical changes observed in the dye from this set of PPE compounds, keys to the selective detection of the amyloid protein conformation include moderate size, negative charge, and substituents that provide high microenvironment sensitivity to the fluorescence yield. These principles can serve as a guide for the further refinement of the effective amyloid-sensing molecules. PMID- 30023690 TI - Synthesis and Reactions of Benzannulated Spiroaminals: Tetrahydrospirobiquinolines. AB - An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o'-diazido-dibenzylidene-acetone, -cyclopentanone, and cyclohexanone derivatives, respectively, and hydrogenation-spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core. PMID- 30023691 TI - Engineering Saccharomyces cerevisiae for Efficient Biosynthesis of Fatty Alcohols Based on Enhanced Supply of Free Fatty Acids. AB - In recent years, production of fatty acid derivatives has attracted much attention because of their wide range of applications in renewable oleochemicals. Microorganisms such as Saccharomyces cerevisiae provided an ideal cell factory for such chemical synthesis. In this study, an efficient strategy for the synthesis of fatty alcohols based on enhanced supply of free fatty acids (FFAs) was constructed. The FAA1 and FAA4 genes encoding two acyl-CoA synthetases in S. cerevisiae were deleted, resulting in the accumulation of FFAs with carbon chain length from C8 to C18. The coexpression of the carboxylic acid reductase gene (car) from Mycobacterium marinum and the phosphopantetheinyl transferase gene (sfp) from Bacillus subtilis successfully converted the accumulated FFAs into fatty alcohols. The concentration of the total fatty alcohols reached 24.3 mg/L, which is in agreement with that of the accumulated FFAs. To further increase the supply of FFAs, the DGAI encoding the acyl-CoA:diacylglycerol acyltransferase involved in the rate-limiting step of triacylglycerols storage was codeleted with FAA1 and FAA4, and the acyl-CoA thioesterase gene (acot) was expressed together with car and sfp, resulting in an enhanced production of fatty alcohols, the content of which increased to 31.2 mg/L. The results herein demonstrated the efficiency of the engineered pathway for the production of fatty acid derivatives using FFAs as precursors. PMID- 30023693 TI - Study of Molecular Mechanisms of alpha-Synuclein Assembly: Insight into a Cross beta Structure in the N-Termini of New alpha-Synuclein Fibrils. AB - Parkinson's disease is characterized by the self-assembly of alpha-synuclein (AS), in which its aggregates accumulate in the substantia nigra. The molecular mechanisms of the self-assembly of AS are challenging because AS is a relatively large intrinsically disordered protein, consisting of 140 residues. It is known that the N-termini of AS contribute to the toxicity of the proteins; therefore, it is important to investigate the self-assembly structure of the N-termini on AS as well. There have been extensive efforts to investigate the structural fibrils of AS(1-140), which have shown that the N-termini are disordered and do not participate in the fibrillary structure. This study illustrates for the first time that the N-termini of AS play a crucial role in the self-assembly of AS. This study reveals a new structure of AS(1-140) fibrils, in which the N-termini are essential parts of the cross-beta structure of the fibrillary structure. This study suggests that there are polymorphic states of the self-assembled AS(1-140). While the polymorphic states of the N-termini do not participate in the fibrillary structure and fluctuate, our predicted new fibrillary structure of the N-termini not only participates in the fibrillary structure but also stabilizes the fibrillary structure. PMID- 30023694 TI - pH and Thermal Dual-Responsive Nanoparticles for Controlled Drug Delivery with High Loading Content. AB - A pH and thermal dual-responsive nanocarrier with silica as the core and block copolymer composed of poly(methacrylic acid) (PMAA) and poly(N isopropylacrylamide) (PNIPAM) as the shell was prepared by surface-initiated reversible addition-fragmentation chain-transfer (SI-RAFT) polymerization. The resulting SiO2-PMAA-b-PNIPAM particles dispersed individually in an aqueous solution at a high pH and a low temperature but reversibly agglomerated under acidic conditions or at elevated temperatures. These dual-responsive nanoparticles were used as carriers to deliver the model drug doxorubicin (DOX) with unusually high entrapment efficiency and loading content, which is due to the small size (15 nm), light weight of the cores, and high graft density (0.619 chains/nm2) achieved by SI-RAFT polymerization. The release rate was controlled by both the pH and temperature of the surrounding medium. Moreover, these particles selectively precipitated at acidic conditions with increased temperature, which may enhance their ability to accumulate at tumor sites. Cytotoxicity studies demonstrated that DOX-loaded nanoparticles are highly active against Hela cells and more effective than free DOX of an equivalent dose. A cellular uptake study revealed that SiO2-PMAA-b-PNIPAM nanoparticles could successfully deliver DOX molecules into the nuclei of Hela cells. All these features indicated that SiO2-PMAA-b-PNIPAM nanoparticles are a promising candidate for therapeutic applications. PMID- 30023696 TI - Cytotoxic Anomoian B and Aplyzanzine B, New Bromotyrosine Alkaloids from Indonesian Sponges. AB - Two new bromotyrosine derivatives, anomoian B (1) and aplyzanzine B (2), were isolated, respectively, from the organic extracts of a Verongida sponge belonging to the Hexadella genus and from a two-sponge association (Jaspis sp. and Bubaris sp.), both collected off the coast of Indonesia. The planar structure of 1 and 2 was determined by 1D and 2D NMR experiments and by high-resolution mass spectrometry, while their absolute stereochemistry was assigned by comparison with optical rotation values of known bromotyrosines and by chemical degradation. Both compounds showed moderate antiproliferative activity against a panel of different cancer cell lines. Their cytotoxic activity is facilitated through the induction of apoptosis, which is mediated neither by the generation of reactive oxygen species nor by the inhibition of histone deacetylases in these cell lines. PMID- 30023692 TI - Pollution Status and Human Exposure of Decabromodiphenyl Ether (BDE-209) in China. AB - Decabromodiphenyl ether (BDE-209/decaBDE) is a high-production-volume brominated flame retardant in China, where the decaBDE commercial mixture is manufactured in Laizhou Bay, Shandong Province, even after the prohibition of penta- and octaBDE mixtures. The demand for flame retardants produced in China has been increasing in recent years as China not only produces electronic devices but also has numerous electronic waste (e-waste) recycling regions, which receive e-wastes from both domestic and foreign sources. High concentrations of BDE-209 have been observed in biotic and abiotic media in each of the different areas, especially within the decaBDE manufacturers and e-waste recycling areas. BDE-209 has been viewed as toxic and bioaccumulative because it might debrominate to less brominated polybrominated diphenyl ethers (PBDEs) (lower molecular weight and hydrophobicity), which are more readily absorbed by organisms. The highest concentration of PBDEs in dust within urban areas reached 40 236 ng g-1 in the Pearl River Delta, and BDE-209 contributed the greatest proportion to the total PBDEs (95.1%). Moreover, the maximum hazard quotient was found for toddlers (0.703) for BDE-209, which was close to 1. This suggests that exposure to BDE-209 might lead to increased potential for adverse effects and organ harm (e.g., the lungs) through inhalation, dust ingestion, and dermal absorption, especially for the group of toddlers compared to others. In daily food and human tissues, the amount of BDE-209 was also extensively detected. However, the toxicity and adverse effect of BDE-209 to humans are still not clear; thus, further studies are required to better assess the toxicological effects and exposure scenarios, a more enhanced environmental policy for ecological risks regarding BDE-209 and its debrominated byproducts in China. PMID- 30023695 TI - A Simple Isomerization of the Purine Scaffold of a Kinase Inhibitor, Roscovitine, Affords a Four- to Seven-Fold Enhancement of Its Affinity for Four CDKs. Could This Be Traced Back to Conjugation-Induced Stiffenings/Loosenings of Rotational Barriers? AB - Roscovitine is an antitumor purine inhibitor of cyclin-dependent kinase CDK5, for which it displays submicromolar affinity. It reached phase IIb clinical trials in 2007. The search for analogues with improved kinase affinities led recently to an isomer, finisterine, having a nearly 10-fold greater affinity for both CDK5 and CDK9. It solely differs by the displacement of one nitrogen atom in the purine ring, from position 6 to position 9. This has no incidence on the intermolecular interaction of either drug with the neighboring sites that anchor the ring in the recognition site. Quantum chemistry calculations combined with conformational and topological analyses of the impact of the purine ring isomerization of roscovitine and finisterine on its conformational stability show that the modified electronic conjugation, on the other hand, results in a stiffening of the rotational barrier around the extracyclic C-NH bond of finisterine, vicinal to N9, and to which an aryl ring is connected, along with a loosening of the barrier around an extracyclic C6-C bond connecting to a shorter, hydrophobic arm. The first effect is proposed to lead to a lesser hydration entropy of solvation in the case of finisterine, thus to a facilitated desolvation term in the overall energy balances. PMID- 30023697 TI - Role of Surface Hydrophobicity of Dicationic Amphiphile-Stabilized Gold Nanoparticles on A549 Lung Cancer Cells. AB - Herein, we report the surface functionality of dicationic cysteamine conjugated cholic acid (DCaC), dicationic cysteamine conjugated deoxycholic acid (DCaDC), and dicationic cysteamine conjugated lithocholic acid (DCaLC) templated gold nanoparticles (AuNPs) on mammalian cells. The haemocompatibility of the synthesized NPs was evaluated by in vitro hemolysis and erythrocyte sedimentation rate using human red blood cells (RBCs). In all of the systems, no toxicity was observed on human erythrocytes (RBCs) up to the concentration of 120 MUg/mL. The anticancer activity of these dicationic amphiphile-stabilized AuNPs on A549 lung cancer cells was demonstrated by in vitro cell viability assay, intracellular reactive oxygen species estimation by DCFH-DA, apoptosis analysis using AO-EtBr fluorescence staining, DNA fragmentation analysis by agarose gel electrophoresis, and western blot analysis of caspase-3 expression. These results suggest that the cytotoxicity of AuNPs to A549 cells increase with the dose and hydrophobicity of amphiphiles and were found to be in the order: DCaLC-AuNPs > DCaDC-AuNPs > DCaC AuNPs. PMID- 30023698 TI - Nutty Carbon: Morphology Replicating Hard Carbon from Walnut Shell for Na Ion Battery Anode. AB - Efficient Na ion intercalation/deintercalation in the semigraphitic lattice of a hard carbon derived from the walnut shell is demonstrated. High-temperature (1000 degrees C) pyrolysis of walnut shells under an inert atmosphere yields a hard carbon with a low surface area (59 m2 g-1) and a large interplanar c axis separation of 0.39-0.36 nm as compared to 0.32 nm for graphite, suitable for Na ion intercalation/deintercalation. A stable reversible capacity of 257 mAh g-1 is observed at a current density of 50 mA g-1 for such nutshell-derived carbon (NDC) with an impressive rate performance. No loss of electrochemical performance is observed for high current cycling (100 mA g-1 -> 2 A g-1 -> 100 mA g-1). Additionally, the NDC shows remarkably stable electrochemical performance up to 300 charge-discharge cycles at 100 mA g-1 with a minimal drop in capacity. PMID- 30023699 TI - In Search of NPY Y4R Antagonists: Incorporation of Carbamoylated Arginine, Aza Amino Acids, or d-Amino Acids into Oligopeptides Derived from the C-Termini of the Endogenous Agonists. AB - The cross-linked pentapeptides (2R,7R)-diaminooctanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr amide) ((2R,7R)-BVD-74D, (2R,7R)-1) and octanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr amide) (2) as well as the pentapeptide Ac-Tyr-Arg-Leu-Arg-Tyr-amide (3) were previously described as neuropeptide Y Y4 receptor (Y4R) partial agonists. Here, we report on a series of analogues of (2R,7R)-1 and 2 in which Arg2, Leu3, or Arg4 were replaced by the respective aza-amino acids. The replacement of Arg2 in 3 with a carbamoylated arginine building block and the extension of the N terminus by an additional arginine led to the high-affinity hexapeptide Ac-Arg Tyr-Nomega-[(4-aminobutyl)aminocarbonyl]Arg-Leu-Arg-Tyr-amide (35), which was used as a precursor for a d-amino acid scan. The target compounds were investigated for Y4R functional activity in assays with complementary readouts: aequorin Ca2+ and beta-arrestin 1 or beta-arrestin 2 assays. In contrast to the parent compounds, which are Y4R agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide Y4R antagonists. PMID- 30023700 TI - Silver-Functionalized Bacterial Cellulose as Antibacterial Membrane for Wound Healing Applications. AB - Bacterial cellulose (BC) functionalized with silver nanoparticles (AgNPs) is evaluated as an antimicrobial membrane for wound-healing treatment. A facile green synthesis of silver nanoparticles inside the porous three-dimensional weblike BC network has been obtained by UV light irradiation. AgNPs were photochemically deposited onto the BC gel network as well as they were chemically bonded to the cellulose fiber surfaces. AgNPs with a narrow size distribution along with some aggregates in the BC network were evidenced from the morphological analyses. A highly crystalline nature of the BC membranes was observed in X-ray diffraction measurements, and the presence of metallic silver confirmed the photochemical reduction of Ag+ -> Ag0 in Ag/BC composites. Antibacterial activity of the hybrid composites, such as pellicles, performed against the Gram-negative bacteria (Escherichia coli) by disk diffusion and growth dynamics methods showed high bacteria-killing performance. No significant amount of silver release was observed from the Ag/BC pellicles even after a long soaking time. As composite pellicles are preserved in a moist environment that also favors wound recovery, by combining all of these properties the material could be useful in wound-healing treatments. PMID- 30023701 TI - Practical Glucosylations and Mannosylations Using Anomeric Benzoyloxy as a Leaving Group Activated by Sulfonium Ion. AB - One obstacle for practical glycosylations is the high cost of promoters and low temperature equipment. This problem has been at least partially solved by using MeSCH2Cl/KI as a low-cost promoter system. MeSCH2Cl has an estimated cost of <$1/mol compared with $1741/mol for AgOTf and $633/mol for TMSOTf. This new promoter system is capable of activating various leaving groups including anomeric Cl, F, trichloroacetimidate, and acyloxy groups. Stable and easy-to prepare anomeric benzoloxy carbohydrate donors were investigated in the glycosylations of carbohydrates, aliphatic alcohols, amino acids, steroids, and nucleoside acceptors. Most of these glycosylations were operationally simple with fast reaction rates and moderate yields of 35-79%. In addition, direct glycosylations of nucleosides using less than 2 equiv of anomeric benzoloxy donors and high stereoselective mannosylation have been achieved. From an economic point of view, this glycosylation method should be highly applicable to industrial processes. PMID- 30023702 TI - Enhanced Extracellular Polysaccharide Production and Self-Sustainable Electricity Generation for PAMFCs by Scenedesmus sp. SB1. AB - In this study, a freshwater microalga, Scenedesmus sp. SB1, was isolated, purified, and identified by its internal transcribed spacer region (ITS1-5.8S ITS2). Media optimization through the Plackett-Burman Design and response surface methodology (RSM) showed a maximum exopolysaccharide (EPS) production of 48 mg/L (1.8-fold higher than that for unoptimized media). Characterization using gas chromatography-mass spectrometry, Fourier transform infrared, X-ray diffraction, and thermogravimetric analysis reveals that the EPS is a sulfated pectin polysaccharide with a crystallinity index of 15.2% and prompt thermal stability. Furthermore, the photoelectrogenic activity of Scenedesmus sp. SB1 inoculated in BG-11 and RSM-optimized BG-11 (ROBG-11) media was tested by cyclic voltammogram studies, revealing the potential of the inoculated strain in ROBG-11 toward photosynthetic algal microbial fuel cells over normal BG-11. To the best of our knowledge, functional group characterization, physical and thermal property and media optimization for EPS production by RSM and electrogenic activity studies are reported for the first time in Scenedesmus sp. SB1. PMID- 30023703 TI - Preferential Mitochondrial Localization of a Goniothalamin Fluorescent Derivative. AB - A fluorescent 2,1,3-benzothiadiazole-containing goniothalamin derivative, BTD-GTN (1), has been synthesized and successfully tested in bioimaging experiments in live cells. The fluorescent compound proved to be capable of transposing the cell membranes, indicating its subcellular localization. The use of the benzothiadiazole core as the fluorophore revealed the favored localization of the GTN analogue 1 in the cytoplasm of live cells, preferentially in the mitochondria, in line with previous results that indicated the loss of mitochondrial transmembrane potential upon treatment with GTN. The results described herein highlight the potential of the BTD-GTN hybrid structures for future studies regarding the cellular mechanism of action of this family of compounds. PMID- 30023705 TI - One-Pot Synthesis of Carbon Nanodots in an Organic Medium with Aggregation Induced Emission Enhancement (AIEE): A Rationale for "Enzyme-Free" Detection of Cholesterol. AB - Addressing the limitations associated with the detection of cholesterol, we present a one-pot synthesis of a carbon nanodot (CD) in an organic medium (CDorg) from a novel bile acid hydrazone-based organogel. Interestingly, CDorg possesses the aggregation-induced emission enhancement (AIEE) phenomenon, which rationally aids in the "enzyme-free" detection of cholesterol through a fluorescence turn-on mechanism. On dilution of the THF/water mixture of CDorg with its poor solvent (water), a 9.8-fold enhancement in its photoluminescence (PL) emission is witnessed. Such an enhancement in PL emission is credited to the occurrence of molecular restrictions due to the formation of nanoaggregates of CDorg, thereby initiating a radiative pathway for exciton decay. Excitingly on adding cholesterol to CDorg, we observed a similar enhancement in its PL emission without the use of any cholesterol oxidase (ChO x ) enzyme. The limit of detection and limit of quantification of cholesterol is found to be as low as 1.09 and 3.64 MUM, respectively. Hence, this contribution highlights the enzyme free fluorescence turn-on detection of cholesterol by a novel CD rationally designed to extend its applicability in an organic medium, where it is still considered a major restraint. PMID- 30023704 TI - Cytotoxic Conjugates of Fibroblast Growth Factor 2 (FGF2) with Monomethyl Auristatin E for Effective Killing of Cells Expressing FGF Receptors. AB - Antibody-drug conjugates (ADCs) are a new class of anticancer therapeutics that combine the selectivity of targeted treatment, ensured by monoclonal antibodies, with the potency of the cytotoxic agent. Here, we applied an analogous approach, but instead of an antibody, we used fibroblast growth factor 2 (FGF2). FGF2 is a natural ligand of fibroblast growth factor receptor 1 (FGFR1), a cell-surface receptor reported to be overexpressed in several types of tumors. We developed and characterized FGF2 conjugates containing a defined number of molecules of highly cytotoxic drug monomethyl auristatin E (MMAE). These conjugates effectively targeted FGFR1-expressing cells, were internalized upon FGFR1 mediated endocytosis, and, in consequence, revealed high cytotoxicity, which was clearly related to the FGFR1 expression level. Among the conjugates tested, the most potent was that bearing three MMAE molecules, showing that the cytotoxicity of protein-drug conjugates in vitro is directly dependent on drug loading. PMID- 30023706 TI - FD5180, a Novel Protein Kinase Affinity Probe, and the Effect of Bead Loading on Protein Kinase Identification. AB - The effects of compound loading on the identification of protein kinases (PKs) was examined using two previously reported sepharose-supported PK inhibitors (PKIs): bisindolylmaleimide X (S1) and CZC8004 (S2). Compound loadings of 0.1, 0.5, 2.5, 5, 10, 25, and 50% content and an ethanolamine-blocked control bead (no compound) were investigated. A 50% bead loading gave the highest level of PK identification for both S1 and S2, extracting 34 and 55 PKs, respectively, from a single cell lysate. Control beads allowed overall identification of 23 PKs, which we term the kinase beadome, whereas sepharose-supported sunitinib (S7; 50% loading) identified 20, 11 of which were common to the control beads. The reliability of bead pull-downs was examined in duplicate experiments using two independently synthesized batches each of S1 and S2. Bead S1 showed high similarity in the absolute numbers of PKs identified across two experiments, at 40 and 35 PKs, of which 26 were common across the two batches of beads, with 14 and 9 unique PKs identified in each experiment. The S2 beads extracted 61 and 64 PKs with 55 PKs common across the two bead batches examined. We also report on the development and use of a novel promiscuous PKI analogue, 2-[(5-chloro-2{[4 (piperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]-N-methylbenzene-sulfonamide (S15), which extracted 12 additional unique PKs over the two parent compounds from which it was designed, the combination of which identifies 160 unique PKs. S15 was based on the common pyrimidine core scaffold of S9 and S10. Thus, S15 expands the utility of kinobeads by broadening the kinome coverage for bead-based pull-down. Combining the data for all beads across 90 and 180 min liquid chromatography-mass spectrometry (LC-MS)/MS analysis identified a total of 160 unique PKs. PMID- 30023707 TI - Small-Molecule Inhibitors of the NusB-NusE Protein-Protein Interaction with Antibiotic Activity. AB - The NusB-NusE protein-protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified N,N'-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 1 as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated 1 as a 20 MUM potent inhibitor of NusB-NusE. Four focused compound libraries based on 1, comprising 34 compounds in total were designed, synthesized, and evaluated as NusB-NusE PPI inhibitors. Ten analogues displayed NusB-NusE PPI inhibition >=50% at 25 MUM concentration in vitro. In contrast to representative Gram-negative Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 MUM. 2-((Z)-4-(((Z)-4-(4-((E) (Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1 carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of <=3 MUg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and <=51 MUg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB-NusE PPI as proposed. PMID- 30023709 TI - Bioimaging Application and Growth-Promoting Behavior of Carbon Dots from Pollen on Hydroponically Cultivated Rome Lettuce. AB - Carbon dots (CDs) obtained from rapeseed pollen with a high production yield, good biocompatibility, good water solubility, low cost, and simple synthesis are systematically characterized. They can be directly added to Hoagland nutrient solution for planting hydroponically cultivated Lactuca sativa L. to explore their influence on the plants at different concentrations. By measuring lettuce indices of growth, morphology, nutrition quality, gas exchange, and content of photosynthetic pigment, amazing growth-promotion effects of CDs were discovered, and the mechanism was analyzed. Moreover, the in vivo transport route of CDs in lettuce was evaluated by macroscopic and microscopic observations under UV light excitation. The results demonstrate that pollen-derived CDs can be potentially used as a miraculous fertilizer for agricultural applications and as a great in vivo plant bioimaging probe. PMID- 30023708 TI - Mapping Putative B-Cell Zika Virus NS1 Epitopes Provides Molecular Basis for Anti NS1 Antibody Discrimination between Zika and Dengue Viruses. AB - B-cell epitope sequences from Zika virus (ZIKV) NS1 protein have been identified using epitope prediction tools. Mapping these sequences onto the NS1 surface reveals two major conformational epitopes and a single linear one. Despite an overall average sequence identity of ca. 55% between the NS1 from ZIKV and the four dengue virus (DENV) serotypes, epitope sequences were found to be highly conserved. Nevertheless, nonconserved epitope-flanking residues are responsible for a dramatically divergent electrostatic surface potential on the epitope regions of ZIKV and DENV2 serotypes. These findings suggest that strategies for differential diagnostics on the basis of short linear NS1 sequences are likely to fail due to immunological cross-reactions. Overall, results provide the molecular basis of differential discrimination between Zika and DENVs by NS1 monoclonal antibodies. PMID- 30023711 TI - Multifunctional Nanohydroxyapatite-Promoted Toughened High-Molecular-Weight Stereocomplex Poly(lactic acid)-Based Bionanocomposite for Both 3D-Printed Orthopedic Implants and High-Temperature Engineering Applications. AB - The current work focuses on the fabrication of high-molecular-weight stereocomplex poly(lactic acid)/nanohydroxyapatite (sPLA/n-HAP)-based bionanocomposite for three-dimensional (3D)-printed orthopedic implants and high temperature engineering applications. To achieve the same, n-HAP is grafted with poly(d-lactic acid) (PDLA) via in situ ring-opening polymerization of d-lactide, followed by blending with poly(l-lactic acid) (PLLA), which yields sPLA/n-HAP biocomposite with improved storage modulus even at temperatures higher than 140 degrees C. X-ray diffraction and calorimetric analysis ensure the presence of 100% stereocomplex crystallites of biocomposite along with significant improvement in the melting temperature (~227 degrees C). Noteworthy improvements in the mechanical and gas-barrier properties of the developed biocomposites are achieved due to the uniform dispersion of n-HAP (~60 nm) confirmed by morphological studies. An unusual improvement in elongation at break (~130% at 1 wt % HAP loading) makes this composite a toughened material. However, the tensile strength is improved by ~16%, whereas oxygen permeability and water vapor transmission rate are found to reduce by ~48 and ~34%, respectively. Interestingly, the developed material is processed as monofilament, followed to 3D printing to yield a middle phalanx bone as a representative example of orthopedic implants. In vitro studies reveal that cell adhesion and proliferation on the surface of the developed biocomposite support its biocompatible nature. This signifies the possible future aspects of the material in commercial biomedical and high-temperature engineering applications. PMID- 30023712 TI - BBB: Permeable Conjugate of Exogenic GABA. AB - Neurotransmitters are the key factors in ameliorating the symptoms of nervous system diseases. Stroke/cerebral ischemia has been proven to be caused by the excess release of excitatory amino acid glutamate in the brain, and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is considered to be the best choice to counteract the action of glutamate. Here, we show that GABA conjugated to a cytoplasmic transduction peptide (YGRRARRRRRR) by means of custom chemical synthesis could penetrate through the blood-brain barrier, increasing the GABA level in the plasma of rats and mice, which, as a result, display a state of calmness and somnolence. PMID- 30023710 TI - Superior Performance of the SQM/COSMO Scoring Functions in Native Pose Recognition of Diverse Protein-Ligand Complexes in Cognate Docking. AB - General and reliable description of structures and energetics in protein-ligand (PL) binding using the docking/scoring methodology has until now been elusive. We address this urgent deficiency of scoring functions (SFs) by the systematic development of corrected semiempirical quantum mechanical (SQM) methods, which correctly describe all types of noncovalent interactions and are fast enough to treat systems of thousands of atoms. Two most accurate SQM methods, PM6-D3H4X and SCC-DFTB3-D3H4X, are coupled with the conductor-like screening model (COSMO) implicit solvation model in so-called "SQM/COSMO" SFs and have shown unique recognition of native ligand poses in cognate docking in four challenging PL systems, including metalloprotein. Here, we apply the two SQM/COSMO SFs to 17 diverse PL complexes and compare their performance with four widely used classical SFs (Glide XP, AutoDock4, AutoDock Vina, and UCSF Dock). We observe superior performance of the SQM/COSMO SFs and identify challenging systems. This method, due to its generality, comparability across the chemical space, and lack of need for any system-specific parameters, gives promise of becoming, after comprehensive large-scale testing in the near future, a useful computational tool in structure-based drug design and serving as a reference method for the development of other SFs. PMID- 30023713 TI - Fluorenyl-Loaded Quatsome Nanostructured Fluorescent Probes. AB - Delivery of hydrophobic materials in biological systems, for example, contrast agents or drugs, is an obdurate challenge, severely restricting the use of materials with otherwise advantageous properties. The synthesis and characterization of a highly stable and water-soluble nanovesicle, referred to as a quatsome (QS, vesicle prepared from cholesterol and amphiphilic quaternary amines), that allowed the nanostructuration of a nonwater soluble fluorene-based probe are reported. Photophysical properties of fluorenyl-quatsome nanovesicles were investigated via ultraviolet-visible absorption and fluorescence spectroscopy in various solvents. Colloidal stability and morphology of the nanostructured fluorescent probes were studied via cryogenic transmission electronic microscopy, revealing a "patchy" quatsome vascular morphology. As an example of the utility of these fluorescent nanoprobes, examination of cellular distribution was evaluated in HCT 116 (an epithelial colorectal carcinoma cell line) and COS-7 (an African green monkey kidney cell line) cell lines, demonstrating the selective localization of C-QS and M-QS vesicles in lysosomes with high Pearson's colocalization coefficient, where C-QS and M-QS refer to quatsomes prepared with hexadecyltrimethylammonium bromide or tetradecyldimethylbenzylammonium chloride, respectively. Further experiments demonstrated their use in time-dependent lysosomal tracking. PMID- 30023714 TI - Real-Time, Wearable, Biomechanical Movement Capture of Both Humans and Robots with Metal-Free Electrodes. AB - We demonstrate an all-carbon-based, flexible, conformal movement-capturing device capable of precisely monitoring biomechanical movements of both humans and robots. Mechanically robust, metal-free electrodes form a unique component of the device responsible for qualitatively and quantitatively transducing biomechanical movements without any signal artifacts. Importantly, the device withstands and operates in a wide dynamic range for both stretching (25% strain) and bending (140 degrees ) actions with minimal cycling hysteresis (2.0), high repeatability (>100 cycles), low creep, and humidity-independent rapid response (~200 ms). Furthermore, the device qualitatively distinguishes movements such as bending of finger, knuckle, and wrist and also provides quantitative information on the extent of such movements. We establish that single-wall carbon nanotubes (CNTs) embedded in ultralow concentration (0.016 wt %) within an elastomeric matrix undergo three-dimensional conformational changes during biomechanical movements that are subsequently transduced as signals. In addition, such CNT-elastomer strips exhibit enhanced stretchability (>100%) and elasticity (~77%) in comparison to those of pure elastomers, leading to a wider dynamic working range of the device. Furthermore, seamless integration of a versatile gesture tracker on ubiquitous platforms, such as human skin, kinesiologic tapes, gloves, and robotic arms, is achieved, thereby catering to applications ranging from healthcare monitoring and physiotherapy to robotics and wearable technologies. PMID- 30023715 TI - Four-Analog Computation Based on DNA Strand Displacement. AB - DNA strand displacement plays an important role in biological computations. The inherent advantages of parallelism, high storability, and cascading have resulted in increased functional circuit realization of DNA strand displacement on the nanoscale. Herein, we propose an analog computation with minus based on DNA strand displacement. The addition, subtraction, multiplication, and division gates as elementary gates could realize analog computation with minus. The advantages of this proposal are the analog computation with negative value and division computation. In this article, we provide the designs and principles of these elementary gates and demonstrate gate performance by simulation. Furthermore, to show the cascade property of gates, we computed a polynomial as an example by these gates. PMID- 30023716 TI - TMPyP Inhibits Amyloid-beta Aggregation and Alleviates Amyloid-Induced Cytotoxicity. AB - The aggregation or misfolding of amyloid-beta (Abeta) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of Abeta aggregation is thought to be an effective strategy for AD treatment. The capability of a water soluble porphyrin, 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit Abeta aggregation and to lower Abeta-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt Abeta aggregation but also disassemble the preformed Abeta aggregates. The atomic force microscopy imaging proves that TMPyP inhibits the formation of both oligomers and fibrils. Molecular dynamic simulations provide an insight into the interaction between TMPyP and Abeta at the molecular level. The half-maximal inhibitory concentrations of TMPyP acting on the oligomers and fibrils were determined to be 0.6 and 0.43 MUM, respectively. As a member of porphyrin family, TMPyP is of rather low cytotoxicity, and the cytotoxicity of the Abeta aggregates was also relieved upon coincubation with TMPyP. The excellent performance of TMPyP thus makes it a potential drug candidate for AD therapy. PMID- 30023717 TI - High-Throughput, Multispecies, Parallelized Plasma Stability Assay for the Determination and Characterization of Antibody-Drug Conjugate Aggregation and Drug Release. AB - The stability of antibody-drug conjugates (ADCs) in circulation is critical for maximum efficacy and minimal toxicity. An ADC reaching the intended target intact can deliver the highest possible drug load to the tumor and reduce off-target toxicity from free drug in the blood. As such, assessment of ADC stability is a vital piece of data during development. However, traditional ADC stability assays can be manually intensive, low-throughput, and require large quantities of ADC material. Here, we introduce an automated, high-throughput plasma stability assay for screening drug release and aggregation over 144 h for up to 40 ADCs across five matrices simultaneously. The amount of ADC material during early drug development is often limited, so this assay was implemented in 384-well format to minimize material requirements to <100 MUg of each ADC and 100 MUL of plasma per species type. Drug release and aggregation output were modeled using nonlinear regression equations to calculate formation rates for each data type. A set of 15 ADCs with different antibodies and identical valine-citrulline-p aminobenzylcarbamate-monomethylauristatin E linker-drug payloads was tested and formation rates were compared across ADCs and between species, revealing several noteworthy trends. In particular, a wide range in aggregation was found when altering only the antibody, suggesting a key role for plasma stability screening early in the development process to find and remove antibody candidates with the potential to create unstable ADCs. The assay presented here can be leveraged to provide stability data on new chemistry and antibody screening initiatives, select the best candidate for in vivo studies, and provide results that highlight stability issues inherent to particular ADC designs throughout all stages of ADC development. PMID- 30023718 TI - Aldehyde Oxidase: Reaction Mechanism and Prediction of Site of Metabolism. AB - Aldehyde oxidase (AO) is a molybdenum-containing enzyme involved in the clearance of drug compounds containing aldehydes and N-containing heterocyclic fragments. AO has gained considerable interest in recent years because of examples of too fast clearance of drug compounds in development. Thus, it is important to be able to predict AO-mediated drug metabolism. Therefore, we have characterized the structural and energetic aspects of different mechanisms with density functional theory using the molybdenum cofactor as a model for the reactive part of the enzyme. For a series of 6-substituted 4-quinazolinones, the trend in activation energies is the same for three tested reaction mechanisms. Using the concerted mechanism as a model for the enzymatic reaction, the transition states (TSs) for the formation of all possible metabolites for a series of known AO substrates were determined. The lowest activation energies correspond in all cases to the experimentally observed sites of metabolism (SOMs). Various molecular properties were calculated and investigated as more easily determinable markers for reactivity. The stabilities of both intermediates and products correlate to some extent with the TS energies and may be used to predict the SOM. The electrostatic potential-derived charges are also good markers for the prediction of the experimental SOM for this set of compounds and may pave the way for the development of fast methods for the prediction of SOM for AO substrates. PMID- 30023719 TI - Printed Combinatorial Sensors for Simultaneous Detection of Ascorbic Acid, Uric Acid, Dopamine, and Nitrite. AB - In this study, an effective and simple direct printing method was developed to create sensing devices on screen-printed carbon electrodes (SPCEs) to detect multiple species simultaneously. Two sensing materials, graphene oxide nanoribbons (GONRs) and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), were printed on one SPCE for detection of multiple biochemical substances. Printed layers of the GONRs and PEDOT:PSS mixture (GONRs & PEDOT:PSS) on SPCE showed embedment of GONRs in the PEDOT:PSS layer and diminished the electrochemical activity of GONRs. In contrast, by printing the GONRs and PEDOT:PSS at separate locations (GONRs + PEDOT:PSS) on the same SPCE, the electrochemical activities of both GONRs and PEDOT:PSS can be preserved. Thus, without synthesizing new materials, the modified electrode is able to simultaneously detect ascorbic acid (AA), uric acid (UA), dopamine (DA), and nitrite (NO2-), with high anodic oxidation currents and well-separated voltammetric peaks, in differential pulse voltammetry measurements. The detection limits for the four analytes are 41 nM (AA), 30 nM (DA), 11 nM (UA), and 18 nM (NO2-), respectively. The electrode can either detect single species separately or simultaneously determine specific concentrations of the four species in aqueous mixtures, and this can be further extended for many other electrochemical sensing applications. PMID- 30023720 TI - Ag/AgFeO2: An Outstanding Magnetically Responsive Photocatalyst for HeLa Cell Eradication. AB - A superfast, room-temperature, one-step carrier-solvent-assisted interfacial reaction process was developed to prepare Ag/AgFeO2 composite nanocrystals (NCs) of less than 10 nm in size within a 1 min reaction time. These composite NCs were with a direct energy band gap of 2.0 eV and were paramagnetic, making them suitable for optical activation and magnetic manipulation. These composite NCs, applied as a photocatalyst for the treatment of HeLa cells, achieved a significant reduction of 74% in cell viability within 30 min. These Ag/AgFeO2 composite NCs proved to be a promising magnetically guidable photocatalyst for cancer cell treatment. PMID- 30023721 TI - Dye-Labeled Polyacryloyl Hydrazide-Ag Nanoparticle Fluorescent Probe for Ultrasensitive and Selective Detection of Au Ion. AB - The efficiency of a fluorescence sensing device based on metal-enhanced fluorescence (MEF) is dependent on the optimization of interaction between the fluorophore and the metal nanoparticle (NP). Herewith, ultrasensitive and selective turn-on sensing of Au3+ is achieved by using a suitable combination of fluorophore and metal NP system through sequential MEF effect. Dansyl hydrazide tagged Ag NPs in the polyacryloyl hydrazide cavity are utilized to sense the picomolar concentration of Au3+ in aqueous media. We demonstrated that the selective Au3+ sensing is due to the selective deposition of Au on the Ag NP surface over the 16 other metal ions studied. The sensitivity is assigned to the strong overlapping of the emission band of the fluorophore with the surface plasmon band of the Au and improvement of fluorescence signal through successive MEF by Ag and Au colloids. The sensing is associated with a fivefold increase in fluorescence intensity and appearance of violet color of the solution. These luminescent Ag-Au bimetallic NPs may be utilized to trace cancer cells in biological systems and for cell imaging applications. PMID- 30023723 TI - Modification of Honeybee Silk by the Addition of Antimicrobial Agents. AB - Honeybee silk proteins can be produced at high levels in recombinant systems, fabricated into materials, and are tolerant of amino acid modifications: properties that make them exciting templates for designing new functional materials. Here, we explore the properties of materials either made from silk antimicrobial peptide (AMP) fusion proteins or silk containing entrapped AMPs or silver nanoparticles. Inclusion of AMP within the silk protein sequence did not affect our ability to express the proteins or process them into films. When AMP silk proteins and Escherichia coli cells were coincubated in solution, a reduction in cell numbers was observed after degradation of the chimeric protein to release a truncated version of the AMP. In films, the AMP was retained in the silk with leaching rates of <1% per day. Films containing silver nanoparticles were antimicrobial, with the silk preventing aggregation of nanoparticles and slowing the rate of dissolution of the particles. PMID- 30023724 TI - Antimicrobial Properties of Copper-Doped ZnO Coatings under Darkness and White Light Illumination. AB - We report the first antimicrobial study of transparent and robust Cu-doped ZnO coatings that displayed potent antimicrobial activity that resulted in bacterial (Escherichia coli) reduction below detection limits within 6 h of illumination via a white light source that is found in hospital environments. The same bacterial reduction rate was observed even under darkness for 4.0 atom % Cu-doped ZnO films thus providing an efficient 24 h disinfection. All films were produced via a novel, inexpensive, and easily scalable route and were also thoroughly analyzed for their material properties. PMID- 30023722 TI - In Silico Screening and Binding Characterization of Small Molecules toward a G Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene. AB - Overexpression of c-MYC oncogene is associated with cancer pathology. Expression of c-MYC is regulated by the G-quadruplex structure formed in the G-rich segment of nuclease hypersensitive element (NHE III1), that is, "Pu27", which is localized in the promoter region. Ligand-induced stabilization of the Pu27 structure has been identified as a novel target for cancer therapeutics. Here, we have explored the library of synthetic compounds against the predefined binding site of Pu27. Three compounds were selected based on the docking analyses; they were further scrutinized using all atom molecular dynamics simulations in an explicit water model. Simulated trajectories were scrutinized for conformational stability and ligand binding free energy estimation; essential dynamic behavior was determined using principal component analysis. One of the molecules, "TPP (1 (3-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-2-hydroxypropyl)-4-carbamoylpiperidinium)", with the best results was considered for further evaluation. The theoretical observations are supported well by biophysical analysis using circular dichroism, isothermal titration calorimetry, and high-resolution NMR spectroscopy indicating association of TPP with Pu27. The in vitro studies were then translated into c MYC overexpression in the T47D breast cancer cell line. Biological evaluation through the MTT assay, flow cytometric assay, RT-PCR, and reporter luciferase assay suggests that TPP downregulates the expression of c-MYC oncogene by arresting its promoter region. In silico and in vitro observations cumulatively suggest that the novel skeleton of TPP could be a potential anticancer agent by stabilizing the G-quadruplex formed in the Pu27 and consequently downregulating the expression of c-MYC oncogene. Derivation of new molecules on its skeleton may confer anticancer therapeutics for the next generation. PMID- 30023725 TI - Characterization of a Thiol-Ene/Acrylate-Based Polymer for Neuroprosthetic Implants. AB - Thiol-ene/acrylate shape-memory polymers can be used as base substrates for neural electrodes to treat neurological dysfunction. Neural electrodes are implanted into the body to alter or record impulse conduction. This study characterizes thiol-ene/acrylate polymers to determine which synthesis methods constitute an ideal substrate for neural implants. To achieve a desired Tg between 50 and 56.5 degrees C, curing conditions, polymer thickness, monomer ratios, and water uptake were all examined and controlled for. Characterization with dynamic mechanical analysis and thermal gravimetric analysis reveals that thin, thiol-ene/acrylate polymers composed of at least 50 mol % acrylate content and cured for at least 1 h at 365 nm are promising as substrates for neural electrodes. PMID- 30023726 TI - Role of CysI-CysIII Disulfide Bond on the Structure and Activity of alpha Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors. AB - alpha-Conotoxins preferentially antagonize muscle and neuronal nicotinic acetylcholine receptors (nAChRs). Native alpha-conotoxins have two disulfide links, CI-CIII and CII-CIV, and owing to the inherent properties of disulfide bonds, alpha-conotoxins have been systematically engineered to improve their chemical and biological properties. In this study, we explored the possibility of simplifying the disulfide framework of alpha-conotoxins Vc1.1, BuIA, ImI, and AuIB, by introducing [C2H,C8F] modification to the CI-CIII bond. We therefore explored the possibility of using hydrophobic packing of standard amino acid side chains to replace disulfide bonds as an alternative strategy to nonnatural amino acid cross-links. The impact of CI-CIII disulfide bond replacement on the conformation of the alpha-conotoxins was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance chemical shift index study. Two electrode voltage clamp techniques and MD simulations were used to study the impact of disulfide bond deletion on the activities of the peptides at human neuronal nAChRs. All disulfide-deleted variants except ImI[C2H,C8F] had reduced potency for inhibiting nAChRs. Our results suggest that the CI-CIII disulfide bond is important to stabilize the secondary structure of alpha-conotoxins as well as their interaction with neuronal nAChR targets. Results from this study enrich our understanding of the function of the CI-CIII disulfide bond and are useful in guiding future structural engineering of the alpha-conotoxins. PMID- 30023728 TI - Conversion of Methyl Mercaptan to Hydrocarbons over H-ZSM-5 Zeolite: DFT/BOMD Study. AB - Methyl mercaptan-a harmful impurity in natural gas-may be selectively converted into H2S and hydrocarbons [methyl mercaptan to hydrocarbon (M2TH) process], using zeolite catalysts. When M2TH is compared with the well-known MTH (methanol to hydrocarbons) process, significant differences emerge, essentially regarding the formation and distribution of products. Density functional theory (DFT) and Born Oppenheimer molecular dynamics (BOMD) were employed to reveal possible origins for the experimentally observed differences. We established a close similarity between DFT intrinsic (electronic) reaction profiles in the stepwise mechanism of methanol and mercaptan dehydration, although no variance in reactivity was revealed. BOMD simulations at the experimental temperature of 823 K reveal rapid hydrogen abstraction from the methyl group in mercaptan, adsorbed in the zeolite cavity in the presence of the methoxy intermediate. The formation of *CH2SH radical is 10 times faster than that of *CH2OH at the same temperature. The varied reactivity of methanol and mercaptan in MTH and M2TH processes, respectively, can therefore first be attributed to very rapid hydrogen abstraction in mercaptan, which occurs in the zeolite cavity, following the formation of surface methoxy. PMID- 30023727 TI - Potent Anticancer Activity with High Selectivity of a Chiral Palladium N Heterocyclic Carbene Complex. AB - Five enantiomeric pairs of palladium complexes of 1,2,4-triazole-derived chiral N heterocyclic carbene ligands were investigated to probe the influence of chirality on the compound's anticancer activity. Although no chirality-related influence was observed for any of the enantiomeric pair, strong anticancer activity was seen for a particular pair, (1S,2S,5R)-1c and (1R,2R,5S)-1c, which was significantly more active than the benchmark drug cisplatin for human breast cancer cells, MCF-7 (ca. 24-27-fold), and human cervical cancer cells, HeLa (ca. three- to fourfold). Broadening its scope of application, (1R,2R,5S)-1c also exhibited antiproliferative activity against lung cancer (A549), skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1) cell lines. Interestingly, (1R,2R,5S)-1c displayed 8- and 16-fold stronger antiproliferative activity toward B16F10 and MCF-7 relative to their respective noncancerous counterparts, L929 (fibroblast skin cells) and MCF10A (epithelial breast cells), thereby upholding the potential of these complexes for further development as anticancer agents. (1R,2R,5S)-1c inhibited tumor-cell proliferation by blocking the cells at the G2 phase. (1R,2R,5S)-1c caused DNA damage in MCF-7 cells, leading to mitochondrial reactive oxygen species production and subsequently cell death. We also present evidence indicating that (1R,2R,5S)-1c induced p53 dependent programmed cell death in MCF-7 cells. PMID- 30023730 TI - A Method for Investigation of Size-Dependent Protein Binding to Nanoholes Using Intrinsic Fluorescence of Proteins. AB - We have developed a novel method to study the influence of surface nanotopography on human fibrinogen adsorption at a given surface chemistry. Well-ordered arrays of nanoholes with different diameters down to 45 nm and a depth of 50 nm were fabricated in silicon by electron beam lithography and reactive ion etching. The nanostructured chip was used as a model system to understand the effect of size of the nanoholes on fibrinogen adsorption. Fluorescence imaging, using the intrinsic fluorescence of proteins, was used to characterize the effect of the nanoholes on fibrinogen adsorption. Atomic force microscopy was used as a complementary technique for further characterization of the interaction. The results demonstrate that as the size of the nanoholes is reduced to 45 nm, fibrinogen adsorption is significantly increased. PMID- 30023729 TI - Expression, Purification, and Biochemical Characterization of the Flavocytochrome P450 CYP505A30 from Myceliophthora thermophila. AB - The cytochrome P450/P450 reductase fusion enzyme CYP505A30 from the thermophilic fungus Myceliophthora thermophila and its heme (P450) domain were expressed in Escherichia coli and purified using affinity, ion exchange, and size exclusion chromatography. CYP505A30 binds straight chain fatty acids (from ~C10 to C20), with highest affinity for tridecanoic acid (KD = 2.7 MUM). Reduced nicotinamide adenine dinucleotide phosphate is the preferred reductant for CYP505A30 (KM = 3.1 MUM compared to 330 MUM for reduced nicotinamide adenine dinucleotide in cytochrome c reduction). Electron paramagnetic resonance confirmed cysteine thiolate coordination of heme iron in CYP505A30 and its heme domain. Redox potentiometry revealed an unusually positive midpoint potential for reduction of the flavin adenine dinucleotide and flavin mononucleotide cofactors (E0' ~ -118 mV), and a large increase in the CYP505A30 heme domain FeIII/FeII redox couple (ca. 230 mV) on binding arachidonic acid substrate. This switch brings the ferric heme iron potential into the same range as that of the reductase flavins. Multiangle laser light scattering analysis revealed CYP505A30's ability to dimerize, whereas the heme domain is monomeric. These data suggest CYP505A30 may function catalytically as a dimer (as described for Bacillus megaterium P450 BM3), and that binding interactions between CYP505A30 heme domains are not required for dimer formation. CYP505A30 catalyzed hydroxylation of straight chain fatty acids at the omega-1 to omega-3 positions, with a strong preference for omega-1 over omega-3 hydroxylation in the oxidation of dodecanoic and tetradecanoic acids (88 vs 2% products and 63 vs 9% products, respectively). CYP505A30 has important structural and catalytic similarities to P450 BM3 but distinct regioselectivity of lipid substrate oxidation with potential biotechnological applications. PMID- 30023731 TI - Magnetic Separation of Autophagosomes from Mammalian Cells Using Magnetic Plasmonic Hybrid Nanobeads. AB - Developments in subcellular fractionation strategies have provided the means to analyze the protein and lipid composition of organelles by proteomics. Here, we developed ultrasmall magnetic-plasmonic hybrid nanobeads and applied them to the isolation of autophagosomes by applying a magnetic field. The beads were chemically synthesized and comprised an Ag/FeCo/Ag core/shell/shell structure with a mean diameter of 15 nm. The Ag core and the FeCo shell conferred imaging and magnetic separation capabilities, respectively. The nanobeads were transfected into mammalian cells by lipofection. Thirty minutes after lipofection, the nanobeads colocalized with Vps26 and subsequently with LC3. Cell lysates were prepared at the appropriate time points and were subjected to magnetic separation. The separated fraction contained LC3-II, transferrin receptor, and LAMP2, but not LC3-I, suggesting that autophagosomes engulfing endosomal origin had been isolated. The magnetic separation process was completed in less than 30 min, providing a rapid method for isolation of autophagosomes. The present organelle isolation technique using the hybrid nanobeads with imaging and magnetic separation capabilities is highly promising for isolation of other types of organelles such as endosomes and endosome-related organelles. PMID- 30023732 TI - DNA Aptamer-Target Binding Motif Revealed Using a Fluorescent Guanine Probe: Implications for Food Toxin Detection. AB - DNA aptamers are single-stranded oligonucleotides that are generated by an in vitro selection method to bind targets with high affinity and specificity. Understanding molecular recognition by DNA aptamers is of fundamental importance in the development of biosensor applications. The small molecule ochratoxin A (OTA) is a fungal-derived food toxin, and OTA DNA aptamers have been established for the development of rapid detection platforms required for food safety. One such OTA aptamer (OTAA) is a guanine-rich DNA oligonucleotide that folds into an antiparallel G-quadruplex (GQ) upon OTA binding, although structural details of the GQ fold and its interaction with OTA are currently unknown. In the present study, the fluorescent nucleobase analogue, 8-thienyl-2'-deoxyguanosine (ThdG), was inserted into various G sites of OTAA to determine the probe impact on GQ folding and OTA binding affinity. Our results suggest that OTAA contains three lateral (l) loops connecting two stacked G-tetrads with an anticlockwise loop progression to afford a -(lll) GQ topology. The phenolic ring system of OTA undergoes pi-stacking interactions with the G-tetrads of OTAA. Our results also demonstrate aptamer sites that can be modified with ThdG to afford a fluorescent light-up signal upon OTA binding. PMID- 30023733 TI - Sol-Gel Synthesis of CaTiO3:Pr3+ Red Phosphors: Tailoring the Synthetic Parameters for Luminescent and Afterglow Applications. AB - Two sol-gel synthetic routes for the preparation of CaTiO3:Pr3+ red emitting phosphors were compared, with the aim of producing nanostructured materials with tailored luminescence/afterglow properties. The effect of the synthetic parameters, such as the addition of a stabilizer and calcination temperature, on the structural, morphological, and optical properties was investigated. The desired perovskite phase was obtained at a calcination temperature of 800 degrees C or higher. Although the use of acetic acid as the chelating agent leads to micrometric particles with heterogeneous composition, the presence of hydroxypropylcellulose (HPC) results in smaller, less aggregated particles as well as in a high phase purity. At the highest HPC content, surface Ca-rich impurities were detected, although no segregated Ca-rich phases were detectable by X-ray powder diffraction analyses. Luminescence properties were found to be positively related to the phase purity of the oxide, with the highest quantum yields at temperatures equal to or higher than 1000 degrees C. On the contrary, persistent luminescence properties were highest at intermediate calcination temperatures and for samples synthesized with acetic acid. Overall, a notable role of oxygen vacancies resulting from local Ca excess was observed, acting as trap levels promoting longer relaxation pathways. Thanks to the small-sized particles and best steady-state luminescent properties due to a substantial decrease of lattice defects, the HPC synthesis is a promising strategy for light emitting diode applications. On the other hand, the acetic acid synthesis promoted a higher defect density, which is required for an efficient yield of light emission in the long time range and is thus more suitable for afterglow applications. PMID- 30023734 TI - In Vitro Protein Stability of Two Naturally Occurring Thiopurine S Methyltransferase Variants: Biophysical Characterization of TPMT*6 and TPMT*8. AB - Thiopurine S-methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism and inactivation of thiopurine substances administered as immunosuppressants in the treatment of malignancies and autoimmune diseases. In this study, the naturally occurring variants, TPMT*6 (Y180F) and TPMT*8 (R215H), have been biophysically characterized. Despite being classified as low and intermediate in vivo enzyme activity variants, respectively, our results demonstrate a discrepancy because both TPMT*6 and TPMT*8 were found to exhibit normal functionality in vitro. While TPMT*8 exhibited biophysical properties almost indistinguishable from those of TPMTwt, the TPMT*6 variant was found to be destabilized. Furthermore, the contributions of the cofactor S-adenosylmethionine (SAM) to the thermodynamic stability of TPMT were investigated, but only a modest stabilizing effect was observed. Also presented herein is a new method for studies of the biophysical characteristics of TPMT and its variants using the extrinsic fluorescent probe 8-anilinonaphthalene-1-sulfonic acid (ANS). ANS was found to bind strongly to all investigated TPMT variants with a Kd of approximately 0.2 MUM and a 1:1 binding ratio as determined by isothermal titration calorimetry (ITC). Circular dichroism and fluorescence measurements showed that ANS binds exclusively to the native state of TPMT, and binding to the active site was confirmed by molecular modeling and simulated docking as well as ITC measurements. The strong binding of the probe to native TPMT and the conformity of the obtained results demonstrate the advantages of using ANS binding characteristics in studies of this protein and its variants. PMID- 30023735 TI - Revealing and Quantifying the Three-Dimensional Nano- and Microscale Structures in Self-Assembled Cellulose Microfibrils in Dispersions. AB - Cellulose microfibrils (CMFs) are an important nanoscale building block in many novel biobased functional materials. The spatial nano- and microscale organization of the CMFs is a crucial factor for defining the properties of these materials. Here, we report for the first time a direct three-dimensional (3D) real-space analysis of individual CMFs and their networks formed after ultrahigh shear-induced transient deagglomeration and self-assembly in a solvent. Using point-scanning confocal microscopy combined with tracking the centerlines of the fibrils and their junctions by a stretching open active contours method, we reveal that dispersions of the native CMFs assemble into highly heterogeneous networks of individual fibrils and bundles. The average network mesh size decreases with increasing CMF volume fraction. The cross-sectional width and the average length between the twists in the ribbon-shaped CMFs are directly determined and compared well with that of fibrils in the dried state. Finally, the generality of the fluorescent labeling and imaging approach on other CMF sources is illustrated. The unique ability to quantify in situ the multiscale structure in CMF dispersions provides a powerful tool for the correlation of process-structure-property relationship in cellulose-containing composites and dispersions. PMID- 30023736 TI - Class I Polyhydroxyalkanoate Synthase from the Purple Photosynthetic Bacterium Rhodovulum sulfidophilum Predominantly Exists as a Functional Dimer in the Absence of a Substrate. AB - Polyhydroxyalkanoates (PHAs) are a family of biopolyesters that accumulate as carbon and energy storage compounds in a variety of micro-organisms. The marine purple photosynthetic bacterium Rhodovulum sulfidophilum is capable of synthesizing PHA. In this study, we cloned a gene encoding a class I PHA synthase from R. sulfidophilum (phaCRs ) and synthesized PhaCRs using a cell-free protein expression system. The specific activity of PhaCRs increased linearly as the (R) 3-hydroxybutyryl-coenzyme A (3HB-CoA) concentration increased and never reached a plateau, even at 3.75 mM 3HB-CoA, suggesting that PhaCRs was not saturated because of low substrate affinity. Size exclusion chromatography and native polyacrylamide gel electrophoresis analyses revealed that PhaCRs exists predominantly as an active dimer even in the absence of 3HB-CoA, unlike previously characterized PhaCs. The linear relationship between the PhaCRs activity and 3HB-CoA concentrations could result from a low substrate affinity as well as the absence of a rate-limiting step during PHA polymerization because of the existence of predominantly active dimers. PMID- 30023737 TI - Screening Platform Based on Robolid Microplate for Immobilized Enzyme-Based Assays. AB - A facile, cost-effective, and high-throughput screening method was developed for enzyme-based assays based on Robolid/Microplate (RLMP) platform. The RLMP platform is constructed by immobilizing enzyme on commercial robolids and combining it with a standard 96-well microplate to achieve high-throughput analysis. The initiation and quenching of enzymatic reaction can be performed by simply sandwiching or unsealing the enzyme-immobilized robolids and the sample containing microplate. This platform enables measurements of multiple target analytes simultaneously based on immobilized enzymatic reactions, with analysis time independent of the number of wells in the microplate. Using urea as the model analyte, we have shown that the RLMP platform exhibits large linear detection range of up to 10 mM, fast analysis time of 30 min/96 samples, as well as good reproducibility and stability. Measurements of urea in human urine and serum samples were performed using the RLMP platform and were compared with the commercial urea test kit. A good correlation was found between the two methods. This study shows that the present RLMP platform has promising prospects for detection of clinical markers and application in disease diagnosis and biochemical analysis. PMID- 30023738 TI - Intermolecular Packing Effects on Singlet Fission in Oligorylene Dimers. AB - Using the density functional theory method, the crystalline packing effect on the singlet fission (SF) rate of oligorylenes, some of which are found to exhibit SF in crystal forms, is revealed by evaluating the effective electronic coupling (|Veff|), the square of which is proportional to the SF rate. The |Veff| values for terrylene and quaterrylene dimer models are investigated for a variety of slip-stacked forms. It is found that these values show similar dependences on the intermolecular packing as a function of lateral and longitudinal displacements of monomer frameworks, and that they are maximized in several configurations of one monomer slipped from another along the longitudinal axis. The present estimation method of the SF rate is also found to qualitatively explain the experimental SF rate difference between terrylene derivatives with different packing forms. Furthermore, by analyzing the effect of electronic couplings on the adiabatic electronic states related to SF, we predict several favorable molecular packings leading to a fast SF with a high triplet yield. PMID- 30023739 TI - Route to Benzimidazol-2-ones via Decarbonylative Ring Contraction of Quinoxalinediones: Application to the Synthesis of Flibanserin, A Drug for Treating Hypoactive Sexual Desire Disorder in Women and Marine Natural Product Hunanamycin Analogue. AB - A simple and practical method to access a variety of benzimidazol-2-ones is reported here. A series of N-alkyl-substituted benzimidazol-2-ones were synthesized by decarbonylative ring contraction starting from corresponding quinoxalinediones for the first time. The utility of the method has been demonstrated by synthesizing recently approved controversial drug flibanserin (Addyi) and a urea analogue of marine antibiotic natural product hunanamycin-A. PMID- 30023740 TI - New Application of Old Material: Chinese Traditional Ink for Photothermal Therapy of Metastatic Lymph Nodes. AB - Finding a simple and effective strategy to eliminate tumor metastatic lymph nodes is highly desired in clinical tumor treatment. Herein, we reported a Chinese traditional ink (Hu-ink)-based treatment for photothermal therapy (PTT) of tumor metastatic lymph nodes. By simple dilution, stable Chinese traditional ink dispersion was obtained, which presents excellent photothermal effect because of its high absorption in near-infrared (NIR) region. Meanwhile, as revealed by staining and photoacoustic imaging, Hu-ink could transfer to nearby lymph nodes after directly injected into the primary tumors. Under the guidance of dual modality mapping, the metastatic sentinel lymph nodes could be subsequently eliminated by NIR irradiation. The good biocompatibility of Hu-ink has also been verified by a series of experiments. Therefore, the Hu-ink-based treatment exhibits great potential for PTT of tumor metastatic lymph nodes in future clinical practice. PMID- 30023742 TI - Gram-Scale Synthesis and Kinetic Study of Bright Carbon Dots from Citric Acid and Citrus japonica via a Microwave-Assisted Method. AB - Tracking dynamic cellular processes necessitates fluorescent materials that are photostable, biocompatible, water-soluble, nanosized, and nontoxic. In this study, highly fluorescent carbon dots (CDs) were produced from cheap and readily available sources, citric acid (CA) and Philippine citrus (Citrus japonica Thunb.) or calamansi juice (CJ) via a microwave-assisted method. A number of synthetic conditions were investigated systematically to optimize the preparation of CDs from CA and CJ. The formation mechanism, surface chemistry, and photoluminescence of CA-based CDs (CA-CDs) and CJ-based CDs (CJ-CDs) were evaluated after each stage of pyrolysis in detail using different characterization techniques, such as dynamic light scattering, diffusion-ordered spectroscopy, atomic force microscopy, zeta potential, X-ray diffraction, Fourier transform infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy, and absorption/emission spectroscopy. Gram-scale pyrolysis of CA with ethylenediamine (EDA) and CJ with EDA were carried out to provide CA-CDs (CA 18) within 18 min total pyrolysis time at 97% yield and CJ-CDs (CJ-14) within 14 min total pyrolysis time at 7% yield. Aqueous suspensions of CA-18 and CJ-14 CDs gave comparable bright blue luminescence at 462 nm. CA-CDs were shown to be nontoxic for mung beans up to 2 mg/mL, whereas CJ-CDs with higher surface negative charges inhibited growth above 0.5 mg/mL. This study demonstrates that bright CA- and CJ-CDs can be produced in gram-scale quantities using inexpensive methods. The size, amount, and extent of EDA incorporation are important in contributing to the formation of highly emissive particles. PMID- 30023741 TI - Expedient Synthesis of Indolo[2,3-b]quinolines, Chromeno[2,3-b]indoles, and 3 Alkenyl-oxindoles from 3,3'-Diindolylmethanes and Evaluation of Their Antibiotic Activity against Methicillin-Resistant Staphylococcus aureus. AB - Easily accessible 3,3'-diindolylmethanes (DIMs) were utilized to generate a focused library of indolo[2,3-b]quinolines (2), chromeno[2,3-b]indoles (3), and 3 alkenyl-oxindoles (4) under 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated oxidative conditions. DIMs with ortho-NHTosyl (NHTs) phenyl group afforded indolo[2,3-b]quinolines (2), whereas DIMs with ortho-hydroxy phenyl groups yielded chromeno[2,3-b]indoles (3) and 3-alkenyl-oxindoles (4). The mild conditions and excellent yields of the products make this method a good choice to access a diverse library of bioactive molecules from a common starting material. Two optimized compounds 2a and 2n displayed excellent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). Compound 2a showed the minimum inhibitory concentration values in the concentration between 1 and 4 MUg/mL, whereas compound 2n revealed the values of 1-2 MUg/mL. Furthermore, both the compounds were highly bactericidal and capable to kill the MRSA completely within 360 min. Collectively, the results suggested that both compounds 2a and 2n possess enormous potential to be developed as anti-MRSA agents. PMID- 30023743 TI - Biological and Pharmacological Characterization of Benzothiazole-Based CK-1delta Inhibitors in Models of Parkinson's Disease. AB - Parkinson's disease (PD), an age-related neurodegenerative disorder that results from a progressive loss of dopaminergic neurons has an enormous economical and human cost. Unfortunately, only symptomatic treatment such as dopamine replacement therapy is available. Therefore, drugs with new mechanisms of action able to protect against neuronal cell death are an urgent need. We here report the in vivo efficacy on dopaminergic neuronal protection in a PD mouse model and the lack of toxicity in zebrafish and Ames test of benzothiazole-based casein kinase-1delta (CK-1delta) nanomolar inhibitors. On the basis of these results, we propose protein kinase CK-1delta inhibitors as the possible disease-modifying drugs for PD, benzothiazole 4 being a promising drug candidate for further development as a new therapy of this neurodegenerative disease. PMID- 30023744 TI - Bioprofiling of Cosmetics with Focus on Streamlined Coumarin Analysis. AB - Facing the widespread use of cosmetic products in daily use and recognizing the very limited information obtained by target analysis, a method suited for comprehensive characterization of cosmetics was aimed at. The biological activity of ingredients of 20 cosmetics taken from 16 different product groups and their coumarin contents were investigated via chromatography linked to bioassays (direct bioautography) and mass spectrometry. It allows for screening a large number of cosmetic products within a short time to generate a more valid database on their coumarin content and their contribution to the overall exposure. Bioactivity profiling of cosmetics with regard to bioactive ingredients opens new avenues for a comprehensive characterization of important substances in products of daily use, helpful for the legally required safety and risk assessment of cosmetic products, especially for multiple product usage. As for coumarin, a ubiquitary fragrance compound of allergenic potential, which is under recurrent discussion due to its hepatoxic properties, it is necessary to be able to estimate the regular intake via cosmetics for a valid risk assessment. This newly developed bioprofiling method allowed a selective determination of coumarin down to 1.3 mg kg-1, even for very matrix-rich cosmetics despite minimalism in sample preparation. The declaration limits according to European Cosmetics Regulation were completely covered. Mean coumarin contents of 20 cosmetic products reached up to 2218 mg kg-1. The repeatabilities (%RSD, n = 3) were between 1.1 and 2.9%, and the mean recoveries (n = 5) were between 96 and 102% for the different cosmetic matrices. PMID- 30023745 TI - Improved Solubility and Bioactivity of Camptothecin Family Antitumor Drugs with Supramolecular Encapsulation by Water-Soluble Pillar[6]arene. AB - Water-soluble pillar[6]arene (WP6) was used to solubilize camptothecin family antitumor drugs. In the presence of WP6, the solubility of camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) was enhanced by 380 and 40 times, respectively. The solubility enhancement is proved to be the result of the host-guest encapsulation by WP6. WP6 has a low cytotoxicity against normal MC 3T3-E1 cells, whereas the bioactivity of CPT and HCPT is substantially improved as a result of the solubility enhancement. PMID- 30023746 TI - Synthesis, Self-Assembly, and Drug Delivery Characteristics of Poly(methyl caprolactone-co-caprolactone)-b-poly(ethylene oxide) Copolymers with Variable Compositions of Hydrophobic Blocks: Combining Chemistry and Microfluidic Processing for Polymeric Nanomedicines. AB - The synthesis, characterization, and self-assembly of a series of biocompatible poly(methyl caprolactone-co-caprolactone)-b-poly(ethylene oxide) amphiphilic block copolymers with variable MCL contents in the hydrophobic block are described. Self-assembly gives rise to polymeric nanoparticles (PNPs) with hydrophobic cores that decrease in crystallinity as the MCL content increases, and their morphologies and sizes show nonmonotonic trends with MCL content. PNPs loaded with the anticancer drug paclitaxel (PAX) give rise to in vitro PAX release rates and MCF-7 GI50 (50% growth inhibition concentration) values that decrease as the MCL content increases. We also show for selected copolymers that microfluidic manufacturing at a variable flow rate enables further control of PAX release rates and enhances MCF-7 antiproliferation potency. These results indicate that more effective and specific drug delivery PNPs are possible through tangential efforts combining polymer synthesis and microfluidic manufacturing. PMID- 30023747 TI - Photodynamic Inactivation of Multidrug-Resistant Staphylococcus aureus Using Hybrid Photosensitizers Based on Amphiphilic Block Copolymer-Functionalized Gold Nanoparticles. AB - Multidrug-resistant Staphylococcus aureus (MRSA) has become one of the major causes of various infections, leading to morbidity in both healthy and immune compromised populations worldwide. Herein, we report a novel type of hybrid photosensitizer based on amphiphilic block copolymer-functionalized gold nanoparticles. The design of the nanoparticles provides a facile means to incorporate hydrophobic photosensitizing molecules for use in aqueous media. The hybrid photosensitizers display greatly enhanced singlet oxygen generation and outstanding photodynamic inactivation (PDI) efficacy against MRSA under light illumination. These hybrid photosensitizers greatly improve the effectiveness of PDI against MRSA while not involving antibiotics. PMID- 30023748 TI - Counterpointing Scenarios on the Fate of Different Prototropic Forms of Norfloxacin Housed in the Pocket of Lysozyme: The Nonelectrostatic Interactions in the Protein Interior Are in the Controlling Role on the Prototropic Equilibria of the Guest. AB - Herein, we report a comprehensive study on the interaction of three protomeric forms of the antibacterial drug norfloxacin (nfx) with the enzymatic protein human lysozyme (lyz). Norfloxacin, having the option for two-stage acid-base equilibria, converts from cationic (nfx+) to zwitterionic (nfx+/-) form, followed by an anionic (nfx-) species, with increasing pH. Among these protomeric forms, lysozyme binds nfx+/- most robustly, whereas nfx- has a weak association and nfx+ does not show any interaction. In lysozyme, the location of the drug was ascertained by competitive binding assay with 8-anilino-1-naphthalenesulfonate, and this was further examined with molecular docking simulation. The binding process was found to be primarily governed by hydrogen bonding and van der Waals interactions. The study has further revealed that preferential binding of nfx+/- by the protein over nfx- led to a switchover of nfx- to nfx+/-; and the resulting increased population of nfx+/- over the other is beneficial for the pharmacological activity of the drug in terms of its accumulation in the target bacterial cells. The present study accomplishes two important objectives. It holds significance regarding the differential interaction of multiprotomeric drugs with biomolecules, such as proteins, enzymes, lipid membranes, etc., and also on such biomolecule-assisted alteration of the acid-base equilibrium and consequent bioavailability of the drug. The findings are useful from the viewpoints of dispensation, distribution, and metabolism of any prototropic drug in living systems as they encounter several biomolecules in vivo. Another importance of this work stems from the study of comparative binding responses of lysozyme toward a drug existing in multiple forms depending on its protonation states or some other chemical processes. PMID- 30023749 TI - Development of Graphene Oxide-/Galactitol Polyester-Based Biodegradable Composites for Biomedical Applications. AB - We have developed nanocomposites based on galactitol/adipic acid in the molar ratio of 1:1 with different weight percentages of graphene oxide (GO). The objective of this study was to analyze the effect of enhanced physicochemical properties achieved due to the addition of GO to the polymers on cellular responses. The chemical structures of the polymer and composites were confirmed by Fourier transform infrared spectroscopy. Scanning electron microscopy revealed the uniform distribution of GO in the polymers. Differential scanning calorimetry showed no significant variation in the glass-transition temperature of the nanocomposites. Dynamic mechanical analysis demonstrated the increase of Young's modulus with the increase in the addition of GO to the polymer from 0.5 to 1 wt % and a dramatic decrease in modulus with the addition of 2 wt % GO to the polyester. Contact angle analysis illustrated a slight increase in hydrophilicity with the addition of GO to the polyester. Investigations on the hydrolytic degradation and dye release were performed and revealed that the degradation and release decreased with the increase in the weight percentages of GO but increased for 2 wt % GO with the polymer. The rates of degradation and dye release followed first-order and Higuchi kinetics, respectively. The initial in vitro cytocompatibility studies exhibited minimal toxicity. Mineralization studies proved that these nanocomposites stimulated osteogenesis. This study has salient implications for designing biodegradable polymers for use as scaffolds with tailored release. PMID- 30023751 TI - New Insights into the Catalytic Mechanism of Aldose Reductase: A QM/MM Study. AB - Aldose reductase is the first enzyme of the polyol pathway in which glucose is converted to fructose via sorbitol. The understanding of this key enzyme is important as it has been linked to some diabetes mellitus complications. The mechanism of the enzyme was investigated using a hybrid quantum mechanics/molecular mechanics (QM/MM) method. It was found that depending on the protonation state of His110 the mechanism can be concerted or stepwise and the proton donor can be either Tyr48 or His110. These findings are different from the previous theoretical studies based on QM/MM calculations using either AM1 or HF/4 31G, in which the reduction is, respectively, a stepwise or one-step process. The QM/MM energy barriers for the reduction of d-glyceraldehyde were evaluated at a B3LYP/6-31G* level for both HIP and HIE protonation states of His110. These were, respectively, 6.5 +/- 2.2 and 16.7 +/- 1.0 kcal/mol, which makes only the HIE protonation state consistent with the experimental value of 14.8 kcal/mol derived from kinetics experiments and makes Tyr48 the most probable proton donor. PMID- 30023750 TI - Two-Photon Macromolecular Probe Based on a Quadrupolar Anthracenyl Scaffold for Sensitive Recognition of Serum Proteins under Simulated Physiological Conditions. AB - The binding interaction of a biocompatible water-soluble polycationic two-photon fluorophore (Ant-PIm) toward human serum albumin (HSA) was thoroughly investigated under simulated physiological conditions using a combination of steady-state, time-resolved, and two-photon excited fluorescence techniques. The emission properties of both Ant-PIm and the fluorescent amino acid residues in HSA undergo remarkable changes upon complexation allowing the thermodynamic profile associated with Ant-PIm-HSA complexation to be accurately established. The marked increase in Ant-PIm fluorescence intensity and quantum yield in the proteinous environment seems to be the outcome of the attenuation of radiationless decay pathways resulting from motional restriction imposed on the fluorophore. Fluorescence resonance energy transfer and site-marker competitive experiments provide conclusive evidence that the binding of Ant-PIm preferentially occurs within the subdomain IIA. The pronounced hypsochromic effect and increased fluorescence enhancement upon association with HSA, compared to that of bovine serum albumin (BSA) and other biological interferents, makes the polymeric Ant-PIm probe a valuable sensing agent in rather complex biological environments, allowing facile discrimination between the closely related HSA and BSA. Furthermore, the strong two-photon absorption (TPA) with a maximum located at 820 nm along with a TPA cross section sigma2 > 800 GM, and the marked changes in the position and intensity of the band upon complexation definitely make Ant PIm a promising probe for two-photon excited fluorescence-based discrimination of HSA from BSA. PMID- 30023752 TI - In Situ Quenching of Trialkylphosphine Reducing Agents Using Water-Soluble PEG Azides Improves Maleimide Conjugation to Proteins. AB - Trialkylphosphines tris(2-carboxy-ethyl)-phosphine and tris(3-hydroxypropyl) phosphine are popular reagents for the reduction of cysteine residues in bioconjugation reactions using maleimides. However, it has been demonstrated that these phosphines are reactive toward maleimide, necessitating their removal before the addition of the Michael acceptor. Here, a method using water-soluble PEG-azides is reported for the quenching of trialkylphosphines in situ, which is demonstrated to improve the level of maleimide conjugation to proteins. PMID- 30023753 TI - Quantification of the Disaccharide Trehalose from Biological Samples: A Comparison of Analytical Methods. AB - Trehalose is a disaccharide that is biosynthesized by many different organisms subjected to extreme conditions, such as dehydration, heat, oxidative stress, and freezing. This disaccharide allows organisms to better survive these environmental stresses; however, the mechanisms by which trehalose exerts its protective effects are not well understood. Methods to accurately measure trehalose from different organisms will help us gain better understanding of these protective mechanisms. In this study, three experimental approaches for the quantification of trehalose from biological samples were compared: an enzymatic trehalose assay (Trehalose Assay Kit; Megazyme International), a high-performance liquid chromatography coupled with refractive index detection-based assay, and a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assay. Limits of detection and quantification for each assay were compared, as were the dynamic ranges for all three assays. The percent recoveries for known amounts of trehalose spiked into bacterial and mammalian cellular lysates were also determined for each of the assays. Finally, endogenous trehalose produced by Escherichia coli cells was detected and quantified using these assays. Results from this study indicate that an LC-MS/MS-based assay is the most direct and sensitive method for the quantification of low concentrations of trehalose from biological samples; however, the enzymatic assay is suitable for the rapid quantification of higher concentrations of trehalose when an LC-MS/MS is unavailable. PMID- 30023754 TI - Discrepancies between Cyclic and Linear Antimicrobial Peptide Actions on the Spectrochemical and Nanomechanical Fingerprints of a Young Biofilm. AB - Antimicrobial peptides (AMPs) are currently known for their potential as an alternative to conventional antibiotics and new weapons against drug-resistant bacteria and biofilms. In the present work, the mechanism of action of a cyclic (colistin) and a linear (catestatin) AMP on a young E. coli biofilm was deciphered from the molecular to the cellular scale. To this end, infrared spectroscopy (attenuated total reflection-Fourier transform infrared) assisted by chemometric analysis was combined with fluorescence and atomic force microscopies to address the very different behaviors of both AMPs. Indeed, the colistin dramatically damaged the bacterial cell wall and the metabolism even though its action was not homogeneous over the whole bacterial population and repopulation can be observed after peptide removal. Conversely, catestatin did not lead to major damages in the bacterial morphology but its action was homogeneous over the whole bacterial population and the cells were unable to regrow after the peptide treatment. Our results strongly suggested that contrary to the cyclic molecule, the linear one is able to cause irreversible damages in the bacterial membrane concomitantly to a strong impact on the bacterial metabolism. PMID- 30023755 TI - In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis. AB - Nitazoxanide has antiparasitic and antibiotic activities including activity against Mycobacterium tuberculosis. We prepared and evaluated a set of its analogues to determine the structure-activity relationship, and identified several amide- and urea-based analogues with low micromolar activity against M. tuberculosis in vitro. Pharmacokinetics in the rat suggested a path forward to obtain bioavailable compounds. The series had a good microbiological profile with bactericidal activity in vitro against replicating and nonreplicating M. tuberculosis. Analogues had limited activity against other Gram-positive bacteria but no activity against Gram-negative bacteria. Our studies identified the key liability in this series as cytotoxicity. Future work concentrating on identifying the target(s) could assist in removing activity against eukaryotic cells. PMID- 30023756 TI - Multiresidue Method for the Rapid Determination of Pesticide Residues in Tea Using Ultra Performance Liquid Chromatography Orbitrap High Resolution Mass Spectrometry and In-Syringe Dispersive Solid Phase Extraction. AB - A method based on in-syringe dispersive solid phase extraction (IS-D-SPE) and ultra performance liquid chromatography Orbitrap high resolution mass spectrometry for the multiresidue analysis of 117 pesticides in tea was developed. Full scan mode was acquired over an m/z range of 100-800 with Orbitrap resolution at 70000, followed by full scan/dd-MS2 mode for confirmation. The identification criteria of retention time and mass accuracy tolerance was +/-0.20 min and +/-5.0 ppm, respectively. MS/MS fragment ions obtained dd-MS2 were necessary to identify the pesticides with the same molecular mass weight. The IS D-SPE technique involved a mixture of 200 mg PSA, 100 mg C18, and 15 mg multiwalled carbon nanotubes for the cleanup of tea matrix. Good linearity (R2 > 0.99) for 117 pesticides was obtained. Satisfactory recoveries in the range of 70 120% were obtained for 105 pesticides, while intraday and interday precisions were below 20%. Limits of quantification were generally 10 MUg kg-1. Finally, this method was employed to analyze 117 pesticides in 70 tea samples. PMID- 30023757 TI - Single-Step Rapid Diagnosis of Dopamine and Serotonin Metabolism Disorders. AB - Early diagnosis of dopamine and serotonin metabolic defects is of importance notably because of the availability of therapeutic strategies able to prevent the associated progressive brain dysfunction. The diagnosis of these diseases relies on the determination of monoamine metabolites and pterins in cerebrospinal fluid (CSF). Current methods involve at least two high-performance liquid chromatography runs of CSF analysis. The first one is devoted to the quantification of dopamine and serotonin metabolites and the second one to the quantification of pterins. Here, we describe a single-step method to measure monoamine neurotransmitter metabolites and pterins of interest in less than 10 min by ultrahigh-performance liquid chromatography coupled to sequential coulometric oxidation and fluorescence detections. All target compounds were quantified in CSF with a small volume (50 MUL) and a single filtration step for sample preparation and analysis. After validation, the proposed method was applied to the determination of age-related reference ranges in the CSF of target compounds from a series of 1372 samples collected in France from 2008 to 2014. In the same period, the results obtained for 19 CSF samples from patients with known neurotransmitter disorders and 115 CSF samples with known immune system activation confirmed the expected pattern of changes in monoamine metabolites and pterins. PMID- 30023758 TI - Application of Sustainable Natural Bioresources in Agriculture: Iodine-Mediated Oxidative Cyclization for Metal-Free One-Pot Synthesis of N-Phenylpyrazole Sarisan Analogues as Insecticidal Agents. AB - In view of potential agricultural activity of sarisan (isolated from many plants or easily synthesized from sesamol, another biorenewable natural product) analogues, many research studies on the application of these biorenewable and abundant natural resources have been proceeded. A series of novel sarisan analogues containing N-phenylpyrazole were synthesized and evaluated for their insecticidal activity against a crop-threatening insect pest, Mythimna separata Walker. Meanwhile, an iodine-mediated oxidative intramolecular C-N bond formation methodology has been established for the one-pot synthesis of these N phenylpyrazole-containing sarisan analogues. This practical one-pot methodology is metal-free and requires no separation of the less stable intermediate hydrazones. In addition, it was found that compounds 8l-r exhibited more promising insecticidal activity with the final mortality rates (FMRs) >62.1%, when compared with the positive control toosendanin. Especially, compound 8r with 2-fluoro-4-bromophenyl showed the most potent insecticidal activity, the FMR of which was 79.3%. On the basis of this, some interesting results of structure activity relationships were also discussed. PMID- 30023759 TI - Chemical Printing of Biological Tissue by Gold Nanoparticle-Assisted Laser Ablation. AB - A chemical printing method based on gold nanoparticle (AuNP)-assisted laser ablation has been developed. By rastering a thin layer of AuNPs coated on a rat kidney tissue section with a UV laser, biomolecules are extracted and immediately transferred/printed onto a supporting glass substrate. The integrity of the printed sample is preserved, as revealed by imaging mass spectrometric analysis. By studying the mechanism of the extraction/printing process, transiently molten AuNPs were found to be involved in the process, as supported by the color and morphological changes of the AuNP thin film. The success of this molecular printing method was based on the efficient laser-nanomaterial interaction, that is, the strong photoabsorption, laser-induced heating, and phase-transition properties of the AuNPs. It is anticipated that the molecular printing method can be applied to perform site-specific printing, which extracts and transfers biochemicals from different regions of biological tissue sections to different types of supporting materials for subsequent biochemical analysis with the preservation of the original tissue samples. PMID- 30023760 TI - Effect of Crystal Shape and Aggregation of Calcium Oxalate Monohydrate on Cellular Toxicity in Renal Epithelial Cells. AB - Renal epithelial cell injury is a key step in inducing kidney stone formation. This injury induced by crystallites with different shapes and aggregation states has been receiving minimal research attention. To compare the shape and aggregation effects of calcium oxalate crystals on their toxicity, we prepared calcium oxalate monohydrate (COM) crystals with the morphology of a hexagonal lozenge, a thin hexagonal lozenge, and their corresponding aggregates. We then compared their toxicities toward human kidney proximal tubular epithelial (HK-2) cells. All four shapes of COM crystals caused cell-membrane rupture, upregulated intracellular reactive oxygen, and decreased mitochondrial membrane potential. This series of phenomena ultimately led to necrotic cell death. The overall damage in cells was determined in terms of both exterior and interior damage. Crystals with a large Ca2+ ion-rich (101) active face showed the greatest toxicity in HK-2 cells and the largest extent of adhesion onto the cell surface. Crystals with sharp edges easily caused cell-membrane ruptures. The aggregation of sharp crystals aggravated cell injury, whereas the aggregation of blunt crystals weakened cell injury. Therefore, crystal shapes and aggregation states were important factors that affected crystal toxicity in renal epithelial cells. All of these findings elucidated the relationship between the physical properties of crystals and cytotoxicity and provided theoretical references for inhibiting stone formation. PMID- 30023761 TI - Scarless Wound Closure by a Mussel-Inspired Poly(amidoamine) Tissue Adhesive with Tunable Degradability. AB - Burn, trauma, and various medical conditions including bacterial infection, diabetes complication, and surgery could lead to an acute cutaneous wound and scar formation. Application of tissue glues instead of sutures could minimize the additional trauma and scar formation. Despite the countless efforts devoted to the development of high-strength tissue glues, little attention has been paid to their influence on the scar formation. Here, we report the development of a new tissue glue with excellent biocompatibility and tunable degradability for scarless wound closure. A series of catechol-containing poly(amidoamine) (CPAA) polymers were synthesized via the one-step Michael addition of dopamine and bisacrylamide. The tertiary amino group in the polymer backbone was used to introduce a zwitterionic sulfobetaine group by one-step ring-opening polymerization. The introduction of the zwitterionic sulfobetaine group could easily tune the hydrophilicity and the degradability of CPAA without influencing the density of the catechol group in the polymer. Lap-shear tests on the porcine skin demonstrated a high adhesion strength of 7 kPa at 1 h, rising to 24 kPa by 12 h. Addition of silica nanoparticles could further enhance the adhesion strength by 50%. In vivo studies further confirmed that the CPAA tissue glue could effectively accelerate the healing process of incisional wounds on the back of Sprague Dawley rats compared with suture and reduce the scar formation. PMID- 30023763 TI - Metal Foam-Based Fenton-Like Process by Aeration. AB - A novel metal foam-based Fenton-like process for wastewater treatment is illustrated in this study. In the system, H2O2 was generated in situ by taking advantage of O2 in air, as metal could activate dissolved O2 to produce *O2- and then generate H2O2. Furthermore, metal foam can enhance the Fe3+/Fe2+ cycling, which eventually improved the efficiency of the Fenton process. The performance of the novel Fenton-like process was assessed by methyl blue (MB), and 94% MB removal could be achieved within 5 min in nickel (Ni) foam system. The degradation of MB in this study was based on both *OH and *O2- radicals, where *O2- radical served as the precursor to generate *OH for MB degradation through a Fenton process. The pH value of 3 with the initial Fe2+ concentration of 0.25 mM was found to be the optimum condition for the Fenton-like process. This study provides a general and new strategy for efficient wastewater treatment just using aeration and metal foams (such as Ni, Al, and Cu foams), which also offers a good alternative for rational design and application of traditional Fenton process. PMID- 30023762 TI - Chemical Profiling of Medical Cannabis Extracts. AB - Medical cannabis has been legally available for patients in a number of countries. Licensed producers produce a variety of cannabis strains with different concentrations of phytocannabinoids. Phytocannabinoids in medical cannabis are decarboxylated when subjected to heating for consumption by the patients or when extracted for preparing cannabis derivative products. There is little understanding of the true chemical composition of cannabis extracts, changes occurring during heating of the extracts, and their relevance to pharmacological effects. We investigated the extract from a popular commercial strain of medical cannabis, prior to and after decarboxylation, to understand the chemical profiles. A total of up to 62 compounds could be identified simultaneously in the extract derived from commercial cannabis, including up to 23 phytocannabinoids. Upon heating, several chemical changes take place, including the loss of carboxylic group from the acidic phytocannabinoids. This investigation attempts to reveal the chemical complexity of commercial medical cannabis extracts and the differences in the chemical composition of the native extract and the one subjected to heat. Comprehensive chemical analyses of medical cannabis extracts are needed for standardization, consistency, and, more importantly, an informed employment of this substance for therapeutic purposes. PMID- 30023764 TI - Soft Nanotubes Derivatized with Short PEG Chains for Thermally Controllable Extraction and Separation of Peptides. AB - By means of a two-step self-assembly process involving three components, including short poly(ethylene glycol) (PEG) chains, we produced two different types of molecular monolayer nanotubes: nanotubes densely functionalized with PEG chains on the outer surface and nanotubes densely functionalized with PEG chains in the nanochannel. Turbidity measurements and fluorescence spectroscopy with an environmentally responsive probe suggested that the PEG chains underwent dehydration when the nanotubes were heated above 44-57 degrees C and rehydration when they were cooled back to 25 degrees C. Dehydration of the exterior or interior PEG chains rendered them hydrophobic and thus able to effectively extract hydrophobic amino acids from the bulk solution. Rehydration of the PEG chains restored their hydrophilicity, thus allowing the extracted amino acids to be squeezed out into the bulk solutions. The nanotubes with exterior PEG chains exhibited selectivity for all of the hydrophobic amino acids, whereas the interior PEG chains were selective for hydrophobic amino acids with an aliphatic side chain over hydrophobic amino acids with an aromatic side chain. The higher selectivity of the latter system is attributable that the extraction and back extraction processes involve encapsulation and transportation of the amino acids in the nanotube channel. As the result, the latter system was useful for separation of peptides that differed by only a single amino acid, whereas the former system showed no such separation ability. PMID- 30023765 TI - Rationally Designed Probe for Reversible Sensing of Zinc and Application in Cells. AB - Biologically compatible fluorescent ion sensors, particularly those that are reversible, represent a key tool for answering a range of fundamental biological questions. We report a rationally designed probe with a 6'-fluoro spiropyran scaffold (5) for the reversible sensing of zinc (Zn2+) in cells. The 6'-fluoro substituent overcomes several limitations normally associated with spiropyran based sensors to provide an improved signal-to-background ratio and faster photoswitching times in aqueous solution. In vitro studies were performed with 5 and the 6'-nitro analogues (6) in HEK 293 and endothelial cells. The new spiropyran (5) can detect exogenous Zn2+ inside both cell types and without affecting the proliferation of endothelial cells. Studies were also performed on dying HEK 293 cells, with results demonstrating the ability of the key compound to detect endogenous Zn2+ efflux from cells undergoing apoptosis. Biocompatibility and photoswitching of 5 were demonstrated within endothelial cells but not with 6, suggesting the future applicability of sensor 5 to study intracellular Zn2+ efflux in these systems. PMID- 30023766 TI - Total Synthesis of Desmethyl Jahanyne and Its Lipo-Tetrapeptide Conjugates Derived from Parent Skeleton as BCL-2-Mediated Apoptosis-Inducing Agents. AB - The total synthesis of highly potent and scarcely available marine natural product (-)-jahanyne was attempted resulting in a solution-phase synthesis of pruned versions with comparable activity. A simple and facile synthetic route was employed for the preparation of pruned congeners and would be scalable. The lipophilic tail of the natural product was synthesized from R-(+)-citronellol, utilizing easily available chemicals. All the synthesized compounds were screened for apoptotic activity against a panel of cell lines. These compounds depicted marked binding to B cell lymphoma 2 till 50 degrees C in cellular thermal shift analysis. PMID- 30023767 TI - Biocompatible Chitosan-Functionalized Upconverting Nanocomposites. AB - Simultaneous integration of photon emission and biocompatibility into nanoparticles is an interesting strategy to develop applications of advanced optical materials. In this work, we present the synthesis of biocompatible optical nanocomposites from the combination of near-infrared luminescent lanthanide nanoparticles and water-soluble chitosan. NaYF4:Yb,Er upconverting nanocrystal guests and water-soluble chitosan hosts are prepared and integrated together into biofunctional optical composites. The control of aqueous dissolution, gelation, assembly, and drying of NaYF4:Yb,Er nanocolloids and chitosan liquids allowed us to design novel optical structures of spongelike aerogels and beadlike microspheres. Well-defined shape and near-infrared response lead upconverting nanocrystals to serve as photon converters to couple with plasmonic gold (Au) nanoparticles. Biocompatible chitosan-stabilized Au/NaYF4:Yb,Er nanocomposites are prepared to show their potential use in biomedicine as we find them exhibiting a half-maximal effective concentration (EC50) of 0.58 mg mL-1 for chitosan-stabilized Au/NaYF4:Yb,Er nanorods versus 0.24 mg mL-1 for chitosan-stabilized NaYF4:Yb,Er after 24 h. As a result of their low cytotoxicity and upconverting response, these novel materials hold promise to be interesting for biomedicine, analytical sensing, and other applications. PMID- 30023768 TI - Small Naked Pt Nanoparticles Confined in Mesoporous Shell of Hollow Carbon Spheres for High-Performance Nonenzymatic Sensing of H2O2 and Glucose. AB - Nonenzyme direct electrochemical sensing of hydrogen peroxide and glucose by highly active nanomaterial-modified electrode has attracted considerable attention. Among the reported electrochemical sensing materials, hollow carbon sphere (HCS) is an attractive carbon support because of its large specific surface area, porous structure, and easy accessibility for target molecules. In this study, naked Pt nanoparticles with average size of 3.13 nm are confined in mesoporous shells of hollow carbon spheres (Pt/HCS) by using one-step synthesis, which can not only produce highly dispersed Pt nanoparticles with clean surface, but also avoid the relatively slow impregnation-reduction process. The surface area of the obtained Pt/HCS (566.30 m2 g-1) is larger than that of HCS, attributing to the enlarged surface area after Pt nanoparticles deposition. The average pore width of Pt/HCS (3.33 nm) is smaller than that of HCS (3.84 nm), indicating the filling of Pt nanoparticles in the mesopores of carbon shells. By using the as-synthesized Pt/HCS as nonenzymatic sensing material, H2O2 and glucose can be detected with high sensitivity and selectivity. The linear range toward H2O2 sensing is from 0.3 to 2338 MUM, and the limit of detection (LOD) is 0.1 MUM. For glucose sensing, Pt/HCS exhibited two linear ranges from 0.3 to 10 mM and from 10 to 50 mM with an LOD of 0.1 mM. In addition, the Pt/HCS exhibited higher electrochemical stability than commercial Pt/C in acid solution. The present study demonstrates that Pt/HCS is a promising sensing material for electrochemical detection of both H2O2 and glucose. PMID- 30023769 TI - X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design. AB - Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the strongest evidence for true multitarget activity of small molecules would be provided by experimentally determined structures of ligand-target complexes. Therefore, we have carried out a systematic search of currently available X-ray structures for compounds forming complexes with different targets. Rather unexpectedly, 1418 such crystallographic ligands were identified, including 702 that formed complexes with targets from different protein families (multifamily ligands). About half of these multifamily ligands originated from the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. From 168 distinct series of analogues containing one or more multifamily ligands, 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity. As a part of our study, all of the multifamily ligands we have identified and the analogue-series based scaffolds are made freely available. PMID- 30023770 TI - Metallofluorescent Nanoparticles for Multimodal Applications. AB - Herein, we describe the synthesis and application of cross-linked polystyrene based dual-function nano- and microparticles containing both fluorescent tags and metals. Despite containing a single dye, these particles exhibit a characteristic dual-band fluorescence emission. Moreover, these particles can be combined with different metal ions to obtain hybrid metallofluorescent particles. We demonstrate that these particles are easily nanofected into living cells, allowing them to be used for effective fingerprinting in multimodal fluorescence based and mass spectrometry-based flow cytometry experiments. Likewise, the in situ reductions of the metal ions enable other potential uses of the particles as heterogeneous catalysts. PMID- 30023771 TI - Ophiosphaerellins A-I, Polyketide-Derived Compounds from the Endolichenic Fungus Ophiosphaerella korrae. AB - Ophiosphaerellins A-I (1-9), the first example of bicyclo[4.1.0]heptenones, as well as their biosynthetic relatives ophiosphaerekorrins A-B (10-11) were isolated from the endolichenic fungus Ophiosphaerella korrae. Biosynthetically, they were derived from the polyketide pathway, and their absolute configurations were determined on the basis of the combination analysis of spectral data, circular dichroism calculations, and single-crystal X-ray diffraction measurement. Preliminary test with thin-layer chromatography bioautography found that this type of compounds showed moderate acetylcholinesterase (AChE) inhibitory effects. PMID- 30023772 TI - Multidisciplinary Approach to the Transfection of Plasmid DNA by a Nonviral Nanocarrier Based on a Gemini-Bolaamphiphilic Hybrid Lipid. AB - A multidisciplinary strategy, including both biochemical and biophysical studies, was proposed here to evaluate the potential of lipid nanoaggregates consisting of a mixture of a gemini-bolaamphiphilic lipid (C6C22C6) and the well-known helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) to transfect plasmid DNA into living cells in an efficient and safe way. For that purpose, several experimental techniques were employed, such as zeta potential (phase analysis light scattering methodology), agarose gel electrophoresis (pDNA compaction and pDNA protection assays), small-angle X-ray scattering, cryo transmission electron microscopy, atomic force microscopy, fluorescence-assisted cell sorting, luminometry, and cytotoxicity assays. The results revealed that the cationic lipid and plasmid offer only 70 and 30% of their nominal positive () and negative charges (), respectively. Upon mixing with DOPE, they form lipoplexes that self-aggregate in typical multilamellar Lalpha lyotropic liquid-crystal nanostructures with sizes in the range of 100-200 nm and low polydispersities, very suitably fitted to remain in the bloodstream and cross the cell membrane. Interestingly, these nanoaggregates were able to compact, protect (from the degrading effect of DNase I), and transfect two DNA plasmids (pEGFP-C3, encoding the green fluorescent protein, and pCMV-Luc, encoding luciferase) into COS-7 cells, with an efficiency equal or even superior to that of the universal control Lipo2000*, as long as the effective +/- charge ratio was maintained higher than 1 but reasonably close to electroneutrality. Moreover, this transfection process was not cytotoxic because the viability of COS-7 cells remained at high levels, greater than 80%. All of these features make the C6C22C6/DOPE nanosystem an optimal nonviral gene nanocarrier in vitro and a potentially interesting candidate for future in vivo experiments. PMID- 30023773 TI - Silica-Calix Hybrid Composite of Allyl Calix[4]arene Covalently Linked to MCM-41 Nanoparticles for Sustained Release of Doxorubicin into Cancer Cells. AB - An inorganic-organic hybrid material, MCM-allylCalix, was synthesized by covalent modification of an MCM-41 surface with a tetra-allyl calixarene conjugate. The synthesized hybrid was characterized by 13C and 29Si MAS-NMR, Fourier transform infrared (FT-IR), Brunauer-Emmett-Teller surface area, thermogravimetric analysis (TGA), and transmission electron microscopy (TEM) analyses. The application of this MCM-allylCalix hybrid has been demonstrated for loading and in vitro release of doxorubicin (Dox) in phosphate-buffered saline (PBS) buffer as well as in the cancer cells, viz., MCF7, HeLa, and MDA-MB231. The Dox-loaded hybrid, MCM allylCalix-Dox, was characterized by TEM, FT-IR, TGA, N2 sorption, diffuse refectance spectroscopy-UV, and fluorescence microscopy to confirm the presence of the drug. The release study of the drug from MCM-allylCalix-Dox was carried out in PBS buffer at pH 5 and 7.4. The results showed ~140% increase in the release of Dox at pH 5 compared to that at pH 7.4 in 144 h, suggesting a pH triggered release of the drug. MCM-allylCalix-Dox releases a greater amount of Dox compared to that released from unmodified MCM-Dox. Cytotoxicity studies suggested that MCM-allylCalix-Dox exhibits anticancer activity that is dependent on the nature of the cell. The Dox-loaded hybrid shows more cytotoxicity for MCF7 compared to that for the HeLa and MDA-MB231 cells. This was further supported by ~120% more internalization of Dox into MCF7 cells compared to that in the other two cell lines. Both fluorescence microscopy and fluorescence-activated cell sorting studies suggested concentration-dependent internalization of Dox into the MCF7 and HeLa cells. The results suggested that the inorganic-organic hybrid can be useful in sustained drug delivery into cancer cells. PMID- 30023774 TI - Pyridinium-Functionalized Pyromellitic Diimides with Stabilized Radical Anion States. AB - In this work, we report the stabilization of the reduced states of pyromellitic diimide by charge-balancing the imide radical anions with cationic pyridinium groups attached to the aromatic core. This structural modification is confirmed by single-crystal X-ray diffraction analysis. Characterization by (spectro)electrochemical experiments and computations reveal that the addition of cationic groups to an already electron-deficient ring system results in up to +0.57 V shifts in reduction potentials, largely as a consequence of charge screening and lowest unoccupied molecular orbital-lowering effects. This formal charge-balancing approach to stabilizing the reduced states of electron-deficient pyromellitic diimides will facilitate their incorporation into spin-based optoelectronic materials and devices. PMID- 30023775 TI - Simultaneous Binding of Folic Acid and Methotrexate to Human Serum Albumin: Insights into the Structural Changes of Protein and the Location and Competitive Displacement of Drugs. AB - Protein structure can be flexible to adopt multiple conformations to house small molecules. In this paper, we have attempted to experimentally figure out how the structure of a transport protein steer the drug-drug competition (DDC) by maintaining the equilibrium distribution of the bound and unbound fractions of drugs. This understanding is an important facet in biophysical and medicinal chemistry to ascertain the effectiveness of drugs. It is important to note that majority of studies involving small-molecule-transport protein interaction aimed at characterizing the binding process, and because these proteins can interact with thousands of molecules, there are hundreds of reports on such interactions. This ultimately led to an impression among the readers that any studies involving serum albumin may not lead to any new findings except for traditional binding explorations. However, in the present paper, we would like to draw the attention of the readers that our findings are very surprising, new, and important, involving the phenomenon of ligand-protein interaction. Here, we have studied two structurally similar drugs methotrexate (MTX) and folic acid (FA), which attempt to bind the primary binding site (subdomain IIA), one at a time, of human serum albumin. Details of binding analyses reveal that when both of the drugs are present, the single-site binding mode of FA prefers to occupy the primary binding site and hence pushes the primary-site-bound MTX to another location (subdomain IIIA), which is the second binding site of MTX. The structural analysis indicates that DDC has occurred in a cooperative fashion so that the loss of the protein secondary structure is minimum when both drugs are bound to the protein, which means that in the case of duo-drug binding, the conventional interaction between the drug and the protein is altered to undergo restoration of the protein structure. This can indeed regulate the DDC by modifying the bound and unbound fractions of MTX in plasma. The present study emphasizes that in vitro structural characterizations of the transport protein provide important information to improve the molecular-level understanding of DDC for further therapeutic applications with combination drug. PMID- 30023776 TI - How Well Can DNA Rupture DNA? Shearing and Unzipping Forces inside DNA Nanostructures. AB - A purely DNA nanomachine must support internal stresses across short DNA segments with finite rigidity, producing effects that can be qualitatively very different from experimental observations of isolated DNA in fixed-force ensembles. In this article, computational simulations are used to study how well the rigidity of a driving DNA duplex can rupture a double-stranded DNA target into single-stranded segments and how well this stress can discriminate between unzipping or shearing geometries. This discrimination is found to be maximized at an optimal length but deteriorates as the driving duplex is either lengthened or shortened. This differs markedly from a fixed-force ensemble and has implications for the design parameters and limitations of dynamic DNA nanomachines. PMID- 30023777 TI - Hydration of the Carboxylate Group in Anti-Inflammatory Drugs: ATR-IR and Computational Studies of Aqueous Solution of Sodium Diclofenac. AB - Diclofenac (active ingredient of Voltaren) has a significant, multifaceted role in medicine, pharmacy, and biochemistry. Its physical properties and impact on biomolecular structures still attract essential scientific interest. However, its interaction with water has not been described yet at the molecular level. In the present study, we shed light on the interaction between the steric hindrance (the intramolecular N-H...O bond, etc.) carboxylate group (-CO2-) with water. Aqueous solution of sodium declofenac is investigated using attenuated total reflection infrared (ATR-IR) and computational approaches, i.e., classical molecular dynamics (MD) simulations and density functional theory (DFT). Our coupled classical MD simulations, DFT calculations, and ATR-IR spectroscopy results indicated that the -CO2- group of the diclofenac anion undergoes strong specific interactions with the water molecules. The combined experimental and theoretical techniques provide significant insights into the spectroscopic manifestation of these interactions and the structure of the hydration shell of the -CO2- group. Moreover, the developed methodology for the theoretical analysis of the ATR-IR spectrum could serve as a template for the future IR/Raman studies of the strong interaction between the steric hindrance -CO2- group of bioactive molecules with the water molecules in dilute aqueous solutions. PMID- 30023778 TI - Fluorescent Small Molecules Are BIG Enough To Sense Biomacromolecule: Synthesis of Aromatic Thioesters and Understanding Their Interactions with ctDNA. AB - The visible fluorescent chromophoric moiety present in the water-soluble photoactive yellow protein (PYP) of Ectothiorhodospira halophila is p hydroxycinnamic acid linked to the cysteine residue (Cys-69) by a thioester bond and it controls the key photoinduced biological processes of the host organism. In the present work, we have synthesized and characterized three structurally different thiophenyl esters [viz., p-hydroxycinnamic-thiophenyl ester (1), p-N,N dimethylaminocinnamic-thiophenyl ester (2), and S-phenyl-3-(4-chlorophenyl)-3 (phenylthio)propanethioate (3)] in addition to a novel (to the best of our knowledge) stilbene-type olefinic compound, N1,N1,N2,N2-tetramethyl-1,2 bis(phenylthio)ethene-1,2-diamine (4), under the same reaction condition. All of these four compounds showed characteristic and distinguishable chromophoric/fluorophoric behavior in ethanol and also at pH 7.4. However, we have observed that the intrinsic chromophoric/fluorophoric activities of (1) and (2) were greatly influenced during their interactions with calf-thymus DNA, studied by a range of spectroscopic and physicochemical measurements. We have also applied density functional theory [B3LYP, 6-311G+(d,p)]-based method to get optimized structures of (1) and (2), which were explored further for molecular docking studies to understand their mode of interaction with DNA. The present study opens up their possible applications as fluorescence probes for biomacromolecules like DNA in future. PMID- 30023779 TI - Validation of Smart Nanoparticles as Controlled Drug Delivery Systems: Loading and pH-Dependent Release of Pilocarpine. AB - Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%-DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH. PMID- 30023780 TI - Improving Antibacterial Activity and Biocompatibility of Bioinspired Electrospinning Silk Fibroin Nanofibers Modified by Graphene Oxide. AB - In this article, the silk fibroin (SF)/graphene oxide (GO)-blended nanofibers with one bioinspired nanostructure are fabricated via electrospinning. The morphology, chemical structure, antibacterial activity, and biocompatibility of the blending nanofibers are investigated. The results indicate that GO plays an important role in preparing the distinctive bioinspired structure. The antibacterial activity and in vivo cell culture test demonstrate that blending of GO could improve the antibacterial activity and biocompatibility of SF nanofibers. The blended nanofibers developed in this study may have considerable potential for wound dressing applications. PMID- 30023781 TI - Copper-Coated Cellulose-Based Water Filters for Virus Retention. AB - Despite recent efforts in modernization of water treatment facilities, the problem of access to healthy drinking water for hundreds of millions of people has still not been solved. A water filter based on Cu-coated nanofibrillated cellulose with controlled porosity was prepared by the "paper-making" method. We have optimized the proper mass and ratio of functionalized and pure nanofibrillated cellulose for the preparation of the filter. MS2 bacteriophages were used to model human pathogenic virions. We tested our filter material in batch experiments and the fixed filters in flow experiments. The fabricated Cu coated nanofibrillated cellulose filters were characterized by scanning electron microscopy, X-ray diffraction, specific surface area measurement (Brunauer-Emmett Teller), dynamic light scattering, and inductively coupled plasma mass spectroscopy. Our measurements proved that the fixation of cellulose nanofibers plays a significant role in the degree of virus retention and it greatly enhances the efficiency of the filtration. By using these functionalized water filters, we were able to achieve a virus retention of at least 5 magnitudes (5Log) at three different pH values: 5.0, 7.5, and 9. PMID- 30023782 TI - Porous Polymer Bearing Polyphenolic Organic Building Units as a Chemotherapeutic Agent for Cancer Treatment. AB - Cancer is one of the most deadly diseases worldwide. Although several chemotherapeutic agents are available at present for its treatment, they have their own limitations. The main problems of these chemotherapeutic agents are cost involvement and severe life-threatening antagonistic effects. Here, we report a new biodegradable N-rich porous organic polymer methylenedianiline triformyl phloroglucinol (MDTFP-1) synthesized via a Schiff base condensation reaction between two reactive monomers, that is, 4,4'-methylenedianiline and 2,4,6-triformyl phloroglucinol under inert atmosphere. Because this porous polymer contains polyphenolic building units and has a high Brunauer-Emmett Teller surface area (283 m2 g-1), it has been explored in the anticancer activity using HCT 116, A549, and MIA PaCa-2 cell lines. We have carried out the flow cytometric assessment using Annexin-V-FITC/PI staining through the exposed level of phosphatidylserine in the outer membrane of cells with MDTFP-1-induced apoptosis. Our results suggested that apoptosis of cells have been enhanced in a time-dependent manner in the presence of this novel porous polymer. PMID- 30023784 TI - Noninvasive Stimulation of Neurotypic Cells Using Persistent Photoconductivity of Gallium Nitride. AB - The persistent photoconductivity (PPC) of the n-type Ga-polar GaN was used to stimulate PC12 cells noninvasively. Analysis of the III-V semiconductor material by atomic force microscopy, Kelvin probe force microscopy, photoconductivity, and X-ray photoelectron spectroscopy quantified bulk and surface charge, as well as chemical composition before and after exposure to UV light and cell culture media. The semiconductor surface was made photoconductive by illumination with UV light and experienced PPC, which was utilized to stimulate PC12 cells in vitro. Stimulation was confirmed by measuring the changes in intracellular calcium concentration. Control experiments with gallium salt verified the stimulation of neurotypic cells. Inductively coupled plasma mass spectrometry data confirmed the lack of gallium leaching and toxic effects during the stimulation. PMID- 30023783 TI - Autonomous Synthesis of Fluorescent Silica Biodots Using Engineered Fusion Proteins. AB - Formation of biological materials is a well-controlled process that is orchestrated by biomolecules such as proteins. Proteins can control the nucleation and mineralization of biomaterials, thereby forming the hard tissues of biological organisms, such as bones, teeth, and shells. In this study, the design and implementation of multifunctional designer proteins are demonstrated for fluorescent silica micro/nanoparticle synthesis. The R5 motif of silaffin polypeptide, which is known for its silicification capability, was fused genetically into three spectrally distinct fluorescent proteins with the intention of forming modified fluorescent proteins. The bifunctional R5 peptide domain served as a tag to provide silica synthesis at ambient conditions. Three functional fusion constructs have been prepared, including GFPmut3-R5, Venus YFP R5, and mCherry-R5. Recombinant fluorescent proteins were purified using silica binding peptide tag through silica gel resin. Purified proteins were tested for their binding affinity to silica using quartz crystal microbalance with dissipation monitoring to make sure they can interact strong enough with the silica surfaces. Later, engineered fluorescent proteins were used to synthesize silica nano/microparticles using silica precursor materials. Synthesized silica particles were investigated for their fluorescence properties, including time resolved fluorescence. Additionally, elemental analysis of the particles was carried out using electron energy loss spectroscopy and energy-filtered transmission electron microscopy. Last, they were tested for their biocompatibility. In this study, we aimed to provide a biomimetic route to synthesize fluorescent silica nanoparticles. Recombinant fluorescent proteins directed silica nanoparticles synthesis offers a one-step, reliable method to produce fluorescent particles both for biomaterial applications and other nanotechnology applications. PMID- 30023785 TI - Effect of Carbon Nanotubes on Direct Electron Transfer and Electrocatalytic Activity of Immobilized Glucose Oxidase. AB - Carbon nanotubes (CNTs) are excellent supports for electrocatalysts because of their large surface area, excellent electronic conductivity, and high chemical and structural stability. In the present study, the activity of CNTs on direct electron transfer (DET) and on immobilized glucose oxidase (GOX) is studied as a function of number of walls of CNTs. The results indicate that the GOX immobilized by the CNTs maintains its electrocatalytic activity toward glucose; however, the DET and electrocatalytic activity of GOX depend strongly on the number of inner tubes of CNTs. The GOX immobilized on triple-walled CNTs (TWNTs) has the highest electron-transfer rate constant, 1.22 s-1, for DET, the highest sensitivity toward glucose detection, 66.11 +/- 5.06 MUA mM-1 cm-2, and the lowest apparent Michaelis-Menten constant, 6.53 +/- 0.58 mM, as compared to GOX immobilized on single-walled and multiwalled CNTs. The promotion effect of CNTs on the GOX electrocatalytic activity and DET is most likely due to the electron tunneling effect between the outer wall and inner tubes of TWNTs. The results of this study have general implications for the fundamental understanding of the role of CNT supports in DET processes and can be used for the better design of more effective electrocatalysts for biological processes including biofuel cells and biosensors. PMID- 30023786 TI - Carboxylate Functional Groups Mediate Interaction with Silver Nanoparticles in Biofilm Matrix. AB - Biofilms causing medical conditions or interfering with technical applications can prove undesirably resistant to silver nanoparticle (AgNP)-based antimicrobial treatment, whereas beneficial biofilms may be adversely affected by the released silver nanoparticles. Isolated biofilm matrices can induce reduction of silver ions and stabilization of the formed nanosilver, thus altering the exposure conditions. We thus study the reduction of silver nitrate solution in model experiments under chemically defined conditions as well as in stream biofilms. Formed silver nanoparticles are characterized by state-of-the art methods. We find that isolated biopolymer fractions of biofilm organic matrix are capable of reducing ionic Ag, whereas other isolated fractions are not, meaning that biopolymer fractions contain both reducing agent and nucleation seed sites. In all of the investigated systems, we find that silver nanoparticle-biopolymer interface is dominated by carboxylate functional groups. This suggests that the mechanism of nanoparticle formation is of general nature. Moreover, we find that glucose concentration within the biofilm organic matrix correlates strongly with the nanoparticle formation rate. We propose a simple mechanistic explanation based on earlier literature and the experimental findings. The observed generality of the extracellular polymeric substance/AgNP system could be used to improve the understanding of impact of Ag+ on aqueous ecosystems, and consequently, to develop biofilm-specific medicines and bio-inspired water decontaminants. PMID- 30023787 TI - Impact of Anions on the Partition Constant, Self-Diffusion, Thermal Stability, and Toxicity of Dicationic Ionic Liquids. AB - Partition constants (KD degrees ), molecular dynamics (T1, T2, and DOSY measurements), thermal stability, and toxicity of dicationic ionic liquids (ILs) were determined. The dicationic ILs derived from 1,n-bis(3-methylimidazolim-1 yl)octane, [BisOct(MIM)2][2X] (in which X = Cl, Br, NO3, SCN, BF4, and NTf2), were evaluated to verify the influence of anion structure on the IL properties. A monocationic IL [Oct(MIM)][Br] was also monitored for comparison. In general, the solubility of the ILs followed the anion free energy of hydration (DeltaG degrees hyd). The thermokinetic and thermodynamic functions of activation of the ILs were determined via thermogravimetric data, and it was observed that polyatomic anions influence the decomposition mechanism of these IL structures. Furthermore, [Oct(MIM)][Br] had a decomposition rate greater than that of the dicationic analogue, and the thermodynamic parameters of activation data corroborate these results. Finally, the dicationic ILs did not indicate toxic effects (LD50 > 40 mM). PMID- 30023788 TI - Facile Chemoselective Strategy toward Capturing Sphingoid Bases by a Unique Glutaraldehyde-Functionalized Resin. AB - Sphingoid bases, which have a 2-amino-1,3-diol common functional group, are the structural backbone units of all sphingolipids. Recently, much attention has been focused on sphingoid bases because of their potentially beneficial bioactivities toward various cancer cells as well as their dietary interest. However, low abundance and the handling complexity caused by their amphiphilic character led to very limited research on them. Glutaraldehyde has two aldehyde groups, and it reacts rapidly with the 2-amino-1,3-diol functional group of sphingosine to give a tricyclic product. Immobilization of glutaraldehyde on a resin was successfully performed by organic synthesis, starting from trans-p-coumaric acid via eight steps. This approach suppresses the self-polymerization of glutaraldehyde, and addition of water to the developed resin causes the formation of cyclic double hemiacetal function, which avoids oxidation like a reducing sugar in nature and makes it stable even for up to 1 year incubation. The resin was applied to the solid-phase extracting experiment of free sphingosine from human serum at a concentration of 280 nM. Another extraction study of edible golden oyster mushrooms showed that the sphingoid base was selectively captured from complex natural extracts. These results demonstrate that the developed glutaraldehyde resin method is a highly selective method, and hence, the combination of it with the o-phthaldialdehyde HPLC method was confirmed as an efficient and sensitive method for analysis of sphingoid bases in biological samples. PMID- 30023789 TI - Leucine-Based Polymer Architecture-Induced Antimicrobial Properties and Bacterial Cell Morphology Switching. AB - To evaluate the comparative antibacterial activity of leucine-based cationic polymers having linear, hyperbranched, and star architectures containing both hydrophilic and hydrophobic segments against Gram-negative bacterium, Escherichia coli (E. coli), herein we performed zone of inhibition study, minimum inhibitory concentration (MIC) calculation, and bacterial growth experiment. The highest antibacterial activity in terms of the MIC value was found in hyperbranched and star architectures because of the greater extent of cationic and hydrophobic functionality, enhancing cell wall penetration ability compared to that of the linear polymer. The absence of the bacterial regrowth stage in the growth curve exhibited the highest bactericidal capacity of star polymers, when untreated cells (control) already reached to the stationary phase, whereas the bacterial regrowth stage with a delayed lag phase was critically observed for linear and hyperbranched architectures displaying lower bactericidal efficacy. Coagulation of E. coli cells, switching of cell morphology from rod to sphere, and lengthening due to stacking in an antimicrobial polymer-treated environment at the bacterial regrowth stage in liquid media were visualized critically by field emission scanning electron microscopy and confocal fluorescence microscopy instruments in the presence of 4',6-diamidino-2-phenylindole stain. PMID- 30023790 TI - Facile and Green Synthesis of Multicolor Fluorescence Carbon Dots from Curcumin: In Vitro and in Vivo Bioimaging and Other Applications. AB - Early detection is the critical phase in the prognostic strategy of various life threatening maladies like infectious diseases and cancer. The mortality rate caused by these diseases could be considerably reduced if they were diagnosed in the early stages of disease development. Carbon dots (C-dots), a relatively new and promising candidate in the fluorescent nanomaterial category, possess a perceptible impact on various bioapplications. Herein, we report a one-step facile hydrothermal synthesis that yields a novel surface-passivated carbon dot (CDP) from curcumin (as a green substrate) displaying high aqueous solubility. The physico-chemical characterization of thus synthesized C-dots was accomplished by an UV-visible spectrophotometer, fluorescence spectrophotometer, zetasizer, TEM, and FE-SEM to understand the formation of carbon dots with a 4-5 nm size near spherical nanoparticle with high colloidal stability. E. coli DH5alpha was engaged as the Gram-negative test organism and S. aureus as the Gram-positive in the biolabeling of bacteria. Cancer cell lines including colon cancer (HCT-15), lung cancer (A549), and mouse fibroblast (NIH 3T3) were evaluated and resulted in good biolabeling potential and less cytotoxicity. Zebrafish (ASWT) embryos as an animal model system were bioimaged, and in vivo toxicity was inferred. Moreover, the synthesized C-dots were shown to have free radical scavenging activity in a dose-dependent manner. The unpassivated C-dots (CD) were found to sense ferric ions at the micromolar concentration level. The findings of our study suggest that the multifunctional potentiality of CDPs serves as high-performance optical nanoprobes and can be a suitable alternative for various biolabeling and contrasting agents. PMID- 30023792 TI - New 1,2-Dihydropyridine-Based Fluorophores and Their Applications as Fluorescent Probes. AB - New 1,2-dihydropyridine (1,2-DHP)-based fluorophores 1a-1h were designed and synthesized by a one-pot four-component condensation reaction using dienaminodioate, aldehydes, and an in situ-generated hydrazone mediated by trifluoroacetic acid. The photophysical properties of 1,2-DHPs were studied in detail, and a few of them exhibited selective mitochondrial staining ability in HeLa cell lines (cervical cancer cells). A detailed photophysical investigation led to the design of 1,2-DHP 1h as an optimal fluorophore suitable for its potential application as a small molecule probe in the aqueous medium. Also, 1,2 DHP 1h exhibited sixfold enhanced emission intensity than its phosphorylated analogue 1h' in the long wavelength region (lambdaem ~ 600 nm), which makes 1,2 DHP 1h' meet the requirement as a bioprobe for protein tyrosine phosphatases, shown in L6 muscle cell lysate. PMID- 30023791 TI - Stability of the Na+ Form of the Human Telomeric G-Quadruplex: Role of Adenines in Stabilizing G-Quadruplex Structure. AB - G-quadruplexes are higher order DNA structures that play significant roles in gene transcription and telomeric maintenance. The formation and stability of the G-quadruplex structures are under thermodynamic control and may be of biological significance for regulatory function of cellular processes. Here, we report the structural influence and energetic contributions of the adenine bases in the loop sequences that flank G-repeats in human telomeric DNA sequence. Spectroscopic and calorimetric techniques are used to measure the thermal stability and thermodynamic contributions to the stability of human telomeric G-quadruplexes that have been designed with systematic changes of A to T throughout the telomeric sequence. These studies demonstrate that the thermal stability of the G quadruplex structure is directly related to the number and position of the adenines that are present in the telomeric sequence. The melting temperature (Tm) was reduced from 59 degrees C for the wild-type sequence to 47 degrees C for the sequence where all four adenines were replaced with thymines (0123TTT). Furthermore, the enthalpy required for transitioning from the folded to unfolded G-quadruplex structure was reduced by 15 kcal/mol when the adenines were replaced with thymines (37 kcal/mol for the wild-type telomeric sequence reduced to 22 kcal/mol for the sequence where all four adenines were replaced with thymines (0123TTT)). The circular dichroism melting studies for G-quadruplex sequences having a single A to T change showed significantly sloping pretransition baselines and their differential scanning calorimetry (DSC) thermograms revealed biphasic melting profiles. In contrast, the deoxyoligonucleotides having sequences with two or more A to T changes did not exhibit sloping baselines or biphasic DSC thermograms. We attribute the biphasic unfolding profile and reduction in the enthalpy of unfolding to the energetic contributions of adenine hydrogen bonding within the loops as well as the adenine stacking to the G tetrads of the G-quadruplex structure. PMID- 30023793 TI - Predicting Ligand-Free Cell Attachment on Next-Generation Cellulose-Chitosan Hydrogels. AB - There is a growing appreciation that engineered biointerfaces can regulate cell behaviors, or functions. Most systems aim to mimic the cell-friendly extracellular matrix environment and incorporate protein ligands; however, the understanding of how a ligand-free system can achieve this is limited. Cell scaffold materials comprised of interfused chitosan-cellulose hydrogels promote cell attachment in ligand-free systems, and we demonstrate the role of cellulose molecular weight, MW, and chitosan content and MW in controlling material properties and thus regulating cell attachment. Semi-interpenetrating network (SIPN) gels, generated from cellulose/ionic liquid/cosolvent solutions, using chitosan solutions as phase inversion solvents, were stable and obviated the need for chemical coupling. Interface properties, including surface zeta-potential, dielectric constant, surface roughness, and shear modulus, were modified by varying the chitosan degree of polymerization and solution concentration, as well as the source of cellulose, creating a family of cellulose-chitosan SIPN materials. These features, in turn, affect cell attachment onto the hydrogels and the utility of this ligand-free approach is extended by forecasting cell attachment using regression modeling to isolate the effects of individual parameters in an initially complex system. We demonstrate that increasing the charge density, and/or shear modulus, of the hydrogel results in increased cell attachment. PMID- 30023794 TI - pH-Responsive Charge-Conversional and Hemolytic Activities of Magnetic Nanocomposite Particles for Cell-Targeted Hyperthermia. AB - Magnetic nanocomposite particle (MNP)-induced hyperthermia therapy has been restricted by inefficient cellular targeting. pH-responsive charge-conversional MNPs can enhance selective cellular uptake in acidic cells like tumors by sensing extracellular acidity based on their charge alteration. We have synthesized new, pH-induced charge-conversional, superparamagnetic, and single-cored Fe3O4 nanocomposite particles coated by N-itaconylated chitosan (NICS) cross-linked with ethylene glycol diglycidyl ether (EGDE) (Fe3O4-NICS-EGDE) using a simple, one-step chemical coprecipitation-coating process. The surface of the Fe3O4-NICS EGDE nanocomposite particles was modified with ethanolamine (EA) via aza-Michael addition to enhance their buffering capacity, aqueous stability, and pH sensitivity. The designed Fe3O4-NICS-EGDE-EA nanocomposite particles showed pH dependent charge-conversional properties, colloidal stability, and excellent hemocompatibility in physiological media. By contrast, the charge-conversional properties enabled microwave-induced hemolysis only under weakly acidic conditions. Therefore, the composite particles are highly feasible for magnetically induced and targeted cellular thermotherapeutic applications. PMID- 30023795 TI - Multifunctional Bismuth Oxychloride/Mesoporous Silica Composites for Photocatalysis, Antibacterial Test, and Simultaneous Stripping Analysis of Heavy Metals. AB - The increasing complexity of environmental pollution nowadays poses a severe threat to the public health, which attracts considerable attentions in searching for nanomaterials of multiproperty. In this study, mesoporous silica of KIT-6 encapsulated bismuth oxychloride (BiOCl), an intrinsically multifunctional material exhibiting bunched structure in the composites, are facilely prepared under hydrothermal conditions. Subsequently, the produced materials of multifunctionality were applied for photocatalysis, antibacterial test, and simultaneous determination of heavy metals including lead and cadmium. A combination of physiochemical characterizations have revealed that the BiOCl-KIT 6 composites exhibit enlarged yet refined surface morphology contributing to the improved photocatalytic ability with a band gap of 3.06 eV at a molecular ratio of 8Bi-Si. Moreover, the antibacterial activities of our BiOCl-KIT-6 composites were explored, and possible antimicrobial mechanism related to the production of reactive oxygen species was discussed. Furthermore, a sensitive electrochemical determination of heavy metals of lead and cadmium using square-wave anodic stripping voltammetry was also achieved. The composites-modified glassy carbon electrode displays a linear range of calibration curve from 0.2 to 300 MUg/L with a detection limit of 0.05 MUg/L (Pb2+) and 0.06 MUg/L (Cd2+), respectively. PMID- 30023796 TI - Small-Molecule Ligands as Potential GDNF Family Receptor Agonists. AB - To find out potential GDNF family receptor alpha1 (GFRalpha1) agonists, small molecules were built up by molecular fragments according to the structure-based drug design approach. Molecular docking was used to identify their binding modes to the biological target GFRalpha1 in GDNF-binding pocket. Thereafter, commercially available compounds based on the best predicted structures were searched from ZINC and MolPort databases (similarity >= 80%). Five compounds from the ZINC library were tested in phosphorylation and luciferase assays to study their ability to activate GFRalpha1-RET. A bidental compound with two carboxyl groups showed the highest activity in molecular modeling and biological studies. However, the relative position of these groups was important. The meta substituted structure otherwise identical to the most active compound 2-[4-(5 carboxy-1H-1,3-benzodiazol-2-yl)phenyl]-1H-1,3-benzodiazole-5-carboxylic acid was inactive. A weaker activity was detected for a compound with a single carboxyl group, that is, 4-(1,3-benzoxazol-2-yl)benzoic acid. The substitution of the carboxyl group by the amino or acetamido group also led to the loss of the activity. PMID- 30023797 TI - Reduction of Feedback Inhibition in Homoserine Kinase (ThrB) of Corynebacterium glutamicum Enhances l-Threonine Biosynthesis. AB - l-Threonine is an important supplement in the food industry. It is currently produced through fermentation of Escherichia coli but requires additional purification steps to remove E. coli endotoxin. To avoid these steps, it is desirable to use Corynebacterium glutamicum, a microorganism generally regarded as safe. Engineering of C. glutamicum to increase production of l-threonine has mainly focused on gene regulation as well as l-threonine export or carbon flux depletion. In this study, we focus on the negative feedback inhibition produced by l-threonine on the enzyme homoserine kinase (ThrB). Although l-threonine binds to allosteric sites of aspartate kinase (LysC) and homoserine dehydrogenase (Hom), serving as a noncompetitive inhibitor, it acts as a competitive inhibitor on ThrB. This is problematic when attempting to engineer enzymes that are nonresponsive to increasing cellular concentrations of l-threonine. Using primary structure alignment as well as analysis of the Methanocaldococcus jannaschii ThrB (MjaThrB) active site in complex with l-threonine (inhibitor of ThrB) and l homoserine (substrate of ThrB), a conserved active-site alanine residue (A20) in C. glutamicum ThrB (CglThrB) was predicted to be important for differential interactions with l-threonine and l-homoserine. Through site-directed mutagenesis, we show that one variant of C. glutamicum ThrB, CglThrB-A20G, retains wild-type enzymatic activity, with dramatically decreased feedback inhibition by l-threonine. Additionally, by solving the first Corynebacterium X ray crystal structure of homoserine kinase, we can confirm that the changes in l threonine affinity to the CglThrB-A20G active site derive from loss of van der Waals interactions. PMID- 30023798 TI - Selective Photoinduced Antibacterial Activity of Amoxicillin-Coated Gold Nanoparticles: From One-Step Synthesis to in Vivo Cytocompatibility. AB - Photoinduced antibacterial gold nanoparticles were developed as an alternative for the treatment of antibiotic-resistant bacteria. Thanks to the amoxicillin coating, they possess high in vivo stability, selectivity for the bacteria wall, a good renal clearance, and are completely nontoxic for eukaryotic cells at the bactericidal concentrations. A simple one-step synthesis of amoxi@AuNP is described at mild temperatures using the antibiotic as both reducing and stabilizing agent. Time-resolved fluorescence microscopy proved these novel nano photosensitizers, with improved selectivity, are bactericidal but showing excellent biocompatibility toward eukaryotic cells at the same dose (1.5 MUg/mL) when co-cultures are analyzed. Their stability in biological media, hemocompatibility, and photo-antibacterial effect against sensitive and antibiotic-resistant Staphylococcus aureus were evaluated in vitro, whereas toxicity, renal clearance, and biodistribution were studied in vivo in male Wistar rats. The use of these nanoparticles to treat antibiotic-resistant infections is promising given their high stability and cytocompatibility. PMID- 30023799 TI - Mechanistic Insight into Size-Dependent Enhanced Cytotoxicity of Industrial Antibacterial Titanium Oxide Nanoparticles on Colon Cells Because of Reactive Oxygen Species Quenching and Neutral Lipid Alteration. AB - This study evaluates the impact of industrially prepared TiO2 nanoparticles on the biological system by using an in vitro model of colon cancer cell lines (HCT116). Industrial synthesis of titanium oxide nanoparticles was mimicked on the lab scale by the high-energy ball milling method by milling bulk titanium oxide particles for 5, 10, and 15 h in an ambient environment. The physiochemical characterization by field emission scanning electron microscopy, dynamic light scattering, and UV-visible spectroscopy revealed alteration in the size and surface charge with respect to increase in the milling time. The size was found to be reduced to 82 +/- 14, 66 +/- 12, and 42 +/- 10 nm in 5, 10, and 15 h milled nano TiO2 from 105 +/- 12 nm of bulk TiO2, whereas the zeta potential increased along with the milling time in all biological media. Cytotoxicity and genotoxicity assays performed with HCT116 cell lines by MTT assay, oxidative stress, intracellular lipid analysis, apoptosis, and cell cycle estimation depicted cytotoxicity as a consequence of reactive oxygen species quenching and lipid accumulation, inducing significant apoptosis and genotoxic cytotoxicity. In silico analysis depicted the role of Sod1, Sod2, p53, and VLDR proteins-TiO2 hydrogen bond interaction having a key role in determining the cytotoxicity. The particles exhibited significant antibacterial activities against Escherichia coli and Salmonella typhimurium. PMID- 30023801 TI - Collagen-Hydroxypropyl Methylcellulose Membranes for Corneal Regeneration. AB - To improve intraocular transparency of collagen matrices, hydroxypropyl methylcellulose (HPMC) was introduced for the first time into cross-linked collagen to form collagen-HPMC composite membranes. Light transmittance and refractive indices of the membranes are enhanced by incorporation of HPMC in comparison to the control of cross-linked collagen membranes. Maximum light transmittance of the collagen-HPMC membrane was up to 92%. In addition, their permeability of nutrients such as glucose, tryptophan, and NaCl was superior or comparable to that of human corneas. In vitro results demonstrated that the collagen-HPMC membrane supported adhesion and proliferation of human corneal epithelial cells (HCECs), showing good cytocompatibility to HCECs. The corneas maintained a smooth surface and clear stroma postoperatively after 7 months of implantation of collagen-HPMC membranes into the corneas of rabbits. The good intraocular biocompatibility was verified by maintaining a high optical clarity for over 6 months after transplantation. Hematoxylin and eosin staining results showed the growth of stromal keratocytes into the collagen-HPMC implants, indicating the ability of the collagen-HPMC membrane to induce corneal cell regeneration. Taken together, the collagen-HPMC membrane might be a promising candidate for use in corneal repair and regeneration. PMID- 30023800 TI - Azide-Alkyne Cycloaddition En Route to 1H-1,2,3-Triazole-Tethered Isatin Ferrocene, Ferrocenylmethoxy-Isatin, and Isatin-Ferrocenylchalcone Conjugates: Synthesis and Antiproliferative Evaluation. AB - Diverse series of isatin-ferrocene conjugates were synthesized via Cu-promoted azide-alkyne cycloaddition reaction with an aim of probing their antiproliferative structure-activity relationship against MCF-7 (estrogen receptor positive) and MDA-MB-231 (triple negative) cell lines. Among the synthesized conjugates, isatin-ferrocenes proved to be more potent against MCF-7, whereas ferrocenylmethoxy-isatins exhibited activity against MDA-MB-231 cell lines. However, the introduction of chalcone moiety among these hybrids resulted in the complete loss of activity against the tested cell lines, as evident by isatin-ferrocenylchalcones. The conjugates 5a and 9c proved to be the most potent among the series against MCF-7 and MDA-MB-213 cell lines, exhibiting IC50 values of 31.62 and 20.26 MUM, respectively. PMID- 30023802 TI - Synthesis and Characterization of Jellified Composites from Bovine Bone-Derived Hydroxyapatite and Starch as Precursors for Robocasting. AB - Hydroxyapatite-starch composites solidify rapidly via jellification, making them suitable candidates for robocasting. However, many aspects related to hydroxyapatite powder characteristics, hydroxyapatite-starch interaction, and composites composition and properties need to be aligned with robocasting requirements to achieve a notable improvement in the functionality of printed scaffolds intended for bone regeneration. This article presents a preliminary evaluation of hydroxyapatite-starch microcomposites. Thermal analysis of the starting powders was performed for predicting composites' behavior during heat induced densification. Also, morphology, mechanical properties, and hydroxyapatite-starch interaction were evaluated for the jellified composites and the porous bodies obtained after conventional sintering, for different starch additions, and for ceramic particle size distributions. The results indicate that starch could be used for hydroxyapatite consolidation in limited quantities, whereas the composites shall be processed under controlled temperature. Due to a different mechanical behavior induced by particle size and geometry, a wide particle size distribution of hydroxyapatite powder is recommended for further robocasting ink development. PMID- 30023803 TI - Plasmonic Oleylamine-Capped Gold and Silver Nanoparticle-Assisted Synthesis of Luminescent Alloyed CdZnSeS Quantum Dots. AB - We report on a novel strategy to tune the structural and optical properties of luminescent alloyed quantum dot (QD) nanocrystals using plasmonic gold (Au) and silver (Ag) nanoparticles (NPs). Alloyed CdZnSeS QDs were synthesized via the organometallic synthetic route with different fabrication strategies that involve alternative utilization of blends of organic surfactants, ligands, capping agents, and plasmonic oleylamine (OLA)-functionalized AuNPs and AgNPs. Ligand exchange with thiol l-cysteine (l-cyst) was used to prepare the hydrophilic nanocrystals. Analysis of the structural properties using powder X-ray diffraction revealed that under the same experimental condition, the plasmonic NPs altered the diffractive crystal structure of the alloyed QDs. Depending on the fabrication strategy, the crystal nature of OLA-AuNP-assisted CdZnSeS QDs was a pure hexagonal wurtzite domain and a cubic zinc-blende domain, whereas the diffraction pattern of OLA-AgNP-assisted CdZnSeS QDs was dominantly a cubic zinc blende domain. Insights into the growth morphology of the QDs revealed a steady transformation from a heterogeneous growth pattern to a homogenous growth pattern that was strongly influenced by the plasmonic NPs. Tuning the optical properties of the alloyed QDs via plasmonic optical engineering showed that the photoluminescence (PL) quantum yield (QY) of the AuNP-assisted l-cyst-CdZnSeS QDs was tuned from 10 to 31%, whereas the PL QY of the AgNP-assisted l-cyst-CdZnSeS QDs was tuned from 15 to 90%. The low PL QY was associated with the surface defect state, while the remarkably high PL QY exhibited by the AgNP-assisted l cyst-CdZnSeS QDs lends strong affirmation that the fabrication strategy employed in this work provides a unique opportunity to create single ensemble, multifunctional, highly fluorescent alloyed QDs for tailored biological applications. PMID- 30023804 TI - Equipment-Free Quantitative Aptamer-Based Colorimetric Assay Based on Target Mediated Viscosity Change. AB - In this paper, we describe an aptamer-based colorimetric assay (ABCA), which integrates enzyme-loaded microparticles for signal amplification with distance measurement for equipment-free quantitative readout. The distance measurement readout is on the basis of target-induced selective reduction in viscosity of reaction solution. Its utility is well demonstrated with inexpensive, sensitive, and selective detection of adenosine (model analyte) in buffer samples and real samples of human serum and urine with the naked eye. This ABCA method just requires operators to simply count the number of colored distance-relevant marked bars on the calibrated glass microsyringes (testing containers) to provide quantitative results. It thus holds great promise for wide applications particularly in limited-resource settings. PMID- 30023805 TI - Engineering of a New Bisphosphonate Monomer and Nanoparticles of Narrow Size Distribution for Antibacterial Applications. AB - In recent years, many bacteria have developed resistance to commonly used antibiotics. It is well-known that calcium is essential for bacterial function and cell wall stability. Bisphosphonates (BPs) have high affinity to calcium ions and are effective calcium chelators. Therefore, BPs could potentially be used as antibacterial agents. This article provides a detailed description regarding the synthesis of a unique BP vinylic monomer MA-Glu-BP (methacrylate glutamate bisphosphonate) and polyMA-Glu-BP nanoparticles (NPs) for antibacterial applications. polyMA-Glu-BP NPs were synthesized by dispersion copolymerization of the MA-Glu-BP monomer with the primary amino monomer N-(3 aminopropyl)methacrylamide hydrochloride (APMA) and the cross-linker monomer tetra ethylene glycol diacrylate, to form cross-linked NPs with a narrow size distribution. The size and size distribution of polyMA-Glu-BP NPs were controlled by changing various polymerization parameters. Near-infrared fluorescent polyMA Glu-BP NPs were prepared by covalent binding of the dye cyanine7 N hydroxysuccinimide to the primary amino groups belonging to the APMA monomeric units on the polyMA-Glu-BP NPs. The affinity of the near-infrared fluorescent polyMA-Glu-BP NPs toward calcium was demonstrated in vitro by a coral model. Cytotoxicity, cell uptake, and antibacterial properties of the polyMA-Glu-BP NPs against two common bacterial pathogens representing Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, and two representing Gram-positive bacteria, Listeria innocua and Staphylococcus aureus, were then demonstrated. PMID- 30023807 TI - Enabling Biocatalysis by High-Throughput Protein Engineering Using Droplet Microfluidics Coupled to Mass Spectrometry. AB - Directed Evolution is a key technology driving the utility of biocatalysis in pharmaceutical synthesis. Conventional approaches to Directed Evolution are conducted using bacterial cells expressing enzymes in microplates, with catalyzed reactions measured by HPLC, high-performance liquid chromatography-mass spectrometry (HPLC-MS), or optical detectors, which require either long cycle times or tailor-made substrates. To better fit modern, fast-paced process chemistry development where solutions are rapidly needed for new substrates, droplet microfluidics interfaced with electrospray ionization (ESI)-MS provides a label-free high-throughput screening platform. To apply this method to industrial enzyme screening and to explore potential approaches that may further improve the overall throughput, we optimized the existing droplet-MS methods. Carryover between droplets, traditionally a significant issue, was reduced to undetectable level by replacing the stainless steel ESI needle with a Teflon needle within a capillary electrophoresis (CE)-MS source. Throughput was improved to 3 Hz with a wide range of droplet sizes (10-50 nL) by tuning the sheath flow within the CE-MS source. The optimized method was demonstrated by screening reactions using two different transaminase libraries. Good correlations (r2 ~ 0.95) were found between the droplet-MS and LC-MS methods, with 100% match on hit variants. We further explored the capability of the system by performing in vitro transcription-translation inside the droplets and directly analyzing the intact reaction mixture droplets by MS. The synthesized protein attained comparable activity to the protein standard, and the complex samples appeared well tolerated by the MS. The success of the above applications indicates that the MS analysis of the microfluidic droplets is an available option for considerably accelerating the screening of enzyme evolution libraries. PMID- 30023806 TI - Impairing Powerhouse in Colon Cancer Cells by Hydrazide-Hydrazone-Based Small Molecule. AB - Mitochondrion has emerged as one of the unconventional targets in next-generation cancer therapy. Hence, small molecules targeting mitochondria in cancer cells have immense potential in the next-generation anticancer therapeutics. In this report, we have synthesized a library of hydrazide-hydrazone-based small molecules and identified a novel compound that induces mitochondrial outer membrane permeabilization by inhibiting antiapoptotic B-cell CLL/lymphoma 2 (Bcl 2) family proteins followed by sequestration of proapoptotic cytochrome c. The new small molecule triggered programmed cell death (early and late apoptosis) through cell cycle arrest in the G2/M phase and caspase-9/3 cleavage in HCT-116 colon cancer cells, confirmed by an array of fluorescence confocal microscopy, cell sorting, and immunoblotting analysis. Furthermore, cell viability studies have verified that the small molecule rendered toxicity to a panel of colon cancer cells (HCT-116, DLD-1, and SW-620), keeping healthy L929 fibroblast cells unharmed. The novel small molecule has the potential to form a new understudied class of mitochondria targeting anticancer agent. PMID- 30023809 TI - Core-Shell Microcapsules Containing Flame Retardant Tris(2-chloroethyl phosphate) for Lithium-Ion Battery Applications. AB - Flame retardant tris(2-chloroethyl phosphate) (TCP) is successfully encapsulated in core-shell poly(urea-formaldehyde) microcapsules by in situ polymerization. The microcapsules are electrochemically stable in lithium-ion (Li-ion) battery electrolytes and thermally stable to ca. 200 degrees C. Thermal triggering of these microcapsules at higher temperatures ruptures the shell wall, releasing the liquid core (flame retardant), and NMR spectroscopy confirms the presence of the flame retardant in the electrolyte solution. Li-ion pouch cell experiments demonstrate that microencapsulation of TCP and its incorporation into the battery electrolyte provide latent fire retardants that improve battery safety while maintaining inherent battery performance and cycling capability. PMID- 30023808 TI - Maltose-Functionalized Hydrophilic Magnetic Nanoparticles with Polymer Brushes for Highly Selective Enrichment of N-Linked Glycopeptides. AB - Efficient enrichment glycoproteins/glycopeptides from complex biological solutions are very important in the biomedical sciences, in particular biomarker research. In this work, the high hydrophilic polyethylenimine conjugated polymaltose polymer brushes functionalized magnetic Fe3O4 nanoparticles (NPs) denoted as Fe3O4-PEI-pMaltose were designed and synthesized via a simple two-step modification. The obtained superhydrophilic Fe3O4-PEI-pMaltose NPs displayed outstanding advantages in the enrichment of N-linked glycopeptides, including high selectivity (1:100, mass ratios of HRP and bovine serum albumin (BSA) digest), low detection limit (10 fmol), large binding capacity (200 mg/g), and high enrichment recovery (above 85%). The above-mentioned excellent performance of novel Fe3O4-PEI-pMaltose NPs was attributed to graft of maltose polymer brushes and efficient assembly strategy. Moreover, Fe3O4-PEI-pMaltose NPs were further utilized to selectively enrich glycopeptides from human renal mesangial cell (HRMC, 200 MUg) tryptic digest, and 449 N-linked glycopeptides, representing 323 different glycoproteins and 476 glycosylation sites, were identified. It was expected that the as-synthesized Fe3O4-PEI-pMaltose NPs, possessing excellent performance (high binding capacity, good selectivity, low detection limit, high enrichment recovery, and easy magnetic separation) coupled to a facile preparation procedure, have a huge potential in N-glycosylation proteome analysis of complex biological samples. PMID- 30023810 TI - Effects of Natural Polyphenols on the Expression of Drug Efflux Transporter P Glycoprotein in Human Intestinal Cells. AB - The drug efflux transporter P-glycoprotein, which is encoded by MDR1 (ABCB1), plays important roles in drug absorption, distribution, and elimination. We previously reported that dietary polyphenols such as quercetin, curcumin, honokiol, magnolol, caffeic acid phenetyl ester (CAPE), xanthohumol, and anacardic acid inhibit P-glycoprotein-mediated drug transport. In the present study, we investigated the effects of polyphenols on the expression of P glycoprotein using human intestinal epithelial LS174T cells and a reporter plasmid expressing 10.2 kbp of the upstream regulatory region of MDR1. Honokiol, magnolol, CAPE, xanthohumol, and anacardic acid activated the MDR1 promoter in LS174T cells, and the cellular uptake of rhodamine 123 and calcein-AM, fluorescent substrates of P-glycoprotein, decreased in polyphenol-treated LS174T cells. These results suggest that dietary natural polyphenols can induce the drug efflux transporter P-glycoprotein and have the potential to promote food-drug interactions. PMID- 30023811 TI - Near-Infrared-Activated Fluorescence Resonance Energy Transfer-Based Nanocomposite to Sense MMP2-Overexpressing Oral Cancer Cells. AB - The matrix metalloproteinases (MMPs) are well-known mediators that are activated in tumor progression. MMP2 is a kind of gelatinase in extracellular matrix remodeling and cancer metastasis processes. MMP2 secretion increased in many types of cancer diseases, and its abnormal expression is associated with a poor prognosis. We fabricated a nanocomposite that sensed MMP2 expression by a red and blue light change. This nanocomposite consisted of an upconversion nanoparticle (UCNP), MMP2-sensitive peptide, and CuInS2/ZnS quantum dot (CIS/ZnS QD). An UCNP is composed of NaYF4:Tm/Yb@NaYF4:Nd/Yb, which has multiple emissions at UV/blue visible wavelengths under 808 nm laser excitation. The conjugated CIS/ZnS QD showed the red-visible fluorescence though the FRET process. The two fluorophores were connected by a MMP2-sensitive peptide to form a novel MMP2 biosensor, named UCNP@p-QD. UCNP@p-QD was highly biocompatible according to cell viability assay. The FRET-based biosensor was employed in the MMP2 determination in vitro and in vivo. Furthermore, it was administrated into the tumor-bearing mouse to check MMP2 expression. UCNP@p-QD could be a promising tool for biological study and biomedical application. In this study, we demonstrated that the CIS/ZnS QD improved the upconversion intensity through a near-infrared-induced FRET process. This nanocomposite has the advantage of light penetration, excellent biocompatibility, and high sensitivity to sense MMP2. The near-infrared-induced composites are a potential inspiration for use in biomedical applications. PMID- 30023812 TI - Design and Evaluation of Short Self-Assembling Depsipeptides as Bioactive and Biodegradable Hydrogels. AB - Described herein is the design of a cell-adherent and degradable hydrogel. Our goal was to create a self-assembling, backbone ester-containing analogue of the cell adhesion motif, arginine-glycine-aspartic acid (RGD). Two depsipeptides containing Fmoc (N-(fluorenyl)-9-methoxycarbonyl), Fmoc-FR-Glc-D, and Fmoc-F-Glc RGD (where "Glc" is glycolic acid) were designed based on the results of integrin binding affinity and cell interaction analyses. Two candidate molecules were synthesized, and their gelation characteristics, degradation profiles, and ability to promote cell attachment were analyzed. We found that ester substitution within the RGD sequence significantly decreases the integrin-binding affinity and subsequent cell attachment, but when the ester moiety flanks the bioactive sequence, the molecule can maintain its integrin-binding function while permitting nonenzymatic hydrolytic degradation. A self-assembled Fmoc-F-Glc-RGD hydrogel showed steady, linear degradation over 60 days, and when mixed with Fmoc diphenylalanine (Fmoc-FF) for improved mechanical stiffness, the depsipeptide gel exhibited improved cell attachment and viability. Though the currently designed depsipeptide has several inherent limitations, our results indicate the potential of depsipeptides as the basis for biologically functional and degradable self assembling hydrogel materials. PMID- 30023813 TI - Structure-Activity Relationships of GAG Mimetic-Functionalized Mesoporous Silica Nanoparticles and Evaluation of Acyclovir-Loaded Antiviral Nanoparticles with Dual Mechanisms of Action. AB - Mesoporous silica nanoparticles (MSNs) are drug delivery agents that are able to incorporate drugs within their pores. Furthermore, MSNs can be functionalized by attachment of bioactive ligands on their surface to enhance their activity, and nanoparticles modified with glycosaminoglycan (GAG) mimetics inhibit the entry of herpes simplex virus (HSV) into cells. In this study, structure-activity relationships of GAGs attached to MSNs were investigated in relation to HSV-1 and HSV-2, and acyclovir was loaded into the pores of MSNs. The sulfonate group was demonstrated to be essential for antiviral activity, which was enhanced by incorporating a benzene group within the ligand. Loading acyclovir into GAG mimetic-functionalized MSNs reduced the viral infection, resulting in nanoparticles that simultaneously target two distinct viral pathways, namely, inhibition of viral entry and inhibition of DNA replication. PMID- 30023814 TI - Polymer-Assisted Biocatalysis: Effects of Macromolecular Architectures on the Stability and Catalytic Activity of Immobilized Enzymes toward Water-Soluble and Water-Insoluble Substrates. AB - The aim of this study is to develop efficient enzyme immobilization media that will enable the reuse of the biocatalysts over multiple cycles, increase their thermal stability, and attenuate their activity toward hydrophobic substrates for "green" transformations in aqueous media. For this purpose, amphiphilic AB and ABA block copolymers were synthesized and tested with laccase (a multicopper oxidase). In all cases, the hydrophilic B block consisted of poly(ethylene glycol), PEG, with molecular masses of 3, 5, 13, 20, or 13 kDa poly(ethylene oxide). The hydrophobic A blocks were made of linear poly(styrene), PS; hyperbranched poly(p-chloromethyl styrene); or dendritic poly(benzyl ether)s of generations 2, 3, and 4 (G2, G3, and G4) with molecular masses ranging from 1 to 24 kDa. A total of 23 different copolymers (self-assembling into micelles or physical networks) were evaluated. Notable activity enhancements were achieved with both micelles (up to 253%) and hydrogels (up to 408%). The highest enzymatic activity and thermal stability were observed with laccase immobilized in hydrogels consisting of the linear ABA block copolymer PS2.7k-PEG3k-PS2.7k (13 290 MUkat/L, 65 degrees C, ABTS test). This represents a 1245% improvement over native laccase at the same conditions. At 25 degrees C, the same complex showed a 1236% higher activity than the enzyme. The highest polymerization yield for a water-insoluble monomer was achieved with laccase immobilized in hydrogels composed of linear-dendritic ABA copolymer G3-PEG5k-G3 (85.5%, 45 degrees C, tyrosine monomer). The broad substrate specificity and reusability of the immobilized laccase were also demonstrated by the successful discoloration of bromophenol blue, methyl orange, and rhodamine B over eight repetitive cycles. PMID- 30023815 TI - Standard Gibbs Energy of Metabolic Reactions: III The 3-Phosphoglycerate Kinase Reaction. AB - The glycolytic pathway is one of the most studied metabolic pathways to date. This work focuses on determining the standard Gibbs energy of reaction (DeltaRg0) of the first adenosine triphosphate-yielding reaction step of glycolysis, namely, the 3-phosphoglycerate kinase (PGK) reaction. Trustworthy values of DeltaRg0 are required for thermodynamic approaches to determine single reaction conversions or even fluxes of metabolic reactions. In literature, the observed DeltaRg0,obs values are usually determined directly from the experimental equilibrium composition data without accounting for the nonideality of the reaction mixture. That is the reason why the observed DeltaRg0,obs values do not present consistent standard data as they are a function of the concentration, pH, and pMg. In this work, a combination of experimentally determined equilibrium composition data and activity coefficients of the reacting agents was used to determine DeltaRg0 values for the temperatures 303, 313, and 323 K at pH 7. The activity coefficients were predicted with the thermodynamic model electrolyte perturbed chain statistical associating fluid theory (ePC-SAFT). The ePC-SAFT parameters were taken from literature or fitted to new experimental osmotic coefficients. At 313.15 K, a value for DeltaRg0 of -16.2 +/- 0.2 kJ/mol was obtained. This value is about 4 kJ/mol less negative than what is usually considered as an accepted standard value. The reason behind this discrepancy was found to be the activity coefficients of the reacting agents, which dramatically influence the equilibrium position of the PGK reaction. On the basis of the temperature-dependent DeltaRg0 values, the standard enthalpy of reaction was determined and found to be DeltaRh0 = -49 +/- 9 kJ/mol. PMID- 30023816 TI - Two-Dimensional Fluorinated Boron Sheets: Mechanical, Electronic, and Thermal Properties. AB - The synthesis of atomically thin boron sheets on a silver substrate opened a new area in the field of two-dimensional systems. Similar to hydrogenated and halogenated graphene, the uniform coating of borophene with fluorine atoms can lead to new derivatives of borophene with novel properties. In this respect, we explore the possible structures of fluorinated borophene for varying levels of coverage (B n F) by using first-principles methods. Following the structural optimizations, phonon spectrum analysis and ab initio molecular dynamics simulations are performed to reveal the stability of the obtained structures. Our results indicate that while fully fluorinated borophene (BF) cannot be obtained, stable configurations with lower coverage levels (B4F and B2F) can be attained. Unveiling the stable structures, we explore the mechanical, electronic, and thermal properties of (B n F). Fluorination significantly alters the mechanical properties of the system, and remarkable results, including direction-dependent variation of Young's modulus and a switch from a negative to positive Poisson's ratio, are obtained. However, the metallic character is preserved for low coverage levels, and metal to semiconductor transition is obtained for B2F. The heat capacity at a low temperature increases with an increasing F atom amount but converges to the same limiting value at high temperatures. The enhanced stability and unique properties of fluorinated borophene make it a promising material for various high-technology applications in reduced dimensions. PMID- 30023817 TI - Ultrafine Highly Magnetic Fluorescent gamma-Fe2O3/NCD Nanocomposites for Neuronal Manipulations. AB - In this work, we describe a low-cost, two-step synthesis of composites of nitrogen-doped carbon quantum dots (NCDs) with gamma-Fe2O3 (NCDs/gamma-Fe2O3), which is based on a hydrothermal cum co-precipitation method. The product is a fine powder of particles having an average diameter of 9 +/- 3 nm. The physical and chemical properties of NCDs/gamma-Fe2O3 were studied, as well as the superconducting quantum interference device and Mossbauer analysis of the magnetic properties of these nanocomposites. The interaction of NCDs/gamma-Fe2O3 nanocomposites with neuron-like cells was examined, showing efficient uptake and low toxicity. Our research demonstrates the use of the nanocomposites for imaging and for controlling the cellular motility. The NCDs/gamma-Fe2O3 nanocomposites are promising because of their biocompatibility, photostability, and potential selective affinity, paving the way for multifunctional biomedical applications. PMID- 30023818 TI - Mechanistic Modeling of Reversed-Phase Chromatography of Insulins within the Temperature Range 10-40 degrees C. AB - In the many published theories on the retention in reversed-phase chromatography (RPC), the focus is generally on the effect of the concentration of the mobile phase modulator(s), although temperature is known to have a significant influence both on the retention and on the selectivity between the adsorbates. The aim of this study was to investigate and model the combined effects of the temperature and the modulator concentrations on RPC of three insulin variants. KCl and ethanol were used as mobile phase modulators, and the experiments were performed on two different adsorbents, with C18 and C4 ligands. The temperature dependence was investigated for the interval 10-40 degrees C and at two different concentrations of each modulator. The model is derived from the expression for the adsorption equilibrium, which assumes that ethanol is adsorbed to the ligands and displaced by the insulin molecules, similar to the displacement of counterions in the steric mass-action model for ion-exchange chromatography. A good model fit to the new linear-range retention data was achieved by only adding and calibrating three parameters for the temperature dependence of the equilibrium. We found that a lower temperature results in a longer retention time for all adsorbates, adsorbents, and modulator concentrations used in this study, indicating that the adsorption process is enthalpy-driven. A comparison of the different contributions to the temperature dependence revealed that the large contribution from the equilibrium constant is dampened by the significant contributions of the opposite sign from the changes in activity coefficients of insulins and ethanol. Neglect of these effects when comparing different adsorbents and modulators might yield incorrect conclusions because the equilibrium constant varies with both, whereas the activity coefficients should be independent of the adsorbent. As expected, the conditions that promote higher retention also give a higher selectivity between the adsorbates. Nonetheless, in relation to its effect on the retention, the influence of the KCl concentration on the selectivity was significantly stronger than that of the temperature or that of the ethanol concentration. PMID- 30023819 TI - Drug-Clinical Agent Molecular Hybrid: Synthesis of Diaryl(trifluoromethyl)pyrazoles as Tubulin Targeting Anticancer Agents. AB - Twenty-three combretastatin A-4 (CA-4) analogues were synthesized by judiciously incorporating a functional N-heterocyclic motif present in Celecoxib (a marketed drug) while retaining essential pharmacophoric features of CA-4. Combretastatin (trifluoromethyl)pyrazole hybrid analogues, i.e., 5-trimethoxyphenyl-3 (trifluoromethyl)pyrazoles with a variety of relevantly substituted aryls and heteroaryls at 1-position were considered as potential tubulin polymerization inhibitors. The cytotoxicity of the compounds was evaluated using MCF-7 cells. Analog 23 (C-23) was found to be the most active among the tested compounds. It showed pronounced cytotoxicity against HeLa, B16F10, and multidrug-resistant mammary tumor cells EMT6/AR1. Interestingly, C-23 displayed significantly lower toxicity toward noncancerous cells, MCF10A and L929, than their cancerous counterparts, MCF-7 and B16F10, respectively. C-23 depolymerized interphase microtubules, disrupted mitotic spindle formation, and arrested MCF-7 cells at mitosis, leading to cell death. C-23 inhibited the assembly of tubulin in vitro. C-23 bound to tubulin at the colchicine binding site and altered the secondary structures of tubulin. The data revealed the importance of (trimethoxyphenyl)(trifluoromethyl)pyrazole as a cis-restricted double bond alternative bridging motif, and carboxymethyl-substituted phenyl as ring B for activities and interaction with tubulin. The results indicated that the combretastatin-(trifluoromethyl)pyrazole hybrid class of analogues has the potential for further development as anticancer agents. PMID- 30023822 TI - Probing Multiple Binding Modes of DNA Hybridization: A Comparison between Single Molecule Observations and Ensemble Measurements. AB - Interactions between biomolecules are generally analyzed by ensemble measurements, assuming that the interactions occur in a single binding manner. However, such interactions may occur via multiple binding modes. We investigated the kinetics of DNA hybridization as a multiple dynamic model of biomolecular interactions. Two kinetic analyses were performed with a single-molecule observation using total internal reflection fluorescence microscopy (TIRFM) and with ensemble measurements using a quartz-crystal microbalance (QCM) biosensor. We observed the DNA hybridization of 8 and 12 bp DNAs with random sequences and dA12-dT12 and calculated the kinetic parameters, including the dissociation rate constant (koff). Hybridization of 8 bp DNA proceeded mainly via a single binding mode. However, hybridization of 12 bp DNA indicated at least two different binding modes and dA12-dT12 hybridization showed multiple binding modes. For the multiple binding interactions, the kinetic parameters obtained from TIRFM and QCM were different because kinetic parameters obtained from QCM indicate average number of molecules, whereas those from TIRFM indicate average association time. The present study revealed the details of multiple interactions, which can be utilized for better understanding of not only DNA hybridization but also biomolecular interaction mechanisms. PMID- 30023820 TI - Enantioselective Synthesis of a Novel Thiazoline Core as a Potent Peroxisome Proliferator-Activated Receptor delta Agonist. AB - The convergent and enantioselective synthesis of a highly potent human peroxisome proliferator-activated receptor delta agonist is presented. More specifically, the thiazoline structure, which constitutes the biosynthetically distinctive core structure of pulicatin (a secondary metabolite of symbiotic bacteria), was synthesized from a commercially available and inexpensive chiral pool of l threonine. PMID- 30023821 TI - Role of Counterions in Constant-pH Molecular Dynamics Simulations of PAMAM Dendrimers. AB - Electrostatic interactions play a pivotal role in the structure and mechanism of action of most biomolecules. There are several conceptually different methods to deal with electrostatics in molecular dynamics simulations. Ionic strength effects are usually introduced using such methodologies and can have a significant impact on the quality of the final conformation space obtained. We have previously shown that full system neutralization can lead to wrong lipidic phases in the 25% PA/PC bilayer (J. Chem. Theory Comput. 2014,10, 5483-5492). In this work, we investigate how two limit approaches to the ionic strength treatment (implicitly with GRF or using full system neutralization with either GRF or PME) can influence the conformational space of the second-generation PAMAM dendrimer. Constant-pH MD simulations were used to map PAMAM's conformational space at its full pH range (from 2.5 to 12.5). Our simulations clearly captured the coupling between protonation and conformation in PAMAM. Interestingly, the dendrimer conformational distribution was almost independent of the ionic strength treatment methods, which is in contrast to what we have observed in charged lipid bilayers. Overall, our results confirm that both GRF with implicit ionic strength and a fully neutralized system with PME are valid approaches to model charged globular systems, using the GROMOS 54A7 force field. PMID- 30023823 TI - Distance-Matched Tagging Sequence Optimizes Live-Cell Protein Labeling by a Biarsenical Fluorescent Reagent AsCy3_E. AB - Cell permeable biarsenical fluorescent dyes built around a cyanine scaffold (AsCy3) create the ability to monitor the structural dynamics of tagged proteins in living cells. To extend the capability of this photostable and bright biarsenical probe to site-specifically label cellular proteins, we have compared the ability of AsCy3 to label two different tagging sequences (i.e., CCKAEAACC and CCKAEAAKAEAAKCC), which were separately engineered onto enhanced green fluorescent proteins (EGFPs) and expressed in Escherichia coli. The cysteine pairs within the shorter protein tag (i.e., Cy3TAG) are designed to specifically match the 14.5 A interarsenic atomic separation within AsCy3, whereas the longer protein tag (Cy3TAG+6) was identified using a peptide screening approach and reported to enhance the binding affinity and brightness. We report that AsCy3 binds both the tagged proteins with similar high affinities (Kd < 1 MUM) under both in vivo labeling conditions and following isolation and labeling of the tagged EGFP protein. Greater experimental reproducibility and substantially larger AsCy3 labeling stoichiometries are observed under in vivo conditions using the shorter Cy3TAG in comparison to the Cy3TAG+6. These results suggest that the use of the distance-matched and conformationally restricted Cy3TAG avoids nonspecific protein interactions, thereby enabling routine measurements of protein localization and conformational dynamics in living cells. PMID- 30023824 TI - Single Platform for Gene and Protein Expression Analyses Using Luminescent Gold Nanoclusters. AB - A single platform for gene and protein expression studies is proposed to pursue rapid diagnostics. A common method to synthesize gold (Au) nanoclusters on both DNA and protein template was developed using a benchtop device. The method of synthesis is rapid and versatile and can be applied to different classes of DNA/protein. Employing luminescent Au nanoclusters as the signal-generating agents, the device enables carrying out reverse transcriptase polymerase chain reaction and array-based analyses of multiple genes/proteins simultaneously using switchable holders and custom-designed software. The device and methods were applied to evaluate gene profiling related to apoptosis in HeLa cancer cells and further to analyze the protein expressions of glutathione-S-transferase (GST) and GST-tagged human granulocyte macrophage colony-stimulating factor (GST-hGMCSF) recombinant proteins purified from bacterial strains of BL21(DE3) Escherichia coli (E. coli). The device with user-friendly methods for diagnosis using the luminescence of Au nanoclusters offers potential use in disease diagnostics with a vision to extend health care facilities especially to remote geographical locations. PMID- 30023825 TI - Visible-Light Controlled Release of a Fluoroquinolone Antibiotic for Antimicrobial Photopharmacology. AB - Owing to the dwindling arsenal of antibiotics, new methodologies for their effective and localized delivery are necessary. The use of optical control over delivery of drugs, also known as photopharmacology, has emerged as an important option for the spatiotemporally controlled generation of drugs and bioactive molecules. In the field of antimicrobial photopharmacology, most strategies utilize ultraviolet light for triggering release of the antibiotic. The use of such short wavelength light may have limitations such as phototoxicity. Here, a small molecule that is activated by visible light to release a fluoroquinolone, a broad-spectrum antibiotic, is reported. A boron-dipyrromethene, which is sensitive to cleavage at 470 nm, was used, and levofloxacin was used as a model fluoroquinolone. BDP-Levo was found to undergo cleavage in the presence of visible light to release the active antibiotic. Using growth inhibitory studies in Gram-positive as well as Gram-negative bacteria, the efficacy of BDP-Levo is demonstrated. Together, our study demonstrates that visible light can be used for optical control over antibiotic release and lays the foundation for visible-light mediated antimicrobial photopharmacology. PMID- 30023826 TI - Chlorogenic Acid Improves Intestinal Development via Suppressing Mucosa Inflammation and Cell Apoptosis in Weaned Pigs. AB - Chlorogenic acid (CGA) is a naturally occurring polyphenol in the human diet and plants, exhibiting antioxidant and anti-inflammatory activities. This study was conducted to investigate the effects of CGA on intestinal development and health in weaned pigs. Twenty-four weaned pigs were randomly assigned to two treatments and fed with a basal diet or a basal diet supplemented with 1000 mg/kg CGA. After a 14 d trial, samples were collected. Compared with the control group, CGA supplementation decreased the serum tumor necrosis factor-alpha, interleukin-6, and interleukin-1betaIL-6 concentrations and elevated the serum immunoglobulin G and jejunal secretory immunoglobulin A concentrations. Meanwhile, jejunal villus height, duodenal and jejunal villus width, and jejunal and ileal villus height/crypt depth were increased by CGA. CGA not only decreased the number of duodenal and jejunal cells in the G0G1 phase but also increased the number of jejunal and ileal cells in the S phase. The percentages of late and total apoptotic cells in jejunum and the ratio of B-cell lymphoma-2-assiciated X protein to B-cell lymphoma-2 (Bcl-2) in duodenum and jejunum were also decreased by CGA supplementation. Finally, CGA upregulated the expression level of Bcl-2 in duodenum and jejunum, whereas it downregulated the expression levels of caspase-3 in duodenum and jejunum, caspase-9 in jejunum, as well as Fas in jejunum and ileum. This study suggested that the beneficial effects of CGA on intestinal development and health are partially due to improvement in immune defense and suppression in excessive apoptosis of intestinal epithelial cells in weaned pigs. PMID- 30023827 TI - Phytochemicals as Dynamic Surface Ligands To Control Nanoparticle-Protein Interactions. AB - The rapid formation of the protein corona on to the nanoparticle (NP) surface is the key that confers biological identity to NPs and subsequently dictates their fate both in vitro and in vivo. Despite significant efforts, the inability to control the spontaneous interaction of serum proteins with the administered NPs remains a major constraint in clinical translation of nanomedicines. The ligands present on the NP surface offer promise in controlling their biological interactions; however, their influence on the NP-protein interaction is not well understood. The current study investigates the potential of phytochemical-capped silver nanoparticles (AgNPs) toward allowing a control over NP interactions with the human serum albumin (HSA), the most abundant protein in the biological fluids. Specifically, we demonstrate the ability of curcumin (Cur) and epigallocatechin-3-gallate (EGCG) to independently act as reducing agents to produce phytochemical-capped AgNPs that show biologically desirable interactions with HSA. The key finding of our study is that the phytochemical-capped AgNPs initially interact with HSA more strongly compared to the citrate-stabilized AgNPs; however, the resultant NP-HSA complexes are less stable in the case of the former, which causes a lesser degree of changes in the protein conformation during interactions. Further, the choice of the phytochemical allows control over NP-HSA interactions, such that Cur- and EGCG-capped AgNPs interacted with HSA in a static versus dynamic manner, respectively. The diversity of the functional groups present in natural phytochemicals and their potential as in situ capping ligands during synthesis offer new opportunities in controlling the interactions of NPs with complex biological fluids, with implications in nanodiagnostics and nanomedicine. PMID- 30023829 TI - High-Performing Biodegradable Waterborne Polyester/Functionalized Graphene Oxide Nanocomposites as an Eco-Friendly Material. AB - The development of high-performing nanocomposites of homogeneously dispersed graphene oxide in a waterborne polyester matrix with controlled interfacial interactions is a daunting challenge owing to the presence of strong cohesive energy in both. Thus, in this study, graphene oxide was functionalized with toluene diisocyanate and butane diol through a simple method and incorporated into the waterborne polyester matrix through a facile in situ bulk polymerization technique without using any compatibilizing agent or organic solvent for the first time. The thermoset of the nanocomposite was formed by curing it with hyperbranched epoxy of glycerol and poly(amido amine). The resultant thermosetting nanocomposites with 0.1-1 wt % functionalized graphene oxide exhibited significant enhancement in mechanical properties such as elongation at break (245-360%), tensile strength (7.8-39.4 MPa), scratch hardness (4 to >10 kg), toughness (17.18-86.35 MJ/m3), Young's modulus (243-358 MPa), impact resistance (8.3 to >9.3 kJ/m), and thermostability. Further, the Halpin-Tsai model was used to predict the alignment of graphene oxide. The nanocomposite was also biodegradable against the Pseudomonas aeruginosa bacterial strain. Furthermore, this nanocomposite exhibited strong catalytic activity for the aza Michael addition reaction. Thus, the nanocomposite can be utilized as a high performing sustainable material in different potential applications including as heterogeneous catalysts. PMID- 30023828 TI - Computational Analysis of LOX1 Inhibition Identifies Descriptors Responsible for Binding Selectivity. AB - Lipoxygenases are a family of cytosolic, peripheral membrane enzymes, which catalyze the hydroperoxidation of polyunsaturated fatty acids and are implicated in the pathogenesis of major human diseases. Over the years, a substantial number of scientific reports have introduced inhibitors active against one or another subtype of the enzyme, but the selectivity issue has proved to be a major challenge for drug design. In the present work, we assembled a dataset of 317 structurally diverse molecules hitherto reported as active against 15S-LOX1, 12S LOX1, and 15S-LOX2 and identified, using supervised machine learning, a set of structural descriptors responsible for the binding selectivity toward the enzyme 15S-LOX1. We subsequently incorporated these descriptors in the training of QSAR models for LOX1 activity and selectivity. The best performing classifiers are two stacked models that include an ensemble of support vector machine, random forest, and k-nearest neighbor algorithms. These models not only can predict LOX1 activity/inactivity but also can discriminate with high accuracy between molecules that exhibit selective activity toward either one of the isozymes 15S LOX1 and 12S-LOX1. PMID- 30023830 TI - Migration and Transformation Characteristics of Niclosamide in a Soil-Plant System. AB - The molluscicide niclosamide is found in most of the wetlands of China. The migration and transformation pathways, and degradation kinetics of niclosamide in the plant-soil system was analyzed by with the use of potting experiment. Experimental results showed that degradation of niclosamide in rhizosphere soil fit the first-order kinetics, and microorganisms played an important role in the degradation of niclosamide. It was found that niclosamide degrades to form a series of aromatic intermediate products both in soil and plants. Niclosamide could be absorbed from soil to plant by the root and then migrate to the stem. At an initial concentration of niclosamide of 2.11 mg.kg-1 in soil, the maximum residue of niclosamide in Artemisia somai aerial was 2.47 mg.kg-1 after 10 days of cultivation. This value is close to the pollution maximum residue limit (3 mg.kg-1) in rice, and niclosamide and its intermediates can remain about 43 days in plants. The experimental results demonstrate that the use of niclosamide in wetlands would have some risk in edible plants and was harmful for human health. PMID- 30023831 TI - Efforts To Access the Potent Antitrypanosomal Marine Natural Product Janadolide: Synthesis of Des-tert-butyl Janadolide and Its Biological Evaluation. AB - To identify novel antitrypanosomal agents based on Janadolide, a potent macrocyclic polyketide-peptide hybrid, a macrolactonization strategy was explored. We prepared des-tert-butyl Janadolide and evaluated its antitrypanosomal activity. Our findings suggest that the tert-butyl group is necessary for the desired bioactivity. PMID- 30023832 TI - Salts of Amoxapine with Improved Solubility for Enhanced Pharmaceutical Applicability. AB - The objective of pharmaceutical cocrystallization is to create crystalline analogues that have vastly different properties, such as solubility, melting point, stability, and bioavailability from that observed in the pure active pharmaceutical ingredients (APIs). Amoxapine is a benzoxazepine derivative and exhibits antidepressant properties. Amoxapine has very low solubility in water, so it was cocrystallized with natural acids in a 1:1 ratio in appropriate solvents by the solvent-drop grinding method. Single crystals of cocrystals were grown by the solvent evaporation method in water, ethanol, and methanol. Crystal structures of API salts were determined by single-crystal X-ray diffraction. Salts were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction. Solubility of salts was determined in water by the shake-flask method at 37 degrees C using UV-vis spectroscopy. Salts of amoxapine with different acids were successfully developed, and their crystal structure was determined. Enhanced solubility was found in the salts of amoxapine for pharmaceutical application in drug formulation. PMID- 30023833 TI - Therapeutic Radiopharmaceuticals Targeting Integrin alphavbeta6. AB - The epithelial integrin alphavbeta6 is expressed by many malignant carcinoma cell types, including pancreatic cancer, and thus represents a promising target for radionuclide therapy. The peptide cyclo(FRGDLAFp(NMe)K) was decorated with different chelators (DOTPI, DOTAGA, and DOTA). The Lu(III) complexes of these conjugates exhibited comparable alphavbeta6 integrin affinities (IC50 ranging from 0.3 to 0.8 nM) and good selectivities against other integrins (IC50 for alphavbeta8 >43 nM; for alpha5beta1 >238 nM; and for alphavbeta3, alphavbeta5, and alphaIIbbeta3 >1000 nM). Although different formal charges of the Lu(III) chelates (ranging from 0 to 4) resulted in strongly varying degrees of hydrophilicity (log D ranging from -3.0 to -4.1), biodistributions in murine H2009 xenografts of the Lu-177-labeled compounds (except the DOTPI derivative) were quite similar and comparable to our previously reported alphavbeta6 integrin positron emission tomography tracer Ga-68-avebehexin. Hence, combinations of existing Ga-68- and Lu-177-labeled c(FRGDLAFp(NMe)K) derivatives could be utilized for alphavbeta6 integrin-targeted theranostics, whereas our data nonetheless suggest that further improvement of pharmacokinetics might be necessary to ensure clinical success. PMID- 30023834 TI - Structural Insight of Amyloidogenic Intermediates of Human Insulin. AB - Engaging Raman spectroscopy as a primary tool, we investigated the early events of insulin fibrilization and determined the structural content present in oligomer and protofibrils that are formed as intermediates in the fibril formation pathway. Insulin oligomer, as obtained upon incubation of zinc-free insulin at 60 degrees C, was mostly spherical in shape, with a diameter of 3-5 nm. Longer incubation produced "necklace"-like beaded protofibrillar assembly species. These intermediates eventually transformed into 5-8 nm thick fibers with smooth surface texture. A broad amide I band in the Raman spectrum of insulin monomer appeared at 1659 cm-1, with a shoulder band at 1676 cm-1. This signature suggested the presence of major helical and extended secondary structure of the protein backbone. In the oligomeric state, the protein maintained its helical imprint (~50%) and no substantial increment of the compact cross-beta-sheet structure was observed. A nonamide helix signature band at 940 cm-1 was present in the oligomeric state, and it was weakened in the fibrillar structure. The 1 anilino-8-naphthalene-sulfonate binding study strongly suggested that a collapse in the tertiary structure, not the major secondary structural realignment, was the dominant factor in the formation of oligomers. In the fibrillar state, the contents of helical and disordered secondary structures decreased significantly and the beta-sheet amount increased to ~62%. The narrow amide I Raman band at 1674 cm-1 in the fibrillar state connoted the formation of vibrationally restricted highly organized beta-sheet structure with quaternary realignment into steric-zipped species. PMID- 30023835 TI - Effect of gamma-Aminobutyric Acid-Chitosan Nanoparticles on Glucose Homeostasis in Mice. AB - Diabetes mellitus is the most common endocrine disease worldwide; hyperglycemia is a hallmark of this disease. To alleviate the pain caused by diabetes, developing and utilizing effective diabetic drugs to maintain or recover the function of the residual beta-cells is an attractive therapeutic approach. gamma aminobutyric acid (GABA) has been shown to have such effects, but it is easy to have reduced GABA activity under physiological conditions. In the present study, GABA-chitosan nanoparticles (GABA-CS NPs) were prepared, and glucose homeostasis, pancreatic beta-cell protection, and anti-inflammatory effects of GABA-CS NPs were investigated in vivo. The results showed that blood glucose levels and IL 1beta levels in the GABA-CS NP-administered group were both significantly lower, whereas the PDX1 expression was significantly higher than that of the impaired group (p < 0.01). This indicates that GABA-CS NPs can efficiently maintain glucose homeostasis, protect beta-cells, and inhibit inflammation. These nanoparticles have the potential to be applied for future diabetes theranostics. PMID- 30023836 TI - Molecular Insights into the Membrane Affinities of Model Hydrophobes. AB - Membrane-active antibiotics are of great interest in fighting bacterial resistance. alpha-Mangostin is a membrane-active molecule, but there are no details of its mechanism of action at the atomistic level. We have employed free energy simulations and microsecond-long conventional molecular dynamics simulations to study the mode of interaction of alpha-mangostin with a model bacterial membrane and compare it with the mechanisms of three hydrophobic molecules (ciprofloxacin, xanthone, and tetracycline). We find that alpha mangostin is thermodynamically more favored to insert into the membrane compared to the other three molecules. Apart from tetracycline, which is largely hydrophilic, the other three molecules aggregate in water; however, only alpha mangostin can penetrate into the lipid tail region of the membrane. When it reaches a high concentration in the lipid tail region, alpha-mangostin can form tubular clusters that span the two head group regions of the membrane, resulting in a large number of water translocations along the transmembrane aggregates. Structure-activity relationship analysis revealed two structural properties that characterize alpha-mangostin, namely, the two isoprenyl groups and the polar groups present in the aromatic rings, which result in "disruptive amphiphilicity" and hence its excellent membrane activity. PMID- 30023837 TI - Cardinal Role of Intraliposome Doxorubicin-Sulfate Nanorod Crystal in Doxil Properties and Performance. AB - The uniqueness of Doxil can be attributed, to a large extent, to its intraliposomal doxorubicin-sulfate nanorod crystal. We re-examine these nanocrystal features and their mechanism of the formation by studying pegylated liposomal doxorubicins (PLDs) of the same lipid composition, size distribution, and extraliposome medium that were prepared at different ammonium sulfate (AS) concentrations. This study includes a comparison of the thermotropic behavior, morphology, and in vitro ammonia-induced doxorubicin release (relevant to Doxil's in vivo performance) of these PLDs. In this study, we confirm that a transmembrane ammonium gradient is critical for doxorubicin remote loading, and we demonstrate that the intraliposomal concentration of sulfate counteranions and ammonium ions determine to a large extent the physical state and stability of the PLDs' remote loaded doxorubicin. "Fully-developed" intraliposome doxorubicin sulfate nanorod crystals (as defined by cryogenic transmission electron microscopy imaging) develop only when the ammonium sulfate (AS) concentration used for PLD preparation is >=150 mM. Less than 10% of PLDs prepared with 100 mM AS show fully developed nanorod crystals. Intraliposomal AS concentration >=200 mM is required to support the stable nanocrystallization in PLDs. The presence of nanocrystals and their melting enthalpy and phase transition co-operativity strongly affect the ammonia-induced doxorubicin release of PLDs. A quick, biphasic release occurs for PLDs that lack the nanorod crystals or have crystals of poor crystallinity, whereas PLDs prepared with >=200 mM AS show a monophasic, zero-order slow release. This study also demonstrates that after remote loading, residual intraliposomal ammonium concentration and the transmembrane pH gradient related to it also play an important role in doxorubicin-sulfate intraliposomal crystallization and ammonia-induced doxorubicin release. PMID- 30023838 TI - Enhanced Optical Collection of Micro- and Nanovesicles in the Presence of Gold Nanoparticles. AB - We describe a process for collecting micro- and nanovesicles on a glass substrate using the optical pressure of a laser beam. The laser beam was focused on a glass substrate that sandwiched a solution containing vesicles prepared using a phospholipid. The optical pressure generated at the surface of the vesicles pulled them into the center of the beam where they formed an aggregate on the glass surface. The vesicles prepared with a buffer solution were successfully collected via adsorption onto the glass surface, whereas the vesicles prepared with pure water exhibited no such tendency. The time required to collect a certain amount of vesicles was inversely proportional to their concentration. To enhance the collection efficiency, we added gold nanoparticles to the vesicle solution. The addition of gold nanoparticles into the solution reduced the collection time to one-tenth of that without it, and this was attributed to thermal mixing promoted by the heat generated by the absorption from the gold nanoparticles in the solution, as well as to an enhancement of light scattering induced by the gold nanoparticles. The optical collection of vesicles coupled with gold nanoparticles shows a promise for the collection of trace amounts of extracellular vesicles in biological fluids. PMID- 30023839 TI - Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques. AB - In this study, we apply a battery of molecular similarity techniques to known inhibitors of kynurenine 3-monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing. PMID- 30023840 TI - Comparative Study of Toluidine Blue O and Methylene Blue Binding to Lysozyme and Their Inhibitory Effects on Protein Aggregation. AB - A comparative binding interaction of toluidine blue O (TBO) and methylene blue (MB) with lysozyme was investigated by multifaceted biophysical approaches as well as from the aspects of in silico biophysics. The bindings were static, and it occurred via ground-state complex formation as confirmed from time-resolved fluorescence experiments. From steady-state fluorescence and anisotropy, binding constants were calculated, and it was found that TBO binds more effectively than MB. Synchronous fluorescence spectra revealed that binding of dyes to lysozyme causes polarity changes around the tryptophan (Trp) moiety, most likely at Trp 62 and 63. Calorimetric titration also depicts the higher binding affinity of TBO over MB, and the interactions were exothermic and entropy-driven. In silico studies revealed the potential binding pockets in lysozyme and the participation of residues Trp 62 and 63 in ligand binding. Furthermore, calculations of thermodynamic parameters from the theoretical docking studies were in compliance with experimental observations. Moreover, an inhibitory effect of these dyes to lysozyme fibrillogenesis was examined, and the morphology of the formed fibril was scanned by atomic force microscopy imaging. TBO was observed to exhibit higher potential in inhibiting the fibrillogenesis than MB, and this phenomenon stands out as a promising antiamyloid therapeutic strategy. PMID- 30023841 TI - Highly Pure Silica Nanoparticles with High Adsorption Capacity Obtained from Sugarcane Waste Ash. AB - Silica nanoparticles (SiO2NPs) from renewable sources can be used in very different materials, such as paints, membranes for fuel cells, Li-ion batteries, adsorbents, catalysts, and so on. Brazil is the world's largest producer of sugarcane and generates huge amounts of sugarcane waste ash (SWA), which is a Si rich source. This study investigates a method to produce highly pure SiO2NPs from SWA. The SiO2NPs were characterized by inductively coupled plasma optical emission spectroscopy, scanning and transmission electron microscopy (TEM), X-ray diffraction analyses, specific surface area and pore distribution, UV and Fourier transform infrared spectroscopy, and thermogravimetric analyses and applied as an adsorbent material in the removal of acid orange 8 (AO8) dye from aqueous solution. The SiO2 content was 88.68 and 99.08 wt % for SWA and SiO2NPs, respectively. TEM images of SWA and SiO2NPs exhibit drastic alterations of the material size ranging from several micrometers to less than 20 nm. The SiO2NPs showed a specific surface area of 131 m2 g-1 and adsorption capacity of around 230 mg g-1 for acid orange 8 dye. Furthermore, the recycling of the SiO2NPs adsorbent after AO8 adsorption was very satisfactory, with reuse for up to five cycles being possible. The results indicate that it was possible to obtain highly pure silica in a nanosize from the waste material and produce an adsorbent with high adsorption capacity and the possibility of reuse. PMID- 30023842 TI - Firefly Luciferase Mutant with Enhanced Activity and Thermostability. AB - The luciferase isolated from the firefly Photinus pyralis (Ppy) catalyzes a two step reaction that results in the oxidation of d-luciferin accompanied by emission of yellow-green light with a peak at 560 nm. Among many applications, Ppy luciferase has been used extensively as a reporter gene in living cells and organisms. However, some biological applications are limited by the low stability of the luciferase and limited intracellular luciferin concentration. To address these challenges, efforts to protein engineer Ppy luciferase have resulted in a number of mutants with improved properties such as thermostability, pH tolerance, and catalytic turn over. In this work, we combined amino acid mutations that were shown to enhance the enzyme's thermostability (Mutant E) with those reported to enhance catalytic activity (LGR). The resulting mutant (YY5) contained eight amino acid changes from the wild-type luciferase and exhibited both improved thermostability and brighter luminescence at low luciferin concentrations. Therefore, YY5 may be useful for reporter gene applications. PMID- 30023843 TI - Toughening Anhydride-Cured Epoxy Resins Using Fatty Alkyl-Anhydride-Grafted Epoxidized Soybean Oil. AB - The aim of this work is to develop a series of advanced biobased tougheners for thermosetting epoxy resins suitable for high-performance applications. These bio rubber (BR) tougheners were prepared via a one-step chemical modification of epoxidized soybean oil using biobased hexanoic anhydride. To investigate their toughening performance, these BR tougheners were blended with diglycidyl ether of bisphenol A epoxy monomers at various weight fractions and cured with anhydride hardeners. Significant improvements in fracture toughness properties, as well as minimal reductions in glass transition temperature (Tg), were observed. When 20 wt % of a BR toughener was utilized, the critical stress intensity factor and critical strain energy release rate of a thermosetting matrix were enhanced by >200 and >500%, respectively, whereas the Tg was reduced by only 20 degrees C. The phase-separated domains were evenly dispersed across the fracture surfaces as observed through scanning electron microscopy and atomic force microscopy. Moreover, domain sizes were demonstrated to be tunable within the micrometer range by altering the toughener molecular structure and weight fractions. These BR tougheners demonstrate the possibility of achieving toughness while having the thermal properties of standard bisphenol epoxy thermosetting resins. PMID- 30023844 TI - Novel Low-Toxic Derivative of Celastrol Maintains Protective Effect against Acute Renal Injury. AB - This study aimed to novelly design and synthesize an amide derivative as a potential substitute of celastrol (CLT). We constituted the compound celastrol glucosamine (CLG) by conjugating 1-(2-aminoethoxy)-2-glucosamine to celastrol (CLT) and confirmed its chemical structure by 1H NMR, 13C NMR, and LC-MS/MS. Then, the potential efficacy of the CLG was investigated on renal ischemia reperfusion injury animal models. The results demonstrated that the decorated compound CLG could completely reverse the disease progression as same as CLT. Furthermore, the toxicity of CLG was also fully evaluated in rat blood, liver, kidney, heart, spleen, lung, and reproductive system. Compared to the performance of CLT on normal organs, CLG could remarkably maintain high safety and significantly reduce the side effects. Taken together, the CLG could keep the same efficacy as CLT while processing lower toxicity in vivo. PMID- 30023845 TI - Synthesis of TMPA Derivatives through Sequential Ir(III)-Catalyzed C-H Alkylation and Their Antidiabetic Evaluation. AB - The synthesis and antidiabetic evaluation of ethyl 2-[2,3,4-trimethoxy-6-(1 octanoyl)phenyl]acetate (TMPA) and its structural analogs are described. The construction of TMPA derivatives has been successfully achieved in only two steps, which involve the iridium(III)-catalyzed alpha-alkylation of acetophenones with alcohols and the ketone-directed iridium(III)- or rhodium(III)-catalyzed redox-neutral C-H alkylation of alpha-alkylated acetophenones using Meldrum's diazo compounds. This synthetic protocol efficiently provides a range of TMPA derivatives with site selectivity and functional group compatibility. In addition, the site-selective demethylation of TMPA derivative affords the naturally occurring phomopsin C in good yield. Moreover, all synthetic compounds were screened for in vitro adenosine 5'-monophosphate-activated protein kinase (AMPK) activation using HepG2 cells. Furthermore, TMPA (5ac) and 5cd showing the most potent AMPK activation were treated for the in vivo antidiabetic experiment. Notably, our synthetic compound 5cd was found to display the powerful antidiabetic effect, stronger than that of metformin and TMPA (5ac). PMID- 30023846 TI - Diiron Hexacarbonyl Complex Induces Site-Specific Release of Carbon Monoxide in Cancer Cells Triggered by Endogenous Glutathione. AB - In this study, we have evaluated a water-soluble, nontarget reagent and a carrier free diiron hexacarbonyl complex, [Fe2{MU-SCH2CH(OH)CH2(OH)}2(CO)6] (TG-FeCORM), that can induce the site-specific release of carbon monoxide (CO) in cancer cells triggered by endogenous glutathione (GSH). The releasing rate of CO was dependent on the amount of endogenous GSH. Being the amount of endogenous GSH higher in cancer cells than in normal cells, the CO-releasing rate resulted faster in cancer cells. Moreover, the anti-inflammatory properties related to the intracellular CO release of TG-FeCORM were also confirmed in the living HeLa cells. PMID- 30023847 TI - Initiation, Elongation, and Termination of Bacterial Cellulose Synthesis. AB - Cellulose is the major component of the plant cell wall and composed of beta linked glucose units. Use of cellulose is greatly impacted by its physical properties, which are dominated by the number of individual cellulose strand within each fiber and the average length of each strand. Our work described herein provides a complete mechanism for cellulose synthase accounting for its processivity and mechanism of initiation. Using ionic liquids and gel permeation chromatography, we obtain kinetic constants for initiation, elongation, and termination (release of the cellulose strand from the enzyme) for two bacterial cellulose synthases (Gluconacetobacter hansenii and Rhodobacter sphaeroides). Our results show that initiation of synthesis is primer-independent. After initiation, the enzyme undergoes multiple cycles of elongation until the strand is released. The rate of elongation is much faster than that of steady-state turnover. Elongation requires cyclic addition of glucose (from uridine diphosphate-glucose) and then strand translocation by one glucose unit. Translocations greater than one glucose unit result in termination requiring reinitiation. The rate of the strand release, relative to the rate of elongation, determines the processivity of the enzyme. This mechanism and the measured rate constants were supported by kinetic simulation. With the experimentally determined rate constants, we are able to simulate steady-state kinetics and mimic the size distribution of the product. Thus, our results provide for the first time a mechanism for cellulose synthase that accounts for initiation, elongation, and termination. PMID- 30023848 TI - Biomimetic Synthesis of Polydopamine Coated ZnFe2O4 Composites as Anode Materials for Lithium-Ion Batteries. AB - Metal oxides as anode materials for lithium storage suffer from poor cycling stability due to their conversion mechanisms. Here, we report an efficient biomimetic method to fabricate a conformal coating of conductive polymer on ZnFe2O4 nanoparticles, which shows outstanding electrochemical performance as anode material for lithium storage. Polydopamine (PDA) film, a bionic ionic permeable film, was successfully coated on the surfaces of ZnFe2O4 particles by the self-polymerization of dopamine in the presence of an alkaline buffer solution. The thickness of PDA coating layer was tunable by controlling the reaction time, and the obtained ZnFe2O4/PDA sample with 8 nm coating layer exhibited an outstanding electrochemical performance in terms of cycling stability and rate capability. ZnFe2O4/PDA composites delivered an initial discharge capacity of 2079 mAh g-1 at 1 A g-1 and showed a minimum capacity decay after 150 cycles. Importantly, the coating layer improved the rate capability of composites compared to that of its counterpart, the bare ZnFe2O4 particle materials. The outstanding electrochemical performance was because of the buffering and protective effects of the PDA coating layer, which could be a general protection strategy for electrode materials in lithium-ion batteries. PMID- 30023849 TI - Porous Polylactide Film Plus Atorvastatin-Loaded Thermogel as an Efficient Device for Peritoneal Adhesion Prevention. AB - Peritoneal adhesion is a common postoperative complication that causes many kinds of organ dysfunctions. It can be minimized by the integration of physical isolation and pharmaceutical treatment. However, the gas permeability of traditional medical devices for adhesion prevention is not satisfactory, which increases the risk of infection and inflammation, thus facilitating the formation of peritoneal adhesion. In this study, a device of porous polylactide (PLA) film plus atorvastatin (ATV)-loaded thermogel was developed for peritoneal adhesion prevention. PLA film acted as a physical barrier to prevent the connection of fibrin bridges between the injured tissues and nearby normal organs. Simultaneously, ATV was released to achieve the antifibrin deposition and anti inflammatory effect. The porous properties of PLA film and thermogel increased the gas permeability and further inhibited the inflammatory responses. The in vivo study demonstrated that the porous PLA film with ATV-loaded thermogel possessed excellent anti-inflammation ability and satisfactory antiadhesion capacity, indicating its great potential for clinical application. PMID- 30023850 TI - Fabrication by Laser Irradiation in a Continuous Flow Jet of Carbon Quantum Dots for Fluorescence Imaging. AB - Fluorescent carbon quantum dots (CQDs) are synthesized by laser irradiation of carbon glassy particles suspended in polyethylene glycol 200 by two methods, a batch and a flow jet configuration. The flow jet configuration is carried out by the simple combination of common laboratory objects to construct a home-made passage reactor of continuous flow. Despite the simplicity of the system, the laser energy is better harvested by the carbon microparticles, improving the fabrication efficiency a 15% and enhancing the fluorescence of CQDs by an order of magnitude in comparison with the conventional batch. The flow jet-synthesized CQDs have a mean size of 3 nm and are used for fluorescent imaging of transparent healthy and cancer epithelial human cells. Complete internalization is observed with a short incubation time of 10 min without using any extra additive or processing of the cell culture. The CQDs are well fixed in the organelles of the cell even after its death; hence, this is a simple manner to keep the cell information for prolonged periods of time. Moreover, the integrated photostability of the CQDs internalized in in vitro cells is measured and it remains almost constant during at least 2 h, revealing their outstanding performance as fluorescent labels. PMID- 30023851 TI - Determination of the Thermodynamic Parameters of DNA Double Helix Unwinding with the Help of Mechanical Methods. AB - For the first time, rupture event scanning (REVS) procedure based on quartz crystal microbalance (QCM) and involving only mechanical action was used to determine the height of the energy barrier for dsDNA unwinding. Melting point was determined with the help of this procedure. To determine the thermodynamic parameters including enthalpy, DNA denaturation was represented as a unimolecular process. This allowed us to recover the energy profiles from the experimental data obtained by force measurements at different scanning times (reaction times) for different temperatures. The thus obtained results were compared with the data obtained with the help of another mechanical method, namely, atomic force microscopy. The mechanism of DNA unwinding in QCM-based experiments through the unzipping mode, as proposed by us in previous works, was confirmed. Thus, we demonstrated that REVS procedure may be used to assess the thermodynamic parameters of dsDNA unwinding. PMID- 30023852 TI - Distributed Representation of Chemical Fragments. AB - This article describes an unsupervised machine learning method for computing distributed vector representation of molecular fragments. These vectors encode fragment features in a continuous high-dimensional space and enable similarity computation between individual fragments, even for small fragments with only two heavy atoms. The method is based on a word embedding algorithm borrowed from natural language processing field, and approximately 6 million unlabeled PubChem chemicals were used for training. The resulting dense fragment vectors are in contrast to the traditional sparse "one-hot" fragment representation and capture rich relational structure in the fragment space. The vectors of small linear fragments were averaged to yield distributed vectors of bigger fragments and molecules, which were used for different tasks, e.g., clustering, ligand recall, and quantitative structure-activity relationship modeling. The distributed vectors were found to be better at clustering ring systems and recall of kinase ligands as compared to standard binary fingerprints. This work demonstrates unsupervised learning of fragment chemistry from large sets of unlabeled chemical structures and subsequent application to supervised training on relatively small data sets of labeled chemicals. PMID- 30023854 TI - Defect-Mediated Reactive Oxygen Species Generation in Mg-Substituted ZnO Nanoparticles: Efficient Nanomaterials for Bacterial Inhibition and Cancer Therapy. AB - Mg-substituted ZnO nanoparticles (MgZnO NPs) were synthesized by a soft chemical approach and were well-characterized by X-ray diffraction, transmission electron microscopy, UV-visible spectroscopy, and photoluminescence spectroscopy. The absorption and photoluminescence spectra show that substitution of Mg ions results in the widening of the band gap and a significant enhancement in the concentration of defects in ZnO NPs. A systemic study of generation of reactive oxygen species (ROS) under dark, daylight, and visible light conditions suggests that the aqueous suspension of MgZnO NPs generates a higher level of ROS because of the surface defects (oxygen vacancies). This capability of MgZnO NPs makes them a more promising candidate for the inhibition of bacterial growth and for killing of cancer cells as compared to pure ZnO NPs, possibly because of the enhanced interaction and accumulation of MgZnO NPs in the cytoplasm or cell membrane in the presence of both Zn2+ and Mg2+ ions. Further, MgZnO NPs exhibit excellent selective killing of nasopharyngeal carcinoma cells (KB) and cervical cancer cells (HeLa) with minimal toxicity to normal fibroblast cells (L929). The results suggest that the generation of ROS and Zn2+ ions are possibly responsible for the higher activity toward the depolarization of cell membrane potential, the lipid peroxidation in bacterial cells, depolarization of the mitochondrial membrane, and cell cycle arrest in the S phase in cancer cells. PMID- 30023855 TI - Ultrasensitive and Highly Selective Electrochemical Detection of Dopamine Using Poly(ionic liquids)-Cobalt Polyoxometalate/CNT Composite. AB - A novel sandwich polyoxometalate (POM) Na12[WCo3(H2O)2(CoW9O34)2] and poly(vinylimidazolium) cation [PVIM+] in combination with nitrogen-doped carbon nanotubes (NCNTs) was developed for a highly selective and ultrasensitive detection of dopamine. Conductively efficient heterogenization of Co5POM catalyst by PVIM over NCNTs provides the synergy between PVIM-POM catalyst and NCNTs as a conductive support which enhances the electron transport at the electrode/electrolyte interface and eliminates the interference of ascorbic acid (AA) at physiological pH (7.4). The novel PVIM-Co5POM/NCNT composite demonstrates a superior selectivity and sensitivity with a lowest detection limit of 500 pM (0.0005 MUM) and a wide linear detection range of 0.0005-600 MUM even in the presence of higher concentration of AA (500 MUM). PMID- 30023853 TI - Highly Regioselective Synthesis of Oxindolyl-Pyrroles and Quinolines via a One Pot, Sequential Meyer-Schuster Rearrangement, Anti-Michael Addition/C(sp3)-H Functionalization, and Azacyclization. AB - A one-pot, sequential Meyer-Schuster (MS) rearrangement of oxindole-derived propargyl alcohols to the corresponding alpha,beta-unsaturated enones and their anti-Michael addition, followed by intramolecular azacyclization is described in a highly regioselective manner using Ca(OTf)2 as the promoter. Further, we described the one-pot MS rearrangement, followed by C(sp3)-H functionalization of 2-methyl azaarenes at alpha-carbon of these doubly activated alkenes. Control experiments and computational calculations were performed to propose the reaction mechanism. PMID- 30023856 TI - Fast Disassembly of Lignocellulosic Biomass to Lignin and Sugars by Molten Salt Hydrate at Low Temperature for Overall Biorefinery. AB - Lignocellulose is a complex of cellulose, hemicellulose, and lignin, whose overall conversion is still a challenge, especially by a fast and efficient method. Here, a very simple method has been developed using acidic molten salt of zinc chloride hydrate as the solvent and catalyst for complete disassembly of lignocellulose at 95 degrees C and atmospheric pressure in 12 min. The major products are lignin and monosaccharides, such as glucose and xylose. It was found that high-purity lignin in yield of about 20 wt % can be obtained with various biomass, and the maximum yield of glucose from bamboo is 40.56 wt % and that of xylose from wheat straw is 16.82 wt %. Importantly, zinc chloride can be recovered through precipitation by ammonia and reused for next cycles. It provides a simple route to separate and efficiently convert lignocellulose, especially high-grade feedstock for biorefinery. PMID- 30023857 TI - Impact of Electrical Conductivity on the Electrochemical Performances of Layered Structure Lithium Trivanadate (LiV3-x M x O8, M= Zn/Co/Fe/Sn/Ti/Zr/Nb/Mo, x = 0.01-0.1) as Cathode Materials for Energy Storage. AB - Pristine trivanadate (LiV3O8) and doped lithium trivanadate (LiV3-x M x O8, M = Zn/Co/Fe/Sn/Ti/Zr/Nb/Mo, x = 0.01/0.05/0.1 M) compounds were prepared by a simple reflux method in the presence of the polymer, Pluronic P123, as the chelating agent. For comparison, pristine LiV3O8 alone was also prepared in the absence of the chelating agent. The Rietveld-refined X-ray diffraction patterns shows all compounds to exist in the layered monoclinic LiV3O8 phase belonging to the space group of P21/m. Scanning electron microscopy analysis shows the particles to exhibit layers of submicron-sized particles. The electrochemical performances of the coin cells were compared at a current density of 30 mA/g in the voltage window of 2-4 V. The cells made with compounds LiV2.99Zr0.01O8 and LiV2.95Sn0.05O8 show a high discharge capacity of 245 +/- 5 mA h/g, with an excellent stability of 98% at the end of the 50th cycle. The second cycle discharge capacity of 398 mA h/g was obtained for the compound LiV2.99Fe0.01O8, and its capacity retention was found to be 58% after 50 cycles. The electrochemical performances of the cells were correlated with the electrical properties and the changes in the structural parameters of the compounds. PMID- 30023858 TI - Synthesis and Biological Evaluation of 8-Quinolinamines and Their Amino Acid Conjugates as Broad-Spectrum Anti-infectives. AB - In the search of therapeutic agents for emerging drug-resistant parasites, the synthesis of newer classes of 8-quinolinamines has emerged as a successful chemotherapeutic approach. We report synthesis of 8-quinolinamines bearing 5 alkoxy, 4-methyl, and 2-tert-butyl groups in the quinoline framework and their amino acid conjugates as broad-spectrum anti-infectives. 8-Quinolinamines exhibited potent in vitro antimalarial activity [IC50 = 20-4760 ng/mL (drug sensitive Plasmodium falciparum D6 strain) and IC50 = 22-4760 ng/mL (drug resistant P. falciparum W2 strain)]. The most promising analogues have cured all animals at 25 mg/kg/day against drug-sensitive Plasmodium berghei and at 50 mg/kg/day against multidrug-resistant Plasmodium yoelii nigeriensis infections in Swiss mice. The in vitro antileishmanial activities (IC50 = 0.84-5.0 MUg/mL and IC90 = 1.95-7.0 MUg/mL) comparable to standard drug pentamidine were exhibited by several of the synthesized 8-quinolinamines. At the same time, very promising antifungal activities (Candida albicans-IC50 = 4.93-19.38 MUg/mL; Candida glabrata-IC50 = 3.96-19.22 MUg/mL; Candida krusei-IC50 = 2.89-18.95 MUg/mL; Cryptococcus neoformans-IC50 = 0.67-18.64 MUg/mL; and Aspergillus fumigatus-IC50 = 6.0-19.32 MUg/mL) and antibacterial activities (Staphylococcus aureus-IC50 = 1.33-18.9 MUg/mL; methicillin-resistant S. aureus-IC50 = 1.38-15.34 MUg/mL; and Mycobacterium intracellulare-IC50 = 3.12-20 MUg/mL) were also observed. None of the 8-quinolinamines exhibited cytotoxicity and therefore are a promising structural class of compounds as antiparasitic and antimicrobials. PMID- 30023860 TI - Reconciling Selectivity Trends from a Comprehensive Kinase Inhibitor Profiling Campaign with Known Activity Data. AB - Kinase inhibitors are among the most intensely investigated compounds in medicinal chemistry and drug development. Profiling experiments and kinome screens reveal binding characteristics of kinase inhibitors and lead to better understanding of selectivity and promiscuity patterns. However, only limited amounts of profiling data are publicly available. By contrast, a large body of activity data for inhibitors of human kinases has become available from medicinal chemistry. In this study, we have correlated selectivity assessment of clinical kinase inhibitors from the most comprehensive profiling campaign reported to date with systematic mining of activity data from other sources. The results of our comparative analysis reveal consistency of orthogonal approaches in the study of kinase inhibitor selectivity versus promiscuity and stress the importance of taking alternative data confidence criteria into account. Moreover, it is also shown that there are little if any detectable differences in selectivity between type I and II kinase inhibitors and that inhibitors designated as chemical probes have very different target profiles. PMID- 30023859 TI - Effect of Urea on Solvation Dynamics and Rotational Relaxation of Coumarin 480 in Aqueous Micelles of Cationic Gemini Surfactants with Different Spacer Groups. AB - The present work highlights the effect of urea on solvation dynamics and the rotational relaxation of Coumarin 480 (C-480) in the Stern layer of aqueous micelles of cationic gemini surfactants, 12-4(OH) n -12 (n = 0, 1, 2). UV-visible absorption, steady-state fluorescence and fluorescence anisotropy, time-resolved fluorescence and fluorescence anisotropy, and dynamic light scattering measurements have been carried out for this study. The formation of micelles becomes disfavored in the presence of urea at high concentration. Solvation dynamics is bimodal in nature with fast solvation as a major component. The average solvation time increases, reaches a maximum, and then decreases with increasing concentration of urea because the degree of counterion dissociation also follows the same order with the addition of urea in the micellar solution. With increased degree of counterion dissociation, the extent of clustering of water molecules is increased, resulting in slower solvation process. The -OH group present in the spacer group of gemini surfactant controls the rate of solvation by shielding the water molecules from the probe molecules forming hydrogen bond. The microviscosity of micelles is decreased with increasing concentration of urea, as a result of which the rotational relaxation process becomes faster. In the presence of the -OH group in the spacer group, the microviscosity of micelles is enhanced, resulting in longer rotational relaxation time. Rotational relaxation process is bimodal in nature with the major contribution from the fast component to the fluorescence depolarization. Slow rotational relaxation is mainly due to the lateral diffusion of C-480 molecules along the surface of the micelle. The tumbling motion of the micelle as a whole is much slower than the lateral diffusion of C-480. Wobbling motion of C-480 becomes faster with increasing concentration of urea as a result of decreased microviscosity of micelles. The alignment of C-480 molecules in micelles might change with changing microviscosity. PMID- 30023861 TI - Graphene as an Imaging Platform of Charged Molecules. AB - Graphene, a single atom layer of carbon atoms, provides a two-dimensional platform with an extremely high sensitivity to charges due to its unique band structure and high surface-to-volume ratio. Graphene field-effect transistor (G FET) biosensors have, indeed, demonstrated a detection limit of subnanomolar or even subpicomolar. However, in G-FET, signal is averaged throughout the whole channel, so there remains a need to visualize the spatial distribution of target molecules on a single G-FET, to provide further insight into target molecules and/or biological functions. Here, we made use of graphene as an imaging platform of charged molecules via Raman microscopy. Positively (or negatively) charged microbeads with a diameter of 1 MUm were dispersed in a buffer solution and were attached on graphene. We found out that Raman peaks of graphene, where positively (or negatively) charged beads contacted, were up-shifted (or down-shifted) significantly, indicating that the carrier density in the graphene was locally modulated by the charged beads and the charge state of the beads was represented by the peak-shift direction. From the peak shift, the change in the carrier density was calculated to be +1.4 * 1012 cm-2 (or -1.0 * 1012 cm-2). By taking Raman peak-shift images, we visualized distribution of charged molecules on graphene with a spatial resolution below 1 MUm. The technique described here overcomes the limitation of spatial resolution of G-FET and provides a new route to graphene-based chemical and biosensors. PMID- 30023863 TI - Structural Switch from Hairpin to Duplex/Antiparallel G-Quadruplex at Single Nucleotide Polymorphism (SNP) Site of Human Apolipoprotein E (APOE) Gene Coding Region. AB - A gradual dementia, which leads to the loss of memory and intellectual abilities, is the main characteristics of Alzheimer's disease. Amyloid-beta (Abeta) plaques are the main components that accumulate and form clumps in the brains of people suffering from Alzheimer's disease. Apolipoprotein E (APOE), an amyloid-binding protein is considered as one of the main genetic risk factor of the late-onset Alzheimer's disease. Different isoforms of APOE gene named APOE2, APOE3, and APOE4 are known to exist, which differ from each other at certain positions involving single-nucleotide polymorphisms (SNPs). Out of these isoforms, APOE4 increases the risk of developing late-onset Alzheimer's disease, whereas APOE3 is the most common among the general population. APOE4 differs from the common APOE3 by only one nucleotide at position +2985 (T to C), which results in immense alteration in the structure and function of the APOE gene. A combination of gel electrophoresis (polyacrylamide gel electrophoresis, PAGE), circular dichroism (CD), CD melting, thermal difference spectra and UV-thermal denaturation (TM) techniques was used to investigate the structural polymorphism associated with T > C single-nucleotide polymorphism (SNP) at the GC-rich sequence (d TGGAGGACGTGTGCGGCCGCCT; APOE22T). Herein, we report that APOE22T DNA sequence switches between hairpin to antiparallel quadruplex from low to high oligomer concentration. On the contrary, its C-counterpart (APOE22C) forms hairpin as well as intermolecular antiparallel duplex structure. This structural change may possibly contribute to the protein recognition pattern, which, in turn, might control the APOE gene expression. PMID- 30023862 TI - Self-Assembly Mechanism of a Peptide-Based Drug Delivery Vehicle. AB - We report the mechanism of the concentration-dependent self-assembly of a tetrapeptide. Peptide Boc-Trp-Leu-Trp-Leu-OMe self-assembles to form discrete nanospheres at a low concentration. Tryptophan side chains point outwards of the nanospheres while leucine side chains point towards the core of the nanospheres. The nanospheres fuse together to become microspheres with the increase in the peptide concentration. At higher concentrations of the peptide, the microspheres start clustering. This is stabilized by the aromatic interactions between the side chains of the tryptophan residues that cover the outer surface of the peptide microspheres. In addition to behaving like the conventional hollow sphere based drug delivery vehicles which entraps the drug and performs stimuli responsive release, this prototype can interact, stabilize, and intercalate hydrophobic dye carboxyfluorescein and anti-cancer drug curcumin even on the surface through aromatic interactions. The dye/drug can be released in acidic pH and in the presence of physiologically relevant ions such as potassium. PMID- 30023864 TI - White-Light-Activated Antibacterial Surfaces Generated by Synergy between Zinc Oxide Nanoparticles and Crystal Violet. AB - The prevalence of hospital-acquired infections (HAIs) caused by multidrug resistant bacteria is a growing public health concern worldwide. Herein, a facile, easily scalable technique is reported to fabricate white-light-activated bactericidal surfaces by incorporating zinc oxide (ZnO) nanoparticles and crystal violet (CV) dye into poly(dimethylsiloxane). The effect of ZnO concentration on photobactericidal activity of CV is investigated, and we show that there is synergy between ZnO and CV. These materials showed highly significant antibacterial activity when tested against Staphylococcus aureus and Escherichia coli under white light conditions. These surfaces have potential to be used in healthcare environments to decrease the impact of HAIs. PMID- 30023866 TI - Comparative Study of DNA Circuit System-Based Proportional and Exponential Amplification Strategies for Enzyme-Free and Rapid Detection of miRNA at Room Temperature. AB - Because circulating microRNAs (miRNAs) have been recognized as a new class of blood-based biomarkers for various diseases, a significant challenge has been the development of point-of-care testing (POCT) systems based on detection of circulating miRNAs directly from serum. A promising approach to POCT systems is considered to be the development of enzyme-free and isothermal detection systems. Here, two types of DNA circuit system based on proportional and exponential amplification strategies were constructed using double-stranded DNA-modified magnetic beads (dsDNA-MBs) and their performances for detection of miRNA were studied comparatively. Both proportional and exponential amplification DNA circuit systems enabled the detection of target miRNA (miR-141) at room temperature without the need for additional enzymes because miR-141 acted as a catalyst for successive toehold-mediated DNA displacement reactions. A significant increase in the noise fluorescence signal was observed for the exponential amplification DNA circuit system because of the leakage (undesired DNA displacement reaction) revealed by the kinetic study on each DNA displacement reaction. Nevertheless, the exponential amplification DNA circuit system showed a lower limit of detection (LOD: 46 pM) and shorter assay time (15 min) compared to those of the proportional amplification DNA circuit system (LOD: 103 pM at 180 min). It is most likely that the exponential amplification DNA circuit system enabled amplification of both the signals and target miR-141, whereas the proportional amplification DNA circuit system enabled amplification of the signals alone. In addition, the exponential amplification DNA circuit system was able to discriminate between mismatched base sequences in miR-200 family members and specifically detect miR-141 even in the presence of serum. These findings are important for the rational design for POCT systems. PMID- 30023865 TI - Liquid Crystalline Nanostructures as PEGylated Reservoirs of Omega-3 Polyunsaturated Fatty Acids: Structural Insights toward Delivery Formulations against Neurodegenerative Disorders. AB - Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are bioactive lipids with considerable impact in medicine and nutrition. These compounds exert structuring effects on the cellular membrane organization, regulate the gene expression, and modulate various signaling cascades and metabolic processes. The purpose of the present work is to demonstrate the structural features of omega-3 PUFA-containing three-dimensional supramolecular lipid assemblies suitable for pharmaceutical applications that require soft porous carriers. We investigate the liquid crystalline structures formed upon mixing of eicosapentaenoic acid (EPA, 20:5) with the lyotropic nonlamellar lipid monoolein and the formation of multicompartment assemblies. Starting with the monoolein-based lipid cubic phase, double membrane vesicles, cubosome precursors, sponge-type particles (spongosomes), mixed intermediate nonlamellar structures, and multicompartment assemblies are obtained through self-assembly at different amphiphilic compositions. The dispersions containing spongosomes as well as nanocarriers with oil and vesicular compartments are stabilized by PEGylation of the lipid/water interfaces using a phospholipid with a poly(ethylene glycol) chain. The microstructures of the bulk mixtures were examined by cross-polarized light optical microscopy. The dispersed liquid crystalline structures and intermediate states were studied by small-angle X-ray scattering, cryogenic transmission electron microscopy, and quasielastic light scattering techniques. They established that PUFA influences the phase type and the sizes of the aqueous compartments of the liquid crystalline carriers. The resulting multicompartment systems and stealth nanosponges may serve as mesoporous reservoirs for coencapsulation of omega-3 PUFA (e.g., EPA) with water-insoluble drugs and hydrophilic macromolecules toward development of combination treatment strategies of neurodegenerative and other diseases. PMID- 30023867 TI - 6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84). AB - GPR84, a Gi protein-coupled receptor that is activated by medium-chain (hydroxy)fatty acids, appears to play an important role in inflammation, immunity, and cancer. Recently, 6-octylaminouracil (4) has been reported to act as an agonist at GPR84. Here, we describe the synthesis of 69 derivatives and analogs of 4, 66 of which represent new compounds. They were evaluated in (a) cyclic adenosine monophosphate accumulation and (b) beta-arrestin assays in human GPR84-expressing cells. Potent nonbiased as well as G protein-biased agonists were developed, e.g., 6-hexylamino-2,4(1H,3H)-pyrimidinedione (20, PSB-1584, EC50 5.0 nM (a), 3.2 nM (b), bias factor: 0) and 6-((p-chloro- and p-bromo phenylethyl)amino)-2,4(1H,3H)-pyrimidinedione (47, PSB-16434, EC50 7.1 nM (a), 520 nM (b), bias factor: 1.9 = 79-fold Gi pathway-selective; 48, PSB-17365, EC50 2.5 nM (a), 100 nM (b), bias factor 1.3 = 20-fold selective), which were selective versus other free fatty acid-activated receptors. Compounds 20 and 48 were found to be metabolically stable upon incubation with human liver microsomes. A pharmacophore model was created on the basis of structurally diverse lipidlike GPR84 agonists. PMID- 30023868 TI - Silk Fibroin Acts as a Self-Emulsifier to Prepare Hierarchically Porous Silk Fibroin Scaffolds through Emulsion-Ice Dual Templates. AB - Silk fibroin (SF) has shown enormous potentials in various fields; however, application of SF in emulsion technology is quite limited. Here, we use SF as a self-emulsifier to form an oil-in-water (O/W) emulsion by emulsifying 1-butanol in SF aqueous solution. This showed that SF possessed strong surface activity to stabilize the O/W emulsion without the need for any other surface-active agent until its solidification because of 1-butanol-induced conformational transition of SF to beta-sheet. After freezing the preformed emulsions at -20 degrees C, robust three-dimensional porous SF scaffolds were prepared without the need for any further post-treatment. The evolution from the O/W emulsion to porous scaffold formation under freezing was tracked, and an emulsion-ice dual template mechanism was proposed for scaffold formation, based on which SF scaffolds with controllable hierarchically porous structures were achieved by tuning the dispersed droplet volume fraction. Furthermore, SF scaffolds with hierarchical porosity showed significantly higher bioactivity toward L929 fibroblasts than that of SF scaffolds with mono macroporosity, highlighting the great asset of this hierarchically porous SF scaffold for broad applications in tissue engineering. Therefore, the strong surface-active characteristic of SF presented here, in addition to its distinct advantages, sheds a bright light on the application of SF in the vast range of emulsion technologies, especially in cosmetic-, food-, and biomedical-related areas. PMID- 30023869 TI - Self-Assembly of Graphene-Encapsulated Cu Composites for Nonenzymatic Glucose Sensing. AB - Cu has recently received great interest as a potential candidate for glucose sensing to overcome the problems with noble metals. In this work, reduced graphene oxide-encapsulated Cu nanoparticles (Cu@RGO) have been prepared via an electrostatic self-assembly method. This core/shell composites were found to be more stable than conventional Cu-decorated graphene composites and bare copper nanoparticles in an air atmosphere because the graphene shell can effectively protect the Cu nanoparticles from oxidation. In addition, the obtained Cu@RGO composites also showed an outstanding electrocatalytic activity toward glucose oxidation with a wide linear detection range of 1 MUM to 2 mM, low detection limit of 0.34 MUM (S/N = 3), and a sensitivity of 150 MUA mM-1 cm-2. Moreover, Cu@RGO composites exhibited a satisfactory reproducibility, selectivity, and long effective performance. These excellent properties indicated that Cu@RGO nanoparticles have great potential application in glucose detection. PMID- 30023870 TI - Total Syntheses and Biological Evaluation of the Ganoderma lucidum Alkaloids Lucidimines B and C. AB - Although a range of pharmacologically active compounds has been obtained from the mycelium and fruiting bodies of Ganoderma lucidum, the biological properties of the alkaloids present in this functional food remain unknown. Herein, we report total syntheses of lucidimines B and C, key members of the first family of alkaloids isolated from G. lucidum, and the evaluation of these synthetically derived materials as antioxidants and antiproliferative agents. Lucidimine B proved to be a better antioxidant than congener C. Similarly, lucidimine B exhibited antiproliferative properties toward MCF-7 cells (an EC50 value of 0.27 +/- 0.02 MUmol/mL), whereas lucidimine C was inactive. The former alkaloid arrested the MCF-7 cell cycle in the S phase by inducing DNA fragmentation, hence reducing the mitochondrial membrane potential. This work thus demonstrates, for the first time, that the alkaloidal constituents derived from G. lucidum are biologically active and may, therefore, contribute to the beneficial health claims made for this nutraceutical. PMID- 30023871 TI - Flexible Electrochemical Transducer Platform for Neurotransmitters. AB - We have designed a flexible electrochemical transducer film based on PEDOT titania-poly(dimethylsiloxane) (PTS) for the simultaneous detection of neurotransmitters. PTS films were characterized using various techniques such as transmission electron microscopy, scanning electron microscopy, atomic force microscopy, four probe electrical conductivity, ac-impedance, and thermomechanical stability. The electrocatalytic behavior of the flexible PTS film toward the oxidation of neurotransmitters was investigated using cyclic voltammetry and differential pulse voltammetry. The fabricated transducer measured a limit of detection of 100 nm +/- 5 with a response time of 15 s and a sensitivity of 63 MUA mM-1 cm-2. The fabricated transducer film demonstrated for the simultaneous determination of epinephrine, dopamine, ascorbic acid, and uric acid with no interference between the analyte molecules. Further, transducer performance is validated by performing with real samples. The results suggested that the fabricated flexible PTS transducer with superior electrocatalytic activity, stability, and low response time can be explored for the sensing of neurotransmitters and hence can be exploited at in vitro and in vivo conditions for the early detection of the various diseases. PMID- 30023872 TI - Design of Pyrene-Fatty Acid Conjugates for Real-Time Monitoring of Drug Delivery and Controllability of Drug Release. AB - Fluorescence probes are usually employed to analyze pharmacokinetics of drug carriers; however, this method using usual probes is not suitable to monitor drug carriers in detail because fluorescence spectra do not change by the disruption of drug carriers. In this study, pyrene-fatty acid conjugates were investigated as probes to monitor the state of drug carriers in real time. 1-Pyrenemethanol was conjugated with fatty acids, such as lauric acid, stearic acid, and behenic acid, and the conjugates were stirred in ethanol, resulting in the formation of submicron particles; these particles exhibited excimer emission. When J774.1 and Colon 26 cells were treated with these particles, the associated fluorescence spectra shifted from excimer emission to monomer emission. Moreover, the degree of change was controlled by the type of fatty acid. These results support the design of drug carriers that can be used to monitor pharmacokinetics in real time and to control the disruption time. PMID- 30023873 TI - Synthetic DNA-Binding Inhibitor of HES1 Alters the Notch Signaling Pathway and Induces Neuronal Differentiation. AB - Synthetic DNA-binding inhibitors capable of gaining precise control over neurogenesis factors could obviate the current clinical barriers associated with the use of small molecules in regenerative medicine. Here, we report the design and bioefficacy of the synthetic ligand PIP-RBPJ-1, which caused promoter specific suppression of neurogenesis-associated HES1 and its downstream genes. Furthermore, PIP-RBPJ-1 alone altered the neural-system-associated Notch signaling factors and remarkably induced neurogenesis with an efficiency that was comparable to that of a conventional approach. PMID- 30023874 TI - Proteomic Investigation of the Binding Agent between Liver Glycogen beta Particles. AB - Glycogen is a highly branched glucose polymer which plays an important role in glucose storage and the maintenance of blood sugar homeostasis. The dimeric protein glycogenin can self-glucosylate to act as a primer for glycogen synthesis, eventually resulting in small (~20 nm diameter) glycogen beta particles with a dimer of glycogenin at their core. In the liver, glycogen is also found in the form of alpha particles: large bound composites of many beta particles. Here, we provide evidence using qualitative and quantitative proteomics and size-exclusion chromatography from healthy rat, mouse, and human liver glycogen that glycogenin is the binding agent linking beta particles together into alpha particles. PMID- 30023875 TI - Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase. AB - Diamine oxidase (DAO) is an enzyme involved in the regulation of cell proliferation and the immune response. This enzyme performs oxidative deamination in the catabolism of biogenic amines, including, among others, histamine, putrescine, spermidine, and spermine. The mechanistic details underlying the reductive half-reaction of the DAO-catalyzed oxidative deamination which leads to the reduced enzyme cofactor and the aldehyde product are, however, still under debate. The catalytic mechanism was proposed to involve a prototropic shift from the substrate-Schiff base to the product-Schiff base, which includes the rate limiting cleavage of the Calpha-H bond by the conserved catalytic aspartate. Our detailed mechanistic study, performed using a combined quantum chemical cluster approach with empirical valence bond simulations, suggests that the rate-limiting cleavage of the Calpha-H bond involves direct hydride transfer to the topaquinone cofactor-a mechanism that does not involve the formation of a Schiff base. Additional investigation of the D373E and D373N variants supported the hypothesis that the conserved catalytic aspartate is indeed essential for the reaction; however, it does not appear to serve as the catalytic base, as previously suggested. Rather, the electrostatic contributions of the most significant residues (including D373), together with the proximity of the Cu2+ cation to the reaction site, lower the activation barrier to drive the chemical reaction. PMID- 30023876 TI - Novel Salt-Tolerant Xylanase from a Mangrove-Isolated Fungus Phoma sp. MF13 and Its Application in Chinese Steamed Bread. AB - A novel glycosyl hydrolase family 11 xylanase gene, xynMF13A, was cloned from Phoma sp. MF13, a xylanase-producing fungus isolated from mangrove sediment. xynMF13A was heterologously expressed in Pichia pastoris, and the recombinant XynMF13A (rXynMF13A) was purified by Ni-affinity chromatography. The temperature and pH optima of purified rXynMF13A were 45 degrees C and pH 5.0, respectively. rXynMF13A showed a high level of salt tolerance, with maximal enzyme activity being seen at 0.5 M NaCl and as much as 53% of maximal activity at 4 M NaCl. The major rXynMF13A hydrolysis products from corncob xylan were xylobiose, xylotriose, xylotetraose, and xylopentaose, but no xylose was found. These hydrolysis products suggest an important potential for XynMF13A in the production of xylooligosaccharides (XOs). Furthermore, rXynMF13A had beneficial effects on Chinese steamed bread production, by increasing specific volume and elasticity while decreasing hardness and chewiness. These results demonstrate XynMF13A to be a novel xylanase with potentially significant applications in baking, XOs production, and seafood processing. PMID- 30023877 TI - Laser-Induced Antibacterial Activity of Novel Symmetric Carbazole-Based Ethynylpyridine Photosensitizers. AB - In this study, two kinds of novel carbazole-based ethynylpyridine salts: 3,6 bis[2-(1-methylpyridinium)ethynyl]-9-pentyl-carbazole diiodide (BMEPC) and 3,6 bis[2-(1-methylpyridinium)ethynyl]-9-methyl-carbazole diiodide (BMEMC) have been employed as photosensitizers owing to their excellent antibacterial activity. These molecules possess symmetric A-pi-D-pi-A-type structures, which would bring in the unique optical properties. The inhibition zone measurement of a gradient concentration from 0 to 100 MUM showed BMEPC and BMEMC photoinduced antibacterial activity against Escherichia coli. Diameters of zone of inhibition were up to 15 and 14 mm under laser irradiations. Under the exposure of the laser of 442 nm with a power density of 20 mW/cm2, the minimum inhibitory concentrations (MICs) of BMEPC on E. coli were between 3.5 and 6.9 MUM and that of BMEMC were between 9.4 and 18.8 MUM, respectively. In the dark experiments as a control, the MIC value is between 6.9 and 13.8 MUM for BMEPC, whereas it is between 187.5 and 225.0 MUM for BMEMC. By the comparison of the MIC values of BMEPC and BMEMC with laser irradiation and in dark, the laser-induced toxicity on bacteria is more evident, though both of the derivatives have dark toxicity. With the laser irradiation duration of 30 s and 10 min for BMEPC and BMEMC, respectively, the survival rate of E. coli approximates zero. An antibacterial mechanism has been proposed based on the electron paramagnetic resonance characterization, which indicates that a nitride radical is generated under laser irradiation. The carbazole-based ethynylpyridine photosensitizers would provide high potential for further applications in photodynamic therapy. PMID- 30023878 TI - On the Mechanism of Action of Dragmacidins I and J, Two New Representatives of a New Class of Protein Phosphatase 1 and 2A Inhibitors. AB - Two new brominated bis(indole) alkaloids, dragmacidins I (1) and J (2), showing low micromolar cytostatic activity, along with three known congeners were isolated from the Tanzanian sponge Dragmacidon sp. and their structures determined by the analysis of their NMR and MS data. From the study of their mechanism of action, it can be concluded that the mitotic arrest at metaphase in treated tumor cells, mediated by inhibition of PP1 and/or PP2A phosphatases is involved in the observed antiproliferative activity. Differences in their bioactivities were rationalized, and a plausible binding mode is proposed on the basis of computational simulations. PMID- 30023879 TI - Combining Similarity Searching and Network Analysis for the Identification of Active Compounds. AB - A variety of computational screening methods generate similarity-based compound rankings for hit identification. However, these rankings are difficult to interpret. It is essentially impossible to determine where novel active compounds might be found in database rankings. Thus, compound selection largely depends on intuition and guesswork. Herein, we show that molecular networks can substantially aid in the analysis of similarity-based compound rankings. A series of networks generated for rankings provides visual access to search results and adds chemical neighborhood and context information for reference compounds that are not available in rankings. Network structure is shown to serve as a diagnostic criterion for the likelihood to successfully select active compounds from rankings. In addition, comparison of different networks makes it possible to prioritize alternative similarity measures for search calculations and optimize the enrichment of active compounds in rankings. PMID- 30023880 TI - Energetics of Preferential Binding of Retinoic Acid-Inducible Gene-I to Double Stranded Viral RNAs with 5' Tri-/Diphosphate over 5' Monophosphate. AB - Retinoic acid-inducible gene-I (RIG-I) is a cytosolic sensor protein that recognizes viral RNAs and triggers an innate immune response in cells. Panhandle like base-paired blunt-ended 5' ppp/pp-dsRNA is a characteristic feature of viral RNAs. Structural studies of RIG-I C-terminal domain bound 5' ppp/pp-dsRNA complexes show the direct interaction between all the 5' terminal phosphates (alpha, beta, and gamma) and protein, suggesting gamma phosphate might be a major recognition determinant for RIG-I binding. Biochemical studies, however, suggest that 5' pp-dsRNA is the minimal determinant for RIG-I binding and antiviral response. Despite biochemical and structural studies, the origin of viral RNA recognition by RIG-I is an unsolved problem. X-ray structures of RIG-I bound dsRNA not only provide atomic insight into the interaction network but also provide sufficiently good models for computational studies. We report structure based molecular dynamics (MD) free energy calculations to quantitatively estimate the energetics of RIG-I binding to dsRNA containing 5' ppp, 5' pp, and 5' p. The results suggest that RIG-I weakly discriminates between 5' ppp-dsRNA and 5' pp dsRNA (favoring former) and strongly disfavors 5' p-dsRNA with respect to the rest. Interestingly, direct interaction between gamma phosphate of 5' ppp-dsRNA and RIG-I is a robust feature of the MD simulations. dsRNA binding to RIG-I is associated with Mg2+ dissociation from the 5' phosphate/s of dsRNA. The higher Mg2+ dissociation penalty from 5' ppp-dsRNA with respect to 5' pp-dsRNA offsets most of the favorable interaction between RIG-I and gamma phosphate of 5' ppp dsRNA. This leads to weak discrimination between 5' ppp-dsRNA and 5' pp-dsRNA. 5' p-dsRNA is discriminated strongly because of the loss of interaction with RIG-I. PMID- 30023881 TI - Colorimetric Immunosensor by Aggregation of Photochemically Functionalized Gold Nanoparticles. AB - A colorimetric immunosensor based on local surface plasmon resonance by gold nanoparticles is presented, and its application for the detection of human immunoglobulin G (IgG) is demonstrated. The color change of the colloidal solution is produced by nanoparticle aggregation, a process that can be tuned by the presence of the analyte once the nanoparticles are functionalized. In comparison to common functionalization techniques, the procedure described here is simpler, low-cost, and effective in binding antibodies upright on the gold surface. The dose-response curve is similar to that resulting in typical immunoassay platforms and is satisfactorily described by the proposed theoretical model. Human IgG at concentration levels of few hundreds of nanograms per milliliter can be detected by eyes within a few minutes, thereby making the colorimetric immunosensor proposed here a powerful tool in several areas, with urine test in medical diagnostics being the most immediate. PMID- 30023882 TI - Predictive Model for the Sequence-Dependent Fluorogenic Response of Forced Intercalation Peptide Nucleic Acid. AB - : The forced-intercalation peptide nucleic acid (FIT-PNA) concept, introduced by Seitz and co-workers, is based on replacing a nucleobase of the PNA sequence with a cyanine dye (such as thiazole orange). The cyanine dye is thus a surrogate base that is forced to intercalate in the duplex (e.g. , PNA: DNA). This allows single mismatch sensitivity as the introduction of a mismatch in the vicinity of the dye increases freedom of motion and leads to a significant depletion of its fluorescence because of the free rotation of the monomethine bond separating the two pi-systems of the cyanine dye. Herein, we designed and synthesized six FIT PNA probes, featuring bisquinoline (BisQ), a red-emitting cyanine dye recently developed in our laboratory for FIT-PNAs. By following PNA-DNA duplex fluorescence, we found new sequence-based factors governing the fluorescence response to the mismatched FIT-PNA:DNA duplex. Fluorogenic properties are correlated with the pi-stacking energy of three distinctive base pair steps (BPSs) in the PNA:DNA duplex. The first two are the two BPSs opposite BisQ, whereas the third is the BPS of the mismatch position, which presumably becomes unstacked due to the mismatch. We suggest a predictive model for FIT-PNA single mismatch detection mechanism, a model that can be used in future research to improve FIT-PNA design. PMID- 30023884 TI - Functionalized Hydrophilic Superparamagnetic Iron Oxide Nanoparticles for Magnetic Fluid Hyperthermia Application in Liver Cancer Treatment. AB - In this work, we report the synthesis of hydrophilic and surface-functionalized superparamagnetic iron oxide nanoparticles (SPIOs) to utilize them as nanomedicines for treating liver cancer via magnetic fluid hyperthermia (MFH) based thermotherapy. For this purpose, initially, we have synthesized the SPIOs through co-precipitation/thermolysis methods, followed by in situ surface functionalization with short-chained molecules, such as 1,4-diaminobenzene (14DAB), 4-aminobenzoic acid (4ABA) and 3,4-diaminobenzoic acid (34DABA) and their combination with terephthalic acid (TA)/2-aminoterephthalic acid (ATA)/trimesic acid (TMA)/pyromellitic acid (PMA) molecules. The as-prepared SPIOs are investigated for their structure, morphology, water dispersibility, and magnetic properties. The heating efficacies of the SPIOs are studied in calorimetric MFH (C-MFH) with respect to their concentrations, surface coatings, dispersion medium, and applied alternating magnetic fields (AMFs). Although all of the as-prepared SPIOs have exhibited superparamagnetic behavior, only 14DAB-, 4ABA-, 34DABA-, and 4ABA-TA-coated SPIOs have shown higher magnetization values (Ms = 55-71 emu g-1) and good water dispersibility. In C-MFH studies, 34DABA coated SPIO-based aqueous ferrofluid (AFF) has revealed faster thermal response to the applied AMF and reached therapeutic temperature even at the lowest concentration (0.5 mg mL-1) compared with 14DAB-, 4ABA-, and 4ABA-TA-coated SPIO based AFFs. Moreover, 34DABA-coated SPIO-based AFF has exhibited high heating efficacies (i.e., specific absorption rate/intrinsic loss power values of 432.1 W gFe-1/5.2 nHm2 kg-1 at 0.5 mg mL-1), which could be mainly due to (i) enhanced pi pi conjugation paths of surface-attached 34DABA coating molecules because of intrafunctional group attractions and (ii) improved anisotropy from the formation of clusters/linear chains of the SPIOs in ferrofluid suspensions, owing to interfunctional group attractions/interparticle interactions. Moreover, the 34DABA-coated SPIOs have demonstrated (i) very good cytocompatibility for 24/48 h incubation periods and (ii) higher killing efficiency of 61-88% (via MFH) in HepG2 liver cancer cells as compared to their treatment with only AMF/water-bath based thermotherapy. In summary, the 34DABA-coated SPIOs are very promising heat inducing agents for MFH-based thermotherapy and thus could be used as effective nanomedicines for cancer treatments. PMID- 30023883 TI - From Live Cells to Caenorhabditis elegans: Selective Staining and Quantification of Lipid Structures Using a Fluorescent Hybrid Benzothiadiazole Derivative. AB - The current article describes the synthesis, characterization, and application of a designed hybrid fluorescent BTD-coumarin (2,1,3-benzothiadiazole-coumarin) derivative (named BTD-Lip). The use of BTD-Lip for live-cells staining showed excellent results, and lipid droplets (LDs) could be selectively stained. When compared with the commercially available dye (BODIPY) for LD staining, it was noted that the designed hybrid fluorescence was capable of staining a considerable larger number of LDs in both live and fixed cells (ca. 40% more). The new dye was also tested on live Caenorhabditis elegans (complex model) and showed an impressive selectivity inside the worm, whereas the commercial dye showed no selectivity in the complex model. PMID- 30023885 TI - Molecules as Biotic Messengers. AB - Chemical ecology has grown as a scientific discipline from its earliest days of tracking the exquisitely potent chemistry of insect pheromones to a deep understanding of the molecular, physiological, and behavioral interactions governed by naturally occurring small molecules. The current practice of the field relies on knowledge of genomes and gene expression patterns, protein biology, and small-molecule chemistry, providing illustrations of ecological and evolutionary patterns in natural communities. PMID- 30023886 TI - Infrared Nanospectroscopy of Phospholipid and Surfactin Monolayer Domains. AB - A main challenge in understanding the structure of a cell membrane and its interactions with drugs is the ability to chemically study the different molecular species on the nanoscale. We have achieved this for a model system consisting of mixed monolayers (MLs) of the biologically relevant phospholipid 1,2-distearoyl-sn-glycero-phosphatidylcholine and the antibiotic surfactin. By employing nano-infrared (IR) microscopy and spectroscopy in combination with atomic force microscopy imaging, it was possible to identify and chemically detect domain formation of the two constituents as well as to obtain IR spectra of these species with a spatial resolution on the nanoscale. A novel method to enhance the near-field imaging contrast of organic MLs by plasmon interferometry is proposed and demonstrated. In this technique, the organic layer is deposited on gold and ML graphene substrates, the latter of which supports propagating surface plasmons. Plasmon reflections arising from changes in the dielectric environment provided by the organic layer lead to an additional contrast mechanism. Using this approach, the interfacial region between surfactin and the phospholipid has been mapped and a transition region is identified. PMID- 30023887 TI - DNA Directed Self-Assembly of Single Walled Carbon Nanotubes into Three-Way Junction Nanostructures. AB - Utilization of a self-assembled two-dimensional DNA nanostructure to arrange single-walled carbon nanotubes (SWNTs) into predetermined structures at controllable angles is presented. A specially designed DNA three-way junction (3WJ) composed of three double-stranded DNA arms containing single-stranded overhang sequences was prepared by annealing of partially complementary ssDNA sequences and ultrasonicated with SWNTs, resulting in DNA-3WJ/SWNT hybrid nanostructures. Utilization of DNA-3WJ not only allowed the precise dispersion of SWNTs but also acted as a rigid template for the self-assembly of SWNTs into three-armed junctions at an angle of approximately 120 degrees to each other as visualized by scanning electron microscopy and atomic force microscopy. Prepared DNA-3WJ/SWNT nanostructures were also demonstrated to have the appropriate binding sites for fluorophores, providing a simple method for the fluorescent labeling of SWNTs. When ssDNA sequences forming the DNA-3WJ are ultrasonicated with SWNTs, followed by annealing of resulting ssDNA wrapped SWNTs, instead of hybrid junctions composed of three SWNT molecules, a web-like structure composed of interconnected SWNT junctions was obtained. The design approaches demonstrated here provide simple methods for the arrangement of SWNTs into desired nanostructures utilizing pre-assembled DNA nanostructures as linkers in aqueous solution through noncovalent interactions which can greatly contribute to efforts along the controlled assembly of SWNTs. PMID- 30023888 TI - Surface Modification of Polymers for Tissue Engineering Applications: Arginine Acts as a Sticky Protein Equivalent for Viable Cell Accommodation. AB - Hydrophobic polymers, for their favorable mechanical properties, are a popular choice as permanent bioimplants. These materials remain absolutely bioinert for years, but throw up challenges when it comes to fast integration with healthy tissue. Addressing this, herein, we present a surface-modification technique of converting the hydrophobic surface of a polymeric film into a hydrophilic one using a layer-by-layer assembly process involving gold nanoparticles and small molecules like amino acids. These films showed much improved animal cell (murine fibroblast) adherence properties compared to commercially available tissue culture plates. Moreover, arginine-modified films exhibited a nearly equivalent cell viability compared to the films modified with the natural extracellular matrix component fibronectin. The surface hydrophilicity and roughness of our novel film were characterized by contact angle measurement and atomic force microscopy. Cell counting, fluorescence microscopy, cell viability, and collagen estimation assay were employed to demonstrate that our film favored a much improved cell adherence, and accommodation in comparison to the commercially available tissue culture plates. PMID- 30023889 TI - Bioelectrochemical Denitrification for the Treatment of Saltwater Recirculating Aquaculture Streams. AB - Maintaining low concentrations of nitrogen compounds (ammonium, nitrate and nitrite) in recirculating aquaculture waters is extremely important for a larger and healthier fish production, as well as for water discharge purposes. Although ammonium removal from aquaculture streams is usually done within a nitrifying step, nitrate removal via denitrification is still partially limited by the low organic matter availability. Therefore, an easy-to-operate autotrophic denitrifying bioelectrochemical system is herein proposed for the treatment of seawater aquaculture streams. The nitrate-containing synthetic stream flows sequentially through a biological denitrifying cathode (placed at the lower portion of a tubular reactor) and an abiotic anode (generating electrons and oxygen from water splitting, at the upper portion). Experimental results with synthetic seawater showed that the system reached denitrification rates of 0.13 +/- 0.01 kg N m-3 day-1, operating with minimum ammonium and nitrite accumulation, as well as minimum chlorine formation in the abiotic anode, despite the high chloride concentration. There results support the technical potential for simultaneous bioelectrochemical denitrification and partial re-oxygenation of aquaculture waters either for recirculation or discharge purposes. PMID- 30023890 TI - Exploring the Scope of Photo-Induced Electron Transfer-Chelation-Enhanced Fluorescence-Fluorescence Resonance Energy Transfer Processes for Recognition and Discrimination of Zn2+, Cd2+, Hg2+, and Al3+ in a Ratiometric Manner: Application to Sea Fish Analysis. AB - A rhodamine-based smart probe (RHES) has been developed for trace-level detection and discrimination of multiple cations, viz. Al3+, Zn2+, Cd2+, and Hg2+ in a ratiometric manner involving photo-induced electron transfer-chelation-enhanced fluorescence-fluorescence resonance energy transfer processes. The method being very fast and highly selective allows their bare eye visualization at a physiological pH. The optimized geometry and spectral properties of RHES and its cation adducts have been analyzed by time-dependent density functional theory calculations. RHES detects as low as 1.5 * 10-9 M Al3+, 1.2 * 10-9 M Zn2+, 6.7 * 10-9 M Cd2+, and 1.7 * 10-10 M Hg2+, whereas the respective association constants are 1.33 * 105 M-1, 2.11 * 104 M-1, 1.35 * 105 M-1, and 4.09 * 105 M-1. The other common ions do not interfere. The probe is useful for intracellular imaging of Zn2+, Cd2+, and Hg2+ in squamous epithelial cells. RHES is useful for the determination of the ions in sea fish and real samples. PMID- 30023891 TI - Multiple-Responsive Mesoporous Silica Nanoparticles for Highly Accurate Drugs Delivery to Tumor Cells. AB - A core-shell nanocarrier with triple layers, where each layer is sensitive to one specific physiological stimulus, has been fabricated for highly accurate cancer therapy. The nanocarrier consists of mesoporous silica nanoparticles (core structure for drug loading), fluorescein isothiocyanate-labeled hyaluronan (FITC HA, first shell for imaging with enzymatic response), disulfide bond-embedded silica (SiO2, second layer with glutathione response), and switchable zwitterionic surface (third layer with pH response). The nanocarrier decorated with zwitterionic surface is able to offer long blood circulation time due to the weak nonspecific protein absorption. After these nanocarriers were gradually gathered around tumor cells through enhanced permeability and retention effect, the zwitterionic surface could switch to positive charge in low-pH environment, which was in favor of cellular uptake due to the strengthened positive nanocarrier-negative cellular membrane interaction. Once internalized into tumor cells, the high concentration of glutathione in cytoplasm could cleave disulfide bonds to remove the SiO2 shell and the HA layer would be exposed, which would be further degraded by hyaluronidase to trigger payload release. The fluorescent spectrum and images reveal that both glutathione and hyaluronidase are required for the release of preloaded drugs from these nanocarriers. By employing the multiple response, our nanocarriers could achieve effective antibiofouling ability while maintaining enhanced cellular internalization and targeted drug delivery, resulting in preferred cancer cell cytotoxicity, which is much higher than that of free doxorubicin. The in vitro data exhibited that our nanocarriers may provide an effective strategy for accurate cancer treatment. PMID- 30023893 TI - CAPLIB: A New Program Library for the Modeling and Analysis of Icosahedrally Symmetric Viral Capsids. AB - A new program library named "CAPLIB" was developed for the modeling and analysis of icosahedrally symmetric virus capsids. CAPLIB is equipped with the mathematical data of 60 rotation matrices of icosahedral symmetry, 15 planes bisecting the entire capsid structure, and a table summarizing how the 60 asymmetric units (cells) are partitioned by the planes. CAPLIB contains the function to determine the cell numbers of atoms from the atomic positions and the function to determine the rotation axes and angles from the rotation matrices. Using CAPLIB, it is possible to generate the structure of any selected protein unit within the entire capsid by rotating a single protein unit structure. CAPLIB can classify Protein Data Bank files of capsids with the directions of rotation axes, rotate the protein structure onto the standard position, and perform various deformations of the entire capsid. The interface to the molecular graphics software, PyMOL, was also developed for efficient modeling of capsids. PMID- 30023892 TI - Mixed Macromolecular Crowding: A Protein and Solvent Perspective. AB - In the living cell, biomolecules perform their respective functions in the presence of not only one type of macromolecules but rather in the presence of various macromolecules with different shapes and sizes. In this study, we have investigated the effects of five single macromolecular crowding agents, Dextran 6, Dextran 40, Dextran 70, Ficoll 70, and PEG 8000 and their binary mixtures on the modulation in the domain separation of human serum albumin using a Forster resonance energy transfer-based approach and the translational mobility of a small fluorescent probe fluorescein isothiocyanate (FITC) using fluorescence correlation spectroscopy (FCS). Our observations suggest that mixed crowding induces greater cooperativity in the domain movement as compared to the components of the mixtures. Thermodynamic analyses of the same provide evidence of crossovers from enthalpy-based interactions to effects dominated by hard sphere potential. When compared with those obtained for individual crowders, both domain movements and FITC diffusion studies show significant deviations from ideality, with an ideal solution being considered to be that arising from the sum of the contributions of those obtained in the presence of individual crowding agents. Considering the fact that domain movements are local (on the order of a few angstroms) in nature while translational movements span much larger lengthscales, our results imply that the observed deviation from simple additivity exists at several possible levels or lengthscales in such mixtures. Moreover, the nature and the type of deviation not only depend on the identities of the components of the crowder mixtures but are also influenced by the particular face of the serum protein (either the domain I-II or the domain II-III face) that the crowders interact with, thus providing further insights into the possible existence of microheterogeneities in such solutions. PMID- 30023894 TI - Fully Conjugated Porphyrin Glass: Collective Light-Harvesting Antenna for Near Infrared Fluorescence beyond 1 MUm. AB - Expanded pi-systems with a narrow highest occupied molecular orbital-lowest unoccupied molecular orbital band gap encounter deactivation of excitons due to the "energy gap law" and undesired aggregation. This dilemma generally thwarts the near-infrared (NIR) luminescence of organic pi-systems. A sophisticated cofacially stacked pi-system is known to involve exponentially tailed disorder, which displays exceptionally red-shifted fluorescence even as only a marginal emission component. Enhancement of the tail-state fluorescence might be advantageous to achieve NIR photoluminescence with an expected collective light harvesting antenna effect as follows: (i) efficient light-harvesting capacity due to intense electronic absorption, (ii) a long-distance exciton migration into the tail state based on a high spatial density of the chromophore site, and (iii) substantial transmission of NIR emission to circumvent the inner filter effect. Suppression of aggregation-induced quenching of fluorescence could realize collective light-harvesting antenna for NIR-luminescence materials. This study discloses an enhanced tail-state NIR fluorescence of a self-standing porphyrin film at 1138 nm with a moderate quantum efficiency based on a fully pi-conjugated porphyrin that adopts an amorphous form, called "porphyrin glass". PMID- 30023895 TI - Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides. AB - The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure-activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors. PMID- 30023897 TI - Indium/Gallium Maltolate Effects on Human Breast Carcinoma Cells: In Vitro Investigation on Cytotoxicity and Synergism with Mitoxantrone. AB - In this study, we aimed to investigate in vitro whether the synthetized indium maltolate (InMal) and gallium maltolate (GaMal) could exert either a toxic effect toward breast cancer cell line MDA-MB-231 or an agonistic activity with mitoxantrone (MTX) in comparison to fibroblast cell line NIH-3T3. Both GaMal and InMal reduced viability of MDA-MB-231, and at a lesser extent of NIH3-T3, in a dose- and time-dependent mode, the outcome was more effective in comparison to MTX sole exposure. Both GaMal and InMal toxicity was reverted by iron citrate addition on NIH3-T3, not on MDA-MB-231, showing indirectly that gallium and indium's mechanisms of action may include iron targeting. The agonistic activity against MDA-MB-231 survival was shown pretreating with 100 MUM InMal for 24 h followed by medium exchange with MTX at 10 ng mL-1 or vice-versa but not with co incubation of both compounds. In particular, InMal pretreating resulted more protective to MTX subsequent exposure. PMID- 30023898 TI - Extracting Compound Profiling Matrices from Screening Data. AB - Compound profiling matrices record assay results for compound libraries tested against panels of targets. In addition to their relevance for exploring structure activity relationships, such matrices are of considerable interest for chemoinformatic and chemogenomic applications. For example, profiling matrices provide a valuable data resource for the development and evaluation of machine learning approaches for multitask activity prediction. However, experimental compound profiling matrices are rare in the public domain. Although they are generated in pharmaceutical settings, they are typically not disclosed. Herein, we present an algorithm for the generation of large profiling matrices, for example, containing more than 100 000 compounds exhaustively tested against 50 to 100 targets. The new methodology is a variant of biclustering algorithms originally introduced for large-scale analysis of genomics data. Our approach is applied here to assays from the PubChem BioAssay database and generates profiling matrices of increasing assay or compound coverage by iterative removal of entities that limit coverage. Weight settings control final matrix size by preferentially retaining assays or compounds. In addition, the methodology can also be applied to generate matrices enriched with active entries representing above-average assay hit rates. PMID- 30023896 TI - Porphyrin-Gold Nanomaterial for Efficient Drug Delivery to Cancerous Cells. AB - With an aim to overcome multidrug resistance (MDR), nontargeted delivery, and drug toxicity, we developed a new nanochemotherapeutic system with tetrasodium salt of meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) armored on gold nanoparticles (TPPS-AuNPs). The nanocarrier is able to be selectively internalized within tumor cells than in normal cells followed by endocytosis and therefore delivers the antitumor drug doxorubicin (DOX) particularly to the nucleus of diseased cells. The embedment of TPPS on the gold nanosurface provides excellent stability and biocompatibility to the nanoparticles. Porphyrin interacts with the gold nanosurface through the coordination interaction between gold and pyrrolic nitrogen atoms of the porphyrin and forms a strong association complex. DOX-loaded nanocomposite (DOX@TPPS-AuNPs) demonstrated enhanced cellular uptake with significantly reduced drug efflux in MDR brain cancer cells, thereby increasing the retention time of the drug within tumor cells. It exhibited about 9 times greater potency for cellular apoptosis via triggered release commenced by acidic pH. DOX has been successfully loaded on the porphyrin-modified gold nanosurface noncovalently with high encapsulation efficacy (~90%) and tightly associated under normal physiological conditions but capable of releasing ~81% of drug in a low-pH environment. Subsequently, DOX-loaded TPPS-AuNPs exhibited higher inhibition of cellular metastasis, invasion, and angiogenesis, suggesting that TPPS-modified AuNPs could improve the therapeutic efficacy of the drug molecule. Unlike free DOX, drug-loaded TPPS-AuNPs did not show toxicity toward normal cells. Therefore, higher drug encapsulation efficacy with selective targeting potential and acidic-pH-mediated intracellular release of DOX at the nucleus make TPPS-AuNPs a "magic bullet" for implication in nanomedicine. PMID- 30023899 TI - Prediction of Compound Profiling Matrices Using Machine Learning. AB - Screening of compound libraries against panels of targets yields profiling matrices. Such matrices typically contain structurally diverse screening compounds, large numbers of inactives, and small numbers of hits per assay. As such, they represent interesting and challenging test cases for computational screening and activity predictions. In this work, modeling of large compound profiling matrices was attempted that were extracted from publicly available screening data. Different machine learning methods including deep learning were compared and different prediction strategies explored. Prediction accuracy varied for assays with different numbers of active compounds, and alternative machine learning approaches often produced comparable results. Deep learning did not further increase the prediction accuracy of standard methods such as random forests or support vector machines. Target-based random forest models were prioritized and yielded successful predictions of active compounds for many assays. PMID- 30023900 TI - Nitrogen and Sulfur Self-Doped Activated Carbon Directly Derived from Elm Flower for High-Performance Supercapacitors. AB - N,S-Doped activated carbon was directly prepared via a facile and cost-efficient hydrothermal reaction, followed by alkali activation of elm flower (EL)-derived biomass. The EL-derived activated carbon (ELAC) had N and S contents of 2.21 and 6.06 atom %, respectively, in addition to a high Brunauer-Emmett-Teller (BET) surface area of 2048.6 m2 g-1 and moderate pore volume of 0.88 cm3 g-1. Owing to its high BET surface area and N/S functional groups, ELAC achieved a specific capacitance of 275 F g-1 at a current density of 1 A g-1 and retained a capacitance of 216 F g-1 at 20 A g-1. In addition, a symmetric supercapacitor based on N,S-self-doped ELAC electrode provided a capacitance of 62 F g-1 at a current density of 10 A g-1, with maximum energy and power densities of 16.8 Wh kg-1 and 600 W kg-1, respectively. The capacitance retention was also high, at 87.2%, at 4 A g-1 after 5000 cycles. PMID- 30023901 TI - Gelatin-Based Hydrogels Blended with Gellan as an Injectable Wound Dressing. AB - Injectable scaffolds are of great interests for skin regeneration because they can fill irregularly shaped defects through minimally invasive surgical treatments. In this study, an injectable hydrogel from biopolymers is developed and its application as wound dressings is examined. Gelatin-based hydrogels were successfully prepared at body temperature upon blending with low content of gellan, and the synergetic effect on the gel formation was carefully characterized through rheological methods. The electrostatic complexation between gelatin and gellan was confirmed to contribute a continuous hydrogel network. The obtained blend hydrogel demonstrates remarkable shear-thinning and self recovering properties. For antibacterial purpose, tannic acid was incorporated into the blend hydrogel. In addition, tannic acid-loaded blend hydrogel was verified to accelerate the wound healing on the mice model, significantly than the control groups. Thus, this paper presents a facile approach without chemical modification to construct injectable gelatin-based hydrogels, which have great potential as a wound dressing or tissue scaffold at body temperature. PMID- 30023902 TI - Retention of Anticancer Activity of Curcumin after Conjugation with Fluorescent Gold Quantum Clusters: An in Vitro and in Vivo Xenograft Study. AB - Gold nanoparticles (Au NPs) have been thoroughly investigated for anti-cancer therapy. However, their undesired high gold content remains a problem when injected into the body for drug delivery applications. In this report, we made an effort to conjugate the curcumin molecules on the surface of gold quantum clusters (Au QCs) by a novel in situ synthesis method which provides an alternative route to not only reduce the metallic content but also increase the water solubility of curcumin and the loading efficiency. Here, curcumin itself acts as a reducing and capping agent for the synthesis of Au QCs. The UV-vis absorption, fluorescence, transmission electron microscopy, and electrospray ionization mass spectrometry results confirmed the synthesis of fluorescent Au QCs. Curcumin-conjugated Au NPs (C-Au NPs) and glutathione (GSH)-conjugated Au QCs (GSH-Au QCs) were also synthesized to visualize the effect of particle size and the capping agent, respectively, on the cytotoxicity to normal and cancer cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the curcumin-conjugated Au QCs (C-Au QCs) were less cytotoxic to normal cells while almost the same cytotoxic to cancer cells in comparison to curcumin itself, which indicates that curcumin preserves its anticancer property even after binding to the Au QCs. However, C-Au NPs and GSH-Au QCs did not show any cytotoxicity against the normal and cancer cells at the concentration used. The western blot assay indicated that C-Au QCs promote apoptosis in cancer cells. Further, the in vivo study on severe combined immunodeficiency mice showed that C Au QCs also inhibited the tumor growth efficiently without showing significant toxicity to internal organs. PMID- 30023903 TI - Antimicrobial and Wound Healing Properties of Polyacrylonitrile-Moringa Extract Nanofibers. AB - A simple and cost-effective material composed of polyacrylonitrile nanofibers containing different concentrations of moringa (MR) leaf extracts was fabricated for antimicrobial properties and wound dressing. The fabricated materials were characterized by scanning electron microscopy, thermal gravimetric analysis, and Fourier transmission infrared spectroscopy. The antibacterial sensitivity of the developed polyacrylonitrile-moringa extract nanofibers was evaluated against Staphylococcus aureus and Escherichia coli by the agar diffusion method. A pronounced antibacterial activity was observed with the increase in the incorporated moringa leaf extract concentration within the polyacrylonitrile moringa extract nanofibers against the bacterial strains. The best antibacterial sensitivity was observed for nanofibers containing 0.5 g of moringa leaf extract which had an inhibitory zone of 15 mm for E. coli and 12 mm for S. aureus. Furthermore, the cost-effective and biodegradable nanofibrous polyacrylonitrile moringa extract nanofiber was also used to conduct further studies regarding wound dressing. The result reveals that the increase in the concentrations of moringa leaf extract influenced the healing properties of the material. For days 1, 4, and 7 of the wound dressing experiment, the % wound closure of the rat was the highest for the nanofiber containing 0.5 g of moringa leaf extract (35, 87, and 95%, respectively) compared to the positive control medical gauze (29, 75, and 93%, respectively). PMID- 30023904 TI - Orthogonal Synthetic Zippers as Protein Scaffolds. AB - Protein scaffolds have proven useful for co-localization of enzymes, providing control over stoichiometry and leading to higher local enzyme concentrations, which have led to improved product formation. To broaden their usefulness, it is necessary to have a wide choice of building blocks to mix and match for scaffold generation. Ideally, the scaffold building blocks should function at any location within the scaffold and have high affinity interactions with their binding partners. We examined the utility of orthogonal synthetic coiled coils (zippers) as scaffold components. The orthogonal zippers are coiled coil domains that form heterodimers only with their specific partner and not with other zipper domains. Focusing on two orthogonal zipper pairs, we demonstrated that they are able to function on either end or in the middle of a multiblock assembly. Surface plasmon resonance was employed to assess the binding kinetics of zipper pairs placed at the start, middle, or end of a construct. Size-exclusion chromatography was used to demonstrate the ability of a scaffold with two zipper domains to bind their partners simultaneously. We then expanded the study to examine the binding kinetics and cross-reactivities of three additional zipper pairs. By validating the affinities and specificities of synthetic zipper pairs, we demonstrated the potential for zipper domains to provide an expanded library of scaffolding parts for tethering enzymes in complex pathways for synthetic biology applications. PMID- 30023905 TI - Optimization of Formulations Consisting of Layered Double Hydroxide Nanoparticles and Small Interfering RNA for Efficient Knockdown of the Target Gene. AB - Layered double hydroxide (LDH) nanoparticles (NPs) are safe and effective vectors for small interfering RNA (siRNA) delivery. However, it is unclear whether there are optimal parameters for the efficient delivery of functional siRNA using LDH NPs. In this research, we comprehensively examined the effect of parameters, such as the mixing method and LDH/siRNA mass ratio on siRNA silencing capability. We first noted that the best way for loading gene segments (25 bp dsDNA and siRNA) is to add gene molecules to 100 nm LDH and then diluting in Dulbecco's modified Eagle's medium. Very interestingly, the optimal LDH/gene mass ratio is around 20:1 in terms of cellular uptake amount of gene segments, whereas this ratio is shifted to around 5:1 in terms of target gene silencing efficacy, which has been reasonably explained. The optimization for LDH NP-based gene delivery system may provide the guidance for more efficient in vitro and in vivo siRNA delivery using the optimal parameters. PMID- 30023906 TI - Roles of Hydrogen Bonding in Proton Transfer to kappaP,kappaN,kappaP-N(CH2CH2P i Pr2)2-Ligated Nickel Pincer Complexes. AB - The nickel PNP pincer complex ( i PrPNP)NiPh ( i PrPNP = kappaP,kappaN,kappaP N(CH2CH2P i Pr2)2) was prepared by reacting ( i PrPNP)NiBr with PhMgCl or deprotonating [( i PrPNHP)NiPh]Y ( i PrPNHP = kappaP,kappaN,kappaP-HN(CH2CH2P i Pr2)2; Y = Br, PF6) with KO t Bu. The byproducts of the PhMgCl reaction were identified as [( i PrPNHP)NiPh]Br and ( i PrPNP')NiPh ( i PrPNP' = kappaP,kappaN,kappaP-N(CH=CHP i Pr2)(CH2CH2P i Pr2)). The methyl analog ( i PrPNP)NiMe was synthesized from the reaction of ( i PrPNP)NiBr with MeLi, although it was contaminated with ( i PrPNP')NiMe due to ligand oxidation. Protonation of ( i PrPNP)NiX (X = Br, Ph, Me) with various acids, such as HCl, water, and MeOH, was studied in C6D6. Nitrogen protonation was shown to be the most favorable process, producing a cationic species [( i PrPNHP)NiX]+ with the NH moiety hydrogen-bonded to the conjugate base (i.e., Cl-, HO-, or MeO-). Protonation of the Ni-C bond was observed at room temperature with ( i PrPNP)NiMe, whereas at 70 degrees C with ( i PrPNP)NiPh, both resulting in [( i PrPNHP)NiCl]Cl as the final product. Protonation of ( i PrPNP)NiBr was complicated by site exchange between Br- and the conjugate base and by the degradation of the pincer complexes. Indene, which lacks hydrogen-bonding capability, was unable to protonate ( i PrPNP)NiPh and ( i PrPNP)NiMe, despite being more acidic than water and MeOH. Neutral and cationic nickel pincer complexes involved in this study, including ( i PrPNP')NiBr, ( i PrPNP)NiPh, ( i PrPNP')NiPh, ( i PrPNP)NiMe, [( i PrPNHP)NiPh]Y (Y = Br, PF6, BPh4), [( i PrPNHP)NiPh]2[NiCl4], [( i PrPNHP)NiMe]Y (Y = Cl, Br, BPh4), [( i PrPNHP)NiBr]Br, and [( i PrPNHP)NiCl]Cl, were characterized by X-ray crystallography. PMID- 30023908 TI - Solvent- and Catalyst-Free One-Pot Green Bound-Type Fused Bis-Heterocycles Synthesis via Groebke-Blackburn-Bienayme Reaction/SNAr/Ring-Chain Azido Tautomerization Strategy. AB - A new, efficient, green, endogenous water-triggered, solvent- and catalyst-free ultrasound-assisted one-pot Groebke-Blackburn-Bienayme reaction/SNAr/ring-chain azido-tautomerization strategy to synthesize bound-type fused bis-heterocycles imidazo or benzo[d]imidazo[2,1-b]thiazoles and 1,5-disubstituted tetrazole (1,5 DsT) containing quinoline moiety is described, which allows synthesis of two types of fused heterocycles in one step under mild green conditions. Antibacterial and antiamebic activities of selected newly synthesized compounds were carried out against three bacterial species: Gram-positive bacterium Staphylococcus aureus ATCC 6538 and Gram-negative bacteria Pseudomonas aeruginosa ATCC 13384 and Escherichia coli O55 and against one amebic species: Entamoeba histolytica. PMID- 30023907 TI - Detection of Lung Cancer: Concomitant Volatile Organic Compounds and Metabolomic Profiling of Six Cancer Cell Lines of Different Histological Origins. AB - In recent years, there has been an extensive search for a non-invasive screening technique for early detection of lung cancer. Volatile organic compound (VOC) analysis in exhaled breath is one such promising technique. This approach is based on the fact that tumor growth is accompanied by unique oncogenesis, leading to detectable changes in VOC emitting profile. Here, we conducted a comprehensive profiling of VOCs and metabolites from six different lung cancer cell lines and one normal lung cell line using mass spectrometry. The concomitant VOCs and metabolite profiling allowed significant discrimination between lung cancer and normal cell, nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as between different subtypes of NSCLC. It was found that a combination of benzaldehyde, 2-ethylhexanol, and 2,4-decadien-1-ol could serve as potential volatile biomarkers for lung cancer. A detailed correlation between nonvolatile metabolites and VOCs can demonstrate possible biochemical pathways for VOC production by the cancer cells, thus enabling further optimization of VOCs as biomarkers. These findings could eventually lead to noninvasive early detection of lung cancer and differential diagnosis of lung cancer subtypes, thus revolutionizing lung cancer treatment. PMID- 30023909 TI - Synthesis and Evaluation of Linear and Macrocyclic Dolastatin 10 Analogues Containing Pyrrolidine Ring Modifications. AB - Because of their potent cytotoxic activity, members of the auristatin family (synthetic analogues of the naturally occurring dolastatin 10) have remained a target of significant research, most notably in the context of antibody drug conjugate payloads. Typically, modifications of the backbone scaffold of dolastatin 10 have focused on variations of the N-terminal (P1) and C-terminal (P5) subunits. Scant attention has been paid thus far to the P4 subunit in the scientific literature. In this paper, we introduce an azide functional group at the P4 subunit, resulting in potent cytotoxic activity seen in vitro. Another highly active compound in this study contained azide functional groups in both the P2 and P4 subunits and required dolavaline as the P1 subunit and a phenylalanine as the P5 subunit. Furthermore, these two azide groups served not only as modifiers of cytotoxicity but also as handles for linker attachment or as a tether for use in the synthesis of a macrocyclic analogue. PMID- 30023910 TI - Effect of Temperature Stress on Antioxidant Defenses in Brassica oleracea. AB - Brassica oleracea crops are exposed to seasonal changes in temperature because of their biennial life cycle. Extreme temperatures (cold and heat) affect the photosynthetic activity and the yield of cabbage (B. oleracea capitata group) and kale (B. oleracea acephala group). We studied the relationship among antioxidant defenses, photosynthesis, and yield under extreme temperatures in both crops. Under these conditions, the plants increase the antioxidant defenses, responding to an increment in reactive oxygen species (ROS). The accumulation of ROS in chloroplasts decreases the chlorophyll content and provokes photoinhibition that leads to a low fixation of CO2 and loss of dry weight. Low temperatures especially increase the antioxidant defenses and decrease the chlorophyll content compared to the heat conditions. However, dry weight losses are higher when plants are grown under heat than under cold conditions, probably because of the inactivation of Rubisco and/or the associated enzymes. Both crops were more resilient to cold than to heat temperatures, the capitata group being more resistant. PMID- 30023911 TI - Photothermal Cellulose-Patch with Gold-Spiked Silica Microrods Based on Escherichia coli. AB - Plasmonic-mediated photothermal heating under near-infrared (NIR) irradiation is an emerging key technology in the field of photothermal therapy and chemical reactions. However, there are few reports of photothermal film (dry-type patch), and thus, in this work, we developed the plasmonic-induced photothermal cellulose patch operating in the NIR region. Hollow and spikelike gold nanostructures, gold spikes, as plasmonic nanoparticles were prepared and decorated on silica microrods, which were prepared based on a unicellular organism, Escherichia coli, as a framework. In addition, freestanding cellulose-patch was prepared by mixing filter-paper pulp and armored golden E. coli (AGE) microrods. The major absorbing peak of AGE solution was revealed to be 873 nm, and the surface temperature of patch was increased to 264 degrees C within a very short time (1 min). When NIR laser was irradiated on the patch dipped in the water, the formation of water vapor and air bubbles was observed. The heating efficiency of indirect heat transfer via conduction from patch-to-water was 35.0%, while that of direct heat transfer via radiation from patch in water was 86.1%. Therefore, the cellulose patch containing AGE microrods has possible applicability to desalination and sterilization because of its fast heating rate and high light-to-heat conversion under the irradiation of low-powered IR laser. PMID- 30023913 TI - Starch Derivatives that Contribute Significantly to the Bonding and Antibacterial Character of Recycled Fibers. AB - The objective of the current research was to fabricate and explore the ability of a renewable resource-based paper strength agent to enhance fiber-fiber bonding and introduce antibacterial properties to recycled fiber paper sheets. The agent corn starch, was modified with diethylenetriamine pentaacetic acid (DTPA), complexed with chitosan, and added to recycled furnishes to provide a plethora of hydrogen bonding sites predicated by acid groups, hydroxyls, and amines. The goal was two-fold: (1) to not only increase interfiber bonding, but (2) afford antibacterial character. The modified corn starch was characterized in previous work by thermal gravimetric analysis, differential scanning calorimeter, and Fourier transform infrared spectroscopy. The recycled pulp slurry was mixed with a ~1.5% modified starch/chitosan agent before manufacturing a two-dimensional paper substrate that was subjected to mechanical testing. The burst, STFI compressive strength, tensile, and interfiber bonding strength increased 48.8, 49.5, 49.9, and 176%, respectively, while significantly increased gloss was obtained despite slightly diminished tear and roughness. The antibacterial character of these substrates was confirmed by the substrates displaying a 97% bacteria kill rate. PMID- 30023912 TI - Ga Ion-Enhanced and Particle Shape-Dependent Generation of Reactive Oxygen Species in X-ray-Irradiated Composites. AB - The reported results test the effects of the collective behavior hypothesized to contribute to the production of more reactive oxygen species (ROS) in vitro and result in an enhanced radiosensitization. The role of particle shape in composites with gallium oxyhydroxide (GaOOH) particles and Matrigel is studied. Particles of two different shapes are embedded into the gel to understand only the materials effect on the generation of ROS rather than cell penetrating variations. The paper reports materials characterization by scanning electron microscopy and X-ray diffraction. The stability of the particles within the composite is assessed by quantification of leached metal using inductively coupled plasma mass spectrometry. The amount of ROS in each construct under variable radiation conditions is quantified in the presence and absence of PC12 cells seeded on top of the composites. The viability of cells is also recorded under different in vitro conditions. The collective materials characterization and the results from the bioassays are used to explain the role of anisotropy on the radiosensitization of nanostructures containing Ga. The presence of Ga ions in composites can have a radiosensitizing effect, and the amount of the available Ga3+ determines the magnitude of the radiosensitization. The shape of the particles determines the stability in aqueous solutions and release of Ga3+ that triggers ROS production. The concentration and shape of Ga-containing materials can be combined to generate an additive effect by increasing the amount of available free metal ions in solution. The studies with GaOOH containing composites enable one to explore the role of key parameters that lead to an increased efficiency of radiation treatments. PMID- 30023914 TI - Artificial 3D Culture Systems for T Cell Expansion. AB - Adoptive cell therapy, i.e., the extraction, manipulation, and administration of ex vivo generated autologous T cells to patients, is an emerging alternative to regular procedures in cancer treatment. Nevertheless, these personalized treatments require laborious and expensive laboratory procedures that should be alleviated to enable their incorporation into the clinics. With the objective to improve the ex vivo expansion of large amount of specific T cells, we propose the use of three-dimensional (3D) structures during their activation with artificial antigen-presenting cells, thus resembling the natural environment of the secondary lymphoid organs. Thus, the activation, proliferation, and differentiation of T cells have been analyzed when cultured in the presence of two 3D systems, Matrigel and a 3D polystyrene scaffold, showing an increase in cell proliferation compared to standard suspension systems. PMID- 30023915 TI - In Silico Designed Axl Receptor Blocking Drug Candidates Against Zika Virus Infection. AB - After a large outbreak in Brazil, novel drugs against Zika virus became extremely necessary. Evaluation of virus-based pharmacological strategies concerning essential host factors brought us to the idea that targeting the Axl receptor by blocking its dimerization function could be critical for virus entry. Starting from experimentally validated compounds, such as RU-301, RU-302, warfarin, and R428, we identified a novel compound 2' (R428 derivative) to be the most potent for this task amongst a number of alternative compounds and leads. The improved affinity of compound 2' was confirmed by molecular docking as well as molecular dynamics simulation techniques using implicit solvation models. The current study summarizes a new possibility for inhibition of the Axl function as a potential target for future antiviral therapies. PMID- 30023916 TI - Glycosaminoglycan Conjugation for Improving the Duration of Therapeutic Action of Glucagon-Like Peptide-1. AB - Glucagon-like peptide-1 (GLP-1) is an incretin peptide that plays a crucial role in lowering blood glucose levels and holds promise for treating type II diabetes. In this study, we synthesized GLP-1 derivatives that were conjugated with glycosaminoglycans (GAGs), i.e., chondroitin (CH) or heparosan (HPN), to address the major limitation in their clinical use of GLP-1, which is its short half-life in the body. After exploring a variety of CHs with different molecular sizes and heterobifunctional linkers having different alkyl chains, we obtained CH conjugated GLP-1 derivatives that stayed in blood circulation much longer (T1/2 elim > 25 h) than unconjugated GLP-1 and showed blood glucose-lowering efficacy up to 120 h after subcutaneous injection in mice. By using the same optimized linker design, we eventually obtained a HPN-conjugated GLP-1 derivative with efficacy lasting 144 h. These results demonstrate that conjugation with GAG is a promising strategy for improving the duration of peptide drugs. PMID- 30023917 TI - Potentiometric Adsorption Isotherm Analysis of a Molecularly Imprinted Polymer Interface for Small-Biomolecule Recognition. AB - In this paper, we report a direct and quantitative analytical method of small biomolecule recognition with a molecularly imprinted polymer (MIP) interface, taking advantage of the potentiometric principle of a field-effect transistor (FET) sensor, which enables the direct detection of ionic charges without using labeling materials such as fluorescent dyes. The interaction of low-molecular weight oligosaccharides such as paromomycin and kanamycin with the MIP interface including phenylboronic acid (PBA) was directly and quantitatively analyzed from the electrical signals of an MIP-coated FET sensor. In particular, the change in the potential response of the FET sensor was derived on the basis of the multi Langmuir adsorption isotherm equations, considering the change in the molecular charges of PBA caused by the adsorption equilibrium of the analytes with the vinyl PBA-copolymerized MIP membrane. Thus, the potentiometric adsorption isotherm analysis can elucidate the formation of selective binding sites at the MIP interface. The electrochemical analysis of the functional biointerface used in this study supports the design and construction of sensors for small biomarkers. PMID- 30023918 TI - Manipulating Metallogel Properties by Luminogens and Their Applications in Cell Imaging. AB - Manipulating gelation properties of the isomeric zinc-terpyridine complexes C-1 (nongelator) and C-2 (gelator) using three different luminescent dyes, viz., acridine yellow (AY), ethidium bromide (EB), and azido-boron dipyrromethene, have been described. Hybrid gels created by the combination of C-1, C-2, and above mentioned dyes have been termed complex-luminogen mixed gels (CLMGs). Ensuing CLMGs have been thoroughly characterized by spectral, morphological, and rheological studies. Cytotoxicity measurements and imaging against breast cancer cell line MDA-MB-231 unveiled that three out of the five CLMGs can be effectively used for cell imaging. Interestingly, direct use of the metal-containing hybrid gels for live cell imaging which is a distinctive approach, has been successfully achieved with significantly encouraging results. PMID- 30023919 TI - Cleavage of Peptides from Amphibian Skin Revealed by Combining Analysis of Gland Secretion and in Situ MALDI Imaging Mass Spectrometry. AB - Peptides from skin secretions of amphibians are considered important components of their immune system and also play a relevant role in their defense mechanism against predators. Herein, by using mass spectrometry (MS), we characterize the sequence of 13 peptides from the gland secretion of the hylid tree frog, Boana punctata. Using in situ matrix-assisted laser desorption ionization imaging MS of a transverse section of the skin tissue, we show that some peptides are stored as longer molecules that are cleaved after being secreted, whereas others do not undergo any modification. Sequence comparison with peptides from other Boana species and analysis of the three-dimensional theoretical structure indicate that this cleavage depends on both the presence of a specific sequence motif and the secondary structure. The fact that peptides undergo a rapid cleavage upon secretion suggests that stored and secreted peptides may have distinct roles for anuran survival, including defense against pathogens and predators. PMID- 30023920 TI - Axial Coordination Site-Turned Surface Confinement, Electron Transfer, and Bio Electrocatalytic Applications of a Hemin Complex on Graphitic Carbon Nanomaterial Modified Electrodes. AB - Understanding the relation between the chemical bonding and the electron-transfer (ET) reaction of surface-confined hemin (a five-coordinated Fe-porphyrin-with chlorine complex) is a special interest in the biomimicking studies of heme proteins. Owing to the difficulty in ET function, scanty electrochemical reports of hemin in aqueous solution were reported. It has been noticed that in most of the reported procedures, the sixth axial coordination position of the hemin complex has been unknowingly turned by attaching with water molecules (potential cycling in alkaline conditions or heating), solvents such as ethanol and dimethyl sulfoxide, and nitrogen-donating compounds that have helped for the heme ET reaction. In this work, a systematic effort has been taken to find out the contribution of hemin and its axial bond coordination with pi-pi interaction, hydrogen bonding, and hydrophobic binding systems toward the ET reaction. Various graphitic carbons such as graphitized mesoporous carbon (GMC), mesoporous carbon hydrophilic and hydrophobic units, graphite nanopowder, graphene oxide, single walled carbon, multiwalled carbon nanotube (MWCNT), and carboxylic acid functionalized MWCNT (as a source for pi-pi interaction, hydrogen bonding, and hydrophobic environment) along with the amino functional group of chitosan (Chit; as an axial site coordinating system) have been tested by modifying them as a hemin hybrid on a glassy carbon electrode (GCE). In addition, a gold nanoparticle (Aunano) system was combined with the above matrix as a molecular wiring agent, and its role was examined. A highly stable and well-defined redox peak at an apparent formal potential (Eo') of -320 mV versus Ag/AgCl with the highest surface excess of 120 * 10-10 mol cm-2 was noticed with the GCE/Aunano-GMC@hemin Chit hybrid system, wherein all interactive features have been utilized. Omitting any of the individual interactions resulted in either decreased (with Aunano) or nil current response. As applications, efficient bio-electrocatalytic reduction and sensing of dissolved oxygen and hydrogen peroxide have been demonstrated. PMID- 30023922 TI - Unraveling the Structural Puzzle of the Giant Glutenin Polymer-An Interplay between Protein Polymerization, Nanomorphology, and Functional Properties in Bioplastic Films. AB - A combination of genotype, cultivation environment, and protein separation procedure was used to modify the nanoscale morphology, polymerization, and chemical structure of glutenin proteins from wheat. A low-polymerized glutenin starting material was the key to protein-protein interactions mainly via SS cross links during film formation, resulting in extended beta-sheet structures and propensity toward the formation of nanoscale morphologies at molecular level. The properties of glutenin bioplastic films were enhanced by the selection of a genotype with a high number of cysteine residues in its chemical structure and cultivation environment with a short grain maturation period, both contributing positively to gluten strength. Thus, a combination of factors affected the structure of glutenins in bioplastic films by forming crystalline beta-sheets and propensity toward the ordered nanostructures, thereby resulting in functional properties with high strength, stiffness, and extensibility. PMID- 30023921 TI - In Vitro Carcinoma Treatment Using Magnetic Nanocarriers under Ultrasound and Magnetic Fields. AB - Nowadays, tumor hypoxia has become a more predominant problem for diagnosis as well as treatment of cancer due to difficulties in delivering chemotherapeutic drugs and their carriers to these regions with reduced vasculature and oxygen supply. In such cases, external physical stimulus-mediated drug delivery, such as ultrasound and magnetic fields, would be effective. In this work, the effect of simultaneous exposure of low-intensity pulsed ultrasound and static magnetic field on colon (HCT116) and hepatocellular (HepG2) carcinoma cell inhibition was assessed in vitro. The treatment, in the presence of anticancer drug, with and without magnetic carrier, significantly increased the reactive oxygen species production and hyperpolarized the cancer cells. As a result, a significant increase in cell inhibition, up to 86%, was observed compared to 50% inhibition with bare anticancer drug. The treatment appears to have relatively more effect on HepG2 cells during the initial 24 h than on HCT116 cells. The proposed treatment was also found to reduce cancer cell necrosis and did not show any inhibitory effect on healthy cells (MC3T3). Our in vitro results suggest that this approach has strong application potential to treat cancer at lower drug dosage to achieve similar inhibition and can reduce health risks associated with drugs. PMID- 30023924 TI - Adsorption Kinetics of Single-Stranded DNA on Functional Silica Surfaces and Its Influence Factors: An Evanescent-Wave Biosensor Study. AB - Thorough understandings on the real-time kinetics involved in DNA adsorption on a solid surface is essential in various fields, such as in DNA hybridization studies, DNA extraction and purification, DNA-based biosensing, and gene-based medicine discovery. Herein, the real-time properties of single-stranded DNA (ssDNA) adsorption onto functional silica surfaces under various conditions were investigated using an evanescent wave optical biosensing platform. Results demonstrated that the driving force and adsorption mechanism of DNA were closely related to the kind of functional groups on the silica surfaces. The main driving forces of DNA adsorption onto hydroxyl- and protein-modified solid surfaces were the hydrophobic interaction, hydrogen bonding, and the interaction between DNA phosphate and functional groups on the silica surface, which strengthened with increased ionic strength. However, the electrostatic attraction between the negative charge of DNA and positive charge of the amino silica surface was likely the most important factor influencing DNA adsorption onto the amino surface. This influence can be reduced by increasing the ionic strength. Although low-ionic strength Mg2+ provided a greater adsorption efficiency than high-ionic-strength Na+, the balance of ssDNA adsorption onto hydroxyl- and ovalbumin (OVA)-modified silica surfaces was achieved faster in the presence of Na+ than in the presence of Mg2+. DNA adsorption was also influenced significantly by pH, and the hydroxyl and OVA-modified surfaces exhibited the strongest adsorption at pH 3.0, whereas DNA adsorption onto the amino surface increased with increased pH. DNA adsorption onto various functional surfaces could be perfectly fitted by second-order Langmuir models, indicating that the process was a single-molecular-layer adsorption. PMID- 30023923 TI - Novel Conducting and Biodegradable Copolymers with Noncytotoxic Properties toward Embryonic Stem Cells. AB - Electroactive biomaterials that are easily processed as scaffolds with good biocompatibility for tissue regeneration are difficult to design. Herein, the synthesis and characterization of a variety of novel electroactive, biodegradable biomaterials based on poly(3,4-ethylenedioxythiphene) copolymerized with poly(d,l lactic acid) (PEDOT-co-PDLLA) are presented. These copolymers were obtained using (2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)methanol (EDOT-OH) as an initiator in a lactide ring-opening polymerization reaction, resulting in EDOT-PDLLA macromonomer. Conducting PEDOT-co-PDLLA copolymers (in three different proportions) were achieved by chemical copolymerization with 3,4 ethylenedioxythiophene (EDOT) monomers and persulfate oxidant. The PEDOT-co-PDLLA copolymers were structurally characterized by 1H NMR and Fourier transform infrared spectroscopy. Cyclic voltammetry confirmed the electroactive character of the materials, and conductivity measurements were performed via electrochemical impedance spectroscopy. In vitro biodegradability was evaluated using proteinase K over 35 days, showing 29-46% (w/w) biodegradation. Noncytotoxicity was assessed by adhesion, migration, and proliferation assays using embryonic stem cells (E14.tg2a); excellent neuronal differentiation was observed. These novel electroactive and biodegradable PEDOT-co-PDLLA copolymers present surface chemistry and charge density properties that make them potentially useful as scaffold materials in different fields of applications, especially for neuronal tissue engineering. PMID- 30023925 TI - Structural Effects of Sulfur-Containing Functional Groups on Apatite Formation on Ca2+-Modified Copolymers in a Simulated Body Environment. AB - Chemical modification with specific functional groups has been the conventional method to develop bone-bonding bioactive organic-inorganic hybrids. These materials are attractive as bone substitutes because they are flexible and have a Young's modulus similar to natural bone. Immobilization of sulfonic acid groups ( SO3H) onto the polymer chain is expected to produce such hybrids because these groups induce apatite formation in a simulated body fluid (SBF) and enhance the activity of osteoblast-like cells. Sulfinic acid groups (-SO2H), which are derivatives of -SO3H, can also induce apatite nucleation. However, the structural effects of such sulfur-containing functional groups on apatite formation have not been elucidated. In the present study, apatite formation on Ca2+-modified copolymers containing -SO2H or -SO3H was investigated in a simulated body environment. The copolymer containing Ca2+ and -SO3H promoted Ca2+ release into the SBF and formed apatite faster (1 day) than the copolymer containing Ca2+ and SO2H (14 days). In contrast, when they were not modified with Ca2+, the copolymer containing only -SO2H deposited the apatite faster (7 days) than that containing only -SO3H (>7 days) in the solution with Ca2+ concentration 1.5 times that of SBF. The former adsorbed larger amounts of Ca2+ than the latter. The measured stability constant of the complex indicated that the interaction of -SO2-...Ca2+ was more stable than that of -SO3-...Ca2+. It was found that both the release and adsorption of Ca2+ governed by the stability played an important role in induction of the apatite formation and that the apatite-forming ability of sulfur containing functional groups drastically changed by the coexistence of Ca2+. PMID- 30023926 TI - Synthesis and Preliminary Antimicrobial Analysis of Isatin-Ferrocene and Isatin Ferrocenyl Chalcone Conjugates. AB - In this study, we outline the synthesis of isatin-ferrocenyl chalcone and 1H 1,2,3-triazole-tethered isatin-ferrocene conjugates along with their antimicrobial evaluation against the human mucosal pathogen Trichomonas vaginalis. The introduction of a triazole ring among the synthesized conjugates improved the activity profiles with most of the compounds in the library, exhibiting 100% growth inhibition in a preliminary susceptibility screen at 100 MUM. IC50 determination of the most potent compounds in the set revealed an inhibitory range between 2 and 13 MUM. Normal flora microbiome are unaffected by these compounds, suggesting that these may be new chemical scaffolds for the discovery of new drugs against trichomonad infections. PMID- 30023928 TI - Solid-Phase Synthesis of Peptide-Conjugated Perylene Diimide Bolaamphiphile and Its Application in Photodynamic Therapy. AB - Here, we describe a rapid and efficient synthetic method of peptide-conjugated perylene diimide (P-PDI) using solid-phase peptide synthesis (SPPS). Due to severe insolubility of perylene dianhydride (PDA) as a starting material of perylene diimide (PDI), PDA was initially conjugated with amino acids to obtain soluble PDI derivatives. Target peptides were synthesized on a 2-chlorotrityl chloride resin using the SPPS method and then conjugated with the amino acid appended PDI. Various conditions such as loading levels, reaction times and solvents were optimized for introducing the peptides to both sides of the amino acid-appended PDI. The final P-PDI was obtained with a maximum yield of 80% in 12 h. Its singlet oxygen-derived phototoxicity on cells was confirmed, which could be applicable to photodynamic therapy. PMID- 30023927 TI - Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti Inflammatory Agents Targeting Cyclooxygenase-2. AB - A library of hybrid molecules was procured by the combination of triazine-indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound 6 having an IC50 value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E2 in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B2 in the calcium ionophore-treated (COX-1 activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound 6 is selective for COX-2. The association constant (Ka) of compound 6 with COX-2 was found to be of the order of 0.48 * 106 M-1. The diffusion spectroscopy experiments and relaxation time (T1) calculations of compound 6 in the presence of COX-2 assisted in identifying the site-specific interactions of 6 with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure-activity relationship studies. With maximum tolerable dose >2000 mg kg 1, compound 6 made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice. PMID- 30023929 TI - Spontaneous Biomacromolecule Absorption and Long-Term Release by Graphene Oxide. AB - Biomacromolecule loading is the popular research in the biomedical field. To control the loading amount and releasing profile, various materials and fabrication techniques were developed. In this study, layer-by-layer assembly of multilayer films between collagen (Col) and graphene oxide (GO) was used to control the release of the loading molecule. By mixing GO into the system, ovalbumin (OVA) can be spontaneously adsorbed onto the GO sheet (denoted as GO/OVA) via the hydrophobic interaction. Two kinds of multilayer films (Col/GO/OVA and Col/GO/OVA) were fabricated. The thickness growth curve, quantitative of each layer adsorption, film morphology, stability, cell viability, and OVA release from multilayer films were investigated. The result has shown excellent film stability, macromolecule loading, and sustained release because of GO ability. PMID- 30023930 TI - Arsenic Removal Using "Green" Renewable Feedstock-Based Hydrogels: Current and Future Perspectives. AB - In the recent times, scanty access to clean water has been one of the most prevalent problems, affecting humankind throughout the world. This calls for a tremendous amount of research to recognize new methods of purifying water at lower cost, minimizing the use of hazardous chemicals and impact on the environment. The interest of the scientific community in the potential applications of renewable feedstock-based hydrogels for heavy-metal adsorption for water remediation has been continuously increasing during the last few decades. This study is an effort to highlight the application of hydrogels for revolutionizing the present research on heavy-metal adsorption, particularly arsenic. Besides, the arsenic chemistry, health hazards of arsenic to human health, and adsorption of arsenic by natural polymer-based hydrogels have been reviewed in detail. In addition, challenges in taking the hydrogel technology forward and future prospectives like cost, handling, and disposal of the adsorbent have been discussed systematically. PMID- 30023931 TI - Chimeric Adeno-Associated Virus-Mediated Cardiovascular Reprogramming for Ischemic Heart Disease. AB - Here, we demonstrated chimeric adeno-associated virus (chimeric AAV), AAV-DJ mediated cardiovascular reprogramming strategy to generate new cardiomyocytes and limit collagen deposition in cardiac fibroblasts by inducing synergism of chimeric AAV-expressing Gata4, Mef2c, Tbx5 (AAV-GMT)-mediated heart reprogramming and chimeric AAV-expressing thymosin beta4 (AAV-Tbeta4)-mediated heart regeneration. AAV-GMT promoted a gradual increase in expression of cardiac specific genes, including Actc1, Gja1, Myh6, Ryr2, and cTnT, with a gradual decrease in expression of a fibrosis-specific gene, procollagen type I and here AAV-Tbeta4 help to induce GMT expression, providing a chimeric AAV-mediated therapeutic cell reprogramming strategy for ischemic heart diseases. PMID- 30023932 TI - Label-Free Imaging and Optical Characterization of Tissues Based on Autofluorescence. AB - Attaining capability of label-free optical characterization of tissues will offer methodological advancement and possibilities for early clinical detection, which is of paramount importance in treating patients under clinical setups, for example, cancer. Here, we demonstrate the potential of autofluorescence exhibited by tissues as an enabling microscopic strategy to achieve high-resolution imagery data offering a wealth of clinically relevant information including possibility of three-dimensional rendering. Furthermore, we elucidate the use of analytic tools to extract numerical read-outs from such data with further implications in histopathology, pharmaceutics, toxicology, and screening purposes. This study summarizes the results obtained through a systematic autofluorescence-based investigation on murine and porcine gut tissues with an example of applying the technique in nanotoxicology. The study provides with a methodological roadmap toward developing a fast, effective, and robust platform enabling in-depth optical characterization of tissues. PMID- 30023933 TI - Encapsulation and Enhanced Delivery of Topoisomerase I Inhibitors in Functionalized Carbon Nanotubes. AB - The topoisomerase I inhibitors SN-38 and camptothecin (CPT) have shown potent anticancer activity, but water insolubility and metabolic instability limits their clinical application. Utilizing carbon nanotubes as a protective shell for water-insoluble SN-38 and CPT while maintaining compatibility with aqueous media via a carboxylic acid-functionalized surface can thus be a strategy to overcome this limitation. Through hydrophobic-hydrophobic interactions, SN-38 and CPT were successfully encapsulated in carboxylic acid functionalized single-walled carbon nanotubes and dispersed in water. The resulting cell proliferation inhibition and drug distribution profile inside the cells suggest that these drug-encapsulated carbon nanotubes can serve as a promising delivery strategy for water-insoluble anticancer drugs. PMID- 30023934 TI - Visible-Light-Mediated Electrocatalytic Activity in Reduced Graphene Oxide Supported Bismuth Ferrite. AB - Reduced graphene oxide (RGO)-supported bismuth ferrite (BiFeO3) (RGO-BFO) nanocomposite is synthesized via a two-step chemical route for photoelectrochemical (PEC) water splitting and photocatalytic dye degradation. The detailed structural analysis, chemical coupling, and morphology of BFO- and RGO-supported BFO are established through X-ray diffraction, Raman and X-ray photoelectron spectroscopy, and high-resolution transmission electron microscopy studies. The modified band structure in RGO-BFO is obtained from the UV-vis spectroscopy study and supported by density functional theory (DFT). The photocatalytic degradation of Rhodamine B dye achieved under 120 min visible light illumination is 94% by the RGO-BFO composite with a degradation rate of 1.86 * 10-2 min-1, which is 3.8 times faster than the BFO nanoparticles. The chemical oxygen demand (COD) study further confirmed the mineralization of an organic dye in presence of the RGO-BFO catalyst. The RGO-BFO composite shows excellent PEC performance toward water splitting, with a photocurrent density of 10.2 mA.cm-2, a solar-to-hydrogen conversion efficiency of 3.3%, and a hole injection efficiency of 98% at 1 V (vs Ag/AgCl). The enhanced catalytic activity of RGO-BFO is explained on the basis of the modified band structure and chemical coupling between BFO and RGO, leading to the fast charge transport through the interfacial layers, hindering the recombination of the photogenerated electron hole pair and ensuring the availability of free charge carriers to assist the catalytic activity. PMID- 30023935 TI - Toxicity and Antigenotoxic Effect of Hispolon Derivatives: Role of Structure in Modulating Cellular Redox State and Thioredoxin Reductase. AB - Hispolon (HS), a bioactive polyphenol, and its derivatives such as hispolon monomethyl ether (HME), hispolon pyrazole (HP), and hispolon monomethyl ether pyrazole (HMEP) were evaluated for comparative toxicity and antigenotoxic effects. The stability of HS derivatives in biological matrices followed the order HS < HP ~ HME < HMEP. The cytotoxicity analysis of HS derivatives indicated that HP and HMEP were less toxic than HS and HME, respectively, in both normal and tumor cell types. The mechanisms of toxicity of HS and HME involved inhibition of thioredoxin reductase (TrxR) and/or induction of reductive stress. From the enzyme kinetic and docking studies, it was established that HS and HME interacted with the NADPH-binding domain of TrxR through electrostatic and hydrophobic bonds, resulting in inhibition of the catalytic activity. Subsequently, treatment with HS, HP, and HMEP at a nontoxic concentration of 10 MUM in Chinese Hamster Ovary (CHO) cells showed significant protection against radiation (4 Gy)-induced DNA damage as assessed by micronuclei and gamma-H2AX assays. In conclusion, the above results suggested the importance of phenolic and diketo groups in controlling the stability and toxicity of HS derivatives. The pyrazole derivatives, HP and HMEP, may gain significance in the development of functional foods. PMID- 30023936 TI - Self-Assembly of a Dentinogenic Peptide Hydrogel. AB - Current standard of care for treating infected dental pulp, root canal therapy, retains the physical properties of the tooth to a large extent, but does not aim to rejuvenate the pulp tissue. Tissue-engineered acellular biomimetic hydrogels have great potential to facilitate the regeneration of the tissue through the recruitment of autologous stem cells. We propose the use of a dentinogenic peptide that self-assembles into beta-sheet-based nanofibers that constitute a biodegradable and injectable hydrogel for support of dental pulp stem cells. The peptide backbone contains a beta-sheet-forming segment and a matrix extracellular phosphoglycoprotein mimic sequence at the C-terminus. The high epitope presentation of the functional moiety in the self-assembled nanofibers may enable recapitulation of a functional niche for the survival and proliferation of autologous cells. We elucidated the hierarchical self-assembly of the peptide through biophysical techniques, including scanning electron microscopy and atomic force microscopy. The material property of the self-assembled hydrogel was probed though oscillatory rheometry, demonstrating its thixotropic nature. We also demonstrate the cytocompatibility of the hydrogel with respect to fibroblasts and dental pulp stem cells. The self-assembled peptide platform holds promise for guided dentinogenesis and it can be tailored to a variety of applications in soft tissue engineering and translational medicine in the future. PMID- 30023937 TI - Synthesis and 3D Interconnected Nanostructured h-BN-Based Biocomposites by Low Temperature Plasma Sintering: Bone Regeneration Applications. AB - Recent advances and demands in biomedical applications drive a large amount of research to synthesize easily scalable low-density, high-strength, and wear resistant biomaterials. The chemical inertness with low density combined with high strength makes h-BN one of the promising materials for such application. In this work, three-dimensional hexagonal boron nitride (h-BN) interconnected with boron trioxide (B2O3) was prepared by easily scalable and energy efficient spark plasma sintering (SPS) process. The composite structure shows significant densification (1.6-1.9 g/cm3) and high surface area (0.97-14.5 m2/g) at an extremely low SPS temperature of 250 degrees C. A high compressive strength of 291 MPa with a reasonably good wear resistance was obtained for the composite structure. The formation of strong covalent bonds between h-BN and B2O3 was formulated and established by molecular dynamics simulation. The composite showed significant effect on cell viability/proliferation. It shows a high mineralized nodule formation over the control, which suggests its use as a possible osteogenic agent in bone formation. PMID- 30023938 TI - Targeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic Therapy. AB - Photodynamic therapy (PDT) involves use of a photosensitizer, whose activation with light leads to the production of singlet oxygen (SOS), generation of reactive oxygen species (ROS), and initiation of associated cell toxicity. Because a cell's mitochondria constitute sites where oxygen levels are high, ROS can be readily produced, and apoptosis is commonly initiated. Therefore, an ideal PDT agent might be a potent photosensitizer that could naturally accumulate in mitochondria. Although a number of mitochondria-targeting moieties, including triphenylphosphine, guanidinium, and bisguanidium, have been identified, a quantitative comparison of their efficacies in targeting mitochondria has not been performed. In this study, we have prepared triphenylphosphine, guanidinium, and bisguanidium derivatives of the FDA-approved PDT agent verteporfin (Visudyne, benzoporphyrin derivative-monoacid ring A: BPD-MA) and compared their abilities to induce the intracellular perturbations common to potent PDT agents. Cellular parameters examined included subcellular localization of the verteporfin, real time monitoring of SOS production, quantitation of reactive oxygen species (ROS) generation, analysis of mitochondria and chromatin integrity, characterization of cytoskeletal disruption and evaluation of cytochrome C release as a measure of apoptosis. An analysis of these parameters demonstrates that the triphenylphosphine derivative (0323) has better mitochondria-targeting efficacy, SOS production, and mitochondria membrane toxicity than either unmodified verteporfin or its guanidinium derivatives. Consistent with this potency, 0323 also induced the most prominent mitochondria swelling, actin depolymerization, pyknosis, and cytochrome C release. We conclude that triphenylphosphine has a better mitochondria-targeting moiety than guanidinium or bis-guanidinium and those PDT photosensitizers with improved cytotoxicities can be prepared by conjugating a mitochondria-targeting moiety to the desired photosensitizer. PMID- 30023939 TI - In Situ Synthesis of Luminescent Au Nanoclusters on a Bacterial Template for Rapid Detection, Quantification, and Distinction of Kanamycin-Resistant Bacteria. AB - Herein, we introduce a new facile method of luminescent gold nanocluster (Au NC) synthesis on the surface of bacteria for detection, counting, and strain differentiation. The limit of detection was 740 +/- 14 colony-forming unit (CFU)/mL for the Gram-negative and was 634 +/- 16 CFU/mL for the Gram-positive bacteria. Brief treatment with lysozyme could differentiate the Gram strains based on their luminescence intensities. The current method could also detect bacterial contaminants from water sources and kanamycin-resistant strains rapidly. This quick synthesis of Au NCs on a bacterial template attributes an easy and rapid method for enumeration and detection of bacterial contaminants and kanamycin-resistant strains. PMID- 30023940 TI - (E)-Ethyl-2-cyano-2-(((2,4,6-trichlorobenzoyl)oxy)imino)acetate: A Modified Yamaguchi Reagent for Enantioselective Esterification, Thioesterification, Amidation, and Peptide Synthesis. AB - Here, the synthesis and applications of (E)-ethyl-2-cyano-2-(((2,4,6 trichlorobenzoyl)oxy)imino)acetate as a racemization suppressing and easily recyclable version of the Yamaguchi reagent that can be used for amide and peptide synthesis are reported. We demonstrated its application in racemization free esterification, thioesterification, amidation, and peptide bond formation. We successfully synthesized oligopeptides on the solid support in dimethylformamide as well as in solution (dichloromethane) by applying this coupling reagent. It is important to note that a mixed-anhydride-based method provides peptide-forming reactions as good as the current methods using built-in coupling reagents. Mechanism investigation, racemization suppression, and recyclability are also discussed. PMID- 30023941 TI - Three-Dimensional Highly Sensitive Diffusion Reflection-Based Imaging Method for the in Vivo Localization of Atherosclerosis Plaques Following Gold Nanorods Accumulation. AB - In this work, we present a novel, simple, and highly accurate three-dimensional (3D) diffusion reflection (DR) imaging system and method for the detection of accumulation sites of gold nanorods (GNRs) within the tissue. GNRs are intensively used for diagnosis purposes of varied diseases, mainly because of their ability to well absorb visible light, which introduces them as terrific contrast agents in various imaging and theranostics methods. Lately, these GNRs unique absorption properties have served in DR intensity-based measurements, suggesting a novel diagnostic tool, DR-GNRs. In this paper, we show a new measurement system and method for DR, based on its radial collection from the tissue. These radial measurements enabled a unique 3D presentation of the DR-GNR, introducing the dimensions rho for the radius, theta for the angle, and Gamma for the reflected intensity. On the basis of the diffusion model, which enables to correlate between the sample's optical properties and its reflectance, a unique, radial map is presented. This map introduces the slopes of the DR curves in each measured angle, which are linearly correlated with the tissue's optical properties and with the GNRs concentrations within the tissue, thus enables the exact radial localization of the GNRs in the sample. We show the detection of macrophage accumulation in tissue-like phantoms, as well as the localization of unstable plaques in hyperlipidemic mice, in vivo. This highly accurate, powerful technology paves the way toward a real-time detection method that can be successfully integrated in the rapid increasing field of personalized medicine. PMID- 30023942 TI - Image-Based Tracking of Anticancer Drug-Loaded Nanoengineered Polyelectrolyte Capsules in Cellular Environments Using a Fast Benchtop Mid-Infrared (MIR) Microscope. AB - Drug delivery monitoring and tracking in the human body are two of the biggest challenges in targeted therapy to be addressed by nanomedicine. The ability of imaging drugs and micro-/nanoengineered drug carriers and of visualizing their interactions at the cellular interface in a label-free manner is crucial in providing the ability of tracking their cellular pathways and will help understand their biological impact, allowing thus to improve the therapeutic efficacy. We present a fast, label-free technique to achieve high-resolution imaging at the mid-infrared (MIR) spectrum that provides chemical information. Using our custom-made benchtop infrared microscope using a high-repetition-rate pulsed laser (80 MHz, 40 ps), we were able to acquire images with subwavelength resolution (0.8 * lambda) at very high speeds. As a proof-of-concept, we embarked on the investigation of nanoengineered polyelectrolyte capsules (NPCs) containing the anticancer drug, docetaxel. These NPCs were synthesized using a layer-by layer approach built upon a calcium carbonate (CaCO3) core, which was then removed away with ethylenediaminetetraacetic acid. The obtained MIR images show that NPCs are attached to the cell membrane, which is a good step toward an efficient drug delivery. This has been confirmed by both three-dimensional confocal fluorescence and stimulated emission depletion microscopy. Coupled with additional instrumentation and data processing advancements, this setup is capable of video-rate imaging speeds and will be significantly complementing current super-resolution microscopy techniques while providing an unperturbed view into living cells. PMID- 30023944 TI - Efficient Removal of Cadmium Using Edible Fungus and Its Quantitative Fluorimetric Estimation Using (Z)-2-(4H-1,2,4-Triazol-4-yl)iminomethylphenol. AB - Microbes accumulate heavy metals after adsorption or absorption. This study exhibited that Trametes versicolor can tolerate up to 5 mg/g concentration of cadmium. Change in fungus morphology due to cadmium along with its absorption were analyzed using SEM, XRD, and EDAX. Cadmium absorption usually increased with time, and it was determined quantitatively by a fluorimetry technique using a synthesized imine fluorophore as a specific probe and compared with results obtained from atomic absorption spectroscopy (AAS). The intensity of the cadmium specific XRD peak gradually increased up to the seventh day, and the absorption by the organisms reduced the concentration of cadmium even from the effluent of the plating industry. After the seventh day, Trametes versicolor absorbed almost 0.300 mg/g concentration of cadmium as visualized under high content screening from the fluorescence appearance of hyphae. Hence it can be concluded that Trametes versicolor may play a key role in reducing cadmium from a contaminated environment. PMID- 30023943 TI - Development of Magnetic Nanocomposite Hydrogel with Potential Cartilage Tissue Engineering. AB - Magnetic nanocomposite hydrogels show high potential to improve tissue engineering. In this study, a magnetic nanocomposite hydrogel was prepared from poly(vinyl alcohol), nano-hydroxyapatite (n-HA), and magnetic nanoparticles (Fe2O3) using the ultrasonic dispersion method and freeze-thaw cross-linking molding. The water content and crystallinity of the magnetic nanocomposite hydrogel were tested. Microscopic morphology assessment, mechanical testing, and characterization were performed. Additionally, the magnetic nanocomposite hydrogel was co-cultured with bone mesenchymal stem cells (BMSCs) to determine its cell compatibility. We found that the magnetic nanocomposite hydrogel had good mechanical properties and that its mechanical properties were enhanced by the addition of n-HA. The BMSCs showed uniform growth on the surface of the magnetic nanocomposite hydrogel and high rates of proliferation. BMSC growth was also enhanced by the addition of Fe2O3 and also significant stimulated chondrocyte-related gene expression. Thus, the magnetic nanocomposite hydrogel scaffold material we describe here could have broad applications in cartilage tissue engineering. PMID- 30023946 TI - Bioconjugated, Single-Use Biosensor for the Detection of Biomarkers of Prostate Cancer. AB - Prostate cancer is prevalent among cancers in men. A simple method for screening of reliable biomarkers is pivotal for early detection of prostate cancer. Prostate-specific antigen (PSA) has been a commonly used biomarker for prostate cancer, in spite of its false-positive limitation. On the other hand, alpha methylacyl-CoA racemase (AMACR), a metabolic enzyme, has been proven to be a highly expressed biomarker in prostate cancer cells. Therefore, a method or tool, which can detect either PSA or AMACR or both simply, cost effectively, and with high sensitivity and selectivity is desirable. We describe a novel bioconjugated, single-use biosensor capable of detecting both PSA and AMACR antigens in undiluted human serum. The preparation of the biosensor by the bioconjugation mechanism occurred within a day, which could be completed prior to actual testing. The effectiveness of the bioconjugation mechanism and the coverage of the electrode surface of the biosensor were experimentally assessed. Measurements of PSA and AMACR antigens and the specificity of the biosensor were carried out using differential pulse voltammetry. This biosensor was single-use and cost effective and required a small quantity of test medium and relatively short preparation time, providing a very attractive biosensor for the detection of the biomarkers of prostate cancer. PMID- 30023947 TI - Nitrogen Isotope Composition, Nitrogen Amount, and Fruit Yield of Tomato Plants Affected by the Soil-Fertilizer Types. AB - Tomatoes (Solanum lycopersicum) are heavy nutrient feeding crops and require high amounts of nitrogen to maximize fruit production. The type of nitrogen applied and timing of fertilizer applications are important to reduce losses due to volatilization and leaching. Previous research suggested that nitrogen stable isotopes are a useful fingerprinting system for indicating if a crop has been grown with synthetic or organic nitrogen applications. To study the effects of fertilization systems on nitrogen isotopic patterns, "Better Bush" tomatoes were grown in a 2 year greenhouse experiment to analyze nitrogen isotopic composition, nitrogen content, and fruit yield. Three main soil fertility treatments were evaluated, and the results were compared to those obtained on plants grown in unfertilized soil: conventional inorganic (synthetic Miracle Grow (MG)), organic (bonemeal and bloodmeal (BB), BB with liquid Earth Juice (BBL), BB with 25% vermicompost (VC), BBL with 25% VC, and 25% VC), and mixed (MG with 25% VC). The soil fertilizers, treated and untreated soil, immature and mature leaflets tomato fruit peels, and fruit juices were analyzed for both nitrogen isotope ratios and nitrogen concentrations. Plant delta15Nair decreased in the order organic treatment-no fertilizer-mixed treatment-conventional treatment. The average delta15Nair values in leaves, fruit peels, and juice from plants grown with organic treatments ranged from 4.5 to 11.9, 5.4 to 10.1, and 6.1 to 11.10/00, respectively, whereas in the case of the inorganic treatment, the average delta15Nair values varied between -3.0 and 0.4, -1.1 and 0.4, and -0.9 and 1.90/00, respectively. Plant nitrogen concentrations in tomato decreased in the following order (from highest to lowest): inorganic soil fertility treatment, mixed treatments, and organic and control (no fertilizer) treatment. The average weight %N values in leaves and fruit peels from plants grown with organic treatments ranged from 1.3 to 4.2 and 1.1 to 2.3%, respectively, whereas in the case of the inorganic treatment, the average weight %N values varied between 3.7 and 5 and 1.3 and 2.8%, respectively. Plants grown under organic treatments have higher delta15Nair, lower weight %N, and are enriched in 15N compared with the original soil than plants grown with inorganic fertilizer, suggesting that the synthetic nitrogen sources are more readily available for plant uptake than the organic ones. The addition of vermicompost increases both delta15Nair and weight %N in plants. Tomato fruit yields did not differ between cluster 1 and cluster 2 harvest, however, total tomato fruit yields differed indicating that synthetically fertilized plants produced the highest total yields (g) (P <= 0.05). However, all treatments with VC soil applications indicated an increase in the amount of plant nitrogen, fruit yield, soil cation exchange capacity, soil organic matter content, and released soil nitrogen. Nitrogen isotope ratios of tomatoes can be used to distinguish among various soil fertility treatments, therefore fingerprinting the organic fertilizer applications. PMID- 30023945 TI - Discovery of Retinoic Acid-Related Orphan Receptor gammat Inverse Agonists via Docking and Negative Image-Based Screening. AB - Retinoic acid-related orphan receptor gammat (RORgammat) has a vital role in the differentiation of T-helper 17 (TH17) cells. Potent and specific RORgammat inverse agonists are sought for treating TH17-related diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. Here, the aim was to discover novel RORgammat ligands using both standard molecular docking and negative image-based screening. Interestingly, both of these in silico techniques put forward mostly the same compounds for experimental testing. In total, 11 of the 34 molecules purchased for testing were verified as RORgammat inverse agonists, thus making the effective hit rate 32%. The pIC50 values for the compounds varied from 4.9 (11 MUM) to 6.2 (590 nM). Importantly, the fact that the verified hits represent four different cores highlights the structural diversity of the RORgammat inverse agonism and the ability of the applied screening methodologies to facilitate much desired scaffold hopping for drug design. PMID- 30023948 TI - Role of the Surface Nanoscale Roughness of Stainless Steel on Bacterial Adhesion and Microcolony Formation. AB - Hospital-acquired infections can cause serious complications and are a severe problem because of the increased emergence of antibiotic-resistant bacteria. Biophysical modification of the material surfaces to prevent or reduce bacteria adhesion is an attractive alternative to antibiotic treatment. Since stainless steel is a widely used material for implants and in hospital settings, in this work, we used stainless steel to investigate the effect of the material surface topographies on bacterial adhesion and early biofilm formation. Stainless steel samples with different surface roughnesses Rq in a range of 217.9-56.6 nm (Ra in a range of 172.5-45.2 nm) were fabricated via electropolishing and compared for adhesion of bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus. It was found that the number of viable cells on the untreated rough surface was at least 10-fold lower than those on the electropolished surfaces after 4 h of incubation time for P. aeruginosa and 15-fold lower for S. aureus. Fluorescence images and scanning electron microscopy images revealed that the bacterial cells tend to adhere individually as single cells on untreated rough surfaces. In contrast, clusters of the bacterial cells (microcolonies) were observed on electropolished smooth surfaces. Our study demonstrates that nanoscale surface roughness can play an important role in restraining bacterial adhesion and formation of microcolonies. PMID- 30023950 TI - Radiolabeling and Preclinical Evaluation of a New S-Alkylated Cysteine Derivative Conjugated to C-Substituted Macrocycle for Positron Emission Tomography. AB - A new S-alkylated cysteine-derivatized tumor targeting agent, 2,2'-(12-(2-((2 acetamido-2-carboxyethyl)thio)acetamido)-11,13-dioxo-1,4,7,10 tetraazacyclotridecane-4,7-diyl)diacetic acid was developed for positron emission tomography (PET) imaging. N-Acetyl cysteine (NAC) was conjugated to ATRIDAT as a specific targeting agent toward L-type and ASC amino acid transporter systems in the oncogenic cells. NAC was attached via S-alkylation to prevent its incorporation at undesired recognition sites affecting the signal-to-noise ratio. NAC-ATRIDAT was subjected to gallium-68 complexation with >75% radiolabeling yield. The radiocomplex was purified through the tc18 cartridge to obtain 99.89% radiochemical yield. IC-50 of the NAC-ATRIDAT conjugate was 0.8 mM in A549 cells as evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide assay. Binding affinity experiments on A549 cells showed noteworthy binding with KD in the nanomolar range. A time course study showed a Km value of 0.19 MUM and Vmax value of 0.49 pmol/MUg protein/min showing reasonable tumor kinetics. Efflux studies showed that the synthesized radioligand is transported majorly by LAT followed by the ASC system. Clearance was found to be renal with 7.67 +/- 1.48% ID/g uptake at 30 min which substantially declined to 0.52 +/- 0.% ID/g at 4 h. A significant uptake of 10.06 +/- 1.056% ID/g was observed at the tumor site in mice at 1 h. MUPET images revealed a high contrast with a tumor-to-kidney ratio of 4.8 and a tumor-to-liver ratio of 35.85 at 1 h after injection. These preclinical in vitro and in vivo evaluation supports its potential on the way of becoming a successful 68Ga-radiolabeled amino acid-based PET imaging agent. PMID- 30023949 TI - Identification of Tobacco Types and Cigarette Brands Using an Electronic Nose Based on Conductive Polymer/Porphyrin Composite Sensors. AB - Three tobacco types (Burley, Flue Cured, and Oriental) and eight cigarette brands were unequivocally identified using an electronic nose formed by only three sensors based on a single novel conducting polymer (PF-BTB) doped with different porphyrins (H2TPP, H2TPFP, and H2BTBOP). The synthesis and characterization of the polymer are also discussed. Small changes in the porphyrin structure caused significant changes in the electrical conductance response patterns of the sensors upon exposure to complex chemical matrixes, representing a novel approach for tuning the selectivity of chemiresistive sensors for e-nose application. This e-nose is fast, cheap, reliable, can be easily operated, and could be a valuable tool for border agents fighting cigarette smuggling around the world, helping them prevent losses of millions in tax revenues and sales. PMID- 30023951 TI - Catalytic Ozonation for the Degradation of 5-Sulfosalicylic Acid with Spinel-Type ZnAl2O4 Prepared by Hydrothermal, Sol-Gel, and Coprecipitation Methods: A Comparison Study. AB - This study presents a novel spinel-type zinc aluminate nanometer catalyst and is applied in catalytic ozonation for wastewater treatment. The zinc aluminate (ZnAl2O4) catalysts were synthesized by hydrothermal, sol-gel, and coprecipitation methods, and their characteristics were analyzed by X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectrum, Fourier transform infrared, and X-ray photoelectron spectroscopy (XPS) techniques. 5-Sulfosalicylic acid (SSal) was selected as the typical pharmaceutical and personal care product and used to evaluate the catalytic activity of ZnAl2O4. Compared to ozonation, an obviously higher removal efficiency for the SSal degradation was achieved with the nanocatalyst addition in catalytic ozonation. The removal of SSal and chemical oxygen demand reached 64.8 and 46.2%, respectively, after 60 min in the presence of ZnAl2O4, whereas it was only 49.4 and 33.2%, respectively, in ozonation. The comparison of catalysts showed that the ZnAl2O4 prepared by the hydrothermal method presented a better catalytic activity in ozonation. The effect of radical scavenger experiment results and the characterization of XPS implied that *OH was the main active oxidative species in catalytic ozonation. The reusability results showed that the ZnAl2O4 catalyst possessed a high stability and could be widely used in catalytic ozonation for wastewater treatment. PMID- 30023952 TI - Surface-Selective Control of Cell Orientation on Cyanobacterial Liquid Crystalline Gels. AB - Liquid crystalline hydrogels (LCGs) with layer structures and oriented pores were created using sacran which is a cyanobacterial heteropolysaccharide possessing functional sulfate, carboxylate, and amide groups in common with glycosaminoglycan. The LCG biocompatibility with L929 mouse fibroblasts was confirmed under the appropriate conditions. Enhanced growth and proliferation of L929 cells without exhibiting any toxicity were confirmed. The water contact angle and protein adsorption ability on the LCG were well-controlled by the cross linking degree. Additionally, fibroblasts were finely oriented on the LCG side face where layer edges made a striped morphology on its surface, whereas the flat top faces of the LCG did not induce any specific cell orientation. PMID- 30023953 TI - Time Trends of Polybrominated Diphenyl Ethers (PBDEs) in Antarctic Biota. AB - Polybrominated diphenyl ethers (PBDEs) are "emerged" contaminants that were produced and used as flame retardants in numerous consumer and industrial applications for decades until banned. They remain ubiquitously present in the environment today. Here, a unique set of >200 biotic samples from the Antarctic was analyzed for PBDEs, including phytoplankton, krill, fish, and fur seal milk, spanning several sampling seasons over 14 years. PBDE-47 and -99 were the dominant congeners determined in all samples, constituting >60% of total PBDEs. A temporal trend was observed for ?7PBDE concentrations in fur seal milk, where concentrations significantly increased (R2 = 0.57, p < 0.05) over time (2000 2014). Results for krill and phytoplankton also suggested increasing PBDE concentrations over time. Trends of PBDEs in fur seal milk of individual seals sampled 1 or more years apart showed no clear temporal trends. Overall, there was no indication of PBDEs decreasing in Antarctic biota yet, whereas numerous studies have reported decreasing trends in the northern hemisphere. Similar PBDE concentrations in perinatal versus nonperinatal milk implied the importance of local PBDE sources for bioaccumulation. These results indicate the need for continued assessment of contaminant trends, such as PBDEs, and their replacements, in Antarctica. PMID- 30023954 TI - Effects of Ultrasound Pretreatment on Eucalyptus Thermal Decomposition Characteristics As Determined by Thermogravimetric, Differential Scanning Calorimetry, and Fourier Transform Infrared Analysis. AB - Samples were pretreated by ultrasound at 300 W and 28 kHz in three different solutions. The thermal degradation characteristics of the samples were then characterized via thermogravimetric, differential scanning calorimetry, and Fourier transform infrared analysis in a nitrogen environment. The characteristic of gas product release, the formation mechanisms of the main products, and the mechanistic basis for the effects of ultrasound on wood components were studied. The results showed that the gaseous products are the same with ultrasound pretreatment but the amounts are changed. The gaseous products mainly constitute of CO, H2O, CO2, CH4, and CH3COOH, and more gaseous products were produced at 361 degrees C than at 308 degrees C. The reaction rates for specimens pretreated in aqueous soda solution proceeded faster than specimens pretreated in aqueous acetic acid solution and distilled water. Moreover, the maximum FTIR spectra absorbance appeared around 341 degrees C for specimens pretreated in aqueous soda solution but appeared around 369 degrees C for the control sample and samples pretreated in distilled water or acetic acid solution. The heat flows for specimens pretreated in aqueous soda solution, compared to control group, was much lower. Additionally, hydroxyl and hydroperoxy radicals provided by ultrasound cavitation in alkaline conditions act to intensify the overall rates of reactions. PMID- 30023955 TI - Novel Microfluidic Analytical Sensing Platform for the Simultaneous Detection of Three Algal Toxins in Water. AB - Globally, the need for "on-site" algal-toxin monitoring has become increasingly urgent due to the amplified demand for fresh-water and for safe, "toxin-free" shellfish and fish stocks. Herein, we describe the first reported, Lab-On-A-Disc (LOAD) based-platform developed to detect microcystin levels in situ, with initial detectability of saxitoxin and domoic acid also reported. Using recombinant antibody technology, the LOAD platform combines immunofluorescence with centrifugally driven microfluidic liquid handling to achieve a next generation disposable device capable of multianalyte sampling. A low-complexity "LED-photodiode" based optical sensing system was tailor-made for the platform, which allows the fluorescence signal of the toxin-specific reaction to be quantified. This system can rapidly and accurately detect the presence of microcystin-LR, domoic acid, and saxitoxin in 30 min, with a minimum of less than 5 min end-user interaction for maximum reproducibility. This method provides a robust "point of need" diagnostic alternative to the current laborious and costly methods used for qualitative toxin monitoring. PMID- 30023956 TI - Enzymatic Synthesis of Glycerol Carbonate Using a Lipase Immobilized on Magnetic Organosilica Nanoflowers as a Catalyst. AB - For synthesizing glycerol carbonate (GC) by a reaction between glycerol (GL) and dimethyl carbonate (DMC), a lipase immobilized on magnetic organosilica nanoflowers was prepared and utilized as a biocatalyst. Candida antarctica lipase B (CALB) was chosen as a model enzyme for preparing an immobilized biocatalyst (CALB@nanoflowers). The obtained CALB@nanoflowers was characterized using scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy. Effects of GL/DMC molar ratio, biocatalyst amount, temperature, surfactant and molecular sieve addition, and reaction time on the conversion of GL and the selectivity of CALB@nanoflowers were investigated. The optimal catalytic performance (yield of GC: 88.66% and conversion of GL: 94.24%) was achieved under the condition of 1:20 molar ratio of GL to DMC with 0.2 g of molecular sieves added at 50 degrees C for 24 h. After recycling seven times, the CALB@nanoflowers maintained over 79% of its initial activity and the yield of GC was 70.31%. PMID- 30023957 TI - Impact of the Ripening Stage of Wax Apples on Chemical Profiles of Juice and Cider. AB - Wax apple fruit (Syzygium aqueum Alston cv. Taaptimjan) is a tropical fruit with many nutritional bioactive compounds and high economic value. However, when fully ripe, the thin-skinned fruit is highly susceptible to physical damage and microbial spoilage that significantly reduce its commercial value. The present study was aimed to find a suitable ripening stage between the ripe and overripe wax apple fruits for developing a value-added beverage specifically cider. The chemical profiles of ripe and overripe wax apple juice and cider were determined by measuring sugar, acid, alcohol, mineral, proximate, ascorbic acid, amino acid, antioxidant, and volatile levels. Overall, the results showed significant variations. The physicochemical and proximate analysis showed highest values for ripe fruit juice than overripe fruit juice and the cider samples. The amino acids in the samples were found almost at similar levels. Polyphenolic content and antioxidant activities were higher in ciders than in unfermented juices. In addition, the overripe fruit cider had more volatile compounds than ripe fruit cider and unfermented juices. Overall, the overripe fruit is suitable for producing cider, whereas the ripe fruit is more suitable for the unfermented beverages. PMID- 30023958 TI - Catecholamine Detection Using a Functionalized Poly(l-dopa)-Coated Gate Field Effect Transistor. AB - A highly sensitive catecholamine (CA) sensor was created using a biointerface layer composed of a biopolymer and a potentiometric detection device. For the detection of CAs, 3-aminophenylboronic acid (3-NH2-PBA) was reacted with the carboxyl side chain of l-3,4-dihydroxyphenylalanine (l-dopa, LD) and the PBA modified l-dopa was directly copolymerized with LD on an Au electrode, resulting in a 3.5 nm thick PBA-modified poly(PBA-LD/LD) layer-coated Au electrode. By connecting the PBA-LD-coated Au electrode to a field-effect transistor (FET), the molecular charge changes at the biointerface of the Au electrode, which was caused by di-ester binding of the PBA-CA complex, were transduced into gate surface potential changes. Effective CAs included LD, dopamine (DA), norepinephrine (NE), and epinephrine (EP). The surface potential of the PBA-LD coated Au changed after the addition of 40 nM of each CA solution; notably, the PBA-LD-coated Au showed a higher sensitivity to LD because the surface potential change could already be observed after 1 nM of LD was added. The fundamental parameter analyses of the PBA-LD to CA affinity from the surface potential shift against each CA concentration indicated the highest affinity to LD (binding constant (Ks): 1.68 * 106 M-1, maximum surface potential shift (Vmax): 182 mV). Moreover, the limit of detection for each CA was 3.5 nM in LD, 12.0 nM in DA, 7.5 nM in NE, and 12.6 nM in EP. From these results, it is concluded that the poly(PBA-LD/LD)-coated gate FET could become a useful biosensor for neurotransmitters, hormones, and early detection of Parkinson's disease. PMID- 30023959 TI - Nanotoxicity of Silver Nanoparticles on HEK293T Cells: A Combined Study Using Biomechanical and Biological Techniques. AB - Human embryonic kidney 293T cells (HEK293T cells) before and after treatment with silver nanoparticles (AgNPs) were measured using advanced atomic force microscopy (AFM) force measurement technique, and the biomechanical property of cells was analyzed using a theoretical model. The biomechanical results showed that the factor of viscosity of untreated HEK293T cells reduced from 0.65 to 0.40 for cells exposure to 40 MUg/mL of AgNPs. Comet assay indicated that significant DNA damage occurred in the treated cells, measured as tail DNA% and tail moment. Furthermore, gene expression analysis showed that for the cells treated with 40 MUg/mL of AgNPs, the antiapoptosis genes Bcl2-t and Bclw were, respectively, downregulated to 0.65- and 0.66-fold of control, and that the proapoptosis gene Bid was upregulated to 1.55-fold of control, which indicates that apoptosis occurred in cells exposed to AgNPs. Interestingly, excellent negative correlations were found between the factor of viscosity and tail DNA%, and tail moment, which suggest that the biomechanical property can be correlated with genotoxicity of nanoparticles on the cells. Based on the above results, we conclude that (1) AgNPs can lead to biomechanical changes in HEK293T cells, concomitantly with biological changes including cell viability, DNA damage, and cell apoptosis; (2) the factor of viscosity can be exploited as a promising label free biomechanical marker to assess the nanotoxicity of nanoparticles on the cells; and (3) the combination of AFM-based mechanical technique with conventional biological methods can provide more comprehensive understanding of the nanotoxicity of nanoparticles than merely by using the biological techniques. PMID- 30023960 TI - Photobactericidal Activity of Dual Dyes Encapsulated in Silicone Enhanced by Silver Nanoparticles. AB - Crystal violet (CV) and methylene blue (MB) dyes with silver (Ag) nanoparticles (NPs) were encapsulated into silicone to produce light-activated antimicrobial surfaces. Optical microscopy and X-ray photoelectron spectroscopy showed that CV and MB were diffused throughout the silicone samples and that Ag NPs were successfully encapsulated by the swell-encapsulation-shrink process. Antimicrobial tests on Staphylococcus aureus and Escherichia coli showed that CV/MB-encapsulated silicone samples have stronger photobactericidal activity than CV or MB samples and the addition of Ag NPs significantly enhanced the antimicrobial activity under white light. The number of viable bacteria decreased below the detection limit (below <103 CFU) on the silicone-incorporating CV/MB/Ag NPs within 3 h for S. aureus and within 5 h for E. coli. In leaching tests over 216 h, the amount of dye leaching from the samples was barely detectable (<0.02 ppm). These surfaces have a potential for use in healthcare settings to decrease hospital-associated infections. PMID- 30023961 TI - Biodiesel Production via Trans-Esterification Using Pseudomonas cepacia Immobilized on Cellulosic Polyurethane. AB - In this work, Pseudomonas cepacia lipase immobilized on cellulosic polyurethane was used as a catalyst for biodiesel production via trans-esterification reactions in order to provide cost-effective methods of enzyme recycling. The efficacy of the immobilized enzyme catalyst at low loading (6.2 wt %) and the effects of temperature, water content, and reaction time in model trans esterification of glyceryl trioctanoate were investigated extensively. It was found that water was necessary for the reaction of glyceryl trioctanoate with ethanol to proceed. A high conversion of glyceryl trioctanoate (~70%) was obtained at 35 degrees C, with only 5.0 wt % of water content over a reaction period of 12 h. PMID- 30023962 TI - Effective Theranostic Cyanine for Imaging of Amyloid Species in Vivo and Cognitive Improvements in Mouse Model. AB - We report herein an investigation of carbazole-based cyanine, (E)-4-(2-(9-(2-(2 methoxyethoxy)ethyl)-9H-carbazol-3-yl)-vinyl)-1-methyl-quinolin-1-iumiodide (SLM), as an effective theranostic agent for Alzheimer's disease (AD). This cyanine exhibited desirable multifunctional and biological properties, including amyloid-beta (Abeta)-oligomerization inhibition, blood-brain barrier permeability, low neurotoxicity, neuroprotective effect against Abeta-induced toxicities, high selectivity and strong binding interactions with Abeta peptide/species, good biostability, as well as strong fluorescence enhancement upon binding to Abeta species for diagnosis and therapy of AD. This cyanine has been successfully applied to perform near-infrared in vivo imaging of Abeta species in transgenic AD mouse model. The triple transgenic AD mice intraperitoneally treated with SLM showed significant recovery of cognitive deficits. Furthermore, those SLM-treated mice exhibited a substantial decrease in both of oligomeric Abeta contents and tau proteins in their brain, which was attributed to the induction of autophagic flux. These findings demonstrated for the first time that SLM is an effective theranostic agent with in vivo efficacy for diagnosis and treatment of AD in mouse models. PMID- 30023963 TI - Enhancing Passive Transport of Micro/Nano Particles into Cells by Oxidized Carbon Black. AB - Uses of micro-/nano-sized particles to deliver biologically active entities into cells are common for medical therapeutics and prophylactics and also for cellular experiments. Enhancing cellular uptake and avoiding destruction by lysosomes are desirable for general particulate drug delivery systems. Here, we show that the relatively nontoxic, negatively charged oxidized carbon black particles (OCBs) can enhance cellular penetration of micro- and nano-particles. Experiments with retinal-grafted chitosan particles (PRPs) with hydrodynamic sizes of 1200 +/- 51.5, 540 +/- 29.0, and 430 +/- 11.0 nm (three-sized model particles) indicate that only the sub-micron-sized particles can penetrate the first layer of multilayered liposomes. However, in the presence of OCBs, the micron-sized PRPs and the two submicron-sized PRPs can rapidly enter the interiors of all layers of the multilayered liposomes. Very low cellular uptakes of micro- and submicron sized PRPs into keratinocytes cells are usually observed. However, in the presence of OCBs, faster and higher cellular uptakes of all of the three-sized PRPs are clearly noticed. Intracellular traffic monitoring of PRP uptake into HepG2 cells in the presence of OCBs revealed that the PRPs did not co-localize with endosomes, suggesting a nonendocytic uptake process. This demonstration of OCB's ability to enhance cellular uptake of micro- and submicron-particles should open up an easy strategy to effectively send various carriers into cells. PMID- 30023964 TI - Silicone-Containing Biodegradable Smart Elastomeric Thermoplastic Hyperbranched Polyurethane. AB - Silicone-containing biobased hyperbranched polyurethane thermoplastic elastomers at different compositions were reported for the first time. The structures of the polymers were evaluated from Fourier transform infrared spectroscopy, NMR, X-ray diffraction, and energy-dispersive X-ray spectroscopy analyses. The synthesized elastomers possess high molecular weight (1.11-1.38 * 105 g.mol-1) and low glass transition temperature (from -40.0 to -27.3 degrees C). These polymers exhibited multistimuli responsive excellent repeatable intrinsic self-healing (100% efficiency), shape recovery (100%), and efficient self-cleaning (contact angle 102 degrees -107 degrees ) abilities along with exceptional elongation at break (2834-3145%), high toughness (123.3-167.8 MJ.m-3), good impact resistance (18.3 20.3 kJ.m-1), and adequate tensile strength (5.9-6.9 MPa). Furthermore, high thermal stability (253-263 degrees C) as well as excellent UV and chemical resistance was also found for the polymers. Most interestingly, controlled bacterial biodegradation under exposure of Pseudomonas aeruginosa bacterial strains demonstrated them as sustainable materials. Therefore, such biobased novel thermoplastic polyurethane elastomers with self-healing, self-cleaning, and shape memory effects possess great potential for their advanced multifaceted applications. PMID- 30023965 TI - Efficient and Site-Specific 125I-Radioiodination of Bioactive Molecules Using Oxidative Condensation Reaction. AB - In this report, the novel and site-specific radioiodination of biomolecules by using aryl diamine and alkyl aldehyde condensation reaction in the presence of a Cu2+ catalyst under ambient conditions was reported. 125I-labeled alkyl aldehyde was synthesized using a tin precursor with a high radiochemical yield (72 +/- 6%, n = 5) and radiochemical purity (>99%). The utility of the radioiodinated precursor was demonstrated through aryl diamine-installed c[RGDfK(C)] peptide and human serum albumin (HSA). Radioiodinated c[RGDfK(C)] peptide and HSA protein were synthesized with high radiochemical yields and purity. 125I-HSA protein showed excellent in vivo stability and negligible thyroid uptake as compared with directly radioiodinated HSA by using the tyrosine group. Excellent reaction kinetics and the in vitro and in vivo stabilities of 125I-labeled alkyl aldehyde have suggested the usefulness of the strategy for the radioiodination of bioactive molecules. PMID- 30023967 TI - Chemically Modified Gellan Gum Hydrogels with Tunable Properties for Use as Tissue Engineering Scaffolds. AB - Gellan gum is a naturally occurring polymer that can cross-link in the presence of divalent cations to form biocompatible hydrogels. However, physically cross linked gellan gum hydrogels lose their stability under physiological conditions, thus restricting the applications of these hydrogels in vivo. To improve the mechanical strength of the gels, we incorporated methacrylate into the gellan gum and chemically cross-linked the hydrogel through three polymerization methods: step growth through thiol-ene photoclick chemistry, chain-growth via photopolymerization, and mixed model in which both mechanisms were employed. Methacrylation was confirmed and quantified by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy. The mechanical properties and chemistry of the cross-linked gels were systematically altered by varying the reaction conditions. The compression moduli of the resulting hydrogels ranged between 6.4 and 17.2 kPa. The swelling ratios of the hydrogels were correlated with the compression moduli and affected by the addition of calcium. In vitro enzymatic degradation rate was found to depend on the degree of methacrylation. NIH/3T3 fibroblast cell proliferation and morphology were related to substrate stiffness, with a high stiffness leading generally to higher proliferation. The proliferation is further affected by the thiol-ene ratio. These results suggest that a hydrogel platform based on the gellan gum can offer versatile chemical modifications and tunable mechanical properties. The influence of these substrates on cell behavior suggests that the gellan gum hydrogels have the flexibility to be engineered for a variety of biomaterials applications. PMID- 30023966 TI - Natural Product-Based 1,2,3-Triazole/Sulfonate Analogues as Potential Chemotherapeutic Agents for Bacterial Infections. AB - Despite the vast availability of antibiotics, bacterial infections remain a leading cause of death worldwide. In an effort to enhance the armamentarium against resistant bacterial strains, 1,2,3-triazole (5a-x) and sulfonate (7a-j) analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive (Streptococcus pneumoniae and Enterococcus faecalis) and four Gram-negative bacterial strains (Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, 5e (derived from carvacrol) and 5u (derived from 2 hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against S. pneumoniae (IC50: 62.53 and 39.33 MUg/mL), E. faecalis (IC50: 36.66 and 61.09 MUg/mL), and E. coli (IC50: 15.28 and 22.57 MUg/mL). Furthermore, 5e and 5u also demonstrated moderate efficacy against multidrug-resistant E. coli strains and were therefore selected for further biological studies. Compound 5e in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant E. coli MRA11 and MRC17 strains, whereas compound 5u was selective against E. coli MRA11 strain. Growth kinetic studies on S. pneumoniae and E. coli treated with 5e and 5u showed an extended lag phase. 5e and 5u did not show significant cytotoxicity up to 100 MUg/mL concentration on human embryonic kidney (HEK293) cells. Transmission electron microscopic (TEM) analysis of bacterial cells (S. pneumoniae and E. coli) exposed to 5e and 5u clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in S. pneumoniae and E. coli strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of Galleria mellonella (an in vivo model for antimicrobial studies) with 5e and 5u did not cause an alteration in the hemocyte density, thereby indicating lack of an immune response, and were nontoxic up to a concentration of 2.5 mg/mL. PMID- 30023969 TI - Surgical approaches for papillary microcarcinomas: Turkey's perspective. AB - Objectives: The incidence of papillary microcarcinomas, which are defined as thyroid cancers of <10mm in size, has been increasing in the last decade. Herein, we present internet-based questionnaire results performed by the Turkish Association of Endocrine Surgery with the aim to evaluate the perspective of the management of papillary microcarcinomas in Turkey. Material and Methods: The user friendly questionnaire consisted of 13 questions in total. These questions mainly addressed the surgical management of nodules and cancer of <1 cm in size. Patient management before, during, and after surgical intervention was also included; additionally, the "active surveillance approach" was questioned. Results: There were 420 responders in total who were of multidisciplinary origin (endocrinologists, surgeons, nuclear medicine specialists, pathologists, and oncologists). Total thyroidectomy was the predominant treatment approach (65%) for the classical type of microcarcinoma limited in one lobe, whereas in cases of microcarcinomas incidentally diagnosed during hemithyroidectomy, complementary surgery approach was advised by 40% of the responders. The responders found capsule invasion (86%) and patient based management (94%) of high importance. The percentage of the responders who recommended radioactive iodine ablation in incidental cancers having no aggressive criteria was 51%. The survey participants that were against routine central dissection in these cases accounted for 73% of the responders. The recommendation of active surveillance (follow-up without any interventional therapy) was limited with 9% responders. Conclusion: The results of the questionnaire demonstrated that there have been various choices in Turkey for the surgical treatment of the papillary microcarcinomas. PMID- 30023970 TI - Effects of body mass index on cecal intubation time in women. AB - Objective: During colonoscopy, cecal intubation time is prolonged with increase in difficulty of the procedure. Cecal intubation time may be affected by age, gender, and body structure. We investigated the relationship between body mass index and cecal intubation time in women. Material and Methods: This prospective study included 61 women who underwent colonoscopy in the endoscopy unit of the General Surgery Clinic in Trabzon Kanuni Training and Research Hospital between January 2016 and September 2016. The colonoscopies were performed by a single surgeon. The height and weight of all the participants were measured, and their body mass index values were calculated before the procedure. The timer was activated as soon as entry was made from the anal region with colonoscope and stopped when the cecum was reached. The cecal intubation time was recorded for each subject. The results were evaluated statistically, and p<0.05 was considered to be significant. Results: The mean body mass index was 29.6+/-6.8 kg/m2. The median cecal intubation time was 4 min. (minimum 2 min; maximum 8 min). A significantly strong positive correlation was found between body mass index and cecal intubation time (r:-0.891, p<0.001). Conclusion: Cecal intubation time was found to be shorter in women whose body mass index values were high. This outcome may help to eliminate the "the colonoscopy will be difficult" preconception, which is common among endoscopists with regard to the colonoscopies for obese female patients. PMID- 30023968 TI - Comments on the new groin hernia guidelines: What has changed? What has remained unanswered? AB - Guidelines are meant to evaluate the options available in the current circumstances and suggest the proper solutions for particular problems. The duty of a guideline is to present a basis for decision-making. Surgical options for the treatment of groin hernias are numerous. Recently, a joint guideline called "International Guidelines for Groin Hernia Management" was developed by five continental hernia societies, the International Endo hernia Society, and the European Association for Endoscopic Surgery. This article aimed to review the methodology, statements, and recommendations of the new guidelines and emphasized the importance of the tailored surgery for groin hernias. Spreading the guidelines may provide surgeons with an up-to-date knowledge and be useful for better outcomes in groin hernia surgery. PMID- 30023971 TI - Importance of informed consent defined by General Surgery Associations in Turkey. AB - Objective: Informed consent is a term based on the idea that every individual has the right to know every medical intervention that is going to be performed on their own body and to learn the issues that she/he may encounter in case of refusal of intervention, and it also defines the protection of personal rights under the guarantee of law. Material and Methods: The website of Turkish Surgical Association and 25 different websites of surgical associations were evaluated according to general surgery association guide, which was published by the Turkish Surgical Association in 2011. Results: Four websites of those surveyed include informed consent sections and these were evaluated. A total of 44 informed consent forms were included in this study. Of these, 29 were in Turk Colon and Rectum Surgery Association, 8 were in Turkish Surgery Association, 5 were in Turk Hepatopancreaticobilier Surgery Association, and 4 were in Endocrine Surgery Association. These informed consent forms were evaluated with regard to the aforementioned criteria. The results and also the distribution according to the associations were summarized. A common feature of the informed consent forms was that all of them included the risks of the intervention/operation and complications to be carried out. On the contrary, none of them included approximate time of surgery, information about surgeons, issues that patients should care about before surgery, the section that permits the use of data for scientific purpose, and the time of signing the informed consent form. Conclusion: We believe that in this context the regulation of informed consent by sub-specialization associations under the flag of Turkish Surgical Association is a very important matter and will standardize informed consents; websites of the associations will be easier to access, and this will be as beneficial for physicians as the patients and also will protect the physicians in probable trials. PMID- 30023972 TI - Self-expandable metallic stent application for the management of upper gastrointestinal tract disease. AB - Objective: The aim of the present study was to share our experiences of the use of self-expandable metallic stent for the upper gastrointestinal tract disease. Material and Methods: We retrospectively reviewed the medical records of 18 patients who underwent self-expandable metallic stent implantation procedure for anastomosis stricture, anastomosis leak, or spontaneous fistula of the upper gastrointestinal tract at two different surgery clinics. Self-expandable metallic stent implantation procedures were performed while keeping the patient under sedation and the correct stent localization was verified using fluoroscopy. The stent localization and possible stent migration were checked using X-ray films taken a few days after the stenting procedure. Results: Overall, 25 self expandable metallic stents were implanted in 18 patients (malignant, 13; benign, 5) aged between 19 and 89 years. The indications for self-expandable metallic stent implantation were as follows: malignant gastric stricture (inoperable; n=6), malignant esophageal stricture (inoperable; n=4), staple line leak (laparoscopic sleeve gastrectomy; n=4), esophagojejunostomy anastomotic leak (total gastrectomy+Roux-en-Yesophagojejunostomy; n=2), and stricture (total gastrectomy+Roux-en-Yesophagojejunostomy; n=1), and esophagopleural fistula (pulmonary tuberculosis; n=1). A favorable outcome was achieved in a single session in 15 patients, whereas more than two sessions of stenting were necessary in the remaining three patients. Among the patients who underwent esophagojejunal anastomosis (n=3), self-expandable metallic stents were successfully deployed in a single session in two patients to relieve anastomosis leak (n=1) and anastomosis stricture (n=1); the remaining patients underwent four self expandable metallic stent implantation procedures to relieve anastomosis leak and subsequent recurrent strictures. No complications developed during the stenting procedure. Three of the four patients who developed mortality had advanced stage esophageal cancer, whereas one patient had morbid obesity and developed staple line leakage. Conclusion: Endoscopic self-expandable metallic stent implantation under fluoroscopic guidance is a low-morbidity and effective procedure for the management of advanced stage tumors of the gastrointestinal tract and the elimination of postoperative complications. PMID- 30023973 TI - Splenectomy proportions are still high in low-grade traumatic splenic injury. AB - Objective: The spleen is the most vulnerable organ in blunt abdominal trauma. Spleen-preserving treatments are non-operative management with or without splenic angioembolization, partial splenectomy, and splenorrhaphy. The aim of the present study was to determine the rate of SPTs and to evaluate the usefulness of Injury Severity Score after traumatic splenic injury. Material and Methods: We searched our institution's database between May 2012 and December 2015. Patients' clinicopathological features, surgeon's title, type of treatment, admission and discharge dates, duration of surgery, intensive care unit requirement, and Glasgow Coma Scale were recorded. Results: The mean age of patients was 33.36+/ 11.58 years. Of the 33 patients, 26 (78.8%) were males, and 7 (21.2%) were females. Thirty (90.9%) had total splenectomy (TS), and 3 (9.1%) had spleen preserving treatment (2 Nonoperative management and 1 partial splenectomy). No fatal hemorrhage developed after nonoperative management. Exitus rates were 5/30 (15.1%) and 0/3 in the total splenectomy and spleen preserving treatment groups, respectively. Of the 18 hemodynamically stable patients, only 2 (11.1%) had spleen preserving treatment. Of the 19 patients with grade I-III splenic injury, only 3 (15.8%) had spleen preserving treatment. For academic and non-academic surgeons, spleen preserving treatment rates were 3/11 (27.3%) and 0/22 (0%), respectively (p<0.05). Injury severity score and mean arterial pressure, number of transfusions, control hematocrit, and GCS had statistically significant relationships. Conclusions: Spleen preserving treatment proportions were low after traumatic splenic injury. Following trauma, guidelines will not only improve spleen preservation rates but also improve the overall health status of the patients and it will also prevent complications of splenectomy. PMID- 30023975 TI - Management of huge and extraordinary metal-penetrating injuries to the hand. AB - Objective: Foreign-body and penetration injuries of the hand are common emergencies. Metallic foreign bodies are common among all foreign masses; however, the examination of huge bodies differs from that of other metallic masses. The purpose of this study was to clarify an algorithm for the management of the huge metallic masses via our therapeutic approaches for metal-penetrating injuries. Material and Methods: Seven patients who had a huge, metallic object penetration injury to their upper extremity were included in our study. Patients were classified according to the age, injury type, character of metallic body, injury zone, diagnostic methods, anesthesia type, and treatment received, and an algorithm to approach the management of foreign metallic bodies was clarified. Results: The causes of injury were knitting hook, iron fence, mixer, and metal nail. Plain radiography was performed for all patients. Prophylactic tetanus was administered and urgent exploration in the operation room under tourniquet followed by foreign-body extraction through cutting and not pulling were conducted. No residue was retained. Conclusion: Many patients referred to emergency services with foreign bodies. For diagnosis, the patient's history and a minimum of two-way radiograms are crucial. For treatment, we recommend surgical exploration under general anesthesia and tourniquet and extraction of the metallic body by cutting and not pulling without retaining any residual mass in the operation room. PMID- 30023974 TI - Effect of sildenafil citrate on the liver structure and function in obstructive jaundice: An experimental study. AB - Objective: We aimed to investigate the effect of 10 mg/kg sildenafil on the structure and function of the liver in a rat model of obstructive jaundice. Material and Methods: Sixty-two male Wistar albino rats were distributed into six different groups. Obstructive jaundice was performed by legating the common bile duct. 10 mg/kg sildenafil citrate in drinking water was delivered orally after the operation before sacrificing them. Rats were sacrificed either after 10 or 28 days according to the study design. The blood and tissue samples from the liver were obtained to perform a biochemical and histopathological analysis to study functional and structural changes in the liver. Results: At the 10th day, there was no difference between the sildenafil-treated and control groups with regard to the aspartate aminotransferase and alanine aminotransferase levels (p=0.423, p=0.661). The alkaline phosphatase total bilirubin levels among the groups were statistically different (p<0.001). At the 28th day, liver function tests except alanine aminotransferase showed significant differences among the groups (p<0.001). Liver function tests did not changed significantly between the 10th and 28th day in sildenafil-treated rats (p>0.05). Significant differences were observed among the groups with regard to cholestasis, fibrosis, inflammation, and necrosis (p<0.001). However, edema increased in the sildenafil-treated group (p<0.001). On the 28th day, the severity of structural changes in the liver after obstructive jaundice, except edema, reduced significantly (p<0.001). The sildenafil-treated groups at different time points didn't show any statistical difference in histopathological changes (p>0.05). Conclusion: Oral administration of 10 mg/kg sildenafil citrate dramatically reverses the biochemical and histopathological liver changes induced by obstructive jaundice in rats. PMID- 30023976 TI - Approach to the diagnosis and treatment of mesenteric panniculitis from the surgical point of view. AB - Objective: To evaluate the diagnostic and treatment approaches for patients diagnosed with mesenteric panniculitis. Material and Methods: We retrospectively reviewed all patients diagnosed with mesenteric panniculitis between January 2010 and March 2016. We recorded the demographic features, clinical symptoms, laboratory values, radiological methods, treatment approach, and outcomes of the patients. Results: We evaluated 22 patients (17 male and five female) with a mean age of 45.8+/-15.7 years. The most frequent complaint was abdominal pain. The patients' histories included colon cancer (n=1), prostatic cancer (n=2), renal cell cancer (n=1), diabetes mellitus (n=4), and chronic obstructive pulmonary disease (n=1). Laboratory values revealed elevated C-reactive protein levels in 14 patients (43%). Computed tomography was performed in all the patients. Only 10 patients were followed up in the surgical ward, the remaining 12 underwent outpatient treatment. No complication associated with hospitalization or during outpatient follow-up period was observed. Conclusion: Mesenteric panniculitis can be successfully treated conservatively without surgical intervention. Clinical doubt is of great importance for diagnosis, and plausible underlying malignancy should be kept in mind. PMID- 30023978 TI - Where do these guests come from? A diagnostic approach for metastatic lymph nodes. AB - Objective: In cases presenting with lymphadenopathies (LAP) without a primary focus detected by simple radiological methods, the primary tumor can be diagnosed by a histopathological evaluation of the metastatic lymph nodes. We aimed to discuss the nonhematological malignancies presenting with lymphadenopathies and the histopathological results for primary tumors. Material and Methods: In this retrospective study, cases diagnosed with metastasis in excisional lymph nodes between January 2013 and June 2016 were assessed for a histopathological diagnostic approach. Results: Among 632 lymph node biopsies, a total of 21 cases, involving 12 male and 9 female patients with a mean age of 57.23 y (range, 33-92 y), of nonhematological solid tumors were included. The most common localizations of the involved lymph nodes were inguinal (n=8), axillary (n=6), cervical (n=4), and supraclavicular (n=3) region. The most common primary tumors were malignant melanoma (n=6), breast carcinoma (n=4), ovarian carcinoma (n=2), squamous cell carcinoma (n=2), and germ cell tumor (n=2). Others were papillary thyroid carcinoma, renal cell carcinoma, urothelial carcinoma, prostate adenocarcinoma, and endometrial adenocarcinoma. Conclusion: Nonhematological malignancies presenting with lymphadenopathies are one of the most complicated cases for clinicians. The histopathological evaluation of the excisional metastatic lymph node biopsies is an important method because of cost effectiveness and easy applicability. PMID- 30023979 TI - Missed thyroid gland after total thyroidectomy. AB - Missed gland is an extremely rare condition. It is a mediastinal thyroid mass found after total thyroidectomy. We report a case of missed gland. The patient underwent total thyroidectomy due to multinodular goiter and thyroid stimulating hormone levels did not increase after surgery. Pathological tests revealed a micropapillary carcinoma. Thyroid ultrasonography and scintigraphy scan revealed mediastinal thyroid mass. The patient underwent redo surgery without sternotomy and there was no morbidity after the second surgical procedure. Most missed thyroid gland cases are due to incomplete removal of plunging thyroid goiter during total thyroidectomy. They also can be attributed to a concomitant, unrecognized mediastinal goiter, which is not connected to the thyroid gland with vessels or a thin fibrous band. It should be noted that absence of signs like mediastinal mass or tracheal deviation in preoperative chest X-ray does not exclude substernal goiter. The presence of a missed thyroid gland should be kept in mind when postoperative thyroid stimulating hormone levels remain unchanged. PMID- 30023977 TI - Survival outcomes after D1 and D2 lymphadenectomy with R0 resection in stage II III gastric cancer: Longitudinal follow-up in a single center. AB - Objective: D2 lymphadenectomy (D2-LND) with curative resection (R0) is the cornerstone of gastric cancer treatment. In this study, we compared survival outcomes of D2-LDN with D1-LDN in patients who had undergone curative resection for Stages II and III primary gastric adenocarcinoma. Material and Methods: Between April 1996 and March 2014, 153 consecutive patients with adenocarcinoma of the stomach underwent total gastrectomy with D1-LND or D2-LND. Among those, 118 patients (38 D1 vs. 80 D2) with a complete history and having been followed for at least 1 year after surgery were enrolled. Both groups were compared in terms of demographic and clinico-pathologic characteristics. Results: The mean follow-up was 42.6+/-52.5 months (mo.). The demographic characteristics of the groups were similar. The Tumor, Node and Metastases (TNM) stage distribution was 25% for Stage II and 75% for Stage III for both groups. Eighteen patients (47.4%) in the D1 and 47 patients (58.8%) in the D2 group were free from locoregional recurrence. The median disease-free survival was 22.0+/-4.1 mo. for the D1 and 28.0+/-4.3 mo. for the D2 group (p=0.36). Eight patients (21%) in the D1 and 39 patients (49%) in the D2 group were alive at the last follow-up. The median overall survival (OS) was 22.0+/-3.7 mo. for the D1 and 31.0+/-5.4 mo. for the D2 group (p=0.13). The 5-year disease-free survival and OS by the Kaplan-Meier estimates were 41% vs. 51% and 30% vs. 42% in the D1 and D2 groups, respectively. The median 5-year OS for patients with Stages IIIB and IIIC tumors was 14.0+/-2.2 mo. for the D1 and 20.0+/-5.0 mo. for the D2 group, respectively (p: 0.048). Conclusion: When compared to D1-LND, D2-LND with R0 resection have yielded a trend toward a better outcome in patients with primary gastric adenocarcinoma. PMID- 30023980 TI - Regression in local recurrence in the contralateral breast following mastectomy in bilateral locally advanced breast cancer: A comparison of neutrophil-to lymphocyte and platelet-to-lymphocyte ratios. AB - The neutrophil-to-lymphocyte ratio is clinically accepted as a marker of systemic inflammatory response. In breast cancer patients, neutrophil-to-lymphocyte ratio can be used as an important prognostic indicator of survival. In routine laboratory tests, the platelet-to-lymphocyte ratio can also be examined in addition to neutrophil-to-lymphocyte ratio. Although the effects on breast cancer survival of platelet-to-lymphocyte ratio, which is accepted as the twin of neutrophil-to-lymphocyte ratio, are not as widely accepted as those of neutrophil to-lymphocyte ratio, platelet activation is known to be a feature of cancer. Here, we present the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio of a patient with locally advanced cancer of the left breast who underwent a simple mastectomy that reduced the tumor load. Following surgical therapy, a remarkable regression was observed in the local recurrence area of the right mastectomy site; at the same time, the patient's neutrophil-to-lymphocyte ratio and PLR values significantly decreased. PMID- 30023981 TI - An incidental giant preperitoneal fibrolipoma diagnosed during laparoscopic cholecystectomy. AB - Preperitoneal lipomas are rare in clinical practice. Here we report an unexpected diagnosis of a giant preperitoneal fibrolipoma detected intraoperatively during laparoscopic cholecystectomy in a 56-year-old woman. The mass was excised and a histopathological examination confirmed fibrolipoma. No recurrence was found on follow-up. In the literature, there have been many cases with unexpected diagnoses during laparoscopy. Here, we present an incidental giant preperitoneal fibrolipoma, which was overlooked by ultrasound and physical examination, but was detected during laparoscopic cholecystectomy. PMID- 30023982 TI - Adrenal angiosarcoma. AB - Adrenal angiosarcoma is an uncommon neoplasm that derives from the vascular endothelium; due to its biological behavior, it should be distinguished from other adrenal tumors. We herein report a case of a 57-year-old woman with diagnosis of an adrenal tumor that was suspected to be malignant. The specimen was histopathologically proved to be an angiosarcoma. The patient was suffering from right upper quadrant pain; after laboratory and radiological workup, a non functioning right adrenal mass, 14 cm in size, was recognized. A right subcostal incision was made, and adrenalectomy was performed successfully with tumor-free surgical margins. Two months after the operation, a positron emission tomography computed tomography scan was ordered for follow-up. No tumor tissue or any other metastatic foci remained. The patient had been referred to our medical oncology department and underwent retroperitoneal radiotherapy. However, unfortunately, the patient died due to cardiac insufficiency during the follow-up period. PMID- 30023983 TI - Hyalinizing trabecular tumor of the thyroid gland. AB - Hyalinizing trabecular tumor was first described by Carney et al. (1) in 1987 and is a rare benign tumor of the thyroid gland that shares some of the microscopic features of medullary and papillary thyroid carcinoma. Hyalinizing trabecular tumor derives from follicular cells, and it is characterized by an apparent trabecular pattern and intratrabecular hyalinization. In this study, we present the case of a 40-year-old female patient with thyroid gland nodules, whose ultrasound results, clinical behavior, and fine-needle aspiration biopsy results were suspicious; the pathology after thyroidectomy indicated hyalinizing trabecular tumor. We aimed to show the role of clinical behavior, radiology, fine needle aspiration, and histological and immunohistochemical analysis in the differential diagnosis of hyalinizing trabecular tumor. Hyalinizing trabecular tumor which can be confused with papillary and medullar carcinoma of the thyroid gland, is mostly benign but some malignant and metastatic cases have been reported. Therefore, diagnosis, treatment, and follow-up steps of Hyalinizing trabecular tumor should be planned in consideration of a malignant potential. PMID- 30023984 TI - Coexistence of gastric multiple neuroendocrine tumors with unusual morphological features and gastric signet-ring cell carcinoma. AB - The coexistence of signet-ring cell carcinoma and neuroendocrine tumors is very rare. We report a 57-year-old man who presented with a history of weight loss and nausea. Gastric mucosal biopsies obtained during gastrointestinal endoscopy revealed a gastric signet-ring cell carcinoma. The patient underwent a total gastrectomy with a standard D2 lymph node dissection. Ten individual tumors were detected in the resected specimen. Based on the histopathological and immunohistochemical findings, the final diagnosis was co-existing signet-ring cell carcinoma and neuroendocrine tumor. Spindle-shaped cells and extracytoplasmic mucin were noted in some tumor cells forming the neuroendocrine component. This case is a rare synchronous tumor because of its unusual neuroendocrine component. PMID- 30023985 TI - Laparoscopic surgical transmesocolic jejunostomy: A new surgical approach. AB - In cancer patients with tumors of the upper gastrointestinal tract, dysphagia and cachexia require gastrostomy or jejunostomy as the only options for enteral access for long-term feeding. In this article, the authors describe a modified placement of laparoscopic feeding jejunostomy applied during laparoscopic oncology layering technique. After performing an exploratory laparoscopy, a feeding jejunostomy is performed using a Foley silicon catheter, through an eyelet in the mesentery of the descending colon. After completing the introduction of the jejunal probe according to the Witzel technique, the intestinal segment of jejunum is attached to the internal sheath of the mesocolon using sutures polysorb 2/0, with the aim of removing the possible internal hernia and a jejunal torque that could cause an intestinal obstruction. There were no intraoperative complications or mortality. The technique described here provides most of the benefits of laparoscopic jejunostomy feeding, avoiding the possible internal hernia. PMID- 30023986 TI - Chronic visceral ischemia: An unusual cause of abdominal pain. AB - Chronic visceral ischemia is described as postprandial abdominal pain caused by intestinal hypoperfusion. Chronic visceral ischemia arising from the stenosis of major mesenteric arteries can cause death. Chronic abdominal pain, weight loss, and sitophobia are the major symptoms. The main cause of chronic visceral ischemia is atherosclerosis; Doppler ultrasonography, tomographic angiography, and magnetic resonance angiography can be used for diagnosis. The gold standard method is mesenteric catheterized angiography. Surgical bypass or endovascular balloon angioplasty and stent replacement can also be performed to prevent serious complications and death. A total of three patients, two male and one female, applied to emergency services with blunt abdominal pain lasting a few hours that started after meals and was located in the epigastric and periumblical regions. The patients were diagnosed with chronic visceral ischemia after screening tests and physical examination. Mesenteric catheterized angiography was performed immediately in all the cases. Balloon angioplasty and stent replacement were performed on the stenoses, and occlusions were detected. Mesenteric catheterized angiography may be preferred in cases with strong clinical suspicion; balloon angioplasty and stent replacement can also be used as treatments with lower rates of complications. PMID- 30023987 TI - The patients with Peutz-Jeghers syndrome have a high risk of developing cancer. AB - Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by mucocutaneous hyperpigmentation, and intestinal and extraintestinal multiple hamartomatous polyps. Development of gastrointestinal and extragastrointestinal cancer risk is markedly increased in patients with Peutz-Jeghers syndrome. We analyzed five patients from two families diagnosed with Peutz-Jeghers syndrome between 1999 and 2012. This study confirms the actual malignancy potency of PJS. Therefore, we suggest a close follow-up of patients with Peutz-Jeghers syndrome for the risk of malignancy. PMID- 30023988 TI - Caffeine Intake and Its Association with Body Composition Measures and Macronutrient Intakes in People Living with HIV in the Miami Adult Studies on HIV Cohort. AB - Background: Caffeine acts as an anorexic agent, increases energy expenditures, and decreases total body fat mass, and could be detrimental to people living with HIV (PLWH). The objective of this study was to explore the relationship between caffeine consumption, body composition measures (fat mass, body mass index [BMI], and lean body mass [LBM]), nutrient intakes, CD4 counts, and HIV viral load in PLWH. Methods: A convenience sample of 130 PLWH was recruited and followed for 3 months. Caffeine intake, body composition measures, and nutrient intakes were collected using Modified Caffeine Consumption Questionnaire, bioimpedance analyses, and 24-hour dietary recalls. Linear regressions were used to analyze the baseline data for relationships between these variables. Linear mixed models (LMMs) were used to determine the overtime changes. Results: In baseline, linear regression analysis, higher caffeine consumption was associated with lower fat mass (beta = -0.994, p = 0.042). However, BMI and LBM did not show any significant association with caffeine intake. LMM analysis showed that the association between caffeine intake and fat mass strengthened overtime (beta = 1.987, p = 0.035). Baseline linear regression analysis showed that higher caffeine intake was significantly associated with lower caloric intakes from fat (beta = -1.902, p = 0.044) and lower total caloric intake (beta = -1.643, p = 0.042). However, LMM analysis showed that these associations diminished and lost significance overtime. There were no associations between body composition measures, nutrient intakes, CD4 counts, and HIV viral load. Conclusions: Caffeine intake adversely affected dietary intakes of macronutrients and total fat mass. Therefore, caffeine, a known anorectic, should be regulated in PLWH. PMID- 30023990 TI - Hybrid Gd3+/cisplatin cross-linked polymer nanoparticles enhance platinum accumulation and formation of DNA adducts in glioblastoma cell lines. AB - Glioblastoma is the most frequent and aggressive primary malignant tumor of the central nervous system with a gloomy prognosis. Platinum derivatives and one among them, cisplatin, exhibited promising results when locally administered into the brain of glioblastoma bearing rats. Nanovectorization of anticancer agents through polymeric nanoparticles may even promote drug accumulation within cells, thus concentrating the drug efficiently at its target. Anchorage of gadolinium complexes on the corona of such smart drug delivery systems could further allow magnetic resonance imaging (MRI) monitoring of the nanoplatform biodistribution in the damaged parenchyma and its therapeutic benefit. For this purpose, a biocompatible amphiphilic triblock copolymer, made of degradable polyester and polycarbonate and bioeliminable polyethylene oxide (PEO), was synthesized by successive ring-opening polymerizations. After micellization in water, gadolinium complexes were grafted onto the PEO micelle corona and the carboxylate functions, located at the surface of the micelle's core, were able to cross-link with Pt(ii) complexes. A macromolecular prodrug was therefore recovered in which more than one third of the carboxylate functions were linked to a platinum atom. By this strategy, stable cisplatin cross-linked nanoparticles were formulated with a mean size in the range of 100.63 +/- 12.04 nm consistent with biological investigations. Relaxometry measurements both in water and in plasma at 7 T, 25 degrees C, confirmed the intrinsic potential of these hybrid nanoparticles as alternative MRI contrast agents with a substantial increase in the r2/r1 ratio by a factor of 3.3 and 2.7, respectively, compared to the conventional low molar mass Gd-DTPA. As a result, their infusion within the striatum of glioblastoma bearing mice resulted in a hypersignal on T2-weighted MR images that persisted over time. Ultimately, the formulated prodrug exhibited up to 50-fold increased accumulation in human glioblastoma cell lines and up to 32-fold enhanced subsequent Pt-DNA adduct formation in comparison with free cisplatin, thus supporting the potential of this innovative bimodal tool for further applications. PMID- 30023991 TI - Copper-mediated intramolecular aminofluorination of 1,3-dienes by using nucleophilic fluorine reagents. AB - A copper-mediated intramolecular aminofluorination of 1,3-dienes is disclosed, in which both AgF and Et3N.3HF can be used as the fluorine source. This protocol provides a variety of pyrrolidines bearing allylic fluorides with excellent regioselectivities and good diastereoselectivities. PMID- 30023998 TI - Polysaccharides from Burkholderia species as targets for vaccine development, immunomodulation and chemical synthesis. AB - Covering: up to 2018Burkholderia species are a vast group of human pathogenic, phytopathogenic, and plant- or environment-associated bacteria. B. pseudomallei, B. mallei, and B. cepacia complex are the causative agents of melioidosis, glanders, and cystic fibrosis-related infections, respectively, which are fatal diseases in humans and animals. Due to their high resistance to antibiotics, high mortality rates, and increased infectivity via the respiratory tract, B. pseudomallei and B. mallei have been listed as potential bioterrorism agents by the Centers for Disease Control and Prevention. Burkholderia species are able to produce a large network of surface-exposed polysaccharides, i.e., lipopolysaccharides, capsular polysaccharides, and exopolysaccharides, which are virulence factors, immunomodulators, major biofilm components, and protective antigens, and have crucial implications in the pathogenicity of Burkholderia associated diseases. This review provides a comprehensive and up-to-date account regarding the structural elucidation and biological activities of surface polysaccharides produced by Burkholderia species. The chemical synthesis of oligosaccharides mimicking Burkholderia polysaccharides is described in detail. Emphasis is placed on the recent research efforts toward the development of glycoconjugate vaccines against melioidosis and glanders based on synthetic or native Burkholderia oligo/polysaccharides. PMID- 30023996 TI - Novel D-A-D based near-infrared probes for the detection of beta-amyloid and Tau fibrils in Alzheimer's disease. AB - Novel D-pi-A-pi-D probes were investigated for the detection of Abeta plaques and NFTs. The probes displayed remarkable optical properties, and DADNIR-2 possessed high affinity towards Tau and Abeta aggregates (Kd = 0.41 nM and 1.04 nM, respectively) with certain selectivity. DADNIR-2 could penetrate the BBB and label Abeta plaques in vivo. PMID- 30024000 TI - An organocatalytic asymmetric Mannich reaction for the synthesis of 3,3 disubstituted-3,4-dihydro-2-quinolones. AB - The first organocatalytic asymmetric Mannich reaction employing 3,4-dihydro-2 quinolones has been developed for the synthesis of biologically important 3,3 disubstituted-dihydro-2-quinolones. N-Boc imine precursor amidosulfones as well as pre-formed N-Boc imine were used for this purpose. Cyclohexyldiamine derived bifunctional amino-thiourea catalysts were employed to provide the products in high enantio- and good diastereoselectivities. PMID- 30023992 TI - Supramolecular nanoparticles based on beta-CD modified hyaluronic acid for DNA encapsulation and controlled release. AB - Supramolecular nanoparticles composed of doubly positively charged adamantane (ADA2+) and beta-CD modified hyaluronic acid (HACD) were constructed. When the ester group in ADA2+ was hydrolyzed to a carboxyl group, the quaternary ammonium chain with a positive charge in ADA2+ converted to a "zwitterionic" structure, and the controlled binding and release of pDNA was realized. PMID- 30024001 TI - Hierarchical MoSe2 nanoflowers as novel nanocarriers for NIR-light-mediated synergistic photo-thermal/dynamic and chemo-therapy. AB - The construction of nanoplatforms that integrate multiple therapies has attracted much attention in the field of cancer treatment. Herein, selenide molybdenum (MoSe2) nanoflowers were synthesized as nanocarriers capable of delivering NIR mediated synergetic photothermal therapy (PTT), photodynamic therapy (PDT), and drug release. All of the MoSe2 nanoflowers (150-180 nm) are made up of many thin nanosheets of about 3-4 layers of MoSe2. With the novel hierarchical nanostructure and small band gap (1.24 eV), the as-synthesized MoSe2 nanoflowers possess strong near-infrared (NIR) absorption and high photothermal conversion efficiency (61.8%). In addition, they also exhibit NIR-stimulated OH generation and this is the first time that MoSe2 nanostructures have been used as a PDT agent. The mechanism was investigated, which revealed that a sufficient number of photo-excited electrons and high O2 and H+ concentrations facilitate OH production. After PEGylation, MoSe2@PEG exhibits high Dox-loading capacity due to electrostatic and pi-pi stacking interactions. After drug loading, the resulting MoSe2@PEG-Dox system exhibits acid/photothermal-triggered drug release. The synergistic effect of chemotherapy, PTT and PDT further induces superior cancer cell apoptosis and improved antitumor effectiveness. PMID- 30024002 TI - Insight into the enhanced photocatalytic activity of SrTiO3 in the presence of a (Ni, V/Nb/Ta/Sb) pair. AB - Increasing applications of SrTiO3 as a photocatalyst in recent times drive the development of various strategies through doping with foreign elements to improve its efficiency under sunlight. Motivated by the recent experimental observation of increased lifetime of photogenerated charge carriers due to codoping of Ta into Ni-doped SrTiO3 (R. Niishiro et al., Phys. Chem. Chem. Phys., 2005, 7, 2241 2245, and A. Yamakata et al., J. Phys. Chem. C, 2016, 120, 7997-8004), we systematically investigate the detailed electronic structure of Ni-doped SrTiO3 in the presence and absence of Ta. The present theoretical study reveals that Ni doping reduces the effective band gap by introducing unoccupied Ni-3d states in the forbidden region, while addition of Ta passivates these states. Here, we have properly explained the fact that improved photoconversion efficiency can be achieved only when the proportion of Ta is double with respect to that of Ni. The defect formation energy for the 1 : 2 type (Ni, Ta)-codoped SrTiO3 is energetically more favourable than that of the 1 : 1 type variety. The present study also explored the possibility of using V, Nb, and Sb in place of Ta to aim at better utilization of visible light activity. Interestingly, we arrive at a conclusion that V and Nb may be better choices over experimentally reported Ta for achieving enhanced photocatalytic activity of Ni-doped SrTiO3 under visible light. Finally, applicability of all these codoped systems for the generation of hydrogen and oxygen through water splitting has been checked by inspecting their band edge levels with respect to water redox levels. PMID- 30024003 TI - BN nanospheres functionalized with mesoporous silica for enhancing CpG oligodeoxynucleotide-mediated cancer immunotherapy. AB - CpG oligodeoxynucleotides (CpG ODNs) possess strong immunostimulatory activity, which hold great promise in cancer immunotherapy. However, their therapeutic efficacy is largely limited due to nuclease degradation and poor cellular internalization. Efficiently delivering CpG ODNs into target cells is crucial to improve their therapeutic efficacy. Boron nitride nanospheres (BNNS) possess advantage as carriers for CpG ODNs. However, their poor aqueous dispersity and low CpG ODN loading capacity became a big obstacle for further applications. Herein, we develop amino group grafted, mesoporous silica (MS)-functionalized BNNS as novel nanovectors for CpG ODN delivery. Modification of BNNS with MS significantly improved the dispersity of BNNS and CpG ODN loading. BNNS@MS-NH2 exhibited no cytotoxicity and enhanced the delivery of CpG ODNs into macrophages. BNNS@MS-NH2/CpG ODN complexes triggered enhanced immunostimulation and induced higher amounts of cytokines. Most importantly, BNNS@MS-NH2/CpG ODN complexes induced bifurcated cytokines, which simultaneously simulated the secretion of IL 6, TNF-alpha and IFN-alpha. In contrast, CpG ODN and BNNS/CpG ODN complexes could not. The result of the Transwell plate assay suggested that BNNS@MS-NH2/CpG ODN complexes were more effective in inhibiting cancer cell growth. Taken together, our findings provide a promising strategy for enhancing CpG ODN-mediated cancer immunotherapy. PMID- 30024004 TI - Spectroscopic characterization of lithium thiophosphates by XPS and XAS - a model to help monitor interfacial reactions in all-solid-state batteries. AB - Inspired by reports of redox active interphases in all-solid-state batteries employing fast conducting lithium thiophosphate solid-state electrolytes, we investigated the compositional depolymerization of interconnected PS4 tetrahedra in (Li2S)x(P2S5)100-x glasses (50 < x < 80) by X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS). Based on the observed energy shifts with composition, we present a structural model of the three different bonding types describing the structures of either crystalline or amorphous thiophosphates. This model and reference data characterizes amorphous thiophosphates based on their inter-tetrahedral connectivity and helps to distinguish malign decomposition reactions from reversible redox reactions at the cathode active material/solid-state electrolyte interface. This work highlights the importance of a combined analytical approach and appropriate reference compounds to elucidate the interface reactions in all-solid-state battery systems. PMID- 30024005 TI - Nanostructuring few-layer graphene films with swift heavy ions for electronic application: tuning of electronic and transport properties. AB - The morphology and electronic properties of single and few-layer graphene films nanostructured by the impact of heavy high-energy ions have been studied. It is found that ion irradiation leads to the formation of nano-sized pores, or antidots, with sizes ranging from 20 to 60 nm, in the upper one or two layers. The sizes of the pores proved to be roughly independent of the energy of the ions, whereas the areal density of the pores increased with the ion dose. With increasing ion energy (>70 MeV), a profound reduction in the concentration of structural defects (by a factor of 2-5), relatively high mobility values of charge carriers (700-1200 cm2 V-1 s-1) and a transport band gap of about 50 meV were observed in the nanostructured films. The experimental data were rationalized through atomistic simulations of ion impact onto few-layer graphene structures with a thickness matching the experimental samples. We showed that even a single Xe atom with energy in the experimental range produces a considerable amount of damage in the graphene lattice, whereas high dose ion irradiation allows one to propose a high probability of consecutive impacts of several ions onto an area already amorphized by the previous ions, which increases the average radius of the pore to match the experimental results. We also found that the formation of "welded" sheets due to interlayer covalent bonds at the edges and, hence, defect-free antidot arrays is likely at high ion energies (above 70 MeV). PMID- 30023989 TI - The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease. AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A2A receptors (A2AR), suggesting a possible involvement of adenosine and A2AR is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A2AR dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD. PMID- 30024006 TI - Non-monoterpenoid azepinoindole alkaloids. AB - Covering: 1969 to 2018Azepinoindole natural products can be broadly classified as being of monoterpenoid or non-monoterpenoid origin. The non-monoterpenoid azepinoindoles have not received as much attention in the literature as their more revered monoterpenoid counterparts. In this review, an overview of all non monoterpenoid azepinoindoles is provided. Various biological and chemical aspects are discussed, including their isolation, biosynthesis and the elegant total synthesis studies that have been inspired by these alkaloids. PMID- 30024007 TI - Heterometallic Cu/Ln cluster chemistry: ferromagnetically-coupled {Cu4Ln2} complexes exhibiting single-molecule magnetism and magnetocaloric properties. AB - A new family of {Cu4Ln2} (Ln = Gd, Tb and Dy) complexes bearing the gem-diol form of di-2-pyridyl ketone [(py)2CO] ligand is reported. Magnetic studies reveal the presence of predominant ferromagnetic exchange interactions between the metal ions. As a result, the hexanuclear compounds exhibit single-molecule magnetism behavior and large magnetic entropy changes, depending on the 4f-metal ion present. PMID- 30024008 TI - Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors. AB - Metal-mediated C-H functionalization of cyclic N-oxides was exploited to access a series of new difluoromethylated analogs of imidazolidinone-based PDE4 inhibitor CMPI in a diastereoselective manner. Among the products synthesized, compounds with fine-tuned activity/selectivity profiles compared to both CMPI and the clinically applied apremilast were identified. From these studies, an unusual fused 1,2-oxazinoimidazolidinone heterocyclic system was suggested as a novel scaffold for the design of potent and selective PDE4 inhibitors. Computational studies suggest that the oxygen atom in the imidazolidinone unit can bind to the metal ion center (most likely Mg2+). DFT calculations of the relative interaction energies of inhibitors with Mg2+ and Zn2+ ions were performed on a model of the bimetal active site of PDE4. PMID- 30024009 TI - Patterned liquid metal contacts for high density, stick-and-peel 2D material device arrays. AB - Two-dimensional materials have shown great promise to enable novel wearable electronic devices ranging from sensors to energy generators. These developments are due to their high mechanical robustness, which allow them to retain high performance even at large deformations. Under these conditions, however, good electrical contacts become an important issue that cannot be addressed with conventional materials. Liquid metals could overcome this limitation by providing soft and compliant electrodes but to date no realistic heterointegration of nanomaterials and complex liquid metal contacts has been attempted. We here demonstrate the application of micrometer-sized electrical contacts to flexible, fragile and rough 2D materials using patterned liquid metal contacts. A novel deposition method enables the scalable and facile production of large arrays of contacts in arbitrary geometries. This ability permitted the single-step, fabrication-free and contamination-free production of concentric liquid metal contacted graphene field effect transistors of comparable performance to traditional devices. We demonstrate that the contacts can be removed without damaging the 2D materials allowing the contacts to be reused. Finally, good contact could be made to complex morphologies and three-dimensional substrates, which highlights the potential of our approach to the characterization and application of nanomaterials in electronics. PMID- 30024010 TI - A critical and quantitative review of the stratification of particles during the drying of colloidal films. AB - For a wide range of applications, films are deposited from colloidal particles suspended in a volatile liquid. There is burgeoning interest in stratifying colloidal particles into separate layers within the final dry film to impart properties at the surface different to the interior. Here, we outline the mechanisms by which colloidal mixtures can stratify during the drying process. The problem is considered here as a three-way competition between evaporation of the continuous liquid, sedimentation of particles, and their Brownian diffusion. In particle mixtures, the sedimentation of larger or denser particles offers one means of stratification. When the rate of evaporation is fast relative to diffusion, binary mixtures of large and small particles can stratify with small particles on the top, according to physical models and computer simulations. We compare experimental results found in the scientific literature to the predictions of several recent models in a quantitative way. Although there is not perfect agreement between them, some general trends emerge in the experiments, simulations and models. The stratification of small particles on the top of a film is favoured when the colloidal suspension is dilute but when both the concentration of the small particles and the solvent evaporation rate are sufficiently high. A higher particle size ratio also favours stratification by size. This review points to ways that microstructures can be designed and controlled in colloidal materials to achieve desired properties. PMID- 30024011 TI - Central substitution of azacalixphyrins: a strategy towards acidochromic NIR dyes. AB - Azacalixphyrin derivatives constitute one of the most intriguing class of macrocyclic compounds. Indeed, these isostructural and isoelectronic analogues of porphyrins intensively absorb light up to the near infrared region, exist in several tautomeric forms and present a bis-zwitterionic structure, with a central dianionic core surrounded by positively-charged trimethine cyanines. However, control of the position of the absorption bands of azacalixphyrin remains an important challenge, as the experimental attempts reported to date have led to very modest auxochromic shifts only. Inspired by previous work demonstrating that the optical signatures of cyanines can be strongly modified by using central substituents, we have evaluated the validity of this strategy for azacalixphyrin considering several substituents positioned in symmetric or asymmetric manners around the core and linked through both single and double bonds, as well as several protonation states of the macrocycles. It turns out that bromine and dimethylamino substituents have a negligible or weak impact on the optical properties of azacalixphyrins with maximal redshifts smaller than 0.10 eV. The imino substitution induces strong geometrical deformations that counterbalance the electronic effects leading to rather modest variations of the optical signatures. In contrast, for keto-substituted macrocycles, electronic effects dominate and very strong acidochromic shifts are predicted with absorption wavelengths going from 811 to 1095 nm upon double deprotonation. PMID- 30024012 TI - High thermoelectric performance of Cu3SbSe4 nanocrystals with Cu2-xSe in situ inclusions synthesized by a microwave-assisted solvothermal method. AB - (Ag,Sn) co-doped Cu3SbSe4 nanocrystals are obtained via a facile microwave assisted solvothermal method, and their thermoelectric properties are investigated in the temperature range from 300 K to 623 K. Sn-doping on Sb sites dramatically increases the carrier concentration and thus the electrical conductivity, promoting the thermoelectric power factor. Further alloying with Ag on Cu sites strongly suppresses the lattice thermal conductivity close to the glass limit. Aside from point defect scattering, such reduction in lattice thermal conductivity largely relies on the formation of Cu2-xSe nanoinclusions, which serve as additional scattering centers for phonons. Overall, the sample with the nominal composition of Cu2.8Ag0.2Sb0.95Sn0.05Se4 reaches a minimum lattice thermal conductivity of 0.27 W m-1 K-1 and a maximum zT of 1.18 at 623 K, which is the best result for the Cu3SbSe4-based materials in the same temperature region. Our results demonstrate that the microwave-assisted synthesis method is capable of fabricating Cu based ternary compounds with high thermoelectric performance. PMID- 30024013 TI - Analysis of epoxy functionalized layers synthesized by plasma polymerization of allyl glycidyl ether. AB - The deposition of epoxide groups by plasma polymerization opens new horizons for robust and quick immobilization of biomolecules on any type of substrate. However, as of now there are just very few papers dealing with the deposition of epoxy layers by plasma polymerization, probably due to the high reactivity of this group leading to a low functionalization efficiency. In this work we carried out an extensive experimental and theoretical investigation of plasma synthesis of epoxide groups from a low pressure allyl glycydyl ether (AGE) plasma. The influence of composite parameter W/F and the working pressure on the density of epoxide groups and the layer stability was thoroughly addressed. It was found that by increasing the working pressure it is possible to sufficiently raise the concentration of epoxide groups. The composite parameter W/F was shown to be a crucial parameter in affecting the density of epoxides. An optimal value of W/F of around 2.3 eV per molecule leading to the highest density of epoxides produced in the process at 15 Pa was revealed through FT-IR and XPS findings. This value correlates well with the ab initio calculations suggesting that the lowest bond dissociation energy belongs to the C-O bond of the epoxide ring. Therefore, in order to increase the density of epoxides deposited by plasma polymerization, a precursor molecule containing at least two epoxide rings is strongly advised to be employed. PMID- 30024014 TI - Open-air spray plasma deposited UV-absorbing nanocomposite coatings. AB - We demonstrate the deposition of mechanically robust UV-absorbing nanocomposite coatings with a newly developed dual-source deposition method involving ultrasonic spraying and open-air plasma deposition. Nanoparticles and the coating matrix are independently deposited which eliminates difficulties associated with preparing composites with high mass fraction of well-dispersed nanoparticles in the matrix. Nanocomposite coatings containing different concentrations of silica, ceria, and both titania and ceria nanoparticles were successfully deposited with good nanoparticle dispersity, high transparency over the visible range, effective absorption in the UV wavelength, and enhanced mechanical properties. Moreover, films were successfully deposited on several substrates including polycarbonate to demonstrate the low processing temperature of this dual-source deposition method. Coatings with different nanoparticle concentrations and film thicknesses were systematically studied in terms of their surface morphology, optical properties and mechanical properties. Accelerated photostability testing of the UV-absorbing nanocomposites demonstrates significantly enhanced performance compared to existing coatings with either a polymeric matrix or organic UV absorbers. PMID- 30024015 TI - Management of High Myopia in Children. PMID- 30024016 TI - My Eye Pressure Is Up Again! PMID- 30024018 TI - Optimal Surgical Results in Infantile Exotropia. PMID- 30024017 TI - A Balancing Act. PMID- 30024019 TI - Ocular Manifestations of Albers-Schoenberg Disease (Osteopetrosis). PMID- 30024020 TI - Comparison of histological characteristics and expression of CD3 and CD79a among the hemal nodes, lymph nodes and spleens of yaks (Bos grunniens). AB - This experiment compared the histological characteristics and distribution of CD3 and CD79a among yak lymph nodes, hemal nodes and spleen. The three organs from ten clinically healthy newborn and adult yaks were studied using histology and immunohistochemistry. The yak hemal nodes, which consisted of blood sinuses, lymphoid follicles, diffuse lymphoid tissue and lymphoid cords, appeared to share the histological characteristics of the spleen and lymph nodes: the lymphoid follicles of the hemal nodes were much like those of the lymph nodes, which were not surrounded by the central artery and periarteriolar lymphoid sheath. The lymphoid cords of the hemal node, which contained many erythrocytes, were much like the splenic cords. The sinuses of the hemal nodes had a similar structure to the lymph sinuses of the lymph nodes but were engorged with erythrocytes rather than lymph as in the lymph nodes. Interestingly, the splenic sinuses of yak were of two different types: the sinuses with obvious endothelial cells or those consisting of reticular cells. The CD3+ cells were mainly located in the paracortex area and medulla of the lymph nodes, the diffuse lymphoid tissues of the hemal nodes, and the periarteriolar lymphoid sheaths and red pulp of the spleen. Most CD79a+ cells were mainly detected in the lymphoid follicles of all examined lymphoid organs. The results suggested that although the three organs had specific characteristics, in some respects, they had similar organizational structural characteristics and immune functions. These may be useful to better understand the relationship between the morphology and function of these organs and provide useful references for normal yak lymphoid organs. PMID- 30024022 TI - Ultrasound is better tolerated than vaginal examination in and before labour. AB - BACKGROUND: Intrapartum ultrasound has been proposed as a method of assessing labour progress but its acceptability has not been comprehensively assessed. AIMS: We evaluated the acceptability of intrapartum ultrasound in women having vaginal examination (VE) and ultrasound (US) assessment (transabdominal (TA) and transperineal (TP)) prior to delivery, with and without regional analgesia (RA). MATERIALS AND METHODS: Women at 24-42 weeks gestation were included in a prospective observational cohort study. The acceptability of digital VE and TP US were assessed pre- and post-examination using the modified validated Wijma Delivery Experience Questionnaire. Acceptability scores ranged 6-36 (6 being most and 36 being least positive) in six domains: positive-trust and relax, negative harmful to baby, worrying, painful, intrusive. RESULTS: Of 119 women recruited, 104 completed both pre- and post-assessment questionnaires. Eighty-nine per cent of women were nulliparous with median gestation 40 + 2 weeks (25-42+1 ). Thirty two per cent had RA before assessment, 91% in total. The combined acceptability scores of both negative and positive experiences (6 = most acceptable, 36 = least acceptable) for VE and US pre-assessment were 15 and 7 respectively (P < 0.0001: Mann-Whitney U-test). VE was associated with less positive / more negative domain scoring post-assessment 12 and 6, respectively (P < 0.0001). Although RA made no difference to the perceived experience pre-VE (P = 0.9), post-VE, women with RAs considered VEs more acceptable than those without RA (P = 0.0022). CONCLUSION(S): This is the first study to comprehensively assess the acceptability of VE and intrapartum US. US assessment prior to delivery is more acceptable than VE. RA ameliorated the negative experience of the VE post-assessment. PMID- 30024021 TI - Analysis of causal effect of APOA5 variants on premature coronary artery disease. AB - Apolipoprotein A5 (APOA5) regulates the metabolisms of triglyceride and HDL. APOA5 variants have been linked to coronary artery disease (CAD), but their causal roles are not well studied yet. This study aims to identify the causal effects of APOA5 variants on premature CAD. Sequencing analysis of APOA5 in 128 premature, familiar CAD patients from GeneQuest identified 11 genomic variants, including p.S19W (rs3135506). SKAT analysis showed that all sequenced variants, in aggregate, significantly increased the risk of premature CAD (P-skat = 0.037). Individually, the p.S19W variant was significantly associated with risk of premature CAD (OR = 2.30, P = 0.008) in an independent set of 342 premature CAD patients and 537 controls after adjusting for covariates of sex, age, hypertension, body mass index, triglycerides (TGs), and total, LDL-, and HDL cholesterol levels. Meanwhile, p.S19W significantly correlated with HDL-C levels (P = 0.048) and TG levels (P = 0.025). Mediation analysis yielded a mediation effect of p.S19W on risk of premature CAD through HDL-C (OR = 0.98, P = 0.040) and TG (OR = 0.98, P = 0.042), suggesting a causal relationship between p.S19W and premature CAD partially through its effects on HDL-C and TG levels. These results suggest that APOA5 variation regulates TG and HDL levels, thus displaying a causal role in the development of CAD. PMID- 30024023 TI - Blood pressure-lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack. AB - BACKGROUND: Stroke is an important cause of death and disability worldwide. Since high blood pressure is an important risk factor for stroke and stroke recurrence, drugs that lower blood pressure might play an important role in secondary stroke prevention. OBJECTIVES: To investigate whether blood pressure-lowering drugs (BPLDs) started at least 48 hours after the index event are effective for the prevention of recurrent stroke, major vascular events, and dementia in people with stroke or transient ischaemic attack (TIA). Secondary objectives were to identify subgroups of people in which BPLDs are effective, and to investigate the optimum systolic blood pressure target after stroke or TIA for preventing recurrent stroke, major vascular events, and dementia. SEARCH METHODS: In August 2017, we searched the Trials Registers of the Cochrane Stroke Group and the Cochrane Hypertension Group, the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE Ovid (1946 to August 2017), Embase Ovid (1974 to August 2017), ClinicalTrials.gov, the ISRCTN Registry, Stroke Trials Registry, Trials Central, and the World Health Organization (WHO) International Clinical Trials Registry Platform Portal. SELECTION CRITERIA: Randomised controlled trials (RCTs) of BPLDs started at least 48 hours after stroke or TIA. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts, selected eligible trials, extracted the data, assessed risk of bias, and used GRADE to assess the quality of the evidence. If necessary, we contacted the principal investigators or corresponding authors for additional data. MAIN RESULTS: We included 11 studies involving a total of 38,742 participants: eight studies compared BPLDs versus placebo or no treatment (35,110 participants), and three studies compared different systolic blood pressure targets (3632 participants). The risk of bias varied greatly between included studies. The pooled risk ratios (RRs) of BPLDs were 0.81 (95% confidence interval (CI) 0.70 to 0.93; 8 RCTs; 35,110 participants; moderate-quality evidence), 0.90 (95% CI 0.78 to 1.04; 4 RCTs; 28,630 participants; high-quality evidence) for major vascular event, and 0.88 (95% CI 0.73 to 1.06; 2 RCTs; 6671 participants; high-quality evidence) for dementia. We mainly observed a reduced risk of recurrent stroke in the subgroup of participants using an angiotensin-converting enzyme (ACE) inhibitor or a diuretic (I2 statistic for subgroup differences 72.1%; P = 0.006). The pooled RRs of intensive blood pressure-lowering were 0.80 (95% CI 0.63 to 1.00) for recurrent stroke and 0.58 (95% CI 0.23 to 1.46) for major vascular event. AUTHORS' CONCLUSIONS: Our results support the use of BPLDs in people with stroke or TIA for reducing the risk of recurrent stroke. Current evidence is primarily derived from trials studying an ACE inhibitor or a diuretic. No definite conclusions can be drawn from current evidence regarding an optimal systolic blood pressure target after stroke or TIA. PMID- 30024026 TI - Digest: Stress and inbreeding depression in Drosophila melanogaster. AB - Do stressful conditions exacerbate inbreeding depression? Using Drosophila melanogaster, Schou et al. (2018) examine the mechanisms underlying the interaction between stress and inbreeding depression. The authors found that gene expression in inbred individuals was highly stochastic under benign conditions, but differential gene expression in inbred individuals was reduced compared to controls under stressful conditions. PMID- 30024024 TI - Bi-directional longitudinal associations between different types of bullying victimization, suicide ideation/attempts, and depression among a large sample of European adolescents. AB - BACKGROUND: The association between bullying victimization and depression, suicide ideation and suicide attempts has been studied mainly in cross-sectional studies. This study aims to test the bidirectional effect and the chronicity versus sporadic effect of physical, verbal, and relational bullying victimization on suicidal ideation/attempts and depression. METHODS: Longitudinal assessments with an interval of 3- and 12-months were performed within a sample of 2,933 adolescents (56.1% females; mean age 14.78, SD = .89) from 10 European countries, participating in the Saving and Empowering Young Lives in Europe (SEYLE) school based multicenter control sample. Multilevel Structural Equation Models were used, controlling for sociodemographic variables. Victimization was considered chronic when a student was victimized in the first two time points and sporadic when it was reported only at one point but not in another. RESULTS: Bidirectional prospective association between all types of victimization and depression were found. Among participants, who reported victimization once (but not twice), physical victimization, but not verbal and relational, was associated with later suicidal ideation and attempts. Chronic victimization of any type increased likelihood for later depression compared with sporadic and no-victimization. Chronic relational victimization increased the likelihood of later suicidal ideation, and chronic physical victimization increased the likelihood for suicidal attempts. CONCLUSIONS: The results support the bidirectional effect of victimization and depression and indicate that there are complex longitudinal associations between victimization and suicidal ideation/attempts. Physical victimization may especially carry effect on suicidal risk over time. Interventions should focus on victimization as a cause of distress but also aim to prevent vulnerable adolescents from becoming targets of victimization. PMID- 30024027 TI - Pilot randomized controlled trial of auricular point acupressure for sleep disturbances in women with ovarian cancer. AB - Sleep disturbance is a significant problem affecting around 50% of cancer patients. Non-pharmacological interventions can be used to improve sleep quality in cancer patients, but little is known about the feasibility, acceptability, and effectiveness of auricular point acupressure (APA) to reduce sleep disturbance in women with ovarian cancer undergoing chemotherapy. A pilot randomized controlled trial was conducted at a publicly funded hospital in southern Taiwan. Fifty-five eligible women were approached and 47 women participated. Women randomly assigned to the control group (n = 24) received sleep hygiene practices alone. Women in the intervention group (n = 23) received sleep hygiene practices and APA treatment which involved gentle fingertip pressure at acupoints on the external ear. The Pittsburgh Sleep Quality Index (PSQI) was completed at four time points. Forty women completed the trial giving a retention rate of 85%. Women receiving the intervention reported a 65% reduction in sleep disturbance according to PSQI global scores from Time 1 (mean = 13.2) to Time 2 (mean = 4.65) after 4 weeks of APA treatment. There was a further 10% decrease in PSQI scores at Time 3 (mean = 4.21) after 6 weeks of APA treatment. Compared to controls, women receiving APA had significantly lower PSQI mean global scores at both Time 2 and Time 3 (p < .001). APA treatment for women with ovarian cancer produced significantly improved sleep. Participants found the procedure easy to perform. Pilot findings support the feasibility of a longitudinal study with a larger, representative sample. PMID- 30024025 TI - Abnormal folate metabolism causes age-, sex- and parent-of-origin-specific haematological defects in mice. AB - KEY POINTS: Folate (folic acid) deficiency and mutations in folate-related genes in humans result in megaloblastic anaemia. Folate metabolism, which requires the enzyme methionine synthase reductase (MTRR), is necessary for DNA synthesis and the transmission of one-carbon methyl groups for cellular methylation. In this study, we show that the hypomorphic Mtrrgt/gt mutation in mice results in late onset and sex-specific blood defects, including macrocytic anaemia, extramedullary haematopoiesis and lymphopenia. Notably, when either parent carries an Mtrrgt allele, blood phenotypes result in their genetically wildtype adult daughters, the effects of which are parent specific. Our data establish a new model for studying the mechanism of folate metabolism in macrocytic anaemia aetiology and suggest that assessing parental folate status might be important when diagnosing adult patients with unexplained anaemia. ABSTRACT: The importance of the vitamin folate (also known as folic acid) in erythrocyte formation, maturation and/or longevity is apparent since folate deficiency in humans causes megaloblastic anaemia. Megaloblastic anaemia is a type of macrocytic anaemia whereby erythrocytes are enlarged and fewer in number. Folate metabolism is required for thymidine synthesis and one-carbon metabolism, though its specific role in erythropoiesis is not well understood. Methionine synthase reductase (MTRR) is a key enzyme necessary for the progression of folate metabolism since knocking down the Mtrr gene in mice results in hyperhomocysteinaemia and global DNA hypomethylation. We demonstrate here that abnormal folate metabolism in mice caused by Mtrrgt/gt homozygosity leads to haematopoietic phenotypes that are sex and age dependent. Specifically, Mtrrgt/gt female mice displayed macrocytic anaemia, which might be due to defective erythroid differentiation at the exclusion of haemolysis. This was associated with increased renal Epo mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis. In contrast, the male response differed since Mtrrgt/gt male mice were not anaemic but did display erythrocytic macrocytosis and lymphopenia. Regardless of sex, these phenotypes were late onset. Remarkably, we also show that when either parent carries an Mtrrgt allele, a haematological defect results in their adult wildtype daughters. However, the specific phenotype was dependent upon the sex of the parent. For instance, wildtype daughters of Mtrr+/gt females displayed normocytic anaemia. In contrast, wildtype daughters of Mtrr+/gt males exhibited erythrocytic microcytosis not associated with anaemia. Therefore, abnormal folate metabolism affects adult haematopoiesis in an age-, sex- and parent-specific manner. PMID- 30024028 TI - Identifying Natural Subgroups of Migraine Based on Comorbidity and Concomitant Condition Profiles: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. AB - OBJECTIVE: To identify natural subgroups of people with migraine based on profiles of comorbidities and concomitant conditions, hereafter referred to as comorbidities. BACKGROUND: Migraine is a heterogeneous disease. Identifying natural subgroups (endophenotypes) may facilitate biological and genetic characterization and the development of personalized treatment. METHODS: The Chronic Migraine Epidemiology and Outcomes Study is a prospective web-based survey study designed to characterize the course of migraine and related comorbidities in a systematic US sample of people with migraine. Respondents were asked if they ever had a specific comorbidity and, if present, whether the comorbidity was confirmed/diagnosed by a "doctor"; 62 comorbidities were available for analysis. Latent class analysis (LCA) modeling determined the optimal number of classes and a parsimonious set of comorbidities. RESULTS: Of the 12,810 respondents with migraine, 11,837 reported >=1 comorbidity and were included in this analysis. After statistical analysis and clinical judgment reduced the number of comorbidities, we selected an 8-class model based on 22 comorbidities. Each class had a distinct pattern summarized as follows: Class 1, Most Comorbidities; Class 2, Respiratory/Psychiatric; Class 3, Respiratory/Pain; Class 4, Respiratory; Class 5, Psychiatric; Class 6, Cardiovascular; Class 7, Pain; Class 8, Fewest Comorbidities. The distribution of individuals across models was variable, with one-third of respondents in Class 8 (Fewest Comorbidities) and <10% in Class 1 (Most Comorbidities). Demographic and headache characteristics, not used in assigning class membership, varied across classes. For example, comparing Class 1 (Most Comorbidities) and Class 8 (Fewest Comorbidities), Class 1 had a greater proportion of individuals with severe disability (Migraine Disability Assessment grade IV; 48.1% vs 22.3% of overall individuals) and higher rates of allodynia (67.6% vs 47.0%), medication overuse (36.4% vs 15.0%), chronic migraine (23.1% vs 9.1%), and aura (40.1% vs 28.8%). CONCLUSIONS: LCA modeling identified 8 natural subgroups of persons with migraine based on comorbidity profiles. These classes show differences in demographic and headache features not used to form the classes. Subsequent research will assess prognostic and biologic differences among the classes. PMID- 30024030 TI - Effect of two periodontal treatment modalities in patients with uncontrolled type 2 diabetes mellitus: A randomized clinical trial. AB - AIM: To evaluate the impact of two non-surgical periodontal treatment modalities on metabolic and periodontal clinical parameters in subjects with type 2 diabetes mellitus (T2DM) and poor glycaemic control and chronic periodontitis. MATERIAL AND METHODS: A randomized controlled clinical trial was conducted. Ninety-three T2DM subjects with glycosylated haemoglobin (HbA1c) > 7% were randomly assigned to one of two groups receiving scaling with root planing in multiple sessions quadrant-by-quadrant (Q by Q) or within 24 hr (one stage). Periodontal parameters, HbA1c, glycaemia blood levels (FPG) and C-reactive protein (CRP) values were assessed at baseline and at 3 and 6 months post-therapy. RESULTS: At 6 months, HbA1c had decreased by 0.48% in the Q by Q group and by 0.18% in the one-stage group (p = 0.455). After therapy, subjects with an initial HbA1c < 9% showed an increase of 0.31% (p = 0.145), compared with a decrease of 0.88% (p = 0.006) in those with an initial HbA1c >= 9%. Periodontal parameters improved significantly (p < 0.0001) post-therapy, with similar results for both treatment modalities. CONCLUSION: Periodontal therapy had the greatest impact on HbA1c reduction on patients with an HbA1c > 9% regardless of treatment modality. Both modalities resulted in significant improvements in periodontal parameters. PMID- 30024029 TI - Sooty mangabeys scavenge on nuts cracked by chimpanzees and red river hogs-An investigation of inter-specific interactions around tropical nut trees. AB - Carrion scavenging is a well-studied phenomenon, but virtually nothing is known about scavenging on plant material, especially on remnants of cracked nuts. Just like meat, the insides of hard-shelled nuts are high in energetic value, and both foods are difficult to acquire. In the Tai forest, chimpanzees (Pan troglodytes) and red river hogs (Potamochoerus porcus) crack nuts by using tools or strong jaws, respectively. In this study, previously collected non-invasive camera trap data were used to investigate scavenging by sooty mangabeys (Cercocebus atys), two species of Guinea fowl (Agelestres meleagrides; Guttera verreauxi), and squirrels (Scrunidae spp.) on the nut remnants cracked by chimpanzees and red river hogs. We investigated how scavengers located nut remnants, by analyzing their visiting behavior in relation to known nut-cracking events. Furthermore, since mangabeys are infrequently preyed upon by chimpanzees, we investigated whether they perceive an increase in predation risk when approaching nut remnants. In total, 190 nut-cracking events were observed in four different areas of Tai National Park, Ivory Coast. We could confirm that mangabeys scavenged on the nuts cracked by chimpanzees and hogs and that this enabled them to access food source that would not be accessible otherwise. We furthermore found that mangabeys, but not the other species, were more likely to visit nut-cracking sites after nut-cracking activities than before, and discuss the potential strategies that the monkeys could have used to locate nut remnants. In addition, mangabeys showed elevated levels of vigilance at the chimpanzee nut-cracking sites compared with other foraging sites, suggesting that they perceived elevated danger at these sites. Scavenging on remnants of cracked nuts is a hitherto understudied type of foraging behavior that could be widespread in nature and increases the complexity of community ecology in tropical rainforests. PMID- 30024032 TI - Selective ablation of dental caries using coaxial Co2 (9.3-MUm) and near-IR (1880 nm) lasers. AB - OBJECTIVE: The purpose of this study was to determine the feasibility of image guided laser ablation of demineralization from tooth occlusal surfaces using coaxial near-infrared (NIR) and CO2 lasers. MATERIALS AND METHODS: A CO2 laser operating at a wavelength of 9.3-MUm was combined with a thulium-doped fiber laser operating at 1880-nm for the selective removal of simulated occlusal caries lesions from 10 tooth samples. Serial NIR reflectance images at 1880-nm were used to guide the CO2 laser for image-guided laser ablation. Polarization-sensitive optical coherence tomography (PS-OCT) was used to assess the initial depth of the lesions before removal and assess the volume of sound and demineralized tissue removed by the CO2 laser. RESULTS: PS-OCT scans indicated that roughly ~99% of the lesion was removed by image-guided laser ablation. A mean volume of 0.191-mm3 or 11.9-MUm/voxel of excess enamel was removed during lesion removal. CONCLUSION: A co-aligned NIR/CO2 laser scanning system has great potential for the highly selective removal of dental decay (demineralization). Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30024031 TI - Validation of a purpose-built chewing gum and smartphone application to evaluate chewing efficiency. AB - OBJECTIVES: To validate a purpose-built two-coloured chewing gum (Hue-Check Gum(r) ), and to test the accuracy of a custom-built smartphone application for a colour-mixing ability test to assess chewing function. METHODS: Fully dentate participants (28D-group) and edentulous participants with implant overdentures (IOD-group) were recruited. They chewed a Hue-Check Gum(r) for 5, 10, 20, 30 and 50 chewing cycles, respectively. Maximum voluntary bite force (MBF) was assessed with a digital gauge. The specimens were analysed according to their colour mixture (variance of hue, VOH) with a validated software (VOH_scan) and a newly developed smartphone application (VOH_app). RESULTS: Participants segregated by dental state were significantly different regarding the number of occluding pairs of teeth, age and MBF. VOH_scan showed a negative logarithmic association with the number of chewing cycles, and VOH could be predicted from chewing cycles, MBF and gender. The clearest discrimination between the IOD and the 28D groups was observed for n = 20 chewing cycles; at this point, VOH was distinguishably different with a P-value < 0.0001. The VOH_app was a very good predictor for VOH_scan with 0.80 < pseudo-R2 < 0.83, depending on light exposure and measuring distance. There was, however, a systematic error in the accuracy of the app for inadequately chewed specimens. CONCLUSIONS: The use of the two-coloured chewing gum would provide a fast, simple and inexpensive method for the assessment of masticatory performance, which could be used in geriatric wards or in private practices without the requirement of specialised equipment or trained staff. PMID- 30024033 TI - Foraging and inter-individual distances of bearded capuchin monkeys. AB - Extractive foraging is a skill young capuchin monkeys learn over time. A key unknown is whether unskilled individuals occupy spatial positions that increase their opportunities to learn. We observed the spatial positions of individuals in a group of capuchin monkeys in Northeastern Brazil. To improve our understanding of the relationship between learning by young capuchin monkeys and inter individual distance, we investigated the associations between the proximity of individuals and their age, activity, and proficiency at extractive foraging. To do this, we used one form of extractive foraging, opening palm nuts, as an index of proficiency at all types of extractive foraging. Our results indicate that, in the subset of the data where dyads consisted of one proficient individual and a partner with any level of proficiency, the distance between individuals was predicted by their foraging activity (i.e., extractive foraging, other foraging, or not foraging). In those dyads, the proficiency of the partner did not significantly improve prediction of inter-individual distances, indicating that spatial proximity of proficient individuals to others does not function primarily to increase opportunities for unskilled individuals to observe extractive foraging. Dyads in which both individuals were engaged in similar foraging activities (e.g., both "extractive foraging") exhibited the shortest inter individual distances. Proximity between individuals engaged in similar foraging activities may result from the spatial distribution of resources or from social learning mechanisms, such as local or stimulus enhancement. PMID- 30024034 TI - A clinical study of choledochoscopic holmium laser lithotripsy for multiple intrahepatic calculi within ERAS programs. AB - OBJECTIVES: Multiple intrahepatic calculi, especially calculi in both sides of the liver, cannot be completely resolved by traditional surgery. In addition, morbidity after liver resection remains high. ERAS programs have been suggested that could relieve surgical stress and accelerate postoperative recovery. This study aimed to evaluate the safety and efficacy of choledocholithotomy combined with holmium laser lithotripsy in the treatment of multiple intrahepatic calculi within ERAS programs. METHODS: In all, 109 patients with multiple intrahepatic calculi were enrolled between January 2012 and September 2016, 42 of whom received choledocholithotomy combined with holmium laser lithotripsy. The remaining 67 patients underwent choledocholithotomy combined with choledochoscopic mechanical lithotripsy. Perioperative outcomes were compared and analyzed. RESULTS: Patient characteristics and preoperative details were similar between the groups (P > 0.05). The implementation of holmium laser lithotripsy could reduce the calculi residual rate (7.1% vs. 22.4%, P = 0.037), and even the liver resection rate (16.7% vs. 35.8%, P = 0.031). Additionally, holmium laser lithotripsy did not result in a higher morbidity (11.9% vs. 16.4%, P = 0.517), readmission rate (0% vs. 6%, P = 0.158), hospital stay (P = 0.189), hospital cost (P = 0.998), transfusion rate (P = 0.576), or operative time (P = 0.638). CONCLUSIONS: Holmium laser lithotripsy is feasible and efficient for treating multiple intrahepatic calculi within ERAS programs, which could reduce the liver resection rate and render refractory hepatic calculi easy to eliminate. In addition, holmium laser lithotripsy could be well coupled to the ERAS program to relieve surgical stress and accelerate postoperative recovery. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30024035 TI - Modelling the details: integrating structure with function. PMID- 30024036 TI - The effect of dutasteride on microscopic and macroscopic changes of testosterone replacement treatment on prostate tissue. AB - Testosterone replacement therapy has a growing interest in daily practice; however, debates on its safety for prostate cancer still continue. Dutasteride-a 5alpha-reductase inhibitor-was shown to be effective in preventing prostate cancer. We therefore aimed to evaluate the effect of testosterone replacement therapy and dutasteride treatment on prostate tissue in castrated rats. Rats were randomised in four groups after bilateral orchidectomy as follows: Group I received testosterone + dutasteride, Group II received only testosterone, Group III had no medical treatment, and Group IV was the control group. After 3 months, rats were sacrificed and laboratory and histopathological examinations were performed. In Groups I and II, prostate volume, T and DHT levels were significantly higher compared to Group III and controls. Groups I and II had also significantly greater preneoplastic histopathological signs; however, in intergroup analyses, Group I showed less premalignant changes compared to Group II. We concluded that dutasteride was effective when combined with testosterone therapy in preventing premalignant histopathological changes in prostate tissue. Further evidence is needed to confirm our findings. PMID- 30024037 TI - The use of aniline blue chromatin condensation test on prediction of pregnancy in mild male factor and unexplained male infertility. AB - The aim of this study was to investigate the possibility of using sperm function tests (hypoosmotic swelling test [HOS], aniline blue [AB] staining test, and sperm chromatin dispersion [SCD]) to predict intrauterine insemination [IUI] success rate. A total of 243 couples with mild male factor or unexplained male infertility who underwent IUI were evaluated prospectively. The results of basic sperm analysis and sperm function tests were compared between pregnant or nonpregnant groups. The HOS (11.9 +/- 9.6% vs. 10.1 +/- 8.5%, p = 0.35) and SCD tests (32.9 +/- 21.0% vs. 29.9 +/- 19.0%, p = 0.48) were not significantly different between pregnant (n = 22) and nonpregnant (n = 221) groups. However, the AB staining negativity rate was significantly higher in the pregnant group compared to the nonpregnant group (35.2 +/- 20.8% and 24.4 +/- 18.0%, p = 0.008). On ROC analysis, a cut-off value of 24% for AB negativity showed a sensitivity and a specificity value of 82.35% and 51.38% (AUC) = 0.653; 95% confidence interval: 0.571-0.72 P (Area = 0.5) = 0.0267, respectively, for prediction of pregnancy. Our study showed that the sperm chromatin maturity, assessed by AB stain, may predict the pregnancy in couples with unexplained female infertility plus mild male factor or unexplained male infertility. The HOS and SCD failed to predict the pregnancy in this group of couples. PMID- 30024039 TI - Plasmonic photothermal therapy: Approaches to advanced strategy. AB - BACKGROUND: The analysis of recent studies on plasmonic photothermal therapy (PPT) after intravenous administration of gold nanorods (GNRs) has demonstrated that the effectiveness of nanoparticle-assisted laser hyperthermia depends on a correct dosage strategy of nanoparticle administration. Accumulation of GNRs in tumor tissue dramatically increases the local heating of the tumor without damage to healthy tissues. However, the optimal doses of GNR intravenous injections (IVIs) for effective accumulation in tumors, and optimal protocols of PPT are not designed yet. The current study aims to improve the efficacy of PPT in tumor bearing rats using multiple fractional intravenous administration of GNRs. MATERIALS AND METHODS: For PPT experiments, the GNRs with aspect ratio of 4.1 were functionalized with thiolated polyethylene glycol (PEG) and their suspensions were used for multiple fractional intravenous administration in outbred albino male rats with experimental model of rat liver cancer (cholangiocarcinoma line PC-1). Doppler ultrasonography was performed to characterize the vascularity of transplanted rat tumors before any treatment. After a final injection of GNRs, tumor was irradiated during 15 minutes by 808-nm NIR diode laser at a power density 2.3 W/cm2 . The animals were withdrawn from the experiment and sampling of tissues for morphological study and gold accumulation was performed 24 hours and 3 weeks after PPT. RESULTS: The multiple IVIs of gold nanorods and further PPT of transplanted cholangiocarcinoma provided significant damage to tumor tissue resulting in pronounced necrotic mass and retardation of the tumor growth. More importantly, the proposed PPT protocol had low toxicity as evidenced by histological examination of internal organs. The efficiency of PPT depends on the presence of newly formed vasculature as revealed by the Doppler ultrasound investigation. CONCLUSION: The repeatable IVIs promote greater of GNR accumulation within the tumor thus resulting in higher PPT efficacy. Accompanying ultrasonography can be useful for prognosis and monitoring of treatment. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30024038 TI - Glycycoumarin protects mice against acetaminophen-induced liver injury predominantly via activating sustained autophagy. AB - BACKGROUND AND PURPOSE: Acetaminophen-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Given the significant limitations associated with N-acetyl cysteine, the only antidote used to treat AILI, the development of novel therapeutic approaches that can offer a wide range of therapeutic time-windows is clearly needed. Glycycoumarin (GCM), a natural coumarin purified from liquorice, has been previously demonstrated to possess potent hepatoprotective effects. In the present study, we aimed to investigate the therapeutic potential of GCM against AILI. EXPERIMENTAL APPROACH: Acetaminophen (300 mg.kg-1 ) was administered to male C57BL/6 mice, with and without GCM. Serum transaminases, haematoxylin and eosin staining and Western blot were used to assess hepatic damage. KEY RESULTS: GCM (50 mg.kg-1 ) was highly effective against acetaminophen-induced hepatotoxicity. Moreover, GCM was superior to N-acetyl cysteine, in terms of the dosage and the therapeutic time windows. Further mechanistic investigations revealed that the therapeutic action of GCM was not a result of inhibition of acetaminophen metabolic activation or associated with Nrf2. Instead, the protective effect of GCM appeared to be predominantly dependent on sustained activation of autophagy, which attenuated acetaminophen-induced mitochondrial oxidative stress and JNK activation. CONCLUSIONS AND IMPLICATIONS: Collectively, our results indicate that GCM alleviated acetaminophen-induced oxidative stress through activating autophagy, thereby protecting against AILI. Our findings suggest that GCM has potential as a novel therapeutic agent for treating AILI. PMID- 30024041 TI - Maternal peripartum antibiotic exposure and the risk of postpartum depression. AB - Postpartum depression is a relatively common occurrence that may carry lifelong consequences. Also common is the exposure of pregnant and postpartum women in the United States to antibiotics, especially during the peripartum period. Antibiotic exposure is known to alter gut microbial composition and structure, contributing to a dysbiotic, or imbalanced gut microbiome, and is a mechanism suggested for the increased risk of depressive symptoms following antibiotic exposure in non pregnant, non-postpartum populations. We sought to determine the relationship between antibiotic exposure intrapartum through the first 14 days postpartum and depressive symptoms within the first 6-months postpartum. In this secondary data analysis, 124 pregnant women from a prospective cohort were enrolled into the study and provided demographic characteristics and health history. Participants completed questionnaires including the Edinburgh Postnatal Depression Scale between 32-36 weeks, and 1- and 2-weeks and 1-, 2-, 3-, and 6-months postpartum. Clinical measures including hours in labor, perineal injury, and mode of giving birth were ascertained by medical record abstraction. Antibiotic exposure was identified by self-report at 1- and 2-weeks postpartum. Antibiotic exposure was found to be independently predictive of postpartum depressive symptoms at 1-month (Beta = 0.43; CI [0.01, 0.86]) and 2-months (Beta = 0.51; CI [0.08, 0.94]) postpartum after controlling for baseline predictors. The relationship between antibiotic exposure and postpartum depressive symptoms did not maintain significance at 3- or 6-months postpartum. Additional studies are needed to further investigate the relationship between onset and duration of antibiotic exposure, the peripartum gut microbiome, and the risk for postpartum depressive symptoms. PMID- 30024040 TI - Long-term group membership and dynamics in a wild western lowland gorilla population (Gorilla gorilla gorilla) inferred using non-invasive genetics. AB - The social organization of a group-living animal is defined by a balance between group dynamic events such as group formation, group dissolution, and dispersal events and group stability in membership and over time. Understanding these processes, which are relevant for questions ranging from disease transmission patterns to the evolution of polygyny, requires long-term monitoring of multiple social units over time. Because all great ape species are long-lived and elusive, the number of studies on these key aspects of social organization are limited, especially for western lowland gorillas (Gorilla gorilla gorilla). In this study, we used non-invasive genetic samples collected within an approximately 100 km2 area of Loango National Park, Gabon to reconstruct group compositions and changes in composition over more than a decade. We identified 98 gorillas and 11 mixed sex groups sampled during 2014-2017. Using published data from 85 individuals and 12 groups surveyed between 2005 and 2009 at the same locality, we tracked groups and individuals back in time. The identification of 11 silverbacks via parentage analyses and the genetic tracking of 39 individuals across studies allowed us to infer six group formations, five group dissolutions, and 40 dispersal events within 12 years. We also observed four groups persisting across the sampling periods with a maximum inferred existence of nearly 17 years and exhibiting variation in membership stability. Our results highlight the variation in composition and stability among groups of western lowland gorillas and illustrate the power of non-invasive genetic sampling for long-term monitoring. PMID- 30024042 TI - Comparison of clinical outcome of bilateral and unilateral varicocelectomy in infertile males with left clinical and right subclinical varicocele: A meta analysis of randomised controlled trials. AB - Varicocele is the most common cause of male infertility. Varicoceles are classified into two types: clinical and subclinical varicoceles. Some researchers reported right subclinical varicoceles are often accompanied with left clinical varicoceles. However, the treatment is controversial. Our aim was to compare the clinical outcome of unilateral varicocelectomy (UV) and bilateral varicocelectomy (BV) in infertile males with left clinical and right subclinical varicocele. A total of four randomised controlled trials (RCT) were enrolled in this study, including 637 cases with left clinical and right subclinical varicocele (318 cases in the BV group and 319 cases in the UV group). The fixed effects model combined difference in progressive sperm motility between the two groups was 6.42% (95% CI: 5.09, 7.75). The random effects model combined difference in normal sperm morphology between the two groups was 2.04% (95% CI: 0.60, 3.48). The odds ratio shown by the fixed effects model in spontaneous pregnancy rate was 1.73 (95% CI: 1.24, 2.43). No statistically significant difference between the two groups was found in sperm concentration and sperm motility. Thus, BV may be superior to UV for infertile male patients with left clinical and right subclinical varicocele. However, more properly conducted RCTs are still needed. PMID- 30024043 TI - Contribution of maternal overweight and obesity to the occurrence of adverse pregnancy outcomes. AB - AIMS: Maternal overweight and obesity in pregnancy are known to increase the risk of a range of complications and adverse pregnancy outcomes. This study estimates the population-level contribution of maternal overweight and obesity to adverse pregnancy outcomes. METHODS: Data derived from the Australian Capital Territory (ACT) Maternal and Perinatal Data Collection were analysed. A total of 24 161 women who had a singleton birth in 2009-2015, with maternal weight and height information available, were included. In this study, the association between risk factors and outcomes was investigated using multilevel regression modelling. Based on model predictions under various hypothetical maternal weight scenarios, the number and proportion of adverse perinatal outcomes that could be potentially prevented were estimated. RESULTS: Maternal overweight and obesity were associated with increased risks of gestational diabetes mellitus (GDM), pre eclampsia, caesarean delivery, preterm birth (PTB), large for gestational age (LGA) and admission to the special care nursery or neonatal intensive care unit (SCN/NICU). The estimated proportions of adverse pregnancy outcomes attributable to overweight and obesity in pregnancy are 29.3% for GDM, 36.2% for pre eclampsia, 15.5% for caesarean delivery, 21.6% for longer antenatal stay in hospital (>=2 days), 16.3% for extreme PTB, 25.2% for LGA and 6.5% for SCN/NICU admission. CONCLUSIONS: Maternal overweight and obesity contribute to a large proportion of obstetric complications and adverse outcomes in the ACT. Effective intervention strategies to reduce the prevalence of overweight and obesity in pregnant women could have significant beneficial effects on pregnancy outcomes. PMID- 30024044 TI - Do Headache Patients Require More Care in Between Visits Than Other Neurology Outpatients? AB - BACKGROUND: There is evidence that time spent in patient care in between patient visits is increasing and a contributor to physician burnout. The extent of this work on providers in the field of headache medicine is unknown. OBJECTIVES: To establish whether headache outpatients require a high level of care in addition to clinic visits, based on the quantity of remote encounters per patient (phone calls and secure email communication to the clinics), in comparison to other neurologic clinics. METHODS: In an academic referral clinic, a total of 3164 established patients were included in this retrospective analysis, 275 from the headache clinic, the remainder from various other neurology clinics (2 physician providers per clinic except 3 physician providers in the headache clinic). Patients presenting for a follow-up visit between January 2014 and April 2016 were observed for a 12-month period during which the number of a) telephone and b) secure email (MyChart) encounters per patient was recorded, and in addition, the number of entries related to each of these encounters. This analysis did not require IRB approval as per institutional guidelines. RESULTS: Headache clinic patients required a high frequency of remote encounters (composite of both telephone and email messages) per patient, second only to the MS clinic patients. Use of secure email messaging (MyChart) per patient was much higher in the headache clinic compared to all other clinics. CONCLUSION: Patients in a headache clinic in an academic tertiary care setting require a high intensity of remote outpatient care, more so than patients in other neurology subspecialty clinics and general neurology clinic, with the exception of the neuroimmunology/MS clinic. This is to a large extent secondary to the very frequent use of secure email linked to the electronic medical record by headache patients. PMID- 30024045 TI - The efficacy of dextrose prolotherapy over placebo for temporomandibular joint hypermobility: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of the systematic review was to analyse the available evidence in order to assess the efficacy of dextrose prolotherapy in improving outcomes in temporomandibular joint (TMJ) hypermobility patients as compared to placebo. METHODS: An electronic search of PubMed, Scopus, CENTRAL and Google scholar databases was performed for English language papers published up to February 2018. Randomised clinical trials (RCTs) and controlled clinical trials (CCTs) comparing dextrose prolotherapy with placebo for TMJ hypermobility were included. RESULTS: Three RCTs were included in the review. Frequency of subluxation/dislocation was reported by two trials which found no difference between dextrose and placebo. A statistical significant difference in reduction of MMO with the use of dextrose prolotherapy was seen on pooling of data (random: MD = -3.32, 95% CI -5.26 to -1.28; P = 0.0008; I2 = 0%). A statistical significant difference in pain reduction was also seen with dextrose as compared to placebo (random: MD = -1, 95% CI -1.58 to -0.42; P = 0.0007; I2 = 0%). CONCLUSION: Within the limitations of the study, dextrose prolotherapy may cause significant reduction in mouth opening and pain associated with TMJ hypermobility. Conclusions with regard to reduction of episodes of subluxation/dislocation cannot be drawn. There is a need of more high-quality RCTs with larger sample size and homogenous prolotherapy protocol to draw stronger conclusions on the effect of dextrose prolotherapy in patients with TMJ hypermobility. PMID- 30024046 TI - Experimental noxious stimulation of the right masseter muscle does not affect bilateral masseter and temporalis muscle activity and force parameters during standardised isometric biting tasks. AB - AIM: To determine if the electromyographic (EMG) activity of the left and right masseter and anterior temporalis muscles is altered by experimental right masseter muscle noxious stimulation during goal-directed isometric biting tasks in asymptomatic humans. METHODS: Isometric biting tasks (slow and fast ramp biting tasks, 2-step biting task) were performed on an intraoral force transducer in 18 participants during the following blocks: baseline block, hypertonic saline infusion into the right masseter muscle (painful block) and isotonic saline infusion into the right masseter (control block). Bipolar surface electrodes recorded EMG activity from the bilateral masseter and anterior temporalis muscles. A 100-mm visual analogue scale (VAS) quantified pain intensity, and the McGill Pain Questionnaire (MPQ), the Depression, Anxiety and Stress Scales-21 (DASS-21) and the Pain Catastrophizing Scale (PCS) were completed. Repeated measures ANOVA assessed the effects of pain on the force rates (N/s), force amplitudes (N) and the root mean square (RMS) jaw muscle EMG activity across blocks. Statistical significance accepted at P < 0.05. RESULTS: VAS scores were significantly (P < 0.001) higher during hypertonic than isotonic saline infusion blocks. There was no significant effect of pain on the force rates, or force levels or the RMS EMG activity of each masseter and anterior temporalis muscle. CONCLUSION: The findings suggest that experimentally induced right masseter muscle pain does not modify force or surface jaw muscle EMG activity during isometric biting tasks. PMID- 30024048 TI - Parkinson's disease, temporomandibular disorders and bruxism: A pilot study. AB - BACKGROUND: Even though bruxism and Parkinson's disease (PD) share common characteristics, their relation is still not clear. Both bruxism and PD are movement disorders in addition, patients with bruxism as well as those with PD complain about musculoskeletal pain, including temporomandibular disorders (TMD) pain. OBJECTIVES: Therefore, the aim of this pilot study was to gain more insight into the possible relation between bruxism and TMD on one hand and PD on the other. METHODS: In total, 801 persons gave their written informed consent and agreed to participate in the study filling in a questionnaire. Complete data were collected from 708 persons (368 with PD or Parkinsonism [PR] and 340 controls) and were included in the analysis. The questionnaire included the graded chronic pain scale, the DC/TMD oral behaviour checklist, the DC/TMD symptom questionnaire and the TMD pain screener. In addition, a question about self-reported tooth wear was included. The chi-square test and independent samples t test were used for the data analysis. RESULTS: Patients with PD/PR reported significantly more often bruxism during sleep and wakefulness than controls. Also, patients with PD/PR had more often possible TMD and reported a significantly higher mean pain intensity in the orofacial region than controls. There was no significant difference in complaints of jaw locking between the patient group and the control group. A tendency towards a significant association was found between PD/PR and tooth wear. CONCLUSION: There is a relation between PD/PR and bruxism. Furthermore, a relation of PD/PR with TMD pain is suggested to be present. PMID- 30024049 TI - Percentage of methylmercury in the muscle tissue of freshwater fish varies with body size and age and among species. AB - It is commonly assumed that most (>95%) of the mercury (Hg) found in fish muscle is the toxic form, methylmercury (MeHg), due to its efficient assimilation and retention in biotic tissue. However, this assumption is largely based on studies examining the percentage of MeHg (%MeHg [the fraction of total Hg as MeHg]) in muscle from mostly large-bodied predatory fish; less is known about the %MeHg in smaller bodied individuals or those of different trophic guilds. The present study analyzed MeHg and total Hg concentrations in the muscle of 2 large-bodied piscivores (walleye and northern pike), one large-bodied benthivore (white sucker), and 2 small-bodied forage fish (sculpins and shiners) across a broad size range. We found substantially lower %MeHg than the commonly assumed 95% in several fish (e.g., 17 individuals had <70% MeHg). Muscle %MeHg significantly increased with size and age in all species except walleye, which had significantly higher %MeHg than pike or suckers, particularly in smaller and younger fish (e.g., 18-21% higher at 10 g; 5-11% higher at 500 g). Results of predictive modeling suggest that muscle %MeHg is higher in pelagic-feeding fish and those with lower lipid content, although model results varied significantly among species. According to our findings, total Hg measurement in muscle is not an appropriate proxy for MeHg in smaller fish from all species, an important consideration for future piscine Hg studies and monitoring. Environ Toxicol Chem 2018;37:2682-2691. (c) 2018 SETAC. PMID- 30024047 TI - Magnitude of acute toxicity of marine sediments amended with conventional copper and nanocopper. AB - It is well known that copper (Cu) is toxic to marine organisms. We measured and compared the acute toxicity of several forms of Cu (including nanoCu) amended into a marine sediment with mysids and amphipods. For all the forms of Cu tested, toxicity, measured as the median lethal concentration, ranged from 708 to > 2400 mg Cu/kg (dry sediment) for mysids and 258 to 1070 mg Cu/kg (dry sediment) for amphipods. Environ Toxicol Chem 2018;37:2677-2681. (c) 2018 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 30024050 TI - The relation of the pelvis and the perineal function in incontinent women: A neglected subject. AB - AIMS: To Compare the angular parameters of the pelvis of continents and incontinent women and to correlate them with the electrical activity and the function of the pelvic floor muscles. METHODS: Cross-sectional study. Incontinent and continent women, aged between 18 and 59 years. The anatomical points were marked following the SAPO protocols, the photographic records were made and analyzed through the SAPO Software. The evaluation of the function of the MPF was performed by bidigital vaginal palpation, using the PERFECT scheme. Surface electromyographic analysis was performed in dorsal decubitus and orthostasis. RESULTS: The sample consisted of 40 women, 20 with SUI (IG) and 20 continents (CG), matched by age. The mean age in the CG was 43.5 years (SD 8.4), while in the IG it was 47.1 years (SD 7.8) (P = 0.16). The pelvic angle in the CG presented a mean of -14.3 +/- 4.6 and the IG -16.6 +/- 4.4 (P = 0.02). When compared to normality, IG presented an accentuation of anterior slope in both analyzed views (P = 0.01). There was a moderate correlation in the IG between the electrical activity of the basal pelvis in orthostasis and the anterior pelvic tilt angles in the right lateral views r = 0.51 (P = 0.02) and left lateral r = 0.46 (P = 0.04). No correlation was found in the CG. CONCLUSIONS: In the present sample, incontinent women have a greater anterior slope of the pelvis, and the greater the degree of anterior slope, the greater the electrical activity of the PFM, during rest, and in orthostasis. PMID- 30024052 TI - What is the utility of urodynamics, including ambulatory, and 24 h monitoring, in predicting upper urinary tract damage in neuro-urological patients and other lower urinary tract dysfunction? ICI-RS 2017. AB - AIMS: This article focuses on how, and if, urodynamics can help to identify which kidneys are in danger of deteriorating in function and also gives recommendations for future research. METHODS: At the International Consultation on Incontinence Research Society (ICI-RS) in 2017, a multi-disciplinary group presented a literature search of what is known about the utility of Urodynamics, including ambulatory, and 24 h monitoring, in predicting upper urinary tract damage in neuro-urological patients and other lower urinary tract dysfunctions. Wider discussions regarding knowledge gaps, and ideas for future research ensued and are presented in this paper along with a review of the evidence. RESULTS: The current treatment strategy both in congenital and acquired neurogenic bladder is rather aggressive and successful when addressing hazards to kidney function. This article has highlighted uncertainties concerning the use of 40 cmH2O DLPP and even the lower value of 20. The current literature suggests that patients with spina bifida and those with spinal cord injury have a higher risk of developing upper urinary tract damage and kidney function impairment than those with multiple sclerosis. CONCLUSIONS: Future research should focus on less invasive methods to assess the risk to the upper and lower urinary tract such as urine and serum measurements of cytokines that are involved in the pathophysiology of urinary tract impairment. PMID- 30024051 TI - Stimulated echo based mapping (STEM) of T1 , T2 , and apparent diffusion coefficient: validation and protocol optimization. AB - PURPOSE: To present a stimulated-echo based mapping (STEM) approach for simultaneous T1 , T2 , and ADC mapping. METHODS: Diffusion-weighted stimulated echo images with various combinations of mixing time (TM), TE, and b-value were acquired to enable simultaneous mapping of T1 , T2 , and ADC. The proposed STEM method was performed by densely sampling the TM-TE-b space in a phantom and in brain and prostate of healthy volunteers. T1 , T2 , and ADC from STEM were compared to reference mapping methods. Additionally, protocol optimization was performed to enable rapid STEM acquisition within 2 min by sparsely sampling the TM-TE-b space. The T1 , T2 , and ADC measurements from rapid acquisitions were compared to the densely sampled STEM for evaluation. Finally, a patient with biopsy-proven high-risk prostate cancer was imaged to demonstrate the ability of STEM to differentiate cancer and healthy tissues. RESULTS: Relative to the reference measurements, densely sampled STEM provided accurate quantitative T1 , T2 , and ADC mapping in phantoms (R2 = 0.999, slope between 0.97-1.03), as well as in brain and prostate. Further, the T1 , T2 , and ADC measurements from the optimized rapid STEM acquisitions agreed closely with densely sampled STEM. Finally, STEM showed decreased T2 and ADC in prostate cancer compared to healthy prostate tissue. CONCLUSION: STEM provides accurate simultaneous mapping of T1 , T2 , and ADC. This method may enable rapid and accurate multi-parametric tissue characterization for clinical and research applications. PMID- 30024053 TI - Computational simulation of medial versus anteromedial tibial tuberosity transfer for patellar instability. AB - The study utilizes dynamic simulation of knee function to determine how tibial tuberosity medialization and anteromedialization influence patellar tracking and contact pressures for knees with patellar instability. Dual limb squatting was simulated with six multibody dynamic simulation models representing knees being treated for patellar instability. Each knee exhibited lateral patellar maltracking in the pre-operative condition based on the bisect offset index. The patellar tendon attachment points on the tibia were medialized by 10 mm to represent tibial tuberosity medialization, with an additional 5 mm of anteriorization applied for anteromedialization. The patellofemoral contact pressure distribution was quantified using discrete element analysis. Data were analyzed with repeated measures analysis of variance with post-hoc tests and linear regressions. Tibial tuberosity medialization and anteromedialization significantly (p < 0.05) decreased the bisect offset index for nearly all flexion angles up to 80 degrees , with the largest changes near full extension. Both procedures significantly decreased the maximum lateral pressure at 55 degrees , but increased the maximum medial pressure from 30 to 80 degrees . The pre operative to post-operative increase in the maximum contact pressure was significantly correlated with the maximum pre-operative bisect offset index for tuberosity medialization (r2 = 0.84), but not for anteromedialization. Statement of Clinical Significance: The results indicate tibial tuberosity medialization decreases patellar lateral maltracking and lateral patellofemoral contact pressures, but increases medial contact pressures. When pre-operative patellar maltracking is relatively low, tibial tuberosity medialization is likely to increase maximum contact pressures. Tibial tuberosity anteromedialization lowers the risk of elevated post-operative contact pressures compared to medialization. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 30024055 TI - Orofacial granulomatosis and erythema multiforme in an adolescent with Crohn's disease. AB - The cutaneous manifestations of Crohn's disease are myriad. A 15-year-old girl presented with recurrent lip swelling and eventual development of diarrhea and targetoid macules on the palms, feet, and back. She was finally diagnosed with Crohn's disease in the setting of a clinical presentation and histopathology consistent with orofacial granulomatosis and erythema multiforme. We review the literature and summarize reported occurrences of these cutaneous diseases in children with Crohn's disease. PMID- 30024054 TI - Impact of falls on depressive symptoms among the oldest old: Results from the AgeQualiDe study. AB - OBJECTIVE: The purpose of this study was to examine the impact of falls on depressive symptoms among the oldest old in Germany longitudinally. METHODS: Data were used from 2 waves of the multicenter prospective cohort "Study on needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" (AgeQualiDe). This study covers primary care patients >=85 years (at baseline: n = 547, average age of 88.9 +/- 3.0 years; ranging from 85 to 100 years). General practitioner-diagnosed falls were used as explanatory variable. The Geriatric Depression Scale was used as outcome measure. RESULTS: Linear fixed effects regressions showed that the occurrence of falls is associated with an increase in depressive symptoms (beta = .60, P = .02), whereas changes in marital status, ageing, social support, functional decline (instrumental activity of daily living), cognitive impairment, and an increase in chronic diseases did not affect depressive symptoms. In sensitivity analysis, an increase in depressive symptoms was associated with functional impairment (basic activities of daily living; Barthel index; beta = -.04, P = .005). CONCLUSIONS: Based on a large, population-based longitudinal study, this study underlined the impact of falls on depressive symptoms and consequently extended previous knowledge about an association between falls and depressive symptoms in the oldest old. Developing strategies to prevent falls might also help to prevent depressive symptoms. PMID- 30024056 TI - miR-26a inhibits proliferation and promotes apoptosis in porcine immature Sertoli cells by targeting the PAK2 gene. AB - Accumulating reports have demonstrated that microRNAs (miRNAs) participate in regulating the complex processes of animal testis development and spermatogenesis; yet, the mechanisms by which miRNAs regulate spermatogenesis are poorly understood. miR-26a was identified as a miRNA that is differentially expressed among different pig testicular tissue developmental stages in our previous study. In this study, p21 activated kinase 2 (PAK2) gene was determined as one target gene of miR-26a by luciferase reporter assay, and miR-26a repressed the PAK2 mRNA abundance in porcine Sertoli cells. The Cell Counting Kit-8 (CCK8) assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay and annexin V-FITC/PI staining assay results showed that miR-26a overexpression inhibited proliferation and promoted apoptosis in porcine Sertoli cells. These phenomena were similar to the siRNA mediated knockdown of the PAK2 gene. Taken together, our results demonstrate that miR-26a inhibits proliferation and promotes apoptosis in porcine Sertoli cells by targeting the PAK2 gene, which may be a regulator of porcine spermatogenesis. PMID- 30024057 TI - Determining integrity of bladder innervation and smooth muscle function 1 year after lower spinal root transection in canines. AB - AIMS: To assess bladder smooth muscle function and innervation after long-term lower spinal root transection in canines. METHODS: Thirteen female mixed-breed hound dogs underwent bladder decentralization, which included transection of all sacral dorsal and ventral roots caudal to L7 and hypogastric nerves, bilaterally (n = 3); all sacral roots and hypogastric nerves plus transection of L7 dorsal roots, bilaterally (n = 4); or a sham operation (n = 6). At a year after initial surgery, bladder function was assessed in vivo by stimulation of the pelvic plexus. The bladder tissue was harvested for ex vivo smooth muscle contractility studies. Remaining bladder was evaluated for nerve morphology immunohistochemically using neuronal marker PGP9.5, apoptotic activity using terminal deoxynucleotidyl transferase dUTP nick end labeling, and histopathology using a hematoxylin and eosin stain. RESULTS: Sacral root decentralization did not reduce maximum strength of pelvic plexus stimulation-induced bladder contraction, although long-term sacral dorsal and ventral root plus L7 dorsal root transection significantly decreased contraction strength. Electric field stimulation-induced contractions of the detrusor from all decentralized animals were preserved, compared to controls. Viable nerves and intramural ganglia were visualized in the bladder wall, regardless of group. There was no difference in amount of apoptosis in bladder smooth muscle between groups. CONCLUSION: Bladder smooth muscle cells maintain their function after long-term bladder decentralization. While pelvic plexus-induced bladder contractions were less robust at 1 year after lower spinal root transection, the absence of atrophy and preservation of at least some nerve activity may allow for successful surgical reinnervation after long-term injury. PMID- 30024059 TI - Response to commentary on "The relationship of bilingualism to cognitive decline: The Australian Longitudinal Study of Ageing". PMID- 30024058 TI - Hyperpolarized 129 Xe gas transfer MRI: the transition from 1.5T to 3T. AB - PURPOSE: Hyperpolarized 129 Xe MRI depicting 3D ventilation, interstitial barrier uptake, and transfer to red blood cells (RBCs) has emerged as a powerful new means of detecting pulmonary disease. However, given the challenging susceptibility environment of the lung, such gas transfer imaging has, thus far, only been implemented at 1.5T. Here, we seek to demonstrate the feasibility of Dixon-based 129 Xe gas transfer MRI at 3T. METHODS: Seven healthy subjects and six patients with pulmonary disorders were recruited to characterize 129 Xe spectral structure, optimize acquisition parameters, and acquire representative images. Imaging used randomized, gradient-spoiled 3D-radial encoding of 1000 gas (0.5 degrees flip) and dissolved (20 degrees flip) views, reconstructed into 3 mm isotropic voxels. The center of k-space was sampled when barrier and RBC compartments were 90 degrees out of phase (TE90 ). A single dissolved phase spectrum was appended to the sequence to measure the global RBC-barrier ratio for Dixon-based decomposition. RESULTS: A 0.69 ms sinc was found to generate minimal off-resonance gas-phase excitation (3.0 +/- 0.3% of the dissolved-phase), yielding a TE90 = 0.47 +/- 0.02 ms. The RBC and barrier resonance frequencies were shifted by 217.6 +/- 0.6 ppm and 197.8 +/- 0.2 ppm. The RBC T2* was estimated to be ~1.1 ms, and therefore each read-out was limited to 1.3 ms. 129 Xe gas and dissolved-phase images have sufficient SNR to produce gas transfer maps of similar quality and sensitivity to pathology, as previously obtained at 1.5T. CONCLUSIONS: Despite short dissolved-phase T2*, 129 Xe gas transfer MRI is feasible at 3T. PMID- 30024060 TI - Activation of O-H and C-O Bonds in Water and Methanol by a Vanadium-Bound Thiyl Radical. AB - The reaction of [V(PS3")]- (1) (PS3"=[P(C6 H3 -3-Me3 Si-2-S)3 ]3- ) with H2 O led to the formation of [VIV (PS3")(PS2"SH )]- (2) (PS2"SH =[P(C6 H3 -3-Me3 Si-2-S)2 (C6 H3 -3-Me3 Si-2-SH)]2- ), indicating a hydrogen atom transfer from H2 O to a bound thiolate in 1. Furthermore, the reaction of 1 with CH3 OH gave the generation of complexes 2 and 3, [VIV (PS3")(PS2"SCH3 )]- (PS2"SCH3 =[P(C6 H3 -3 Me3 Si-2-S)2 (C6 H3 -3-Me3 Si-2-SCH3 )]2- ), implying that C-O and O-H bonds are cleaved by 1. Quantum mechanical calculations were performed to provide the mechanistic understanding for the reactivity of 1 with water. A key transition state with a lower kinetic barrier is identified. It involves an O-H bond cleavage by a dissociated thiyl radical with an interaction between an OH group and a neighboring bound sulfur donor. To our knowledge, the reactivity of 1 represents a new mode for water activation conducted through cooperation between a metal-stabilized thiyl radical and a neighboring thiolato donor. PMID- 30024061 TI - Precision and accuracy of cross-sectional area measurements used to measure coronary endothelial function with spiral MRI. AB - PURPOSE: Coronary endothelial function (CEF) reflects vascular health and conventional invasive CEF measures predict cardiovascular events. MRI can now noninvasively measure CEF by quantifying coronary artery cross-sectional area changes in response to isometric handgrip exercise, an endothelial-dependent stressor. Area changes (10 to 20% in healthy; 2 to -12% in impaired vessels) are only a few imaging voxels because of MRI's limited spatial resolution. Here, with numerical simulations and phantom studies, we test whether Fourier interpolation enables sub-pixel area measurement precision and determine the smallest detectable area change using spiral MRI. METHODS: In vivo coronary SNR with the currently used CEF protocol at 3T was measured in 7 subjects for subsequent in vitro work. Area measurements of circular vessels were simulated by varying partial volume, vessel diameter, voxel size, SNR, and Fourier interpolation factor. A phantom with precision-drilled holes (diameters 3-3.42 mm) was imaged 10 times with the current CEF protocol (voxel size, Deltax = 0.89 mm) and a high resolution protocol (Deltax = 0.6 mm) to determine precision, accuracy, and the smallest detectable area changes. RESULTS: In vivo coronary SNR ranged from 30 76. Eight-fold Fourier interpolation improved area measurement precision by a factor 6.5 and 4.9 in the simulations and phantom scans, respectively. The current CEF protocol can detect mean area changes of 4-5% for SNR above 30, and 3 3.5% for SNR above 40 with a higher-resolution protocol. CONCLUSION: Current CEF spiral MRI with in vivo SNR allows detection of a 4-5% area change and Fourier interpolation improves precision several-fold to sub-voxel dimensions. PMID- 30024062 TI - Scanning Nanowelding Lithography for Rewritable One-Step Patterning of Sub-50 nm High-Aspect-Ratio Metal Nanostructures. AB - The development of a new nanolithographic strategy, named scanning nanowelding lithography (SNWL), for the one-step fabrication of arbitrary high-aspect-ratio nanostructures of metal is reported in this study. Different from conventional pattern transfer and additive printing strategies which require subtraction or addition of materials, SNWL makes use of a sharp scanning tip to reshape metal thin films or existing nanostructures into desirable high-aspect-ratio patterns, through a cold-welding effect of metal at the nanoscale. As a consequence, SNWL can easily fabricate, in one step and at ambient conditions, sub-50 nm metal nanowalls with remarkable aspect ratio >5, which are found to be strong waveguide of light. More importantly, SNWL outweighs the existing strategies in terms of the unique ability to erase the as-made nanostructures and rewrite them into other shapes and orientations on-demand. Taking advantages of the serial and rewriting capabilities of SNWL, the smart information storage-erasure of Morse codes is demonstrated. SNWL is a promising method to construct arbitrary high aspect-ratio nanostructure arrays that are highly desirable for biological, medical, optical, electronic, and information applications. PMID- 30024063 TI - Association between obesity and pediatric psoriasis. AB - Obese children are at higher risk of developing psoriasis, and obesity severity is correlated with psoriasis severity. The relationship between obesity and pediatric psoriasis was explored in a well-defined population. Obesity and psoriasis coexist at diagnosis, but it is likely that obesity commonly precedes psoriasis in children. PMID- 30024064 TI - Strong Graphene 3D Assemblies with High Elastic Recovery and Hardness. AB - The rational design and construction of 3D graphene assemblies is a crucial step to extend the graphene properties for practical applications. Here, a novel interfacially reactive self-assembling process is reported to prepare well organized 3D honeycomb-like graphene assemblies with unique polygonal nanopores interconnected by silicon-oxygen chemical bonds. The newly developed silicate bridged graphene assembly (SGA) exhibits an exceptionally high hardness of 13.09 GPa, outperforming all existing 3D graphene materials, while maintains high Young's modulus (162.96 GPa), elastic recovery (75.27%), and superb thermal stability (600 degrees C in air). The observed unusual merits are resulted from unique pore structure combining the mechanical stability of the trihedral nanopore structure and the deformability of the other polygonal nanopores. As a filling material, a merely 0.05% (w/w) addition of SGA could double the impact resistance of unsaturated resins (e.g., polyester). While SGA is attractive for various applications, including body armors, wearable electronics, space elevators, and multifunctional reinforcement fibers for automobiles, and aerospace vehicles, the novel liquid sodium-water interfacial reactive self assembling developed in this study could open avenues for further development of various well-defined 3D assemblies from graphene and many other materials. PMID- 30024065 TI - Strong, Conductive, Foldable Graphene Sheets by Sequential Ionic and pi Bridging. AB - The goal of this work is to develop an inexpensive low-temperature process that provides polymer-free, high-strength, high-toughness, electrically conducting sheets of reduced graphene oxide (rGO). To develop this process, we have evaluated the mechanical and electrical properties resulting from the application of an ionic bonding agent (Cr3+ ), a pi-pi bonding agent comprising pyrene end groups, and their combinations for enhancing the performance of rGO sheets. When only one bonding agent was used, the pi-pi bonding agent is much more effective than the ionic bonding agent for improving both the mechanical and electrical properties of rGO sheets. However, the successive application of ionic bonding and pi-pi bonding agents maximizes tensile strength, toughness, long-term electrical stability in various corrosive solutions, and resistance to mechanical abuse and ultrasonic dissolution. Using a combination of ionic bonding and pi-pi bonding agents, high tensile strength (821 MPa), high toughness (20 MJ m-3 ), and electrical conductivity (416 S cm-1 ) were obtained, as well as remarkable retention of mechanical and electrical properties during ultrasonication and mechanical cycling by both sheet stretch and sheet folding, suggesting high potential for applications in aerospace and flexible electronics. PMID- 30024066 TI - Combined angiography and perfusion using radial imaging and arterial spin labeling. AB - PURPOSE: To demonstrate the feasibility of a novel noninvasive MRI technique for the comprehensive evaluation of blood flow to the brain: combined angiography and perfusion using radial imaging and arterial spin labeling (CAPRIA). METHODS: In the CAPRIA pulse sequence, blood labeled with a pseudocontinuous arterial spin labeling pulse train is continuously imaged as it flows through the arterial tree and into the brain tissue using a golden ratio radial readout. From a single raw data set, this flexible imaging approach allows the reconstruction of both high spatial/temporal resolution angiographic images with a high undersampling factor and low spatial/temporal resolution perfusion images with a low undersampling factor. The sparse and high SNR nature of angiographic images ensures that radial undersampling artifacts are relatively benign, even when using a simple regridding image reconstruction. Pulse sequence parameters were optimized through sampling efficiency calculations and the numerical evaluation of modified pseudocontinuous arterial spin labeling signal models. A comparison was made against conventional pseudocontinuous arterial spin labeling angiographic and perfusion acquisitions. RESULTS: 2D CAPRIA data in healthy volunteers demonstrated the feasibility of this approach, with good vessel visualization in the angiographic images and clear tissue perfusion signal when reconstructed at 108-ms and 252-ms temporal resolution, respectively. Images were qualitatively similar to those from conventional acquisitions, but CAPRIA had significantly higher SNR efficiency (48% improvement on average, P = 0.02). CONCLUSION: The CAPRIA technique shows potential for the efficient evaluation of both macrovascular blood flow and tissue perfusion within a single scan, with potential applications in a range of cerebrovascular diseases. PMID- 30024067 TI - Compression of cognitive morbidity by higher education in individuals aged 75+ living in Germany. AB - BACKGROUND: Previous studies have shown that higher education may reduce dementia risk and promote a better cognitive functioning in older age. OBJECTIVE: The study investigated to what extent higher education leads to compression of cognitive morbidity, and thus a shorter lifetime affected by cognitive impairment and dementia, in individuals aged 75 years and older living in Germany. METHODS: Our sample included n = 742 individuals of the population-based Leipzig Longitudinal Study of the Aged (LEILA75+; 1998-2013), who were free of dementia at baseline. The impact of higher education on compression of cognitive morbidity was studied by analyzing the association between education and (1) cognitive functioning over the study period and age at dementia onset, (2) age at death, and (3) the cumulative lifetime cognitive morbidity. RESULTS: Individuals with more years of education had a higher cumulative cognitive functioning over the lifetime period 75 to 100 years (weighted for survival probability), but not a later age of dementia onset nor a later age at death. CONCLUSION: Our results suggest, in individuals aged 75 years and older, higher education only compresses cognitive morbidity prior to dementia onset. Findings may be specific to countries where education is not a necessary requirement for access to good quality health care services. PMID- 30024068 TI - Fluorescent Sulphur- and Nitrogen-Containing Porous Polymers with Tuneable Donor Acceptor Domains for Light-Driven Hydrogen Evolution. AB - Light-driven water splitting is a potential source of abundant, clean energy, yet efficient charge-separation and size and position of the bandgap in heterogeneous photocatalysts are challenging to predict and design. Synthetic attempts to tune the bandgap of polymer photocatalysts classically rely on variations of the sizes of their pi-conjugated domains. However, only donor-acceptor dyads hold the key to prevent undesired electron-hole recombination within the catalyst via efficient charge separation. Building on our previous success in incorporating electron-donating, sulphur-containing linkers and electron-withdrawing, triazine (C3 N3 ) units into porous polymers, we report the synthesis of six visible-light active, triazine-based polymers with a high heteroatom-content of S and N that photocatalytically generate H2 from water: up to 915 MUmol h-1 g-1 with Pt co catalyst, and-as one of the highest to-date reported values -200 MUmol h-1 g-1 without. The highly modular Sonogashira-Hagihara cross-coupling reaction we employ, enables a systematic study of mixed (S, N, C) and (N, C)-only polymer systems. Our results highlight that photocatalytic water-splitting does not only require an ideal optical bandgap of ~2.2 eV, but that the choice of donor acceptor motifs profoundly impacts charge-transfer and catalytic activity. PMID- 30024069 TI - Does sacrocolpopexy present heterogeneity in its surgical technique? A systematic review. AB - AIMS: Sacrocolpopexy (SCP) is an extensively studied and highly efficacious treatment for female pelvic organ prolapse (POP). We aimed to analyze the technical steps for performance of a SCP among all RCTs in the literature that compared it with different procedures, or that studied different routes for performing SCP. METHODS: Systematic review searching electronic databases for RCTs only. We extracted data for 13 points of interest; main outcomes were procedure standardization; depth of vaginal dissection; number of sutures in the vaginal wall; type of suture in the vaginal wall; type of mesh fixation to the sacrum; and type and shape of mesh used. RESULTS: Twenty-two RCTs were included. Most of them did not provide a full standardized description of the procedure steps. There was great heterogeneity in almost all steps of the operation, including the choice of materials for attaching the mesh to the vagina and sacrum with both absorbable and non-absorbable sutures being used-and the extent of vaginal dissection for mesh fixation, with some studies dissecting only the apex, superficially, while others performed a full-length dissection. Choice of mesh material was more consensual, with polypropylene mesh being the most commonly used. CONCLUSIONS: SCP is a highly unstandardized procedure in the literature, albeit being used as a major comparator. Various RCTs compared alternative procedures with SCP, but the technical aspects have varied greatly, and studied outcomes could have been potentially influenced by these technical choices. PMID- 30024070 TI - Congenital fibroblastic connective tissue nevi: Unusual and misleading presentations in three infantile cases. AB - BACKGROUND: Fibroblastic connective tissue nevi (FCTN) are benign skin conditions characterized by bland spindle cells infiltrating the reticular dermis and the upper subcutis with preservation of adnexal structures. A subset of FCTN expresses CD34, which may cause difficulties in the differential diagnosis, in particular with dermatofibrosarcoma (DFSP). We aim to study clinical and histological main features of congenital FCTN to better understand their heterogeneity. METHODS: We present 3 cases of congenital FCTN with misleading pseudo-tumoral presentations and compare them with published cases in literature. We provide a diagnostic algorithm for congenital neonatal connective tissue tumors. RESULTS: Clinically, FCTN mostly present as well-limited and nontender plaques or nodules mainly located in the neck and face areas or in the trunk. Histologically, FCTN are composed of irregularly distributed fascicles of bland spindled cells and are defined by a list of fundamental features: (i) no atypia, pleomorphism, or mitotic activity; (ii) skin appendages entrapped but unaffected; (iii) no evidence for malignancy. In most cases CD34 is positive, but in some cases, cells can express SMA or are even CD34- and SMA-. CONCLUSION: The initial presentation and natural history of FCTN fit better with a neoplasm than with a hamartoma. Thus, we suggest replacing the term "nevus" with tumor and considering fibroblastic connective tissue tumor (FCTT) as the right denomination of this clinico-pathological entity. FCTTs are difficult to diagnose due to their clinical heterogeneity. Clinical and histological malignant and benign differential diagnoses are discussed. PMID- 30024071 TI - Contribution of herpesviruses in the progression of periodontal and peri-implant diseases in systemically healthy individuals. AB - The aim of this review was to assess the contribution of herpesviruses in the subgingival oral biofilm in the progression of periodontal and peri-implant diseases in systemically healthy individuals. The literature review was customized to summarize the pertinent information for the following reasons: (1) A systematic review regarding the role of herpesviruses in the etiopathogenesis of periodontal disease has recently been published; and (2) a limited number of studies have assessed the association of herpesviruses with peri-implant diseases. To date, five observational studies have assessed the presence of herpesviruses in the subgingival oral biofilm of individuals with peri-implant diseases. In these studies, dental implants were in place for up to approximately 8 years. In two studies, human cytomegalovirus (HCMV) was more often isolated from the peri-implant sulci of sites with than without peri-implantitis. In one study, a low prevalence of HCMV compared with Epstein-Barr virus (EBV) was associated with the progression of peri-implantitis. In previous studies, the presence of EBV in the subgingival oral biofilm was associated with the onset of peri-implantitis and peri-implant mucositis, respectively. Major limitations of the studies assessed were the absence of blinding and lack of power analysis for sample size estimation. In conclusion, the presence of herpesviruses in the periodontal and peri-implant subgingival oral biofilm is an indicator of periodontal and peri-implant diseases in systemically healthy individuals; however, further studies with a statistically justified sample-size are needed to understand and refine this association. PMID- 30024072 TI - Do we have to consider acidosis induced by exercise as deleterious in sickle cell disease? AB - NEW FINDINGS: What is the topic of this review? The aim of this review is to discuss the potential involvement of exercise-induced acidosis in the commonly reported complications in sickle cell disease. What advances does it highlight? Blood acidosis appears clearly to be a risk factor for HbS polymerization, red blood cell sickling and the occurrence of vaso-occlusive crisis and could induce hyperkalaemia-related complications. It could be of great interest to try to avoid blood acidosis during exercise, which could be done using some alkalinizing solutions or adapted endurance training interventions. ABSTRACT: Sickle cell disease (SCD) is an inherited haemoglobin (Hb) disorder and the most common monogenic disease in the world. The root cause of this pathology is the synthesis of an abnormal Hb (HbS) that polymerizes in deoxygenated conditions, leading to the sickling of red blood cells. Acidosis is well recognized as a promoter of HbS polymerization and therefore red blood cell sickling. Indeed, it has been shown in vitro that the relative amount of sickled red blood cells increases markedly from 1% at pH 7.4 to >90% at pH 7.0. Nevertheless, no study has directly tested whether exercise-induced acidosis could favour SCD complications. Greater knowledge of the effects of metabolic acidosis during exercise could be of importance given the conclusions reached in several studies that proposed regular physical exercise as a therapeutic strategy in the management of SCD. In this review, we discuss the potential consequences of exercise-induced acidosis for the pathophysiology of SCD. We also propose some potential therapeutic interventions with the aim of reducing the metabolic acidosis related to exercise. PMID- 30024075 TI - On the origin of lognormal network synchrony in CA1. AB - The sharp wave ripple complex in rodent hippocampus is associated with a network burst in CA3 (NB) that triggers a synchronous event in the CA1 population (SE). The number of CA1 pyramidal cells participating in a SE has been observed to follow a lognormal distribution. However, the origin of this skewed and heavy tailed distribution of population synchrony in CA1 remains unknown. Because the size of SEs is likely to originate from the size of the NBs and the underlying neural circuitry, we model the CA3-CA1 circuit to study the underlying mechanisms and their functional implications. We show analytically that if the size of a NB in CA3 is distributed according to a normal distribution, then the size of the resulting SE in CA1 follows a lognormal distribution. Our model predicts the distribution of the NB size in CA3, which remains to be tested experimentally. Moreover, we show that a putative lognormal NB size distribution leads to an extremely heavy-tailed SE size distribution in CA1, contradicting experimental evidence. In conclusion, our model provides general insight on the origin of lognormally distributed network synchrony as a consequence of synchronous synaptic transmission of normally distributed input events. PMID- 30024073 TI - Developmental progress of CRISPR/Cas9 and its therapeutic applications for HIV-1 infection. AB - The CRISPR/Cas9 system has been developed as a powerful tool for targeted gene editing. As a result of technical enhancements in recent years, this technology has become the method of choice for efficiently modifying targeted HIV-1 genome efficiently as part of HIV therapy. CRISPR can be modified to target specific sequences that Cas9 then cuts. In this article, we outline the development of the CRISPR/Cas9 system. We also show how this technology can be used for the prevention and treatment of HIV-1 infection. Optimistically, this technology promises to make a significant impact on the fight against HIV-1 in the future. PMID- 30024074 TI - Gastroprotective and anti-ulcer effects of oxymatrine against several gastric ulcer models in rats: Possible roles of antioxidant, antiinflammatory, and prosurvival mechanisms. AB - Oxymatrine (OXY) has antioxidative and antiinflammatory activities. In the present work, we investigate the effects of OXY on gastric ulcer models and elucidate the underlying mechanisms of action. Ethanol, indometacin, and restraint water immersion stress-induced ulcerated models were used. The ulcer area was measured, and samples of gastric tissue were taken for pathological, histochemical, and biochemical analyses. OXY effectively reduced the area of gastric ulcers and improved the pathological changes of ulcerated tissue. OXY enhanced expression of Bcl-2, reduced Bax protein expression, and inhibited alcohol-induced apoptotic death in both ulcerated tissue and human gastric epithelial cells. OXY increased the prostaglandin E2 level and improved oxidative stress (malondialdehyde, superoxide dismutase, catalase, and nitric oxide) and inflammatory parameters (TNF-a, IL-6, and IL-1) of ulcer tissue. OXY prevented an inflammatory response via decreasing expression of p38, p-ERK, p-JNK, and inhibiting NF-kappaB p65 translocation from the cytoplasm to the nucleus. Our results reveal that OXY has remarkable protective effects on gastric ulcers. The action of OXY may be mediated via suppression of gastric inflammatory reactions, oxidative stress, and pro-apoptotic actions, which were the results of blockades of MAPKs and NF-kappaB signaling pathways. Our results provide evidence for the beneficial effects of OXY for treating peptic ulcers. PMID- 30024077 TI - Repurposing metformin to prevent and treat tuberculosis. PMID- 30024076 TI - Comparison of three measurement models of discounting among individuals with methamphetamine use disorder. AB - BACKGROUND AND OBJECTIVES: Delay discounting is associated with numerous clinically significant aspects of substance use disorders (SUDs). Recent studies have demonstrated that different models for assessing discounting may result in disparate conclusions. The current study compared two discounting tasks: money now versus money later (M-M) and methamphetamine now versus money later (MA-M) among non-treatment seeking individuals (N = 59) with methamphetamine use disorder (MAUD). Results from each task were assessed using three different models for assessing delay discounting. METHODS: Discounting data were fit to three models of discounting, log k using Mazur's hyperbolic formula, area under the curve (AUC), and an alternative AUC model in which the delay values have been log transformed (AUClog). RESULTS: For both discounting tasks, the distribution of model-related outcomes were normally distributed when using log k and AUClog, but skewed for AUC. Discounting in the MA-M task was significantly greater compared to the M-M task when using log k and AUClog but not AUC. CONCLUSION: To our knowledge, the current study is the first to report significantly greater discounting in a MA-M relative to M-M discounting task among individuals with MAUD, an outcome consistent with other psychomotor stimulants and drugs of abuse. SCIENTIFIC SIGNIFICANCE: The differential results observed across the three discounting models reaffirm potential issues with AUC noted in recent studies and highlight that researchers must be cautious when deciding on their final model of discounting. (Am J Addict 2018;XX:1-8). PMID- 30024078 TI - A Feasibility Study of Percutaneous Peripheral Nerve Stimulation for the Treatment of Postoperative Pain Following Total Knee Arthroplasty. AB - INTRODUCTION: The objective of the present feasibility study was to investigate the use of a new treatment modality-percutaneous peripheral nerve stimulation (PNS)-in controlling the often severe and long-lasting pain following total knee arthroplasty (TKA). METHODS: For patients undergoing a primary, unilateral TKA, both femoral and sciatic open-coil percutaneous leads (SPR Therapeutics, Cleveland, OH) were placed up to seven days prior to surgery using ultrasound guidance. The leads were connected to external stimulators and used both at home and in the hospital for up to six weeks total. RESULTS: In six of seven subjects (86%), the average of daily pain scores across the first two weeks was <4 on the 0-10 Numeric Rating Scale for pain. A majority of subjects (four out of seven; 57%) had ceased opioid use within the first week (median time to opioid cessation for all subjects was six days). Gross sensory/motor function was maintained during stimulation, enabling stimulation during physical therapy and activities of daily living. At 12 weeks following surgery, six of seven subjects had improved by >10% on the Six-Minute Walk Test compared to preoperative levels, and WOMAC scores improved by an average of 85% compared to before surgery. No falls, motor block, or lead infections were reported. CONCLUSIONS: This feasibility study suggests that for TKA, ultrasound-guided percutaneous PNS is feasible in the immediate perioperative period and may provide analgesia without the undesirable systemic effects of opioids or quadriceps weakness induced by local anesthetics-based peripheral nerve blocks. PMID- 30024079 TI - Arylfluorosulfate-Based Electrophiles for Covalent Protein Labeling: A New Addition to the Arsenal. AB - Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off-target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context-specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery. PMID- 30024081 TI - Extreme hypercalcaemia due to accidental vitamin D intoxication. PMID- 30024082 TI - Clinical practice guidelines for surgical antimicrobial prophylaxis: Qualitative appraisals and synthesis of recommendations. AB - RATIONALE, GOALS, AND OBJECTIVES: Clinical practice guidelines (CPGs) for preoperative care have been developed for surgical antimicrobial prophylaxis (SAP). The objective of this study was to synthetize recommendations for SAP based on best-evaluated CPGs. METHODS: A systematic literature search for documents related to SAP, published between January 2011 and December 2016, was conducted on MEDLINE (PubMed), EMBASE, and specific CPG websites. Three reviewers independently assessed the rigour of development and editorial independence of CPGs based on domains 3 and 6 of the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument. CPGs with domain 3 scores of 50% and greater were selected for synthesis of recommendations. Two reviewers independently extracted CPG recommendations from among these documents. A third reviewer performed the synthesis of recommendations. RESULTS: The search retrieved 363 documents, of which 29 CPGs were appraised using AGREE II. Only eight (28%) scored 50% and greater in domain 3. Most CPGs addressed topics related to preoperative care, including SAP. No conflicting recommendations were found, and most recommendations were based on clinical practice. The only recommendation for which there was a difference among CPGs was with respect to the time to initiate the administration of antibiotics (1 hour before or close to the time of the surgical incision). Four CPGs provide recommendations that demonstrate concern about inadequate SAP prolongation. CONCLUSION: Several CPGs for SAP were developed without the desired methodological rigour or transparency. Synthesis of recommendations for best-evaluated CPGs provides a broad approach owing to the complementarity of the recommendations. PMID- 30024080 TI - Curcumin analog, GO-Y078, overcomes resistance to tumor angiogenesis inhibitors. AB - Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75 MUmol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078. PMID- 30024083 TI - Increasing diversity within the Global Lung Function Initiative. PMID- 30024085 TI - Combining Electrodeposition and Optical Microscopy for Probing Size-Dependent Single-Nanoparticle Electrochemistry. AB - Electrodeposition of nanoparticles (NPs) is a promising route for the preparation of highly electroactive nanostructured electrodes. By taking advantage of progressive electrodeposition, disordered arrays with a wide size distribution of Ag NPs are produced. Combined with surface-reaction monitoring by using highly sensitive backside absorbing-layer optical microscopy (BALM), such arrays offer a platform for screening size-dependent electrochemistry at the single NP level. In particular, this strategy allows rationalizing the electrodeposition dynamics at the single-NP level (>10 nm), up to the point of quantifying the presence of metal nanoclusters (<2 nm), and probing easier NP oxidation with size decrease, either through electrochemical or galvanic reactions. PMID- 30024086 TI - Letter from India. PMID- 30024084 TI - Fluency in symbolic arithmetic refines the approximate number system in parietal cortex. AB - The objective of this study was to investigate, using a brain measure of approximate number system (ANS) acuity, whether the precision of the ANS is crucial for the development of symbolic numerical abilities (i.e., scaffolding hypothesis) and/or whether the experience with symbolic number processing refines the ANS (i.e., refinement hypothesis). To this aim, 38 children solved a dot comparison task inside the scanner when they were approximately 10-years old (Time 1) and once again approximately 2 years later (Time 2). To study the scaffolding hypothesis, a regression analysis was carried out by entering ANS acuity at T1 as the predictor and symbolic math performance at T2 as the dependent measure. Symbolic math performance, visuospatial WM and full IQ (all at T1) were entered as covariates of no interest. In order to study the refinement hypothesis, the regression analysis included symbolic math performance at T1 as the predictor and ANS acuity at T2 as the dependent measure, while ANS acuity, visuospatial WM and full IQ (all at T1) were entered as covariates of no interest. Our results supported the refinement hypothesis, by finding that the higher the initial level of symbolic math performance, the greater the intraparietal sulcus activation was at T2 (i.e., more precise representation of quantity). To the best of our knowledge, our finding constitutes the first evidence showing that expertise in the manipulation of symbols, which is a cultural invention, has the power to refine the neural representation of quantity in the evolutionarily ancient, approximate system of quantity representation. PMID- 30024087 TI - Parental perception of child vulnerability in childhood cancer survivors. AB - BACKGROUND: Parents' perception of their children's vulnerability to illness following cancer treatment is largely unknown, but is important to understand given known challenges of transitioning survivors to postcancer care. We investigated the frequency of and factors associated with perceived vulnerability by parents of childhood cancer survivors attending a regional survivorship clinic. PROCEDURE: This cohort study was offered to all parents of pediatric patients (currently <=18 years) attending the Yale childhood cancer survivorship clinic January 2010 to October 2016 who were >=1 year postcurative cancer therapy. Participating parents (one per patient) completed the standardized Child Vulnerability Scale at the beginning of the clinic visit (cutoff score >=10 for perceived vulnerability). Patient sociodemographics, cancer history, and posttherapy complications were abstracted from medical records. RESULTS: Overall, 116 parents participated (98% participation rate) consisting of 89% mothers; survivors were 46% female, had a current mean age of 12.7 +/- 3.9 years, and were a mean of 6.4 +/- 3.8 years posttherapy. Twenty-eight percent (n = 33) of parents perceived their children as vulnerable. Survivor sociodemographics (age, sex, race/ethnicity, family income, insurance, parental marital status, number of siblings), cancer diagnosis, years off-therapy, survivorship visit number, treatment intensity, and late complications (number, type, severity) were not associated with perception of vulnerability. CONCLUSIONS: A sizeable proportion of parents continue to perceive their children as vulnerable even years after cancer therapy completion independent of current health status or past cancer history. Our data suggest the need to educate all parents of childhood cancer survivors regarding health risk, including those at lower risk for late complications. PMID- 30024088 TI - Structural alerts for the identification of bioaccumulative compounds. AB - Legislators have included bioaccumulation in the evaluation of chemicals in the framework of the European Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. REACH requires information on the bioconcentration factor (BCF), which is a parameter for assessing bioaccumulation and encourages the use of a weight-of-evidence approach, including predictions from quantitative structure-activity relationships (QSARs). This study presents a novel approach, based on structural alerts, to be used as a decision-support system for the identification of substances with bioaccumulation potential. In a regulatory framework, these alerts can be integrated with other sources of information, such as experimental and in silico data, to reduce the uncertainty of the assessment, thereby supporting a weight-of-evidence approach. Moreover, the identified alerts have a direct connection with relevant structural features, thus fostering the applicability and interpretability of the approach. The structural alerts were identified on 779 chemicals annotated for their fish BCF, and the approach was then validated on 278 external molecules. The developed decision-support system allowed identification of 77% of bioaccumulative chemicals and was competitive with more complex QSAR models used in regulatory assessments. The approach is implemented in an easy-to-use workflow, provided free of charge. Integr Environ Assess Manag 2018;00:000-000. (c) 2018 SETAC. PMID- 30024090 TI - Unresectable VIP-secreting neuroblastoma: Efficacy of debulking and steroids for symptom control. PMID- 30024089 TI - Gene transcription in bursting: a unified mode for realizing accuracy and stochasticity. AB - There is accumulating evidence that, from bacteria to mammalian cells, messenger RNAs (mRNAs) are produced in intermittent bursts - a much 'noisier' process than traditionally thought. Based on quantitative measurements at individual promoters, diverse phenomenological models have been proposed for transcriptional bursting. Nevertheless, the underlying molecular mechanisms and significance for cellular signalling remain elusive. Here, we review recent progress, address the above issues and illuminate our viewpoints with simulation results. Despite being widely used in modelling and in interpreting experimental data, the traditional two-state model is far from adequate to describe or infer the molecular basis and stochastic principles of transcription. In bacteria, DNA supercoiling contributes to the bursting of those genes that express at high levels and are topologically constrained in short loops; moreover, low-affinity cis-regulatory elements and unstable protein complexes can play a key role in transcriptional regulation. Integrating data on the architecture, kinetics, and transcriptional input-output function is a promising approach to uncovering the underlying dynamic mechanism. For eukaryotes, distinct bursting features described by the multi-scale and continuum models coincide with those predicted by four theoretically derived principles that govern how the transcription apparatus operates dynamically. This consistency suggests a unified framework for comprehending bursting dynamics at the level of the structural and kinetic basis of transcription. Moreover, the existing models can be unified by a generic model. Remarkably, transcriptional bursting enables regulatory information to be transmitted in a digital manner, with the burst frequency representing the strength of regulatory signals. Such a mode guarantees high fidelity for precise transcriptional regulation and also provides sufficient randomness for realizing cellular heterogeneity. PMID- 30024091 TI - Macroinvertebrate sensitivity thresholds for sediment in Virginia streams. AB - Sediment is the most commonly identified pollutant associated with macroinvertebrate community impairments in freshwater streams nationwide. Management of this physical stressor is complicated by the multiple measures of sediment available (e.g., suspended, dissolved, bedded) and the variability in natural "healthy" sediment loadings across ecoregions. Here we examine the relative importance of 9 sediment parameters on macroinvertebrate community health as measured by the Virginia Stream Condition Index (VSCI) across 5 ecoregions. In combination, sediment parameters explained 27.4% of variance in the VSCI in a multiregion data set and from 20.2% to 76.4% of variance for individual ecoregions. Bedded sediment parameters had a stronger influence on VSCI than did dissolved or suspended parameters in the multiregion assessment. However, assessments of individual ecoregions revealed conductivity had a key influence on VSCI in the Central Appalachian, Northern Piedmont and Piedmont ecoregions. In no case was a single sediment parameter sufficient to predict VSCI scores or individual biological metrics. Given the identification of embeddedness and conductivity as key parameters for predicting biological condition, we developed family-level sensitivity thresholds for these parameters, based on extirpation. Resulting thresholds for embeddedness were 68% for combined ecoregions, 65% for the Mountain bioregion (composed of Central Appalachian, Ridge and Valley, and Blue Ridge ecoregions), and 88% for the Piedmont bioregion (composed of Northern Piedmont and Piedmont ecoregions). Thresholds for conductivity were 366 MUS/cm for combined ecoregions, 391 MUS/cm for the Mountain bioregion, and 136 MUS/cm for the Piedmont bioregion. These thresholds may help water quality professionals identify impaired and at-risk waters designated to support aquatic life and develop regional strategies to manage sediment-impaired streams. Inclusion of embeddedness as a restoration endpoint may be warranted; this could be facilitated by application of more quantitative, less time intensive measurement approaches. We encourage refinement of thresholds as additional data and genus-based metrics become available. Integr Environ Assess Manag 2018;00:000-000. Published 2018. This article has been contributed to by US Government employees and their work is in the public domain in the USA. PMID- 30024092 TI - MircoRNA-1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1. AB - This study was designed to explore the relationship between miR-1275 and SERPINE1 and its effects on glioma cell proliferation, migration, invasion and apoptosis. Differentially expressed miRNAs and mRNAs in glioma tissues were screened out by bioinformatic analysis. Dual-luciferase reporter gene assay was used to validate the targeted relationship between miR-1275 and SERPINE1. qRT-PCR was used to detect the expression of miR-1275 and SERPINE1 in glioma tissues. The expressions of SERPINE1 and p53 pathway-related proteins in glioma cells were detected by western blot. Glioma cell proliferation, apoptosis, migration and invasion were respectively detected by CCK-8 assay, flow cytometry, wound healing assay and transwell assay. Tumour xenograft model was developed to study the influence of miR-1275 and SERPINE1 on glioma growth in vivo. The results of microarray analysis, qRT-PCR and western blot showed that miR-1275 was low-expressed while SERPINE1 was high-expressed in glioma. Dual-luciferase assay showed that miR-1275 could bind to SERPINE1. Overexpression of miR-1275 could promote the p53 pathway related proteins' expression. Highly expressed miR-1275 could repress the migration, proliferation and invasion of glioma cells while highly expressed SERPINE1 had inverse effects. Tumour xenograft showed that up-regulated miR-1275 or down-regulated SERPINE1 could repress glioma growth in vivo. Up-regulation of miR-1275 activated p53 signalling pathway via regulating SERPINE1 and therefore suppressed glioma cell proliferation, invasion and migration, whereas promoted cell apoptosis. PMID- 30024094 TI - Larger pore size hollow fiber membranes as a solution to the product retention issue in filtration-based perfusion bioreactors. AB - Tangential flow filtration (TFF) and alternating tangential flow (ATF) filtration technologies using hollow fiber membranes are commonly utilized in perfusion cell culture for the production of monoclonal antibodies; however, product retention remains a known and common problem with these systems. To address this issue, commercially available hollow fibers ranging from several hundred kilo-Daltons (kDa) to 0.65 MUm in nominal pore size were tested and were all demonstrated to undergo moderate to severe product retention. Further investigation revealed accumulation of particles in the same size range (approximately 20-200 nm) as the pores. Based on the assumption that these particles contribute to product retention and membrane plugging, a hollow fiber with an unconventionally larger pore size was subsequently identified and demonstrated to drastically reduce product retention with no impact to cell clarification, Furthermore, these hollow fibers demonstrated surprisingly high membrane capacities, making them an attractive solution to the problem of product retention in perfusion reactors. PMID- 30024093 TI - Photobiomodulation and different macrophages phenotypes during muscle tissue repair. AB - Macrophages play a very important role in the conduction of several regenerative processes mainly due to their plasticity and multiple functions. In the muscle repair process, while M1 macrophages regulate the inflammatory and proliferative phases, M2 (anti-inflammatory) macrophages direct the differentiation and remodelling phases, leading to tissue regeneration. The aim of this study was to evaluate the effect of red and near infrared (NIR) photobiomodulation (PBM) on macrophage phenotypes and correlate these findings with the repair process following acute muscle injury. Wistar rats were divided into 4 groups: control; muscle injury; muscle injury + red PBM; and muscle injury + NIR PBM. After 2, 4 and 7 days, the tibialis anterior muscle was processed for analysis. Macrophages phenotypic profile was evaluated by immunohistochemistry and correlated with the different stages of the skeletal muscle repair by the qualitative and quantitative morphological analysis as well as by the evaluation of IL-6, TNF alpha and TGF-beta mRNA expression. Photobiomodulation at both wavelengths was able to decrease the number of CD68+ (M1) macrophages 2 days after muscle injury and increase the number of CD163+ (M2) macrophages 7 days after injury. However, only NIR treatment was able to increase the number of CD206+ M2 macrophages (Day 2) and TGF-beta mRNA expression (Day 2, 4 and 7), favouring the repair process more expressivelly. Treatment with PBM was able to modulate the inflammation phase, optimize the transition from the inflammatory to the regeneration phase (mainly with NIR light) and improve the final step of regeneration, enhancing tissue repair. PMID- 30024095 TI - Self-Assembled Supramolecular Nanoparticles for Targeted Delivery and Combination Chemotherapy. AB - It is challenging but imperative to merge imaging agents and small molecule therapeutics into one nanoentity for diagnosis and treatment. Herein, we constructed polymeric nanoparticles for targeted delivery and combination chemotherapy, which formed through host-guest interactions among three elements: 1) beta-cyclodextrin polymer (poly-beta-CD), as the backbone of nanoparticles; 2) two antitumor drugs-doxorubicin (DOX) and docetaxel (DTX); and 3) aptamers labeled with adamantane and fluorescein (Ad-aptamer-FAM), as recognition elements. First, polymeric nanoparticles, termed self-assembled supramolecular nanoparticles (SSNPs), were formulated by combining hydrophobic DTX and DOX with poly-beta-CD via host-guest interactions. Then, the surface of SSNPs modified the aptamer to acquire targeting ability; such nanoparticles were termed targeted self-assembled supramolecular nanoparticles (T-SSNPs). As evidenced by MTS assay data, T-SSNPs exhibited significant selective cytotoxicity toward target cells. The results also indicated that combination drugs achieved a good synergistic effect with a combination index of 0.43. Thus, an effective and simple drug delivery system was constructed for targeted delivery and combination chemotherapy. PMID- 30024096 TI - Recommendations for Comparison of Productivity Between Fed-Batch and Perfusion Processes. AB - Due to the growing interest in integrated continuous processing in the biopharmaceutical industry, productivity comparison of batch-based and continuous processes is considered a challenge. Integrated continuous manufacturing of biopharmaceuticals requires scientists and engineers to collaborate effectively. Differing definitions, for example, of volumetric productivity, may cause confusion in this interdisciplinary field. Therefore, the aim of this communication is to reiterate the standard definitions and their underlying assumptions. Applying them to an exemplary model scenario allows to demonstrate the differences and to develop recommendations for the comparison of productivity of different upstream processes. PMID- 30024098 TI - Modulated Triple-Material Nano-Heterostructures: Where Gold Influenced the Chemical Activity of Silver in Nanocrystals. AB - For efficient charge separations, multimaterial hetero-nanostructures are being extensively studied as photocatalysts. While materials with one heterojunction are widely established, the chemistry of formation of multijunction heterostructures is not explored. This needs a more sophisticated approach and modulations. To achieve these, a generic multistep seed mediated growth following controlled ion diffusion and ion exchange is reported which successfully leads to triple-material hetero-nanostructures with bimetallic-binary alloy-binary/ternary semiconductors arrangements. Ag2 S nanocrystals are used as primary seeds for obtaining AuAg-AuAgS bimetallic-binary alloyed metal-semiconductor heterostructures via partial reduction of Ag(I) using Au(III) ions. These are again explored as secondary seeds for obtaining a series of triple-materials heterostructures, AuAg-AuAgS-CdS (or ZnS or AgInS2 ), with introduction of different divalent and trivalent ions. Chemistry of each step of the gold ion induced changes in the rate of diffusion and/or ion exchanges are investigated and the formation mechanism for these nearly monodisperse triple material heterostructures are proposed. Reactions without gold are also performed, and the change in the reaction chemistry and growth mechanism in presence of Au is also discussed. PMID- 30024097 TI - BMSCs and miR-124a ameliorated diabetic nephropathy via inhibiting notch signalling pathway. AB - BMSCs are important in replacement therapy of diabetic nephropathy (DN). MiR-124a exerts effect on the differentiation capability of pancreatic progenitor cells. The objective of this study was to explore the molecular mechanisms, the functions of miR-124a and bone marrow mesenchymal stem cells (BMSCs) in the treatment of DN. Characterizations of BMSCs were identified using the inverted microscope and flow cytometer. The differentiations of BMSCs were analysed by immunofluorescence assay and DTZ staining. The expression levels of islet cell specific transcription factors, apoptosis-related genes, podocytes-related genes and Notch signalling components were detected using quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot assays. The production of insulin secretion was detected by adopting radioimmunoassay. Cell proliferation and apoptosis abilities were detected by CCK-8, flow cytometry and TUNEL assays. We found that BMSCs was induced into islet-like cells and that miR-124a could promote the BMSCs to differentiate into islet-like cells. BMSCs in combination with miR-124a regulated islet cell-specific transcription factors, apoptosis related genes, podocytes-related genes as well as the activity of Notch signalling pathway. However, BMSCs in combination with miR-124a relieved renal lesion caused by DN and decreased podocyte apoptosis caused by HG. The protective effect of BMSCs in combination with miR-124a was closely related to the inactivation of Notch signalling pathway. MSCs in combination with miR-124a protected kidney tissue from impairment and inhibited nephrocyte apoptosis in DN. PMID- 30024099 TI - Does L-Carnitine Supplementation Improve Sleep Quality in Children with Autism? PMID- 30024100 TI - Staged treatment and acceptability guidelines in early psychosis study (STAGES): A randomized placebo controlled trial of intensive psychosocial treatment plus or minus antipsychotic medication for first-episode psychosis with low-risk of self harm or aggression. Study protocol and baseline characteristics of participants. AB - AIM: It is now necessary to investigate whether recovery in psychosis is possible without the use of antipsychotic medication. This study will determine (1) whether a first-episode psychosis (FEP) group receiving intensive psychosocial interventions alone can achieve symptomatic remission and functional recovery; (2) whether prolonging the duration of untreated psychosis (DUP) in a sub-group according to randomisation will be associated with a poorer outcome and thereby establish whether the relationship between DUP and outcome is causative; and (3) whether neurobiological changes observed in FEP are associated with the psychotic disorder or antipsychotic medication. Baseline characteristics of participants will be presented. METHODS: This study is a triple-blind randomized placebo controlled non-inferiority trial. The primary outcome is the level of functioning measured by the Social and Occupational Functioning Assessment Scale at 6 months. This study is being conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne and includes young people aged 15 to 24 years with a DSM-IV psychotic disorder, a DUP less than 6 months and not high risk for suicide or harm to others. Strict discontinuation criteria are being applied. Participants are also undergoing three 3-Tesla-MRI scans. RESULTS: Ninety participants have been recruited and baseline characteristics are presented. CONCLUSIONS: Staged treatment and acceptability guidelines in early psychosis will determine whether antipsychotic medications are indicated in all young people with a FEP and whether antipsychotic medication can be safely delayed. Furthermore, the relative contribution of psychotic illness and antipsychotic medication in terms of structural brain changes will also be elucidated. The findings will inform clinical practice guidelines. PMID- 30024101 TI - Single Copy Transgene Integration in a Transcriptionally Active Site for Recombinant Protein Synthesis. AB - For the biomanufacturing of protein biologics, establishing stable cell lines with high transgene transcription is critical for high productivity. Modern genome engineering tools can direct transgene insertion to a specified genomic locus and can potentially become a valuable tool for cell line generation. In this study, the authors survey transgene integration sites and their transcriptional activity to identify characteristics of desirable regions. A lentivirus containing destabilized Green Fluorescent Protein (dGFP) is used to infect Chinese hamster ovary cells at a low multiplicity of infection, and cells with high or low GFP fluorescence are isolated. RNA sequencing and Assay for Transposase Accessible Chromatin using sequencing data shows integration sites with high GFP expression are in larger regions of high transcriptional activity and accessibility, but not necessarily within highly transcribed genes. This method is used to obtain high Immunoglobulin G (IgG) expressing cell lines with a single copy of the transgene integrated into transcriptionally active and accessible genomic regions. Dual recombinase-mediated cassette exchange is then employed to swap the IgG transgene for erythropoietin or tumor necrosis factor receptor-Fc. This work thus highlights a strategy to identify desirable sites for transgene integration and to streamline the development of new product producing cell lines. PMID- 30024102 TI - Transcatheter valve-in-valve versus redo surgical aortic valve replacement for the treatment of degenerated bioprosthetic aortic valve: A systematic review and meta-analysis. AB - OBJECTIVE: To determine the safety and efficacy of valve-in-valve transcatheter aortic valve replacement (ViV) versus redo surgical aortic valve replacement (SAVR) for the treatment of previously failed aortic bioprostheses. BACKGROUND: Valve-in-valve has emerged as a treatment option for patients with a failed aortic bioprosthesis. Evidence for safety and efficacy remains limited to small studies. METHODS: Medline and Embase were searched to 2017 for studies that directly compared ViV to redo SAVR. A random effects meta-analysis was performed. RESULTS: Four unadjusted (n = 298) and two propensity-matched (n = 200) observational studies were included. Valve-in-valve patients were 2.85-years older (P = 0.03) and were 23% higher in predicted mortality risk (ratio of means: 1.23, 95% confidence interval (95%CI): 1.02-1.48). There was no difference in peri-operative mortality (4.4% vs. 5.7%, P = 0.83;I2 = 0%) or late mortality, reported at median one year follow-up (incident rate ratio (IRR) 0.93, 95%CI: 0.74-1.16, P = 0.51, I2 = 0%) between ViV and redo SAVR. The incidence of permanent pacemaker implantation (8.3% vs 14.6%; P = 0.05;I2 = 0%) and dialysis (3.2% vs. 10.3%; P = 0.03; I2 = 0%) were lower in ViV. There was a reduction in the incidence of severe patient-prosthesis mismatch (3.3% vs 13.5%; P = 0.03; I2 = 0%) and mild or greater paravalvular leak (5.5% vs 21.1%; P = 0.03; I2 = 37%) in the redo SAVR group compared to ViV. CONCLUSIONS: Despite higher predicted surgical risk of ViV patients, there was no difference in mortality but less permanent pacemaker implantation and dialysis compared to redo SAVR. Choice of treatment must be individualized for both anatomical and patient risk factors; in high risk patients with favorable previous prosthesis size, valve-in-valve may be preferred. PMID- 30024103 TI - Combined Ligand- and Receptor-Based Virtual Screening Methodology to Identify Structurally Diverse Protein Tyrosine Phosphatase 1B Inhibitors. AB - Protein tyrosine phosphatase 1B (PTP1B) is a potential drug target for diabetes and obesity. However, the design of PTP1B inhibitors that combine potency and bioavailability is a great challenge, and new leads are needed to circumvent this problem. Virtual screening (VS) workflows can be used to find new PTP1B inhibitors with little chemical similarity to existing inhibitors. Unfortunately, previous VS workflows for the identification of PTP1B inhibitors have several limitations, such as a small number of experimentally tested compounds and the low bioactivity of those compounds. We developed a VS workflow capable of identifying 15 structurally diverse PTP1B inhibitors from 20 compounds, the bioactivity of which was tested in vitro. Moreover, we identified two PTP1B inhibitors with the highest bioactivity reported by any VS campaign (i.e., IC50 values of 1.4 and 2.1 MUm), which could be used as new lead compounds. PMID- 30024104 TI - Response to 'Does l-Carnitine Supplementation Improve Sleep Quality in Children with Autism?' PMID- 30024107 TI - Endotoxin-Free E. coli-Based Cell-Free Protein Synthesis: Pre-Expression Endotoxin Removal Approaches for on-Demand Cancer Therapeutic Production. AB - Approximately one third of protein therapeutics are produced in Escherichia coli, targeting a wide variety of diseases. However, due to immune recognition of endotoxin (a lipid component in the E. coli cell membrane), these protein products must be extensively purified before application to avoid adverse reactions such as septic shock. E. coli-based cell-free protein synthesis (CFPS), which has emerged as a promising platform for the development and production of enhanced protein therapeutics, provides a unique opportunity to remove endotoxins prior to protein expression due to its open environment and the absence of live cells. Pre-expression endotoxin removal from CFPS reagents could simplify downstream processing, potentially enabling on-demand production of unique protein therapeutics. Herein, three strategies for removing endotoxins from E. coli cell lysate are evaluated: Triton X-114 two-phase extraction, polylysine affinity chromatography, and extract preparation from genetically engineered, endotoxin-free ClearColi cells. It is demonstrated that current protocols for endotoxin removal treatments insufficiently reduce endotoxin and significantly reduce protein synthesis yields. Further, the first adaptation of ClearColi cells to prepare cell-free extract with high protein synthesis capability is demonstrated. Finally, production of the acute lymphoblastic leukemia therapeutic crisantaspase from reduced-endotoxin extract and endotoxin-free ClearColi extract is demonstrated. PMID- 30024106 TI - Transcriptome Analysis of CHO Cell Size Increase During a Fed-Batch Process. AB - In a Chinese Hamster Ovary (CHO) cell fed-batch process, arrest of cell proliferation and an almost threefold increase in cell size occurred, which is associated with an increase in cell-specific productivity. In this study, transcriptome analysis is performed to identify the molecular mechanisms associated with this. Cell cycle analysis reveals that the cells are arrested mainly in the G0 /G1 phase. The cell cycle arrest is associated with significant up-regulation of cyclin-dependent kinases inhibitors (CDKNs) and down-regulation of cyclin-dependent kinases (CDKs) and cyclins. During the cell size increase phase, the gene expression of the upstream pathways of mechanistic target of rapamycin (mTOR), which is related to the extracellular growth factor, cytokine, and amino acid conditions, shows a strongly synchronized pattern to promote the mTOR activity. The downstream genes of mTOR also show a synchronized pattern to stimulate protein translation and lipid synthesis. The results demonstrate that cell cycle inhibition and stimulated mTOR activity at the transcriptome level are related to CHO cell size increase. The cell size increase is related to the extracellular nutrient conditions through a number of cascade pathways, indicating that by rational design of media and feeds, CHO cell size can be manipulated during culture processes, which may further improve cell growth and specific productivity. PMID- 30024105 TI - Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence. AB - We report here numerous novel genes and multiple new signatures which robustly predict prostate cancer (PC) recurrence. We extracted 696 differentially expressed genes relative to a reported PC signature from the TCGA dataset (n = 492) and built a 15-gene signature (SigMuc1NW) using Elastic-net with 10-fold cross-validation through analyzing their expressions at 1.5 standard deviation/SD below and 2 SD above a population mean. SigMuc1NW predicts biochemical recurrence (BCR) following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free (MMDF) (P = 1.12e-12). The prediction accuracy is improved with the use of SigMuc1NW's cutpoint (P = 3e-15) and is further enhanced (sensitivity 67%, specificity 75.7%, MMDF 45.2, P = 0) when all 15 genes were analyzed through their cutpoints instead of their SDs. These genes individually associate with BCR using either SD or cutpoint as the cutoff points. Eight of 15 genes are individual risk factors after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Eleven of 15 genes are novel to PC. SigMuc1NW discriminates BCR with time-dependent AUC (tAUC) values of 76.6% at 11.5 months (76.6%-11.5 m), 73.8%-22.3 m, 78.5%-32.1 m, and 76.4%-48.4 m. SigMuc1NW is correlated with adverse features of PC, high Gleason scores (odds ratio/OR 1.48, P < 2e-16), and advanced tumor stages (OR 1.33, P = 4.37e-13). SigMuc1NW remains an independent risk factor of BCR (HR 2.44, 95% CI 1.53-3.87, P = 1.62e-4) after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. In an independent PC (MSKCC) cohort (n = 140), these 15 genes were altered in PC vs normal tissue, metastatic PCs vs primary PCs, and recurrent PCs vs nonrecurrent PCs. Importantly, a 10-gene subsignature SigMuc1NW1 predicts BCR in MSKCC (P = 3.11e-15) and TCGA (P = 3.13e-12); SigMuc1NW1 discriminates BCR at 18.4 m with tAUC as 82.5%. Collectively, our analyses support SigMuc1NW as a novel and robust signature in predicting BCR of PC. PMID- 30024108 TI - Cloaked Exosomes: Biocompatible, Durable, and Degradable Encapsulation. AB - Exosomes-nanosized extracellular vesicles (EVs) naturally secreted from cells have emerged as promising biomarkers and potential therapeutic vehicles, but methods to manipulate them for engineering purposes remain elusive. Among the technical obstacles are the small size and surface complexity of exosomes and the complex processing steps required, which reduce the biocompatibility of currently available methods. The encapsulation of exosomes with a nanofilm of supramolecular complexes of ferric ions (Fe3+ ) and tannic acid is demonstrated here. The resulting natural polyphenol, ~10 nm thick, protects exosomes from external aggressors such as UV-C irradiation or heat and is controllably degraded on demand. Furthermore, gold nanoparticles can be covalently attached for single exosome level visualization. To fully exploit their therapeutic potential, chemotherapeutic drug-loaded EVs are functionalized to achieve the targeted, selective killing of cancer cells preferentially over normal cells. This nanofilm not only preserves the native size and chemical makeup of the intrinsic exosomes, but also confers new capabilities for efficient tumor targeting and pH-controlled release of drugs. Demonstrating a scalable method to produce biocompatible, durable, on-demand degradable, and chemically controllable shields for exosome modification and functionalization, the methods introduced here are expected to bring the potential of exosome-based nanomedicine applications closer to reality. PMID- 30024109 TI - Arylpyrrolyldiketone Boron Complexes Exhibiting Various Anion-Binding Modes Based on Dynamic Conformation Changes. AB - Arylpyrrolyldiketone boron complexes as anion-responsive pi-electronic molecules were synthesized by Claisen condensations of acetylpyrrole and corresponding aryl esters. The synthesized pi-electronic molecules exhibited anion-binding behavior with various binding modes including pyrrole-inverted and non-inverted [1+1]-type anion complexes as well as [2+1]-type complexes owing to the presence of only a single pyrrole ring. Furthermore, solid-state ion-pairing assemblies, comprising receptor-anion complexes and countercations, were constructed based on fairly planar [2+1]-type complexes. PMID- 30024110 TI - Identification and Antibiotic-Susceptibility Profiling of Infectious Bacterial Agents: A Review of Current and Future Trends. AB - Antimicrobial resistance is one of the most worrying threats to humankind with extremely high healthcare costs associated. The current technologies used in clinical microbiology to identify the bacterial agent and profile antimicrobial susceptibility are time-consuming and frequently expensive. As a result, physicians prescribe empirical antimicrobial therapies. This scenario is often the cause of therapeutic failures, causing higher mortality rates and healthcare costs, as well as the emergence and spread of antibiotic resistant bacteria. As such, new technologies for rapid identification of the pathogen and antimicrobial susceptibility testing are needed. This review summarizes the current technologies, and the promising emerging and future alternatives for the identification and profiling of antimicrobial resistance bacterial agents, which are expected to revolutionize the field of clinical diagnostics. PMID- 30024112 TI - Empagliflozin, calcium, and SGLT1/2 receptor affinity: another piece of the puzzle. PMID- 30024113 TI - Combining value chain and social network analysis as a viable tool for informing targeted disease surveillance in the rural poultry sector of Zambia. AB - Diseases are among the greatest challenges to the rural poultry sector in sub Saharan Africa. The lack of a sustainable poultry disease surveillance system and the possible existence of communities and occasions where the interaction between birds is high present an opportunity for targeted surveillance of poultry diseases in these regions. However, the establishment of such a system requires adequate knowledge of the sector in the targeted area. Zambia is an example of a developing country located in the tropics that faces the challenge of frequent poultry disease outbreaks. Consequently, an interview-based survey to study the poultry sector's market chain and social networks was conducted in Eastern Zambia to derive information required for configuring targeted surveillance. This survey involved a poultry value chain analysis that also included an assessment of trading practices to identify biosecurity hot spots within the chain that could be targeted for disease surveillance. A social network analysis of poultry movement within Eastern Zambia was also conducted using whole-network analysis and ego network analysis to identify poultry trade hubs that could be targeted for poultry disease surveillance based on their centrality within the network and their size and influence within their ego networks. Rural farmers, middlemen and market traders were identified as biosecurity risk hot spots whose poultry and utensils could be targeted for disease surveillance within the value chain. Furthermore, social network analysis identified four districts as poultry trade hubs that could be targeted for disease surveillance. This study is the first to formally describe poultry movement networks within Zambia and the surrounding region. Its findings provide data required to implement targeted surveillance in regions where resources are either inadequate or non-existent, and the results provide a deeper understanding of the cultural and practical constraints that influence trade in developing countries. PMID- 30024114 TI - [Robotics and occupational risks]. PMID- 30024111 TI - The emergence of a highly pathogenic porcine reproductive and respiratory syndrome virus with additional 120aa deletion in Nsp2 region in Jiangxi, China. AB - Highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRS), which emerged in China in 2006, was characterized by high fever, high morbidity and high mortality. The causative agent of the disease was a highly pathogenic variant of porcine reproductive and respiratory syndrome virus (also called HP PRRSV), which has a discontinuous deletion of 1 + 29 amino acids (aa) in the Nsp2 coding region, compared to classical PRRSV. In 2014, fattened pigs on a pig farm in Jiangxi Province suffered from clinical symptoms of high fever, dyspnoea and death. A PRRSV, termed JX2014T2, was isolated from samples of the dead pigs. Genomic analysis of the isolated PRRSV indicated that the genome of the virus was 14,960 bp in length and belonged to the North American genotype. In the Nsp2 coding region, there was a discontinuous deletion of 1 + 29 aa, similar to HP PRRSV; however, an additional continuous deletion of 120 amino acids between aa 628 and 747 was found. Further analysis of the pathogenicity of PRRSV JX2014T2 was performed in piglets, and the results indicated that all infected piglets suffered from typical clinical symptoms of PRRS, such as high fever, cough, mental depression, anorexia, dyspnoea and palpebral swelling and died within 15 days postinfection (dpi). This demonstrated that the newly isolated PRRSV JX2014T2 strain containing an additional deletion of 120 aa is highly pathogenic to piglets, suggesting that a highly pathogenic variant with new genetic features is circulating in China. PMID- 30024115 TI - [Validation of workload scale in peruvian workers]. AB - The objective of this study was to validate the Workload Scale in Peruvian workers. The sampling was purposive -170 industrial workers at a chemical and detergent company with a technical education (83 of whom were women)- located in Metropolitan Lima. We used confirmatory factor analysis to evaluate the dimensionality of the items and the equivalence between men and women; reliability estimates of internal consistency; and linear regression of demographic variables on the workload were estimated. A one-dimensional factorial structure was found, and the metric equivalence of the items was similar between men and women; the reliability was acceptable, and workload intensity varied slightly by the type of labor contract. PMID- 30024117 TI - [Archivos and the hidden task of the Editor-in-Chief: improving research skills in occupational health]. PMID- 30024118 TI - [Occupational cohort studies in Spain]. PMID- 30024116 TI - [Scoping review on formaldehyde toxicity in occupationally exposed workers]. AB - The presence of formaldehyde at workplace remains significant. Exposure to it results in local irritation of the eye, nose and upper respiratory tract mucous membranes, and it has been chronically related to a higher risk of cancer development at the paranasal sinuses, naso-oropharynx and lungs. The aim of our work has been the updating of the bibliography and the categorization of the most up to date scientific evidence of formaldehyde effects on human body. Bibliographic search on the electronic database Medline / PubMed, restricted to the last 10 years through a combination of free and controlled language.Review of 185 scientific articles, finally including 54 due to duplicity, language, and inclusion criteria. We find among the main results a major evidence regarding genotoxicity; limited, inconsistent, and contradictory evidence regarding various neoplastic pathologies; and lack of evidence regarding bronchial asthma. Further studies have to be carried out, especially longitudinal studies and greater epidemiological power, to generate new knowledge about the behavior of this toxic. PMID- 30024119 TI - [In memory of Jordi Castejon]. PMID- 30024120 TI - The IARC Perspective on Colorectal Cancer Screening. PMID- 30024121 TI - Recent Developments in Medicine and the Law. AB - This article discusses recent developments in three areas, all of which relate to discovery in medical malpractice cases. The first topic is claims of spoliation in the context of medical malpractice. The second topic is the evolving peer review privilege and its limitation or expansion by state courts. Finally, we discuss two important cases in which state courts have interpreted HIPAA's privacy rules and applied them in the context of ex parte communications with treating physicians and pre-suit discovery of a plaintiff's medical information. PMID- 30024122 TI - Recent Developments in Workers' Compensation and Employers' Liability Law. AB - This survey reviews significant statutory developments and appellate court decisions addressing workers' compensation issues for the period from October 2014 through September 2015. Workers' compensation systems are state statutory programs, and the direct effect of laws and case precedents outside of their state of origin is limited. Nevertheless, compensation principles and statutes have much in common among states and much can be learned from studying how legislatures and courts of other jurisdictions have treated similar issues. Notably, when state courts cannot adjudicate an issue based solely upon a statute's plain language, and no precedent of the jurisdiction is determinative, they often look to authority from other states. PMID- 30024123 TI - Validity of electrical impedance myography to estimate percent body fat: comparison to bio-electrical impedance and dual-energy x-ray absorptiometry. AB - BACKGROUND: Assessment of percent body fat (%BF) is typically measured with bioelectrical impedance (BIA) as a proxy for dual-energy x-ray absorptiometry (DXA). Notably, poorer agreement between BIA and DXA among persons who are overweight or obese has been reported. The use of electrical impedance myography (EIM) as a proxy for DXA has not been validated. The objective was to evaluate an EIM device and two multi-frequency BIA devices with the reference standard (DXA) stratified by weight status and gender. METHODS: In a convenience sample of 82 adults, %BF assessed by EIM and two BIA devices was compared to DXA. Agreement between devices was tested with intra-class correlation coefficients (ICC) and Bland-Altman plots. RESULTS: Agreement between DXA and EIM (ICC=0.77) was poorer than the agreement between either BIA device with DXA (ICC >0.87). Stratified by sex, agreement between EIM and DXA was greater for men than women (ICC=0.81 and 0.61, respectively). Stratified by BMI, agreement between EIM and DXA was best for normal-weight individuals (ICC=0.89) and progressively more poor for overweight (ICC=0.80) and obese (ICC=0.67) individuals. Bland Altman plots revealed wide limits of agreement and an increase in EIM mean difference as average %BF increased. Similar trends were seen in BIA assessments. CONCLUSIONS: EIM and BIA substantially underestimate %BF in overweight and obese individuals. Wide limits of agreement coupled with variable ICC limit device interchangeability with one another and limit clinical utility. PMID- 30024124 TI - Effects of body weight loss program on parameters of muscle performance in female obese adults. AB - BACKGROUND: Body weight loss program may lead to a decrease in lean body mass affecting negatively muscle performance in obese subjects. Thus, the aim of this study was to examine the effect of weight loss on muscle performance in female obese subjects. METHODS: Eighty obese female adults were enrolled for a 2-month unsupervised aerobic training (UAT) plus nutritional program. In the pre- and post-intervention body composition was evaluated by hand-to-foot bioelectrical impedance method, body strength using handgrip test, and lower muscle power was assessed by a 5-repetition chair stand test (CST) and 30-s chair stand test (30sCST) wearing a dynamometer. RESULTS: Thirty-six subjects completed the protocol, 39% had high compliance (HC), while 61% had low compliance (LC) to exercise prescription. HC group showed a significant decreased body weight, percent of fat mass and lean muscle mass after training. Both groups significantly increased CST performance while only HC significantly increased 30sCST. No differences were found in CST muscle power in both groups between pre- and post-training. However, evaluation of muscle power during 30sCST showed significantly higher value in HC group than LC group after training. CONCLUSIONS: The results of our study show that although total lean muscle mass decreased after UAT, lower body muscle efficiency increased while muscle power did not change suggesting that in obese patients UAT can help to optimize weight loss and body efficiency. The data might be helpful for exercise professionals to evaluate correctly the muscle performance in obese adults after weight loss programs. PMID- 30024125 TI - The use of a smart-textile garment during high-intensity functional training. A Pilot Study. AB - BACKGROUND: Wearable devices are common in the health and fitness industry and provide valuable information to improve and achieve fitness goals. The Hexoskin shirt (Hx) is one such device that has been shown to be valid and reliable. The purpose of this pilot study was to compare the Hx to established methods during a maximal graded exercise test (TM) and a High-Intensity Functional Training (HIFT) session. METHODS: Ten healthy individuals (31.0 +/- 7.6 years, 76.4 +/- 11.4 kg; 1.7 +/- 0.1 m) volunteered for this study and completed a TM and a HIFT exercise session. During both testing sessions, respiratory measures [Respiratory Rate (RR), and Respiratory Volume (RV)] were assessed using a portable metabolic system (Cosmed K4b2; K4), and heart rate (HR) was determined via ECG in a standard 12-lead configuration. The Hx was worn during both sessions. RESULTS: During TM, a 4% difference was noted for HR during cool down, while exercising HR and RV, along with RR during cool down were all under 10%. During HIFT, HR at rest and cool down, as well as RR during exercise were less than 10%. The variation between technologies for the remaining variables ranged between 12.3 - 39.9% and 10.9 - 41.1% for TM and HIFT, respectively. CONCLUSIONS: The Hx smart garment may be utilized to provide select cardiorespiratory data in a TM and HIFT session. We recommend that the validity and reliability be fully established before the Hx smart garment is entirely utilized for all cardiorespiratory data and research purposes in a field-based environment. PMID- 30024126 TI - Functional performance, anthropometric parameters and contribution to team success among elite goalkeepers of the Italian "Serie A", season 2016-2017. AB - BACKGROUND: Soccer is the world's game, played by more than 120 million people. Different physical abilities, morphological and physiological characteristics are required for different playing positions. The purpose of this study is to describe anthropometric parameters and functional performances of goalkeepers, and these relationship with team success. METHODS: The study population consisted of 92 professional goalkeepers from the Italian soccer league "Serie A". Anthropometric measurements and indicators of performance of matches were obtained from the Italian soccer league. Goalkeepers were divided into first choice and substitutes. RESULTS: Goalkeepers who played at least one match were significantly older and heavier than those who did not play any game (p<0.0001). Minutes on the pitch, goals conceded, total saves and saves from both play sets and free kicks were significantly higher in the first-choice goalkeepers as compared to substitutes. However by comparing first-choice with substitutes no significant differences for the ratio between goals against and saves by minutes played were observed. A significant positive correlation between points obtained by the team and ratio of goals conceded by minutes played (R=0.55; p<0.0001) as well as ranking position of the team achieved at the end of the season and the ratio of total saves by minutes played (R=0.51; p=0.001) was observed. A significant but inverse correlation between points obtained by the team and goal conceded was reported (R=-0.80; p<0.0001), as well as point obtained and ratio of total saves by minutes played (R=0.51; p=0.001). A lower ratio of goals conceded by minutes played was a significant predictor of total points achieved by the team (Beta = 0.712, SE = 0.15; p < 0.0001). Finally, a higher ratio of goal conceded by minutes played was also associated with a higher probability of success for the team at the end of the season. Goalkeepers who completed the season with a ratio of goal against by minutes played greater than 57.5 minutes had an increased probability of leading their team to the first 6 positions of the final ranking (OR 24.7, 95%CI 2.1-297.3; p=0.01). CONCLUSIONS: Performance activities of the goalkeepers included in the rosters of the Italian soccer league significantly influenced the success of their team. A lower ratio of goals conceded by minutes played resulted to be the most significant predictor of overall team success. The present research extended previous research underlining the central role of goalkeeper for team success. PMID- 30024127 TI - Human calf muscles changes after strength training as revealed by diffusion tensor imaging. AB - BACKGROUND: Diffusion tensor imaging (DTI) is a non-invasive MR technique widely employed to study muscle anatomy. DTI parameters have been use to investigate changes in microstructures dependent on demographic factors or transient condition such as exercise. The present study is aimed at investigating the diffusion parameters changes of the human calf muscles after a 3-months strength training protocol. METHODS: Ten young men were trained for improving size and strength of the medial (GCM), lateral gastrocnemius (GCL) and soleus (SL) three times a week, with at least 24 hours between training sessions, for a period of three months. Diffusion weighted magnetic resonance images were acquired at the beginning of the training period (TPRE) and at three months (TPOST) using a 3T scanner. The fractional anisotropy (FA), mean diffusivity (MD) and tensor eigenvalues (lambda1, lambda2, lambda3) were derived from the diffusion weighted imaging data. RESULTS: We found a significant increase in lambda1, lambda2, lambda3 and MD values and muscle volumes between TPRE and TPOST in all the examined muscles both for the left and right side. No significant differences were highlighted for FA. CONCLUSIONS: DTI enables the investigation of muscle microstructure, allowing for the assessment of diffusion parameters variation of the muscle tissue in response to training thus being a useful tool to investigate physiological and pathological changes in skeletal muscle microstructure which could be employed to test the outcomes and the effectiveness of a given training protocol. PMID- 30024128 TI - Prediction of male basketball players' adult stature from the age of 13 years using chronological age and maturity. AB - BACKGROUND: The purpose of this study was to cross-validate and demonstrate how adult stature can be predicted in 13-year-old basket-ball players by using a new reference specific growth curve obtained from chronological age, and maturity of sedentary boys. METHODS: The prediction of adult stature of young male basketball players was established from the results of a longitudinal study in which we developed from 125 sedentary boys aged from 12 to 17.5 years new growth curves using chronological and biological maturation. In partnership with the French basketball federation, we collected information on stature, age and secondary pubertal stages from a sample of 106 boys aged from 160 and 164 months. The participants were regional level basketball players whose adult statures were known. The association of biological maturation at a chronological age was the determining criterion to predict individual adult stature with advanced, standard and delayed puberty. RESULTS: The average longitudinal growth curves enabled the prediction of adult stature within +/- 3cm, 98 % of the time in male basketball players. The relationship between estimated adult stature and final stature was high (r=0.98) with a low standard error estimate (SEE= 1.65 cm). Mean and standard deviation of the differences between estimated stature and adult stature were 0.7 +/- 1.7. CONCLUSIONS: This technique is a valid, nonintrusive and accurate method of predicting adult stature in adolescent basketball players. It constitutes an advance in the detection and the orientation of future basketball players. PMID- 30024129 TI - Changes in lactate, ferritin, and uric acid in saliva after repeated explosive effort sequences. AB - BACKGROUND: The aim of the present study was to evaluate the changes in a panel of biomarkers including lactate, ferritin and uric acid in saliva of untrained and trained subjects after repeated explosive effort sequences, and to analyse the differences in interpretation of these biomarkers depending on the way the data is expressed (without any correction or corrected by protein content or flow). METHODS: Eighteen volunteers (11 untrained and 7 trained) performed 8 consecutive explosive effort sequences (60 m sprints). Blood and saliva samples were collected before and after each sequence. Salivary data was analysed as absolute concentration and after correcting by their protein content and flow. RESULTS: Lactate in saliva showed increases with acute exercise, being these increases of higher magnitude in non-trained subjects. In addition, when corrected by total protein, lactate in saliva correlates with blood lactate in non-trained subjects. Ferritin and uric acid in saliva did not show changes after the effort sequences. CONCLUSIONS: From the biomarkers evaluated, the measurement of lactate in saliva corrected by total protein could be useful for the assessment of fatigue induced during repeated explosive effort sequences and could be potentially used as a non-invasive alternative to blood lactate. This report also points out that way of reporting the saliva analytes could greatly influence the interpretation of the results and that lactate in saliva has a different dynamic in trained and non-trained individuals that should be further explored. PMID- 30024130 TI - Acoustic and visual pacesetter influence on the energy expenditure in a cycling exercise. AB - AIM: The aim of this study was to evaluate the effects of acoustic and visual pacesetters on the energy expenditure in a steady state 30-minute long cycling. METHODS: Eighteen healthy male subjects (age 27.6 +/- 4.59 years; height 1.78 +/- 0.07 m; body mass 80.1 +/- 7.85 kg) performed a 30-minute submaximal exercise at a constant workload on a cycle ergometer. The imposed workload required a metabolic expenditure corresponding to 70% of ventilatory threshold for each subject. Energy expenditure - expressed as a caloric equivalent relative to the total net oxygen consumption during exercise - was evaluated using three conditions: control (CT), no external pacesetter; acoustic (AT), listening to rhythmic acoustic stimuli at 120 beat per minute; and visual (VT), seeing footage consisting of eight different images in a looped sequence at 120 frames per minute. RESULTS: All measured parameters qualified the exercise as requiring mainly an aerobic metabolism, showing no pain and no fatigue. AT and VT energy expenditure (5.0+/-0.44 and 4.9+/-0.39 MET respectively) were significantly lower compared to CT (5.5+/-0.49 MET), while no difference between AT and VT were recognised. CONCLUSIONS: This study confirmed the ergogenic effect of the acoustic pacesetter on a 30-minute steady state rhythmic exercise. Novelty is that the visual pacesetter too was able to increase the mechanical efficiency as the same manner than the acoustic one. The present setting adopting visual pacesetter could be used in special categories, such as the deaf or in innovative technological tools as head-mounted display devices. PMID- 30024131 TI - [The influence of local anthropogenic factors on soil emission of biogenic greenhouse gases in cryogenic ecosystems]. AB - For the first time were the results of studies on influence of main kinds of local anthropogenic factors on soil emission of biogenic greenhouse gases (CO2, CH4, and N2O) in permafrost ecosystems of Arctic and North-Boreal zones of the Russian Federation, and also of the Spitsbergen Archipelag summarized. Different types of land use can, depending on their manner, lead to significant enhancing or suppression of soil CO2 emission. On average, anthropogenic factors (AFs), acting in concert, favor the enhancement of local CO2 soil emission, promoting, at the same time, an increase in its dispersion. AFs directly influence the microbial-root respiration in soil, modify the soil itself, and indirectly affect important natural respiration regulators, phytomass reserves in particular, which makes them primary factors with relation to respiration pattern. AFs influence also the emission of other biogenic greenhouse gases (CH4 and N2O), though this influence can be exercised in different ways. Methane emission is mediated by degree of the territory drainage. However, in all studied cases, AFs have led to source reduction or sink intensification of this gas from the atmosphere. Unlike methane emission, N2O emission increased under the influence of AFs considered. As for the whole complex of AFs that impacts the carbon balance and fluxes of CO2 in cryogenic ecosystems, its role is expressed through the enhancement of soil respiration at the beginning of the cold season, when AFs are capable of soil emission increasing, at the level of meso-landscape, almost by 50%. PMID- 30024132 TI - Recent Developments in Health Insurance, Life Insurance, and Disability Insurance Law. AB - This year's article covers key recent developments in life, health, and disability insurance law, including Supreme Court decisions on the constitutionality of the Affordable Care Act's contraception coverage provisions and on the enforceability of legal actions limitations period provisions in Employee Retirement Income Security Act (ERISA) plan documents; an alarming (but potentially short-lived) expansion of restitution as a form of "equitable relief" under ERISA; the latest battles in the stranger originated life insurance (STOLI) wars; and perennial issues arising out of disability and accident insurance cases. PMID- 30024134 TI - [Female song in Passeriformes: An exception or the rule?]. AB - We analyzed the occurrence of female song in different families of Passeriformes aiming to better understanding of evolutionary prerequisites of this phenomenon and its relation with species biological traits and patterns of main passerine groups dispersion. Examined are 18 complete families, two Turdidae subfamilies, and three Sylviidae subfamilies among songbirds, also 4 complete families and two Tyrannidae subfamilies among bronchophone birds. As the data obtained indicate, female singing had appeared independently in different Passeriformes families, both songbirds and bronchophone ones, and seems not to be ancestral for all birds of this order. We did not find any direct connection of female song phenomenon with sexual dimorphism, duet singing or lipochrome coloration. PMID- 30024133 TI - [The flight of pterosaurs]. AB - There are known three groups of vertebrates, representatives of which are gifted in active flight, namely birds, bats, and pterosaurs. Among them, the group biologists and engineers are most interested in is birds. In essence, the flight of birds is considered as a basic type, with which other groups are to be compared when studying the flight of vertebrates or trying to reconstruct it. However, while aerodynamic principles are common for all groups due to environmental uniformity, biomechanical means of flying turn out to be dependent on the wing morphological features that evolved within a specific group. At that, as for birds and bats, there is a possibility for making direct observations of the flight and comparisons between presumable and actual states, while for pterosaurs such a possibility is lacking. So, the principles of pterosaurs' flight have to be reconstructed using only paleontological data on their wing morphology and evolution. PMID- 30024135 TI - [Adaptation of Drosophila melanogaster to stressful nutritional conditions leads to the expansion of the trophic niche]. AB - Adaptation to stress factors is often accompanied by negative side effects that are manifested in lower fitness in the absence of the stress factor. This can lead to ecological specialization of the populations adapted to stressful environment and, ultimately, to ecological speciation. However, the existence of eurytopic species with a wide spectrum of ecological tolerance implies that adaptation to marginal conditions apparently can proceed without negative side effects or even involve positive effects, leading to niche expansion. Experimental evidence in favour of this evolutionary scenario is scarce. In the course of the evolutionary experiment that lasted for 20 generations, the laboratory populations of Drosophila melanogaster successfully adapted to stressful media with high NaCl concentration. The adaptation is manifested through the higher number of offspring produced during a fixed time interval by a pair of parents from the adapted lineages on the stressful medium compared to the control (unadapted) lineage, and in the less pronounced delay in larval development caused by high NaCl concentration. The adaptation to stressful medium did not entail fitness costs on the standard (favorable) medium; moreover, it resulted in more effective reproduction in favorable conditions (expansion of the trophic niche). These results, together with those obtained earlier during the study of adaptation of D. melanogaster to nutrient-poor starch based medium, imply that adaptation to marginal conditions accompanied by positive (rather than negative) side effects, leading to the expansion of the trophic niche, may be a frequent phenomenon in eurytopic species like D. melanogaster, probably explaining, to some extent, their ecological tolerance. Scarcity of experimentally confirmed examples of such evolutionary scenario is probably due to low number of attempts to find them. One possible mechanism of 'multi-purpose adaptations' obtained during the acclimation to environmental stress is the adaptive changes of symbiotic microbiota which, in Drosophila, is efficiently transferred between generations if offspring eat the medium on which their parents had lived. For instance, high quantities of symbiotic lactobacilli in the gut can enhance larval growth, life span of adults, and the efficiency of substrate utilization. Further studies are needed to reveal the mechanisms responsible for the changes in fitness observed in the course of the experiment. PMID- 30024136 TI - Cracking the Medicare Secondary Payer Enigma Code. PMID- 30024137 TI - [Spatial-temporal dynamics of the pine marten (Martes martes L.), mountain hare (Lepus timidus L.) and red squirrel (Sciurus vulgaris L.) trail activity in the European southern taiga]. AB - Observations of trail activity of the martens, mountain hares, and red squirrels in winter along fixed routes in the Central Forest Reserve showed its high variability and synchronism in time and space. Polynomial dependence of the trail activity and correlation between spatial distribution of marten, mountain hare and squirrel are detected. The influence of weather on the trail activity is smaller, but statistically significant. It is proved that the space-time dynamics of the trail activity is governed by the Moran effect which is amplified by relations between the predator and prey. PMID- 30024139 TI - [Ecological interpretation of higher units of steppe vegetation in southern mountains of Middle Siberia via quantitative ordination method]. AB - Detrended correspondent analysis is used for constructing an ecological ordination model of higher units of steppe vegetation in southern mountains of Middle Siberia. The model is based on 326 complete geobotanical descriptions and correlation analysis between the values of major axes and climatic, soil-ground, and geographical parameters. In the space of two first principal ordination axes, ecological series of steppe vegetation coenofloras are observed which are orientated along climatic factors of annual and seasonal precipitation, temperature, oceanity-continentality, and ground stoniness. A syntaxonomic interpretation of observed ecological-geographical steppe types is given, and the hierarchy of higher classification units is substantiated from the ecological point of view. PMID- 30024138 TI - [Interpopulation variability of endocrine-metabolic reaction to cold stress in northern red-backed vole (Myodes rutilus)]. AB - In natural environment, stresses, when animals happen to be exposed to them, influence the functional activity of adrenal cortex. It can be expected that in animals, living under unfavorable conditions, basal concentration of glucocorticoid hormones would be increased while adrenocortical response to acute stress would be weakened. Since the main function of stress-reaction is resources mobilization meant to compensate an environmental impact, its weakening should lead to reduction of reserve metabolic capacities. To test this hypothesis, we compared energy metabolism, body temperature, and corticosterone concentration in blood plasma measured in northern red-back voles (Myodes rutilus) before and after acute cooling in helium-oxygen mixture. Voles belonged to two populations that deffered in relative abundance. It is found out that voles from a population of low relative abundance inhabiting the recreational forest of Novosibirsk Scientific Center, despite their being more stress-prone and having weakened stress-reaction, have higher maximum metabolic rate than voles from the mountain taiga polulation with high relative abundance. The results obtained suggest that living under unfavorable conditions leads to physiological adaptations which enhance resistance to acute stress, yet increase the risk of chronic stresses that have negative effect on fitness. PMID- 30024140 TI - Recent Developments in Health Insurance, Life Insurance, and Disability Insurance Law. PMID- 30024141 TI - [A syntaxonomic analysis of the initial stage effect on secondary autogenous succession of broad-leaved forest]. AB - Using successional system of Stachyo sylvaticae-Tilietum cordatae association as a case study, the possibilities are considered of applying syntaxonomy as developed on the basis of floristic classification principles. Characteristics of restorative successions on cut-over lands have been analysed at strong and weak disturbance of soil cover as well as in plantings of coenotically weak species Pinus sylvestris and coenotically strong species Picea obovata. High self restoring potential of the association studied is emphasised. PMID- 30024142 TI - [Biochemical processes of greenhouse gasses generation in swamplands of the Gorny Altai]. AB - Starting from 2009, monitoring studies of swamp regimes have been conducted at the swampland station located in the north-eastern Altai. Here, we present the results of biological activity (indices of microorganisms abundance, respirometric indicator, catalase activity) in peat deposits of eutrophic (Turochak) and mesotrophic (Kutyushskoye) swamps during 2012-2013 vegetation periods with different levels of marsh water and oxidation-reduction conditions. PMID- 30024143 TI - [Evolution of nitrogen-fixing symbioses based on the migration of bacteria from mycorrhizal fungi and soil into the plant tissues]. AB - The hypothesis is suggested on the emergence of N2-fixing plant symbionts from soil diazotrophs and from the satellites of Glomeromycota fungi forming arbuscular mycorrhizae (AM). This universal form of plant-microbe symbiosis possibly appeared from integration of ancestral land plants (rhyniophytes, psylophytes) and microbial consortia composed of AM-fungi assimilating soil phosphates and bacteria fixing atmospheric CO2 and/or N2. Releasing of these bacteria from AM-fungal hyphae into the plant tissues elicited the selection of genotypes capable of the fungi-independent multiplication in planta, as well as the fixation in bacterial genomes of the genes for synthesis of chitin-like signal factors stimulating the development of symbiotic structures. An early stage of this evolution might been represented by formation of N2-fixing syncyanoses, the late stage - by formation of nodular symbioses of dicots from Eurosid I clade with rhizobia (alpha- and beta-proteobacteria) and with actinobacteria Frankia. Emergence of these symbioses was possibly based on the migration of soil and endophytic bacteria into the storage organs (modified stems or lateral roots), where the optimal conditions were established not only for N2 fixation but also for the evolution of bacteria towards an increased symbiotic activity. This evolution resulted in the emergence of primary rhizobia (Bradyrhizobium, Burkholderia) which acted as the donors of sym-genes for a broad spectrum of microbes transformed into the secondary rhizobia (Rhizobium, Sinorhizobium). The succeeding evolution of nodular symbioses was directed at an increased efficiency of symbiotrophic nitrogen nutrition in host plants following two scenarios: (i) "expensive", based on the increase of N2- fixing activity via transformation of bacteria into non-reproducible bacteroids; (ii) "economic", based on acquiring the determinate nodule structure and ureide nitrogen assimilation. PMID- 30024144 TI - Recent Developments in Insurance Coverage. AB - This article highlights significant insurance coverage cases from October 1, 2016, to September 30, 2017. This past year, insurance coverage law saw many developments addressing a wide variety of issues. While state and federal courts are frequently divided on their approach to coverage issues, this article attempts to identify regional trends with the aim of assisting practitioners nationwide. The following sections are a review of particularly important decisions in insurance coverage law, including cyber insurance, the efficient proximate cause doctrine, declaratory judgment actions, and recent developments in the application of the pollution exclusion in general liability policies. PMID- 30024145 TI - Lipid Stabilized Solid Drug Nanoparticles for Targeted Chemotherapy. AB - Nanoparticle-based chemotherapeutics have gained widespread interest in medicine due to their tunable pharmacokinetics and pharmacodynamics. Various drug delivery vehicles have been developed including polymer, liposome nanoparticles, and some of them have already made clinical impacts. Despite these advances, drug payload of these formulations is limited (typically <10%). Here, we report a general and scalable approach to prepare lipid-coated solid drug nanoparticles by combining flash nanoprecipitation and extrusion technique, which enables optimization of individual steps separately and flexibility in selection of nanoparticle surface functionalities. Using methotrexate as a model drug, the nanoparticles significantly outperformed free drug in tumor growth suppression. PMID- 30024146 TI - Raman Imaging of Individual Membrane Lipids and Deoxynucleoside Triphosphates in Living Neuronal Cells during Neurite Outgrowth. AB - Recent developments in Raman imaging at the microscopic scale were exploited here with the specific purpose of locating spectral fingerprints of individual membrane lipids and deoxynucleoside triphosphates during neuronal cell networking and separation. After carefully screening the Raman spectra of isolated lipid components, we located an in situ mapped specific Raman fingerprints from individual phospholipids at the micrometric level in comparison with the total lipid distribution within single living cells. We concurrently examined silent zones of lipid emissions and exploited those peculiar spectral ranges for mapping both abundance and localization of individual DNA nucleoside triphosphates. This work represents a first step toward label-free/molecular-selective Raman patterning with high spectral resolution of the relevant chemical species involved with the functionality of neuronal cells. PMID- 30024147 TI - Tumoral Acidic pH-Responsive cis-Diaminodichloroplatinum-Incorporated Cy5.5-PEG- g-A-HA Nanoparticles for Targeting Delivery of CDDP against Cervical Cancer. AB - Cisplatin (CDDP) has been considered as one of the most effective anticancer drugs against cervical cancer, but the lack of selectivity of CDDP to tumor tissues often leads to serious toxic side effects. In this study, CDDP incorporated Cy5.5-PEG- g-A-HA nanoparticles were prepared to endue CDDP the ability to selectively target tumors and fluorescence imaging in vivo. The nanoparticles exhibited a spherical shape with particle sizes between 216.4 and 281.5 nm and had a pH and Cl- concentration dependence on controlled and sustained CDDP release, which was favorable for nanoparticles to release more drugs at acidic tumor microenvironment. Cell biology experiments demonstrated that the nanoparticles had good biocompatibility and tumor targeting; the nanoparticles could selectively bind and internalize into HeLa cells and induce apoptosis, but lead to less cytotoxicity on NIH3T3 cells. What is more, the nanoparticles could be clearly fluorescent-imaged in vivo and showed an effective accumulation at the tumor site. Antitumor test in vivo displayed that the nanoparticles had good antitumor efficiency and low systemic toxicity which improved the life quality of mice. Hence, the CDDP-incorporated Cy5.5-PEG- g-A-HA nanoparticles were a potential delivery system for targeting delivery of CDDP against cervical cancer. PMID- 30024148 TI - Probing Perovskite Inhomogeneity beyond the Surface: TOF-SIMS Analysis of Halide Perovskite Photovoltaic Devices. AB - Understanding the origins and evolution of inhomogeneity in halide perovskite solar cells appears to be a key to advancing the technology. Time-of-flight secondary-ion mass spectrometry (TOF-SIMS) is one of the few techniques that can obtain chemical information from all components of halide organic-inorganic perovskite photovoltaics in one-dimension (standard depth profiling), two dimensions (high-resolution 100 nm imaging), as well as three-dimensions (tomography combining high-resolution imaging with depth profiling). TOF-SIMS has been used to analyze perovskite photovoltaics made by a variety of methods, and the breadth of insight that can be gained from this technique is illustrated here including: cation uniformity (depth and lateral), changes in chemistry upon alternate processing, changes in chemistry upon degradation (including at interfaces), and lateral distribution of passivating additives. Using TOF-SIMS on multiple perovskite compositions, we show that the information regarding halide perovskite formation as well as inhomogeneity critical to device performance can be extracted providing one of the best proxies for understanding compositional changes resulting from degradation. We also describe in detail the measurement artifacts and recommend the best practices that enable unique insight regarding halide perovskite solar cell materials and devices. PMID- 30024149 TI - Understanding the Nonplanarity in Aromatic Metallabenzenes: A sigma-Control Mechanism. AB - Metallabenzenes, the organometallic counterparts of benzene with one of the C atoms being replaced by a metal atom, expand the family of aromatics and further create prospective candidates for novel applications as functional materials. One intriguing feature of these complexes is that their MC5 rings do not always constrict into a planar configuration as in the C6 ring of benzene. Such a deviation has often been attributed to the unfavorable antibonding interactions between an occupied metal d orbital and the pi orbitals of the C5 moiety. We herein scrutinize the frontier orbital interactions in both sigma and pi spaces in a plethora of metallabenzene complexes using extensive density functional theory calculations. Unexpectedly, the nonplanarity in metallabenzenes is found to be hardly related to the pi orbitals. It is the antibonding interaction between an occupied metal d orbital and the sigma orbitals of the C5 moiety that dominates the observed distortion. Such a sigma-control mechanism not only provides an explanation for the commonly observed nonplanarity in metallabenzenes but also points out a novel direction toward the rational design of functional materials with enhanced metalla-aromaticity. PMID- 30024151 TI - Monothioarsenate Uptake, Transformation, and Translocation in Rice Plants. AB - Thioarsenates form under sulfur-reducing conditions in paddy soil pore waters. Sulfur fertilization, recently promoted for decreasing total arsenic (As) grain concentrations, could enhance their formation. Yet, to date, thioarsenate toxicity, uptake, transformation, and translocation in rice are unknown. Our growth inhibition experiments showed that the toxicity of monothioarsenate (MTA) was similar to that of arsenate but lower than that of arsenite. Higher toxicity of MTA with lower phosphate availability might imply uptake through phosphate transporters similar to arsenate. To demonstrate direct uptake of MTA by rice plants, a species-preserving extraction method for plant samples was developed. When plants were exposed to 10 MUM MTA for 72 h, up to 19% and 4% of total As accumulated in roots and shoots, respectively, was MTA. Monothioarsenate was detected in xylem sap and root exudates, and its reduction to arsenite in rice roots and shoots was shown. Total As uptake was lower upon exposure to MTA compared to arsenate, but root to shoot translocation was higher, resulting in comparable As shoot concentrations. Thus, before promoting sulfur fertilization, uptake and detoxifying mechanisms of thioarsenates as well as potential contribution to grain As accumulation need to be better understood. PMID- 30024152 TI - Singlet Oxygen Phosphorescence as a Probe for Triplet-State Dissolved Organic Matter Reactivity. AB - Triplet-state chromophoric dissolved organic matter (3CDOM*) plays an important role in aquatic photochemistry, yet much remains unknown about the reactivity of these intermediates. To better understand the kinetic behavior and reactivity of 3CDOM*, we have developed an indirect observation method based on monitoring time resolved singlet oxygen (1O2) phosphorescence kinetics. The underpinning principle of our approach relies on the fact that O2 quenches almost all triplets with near diffusion limited rate constants, resulting in the formation of 1O2, which is kinetically linked to the precursors. A kinetic model relating 1O2 phosphorescence kinetics to triplet excited states produced from isolated humic substances and in whole natural-water samples (hereafter referred to as 3CDOM*) was developed and used to determine rate constants governing 3CDOM* natural lifetimes and quenching by oxygen and 2,4,6-trimethylphenol (TMP), a common triplet probe molecule. 3CDOM* was found to exhibit smaller O2 and TMP quenching rate constants, ~9 * 108 and ~8 * 108 M-1 s-1, respectively, compared with model sensitizers, such as aromatic ketones. Findings from this report shed light on the fundamental photochemical properties of CDOM in organic matter isolates and whole waters and will help refine photochemical models to more accurately predict pollutant fate in the environment. PMID- 30024153 TI - Bioactive Sesquiterpenoids from the Peeled Stems of Syringa pinnatifolia. AB - Fourteen new sesquiterpenoids, alashanoids A-H (1, 2, and 4-9), (+)-2,9 humuladien-6-ol-8-one (3b), and five pairs of enantiomers (1 and 4-7), along with eight known analogues (3a and 10-16) were isolated from the stems of Syringa pinnatifolia. The structures were established using IR, UV, MS, and NMR data. The absolute configurations of the new compounds were resolved by X-ray diffraction, a modification of Mosher's method, and experimental and calculated ECD data analysis. The new sesquiterpenoids represent three skeletons: a rare 2,2,5,9 tetramethylbicyclo[6.3.0]-undecane (1), a humulane-type (2-8), and a caryophyllene-type (9) skeleton. Compounds 6a, 7, and 11 showed protective effects against hypoxia-induced injury to H9c2 cells at a concentration of 40 MUM, and 5-7, 11, and 13 inhibited NO production in LPS-induced RAW264.7 macrophage cells with IC50 values ranging from 13.6 to 70.6 MUM. These compounds decreased the TNF-alpha and IL-6 levels in RAW264.7 cells in a concentration dependent manner at 20-80 MUM. PMID- 30024150 TI - Redox Interconversion between Cobalt(III) Thiolate and Cobalt(II) Disulfide Compounds. AB - The redox interconversion between Co(III) thiolate and Co(II) disulfide compounds has been investigated experimentally and computationally. Reactions of cobalt(II) salts with disulfide ligand L1SSL1 (L1SSL1 = di-2-(bis(2-pyridylmethyl)amino) ethyl disulfide) result in the formation of either the high-spin cobalt(II) disulfide compound [CoII2(L1SSL1)Cl4] or a low-spin, octahedral cobalt(III) thiolate compound, such as [CoIII(L1S)(MeCN)2](BF4)2. Addition of thiocyanate anions to a solution containing the latter compound yielded crystals of [CoIII(L1S)(NCS)2]. The addition of chloride ions to a solution of [CoIII(L1S)(MeCN)2](BF4)2 in acetonitrile results in conversion of the cobalt(III) thiolate compound to the cobalt(II) disulfide compound [CoII2(L1SSL1)Cl4], as monitored with UV-vis spectroscopy; subsequent addition of AgBF4 regenerates the Co(III) compound. Computational studies show that exchange by a chloride anion of the coordinated acetonitrile molecule or thiocyanate anion in compounds [CoIII(L1S)(MeCN)2]2+ and [CoIII(L1S)(NCS)2] induces a change in the character of the highest occupied molecular orbitals, showing a decrease of the contribution of the p orbital on sulfur and an increase of the d orbital on cobalt. As a comparison, the synthesis of iron compounds was undertaken. X-ray crystallography revealed that structure of the dinuclear iron(II) disulfide compound [FeII2(L1SSL1)Cl4] is different from that of cobalt(II) compound [CoII2(L1SSL1)Cl4]. In contrast to cobalt, reaction of ligand L1SSL1 with [Fe(MeCN)6](BF4)2 did not yield the expected Fe(III) thiolate compound. This work is an unprecedented example of redox interconversion between a high-spin Co(II) disulfide compound and a low-spin Co(III) thiolate compound triggered by the nature of the anion. PMID- 30024154 TI - Direct Measurements of kT-Scale Capsule-Substrate Interactions and Deposition Versus Surfactants and Polymer Additives. AB - We report a novel approach to directly measure the interactions and deposition behavior of functional capsule delivery systems on glass substrates versus the concentration of an anionic surfactant sodium lauryl ether sulfate (SLES) and a cationic acrylamide-acrylamidopropyltrimonium copolymer (AAC). Analyses of three dimensional optical microscopy trajectories were used to quantify lateral diffusive dynamics, deposition lifetimes, and potentials of mean force for different solution conditions. In the absence of additives, negatively charged capsule surfaces yield electrostatic repulsion with the negatively charged substrate, which inhibits deposition. With an increasing SLES concentration below the critical micelle concentration (CMC), capsule-substrate electrostatic repulsion is mediated by the charged surfactant solution that decreases the Debye length. Above the SLES CMC, depletion attraction causes enhanced deposition until eventually depletion repulsion inhibits deposition at concentrations ~10 wt %. Addition of an ACC causes deposition via capsule-substrate bridging at all concentrations; the weakest deposition occurs at intermediate AAC concentrations from a competition of steric repulsion and attraction via a few extended bridges. The novel measurements and models of capsule interactions and deposition on substrates in this work provide a basis to fundamentally understand and rationally design complex rinse-off cleansing formulations with optimal characteristics. PMID- 30024155 TI - Structural Diversity and Electronic Properties of 3d Transition Metal Tetraphosphides, TMP4 (TM = V, Cr, Mn, and Fe). AB - Transition-metal (TM) phosphides attract increasing attention with applications for energy conversion and storage, due to their outstanding physical, chemical, and electronic properties. The 3d transition metal tetraphosphides (TMP4, TM = V, Cr, Mn, and Fe) possess multiple allotropies and rich electronic properties. Here, we perform the investigations of the structural, electronic, and elastic properties for 3d-TMP4 (TM = V, Cr, Mn, and Fe) using density functional theory (DFT) calculations. These compounds are featured with alternating buckled phosphorus sheets with ten-numbered phosphorus rings and varied transition-metal layers. Hybrid DFT calculations reveal that TMP4 compounds exhibit a wide range of electrical properties, ranging from metallic behavior for VP4 to semiconducting behavior for CrP4 with the narrow direct band gap of 0.63 eV to enlarged semiconducting MnP4 and FeP4 with band gap of 1.6-2.1 eV. The bonding analysis indicates that P-P and TM-P covalent interactions dominate in the phosphorus sheets and TMP6 octahedrons, which are responsible for the structural and electronic diversity. PMID- 30024157 TI - In Vitro Research on Dietary Polyphenols and Health: A Call of Caution and a Guide on How To Proceed. PMID- 30024158 TI - Fighting at the Interface: Structural Evolution during Heteroepitaxial Growth of Cyanometallate Coordination Polymers. AB - Hybridization of coordination polymers allows for combining two or more distinct structures into one material. Here, we explore the core/shell-type materials of Prussian blue analogues (PBAs) by heteroepitaxial growth and demonstrate how one phase structurally dominates the other. The volumetric ratio between the shell and core crystals determine the final structure of the hybrids. The outermost dominated the Na+ ion insertion/extraction, illustrating how the hybridization can adjust the function of PBAs. PMID- 30024156 TI - Unraveling Mechanisms of Chiral Induction in Double-Helical Metallopolymers. AB - Self-assembled helical polymers hold great promise as new functional materials, where helical handedness controls useful properties such as circularly polarized light emission or electron spin. The technique of subcomponent self-assembly can generate helical polymers from readily prepared monomers. Here we present three distinct strategies for chiral induction in double-helical metallopolymers prepared via subcomponent self-assembly: (1) employing an enantiopure monomer, (2) polymerization in a chiral solvent, (3) using an enantiopure initiating group. Kinetic and thermodynamic models were developed to describe the polymer growth mechanisms and quantify the strength of chiral induction, respectively. We found the degree of chiral induction to vary as a function of polymer length. Ordered, rod-like aggregates more than 70 nm long were also observed in the solid state. Our findings provide a basis to choose the most suitable method of chiral induction based on length, regiochemical, and stereochemical requirements, allowing stereochemical control to be established in easily accessible ways. PMID- 30024159 TI - Facile Axial Ligand Substitution in Linear Mo?Mo-Ni Complexes. AB - Clean axial ligand substitution reactions of heterometallic extended metal atom chains (HEMACs) supported by the dpa ligand (dpa = 2,2'-dipyridylamine) have been synthetically challenging due to side reactions that alter the trimetallic core. Following the hypothesis that a heterometallic core containing second-row transition metals would be more robust toward ligand substitution, we report the synthesis of three new heterotrimetallic compounds, Mo2Ni(dpa)4(OTf)2 (1), Mo2Ni(dpa)4(NCS)2 (2), and Mo2Ni(dpa)4(NCSe)2 (3) that are obtained cleanly and in good yield. Compound 1 may be synthesized either directly by reaction of Ni(OTf)2 with Mo2(dpa)4 (4) or indirectly, by reaction of Mo2Ni(dpa)4Cl2 (5) with 2 equiv of TlOTf. Axial ligand substitution on 1 via solutions containing NaNCS or KNCSe afford 2 or 3, respectively. X-ray crystal structures of 1, 2, and 3 present short Mo-Ni distances of 2.458(8)A /2.47(1) A, 2.548(1), and 2.546(1), respectively. Density functional theory (DFT) calculations indicate a 3-center 3 electron sigma bonding interaction between the Mo2 quadruply bonded core and the Ni in both 1 and 2. These complexes were analyzed by SQUID magnetometry, supporting the presence of a high spin Ni2+ center with S = 1. PMID- 30024160 TI - Dynamically Disordered Lattice in a Layered Pb-I-SCN Perovskite Thin Film Probed by Two-Dimensional Infrared Spectroscopy. AB - The dynamically flexible lattices in lead halide perovskites may play important roles in extending carrier recombination lifetime in 3D perovskite solar-cell absorbers and in exciton self-trapping in 2D perovskite white-light phosphors. Two-dimensional infrared (2D IR) spectroscopy was applied to study a recently reported Pb-I-SCN layered perovskite. The Pb-I-SCN perovskite was spin-coated on a SiO2 surface as a thin film, with a thickness of ~100 nm, where the S12CN- anions were isotopically diluted with the ratio of S12CN:S13CN = 5:95 to avoid vibrational coupling and excitation transfer between adjacent SCN- anions. The 12CN stretch mode of the minor S12CN- component was the principal vibrational probe that reported on the structural evolution through 2D IR spectroscopy. Spectral diffusion was observed with a time constant of 4.1 +/- 0.3 ps. Spectral diffusion arises from small structural changes that result in sampling of frequencies within the distribution of frequencies comprising the inhomogeneously broadened infrared absorption band. These transitions among discrete local structures are distinct from oscillatory phonon motions of the lattice. To accurately evaluate the structural dynamics through measurement of spectral diffusion, the vibrational coupling between adjacent SCN- anions had to be carefully treated. Although the inorganic layers of typical 2D perovskites are structurally isolated from each other, the 2D IR data demonstrated that the layers of the Pb-I-SCN perovskite are vibrationally coupled. When both S12CN- and S13CN- were pumped simultaneously, cross-peaks between S12CN and S13CN vibrations and an oscillating 2D band shape of the S12CN- vibration were observed. Both observables demonstrate vibrational coupling between the closest SCN- anions, which reside in different inorganic layers. The thin films and the isotopic dilution produced exceedingly small vibrational echo signal fields; measurements were made possible using the near-Brewster's angle reflection pump-probe geometry. PMID- 30024162 TI - Innovations in Proteomics: The Drive to Single Cells. PMID- 30024161 TI - Photophysics of a Ruthenium Complex with a pi-Extended Dipyridophenazine Ligand for DNA Quadruplex Labeling. AB - The light-switch mechanism of the complex [Ru(bpy)2(Br-dpqp)](PF6)2 (1, bpy = 2,2'-bipyridine, Br-dpqp = 12-bromo-14-ethoxydipyrido[3,2- a:2',3'- c]quinolino[3,2- h]phenazine), i.e., a light-up probe for the selective labeling of G-quadruplexes, is investigated by time-resolved transient absorption and emission spectroscopy. We show that, in contrast to the prototypical light-switch complex [Ru(bpy)2(dppz)](PF6)2 (2, dppz = dipyrido[3,2- a:2',3'- c]phenazine), a 3pipi* state localized on the pi-extended ligand is the state determining the excited-state properties in both protic and aprotic environments. In aprotic environments, emission originates from a bright 3MLCTphen state, which is thermally accessible from the 3pipi* state at ambient temperature. In the presence of water, i.e., in environments resembling in cellulo situations, the thermally accessible 3MLCT state is altered and becomes close in energy to the 3pipi* state, which induces a rapid excited-state deactivation of the 3pipi* state and a comparably weak emission. PMID- 30024163 TI - Spin-Unrestricted Self-Energy Embedding Theory. AB - We present a new theoretical approach, unrestricted self-energy embedding theory (USEET), that is a Green's function embedding theory used to study problems in which an open, embedded system exchanges electrons with the environment. USEET has a high potential to be used in studies of strongly correlated systems with an odd number of electrons and open shell systems such as transition metal complexes important in inorganic chemistry. In this paper, we show that USEET results agree very well with common quantum chemistry methods while avoiding typical bottlenecks present in these methods. PMID- 30024164 TI - Vibrational Relaxation in EDTA Is Ion-Dependent. AB - Ion binding by carboxylate groups is common in biomolecules such as metalloproteins, but dynamical aspects of ion binding are not fully understood. We present ultrafast spectroscopic measurements of vibrational relaxation in the ion-coordinating carboxylate groups of EDTA, which we use as a model of carboxylate-mediated ion binding, as EDTA binds a series of divalent and trivalent metal ions with high affinity. The measurements are interpreted using a Redfield-based anharmonic model of vibrational relaxation that rationalizes trends in vibrational lifetimes in terms of vibrational energy transfer between EDTA's asymmetric carboxylate stretching vibrational modes and lower-lying modes. Results show ion-dependent changes in complex structure and dynamics well outside the temporal and spatial resolution of common structural methods and demonstrate how vibrational relaxation measurements may contribute to exploration of ion binding dynamics on ultrashort length and time scales. PMID- 30024166 TI - Carbon Nanotubes and Graphene Promote Pyrolysis of Free-Base Phthalocyanine. AB - Unsubstituted phthalocyanines (including free-base H2Pc and many of its metal complexes) are among the most stable organic compounds. They can sublime without decomposition under reduced pressure and temperatures of up to 550 degrees C. This property was previously employed to design a novel approach to noncovalent functionalization of pristine single-walled carbon nanotubes (SWNTs) with 3d metal(II) phthalocyanine complexes. However, when we attempted to use the same sublimation protocol to prepare a SWNTs-H2Pc hybrid, an unexpected side effect of partial H2Pc pyrolysis was detected, phthalonitrile being a main decomposition product, under the conditions when H2Pc is supposed to be totally stable. By using density functional theory calculations, we offer an explanation for the thermal behavior of H2Pc based on its covalent attachment to the pentagonal-ring topological defects, which are very common in all graphene-derived carbon nanomaterials and capable of reacting with amines via nucleophilic addition process. PMID- 30024165 TI - Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates. AB - We introduce a novel method called restrain-free energy perturbation-release (R FEP-R) to estimate conformational free energy changes via an alchemical path, which for some conformational landscapes like those associated with cellular signaling proteins in the kinase family is more direct and readily converged than the corresponding free energy changes along the physical path. The R-FEP-R method was developed from the dual topology free energy perturbation method that is widely applied to estimate the binding free energy difference between two ligands. In R-FEP-R, the free energy change between two conformational basins is calculated by free energy perturbations that remove those atoms involved in the conformational change from their initial conformational basin while simultaneously growing them back according to the final conformational basin. Both the initial and final dual topology states are unphysical, but they are designed in a way such that the unphysical contributions to the initial and final partition functions cancel. Compared with other advanced sampling algorithms such as umbrella sampling and metadynamics, the R-FEP-R method does not require predetermined transition pathways or reaction coordinates that connect the two conformational states. As a first illustration, the R-FEP-R method was applied to calculate the free energy change between conformational basins for alanine dipeptide in solution and for a side chain in the binding pocket of T4 lysozyme. The results obtained by R-FEP-R agree with the benchmarks very well. PMID- 30024167 TI - Additional Insights into Hypericum perforatum Content: Isolation, Total Synthesis, and Absolute Configuration of Hyperbiphenyls A and B from Immunomodulatory Root Extracts. AB - Phytochemical investigation of the root extracts of Hypericum perforatum led to the isolation of two biphenyl derivatives named hyperbiphenyls A and B (1 and 2) and four known xanthones (3-6). These structures were elucidated by spectroscopic and spectrometric methods including UV, NMR, and HRMS. The absolute configuration of the biphenyl derivatives was defined by two different approaches: biomimetic total synthesis of racemic hyperbiphenyl A followed by 1H and 19F NMR Mosher's esters analysis and stereoselective total synthesis of hyperbiphenyl B, permitting assignment of the S absolute configuration for both compounds. The bioactivity of compounds 1-6 toward a set of biomolecules, including major histocompatibility complex (MHC) molecules expressed on vascular endothelial cells, was measured. The results showed that the major xanthone, i.e., 5- O methyl-2-deprenylrheediaxanthone B (3), is a potent inhibitor of MHC that efficiently reduces HLA-E, MHC-II, and MICA biomolecules on cell surfaces. PMID- 30024168 TI - Control of Interfacial Cl2 and N2O5 Reactivity by a Zwitterionic Phospholipid in Comparison with Ionic and Uncharged Surfactants. AB - Gas-liquid scattering experiments reveal that charge-separated but neutral (zwitterionic) surfactants catalyze the oxidation of dissolved Br- to Br2 by gaseous Cl2 at the surface of a 0.3 M NaBr/glycerol solution. Solutions of NaBr dissolved in glycerol with no surfactant were compared with solutions coated with zwitterionic, cationic, and anionic surfactants at dilute surface concentrations of 1.1 to 1.5 * 1014 cm-2 (less than 65% of maximum chain packing). The zwitterionic phospholipid enhances Cl2 conversion of Br- to Br2 by a factor of 1.61 +/- 0.15, in comparison with a 14-fold enhancement by a cationic surfactant (tetrahexylammonium) and a five-fold suppression by an anionic surfactant (dodecyl sulfate). Further studies indicate that even an uncharged surfactant, monododecanoylglycerol, enhances Cl2 -> Br2 production. Similar behavior is observed for the oxidation of Br- to Br2 by N2O5; it is just slightly suppressed by the phospholipid and strongly enhanced by the cationic surfactant. Collectively, these results suggest that attractions and repulsions between the negative Br- ions and the positive and negative charges of the surfactant headgroups draw Br- ions to the surface or repel them away. At low coverages, ion induced dipole and dispersion interactions between the CH2 groups and Br- or Cl2 may also enhance reactivity. These results demonstrate that the hydrocarbon chains of loosely packed surfactants do not necessarily block gas-liquid reactions but that positively charged, and even uncharged, groups can instead facilitate reactions by bringing gas-phase and solution-phase reagents together in the interfacial region. PMID- 30024169 TI - Open-Resonance-Assisted Hydrogen Bonds and Competing Quasiaromaticity. AB - The delocalization of electron density upon tautomerization of a proton across a conjugated bridge can alter the strength of hydrogen bonds. This effect has been dubbed resonance-assisted hydrogen bonding (RAHB) and plays a major role in the energetics of the tautomeric equilibrium. The goal of this work was to investigate the role that pi-delocalization plays in the stability of RAHBs by engaging other isomerization processes. Similarly, acid-base chemistry has received little experimental attention in studies of RAHB, and we address the role that acid-base effects play in the tautomeric equilibrium. We find that pi delocalization and the disruption of adjacent aromatic rings is the dominant effect in determining the stability of a RAHB. PMID- 30024170 TI - Metabolic Response in Rabbit Urine to Occurrence and Relief of Unilateral Ureteral Obstruction. AB - Ureteral obstruction will lead clinically to hydronephrosis, which may further develop into partial or complete loss of kidney function and even cause permanent histological damage. However, there is little knowledge of metabolic responses during the obstructed process and its recoverability. In this study, a complete unilateral ureteral obstruction (CUUO) model was established in the rabbit, and 1H NMR-based metabolomic analysis of urine was used to reveal the metabolic perturbations in rabbits caused by CUUO and the metabolic recovery after the CUUO was relieved. Univariate and multivariate statistical analyses were used to identify metabolic characteristics. The gradually decreased levels of 3 hydroxykynurenine, 3-methylhistidine, creatinine, guanidoacetate, meta- and para hydroxyphenylacetate, and phenylacetylglycine and the gradually increased levels of acetate, alanine, citrate, glycine, lactate, and methionine in urine could be regarded as potential biomarkers for the occurrence and severity of ureteral obstruction. And the reduced levels of 3-methylhistidine, creatinine, guanidoacetate, hippurate, meta-hydroxyphenylacetate, and methylguanidine and the elevated levels of 2-aminoisobutyrate, acetylcholine, citrate, lactate, lysine, valine, and alpha-ketoglutarate in urine compared with the obstructed level could characterize the metabolic recovery of ureteral obstruction. Our results depicted the disturbed biochemical pathways involved in ureteral obstruction and demonstrated the practicability of recovering renal functions for the patients with severe hydronephrosis in clinical practice by removing causes for obstruction. PMID- 30024171 TI - Soft X-ray Spectroscopy of the Amine Group: Hydrogen Bond Motifs in Alkylamine/Alkylammonium Acid-Base Pairs. AB - We use N K-edge absorption spectroscopy to explore the electronic structure of the amine group, one of the most prototypical chemical functionalities playing a key role in acid-base chemistry, electron donor-acceptor interactions, and nucleophilic substitution reactions. In this study, we focus on aliphatic amines and make use of the nitrogen 1s core electron excitations to elucidate the roles of N-H sigma* and N-C sigma* contributions in the unoccupied orbitals. We have measured N K-edge absorption spectra of the ethylamine bases Et xNH3- x ( x = 0...3; Et- = C2H5-) and the conjugate positively charged ethylammonium cation acids Et yNH4- y+ ( y = 0...4; Et- = C2H5-) dissolved in the protic solvents ethanol and water. Upon consecutive exchange of N-H for ethyl-groups, we observe a spectral shift, a systematic decrease of the N K-edge pre-edge peak, and a major contribution in the post-edge region for the ethylamine series. Instead, for the ethylammonium ions, the consecutive exchange of N-H for ethyl groups leads to an apparent reduction of pre-edge and post-edge intensities relative to the main-edge band, without significant frequency shifts. Building on findings from our previously reported study on aqueous ammonia and ammonium ions, we can rationalize these observations by comparing calculated N K-edge absorption spectra of free and hydrogen-bonded clusters. Hydrogen bonding interactions lead only to minor spectral effects in the ethylamine series, but have a large impact in the ethylammonium ion series. Visualization of the unoccupied molecular orbitals shows the consecutive change in molecular orbital character from N-H sigma* to N-C sigma* in these alkylamine/alkylammonium ion series. This can act as a benchmark for future studies on chemically more involved amine compounds. PMID- 30024172 TI - Multiple Interacting Collective Modes and Phonon Gap in Phospholipid Membranes. AB - We combine Brillouin neutron scattering measurements with recent inelastic X-ray scattering [ Zhernenkov et al. Nat. Commun. 2016 , 7 , 11575 ] to propose a model for the collective dynamics of phospholipid bilayers. Neutron and X-ray spectra were fitted by the model response function associated with the Hamiltonian of an interacting-phonon system. This approach allows for a comprehensive and unprecedented picture of the vibrational collective features of phospholipids. At low wavevectors Q, the dispersion relations can be interpreted in terms of two acoustic-like modes, one longitudinal and one transverse, plus a dispersionless optic-like mode. The transverse mode of the liquid phase shows a phonon gap that can be linked to a passive transport mechanism through membranes, an interpretation that was proposed in Zhernenkov et al. At higher Q values, the interaction of the longitudinal acoustic excitation with the dispersionless mode gives rise to a pattern that is consistent with avoided-crossing behavior. Evidence is found for a slow- to fast-sound transition, similar to bulk water and other biomolecules. PMID- 30024173 TI - Iron-Catalyzed Decarboxylative Olefination of Cycloketone Oxime Esters with alpha,beta-Unsaturated Carboxylic Acids via C-C Bond Cleavage. AB - An iron-catalyzed redox-neutral, decarboxylative olefination of cycloketone oxime esters with alpha,beta-unsaturated carboxylic acids has been developed. This reaction involves an iminyl radical mediated C-C bond cleavage/radical addition/decarboxylation cascade. This protocol is highlighted by its low-cost catalytic system and readily accessible starting materials, as well as broad substrate scope, thus providing facile access to structurally diverse cyano containing alkenes. PMID- 30024174 TI - Zinc-Mediated Decarboxylative Alkylation of Gem-difluoroalkenes. AB - An efficient and mild zinc-mediated decarboxylative alkylation of gem difluoroalkenes with N-hydroxyphthalimide (NHP) esters, to give monofluoroalkenes in moderate to excellent yields with high Z-selectivity is reported. The reaction tolerates a broad range of functional groups and can be easily scaled up, which thus may pave the way for its further applications in medicinal chemistry and materials science. PMID- 30024175 TI - [4 + 2] Annulation Cascades of 2-Bromo-1-arylpropan-1-ones with Terminal Alkynes Involving C-Br/C-H Functionalization. AB - Straightforward access to various substituted naphthalenones by copper-catalyzed [4 + 2] annulation cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes is presented. Employing a Cu(MeCN)4PF4 catalyst and 1,10-phenanthroline (1,10 Phen) ligand enables the formation of three new C-C bonds in a single reaction via [4 + 2] annulation of a 2-bromo-1-arylpropan-1-one with an alkyne followed by alpha-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step efficiency. PMID- 30024176 TI - Enantioselective Synthesis of 2,2,3-Trisubstituted Indolines via Bimetallic Relay Catalysis of alpha-Diazoketones with Enones. AB - An efficient asymmetric intramolecular trapping of ammonium ylides of alpha diazoketones with enones to synthesize indoline derivatives was realized. A Rh(II)/chiral N,N'-dioxide-Sc(III) complex bimetallic relay catalytic system was established. A series of optically active 2,2,3-trisubstituted indolines were obtained in high yields (up to 99%), good enantioselectivities (up to 99% ee), and excellent diastereoselectivities (up to >19:1 dr) under mild reaction conditions. PMID- 30024177 TI - Bayesian argumentation and the value of logical validity. AB - According to the Bayesian paradigm in the psychology of reasoning, the norms by which everyday human cognition is best evaluated are probabilistic rather than logical in character. Recently, the Bayesian paradigm has been applied to the domain of argumentation, in which the fundamental norms are traditionally assumed to be logical. Here, we present a major generalization of extant Bayesian approaches to argumentation that (a) utilizes a new class of Bayesian learning methods that are better suited to modeling dynamic and conditional inferences than standard Bayesian conditionalization, (b) is able to characterize the special value of logically valid argument schemes in uncertain reasoning contexts, (c) greatly extends the range of inferences and argumentative phenomena that can be adequately described in a Bayesian framework, and (d) undermines some influential theoretical motivations for dual function models of human cognition. We conclude that the probabilistic norms given by the Bayesian approach to rationality are not necessarily at odds with the norms given by classical logic. Rather, the Bayesian theory of argumentation can be seen as justifying and enriching the argumentative norms of classical logic. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024178 TI - The association of parentification indicators with substance use patterns among military-connected adolescents. AB - Military-connected youths are a vulnerable population exposed to a unique set of stressors, which may put them at increased risk for adverse mental and behavioral health outcomes, compared to their civilian counterparts. Among military connected adolescents, emotional and instrumental parentification are mechanisms hypothesized to account for negative outcomes, including substance use. However, parentification may be protective in some cultures and has not been examined in the military population. Data were drawn from 1,441 7th-, 9th-, and 11th-graders who had a parent in the military and completed the 2013 California Healthy Kids Survey. Latent class analysis was used to examine patterns of instrumental parentification indicators among military-connected youths and associated patterns of substance use. Military-connected students in the high parentification class were significantly less likely to be in the frequent polysubstance using class (odds ratio = 0.376, 95% confidence interval [0.180, 0.782]). Findings suggest that experiences of instrumental parentification, including having more responsibilities at home, being more independent, and being able to solve problems better than peers, may be protective. For military connected youths, these skills, developed in the context of their families, may translate to better coping with other stressful situations. Professionals may be able to build on these strengths and develop adaptive coping strategies to support military-connected youths in managing the stressors of wartime military life. (PsycINFO Database Record PMID- 30024179 TI - A novel intervention for system-involved female intimate partner violence survivors: Changes in mental health. AB - Female intimate partner violence (IPV) survivors who are their children's primary caregivers are often mandated to services by child protection services (CPS) and/or the courts. Unfortunately, scant evidence exists regarding mandated programs for CPS- and/or court-involved IPV survivors, particularly the mental health outcomes of such programs. Two human service agencies in the southeastern United States collaborated to develop and implement a novel 13-week intervention to address the needs of these mothers' as related to safety, parenting, and mental health. The intervention uses a psychoeducation approach and participants are provided dinner, childcare, transportation, and on-site security. This community-based, quasi-experimental study gathered preliminary evidence regarding whether the intervention enhanced participants' (N = 70) mental health (i.e., depression and posttraumatic stress symptoms). Growth curve analyses using hierarchical linear modeling examined whether participants experienced improvements in mental health at completion (3 months) and follow-up (6 months). Participants reported significant improvements on depression and posttraumatic stress symptoms at both postintervention time points. This exploratory study provides preliminary support for engaging court- and CPS-involved female IPV survivors in specialized, group-based interventions designed to address their mental health needs. Future research should investigate this and other similar programming using (a) larger samples, (b) comparison groups, and (c) randomized designs. It will also be important to replicate this program in other settings to establish evidence for the intervention's underlying approach. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024180 TI - Development and validation of the Facial Expression Recognition Test (FERT). AB - Detecting the emotional state of others from facial expressions is a key ability in emotional competence and several instruments have been developed to assess it. Typical emotion recognition tests are assumed to be unidimensional, use pictures or videos of emotional portrayals as stimuli, and ask the participant which emotion is depicted in each stimulus. However, using actor portrayals adds a layer of difficulty in developing such a test: the portrayals may fail to be convincing and may convey a different emotion than intended. For this reason, evaluating and selecting stimuli is of crucial importance. Existing tests typically base item evaluation on consensus or expert judgment, but these methods could favor items with high agreement over items that better differentiate ability levels and they could not formally test the item pool for unidimensionality. To address these issues, the authors propose a new test, named Facial Expression Recognition Test (FERT), developed using an item response theory two-parameter logistic model. Data from 1,002 online participants were analyzed using both a unidimensional and a bifactor model, and showed that the item pool could be considered unidimensional. The selection was based on the items' discrimination parameters, retaining only the most informative items to investigate the latent ability. The resulting 36-item test was reliable and quick to administer. The authors found both a gender difference in the ability to recognize emotions and a decline of such ability with age. The PsychoPy implementation of the test and the scoring script are available on a Github repository. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024181 TI - Development and initial validation of the HEXACO-Triarchic scales. AB - The Triarchic Model posits that psychopathic personality traits are captured by three dimensions-boldness, meanness, and disinhibition. Recent findings indicate considerable overlap between the Triarchic constructs and the six-factor HEXACO (honesty-humility, emotionality, extraversion, agreeableness, conscientiousness, and openness to experience) model of normal personality traits (Ruchensky & Donnellan, 2017). The current study describes the development and validation of Triarchic proxy scales drawn from the HEXACO-100 item pool (Lee & Ashton, 2016) using two large undergraduate samples (Ns = 545, 398) and a community sample from MTurk (N = 391). The HEXACO-Triarchic scales were strongly correlated with other Triarchic measures and showed theoretically predicted relations with criterion variables. The HEXACO-Triarchic scales also appear to have greater discrimination between the three Triarchic dimensions compared with alternative measures. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024183 TI - Moral self-regulation, moral identity, and religiosity. AB - The association between religiosity and morality identified in self-reports has received limited support from studies of actual behavior. We propose that religiosity variables are likely to contribute to moral behavior in the context of moral self-regulation. Five studies examined the prediction that people who strongly endorse the items "I try hard to live all my life according to my religious beliefs" and "My whole approach to life is based on my religion" and people who report strong God belief would exhibit heightened moral emotions and prosocial behaviors after moral self-image (MSI) threats. Study 1 (N = 169) demonstrated that considering a recent moral transgression (the manipulation used in Studies 2-5) resulted in lower MSI, regardless of participants' levels of endorsement of religion-related items. Study 2 (N = 207) showed that following a threat to MSI, religiosity variables predicted heightened negative affect and self-conscious moral emotions. Studies 3 through 5 (combined N = 616) showed that following MSI threats, individuals endorsing intrinsic religiosity and God belief items showed increased prosocial task completion (Studies 3 and 5) and decreased cheating on a word-solving task (Study 4). Study 5 demonstrated that moral identity accounted for the role of religiosity variables in promoting moral self regulation following MSI threat. Noting that these findings are limited to people representative of the participants in these samples (Mechanical Turk workers; University of Missouri undergraduate students), and to the precise measures and manipulations used, implications of these findings and constraints on their generalizability are discussed. (PsycINFO Database Record PMID- 30024182 TI - Diurnal cortisol profiles, inflammation, and functional limitations in aging: Findings from the MIDUS study. AB - OBJECTIVE: The current study examined the association between diurnal cortisol profiles, inflammation, and functional limitations, among adults ranging in age from 34-84 years. METHOD: Participants (N = 799) completed Waves 2 (between 2004 and 2006) and 3 (between 2014 and 2016) of the Midlife Development in the United States Survey. At Wave 2, participants provided saliva samples across 4 consecutive days, from which cortisol was assayed. Previously validated diurnal cortisol profiles (i.e., normative, flattened, or elevated) were examined in relation to concurrent inflammation risk burden and to predict long-term changes in functional limitations. RESULTS: Compared with participants with normative profiles across all interview days, participants with dysregulated profiles across all interview days (i.e., all days elevated, flattened, or a combination of elevated and flattened) showed greater concurrent inflammation risk burden and more functional limitations at follow-up. Regions of significance testing indicated that the association was significant beginning at age 60 for inflammation risk burden and beginning at age 66 for functional limitations. Variable profiles (i.e., a mix of normative and flattened and/or elevated across the four days of assessment) were not significantly associated with these health indices. CONCLUSIONS: Findings, consistent with the theoretical model of Strength and Vulnerability Integration, illustrate the importance of considering age when examining cortisol and its association with other health indices. (PsycINFO Database Record PMID- 30024186 TI - Safety training transfer: The roles of coworkers, supervisors, safety professionals, and felt responsibility. AB - The aim of this study is to identify the influence of social dimensions of the work environment and the employees' felt responsibility on the transfer of safety training. We tested a model in which responses and reactions from safety players such as coworkers, supervisors, and safety professionals are positively related to the transfer of training (TT), through the mediating effect of the employees' felt responsibility and the moderating influence of supervisor support and sanctions. A two-time data collection was implemented among blue-collar employees, all low qualified, from four city councils who attended a fundamental safety training program delivered by in-house safety trainers, all safety professionals (n = 203). Data analysis revealed that (a) supervisors' safety responses, coworkers' safety responses, and safety professionals' reactions positively influenced the TT, an effect (b) mediated by employees' felt responsibility and (c) moderated by supervisor sanctions, but not by supervisor support. The results suggest that high sanctions enhance the positive effect of high self-responsibility on TT, and, importantly, aggravate the negative effect of low self-responsibility on TT. This is the first study to empirically test both the influence of felt responsibility and the safety professionals' reactions in the transfer process. Research should continue to examine the former construct's influence on the transfer process including, for example, its effect on supervisor support, and the latter as a safety-related social dimension variable of the work environment. (PsycINFO Database Record PMID- 30024184 TI - What doesn't kill you makes you stronger: Psychological trauma and its relationship to enhanced memory control. AB - Control processes engaged in halting the automatic retrieval of unwanted memories have been shown to reduce the later recallability of the targets of suppression. Like other cognitive skills that benefit from practice, we hypothesized that memory control is similarly experience dependent, such that individuals with greater real-life experience at stopping retrieval would exhibit better inhibitory control over unwanted memories. Across two experiments, we found that college students reporting a greater history of trauma exhibited more suppression induced forgetting of both negative and neutral memories than did those in a matched group who had reported experiencing little to no trauma. The association was especially evident on a test of suppression-induced forgetting involving independent retrieval cues that are designed to better isolate the effects of inhibitory control on memory. Participants reporting more trauma demonstrated greater generalized forgetting of suppressed material. These findings raise the possibility that, given proper training, individuals can learn to better manage intrusive experiences, and are broadly consistent with the view that moderate adversity can foster resilience later in life. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024187 TI - A cluster-analytic approach to determining drinking motives and personality typologies: Trauma group differences and respective relations to PTSD and problematic alcohol use. AB - Veterans with posttraumatic stress disorder (PTSD) are at elevated risk for alcohol use problems, a relationship commonly explained by using alcohol to cope with unpleasant symptoms of PTSD. However, patterns of alcohol use motives, more broadly, have not been well characterized in veteran samples, nor have they been evaluated in the context of other relevant factors, such as normative personality traits. The aims of the present study were to identify empirically derived drinking motive and personality typologies to determine whether these typologies differ as a function of PTSD status (i.e., nontrauma control, trauma exposed-no PTSD, and PTSD) and to evaluate associations between typology and PTSD symptom severity and alcohol consumption, respectively. Cluster analyses identified a 4 cluster solution. Results indicated that these typologies differed significantly according to trauma group as well as across levels of PTSD symptom severity and alcohol use. Specifically, Cluster 4 represented individuals at highest risk for both PTSD symptom severity and alcohol use compared to all the other typologies; Cluster 1 demonstrated lowest risk for PTSD symptom severity and alcohol use compared to all other typologies; and although Clusters 2 and 3 did not differ according to PTSD symptom severity, individuals in Cluster 2 had significantly higher alcohol use. These results represent certain "at risk" versus "protective" typologies that may facilitate the identification of individuals at risk for comorbid PTSD and problematic alcohol use. (PsycINFO Database Record PMID- 30024189 TI - Diary of an aircraft carrier psychologist. AB - U.S. Navy Psychologists have distinctive jobs in service to our Armed Forces that occasionally take them out of traditional clinic settings and into operational environments. This article highlights the unique role of psychologists serving on aircraft carriers, living and working among the population that they serve onboard massive warships to bring mental health services to deploying warfighters. Despite unconventional work surroundings, clinical conundrums, and a sometimes isolating occupational role, the adventures and professional rewards are boundless in service of those who sacrifice for our nation. (PsycINFO Database Record PMID- 30024188 TI - Technology-mediated addictive behaviors constitute a spectrum of related yet distinct conditions: A network perspective. AB - An important ongoing debate in the addiction field is whether certain technology mediated behaviors constitute tenable and independent constructs. This study investigated whether problematic technology-mediated behaviors could be conceptualized as a spectrum of related, yet distinct disorders (spectrum hypothesis), using the network approach, which considers disorders as networks of symptoms. We used data from the Cohort Study on Substance Use and Risk Factors (C SURF; Swiss National Science Foundation), with a representative sample of young Swiss men (subsample of participants engaged in technology-mediated behaviors, n = 3,404). Four technology-mediated addictive behaviors were investigated using symptoms derived from the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) and the component model of addiction: Internet, smartphone, gaming, and cybersex. Network analyses included network estimation and visualization, community detection tests, and centrality indices. The network analysis identified four distinct clusters corresponding to each condition, but only Internet addiction had numerous relationships with the other behaviors. This finding, along with the finding that there were few relationships between the other behaviors, suggests that smartphone addiction, gaming addiction, and cybersex addiction are relatively independent constructs. Internet Addiction was often connected with other conditions through the same symptoms, suggesting that it could be conceptualized as an "umbrella construct," that is, a common vector that mediates specific online behaviors. The network analysis thus provides a preliminary support to the spectrum hypothesis and the focus on the specific activities performed online, while showing that the construct of Internet addiction is inadequate. (PsycINFO Database Record PMID- 30024185 TI - Implementing an intervention to address challenging behaviors for autism spectrum disorder in publicly-funded mental health services: Therapist and parent perceptions of delivery with Latinx families. AB - OBJECTIVES: As implementation of evidence-based practices (EBPs) in publicly funded children's mental health services has become increasingly common, concerns have been raised about the appropriateness of specific EBPs to the diverse client populations served in these settings. Exploring stakeholder perspectives can provide direction for refinements of EBPs when delivered with Latinx families. The current study used qualitative methods to examine therapist and Latinx parent perceptions of therapist-parent interactions and the intervention process when therapists are trained to deliver AIM HI (An Individualized Mental Health Intervention for ASD), a structured, parent-mediated intervention for autism spectrum disorder (ASD). METHOD: Therapist and parent participants were a subset of participants from a large-scale community effectiveness trial. Perceptions were gathered through focus groups with therapists (n = 17) and semistructured interviews with Latinx parents (n = 29). Therapists were 94% female, 35% Latinx, and 47% were fluent in Spanish. Parents were 93% female, 100% Latinx, and 66% preferred Spanish. A coding, consensus, co-occurrence and comparison approach was used to analyze data. RESULTS: Three primary themes emerged: (a) limited parental knowledge about ASD and the need to address knowledge gaps; (b) differing perceptions regarding parental participation in treatment; and (c) identification of influences on parent-therapist interaction, including the cultural value of respeto/deference (emphasized by therapists), and importance of personalismo/personal connection (emphasized by parents). CONCLUSIONS: The themes provide specific direction for enhancements to AIM HI to maximize engagement of Latinx families. The themes also have broader implications for intervention development and community implementation including refinement of EBPs to facilitate fit and sustained implementation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024190 TI - Development of the Perceived Access Inventory: A patient-centered measure of access to mental health care. AB - According to recent Congressional testimony by the Secretary for Veterans Affairs (VA), improving the timeliness of services is one of five current priorities for VA. A comprehensive access measure, grounded in veterans' experience, is essential to support VA's efforts to improve access. In this article, the authors describe the process they used to develop the Perceived Access Inventory (PAI), a veteran-centered measure of perceived access to mental health services. They used a multiphase, mixed-methods approach to develop the PAI. Each phase built on and was informed by preceding phases. In Phase 1, the authors conducted 80 individual, semistructured, qualitative interviews with veterans from 3 geographic regions to elicit the barriers and facilitators they experienced in seeking mental health care. In Phase 2, they generated a preliminary set of 77 PAI items based on Phase 1 qualitative data. In Phase 3, an external expert panel rated the preliminary PAI items in terms of relevance and importance, and provided feedback on format and response options. Thirty-nine PAI items resulted from Phase 3. In Phase 4, veterans gave feedback on the readability and understandability of the PAI items generated in Phase 3. Following completion of these 4 developmental phases, the PAI included 43 items addressing 5 domains: logistics (five items), culture (three items), digital (nine items), systems of care (13 items), and experiences of care (13 items). Future work will evaluate concurrent and predictive validity, test/retest reliability, sensitivity to change, and the need for further item reduction. (PsycINFO Database Record PMID- 30024191 TI - Self-affirming values to increase student veterans' intentions to seek counseling. AB - Student veterans experiencing mental health concerns could benefit from seeking counseling (Rudd, Goulding, & Bryan, 2011), though they often avoid these services. Self-affirmation interventions have been developed to increase openness to health-related behaviors (Sherman & Cohen, 2006), and may also help promote psychological help-seeking intentions. This study explored whether a self affirmation intervention increased intentions to seek counseling in a sample of 74 student veterans who had not previously sought counseling services. Participants completed pretest (Time 1) measures of distress and help seeking (i.e., self-stigma, attitudes, and intentions to seek counseling). A week later (Time 2), participants completed one of two conditions: (1) a self-affirmation intervention before viewing a psychoeducational video and brochure or (2) only the psychoeducational video and brochure before completing the same help-seeking measures as Time 1. A week after the intervention (Time 3), participants again completed the help-seeking measures. A focused longitudinal mediation model was conducted, examining the effect of the self-affirmation experimental condition on help-seeking intentions. Compared with those in the psychoeducation-only group, student veterans who completed the self-affirmation intervention reported increased intentions to seek counseling both immediately postintervention (Time 2) and a week later (Time 3). (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024192 TI - Career development among undocumented immigrant young adults: A psychology of working perspective. AB - Undocumented immigrants are among the most vulnerable of workers in the U.S. and face a unique set of barriers to obtaining adequate education and decent work. In the current study, we conducted a qualitative examination of the career development of undocumented young adults. Drawing from the Psychology of Working Theory (PWT; Duffy, Blustein, Diemer, & Autin, 2016), we examined barriers (e.g., economic constraints, marginalization) and resources (e.g., social support, critical consciousness, proactive personality) to participants' career development and sense of work volition. As a secondary aim, we explored general work attitudes. Using Consensual Qualitative Research methods, we interviewed 12 undocumented young adults between the ages of 18 and 26. All participants were DACA recipients. Barriers that most impacted work volition were economic strain and limited mobility; resources that were most supportive for work volition were social support, institutional support, and public policy changes. Regarding work attitudes, participants endorsed a high value of a strong work ethic, a variety of motivations to work, and a high degree of resilience. Implications for counseling psychologists, career development specialists, educators, and policymakers are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024193 TI - Moderators of congruent alliance between therapists and clients: A realistic accuracy model. AB - Congruence between therapists' and their clients' alliance ratings was found to be beneficial to therapeutic processes and outcomes. To date, however, less is known about the possible moderators of such congruence. The current study adapted Funder's (1995) realistic accuracy model to identify a judge characteristic (therapists' affiliative tendencies), a target characteristic (clients' affiliative tendencies), information (time elapsed in therapy), and traits (bond vs. task/goal aspects of the alliance) that may moderate this congruence. These were examined using the innovative truth-and-bias model (West & Kenny, 2011), which allows the simultaneous estimation of two different congruence indices within repeatedly measured data: therapist/client temporal congruence (i.e., the correlation over time between therapists' and their clients' alliance ratings) and directional discrepancy (i.e., the average difference between therapists' and their clients' alliance ratings across sessions). Clients (n = 109) and therapists (n = 62) at a university-based clinic rated their affiliation tendencies at the beginning of treatment and rated their alliance perception after each session. Time elapsed in therapy, as well as therapists' (but not clients') affiliative tendencies were linked to higher therapist/client temporal congruence and to lower therapist directional discrepancy. In addition, congruence was higher for the bond aspect of the therapeutic alliance than for goals/tasks. Consistent with Funder's model, multiple factors (including judge, information, and trait) were associated with therapist/client congruence in alliance. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024194 TI - Personality disorder traits: Testing insight regarding presence of traits, impairment, and desire for change. AB - Mixed findings exist as to whether personality pathology involves a critical lack of awareness and insight. Research questions about insight and awareness in personality pathology are typically assessed via comparing self- and informant reports of traits. However, recent studies have measured insight by asking individuals to evaluate additional questions about impairment and desire to change. The present study uses a variety of approaches to examine these issues, including investigations of convergence between self- and informant reports (N = 197 dyads; correlations and comparisons of means) of personality psychopathology, desired trait levels, and perceptions of impairment. Convergence was observed between levels of self- and informant-reported traits, desired traits, and impairment. However, individuals rated themselves higher on pathological trait levels and impairment than did their informants. Furthermore, individuals with relatively higher pathological traits desired higher levels of these traits (but lower than their actual scores) than individuals with lower scores; on the actual measurement scale, however, these higher scorers rated their desired level below the neutral point. Overall, individuals with pathological personality traits possess a reasonable degree of insight into their actual trait levels and associated impairment. (PsycINFO Database Record PMID- 30024195 TI - Momentary assessment of everyday physical pain in outpatients with borderline personality disorder. AB - Borderline personality disorder (BPD) is a severe psychiatric disorder associated with dysregulation in multiple domains of functioning. Physical health, and specifically pain, is one such domain that has gone understudied. Although evidence suggests that BPD is associated with chronic pain, few studies have examined nonchronic pain in the disorder. The current study used ambulatory assessment to examine momentary physical pain in everyday life in BPD outpatients (N = 26) and community comparisons (COM; N = 26) not in treatment for chronic pain (Nobservations = 5,458). We predicted and observed that BPD outpatients would report greater pain intensity and greater pain variability than COM comparisons. We also examined the relationship of pain and emotion dysregulation, a core feature of BPD, by testing the association between pain and negative affect concurrently and lagged over time. We predicted that momentary pain and negative affect would be associated in both groups, but that pain would predict negative affect more strongly in the BPD group. As predicted, concurrent pain and negative affect were associated in both groups, and groups differed significantly in terms of the association of lagged pain and next-assessment negative affect, with a negative association in the COM group. The current study represents a preliminary first step, finding that pain is relevant to the everyday experience of BPD individuals. This pain propensity may contribute to the elevated prevalence of BPD in chronic pain samples. Further, BPD individuals demonstrated emotional reactivity to pain, suggesting that pain may be a contributor to emotion dysregulation in this disorder. (PsycINFO Database Record PMID- 30024196 TI - Transactive memory systems in context: A meta-analytic examination of contextual factors in transactive memory systems development and team performance. AB - Research on transactive memory systems (TMS) has been conducted in a variety of teams, a range of task types and increasingly, in settings around the world. Despite this proliferation, there has been relative inattention to contextual factors that produce TMS and explain heterogeneity in the TMS to team performance relationship. TMS studies are typically conducted in homogeneous settings (i.e., teams located in a single country) and often with sources of potential variation (i.e., environmental volatility, leadership, team human capital, and diversity) in TMS development controlled. Collating these individual studies, we use meta analytic techniques to illuminate key contextual factors that may shape TMS and influence the TMS-performance association. Using 76 empirical studies representing 6,869 sampling units, we find that the strength of the TMS to performance relationship varies, depending on features of the national cultural context-the impact of TMS is stronger in cultural contexts where power distance and in-group collectivism are higher. Our results also suggest that environmental volatility, leadership effectiveness, and team human capital are positively associated with TMS, and informational and gender diversity are negatively associated with TMS development. Our findings also indicate fruitful areas for future research specifically aimed toward disentangling the effects of environmental, team, and national cultural context on TMS and team performance. (PsycINFO Database Record PMID- 30024197 TI - Gender productivity gap among star performers in STEM and other scientific fields. AB - We examined the gender productivity gap in science, technology, engineering, mathematics, and other scientific fields (i.e., applied psychology, mathematical psychology), specifically among star performers. Study 1 included 3,853 researchers who published 3,161 articles in mathematics. Study 2 included 45,007 researchers who published 7,746 articles in genetics. Study 3 included 4,081 researchers who published 2,807 articles in applied psychology and 6,337 researchers who published 3,796 articles in mathematical psychology. Results showed that (a) the power law with exponential cutoff is the best-fitting distribution of research productivity across fields and gender groups and (b) there is a considerable gender productivity gap among stars in favor of men across fields. Specifically, the underrepresentation of women is more extreme as we consider more elite ranges of performance (i.e., top 10%, 5%, and 1% of performers). Conceptually, results suggest that individuals vary in research productivity predominantly because of the generative mechanism of incremental differentiation, which is the mechanism that produces power laws with exponential cutoffs. Also, results suggest that incremental differentiation occurs to a greater degree among men and certain forms of discrimination may disproportionately constrain women's output increments. Practically, results suggest that women may have to accumulate more scientific knowledge, resources, and social capital to achieve the same level of increase in total outputs as their male counterparts. Finally, we offer recommendations on interventions aimed at reducing constraints for incremental differentiation among women that could be useful for narrowing the gender productivity gap specifically among star performers. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024198 TI - Too many sheep in the flock? Span of control attenuates the influence of ethical leadership. AB - There has been growing interest in ethical leadership from both scholars and practitioners because of the positive effects that ethical leaders can have on their subordinates. These benefits come not only from ethical leaders acting as moral exemplars, but also from the tendency for ethical leaders to forge high quality social exchange relationships with subordinates that help to establish expectations for appropriate conduct and ensure accountability through reciprocal obligation. However, the act of developing and maintaining strong social exchange relationships is resource intensive and requires considerable personal investment from ethical leaders. Extending current theory, we propose that wider spans of control attenuate the positive relationship between ethical leadership and leader member exchange (LMX). Across two organizational samples, we developed and tested a moderated mediation model in which the effects of ethical leadership on performance, organizational citizenship behavior, and reduced production deviance via LMX were weakened by a widened span of control. Results in both studies supported the hypothesized model. Although it may be tempting to increase the number of subordinates assigned to ethical leaders in an effort to maximize their positive impact, the current findings suggest that the benefits of ethical leadership are diminished as span of control widens. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024200 TI - Development of the Multiple Sclerosis Resiliency Scale (MSRS). AB - OBJECTIVES: While resilience has been an area of increasing research, there are no measures that are specific to the psychological, social, and physical factors associated with resilience in persons with multiple sclerosis (PwMS). This study aimed to develop the MS Resiliency Scale (MSRS), a multidimensional measure. Items were created based on a review of the literature, with five hypothesized subscales, and then evaluated in a large sample of PwMS. METHOD: Participants (N = 932) were primarily recruited through the North American Research Committee on MS (NARCOMS) and completed the study electronically. Principal components analysis was utilized to determine the number of factors and whether they aligned with the theorized model. RESULTS: Using an unforced solution with oblique (promax) rotation and Kaiser normalization, and suppressing items with coefficients below 0.4, 25 items were retained in five subscales that accounted for 42.75% of the variance: Emotional and Cognitive Strategies (13 items; alpha = .92), Physical Activity and Diet (3 items; alpha = .77), MS Peer Support (2 items; alpha = .82), Support from Family and Friends (5 items; alpha = .79), and Spirituality (2 items; alpha = .91). The total score was negatively correlated with depression, r = -.72, p < .001 and anxiety, r = -.56, p < .001. IMPLICATIONS: The 25-item MSRS assesses several psychological, social, and physical factors associated with resilience in PwMS, and may be a helpful tool in identifying individuals in need of additional assistance or support. (PsycINFO Database Record PMID- 30024201 TI - Qualitative study of barriers and facilitators to cigarette smoking after spinal cord injury. AB - OBJECTIVE: Persons with spinal cord injury (SCI) have been shown to have rates of smoking as high as or higher than the general population. As those with SCI are at increased risk for negative health outcomes and early mortality, smoking can be especially dangerous. Our purpose was to assess barriers and facilitators of smoking cessation as defined by those with SCI. METHOD: Participants (N = 30) were identified through a state surveillance registry (n = 27) and volunteers from the statewide SCI Association (n = 3). All participants reported smoking cigarettes at some point postinjury. Both current smokers and former smokers were included. A semistructured focus group interview format included questions about health, personal, and policy factors related to smoking and smoking cessation after SCI. Groups discussions were recorded, transcribed, and coded into conceptual categories to identify themes and patterns, and inferences were drawn about their meaning using NVivo software for data analysis. RESULTS: We categorized preliminary results into two categories: barriers to smoking cessation and facilitators of smoking cessation. Within barriers to smoking cessation, themes included comorbid alcohol use, boredom, and the social environment that encourages smoking. Within facilitators of smoking cessation, themes included cost, health concerns, health care professionals, and social support that encourages quitting. CONCLUSIONS: These categories and themes identify the key barriers and facilitators of smoking cessation in this sample of persons with SCI. Future studies should further quantify specific facilitators and barriers within smoking-related studies and address these in intervention programs and studies of smoking cessation. (PsycINFO Database Record PMID- 30024199 TI - A comparison of PHQ-9 and TBI-QOL depression measures among individuals with traumatic brain injury. AB - PURPOSE/OBJECTIVE: To compare and contrast how individuals with traumatic brain injury (TBI) are classified (positive or negative screen) by different cut-offs on two self-report measures of depressive symptoms: the PHQ-9, which assesses somatic symptoms, and the TBI-QOL Depression item bank, which does not. Research Method/Design: Three hundred eighty-five individuals with TBI were recruited from six rehabilitation hospitals in the U.S. as part of the calibration data collection for the TBI-QOL patient-reported outcome measurement system. RESULTS: The TBI-QOL and PHQ-9 total scores correlated strongly (disattenuated r = .83). The correlation was even stronger (disattenuated r = .92) when the four PHQ-9 somatic items were removed from the total score. When the PHQ-9 was scored traditionally, the rate of agreement was approximately 80-85% using standard cut offs for each scale. Depending on the cut-off score, 23-26% of participants screened positive on the PHQ-9, whereas 9-38% screened positive on the TBI-QOL Depression. Individuals who screened positive on the PHQ-9 alone reported more somatic symptoms than those who screened positive on the TBI-QOL alone. Individuals who screened positive on the TBI-QOL alone were at slightly greater risk for other negative psychological functioning than individuals who screened positive on the PHQ-9 alone. CONCLUSIONS/IMPLICATIONS: The PHQ-9 and TBI-QOL Depression performed similarly in screening for depressive symptoms among individuals with TBI. The PHQ-9 identified more individuals with somatic symptoms, which may overlap with other medical issues, whereas the TBI-QOL Depression instrument identified more individuals who reported other forms of emotional distress. (PsycINFO Database Record PMID- 30024202 TI - Impact of frontal neurobehavioral symptoms on employment in individuals with TBI. AB - OBJECTIVE: To explore the contribution of frontal systems behavioral dysfunction on employment outcomes in individuals with traumatic brain injury (TBI), in the context of relevant predictors of work status. METHOD: Forty-two participants with history of moderate-to-severe TBI were classified as either "Employed" or "Unemployed." Groups did not differ on most demographic or injury variables, although the Unemployed sample reported greater symptoms of depression, pain, and fatigue (ps < 0.05). Participants completed a neuropsychological evaluation emphasizing frontal systems and Frontal Systems Behavior Scale (FrsBe; self- and informant-rated forms). RESULTS: T tests using cognitive indicators of frontal dysfunction revealed no significant differences between groups (ps > 0.05). T tests using neurobehavioral indicators of frontal dysfunction (i.e., FrSBe) revealed differences between groups on both self- (Hedge's g = 0.71; p = .046) and informant-rated (g = 1.12; p = .001) FrSBe total T scores. Two logistic regressions for each FrSBe score were conducted, including relevant variables on which samples differed as covariates. Only the informant-rated FrSBe score remained a significant predictor of employment (FrSBe-informant: p = .038; R squared change = 0.177). Self- and informant-rated FrSBe scores were significantly correlated in the Unemployed group (r = .403; p = .037) but not in the Employed sample (r = .102; p = .717). CONCLUSIONS: These results suggest that behavioral indicators of frontal systems dysfunction are predictive of employment status in individuals with TBI. Future work should aim to test the efficacy of strategies to reduce dysfunctional frontal behaviors as a means to gain and maintain employment. (PsycINFO Database Record PMID- 30024203 TI - Promoting resilience in individuals aging with multiple sclerosis: Results from a pilot randomized controlled trial. AB - PURPOSE/OBJECTIVE: Starting in middle adulthood, individuals living with multiple sclerosis (MS) are confronted with the simultaneous challenge of coping with advancing MS alongside age-related changes. Psychological resilience is thought to play an important role in promoting healthy aging and thus may be important in the context of aging with MS. This study aimed to evaluate whether Everyday Matters, a novel positive psychology program, had a positive effect on resilience and other related outcomes in adults with MS relative to a wait-list control group. Research Method/Design: This was a single-center two-group pilot randomized (1:1) controlled trial comparing the Everyday Matters intervention to a waitlist control. Randomized participants were N = 31 adults with MS aged >= 45 years. The 6-week program, developed by the National MS Society, was delivered via group teleconference and supplemented with readings, videos, and online participation. Participants in both groups completed outcome assessments measuring resilience, satisfaction with social roles, mood, pain, fatigue, and sleep at baseline and posttreatment. RESULTS: Analyses on N = 27 participants who completed study assessments revealed a significant group effect for resilience and satisfaction with social roles, and trend differences for positive affect and well-being and depressive symptom severity. At posttreatment, participants in the intervention group reported the group to be very helpful, found the telephone based delivery convenient, and felt the benefits of participating outweighed the effort. CONCLUSIONS/IMPLICATIONS: These results suggest that the Everyday Matters program shows promise for increasing resilience in adults with MS and that a full scale randomized controlled trial is warranted. (PsycINFO Database Record PMID- 30024204 TI - Moving forward on the journey: Spirituality and family resilience after spinal cord injury. AB - PURPOSE/OBJECTIVE: The aim of this exploratory study was to consider how spirituality (encompassing meaning, hope and purpose), may facilitate family resilience after spinal cord injury (SCI) over time. Research Method/Design: A qualitative, longitudinal study design was adopted. Semistructured interviews were conducted with 10 family dyads (consisting of the individual with SCI and a nominated family member) on 2 occasions, 6 months apart. A thematic analysis was conducted. RESULTS: Participants reported drawing upon a range of different sources of spirituality, including religious faith, the natural world, inner strength, and meaningful connectedness with others. These sources of spirituality were often tested in some way after the SCI. Meaning-making responses to these tests were linked with 3 key outcomes: gratitude, hope, and deeper connectedness with others, assisting families to move forward in their journey after SCI. Over time sources of spirituality did not change significantly; however, the intensity of spiritual experience lessened for some families. CONCLUSIONS: This study indicated that spirituality after SCI plays an important role for both the injured individual and their family members. Families draw upon a range of sources of spirituality, and these sources of spirituality may assist the family to move forward together after SCI. Further investigation of how health professionals can better address spirituality during spinal rehabilitation is warranted. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024205 TI - Yellow flags as predictors of rehabilitation outcome in chronic low back pain. AB - OBJECTIVE: While it is agreed that yellow flags (prognostic psychosocial factors for poor recovery in low back pain) predict pain-related outcomes, uncertainty remains regarding which constructs are the central ones, particularly as there is considerable conceptual overlap between constructs. Therefore, the aim of our study was to analyze the distinctiveness of different psychological factors in predicting rehabilitation outcomes in a sample of patients with chronic low back pain (CLBP) in a rehabilitation setting. Research Method/Design: We conducted a longitudinal study using multivariable modeling taking into account a broad set of psychological variables as potential predictors. Rehabilitation outcome was assessed via health related quality of life (HRQL) and disease-specific functioning at the end of rehabilitation and six months later. The sample comprised N = 214 patients. RESULTS: When considered separately, a range of psychological factors were significant predictors of HRQL and functioning at the end of rehabilitation and at six months follow-up, even if baseline values of outcome variables, sociodemographic variables, and baseline pain intensity are controlled. When considered in combination, a better work prognosis, self efficacy and intensity of depressive symptoms were verified as independently significant predictors of HRQL. None of the psychological constructs remained significant predictors for disease-specific functioning. The incremental variance explained by the psychological constructs varied between 3 and 24%. CONCLUSIONS: The contribution of psychological factors may be different depending on the sample (acute vs. chronic) and the outcome domain. Future research should validate these results with respect to other patient-centered outcomes and in other CLBP samples. (PsycINFO Database Record PMID- 30024206 TI - People can change: Measuring individual variability in rehabilitation science. AB - PURPOSE/OBJECTIVE: The purpose of this report is to provide rehabilitation researchers with an explanation of multilevel item response theory (MLIRT), specifically applied to data collected using ecological momentary assessment (EMA) methods. DESIGN: This is a didactic brief report of a statistical method. The advantages of the method are illustrated using examples from the literature or clinical experience, and potential implications for rehabilitation science are highlighted. RESULTS: Multilevel item response theory can be a used in rehabilitation research to develop items that characterize within-individual changes in disability, measure disability with instruments that have not yet been used in an EMA framework, examine temporal patterns of behaviors or symptoms that are associated with disability, or create adaptive tests based on individual performance. CONCLUSIONS: MLIRT methods are underutilized in rehabilitation research despite their unique advantages. Psychometric properties of instruments used to measure change over time should be evaluated at the within-individual level. Additionally, MLIRT offers opportunity to investigate temporal variability of behaviors or symptoms, and can potentially reduce participant burden when used in adaptive testing. (PsycINFO Database Record PMID- 30024208 TI - Retrieval effort cues predict eyewitness accuracy. AB - Previous research has documented that correct eyewitness memories are more rapidly recalled and recognized than are incorrect ones, suggesting that retrieval ease is diagnostic of memory accuracy. Building on these findings, the current research explores whether verbal and paraverbal cues to retrieval effort could be used to determine the accuracy of honestly reported eyewitness statements about a crime event. Moreover, we examine the relative role of such effort cues and witnesses' subjective confidence in predicting memory accuracy. The results of 2 studies demonstrate that objectively verifiable verbal and paraverbal cues to retrieval effort are strongly related to honest witnesses' memory accuracy and that several of these cues contribute uniquely to predict accuracy. Moreover, we show that subjective confidence in a memory rests on these effort cues and that the cues mediate the confidence-accuracy relation. Given research showing that most people have vast difficulties in judging the quality of others' memories, combined with the scarcity of research on predictors of genuinely reported memories, these initial findings suggest unexplored alternatives that may prove highly useful for improving accuracy judgments, with potentially far-reaching significance not the least in the legal context. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024207 TI - Social Participation and Navigation (SPAN) program for adolescents with acquired brain injury: Pilot findings. AB - PURPOSE/OBJECTIVE: Our goal was to examine the feasibility and preliminary efficacy of an app-based coaching intervention (Social Participation and Navigation; SPAN) to help survivors of acquired brain injury attain social participation goals. Research Method/Design: This is a nonrandomized pilot trial of SPAN, including 15 adolescents (9 with traumatic brain injury, 6 with brain tumor) between the ages of 14-22. The SPAN intervention consisted of a mobile app to support the development and implementation of social participation goals, weekly video-conference coaching sessions to identify goals and step-by-step action plans, and online didactic materials. Assessments were completed pre- and postintervention. Satisfaction with the intervention, confidence in the adolescents' ability to participate in and plan social activities and manage their emotions and behaviors, and frequency and satisfaction with social participation were assessed via self- and parent-report questionnaires developed for this project. Behavior problems, social competence, and social problems were measured by using the Child Behavior Checklist and the Youth Self-Report. RESULTS: High levels of participant and parent satisfaction were reported. Increases in parent-reported frequency of social participation and teen-reported confidence in their ability to participate and develop social participation goals and plans were observed. A decline in parent-reported total problems, internalizing problems, externalizing problems, and social problems was noted. CONCLUSION/IMPLICATIONS: Results support the feasibility of the program, because participants were able to successfully meet with their coaches and use the app to develop and accomplish social participation goals. Further research will be needed to refine the app and program, particularly when reaching out to populations beyond traumatic brain injury. (PsycINFO Database Record PMID- 30024209 TI - Disadvantaged but not dissatisfied: How agency ameliorates negative reactions to unequal pay. AB - Workers tend to be dissatisfied when their peers receive more than them for doing the same work. The fear of creating such dissatisfaction may cause leaders in organizations to waste resources that cannot be allocated equally between their workers. Here we explore the effectiveness of a procedure designed to reduce such waste by empowering workers with the agency to decide whether or not to pay other workers more. We predict that workers' sense of agency reduces their dissatisfaction with others' better outcomes. Seven studies supported this prediction by demonstrating that agentic participants, who were involved in creating allocations, tended to be more satisfied with others' better outcomes than nonagentic participants, who were not involved in creating allocations. Longitudinal lab studies, measuring real behavior, showed that agentic participants remained more satisfied than nonagentic ones even five weeks after their initial decision. The findings provided evidence for two mechanisms underlying the effect: increased feelings of generosity, and reduced perception of unfairness. We found that the agency procedure was comparable with other fair procedures in its ability to improve worker satisfaction. We discuss our findings in relation to the literatures on social preference, fairness, and voice, and highlight the implications for organizational efficiency. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024210 TI - Making the leader identity salient can be demotivating. AB - Extensive research has shown that when a social identity is made salient, people tend to embrace positive identities (e.g., being a voter) and shy away from negative identities (e.g., being a cheater). The present research proposes that this effect of identity salience could be reversed for identities that cannot be attained or rejected by engaging in simple behaviors (e.g., being a leader). People perceived leadership education programs that highlighted the leader identity as more difficult (Studies 1 and 3), and were less interested in signing up for such programs (Study 2). People performed worse when learning educational material framed in terms of the leader identity (Study 4). However, a growth mindset about leadership ability reduced the negative effects of identity frames on performance (Study 4). These findings highlight that the motivational effects of making identities salient might not hold for identities that cannot be attained by executing simple behaviors. (PsycINFO Database Record PMID- 30024211 TI - Experts integrate explicit contextual priors and environmental information to improve anticipation efficiency. AB - The understanding of how experts integrate prior situation-specific information (i.e., contextual priors) with emergent visual information when performing dynamic and temporally constrained tasks is limited. We used a soccer-based anticipation task to examine the ability of expert and novice players to integrate prior information about an opponent's action tendencies with unfolding environmental information such as opponent kinematics. We recorded gaze behaviors and ongoing expectations during task performance. Moreover, we assessed their final anticipatory judgments and perceived levels of cognitive effort invested. Explicit contextual priors biased the allocation of visual attention and shaped ongoing expectations in experts but not in novices. When the final action was congruent with the most likely action given the opponent's action tendencies, the contextual priors enhanced the final judgments for both groups. For incongruent trials, the explicit priors had a negative impact on the final judgments of novices but not experts. We interpreted the data using a Bayesian framework to provide novel insights into how contextual priors and dynamic environmental information are combined when making decisions under time pressure. Moreover, we provide evidence that this integration is governed by the temporal relevance of the information at hand as well as the ability to infer this relevance. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024212 TI - A bias for action in cancer screening? AB - Research that has explored public enthusiasm for cancer screening has suggested that the public may be overly enthusiastic about being screened with certain tests, and this has been attributed, in part, to lack of knowledge about the risks and benefits. In this article the authors considered the possibility that some people may be enthusiastic about screening even when they are informed and also accept that the test unquestionably does not save lives. Two studies were conducted, one that involved a nationally representative U.S. sample and another that involved an online convenience sample. All participants were asked whether they would want to receive a hypothetical screening test for breast (women) or prostate (men) cancer that does not reduce the chance of cancer death or extend the length of life. Over half of participants wanted to receive the described screening test. Many people did not believe that cancer screening might not save lives, yet screening preferences were not due to disbelief alone. Results further suggested that cancer worry, reassurance, and a desire for health information explained variance in preferences for unbeneficial screening, adjusting for beliefs about screening benefits, perceptions of screening risks, family history, perceptions of cancer risk, and demographics. (PsycINFO Database Record PMID- 30024213 TI - Godless by association: Deficits in trust mediate antiatheist stigma-by association. AB - In the United States, atheists elicit high levels of sociopolitical rejection that is primarily motivated by a lack of trust. Across three studies, we use evaluative conditioning (EC) as a theoretical framework to evaluate whether these deficits extended to candidates who are not atheists themselves but merely perceived to be associated with atheism. Study 1 found that implicit trust, explicit trust, and voting intentions toward target candidates were all negatively impacted by an EC procedure that paired a candidate's face with words related to atheism. Study 2 found that trust and political support for a Christian candidate was eroded when he expressed proatheist public policy position. In both experiments, trust mediated the effects of atheist associations on voting intentions for religiously affiliated participants. Study 3 found the same moderated-mediation pattern. Religiously affiliated participants who perceived Barack Obama as being more favorable toward atheists were less likely to vote for him, in large part due to a lack of trust. (PsycINFO Database Record PMID- 30024214 TI - The future of sex and gender in psychology: Five challenges to the gender binary. AB - The view that humans comprise only two types of beings, women and men, a framework that is sometimes referred to as the "gender binary," played a profound role in shaping the history of psychological science. In recent years, serious challenges to the gender binary have arisen from both academic research and social activism. This review describes 5 sets of empirical findings, spanning multiple disciplines, that fundamentally undermine the gender binary. These sources of evidence include neuroscience findings that refute sexual dimorphism of the human brain; behavioral neuroendocrinology findings that challenge the notion of genetically fixed, nonoverlapping, sexually dimorphic hormonal systems; psychological findings that highlight the similarities between men and women; psychological research on transgender and nonbinary individuals' identities and experiences; and developmental research suggesting that the tendency to view gender/sex as a meaningful, binary category is culturally determined and malleable. Costs associated with reliance on the gender binary and recommendations for future research, as well as clinical practice, are outlined. (PsycINFO Database Record PMID- 30024215 TI - Evaluating the effectiveness and implementation of evidence-based treatment: A multisite hybrid design. AB - The gap between treatment development and efficacy testing to scaled up implementations of evidence-based treatment (EBT) is an estimated 20 years, and hybrid research designs aim to reduce the gap. One was used for a multisite study in cancer control, testing coprimary aims: (a) determine the feasibility and utility of a flexible EBT implementation strategy and (b) determine the clinical effectiveness of an EBT as implemented by newly trained providers. Therapists from 15 diverse sites implemented the biobehavioral intervention (BBI) for cancer patients (N = 158) as part of standard care. For implementation, therapists determined treatment format, number of sessions, and so forth and reported session-by-session fidelity. Patients completed fidelity and outcome assessments. Results showed therapists BBI implementation was done with fidelity, for example, session "dose" (59%), core content coverage (60-70%), and others. Patient reported fidelity was favorable and comparable to the BBI efficacy trial. Effectiveness data show the primary outcome, patients' scores on the Profile of Mood States total mood disturbance, significantly improved (R2 = 0.06, beta = 0.24, p < .01) as did a secondary outcome, physical activity (R2 = 0.02, beta = 0.13, p < .05). This first use of a hybrid design in health psychology provided support for a novel strategy that allowed providers implementation flexibility. Still, the EBT was delivered with fidelity and in addition, therapists generated novel procedures to enhance setting-specific usage of BBI and its ultimate effectiveness with patients. This research is an example of translational research spanning theory and efficacy tests to dissemination and implementation. (PsycINFO Database Record PMID- 30024217 TI - Shattered cell phones, but not shattered lives: A comparison of reports of illusory posttraumatic growth on the Posttraumatic Growth Inventory and the Stress-Related Growth Scale-Revised. AB - OBJECTIVE: Existing measures of posttraumatic growth (PTG), such as the Posttraumatic Growth Inventory (PTGI), have been criticized on their ability to assess genuine PTG. Specifically, individuals tend to report illusory growth after a traumatic experience, when no true growth has taken place, as a coping mechanism. Recent evidence suggests a new measure, the Stress Related Growth Scale-Revised (SRGS-R), is less prone to reports of illusory PTG. The aim of the current study is to evaluate the extent to which participants report PTG on the PTGI and SRGS-R to an event that may be distressing, but incapable of resulting in genuine PTG-a cracked cell phone screen. METHOD: Participants (N = 613) who experienced a cracked cell phone screen were randomly assigned to complete either the SRGS-R or the PTGI, along with several measures of distress and coping. RESULTS: The results revealed that participants who completed the PTGI reported significantly higher levels of PTG, than did participants who completed the SRGS R. In addition, scores on the PTGI were significantly correlated with PTSD symptoms, distress, anxiety, depression, avoidance coping, and denial coping. In contrast, scores on the SRGS-R were not significantly related to any of the aforementioned measures. CONCLUSIONS: These findings provide evidence that (a) existing measures of PTG can be contaminated with reports of illusory growth, and (b) the SRGS-R is less prone to such reports of illusory growth. The authors believe the SRGS-R is an important step forward in improving our ability to measure actual PTG. (PsycINFO Database Record PMID- 30024218 TI - Can the Trauma Symptom Inventory-2 distinguish coached simulators from dissociative disorder patients? AB - OBJECTIVE: The first objective was to understand how individuals with complex dissociative disorders (CDD) score on the Trauma Symptom Inventory-2 (TSI-2). These individuals have high elevations on many psychological measures' validity and clinical scales because of the severe traumatic reactions they experience; thus, creating a challenge for clinicians who seek to determine whether these individuals are exaggerating reported symptoms. The second objective was to compare coached CDD simulators to CDD profiles on the TSI-2s clinical and validity scales. The third objective was to examine the utility rates of the TSI 2s Atypical Response Scale (ATR) in distinguishing feigned CDD from clinical CDD. METHOD: This study compared 39 CDD inpatients to 51 coached CDD simulators on the TSI-2. A profile analysis compared the CDD group and coached simulators on the TSI-2 scales, and post hoc 1-way analysis of covariances (ANCOVAS) examined significant differences between the groups. RESULTS: The CDD patients elevated on most of the TSI-2 clinical scales and factors. There were significant differences between CDD patients' and CDD simulators' TSI-2 profiles, with simulators failing to endorse some of the co-occurring symptoms common in CDD. The ATR correctly classified only 60-73% of participants and its specificity scores were low. CONCLUSIONS: It is important to understand how CDD individuals score on the TSI-2 so that their results can be recognized and meaningfully interpreted. The TSI-2 may not be a useful measure for distinguishing feigned CDD from CDD. (PsycINFO Database Record PMID- 30024219 TI - Transcendental meditation for veterans with post-traumatic stress disorder. AB - OBJECTIVE: Transcendental Meditation (TM) is a mental technique using a mantra to facilitate meditation. TM has a potential for treating symptoms of posttraumatic stress disorder (PTSD), but its clinical efficacy remains to be clarified. This pilot study evaluated the acceptability, preliminary effectiveness, and neurophysiology of TM for veterans with PTSD. METHOD: Twenty-nine veterans (20.7% female) were recruited from a major medical center and enrolled in the study. TM instruction was provided by certified TM teachers from the Maharishi Foundation and consisted of 8 weeks of individual and group-based meditation instruction and practice. Outcomes were assessed at baseline, during treatment, posttreatment, and at 2-month follow-up, and included clinical interviews, self-report questionnaires, and electroencephalography (EEG) recorded during resting and meditation states. RESULTS: From baseline to posttreatment, participants reported reductions in PTSD symptoms, experiential avoidance, and depressive and somatic symptoms, as well as increases on measures of mindfulness and quality of life. Gains were either maintained or continued to improve through the 2-month follow up. Compared to baseline, EEG spectral power increased in low-frequency bands (1 7 Hz) at posttreatment and follow-up and only during meditation states suggesting TM-specific changes in brain state associated with the intervention. CONCLUSIONS: TM appears to be an acceptable and effective treatment for veterans with PTSD that warrants further study regarding specific outcomes and beneficial changes in brain function. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024220 TI - Predictors of treatment noninitiation, dropout, and response for cognitive behavioral therapy for trauma nightmares. AB - OBJECTIVE: This report aims to extend previous findings on predictors of treatment dropout and response within nightmare treatment. METHOD: Factors predicting treatment noninitiation, dropout, and response were examined in 70 trauma-exposed individuals treated in a randomized controlled trial of 2 conditions (exposure [EX] and nonexposure) of a therapy for trauma nightmares. RESULTS: Together, treatment noninitiation and dropout was predicted by younger age for the EX condition only and by fewer nights with nightmares at baseline for both conditions. Treatment noninitiation was predicted by fewer nights with nightmares. Treatment dropout was not predicted by any variables. For the EX condition, more baseline nightmares predicted more posttreatment nightmares, whereas more reported nights with nightmares at baseline predicted fewer nightmares at posttreatment. Baseline sleep quality and total posttraumatic stress disorder (PTSD) severity predicted posttreatment sleep quality and PTSD severity, respectively. In the nonexposure condition, more traumatic events predicted fewer nightmares at posttreatment, whereas more nightmares predicted more nightmares at posttreatment. Baseline daytime sleepiness predicted worse posttreatment sleep quality, and total PTSD symptom severity predicted posttreatment PTSD severity. CONCLUSIONS: Baseline symptom severity on constructs targeted in treatment are the best indicators of response. Treatment initiation appears to be more significant than dropout. Identifying reasons for treatment noninitiation is needed to maximize engagement. (PsycINFO Database Record PMID- 30024216 TI - Racial/ethnic discrimination and well-being during adolescence: A meta-analytic review. AB - This meta-analytic study systematically investigates the relations between perceived racial/ethnic discrimination and socioemotional distress, academics, and risky health behaviors during adolescence, and potential variation in these relations. The study included 214 peer-reviewed articles, theses, and dissertations, with 489 unique effect sizes on 91,338 unique adolescents. Random effects meta-analyses across 11 separate indicators of well-being identified significant detrimental effects. Greater perceptions of racial/ethnic discrimination were linked to more depressive and internalizing symptoms; greater psychological distress; poorer self-esteem; lower academic achievement and engagement; less academic motivation; greater engagement in externalizing behaviors, risky sexual behaviors, and substance use; and more associations with deviant peers. Metaregression and subgroup analyses indicated differences by race/ethnicity, Gender * Race/Ethnicity interactions, developmental stage, timing of retrospective measurement of discrimination, and country. Overall, this study highlights the pernicious effects of racial/ethnic discrimination for adolescents across developmental domains and suggests who is potentially at greater risk. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024222 TI - Coping self-efficacy and trauma-related shame mediate the association between negative social reactions to sexual assault and PTSD symptoms. AB - Previous research has identified trauma-related shame as a mediator of the association between negative social reactions to sexual assault disclosure and psychological distress, including posttraumatic stress disorder (PTSD) symptoms. However, few studies have considered protective factors that may mitigate the effects of trauma-related shame. This study evaluated trauma-coping self-efficacy and trauma-related shame as mediators of the association between negative reactions to sexual assault disclosure and PTSD symptoms. It was hypothesized that both trauma-coping self-efficacy and trauma-related shame would mediate this association. One hundred thirty-two psychology undergraduates, who reported experiencing sexual assault and had disclosed the sexual assault to at least 1 other person, completed self-report measures of history of sexual assault, negative social reactions, trauma-related shame, trauma-coping-self-efficacy, and PTSD symptoms online. The hypothesized mediation model was evaluated via a series of regressions and included gender and history of sexual assault as covariates. Participants reported significant histories of sexual assault and elevated symptoms of PTSD. Both trauma-related shame and trauma-coping self-efficacy significantly mediated the association between negative social reactions and PTSD symptoms. Trauma-coping self-efficacy and trauma-related shame are significant intervening variables with regard to the association between negative social reactions and PTSD symptoms. These malleable points of therapeutic intervention warrant additional research and highlight the need for clinical practice that explicitly addresses shame and enhances coping self-efficacy among undergraduates who disclose sexual assault. (PsycINFO Database Record PMID- 30024221 TI - Correlates of exposure to potentially traumatic experiences: Results from a national household survey. AB - OBJECTIVE: Prior studies have indicated that exposure to potentially traumatic events (PTEs) may increase the risk of poor mental and physical health outcomes. This study's main goal is to examine the association between PTE exposures and having any past year mental disorder, substance use disorder (SUD), or functional impairment and to explore the moderating effects of age and gender on these associations in a nationally representative sample of civilian adults living in U.S. households. METHOD: The sample included adults aged 18 or older (n = 5,653) from the 2008-2012 Mental Health Surveillance Study. RESULTS: PTE exposure was significantly associated with having any past year mental disorder and any past year SUD (odds ratio [OR] = 1.85, 95% CI [1.48, 2.32] and OR = 1.59, 95% CI [1.16, 2.18], respectively), as well as lower functioning scores as measured by the abbreviated World Health Organization Disability Assessment Schedule (WHODAS) and the Global Assessment of Functioning scale in models adjusted for sociodemographic characteristics. A single significant interaction (p = .002) indicated that the magnitude of the PTE exposure-WHODAS-measured functional impairment association was stronger among females than males. CONCLUSIONS: These findings from a nationally representative study of civilian adults living in U.S. households suggest that PTE exposure may have significant public health implications beyond those associated with the development of posttraumatic stress disorder. (PsycINFO Database Record PMID- 30024223 TI - Failure generates impulsivity only when outcomes cannot be controlled. AB - Verbruggen, Chambers, Lawrence, and McLaren (2017) recently challenged the view that individuals act with greater caution following the experience of a negative outcome by showing that a gambled loss resulted in faster reaction time (RT) on the next trial. Over three experiments, we replicate and establish the boundary conditions of this effect in the context of a simple game (rock, paper, scissors [RPS]). Choice responding against unexploitable opponents replicated the link between failure and faster responding. However, individuals with high win-rates against exploitable opponents initiated slower rather than faster responding following loss. The data suggest that the link between failure and impulsivity is limited to contexts where participants cannot exert control over outcomes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024224 TI - The role of temporal integration in auditory stream segregation. AB - Grouping distinct, temporally separated sounds is assumed to follow Gestalt principles, such as similarity or proximity. In the auditory streaming paradigm, the probability of perceiving all sounds as part of the same repeating pattern (the integrated percept) increases when the interstimulus interval (ISI) is increased from medium to long intervals. However, ISIs shorter than 50 ms have not been systematically explored. Here we show that below ca. 60-ms intervals the direction of the effect of ISI on perception is reversed compared to longer ISIs: Decreasing the ISI increases the probability of the integrated percept. This suggests that temporal proximity plays a different role in auditory stream segregation at very short than at longer ISIs. As the effect of temporal proximity may vary among individuals, we tested whether the proportion of the integrated reports with short ISIs could be associated with individual differences in the temporal resolution of the central auditory system. We found that individual differences in the temporal integration threshold (as measured by a temporal order judgment task) correlated with the percentage of integrated percept reports in some of the short-ISI regions. Although this result cannot be regarded as strong evidence, it is compatible with the notion that temporal integration plays a role in auditory stream segregation at short ISIs. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024225 TI - Parallel regulation of past, present, and future actions during sequencing. AB - Past, present, and future actions must be regulated online to produce sequences of actions, but the regulation process is not well understood because of measurement limitations. We provide the first direct tests of the parallel action regulation hypothesis during sequencing in humans. We used transcranial magnetic stimulation to probe the level of excitation for flexion of the right index finger during typing. Motor evoked potentials (MEPs) were recorded at the onset of typing 5-letter words and nonwords. A single letter typed by the right index finger varied across letter positions 1 to 5. MEP amplitude was largest for the upcoming action in the second position and decreased monotonically across future serial positions, suggesting a serial inhibition process regulates all future actions in parallel during sequencing. This is the most direct human evidence to date corroborating models of sequence production that assume parallel regulation of actions. (PsycINFO Database Record PMID- 30024226 TI - Perceptual biases during cued task switching relate to decision process differences between children and adults. AB - Previous work suggests that children engage preparatory processing differently than adults in cued task switching. One potential consequence is that they are differentially biased by visual properties of the stimuli, for example, target choice similarity. We tested this possibility in 215 children and young adults ranging from 6 to 27 years of age. Participants played a cue-target game with varying levels of working memory and attentional demand where they matched multidimensional stimuli according to a cued dimension. Younger age, low working memory demand, and matching fine grained dimensions (i.e., pattern) increased the bias of target-choice similarity on task performance. Older age, high working memory, and matching global dimensions (i.e., shape) mitigated the bias. Developmental transitions to adult performance differed by task demands but generally occurred during adolescence. A drift diffusion analysis revealed age and task differences in decision making strategies consistent with how similarity impacted task performance, indicating that, especially with low working memory demand, children made impulsive, similarity-driven decisions. Our findings support the idea that children engage in preparation strategies that exacerbate perceptual biases on task performance; improvements are observed with age or through changes in task structure and stimuli. These results have implications for interpreting cognitive control performance in children. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024228 TI - Depressive symptoms and diabetes management from late adolescence to emerging adulthood. AB - OBJECTIVE: To examine changes in depressive symptoms as well as between- and within-person associations between depressive symptoms and Type 1 diabetes (T1D) management across the transition from late adolescence to emerging adulthood. METHOD: Beginning in the senior year of high school, 197 late adolescents with T1D (Mage = 17.77) reported on their student status and living situation, and completed self-report measures of depressive symptoms and adherence to the diabetes regimen, annually at 3 time points. Glycemic control was gathered from hemoglobin A1c (HbA1c) assay kits at the same time points. RESULTS: Results of multilevel models demonstrated high depressive symptoms at baseline, with significant increases in depressive symptoms across time when participants were not living in their parental home, but no change when living with parents. Participants with higher mean levels of depressive symptoms relative to peers (between-person association) had poorer adherence and glycemic control (i.e., higher HbA1c) on average. Within-person fluctuations in depressive symptoms were significantly associated with adherence: greater increases in depressive symptoms (relative to adolescents' own average) were associated with greater deteriorations in adherence. There was not a significant within-person effect of depressive symptoms on glycemic control. CONCLUSIONS: The transition from late adolescence to emerging adulthood is particularly challenging for those with T1D. The findings that individuals with greater depressive symptoms have poorer adherence and glycemic control relative to those with lower depressive symptoms, and that increases in depressive symptoms are associated with declines in adherence, highlight the importance of screening and monitoring depressive symptoms during this life transition. (PsycINFO Database Record PMID- 30024227 TI - Cumulative childhood adversity and adult cardiometabolic disease: A meta analysis. AB - OBJECTIVE: Adverse childhood experiences may be associated with cardiometabolic morbidity and mortality in adulthood. There is heterogeneity in this literature regarding the type of items in cumulative adversity indices, sample sizes, demographics, and covariates. The present review used quantitative meta-analysis to examine this association and potential moderators. METHOD: Included studies had a measure of cumulative adversity (an index of at least 2 adverse childhood experiences from age 0 to 18) and a measure of cardiometabolic disease: cardiovascular disease (CVD) clinical outcomes (hypertension, coronary heart disease, ischemic heart disease, myocardial infarction, stroke, cerebrovascular disease) and metabolic outcomes (diabetes, metabolic syndrome) at age 18 or older. Given different interpretations of odds ratios (OR) versus hazard ratios (HR), effects were pooled separately. Overall, 9 HR studies (15 effects) based on 179,612 participants and 29 OR studies (62 effects) based on 247,393 participants were included. RESULTS: On the basis of retrospectively assessed adversity, combined studies showed a significant estimated effect of cumulative childhood adversity on adult cardiometabolic disease (HR = 1.42, 95% CI [1.20, 1.67]; OR = 1.36 [1.27, 1.46]). Results varied somewhat by type of cardiometabolic disease, analytic strategy, and number and type of covariates. CONCLUSIONS: The literature suggests that cumulative childhood adversity is modestly related to adult cardiometabolic disease, with effects somewhat stronger for CVD clinical outcomes. The absence of a consistent operational and conceptual definition of adversity and paucity of prospective designs temper the conclusions. It is time for further evaluation of the types and timing of childhood events that have maximal impact on adult cardiometabolic disease. (PsycINFO Database Record PMID- 30024230 TI - Audiovisual interventions for parental preoperative anxiety: A systematic review and meta-analysis. AB - OBJECTIVE: To systematically review and meta-analyze studies assessing the effectiveness of audiovisual (AV) interventions aimed at reducing anxiety in parents whose children are undergoing elective surgery. METHODS: A comprehensive search of multiple electronic databases was performed. A narrative synthesis of findings and random-effects meta-analyses were used to summarize the results. Our primary outcome was parental anxiety. Secondary outcomes included children's preoperative anxiety and postoperative outcomes; parental satisfaction, knowledge, and need for anesthesia information. Risk of bias was appraised within and across studies. RESULTS: Our search yielded 723 studies and 11 were included. A Standardized Mean Difference (SMD) of -0.53 (95% CI [-0.91, -0.15], p < .01) was found between parental anxiety scores in AV interventions and control groups. In terms of children's preoperative anxiety, there was a SMD of -0.59 (95% CI [ 1.11, -0.07], p < .05) between children's anxiety scores in AV intervention and nonintervention participants. Furthermore, AV interventions were shown to shorten the recovery time for children undergoing surgery (SMD = -0.21; 95% CI [-0.39, 0.02], p = .03) but did not lead to improvements on other postoperative outcomes. CONCLUSIONS: These findings suggest that AV interventions have modest, positive effects on both parental and children's preoperative anxiety. Although a statistically significant medium size effect was detected, the clinical significance of this finding requires further exploration. Further research aimed at developing better AV interventions to help guide future practice is warranted. (PsycINFO Database Record PMID- 30024229 TI - Trajectories of child and caregiver psychological adjustment in families of children with cancer. AB - OBJECTIVE: To describe the trajectory of patient and caregiver mental health from diagnosis through the first year of treatment for pediatric cancer and assess whether rates of clinically relevant symptoms were elevated compared with norms. We examined mean levels of internalizing and externalizing symptoms and posttraumatic stress symptoms (PTSS) in children with cancer, and depression, anxiety, and PTSS in caregivers during the first year of treatment; the proportion of patients and caregivers that scored in the clinical range at each time point; and the typical trajectory of symptoms in patients and caregivers and whether trajectories differed between individuals. METHOD: Families (N = 159) of children newly diagnosed with cancer (Mage = 5.6 years; range = 2-18 years) participated in a short-term prospective study. Primary caregivers provided monthly reports of their own and their children's psychological adjustment. RESULTS: On average, children were well-adjusted. However, compared with norms, there was a higher than expected proportion of children with clinically relevant internalizing symptoms around the time of diagnosis. On average children's symptoms declined over time, though variability was observed. Caregivers were less well-adjusted on average, with a high proportion reporting clinically relevant symptoms over time for depression and anxiety. Caregiver symptoms also declined over time, though considerable variability was observed. CONCLUSION: Although most children remain well-adjusted during the first year of treatment, many caregivers experience clinically relevant symptoms of psychological distress. Implications for development of interventions targeting at-risk patients and caregivers are discussed. Identifying processes that predict between family variability in trajectories of psychopathology is an important next step. (PsycINFO Database Record PMID- 30024231 TI - Exercise-specific volition and motivation for weight loss maintenance following an intensive lifestyle intervention. AB - OBJECTIVE: The present study investigated the influence of exercise-specific motivation and volition on weight loss maintenance following an intensive lifestyle intervention (ILI). METHOD: The study participants were 164 individuals with obesity (body mass index [BMI] > 30 kg/m2) that participated in an ILI. Participants' exercise-specific volition and motivation were assessed before and after the intervention as well as 3 and 12 months after completion. Volition was measured with the Volition in Exercise Questionnaire and motivation was measured with the context translated Sport Motivation Scale. RESULTS: Mixed model analysis revealed that when adjusting for gender, age, and education, the 6 volitional scales and intrinsic motivation predicted BMI across the 4 time points, whereas 6 volitional scales and 2 extrinsic regulation scales showed a time interaction. Backward elimination multiple mixed model analysis revealed that Volitional Inhibition - Postponing Training and Volitional Facilitation - Self-Confidence predicted BMI development, whereas Volitional Inhibition - Unrelated Thoughts, Identified Regulation, and Introjected Regulation showed a time interaction above and beyond the other scales. CONCLUSION: Exercise-specific volition and motivation influence weight loss maintenance following an ILI. Volitional self confidence and the tendency to postpone training are of importance above and beyond the previously identified predictor of autonomous exercise motivation. Results of the study also indicate that extrinsic motivation can be either facilitating or counterproductive depending on the level of self-determination. (PsycINFO Database Record PMID- 30024233 TI - Effects of a methodological infographic on research participants' knowledge, transparency, and trust. AB - OBJECTIVE: Given participants' research literacy is essential for clinical trial participation, evidence-based strategies are needed that improve literacy and easily accessed online. We tested whether an infographic letter-that illustrated how dropouts can distort study conclusions-improved participant knowledge about the impact of dropouts relative to a control letter. METHOD: In three distinct online samples purposely recruited to assess reproducibility, young ethnically diverse adults were randomized to read an infographic letter or control letter in a hypothetical scenario. Secondary outcomes included participants' perceived transparency of the research organization, perceived value of retention, and perceived trust of the organization. We purposely included two discriminant items, perceived value for the trial outcome and keeping commitments in general, both hypothesized not to change. RESULTS: Across samples, ~20% more infographic participants correctly answered how dropouts affected study conclusions than control participants. For example (Experiment 3), nearly 90% of infographic participants correctly answered versus only two thirds of controls (88.7% vs. 66.7%, absolute percentage difference 22.0%, p < .0001). Infographic participants had substantially higher transparency, perceived value for retention, and trust (Cohen's ds = 0.4-1.0, ps < .0001), yet importantly did not value the study outcome or report keeping commitments more than control participants (Cohen's ds = 0.0-0.1, ps > .10). CONCLUSIONS: Promisingly, this transparent, visually powerful methodological infographic improved knowledge and trust. Future trials could embed and experimentally test whether such low-cost online infographics improve not only research literacy, but also trial retention, especially among populations with less initial trust about research. (PsycINFO Database Record PMID- 30024232 TI - Perceived weight and barriers to physical activity in parent-adolescent dyads. AB - OBJECTIVE: Family-based physical activity interventions have the potential to reduce obesity, but more information is needed regarding physical activity in the family context. This study used an actor-partner interdependence model to estimate the dyadic association between perceived weight status and barriers to physical activity in dyads of adults and their adolescent children. It was hypothesized that greater perceived weight would be associated with greater barriers perceived by both one's self and one's partner. METHOD: Data from 1,568 dyads in the Family Life, Activity, Sun, Health, and Eating study were used to examine the dyadic association between perceived weight status (i.e., greater perceived weight category) and barriers to physical activity. Models were stratified by actual weight (an overweight or obese dyad member vs. two normal weight dyad members) and adjusted for parent education, parent and adolescent age, gender, and race. RESULTS: Among dyads with at least 1 overweight/obese member, greater perceived weight status was positively associated with one's own perceived barriers (significant actor effects, betas = 1.17 and 1.03, ps < 0.01) and one's partner's perceived barriers (significant partner effects, betas = 0.38 and 0.62, ps < 0.01). No statistically significant relationships were found for dyads with only normal weight members. CONCLUSIONS: Among dyads with at least 1 overweight or obese member, significant partner effects for parents and adolescents demonstrate that the weight perception of 1 dyad member correlates with the barriers of the other member. These dyadic associations highlight the potential importance of family-based interventions for physical activity. (PsycINFO Database Record PMID- 30024234 TI - What can human personality psychology learn from behavioral ecology? AB - Personality research has a long and fruitful history in psychology. In the past 15 years, this topic emerged as an important subfield in behavioral ecology as well. A large amount of empirical data has been gathered, and promising theoretical models have been developed. Despite all of this, there is almost no communication between personality research in humans and the behavioral ecology of animal personality. The aim of this article is to present contemporary research on animal personality and thus, to facilitate its integration into human personality psychology. We describe three major topics in the behavioral ecology of personality: the attempts to explain (a) individual differences in personality, (b) temporal stability of personality traits, and (c) the emergence and stability of behavioral syndromes (correlations between personality traits). In all three topics, we suggest how behavioral ecological research and its conceptual apparatus could be implemented in human personality psychology. We also highlight the importance of the empirical measuring of fitness indicators and the adequate translation of concepts from behavioral ecology to human personality psychology and vice versa. Our analysis shows that behavioral ecology represents a fruitful explanatory and empirical framework with high heuristic potential in explaining key problems of personality. The majority of hypotheses developed in this discipline can be tested in human personality psychology; however, some of them demand complex research designs. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024235 TI - Emotion processing across and within species: A comparison between humans (Homo sapiens) and chimpanzees (Pan troglodytes). AB - For social species, recognizing and adequately yet quickly responding to the emotions of others is crucial for their survival. The current study investigates attentional biases toward emotions in two closely related species, humans and chimpanzees. Prior research has demonstrated that humans typically show an attentional bias toward emotions. We here build on that literature by studying the underlying unconscious mechanisms within and across humans and chimpanzees and aim to gain insight into the evolutionary continuity of expressions. Experiment 1 tested whether chimpanzees show an attentional bias toward the expressions of conspecifics and whether this putative bias is modulated by the stimulus presentation duration, being 33 ms or 300 ms. The stimuli were followed by a visual mask in the form of a neutral body image. This backward-masking procedure eliminated the visibility of the stimuli that were presented for 33 ms, rendering their presentation subliminal. In contrast to our prediction, no attentional bias toward emotions was observed in chimpanzees. The goal of Experiment 2 was to verify this finding and to investigate chimpanzees' reaction to human stimuli. Replicating Experiment 1, no evidence of an attentional bias toward emotions was observed in chimpanzees. In Experiment 3 we used the same chimpanzee and human expressions in 711 museum visitors and confirmed that humans do have an attentional bias toward emotions. Interestingly, this bias was independent of the stimulus presentation duration and most strikingly, independent of the species that was observed. Implications for theorizing about species differences in attentional mechanisms in processing emotions are discussed, as well as directions for future research, to investigate our preliminary findings and this potential species difference further. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024236 TI - Why human environments enhance animal capacities to use objects: Evidence from keas (Nestor notabilis) and apes (Gorilla gorilla, Pan paniscus, Pongo abelii, Pongo pygmaeus). AB - Formal training programs, which can be called education, enhance cognition in human and nonhuman animals alike. However, even informal exposure to human contact in human environments can enhance cognition. We review selected literature to compare animals' behavior with objects among keas and great apes, the taxa that best allow systematic comparison of the behavior of wild animals with that of those in human environments such as homes, zoos, and rehabilitation centers. In all cases, we find that animals in human environments do much more with objects. Following and expanding on the explanations of several previous authors, we propose that living in human environments and the opportunities to observe and manipulate human-made objects help to develop motor skills, embodied cognition, and the use of objects to extend cognition in the animals. Living in a human world also furnishes the animals with more time for such activities, in that the time needed for foraging for food is reduced, and furnishes opportunities for social learning, including emulation, an attempt to achieve the goals of a model, and program-level imitation, in which the imitator reproduces the organizational structure of goal-directed actions without necessarily copying all the details. All these factors let these animals learn about the affordances of many objects and make them better able to come up with solutions to physical problems. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024237 TI - Wolf (Canis lupus) hybrids highlight the importance of human-directed play behavior during domestication of dogs (Canis familiaris). AB - The domestication of animals and plants offers an exceptional opportunity to study evolutionary adaptations. In particular, domesticated animals display several behavioral alterations, including increased sociability and decreased fearfulness and aggression, when compared with their wild ancestors. However, studies quantifying simultaneous changes in multiple behaviors during domestication are lacking. Moreover, the role of human-directed play behavior has been largely neglected when studying the domestication process. Here we address these issues by examining behavioral changes during the domestication of the dog (Canis familiaris) from the gray wolf (Canis lupus) using a standardized behavioral test applied to wolf hybrids and several dog breeds. Contrary to expectations, our study provides little support for collective behavioral alterations. Specifically, although we found that wolf hybrids were less playful and overall more fearful than dogs, we did not detect any differences in sociability or aggression between wolf hybrids and dog breeds. Instead, our results suggest that behavioral alterations during domestication do not necessarily occur in concert and point to an important, but previously overlooked, role of selection on play behavior directed at humans during the domestication of dogs. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024238 TI - Behavioral conservatism is linked to complexity of behavior in chimpanzees (Pan troglodytes): Implications for cognition and cumulative culture. AB - Cumulative culture is rare, if not altogether absent in nonhuman species. At the foundation of cumulative learning is the ability to modify, relinquish, or build upon previous behaviors flexibly to make them more productive or efficient. Within the primate literature, a failure to optimize solutions in this way is often proposed to derive from low-fidelity copying of witnessed behaviors, suboptimal social learning heuristics, or a lack of relevant sociocognitive adaptations. However, humans can also be markedly inflexible in their behaviors, perseverating with, or becoming fixated on, outdated or inappropriate responses. Humans show differential patterns of flexibility as a function of cognitive load, exhibiting difficulties with inhibiting suboptimal behaviors when there are high demands on working memory. We present a series of studies on captive chimpanzees that indicate that behavioral conservatism in apes may be underlain by similar constraints: Chimpanzees showed relatively little conservatism when behavioral optimization involved the inhibition of a well-established but simple solution, or the addition of a simple modification to a well-established but complex solution. In contrast, when behavioral optimization involved the inhibition of a well-established but complex solution, chimpanzees showed evidence of conservatism. We propose that conservatism is linked to behavioral complexity, potentially mediated by cognitive resource availability, and may be an important factor in the evolution of cumulative culture. (PsycINFO Database Record PMID- 30024239 TI - Why I don't always know what I'm feeling: The role of stress in within-person fluctuations in emotion differentiation. AB - Emotion differentiation, the ability to make fine-grained distinctions between emotional states, has mainly been studied as a trait. In this research, we examine within-person fluctuations in emotion differentiation and hypothesize that stress is a central factor in predicting these fluctuations. We predict that experiencing stress will result in lower levels of emotion differentiation. Using data from a 3-wave longitudinal experience sampling study, we examined the within person fluctuations in the level of emotion differentiation across days and months and tested if these fluctuations related to changes in stress levels. On the day-level, we found that differentiation of negative emotions varied significantly within individuals, that high stress levels were associated with lower levels of emotion differentiation, and that stress on 1 day negatively predicted the level of differentiation of negative emotions on a next day (but not vice versa). On the wave-level, we found a concurrent, but not a prospective relationship between stress and emotion differentiation. These results are the first to directly demonstrate the role of stress in predicting fluctuations in emotion differentiation and have implications for our theoretical understanding of emotion differentiation, as well as for interventions. (PsycINFO Database Record PMID- 30024240 TI - Beautiful mess effect: Self-other differences in evaluation of showing vulnerability. AB - Confessing romantic feelings, asking for help, or taking responsibility for a mistake constitute just a few examples of situations that require showing one's vulnerability. Out of fear, many individuals decide against it. To explore whether these fears are reflected in the evaluation of others, we investigate self-other differences in evaluation of showing vulnerability. Drawing on construal level theory, we hypothesize that the mental representations of individuals who find themselves in a vulnerable situation are rather concrete, shifting the focus on the negative aspects of making oneself vulnerable and resulting in a relatively negative evaluation of showing vulnerability. By contrast, when depicting others in a vulnerable situation, individuals are expected to represent it more abstractly, focus more on the positive aspects of showing vulnerability, and, therefore, evaluate it more positively. A total of seven studies demonstrate the predicted self-other differences in the evaluation of showing vulnerability in various situations, such as confessing love, revealing imperfections of one's body, or asking for help, including evidence on the generalizability of the effect in a real-life situation. Moreover, we report empirical evidence on the crucial role of level of construal in the emergence of the observed self-other differences. (PsycINFO Database Record PMID- 30024241 TI - Social decoys: Leveraging choice architecture to alter social preferences. AB - Many of society's most significant social decisions are made over sets of individuals: for example, evaluating a collection of job candidates when making a hiring decision. Rational theories of choice dictate that decision makers' preferences between any two options should remain the same irrespective of the number or quality of other options. Yet people's preferences for each option in a choice set shift in predictable ways as function of the available alternatives. These violations are well documented in consumer behavior contexts: for example, the decoy effect, in which introducing a third inferior product changes consumers' preferences for two original products. The current experiments test the efficacy of social decoys and harness insights from computational models of decision-making to examine whether choice set construction can be used to change preferences in a hiring context. Across seven experiments (N = 6312) we find that participants have systematically different preferences for the exact same candidate as a function of the other candidates in the choice set (Experiments 1a 1d, 2) and the salience of the candidate attributes under consideration (Experiments 2, 3a, 3b). Specifically, compromise and (often) asymmetric dominance decoys increased relative preference for their yoked candidates when candidates were counterstereotypical (e.g., high warmth/low competence male candidate). More importantly, we demonstrate for the first time that we can mimic the effect of a decoy in the absence of a third candidate by manipulating participants' exposure to candidates' attributes: balanced exposure to candidates' warmth and competence information significantly reduced bias between the two candidates. (PsycINFO Database Record PMID- 30024242 TI - Proactive control of implicit bias: A theoretical model and implications for behavior change. AB - Four experiments examined the effect of proactive control on expressions of implicit racial bias. Whereas reactive control is engaged in response to a biasing influence (e.g., a stereotype, temptation, or distraction), proactive control is engaged in advance of such biases, functioning to strengthen task focus and, by consequence, limiting the affordance for a bias to be expressed in behavior. Using manipulations of response interference to modulate proactive control, proactive control was found to eliminate expressions of weapons bias, prejudice, and stereotyping on commonly used implicit assessments. Process dissociation analysis indicated that this pattern reflected changes in controlled processing but not automatic associations, as theorized, and assessments of neural activity, using event-related potentials, revealed that proactive control reduces early attention to task-irrelevant racial cues while increasing focus on task-relevant responses. Together, these results provide initial evidence for proactive control in social cognition and demonstrate its effectiveness at reducing expressions of implicit racial bias. Based on these findings and past research, we present a model of proactive and reactive control that offers a novel and generative perspective on self-regulation and prejudice reduction. (PsycINFO Database Record PMID- 30024243 TI - Procedural Frames in Negotiations: How Offering My Resources Versus Requesting Yours Impacts Perception, Behavior, and Outcomes: Correction to Trotschel et al. (2015). AB - Reports an error in "Procedural frames in negotiations: How offering my resources versus requesting yours impacts perception, behavior, and outcomes" by Roman Trotschel, David D. Loschelder, Benjamin P. Hohne and Johann M. Majer (Journal of Personality and Social Psychology, 2015[Mar], Vol 108[3], 417-435). In the article "Procedural Frames in Negotiations: How Offering My Resources Versus Requesting Yours Impacts Perception, Behavior, and Outcomes" by Roman Trotschel, David D. Loschelder, Benjamin P. Hohne, and Johann M. Majer (Journal of Personality and Social Psychology, 2015, Vol. 108, No. 3, pp. 417-435. http://dx.doi.org/10.1037/pspi0000009), rounding errors in p values occur in the Results under the Concession rate section of Experiment 4a and in the Outcome profits section of Experiment 5. The second sentence of the Discussion section of Experiment 4a should read as follows: Averaged across roles (i.e., buyers and sellers) parties made lower concessions and achieved higher individual outcomes when offering rather requesting resources. The last sentence of the Concession rates section of Experiment 5 should read as follows: This pattern was reversed when animals from zoo Y were addressed first, although this contrast effect did not reach significance. (The following abstract of the original article appeared in record 2015-09924-002.) Although abundant negotiation research has examined outcome frames, little is known about the procedural framing of negotiation proposals (i.e., offering my vs. requesting your resources). In a series of 8 experiments, we tested the prediction that negotiators would show a stronger concession aversion and attain better individual outcomes when their own resource, rather than the counterpart's, is the accentuated reference resource in a transaction. First, senders of proposals revealed a stronger concession aversion when they offered their own rather than requested the counterpart's resources-both in buyer-seller (Experiment 1a) and in classic transaction negotiations (Experiment 2a). Expectedly, this effect reversed for recipients: When receiving requests rather than offers, recipients experienced a stronger concession aversion in buyer-seller (Experiment 1b) and transaction negotiations (Experiment 2b). Experiments 3-5 investigated procedural frames in the interactive process of negotiations-with elementary schoolchildren (Experiment 3), in a buyer-seller context (Experiments 4a and 4b), and in a computer-mediated transaction negotiation void of buyer and seller roles (Experiment 5). In summary, 8 experiments showed that negotiators are more concession averse and claim more individual value when negotiation proposals are framed to highlight their own rather than the counterpart's resources. (PsycINFO Database Record PMID- 30024244 TI - The art of influence: When and why deviant artists gain impact. AB - Some artists rise to fame, while others sink into oblivion. What determines whether artists make an impact? Considering deviance in its sociohistorical context, we propose that artists whose work deviates from their own previous style (intrapersonal deviance) and other artists' styles (interpersonal deviance) gain greater impact than nondeviant artists, as long as deviance is directed toward a progressive style. A preliminary study showed that in western cultures nonrealistic styles are considered more progressive than realistic styles (Study 1). Five more studies provide evidence for the effects of the two types of artistic deviance on several aspects of impact (i.e., perceived influence of the artist, valuation of the artwork, and visual attention to the artwork). First, individuals considered artists who deviated from their previous style more impactful than artists who consistently followed a single style (Study 2), effects that were stronger when artists transitioned from a retrogressive style to a progressive one (Study 3). Second, artists who deviated from their contemporaries' style were considered more impactful than artists who followed the predominant style, effects that were stronger when artists strayed from a predominant retrogressive style by using progressive means of expression (Studies 4 and 5). When the historical context prevented observers from inferring the progressiveness of the deviant artists' expressive means, artistic deviance enhanced perceived impact regardless of the means by which the artists deviated (Study 6). Supporting our theoretical model, the effects of intrapersonal and interpersonal deviance on impact were mediated by perceived will-power (Studies 3, 5, and 6). (PsycINFO Database Record PMID- 30024245 TI - Stereotypes of age differences in personality traits: Universal and accurate: Correction to Chan et al. (2012). AB - Reports an error in "Stereotypes of age differences in personality traits: Universal and accurate" by Wayne Chan, Robert R. Mccrae, Filip De Fruyt, Lee Jussim, Corinna E. Lockenhoff, Marleen De Bolle, Paul T. Costa, Angelina R. Sutin, Anu Realo, Juri Allik, Katsuharu Nakazato, Yoshiko Shimonaka, Martina Hrebickova, Sylvie Graf, Michelle Yik, Marina Brunner-sciarra, Nora Leibovich De Figueroa, Vanina Schmidt, Chang-kyu Ahn, Hyun-nie Ahn, Maria E. Aguilar-vafaie, Jerzy Siuta, Barbara Szmigielska, Thomas R. Cain, Jarret T. Crawford, Khairul Anwar Mastor, Jean-pierre Rolland, Florence Nansubuga, Daniel R. Miramontez, Veronica Benet-martinez, Jerome Rossier, Denis Bratko, Iris Marusic, Jamin Halberstadt, Mami Yamaguchi, Goran Knezevic, Thomas A. Martin, Mirona Gheorghiu, Peter B. Smith, Claudio Barbaranelli, Lei Wang, Jane Shakespeare-finch, Margarida P. Lima, Waldemar Klinkosz, Andrzej Sekowski, Lidia Alcalay, Franco Simonetti, Tatyana V. Avdeyeva, V. S. Pramila and Antonio Terracciano (Journal of Personality and Social Psychology, 2012[Dec], Vol 103[6], 1050-1066). In the article "Stereotypes of Age Differences in Personality Traits: Universal and Accurate?" by Wayne Chan, Robert R. McCrae, Filip De Fruyt, Lee Jussim, Corinna E. Lockenhoff, Marleen De Bolle, Paul T. Costa Jr., Angelina R. Sutin, Anu Realo, Juri Allik, Katsuharu Nakazato, Yoshiko Shimonaka, Martina Hrebikova, Sylvie Graf, Michelle Yik, Marina Brunner-Sciarra, Nora Leibovich de Figueroa, Vanina Schmidt, Chang-kyu Ahn, Hyun-nie Ahn, Maria E. Aguilar-Vafaie, Jerzy Siuta, Barbara Szmigielska, Thomas R. Cain, Jarret T. Crawford, Khairul Anwar Mastor, Jean-Pierre Rolland, Florence Nansubuga, Daniel R. Miramontez, Veronica Benet Martinez, Jerome Rossier, Denis Bratko, Iris Marusic, Jamin Halberstadt, Mami Yamaguchi, Goran Knezevic, Thomas A. Martin, Mirona Gheorghiu, Peter B. Smith, Claudio Barbaranelli, Lei Wang, Jane Shakespeare-Finch, Margarida P. Lima, Waldemar Klinkosz, Andrzej Sekowski, Lidia Alcalay, Franco Simonetti, Tatyana V. Avdeyeva, V. S. Pramila, and Antonio Terracciano (Journal of Personality and Social Psychology, 2012, Vol. 103, No. 6, pp. 1050-1066. http://dx.doi.org/10 .1037/a0029712), the 17th author's name was misspelled in the byline and author note. The correct spelling is Nora Leibovich de Figueroa. (The following abstract of the original article appeared in record 2012-28195-001.) Age trajectories for personality traits are known to be similar across cultures. To address whether stereotypes of age groups reflect these age-related changes in personality, we asked participants in 26 countries (N = 3,323) to rate typical adolescents, adults, and old persons in their own country. Raters across nations tended to share similar beliefs about different age groups; adolescents were seen as impulsive, rebellious, undisciplined, preferring excitement and novelty, whereas old people were consistently considered lower on impulsivity, activity, antagonism, and Openness. These consensual age group stereotypes correlated strongly with published age differences on the five major dimensions of personality and most of 30 specific traits, using as criteria of accuracy both self-reports and observer ratings, different survey methodologies, and data from up to 50 nations. However, personal stereotypes were considerably less accurate, and consensual stereotypes tended to exaggerate differences across age groups. (PsycINFO Database Record PMID- 30024246 TI - Personality development and adjustment in college: A multifaceted, cross-national view. AB - The current study is among the first to examine rank-order stability and mean level change across college in both broad Big Five personality trait domains (e.g., Neuroticism) and the narrower facets underlying these domains (i.e., self reproach, anxiety, and depression). In addition, the current study tests longitudinal associations between Big Five domains and facets and 3 aspects of adjustment: self-esteem, academic adjustment, and social adjustment in college. Specifically, the study examines codevelopment (correlated change), personality effects on later changes in adjustment, and adjustment effects on later changes in personality. Two large longitudinal samples from different countries were employed. Results suggested that rank-order stabilities of facets were generally large (i.e., >.50) across samples, and comparable with those observed for trait domains. Mean-level findings were largely in line with the maturity principle: levels of neuroticism and (most of) its facets decreased, whereas levels of the other domains and facets were either stable or increased. However, patterns sometimes slightly differed between facets of the same trait domain. All 3 types of longitudinal associations between personality and adjustment were found, but unlike mean-level change often varied by facet. The Extraversion facet of positive affect and the Conscientiousness facets of goal-striving and dependability were positively associated with all 3 adjustment indicators in both samples, whereas the Neuroticism facets of depression and self-reproach were consistently negatively associated with adjustment. In sum, our findings demonstrate that considering Big Five trait facets may be useful to reveal the nuanced ways in which personality develops in tandem with adjustment in college. (PsycINFO Database Record PMID- 30024247 TI - A memory-based judgment account of expectancy-liking dissociations in evaluative conditioning. AB - Evaluative conditioning (EC) is a change in liking of neutral conditioned stimuli (CS) following pairings with positive or negative stimuli (unconditioned stimulus, US). A dissociation has been reported between US expectancy and CS evaluation in extinction learning: When CSs are presented alone subsequent to CS US pairings, participants cease to expect USs but continue to exhibit EC effects. This dissociation is typically interpreted as demonstration that EC is resistant to extinction, and consequently, that EC is driven by a distinct learning process. We tested whether expectancy-liking dissociations are instead caused by different judgment strategies afforded by the dependent measures: CS evaluations are by default integrative judgments-summaries of large portions of the learning history-whereas US expectancy reflects momentary judgments that focus on recent events. In a counterconditioning and two extinction experiments, we eliminated the expectancy-liking dissociation by inducing nondefault momentary evaluative judgments, and demonstrated a reversed dissociation when we additionally induced nondefault integrative expectancy judgments. Our findings corroborated a priori predictions derived from the formal memory model MINERVA 2. Hence, dissociations between US expectancy and CS evaluation are consistent with a single-process learning model; they reflect different summaries of the learning history. (PsycINFO Database Record PMID- 30024248 TI - How environmental regularities affect people's information search in probability judgments from experience. AB - In everyday life, people encounter smaller rewards with higher probability than larger rewards. Do people expect this reward-probability regularity to hold in experimental settings? To answer this question, we tested whether people's behavior in probability judgment tasks is affected by the correlation between reward size and reward probabilities. In Study 1, we asked people to judge reward probabilities under uncertainty. In line with the ecological reward-probability correlation, people assumed that larger rewards were less likely than smaller rewards. In Study 2, we tested the prediction that people's information search and integration depend on the representativeness of the environment. Participants performed an experience-based probability judgment task in which they sampled outcomes from unknown gambles until they felt confident to estimate the probabilities of the gambles' outcomes. We manipulated the reward-probability relationship of the gambles in 3 experimental groups. Rewards and reward probabilities were negatively correlated, positively correlated, or not correlated at all. A negative correlation mimics the ecological reward probability relationship often present in real life. We analyzed people's search effort and whether they integrated sample-based uncertainty into their judgments. We found that people sampled fewer outcomes in the ecologically representative condition than in the other 2 conditions. However, people did not integrate sample-based uncertainty in their judgments: In all conditions people treated the observed outcomes as representative of the underlying outcome distribution. People's prior beliefs about regularities in environments provides a potential explanation of why people often rely on small sample sizes when making judgments and decisions from experience. (PsycINFO Database Record PMID- 30024249 TI - Metamemory expectancy illusion and schema-consistent guessing in source monitoring. AB - Source monitoring involves attributing information to one of several sources. Schemas are known to influence source-monitoring processes, with enhanced memory for schematically unexpected sources (inconsistency effect) and biased schema consistent source guessing. The authors investigated whether this guessing bias reflects a compensatory guessing strategy based on metacognitive awareness of the inconsistency effect, or reflects other strategies as proposed by the probability matching account. To determine people's awareness of the inconsistency effect, the authors investigated metamemory predictions in a source-monitoring task. In four experiments, participants studied object word items that were presented with one of two scene labels as sources. Items were either presented with their schematically expected source (e.g., kitchen-oven) or with their schematically unexpected source (e.g., kitchen-toothpaste). In Experiments 1 and 2, participants predicted their item memory and their source memory after each source-item presentation. In Experiment 1, people incorrectly predicted both their item memory and, even more so, their source memory to be better for expected than for unexpected source-item pairs. In Experiment 2, this effect replicated with different types of judgment probes. Crucially, item-wise memory predictions did not predict source guessing. In Experiment 3, metacognitive awareness of the inconsistency effect on source memory changed during the test phase. However, metamemory convictions never predicted source guessing. In Experiment 4, the authors manipulated participants' convictions concerning the impact of schematic expectations on source memory. These convictions also did not predict source guessing. Thus, the results show that schema-consistent source guessing does not reflect a compensatory strategy. (PsycINFO Database Record PMID- 30024250 TI - What do people typically do between list items? The nature of attention-based mnemonic activities depends on task context. AB - It is commonly assumed that attention-demanding postencoding processes take place during the free time immediately following encoding of each memory item in a list. These processes are thought to prevent loss of information from working memory (WM). We tested whether interitem pauses during presentation of a list are used to focus attention (a) on the last-presented memory item or (b) on all items currently in WM, and (c) whether this changes over time. Here, we presented black probe letters between to-be-remembered red letters. Participants judged whether each probe letter corresponded to the last-presented memory item (last-item match group) or to any of the memory items presented up to that point in the list (any item match group). To examine mnemonic processing as a function of time, the delay between the to-be-remembered letter and the following probe was manipulated in three experiments. When preprobe delays and interitem intervals were relatively short (Experiment 1), recall performance was observed to be better in the last-item match group and this did not change as a function of the duration of the delay before the probe. When preprobe delays and interitem intervals were longer however (Experiment 2), this disruptive effect of Any-item match instructions was no longer observed. This pattern was found again in Experiment 3 and suggests that the nature of the attention-demanding postencoding processes taking place in between memory items depends on task context in a systematic manner. The results are discussed in terms of previously proposed attention demanding processes; specifically, consolidation and refreshing. (PsycINFO Database Record PMID- 30024251 TI - Task demands and segment priming effects in the naming task. AB - A central issue in the study of speech production is whether phonological encoding occurs sequentially or in parallel. Some of the strongest evidence for sequential phonological encoding comes from the number of segments primed effect response latencies decrease when increasing the number of primed segments from 0 to 1 to 2 (e.g., Meyer, 1991). Although it is often assumed that all participants adopt the same response criterion in the naming task, standard instructions can lead to the strategic adoption of different response criteria (such as an initial segment-based criterion or a syllable-based criterion). Furthermore, the number of segments primed effect might be driven by the manner of the initial segment such as the acoustic characteristics of plosives. In this study, participants named monosyllabic words varying in initial segment plosivity in a 0, 1, or 2 segments primed naming task and were instructed in ways to induce either a segment or syllable criterion. Data were analyzed by acoustic latency, articulatory latency, and initial segment duration, as distinguishing between a segment and syllable criterion and sequential and parallel encoding requires more than just a single point in the time-course of articulation. Shorter acoustic latencies when priming 2 segments over 1 were contingent on the manner of the initial segment and the adoption of a segment criterion, clarifying the nature of the number of segments primed effect. Moreover, the similar acoustic latencies found across priming conditions when a syllable criterion was adopted support parallel phonological encoding. (PsycINFO Database Record PMID- 30024252 TI - The influence of lexical selection disruptions on articulation. AB - Interactive models of language production predict that it should be possible to observe long-distance interactions; effects that arise at one level of processing influence multiple subsequent stages of representation and processing. We examine the hypothesis that disruptions arising in nonform-based levels of planning specifically, lexical selection-should modulate articulatory processing. A novel automatic phonetic analysis method was used to examine productions in a paradigm yielding both general disruptions to formulation processes and, more specifically, overt errors during lexical selection. This analysis method allowed us to examine articulatory disruptions at multiple levels of analysis, from whole words to individual segments. Baseline performance by young adults was contrasted with young speakers' performance under time pressure (which previous work has argued increases interaction between planning and articulation) and performance by older adults (who may have difficulties inhibiting nontarget representations, leading to heightened interactive effects). The results revealed the presence of interactive effects. Our new analysis techniques revealed these effects were strongest in initial portions of responses, suggesting that speech is initiated as soon as the first segment has been planned. Interactive effects did not increase under response pressure, suggesting interaction between planning and articulation is relatively fixed. Unexpectedly, lexical selection disruptions appeared to yield some degree of facilitation in articulatory processing (possibly reflecting semantic facilitation of target retrieval) and older adults showed weaker, not stronger interactive effects (possibly reflecting weakened connections between lexical and form-level representations). (PsycINFO Database Record PMID- 30024253 TI - Is preparing for a language switch like preparing for a task switch? AB - A key index of top-down control in task switching-preparation for a switch-is underexplored in language switching. The well-documented EEG "signature" of preparation for a task switch-a protracted positive-polarity modulation over the posterior scalp-has thus far not been reported in language switching, and the interpretation of previously reported effects of preparation on language switching performance is complicated by confounding factors. In an experiment using event-related potentials (ERPs) and an optimized picture-naming paradigm that addressed these confounds the language was specified by an auditory cue on every trial and changed unpredictably. There were two key manipulations. First, the cue-stimulus interval allowed either generous (1,500 ms) or little (100 ms) opportunity for preparation. Second, to explore the interplay between bottom-up and top-down language selection, we compared a highly transparent and familiar "supercue"-the name of the language spoken in that language to a relatively opaque cue (short speeded-up fragment of national anthem). Preparation for a switch elicited a brain potential strongly reminiscent of the posterior switch positivity documented in task switching. As previously shown in task switching, its amplitude inversely predicted the performance "switch cost," demonstrated by our ERP analyses contingent on reaction time (RT). This overlap in the electrophysiological correlates of preparing to switch tasks and languages suggests domain-general processes for top-down selection of task-set and language for production. But, the surprisingly small language switch cost following the supercue in the short CSI suggests that rapid and (possibly automatic) bottom-up selection-not typically observed in task switching-may also occur. (PsycINFO Database Record PMID- 30024254 TI - The benefit of generating errors during learning: What is the locus of the effect? AB - Guessing translations of foreign words (hodei?), before viewing corrective feedback (hodei-cloud), leads to better subsequent memory for correct translations than studying intact pairs (hodei-cloud), even when guesses are always incorrect (Potts & Shanks, 2014), but the mechanism underlying this effect is unknown. Possible explanations fall into two broad classes. One puts the locus of the effect at retrieval: Items studied through a generation process have more potential retrieval cues associated with them, or a more distinctive context, and are therefore more accessible at final test. The other puts the locus at encoding and involves enhanced encoding of the correct answer following the generation of an error compared with passive studying (Potts & Shanks, 2014). In 6 experiments we found support for the proposal that generating errors benefits memory through stimulating curiosity to learn correct answers following an incorrect guess, leading to enhanced processing of targets following generation. In Experiment 1, generating possible translations after seeing correct answers did not produce better memory than studying without generating, suggesting that an element of surprise or anticipation is necessary for generating to benefit memory. Experiments 2a-2c found enhanced recognition memory for targets following generating, suggesting increased focus on targets following a guess. In Experiments 3 and 4, participants rated their curiosity to learn correct answers higher when ratings were given after generating than before, suggesting that the act of generation increases curiosity to learn the answers. These findings imply that enhanced processing of feedback is a key consequence of errorful generation. (PsycINFO Database Record PMID- 30024255 TI - Individual differences in learning social and nonsocial network structures. AB - How do people acquire knowledge about which individuals belong to different cliques or communities? And to what extent does this learning process differ from the process of learning higher-order information about complex associations between nonsocial bits of information? Here, the authors use a paradigm in which the order of stimulus presentation forms temporal associations between the stimuli, collectively constituting a complex network. They examined individual differences in the ability to learn community structure of networks composed of social versus nonsocial stimuli. Although participants were able to learn community structure of both social and nonsocial networks, their performance in social network learning was uncorrelated with their performance in nonsocial network learning. In addition, social traits, including social orientation and perspective-taking, uniquely predicted the learning of social community structure but not the learning of nonsocial community structure. Taken together, the results suggest that the process of learning higher-order community structure in social networks is partially distinct from the process of learning higher-order community structure in nonsocial networks. The study design provides a promising approach to identify neurophysiological drivers of social network versus nonsocial network learning, extending knowledge about the impact of individual differences on these learning processes. (PsycINFO Database Record PMID- 30024256 TI - Direct evidence for linguistic influences in two-digit number processing. AB - Language-specific differences in number words influence number processing even in nonverbal numerical tasks. For instance, the unit-decade compatibility effect in two-digit number magnitude comparison (compatible number pairs [42_57: 4 < 5 and 2 < 7] are responded to faster than incompatible pairs [47_62: 4 < 6 but 7 > 2]) was shown to be influenced by the inversion of number words (e.g., in German the number word for 42 is zweiundvierzig [literally: two-and-forty]). In two studies, we used articulatory suppression to investigate whether previously observed cross linguistic differences in two-digit number processing are indeed driven by differences in number word formation. In a two-digit number comparison task, German- and English-speaking participants had to identify the larger of two numbers presented in Arabic digits. In Study 1, participants performed the same task twice, with and without articulatory suppression. In Study 2, the percentage of within-decade filler items (36_39) was manipulated additionally. As expected, in both studies between-groups differences in the compatibility effect disappeared under articulatory suppression irrespective of the percentage of fillers included. Furthermore, paralleling results of previous studies including 33% or less filler items, we found that the compatibility effect was larger in German compared with English speakers in the 20% filler condition. However, this pattern was reversed in the 50% filler condition in both studies. Thus, results provide first direct evidence for influences of verbal number word formation on symbolic number processing. Moreover, these new findings suggest that linguistic influences and those of cognitive control processes associated with characteristics of the stimulus set interact in symbolic number processing. (PsycINFO Database Record PMID- 30024257 TI - Barriers block the effect of joint attention on working memory: Perspective taking matters. AB - Joint focus of attention between two individuals can influence the way that observers attend, encode, and value items. Using a nonpredictive gaze cuing task we previously found that working memory (WM) was better for jointly attended (validly cued) versus invalidly cued colored squares. Here we examine whether this influence of gaze on WM is driven by observers sharing the perspective of the face cue (mental state account), or simply by increased attention to the cued location (social attention account). To manipulate perspective taking, a closed barrier obstructed the cue face's view of the memoranda, while an open barrier allowed the cue face to "see" the colors. A central cue face flanked by two identical barriers looked left or right, followed 500 ms later by colored squares for encoding which appeared equally often in the validly and invalidly cued locations. After a blank 1,000 ms maintenance interval, participants stated whether a probe color was present or not in the preceding display. When the barrier was open, WM was significantly impaired for invalidly versus validly cued items. When the barrier was closed, the effect of gaze cues on WM was abolished. In contrast, further experiments showed a significant cuing effect on the speed of simple target localization and color discrimination regardless of barrier type. These findings support the mental state account of joint attention in WM, whereby the attentional focus of another alters WM via higher level engagement with the second person perspective. A goal-specific model of perspective taking is proposed. (PsycINFO Database Record PMID- 30024258 TI - Assumptions of the process-dissociation procedure are violated in implicit sequence learning. AB - In implicit sequence learning, a process-dissociation (PD) approach has been proposed to dissociate implicit and explicit learning processes. Applied to the popular generation task, participants perform two different task versions: inclusion instructions require generating the transitions that form the learned sequence; exclusion instructions require generating transitions other than those of the learned sequence. Whereas accurate performance under inclusion may be based on either implicit or explicit knowledge, avoiding to generate learned transitions requires controllable explicit sequence knowledge. The PD approach yields separate estimates of explicit and implicit knowledge that are derived from the same task; it therefore avoids many problems of previous measurement approaches. However, the PD approach rests on the critical assumption that the implicit and explicit processes are invariant across inclusion and exclusion conditions. We tested whether the invariance assumptions hold for the PD generation task. Across three studies using first-order as well as second-order regularities, invariance of the controlled process was found to be violated. In particular, despite extensive amounts of practice, explicit knowledge was not exhaustively expressed in the exclusion condition. We discuss the implications of these findings for the use of process-dissociation in assessing implicit knowledge. (PsycINFO Database Record PMID- 30024259 TI - Semantic processes in preferential decision making. AB - This article examines how semantic memory processes influence the items that are considered by decision makers in memory-based preferential choice. Experiments 1A through 1C ask participants to list the choice items that come to their minds while deliberating in a variety of everyday choice settings. These experiments use semantic space models to quantify the semantic relatedness between pairs of retrieved items and find that choice item retrieval displays robust semantic clustering effects, with retrieved items increasing the retrieval probabilities of related items. Semantic clustering can be disassociated from the effect of item desirability and can lead to inefficiencies such as the consideration and evaluation of undesirable items early on in the decision. Experiments 2A through 2C use a similar approach to study the effects of contextual cues on item retrieval and find that decision makers are biased toward retrieving choice items that are semantically related to the choice context. This effect is usually strongest early on in deliberation and weakens as additional items are retrieved. Overall, the results highlight the role of semantic memory processes in guiding the generation of memory-based choice sets, and illustrate the value of semantic space models for studying preferential decision making. (PsycINFO Database Record PMID- 30024260 TI - Bias to (and away from) the extreme: Comparing two models of categorical perception effects. AB - Categorical perception (CP) effects manifest as faster or more accurate discrimination between objects that come from different categories compared with objects that come from the same category, controlling for the physical differences between the objects. The most popular explanations of CP effects have relied on perceptual warping causing stimuli near a category boundary to appear more similar to stimuli within their own category and/or less similar to stimuli from other categories. Hanley and Roberson (2011), on the basis of a pattern not previously noticed in CP experiments, proposed an explanation of CP effects that relies not on perceptual warping, but instead on inconsistent usage of category labels. Experiments 1 and 2 in this article show a pattern opposite the one Hanley and Roberson pointed out. Experiment 3, using the same stimuli but with different choice statistics (i.e., different probabilities of each face being the target), obtains the same pattern as the one Hanley and Roberson showed. Simulations show that both category label and perceptual models are able to reproduce the patterns of results from both experiments, provided they include information about the choice statistics. This suggests 2 conclusions. First, the results described by Hanley and Roberson should not be taken as evidence in favor of a category label model. Second, given that participants did not receive feedback on their choices, there must be some mechanism by which participants monitor their own choices and adapt to the choice statistics present in the experiment. (PsycINFO Database Record PMID- 30024261 TI - Compound reading in German: Effects of constituent frequency and whole-word frequency in children and adults. AB - Current models of morphological processing differ in their assumptions about the recognition of compound words. The relative contribution of the first and second constituent and the whole-word remains unsolved. Particularly for beginning readers, the first constituent might have a privileged role attributable to more sequential decoding strategies. In a series of lexical decision experiments, the influence of constituent and whole-word frequencies on compound recognition was examined in German developing readers as well as adults. Results showed that whole-word and first constituent frequency interactively influenced response times in children. For adults, an effect of whole-word frequency only was obtained for the children's stimuli set, and noninteracting effects of whole-word frequency and first constituent frequency were found when using adult frequency measures. Together, the results suggest that developing readers already decompose compounds and that hybrid interactive models of morphological processing are most suitable to explain compound recognition across development. The applicability of amorphous models is also discussed. (PsycINFO Database Record PMID- 30024262 TI - Post-conflict speeding: Evidence of sequential effects in motivational conflicts. AB - Sequential effects in conflict processing (postconflict slowing and conflict adaptation) have primarily been studied in stimulus-response compatibility (SRC) tasks. Moreover, results obtained in SRC paradigms are often proposed as a model of higher-level motivational conflicts. The authors present 3 experiments suggesting that motivational conflicts, such as approach-approach (AA) and avoidance-avoidance (VV) conflicts partially engage different processes than SRC conflicts and thus result in different sequential effects. Instead of postconflict slowing, they predicted speeding after AA conflicts because they expect the approach motivation component of AA conflicts to briefly increase action readiness. Second, the authors expected larger conflict adaptation in VV than AA conflicts because conflict adaptation is known to be enhanced by inducing negative affect. They conducted 3 experiments with varying intertrial intervals (intertrial interval [ITI]) in which participants repeatedly solved hypothetical motivational conflicts (AA, VV) and nonconflicts (NC). In all three experiments, the authors observed postconflict speeding after AA conflicts compared to NC when the ITI was short. Conflict adaptation proved to be less reliable. These results extend previous research on sequential effects in conflict resolution by showing that sequential effects emerge also in higher-level motivational AA and VV conflicts but partially follow different rules than in SRC paradigms. (PsycINFO Database Record PMID- 30024263 TI - A hybrid model of source monitoring in paired-associates learning. AB - Three source-monitoring models were tested using the data of Bellezza, Elek, and Zhang (2016), who presented word pairs with each word in 1 of 4 locations. Given 1 word as a cue, participants had to remember the other word as well as the 2 corresponding locations. Results included (a) locations of the cue and target words were identified equally well; (b) source identification of unrecalled words was above chance; (c) the correct identification of the cue word was positively correlated with that of the target word; and (d) the location of the cue word was frequently confused with the location of the target. Three multinomial processing tree models were tested to explain these results: a word-code model, an event code model, and a hybrid model. The hybrid model was able to fit the data from the 5 experimental conditions of Bellezza et al. data. The model also fit data both from an experiment using four background colors as the source attributes and from a validation experiment manipulating visual-imagery instructions. The parameter values of the hybrid model suggested that source performance using locations was based predominantly on a memory code labeled an event code that included a source axis describing the locations of the 2 words, whereas performance using color relied more on word codes that associated each word with its color. It appears that different source attributes draw upon different combinations of cognitive processes, but each process occurs within the framework of the hybrid model. (PsycINFO Database Record PMID- 30024264 TI - Further studies on the role of attention and stimulus repetition in item-item binding processes in visual working memory. AB - A fundamental question for human memory research relates to the role of attention during the binding of distinct components into an integrated representation. A number of important differences exist between the working memory and episodic memory literature in terms of methodological implementation and empirical outcomes. For instance, episodic memory studies indicate that, although divided attention reduces performance, the magnitude of this reduction is similar regardless of whether distinct item components or the associative binding between these components is tested (e.g., Naveh-Benjamin, Guez, & Marom, 2003). In contrast, recent examinations of working memory indicate that reductions in performance under divided attention are larger during tests of item-item binding compared with item tests (Peterson & Naveh-Benjamin, 2017). The current study used methods typical of both episodic and working memory paradigms to further examine the role of attention in item-item binding in visual working memory. Faces and scenes used to create face-scene pairs were either sampled with replacement (i.e., repeated across trials as is typical in working memory experiments) or without replacement (i.e., nonrepeated across trials as is typical in episodic memory experiments) to examine visual working memory performance under parametric variation of concurrent load. Results from Experiment 1 (no load, articulatory suppression) and Experiment 2 (articulatory suppression, backward counting by two) revealed greater reductions in item-item binding relative to single item performance under divided attention regardless of whether item components were repeated or not repeated across trials of each experiment. These results provide further evidence that visual working memory binding requires attention. (PsycINFO Database Record PMID- 30024265 TI - Dynamics of brain activity reveal a unitary recognition signal. AB - Dual-process models of recognition memory typically assume that independent familiarity and recollection signals with distinct temporal profiles can each lead to recognition (enabling 2 routes to recognition), whereas single-process models posit a unitary "memory strength" signal. Using multivariate classifiers trained on spectral electroencephalogram (EEG) features, we quantified neural evidence for recognition decisions as a function of time. Classifiers trained on a small portion of the decision period performed similarly to those also incorporating information from previous time points indicating that neural activity reflects an integrated evidence signal. We propose a single-route account of recognition memory that is compatible with contributions from familiarity and recollection signals, but relies on a unitary evidence signal that integrates all available evidence. (PsycINFO Database Record PMID- 30024267 TI - Mycobacteria produce proteins involved in biofilm formation and growth-affecting processes. AB - The aim of this study was to determine the effect of mycobacterial proteins on mycobacterial biofilm formation and growth processes. We separated growth affecting proteins (GEPs) from wild type of Mycobacterium bovis and ATCC strain of Mycobacterium avium subsp. avium. Our results showed that these mycobacteria secreted GEPs are involved in biofilm formation, growth stimulatory, and inhibitory processes. Our findings suggest that GEP stimulated M. avium subsp. avium growth in vitro. Stimulation process was observed in mycobacteria affected with GEP extracted from M. avium subsp. avium. We found that both GEPs inhibited the growth of the M. bovis. Optical density measurement and visual analysis confirm that GEP plays an important role in biofilm formation process. Most of M. bovis GEP are associated with the type VII secretion and general secretion pathways. Our results contribute to a better understanding of the mechanisms underlying mycobacterial biofilm formation and growth-affecting processes and better characterization of mycobacterial proteins and their functions. It is noteworthy that this finding represents the first demonstration of GEP-mediated growth effects on a solid and liquid medium. PMID- 30024266 TI - Contributions of reader- and text-level characteristics to eye-movement patterns during passage reading. AB - The present research presents a novel method for investigating how characteristics of texts (words, sentences, and passages) and individuals (verbal and general cognitive skills) jointly influence eye-movement patterns over the time-course of reading, as well as comprehension accuracy. Fifty-one proficient readers read passages of varying complexity from the Gray Oral Reading Test, while their eye-movements were recorded. Participants also completed a large battery of tests assessing various components of reading comprehension ability (vocabulary size, decoding, phonological awareness, and experience with print), as well as general cognitive and executive skills. We used the Random Forests nonparametric regression technique to simultaneously estimate relative importance of all predictors. This method enabled us to trace the temporal engagement of individual predictors and entire predictor groups on eye-movements during reading, while avoiding the problems of model overfitting and collinearity, typical of parametric regression methods. Our findings both confirmed well established results of prior research and pointed to a space of hypotheses that is as yet unexplored. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30024269 TI - Fecal Helicobacter pylori glmM and 16S rRNA genes correlate with serum TNF-alpha and IL-1beta cytokine fluctuations. AB - The proinflammatory cytokines of TNF-alpha and IL-1beta have been reported to be increased in gastric mucosal surfaces in people with Helicobacter pylori infection. Accordingly, this study was conducted to investigate the relationship between the presence of H. pylori genes and the serum oscillations of these cytokines. In this study, DNA was first extracted from the stool samples of infected individuals and used as DNA template to investigate the presence of glmM and 16S rRNA genes in PCR. The ELISA assay was employed to examine serum levels of TNF-alpha and IL-1beta cytokines. According to statistical analysis, there was a significant correlation between the presence of glmM and 16S rRNA genes in the stool samples of infected persons and the serum oscillations of TNF-alpha and IL 1beta cytokines. At the end of study and analysis of the data in case group with HPSAg+, 47.6% of the glmM gene and 23.6% of the 16S rRNA gene were positive. In addition, a significant correlation was observed between the presence of glmM and 16S rRNA genes in the stool specimens of infected individuals and the serum levels of TNF-alpha and IL-1beta cytokines (p < 0.05). Considering the results, it can be concluded that fluctuations in the amount of HPSA, TNF-alpha, and IL 1beta in H. pylori infection depend on the presence of glmM and 16S rRNA genes. The presence of glmM and 16S rRNA in the stool sample increases by boosting the response level to stool antigen (HPSA), IL-1beta, and TNF-alpha, suggesting the prognosis of the disease with a bacterial virulence form using stool tests. PMID- 30024268 TI - The emergence of blaOXA-48 and blaNDM among ESBL-producing Klebsiella pneumoniae in clinical isolates of a tertiary hospital in Iran. AB - The aim of this study was to investigate the prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) and the most common types of carbapenemases, metallo beta-lactamases (MBLs), and extended-spectrum beta-lactamases (ESBLs) among CRKP isolates in a tertiary hospital in Isfahan, Iran. Eighty non-repetitive clinical isolates of K. pneumoniae were obtained from different clinical specimens. Antibiotic resistance pattern of isolates was determined by disk diffusion method and production of carbapenemases and MBLs was confirmed using modified Hodge test and E-test, respectively. Molecular detection of the antibiotic resistance genes was performed using PCR. Fifty-one (63.8%) isolates have decreased susceptibility to carbapenems, of which 46 (90.2%) isolates were as carbapenemase producer and four (7.8%) isolates were positive for MBLs, phenotypically. The results of PCR showed that the prevalence of blaOXA-48, blaNDM, blaSHV, blaCTX-M, and blaTEM genes among CRKP isolates were 90.2%, 15.7%, 98%, 96.1%, and 90.2%, respectively. No isolates carrying the blaKPC, blaGES, blaIMI, blaVIM, and blaIMP genes were detected. This study showed that the production of OXA-48 is one of the main mechanisms of resistance to carbapenems in CRKP isolates in Isfahan. In addition, the dissemination of NDM-producing CRKP isolates is a potential risk for the health care system of this area in the near future. PMID- 30024270 TI - Physical activity and atrial fibrillation risk in the middle-aged and elderly. PMID- 30024271 TI - A viewpoint on rational and irrational fixed-drug combinations. AB - INTRODUCTION: Considering that there are around 30% of patients with epilepsy resistant to monotherapy, the use of synergistic combinations of antiepileptic drugs is of particular importance. This review shows most beneficial as well as irrational combined treatments both from an experimental and clinical point of view. Areas covered: Preferably, experimental data derived from studies evaluating synergy, additivity, or antagonism by relevant methods, in terms of anticonvulsant or neurotoxic effects and pharmacokinetic data have been considered. Although there have been no randomized clinical trials on this issue, the clinical data have been analyzed from studies on considerable numbers of patients. Case-report studies have been not considered. Expert commentary: The experimental data provide a strong support that co-administration of lamotrigine with carbamazepine is negative, considering the anticonvulsant and neurotoxic effects. Clinical reports do not entirely support this conclusion. Other experimentally documented negative combinations comprise lamotrigine+ oxcarbazepine and oxcarbazepine+ phenytoin. From the experimental and clinical point of view, a combination of lamotrigine+ valproate may deserve recommendation. Other most positive experimental and clinical combinations include carbamazepine+valproate, phenytoin+phenobarbital, carbamazepine+gabapentin, carbamazepine+topiramate, levetiracetam+valproate, levetiracetam+carbamazepine. Certainly, experimental data have some limitations (non-epileptic animals, acute administration of antiepileptic drugs) so all experimental recommendations need a careful clinical evaluation. PMID- 30024272 TI - Purification of mRNA Encoding Chimeric Antigen Receptor Is Critical for Generation of a Robust T-Cell Response. AB - T cells made with messenger RNA (mRNA) encoding chimeric antigen receptor (CAR) offer a safe alternative to those transduced with viral CARs by mitigating the side effects of constitutively active T cells. Previous studies have shown that mRNA CAR T cells are transiently effective but lack persistence and potency across tumor types. It was hypothesized that the efficacy of mRNA CARs could be improved by utilizing recent advancements in RNA technology, such as incorporating a modified nucleoside, 1-methylpseudouridine, into the mRNA and applying a novel purification method using RNase III to eliminate dsRNA contaminants. T cells electroporated with nucleoside-modified and purified mRNA encoding CD19 CAR showed an initial twofold increase in CAR surface expression, as well as a twofold improvement in cytotoxic killing of leukemia cells that persisted up to 5 days. T cells generated with nucleoside-modified and purified CAR mRNA also showed reduced expression of checkpoint regulators and a differential pattern of genetic activation compared to those made with conventional mRNA. In vivo studies using a leukemia mouse model revealed that the most robust 100-fold suppression of leukemic burden was achieved using T cells electroporated with purified mRNAs, regardless of their nucleoside modification. The results provide a novel approach to generate mRNA for clinical trials, and poise mRNA CAR T cells for increased efficacy during testing as new CAR targets emerge. PMID- 30024273 TI - "They aren't all like that": Perceptions of clinical services, as told by self harm online communities. AB - Self-harm is a critical public health issue, with strikingly low rates of attendance to clinical services. By offering support, anonymity, and open discussions, online communities hold useful insights into the factors which influence help-seeking behavior. We explore the perceptions of clinical services in three self-harm online communities to understand which services are being used and why. Message threads from each community were extracted randomly until saturation, providing 513 messages across 60 threads. A thematic analysis was performed resulting in four key themes: access to appropriate services during an episode of self-harm, service preference, fears surrounding disclosure, and support. PMID- 30024274 TI - Diabetes alters the association between high-density lipoprotein subfractions and carotid intima-media thickness: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - INTRODUCTION:: High-density lipoprotein cholesterol comprises a group of heterogeneous subfractions that might have differential effects on atherosclerosis. Moreover, prior investigations suggest that the presence of diabetes (T2D) modifies the impact of some subfractions on atherosclerosis. In this study, we aimed to evaluate the association between high-density lipoprotein cholesterol subfractions and carotid intima-media thickness in the baseline assessment of the Brazilian Longitudinal Study of Adult Health participants from the Sao Paulo investigation centre. METHODS:: We evaluated 3930 individuals between 35 and 74 years without previous cardiovascular disease not using lipid lowering drugs. High-density lipoprotein cholesterol subfractions (HDL2-C and HDL3-C) were measured by vertical ultracentrifugation (vertical auto profile). The relationship between each high-density lipoprotein cholesterol subfraction and carotid intima-media thickness was analysed by multiple linear regression models. RESULTS:: Total high-density lipoprotein cholesterol, as well as HDL2-C and HDL3-C, was negatively associated with carotid intima-media thickness after adjustment for demographic data (all p < 0.001) and traditional risk factors (all p < 0.05). When stratified by T2D status, the HDL2-C/HDL3-C ratio showed a negative association with carotid intima-media thickness in participants with T2D ( p = 0.032), even after fully controlling for confounding variables, including total high-density lipoprotein cholesterol. CONCLUSION:: HDL2-C, HDL3-C and HDL2/HDL3-C ratio are inversely associated with carotid intima-media thickness after adjustment for traditional risk factors. Association of the HDL2-C/HDL3-C ratio is modified by the presence of diabetes, being more pronounced in diabetic individuals. PMID- 30024275 TI - Circulating and Synovial Fluid Heat Shock Protein 70 Are Correlated with Severity in Knee Osteoarthritis. AB - Objective Heat shock proteins are molecules rapidly produced under conditions of environmental stress, and involve in protecting the cells structural integrity and function. Osteoarthritis (OA) is a chronic destructive disorder of the joints manifested by the ongoing deterioration and loss of articular cartilage. The present study aimed to analyze circulating and synovial heat shock protein (Hsp70) values in knee osteoarthritis patients and healthy controls and to determine their relationship with the radiographic grading of the severity of knee OA. Design Seventy-two subjects with knee OA and 30 control participants were recruited. Circulating and joint fluid Hsp70 values were quantified by commercially available enzyme-linked immunosorbent assay. Results Circulating Hsp70 was markedly higher in knee OA patients compared with that of healthy volunteers ( P = 0.01). Correspondingly, synovial fluid Hsp70 was 3-fold greater than paired circulating Hsp70 samples ( P < 0.001). Further analysis revealed that circulating and joint fluid Hsp70 values were significantly related with the radiographic severity of knee OA ( r = 0.413, P < 0.001 and r = 0.658, P < 0.001, respectively). Subsequently, circulating Hsp70 value was directly associated with joint fluid Hsp70 value ( r = 0.704, P < 0.001). Conclusions Circulating and synovial Hsp70 levels were positively correlated with the radiographic severity of knee OA. Hsp70 could represent a potential biochemical marker for predicting the severity and may play a fundamental part in the pathogenic mechanism of knee OA. PMID- 30024276 TI - Neuroprotective effect of glucagon-like peptide-1 receptor agonist is independent of glycaemia normalization in type two diabetic rats. AB - OBJECTIVE:: Stroke is a severe complication of type 2 diabetes mellitus. Glucagon like peptide-1 receptor agonists have been shown to have a neuroprotective effect in experimental diabetes. The aim of this study was to determine if their neuroprotective effect is an independent property of the drug independent of glycaemic control. METHODS:: This two-phase study used male Wistar rats. In the first phase, experimental animals were pretreated with liraglutide, while controls received only vehicle. After transient focal brain ischaemia modelling, neurological deficit and brain infarct volume were measured. In the second phase, the first and the second groups of experimental animals with type 2 diabetes mellitus received liraglutide and metformin, respectively, while control animals with diabetes received only vehicle. After transient focal brain ischaemia modelling, neurological deficit and brain infarct volume were evaluated. RESULTS:: Pretreatment with liraglutide in diabetic and non-diabetic animals reduced infarct size as compared to controls, while only non-diabetic liraglutide treated rats presented neurologic deficit decreases. Despite glycaemia normalization, metformin-treated diabetic rats had no differences in stroke outcome when compared to the control group. CONCLUSION:: The neuroprotective effect of liraglutide is not associated with glycaemic control amelioration in experimental type 2 diabetes mellitus. PMID- 30024277 TI - Focal Neurologic Deficits in a Febrile Adolescent. PMID- 30024278 TI - Trends in Utilization of Upper Extremity Reconstructive Surgery Following Traumatic Brain Injury and Stroke. AB - BACKGROUND: Spasticity resulting from traumatic brain injury (TBI) or stroke can lead to debilitating sequelae, including deformities from joint subluxation and spasticity, causing a loss of functional independence. Despite the effectiveness of surgery to address these issues, it is unclear how often these procedures are performed. The objective of the study was to determine the rate of, and trends associated with, reconstructive upper extremity surgery in patients following TBI or stroke. METHODS: The National Inpatient Sample was queried for International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes for TBI and stroke as well as procedural codes representing functional upper extremity reconstruction from 2001 to 2012. Temporal trends were assessed for case volume, patient demographics, financial considerations, and hospitalizations. RESULTS: A total of 2132 reconstructive procedures were performed in patients with TBI or stroke during the study period, with fewer than 230 cases conducted in any given year and no appreciable increase in case volume over time. This represented less than 1% of eligible, appropriate candidates undergoing surgery. Middle-aged, white females were the most common patients to have such surgery. Medicare was the primary payer for reconstruction, and the cost of surgery increased substantially over time. There was a trend toward longer hospital stays, and the inpatient mortality was approximately 0.5%. CONCLUSIONS: There is a substantial underutilization of upper extremity reconstructive surgery for patients with spasticity following TBI or stroke. Increasing costs and limited access to appropriate care may be contributing to differences in use among specific patient subgroups. PMID- 30024279 TI - Improving Heart Failure Readmission Costs and Outcomes With a Hospital-to-Home Readmission Intervention Program. AB - A retrospective cohort study was performed of the Hospital-to-Home (H2H) program, a rapid clinic follow-up program for patients with recent heart failure (HF) admissions at the University of Virginia Health System. There were 6761 hospitalizations among 4685 patients (age 67.5 +/- 14.2 years, 43.9% female), and 759 had H2H follow-up. Thirty day mortality after the initial HF hospitalization was lower in H2H patients (1.84% vs 3.13%; P = .049), and this difference remained significant after adjustment in a multivariable logistic regression model (odds ratio = 0.56 [95% CI = 0.31-099]; P = .046). There also was a 24% reduction in readmission days within the first 30 days after the index admission ( P < .0001), and readmission cost savings were found to be greater than the costs of staffing the H2H clinic. In summary, the H2H program is cost-effective, with significant improvements in survival, readmission days, and readmission costs over 30 days. PMID- 30024280 TI - Artificial MicroRNA-Mediated Tgfbr2 and Pdgfrb Co-Silencing Ameliorates Carbon Tetrachloride-Induced Hepatic Fibrosis in Mice. AB - Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-beta1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their receptors may achieve therapeutic effects. A novel RNAi strategy based on HSC-specific GFAP promoter-driven and lentiviral-expressed artificial microRNAs (amiRNAs) was devised that consists of an microRNA-30a backbone and effective shRNAs against mouse Pdgfrbeta and Tgfbr2. Then, its antifibrotic efficacy was tested in primary and cultured HSCs and in mice affected with carbon tetrachloride-induced hepatic fibrosis. The study shows that amiRNA-mediated Pdgfrbeta and Tgfbr2 co-silencing inhibits HSC activation and proliferation. After recombinant lentiviral particles were delivered into the liver via tail vein injection, therapeutic amiRNAs were preferentially expressed in HSCs and efficiently co-knocked down in situ Tgfbr2 and Pdgfrbeta expression, which correlates with downregulated expression of target or effector genes of their signaling, which include Pai-1, P70S6K, and D-cyclins. amiRNA-based HSC-specific co-silencing of Tgfbr2 and Pdgfrbeta significantly suppressed hepatic expression of fibrotic markers alpha-Sma and Col1a1, extracellular matrix regulators Mmps and Timp1, and phenotypically ameliorated liver fibrosis, as indicated by reductions in serum alanine aminotransferase activity, collagen deposition, and alpha-Sma-positive staining. The findings provide proof of concept for the use of amiRNA-mediated co-silencing of two profibrogenic pathways in liver fibrosis treatment and highlight the therapeutic potential of concatenated amiRNAs for gene therapy. PMID- 30024281 TI - Psychometric Properties of the Spanish Adaptation of the Personality Assessment Inventory in Correctional Settings: An ESEM Study. AB - The Personality Assessment Inventory (PAI; Morey, 1991 , 2007 ) is among the most important personality and psychopathology assessment tools. However, its psychometric properties in the Spanish-speaking prison population have not yet been studied. We aimed to explore the factor structure of the Spanish adaptation of the PAI (Ortiz-Tallo et al., 2011 ) in an Ecuadorian sample of 811 convicted men using exploratory structural equation modeling, with the further objective of confirming its internal consistency. Hoelzle and Meyer ( 2009 ) identified three dimensions that are highly congruent across samples: general distress, elevated mood and dominance, and substance abuse and psychopathy. Taking these findings and the internalizing and externalizing dimensions (Ruiz & Edens, 2008 ) as a theoretical basis, three- and two-factor models were tested for the 22 scales and 11 clinical scales, respectively. We also tested four- and three-factor models that grouped the scales related to substance abuse as an independent factor, leaving intact the distribution presented by the remaining scales in the previous models. Although the original models showed a good fit, the 4- and 3-factor models obtained significantly better fit indexes. With respect to reliability, the Cronbach's alpha coefficients ranged from .49 to .89. This version shows acceptable psychometric properties in correctional settings. PMID- 30024282 TI - Patterns of sensitivity to a panel of drugs are highly individualised for undifferentiated/unclassified soft tissue sarcoma (USTS) in patient-derived orthotopic xenograft (PDOX) nude-mouse models. AB - Undifferentiated/unclassified soft tissue sarcoma (USTS) is a recalcitrant disease; therefore, precise individualised therapy is needed. Toward this goal, we previously established patient-derived orthotopic xenograft (PDOX) models of USTS in nude mice. Here, we determined the extent of uniqueness of drug response in a panel on USTS PDOX models from 5 different patients. We previously showed that 3 of the 5 patients were resistant to doxorubicin (DOX) despite DOX being first-line therapy. Two weeks after orthotopic tumour implantation, PDOX mouse models were randomised into five groups: untreated control, DOX, gem citabine/docetaxel (GEM/DOC), pazopanib (PAZ), temozolomide (TEM). Three PDOX cases were completely resistant to DOX. TEM had high efficacy for 4 USTS PDOX models, including DOX-resistant cases. GEM/DOC and PAZ were effective in three USTS PDOX. One case was completely resistant to TEM. Two cases were completely resistant to PAZ. The results showed the drug sensitivity pattern for each USTS PDOX was highly individualised and that at least one effective drug could be found for each. The PDOX model could be effective in precise individualised drug sensitivity testing which is especially important for heterogeneous cancers such as USTS, and can give the patient a greater chance to be treated with an effective drug. PMID- 30024284 TI - An Examination of the Folk Healing Practice of Curanderismo in the Hispanic Community. AB - Curanderismo is a system of traditional folk practices and beliefs that address health and healing in the Hispanic community. Curanderismo serves a function in the daily lives of Hispanics worldwide, providing them access to culturally appropriate healthcare, and agency over their own, and their family's health. Cultural competency in the area of curanderismo is invaluable, as curanderismo is a folk resource that if acknowledged and embraced by nurses and healthcare practitioners can aid in healthcare delivery and increased healthcare utilization among Hispanic populations. PMID- 30024283 TI - Numerical analysis and comparison of flow fields in normal larynx and larynx with unilateral vocal fold paralysis. AB - In this study, laryngeal flow fields are investigated and compared in normal larynx and models of larynx with unilateral vocal fold paralysis (UVFP). In paralytic models, three fixed initial glottal gaps are considered to understand the positive or probable negative impacts of surgical operation on unilaterally paralytic larynx, by which the paralyzed vocal fold is brought closer to the mid plane. Various features of the flow fields have been discussed in detail including glottal gap width, glottal flow rate, glottal exit pressure pattern and glottal jet evolution. The numerical solution of fluid-structure interaction is carried out using ANSYS, and the results confirm some of the favorable effects of surgery on the patient's larynx. It is also shown that by tightening the glottal gap, some of the problems caused by the presence of a motionless vocal fold, such as leakage through glottal gap in the closure phase resulting in breathy voice can be moderated, although some of the symptoms of this disorder remain relatively unchanged. PMID- 30024285 TI - Home Health Nurses' Perspectives and Care Processes Related to Older Persons with Frailty and Depression: A Mixed Method Pilot Study. AB - The objectives of this study were (1) to describe home health care (HHC) nurses' perception of and care processes related to geriatric depression and frailty, and (2) to identify barriers to care delivery for older persons with these two conditions. Ten semi-structured interviews were conducted with HHC nurses, and 16 HHC nursing visits to 16 older patients (>=65 years) were observed. Mixed method analysis showed that HHC nurses did not routinely assess for frailty and depression. Major barriers to care delivery included insufficient training, documentation burden, limited reimbursement, and high caseload. Addressing these barriers would facilitate HHC nursing care for frail, depressed elders. PMID- 30024287 TI - A Culture-Based Talking Circle Intervention for Native American Youth at Risk for Obesity. AB - This community-based study explored the effectiveness of an after-school cultural based intervention for Native American youth at risk for obesity. A standard health education after-school program served as the comparison control condition. Cherokee self-reliance (cultural identity), perceived stress, and obesity knowledge and related behaviors were the three outcome measures evaluated at baseline and immediate post-intervention. Findings revealed that participants who completed the cultural-based intervention had better results on the three outcome measures in comparison to the standard health education program. PMID- 30024286 TI - Engaging African American Women in Community-Based Health Promotion Programs: Key Informant Recommendations. AB - This explorative qualitative study describes the lived experiences of urban dwelling African American (AA) women who participated in a nurse-led community based health-promotion program for up to 20 years. Data were collected using semistructured interviews and analyzed using a phenomenological approach. Two central themes arose, the program facilitated behavior change and supported retention and recruitment. The findings suggest that AA women will attend classes and invite other participants when facilitators embed relevant community-engaged principles in the program. The participants recommended essential elements that supported the longevity of the program. Future studies may determine if these suggestions resonate with other AA women. PMID- 30024289 TI - Perceptions, Attitudes, and Behaviors of Primary Care Providers Toward Obesity Management: A Qualitative Study. AB - : Background and Problem Statement: Obesity is a prevalent chronic disease associated with decreased life expectancy, increased morbidity and mortality, and escalating health care costs. PURPOSE: To explore perceptions, attitudes, and behaviors toward obesity management by providers in primary care. METHOD: Data were collected through a descriptive qualitative design using semi-structured face-to-face interviews at primary care practices. RESULTS: Common barriers to obesity management were identified and three major themes emerged; provider centered obstacles, perceived organizational obstacles, and provider perception of patient obstacles. CONCLUSION: Obesity is not being effectively managed in these primary care practices and three common themes/obstacles must be addressed. PMID- 30024290 TI - Compositional complexity of rods and rings. AB - Rods and rings (RRs) are large linear- or circular-shaped structures typically described as polymers of IMPDH (inosine monophosphate dehydrogenase). They have been observed across a wide variety of cell types and species and can be induced to form by inhibitors of IMPDH. RRs are thought to play a role in the regulation of de novo guanine nucleotide synthesis; however, the function and regulation of RRs is poorly understood. Here we show that the regulatory GTPase, ARL2, a subset of its binding partners, and several resident proteins at the endoplasmic reticulum (ER) also localize to RRs. We also have identified two new inducers of RR formation: AICAR and glucose deprivation. We demonstrate that RRs can be disassembled if guanine nucleotides can be generated by salvage synthesis regardless of the inducer. Finally, we show that there is an ordered addition of components as RRs mature, with IMPDH first forming aggregates, followed by ARL2, and only later calnexin, a marker of the ER. These findings suggest that RRs are considerably more complex than previously thought and that the function(s) of RRs may include involvement of a regulatory GTPase, its effectors, and potentially contacts with intracellular membranes. PMID- 30024291 TI - Optic nerve sonographic examination to predict raised intracranial pressure in idiopathic intracranial hypertension: The cut-off points. AB - Purpose Monitoring of raised intracranial pressure (ICP) in patients with idiopathic intracranial hypertension (IIH) is required to prevent secondary optic nerve damage. Sonographic measurement of the optic nerve sheath diameter (ONSD) is a noninvasive method to evaluate intracranial hypertension. Different ONSD cut off values have been reported probably due to ethnic variations. Our aim was to determine optic nerve sonographic examination cut-off points to predict raised ICP in IIH patients. Methods This case-control study was conducted on 99 IIH post pubertal female patients (both probable and definite) and 35 age- and sex-matched healthy volunteers. Sonographic ONSD and optic nerve diameter (OND) were obtained 3 mm behind the posterior edge of the globe in a horizontal plane via a 7-13 MHz linear probe. Lumbar puncture was then carried out on the patients. Results The opening cerebrospinal fluid pressure documented in the patient group was 279.64 +/- 65.97 mm H2O. A statistically significant difference was found between IIH patients and controls regarding ONSD. The best ONSD cut-off value indicating raised ICP was 6.05 mm with an area under the curve of 0.850 (95% confidence interval 0.805 to 0.894, 73.2% sensitivity and 91.4% specificity). Regarding OND/ONSD ratio, there was an insignificant difference between both groups. Conclusion Sonographic ONSD but not OND/ONSD ratio could offer a bedside adjunct or alternative indicator of elevated ICP in IIH patients. Ethnic differences, however, should be noted when using this parameter. PMID- 30024292 TI - Life events and depressive symptoms among pregnant women in India: Moderating role of resilience and social support. AB - BACKGROUND: Recent life events may be significant risk factors for depression during pregnancy. However, its association with the individual's resilience and social support is not clear. AIMS: To understand the association between life events and depression during pregnancy and whether the association is moderated by resilience and social support. METHODS: This study is part of a prospective cohort study on perinatal mental health in an urban antenatal clinic, which included 589 women recruited in the first and early second trimester. Participants were administered the Life Events Checklist adapted from the Social Readjustment Rating Scale by the authors to assess life events; Edinburgh Postnatal Depression Scale (EPDS) and Connor-Davidson Resilience Scale-10 to assess depression and resilience, respectively. The relationship between life events (12 months prior to the time of assessment) and antenatal depression and the moderating role of resilience and social support was analysed. RESULTS: Thirty-eight women (6.5%) who had depression (EPDS score ? 11) had significantly higher number of life events (i.e. on average three; U = 3,826; p < .01), lower resilience scores ( U = 4,053; p < .01) and lower perceived social support ( U = 2,423; p < .01) as compared to those who were negative for depression on EPDS. Life events predicted depression during pregnancy; however, the relationship was moderated by social support but not by resilience. CONCLUSION: The pregnant women who experienced life events may experience depression during the first trimester of pregnancy, but the effect could possibly be reduced by enhancing the social support. PMID- 30024293 TI - Immunosuppressive therapy in myelodysplastic syndromes: a borrowed therapy in search of the right place. AB - INTRODUCTION: Myelodysplastic syndromes (MDS) encompass a heterogenous collection of clonal hematopoietic stem cell disorders defined by dysregulated hematopoiesis, peripheral cytopenias, and a risk of leukemic progression. Increasing data support the role of innate and adaptive immune pathways in the pathogenesis and disease course of MDS. The role of immunosuppressive therapy has an established role in the treatment of other hematologic diseases, such as aplastic anemia whose pathogenesis is postulated to reflect that of MDS with regards to many aspects of immune activation. Areas covered: This paper discusses the current understanding of immune dysregulation as it pertains to MDS, the clinical experience with immunosuppressive therapy in the management of MDS, as well as future prospects which will likely improve therapeutic options and outcomes for patients with MDS. Expert commentary: Though limited by paucity of high quality data, immunomodulatory and immunosuppressive therapies for the treatment of MDS have shown meaningful clinical activity in selected patients. Continued clarification of the immune pathways that are dysregulated in MDS and establishing predictors for clinical benefit of immunosuppressive therapy are vital to improve the use and outcomes with these therapies. PMID- 30024294 TI - Transient Loneliness and the Perceived Provision and Receipt of Capitalization Support Within Event-Disclosure Interactions. AB - Research affirms that loneliness is a distressing experience with social perceptual and behavioral consequences. Yet, little is known about consequences of transient loneliness, particularly within social interactions. The current study builds on reaffiliation motive and evolutionary models of state loneliness to investigate the effects of experimentally manipulated loneliness on individual and interaction partner perceptions during an event-sharing interaction, within 97 female dyads. Actor-partner interdependence mediation analyses revealed indirect effects for induction group (high vs. low loneliness) on positive affect, enjoyment, responsiveness, and partner positive affect, via induced state loneliness. Furthermore, state loneliness influenced actor and partner provision of responsiveness, via perceived responsiveness. Results reveal interpersonal consequences of transient loneliness, offering preliminary insight into conditions through which state perceptions of isolation may interfere with engagement in positive social interactions. Furthermore, implications for previously theorized evolutionary models of state loneliness and the reaffiliation motive are discussed. PMID- 30024295 TI - Sluggish Cognitive Tempo in Adults Referred for an ADHD Evaluation: A Psychometric Analysis of Self- and Collateral Report. AB - OBJECTIVE: Sluggish cognitive tempo (SCT) symptoms uniquely contribute to psychiatric and functional outcomes in child samples; however, the psychometric properties of SCT measures among adult outpatients are unknown. METHOD: Adults ( n = 124) presenting for an ADHD evaluation provided self- and collateral report of SCT symptoms. RESULTS: The SCT scale had good internal consistency and yielded three factors across raters: Slow/Daydreamy, Sleepy/Sluggish, and Low Initiation/Persistence. SCT scores exhibited convergent validity with ADHD symptoms across raters. Individuals with ADHD received higher SCT ratings than those without ADHD via collateral report, a pattern that was similar when comorbidity was considered. SCT was associated with poorer functioning after accounting for ADHD symptoms with some differential effects based on reporting source. CONCLUSION: Findings support the internal consistency and validity of a three-factor SCT scale among adult outpatients. Differential results between self and collateral report demonstrate the importance of multiple reporters of SCT in clinical settings. PMID- 30024297 TI - Evaluation of simulation debriefing methods with interprofessional learning. AB - Interprofessional education (IPE) using simulations provides a rich environment for mastery learning and deliberate practice. The debriefing phase is identified as the most valuable by learners, yet investigation into the most effective format for debriefing interprofessional (IP) groups has largely gone unexplored. To determine the best practices in IP simulation debriefing, we compared perceived effectiveness of in-person versus teledebriefing, and single versus IP co-debriefer models according to 404 Debriefing Assessment for Simulation in Healthcare Student-Version (DASH-SV) scores from students in medicine, nursing, and respiratory therapy (n = 135) following three critical care simulations. All calculated total mean scores were in the acceptable range (above 4.0), indicating a positive experience for all methods. We found statistically significantly higher scores for in-person (M = 5.79) compared to teledebriefing (M = 4.96, p < .001). Single debriefer (M = 6.09) compared to IP co-debriefer DASH scores (M = 5.93) for all scenarios were not significantly different (p = .059). Our results suggest that teledebriefing may provide a solution for simulation programs with off-site or rural learners, and that a single in-person debriefing can be equally effective as co-debriefing for IP students. PMID- 30024296 TI - Substance Use Patterns of Gay and Bisexual Men in the Momentum Health Study. AB - Research with male sexual minorities frequently combines gay and bisexual men as Men Who Have Sex with Men or Gay and Bisexual Men. When analyzed separately, bisexual men consistently feature negative health differentials, exemplified by higher substance use levels. This interpretation is not clear-cut because studies may combine bisexual men and women, use different dimensions of sexual orientation to define bisexuality, and/or not consider number of sexual partners as a possible confounding factor. This study conducted separate bivariate and multivariate analyses comparing gay to bisexual Momentum Study participants based on self-identity, sexual attraction, and sexual behavior, while controlling for number of sexual partners and sociodemographic, psychosocial, and sexual behavior measures. The study hypothesized that, regardless of definition, bisexual men feature higher substance use levels compared to gay men. Bivariate analyses revealed significantly higher ( p < .05) use among bisexual men for multiple substances in all samples. Nonprescription stimulants and heroin were significant in all multivariate logistic regression models. In contrast, all bisexual samples reported lower use of erectile dysfunction drugs and poppers, substances associated with anal sex among gay men. Subsequent analysis linked these results to lower levels of anal sex in all bisexual samples. Bivariate analyses also revealed that bisexual men featured significantly lower educational levels, annual incomes, and Social Support Scales scores and higher Anxiety and Depression Sub-Scale Scores. In summary, findings revealed bisexual men's distinctive substance use, sexual behavior, psychosocial, and sociodemographic profiles, and are important for tailoring specific health programs for bisexual men. PMID- 30024298 TI - Protracted aortic valve closure during peripheral veno-arterial extracorporeal life support: is intra-aortic balloon pump an effective solution? AB - BACKGROUND: Left ventricular (LV) afterload increase with protracted aortic valve (AV) closure may represent a complication of veno-arterial extracorporeal membrane oxygenation (V-A ECMO). The aim of the present study was to assess the effects of an intra-aortic balloon pump (IABP) to overcome such a hemodynamic shortcoming in patients submitted to peripheral V-A ECMO. METHODS: Among 184 adult patients who were treated with peripheral V-A ECMO support at Medical University Center Maastricht Hospital between 2007 and 2018, patients submitted to IABP implant for protracted AV closure after V-A ECMO implant were retrospectively identified. All clinical and hemodynamic data, including echocardiographic monitoring, were collected and analyzed. RESULTS: During the study period, 10 subjects (mean age 60 years old, 80% males) underwent IABP implant after peripheral V-A ECMO positioning due to the diagnosis of protracted AV closure and inefficient LV unloading as assessed by echocardiography and an absence of pulsation in the arterial pressure wave. Recovery of blood pressure pulsatility and enhanced LV unloading were observed in 8 patients after IABP placement, with no significant differences in the main hemodynamic parameters, inotropic therapy or in the ECMO flow (p=0.48). The weaning rate in this patient subgroup (mean ECMO duration 8 days), however, was only 10%, with another patient finally transplanted, leading to a 20% survival-to-hospital discharge. CONCLUSION: IABP placement was an effective solution in order to reverse the protracted AV closure and impaired LV unloading observed during peripheral V-A ECMO support. However, the impact on the weaning rate and survival needs further investigations. PMID- 30024299 TI - Violence Exposure in South African Adolescents: Differential and Cumulative Effects on Psychological Functioning. AB - This study examined the associations between different types of violence victimization and psychological functioning in South African adolescents. Both differential and cumulative effects of violence were investigated. A multi-ethnic (Black, White, people of mixed heritage, and people of Indian/Asian descent) sample of adolescents in secondary schools in the Western Cape Province ( N = 1,574; boys = 46.5%, girls = 53.5%; Mage = 16 years) completed a survey on their experiences of exposure to violence (across different contexts and polyvictimization) and their levels of hopelessness, anxiety, depression, perceived stress, and suicidal ideation. The results showed that indirect and direct victimization in the community, and indirect political victimization were consistent predictors for adverse psychological functioning, whereas victimization in home and school contexts did not emerge to be significant. Polyvictimization had a consistent linear effect on psychological symptoms. Interventions in South Africa should focus on addressing the psychological effects of community and political victimization on adolescents. Adopting a holistic treatment approach would be useful to gain a comprehensive understanding of adolescents' victimization experiences and maximize the impact of support to enhance their psychological functioning. PMID- 30024300 TI - Effect of cationic lipid in cationic liposomes on siRNA delivery into the lung by intravenous injection of cationic lipoplex. AB - Cationic liposomes composed of dialkyl cationic lipid such as 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP) can efficiently deliver siRNA to the lungs following the intravenous injection of cationic liposome/siRNA complexes (lipoplexes). In this study, we examined the effect of cationic lipid of cationic liposomes on siRNA delivery to the lungs after intravenous injection. We used six kinds of cationic cholesterol derivatives and 11 kinds of dialkyl or trialkyl cationic lipids as cationic lipids, and prepared 17 kinds of cationic liposomes composed of a cationic lipid and 1,2-dioleoyl-L-alpha-glycero-3 phosphatidylethanolamine (DOPE) for evaluation of siRNA biodistribution and in vivo gene silencing effects. Among cationic liposomes, those composed of N hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16), N,N-dimethyl-N octadecyloctadecan-1-aminium bromide (DC-1-18), 2-((1,5-bis(octadecyloxy)-1,5 dioxopentan-2-yl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride (DC-3-18D), 11-((1,3-bis(dodecanoyloxy)-2-((dodecanoyloxy)methyl)propan-2-yl)amino)-N,N,N trimethyl-11-oxoundecan-1-aminium bromide (TC-1-12), or cholesteryl (3-((2 hydroxyethyl)amino)propyl)carbamate hydroiodide (HAPC-Chol) with DOPE exhibited high accumulation of siRNA in the lung and significant suppression of Tie2 mRNA expression after the intravenous injection of cationic lipoplexes with Tie2 siRNA. Furthermore, DC-1-16/DOPE and DC-1-18/DOPE lipoplexes with protein kinase N3 (PKN3) siRNA could suppress the tumour growth when intravenously injected into mice with lung LLC metastasis. These findings indicate that the siRNA biodistribution and in vivo knockdown efficiency after the intravenous injection of cationic lipoplexes were strongly affected by the type of cationic lipid of cationic liposomes. PMID- 30024301 TI - Laparoscopic Nephrectomy for the Management of Xanthogranulomatous Pyelonephritis: Still a Challenging Procedure. AB - OBJECTIVE: The aim of the study was to assess the feasibility of laparoscopic nephrectomy (LN) in the treatment of patients with xanthogranulomatous pyelonephritis (XGP). METHODS: Retrospective review of medical records of 17 patients (mean age 60.0 +/- 13.3 years) who underwent LN by a single surgeon from 2010 to 2018. Sociodemographic and clinical data including diagnosis, presenting clinical features, surgical management, and postoperative course were analyzed. RESULTS: LN was successfully performed in 15 (88.2%) patients. Two (12.5%) patients with disseminated disease were electively converted to open nephrectomy (ON) due to failure to progress. Two (11.8%) patients experienced intraoperative complications (grades 3b and 4b). Among patients in whom LN was successfully performed (n = 15), the mean operative time was 198.0 +/- 107.1 min and was shorter when no intraoperative complications occurred (169.0 +/- 48.1 min). Three (20%) of these patients required transfusions and nine (60.0%) required postoperative pelvic drainage (PD). Six (40%) patients experienced postoperative complications: one grade 1, four grade 2, and one grade 5. Mean hospital stay was 4.4 +/- 4.3 days, and 3.4 +/- 2.2 for those experiencing manageable or no complications. Among patients without postoperative complications (n = 6), mean hospital stay was shorter when no PD was placed (1.6 vs 2.6 days). CONCLUSION: LN is a feasible surgical option in patients with XGP although given the nature of XGP, it is associated with complications-nearly all manageable-which makes it a challenging surgical procedure. Advanced laparoscopic skills and experiences are needed. Dissemination of the disease is associated with the occurrence of more severe complications and conversion to ON. PD placement seems associated with shorter hospital stay. PMID- 30024302 TI - Advances in understanding the role of cytokines in inflammatory bowel disease. AB - INTRODUCTION: Cytokines represent the key pathophysiologic elements that govern the initiation, progression, and, in some circumstances, the resolution of the inflammation occurring in inflammatory bowel disease (IBD). Areas covered: In this review, we will focus on the main effector and anti-inflammatory cytokines produced in IBD and discuss the results of recent trials in which cytokine-based therapy has been used for treating IBD patients. Expert commentary: The possibility to sample mucosal biopsies from IBD patients and analyze which molecular pathways are prominent during the active phases of the disease and the easy access to various models of experimental colitis has largely advanced our understanding about the role of cytokines in IBD. These progresses have facilitated the development of several therapeutic compounds, which either target inflammatory cytokines or enhance the regulatory function of immunosuppressive cytokines. While some of such drugs are effective in the induction and maintenance of remission of the disease, other compounds are not useful for attenuating the ongoing mucosal inflammation, thus establishing a hierarchical scale of the relevance of cytokines in IBD. Further work is needed to identify biomarkers, which could help personalize cytokine-targeted therapy and minimize potential side effects. PMID- 30024303 TI - Some Pitfalls in the Promises of Automated and Autonomous Vehicles. AB - Differing forms of self-operating transportation are already among us and some have been in operation now for an extended period of time. From elevators and escalators to airport transit trams we already use many fully automatic systems. Now such technologies are very publicly and prominently penetrating into the on road environment of everyday personal vehicle usage. The present paper raises and addresses a number of the specific and more general human factors/ergonomic issues associated with such an evolutionary step. One particular concern is that of identified responsibility when such systems fail to perform flawlessly. The ways in which this (r)evolution will impact the social and cultural fabric of affected societies is also considered. Further observations as to the vector of the future characteristics of these vehicular forms and how they and other autonomous systems will affect our world are examined. The very future of the human experience depends upon the ways in which such systems are designed, enacted, and integrated into everyday life and these are fundamentally ergonomic endeavours. PMID- 30024304 TI - MicroRNA dysregulation in lung injury: the role of the miR-26a/EphA2 axis in regulation of endothelial permeability. AB - MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression in many diseases, although the contribution of miRNAs to the pathophysiology of lung injury remains obscure. We hypothesized that dysregulation of miRNA expression drives the changes in key genes implicated in the development of lung injury. To test our hypothesis, we utilized a model of lung injury induced early after administration of intratracheal bleomycin (0.1 U). Wild-type mice were treated with bleomycin or PBS, and lungs were collected at 4 or 7 days. A profile of lung miRNA was determined by miRNA array and confirmed by quantitative PCR and flow cytometry. Lung miR-26a was significantly decreased 7 days after bleomycin injury, and, on the basis of enrichment of predicted gene targets, it was identified as a putative regulator of cell adhesion, including the gene targets EphA2, KDR, and ROCK1, important in altered barrier function. Lung EphA2 mRNA, and protein increased in the bleomycin-injured lung. We further explored the miR 26a/EphA2 axis in vitro using human lung microvascular endothelial cells (HMVEC L). Cells were transfected with miR-26a mimic and inhibitor, and expression of gene targets and permeability was measured. miR-26a regulated expression of EphA2 but not KDR or ROCK1. Additionally, miR-26a inhibition increased HMVEC-L permeability, and the disrupted barrier integrity due to miR-26a was blocked by EphA2 knockdown, shown by VE-cadherin staining. Our data suggest that miR-26a is an important epigenetic regulator of EphA2 expression in the pulmonary endothelium. As such, miR-26a may represent a novel therapeutic target in lung injury by mitigating EphA2-mediated changes in permeability. PMID- 30024306 TI - Ischemia-reperfusion induces death receptor-independent necroptosis via calpain STAT3 activation in a lung transplant setting. AB - Ischemia-reperfusion (I/R)-induced lung injury undermines lung transplantation (LTx) outcomes by predisposing lung grafts to primary graft dysfunction (PGD). Necrosis is a feature of I/R lung injury. However, regulated necrosis (RN) with specific signaling pathways has not been explored in an LTx setting. In this study, we investigated the role of RN in I/R-induced lung injury. To study I/R induced cell death, we simulated an LTx procedure using our cell culture model with human lung epithelial (BEAS-2B) cells. After 18 h of cold ischemic time (CIT) followed by reperfusion, caspase-independent cell death, mitochondrial reactive oxygen species production, and mitochondrial membrane permeability were significantly increased. N-acetyl-Leu-Leu-norleucinal (ALLN) (calpain inhibitor) or necrostatin-1 (Nec-1) [receptor interacting serine/threonine kinase 1 (RIPK1) inhibitor] reduced these changes. ALLN altered RIPK1/RIPK3 expression and mixed lineage kinase domain-like (MLKL) phosphorylation, whereas Nec-1 did not change calpain/calpastatin expression. Furthermore, signal transducer and activator of transcription 3 (STAT3) was demonstrated to be downstream of calpain and regulate RIPK3 expression and MLKL phosphorylation during I/R. This calpain-STAT3-RIPK axis induces endoplasmic reticulum stress and mitochondrial calcium dysregulation. LTx patients' samples demonstrate that RIPK1, MLKL, and STAT3 mRNA expression increased from CIT to reperfusion. Moreover, the expressions of the key proteins are higher in PGD samples than in non-PGD samples. Cell death associated with prolonged lung preservation is mediated by the calpain-STAT3-RIPK axis. Inhibition of RIPK and/or calpain pathways could be an effective therapy in LTx. PMID- 30024305 TI - The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms. AB - Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-1 (HO-1) is disproportionally increased compared with Nrf2 target NADPH quinone oxidoreductase-1 (Nqo1). HO-1 has been investigated as a potential therapeutic target in both ARDS and BPD. TXNRD1 is predominantly expressed in airway epithelial cells; however, the mechanism of HO 1 induction by TXNRD1 inhibitors is unknown. We tested the hypothesis that TXNRD1 inhibition induces HO-1 via Nrf2-dependent mechanisms. Wild-type (WT), Nrf2KO1.3, and Nrf2KO2.2 cells were morphologically indistinguishable, indicating that Nrf2 can be deleted from murine-transformed club cells (mtCCs) using CRISPR/Cas9 gene editing. Hemin, a Nrf2-independent HO-1-inducing agent, significantly increased HO-1 expression in WT, Nrf2KO1.3, and Nrf2KO2.2. Auranofin (AFN) (0.5 uM) inhibited TXNRD1 activity by 50% and increased Nqo1 and Hmox1 mRNA levels by 6- and 24-fold, respectively, in WT cells. Despite similar levels of TXNRD1 inhibition, Nqo1 mRNA levels were not different between control and AFN-treated Nrf2KO1.3 and Nrf2KO2.2. AFN slightly increased Hmox1 mRNA levels in Nrf2KO1.3 and Nrf2KO2.2 cells compared with controls. AFN failed to increase HO-1 protein in Nrf2KO1.3 and Nrf2KO2.2 compared with a 36-fold increase in WT mtCCs. Our data indicate that Nrf2 is the primary mechanism by which TXNRD1 inhibitors increase HO-1 in lung epithelia. Future studies will use ARDS and BPD models to define the role of HO-1 in attenuation of lung injury by TXNRD1 inhibitors. PMID- 30024307 TI - Human pulmonary endothelial cell permeability after exposure to LPS-stimulated leukocyte supernatants derived from patients with early sepsis. AB - Systemic immune activation is the hallmark of sepsis, which can result in endothelial injury and the acute respiratory distress syndrome (ARDS). The aim of this study was to investigate heterogeneity in sepsis-mediated endothelial permeability using primary human pulmonary microvascular endothelial cells (HPMECs) and the electric cell-substrate impedance sensing (ECIS) platform. After plasma removal, cellular component of whole blood from 35 intensive care unit (ICU) patients with early sepsis was diluted with media and stimulated with either lipopolysaccharide (LPS) or control media. Resulting supernatants were cocultured with HPMECs seeded on ECIS plates, and resistance was continually measured. A decrease in resistance signified increased permeability. After incubation, HPMECs were detached and cell adhesion proteins were quantified using flow cytometry and immunohistochemistry, and gene expression was analyzed with quantitative PCR. Significant heterogeneity in endothelial permeability after exposure to supernatants of LPS-stimulated leukocytes was identified. ICU patients with sepsis stratified into one of the following three groups: minimal (9/35, 26%), intermediate (18/35, 51%), and maximal (8/35, 23%) permeability. Maximal permeability was associated with increased intercellular adhesion molecule-1 protein and mRNA expression and decreased vascular endothelial cadherin mRNA expression. These findings indicate that substantial heterogeneity in pulmonary endothelial permeability is induced by supernatants of LPS stimulated leukocytes derived from patients with early sepsis and provide insights into some of the mechanisms that induce lung vascular injury. In addition, this in vitro model of lung endothelial permeability from LPS stimulated leukocytes may be a useful method for testing therapeutic agents that could mitigate endothelial injury in early sepsis. PMID- 30024308 TI - How are children who are delayed in the Childhood Vaccination Programme vaccinated: A nationwide register-based cohort study of Danish children aged 15 24 months and semi-structured interviews with vaccination providers. AB - AIMS: Delay of childhood vaccinations is common and influences efforts to reduce targeted diseases. In Denmark, the diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine is recommended at ages 3, 5 and 12 months and the first measles-mumps-rubella vaccine (MMR-1) at 15 months. Following guidelines, children delayed at age 15 months should receive MMR-1 and DTaP-IPV-Hib-3 simultaneously, unless DTaP-IPV-Hib-2 was received less than 6 months ago, when MMR-1 alone is recommended. We studied compliance with these guidelines and the reasons for non-compliance with a focus on vaccination providers. METHODS: We used a nationwide register-based cohort study of children born in Denmark between January 2000 and June 2013, who were lacking MMR-1 and DTaP-IPV-Hib-3 at age 15 months and were followed to 24 months. We also performed semi-structured telephone interviews with vaccination providers. RESULTS: The study consisted of 156,921 children (18% of the children born in the period). Among the 40,060 children who had received DTaP-IPV-Hib-2 less than 6 months ago, 37,892 (95%) received MMR-1 alone. Among the 88,469 children who had received DTaP-IPV-Hib-2 more than 6 months ago, 6334 (7%) received DTaP-IPV-Hib-3 and MMR 1 simultaneously. The interviews indicated that some vaccination providers are reluctant to give multiple vaccinations at the same visit and some have a preference of following the usual sequence in the programme. CONCLUSIONS: Vaccination providers generally complied with the recommended minimum 6 months' interval between DTaP-IPV-Hib-2 and DTaP-IPV-Hib-3. Conversely, there was a low compliance with the recommendation to administer DTaP-IPV-Hib-3 and MMR-1 simultaneously. More efforts are needed to ensure timely vaccination. PMID- 30024309 TI - Changes in state legislation and the impacts on elder financial fraud and exploitation. AB - OBJECTIVES: The purpose of this paper is to summarize how state legislators are responding to the increasing incidence of elder financial fraud and exploitation (EFFE) and investigate the impact of new state legislation. METHODS: Our empirical model investigates the impact of recent changes in state legislation, after controlling for relevant state demographics, on the prevalence of EFFE claims reported in the Consumer Sentinel Network database. We use panel data in a fixed effects model with and without time dummy variables. RESULTS: States with additional penalties targeting EFFE have a significantly lower percentage of complaints from elders, whereas the impact of mandatory and protected voluntary reporting laws is not significant in this sample. DISCUSSION: State legislators have increased their awareness of and are acting to produce legislation protecting the elderly from EFFE. Increased information, training and data sharing across states can go a long way to detecting and prosecuting EFFE cases. PMID- 30024310 TI - One is all you need: intrahemispheric processing benefits nonverbal visual recognition. AB - Several attempts have been made to understand when and how the two hemispheres of the brain work together to encode and retrieve information during memory tasks, but it remains unclear whether they are equally capable of encoding and retrieval, particularly when the stimuli do not evoke a leftward processing asymmetry. Using a divided visual field paradigm, we presented nonverbal visual stimuli to one visual field/hemisphere at encoding, and at retrieval presented the stimuli either to the same or opposite visual field/hemisphere. Recognition responses were faster and more accurate when the stimuli were initially presented at encoding and retrieval to the same hemisphere (Experiment 1), even when delay intervals between study and test were short (Experiment 2). Taken together, these findings suggest that recognition decisions for stimuli initially presented to a single hemisphere occur more quickly at shorter lags, perhaps due to a stronger memory representation in the original hemisphere of input compared to the indirectly activated hemisphere. Our results are significant because they demonstrate that each hemisphere of the brain can function to encode and retrieve memory representations equally well, as long as the stimuli contain no linguistic information. PMID- 30024311 TI - Impact of posture and upper-limb muscle activity on grip strength. AB - PURPOSE: The current research was carried out to determine grip strength (GS) with change in posture and upper-limb muscle activity of manual workers and investigate the impacts of these changes. METHODS: For the current research, 120 male and 80 female participants were selected and GS was assessed using a digital hand grip dynamometer in various conditions. RESULTS: The outcomes showed that male participants had higher GS as compared to female participants. Maximum GS was found in a standing posture with the fixed forward shoulder at 45 degrees , elbow at 90 degrees and a neutral position of the wrist and forearm for all participants. CONCLUSIONS: Higher values of GS were attained in standing postures which may result in attainment of higher performance levels by the workers. The outcomes justify the importance of correct postures during manual work in industries employing traditional methods. PMID- 30024312 TI - Exploiting Textile Mechanical Anisotropy for Fabric-Based Pneumatic Actuators. AB - Knit, woven, and nonwoven fabrics offer a diverse range of stretch and strain limiting mechanical properties that can be leveraged to produce tailored, whole body deformation mechanics of soft robotic systems. This work presents new insights and methods for combining heterogeneous fabric material layers to create soft fabric-based actuators. This work demonstrates that a range of multi-degree of-freedom motions can be generated by varying fabrics and their layered arrangements when a thin airtight bladder is inserted between them and inflated. Specifically, we present bending and straightening fabric-based actuators that are simple to manufacture, lightweight, require low operating pressures, display a high torque-to-weight ratio, and occupy a low volume in their unpressurized state. Their utility is demonstrated through their integration into a glove that actively assists hand opening and closing. PMID- 30024313 TI - Stroke admission outside daytime working hours delays mechanical thrombectomy and worsens short-term outcome. AB - Background and purpose Rapid therapeutic decisions in acute stroke patients leading to earlier initiation of revascularization therapies are associated with better outcome. An association between regular working hours and reduced time to initiation of intravenous thrombolysis has been reported. However, its influence on mechanical thrombectomy (MT) remains uncertain. We aimed to analyze the effects of admission time on door-to-groin time and stroke outcome in a large prospective stroke registry of the Neurovascular Net Ruhr in Germany. Methods Procedural times of a total of 512 patients treated with MT were analyzed. Admission to hospital during regular working days and hours (Monday to Friday, 8 am to 4 pm) was compared with admission outside these times. Door-to-groin time and the difference in NIH Stroke Scale between admission and discharge served as primary outcome parameters. Long-term functional outcome was centrally assessed with modified Rankin scale. Results MT outside regular working hours was associated with a significant mean initiation delay of 20 min. By multivariate regression analysis, every 20 min delay of MT reduced the difference in NIHSS score between admission and discharge by 0.76 points (95% CI -1.24 to -0.28, p = 0.002). Favorable long-term outcome did not differ between both treatment groups. Conclusions Treatment outside regular working hours caused a significant delay in the initiation of MT, which was associated with a decreased short-term clinical efficacy of thrombectomy. Strategies like compulsory attendance of the interventional neuroradiologist at the hospital 24/7 might result in shorter door to-groin times and consecutive in better stroke outcome. PMID- 30024315 TI - The Structuration of Community-Based Mental Health Care: A Duality Analysis of a Volunteer Group's Local Agency. AB - Using a lens of structuration theory, this study highlights the ways that specific structures within the current community-based model of mental health care might enable and constrain individuals and families living with mental illness. Through a case study of a volunteer mental illness advocacy group, the authors employed a duality analysis on a variety of data collected from the case (i.e., interviews, organizational documents, and community health care data). Findings indicate that while group members encountered structural barriers to their organizational mission, they also used communicative agency creatively and collectively to (re)create structures within the current community-based model of mental health care. Member agency is examined in relation to perceived structural influence. Theoretical and practical applications of the findings are discussed. PMID- 30024314 TI - Influence of Retronectin-Mediated T-Cell Activation on Expansion and Phenotype of CD19-Specific Chimeric Antigen Receptor T Cells. AB - Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin mediated T-cell activation for CD19-specific CART cell production. Peripheral blood mononuclear cells of healthy donors and untreated chronic lymphocytic leukemia (CLL) patients without or with positive selection for CD3+ T cells were transduced with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Activation of peripheral blood mononuclear cells was performed by CD3/CD28, CD3/CD28/retronectin, or CD3/retronectin. Interleukin-7 and -15 were supplemented to all cultures. Retronectin was used in all three activation protocols for retroviral transduction. Expansion was assessed by trypan blue staining. Viability, transduction efficiency, immune phenotype, and cytokine production were longitudinally analyzed by flow cytometry. Cytotoxic capacity of generated CART cells was evaluated using a classical chromium-51 release assay. Retronectin mediated activation resulted in an enrichment of CD8+ cytotoxic CART cells and less-differentiated naive-like T cells (CD45RA+CCR7+). Retronectin-activated CART cells showed increased cytotoxic activity. However, activation with retronectin decreased viability, expansion, transduction efficiency, and cytokine production, particularly of CLL patient-derived CART cells. Both retronectin-mediated activation protocols promoted a less-differentiated CART cell phenotype without comprising cytotoxic properties of healthy donor-derived CART cells. However, up front retronectin resulted in reduced viability and expansion in CLL patients. This effect is probably attributed to the retronectin-mediated activation of B cells with prolonged CLL persistence. Consequently, CART cell expansion and generation failed. In summary, activation with retronectin should be performed with caution and may be limited to patients without a higher percentage of tumor cells in the peripheral blood. PMID- 30024316 TI - Qualitative Reports of How and When Therapists Adapt Children's Evidence-Based Practices during Community Implementation. AB - This study analyzed qualitative therapist reports of adaptations to the delivery of multiple evidence-based practices (EBPs) within the context of a system-driven reform of children's community mental health services to understand how therapists adapt EBPs as well as contexts of these adaptations to identify when these adaptations are made. The study sought to complement and expand upon previous quantitative survey findings of two categories of Augmenting and Reducing/Reordering adaptations to EBPs. Data included interviews from 60 therapists (88.3% female, 61.7% Latina/o, 80.0% unlicensed) across 20 program sites in 11 mental health agencies that served racial/ethnically diverse children. Interviews were coded to identify themes surrounding the types of adaptations made and the contexts for these adaptations. The majority of therapists' qualitative descriptions of adaptations converged with the 2 broad categories in the Augmenting and Reducing/Reordering Framework, with therapists describing augmenting (e.g., modifying presentation, lengthening or extending pacing) most often, and reducing/reordering adaptations were discussed less frequently. Child and family characteristics were most frequently cited as indications prompting adaptations; however, the specific characteristics motivating adaptations differed by type. Therapists reporting using augmenting adaptations in the context of a wide range of client characteristics, whereas reducing/reordering adaptations occurred more specifically as a function of clinical presentation, family and caregiver functioning, and emergent life events. Therapists described making adaptations to improve the fit of multiple EBPs for the clients they served. Findings could have implications for implementation efforts with diverse clients served in community settings. PMID- 30024317 TI - A Guide to Multisite Qualitative Analysis. AB - The aims of multisite qualitative research, originally developed within the case study tradition, are to produce findings that are reflective of context, while also holding broader applicability across settings. Such knowledge is ideal for informing health and social interventions by overcoming the limitations of research developed through methodological approaches that either "strip" context, or that hold relevance for a site-specific group or population. Yet, despite the potential benefits of multisite qualitative research, there is a paucity of analytical guidance to support researchers in achieving these yields. In this article, we present an analytical approach for conducting multisite qualitative analysis (MSQA) across various methodologies to maximize the potential of qualitative research, enhance rigor, and support the development of interventions that are tailored to the populations that they are intended to serve. PMID- 30024318 TI - The Quantified Behavioral Test Failed to Differentiate ADHD in Adolescents With Neurodevelopmental Problems. AB - OBJECTIVE: The Quantified Behavioral Test (QbTest) is a computerized diagnostic test for ADHD, used in clinical psychiatric care, but its validity may be questioned. We analyzed the QbTest's diagnostic validity and its relation to cognitive ability and psychosocial factors in an adolescent population with a high occurrence of neurodevelopmental disorders. METHOD: In total, 340 participants aged 15 years, completed the QbTest, along with questionnaires, clinical and intelligence quotient (IQ) assessments. RESULTS: The clinical assessment resulted in 89 (26%) participants with ADHD. Area under curve (AUC) scores indicated a random to poor validity of the QbTest (AUC range = 0.48-0.64). QbTest scores of inattention and impulsivity correlated with IQ. CONCLUSION: The QbTest was insufficient as a diagnostic test for ADHD, and was not able to differentiate ADHD from other neurodevelopmental conditions. Clinicians should be aware of the dubious discriminating power of the QbTest. PMID- 30024319 TI - Fenofibrate Ameliorates Oxidative Stress-Induced Retinal Microvascular Dysfunction in Diabetic Rats. AB - PURPOSE: The aim of this study is to investigate the effects of fenofibrate (FA) on microvascular dysfunction in the retina of diabetic rats, and to determine the underlying mechanism. METHODS: Streptozotocin (STZ)-induced diabetic rats and control rats were used in this study. A subgroup of STZ-induced diabetic rats was treated orally with vehicle or FA (100 mg/kg/day) for 24 weeks along with regular monitoring of body weight and serum parameters. At the end of the 24-week treatment, retinal vascular permeability was quantified by confocal microscopy using Evans blue as a tracer. Retinal capillary basement membrane thickness (BMT) was examined by transmission electron microscopy. The retinal reactive oxygen species (ROS) level was quantified by flow cytometry using a fluorescent probe. Levels of vascular endothelial growth factor (VEGF), nuclear facto (NF)-kappaB (p65), and thioredoxin interacting protein (TXNIP) were measured by Western blotting or enzyme-linked immunosorbent assay and real-time reverse transcription polymerase chain reaction. RESULTS: Retinal vascular permeability and BMT were significantly increased in diabetic rats compared to in non-diabetic control rats. Diabetes also increased the retinal ROS levels. These effects were associated with increased levels of VEGF, phosphorylation of p65(P-p65), and TXNIP. FA significantly ameliorated the retinal vascular permeability, alleviated retinal BMT, and reduced retinal ROS level. Consistent with these effects, FA also decreased VEGF and P-p65 expression and, at the same time, decreased TXNIP expression. CONCLUSIONS: FA prevents the retinal microvascular dysfunction induced by diabetes, likely by restoring VEGF and P-p65 levels, and possibly by reducing oxidative stress and TXNIP expression. PMID- 30024320 TI - A formidable foe: carbapenem-resistant Acinetobacter baumannii and emerging nonantibiotic therapies. PMID- 30024321 TI - Age-related changes in vascular responses to angiotensin-(1-7) in female mice. AB - The vasodilatory effect of angiotensin-(1-7) seems to vary between sexes, and estradiol (E2) can modulate the magnitude of the Ang-(1-7) vasodilatory response in female rats. However, there are few studies addressing the influence of sex on the age-related vasodilatory effect of Ang-(1-7). Here, we evaluated the vasodilatory response to Ang-(1-7) on vascular ageing. Ang-(1-7) dose-response curves were determined in mice aortic rings from males (old and young) and females (E2 treated/non-treated old and young) mounted in an isolated organ chamber. Abdominal aortic rings were used for protein expression analysis and determination of reactive oxygen species (ROS) and nitric oxide (NO) production. Our results showed that the Ang-(1-7) vasodilatory effect was absent in aorta from old females, contrasting with a full response in vessels from young females. The Ang-(1-7) vasodilatory effect was restored by E2 replacement in old females. A robust increase in Mas receptor, SOD2, NRF-2 and NOX2 expression was observed in aorta from old females, which was normalized by E2. This effect of E2 was also associated with lower production of ROS and normal levels of NO. In conclusion, our data demonstrated that pathways involved in the Ang-(1-7) vasodilatory response in female mice is affected by hormonal changes in ageing and rescued by E2. PMID- 30024322 TI - The peak duration-specific locomotor demands and concurrent collision frequencies of European Super League rugby. AB - Understanding the most demanding passages of European Super League competition can optimise training prescription. We established positional and match half differences in peak relative distances (m.min-1) across durations, and the number of collisions, high-speed- and very-high-speed-distance completed in the peak 10 min period. Moving-averages (10 s, 30 s, 1 min, 5 min, 10 min) of instantaneous speed (m.s-1) were calculated from 25 professional rugby league players during 25 matches via microtechnology. Maximal m.min-1 was taken for each duration for each half. Concurrently, collisions (n), high-speed- (5 to 7 m.s-1; m) and very-high speed-distance (> 7 m.s-1; m) were coded during each peak 10 min. Mixed-effects models determined differences between positions and halves. Aside from peak 10 s, trivial differences were observed in peak m.min-1 between positions or halves across durations. During peak 10 min periods, adjustables, full- and outside backs ran more at high-speed and very-high-speed whilst middle- and edge-forwards completed more collisions. Peak m.min-1 is similar between positional groups across a range of durations and are maintained between halves of the match. Practitioners should consider that whilst the overall peak locomotor "intensity" is similar, how they achieve this differs between positions with forwards also exposed to additional collision bouts. PMID- 30024323 TI - Daytime naps can be used to supplement night-time sleep in athletes. AB - This study examined the efficacy of daytime napping to supplement night-time sleep in athletes. Twelve well-trained male soccer players completed three conditions in a randomised, counterbalanced order: 9 h in bed overnight with no daytime nap (9 h + 0 h); 8 h in bed overnight with a 1-h daytime nap (8 h + 1 h); and 7 h in bed overnight with a 2-h daytime nap (7 h + 2 h). Sleep was assessed using polysomnography. The total amount of sleep obtained in the three conditions was similar, i.e. 8.1 h (9 h + 0 h), 8.2 h (8 h + 1 h), and 8.0 h (7 h + 2 h). Daytime napping may be an effective strategy to supplement athletes' night-time sleep. PMID- 30024324 TI - 23rd International Symposium on Shiftwork and Working Time: Towards a Global Consensus. AB - The Working Time Society (WTS), and the International Commission on Occupational Health (ICOH) Scientific Committee on Shiftwork and Working Time, are twin organisations focused on conducting research, and informing practice, regarding the impact of work hours in general, and shiftwork in particular, on the efficiency, productivity, safety, well-being, health, and biological rhythms, of employees. Every 2-3 years since 1969, the WTS and ICOH have conducted a series of international symposia in Europe, Asia, Australia, North America, and South America. The purpose of these symposia is to provide a forum for the exchange of knowledge, and the discussion of contested issues, with researchers, employee representatives, regulators, and employers. The most recent symposium in this series - the 23rd International Symposium on Shiftwork and Working Time, entitled "Toward a Global Consensus" - was held on 19-23 June 2017, at Yulara, Australia, near Uluru. Since 2004, Chronobiology International has released a special issue after each symposium, and that tradition continues with a special issue that includes 17 contributions based on a selection of the 128 papers that were presented at the most recent symposium. Here, we provide an overview of the papers that comprise the special issue, and we briefly comment on the implications of the findings for shiftworkers and their employers. PMID- 30024325 TI - "Family Is Who They Say They Are"a: Examining the Effects of Cancer on the Romantic Partners of Adolescents and Young Adults. AB - In this article, we discuss a study we conducted to examine the effects of cancer on romantic partners (i.e., boyfriends and girlfriends, social/romantic/intimate partners) of adolescents and young adults experiencing, or who have experienced, cancer. In this hermeneutic study, we interviewed partners who were involved with an adolescent/young adult with cancer, a cancer survivor who was in a relationship during his treatment, and two healthcare professionals who have worked with these couples and witnessed many other situations of impact, effect, and repercussion. Out of this study, we suggest that partners are affected in many ways that can vary from estrangement, to termination of the relationship, to premature decisions about remaining in the relationship, to family disregard of the partner, and to disregard of the family due to influence of, or relationship with, the partner. We discuss these findings within the context of the larger picture of the psychosocial relational impact of cancer on members beyond those in the immediate and biological family. PMID- 30024326 TI - Preserved Object Weight Processing after Bilateral Lateral Occipital Complex Lesions. AB - Object interaction requires knowledge of the weight of an object, as well as its shape. The lateral occipital complex (LOC), an area within the ventral visual pathway, is well known to be critically involved in processing visual shape information. Recently, however, LOC has also been implicated in coding object weight before grasping-a result that is surprising because weight is a nonvisual object property that is more relevant for motor interaction than visual perception. Here, we examined the causal role of LOC in perceiving heaviness and in determining appropriate fingertip forces during object lifting. We studied perceptions of heaviness and lifting behavior in a neuropsychological patient (M.C.) who has large bilateral occipitotemporal lesions that include LOC. We compared the patient's performance to a group of 18 neurologically healthy age matched controls. Participants were asked to lift and report the perceived heaviness of a set of equally weighted spherical objects of various sizes-stimuli which typically induce the size-weight illusion, in which the smaller objects feel heavier than the larger objects despite having identical mass. Despite her ventral stream lesions, M.C. experienced a robust size-weight illusion induced by visual cues to object volume, and the magnitude of the illusion in M.C. was comparable to age-matched controls. Similarly, M.C. evinced predictive fingertip force scaling to visual size cues during her initial lifts of the objects that were well within the normal range. These single-case neuropsychological findings suggest that LOC is unlikely to play a causal role in computing object weight. PMID- 30024327 TI - Visual Selection of the Future Reach Path in Obstacle Avoidance. AB - In two EEG experiments, we studied the role of visual attention during the preparation of manual movements around an obstacle. Participants performed rapid hand movements to a goal position avoiding a central obstacle either on the left or right side, depending on the pitch of the acoustical go signal. We used a dot probe paradigm to analyze the deployment of spatial attention in the visual field during the motor preparation. Briefly after the go signal but still before the hand movement actually started, a visual transient was flashed either on the planned pathway of the hand (congruent trials) or on the opposite, movement irrelevant side (incongruent trials). The P1/N1 components that were evoked by the onset of the dot probe were enhanced in congruent trials where the visual transient was presented on the planned path of the hand. The results indicate that, during movement preparation, attention is allocated selectively to the planned trajectory the hand is going to take around the obstacle. PMID- 30024328 TI - The Neural Correlates of Relational Reasoning: A Meta-analysis of 47 Functional Magnetic Resonance Studies. AB - It is a core cognitive ability of humans to represent and reason about relational information, such as "the train station is north of the hotel" or "Charles is richer than Jim." However, the neural processes underlying the ability to draw conclusions about relations are still not sufficiently understood. Central open questions are as follows: (1) What are the neural correlates of relational reasoning? (2) Where can deductive and inductive reasoning be localized? (3) What is the impact of different informational types on cerebral activity? For that, we conducted a meta-analysis of 47 neuroimaging studies. We found activation of the frontoparietal network during both deductive and inductive reasoning, with additional activation in an extended network during inductive reasoning in the basal ganglia and the inferior parietal cortex. Analyses revealed a double dissociation concerning the lateral and medial Brodmann's area 6 during deductive and inductive reasoning, indicating differences in terms of processing verbal information in deductive and spatial information in inductive tasks. During semantic and symbolic tasks, the frontoparietal network was found active, whereas geometric tasks only elicited prefrontal activation, which can be explained by the reduced demand for the construction of a mental representation in geometric tasks. Our study provides new insights into the cognitive mechanisms underlying relational reasoning and clarifies previous controversies concerning involved brain areas. PMID- 30024329 TI - Attenuated Face Processing during Mind Wandering. AB - Mind wandering (MW) has been recently investigated in many studies. It has been suggested that, during MW, processing of perceptual stimuli is attenuated in favor of internal thoughts, a phenomenon referred to as perceptual decoupling. Perceptual decoupling has been investigated in ERP studies, which have used relatively simple perceptual stimuli, yet it remains unclear if MW can impact the perceptual processing of complex stimuli with real-world relevance. Here, we investigated the impact of MW on behavioral and neural responses to faces. Thirty six participants completed a novel sustained attention to response task with faces. They were asked to respond to upright faces (nontargets) and withhold responses to inverted faces (targets) and to report intermittently if they were "On task" or "Off task." Behavioral analyses revealed greater intraindividual coefficient of variation for nontarget faces preceding Off task versus On task. ERP analyses focused primarily on the N170 component associated with face processing but also included the P1 and P3 components. The results revealed attenuated amplitudes to nontarget faces preceding Off task versus On task for the N170, but not for the P3 or P1. These findings suggest decoupled visual processing of faces during MW, which has implications for social neuroscience research. PMID- 30024330 TI - Neuropsychology of Human Body Parts: Exploring Categorical Boundaries of Tactile Perception Using Somatosensory Mismatch Responses. AB - The focus of the current study is on a particular aspect of tactile perception: categorical segmentation on the body surface into discrete body parts. The MMN has been shown to be sensitive to categorical boundaries and language experience in the auditory modality. Here we recorded the somatosensory MMN (sMMN) using two tactile oddball protocols and compared sMMN amplitudes elicited by within- and across-boundary oddball pairs. Both protocols employed the identity MMN method that controls for responsivity at each body location. In the first protocol, we investigated the categorical segmentation of tactile space at the wrist by presenting pairs of tactile oddball stimuli across equal spatial distances, either across the wrist or within the forearm. Amplitude of the sMMN elicited by stimuli presented across the wrist boundary was significantly greater than for stimuli presented within the forearm, suggesting a categorical effect at an early stage of somatosensory processing. The second protocol was designed to investigate the generality of this MMN effect, and involved three digits on one hand. Amplitude of the sMMN elicited by a contrast of the third digit and the thumb was significantly larger than a contrast between the third and fifth digits, suggesting a functional boundary effect that may derive from the way that objects are typically grasped. These findings demonstrate that the sMMN is a useful index of processing of somatosensory spatial discrimination that can be used to study body part categories. PMID- 30024333 TI - Measurement of force and calcium release using mechanically skinned fibers from mammalian skeletal muscle. AB - The mechanically skinned (or "peeled") skeletal muscle fiber technique is a highly versatile procedure that allows controlled examination of each of the steps in the excitation-contraction (EC)-coupling sequence in skeletal muscle fibers, starting with excitation/depolarization of the transverse tubular (T) system through to Ca2+ release from sarcoplasmic reticulum (SR) and finally force development by the contractile apparatus. It can also show the overall response of the whole EC-coupling sequence together, such as in twitch and tetanic force responses. A major advantage over intact muscle fiber preparations is that it is possible to set and rapidly manipulate the "intracellular" conditions, allowing examination of the effects of key variables (e.g., intracellular pH, ATP levels, redox state, etc.) on each individual step in EC coupling. This Cores of Reproducibility in Physiology (CORP) article describes the rationale, procedures, and experimental details of the various ways in which the mechanically skinned fiber technique is used in our laboratory to examine the physiological mechanisms controlling Ca2+ release and contraction in skeletal muscle fibers and the aberrations and dysfunction occurring with exercise and disease. PMID- 30024332 TI - 2017 Impact factor. PMID- 30024334 TI - Remodeling of myelinated fibers and internal capillaries in distal peripheral nerves following aerobic exercise in aged rats. AB - The aim of this study was to determine whether aerobic exercise (AE) in old age contributes to improving the morphologies of myelinated fibers (MFs) in peripheral nerves as well as capillaries. Furthermore, we investigated whether such processes are associated with complementary activity of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the circulating blood and peripheral nerve tissue. Fourteen male Wistar rats (age: 95 wk) were randomly divided into moderate AE ( n = 8) and sedentary (SED; n = 6) groups. Rats in the AE group performed treadmill running for 1 h per day for 2 wk, following which the bilateral tibial nerves of the two groups were removed to examine MF and capillary structure. Levels of BDNF and VEGF in the serum and peripheral nerves were analyzed via enzyme-linked immunosorbent assay. Myelin thickness, axon diameter, and capillary luminal diameter were significantly larger in the AE group than in the SED group ( P < 0.0001). Levels of serum BDNF and VEGF were significantly lower and higher, respectively, in the AE group than in the SED group ( P < 0.001). Conversely, BDNF and VEGF levels in tibial nerve tissue were significantly higher, respectively, and lower in the AE group than in the SED group ( P < 0.001). In conclusion, our study indicates that regular AE induces enlargement of the capillaries and thickens the myelin in aged peripheral nerves, likely via a complementary process involving BDNF and VEGF. NEW & NOTEWORTHY Accumulating evidence indicates that age-related sarcopenia is accompanied by the degeneration of myelinated fibers (MFs) in peripheral nerves. Our study indicates that regular aerobic exercise contributes to increased thickness of the myelin surrounding MFs and enlargement of the capillaries, likely via a complementary process involving brain-derived neurotrophic factor and vascular endothelial growth factor. Our findings demonstrate that regular, moderate-intensity aerobic exercise may help to prevent and reverse peripheral nerve regression in older adults. PMID- 30024335 TI - Airway smooth muscle proliferation and inflammation in asthma. AB - In asthma, it is unclear if the airway smooth muscle cells proliferate more or are increased at the onset of asthma and remain stable. This study aimed to compare smooth muscle cell proliferation in individuals with and without asthma and correlate proliferation rates with cell size and number and with granulocytic airway inflammation. Postmortem airway sections were labeled with proliferating cell nuclear antigen (PCNA) and percent positive muscle cells calculated. On the same sections, smooth muscle cell size and number and the number of eosinophils and neutrophils were estimated and compared in cases of nonfatal ( n = 15) and fatal ( n = 15) asthma and control subjects ( n = 15). The %PCNA+ muscle cells was not significantly different in fatal (29.4 +/- 7.7%, mean +/- SD), nonfatal asthma (28.6 +/- 8.3%), or control subjects (24.6 +/- 6.7%) and not related to mean muscle cell size ( r = 0.09), number ( r = 0.36), thickness of the muscle layer ( r = 0.05), or eosinophil numbers ( r = 0.04) in the asthma cases. These data support the hypothesis that in asthma the increased thickness of the smooth muscle layer may be present before or at the onset of asthma and independent of concurrent granulocytic inflammation or exacerbation. NEW & NOTEWORTHY There is debate regarding the origins of the increased airway smooth muscle in asthma. It may be independent of inflammation or arise as a proliferative response to inflammation. The present study found no increase in the proportion of proliferating smooth muscle cells in asthma and no relation of proliferation to numbers of airway smooth muscle cells or inflammation. These results support a stable increase in smooth muscle in asthma that is independent of airway inflammation. PMID- 30024336 TI - Higher muscle fiber conduction velocity and early rate of torque development in chronically strength trained individuals. AB - Strength trained individuals (ST) develop greater levels of force when compared to untrained subjects. These differences are partly of neural origin and can be explained by training induced changes in the neural drive to the muscles. In the present study we hypothesize a greater rate of torque development (RTD) and faster recruitment of motor units with greater muscle fiber conduction velocity (MFCV) in ST when compared to a control cohort. MFCV was assessed during maximal voluntary isometric explosive contractions of the elbow flexors in eight ST and eight control individuals. MFCV was estimated from high-density surface electromyogram recordings (128 electrodes) in intervals of 50 ms starting from the onset of the EMG. The rate of torque development (RTD) and MFCV were computed and normalized to their maximal voluntary torque (MVT) values. The explosive torque of the ST was greater than in the control group in all time intervals analyzed (p<0.001). The absolute MFCV values were also greater for the ST than controls at all time intervals (p<0.001). ST also achieved greater normalized RTD in the first 50 ms of contraction (887.6 +/- 152 vs. 568.5 +/- 148.66 %MVT?s-1, p<0.001) and normalized MFCV before the rise in force when compared to controls. We have shown for the first time that ST can recruit motor units with greater MFCV in a shorter amount of time when compared to untrained subjects during maximal voluntary isometric explosive contractions. PMID- 30024337 TI - Optimal electrode position for abdominal functional electrical stimulation. AB - Abdominal functional electrical stimulation (abdominal FES) improves respiratory function. Despite this, clinical use remains low, possibly due to lack of agreement on the optimal electrode position. This study aimed to ascertain the optimal electrode position for abdominal FES, assessed by expiratory twitch pressure. Ten able-bodied participants received abdominal FES using electrodes placed: 1) on the posterolateral abdominal wall and at the motor points of 2) the external oblique muscles plus rectus abdominis muscles, and 3) the external obliques alone. Gastric (Pga) and esophageal (Pes) twitch pressures were measured using a gastroesophageal catheter. Single-stimulation pulses were applied at functional residual capacity during step increments in stimulation current to maximal tolerance or until Pga plateaued. Stimulation applied on the posterolateral abdominal wall led to a 71% and 53% increase in Pga and Pes, respectively, compared with stimulation of the external oblique and rectus abdominis muscles ( P < 0.001) and a 95% and 56% increase in Pga and Pes, respectively, compared with stimulation of the external oblique muscles alone ( P < 0.001). Stimulation of both the external oblique and rectus abdominis muscles led to an 18.3% decrease in Pga compared with stimulation of only the external oblique muscles ( P = 0.040), with inclusion of the rectus abdominis having no effect on Pes ( P = 0.809). Abdominal FES applied on the posterolateral abdominal wall generated the highest expiratory twitch pressures. As expiratory pressure is a good indicator of expiratory muscle strength and, thus, cough efficacy, we recommend this electrode position for all therapeutic applications of abdominal FES. NEW & NOTEWORTHY While abdominal functional electrical stimulation (abdominal FES) can improve respiratory function, clinical use remains low. This is at least partly due to lack of agreement on the optimal electrode position. Therefore, this study aimed to ascertain the optimal electrode position for abdominal FES. We show that electrodes placed on the posterolateral abdominal wall generated the highest expiratory twitch pressures. As such, we recommend this electrode position for all therapeutic applications of abdominal FES. PMID- 30024338 TI - Cutaneous adrenergic nerve blockade attenuates sweating during incremental exercise in habitually trained men. AB - It remains unknown whether cutaneous adrenergic nerves functionally contribute to sweat production during exercise. This study examined whether cutaneous adrenergic nerve blockade attenuates sweating during incremental exercise, specifically in habitually trained individuals. Accordingly, 10 habitually trained and 10 untrained males (Vo2max: 56.7 +/- 5.4 and 38.9 +/- 6.7 ml.kg-1.min 1, respectively; P < 0.001) performed incremental semirecumbent cycling (20 W/min) until exhaustion. Sweat rates (ventilated capsule) were measured at two bilateral forearm skin sites on which either 10 mM bretylium tosylate (BT) (an inhibitor of neurotransmitter release from sympathetic adrenergic nerve terminals) or saline (Control) was transdermally administered via iontophoresis. BT treatment delayed sweating onset in both groups (~0.66 min; P = 0.001) and suppressed the sweat rate relative to the Control treatment at >=70% relative total exercise time in trained individuals (each 10% increment; all P <= 0.009) but not in untrained counterparts ( P = 0.122, interaction between relative time * treatment). Changes in total sweat production at the BT site relative to the Control site were greater in trained individuals than in untrained counterparts (area under the curve, -0.86 +/- 0.67 and -0.22 +/- 0.39 mg/cm2, respectively; P = 0.023). In conclusion, we demonstrated that cutaneous adrenergic nerves do modulate sweating during incremental exercise, which appeared to be more apparent in habitually trained men (e.g., >=70% maximum workload). Although our results indicated that habitual exercise training may augment neural adrenergic sweat production during incremental exercise, additional studies are required to confirm this possibility. NEW & NOTEWORTHY We demonstrated for the first time that cutaneous adrenergic nerves do modulate sweating during high-intensity exercise in humans (>=70% maximum workload). In addition, neural adrenergic sweating appeared to be greater in habitually trained individuals than in untrained counterparts, although further studies are necessary to confirm such a possibility. Nonetheless, the observations presented herein advance our understanding on human thermoregulation while providing new evidence for the neutral mediation of adrenergic sweating during exercise. PMID- 30024339 TI - Repeated exposure to heat stress induces mitochondrial adaptation in human skeletal muscle. AB - The heat stress response is associated with several beneficial adaptations that promote cell health and survival. Specifically, in vitro and animal investigations suggest that repeated exposures to a mild heat stress (~40 degrees C) elicits positive mitochondrial adaptations in skeletal muscle comparable to those observed with exercise. To assess whether such adaptations translate to human skeletal muscle, we produced local, deep tissue heating of the vastus lateralis via pulsed shortwave diathermy in 20 men (n=10) and women (n=10). Diathermy increased muscle temperature by 3.9 degrees C within 30 minutes of application. Immediately following a single 2-hr heating session, we observed increased phosphorylation of AMPK and ERK1/2, but not of p38 MAPK nor JNK. Following repeated heat exposures (2-hr daily for 6 consecutive days), we observed a significant cellular heat stress response, as heat shock protein 70 and 90 increased 45% and 38%, respectively. In addition, PGC-1alpha and mitochondrial electron transport protein complexes I and V expression were increased after heating. These increases were accompanied by augmentation of maximal coupled, and uncoupled, respiratory capacity, measured via high resolution respirometry. Our data provide the first evidence that mitochondrial adaptation can be elicited in human skeletal muscle in response to repeated exposures to mild heat stress. PMID- 30024340 TI - Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: Protection against CNS oxygen toxicity. AB - Exposure to extreme-hyperbaric oxygen (HBO2), > 5-6 atmospheres absolute (ATA), produces baroreflex impairment, sympathetic hyperactivation, hypertension, tachycardia, and cerebral hyperemia, known as Phase II, culminating in seizures. We hypothesized that attenuation of the effects of high sympathetic outflow would preserve regional cerebral blood flow (rCBF) and protect against HBO2-induced seizures. To explore this possibility, we tested four adrenoceptor antagonists in conscious and anesthetized rats exposed to HBO2 at 5 and 6 ATA, respectively: phentolamine (nonselective alpha1 and 2), prazosin (selective alpha1), propranolol (nonselective beta1 and 2) and atenolol (selective beta1). In conscious rats, 4 drug-doses were administered to rats prior to HBO2 exposures, and seizure latencies were recorded. Drug-doses that provided similar protection against seizures were administered before HBO2 exposures in anesthetized rats to determine the effects of adrenoceptor blockade on mean arterial pressure, heart rate, rCBF and EEG spikes. All four drugs modified cardiovascular and rCBF responses in HBO2 that aligned with epileptiform discharges, but only phentolamine and propranolol effectively increased EEG spike latencies by ~20 and 36 min, respectively. When phentolamine and propranolol were delivered during HBO2 at the onset of phase II, only propranolol led to sustained reductions in heart rate and rCBF, preventing the appearance of epileptiform discharges. The enhanced effectiveness of propranolol may extend beyond beta-adrenoceptor blockade, i.e. membrane stability and reduced metabolic activity. These results indicate that adrenoceptor drug pre-treatment will minimize the effects of excessive sympathetic outflow on rCBF and extend HBO2 exposure time. PMID- 30024341 TI - Sex differences in large conducting airway anatomy. AB - Airway luminal area is the major determinant of resistance to airflow in the tracheobronchial tree. Women may have smaller central conducting airways than men; however, previous evidence is confounded by an indirect assessment of airway geometry and by subjects with prior smoking history. The purpose of this study was to examine the effect of sex on airway size in healthy nonsmokers. Using low dose high-resolution computed tomography, we retrospectively assessed airway luminal area in healthy men ( n = 51) and women ( n = 73) of varying ages (19-86 yr). Subjects with a positive smoking history, cardiopulmonary disease, or a body mass index > 40 kg/m2 were excluded. Luminal areas of the trachea, right and left main bronchus, bronchus intermediate, left and right upper lobes, and the left lower lobe were analyzed at three discrete points. The luminal areas of the conducting airways were ~26%-35% smaller in women. The trachea had the largest differences in luminal area between men and women (298 +/- 47 vs. 195 +/- 28 mm2 or 35% smaller for men and women, respectively), whereas the left lower lobe had the smallest differences (57 +/- 15 vs. 42 +/- 9 mm2 or 26% smaller for men and women, respectively). When a subset of subjects was matched for height, the sex differences in airway luminal area persisted, with women being ~20%-30% smaller. With all subjects, there were modest relationships between height and airway luminal area ( r = 0.73-0.53, P < 0.05). Although there was considerable overlap between sexes, the luminal areas of the large conducting airways were smaller in healthy women than in men. NEW & NOTEWORTHY Previous evidence for sex differences in airway size has been confounded by indirect measures and/or cohorts with significant smoking histories or pathologies. We found that central airways in healthy women were significantly smaller (~26%-35%) than men. The significant sex difference in airway size was attenuated (20%-30% smaller) but preserved in a subset of subjects matched for height. Over a range of ages, healthy women have smaller central airways than men. PMID- 30024342 TI - A Test of the Three-Step Theory of Suicide among Chinese People: A Study Based on the Ideation-to-Action Framework. AB - The aim of this study was to test the Three-Step Theory (3ST) of suicide in a sample of college students in China (N = 1,097). All participants completed a battery of questionnaires indexing psychological pain, hopelessness, connectedness, suicide capacity, suicide ideation, and suicide attempt. The prevalence of suicide ideation and suicide attempt among the sample were 21.42% and 3.83%, respectively. The hierarchical regression analysis showed that psychological pain and hopelessness interacted to predict suicide ideation, and that connectedness was the most protective against ideation in those high on both pain and hopelessness. Suicide capacity differentiated attempters from ideators above and beyond current suicide ideation. These findings provide preliminary evidence for the validity of 3ST of suicide within Chinese contexts. Implications for suicide prevention and intervention and future research directions are also discussed. PMID- 30024343 TI - Longitudinal Resting State Functional Connectivity Predicts Clinical Outcome in Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) affects about 42 million people worldwide. It is often associated with headache, cognitive deficits, and balance difficulties but rarely shows any abnormalities on conventional computed tomography (CT) or magnetic resonance imaging (MRI). Although in most mTBI patients the symptoms resolve within 3 months, 10-15% of patients continue to exhibit symptoms beyond a year. Also, it is known that there exists a vulnerable period post-injury, when a second injury may exacerbate clinical prognosis. Identifying this vulnerable period may be critical for patient outcome, but very little is known about the neural underpinnings of mTBI and its recovery. In this work, we used advanced functional neuroimaging to study longitudinal changes in functional organization of the brain during the 3-month recovery period post-mTBI. Fractional amplitude of low frequency fluctuations (fALFF) measured from resting state functional MRI (rs-fMRI) was found to be associated with symptom severity score (SSS, r = -0.28, p = 0.002). Decreased fALFF was observed in specific functional networks for patients with higher SSS, and fALFF returned to higher values when the patient recovered (lower SSS). In addition, functional connectivity of the same networks was found to be associated with concurrent SSS, and connectivity immediately after injury (<10 days) was capable of predicting SSS at a later time-point (3 weeks to 3 months, p < 0.05). Specific networks including motor, default-mode, and visual networks were found to be associated with SSS (p < 0.001), and connectivity between these networks predicted 3-month clinical outcome (motor and visual: p < 0.001, default-mode: p < 0.006). Our results suggest that functional connectivity in these networks comprise potential biomarkers for predicting mTBI recovery profiles and clinical outcome. PMID- 30024345 TI - Supplement: ISNPR conference abstracts. PMID- 30024346 TI - Stronger together. PMID- 30024344 TI - Validation of a Composite Test for Assessment of Readiness for Return to Sports After Anterior Cruciate Ligament Reconstruction: The K-STARTS Test. AB - BACKGROUND:: There is limited information on the appropriate timing of return to sports after anterior cruciate ligament (ACL) reconstruction. A composite test was developed to assess the athlete's ability to return to sports after ACL reconstruction: the Knee Santy Athletic Return To Sport (K-STARTS) test. HYPOTHESIS:: The K-STARTS test meets validation criteria for an outcome score assessing readiness for return to sports after ACL reconstruction. STUDY DESIGN:: Diagnostic study. LEVEL OF EVIDENCE:: Level 3. METHODS:: A prospective comparative study identified 410 participants: 371 participants who had undergone ACL reconstruction and a control group of 39 healthy participants. The K-STARTS score is calculated as the sum of 7 tests (8 components), for a maximal value of 21 points. Construct validity, internal consistency, discriminant validity, and sensitivity to change were used to validate this new test. RESULTS:: The K-STARTS assessment showed a high completion rate (100%), high reproducibility (intraclass correlation coefficient, 0.87; coefficient of variation, 7.8%), and high sensitivity to change. There was moderate correlation with the ACL Return to Sports after Injury scale (ACL-RSI) and hop tests. There were no ceiling or floor effects. There was a significant difference between K-STARTS scores assessed at 6 and 8 months postoperatively (11.2 +/- 2.7 vs 17.1 +/- 3.2; P < 0.001). The K STARTS score in the control group was significantly higher than that in the ACL reconstruction group (17.3 +/- 2.1 and 13.7 +/- 3.8, respectively; P < 0.001). CONCLUSION:: The K-STARTS test is an objective outcome measure for functional improvement after ACL reconstruction. CLINICAL RELEVANCE:: It is important for the clinician to determine when return to sports is optimal after ACL reconstruction to reduce the current high risk of reinjury. PMID- 30024347 TI - Nde1 promotes diverse dynein functions through differential interactions and exhibits an isoform-specific proteasome association. AB - Nde1 is a key regulator of cytoplasmic dynein, binding directly to both dynein itself and the dynein adaptor, Lis1. Nde1 and Lis1 are thought to function together to promote dynein function, yet mutations in each result in distinct neurodevelopment phenotypes. To reconcile these phenotypic differences, we sought to dissect the contribution of Nde1 to dynein regulation and explore the cellular functions of Nde1. Here we show that an Nde1-Lis1 interaction is required for spindle pole focusing and Golgi organization but is largely dispensable for centrosome placement, despite Lis1 itself being required. Thus, diverse functions of dynein rely on distinct Nde1- and Lis1-mediated regulatory mechanisms. Additionally, we discovered a robust, isoform-specific interaction between human Nde1 and the 26S proteasome and identify precise mutations in Nde1 that disrupt the proteasome interaction. Together, our work suggests that Nde1 makes unique contributions to human neurodevelopment through its regulation of both dynein and proteasome function. PMID- 30024348 TI - Comparison of intraoral and extraoral scanners on the accuracy of digital model articulation. AB - : Digital dental technology is increasingly becoming an integral part of the modern orthodontic practice. The accuracy of digitally articulated models is critical when developing orthodontic treatment plans. OBJECTIVE: to determine the accuracy of model articulation generated by extraoral and intraoral scanners. DESIGN: One extraoral scanner with a wax (EOW) or vinyl polysiloxane bite registration (EOVPS), and three intraoral digital scanners utilizing confocal static (IOCS), confocal continuous (IOCC), and blue LED light technologies (IOLED) were used. METHODS: On each scanned image (n = 25 per group), measurements between the maxillary and mandibular molars and canines were performed and then compared to the gold standard values. A deviation of +/- 0.5 mm from the gold standard value was considered acceptable. The significance level was kept at 0.05. RESULTS: IOCS and IOCC were accurate for all six interarch measurements. IOLED and EOVPS groups produced the next most accurate articulation of the digital models. EOW group resulted in the least accurate articulation. Also, of the software platforms used, the OrthoCADTM was found to be the most accurate system for making measurements on digital casts. CONCLUSIONS: Only the scanners with the confocal imaging technology produced accurately articulated models. Differences between the scanners may be related to measurement errors inherent to the technologies employed and the software systems used to process the images. PMID- 30024349 TI - Functional Outcomes and Accuracy of Patient-Specific Instruments for Total Knee Arthroplasty. AB - BACKGROUND: Patient-specific instruments (PSIs) were developed to improve mechanical axis alignment for patients undergoing total knee arthroplasty (TKA) as neutral alignment (180 degrees ) is a predictor of long-term success. This study examines alignment accuracy and functional outcomes of PSI as compared with standard instruments (SIs). METHODS: We retrospectively reviewed a consecutive series of TKA procedures using PSI. A total of 85 PSI procedures were identified, and these were compared with a matched cohort of 85 TKAs using SI. Intraoperative decision-making, estimated blood loss, efficiency, Knee Society Scores, and postoperative radiographs were evaluated. RESULTS: One hundred and seventy patients with comparable patient demographics were reviewed. Eighty-one percent of the PSI procedures were within target (180 +/- 3 degrees ) mechanical alignment, while the SI group had 70% of cases within the target plane ( P = .132). Mean target alignment (2.0 degrees PSI vs 2.2 degrees SI, P = .477) was similar between groups. Twenty-seven percent of patients in the PSI group had surgeon-directed intraoperative recuts to improve the perceived coronal alignment. The change in hematocrit was reduced in the PSI group (8.89 vs 7.21, P = .000). Procedure time and total operating room time were equivalent. Knee Society Scores did not differ between groups at 6 months or at 1 year. CONCLUSION: Patient-specific instrumentation decreased change in hematocrit, though coronal alignment and efficiency were equivalent between groups. Surgeons must evaluate cuts intraoperatively to confirm alignment. Functional outcomes are equivalent for PSI and SI groups. PMID- 30024350 TI - Anaerobic digestion of food waste with aerobic post-treatment: Effect of fruit and vegetable content. AB - A mesophilic anaerobic digester, followed by a psychrophilic aerobic post treatment, was used to treat food waste (FW) with different proportions of fruit and vegetable waste (FVW). Two types of FW were used: low fruit and vegetable mix (LFV, with 56.5% of FVW) and high fruit and vegetable mix (HFV, with 78.3% of FVW). The anaerobic digester fed with LFV failed at an organic loading rate of 1.6 g VS.L-1.d-1 (volatile fatty acid (VFA) = 6000 mg.L-1) due to high ammonia (reaching 3000 mg.L-1). It was shown that, in an unstable anaerobic environment, ammonia is highly correlated ( r2 = 0.77) with VFA and is negatively correlated with volatile solids, total solids, and chemical oxygen demand (COD) removal rates ( r2 = 0.88, r2 = 0.71, and r2 = 0.91, respectively). In contrast, the anaerobic digester fed with HFV exhibited a stable performance (VFA = 1243 mg.L 1), with limited ammonia accumulation (940 mg.L-1). Methane generation was affected by the FVW content and reached 531 ml CH4.g VS-1 (CH4 = 52%) with LFV feed and 478 ml CH4.g VS-1 (CH4 = 57.4%) with HFV. The overall TS, VS and COD removal rates (all ranging between 94% and 97%), were closely similar for LFV and HFV. Accordingly, the aerobic post-treatment seems to compensate for the reduced performance of the disturbed anaerobic system fed with LFV. PMID- 30024351 TI - Protective factors of suicide and suicidal behaviour relevant to emergency healthcare settings: A systematic review and narrative synthesis of post-2007 reviews. AB - OBJECTIVES: Suicide is a major public health concern and, with recent societal changes, such as economic and technological changes, there may be emerging protective factors that mitigate suicide risk which are unrecognised in emergency healthcare. This systematic review aims to identify protective factors for suicide that can feasibly be assessed in time-limited emergency healthcare settings. METHODS: A systematic review of reviews was conducted via PsycINFO, CINAHL and Medline (2007-2015). Reviews were assessed for methodological quality using AMSTAR. RESULTS: Twenty-four reviews met the inclusion criteria, eight were assessed as high quality and included in a narrative synthesis. Known protective factors were identified (e.g., social support), along with emerging protective factors (e.g., internet support). CONCLUSION: The review synthesises recent research evidence on protective factors and discusses their relevance to emergency healthcare. PMID- 30024352 TI - Comparative environmental assessment of alternative waste management strategies in developing regions: A case study in Kazakhstan. AB - The management of municipal solid waste in the Republic of Kazakhstan is still in its infancy. This situation poses a potential threat to the environment and public health and, therefore, it is necessary to introduce improved management schemes in the country. In this study, the life cycle assessment methodology was followed to evaluate the potential environmental benefits of implementing alternative management schemes based on low-waste generation and renewable energy production. The current situation of the capital city Astana was considered as the base case. Environmental results showed that air emissions in terms of landfill gases are the major contributor to climate change impacts, while landfill disposal of the non-recovered fraction of recyclable materials was responsible for the highest impacts in the other categories (especially land use). However, the reuse of recycled materials largely offsets the related environmental burdens, along with energy generation. In comparative terms, it was demonstrated that the proposed waste management scenarios are more environmentally friendly than current practices (S0), mainly owing to the credits associated with the valorisation of renewable energy (S2) and recovered materials (S3). Consequently, the evaluation showed that greater efforts should be made to exploit the energy potential of organic fraction, together with higher recycling rates, to move towards lower environmental impacts associated with municipal solid waste management. PMID- 30024353 TI - Engagement or dismissiveness? Intersecting international theory and global health. AB - International relations theorists and global health politics scholars largely fail to communicate with one another. We argue that drawing on insights from classic and contemporary international theory more explicitly will positively augment the study of global health politics. This paper highlights four major theoretical orientations in the international relations literature (realism, neoliberal institutionalism, constructivism, and feminism) and discusses how an understanding of these perspectives can strengthen our understanding of global health policy. PMID- 30024354 TI - Prediction and job-related outcomes of procrastination in the workplace. AB - In the current study, we examined whether the impact of the Big Five on procrastination in an organizational context is similar to that in academic settings, and examined the role of dis-regulation of anxiety as a potential moderator of these relationships. One hundred and seven Israeli employees participated in the study. The results showed that agreeableness and conscientiousness were negatively associated with procrastination, while neuroticism was positively associated with procrastination in the workplace. Moreover, the findings supported the hypothesis that dis-regulation of anxiety moderates the relationships between personality traits and workplace procrastination. These findings suggest that the link between personality traits and workplace procrastination is not stable, is affected by different contexts, and interacts with other personality characteristics (specifically, dis regulation of anxiety). PMID- 30024355 TI - Causes for procrastination in a unique educational workplace. AB - Teachers in hospitals are a unique phenomenon. Their students are sick, hospitalized children with a range of physical, emotional, and cognitive needs. Teachers are expected to be dynamic, flexible, creative, open-minded, and efficient to function in the most appropriate manner. However, a recent study showed that these teachers tend to procrastinate on some of the most common tasks that teachers perform on a daily basis in the regular school system. The present study was an initial investigation into the reasons for procrastination in teachers who work in two hospitals in Israel. Thirty-two teachers were interviewed. The findings indicated that the primary reason for procrastination among teachers in the hospital was professional role ambiguity, with emotional factors and situational determinants which were identified. Future research should further explore reasons for procrastination in the workplace, in general, and its association with professional role ambiguity specifically. PMID- 30024356 TI - Decisional, general and online procrastination: Understanding the moderating role of negative affect in the case of computer professionals. AB - Following the development of the internet as an essential tool for communication at home and at work, the concept of online procrastination was introduced to the literature. The present study examined the relationships between online procrastination and two well-established forms of procrastination, namely decisional and general procrastination; as well as the moderating effect of negative affect on these relationships. The sample consisted of 236 computer professionals from Israel who filled self-reported questionnaires on procrastination and negative feelings. To examine the relationships between our variables, we used multiple linear regression and moderation analyses. The findings indicated that higher levels of general and decisional procrastination were associated with higher levels of online procrastination. Higher levels of negative affect were also associated with online procrastination. Moreover, negative affect moderated the effect of general and decisional procrastination on online procrastination, and for participants with higher levels of negative affect, this effect was stronger. These findings suggest that both a personality based tendency to procrastinate and the tendency to delay decision making may affect online behavior and that negative affect strengthens these tendencies. Future studies will need to further explore online procrastination and examine the personality and situational variables that contribute to it. PMID- 30024357 TI - Correlates of procrastination and performance at work: The role of having "good fit". AB - Occupational research often emphasizes the importance of workplace characteristics for understanding job stress and employee well-being, but the role of personal characteristics and having a good match with the job is mostly neglected. We explored how job crafting and feelings of being authentic at work were related to work engagement, work engagement of performance, and procrastination. A structural equation model analyzed self-reports from 380 Dutch office employees. Job crafting and authenticity were positively related to work engagement, and high work engagement predicted? better in-role and extra-role performance and less work procrastination. Moreover, performance and procrastination were negatively related. Results emphasize the importance of having a "good fit" between the employment settings and employees to promote engagement. By improving employee's work engagement, organizations might improve the likelihood that personnel respond favorably with organizational goals and reduce the chances of engaging in workplace procrastination. PMID- 30024358 TI - Introduction: Towards a wider understanding of workplace procrastination. PMID- 30024359 TI - Two faces of employee inactivity: Procrastination and recovery. AB - The present study aims to investigate whether the two kinds of employee inactivity, namely procrastination and recovery at work can be empirically distinguished. Online survey data collected from 116 Dutch white-collar employees were analyzed in terms of (a) the factorial distinction of recovery and procrastination (internal validity evidence) and (b) their association with performance and work engagement (external validity evidence). The results of confirmatory factory analysis revealed the best fit for the model in which recovery and subdimensions of procrastination (soldiering and cyberslacking) loading to separate latent constructs. Moreover, recovery was positively related to work engagement and performance, whereas, procrastination did not show any significant relationship to these two concepts. In sum, findings of this study suggest that employee non-work related activity during work hours can be differentiated empirically. These results enhance the workplace procrastination literature by providing further validation evidence. PMID- 30024360 TI - Linking leadership style and workplace procrastination: The role of organizational citizenship behavior and turnover intention. AB - The primary aim of the present study was to explore whether paternalistic or transformational leadership styles of supervisors were significantly related to workplace procrastination. Moreover, the potential mediation effects of organizational citizenship behaviors (specifically, civic virtue, and conscientiousness) and turnover intention in the link between leadership style and procrastination of the employees were investigated on a heuristic model. Data was collected through online surveys from 126 Turkish full-time office employees. The goodness-of-fit of the proposed model was tested using structural equation modeling and the mediation analysis was performed by bootstrapping. As expected, transformational leadership and organizational citizenship behaviors were negatively related to workplace procrastination. However, there was no significant link between paternalistic leadership and procrastination. Moreover, turnover intention and organizational citizenship behaviors did not mediate this relationship. These findings suggest that transformational leadership style could be a more effective style for diminishing employees' excessive nonwork related behaviors. PMID- 30024361 TI - Some facts about the respiratory enzymes of Pseudomonas pseudoalcaligenes KF707 recently renamed as Pseudomonas furukawaii sp. nov., type strain KF707. AB - Kimura and co-workers (Kimura N et al. Int J Syst Evol Microbiol 2018;68:1429 1435) recently proposed renaming the obligate aerobe Pseudomonas pseudoalcaligenes KF707 as Pseudomonas furukawiisp. nov. type strain KF707. Since the first quasi-complete genome sequence of KF707 was reported in 2012 (accession number: PRJNA83639) numerous reports on chemotaxis and function/composition of the respiratory redox chain of KF707 have been published, demonstrating that KF707 contains three cheA genes for aerobic motility, four cytochrome oxidases of c(c)aa3- and cbb3-type and one bd-type quinol oxidase. With this background in mind, it has been quite a surprise to read within Table 1 of the paper by Kimura et al. that strain KF707 is phenotypically characterized as cytochrome oxidase negative. Further, Table 1 also reports that KF707 is beta-galactosidase positive, an affirmation that is not consistent with results documented in the current literature. In this present 'Letter to the Editor' we show that Kimura et al. have contradicted themselves and provided inaccurate information in respect to the respiratory phenotypic features of P. furukawii. Based on this, an official corrigendum is requested since the publication, as it is, blurs the credibility of the International Journal of Systematic and Evolutionary Microbiology. PMID- 30024363 TI - A transcriptomic analysis of the mycobacteriophage D29 genome reveals the presence of novel stoperator-associated promoters in its right arm. AB - Mycobacteriophage D29 is a lytic phage that infects various species of Mycobacterium including M. tuberculosis. Its genome has 77 genes distributed almost evenly between two converging operons designated as left and right. Transcription of the phage genome is negatively regulated by multiple copies of an operator-like element known as stoperator that acts by binding the phage repressor Gp71. The function of the D29 genes and their expression status are poorly understood and therefore we undertook a transcriptome analysis approach to address these issues. The results indicate that the average transcript intensity of the right arm genes was higher than of those on the left, at the early stage of infection. Moreover, the fold increase from early to the late stage was found to be less for the right arm genes than for the left. Both observations support the prediction that the right arm genes are expressed early whereas the left arm ones are expressed late. The analysis further revealed a break in the continuity of the right arm operon between 89, the first gene in it, and 88, the next. Gene 88 was found to be expressed from a newly identified promoter located between 88 and 89. Another new promoter was found upstream of 89. Thus, the promoter Pleft, identified earlier, is not the only one that drives expression of the right arm genes. All these promoters overlap with stoperators, with which they share a conserved sequence motif, TTGACA, commonly known as the -35 promoter element. We demonstrate mutually exclusive binding of RNA polymerase and Gp71 to the stoperator-promoters and conclude that stoperators can function as -35 promoter elements and that they can control gene expression not only negatively as was believed earlier but in many cases positively as well. PMID- 30024362 TI - Pseudomonas tianjinensis sp. nov., isolated from domestic sewage. AB - A novel Gram-stain-negative bacterium, designated as type strain 68T, was isolated from domestic sewage in Tianjin, China. Cells of strain 68T were aerobic, motile and rod-shaped. The organism grew at 15-42 degrees C, pH 6.0 11.0 and with 0-4 % NaCl (w/v). The DNA G+C content was 61.9 mol%. The major fatty acids (>10 %) were summed feature 8 (C18 : 1omega7c), summed feature 3 (C16 : 1omega7c or C16 : 1omega6c), C16 : 0 and C12 : 0. The respiratory quinone was Q9. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine and an unidentified aminophospholipid. Phylogenetic analysis based on full 16S rRNA gene sequences showed that strain 68T was a member of the genus Pseudomonas and showed similarities to Pseudomonas toyotomiensis HT-3T (98.58 %), Pseudomonas chengduensis MBRT (98.53 %), Pseudomonas alcaliphila AL15-21T (98.44 %), Pseudomonas composti C2T (97.75 %) and Pseudomonas anguilliseptica NCIMB 1949T (97.66 %). Strain 68T exhibited low DNA-DNA hybridization homology with P. alcaliphila AL15-21T (35.40 %), P. toyotomiensis HT-3T (33.30 %), P. chengduensis MBRT (35.40 %), P. anguilliseptica NCIMB 1949T (14.40 %) and P. composti C2T (20.40 %). On the basis of phenotypic, genotypic and phylogenetic evidence, strain 68T is considered to represent a novel species of the genus Pseudomonas, for which the name Pseudomonas tainjinensis sp. nov. is proposed. The type strain is 68T (=CICC 24204T=KCTC 52977T). PMID- 30024364 TI - Deletion-based escape of CRISPR-Cas9 targeting in Lactobacillus gasseri. AB - Lactobacillus gasseri is a human commensal which carries CRISPR-Cas, an adaptive immune system that protects the cell from invasive mobile genetic elements (MGEs). However, MGEs occasionally escape CRISPR targeting due to DNA mutations that occur in sequences involved in CRISPR interference. To better understand CRISPR escape processes, a plasmid interference assay was used to screen for mutants that escape CRISPR-Cas targeting. Plasmids containing a target sequence and a protospacer adjacent motif (PAM) were transformed for targeting by the native CRISPR-Cas system. Although the primary outcome of the assay was efficient interference, a small proportion of the transformed population overcame targeting. Mutants containing plasmids that had escaped were recovered to investigate the genetic routes of escape and their relative frequencies. Deletion of the targeting spacer in the native CRISPR array was the dominant pattern of escape, accounting for 52-70 % of the mutants from two L. gasseri strains. We repeatedly observed internal deletions in the chromosomal CRISPR array, characterized by polarized excisions from the leader end that spanned 1-15 spacers, and systematically included the leader-proximal targeting spacer. This study shows that deletions of spacers within CRISPR arrays constitute a key escape mechanism to evade CRISPR targeting, while preserving the functionality of the CRISPR-Cas system. This mechanism enables cells to maintain an active immune system, but allows the uptake of potentially beneficial plasmids. Our study revealed the co-occurrence of other genomic mutations associated with various phenotypes, showing how this selection process uncovers population diversification. PMID- 30024365 TI - Development of a species-specific PCR-RFLP targeting rpoD gene fragment for discrimination of Aeromonas species. AB - PURPOSE: The taxonomy of Aeromonas keeps expanding and their identification remains problematic due to their phenotypic and genotypic heterogeneity. In this study, we aimed to develop a rapid and reliable polymerase chain reaction restriction fragment length polymorphism assay targeting the rpoD gene to enable the differentiation of aeromonads into 27 distinct species using microfluidic capillary electrophoresis. METHODOLOGY: A pair of degenerate primers (Aero F: 5' YGARATCGAYATCGCCAARCGB-3' and Aero R: 5'-GRCCDATGCTCATRCGRCGGTT-3') was designed that amplified the rpoD gene of 27 Aeromonas species. Subsequently, in silico analysis enabled the differentiation of 25 species using the single restriction endonuclease AluI, while 2 species, A. sanarelli and A. taiwanensis, required an additional restriction endonuclease, HpyCH4IV. Twelve type strains (A. hydrophila ATCC7966T, A. caviae ATCC15468T, A. veronii ATCC9071T, A. media DSM4881T, A. allosaccharophila DSM11576T, A. dhakensis DSM17689T, A. enteropelogens DSM7312T, A. jandaei DSM7311T, A. rivuli DSM22539T, A. salmonicida ATCC33658T, A. taiwanensis DSM24096T and A. sanarelli DSM24094T) were randomly selected from the 27 Aeromonas species for experimental validation.Results/key findings. The twelve type strains demonstrated distinctive RFLP patterns and supported the in silico digestion. Subsequently, 60 clinical and environmental strains from our collection, comprising nine Aeromonas species, were used for screening examinations, and the results were in agreement. CONCLUSION: This method provides an alternative method for laboratory identification, surveillance and epidemiological investigations of clinical and environmental specimens. PMID- 30024366 TI - Trends in fluoroquinolone resistance in Campylobacter. AB - Members of the genus Campylobacter remain a leading cause of bacterial gastroenteritis worldwide. Infection is usually self-limiting but in severe cases may require antibiotic treatment. In a recent statement by the World Health Organization (WHO) Campylobacter was named as one of the 12 bacteria that pose the greatest threat to human health because they are resistant to antibiotics. In this mini review we describe recent trends in fluoroquinolone (FQ) (particularly ciprofloxacin) resistance in strains of members of the genus Campylobacter isolated from livestock and clinical samples from several countries. Using evidence from phenotyping surveys and putative resistance prediction from DNA sequence data, we discuss the acquisition and spread of FQ resistance and the role of horizontal gene transfer and describe trends in FQ-resistance in samples from livestock and clinical cases. This review emphasises that FQ resistance remains common among isolates of members of the genus Campylobacter from various sources. PMID- 30024367 TI - Isolation and characterization of Leptospira interrogans from two patients with leptospirosis in Western Province, Sri Lanka. AB - Leptospirosis is an endemic infectious disease causing considerable morbidity and mortality in Sri Lanka; however, reports on the isolation of Leptospira from infected patients in Sri Lanka have been largely unavailable since the 1970s. Two isolates were obtained and characterized from 100 blood cultures from leptospirosis-suspected patients. Phylogenic analysis of partial flaB gene sequences identified the isolates as Leptospira interrogans. The patient serum samples from which Leptospira was isolated reacted with the Leptospira serogroups Sejroe and Canicola at a titre of 1 : 200. Exposure to domestic sewage and gutters filled with muddy water was suspected to be the source of infection in these two culture-positive patients. This study reports the successful isolation of pathogenic Leptospira from two patients in Western Province, Sri Lanka. PMID- 30024368 TI - Molecular determinants of Burkholderia pseudomallei BpeEF-OprC efflux pump expression. AB - Burkholderia pseudomallei, the cause of melioidosis, is intrinsically resistant to many antibiotics. Acquired multidrug resistance, including resistance to doxycycline and co-trimoxazole used for melioidosis eradication phase therapy, is mainly attributed to constitutive expression of the BpeEF-OprC efflux pump. Constitutive expression of this pump is caused by mutations affecting two highly similar LysR-type transcriptional regulators (LTTR), BpeT and BpeS, but their interaction with the regulatory region governing BpeEF-OprC expression has not yet been studied. The bpeE-bpeF-oprC genes are distally located in the llpE-bpeE bpeF-oprC operon. The llpE gene encodes a putative lipase/esterase of unknown function. We show that in a bpeT mutant llpE is constitutively co-transcribed with bpeE-bpeF-oprC. As expected from previous studies with B. cenocepacia, deletion of llpE does not affect antibiotic efflux. Using transcriptional bpeE' lacZ fusions, we demonstrate that the 188 bp bpeT-llpE intergenic region located between bpeT and the llpE-bpeE-bpeF-oprC operon contains regulatory elements needed for control of bpeT and llpE-bpeE-bpeF-oprC operon expression. By native polyacrylamide gel electrophoresis and electrophoretic mobility shift assays with purified recombinant BpeT and BpeS proteins, we show BpeT and BpeS form oligomers that share a 14 bp binding site overlapping the essential region required for llpE-bpeE-bpeF-oprC expression. The binding site contains the conserved T-N11-A LTTR box motif involved in binding of LysR proteins, which in concert with two other possible LTTR boxes may mediate BpeT and BpeS regulation of BpeEF-OprC expression. These studies form the basis for further investigation of BpeEF-OprC expression and regulation at the molecular level by yet unknown external stimuli. PMID- 30024369 TI - The Gram-negative phytopathogen Xanthomonas campestris pv. campestris employs a 5'UTR as a feedback controller to regulate methionine biosynthesis. AB - The synthesis of methionine is critical for most bacteria. It is known that cellular methionine has a feedback effect on the expression of met genes involved in de novo methionine biosynthesis. Previous studies revealed that Gram-negative bacteria control met gene expression at the transcriptional level by regulator proteins, while most Gram-positive bacteria regulate met genes at post transcriptional level by RNA regulators (riboregulators) located in the 5'UTR of met genes. However, despite its importance, the methionine biosynthesis pathway in the Gram-negative Xanthomonas genus that includes many important plant pathogens is completely uncharacterized. Here, we address this issue using the crucifer black rot pathogen Xanthomonas campestris pv. campestris (Xcc), a model bacterium in microbe-plant interaction studies. The work identified an operon (met) involved in de novo methionine biosynthesis in Xcc. Disruption of the operon resulted in defective growth in methionine-limited media and in planta. Western blot analysis revealed that the expression of the operon is dependent on methionine levels. Further molecular analyses demonstrated that the 5'UTR, but not the promoter of the operon, is involved in feedback regulation on operon expression in response to methionine availability, providing an example of a Gram negative bacterium utilizing a 5'UTR region to control the expression of the genes involved in methionine biosynthesis. PMID- 30024371 TI - Review of the genus Methylobacterium and closely related organisms: a proposal that some Methylobacterium species be reclassified into a new genus, Methylorubrum gen. nov. AB - The genus Methylobacterium, when first proposed by Patt et al. in 1976, was a monospecific genus created to accommodate a single pink pigmented facultatively methylotrophic bacterium. The genus now has over 50 validly published species, however, the percentage 16S rRNA sequence divergence within Methylobacterium questions whether or not they can still be accommodated within one genus. Additionally, several strains are described as belonging to Methylobacterium, but nodulate legumes and in some cases are unable to utilize methanol as a sole carbon source. This study reviews and discusses the current taxonomic status of Methylobacterium. Based on 16S rRNA gene, multi-locus sequence analysis, genomic and phenotypic data, the 52 Methylobacterium species can no longer be retained in one genus. Consequently, a new genus, Methylorubrum gen. nov., is proposed to accommodate 11 species previously held in Methylobacterium. The reclassified species names are proposed as: Methylorubrum aminovorans comb. nov. (type strain TH-15T=NCIMB 13343T=DSM 8832T), Methylorubrum extorquens comb. nov. (type strain NCIMB 9399T=DSM 1337T), Methylorubrum podarium comb. nov. (type strain FM4T=NCIMB 14856T=DSM 15083T), Methylorubrum populi comb. nov. (type strain BJ001T=NCIMB 13946T=ATCC BAA-705T), Methylorubrum pseudosasae comb. nov. (type strain BL44T=ICMP 17622T=NBRC 105205T), Methylorubrum rhodesianum comb. nov. (type strain NCIMB 12249T=DSM 5687T), Methylorubrum rhodinum comb. nov. (type strain NCIMB 9421T=DSM 2163T), Methylorubrum salsuginis comb. nov. (type strain MRT=NCIMB 14847T=NCCB 100140T), Methylorubrum suomiense comb. nov. (type strain F20T=NCIMB 13778T=DSM 14458T), Methylorubrum thiocyanatum comb. nov. (type strain ALL/SCN-PT=NCIMB 13651T=DSM 11490T) and Methylorubrum zatmanii comb. nov. (type strain NCIMB 12243T=DSM 5688T). The taxonomic position of several remaining species is also discussed. PMID- 30024370 TI - A severe outbreak of listeriosis in central Italy with a rare pulsotype associated with processed pork products. AB - PURPOSE: From May 2015 to March 2016, an outbreak due to Listeria monocytogenes serotype 1/2a and clinical pulsotype never previously isolated in Europe occurred in central Italy, involving 24 confirmed clinical cases. The article provides a description of the outbreak and the investigation carried out by a multidisciplinary network. METHODOLOGY: Epidemiological and microbiological surveillance was conducted to confirm the outbreak and to detect the food vehicle of infection. The origin and destination of the implicated food and its ingredients were investigated by tracing-back and -forward investigation. RESULTS: Next-generation sequencing confirmed the unique outbreak strain. On 4 January 2016, a L. monocytogenes strain with pulsotype indistinguishable from that isolated from clinical cases in the outbreak was detected in a sample of hog head cheese purchased from a retail supermarket by one of the patients. The hog head cheese was produced by a small meat processing plant in the Marche region, where microbiological investigation confirmed environmental and food contamination by the outbreak strain. Plant production was suspended and all contaminated batches of the hog head cheese were withdrawn from the market by 19 February by local health authority. We subsequently observed a sharp decline in clinical cases, the last being reported on 11 March 2016. CONCLUSION: The key factor in the timely conclusion of this investigation was intersectoral collaboration among epidemiologists, microbiologists, veterinarians, statisticians and health and food safety authorities at national, regional and local levels. PMID- 30024372 TI - Oxyresveratrol-induced DNA cleavage triggers apoptotic response in Candida albicans. AB - Oxyresveratrol is a naturally occurring phytoalexin produced by plants in response to infection. Biological activities of oxyresveratrol have been studied such as antioxidant, anticancer and anti-inflammation. However, further antimicrobial activity and its mechanism need to be investigated. This study exhibited growth inhibition against pathogenic fungi and investigated its mode of action. Oxyresveratrol inflicted cleavage on DNA, leading to G2/M phase arrest. DNA damage by oxyresveratrol was not the result of oxidative stress but it was triggered by direct binding to DNA. Oxyresveratrol-treated cells showed an apoptotic pathway characterized by phosphatidylserine exposure, apoptotic volume decrease and metacaspase activation. Mitochondria-associated apoptotic features also appeared. Oxyresveratrol-induced Ca2+ overload led to mitochondrial membrane depolarization and release of cytochrome c from mitochondria to cytosol. In conclusion, oxyresveratrol with DNA-binding affinity induces DNA cleavage, and eventually leads to mitochondria-mediated apoptosis in Candida albicans. PMID- 30024373 TI - Comparison of the clinical performance of OmniPlex-HPV and GeneFinder HPV for the detection and genotyping of human papillomaviruses in cervical specimens. AB - PURPOSE: Human papillomavirus (HPV) infection in women is known to promote the development of cervical neoplasia. Specific HPV genotypes are more highly associated with disease, and therefore detection and genotyping of HPV infection is critical for preventing and effectively treating cervical cancer. Consequently, various assays using diverse technologies have been developed to detect HPV genotype. Recently the OmniPlex-HPV and GeneFinder HPV methods, based on PCR and Luminex xMAP liquid bead microarray technologies, were developed for the detection of 40 and 32 HPV genotypes, respectively. The purpose of this study was to compare the clinical performance of OmniPlex-HPV and GeneFinder HPV. METHODOLOGY: The study included 300 cytology-confirmed cervical swab specimens. In cases where there was a discrepancy between the two assay results, type specific direct sequencing was performed. RESULT: We found a high overall agreement between OmniPlex-HPV and GeneFinder HPV for detecting the presence or absence of high-risk HPV (HR HPV) (90.7 %, kappa=0.810). However, OmniPlex-HPV showed greater sensitivity than GeneFinder HPV in the identification of multiple genotype-infected samples. Specifically, diagnostic sensitivities for HR HPV positivity in high-grade squamous intra-epithelial lesions (HSIL) were 100.0 % for OmniPlex-HPV and 96.8 % for GeneFinder HPV. CONCLUSIONS: Our results suggest that OmniPlex-HPV and GeneFinder HPV are highly comparable for the detection and genotyping of HPV, but OmniPlex-HPV displays greater accuracy in cases of multiple HPV infection. PMID- 30024374 TI - Hymenobacter bucti sp. nov., isolated from subsurface sandstone sediment. AB - A Gram-reaction-negative, strictly aerobic, non-motile, non-spore-forming bacterial strain, designated DK6-66T, was isolated from subsurface sandstone sediment located in the Qilian Mountains in Qinghai Province, Northwest China. Strain DK6-66T was found to grow optimally at pH 7.0 and 22 degrees C. The 16S rRNA gene sequence analysis indicated that strain DK6-66T belonged to the genus Hymenobacter and clustered with the type strain of Hymenobacter arcticus, with which it exhibited a 16S rRNA gene sequence similarity value of 98.2 %. The DNA G+C content was 60.4 mol%. The major respiratory quinone was MK-7 and the major polar lipid was phosphatidylethanolamine. The major fatty acids were C16 : 1omega7c and/or C16 : 1omega6c, anteiso-C17 : 1 B and/or iso-C17 : 1 I, iso-C15 : 0, anteiso-C15 : 0 and C16 : 1omega5c. On the basis of phylogenetic and phenotypic data, strain DK6-66T was classified in the genus Hymenobacter as a member of a novel species, for which the name Hymenobacterbucti sp. nov. is proposed. The type strain is DK6-66T (=CGMCC 1.15795T=KCTC 52629T). PMID- 30024375 TI - A brighter force gauge for cells. AB - An improved biosensor sheds new light on tension within proteins. PMID- 30024376 TI - Coevolution-based inference of amino acid interactions underlying protein function. AB - Protein function arises from a poorly understood pattern of energetic interactions between amino acid residues. Sequence-based strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in several homologs of a protein family - a deep coupling scan (DCS). The data show that cooperative interactions between residues are loaded in a sparse, evolutionarily conserved, spatially contiguous network of amino acids. The pattern of amino acid coupling is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work exposes the collective nature of physical constraints on protein function and clarifies its link with sequence analysis, enabling a general practical approach for understanding the structural basis for protein function. PMID- 30024377 TI - PDF-1 neuropeptide signaling regulates sexually dimorphic gene expression in shared sensory neurons of C. elegans. AB - Sexually dimorphic behaviors are a feature common to species across the animal kingdom, however how such behaviors are generated from mostly sex-shared nervous systems is not well understood. Building on our previous work which described the sexually dimorphic expression of a neuroendocrine ligand, DAF-7, and its role in behavioral decision-making in C. elegans (Hilbert and Kim, 2017), we show here that sex-specific expression of daf-7 is regulated by another neuroendocrine ligand, Pigment Dispersing Factor (PDF-1), which has previously been implicated in regulating male-specific behavior (Barrios et al., 2012). Our analysis revealed that PDF-1 signaling acts sex- and cell-specifically in the ASJ neurons to regulate the expression of daf-7, and we show that differences in PDFR-1 receptor activity account for the sex-specific effects of this pathway. Our data suggest that modulation of the sex-shared nervous system by a cascade of neuroendocrine signals can shape sexually dimorphic behaviors. PMID- 30024378 TI - Tunable molecular tension sensors reveal extension-based control of vinculin loading. AB - Molecular tension sensors have contributed to a growing understanding of mechanobiology. However, the limited dynamic range and inability to specify the mechanical sensitivity of these sensors has hindered their widespread use in diverse contexts. Here, we systematically examine the components of tension sensors that can be altered to improve their functionality. Guided by the development of a first principles model describing the mechanical behavior of these sensors, we create a collection of sensors that exhibit predictable sensitivities and significantly improved performance in cellulo. Utilized in the context of vinculin mechanobiology, a trio of these new biosensors with distinct force- and extension-sensitivities reveal that an extension-based control paradigm regulates vinculin loading in a variety of mechanical contexts. To enable the rational design of molecular tension sensors appropriate for diverse applications, we predict the mechanical behavior, in terms of force and extension, of additional 1020 distinct designs. PMID- 30024379 TI - Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. AB - The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. Chondrocyte survival is enabled, cell autonomously, by CHOP and dual CHOP-ATF4 transactivation of Fgf21. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress induced skeletal disorders. PMID- 30024381 TI - Expanding the Concept of Translational Research: Making a Place for Environmental Health Sciences. AB - SUMMARY: The National Institute of Environmental Health Sciences (NIEHS) introduces a new translational research framework that builds upon previous biomedical models to create a more comprehensive and integrated environmental health paradigm. The framework was developed as a graphical construct that illustrates the complexity of designing, implementing, and tracking translational research in environmental health. We conceptualize translational research as a series of concentric rings and nodes, defining "translation" as movement either from one ring to another or between nodes on a ring. A "Fundamental Questions" ring expands upon the research described in other frameworks as "basic" to include three interrelated concepts critical to basic science research: research questions, experimental settings, and organisms. This feature enables us to capture more granularity and thus facilitates an approach for categorizing translational research and its growth over time. We anticipate that the framework will help researchers develop compelling long-term translational research stories and accelerate public health impacts by clearly mapping out opportunities for collaborations. By using this paradigm, researchers everywhere will be better positioned to design research programs, identify research partners based on cross disciplinary research needs, identify stakeholders who are likely to use the research for environmental decision-making and intervention, and track progress toward common goals. https://doi.org/10.1289/EHP3657. PMID- 30024380 TI - Importance of miRNA stability and alternative primary miRNA isoforms in gene regulation during Drosophila development. AB - Mature microRNAs (miRNAs) are processed from primary transcripts (pri-miRNAs), and their expression is controlled at transcriptional and post-transcriptional levels. However, how regulation at multiple levels achieves precise control remains elusive. Using published and new datasets, we profile a time course of mature and pri-miRNAs in Drosophila embryos and reveal the dynamics of miRNA production and degradation as well as dynamic changes in pri-miRNA isoform selection. We found that 5' nucleotides influence stability of mature miRNAs. Furthermore, distinct half-lives of miRNAs from the mir-309 cluster shape their temporal expression patterns, and the importance of rapid degradation of the miRNAs in gene regulation is detected as distinct evolutionary signatures at the target sites in the transcriptome. Finally, we show that rapid degradation of miR 3/-309 may be important for regulation of the planar cell polarity pathway component Vang. Altogether, the results suggest that complex mechanisms regulate miRNA expression to support normal development. PMID- 30024382 TI - The Urban Exposome during Pregnancy and Its Socioeconomic Determinants. AB - BACKGROUND: The urban exposome is the set of environmental factors that are experienced in the outdoor urban environment and that may influence child development. OBJECTIVE: The authors' goal was to describe the urban exposome among European pregnant women and understand its socioeconomic determinants. METHODS: Using geographic information systems, remote sensing and spatio-temporal modeling we estimated exposure during pregnancy to 28 environmental indicators in almost 30,000 women from six population-based birth cohorts, in nine urban areas from across Europe. Exposures included meteorological factors, air pollutants, traffic noise, traffic indicators, natural space, the built environment, public transport, facilities, and walkability. Socioeconomic position (SEP), assessed at both the area and individual level, was related to the exposome through an exposome-wide association study and principal component (PC) analysis. RESULTS: Mean+/-standard deviation (SD) NO2 levels ranged from 13.6+/-5.1 MUg/m3 (in Heraklion, Crete) to 43.2+/-11 MUg/m3 (in Sabadell, Spain), mean+/-SD walkability score ranged from 0.22+/-0.04 (Kaunas, Lithuania) to 0.32+/-0.07 (Valencia, Spain) and mean+/-SD Normalized Difference Vegetation Index ranged from 0.21+/ 0.05 in Heraklion to 0.51+/-0.1 in Oslo, Norway. Four PCs explained more than half of variation in the urban exposome. There was considerable heterogeneity in social patterning of the urban exposome across cities. For example, high-SEP (based on family education) women lived in greener, less noisy, and less polluted areas in Bradford, UK (0.39 higher PC1 score, 95% confidence interval (CI): 0.31, 0.47), but the reverse was observed in Oslo (-0.57 PC1 score, 95% CI: -0.73, 0.41). For most cities, effects were stronger when SEP was assessed at the area level: In Bradford, women living in high SEP areas had a 1.34 higher average PC1 score (95% CI: 1.21, 1.48). CONCLUSIONS: The urban exposome showed considerable variability across Europe. Pregnant women of low SEP were exposed to higher levels of environmental hazards in some cities, but not others, which may contribute to inequities in child health and development. https://doi.org/10.1289/EHP2862. PMID- 30024385 TI - Mucoadhesive assessment of different antifungal nanoformulations. AB - Oral candidiasis is an important opportunistic fungal infection and polyenes and azoles are still the most used antifungal agents. However, the oral absorption resulting from most available treatments is generally poor and, consequently, a very high frequency of administrations of antifungal agents is strongly required. Therefore, the major challenge is to improve the retention of the antifungal agents in buccal mucosa, and the encapsulation into mucoadhesive systems may be considered as a possible strategy to achieve this objective. Three types of mucoadhesive polymeric nanoparticles (polylactic acid (PLA), polylactic-co glycolic acid (PLGA) and alginate) were prepared using nystatin as model drug. The drug-loaded nanoparticles were then included in toothpaste, oral gel and oral films, respectively. The results demonstrated that the loaded nanoparticles were successfully produced, presenting a mean size between 300-900 nm and with a negative surface charge. Also, the determination of the encapsulation efficiency of all nanoparticles showed values above 70%. In terms of the in vitro mucoadhesion, the best formulation was the oral film loaded with the PLGA nanoparticles followed by the oral gel with PLA nanoparticles and thirdly the toothpaste with alginate nanoparticles. This was confirmed in an in vitro rinsing model with mucus producing HT29-MTX cells, where the percentage of nystatin retained to the cells after 40 min of simulated saliva flow was between 10-27% when formulations were used and only 4% for free nystatin. Further studies will include in vivo testing using animal models. PMID- 30024383 TI - Evaluation of a Physiologically Based Pharmacokinetic (PBPK) Model for Inorganic Arsenic Exposure Using Data from Two Diverse Human Populations. AB - BACKGROUND: Multiple epidemiological studies exist for some of the well-studied health endpoints associated with inorganic arsenic (iAs) exposure; however, results are usually expressed in terms of different exposure/dose metrics. Physiologically based pharmacokinetic (PBPK) models may be used to obtain a common exposure metric for application in dose-response meta-analysis. OBJECTIVE: A previously published PBPK model for inorganic arsenic (iAs) was evaluated using data sets for arsenic-exposed populations from Bangladesh and the United States. METHODS: The first data set was provided by the Health Effects of Arsenic Longitudinal Study cohort in Bangladesh. The second data set was provided by a study conducted in Churchill County, Nevada, USA. The PBPK model consisted of submodels describing the absorption, distribution, metabolism and excretion (ADME) of iAs and its metabolites monomethylarsenic (MMA) and dimethylarsenic (DMA) acids. The model was used to estimate total arsenic levels in urine in response to oral ingestion of iAs. To compare predictions of the PBPK model against observations, urinary arsenic concentration and creatinine-adjusted urinary arsenic concentration were simulated. As part of the evaluation, both water and dietary intakes of arsenic were estimated and used to generate the associated urine concentrations of the chemical in exposed populations. RESULTS: When arsenic intake from water alone was considered, the results of the PBPK model underpredicted urinary arsenic concentrations for individuals with low levels of arsenic in drinking water and slightly overpredicted urinary arsenic concentrations in individuals with higher levels of arsenic in drinking water. When population-specific estimates of dietary intakes of iAs were included in exposures, the predictive value of the PBPK model was markedly improved, particularly at lower levels of arsenic intake. CONCLUSIONS: Evaluations of this PBPK model illustrate its adequacy and usefulness for oral exposure reconstructions in human health risk assessment, particularly in individuals who are exposed to relatively low levels of arsenic in water or food. https://doi.org/10.1289/EHP3096. PMID- 30024386 TI - Design and demonstration of a seabird-inspired fixed-wing hybrid UAV-UUV system. AB - This paper looks to the natural world for solutions to many of the challenges associated with the design of fixed-wing cross-domain vehicles. One example is the common murre, a seabird that flies from nesting locations to feeding areas, dives underwater to catch prey and returns. This hunting expedition provides an outline of a possible mission for a cross-domain vehicle. While the challenges of cross-domain vehicles are many, the focus of this paper was on buoyancy management and propulsion. Potential solutions to each challenge, inspired by multiple animals that cross between aerial and underwater domains, are investigated. From these solutions, three design concepts are considered, a quadrotor/fixed-wing hybrid, a vertical takeoff and landing (VTOL) tailsitter aircraft, and a waterjet-assisted takeoff vehicle. A comparison was made between the capability of each concept to complete two missions based on the common murres' hunting expedition. As a result of this comparison, the VTOL tailsitter design was selected for further study. In-depth design was conducted and a prototype vehicle was built. The completed vehicle prototype successfully conducted submerged operation as well as four air flights. Flights consisted of egress from water, flight in air, ingress into water in each flight, and water locomotion. A total of 11 min, 23 s of flight time was recorded as well as underwater swims down to 12 ft (3.7 m) below the surface. PMID- 30024387 TI - Ferroelectric monoclinic phases in strained K0.70Na0.30NbO3 thin films promoting selective surface acoustic wave propagation. AB - We present a detailed analysis of the ferroelectric domain structure of K0.70Na0.30NbO3 thin films on (110) TbScO3 grown by metal-organic chemical vapor deposition. Upon piezoresponse force microscopy and nanofocus x-ray diffraction measurements we derive a domain model revealing monoclinic MC domains. The complex domain pattern is formed out of four co-existing in-plane orientations of the shearing direction of the monoclinic unit cell resulting in four types of superdomains each being composed of well-ordered stripe domains. Finally, we present surface acoustic wave (SAW) experiments that exhibit extraordinary signal intensities given the low thickness of the tested film. Moreover, the SAW propagation is found to occur selectively along the identified shearing directions. PMID- 30024384 TI - Weight of Evidence for Hazard Identification: A Critical Review of the Literature. AB - BACKGROUND: Transparency when documenting and assessing weight of evidence (WOE) has been an area of increasing focus for national and international health agencies. OBJECTIVE: The objective of this work was to conduct a critical review of WOE analysis methods as a basis for developing a practical framework for considering and assessing WOE in hazard identification in areas of application at the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). METHODS: Based on a review of the literature and directed requests to 63 international and national agencies, 116 relevant articles and guidance documents were selected. The WOE approaches were assessed based on three aspects: the extent of their prescriptive nature, their purpose-specific relevance, and their ease of implementation. RESULTS: Twenty-four approaches meeting the specified criteria were identified from selected reviewed documents. Most approaches satisfied one or two of the assessed considerations, but not all three. The approaches were grouped within a practical framework comprising the following four stages: (1) planning the assessment, including scoping, formulating the question, and developing the assessment method; (2) establishing lines of evidence (LOEs), including identifying and selecting studies, assessing their quality, and integrating with studies of similar type; (3) integrating the LOEs to evaluate WOE; and (4) presenting conclusions. DISCUSSION: Based on the review, considerations for selecting methods for a wide range of applications are proposed. Priority areas for further development are identified. https://doi.org/10.1289/EHP3067. PMID- 30024388 TI - Soft-molecular imprinted electrospun scaffolds to mimic specific biological tissues. AB - The fabrication of bioactive scaffolds able to mimic the in vivo cellular microenvironment is a challenge for regenerative medicine. The creation of sites for the selective binding of specific endogenous proteins represents an attractive strategy to fabricate scaffolds able to elicit specific cell response. Here, electrospinning (ESP) and soft-molecular imprinting (soft-MI) techniques were combined to fabricate a soft-molecular imprinted electrospun bioactive scaffold (SMIES) for tissue regeneration. Scaffolds functionalized using different proteins and growth factors (GFs) arranged onto the surface were designed, fabricated and validated with different polyesters, demonstrating the versatility of the developed approach. The scaffolds bound selectively each of the different proteins used, indicating that the soft-MI method allowed fabricating high affinity binding sites on ESP fibers compared to non-imprinted ones. The imprinting of ESP fibers with several GFs resulted in a significant effect on cell behavior. FGF-2 imprinted SMIES promoted cell proliferation and metabolic activity. BMP-2 and TGF-beta3 imprinted SMIES promoted cellular differentiation. These scaffolds hold the potential to be used in a cell-free approach to steer endogenous tissue regeneration in several regenerative medicine applications. PMID- 30024389 TI - Percutaneous coronary intervention for bifurcation: Jailed semi-inflated balloon technique. PMID- 30024390 TI - Assessment of side branch patency using a jailed semi-inflated balloon technique with coronary bifurcation lesions. AB - OBJECTIVE: Many interventional cardiologists are concerned about the risk of side branch (SB) loss during main vessel (MV) stenting in complex bifurcation lesions. Therefore, novel techniques are required to reduce the risk of SB occlusion. The jailed semi-inflated balloon technique (JSBT) is one of these techniques. This article is a description of clinical experience with SB patency assessment using the JSBT. METHODS: A total of 64 patients with 82 distinct coronary bifurcation lesions underwent percutaneous coronary intervention (PCI) via JSBT at this institution. In the majority of patients, the SB balloon was inflated with a greater pressure (4.8+/-2.0 atm) than in the standard JSBT. Procedural and immediate clinical outcomes were reviewed via baseline and post-procedural quantitative coronary angiography analysis. RESULTS: The majority of the patients had acute coronary syndrome (60.9%) and almost one-third of the patients were Medina class 1.1.1. (32.8%). A jailed-balloon or wire was not entrapped during any PCI. SB ostial dissection was seen in only 2 patients. The minimal lumen diameter was improved in the MV and SB following PCI. There were no adverse cardiac events during in-hospital stay or at 1-month follow-up. CONCLUSION: JSBT provides maximum SB protection with bifurcation lesions and requires less time than a complex technique. There was no significant SB occlusion risk even though the SB balloon was inflated with a slightly higher pressure. The immediate clinical outcomes and procedural success of this study may encourage interventional cardiologists to use this technique safely with reliable preservation of SB patency. PMID- 30024391 TI - Association between high on-treatment platelet reactivity to clopidogrel and hepatosteatosis in patients undergoing elective stent implantation. AB - OBJECTIVE: The present study is an investigation of the association between high on-treatment platelet reactivity to clopidogrel (HTPRC) and hepatosteatosis in patients who had elective stent implantation due to coronary artery disease. METHODS: A total of 190 consecutive patients who underwent an elective coronary stent implantation due to coronary artery disease were prospectively enrolled in the study. Eligible patients were given a 300 mg loading dose of clopidogrel before percutaneous coronary intervention. All of the patients underwent an ultrasound assessment for fatty liver. The patients were divided into 2 groups according to the detection of HTPRC: patients with HTPRC and patients without HTPRC. RESULTS: HTPRC was present in 54.2% (103 of 190 patients) of the total study population. The age and body mass index data were similar between the 2 groups. In all, 111 (58.6%) patients had hepatosteatosis. The HTPRC ratio was statistically higher in female patients (p=0.032). Hepatosteatosis was significantly greater in patients with HTPRC (p<0.001); 84 (81.6%) patients with HTPRC had hepatosteatosis (p=0.001). There was also a statistically significant association between the hepatosteatosis grade and HTPRC (p<0.001). The percentage of HTPRC was greater in patients with >=grade 2 hepatosteatosis than grade 1 (p<0.001). Logistic regression analysis indicated that hepatosteatosis (odds ratio: 9.403, 95% confidence interval: 4.519-19.566; p<0.001), fasting blood glucose, and hypertension were independent predictors of HTPRC. CONCLUSION: To the best of our knowledge, this is the first study to demonstrate a relationship between hepatosteatosis and HTPRC. PMID- 30024392 TI - Assessment of subclinical atherosclerosis in psoriatic arthritis patients without clinically overt cardiovascular disease or traditional atherosclerosis risk factors. AB - OBJECTIVE: Cardiovascular disease (CVD) is more prevalent in almost all patients with chronic inflammatory musculoskeletal diseases than in their healthy counterparts. The aim of this study was to assess the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) in comparison with patients with rheumatoid arthritis (RA) and healthy controls. METHODS: A total of 30 patients with PsA, 30 patients with RA, and 30 healthy controls were enrolled in this parallel group study. Demographic, clinical, and laboratory data of the groups were recorded. The Disease Activity Score-28 tool was used for joint assessment. The erythrocyte sedimentation rate and C-reactive protein level were measured as acute phase reactants. Flow-mediated dilatation (FMD) and carotid intima media thickness (CIMT) were also measured in all participants. RESULTS: The median duration of disease in patients with PsA was 60 months (range: 8-216 months). A total of 22 of 30 (73.3%) PsA patients had a diagnosis of psoriasis and 13 (48.1%) had active disease. The study groups were similar with regard to age, gender, and body mass index data. In all, 23 (76.7%) of the PsA patients and 5 (16.7%) of the RA patients were using an anti-tumor necrosis factor alpha therapy (p<0.001). The FMD percentage was significantly smaller in both the PsA and the RA patients than in the healthy controls (p<0.001). The median CIMT was greater in the RA patients compared with the PsA patients and the healthy controls (p=0.008). There was no significant difference in FMD or CIMT between patients with and without an active joint lesion. CONCLUSION: Endothelial functions were impaired in PsA, as in RA, in the absence of conventional risk factors or overt CVD. This finding may show a potential association between PsA, atherosclerosis, and CVD. PMID- 30024393 TI - Impaired oscillometric arterial stiffness parameters in patients with coronary artery ectasia. AB - OBJECTIVE: The aim of this study was to investigate the oscillometric measurements of the elastic properties of the aorta in patients with isolated coronary artery ectasia (CAE). METHODS: This study included 137 patients (92 men and 45 women; mean age: 60.8+/-11.7 years) who underwent coronary angiography to investigate ischemic heart disease. The patients were divided into 3 groups; the first group consisted of 51 patients with CAE, the second group comprised 36 patients with coronary artery disease (CAD), and the third group was made up of 50 patients with normal coronary arteries. Aortic stiffness (AS) measurements, including pulse wave velocity (PWV) and augmentation index (AIx), were measured using the oscillometric method. RESULTS: The mean PWV was significantly higher in the CAE group compared with the CAD and control groups (9.1+/-2.3 vs. 8.2+/-1.3 and 8.0+/-1.6; p=0.008), whereas the median AIx was significantly lower in the CAE group compared with the CAD and control groups (10.0% [-3.0-63.0] vs. 15.5% [ 2.0-57.0] and 21.5% [-1.0-45.0]; p=0.010). Multinomial logistic regression analysis demonstrated that gender, hypertension, highdensity lipoprotein cholesterol level, PWV, and AIx were independently associated with CAE. CONCLUSION: The oscillometric elastic properties of the aorta, including PWV and AIx, are impaired in patients with CAE. PMID- 30024394 TI - Tools to improve the diagnostic accuracy of exercise electrocardiograms in patients with atypical angina pectoris. AB - OBJECTIVE: Although frequently utilized, an exercise electrocardiogram (ECG) provides limited diagnostic accuracy in patients with atypical angina pectoris. The purpose of this study was to determine the possible incremental value of pretest probability (PTP) scores and exercise parameters in discriminating coronary artery disease (CAD) and to identify PTP cutoff values. METHODS: In a retrospective cohort of 207 patients with atypical angina (76 women, 131 men; mean age: 57.6+/-8.2 years) who underwent coronary angiography (CAG) after a positive exercise ECG, the PTP was calculated according to the CAD Consortium basic and clinical models along with exercise parameters of blood pressure (BP), heart rate (HR), exercise duration, maximal metabolic equivalents (METs), HR reserve, HR recovery, chronotropic index, BP reserve, BP recovery, and ST/HR ratio. Patients were categorized into true positive (TP) or false positive (FP) groups, depending on the ultimate determination of a presence of obstructive CAD. RESULTS: A TP result was associated with older age, male gender, hypertension, diabetes, hyperlipidemia, and higher basic and clinical PTP, as well as higher maximal BP, maximal ST deviation and ST/HR, but lower maximal METs, chronotropic index, and HR recovery. The basic and clinical PTP, and the chronotropic index could predict a TP test result irrespective of gender. Logistic regression analysis revealed that clinical PTP was the only independent predictor of TP results. A cutoff score of 18 for the basic and 21 for the clinical PTP were determined to discriminate CAD. CONCLUSION: This study has shown that, among various electrocardiographic and hemodynamic parameters, the clinical PTP and the chronotropic index are the most helpful tools to discriminate patients with CAD among patients with atypical angina. PMID- 30024395 TI - Early and mid-term outcomes after surgical repair of congenital supravalvular aortic stenosis with the Doty technique. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of the Doty surgical approach in pediatric patients with congenital supravalvular aortic stenosis (SVAS) by examining early and mid-term outcomes. METHODS: Surgical repair using the Doty technique was performed in a total of 10 pediatric patients with SVAS between January 2005 and July 2015 at this clinic. These patients were evaluated retrospectively. Demographic characteristics, echocardiographic findings, and clinical outcomes were analyzed. RESULTS: The mean patient age was 4.8+/-3.9 years. Williams-Beuren syndrome was diagnosed in 4 of the patients. Early mortality was observed in 1 patient with diffuse SVAS. At the final follow up (mean follow-up: 3.7+/-1.2 years; range: 6-61 months), echocardiograms revealed a mean pressure gradient of 14+/-4.2 mmHg. Two patients displayed minimal aortic insufficiency during the follow-up period. No reoperation or reintervention was required. CONCLUSION: The Doty technique is an anatomically and technically effective surgical approach to treating SVAS. PMID- 30024396 TI - Multivessel coronary-cameral fistulas associated with ventricular fibrillation: an unusual case. AB - Coronary-cameral fistula (CCF) is a rare connection between a coronary artery and a chamber of the heart. It most often derives from the right coronary artery and drains into the right ventricle. CCF originating from all 3 major coronary vessels and draining into the left heart is an extremely rare coronary artery malformation. A 47-yearold-man who was admitted to the clinic with angina pectoris and positive cardiac markers suddenly developed ventricular fibrillation (VF) while being prepared for coronary catheterization. He was successfully defibrillated and sinus rhythm was restored. The coronary angiography revealed normal epicardial coronary arteries with multiple diffuse fistulas originating from both the right and left coronary artery systems, terminating in the left ventricle. This is a very rare case of multiple CCFs originating from the epicardial coronary arteries and associated with myocardial ischemia and VF. PMID- 30024398 TI - Acute myocardial infarction associated with clomiphene citrate in a young woman. AB - Clomiphene citrate is a drug that stimulates ovulation and is commonly used in cases of female infertility. Generally, it is recognized as a safe agent for ovulation induction, but rarely, it is associated with life-threatening conditions. A 36-year-old woman who had been prescribed clomiphene citrate for infertility was admitted to the emergency department for chest pain lasting for 2 hours. She had no history of smoking, and she did not have any cardiac risk factor for myocardial infarction (MI). An electrocardiogram performed on admission revealed ST-elevation in the precordial leads. She was taken to the catheter laboratory for ST-elevation myocardial infarction, and the coronary angiography revealed total occlusion of the midportion of the left anterior descending artery (LAD) with a heavy thrombus burden. The circumflex and right coronary arteries were normal. After balloon dilatation, a 2.75x15-mm drug eluting stent was implanted in the mid part of the LAD. The patient had an uncomplicated recovery. Before discharge, echocardiography revealed apical akinesis; anterior and lateral hypokinesis; and an ejection fraction of 45% with mild mitral regurgitation. Although clomiphene citrate is a relatively safe drug for ovarian stimulation, it has been associated with serious side effects, such as MI. Physicians should be aware of the potential risks of clomiphene citrate, especially in patients with risk factors for coronary artery disease. PMID- 30024397 TI - Transient ST-segment elevation due to coronary slow flow during cryoballoon application. AB - This report is a description of a rare case of transient ST-segment elevation during cryoballoon application for paroxysmal atrial fibrillation (PAF). A 74 year-old male with symptomatic PAF was referred to the center for ablation. During cryoablation of the left superior pulmonary vein (188 seconds, -48 degrees C), ST-segment elevation in the anterolateral leads was observed suddenly, though without any significant complaint. Upon the increase in the ST segment, the cryoapplication was immediately terminated. Coronary artery angiography was performed less than 5 minutes after balloon deflation and demonstrated coronary slow flow with a corrected Thrombolysis In Myocardial Infarction (TIMI) frame count of 48.4 (normal range: 21+/-3) in the left anterior descending artery (LAD). There was no significant flow-limiting lesion, coronary vasospasm, thromboembolus, or air embolus in any coronary vessel. The TIMI frame count for the right coronary artery and the circumflex artery was normal. The ST-segment elevation gradually returned to the baseline in 14 minutes without any intervention. A control TIMI frame count of the LAD was 22. A decision was made not to repeat the cryoapplication in this vein because there was both an entrance and an exit block. The other 3 pulmonary veins were then isolated uneventfully. The patient was discharged from the hospital the next day without symptoms or unusual electrocardiogram activity. PMID- 30024399 TI - Successful cryoablation of incessant fast-slow atypical atrioventricular nodal reentrant tachycardia in a child with tachycardia-induced cardiomyopathy. AB - A 15-year-old female patient presented at the clinic with heart failure (HF). A 12-lead electrocardiogram showed a heart rate of 170 bpm; negative P waves in leads DII, DIII, aVF; and long RP tachycardia (LRPT). Echocardiography demonstrated a shortening fraction (SF) of 20%. An electrophysiology study during tachycardia revealed an atrial-His time of 52 milliseconds and a His-atrial interval of 295 milliseconds. During ventricular entrainment, the postpacing interval-tachycardia cycle length was measured at 225 milliseconds. There was a pseudo V-A-A-V response. These findings confirmed the diagnosis of atypical atrioventricular nodal re-entrant tachycardia (aAVNRT). Successful slow pathway cryoablation was performed with an 8-mm-tip cryocatheter. After 2 weeks, the SF was measured as 34%. During a 2-year follow-up period, no recurrence was observed. In conclusion, fast-slow aAVNRT should be a part of the differential diagnosis of incessant LRPT leading to HF. Cryoablation can be used successfully in cases of aAVNRT. PMID- 30024400 TI - Pulmonary embolism due to synthetic cannabinoid use: Case report. AB - A 29-year-old male patient was treated and followed up for a pulmonary embolism. The patient had no relevant medical history, other than the fact that he had smoked bonzai, a synthetic cannabinoid derivative, for 2 years. Hypercoagulability tests were normal. The use of synthetic cannabinoids is increasing in the young population and should be kept in mind among the causes of pulmonary embolism. PMID- 30024401 TI - A review of significant research on epileptic seizure detection and prediction using heart rate variability. AB - Epilepsy is a brain disorder that many people struggle with all over the world. Despite extensive research, epilepsy is still an important challenge without a clear solution. There may be confusion about providing a specific approach due to the variety of epileptic seizures and the effectiveness in different environmental conditions. Some patients with epilepsy undergo treatment through medication or surgery. Epileptic patients suffer from unpredictable conditions that may occur at any moment. Given the origins of these seizures, researchers have focused on predicting epileptic seizures via electroencephalogram (EEG). The results indicate some success in this regard. This success led to a focus on optimizing these methods and the evaluation of epilepsy seizure prediction through other vital signals. Both sympathetic and parasympathetic inhibitory effects are undeniable during epileptic seizures. This conflict is visible in the change in heart rate. In recent years several investigations have focused on a behavioral study of heart rate changes before the seizures. The results have led to the development of algorithms for classifying and predicting epileptic seizures using the electrocardiogram (ECG) and the more distinct heart rate variability (HRV). This article presents an overview of seizure detection and prediction methods and discusses their potential to improve the quality of life of epileptic patients. PMID- 30024402 TI - [Case Image: Successful endovascular graft stent to edge dissection and aneurysm on the descending aorta after a previous left subclavian-to-descending aortic bypass for coarctation of the aorta]. PMID- 30024403 TI - Case Image: A rare coronary anomaly: Left anterior descending artery emerging as a distal branch of the right coronary artery. PMID- 30024404 TI - Case Image: Connection between the left ventricular outflow tract and the main pulmonary artery in a patient with a history of tetralogy of Fallot total correction and aortic valve replacement. PMID- 30024405 TI - Case Image: Prolonged ventricular fibrillation in a patient with left ventricular assist device. PMID- 30024406 TI - [Assessment of cardiac autonomic functions by heart rate variability in patients with restless leg syndrome]. PMID- 30024407 TI - [Authors reply]. PMID- 30024408 TI - Healthy lifestyle behaviors after coronary bypass surgery: What about cardiac rehabilitation? PMID- 30024409 TI - Authors reply. PMID- 30024410 TI - Vitamin D level and endothelial dysfunction. PMID- 30024411 TI - Improved Gray Matter Atrophy Detection in Alzheimer Disease in Chinese Populations Using Chinese Brain Template. AB - OBJECTIVE: This study aimed to test the hypothesis that the statistical Chinese brain template would be more effective to detect gray matter (GM) changes in patients with Alzheimer disease (AD) in Chinese populations. MATERIALS AND METHODS: In total, 50 patients with AD and 50 sex-matched and age-matched healthy controls were included in this study. Chinese2020, a typical statistical Chinese brain template, and MNI152, a typical Caucasian template were used for spatial normalization respectively. The GM volume alterations in patients with AD were examined by using voxel-based morphometry with education level and total intracranial volume as nuisance variables. The GM proportions of the identified brain areas with group difference were compared. RESULTS: By using Chinese2020 and MNI152, significant GM atrophies in patients with AD were commonly detected in the bilateral medial temporal lobe, lateral temporal lobe, inferior/medial frontal cortex, as well as left thalamus. However, higher GM percentages of detected regions were acquired when Chinese2020 was used rather than MNI152. Furthermore, stronger statistical powers in the detected clusters were observed using Chinese2020 than MNI152. In addition, the laterality index analysis showed the bilateral atrophies with no hemispheric laterality in the para/hippocampus when using population-specific brain atlas (ie, Chinese2020). CONCLUSIONS: These findings indicated that applying the population-specific brain atlas to neuroimaging studies may achieve higher accuracy in activation detection. This may have implications to the imaging study of neurodegenerative diseases. PMID- 30024412 TI - Indeterminate Cell Histiocytosis and Mycosis Fungoides. A Hitherto Unreported Association. PMID- 30024413 TI - Campbell de Morgan Spots (Cherry Angiomas) Show Endothelial Proliferation. AB - Campbell de Morgan spots (also known as adult hemangiomas, cherry angiomas, or senile angiomas) show clinical and histopathological features that make them distinct. Despite this, they are not included as benign vascular tumors in the current classification by the International Society for Vascular Anomalies (ISSVA). In the current study, we investigated the proliferation rate (Ki67) of the endothelia of 23 cases of Campbell de Morgan spots, as well as the immunoexpression of Wilms tumor protein 1 (WT1) by these vascular anomalies. The youngest patient was 24 years old (range: 24-80; mean: 52.61). Ten patients were women (43.48%). All cases showed intense cytoplasmic expression of WT1 by the endothelia in 80%-100% of the endothelial cells. Ki67 demonstrated proliferation by the endothelia of all vascular lesions. A mean of 1077.6 nuclei were evaluated per case. Eight cases showed a very low proliferation (less than 0.5% of the nuclei). In the other 15 cases, the proliferation ranged from 0.59% to 3.59% (mean: 1.89%). PMID- 30024414 TI - Uncommon Histopathological Variants of Malignant Melanoma: Part 1. AB - Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinicopathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma. PMID- 30024415 TI - Facilitating cells: role in inducing transplantation tolerance. AB - PURPOSE OF REVIEW: This review discusses the role and mechanisms by which facilitating cells promote stem cell engraftment and induce tolerance in HLA disparate kidney transplant recipients. RECENT FINDING: Facilitating cells in both mice and human are heterogeneous, consisting of several subpopulations. They have been shown to enhance stem cell engraftment in allogeneic recipients. They also increase hematopoietic stem cells (HSC) clonogenicity, enhance migration and homing of stem cells via secretion of cytokines/chemokines/growth factors, prevent apoptosis of stem cells and induce regulatory cells. This review summarizes the findings that led to the development of chimerism-based induction of tolerance using FCRx (a mobilized blood product enriched in stem cells and facilitating cells) in allogenic kidney transplant patients. SUMMARY: A phase-2 clinical trial based on FCRx therapy has been successful in inducing tolerance to living donor kidney allografts, leading to withdrawal of immunosuppression in over 70% of patients transplanted. The ultimate goal of establishing tolerance in the absence of immunosuppresive drugs can be achieved using FCRx therapy. PMID- 30024417 TI - Optimizing regulatory T cells for therapeutic application in human organ transplantation. AB - PURPOSE OF REVIEW: Initial clinical trials of adoptive regulatory T-cell (Treg) therapy in solid organ transplantation have proven to be both feasible and well tolerated. With Phase 2 trials underway, efforts have been focused on the optimization of the Treg product. RECENT FINDINGS: With science and our knowledge on the biology of these cells constantly advancing, we have been able to refine our search for a Treg population that would be ideally suited for therapeutic application. This idealized population must be readily isolated, allow for in vitro expansion, demonstrate potent and specific suppressor function, maintain lineage stability and demonstrate a relevant homing profile. With the advent of innovative cell analysis/isolation techniques and genetic modifications, we are able to choose and design Tregs to fulfil these criteria. SUMMARY: By utilizing advances in science and technology, we can optimize Treg therapy in human organ transplantation maximizing their prospects in the arena of transplantation tolerance. PMID- 30024418 TI - Functional considerations in oral cavity reconstruction. AB - PURPOSE OF REVIEW: The treatment of oral cavity cancer may impair speech and swallowing function. Optimizing posttreatment function may lead to significant improvement of quality of life. RECENT FINDINGS: Although oncologic control remains the main goal of treatment for oral cavity cancer, posttreatment function for surviving patients has over the last decades been recognized as an important secondary outcome. Reconstruction of oral cavity defects range from primary closure to advanced microvascular reconstruction, including multiple tissue types. Free flap reconstruction has greatly enhanced the ability to tailor transferred tissue to specific defects. In this review, we describe recent findings in reconstruction of tongue defects, including data from perforator flaps. We also summarize recent evidence regarding reinnervated flaps. SUMMARY: When vascularized tissue is needed, it remains unclear how the reconstructive choice impacts postoperative outcome, although in many situations it appears to be dominated by the donor site morbidity rather than the reconstructive technique. Despite numerous case series, the functional impact of motor and sensory reinnervation in vascularized tissue remains unknown. Although perforator flaps have emerged as a promising flap option, with favorable donor site morbidity, their ultimate impact on functional outcomes remains unclear, whereas the success rate appears to be lower than traditional flaps. PMID- 30024419 TI - Pearls for the middle fossa approach in acoustic neuroma surgery. AB - PURPOSE OF REVIEW: To discuss the use of the middle fossa craniotomy for resection of vestibular schwannomas; to present pearls of and modifications to the approach. RECENT FINDINGS: The middle fossa craniotomy allows for hearing preservation in the resection of intracanalicular vestibular schwannomas. Over recent years, the approach has been modified to address larger tumors with a limited cerebellopontine angle component. Positive identification of the superior semicircular canal allows for rapid exposure of the internal auditory canal (IAC). Removal of cerebrospinal fluid from the posterior fossa during exposure of the IAC allows for removal of the middle fossa retractor; reinforced silicone sheeting is used to protect the middle fossa dura during further drilling. The use of the endoscope has allowed for more complete dissection at the fundus of the IAC, including tumors lateral to the transverse crest. SUMMARY: Technical modifications to the middle fossa craniotomy have allowed for a shorter duration of temporal lobe retraction intraoperatively and more complete resection of tumors with fundal involvement. PMID- 30024416 TI - Apoptotic cell-based therapies for promoting transplantation tolerance. AB - PURPOSE OF REVIEW: This article is aimed to provide readers with an updated review on the applicability, efficacy, and challenges of employing donor apoptotic cell-based therapies to promote transplantation tolerance in various experimental and clinical settings. RECENT FINDINGS: Recently, donor apoptotic cell-based therapies have been employed in various models of cell (including pancreatic islets and bone marrow hematopoietic stem cells) and solid organ (heart and kidney) transplantation to promote donor-specific tolerance. Published data, thus far, have revealed a high potential of this approach in inducing robust transplantation tolerance. Recent clinical trials have also underscored the safety and potential efficacy of this approach in alleviating graft-versus host disease (GVHD) in bone marrow transplantation (BMT). Host factors including prior allo-sensitization and opportunistic infections pose major obstacles in establishing transplantation tolerance employing this strategy. However, emerging data provide strategies for overcoming such obstacles in these clinically relevant settings. SUMMARY: Donor apoptotic cell therapy is an emerging strategy in promoting transplantation tolerance, with recent data emphasizing its efficacy and applicability for transplantation tolerance in the clinic. PMID- 30024420 TI - Situational expectations mediate the effect of global beliefs on depressive symptoms: a 1-year prospective study using a student sample. AB - PURPOSE OF REVIEW: Recent research suggests that expectations might be a particularly important subgroup of cognitions in major depression. The present study aimed to further specify the role of situation-specific dysfunctional expectations (SDEs) in the development of depressive symptoms. It was hypothesized that the effects of intermediate beliefs and dispositional optimism on depressive symptoms would be mediated via SDEs. RECENT FINDINGS: We examined 125 students (age M = 22.05, SD = 4.00, 74.6% women) using a longitudinal design with a 1-year follow-up. Questionnaires used in the study included the Depressive Expectations Scale, Dysfunctional Attitudes Scale, Life Orientation Test and Beck's Depression Inventory. When considering SDEs at baseline as mediator variable, neither intermediate beliefs nor dispositional optimism had significant direct effects on depressive symptoms. Instead, their effects were fully mediated via SDEs. When considering SDEs at the follow-up as the mediator variable, SDEs partly mediated the effects of intermediate beliefs and dispositional optimism on depressive symptoms. SUMMARY: The study provides further evidence for a cognitive mediational model, suggesting that SDEs mediate the effects of rather global beliefs (such as intermediate beliefs and dispositional optimism) on depressive symptoms. Due to their high level of situational specificity, SDEs might be an effective target for cognitive-behavioural interventions. PMID- 30024421 TI - Management of Upper Extremities in Tetraplegia: Current Concepts. AB - Individuals with tetraplegia face many obstacles with activities of daily living. Although approximately 65% to 75% of individuals with tetraplegia would benefit from upper extremity surgery that could make many of their activities of daily living more spontaneous, only 14% of patients who are surgical candidates undergo tendon transfer procedures. A good surgical candidate has an injury at one of the cervical spine levels and an International Classification for Surgery of the Hand in Tetraplegia group of 1 or better, has functional goals, and is committed to the postoperative rehabilitation process. Surgery primarily consists of tendon transfers, tenodesis, and arthrodesis to restore elbow extension and hand pinch, grasp, and release. Nerve transfers and functional electrical stimulation are also options for treatment. PMID- 30024422 TI - Electrophysiological Monitoring During Percutaneous Trigeminal Nerve Ganglion Block. PMID- 30024423 TI - Cardiovascular aging: the unveiled enigma from bench to bedside. AB - : The rapid increase in the median age of the world's population requires particular attention towards older and more fragile people. Cardiovascular risk factors, time and comorbidities play a vicious role in the development of heart failure, both with reduced and preserved ejection fraction, in the elderly. Understanding the mechanisms underlying the pathophysiological processes observed with aging is pivotal to target those patients and their therapeutic needs properly. This review aims to investigate and to dissect the main pathways leading to the aging cardiomyopathy, helping to understand the relationship from bench to bedside of the clinical phenotype. PMID- 30024424 TI - Comparison of 22C3 PharmDx and SP263 Assays to Test PD-L1 Expression in NSCLC. AB - Immunohistochemical assays for programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) are either required or recommended to guide therapy with immune checkpoint inhibitors. Four commercially available immunohistochemical assays are currently available as either complimentary or companion diagnostic assay for their counterpart therapy. Harmonization or exchangeability of one assay for the other is a highly sought for goal. The aim of this study was to compare one assay, 22C3, with another, SP263, and examine whether they can be exchanged one for the other. Seventy samples from 70 patients with NSCLC were tested for PD-L1 using the SP263 and then the 22C3 antibody clones according to the manufacturer's instructions in case of the SP263 assay and according to a previously described and reported method for the 22C3 assay on the Ventana's ultra immunstainer. Results were evaluable in 51 cases, which were interpreted independently by 2 different pathologists on 2 different occasions for each case. The cases were given a percentage score based on the tumor proportion score. The Pearson correlation coefficient was calculated. A high concordance rate was found between the 2 assays. The Pearson correlation coefficient was 0.95, which indicates an almost perfect correlation (95% confidence limits, 0.92-0.97 and P<0.0001). The findings indicate that SP263 assay can be used in place of the 22C3 assay for PD-L1 assay in NSCLC, and it can be used on the Ventana platform. PMID- 30024425 TI - NordiQC Assessments of MSH6 Immunoassays. AB - This paper is number 4 in a series developed through a partnership between ISIMM and Nordic immunohistochemical Quality Control for the purpose of reporting research assessing the performance characteristics of immunoassays in an external proficiency testing program. PMID- 30024426 TI - Impact of obesity on heparin-induced thrombocytopenia in cardiac surgery patients. PMID- 30024427 TI - Interpreting and Implementing the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption Clinical Practice Guideline. PMID- 30024428 TI - New Morbidity and Discharge Disposition of Pediatric Acute Respiratory Distress Syndrome Survivors. AB - OBJECTIVES: Much of the research related to pediatric acute respiratory distress syndrome has focused on inhospital mortality and interventions affecting this outcome. Limited data exist on survivors' morbidity, hospital disposition, and 1 year survival. The aim of this study was to determine new morbidity rate, discharge disposition, and 1-year mortality for survivors of pediatric acute respiratory distress syndrome. DESIGN: Secondary analysis of prospective cohort study. SETTING: Quaternary children's hospital. PATIENTS: Three-hundred sixteen mechanically ventilated children with pediatric acute respiratory distress syndrome (Berlin and Pediatric Acute Lung Injury Consensus Conference criteria) between July 2011 and December 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed secondary analysis of a prospectively recruited cohort of 316 mechanically ventilated children with pediatric acute respiratory distress syndrome between July 2011, and December 2014. Preillness and hospital discharge Functional Status Scale score were determined via chart review, and factors associated with new morbidity, defined as an increase of Functional Status Scale score of 3 or more, were analyzed. Demographic variables, pediatric acute respiratory distress syndrome characteristics, and ventilator management were tested for association with development of new morbidity, discharge disposition, and 1-year mortality. Inhospital mortality of pediatric acute respiratory distress syndrome was 13.3% (42/316). Of 274 survivors to hospital discharge, new morbidity was seen in 63 patients (23%). Discharge to rehabilitation rate was 24.5% (67/274) and associated with development of new morbidity. One- and 3-year mortality of survivors was 5.5% (15 deaths) and 8% (22 deaths) and was associated with baseline Functional Status Scale, immunocompromised status, Pediatric Risk of Mortality III, and organ failures at pediatric acute respiratory distress syndrome onset, but not with pediatric acute respiratory distress syndrome severity. CONCLUSIONS: New morbidity was common after pediatric acute respiratory distress syndrome and appears to be intermediate phenotype between survival without morbidity and death, making it a useful metric in future interventional and outcome studies in pediatric acute respiratory distress syndrome. PMID- 30024429 TI - Handovers Among Staff Intensivists: A Study of Information Loss and Clinical Accuracy to Anticipate Events. AB - OBJECTIVES: Handovers are associated with medical errors, and our primary objective is to identify missed diagnosis and goals immediately after a shift handover. Our secondary objective is to assess clinicians' diagnostic accuracy in anticipating clinical events during the night shift. DESIGN: Single-center prospective observational cohort study. SETTING: Thirty-bed tertiary ICU in Sao Paulo, Brazil. PATIENTS: Three-hundred fifty-two patient encounters over 44 day to-night handovers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used a multimethods approach to measure transmission of information among staff physicians on diagnoses and goals for the night shift. We surveyed clinicians immediately after a handover and identified clinical events through chart abstractions and interviews with clinicians the next morning. Nighttime clinicians correctly identified 454 of 857 diagnoses (53%; 95% CI 50-56) and 123 of 304 goals (40%; 95% CI, 35-46). Daytime clinicians were more sensitive (65% vs 46%; p < 0.01) but less specific (82% vs 91%; p < 0.01) than nighttime clinicians in anticipating clinical events at night, resulting in similar accuracy (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.68-0.79] vs 0.68 [95% CI 0.63-0.74]; p = 0.09). The positive predictive value of both daytime and nighttime clinicians was low (13% vs 17%; p = 0.2). Gaps in diagnosis and anticipation of events were more pronounced in neurologic diagnoses. CONCLUSIONS: Among staff intensivists, diagnoses and goals of treatment are either not conveyed or retained 50-60% of the cases immediately after a handover. Clinicians have limited ability to anticipate events, and the expectation that anticipatory guidance can inform handovers needs to be balanced against information overload. Handovers among staff intensivists showed more gaps in the identification of diagnostic uncertainty and for neurologic diagnoses, which could benefit from communication strategies such as cognitive checklists, prioritizing discussion of neurologic patients, and brief combined clinical examination at handover. PMID- 30024430 TI - Assessing Variability in Hospital-Level Mortality Among U.S. Medicare Beneficiaries With Hospitalizations for Severe Sepsis and Septic Shock. AB - OBJECTIVES: To assess the variability in short-term sepsis mortality by hospital among Centers for Medicare and Medicaid Services beneficiaries in the United States during 2013-2014. DESIGN: A retrospective cohort design. SETTING: Hospitalizations from 3,068 acute care hospitals that participated in the Centers for Medicare and Medicaid Services inpatient prospective payment system in 2013 and 2014. PATIENTS: Medicare fee-for-service beneficiaries greater than or equal to 65 years old who had an inpatient hospitalization coded with present at admission severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Individual level mortality was assessed as death at or within 7 days of hospital discharge and aggregated to calculate hospital-level mortality rates. We used a logistic hierarchal linear model to calculate mortality risk adjusted for patient characteristics. We quantified variability among hospitals using the median odds ratio and calculated risk-standardized mortality rates for each hospital. The overall crude mortality rate was 34.7%. We found significant variability in mortality by hospital (p < 0.001). The middle 50% of hospitals had similar risk-standardized mortality rates (32.7-36.9%), whereas the decile of hospitals with the highest risk-standardized mortality rates had a median mortality rate of 40.7%, compared with a median of 29.2% for hospitals in the decile with the lowest risk-standardized mortality rates. The median odds ratio (1.29) was lower than the adjusted odds ratios for several measures of patient comorbidities and severity of illness, including present at admission organ dysfunction, no identified source of infection, and age. CONCLUSIONS: In a large study of present at admission sepsis among Medicare beneficiaries, we showed that mortality was most strongly associated with underlying comorbidities and measures of illness on arrival. However, after adjusting for patient characteristics, mortality also modestly depended on where a patient with sepsis received care, suggesting that efforts to improve sepsis outcomes in lower performing hospitals could impact sepsis survival. PMID- 30024431 TI - Emergency Department Documentation of Alleged Police Use of Excessive Force in Cases Where Formal Complaints Are Ultimately Filed. AB - BACKGROUND: Emergency physicians encounter patient concerns of police use of excessive force (UOEF). However, unlike other forms of potential assault, there are no guidelines for documentation of these encounters. Our objective was to examine the adequacy of emergency department documentation of injuries from police encounters where formal complaints of UOEF were later filed with the law enforcement agency. METHODS: A retrospective cohort design was used, identifying all citizen complaints of UOEF to a single police department in a 3-year period. Emergency department records associated with these encounters were then accessed and evaluated using standards for other forms of abuse and assault. RESULTS: Of 235 complaints, 33 (14.0%) presented to the emergency department within 7 days of the incident and were able to provide a history. For these subjects, 13 charts (39.4%) contained 3 or more of the 4 components thought to be necessary in cases of potential assault, and 11 (33.3%) contained documentation that should not be present: the guilt of the patient, subjective terminology by the provider, and/or documentation of law enforcement's description of the events as the only factual history. Of the total, 14 charts (42.4%) documented the patient's concern for UOEF. CONCLUSIONS: In this limited study, documentation of encounters where patients later filed a formal complaint of UOEF by law enforcement did not meet the standards for other forms of assault and abuse, having the potential to impact both the citizens and officers involved. Further study is necessary to identify the best practice guidelines for emergency physicians when they encounter patients injured in police encounters. PMID- 30024432 TI - Empty Delta Sign on Unenhanced Postmortem Computed Tomography Scan in Cerebral Venous Thrombosis. AB - Cerebral venous thrombosis is a rare condition which constitutes 0.5% to 2% of all types of stroke and carries a mortality of up to 20% to 50%. It leads to cerebral edema, infarction, hemorrhage and venous hypertension. Clinically the diagnosis is confirmed using enhanced computed tomography (CT) angiography which demonstrates an empty delta sign in cerebral veins, particularly in the superior sagittal sinus. However, postmortem CT (PMCT) findings on cerebral venous thrombosis have not been documented in the literature. We present a case report of a 69-year-old man who on unenhanced PMCT scan showed an empty delta sign in the cerebral veins. The empty delta sign was able to be demonstrated in unenhanced PMCT which can be explained by hyper attenuation of the dural veins at postmortem forming an internal contrast highlighting the thrombus. PMID- 30024433 TI - Diagnostic accuracy of the [-2]Pro-PSA and Prostate Health Index versus the Gleason score for determining the aggressiveness of prostate cancer: a systematic review protocol. AB - REVIEW QUESTIONS. PMID- 30024434 TI - Experience based co-design in acute healthcare services: a scoping review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objective of this scoping review is to examine, map and analyze qualitative and quantitative literature on experience-based co design (EBCD) within acute care health settings. Specifically, the review questions are. PMID- 30024435 TI - Experience of patients following lower limb joint replacement: a systematic review protocol. AB - REVIEW OBJECTIVE AND REVIEW QUESTION: The objective of this proposed review is to explore the postoperative experiences of adult patients who have undergone lower limb joint replacement. Specifically, the review question is: What are the postoperative experiences during the six-week post-discharge period of adult patients who have undergone lower limb joint replacement? PMID- 30024436 TI - The impact of nurse staffing on patient and nurse workforce outcomes in acute care settings in low and middle income countries: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to demonstrate the effect of nurse staffing on patient and nurse workforce outcomes in acute care settings in low and middle income countries. PMID- 30024437 TI - Morning Fatigue Severity Profiles in Oncology Outpatients Receiving Chemotherapy. AB - BACKGROUND: Morning fatigue is a distinct symptom experienced during chemotherapy that demonstrates significant interindividual variability. OBJECTIVES: The aims of this study were to identify subgroups with distinct morning fatigue profiles and evaluate how these subgroups differed by demographic, clinical, and symptom characteristics. METHODS: Outpatients (N = 1332) with breast, gastrointestinal, gynecological, or lung cancer completed questionnaires 6 times over 2 cycles of chemotherapy. Morning fatigue was assessed with the Lee Fatigue Scale. Latent profile analysis was used to identify distinct morning fatigue profiles. RESULTS: Four morning fatigue profiles (ie, very low, low, high, and very high) were identified. In the high and very high classes, all 6 morning fatigue scores were higher than the clinical cutoff score. Compared with those in the very low and low classes, patients in the very high class were younger and not married/partnered; lived alone; had higher incomes, higher comorbidity, and higher body mass index; and did not exercise regularly. Across the 4 classes, functional status and attentional function scores decreased and anxiety, depression, sleep disturbance, morning fatigue, and evening fatigue scores increased across the 2 cycles. CONCLUSION: Results provide insights into modifiable risk factors for morning fatigue. These risk factors can be used to develop more targeted interventions. IMPLICATIONS FOR PRACTICE: Patients in the high and very high morning fatigue classes experienced high symptom and comorbidity burdens and significant decrements in functional status. Using this information, clinicians can identify patients who are at an increased risk for higher levels of morning fatigue and prescribe interventions to improve this devastating symptom. PMID- 30024438 TI - Trajectories of Fasting Blood Glucose in Autologous Hematopoietic Cell Transplantation. AB - BACKGROUND: Patients who receive autologous hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies are at risk of serious adverse outcomes including infections and death. Hyperglycemia following the HCT is associated with increased risk of these adverse outcomes. However, limited information is available on demographic and clinical characteristics that contribute to changes in blood glucose levels following HCT. OBJECTIVE: The objective of this study was to determine the trajectories of fasting blood glucose (FBG) levels as well as the demographic and clinical characteristics that predicted interindividual differences in these FBG trajectories. METHODS: A sample of adult patients with hematologic malignancies who were scheduled to receive autologous HCT (n = 53) was enrolled in the study. Patients with preexisting diabetes were excluded. Demographic and clinical characteristics were abstracted from electronic medical records. Morning fasting laboratory tests (ie, FBG and absolute neutrophil counts) were obtained. Data were analyzed using hierarchical linear modeling from the day of HCT (day 0) through 14 days post HCT. RESULTS: Among 8 characteristics evaluated, pre-HCT FBG was associated with variability in both the initial levels and the trajectories of FBG. Body mass index was only associated with initial levels of FBG. CONCLUSIONS: The large amount of interindividual variability in the trajectories of FBG levels following autologous HCT suggests that glucose control in these patients warrants ongoing assessments and preemptive tailoring. IMPLICATIONS FOR PRACTICE: Fasting blood glucose monitoring is warranted. Additional research with larger samples is warranted to identify additional modifiable and nonmodifiable characteristics associated with interindividual variability in FBG levels. PMID- 30024439 TI - Meaning-Centered Interventions for Patients With Advanced or Terminal Cancer: A Meta-analysis. AB - BACKGROUND: For patients with advanced or terminal cancer undergoing hospice or palliative care, spiritual care based on meaning-centered intervention (MCI) has become an essential form of support. OBJECTIVE: The aim of this study was to characterize MCI systematically and the effectiveness of hospice and palliative care for patients with advanced or terminal cancer. METHODS: MEDLINE via PubMed, Cochrane Library CENTRAL, EMBASE, CINAHL, and several Korean electronic databases were searched from inception to May 2017. The RevMan 5.3 program of the Cochrane Library was used for data analysis. RESULTS: A meta-analysis was conducted of 10 controlled trials (6 randomized and 4 nonrandomized) featuring 623 patients with cancer. Meaning-centered interventions were compared with usual care control groups or other psychosocial interventions. The weighted average effect sizes across studies were -0.96 (P < .001, I = 7%) for meaning in life, -0.37 (P = .002, I = 0%) for spiritual well-being, -0.48 (P < .001, I = 0%) for quality of life, -0.28 (P = .02, I = 0%) for anxiety, and -0.31 (P = .02, I = 17%) for physical symptoms. CONCLUSION: Spiritual care based on MCI may help to improve the physical, psychosocial, and spiritual well-being of patients with advanced or terminal cancer. IMPLICATION FOR PRACTICE: Meaning-centered interventions could be a valuable way to enhance quality of life at the end stage for patients with advanced or terminal cancer. PMID- 30024440 TI - Trying to Feel Normal Again: Early Survivorship for Adolescent Cancer Survivors. AB - BACKGROUND: Despite knowing the potential medical consequences of cancer treatment, little is known about how adolescents cognitively and emotionally frame, process, and manage in the early survivorship period. OBJECTIVE: The specific aims were to describe the worries, perceived challenges, and ways of dealing with these issues for adolescent cancer survivors in the early period of survivorship. METHODS: Twenty-nine adolescent survivors (12-18 years) completed a semistructured interview. Inductive coding methods adapted from grounded theory were used to analyze the data. RESULTS: Seven domains and 18 categories organized the adolescent's experience with early posttreatment survivorship. The domains included getting back to school; relationships with parents, siblings, friends; feeling changed by the experience; and concerns about relapse. CONCLUSIONS: This study contributes to our understanding of survivors' relationships with parents, siblings, and friends and survivors' models of the illness. Future studies are needed to understand how parents can help adolescents assume greater responsibility for their care, to understand what it is like for friends to have a peer with cancer and what behaviors by healthcare providers contribute to feelings of abandonment later in survivorship, and to better understand adolescent survivors' models of the illness and survivorship. IMPLICATIONS FOR PRACTICE: Study results suggest that nurses are in an ideal position to begin and to continue discussions with adolescent survivors about the adolescent's view of medical follow- up, its purpose and importance, and ways in which the adolescent can begin, early on, to engage in planning their own health during survivorship. PMID- 30024441 TI - Efficacy of Parenteral Amantadine Therapy in the Treatment of Multiple System Atrophy With Predominant Parkinsonism. AB - OBJECTIVE: The aim of this study was to assess clinical response to a high-dose intravenous (IV) amantadine given for 5 consecutive days in patients with multiple system atrophy parkinsonism (MSA-P). METHODS: Subjects with a diagnosis of MSA-P treated with IV amantadine were included. Patients' disease severity before and after therapy was evaluated using the Unified Multiple System Atrophy Rating Scale (UMSARS). RESULTS: Fourteen subjects (8 females) were included. In 10 subjects (71.4%), clinical improvement was noted. The UMSARS score after treatment decreased by 2 points (median [interquartile range, 0-3]) when compared with UMSARS score at baseline (P = 0.0020). Upon examining the walking parameter, a trend of improvement was shown (P = 0.0625) (range, 0-1 points). Neither specific demographic parameters nor occurrence of adverse effects was found to be a predictive factor for improvement. Adverse events were mild and transient except for one patient who experienced acute psychosis prompting treatment cessation, upon which psychosis resolved. CONCLUSIONS: Our preliminary data show that IV amantadine may be a safe and effective therapy in MSA-P. A double-blind placebo-controlled trial is needed to establish the true benefit of amantadine therapy. PMID- 30024442 TI - Fluoxetine-Induced Skin Picking and Compulsive Behaviors in a Preschool Girl. AB - Skin-picking disorder is regarded as a type of obsessive-compulsive and related disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in the treatment of skin-picking disorder. However, these agents can cause opposite effects in some cases. There is a report on SSRI-induced skin picking disorder in adults. However, to our knowledge, there are no data regarding SSRI-induced skin picking in children. We present the case of a preschool girl with separation anxiety disorder who displayed skin-picking and compulsive-asking behaviors after fluoxetine therapy. PMID- 30024443 TI - Tetrahydrocannabinol/Cannabidiol Oromucosal Spray in Patients With Multiple Sclerosis: A Pilot Study on the Plasma Concentration-Effect Relationship. AB - OBJECTIVES: We aimed to assess the potential relationship between intrasubject 9 tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray plasma profiles and clinical effects elicited by subacute dosing in chronically treated patients with multiple sclerosis (MS). METHODS: The study design was pilot, single center, open, and prospective. The patients were challenged with a morning test dose of 2 THC/CBD sprays at a 15-minute interval. Venous blood samples were collected before the first spray administration and every 30 minutes after the second spray, until 240 minutes postdosing. Patients rated their spasticity by the Numerical Rating Scale (NRS) simultaneously with blood drawings. Postural and motor tests were performed before the first spray and 90 and 180 minutes thereafter. RESULTS: Twelve patients were recruited. Peak plasma concentrations of THC/CBD largely varied among patients, from 0.60 to 13.29 ng/mL for THC and 0.55 to 11.93 ng/mL for CBD. Time to peak plasma concentrations ranged from 150 to 240 minutes for THC and 90 to 240 minutes for CBD. Patients' NRS serial scores decreased after dosing, from a median value of 6 to 3.5 (P < 0.001). A significant inverse correlation was observed between median intrasubject repeated NRS scores and corresponding median values of both THC (P < 0.01) and CBD (P < 0.002) plasma concentrations. No significant effect of cannabinoids dosing could be appreciated according to posturographic and motor tests. CONCLUSIONS: Our kinetic dynamic findings from THC/CBD oromucosal spray are the first obtained in real MS patients. Although preliminary, they suggest that subacute dosing might elicit a subjective clinically significant effect on MS-related spasticity, paralleling cannabinoids measurable plasma concentrations. PMID- 30024444 TI - Cardiovascular disease in Noonan syndrome. AB - PURPOSE OF REVIEW: To provide information on the scope of cardiac disease in Noonan syndrome. RECENT FINDINGS: Noonan syndrome is a common autosomal dominant RASopathy disorder characterized by clinical findings of facial dysmorphism, congenital heart disease, and short stature. The degree of genetic heterogeneity has recently become evident in that Noonan syndrome is now known to be caused by mutations in a large variety of genes which produce dysregulation of the RAS-MAPK (mitogen-activated protein kinase) signaling pathway. The scope of cardiac disease in Noonan syndrome is quite variable depending on the gene mutation, with some mutations usually associated with a high incidence of congenital heart defects (PTPN11, KRAS, and others) while those with predominantly hypertrophic cardiomyopathy (HCM) have higher risk and morbidity profiles (RAF1, RIT1, and those associated with multiple lentigines). SUMMARY: Cardiac disease in Noonan syndrome varies according to the type of gene mutation. The most common forms of cardiac disease include pulmonary stenosis, HCM, and atrial septal defect. HCM in general is associated with increased risk, mortality, and morbidity. New concepts for potential treatments are discussed. PMID- 30024445 TI - Mini Screws for Improving Accuracy in Navigation-assisted Spine Surgery. AB - STUDY DESIGN: Presentation of a surgical technique with accompanying video (Supplemental Digital Content 1, http://links.lww.com/CLINSPINE/A67) of an illustrative case. OBJECTIVE: The objective of this study was to present a helpful and easy-to-implement technique for improving initial referencing accuracy, as well as rereferencing accuracy in cases of multilevel instrumentation or in cases of dislocation of the reference array. SUMMARY OF BACKGROUND DATA: Navigation-assisted spine surgery has become standard of care in most hospitals performing complex spine interventions. Although short-segment instrumentations are fairly straight-forward with current hardware and software solutions, obtaining ideal accuracies and troubleshooting reference array disruptions remain challenging. METHODS: A surgical technique is presented as a step-by-step guide using intraoperative videos and photographs as well as imaging data in an illustrative case of thoracic hemivertebra resection and dorsal instrumentation. TECHNIQUE/RESULTS: After skin incision is performed at the index level, posterior soft tissue preparation is performed. Before firmly attaching the reference array to a spinous process we then insert a minimum of four 5 mm mini screws at any bony structure within the exposure. Then an intraoperative navigation scan (3-dimensional computed tomography or x-ray) is obtained, and initial referencing is performed using the previously inserted mini screws as landmarks. This yields mean accuracies of 1 mm or lower and is easily verifiable by placing the navigation probe on a mini screw head. This action can be swiftly repeated at any time to prevent reduced accuracy because of insertion forces applied during pedicle screw placement. In addition, this allows for easy rereferencing in cases of disruption or complete removal of the navigation array, eliminating the need to perform additional computed tomography or x-ray scans during the procedure. CONCLUSIONS: The technique presented allows for rapid and highly accurate initial referencing and can be used in all cases of navigation assisted spine surgery. It also allows for hassle-free rereferencing in cases of disruption or accidental removal of the reference array. PMID- 30024446 TI - In-Hospital Outcomes of Patients With Advanced Chronic Kidney Disease, Dialysis, and Kidney Transplant Undergoing Spinal Fusion: Analysis of a Nationwide Database. AB - STUDY DESIGN: A retrospective analysis of population-based national hospital discharge data collected for the nationwide inpatient sample (NIS). OBJECTIVES: To examine the in-hospital outcomes of patients with advanced chronic kidney disease (CKD), dialysis, and kidney transplant undergoing spinal fusion on a national level. SUMMARY OF BACKGROUND DATA: Patients with advanced CKD have been living longer with the support and improvement of medical treatment, dialysis, and organ transplant. Some of those patients undergo spinal fusion surgery. However, there is limited information regarding the outcomes of patients with advanced CKD, dialysis, and kidney transplant, undergoing spinal fusion. METHODS: Clinical data were derived from the US Nationwide Inpatient Sample (NIS) between 2000 and 2009. Patients who underwent spinal fusion were identified and divided into 4 groups: those with advanced CKD, dialysis, and kidney transplant, and those without advanced CKD. Data regarding, patient-system and health care system related characteristics, comorbidities, in-hospital complications, and mortality were retrieved and analyzed. In-hospital outcomes were compared between the groups and analyzed with the use of multivariate logistic regression. RESULTS: Among the all groups, overall in-hospital complications rate was the highest (42.0%) for patients with advanced CKD and in-hospital mortality rate was the highest (5.2%) for those with dialysis, undergoing spinal fusion. Patients with dialysis had 8.7 and 9.5 times higher risk of in-hospital mortality compared with those with kidney transplant and those without advanced CKD. CONCLUSIONS: Patients with advanced CKD, dialysis, and kidney transplant had significant higher rates and risks of in-hospital morbidity or mortality than those without advanced CKD, undergoing spinal fusion. Particularly, patients with dialysis undergoing spinal fusion need to be informed with high mortality risk. PMID- 30024447 TI - Bracing Following Transforaminal Lumbar Interbody Fusion is not Necessary for Patients With Degenerative Lumbar Spine Disease: A Prospective, Randomized Trial. AB - STUDY DESIGN: This is a prospective, randomized trial. OBJECTIVE: This study aimed to evaluate the outcome of bracing following transforaminal lumbar interbody fusion (TLIF) in patients with degenerative lumbar spine diseases. SUMMARY OF BACKGROUND DATA: Bracing following spinal fusion for lumbar degenerative disease is common. However, the necessity of postoperative bracing is still controversial. A paucity of high-quality studies have assessed the efficacy of bracing. MATERIALS AND METHODS: In total, 90 patients with degenerative lumbar disease receiving instrumented TLIF were randomly assigned to brace and no brace groups for postoperative care. Patients in the brace group were instructed to wear a rigid brace full-time for 12 weeks. Patients in the no brace group were instructed to wear a soft corset for 2 weeks, after which it was weaned off. In all patients, the Visual Analogue Scale and Oswestry Disability Index scores were evaluated preoperatively; postoperatively; and at 6 weeks, 3, 6, and 12 months of follow-up. The fusion rates, complications, and reoperation rates were recorded. RESULTS: In total, 44 patients were assigned to the brace group (mean age, 69.2+/-10.7 y), and 46 were assigned to the no brace group (mean age, 68.8+/-11.9 y). All patients received at least 12 months of follow-up. There were no significant differences between the 2 groups with regard to patient demographic characteristics. The Visual Analogue Scale and Oswestry Disability Index scores at each follow-up were not significantly different between the 2 groups. The fusion rate and complications at the 12-month postoperative follow-up were not significantly different between the 2 groups. CONCLUSIONS: Our study showed that in patients with degenerative spinal disease who receive TLIF, wearing a rigid brace postoperatively is unnecessary. In addition, the fusion rate was not related to bracing, and there were no complications or reoperations whether a brace was worn. LEVEL OF EVIDENCE: Level II-therapeutic. PMID- 30024448 TI - A Collaborative Approach to Prepare Nursing Students to Implement Relationship Based Care. AB - The author proposes the use of a collaborative approach to prepare nursing students to implement relationship-based care through the use of a dedicated education unit. This collaboration would use the phases of relationship-based care, Benner's novice-to-expert stages, and the semesters of the typical upper division nursing curriculum. The ways in which relationship-based care can enhance the learning process for nursing students are discussed. PMID- 30024450 TI - A Retrospective Study of Aimed Patch Testing With Aqueous Nickel Sulfate Hexahydrate at 30% and 15% in Patients With Dermatitis. AB - BACKGROUND: Sometimes, patients with a history of metal intolerance react negatively or doubtfully to nickel at patch testing. OBJECTIVE: The aim of the study was to investigate whether aqueous nickel sulfate hexahydrate at 15% and 30% traces more contact allergy than the nickel preparation in the baseline series at 5%. METHODS: In the period 1995-2015, more than 800 of 16,059 patients with a negative or doubtful patch test reaction to the petrolatum preparation of nickel at 5% on the day 3 reading were additionally tested with aqueous nickel at 15% and/or 30%. CONCLUSIONS: In this retrospective study with aimed patch testing with aqueous nickel solutions, significantly more (P < 0.001) contact allergy was obtained as compared with the 5% preparation in petrolatum. The 30% solution was significantly better (P < 0.001) than the 15% solution. To demonstrate that patch testing with nickel at 15% or 30% is better than the present testing with 5% requires simultaneous testing with the 3 nickel preparations. PMID- 30024452 TI - Allergic Contact Dermatitis and Food and Drug Administration Reporting: A Survey of Current Member Practices. PMID- 30024453 TI - Comparison Between Q-Adjusted LASIK and Small-Incision Lenticule Extraction for Correction of Myopia and Myopic Astigmatism. AB - PURPOSE: To compare Q-adjusted femtosecond-assisted laser in situ keratomileusis (FS-LASIK) and small-incision lenticule extraction (SMILE) in terms of safety, efficacy, and predictability, as well as in terms of changes in dry eye parameters, corneal biomechanics, higher-order aberrations (HOAs), and corneal asphericity. METHODS: A total of 60 eyes were enrolled in this prospective comparative study: 30 underwent SMILE and 30 underwent FS-LASIK. Changes in manifest refraction, uncorrected distance visual acuity and corrected distance visual acuity, corneal topography, corneal hysteresis (CH), and corneal resistance factor (CRF) (Ocular Response Analyzer, ORA), and dry eye parameters were evaluated during a 3-month follow-up. RESULTS: Mean manifest refraction spherical equivalent (MRSE) was -4.17 (+/-1.86) preoperatively in FS-SMILE group and -3.97 (+/-2.02) in FS-LASIK group (P=0.69). Mean postoperative MRSE in FS SMILE group was -0.25+/-0.38 diopter (D) and -0.183+/-0.33 D in FS-SMILE group (P=0.50). A total of 93% of treated eyes in both groups had a MRSE within +/-0.5 D. The mean percentage change of CH was 14.23+/-17.59 and 18.89+/-7.2 mm Hg (P=0.1871) in FS-SMILE and FS-LASIK groups, respectively. The mean percentage change of CRF was 27.43+/-16.8 and 21.32+/-17.1 mm Hg (P=0.1682) in FS-SMILE and FS-LASIK groups, respectively. A statistically significant difference between techniques were found in the values of Schirmer test (P=0.0002) and tear breakup time (P=0.0035). Regarding corneal HOAs, no statistically significant differences between groups were found in the change in the root mean square of HOAs (P=0.2), coma aberration (P=0.0589), and spherical aberration (P=0.0543). CONCLUSION: SMILE is as safe and predictable as FS-LASIK. According to the ORA system, SMILE is not better than FS-LASIK in terms of biomechanical changes. However, SMILE causes less effect on dry eye parameters during the first 3 postoperative months. PMID- 30024451 TI - Textile and Shoe Allergic Contact Dermatitis in Military Personnel. AB - BACKGROUND AND OBJECTIVES: Allergic contact dermatitis is a common dermatosis among military personnel. Given the unique military demands, it is not surprising that shoe dermatitis and textile dermatitis are common. Our study aimed to compare the clinical and demographic parameters between military personnel and civilians evaluated for the suspicion of shoe and textile dermatitis in a tertiary clinic in Israel. METHODS: This retrospective cross-sectional study included 295 patients who were referred to a tertiary clinic for evaluation because of suspected shoe or textile dermatitis. Eighty-eight of the patients were soldiers. The patch tests were tailored according to the clinical presentation and relevant exposures. RESULTS: The 2 populations differed in several parameters. The duration of the dermatitis was longer in the civilian group. The atopy rate was significantly higher among military conscripts. The patch test reactivity and multiple patch test reactivity were lower in the army group. Dermatitis seen in the military group tended to be more widely distributed. CONCLUSIONS: Distinctive demographic and exposure patterns explain the differences observed between the 2 study groups. It is not surprising that irritant dermatitis is more common among military personnel, given the extreme military demands and higher atopy rate among soldiers. PMID- 30024454 TI - Trigeminal Hyperexcitability in Idiopathic Intracranial Hypertension: A Blink Reflex Study. AB - PURPOSE: To compare blink reflex examination findings in patients with idiopathic intracranial hypertension (IIH) with migraineurs and controls and to investigate the role of blink reflex data in the follow-up by evaluating their relationship with clinical symptoms. METHODS: We included 23 patients with IIH, 15 migraineurs, and 16 controls. Blink reflex was studied with bilateral paired stimulations, and the 2R2/1R2 and 2R2c/1R2c area ratios, 1R2, 2R2, 1R2c, and 2R2c latencies were compared (R2:ipsilateral R2 response, R2c:contralateral R2 response). RESULTS: 2R2/1R2 area ratios at 200, 300, and 500 ms interstimulus intervals were significantly higher in the IIH group compared with the controls, and significantly higher 2R2/1R2 area ratio at 200 ms interstimulus interval was also detected in the IIH group compared with the migraine group. Significantly shorter 2R2 latencies were found at 500 and 800 ms interstimulus intervals in IIH group compared with the migraine group and controls. Significantly higher 2R2/1R2 area ratios at 500, 800 ms, and 2R2c/1R2c area ratios at 300, 500, and 800 ms were detected in patients with IIH in remission compared with patients with attacks. CONCLUSIONS: The significant increase in R2 recovery rates in patients with IIH in remission suggests that there is an increased excitability in the trigeminal pathways. Our findings may provide a new perspective for IIH mechanism related to trigeminal hyperexcitability and evaluating new management strategies. PMID- 30024455 TI - Influence of the Montage of Stimulation Electrodes for Intraoperative Neuromonitoring During Orthopedic Spine Surgery. AB - PURPOSE: In transcranial electrical stimulation, induced motor evoked potentials (MEPs) are influenced by the montage of stimulation electrodes. Differences are to be examined between coronal and sagittal stimulation. METHODS: Forty-five patients with idiopathic scoliosis were included. Coronal and sagittal montages were obtained by electrode placement at C3C4 and Cz'F using large contact electrodes. Corkscrew and short needle electrodes were additionally placed at C3C4 in five patients. Voltage motor thresholds (MTvoltage) and MEP amplitudes at 2 times MTvoltage (MEP2MTvoltage) were obtained of upper and lower extremity muscles. Differences of MTvoltage and MEP2MTvoltage at Cz'F and C3C4 and between electrodes were analyzed. RESULTS: MEP2MTvoltage benefits from coronal positioning. Correlations between MTvoltage and impedance were not significant for large electrodes at Cz'F, very low for C3C4, and high for short needles or corkscrew electrodes. MTvoltage of short needles and corkscrews was up to 200% higher compared with MTvoltage of long needles. MTcurrent is increased by 20% to 30% and 2% to 10% for the arm and leg muscles, respectively. CONCLUSIONS: Biphasic stimulation at C3C4 is advised when constant voltage stimulation is used to monitor the spinal cord during orthopedic spine surgery. MTvoltage of corkscrew and small needle electrodes are highly sensitive to electrode impedances. PMID- 30024456 TI - Intramuscular Ketamine Protocol as an Alternative to Physical Restraints for Electroconvulsive Therapy Administration in a Psychotic Patient: A Case Report. PMID- 30024457 TI - Online Theta Frequency Transcranial Alternating Current Stimulation for Cognitive Remediation in Schizophrenia: A Case Report and Review of Literature. AB - Transcranial alternating current stimulation (tACS), a noninvasive brain stimulation technique that uses low-intensity alternating current, has been postulated to be a potential therapeutic option in treating the cognitive deficits in schizophrenia. Transcranial alternating current stimulation synchronizes the neural oscillations to the applied stimulation frequency in the stimulated cortical regions. In this report, we have reviewed the literature pertinent to the clinical application of tACS in psychiatric disorders; in addition, we have described the clinical use of online theta tACS in a schizophrenia patient with cognitive deficits. Online theta tACS led to improvement in working memory, attention, processing speed, and emotional processing. The beneficial effect of tACS persisted during reassessment of the patient after 50 days. Transcranial alternating current stimulation, given its noninvasiveness, safety, and ease of administration, has the potential to ameliorate cognitive deficits in neuropsychiatric disorders like schizophrenia. PMID- 30024458 TI - A Review of the Effects of Transcranial Direct Current Stimulation for the Treatment of Hallucinations in Patients With Schizophrenia. AB - Some 25% to 30% of patients with schizophrenia report auditory verbal hallucinations (AVHs) that fail to respond adequately to antipsychotic treatments. In such cases, transcranial direct current stimulation (tDCS) has been proposed as a therapeutic option. Here, we aim to provide an exhaustive review of the literature examining the clinical effects of tDCS on AVH in patients with schizophrenia. A systematic search in the PubMed and Web of Science databases yielded 14 results, 7 randomized controlled trials (RCTs) and 7 open label studies. Among them, 4 RCTs and 7 open-label studies reported a significant reduction of AVH after repeated sessions of tDCS, whereas 3 RCTs did not show any advantage of active tDCS over sham tDCS. Altogether, current studies showed an overall decrease of approximately 26% of AVH after active tDCS and 11% after sham tDCS. One suitable approach to decreasing AVH was to deliver twice-daily sessions of tDCS over 5 consecutive days (10 sessions at 20 minutes each, 2 mA) with the anode over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Demographic and clinical parameters such as young age, nonsmoking status, and higher frequencies of AVH occurrence seemed to be predictors of clinical improvement. Further RCTs, with larger sample sizes, are needed to confirm the usefulness of tDCS for AVH. PMID- 30024459 TI - External Beam Irradiation Preferentially Inhibits the Endochondral Pathway of Fracture Healing: A Rat Model. AB - BACKGROUND: External beam irradiation is an accepted treatment for skeletal malignancies. Radiation acts on both cancerous and normal cells and, depending on the balance of these effects, may promote or impair bone healing after pathologic fracture. Previous studies suggest an adverse effect of radiation on endochondral ossification, but the existence of differential effects of radiation on the two distinct bone healing pathways is unknown. QUESTIONS/PURPOSES: The purpose of this study was to investigate the differential effects of external beam irradiation on endochondral compared with intramembranous ossification with intramedullary nail and plate fixation of fractures inducing the two respective osseous healing pathways through assessment of (1) bone biology by histomorphometric analysis of cartilage area and micro-CT volumetric assessment of the calcified callus; and (2) mechanical properties of the healing fracture by four-point bending failure analysis of bending stiffness and strength. METHODS: Thirty-six male Sprague-Dawley rats underwent bilateral iatrogenic femur fracture: one side was repaired with an intramedullary nail and the other with compression plating. Three days postoperatively, half (n = 18) received 8-Gray external beam irradiation to each fracture. Rodents were euthanized at 1, 2, and 4 weeks postoperatively (n = 3/group) for quantitative histomorphometry of cartilage area and micro-CT assessment of callus volume. The remaining rodents were euthanized at 3 months (n = 9/group) and subjected to four-point bending tests to assess stiffness and maximum strength. RESULTS: Nailed femurs that were irradiated exhibited a reduction in cartilage area at both 2 weeks (1.08 +/- 1.13 mm versus 37.32 +/- 19.88 mm; 95% confidence interval [CI] of the difference, 4.32-68.16 mm; p = 0.034) and 4 weeks (4.60 +/- 3.97 mm versus 39.10 +/- 16.28 mm; 95% CI of the difference, 7.64-61.36 mm; p = 0.023) compared with nonirradiated fractures. There was also a decrease in the volume ratio of calcified callus at 4 weeks (0.35 +/- 0.08 versus 0.51 +/- 0.05; 95% CI of the difference, 0.01-0.31; p = 0.042) compared with nonirradiated fractures. By contrast, there was no difference in cartilage area or calcified callus between irradiated and nonirradiated plated femurs. The stiffness (128.84 +/- 76.60 N/mm versus 26.99 +/- 26.07 N/mm; 95% CI of the difference, 44.67-159.03 N/mm; p = 0.012) and maximum strength (41.44 +/- 22.06 N versus 23.75 +/- 11.00 N; 95% CI of the difference, 0.27-35.11 N; p = 0.047) of irradiated plated femurs was greater than the irradiated nailed femurs. However, for nonirradiated femurs, the maximum strength of nailed fractures (36.05 +/- 17.34 N versus 15.63 +/- 5.19 N; 95% CI of the difference, 3.96-36.88 N; p = 0.022) was greater than plated fractures, and there was no difference in stiffness between the nailed and plated fractures. CONCLUSIONS: In this model, external beam irradiation was found to preferentially inhibit endochondral over intramembranous ossification with the greatest impairment in healing of radiated fractures repaired with intramedullary nails compared with those fixed with plates. Future work with larger sample sizes might focus on further elucidating the observed differences in mechanical properties. CLINICAL RELEVANCE: This work suggests that there may be a rationale for compression plating rather than intramedullary nailing of long bone fractures in select circumstances where bony union is desirable, adjunctive radiation treatment is required, and bone stock is sufficient for plate and screw fixation. PMID- 30024460 TI - Elevated Expression of Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) Is Associated With a Poor Prognosis in Osteosarcoma. AB - BACKGROUND: Transforming acidic coiled-coil containing protein 3 (TACC3) is expressed during the mitotic phase of nuclear division and regulates microtubules. Recently, high TACC3 expression in tumor cells of various cancers including soft tissue sarcoma has been reported. However, its role in osteosarcoma remains unknown. Because we have few prognostic markers for survival in osteosarcoma, we wanted to investigate the potential role of TACC3 in human osteosarcoma and determine if it is associated with survival. QUESTIONS/PURPOSES: (1) Is there a relationship between TACC3 expression and clinicopathologic characteristics such as sex, age (< 20 or >= 20 years), histologic type (osteoblastic or others), tumor location (femur or others), American Joint Committee on Cancer staging system (AJCC stage IIA or IIB), tumor necrosis percentage after chemotherapy (< 90% or >= 90%), p53 expression (low or high), and Ki-67 expression (low or high)? (2) Is TACC3 expression associated with event free and overall survival in patients with osteosarcoma? METHODS: Forty-six conventional patients with osteosarcoma were treated at our institution from 1989 to 2013. Patients were excluded because of unresectable primary site (two patients) and no chemotherapy (two patients). Patients with metastasis at the initial visit (five patients), without pretreatment biopsy samples (two patients), or clinical charts (two patients) were also excluded. The left 33 patients who received neoadjuvant and adjuvant chemotherapy, which consisted of cisplatin/doxorubicin/methotrexate or cisplatin/doxorubicin/methotrexate/ifosfamide, and completed surgical resection with histologic wide tumor margins. Primary tumor samples before chemotherapy were used in this study. We investigated TACC3 expression using immunohistochemical staining and statistically analyzed the TACC3 expression, clinicopathologic characteristics, and event-free and overall survival in patients with osteosarcoma. RESULTS: High TACC3 expression was observed in 19 of 33 osteosarcoma specimens (58%), and this was associated with larger tumor size (ie, AJCC stage IIB in this study; p = 0.002), higher p53 expression (p = 0.007), and higher Ki-67 expression (p = 0.002). The estimated metastasis-free survival at 5 years was 21% (95% confidence interval [CI], 7%-41%) in patients with high TACC3 expression and 79% (95% CI, 47%-93%) in patients with low TACC3 expression (p < 0.001), and the estimated overall survival at 5 years was 34% (95% CI, 13% 56%) in patients with high TACC3 expression and 86% (95% CI, 54%-96%) in patients with low TACC3 expression (p < 0.001). Furthermore, high TACC3 expression was an independent poor prognostic factor for metastasis-free survival with a hazard ratio of 3.89 (95% CI, 1.07-19.78; p = 0.039) as well as overall survival with 4.41 (95% CI, 1.01-32.97; p = 0.049). CONCLUSIONS: High TACC3 expression was associated with aggressive clinicopathologic features and unfavorable prognosis in these patients with osteosarcoma. Our preliminary results suggest that further analysis about mutation or an inactive form of TACC3 would be useful to understand the mechanism of abnormal TACC3 expression in patients with osteosarcoma. If these findings are substantiated in larger studies, TACC3 might be useful for predicting survival and a potential therapeutic target for osteosarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 30024461 TI - What Are the Reference Values and Associated Factors for Center-edge Angle and Alpha Angle? A Population-based Study. AB - BACKGROUND: The available evidence regarding normal ranges for the center-edge angle and the alpha angle derives from a few small studies, and associated factors such as sex and anthropometric factors have not been well evaluated. Knowing more about normal values for these parameters is critical, because this can inform decisions about when to perform elective hip preservation surgery. Population-level studies would provide considerable clarity on these issues, but to our knowledge, no such studies are available. QUESTIONS/PURPOSES: The purposes of this study were (1) to use MRI in patients of a population-based study to establish normal values for the alpha and center-edge angles in the normal adult hip; and (2) to determine whether age, sex, or anthropometric variables were associated with differences in these values. METHODS: We used MRI images (1.5 T) of 3226 participants of the Study of Health in Pomerania (SHIP). SHIP is a population-based study that started with 4308 participants in 1997. Participants were recruited randomly from official inhabitant data files as a stratified cluster sample of the population from a defined region in northeastern Germany. To ensure a representative epidemiologic cohort, stratification variables were sex, age, and city of residence. Between 2008 and 2012, 1094 of these participants underwent whole-body MRI with pelvic sequences in the second followup. In parallel, the next cohort, SHIP-Trend, started with the same protocol in which 2132 participants underwent MRI examination. Reference values were calculated by quantile regressions for the 2.5 and 97.5 percentiles. Associations with the demographic features sex, age, weight, height, body mass index (BMI), and waist circumference were analyzed by bivariate linear regression models. RESULTS: The mean center-edge angle was 31 degrees (+/- 7 degrees ) with a corresponding calculated normal range of 17 degrees to 45 degrees . The mean alpha angle was 55 degrees (+/- 8 degrees ) with a corresponding calculated normal range between 39 degrees and 71 degrees . Men (30 degrees +/- 7 degrees ) had a lower center-edge angle than women (32 degrees +/- 8 degrees ) (p < 0.001, beta = 1.4 degrees ; 95% confidence interval [CI], 0.9 degrees -1.9 degrees ) and a higher alpha angle (57 degrees +/- 8 degrees versus 52 degrees +/- 7 degrees , p < 0.001, beta = 5.7 degrees ; 95% CI, 5.2 degrees -6.3 degrees ). Moreover, a higher center-edge angle for the left side was found (33 degrees +/- 8 degrees versus 30 degrees +/- 8 degrees , p < 0.001, beta =3.2 degrees ; 95% CI, 3.0 degrees -3.4 degrees ). In addition to sex, we found that age, height, waist circumference, and BMI affected both center-edge angle and alpha angle. Weight was associated with the alpha angle as well. Because of these associations, age- and sex-adjusted reference values with belonging formulas were calculated. CONCLUSIONS: The range of normal center-edge and alpha angles is quite wide. Therefore, only markedly abnormal angles may be associated with pathology. Moreover, center-edge angle and alpha angle are associated with age, sex, and anthropometric factors, which have to be taken into account for better interpretation. CLINICAL RELEVANCE: The association of abnormal radiographic values with true clinical hip pathology is tenuous at best. Assuming that a patient with an abnormal radiograph requires treatment is unwise. The clinical picture has to be substantial for therapeutic decisions. PMID- 30024462 TI - Does THA Improve Social Status Among Turkish Women With Developmental Dysplasia of the Hip? AB - BACKGROUND: In traditional societies, patients who reach adulthood with developmental dysplasia of the hip (DDH) may be labeled "disabled" and may be considered "defective," causing them psychologic pain and problems with social interactions. In some patriarchal societies, women disproportionately experience these problems, because they may be seen as insufficient in terms of marriage and sexual intercourse owing to hip-related limitations, and they may be married through arranged marriages to people who also have disabilities. This patriarchal structure limits the ways women can engage in society and may lower their quality of life (QOL). The degree to which THA can improve the lives of women in these specific ways in a patriarchal culture has not, to our knowledge, been studied. QUESTIONS/PURPOSES: (1) Does THA improve the social standing of young women with DDH in Turkey? (2) Does THA improve QOL of young women with DDH in Turkey? (3) Does THA improve pain and physical function in these patients? METHODS: This study was a retrospective, comparative study performed at Karabuk University Research and Training Hospital in Karabuk, Turkey, from 2012 to 2017. A total of 217 women with DDH were followed at our center between the study dates. All of these patients were evaluated for inclusion into the study. Among these, 175 women with DDH (aged 20-45 years) were included in the study according to inclusion/exclusion criteria. We offered THA to all patients in whom surgery was technically feasible; 84 chose to undergo THA, whereas 91 declined the procedure. Whether THA had any effects on the study questions was determined by comparison of the following findings at baseline and after intervention. The social standing of patients was assessed through their marital status and proportions of employment and depression; the patients' QOL was assessed with the SF-36 at baseline for all patients and at 1 year postoperatively for those who underwent THA; and pain and dysfunction were evaluated by determination of the proportion of patients who had scoliosis, knee valgus, and knee and lumbar pain. At baseline, patients were not different in regard to all parameters except knee and lumbar pain, which were greater in those who had decided to undergo THA. The SF 36 scores of patients who underwent THA were compared with their postoperative scores as well as with the baseline scores of patients who did not undergo THA. RESULTS: In terms of measures of social standing, women who underwent THA appeared better at followup than did the patients who did not undergo THA. Those who underwent THA had higher percentages of marriage and employment and less depression. Regarding QOL, postintervention comparisons revealed that women who underwent THA had higher SF-36 scores compared with the initial results of women who did not have surgery. Compared with preoperative scores, the highest improvements were found in social role function (mean difference +/- standard error [SE] = 58.64 +/- 0.88; 95% confidence interval [CI], 56.91-60.37; p < 0.001) and mental health (mean difference +/- SE = 53.00 +/- 0.86; 95% CI, 51.31 54.69; p < 0.001) subdimensions of the SF-36. Finally, patients who underwent THA had improvements in pain and function as measured by Harris hip score than did patients who did not undergo THA. At initial evaluation, two groups were found to be similar in terms of Harris hip scores (THA: 61.6 +/- 7.4 versus non-THA: 63.7 +/- 7.6, p = 0.066), whereas the THA group was found to be superior at followup evaluation (THA: 83.5 +/- 6.2 versus non-THA: 62.1 +/- 7.8, p = 0.001). CONCLUSIONS: Young women with DDH are severely affected by social and cultural norms in Turkey, which is an example of a patriarchal culture. We believe that in this setting, some patients who improve their appearance, gait, and physical function through THA may benefit from a better social perception and higher self esteem, which may, in turn, increase their QOL and provide more freedom in terms of life choices. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 30024463 TI - Value-based Healthcare: Measuring What Matters-Engaging Surgeons to Make Measures Meaningful and Improve Clinical Practice. PMID- 30024464 TI - CORR Insights(r): American Joint Replacement Registry Risk Calculator Does Not Predict 90-day Mortality in Veterans Undergoing Total Joint Replacement. PMID- 30024465 TI - CORR Insights(r): Do Early Results of Proximal Humeral Allograft-Prosthetic Composite Reconstructions Persist at 5-year Followup? PMID- 30024466 TI - CORR Insights(r): No Clinically Important Difference in Pain Scores After THA Between Periarticular Analgesic Injection and Placebo: A Randomized Trial. PMID- 30024467 TI - CORR Insights(r): What Is the Survivorship of Revision Surgery Performed for the Chronically Dislocated THA? PMID- 30024468 TI - Letter to the Editor: On Patient Safety: Limiting Opioid Exposure-We Can Do Our Part. PMID- 30024469 TI - Editorial: Threshold P Values in Orthopaedic Research-We Know the Problem. What is the Solution? PMID- 30024470 TI - The Evolution of the Clinician-Educator in the United States and Canada: Personal Reflections Over the Last 45 Years. AB - The challenging and changing face of medicine over the last 45 years of the author's career has dictated where faculty members' primary interaction with patients occurs, how they teach trainees, and how they measure educational outcomes. The transfer of patient care from the inpatient to the ambulatory setting in the late 20th century was instrumental in creating a "new' model for faculty-that is, the clinician-educator (CE). This individual has been defined as a faculty member whose primary responsibility as part of the academic mission is patient care and whose focus is on the theoretical constructs that inform excellent teaching and effective learning, applying these to create and inform educational scholarship. Three major forces have affected the CE over time namely, faculty development, educational scholarship, and the advent of communities of learners. This Invited Commentary traces the evolvement of the CE from the perspective of the author. PMID- 30024471 TI - Advancing Holistic Review for Faculty Recruitment and Advancement. AB - PROBLEM: The challenges to developing a physician and scientific workforce that both reflects and provides quality care for the complex and richly diverse population of the United States are considerable. APPROACH: One medical school (Baylor College of Medicine) sought to adapt the Holistic Review in Admissions process developed by the Association of American Medical Colleges and apply it to faculty. In the fall of 2016, academic leaders received on-site training and completed several workshop exercises. The goal was for the leaders to build consensus around a holistic review framework for hiring and advancing faculty that is based on the institution's mission, vision, and values. OUTCOMES: This training occurred during Baylor's ongoing strategic planning and helped inform improvements in the faculty recruitment and hiring process, in the guidelines for faculty appointment and promotion, and in the pilot of an administrative leadership candidate rating tool, the "experiences-attributes-academic metrics model." The model that developed from the pilot translates the holistic review concept into a tool for identifying, hiring, and promoting faculty members and administrative leaders that is aligned to the values of Baylor. The utility of this framework lies in the clear delineation of metrics and qualifications along with the prioritization of attributes and experiences. NEXT STEPS: This innovation is being piloted and evaluated to determine its effect on advancing the institutional mission of Baylor. PMID- 30024472 TI - Ethical Issues and Recommendations in Grateful Patient Fundraising and Philanthropy. AB - Grateful patients provide substantial philanthropic funding for health care institutions, resulting in important societal benefits. Although grateful patient fundraising (GPFR) is widespread, it raises an array of ethical issues for patients, physicians, development professionals, and institutions. These issues have not been described comprehensively, and there is insufficient guidance to inform the ethical practice of GPFR. Consequently, the authors convened a "Summit on the Ethics of Grateful Patient Fundraising," with the goal of identifying primary ethical issues in GPFR and offering recommendations regarding how to manage them. Participants were 29 experts from across the United States who represented the perspectives of bioethics, clinical practice, development, law, patients, philanthropy, psychology, and regulatory compliance. Intensive discussions resulted in articulating ethical issues for physicians and other clinicians (discussions with patients about philanthropy; physician-initiated discussions; clinically vulnerable patients; conflicts of obligation and equity regarding physician's time, attention, and responsiveness and the provision of special services; and transparency and respecting donor intent) as well as for development officers and institutions (transparency in the development professional-donor relationship; impact on clinical care; confidentiality and privacy; conflicts of interest; institution-patient/donor relationship; concierge services for grateful patients; scientific merit and research integrity; transparency in use of philanthropic gifts; and institutional policies and training in responsible GPFR). While these recommendations promise to mitigate some of the ethical issues associated with GPFR, important next steps include conducting research on the ethical issues in GPFR, disseminating these recommendations, developing standardized training for clinicians regarding them, and revising them as warranted. PMID- 30024473 TI - Examining Demographics, Prior Academic Performance, and United States Medical Licensing Examination Scores. AB - PURPOSE: To examine whether demographic differences exist in United States Medical Licensing Examination (USMLE) examination scores and the extent to which any differences are explained by students' prior academic achievement. METHOD: Hierarchical linear modeling of data for U.S. and Canadian allopathic and osteopathic medical graduates testing on USMLE Step 1 during or after 2010, and completing USMLE Step 3 by 2015. Main outcome measures were computer-based USMLE examinations: Step 1, Step 2 Clinical Knowledge, and Step 3. Test-taker characteristics included sex, self-identified race, U.S. citizenship status, English as a second language, and age at first Step 1 attempt. Covariates included composite Medical College Admission Test (MCAT) scores, undergraduate grade point average (GPA), and previous USMLE scores. RESULTS: A total of 45,154 examinees from 172 medical schools met criteria. The sample was 67% white and 48% female; 3.7% non-U.S. citizens; and 7.4% with English as a second language. Hierarchical linear models examined demographic variables with and without covariates including MCAT scores and GPA. All Step examinations showed significant differences by gender after adding covariates, varying by Step. Racial differences were observed for each Step, attenuated by the addition of covariates. CONCLUSIONS: Demographic differences in USMLE performance were tempered by previous examination performance and undergraduate performance. Additional research is required to identify factors that contribute to demographic differences, can aid educators' identification of students who would benefit from assistance preparing for USMLE, and can assist residency program directors in assessing performance measures while meeting diversity goals. PMID- 30024474 TI - Does Reducing Clerkship Lengths by 25% Affect Medical Student Performance and Perceptions? AB - PURPOSE: Transforming a medical school curriculum wherein students enter clerkships earlier could result in two cohorts in clerkships simultaneously during the transition. To avoid overlapping cohorts at the University of Michigan Medical School, the length of all required clerkships was decreased by 25% during the 2016-2017 academic year, without instituting other systematic structural changes. The authors hypothe sized that the reduction in clerkship duration would result in decreases in student perfor mance and changes in student perceptions. METHOD: One-way analyses of variance and Tukey post hoc tests were used to compare the 2016-2017 shortened clerkship cohort with the preceding traditional clerkship cohorts (2014-2015 and 2015-2016) on the following student outcomes: National Board of Medical Examiners (NBME) subject exam scores, year-end clinical skills exam scores, evaluation of clerkships, perceived stress, resiliency, well being, and perception of the learning environment. RESULTS: There were no significant differences in performance on NBME subject exams between the shortened clerkship cohort and the 2015-2016 traditional cohort, but scores declined significantly over the three years for one exam. Perceptions of clerkship quality improved for three shortened clerkships; there were no significant declines. Learning environment perceptions were not worse for the shortened clerkships. There were no significant differences in performance on the clinical skills exam or in perceived stress, resiliency, and well-being. CONCLUSIONS: The optimal clerkship duration is a matter of strong opinion, supported by few empirical data. These results provide some evidence that accelerating clinical education may, for the studied outcomes, be feasible. PMID- 30024475 TI - It's Time for Medical Schools to Introduce Climate Change Into Their Curricula. AB - Climate change presents unprecedented health risks and demands universal attention to address them. Multiple intergovernmental organizations, health associations, and health professions schools have recognized the specific importance of preparing physicians to address the health impacts of climate change. However, medical school curricula have not kept pace with this urgent need for targeted training.The authors describe the rationale for inclusion of climate change in medical education and some potential pathways for incorporating this broad topic into physician training and continuing medical education. Reasons include the magnitude and reach of this transboundary issue, the shared responsibility of the U.S. health care sector as a major contributor to greenhouse gas emissions, and the disproportionate effects of climate change on vulnerable populations. The integration of climate-change-related topics with training of essential physician skills in a rapidly changing environment is feasible because many health topic areas already exist in medical school curricula in which climate change education can be incorporated. To fully integrate the health topics, underlying concepts, and the needed clinical and system-wide translations, content could be included across the scope of training and into continuing medical education and faculty development. The authors provide examples of such an approach to curricular inclusion. PMID- 30024476 TI - A Prognosis for Health Systems Science Courses: Observations From Current Students. AB - Certain medical schools have begun teaching courses in health systems science (HSS) to train medical students in skills aimed to improve health care in the United States. Although substantial research has been done on the potential benefit of HSS courses, reactions from students have not been reported. In this Invited Commentary, five medical students who have completed the first year of a longitudinal HSS course at the Arizona campus of the Mayo Clinic School of Medicine offer their observations of how early exposure to HSS affected their reactions to subsequent course work and current events in health care. The authors describe the HSS course and outline three benefits they have observed from their experience so far: (1) thinking more critically about health care delivery during all educational experiences, (2) gaining a better understanding of the complexity of the health care system, and (3) having a greater consideration for the many facets of health care delivery. The HSS course helped the authors identify health systems problems, develop solutions that incorporated diverse domains of health care delivery, and recognize the role and responsibility of the physician as an agent of change in a health care system. PMID- 30024477 TI - Interprofessional Practice and Education in Clinical Learning Environments: Frontlines Perspective. AB - This Invited Commentary is written by coauthors working to implement and study new models of interprofessional practice and education in clinical learning environments. There are many definitions and models of collaborative care, but the essential element is a spirit of collaboration and shared learning among health professionals, patients, and family members. This work is challenging, yet the benefits are striking. Patients and family members feel seen, heard, and understood. Health care professionals are able to contribute and feel appreciated in satisfying ways. Learners feel included. Care interactions are richer and less hierarchical, and human dimensions are more central. A crucial insight is that collaborative care requires psychological safety, so that people feel safe to speak up, ask questions, and make suggestions. The most important transformation is actively engaging patients and families as true partners in care creation. A leveling occurs between patients, family members, and health professionals, resulting from closer connections, deeper understandings, and greater mutual appreciation. Leadership happens at all levels in collaborative care, requiring team-level capabilities that can be learned and modeled, including patience, curiosity, and sharing power. These abilities grow as teams work and learn together, and can be intentionally advanced by reconfiguring organizational structures and care routines to support collective team reflection. Collaborative care requires awareness and deliberate practice both individually and as a team together. Respectful work is required, and setbacks should be considered normal at first. Once people have experienced the benefits of collaborative care, most "never want to go back." PMID- 30024478 TI - SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FINDINGS IN WAARDENBURG SYNDROME. AB - PURPOSE: Waardenburg syndrome (WS) is a rare condition characterized by six main features. It has been previously observed that WS is also associated with hypopigmentation of the choroid through multimodal imaging. To our knowledge, this is the first report of using swept-source optical coherence tomography angiography (OCTA) on a patient with known WS. METHODS: Report of a single case. The swept-source OCT images were captured using Topcon DRI OCT Triton (Topcon, Inc, Tokyo, Japan), whereas swept-source OCTA images were captured by Optovue AngioVue (Optovue, Inc, Fremont, CA) using DualTrack Motion Correction Technology. RESULTS: In this case, OCTA demonstrated evidence of normal vasculature of all layers (superficial, deep, and choricocapillaris), a normal foveal avascular zone measuring 0.267 mm in the right eye and 0.307 mm in the left eye, and a normal capillary density measuring 49.8% in the right eye and 52.6% in the left eye. CONCLUSION: There are many conditions that may mimic the hypopigmentation of the choroid associated with WS; it has been documented that these similar conditions such as choroidal nevus, choroidal melanoma, and Vogt Koyanagi-Harada syndrome all demonstrated abnormal OCTA findings. Unlike these conditions, our patient with WS had unremarkable OCTA findings. PMID- 30024479 TI - Nonpharmacological Management of Persistent Pain in Elite Athletes: Rationale and Recommendations. AB - Persistent pain is common in elite athletes. The current review arose from a consensus initiative by the International Olympic Committee to advance the development of a standardized, scientific, and evidence-informed approach to management. We suggest that optimal management of persistent pain in elite athletes requires an understanding of contemporary pain science, including the rationale behind and implementation of a biopsychosocial approach to care. We argue that athletes and clinicians need to understand the biopsychosocial model because it applies to both pain and the impact of pain with special reference to the sport setting. Management relies on thorough and precise assessment that considers contributing factors across nociceptive, inflammatory, neuropathic, and centrally acting domains; these can include contextual and psychosocial factors. Pain management seeks to remove contributing factors wherever possible through targeted education; adjustment of mechanical loading, training, and performance schedules; psychological therapies; and management of inflammation. PMID- 30024480 TI - Effect of Varying Self-myofascial Release Duration on Subsequent Athletic Performance. AB - Phillips, J, Diggin, D, King, DL, and Sforzo, GA. Effect of varying self myofascial release duration on subsequent athletic performance. J Strength Cond Res XX(X): 000-000, 2018-Self-myofascial release (SMR) treatments can enhance joint range-of-motion and restore movement function. The effects of different SMR durations on athletic performance have yet to be examined. Twenty-four volunteers had ankle and knee joint range-of-motion assessed using modified weight-bearing and kneeling lunge (KL) tests. Vertical jump and pro-agility sprint performance were also examined. All tests were conducted before and immediately after 1 (SMR_1) and 5 minutes (SMR_5) of foam rolling, and immediately after a control (CONTR) condition. Results showed KL scores increased after SMR_5 (16.4%; effect size [ES] = 0.85) when compared with SMR_1 (12.5%; ES = 0.58). Weight-bearing lunge scores showed little change after either SMR treatment. The CONTR condition exhibited little effect on joint range-of-motion. Vertical jump performance decreased after SMR_5 (5.1%; ES = 0.26) but changed little after SMR_1 (0.7%; ES = 0.03) and CONTR (1.9%; ES = 0.10) conditions. Pro-agility performance improved slightly after SMR_1 (1.1%) but deteriorated after CONTR (1.2%) and SMR_5 (0.5%). Effect size calculations for changes in pro-agility sprint times were trivial across all conditions (0.06-0.15). Data suggest that extended periods of SMR may be recommended, should improvements in joint range-of-motion be required. If power output is a critical requirement of subsequent exercise/performance tasks, prolonged SMR treatment (i.e., 5 minutes) should be avoided. Practitioners should be cautious when implementing SMR treatments within warm-ups. PMID- 30024481 TI - Acute Effects of Battle Rope Exercise on Performance, Blood Lactate Levels, Perceived Exertion, and Muscle Soreness in Collegiate Basketball Players. AB - Chen, WH, Yang, WW, Lee, YH, Wu, HJ, Huang, CF, and Liu, C. Acute effects of battle rope exercise on performance, blood lactate levels, perceived exertion, and muscle soreness in collegiate basketball players. J Strength Cond Res XX(X): 000-000, 2018-This study investigated the acute effects of battle rope (BR) exercise on basketball players' performance, blood lactate levels, rating of perceived exertion (RPE), and perceived muscle soreness. Fifteen well-trained Division-I male basketball players underwent the same test procedure at baseline, before BR exercise (30 minutes of rest after the baseline test), and after BR exercise. The 30-minute experimental protocol comprised 6 BR exercises at a work to-rest ratio of 1:2 (20-second exercise and 40-second rest). Shooting accuracy, basketball chest pass speed, countermovement jump (CMJ) height, blood lactate levels, RPE (Borg Category-Ratio-10 scale), and perceived muscle soreness (visual analog scale, 0-100 mm) were measured in each test. The results indicated no change for any variables between baseline and before BR exercise. After BR exercise, performance decrements (p < 0.05) were recorded in shooting accuracy (16.9%) and basketball chest pass speed (9.1%), but no significant changes were observed for CMJ height. Battle rope exercise caused increases in blood lactate levels (13.6 mmol.L), RPE (9.9), and perceived muscle soreness (upper-limb: 63-67 mm; trunk: 43-68 mm; and lower-limb: 45-52 mm). In conclusion, BR exercise is physically demanding on the upper body, resulting in decreased performance in shooting accuracy and basketball chest pass speed. Battle rope exercise may not be beneficial before a practice or game because it triggers acute exercise induced performance decrements and fatigue. However, BR exercise may be suitable for basketball training sessions in which the objective is to strengthen technical skills under fatiguing conditions. PMID- 30024482 TI - Effects of an Upper-Body Training Program Involving Resistance Exercise and High Intensity Arm Cranking on Peak Handcycling Performance and Wheelchair Propulsion Efficiency in Able-Bodied Men. AB - Chaikhot, D, Reed, K, Petroongrad, W, Athanasiou, F, van Kooten, D, and Hettinga, FJ. Effects of an upper-body training program involving resistance exercise and high-intensity arm cranking on peak handcycling performance and wheelchair propulsion efficiency in able-bodied men. J Strength Cond Res XX(X): 000-000, 2018-The aim of this study was to determine the training effects of an upper-body training program involving resistance exercise and high-intensity arm cranking on peak handcycling performance, propulsion efficiency, and biomechanical characteristics of wheelchair propulsion in able-bodied men. The training group (n = 10) received a 4-week upper-body resistance training (RT), 70% of 1 repetition maximum, 3 sets of 10 repetitions, 8 exercise stations, 2 times per week, combined with high-intensity interval training (HIIT) 2 times per week. High-intensity interval training consisted of arm-crank exercise, 7 intervals of 2 minutes at 80-90% of peak heart rate (HRpeak) with 2-minute active rest at 50 60% of HRpeak. The control group (n = 10) received no training. Both groups performed a preincremental and postincremental handcycling test until volitional exhaustion to evaluate fitness and a 4-minute submaximal wheelchair propulsion test at comfortable speed (CS), 125 and 145% of CS, to evaluate gross mechanical efficiency (GE), fraction of effective force (FEF), percentage of peak oxygen consumption (% V[Combining Dot Above]O2peak), and propulsion characteristics. Repeated-measures analysis of variance was performed (p < 0.05). Training resulted in a 28.2 +/- 16.5% increase in peak power output, 13.3 +/- 7.5% increase in V[Combining Dot Above]O2peak, 5.6 +/- 0.9% increase in HRpeak, and 3.8 +/- 1.5% decrease in HRrest. No training effects on FEF, GE, % V[Combining Dot Above]O2peak, and push characteristics were identified. In conclusion, the combined RT and arm-cranking HIIT improved fitness. However, it seems that this training did not result in improvements in propulsion efficiency and push characteristics. Additional wheelchair skill training may be needed to fully benefit from this advantage in daily life propulsion. PMID- 30024484 TI - Prior Knowledge of the Grading Criteria Increases Functional Movement Screen Scores in Youth Soccer Players. AB - Bryson, A, Arthur, R, and Easton, C. Prior knowledge of the grading criteria increases Functional Movement Screen scores in youth soccer players. J Strength Cond Res XX(X): 000-000, 2018-We sought to determine whether familiarity with the grading criteria of the Functional Movement Screen (FMS) impacted the outcome score in elite youth soccer players. Thirty-two trained male youth soccer players (aged 17 +/- 1 years) participated in a randomized control trial. Participants were randomly assigned to evenly sized control and experimental groups, who each completed the FMS on 2 separate occasions. Participants in the experimental group were provided the FMS grading criteria between their first and second screens. Time-synchronized video footage was used to grade the FMS using standardized criteria. Structured interviews were then conducted with selected participants (n = 4) in the experimental group to establish athletes' perception of the FMS. The experimental group had a large increase in overall FMS score from the first to the second screen in comparison with the control group (Delta2.0 +/- 1.0, p < 0.001, d = 1.3). Scores for the deep squat, hurdle step, and rotary stability tests components of the FMS all increased in the experimental group in comparison with the control group (p < 0.05). Thematic analysis of the interview data suggested that the participants in the experimental group improved their understanding between good and poor technique during the FMS. These findings support the notion that FMS scores are influenced by awareness of the grading criteria. As a consequence, the FMS may not be suitable for objectively predicting injury in youth soccer players. PMID- 30024483 TI - Biochemical and Muscle Mechanical Postmarathon Changes in Hot and Humid Conditions. AB - Gutierrez-Vargas, R, Martin-Rodriguez, S, Sanchez-Urena, B, Rodriguez-Montero, A, Salas-Cabrera, J, Gutierrez-Vargas, JC, Simunic, B, and Rojas-Valverde, D. Biochemical and muscle mechanical postmarathon changes in hot and humid conditions. J Strength Cond Res XX(X): 000-000, 2018-The aim of this study was to compare biochemical changes and mechanical changes in the lower-limb muscles before and after a marathon race in hot and humid conditions. Eighteen healthy runners participated in a marathon at between 28 and 34 degrees C and 81% humidity in Costa Rica. Serum magnesium (Mg), creatine phosphokinase (CPK), lactate dehydrogenase, and hematocrit (HCT) were measured before and after the marathon. Tensiomyography measurements from the rectus femoris (RF) and vastus medialis, muscle displacement (Dm), contraction time (Tc), and velocities of contraction to 10 and 90% of Dm (V10 and V90) were obtained before and after the marathon. Postrace measurements showed a 544% increase in CPK (t(17): -6.925, p < 0.01), a 16% increase in HCT (t(17): -7.466, p < 0.01), a 29% decrease in Mg (t(17): 3.91, p = 0.001), a 2% decrease in body mass (t(17): 4.162, p = 0.001), a 4% increase in Tc of the RF (t(17): -2.588, p = 0.019), and a 12% increase in Dm of the RF (t(17): -2.131, p < 0.048) compared with prerace measurements. No significant biochemical or mechanical differences were found between runners in terms of their finish times. These findings showed that completing a marathon in hot and humid conditions induced a significant reduction in lower-limb muscle stiffness, body mass, and Mg, and increased neuromuscular fatigue, CPK, and HCT, because of muscle damage and dehydration. Knowledge of the effects of heat and humidity may be of value for coaches and sports medicine practitioners in developing effective hydration and recovery protocols for marathon runners in these special conditions. PMID- 30024485 TI - Effects of Endurance Exercise Bouts in Hypoxia, Hyperoxia, and Normoxia on mTOR Related Protein Signaling in Human Skeletal Muscle. AB - Przyklenk, A, Aussieker, T, Gutmann, B, Schiffer, T, Brinkmann, C, Struder, HK, Bloch, W, Mierau, A, and Gehlert, S. Effects of endurance exercise bouts in hypoxia, hyperoxia, and normoxia on mTOR-related protein signaling in human skeletal muscle. J Strength Cond Res XX(X): 000-000, 2018-This study investigated the effects of short-term hypoxia (HY), hyperoxia (PER), and normoxia on anabolic signaling proteins in response to an acute bout of moderate endurance exercise (EEX) before and after an endurance exercise training intervention. Eleven healthy male subjects conducted one-legged cycling endurance exercise (3 * 30 min.wk for 4 weeks). One leg was trained under hypoxic (12% O2) or hyperoxic conditions (in a randomized cross-over design), and the other leg was trained in normoxia (20.9% O2) at the same relative workload. Musculus vastus lateralis biopsies were taken at baseline (T0) as well as immediately after the first (T1) and last (T2) training session to analyze anabolic signaling proteins and the myofiber cross-sectional area (FCSA). No significant differences were detected for FCSA between T0 and T2 under all oxygen conditions (p > 0.05). No significant differences (p > 0.05) were observed for BNIP3, phosphorylated RSK1, ERK1/2, FoxO3a, mTOR, and S6K1 between all conditions and time points. Phosphorylated Akt/PKB decreased significantly (p < 0.05) at T1 in PER and at T2 in HY and PER. Phosphorylated rpS6 decreased significantly (p < 0.05) at T1 only in PER, whereas nonsignificant increases were shown in HY at T2 (p = 0.10). Despite no significant regulations, considerable reductions in eEF2 phosphorylation were detected in HY at T1 and T2 (p = 0.11 and p = 0.12, respectively). Short-term hypoxia in combination with moderate EEX induces favorable acute anabolic signaling responses in human skeletal muscle. PMID- 30024486 TI - The Role of Oxygen Therapy in Normoxemic Acute Coronary Syndrome: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Supplemental oxygen has been commonly used in the cases of acute coronary syndrome (ACS); however, recent evidence suggests that high concentration oxygen supplementation and hyperbaric oxygen in ACS patients are associated with adverse cardiovascular effects. OBJECTIVE: The purpose of this article is to systematically review the role of supplemental oxygen therapy in normoxemic patients with ACS. METHODS: A search for randomized controlled trials before November 2017 in biomedical databases was performed, and a total of 6 eligible studies with 7508 participants were identified. Four studies reported all-cause mortality after randomization, whereas 3 studies measured myocardial infarct size using cardiac enzyme levels and magnetic resonance imaging. The effect size of our primary end point was the odds ratio for all-cause mortality. The mean difference was calculated as a secondary outcome for myocardial infarct size. RESULTS: Compared with ambient air or titrated oxygen, high-concentration oxygen therapy did not significantly decrease all-cause mortality (odds ratio, 1.01; 95% confidence interval [CI], 0.81-1.25; P = .95) within 1 year nor infarct size detected by peak cardiac troponin (mean difference, -0.53 ng/mL; 95% CI, 1.20 to 0.14; P = .12) and magnetic resonance imaging (mean difference, 1.45 g; 95% CI, -1.82 to 4.73; P = .39). These outcomes were listed through a fixed effects model because of low statistical heterogeneity across the studies. CONCLUSIONS: Oxygen therapy did not significantly reduce clinical all-cause mortality and myocardial infarct size in ACS patients with normoxemia. Further large-scale randomized clinical trials are warranted to evaluate the cardiovascular effects in this field. PMID- 30024487 TI - Validation of a Spanish Version of the Information Needs in Cardiac Rehabilitation Scale to Assess Information Needs and Preferences in Cardiac Rehabilitation. AB - BACKGROUND: The identification of information needs is considered the first step to increase knowledge that ultimately could improve health outcomes in cardiac rehabilitation (CR). OBJECTIVE: The aim of this study was to psychometrically validate the Spanish Information Needs in Cardiac Rehabilitation (INCR). METHODS: The Spanish INCR was psychometrically tested in 184 patients undergoing CR. The internal consistency was assessed using Cronbach alpha, factor structure was assessed using exploratory factor analysis, and criterion validity regarding educational level, occupation, and duration in CR was assessed. RESULTS: Cronbach alpha was .97. Factor analysis revealed 10 factors, all internally consistent. Criterion validity was supported by significant differences in total INCR scores by educational level (P < .01), occupation (P < .01), and duration in CR (P < .05). Emergency/safety was the greatest information need perceived by patients. CONCLUSIONS: The Spanish INCR was demonstrated to have good reliability and validity. This tool can be applicable in clinical and research settings, assessing patients' information needs during CR and as part of education programming. PMID- 30024488 TI - Acute Lower Leg Heating Increases Exercise Capacity in Patients With Peripheral Artery Disease. AB - BACKGROUND/OBJECTIVE: In this pilot study, we tested the hypothesis that acute lower leg heating (LLH) increases postheating popliteal artery blood flow and 6 minute walk distance in patients with peripheral artery disease (PAD). METHODS: Six patients (5 male, 1 female) with PAD (69 +/- 6.9 years; claudication: ankle brachial index < 0.90) participated in 3 randomized treatment sessions (2-7 days apart): control or bilateral LLH conducted via water bath immersion (42 degrees C; ~40-cm depth) for either 15 or 45 minutes. Popliteal artery blood flow (Doppler ultrasound) and arterial pressure were measured before and after LLH. Six-minute walk distance was measured on the control day and each experimental day 35 minutes post-LLH. RESULTS: Popliteal artery blood flow increased after heating in a duration-dependent manner (P < .05, postheating vs control for both heating conditions and between them). Six-minute walk distance increased by 10% and 12% after 15- and 45-minute heating treatments, respectively (P < .05 vs control session). CONCLUSIONS: Lower leg heating, for as short as 15 minutes, increases postheating leg perfusion and exercise capacity in patients with PAD. PMID- 30024489 TI - Insulin resistance does not impair response of chronic hepatitis C virus to direct-acting antivirals, and improves with the treatment. AB - BACKGROUND: Insulin resistance (IR) is a common complication in chronic hepatitis C virus (HCV) patients. The impact of IR on outcome of therapy with direct antivirals has not been studied. AIM: The aim was to assess the impact of direct acting antiviral (DAA) therapy on IR status in chronic HCV patients. PATIENTS AND METHODS: A total of 511 patients [mean age: 50.7+/-10.4 years, 29.7% pegylated interferon and ribavirin (RBV) experienced] were enrolled. Patients with uncontrolled diabetes, decompensated liver disease, or previous nonresponse to DAAs were excluded. Homeostatic model assessment (HOMA) was calculated before and 12 weeks after treatment, and IR was defined as HOMA greater than 1.9. Patients were treated according to the treating physician's choice, and received 12 weeks of either ombitasvir/ritonavir/paritaprevir/RBV (n=28); sofosbuvir (SOF)/simeprevir (n=36); SOF/ravidasvir (n=101); SOF/pegylated interferon/RBV (n=192); or 24 weeks of SOF/RBV (n=154). RESULTS: Most patients received IR pretreatment (80.6%); 51.3% had fibrosis stage F4 and 24.7% had diabetes. A sustained virological response (SVR) at 12 weeks after treatment (SVR12) was achieved in 465 (91%) patients. SVR12 was achieved in 90.5% of patients with IR and in 92.9% of patients without IR (P=0.560), and pretreatment HOMA was not different in responders and nonresponders (P=0.098). The number of patients with IR decreased significantly in patients who achieved an SVR much more than in nonresponders (P<0.0001) and HOMA improved significantly more in patients with SVR than in nonresponders (P=0.001). All treatment protocols were associated with a comparable improvement in HOMA (P=0.101). Predictors of SVR12 included age, platelets, and liver stiffness, but not pretreatment IR. CONCLUSION: IR does not impair the response of patients with HCV treated with DAAs, and improves significantly in patients who achieve an SVR. PMID- 30024490 TI - Risk factors for anastomotic recurrence after primary ileocaecal resection in Crohn's disease. AB - OBJECTIVE: Ileocaecal resection is the most common operation performed in Crohn's disease. Our study aimed to identify the risk factors for anastomotic recurrence following primary ileocaecal resection. PATIENTS AND METHODS: We retrospectively analysed data from all Crohn's disease surgical patients in a single colorectal unit between 2006 and 2016, including all patients who underwent primary ileocaecal resection. We defined anastomotic recurrence as the postoperative need for endoscopic dilatation of the ileocolic anastomosis or neoterminal ileal resection, and used Cox regression to determine the risk factors for such recurrence. RESULTS: In total, 101 patients underwent primary ileocaecal resection during the study period. Nine (8.9%) patients were excluded because of follow-up less than 1 year and 12 (13.0%) patients had anastomotic recurrence. The median follow-up was 4.7 (1.3-10.8) years. At 3 years, 93.1% of patients required no neoterminal ileal resection or dilatation of the ileocolic anastomosis. Urgent primary ileocaecal resection [hazard ratio (HR)=4.98, 95% confidence interval (CI)=1.45-17.11, P=0.011], stapled anastomosis (HR=20.34, 95% CI=5.06-81.77, P<0.001) and need for postoperative corticosteroid treatment after the primary ileocaecal resection (HR=3.58, 95% CI=1.03-12.40, P=0.044) emerged as significant risk factors for anastomotic recurrence. CONCLUSION: Urgent surgery and postoperative corticosteroid need represented risk factors for anastomotic recurrence. Hand-sewn anastomosis with an opening of the bowel's antimesenteric border seems to be a safe choice for ileocaecal resection. PMID- 30024491 TI - Impact of immigration in presentation and outcomes of hepatocellular carcinoma in the USA. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma's (HCC) epidemiology and prognosis differs among regions across the globe, largely because of environmental factors and underlying liver disease. Little is known about the changes led by immigration and the effect on HCC outcome. We aimed to understand the effect of immigration on HCC. PATIENTS AND METHODS: A retrospective cohort study of patients diagnosed with HCC was carried out in a tertiary center in the USA between 2005 and 2016. We characterized individuals as US born or having immigrated there after being born elsewhere. Variables related to clinical presentation, surveillance, therapy, and survival were evaluated. RESULTS: A total of 232 HCC cases were included, 169 US born (73%) and 63 immigrants (27%). Both groups were diagnosed with HCC at similar ages (60 vs. 62 years, P=0.13). Hepatitis C was the most common underlying liver disease in the US-born population compared with the immigrant population (83 vs. 52%, P<0.001), whereas hepatitis B was more common in the latter (4 vs. 29%, P<0.001). Interestingly, hepatitis B virus-related HCC was diagnosed at similar ages in US-born and immigrant individuals (59 and 57 years). At the time of diagnosis, both populations had similar tumor sizes, rates of metastasis, and diagnosis during surveillance. One-year survival was similar in both groups (65 vs. 63%). CONCLUSION: Immigrants that develop HCC have different underlying liver disease than those born in the USA, but similar HCC characteristics and outcomes, even when including hepatitis B virus-related HCCs. Our study, albeit small, suggests that changes in the environment by immigration leads to clinical adaptation of HCC. PMID- 30024492 TI - What to do when percutaneous Achilles tenotomy fails in Ponseti technique? PMID- 30024493 TI - High Completion Rate for 12 Weekly Doses of Isoniazid and Rifapentine as Treatment for Latent Mycobacterium tuberculosis Infection in the Federal Bureau of Prisons. AB - CONTEXT: Correctional facilities provide unique opportunities to diagnose and treat persons with latent tuberculosis infection (LTBI). Studies have shown that 12 weekly doses of isoniazid and rifapentine (INH-RPT) to treat LTBI resulted in high completion rates with good tolerability. OBJECTIVE: To evaluate completion rates and clinical signs or reported symptoms associated with discontinuation of 12 weekly doses of INH-RPT for LTBI treatment. SETTING/PARTICIPANTS: During July 2012 to February 2015, 7 Federal Bureau of Prisons facilities participated in an assessment of 12 weekly doses of INH-RPT for LTBI treatment among 463 inmates. MAIN OUTCOME MEASURES: Fisher exact test was used to assess the associations between patient sociodemographic characteristics and clinical signs or symptoms with discontinuation of treatment. RESULTS: Of 463 inmates treated with INH-RPT, 424 (92%) completed treatment. Reasons for discontinuation of treatment for 39 (8%) inmates included the following: 17 (44%) signs/symptoms, 9 (23%) transfer or release, 8 (21%) treatment refusal, and 5 (13%) provider error. A total of 229 (49.5%) inmates reported experiencing at least 1 sign or symptom during treatment; most frequently reported were fatigue (16%), nausea (13%), and abdominal pain (7%). Among these 229 inmates, signs/symptoms significantly associated with discontinuation of treatment included abdominal pain (P < .001), appetite loss (P = .02), fever/chills (P = .01), nausea (P = .03), sore muscles (P = .002), and elevation of liver transaminases 5* upper limits of normal or greater (P = .03). CONCLUSIONS: The LTBI completion rates were high for the INH RPT regimen, with few inmates discontinuing because of signs or symptoms related to treatment. This regimen also has practical advantages to aid in treatment completion in the correctional setting and can be considered a viable alternative to standard LTBI regimens. PMID- 30024494 TI - High loss to follow-up of children on antiretroviral treatment in a primary care HIV clinic in Johannesburg, South Africa. AB - Outcomes of HIV-infected children have improved dramatically over the past decade, but are undermined by patient loss to follow-up (LTFU). We assessed patterns of LTFU among HIV-infected children receiving antiretroviral treatment (ART) at a large inner-city HIV clinic in Johannesburg, South Africa between 2005 and 2014.Demographic and clinical data were extracted from clinic records of children under 12 years. Differences between characteristics of children retained in care and LTFU were assessed using Wilcoxon rank sum tests or Pearson chi tests. Cox proportional hazard models then identified characteristics associated with LTFU.Of 135 children, the median age at ART initiation was 21.5 months (IQR: 6.3-47.7) with a median follow-up time of 3.3 years (IQR: 1.4-5.0). The incidence rate of LTFU was 10.8 per 100 person-years (95% CI: 8.2-14.4); cumulatively 36% of children were LTFU. Almost a third (n = 39) of children missed a clinic visit, but then returned to care; 77% of these were eventually LTFU. In total, 18% of children had elevated viral loads after 6 or more months of ART. Older age at ART initiation (18-59 months: aHR 1.6, 95% CI: 3.9-14.2) and ever missing a clinic visit (aHR 7.4 95% CI: 3.9-14.2) were independent predictors of LTFU.High rates of LTFU were observed in this primary care clinic. Risks for LTFU included older age (>18 months old) and missed clinic visits. Identifying children who miss scheduled visits and developing strategies directed at retaining them in care is critical to improving long-term pediatric HIV outcomes. PMID- 30024495 TI - Clinical significance of matrix metalloproteinase-2 in endometrial cancer: A systematic review and meta-analysis. AB - BACKGROUND: Matrix metalloproteinase-2 (MMP-2), a member of the zinc-dependent metalloproteinase gene family, plays a vital role in cancer invasion, metastasis, and progression. This systematic review and meta-analysis aims to explore the clinical significance of MMP-2 expression in endometrial cancer. METHODS: PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were systematically searched up to September 30, 2017, supplemented by manual searches of bibliographies. Two reviewers independently identified articles, extracted data, assessed quality, and cross-checked the results. Meta-analysis was conducted to explore the difference in the positive rate of MMP-2 expression between patients with endometrial cancer and those with endometriosis or normal endometrium, and to investigate the associations of MMP-2 expression with clinicopathologic characteristics of patients with endometrial cancer. Weighted mean differences and risk ratios (RRs) with 95% confidence interval (CI) were calculated for continuous and dichotomous variables, respectively. RESULTS: Totally 20 studies were selected for this systematic review and meta-analysis. Compared with those with endometriosis or normal endometria, the positive rate of MMP-2 expression is significantly higher in patients with endometrial cancer (RR = 2.31, 95% CI: 1.78-3.00, P < .01). MMP-2 expression was significantly associated with Federation of Gynecology and Obstetrics stage (RR = 1.19, 95% CI: 1.09-1.31, P < .01), histologic grade (RR = 1.10, 95% CI: 1.01-1.19, P = .02), lymph node metastasis (RR = 1.32, 95% CI: 1.15-1.51, P < .01), and myometrial invasion (RR = 1.25, 95% CI: 1.12-1.38, P < .01). CONCLUSION: The results showed that MMP-2 was expressed in high percentage of endometrial cancer and its expression may be associated closely with clinical stage, and tumor invasion and metastasis, indicating that MMP-2 overexpression may serve as a predictive factor for poor prognosis of endometrial cancer. PMID- 30024496 TI - Mechanism of cognitive impairment in chronic patients with putaminal hemorrhage: A diffusion tensor tractography. AB - It is not clear whether the fornix and cingulum are involved in cognition after putaminal hemorrhage (PH). We investigated structural changes and differences of the neural tracts, and the relationship between the integrity of the neural tracts and cognition not only at the affected but also at the unaffected side.Sixteen patients with left chronic putaminal hemorrhage and 20 healthy volunteers were enrolled. Using diffusion tensor tractography (DTT), we compared fiber number (FN), fractional anisotropy (FA), and apparent diffusion coefficient (ADC) of the neural tracts between patient and control groups. The relationship between the neural tract parameters and neuropsychological results was also analyzed.The left fornix FN was significantly lower than the right fornix FN in the patient group. Except for the cingulum FA, the neural tracts parameters for both the affected and unaffected hemispheres differed significantly between the groups. The fornix FA and ADC at the affected side were significantly correlated with intelligence quotient (IQ), mini-mental status examination (MMSE), and short term memory. Interestingly, the fornix ADC at the unaffected side was significantly correlated with MMSE. However, none of the cingulum parameters was correlated with neuropsychological results.The fornix integrity is critical for cognitive impairment after putaminal hemorrhage. PMID- 30024497 TI - MiRNA-221 from tissue may predict the prognosis of patients with osteosarcoma. AB - This study was aimed to investigate the relationship between miR-221 expression and prognosis in patients with osteosarcoma.miR-221 expression in 69 osteosarcoma specimens and corresponding noncancer tissues were characterized by quantitative reverse transcription polymerase chain reaction. The associations of miR-221 expression with clinicopathologic factors and prognosis in patients with osteosarcoma were statistically analyzed.miR-221 expression in patients with osteosarcoma was significantly higher than in the corresponding noncancer tissues (P < .01). miR-221 overexpression was significantly associated with tumor stage, metastatic status, and response to chemotherapy pretreatment. Cox regression analysis revealed that miR-221expression, metastasis, and response to chemotherapy were independent prognostic indicators for osteosarcoma.miR-221 upregulation may predict clinical outcomes in patients with osteosarcoma. PMID- 30024498 TI - Antiarrhythmic drug-induced smell and taste disturbances: A case report and literature review. AB - RATIONALE: Metoprolol and amiodarone are common antiarrhythmic drugs used in clinics throughout the world. The taste and smell alterations induced by antiarrhythmic drugs remain uncommon throughout the world, with less than 10 reported cases. PATIENT CONCERNS: In this case report, we describe a case of a 73 year-old female, diagnosed with arrhythmias, was treated for metoprolol. At the third week of metoprolol treatment, the patient noticed a qualitative change in her ability to smell, also called dysosmia. After the metoprolol was tapered, her ability to smell was recovered. However, her arrhythmia was getting worse and the patient was given amiodarone. After using amiodarone for about 2 weeks, the patient felt hypogeusia, or loss of taste sensation. DIAGNOSES: The patient was diagnosed as dysosmia and taste disturbance induced by the antiarrhythmic drugs. INTERVENTIONS: After noticed the side effects of the antiarrhythmic drugs, we asked the patient to abandon the drugs and have a radiofrequency ablation. OUTCOMES: Her ability of smell and taste were recovered after withdrawing the antiarrhythmic drugs. Also, in the follow-up appointment, she reported no complaints of smell or taste anymore. LESSONS: These rare sensory disorders induced by anti-arrhythmic drugs were less documented in past literature. Our case report describes a patient with an arrhythmia who suffered reversible dysosmia and hypogeusia after taking metoprolol and amiodarone, respectively. We conclude that smell and taste disorders should be made aware to patients during the anti-arrhythmic treatment, helping to promote the safety of patients and drug compliance. PMID- 30024499 TI - Hemophilic arthropathy in a patient with multi-joint replacement: A case report and literature review. AB - RATIONALE: Hemophilic arthropathy (HA) is a crucial morbidity and a major cause of joint pain and disability in patients with hemophilia A. Surgical methods, such as total joint arthroplasty, are of vital importance for end-stage HA treatment, but the feasibility and effects of multi-joint replacement surgery remain debatable. PATIENT CONCERNS: A 24-year-old patient with advanced HA presented multiple joint pain. Physical examination revealed joint tenderness, swelling, and limited activity. Radiographs revealed bilateral knee joints and left elbow joint damage with joint space narrowing, articular facet erosion, and bone deformation. DIAGNOSES: The patient was diagnosed with hemophilic arthropathy with multi-joint lesions. INTERVENTIONS: The key points of this case include arthropathy in multiple joints and the management of simultaneous total multi-joint arthroplasty. We performed bilateral total knee arthroplasty and total left elbow arthroplasty simultaneously after adequate preparations. Special attention was paid to factor VIII infusion, hemorrhage control, and other safety precautions perioperatively. OUTCOMES: After the surgery, no complications, such as infection or aseptic loosening, occurred, and the joints functioned well at follow-up. LESSONS: The surgical outcome and safety of multi-joint replacement for HA are attested. Simultaneous multi-joint arthroplasty can ameliorate the quality of life for patients with hemophilia A. PMID- 30024500 TI - Gemstone spectral imaging in lung cancer: A preliminary study. AB - The present study aimed to evaluate the application of gemstone spectral imaging (GSI) for multi-parameter quantitative measurement in lung cancer.The study retrospectively enrolled 30 patients with lung cancer who underwent chest contrast enhanced CT scan with GSI mode. The GSI viewer was used for image display and data analysis. Optimal energy value, CT values at 40 keV, 70 keV and optimal energy level, spectral curve slope, effective atomic number (Zeff), iodine concentration (IC), and water concentration (WC) at the region of interest were measured and analyzed by statistical methods.The optimal energy value for optimal contrast-to-noise ratio on plain scan, arterial phase and venous phase was 62.2 +/- 5.38 keV, 50.63 +/- 3.84 keV, and 52.5 +/- 3.7 keV, respectively. There were significant differences in CT values at different energy levels on each scan phase (P = .033). The spectral curve slope values among 40 to 70 keV, 40 to 100 keV, and 40 to 140 keV were significantly different (P < .001). No significant difference with the slope between arterial phase and venous phase at each energy level interval was observed. Zeff on plain scan, arterial phase, and venous phase was 7.75 +/- 0.15, 8.38 +/- 0.37, and 8.38 +/- 0.30, respectively. Positive correlation was observed among IC, normalized IC, and Zeff on enhanced scan.Multiparameter of GSI can be used for lung tumor lesion evaluation. Different parameters were correlated and provide multiple qualitative and quantitative information together. PMID- 30024501 TI - Transperitoneal versus extraperitoneal approach in laparoscopic radical prostatectomy: A meta-analysis. AB - BACKGROUND: To compare the transperitoneal approach with extraperitoneal approach in laparoscopic radical prostatectomy (LRP) (including pure and robotic-assisted LRP) using meta-analytic techniques. METHODS: Medline (PubMed), Embase, Ovid, CMB, and Cochrane databases were searched for studies that compared the transperitoneal and extraperitoneal approaches in LRP from January 2000 to January 2017. Outcomes included were operative time, operative bloods joss (milliliters), rate of transfusion, rate of open conversion, rate of intraoperative complications, rate of postoperative complications, and time of postoperative catheterization. RESULTS: Thirteen studies including 1674 patients were selected for the meta-analysis. 850 (50.8%) cases had undergone transperitoneal LRP (TLRP) and 824 (49.2%) cases had undergone the extraperitoneal LRP (ELRP). Comparison of operative time between the TLRP group and the ELRP group showed no significant differences (weighted mean difference [WMD] = 21.21,95%CI = -1.16-43.57, P = .06). No significant differences were observed in blood loss (WMD = -6.04, 95%CI = -43.38-31.29, P = .75) and the rate of transfusion (odds ratio [OR] = 1.03, 95%CI = 0.55-1.96, P = .92) between the 2 groups. No significant differences were observed for the rate of intraoperative complications (OR = 1.25, 95%CI = 0.57-2.21, P = .75) and the rate of open conversion (OR = 1.12, 95%CI = 0.32-4.97, P = .75). Significant differences were observed in the TLRP group compared with the ELRP group (OR = 1.69, 95%CI: 1.23 2.32, P = .001) regarding the rate of postoperative complications. CONCLUSIONS: Our meta-analysis findings revealed that the TLRP group showed no significant differences in most important indicators compared with ELRP. Moreover, TLRP showed higher rate of postoperative complications compared with ELRP. PMID- 30024502 TI - Intracranial tuberculous mass lesions treated with thalidomide in an immunocompetent child from a low tuberculosis endemic country: A case report. AB - RATIONALE: Tuberculous meningitis is a highly morbid, often fatal disease. PATIENT CONCERN: We describe a case of an Italian child. DIAGNOSES:: we diagnosed early a Tuberculous meningitis complicated by the occurrence of hydrocephalus, stroke, and paradoxical reaction with brain pseudo-abscesses. INTERVENTIONS: The child started readily a specific therapy associated with steroids and thalidomide was introduced few month later. OUTCOMES: the patient had a favorable outcome without neurologic sequelae. LESSONS: Despite the prompt specific anti-tubercular and adjuvant corticosteroid therapies, only the addition of thalidomide to the treatment allow to a favorable clinical outcome. PMID- 30024503 TI - Diagnosis and follow-up of patients with Hunter syndrome in Spain: A Delphi consensus. AB - Hunter syndrome or mucopolysaccharidosis type II (MPSII) is a progressive multisystem X-linked lysosomal storage disease caused by mutations in the IDS gene that shows a wide spectrum of clinical symptoms and severity. Idursulfase, a specific enzyme replacement therapy (ERT) for MPSII, has been available since 2007. ERT, along with symptomatic management of patients, is fundamental for improving patient prognosis and quality of life. The aims of this study were to investigate whether Spanish pediatricians who are experts in managing the disease agreed with current international guidelines regarding MPSII patient diagnosis and follow-up; and to reach a consensus regarding which items are essential for the diagnosis, follow-up, and treatment of these patients in Spain.An advisory panel of 5 experts from the Hunter Spanish Working Group reviewed key studies, developed a questionnaire based on a modified Delphi method, sent the questionnaire to selected experts, and reviewed the responses. The final questionnaire had 83 items in the following categories: diagnosis, ERT considerations after diagnosis, Periodic assessments, and ERT considerations during follow-up. A total of 85 experts were invited to participate; 28 (35%) responded and showed a strong consensus for most items. The advisory panel decided not to perform a second Delphi round. There was strong agreement (>3.1 median value; range, 1 to 4) for 43/56 items in Diagnosis, for 4/6 items in "ERT considerations after diagnosis," for 6/16 items in "Periodic assessments," and for 3/5 items in "ERT considerations during follow-up." Most responses were in agreement with international guidelines, and controversial items were discussed by the advisory panel. Based on the results, on the key studies, and on clinical experience and opinions, the panel developed and scheduled recommendations for the diagnosis and follow-up of patients with MPSII.An expert 5-person panel oversaw a Delphi survey of 28 pediatricians and reached a consensus on recommendations for the diagnosis and follow-up of MPSII patients. This document will help guide clinicians involved in the diagnosis, management, and treatment of MPSII. PMID- 30024504 TI - Mini-invasive treatment of a large pseudoaneurysm of the neck related to central venous catheter placement: A case report. AB - RATIONALE: Central venous catheter (CVC) placement, particularly in emergency setting, may be associated with significant morbidity and mortality. PATIENT CONCERNS: A 33-year old woman with suspected pulmonary embolism, developed a pseudoaneurysm of the neck three days after a CVC placement in the right internal jugular vein, determining compression to adjacent neck structures. DIAGNOSES: Computed tomography angiography and selective angiography demonstrated the presence of the pseudoaneurysm originating from the thyro-cervical trunk. INTERVENTIONS: The treatment was minimally invasive with endovascular exclusion first, and an open thrombectomy to resolve compressive syndrome two days later. OUTCOMES: The color Doppler ultrasound confirmed the complete exclusion of the pseudoaneurysm with patency of the thyroid artery. A comprehensive review of literature on the risk factors and management of the unintended artery puncture was included. LESSONS: A correct technique under ultrasound guidance may reduce the incidence of unintended arterial injury during CVC placement. In patients with suitable anatomy and unfit for open repair, a minimally invasive approach provides a safe alternative to open surgery with excellent results. PMID- 30024505 TI - Intrafascial nerve-sparing radical prostatectomy improves patients' postoperative continence recovery and erectile function: A pooled analysis based on available literatures. AB - BACKGROUND: Intrafascial nerve-sparing prostatectomy has been currently applied based on the updated anatomic understanding of periprostatic cavernous nerves, in order to provide patients better postoperative recovery of continence and potency. The aim of our study is to perform a pooled analysis of available literatures regarding the functional outcomes following intrafascial nerve sparing technique. METHODS: The authors performed database searches of articles published till October 2017 on PubMed using following keywords across the "title" and "abstract" field of the records: intrafascial, veil, curtain dissection, high anterior release, incremental nerve sparing, and radical prostatectomy. Fulfilled papers were screened and data were extracted independently by 3 reviewers. Main outcome was the postoperative continence and potency rate stratified by follow-up durations. Both 1-arm and comparative meta-analyses were performed and meta regression models were conducted to evaluate the confounding factors. RESULTS: Using the electronic search strategy, a total of 71 records were retrieved and 20 studies were finally included, of which 6 were surgical series and 14 were controlled studies. Our 1-arm meta-analysis summarized the pooled continence rates after intrafascial prostatectomy were 59.4%, 76.2%, 89.9%, and 92.2% at postoperative follow-up of 1, 3, 6, and 12 months, respectively. Regardless of the variance in potency definition, the pooled potency rates after intrafascial prostatectomy were 42.2%, 54.2%, and 72.2% at 3, 6, and 12 months, respectively. Comparative analysis showed that the intrafascial group offered better continence rates at 1, 3, and 6 months with an odds ratio (OR) of 2.38 (95% confidence interval [CI]: 1.73-3.26), 1.82 (95% CI: 1.18-2.82), and 2.19 (95% CI: 1.43-3.34) as compared with the interfascial group. Moreover, potency rate in the intrafascial group was higher at 12 months than in the interfascial group, with an OR of 2.44 (95% CI: 1.35-4.42). CONCLUSION: Based on the limited evidence, our study demonstrated that intrafascial nerve-sparing prostatectomy could provide patients with earlier recovery of continence and better erectile function compared with conventional interfascial approach, but physiological mechanisms about this technique still need further study. PMID- 30024506 TI - Pleomorphic rhabdomyosarcoma of the liver with a hepatic cyst in an adult: Case report and literature review. AB - RATIONALE: Rhabdomyosarcoma (RMS), a malignant tumor with striated muscle differentiation, is the most common type of soft-tissue sarcoma in children and adolescents, but rarely occurs in adults, and especially in human livers. Moreover, this disease has a very poor prognosis. Here we report a case of primary RMS of the liver in a 66-year-old woman. This case is rare with respect to the location and clinical course of the tumor. The tumor had enlarged rapidly, ruptured, and eventually caused the patient's death after a long history of a stable abdominal mass that indicated a hepatic cyst. PATIENT CONCERNS: Before admission, a patient with a 5-year history of an abdominal mass was admitted to another hospital with symptoms of aggravated epigastric pain for the past 10 days. She was diagnosed with a hepatic cyst that had ruptured and hemorrhaged and was infected. This initial diagnosis was based on operative and pathologic findings. DIAGNOSES: Pleomorphic RMS of the liver with a hepatic cyst was diagnosed and confirmed by imaging, surgery, and histopathological evaluation. INTERVENTIONS: Following admission, an emergency laparotomy was performed to treat the intra-abdominal hemorrhaging while further examinations were performed. Post-surgical histopathological evaluation found pleomorphic RMS tissue in the large mass that occupied the right lobe of the liver. No adjuvant chemotherapy was administered. OUTCOMES: The patient died from malnutrition and multiple organ failure 141 days after her initial admission. LESSONS: Rhabdomyosarcomas in the liver are highly malignant tumors; therefore, early diagnosis and timely surgical resection are necessary to improve a patient's prognosis. We recommend that greater attention should be paid to a differential diagnosis of RMS for patients with hepatic masses that have ruptured. Moreover, preoperative imaging studies and percutaneous biopsy would be helpful for making a more specific diagnosis, and adjuvant chemotherapy should be administered for further treatment and for the purposes of future research. PMID- 30024507 TI - Factors associated with surgical outcomes of cervical ossification of the posterior longitudinal ligament. AB - To investigate factors associated with surgical outcomes of cervical ossification of the posterior longitudinal ligament (OPLL). This retrospective study included patients (662 males and 251 females; mean age 55.8 years) with symptomatic OPLL. All patients had been diagnosed with OPLL based on cervical magnetic resonance imaging and computed tomography scans. Demographic, surgical outcome was measured using visual analog scale (VAS) and Japanese Orthopedic Association (JOA) scale scores. The results of our study indicated radicular pain was more common in segmental and circumscribe OPLL subtypes (P < 0.05). An anterior approach was favored in patients with less than 3 involved vertebral levels (P < 0.05). All surgical methods showed good outcomes (P < 0.05). Continuous and mixed OPLL subtypes showed worse surgical outcome with higher VAS and JOA scores (P < 0.05). Laminoplasty and anterior cervical discectomy and fusion were significantly associated with a higher recovery rate (P < 0.05). Among these patients, there were more complications with the anterior approach (P < 0.05). Male gender, open door laminoplasty ipsilateral, and ipsilateral-to-symptom-side opening were associated with postoperative C5 palsy (P < 0.05). Cervical OPLL may cause myelopathy, surgery is a safe and effective treatment for OPLL. There were no differences in clinical outcome according to surgical type, but complication rates varied depending on sex and surgical approach to symptom. PMID- 30024508 TI - Predictors of dysfunction and health-related quality of life in the flexion pattern subgroup of patients with chronic lower back pain: The STROBE study. AB - Findings about predictors of chronic lower-back pain (CLBP) were inconsistent and inconclusive in previous studies because patients with CLBP are heterogeneous. Subgrouping patients with CLBP, according to a CLBP classification system, might thus clarify the research findings. CLBP in the direction of lumbar flexion movement, that is, the flexion pattern, is common in clinical situations. Therefore, the purpose of this study was to determine the predictors of dysfunction (pain, disability) and health-related quality of life in the flexion pattern subgroup of patients with CLBP.A cross-sectional study of prospectively collected data. One hundred eight subjects in the flexion pattern subgroup of CLBP. Thirteen variables were measured: the visual analog scale (VAS), the Oswestry Disability Index (ODI), the Short Form-36 (SF-36), the Beck Depression Inventory (BDI), hip internal rotation range of motion, hip flexion range of motion, knee extension range of motion, knee extension with dorsiflexion range of motion, ratio forward flexion, knee extension strength, hip extension strength, hip flexion strength, and lumbopelvic stability.The models for predictors of lower-back pain in the CLBP flexion pattern subgroup included knee extension and the BDI as predictor variables that accounted for 8.1% of the variance in the VAS (P < .05); predictors for disability included the BDI, age, and hip flexion strength, which accounted for 21.2% of the variance in the ODI (P < .05); predictors for health-related quality of life included the BDI, sex, knee extension with dorsiflexion range of motion, and age, which accounted for 38.8% of the variance in the SF-36 (P < .05) in multiple regression models with a stepwise selection procedure.The current results suggest that knee extension, the BDI, age, hip flexion strength, knee extension with dorsiflexion, and sex should be considered when determining appropriate prediction, prevention, and intervention in the flexion pattern subgroup of patients with CLBP. PMID- 30024509 TI - The effect of marital status on the survival of patients with bladder urothelial carcinoma: A SEER database analysis. AB - To identify whether marital status is associated with survival in patients with bladder urothelial carcinoma (UC). Using Surveillance, Epidemiology, and End Results population-based data, 133,846 patients diagnosed with bladder UC between 1988 and 2009 were identified. Kaplan-Meier methods and multivariable Cox regression models were used for survival analyses and evaluation of the association between marital status and survival, after controlling for gender, age, race, primary site, tumor (topography), lymph node, metastasis stage, pathological grading, and surgery. Patients in the married group had a higher proportion of men within group comparisons, more often white, older, earlier clinical stage at diagnosis, surgical treatment, all of which were statistically significant (P < .001). Widowed patients had the worst bladder UC cause-specific survival (CSS) compared with married, never married, and so on groups classified by stage and grade. The 5-year CSS of widowed patients compared with that of married patients was, respectively, all (P < .001), 89.8% versus 95.8% at noninvasive papillary carcinoma stage, 84.1% versus 91.6% at occur in situ stage, 74.3% versus 86.1% at I stage, 41.2% versus 61.6% at II stage, 39.2 versus 52.5% at III stage, and 8.8% versus 17.0% at IV stage. Widowed patients tend to have a significantly higher risk of bladder-cancer-specific mortality. Marital status was relevant to improved CSS in patients with bladder UC. PMID- 30024510 TI - Serum gamma-glutamyl transferase is a predictor of mortality in patients with acute myocardial infarction. AB - Gamma-glutamyl transferase (GGT) is involved in the pathogenesis of atherosclerosis and has been associated with adverse cardiovascular outcomes in patients with ischemic heart disease. However, the association between GGT and long-term mortality has not been studied in patients with acute myocardial infarction (AMI).A total of 2239 AMI patients for whom serum GGT values were available and who underwent percutaneous coronary intervention (PCI) were enrolled in the COREA-AMI (CardiOvascular Risk and idEntificAtion of potential high-risk population in Korean patients with AMI) registry. Patients with acute liver injury were excluded. Patients were classified into 2 groups according to normal (n = 1983) or elevated (n = 256) levels of serum GGT. The primary clinical outcome was all-cause mortality. The secondary outcome was cardiac death and recurrent non-fatal myocardial infarction (MI).The median follow-up period was 3.7 years, and both groups had similar characteristics. Patients with elevated GGT had significantly higher all-cause mortality compared to patients with normal GGT (21.9% vs. 14.4%, P = .001). The multivariate Cox proportional hazards model showed that elevated serum GGT level was independently correlated with mortality (hazard ratio 2.12[1.44-3.11]; P < .001). Although elevated serum GGT was independently associated with long-term mortality after 30 days after PCI, there was no association within 30 days after PCI. Elevated GGT was also associated with death of cardiac causes with statistical significance. In the subgroup analysis, stronger associations were observed in the young and female patients and in patients who had ST-segment elevation MI and preserved left ventricular ejection fraction at the first echocardiography after the indexed PCI.Elevated serum GGT is an independent predictor of long-term mortality in AMI patients. PMID- 30024511 TI - Using the recurrence risk score by Joensuu to assess patients with gastrointestinal stromal tumor treated with adjuvant imatinib: A retrospective cohort study. AB - In 2014, Joensuu and colleagues devised the first recurrence risk score (RRS) to identify the risk factors for gastrointestinal stromal tumor (GIST) recurrence. However, there are scarce data available on RRS effectiveness and efficiency. Therefore, we retrospectively analyzed clinical data to validate Joensuu's RRS in patients treated with adjuvant imatinib.In this retrospective cohort study, data were collected from patients with GIST who were treated with adjuvant imatinib between December 2005 and May 2017 in the West China Hospital. The study consisted of 137 patients, after application of inclusion and exclusion criteria. Recurrence-free survival (RFS) was the primary end point.The RRSs for 137 patients were divided into 3 groups: low (n = 46), medium (n = 48), and high (n = 43). The RFSs of the 3 groups were significantly different (P < .001). In patients who received adjuvant imatinib for <36 months, the RFS difference was also significant (P < .001), and the result was similar in patients treated with adjuvant imatinib for >=36 months (P = .03). The area under the curve of the RRS was 0.84 ([95% confidence interval] 0.76-0.92, P < .001), suggesting that the RRS method could accurately assess recurrence risks for patients with GIST who were treated with adjuvant imatinib.It is appropriate to apply the RRS method to assess recurrence risks for patients with GIST who were treated with adjuvant imatinib. A longer adjuvant imatinib duration is recommended for high-risk patients with GIST. It is also important to identify a more effective treatment for patients who are resistant to imatinib. PMID- 30024512 TI - Prostaglandin E1 administration for prevention of contrast-induced acute kidney injury: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: PGE1 has been studied for prevention of CI-AKI in several RCTs and significant heterogeneous results exist. METHODS: We searched PubMed, EMBase, and Cochrane Central Register of Controlled Trials up to December 26, 2017 for RCTs comparing PGE1 with placebo or other active medications for the prevention of CI AKI in patients. Odds ratio and 95% confidence interval (CI) were used for pooling dichotomous data, while mean difference and 95% confidence interval for pooling continuous data. RESULTS: Seven RCTs involving 1760 patients were included in this meta-analysis. All these 7 trials reported the incidence of CI AKI and compared with placebo or other treatment options, PGE1 was associated with a reduced risk of CI-AKI (OR: 0.38, 95% CI: 0.28-0.53; P < .001) and only a trend for lower post procedure serum creatinine (Scr) levels compared with control groups at 48 hours (MD: -0.03 mg/dL, 95% CI: -0.08 to 0.02 mg/dL; P = .25; 6 trials combined). But the postprocedure Scr levels were significantly reduced in PGE1 groups compared with control groups at 72 hours (MD: -0.07 mg/dL, 95% CI: -0.11 to -0.04 mg/dL; P < .001; 4 trials combined). We also meta-analyzed the postprocedure cystatin C (CysC) at 24 and 48 hours with 2 trials. There were lower postprocedure CysC levels in PGE1 groups than those in control groups (MD: 0.18 mg/L, 95% CI: -0.33 to -0.03 mg/L; P = .02 at 24 hours and MD: -0.14 mg/L, 95% CI: -0.23 to -0.06 mg/L; P = .001 at 48 hours). CONCLUSIONS: PGE1 provides effective nephroprotection against CI-AKI and may act as a part of effective prophylactic pharmacological regimens. PMID- 30024513 TI - Genetic association of CTLA4 gene with polycystic ovary syndrome in the Chinese Han population. AB - The autoimmune and gene etiology are implicated in the pathogenesis of polycystic ovary syndrome (PCOS). The cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is important for negative regulation of T-cell activation, and CTLA4 gene has been identified as a risk factor for some autoimmune diseases. However, none studies have been performed about the association between PCOS and the CTLA4 gene before. Here, we aimed to investigate the association of CTLA4 with PCOS in the Chinese Han population though a case-control association analysis of 606 individuals. The tagging variants rs733618 and rs231775 in the CTLA4 gene were detected using polymerase chain reaction-denaturing gradient gel electrophoresis method. Further analysis found the rs733618 was significantly different between case and control groups in either genotypic or allelic distribution (P = .01 and .009, respectively) while rs231775 not. Moreover, rs733618 was significantly associated with higher body mass index in the dominant model (P = .003) and with higher waist/hip ratio in the recessive model (P = .02). Interestingly, rs733618 was only found to have significant association with homeostatic model assessment for insulin resistance (HOMA-IR) in both dominant and recessive model (P = .009 and .0065, respectively). This is the first study to investigate the association of CTLA4 gene with PCOS. The CTLA4 gene is suggested to correlated with PCOS, and influence PCOS through regulating obesity and the HOMA-IR in a novel way. PMID- 30024514 TI - Coronary angiography using second-generation dual source computed tomography: Feasibility of low dose and low flow rate to achieve appropriate individual contrast enhancement using a test bolus-based contrast medium protocol-A CONSORT compliant article. AB - Improved contrast enhancement consistency can be achieved using an individualized contrast media (CM) protocol. This study aimed to assess the feasibility of a low dose, low-flow rate CM protocol to achieve appropriate individual contrast enhancement using a newly advocated individualized test bolus-based protocol for second-generation dual-source computed tomography angiography.CM containing iodine (370 mg I/mL) was used in this study. A CM flow rate of 3.5 mL/s for patients with a body mass index (BMI) <25.0 kg/m, and 4.5 mL/s for those with BMI >=25.0 kg/m was used in group 1 (n = 189). An individualized test-bolus based contrast injection protocol was then derived from the information gained from the test bolus and coronary enhancements in group 1. The proposed individualized test bolus based CM injection protocol was applied in group 2 (n = 219). Ascending aortic attenuations (AAo) were measured and compared with both groups.The contrast enhancement consistency of AAo in group 2 improved significantly (31.8 vs 56.3 Hounsfield units [HU]; P < .001). The number of patients in group 2 with a contrast flow rate <=3 mL/s was 63 (28.8%), with 77 (35.2%) using a contrast dose <=40 mL. In group 2, no significant differences in mean AAo were found among subgroups with contrast flow rates <=3.0, 3.1 to 4.0, 4.1 to 5.0 and >5.0 mL/s (351, 344, 346, and 348 HU, respectively), nor among subgroups with contrast doses <=40, 41 to 50, 51 to 60, and >60 mL (349, 345, 344, and 350 HU, respectively).Improved individual contrast enhancement uniformity can be achieved using an individualized CM protocol tailored to a test bolus. Approximately, one third of patients received CM at a flow rate of no more than 3 mL/s and a total dose of no more than 40 mL. PMID- 30024515 TI - Long-term follow up of patients with obscure gastrointestinal bleeding examined with video capsule endoscopy. AB - BACKGROUND: Video capsule endoscopy (VCE) is a commonly used test for the evaluation of obscure gastrointestinal bleeding. However, long-term outcomes of patients undergoing VCE are unclear. AIMS: To evaluate the long-term outcomes in patients undergoing VCE for suspected obscure bleeding including iron deficiency anemia (IDA), and determine the need for additional intervention for persistence or recurrence of symptoms in patients with a diagnostic as well as non-diagnostic VCE. DESIGN: Retrospective cohort study within a large county hospital system. METHODS: We collected information on indications and findings of VCE and outcomes including further testing, bleeding, and hemoglobin (Hgb) at last follow-up through structured review of the electronic health records. VCE findings were classified as active bleeding or high potential for bleeding (P2), intermediate potential (P1) or without any disruption of the mucosa, and no potential for bleeding (P0). We compared demographic and clinical characteristics between patients with and without normal Hgb at the time of last follow up. RESULTS: We examined 116 patients who underwent VCEs performed for obscure gastrointestinal (GI) bleeding during 2010 to 2012 with mean duration of follow up after VCE completion of 571 days (standard deviation [SD] = 248). Abnormal VCE findings (37.9% for P1 lesions, 44.8% for P2 lesions) were seen in 106 (87.9%) patients. Additional diagnostic testing was performed in 55/116 (47.4%) (67.7% GI procedures). Hgb was restored to normal range in 59/116 (50.9%) by end of follow up which were attributed to iron supplementation and/or discontinuation of non steroidal anti-inflammatory drugs (NSAIDs) in a majority. Twenty six of 116 patients experienced rebleeding (22.4%). CONCLUSIONS: The diagnostic yield of VCE is high among patients with obscure GI bleeding. More than 50% of patients achieve normal Hgb in the long term with conservative measures such as iron supplementation and the discontinuation of NSAIDs. PMID- 30024517 TI - The diagnostic accuracy of a real-time optoelectronic device in cervical cancer screening: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: This study aimed to assess the diagnostic accuracy of a real-time optoelectronic device (TruScreen) for uterine cervical cancer screening. METHODS: On the basis of Preferred Reporting Items for Systematic Reviews and Meta analyses (the PRISMA statement) we performed this systematic review and meta analysis. We searched PubMed, EMBASE, the Cochrane Library, CNKI, CBM, and WanFang Data using medical subject headings (MeSH) and text words. Title/abstract screening, full text check, data extraction, and methodological quality assessment (with the QUADAS-2 tool) were performed by 2 reviewers independently. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), the summary receiver operator characteristic curve, and the area under the curve (AUC) were analyzed with Meta-DiSc software. Statistical heterogeneity was evaluated by Cochran's Q test and I, meta-regression was conducted based on patient type, and the possibility of publication bias was evaluated using Deeks funnel plot in Stata software. RESULTS: Of 293 publications, nine met our inclusion criteria. These studies included a total of 2730 patients and 567 cervical intraepithelial neoplasias. The pooled test characteristics for the TruScreen were as follows: sensitivity 76% (95% CI, 73-80%), specificity 69% (95% CI, 67%-71%), PLR 2.30 (95% CI, 1.59-3.33), and NLR 0.34 (95% CI, 0.23-0.51). The corresponding pooled DOR was 7.03 (95% CI, 3.40-14.55). The AUC was 0.7859 (Q = 0.7236). CONCLUSION: The diagnostic accuracy of the TruScreen device is moderately good. The study findings are based on Chinese studies only and could not be generalized to other populations. PMID- 30024518 TI - Comparison of clinical and radiological outcomes between modified Gallie graft fusion-wiring technique and posterior cervical screw constructs for Type II odontoid fractures. AB - The aim of this study was to compare clinical and radiological outcomes between modified Gallie graft fusion-wiring technique and posterior cervical screw constructs for Type II odontoid fractures, and hope to provide references in decision making and surgical planning for both spinal surgeons and surgically treated patients.This is a retrospective study. By retrieving the medical records from January 2005 to July 2015 in our hospital, 53 Type II odontoid fracture patients were reviewed. According to the instrumentation type, patients were divided into 2 groups: Wiring group and Screw group. Three categorized factors were analyzed statistically: patient characteristics: age, body mass index, preoperative neurological status, duration, complicated injuries; surgical variables: surgery time, blood loss, vertebral artery injury, spinal cord or nerve root injury, major systemic complications, wound infection, pain at the bone donor area, instrumentation failure, revision rate; and radiographic parameters: preoperative and final follow-up data of C0-2 curvature, C2-7 curvature, C2-C7 sagittal vertical axis, C7 slope, fracture classification, separation, and displacement of odontoid fracture, fusion rate. An additional comparison of surgical outcomes was done, including patient satisfaction, visual analog scale score for neck pain, neck stiffness, medical expense.There was no statistically significant difference between the 2 groups in patient characteristics of age, sex, body mass index, preoperative neurological status, duration, and complicated injuries. No statistically significant difference was noted in surgical variables of blood loss, vertebral artery injury, spinal cord or nerve root injury, major systemic complications, wound infection, bone harvested zone pain, instrumentation failure, revision rate. The surgery time was shorter in Wiring group than that in Screw group, with a statistically significant difference. We noted no significant difference between the 2 groups when comparing radiographic parameters of preoperative and final follow-up data of C0-2 curvature, C2-C7 sagittal vertical axis, fracture classification, the separation and displacement of odontoid fracture, and fusion rate. Although we noted no significant difference in preoperative C2-7 curvature and C7 slope, the final follow-up data showed that C2-7 curvature and C7 slope were smaller in Wiring group than that in Screw group. We noted no significant difference in visual analog scale score, neck stiffness, and neurological status at final follow-up. The medical expense was less in Wiring group; the patient satisfaction was lower in the Wiring group than that in the Screw group.The modified Gallie graft fusion-wiring technique provided solid fusion and stabilization for patients with Type II odontoid fractures, Gallie graft fusion-wiring resulted in less surgery time, less medical expense, but lower patient satisfaction when compared with the posterior cervical screw constructs. PMID- 30024519 TI - Atypical CT findings of pulmonary sarcoidosis: A case report. AB - RATIONALE: Pulmonary involvement occurs in about 90% of patients with sarcoidosis. However, delayed diagnosis sometimes occurs due to atypical thoracic imaging findings. PATIENT CONCERNS: A 52-year-old woman presented with recurrent uveitis and fever of unknown origin. She had been admitted to the hospital due to fever, but its cause was not determined. DIAGNOSES: Chest computed tomography (CT) revealed a solitary pulmonary nodule and an enlarged right axillary lymph node. The nodule had showed an interval growth from 0.7 cm to 1.1 cm over 18 months, when compared to the previous chest CT. Mosaic attenuation was also observed. INTERVENTIONS: The patient underwent thoracoscopic wedge resection of the nodule and excisional biopsy of the enlarged lymph node to exclude malignancy and non-caseating granulomas consistent with sarcoidosis was confirmed. OUTCOMES: Medical treatment with prednisolone and azathioprine was administered. Fever and uveitis no longer recurred after 6 months of medication. We demonstrated that sarcoidosis shows only atypical pulmonary imaging findings, with an enlarged solitary nodule, an axillary lymphadenopathy, and mosaic attenuation, mimicking a malignancy. LESSONS: Awareness on atypical CT manifestations that are correlated with pathologic findings may be helpful for early diagnosis of sarcoidosis. PMID- 30024516 TI - Serum adiponectin in breast cancer: A meta-analysis. AB - BACKGROUND: Accumulating data have found that adiponectin is involved in development of breast cancer (BC). However, these results were inconsistent. METHOD: A systematic search in PubMed, Embase, ISI Web of Science, and Chinese National Knowledge Infrastructure databases were conducted up to October 1, 2017. The standardized mean difference (SMD) with 95% confidence interval was applied to pool the effect size. RESULTS: Finally, 31 eligible studies were included in this meta-analysis. The overall results indicated that serum adiponectin levels in BC cases were significantly lower than the controls (SMD = -0.33, P < 0.0001). As for the subgroup analysis of menstrual status, serum adiponectin levels were significantly lower in pre- and postmenopausal BC cases. Moreover, the subgroup analysis by ethnicity in pre- and postmenopausal group indicated an inverse association between adiponectin levels and BC risk in Asian population, but not in Caucasian population. CONCLUSION: The present meta-analysis suggests that low serum adiponectin concentration may be associated with an increased BC risk in premenopausal and postmenopausal women, especially among Asians. Adiponectin may serve as a biomarker of BC risk and help to identify subjects at high risk for BC development. PMID- 30024520 TI - Recurrent spontaneous hepatic rupture in pregnancy: A case report. AB - RATIONALE: Spontaneous and repeated hepatic ruptures caused by hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are uncommon but life threatening conditions that rarely occur early in the second trimester of pregnancy. PATIENT CONCERNS: We describe a patient who experienced spontaneous hepatic ruptures in the absence of hypertension during the early second trimesters of both her first and second pregnancies. DIAGNOSES: A 34-year-old multiparous woman without hypertension was admitted at 21 weeks' gestation because of a spontaneous hepatic rupture with hemoperitoneum. Four years previously, the patient had undergone an exploratory laparotomy during her first pregnancy that involved the ligation of bleeders, because a hepatic capsule rupture had caused hemoperitoneum development. INTERVENTIONS: Unlike the first pregnancy, she was managed nonsurgically and conservatively during the second pregnancy, and she underwent frequent laboratory analyses and magnetic resonance imaging follow-up. On day 11 of the patient's hospital admission, we decided to deliver the baby at 23 weeks' gestation, because her condition had deteriorated. OUTCOMES: Non-surgical management improved the patient's outcome, and the baby was born alive, even though the pregnancy was in the early second trimester and the maternal condition was deteriorating rapidly. LESSONS: HELLP syndrome without hypertension and the recurrence of an intrahepatic rupture at an extremely premature gestational age are rare. This patient's findings suggested HELLP syndrome, which was subsequently diagnosed. This patient's clinical course highlights the difficult decisions made by clinicians for mothers and fetuses. PMID- 30024521 TI - Epidemiological study on accidental poisonings in children from northeast romania. AB - Accidental poisonongs are an important cause of morbidity and even mortality, especially in young children.We performed a retrospective observational study on a group of children admitted at the Regional Center of Toxicology at the Children's Emergency Hospital "St. Mary" Iasi with accidental intoxication within a period of 3 years. Data were collected from patients' files and processed with a SPPS 18.0 database and a 95% confidence interval.During this period, 480 children were admitted with accidental intoxication. Most of them were in the age group of 1 to 2 years (120 cases-24.3%). The etiology of these intoxications was dominated by nonmedication (67%), the most frequent being household chemicals, carbon monoxide, and insecticides. Accidental drug intoxication accounted for 33% of the cases, the main drugs involved being anticonvulsants, nonsteroidal anti inflammatory drugs, and paracetamol. The mortality caused by accidental poisoning was 0.62%, all deaths owing to nonmedication intoxication.Identifying the epidemiological and evolutionary aspects of accidental intoxications must be a major objective for the health system, given that this pathology can be at least partially avoided and its incidence and severity may be reduced using appropriate measures. PMID- 30024522 TI - Prenatal limb defects: Epidemiologic characteristics and an epidemiologic analysis of risk factors. AB - To analyze prenatal ultrasound data for fetal limb deformities in high-risk pregnant women and the risk factors for prenatal limb defects in high-risk pregnant women.This was a retrospective study of high-risk pregnant women at the multidisciplinary consultation center from January 2006 to December 2015. When deformities were definitively diagnosed in the first trimester by ultrasound, patients were recommended to undergo an abortion, and fetal abnormalities were confirmed by pathological examination (both gross anatomic examinations and fetal chromosome and genetic tests). The risk factors for fetal limb deformities and other congenital malformations were analyzed by multifactor analysis.Of the 4088 fetuses recorded, 144 (3.52%) were diagnosed with limb abnormalities. The abnormalities included 70 (48.61%) clubfoot/clubhand cases, with 5 polydactyly, 5 syndactyly, 4 flexion toe, 4 split hand/foot malformation, 3 overlapping fingers, and 49 congenital talipes equinovarus. A total of 6 (4.17%) and 13 (9.02%) fetuses had phocomelia and imperfect osteogenesis, respectively; 22 (15.28%) cases showed achondrogenesis; 19 (13.19%) and 12 (8.33%) had partial limb deletion absence and joint movement malfunction, respectively.In the high-risk population with limb deformities (144 patients), 19 (13.19%) were >=35 years old, 6 (4.17%) had family history of congenital malformations, 14 (9.72%) had abnormal reproductive history, 21 (14.6%) had harmful chemical exposure, 6 (4.2%) had early TORCH infections, 16 (11.1%) had gestational diabetes, 9 (6.3%) had hypertension, 3 (2.1%) took glucocorticoid, 9 (6.3%) took sedatives.In the high risk population with other congenital malformations except limb deformities (3766 patients), 144 pregnant women were randomly selected. In the high-risk population with other congenital malformations (144 patients), 9 (6.25%) were >=35 years old, 7 (4.86%) had family history of congenital malformations, 10 (6.94%) had abnormal reproductive history, 22 (15.28%) had harmful chemical exposure, 5 (3.47%) had early TORCH infections, 12 (8.33%) had gestational diabetes, 11 (7.64%) had hypertension, 4 (2.78%) took glucocorticoid, 11 (7.64%) took sedatives.Ultrasound can provide adequate evidence for fetal limb deformities evaluation in most patients. Fetal limb deformity cases showed a significantly higher rate than other congenital malformations for advanced maternal age (>=35 years old). PMID- 30024523 TI - Gastrointestinal endoscopy satisfaction questionnaire is a valid tool to measure patient satisfaction in Asian country. AB - Patient satisfaction is a key quality indicator of gastrointestinal endoscopy (GIE). The gastrointestinal endoscopy satisfaction questionnaire (GESQ) was recently developed to assess patient satisfaction undergoing GIE in Europe; however, it was not validated in Asian countries. We aimed to translate and validate the GESQ in Korea and identify predictors for patient satisfaction during GIE.Translation of the original GESQ was performed according to accepted linguistic validation guidelines. Between March 2016 and July 2016, 350 consecutive patients were asked to complete a GESQ after GIE at Kyung Hee University Hospital. Total sum of scores was transformed from 0 to 100 by the formula: (Score-lowest possible/Score range) * 100.Exploratory and confirmatory factor analyses for construct validation reconfirmed that 4 factors were extracted from the Korean GESQ. Internal consistency reliability was acceptable with an overall Cronbach alpha score of 0.87. Female and nonsmoker were associated with less satisfaction with GIE (P = .021 and .006, respectively). Other factors, including age, alcohol, education or economic level, sedative endoscopy, gastroscopy with or without colonoscopy, experience of previous endoscopy, and additional examinations such as biopsy, were not associated with patient satisfaction during GIE.The Korean version of the GESQ was a valid and acceptable tool to measure satisfaction in patients who had undergone a GIE in Korea. Patient satisfaction measurement could contribute to systematic improvement of qualified GIE. PMID- 30024524 TI - Neuromuscular electrical stimulation as an adjunctive therapy to drotaverine hydrochloride for treating patients with diarrhea-predominant irritable bowel syndrome: A retrospective study. AB - This retrospective study investigated the effectiveness and safety of neuromuscular electrical stimulation (NMES) as an adjunctive therapy to drotaverine hydrochloride (DHC) in patients with diarrhea-predominant irritable bowel syndrome (BP-IBS).A total of 108 patient cases with BP-IBS were included in this study. Of these, 54 cases were assigned to a treatment group and received NMES and DHC, whereas the other 54 subjects were assigned to a control group and underwent DHC alone. All patients were treated for a total of 4 weeks. Primary outcomes were measured by the visual analog scale (VAS), and average weekly stool frequency. Secondary outcome was measured by the Bristol scale. In addition, adverse events were documented. All outcome measurements were analyzed before and after 4-week treatment.Patients in the treatment group did not show better effectiveness in VAS (P = .14), and average weekly stool frequency (P = .42), as well as the Bristol scale (P = .71), compared with the patients in the control group. Moreover, no significant differences in adverse events were found between 2 groups.The results of this study showed that NMES as an adjunctive therapy to DHC may be not efficacious for patients with BP-IBS after 4-week treatment. PMID- 30024525 TI - Disseminated histoplasmosis in an immunocompetent patient from an endemic area: A case report. AB - RATIONALE: Disseminated histoplasmosis is a rare fungal infection and most documented cases are in immunocompromised individuals such as those with acquired immunodeficiency syndrome. However, histoplasmosis easily goes unrecognized in immunocompetent populations. PATIENT CONCERNS: We report a rare case of histoplasmosis that was manifested as persistent fever and abnormal liver function in a 45-year-old immunocompetent female from Jiangsu Province. DIAGNOSES: Investigations revealed anemia and thrombocytopenia. Giemsa-stained bone marrow aspirate showed yeast-like cells, suggestive of Histoplasma capsulatum. Wright-stained bone marrow aspirate confirmed the diagnosis. INTERVENTIONS: The patient was treated by amphotericin B (amphotericin B liposome) and itraconazole. OUTCOMES: Our patient responded well to the treatment. LESSONS: Emphasizing histoplasmosis as a cause of fever of unknown origin in an immunocompetent patient, this case highlights the need for an index of suspicion and the importance of prompt diagnosis, as any delay of treatment can be life threatening. PMID- 30024526 TI - Neuroendocrine carcinoma in the extrahepatic biliary tract: A case report and literature review. AB - RATIONALE: Neuroendocrine carcinoma (NEC) arising from the extrahepatic biliary tracts (EHBTs) is rare, and thus its management and prognosis remain poorly clarified. We herein describe a case of NEC in the perihilar EHBTs, and review the literature, together with a comparison between NECs in the perihilar and distal EHBTs, to elucidate the management strategy and oncological outcome of this rare entity. PATIENT CONCERNS: A 62-year-old Chinese male was admitted with complaints of painless jaundice. Imaging studies revealed a 2-cm mass in the hepatic hilum, regional lymph node involvement, and severe stenosis at the junction of the common hepatic ducts. DIAGNOSES: The histopathological examination of the resected specimen demonstrated small tumor cells with round hperchromatic nuclei and scant cytoplasm. A detailed immunohistochemical analysis showed that the tumor was strongly positive for synaptophysin, CD56 and chromogranin A, with a Ki-67 labeling index greater than 80%. These results led to a diagnosis of NEC in the perihilar bile duct. INTERVENTIONS: The patient underwent surgical resection including a left hemihepatectomy, cholecystectomy, lymphadenectomy and Roux-en-Y hepaticojejunostomy. OUTCOMES: During the two months of follow-up, repeated imaging studies indicated tumor recurrence in the liver. The patient died 6 months after surgery. LESSONS: NEC in the EHBTs is extremely challenging to diagnose preoperatively because of mimicking other bile duct cancers. The prognosis of this disease entity is dismal, and most patients die within 2 years after diagnosis. Subtyping of NECs into perihilar NECs and distal NECs is beneficial for clinical applications, including guiding therapy selection and predicting survival. PMID- 30024527 TI - Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: A structural equation modeling approach. AB - BACKGROUND: This study sought to identify factors that impact the total health care costs associated with hospitalization of young Japanese children with respiratory syncytial virus (RSV). METHODS: Children admitted between April 2014 and March 2015 with at least a confirmed diagnosis of RSV and 2 days of hospital stay were considered for inclusion. Data analyses of hospital claims were performed using a structural equation modeling approach. RESULTS: A total of 6811 Japanese inpatients (<5 years old) diagnosed with RSV were included. The average length of stay was 7.5 days with a mean total health care cost of US Dollars (USD) $3344 per hospitalization. Intensive care unit hospitalizations were associated with greater costs (USD +$4951) compared to routine hospitalizations. The highest procedure-related cost drivers were blood transfusions (USD +$6402) and tube feedings (USD +$3512). CONCLUSION: The economic burden of RSV-related infection hospitalizations in Japan is considerable. Efforts should be toward immunization and therapeutic treatment strategies that reduce severity, prevent, or reduce the duration of hospitalization. PMID- 30024528 TI - A totally implantable venous access port associated with bloodstream infection caused by Mycobacterium fortuitum: A case report. AB - RATIONALE: Rapidly growing mycobacteria (RGM) are well-known causative agents of human infections, particularly in immunocompromised hosts. However, Mycobacterium fortuitum, a predominant organism, in catheter-associated infections, has rarely been documented in totally implantable venous access port (TVIAP)-associated bloodstream infections. PATIENT CONCERNS: A 25-year-old woman with breast cancer presented to hospital with repeated fever for several days. The patient first refused to remove the TVIAP in her body, and had a relapse of M. fortuitum bacteraemia four months later. DIAGNOSES: Bacteria isolated from patient's blood and TVIAP were identified as M. fortuitum by Matrix-assisted laser desorption/ionization-time of flight spectrometry and bacterial 16s rDNA sequencing. The patient was diagnosed as a TVIAP-associated bloodstream infection. INTERVENTIONS: The TVIAP was eventually surgically removed, and M. fortuitum was found to have localized on the tip of the catheter. The patient was treated by anti-infection therapy. OUTCOMES: The patient was treated with 4 weeks of intravenous amikacin and levofloxacin followed by 4 weeks of oral levofloxacin. No episodes of fever occurred during the follow-up to date. LESSONS: RGM infections remain a challenging issue for TIVAPs. Accurate species identification, timely intravascular catheter removal and appropriate antibiotic therapy are recommended to ensure successful outcomes. PMID- 30024529 TI - Nephrotic syndrome with acute pulmonary embolism in young adults: Two case reports. AB - INTRODUCTION: Pulmonary embolism (PE) is often misdiagnosed, or the diagnosis is delayed because of its diverse clinical manifestations, it may even remain asymptomatic until sudden death. Most risk factors are not associated with young people, and there is a paucity of literature regarding PE in children and young adults. CASE PRESENTATION: Patient 1 who died was diagnosed with nephrotic syndrome more than 10 years before. He presented to a clinic with gradually worsening dyspnea, which was initially misdiagnosed as myocarditis. Patient 2 presented with sudden shortness of breath after treatment for nephrotic syndrome. His PE was quickly diagnosed, allowing prompt initiation of anticoagulant therapy. At follow-up 30 days after hospital discharge, his symptoms had disappeared, and his abnormal laboratory results had returned to almost normal. CONCLUSION: The diagnosis and treatment of the above 2 patients suggest that the possible occurrence of PE in a young person with nephrotic syndrome should not be ignored. The early diagnosis and delayed diagnosis will have different clinical outcomes. PMID- 30024530 TI - Effectiveness of paroxetine in the treatment of poststroke depression. AB - This study retrospectively investigated the effectiveness of paroxetine for the treatment of poststroke depression (PSD).Seventy patient cases with PSD were included in this study, and were assigned to an intervention group and a control group equally. All patients received routine treatment in both groups. Additionally, patients in the intervention group underwent paroxetine, while patients in the control group received psychotherapy for a total of 8 weeks intervention. The primary outcomes included depression, measured by Hamilton depression rating scale (HAMD); and anxiety, measured by Hamilton Anxiety Rating Scale (HAMA). The secondary outcomes consisted of neurological impairment, measured by Scandinavian Stroke Scale (SSS), and activities of daily living, measured by Barthel index (BI), as well as the adverse events. All outcomes were assessed before and after 8-week treatment.After 8-week treatments, patients in the intervention group did not show greater effectiveness in depression, measured by HAMD (P = .11), and anxiety, assessed by HAMA (P = .13), as well as the neurological impairment, evaluated by SSS (P = .24), and activities of daily, performed by BI (P = .19), compared with patients in the control group. In addition, no significant differences regarding adverse events were found between the 2 groups.The results of this study indicated that paroxetine may not bring promising effectiveness for patients with PSD. Future studies are still needed to warrant the results of this study. PMID- 30024531 TI - Use of sodium nitroprusside in retrograde percutaneous coronary intervention for chronic total occlusion: A case report. AB - RATIONALE: Chronic total occlusion continues to be a challenging lesion subset for percutaneous coronary intervention. PATIENT CONCERNS: A 65-year-old male patient was admitted with symptoms of angina pectoris for 9 months. DIAGNOSES: Coronary angiography showed a severe stenosis in the proximal left anterior descending artery and a chronic total occlusion (CTO) in the proximal right coronary artery. The complexity of the CTO was stratified using the J-CTO score and the PROGRESS CTO score. INTERVENTIONS: Antegrade wire escalation for CTO of RCA failed. The septal collaterals to RCA were initially judged to be poor and not suitable for intervention. OUTCOMES: However, administration of sodium nitroprusside improved collateral flow and enabled the identification of retrograde channels suitable for wire crossing and successful retrograde PCI. LESSIONS: The study showed that faintly visible to even invisible septal collateral connections can be crossed with the septal "trial and error" surfing technique after the administration of sodium nitroprusside. PMID- 30024532 TI - Transanal hemorrhoidal dearterialization versus stapled hemorrhoidectomy in the treatment of hemorrhoids: A PRISMA-compliant updated meta-analysis of randomized control trials. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to compare the outcomes of transanal hemorrhoidal dearterialization (THD) and stapled hemorrhoidectomy (SH) in the treatment of hemorrhoids by a meta-analysis. METHODS: Randomized control trials (RCTs) comparing SH with THD were searched for in databases, including MEDLINE, PubMed, Web of science, Embase, and the Cochrane Library database. Data were independently extracted from each study, and a meta-analysis was performed using RevMan5.2 software. RESULTS: Eight RCTs, including 977 patients, were included in this meta-analysis. No statistically significant differences were noted between THD and SH in terms of total complications (OR, 0.93; 95% CI, 0.69, 1.25), but a significant differences were noted in terms of bleeding (OR, 1.85; 95% CI, 1.10, 3.10). The total recurrence rate was higher in THD than in SH on short-term follow-up; however, the recurrence rate was equal in both the THD and SH groups on long-term follow-up. The present study showed that no significant difference between SH and THD in terms of postoperative pain (OR, 0.43; 95% CI, 0.43, 1.29), operative time (OR, -3.12; 95% CI, -7.01, 0.77), hospital time (OR, 0.00; 95% CI, -0.21, 0.20), time before returning to work (OR,-0.50; 95%CI, 4.42,3.43), and reoperation rate (OR, 1.81; 95% CI, 0.93, 3.54). CONCLUSION: Our meta-analysis indicated that THD and SH are equally effective techniques for the treatment of hemorrhoids. However, future studies addressing cost-effectiveness, satisfaction rate, and recurrence rate over a long follow-up period are needed to validate these results. PMID- 30024533 TI - Vitamin D receptor gene polymorphism, serum 25-hydroxyvitamin D levels, and risk of vitiligo: A meta-analysis. AB - OBJECTIVES: To explore the relationship among the vitamin D receptor (VDR) gene polymorphisms, serum 25-hydroxyvitamin D levels, and vitiligo. METHODS: Databases including PubMed, Cochrane Library, Ovid, Web of Science, CNKI, SinoMed, and Wanfang Data were systematically searched. The association was assessed using odds ratios (ORs), standard mean difference (SMD), and 95% confidence intervals (CIs). The statistical tests were performed using Review Manager 5.3.3. RESULTS: We identified a total of 17 studies. The relationship between VDR gene polymorphisms (BsmI, ApaI, TaqI, and FokI), serum 25 (OH)D levels, and incidence of vitiligo was investigated. The results of this meta-analysis showed that the dominant genetic model (CC+AC vs AA, P = .007, OR = 1.41, 95% CI = 1.10-1.80), recessive genetic model (CC vs AC+AA, P = .01, OR = 4.10, 95% CI = 1.36-12.35), and allelic contrast model (C vs A, P = .005, OR = 1.87, 95% CI = 1.21-2.90) of VDR Apal locus increased the risk of vitiligo, and BsmI, TaqI, and FokI loci and the risk of vitiligo have no obvious correlation. Serum 25 (OH)D deficiency was positively associated with the incidence of vitiligo (P < .0001, SMD = -0.94, 95% CI = -1.39, -0.48). CONCLUSION: This meta-analysis revealed that VDR Apal polymorphism increased the susceptibility risk of vitiligo, and there is a positive correlation between serum 25 (OH)D deficiency and the incidence of vitiligo. PMID- 30024534 TI - Prevalence of previously unrecognized peripheral arterial disease in patients undergoing coronary angiography. AB - Coronary artery disease (CAD) and peripheral arterial disease (PAD) are serious manifestations of systemic atherosclerosis. A considerable proportion of patients with CAD have associated PAD; however, many are asymptomatic and this condition remains underdiagnosed. Little is known about the prevalence and clinical implication of PAD in patients undergoing coronary angiography in the Middle East with no history of the disease.To study the prevalence of previously unrecognized PAD of the lower limbs in patients undergoing coronary angiography, and to determine the correlation with CAD.This is a prospective study conducted at a university tertiary referral hospital. A total of 2120 patients referred for coronary angiography without a prior diagnosis of PAD, between January 1, 2014 and December 31, 2014, were included. Patients were evaluated through detailed medical history taking, a questionnaire survey to assess symptoms and functional status, ankle-brachial index (ABI) measurement, and coronary angiography. PAD was considered present if the ABI was <0.90 in either leg.In all patients, the prevalence of previously unrecognized PAD was 12.8%. There was no significant difference between men and women (13.4% vs 11.7%, P = .485). Abnormal angiographic results were seen in 82% (1739 of 2120). The prevalence of PAD was 14.7% in patients with abnormal coronary angiographic result, significantly higher than that in patients with normal results (4.5%, P < .0001). The prevalence of abnormal angiographic results among patients with and without PAD was 96% and 80%, respectively (P = .001). Factors independently related to PAD were age (odds ratio [OR] 1.081, 95% confidence interval [CI] 1.053-1.109; P < .001), hypertension (OR 3.122, 95% CI: 1.474-5.678; P < .004), diabetes (OR 1.827, 95% CI: 0.975-2.171; P = .04), smoking (OR 1.301, 95% CI: 0.725-2.076; P < .001), previous coronary artery bypass grafting (OR 2.939, 95% CI: 1.385-5.219; P = .004), previous cerebrovascular accident (OR 3.212, 95% CI: 1.872-9.658; P = .003), left main CAD (OR 9.535, 95% CI: 3.978-20.230; P = .002), and multivessel CAD (OR 1.869, 95% CI: 1.018-2.798; P = .03). Patients with CAD and PAD were associated with a higher prevalence of multivessel CAD (58.2% vs 42.6%, P < .005) and left main disease (3% vs 0.3%, P < .0001).The prevalence of undiagnosed PAD in patients undergoing coronary angiography was 12.8% (14.7% in patients with CAD) and associated with a higher incidence of cardiovascular risk factors, multivessel disease, and left main disease. The high prevalence of PAD in patients with CAD confirms the importance of active screening for PAD by using ABI. Routine determination of ABI in the clinical evaluation of all patients with CAD may help identify high-risk patients. PMID- 30024535 TI - Long-term outcome of radiofrequency catheter ablation for persistent atrial fibrillation. AB - Catheter ablation has been wildly used to treat atrial fibrillation (AF) and has achieved a better efficacy for paroxysmal AF (PAF) but not for persistent AF (PerAF). Furthermore, a few data on the efficacy and safety of catheter ablation for PerAF were reported. This study aimed to investigate long-term efficacy of radiofrequency catheter ablation (RFCA) for PerAF and explore predictors of late recurrence of atrial fibrillation (LRAF).A total of 92 consecutive patients with PerAF (64 males, aged 56.42 +/- 11.24 years) were enrolled in this study and accepted circumferential pulmonary vein isolation (CPVI) alone or CPVI combined additional ablation.Maintenance rate of sinus rhythm (SR) was 40.2% after a single procedure with median follow-up of 15 months and 52.2% after mean 1.3 +/- 0.6 procedures with median follow-up of 26 months. Long-term SR maintenance rate was no statistical difference between patients with CPVI alone and with CPVI combined additional ablation (48.6% vs 35.1%, log rank test, P = .152). Patients with AF duration < 24 months had a higher long-term SR maintenance rate than those with AF duration >= 24 months (55.6% vs 30.4%, log rank test, P = .022). AF duration (OR = 1.015, 95%CI 1.001-1.030, P = .015), and early recurrence of AF (ERAF) (OR = 10.654, 95%CI 3.853-29.460, P < .001) were predictors of LRAF after a single procedure.In conclusion, long-term maintenance SR rate was 52.2% in patients with PerAF after multiple procedures with a median over 2-year follow up. Patients with AF duration < 24 months had better outcome. AF duration and ERAF were predictors of LRAF after a single procedure. PMID- 30024537 TI - Prognostic role of chromodomain helicase DNA binding protein 1-like protein in human solid cancers: A meta-analysis. AB - BACKGROUND: Chromodomain helicase DNA binding protein 1-like (CHD1L) played vital roles in tumorigenesis and development. Its aberrant expression was reported to be related to progression and prognosis in various tumors. However, no consensus on the prognostic value of CHD1L protein has been made. This meta-analysis was aimed to assess the clinical significance of CHD1L protein in human solid tumors. METHODS: Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases were extensively searched to retrieve publications that reported the association between CHD1L expression and cancer prognosis. Hazard ratios (HRs) or odds ratios (ORs) with their 95% confidence intervals (95% CIs) were applied to assess the strength of the associations through Stata statistical software version 12.0 or Revman software 5.3, respectively. RESULT: A total of 14 studies were screened according to the inclusion criteria. The pooled results revealed patients with higher CHD1L expression manifested with decreased overall survival (OS) (HR: 1.59, 95% CI: 1.29-1.89, P < .001) and poorer disease free survival (DFS) (HR: 1.66, 95% CI: 1.17-2.15, P < .001). The prognostic value of CHD1L protein for OS was further confirmed by performing subgroup meta analysis. Furthermore, the pooled results revealed a positive correlation of CHD1L protein expression with tumor depth (OR: 1.87, 95% CI: 1.48-2.37), lymph node metastasis (OR: 1.46, 95% CI: 1.01-2.11), and distant metastasis (OR: 1.86, 95% CI: 1.45-2.38). CONCLUSION: CHD1L overexpression was associated with poor prognosis and advanced clinicopathological features, CHD1L may be a valuable biomarker for prognostication of cancer patients. PMID- 30024536 TI - Alobar holoprosencephaly associated with a rare chromosomal abnormality: Case report and literature review. AB - RATIONALE: Holoprosencephaly is a structural malformation of the brain that results from the complete or incomplete noncleavage of the forebrain of the embryo into 2 hemispheres. We report a severe case of alobar holoprosencephaly diagnosed at 38 weeks, associated with cebocephaly, microcephaly, and craniosynostosis. PATIENT CONCERN: The main knowledge added by this case is the late ultrasound diagnosis and chromosomal analysis that revealed a very rare abnormality (45X/46,XX/47,XX) with mosaicism at chromosome 18. DIAGNOSES: Investigation of the mother revealed nothing remarkable from clinical point of view and on laboratory tests. Ultrasonography identified a fetal biometry appropriate for gestational age, except for the head biometry and abdominal circumference, that were appropriate for less than the fifth percentile. Microcephaly, a large midline monoventricle, absent midlinestructures, cleft lip, cebocephaly (hypotelorism, single-nostril nose), ethmocephaly (hypotelorism, interorbital proboscis) and craniosynostosis, were also present. Fetal magnetic resonance imaging of fetus revealed an absent midline structure, a central monoventricle, abnormal corpus calosum, and abnormal gyri. INTERVENTIONS: A cesarean section at 38 weeks was indicated for fetal bradycardia and a female baby was delivered, with Apgar score 6, weight 2290g. After birth, the diagnosis of the fetus confirmed holoprosencephaly with facial anomalies and demonstrated repeated tonic-clonic seizure, severe respiratory failure, cyanosis, decreased muscle tone, palor, and apnea. Laboratory examination of the newborn revealed acidosis and a prolonged of prothrombin time. The neonate was treated for severe respiratory distress syndrome, with immediate intubation and resuscitation. Vitamin K, fresh frozen plasma, and antibiotics were also administered. OUTCOMES: After delivery, exitus of the fetus occurred at 3 days and 18hours due to massive pulmonary hemorrhage. LESSONS: We described a case of alobar holoprosencephaly diagnosed at 38 weeks of gestation and associated with a rare chromosomal abnormality (45X/46,XX/47,XX) with mosaicism at chromosome 18. Emotional implications could have been less severe if the patient underwent regular ultrasonography allowing a diagnosis in the first or early second trimester. PMID- 30024538 TI - Fatal pulmonary infection with respiratory syncytial virus in an immunocompromised adult patient: A case report. AB - RATIONALE: Respiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that belongs to the family of paramyxoviruses. RSV is the most common pathogen that causes acute lower respiratory tract infection in infants and young children. However, its incidence in immunocompromised adults remains unclear. In the present study, we report an adult patient with chronic nephropathy, who received long-term immunosuppressants and died of rapid respiratory failure due to RSV infection. PATIENT CONCERNS: A 54-year-old male patient with chronic nephropathy, who received long-term immunosuppressants, was admitted to the Department of Respiratory Medicine due to the symptoms of fever, cough, expectoration, and dyspnea. DIAGNOSES: Pulmonary radiology revealed multiple bilateral ground-glass opacity. Laboratory tests revealed elevated inflammation indicators, implying infection with bacteria, viruses, and/or fungi. Furthermore, the patient was positive for RSV antibodies, without positive results for other pathogens. Moreover, the patient was immunocompromised due to the long-term use of corticosteroids and immunosuppressants, as evidenced by decreased total IgG levels and reduced CD4 and CD8 T-lymphocyte counts. INTERVENTIONS AND OUTCOME: Despite the intensive anti-infection treatment and respiratory support, the patient developed rapid progression, and subsequently died of respiratory failure. LESSONS: RSV infection should be fully considered in adults who are immunocompromised or have underlying diseases, such as nephropathy patients receiving long-term immunosuppressants, especially in the presence of respiratory symptoms and computed tomography (CT) chest findings of diffuse ground-glass opacities. PMID- 30024539 TI - Hyperbaric oxygen therapy can ameliorate the EMT phenomenon in keloid tissue. AB - BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been widely used in the clinical setting. In this study, HBOT therapy was evaluated for its ability to ameliorate the epithelial-to-mesenchymal transition (EMT) phenomenon in keloid tissue. METHODS: Keloid patients were randomly divided into two groups: keloid patients (K group, 9 patients) and keloid patients receiving HBOT (O group, 9 patients). A third group with normal skin (S group, 9 patients) was established for control. Before HBOT and surgery, a laser Doppler flowmeter was used to measure the keloid blood supply of patients in the O group. Hematoxylin and eosin (H&E) staining was used to observe morphology. E-cadherin, ZO-1, vimentin, fibronectin, vascular endothelial growth factor (VEGF), and hypoxia inducible factor (HIF)-1alpha were measured by immunofluorescence staining and Western blot analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the mRNA expression level of these factors as well. RESULTS: In the O group, keloid blood perfusion was significantly reduced after patients received HBOT. Compared with the K group, lower expression levels of vimentin, vibronectin, VEGF, and HIF 1alpha were observed in the O group, whereas the expression of E-cadherin and ZO 1 was significantly higher. The mRNA expression of E-cadherin and ZO-1 was also increased after HBOT. CONCLUSIONS: The expression levels of factors related to the EMT phenomenon were significantly reversed in keloid patients after they received HBOT, indicating that HBOT may be an effective therapy against the EMT phenomenon in keloid patients. PMID- 30024540 TI - Association of serum/plasma high mobility group box 1 with autoimmune diseases: A systematic review and meta-analysis. AB - BACKGROUND: High mobility group box 1 (HMGB1) is a kind of proinflammatory mediator to stimulate the innate and adaptive immune system and participates in a number of acute and chronic inflammatory processes after sterile injury or microbial invasion. HMGB1 has been suggested to be involved in the pathogenesis of many autoimmune diseases. However, the results are contradictory or inconclusive among these findings. The aim of this study was to investigate whether serum/plasma HMGB1 levels are associated with autoimmune diseases by comparing the serum/plasma HMGB1 levels in patients with autoimmune disease and healthy controls and to further evaluate whether serum/plasma HMGB1 levels are associated with disease state. METHODS: PubMed, Medline, and Web of science databases (up to October 1, 2017) were used to obtain all relative published literature. Study quality was assessed by the Newcastle-Ottawa scale (NOS). Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effects or random-effect model analysis. RESULTS: A total of 23 original articles of autoimmune diseases were finally included in the meta analysis. Results revealed that the serum/plasma HMGB1 levels were increased in patients with autoimmune disease, compared to healthy controls. Subgroup analysis showed that serum/plasma HMGB1 levels in patients with active disease state were significantly higher than in those with inactive state. In addition, subgroup analysis based on disease type has indicated that the serum/plasma HMGB1 levels in patients with small vessel vasculitis, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis and sjogren syndrome were significantly higher, compared to healthy controls. Further subgroup analyses by region showed that plasma/serum HMGB1 levels were higher in Asian and European patients with autoimmune diseases. CONCLUSIONS: Serum/plasma HMGB1 levels in patients with autoimmune diseases are significantly higher than in healthy controls, and may reflect the disease activity. PMID- 30024541 TI - Two novel TSC2 mutations in pediatric patients with tuberous sclerosis complex: Case report. AB - RATIONALE: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder. The TSC1 and TSC2 genes have been identified as pathogenic genes. PATIENT CONCERNS: In this report, we are discussing a novel frameshift mutation and a novel missense mutation in the TSC2 gene. DIAGNOSES: The two cases discussed in this study met the latest diagnostic criteria for TSC published by the International Tuberculosis Sclerosis Complex Consensus Conference in 2012. INTERVENTIONS: High-throughput sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to examine tuberous sclerosis complex (TSC) related genes (TSC1 and TSC2) and their splicing regions using peripheral blood DNA from two probands in two families with TSC and to identify the genetic mutation sites. Amplification primers were designed for the mutation sites, and polymerase chain reaction and Sanger sequencing were used to verify the peripheral blood DNA sequences from the probands and their parents. OUTCOME: Proband 1 had the c.1228 (exon 12)_c.1229 (exon 12) insG (p.L410RfsX11) heterozygous mutation in the TSC2 gene (chr16), which was a new frameshift mutation. Proband 2 had the c.4925G>A (exon 38) (p.G1642D) heterozygous mutation in the TSC2 gene (chr16), which was a new missense mutation. LESSONS: These two novel mutations may be pathogenic mutations for TSC, and their association with the disease needs to be further verified by mutant protein function cell model and animal model. PMID- 30024542 TI - A preliminary study: The sequential use of the risk malignancy index and contrast enhanced ultrasonography in differential diagnosis of adnexal masses. AB - The aim of this study was to explore the sequential use of risk malignancy index (RMI) combined with contrast-enhanced ultrasonography (CEUS) in identification diagnosis of adnexal masses.This study contained 2 steps: first, 151 patients were analyzed retrospectively with RMI 1, RMI 2, and RMI 3 indices; receiver operating characteristic (ROC) curves were plotted to analyze area under the curves (AUC), and then RMI cut-off value was obtained according to maximum Youden index (YI, Sensitivity + Specificity - 1) and calculating diagnostic sensitivity, specificity, positive/negative predictive value, and accuracy. Second, 151 cases were divided into 2 groups randomly (105 in study group and 46 in test group); in the study group, the lower cut-off value (LC), upper cut-off value (UC), CEUS cut off value according to maximum YI, and then these cut-offs were validated in test group.There was no statistical significance in 3 RMI models (P = .35), and RMI1 model was established randomly for following study. When the RMI1 cut-off value was 149, the YI was maximal (0.53), and the sensitivity, specificity, positive/negative predictive value, and accuracy were 71.0%, 81.7%, 77.1%, 75.6%, and 76.2%, respectively. The LC was 15 (sensitivity was 98.0%), the UC was 3000 (specificity was 98.0%), and the CEUS cut-off value was 7 (maximal YI was 0.81). In the test group (46 cases), combining RMI1 LC (15) and UC (3000) with CEUS cut off value (7), the sensitivity, specificity, positive/negative predictive value, and accuracy were up to 85.7%, 92.0%, 90.0%, 88.5%, and 89.1%, respectively.CEUS can help RMI to make a more effective differential diagnosis of the adnexal mass. Further validation by additional multicenter prospective trials is required. PMID- 30024543 TI - The comparative efficacy of group- versus home-based exercise programs in patients with ankylosing spondylitis: Protocol for a meta-analysis. AB - BACKGROUND: Ankylosing spondylitis (AS) is an important factor to not only cause employment obstacle, but also result in serious social economic load. Several randomized controlled trials investigated the efficacy of group- versus home based exercise programs in patients with AS. This systematic review will collect and summarize the available evidence to realize the effectiveness of group- and home-based programs in patients with AS. METHODS: A search in PubMed, Web of Science, EMBASE, and the Cochrane Library will be electronically performed by 2 independent investigators to capture all potential studies comparing group- and home-based in patients with AS. The time limit of search will be from their inception to April 2018. Two independent investigators provide their agreement in presencial meeting for a final selection, and at a later stage, the articles will be reviewed in full-text by the all authors. Quantitative analysis will be performed with Review Manager (RevMan) software (version 5.3.0). RESULTS: This meta-analysis will provide a high-quality synthesis of current evidence of group- versus home-based exercise programs in patients with AS. CONCLUSION: The conclusion of our meta-analysis will provide the evidence which program is an effective intervention for patient with AS. PMID- 30024544 TI - Maekmoondong-tang in treatment of postoperative cough in patients with lung cancer: Study protocol for a randomized, double-blind, placebo-controlled, multicenter trial. AB - BACKGROUND: Cough is a common symptom that occurs in 25% of patients after lung cancer surgery. It might last a long time and degrade the quality of life of patients. Maekmoondong-tang (Bakumondo-to in Japanese or Mai-Men-Dong-Tang in Chinese) is a herbal medicine which has been widely used for respiratory diseases with cough in Korea, China, and Japan. AIMS: The aim of the present study is to evaluate the efficacy and safety of Maekmoondong-tang for postoperative cough in patient with lung cancer. METHODS/DESIGN: This study is a randomized, double blind, placebo-controlled, multicenter trial of Maekmoondong-tang. A total of 96 participants will be enrolled and allocated to 2 parallel groups: the Maekmoondong-tang group and the placebo group from 5 university hospitals. The participants will be administered either Maekmoondong-tang or a placebo 3 times a day for 4 weeks. The primary outcome measurement is the change in the Leicester Cough Questionnaire (LCQ) score. The secondary outcome measurements are the changes in the cough visual analog scale and Yin Deficiency Scale. The participants will visit 4 times in total for 4 weeks of trial period. DISCUSSION: The present study will be the first multicener study to evaluate the efficacy and safety of Maekmoondong-tang for postoperative cough in patient with lung cancer surgery. The results of this study will provide a new treatment for cough using herbal medicine and will be a reference for planning clinical trial of herbal medicine in patient with cough. PMID- 30024545 TI - Comparison of laminoplasty versus laminectomy and fusion in the treatment of multilevel cervical ossification of the posterior longitudinal ligament: A systematic review and meta-analysis. AB - BACKGROUND: Laminoplasty (LP) and laminectomy with fusion (LF) were recognized as two reliable and effective way in treating multilevel cervical ossification of the posterior longitudinal ligament (OPLL). However, there was no clear conclusion on which method is better. A meta-analysis was conducted to evaluate the clinical results between LP and LF in the treatment of multilevel cervical OPLL. METHODS: An extensive search of literature was performed in PubMed, Embase, the Cochrane library, CNKI (Chinese database), and WANFANG (Chinese database). The following outcomes were extracted: the Japanese Orthopedic Association (JOA) scores, visual analog scale (VAS), cervical lordosis, cervical range of motion (ROM), complications, blood loss, and operation time. Data analysis was conducted with RevMan 5.3. RESULTS: A total of 11 studies were included in the final analysis. The results indicated that no significant differences between LP and LF group in terms of preoperative JOA scores (P = .58), postoperative JOA scores (P = .60), JOA scores improvement rate (P = 0.64), preoperative VAS (P = .34), postoperative VAS (P=.20), preoperative range of motion (ROM) (P = .10), postoperative ROM (P = .18), preoperative cervical lordosis (P = .56), C5 palsy (P = .16), and axial pain (P = .21). LF group showed larger postoperative cervical lordosis than LP group [standardized mean difference (SMD) = 1.13 (2.03, 0.24), P = .01]. However, LP group showed lower operation time [mean difference (MD) = 19.42 (26.87, 11.97), P < .001] and blood loss [MD = 94.78 (179.05, 10.51), P = .03] than LF group. CONCLUSION: Both LP and LF can achieve clinical improvement in the treatment of multilevel cervical OPLL. LF was superior to LP in maintaining cervical lordosis. However, LP showed lower surgical trauma than LF. Kyphosis line (K-line) may be a good criterion in the selection of posterior surgery. LP was performed for the patients with K-line (+) and LF for K-line (-). PMID- 30024547 TI - Quality of life in Chinese patients with laryngeal cancer after radiotherapy. AB - This retrospective study explored the quality of life (QoL) in Chinese patients with laryngeal cancer (LC) after radiotherapy.Fifty-nine eligible patients with Tis-T4 LC were included in this retrospective study. All patients received radiotherapy. Outcomes were measured by the core measure Questionnaire-C30 (QLQ C30), and the disease-specific Head & Neck cancer module (QLQ-H&N35). All outcomes were assessed before and 3 months after the radiotherapy.Three months after the radiotherapy, all items of QLQ-C30 and QLQ-H&N35 scales changed significantly (P < .05), except the social functioning (P = .09), role activities (P = .81), and global (P = .12) in QLQ-C30 scale and social contacts (P = 1.00), teeth problems (P = .21), trismus (P = 1.00), and feeling ill (P = .07) in QLQ H&N35 scale, compared with these items before the radiotherapy.The results of this study showed that most items of QoL changed significantly after 3 months of radiotherapy in Chinese patients with LC. PMID- 30024546 TI - Network meta-analysis of percutaneous vertebroplasty, percutaneous kyphoplasty, nerve block, and conservative treatment for nonsurgery options of acute/subacute and chronic osteoporotic vertebral compression fractures (OVCFs) in short-term and long-term effects. AB - BACKGROUND: Osteoporotic vertebral compression fractures (OVCFs) commonly afflicts most aged people resulting back pain, substantial vertebral deformity, functional disability, decreased quality of life, and increased adjacent spinal fractures and mortality. Percutaneous vertebral augmentation (PVA) included percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP), nerve block (NB), and conservative treatment (CT) are used for the nonsurgery treatment strategy of OVCFs, however, current evaluation of their efficacy remains controversial. METHODS AND ANALYSIS: A systematic literature search was carried out in PubMed, EMBASE, Web of Knowledge, and the Cochrane Central Register of Controlled Trials up to October 31, 2017. Randomized controlled trials (RCTs) were compared PVP, PKP, NB, or CT for treating OVCFs. The risk of bias for each trial was rated according to the Cochrane Handbook. Mean differences (MDs) with 95% confidence intervals (CIs) were utilized to express VAS (visual analog scale) outcomes. The network meta-analysis (NMA) of the comparative efficacy measured by change of VAS on acute/subacute and chronic OVCFs was conducted for a short-term (<4 weeks) and long-term (>=6-12months) follow-up with the ADDIS software. RESULTS: A total of 18 trials among 1994 patients were included in the NMA. The PVA (PVP and PKP) had better efficacy than CT. PKP was first option in alleviating pain in the case of the acute/subacute OVCFs for long term, and chronic OVCFs for short term and long term, while PVP had the most superiority in the case of the acute/subacute OVCFs for short term. NB ranks higher probability than PKP and PVP on acute/subacute OVCFs in short and long-term, respectively. CONCLUSIONS: The present results suggest that PVA (PVP/PKP) had better performance than CT in alleviating acute/subacute and chronic OVCFs pain for short and long-term. NB may be used as an alternative or before PVA, as far as pain relief is concerned. Various nonsurgery treatments including CT, PVA (PVP/PKP), NB, or a combination of these treatments are performed with the goal of reducing pain, stabilizing the vertebrae, and restoring mobility. PMID- 30024548 TI - The role of TERT promoter mutations in postoperative and preoperative diagnosis and prognosis in thyroid cancer. AB - BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations have been described in different pathological types of thyroid cancers (TC). After many types of research focusing on the mutations rate in malignant tumors, the main role of TERT promoter mutations has been changed to the preoperative diagnosis and prognosis of TC, according to their high prevalence in aggressive TC. METHODS: We searched Pubmed, Web of Science, Scopus, and VHL and reviewed the most common 2 mutations C288T and C250T in different types of TC, the association between them and some specific clinicopathological features, and their significance in preoperative diagnosis and prognosis of TC. we chose 38 studies into our qualitative research. We also chose 22 studies to do a meta-analysis on this subject. RESULTS: The overall rate of these mutations in different types of TC was 10.0%, with 86.1% C228T mutation, 12% C250T mutation, and 2.1% other type mutations. The rate increases significantly as the TC become more aggressive, and reaches 56.8% in anaplastic thyroid cancer (ATC). Statistically meaningful association is found between TERT promoter mutations and older age, larger tumor size, extrathyroidal extension, lymph node metastasis, distance metastasis, advanced TNM stage, recurrence, and BRAF V600E mutation. Some studies concentrating on DNA sequencing based on fine needle aspiration biopsy (FNAB) also proved their significance in preoperative stage, with 7% to 16.5% sensitivity. CONCLUSIONS: TERT promoter mutations were likely to occur in BRAF V600E positive TC. Patients with these 2 combined mutations were more likely to have a poor prognosis and outcome. TERT promoter mutations is an essential part of the ThySeq gene panel. The mechanism of how they influence the appearance and development of TC has not been expounded. The next study direction may be the mechanism exploration and the further study to prove their significance in preoperative diagnosis. PMID- 30024549 TI - Prior vaccinations improve immunogenicity of inactivated influenza vaccine in young children aged 6 months to 3 years: A cohort study. AB - In young children, infrequent antigen exposure, which is partly characterized by fewer vaccinations, may be a factor impairing the immunogenicity of inactivated influenza vaccine.We assessed the effects of prior vaccinations on age-specific immune responses in Japanese children aged 6 months to 3 years, using data from a cohort study with 266 children who had received 2 doses (0.25 mL/dose for < 3 years old, 0.5 mL/dose for 3 years old) in the 2006/2007 season. Serological measures, primarily seroprotection rates, between previously vaccinated and vaccine-naive children were compared within 1-year age strata. The seroprotection rate was defined in 2 ways as the proportion of subjects who achieved an antibody titer of 1:40 or 1:160. Multivariate logistic regression was also performed to estimate the independent effect of prior vaccination on seroprotection rate.After the first dose, seroprotection rates with the threshold of 1:40 in vaccine-naive 1-year-olds remained low (28% for AH1, 26% for AH3, 2% for B), similar to those of 0-year-olds. In contrast, seroprotection rates in previously vaccinated 1-year olds (77% for AH1, 86% for AH3, 18% for B) were significantly higher than those in vaccine-naive 1-year-olds. These seroprotection rates for AH1 and AH3 were comparable with those in previously vaccinated 2- and 3-year-olds. Although seroprotection rates for B remained low in every age stratum even after the second dose, seroprotection rate in previously vaccinated 1-year-olds (50%) was similar to that in 3-year-olds. After adjustment for age, baseline antibody titer and experience of acute febrile respiratory illness in the preceding season, odds ratios showed a significant independent positive effect of prior vaccination on seroprotection rate for every strain. After the seroprotection threshold was changed from 1:40 to 1:160, the results of the effects of prior vaccinations on immunogenicity were similar or became more evident, which demonstrate the robustness of our findings.Our study found that prior vaccinations improved poor immunogenicity among young children, especially in 1-year-olds. PMID- 30024552 TI - Association between rs1800795 polymorphism in the interleukin-6 gene and the risk of polycystic ovary syndrome: A meta-analysis. AB - OBJECTIVE: Several published articles have investigated the association between the -174 G/C (rs1800795) polymorphism in the interleukin-6 (IL-6) gene and the risk of polycystic ovary syndrome (PCOS). However, the results were inconsistent. In the present study, a meta-analysis was performed to resolve this inconsistency. METHODS: Eligible studies reporting an association between the IL 6 rs1800795 polymorphism and PCOS susceptibility were included from PubMed, Embase, Web of Science, and the Cochrane Library up to December 1, 2017. The odds ratio (OR) with the 95% confidence interval (CI) was used to calculate the strength of the associations. Publication bias detection was conducted using Begg test. We used STATA 11.0 software to perform the statistical analyses. RESULTS: Six articles detailing case-control studies were included, reporting a total of 512 cases and 606 controls. The meta-analysis results indicated that rs1800795 was associated with decreased PCOS susceptibility in the overall population under the allelic model (G vs. C, OR = 0.59, 95% CI: 0.41-0.85, P = .005), the homozygous model (GG vs. CC, OR = 0.45, 95% CI: 0.28-0.73, P = .001), heterozygous model (GG vs. CG, OR = 0.50, 95% CI: 0.26-0.95, P = .036), and the dominant model (GC + CC vs. GG, OR = 0.48, 95% CI: 0.26-0.89, P = .020). However, a threshold P value of .05 was found under the recessive model (CC vs. GG + CG, OR = 0.62, 95% CI: 0.39-1.00). CONCLUSIONS: This meta-analysis concluded that IL 6 rs1800795 polymorphism has a decreased association with PCOS risk among all populations studied. The results suggested that the IL-6 rs1800795 polymorphism is a protective factor for PCOS susceptibility. Given the limited ethnic groups and sample size, further studies are required to validate the association. PMID- 30024550 TI - Successful treatment of Gorham-Stout syndrome in the spine by vertebroplasty with cement augmentation: A case report and literature review. AB - RATIONALE: Gorham-Stout syndrome in the spine is extremely rare, and there is no standard curative management thus far. The objective of this article is to report a very rare case of Gorham-Stout syndrome of the lumbar and sacral spine with chylothorax and chyloperitoneum successfully treated by combination of vertebroplasty with cement augmentation and medication treatment. We described the clinical characteristics and postoperative therapy of the patient, and reviewed all of the published cases of Gorham-Stout syndrome of the lumbar and sacral spine. PATIENT CONCERNS: A 31-year-old man presented with increasingly serious abdominal distention and back pain. MRI showed massive bony destruction of the spine and pelvis. CT and ultrasonography demonstrated massive ascites and mild hydrothorax. DIAGNOSES: We believe this is the first report of a case of Gorham-Stout syndrome with both chylothorax and chyloperitoneum. INTERVENTIONS: Chest and abdominal cavity puncture was performed for symptomatic relief and the test results confirmed chylothorax and chyloperitoneum. Tissue biopsy and percutaneous vertebroplasty at L5 were performed and the postoperative pathology together with symptoms and examinations were reported to be consistent with Gorham-Stout syndrome. Subsequently, we administered combination medical treatment consisting of interferon-alpha-2b, zoledronic acid and calcitriol. OUTCOMES: At the 1-year and 2-year follow-up visit, he had nearly full complete remission and reported palliative back pain. Moreover, the amount of pleural and peritoneal fluid was successfully reduced gradually. LESSONS: Vertebroplasty by cement augmentation may be a treatment option for patients with Gorham-Stout Syndrome in the spine who cannot undergo appropriate surgery or decline open surgery. This represents a safe and minimally invasive approach to sustainably relieve pain and stabilize vertebral bodies with Gorham-Stout syndrome in the spine. PMID- 30024553 TI - Zhenwu decoction for chronic heart failure: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Chronic heart failure (CHF), not only a severe personal healthy problem but also a social financial burden, has become a global health concern. Zhenwu decoction (ZWD) has been widely adopted to clinical practice for patients with CHF. It is necessary to update the researches to reevaluate the efficacy and safety of ZWD to provide the up-to-date evidence for CHF management. Therefore, we provide a protocol of systematic review regarding ZWD for CHF. METHODS: The aim of this study was to retrieve papers on the topic of ZWD treatment for CHF in the electrical databases, including PubMed, Cochrane Library, EMBASE, Chinese Biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, and Chinese Science and Technology Periodical database (VIP). The included literatures are those delivered from the time when the databases were established to May 2018. The therapeutic effects based on the mortality and the New York Heart Association (NYHA) function classification will be marked as the primary outcomes. We will use RevMan V.5.3 software to calculate the data synthesis as well as to perform meta-analysis if the results are appropriate. RESULTS: The literature will provide a high-quality synthesis of current evidence of ZWD for CHF from various comprehensive assessment, including mortality, NYHA function classification, left ventricular ejection fraction, 6-minute walk test (6MWT), life quality, and adverse events. CONCLUSION: The systematic review will provide up-to-date evidence to assess ZWD treatment effect for patient with CHF. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42018083813. PMID- 30024551 TI - Accuracy of 11C-choline positron emission tomography in differentiating glioma recurrence from radiation necrosis: A systematic review and meta-analysis. AB - OBJECTIVES: Distinguishing glioma recurrence from the necrosis after radiation therapy and/or chemotherapy is a crucial clinical issue, for the different diagnosis will lead to divergent treatments. The accurate judgment is barely achieved by conventional imaging methods. We therefore assume it is of need to exert a meta-analysis to evaluate the diagnostic accuracy of 11C-choline positron emission tomography (PET), to achieve this goal. MATERIAL AND METHODS: We searched the PubMed, Embase, and Chinese Biomedical databases comprehensively to select eligible studies and assessed the quality of each article included (up to May 31, 2018). Fixed-effects models were used. Summary diagnostic accuracy of 11C choline PET was obtained from pooled analysis. RESULTS: Five articles comprising 6 studies with total 118 patients (134 scans) were enrolled for the meta analysis. There was no heterogeneity or publication bias among the included studies. The pooled sensitivity and specificity were 0.87 (95% confidence interval [CI]: 0.78, 0.93) and 0.820 (95% CI: 0.69, 0.91), respectively. The pooled diagnostic odds ratio was 35.50 (95% CI: 11.70, 107.75). The area under the curve was 0.9170 (95% CI: 0.8504, 0.9836), with Q* index equaling to 0.8499. The diagnostic accuracy of each subgroup showed no statistical differences with that of the overall group. CONCLUSIONS: This meta-analysis indicated 11C-choline has high diagnostic accuracy for the identification of tumor relapse from radiation induced necrosis in gliomas. PMID- 30024554 TI - Complications of percutaneous pedicle screw fixation in treating thoracolumbar and lumbar fracture. AB - Percutaneous pedicle screw fixation (PPSF) has been a popular approach for treating thoracolumbar and lumbar fracture, and its relevant complications have been gradually recognized. This study aimed to summarize the complications of PPSF in treating thoracolumbar and lumbar fracture as well as the management and outcomes of the complications.We retrospectively analyzed the patients with thoracolumbar and lumbar fracture who were admitted to our department from February 2011 to February 2015 and underwent posterior PPSF. Information on demographics, medical comorbidities, radiographs, and treatment was obtained from hospital medical records and follow-up records. Main outcome indexes included adverse clinical and radiological outcomes during and after surgery.A total of 781 patients were included in this study. Forty-six patients (5.9%) presented with complications during or after surgery. The complications included intraoperative guide wire breakage, abdominal artery injury, spinal dura mater injury, postoperative pedicle screw misplacement, screw breakage, plug screw falling off, connecting rod loosening, poor reduction, and late infection. Among the 39 cases with postoperative complications, 14 underwent revision surgery, and the remaining patients underwent conservative treatment and presented good outcomes.PPSF is associated with the following complications: guide wire rupture, blood vessel injury, cerebrospinal fluid leakage, screw misplacement, poor reduction, failed internal fixation, and infection. A thorough preoperative evaluation, accurate operation, and timely and correct management of complications are critical to achieving satisfactory surgical outcomes. PMID- 30024555 TI - Value of virtual monochromatic spectral images with metal artifact reduction algorithm in dual-energy computed tomography-guided microcoil localization of pulmonary nodules. AB - To evaluate the clinical value of virtual monochromatic spectral (VMS) images with metal artifact reduction (MAR) algorithm in dual-energy computed tomography (DECT)-guided microcoil localization of pulmonary nodules.Fifty-one patients underwent DECT after placement of microcoils on small pulmonary nodules before video-assisted thoracoscopic surgery (VATS). Optimal energy level (in keV) was defined as the level at which CT values of nodules were equivalent to those of 120 kVp images and with no serious metal artifacts. VMS images at optimal keV and at 50, 90,110, and 140 keV with and without MAR were reconstructed. Image quality was scored using a 3-point scale: 1 = excellent, minimal artifacts; 2 = good, mild artifacts; and 3 = poor, extensive artifacts. Image quality scores between the VMS-only and VMS + MAR groups were compared;74 keV was found to be the optimal level for VMS images. The image quality of the VMS + MAR images at 74 keV were significantly better than VMS-only images (1.35 +/- 0.59 vs 2.11 +/- 0.87, P = .005). There was no difference in image quality score among VMS + MAR images at 74 keV and higher energy levels.VMS images from DECT at 74 keV with MAR can reduce artifacts from microcoils and improve image quality for microcoil localization of pulmonary nodules. PMID- 30024556 TI - Desmoplastic melanoma versus spindle cell melanoma: Incidence and survival, 1973 to 2017. AB - Desmoplastic melanoma (DM) and spindle cell melanoma (SCM) are 2 rare subtypes of melanoma. This study aims to investigate these 2 melanomas comprehensively by comparison.Cases were identified in the Surveillance, Epidemiology, and End Results (SEER) database (1973-2017).A total of 3657 DM and 4761 SCM cases were identified. DM's female-to-male ratio was 1:2 and SCM's was 0.62:1. The age distribution was similar. Both tumor mostly originated from skin and the eye and orbit was SCM-specific tumor site. Comparing both tumors with DM as reference, significant overall survival (OS) were found depending on sex (women, P < .001), age (age <=65 years, P < .001), race (white, P = .01), tumor orientation (skin, P < .001), T stage (T3 + T4, P = .001), SEER historic stage (regional tumor, P = .04), and surgery (P = .01). Meanwhile, significant disease specific survival (DSS) differences were found depending on sex (men, P < .001), age (age <=65 years, P < .001), race (white, P < .001), tumor orientation (skin, P < .001), T early stage (T1 + T2, P = .02), T advanced stage (T3 + T4 stage, P = .001), SEER historic stage (regional tumor, P < .001), and surgery (P < .001). The chance of DSS and OS of SCM were significantly higher comparing to DM for female patients (HR = 1.268, for OS; HR = 1.711, for DSS), patients age <=65 years (HR = 1.290, for OS; HR = 1.638, for DSS), No-Spanish-Hispanic-Latino patients (HR = 1.098, for OS; HR = 1.426, for DSS), patients with skin tumor (HR = 1.174; for OS; HR = 1.444; for DSS) and patients who received surgery (HR = 1.091; for OS; HR = 1.398, for DSS).DM and SCM mostly occurred in white people' skin at 60 to 80 years old and eye and orbit was another most affected site for SCM. SCM had slightly higher occurrence in women and the risk of DSS and OS were significantly higher comparing to DM depending on the women, patients age <=65 years, patients with skin tumor, No-Spanish-Hispanic-Latino patients and patients who received surgery. PMID- 30024558 TI - A meta-analysis supports core needle biopsy by radiologists for better histological diagnosis in soft tissue and bone sarcomas. AB - BACKGROUND: Although surgical biopsy has historically been considered to be the standard diagnostic biopsy for soft tissue and bone sarcomas, recent literature suggests that percutaneous core needle biopsy yields similar results. Therefore, an evaluation of the exact diagnostic accuracy and associated influential variables of core needle biopsy that is based on a large data set would be useful. METHODS: We searched MEDLINE, Web of Science, and EMBASE to identify core needle biopsy studies for predicting final histological subtypes of musculoskeletal lesions. The diagnostic accuracies of core needle biopsy and of surgical biopsy were assessed and compared by using random-effect meta-analyses. The factors relevant to diagnostic accuracy were evaluated by meta-regression and subgroup analyses. RESULTS: We selected 32 studies comprising 7209 musculoskeletal lesions. The pooled proportion estimate for the diagnostic accuracy of core needle biopsy was 0.84 (95% confidential interval, CI: 0.81 0.87), which indicated an approximate 84% concordance between core needle biopsy results and final histological diagnoses. The findings of meta-regression and subgroup analyses suggested that radiologists were better core needle biopsy operators than surgeons. An additional meta-analysis for direct comparison between core needle biopsy and surgical biopsy demonstrated that diagnostic accuracy was significantly lower for core needle biopsy than for surgical (pooled odds ratio: 0.39, 95% CI: 0.20-0.76). CONCLUSION: Our results suggested that core needle biopsy should be performed by expert radiologists and that surgical biopsy should be performed if diagnosis following core needle biopsy does not match the clinical presentation and radiographic findings. PMID- 30024557 TI - Classification of death causes after transplantation (CLASS): Evaluation of methodology and initial results. AB - Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8 48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry. PMID- 30024559 TI - Titanium elastic nailing versus locking compression plating in school-aged pediatric subtrochanteric femur fractures. AB - The treatment of children between 5 and 12 years of age suffering from subtrochanteric femoral fracture is challenging. The optimal choice of internal fixation for these patients is controversial. The purpose of this study is to compare the outcomes and complications of titanium elastic nail and open reduction with plate fixation of subtrochanteric femur fractures in school-aged children.A total of 67 children aged 5 to 12 years with subtrochanteric femur fractures treated with titanium elastic nails or open plating were identified at our institution from January 2007 to December 2017. We retrospectively compared 39 children treated with titanium elastic nails with 28 children treated with open reduction and plate fixation. The data included age, sex, body weight, fracture pattern, operation time, blood loss, and length of hospitalization. The follow-up investigations included radiograph of pelvis, bilateral hip range of motion, bilateral femoral neck shaft angle, and length of lower extremity. The outcomes were classified according to Flynn classification as excellent, satisfactory, or poor. All the demographic characteristics were compared with statistical analyses.All 67 fractures united properly. No major postoperative complications were noted in both groups. No significant difference was found between the titanium elastic nail and open plating groups in terms of sex, fracture pattern, and length of hospitalization. We noted a significant difference between 2 groups in terms of age, weight, operation time, and blood loss. In total, we observed 24 excellent and 15 satisfactory results in the titanium elastic nail group, and 19 excellent results and 9 satisfactory results in the open plating group. There was no significant statistical difference between involved and uninvolved side of hip regarding range of motion and femoral neck shaft angle in both groups.Titanium elastic nail and pediatric hip plate fixation represent safe and effective methods in the treatment of subtrochanteric fractures in school-aged children. Titanium elastic nail internal fixation is a minimal invasive and simpler technique and suitable for young children of lower body weight. Open plate fixation is a more rigid fixation associated with a lower complication rate. PMID- 30024560 TI - Diffusion tensor imaging for evaluating perianal fistula: Feasibility study. AB - To explore the feasibility of using diffusion tensor imaging (DTI) in the diagnosis of anal fistula and evaluating its activity.Thirty-four patients with perianal fistulas were examined with DTI on a 3.0 T magnetic resonance imaging (MRI) before undergoing surgery. Based on the surgery requirement and preoperative examinations, the lesions fell into 2 groups: the positive inflammation activity (PIA) group and the negative inflammation activity (NIA) group. Each lesion was divided into 3 regions of interest (ROIs) (i.e., the fistula area, edema area, and distant normal-appearing area). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were calculated and analyzed.There were statistically significant differences in FA and ADC values of the fistula area, edema area, and distant normal-appearing area. The FA values of the fistula area, edema area, and distant normal-appearing area in PIA were 0.134 +/- 0.046, 0.225 +/- 0.060, 0.343 +/- 0.070, respectively. The ADC values (*10 mm/s) of the fistula area, edema area, and distant normal-appearing area in PIA were 0.979 +/- 0.441, 1.542 +/- 0.274, 1.864 +/- 0.336, respectively. The FA values of the fistula area, edema area, and distant normal-appearing area in NIA were 0.183 +/- 0.057, 0.286 +/- 0.059, 0.382 +/- 0.084, respectively. The ADC values (*10 mm/s) of the fistula area, edema area, and distant normal appearing area in NIA were 1.393 +/- 0.256, 1.518 +/- 0.274, 1.703 +/- 0.432, respectively. Regarding the activity, the FA and ADC values of the PIA group were lower than those of the NIA group in the fistula area, and the differences were statistically significant (P = .009, .004). The FA values of the edema area in the PIA group were lower than those in the NIA group, and the difference was statistically significant. The ADC values of the edema area, and both the FA and ADC values of the distant normal-appearing area all exhibited no statistically significant differences between the 2 groups.DTI parameters may reflect microstructures of perianal fiatulas via quantitative information. FA and ADC values were instrumental in evaluating the activity of perianal fistulas. PMID- 30024561 TI - Splenic artery pseudoaneurysm with splenic infarction induced by a benign gastric ulcer: A case report. AB - RATIONALE: Splenic artery pseudoaneurysm induced by benign gastric ulcer is extremely rare and can lead to a fatal clinical situation. To the best of our knowledge, there are only five cases in the literature review. Therefore, it can be a diagnostic challenge for radiologists and clinicians because of rare incidence. PATIENT CONCERNS: The patient visited our hospital due to melena and dizziness. DIAGNOSES: The patient showed a huge ulcer and an exposed vessel in the posterior wall of the gastric high body during endoscopy. Angiography revealed a pseudoaneurysm of the splenic artery and contrast extravasation into the gastric lumen. INTERVENTIONS: We performed coil embolization of splenic artery and gastrectomy. OUTCOMES: Postprocedural course was uneventful and led to patient discharge on day 8. LESSONS: We suggest that the splenic artery pseudoaneurysm should be considered differential diagnosis in the patients with acute upper gastrointestinal bleeding, and the presence of a splenic infarction may provide a diagnostic clue. PMID- 30024562 TI - Rheumatoid arthritis-like features in Hansen disease: A case report. AB - RATIONALE: Hansen disease is an infectious chronic disease with various clinical manifestations. Its joint performance may easily mimic rheumatoid arthritis. PATIENT CONCERNS: We report a case of a 57-year-old woman diagnosed with Hansen disease 10 years ago, who suffered from joints swelling, pain and joints deformities of both hands for 19 years. The skin on the hands showed rashes, thickening, desquamation and chapping, with both thenar muscles atrophy. She also had severe hypoalgesia of the whole body, and morning stiffness for one hour. DIAGNOSES: The final diagnosis was joint damage and peripheral neuropathy due to Hansen disease. INTERVENTIONS: The patient received neurotrophic treatment instead of anti-rheumatic treatment. OUTCOMES: At 1-year follow up, no further aggravation of joint swelling and pain was detected. LESSONS: The correct diagnosis of Hansen disease involving joints depends on the combination of medical history, careful physical examination, and laboratory examination. PMID- 30024563 TI - Prognostic value and susceptibility of BAX rs4645878 polymorphism in cancer: A systematic review and meta-analysis. AB - BACKGROUND: BCL-2 Associated X (BAX) is an important modulator of apoptosis. The associations between BAX gene polymorphism and cancer susceptibility and prognosis in different ethnic groups and types of cancer have yielded controversial results. To reconcile the results, a systematic review followed by meta-analysis was performed to assess the associations. METHODS: A systematic search of Medline database (PubMed), EMBASE, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang databases for publications on BAX polymorphisms, and susceptibility and prognosis was carried out until July 2017. Retrieved 14 articles met the inclusions. Summary odds ratios (ORs) and hazard ratios (HRs) with their 95% confidence intervals (CIs) were harnessed to determine the strength of correlation between BAX polymorphisms and cancer susceptibility and prognosis, which were combined using fixed- or random-effects models as appropriate. RESULTS: A total of 12 trials involving 3321 cases and 3209 controls were included in our pooled analysis regarding the polymorphisms and the susceptibility of cancers. Overall, results of the present meta-analysis demonstrated that there was no significant association between BAX polymorphisms and susceptibility of cancers (OR = 1.052, 95% CI: 0.827-1.339, P = .679, A vs G). Even in a stratified analysis by ethnicity and the sources of control groups, the results were consistent. Four retrospective studies of 549 cases qualified for meta-analysis were identified to set forth the associations of the polymorphisms with cancer prognosis. Our results suggested that BAX gene polymorphisms were significantly associated with unfavorable prognosis (HR = 1.735, 95% CI: 1.368-2.202, P = .000, GG vs GA/AA). CONCLUSION: There is no significant association between BAX gene polymorphism and cancer susceptibility, but it probably contributes to increased adverse prognosis to cancer. PMID- 30024564 TI - Adjuvant treatment with Yupingfeng formula for primary nephrotic syndrome in children: A PRISMA systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Yupingfeng formula (YPFF) has been prescribed as adjuvant treatment for pediatric patients with primary nephrotic syndrome (PNS) in China for years. However, the efficacy and adverse effects of these formulations are controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to evaluate the benefits and harms of YPFF in treating PNS in children. METHODS: The MEDLINE, EMBASE, Cochrane Library, CNKI, VIP, WanFang, and CBM databases were searched for RCTs comparing therapies with and without YPFF for PNS from inception to May 13, 2017. Relative risk (RR) and 95% confidence intervals (CI) were expressed for dichotomous outcomes, and weighted mean difference (WMD) with 95% CI for continuous outcomes. Cochrane collaboration tool was used to evaluate the risk of bias of methodologies. RESULTS: Eight studies with 538 participants were identified. Treatment with YPFF significantly increased serum levels of IgA (WMD, 0.48, 95% CI, 0.40-0.56, P < .001), IgG (WMD, 3.36, 95% CI, 2.61-4.12, P < .001), CD4 T-lymphocytes (WMD, 3.35, 95% CI, 2.26-4.43, P < .001), but decreased the level of CD8 T-lymphocytes (WMD, -3.38, 95% CI -5.48 to -1.28, P = .002). YPFF also increased the rates of complete remission (RR: 1.35, 95% CI, 1.09-1.67, P = .005), and decreased the rates of relapse (RR: 0.57, 95% CI, 0.45-0.71, P < .001), and infection (RR: 0.72, 95% CI 0.62-0.83, P < .001). There was no significant difference in the level of IgM between the groups (WMD, 0.12, 95% CI -0.11-0.35, P = .322). CONCLUSIONS: YPFF could improve total remission rate and decrease the frequency of relapse and infection rate. The beneficial influence of YPFF may be associated with its immunomodulatory effects. More high-quality studies with larger sample sizes are needed to further identify its efficacy and safety. PMID- 30024567 TI - Tuina for osteoporosis: A systematic review protocol: Erratum. PMID- 30024568 TI - The outcomes and prognostic factors of the patients with unplanned intensive care unit readmissions: Erratum. PMID- 30024565 TI - Preoperative albumin-bilirubin grade plus platelet-to-lymphocyte ratio predict the outcomes of patients with BCLC stage A hepatocellular carcinoma after liver resection. AB - There is little information regarding the predictive ability of albumin-bilirubin grades (ALBI) plus platelet-to-lymphocyte ratio (PLR) in patients with hepatocellular carcinoma (HCC) following liver resection. In this study, we aimed to evaluate the prognostic power of the ALBI-PLR score in patients with hepatitis B virus-related (HBV-related) HCC within Barcelona Clinic Liver Cancer (BCLC) stage A after liver resection.Around 475 patients were included in this study. Patients with preoperative ALBI grades 1, 2, or 3 were allocated a score of 0, 1, or 2, respectively. Patients with preoperative PLR >150 or <=150 were allocated a score of 0 or 1, respectively. The ALBI-PLR score was the summary of the ALBI and PLR scores.During the follow-up period, 256 patients experienced recurrence, and 150 patients died. Multivariate analysis revealed tumor size, multiple tumors, positive HBV-DNA load, cirrhosis, and ALBI-PLR score as being independently associated with postoperative recurrence, whereas tumor size, high preoperative alpha-fetoprotein level, and ALBI-PLR score were independent risk factors for postoperative mortality. HCC patients with high ALBI-PLR score had poor recurrence-free and overall survival.The preoperative ALBI-PLR score is a surrogate marker for predicting HBV-related HCC patient's prognosis after liver resection. A high ALBI-PLR score is associated with a high incidence of postoperative recurrence and mortality. PMID- 30024566 TI - Remote intervention using smartphone for rural women suffering from premenstrual syndrome: A propensity score matched analysis. AB - Timely treatment of premenstrual syndrome (PMS) is not always available for rural women, because the local medical resources are insufficient. The efficacy of remote intervention by smartphone on PMS has not been confirmed.A retrospective analysis was performed on rural PMS patients between January 2014 and December 2015. After a propensity score matched analysis, 60 patients were enrolled and evenly divided into remote group and outpatient group. Multidisciplinary therapy including cognitive-behavioral therapy (CBT), oral medication, and physical exercise education was used individually, in accordance with their symptoms evaluated by Daily Record of Severity of Problems (DRSP) questionnaire. Patients in remote group utilized WeChat software by smartphone for therapy guidance, while those in outpatient group attended face-to-face interview. Their DRSP scores in 5 new menstrual cycles after therapy were recorded. Then, they were followed up for 1 year.Total DRSP scores of the cases in both groups after initial intervention were less than those before therapy (P < .001), without group difference (P > .05). However, patients in remote group indicated a higher satisfactory rate than the outpatient group (P = .03). On the 1-year follow up, patients in both groups demonstrated similar DRSP scores (P = .07), but the satisfactory rate in remote group was encouragingly higher than that in the outpatient group (P = .02).The efficacy of remote intervention using smartphone on PMS is noninferior to traditional outpatient visits. Nevertheless, high quality trials are needed. PMID- 30024569 TI - Alveolar paratesticular rhabdomyosarcoma mimicing epididymitis: Case report and literature review: Erratum. PMID- 30024570 TI - The Pediatric Index of Mortality as a Trigger Tool for the Detection of Serious Errors and Adverse Events. AB - OBJECTIVES: To test the hypothesis that patients who die in a PICU despite a low predicted mortality at PICU admission are affected by serious errors and adverse events. DESIGN: Retrospective cross-sectional review of medical records for serious errors and adverse events. SETTING: Tertiary interdisciplinary neonatal PICU. PATIENTS: All admissions to our PICU who died despite a low expected mortality (Pediatric Index of Mortality) of less than 10% (trigger-positive admissions). They were compared with a random sample of 100 PICU admissions with a Pediatric Index of Mortality of less than 10% who survived (trigger-negative admissions). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 7,383 admissions (91%) with a Pediatric Index of Mortality 2 below 10%. Seventy-two trigger-positive admissions and 100 trigger-negative admissions met the criteria for detailed chart review. Forty-five serious errors and adverse events were identified, 0.47 per trigger-positive admission and 0.11 per trigger-negative admission (p < 0.001). Nineteen serious errors and adverse events (42%) were related to clinical sepsis acquired during the PICU stay, 17 (89%) in trigger positive admissions and two (11%) in trigger-negative admissions (p < 0.001). A further 18 serious errors and adverse events (40%) were intervention related, nine (50%) in trigger-positive admissions and nine (50%) in trigger-negative admissions (p = 0.46). Eight serious errors and adverse events (18%) were associated with medication use, all of which occurred in trigger-positive admissions (p = 0.001). The median (interquartile range) age for admissions with and without serious errors and adverse events was 0.3 months (0.0-4.6 mo) and 7.4 months (0.4-58.4 mo) (p < 0.001), and their median (interquartile range) duration of invasive ventilation was 140 hours (50-451 hr) and 2 hours (0-41 hr) (p < 0.001), respectively. CONCLUSIONS: The records of PICU patients with a low expected mortality at admission and death in PICU should be reviewed routinely and/or discussed at morbidity and mortality meetings. These patients may have experienced more in-hospital safety-related events compared with PICU patients with a low Pediatric Index of Mortality who survived. Such adverse events may be amenable to system changes, thus improving patient care. PMID- 30024571 TI - Mitral Annular Plane Systolic Excursion as a Predictor of Mortality in Children With Septic Shock. AB - OBJECTIVES: Myocardial dysfunction is well recognized in severe sepsis and septic shock. Echocardiography provides rapid, noninvasive, and bedside evaluation of cardiac function in patients with hemodynamic instability. Mitral annular plane systolic excursion is an M-mode-derived echocardiographic variable used to assess longitudinal left ventricular systolic function. No data are available about the uses of mitral annular plane systolic excursion in children with septic shock. Therefore, we aimed to assess the prognostic significance of mitral annular plane systolic excursion in children with septic shock and to correlate it with the most commonly used measures of left ventricular systolic function and myocardial injury. DESIGN: A prospective cohort study. SETTING: The study carried out at the PICU of Menoufia University Hospital in the period from March 2015 to September 2016. PATIENTS: We serially enrolled 50 children with septic shock. INTERVENTIONS: Complete diagnostic workup was performed for each patient including calculation of Pediatric Risk of Mortality III score. Transthoracic echocardiography was done to obtain mitral annular plane systolic excursion and the left ventricular ejection fraction measurement within 24 hours of inclusion then repeated on third and fifth days. Patients were followed up until hospital discharge or death. The predictive power of mitral annular plane systolic excursion was determined using the receiver operating characteristic curve. MEASUREMENTS AND MAIN RESULTS: Mitral annular plane systolic excursion was significantly lower in nonsurvivors compared with survivors (p < 0.001). Receiver operating characteristic curve analysis showed an area under the curve of 0.892 for mitral annular plane systolic excursion on day 1. The cut-off point was 7.9 mm with 82.76% sensitivity and 80.95% specificity. Furthermore, follow-up of the patient's systolic function showed that mitral annular plane systolic excursion was significantly lower in nonsurvivors compared with survivors on days of follow up, whereas left ventricular ejection fraction was not significantly different between survivors and nonsurvivors at any day. Mitral annular plane systolic excursion was positively correlated with left ventricular ejection fraction (p = 0.044) and duration of hospital stay (p < 0.001) and negatively correlated with Pediatric Risk of Mortality III score (p < 0.001) and cardiac troponin I level (p < 0.001). CONCLUSIONS: Measurement of mitral annular plane systolic excursion at admission added a prognostic value in septic shock children. Compared with the left ventricular ejection fraction, longitudinal systolic function might be more sensitive in the detection of myocardial dysfunction in critically ill children and should receive more attention. PMID- 30024572 TI - Albumin 5% Versus Crystalloids for Fluid Resuscitation in Children After Cardiac Surgery. AB - OBJECTIVES: To determine the clinical benefit of using colloids versus crystalloids for volume resuscitation in children admitted after cardiac surgery. DESIGN: Retrospective pre-/postintervention cohort study. SETTING: Stollery Children's Hospital tertiary care pediatric cardiac ICU. PATIENTS: Children admitted to the pediatric cardiac ICU after cardiac surgery. INTERVENTIONS: Fluid resuscitation policy change in which crystalloids replaced albumin 5% as the primary fluid strategy for resuscitation after cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Children who underwent cardiac surgery in the 6 months prior to the policy change (5% albumin group) were compared with children admitted during the 6 months after (crystalloid group). Demographic, perioperative, and outcome variables (fluid intake days 1-4 postoperative, vasoactive therapy, blood products, time to negative fluid balance, renal replacement therapies, mechanical ventilation, pediatric cardiac ICU, and length of stay) were collected. Data were analyzed using linear and logistic multivariate analysis. The study included 360 children. There was no association between fluid group and fluid intake (mL/kg) on day 1 postoperatively (coefficient, 2.84; 95% CI, 5.37-11.05; p = 0.497). However, crystalloid group was associated with significantly less fluid intake on day 2 (coefficient, -12.8; 95% CI, -22.0 to -3.65; p = 0.006), day 3 (coefficient, -14.9; 95% CI, -24.3 to -5.57; p = 0.002), and on the first 48 hours postoperative (coefficient, 10.1; 95% CI, -27.9 to -1.29; p = 0.032). Pediatric cardiac ICU stay (coefficient, -1.29; 95% CI, -2.50 to -0.08; p = 0.036) was shorter for the crystalloid group. There were no significant differences in the time to negative balance, need for renal replacement therapy, mechanical ventilation days, hospital stay, or pediatric cardiac ICU survival. CONCLUSIONS: In our study, the use of albumin 5% for resuscitation after cardiac surgery was not associated with less fluid intake but rather the opposite. Albumin administration did not provide measured clinical benefit while exposing children to side effects and generating higher costs to the healthcare system. PMID- 30024573 TI - Major Adverse Events Following Over-Shunting Are Associated With Worse Outcomes Than Major Adverse Events After a Blocked Systemic-to-Pulmonary Artery Shunt Procedure. AB - OBJECTIVES: Causes of major adverse event after systemic-to-pulmonary shunt procedure are usually shunt occlusion or over-shunting. Outcomes categorized on the basis of these causes will be helpful both for quality improvement and prognostication. DESIGN: Retrospective cohort analysis of children who underwent a systemic-to-pulmonary shunt after excluding those who had it for Norwood or Damus-Kaye-Stansel procedure. SETTING: The Royal Children's Hospital, Melbourne, VIC, Australia. PATIENTS: From 2008 to 2015, 201 children who had a systemic-to pulmonary shunt were included. INTERVENTIONS: Major adverse event is defined as one or more of cardiac arrest, chest reopening, or requirement for extracorporeal membrane oxygenation. Study outcome is a "composite poor outcome," defined as one or more of acute kidney injury, necrotizing enterocolitis, brain injury, or in hospital mortality. MEASUREMENTS AND MAIN RESULTS: Median (interquartile range) age was 12 days (6-38 d) and median (interquartile range) time to major adverse event was 5.5 hours (2-17 hr) after admission. Overall, 36 (18%) experienced a major adverse event, and reasons were over-shunting (n = 17), blocked shunt (n = 13), or other (n = 6). Fifteen (88%) in over-shunting group suffered a cardiac arrest compared with two (15%) in the blocked shunt group (p < 0.001). The composite poor outcome was seen in 15 (88%) in over-shunting group, four (31%) in the blocked shunt group, and 56 (34%) in those who did not experience a major adverse event (p < 0.001). By multivariable analysis, predictors for composite poor outcome were major adverse event due to over-shunting (no major adverse event-reference; over-shunting odds ratio, 18.60; 95% CI, 3.87-89.4 and shunt block odds ratio, 1.57; 95% CI, 0.46-5.35), single ventricle physiology (odds ratio, 4.70; 95% CI, 2.34-9.45), and gestation (odds ratio, 0.84/wk increase; 95% CI, 0.74-0.96). CONCLUSIONS: Infants who suffer major adverse event due to over shunting experience considerably poorer outcomes than those who experience events due to shunt block. A mainly hypoxic event with maintenance of systemic perfusion (as often seen in a blocked shunt) is less likely to result in poorer outcomes than those after a hypoxic-ischemic event (commonly seen in over-shunting). PMID- 30024574 TI - TYPICAL POLYPOIDAL CHOROIDAL VASCULOPATHY AND POLYPOIDAL CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: To compare typical polypoidal choroidal vasculopathy (T-PCV) and polypoidal choroidal neovascularization (P-CNV), which can be defined as two subtypes of PCV, and to elucidate the significance of the classification. METHODS: Seventy-seven patients diagnosed with PCV and followed up for more than 12 months were reviewed. The PCV cases were divided into a T-PCV group (n = 36) and a P-CNV group (n = 41) according to the presence of features of pachychoroid or age-related macular degeneration. Angiographic and tomographic characteristics and changes in vision during the follow-up period were compared between the two groups. RESULTS: Logarithm of the minimum angle of resolution visual acuity of T PCV and P-CNV was 0.27 +/- 0.31 and 0.62 +/- 0.47 at baseline (P < 0.001) and 0.28 +/- 0.41 and 0.54 +/- 0.52 at the final visit (P = 0.006), respectively. A marginally higher rate of complete response to anti-vascular endothelial growth factor treatment was noted in the T-PCV group (47.2%) compared with the P-CNV group (26.8%) (P = 0.05). At the final visit, subfoveal fibrosis was noted in 11.1% of the T-PCV group and 39.0% of the P-CNV group (P = 0.009). CONCLUSION: The two subtypes of PCV, P-CNV and T-PCV, behave differently in terms of angiographic and tomographic manifestations and visual outcomes. Classifying PCVs would be helpful not only for pathogenic implications, but also for prognostic significance. PMID- 30024575 TI - 27-GAUGE SUTURELESS INTRASCLERAL FIXATION OF INTRAOCULAR LENSES WITH HAPTIC FLANGING: Short-Term Clinical Outcomes and a Disinsertion Force Study. AB - PURPOSE: To determine whether haptic flanging during 27-gauge sutureless intrascleral fixation of intraocular lenses (IOLs) increases IOL stability and to report the short-term clinical outcomes of sutureless intrascleral surgery using 27-gauge trocar cannulas with haptic flanging. METHODS: Retrospective surgical case series using live and cadaveric human eyes. RESULTS: In the cadaveric experiment using five eyes, flanged haptics required more force to dislocate the IOL compared with unflanged haptics (14 +/- 4 vs. 3 +/- 1 g, P = 0.03). The clinical series included 52 eyes from 52 patients. The average age at the time of surgery was 73 +/- 14 years, with a mean follow-up of 27 +/- 19 weeks. The most common indication for surgery was IOL dislocation/subluxation (n = 43, 83%). Mean visual acuity improved from 20/140 preoperatively to 20/50 at postoperative Month 1 (P < 0.001). The most common postoperative issue was intraocular pressure elevation (n = 12, 23%). Two patients (4%) needed a reoperation for IOL dislocation. CONCLUSION: Haptic flanging during 27-gauge sutureless intrascleral surgery creates a more stable scleral-fixated IOL compared with the traditional unflanged technique based on a cadaveric human eye study. In addition, this variation of sutureless intrascleral surgery seems safe and effective for patients who require secondary IOLs. PMID- 30024576 TI - AMPLITUDE LOSS OF THE HIGH-FREQUENCY FLICKER ELECTRORETINOGRAM IN EARLY DIABETIC RETINOPATHY. AB - PURPOSE: To evaluate retinal dysfunction in diabetic patients who have mild or no nonproliferative diabetic retinopathy (DR) using the high-frequency flicker electroretinogram. METHODS: Light-adapted flicker electroretinograms were recorded from 15 diabetic patients who have no clinically apparent retinopathy, 15 diabetic patients who have mild nonproliferative DR, and 15 nondiabetic, age equivalent controls. Electroretinograms were elicited by full-field flicker at 2 temporal frequencies, 31.25 and 62.5 Hz, and were recorded using conventional techniques. Amplitude and timing of the flicker responses were compared among the groups and correlated with clinical characteristics including age, acuity, disease duration, and HbA1c. RESULTS: The 31.25-Hz flicker amplitude was slightly, but nonsignificantly, smaller for subjects with no DR and mild nonproliferative DR , compared with the control group (both t < 1.38, P > 0.31); small, nonsignificant response delays for both patient groups were also observed (both t < 1.57, P > 0.12). By contrast, there were significant amplitude reductions for the 62.5-Hz flicker stimulus: mean amplitude was reduced by 32% for subjects with no DR and by 41% for subjects with mild nonproliferative DR (both t > 2.92 and P < 0.01). Response timing at 62.5 Hz did not differ significantly from control for either group (both t < 1.2 and P > 0.39). Electroretinogram amplitude and timing were not correlated significantly with clinical characteristics. CONCLUSION: The 62.5-Hz flicker electroretinogram is useful for evaluating retinal dysfunction in diabetic patients who have mild or no DR because this response can be significantly reduced. Attenuation of the high frequency flicker electroretinogram, which is primarily generated by bipolar cells, suggests a relatively early retinal site of neural dysfunction. PMID- 30024577 TI - High-yield graphene produced from the synergistic effect of inflated temperature and gelatin offers high stability and cellular compatibility. AB - The direct exfoliation of graphite (Gr) is highly desirable and feasible compared to conventional processes owing to its non-oxidative, facile and controlled synthesis conditions. Herein, gelatin (gel), a hydrolysed form of collagen, was used as an exfoliant to directly exfoliate Gr. The main advantages of exploring gel as an exfoliant is its easy availability, low cost and high biocompatibility, which alleviate the drawbacks of previous exfoliation methods. The effect of the exfoliation parameters such as temperature, ratio of interacting species and pH of the solution offers a high yield of graphene (G) with the added advantages of good solubility, easy dispersibility and high stability. The temperature elevation caused by the dissipation of sonic waves facilitates a high exfoliation yield. Yield of 4.37 mg mL-1 of G was achieved under the conditions of 7 h sonication at 60 degrees C, pH 7 and Gr to gel ratio of 60 : 40, whereas yield of 1 mg mL-1 was achieved under sonication at 30 degrees C. Raman spectroscopy and transmission electron microscopy indicated the production of G sheets with 3 5 layers. The adsorption of gel on the surface of G via pi-pi interactions offers high stability and retains its inherent crystallinity. The as-synthesized G dispersion exhibits good cyto- and hemocompatibility. Unlike graphene oxide, the G dispersion does not affect RBCs at a relatively high concentration of 10 mg mL 1. These findings offer new avenues for the large-scale production of G and promote its biomedical applications, particularly in scaffold materials and intravenous drug delivery. PMID- 30024578 TI - Chiral supramolecular coordination cages as high-performance inhibitors against amyloid-beta aggregation. AB - Four pairs of chiral supramolecular coordination cages were facilely synthesized, and they could efficiently inhibit amyloid-beta (Abeta) aggregation with a high inhibition rate of 0.64-0.86. This research provides a new perspective on the design of chiral Abeta inhibitors using supramolecular metal-organic cages. PMID- 30024579 TI - Catalytic chemistry of glucose oxidase in cancer diagnosis and treatment. AB - Glucose oxidase (GOx) is an endogenous oxido-reductase that is widely distributed in living organisms. Over recent years, GOx has attracted increasing interest in the biomedical field due to its inherent biocompatibility, non-toxicity, and unique catalysis against beta-d-glucose. GOx efficiently catalyzes the oxidization of glucose into gluconic acid and hydrogen peroxide (H2O2), which can be employed by various biosensors for the detection of cancer biomarkers. Various cancer therapeutic strategies have also been developed based on the catalytic chemistry of GOx: (1) the consumption of glucose provides an alternative strategy for cancer-starvation therapy; (2) the consumption of oxygen increases tumor hypoxia, which can be harnessed for hypoxia-activated therapy; (3) the generation of gluconic acid enhances the acidity of the tumor microenvironment, which can trigger pH-responsive drug release; (4) the generation of H2O2 increases the levels of tumor oxidative stress, and the H2O2 can be converted into toxic hydroxyl radicals that can kill cancer cells upon exposure to light irradiation or via the Fenton reaction. More importantly, GOx can be combined with other enzymes, hypoxia-activated prodrugs, photosensitizers or Fenton's reagents, to generate multi-modal synergistic cancer therapies based on cancer starvation therapy, hypoxia-activated therapy, oxidation therapy, photodynamic therapy, and/or photothermal therapy. Such multi-modal approaches are anticipated to exert a stronger therapeutic effect than one therapeutic mode alone. Thus, maximizing the potential of GOx in a biomedical context will offer novel clinical solutions to diagnose and treat cancer. In this tutorial review, we introduce the recent advances of GOx in cancer diagnosis and treatment. We then emphasize the design principles and biomedical applications of GOx-based biosensors and cancer therapeutic approaches. Finally, we discuss the challenges and future prospects of GOx-based catalytic systems in biomedicine. PMID- 30024581 TI - Asymmetric iodine catalysis-mediated enantioselective oxidative transformations. AB - The implementation of chiral iodine catalysis has tremendously been developed in the field of asymmetric synthesis over the past decade. It enables the stereoselective creation of C-O as well as C-C, C-N and C-X (X = halogen) bonds through oxidative transformations. Thanks to the low toxicity and ease of handling of iodine compounds, this strategy offers many advantages over classical metal-catalyzed oxidations with chiral ligands. The approaches rely on iodine(i/iii) or (-i/+i) catalysis by using a chiral aryliodine or ammonium iodide respectively in combination with a suitable terminal oxidant. As such, the design of iodine compounds with central, axial or even planar chirality has allowed us to achieve high enantioselectivities. The goal of this review is to cover the different chiral iodine compound-catalyzed oxidative transformations including alpha-functionalization of carbonyl compounds, dearomatization of phenol derivatives and difunctionalization of alkenes which should demonstrate that iodine catalysis has now found its place in the realm of asymmetric organocatalysis. PMID- 30024580 TI - Peripheral cyclic beta-amino acids balance the stability and edge-protection of beta-sandwiches. AB - Engineering water-soluble stand-alone beta-sandwich mimetics is a current challenge because of the difficulties associated with tailoring long-range interactions. In this work, single cis-(1R,2S)-2-aminocyclohexanecarboxylic acid mutations were introduced into the edge strands of the eight-stranded beta sandwich mimetic structures from the betabellin family. Temperature-dependent NMR and CD measurements, together with thermodynamic analyses, demonstrated that the modified peripheral strands exhibited an irregular and partially disordered structure but were able to exert sufficient shielding on the hydrophobic core to retain the predominantly beta-sandwich structure. Although the frustrated interactions decreased the free energy of unfolding, the temperature of the maximum stabilities increased to or remained at physiologically relevant temperatures. We found that the irregular peripheral strands were able to prevent edge-to-edge association and fibril formation in the aggregation-prone model. These findings establish a beta-sandwich stabilization and aggregation inhibition approach, which does not interfere with the pillars of the peptide bond or change the net charge of the peptide. PMID- 30024582 TI - Complex coacervation-based loading and tunable release of a cationic protein from monodisperse glycosaminoglycan microgels. AB - Glycosaminoglycans (GAGs) are of interest for biomedical applications because of their ability to retain proteins (e.g. growth factors) involved in cell-to-cell signaling processes. In this study, the potential of GAG-based microgels for protein delivery and their protein release kinetics upon encapsulation in hydrogel scaffolds were investigated. Monodisperse hyaluronic acid methacrylate (HAMA) and chondroitin sulfate methacrylate (CSMA) micro-hydrogel spheres (diameters 500-700 MUm), were used to study the absorption of a cationic model protein (lysozyme), microgel (de)swelling, intra-gel lysozyme distribution and its diffusion coefficient in the microgels dispersed in buffers (pH 7.4) of varying ionic strengths. Upon incubation in 20 mM buffer, lysozyme was absorbed up to 3 and 4 mg mg-1 dry microspheres for HAMA and CSMA microgels respectively, with loading efficiencies up to 100%. Binding stoichiometries of disaccharide : lysozyme (10.2 : 1 and 7.5 : 1 for HAMA and CSMA, respectively) were similar to those for GAG-lysozyme complex coacervates based on soluble GAGs found in literature. Complex coacervates inside GAG microgels were also formed in buffers of higher ionic strengths as opposed to GAG-lysozyme systems based on soluble GAGs, likely due to increased local anionic charge density in the GAG networks. Binding of cationic lysozyme to the negatively charged microgel networks resulted in deswelling up to a factor 2 in diameter. Lysozyme release from the microgels was dependent on the ionic strength of the buffer and on the number of anionic groups per disaccharide, (1 for HAMA versus 2 for CSMA). Lysozyme diffusion coefficients of 0.027 in HAMA and <0.006 MUm2 s-1 in CSMA microgels were found in 170 mM buffer (duration of release 14 and 28 days respectively). Fluorescence Recovery After Photobleaching (FRAP) measurements yielded similar trends, although lysozyme diffusion was likely altered due to the negative charges introduced to the protein through the FITC-labeling resulting in weaker protein matrix interactions. Finally, lysozyme-loaded CSMA microgels were embedded into a thermosensitive hydrogel scaffold. These composite systems showed complete lysozyme release in ~58 days as opposed to only 3 days for GAG-free scaffolds. In conclusion, covalently crosslinked methacrylated GAG hydrogels have potential as controlled release depots for cationic proteins in tissue engineering applications. PMID- 30024583 TI - Csp3-H bond functionalization of amines via tunable iminium ions: divergent synthesis of trifluoromethylated arylamines. AB - A series of tunable iminium ions, generated in situ by the condensation of 4 trifluoromethyl-p-quinols with cyclic amines, can lead to the divergent synthesis of trifluoromethylated arylamines in a single step via redox-neutral isomerization. The direct alpha- and beta-functionalization of saturated amines can be achieved regioselectively under mild conditions. PMID- 30024584 TI - Janus-faced role of water in defining nanostructure of choline chloride/glycerol deep eutectic solvent. AB - Deep eutectic solvents (DESs) have emerged as a set of intrinsically "designer solvents" for many bio-applications such as DNA nanotechnology and biocatalysis. However, the high viscosity of DESs tends to prevent bioactive components from being incorporated into the solvent. Although dilution with water may effectively reduce the viscosity of DES, the effect of water on its cooperative hydrogen bonding network has not been evaluated systematically. This study conducted a series of molecular dynamics simulations on the DES made of choline chloride and glycerol at different hydration levels. We discovered a Janus-faced role of water in defining the interactive network between choline chloride and glycerol. Chloride played a critical role in bridging choline and glycerol in the anhydrous mixture. But the addition of water results in the decrease in the number of choline-chloride-glycerol supramolecular complexes and the number of hydrogen bonds between choline and glycerol, demonstrating the de-structuring effect of water. Interestingly, we also found that water could link choline to glycerol in place of chloride. The structuring role of water in bridging choline and glycerol reached its maximum in the presence of 35.8 wt% water. The findings in this study will provide valuable guidance to determine the optimal water content that can sufficiently "liquidize" DESs and meanwhile maintain the majority of the eutectic stoichiometry in the DESs, paving the way for tapping the full potential of DESs as the intrinsically "designer solvents". PMID- 30024586 TI - Electrophilic carbocyclization reactions of 2-(2-alkynylphenyl)amino-1,4 naphthoquinones. AB - An efficient Ag(i)-catalyzed method for the synthesis of 5H-benzo[b]naphtho[2,3 f]azepine-6,11-diones from 2-(2-ethynylphenyl)amino substituted 1,4 naphthoquinones has been developed. In this transformation new C-C bond formation occurred regioselectively via a 7-endo-dig cyclization. The related 13-iodine substituted benzazepine derivatives could also be produced exclusively by the I2 induced carbocyclization reaction of 2-(2-alkynylphenyl)amino substituted 1,4 naphthoquinones. This process has advantages such as mild reaction conditions and tolerance of a broad range of functional groups. PMID- 30024585 TI - Thermodynamics of Sr2NiMoO6 and Sr2CoMoO6 and their stability under reducing conditions. AB - The values of standard enthalpy of formation at 298.15 K and 1 atm for the double perovskites Sr2NiMoO6 and Sr2CoMoO6, measured by means of drop solution calorimetry, were found to be -2418.1 +/- 12.4 and -2422.9 +/- 9.6 kJ mol-1, respectively. Heat capacity of Sr2NiMoO6 and Sr2CoMoO6 was measured between 2 and 370 K using relaxation and adiabatic calorimetry, and the enthalpy increments - between 373 and 1273 K using drop calorimetry. Low-temperature magnetic and higher-temperature structural phase transformations in Sr2NiMoO6 and Sr2CoMoO6 were discussed from the thermodynamic point of view. Specific heat (Cp), standard enthalpy (DeltaT0H0) and standard entropy (S0) functions were derived from the experimental data for both double perovskites. The values of Cp, DeltaT0H0 and S0 at 298.15 K were determined to be 202.31 +/- 0.61 J mol-1 K-1, 36.12 +/- 0.18 kJ mol-1 and 231.3 +/- 1.6 J mol-1 K-1 for Sr2NiMoO6, and 212.66 +/- 0.64 J mol-1 K 1, 38.25 +/- 0.19 kJ mol-1 and 244.4 +/- 1.7 J mol-1 K-1 for Sr2CoMoO6, respectively. Additionally, using the thermodynamic data available, phase diagrams with respect to T and pO2 showing stability limits and decomposition products were calculated for Sr2NiMoO6 and Sr2CoMoO6. Though the cobaltite's stability range is wider than nickelate's both in terms of T and pO2, both complex oxides were found to be stable only at reasonably high temperatures and in oxidizing conditions, and metastable at low temperatures. PMID- 30024587 TI - Photodynamic therapy-mediated remote control of chemotherapy toward synergistic anticancer treatment. AB - Stimuli-responsive nanomedicine (NM) with an on-demand drug release property has demonstrated promising utility toward cancer therapy. However, sensitivity and cancer selectivity still remain critical challenges for intelligent NM, which will compromise its therapeutic efficacy and lead to undesired toxicity to normal tissues. Herein, we report a convenient and universal approach to spatiotemporally control the chemodrug release via the photodynamic therapy (PDT) mediated alteration of the tumor microenvironment. An arylboronic ester (BE) modified amphiphilic copolymer (mPEG-PBAM) was designed to form micelles and encapsulate doxorubicin (Dox) and hematoporphyrin (Hp). The Dox/Hp co encapsulated micelles (PB-DH) were stable under normal physiological environment with a uniform size distribution (~100 nm). In contrast, under tumor-specific light irradiation, extensive reactive oxygen species (ROS) will be generated from Hp in the tumor sites, thus quickly dissociating the micelles and selectively releasing the chemodrug Dox as a consequence of the ROS-mediated cleavage of the hydrophobic BE moieties on the polymers. As such, synergistic anti-cancer efficacy was achieved between the Dox-mediated chemotherapy and the Hp-mediated PDT. This study therefore provides a useful approach to realize the precise and selective control over chemodrug delivery, and it renders promising utilities for the programmable combination of PDT and chemotherapy. PMID- 30024588 TI - A two-stage assembly with PEI induced emission enhancement of Au-AgNCs@AMP and the intrinsic mechanism. AB - Recently, aggregation-induced emission (AIE) properties have been revealed for some metal nanoclusters (NCs), providing a new approach to improve the quantum yields (QY). In the present study, a two-stage assembly was carried out between adenosine monophosphate capped bimetallic nanoclusters of gold and silver (Au AgNCs@AMP) and polyethylenimine (PEI), in which the QY was improved from 8.64% to 25.02%, showing obvious assembly induced emission enhancement (AIEE) properties. The intrinsic mechanisms of the assembly and emission enhancement in two stages were studied in depth, which indicated that the electrostatic interaction between the phosphate group in AMP and the amino group in PEI restricted the intramolecular vibration and rotation of capping ligands, and reduced the non radiative relaxation of the corresponding excited states in stage I; in stage II, the micellization of PEI at high concentration pushed the NCs into a less polar environment and greatly enhanced the metal-metal interaction between them, which facilitated the excited state relaxation dynamics via a radiative pathway. Therefore, the luminescence enhancement depended on the assembly process in two stages directly. The present study is beneficial to understand the AIEE mechanism and the design principles, which will expand the applications of metal NCs. PMID- 30024589 TI - Clinical and radiographic assessment of implant-supported rehabilitation of partial and complete edentulism: a 2 to 8 years clinical follow-up. AB - OBJECTIVE: The aim of this study was to find out the rates of survival and success of implant rehabilitation, and the influence of some risk indicators on the medium- and long-term prognosis. PATIENTS AND METHODS: Of the 102 patients eligible for this study rehabilitated with dental implants during the years 2009 2015, 75 patients with 156 implants of different implant systems placed and loaded by the same team were recalled. For each subject, pocket-probing depth, bleeding on probing, plaque buildup, mobility of the fixtures, and the presence/absence of prosthetic complications were recorded. Radiographic evaluation was based on the analysis of bone levels around the fixtures, as shown by intraoral radiographs. RESULTS: The average follow-up was 4.4 years, ranging from 1.5 to 7.8 years. One hundred and fifty-four of the implants survived, while two implants failed; 98.8% of the prostheses survived, while 75.9% were successful. Success was achieved in 90.4% of implants and in 80% of patients. The sample showed average radiographic bone resorption of 1.09 mm. The average pocket probing depth was 2.79 mm. Bleeding on probing was found in 18% of all sites, and 59.6% of implants showed bleeding on probing in at least one site. Mucositis was found in 90% of patients, and peri-implantitis was found in 16% of patients. CONCLUSIONS: The rates of success and survival showed the reliability of implant therapy. Plaque accumulation, smoking and upper jaw location, seem to increase the risk of failure of implant-supported rehabilitation. PMID- 30024590 TI - MiR-181d promotes steroid-induced osteonecrosis of the femoral head by targeting SMAD3 to inhibit osteogenic differentiation of hBMSCs. AB - OBJECTIVE: We aimed to investigate whether miR-181d may be involved in steroid induced osteonecrosis of the femoral head (ONFH) and its underlying mechanism. PATIENTS AND METHODS: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-181d in bone marrow of 5 cases of steroid-induced femoral head necrosis and 5 cases of femoral head necrosis secondary to femoral neck fractures. Marrow-derived mesenchymal stem cells (MSCs) were obtained from bone marrow samples and identified. Subsequently, the effects of miR-181d on osteogenic differentiation were evaluated by alizarin red staining and alkaline phosphatase. Meanwhile, qRT-PCR was performed to detect the levels of osteoblast-specific genes. RESULTS: The expression of miR-181d in the bone marrow of patients with steroid-induced osteonecrosis of the femoral head was significantly higher than that in the control group. When the expression of miR-181d in MSCs was upregulated, the ALP staining became lighter and the number of calcified nodules, as well as the expression of osteoblast-specific genes, decreased significantly. Meanwhile, the opposite results were observed when miR-181d expression was inhibited. Western blot and luciferase reporting assay proved that miR-181d could negatively regulate the expression of SMAD3. CONCLUSIONS: MiR-181d can inhibit the differentiation of hBMSCs into osteoblasts by regulating the expression of SMAD3. PMID- 30024591 TI - The study on pathological mechanism and solution method for spinal cord ischemia reperfusion injury. AB - OBJECTIVE: We aimed at investigating the pathological mechanism changing of injury during reperfusion injury, reperfusion time correlation and compliance, finding the blood supply and improving the secondary damage. MATERIALS AND METHODS: A total of 180 patients who underwent a surgical procedure and that received normal saline intraperitoneally immediately after the patients' aortic occlusions were investigated. Patients were divided in three groups. Experimental conditions and programs were designed for various approaches. RESULTS: Thirty min after the onset of ischemia, we found a decrease in the local blood flow in the lumbar spinal cord, almost -77.48% of the baseline, which was reversed partially by initial reperfusion, even exceeding the baseline level. However, 1 hour after reperfusion, the blood flow was again decreased to the level below the baseline, followed by a decline to 207.13% +/- 38.25 PU for 3 h without any recovery. Attenuating this secondary damage with neuroprotective strategies requires an understanding of these pathophysiologic processes. CONCLUSIONS: This study showed the pathological mechanism changes during reperfusion injury and reperfusion time correlation and compliance, and analyzed some of the important pathophysiologic processes involved in secondary damage after spinal cord injury. Moreover, our research discusses a number of pharmacologic therapies that have either been studied or have future potential for this devastating injury. PMID- 30024592 TI - The regulation of DLTA gene in bacterial growth and biofilm formation by Parvimonas micra. AB - OBJECTIVE: To evaluate the effect of dltA-deficient mutant on the bacterial growth and biofilm formation by P. micra ATCC 33270. Parvimonas micra contributes to many human polymicrobial infections, and is common in dental plaque biofilms of patients with periodontal and endodontic conditions. Lipoteichoic acid (LTA) performs several functions in gram-positive bacteria, including maintenance of cationic homeostasis and modulation of autolytic activities. The activation of dltA gene expression protects LTA expressing gram-positive bacteria from innate immune anti-microbial defense. MATERIALS AND METHODS: Deficient mutant of the dltA gene was created from P. micra ATCC 33270 by homologous recombination. Colony-forming units (CFUs) and turbidity helped estimate the growth of P. micra. Crystal violet staining, Confocal Scanning Laser Microscopy (CSLM) and Scanning Electron Microscopy (SEM) evaluated biofilm mass and structure. RESULTS: P. micra ATCC 33270 with dltA-deficient mutant was successfully established. CFUs of the wild-type strains were significantly higher than that of the dltA-deficient mutant strains after 24 h, 48 h, 72 h and 7 d culture (all p < 0.05). The growth rate of dltA-deficient mutant strains was significantly lower than their wild type counterparts. Furthermore, crystal violet staining showed that the dltA mutant formed significantly less biofilm as compared to wild-type strains. The dltA-deficient mutant synthesized a thin and incomplete biofilm after incubation for 48 h. With increasing incubation time, all biofilm units were seen to shrink, and this structure almost disappeared after 7 days of culture as observed by CSLM and SEM. CONCLUSIONS: The dltA gene is associated with bacterial growth and biofilm formation by P. micra ATCC 33270. PMID- 30024593 TI - MiR-6836-3p promotes proliferation of hypertrophic scar fibroblasts by targeting CTGF. AB - OBJECTIVE: To explore the role of micro ribonucleic acid (miR)-6836-3p in regulating hypertrophic scar (HS) and its potential mechanism. PATIENTS AND METHODS: The level of miR-6836-3p in HS or normal skin was determined by Real Time Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Cell counting kit 8 (CCK8) and flow cytometry were applied to explore the effect of miR-98 on the growth and apoptosis of HS fibroblasts (HSFBs). Luciferase assay was employed to acknowledge whether connective tissue growth factor (CTGF) is a target of miR 6836-3p. Western blotting was used to detect the protein expression of CTGF after transfection with miR-6836-3p mimic or inhibitor. RESULTS: MiR-6836-3p expression was much higher in HS than that in normal skin. MiR-6836-3p mimic promoted fibroblast growth, and CTGF was confirmed to be a direct target of miR-6836-3p. The results of Western blotting clarified that miR-6836-3p mimic raised the level of CTGF, and its expression was positively correlated with that of CTGF. CONCLUSIONS: MiR-6836-3p promoted the development of HS by increasing the expression of CTGF. MiR-6836-3p may be a potential novel molecular target for the treatment of HS. PMID- 30024594 TI - NF-kappaB inhibits the differentiation of hysteromyoma cells by reducing myocardin expression. AB - OBJECTIVE: To investigate the effect of nuclear factor-kappaB (NF-kappaB) on the myocardin-mediated differentiation of hysteromyoma cells. MATERIALS AND METHODS: Expression levels of myocardin in hysteromyoma cells from patients with hysteromyoma were detected. Normal uterine smooth muscle cells were used as control group. Overexpression of myocardin in hysteromyoma cells was achieved through lentivirus infection. Changes in expression levels of uterine smooth muscle cell maker p21, p57, Cyclin D1, PCNA, SM22alpha, and alphaSMA were detected. Hysteromyoma cells with lentivirus infection were stimulated by lipopolysaccharide (LPS), and changes in expression levels of myocardin were detected. RESULTS: Compared with normal uterine smooth muscle cells, the expression level of myocardin in hysteromyoma cells was extremely low, or even undetectable, and expression levels of smooth muscle cell differentiation markers were also minimal, and cells were in the de-differentiated state. Expression of exogenous myocardin can improve the expression of smooth muscle cell differentiation markers to induce cell re-differentiation. LPS stimulation can activate NF-kappaB to inhibit myocardin expression, thereby inducing cell dedifferentiation. CONCLUSIONS: NF-kappaB can inhibit the differentiation of hysteromyoma cells by decreasing the expression level of myocardin. PMID- 30024595 TI - MiR-200a promotes cell invasion and migration of ovarian carcinoma by targeting PTEN. AB - OBJECTIVE: To explore the role of miR-200a combined with PTEN in the progression of ovarian carcinoma. PATIENTS AND METHODS: The human ovarian cancer tissues and normal adjacent tissues (n = 57) were obtained from our hospital. The human ovarian cancer cell lines OVCAR3 and A2780, the human ovarian surface epithelial cell line (HOSEpiC), and HEK293T cells were used in this study. Cell migration assay and invasion assay were used to detect the ability of cell migratory. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blotting were used to detect the expression of miRNA and proteins. RESULTS: The clinic pathological analysis suggested a significant correlation with lymph node metastasis and tumor-lymph node metastasis (TNM) stage. Moreover, miR-200a was identified as aberrantly up-regulated in ovarian carcinoma tissues and cell lines. Through transwell analysis, the miR-200a overexpression significantly enhanced the cell migratory and invasive abilities. Luciferase assay validated phosphatase and tensin homolog (PTEN) was a miR-200a's direct and functional target gene. The miR-200a overexpression reduced the PTEN expression in OVCAR3 cells while the expression of PTEN was increased via miR-200a inhibitor as confirmed by Western blot. Furthermore, over-expression of PTEN was found reversing the inhibition of cell migration and invasion caused by miR-200a. CONCLUSIONS: MiR-200a has a carcinogenic effect on ovarian cancer through regulating PTEN. PMID- 30024596 TI - LncRNA NEAT1 regulates cervical carcinoma proliferation and invasion by targeting AKT/PI3K. AB - OBJECTIVE: Cervical cancer is a common tumor in gynecological malignancies. Recent studies showed that long non-coding RNAs (lncRNAs) play a key role in tumorigenesis and development. LncRNA nuclear-rich transcripts 1 (NEAT1) has been found to play a role in gynecological tumors, such as endometrial cancer. However, expression of lncRNA NEAT1 and mechanism in cervical cancer has not been elucidated. MATERIALS AND METHODS: The tumor tissue and adjacent tissue of cervical cancer patients were collected. HeLa cells were cultured in vitro and lncRNA NEAT1 expression was interfered with small interfere RNA (siRNA). Cell proliferation was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H tetrazolium bromide (MTT) assay. Cell invasion ability was assessed by transwell assay. LncRNA NEAT1, Cyclin D1, and cyclin-dependent kinase 4 (CDK4) expressions were detected by Real-time PCR. Caspase 3 expression was detected by caspase 3 activity kit. Phosphorylated protein kinase B (p-AKT), phosphatidylinositol 3 kinase (p-PI3K), and matrix metalloproteinase-2 (MMP2) levels were evaluated by Western blot. RESULTS: Compared with the adjacent tissue, lncRNA NEAT1 expression was significantly increased in cervical cancer (p<0.05). LncRNA NEAT1 level was decreased in HeLa cells transfected by siRNA, which inhibited the proliferation and invasion of tumor cells, reduced cyclin D1 and CDK4 expressions, enhanced caspase 3 activity, and declined the expressions of p-AKT, p-PI3K, and MMP2 (p<0.05). CONCLUSIONS: LncRNA NEAT1 siRNA transfection can inhibit the proliferation of cervical cancer by regulating the AKT/PI3K signaling pathway, promote cell apoptosis, and restrain cell invasion. Therefore, the lncRNA NEAT1 may be used as a molecular potential for the diagnosis and treatment of cervical cancer through regulating AKT/PI3K signaling pathway, which would be confirmed in the following study. PMID- 30024597 TI - SiRNA interfering STAT3 enhances DDP sensitivity in cervical cancer cells. AB - OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is an important regulatory protein in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which regulates cell proliferation, apoptosis, and other biological processes. It is closely related to tumor occurrence, progress, and resistance. Cisplatin (DDP) resistant cervical cancer cell line was established by shock induction to investigate the role of STAT3 in cervical cancer cells drug resistance. PATIENTS AND METHODS: The expression of STAT3 in different chemotherapy response cervical cancer tissues was compared. The cervical cancer was divided into two groups upon STAT3 median level. Cervical cancer cell inhibitory rate by DDP treatment was compared. Western blot was used to detect STAT3 and phosphorylated STAT3 (p-STAT3) expressions in CaSki and CaSki/DDP cells. Cell apoptosis rate was tested by flow cytometry. CaSki/DDP cells were divided into small interfere RNA-normal control (siRNA-NC) group and siRNA-STAT3 group. Cell proliferation was evaluated by EdU staining. RESULTS: The rate of STAT3 over-expression in cervical cancer patients with no significant chemotherapy response was markedly higher than that with a significant response. The inhibitory effect of DDP on tumor cells derived from patients with low STAT3 expression was significantly higher, while the apoptosis rate was apparently lower than that of CaSki/DDP cells from patients with high STAT3 expression. siRNA-STAT3 transfection significantly reduced the expressions of STAT3 and p STAT3, decreased cell proliferation, and enhanced cell apoptosis in CaSki/DDP cells. CONCLUSIONS: STAT3 over-expression is associated with DDP resistance in cervical cancer. Decreasing STAT3 can significantly promote the apoptosis of cervical cancer CaSki cells and decrease the DDP resistance. PMID- 30024598 TI - MiR-613 promotes cell proliferation and invasion in cervical cancer via targeting PTPN9. AB - OBJECTIVE: To investigate the potential effects of miR-613 on the development of cervical cancer (CC) and the relevant mechanism. PATIENTS AND METHODS: The expression level of miR-613 was detected in CC tissues and cells (siHa) by comparing with corresponding adjacent normal tissues and normal human embryonic kidney cells (293T). Luciferase assay was performed to evaluate the interaction between miR-613 and PTPN9. The effects of the miR-613 on siHa cells were determined by subsequent experiments including cell proliferation, invasion and migration. RESULTS: In our study, miR-613 was found up-regulated in CC tissues and the same result was found at cellular level. The potential target of miR-613 was analyzed by three public databases. We found that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) was a direct target of miR-613, and Luciferase assays confirmed our hypothesis. The subsequent experiments showed that decreased expression of PTPN9 resulting from up-regulation of miR-613 could promote the cell proliferation, invasion and migration of CC cells. CONCLUSIONS: We showed the promotion function of miR-613 on CC by targeting PTPN9 and revealed that miR-613/PTPN9 axis might be a potential therapeutic target for the treatment of CC. PMID- 30024599 TI - High expression of long non-coding RNA LOC730101 correlates with distant metastasis and exhibits a poor prognosis in patients with osteosarcoma. AB - OBJECTIVE: Expression of long non-coding RNA LOC730101 (LOC730101) has been closely linked to the carcinogenesis of osteosarcoma and has been shown to function as a tumor promoter. However, the clinical significance of LOC730101 remains unknown. Our present study aimed to investigate the feasibility of LOC730101 as a novel prognostic biomarker for osteosarcoma. PATIENTS AND METHODS: Quantitative Real-time RT-PCR (qRT-PCR) was performed to examine LOC730101 expression in osteosarcoma tissues and adjacent non-cancerous tissues. The correlation between LOC730101 expression and clinicopathological features and the overall survival rate was determined. Cox regression analyses were performed to explore whether LOC730101 was an independent predictor of survival for osteosarcoma patients. RESULTS: We found that LOC730101 was significantly upregulated in human osteosarcoma tissues compared with corresponding adjacent normal tissues (p < 0.01). Elevated LOC730101 expression was correlated with advanced clinical stage (p = 0.001) and distant metastasis (p = 0.005). Furthermore, survival assay revealed that osteosarcoma patients in the high LOC730101 expression group had significantly shorter 5-year overall survival time than those in the low LOC730101 expression group (p = 0.0002). In addition, multivariate analysis showed that LOC730101 maintained an independent prognostic influence on overall survival (p = 0.006). CONCLUSIONS: Our present study, for the first time, revealed that LOC730101 may serve as a poor prognostic indicator in patients with osteosarcoma. PMID- 30024600 TI - Reversing effect of NOTCH1 inhibitor LY3039478 on drug-resistance cells SGC7901/DDP of human gastric cancer and its mechanism. AB - OBJECTIVE: To investigate the reversing effects of NOTCH1 inhibitor LY3039478 on cancer of the stomach's drug-resistance cells SGC7901/DDP and its relevant mechanism. MATERIALS AND METHODS: Drug-resistance cells SGC7901/DDP of human gastric cancer before and after reversal via NOTCH1 inhibitor LY3039478 were used as objects of study. Changes in the expression of Hes protein in cells were detected via Western blotting; the inhibitory effect of drugs on cell multiplication was detected via cell counting kit-8 (CCK-8), and the Rhodamin123 (Rh123) efflux and P-glycoprotein (P-GP) expression level in cells were detected by flow cytometry. RESULTS: NOTCH1 inhibitor LY3039478 could inhibit the expression of Hes protein in SGC7901/DDP cells. Under the effect of 1 MUmol/L and 2 MUmol/L NOTCH1 inhibitor LY3039478, drug sensitivity of SGC7901/DDP cells to cisplatin was increased by 2.2 times and 2.86 times, respectively. The content of Rh123 in cells was increased by 1.41 times and 2.62 times, respectively, but the P-GP expression level was decreased by 67.5% and 45%, respectively. CONCLUSIONS: NOTCH1 inhibitor LY3039478 can inhibit or even reverse the multidrug resistance associated protein in SGC7901/DDP cells. The mechanism of drug resistance may be related to the decrease of Rh123 efflux and P-GP expression level in cancer cells. PMID- 30024601 TI - Long non-coding RNA NEAT1 promotes viability and migration of gastric cancer cell lines through up-regulation of microRNA-17. AB - OBJECTIVE: Gastric carcinoma (GC) is a common cancer with heavy mortality and poor outcome at advanced stages and metastasis. Long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to be an oncogene in GC recently. However, the underlying mechanism is far from understood. We aimed to explore the role of NEAT1 in GC as well as the underlying mechanisms. PATIENTS AND METHODS: The expression of NEAT1 in clinical human GC tissues and GC cell lines were assessed by quantitative reverse transcription PCR. Then, NEAT1 was non-physiologically expressed in GC cells (SGC-7901 and MKN45 cells), followed by estimation of cell viability, migration, invasion, apoptosis, activation of the phosphatidylinositol-3-kinase (PI3K)/AKT and glycogen synthase kinase 3beta (GSK3beta) pathways, and microRNA (miR)-17 level. Moreover, the effects of miR-17 inhibition on cell viability, migration, and activation of the PI3K/AKT and GSK3beta pathways in GC cells overexpressing NEAT1 were also explored. RESULTS: NEAT1 was up-regulated in GC tissues and cell lines. Then, cell viability and migration of GC cells were markedly increased by NEAT1 overexpression, while the cell invasion and apoptosis were unchanged. The phosphorylated level of PI3K, AKT, and GSK3beta were increased by NEAT1 overexpression. Subsequently, we found miR-17 level was positively correlated with NEAT1 expression, and NEAT1 functions through up-regulating miR-17. CONCLUSIONS: NEAT1 was up-regulated in GC tissues and cell lines. Its overexpression enhanced cell viability and migration through up-regulating miR-17, along with activation of the PI3K/AKT and GSK3beta pathways. PMID- 30024602 TI - The role of miR-144/GSPT1 axis in gastric cancer. AB - OBJECTIVE: To investigate the potential effects of miR-144/GSPT1 axis on the development of gastric cancer. PATIENTS AND METHODS: The expressions of GSPT1 (G1 to S Phase Transition 1) and miR-144 were detected in gastric cancer tissues and the adjacent normal tissues. We also explored the levels of GSPT1 and miR-144 in both normal gastric cell line (GES-1) and gastric cells (SGC7901). Luciferase assay was conducted to evaluate the interaction between miR-144 and GSPT1. The effects of the miR-144/GSPT1 axis on SGC7901 cells were determined via investigating cell proliferation, invasion and metastasis. RESULTS: miR-144 was found to be down-regulated in gastric cancer tissues while GSPT1 expression level was markedly increased. Bioinformatics analysis showed that GSPT1 was a direct target of miR-144. Luciferase assays confirmed our hypothesis. The subsequent experiments showed that miR-144 could promote cell proliferation, invasion and migration in gastric cancer cells via inhibiting GSPT1. CONCLUSIONS: We showed that miR-144/GSPT1 axis could be a potential therapeutic target in treatment of gastric cancer. PMID- 30024603 TI - CT quantitative analysis study for angiogenesis, and degree of ischemic necrosis and glucose metabolite in non-small cell lung cancer. AB - OBJECTIVE: We aimed at exploring the feasibility of noninvasive late arterial phase enhanced CT imaging in evaluating tumor angiogenesis, ischemic necrosis, and glucose metabolism, thereby providing pathological information for the comprehensive treatment plan in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: 52 cases of NSCLC were enrolled in this study. The mean ischemia necrosis CT quantitative value (INCTQ) and CT enhanced value (CTe) of the tumor were determined, and the immunohistochemical staining of factors relating to tumor angiogenesis, ischemic necrosis and glucose metabolism, including VEGF, VEGFR-2, HIF-1alpha, CAIX, GLUT1, and GLUT3, were conducted. RESULTS: The mean INCTQ values of different expression grades of VEGF, VEGFR-2, HIF-1alpha, and CAIX have no significant difference, but the mean INCTQ values of different expression grades of GLUT1 or GLUT3 have significant differences (p < 0.001), respectively. However, INCTQ value has a positive correlation with CAIX expression. In addition, CTe value was positively correlated with VEGF. CONCLUSIONS: To sum up, late arterial phase CT enhanced images of NSCLC not only can assess the tumor angiogenesis, but also can reflect the degree of ischemic necrosis, effectively reflecting the level of glucose metabolism in tumor and tumor angiogenesis, for the comprehensive treatment program. PMID- 30024604 TI - MiR-550a-3p promotes non-small cell lung cancer cell proliferation and metastasis through down-regulating TIMP2. AB - OBJECTIVE: MicroRNAs (miRNAs) have been identified to play a crucial regulatory role in the development and progression of malignant tumors, including lung cancer. However, the function of miR-550a-3p on the progression of non-small cell lung cancer (NSCLC) remains poorly understood. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction was employed to estimate the expression level of miR-550a-3p in NSCLC tissue and cell samples. Cell proliferation was measured by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and colony formation assays. Transwell assay was recruited to demonstrate the abilities of cell invasion and migration. Luciferase analysis and Western-blot assay were performed to elucidate the underlying mechanism of miR-550a-3p in NSCLC. RESULTS: The level of miR-550a-3p expressed in NSCLC tissues was significantly higher than that in para-tumor control tissues. Over-expression of miR-550a-3p significantly promoted proliferation, invasion, and migration of A549 cells while knockdown of miR-550a-3p inhibited growth and metastasis of H460 cells. TIMP2 was verified as a direct target of miR-550a-3p in NSCLC. Restoration of TIMP2 rescued the influence of miR-550a-3p over-expression. CONCLUSIONS: We demonstrated that miR-550a-3p regulated the progression of NSCLC cells through TIMP2. Thus, miR-550a-3p axis could serve as a potential therapeutic target for NSCLC treatment. PMID- 30024605 TI - Elevated miR-21 is associated with poor prognosis in non-small cell lung cancer: a systematic review and meta-analysis. AB - OBJECTIVE: Increasing studies have investigated the prognostic value of high miR 21 expression in non-small cell lung cancer (NSCLC) with inconsistent results. We conducted this meta-analysis to explore whether the expression of miR-21 was associated with prognosis in NSCLC patients. MATERIALS AND METHODS: We systematically searched Medline, EMBASE, Web of Science and Cochrane Library for relevant studies. Studies exploring the relationship between miR-21 expression and NSCLC prognosis and clinical pathology, and reporting enough data to get the hazard ratio (HR) and 95% confidence intervals (CIs), were included. Random- or fixed-effect models were employed to calculated pooled hazard ratios (HRs) or risk ratio and 95% confidence intervals (95% CIs). RESULTS: A total of 28 eligible studies, including 24 for prognosis, 16 for clinicopathological features were identified. Our results revealed that elevated miR-21 was related to unfavorable overall survival (OS) in NSCLC (HR = 1.960, 95% CI = 1.510-2.554, p = 0.000). Similar results were found in disease-free survival, relapse-free survival, and cancer-special death. In a meta-analysis of clinical pathology, overexpressed miR-21 was significantly related to lung adenocarcinoma, larger tumor size, and advanced clinical stage. CONCLUSIONS: Our meta-analysis suggested that miR-21 may function as an unfavorable biomarker of prognosis in NSCLC patients. PMID- 30024606 TI - HOTTIP participates in mammary cancer by promoting cell proliferation via PI3K/AKT pathway. AB - OBJECTIVE: To investigate the role of HOTTIP in the development of mammary cancer and its underlying mechanism. PATIENTS AND METHODS: 70 mammary cancer tissues and paracancerous tissues surgically resected from mammary cancer patients were enrolled in this study. HOTTIP expressions in these mammary cancer tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). The relationship between HOTTIP expression, prognosis, tumor size, and stage of mammary cancer patients was analyzed. Subsequently, we constructed lentivirus of HOTTIP. Proliferation, apoptosis, cell cycle, and invasion of mammary cancer cells transfected with HOTTIP lentivirus were detected by CCK-8 (cell counting kit-8), colony formation, flow cytometry, and transwell assay, respectively. The effect of overexpressed HOTTIP on PI3K/AKT pathway was detected by Western blot. RESULTS: HOTTIP was overexpressed in mammary cancer tissues than that of paracancerous tissues. HOTTIP expression was negatively correlated with the prognosis of mammary cancer. Overexpressed HOTTIP remarkably promoted cell cycle, and increased expressions of CyclineD1 and PCNA. Meanwhile, overexpressed HOTTIP inhibited cell apoptosis, whereas promoted proliferation and colony formation abilities. Western blot results demonstrated that overexpressed HOTTIP promotes proliferation of mammary cancer cells via PI3K/AKT pathway. CONCLUSIONS: HOTTIP remarkably promotes proliferative and invasive abilities, but inhibits cell apoptosis of mammary cancer cells via PI3K/AKT pathway. PMID- 30024607 TI - Prostate specific antigen as a biomarker for breast cancer: a meta-analysis study. AB - OBJECTIVE: To determine whether prostate-specific antigen (PSA) could serve as a biomarker for breast cancer. MATERIALS AND METHODS: We performed an electronic search on Medline, PubMed, SPRINGER, John Wiley, Science Direct, EBSCO, CNKI and Wanfang Data to identify relevant studies for our meta-analysis. The search terms included ['prostate specific antigen' or 'PSA' (MESH)] and ['breast cancer' or 'breast carcinoma' (MESH)]. RESULTS: A comprehensive meta-analysis of 10 studies comprising of 770 cases and 799 controls were included. Among the studies considered, the sensitivity of the tPSA test for diagnosis was 0.718 (95% CI: 0.630, 0.792), the specificity was 0.528 (95% CI: 0.299, 0.746) and the diagnostic odds ratios (DOR) was 2.852 (95% CI: 1.021, 7.969). The sensitivity of fPSA test for diagnosis was 0.783 (95% CI: 0.541, 0.917), specificity was 0.679 (95% CI: 0.209, 0.944) and diagnostic odds ratio (DOR) was 7.668 (95% CI: 0.331, 177.451). CONCLUSIONS: Serum PSA could be a useful biomarker for the diagnosis of breast cancer, and a biomarker for the differential diagnosis of breast cancer from benign breast tumors. PMID- 30024608 TI - Correlations between claudin-1 and PIGF expressions in retinoblastoma. AB - OBJECTIVE: To investigate the expressions of claudin-1 and placental growth factor (PlGF) proteins in retinoblastoma (RB) and their relationships with the differentiation of RB, the infiltration of optic nerve and choroid and clinical stages. PATIENTS AND METHODS: Immunohistochemical (IHC) method was used to detect the expressions of claudin-1 and PlGF proteins in 56 cases of RB paraffin embedded tissue samples. The x2-test and Fisher exact test were used to compare the qualitative variables. The Pearson correlation coefficient was used to detect the correlation of the expression of claudin-1 with that of PlGF in RB tissues. RESULTS: 1) Among RB tissues, the positive expression rates of claudin-1 in clinical stage I tumors and clinical stage III tumors were 69.2% and 38.9%, respectively, and claudin-1 was not expressed in all clinical stage II tumors (p=0.002). In case of optic nerve invasion, the lowly positive expression of claudin-1 was detected, and the difference was significant (p=0.001). 2) The positive expression rate of PlGF proteins in RB was 73.8%, which was higher in tumors with optic nerve invasion than in tumors without the invasion; the expression was significantly different (p=0.001). In addition, the positive expression rate of PlGF in tumors with choroidal invasion was 74.1%. 3) The expression of claudin-1 in RB was negatively correlated with the presence of choroidal invasion (r=0.52, p<=0.0001) and optic nerve infiltration (r=0.49, p=0.0003). There was a significant positive correlation between the expression of PlGF and the presence of optic nerve invasion (r=0.30, p=0.009). In addition, there was a significant positive correlation between the expression of claudin-1 and that of PlGF (r=0.41, p=0.006). CONCLUSIONS: The expression level of claudin 1 is negatively correlated with the differentiation of RB cells, optic nerve infiltration and clinical stages, while the expression of PlGF was positively correlated with the optic nerve infiltration and clinical stages of RB. The role of claudin-1 may be opposite to that of matrix metalloproteinase-2 (MMP-2) in the development of RB. PMID- 30024609 TI - LncRNA MT1JP acts as a tumor inhibitor via reciprocally regulating Wnt/beta Catenin pathway in retinoblastoma. AB - OBJECTIVE: The aim of this study was to investigate the roles of MT1JP and beta catenin in retinoblastoma. PATIENTS AND METHODS: We performed quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) to quantify the expressions of MT1JP and beta-catenin in 44 retinoblastoma tissues and matched non-tumor tissues. What's more, retinoblastoma cell lines were transfected with pcDNA3.1-MT1JP, after which proliferation, cell cycle, apoptosis, and expression of beta-catenin as well as its downstream targets were assayed. We also conducted TOP-Flash reporter assay to explore the activity of Wnt/beta-catenin signaling pathway. RESULTS: The results revealed that MT1JP was down-regulated, while beta catenin was highly expressed in retinoblastoma cells. Meanwhile, the forced expression of MT1JP impaired the expression of the beta-catenin protein and its downstream targets such as cyclin D1, c-myc. CONCLUSIONS: We demonstrated that MT1JP was a tumor suppressor by negatively modulating the activity of the Wnt/beta-catenin signaling pathway in the development of retinoblastoma and might function as a prognostic biomarker and therapeutic target. PMID- 30024610 TI - miR-135a inhibits glioma cell proliferation and invasion by directly targeting FOXO1. AB - OBJECTIVE: To investigate the potential function of miR-135a in glioma. PATIENTS AND METHODS: A total of 50 pairs of glioma tissue samples and para-carcinoma tissue samples were collected. Human glioma cell line (U251) and normal human astrocyte (NHA) were cultured. The expression of RNA and protein was detected by quantitative Real time-polymerase chain reaction (qRT-PCR) and Western blot, respectively. Cell proliferation assay and transwell assay were used to detect the activities of proliferation and invasion. Luciferase reporter assays were carried out to determine the binding efficiency between forkhead box O1 (FOXO1) and miR-135a in U251 cells. RESULTS: qRT-PCR results showed that miR-135a expression was significantly reduced while FOXO1 was up-regulated in glioma tissues. miR-135a overexpression in U251 cells could prominently inhibit proliferation and invasion according to the transwell assays. Moreover, FOXO1 was recognized as the target for miR-135a and may partially reverse the functions of miR-135a in U251 cells. CONCLUSIONS: We showed that miR-135a inhibits glioma cell proliferation and invasion by down-regulating the target gene FOXO1. PMID- 30024611 TI - Using changes in pro-brain natriuretic peptide of plasma amino-terminal and norepinephrine levels as prognostic and diagnostic factors in hand-foot-and-mouth disease. AB - OBJECTIVE: We explored the possibility of using the variations in the pro-brain natriuretic peptide (NT-proBNP) of serum amino-terminal and norepinephrine (NE) levels as prognostic as well as diagnostic factors in children suffering from severe hand-foot-and-mouth disease (HFMD). PATIENTS AND METHODS: From February 2014 to February 2015, 102 HFMD patients were enrolled in this study. They were divided into the common group (n=55) and the severe group (n=47). During the same period, 30 healthy children were enrolled in the control group. NT-proBNP and NE levels were evaluated in all patients. RESULTS: Our results revealed that NT proBNP and NE levels in the common group were not evidently different compared with those of the control group. However, these levels in the severe group were significantly higher than other groups. After treatment, NT-proBNP and NE levels in the severe group were lower than those measured before treatment. CONCLUSIONS: We suggest that serum level of NT-proBNP can be used as a valuable index to judge the severity of HFMD and to predict the prognosis. We believe that NT-proBNP and NE levels can be added to other HFMD diagnostic tools. PMID- 30024612 TI - PKC delta gene can induce macrophages to release inflammatory factors against Mycobacterium tuberculosis infection. AB - OBJECTIVE: To investigate the effect of PKC delta gene on the anti-tuberculosis activity of macrophages and the mechanism. MATERIALS AND METHODS: Bone marrow cells of PKC delta knockout mice and wild-type mice were cultured and L929 cells were induced to differentiate into macrophages. Lipopolysaccharide (LPS) and trehalose 6,6'-dimycolate (TDM) were used to stimulate macrophages respectively. After 24 and 96 hours, cells and the supernatant were collected to evaluate the inflammatory cytokines produced by macrophages using ELISA method. Real-time PCR was performed to detect the expression of macrophage mRNA level and nitric oxide (NO) production of macrophages was measured by NO assay. RESULTS: The results showed that, after TDB stimulation, IL-1beta, IL-6, and other cytokines, as well as NO produced by macrophages of PKC delta knockout mice, were significantly decreased (p < 0.01) compared with the wild-type mice. In PKC delta knockout macrophages, the above protein-coding genes were also decreased significantly at the transcriptional level (p < 0.01). CONCLUSIONS: PKC delta can enhance the anti tuberculosis capacity of macrophages by inducing to the release of inflammatory factors by macrophages. PMID- 30024613 TI - Research on the diagnostic effect of PCT level in serum on patients with sepsis due to different pathogenic causes. AB - OBJECTIVE: To investigate the diagnostic effect of procalcitonin level in serum for patients with sepsis due to different pathogenic causes. PATIENTS AND METHODS: The clinical data of 132 sepsis patients were analyzed. Those patients were admitted to the Affiliated Hospital of Medical School of Ningbo University from January 2014 to January 2017. According to the blood culture results before antimicrobial therapy, patients were divided into two groups: Gram-negative bacteria group (G- group) and Gram-positive bacteria group (G+ group). The indexes, such as SOFA score, APACHE II score, length of stay in hospital and mortality rate, were used to evaluate disease severity of the two groups. The procalcitonin, WBC, hs-CRP and NEU% were detected and compared between the two groups of patients. RESULTS: A total of 132 pathogenic bacteria were detected in 132 patients, of which 44 patients were infected with G- bacteria and 88 patients were infected with G+ bacteria. Patients in G- group were mainly infected with Escherichia coli, Acinetobacter baumannii, and Klebsiella pneumoniae, while patients in G+ group were mainly infected with Staphylococcus epidermidis and Staphylococcus aureus. The SOFA score, APACHE II score and mortality rate in G- group were higher than those in G+ group. The PCT levels in G- group and G+ group were (54.89+/-21.64) ng/mL and (21.13+/-1.30) ng/mL, respectively. The PCT level in G- group was higher than that in G+ group, and the difference was statistically significant between them (p<0.05). There was no statistically significant difference in length of stay in hospital between the two groups (p>0.05). There were no statistically significant differences in WBC, hs-CRP and NEU% between the two groups (p>0.05). CONCLUSIONS: The procalcitonin level in serum of sepsis patients at early stage of bloodstream infection is significantly elevated and has diagnostic value for different pathogenic bacteria groups. It can also reflect the disease severity and predict the prognosis of sepsis patients. PMID- 30024614 TI - Enhanced glycolysis in the process of renal fibrosis aggravated the development of chronic kidney disease. AB - OBJECTIVE: To explore the effect of glycometabolism on renal fibrosis and its underlying mechanism. MATERIALS AND METHODS: For in vivo experiments, unilateral ureteral obstruction (UUO) mouse model was constructed to induce renal interstitial fibrosis. Fibrosis and proliferation indicators in renal tissues were detected to observe the fibroblast phenotype changes during the process of renal fibrosis. Moreover, mRNA and protein levels of key enzymes in glycometabolism were also detected. For in vitro experiments, plasmid transfection was performed to overexpress pyruvate kinase M2 (PKM2) to explore the relationship between PKM2 and renal interstitial fibrosis. Energy metabolism monitoring was performed to detect changes in aerobic glycolysis and oxidative phosphorylation during the process of TGF-beta1-induced fibroblast phenotype changes. RESULTS: Fibroblast phenotype was changed. Both fibrosis and proliferation indicators were upregulated during renal fibrosis. Meanwhile, elevated expressions of key enzymes in glycometabolism and metabolic reprogramming of fibroblasts were observed. Overexpressed PKM2 activated fibroblasts and induced renal interstitial fibrosis, accompanied by increased glycometabolism level. CONCLUSIONS: Metabolic reprogramming promoted renal interstitial fibrosis, which leads to alteration of cell energy metabolism model. PMID- 30024615 TI - miR-192 prevents renal tubulointerstitial fibrosis in diabetic nephropathy by targeting Egr1. AB - OBJECTIVE: Diabetic nephropathy (DN), as the most common and serious diabetic microvascular complication, has become the first cause of end-stage renal disease (ESRD) in many countries and regions. However, the pathogenesis of renal fibrosis during the development of DN remains unknown. MATERIALS AND METHODS: The expression levels of miR-192 and early growth response factor 1 (Egr1) were determined by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blotting in the renal tissues of Otsuka-Long-Evans-Tokushima-Fatty (OLETF) and Long-Evans-Tokushima-Otsuka (LETO) rats. The diabetic kidney environment was simulated by a high-sugar medium. The expression levels of miR 192 and Egr1 were further measured in the HK-2 cell line. Egr1 was verified as a potential target of miR-192 by using bioinformatics analysis and luciferase activity assay. The expression level of Egr1 was determined by overexpressing and knocking down the expression of miR-192. In addition, Western blotting was used to determine changes in Transforming growth factor-beta 1 (TGF-beta1) and fibronectin (FN). RESULTS: Compared with the kidney tissue of LETO rats, the expression of miR-192 was decreased in OLETF rats, whereas the expression of Egr1 was increased. We found the same phenomenon in the HK-2 cell line cultured in the high-glucose medium. Next, miR-192 can act on Egr1 through 3'-UTR to reduce the expression of Egr1 verified by luciferase assay. In addition, the expression levels of TGF-beta1 and FN changed significantly, as the expression level of Egr1 increased or decreased. CONCLUSIONS: MiR-192 causes degradation of TGF-beta1 and FN through targeting Egr1 and affects the progression of TIF and even DN. PMID- 30024616 TI - Therapeutic effects of long-term continuous positive airway pressure treatment on improving leptomeningeal collateral circulation in obstructive sleep apnea syndrome patients. AB - OBJECTIVE: This study aims to use methods of scoring collaterals on CT angiography to analyze changes in collateral circulation in untreated patients with moderate and severe OSAS before and after nasal continuous positive airway pressure (CPAP) treatment. PATIENTS AND METHODS: Ninety-eight moderate and severe OSAS patients treated with nasal CPAP and seventy-four controls that weren't treated with CPAP, were involved in this study. Two independent neuroradiologists evaluated intracranial collaterals by using Miteff scale, modified Tan scale. Intracranial collaterals differences were compared between OSAS group (before and after treated) and control group. Correlations between intracranial collaterals and clinical parameters were analyzed. RESULTS: Compared with pre-therapy of moderate and severe groups, apnea-hypopnea index (AHI), oxygen desaturation index (ODI), epworth sleepness scale (ESS) were lower after treatment. The lowest oxygen saturation, average blood oxygen saturation, Miterff scale, modified Tan scale in moderate and severe groups were significantly increased after treatment. We documented significant decrease of Miterff scale after two years in moderate and severe OSAS group without CPAP therapy (n = 32, p < 0.01). Conversely, mild OSAS group without CPAP therapy did not change Miterff scale after two years (n = 32, p > 0.05). Multivariate Logistic regression analysis showed that AHI had significant impact on Miterff scale and modified Tan scale. Severe OSAS were independently related with Miterff scale (odds ratio 0.343, 95% confidence interval 0.301-0.391, p < 0.01) and modified Tan scale (odds ratio 0.267, 95% confidence interval 0.095-0.754, p = 0.013). CONCLUSIONS: Long-term CPAP treatment is a viable therapeutic choice for improving leptomeningeal collateral circulation in OSAS patients. PMID- 30024617 TI - Satb1 promotes Schwann cell viability and migration via activation of PI3K/AKT pathway. AB - OBJECTIVE: Satb1 regulates chromatin structure and gene expression, and is aberrantly expressed in many tumors. However, there is still no report about Satb1 functions in peripheral nerve injury until now. In this study, we explored the regulatory effect of Satb1 on Schwann cells. MATERIALS AND METHODS: MTT assay, transwell assay, and flow cytometry assay were respectively used to determine Schwann cell viability, migration, and apoptosis. The mRNA and phosphorylation levels of Satb1 and SHIP1 were assessed by RT-PCR and Western blotting analysis, respectively. The correlation between Satb1 and SHIP1 was examined by ChIP assay. The expressions of PI3K/AKT pathway related factors were detected by Western blotting. RESULTS: In the present study, we found that knock out of Satb1 significantly inhibited cell viability and migration, and promoted Schwann cells apoptosis. Conversely, over-expression of Satb1 promoted cell viability, migration, and inhibited apoptosis. Satb1 inhibited SHIP1 expression by recruiting HDAC1. Furthermore, results showed that Satb1 activated the PI3K/AKT signaling pathway by inhibiting the expression of SHIP1. SHIP1 showed significant reversal effects on the regulatory roles of Satb1 in Schwann cells. Over-expression of Satb1 and SHIP1 inhibited cell viability, migration, and promoted apoptosis. CONCLUSIONS: Our study demonstrated that the Satb1 knock-out could inhibit the activation of PI3K/AKT pathway by up-regulating SHIP1, thus inhibiting cell viability and migration, and promoting Schwann cell apoptosis. PMID- 30024619 TI - Nutritional support in mitochondrial diseases: the state of the art. AB - Mitochondrial diseases are a group of rare multisystem disorders characterized by genetic heterogeneity and pleomorphic clinical manifestations. The clinical burden may be heavy for patients and their caregivers. There are no therapies of proven efficacy until now and a multidisciplinary supportive care is therefore necessary. Since the common pathogenic mechanism is the insufficient energy production by defective mitochondria, nutrition may play a crucial role. However, no guidelines are still available. The article reports the current evidence, highlighting nutrition both as support and as therapy. The estimate of nutritional status, energy needs and nutritional behaviors are firstly discussed. Then, we go in-depth on the scientific rationale and the clinical evidence of the use of anti-oxidants and enzyme-cofactors in the clinical practice. In particular, we analyze the role of Coenzyme Q10, Creatine monohydrate, alpha lipoic acid, riboflavin, arginine and citrulline, folinic acid, carnitine, vitamin C, K, and E. Every attempt at nutritional intervention should be made knowing patient's disease and focusing on his/her energy and nutrients' requirements. For this reason, clinicians expert in mitochondrial medicine and clinical nutritionists should work together to ameliorate care in these fragile patients. PMID- 30024618 TI - Protective effects of 8-MOP on blood-brain barrier via the Nrf-2/HO-1 pathway in mice model of cerebral infarction. AB - OBJECTIVE: To explore the effect of 8-MOP on the blood-brain barrier in mice model of cerebral infarction and the underlying mechanism. MATERIALS AND METHODS: Middle cerebral artery occlusion (MCAO) model was established to induce permanent cerebral infarction. The neurological function was observed and scored by the modified longa score method after model establishment. Besides, the water content of brain tissue was measured by the standard dry weight method. Evans blue exudation rate was used to evaluate the effect of 8-MOP on the permeability of the blood-brain barrier. Western-blot and quantitative polymerase chain reaction (qPCR) were used to detect the expression of MMP-9, claudin-5, vascular endothelial growth factor (VEGF), as well as the NFE2-related factor 2 (Nrf 2)/hemeoxygenase 1 (HO-1) pathway. RESULTS: 8-MOP could reduce the neurological deficit scores in a dose-dependent manner, thereby reducing cerebral edema. After 8-MOP treatment, the expression of MMP-9 decreased in ischemic brain tissue, whereas the expression of claudin-5, VEGF, and GFAP increased, suggesting that the blood-brain barrier ultrastructure was improved. In addition, the expression of Nrf-2 and HO-1 decreased after the model establishment of cerebral infarction. However, the expression of Nrf-2 and HO-1 increased in ischemic brain tissue after 8-MOP treatment. CONCLUSIONS: 8-MOP may protect the blood-brain barrier via the Nrf-2/HO-1 pathway. PMID- 30024620 TI - Serum calprotectin correlates with risk and disease severity in psoriasis patients and the decrease of calprotectin predicts better response to tumor necrosis factor inhibitors. AB - OBJECTIVE: This study aimed to investigate the correlation of serum calprotectin expression with risk and severity of psoriasis, as well as its predictive value for clinical response to tumor necrosis factor inhibitors (TNFi) treatment in psoriasis patients. PATIENTS AND METHODS: 72 psoriasis patients and 70 health controls (HCs) were enrolled. Blood samples were collected, and serum calprotectin was determined by commercial enzyme-linked immuno sorbent assay (ELISA). All patients were treated by TNFi treatment, and followed up at 6 months, and the last follow-up date was 2016/11. RESULTS: Calprotectin level was elevated in psoriasis patients compared to HCs (p < 0.001), and it disclosed a good diagnostic value of psoriasis with area under curve (AUC) 0.872, 95% CI: 0.810-0.935. Calprotectin expression was positively associated with Psoriasis Area and Severity Index (PASI) score (R = 0.452, p < 0.001), while it was not associated with BSA (R = 0.125, p = 0.297). 58.3% patients achieved PASI75 and 43.1% patients achieved PASI90 at M6. Calprotectin was decreased during the 6 month treatment (p < 0.001). Changes of calprotectin during the first month (?calprotectin (M0-M1)) in PASI75 group were more than that of non-PASI75 group (p < 0.001). Also, multivariate logistic analysis revealed that ?calprotectin (M0 M1) (p = 0.001) was an independent factor for PASI75 achievement at M6 after TNFi treatment, while pre-systemic biologic treatment (p = 0.001) was an independent factor for non-PASI75 achievement. CONCLUSIONS: Serum calprotectin expression is correlated with risk and severity of psoriasis, and the decrease of calprotectin during the first month could predict better clinical response to TNFi treatment in psoriasis patients. PMID- 30024622 TI - Impact of ketamine intervention for acute lung injury on RAGE and TLR9. AB - OBJECTIVE: The purpose of this study was to explore the benefits of ketamine intervention for acute lung injury (ALI) and its effects on the receptor for advanced glycation end-product (RAGE) and toll-like receptor 9 (TLR9). MATERIALS AND METHODS: Lipopolysaccharide (LPS, 3 mg/kg) was used to induce ALI rat model. Forty healthy Sprague-Dawley rats (6-8 weeks) were assigned into control, model, low ketamine (5 mg/kg), and high ketamine (50 mg/kg) groups. After 24 h, these rats were sacrificed and lungs were collected. RESULTS: The pathological score, lung W/D ratio, the percentage of leukocytes and epithelial in bronchoalveolar lavage fluids (BALF), the expression levels of RAGE, TLR9, and other inflammation markers in serum and lungs were significantly higher in the Model group, indicating a good ALI model. Ketamine intervention restored all these parameters, with more benefits in the High dose group. CONCLUSIONS: The high dose ketamine decreased the degree of ALI by inhibiting the expression of RAGE, TLR9, TNF alpha, NF-kappaB, IL-6 and MPO in tissues. PMID- 30024621 TI - Long-term pancreatic exocrine and endometabolic functionality after pancreaticoduodenectomy. Comparison between pancreaticojejunostomy and pancreatic duct occlusion with fibrin glue. AB - OBJECTIVE: Even if pancreatic pathologies, residual fibrosis, residual amount of parenchyma, and anastomotic patency are recognized as main causes of exocrine and glycemic impairment after pancreaticoduodenectomy (PD), few data are reported concerning the role of the different pancreatic remnant treatment techniques. The objective of the study is to assess and compare exocrine functionality, glycemic pattern, nutritional status, and quality of life (QoL) after PD between pancreaticojejunostomy (PJ) and pancreatic duct occlusion (PDO), both in an objective and a subjective manner. PATIENTS AND METHODS: Thirty-two patients (16 PJ and 16 PDO) were evaluated after a mean follow-up of 21 months after surgery. Exocrine insufficiency was objectively evaluated through the 13C-labelled mixed triglyceride breath test. Fasting glucose, fasting insulin, HbA1c and HOMA-IR values were used to assess glucose metabolism. For these two outcomes, anamnestic data were also collected. QoL was assessed with GIQLI, SF-36, EORTC-QLQ-C30, and EORTC-PAN-26 questionnaires. RESULTS: The 13C-labelled mixed triglyceride breath test detected a lipid digestive insufficiency in 56% of patients after PJ and 100% after PDO respectively (p = 0.007). However, no difference was observed between the two groups regarding postoperative necessity of substitutive pancreatic enzymes. Nutritional status, fasting plasma glucose, fasting insulin, HbA1c levels, HOMA-IR values and postoperative necessity of insulin or oral antidiabetic agents were comparable between the two groups. QoL measurements showed similar results. However, in the subdomains analysis, better outcomes were reported regarding digestive symptoms and physical functioning for PJ and PDO respectively. CONCLUSIONS: Even if an objective exocrine major impairment was evidenced after PDO, this result did not impact the need for a higher rate of postoperative substitutive enzymes. In terms of glycemic pattern, nutritional status, and QoL, the two techniques turn out to be comparable. PMID- 30024623 TI - Propofol induces apoptosis of non-small cell lung cancer cells via ERK1/2 dependent upregulation of PUMA. AB - OBJECTIVE: Propofol is one of the most commonly used intravenous anesthetic agents used in cancer resections, but the effect of propofol on non-small cell lung cancer (NSCLC) remains unclear. Previous researches have reported that propofol can inhibit extracellular signal-regulated kinase (ERK) 1/2 phosphorylation or activate p53-upregulated modulator of apoptosis (PUMA) signaling, resulting in apoptosis. In addition, PUMA is negatively regulated by ERK1/2 activation. In the present work, we determined the effect of propofol on NSCLC A549 cells and explored its signaling pathway. MATERIALS AND METHODS: A549 cells were treated with different concentrations of propofol (1-10 MUg/mL) for 6 h. After washing, cells were cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum and antibiotics for another 72 h. Cell survival and apoptosis were determined by MTT, flow cytometry, and TUNEL analyses. To assess whether propofol functions via ERK1/2 and PUMA signaling pathways, A549 cells were transfected with small interfering RNA (siRNA) to target PUMA, or treated with human recombinant ERK1/2 (hrERK1/2) to activate ERK1/2. RESULTS: Propofol treatment inhibited viability and induced apoptosis of A549 cells in a dose-dependent manner in vitro. Propofol inhibited phosphorylation of ERK1/2 (pERK1/2) and increased ERK1/2-dependent PUMA expression. Knockdown of PUMA by siRNA or treatment with hrERK1/2 to activate ERK1/2 blocked propofol-induced apoptosis and cell viability. Upregulation of PUMA expression by propofol requires pERK1/2 inactivation. CONCLUSIONS: Propofol inhibits viability and induces apoptosis of A549 cells via an ERK1/2-dependent PUMA signaling. PMID- 30024624 TI - LncRNA-CARl in a rat model of myocardial infarction. AB - OBJECTIVE: To investigate how long non-coding ribonucleic acid-cardiac apoptosis related (lncRNA-CARL) regulates apoptosis of primary endothelial cells. The specific role of lncRNA-CARL in the occurrence and development of myocardial infarction (MI) and atherosclerosis is also explored. MATERIALS AND METHODS: A rat model of arteriosclerosis was prepared by extracting myocardial endothelial cells of rats. After the overexpression or inhibition of lncRNA-CARL, cell counting kit-8 (CCK-8) assay was used to detect cell activity. LncRNA-CARL plasmids were constructed and injected into the carotid artery in rats, and hematoxylin and eosin staining (HE) was used to observe the neointima of the carotid artery in rats. The activity of apoptosis protein Caspase-3 in endothelial cells was detected by Caspase-3 activity assay kit. Expressions of prohibitin-2 (PHB2), B-cell lymphoma-2 (Bcl-2) and Bcl-2-Associated X (Bax) protein were gauged by Western blot. RESULTS: The over-expression of lncRNA-CARL in primary endothelial cells in rats could increase cell viability. LncRNA-CARL also down-regulated the expressions of PHB2 and Bax, reduced the activity of Caspase-3 and increased the expression of anti-apoptotic protein Bcl-2. LncRNA CARL inhibition could significantly increase Caspase-3 activity and Bax expression, whereas decrease Bcl-2 expression (p<0.05). Local silencing of lncRNA CARL in rats resulted in decreased intravascular intima-media thickness ratio and Bcl-2 expression, as well as increased activity of Caspase-3 and Bax expression (p<0.05). CONCLUSIONS: Long non-coding ribonucleic acid-cardiac apoptosis-related lncRNA (lncRNA-CARL) regulates cell apoptosis and participates in the occurrence and development of MI. PMID- 30024625 TI - Role of microRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by inflammatory cell activation and the release of inflammatory mediators. By measuring microRNA expression in the plasma of COPD subjects, we aimed to identify the clinical relevance of plasma miRNA levels in these patients. PATIENTS AND METHODS: A total of 40 COPD patients and 40 healthy controls were enrolled in the study. The COPD model of C57BL/6 mice was also developed by exposing them to cigarette smoke (CS). The expression of microRNA 218-5p was detected by qRT-PCR in all the subjects and mice. The serum level of IL-18 and TGF-beta1 was also detected via ELISA kit. To investigate the effects of miR-218-5p, 10 mg/kg of miR-218-5p inhibitor (miR-218-5p antagonist), a scrambled control or PBS (solvent) was intranasally administered on the first and the fourth exposure day, before the start of CS exposure. RESULTS: The results showed that miR-218-5p was significantly down-regulated in patients with COPD, compared to normal subjects. There was a negative correlation between the plasma miR-218-5p level and the duration of disease since diagnosis in COPD ex-smokers. CS-induced COPD mice experiments with a miR-218-5p inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. CONCLUSIONS: These findings supported that miR-218-5p may, therefore, play an important role in the pathogenesis of COPD. PMID- 30024626 TI - Comorbidities in coexisting chronic obstructive pulmonary disease and obstructive sleep apnea - overlap syndrome. AB - OBJECTIVE: Chronic Obstructive Pulmonary Disease (COPD) and Obstructive Sleep Apnea (OSA) are separately associated with several comorbidities. The coexistence of the two diseases, referred to as overlap syndrome, may act as a predisposing factor for a higher prevalence of comorbidities compared to those associated with each disease separately. The objective of the study was to evaluate the relative prevalence of cardiovascular as well as other comorbidities, in patients with the overlap syndrome, as compared to patients that are diagnosed solely with OSA. PATIENTS AND METHODS: We examined thirty-eight (38) patients (27 men, 11 women) with coexisting COPD and OSA - overlap syndrome (Group 1) vs. 38 patients with OSA-only (Group 2), matched for sex, age, and Body Mass Index (BMI). All patients underwent pulmonary function tests (PFTs), oximetry and overnight polysomnography and were asked about other coexisting chronic diseases and medications. RESULTS: The two groups differed significantly, as expected, in PFTs (Forced Vital Capacity - FVC, p=0.005, Forced Expiratory Volume in 1 s - FEV1, p<0.001) and in daytime oximetry (p=0.007). Three (3) overlap (7.89%) and 9 OSA patients (23.69%) had no other known diseases. All others suffered from 1 - >= 4 comorbidities. Overlap patients suffered more often from multiple (>= 4) comorbidities than OSA only patients (11, 28.95% vs. 4, 10.52%, respectively). The most common coexisting diseases were hypertension (50% vs. 42.1%), cardiovascular disease (CVD) (44.74% vs. 26.31%), diabetes mellitus (DM) (28.95% vs. 13.16%), dyslipidemia (21.05% vs. 26.31%) and depression (7.89% vs. 13.16%). CONCLUSIONS: We conclude that comorbidities, especially cardiovascular, in patients with overlap syndrome are at least as prevalent as in sleep apneic only patients and may contribute to the overall severity and prognosis of the disease. PMID- 30024627 TI - Low-dose vitamin A therapy on T lymphocyte function in neonatal pneumonia. AB - OBJECTIVE: We aimed at studying the effect of adjuvant therapy with low-dose vitamin A on the function of T lymphocytes in neonatal pneumonia. PATIENTS AND METHODS: We recruited 60 cases of neonatal pneumonia which were randomly divided in two equal groups. The control group was treated with conventional anti inflammatory therapy and aerosol inhalation. The experimental group received oral vitamin A soft capsules for 7 days. RESULTS: Pre-treatment levels vitamin A level and vitamin A deficiency disorders (VADD) percentage revealed no differences between the two groups. The treatment course for the experimental group was shorter than the control group. Serum IgM, IgG, and glutathione peroxidase (GSH Px) levels were increased, whereas the levels of malondialdehyde were decreased in the experimental group after treatment. The control group showed no changes in these factors. After treatment, both groups showed increased percentages of CD4+ and CD8+ T cells, but the experimental group showed a larger increase. CONCLUSIONS: Neonatal pneumonia is often accompanied by a low level of vitamin A, and adjuvant therapy can shorten its disease course, improve IgM and IgG levels, and improve anti-oxidative and cellar immune function. PMID- 30024628 TI - HMTH1 induces the metastasis and recurrence of the parotid adenoma by repairing DNA damage. AB - OBJECTIVE: To investigate the effect of hMTH1 (human mutT homologue 1) on inducing the metastasis and recurrence of parotid adenoma, which may provide a new therapeutic direction for the prevention and treatment of parotid adenoma. PATIENTS AND METHODS: 30 cases of paraffin-embedded specimens of parotid adenoid cystic carcinoma (ACC) tissues and fresh parotid glands surgically resected in our hospital were collected as experimental group. 30 cases of surgically resected pleomorphic adenoma (PA) in the same period were selected as another experimental group. Meanwhile, 30 cases of normal parotid gland tissues (N) were collected as control group. The mRNA and protein expressions of hMTH1 in parotid gland tissues of patients with parotid adenoma before and after surgery were detected by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blotting, respectively. HMTH1 expression levels in parotid gland tissues were also detected by immunohistochemistry. Proliferation, apoptosis and DNA damage of ACC-M cells treated with S-Crizotinib were detected by cell counting kit-8 (CCK-8) assay, flow cytometry and single cell gel electrophoresis, respectively. RESULTS: Both mRNA and protein expressions of hMTH1 in experimental group were significantly higher than those of control group. Moreover, a higher expression of hMTH1 was observed in ACC than that of PA, indicating that hMTH1 expression was positively correlated with the malignant degree of parotid adenoma. Furthermore, postoperative hMTH1 expression levels in patients with parotid adenoma were significantly lower than those before treatment, which were remarkably increased in recurrent patients. In vitro experiments demonstrated that S-Crizotinib, the hMTH1 inhibitor, could inhibit proliferation and induce apoptosis and DNA damage of ACC-M cells. CONCLUSIONS: HMTH1 was upregulated in patients with parotid adenoma and recurrent patients after surgery. Meanwhile, S Crizotinib induced DNA damage in ACC-M cells, indicating that hMTH1 induced the metastasis and recurrence of parotid adenoma by repairing DNA damage, providing a new strategy for the prevention and treatment of parotid adenoma. PMID- 30024629 TI - Clomiphene citrate changes metabolite content of follicular fluid of PCOS women. AB - OBJECTIVE: To determine whether clomiphene citrate (CC) treatment affects the metabolite contents of a dominant follicle in polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: Twenty non-obese primary infertile anovulatory PCOS women undergoing CC treatment and ten fertile women were enrolled. 6 out of 20 patients had impaired glucose tolerance test (IGT). CC was given at a dose of 150 mg on days 3-7 of cycles in the first group. 10 fertile women with a regular menstrual cycle and normal ovaries during ultrasound examination were accepted as control group. They were not given any drug for ovarian stimulation. Transvaginal sonography and follicular tracking were done to each group of participant. Both groups of subjects underwent magnetic resonance spectroscopy when the dominant follicle with a mean diameter of at least 16-18 mm was detected. Lactate (Lac), N acetylaspartate (NAA), creatine 1 (Cr1), creatine 2 (Cr2) and choline (Cho) signal of dominant follicles were measured. Peak of each metabolite was measured in units. Voxels were placed in the center of dominant follicle. RESULTS: Compared to control group significantly decreased Cho signal was found in follicular fluid of PCOS subjects taking clomiphene. Almost three-fold decline in Cho signal was detected in PCOS group compared to Cho signal of control group (0.64+/-1.01 vs. 2.01 +/-1.13). On the other hand, significantly increased Lac signal was detected in the dominant follicle of PCOS subjects taking clomiphene compared to control group. Almost 2 fold increase in Lac signal was noted after clomiphene treatment (1.90+/-0.32 vs. 0.93+/-2.21). The results of spectroscopy signals obtained from PCOS subjects without IGT and PCOS subjects with IGT were similar. CONCLUSIONS: Unbalanced production of Cho signal in the follicular fluid may have occurred secondary to membrane damage of cumulus-oocyte-complexes due to CC therapy. PMID- 30024630 TI - Scurvy as cause of purpura in the XXI century: a review on this "ancient" disease. AB - OBJECTIVE: Scurvy is defined as a deficiency of ascorbic acid, which is an essential exogenous vitamin in humans. Vitamin C is involved in collagen synthesis and its deficit can cause disorders of connective tissue. The most frequent symptoms are weakness, arthralgias, anorexia and depression, commonly associated with follicular hyperkeratosis and perifollicular hemorrhage, with purpura. PATIENTS AND METHODS: A young woman, with a history of malnutrition, manifested purpura and hematoma of the left lower limb. The laboratory tests didn't detect alterations either in coagulation, the platelet count or in the autoimmunity. The total body TC scan didn't show neoplasia or other suspected lesions. Excluding the most important causes of purpura, in consideration of malnutrition, scurvy was suspected. RESULTS: A skin biopsy confirmed the diagnosis. Accordingly to this finding, a treatment with a daily intravenous infusion of vitamin C was started with consequent improvement of hematoma and purpura. CONCLUSIONS: Scurvy is a re-emerging disease, also in western countries. When purpura appears in young adults, scurvy has to be investigated, especially when a history of malnutrition is present. The treatment with vitamin C infusions should be started as soon as possible in order to prevent any complications. PMID- 30024631 TI - Evaluation of medical prescriptions and off-label use on board ships to improve healthcare quality. AB - OBJECTIVE: This study analyzed the appropriateness of drug therapies prescribed for a particular category of patients: the seafarers. We investigated an important problem of this area: the off-label use of drugs, which resulted to be a consequence of major shortcomings in the on-board pharmacies of ships. The off label use of drugs is allowed, but can lead to some not negligible ethical and health problems, compromising the quality of provided healthcare. MATERIALS AND METHODS: The analysis was performed on electronic health records of patients onboard ships without physicians, and assisted by the CIRM from 2011 to 2015. This work is divided into two phases: in the first one, we classified the diagnoses registered onboard on the basis of the ICD-10 classification proposed by the WHO. In the second phase, we evaluated the congruence of the pharmacological therapies prescribed by CIRM physicians, according to the MICROMEDEX Database, which provides comprehensive information about drugs and their use. RESULTS: From the analysis emerged that prescribed drugs were not always corresponded to their primary indication of use. In particular, in 2011 off-label drug use was widely spread (more than 30%) in some ICD-10 classes. In the following years (2012-2015) a decrease of off-label use of drugs was noticed. CONCLUSIONS: The results suggest that a standardization of onboard pharmacies is crucial, in order to have a complete on-board pharmacy that will allow preventing and counteracting any situation of health danger, which may occur onboard, ensuring high quality healthcare to seafarers all over the world. PMID- 30024632 TI - Cellular enzymatic anti-oxidants of fractionated mucus proteins from Eudrilus eugeniae (African night crawler) and Perionyx excavatus (Blue worm) in MC3T3. AB - OBJECTIVE: To investigate SOD-liked, GPx-liked and cellular anti-oxidation activities of fractionated mucus proteins from Perionyx excavatus (Pe) and Eudrilus eugeniae (Ee) in the MC3T3 osteoblast precursor cell line. MATERIALS AND METHODS: The crude mucus proteins were extracted from Pe and Ee and fractionated using the anion exchange chromatography method with FPLC. The fractionated proteins were studied to determine their SOD-liked and GPx-liked activities. The most efficient fractions were studied for cellular anti-oxidation activities in the MC3T3 cell line including scavenging, protecting and repairing conditions. RESULTS: The results showed that the highest SOD-liked activities of EeANX1 were found at 4.17 ug/ml and GPx-liked activities of EeANX4 were found at 5.26 ug/mL. EeANX1 had no cytotoxic effect on MC3T3 at 500 ug/mL, and the IC50 of EeANX4 was over 300 ug/mL. When both EeANX1 and EeANX4 were investigated for cellular anti oxidation activity in MC3T3 cells at 20 ug/mL, the cellular superoxide and total ROS production of were significantly (p<0.05) lower than those of 250 uM pyocyanin (ROS inducer) in ROS scavenging, protecting and repairing conditions. The 20 ug/mL of EeANX1 and EeANX4 demonstrated increased SOD and GPx activities in MC3T3. Investigation of the scavenging, protection and repairing conditions of MC3T3 treated with 20 ug/mL each of EaANX1, EaANX4 and 250 uM pyocyanin demonstrated that the proteins had significantly lower SOD activities and higher GPx activities than the 250 uM pyocyanin. CONCLUSIONS: The EeANX1 and EeANX4 fractions demonstrate SOD-liked and GPx-liked activities, as well as cellular anti-oxidation activities. These fractions could be developed as a natural anti oxidant. This research could provide benefit to the study of cellular anticancer. PMID- 30024633 TI - Greater Occipital Nerve Treatment in the Management of Chronic Headache Secondary to Accidental Dural Puncture: A Case Report. PMID- 30024635 TI - Codeine-Induced Sensory Neuropathy, Autonomic Dysfunction, and Myopathy. PMID- 30024634 TI - Vitamin D as an adjunct to antibiotics for the treatment of acute childhood pneumonia. AB - BACKGROUND: Children with acute pneumonia may be vitamin D deficient. Clinical trials have found that prophylactic vitamin D supplementation decreases the risk of developing pneumonia in children. Data on the therapeutic effects of vitamin D in acute childhood pneumonia are limited. OBJECTIVES: To evaluate the efficacy and safety of vitamin D supplementation as an adjunct to antibiotics for the treatment of acute childhood pneumonia. SEARCH METHODS: We searched CENTRAL (2017, Issue 7), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register; Ovid MEDLINE Epub Ahead of Print; In-Process & Other Non Indexed Citations; Ovid MEDLINE Daily and Ovid MEDLINE (1946 to July Week 4, 2017); and Embase (2010 to 28 July 2017). We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 28 July 2017. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) including children (aged over one month and up to five years) hospitalised with acute community-acquired pneumonia, as defined by the WHO acute respiratory infection guidelines, that compared vitamin D supplementation with control. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. For dichotomous data, we extracted the number of participants experiencing the outcome and the total number of participants in each treatment group. For continuous data, we used the arithmetic mean and standard deviation (SD) for each treatment group together with numbers of participants in each group. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included seven RCTs conducted in low-income countries that involved 1529 children (780 with pneumonia and 749 with severe or very severe pneumonia). Four studies used a single 100,000 IU dose of vitamin D3 at the onset of illness or within 24 hours of hospital admission; two used a daily dose of oral vitamin D3 (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used a daily dose of oral vitamin D3 (50,000 IU) for two days. One study reported microbiological and radiological diagnosis of pneumonia.The effects of vitamin D on outcomes were inconclusive when compared with control: time to resolution of acute illness (hours) (mean difference (MD) -0.95, 95% confidence interval (CI) -6.14 to 4.24; 3 studies; 935 children; low-quality evidence) mortality rate (risk ratio (RR) 0.97, 95% CI 0.06 to 15.28; 1 study; 193 children; very low-quality evidence); duration of hospitalisation (MD 0.49, 95% CI -8.41 to 9.4; 4 studies; 835 children; very low-quality evidence) and time to resolution of fever (MD 1.66, 95% CI -2.44 to 5.76; 4 studies; 584 children; very low-quality evidence).No major adverse events were reported.The GRADE assessment found very low-quality evidence (due to serious study limitations, inconsistencies, indirectness, and imprecision) for all outcomes except time to resolution of acute illness.One study was funded by the New Zealand Aid Corporation; one study was funded by an institutional grant; and five studies were unfunded. AUTHORS' CONCLUSIONS: We are uncertain as to whether vitamin D has an important effect on outcomes because the results were imprecise. No major adverse events were reported. We assessed the quality of the evidence as very low to low. Several trials are ongoing and may provide additional information. PMID- 30024636 TI - Clinical outcomes and patient satisfaction following total hip and knee arthroplasty in patients with inherited bleeding disorders: A 20-year single surgeon cohort. AB - INTRODUCTION: Persons with haemophilia and other inherited bleeding disorders are prone to disabling joint arthropathy frequently requiring arthroplasty for end stage joint disease. Higher complication rates and more modest post-operative functional outcomes have previously been described. AIM: To evaluate the clinical outcomes and patient satisfaction of persons with inherited bleeding disorders (predominantly haemophilia) undergoing total hip and knee replacement. METHODS: Retrospective, single-centre cohort study with longitudinal assessment of patients with inherited bleeding disorders who underwent total hip and knee replacement over a 20-year period. Eligible patients were clinically assessed with Harris Hip Score (HHS), Knee Society Score (KSS), pain visual analogue scale (VAS) and a patient satisfaction questionnaire. RESULTS: Thirty-one patients (48 joints) met the inclusion criteria. Mean age at surgery was 49.3 years (SD: 13.1, range 21-75 years) with a mean follow-up of 9.33 years (1.7-19.3). The majority (26/31) of patients had haemophilia A, predominantly severe haemophilia A (22/26). Reported pain levels were low, and patient satisfaction was high. Joint specific outcome scores were "good" to "excellent" in 67% of total hip replacement patients and 92% of total knee replacement patients. A low complication rate was observed, with 2 patients requiring revision surgery and 4 patients requiring re-operation without implant revision. CONCLUSION: Arthroplasty is a reliable procedure in patients with inherited bleeding disorders with end-stage hip or knee arthropathy. The overall complexity of this group is highlighted, and the need for multidisciplinary care is emphasised. PMID- 30024637 TI - Pancreas-sparing, ampulla-preserving duodenectomy for major duodenal (D1-D2) perforations. AB - BACKGROUND: Ideal surgical treatment for acute duodenal injuries should offer a definitive treatment, with low morbidity and mortality. It should be simple and easily reproducible by acute care surgeons in an emergency. Duodenal injury, due to major perforated or bleeding peptic ulcers or iatrogenic/traumatic perforation, represents a surgical challenge, with high morbidity and mortality. The aim was to review definitive surgery with pancreas-sparing, ampulla preserving duodenectomy for these patients. METHODS: Pancreas-sparing, ampulla preserving D1-D2 duodenectomy was used for patients presenting with major duodenal injuries over a 5-year interval. The ampulla was identified and preserved using a transcystic/transpapillary tube. The outcomes were recorded. RESULTS: Ten patients were treated with this technique; seven had perforated or bleeding peptic ulcers, two had iatrogenic perforations and one blunt abdominal trauma. Their mean age was 78 (range 65-84) years. Four patients were haemodynamically unstable. The location of the duodenal injury was always D1 and/or D2, above or in close proximity to the ampulla of Vater. The surgical approach was open in nine patients and laparoscopic in one. The mean duration of surgery was 264 (range 170-377) min. All patients were transferred to the ICU after surgery (mean ICU stay 4.4 (range 1-11) days), and the overall mean hospital stay was 17.8 (range 10-32) days. Six patients developed major postoperative complications: cardiorespiratory failure in five and gastrointestinal complications in four. Surgical reoperation was needed in one patient for postoperative necrotizing and bleeding pancreatitis. Two patients died from their complications. CONCLUSION: Pancreas-sparing, ampulla-preserving D1-D2 duodenectomy for emergency treatment of major duodenal perforations is feasible and associated with satisfactory outcomes. PMID- 30024638 TI - Postanalytical considerations that may improve the diagnosis or exclusion of haemophilia and von Willebrand disease. AB - von Willebrand disease (VWD) and haemophilia represent the most common inherited or acquired bleeding disorders. However, many laboratories and clinicians may be challenged by their accurate diagnosis or exclusion. Difficulties in diagnosis/exclusion may include analytical issues, where assays occasionally generate an incorrect result (ie representing an analytical error) or have limitations in their measurement range of and/or low analytical sensitivity. Also increasingly recognized is the influence of preanalytical issues on the diagnosis of VWD or haemophilia. Unfortunately, postanalytical considerations are often not well considered in the diagnostic process. Therefore, this narrative review aims to provide an overview of some important postanalytical considerations that may help improve the diagnosis of VWD and haemophilia. This review primarily discusses aspects around reporting of test results. However, we also discuss other less well-recognized postanalytical considerations, including the use of assay ratios to help identify differential diagnoses and then guide further investigation. PMID- 30024639 TI - The feasibility and acceptability of a novel anxiety in bipolar disorder intervention compared to treatment as usual: A randomized controlled trial. AB - BACKGROUND: Comorbid anxiety is common in bipolar disorder (BD) and associated with worse clinical outcomes including increased suicidality. Despite effective psychological treatments for anxiety, research into treating anxiety in BD is underdeveloped. This paper describes a novel psychological intervention to address anxiety in context of bipolar disorder (AIBD). METHODS: Adults with BD and clinically significant anxiety symptoms were randomized to AIBD plus treatment as usual (TAU) or TAU alone. AIBD offered 10 sessions of psychological therapy using a formulation-based approach. Feasibility and acceptability were evaluated through recruitment, retention, therapy attendance, alliance, fidelity, and qualitative feedback. Clinical outcomes were assessed at baseline, 16, 48, and 80 weeks: interim assessments of relapse at 32 and 64 weeks. RESULTS: Seventy two participants were recruited with 88% retention to 16 weeks and 74% to 80 weeks (similar between arms). Therapy participants attended x - 7.7 (SD 2.8) sessions. Therapeutic alliance and therapy fidelity were acceptable. Qualitative interviews indicated that participants valued integrated support for anxiety with BD and coping strategies. Some suggested a longer intervention period. Clinical outcomes were not significantly different between arms up to 80 weeks follow-up. CONCLUSIONS: AIBD is feasible and acceptable but lack of impact on clinical outcomes indicates that adaptations are required. These are discussed in relation to qualitative feedback and recent literature published since the trial completed. PMID- 30024641 TI - The Vouros Odyssey. Liquid chromatography/mass spectrometry from a chromatographic perspective and a Theseus Paradox. AB - This article tracts Paul Vouro's contributions to the field of liquid chromatography - mass spectrometry in the context of the history of the development of modern day LC/MS. PMID- 30024640 TI - Plant diversity and density predict belowground diversity and function in an early successional alpine ecosystem. AB - Despite decades of interest, few studies have provided evidence supporting theoretical expectations for coupled relationships between aboveground and belowground diversity and ecosystem functioning in non-manipulated natural ecosystems. We characterized plant species richness and density, soil bacterial, fungal and eukaryotic species richness and phylogenetic diversity (using 16S, ITS, and 18S gene sequencing), and ecosystem function (levels of soil C and N, and rates of microbial enzyme activities) along a natural gradient in plant richness and density in high-elevation, C-deficient soils to examine the coupling between above- and belowground systems. Overall, we observed a strong positive relationship between aboveground (plant richness and density) and belowground (bacteria, fungi, and non-fungal eukaryotes) richness. In addition to the correlations between plants and soil communities, C and N pools, and rates of enzyme activities increased as plant and soil communities became richer and more diverse. Our results suggest that the theoretically expected positive correlation between above- and belowground communities does exist in natural systems, but may be undetectable in late successional ecosystems due to the buildup of legacy organic matter that results in extremely complex belowground communities. In contrast, microbial communities in early successional systems, such as the system described here, are more directly dependent on contemporary inputs from plants and therefore are strongly correlated with plant diversity and density. PMID- 30024642 TI - Use of seasonal forecasting to manage weather risk in ecological restoration. AB - Ecological restoration has widely variable outcomes from successes to partial or complete failures, and there are diverse perspectives on the factors that influence the likelihood of success. However, not much is known about how these factors are perceived, and whether people's perceptions match realities. We surveyed 307 people involved in the restoration of native vegetation across Australia to identify their perceptions on the factors influencing the success of restoration projects. We found that weather (particularly drought and flooding) has realized impacts on the success of restoration projects, but is not perceived to be an important risk when planning new projects. This highlights the need for better recognition and management of weather risk in restoration and a potential role of seasonal forecasting. We used restoration case studies across Australia to assess the ability of seasonal forecasts provided by the Predictive Ocean Atmosphere Model for Australia, version M24 (POAMA-2) to detect unfavorable weather with sufficient skill and lead time to be useful for restoration projects. We found that rainfall and temperature variables in POAMA-2 predicted 88% of the weather issues encountered in restoration case studies apart from strong winds and cyclones. Of those restoration case studies with predictable weather issues, POAMA-2 had the forecast skill to predict the dominant or first encountered issue in 67% of cases. We explored the challenges associated with uptake of forecast products through consultation with restoration practitioners and developed a prototype forecast product using a local case study. Integrating seasonal forecasting into decision making through (1) identifying risk management strategies during restoration planning, (2) accessing the forecast a month prior to revegetation activities, and (3) adapting decisions if extreme weather is forecasted, is expected to improve the establishment success of restoration. PMID- 30024643 TI - In silico and in vitro immunogenicity assessment of B-domain-modified recombinant factor VIII molecules. AB - INTRODUCTION: B-domain modification can improve production of recombinant factor VIII (rFVIII) proteins. However, the engineered junction results in non-native peptide sequences with the potential to elicit immune responses via major histocompatibility complex class-II (MHC-II)-binding and CD4+ T cell activation. AIM: Assess the immunogenic potential of B-domain junction peptides of turoctocog alfa and other B-domain-modified rFVIII proteins using in silico and in vitro immunogenicity assessment techniques. METHODS: Peptides with amino acid sequences identical to the B-domain junction of turoctocog alfa, simoctocog alfa and moroctocog alfa were evaluated by in silico peptide-MHC-II binding prediction, in vitro peptide-MHC-II-binding measurement and in vitro T cell-activation assays. Moreover, turoctocog alfa was assessed for peptide presentation on dendritic cells (DCs) using MHC-associated peptide proteomics. RESULTS: In silico analysis predicted virtually no neo-epitopes in the B-domain junction for turoctocog alfa, whereas some were predicted for simoctocog alfa and moroctocog alfa. Turoctocog alfa and moroctocog alfa peptides showed minimal capacity to bind high-frequency MHC-II molecules in vitro, whereas simoctocog alfa peptide demonstrated some degree of binding to approximately half of the MHC-II molecules tested. In line with this, no B-domain peptides from turoctocog alfa were found to be presented on MHC-II complexes on DCs. B-domain junction peptides from all 3 compounds induced T cell responses in only a few percentages of donors. CONCLUSION: All 3 junction peptides were found to have a low immunogenicity potential, suggesting that modification of the B-domain does not constitute an increased immunogenicity risk for any of the products examined. PMID- 30024644 TI - Assessment of the red blood cell proteome in a dog with unexplained hemolytic anemia. AB - A 7-year-old female neutered Jack Russell Terrier was presented to Langford Vets, the University of Bristol, with a history of chronic intermittent lethargy. Investigations and clinical course were compatible with hereditary hemolysis due to a red blood cell membrane defect. Proteomics was used to explore protein alterations in the presence of a hypothesized red blood cell membrane protein deficiency. Proteomic analysis revealed downregulation of the band 3, and alpha- and beta-adducin proteins, and alterations in the red blood cell proteome consistent with previous reports of changes due to the presence of reticulocytosis and ongoing hemolysis. The spectrum of protein alterations identified in the affected dog may be homologous to a band 3 protein deficiency secondary to hereditary spherocytosis, as described in people. PMID- 30024645 TI - Recent Progress on Nickel-Based Oxide/(Oxy)Hydroxide Electrocatalysts for the Oxygen Evolution Reaction. AB - Developing clean and sustainable energies as alternatives to fossil fuels is in strong demand within modern society. The oxygen evolution reaction (OER) is the efficiency-limiting process in plenty of key renewable energy systems, such as electrochemical water splitting and rechargeable metal-air batteries. In this regard, ongoing efforts have been devoted to seeking high-performance electrocatalysts for enhanced energy conversion efficiency. Apart from traditional precious-metal-based catalysts, nickel-based compounds are the most promising earth-abundant OER catalysts, attracting ever-increasing interest due to high activity and stability. In this review, the recent progress on nickel based oxide and (oxy)hydroxide composites for water oxidation catalysis in terms of materials design/synthesis and electrochemical performance is summarized. Some underlying mechanisms to profoundly understand the catalytic active sites are also highlighted. In addition, the future research trends and perspectives on the development of Ni-based OER electrocatalysts are discussed. PMID- 30024646 TI - rFIXFc for Immune Tolerance Induction in a Severe Hemophilia B Patient with an Inhibitor and Prior History of ITI Related Nephrotic Syndrome. PMID- 30024647 TI - Ionic Co-Crystal Formation as a Path Towards Chiral Resolution in the Solid State. AB - The preparation and characterization of a whole family of hydrated ionic co crystals formed by both enantiopure l-proline and racemic dl-proline with LiX (X=Cl, Br, I) are reported. The chiral preference of the lithium cation for homochiral coordination, both in the formation of crystalline conglomerates (with Cl and Br) and racemates (with Cl and I), in which molecules of opposite chirality are confined to distinct crystal layers, is discussed. Dehydration processes for all hydrated crystals have also been investigated. PMID- 30024648 TI - The Importance of Individualized Vancomycin Dosing to Ensure Optimal Exposure Early in Therapy. PMID- 30024649 TI - Elucidating the role of Demodex folliculorum in the pathogenesis of rosacea: exciting first steps.... PMID- 30024650 TI - Designing Cross-Coupling Reactions using Aryl(trialkyl)silanes. AB - Organo(trialkyl)silanes have several advantages, including high stability, low toxicity, good solubility, easy handling, and ready availability compared with heteroatom-substituted silanes. However, methods for the cross-coupling of organo(trialkyl)silanes are limited, most probably because of their exceeding robustness. Thus, a practical method for the cross-coupling of organo(trialkyl)silanes has been a long-standing challenging research target. This article discusses how aryl(trialkyl)silanes can be used in cross-coupling reactions. A pioneering example is CuII catalytic conditions with the use of electron-accepting aryl- or heteroaryl(triethyl)silanes and aryl iodides. The reaction forms biaryls or teraryls. This design concept can be extended to Pd/CuII -catalyzed cross-coupling polymerization reactions between such silanes and aryl bromides or chlorides and to CuI -catalyzed alkylation using alkyl halides. PMID- 30024651 TI - The role of IL-23/IL-17 axis in human kidney allograft rejection. AB - Th17 cell subset has been implicated in autoimmune diseases, tumor immunity and, transplant rejection. In order to investigate the role of IL-17/IL-23 pathway in allograft outcome, intragraft expression of IL-17 mRNA and single nucleotide polymorphisms (SNPs) of IL-17A, IL-17F, IL-17RC, and IL23R genes were evaluated with a quantification of IL-17A, IL-17F, and IL-23 plasma levels. This study revealed that recipients with acute rejection (AR) had a significant increase in IL-17A mRNA expression levels after transplantation compared to controls (P = 0.037). Moreover, IL-17A plasma levels were significantly higher in AR group; pretransplantation (Day-1 [D-1]): P = 0.00022 and posttransplantation (Day 7 [D7]): P < 10-14 . IL-17F and IL-23 plasma levels were significantly higher in AR at D7 only (47.86 vs. 22.99 pg/ml; and 33.82 vs. 18.811 pg/ml; P = 0.015 and P < 10-17 , respectively). Using receiver-operating characteristic curves, D7 IL-17A and IL-23 plasma levels exhibited excellent sensitivities and specificities for predicting AR. Genetic study revealed no association between IL-17A, IL-17F, IL 17RC, and IL23R studied SNPs and AR. Nevertheless, a significant improvement of graft survival was found in kidney transplant recipients carrying IL-17F rs763780*A/A, IL-17RC*G/G, and *G/A genotypes. Besides, IL-17A mRNA levels were significantly higher in patients carrying the IL-23R*G/G genotype comparatively to those with *G/A genotype. Based on these findings, significant increase of IL 17A mRNA and protein levels in AR recipients that are genetically controlled highlights the role of this cytokine that can be a useful clinical biomarker to predict early acute renal allograft rejection. PMID- 30024652 TI - Thrombocytosis and central nervous system involvement in a case of canine acute megakaryoblastic leukemia. AB - This case report presents a 14-month-old female Poodle mix with acute megakaryoblastic leukemia based on a marked thrombocytosis, abnormal platelet morphology, circulating dwarf megakaryocytes, and blast cells in the blood. Bone marrow abnormalities included dysmegakaryopoiesis dygranulopoiesis, and an increased number of blast cells was observed in the blood. Extensive leukemic involvement was also found in the liver, spleen, lymph nodes, lungs, kidneys, and brain. The cytopathologic features of the abnormal circulating cells were highly suggestive of being megakaryocytic in origin, which was supported by negative myeloperoxidase staining and positive von Willebrand factor staining on immunocytochemistry (ICC). The neoplastic cells were also CD61 positive and had variable von Willebrand factor expression on ICC. Although there were only 25% blast cells in the bone marrow, which theoretically supported myelodysplastic syndrome, the hypothesis that this case represented acute myeloid leukemia of megakaryoblastic origin was confirmed by the continuous increase in circulating blast cell numbers during follow-up visits and the extensive leukemic involvement of parenchymal organs. PMID- 30024654 TI - Unexpectedly high response to DDAVP in two patients with moderate haemophilia A. PMID- 30024655 TI - The integration of LC-MS and NMR for the analysis of low molecular weight trace analytes in complex matrices. AB - This review discusses the integration of liquid chromatography (LC), mass spectrometry (MS), and nuclear magnetic resonance (NMR) in the comprehensive analysis of small molecules from complex matrices. We first discuss the steps taken toward making the three technologies compatible, so as to create an efficient analytical platform. The development of online LC-MS-NMR, highlighted by successful applications in the profiling of highly concentrated analytes (LODs 10 MUg) is discussed next. This is followed by a detailed overview of the alternative approaches that have been developed to overcome the challenges associated with online LC-MS-NMR that primarily stem from the inherently low sensitivity of NMR. These alternative approaches include the use of stop-flow LC MS-NMR, loop collection of LC peaks, LC-MS-SPE-NMR, and offline NMR. The potential and limitations of all these approaches is discussed in the context of applications in various fields, including metabolomics and natural product discovery. PMID- 30024653 TI - Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. AB - STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups (GDGs), and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (a) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (b) reducing unnecessary testing; (c) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (d) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. PMID- 30024656 TI - Blockade of deubiquitinase USP7 overcomes bortezomib resistance by suppressing NF kappaB signaling pathway in multiple myeloma. AB - The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ-resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ-resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing IotakappaBetaalpha and blocking the NF-kappaB pathway. Not surprisingly, when IkappaBalpha was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF-kappaB and combination with BTZ triggered the synergistic antitumor activity in BTZ-resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM. PMID- 30024657 TI - Family-based study of association between MAFB gene polymorphisms and NSCL/P among Western Han Chinese population. AB - BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) are the most common human congenital birth defects with a complex etiology. MAFB has been reported as a candidate gene involved in the pathogenesis of NSCL/P from genome wide association study (GWAS) findings, and no replication studies have been performed in Western Han Chinese. OBJECTIVES: The aim of this study was to investigate the associations of MAFB among NSCL/P trios in Western Han Chinese. MATERIAL AND METHODS: We selected 6 single nucleotide polymorphisms (SNPs) (rs6072081, rs6065259, rs17820943, rs13041247, rs11698025 and rs6102085) near MAFB based on previous GWAS findings and recruited 298 case-parents trios with NSCL/P from Western Han Chinese population, while genotypes were done by SNPscan technology. RESULTS: Strong evidence of an association was found at rs17820943 (p = 0.0023; odds ratio - ORtranmission = 0.7 and 95% confidence interval [CI]: 0.55 0.88) and rs13041247 (p = 0.0023; ORtranmission = 0.7 and 95% CI: 0.55-0.88) among NSCL/P; genotypic transmission-disequilibrium test (TDT) analysis further confirmed this. C/C homozygote at rs17820943 (z = 3.44 and p = 0.00058) and T/T homozygote at rs13041247 (z = 3.14 and p = 0.0017) was over-transmitted among NSCL/P, which indicated they could increase the risk of having an affected baby. Sliding window haplotype analysis showed that haplotypes consisting of C allele at rs17820943 and T allele at rs13041247 were still over-transmitted among NSCL/P (lowest p = 0.0021). CONCLUSIONS: This study further confirmed that the targeted SNPs at MAFB were associated with NSCL/P trios from Western Han Chinese population, which provides more scientific evidence for the future research and genetic counseling. PMID- 30024658 TI - Anti-CCP antibodies and rheumatoid factor in systemic sclerosis: Prevalence and relationships with joint manifestations. AB - BACKGROUND: It is known that anti-citrullinated protein (a-CCP) antibodies and rheumatoid factor (RF) can be present in systemic sclerosis (SSc) patients, particularly with joint involvement. OBJECTIVES: The aim of the study was to assess the prevalence of a-CCP antibodies and immunoglobulin M class (IgM) RF, and the relationships between their presence and joint manifestations in patients with SSc. MATERIAL AND METHODS: The study included 100 European Caucasian SSc patients hospitalized consecutively in the Department of Rheumatology and Connective Tissue Diseases (Lublin, Poland). Anti-citrullinated protein antibodies and IgM RF were determined using a commercial enzyme-linked immunosorbent assay (ELISA) test. RESULTS: Anti-citrullinated protein antibodies were found in 10 out of 100 (10%) SSc patients and IgM RF in 71 out of 100 (71%) SSc patients. In the study, 90/100 (90%) SSc patients had joint manifestations (arthralgia or arthritis), 34/100 (34%) had arthritis and 6/100 (6%) had a systemic sclerosis-rheumatoid arthritis (SSc-RA) overlap syndrome. Significantly higher a-CCP antibody levels (p = 0.012), erythrocyte sedimentation rate (ESR) (p = 0.029) and C-reactive protein (CRP) levels (p = 0.020) were observed in the SSc group with arthritis. A significant correlation was found between the group with arthritis and the presence of a-CCP antibodies, and between the arthralgia group and the presence of IgM RF. CONCLUSIONS: The prevalence of RF and a-CCP antibodies is relatively high in SSc, and joint involvement occurs frequently. There was a significantly higher prevalence of IgM RF in the group with joint manifestations. About 1/3 of SSc patients had symptoms of arthritis. Arthritis is connected with the presence of a-CCP antibodies, while arthralgia is connected with the presence of IgM RF. PMID- 30024659 TI - A need for intervention: Childhood adversities are a significant determinant of health-harming behavior and poor self-efficacy in patients with alcohol dependence. An observational, cross-sectional study on the population of Central Poland. AB - BACKGROUND: Adverse childhood experiences (ACEs) are known to be associated with a lasting effect on physical and psychological well-being in adulthood. Patients with alcohol dependence (AD) are a particular clinical subgroup who report a higher number of ACE categories than the general population and who develop several health-harming behaviors and poor social skills. OBJECTIVES: To our knowledge, this is the first study on patients with AD that aimed to assess whether ACEs correlate with health habits and general self-efficacy in adulthood. MATERIAL AND METHODS: The study comprised 196 patients with AD (F = 50) with a mean age of 43.8 years. The following research tools were used: the Health Behavior Inventory (HBI), the Generalized Self-Efficacy Scale (GSES) and the ACE Study score, expanded with 3 more questions about exposure to sudden stress and violence outside the family. Additionally, the patients' sociodemographic and clinical characteristics were assessed and included in the multiple stepwise regression analysis for variation in health habits and general self-efficacy. RESULTS: The mean scores of the patients were 64.4 +/-16.6 points on the HBI and 28.4 +/-6.2 points on the GSES. The study revealed a mean number of 3.3 +/-2.7 ACEs. The multiple regression analysis showed that the ACEs were significantly and inversely associated with self-efficacy assessed by the GSES and with health habits evaluated by the HBI (beta = -0.377; p = 0.026 and beta = -1.210; p = 0.007, respectively). The ACEs accounted for 3.2% of the GSES model variability and 3.9% of the HBI variability. CONCLUSIONS: Adverse childhood experiences might promote the development of health-harming behaviors and inferior general self efficacy in adult patients with AD. The study suggests the need for primary and secondary preventive strategies targeted at ACEs and at general self-efficacy impaired by childhood adversities for further better well-being. However, although the influence of the ACEs was significant, there are many other factors that were not included in the analysis, which explain the remaining variability of health behaviors and general self-efficacy. PMID- 30024660 TI - Denture adhesives' effect on retention of prostheses in patients with xerostomia. AB - BACKGROUND: Patients with xerostomia have difficulties using dentures. Application of denture adhesives (DAs) can improve the stabilization of prostheses. OBJECTIVES: The aim of the study was to determine the retention capability of complete maxillary dentures in patients with xerostomia, determined with and without the use of prosthetic DAs. MATERIAL AND METHODS: This study evaluated the retention force of prostheses in a group of 60 patients diagnosed with xerostomia. Completely edentulous patients were classified into groups and all used the same kind of DAs during the study. The evaluation was performed 1, 3 and 6 h after application. RESULTS: All patients had poor retention of maxillary dentures without DAs. Maxillary denture retention was much better when DAs were used. The majority of the DAs used were most effective in terms of retention after 1 h. Denture adhesives in the form of glue had the best retention in this study of patients with xerostomia. CONCLUSIONS: The results of the present study revealed the impact of DAs on average retention forces in complete maxillary denture patients with xerostomia. Patients affected by a reduced secretion of saliva have difficulties using prosthetics. In some cases, such use becomes impossible because of a complete lack of retention. The application of DAs could be a solution in these cases. Denture adhesives in glue form had the best retention during the study for patients with xerostomia. PMID- 30024661 TI - Extremely low frequency electromagnetic field reduces oxidative stress during the rehabilitation of post-acute stroke patients. AB - BACKGROUND: One of the therapeutic methods used in stroke rehabilitation is magnetotherapy using extremely low frequency and variable pulse shape electromagnetic field (ELF-EMF). OBJECTIVES: The aim of our study was to investigate the effect of magnetotherapy on the condition of postacute stroke patients, as measured by plasma oxidative stress markers and clinical parameters which show the progress of rehabilitation. MATERIAL AND METHODS: The selected 57 post-stroke patients were divided into 2 groups, those with ELFEMF therapy and those without. The level of oxidative stress in the plasma was estimated by typical markers: thiobarbituric acid reactive substances (TBARS), thiol groups, and carbonyl groups. The effect of ELF-EMF on the course of the patients' rehabilitation following ischemic stroke was evaluated with the use of scales of physical activity and mental state: Activities of Daily Living (ADL), Mini-Mental State Examination (MMSE) and Geriatric Depression Scale (GDS). RESULTS: Our comparative analysis showed that all parameters of oxidative stress are significantly reduced during rehabilitation using ELF-EMF, compared to the control group rehabilitated only by kinesiotherapy. We also recorded much higher therapeutic benefits using magnetotherapy, which revealed a significant improvement of clinimetric parameters. CONCLUSIONS: The ELF-EMF therapy meaningfully improves the overall condition of patients through a decrease of oxidative stress markers and it significantly affects the psychophysical abilities of patients after stroke. The change in carbonyl group level correlates with the change in the degree of physical and mental disability; therefore, it could be a marker for the effectiveness of rehabilitation. PMID- 30024662 TI - Labor in pregnancies with small for gestational age suspected fetuses. AB - BACKGROUND: Fetal growth restriction (FGR) is an unclearly defined condition described as a fetal weight which is too low in relation to gestational age. It is recognized in 10-15% of singleton pregnancies and can lead to severe complications, including stillbirth. To reduce the adverse fetal and neonatal outcomes, many medical interventions are being introduced by obstetricians. These, like all medical procedures, may induce further complications, such as preterm labor and its consequences. OBJECTIVES: The aim of this study was to assess in terms of perinatal and neonatal outcomes such management procedures as expectant monitoring, induction or elective cesarean section (ECS) in pregnancies where the fetus is suspected of being small for gestational age (SGA). There was also the goal of determining the specificity of ultrasound examination in the recognition of SGA. MATERIAL AND METHODS: The single-center retrospective study was carried out among 146 patients who were prenatally suspected of having SGA pregnancies and who delivered in our hospital. Small for gestational age was defined as estimated fetal weight (EFW) in the 10th percentile or below. The output cohort was divided into 2 subgroups: group A - with antenatally confirmed hypotrophy, and group B - without antenatally confirmed hypotrophy. RESULTS: Out of 146 newborns suspected of being SGA, 65 had a birth weight in the 10th percentile or below, and the estimated positive predictive value of ultrasound examination amounted to 44.5%. Underweight mothers correlated with 5 times higher rates of SGA overdiagnosis. Serious neonatal complications, such as neonatal deaths, respiratory or cardiovascular dysfunctions, and admission to the neonatal intensive care unit (NICU), occurred significantly more often in confirmed SGA cases (46% vs 19% in group B, with a p-value of 0.0066, 0.0253, 0.0027, and 0.0253, respectively). The highest rate of ECS concerned patients from group A (44.6% vs 30.9% in unconfirmed samples; p = 0.04), while expectant management was more often associated with neonatal death and admission to the NICU than with elective procedures (18.2% vs 7.4% and 36.4% vs 27.8%, respectively). CONCLUSIONS: Customized charts used during ultrasound examination, which evaluate additional parameters such as body mass index (BMI), may decrease the overdiagnosis of SGA. PMID- 30024663 TI - Recent Developments in Workers' Compensation and Employers' Liability Law. AB - This survey reviews significant statutory developments and appellate court decisions addressing workers' compensation issues for the period from October 2016 through September 2017. Workers' compensation systems are state statutory programs; the direct effect of statutes and precedents outside of their state of origin is limited. Nevertheless, compensation principles and laws have much in common among states and much can be learned from studying how legislatures and courts of other jurisdictions have treated similar issues. It is notable that when state courts cannot adjudicate an issue based solely upon a statute's plain language, and no precedent of the jurisdiction is determinative, they often consider authority from other states. Given the state-based character of compensation laws, not all of the cases discussed here can be considered to be landmark decisions, but they are significant for what they can teach lawyers and judges about how workers' compensation laws are structured and interpreted. PMID- 30024664 TI - [Spatio-ethological aspects of interactions between small mammals and wood ants]. AB - Mechanisms of interactions between species present one of the central problems of contemporary behavioral and evolutionary ecology. Field observations of possible resource redistribution and mutual behavioral adaptations between representatives of different guilds with substantially overlapping niche parameters are, so far, few. Using the methods of small mammals censuring, with account for their mobility and burrowing activity, at the sites with high and low dynamical density of wood ants Formica aquilonia, as well as in anthills proper, spatial interactions between these animals are revealed for the first time which are based on seasonal transformations of topic competition and synoecism. Species composition and domination structure of small mammals communities appear to be similar in those territories controlled by F. aquilonia and almost free of them. However, judging by animals' spatial distribution and activity it can be suggested that wood ants, being a disturbing factor, markedly reduce the numbers and burrowing activity of small mammals in their territory and, apparently, hinder mammals dispersion. During seasonal resting of ants, when they move down into the soil, anthills attract a lot of small animals: from October to May up to 84% ant nests are burrowed by murine rodents and insectivore mammals. It seems to be possible that there are trophic relationships between small mammals and wood ants, with mammals consuming nest substrate as well as insects themselves. PMID- 30024665 TI - [Tree-rings width variability along latitudinal and paleolatitudinal gradients]. AB - Processed are 57596 dated series of tree-rings width (TRW ) from the International Tree-ring Data Bank. The results obtained indicate that: 1. The TRW is strongly correlated with tree age. Periods of cambium activity are strictly dependent on the age of the trees. Therefore, there is a strong correlation between TRW and periods of radial growth. It is suggested that synchronization of the periods of radial growth in the first 150 years of trees life with cycles of climatic factors leads to increase in TRW . 2. Satisfactory coincidence between latitudinal profiles of TRW , on the one hand, and climatic and biological indicators, on the other hand, is observed. Latitudinal profile of TRW gets its form under the influence of climate and assimilating mass productivity. 3. Latitudinal change of the TRW in the Cretaceous had a pronounced displacement of a maximum from equator toward 30 degrees NL. Growth gain of Cretaceous gymnosperms was about twice higher than that of modern trees. Such asymmetry of paleolatitudinal profile of TRW sharply distinguishes it from modern latitudinal profiles that follow climatic parameters. PMID- 30024666 TI - [From uncertainty to an exact number: Developing a method to estimate the fitness of a clonal species with poly variant ontogeny]. AB - The task to estimate the fitness of a clonal plant with polyvariant ontogeny reduces to compiling a life cycle graph, constructing and calibrating the corresponding matrix model of the discrete-structured population, and calculating the dominant eigenvalue (lambda1) of the model matrix. We demonstrate a solution to this task with a sample of Calamagrostis epigeios , a perennial long-rhizome grass propagating vegetatively, and data on the age-stage structure of its local population. A traditional technique of successive censuses fixing the age-stage status of all individuals on a permanent sample plot (SP) provides for calculating frequencies of ontogenetic transitions directly from the data, but leaves uncertain the status-specific reproduction rates as the recruit parents are unknown ("reproductive uncertainty"). Uncertainty in data was leading to that in the estimation and dictating a need to change the method of field study: the description of above-ground parts of plants has been completed with the analyses of rhizome parent-daughter links revealed after digging SPs out. However, the traditional, fixed area of SPs (1 m 2) forced cutting the links off along its perimeter, while those within the SP turned out quite entangled already in a 4 year-old colony. A result, the reproductive uncertainty were not eliminated completely, and the next step in the method development has become to determine the contour of the entire woodreed colony and to carefully dig it out. Analysing both the above- and below-ground spheres of the colony has enabled us to calculate uniquely all the elements of the matrix model, hence the value of lambda1, while accounting for the actual area of the contour in the current and previous years amends the value of lambda1 needed for comparison with the results of previous studies. PMID- 30024667 TI - [Effect of fires on phytomass and primary production dynamics of the mesotrophic undershrub-sphagnum bog in the Amur region]. AB - Data are presented on the dynamics of phytomass and primary production of the undershrub-sphagnum bog. Comparison of productivity parameters in sites with unimpaired and bumt-out vegetation is used as a method of analysis of the phytocenosis functioning during its 6-year recovery after a fire. Net primary production varied from 4.9 to 9.6 tons/ha * yr in the unimpaired bog site and from 5.3 to 15.1 tons/ha * yr in the burnt-out one. By the end of the fifth year of recovery, the phytocenosis fully compensated the loss of carbon due to the fire, mainly at the expense of roots production. Recurrent fires have a result of more profound changes in phytomass structure and reduction of primary production. PMID- 30024668 TI - [Evolutionary trajectories in the parameter space of the sectional model of green spruce crown biomass. The emergence of a "proto-plant"]. AB - The sectional model of system dynamics of regular branches of a tree together, with submodels for initial growth inhibition and inter-verticil branches, has been extended to the range (0, 3) of fractal parameter ts that connects green biomass and a spruce size, V ~ H u . It is shown that spruce branches of first three orders appear in the subrange of u (0, 1). Branches of the first order appear at u ~ 0.25. Inter-verticil branches appear at u ~ 1.4, which may be viewed as a means of spruce adaptation to unstable lighting conditions. The presence of green biomass at u < 1.0 indicates that it can be represented as a set of photosynthesizing points (hypothetical cyanobacteria) placed in space. Therefore, the fractal properties of the set of points on the line segment have been considered as a model. It is shown that the condition u < 1.0 can be fulfilled only if the points are arranged in groups. At that, u is practically independent of groups alignment while depends on the number of groups and the number and type of points distribution within groups. Based on these fractal properties of points alignment within groups along the segment, and the hypothesis of trophic nature of organelles symbio-genesis in eukaryotic cells, an idea of a two-stage mechanism of proto-plants emergence was formulated. The mechanism is manifested through the motion along the trajectory of endosymbiosis, beginning with a fixed number of points in the group and then with an increase in the number of groups, until, in course of evolution, the host of endosymbiosis would create an infrastructure for the supply and inter-group interaction of cyanobacteria. At this stage, u decreases from 1 to ~ 0.25. When the infrastructure is created and it becomes possible to increase the number of points in the group, the motion along the trajectory occurs through doubling the number of cyanobacteria in a group. At this stage, u value increases to 1. At the first stage, motion along such a composite trajectory results in slow growth of the photosynthetic system size, even with an exponential increase in the number of cyanobacteria groups. The size grows rapidly at the second stage, after the limitations on growth of cyanobacteria number within groups are taken off. It should be noted that such an initial growth inhibition occurs also in modern trees, and is reflected in the initial slow increase in the number of the orders of tree's branches. PMID- 30024669 TI - [Analyzing the fine-scale dynamics of two dominant species in a Polytrichum Myrtillus pine forest. I. A homogeneous Markov chain and cyclicity indices]. AB - Using long-term direct observations in a Polytrichum-Myrtillus pine forest, we have constructed and verified a homogeneous Markov chain model for two dominant species (Vaccinium myrtillus and V. vitis-idaed) at the late stages of succession. The sampling design features a large sample size (2000 quadrats) on permanent transects, several re-examinations with the interval of 5 years, and the use of species rooted frequency. As a model of the process under concern, the discrete Markov chain accounts for the following four states: both species being absent on the quadrat, one of them being present alone, and the joint presence of the both; the model time step coincides with the time interval between observations. The model is calibrated on the data of two successive examinations and verified on that of one more examination. All possible transitions between the states are revealed to realize in quadrats for one time interval, as well as the absence of transitions at each state, which results in the complete digraph (directed graph) of transitions. Major model results are obtained by the formulae of finite Markov chain theory: the steady-state square distribution, cyclicity characteristics, and the mean durations of stages in the fine-scale dynamics. As a steady-state (stable) outcome of succession, the distribution among quadrats is expected where 30% of quadrats are occupied by V. myrtillus alone, 11% by V. vitis-idaea alone, both species are present on 18% of quadrats, and 41% of quadrats are 'empty'. This demonstrates a possibility for V. myrtillus and V. vitis-idaea to coexist stably at the latest stages of succession, with the clear predominance of V. myrtillus, yet without competitive exclusion. The quantitative characteristics of cyclicity and the durations of stages in the fine-scale dynamics enable us to estimate the total duration of secondary post-fire succession as about 45 years (to reach a distribution of states that differs less than 5% from the steady-state one). Out of the four states specified, the quadrats with V. vitis-idaea alone persist for the least time (8 years) on the average, while 'empty' ones persist for the greatest time (18 years). Forecasting the dynamics for one model time step forward and comparing the forecast with the real square distribution have revealed the measure of difference to be 5.4%. This illustrates the efficiency of the (time-)homogeneous Markov chain as a short-term forecast tool, yet leaves open the question whether the homogeneity hypothesis be true in the longer term. PMID- 30024670 TI - [On physiological role of permanent and temporary accumulation of anthocyanin pigments in leaves of woody plants]. AB - The emergence of plants with red leaves is related to accumulation of permanent anthocyanin pigments. Their temporary production under unfavorable environmental conditions is usually treated as an adaptive trait facilitating thermal stability and resistance to pests and diseases. The main pigment that is produced temporarily in almost all plant species is cyanidin monoglycoside. Using common barberry and its purple-leaf variant as a case study we found out that the predominant pigment in red leaves turns out to be the methylated derivative of cyanidin, namely peonidin-monoglycoside, although that does not alter the qualitative composition of anthocyanin pigments in red and green leaves. Ample accumulation of peonidin in the plants is shown to be inert with regard to basic functional properties: the plants continued to grow and bear fruits, though in different proportions. It is pointed out that more intense illumination leads to changes in energetic state of photosynthetic apparatus which are most prominent in the purple-leaf variant. Judging by the changes in fast fluorescence at different levels of illumination, red leaves at a low level of illumination utilize solar energy less efficiently by comparison with green ones. PMID- 30024671 TI - [Dissociation-reaggregation experiments in cnidarians as a model system for study of regulative capacity of metazoan development]. AB - Developmental processes of cnidarians, the basal metazoan representatives, possess extremely high regulative ability. It is known that any isolated fragment of the freshwater polyp hydra's body can regenerate an intact animal. Moreover, in many cnidarian species, suspension of single dissociated cells can form aggregates, which regenerate normal body plan of polyp or medusa. This process can be considered as an extreme case of regeneration. The development of cell reaggregates of Hydra is a conventional experimental system to study the physical basis of morphogenesis. Investigations of the cnidarians' reaggregate development help to clarify basic rules and mechanisms of the metazoan body plan formation and the role of self-organization in the metazoan early development. In this review, we summarize the data revealed by dissociation - reaggregation experiments performed on the representatives of different cnidarian taxa. We also analyze the data on the morphogenetic and molecular basis of the reaggregate development from randomly organized group of cells to cnidarian-specific body plan. PMID- 30024672 TI - [Transgenerational epigenetic effects: The influence of heightened temperature on Drosophila melanogaster life span]. AB - Epigenetic phenomena are defined as morpho-physiological changes not related to impairments of DNA sequence. The results of our study indicate that a pulsed non mutagenic thermal stress inflicted on developing ova (pro-embryos) gives rise to positive transgenerational epigenetic changes in the life span of offspring. At that, this effect depends on heterozygosity by lgl-mutation inherited from mothers. In generation Fl, determination of higher survival trait occurs even at early stages of oogenesis. The most pronounced effect is observed when heating is applied to the cells at the earliest stages of pro-embryo development. This study is the first experimental work on modeling the transgenerational aftereffects of pre-zygotic (pro-embryo) stress on offspring survivability and longevity when tumor suppressor lgl is operating. The significance of the results with regard to human epigenetics is discussed. PMID- 30024673 TI - [Phylogenesis of reproductive strategies in labyrinth fishes (Anabantoidei) and their sisterly groups]. AB - Clado- and semogenetic approaches, when used in concert, make it possible to resolve questions concerning phylogenetic relationships between a group representatives as well as phylogenesis of those representatives' traits. Parental care patterns and other forms of reproductive behavior, along with a reproductive strategy as a whole, can be subjects for semogenetic analysis to no lesser extent than morphological structures sensu stricto. One of the highly specialized forms of parental care in fishes, including suborder of labyrinth fishes and their sisterly groups, appears to be parental food provisioning. In my view, evolutionary origin of post-embryonic brood provisioning in bony fishes is related with three distinctive features, namely: 1) In fishes, different forms of post-embryonic food provisioning are convergent in their origin. 2) Any kind of brood provisioning is realized through exploiting the trait already existent and maintained by selection due to offspring fitness enhancement. 3) The main evolutionary path of this phenomenon emergence and development consists in the function expansion and replacement. This hypothesis does have the heuristic power, since it allows predicting the presence of the reproductive strategy component in question through identification of adequate basic adaptations. Despite the fact that parental care occurs in a majority of anabantoid fishes, there still are several species for which such care is not known. On cladogram, these species by no means take the basal position but are surrounded by fishes providing care for their eggs or even hatchlings. The parsimony principle leads to the suggestion that parental care is a plesiomorphic trait in the suborder Anabantoidei (or in the order Anabantiformes). It seems that the ancestors of present day non-caring species that take various positions within this phylogenetic group were fishes showing parental care. Later on, their reproductive strategy has changed as a result of r-selection. If this hypothesis is correct, the absence of parental care should be considered as a case of reproductive strategy degradation. It is quite probable that parental food provisioning was a component of the ancestral reproductive strategies. It is also possible that reproductive strategy of the present day Anabantiformes supposedly not caring for their offspring, actually includes some optional forms of parental care. PMID- 30024674 TI - [On the problem of female infertility: A search for genetic markers]. AB - In every one case out often, the reason behind female infertility turns out to be an orphan disease called 'hypogonadotropic hypogonadism', the single symptom of which is the reduced level of gonadotropins and, as a consequence, amenorrhea in females. Most often, hypogonadotropic hypogonadism is caused by disorder in secretion of gonadoliberin, the product of gene GNRH1. However, the disease is heterogeneous one, so it may origin from either genetic or non-genetic causes. To study the genetic component of the disease pathogenesis, we conducted molecular genetic analysis of 11 gene-candidates controlling synthesis and secretion of gonadoliberin as well as several gene-candidates functioning as neurodevelopmental and neuroendocrine regulators. In the study participated a group of patients afflicted by hypogonadotropic hypogonadism of an isolated form (n = 10), and a control group of healthy women (n = 20). All women were of reproductive age, with no detected mutations in gene-candidates that could cause any pathological effect. The data on gene-candidates expression in white blood cells are indicative of an increased expression of gene GNRH1 in the sampled patients as compared to the control group (p < 0.05). Other genes demonstrate heterogeneous expression both in the patients group and the control group. Thus, increased expression of gene GNRH1 in blood cells appears to be associated with the isolated form of hypogonadotropic hypogonadism and, in prospect, may be used as one of the disease markers. PMID- 30024675 TI - [Female mate choice, male-male competition, and male sexual traits: Experimental study of sexual selection directedness in Campbell's dwarf hamster (Phodopus campbelli Thomas 1905)] AB - We studied the relationship between female mate choice and male-male competition in Campbell's dwarf hamster. Sexually motivated (SM) females chose between two tethered male siblings that differed in expression of sexual traits. Males were unrelated to the female and able to contact and copulate with her. The same males were used in encounter experiment with the following free access of competing male to another SM female. We measured males' sex-related morphology of body mass, mid-ventral specific skin gland, ano-genital distance, and external testicular diameter. We also estimated levels of blood testosterone and cortisol, specific T- and B-cell immune responses to antigens, as well as aggressive and sexual dominance. We found out that female mate choice was not dependent on male aggressive and sexual dominance estimated through encounter experiments. Both in female mate choice and male-male competition experiments (encounter of males and free excess of males to receptive female) successful males did not differ from unsuccessful males in expression of sexual traits (ST). Among males with higher expression of ST mate choice by the female was not associated with aggressive dominance and sexual dominance of a male. There were no significant differences between successful and unsuccessful males in variables treated as potential predictors of male's success, both in female mate choice and male-male competition experiments. Variables explaining female's preference and male's aggressive dominance, which were revealed by General Regression Model analysis, did not coincide. Our results suggest that there are no reasons to discuss the expression of ST in Campbell dwarf hamster males in terms of intersexual or intrasexual selection mechanisms or in terms of their interaction. At the same time, our study demonstrates that testing theoretical models such as "Handicap hypothesis" or "Immunity handicap hypothesis" may face difficulties, which are discussed in the text. PMID- 30024676 TI - [Interconnectedness between ecological successions and catenary arrangement of space]. AB - e-mail: mu4@eco.nsc.ru Four aspects related to succession theory are highly disputed. The first aspect concerns broad usage of the term "succession" for any level of life organization. The second aspect concerns the compatibility of chronological and chorological community successions. The third aspect deals with the semantics of the "succession" notion. And the fourth aspect relates to the compatibility of the concepts "succession" and "ecosystem evolution". Indiscriminant use of the term "succession" has been eroding its original meaning. Succession pertains only to the coenotic level of life organization, rather than any level. Succession is not a mere substitution of living forms at different ontogenetic stages, nor merely a change in population structure or biological species composition: succession is an optimization process of a coenotic relations system. Biotic changes at other levels take place independently of coenotic processes. Succession gives an impression of a stochastic chorological sequence only when considered within the frameworks of one subjectively or arbitrary chosen habitat. The latter is regarded as a reference one, while ignoring other neighbouring habitats where biota also undergoes complementary successional changes in different degrees. Recently an importunate postulate urging to believe succession to embrace only chronological community sequences, occurring in one and the same habitat during long time, is being increasingly discussed. This claim is not justified as any succession inevitably embraces several habitats, either successively or simultaneously. The stock of biota in one habitat is evidently not enough for the constant stochastic process. All habitats undergoing successional changes, rather than being isolated and functionally self-sufficient, are arranged in catenas, i.e. standardized chorological sequences determined by geomorphology, drainage, hydrology, microclimatic trends and biotic interchange within the corresponding biome. Therefore succession represents not just a chronological, but rather chrono chorological phenomenon. Such notion perfectly complies with the gnoseological principle of indivisibility of time and space, which can transform accordingly from one into another. The term "succession", both literally and semantically, denotes inheritance and stereotyping of the environmental experience in an ecosystem, conventional and optimal for the given biome, rather than ecosystem transition into a critically different state. Deviation from a stereotype is possible only in the eluvial ecosystems of catenas, where matter turnover is highly imbalanced, thus providing biota a chance to implement its evolutionary potential. The other ecosystems of a catena exclude this possibility due to predetermination of their ecological regimes. In those ecosystems successions are often interrupted and then resumed at different starting points, thus ensuring persistent mitigation to ecosystem evolution, which is a revolutionary and irreversible process that cannot be reproduced by definition. PMID- 30024677 TI - [Tropisms in underground shoots - stolons and rhizomes]. AB - In the review, the problem of plant movements (photo- and gravitropism) is discussed. The contemporary data on physiological and molecular mechanisms of tropisms in underground shoots and roots are presented. Special attention is paid to diagravitropism phenomenon in underground shoots (stolons and rhizomes) that grow in perpendicular direction to the Earth's gravitational axis. The role of phytochrome control in maintaining the horizontal growth of stolons and rhizomes is demonstrated, and physiological mechanisms of photo- and diagravitropism are discussed. It is shown that switching of an underground shoot tip from diatropic to ortotropic (vertical) growth is dependent on the carbohydrate and phytohor mone balance. The perspectives are outlined for further exploratory studies on mechanisms of growth orientation and morphogenesis of underground diagravitropic shoots. PMID- 30024678 TI - [Coenotic distribution and ecological preferences of Betula pendula and Betula pubescens in Central Russia]. AB - Betula pendula and B. pubescens are widespread species inhabiting the forest zone of Russia. At the same time, they are closely related species making up transitional forms. It is believed that their ecological ranges are overlapping to a great extent, although B. pubescens is more hydrophilic than B. pendula and less exigent to sunlight. These data, obtained by means of empirical observations, help to understand the ecology of both birch species but so far are not statistically proved. An analysis of habitat distribution of the two birch species is carried out, and a comparison is performed of their ecological relations with such factors as humidification, trophic status, acidity, illumination, and nitrogen soil richness (graded by D. Tzyganov scales). It is shown that B. pendula and B. pubescens differ significantly with relation to humidification, soil richness, nitrogen concentration, and illumination, while do not differ with relation to acidity. Habitat preferences indicate that B. pubescens is more eurytopic species than B. pendula. Although synecolog-ical ranges of both species overlap, their synecological optima still clearly stand apart. PMID- 30024679 TI - [On the mechanism of evolution at the ecosystem level of life organization]. AB - Just like the studies of species adaptations phenomenology do not reveal the mechanism of a new species adaptation emerging (speciation), so the enormous bulk of data on phenomenology of ecosystem processes, collected to date, does not disclose the mechanism of evolution at the ecosystem level of living matter organization. An attempt is made to mark out, among the whole variety of evolutionary events in ecosystem form of life, those components attributable to rnicroevolution (by analogy with successful studies of 1940s applied to population-species form of life). It is assumed that at the ecosystem level biogeocenosis (BGC) should be designated as an elementary evolutionary structure, alteration of a BGC species composition - as an elementary evolutionary event, gene pool of a species population (cenogenome) - as elementary evolutionary material, and natural group (cenogenetic) selection - as a directed elementary evolutionary factor. An origin of a new or destruction of an old BGC turns out to be a qualitative stage of microevolutionary process at the ecosystem level. PMID- 30024680 TI - [Guideline for breast reconstruction after mastectomy]. PMID- 30024681 TI - [Application of the digital osteotomy template in the mandibular angle osteotomy ]. AB - Objective: To investigate the application of the digital osteotomy template in the mandibular angle osteotomy,so as to increase the precision and symmetry of the osteotomy. Methods: 8 cases were included in our study (female,average age 25.5).The CT data (DICOM format) were reformatted into 3D images using 3D imaging software (ProPlan).The osteotomy lines were designed on digital 3D theoretical model with ProPlan.Then the statistics of the ostectomy were imported into GeoMagic in the form of STL file to design the 3D osteotomy template.The osteotomy template was fabricated with FDA certificated PLA through RP machine. During operation,the template was inserted into operation area to guide the osteotomy.A line was drawn along the edge of ostectomy plate with a grinding ball and osteotomy was done along the curvilinear line using a goose saw. Results: The removed bone proved to be highly matched with the template.All the post-operative results were satisfactory.There were no complications such as fracture,life threatening hemorrhage and infection.The post-operative measurement showed good symmetry. Conclusions: With the guidance of osteotomy templates,the surgeon can perform the osteotomy in an accurate way.The precision and symmetry of the osteotomy are greatly improved. PMID- 30024682 TI - [Application of Le Fort III osteotomy with minimal invasive approach in the treatment of midfacial hypoplasia]. AB - Objective: To describe a minimal invasive approach in the Le Fort III osteotomy procedure. Methods: 33 cases with midfacial hypoplasia were treated by Le Fort III osteotomy.Incisions were performed with minimal invasive approach,through lower eyelid,intraoral and upper eyelid crease or medial part of eyebrow instead of coronal incision.After the completion of osteotomy,distraction osteogenesis or orthognathic procedures were followed. Results: The midfacial segments achieved enough advancement without obvious relapse.Bleeding and operative time were reduced compared with coronal approach.No obvious scar was left. Conclusion: The Le Fort III osteotomy procedure could be successfully performed through minimal approach with steady results and minimal scars. PMID- 30024683 TI - [Reconstruction of trunk soft-tissue defect using the propeller flaps based on the perforators of the posterior intercostal artery ]. AB - Objective: To explore the feasibility and technical tips of the posterior intercostal artery perforator (PICAP) flaps for trunk defect reconstruction. Methods: The PICAPs were thoroughly explored with the hand-held ultrasound Doppler.According to the size,shape and location of the defect,a perforator flap was raised based on the chosen PICAP,rotated in a certain degree and used to reconstruct the torso defect. Results: From October 2009 to October 2015,22 patients underwent defect reconstruction using the PICAP propeller flaps.The chosen perforators derived from the vertebral segments of the posterior intercostal arteries in 2 patients,from costal groove segments in 15,from intermuscular segments in 4,and from subcostal artery in 1.The skin paddle dimension ranged from 12 cm * 4 cm-30 cm * 10 cm.The length of the perforator pedicle was 3.5-7.0 cm (average 4.8 cm).The flaps were rotated 180 degrees in 15 patients,150 degrees in 4 patients,and 90 degrees in 3 patients.19 flaps survived completely.Distal partial flap necrosis occurred in two flaps and total flap necrosis in one.All wounds at donor sites were closed directly.The patients were followed up for 1 to 5 years (average 3.5 years) with satisfactory outcomes and no tumor recurrence. Conclusions: The PICAP propeller flap provides a valuable option for different torso defects reconstruction. PMID- 30024684 TI - [Reconstruction of totally degloved fingers with a spiraled parallelogram medial arm free flap ]. AB - Objective: To investigate the therapeutic results of completely degloved digital injury using a parallelogram free flap from the medial arm in a spiral fashion. Methods: From January 2011 to June 2013,13 defects in 13 patients with non replantable degloved digital injury were treated with a parallelogram free flap from the medial arm in a spiral fashion.The longitudinal axis of the flap was along the line from the axilla to the medial humeral epicondyle.The medial brachial cutaneous nerve of the arm was harvested for sensory restoration.The non replantable degloved finger was reconstructed with the medial arm flap in a spiral fashion.The digital artery and dorsal veins were prepared as the recipient pedicle,and the medial brachial cutaneous nerve was sutured to the digital nerve stump.All the wounds at the donor sites were closed directly. Results: The dimension of the flaps ranged from 5.0 cm * 2.0 cm to 7.5 cm * 4.0 cm.Excetp for one partial flap loss,all the other flaps survived uneventfully with conservative therapy.The static 2-point discrimination test varied from 6 to 13 mm.No linear scar contracture was recorded in these patients.All the patients were satisfied with the overall results. Conclusion: Resurfacing the defect in a spiral fashion is a valuable and reliable technique for the reconstruction of complete finger degloved injuries.The medial arm flap is a good option for this procedure,with satisfactory functional recovery and good aesthetic restoration. PMID- 30024685 TI - [Repair of the skin and soft tissue defect on upper calf with the lateral popliteal artery perforator flap]. AB - Objective: To explore the feasibility and effect of the lateral popliteal artery perforator flap in repairing the skin and soft tissue defect on upper calf. Methods: The position and course of the perforators were confirmed with the color Doppler ultrasound. The flap was designed with the lateral popliteal artery perforator as the pedicle artery to repair the skin and soft tissue defect on upper calf according to the shape and size of the wound. Results: From January 2010 to January 2014,10 patients with traumatic upper calf skin and soft tissue defect were admitted. The wound size ranged from 3 cm *2 cmto9 cm*6 cm, and the flap size ranged from3 cm*3 cm to 10 cm*8 cm. The wounds at donor sites were closed directly in 4 cases and were covered with split thickness skin graft in 6 cases. All flaps survived completely. Surgical incisions and wounds at donor sites and recipient sites healed primarily. All cases were followed up for 6-15 months (10 months on average) with good flaps color, texture and shape. Conclusions: The lateral popliteal artery perforator flap has reliable blood supply and is easily performed. It is one of the optional methods for repairing wound of the upper calf. PMID- 30024687 TI - [Application of popliteal intermediate cutaneous artery descending branch island flap for treatment of knee joint scar]. AB - Objective: To investigate the effect with the popliteal intermediate cutaneous artery descending branch island flap repair the wound in the knee joint after resection of scar. Methods: From January 2006 to December 2014,A total of 12 cases of knee joint contracture patients,8 cases were male,4 were female; the age ranged from 4 to 58 years old;8 cases of hot water scald, electric injury in 2 cases,2 cases of scar radioactive contracture,3 cases with ulcer. The knee extension 10 degrees to 30 degrees. For scar excision of knee joint loosening, the scar excision wound size (3-5) cm * (10-14) cm, popliteal intermediate cutaneous wounds with artery descending branch island flap, The flap size (4-6) cm * (11-15) cm. Donor sites were closed directly in 2 cases,10 cases of skin graft. Results: The all were followed up after operation. Follow-up 6 to 24 months, the 12 cases survived completely, and the skin graft donor site homogeneity of survival, the skin color and similar to the surrounding mucosa, soft texture, shape is not bloated, the knee extension of up to 0 degree, and the walking without a limp. Conclusions: The popliteal intermediate cutaneous artery descending branch island flap blood supply is reliable, donor and recipient adjacent region, which has the advantages of simple operation, is one of the ideal flap for repairing the knee joint wound. PMID- 30024686 TI - [Application of the lobulated flap or unilobular flap pedicled with the descending branch of lateral femoral circumflex artery in reconstruction of defects resulted from perineal and hypogastric tumor resection]. AB - Objective: To summarize the clinical application of the lobulated flap or unilobular flap pedicled with the descending branch of lateral femoral circumflex artery in reconstruction of defects resulted from perineal and hypogastric tumor resection. Methods: From September 2010 to June 2014,according to the characteristics of the tissue defects after perineal or hypogastric tumor resection, and also based on the anatomical characteristics of the perforator artery which derived from the descending branch of lateral circumflex artery, unilobular skin flap or bilobulate skin flap was designed for one-stage reconstruction.7 males and 10 females, aged from 34 to 72 years old (average,56 years old), were included. There were 6 cases of dermatofibrosarcoma protuberance (DFSP),7 cases of squamous-cell carcinoma and 4 cases of Bowen disease. Tumors in 7 patients were located in hypogastrium and 10 in perineum. The defects size after tumor resection ranged from 3 cm * 4 cm to 8 cm * 16 cm. Among the patients,13 cases were treated with unilobular flaps, of which the area ranged from 6 cm * 10 cm to 13 cm * 18 cm;4 cases were treated with bilobular flaps, of which the area ranged from 3 cm *5 cm to 8 cm *12 cm.The wounds at donor sites were closed directly in 13 patients, and covered with skin graft in 4 patients. All patients underwent tumor extensive resection and subsequently reconstruction with flaps. The clinical courses ranged from 3 to 24 months. Results: All the flaps survived without vascular crisis. The wounds and incisions at donor sites healed primarily.12 patients were followed up for 3 to 26 months. The average follow-up duration was 16 months.During the follow-up period, the flaps were in good color and texture. Furthermore, patients were satisfied with vulvar appearance and even their sex life.Local tumor recurrence was not observed during the follow-up period. Conclusion: The flap pedicled with the descending branch of lateral femoral circumflex artery has a relatively long vascular pedicle, which may meet the requirement for reconstruction of defects in perineal and hypogastric region. Moreover, this flap could be designed as lobulated flap to repair two wounds at one-stage.This flap is an ideal option for reconstruction of perineal and hypogastric soft tissue defects with a reliable blood supply and unobvious donor sites. PMID- 30024690 TI - [Anatomy study and clinical application of island flap based on second dorsal metacarpal artery ]. AB - Objective: Through the anatomy study of the second dorsal metacarpal arteries (SDMA) and its cutaneous branches in fresh hand specimens, we explore the therapeutic effect of the island flap for the defect resulted from degloved avulsion injury of the fingers. Methods: From January 2009 to September 2014,the cutaneous branches of second dorsal metacarpal arteries from 12 fresh hand specimens perfused by red latex were explored.21 fingers in 21 cases were treated with island flap based on SDMA and its cutaneous branches for skin defects at 11 index fingers,7 middle fingers or 3 thumbs.4 cases had combined fracture,5 cases had combined tendon injury.3 cases had combined neurovascular injury. The flaps size ranged from 5.0 cm * 6.5 cm to 2.5 cm * 5.0 cm. Results: SDMA was originated from dorsal perforating branch of deep palmar arch. There were 4-6 cutaneous branches from SDMA distal intertendinous junction. The branches divided superfical vascular web to supply the dorsal skin on the second and third metacarpal.21 flaps based on SDMA survived successfully. After 5-27 months' follow up period, all these flaps recovered with satisfactory texture, grade S3 + sensation, and 7-11 mm two point discrimination. There were no obvious comphcations at the donor sites. Conclusions: The cutaneous branches of distal SDMA is stable. The branches are composed of superfical vascular web above the second and third metacarpal. The flap based on SDMA is not necessary to sacrifice a major artery and can achieve good flap contour. The technique is recommendable. It can be easily and conveniently performed. PMID- 30024691 TI - [Clinical application of orbicularis flap for eyelid groove deformity ]. AB - Objective: To discuss the correction of lower baggy eyelid with severe tear trough and eyelid sulcus (groove deformity) and its therapeutic effect. Methods: Through incision at the lower eyelid margin, the dissection was performed at the deep surface of the orbicularis muscle to expose the orbital septum and inferior orbital rim periosteum. The orbital fat which was released from orbital septum was repositioned at the inferior orbital rim and fixed on periosteum. If the depression was not completely corrected, the extra orbicularis fixed with periosteum. If the depression was not completely corrected, the extra orbicularis muscle was designed as muscle flap with interior pedicle to further correct the groove deformity. Results: 60 cases were treated with no depression or unsmooth deformity. All the cases were followed up for 3-12 months with satisfactory aesthetic effect. Conclusions: Orbicularis flap combined with orbital fat reposition is a simple and effective method for correction of tear trough and eyelid sulcus deformity. PMID- 30024692 TI - [The feasibility of adenoviral co-transduction of BMP2 and BMP7 for the expression of recombinant human BMP2/7 heterodimer in rat bone marrow mesenchymal stem cells]. AB - Objective: To investigate the feasibility of rat bone marrow mesenchymal stem cells (BMSCs) as the target cell of adenovirus-mediated co-transduction of BMP2 and BMP7 genes and then facilitate the expression of recombinant BMP2/7 heterodimer protein. Methods: 3 adult male Fischer 344 rats of about 10 weeks of age were used for harvest and in vitro culture of rat BMSCs. Recombinant adenovirus vector carrying BMP2 or BMP7 target genes were constructed with AdMax vector system, and production of high-titer adenoviruses were packaged with HEK293T cells and then concentrated with CSCl2 density-gradient ultra centrifugation. Rat BMSCs from passage 3 were seeded in 6-well plates at the concentration of 10 000 cells/cm2.After overnight pre-culture, BMSCs were allowed to culture in 200 MUl serum-free alpha MEM containing both Ad-BMP2 and Ad-BMP7 adenovirus (100 MOI of each virus). After 7 days in vitro culture, conditioned cell culture supernatants were collected and followed by immunoprecipitation through immune protein G columns pre-loaded with mouse anti-human BMP7 antibody. The resulted protein immune-precipitates were used to assay the expression of BMP2/7 heterodimers via Western Blot and ELISA assay. As a negative control, Rat BMSCs were also genetically transduced with Ad-GFP virus at a concentration of 200 MOI. Results: Our data demonstrated that recombinant adenoviruses carrying BMP2 or BMP7 target gene was successfully reconstructed, packaged, and confirmed via Western Blot assay, which as respected, presented as an unique band at 55 000 size for BMP2 or 49 000 size for BMP7.Adenovirus Ad-GFP was used to verify the integrity of recombinant virus and its transfection efficiency in rat BMSCs, which showed well cell attachment to culture plate and had no cytotoxicity. Green fluorescent protein in BMSCs was also noted eminently under fluorescent microscope. Combined transduction with AdBMP2 plus Ad-BMP7 resulted in the formation of BMP2/7 heterodimers from rat BMSCs. Analysis of conditioned medium via Western Blot assay showed a single protein band of about 47 000 size, just as expected. Quantitative ELISA analysis presented a prominent expression of about (4.33 +/- 0.42) ng/ml for recombinant BMP2/7 heterodimers. A paired t test showed significant difference (P < 0.05),when compare to control groups of (0.08 +/- 0.02) ng/ml. Conclusions: As an ideal cell source for tissue engineering, rat BMSCs can be genetically modified with Ad-BMP2 plus Ad-BMP7 mediated co transduction strategy, and efficiently produce recombinant human BMP2/7 heterodimers in vitro, which should facilitate further studies on the beneficial effect of BMP2/7 heterodimers to ex vivo osteogenesis of BMSCs PMID- 30024693 TI - [Different effects of simvastatin on keloid fibroblasts under hypoxia and TGF beta1 treatment]. AB - Objective: To explore the effect of simvastatin on the proliferation, apoptosis and protein expressions of keloid fibroblasts under normoxia,hypoxia or TGF-beta1 treatment. Methods: Keloid fibroblasts (KFs) were isolated by explants culture method. KFs were treated with different concentrations of simvastatin under normoxia or hypoxia (2% O2) for 24 h and 48 h. The effects of simvastatin on cell proliferation were detected by CCK-8.Flow cytometer was used to detect the apoptosis of KFs treated with 10 MU mol/L simvastatin for 24 h or 48 h under normoxia, hypoxia or 10 ng/ml TGF-beta1 treatment. Then the expressions of keloid related proteins were analyzed by Western Blot. Results: It showed that simvastatin could inhibit the proliferation of KFs in a concentration-and time dependent manner with the concentration range of 10-500 MU mol/L for 24 h and 0.1 500 MU mol/L for 48 h. This inhibitory effect could be significantly enhanced when cells were incubated under hypoxia for 48h with 10-500 MU mol/L simvastatin.10 MU mol/L simvastatin could not influence the apoptosis of KFs under normoxia or TGF-beta1 treatment, neither incubated for 24 h nor 48 h.When incubated under hypoxia,10 MU mol/L simvastatin could significantly induce the apoptosis of KFs, with the rate of 155.6% for 24 h and 478.8% for 48 h, compared with no-drug control. There are no significant influences on the expression of type I collagen, CTGF or TIMP-1 when KFs were treated with 10 MU mol/L simvastatin under normoxia for 48 h. When incubated with 10 ng/ml TGF-beta1 together with 10 MUmol/L simvastatin for 48 h, the expression of CTGF was significantly inhibited. KFs treated with 10 MU mol/L simvastatin under hypoxia for 48 h showed a significant decrease of type I collagen and CTGF, and a significant increase of TIMP-1. Conclusions: Simvastatin has different effects on the proliferation, apoptosis and protein expressions of KFs in a dosedependent manner under different conditions. The effects are enhanced under hypoxia. PMID- 30024694 TI - [The experimental study of the effect of ASCs on the skin expansion rate in rabbit]. AB - Objective: To explore the effect of adipose-derived stem cells (ASCs) on the skin expansion rate in rabbit. Methods: The rabbit ASCs were isolated from fat tissue and cultured in vitro. The ADSCs were identified by cell immunofluorescence and marked by Edu staining.20 new Zealand rabbits were randomly divided into experimental(n =10) and control group(n =10).An area of 1.5 cm *1.5 cm on the one side back of each rabbit was tattooed and one 30 ml round expander was implanted subcutaneously. ASCs suspension (1 ml) was injected subcutaneously in the experimental group, while serum free DMEM medium(1 ml) in control group. The expansion was proceeded regularly under constant pressure for 4 weeks.The expanded tattooed square area was measured on the 7th,14th,28th day and analyzed statistically. The expanded skin was harvested for histological study. Immunohistochemical staining was used to detect the expression of vascular endothelial cell marker CD31,and the microvessel density determination. The expression of epidermal growth factor (EGF) and vascular endothelial growth factor(VEGF)was detected by ELISA for skin tissue specificity. Western Blot was used for detection of CK19 in the epidermal cells. Results: The expanded skin thickness and expansion rate in experimental group were significant higher than those in control group (P < 0.05). Compared with control group, the expression of CK19,CD31 and EGF, VEGF, as well as the microvessel density were all markedly increased in experimental group(P <0.05). Conclusions: ASCs can increase the expansion rate of skin tissue by promotion of angiogenesis and tissue regeneration. PMID- 30024695 TI - Frequency of food hypersensitivity in patients with Functional Gastrointestinal Disorders. AB - BACKGROUND AND STUDY AIMS: Food hypersensitivity (FH), irritable bowel syndrome (IBS) and functional dyspepsia (FD) have many overlapping symptoms, including abdominal discomfort, bloating, and altered bowel habits. We aimed to determine the frequency of FH in patients with IBS and functional FD. PATIENTS AND METHODS: Adult patients of either gender diagnosed with IBS and/or FD as per the Rome III criteria were recruited. Patients underwent serological testing against 6 food allergens: beef, shrimp, egg white, milk, peanut, and soy-bean. Those testing positive were subjected to a food elimination diet for 4 weeks. Those showing improvement on elimination diet were subjected to re-challenge. Changes in symptoms were documented by the Global overall improvement scale (GOS) and Gastrointestinal symptom rating scale (GSRS). RESULTS: Two hundred patients were screened. Average age of the patients was 38.6, and 55 % were male. Nineteen (38%) patients tested positive, and were subjected to a food elimination diet. The most common food hypersensitivity was shrimp (17/89%), followed by 4/21% for egg-white, and peanut. Off these, 8 showed improvement. They were re-challenged, and were evaluated 2 weeks later, when all suffered symptom relapse. These 8 (4%) patients were diagnosed with FH. There was a statistically significant difference in both GSRS (total and component) and GOS scores at baseline between patients testing (+) and (-) on food allergen testing, mainly for diarrhoea (p=0.001), abdominal pain (p=0.001) and indigestion p=<0.001). CONCLUSIONS: FH is present in 4 % of patients with a functional gastrointestinal disorder. PMID- 30024696 TI - Can we better protect patients with inflammatory bowel disease against infections - patient attitude and personal immunization knowledge. AB - BACKGROUND AND STUDY AIMS: Inflammatory bowel disease (IBD) predisposes patients to a severe course of infections yet adherence to vaccination guidelines is low. Little is known about IBD patient attitude towards immunizations. We aimed to investigate patient attitude towards vaccinations and its influence on personal immunization coverage. PATIENTS AND METHODS: A self-completed survey was completed by 195 IBD patients. The author-designed questionnaire comprised: demographic data, IBD medical history, vaccination history, reasons of influenza vaccine refusal, and the most reliable source of information about immunizations. Moreover, patients were asked if they agree with the statement that immunizations are beneficial for a person with IBD. RESULTS: 99 patients (50%) claimed that prevention of infectious diseases is beneficial for a person with IBD but this opinion had no influence on recommended vaccination uptake. There was suboptimal vaccination coverage : hepatitis B (55%); diphteria, pertussis, tetanus (12%); hepatitis A (7%); annual influenza (6%); varicella-zoster (3%), and pneumococcal vaccine (2%). Top reasons for nonvaccination were: lack of information from a physician (47,5%), unawareness (35%), perceived lack of benefit (33%) and concerns about adverse events (26%). The most reliable source of information concerning immunizations was a gastroenterologist for the majority of IBD patients (58%) while more than 35% chose their general practitioner. CONCLUSIONS: Active promotion and information regarding beneficial role of immunizations among IBD patients and other chronically ill individuals significantly improves the quality of care. It is important to explain misconceptions about vaccines by the most reliable sources. We propose implementing an uniformed "immunization chart" for every chronically ill individual. PMID- 30024697 TI - Evaluation of the cost and length of hospital stays related to the management of an intestinal Clostridium difficile infection. AB - INTRODUCTION: Intestinal Clostridium difficile Infection (CDI) treated in hospitals may concern patients whose reason for admission is CDI (primary diagnosis) or who have acquired CDI during their stay (secondary diagnosis). OBJECTIVES: The objective of this study is to evaluate the cost for social security and hospitals and the length of hospital stays related to CDIs as the main reason for admission. METHOD: This study was carried out in 2012 in 13 Belgian hospitals. Cases were selected by using diagnosis recorded in minimum discharge summaries. Pediatric stays are not part of the inclusion criteria (n= 86). RESULTS: The average length of stay (standard deviation) was 13.53 days (11.95). The average cost (standard deviation) covered by social security/hospitals was ?5,019.51 / ?6,286.39 (9,638.42/ 6,368.45). 7% of patients were admitted to the Intensive Care Unit during hospitalization, for an average duration (standard deviation) of 8.18 days (2.93). The mortality rate was 8.1%. 19.8% of patients used vancomycin during the stay, 43% were treated with metronidazole only, 12.8% used vancomycin and metronidazole and 24.4% do not received vancomycin or metronidazole. No patients received fidaxomycin. CONCLUSION: This study made it possible to approach the cost of CDI as the main reason for admission. Such data should allow contributing to optimally assess both the pharmacoeconomic impact of the implementation of prevention strategies and also therapeutic management making use of more expensive medicinal products but associated with decreased risk of recurrence. PMID- 30024698 TI - Economic evaluation of S. boulardii CNCM I-745 for prevention of antibioticassociated diarrhoea in hospitalized patients. AB - Interest in administration of probiotics to prevent antibiotic-associated diarrhoea (AAD) in hospitalized patients is increasing. We determined the cost of antibiotic-associated diarrhoea in hospital settings for non-complicated and Clostridium difficile (C.diff) complicated AAD, and performed a health-economic analysis of AAD prevention with S. boulardii CNCM I-745 (S. boulardii) from data collected in 1 university and 3 regional hospitals in Flanders. Using a decision tree analytic model, costs and effects of S. boulardii for AAD prevention are calculated. Incremental costs due to AAD, including increased length of hospitalization, were calculated using bottom-up and top-down costing approaches from a hospital, healthcare payer (HCP) and societal perspective. Model robustness was tested using sensitivity analyses. Additional costs per hospitalized patient range from ? 277.4 (hospital) to ? 2,150.3 (societal) for non-complicated and from ? 588.8 (hospital) to ? 2,239.1 (societal) for C. diff. complicated AAD. Using S. boulardii as AAD prevention results in cost savings between ? 50.3 (bottom-up) and ? 28.1 (topdown) per patient treated with antibiotics from the HCP perspective; and ? 95.2 and ? 14.7 per patient from the societal and hospital perspectives. Our analysis shows the potential for using S. boulardii as AAD prophylactic treatment in hospitalized patients. Based on 831,655 hospitalizations with antibiotic administration in 2014 and ? 50.3 cost saving per patient on antibiotics, generalized use of S. boulardii could result in total annual savings up to ? 41.8 million for the Belgian HCP. PMID- 30024699 TI - The predictive value of colon transit time and anorectal manometry in the approach of faecal continence in children with spina bifida. AB - PURPOSE: The aim of this study is to analyse colon transit time (CTT) and anorectal manometry (ARM) in children with spina bifida (SB) as a predictor for achieving spontaneous faecal continence. METHODS: SB patients (2.5-7 years old) followed at the SB Reference Centre Ghent University Hospital underwent CTT and/or ARM before starting bowel management. A standardized questionnaire about the presence of constipation and faecal incontinence was completed. CTT was measured using a 6-day pellet abdominal X-ray method. ARM was performed in nonsedated children using a latex-free catheter. RESULTS: Twenty-two patients were studied, with a median age of 4.57 years. They all underwent a CTT study, 17 (77%) also agreed to ARM. 10/22 patients (45.5%) were constipated. 5/22 patients (22.7%) became spontaneously continent, 10/22 (45.5%) became pseudocontinent with bowel management, the others remained incontinent. SB patients had a significant prolonged CTT compared to healthy controls. In the group with an abnormal CTT study (12 patients), none of the patients developed faecal continence spontaneously, irrespective of the ARM result. In case of a normal CTT study (10 patients), 7 agreed to ARM. All children with normal resting pressure (4 patients) gained continence spontaneously. The 3 children with abnormal low resting pressure remained incontinent. CONCLUSIONS: This prospective study confirms the predictive value of normal CTT and normal resting pressure, in the evolution towards spontaneous faecal continence. If CTT is abnormal, irrespective of the ARM, bowel management will be necessary to obtain pseudo-continence. In these cases, ARM is not a designated examination. PMID- 30024700 TI - Endoscopic treatment of biliary complications after living donor liver transplantation in a high volume transplant center in Turkey; a single-center experience. AB - BACKGROUND AND AIM: Biliary complications are an important cause of mortality and morbidity after living donor liver transplantation (LDLT). We present our endoscopic treatment results after LDLT as a single center with high volume. METHODS: Patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) after LDLT between 2005 and 2015 were included. Clinical data included patient demographics, ERCP indications (stricture or leak), and treatment outcomes, including need for percutaneous and surgical interventions. RESULTS: ERCP was performed in 446 (39.2%) patients with duct-to-duct anastomosis of 1136 LDLT patients. The most common biliary complication was stricture +/- stone (70.6%, 315/446). Stricture and leak occurred in 60 (13.4%) patients. Only biliary leak was found in 40 (8.9%) patients. Our endoscopic treatment success rate in patients with biliary stricture after LDLT was 65.1%. Overall endoscopic success rates in our patients were 55.0% in patients with both leak and stricture, and only leak. In all, our percutaneous transhepatic biliary interventions (PTBI) and ERCP success rate was 90.6% in patients with biliary complications after LDLT. CONCLUSIONS: Endoscopic treatments are highly effective for biliary complications after LDLT. Effective use of percutaneous interventions in collaboration with endoscopic treatments significantly reduces the need for surgical treatment. PMID- 30024701 TI - Bioinformatic analysis of differentially expressed genes involved in the hepatitis B virus-associated acute liver failure. AB - BACKGROUND: The rarity of acute liver failure, along with its severity and heterogeneity, has resulted in a very limited evidence to understand of the molecular mechanism. To analyze the differentially expressed genes (DEGs) in the Hepatitis B Virus -Associated Acute Liver Failure and elucidate the biological significance of the DEGs. METHODS: Firstly, differentially expressed genes (DEGs) between seventeen HBV-associated acute liver failure liver samples and ten control normal liver samples were identified by R package. Then, the enriched GO terms and KEGG pathways of those DEGs were obtained using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Finally, protein protein interactions (PPI) network of those DEGs were constructed using STRING database and visualized by Cytoscape software. RESULTS: A total of 328 DEGs were identified in Hepatitis B Virus-Associated Acute Liver Failure group compared with the control group. Several novel biomarkers that might play important roles in HBV-associated acute liver failure were identified through the analysis of gene microarray in GEO. Furthermore, DEGs with high connectivity degrees, such as KNG1, PLG, F2 and pathways such as complement and coagulation cascades were noticed. CONCLUSION: DEGs with high connectivity degrees, such as KNG1, PLG and their relative pathway complement and coagulation cascades may be important for further understanding of the molecular mechanism of HBV-associated acute liver failure. PMID- 30024702 TI - Management of esophageal motility disorders in children : a review. AB - Diagnostic criteria for esophageal motor disorders have recently been updated with the advent of high-resolution manometry that gives a precise mapping of peristaltic abnormalities and an indirect view of bolus transit problems. Achalasia, the best-defined motor disorder, is now divided in subsets of manometric phenotypes that predict outcome of treatment and guide our therapeutic approach. Pharmacological therapy using smooth muscle relaxants for spastic esophageal disorders remains poorly effective and used only as a bridge to more effective therapies : endoscopic balloon dilation and surgical myotomy are both effective therapies in achalasia, myotomy being considered as the preferred approach in children because it is aimed to be definitive, while dilations usually have to be repeated. Recently, peroral endoscopic myotomy was introduced as an alternative to surgical myotomy for achalasia, and was rapidly adopted in tertiary referral centers. Showing excellent short-term results, this technique might be also proposed for other esophageal spastic disorders. Gastroesophageal reflux disease and eosinophilic esophagitis, two prevalent diseases in children that may be associated with hypotensive and hypertensive peristaltic abnormalities, have to be searched because specific effective therapies exist for these diseases that may cure the motility disorders. PMID- 30024703 TI - Gastroesophageal variceal bleeding - An overview of current treatment options. AB - Gastroesophageal variceal hemorrhage is the most important clinical event that results from portal hypertension. It is a lifethreatening condition that demands rapid and efficient treatment. The first step in bleeding control is hemodynamic stabilization and pharmacological treatment, which includes administration of vasoactive drugs and short-term antibiotic prophylaxis. After initial hemodynamic stabilization, endoscopic therapy should be performed. The first choice of endoscopic treatment for esophageal bleeding is endoscopic variceal ligation (EVL), or endoscopic injection sclerotherapy (EIS) if EVL cannot be performed. Several rescue therapies, such as application of balloon tamponade, a selfexpandable metal stent (SEMS), or a transjugular intrahepatic portosystemic shunt (TIPS), are available in cases of resistant variceal bleeding that cannot be controlled with endoscopic therapies. Gastric varices have a lower incidence than esophageal varices, but bleeding from gastric varices is associated with higher mortality and morbidity rates. The first-line treatment, as with esophageal variceal bleeding, is stabilization of the patient. After that, control of bleeding can be attempted. Optimal management of gastric variceal bleeding is not yet standardized due to diverse underlying pathologies and the lack of large, randomized controlled trials. Among endoscopic techniques, endoscopic variceal obturation (EVO) has been acknowledged as reliable. Among rescue therapies, balloon-occluded retrograde transvenous obliteration (B-RTO) of gastric varices and TIPS are the most common techniques. PMID- 30024704 TI - Acute non-cirrhotic portal vein thrombosis : review. AB - A 35-year-old man with a medical history of myocardial infarction, presenting with fever, general malaise and vague abdominal discomfort, was diagnosed with a portomesenteric venous thrombosis and acute cytomegalovirus (CMV) infection. Thrombophilia screening resulted in detection of heterozygosity for factor II G20210A gene mutation. Low molecular weight heparin in therapeutic dose was started, followed by disappearance of thrombus on imaging CT two months after diagnosis. The multifactorial origin of portal thrombosis and the importance of awareness of the link between CMV infection and an increased risk of thrombosis is emphasized with this case and review of the literature. Identifying CMV infection as a trigger for thrombosis can help to avoid extended anticoagulation. Acute non-cirrhotic PVT is a rare but probably underestimated condition as symptoms may be discrete or non-specific. The origin of portal thrombosis is frequently multifactorial. Recent literature has emphasized the increasing prevalence of CMV-induced PVT in immunocompetent patients. The multifactorial origin of portal thrombosis and the importance of awareness of the link between CMV infection and an increased risk of thrombosis is emphasized with this review of the literature and included case. Identifying CMV infection as a trigger for thrombosis can help to avoid extended anticoagulation. PMID- 30024705 TI - Eikenella corrodens perirenal abscess resulting from a pancreatic fistula in a patient with chronic pancreatitis. Case report and literature review. AB - We present a case of a right perirenal Eikenella corrodens abscess in a patient with chronic pancreatitis and poor dental hygiene. Endoscopic Retrograde CholangioPancreaticography (ERCP) revealed a pancreatic fistula draining to the right perirenal loge. The patient was treated with broad-spectrum antibiotics, percutaneous drainage and endoscopic stenting of the duct of Wirsung, stopping the supply of the fistula. A full recovery in our patient was observed. Considering the uncommon location of the abscess, a review of the different aetiologies of perirenal abscesses and their distrubution patterns, and the endoscopic treatment of symptomatic pancreatic fistulas seemed worthwhile. PMID- 30024706 TI - A case of unusual histiocytic colitis in a chronic alcoholic obese patient with ankylosing spondylitis. AB - A 64 year-old Caucasian man was first investigated 21 years ago for persistent diarrhoea. A colonoscopy revealed an erosive pancolitis with unusual vacuolated macrophages. Characteristics of ulcerative colitis or Crohn's disease were absent. Similar findings were observed consistently over the following years. A treatment with Sulfasalazine, Methotrexate or Budesonide was efficient. Histiocytic colitis is rare, and the various causes and different diagnoses are reviewed. The cause for the chronic pancolitis in this obese chronic alcoholic remains unknown at the time of writing. Links to the dyslipidaemia and chronic ankylosing spondylitis presented by the patient are possible hypotheses worth investigating further. PMID- 30024707 TI - Favourable long term effect of ursodeoxycholic acid treatment on congenital vanishing bile duct syndromes. PMID- 30024708 TI - The combination of acute pancreatitis and toxic hepatitis developing secondary to exposure to malathion : a case report. AB - Organophosphate(OPH) compounds are cholinesteraseinhibiting chemicals used as pesticide. Pancreatitis secondary to malathion toxicity is rare and toxic hepatitis has been reported in only one case. In this paper, we report the case of the combination of acute pancreatitis and toxic hepatitis, which developed in a 30-year old farm worker and the mechanism is discussed in this first report of its kind. Awareness of this complication should prompt earlier investigation because early diagnosis coupled with timely therapeutic measures may improve patient prognosis. PMID- 30024709 TI - Pancreatic hydatid cyst as an incidental finding. PMID- 30024710 TI - A falling row of dominoes. PMID- 30024711 TI - A rare case of drug-induced liver injury caused by an epinephrine-autoinjector. PMID- 30024712 TI - An adult patient with alcoholic liver cirrhosis and IgA vasculitis. PMID- 30024713 TI - An unusual case of false positive hepatitis C infection. PMID- 30024714 TI - Recurrent pancreatitis : it can get on your nerves! A rare case of B-cell lymphoma presenting as recurrent pancreatitis and multiple cranial neuropathy. PMID- 30024715 TI - Beyond colonic neoplasia. PMID- 30024716 TI - An uncommon cause of overt small bowel bleeding. PMID- 30024717 TI - A rare cause of rectal bleeding. PMID- 30024718 TI - WITHDRAWN: A single center experience in resectable pancreatic ductal adenocarcinoma : the limitations of the surgery-first approach. Critical review of the literature and proposals for practice update. AB - The article has been withdrawn at the request of the authors and editor because of incorrect authorship, which is considered a form of unethical publication. The Publisher apologizes for any inconvenience this may cause. PMID- 30024720 TI - High-Temperature Stable and Metal-Free Electromagnetic Wave-Absorbing SiBCN Ceramics Derived from Carbon-Rich Hyperbranched Polyborosilazanes. AB - High-temperature stable and metal-free siliconboron carbonitride ceramics with high electromagnetic (EM) wave-absorbing efficiency were achieved through the structural design and pyrolysis of carbon-rich hyperbranched polyborosilazane precursors with pendent phenyl groups. The introduction of benzene rings into the precursors dramatically changes the microstructure and the EM wave-absorbing property of ceramics. It reveals that the ceramics pyrolyzed from the benzene ring-containing preceramic precursors have a higher carbon content and a larger number of sp2 carbons and generate crystalline carbons (graphitic carbons and tubular carbons) in situ, which lead to excellent EM wave-absorbing properties. The EM wave absorption efficiency and effective absorption bandwidth (EAB, reflection coefficient (RC) below -10 dB) can be tuned via annealing of the ceramics. The ceramics stable at 1320 degrees C exhibit their optimized EM wave absorbing performance with a minimum RC (RCmin) of -71.80 dB and an EAB of 3.65 GHz (8.2-11.85 GHz). We believe that the research extends the design strategy of advanced EM wave-absorbing functional materials, which have great potential as promising absorbers in commercial or military applications. PMID- 30024719 TI - Amorphous Carbon-Derived Nanosheet-Bricked Porous Graphite as High-Performance Cathode for Aluminum-Ion Batteries. AB - Graphite is an attractive cathode material for energy storage because it allows reversible intercalation/deintercalation of many compound anions at high potentials. However, because the sizes of the compound anions are greatly larger than the lamellar spacing of graphite, common graphite used as cathode may suffer from slow kinetics and large volume expansion. Here, it is demonstrated that graphite with high crystallinity and nanosheet-bricked porous structure can be an excellent cathode for aluminum-ion batteries. This porous graphite is derived from carbon black via a simple electrochemical graphitization in molten CaCl2, and the high crystallinity and thin layer characters facilitate the high capacity and high rate storage of aluminum tetrachloride ions. Moreover, the bricked porous structure endows the fabricated cathode with a providential porosity to perfectly match the huge volume expansion of graphite (650% against a charging capacity of 100 mA h g-1), thus this electrochemical graphite exhibits integrated high gravimetric and volumetric capacities as well as high structural stability during cycling. PMID- 30024721 TI - Mode-Selective Raman Imaging of Dopamine-Human Dopamine Transporter Interaction in Live Cells. AB - Dopamine (DA) is the catecholamine neurotransmitter which interacts with dopamine receptors (DARs) to generate dopaminergic signals in the nervous system. Dopamine transporter (DAT) interacts with DA to maintain DA's homeostasis in synaptic and perisynaptic space. DAT and DARs have great importance in the central nervous system (CNS) because they are associated with the targeted binding of drugs. Interactions of DA, its analogue with DARs, or DAT have been studied extensively to understand the mechanism of the dopaminergic signaling process and several neurodegenerative diseases, including schizophrenia, Parkinson's diseases, addiction, attention deficit hyperactivity disorder, and bipolar disorder. However, there is still a lack of a risk-free, label-free, and minimally invasive imaging approach to probe the interaction between DA and DAT or DARs. Here, we probed the DA, human dopamine transporter (hDAT), and DA-hDAT interactions in live cells using combined approach of two-photon excited (2PE) fluorescence imaging and mode-selective Raman measurement. We utilized the signature Raman peak at 1287 cm-1 to probe the location of DA and 807 and 1076 cm-1 to probe the DA-hDAT interaction in live cells. We found that the combined approach of mode selective Raman imaging, 2PE fluorescence imaging, and computational methods is successful to probe and confirm the DA-hDAT interactions in living cells. The probing of the interactions of DARs or DAT with DA or other targeting drugs is crucial for the diagnosis and cure of several neurodegenerative diseases. Also, this analytical approach could be extended to probe other types of protein-ligand interactions. PMID- 30024722 TI - Visible Light Photoinitiation of Cell-Adhesive Gelatin Methacryloyl Hydrogels for Stereolithography 3D Bioprinting. AB - We present the first cell-attachable and visible-light-crosslinkable bioinks based on gelatin methacryloyl (GelMA) with eosin Y (EY) photoinitiation for stereolithography three-dimensional (3D) bioprinting. To develop a visible-light crosslinkable hydrogel, we systematically studied five combinations of GelMA and EY photoinitiator with various concentrations. Their mechanical properties, microstructures, and cell viability and confluency after encapsulation were investigated rigorously to elucidate the effects of the EY and GelMA macromer concentrations on the characteristics of the hydrogel. Experimental results show that the compressive Young's modulus and pore size are positively affected by the concentration of EY, whereas the mass swelling ratio and cell viability are negatively affected. Increasing the concentration of GelMA helps in improving the compressive Young's modulus and cell attachment. We further employed the developed visible-light-based stereolithography bioprinting system to print the patterned cell-laden hydrogels to demonstrate the bioprinting applications of the developed hydrogel. We observed good cell proliferation and the formation of a 3D cellular network inside the printed pattern at day 5, which proves the great feasibility of using EY-GelMA as the bioinks for biofabrication and tissue engineering. PMID- 30024723 TI - Ice-Liquid Oscillations in Nanoconfined Water. AB - Nanoscale confinement has a strong effect on the phase behavior of water. Studies in the last two decades have revealed a wealth of novel crystalline and quasicrystalline structures for water confined in nanoslits. Less is known, however, about the nature of ice-liquid coexistence in extremely nanoconfined systems. Here, we use molecular simulations to investigate the ice-liquid equilibrium for water confined between two nanoscopic disks. We find that the nature of ice-liquid phase coexistence in nanoconfined water is different from coexistence in both bulk water and extended nanoslits. In highly nanoconfined systems, liquid water and ice do not coexist in space because the two-phase states are unstable. The confined ice and liquid phases coexist in time, through oscillations between all-liquid and all-crystalline states. The avoidance of spatial coexistence of ice and liquid originates on the non-negligible cost of the interface between confined ice and liquid in a small system. It is the result of the small number of water molecules between the plates and has no analogue in bulk water. PMID- 30024724 TI - In Silico Screening of Metal-Organic Frameworks for Adsorption-Driven Heat Pumps and Chillers. AB - A computational screening of 2930 experimentally synthesized metal-organic frameworks (MOFs) is carried out to find the best-performing structures for adsorption-driven cooling (AC) applications with methanol and ethanol as working fluids. The screening methodology consists of four subsequent screening steps for each adsorbate. At the end of each step, the most promising MOFs for AC application are selected for further investigation. In the first step, the structures are selected on the basis of physical properties (pore limiting diameter). In each following step, points of the adsorption isotherms of the selected structures are calculated from Monte Carlo simulations in the grand canonical ensemble. The most promising MOFs are selected on the basis of the working capacity of the structures and the location of the adsorption step (if present), which can be related to the applicable operational conditions in AC. Because of the possibility of reversible pore condensation (first-order phase transition), the mid-density scheme is used to efficiently and accurately determine the location of the adsorption step. At the end of the screening procedure, six MOFs with high deliverable working capacities (~0.6 mL working fluid in 1 mL structure) and diverse adsorption step locations are selected for both adsorbates from the original 2930 structures. Because the highest experimentally measured deliverable working capacity to date for MOFs with methanol is ca. 0.45 mL mL-1, the selected six structures show the potential to improve the efficiency of ACs. PMID- 30024725 TI - Asymmetric Aerogel Membranes with Ultrafast Water Permeation for the Separation of Oil-in-Water Emulsion. AB - Owing to highly porous and low density attributes, aerogels have been actively utilized in catalysis and adsorption processes, but their great potential in filtration requires exploitation. In this study, an asymmetric aerogel membrane is fabricated via one-pot hydrothermal reaction-induced self-cross-linking of poly(vinyl alcohol) (PVA), which exhibits ultrafast permeation for the separation of oil-in-water emulsion. Meanwhile, carbon nanotubes are added to improve the mechanical strength of the aerogel membranes. The self-cross-linking of PVA forms the supporting layer, and the exchange of water and vapor at the interface of PVA solution and air generates the separating layer as well as abundant hydroxyl groups on the membrane surface. The density, porosity, pore size, and wettability of the aerogel membrane can be tuned by the PVA concentration. Owing to high porosity (>95%) and suitable pore size (<85 nm), the aerogel membrane exhibits high rejection (99.0%) for surfactant-stabilized oil-in-water emulsion with an ultrahigh permeation flux of 135.5 * 103 L m-2 h-1 bar-1 under gravity-driven flow, which is 2 orders of magnitude higher than commercial filtration membranes with similar rejection. Meanwhile, the aerogel membrane exhibits superhydrophilicity, superoleophobicity underwater, and excellent antifouling properties for various surfactant-stabilized oil-in-water emulsions, as indicated by the fact that the flux recovery ratio maintains more than 93% after five cycles of the filtration experiment. The findings in this study may offer a novel idea to fabricate high-throughput filtration membranes. PMID- 30024726 TI - Highly Accurate Detection and Identification Methodology of Xenobiotic Metabolites Using Stable Isotope Labeling, Data Mining Techniques, and Time Dependent Profiling Based on LC/HRMS/MS. AB - A generally applicable method to discover xenobiotic metabolites is important to safely and effectively develop xenobiotics. We propose an advanced method to detect and identify comprehensive xenobiotic metabolites using stable isotope labeling, liquid chromatography coupled with benchtop quadrupole Orbitrap high resolution tandem mass spectrometry (LC/HRMS/MS), data mining techniques (alignment, peak picking, and paired-peaks filtering), in silico metabolism prediction, and time-dependent profiling. The LC/HRMS analysis was carried out using Arabidopsis T87 cultured cells treated with unlabeled or with 13C- or 2H labeled 2,4-dichlorophenoxyacetic acid (2,4-D). Paired-peak filtering enabled the accurate detection of 83 candidates for 2,4-D metabolites without any false positive peaks derived from solvents or the biological matrix. We confirmed 10 previously reported 2,4-D metabolites and identified 16 novel 2,4-D metabolites. Our method provides accurate detection and identification of comprehensive xenobiotic metabolites and represents a potentially useful tool for elucidating xenobiotic metabolism. PMID- 30024727 TI - Surface Modification of CdSe Quantum-Dot Floating Gates for Advancing Light Erasable Organic Field-Effect Transistor Memories. AB - Photoresponsive transistor memories that can be erased using light-only bias are of significant interest owing to their convenient elimination of stored data for information delivery. Herein, we suggest a strategy to improve light-erasable organic transistor memories, which enables fast "photoinduced recovery" under low intensity light. CdSe quantum dots (QDs) whose surfaces are covered with three different organic molecules are introduced as photoactive floating-gate interlayers in organic transistor memories. We determine that CdSe QDs capped or surface-modified with small molecular ligands lead to efficient hole diffusion from the QDs to the conducting channel during "photoinduced recovery", resulting in faster erasing times. In particular, the memories with QDs surface-modified with fluorinated molecules function as normally-ON type transistor memories with nondestructive operation. These memories exhibit high memory ratios over 105 between OFF and ON bistable current states for over 10 000 s and good dynamic switching behavior with voltage-driven programming processes and light-assisted erasing processes within 1 s. Our study provides a useful guideline for designing photoactive floating-gate materials to achieve desirable properties of light erasable organic transistor memories. PMID- 30024728 TI - Toward Tandem Solar Cells for Water Splitting Using Polymer Electrolytes. AB - Tandem photoelectrochemical cells, formed by two photoelectrodes with complementary light absorption, have been proposed to be a viable approach for obtaining clean hydrogen. This requires the development of new designs that allow for upscaling, which would be favored by the use of transparent polymer electrolyte membranes (PEMs) instead of conventional liquid electrolytes. This article focuses on the photoelectrochemical performance of a water-splitting tandem cell based on a phosphorus-modified alpha-Fe2O3 photoanode and on an iron modified CuO photocathode, with the employment of an alkaline PEM. Such a photoelectrochemical cell works even in the absence of bias, although significant effort should be directed to the optimization of the photoelectrode/PEM interface. In addition, the results reveal that the employment of polymer electrolytes increases the stability of the device, especially in the case of the photocathode. PMID- 30024729 TI - Label-Free Multiplexed Electrical Detection of Cancer Markers on a Microchip Featuring an Integrated Fluidic Diode Nanopore Array. AB - We introduce an integrated array of glass nanopores on a silicon microchip fabricated in a batch process through low-resolution photolithography and standard semiconductor processing tools. By functionalizing each nanopore against a distinct target, we further demonstrate ultrasensitive, label-free, multiplexed electrical detection of cancer-marker proteins in real time through charge dependent ionic current rectification. As nanofluidic diode biosensors, the nanopores return rapid results, with a limit of detection reaching concentrations as low as attomolars in assay buffer and femtomolars in undiluted untreated human serum, a rare achievement for this class of nanosensors. Multiplexed detection capability has been demonstrated on proteins carcinoembryonic antigen, alpha fetoprotein antigen, and human epidermal growth factor receptor-2, with the assay further scalable to a size that is limited by the readout electronics. The nanopores are also found with a considerably advanced detection limit as well as dynamic range in relation to the nanoslit counterparts, validated by the measurements on cardiac protein troponin T. This highly robust assay platform draws from rich nanopore physics and could provide further enhanced detection through concentration polarization, subsequent target enrichment, and serum desalting, all potentially induced by the nanopores presently redundant in the array. This integration would be crucial for removing major obstacles for the practical use of nanopore-based assays. PMID- 30024730 TI - Proton Transfer and Tautomerism in 2-Aminopurine-Thymine and Pyrrolocytosine Guanine Base Pairs. AB - Pyrrolocytosine (PC) and 2-aminopurine (2AP) are fluorescent nucleobase analogues of the DNA nucleobases cytosine and adenine, respectively, and form base pairs with guanine and thymine. Both fluorescent nucleobases are used extensively as probes for local structure in nucleic acids as the fluorescence properties of PC and 2AP are very sensitive to changes such as helix formation, although the reasons for this sensitivity are not clear. To address this question, ab initio calculations have been used to calculate energies, at the MP2 and CIS level, of three different tautomer pairings of PC-G, and two of 2AP-T, which can potentially be interconverted by double proton transfer between the bases. Potential energy curves linking the different tautomer pairs have been calculated. For both PC-G and 2AP-T, the most stable tautomer pair in the electronic ground state is that analogous to the natural C-G and A-T base pair. In the case of 2AP-T, an alternative, stable, tautomer base pair was located in the first electronically excited state; however, it lies higher in energy than the tautomer pair analogous to A-T, making conversion to the alternative form unlikely. In contrast, in the case of PC-G, an alternative tautomer base pair is found to be the most stable form in the first electronically excited state, and this form is accessible following initial excitation from the ground state tautomer pair, thus suggesting an alternative deactivation route via double proton transfer may be possible when PC is involved in hydrogen bonding, such as occurs in helical conformations. PMID- 30024731 TI - Mo6+ Cation Enrichment of the Structure Chemistry of Iodates: Syntheses, Structures, and Calculations of Ba(MoO2)2(IO3)4O, Ba3[(MoO2)2(IO3)4O(OH)4].2H2O, and Sr[(MoO2)6(IO4)2O4].H2O. AB - The three metal iodates Ba(MoO2)2(IO3)4O (1), Ba3[(MoO2)2(IO3)4O(OH)4].2H2O (2), and Sr[(MoO2)6(IO4)2O4].H2O (3) have been successfully synthesized by introducing second-order Jahn-Teller distorted Mo6+ cations by a mild hydrothermal method. Single-crystal X-ray diffraction (XRD) was used to determine the structures of the three title compounds. In compound 1, the [Mo2O11]10- dimers connect with the [IO3]- units by sharing oxygen atoms to form two-dimensional (2D) layers that are separated by the Ba2+ cations. For comparison, the [Mo2O11]10- dimers and the [IO3]- units are isolated in compound 2, and they are connected by the [BaO11]20- polyhedra forming a 3D network. For compound 3, the [MoO6]6- polyhedra link with each other by corner and edge sharing to build 2D corrugated layers with tunnels containing isolated [IO4]3- units. The [SrO9]16- polyhedra link the 2D corrugated layers to form a 3D network. The infrared (IR) spectra, the ultraviolet-visible near-infrared (UV-vis-NIR) diffuse reflectance spectra, and thermal stabilities of compounds 1 and 2 are presented. In addition, the theoretical calculations are also carried out to evaluate their band gaps and density of states. PMID- 30024732 TI - Quantitative Investigation of Terbinafine Hydrochloride Absorption into a Living Skin Equivalent Model by MALDI-MSI. AB - The combination of microspotting of analytical and internal standards, matrix sublimation, and recently developed software for quantitative mass spectrometry imaging has been used to develop a high-resolution method for the determination of terbinafine hydrochloride in the epidermal region of a full thickness living skin equivalent model. A quantitative assessment of the effect of the addition of the penetration enhancer (dimethyl isosorbide (DMI)) to the delivery vehicle has also been performed, and data have been compared to those obtained from LC-MS/MS measurements of homogenates of isolated epidermal tissue. At 10% DMI, the levels of signal detected for the drug in the epidermis were 0.20 +/- 0.072 mg/g tissue for QMSI and 0.28 +/- 0.040 mg/g tissue for LC-MS/MS at 50% DMI 0.69 +/- 0.23 mg/g tissue for QMSI and 0.66 +/- 0.057 mg/g tissue for LC-MS/MS. Comparison of means and standard deviations indicates no significant difference between the values obtained by the two methods. PMID- 30024733 TI - A Key Factor Dominating the Competition between Photolysis and Photoracemization of [Ru(bipy)3]2+ and [Ru(phen)3]2+ Complexes. AB - Photolysis and photoracemization are two important photochemical phenomena of the prototype complexes [Ru(bipy)3]2+ and [Ru(phen)3]2+ (bipy = 2,2'-bipyridine, phen = 1,10-phenanthroline), but little is known about their relations. To solve this issue, the photoinduced chiral inversion Delta?Lambda of the complexes was analyzed theoretically. The results indicated that the photoracemization reaction proceeds on the lowest triplet potential energy surface in three steps 3CTDelta< >3MCDelta, 3MCDelta<->3MCLambda, and 3MCLambda<->3CTLambda (CT = charge transfer state; MC = metal-centered state). Where the first and third steps are fast processes of picoseconds, the second is the rate-determining step (RDS) of microseconds. Such a slow step for the racemization leads to the excited molecule lingering around the bottom of 3MC state after the first step and, therefore, greatly enhances the possibility of deexcitation and photolysis mostly at the triplet-singlet crossing point. In other words, the photoracemization and photolysis of the complexes have a competition relation, not a slave relation as assumed by the photoracemization model suggested in literature. They are dominated by the RDS. This conclusion is also consistent with the Delta(delta S)?Lambda(delta S) chiral inversion of the [Ru(bipy)2(L-ser)]+ series complexes, which is reversible with no detectable photolysis, as its second step is a fast one. Note that, although the photoracemization of the prototype complexes is very slow, it passes through the three steps reversibly and ends with a photon emitting, which could be detected with the time-resolved circularly polarized luminescence and related techniques. These findings are helpful to understand and control the photochemical behavior of the complexes in practice. PMID- 30024734 TI - Retinol-Binding Protein Interferes with Transthyretin-Mediated beta-Amyloid Aggregation Inhibition. AB - beta-Amyloid (Abeta) aggregation is causally linked to Alzheimer's disease. On the basis of in vitro and transgenic animal studies, transthyretin (TTR) is hypothesized to provide neuroprotection against Abeta toxicity by binding to Abeta and inhibiting its aggregation. TTR is a homotetrameric protein that circulates in blood and cerebrospinal fluid; its normal physiological role is as a carrier for thyroxine and retinol-binding protein (RBP). RBP forms a complex with retinol, and the holoprotein (hRBP) binds with high affinity to TTR. In this study, the role of TTR ligands in TTR-mediated inhibition of Abeta aggregation was investigated. hRBP strongly reduced the ability of TTR to inhibit Abeta aggregation. The effect was not due to competition between Abeta and hRBP for binding to TTR, as Abeta bound equally well to TTR-hRBP complexes and TTR. hRBP is known to stabilize the TTR tetrameric structure. We show that Abeta partially destabilizes TTR and that hRBP counteracts this destabilization. Taken together, our results support a mechanism wherein TTR-mediated inhibition of Abeta aggregation requires not only TTR-Abeta binding but also destabilization of TTR quaternary structure. PMID- 30024735 TI - Electrical Signal Reporter, Pore-Forming Protein, for Rapid, Miniaturized, and Universal Identification of Microorganisms. AB - Despite recent advances in signal reporter-based assays for bacteria detection and profiling, the low-cost, ultrasensitive, accurate, and fast diagnosis remains a challenge for better patient care. Herein, we present a novel bacteria identification method based on alpha-hemolysin-labeled sandwich assay (HLSA). A pore-forming protein, alpha-hemolysin, is used as an electrical signal reporter. The assay takes advantage of the specific binding of target nucleic acid with two hybridization probes: capture probe decorated magnetic microparticles and oligonucleotides detecting probe and alpha-hemolysin modified gold nanoparticles. alpha-Hemolysin was then released by competitive gold binding peptide incubation into an electric cell with a lipid bilayer between the electrodes. The nanopores formed by alpha-hemolysin on the lipid layer allowed target nucleic acid concentration-dependent currents for quantification. Sandwich probes against 16S rRNAs of 10 common bacteria pathogens were designed and single cell level nucleic acid concentration detection was achieved. Compared with nanopore technique-based DNA sequencing, HLSA gives a quantitive and straightforward readout that is not dependent on an ultrasensitive and expensive instrument (Axopatch 200B amplifier), thus, is faster and requires no large-scale instruments. Also, since alpha-hemolysin-modified nanoparticles will be washed out before the alpha hemolysin releasing step without the target nucleic acid, no current will be detected, and thus, the assay is more specific. The current strategy based on the electrical signal reporter offers a new insight for pathogen and virus diagnostics. PMID- 30024736 TI - Conserved S/T Residues of the Human Chaperone DNAJB6 Are Required for Effective Inhibition of Abeta42 Amyloid Fibril Formation. AB - The human molecular chaperone DNAJB6, an oligomeric protein with a conserved S/T rich region, is an efficient suppressor of amyloid fibril formation by highly aggregation-prone peptides such as the Abeta and polyQ peptides associated with Alzheimer's and Huntington's disease, respectively. We previously showed that DNAJB6 can inhibit the processes through which amyloid fibrils are formed via strong interactions with aggregated forms of Abeta42 that become sequestered. Here we report that the concentration-dependent capability of DNAJB6 to suppress fibril formation in thioflavin T fluorescence assays decreases progressively with an increasing number of S/T substitutions, with an almost complete loss of suppression when 18 S/T residues are substituted. The kinetics of primary nucleation in particular are affected. No detectable changes in the structure are caused by the substitutions. Also, the level of binding of DNAJB6 to Abeta42 decreases with the S/T substitutions, as determined by surface plasmon resonance and microscale thermophoresis. The aggregation process monitored using nuclear magnetic resonance spectroscopy showed that DNAJB6, in contrast to a mutational variant with 18 S/T residues substituted, can keep monomeric Abeta42 soluble for an extended time. The inhibition of the primary nucleation is likely to depend on hydroxyl groups in side chains of the S/T residues, and hydrogen bonding with Abeta42 is one plausible molecular mechanism, although other possibilities cannot be excluded. The loss of the ability to suppress fibril formation upon S/T to A substitution was previously observed also for polyQ peptides, suggesting that the S/T residues in the DNAJB6-like chaperones have a general ability to inhibit amyloid fibril formation by different aggregation-prone peptides. PMID- 30024737 TI - Development and Characterization of Peptide Ligands of Immunoglobulin G Fc Region. AB - Affinity chromatography based on bacterial immunoglobulin (Ig)-binding proteins represents the cornerstone of therapeutic antibody downstream processing. However, there is a pressing need for more robust affinity ligands that would withstand the harsh column sanitization conditions, while still displaying high selectivity for antibodies. Here, we report the development of linear peptide IgG ligands, identified from combinatorial phage-display library screens. The lead peptide was shown to compete with staphylococcal protein A for the IgG Fc region. Trimming analysis and alanine scanning revealed the minimal structural requirements of the peptide for Fc binding, and the minimized peptide GSYWYQVWF recognized all human IgG subtypes. Mutation of glutamine located at the nonessential position 6 to aspartate led to the optimized peptide GSYWYDVWF with 18-fold higher affinity ( KD app. 0.6 MUM) compared to the parent peptide. When coupled to paramagnetic beads or a chromatographic matrix, the optimized ligand was shown to selectively enrich antibodies from complex protein mixtures. PMID- 30024738 TI - Increase of Direct C-C Coupling Reaction Yield by Identifying Structural and Electronic Properties of High-Spin Iron Tetra-azamacrocyclic Complexes. AB - Macrocyclic ligands have been explored extensively as scaffolds for transition metal catalysts for oxygen and hydrogen atom transfer reactions. C-C reactions facilitated using earth abundant metals bound to macrocyclic ligands have not been well-understood but could be a green alternative to replacing the current expensive and toxic precious metal systems most commonly used for these processes. Therefore, the yields from direct Suzuki-Miyaura C-C coupling of phenylboronic acid and pyrrole to produce 2-phenylpyrrole facilitated by eight high-spin iron complexes ([Fe3+L1(Cl)2]+, [Fe3+L4(Cl)2]+, [Fe2+L5(Cl)]+, [Fe2+L6(Cl)2], [Fe3+L7(Cl)2]+, [Fe3+L8(Cl)2]+, [Fe2+L9(Cl)]+, and [Fe2+L10(Cl)]+) were compared to identify the effect of structural and electronic properties on catalytic efficiency. Specifically, catalyst complexes were compared to evaluate the effect of five properties on catalyst reaction yields: (1) the coordination requirements of the catalyst, (2) redox half-potential of each complex, (3) topological constraint/rigidity, (4) N atom modification(s) increasing oxidative stability of the complex, and (5) geometric parameters. The need for two labile cis-coordination sites was confirmed based on a 42% decrease in catalytic reaction yield observed when complexes containing pentadentate ligands were used in place of complexes with tetradentate ligands. A strong correlation between iron(III/II) redox potential and catalytic reaction yields was also observed, with [Fe2+L6(Cl)2] providing the highest yield (81%, -405 mV). A Lorentzian fitting of redox potential versus yields predicts that these catalysts can undergo more fine-tuning to further increase yields. Interestingly, the remaining properties explored did not show a direct, strong relationship to catalytic reaction yields. Altogether, these results show that modifications to the ligand scaffold using fundamental concepts of inorganic coordination chemistry can be used to control the catalytic activity of macrocyclic iron complexes by controlling redox chemistry of the iron center. Furthermore, the data provide direction for the design of improved catalysts for this reaction and strategies to understand the impact of a ligand scaffold on catalytic activity of other reactions. PMID- 30024739 TI - Promoter Engineering for Enhanced P(3HB- co-4HB) Production by Halomonas bluephagenesis. AB - Promoters for the expression of heterologous genes in Halomonas bluephagenesis are quite limited, and many heterologous promoters function abnormally in this strain. Pporin, a promoter of the strongest expressed protein porin in H. bluephagenesis, is one of the few promoters available for heterologous expression in H. bluephagenesis, yet it has a fixed transcriptional activity that cannot be tuned. A stable promoter library with a wide range of activities is urgently needed. This study reports an approach to construct a promoter library based on the Pporin core region, namely, from the -35 box to the transcription start site, a spacer and an insulator. Saturation mutagenesis was conducted inside the promoter core region to significantly increase the diversity within the promoter library. The promoter library worked in both E. coli and H. bluephagenesis, covering a wide range of relative transcriptional strengths from 40 to 140 000. The library is therefore suitable for the transcription of many different heterologous genes, serving as a platform for protein expression and fine-tuned metabolic engineering of H. bluephagenesis TD01 and its derivative strains. H. bluephagenesis strains harboring the orfZ gene encoding 4HB-CoA transferase driven by selected promoters from the library were constructed, the best one produced over 100 g/L cell dry weight containing 80% poly(3-hydroxybutyrate- co 11 mol % 4-hydroxybutyrate) with a productivity of 1.59 g/L/h after 50 h growth under nonsterile fed-batch conditions. This strain was found the best for P(3HB- co-4HB) production in the laboratory scale. PMID- 30024740 TI - Multiplexed Quantitative MALDI MS Approach for Assessing Activity and Inhibition of Protein Kinases Based on Postenrichment Dephosphorylation of Phosphopeptides by Metal-Organic Framework-Templated Porous CeO2. AB - Protein kinase is regarded as a potential target for anticancer therapeutics due to its relation to many diseases, in which more than one kinase participates in the cell signaling cascades. We herein demonstrate a multiplexed quantitative matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) approach to simultaneously assess the activity and inhibition of multiple protein kinases. In this design, substrate peptides phosphorylated by kinases of interest are specifically harvested by metal-organic framework (MOF)-templated porous CeO2 and consequently transformed to the dephosphorylated forms due to the phosphatase like activity of CeO2, resulting in a unique quantitative MS signal with an enhanced intensity. Based on the peak area ratios of dephosphorylated variants of the phosphorylated product to respective deuterated internal standard, the activity and inhibition of each kinase can be independently profiled. In addition to the accurate characterization of protein kinase A (PKA) activity and inhibition induced by H-89, the multiplexing capability of the MS-based method allowed quantitative evaluation of the activity of Abl and Src, the two tightly associated kinases in the occurrence of chronic myeloid leukemia (CML) in a multiplexed format, exhibiting excellent orthogonality for the dual signal readout channels. Moreover, the inactivation of both Abl and Src by the inhibitor imatinib, dasatinib, and ponatinib was simultaneously traced, giving a whole picture of the competition behavior between the kinases for binding therapeutic molecules. This approach holds great promise in global investigation of kinase signal pathways and high-throughput screening of effective protein kinase inhibitors. PMID- 30024741 TI - Lys-C/Arg-C, a More Specific and Efficient Digestion Approach for Proteomics Studies. AB - Nowadays, bottom-up approaches are predominantly adopted in proteomics studies, which necessitate a proteolysis step prior to MS analysis. Trypsin is often the best protease in choice due to its high specificity and MS-favored proteolytic products. A lot of efforts have been made to develop a superior digestion approach but hardly succeed, especially in large-scale proteomics studies. Herein, we report a new tandem digestion using Lys-C and Arg-C, termed Lys-C/Arg C, which has been proven to be more specific and efficient than trypsin digestion. Reanalysis of our previous data ( Anal. Chem. 2018, 90 (3), 1554-1559) revealed that both Lys-C and Arg-C are trypsin-like proteases and perform better when considered as trypsin. In particular, for Arg-C, the identification capacity is increased to 2.6 times and even comparable with trypsin. The good complementarity, high digestion efficiency, and high specificity of Lys-C and Arg C prompt the Lys-C/Arg-C digestion. We systematically evaluated Lys-C/Arg-C digestion using qualitative and quantitative proteomics approaches and confirmed its superior performance in digestion specificity, efficiency, and identification capacity to the currently widely used trypsin and Lys-C/trypsin digestions. As a result, we concluded that the Lys-C/Arg-C digestion approach would be the choice of next-generation digestion approach in both qualitative and quantitative proteomics studies. Data are available via ProteomeXchange with identifier PXD009797. PMID- 30024742 TI - Electrospray Ionization of Polypropylene Glycol: Rayleigh-Charged Droplets, Competing Pathways, and Charge State-Dependent Conformations. AB - Recent molecular dynamics (MD) simulations from various laboratories have advanced the general understanding of electrospray ionization (ESI)-related processes. Unfortunately, computational cost has limited most of those previous endeavors to ESI droplets with radii of ~3 nm or less, which represent the low end of the size distribution in the ESI plume. The current work extends this range by conducting simulations on aqueous ESI droplets with radii of 5.5 nm (~23 000 water molecules). Considering that computational cost increases with r6, this is a significant step forward. We focused on the ESI process for polypropylene glycol (PPG) which is a common ESI-MS calibrant. Different chain lengths (PPG10, 30, and 60) were tested in droplets that were charged with excess Na+. Solvent evaporation and Na+ ejection, with occasional progeny droplet formation, kept the systems at 80-100% of the Rayleigh limit throughout their life cycle. PPG chains migrated to the droplet surface where they captured Na+ via binding to ether oxygens. Various possible pathways for PPG release into the gas phase were encountered. Some PPG10 runs showed ejection from the droplet surface, consistent with the ion evaporation model (IEM). In other instances, PPG was released after near-complete solvent evaporation, as envisioned by the charged residue model (CRM). A third avenue was the partial separation from the droplet to form double or single-tailed structures, with subsequent chain detachment from the droplet. This last pathway is consistent with the chain ejection model (CEM). Immediately after detachment many chains were electrostatically stretched, but they subsequently collapsed into compact conformers. Extended structures were retained only for the most highly charged ions. Our simulations were complemented by ESI MS and ion mobility measurements. MD-predicted charge states and collision cross sections were in agreement with these experimental data, supporting the mechanistic insights obtained. PMID- 30024743 TI - Highly-Selective Optoelectronic Nose Based on Surface Plasmon Resonance Imaging for Sensing Volatile Organic Compounds. AB - Monitoring volatile organic compounds (VOCs) is an important issue, but difficult to achieve on a large scale and on the field using conventional analytical methods. Electronic noses (eNs), as promising alternatives, are still compromised by their performances due to the fact that most of them rely on a very limited number of sensors and use databases devoid of kinetic information. To narrow the performance gap between human and electronic noses, we developed a novel optoelectronic nose, which features a large sensor microarray that enables multiplexed monitoring of binding events in real-time with a temporal response. For the first time, surface plasmon resonance imaging is demonstrated as a promising novel analytical tool for VOC detection in the gas phase. By combining it with cross-reactive sensor microarrays, the obtained optoelectronic nose shows a remarkably high selectivity, capable of discriminating between homologous VOCs differing by only a single carbon atom. In addition, the optoelectronic nose has good repeatability and stability. Finally, the preliminary assays using VOC binary and ternary mixtures show that it is also very efficient for the analysis of more complex samples, opening up the exciting perspective of applying it to "real-world" samples in diverse domains. PMID- 30024744 TI - Synthesis of Zwitterionic Pluronic Analogs. AB - Novel polymer amphiphiles with chemical structures designed as zwitterionic analogs of Pluronic block copolymers were prepared by controlled free radical polymerization of phosphorylcholine (PC) or choline phosphate (CP) methacrylate monomers from a difunctional poly(propylene oxide) (PPO) macroinitiator. Well defined, water-dispersible zwitterionic triblock copolymers, or "zwitteronics", were prepared with PC content ranging from 5 to 47 mol percent and composition independent surfactant characteristics in water, which deviate from the properties of conventional Pluronic amphiphiles. These PC-zwitteronics assembled into nanoparticles in water, with tunable sizes and critical aggregation concentrations (CACs) based on their hydrophilic-lipophilic balance (HLB). Owing to the lower critical solution temperature (LCST) miscibility of the hydrophobic PPO block in water, PC-zwitteronics exhibited thermoreversible aqueous solubility tuned by block copolymer composition. The chemical versatility of this approach was demonstrated by embedding functionality, in the form of alkyne groups, directly into the zwitterion moieties. These alkynes proved ideal for cross linking the zwitteronic nanoparticles and for generating nanoparticle-cross linked hydrogels using UV-initiated thiol-yne "click" chemistry. PMID- 30024745 TI - Density Functional Theory Computational Reexamination of the Anomeric Effect in 2 Methoxy- and 2-Cyano-1,3-dioxanes and 1,3-Dithianes. Stereoelectronic Interactions Involving the Cyano (C=N:) Group Revealed by Natural Bond Orbital (NBO) Analysis. AB - This study reports DFT geometry optimization of the anancomeric (ring conformationally anchored) axial r2-methoxy- trans-4, trans-6-dimethyl- and r-2 cyano- trans-4, trans-6-dimethyl-1,3-dioxanes (1-ax and 3-ax, respectively), the equatorial isomers (2-eq and 4-eq, respectively), the axial r2-methoxy- and r2 cyano- trans-4, trans-6-dimethyl-1,3-dithianes (5-ax and 7-ax, respectively), and the equatorial isomers (6-eq and 8-eq, respectively). The computational results reproduce the anomeric effect in 1-8, and most importantly, Weinhold's NBO analysis supports the contribution of n(X) -> sigma*(C-Y) stereoelectronic interactions that stabilize the axial isomers. Furthermore, NBO analysis of delocalization energy E(2) of properly aligned filled/empty orbitals in these isomeric 2-polar-substituted heterocycles reveals that n(O) -> sigma*(C-Hax) is responsible for the increased charge density at C(2)-Hax in the equatorial isomers, providing an explanation for the computational observation that very recently led Wiberg, Bailey, Lambert, and Stempel ( J. Org. Chem. 2018, 83, 5242 5255) to discard a potential contribution of n(X) -> sigma*(C-Y) stereoelectronic interactions that stabilize the axial isomers. Interestingly, during the course of this study, two relevant stereoelectronic interactions involving the cyano group were revealed, n(N) -> sigma*(NC-C) and sigma(C(2)-H) -> sigma*(C-N). PMID- 30024746 TI - Benchmarking Semiempirical Methods To Compute Electrochemical Formal Potentials. AB - Computational methods to predict and tune electrochemical redox potentials are important for the development of energy technologies. Here, we benchmark several semiempirical models to compute reduction potentials of organic molecules, comparing approaches based on (1) energy differences between the S0 and one electron-reduced D0 states of the isolated molecules and (2) an orbital energy shift approach based on tuning the charge-transfer triplet energy of the Ag20 molecule complex; the second model enables explicit modeling of electrode molecule interactions. For molecules in solution, the two models yield nearly identical results. Both PM7 and PM6 predict formal potentials with only a slight loss of accuracy compared to standard density functional theory models, and the results are robust across several choices of geometries and implicit solvent models. PM6 and PM7 show dramatically improved accuracy over older semiempirical Hamiltonians (MNDO, AM1, PM3, and INDO/S). However, our recently developed INDO parameters model the electronic properties of our Ag20 model electrode much more accurately than does PM7. These results demonstrate the need for further development of semiempirical models to accurately model molecules on surfaces. PMID- 30024747 TI - From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen Heterocycles. AB - Oxygen heterocycles are the second most common type of heterocycles that appear as structural components of U.S. Food and Drug Administration (FDA) approved pharmaceuticals. Analysis of our database of drugs approved through 2017 reveals 311 distinct pharmaceuticals containing at least one oxygen heterocycle. Most prevalent among these are pyranoses, with furanoses, macrolactones, morpholines, and dioxolanes rounding off the top five. The main body of this Perspective is organized according to ring size, commencing with three- and four-membered rings and ending with macrocycles, polymers, and unusual oxygen-containing heterocycles. For each section, all oxygen heterocycle-containing drugs are presented along with a brief discussion about structural and drug application patterns. PMID- 30024748 TI - Branch-Selective and Enantioselective Iridium-Catalyzed Alkene Hydroarylation via Anilide-Directed C-H Oxidative Addition. AB - Tertiary benzylic stereocenters are accessed in high enantioselectivity by Ir catalyzed branch selective addition of anilide ortho-C-H bonds across styrenes and alpha-olefins. Mechanistic studies indicate that the stereocenter generating step is reversible. PMID- 30024749 TI - How To Design for a Tailored Subcellular Distribution of Systemic Agrochemicals in Plant Tissues. AB - Foliar-applied systemic agrochemicals require entrance into the plant vascular system or into specific subcellular compartments to reach their target in planta or to be imbibed by piercing/sucking pests. An inappropriate subcellular localization, like accumulation of aphicides in vacuoles, might lower the compound's efficiency due to reduced exposure to the target. Permeabilities and mass distributions of 16 compounds covering a broad range of properties were measured across a pH gradient in a PAMPA ("parallel artificial membrane permeability assay") system, providing experimental evidence for ion trapping of acids and bases in basic and acidic compartments, respectively. The results validated a predictive model which was then expanded to simulate a standardized plant cell (cytosol and vacuole) with a vascular system (phloem and xylem). This approach underlined that the absolute mass distribution across aqueous phases is defined by membrane retention, whereas the relative mass distribution is determined by the species (neutral, acidic, basic) of compounds. These processes depend largely on p Ka and log Kow of the test compounds, which subsequently determine the partitioning of the substances in plant cell compartments. The validated model can be used as a tool in agrochemistry research to tailor the subcellular distribution by chemistry design and to interpret biology results. PMID- 30024750 TI - Hawaiienols A-D, Highly Oxygenated p-Terphenyls from an Insect-Associated Fungus, Paraconiothyrium hawaiiense. AB - Four new highly oxygenated p-terphenyls, hawaiienols A-D (1-4), have been isolated from cultures of Paraconiothyrium hawaiiense, a fungus associated with the Septobasidium-infected insect Diaspidiotus sp.; their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2-4 were assigned by single-crystal X-ray diffraction analysis using Cu Kalpha radiation and via electronic circular dichroism calculations, respectively. Compound 1 incorporated the first naturally occurring 4,7 dioxatricyclo[3.2.1.03,6]octane unit in its p-terphenyl skeleton and showed cytotoxicity toward six human tumor cell lines. PMID- 30024751 TI - Interaction of Polyphenols with Other Food Components as a Means for Their Neurological Health Benefits. AB - Over the last few years, there has been increasing interest in the possible beneficial effect of polyphenol consumption on neurodegenerative disorders. Because there is a clear impact of environmental factors on the onset and evolution of neurodegenerative conditions, food arises as a promising factor that might be influencing this group of pathologies. The mechanisms by which polyphenols can affect these processes can be through direct interaction with redox signaling or inflammatory pathways but can also be explained by the interaction of dietary polyphenols with either micro- and macronutrients that are known to have neurological effects or interaction with food contaminants or food associated toxins, avoiding their neuronal toxicity. PMID- 30024753 TI - Asymmetric Synthesis of 1-Phenylethylamine from Styrene via Combined Wacker Oxidation and Enzymatic Reductive Amination. AB - An enantioselective chemoenzymatic two-step one-pot transformation of styrene to 1-phenylethylamine has been developed based on combining an initial Pd/Cu catalyzed Wacker oxidation of styrene with a subsequent reductive amination of the in situ formed acetophenone. As a nitrogen source only ammonia is needed. The incompatible catalysts were separated by means of a polydimethylsiloxane membrane, thus leading to quantitative conversion and an excellent enantiomeric excess of the corresponding amine. The overall one-pot process formally corresponds to an asymmetric hydroamination of styrene with ammonia. PMID- 30024754 TI - Achieving Large Volumetric Gas Storage Capacity in Metal-Organic Frameworks by Kinetic Trapping: A Case Study of Xenon Loading in MFU-4. AB - One of the main problems of gas storage in porous materials is that many molecules of interest adsorb too weakly to be retained effectively. To enhance gas storage in metal-organic frameworks (MOFs), we propose the use of kinetic trapping, i.e., a process where the guest gas is captured in the voids at loading conditions and not released immediately at normal conditions. In this approach, the diffusion-limiting pore size and the framework flexibility have to be matched to the gas, requiring flexible pore apertures to be smaller than the van der Waals diameter of the trapped guest. We selected the Metal-Organic Framework Ulm University-4 (MFU-4) with a pore aperture of 2.52 A as a model coordination framework and used it for storage of xenon (with van der Waals diameter of 4.4 A). Although xenon atoms are substantially larger than the MOF pore aperture, MFU 4 could be loaded with xenon by applying moderately high gas pressures. This is demonstrated to be due to the pore flexibility as confirmed by computational studies. The xenon loading could be tuned (from 0 wt % to more than 44.5 wt %) by changing the loading parameters such as pressure, temperature, and time, and the xenon atoms remained inside the pores upon exposing the material to air atmosphere at room temperature. To understand the material behavior, TGA, XRPD, and 129Xe NMR spectroscopy and computational studies were carried out. PMID- 30024752 TI - MnOx/IrOx as Selective Oxygen Evolution Electrocatalyst in Acidic Chloride Solution. AB - The oxygen evolution reaction (OER) and chlorine evolution reaction (CER) are electrochemical processes with high relevance to water splitting for (solar) energy conversion and industrial production of commodity chemicals, respectively. Carrying out the two reactions separately is challenging, since the catalytic intermediates are linked by scaling relations. Optimizing the efficiency of OER over CER in acidic media has proven especially difficult. In this regard, we have investigated the OER versus CER selectivity of manganese oxide (MnOx), a known OER catalyst. Thin films (~5-20 nm) of MnOx were electrodeposited on glassy carbon-supported hydrous iridium oxide (IrOx/GC) in aqueous chloride solutions of pH ~0.9. Using rotating ring-disk electrode voltammetry and online electrochemical mass spectrometry, it was found that deposition of MnOx onto IrO x decreases the CER selectivity of the system in the presence of 30 mM Cl- from 86% to less than 7%, making it a highly OER-selective catalyst. Detailed studies of the CER mechanism and ex-situ structure studies using SEM, TEM, and XPS suggest that the MnOx film is in fact not a catalytically active phase, but functions as a permeable overlayer that disfavors the transport of chloride ions. PMID- 30024755 TI - Two-Dimensional Hierarchical Semiconductor with Addressable Surfaces. AB - Surfaces play a key role in determining material properties, and their importance is further magnified in the two-dimensional (2D) limit. Though monolayers are entirely composed of surfaces, there is no chemical approach to covalently address them without breaking intralayer bond. Here, we describe a 2D semiconductor that offers two unique features among 2D materials: structural hierarchy within the monolayer and surface reactive sites that enable functionalization. The 2D semiconductor is composed of a single layer of strongly interconnected Re6Se8 clusters arranged in an oblique lattice capped by substitutionally labile Cl atoms. We show that a simple ligand substitution strategy borrowed from traditional coordination chemistry can be used to modify the surface of the 2D material while preserving its internal structure. The potential generality of this approach establishes a promising route toward multifunctional 2D materials with tunable physical and chemical properties and may also facilitate better electrical top contact to 2D semiconductors. PMID- 30024756 TI - Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization. AB - The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed. PMID- 30024757 TI - Trisulfur Radical Anion (S3*-) Involved [1 + 2 + 2] and [1 + 3 + 1] Cycloaddition with Aromatic Alkynes: Synthesis of Tetraphenylthiophene and 2 Benzylidenetetrahydrothiophene Derivatives. AB - S3*--mediated [1 + 2 + 2] and [1 + 3 + 1] cycloaddition reactions of aromatic alkynes to give tetraphenylthiophene and 2-benzylidenetetrahydrothiophene derivatives via two C-S bond formations are developed. These two protocols provide new, simple, and straightforward strategies to construct tetraphenylthiophene and 2-benzylidenetetrahydrothiophene derivatives under transition-metal-free conditions. This study also expands the application of S3*- in organic reactions. PMID- 30024758 TI - Widening the Therapeutic Perspectives of Clofazimine by Its Loading in Sulfobutylether beta-Cyclodextrin Nanocarriers: Nanomolar IC50 Values against MDR S. epidermidis. AB - Clofazimine (CLZ) is an antibiotic with a promising behavior against Gram positive bacteria; however, the drug is completely insoluble in water and accumulates in fat tissues. We explored nanocarriers, labeled and not labeled with rhodamine, consisting of negatively charged sulfobutylether-beta cyclodextrins for CLZ loading. A new oligomeric carrier was obtained cross linking betaCyD with epichlorohydrin followed by sulfonation in a strongly alkaline aqueous medium. The oligomeric carrier has a MW of 53 kDa and forms small nanoparticles of a few tens of nm. With aqueous solutions containing a 25 mg/mL oligomeric carrier, we loaded up to 0.5 mg/mL of drug. The oligomers exhibited a 10-fold better loading capacity compared to monomers and formed nanoparticles with a size in the 20-60 nm range after drug loading. Circular dichroism confirmed encapsulation of the CLZ in the nanocarriers. All carriers with or without CLZ are not cytotoxic up to 1 MUM, while CLZ alone is highly cytotoxic at the same concentration. The drug has IC50 values below 100 nM against S. epidermidis. The same holds true also for clinical isolates of S. epidermidis, some displaying MDR. So, the selectivity index significantly increased for CLZ/carrier systems compared to the drug alone. Taken all together, our results open new avenues for the clinical application of this antibiotic. PMID- 30024759 TI - Microstructural Distinction of Electrospun Nanofibrous Drug Delivery Systems Formulated with Different Excipients. AB - The electrospun nanofiber-based orally dissolving webs are promising candidates for rapid drug release, which is due to the high surface area to volume ratio of the fibers and the high amorphization efficacy of the fiber formation process. Although the latter is responsible for the physical and/or chemical instability of these systems. The primary aim of the present study was to elucidate how the addition of polysorbate 80 (PS80) and hydroxypropyl-beta-cyclodextrin (HP-beta CD) influenced the electrospinning process, the properties, and the behavior of the obtained nanofibers. In order to reveal any subtle changes attributable to the applied excipients, the prepared samples were subjected to several state of the art imaging and solid state characterization techniques at both macroscopic and microscopic levels. Atomic force microscopy (AFM) revealed the viscoelastic nature of the fibrous samples. At relatively low forces mostly elastic deformation was observed, while at higher loads plasticity predominated. The use of polysorbate led to about two times stiffer, less plastic fibers than the addition of cyclodextrin. The 1H-13C nuclear magnetic resonance (NMR) cross polarization build-up curves pointed out that cyclodextrin acts as an inner, while polysorbate acts as an outer plasticizer and, due to its "liquid-like" behavior, can migrate in the polymer-matrix, which results in the less plastic behavior of this formulation. Positron annihilation lifetime spectroscopy (PALS) measurements also confirmed the enhanced mobility of the polysorbate and the molecular packing enhancer properties of the cyclodextrin. Solid-state methods suggested amorphous precipitation of the active ingredient in the course of the electrospinning process; furthermore, the nature of the amorphous systems was verified by NMR spectroscopy, which revealed that the use of the examined additives enabled the development of a molecularly dispersed systems of different homogeneities. An accelerated stability study was carried out to track physical state related changes of the incorporated drug and the polymeric carrier. Recrystallization of the active ingredient could not be observed, which indicated a large stress tolerance capacity, but time-dependent microstructural changes were seen in the presence of polysorbate. Raman mapping verified homogeneous drug distribution in the nanofibrous orally dissolving webs. The performed dissolution study indicated that the drug dissolution from the fibers was rapid and complete, but the formed stronger interaction in the case of the PVA-CD-MH system resulted in a little bit slower drug release, compared to the PS80 containing formulation. The results obviously show that the complex physicochemical characterization of the polymer-based fibrous delivery systems is of great impact since it enables the better understanding of material properties including the supramolecular interactions of multicomponent systems and consequently the rational design of drug-loaded nanocarriers of required stability. PMID- 30024760 TI - Perovskite Solar Cells: Toward Industrial-Scale Methods. AB - Research progress in hybrid perovskite solar cells has increased enormously over the last years, making perovskites very promising candidates for future PV technologies. Perovskite solar cells use abundant and low-cost starting materials, providing economic advantages for large-scale implementation. A transition from laboratory-scale fabrication to industrial manufacturing requires scaling up of the dimension of the devices; manufacturing of large-area modules, considering the development of interconnection as an important step toward upscaling; and development of deposition methods alternative to spin coating, which are industrially compatible and facilitate high power conversion efficiency of the manufactured devices. This Perspective provides an overview of the recent developments toward industrial-scale manufacturing. Advances and perspectives in the developments of sheet-to-sheet and roll-to-roll deposition methods are discussed along with other related technologies required for industrial-scale methods, e.g., laser ablation, drying, post-treatment, and the use of alternative industry-compatible solvents for manufacturing of perovskite solar cells. PMID- 30024761 TI - Machine-Learned Coarse-Grained Models. AB - Optimizing force-field (FF) parameters to perform molecular dynamics (MD) simulations is a challenging and time-consuming process. We present a novel FF optimization framework that integrates MD simulations with particle swarm optimization (PSO) algorithm and artificial neural network (ANN). This new ANN assisted PSO framework was used to develop transferable coarse-grained (CG) models for D2O and DMF as a proof of concept. The PSO algorithm was used to generate the set of input FF parameters for the MD simulations of the CG models of these solvents, which were optimized to reproduce their experimental properties. Herein, for the first time, a reverse approach was employed for on the-fly training of the ANN model, where results (solvent properties) obtained from the MD simulations and their corresponding FF parameters were used as inputs and outputs, respectively. The ANN model was then required to predict a set of new FF parameters, which were tested for their ability to predict the desired experimental properties. This new framework can be extended to integrate any optimization algorithm with ANN and MD simulations to accelerate the FF development. PMID- 30024762 TI - Low- q Bicelles Are Mixed Micelles. AB - Bicelles are used in many membrane protein studies because they are thought to be more bilayer-like than micelles. We investigated the properties of "isotropic" bicelles by small-angle neutron scattering, small-angle X-ray scattering, fluorescence anisotropy, and molecular dynamics. All data suggest that bicelles with a q value below 1 deviate from the classic bicelle that contains lipids in the core and detergent in the rim. Thus not all isotropic bicelles are bilayer like. PMID- 30024763 TI - Discovery of Presaccharothriolide X, a Retro-Michael Reaction Product of Saccharothriolide B, from the Rare Actinomycete Saccharothrix sp. A1506. AB - The highly reactive precursor molecule, presaccharothriolide X, was successfully isolated from the rare actinomycete Saccharothrix sp. A1506. The comparable biological activity of presaccharothriolide X and its Michael addition product saccharothriolide B unveils a unique masking/activating property of 2 aminophenol. Unexpectedly, 2-aminophenol in saccharothriolide B was eliminated through a retro-Michael reaction, to yield presaccharothriolide X under physiological conditions. 2-Aminophenol might be developed into a useful protecting group for bioactive small molecules with an alpha,beta-unsaturated ketone. PMID- 30024764 TI - Copper-Catalyzed Reductive Trifluoromethylation of Alkyl Iodides with Togni's Reagent. AB - This work illustrates a reductive cross-electrophile coupling protocol for trifluoromethylation of alkyl iodides under Cu-catalyzed/Ni-promoted reaction conditions. The use of diboron esters as the terminal reductant allows the effective generation of the alkyl-CF3 products with excellent functional group tolerance and broad substrate scope. A mechanism involving a reaction of alkyl-Cu with Togni's reagent was proposed. PMID- 30024765 TI - Fully Atomistic Real-Time Simulations of Transient Absorption Spectroscopy. AB - We have implemented an electron-nuclear real-time propagation scheme for the calculation of transient absorption spectra. When this technique is applied to the study of ultrafast dynamics of Soret-excited zinc(II) tetraphenylporphyrin in the subpicosecond time scale, quantum beats in the transient absorption caused by impulsively excited molecular vibrations are observed. The launching mechanism of such vibrations can be regarded as a displacive excitation of the zinc-pyrrole and pyrrole C-C bonds. PMID- 30024766 TI - Identification and Self-Reaction Kinetics of Criegee Intermediates syn-CH3CHOO and CH2OO via High-Resolution Infrared Spectra with a Quantum-Cascade Laser. AB - The Criegee intermediates, carbonyl oxides produced in ozonolysis of unsaturated hydrocarbons, play important roles in atmospheric chemistry. The two conformers of CH3CHOO exhibit distinct reactivity toward several atmospheric species, but a distinct conformer-specific probe is challenging because ultraviolet and infrared absorption bands of syn- and anti-CH3CHOO overlap at low-resolution. Employing a quantum-cascade laser and a Herriott cell, we recorded the O-O stretching bands of CH2OO and syn-CH3CHOO in region 880-932 cm-1 at resolution 0.0015 cm-1. In addition to completely resolved vibration-rotational lines of CH2OO extending over 50 cm-1, some spectral lines associated with hot bands were identified. Spectral lines solely due to syn-CH3CHOO were also identified. Probing these lines, we determined the rate coefficient for the self-reaction of syn-CH3CHOO to be kself = (1.6 +/- 0.60.5) * 10-10 cm3 molecule-1 s-1, about twice that of CH2OO. PMID- 30024768 TI - Driving under the influence of drugs: prevalence in road traffic accidents in Italy and considerations on "per se" limits legislation. AB - OBJECTIVE: To present the prevalence and concentrations of drugs in blood samples of drivers involved in road traffic accidents (RTA) and to discuss the effects of adopting different concentration cut-off values proposed or applied in other European countries on the number of driving under the influence of drugs (DUID) offences. METHODS: Blood samples from drivers involved in RTA in the Padova province, from 2014 to 2017, were analysed for the presence of alcohol and drugs. The prevalence of positive subjects was reported for each substance adopting the limits of quantification (LOQs) of our laboratory and the concentration cut-off values proposed and/or used in other European countries. The reduction of cases of driving under the influence of illicit drugs in applying different cut-offs was calculated. RESULTS: 4443 blood samples were analysed: 23.7% were positive for alcohol and 19.9% for psychoactive drugs, with a prevalence of poly-drug and alcohol-drug abuse of 4.5% and 6% respectively. The most frequently detected drugs were cannabinoids (9.7%) and cocaine (7.2%) followed by benzodiazepines (4.1%), opiates (1.9%) and other opioids (1.7%). Barbiturates, amphetamines and ketamine have been identified in a much smaller number of cases. The overall decrease of DUID cases when adopting different cut-offs with respect to the cases "above the LOQs" was between 8% and 84%. The adoption of high LOQs such as those used in the "European Union's research project on Driving Under the Influence of Drugs, Alcohol and Medicines" (DRUID), decreases the hypothetical number of DUID offences by a quarter, while per se limits proposed as broadly equivalent to a blood alcohol concentration (BAC) between 0.2 and 0.8 g/L dramatically reduce the cases of DUID (cocaine -81%, cannabis -79%, opioids -97%, opiates -96%, and amphetamines -77%) and no ketamine positive samples were above the cut-off. CONCLUSIONS: The implementation of high analytical limits or of per se limits based on impairing concentrations in the Italian legislation could result in the persecution of a much lower number of drugged drivers involved in RTA, with a decrease from 25% to more than 80% depending on the limits. PMID- 30024767 TI - Optics-Free, Non-Contact Measurements of Fluids, Bubbles, and Particles in Microchannels Using Metallic Nano-Islands on Graphene. AB - Despite the apparent convenience of microfluidic technologies for applications in healthcare, such devices often rely on capital-intensive optics and other peripheral equipment that limit throughput. Here, we monitored the transit of fluids, gases, particles, and cells as they flowed through a microfluidic channel without the use of a camera or laser, i.e., "optics-free" microfluidics. We did this by monitoring the deformation of the side walls caused by the analyte passing through the channel. Critically, the analyte did not have to make contact with the channel walls to induce a deflection. This minute deformation was transduced into a change in electrical resistance using an ultrasensitive piezoresitive film composed of metallic nano-islands on graphene. We related changes in the resistance of the sensor to the theoretical deformation of the channel at varying flow rates. Then, we used air bubbles to induce a perturbation on the elastomeric channel walls and measured the viscoelastic relaxation of the walls of the channel. We obtained a viscoelastic time constant of 11.3 +/- 3.5 s 1 for polydimethylsiloxane, which is consistent with values obtained using other techniques. Finally, we flowed silica particles and human mesenchymal stem cells and measured the deformation profiles of the channel. This technique yielded a convenient, continuous, and non-contact measurement of rigid and deformable particles without the use of a laser or camera. PMID- 30024769 TI - The First Decade of Web-Based Sports Injury Surveillance (2004-2005 Through 2013 2014): Methods of the National Collegiate Athletic Association Injury Surveillance Program and High School Reporting Information Online. AB - OBJECTIVE: : To describe the methods of the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) and High School Reporting Information Online (HS RIO) system as a complement to the sport-specific manuscripts that will follow. BACKGROUND: : The NCAA-ISP and HS RIO collect injury and exposure data from samples of collegiate and high school sports programs, respectively. The NCAA-ISP, which the NCAA has maintained since 1982, was relaunched as a Web-based platform at the beginning of the 2004-2005 academic year. In 2005, the HS RIO was introduced to capture data on high school athletes and modeled after the NCAA-ISP. Relevant data are shared with the NCAA and high school sport and policy committees to develop evidence-based rules and programs that help protect the health and safety of student-athletes. DESCRIPTION: : The NCAA-ISP and HS RIO monitor participation in school-sanctioned competitions and practices that occur from the first preseason practice to the final postseason contest for more than 25 sports. For this series of publications in the Journal of Athletic Training, injury information on 13 sports at the collegiate level during the 2004-2005 through 2013-2014 academic years and the high school level during the 2005-2006 through 2013-2014 academic years was evaluated. CONCLUSIONS: : Athletic trainers have been a vital source of data collection over the past decade to help produce the largest datasets of collegiate and high school sports injuries. Such data have helped various sport and policy committees advance protocols that aim to increase sports safety. This series of publications will aid by continuing to provide data to stakeholders in the sports community. PMID- 30024770 TI - Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts. AB - Loss of retinyl ester (RE)-rich lipid droplets (LDs) from hepatic stellate cells (HSCs) is cited as a key event in their cellular transdifferentiation to activated, pro-fibrotic myofibroblasts; however, it remains unclear if changes in LD morphology or RE content are causal for transdifferentiation. To better understand LD dynamics in vitro within a common model of HSC activation, we used novel approaches preserving LD morphology and allowing for quantitation of RE. The size and quantity of LDs within in vitro and in vivo bile duct ligation (BDL) activated HSCs were quantitated using adipocyte differentiation-related protein (ADRP) labeling and oil red o (ORO) staining (gold standard), and RE content was determined using fluorescence microscopy. We found during HSC activation in vitro that LD number differed significantly when measured by ADRP and ORO, respectively ( day 1: 56 vs. 5, P = 0.03; day 4: 101 vs. 39, P = 0.03; day 14: 241 vs. 12, P = 0.02). Ex vivo HSCs activated in vivo contained the same number of LDs as day 4 in vitro activated HSCs (118 vs. 101, P = 0.54). Decline in LD RE occurred beyond day 4 in vitro and day 1 ex vivo , after HSC transdifferentiation was underway. Lastly, in situ HSCs examined using electron microscopy show LDs tend to be smaller but are ultimately retained in BDL injured livers. Therefore, we conclude that during HSC transdifferentiation, LDs are not lost but are retained, decreasing in size. Additionally, RE content declines after transdifferentiation is underway. These data suggest that these LD changes are not causal for HSC transdifferentiation. NEW & NOTEWORTHY Loss of retinoid-laden lipid droplets from hepatic stellate cells has long been held as a hallmark of their transdifferentiation into activated myofibroblasts, the dominant cells that drive hepatic fibrosis. This study demonstrates that stellate cells activated in culture and after liver injury in vivo retain their lipid droplets and that these droplets become smaller and more numerous, with decreases in droplet retinoid concentration occurring only after cellular transdifferentiation is underway. PMID- 30024771 TI - Mass Mortality of Green Frog ( Rana clamitans) Tadpoles in Wisconsin, USA, Associated with Severe Infection with the Pathogenic Perkinsea Clade. AB - We documented mortality of green frog ( Rana clamitans) tadpoles in Wisconsin, US, attributed to severe Perkinsea infection. Final diagnosis was determined by histopathology. followed by molecular detection of pathogenic Perkinsea clade (PPC) of frogs in the liver. To our knowledge, this represents the first detection of PPC in the midwestern US. PMID- 30024772 TI - Urinary clusterin and glutathione-s-transferase levels in HIV positive normotensive and preeclamptic pregnancies. AB - OBJECTIVE: To determine the level and effect of urinary clusterin (CLU) and glutathione-s-transferase (GST) proteins in normotensive and preeclamptic pregnant women with HIV infection. METHODS: The urine concentration of CLU and GST in normotensive (n = 38) and preeclamptic pregnant (n = 38) women stratified by HIV status were estimated using the Bio-Plex(r) ProTM immunoassay. RESULTS: Across the group, a significant down-regulation of CLU (p = 0.039) with a reduced trend in GST was shown in HIV positive preeclampsia. CONCLUSION: HIV infection affects the activity of urinary CLU protein in HIV positive preeclampsia. However, the cytoprotective role of these proteins neutralizes the oxidative radicals associated with preeclampsia development through complement response in HIV infection. PMID- 30024773 TI - Influence of demographic factors and clinical status parameters on long-term neurological, psychological and vegetative outcome following traumatic brain injury. AB - PRIMARY OBJECTIVE: We evaluated the neurologic, psychological and vegetative outcome, the health status and changes of the personal and occupational status of patients after traumatic brain injuries (TBIs). Correlations between outcome parameters and basic demographic factors and initial clinical status parameters of the patients were assessed. RESEARCH DESIGN: Monocentric, retrospective follow up analysis. METHODS AND PROCEDURES: We evaluated the neurologic, psychological and vegetative outcome and health status of patients, who survived TBI with a mean follow-up time of 54 months. Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS) and a questionnaire on Quality of Life were used for outcome measurement. The personal and occupational status, trauma-derived changes to that status and medical and demographic factors that have an impact on the health condition of patients after TBI were assessed. MAIN OUTCOMES AND RESULTS: With a median GOS of 5.0 and median DRS of 3.0, our patients showed just moderate disabilities. Fifty-six per cent of the patients felt 'very good' or 'good'. Age, gender, the preclinical Glasgow Coma Scale (GCS), state of pupil reaction and surgical treatment did not seem to affect the GOS or DRS. Correlations between body mass index, age and gender and distinct neurologic, psychological and vegetative symptoms were found. The personal status did not change significantly after TBI. Changes to occupational and socioeconomic status were evident. CONCLUSIONS: One-third of the patients are heavily affected by neurological, psychological and vegetative symptoms after surviving TBI. Some demographic factors affected this integrity. PMID- 30024774 TI - Salt-sensitive (Rapp) Rats from Envigo Spontaneously Develop Accelerated Hypertension Independent of Ovariectomy on a Low Sodium Diet. AB - Inbred salt-sensitive (SS) rats developed by John Rapp and distributed by Harlan (SS/JrHsd) were shown to model ovariectomy-induced hypertension since on a low sodium (LS) diet, ovariectomized SS (SS-OVX) animals became hypertensive in contrast to their sham-operated (SS-SHAM) normotensive littermates. After Harlan merged with Envigo in 2015, inconsistencies in the LS normotensive phenotype were reported. To further investigate these inconsistencies, we studied the effects of ovariectomy on SS and salt-resistant (SR) rats purchased from Envigo (SS/JrHsd/Env) between 2015-2017. The mean arterial pressure (MAP) in SS rats on a LS diet exceeded 160 mmHg at 7 months old (mo). Ovariectomy at 3mo had no detectable effect on MAP from 4-7mo nor did ovariectomy at 1.5mo significantly affect MAP at 10mo [MAP (mmHg): SR-SHAM (n=7), 102+/-3; SR-OVX (n=6), 114+/-1; *SS-SHAM (n=7), 177+/-6; *SS-OVX (n=5), 190+/-12; *p<0.0001 vs. SR, same ovarian status]. Whole genome sequencing revealed more genomic variants of SS/JrHsd/Env including single nucleotide and insertion deletion polymorphisms and higher heterozygous/homozygous ratios compared to the reference genome than for SS/JrHsd/Mcwi and SS/Jr rats, maintained in Milwaukee, WI and Toledo, OH, respectively, and which still exhibit normal blood pressure on a LS diet. These findings demonstrate the female SS/JrHsd/Env rat has genetically diverged from the original phenotype which was normotensive on a LS diet when the ovaries were intact but which rapidly developed hypertension when the ovaries were removed. Nonetheless, the SS/JrHsd/Env rat could be a valuable model that complements other animal models of spontaneous hypertension used to investigate mechanisms of essential hypertension. PMID- 30024776 TI - Dietary proteins improve hibernation and subsequent reproduction in the European hamster, Cricetus cricetus. AB - The reproductive success of hibernators depends not only on food quality during reproduction but also on their body condition when emerging after hibernation, which, in turn, is highly dependent on the hibernation pattern. To date, no studies, to our knowledge, have fully investigated the role of macronutrients throughout the annual lifecycle of hibernators and the strong interdependency between its different phases. This study tested the effects of two diets with different lipid and protein composition on the prehibernation body condition, hibernation pattern, and reproduction of captive-reared European hamsters. Hamsters fed the high-lipid diet gained more body mass in the prehibernation period than those eating the high-protein diet, spent less time in torpor, and thus lost more body mass during hibernation. Despite similar body conditions in both groups at the start of reproduction, the group fed the high-protein diet had higher reproductive success, with more numerous and larger pups than in the high lipid group. This study reveals that the macronutrient content of diets affects the different phases of the annual lifecycle in hamsters, each of which affects the next. Thus, a high-lipid diet induces less torpor use during hibernation because of a better prehibernation body condition and negatively impacts subsequent reproduction. PMID- 30024775 TI - Limiting feeding to the active phase reduces blood pressure without the necessity of caloric reduction or fat mass loss. AB - Reducing body weight has been shown to lower blood pressure in obesity-related hypertension. However, success of those lifestyle interventions is limited due to poor long-term compliance. Emerging evidence indicates that feeding schedule plays a role on the regulation of blood pressure. With two studies, we examined the role of feeding schedule on energy homeostasis and blood pressure. In study 1, rats were fed a high-fat diet (HFD) ad libitum for 24 h (Control) or for 12 h during the dark phase (time-restricted feeding, TRF). In study 2, rats fed a HFD were administered a long-acting alpha-MSH analog at either light onset [melanotan II (MTII) light] or dark onset (MTII dark) or saline (Control). MTII light animals ate most of their calories during the active phase, similar to the TRF group. In study 1, Control and TRF rats consumed the same amount of food and gained the same amount of weight and fat mass. Interestingly, systolic and mean arterial pressure (MAP) was lower in the TRF group. In study 2, food intake was significantly lower in both MTII groups relative to Control. Although timing of injection affected light versus dark phase food consumption, neither body weight nor fat mass differed between MTII groups. Consistent with study 1, rats consuming their calories during the active phase displayed lower MAP. These data indicate that limiting feeding to the active phase reduces blood pressure without the necessity of reducing calories or fat mass, which could be relevant to obesity-related hypertension. PMID- 30024778 TI - Interpretation of compound words by Greek-speaking children with autism spectrum disorder plus language impairment (ASD-LI). AB - The language abilities of children with autism spectrum disorder (ASD) are highly variable. More insight is needed into the mechanisms that underlie co-morbid language impairments (LI) in children with ASD (henceforth, ASD-LI) across complex lexical and/or grammatical phenomena, particularly for languages beyond English. The present study tested the comprehension and production of two constituent compound words at the single-word level for Greek (e.g., pondikopayideltaa 'mouse trap'). The Compound Word Test, measured on a range of psycholinguistic variables, was used to assess the (compound) constitutent recognition, comprehension/definition, and production of compositional noun-noun compounds in four school-aged children diagnosed with ASD-LI. Their results were compared to age-matched peers with typical language development as a group and as single cases. Comprehension was probed in relation to the word's constituents, for which semantic interpretation involved explaining the meaning of the compound. Production of compound words was tested using a picture confrontation naming task. The results revealed that the four children with ASD-LI who participated had less difficulty recognizing the compound constituents but showed a significant deficit in deriving the compound meaning. Naming compounds was exceptionally difficult despite generally intact comprehension of the object pictures. This leads us to suggest a dissociation between linguistic and conceptual knowledge about the constituents and the compound word. Moreover, the children with ASD-LI produced semantically infelicitous responses when explaining the meaning of compounds, an error not evident in their typically developing peers. Generalizing over the four single clinical cases, we hypothesize that children with ASD-LI have difficulties at the interface of (morpho)syntax with semantics and pragmatics, that is, at the conceptual-intentional system. PMID- 30024779 TI - The Two-Arm Coordination Test: Maturation of Bimanual Coordination in Typically Developing Children and Deficits in Children with Unilateral Cerebral Palsy. AB - BACKGROUND: Tools to assess bimanual coordination are scant. We aimed to: 1) provide normative data of maturation of bimanual coordination in tipically developing (TD) children measured by the Two Arm Coordination Test (TACT), and 2) validate the TACT as an instrument to specifically discriminate impairment of bimanual coordination in children with unilateral cerebral palsy (UCP). PROCEDURE: Cross-sectional observational study. 252 TD children and 26 children with UCP performed 8 trials of TACT (following a star pattern with a pointer steered by coordinated movements of both arms). Number of errors and time were combined in a performance index of motor learning. RESULTS: In TD children, bimanual coordination improved with age (F(7,244)=36.888, p<.001). Children with UCP had a poorer bimanual coordination than TD children (all t>24.25, all p<.01). TACT scores were correlated moderately to manual dexterity and manual ability (all r>-.452, all p<.039), showing the capacity of the TACT to provide information on different aspects of hand function. CONCLUSION: TACT is a valid instrument to assess bimanual coordination. PMID- 30024777 TI - Regulation of amniotic fluid volume: insights derived from amniotic fluid volume function curves. AB - Recent advances in understanding the regulation of amniotic fluid volume (AFV) include that AFV is determined primarily by the rate of intramembranous absorption (IMA) of amniotic fluid across the amnion and into fetal blood. In turn, IMA rate is dependent on the concentrations of yet-to-be identified stimulator(s) and inhibitor(s) that are present in amniotic fluid. To put these concepts in perspective, this review 1) discusses the evolution of discoveries that form the current basis for understanding the regulation of AFV, 2) reviews the contribution of IMA to this regulation, and 3) interprets experimentally induced shifts in AFV function curves and amnioinfusion function curves in terms of the activity of the amniotic fluid stimulator and inhibitor of IMA. In the early 1980s, it was not known whether AFV was regulated. However, by the late 1980s, IMA was discovered to be a "missing link" in understanding the regulation of AFV. Over the next 25 years the concept of IMA evolved from being a passive process to being an active, unidirectional transport of amniotic fluid water and solutes by vesicles within the amnion. In the 2010s, it was demonstrated that a renally derived stimulator and a fetal membrane-derived inhibitor are present in amniotic fluid that regulate IMA rate and hence are the primary determinants of AFV. Furthermore, AFV function curves and amnioinfusion function curves provide new insights into the relative efficacy of the stimulator and inhibitor of IMA. PMID- 30024780 TI - Objective assessment of obstructive sleep apnea in normal pregnant and preeclamptic women. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is a risk factor for adverse pregnancy outcomes. The aim of this study was to evaluate the association between OSA and preeclampsia. METHODS: Between 30 and 39 weeks gestation, objective sleep apnea were evaluated in 38 normal pregnant and 40 preeclamptic women. Preeclampsia was defined by having a blood pressure (BP) > 140/90 mmHg on two occasions after the 20th week of pregnancy with excess protein in the urine (> 300 mg in 24 h) or 30 mg persistent proteinuria (+ 1 in dipsticks) in random samples. Objective sleep apnea was evaluated using an overnight in-hospital sleep evaluation using the SOMNOwatch plus Respiratory Screener. OSA was defined as an apnea-hypopnea index (AHI) >= 5, and further grouped into severity categories: mild (5-14.9), moderate (15-29.9), and severe (>= 30). RESULTS: Mean AHI was 33.3 +/- 12.1 in preeclamptic women and was 23.8 +/- 15.8 in normal pregnant women (p = 0.008). There was significant difference in prevalence of OSA severity (none, mild, moderate, or severe) between groups. Out of 33 preeclamptic women, 11 women had moderate and 22 women had severe OSA. Whereas, among 33 normal pregnant women, 8, 13, and10 women had mild, moderate, and severe OSA, respectively. Two normal pregnant women had no OSA (AHI< 5). CONCLUSION: Our study suggests women are susceptible to developing OSA during pregnancy that is associated with an increased risk of preeclampsia. PMID- 30024781 TI - Longitudinal changes in brain volumetry and cognitive functions after moderate and severe diffuse axonal injury. AB - BACKGROUND AND OBJECTIVE: Diffuse axonal injury (DAI) induces a long-term process of brain atrophy and cognitive deficits. The goal of this study was to determine whether there are correlations between brain volume loss, microhaemorrhage load (MHL) and neuropsychological performance during the first year after DAI. METHODS: Twenty-four patients with moderate or severe DAI were evaluated at 2, 6 and 12 months post-injury. MHL was evaluated at 3 months, and brain volumetry was evaluated at 3, 6 and 12 months. The trail making test (TMT) was used to evaluate executive function (EF), and the Hopkins verbal learning test (HVLT) was used to evaluate episodic verbal memory (EVM) at 6 and 12 months. RESULTS: There were significant white matter volume (WMV), subcortical grey matter volume and total brain volume (TBV) reductions during the study period (p < 0.05). MHL was correlated only with WMV reduction. EF and EVM were not correlated with MHL but were, in part, correlated with WMV and TBV reductions. CONCLUSIONS: Our findings suggest that MHL may be a predictor of WMV reduction but cannot predict EF or EVM in DAI. Brain atrophy progresses over time, but patients showed better EF and EVM in some of the tests, which could be due to neuroplasticity. PMID- 30024783 TI - The economic costs of jail-based methadone maintenance treatment. AB - BACKGROUND: The US has the highest incarceration rate in the world and spends $40 $80 billion to house inmates per year. It is well-known that a significant correlation is present between substance use and crime, especially over recent years as opioid use disorder (OUD) has grown exponentially. To mitigate OUD, methadone maintenance treatment (MMT) has demonstrated effectiveness in numerous randomized and quasi-experimental studies. A potentially fruitful environment for MMT is correctional facilities, particularly short-term facilities, such as city and county jails. However, little is known about the economic implications of MMT within correctional facilities. OBJECTIVE: The aim of the present study was to estimate the economic costs of jail-based MMT using data from a novel, established MMT program located within a large urban jail in New Mexico. METHODS: Data were collected using administrative records and by interviewing program administrators using a modified version of the Drug Abuse Treatment Cost Analysis Program (DATCAP). Both sensitivity analysis and cost-structure analysis were conducted to gauge the robustness of the findings. RESULTS: The average (per patient) weekly cost of MMT is $115 and the total treatment cost for an average treatment episode is $689. These costs are generally in-line with non-jail-based MMT programs of similar size. Weekly cost estimates range from $86 to $185 depending on the size of the treatment facility, with larger programs exhibiting lower per-patient costs. CONCLUSION: Results provide a valuable economic benchmark to policy makers, criminal justice officials, and program administrators considering establishing and/or expanding MMT in jail settings. PMID- 30024782 TI - Rest-activity rhythms characteristics and seasonal changes in seasonal affective disorder. AB - Identifying objectively measurable seasonal changes in 24-h activity patterns (rest-activity rhythms or RARs) that occur in seasonal affective disorder (SAD) could help guide research and practice towards new monitoring tools or prevention targets. We quantified RARs from actigraphy data using non-parametric and extended cosine based approaches, then compared RARs between people with SAD and healthy controls in the summer (n = 70) and winter seasons (n = 84). We also characterized the within-person seasonal RAR changes that occurred in the SAD (n = 19) and control (n = 26) participants who contributed repeated measures. Only controls had significant winter increases in RAR fragmentation (intra-daily variability; in controls mean winter-summer changes (log scale) = 0.05, 0.21 standard deviation, p = 0.03). In SAD participants only, estimated evening settling times (down-mesor) were an average of 30 min earlier in the winter compared with the summer (1-h standard deviation, p = 0.045). These RAR characteristics correlated with greater fatigue (Spearman r = 0.36) but not depression symptom severity. Additional research is needed to ascertain why healthy controls, but not people with SAD, appear to have increased RAR fragmentation in the winter. People with SAD lacked this increase in RAR fragmentation, and instead had earlier evening setting in the winter. Prospective and intervention studies with greater temporal resolution are warranted to ascertain how these seasonal behavioral differences relate to fatigue pathophysiology in SAD. Future research is needed to determine whether extending the winter active period, even in relatively fragmented bouts, could help reduce the fatigue symptoms common in SAD. PMID- 30024785 TI - DNA electromagnetic properties and interactions -An investigation on intrinsic bioelectromagnetism within DNA. AB - The question whether intrinsic bioelectromagnetism exists within DNA or not is an important and so far unexplored area of biology. We carried out a study of isolated genetic material, utilizing both prokaryotic and eukaryotic DNA, to measure any possible intrinsic electromagnetic effects or fields emanated within the molecules. Studies were carried out with extremely sensitive ultra-low-noise trans-impedance amplifiers and a high-precision data acquisition system to record any possible faintest electromagnetic signals from the concentrated, as well as diluted DNA, in vitro. Some experiments were performed to investigate any possible electromagnetic effects of high-frequency (HF) RF fields on the DNA under test. However, after extensive testing and careful measurements, we failed to detect any possible intrinsic or induced electromagnetic activity from the DNA as compared to simple water or empty chambers. We reached a conclusion that there does not seem to be any measurable intrinsic electromagnetic activity or fields present in the DNA material, whether in concentrated or diluted form, and if there were, any such activity or fields would be extremely minuscule to be detected with scientific precision by current human measurement methods. PMID- 30024784 TI - CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. AB - Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy. PMID- 30024787 TI - Febuxostat for the treatment of hyperuricaemia in gout. AB - INTRODUCTION: Febuxostat is a potent non-purine selective xanthine oxidase inhibitor approved by the FDA in 2009 for management of hyperuricemia in people with gout. Areas covered: The authors summarize the pre-clinical studies and pivotal randomized controlled trials of febuxostat when used as a treatment for hyperuricaemia in gout Expert opinion: Febuxostat has clinical efficacy in serum urate lowering, and long-term use leads to improved outcomes such as gout flare frequency and tophus burden. Recently published post-approval placebo-controlled trials have demonstrated urate-lowering efficacy and safety of febuxostat in patients with chronic kidney disease, and reduced frequency of gout flares in people with early onset of gout. In November 2017, the FDA issued a drug safety communication based on the preliminary results of the CARES trial. This cardiovascular safety study of 6190 patients with gout and established cardiovascular disease comparing febuxostat and allopurinol showed no difference in the primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization), but did report higher all-cause mortality (hazard ratio 1.22) and cardiovascular mortality (hazard ratio 1.34) with febuxostat. Based on currently available data, it seems likely that allopurinol, rather than febuxostat, will remain first line urate-lowering therapy for people with gout. PMID- 30024786 TI - Sensory dysfunction and traumatic brain injury severity among deployed post-9/11 veterans: a chronic effects of neurotrauma consortium study. AB - OBJECTIVES: To describe the prevalence of sensory dysfunction (i.e. auditory, visual, vestibular, chemosensory and multiple sensory problems) and explore associations with traumatic brain injury (TBI) severity and injury mechanism among deployed Post-9/11 Veterans. METHODS: This retrospective cohort analysis used Departments of Defense and Veterans Affairs diagnostic codes and administrative data. RESULTS: Among the 570,248 Veterans in this cohort, almost 23% had at least one diagnosis of sensory dysfunction. In the multinomial regression analysis, the odds of all types of sensory dysfunction were greater among those with any TBI relative to those with no TBI. The odds for auditory or multisensory problems were higher among those that indicated exposure to blast. In particular, exposure to quaternary blast injury (e.g. crush, respiratory and burn injuries) was associated with increased odds for auditory, visual, vestibular and multisensory problems. CONCLUSIONS: Sensory problems affect a substantial number of deployed Post-9/11 Veterans and are more common among those with TBI or with exposure to deployment-related blast exposure. Because sensory problems profoundly impact quality of life, their identification and enhanced education and therapy are vital tools to improve prognosis for these relatively young Veterans. PMID- 30024788 TI - A novel nutritional intervention improves lung function in overweight/obese adolescents with poorly controlled asthma: the Supplemental Nutrition in Asthma Control (SNAC) pilot study. AB - Asthma in the obese is often severe, difficult to treat, and characterized by less eosinophilic inflammation than asthma in the nonobese. Obesity-associated metabolic dysregulation may be a causal factor. We previously reported that a nutrient- and fiber-dense bar [Children's Hospital Oakland Research Institute (CHORI)-bar], which was designed to fill gaps in poor diets, improved metabolism in healthy overweight/obese (OW/OB) adults. In this pilot trial, OW/OB adolescents with poorly controlled asthma were randomized to weekly nutrition/exercise classes with or without twice-daily CHORI-bar consumption. Intent-to-treat analysis did not indicate CHORI-bar-specific effects. However, restricting the analysis to participants with acceptable compliance and a relatively low fraction of exhaled nitric oxide (FENO; <50/ ppb, a surrogate for noneosinophilic asthma; study participants: CHORI-bar, n = 16; controls, n = 15) indicated that CHORI-bar-specific, significant improvements in lung function (forced vital capacity, percent-predicted forced expiratory volume in 1 s, and percent-predicted forced expiratory flow between 25 and 75% of forced vital capacity), primarily in participants with low chronic inflammation (high sensitivity C-reactive protein <1.5 mg/L). (We previously observed that chronic inflammation blunted CHORI-bar-induced metabolic improvements in healthy OW/OB adults.) Lung function improvement occurred without weight loss and was independent of improvements in metabolic and anthropometric end points and questionnaire-based measures of asthma control and quality of life. This study suggests that a nutritional intervention can improve lung function in OW/OB adolescents with asthma and relatively low FENO without requiring major changes in dietary habits, lifestyle, or weight loss and that this effect is blunted by chronic inflammation.-Bseikri, M., McCann, J. C., Lal, A., Fong, E., Graves, K., Goldrich, A., Block, D., Gildengoren, G. L., Mietus-Snyder, M., Shigenaga, M., Suh, J., Hardy, K., Ames, B. N. A novel nutritional intervention improves lung function in overweight/obese adolescents with poorly controlled asthma: the Supplemental Nutrition in Asthma Control (SNAC) pilot study. PMID- 30024789 TI - Nogo-A promotes inflammatory heat hyperalgesia by maintaining TRPV-1 function in the rat dorsal root ganglion neuron. AB - Nogo-A is a key inhibitory molecule of axon regeneration in oligodendrocytes. However, little is known about its role in adult neurons. In this study, we showed an important function of Nogo-A on regulation of inflammatory pain in dorsal root ganglion (DRG) neurons. In adult rats with complete Freund's adjuvant (CFA) hind paw inflammation, DRG neurons showed a significant increase in Nogo-A expression. Disruption of Nogo-A signaling with Nogo-66 receptor antagonist peptide, Nogo-A blocking antibody, Nogo-A short hairpin RNA, or Nogo-A gene knockout attenuated CFA-induced inflammatory heat hyperalgesia. Moreover, disruption of Nogo-A signaling suppressed the function and expression in DRG neurons of the transient receptor potential vanilloid subfamily member (TRPV)-1 channel, which is known to be the endogenous transducer of noxious heat during inflammation. These effects were accompanied with a reduction in LIM domain kinase (LIMK)/cofilin phosphorylation and actin polymerization. Similar disruption of actin filament architecture by direct action of Latrunculin A reduced the TRPV-1 activity and up-regulation of TRPV-1 protein caused by CFA. We conclude that Nogo-A plays an essential role in the development of inflammatory heat hyperalgesia, partly through maintaining TRPV-1 function via activation of the LIMK/cofilin pathway, which regulates actin filament dynamics. These findings support a therapeutic potential of modulating Nogo-A signaling in pain management.-Hu, F., Liu, H.-C., Su, D.-Q., Chen, H.-J., Chan, S.-O., Wang, Y., Wang, J. Nogo-A promotes inflammatory heat hyperalgesia by maintaining TRPV-1 function in the rat dorsal root ganglion neuron. PMID- 30024790 TI - Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function. AB - Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. We used 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK transiently before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) animals. In contrast to AMPK activities during stress, in unstressed hearts, AICAR induced a mild activation of Akt signaling, and, in SRC-2-CKO mice, partially relieved an NAD+ deficiency and increased antioxidant signaling. These molecular changes translated to a mild hypertrophic response to TAC with decreased maladaptive remodeling, including markedly decreased fibrosis. Additionally, preactivation of AMPK in SRC-2-CKO mice was accompanied by a dramatic improvement in cardiac function compared with saline-treated SRC-2-CKO mice. Our results show that altered molecular signaling before stress onset has extended effects on sustained cardiac stress responses, and prestress modulation of transient growth and metabolism pathways may control those effects.-Nam, D. H., Kim, E., Benham, A., Park, H.-K., Soibam, B., Taffet, G. E., Kaelber, J. T., Suh, J. H., Taegtmeyer, H., Entman, M. L., Reineke, E. L. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function. PMID- 30024791 TI - Interplay between SUMOylation and NEDDylation regulates RPL11 localization and function. AB - The ribosomal protein L11 (RPL11) integrates different types of stress into a p53 mediated response. Here, we analyzed the impact of the ubiquitin-like protein SUMO on the RPL11-mouse double-minute 2 homolog-p53 signaling. We show that small ubiquitin-related modifier (SUMO)1 and SUMO2 covalently modify RPL11. We find that SUMO negatively modulates the conjugation of the ubiquitin-like protein neural precursor cell-expressed developmentally downregulated 8 (NEDD8) to RPL11 and promotes the translocation of the RP outside of the nucleoli. Moreover, the SUMO-conjugating enzyme, Ubc9, is required for RPL11-mediated activation of p53. SUMOylation of RPL11 is triggered by ribosomal stress, as well as by alternate reading frame protein upregulation. Collectively, our data identify SUMO protein conjugation to RPL11 as a new regulator of the p53-mediated cellular response to different types of stress and reveal a previously unknown SUMO-NEDD8 interplay. El Motiam, A, Vidal, S., de la Cruz-Herrera, C. F., Da Silva-Alvarez, S., Baz Martinez, M., Seoane, R., Vidal, A., Rodriguez, M. S., Xirodimas, D. P., Carvalho, A. S., Beck, H. C., Matthiesen, R., Collado, M., Rivas, C. Interplay between SUMOylation and NEDDylation regulates RPL11 localization and function. PMID- 30024792 TI - miR-132-3p boosts caveolae-mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav-1 signaling pathway. AB - Blood-brain tumor barrier (BTB) impedes the transportation of antitumor therapeutic drugs into brain tumors. Its mechanism is still unknown, but learning how to improve the BTB permeability is critical for drug intervention. Recently, microRNAs (miRNAs) have appeared as regulation factors of numerous biologic processes and therapeutic targets of diverse diseases. In this study, we have identified that miR-132-3p is an essential miRNA by increasing the transcellular transport through the BTB. We found that miR-132-3p expression was significantly up-regulated in glioma endothelial cells (GECs). Furthermore we showed that miR132-3p+ greatly induced the endocytosis of cholera toxin subunit B and FITC bovine serum albumin and up-regulated the expression of p-PKB, p-Src and Tyr14 phosphorylation of caveolin-1 (p-Cav-1), while phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression was markedly down-regulated in GECs. Our results identify PTEN as a direct and functional downstream target of miR-132 3p, which is involved in the regulation of p-PKB, p-Src, and p-Cav-1. The inhibitors for PI3K and Src significantly reversed the increase of p-Cav-1 induced by miR-132-3p. Moreover, overexpression of PTEN greatly reduced the endocytosis of cholera toxin subunit B and the up-regulation of p-Cav-1 induced by agomiR132-3p, suggesting that miR132-3p+ increases the endothelial permeability by inhibition of PTEN expression. In addition, miR132-3p+ significantly increased the delivery of doxorubicin across the BTB in vitro and contributed to the accumulation of doxorubicin within the brain tumor tissue. Our results show that miR-132-3p contributes to the increased permeability of BTB by targeting PTEN/PI3K/PKB/Src/Cav-1, thereby revealing a novel drug target for the treatment of brain gliomas.-Gu, Y., Cai, R., Zhang, C., Xue, Y., Pan, Y., Wang, J., Zhang, Z. miR-132-3p boosts caveolae-mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav-1 signaling pathway. PMID- 30024793 TI - Spatial Methods to Enhance Public Health Surveillance and Resource Deployment in the Opioid Epidemic. AB - OBJECTIVES: To improve public health surveillance and response by using spatial optimization. METHODS: We identified cases of suspected nonfatal opioid overdose events in which naloxone was administered from April 2013 through December 2016 treated by the city of Pittsburgh, Pennsylvania, Bureau of Emergency Medical Services. We used spatial modeling to identify areas hardest hit to spatially optimize naloxone distribution among pharmacies in Pittsburgh. RESULTS: We identified 3182 opioid overdose events with our classification approach, which generated spatial patterns of opioid overdoses within Pittsburgh. We then used overdose location to spatially optimize accessibility to naloxone via pharmacies in the city. Only 24 pharmacies offered naloxone at the time, and only 3 matched with our optimized solution. CONCLUSIONS: Our methodology rapidly identified communities hardest hit by the opioid epidemic with standard public health data. Naloxone accessibility can be optimized with established location-allocation approaches. Public Health Implications. Our methodology can be easily implemented by public health departments for automated surveillance of the opioid epidemic and has the flexibility to optimize a variety of intervention strategies. PMID- 30024794 TI - Medicaid Expansion as an Employment Incentive Program for People With Disabilities. AB - Before the Patient Protection and Affordable Care Act (ACA), many Americans with disabilities were locked into poverty to maintain eligibility for Medicaid coverage. US Medicaid expansion under the ACA allows individuals to qualify for coverage without first going through a disability determination process and declaring an inability to work to obtain Supplemental Security Income. Medicaid expansion coverage also allows for greater income and imposes no asset tests. In this article, we share updates to our previous work documenting greater employment among people with disabilities living in Medicaid expansion states. Over time (2013-2017), the trends in employment among individuals with disabilities living in Medicaid expansion states have become significant, indicating a slow but steady progression toward employment for this group post ACA. In effect, Medicaid expansion coverage is acting as an employment incentive program for people with disabilities. These findings have broad policy implications in light of recent changes regarding imposition of work requirements for Medicaid programs. PMID- 30024796 TI - Brief Standing Desk Intervention to Reduce Sedentary Behavior at a Physical Activity Conference in 2016. AB - OBJECTIVES: To examine the impact of environmental restructuring on attendees at a physical activity conference when provided with standing tables and given point of-decision prompts (PODPs; e.g., health messages). METHODS: This randomized controlled trial took place at the Health-Enhancing Physical Activity Europe 2016 conference in Belfast, United Kingdom, September 2016. We randomly allocated 14 oral sessions to either the intervention group (standing tables + PODPs; n = 7) or the control group (PODPs only; n = 7). Conference volunteers discreetly recorded the number of attendees standing and sitting and estimated the number of women and attendees aged 40 years or older. RESULTS: There was a significant difference (P = .04) in the proportion of attendees standing during the intervention (mean = 16.8%; SD = 9.5%) than during control sessions (mean = 6.0%; SD = 5.8%). There was no differential response between gender and age groups in the proportion standing during intervention sessions (P > .05). CONCLUSIONS: Providing standing tables may be a feasible and effective strategy to reduce sitting at physical activity conferences. PMID- 30024795 TI - Opioid Overdose Mortality Among Former North Carolina Inmates: 2000-2015. AB - OBJECTIVES: To examine differences in rates of opioid overdose death (OOD) between former North Carolina (NC) inmates and NC residents and evaluate factors associated with postrelease OOD. METHODS: We linked NC inmate release data to NC death records, calculated OOD standardized mortality ratios to compare former inmates with NC residents, and calculated hazard ratios to identify predictors of time to OOD. RESULTS: Of the 229 274 former inmates released during 2000 to 2015, 1329 died from OOD after release. At 2-weeks, 1-year, and complete follow-up after release, the respective OOD risk among former inmates was 40 (95% confidence interval [CI] = 30, 51), 11 (95% CI = 9.5, 12), and 8.3 (95% CI = 7.8, 8.7) times as high as general NC residents; the corresponding heroin overdose death risk among former inmates was 74 (95% CI = 43, 106), 18 (95% CI = 15, 21), and 14 (95% CI = 13, 16) times as high as general NC residents, respectively. Former inmates at greatest OOD risk were those within the first 2 weeks after release, aged 26 to 50 years, male, White, with more than 2 previous prison terms, and who received in-prison mental health and substance abuse treatment. CONCLUSIONS: Former inmates are highly vulnerable to opioids and need urgent prevention measures. PMID- 30024797 TI - Risk of Police-Involved Death by Race/Ethnicity and Place, United States, 2012 2018. AB - OBJECTIVES: To estimate the risk of mortality from police homicide by race/ethnicity and place in the United States. METHODS: We used novel data on police-involved fatalities and Bayesian models to estimate mortality risk for Black, Latino, and White men for all US counties by Census division and metropolitan area type. RESULTS: Police kill, on average, 2.8 men per day. Police were responsible for about 8% of all homicides with adult male victims between 2012 and 2018. Black men's mortality risk is between 1.9 and 2.4 deaths per 100 000 per year, Latino risk is between 0.8 and 1.2, and White risk is between 0.6 and 0.7. CONCLUSIONS: Police homicide risk is higher than suggested by official data. Black and Latino men are at higher risk for death than are White men, and these disparities vary markedly across place. Public Health Implications. Homicide reduction efforts should consider interventions to reduce the use of lethal force by police. Efforts to address unequal police violence should target places with high mortality risk. PMID- 30024798 TI - Comprehensive Diabetes Self-Management Support From Food Banks: A Randomized Controlled Trial. AB - OBJECTIVES: To determine whether food bank provision of self-management support and diabetes-appropriate food improves glycemic control among clients with diabetes. METHODS: We screened 5329 adults for diabetes at food pantries (n = 27) affiliated with food banks in Oakland, California; Detroit, Michigan; and Houston, Texas, between October 2015 and September 2016. We individually randomized 568 participants with hemoglobin A1c (HbA1c) 7.5% or greater to waitlist control or 6-month intervention including food, diabetes education, health care referral, and glucose monitoring. The primary outcome was HbA1c at 6 months. RESULTS: Food security (relative risk [RR] = 0.85; 95% confidence interval [CI] = 0.73, 0.98), food stability (RR = 0.77; 95% CI = 0.64, 0.93), and fruit and vegetable intake (risk difference [RD] = 0.34; 95% CI = 0.34, 0.34) significantly improved among intervention participants. There were no differences in self-management (depressive symptoms, diabetes distress, self-care, hypoglycemia, self-efficacy) or HbA1c (RD = 0.24; 95% CI = -0.09, 0.58). CONCLUSIONS: Food banks are ideally situated to provide diabetes-appropriate food to food-insecure households. Effective strategies for food banks to support improvements in diabetes clinical outcomes require additional study. Public Health Implications. Moving chronic disease support from clinics into communities expands reach into vulnerable populations. However, it is unclear how community interventions should be integrated with clinical care to improve disease outcomes. TRIAL REGISTRATION NUMBER: NCT02569060. PMID- 30024799 TI - Continued Increase in Prevalence of Coal Workers' Pneumoconiosis in the United States, 1970-2017. AB - OBJECTIVES: To update prevalence estimates for coal workers' pneumoconiosis (CWP) among working underground coal miners in the United States. METHODS: We conducted a prevalence study using radiographs collected from 1970 to 2017. We classified each radiograph using international standards. We defined CWP as the presence of small opacities, with profusion greater than or equal to subcategory 1/0, or the presence of a large opacity larger than 1 centimeter. RESULTS: Following a low point in the late 1990s, the national prevalence of CWP in miners with 25 years or more of tenure now exceeds 10%. In central Appalachia (Kentucky, Virginia, West Virginia), 20.6% of long-tenured miners have CWP. When we excluded miners from central Appalachia, the prevalence for the remainder of the United States was lower, but an increase since 2000 remains evident. CONCLUSIONS: The national prevalence of CWP among working coal miners is increasing. This increase is most pronounced in central Appalachia. Current CWP prevalence estimates will likely be reflected in future trends for severe and disabling disease, including progressive massive fibrosis. Public Health Implications. Recently enacted protections to prevent coal mine dust exposure and identify CWP at its early stage remain essential to protect US coal miners. PMID- 30024800 TI - Prevalence and Risk Factors Associated With Workplace Violence Against General Practitioners in Hubei, China. AB - OBJECTIVES: To assess the prevalence and factors associated with physical and nonphysical violence in a sample of general practitioners (GPs). METHODS: We used a cross-sectional design to collect data from December 2014 to March 2015 with a structured self-administered questionnaire from 1015 GPs in Hubei Province, Central China (response rate, 85.6%). We used a multivariable logistic regression model to identify the predictors associated with workplace violence toward GPs. RESULTS: Of the respondents, 62.2% of respondents reported exposure to workplace violence in the preceding year, including 18.9% and 61.4% who encountered physical and nonphysical violence, respectively. Multivariable logistic regression analysis suggested that GPs who were male, at a higher professional level, and who had a lower average monthly income were more likely to experience physical violence. Male GPs, less-experienced GPs, and those with administrative responsibility were more likely than their counterparts to encounter nonphysical violence. CONCLUSIONS: This study shows that the prevalence of workplace violence against GPs is high in Hubei, China. Creating a prevention strategy and providing safer workplace environments for GPs should be urgently prioritized. PMID- 30024801 TI - Cancers Disproportionately Affecting the New York State Transgender Population, 1979-2016. AB - OBJECTIVES: To summarize what is known about cancer among the transgender population in New York State. METHODS: We identified transgender patients diagnosed between 1979 and 2016 in the New York State Cancer Registry using reported sex, text search of the case abstract, and linkage to statewide hospitalization records. RESULTS: We identified 230 transgender patients, including 125 natal males, 48 natal females, and 57 with unknown natal sex. Median age at diagnosis was 47.4 years, compared with 66.0 years for all patients. Transgender patients were more than 2.5 times more likely to use cigarettes than were other cancer patients. Kaposi sarcoma had the highest proportional incidence ratio (71.7). CONCLUSIONS: In New York State, HIV- and human papillomavirus-related cancers disproportionately affect the transgender population. Public Health Implications. To our knowledge, this is the first report of cancer among the transgender population that incorporates more detailed codes that took effect in 2015. Awareness of the differences in transgender cancer incidence from the general population is vital to ensure that necessary preventive care and screenings are accessible and offered appropriately to this population. PMID- 30024802 TI - HIV Preexposure Prophylaxis as a Gateway to Primary Care. AB - OBJECTIVES: To determine whether HIV preexposure prophylaxis (PrEP) use is associated with use of non-HIV-related health care. METHODS: We conducted a cross sectional study of potential PrEP candidates at a Boston, Massachusetts, community health clinic during 2012 to 2016, comparing the proportion of PrEP users and non-PrEP users receiving primary care. RESULTS: Of 5857 PrEP candidates, 2047 (35%) were prescribed PrEP. After adjustment for demographics and number of visits, more PrEP users received influenza vaccination (prevalence ratio [PR] = 1.28; 95% confidence interval [CI] = 1.20, 1.37), tobacco screening (PR = 1.06; 95% CI = 1.02, 1.09), and depression screening (PR = 1.07; 95% CI = 1.04, 1.11) compared with non-PrEP users. After additional adjustment for diabetes, hypertension, and overweight or obesity, more PrEP users received glucose testing (PR = 1.64; 95% CI = 1.56, 1.72) but fewer received hemoglobin A1c testing (PR = 0.81; 95% CI = 0.71, 0.93) compared with non-PrEP users. CONCLUSIONS: PrEP use was associated with receipt of influenza vaccination, tobacco and depression screening, and glucose but not hemoglobin A1c testing. Among PrEP users receiving routine care, the benefits of PrEP may extend to behavioral health, mental health, and prevention and treatment of other infectious and chronic diseases. PMID- 30024803 TI - Human Papillomavirus Vaccine Initiation for Adolescents Following Rhode Island's School-Entry Requirement, 2010-2016. AB - OBJECTIVES: To assess changes in human papillomavirus (HPV) vaccine initiation for adolescent girls and boys in Rhode Island compared with all other states. METHODS: We estimated the gender-specific effects of Rhode Island's school-entry HPV vaccination policy on self-reported HPV vaccination initiation by using a difference-in-differences design with the National Immunization Survey-Teen from 2010 through 2016. RESULTS: Compared with boys in other states, boys in Rhode Island increased their HPV vaccine initiation rate by 11% (b = 0.11; 95% confidence interval [CI] = 0.05, 0.18) after enactment of the requirement. No difference was seen in the probability of HPV vaccine initiation among girls in Rhode Island compared with girls in the multistate control (b = -0.01; 95% CI = 0.08, 0.05). CONCLUSIONS: Our analysis identified an 11% increase in HPV vaccine initiation rate among boys in Rhode Island after the school-entry requirement was enacted, whereas no significant change was observed for girls. Public Health Implications. Given suboptimal vaccine uptake rates in the United States, continued pursuit of state-level public policy to improve HPV vaccination is needed. School-entry requirements for HPV vaccination may be a strategy for closing the gap in HPV vaccine uptake for boys and girls. PMID- 30024804 TI - Evaluating Public Health Interventions: 8. Causal Inference for Time-Invariant Interventions. AB - We provide an overview of classical and newer methods for the control of confounding of time-invariant interventions to permit causal inference in public health evaluations. We estimated the causal effect of gender on all-cause mortality in a large HIV care and treatment program supported by the President's Emergency Program for AIDS Relief in Dar es Salaam, Tanzania, between 2004 and 2012. We compared results from multivariable modeling, three propensity score methods, inverse-probability weighting, doubly robust methods, and targeted maximum likelihood estimation. Considerable confounding was evident, and, as expected by theory, all methods considered gave the same result, a statistically significant approximately 20% increased mortality rate in men. In general, there is no clear advantage of any of these methods for causal inference over classical multivariable modeling, from the point of view of either bias reduction or efficiency. Rather, given sufficient data to adequately fit the multivariable model to the data, multivariable modeling will yield causal estimates with the greatest statistical efficiency. All methods can adjust only for well-measured confounders-if there are unmeasured or poorly measured confounders, none of these methods will yield causal estimates. PMID- 30024805 TI - Community Health Workers, Access to Care, and Service Utilization Among Florida Latinos: A Randomized Controlled Trial. AB - OBJECTIVES: To determine whether a 1-year community health worker intervention improves access to care and service utilization among Latinos with diabetes. METHODS: We conducted a single-blind randomized trial of 300 adults with poorly controlled diabetes treated in 2 public hospital clinics in Miami, Florida. We began enrollment in 2010 and completed follow-up in 2015. We examined access and utilization using self-reported measures and data from electronic medical records. RESULTS: Participants randomized to the community health worker intervention self-reported fewer problems accessing needed care and prescriptions than did those in the usual care group (30% vs 43% and 28% vs 41%, respectively; P < .05 for both). Adjusting for age, gender, education, depression, and comorbidities showed similar results (odds ratio [OR] = 0.52; 95% confidence interval [CI] = 0.29, 0.93 and OR = 0.45; CI = 0.24, 0.82, respectively). We found no significant utilization differences in primary care visits, emergency department utilization, or hospitalization between the 2 groups. CONCLUSIONS: Among Latinos with poorly controlled diabetes, a 1-year community health worker intervention was associated with improvements in self-reported access to care but not service utilization. PMID- 30024806 TI - Open Defecation Sites, Unmet Sanitation Needs, and Potential Sanitary Risks in Atlanta, Georgia, 2017-2018. AB - OBJECTIVES: To survey the spatial distribution and enteric pathogen profile of discarded human feces in the city of Atlanta, Georgia. METHODS: After defining priority search areas in central Atlanta, we conducted 5 searches of open defecation sites totaling 15 hours during the period from October 2017 to January 2018. We collected fresh stools for analysis via multiplex reverse-transcription polymerase chain reaction to identify presence of 15 common parasitic, bacterial, and viral enteric pathogens. RESULTS: We identified and mapped 39 open defecation sites containing 118 presumptive human stools; 23% of the 26 collected fresh stools tested positive for 1 or more pathogens. An estimated 12% of stools were positive for enterotoxigenic Escherichia coli, 7.7% for Giardia spp., 3.8% for norovirus, and 3.8% for Salmonella spp. The majority (92%) of identified open defecation sites were within 400 meters of a shelter or soup kitchen. CONCLUSIONS: Though this study was constrained by a small sample size, results suggest that open defecation in Atlanta is common and may pose risks to public health. Public Health Implications. Open defecation may pose health risks to people experiencing homelessness and the general public. PMID- 30024808 TI - Revisiting the Corporate and Commercial Determinants of Health. AB - We trace the development of the concept of the corporate determinants of health. We argue that these determinants are predicated on the unchecked power of corporations and that the means by which corporations exert power is increasingly unseen. We identify four of the ways corporations influence health: defining the dominant narrative; setting the rules by which society, especially trade, operates; commodifying knowledge; and undermining political, social, and economic rights. We identify how public health professionals can respond to these manifestations of power. PMID- 30024807 TI - Employment Trends Among Public Health Doctoral Recipients, 2003-2015. AB - OBJECTIVES: To examine postgraduation employment trends among graduates of doctoral programs in public health from 2003 to 2015. METHODS: We analyzed pooled cross-sectional data from a census of graduates receiving a research doctorate from US accredited institutions. The outcome of interest was employment status. Covariates included public health discipline, sociodemographic characteristics, and institutional attributes. RESULTS: Of 11 771 graduates, nearly two thirds secured employment in either academic (34.8%) or nonacademic (31.4%) settings at the time of graduation. The proportion of those still seeking employment increased over time. Individuals who were White, younger, trained in either biostatistics or epidemiology, or from an institution with the highest level of research intensity were significantly more likely to secure employment. Academic employment was the most common setting for all 5 public health disciplines, but we observed differences in employment patterns (e.g., government, nonprofit, for profit) across disciplines. CONCLUSIONS: Certain characteristics among public health doctoral recipients are correlated with postgraduation employment. More research is needed, but the observed increase in individuals still seeking employment may be attributable to increases in general public health graduates from for-profit institutions. PMID- 30024809 TI - Opioid Prescribing Rates by Congressional Districts, United States, 2016. AB - OBJECTIVES: To determine the extent to which opioid prescribing rates vary across US congressional districts. METHODS: In an observational cross-sectional framework using secondary data, we constructed 2016 congressional district-level opioid prescribing rate estimates using a population-weighted methodology. RESULTS: High prescribing rate districts were concentrated in the South, Appalachia, and the rural West. Low-rate districts were concentrated in urban centers. CONCLUSIONS: In the midst of an opioid overdose crisis, we identified congressional districts of particular concern for opioid prescription saturation. Public Health Implications. The congressional district geography represents a policy-relevant boundary and a politically important level at which to monitor the crisis and determine program funding. Furthermore, in the context of the opioid crisis, knowing how congressional districts rank across the country and in states is useful in the creation of policies targeted to areas in need. PMID- 30024810 TI - Racial/Ethnic Differences in the Effectiveness of a Multisector Childhood Obesity Prevention Intervention. AB - OBJECTIVES: To investigate racial/ethnic and language differences in the effectiveness of the Massachusetts Childhood Obesity Research Demonstration (MA CORD) study among children aged 2 to 4 years enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). METHODS: We performed a multisector quasiexperimental study in 2 MA-CORD intervention communities and 1 comparison community. Using WIC data from 2010 to 2015, we examined intervention effect on child weight and behavior outcomes by child race/ethnicity and parental primary language using multilevel linear regression models with an interaction term. RESULTS: Non-Hispanic Black children exposed to the intervention demonstrated a greater decrease in body mass index (BMI) than did other children (P < .05). Racial/ethnic minority children in the comparison site had greater increases in BMI than did their White counterparts (P < .05). There were no differences in intervention effectiveness by race/ethnicity or language for health behaviors. CONCLUSIONS: White children demonstrated decreased BMI in both the intervention and control groups. However, intervention minority children demonstrated greater improvements in BMI than did control minority children. Public Health Implications. To reduce racial/ethnic disparities, we need to disseminate effective obesity prevention interventions during early childhood in low-income settings. PMID- 30024812 TI - Involutional entropion repair combining the modified Bick quick strip procedure with Quickert rotational sutures. AB - PURPOSE: The purpose of the study was to determine the results of involutional entropion repair by combining the modified Bick strip procedure with Quickert rotational sutures. METHODS: A retrospective review of consecutive patients with involutional entropion who underwent repair by combined Bick and Quickert technique from January 2013 to December 2017 was performed. RESULTS: A total of 43 cases of involutional entropion repair were preformed in this time period. Fourteen eyelids of 12 patients had the combined procedure. There were no failures with a median follow-up of 29 months. Mean operative time, recorded in 10 patients, was 15 +/- 2.2 minutes. Complications were minimal. CONCLUSIONS: The combination of the modified Bick quick strip procedure and Quickert sutures requires minimal surgical dissection and provides excellent results for the treatment of involutional entropion. PMID- 30024811 TI - A Community Health Worker Intervention to Increase Childhood Disease Treatment Coverage in Rural Liberia: A Controlled Before-and-After Evaluation. AB - OBJECTIVES: To assess a community health worker (CHW) program's impact on childhood illness treatment in rural Liberia. METHODS: We deployed CHWs in half of Rivercess County in August 2015 with the other half constituting a comparison group until July 2016. All CHWs were provided cash incentives, supply chain support, and monthly clinical supervision. We conducted stratified cluster-sample population-based surveys at baseline (March-April 2015) and follow-up (April-June 2016) and performed a difference-in-differences analysis, adjusted by inverse probability of treatment weighting, to assess changes in treatment of fever, diarrhea, and acute respiratory infection by a qualified provider. RESULTS: We estimated a childhood treatment difference-in-differences of 56.4 percentage points (95% confidence interval [CI] = 36.4, 76.3). At follow-up, CHWs provided 57.6% (95% CI = 42.8, 71.2) of treatment in the intervention group. The difference-in-differences diarrhea oral rehydration therapy was 22.4 percentage points (95% CI = -0.7, 45.5). CONCLUSIONS: Implementation of a CHW program in Rivercess County, Liberia, was associated with large, statistically significant improvements treatment by a qualified provider; however, improvements in correct diarrhea treatment were lower than improvements in coverage. Findings from this study offer support for expansion of Liberia's new National Community Health Assistant Program. PMID- 30024814 TI - Association of ABCC2 polymorphism and gender with high-density lipoprotein cholesterol response to simvastatin. AB - AIM: The clinical benefits of lipid-lowering therapy with statins are widely recognized. However, the lipid-lowering efficacy of statins shows significant differences between individuals. ABCC2 has been demonstrated to contribute to the transmembrane transport of the substrate compounds. The ABCC2 SNPs may be important factors that affect individual differences in clinical drug response. The aim of this study was to evaluate the association of rs717620 of ABCC2 with treatment response to simvastatin in a Chinese Han population. METHODS: A total of 318 subjects were medicated with simvastatin 20 mg/day for 12 weeks after enrollment. Venous blood was obtained before and after simvastatin treatment for measurement of blood lipid profile. Subjects were classified into high-response and low-response groups depending on whether their lipid profile change was higher or lower than median change values. The ABCC2 SNP rs717620 was genotyped from blood samples with a snapshot assay. RESULTS: A total of 12 weeks of treatment with simvastatin significantly decreased low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TGs) and significantly increased high-density lipoprotein cholesterol (HDL-C; p < 0.05). In multivariate analysis, there were no significant genetic effects of SNP rs717620 on the incidence of high- or low-response patients among TC, TG and LDL C groups. However, rs717620 A-allele and female gender are significantly associated with the risk of low-response of HDL-C elevation after simvastatin treatment. CONCLUSION: ABCC2 rs717620 and female gender may be related to the low effect of simvastatin treatment on the HDL-C level in the Chinese Han population. Female Chinese patients with hyperlipidemia carrying rs717620 GA/AA genotypes might have reduced benefit from simvastatin treatment. PMID- 30024815 TI - Degradation dynamics, residues and risk assessment of Dufulin enantiomers in corn plants and corn by LC/MS/MS. AB - The degradation dynamics and terminal residues of dufulin enantiomers were investigated in two typical corn plants. A convenient and precise chiral method by high-performance liquid chromatography coupled with tandem triple quadrupole mass spectrometry (HPLC/MS/MS) using a Chiralpak IC column was developed and validated for measuring dufulin enantiomers in corn plants and corn. The two enantiomers of dufulin quickly dissipated in the corn plant, and no noticeable stereoselectivity was observed during degradation or in the final residues. After 30% rac-dufulin wettable powder with a 1- to 1.5-fold dose of the recommended value was sprayed two to three times on corn plants, the residue levels of S-(+) dufulin and R-(-)-dufulin in corn from both sites were lower than or equal to 0.0520 mg kg-1 on days 7, 14 and 21 after the last application. The dietary risk assessment indicated that dufulin did not exhibit obvious dietary health risks in corn samples when good agricultural practices were implemented. The findings from this study may be used to better understand the chiral profiles of dufulin in the environment and the effect of dufulin residues in corn on health. PMID- 30024813 TI - The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells. AB - Inhibitors of PARP1 are approved therapeutic agents in ovarian carcinomas. We determined whether the novel clinically relevant CHK1 inhibitor SRA737 interacted with PARP1 inhibitors to kill carcinoma cells. In multiple mammary and ovarian cancer lines SRA737 synergized with the PARP1 inhibitors olaparib and niraparib to cause cell death. The [SRA737 + niraparib] drug combination activated an ATM AMPK-ULK1-mTOR pathway which resulted in the formation of autophagosomes, temporally followed by autolysosome formation. Phosphorylation of ULK1 S317 was essential for kinase activation against ATG13. The drug combination elevated eIF2alpha phosphorylation which was causal at increasing Beclin1 and ATG5 expression, reducing MCL-1 and BCL-XL levels, and causing CD95 activation. Knock down of CD95, eIF2alpha, ATM, AMPKalpha, ULK1, Beclin1 or ATG5 reduced drug combination lethality. Blockade of either caspase 9 function or that of AIF each partially prevented cell death. Expression of activated mTOR or of c-FLIP-s or of BCL-XL reduced cell killing. In vivo, SRA737 and niraparib interacted in an additive fashion to suppress the growth of mammary tumors. Multiplex analyses revealed that drug combination treated tumors had reduced their plasma levels of sERBB1, sERBB2, sVEGFR1, sVEGFR2, sIL-6R, HGF, PDGFAB/BB and CXCL16 and enhanced the levels of CCL26, IL-8 and MIF. Surviving tumors had activated ERK1/2 and AKT. This finding argues that IL-8/ERK/AKT signaling may be an evolutionary survival response to [SRA737 + niraparib]. PMID- 30024816 TI - Transmission transmissible hepatitis B virus markers of infection among sickle cell disease patients receiving care at a tertiary health facility in Ibadan, southwest Nigeria. AB - INTRODUCTION: Hepatitis B virus infection attacks the liver and can cause both acute and chronic disease. Sickle cell disease (SCD) patients are at risk of transmission transmissible viral hepatitis due to their constant need for blood transfusion. However, these patients could have been infected with HBV but may not know their status due to asymptomatic nature of the infection. Therefore, this study was designed to determine the burden of HBV markers of infection among SCD patients attending the hematology clinic at a tertiary health facility in Ibadan, Nigeria. METHODOLOGY: A cross-sectional study was investigated among 112 consenting SCD patients (M = 45; F = 67) age ranged 15-60 years (mean age = 26.9; mean PCV = 24 +/- 4.8) attending a hematology clinic at the University College Hospital, Ibadan. A structured questionnaire was administered to capture demographic and other relevant information. Blood samples from each participant were tested for HBV markers by ELISA technique, while data were analyzed using SPSS version 21 with P < 0.05 considered significant. RESULTS: A total of 5 (4.5%), 0 (0.0%), and 15 (13.4%) were positive for HBsAg, HBeAg, and HBeAb, respectively. Also, 63 (56.3%) of the participants have never been transfused, while 49 (43.8%) had received blood transfusion at a point in time. No significant difference (P = 0.095) found a prevalence of HBV markers among those that had received blood transfusion and those that did not. Highest rates for HBsAg (3.6%) and HBeAb (10.7%) were observed among female than their male (HBsAg (0.9%) and HBeAb (2.8%) counterparts (P = 0.065)). No significant associations (P > 0.05) were found among those with incisions, among those who are sexually active and among the vaccinated individuals for HBV markers. There was a significant difference (P = 0.025) among the married participants for HBeAb with higher HBeAb rate (64.3%). CONCLUSION: This study reported high rates of HBV markers of infection among SCD patients. It is therefore advocated that donated blood must pass through rigorous screening processes before it is transfused. PMID- 30024818 TI - National short-term dietary exposure assessment of a selected group of pesticides in Argentina. AB - An evaluation of acute dietary exposure to pesticide residues, applying deterministic and stochastic methods, was performed for a selected group of pesticides in two representative age groups from Argentina. Thus, 28 active ingredients (a.i.) and 75 food items were evaluated for the group of 2-5-year-old children, while 9 a.i. and 59 food items were considered for the 10-49-year-old women group. A deterministic assessment was conducting following the Food and Agriculture Organization (FAO) and World Health Organization (WHO) procedure but using the national maximum residue limits (MRLs) as pesticide residue concentration data, while in the stochastic approach, a theoretical distribution modeled with the available information was used. Food consumption data were obtained from the 2004-2005 comprehensive national nutrition and health survey. The risk was estimated by comparing the short-term dietary exposure with the acute reference dose (ARfD) values for each pesticide-food combination evaluated. In the deterministic assessment, 173 (39.1%) and 40 (31.3%) combinations exceeded the ARfD thresholds for the 2-5-year-old children and 10-49-year-old women groups, respectively. This conservative study generated relevant information as a first stage of acute dietary risk assessment in Argentina. PMID- 30024819 TI - School Nurse Advocacy: The Dilemma of Ethical Interpretation Versus Legal Protection. AB - This article summarizes the facts and rulings of a recent, representative federal court decision concerning the legal claims of a school nurse who had engaged in advocacy for student safety, with particular attention to a student with insulin dependent diabetes who committed suicide. The discussion of the court's rulings for the school nurse's various legal claims identifies the difference between ethical interpretation in terms of prevailing perceptions among school nurses and legal protection in terms of the current state of the case law specific to such advocacy. PMID- 30024820 TI - Epilepsy Disorders and Treatment Modalities. AB - Epilepsy disorders are the most common treatable neurological disorders in childhood. Diagnosis and treatment of these disorders has improved over time. Children with epilepsy/seizure disorder are more likely to have or develop mental health and developmental comorbidities such as depression, anxiety, attention deficit hyperactivity disorder, learning disabilities, and developmental delay compared to children without epilepsy/seizure disorder. If seizures can be controlled, quality of life will improve. This article will review the current medical treatment for seizures and epilepsy, including medications, vagus nerve stimulation (VNS), dietary modifications, and surgical intervention. PMID- 30024817 TI - Bifidobacterium animalis subspecies lactis modulates the local immune response and glucose uptake in the small intestine of juvenile pigs infected with the parasitic nematode Ascaris suum. AB - An evaluation of a localized intestinal allergic type-2 response concomitant with consumption of probiotic bacteria is not well documented. This study investigated the effect of feeding probiotic Bifidobacterium animalis subspecies lactis (Bb12) or a placebo in weaned pigs that were also inoculated with Ascaris suum (A. suum) eggs to induce a strong Th2-dependent allergic type 2 immune response. Sections of jejunal mucosa were mounted in Ussing chambers to determine changes in permeability and glucose absorption, intestine and liver samples were collected for analysis of type-2 related gene expression, jejunum examined histologically, and sera and intestinal fluid were assayed for parasite antigen specific antibody. The prototypical parasite-induced secretory response to histamine and reduced absorption of glucose in the jejunum were attenuated by feeding Bb12 without a change in mucosal resistance. Parasite antigen-specific IgA response in the serum and IgG1 and IgG2 response in the ileal fluid were significantly increased in A. suum-infected pigs treated with Bb12 compared to infected pigs given the placebo. Ascaris suum-induced eosinophilia in the small intestinal mucosa was inhibited by Bb12 treatment without affecting the normal expulsion of A. suum 4th stage larvae (L4) or the morphometry of the intestine. Expression of genes associated with Th1/Th2 cells, Treg cells, mast cells, and physiological function in the intestine were modulated in A. suum infected-pigs treated with Bb12. These results suggested that Bb12 can alter local immune responses and improve intestinal function during a nematode infection by reducing components of a strong allergenic type-2 response in the pig without compromising normal parasite expulsion. PMID- 30024821 TI - Link for Schools: A System to Prevent Trauma and Its Adverse Impacts. AB - School-age children experience trauma at alarming rates. Children's ability to attend, concentrate, and participate in the educational process can be adversely impacted by trauma. How can school staff, especially school nurses, best listen, support, and encourage a student with trauma in their lives? Link for Schools is an evidence-informed intervention program that provides information and training for school staff. Link provides tools for listening or responding to a traumatized student with a focus on the principles of trauma-informed care, psychological first aid, and elements of motivational interviewing. Link-trained staff are better equipped to develop a relationship with a student, but future research is recommended to supports its evidence base. PMID- 30024823 TI - Should human papillomavirus vaccination target women over age 26, heterosexual men and men who have sex with men? A targeted literature review of cost effectiveness. AB - BACKGROUND: Human papillomavirus (HPV) vaccination for young women up to age 26 is highly cost-effective and has been implemented in 65 countries globally. We investigate the cost-effectiveness for HPV vaccination program in older women (age > 26 years), heterosexual men and men who have sex with men (MSM). METHOD: A targeted literature review was conducted on PubMed for publications between January 2000 and January 2017 according to the PRISMA guidelines. We included English-language articles that reported the incremental cost-effectiveness ratio (ICER) of HPV vaccination programs for women over age 26, heterosexual men, and MSM and identified the underlying factors for its cost-effectiveness. RESULTS: We included 36 relevant articles (six, 26 and four in older women, heterosexual men and MSM, respectively) from 17 countries (12 high-income (HICs) and five low- and middle-income (LMICs) countries). Most (4/6) studies in women over age 26 did not show cost-effectiveness ($65,000-192,000/QALY gained). Two showed cost effectiveness, but only when the vaccine cost was largely subsidised and protection to non-naive women was also considered. Sixteen of 26 studies in heterosexual men were cost-effective (ICER = $19,600-52,800/QALY gained in HICs; $49-5,860/QALY gained in LMICs). Nonavalent vaccines, a low vaccine price, fewer required doses, and a long vaccine protection period were key drivers for cost effectiveness. In contrast, all four studies on MSM consistently reported cost effectiveness (ICER = $15,000-$43,000/QALY gained), particularly in MSM age < 40 years and those who were HIV-positive. Countries' vaccination coverage did not significantly correlate with its per-capita Gross National Income. CONCLUSION: Targeted HPV vaccination for MSM should be next priority in HPV prevention after having established a solid girls vaccination programme. Vaccination for heterosexual men should be considered when 2-dose 4vHPV/9vHPV vaccines become available with a reduced price, whereas targeted vaccination for women over age 26 is unlikely to be cost-effective. PMID- 30024822 TI - Experience and challenges on influenza and pertussis vaccination in pregnant women. AB - Young infants contribute to relatively high burden of vaccine-preventable diseases, including infections by influenza virus and Bordetella pertussis. Vaccination of pregnant women can enhance transplacental transfer of protective antibody to the fetus and protect the infant against disease during the first few months of life. Pregnant women are a priority group for seasonal influenza vaccination, due to third-trimester pregnancy being a risk-factor for severe influenza illness. Furthermore, randomized controlled trials confirmed that influenza vaccination during pregnancy confers protection against influenza confirmed illness in the women, and their infants up to 3 months of age; and is also associated with 20% reduction in all-cause pneumonia among young-infants. Maternal influenza vaccination might also reduce the risk of low-birth weight, preterm births, and stillbirths however, data on this is conflicting. Vaccination of pregnant women with acellular pertussis vaccines reduces pertussis in their young infants by up to 93%. The increase in specific pertussis antibody among the infants born to vaccinated women might, however, interfere with the active pertussis vaccination of the infant following the primary series of vaccines. The clinical implication of this is yet to be ascertained, particularly since immune responses following the booster vaccine are unaffected. Vaccination of pregnant women with inactivated influenza vaccine and acellular pertussis vaccine have been demonstrated to confer protection to their young infants, and warrants consideration for inclusion into public health immunization programs, including in low and middle income countries. PMID- 30024825 TI - Exploring immunisation inequities among migrant and refugee children in New Zealand. AB - Migrants may experience immunisation inequities compared with the host population related to barriers with accessing immunisations in their home countries, while migrating and/or post-arrival. This retrospective cohort study explored vaccination rates among migrant and non-migrant children in New Zealand (NZ). Linked de-identified data from various government sources from 1 January 2006 to 31 December 2015 were analysed using Statistic NZ's Integrated Data Infrastructure. Vaccination rates were compared between three cohorts of children aged up to 5 years: foreign-born children who migrated to NZ; children born in NZ of migrant mothers; and a comparator group of children born in NZ to non-migrant mothers. Less than half of foreign-born children (46%) had a record in the NZ National Immunisation Register compared with 95% and 96% among migrant and non migrant NZ-born children, respectively. Foreign-born migrant children had lower age-appropriate reported vaccination rates by vaccine of interest, ethnicity and visa category compared with NZ-born children. Migrant children from Pacific ethnicities had lower reported coverage than other ethnicities. High rates of not age-appropriately vaccinated were noted among foreign-born children on refugee, Pacific and humanitarian visa schemes. This study highlights possible shortfalls around immunisation data, particularly about recording vaccinations given overseas for foreign-born children, and potential challenges around engagement with immunisation services for migrant children. However, results highlight the successful engagement of quota refugee children as part of NZ's refugee orientation programme. It is important to monitor vaccination coverage by migrant and refugee background to inform improvements to policy and practice for wider population health benefits. PMID- 30024824 TI - Assessment of boscalid and pyraclostrobin disappearance and behavior following application of effective microorganisms on apples. AB - The aim of this study is to assess the disappearance of boscalid (IUPAC name: 2 chloro-N-[2-(4-chlorophenyl)phenyl]pyridine-3-carboxamide) and pyraclostrobin (IUPAC name: methyl N-[2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]phenyl]-N methoxycarbamate) residues in apple fruit, and to verify whether an organic fertilizer enriched with strains of antagonistic microorganisms can reduce pesticide residue levels. Field trials were conducted in a commercial orchard on apples of the Gloster variety, during 21 days after the treatment with Bellis 38 WG and the subsequent application of Zumba Plant formulation containing Bacillus spp., Trichoderma spp. and Glomus spp. In control samples, the decrease rate of boscalid and pyraclostrobin residue levels followed an exponential function, described by formulae Rt = 0.2824e-0.071t and Rt = 0.1176e-0.060t, with the coefficient of determination of r2 = 0.8692 and r2 = 0.9268, respectively. These levels dropped to half (t1/2) of their initial values after 9.8 and 11.5 days, respectively. The treatment with Zumba Plant resulted in a reduction in boscalid and pyraclostrobin residue levels by 52% and 41%, respectively. The results of this study are of importance for horticulture sciences and for producers of apples using plant protection products (PPPs). PMID- 30024826 TI - Over ten-year insulin independence following single allogeneic islet transplant without T-cell depleting antibody induction. AB - Islet cell transplantation is a promising functional cure for type 1 diabetes; however, maintaining long-term islet graft function and insulin independence is difficult to achieve. In this short report we present a patient with situs inversus, who at the time of islet transplantation had a 26-year history of type 1 diabetes, complicated by hypoglycemic unawareness and severe hypoglycemic events. After a single allogeneic islet transplant of a low islet mass, and despite developing de novo anti-insulin and anti-GAD65 autoantibodies, the patient has remarkably maintained insulin independence with tight glycemic control and normal metabolic profiles for 10 years, after receiving prolonged non T-cell depleting immunosuppression. PMID- 30024827 TI - A post hoc analysis utilizing the FDA toxicity grading scale to assess injection site adverse events following immunization with the live attenuated Zoster Vaccine (ZVL). AB - BACKGROUND: ZOSTAVAX (ZVL; Zoster Virus Live), is a single dose, live, attenuated vaccine licensed for the prevention of herpes zoster (HZ) and post herpetic neuralgia (PHN) in adults >=50 years of age. Injection site adverse events (AEs) of erythema, swelling and pain were solicited within 5 days post vaccination in the 2 pivotal studies of ZVL; ZEST (ZOSTAVAX Efficacy and Safety Trial) and SPS (Shingles Prevention Study). Protocol specified criteria were used to report the frequency and intensity of injection site AEs in ZEST and SPS studies. Subsequently, the FDA Toxicity Grading Scale provided guidance for uniform assessment of AEs across all adult vaccine clinical trials. The objective of this post-hoc analysis was to categorize the previously reported injection site AEs in two pivotal trials of ZVL according to the current FDA Toxicity Grading Scale. METHODS: The current FDA Toxicity Grading Scale provides a measure for classifying injection site AEs by four grades [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe) and Grade 4 (life threatening)]. Injection site erythema, swelling, and pain intensity gradings were assigned to the respective FDA Toxicity Grade based on this appropriation. A descriptive analysis of the proportion and risk difference (within 95% confidence intervals) of injection site AEs per the FDA Toxicity Grading Scale is provided. RESULTS: The frequency of injection site AEs (erythema, swelling, pain) after subcutaneous vaccination with ZVL were higher in recipients of ZVL compared with placebo. Majority of the injection site AEs observed were Grade 1 (mild) or Grade 2 (moderate) in intensity. Additionally, Grade 3 (severe) injection site AEs were observed infrequently. CONCLUSIONS: Application of the FDA Toxicity Grading Scale provides a uniform AE assessment tool across different adult vaccines. This post hoc summary of injection site AEs using FDA Toxicity Grading Scale provides further evidence of low frequency of severe injection site AEs post ZVL vaccination. PMID- 30024828 TI - Readability of online information about HPV Immunization. AB - The human papillomavirus (HPV) vaccine is highly effective in preventing anogenital cancers, but vaccination rates in the United States remain low. In deciding whether to vaccinate their children, parents are increasingly using the internet to gather information. This study aimed to examine the level of readability of information on HPV vaccines written on 100 websites that were found via an internet search. To create the website sample, the first 50 websites from the search "HPV immunization" were recorded, followed by the first 50 non duplicated websites from the search "Gardasil." The content of the sites was analyzed using established readability scales. Websites were compared based on keyword search and on whether they had a commercial or non-commercial URL extension. The majority of websites were found to have information of a difficult reading level. Websites with commercial URL extensions and websites found using the search "Gardasil" had higher mean readability scores. These results suggest that many parents may not understand the information currently presented on the internet and that interventions aimed at improving the readability of online information could help to increase parental approval of the vaccine. PMID- 30024829 TI - Age-appropriate compliance and completion of up to five doses of pertussis vaccine in US children. AB - BACKGROUND: In the United States (US), diphtheria, tetanus, and acellular pertussis (DTaP) vaccination is recommended at 2, 4, and 6 months (doses 1-3), 15 18 months (dose 4), and 4-6 years (dose 5). The objective of this study (GSK study identifier: HO-14-14383) was to examine DTaP completion and compliance rates among commercially insured and Medicaid-enrolled children. Secondarily, the study aimed at identifying predictors of compliance/completion. METHODS: Truven Health MarketScan Commercial and Multi-State Medicaid databases (2005-2013) were analyzed separately. Children born during 2005-2011 with >= 2 years continuous enrollment from birth provided data for doses 1-4; those with continuous enrollment from birth to their seventh birthday provided dose 5 data. Series compliance (each recommended dose by 3, 5, and 7 months; 19 months; seventh birthday) and completion (3 doses by 8 months; 4 by 24 months; 5 by seventh birthday) were calculated. Predictors of compliance/completion were identified using multivariable logistic regression. RESULTS: A total of 367,493 commercially insured and 766,153 Medicaid-enrolled children were followed for >= 2 years; and 23,574 and 41,284, respectively, for >= 7 years. Series compliance to doses 1-3, 1-4, and 1-5 were 67.2%, 55.3%, 47.5% (commercial) and 37.4%, 27.3%, 14.4% (Medicaid), respectively. Predictors of better compliance/completion included: later birth year (commercial/Medicaid) and higher household income (commercial); predictors of worse compliance/completion included: Northeast residence (commercial), birth hospitalization >= 14 days (commercial/Medicaid), and Black race/ethnicity (Medicaid). CONCLUSIONS: DTaP series compliance/completion improved over time, but appear to be suboptimal. As this could increase pertussis risk, greater awareness of the importance of timely vaccination completion is needed. GSK study identifier: HO-14-14383. PMID- 30024830 TI - Analysis of lipid peroxidation in animal and plant tissues as field-based biomarker in Mediterranean irrigated agroecosystems (Extremadura, Spain). AB - The development of field-based biomarkers can allow for a more reliable assessment of the exposure of organisms to pollutants. Different sampling sites, along two streams running through an irrigable agricultural area, were selected to evaluate the effect of agrochemical load on the measured endpoints. The levels of lipid peroxidation were evaluated in several organs of Procambarus clarkii. The same method was applied to leaves of two woody species. Determining levels of MDA (malonaldehyde) by thiobarbituric acid reactive substances assay allows measuring the levels of lipid peroxidation. Differences in lipid peroxidation levels were observed in P. clarkii individuals collected at different sites; however, the patterns varied depending on the organ (when accounting for variations due to sex). The use of a MDA-gills/MDA-hepatopancreas index allowed for discrimination between reference and polluted sites. Significant differences in oxidative damage between sites were found in the leaves of Quercus rotundifolia but not in Salix sp. The lipid peroxidation of crayfish organs and holm oak leaves as a suitable biomarker of environmental pollution deserves further investigation. PMID- 30024831 TI - Live attenuated influenza vaccine viral vector induces functional cytotoxic T cell immune response against foreign CD8+ T-cell epitopes inserted into NA and NS1 genes using the 2A self-cleavage site. AB - The development of viral vector vaccines against various pathogens for which conventional vaccination approaches are not applicable has been a priority for a number of years. One promising approach is the insertion of immunodominant conservative cytotoxic T-cell (CTL) epitopes into the genome of a viral vector, which then delivers these epitopes to target cells, inducing immunity. Many different viruses have been assessed as viral vectors for CTL-based vaccines, but only a few of them are clinically relevant, mainly because of safety issues and limited knowledge about their performance in humans. In this regard, the use of licensed cold-adapted live attenuated influenza vaccine (LAIV) viruses as a vector delivery system has clear advantages for CTL-based vector vaccines against other respiratory pathogens: LAIV is known to induce all arms of the adaptive immune system and is administered via nasal spray, and its production process is relatively easy and inexpensive. Here we present the first results of the use of an LAIV backbone for designing a CTL epitope-based vaccine against respiratory syncytial virus (RSV). The chimeric LAIV-RSV vaccine candidates were attenuated in mice and induced strong, fully functional CTL immunity in this animal model. PMID- 30024833 TI - Sample size calculations for comparing two groups of count data. AB - A sample size formula for comparing two groups of count data is derived using the method of moments by matching the first and second moments of the distribution of the count data, and it does not need any further distributional assumption. Compared to sample size formulas derived using a likelihood-based approach or using simulations, the proposed sample size formula applies to count data following any distribution in addition to the negative binomial distribution. The proposed sample size formula can be used even when the study is analyzed with a likelihood-based approach. Because asymptotically, the method of moments is no more efficient than likelihood-based approaches, the proposed sample size formula can be viewed as an upper bound of the required sample size by likelihood-based approaches to start the study. Applications of the sample size formula are illustrated using an asthma study design. PMID- 30024834 TI - Corrigendum: Ending the Reading Wars: Reading Acquisition From Novice to Expert. PMID- 30024835 TI - Selective effects of specificity inductions on episodic details: evidence for an event construction account. AB - Prior research has suggested that an episodic specificity induction - brief training in recollecting the details of a past event - affects downstream performance on remembering past and imagining future events, solving problems, and thinking creatively. We have hypothesised that a process common to these tasks that the induction may target is event construction - assembling and maintaining a mental scenario filled with details related to settings, people, and actions. We test this hypothesis by having participants receive a memory specificity induction, imagination specificity induction, or control induction not requiring event construction prior to memory and imagination tasks that involve event construction, and a picture description task that involves describing but not mentally constructing an event. We predicted that induction effects would be specific to episodic detail production on subsequent memory and imagination because these details assay critical elements of a constructed event. In line with an event construction account, the two specificity inductions produced significant and indistinguishable increases in the number of episodic - but not semantic - details generated during memory and imagination relative to the control. Induction did not increase detail generation on picture description. The findings provide novel evidence that event construction is a key process targeted by specificity inductions. PMID- 30024836 TI - Revisiting the Veterans Cohort Mortality Study: New results and synthesis. AB - The Veterans Cohort Mortality Study began in 1999 in collaboration with Washington University in St. Louis, comprising ~70,000 male military veterans. We published six research papers on this cohort, considering the dynamics of all cause mortality as the subjects aged and environmental parameters changed. This paper summarizes those results and presents new results by age group. Pollutants included monitored and modeled criteria pollutants, vehicular traffic density (annual km driven per unit of county land area), and modeled nationwide levels of hazardous species. In addition to spatial relationships, we examined the effects of exposure timing through separate analyses of sequential follow-up and exposure periods from 1976 to 2001. Risks associated with peak ozone decreased with lag between exposure and response, suggesting acute effects. Risks associated with traffic were invariant over time and consistent across five exposure databases. Associations with ozone were also coherent across databases; we found no consistent associations with particulate matter. Epidemiology considers both spatial and temporal relationships; most long-term studies focus on spatial gradients at a given time, thus masking effects of cohort aging and other trends during follow-up. Our new analyses distinguished between these temporal effects by analyzing age deciles for which separate mortality risks had been estimated for nationwide levels of nitrogen oxides (NOx), benzene, and traffic density during four sequential follow-up subperiods, thus providing 40 sets of mortality risk coefficients. We used ordinary least squares regression to define relationships with subject age and follow-up year for the data set of 40 coefficients. We found strong nonlinear relationships between subject age and mortality coefficients for smoking, climate, poverty status, and air pollution; only smoking and climate coefficients changed over time as well. We concluded that these pollutant-mortality relationships reflected differences among the veterans' residential locations rather than changes in their pollution exposures during follow-up. We saw no evidence that cleaner air reduced mortality. Implications: Recent air pollution mortality studies emphasize PM2.5 (particulate matter with an aerodynamic diameter <2.5 MUm); we show associations with many other pollutants and a measure of traffic intensity. Control policies should thus be based on multipollutant analyses. We found no reduced risks with improved air quality after distinguishing cohort aging from purely temporal effects; longitudinal studies of accountability must thus account for changes in demography and exposures. Our studies of exposure timing indicate mainly coincident responses and no evidence for cumulative effects typical of smoking; we had no information on personal exposures. We found the strongest risks were associated with high-traffic locations rather than outdoor air quality per se. PMID- 30024837 TI - Corrigendum. PMID- 30024838 TI - Simulations of dust dynamics around a cone hood in updraft conditions. AB - A cone hood is an efficient device for capturing dust releases generated by a variety of process equipment. For stationary airflow conditions, a circular cone hood with a round flange is the most efficient design. The goal of this article is to determine the effect that inflow velocity, suction velocity, and terminal settling velocity of dust particles have on the aspiration coefficient in combination with hood length and inclination angle. No studies have yet addressed the efficiency of an exhaust hood facing an updraft flow of air with suspended dust particles. To simulate the moving fluid, we used the discrete vortices method accounting for flow separation at sharp edges of the cone hood. A custom test bench was built to validate the velocity field distribution around the exhaust hood. To evaluate capture efficiency, we determined the aspiration coefficient using plotted limiting trajectories of dust particles by solving equations of particle dynamics numerically in view of gravity and streamlining airflow patterns. In order to validate our estimate of the aspiration coefficient, we compared our findings with regularities identified by earlier researchers for a simpler problem of dust-air mixture approaching a circular exhaust opening. The following conditions were considered: the ratio of updraft velocity to the exhaust hood suction velocity varying between 0.01 and 0.5; the ratio of dust particle terminal velocity to the suction velocity varying between 0.000625 and 0.2; flange angle varying between 0 degrees and 90 degrees ; and the ratio of flange length to the exhaust opening radius varying between 1 and 4. Using regularities discovered by us, exhaust hood designs can be tailored to a variety of application conditions in terms of dust release capture efficiency. PMID- 30024839 TI - The influence of MTHFR genetic polymorphisms on adverse reactions after methotrexate in patients with hematological malignancies: a meta-analysis. AB - OBJECTIVES: The effect of methotrexate (MTX)-related adverse reaction on hematologic neoplasms patients is controversial. We performed this meta-analysis to assess the association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphism and the adverse reaction after MTX using. METHODS: We searched for qualified studies according to PubMed, the Cochrane Library, and the Web of Science. The meta-analysis was performed by Review Manager 5.3. The analysis was conducted to compare risk ratios (RRs) with the corresponding 95% confidence interval (95% CI) to evaluate the relationship between different toxicity reactions and the genotype of MTHFR. RESULTS: We included 17 studies which satisfied with the criteria in this meta-analysis. The results of our statistical analysis showed that no significant correlation between MTHFR C677T/A1298C genetic polymorphism and patients' toxicity or the relapse and survival associated with MTX chemotherapy (P > .05). But we observed that a tendency toward increased risk of hepatotoxicity was also present for acute lymphoblastic leukemia in the mutation model (CT/TT vs. CC: RR: 1.92, 95% CI: 1.01-3.67; P = .05). CONCLUSION: The polymorphism of MTHFR C677T/A1298C may not be an important indicator for the accurate detection of side effects of chemotherapy after using MTX. More relative research is needed. PMID- 30024841 TI - Letter from the Editor. PMID- 30024840 TI - Human Vaccines & Immunotherapeutics: News. PMID- 30024842 TI - Resumenes al Espanol. PMID- 30024843 TI - Exploring Retirement for Individuals With Intellectual and Developmental Disabilities: An Analysis of National Core Indicators Data. AB - To begin to understand retirement, we examined age-related differences in (a) employment rates, employment hours, and rates of individual-plan employment goals; and (b) participation rates in unpaid formal day programs. We report weighted analyses of 2014-15 National Core Indicators data from 32 states. Unlike younger age groups, a similar proportion of workers with intellectual and developmental disabilities continued working beyond age 65 as for the general community. We found that most workers with intellectual and developmental disabilities retire in older age and that their retirement appears to be sudden, rather than a gradual reduction in work hours. Facility-based day programs were the only program with an increased participation rate in older age groups, revealing an even greater reliance on facility-based services for older participants. PMID- 30024845 TI - Resumes en Francais. PMID- 30024844 TI - The Responsibility to Build Contexts That Enhance Human Functioning and Promote Valued Outcomes for People With Intellectual Disability: Strengthening System Responsiveness. AB - This article describes a model that systems can use to build contexts that enhance human functioning and promote valued outcomes for individuals with intellectual disability (ID). Our premise is that that systems have a responsibility to build contexts that enhance human functioning and promote valued outcomes for people with ID, and that this obligation can be met through the use of contextual analysis to deliberately design and implement support strategies that are responsive to identified contextual factors. The model employs a 2-step process to identify context-based independent and intervening variables and align support strategies with identified context-based influencing factors, disability policy goals, and associated outcome domains. We propose a number of indicators that can be used to assess the quality of a system's responsiveness based on their implementation of the model. Implications for research and practice are discussed. PMID- 30024846 TI - Lost in Translation: A Reply to Shyman (2016). AB - A recently published article sought to determine the extent to which behaviorism and humanism can be reconciled ( Shyman, 2016 ). However, the "current" conceptions of behaviorism and applied behavior analysis (ABA) used for the analysis were based on mischaracterizations, rendering moot many of the points made. Nevertheless, Shyman (2016) highlighted a very important question we believe all helping professionals should attend to: Should normalization be the focus of therapeutic goals? This response article was written to provide readers of this journal an accurate representation of behaviorism and ABA. We have also offered an alternative approach to answering the question of normalization that uses a behavior-by-behavior approach and individual client values as the deciding factors. PMID- 30024847 TI - Direct Support Professionals and Quality of Life of People With Intellectual and Developmental Disabilities. AB - Direct Support Professionals (DSPs) are the "backbone" of long term services and supports (LTSS) in the United States ( Bogenschutz, Hewitt, Nord, & Hepperlen, 2014 , p. 317). This study examined the relationship between DSPs and people with intellectual and developmental disabilities' (IDD) quality of life. To do so, we utilized Personal Outcome Measures(r) interviews from over 1,300 people with IDD to examine the impact DSP change has at individual and organizational levels. We found DSP continuity is central to quality of life of people, including human security, community, relationships, choice, and goals. States cannot continue to provide near-poverty level reimbursement rates for DSPs and still ensure quality of life. PMID- 30024848 TI - Reflections From Co-Researchers With Intellectual Disability: Benefits to Inclusion in a Research Study Team. AB - Participatory action research methodologies may empower and protect marginalized individuals; however, they remain underutilized. Limited studies have investigated the impact of participatory action research, specifically on individuals with intellectual disability (ID). This study examines (1) the perspectives of co-researchers with ID on their involvement in the research process and (2) the feasibility of their inclusion based on perspectives of research staff (academic faculty and graduate students without ID). Three co researchers with ID were interviewed regarding their research participation. Thematic analysis of interviews identified four themes: (1) Shared Experience of Disability, (2) Teaching and Guidance, (3) Acquisition of Skills and Knowledge, and (4) Value of Participation. Research staff reviewed field notes and identified benefits and challenges to feasibility of including co-researchers with ID. Inclusion of co-researchers with ID was found to be both meaningful and feasible. PMID- 30024849 TI - Transition to Adulthood as a Joint Parent-Youth Project for Young Persons With Intellectual and Developmental Disabilities. AB - Eight dyads ( N = 16) residing in Western Canada participated in this investigation of how young adults with intellectual and developmental disabilities (IDD) and their parents jointly construct, articulate, and act on goals pertinent to the young adults' transition to adulthood. Using the action project method to collect and analyze conversations and video recall data, cases were grouped representing the ways goal-directed projects brought relationship ( n = 4), planning ( n = 3) or both ( n = 1) to the foreground as joint projects. Resources internal to the dyad such as emotional resources, and external to the dyad, facilitated formulation and pursuit of projects. Lack of external supports and limited parental knowledge about IDD hindered joint project formulation. PMID- 30024852 TI - A New Class of Robust Two-Sample Wald-Type Tests. AB - Parametric hypothesis testing associated with two independent samples arises frequently in several applications in biology, medical sciences, epidemiology, reliability and many more. In this paper, we propose robust Wald-type tests for testing such two sample problems using the minimum density power divergence estimators of the underlying parameters. In particular, we consider the simple two-sample hypothesis concerning the full parametric homogeneity as well as the general two-sample (composite) hypotheses involving some nuisance parameters. The asymptotic and theoretical robustness properties of the proposed Wald-type tests have been developed for both the simple and general composite hypotheses. Some particular cases of testing against one-sided alternatives are discussed with specific attention to testing the effectiveness of a treatment in clinical trials. Performances of the proposed tests have also been illustrated numerically through appropriate real data examples. PMID- 30024851 TI - Urinary albumin strip assay as a screening test to replace quantitative technology in certain conditions. AB - Background The clinical laboratory plays a crucial role in the diagnosis and monitoring of chronic kidney disease. The quantitative measurement of urine albumin in a spot sample, expressed as ratio per creatinine (ACR) is the most frequently used biomarker for such a purpose. Our aim was to evaluate the diagnostic performances of a strip for measuring ACR for differentiating patients who are candidates for subsequent albumin quantification, and to evaluate the economic effects of its implementation. Methods We systematically measured strip analysis when quantitative urinary albumin was requested. Semiquantitative urinary albumin was measured using a UC-3500 (Sysmex, Kobe, Japan), based on the protein error of a pH indicator. We collected and reviewed all the values of quantified urinary albumin and their corresponding results in ACR strip tests. We calculated the diagnostic indicators for ACR at different albumin and creatinine values using the quantitative ACR measurement as a "gold standard". We also studied the economic effects based on both tests prices (?1.31 for quantitative albumin plus creatinine, and ?0.04 for an albumin strip). Results The study included 9148 patients (mean age 63, 46.3% men). The results at different albumin and creatinine cutoffs showed the best performance when 10 mg/L and above 50 mg/dL, respectively. Based on our results, we would have saved 3506 urine albumin and creatinine tests in the study period, corresponding to ?4226.94. Conclusions The present study supports the use of the ACR strip test to identify pathological albuminuria values to be measured through quantitative methods. Considerable economic savings are possible. PMID- 30024853 TI - Association between a guided meditation practice, sleep and psychological well being in type 2 diabetes mellitus patients. AB - Background Type 2 diabetes mellitus [T2DM] is one of the leading causes for mortality. This study examined the role of an self-awareness based guided meditation practice, Cyclic Meditation [CM] on perceived stress, anxiety, depression, sleep and quality of life in T2DM patients. Design A single arm pre post design was used for the study. Setting The study was conducted in an auditorium for general public diagnosed with T2DM in Ernakulam, Kerala, India. Subjects Subjects were 30 T2DM patients, both male and female of age 50.12 +/- 11.15 years and BMI 25.14 +/- 4.37 Kg/m2 and not having a history of hospitalisation were randomly recruited for the study following advertisements in national dailies. Intervention Participants completed a supervised CM programs in the evenings, 5 days a week for 4 weeks, in addition to their regular medication. Measures Perceived stress, anxiety and depression were assessed with Perceived Stress Scale, State Anxiety Inventory and Beck's depression inventory, respectively. Sleep and quality of life were assessed with Pittsburgh Sleep Quality Index and WHO-Quality of Life - BREF respectively. Analysis Changes in the outcome measures from baseline to 4 weeks were compared using paired "t" test. Results After 4 weeks, the quality of life and sleep scores increased 7.1% [p = 0.001] and 32.7% [p = 0.001], respectively. The perceived stress, anxiety and depression reduced 26.1% [p = 0.001], 16.01% [p = 0.003] and 37.63% [p = 0.006] as compared to their baseline reports. The CM practice also reduced daytime dysfunction. Conclusions A guided self-awareness based meditation program was safe and effective in improving depression, anxiety, perceived stress and enhance sleep and quality of life in T2DM patients, which could be helpful in reducing the future complications of T2DM. Mind management is essential along with medical management to achieve better clinical results. PMID- 30024850 TI - The major beta-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo. AB - In vivo, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. Here we find the molecular stretching of the highly conserved Y654-beta-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the beta-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45% stretching between the two alpha-helices linked by the site and a 15% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating Drosophila embryos. This is followed by the predicted release of 16% of beta-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the beta-catenin pathway process. PMID- 30024854 TI - Effect of yoga and naturopathy on liver, renal and cardiorespiratory functions of a patient with hepatic cirrhosis with portal hypertension and ascites: a case report. AB - A 39-year-old, married man was diagnosed with hepatic cirrhosis with portal hypertension and ascites in February 2016. His symptoms as described by him began with generalized body weakness, breathlessness and sudden weight gain of 16 kg within 3 weeks. History of regular intake of alcohol since 7 years and tremendous family stress were present. Patient underwent conventional medication for 6 months and ayurvedic medications for 4 months. In January 2017, he visited our hospital with the same complaints and underwent integrated naturopathy and yoga therapies (INYTs) for 4 weeks along with Ayurveda and conventional medications. The results of this study showed a better reduction in body weight, body mass index, abdominal girth, systolic blood pressure and diastolic blood pressure along with improvement in breath holding time, hemoglobin level, liver function test and renal function test. It suggests that 4 weeks of INYT with Ayurveda and conventional medications was effective in patients with hepatic cirrhosis with portal hypertension and ascites. Further studies are required to warrant these results. PMID- 30024855 TI - Complementary medicine for laboring women: a qualitative study of the effects of reflexology. AB - Background Despite pharmacological interventions, labor pain and anxiety still remain a challenge, and can carry long-term psychological complications. The goal of this study was to assess the effect of reflexology on these symptoms and to explore the physical and psychological components of women's experience associated with this treatment. Methods This qualitative study was conducted in an Israeli university hospital that offers integrative medicine services. Reflexology was offered to laboring women in the hospital, by the medical staff. In-depth, open interviews were conducted with 36 women, still in hospital, who consented to be interviewed, within 48 h after delivery. Questions referred to their labor experience with reflexology treatment. Results Of the 36 participants, 34 (94%) described a positive and empowering experience. They reported reduced pain and anxiety, and an increased sense of self-efficacy brought about by the ability to become active and manage labor. Conclusions Using reflexology as one of the complementary medicine treatment available can contribute greatly to the entire labor experience as it empowers women and increases self-confidence and ability to self-manage labor and delivery. PMID- 30024856 TI - Comparison of two different treatments in depressed pregnant women: fetal growth characteristics and neonatal outcomes. AB - Background In this pilot study, the effects of selective serotonin reuptake inhibitors (SSRIs) and psychological intervention on fetal growth characteristics and neonatal outcomes were evaluated in two different groups of women affected by prenatal depression. Methods Forty-seven pregnant women diagnosed with major depression were divided into two different treatment groups according to the severity of their depression. The first group was treated with a combination of pharmacotherapy and psychological support. The second group (milder depression) was treated with psychological support only. The control group (CG) was made up of 26 healthy pregnant women. All of the patients and controls were assessed by means of a structured clinical interview and different self-reported questionnaires. Fetal ultrasonography assessments were performed in the second and third trimesters. Neonatal outcomes were evaluated at delivery. Results The infants of both treatment groups showed significant alterations in fetal biometry and a higher rate of low birth weight (LBW) with respect to controls. The infants of the patients treated with psychological support showed only a significantly higher rate of head circumference, <10th percentile with respect to controls. No significant difference was found between the two patient groups when fetal growth characteristics and neonatal outcomes were taken into account. Conclusions The data obtained from this study shed light on the effects of pharmacological and psychological treatment of prenatal depression on fetal growth. PMID- 30024857 TI - JAK2-V617F promotes venous thrombosis through beta1/beta2 integrin activation. AB - JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, beta1 and beta2, may contribute to CMN pathophysiology remained unclear. beta1 (alpha4beta1; VLA-4) and beta2 (alphaLbeta2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of beta1 and beta2 integrins for their respective ligands. For beta1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-beta2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-beta2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen. PMID- 30024858 TI - ASK1 contributes to fibrosis and dysfunction in models of kidney disease. AB - Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS 444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD. PMID- 30024859 TI - HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers. AB - HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems. PMID- 30024862 TI - Preparation of Powdered Infant Formula: Could Product's Safety Be Improved? AB - The recent outbreak of Salmonella Agona linked to the consumption of infant formula (powdered formula) has rekindled the attention about the correct procedures for preparation and use of these products. International guidelines have already been published so far, particularly in association with Cronobacter sakazakii in early 2000s. FAO/WHO suggested to reconstitute formula with water at no less than 70 degrees C. We therefore contaminated powdered formula with low levels of Salmonella spp and C sakazakii to evaluate the pathogens inactivation during the formula preparation using water at 70 degrees C. In these conditions we observed a survival of both pathogens, indicating that the suggested recommendations may be not enough to guarantee the safety of this product. Higher temperatures are needed to reduce the biological risk, even if it may be not easily realized in actual domestic conditions. Moreover, the impact on the nutritional value of reconstituted formulas should be evaluated. PMID- 30024860 TI - Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth. AB - The paracaspase MALT1 plays an essential role in activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1-inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells. PMID- 30024861 TI - Th1 memory differentiates recombinant from live herpes zoster vaccines. AB - The adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50 to 85 years old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su), gE-specific CD4+ and CD8+ T cell responses were 10-fold or more higher in HZ/su compared with ZV recipients. Comparing the vaccines, T cell memory responses, including gE-IL-2+ and VZV-IL-2+ spot-forming cells (SFCs), were higher in HZ/su recipients and cytotoxic and effector responses were lower. At 1 year after vaccination, all gE-Th1 and VZV-IL-2+ SFCs remained higher in HZ/su compared with ZV recipients. Mediation analyses showed that IL-2+ PMR were necessary for the persistence of Th1 responses to either vaccine and VZV-IL-2+ PMR explained 73% of the total effect of HZ/su on persistence. This emphasizes the biological importance of the memory responses, which were clearly superior in HZ/su compared with ZV participants. PMID- 30024863 TI - Use of Family Planning Methods and Influencing Factors Among Women in Erzurum. AB - BACKGROUND Our study aimed to determine the prevalence of family planning methods, socio-demographic characteristics and the relationship between pregnancy histories and usage of family planning methods among women aged 15-49 years old living in the Erzurum provincial center. MATERIAL AND METHODS This is a descriptive, cross-sectional study. From the total 106 669 women aged 15-49 years old living in the Erzurum provincial center, a sample of 627 individuals was selected. A questionnaire consisting of items inquiring into women's socio demographic characteristics, birth and pregnancy history, and the use of family planning methods was administered using face-to-face interviews. Statistical analysis was performed using the SPSS 20.00 software. Descriptive statistics were expressed as mean, median, n, percentage, and standard deviation. The chi square, chi square trend, Mann-Whitney U tests, and logistic regression analysis were used for data analysis. RESULTS The mean age of the women in the study was 33.03 years (SD=7.1 years). The mean total number of pregnancies was 3.07 (SD=1.7). Of the women in the study, 77.7% (n=487) used some kind of FP, with 48.2% (n=302) using modern methods and 29.5% (n=185) using traditional techniques. The most commonly used modern methods were intra-uterine devices (IUDs) and condoms, and the most common traditional method used was withdrawal. The use of modern methods was higher among women working outside of the house. It was positively associated with higher education and income and negatively associated with the total number of pregnancies. CONCLUSIONS Appropriate use of family planning services rises in line with improvements in women's education, prosperity, and employment status. PMID- 30024865 TI - World Hepatitis Day - July 28, 2018. AB - World Hepatitis Day is commemorated each year on July 28 with the goal of promoting awareness and inspiring action to prevent and treat viral hepatitis. The World Health Organization's (WHO's) theme of this year's World Hepatitis Day is "Test. Treat. Hepatitis" to underscore the urgent need to scale up testing and treatment activities. PMID- 30024864 TI - HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Black Men Who Have Sex with Men - Non-Health Care Facilities, 20 Southern U.S. Jurisdictions, 2016. AB - Identifying HIV-infected persons who are unaware of their human immunodeficiency virus (HIV) infection status, linking them to care, and reducing health disparities are important national HIV prevention goals (1). Gay, bisexual, and other men who have sex with men (collectively referred to as MSM) accounted for 70% of HIV infection diagnoses in the United States in 2016, despite representing only 2% of the population (2,3). African American or black (black) MSM accounted for 38% of all new diagnoses of HIV infection among MSM (2). Nearly two thirds (63%) of all U.S. black MSM with diagnosed HIV infection reside in the southern United States (2), making targeted HIV prevention activities for black MSM in this region critical. Analysis of CDC-funded HIV testing data for black MSM submitted by 20 health departments in the southern United States in 2016 revealed that although black MSM received 6% of the HIV tests provided, they accounted for 36% of the new diagnoses in non-health care facilities. Among those who received new diagnoses, 67% were linked to HIV medical care within 90 days of diagnosis, which is below the 2020 national goal of linking at least 85% of persons with newly diagnosed HIV infection to care within 30 days (1). Black MSM in the southern United States are the group most affected by HIV, but only a small percentage of CDC tests in the southern United States are provided to this group. Increasing awareness of HIV status through HIV testing, especially among black MSM in the southern United States, is essential for reducing the risk for transmission and addressing disparities. HIV testing programs in the southern United States can reach more black MSM by conducting targeted risk-based testing in non-health care settings and by routine screening in agencies that also provide health care services to black MSM. PMID- 30024866 TI - Identification of Primary Congenital Hypothyroidism Based on Two Newborn Screens Utah, 2010-2016. AB - Newborn screening for primary congenital hypothyroidism is part of the U.S. Recommended Uniform Screening Panel (1,2). Untreated congenital hypothyroidism can result in cognitive impairment and growth complications (decreased height/length). Initial newborn screening for congenital hypothyroidism is typically performed 24-48 hours after birth. Fourteen states, including Utah, perform a routine second screen at approximately 2 weeks of age.* During 2010 2016, a total of 359,432 infants in Utah were screened for congenital hypothyroidism, and 130 cases were diagnosed; among these, 98 had an abnormal first screen, and 25 had an abnormal second screen (seven infants were excluded because of missing data). A retrospective examination of Utah's screening data indicated that 20% of congenital hypothyroidism cases could not have been efficiently identified by a single screen alone. This study highlights the utility of a two-screen process and demonstrates that differential cutoff values for the first and second screens could optimize both screening sensitivity and specificity. PMID- 30024867 TI - Notes from the Field: Occupational Carbon Monoxide Exposure in an Industrial Kitchen Facility - Wisconsin, 2017. PMID- 30024868 TI - Notes from the Field: Widespread Transmission of Circulating Vaccine-Derived Poliovirus Identified by Environmental Surveillance and Immunization Response - Horn of Africa, 2017-2018. PMID- 30024869 TI - QuickStats: Percentage* of Residential Care Community Residents with an Advance Directive,? by Census DivisionS - National Study of Long-Term Care Providers, 2016. PMID- 30024870 TI - Binary addition in a living cell based on riboregulation. AB - Synthetic biology aims at (re-)programming living cells like computers to perform new functions for a variety of applications. Initial work rested on transcription factors, but regulatory RNAs have recently gained much attention due to their high programmability. However, functional circuits mainly implemented with regulatory RNAs are quite limited. Here, we report the engineering of a fundamental arithmetic logic unit based on de novo riboregulation to sum two bits of information encoded in molecular concentrations. Our designer circuit robustly performs the intended computation in a living cell encoding the result as fluorescence amplitudes. The whole system exploits post-transcriptional control to switch on tightly silenced genes with small RNAs, together with allosteric transcription factors to sense the molecular signals. This important result demonstrates that regulatory RNAs can be key players in synthetic biology, and it paves the way for engineering more complex RNA-based biocomputers using this designer circuit as a building block. PMID- 30024871 TI - Global "worming": Climate change and its projected general impact on human helminth infections. PMID- 30024872 TI - Hair cell identity establishes labeled lines of directional mechanosensation. AB - Directional mechanoreception by hair cells is transmitted to the brain via afferent neurons to enable postural control and rheotaxis. Neuronal tuning to individual directions of mechanical flow occurs when each peripheral axon selectively synapses with multiple hair cells of identical planar polarization. How such mechanosensory labeled lines are established and maintained remains unsolved. Here, we use the zebrafish lateral line to reveal that asymmetric activity of the transcription factor Emx2 diversifies hair cell identity to instruct polarity-selective synaptogenesis. Unexpectedly, presynaptic scaffolds and coherent hair cell orientation are dispensable for synaptic selectivity, indicating that epithelial planar polarity and synaptic partner matching are separable. Moreover, regenerating axons recapitulate synapses with hair cells according to Emx2 expression but not global orientation. Our results identify a simple cellular algorithm that solves the selectivity task even in the presence of noise generated by the frequent receptor cell turnover. They also suggest that coupling connectivity patterns to cellular identity rather than polarity relaxes developmental and evolutionary constraints to innervation of organs with differing orientation. PMID- 30024873 TI - Patterns and predictors of off-label prescription of psychiatric drugs. AB - Off-label prescribing of psychiatric drugs is common, despite lacking strong scientific evidence of efficacy and potentially increasing risk for adverse events. The goal of this study was to characterize prevalence of off-label prescriptions of psychiatric drugs and examine patient and clinician predictors of off-label use. This manuscript presents a retrospective, cross-sectional study using data from the 2012 and 2013 National Ambulatory Medical Care Surveys (NAMCS). The study examined all adult outpatient visits to psychiatric practices for chronic care management with a single listed visit diagnosis in which at least one psychiatric drug was prescribed. The main outcome measure was off-label prescribing of at least one psychiatric drug, defined as prescription for a condition for which it has not been approved for use by the FDA. Among our sample representative of 1.85 billion outpatient visits, 18.5 million (1.3%) visits were to psychiatrists for chronic care management in which at least one psychiatric drug was prescribed. Overall, the rate of off-label use was 12.9% (95% CI: 12.2 15.7). The most common off-label uses were for manic-depressive psychosis treated with citalopram and primary insomnia treated with trazodone. Several patient and clinician characteristics were positively associated with off-label prescribing, including seeing a psychiatrist (OR: 1.06, 95% CI, 1.01-1.12; p = 0.03) instead of another type of clinician, the office visit taking place in the Western region of the country (OR: 1.09, 95% CI, 1.01-1.17; p = 0.02), and the patient having 3 or more chronic conditions (OR: 1.12, 95% CI, 1.02-1.14; p = 0.003). In contrast, having Medicare coverage (OR: 0.93, 95% CI, 0.84-0.97; p = 0.04) and receiving payment assistance from a medical charity (OR: 0.91, 95% CI, 0.88-0.96; p = 0.03) instead of private insurance were negatively associated with off-label prescribing. These results suggest that certain classes of psychiatric medications are being commonly prescribed to treat conditions for which they have not been determined by the FDA to be clinically efficacious and/or safe. PMID- 30024874 TI - Patient and health worker experiences of differentiated models of care for stable HIV patients in Malawi: A qualitative study. AB - INTRODUCTION: Several models of differentiated care for stable HIV patients on antiretroviral therapy (ART) in Malawi have been introduced to ensure that care is efficient and patient-centered. Three models have been prioritized by the government for a deeper and broader understanding: adjusted appointment spacing through multi-month scripting (MMS); fast-track drug refills (FTRs) on alternating visits; and community ART groups (CAGs) where rotating group members collect medications at the facility for all members. This qualitative study aimed to understand the challenges and successes of implementing these models of care and of the process of patient differentiation. METHODS: A qualitative study was conducted as a part of a broader process evaluation in 30 purposefully selected ART facilities between February and May 2016. Semi-structured, in-depth interviews with 32 health workers that managed and coordinated ART clinics and 30 focus groups were held with 216 ART patients. Interviews and focus groups were audio recorded, transcribed, and coded thematically. RESULTS: Participants reported that the models of differentiated care have yielded key benefits, including: reduced patients' travel and visit time, decongestion of facilities, and enhanced social support. Participants suggested that these benefits could lead to improved HIV treatment outcomes for patients. At the same time, some challenges were reported, such as inconsistent stocks of drugs, which can inhibit implementation of MMS. For CAGs, the group-based nature of the model presented some unique problems, such as conflicts within groups or concerns about privacy. Health workers also described some of the reasons why eligible patients may not receive the models or conversely why ineligible patients sometimes get the models. CONCLUSIONS: Documenting patient and health worker perspectives on models of differentiated care is critical to understanding and improving these models. While these models can offer important benefits, the models may not be appropriate for all sites or patients, and patient status and needs may change over time. Key challenges should be recognized and addressed for optimal utilization of the models. PMID- 30024876 TI - Factorial validity and invariance of the Patient Health Questionnaire (PHQ)-9 among clinical and non-clinical populations. AB - The Patient Health Questionnaire-9 (PHQ-9) is commonly used to screen for depressive disorder and for monitoring depressive symptoms. However, there are mixed findings regarding its factor structure (i.e., whether it has a unidimensional, two-dimensional, or bi-factor structure). Furthermore, its measurement invariance between non-clinical and clinical populations and that between patients with major depressive disorder (MDD) and MDD with comorbid anxiety disorder (AD) is unknown. Japanese adults with MDD (n = 406), MDD with AD (n = 636), and no psychiatric disorders (non-clinical population; n = 1,163) answered this questionnaire on the Internet. Confirmatory factor analyses showed that the bi-factor model had a better fit than the unidimensional and two dimensional factor models did. The results of a multi-group confirmatory factor analysis indicated scalar invariance between the non-clinical and only MDD groups, and that between the only MDD and MDD with AD groups. In conclusion, the bi-factor model with two specific factors was supported among the non-clinical, only MDD, and MDD with AD groups. The scalar measurement invariance model was supported between the groups, which indicated the total or sub-scale scores were comparable between groups. PMID- 30024875 TI - Epidemiology and morbidity of hookworm-related cutaneous larva migrans (HrCLM): Results of a cohort study over a period of six months in a resource-poor community in Manaus, Brazil. AB - BACKGROUND: Hookworm-related cutaneous larva migrans (HrCLM) is a neglected parasitic skin disease, widespread in resource-poor communities in tropical and subtropical countries. Incidence and risk factors have never been investigated in a cohort study. METHODOLOGY/PRINCIPAL FINDINGS: To understand the seasonal epidemiology of HrCLM, an open cohort of 476 children in a resource-poor community in Manaus, Brazil was examined for HrCLM monthly over a period of 6 months. Monthly prevalence and intensity of infection were correlated with the amount of monthly precipitation. Multivariable Cox regression analysis indicated male sex (hazard ratio [HR] 3.29; 95% confidence interval [CI] 1.95-5.56), walking barefoot on sandy ground (HR 2.30; 95% CI 1.03-5.16), poverty (HR 2.13; 95% CI 1.09-4.17) and age between 10 and 14 years (HR 1.87; 95% CI 1.01-3.46) as predictors of HrCLM. Monthly incidence rates ranged between 0.21 and 1.05 cases per person-year with an overall incidence of 0.52 per person-year. CONCLUSIONS/SIGNIFICANCE: HrCLM is a frequent parasitic skin disease in this resource-poor community. Every second child theoretically becomes infected during one year. Boys, 10 to 14 years old, belonging to the poorest households of the community, are the most vulnerable population group. Even in the tropical monsoonal climate of Amazonia there is a considerable seasonal variation with monthly incidence and number of lesions peaking in the rainy season. PMID- 30024877 TI - Stabilization benefits of single and multi-layer self-nanoemulsifying pellets: A poorly-water soluble model drug with hydrolytic susceptibility. AB - Solidified self-nanoemulsifying drug delivery systems (SNEDDS) offer strong option to enhance both drug aqueous solubility and stability. The current study was designed to evaluate the potential stabilization benefits of solidifying cinnarizine (CN) liquid SNEDDS into single and multi-layer self-nanoemulsifying pellets (SL-SNEP and ML-SNEP, respectively). The selected formulations were enrolled into accelerated, intermediate and long-term stability studies. The chemical stability was assessed based on the % of intact CN remaining in formulation. The physical stability was assessed by monitoring the in-vitro dissolution and physical appearance of the formulations. The degradation pathway of CN within lipid-based formulation was proposed to involve a hydroxylation reaction of CN molecule. The chemical stability study revealed significant CN degradation in liquid SNEDDS, SL-SNEP and ML-SNEP (lacking moisture-sealing) within all the storage conditions. In contrast, the moisture sealed ML-SNEP showed significant enhancement of CN chemical stability within the formulation. In particular, ML-SNEP coated with Kollicoat Smartseal 30D showed superior CN stabilization and no significant decrease in dissolution efficiency, at all the storage conditions. The observed stability enhancement is owing to the complete isolation between CN and SNEDDS layer as well as the effective moisture protection provided by Kollicoat Smartseal 30D. Hence, the degradation problem could be eradicated completely. The incorporation of silicon dioxide had an important role in the inhibition of pellet agglomeration upon storage. Accordingly, ML-SNEP coated with Kollicoat Smartseal 30D and/or silicon dioxide could be an excellent dosage form that combine dual enhancement of CN solubilization and stabilization. PMID- 30024878 TI - A minimally invasive neurostimulation method for controlling abnormal synchronisation in the neuronal activity. AB - Many collective phenomena in Nature emerge from the -partial- synchronisation of the units comprising a system. In the case of the brain, this self-organised process allows groups of neurons to fire in highly intricate partially synchronised patterns and eventually lead to high level cognitive outputs and control over the human body. However, when the synchronisation patterns are altered and hypersynchronisation occurs, undesirable effects can occur. This is particularly striking and well documented in the case of epileptic seizures and tremors in neurodegenerative diseases such as Parkinson's disease. In this paper, we propose an innovative, minimally invasive, control method that can effectively desynchronise misfiring brain regions and thus mitigate and even eliminate the symptoms of the diseases. The control strategy, grounded in the Hamiltonian control theory, is applied to ensembles of neurons modelled via the Kuramoto or the Stuart-Landau models and allows for heterogeneous coupling among the interacting unities. The theory has been complemented with dedicated numerical simulations performed using the small-world Newman-Watts network and the random Erdos-Renyi network. Finally the method has been compared with the gold-standard Proportional-Differential Feedback control technique. Our method is shown to achieve equivalent levels of desynchronisation using lesser control strength and/or fewer controllers, being thus minimally invasive. PMID- 30024880 TI - Multiculturalism is good for flies, too. PMID- 30024879 TI - Binucleate germ cells in Caenorhabditis elegans are removed by physiological apoptosis. AB - Cell death plays a major role during C. elegans oogenesis, where over half of the oogenic germ cells die in a process termed physiological apoptosis. How germ cells are selected for physiological apoptosis, or instead become oocytes, is not understood. Most oocytes produce viable embryos when apoptosis is blocked, suggesting that physiological apoptosis does not function to cull defective germ cells. Instead, cells targeted for apoptosis may function as nurse cells; the germline is syncytial, and all germ cells appear to contribute cytoplasm to developing oocytes. C. elegans has been a leading model for the genetics and molecular biology of apoptosis and phagocytosis, but comparatively few studies have examined the cell biology of apoptotic cells. We used live imaging to identify and examine pre-apoptotic germ cells in the adult gonad. After initiating apoptosis, germ cells selectively export their mitochondria into the shared pool of syncytial cytoplasm; this transport appears to use the microtubule motor kinesin. The apoptotic cells then shrink as they expel most of their remaining cytoplasm, and close off from the syncytium. Shortly thereafter the apoptotic cells restructure their microtubule and actin cytoskeletons, possibly to maintain cell integrity; the microtubules form a novel, cortical array of stabilized microtubules, and actin and cofilin organize into giant cofilin-actin rods. We discovered that some apoptotic germ cells are binucleate; the binucleate germ cells can develop into binucleate oocytes in apoptosis-defective strains, and appear capable of producing triploid offspring. Our results suggest that the nuclear layer of the germline syncytium becomes folded during mitosis and growth, and that binucleate cells arise as the layer unfolds or everts; all of the binucleate cells are subsequently removed by apoptosis. These results show that physiological apoptosis targets at least two distinct populations of germ cells, and that the apoptosis machinery efficiently recognizes cells with two nuclei. PMID- 30024882 TI - Resistance to commonly used insecticides and phosphine fumigant in red palm weevil, Rhynchophorus ferrugineus (Olivier) in Pakistan. AB - The red palm weevil Rhynchophorus ferrugineus (Olivier) is an important pest of date palms in many regions of the world. This paper reports the first survey of insecticide resistance in field populations of R. ferrugineus in Pakistan which were collected from seven date palm growing areas across Punjab and Khyber Pakhtunkhwa (KPK) provinces, Pakistan. The resistance was assessed by the diet incorporation method against the formulated commonly used chemical insecticides profenophos, imidacloprid, chlorpyrifos, cypermethrin, deltamethrin, spinosad, lambda-cyhalothrin and a fumigant phosphine. Elevated levels of resistance were recorded for cypermethrin, deltamethrin and phosphine after a long history of insecticide use in Pakistan. Resistance Ratios (RRs) were 63- to 79-fold for phosphine, 16- to 74-fold for cypermethrin, 13- to 58-fold for deltamethrin, 2.6- to 44-fold for profenophos, 3- to 24-fold for chlorpyrifos, 2- to 12-fold for lambda-cyhalothrin and 1- to 10-fold for spinosad compared to a susceptible control line. Resistant R. ferrugineus populations were mainly found in southern Punjab and to some extent in KPK. The populations from Bahawalpur, Vehari, Layyah and Dera Ghazi Khan were most resistant to chemical insecticides, while all populations exhibited high levels of resistance to phosphine. Of the eight agents tested, lower LC50 and LC90 values were recorded for spinosad and lambda cyhalothrin. These results suggest that spinosad and lambda-cyhalothrin exhibit unique modes of action and given their better environmental profile, these two insecticides could be used in insecticide rotation or assist in phasing out the use of older insecticides. A changed pattern of both insecticides can be used sensibly be recommended without evidence of dose rates and frequencies used. PMID- 30024881 TI - Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier. AB - Classical non-homologous end joining (C-NHEJ) and homologous recombination (HR) compete to repair mammalian chromosomal double strand breaks (DSBs). However, C NHEJ has no impact on HR induced by DNA nicking enzymes. In this case, the replication fork is thought to convert the DNA nick into a one-ended DSB, which lacks a readily available partner for C-NHEJ. Whether C-NHEJ competes with HR at a non-enzymatic mammalian replication fork barrier (RFB) remains unknown. We previously showed that conservative "short tract" gene conversion (STGC) induced by a chromosomal Tus/Ter RFB is a product of bidirectional replication fork stalling. This finding raises the possibility that Tus/Ter-induced STGC proceeds via a two-ended DSB intermediate. If so, Tus/Ter-induced STGC might be subject to competition by C-NHEJ. However, in contrast to the DSB response, where genetic ablation of C-NHEJ stimulates HR, we report here that Tus/Ter-induced HR is unaffected by deletion of either of two C-NHEJ genes, Xrcc4 or Ku70. These results show that Tus/Ter-induced HR does not entail the formation of a two-ended DSB to which C-NHEJ has competitive access. We found no evidence that the alternative end-joining factor, DNA polymerase theta, competes with Tus/Ter induced HR. We used chromatin-immunoprecipitation to compare Rad51 recruitment to a Tus/Ter RFB and to a neighboring site-specific DSB. Rad51 accumulation at Tus/Ter was more intense and more sustained than at a DSB. In contrast to the DSB response, Rad51 accumulation at Tus/Ter was restricted to within a few hundred base pairs of the RFB. Taken together, these findings suggest that the major DNA structures that bind Rad51 at a Tus/Ter RFB are not conventional DSBs. We propose that Rad51 acts as an "early responder" at stalled forks, binding single stranded daughter strand gaps on the arrested lagging strand, and that Rad51-mediated fork remodeling generates HR intermediates that are incapable of Ku binding and therefore invisible to the C-NHEJ machinery. PMID- 30024884 TI - C. elegans germline cell death, live! PMID- 30024885 TI - A gesture-based design tool: Assessing 2DOF vs. 4DOF steerable instrument control. AB - Iterative prototyping is costly and time-consuming. Particularly when designing medical instruments, human factors related design choices significantly impact performance and safety. A tool is presented that allows for the evaluation of steerable instrument controls before the onset of the prototyping stage. The design tool couples gestural input to virtually simulated instrument motions using hand motion tracking. We performed a human-subject evaluation of two manual control strategies that differed in their degrees of freedom (DOF). 2DOF thumb control was compared to 4DOF thumb-index finger control. Results identified regions within the instrument workspace that are difficult to reach and showed participants to favor using the thumb for gross and fine-tuning motions at both control strategies. Index finger ab/adduction was found to be least functional. A strong learning effect was observed at 4DOF control. Based on the results, gesture-based instrument design is a viable design tool. PMID- 30024883 TI - Drosophila species learn dialects through communal living. AB - Many species are able to share information about their environment by communicating through auditory, visual, and olfactory cues. In Drosophila melanogaster, exposure to parasitoid wasps leads to a decline in egg laying, and exposed females communicate this threat to naive flies, which also depress egg laying. We find that species across the genus Drosophila respond to wasps by egg laying reduction, activate cleaved caspase in oocytes, and communicate the presence of wasps to naive individuals. Communication within a species and between closely related species is efficient, while more distantly related species exhibit partial communication. Remarkably, partial communication between some species is enhanced after a cohabitation period that requires exchange of visual and olfactory signals. This interspecies "dialect learning" requires neuronal cAMP signaling in the mushroom body, suggesting neuronal plasticity facilitates dialect learning and memory. These observations establish Drosophila as genetic models for interspecies social communication and evolution of dialects. PMID- 30024886 TI - Correction of copy number induced false positives in CRISPR screens. AB - Cell autonomous cancer dependencies are now routinely identified using CRISPR loss-of-function viability screens. However, a bias exists that makes it difficult to assess the true essentiality of genes located in amplicons, since the entire amplified region can exhibit lethal scores. These false-positive hits can either be discarded from further analysis, which in cancer models can represent a significant number of hits, or methods can be developed to rescue the true-positives within amplified regions. We propose two methods to rescue true positive hits in amplified regions by correcting for this copy number artefact. The Local Drop Out (LDO) method uses the relative lethality scores within genomic regions to assess true essentiality and does not require additional orthogonal data (e.g. copy number value). LDO is meant to be used in screens covering a dense region of the genome (e.g. a whole chromosome or the whole genome). The General Additive Model (GAM) method models the screening data as a function of the known copy number values and removes the systematic effect from the measured lethality. GAM does not require the same density as LDO, but does require prior knowledge of the copy number values. Both methods have been developed with single sample experiments in mind so that the correction can be applied even in smaller screens. Here we demonstrate the efficacy of both methods at removing the copy number effect and rescuing hits from some of the amplified regions. We estimate a 70-80% decrease of false positive hits with either method in regions of high copy number compared to no correction. PMID- 30024887 TI - Towards a science of global health delivery: A socio-anthropological framework to improve the effectiveness of neglected tropical disease interventions. AB - BACKGROUND: Over the last decade, implementation research and a science of global health delivery have emerged as important vehicles to improve the effectiveness of interventions. Efforts to control neglected tropical diseases (NTD) operate in challenging circumstances and with marginalized populations, making attention to context-specific details particularly relevant. Socio-anthropological insights have much to offer a science of NTD delivery. In this paper, an accessible and actionable framework for understanding NTD intervention effectiveness, based on socio-anthropological research, is presented and its utility for program planning and monitoring and evaluation is outlined. METHODOLOGY/PRINCIPAL FINDINGS: The framework was developed inductively by comparatively analyzing three rapid ethnographic studies undertaken in Eastern Africa (2010-2013) on three different large-scale NTD interventions: rabies elimination in Tanzania, sleeping sickness control in Uganda and the prevention of parasitic worms in Zambia. The framework includes five "intervention domains" where the effectiveness of these interventions was negotiated and determined at the local level. This involves: 1) the terrain of intervention (including seasonality and geographical variability); 2) community agency (including local knowledge, risk perceptions, behaviors, leadership and social pressure); 3) the strategies and incentives of field staff (skills, motivations, capabilities and support); 4) the socio-materiality of technology (characteristics of intervention tools and the adoption process itself); and 5) the governance of interventions (policy narratives, available expertise, bureaucracy, politics and the utilization of knowledge). The paper illustrates the importance of each of these domains by drawing on the case study research, presenting lessons learnt and practical recommendations for how such insights could improve intervention delivery. CONCLUSIONS/SIGNIFICANCE: To help close the gap between efficacy and effectiveness in NTD programs, it is important that field staff: 1) generate meaningful knowledge about contextual factors; 2) use this knowledge to tailor field strategies; and 3) create routine mechanisms to account for the dynamic process of implementation itself. The framework presented here offers a simple analytical tool to strengthen these knowledge-to action relationships existing project planning tools, drawing on the insights of socio-anthropology. PMID- 30024888 TI - High mortality due to snakebites in French Guiana: Time has come to re-evaluate medical management protocols. PMID- 30024890 TI - Delayed diagnosis and treatment of tuberculosis in HIV+ patients in Mozambique: A cost-effectiveness analysis of screening protocols based on four symptom screening, smear microscopy, urine LAM test and Xpert MTB/RIF. AB - BACKGROUND: Tuberculosis (TB) represents the ninth leading cause of death worldwide. In 2016 are estimated 1.3 million TB deaths among HIV negative people and an additional 374,000 deaths among HIV positive people. In 2016 are estimated 1.4 million new cases of TB in people living with HIV (PLHIV), 74% of whom were living in Africa. In light of these data, the reduction of mortality caused by TB in PLHIV is strongly required specially in low-income countries as Mozambique. According to international guidelines, the initial TB screening in HIV+ patients should be done with the four symptoms screening (4SS: fever, current cough, night sweats and weight loss). The diagnostic test more used in resource-limited countries is smear microscopy (SMEAR). World Health Organization (WHO) recommended Lateral Flow urine LipoArabinoMannan assay (LF-LAM) in immunocompromised patients; in 2010 WHO endorsed the use of Xpert Mycobacterium Tuberculosis/Rifampicin (MTB/RIF) test for rapid TB diagnosis but the assay is not used as screening test in all HIV+ patients irrespectively of symptoms due to cost and logistical barriers. The paper aims to evaluate the cost-effectiveness of three screening protocols: standard (4SS and SMEAR in positive patients to 4SS); MTB/RIF; LF-LAM / MTB/RIF. METHODS: We developed a model to assess the cost effectiveness of the MTB/RIF protocol versus the common standard and LF-LAM / MTB/RIF protocol. The model considered a sample of 1,000 HIV+ antiretroviral treatment naive patients in Mozambique. We evaluated disability-adjusted life year (DALY) averted for each protocol, cost per DALY, and incremental cost effectiveness ratio (ICER), over 1-year, assuming a national healthcare system perspective. The model considered the delayed diagnosis as the time elapsed between a false negative test and the diagnosis and treatment of TB. Additional health system organization delay is defined as the time interval between positive test and treatment initiation caused by a delay in the delivery of results due organization of services. We conducted a sensitivity analysis on more relevant variables. RESULTS: The MTB/RIF protocol was cost-effective as compared to the standard protocol with an ICER of $56.54 per DALY saved. In a cohort of 1,000 patients MTB/RIF and LF-LAM / MTB/RIF protocol generated 1,281 and 1,254 DALY's saved respectively, with a difference of 174 and 147 DALY respect to the standard protocol. The total cost of MTB/RIF protocol was lower ($92,263) than the standard ($147,226) and the LF-LAM / MTB/RIF ($113,196). Therefore, the cost per DALY saved including new infections due to delayed diagnosis with the standard protocol was $79.06, about 5 fold higher than MTB/RIF and LF-LAM / MTB/RIF protocols. The cost of additional TB infections due to delays in diagnosis plus health system delay seemed the more relevant costs. The low sensibility and sensitivity of the standard protocol led to a high number of false negatives, thus delayed TB diagnoses and treatment lead to the development of newly transmitted TB infections. CONCLUSIONS: Our study shows that the MTB/RIF adoption could lead to an increasing of TB case-finding and a reduction in costs compared with standard and LF-LAM / MTB/RIF protocols. PMID- 30024889 TI - Associations of artificially sweetened beverage intake with disease recurrence and mortality in stage III colon cancer: Results from CALGB 89803 (Alliance). AB - PURPOSE: Observational studies have demonstrated increased colon cancer recurrence and mortality in states of excess energy balance, as denoted by factors including sedentary lifestyle, diabetes, increased dietary glycemic load, and increased intake of sugar-sweetened beverages. Nonetheless, the relation between artificially sweetened beverages, a popular alternative for sugar sweetened beverages, and colon cancer recurrence and survival is unknown. METHODS: We analyzed data from 1,018 patients with stage III colon cancer who prospectively reported dietary intake during and after chemotherapy while enrolled in a National Cancer Institute-sponsored trial of adjuvant chemotherapy. Using Cox proportional hazards regressions, we assessed associations of artificially sweetened beverage intake with cancer recurrence and mortality. RESULTS: Patients consuming one or more 12-ounce servings of artificially sweetened beverages per day experienced an adjusted hazard ratio for cancer recurrence or mortality of 0.54 (95% confidence interval, 0.36 to 0.80) when compared to those who largely abstained (Ptrend = .004). Similarly, increasing artificially sweetened beverage intake was also associated with a significant improvement in both recurrence-free survival (Ptrend = .005) and overall survival (Ptrend = .02). Substitution models demonstrated that replacing a 12-ounce serving of a sugar-sweetened beverage with an isovolumetric serving of an artificially sweetened beverage per day was associated with a 23% lower risk of cancer recurrence and mortality (relative risk, 0.77; 95% confidence interval, 0.63 to 0.95; P = .02). CONCLUSION: Higher artificially sweetened beverage consumption may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer. This association may be mediated by substitution for sugar-sweetened alternatives. Further studies are needed to confirm these findings. PMID- 30024891 TI - Genistein induces macrophage polarization and systemic cytokine to ameliorate experimental colitis. AB - Mucosal changes in Crohn's disease (CD) and ulcerative colitis (UC), two major forms of inflammatory bowel disease (IBD), are characterized by a prominent infiltration of inflammatory cells including lymphocytes, macrophages, T cells and neutrophils. The precise etiology of IBD is unknown but it involves a complex interplay of factors associated with the immune system, environment, host genotype and enteric commensal bacteria. As there is no known safe cure for IBD, natural alternative therapeutic options without side effects are urgently needed. To this end, Soy-based foods, which have been eaten for centuries in Asian countries, have potential benefits, including lowering the incidence of coronary heart disease, atherosclerosis, type-2 diabetes, allergic response, and autoimmune diseases. This study describes the effect of Soy isoflavons 4', 5, 7 Trihydroxyisoflavone (genistein) on dextran sodium sulphate (DSS) induced experimental colitis. The extent and severity of disease was analyzed through body weight, histopathological analysis, cellular immune response, systemic cytokine levels, and inflammation score using a disease activity index. Genistein treatment significantly attenuated DSS-induced colitis severity and resulted in increase in body weight, colon length and reduction in inflammation score. Genistein also skews M1 macrophages towards the M2 phenotype. Further, gen also reduced the systemic cytokine levels as compared to vehicle control. This serves as the first detailed study towards natural soya based product that shows the polarization of M1 towards M2 macrophages, and reduction of systemic cytokine in part to attenuate the colitis symptoms. Thus, our work demonstrates that genistein, a soya compound, may be useful for the treatment of IBD. PMID- 30024892 TI - Numerical simulation of unsteady aerodynamic interactions of contra-rotating axial fan. AB - This paper describes the investigations performed to better understand unsteady effect that develop in a contra-rotating axial fan. More specifically, this study focuses on rotor-rotor interactions effects on unsteady characteristic and blade aerodynamic force. The investigation method is based on three-dimensional URANS simulations, in conjunction with SST turbulence model. At first, the experimental measurements are compared to evaluate ability of the numerical method in estimation of unsteady flows. The results show that rotor-rotor interaction in the contra-rotating fan played an important role in aerodynamic efficiency. Unsteady effect increased flow losses of rotor 1, but effectively inhibited flow losses of rotor 2. The inhibition effect was mainly caused by wake recovery effect of upstream wakes in the flow passage of rotor 2. Meanwhile, negative jet flow enhanced boundary layer energy of the blade of rotor 2, so that flow separation was postponed. Different configurations consider five sets of axial spacing dimensions. Specific survey of flows under the same operation conditions indicates that axial spacing is responsible for the unsteady interaction effect. The blade aerodynamics analysis shows that the influence of the downstream potential flow disturbance on rotor 1 is greater than the effect of the upstream wake on rotor 2. PMID- 30024893 TI - High-impact and transformative science (HITS) metrics: Definition, exemplification, and comparison. AB - Countries, research institutions, and scholars are interested in identifying and promoting high-impact and transformative scientific research. This paper presents a novel set of text- and citation-based metrics that can be used to identify high impact and transformative works. The 11 metrics can be grouped into seven types: Radical-Generative, Radical-Destructive, Risky, Multidisciplinary, Wide Impact, Growing Impact, and Impact (overall). The metrics are exemplified, validated, and compared using a set of 10,778,696 MEDLINE articles matched to the Science Citation Index ExpandedTM. Articles are grouped into six 5-year periods (spanning 1983-2012) using publication year and into 6,159 fields constructed using comparable MeSH terms, with which each article is tagged. The analysis is conducted at the level of a field-period pair, of which 15,051 have articles and are used in this study. A factor analysis shows that transformativeness and impact are positively related (rho = .402), but represent distinct phenomena. Looking at the subcomponents of transformativeness, there is no evidence that transformative work is adopted slowly or that the generation of important new concepts coincides with the obsolescence of existing concepts. We also find that the generation of important new concepts and highly cited work is more risky. Finally, supporting the validity of our metrics, we show that work that draws on a wider range of research fields is used more widely. PMID- 30024894 TI - Deterring delinquents with information. Evidence from a randomized poster campaign in Bogota. AB - In this article, we test whether an isolated information campaign can deter criminals by appealing to their apprehension risk perception. A randomized trial was conducted around 154 high crime housing blocks in Bogota. With support of the Colombian Police, half of the blocks were exposed to a three month poster campaign reporting the number of "arrests around this street block" and half to a no-treatment control condition. The main outcome measure (total registered crime) and secondary outcome measures (calls to the emergency line for thefts and attacks, and minor wrongdoings) were provided by the Police. Additionally, trust in police, security perception, and police performance perception were measured among residents and workers in the treatment and control areas (N = 616) using a post-treatment survey. Measures were analyzed with linear regression analysis and two-sample t-tests. Over the course of the treatment period, premeditated crime was reduced, while spontaneous crime remained unchanged. Overall levels of crime were not significantly altered. Also, a moderate crime reduction is detectable during the first month of the treatment period. The posters were highly visible (93% of respondents in the treated areas recalled them) and positively received (67% "liked" them). Perceptions of security and police among locals improved, though not significantly. Inherent among residents of Bogota is a pervasive feeling of impunity and low trust in authorities, making the city a hard test case for an offender-targeted advertising campaign. Initial reductions of crime and overall reductions of premeditated crime are thus noteworthy. These results align with key principles of apprehension risk updating theory. PMID- 30024895 TI - Regulation of locomotor pointing across the lifespan: Investigating age-related influences on perceptual-motor coupling. AB - INTRODUCTION: The regulation of one's step length by placing one's foot at a specific position within gait, otherwise known as 'locomotor pointing', is well understood in walking and running gait. The current study was the first to broaden this understanding to a larger cohort and to describe the influence of age on the regulation of locomotor pointing when walking up to and stepping onto a curb-like platform. METHODS: Younger (n = 17, mean age: 25.35 years, range: 19 33) and older adults (n = 105, mean age: 71.49 years, range: 61-86) participated in a walking experiment, requiring them to approach and step onto a curb-like platform. Linear mixed effects modeling was used to study the main outcome variables: onset of regulation, the regulation strategy and the strength of perceptual-motor coupling. RESULTS: Results showed that with older age, participants showed less variability in foot placement during their approach and seemed to prefer to shorten their steps. Furthermore, the strength of the perceptual-motor relationship was found to be related to age; regulation of step length of both younger and older participants was based on a participant's current foot position. The strength of this relationship increased as participants got closer to the curb and was stronger with increasing age. Furthermore, younger adults on average lengthened their steps as they got closer to the curb, whereas older adults showed significantly less lengthening compared to their younger counterparts. No age-related differences were found in terms of onset of regulation. DISCUSSION: The results suggest that the strength of the perceptual-motor relationship in gait is related to age. It is argued that this age-related increase in the strength of perceptual-motor coupling is required to cope with increasing demands linked to the age-related declines of action capabilities. The implications of the findings are discussed in the context of increased falls risks and deficits in perceptual-motor functioning. PMID- 30024896 TI - Performance profiles of professional female tennis players in grand slams. AB - INTRODUCTION: The aim of the study was to (i) analyze the match performance of professional female tennis players in different Grand Slams; (ii) model the relationships between match performance variables and relative quality; and (iii) build typical performance profiles for those players in Grand Slams. METHOD: Data of a total of 1369 matches were collected within 2014-2017 four Grand Slams (Australian Open: n = 499; Roland Garros: n = 249; Wimbledon: n = 249 and US Open, n = 372). Correlations between 37 performance variables and relative quality (difference of expected rounds between two competing players of given ranking) were determined and automatically classified into two groups of magnitudes via two-step cluster analysis. Higher-correlated variables were used to build players' typical performance profiles via regression-based technique to give percentage evaluation scores (%ES), which means the percentage of matches where a performance variable value would be expected to be lower than the observed value considering the RQ of two competing players. RESULTS: Players had more service winners, double faults, return winners and return unforced errors in the Australian Open and US Open, implying a "fast-fast" serve strategy, and higher dominance ratio and better serving performance in Wimbledon. While receiving players had better chances to break opponents' service game in Roland Garros. Distance covered became similar in all Grand Slams. All studied variables showed obvious correlation with RQ expect for those of physical performance. CONCLUSIONS: The findings (i) indicate that female game in Grand Slams remained to be a contest over baseline, although players had good efficiency at net; (ii) demonstrate the influence of relative quality on serve and return, break point, net point and efficiency performance; and (iii) evidence the usefulness of applying %ES to evaluate performance of individual player. PMID- 30024897 TI - Microsatellite polymorphism in the Heme oxygenase-1 gene promoter is associated with dermal collagen density in Japanese obese male subjects. AB - We previously reported elevated oxidative stress-related mechanical vulnerabilities of the skin as sparse distributions of hyperechoic areas. Although this helped establish a personalized skin care system to prevent skin disorders related to mechanical stress, obesity-related skin vulnerability involves individual differences. Here, we hypothesized that individual differences are caused by polymorphisms of GT repetitive sequences in the heme oxygenase1 (HMOX1) promoter region, which encodes an antioxidant enzyme. This cross-sectional study enrolled healthy male volunteers in a walking classroom aimed at weight control. Subjects with a body mass index <25 kg/m2 were classified as non-obese and those with body mass index >=25 kg/m2 were classified as obese. Subject skin was categorized into sparse dermis or normal groups according to the distribution of hyperechoic areas by high-resolution skin ultrasonography (20 MHz). Genomic DNA and mRNA extracted from three body hairs with attached follicle cells were used to analyze GT repetitive sequences of the HMOX1 promoter, HMOX1 mRNA expression levels, and oxidative stress levels (8 hydroxy-2'-deoxyguanosine). Classifications of GT repetitive sequence of HMOX1 promoter were Short (<27 times) and Long (>=27 times). Higher numbers of subjects with sparse dermis were in the obese group compared with the non-obese group. In obese subjects, the number of subjects that had the Long allele of the HMOX1 promoter with sparse dermis was significantly higher compared with the normal group, whereas no association was observed between the polymorphism and ultrasonographic features in non-obese subjects. Thus, HMOX1 polymorphisms detected a risk of low collagen density in Japanese obese male subjects. PMID- 30024898 TI - Using animated vehicles with real emotional faces to improve emotion recognition in Chinese children with autism spectrum disorder. AB - The objective of the present study was to conduct an intervention study which aimed to improve emotion recognition for Chinese children with ASD by using animated vehicles with real emotional faces. A total of 21 children participated in the current study; participants consisted of 14 children (2 girls) with a formal diagnosis of ASD and 7 typically developing children. Participants were measured on emotional vocabulary and situation-facial expression matching before and after the intervention. Results indicated that the intervention significantly improved ASD children's emotion recognition compared to their pre-intervention scores. Our findings suggest that this emotional recognition intervention using animated vehicles (i.e. The Transporters) is an effective early intervention for Chinese children with ASD. PMID- 30024899 TI - Impact of congenital cytomegalovirus infection on transcriptomes from archived dried blood spots in relation to long-term clinical outcome. AB - Congenital Cytomegalovirus infection (cCMV) is the leading infection in determining permanent long-term impairments (LTI), and its pathogenesis is largely unknown due to the complex interplay between viral, maternal, placental, and child factors. The cellular activity, considered to be the result of the response to exogenous and endogenous factors, is captured by the determination of gene expression profiles. In this study, we determined whole blood transcriptomes in relation to cCMV, CMV viral load and LTI development at 6 years of age by using RNA isolated from neonatal dried blood spots (DBS) stored at room temperature for 8 years. As DBS were assumed to mainly reflect the neonatal immune system, particular attention was given to the immune pathways using the global test. Additionally, differential expression of individual genes was performed using the voom/limma function packages. We demonstrated feasibility of RNA sequencing from archived neonatal DBS of children with cCMV, and non-infected controls, in relation to LTI and CMV viral load. Despite the lack of statistical power to detect individual genes differences, pathway analysis suggested the involvement of innate immune response with higher CMV viral loads, and of anti inflammatory markers in infected children that did not develop LTI. Finally, the T cell exhaustion observed in infected neonates, in particular with higher viral load, did not correlate with LTI, therefore other mechanisms are likely to be involved in the long-term immune dysfunction. Despite these data demonstrate limitation in determining prognostic markers for LTI by means of transcriptome analysis, this exploratory study represents a first step in unraveling the pathogenesis of cCMV, and the aforementioned pathways certainly merit further evaluation. PMID- 30024900 TI - Missing single nucleotide polymorphisms in Genetic Risk Scores: A simulation study. AB - Using a genetic risk score (GRS) to predict a phenotype in a target sample can be complicated by missing data on the single nucleotide polymorphisms (SNPs) that comprise the GRS. This is usually addressed by imputation, omission of the SNPs or by replacing the missing SNPs with proxy SNPs. To assess the impact of the omission and proxy approaches on effect size estimation and predictive ability of weighted and unweighted GRS with small numbers of SNPs, we simulated a dichotomous phenotype conditional on real genotype data. We considered scenarios in which the proportion of missing SNPs ranged from 20-70%. We assessed the impact of omitting or replacing missing SNPs on the association between the GRS and phenotype, the corresponding statistical power and the area under the receiver operating curve. Omission resulted in a larger bias towards the null value of the effect size, a smaller predictive ability and greater loss of statistical power than proxy approaches. The predictive ability of a weighted GRS that includes SNPs with large weights depends of the availability of these large weight SNPs. PMID- 30024902 TI - A systematic review of mental health care workers' constructions about culturally and linguistically diverse people. AB - A systematic review of research published in English was conducted across seven electronic databases in psychology, health and social sciences. The aim was to ascertain the nature of mental health care workers' constructions about culturally and linguistically diverse individuals in order to facilitate provision of culturally appropriate service delivery and multicultural training. The constructs and perspectives of 5,870 mental health workers with regards to minority populations are represented across the 38 studies included. Key themes comprised: Aetiology of Constructions; Content of Constructions, Factors that Influence Constructions; Implications for Cultural Competence, Implications for the Therapeutic Alliance, Recommendations for Training, Recommendations for Practice and Recommendations for Research. The therapeutic alliance was most at risk when practitioners displayed low levels of cultural competency and high levels of racial and ethnic blindness. The changing and increasingly multicultural context within most countries means that mental health systems and workers need to prepare for an increasing range of culturally and linguistically diverse clients in need of support. Recommendations are explored for training, practice and research. PMID- 30024901 TI - High rates of posttraumatic stress symptoms in women living with HIV in Canada. AB - PURPOSE: Women living with HIV experience high levels of trauma exposure before and after diagnosis. One of the most challenging outcomes following trauma exposure is posttraumatic stress disorder. Despite high exposure to traumatic events, the presence and contributors to posttraumatic stress disorder symptoms have not been examined in women living with HIV in Canada. METHODS: The current study examines the presence of, contributors to, and geographical regions associated with self-reported posttraumatic stress symptoms (PTSS) among 1405 women enrolled in the Canadian HIV Women's Sexual & Reproductive Health Cohort Study (CHIWOS). RESULTS: Separate linear regression models were run for the three provinces in the cohort: British Columbia, Ontario and Quebec. Scores consistent with posttraumatic stress disorder were reported by 55.9%, 39.1% and 54.1% of the participants in each province, respectively (F(2, 1402) = 13.53, p < .001). CONCLUSIONS: The results demonstrate that women living with HIV have high rates of PTSS, and that rates and variables associated with these symptoms vary by province. These results suggest the need for trauma-informed practices and care for women living with HIV in Canada, which may need to be tailored for the community and identities of the women. PMID- 30024903 TI - To switch or not to switch: Intentions to switch to injectable PrEP among gay and bisexual men with at least twelve months oral PrEP experience. AB - BACKGROUND: Phase III trials of long-acting injectable (LAI) PrEP, currently underway, have great potential for expanding the menu of HIV prevention options. Imagining a future in which multiple PrEP modalities are available to potential users of biomedical HIV prevention, we investigated which factors might help direct a patient-physician shared-decision making process to optimize the choice of biomedical HIV prevention method. METHODS: Participants (n = 105; ages 19-63; 46.7% men of color) were former participants in a PrEP demonstration project and had taken daily oral PrEP for >= 12 months. Participants were given information about LAI PrEP and asked whether they would be interested in switching from oral to LAI PrEP. Participants were also asked about specific pros/cons of LAI PrEP, PrEP attitudes and experiences, and personality factors. RESULTS: Two-thirds (66.7%) of current oral PrEP users would switch to LAI PrEP. Intention to switch was associated with product-level and psychosocial factors. Attitudes towards logistical factors (i.e. getting to regular clinic visits for recurring shots) featured more prominently than factors related to the physical experience of PrEP modality (i.e., concerns about injection pain) as motivators for switching. In a multivariate regression model, psychosocial factors including the emotional burden of daily pill taking, deriving a sense of responsibility from PrEP use, and self-identifying as an early adopter, were the strongest predictors of switching. CONCLUSIONS: These data underscore the importance of attending not only to product-level factors, but also to the logistical and psychological experience of prevention methods for users. Findings have significant implications for the development of patient education materials and patient provider shared decision aids. PMID- 30024904 TI - Reducing residential mortgage default: Should policy act before or after home purchases? AB - We examine two possible approaches to reducing residential mortgage default using a dynamic model of heterogeneous infinitely-lived agents acting optimally subject to uninsurable idiosyncratic earnings shocks and systemic house price shocks. We find higher down payments are very effective in minimizing residential mortgage foreclosures, even in periods of house price declines and recessions. In contrast, the length of the credit exclusionary period for people who experience bankruptcy or foreclosure has a much smaller impact on mortgage defaults. Thus, it is much more effective to prevent mortgage default before the mortgage closes than to pressure homeowners not to default once they are in financial trouble. This also suggests a major aspect of credit scores and credit policy is non productive and punitive, harming people in return for little societal gain. PMID- 30024905 TI - Inferotemporal cortex multiplexes behaviorally-relevant target match signals and visual representations in a manner that minimizes their interference. AB - Finding a sought visual target object requires combining visual information about a scene with a remembered representation of the target to create a "target match" signal that indicates when a target is in view. Target match signals have been reported to exist within high-level visual brain areas including inferotemporal cortex (IT), where they are mixed with representations of image and object identity. However, these signals are not well understood, particularly in the context of the real-world challenge that the objects we search for typically appear at different positions, sizes, and within different background contexts. To investigate these signals, we recorded neural responses in IT as two rhesus monkeys performed a delayed-match-to-sample object search task in which target objects could appear at a variety of identity-preserving transformations. Consistent with the existence of behaviorally-relevant target match signals in IT, we found that IT contained a linearly separable target match representation that reflected behavioral confusions on trials in which the monkeys made errors. Additionally, target match signals were highly distributed across the IT population, and while a small fraction of units reflected target match signals as target match suppression, most units reflected target match signals as target match enhancement. Finally, we found that the potentially detrimental impact of target match signals on visual representations was mitigated by target match modulation that was approximately (albeit imperfectly) multiplicative. Together, these results support the existence of a robust, behaviorally-relevant target match representation in IT that is configured to minimally interfere with IT visual representations. PMID- 30024906 TI - Changes in breakfast frequency and composition during adolescence: The Adolescent Nutritional Assessment Longitudinal Study, a cohort from Brazil. AB - OBJECTIVES: To estimate changes over time of breakfast frequency and foods/food groups consumed at breakfast. METHODS: Cohort of 809 students aged 10-16 years old from Rio de Janeiro, Brazil, enrolled in 2010, and followed for three years. Breakfast skippers were those not eating breakfast. Those with breakfast frequency of 4 or less times per week were considered irregular breakfast eaters. Changes over time of breakfast frequency and breakfast foods/food groups were analyzed by generalized estimating equations. RESULTS: At baseline, overweight/obese girls had higher prevalence of irregular breakfast than those non-overweight/obese (40% vs. 26%; p = 0.005); among boys, there was no significant difference in the prevalence of irregular breakfast according to weight status. After three years, among girls there was an increase in the risk of irregular breakfast consumption (RR = 1.29; 95% CI: 1.08; 1.54) and breakfast skipping (RR = 1.63; 95% CI: 1.12; 2.38). Also, overweight/obese boys (RR = 1.40, 95% CI: 1.03, 1.89) and non-overweight/obese girls (RR = 1.54, 95% CI: 1.17, 2.04) had higher risk of irregular breakfast in three years, compared to baseline. After three years, boys changed the consumption of foods/food groups at breakfast and presented higher risk of decreased intake of fruits (RR = 1.60, 95% CI: 1.20, 2.13), sandwiches and snacks (RR = 1.58, 95% CI: 1.12, 2.22), chips (RR = 1.43, 95% CI: 1.01, 2.13), and ham (RR = 1.52, 95% CI: 1.12, 2.07), and lower risk of cheese intake (RR = 0.73, 95% CI: 0.53, 1.00). Girls had higher risk of decreased intake of fruits (RR = 2.08, 95% CI: 1.47, 2.95), milk (RR = 1.49, 95% CI: 1.07, 2.08), chocolate powder (RR = 1.54, 95% CI: 1.11, 2.14) and ham (RR = 1.65, 95% CI: 1.16, 2.36). CONCLUSIONS: Changes in breakfast patterns are different according to sex. Also, different changes in breakfast frequency according to BMI category were found. Consumption patterns of some foods/food groups have a tendency to become changed from initial to middle adolescence. PMID- 30024907 TI - Red blood cell aggregates and their effect on non-Newtonian blood viscosity at low hematocrit in a two-fluid low shear rate microfluidic system. AB - Red blood cells (RBCs) are the most abundant cells in human blood. Remarkably RBCs deform and bridge together to form aggregates under very low shear rates. The theory and mechanics behind aggregation are, however, not yet completely understood. The main objective of this work is to quantify and characterize RBC aggregates in order to enhance the current understanding of the non-Newtonian behaviour of blood in microcirculation. Suspensions of human blood were flowed and observed in vitro in poly-di-methyl-siloxane (PDMS) microchannels to characterize RBC aggregates. These microchannels were fabricated using standard photolithography methods. Experiments were performed using a micro particle image velocimetry (MUPIV) system for shear rate measurements, coupled with a high-speed camera for flow visualization. RBC aggregate sizes were quantified in controlled and measurable shear rate environments for 5, 10 and 15% hematocrit. Aggregate sizes were determined using image processing techniques, while apparent viscosity was measured using optical viscometry. For the samples suspended at 5% H, aggregate size was not strongly correlated with shear rate. For the 10% H suspensions, in contrast, lowering the shear rate below 10 s-1 resulted in a significant increase of RBC aggregate sizes. The viscosity was found to increase with decreasing shear rate and increasing hematocrit, exemplifying the established non-Newtonian shear-thinning behaviour of blood. Increase in aggregation size did not translate into a linear increase of the blood viscosity. Temperature was shown to affect blood viscosity as expected, however, no correlation for aggregate size with temperature was observed. Non-Newtonian parameters associated with power law and Carreau models were determined by fitting the experimental data and can be used towards the simple modeling of blood's non-Newtonian behaviour in microcirculation. This work establishes a relationship between RBC aggregate sizes and corresponding shear rates and one between RBC aggregate sizes and apparent blood viscosity at body and room temperatures, in a microfluidic environment for low hematocrit. Effects of hematocrit, shear rate, viscosity and temperature on RBC aggregate sizes have been quantified. PMID- 30024908 TI - How empowered are girls/young women in their sexual relationships? Relationship power, HIV risk, and partner violence in Kenya. AB - BACKGROUND: Gendered power dynamics within couple relationships can constrain women from achieving positive sexual and reproductive health outcomes. But little is known about relationship power among adolescents, and tools to measure it are rarely validated among adolescents. We tested the Sexual Relationship Power Scale (SRPS) among adolescent girls and young women (AGYW) and examined associations with select health outcomes. METHODS: A 16-item adaptation of the SRPS was administered to AGYW aged 15-24 in Kenya (n = 1,101). Confirmatory factor analysis (CFA) and theta coefficients assessed scale performance for three age bands: 15-17, 18-20, and 21-24 years old. Relationship power levels were examined and multivariate logistic regressions assessed the relationship between power, and partner violence and HIV risk outcomes. RESULTS: CFAs confirmed a one factor structure for each subgroup, and thetas for final 15-item scales were robust (>.82). Most respondents reported limited power in their sexual relationships, however older respondents consistently reported lower levels of power. Relationship power was strongly associated with several outcomes, even when controlling for socioeconomic status and schooling. For example, AGYW who reported more relationship power were 12, 6, and 7 times less likely (ages 21-24, 18-20, and 15-17, respectively) to experience sexual violence (p<0.001). Significant relationships were also found in multivariate analyses for physical partner violence (all three age bands), using a condom at last sex (18-20-year olds), and increased knowledge of partner's HIV status (21-24-year-olds). CONCLUSIONS: The SRPS is a good measure of relationship power for several age bands within AGYW, and power is experienced differently by older and younger AGYW. Low relationship power was a consistent predictor of partner violence, as well as an important predictor of HIV risk. Interventions seeking to address HIV and violence should also explicitly address relationship power and utilize validated tools (like the SRPS) to evaluate impacts. PMID- 30024909 TI - Yield of testing and treatment for tuberculosis among foreign-born persons during contact investigations in the United States: A semi-systematic review. AB - BACKGROUND: Contact investigation is an important strategy for maintaining control of tuberculosis (TB) in the United States. However, testing and treatment outcomes specifically to foreign-born populations are poorly understood. We reviewed literature on testing and LTBI identified during contact investigations in foreign-born populations living in the US. METHODS: We conducted a comprehensive search of peer-reviewed and grey literature using Cochrane systematic review methods. We included studies with adult and adolescent populations that were at least 50% foreign-born. Pooled proportions and 95% confidence intervals (CIs) were calculated via inverse-variance weighted meta analysis, and cumulative proportions were calculated as products of adjacent step proportions. RESULTS: We identified 22 studies published between 1997 and 2014 that included at least 50% foreign-born participants. From studies of predominantly (>90%) foreign-born populations, almost all identified contacts were recruited and had valid test results, and 54.8% (95% CI 45.1-62.5%) of contacts with valid test results tested positive. From studies of majority (50% to 90%) foreign-born populations, 78.4% (95% CI 78.0-78.9%) of identified contacts were recruited, 92.0% (95% CI 91.6-92.3%) of recruited contacts had valid test results, and 38.5% (95% CI 31.9%-44.2%) of persons with valid results tested positive. These proportions varied by test type in studies of predominantly foreign-born populations. For every 1000 contacts identified in predominantly foreign-born populations, we estimate that 535 (95% CI 438 to 625) will test positive, and 354 (95% CI 244 to 453) will complete LTBI treatment. For every 1000 contacts identified in majority foreign-born populations, these estimates are 276 (95% CI 230 to 318), and 134 (95% CI 44 to 264), respectively. CONCLUSIONS: Contact investigation is a high yield activity for identifying and treating foreign-born persons with LTBI, but must be complemented by other tuberculosis control activities in order to achieve continued progress toward TB elimination. PMID- 30024910 TI - Molecular and antigenic characterization of group C orthobunyaviruses isolated in Peru. AB - Group C orthobunyaviruses (GRCVs) are a complex of viruses in the genus Orthobunyavirus and are associated with human febrile disease in tropical and subtropical areas of South and Central America. While numerous GRCVs have been isolated from mosquitoes, animals, and humans, genetic analysis of these viruses is limited. In this study, we characterized 65 GRCV isolates from febrile patients identified through clinic-based surveillance in the northern and southern Peruvian Amazon. A 500 base pair region of the S segment and 750 base pair regions of the M and L segments were sequenced. Pairwise sequence analysis of the clinical isolates showed nucleotide identities ranging from 68% to 100% and deduced amino acid sequence identities ranging from 72% to 100%. Sequences were compared with reference strains of the following GRCVs: Caraparu virus (CARV), Murutucu virus (MURV), Oriboca virus (ORIV), Marituba virus (MTBV), Itaqui virus (ITQV), Apeu virus (APEUV), and Madrid virus (MADV). Sequence comparison of clinical isolates with the prototype strains based on the S and L segments identified two clades; clade I included isolates with high genetic association with CARV-MADV, and clade II included isolates with high genetic association with MURV, ORIV, APEUV, and MTBV. Genetic relationships based on the M segment were at time inconsistent with those based on the S and L segments. However, clade groupings based on the M segment were highly consistent with relationships based on microneutralization assays. These results advance our understanding of the genetic and serologic relationships of GRCVs circulating in the Peruvian Amazon. PMID- 30024911 TI - Diagnostic algorithm for determining primary tumor sites using peritoneal fluid. AB - This study was conducted to develop a novel algorithm for determining the origin of tumors by combining analysis of cluster patterns with immunocytochemistry (ICC) for markers in cells from fine-needle aspirates of ascites. We used LBC, based on SurePathTM (BD Diagnostics) technology, to screen 96 peritoneal fluid samples from patients with known malignancies and from 10 control patients with cirrhosis. Following dual ICC staining for cytokeratin 7 (CK7) and paired box gene 8 (PAX8), we developed an algorithm using immunoreactivity and three dimensional (3D) cluster patterns to correlate staining and 3D cluster patterns with common primary origins that included stomach, ovarian, pancreatobiliary tract, colon, lung, and breast cancers. With the application of an automatic digitalized image analyzer, competence performance was analyzed using receiver operating characteristics (ROC) curve analysis. CK7 and PAX8 staining and 3D cluster patterns were used to differentiate primary origins. Samples from patients with stomach cancer were no 3D cluster /CK7+/PAX8- with area under the curve (AUC) of 0.8699 in ROC curve analysis. Samples from ovarian cancer patients were large 3D cluster/CK7+/PAX8+ with AUC of 0.9812. Samples from pancreatobiliary tract cancer patients were small 3D cluster/CK7+/PAX8- with AUC of 0.8772. The remaining cancer samples, including breast, lung and colon cancer samples, had similar patterns of large 3D clusters/CK7+/PAX8- with AUC of 0.882, especially for lung cancer. SurePathTM technology, using 3D cluster patterns and dual ICC for CK7 and PAX8 in peritoneal fluid samples, can provide important information for determining specific primary origins in cases of unknown primary carcinoma. PMID- 30024912 TI - Differences in adiposity and diet quality among individuals with inflammatory bowel disease in Eastern Canada. AB - The objective of the current study was to characterize the relationship between diet quality and body composition in participants living with IBD, specifically Crohn's disease (CD) or ulcerative colitis (UC), in Atlantic Canada. Participants from the Atlantic Partnership for Tomorrow's Health (PATH) study are residents of one of the four Atlantic Canada provinces. Participants who completed the dietary questionnaire and had body composition measured were included in the study (n = 12,462 without IBD, n = 111 CD, n = 119 UC). A greater number of participants with IBD reported having multiple chronic conditions compared to those without IBD. Those with UC had statistically higher body weight and body mass index (BMI) compared to those without IBD. Overall, significant positive correlations were observed between adiposity and servings of refined grains, and meats and alternatives such as eggs and fish, whereas negative correlations were observed with servings of vegetables, fruit, whole grains, and alternatives such as tofu, and nuts/seeds. Participants with IBD (both CD and UC) consumed more refined grains than those without IBD. Using logistic regression analysis, participants consuming more servings of vegetables and whole grains were less likely to have CD where as those consuming more serving of fruit and bean/legumes were less likely to have UC. In the Atlantic PATH cohort, which includes a region of the world with a high incidence of IBD, distinct differences in adiposity and diet quality were observed in individuals with specific types of IBD compared to those without. There is a need for collaborative efforts to address weight management and diet quality issues in those living with IBD in the Atlantic Canadian region. PMID- 30024914 TI - Multiqubit and multilevel quantum reinforcement learning with quantum technologies. AB - We propose a protocol to perform quantum reinforcement learning with quantum technologies. At variance with recent results on quantum reinforcement learning with superconducting circuits, in our current protocol coherent feedback during the learning process is not required, enabling its implementation in a wide variety of quantum systems. We consider diverse possible scenarios for an agent, an environment, and a register that connects them, involving multiqubit and multilevel systems, as well as open-system dynamics. We finally propose possible implementations of this protocol in trapped ions and superconducting circuits. The field of quantum reinforcement learning with quantum technologies will enable enhanced quantum control, as well as more efficient machine learning calculations. PMID- 30024913 TI - Neurons in the dorsomedial medulla contribute to swallow pattern generation: Evidence of inspiratory activity during swallow. AB - Active contraction of the diaphragm and other inspiratory pump muscles during swallow create a negative thoracic pressure to improve the movement of the bolus (food/liquid) into the esophagus. We tested the hypothesis that dorsomedial medullary inspiratory neurons, including the nucleus tractus solitarius (NTS, pre motor to the phrenic) would be active during swallow induced by oral water infusion. We recorded neurons in the NTS and medial reticular formation in anesthetized spontaneously breathing cats, and induced swallow by injection of water into the oropharynx. Our results indicate that: 1) a majority of inspiratory cells in the dorsomedial medulla are active during swallow, 2) expiratory neurons are present in the medial reticular formation (deeper to the NTS) in unparalyzed cats and a majority of these cells decreased firing frequency during swallow. Our findings suggest that the dorsomedial medulla is a source of inspiratory motor drive during swallow and that a novel population of breathing modulated neurons that also are modulated during swallowing exist in the medial reticular formation in unparalyzed animals. PMID- 30024915 TI - Association of maternal uric acid and cystatin C serum concentrations with maternal and neonatal cardiovascular risk markers and neonatal body composition: The Ulm SPATZ Health Study. AB - PURPOSE: In utero exposure to cardiometabolic risk factors may determine health related outcomes at birth and in later life. The aim of this analysis was to describe the relationship of maternal serum uric acid (SUA) and cystatin C with maternal and neonatal cardiometabolic risk markers and with birth weight and risk of small-for-gestational age (SGA) as well as large-for gestational age (LGA). MATERIAL AND METHODS: In the Ulm SPATZ Health Study, 934 singleton newborns and their mothers were recruited during their hospital stay in the University Medical Center Ulm between 04/2012 and 05/2013 (overall response 49%). The association between SUA and cystatin C (both in quartiles and as continuous measures) with risk for SGA as well as with LGA was quantified by means of multivariable logistic regression. RESULTS: Overall, n = 885 mother-newborn pairs were included in the final analysis. Most of the mothers were of German nationality (85%) and were between 26 and 35 years of age at delivery (69%). Maternal SUA was associated with maternal age, body mass index, alcohol consumption and history of hypertension as well as with many other maternal and neonate cardiovascular risk markers. Cystatin C was associated with parity. No clear association of SUA with SGA and LGA was observed in fully adjusted models. However, cystatin C was negatively associated with SGA with an odds ratio (OR) of 0.35 (95% CI: 0.16 0.77; p for trend 0.04) comparing the top quartile vs. the bottom quartile and was positively associated with LGA with an OR of 5.92 (95% CI: 2.27-15.44; p for trend <0.0001) after adjustment for covariates. CONCLUSIONS: We found a positive association of cystatin C with birth weight and a clearly increased risk for LGA with maternal increased cystatin C values in a population with fairly normal renal function. PMID- 30024916 TI - Phylogeny and genetic structure in the genus Secale. AB - Secale L. is a small but important genus that includes cultivated rye. Although genetic diversity of cultivated rye is high, patterns of genetic diversity in the whole genus, and potential factors affecting the distribution of genetic diversity remain elusive. The population structure and distribution of genetic variation within Secale, and its correlation with taxonomic delimitation, cultivation status or spatial distribution in relation to geography and climate zones were analyzed in this study. A collection of 726 individual plants derived from 139 different accessions representing Secale cereale, S. vavilovii, S. strictum, and S. sylvestre were investigated using SSR analysis and sequence diversity analysis of a nuclear EST region. Our results indicated that perennial S. strictum subspecies are genetically divergent from annual forms of the genus. Existence of two distinct clusters within the annual taxa was observed, one corresponding to samples from Asia, and a second to those outside of Asia. No clear genetic structure was observed between different annual species/subspecies, indicating introgression between these taxa. The analysis of cultivated rye revealed that landrace populations from the Middle East have the highest genetic diversity, supporting the idea of the area being the center of origin for cultivated rye. Considering high adaptive potential of those populations, Middle Eastern landraces should be regarded as genetic resources reservoirs for new niches and future breeding programs. PMID- 30024918 TI - Predicting acute kidney injury in cancer patients using heterogeneous and irregular data. AB - How can we predict the occurrence of acute kidney injury (AKI) in cancer patients based on machine learning with serum creatinine data? Given irregular and heterogeneous clinical data, how can we make the most of it for accurate AKI prediction? AKI is a common and significant complication in cancer patients, and correlates with substantial morbidity and mortality. Since no effective treatment for AKI still exists, it is important to take timely preventive measures. While several approaches have been proposed for predicting AKI, their scope and applicability are limited as they either assume regular data measured over a short hospital stay, or do not fully utilize heterogeneous data. In this paper, we provide an AKI prediction model with a greater applicability, which relaxes the constraints of existing approaches, and fully utilizes irregular and heterogeneous data for learning the model. In a cohort of 21,022 cancer patients who were registered into Korea Central Cancer Registry (KCCR) in Seoul National University Hospital between January 1, 2004 and December 31, 2013, our method achieves 0.7892 precision, 0.7506 recall, and 0.7576 F-measure in predicting whether a patient will develop AKI during the next 14 days. PMID- 30024917 TI - Bacterial diversity of bat guano from Cabalyorisa Cave, Mabini, Pangasinan, Philippines: A first report on the metagenome of Philippine bat guano. AB - Bats are highly diverse and ecologically valuable mammals. They serve as host to bacteria, viruses and fungi that are either beneficial or harmful to its colony as well as to other groups of cave organisms. The bacterial diversity of two bat guano samples, C1 and C2, from Cabalyorisa Cave, Mabini, Pangasinan, Philippines were investigated using 16S rRNA gene amplicon sequencing. V3-V4 hypervariable regions were amplified and then sequenced using Illumina MiSeq 250 PE system. Reads were processed using Mothur and QIIME pipelines and assigned 12,345 OTUs for C1 and 5,408 OTUs for C2. The most dominant OTUs in C1 belong to the Proteobacteria (61.7%), Actinobacteria (19.4%), Bacteroidetes (4.2%), Firmicutes (2.7%), Chloroflexi (2.5%), candidate phylum TM7 (2.3%) and Planctomycetes (1.9%) while Proteobacteria (61.7%) and Actinobacteria (34.9%) dominated C2. Large proportion of sequence reads mainly associated with unclassified bacteria indicated possible occurrence of novel bacteria in both samples. XRF spectrophotometric analyses of C1 and C2 guano revealed significant differences in the composition of both major and trace elements. C1 guano recorded high levels of Si, Fe, Mg, Al, Mn, Ti and Cu while C2 samples registered high concentrations of Ca, P, S, Zn and Cr. Community structure of the samples were compared with other published community profiling studies from Finland (SRR868695), Meghalaya, Northeast India (SRR1793374) and Maharashtra State, India (CGS). Core microbiome among samples were determined for comparison. Variations were observed among previously studied guano samples and the Cabalyorisa Cave samples were attributed to either bat sources or age of the guano. This is the first study on bacterial diversity of guano in the Philippines through high throughput sequencing. PMID- 30024919 TI - Effects of transgenic Bacillus thuringiensis cotton on insecticide use, heliothine counts, plant damage, and cotton yield: A meta-analysis, 1996-2015. AB - The primary management tactic for lepidopteran pests of cotton in the United States of America (USA) is the use of transgenic cotton that produces Bacillus thuringiensis Berliner (Bt) toxins. The primary target pests of this technology are Helicoverpa zea (Boddie) and Heliothis virescens (F.) in the eastern and central Cotton Belt of the USA. Concerns over the evolution of resistance in H. zea to Bt toxins and scrutiny of the necessity of Bt crops has escalated. We reviewed published and unpublished data from field trials of Bt cotton in the eastern and central Cotton Belt of the USA through 2015 to evaluate the effectiveness of Bt cotton (Bollgard, Bollgard II, WideStrike, WideStrike 3, and TwinLink). Bt cotton reduced insecticide usage, reduced heliothine pest numbers and damage, and provided a yield benefit, but Bollgard II and WideStrike efficacy declined in the Midsouth over the period evaluated. In the Southeastern region, heliothine damage remained constant through 2015, but yield benefits declined from 2010 until 2015. Resistance of H. zea to several Bt toxins is the most plausible explanation for the observed changes in Bt cotton efficacy. The introduction of new Bt toxins such as found in Widestrike 3 and Twinlink may preserve the benefits of Bt crops. However, while both Widestrike 3 and Twinlink had less damage than Widestrike, damage levels of both were similar to Bollgard II. PMID- 30024920 TI - Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells. AB - Mutations in the gene Adenomatous Polyposis Coli or APC appear in most sporadic cases of colorectal cancer and it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis. The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood. This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation. We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids. In order to minimize genetic background effects, we also established an isogenic platform using TALEN-mediated gene editing. Comparison of normal and APC mutant iPSC revealed a significant defect in cell identity and polarity due to the presence of APC in heterozygosity as well as chromosomal aberrations including abnormal anaphases and centrosome numbers. Importantly, upon specification into intestinal progeny, APC heterozygosity was responsible for a major change in the transcriptional identity of the cells with dysregulation of key signaling pathways, including metabolic reprogramming, abnormal lipid metabolism and intestinal-specific cadherin expression. In conclusion, we have developed a novel iPSC/intestinal model of APC mutagenesis and provide strong evidence that APC in heterozygosity imparts a clear phenotypic and molecular defect, affecting basic cellular functions and integrity, providing novel insights in the earlier events of APC-mediated tumorigenesis. PMID- 30024921 TI - Geometric feature descriptor and dissimilarity-based registration of remotely sensed imagery. AB - Image registration of remotely sensed imagery is challenging, as complex deformations are common. Different deformations, such as affine and homogenous transformation, combined with multimodal data capturing can emerge in the data acquisition process. These effects, when combined, tend to compromise the performance of the currently available registration methods. A new image transform, known as geometric mean projection transform, is introduced in this work. As it is deformation invariant, it can be employed as a feature descriptor, whereby it analyzes the functions of all vertical and horizontal signals in local areas of the image. Moreover, an invariant feature correspondence method is proposed as a point matching algorithm, which incorporates new descriptor's dissimilarity metric. Considering the image as a signal, the proposed approach utilizes a square Eigenvector correlation (SEC) based on the Eigenvector properties. In our experiments on standard test images sourced from "Featurespace" and "IKONOS" datasets, the proposed method achieved higher average accuracy relative to that obtained from other state of the art image registration techniques. The accuracy of the proposed method was assessed using six standard evaluation metrics. Furthermore, statistical analyses, including t-test and Friedman test, demonstrate that the method developed as a part of this study is superior to the existing methods. PMID- 30024922 TI - Educational benefits for nurses and nursing students of the dementia supporter training program in Japan. AB - In Japan, which is thought to be a rapidly growing super-aging society, a national campaign named "the Dementia Supporter Caravan" has been deployed. The aim of this study was to assess the educational benefits of the dementia supporter training program for nurses and nursing students. We conducted dementia supporter training, and measured knowledge and attitudes regarding people with dementia as educational benefits pre- and post-training. Data sets of 134 nursing students and 63 nurses were analyzed. The results indicated that the two groups gained knowledge, understanding, and the confidence to care for people with dementia after attending the dementia supporter training program. Moreover, the two groups derived different benefits from the program. Nursing students gained substantial knowledge and learnt the importance of early detection and treatment, to levels similar to those of nurses prior to training. The training program reduced the difficulties of nurses to interact with and care for people with dementia. We can conclude that the dementia supporter training program has considerable educational benefits for nurses and nursing students. PMID- 30024923 TI - Cardiorespiratory effects of medetomidine and dexmedetomidine combined with tiletamine-zolazepam for the immobilization of Asiatic black bears (Ursus thibetanus) under isoflurane general anesthesia. AB - The aim of this paper was to compare the cardiorespiratory effects of the two combinations (medetomidine-tiletamine-zolazepam (MTZ) or dexmedetomidine tiletamine-zolazepam (DTZ)) used for Asiatic black bear (Ursus thibetanus) immobilization. A retrospective analysis was carried out, reviewing the anesthetic records of captive bears. Sixty-six records were reviewed. The bears were immobilized, and general anesthesia was maintained with isoflurane vaporized in 100% oxygen. The mean sedation time and score were evaluated. The cardiorespiratory parameters were recorded every 10 minutes from intubation until extubation. Mean sedation time was 26.1 +/- 14.5 minutes for the MTZ group and 25.6 +/- 19.4 minutes for the DTZ group. The heart rate and the respiratory rate were higher in the bears immobilized with DTZ (66 +/- 19 beats/min; 13 +/- 5.2 breaths/min) as compared with the bears immobilized with MTZ (57 +/- 14.5 beats/min; 10 +/- 4.7 breaths/min) whereas the mean arterial pressure did not differ significantly between the groups. The body temperature was in the normal range throughout the procedures in all bears (MTZ 36.3 +/- 0.9 degrees C; DTZ 37 +/- 1 degrees C). In conclusion, the two protocols used in this study have been proven to be safe and reliable for the immobilization of Asiatic black bears, and the DTZ combination seemed to be associated with less cardiorespiratory depression than the MTZ one. PMID- 30024924 TI - Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial. AB - The emergence of multidrug resistant-tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis strains with in vitro resistance to at least isoniazid and rifampicin, has necessitated evaluation and validation of appropriate surrogate endpoints for treatment response in drug trials for MDR-TB. The trial that has demonstrated efficacy of bedaquiline, a diarylquinoline that inhibits mycobacterial ATP synthase, possesses the requisite features to conduct this evaluation. Approval of bedaquiline for use in MDR-TB was based primarily on the results of the controlled C208 Stage II study (ClinicalTrials.gov number, NCT00449644) including 160 patients randomized 1:1 to receive bedaquiline or placebo for 24 weeks when added to an 18-24-month preferred five-drug background regimen. Since randomization in C208 Stage II was preserved until study end, the trial results allow for the investigation of the complex relationship between sustained durable outcome with either Week 8 or Week 24 culture conversion as putative surrogate endpoints. The relationship between Week 120 outcome with Week 8 or Week 24 culture conversion was investigated using a descriptive analysis and with a recently developed statistical methodology for surrogate endpoint evaluation using methods of causal inference. The results demonstrate that sputum culture conversion at 24 weeks is more reliable than sputum culture conversion at 8 weeks when assessing the outcome of adding one new drug to a MDR-TB regimen. PMID- 30024925 TI - Printable nanocomposites of polymers and silver nanoparticles for antibacterial devices produced by DoD technology. AB - Silver nanoparticles (Ag-NPs) are known for their efficient bactericidal activity and are widely used in industry. This study aims to produce printable antibacterial devices by drop-on-demand (DoD) inkjet technology, using Ag-NPs as the active part in complex printable fluids. The synthesis of this active part is described using two methods to obtain monodisperse NPs: chemical and microwave irradiation. The synthesized NPs were characterized by UV-VIS, STEM, TEM, DLS and XRD. Two printable fluids were produced based: one with Ag-NPs and a second one, a polymeric nanocomposite, using silver nanoparticles and polyvinyl butyral (Ag NPs/PVB). Cellulose acetate was used as a flexible substrate. The ecotoxicity analysis of fluids and substrate was performed with Artemia franciscana nauplii. Optimized electric pulse waveforms for drop formation of the functional fluids were obtained for the piezoelectric-based DoD printing. Activity of printed antibacterial devices was evaluated using the Kirby-Bauer method with Staphylococcus aureus and Escherichia coli. The results show that the printed device with Ag-NP fluids evidenced a bacterial inhibition. An important advantage in using the DoD process is the possibility of printing, layer by layer or side by side, more than one active principle, allowing an interleaved or simultaneous release of silver NP and other molecules of interest as for example with a second functional fluid to ensure effectiveness of Ag activity. PMID- 30024926 TI - Tyrosine 870 of TLR9 is critical for receptor maturation rather than phosphorylation-dependent ligand-induced signaling. AB - Toll like receptors (TLRs) share a conserved structure comprising the N-terminal ectodomain, a transmembrane segment and a C-terminal cytoplasmic Toll/IL-1 receptor (TIR) domain. Proper assembly of the TIR domain is crucial for signal transduction; however, the contribution of individual motifs within the TIR domain to TLR trafficking and signaling remains unclear. We targeted a highly conserved tyrosine (Y870) located in the box 1 region of the TIR domain of most TLRs, including TLR9, previously described to be a critical site of phosphorylation in TLR4. We reconstituted bone marrow-derived dendritic cells (BMDC) from Tlr9-/- mice WT TLR9 or Y870F or Y870A mutants. Despite normal interactions with the luminal chaperones GRP94 and UNC93B1, Y870F conferred only partial responsiveness to CpG, and Y870A had no activity and functioned as a dominant negative inhibitor when coexpressed with endogenous TLR9. This loss of function correlated with reduction or absence, respectively, of the 80 kDa mature form of TLR9. In Y870F-expressing cells, CpG-dependent signaling correlated directly with levels of the mature form, suggesting that signaling did not require tyrosine phosphorylation but rather that the Y870F mutation conferred reduced receptor levels due to defective processing or trafficking. Microscopy revealed targeting of the mutant protein to an autophagolysosome-like structure for likely degradation. Collectively we postulate that the conserved Y870 in the TIR domain does not participate in phosphorylation-induced signaling downstream of ligand recognition, but rather is crucial for proper TIR assembly and ER egress, resulting in maturation-specific stabilization of TLR9 within endolysosomes and subsequent pro-inflammatory signaling. PMID- 30024927 TI - CCR8 is expressed by post-positive selection CD4-lineage thymocytes but is dispensable for central tolerance induction. AB - Following positive selection, thymocytes migrate into the medulla where they encounter diverse self-antigens that induce central tolerance. Thymocytes expressing T cell receptors (TCRs) with high affinity for self-antigens displayed by medullary antigen presenting cells (APCs) undergo either negative selection or diversion to the regulatory T cell (Treg) lineage, thus ensuring maturation of non-autoreactive T cells. Because many self-antigens are expressed by only a small percentage of medullary thymic epithelial cells, thymocytes must enter the medulla and efficiently scan APCs therein to encounter the full array of self antigens that induce central tolerance. Chemokine receptors play a critical role in promoting medullary entry and rapid motility of post-positive selection thymocytes. We found that the chemokine receptor CCR8 is expressed by post positive selection CD4+ single positive (SP) thymocytes in mice, while the corresponding chemokine ligands are expressed by medullary APCs, and thus hypothesized that CCR8 would promote thymocyte medullary entry and/or rapid motility to induce negative selection. However, despite a subtle decline in thymocyte medullary accumulation and the presence of autoantibodies in aged CCR8 deficient mice, CCR8 was not required for thymocyte differentiation, rapid motility, or negative selection. PMID- 30024928 TI - Enhancement of the heat conduction performance of boron nitride/cellulosic fibre insulating composites. AB - The continuous development of high electrical equipment towards high power output requires better heat dissipation performance of internal insulation structure. It challenges the traditional paper-based insulating materials, with poor thermal conductivity. Introducing thermally conductive and electrically insulating filler into cellulose-based insulating material can enhance heat conduction performance. This work provided a method to prepare thermally conductive and electrically insulating BN/cellulosic fibre composites. And the thermal conductivity of the composites was remarkably increased via grafting APTES and adding dual-sized fillers. The thermal conductivity of the composite reached 0.682 W/(m*k) that increased by 387% with h-BN loading of 41.08 wt%. Simultaneously, BN fillers improved the insulating properties of the resultant composites. The dielectric constant, breaking strength of and volume resistivity of the composites reached 4.75, 9.2 kV/mm-1 and 4.72*1014 Omega*m, respectively. The resultant insulating material which has better heat conduction property may have a vast potential for future development in electrical equipment. PMID- 30024929 TI - Variability in the anatoxin gene clusters of Cuspidothrix issatschenkoi from Germany, New Zealand, China and Japan. AB - Anatoxin-a and homoanatoxin-a are neurotoxic cyanotoxins produced by benthic and planktonic cyanobacteria worldwide. These toxins are produced by the cyanobacterial genera Dolichospermum, Cuspidothrix, Phormidium, Oscillatoria, Tychonema and Cylindrospermum. In the present study the ana gene clusters (anaA anaG; c. 21.1 kilobases) of two anatoxin producing Cuspidothrix issatschenkoi strains from Germany: (NIVA-CYA 711) and New Zealand (CAWBG02) were sequenced and compared with the ana gene clusters of two C. issatschenkoi strains from Japan (RM-6 and LBRI48) and one from China (CHABD3). All five ana gene clusters are characterized by the same gene order for anaA-anaG. Similarities were highest (99.56-99.57%) between German (NIVA-CYA 711), New Zealand (CAWBG02) and Chinese (CHABD3) strains. Similarities were lower (91.40-91.67%) when compared to the Japanese strains (RM-6 and LBRI48). Collectively, 2,037 variable sites (328 single nucleotide polymorphisms and 9 insertions/deletions, comprising 1,709 nucleotides) were found in the ana gene clusters of the German, New Zealand and Japanese strains compared to the Chinese strain (CHABD3). The ana gene clusters of the German (NIVA-CYA 711), New Zealand (CAWBG02) and Japanese (RM-6 and LBRI48) strains were characterized by 83, 84, 255 and 231 SNP's compared to the Chinese strain (CHABD3), respectively. The anaE and anaF genes showed the highest variability in all five strains and are recommended as the best genetic markers for further phylogenetic studies of the ana gene cluster from C. issatschenkoi. PMID- 30024930 TI - Evaluation of transient respiratory motion artifact at gadoxetate disodium enhanced MRI-Influence of different contrast agent application protocols. AB - PURPOSE: To evaluate transient severe respiratory motion artifacts (TSM) at gadoxetate disodium-enhanced MRI dependent on the mode of contrast agent application. METHODS: 200 patients (71f, 129m; mean 51y) were included in this retrospective IRB-approved study. Contrast application protocols (n = 4) differed with regards to injection rate (2ml or 1ml/sec), dose (weight-based or fixed 10ml) and supplemental oxygen administration (yes/no). SNR measurements were performed in the aorta and portal vein. Qualitatively, three readers assessed arterial phase image quality and TSM independently (4- and 5-point scale, respectively). Quantitative and qualitative results were compared (Kruskal-Wallis test, Dunn's multiple comparison test). The influence of different contrast agent application parameters on the occurrence of respiratory motion artifacts was assessed (univariate analysis). Interrater agreement and reliability were calculated (intraclass correlation coefficient, ICC)). RESULTS: Use of a lower contrast injection rate resulted in significantly higher arterial SNR in the aorta and portal vein (p<0.05). TSM was observed in 12% of examinations. Neither injection rate, contrast dose, nor oxygen had a significant influence. Interrater agreement and reliability for evaluation of image quality and respiratory motion were substantial/ almost perfect (ICC = 0.640-0.915). CONCLUSIONS: Technical factors regarding the specific mode of contrast application do not seem to significantly reduce the incidence of severe transient respiratory motion artifacts. PMID- 30024932 TI - Modeling the role of microRNA-449a in the regulation of the G2/M cell cycle checkpoint in prostate LNCaP cells under ionizing radiation. AB - Recent studies showed that induced microRNA-449a (miR-449a) enhances a G2/M cell cycle checkpoint arrest in prostate cancer (LNCaP) and lung adenocarcinoma cell lines. In the case of LNCaP cells, upregulated miR-449a directly downregulates c Myc that is required to induce the cell cycle regulators Cdc25A and Cdc2/CyclinB whose inactivation blocks G2 to M phase transition. However, the molecular mechanisms involved are yet unclear, although in other prostate cancer cells the interactions among p53, miR-449a and Sirt-1 can affect the induction of the G2/M arrest. In order to clarify these molecular mechanisms, in this work we propose a boolean model of the G2/M checkpoint arrest regulation contemplating the influence of miR-449a. The model shows that the cell fate determination between two cellular phenotypes: G2/M-Arrest for DNA repair and G2/M-induced apoptosis is stochastic and influenced by miR-449a state of activation. The results were compared with experimental data available presenting agreement. We also found that several feedback loops are involved in this cell fate regulation and we indicate, through in silico gain or loss of function perturbations of genes, which of these feedback loops are more efficient to favor a specific phenotype. PMID- 30024931 TI - PNPase knockout results in mtDNA loss and an altered metabolic gene expression program. AB - Polynucleotide phosphorylase (PNPase) is an essential mitochondria-localized exoribonuclease implicated in multiple biological processes and human disorders. To reveal role(s) for PNPase in mitochondria, we established PNPase knockout (PKO) systems by first shifting culture conditions to enable cell growth with defective respiration. Interestingly, PKO established in mouse embryonic fibroblasts (MEFs) resulted in the loss of mitochondrial DNA (mtDNA). The transcriptional profile of PKO cells was similar to rho0 mtDNA deleted cells, with perturbations in cholesterol (FDR = 6.35 x 10-13), lipid (FDR = 3.21 x 10 11), and secondary alcohol (FDR = 1.04x10-12) metabolic pathway gene expression compared to wild type parental (TM6) MEFs. Transcriptome analysis indicates processes related to axonogenesis (FDR = 4.49 x 10-3), axon development (FDR = 4.74 x 10-3), and axonal guidance (FDR = 4.74 x 10-3) were overrepresented in PKO cells, consistent with previous studies detailing causative PNPase mutations in delayed myelination, hearing loss, encephalomyopathy, and chorioretinal defects in humans. Overrepresentation analysis revealed alterations in metabolic pathways in both PKO and rho0 cells. Therefore, we assessed the correlation of genes implicated in cell cycle progression and total metabolism and observed a strong positive correlation between PKO cells and rho0 MEFs compared to TM6 MEFs. We quantified the normalized biomass accumulation rate of PKO clones at 1.7% (SD +/- 2.0%) and 2.4% (SD +/- 1.6%) per hour, which was lower than TM6 cells at 3.3% (SD +/- 3.5%) per hour. Furthermore, PKO in mouse inner ear hair cells caused progressive hearing loss that parallels human familial hearing loss previously linked to mutations in PNPase. Combined, our study reports that knockout of a mitochondrial nuclease results in mtDNA loss and suggests that mtDNA maintenance could provide a unifying connection for the large number of biological activities reported for PNPase. PMID- 30024933 TI - miR-122 inhibition in a human liver organoid model leads to liver inflammation, necrosis, steatofibrosis and dysregulated insulin signaling. AB - : To investigate the role of miR-122 in the development and regression of non alcoholic fatty liver disease (NAFLD) in vitro, we used multicellular 3D human liver organoids developed in our laboratory. These organoids consist of primary human hepatocytes, Kupffer cells, quiescent stellate cells and liver sinusoidal endothelial cells. They remain viable and functional for 4 weeks expressing typical markers of liver function such as synthesis of albumin, urea, and alpha-1 p450 drug metabolism. Before mixing, hepatic cells were transduced with lentivirus to inhibit miR122 expression (ABM, CA). Immediately after the organoids were fully formed (day 4) or after 1 or 2 weeks of additional incubation (days 11 or 18), the organoids were analyzed using fluorescent live/dead staining and ATP production; total RNA was extracted for qPCR gene expression profiling. Our results show that miR-122 inhibition in liver organoids leads to inflammation, necrosis, steatosis and fibrosis. This was associated with increase in inflammatory cytokines (IL6, TNF), chemokines (CCL2, CCL3) and increase in a subset of Matrix Metaloproteinases (MMP8, MMP9). An altered expression of key genes in lipid metabolism (i.e LPL, LDLR) and insulin signaling (i.e GLUT4, IRS1) was also identified. CONCLUSION: Our results highlight the role of miR-122 inhibition in liver inflammation, steatofibrosis and dysregulation of insulin signaling. Patients with NAFLD are known to have altered levels of miR 122, therefore we suggest that miR-122 mimics could play a useful role in reversing liver steatofibrosis and insulin resistance seen in patients with NAFLD. PMID- 30024934 TI - Risk factors of vitamin D deficiency among 15-year-old adolescents participating in the Malaysian Health and Adolescents Longitudinal Research Team Study (MyHeARTs). AB - BACKGROUND: This study is to determine the prevalence and risk factors of vitamin D deficiency (vitamin D <= 50 nmol/L) among 15-year-old Malaysian adolescents. By identifying potential risk factors, prevention strategies and interventions can be carried out to improve the vitamin D status in adolescents. METHODS AND FINDINGS: Stratified random sampling design was used to select adolescents from 15 urban and rural secondary schools in Selangor, Perak and Kuala Lumpur, Malaysia. Data collection was carried out from 1st April 2014 to 30th June 2014. Information regarding socio-demographic characteristics, sun exposure and sun protective behaviours, clinical data and environmental factors were collected. Blood for total vitamin D was sampled. Descriptive and multivariate logistic regressions were performed. Total 1061 participants were analyzed (62% were female; mean age 15.1 +/- 0.4 years). The prevalence of vitamin D deficiency was 33%. Mean vitamin D was lower in female (53 +/- 15 nmol), obese (body fat percentage (>=25%m; >=33.8%f) (56 +/- 16 nmol/L), Malays (58 +/- 18 nmol/L) and Indians (58 +/- 15 nmol/L). In multivariate analysis, female (OR = 5.5; 95% CI: 3.4-7.5), Malay (OR = 3.2; 95% CI: 1.3-8.0), Indian (OR = 4.3; 95% CI: 1.6-12.0) and those always wearing long sleeve (OR = 2.4; 95% CI: 1.1-5.4) were more likely to have vitamin D deficiency. For female participants, ethnicity {Malays (OR = 6.7; 95% CI: 2.0-18.5), Indian (OR = 4.5; 95% CI: 1.8-19.3)} was an important risk factors. Cloud cover, school residence, skin pigmentation, sun-exposure and sun-protective behaviours were not significant risk factors. The limitation of this study was recall bias as it relied on self-reported on the sun exposure and protective behaviours. The diet factors were not included in this analysis. CONCLUSIONS: The prevalence of Vitamin D deficiency among Malaysian adolescents was considerable. Gender, ethnicity and clothing style were important risk factors. PMID- 30024937 TI - Is there more than the sewage plant? University freshmen's conceptions of the urban water cycle. AB - The concepts of 340 university freshmen concerning urban water cycles include various misconceptions (or intuitive conceptions) which severely contrast with correct scientific ones. Almost no student knew the correct urban water cycle in total, including cycle steps in the appropriate sequence: consumer (given), sewage-plant, nature and waterworks. Concepts mainly omit nature and waterworks, only the sewage plant is included in almost all concepts. This reflects an exaggeration of the importance of the cycle-step sewage plant relative to the other steps, when the topic is taught in school. Students acquired knowledge from two main sources: School and media. Most students are aware of the origin of drinking water, although several concepts reflect a pipe-to-pipe system, where wastewater is cleared in sewage plants and brought back to consumers, skipping the roles of nature and waterworks. Everyday matters with an important impact on our life-standards, like the urban water cycle, need specific attention during school time. Currently, only primary school syllabi include the issue of urban water cycles in Germany. More effort is needed to explain wastewater and drinking water issues in order to correct misconceptions. PMID- 30024936 TI - The importance of stool DNA methylation in colorectal cancer diagnosis: A meta analysis. AB - A large number of tumor-related methylated genes have been suggested to be of diagnostic and prognostic values for CRC when analyzed in patients' stool samples; however, reported sensitivities and specificities have been inconsistent and widely varied. This meta-analysis was conducted to assess the detection accuracy of stool DNA methylation assay in CRC, early stages of CRC (advanced adenoma, non-advanced adenomas) and hyperplastic polyps, separately. We searched MEDLINE, Web of Science, Scopus and Google Scholar databases until May 1, 2016. From 469 publications obtained in the initial literature search, 38 studies were included in the final analysis involving 4867 individuals. The true positive, false positive, true negative and false negative of a stool-based DNA methylation biomarker using all single-gene tests considering a certain gene; regardless of a specific gene were pooled and studied in different categories. The sensitivity of different genes in detecting different stages of CRC ranged from 0% to 100% and the specificities ranged from 73% to 100%. Our results elucidated that SFRP1 and SFRP2 methylation possessed promising accuracy for detection of not only CRC (DOR: 31.67; 95%CI, 12.31-81.49 and DOR: 35.36; 95%CI, 18.71-66.84, respectively) but also the early stages of cancer, adenoma (DOR: 19.72; 95%CI, 6.68-58.25 and DOR: 13.20; 95%CI, 6.01-28.00, respectively). Besides, NDRG4 could be also considered as a significant diagnostic marker gene in CRC (DOR: 24.37; 95%CI, 10.11-58.73) and VIM in adenoma (DOR: 15.21; 95%CI, 2.72-85.10). In conclusion, stool DNA hypermethylation assay based on the candidate genes SFRP1, SFRP2, NDRG4 and VIM could offer potential diagnostic value for CRC based on the findings of this meta-analysis. PMID- 30024935 TI - Natural biocide cocktails: Combinatorial antibiotic effects of prodigiosin and biosurfactants. AB - Bacterial secondary metabolites are naturally produced to prevail amongst competitors in a shared habitat and thus represent a valuable source for antibiotic discovery. The transformation of newly discovered antibiotic compounds into effective drugs often requires additional surfactant components for drug formulation. Nature may also provide blueprints in this respect: A cocktail of two compounds consisting of the antibacterial red pigment prodigiosin and the biosurfactant serrawettin W1 is naturally produced by the bacterium Serratia marcescens, which occurs in highly competitive habitats including soil. We show here a combinatorial antibacterial effect of these compounds, but also of prodigiosin mixed with other (bio)surfactants, against the soil-dwelling bacterium Corynebacterium glutamicum taken as a model target bacterium. Prodigiosin exerted a combinatorial inhibitory effect with all tested surfactants in a disk diffusion assay which was especially pronounced in combination with N myristoyltyrosine. Minimal inhibitory and bactericidal concentrations (MIC and MBC) of the individual compounds were 2.56 MUg/mL prodigiosin and 32 MUg/mL N myristoyltyrosine, and the MIC of prodigiosin was decreased by 3 orders of magnitude to 0.005 MUg/mL in the presence of 16 MUg/mL N-myristoyltyrosine, indicative of synergistic interaction. Investigation of bacterial survival revealed similar combinatorial effects; moreover, antagonistic effects were observed at higher compound concentrations. Finally, the investigation of microcolony formation under combined application of concentrations just below the MBC revealed heterogeneity of responses with cell death or delayed growth. In summary, this study describes the combinatorial antibacterial effects of microbial biomolecules, which may have ecological relevance by inhibiting cohabiting species, but shall furthermore inspire drug development in the combat of infectious disease. PMID- 30024938 TI - Use of rheumatology-specific patient navigators to understand and reduce barriers to medication adherence: Analysis of qualitative findings. AB - OBJECTIVE: Adherence to medications among patients with rheumatic diseases is often suboptimal. Patient navigators, individuals trained in care coordination, motivational interviewing and basic rheumatology and pharmacology, have not been employed to explore and address this issue. We piloted a single-site, single arm intervention to determine the feasibility and acceptability of using rheumatology specific navigators to understand and reduce barriers to adherence to oral disease modifying anti-rheumatic drugs (DMARDs). We analyzed our qualitative findings from navigator-patient interactions as well as patient satisfaction with the intervention. METHODS: We recruited patients >=18 years with a systemic rheumatic disease who initiated an oral DMARD within the prior 6 months. Navigators conducted baseline needs assessments and 2-4 week follow-up calls to understand and address issues related to medication adherence. We analyzed patient-navigator encounters qualitatively using content analysis to identify key themes related to barriers to adherence and navigator actions performed in response to the barriers described. We also categorized intentional and unintentional nonadherent behavior and assessed satisfaction with the navigator experience (range 0-5, 5 = most satisfied). RESULTS: 107 rheumatology patients were followed for up to 6 months. Mean patient age was 55 years (+17) and 93% were female; 36% described one or more episode of intentional or unintentional nonadherence. The three most common themes identified as barriers to adherence were fear of adverse events (raised by 54%), concerns about medication effectiveness (43%), and challenges with medication acquisition (32%). 86% of participants described at least one adherence-related barrier. Frequent navigator actions included facilitation of patient-doctor communication (38%), medication and diagnosis education (27%), and development of individualized strategies to improve adherence (16%). Patients were satisfied with the navigator experience (mean 4.4 + 0.9). CONCLUSION: Navigators uncovered and addressed a number of medication adherence-related concerns and patients were satisfied with the services provided. PMID- 30024939 TI - iTRAQ-based quantitative proteomic analysis of alterations in the intestine of Hu sheep under weaning stress. AB - When Lambs are weaned off ewe's milk, metabolic, structural, and functional changes often occur in the small intestine. Because information on the effects of weaning stress on the proteome of the intestine is limited, an animal model was established with eight pairs of twin lambs divided into artificially reared and ewe-reared groups, which was followed by proteome analysis using iTRAQ technology. Changes occurred in the morphology of the intestine and 5,338 proteins in three biological replicates with less than a 1.2% false discovery rate were identified and quantified. Among them, a subset of 389 proteins were screened as significantly up- (143) and down-regulated (246) in artificially reared compared with ewe-reared. According to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, the differentially expressed proteins that were strongly down-regulated were enriched in immune system processes, biological adhesion, and metabolic processes. The up-regulated proteins were enriched in gene expression, cellular biosynthetic processes, ribosome and RNA binding in response to weaning stress. A series of proteins associated with intestine morphology and immune function were identified, and levels of the mRNAs encoding these proteins were analyzed by real-time quantitative reverse transcription PCR. The results of this study increased our understanding of the response of lambs weaned off ewe's milk and helped to determine the mechanisms underlying weaning stress. PMID- 30024940 TI - Influenza A/H3N2 virus infection in immunocompromised ferrets and emergence of antiviral resistance. AB - Influenza viruses can cause severe life threatening infections in high-risk patients, including young children, the elderly and patients with compromised immunity due to underlying medical conditions or immunosuppressive treatment. The impaired immunity of these patients causes prolonged virus infection and combined with antiviral treatment facilitates the emergence of viruses with resistance mutations. The diverse nature of their immune status makes them a challenging group to study the impact of influenza virus infection and the efficacy of antiviral therapy. Immunocompromised ferrets may represent a suitable animal model to assess influenza virus infection and antiviral treatment strategies in immunocompromised hosts. Here, ferrets were given a daily oral solution of mycophenolate mofetil, tacrolimus and prednisolone sodium phosphate to suppress their immune system. Groups of immunocompromised and immunocompetent ferrets were inoculated with an A/H3N2 influenza virus and were subsequently treated with Oseltamivir or left untreated. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed on the throat and nose specimens to study virus replication during the course of infection. All immunocompromised ferrets had prolonged presence of viral RNA and a higher total amount of virus shedding compared to the immunocompetent ferrets. Although Oseltamivir reduced the total amount of virus shedding from the nose and throat of treated ferrets, it also resulted in the emergence of the neuraminidase R292K resistance substitution in all these animals, as determined by mutation specific RT-PCR and next-generation sequencing. No additional mutations that could be associated with the emergence of the R292K resistance mutation were detected. The immunocompromised ferret model can be used to study A/H3N2 virus shedding and is a promising model to study new antiviral strategies and the emergence of antiviral resistance in immunocompromised hosts. PMID- 30024941 TI - Quantification of microRNA levels in plasma - Impact of preanalytical and analytical conditions. AB - Numerous studies have reported a potential role for circulating microRNAs as biomarkers in a wide variety of diseases. However, there is a critical reproducibility challenge some of which might be due to differences in preanalytical and/or analytical factors. Thus, in the current study we systematically investigated the impact of selected preanalytical and analytical variables on the measured microRNA levels in plasma. Similar levels of microRNA were found in platelet-poor plasma obtained by dual compared to prolonged single centrifugation. In contrast, poor correlation was observed between measurements in standard plasma compared to platelet-poor plasma. The correlation between quantitative real-time PCR and droplet digital PCR was found to be good, contrary to TaqMan Low Density Array and single TaqMan assays where no correlation could be demonstrated. Dependent on the specific microRNA measured and the normalization strategy used, the intra- and inter-assay variation of quantitative real-time PCR were found to be 4.2-6.8% and 10.5-31.4%, respectively. Using droplet digital PCR the intra-assay variation was 4.4-20.1%, and the inter-assay variation 5.7-26.7%. Plasma preparation and microRNA purification were found to account for 39-73% of the total intra-assay variation, dependent on the microRNA measured and the normalization strategy used. In conclusion, our study highlighted the importance of reporting comprehensive methodological information when publishing, allowing others to perform validation studies where preanalytical and analytical variables as causes for divergent results can be minimized. Furthermore, if microRNAs are to become routinely used diagnostic or prognostic biomarkers, the differences in plasma microRNA levels between health and diseased subjects must exceed the high preanalytical and analytical variability. PMID- 30024942 TI - Prefrontal cortex-dependent innate behaviors are altered by selective knockdown of Gad1 in neuropeptide Y interneurons. AB - GABAergic dysfunction has been implicated in a variety of neurological and psychiatric disorders, including anxiety disorders. Anxiety disorders are the most common type of psychiatric disorder during adolescence. There is a deficiency of GABAergic transmission in anxiety, and enhancement of GABA transmission through pharmacological means reduces anxiety behaviors. GAD67-the enzyme responsible for GABA production-has been linked to anxiety disorders. One class of GABAergic interneurons, Neuropeptide Y (NPY) expressing cells, is abundantly found in brain regions associated with anxiety and fear learning, including prefrontal cortex, hippocampus and amygdala. Additionally, NPY itself has been shown to have anxiolytic effects, and loss of NPY+ interneurons enhances anxiety behaviors. A previous study showed that knockdown of Gad1 from NPY+ cells led to reduced anxiety behaviors in adult mice. However, the role of GABA release from NPY+ interneurons in adolescent anxiety is unclear. Here we used a transgenic mouse that reduces GAD67 in NPY+ cells (NPYGAD1-TG) through Gad1 knockdown and tested for effects on behavior in adolescent mice. Adolescent NPYGAD1-TG mice showed enhanced anxiety-like behavior and sex-dependent changes in locomotor activity. We also found enhancement in two other innate behavioral tasks, nesting construction and social dominance. In contrast, fear learning was unchanged. Because we saw changes in behavioral tasks dependent upon prefrontal cortex and hippocampus, we investigated the extent of GAD67 knockdown in these regions. Immunohistochemistry revealed a 40% decrease in GAD67 in NPY+ cells in prefrontal cortex, indicating a significant but incomplete knockdown of GAD67. In contrast, there was no decrease in GAD67 in NPY+ cells in hippocampus. Consistent with this, there was no change in inhibitory synaptic transmission in hippocampus. Our results show the behavioral impact of cell-specific interneuron dysfunction and suggest that GABA release by NPY+ cells is important for regulating innate prefrontal cortex-dependent behavior in adolescents. PMID- 30024944 TI - Small molecule disruption of G protein betagamma subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats. AB - The purpose of this study was to determine whether blocking of G protein betagamma (Gbetagamma) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gbetagamma signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gbetagamma signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gbetagamma might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gbetagamma inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule Gbetagamma inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages. PMID- 30024945 TI - A framework for the extended monitoring of levels of cognitive function in unresponsive patients. AB - Generally, prognostication of coma outcome currently combines behavioral, reflex, and possibly neuroimaging tests that are interpreted by an attending physician. Electroencephalography, particularly, event-related brain potentials (ERP) have received attention due to evidence demonstrating the positive predictive value of certain ERP including the mismatch negativity (MMN) and the P3a, for coma emergence. We describe a set of ERP paradigms designed to require and reflect increasing levels of cognitive processing with the added objective of determining the influence of each paradigm's context strength on its ability to elicit ERPs. These paradigms were then used without explicit instructions to participants to attend to the stimuli to determine which paradigms possessed sufficient context "strength" to elicit ERPs in the absence of active participation on the part of the subject; a circumstance often encountered in brain injury patients. These paradigms were then validated on two groups of adults-younger and older, and the difference due to active participation was validated on another group of younger adults. Results show that paradigms with stronger stimulus context features performed better than those with weaker contexts, and that older adults generally had significantly attenuated and delayed responses compared to younger adults. Based on these findings, it is recommended the use of the auditory oddball paradigm that includes novel stimuli to elicit the mismatch negativity and P300, and semantic violation sentences to elicit the N400. These findings also reinforce the procedure of instructing participants about the requirements of a protocol-regardless of the patient's diagnosis or apparent state-in order to help those who are able to attend to show the most robust responses possible. PMID- 30024943 TI - The draft genomes of Elizabethkingia anophelis of equine origin are genetically similar to three isolates from human clinical specimens. AB - We report the isolation and characterization of two Elizabethkingia anophelis strains (OSUVM-1 and OSUVM-2) isolated from sources associated with horses in Oklahoma. Both strains appeared susceptible to fluoroquinolones and demonstrated high MICs to all cell wall active antimicrobials including vancomycin, along with aminoglycosides, fusidic acid, chloramphenicol, and tetracycline. Typical of the Elizabethkingia, both draft genomes contained multiple copies of beta-lactamase genes as well as genes predicted to function in antimicrobial efflux. Phylogenetic analysis of the draft genomes revealed that OSUVM-1 and OSUVM-2 differ by only 6 SNPs and are in a clade with 3 strains of Elizabethkingia anophelis that were responsible for human infections. These findings therefore raise the possibility that Elizabethkingia might have the potential to move between humans and animals in a manner similar to known zoonotic pathogens. PMID- 30024946 TI - Informal caregiving and markers of adiposity in the UK Household Longitudinal Study. AB - OBJECTIVES: The aim was to investigate associations between caregiving and adiposity using a representative UK longitudinal study. We also investigated whether associations differed by age, gender and caregiving characteristics. METHODS: Data on 9,421 participants aged 16+ from three waves (2009-2012) of the UK Household Longitudinal Study were used. Body mass index, waist circumference and percentage body fat were assessed. Caregiving and caregiving characteristics (hours per week, number of people cared for, co-resident caregiving and combining working and caregiving) was available from the prior wave. Gender-stratified associations between caregiving/caregiving characteristics with adiposity were tested. Covariates included caregiver's health, socioeconomic position, parenthood and partnerships. RESULTS: Caregiving was associated with higher adiposity for women but not men. Younger women caregivers had particularly higher levels of adiposity. Men combining part-time paid work with caregiving had higher levels of adiposity than men working full-time and not caregiving. Women aged 16 44 or 65+ had particularly high levels of adiposity when combining full-time work and caregiving, compared to full-time work alone. CONCLUSION: The health of caregivers should be a public health priority, particularly for younger women and those combining paid work with caregiving responsibilities. PMID- 30024947 TI - Distribution of vesicle pools in cerebellar parallel fibre terminals after depression of ectopic transmission. AB - At parallel fibre terminals in the cerebellar cortex, glutamate released outside of the active zone can activate AMPA receptors on juxtaposed Bergmann glial cell processes. This process is termed "ectopic" release, and allows for directed transmission to astroglial cells that is functionally independent of synaptic transmission to postsynaptic Purkinje neurons. The location of ectopic sites in presynaptic terminals is uncertain. Functional evidence suggests that stimulation of parallel fibres at 1 Hz exhausts ectopic transmission due to a failure to rapidly recycle vesicles to the ectopic pool, and so would predict a loss of vesicles in the near vicinity of extrasynaptic glial processes. In this study we used this stimulation protocol to investigate whether the distribution of vesicles within the presynaptic terminal is altered after suppression of ectopic release. Stimulation at 1 Hz had only a minor impact on the distribution of vesicles in presynaptic terminals when analysed with electron microscopy. Vesicle number and terminal size were unaffected by 1 Hz stimulation, but the relative abundance of vesicles in close proximity to the active zone was marginally reduced. In contrast, the fraction of vesicles facing glial membranes was unchanged after suppression of ectopic transmission. 1 Hz stimulation also resulted in a small but statistically-significant increase in the distance between glial membrane and presynaptic terminal, suggesting withdrawal of glial membranes from synapses is detectable in ultrastructural anatomy within minutes. These results raise doubts about the location of ectopic release sites, but indicate that neuron-glial association varies on a dynamic time scale. PMID- 30024948 TI - Prevalence and risk factors of intimate partner violence among women in four districts of the central region of Ghana: Baseline findings from a cluster randomised controlled trial. AB - Intimate partner violence (IPV) is a significant global public health problem. Understanding risk factors is crucial for developing prevention programmes. Yet, little evidence exists on population-based prevalence and risk factors for IPV in West Africa. Our objective was to measure both lifetime and past year prevalence of IPV and to determine factors associated with past year physical or sexual IPV experience. This population-based survey involved 2000 randomly selected women aged 18 to 49 years living in 40 localities within four districts of the Central Region of Ghana. Questionnaires were interviewer-administered from February to May 2016. Respondents were currently or ever-partnered, and resident in study area >=12months preceding the survey. Data collected included: socio demographics; sexual behavior; mental health and substance use; employment status; 12-month and lifetime experience of violence; household food insecurity; gender norms/attitudes; partner characteristics and childhood trauma. Logistic regression modelling was used to determine factors associated with sexual or physical IPV, adjusting for age and survey design. About 34% of respondents had experienced IPV in the past year, with 21.4% reporting sexual and or physical forms. Past year experience of emotional and economic IPV were 24.6% and 7.4% respectively. Senior high school education or higher was protective of IPV (AOR = 0.51[0.30-0.86]). Depression (AOR = 1.06[1.04-1.08], disability (AOR = 2.30[1.57 3.35]), witnessing abuse of mother (AOR = 2.1.98[1.44-2.72]), experience of childhood sexual abuse (AOR = 1.46[1.07-1.99]), having had multiple sexual partners in past year (AOR = 2.60[1.49-4.53]), control by male partner (AOR = 1.03[1.00-1.06]), male partner alcohol use in past year (AOR = 2.65[2.12-3.31]) and male partner infidelity (AOR = 2.31[1.72-3.09]) were significantly associated with increased odds of past year physical or sexual IPV experience. Male perpetrated IPV remains a significant public health issue in Ghana. Evidence based interventions targeting women's mental health, disabilities, exposure to violence in childhood, risky sexual behavior and unequal power in relationships will be critical in reducing IPV in this setting. PMID- 30024949 TI - Myracrodruon urundeuva seed exudates proteome and anthelmintic activity against Haemonchus contortus. AB - Seed exudates are plant-derived natural bioactive compounds consisting of a complex mixture of organic and inorganic molecules. Plant seed exudates have been poorly studied against parasite nematodes. This study was undertaken to identify proteins in the Myracrodruon urundeuva seed exudates and to assess the anthelmintic activity against Haemonchus contortus, an important parasite of small ruminants. M. urundeuva seed exudates (SEX) was obtained after immersion of seeds in sodium acetate buffer. SEX was fractionated with ammonium sulfate at 0 90% concentration to generate the ressuspended pellet (SEXF1) and the supernatant (SEXF2). SEX, SEXF1, and SEXF2 were exhaustively dialyzed against distilled water (cut-off: 12 kDa) and the protein contents determined. Mass spectrometry analyses of SEX, SEXF1, and SEXF2 were done to identify proteins and secondary metabolites. The seed exudates contained protease, protease inhibitor, peptidase, chitinase, and lipases as well as the low molecular weight secondary compounds ellagic acid and quercetin rhamnoside. SEX inhibited H. contortus larval development (LDA) (IC50 = 0.29 mg mL-1), but did not affect larval exsheathment (LEIA). On the other hand, although SEXF1 and SEXF2 inhibited H. contortus LEIA (IC50 = 1.04 and 0.93 mg mL-1, respectively), they showed even greater inhibition efficiency of H. contortus larval development (IC50 = 0.29 and 0.42 mg mL-1, respectively). To the best of our knowledge, this study is the first to show the anthelmintic activity of plant exudates against a gastrointestinal nematode. Moreover, it suggests the potential of exuded proteins as candidates to negatively interfere with H. contortus life cycle. PMID- 30024951 TI - Mosquito control practices and perceptions: An analysis of economic stakeholders during the Zika epidemic in Belize, Central America. AB - The tourist-based economy of Belize, a tropical hub for eco-tourism, is at high risk to be disproportionately impacted by established and emerging mosquito-borne diseases such as Zika. An online survey was used to probe economic stakeholders working in the Belize tourism industry about their mosquito control practices and perceptions. Responses demonstrated that the respondents have good working knowledge of mosquitoes and mosquito-borne illnesses. Most businesses surveyed engage in some means of mosquito control, either through larval source reduction or use of insecticides on the premises. Larvicide use was significantly correlated with a general willingness to use insecticides, as well as belief that treatment of water will reduce mosquito densities and disease transmission. A majority of the respondents agreed that they would be interested in buying a new larvicide to be used on the business premises if it were shown to be safe and effective. The safety of mosquito control products for humans, animals, plants, and the environment in general, followed by product effectiveness, are the most critical determinants of mosquito control purchasing decisions. A majority of respondents agreed that control of mosquitoes and mosquito-borne illnesses is central to the success of their tourist-based industry. Respondents expressed significant concern that the Zika epidemic was over-sensationalized by the media, and that this negatively impacted their livelihoods. The respondents, many of whom are associated with eco/sustainable businesses, also voiced concerns that chemical pesticides could have a negative impact on human health and the environment and expressed a desire for balance between effective mosquito control and preservation of the rich biodiversity of Belize. This study provided a framework for further engagement activities in Belize and other Caribbean nations, uncovered both concerns and support for emerging mosquito control technologies, and revealed opportunities for further debate and educational outreach efforts. PMID- 30024950 TI - Evolution and expression analyses of the MADS-box gene family in Brassica napus. AB - MADS-box transcription factors are important for plant growth and development, and hundreds of MADS-box genes have been functionally characterized in plants. However, less is known about the functions of these genes in the economically important allopolyploid oil crop, Brassica napus. We identified 307 potential MADS-box genes (BnMADSs) in the B. napus genome and categorized them into type I (Malpha, Mbeta, and Mgamma) and type II (MADS DNA-binding domain, intervening domain, keratin-like domain, and C-terminal domain [MIKC]c and MIKC*) based on phylogeny, protein motif structure, and exon-intron organization. We identified one conserved intron pattern in the MADS-box domain and seven conserved intron patterns in the K-box domain of the MIKCc genes that were previously ignored and may be associated with function. Chromosome distribution and synteny analysis revealed that hybridization between Brassica rapa and Brassica oleracea, segmental duplication, and homologous exchange (HE) in B. napus were the main BnMADSs expansion mechanisms. Promoter cis-element analyses indicated that BnMADSs may respond to various stressors (drought, heat, hormones) and light. Expression analyses showed that homologous genes in a given subfamily or sister pair are highly conserved, indicating widespread functional conservation and redundancy. Analyses of BnMADSs provide a basis for understanding their functional roles in plant development. PMID- 30024953 TI - Metabolic equivalent of task (METs) thresholds as an indicator of physical activity intensity. AB - The purpose of the study was to identify and compare validity parameters of different absolute intensity thresholds in METs, using relative intensity classification as criterion measure. Convenience sampling was used to recruit total of 112 adults. The participants carried out an incremental maximal cycle ergometer test and asked to perform nine free-living activities. The oxygen uptake was measured by a VO2000(r) gas analyser throughout the tests. The intensity thresholds were identified using Receiver Operator Characteristic (ROC) curve analysis, having relative intensity categories as criterion measure. A total of 103 participants attended the two visits. Among 54 men and 49 women, the mean (+/- SD) ages were 36.1 (+/- 11.1) and 33.9 (+/- 10.6) years, respectively. The intensity thresholds identified were 4.9 METs for moderate and 6.8 METs for vigorous physical activity. In conclusion, the physical activity thresholds, generated according to the entire sample, were higher and presented improved specificity when compared to thresholds currently recommended. Moreover, these parameters presented relatively high accuracy, even when applied to specific groups such as sex, age, nutritional status and physical fitness. PMID- 30024954 TI - The establishment of hybrids of the Daphnia longispina complex explained by a mathematical model incorporating different overwintering life history strategies. AB - Interspecific hybridization (i.e. mating between species) occurs frequently in animals. Among cyclical parthenogens, hybrids can proliferate and establish through parthenogenetic reproduction, even if their sexual reproduction is impaired. In water fleas of the Daphnia longispina species complex, interspecific hybrids hatch from sexually produced dormant eggs. However, fewer hybrid genotypes contribute to the dormant egg bank and their hatching rate from dormant eggs is reduced, compared to eggs resulting from intraspecific crosses. Therefore, Daphnia hybrids would benefit from adaptations that increase their survival over winter as parthenogenetic lineages, avoiding the need to re establish populations after winter from sexually produced dormant eggs. Here, we constructed a mathematical model to examine the conditions that could explain the frequently observed establishment of hybrids in the D. longispina species complex. Specifically, we compared the outcome of hybrid and parental taxa competition given a reduced contribution of hybrids to hatchlings from the sexually produced dormant egg bank, but their increased ability to survive winter as parthenogenetic lineages. In addition, different growth rates of parental species and differences in average annual temperatures were evaluated for their influence on hybrid production and establishment. Our model shows that increased overwinter performance as parthenogenetic females can compensate for reduced success in sexual reproduction, across all tested scenarios for varying relative growth rates of parental species. This pattern holds true for lower annual temperatures, but at higher temperatures hybrids were less successful. Consequently, hybrids might become less abundant as temperatures rise due to climate change, resulting in reduced diversity and faster differentiation of the parental species. PMID- 30024952 TI - Justifications for using complementary and alternative medicine reported by persons with musculoskeletal conditions: A narrative literature synthesis. AB - BACKGROUND: Complementary and alternative medicine (CAM) is very popular with patients frequently combining it with orthodox health care. The high prevalence of CAM use and satisfaction with CAM reported by patients directly challenges an orthodox system that can only approve such use if it results from the application of biomedical concepts and science. Studies highlighting this as a cultural, sociological and historical phenomenon emphasise the value of choice for consumers of health care. Musculoskeletal conditions typify common problems for which the effectiveness of orthodox care is often unclear. We postulated that the reasons people give for using or not using CAM for musculoskeletal conditions, would therefore indicate the full range of expectations that people have of health care. Furthermore, these reasons would indicate how much people feel orthodox health care is or is not meeting their expectations. Therefore, this study aims to investigate people's reasons for choosing or avoiding CAM for non traumatic musculoskeletal conditions. METHODS: A systematic search and narrative synthesis was conducted of published qualitative and quantitative studies related to CAM and non-traumatic musculoskeletal conditions. RESULTS: We identified 169 relevant papers detailing 152 separate studies, from which 1486 justifications were extracted concerning CAM use. Content analysis resulted in 11 distinct categories across four themes: practical aspects of care, clinical effectiveness, non-clinical outcomes of care, and a person's philosophy of illness and care. People provided similar rationales for both using and avoiding CAM, emphasising that, whilst CAM is perceived by many patients with musculoskeletal conditions to fill gaps in care (such as practitioner time or quality of the therapeutic relationship), orthodox care also seeks to deliver these aspects of care. However, people who used CAM also highlighted its alignment with their general philosophy and ideas about illness and health care, and often emphasised CAM's capacity to give them control over their condition and its treatment. CONCLUSION: Currently, CAM appears to have a significant role for patients with common painful long-term conditions in providing choices to enable individual needs to be met. PMID- 30024956 TI - Retraction: Atomic resolution studies detect new biologic evidences on the Turin Shroud. PMID- 30024955 TI - Urine proteome analysis by C18 plate-matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allows noninvasive differential diagnosis and prediction of diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the most common complications in diabetic patients. New noninvasive markers are still needed for the early detection of DN before identifiable alternations in kidney function or urine albumin excretion occurs. A C18 plate and matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) were used to compare the urinary protein profiles of 238 subjects from the following 4 groups: patients with type 2 diabetic (T2D) with microalbuminuria, patients with DM without micro- or macroalbuminuria, patients with micro- or macroalbuminuria due to nondiabetic disease, and healthy controls. beta2-microglobulin (B2M) and Clara-cell protein (CC16) were found to be highly released in the urine of patients with proteinuria due to nondiabetic or diabetic diseases. In differentiating nephropathy from healthy subject, the B2M and CC16 markers have a combined sensitivity and specificity of 77.3% and 91.8%, respectively. In distinguishing T2D with microalbuminuria from T2D patients, the combined markers have sensitivity and specificity of 66% and 73%, respectively. The predictive ability of B2M and CC16 for early renal functional decline (ERFD) was validated in 125 T2D patients with a follow-up times. The odds ratio (OR) of combined B2M and CC16 markers for developing ERFD was 7.59 (95% CI: 1.97-29.24). The detection of B2M and CC16 with the C18 plate-MALDI-TOF MS approach could be an attractive and practical assay for rapid diagnosis of nephropathy in nondiabetic/diabetic patients and as a predictor of ERFD among T2D patients who had not manifested significant kidney disease at baseline. PMID- 30024957 TI - Correction: The diagnosis, burden and prognosis of dementia: A record-linkage cohort study in England. AB - [This corrects the article DOI: 10.1371/journal.pone.0199026.]. PMID- 30024958 TI - Simultaneous observation of intermittent locomotion of multiple fish by fine scale spatiotemporal three-dimensional positioning. AB - Recent advances in biotelemetry techniques, especially positioning methods, have revealed the detailed behaviour and movement of aquatic organisms. Behavioural intermittence in animal locomotion, such as the Levy walk, is a popular topic in the field of movement ecology. Previous attempts to describe intermittent locomotion quantitatively have been constrained by the spatial and temporal resolution possible with conventional biotelemetry systems. This study developed a fine-scale spatiotemporal three-dimensional positioning method using a new biotelemetry system with a positional precision of <10 cm and positioning interval of <10 s. Using this proposed positioning method, the intermittent stop and-go locomotion of Siebold's wrasses (Pseudolabrus sieboldi) was observed during travel from an unsuitable to a suitable location following displacement. The fish displayed behavioural intermittence in relocating to a suitable location. Initially, their movement halted for reorientation, after which they moved intermittently yet in a straight line to the suitable location. To test the positioning ability of the proposed method, data sets were resampled at intervals of 5, 10, 30, 60, and 300 s. Longer sampling intervals failed to identify reorientations and underestimated the number of stops, distance travelled, and speed. Overall, the results highlighted the adequacy and ability of the proposed positioning method to observe the intermittent locomotion of fish, such as stop and-go behaviour, in a natural environment. PMID- 30024959 TI - sFasL-mediated induction of neutrophil activation in patients with type 2 diabetes mellitus. AB - Fas/Fas ligand system was shown to be related to insulin resistance and type 2 diabetes mellitus (T2DM). However, the role of soluble Fas ligand (sFasL) in functioning of immune cells in type 2 diabetes mellitus (T2DM) has not been studied yet. The aim of the present study was to determine in vitro effects of sFasL on neutrophil activation and apoptosis. We demonstrate here that sFasL exhibited proinflammatory effect and induced mRNA levels of caspase-1, NF-kappaB, IL-1beta and CD18 expression. At the same time, sFasL induced reactive oxygen species (ROS) production. Activation of caspase-1 activity abolished sFasL dependent apoptosis, and suppressed Fas expression and mRNA levels of caspase-3 in neutrophils from T2DM patients. Collectively, our findings identify a novel proinflammatory role of sFasL in T2DM neutrophils that is dependent of caspase activity. Thus, sFasL enhances inflammatory response of neutrophils from T2DM patients without increasing apoptosis suggesting its triggering role in T2DM inflammation. PMID- 30024960 TI - Correction: The impact of tackle football injuries on the American healthcare system with a neurological focus. AB - [This corrects the article DOI: 10.1371/journal.pone.0195827.]. PMID- 30024962 TI - Forced expiratory volume in one second: A novel predictor of work disability in subjects with suspected obstructive sleep apnea. AB - Whether the association of work disability with obstructive sleep apnea (OSA) is mainly due to the disease, i.e. the number and frequency of apneas-hypoapneas, or to coexisting factors independent from the disease, is not well-established. In this study, we aim to evaluate work ability in a group of subjects undergoing OSA workup and to identify the major contributors of impaired work ability. In a cross-sectional study, we enrolled 146 consecutive subjects who have been working for the last five years and referred to the sleep disorders outpatients' clinic of the University-Hospital of Ferrara, Italy, with suspected OSA. After completing an interview in which the Work Ability Index (WAI) and the Epworth Sleepiness Scale (ESS) questionnaires were administered to assess work ability and excessive daytime sleepiness, respectively, subjects underwent overnight polysomnography for OSA diagnosing and spirometry. Of the 146 subjects, 140 (96%) completed the tests and questionnaires and, of these, 66 exhibited work disability (WAI < 37). OSA was diagnosed (apnea-hypopnea index >= 5) in 45 (68%) of the 66 subjects. After controlling for confounders, a lower level of forced expiratory volume at 1 second (FEV1), [odds ratio 0.97 (95% CI 0.95-1.00)], older age [1.09 (95% CI 1.03-1.15)], excessive daytime sleepiness [3.16 (95% CI 1.20 8.34)] and a worse quality of life [0.96 (95% CI 0.94-1.00)], but not OSA [1.04 (95% CI 0.41-2.62)], were associated with work disability. Patients with a higher number of diseases, in which OSA was not included, and a lower quality of life had an increased probability of absenteeism in the previous 12 months. In subjects with suspected OSA, FEV1 can be an important predictor of work disability. PMID- 30024963 TI - Germination ecology of turnip weed (Rapistrum rugosum (L.) All.) in the northern regions of Australia. AB - In Australia, turnip weed has been rapidly emerging as one of the major weeds in conservation agricultural systems. Germination and emergence of turnip weed were examined for two populations collected from Gatton and St George regions of Australia; two locations with high and low rainfall, respectively. The seeds of turnip weed germinated at all the tested temperatures, but germination was the lowest at 15/5 degrees C, intermediate at 20/10 degrees C and highest at 25/15 degrees C and 30/20 degrees C. The results indicated a high adaptability of turnip weed to warm environmental conditions, although it is a major problem in the winter season. Germination was higher in dark than light/dark regimes except at 30/20 degrees C. Three was a concomitant reduction in germination as the osmotic potential values decreased from 0 to -1.0 MPa. There was 2 and 4% germination at -0.8 MPa for Gatton and St George populations, respectively, and no germination occurred at an osmotic potential of -1.0 MPa. There was a reduction in germination when the sodium chloride (NaCl) concentration was increased from 0 to 150 mM, and no germination was observed at 200 and 250 mM of NaCl. Turnip weed germinated over a broad range of pH (4 to 10). Seedling emergence was higher at 1 cm depth compared to 0.5 cm or at the soil surface. There was 28 and 33% emergence at the surface for the Gatton and St George populations, respectively, compared to 48 and 56% emergence from 1 cm depth for the Gatton and St George populations, respectively and no emergence was observed from 6 cm depth. The results indicated that tillage leading to shallow burial would promote the emergence of turnip weed; on the contrary, tillage that could bury seeds deep into the soil profile might minimise the emergence. Under ideal conditions and lack of integrated weed management programmes, this weed will emerge, set seeds and enrich the soil seed bank and thereby continue to be a problem in the northern grain region of Australia. PMID- 30024961 TI - Alpha and beta band correlates of haptic perceptual grouping: Results from an orientation detection task. AB - Behavioral and neurophysiological findings in vision suggest that perceptual grouping is not a unitary process and that different grouping principles have different processing requirements and neural correlates. The present study aims to examine whether the same occurs in the haptic modality using two grouping principles widely studied in vision, spatial proximity and texture similarity. We analyzed behavioral responses (accuracy and response times) and conducted an independent component analysis of brain oscillations in alpha and beta bands for haptic stimuli grouped by spatial proximity and texture similarity, using a speeded orientation detection task performed on a novel haptic device (MonHap). Behavioral results showed faster response times for patterns grouped by spatial proximity relative to texture similarity. Independent component clustering analysis revealed the activation of a bilateral network of sensorimotor and parietal areas while performing the task. We conclude that, as occurs in visual perception, grouping the elements of the haptic scene by means of their spatial proximity is faster than forming the same objects by means of texture similarity. In addition, haptic grouping seems to involve the activation of a network of widely distributed bilateral sensorimotor and parietal areas as reflected by the consistent event-related desynchronization found in alpha and beta bands. PMID- 30024964 TI - Salmonella spp. transmission in a vertically integrated poultry operation: Clustering and diversity analysis using phenotyping (serotyping, phage typing) and genotyping (MLVA). AB - The transmission of Salmonella enterica within a vertically integrated poultry operation was investigated longitudinally over an 18-month period (2013-2014). Thirty six percent of all samples collected (1503 of 4219) were positive for salmonellae with seven Salmonella enterica subsp. enterica serovars, and one Salmonella enterica subsp. salamae serovar detected. Both Salmonella enterica subsp. enterica serovars Infantis and Typhimurium were detected in all locations sampled. Salmonella Typhimurium was the most frequently detected serovar (63% of serotyped samples) with 8 phage types (PT) and 41 multiple-locus variable-number tandem-repeats analysis (MLVA) profiles identified. The most frequently identified phage types were PT135a and DT135. A total of 62 PT/MLVA combinations were observed. MLVA profiles 03-14-10-09-525 and 03-15-11-11-525 were the most frequently identified and 83% of the isolates shared at least one MLVA profile with an isolate from another phage type. The use of phage typing and MLVA profiling, on their own or in combination, were insufficient to understand the complexity of the epidemiological relationships between locations within this production system. Despite the high level of apparent diversity, cluster analysis was unable to differentiate the transmission pathways of all S. Typhimurium variants detected within the integrated enterprise. Using additional epidemiological information, the parent breeder rearing site was identified as the most likely point of introduction of two S. Typhimurium isolates into the production system with subsequent dissemination to the broiler flocks via the hatchery. This complexity is unable to be resolved in the absence of intensive sampling programs at all generations of the production system. PMID- 30024965 TI - Multi-locus sequence typing of Treponema pallidum subsp. pallidum present in clinical samples from France: Infecting treponemes are genetically diverse and belong to 18 allelic profiles. AB - Treponema pallidum subsp. pallidum, the causative agent of sexually transmitted syphilis, detected in clinical samples from France, was subjected to molecular typing using the recently developed Multilocus Sequence Typing system. The samples (n = 133) used in this study were collected from 2010-2016 from patients with diagnosed primary or secondary syphilis attending outpatient centers or hospitals in several locations in France. Altogether, 18 different allelic profiles were found among the fully typed samples (n = 112). There were five allelic variants identified for TP0136, 12 for TP0548, and eight for TP0705. Out of the identified alleles, one, seven, and three novel alleles were identified in TP0136, TP0548, and TP0705, respectively. Partial allelic profiles were obtained from 6 samples. The majority of samples (n = 110) belonged to the SS14-like cluster of TPA isolates while 7 clustered with Nichols-like isolates. Patients infected with Nichols-like samples were more often older (p = 0.041) and more often diagnosed with secondary syphilis (p = 0.033) compared to patients infected with SS14-like samples. In addition, macrolide resistance caused by the A2058G mutation was found to be associated with allelic profile 1.3.1 or with strains belonging to the 1.3.1 lineage (p<0.001). The genetic diversity among TPA strains infecting the European population was surprisingly high, which suggests that additional studies are needed to reveal the full genetic diversity of TPA pathogens infecting humans. PMID- 30024966 TI - Prediction of major depressive episodes and suicide-related ideation over a 3 year interval among Japanese undergraduates. AB - BACKGROUND: Suicide has been a leading cause of death among young adult populations in Japan. The aim of this study was to predict major depressive episodes (MDEs) and suicide-related ideation among university students using the Patient Health Questionnaire-9 (PHQ-9) and the Temperament and Character Inventory (TCI). METHODS: The subjects were 2194 university students who completed the PHQ-9 and TCI in the 1st year (T1) and the PHQ-9 in the 4th year (T2) of university. Multiple logistic regression analysis was performed to predict MDEs and suicide-related ideation at T2. Moreover, recursive partitioning analyses were conducted to reveal the future risk of MDEs and suicide-related ideation. RESULTS: The multiple logistic regression analyses of MDEs and suicide related ideation at T2 revealed that depressive episodes, suicide-related ideation, and low self-directedness(SD) scores at T1 were significant predictors. The area under the curve of the model for MDEs was 0.858 and that for suicide related ideation was 0.741. The recursive partitioning analyses revealed that a PHQ-9 summary score >=15 at T1 predicted a high risk of MDEs at T2 and that both a PHQ-9 summary score >=5 and a PHQ-9 #9 score >=1 predicted a high risk of suicide-related ideation at T2. CONCLUSIONS: MDEs, suicide-related ideation, and low SD scores are significant predictors of future MDEs and suicide-related ideation. PMID- 30024967 TI - The spinal NR2BR/ERK2 pathway as a target for the central sensitization of collagen-induced arthritis pain. AB - OBJECTIVE: Pain management is a huge challenge in the treatment of rheumatoid arthritis (RA), and central sensitization is reportedly involved in the development of pain. The current study was undertaken to explore the possible role of N-methyl-D-aspartate receptors (NMDARs) in the spinal mechanism of central sensitization in RA using a collagen-induced arthritis (CIA) model. METHODS: Mechanical hypersensitivity was assessed in C57BL/6 mice, before and after the induction of CIA via administration of chick type II collagen. Analgesic drugs, receptor antagonist, and kinase inhibitor were administrated intrathecally in the spinal cord. Protein expression and phosphorylation changes were detected via immunoblotting. RESULTS: CIA mice developed significant mechanical hypersensitivity, and spinal administration of the NMDAR antagonist D 2-amino-5-phosphonovaleric acid (D-APV) effectively attenuated peripheral pain hypersensitivity. There was specific enhancement of synaptic NR2B-containing NMDAR (NR2BR) expression in the spinal dorsal horns of the mice. Both the increased total protein expression of NR2B subunit and the enhanced total phosphorylation level of NR2B subunit at 1472 tyrosine promoted the synaptic expression of NMDAR in the mice. Intrathecal injection of tramadol suppressed synaptic NMDAR expression mainly by changing the synaptic phosphorylation state of NR2B subunit at Tyr1472. Extracellular signal-regulated protein kinases 2 (ERK2) activity synchronized with the synaptic expression of NR2BR, which was downregulated by the action of tramadol. CONCLUSION: Specific enhancement of NR2BR in the spinal dorsal horn may be vital for central sensitization in the CIA model of RA. The NR2BR/ERK2 pathway may be a promising target for pain management in RA patients. PMID- 30024970 TI - Retraction: Comparison of acupuncture and other drugs for chronic constipation: A network meta-analysis. PMID- 30024969 TI - Stenotrophomonas maltophilia colonization during allogeneic hematopoietic stem cell transplantation is associated with impaired survival. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients. PMID- 30024968 TI - Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB. AB - Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells. PMID- 30024971 TI - Characterization of spliced leader trans-splicing in a photosynthetic rhizarian amoeba, Paulinella micropora, and its possible role in functional gene transfer. AB - Paulinella micropora is a rhizarian thecate amoeba, belonging to a photosynthetic Paulinella species group that has a unique organelle termed chromatophore, whose cyanobacterial origin is distinct from that of plant and algal chloroplasts. Because acquisition of the chromatophore was quite a recent event compared with that of the chloroplast ancestor, the Paulinella species are thought to be model organisms for studying the early process of primary endosymbiosis. To obtain insight into how endosymbiotically transferred genes acquire expression competence in the host nucleus, here we analyzed the 5' end sequences of the mRNAs of P. micropora MYN1 strain with the aid of a cap-trapper cDNA library. As a result, we found that mRNAs of 27 genes, including endosymbiotically transferred genes, possessed the common 5' end sequence of 28-33 bases that were posttranscriptionally added by spliced leader (SL) trans-splicing. We also found two subtypes of SL RNA genes encoded by the P. micropora MYN1 genome. Differing from the other SL trans-splicing organisms that usually possess poly(A)-less SL RNAs, this amoeba has polyadenylated SL RNAs. In this study, we characterize the SL trans-splicing of this unique organism and discuss the putative merits of SL trans-splicing in functional gene transfer and genome evolution. PMID- 30024972 TI - If it doesn't help, it doesn't hurt? Information elaboration harms the performance of gender-diverse teams when attributions of competence are inaccurate. AB - Information elaboration-the act of exchanging, discussing, and integrating information and perspectives through verbal communication-tends to be considered as the silver bullet that drives the performance of diverse teams. We challenge this notion by proposing that the effect of information elaboration on team performance depends on the accuracy of within-group competence attributions, i.e. the extent to which attributions of task competence among team members correspond with members' actual task competence. We argue that information elaboration may actually harm performance when within-group competence attributions are inaccurate, given that in such teams decisions are likely to be based on suggestions from members who have much influence but little competence. We conducted an experiment with 97 gender-heterogeneous teams working on gender typical problems and coded their interactions. Our findings support our hypotheses that members who are perceived as more competent are more influential in the information elaboration process, and that information elaboration harms performance when competence attributions are not accurate. In contrast to our expectations, pro-diversity beliefs did not mitigate this negative effect of inaccurate competence attributions. We argue that this speaks to the robustness of our findings regarding the detrimental effects of information elaboration when competence attributions are inaccurate. PMID- 30024973 TI - Anxiety and the severity of Tension-Type Headache mediate the relation between headache presenteeism and workers' productivity. AB - The primary objective of this study was to explore the mechanisms and conditions whereby Tension-Type Headache (TTH) presenteeism relates to health-related loss of productivity as a result of both reduced physical and mental health. To this end, Structural Equation Modeling (SEM) was used to conduct a secondary data analysis of a randomized clinical trial involving 78 Tension-type Headache (TTH) patients. The results showed that TTH presenteeism did not directly relate to health-related loss of productivity, either due to physical, or mental health problems. However, through anxiety-state, TTH presenteeism decreased patients' productivity, as consequence of reduced physical and mental health. Moreover, by increasing the severity of the Tension-Type Headache, TTH presenteeism indirectly decreased patients' productivity as consequence of reduced physical health (but not mental health). Finally, our results show that such indirect effects only occur when the cause of TTH is non-mechanical (e.g., hormonal causes, etc.). Our work provides an integrative model that can inform organizational behaviorists and health professionals (e.g., physiotherapists). Implications for organizational health are discussed. PMID- 30024974 TI - Retraction: Cell-Substrate Interactions Feedback to Direct Cell Migration along or against Morphological Polarization. PMID- 30024975 TI - Potential activities and mechanisms of extracellular polysaccharopeptides from fermented Trametes versicolor on regulating glucose homeostasis in insulin resistant HepG2 cells. AB - Polysaccharides derived from mushrooms have potential to control blood sugar, reduce insulin resistance and prevent diabetic complications. The intracellular polysaccharopeptides of Trametes versicolor (TV) have been used as immunologic and oncologic adjuvants. The aim of this study was to investigate the potential activities and mechanisms of extracellular polysaccharopeptides (ePSP) obtained from TV strain LH-1 on regulating glucose homeostasis. Human hepatoma HepG2 cells incubated with normal glucose (5.5 mM, NG model), high glucose (33 mM, HG model), or high glucose (33 mM) plus high insulin (10-7 M, HGI model) concentrations were administered with TV LH-1 ePSP (50, 100, and 1000 MUg/ml) for 24 hr. Glucose uptake of HepG2 cells, determined by flow cytometry, was significantly decreased in the HG and HGI models with insulin stimulation, suggesting insulin resistance of these cells; however, ePSP reversed this decrease in a dose-dependent manner (one-way ANOVA, p<0.05). In the HG and HGI models, ePSP significantly increased glycogen content, insulin receptor substrate-2 protein and phosphorylated AMP activated protein kinase (AMPK), as determined by western blot analysis. In addition, ePSP significantly increased glucokinase in the NG and HG models, increased membrane glucose transporter-1 and decreased glycogen synthase kinase 3beta in the HGI model, and increased glucose-6-phosphatase in the NG and HGI models (one-way ANOVA, p<0.05). In summary, TV LH-1 ePSP may elevate cellular glucose uptake to regulate glucose homeostasis via the activation of AMPK and glycogen synthesis in an insulin-independent manner. These results suggest that TV LH-1 ePSP may be a nutraceutical with anti-hyperglycemic activity. PMID- 30024976 TI - Ischemic stroke risk during long-term follow up in patients with successful catheter ablation for atrial fibrillation in Korea. AB - The interruption of oral anticoagulation therapy (OAC) after CA of atrial fibrillation (AF) is controversial. The purpose of this study was to evaluate the relationship between successful long-term outcomes of catheter resection and SR maintenance and ischemic stroke risk in Korea. We studied 1,548 consecutive patients who were followed up for more than 2 years after CA of AF. We investigated the incidence of ischemic stroke during long-term follow-up. Compared to the AF recurrence group (n = 619), the sinus rhythm (SR) maintenance group (n = 929) had more paroxysmal AF (74.6% versus 44.4%, p<0.001), smaller LA size (39.9+/-5.7mm versus 42.3+/-6.0mm, p<0.001), and younger age (54.2+/-10.9 years versus 56.4+/-10.6 years, p<0.001). However, CHA2DS2-VASc scores were not significantly different between the two groups (0.9 vs. 1.1, p = 0.053). The overall incidence of ischemic stroke during the mean follow-up period of 54 months after CA was 0.6%, and was significantly lower in the SR group than the AF recurrence group (0.3% vs. 1.1%, log-rank test p<0.001). However, in sub-analysis in the SR group, the rate of ischemic stroke was significantly increasing in patients with a CHA2DS2-VASc score >= 4 compared to those with a CHA2DS2-VASc score < 4 (4.3% vs. 0.2%, log-rank test p<0.001). In conclusion, this long-term follow-up data in patients with AF who underwent successful CA showed that SR maintenance was correlated with a lower rate of ischemic stroke in Korea. However, it was only observed in patients with CHA2DS2-VASc score <=3. PMID- 30024977 TI - Tuberculosis and the sexual and reproductive lives of women in Bangladesh. AB - When they do not meet norms related to sexuality and reproduction, Bangladeshi women often face abandonment and are thus deprived of an active sexual life, a marital relationship, and motherhood. Little is known about how a stigmatised disease such as tuberculosis (TB) may constrain the reproductive health and sexual lives of women. This article, derived from a larger study on the impact of TB on women's sexual and reproductive health and rights in Narsingdi district and Dhaka, Bangladesh, aims to fill this gap. Based on interviews with nine married women who have or had TB, four husbands, and two mothers-in-law, this article highlights that the ways in which TB impedes on the sexual and reproductive lives of women depends on the stigma within their family and community, their relationships with their husbands, motherhood, their living arrangements, their economic contribution to the family and/or their disclosure of their TB diagnosis. Women with children and supportive husbands retain a stronger position among their in-laws and are less likely to be isolated or rejected. The patients' narratives revealed that the instructions of health workers influenced their decisions about intercourse or abstinence. Future studies should examine the instructions patients receive from health workers regarding their living and sleeping arrangements, sexual intercourse, and pregnancy, as well as policy documents on TB treatment and prevention. PMID- 30024978 TI - Quality of life and health status of Indonesian women with breast cancer symptoms before the definitive diagnosis: A comparison with Indonesian women in general. AB - OBJECTIVES: Breast cancer (BC) is prevalent in low and middle-income countries (LMICs) where the majority of cases are diagnosed in late stages. The aims of this study were: (1) to assess quality of life (QOL) and health status of Indonesian women with BC symptoms before definitive diagnosis; (2) to compare QOL and health status between women with BC symptoms before definitive diagnosis and Indonesian women in general; (3) to evaluate the association between demographic variables (age, residence, social economic status and education level) and QOL within the Indonesian women with BC symptoms before definitive diagnosis. METHODS: We used WHOQOL-BREF to measure QOL and EQ-5D-5L for health status. Multivariate analysis of covariance (MANCOVA) was used to compare QOL and health status between women with BC symptoms and women from the general Indonesian population in order to control for confounders. Regression analyses were used for testing the association between the demographic variables, QOL, and health status. RESULTS: In comparison with the data from the women from the general population (n = 471), the women with BC symptoms (n = 132) reported lower QOL, especially in physical and psychological domains. They also reported more problems in all dimensions of health status. Higher education and monthly income were positively associated with QOL and health status among the women with BC symptoms. CONCLUSION: Before receiving a definitive diagnosis, women who visit hospitals with symptoms of BC, report a lower QOL and health status than women in general. Our results suggest that healthcare providers should provide targeted strategies for women with BC symptoms to improve their QOL. PMID- 30024980 TI - Blood and guts: The intestinal vasculature during health and helminth infection. PMID- 30024979 TI - Bi-frontal pneumocephalus is an independent risk factor for early postoperative agitation in adult patients admitted to intensive care unit after elective craniotomy for brain tumor: A prospective cohort study. AB - : Postoperative agitation frequently occurs after general anesthesia and may be associated with serious consequences. However, studies in neurosurgical patients have been inadequate. We aimed to investigate the incidence and risk factors for early postoperative agitation in patients after craniotomy, specifically focusing on the association between postoperative pneumocephalus and agitation. Adult intensive care unit admitted patients after elective craniotomy under general anesthesia were consecutively enrolled. Patients were assessed using the Sedation Agitation Scale during the first 24 hours after operation. The patients were divided into two groups based on their maximal Sedation-Agitation Scale: the agitation (Sedation-Agitation Scale >= 5) and non-agitation groups (Sedation Agitation Scale <= 4). Preoperative baseline data, intraoperative and intensive care unit admission data were recorded and analyzed. Each patient's computed tomography scan obtained within six hours after operation was retrospectively reviewed. Modified Rankin Scale and hospital length of stay after the surgery were also collected. Of the 400 enrolled patients, agitation occurred in 13.0% (95% confidential interval: 9.7-16.3%). Body mass index, total intravenous anesthesia, intraoperative fluid intake, intraoperative bleeding and transfusion, consciousness after operation, endotracheal intubation kept at intensive care unit admission and mechanical ventilation, hyperglycemia without a history of diabetes, self-reported pain and postoperative bi-frontal pneumocephalus were used to build a multivariable model. Bi-frontal pneumocephalus and delayed extubation after the operation were identified as independent risk factors for postoperative agitation. After adjustment for confounding, postoperative agitation was independently associated with worse neurologic outcome (odd ratio: 5.4, 95% confidential interval: 1.1-28.9, P = 0.048). Our results showed that early postoperative agitation was prevalent among post-craniotomy patients and was associated with adverse outcomes. Improvements in clinical strategies relevant to bi-frontal pneumocephalus should be considered. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02318199). PMID- 30024981 TI - Population genomics shows no distinction between pathogenic Candida krusei and environmental Pichia kudriavzevii: One species, four names. AB - We investigated genomic diversity of a yeast species that is both an opportunistic pathogen and an important industrial yeast. Under the name Candida krusei, it is responsible for about 2% of yeast infections caused by Candida species in humans. Bloodstream infections with C. krusei are problematic because most isolates are fluconazole-resistant. Under the names Pichia kudriavzevii, Issatchenkia orientalis and Candida glycerinogenes, the same yeast, including genetically modified strains, is used for industrial-scale production of glycerol and succinate. It is also used to make some fermented foods. Here, we sequenced the type strains of C. krusei (CBS573T) and P. kudriavzevii (CBS5147T), as well as 30 other clinical and environmental isolates. Our results show conclusively that they are the same species, with collinear genomes 99.6% identical in DNA sequence. Phylogenetic analysis of SNPs does not segregate clinical and environmental isolates into separate clades, suggesting that C. krusei infections are frequently acquired from the environment. Reduced resistance of strains to fluconazole correlates with the presence of one gene instead of two at the ABC11 ABC1 tandem locus. Most isolates are diploid, but one-quarter are triploid. Loss of heterozygosity is common, including at the mating-type locus. Our PacBio/Illumina assembly of the 10.8 Mb CBS573T genome is resolved into 5 complete chromosomes, and was annotated using RNAseq support. Each of the 5 centromeres is a 35 kb gene desert containing a large inverted repeat. This species is a member of the genus Pichia and family Pichiaceae (the methylotrophic yeasts clade), and so is only distantly related to other pathogenic Candida species. PMID- 30024982 TI - Therapeutic effects of recombinant human interleukin 2 as adjunctive immunotherapy against tuberculosis: A systematic review and meta-analysis. AB - BACKGROUND: Interleukin 2 (IL-2) is a cytokine secreted by activated T cells. Studies exploring recombinant human interleukin 2 (rhuIL-2) as an adjunctive immunotherapeutic agent to treat tuberculosis (TB) have shown variable results; however, the true therapeutic efficacy of rhuIL-2 administration in TB patients has not been determined. METHODS: A systematic review to identify publications exploring the association between rhuIL-2-based immunotherapy for TB and outcomes (sputum culture conversion, sputum smear conversion, radiographic changes, and leukocyte phenotype changes) in patients with pulmonary TB published before June 8, 2018 was performed. Data were extracted and analyzed by two investigators independently. RESULTS: A total of 2,272 records were screened. Four randomized controlled trials (RCTs) comprising 656 pulmonary TB patients were finally included. The rhuIL-2 treatment could significantly improve the sputum culture conversion of TB (RR, 1.18; 95%CI: 1.03-1.36; I2 < 0.01; P = 0.019) after at least 3 months of anti-TB therapy and the sputum smear conversion of TB during anti-TB therapy. Treating multidrug-resistant tuberculosis (MDR-TB) with rhuIL-2 could improve the sputum culture conversion (RR, 1.28; 95%CI: 1.05-1.57; I2 < 0.01; P = 0.016) and smear conversion (RR, 1.28; 95%CI: 1.09-1.51; I2 < 0.01; P = 0.003) at the end of anti-TB treatment. Meanwhile, rhuIL-2-based adjunctive immunotherapy could expand the proliferation and conversion of CD4+ and natural killer (NK) cells. Three of the included studies suggested that radiographic changes could not be improved by the use of rhuIL-2 as adjunctive immunotherapy. Publication bias did not exist. CONCLUSIONS: Based on this first meta-analysis, rhuIL-2-based adjunctive immunotherapy appears to expand the proliferation and conversion of CD4+ and NK cells, as well as improve the sputum culture (at 3 months and later) and smear conversion of TB patients. PMID- 30024983 TI - Internal limiting membrane peeling versus no peeling during primary vitrectomy for rhegmatogenous retinal detachment: A systematic review and meta-analysis. AB - BACKGROUND: Internal limiting membrane (ILM) peeling during primary vitrectomy for rhegmatogenous retinal detachment (RRD) prevents the formation of postoperative macular epiretinal membrane (ERM). However, studies that compared vitrectomy with and without ILM peeling for RRD, have reported controversial outcomes. OBJECTIVE: To assess the efficacy of ILM peeling versus non-ILM peeling during vitrectomy for RRD by a systematic review and meta-analysis of published studies. METHODS: PubMed, Medline, Web of Science, Embase databases, and the Cochrane Library were searched up to April 2018 to identify studies that compared primary vitrectomy with and without ILM peeling for RRD with at least six months follow-up. Primary outcomes were the rate of postoperative ERM formation and mean best corrected visual acuity (BCVA) change after vitrectomy. Rate of recurrence of retinal detachment (RD) was assessed as secondary outcome. Risk ratios (RRs) with 95% confidence intervals (CIs) expressed pooled results for rate of ERM formation and rate of RD recurrence in ILM peeling and non-ILM peeling groups. Pooled results for BCVA change in the two groups were expressed as Weighted Mean Difference (WMD) with 95% CIs. RESULTS: Nine studies, one of which was a randomized controlled trial (RCT), with a total number of 404 eyes in the ILM peeling group and 365 eyes in the non-ILM peeling group, were included. The analysis from pooled data indicated a significant lower rate of postoperative ERM formation in the ILM peeling group compared to the non-ILM peeling group (9 studies, 769 eyes, RR = 0.14; CI: 0.07 to 0.28; P < 0.001). There was no statistical difference in mean BCVA change (9 studies, 769 eyes, WMD = 0.02; CI: 0.11 to 0.16; P = 0.75). Rate of recurrence of RD was lower in the ILM peeling group (6 studies, 603 eyes, RR = 0.32; CI = 0.17 to 0.61; P< 0.001). CONCLUSION: ILM peeling during vitrectomy for RRD prevents the formation of macular epiretinal membrane postoperatively and reduces the incidence of RD recurrence, but better visual outcome was not found compared to non-ILM peeling vitrectomy. PMID- 30024985 TI - Murine macrophage TLR2-FcgammaR synergy via FcgammaR licensing of IL-6 cytokine mRNA ribosome binding and translation. AB - Macrophages (MOs) are sentinels of the immune system that use pattern recognition receptors such as Toll-like receptors (TLR) to detect invading pathogens and immune receptors such as FcgammaR to sense the host's immune state. Crosstalk between these two signaling pathways allows the MO to tailor the cell's overall response to prevailing conditions. However, the molecular mechanisms underlying TLR-FcgammaR crosstalk are only partially understood. Therefore, we employed an immunologically-relevant MO stimulus, an inactivated gram-negative bacterium that bears TLR2 agonists but no TLR4 agonist (iBTLR2) opsonized with a monoclonal antibody (mAb-iBTLR2), as a tool to study FcgammaR regulation of TLR2-driven production of IL-6, a key inflammatory cytokine. We chose this particular agonist as an investigational tool because MO production of any detectable IL-6 in response to mAb-iBTLR2 requires both TLR2 and FcgammaR signaling, making it an excellent system for the study of receptor synergy. Using genetic, pharmacological and immunological approaches, we demonstrate that the murine MO IL-6 response to mAb-iBTLR2 requires activation of both the TLR/NF-kappaB and FcgammaR/ITAM signaling pathways. mAb-iBTLR2 engagement of TLR2 drives NF-kappaB activation and up-regulation of IL-6 mRNA but fails to result in IL-6 cytokine production/release. Here, Src family kinase-driven FcgammaR ITAM signaling is necessary to enable IL-6 mRNA incorporation into polysomes and translation. These results reveal a novel mechanism by which FcgammaR ITAM signaling synergizes with TLR signaling, by "licensing" cytokine mRNA ribosome binding/translation to drive a strong murine MO cytokine response. PMID- 30024984 TI - Amyloidogenic cross-seeding of Tau protein: Transient emergence of structural variants of fibrils. AB - Amyloid aggregates of Tau protein have been implicated in etiology of many neurodegenerative disorders including Alzheimer's disease (AD). When amyloid growth is induced by seeding with preformed fibrils assembled from the same protein, structural characteristics of the seed are usually imprinted in daughter generations of fibrils. This so-called conformational memory effect may be compromised when the seeding involves proteins with non-identical sequences leading to the emergence of distinct structural variants of fibrils (amyloid 'strains'). Here, we investigate cross-seeding of full-length human Tau (FL Tau) with fibrils assembled from K18 and K18DeltaK280 fragments of Tau in the presence of poly-L-glutamate (poly-Glu) as an enhancer of Tau aggregation. To study cross seeding between Tau polypeptides and the role of the conformational memory effect in induction of Tau amyloid polymorphism, kinetic assays, transmission electron microscopy, infrared spectroscopy and limited proteolysis have been employed. The fastest fibrillization was observed for FL Tau monomers seeded with preformed K18 amyloid yielding daughter fibrils with unique trypsin digestion patterns. Morphological features of daughter FL Tau fibrils induced by K18 and K18DeltaK280 seeds were reminiscent of the mother fibrils (i.e. straight paired fibrils and paired helical filaments (PHFs), respectively) but disappeared in the following generations which became similar to unpaired FL Tau amyloid fibrils formed de novo. The structural evolution observed in our study was accompanied by disappearance of the unique proteolysis profile originated from K18. Our findings may have implications for understanding molecular mechanisms of the emergence and stability of Tau amyloid strains. PMID- 30024986 TI - Antibody to Poly-N-acetyl glucosamine provides protection against intracellular pathogens: Mechanism of action and validation in horse foals challenged with Rhodococcus equi. AB - Immune correlates of protection against intracellular bacterial pathogens are largely thought to be cell-mediated, although a reasonable amount of data supports a role for antibody-mediated protection. To define a role for antibody mediated immunity against an intracellular pathogen, Rhodococcus equi, that causes granulomatous pneumonia in horse foals, we devised and tested an experimental system relying solely on antibody-mediated protection against this host-specific etiologic agent. Immunity was induced by vaccinating pregnant mares 6 and 3 weeks prior to predicted parturition with a conjugate vaccine targeting the highly conserved microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG). We ascertained antibody was transferred to foals via colostrum, the only means for foals to acquire maternal antibody. Horses lack transplacental antibody transfer. Next, a randomized, controlled, blinded challenge was conducted by inoculating at ~4 weeks of age ~10(6) cfu of R. equi via intrabronchial challenge. Eleven of 12 (91%) foals born to immune mares did not develop clinical R. equi pneumonia, whereas 6 of 7 (86%) foals born to unvaccinated controls developed pneumonia (P = 0.0017). In a confirmatory passive immunization study, infusion of PNAG-hyperimmune plasma protected 100% of 5 foals against R. equi pneumonia whereas all 4 recipients of normal horse plasma developed clinical disease (P = 0.0079). Antibodies to PNAG mediated killing of extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms depended on antibody recognition of surface expression of PNAG on infected cells, along with complement deposition and PMN-assisted lysis of infected macrophages. Peripheral blood mononuclear cells from immune and protected foals released higher levels of interferon-gamma in response to PNAG compared to controls, indicating vaccination also induced an antibody-dependent cellular release of this critical immune cytokine. Overall, antibody-mediated opsonic killing and interferon-gamma release in response to PNAG may protect against diseases caused by intracellular bacterial pathogens. PMID- 30024987 TI - Response mechanisms induced by exposure to high temperature in anthers from thermo-tolerant and thermo-sensitive tomato plants: A proteomic perspective. AB - Constant global warming is one of the most detrimental environmental factors for agriculture causing significant losses in productivity as heat stress (HS) conditions damage plant growth and reproduction. In flowering plants such as tomato, HS has drastic repercussions on development and functionality of male reproductive organs and pollen. Response mechanisms to HS in tomato anthers and pollen have been widely investigated by transcriptomics; on the contrary, exhaustive proteomic evidences are still lacking. In this context, a differential proteomic study was performed on tomato anthers collected from two genotypes (thermo-tolerant and thermo-sensitive) to explore stress response mechanisms and identify proteins possibly associated to thermo-tolerance. Results showed that HS mainly affected energy and amino acid metabolism and nitrogen assimilation and modulated the expression of proteins involved in assuring protein quality and ROS detoxification. Moreover, proteins potentially associated to thermo-tolerant features, such as glutamine synthetase, S-adenosylmethionine synthase and polyphenol oxidase, were identified. PMID- 30024988 TI - Cancer as the "perfect storm"? A qualitative study of public attitudes to health conditions. AB - Aims: Our aim is to identify important attributes of major diseases that shape how they are perceived by the public. Methods and Results: Four focus groups among members of the public were recruited, in March and October 2016, and used semistructured discussion to explore important attributes of cancer, heart disease, stroke, dementia, mental illness, and infectious disease. Common themes were identified by using inductive thematic analysis.Five themes were identified: fear, impact on family and friends, hope, detection, and prevention. Fear of cancer includes not only fear of death but also of aggressive treatments. Loss of dignity is feared in dementia, while infectious disease raises fear of uncontrollable "plague"; in contrast, people with mental illness may themselves be seen as a potential threat. The impact of cancer and its treatment on family and friends was described as intense and all-consuming, even for those not involved directly in caring; with dementia and stroke, the family impact is taking on care, including funding, over the long term with little expectation of improvement. Hope is a major theme in cancer and stroke recovery, linked with the need to take action, often expressed in aggressive language of "fighting," but seen as futile in dementia. Detection difficulties for "silent" cancers mean that real treatment opportunities are missed; cardiovascular and infection risk, however, are seen as easy to identify and act on, whereas mental illness and dementia are seen as poorly diagnosed and with limited treatment options. Prevention awareness is high for cardiovascular disease and infection, lower for cancer, and limited for dementia and mental health. Conclusion: Although themes overlap across diseases, the specific concerns are different and each condition has a unique profile. Quantifying the relative importance of these themes could allow their incorporation in decision-making, not only when they occur as a named disease but also in any relevant condition. PMID- 30024990 TI - Effects of Low-Profile Stud Attachment Configurations on Stress Distribution Characteristics of Implant-Retained Overdentures. AB - PURPOSE: Implant-retained mandibular overdentures are a proven treatment modality for edentulous patients. Low-profile stud attachments may allow divergence between the abutments up to 40 degrees. The purpose of this study was to investigate load transfer characteristics of various locations and nylon male configurations of low-profile stud attachment-retained overdentures. MATERIALS AND METHODS: Three tapered dental implants were placed into three photoelastic mandibular models. The center implants were placed vertically onto the midline, and the distal implants were inclined 20 degrees corresponding to centralized implants. Three different distances (11, 18, and 25 mm) between the centralized and the distal implants were set on the models. Low-profile stud attachment (Locator)-retained mandibular overdentures were fabricated for each photoelastic model. Five different nylon male configurations of this stud attachment were established. The load transfer characteristics of the configurations were tested using a circular polariscope. RESULTS: The observed stress levels for the tested configurations were moderate except for group 25C (photoelastic model with 25-mm interimplant distances and clear nylon male), which illustrated a high stress level. For the 11-mm photoelastic model, little or no discernible stress was noted around the dental implants for group 11R (red nylon male), group 11G (green nylon male), and configurations of clear and red or green nylon males (group 11CR [clear and red nylon males] and group 11CG [clear and green nylon males]). CONCLUSION: The applied loads were distributed to the supported dental implants and denture-bearing areas for tested designs. Equitable load distribution and less stress may be gathered using nylon males for angulated implants (red and green) when dental implants are placed inclined. PMID- 30024989 TI - Comparative In Vitro Study of Implant-Supported Restorations: Implant-Abutment Complex With and Without Prosthetic Finishing Line. AB - PURPOSE: The aim of this study was to evaluate the mechanical behavior of implant supported cemented restorations placed on two types of abutment design, with and without a prosthetic finish line, evaluating fracture resistance and the type of fracture produced in the abutment-crown complex. MATERIALS AND METHODS: Eighty zirconia restorations supported by tapered implants were divided into two groups: group I, with 40 zirconia crowns cemented onto individualized zirconia abutments with a chamfered finish line (1 mm deep); and group II, with 40 zirconia crowns cemented onto individualized zirconia abutments without a finish line. All specimens underwent thermocycling and dynamic loading before static load testing to evaluate their fracture resistance. RESULTS: Fracture resistance values (N) and the type of fracture were analyzed. The mean fracture resistance was 462.1 +/ 66.3 N in group I and 343 +/- 40 N in group II. In group I, fractures were produced in the prosthetic fixation screw; in group II, all mechanical failures were produced in the transepithelial abutment's cervical area. CONCLUSION: Group I specimens showed greater fracture resistance than group II. The fracture type in group I occurred in the prosthetic screw. Group II fractures occurred in the zirconium oxide abutment. PMID- 30024991 TI - Influence of Rigid Bar and Nonrigid Double Crown Attachments on Maxillary Implant Overdentures: An In Vitro Study with Differential Bone Quality. AB - PURPOSE: To evaluate the bending strain exerted on a maxillary implant overdenture supported by rigid bar and nonrigid double crown connectors in models of high- and low-quality bone. MATERIALS AND METHODS: Four implants were embedded in acrylic resin models of an edentulous maxilla simulating good- and poor quality bone at the canine and second premolar regions bilaterally. A bar (cross section dimension: 5 * 5 mm; bilateral distal extension: 10 mm) and double crown connectors with a metal framework (same morphology as the bar) were attached to these implants and placed under a constant 49 N vertical load at the anterior and cantilever regions of both superstructures. The bending strain on the implants was measured by strain gauges attached to the implant surfaces. RESULTS: In good quality bone with cantilever loading, the strain--which was highest near the load for both attachment systems--was highly concentrated in the rigid bar system but dissipated through the double crown connector. The directionality of the bending moment was homogenous on the two attachments. In poor-quality bone, strains were significantly lower and more variable, especially for double crown connectors, and there was heterogeneity in the directions of the bending moment. CONCLUSION: Within the limitations of this study, bar and double crown connectors have identical biomechanical features in good-quality edentulous maxillary bone, but have divergent properties in poor-quality bone. PMID- 30024992 TI - Prevalence of Peri-implant Disease According to Periodontal Probing Depth and Bleeding on Probing: A Systematic Review and Meta-Analysis. AB - PURPOSE: To compare changes in the prevalence of peri-implantitis when the unit of analysis is the subject and when the unit of analysis is the implant, by means of meta-analysis with subgroup and sensitivity analyses, according to the case definition and cutoffs. Periodontal probing depth (PPD) and bleeding on probing (BOP) were considered the primary variables. MATERIALS AND METHODS: Electronic and manual searches of observational studies of implants with loading of more than 6 months were conducted. The quality of the studies was evaluated, and finally, a description (qualitative analysis) and a meta-analysis (quantitative analysis) of the available studies were performed. RESULTS: Fifty-five studies were included in this systematic review, 32 of which met the criteria for evaluation of disease based on PPD and BOP. A total of 2,734 subjects and 7,849 implants were evaluated. The prevalence of peri-implantitis, defined by PPD and BOP, was 17% when the unit of analysis was the subject, and 11% when it was the implant. If the clinical criterion was PPD >= 4 mm, the prevalence by subject was 34% and by implant 11%. If PPD was >= 5 mm, the prevalence by subject was 12% and by implant 10%. Finally, if the clinical criterion was PPD >= 6 mm, the prevalence by subject was 18% and by implant 10%. CONCLUSION: The prevalence of peri-implantitis is influenced by the criteria used for the case definition, and the true prevalence may currently be incorrectly estimated. PMID- 30024993 TI - Impact of Surface Chemistry Modifications on Speed and Strength of Osseointegration. AB - PURPOSE: To compare the bone responses of chemically modified implants using the plasma immersion ion implantation and deposition method with those of blasted implants. MATERIALS AND METHODS: The titanium implants were blasted with resorbable blasting media (RBM) and designated as controls. The ion-implanted implants were divided into two test groups, namely, calcium (Ca) and magnesium (Mg) implants. Six implants (two implants per group) were placed into the proximal tibias of 11 New Zealand white rabbits. Fluorochrome labeling was administered at 2 and 4 weeks after surgery. Resonance frequency analysis (RFA) was conducted immediately after surgery and at 6 weeks of healing. The removal torque was measured in half of the tibiae. The implants in another tibia were subjected to fluorescence analysis and histologic and histomorphometric evaluations. RESULTS: The fluorescence analysis suggested that osteoconductivity was improved in the early osseointegration stages in the Ca and Mg implants. In the cortical region, the bone-to-implant contact in the Mg implants and the bone area % in the Ca and Mg implants were higher than those in the RBM implants (P < .05). All groups demonstrated similar biomechanical strengths with respect to the RFA and the removal torque measurements. CONCLUSION: The osseointegration speed and the bone contact were positively affected by the Ca and Mg ion implantation, especially in the Mg implants, because of the synergistic effect. However, no remarkable differences were found in biomechanical strength in the later osseointegration stages. PMID- 30024994 TI - Effects of Axial Loading on the Pull-out Force of Conical Connection Abutments in Ankylos Implant. AB - PURPOSE: The aim of this study was to assess the effects of simulated axial loadings on the pull-out force required to disengage a two-piece conical connection abutment from an implant. MATERIALS AND METHODS: Ten conical connection abutments (Ankylos Regular/X Abutment, Dentsply-Friadent) and 10 implants (Ankylos C/X Implant) were used. The implant-abutment assemblies were divided randomly into two groups: control group (C) and experimental group (E). For group E (n = 5), a cyclic load of 18 to 180 N at a frequency of 10 Hz to 106 cycles was applied centrally and along the long axis of the implant, whereas for group C (n = 5), each sample was put on a workbench without cyclic loading at the same time during the testing period. Before mechanical loading, the initial torque values and the total lengths of tested samples of groups C and E were recorded. After cyclic loading, the postloading reverse torque value, the total length, and the pull-out force of tested samples of groups C and E were recorded. The difference between the initial torque value and the postloading reverse torque value was defined as the total torque loss. The difference between the initial total length and the postloading total length was defined as the axial displacement. The data were analyzed by independent t test. RESULTS: The mean pull-out force of the experimental group was 77.60 N (SD = 6.16 N), which was significantly larger than that of the control group (mean = 55.28 N; SD = 9.41 N) (P < .05). The mean total torque loss and the mean axial displacement of the experimental group were both significantly higher than those of the control group (P < .05). CONCLUSION: Simulated axial loading increased the pull-out force of loaded abutments in comparison with unloaded abutments. Under simulated axial loading, the pull-out force of abutments tended to increase as the axial displacement of abutments and the total torque loss of abutment screws were both increased. PMID- 30024995 TI - Impact of Implant Number on Mandibular Implant-Supported Profile Prostheses: A Systematic Review. AB - PURPOSE: To assess studies on edentulous patients rehabilitated using mandibular implant-supported profile prostheses and analyze the impact of different numbers of implants used on the implant survival rate, peri-implant bone loss, and prosthesis survival rate. MATERIALS AND METHODS: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement and was registered on PROSPERO. The PubMed/MEDLINE database was searched for articles published before July 18, 2016. The study attempted to answer the following PICO question: In edentulous patients, do full-arch fixed prostheses supported by three implants have a satisfactory implant survival rate, marginal bone loss, and prosthesis survival rate compared with those supported by different numbers of implants? Evidence levels of each study were evaluated using the Oxford Centre for Evidence-Based Medicine (OCEBM); methodologic quality was evaluated using the Methodological Index for Nonrandomized Studies (MINORS) scale and Cochrane Risk of Bias Tool. Descriptive statistics were performed when applicable. Implant survival curves were constructed using the Kaplan-Meier method, and marginal bone loss was analyzed using the Kruskal-Wallis, Dunn's, and Mann-Whitney tests. RESULTS: This analysis included 21 published studies of 4,712 implants and 1,245 mandibular implant-supported profile prostheses in 1,245 patients. The patients were grouped by the number of implants used: group 1 (three implants) had an implant survival rate of 90%; group 2 (four implants) had a rate of 95%; and group 3 (five implants) had the lowest rate, 74%. Groups 1 and 3 had the lowest first-year bone losses (median: 0.73 and 0.70 mm, respectively), and were significantly different from group 2 (median: 1.31 mm; P < .001). CONCLUSION: Despite the limitations in the studies with low levels of evidence and the methodology of MeSH term research, it was concluded that the implant survival rate and first-year bone loss of full-arch fixed prostheses supported by three implants were satisfactory. However, the prosthesis survival rate was inferior to that of other groups, which suggests a longer follow-up of these rehabilitations. PMID- 30024996 TI - Marginal and Internal Adaptation of Hybrid Abutment Assemblies After Central and Local Manufacturing, Respectively. AB - PURPOSE: Central manufacturing of two-piece computer-aided design/computer-aided manufacture (CAD/CAM) zirconia abutments may provide a higher accuracy of internal and external adaptation at the expense of delayed restoration delivery. The aim of this study was to compare the fit of two-part zirconia abutments that were either fabricated centrally with the DEDICAM system or at a local laboratory. The field of interest was the marginal, external, and internal luting gap between the titanium insert and CAD/CAM zirconia coping. MATERIALS AND METHODS: Two groups of nine two-piece CAD/CAM zirconia hybrid abutments were subjected to scanning electron microscopy (SEM) to evaluate the precision of fit and thickness of the adhesive joint. Control specimens were fabricated with the CAMLOG DEDICAM system at the manufacturer's site; the test specimens were produced in a local laboratory. After embedding all samples (n = 18) in resin, they were sectioned, and the external, marginal, and internal luting gaps between the titanium base and zirconia coping were measured with SEM. Welch's t test was used for statistical analysis of the obtained data. RESULTS: The overall range of measured gaps between the components of two-piece CAD/CAM zirconia abutments was 0 to 115.5 MUm; the mean overall gap size and standard deviation was 45.61 +/- 5.88 MUm and showed no appreciable difference between the test and control groups. The mean sizes of the marginal/external and internal gaps showed only negligible differences. The internal gap size was generally larger and showed a higher variability than the marginal/external gaps, albeit on a very low level. None of the reported differences between the test and control specimens were statistically significant. CONCLUSION: Luting-gap sizes of CAMLOG DEDICAM- and locally fabricated CAD/CAM zirconia hybrid abutments showed no appreciable difference. Both configurations of two-piece abutments provided a highly precise fit of hybrid components, overmatching the high-quality standards in CAD/CAM implant-based prosthetic dentistry. PMID- 30024998 TI - Correlation Between Implant Geometry, Implant Surface, Insertion Torque, and Primary Stability: In Vitro Biomechanical Analysis. AB - PURPOSE: Primary implant stability represents the first step for successful osseointegration. The knowledge of the correlation between host bone density, insertion torque, and implant macrogeometry seems to be fundamental to achieve sufficient primary implant bone fixation in each clinical situation. The purpose of this study was to measure, in vitro, the impact of dental implant macrogeometry and insertion torque values on primary stability in relation to different bone densities, representing both the human mandible and maxilla. MATERIALS AND METHODS: One hundred twenty 3.8 +/- 11-mm commercial dental implants were used. Forty implants had small threads with a machined neck, 40 implants had small threads with a microthreaded neck, and the last 40 implants had large threads with a reverse neck design. Fresh bovine ribs, representing a medium-dense bone density (D2-D3), and fresh ovine iliac crest, representing a soft bone density (D4), were used. Insertion torque and micromobility under lateral force data were recorded for each implant. RESULTS: In the medium-dense bone type, the reverse neck implant design showed less primary implant stability than the conventional straight implant neck. In soft bone, both implants with the large thread design and microthreaded neck implants showed better implant stability than the implant with a small thread design with a straight machined neck. Implants with large and self-cutting threads showed significantly (P < .05) lower micromobility values than other implants in postextractive sites in low density bone. CONCLUSION: Implant geometries and bone density are the main factors involved in the degree of primary implant stability. Large-thread implant designs are highly desirable in cases of poor bone quality. Each implant geometry generates an insertion torque value, which is correlated to the stability of that specific implant in a specific bone quality, but the insertion torque is not an objective value to compare primary stability between different implant types. PMID- 30024997 TI - Does the Presence of a Cantilever Influence the Survival and Success of Partial Implant-Supported Dental Prostheses? Systematic Review and Meta-Analysis. AB - PURPOSE: To investigate if the presence of a cantilever influences the survival and success of partial fixed implant-supported prostheses, through a systematic review and meta-analysis, with additional analysis of the survival and marginal bone loss rates and prosthesis complications. MATERIALS AND METHODS: The register protocol of the review in the PROSPERO database is CRD42016052008. The MEDLINE and Scopus databases were used for an electronic search of relevant studies up to November 2016, by means of two independent reviewers. The keywords included the combinations "fixed partial denture" with "dental implants", and with "extension" or "cantilever"; and "implant-supported dental prosthesis" with "extension" or "cantilever". The inclusion criteria were randomized clinical trials and prospective and retrospective clinical studies in English that addressed the comparison of success and survival of the use of implant-supported fixed prostheses, with and without cantilevers. Data from the selected studies were used to perform the statistical analysis. RESULTS: Among the 408 articles identified, 4 articles met the eligibility criteria. The presence of a cantilever did not compromise marginal bone loss or the survival of the prostheses. However, minor complications were encountered for the group of partial fixed prostheses without cantilevers, with a statistical difference (P = .008). CONCLUSION: Cantilevers can be used in fixed prostheses and do not interfere negatively in the survival or success of the prosthesis or the marginal bone loss. However, there are minor complications when prostheses without cantilevers, or short cantilevers, are used. PMID- 30024999 TI - Antimicrobial Efficacy of Photodynamic Therapy and Light-Activated Disinfection Against Bacterial Species on Titanium Dental Implants. AB - PURPOSE: The aim of this study was to evaluate the efficacy of photodynamic therapy (PDT) and light-activated disinfection (LAD) against a 3-day-old bacterial suspension prepared from three different bacterial species present on titanium dental implants, and to analyze the possible alterations of the implant surfaces as a result of the PDT and LAD. MATERIALS AND METHODS: The study was conducted on 72 titanium dental implants contaminated with a bacterial suspension prepared from three bacterial species: Prevotella intermedia, Aggregatibacter actinomycetemcomitans, and Porphyromonas gingivalis. The contaminated implants were incubated under anaerobic conditions for 72 hours and then were randomly divided into four experimental groups and two control groups (n = 12 each), according to the following treatment protocols: group 1 (PDT1): PDT (660 nm, 100 mW, 60 seconds) with toluidine blue; group 2 (PDT2): PDT (660 nm, 100 mW, 60 seconds) with phenothiazine chloride dye; group 3 (LAD): light-emitting diode (LED) with toluidine blue; group 4 (toluidine blue): treatment with only toluidine blue for 60 seconds. In the positive control group, the implants were treated with a 0.2% chlorhexidine-based solution for 60 seconds, and in the negative control group, no treatment was used. RESULTS: The highest bacterial reduction was recorded in the PDT1 (98.3%) and PDT2 (97.8%) groups. The results of this study showed that there was a statistically significant reduction of bacteria in the PDT1 and PDT2 groups compared with the negative control group (P < .05), individually for each bacterial species as well as for all three species together. LAD was less effective than PDT1 and PDT2, and did not show a statistically significant difference compared with the negative control or any other treatment group. Toluidine blue was the least effective treatment in terms of both the total bacterial count and the individual count for each bacterial species. CONCLUSION: Both PDT1 and PDT2 protocols showed a high efficacy against a 3-day-old bacterial biofilm on dental implants and were more effective compared with LAD. PMID- 30025000 TI - Interventions to Maintain Locator-Retained Mandibular Overdentures on Both External Hex and Internal Connection Implants: A Retrospective Study. AB - PURPOSE: To quantify the rate of maintenance interventions of mandibular prostheses: complete dentures and overdentures retained by two implants, with either internal hex or external hex connections. MATERIALS AND METHODS: This study analyzed patients with edentulous mandibles treated with distinct treatment protocols: a control group received complete dentures; a second group received Locator-retained overdentures supported by two external hex connection implants; and a third group received overdentures supported by internal hex connection implants. All of the maintenance interventions associated with the prosthetic treatment after delivery were recorded (starting from 2000 until the final assessment in 2012). Moreover, patient satisfaction was assessed using a 0 to 10 visual analog scale. RESULTS: The final sample was composed of 136 patients: 56 in the control group, 31 in the hex implant overdenture group, and 49 in the internal connection overdenture group followed over a period of 60 months (ranging from 3 to 144 months). Prosthetic adjustment was the most frequent intervention carried out, particularly within the control group (a mean rate of 1.1 +/- 1.9 times/subject/year) in comparison with the internal connection (0.6 +/- 0.8 times/subject/year) and hex implant overdenture groups (0.3 +/- 0.2 times/subject/year). Relining was also frequently required, occurring on average every 4 years in the control group and every 7 years in the overdenture groups. Abutment loosening was more frequent in the hex implant overdenture group than in the internal connection overdenture group (8/31 versus 8/49), as well as abutment wear (5/31 versus 5/49). Gingival inflammation was significantly more common in the hex implant overdenture group (19/31 patients), as compared with the controls (16/56 subjects), and satisfaction was higher in patients in the two overdenture groups (mean Oral Satisfaction Scale [OSS] score of 8.1 +/- 1.9 for external and 8.4 +/- 1.6 for internal connections) than in the control group (5.3 +/- 3.3). CONCLUSION: Locator-retained overdentures needed less than half the number of maintenance interventions when compared with the control group, and maintenance was required every 2 to 4 years. PMID- 30025001 TI - Are Intraoral Radiographs Accurate in Determining the Peri-implant Marginal Bone Level? AB - PURPOSE: The primary objective of this study was to assess the accuracy of periapical radiographs in determining the peri-implant marginal bone level. The accuracy of the linear measurements on radiographs was considered as the absolute difference between the true, intraoperative or surgical marginal bone level measurements (direct bone measurements during surgical procedures) and the radiographic measured distances. The secondary aims were to identify the variables influencing the radiographic evaluation (arch: mandible/maxilla; implant location: anterior/posterior; timing of implant placement: "early delayed" and "prolonged delayed"). The influence of vestibular and palatal/lingual crestal bone levels was also investigated. MATERIALS AND METHODS: STROBE guidelines were followed. As soon as the implant was inserted, the marginal bone levels were recorded using a straight periodontal probe (intraoperative or surgical measurements). At the same time, periapical radiographs were taken. To standardize the radiographic images, periapical radiographs were acquired using the long-cone parallel technique and film holding system. All radiographs were analyzed by two examiners blinded to the surgical measurements. Intraclass correlation coefficient (ICC) was employed to assess the intraobserver and interobserver variability. The descriptive statistics, t test, and multivariate statistics were used; the threshold for statistical significance was P <= .05. RESULTS: Two hundred sixty-eight implants were inserted in 142 patients. The interobserver agreement was 0.980; the intraobserver variability was 0.990 and 0.993. The mean difference between the radiographic and surgical measurements was 0.45 mm (range: 0 to 8 mm; SD: 1.76). Comparing the radiographic and surgical measurements, a statistically significant difference (P = .000) was detected. None of the variables considered (arch, implant location, and timing of implant placement) significantly influenced the accuracy. Neither the vestibular alveolar edge (P = .908) nor the lingual/palatal (P = .485) significantly influenced the accuracy. CONCLUSION: The periapical radiograph statistically significantly overestimates the level of peri-implant marginal bone compared with surgical measurements. The arch, implant location, timing of implant placement, and level of vestibular or lingual/palatal alveolar edge do not influence deviation between the intraoperative peri-implant marginal bone level measurements and the radiographically determined marginal bone levels. PMID- 30025002 TI - Evaluation of Microbial Contamination in the Inner Surface of Titanium Implants Before Healing Abutment Connection: A Prospective Clinical Trial. AB - PURPOSE: The objective of this investigation was to assess the microbiologic contamination in the inner surface of titanium implants prior to prosthetic abutment placement. MATERIALS AND METHODS: The study population consisted of partially edentulous individuals who had previously received at least one internal hexagon titanium dental implant. A bacterial sample of the inner surface of the individual dental implant was taken after surgical reopening for healing abutment placement. The samples were allocated in order to evaluate three distinctive variables as follows: (1) location (mandible vs maxilla), (2) early exposure of implants to the oral cavity (cover screw) throughout the healing stage (exposed vs not exposed), and (3) existence or lack of keratinized mucosa (KM). The microorganism species detected were examined by checkerboard DNA-DNA hybridization. RESULTS: A total of 32 partially edentulous patients with 78 implants placed in both the maxilla and mandible were enrolled: 8 men and 24 women, ranging in age from 27 to 64 years (mean age: 47.7 years). Bacteria were detected in 20 patients, distributed in 41 implants. Spontaneous early implant exposure and absence of KM did not increase bacterial contamination in the inner surface of implants. A significant increase in the detection of 22 bacterial species was found in the mandible when compared with the maxilla. CONCLUSION: Microbial biofilm accumulation in the implant's internal surface might happen before healing abutment placement. Exposure of implants to the oral cavity and absence of KM were not directly related to a greater microbial biofilm count. The results suggested that submerged healing does not protect implants against bacterial colonization. PMID- 30025003 TI - Predicting Patient-Reported Outcomes of Dental Implant Treatment. AB - PURPOSE: To investigate whether pretreatment patient-related factors are associated with the outcomes of dental implant treatment through multidimensional evaluations of oral health-related quality of life and health-related quality of life using the Oral Health Impact Profile (OHIP) and the 36-Item Short Form Health Survey (SF-36) developed from the Medical Outcomes Study, respectively. MATERIALS AND METHODS: Oral health-related quality of life was evaluated using the Japanese version of the OHIP, and health-related quality of life was evaluated using scores for the mental component summary (MCS) and physical component summary (PCS) dimensions of the SF-36. Data were collected before treatment (baseline) and 1 month after delivery of the prostheses (follow-up). Stepwise multivariate regression analysis was used to explore the associations of posttreatment OHIP and SF-36 scores and changes in these scores after treatment (dependent variables) with age, sex, educational background, number of missing teeth, Eichner's classification, pretreatment state, site of the embedded implant, number of implants, types of definitive prostheses, and baseline OHIP and SF-36 scores (independent variables). RESULTS: Data from 150 consecutive patients (mean age: 58.1 +/- 11.5 years) who underwent dental implant treatment between April 2008 and April 2016 were analyzed. The mean OHIP summary score, OHIP dimension scores (oral function, orofacial pain, orofacial appearance, and psychosocial impact), and MCS score showed significant improvements after treatment (P < .05). The baseline OHIP and SF-36 scores were consistently and significantly associated with the treatment outcome (ie, dependent) variables (P < .05). Moreover, the site of the embedded implant was identified as a significant predictor of the posttreatment status and changes in the OHIP summary score, oral function and orofacial appearance dimension scores (OHIP), and MCS score. CONCLUSION: These results suggest that patient perceptions of health and oral health conditions may help in the prediction of the outcomes of dental implant treatment. PMID- 30025004 TI - Classification Systems for Peri-implantitis: A Narrative Review with a Proposal of a New Evidence-Based Etiology Codification. AB - PURPOSE: To present the different definitions of peri-implantitis proposed in the literature and to propose a new evidence-based etiology-driven classification of peri-implantitis to accurately and fully describe the etiology of peri implantitis. MATERIALS AND METHODS: Full-text papers on the selected topic were obtained for all abstracts and titles that appeared to meet the inclusion criteria. Additional papers were included from the reference lists of the selected studies. No methodologic and reporting quality of the included papers was applied in order to collect the greatest number of articles. RESULTS: One hundred twenty-two studies were found according to the search criteria. After filter activation, abstract evaluation, and duplicate removal, 16 articles were deemed useful for the aim of the present narrative review. A manual search using personal contact and references of published works and contributions by the authors included another 16 articles, resulting in a total of 32 articles. After full-text article selection and reading, 15 articles were finally included. CONCLUSION: There is not a generally accepted classification system of the various degrees of peri-implantitis. An etiology-driven classification was proposed as a tool to assist the clinician in properly detecting and classifying etiology-based peri-implantitis. This classification may also support the assignment of prognosis, and if needed, therapy to arrest/prevent peri implantitis. PMID- 30025005 TI - Cone Beam Computed Tomography Assessment of the Buccal Bone Thickness in Anterior Maxillary Teeth: Relevance to Immediate Implant Placement. AB - PURPOSE: Peri-implant bone thickness is an important local factor that could influence esthetic outcomes in immediate implant therapy. The aim of this study was to assess the thickness of the buccal bone overlying the anterior maxillary teeth in Kenyans. MATERIALS AND METHODS: A total of 184 cone beam computed tomography (CBCT) scans that met the inclusion criteria were retrospectively studied. Buccal bone thickness of all maxillary anterior teeth was assessed, resulting in a total of 1,104 teeth. Measurements were taken on sagittal views at a point 4 mm below the cementoenamel junction (M1) and at the mid-root level (M2). The data were analyzed using SPSS software (version 20, IBM), and statistical significance was set at P <= .05. RESULTS: Mean buccal bone thickness of the teeth studied was 0.55 +/- 0.38 mm at M1 and 0.60 +/- 0.30 mm at M2. Missing buccal bone wall was observed in 31.61% (349 teeth) of all teeth at M1 and in 21.38% (236 teeth) of all teeth at M2. The majority of the teeth had a thin buccal bone wall (< 1 mm) at M1 (56.34%) and at M2 (68.48%), whereas a thick buccal bone (>= 1 mm) was only observed in 12.05% of teeth at M1 and in 10.14% of teeth at M2. Thin buccal bone was mainly found in central incisors, while thick buccal bone wall was found mainly in canines. The thickness of buccal bone at M1 decreased with an increase in age. CONCLUSION: Contour augmentation would be necessary in most of these cases, as the buccal bone was typically thin. The thickness at the cervical portion was inversely correlated with age. One in every four of the cases would not be ideal for flapless immediate implant placement due to a missing buccal bone wall. Preoperative CBCT analysis of the buccal wall is recommended for appropriate treatment planning. PMID- 30025006 TI - Bone Volume Dynamics and Implant Placement Torque in Horizontal Bone Defects Reconstructed with Autologous or Xenogeneic Block Bone: A Randomized, Controlled, Split-Mouth, Prospective Clinical Trial. AB - PURPOSE: The aim of this study was to evaluate volumetric stability of autologous and xenogeneic block grafts and primary stability of implants in maxillary grafted areas. MATERIALS AND METHODS: Each patient received one autologous block and xenogeneic block, both covered with a membrane. Bone thickness measurements clinically and tomographically were made before, immediately, and 6 months postoperatively. After 6 months, identical implants were placed in each grafted area, and primary stability was measured. RESULTS: Eight patients with anterior horizontal bone defects were selected. Clinical outcomes at 6 months postgrafting in the autologous block revealed a mean thickness of 7.4 +/- 1.6 mm, with an initial mean measurement of 3.4 +/- 1.7 mm and 2.6% resorption, whereas the mean in the xenogeneic block was 8.9 +/- 1.5 mm, 3.3 +/- 1.6 mm, and 7.3%, respectively. Tomographic evaluation of the thickness at 6 months postgrafting in the autologous block was a mean 7.8 +/- 1.8 mm, with an initial mean of 3.7 +/- 1.6 mm and resorption of 0%, while the mean in the xenogeneic block was 9.3 +/- 1.6 mm, 3.6 +/- 1.4 mm, and 2.1%, respectively. No significant difference in bone thickness was observed immediately or 6 months after the procedure. The mean implant placement torque was 32 +/- 22 Ncm in the autologous block and 18 +/- 9 Ncm in the xenogeneic block (P = .004). CONCLUSION: Xenogeneic block was shown to be a suitable alternative to reconstruct horizontal defects in the alveolar ridge that had undergone extensive resorption, though lower insertion torques were obtained during implant placement. PMID- 30025007 TI - Molecular Assessment of Human Peri-implant Mucosal Healing at Laser-Modified and Machined Titanium Abutments. AB - PURPOSE: To compare, by gene profiling analysis, the molecular events underscoring peri-implant mucosa formation at machined vs laser-microgrooved implant healing abutments. MATERIALS AND METHODS: Forty endosseous implants were placed by a one-stage approach in 20 healthy subjects in nonadjacent sites for single-tooth restorations. In a split-mouth design, machined smooth and laser microgrooved healing abutments were randomly assigned in each subject. Peri implant mucosa adjacent to healing abutments was harvested by tissue punch biopsy at either 1, 2, 4, or 8 weeks following abutment placement. Total RNA was isolated from the peri-implant transmucosal soft tissues. A whole genome microarray using the Affymetrix Human Gene 2.1 ST Array was performed to describe gene expression profiles in relation to abutment topography and healing time duration. Data analysis was completed using GeneSpring software v.12.6. RESULTS: Differential gene expression was revealed at all time points and among surfaces. Five hundred one genes were differentially expressed (fold change >= 2.0) at machined versus laser-modified abutments, and 459 of these were statistically significant (P <= .05). At 1 week, unique expression of IL-24 and MMP1 was observed in tissues from laser-treated surfaces. At 2, 4, and 8 weeks, mRNAs encoding keratins and protective proteins of cornified epithelium were upregulated in tissues from laser-modified abutments. At 4 weeks, upregulation (> 2-fold) of mRNAs encoding proteins associated with collagen fibril formation and function was observed in tissue from laser-modified abutments. In both tissues of machined and laser-modified abutments, mRNAs encoding junctional epithelium specific proteins, ostogenic ameloblast associated protein (ODAM) and follicular dendritic cell secreted protein (FDCSP) were highly upregulated throughout weeks 2 to 8. CONCLUSION: Peri-implant abutment mucosal wound healing involves selective differentiation of epithelium and induction of the junctional epithelium. Laser-mediated alterations in abutment topography enhance collagen fibril-associated gene expression and alter epithelium/junctional epithelial gene expression. Clinically, shallower probing depths are measured at laser-mediated versus machined implant abutments. PMID- 30025009 TI - A Prospective Multicenter Study on Radiographic Crestal Bone Changes Around Dental Implants Placed at Crestal or Subcrestal Level: One-Year Findings. AB - PURPOSE: To compare the peri-implant radiographic crestal bone changes around implants placed at the subcrestal or crestal level. MATERIALS AND METHODS: Systemically healthy patients with at least two missing teeth requiring implant supported fixed prosthetic restorations were enrolled in the study. Implants were randomly placed either 1 mm subcrestally or at the bone crest level. Radiographic examination was performed using the long-cone parallel technique and customized film holders. Digital periapical radiographs were obtained at the time of implant placement (T0), at the time of prosthesis delivery (T1), and 12 months (T2) after prosthetic loading. Marginal bone levels were measured at the mesial and distal aspects of each implant with digital image software. RESULTS: A total of 54 implants were present for the radiographic analysis at the 12-month follow-up. No implant showed mechanical or biologic complications throughout the follow-up period. The implant survival percentage was 100%. After 1 year, the mean bone loss was 0.711 +/- 0.721 mm in the subcrestal group and 0.224 +/- 0.418 mm in the crestal group. Furthermore, only the subcrestal group showed statistically significant radiographic bone resorption at the end of the follow-up. CONCLUSION: Within the limitations of this study, implants placed at the crestal level showed greater peri-implant bone stability during the 1-year follow-up. Studies with larger samples and longer follow-up are needed to confirm the results of this investigation. PMID- 30025008 TI - Long-Term Esthetic Outcome of Tissue-Level and Bone-Level Implants in the Anterior Maxilla. AB - PURPOSE: The aim of this study was to assess and compare the esthetic outcome of tissue-level (TL) and bone-level (BL) implants that had been placed as single implants in the anterior maxilla. MATERIALS AND METHODS: Between 2001 and 2008, patients were treated using TL implants (Straumann). From 2008 until 2012, patients received the newly developed BL implant (Straumann). All patients with a single anterior maxillary implant who came to check-ups regularly were contacted and invited to take part in the study. Standardized photographs were taken to conduct the evaluation. Five observers analyzed the esthetic outcome using the pink esthetic score (PES). For the purpose of statistical analysis, the Wilcoxon rank sum test was applied. Interobserver reliability was evaluated with Krippendorff's alpha. RESULTS: Forty-six patients agreed to take part in the study. The study comprised 10 immediate (TL = 6, BL = 4), 21 early (TL = 6, BL = 15), and 15 delayed implantations (TL = 11, BL = 4). All implant sites were simultaneously augmented. The prosthetic restorations were delivered 6 to 24 weeks after implant placement in the TL group and 10 to 14 weeks after implant placement in the BL group. Esthetic evaluation was performed after a mean period of 9.5 years for TL implants (range: 5.5 to 12.0) and 3.7 years for BL implants (range: 2.6 to 7.1). The overall PES was 8.49 (SD: 2.35) for TL implants and 9.29 (SD: 1.90) for BL implants (P = .37). Comparison of single parameters was between P = .24 and P = .83, indicating no statistically significant difference between the two implant types. CONCLUSION: Within the limits of this study, it can be stated that both implant designs showed comparably satisfying esthetic results. PMID- 30025010 TI - A Comparison of Esthetic Features of Pre-existing Natural Tooth Versus Post Implant Restoration in the Esthetic Zone: A Retrospective 12-month Follow-up. AB - PURPOSE: To correlate the link between natural teeth located in esthetic regions of the arches before extraction with their definitive dental implant restorations, and to propose a new and contemporary esthetic index based on the natural dentition (EIND) preoperatively. MATERIALS AND METHODS: Patients possessing a high smile line with teeth requiring implant replacement therapy in the maxillary anterior region were included. Clinical intraoral photographs and periapical digital radiographs taken before extraction and 10 +/- 1.5 months (range: 9 to 12 months) after the delivery of implant-supported permanent restorations were used to make the measurements and evaluations according to the proposed index. Pink esthetic score (PES) parameters were analyzed. Statistical analyses of preimplant and postimplant parameters between tooth sites and implant sites were carried out with a computer software program. RESULTS: The study included 51 patients (35 women, 16 men), with a mean age of 39.6 years, with a total of 83 dental implants placed in the maxillary anterior region. Of these, there were 6 right canines, 22 right lateral incisors, 11 right central incisors, 22 left central incisors, 17 left lateral incisors, and 5 left canines. Of the 83 included implants, 67 were immediately and 16 were delayed placed. Statistical analyses between tooth sites and implant sites showed significant differences in tissue contour (P = .001), texture (P = .001), alveolar deficiency (P = .001), and total PES (P = .007). No statistically significant difference was detected in mesial papilla, distal papilla, tissue margin, tissue biotype, and the amount of keratinized mucosa. Additionally, R2 value presented a higher variance and lower predictable values of peri-implant tissue parameters compared with those of the natural dentition. CONCLUSION: This study analyzed various periodontal and peri implant soft and hard tissue parameters, and a new index system, EIND, was proposed. This index could be used to collect the esthetic-related parameters for pre-extraction treatment planning and provide valuable information for esthetic risk assessment. PMID- 30025011 TI - Infraposition of Implant-Retained Maxillary Incisor Crown Placed in an Adult Patient: Case Report. AB - Several studies have clearly shown that osseointegrated implants, when inserted in growing bone, such as in adolescents, do not follow the eruptive path of adjacent teeth; instead, they act like ankylosed teeth, remaining in a stationary position for the lifetime, thus developing a progressive infraposition of the implant-supported crown. However, further studies have demonstrated that similar changes also occur in adult patients, although mostly in a small amount and over long time spans. Here the case of a female patient aged 35 years is presented, in which infraposition of the maxillary central incisor developed in a very short time (15 months). The treatment provided was a combined orthodontic/prosthetic approach with a 4-year follow-up. PMID- 30025013 TI - QTLseqr: An R Package for Bulk Segregant Analysis with Next-Generation Sequencing. AB - Next-Generation Sequencing Bulk Segregant Analysis (NGS-BSA) is efficient in detecting quantitative trait loci (QTL). Despite the popularity of NGS-BSA and the R statistical platform, no R packages are currently available for NGS-BSA. We present QTLseqr, an R package for NGS-BSA that identifies QTL using two statistical approaches: QTL-seq and G'. These approaches use a simulation method and a tricube smoothed G statistic, respectively, to identify and assess statistical significance of QTL. QTLseqr can import and filter SNP data, calculate SNP distributions, relative allele frequencies, G' values, and log ( values), enabling identification and plotting of QTL. The source code is available at . PMID- 30025012 TI - Inferior Alveolar Nerve Medialization for Dental Implant Placement: Case Report with the Introduction of a New Technique. AB - Inferior alveolar nerve repositioning is an option for treating the edentulous posterior mandible with insufficient bone height above the inferior alveolar canal. This report presents a case in which inferior alveolar nerve medialization was performed for placing dental implants. In the second postoperative week, mandibular fracture occurred after biting on a relatively solid piece of food, which was treated conservatively. PMID- 30025014 TI - Genomic-enabled Prediction Accuracies Increased by Modeling Genotype * Environment Interaction in Durum Wheat. AB - Genomic prediction studies incorporating genotype * environment (G*E) interaction effects are limited in durum wheat. We tested the genomic-enabled prediction accuracy (PA) of Genomic Best Linear Unbiased Predictor (GBLUP) models-six non-G * E and three G * E models-on three basic cross-validation (CV) schemes- in predicting incomplete field trials (CV2), new lines (CV1), and lines in untested environments (CV0)- in a durum wheat panel grown under yield potential, drought stress, and heat stress conditions. For CV0, three scenarios were considered: (i) leave-one environment out (CV0-Env); (ii) leave one site out (CV0-Site); and (iii) leave 1 yr out (CV0-Year). The reaction norm models with G * E effects showed higher PA than the non-G * E models. Among the CV schemes, CV2 and CV0-Env had higher PA (0.58 each) than the CV1 scheme (0.35). When the average of all the models and CV schemes were considered, among the eight traits- grain yield, thousand grain weight, grain number, days to anthesis, days to maturity, plant height, and normalized difference vegetation index at vegetative (NDVIvg) and grain filling (NDVIllg)-, plant height had the highest PA (0.68) and moderate values were observed for grain yield (0.34). The results indicated that genomic selection models incorporating G * E interaction show great promise for forward prediction and application in durum wheat breeding to increase genetic gains. PMID- 30025015 TI - Effective Genomic Selection in a Narrow-Genepool Crop with Low-Density Markers: Asian Rapeseed as an Example. AB - Genomic selection (GS) has revolutionized breeding for quantitative traits in plants, offering potential to optimize resource allocation in breeding programs and increase genetic gain per unit of time. Modern high-density single nucleotide polymorphism (SNP) arrays comprising up to several hundred thousand markers provide a user-friendly technology to characterize the genetic constitution of whole populations and for implementing GS in breeding programs. However, GS does not build upon detailed genotype profiling facilitated by maximum marker density. With extensive genome-wide linkage disequilibrium (LD) being a common characteristic of breeding pools, fewer representative markers from available high-density genotyping platforms could be sufficient to capture the association between a genomic region and a phenotypic trait. To examine the effects of reduced marker density on genomic prediction accuracy, we collected data on three traits across 2 yr in a panel of 203 homozygous Chinese semiwinter rapeseed ( L.) inbred lines, broadly encompassing allelic variability in the Asian genepool. We investigated two approaches to selecting subsets of markers: a trait-dependent strategy based on genome-wide association study (GWAS) significance thresholds and a trait-independent method to detect representative tag SNPs. Prediction accuracies were evaluated using cross-validation with ridge-regression best linear unbiased predictions (rrBLUP). With semiwinter rapeseed as a model species, we demonstrate that low-density marker sets comprising a few hundred to a few thousand markers enable high prediction accuracies in breeding populations with strong LD comparable to those achieved with high-density arrays. Our results are valuable for facilitating routine application of cost-efficient GS in breeding programs. PMID- 30025016 TI - Genomic Prediction in a Multiploid Crop: Genotype by Environment Interaction and Allele Dosage Effects on Predictive Ability in Banana. AB - Improving the efficiency of selection in conventional crossbreeding is a major priority in banana ( spp.) breeding. Routine application of classical marker assisted selection (MAS) is lagging in banana due to limitations in MAS tools. Genomic selection (GS) based on genomic prediction models can address some limitations of classical MAS, but the use of GS in banana has not been reported to date. The aim of this study was to evaluate the predictive ability of six genomic prediction models for 15 traits in a multi-ploidy training population. The population consisted of 307 banana genotypes phenotyped under low and high input field management conditions for two crop cycles. The single nucleotide polymorphism (SNP) markers used to fit the models were obtained from genotyping by sequencing (GBS) data. Models that account for additive genetic effects provided better predictions with 12 out of 15 traits. The performance of BayesB model was superior to other models particularly on fruit filling and fruit bunch traits. Models that included averaged environment data were more robust in trait prediction even with a reduced number of markers. Accounting for allele dosage in SNP markers (AD-SNP) reduced predictive ability relative to traditional bi allelic SNP (BA-SNP), but the prediction trend remained the same across traits. The high predictive values (0.47- 0.75) of fruit filling and fruit bunch traits show the potential of genomic prediction to increase selection efficiency in banana breeding. PMID- 30025017 TI - Genetic Mapping of Milling Quality Traits in Lentil (Lens culinaris Medik.). AB - Milling qualities are key traits for the red lentil ( Medik.) industry as price is largely determined by recovery yield. milling involves removal of the seed coat and splitting of the cotyledon to produce either splits or footballs (cotyledons still attached). The objectives of the study were to determine the heritability of the milling traits dehulling efficiency (DE), milling recovery (MR), and football recovery (FR) and to identify the genomic regions controlling them. We used a lentil recombinant inbred population from the cross 'CDC Robin' * '946a-46', which have contrasting seed characteristics. The mapping population consists of 127 F-derived lentil recombinant inbred lines that were phenotyped for milling quality parameters from four site-years in Saskatchewan, Canada. A total of 534 single nucleotide polymorphism markers, seven simple sequence repeat markers, and four morphological markers were used for quantitative trait locus (QTL) mapping. The broad-sense heritability was moderate for DE and MR and relatively low for FR. Milling quality traits were significantly correlated with seed shape (seed diameter and seed plumpness). Multiple QTLs for milling traits were detected in six of seven linkage groups (LGs). The most stable QTLs governing DE and MR were clustered on LGs 1, 2, 3, and 7, whereas FR QTLs were clustered on LGs 4, 5, 6, and 7. The molecular markers identified for these traits could be used for improving milling quality in lentil breeding programs. PMID- 30025018 TI - Selection in Early Generations to Shift Allele Frequency for Seminal Root Angle in Wheat. AB - A current challenge for plant breeders is the limited ability to phenotype and select for root characteristics to enhance crop productivity. The development of a high-throughput phenotyping method has recently offered new opportunities for the selection of root characteristics in breeding programs. Here, we investigated prospects for phenotypic and molecular selection for seminal root angle (SRA), a key trait associated with mature root system architecture in wheat ( L.). We first investigated genetic diversity for this trait in a panel of 22 wheat lines adapted to Australian environments. The angle between the first pair of seminal roots ranged from 72 to 106 degrees . We then evaluated selection gain via direct phenotypic selection in early generations by comparing the resulting shift in population distribution in tail populations selected for "narrow" and "wide" root angle. Overall, two rounds of selection significantly shifted the mean root angle as much as 10 degrees . Furthermore, comparison of allele frequencies in the tail populations revealed genomic regions under selection, for which marker-assisted selection appeared to be successful. By combining efficient phenotyping and rapid generation advance, lines enriched with alleles for either narrow or wide SRA were developed within only 18 mo. These results suggest that there is a valuable source of allelic variation for SRA that can be harnessed and rapidly introgressed into elite wheat lines. PMID- 30025019 TI - Genetic Fine-Mapping of a Quantitative Trait Locus (QTL) Associated with Embryogenic Tissue Culture Response and Plant Regeneration Ability in Maize (Zea mays L.). AB - Embryogenic and regenerable tissue cultures are widely utilized in plant transformation, clonal propagation, and biological research applications. Germplasm utilized in those applications are limited, however, due to genotype dependent culture response. The goal of this study was to identify genomic regions controlling embryogenic and regenerable tissue culture response in the globally important crop, maize ( L.), toward the long-term objective of developing approaches for genotype-independent plant genetic engineering and clonal propagation systems. An inbred maize line, WCIC2, nearly-isogenic to reference inbred B73, was developed by phenotypic selection and molecular marker analysis. WCIC2 has over 50x increase in tissue culture response relative to the recurrent parent, B73. This line was used to genetically fine-map a region on chromosome 3 controlling embryogenic and regenerable tissue culture response to a 23.9 Mb region. WCIC2 and derivatives will be useful materials to enable maize research in a genetic background similar to B73, and our genetic mapping results will advance research to identify causal genes controlling somatic embryo formation and plant regeneration in maize. PMID- 30025021 TI - Association Mapping of Flowering and Height Traits in Germplasm Enhancement of Maize Doubled Haploid (GEM-DH) Lines. AB - Flowering and height related traits are extensively studied in maize for three main reasons: 1) easily obtained phenotypic measurements, 2) highly heritable, and 3) importance of these traits to adaptation and grain yield. However, variation in flowering and height traits is extensive and findings from previous studies are genotype specific. Herein, a diverse panel of exotic derived doubled haploid lines, in conjunction with genome-wide association analysis, is used to further explore adaptation related trait variation of exotic germplasm for potential use in adapting exotic germplasm to the U.S. Corn-Belt. Phenotypes for the association panel were obtained from six locations across the central-U.S. and genotyping was performed using the genotyping-by-sequencing method. Nineteen flowering time candidate genes were found for three flowering traits. Eighteen candidate genes were found for four height related traits, with the majority of the candidate genes relating to plant hormones auxin and gibberellin. A single gene was discovered for ear height that also had effects on -like flowering gene expression levels. Findings will be used to inform future research efforts of the USDA Germplasm Enhancement of Maize project and eventually aid in the rapid adaptation of exotic germplasm to temperate U.S. environments. PMID- 30025022 TI - Novel Grain Weight Loci Revealed in a Cross between Cultivated and Wild Sorghum. AB - Grain weight has increased during domestication of cereals. Together with grain number it determines yield, but the two are often negatively correlated. Understanding the genetic architecture of grain weight and its relationship with grain number is critical to enhance crop yield. Sorghum is an important food, feed, and biofuel crop well-known for its adaptation to drought and heat. This study aimed to dissect the genetic basis of thousand grain weight (TGW) in a BCF population between a domesticated sorghum accession and its wild progenitor, subsp. and investigate its relationship with grain number. Thousand grain weight, grain number, and yield were measured in field trials in two successive years. A strong negative correlation between TGW and grain number was observed in both trials. In total, 17 TGW quantitative trait loci (QTL) were identified, with 11 of them exhibiting an opposing effect on grain number, implying the correlation between TGW and grain number is due to pleiotropy. Nine grain size candidate genes were identified within 6 TGW QTL, and of these 5 showed signatures of selection during sorghum domestication. Large-effect QTL in this study that have not been identified previously in cultivated sorghum were found to contain candidate genes with domestication signal, indicating that these QTL were affected during sorghum domestication. This study sheds new light on the genetic basis of TGW, its relationship with grain number, and sorghum domestication. PMID- 30025023 TI - Quantitative Trait Locus Mapping for Flowering Time in a Lowland * Upland Switchgrass Pseudo-F2 Population. AB - Flowering is an important developmental event in switchgrass (), as the time to complete the life cycle affects overall biomass accumulation. The objective of this study was to generate a linkage map using single nucleotide polymorphism (SNP) markers to identify quantitative trait loci (QTL) associated with flowering time. A pseudo-F population was created by crossing two siblings derived from an initial cross between the lowland population Ellsworth and the upland cultivar Summer. Heading and anthesis dates were collected for 2 yr at two locations: DeKalb, IL and Lafayette, IN. Nine QTL for flowering time were detected, two of which were heading-associated, four anthesis-associated, and three associated with both heading and anthesis. One QTL on linkage group (LG) 2a was detected for heading and anthesis in each location and year when environments were analyzed separately, and in a combined analysis across both locations and years. The effect on heading and anthesis of the QTL on LG 2a ranged from 4 to 13 and 5 to 9 d, respectively, depending on environment. Our findings validate QTL for switchgrass flowering time from previous research and identified additional QTL. Based on the switchgrass reference genome version 1.1, flowering time gene homologs reside near the LG 2a QTL and include PSEUDO RESPONSE REGULATOR 5, SUPPRESSOR OF FRIGIDA 4, and APETALA 1, respectively involved in the circadian clock, vernalization, and floral meristem identity. Markers linked to the QTL can be used to improve the efficiency of breeding switchgrass for delayed flowering to increase biomass yield. PMID- 30025024 TI - Genomic Prediction Using Prior Quantitative Trait Loci Information Reveals a Large Reservoir of Underutilised Blackleg Resistance in Diverse Canola (Brassica napus L.) Lines. AB - Genomic prediction is becoming a popular plant breeding method to predict the genetic merit of lines. While some genomic prediction results have been reported in canola, none have been evaluated for blackleg disease. Here, we report genomic prediction for seedling emergence, survival rate, and internal infection), using 532 Spring and Winter canola lines. These lines were phenotyped in two replicated blackleg disease nurseries grown at Wickliffe and Green Lake, Victoria, Australia. A transcriptome genotyping-by-sequencing approach revealed 98,054 single nucleotide polymorphisms (SNPs) after quality control. We assessed various genomic prediction scenarios based on Genomic Best Linear Unbiased Prediction (GBLUP), BayesR and BayesRC, which can make use of prior quantitative trait loci information, via cross-validation. Clustering based on genomic relationships showed that Winter and Spring lines were genetically distinct, indicating limited gene flow between sets. Genetic correlations within traits between Spring and Winter lines ranged from 0.68 and 0.90 (mean = 0.76). Based on GBLUP in the whole population, moderate to high genomic prediction accuracies were achieved within environments (0.35-0.74) and were reduced across environments (0.28-0.58). Prediction accuracy within the Spring set ranged from 0.30-0.69, and from 0.19 0.71 within the Winter set. The BayesR model resulted in slightly lower accuracy to GBLUP. The proportion of genetic variance explained by known blackleg quantitative trait loci (QTL) was < 30%, indicating that there is a large reservoir of genetic variation in blackleg traits that remains to be discovered, but can be captured with genomic prediction. However, providing prior information of known QTL in the BayesRC method resulted in an increased prediction accuracy for survival and internal infection, particularly with Spring lines. Overall, these promising results indicate that genomic prediction will be a valuable tool to make use of all genetic variation to improve blackleg resistance in canola. PMID- 30025025 TI - Genome-Wide Association Mapping of Anthracnose (Colletotrichum sublineolum) Resistance in the U.S. Sorghum Association Panel. AB - The productivity and profitability of sorghum [ (L.) Moench] is reduced by susceptibility to fungal diseases, such as anthracnose ( P. Henn.). A limited number of resistant accessions are present in the temperate-adapted germplasm; other exotic sources of resistance are not currently available for breeding programs. Among 335 accessions available to breeders from a previously genotyped sorghum association panel (SAP), we found that 75 were resistant to anthracnose. A phylogenetic analysis of these accessions showed high genetic diversity and multiple resistance sources. Genome-wide association scans (GWAS) were conducted using 268,289 single-nucleotide polymorphisms to identify loci associated with anthracnose resistance. Using logistic regressions for binary measures of resistance responses, we identified three loci within a region on chromosome 5 that have been previously associated with three sources of anthracnose resistance. A GWAS limited to Caudatum germplasm identified an association with a region on chromosome 1 and with the same previous region on chromosome 5. Candidate genes within these loci were related to R-gene families, signaling cascades, and transcriptional reprogramming, suggesting that the resistance response is controlled by multiple defense mechanisms. The strategic integration of exotic resistant germplasm into the SAP is needed to identify additional rare resistance alleles via GWAS. PMID- 30025026 TI - Four Parent Maize (FPM) Population: Effects of Mating Designs on Linkage Disequilibrium and Mapping Quantitative Traits. AB - Multiparent advanced generation inter-cross (MAGIC) populations can provide improved genetic mapping resolution by increasing allelic diversity and effective recombination. The Four Parent Maize (FPM; L.) population implemented five different mating designs used in MAGIC and bi-parental populations to compare empirical effects on genetic resolution and power of quantitative trait locus (QTL) detection; the combined population here comprised of 1149 individuals with 118,509 genetic markers. Measurements were recorded for plant height (PH), ear height (EH), days to anthesis (DTA) and silking (DTS) in seven environments, spanning three years. Linkage disequilibrium (LD) analysis of subpopulations indicated MAGIC population designs should incorporate generations of intermating to overcome initial LD increase caused by population admixture in a non intermated four parent population (4way0sib). A 3- to 4-fold increase in genetic resolution (<0.8) and a 2.5-fold decrease in the extent of LD decay (<0.2) compared to the biparental populations was found for the four parent cross at the third generation of intermating (4way3sib). Power of QTL detection was affected to a greater extent by sample size rather than by mating designs. The FPM power simulations indicated that MAGIC populations have the ability to meet or exceed the mapping power of nested association panels with fewer individuals and diversity inputs. Using association mapping software we identified 2, 5, 7, and 6 QTL for PH, EH, DTA, and DTS, respectively. The FPM population is a valuable resource for quantifying empirical improvements of parent number, intermating, and the number of progeny for QTL linkage mapping. PMID- 30025027 TI - Identification of Novel Genomic Loci Associated with Soybean Shoot Tissue Macro- and Micronutrient Concentrations. AB - The mineral composition of crop shoot tissues is important for yield formation and nutrient remobilization to seeds. The natural diversity that exists within crop species can be used to investigate mechanisms that define plant mineral composition and to identify important genomic loci for these processes. The objective of this study was to determine shoot mineral nutrient concentrations in genetically diverse soybean [ (L.) Merr.] genotypes and to identify genomic regions associated with concentrations of different nutrients in shoot tissue. The genotypes were grown at two locations in 2 yr and characterized for macronutrient (Ca, Mg, P, K, and S) and micronutrient (B, Cu, Fe, Mn, and Zn) concentrations in shoot tissues. Genome-wide association studies were conducted with 31,748 single nucleotide polymorphisms (SNPs) via a unified mixed model to identify SNPs associated with macro- and micronutrient concentrations. The number of putative loci identified for the macronutrients ranged from 11 for Ca to 20 for K. For the micronutrients, the number ranged from 10 for Mn to 24 for Fe. In addition to colocated loci for multiple nutrients, 22 individual SNPs were associated with more than one nutrient such that 11 different nutrient combinations were encompassed by these SNPs. Ultimately, the putative loci identified in this study will need to be confirmed and are expected to aid in the identification of new sources of variation for use in soybean breeding programs as well as for mechanistic studies aimed at understanding the regulation of mineral nutrient uptake, translocation, and shoot tissue concentrations. PMID- 30025028 TI - Applications of Machine Learning Methods to Genomic Selection in Breeding Wheat for Rust Resistance. AB - New methods and algorithms are being developed for predicting untested phenotypes in schemes commonly used in genomic selection (GS). The prediction of disease resistance in GS has its own peculiarities: a) there is consensus about the additive nature of quantitative adult plant resistance (APR) genes, although epistasis has been found in some populations; b) rust resistance requires effective combinations of major and minor genes; and c) disease resistance is commonly measured based on ordinal scales (e.g., scales from 1-5, 1-9, etc.). Machine learning (ML) is a field of computer science that uses algorithms and existing samples to capture characteristics of target patterns. In this paper we discuss several state-of-the-art ML methods that could be applied in GS. Many of them have already been used to predict rust resistance in wheat. Others are very appealing, given their performance for predicting other wheat traits with similar characteristics. We briefly describe the proposed methods in the Appendix. PMID- 30025029 TI - Resequencing of Common Bean Identifies Regions of Inter-Gene Pool Introgression and Provides Comprehensive Resources for Molecular Breeding. AB - Common bean ( L.) is the most important grain legume for human consumption and is a major nutrition source in the tropics. Because bean production is reduced by both abiotic and biotic constraints, current breeding efforts are focused on the development of improved varieties with tolerance to these stresses. We characterized materials from different breeding programs spanning three continents to understand their sequence diversity and advance the development of molecular breeding tools. For this, 37 varieties belonging to , (A. Gray), and L. were sequenced by whole-genome sequencing, identifying more than 40 million genomic variants. Evaluation of nuclear DNA content and analysis of copy number variation revealed important differences in genomic content not only between and the two other domesticated species, but also within , affecting hundreds of protein-coding genomic regions. A large number of inter-gene pool introgressions were identified. Furthermore, interspecific introgressions for disease resistance in breeding lines were mapped. Evaluation of newly developed single nucleotide polymorphism markers within previously discovered quantitative trait loci for common bacterial blight and angular leaf spot provides improved specificity to tag sources of resistance to these diseases. We expect that this dataset will provide a deeper molecular understanding of breeding germplasm and deliver molecular tools for germplasm development, aiming to increase the efficiency of bean breeding programs. PMID- 30025030 TI - Resequencing of Common Bean Identifies Regions of Inter-Gene Pool Introgression and Provides Comprehensive Resources for Molecular Breeding. PMID- 30025031 TI - Simulated Soil Organic Carbon Changes in Maryland Are Affected by Tillage, Climate Change, and Crop Yield. AB - The impact of climate change on soil organic C (SOC) stocks in no-till (NT) and conventionally tilled (CT) agricultural systems is poorly understood. The objective of this study was to simulate the impact of projected climate change on SOC to 50-cm soil depth for grain cropping systems in the southern Mid-Atlantic region of the United States. We used SOC and other data from the long-term Farming Systems Project in Beltsville, MD, and CQESTR, a process-based soil C model, to predict the impact of cropping systems and climate (air temperature and precipitation) on SOC for a 40-yr period (2012-2052). Since future crop yields are uncertain, we simulated five scenarios with differing yield levels (crop yields from 1996-2014, and at 10 or 30% greater or lesser than these yields). Without change in climate or crop yields (baseline conditions) CQESTR predicted an increase in SOC of 0.014 and 0.021 Mg ha yr in CT and NT, respectively. Predicted climate change alone resulted in an SOC increase of only 0.002 Mg ha yr in NT and a decrease of 0.017 Mg ha yr in CT. Crop yield declines of 10 and 30% led to SOC decreases between 2 and 8% compared with 2012 levels. Increasing crop yield by 10 and 30% was sufficient to raise SOC 2 and 7%, respectively, above the climate-only scenario under both CT and NT between 2012 and 2052. Results indicate that under these simulated conditions, the negative impact of climate change on SOC levels could be mitigated by crop yield increases. PMID- 30025032 TI - Simulated Soil Organic Carbon Response to Tillage, Yield, and Climate Change in the Southeastern Coastal Plains. AB - Intensive tillage, low-residue crops, and a warm, humid climate have contributed to soil organic carbon (SOC) loss in the southeastern Coastal Plains region. Conservation (CnT) tillage and winter cover cropping are current management practices to rebuild SOC; however, there is sparse long-term field data showing how these management practices perform under variable climate conditions. The objectives of this study were to use CQESTR, a process-based C model, to simulate SOC in the top 15 cm of a loamy sand soil (fine-loamy, kaolinitic, thermic Typic Kandiudult) under conventional (CvT) or CnT tillage to elucidate the impact of projected climate change and crop yields on SOC relative to management and recommend the best agriculture management to increase SOC. Conservation tillage was predicted to increase SOC by 0.10 to 0.64 Mg C ha for six of eight crop rotations compared with CvT by 2033. The addition of a winter crop [rye ( L.) or winter wheat ( L.)] to a corn ( L.)-cotton ( L.) or corn-soybean [ (L.) Merr.] rotation increased SOC by 1.47 to 2.55 Mg C ha. A continued increase in crop yields following historical trends could increase SOC by 0.28 Mg C ha, whereas climate change is unlikely to have a significant impact on SOC except in the corn cotton or corn-soybean rotations where SOC decreased up to 0.15 Mg C ha by 2033. The adoption of CnT and cover crop management with high-residue-producing corn will likely increase SOC accretion in loamy sand soils. Simulation results indicate that soil C saturation may be reached in high-residue rotations, and increasing SOC deeper in the soil profile will be required for long-term SOC accretion beyond 2030. PMID- 30025033 TI - Degradation of Chloramphenicol in Synthetic and Aquaculture Wastewater Using Electrooxidation. AB - Chloramphenicol (CAP) is a broad-spectrum antibiotic widely used in animal farming and aquaculture industries. Despite its ban in many countries around the world, it is still used in several developing countries, with harmful effects on the surrounding aquatic environment. In this study, an electrooxidation process using a Ti/PbO anode was used to investigate the degradation of CAP in both synthetic solution and real aquaculture wastewater. A central composite design was used to determine the optimum conditions for CAP removal. Current intensity and treatment time had the most impact on the CAP removal. These two factors accounted for ~90% of CAP removal. The optimum conditions found in this study were current intensity of 0.65 A, treatment time of 34 min, and CAP initial concentration of 0.5 mg L. Under these conditions, 98.7% of CAP removal was achieved with an energy consumption of 4.65 kW h m. The antibiotic was not present in the aquaculture wastewater, which received 0.5 mg L of CAP and was treated (by electrooxidation) under the optimum conditions. A complete removal of CAP was obtained after 34 min of treatment. According to these results, electrooxidation presents an option for the removal of antibiotics, secondary compounds, and other organic and inorganic compounds from solution. PMID- 30025034 TI - A Modeling Framework to Evaluate the Impacts of Future Climate on Soil Organic Carbon Dynamics. AB - Soil organic C (SOC) is significantly affected by changes in climate that control the physical, chemical, and biological processes in the soil. Simulating the impacts of future climate on SOC is challenging due to the limited availability of soil and climate variables required to properly simulate future SOC dynamics. The main objective of this study was to develop a modeling framework to quantify the impacts of future climate on SOC dynamics. The framework was developed for the Model for Nitrogen and Carbon in Agro-Ecosystems (MONICA) using the data collected from three University of Illinois Crop Science Research Centers. Projected precipitation and air temperature, collected from 32 global circulation models, were used to estimate the climate variables and cropping operation schedules required as inputs in MONICA. Six corn ()-soybean [ (L.) Merr.] rotation scenarios were considered in the simulations. Results showed that the total SOC in the upper 30 cm of the soil was expected to decrease from 43 to 70% in 2015 to 2075, with an uncertainty range of 13 to 16% due to the variation in climate prediction. The SOC in corn-soybean rotation schemes did not vary significantly from that of continuous corn scheme. The ability of a model to simulate realistic results depends significantly on the reliability of input data used to parameterize the model. A methodology that comprehensively estimates the impacts of future climatic conditions on SOC allows for realistic model results that can be used as a basis for environmental options, leading to a sustainable agro-production system. PMID- 30025035 TI - Temperature and Manure Placement in a Snowpack Affect Nutrient Release from Dairy Manure during Snowmelt. AB - Agricultural nutrient management is an issue due to N and P losses from fields and water quality degradation. Better information is needed on the risk of nutrient loss in runoff from dairy manure applied in winter. We investigated the effect of temperature on nutrient release from liquid and semisolid manure to water, and of manure quantity and placement within a snowpack on nutrient release to melting snow. Temperature did not affect manure P and NH-N release during water extraction. Manure P release, but not NH-N release, was significantly influenced by the water/manure solids extraction ratio. During snowmelt, manure P release was not significantly affected by manure placement in the snowpack, and the rate of P release decreased as application rate increased. Water extraction data can reliably estimate P release from manure during snowmelt; however, snowmelt water interaction with manure of greater solids content and subsequent P release appears incomplete compared with liquid manures. Manure NH-N released during snowmelt was statistically the same regardless of application rate. For the semisolid manure, NH-N released during snowmelt increased with the depth of snow covering it, most likely due to reduced NH volatilization. For the liquid manure, there was no effect of manure placement within the snowpack on NH-N released during snowmelt. Water extraction data can also reliably estimate manure NH-N release during snowmelt as long as NH volatilization is accounted for with liquid manures for all placements in a snowpack and semisolid manures applied on top of snow. PMID- 30025036 TI - Spatial Gradients of Ecosystem Health Indicators across a Human-Impacted Semiarid Savanna. AB - Drivers of soil organic carbon (SOC) dynamics involve a combination of edaphic, human, and climatic factors that influence and determine SOC distribution across the landscape. High-resolution maps of key indicators of ecosystem health can enable assessments of these drivers and aid in critical management decisions. This study used a systematic field-based approach coupled with statistical modeling and remote sensing to develop accurate, high-resolution maps of key indicators of ecosystem health across savanna ecosystems in South Africa. Two 100 km landscapes in Bushbuckridge Local Municipality were surveyed, and 320 composite topsoil samples were collected. Mid-infrared spectroscopy was used to predict soil properties, with good performance for all models and root mean squared error of prediction (RMSEP) values of 1.3, 0.2, 5, and 3.6 for SOC, pH, sand, and clay, respectively. Validation results for the mapping of soil erosion prevalence and herbaceous cover using RapidEye imagery at 5-m spatial resolution showed good model performance with area under the curve values of 0.80 and 0.86, respectively. The overall (out-of-bag) random forest model performance for mapping of soil properties, reported using , was 0.8, 0.77, and 0.82 for SOC, pH, and sand, respectively. Calibration model performance was good, with RMSEP values of 2.6 g kg for SOC, 0.2 for pH, and 6% for sand content. Strong gradients of increasing SOC and pH corresponded with decreasing sand content between the study sites. Although both sites had low SOC overall, important driving factors of SOC dynamics included soil texture, soil erosion prevalence, and climate. These data will inform strategic land management decisions focused particularly on improving ecosystem conditions. PMID- 30025037 TI - Availability of Phosphorus after Long-term Whole and Separated Slurry Application to Perennial Grass prior to Corn Silage. AB - Removing solids from whole dairy slurry (WS) can reduce P loading on fields. This study investigated the effects of 11 yr of applications of WS, separated liquid fraction (LF), commercial fertilizer, WS plus fertilizer, and a control on total and extractable (Kelowna) soil P in perennial grass ( Schreb.) and two subsequent silage corn ( L.) crops. Plots received 200 kg N ha with or without 40 kg P ha. Shoot biomass, P uptake, arbuscular mycorrhizal fungi root colonization, and soil microbial P were determined for corn at six leaves. Whole-crop and grain yield, P uptake, dry matter, and grain content were determined at maturity. The LF treatment received 30% less manure P than WS, had lower extractable soil P at 0 to 15 and 15 to 30 cm, and had lower total P at 0 to 15 cm. Historical treatments had no effect on soil microbial P or arbuscular mycorrhizal fungi colonization. At six leaves, corn shoot biomass, P concentration, and P uptake were related to historical P rates in Year 2, but the relationship was not apparent in Year 1. Starter P fertilizer increased shoot yield and P uptake for all treatments in both years. At maturity, most yield parameters for WS and LF were similar in Year 1, but in Year 2, there was a significant response to starter P fertilizer and a positive relationship between historical P rate and corn performance. This study shows that long-term LF treatments reduced the risk of P pollution with relatively little effect on the P response of subsequent corn crops. PMID- 30025038 TI - Carbon Dosing Increases Nitrate Removal Rates in Denitrifying Bioreactors at Low Temperature High-Flow Conditions. AB - Nitrogen losses from croplands contribute to impairment of water bodies. This laboratory experiment evaluated various C sources for use in a denitrifying bioreactor, a conservation practice designed to reduce N losses. The nitrate removal efficiency of candidate treatments (corn cobs [CC], corn cobs with modified coconut coir [CC+MC], corn cobs with modified coconut coir and modified macadamia shell biochar [CC+MC+MBC], wood chips [WC], wood chips with hardwood biochar [WC+BC], and wood chips with continuous sodium acetate addition [WC+A]) were tested with up-flow direction. Effluent was sampled after a repeated weekly flow regime with hydraulic residence times of 1.5, 8, 12, and 24 h. Column temperatures were 15 degrees C for 14 wk (warm), 5 degrees C for 13 wk (cold), and again 15 degrees C for 7 wk (rewarm). Cumulative nitrate N load reduction was greatest for WC+A (80, 80, and 97% during the warm, cold, and rewarm runs, respectively). Corn cob treatments (CC, CC+MC, and CC+MC+MBC) had the second greatest cumulative load reductions for all three temperature experiments, and WC and WC+BC had the lowest performance under these conditions. The nitrate removal rate was optimum at the 1.5-h hydraulic residence time for the WC+A treatment: 43, 30, and 121 g N m d for the warm, cold, and rewarm runs, respectively. Furthermore, acetate addition greatly improved wood chip performance and could be used to enhance nitrate N removal under the cold and high-flow-rate conditions of springtime drainage for the north-central United States. PMID- 30025039 TI - Modeling Regional Effects of Climate Change on Soil Organic Carbon in Spain. AB - Soil organic C (SOC) stock assessments at the regional scale under climate change scenarios are of paramount importance in implementing soil management practices to mitigate climate change. In this study, we estimated the changes in SOC sequestration under climate change conditions in agricultural land in Spain using the RothC model at the regional level. Four Intergovernmental Panel on Climate Change (IPCC) climate change scenarios (CGCM2-A2, CGCM2-B2, ECHAM4-A2, and ECHAM4 B2) were used to simulate SOC changes during the 2010 to 2100 period across a total surface area of 2.33 * 10 km. Although RothC predicted a general increase in SOC stocks by 2100 under all climate change scenarios, these SOC sequestration rates were smaller than those under baseline conditions. Moreover, this SOC response differed among climate change scenarios, and in some situations, some losses of SOC occurred. The greatest losses of C stocks were found mainly in the ECHAM4 (highest temperature rise and precipitation drop) scenarios and for rainfed and certain woody crops (lower C inputs). Under climate change conditions, management practices including no-tillage for rainfed crops and vegetation cover for woody crops were predicted to double and quadruple C sequestration rates, reaching values of 0.47 and 0.35 Mg C ha yr, respectively. PMID- 30025040 TI - Dynamic, Intermediate Soil Carbon Pools May Drive Future Responsiveness to Environmental Change. AB - Accurately capturing dynamic soil response to disturbance effects in agroecosystem models remains elusive, thereby limiting projections of climate change mitigation potential. Perennial grasses cultivated in zero-tillage management systems hold promise as sustainable agroecosystems. High-yielding tropical C grasses often have extensive rooting systems, and the belowground processes of root turnover, aggregate formation, and mineral stabilization drove rapid C accumulation after cultivation in a recent study. We sought (i) to understand and constrain the size and responsiveness of dynamic, intermediate cycling C pools contributing to the observed C accrual rates, and (ii) to simulate C stocks over time under the disturbance of elevated temperature using soil incubation at multiple temperatures and physical fractionation via density and sonication. Three-pool transfer modeling of soil incubations revealed small pools of readily available (i.e., days to months) microbial substrate that were responsive to temperature, time since cultivation, and inputs. Larger, kinetically slow-cycling pools were more indicative of long-term (i.e., years to decades) changes in C stock and strongly connected to measured changes in physical fractions. Combining the sensitivity of readily available microbial substrate with three-pool transfer modeling of the physical fractions over time since cultivation revealed that dynamic transfers of inputs occurred between the free organic and aggregate-protected fractions, and from these fractions to the mineral-associated dense fraction. Under 5 degrees C temperature elevation, increased transfer rates outweighed elevated decomposition losses to sustain soil C accrual into the future. To effectively plan managed landscapes and monitor sustainable agroecosystems for climate change mitigation, tools must incorporate the complexity of soil response to change. PMID- 30025041 TI - A Field-Scale Approach to Estimate Nitrate Loading to Groundwater. AB - The quantification of groundwater NO loading associated with a specific field or set of management practices so that groundwater quality improvements can be objectively assessed is a major challenge. The magnitude and timing of NO export from a single agricultural field under raspberry ( L.) production were investigated by combining high-resolution groundwater NO concentration profiles (sampled using passive diffusion samplers) with Darcy's flux estimation at the field's down-gradient edge (based on field-measured hydraulic gradients and laboratory-estimated hydraulic conductivity). Annual recharge estimated using Darcy's law (1002 mm) was similar to that obtained using two other approaches. The similarity in the rate of Cl applied to the field and the estimated export flux over the 1-yr monitoring period (51 vs. 56 kg Cl ha) suggested the mass flux estimation approach was robust. An estimated 80 kg NO-N ha was exported from the agricultural field over the 1-yr monitoring period. The greatest monthly groundwater mass flux exported was observed in February and March (~11 kg NO-N ha), and was associated with NO leached from the soil zone during the onset of precipitation in the previous autumn. Provided the groundwater recharged from the field of interest can be isolated within a vertical profile, this approach is an effective method for obtaining spatially integrated estimates of the magnitude and timing of NO loading to groundwater. PMID- 30025042 TI - Phosphorus Retention in Intact and Drained Prairie Wetland Basins: Implications for Nutrient Export. AB - Draining of geographically isolated (no defined inlet or outlet) freshwater mineral soil wetlands has likely converted areas that acted historically as important P sinks to sources of P. To explore the role of wetland drainage on nonpoint-source P pollution, differences in the chemical characteristics and P sorption parameters of drained and intact wetlands were investigated in a small watershed situated in the Prairie Pothole Region of southwestern Manitoba, Canada. Chemical characteristics and P sorption parameters varied across landscape positions, particularly for landscape positions that were submerged. Intact wetlands had slightly higher concentrations of organic and total P relative to drained wetlands, which is indicative of their P trapping capacity. More importantly, the maximum P sorption capacity and P buffering capacity of intact wetlands were 3.6 (1752 vs. 492 mg kg) and 17 (1394 vs. 84 L kg) times greater than those in drained wetlands. Conversely, equilibrium P concentrations and bioavailable P concentrations in drained wetlands were an order of magnitude greater than those in intact prairie wetlands. Our study suggests that intact prairie wetlands may be effective sinks for P. As a result, prairie wetlands may play an important role in mitigating nonpoint-source pollution. Conversely, our findings suggest that drained prairie wetlands are potentially a high risk for P export and should be treated as important critical source areas within prairie watersheds. PMID- 30025043 TI - Measurements and Models to Identify Agroecosystem Practices That Enhance Soil Organic Carbon under Changing Climate. AB - A the anticipated impacts of climate change is a pressing issue facing agriculture, as precipitation and temperature changes are expected to have major effects on agricultural production in many regions of the world. These changes will also affect soil organic matter decomposition and associated stocks of soil organic C (SOC), which have the potential to feed back to climate change and affect agroecosystem resiliency. This special section brings together multiple efforts to assess effects of climate change on SOC stocks around the globe in grassland, pasture, and crop agroecosystems under varying management practices. The overall goal of these efforts is to identify optimum practices to enhance SOC accumulation. In this article, we summarize the highlights of these papers and assess their broader implications for future research to enhance agroecosystem SOC accumulation and resiliency to climate change. Fourteen of the twenty contributions apply dynamic process-based models to assess climate and/or long term management impacts on SOC stocks, and four papers use statistical SOC models across landscapes or regions. Also included are one meta-analysis and one long term study. The models applied in this collection performed well when reliable input data were available, underlining the usefulness of modeling efforts to inform management decisions that enhance SOC stocks. Overall, the findings confirm that most agroecosystems have the potential to store SOC through improved management. However, this will be challenging, particularly for dryland agriculture, unless crop yield and crop biomass increase under projected climate change. PMID- 30025044 TI - A Global Meta-Analysis of Grazing Impacts on Soil Health Indicators. AB - Grazing lands support the livelihoods of millions of people across nearly one half of the globe. Soils are the backbone of stability and resilience in these systems. To determine livestock grazing impacts on soil health, we conducted a global meta-analysis of soil organic carbon (SOC), total N, C/N ratio, and bulk density responses to grazing strategies (continuous, rotational, and no grazing) and intensities (heavy, moderate, and light grazing) from 64 studies around the world. Across all studies and grazing intensities, continuous grazing significantly reduced SOC, C/N, and total N compared with no grazing. Soil compaction (i.e., increased bulk density) was greater under both continuous and rotational grazing compared with no grazing; however, rotational grazing had lower bulk density than continuous grazing. Rotational grazing had greater SOC than continuous grazing and was not different from no grazing. The positive responses of SOC to rotational grazing could create climate change mitigation opportunities. Grazing strategy comparisons were minimally conditioned by aridity class (i.e., arid, subhumid, and humid); however, complete observations were notably limited or missing for many rotational grazing comparisons. For continuous and no grazing strategy comparisons, we found that grazing management can significantly influence soil function and health outcomes; however, site specific environmental factors play important moderating roles. Greater coordination across regional, national, and global efforts, as well as consistent guidelines for soil health evaluation, would help overcome these knowledge gaps and vastly improve our collective understanding of grazing impacts on soil health, providing greater management and policy impacts. PMID- 30025045 TI - Simulated Soil Organic Carbon Responses to Crop Rotation, Tillage, and Climate Change in North Dakota. AB - Understanding how agricultural management and climate change affect soil organic carbon (SOC) stocks is particularly important for dryland agriculture regions that have been losing SOC over time due to fallow and tillage practices, and it can lead to development of agricultural practice(s) that reduce the impact of climate change on crop production. The objectives of this study were: (i) to simulate SOC dynamics in the top 30 cm of soil during a 20-yr (1993-2012) field study using CQESTR, a process-based C model; (ii) to predict the impact of changes in management, crop production, and climate change from 2013 to 2032; and (iii) to identify the best dryland cropping systems to maintain or increase SOC stocks under projected climate change in central North Dakota. Intensifying crop rotations was predicted to have a greater impact on SOC stocks than tillage (minimum tillage [MT], no-till [NT]) during 2013 to 2032, as SOC was highly correlated to biomass input ( = 0.91, = 0.00053). Converting from a MT spring wheat (SW, L.)-fallow rotation to a NT continuous SW rotation increased annualized biomass additions by 2.77 Mg ha (82%) and SOC by 0.22 Mg C ha yr. Under the assumption that crop production will stay at the 1993 to 2012 average, climate change is predicted to have a minor impact on SOC (approximately -6.5%) relative to crop rotation management. The CQESTR model predicted that the addition of another SW or rye ( L.) crop would have a greater effect on SOC stocks (0- to 30-cm depth) than conversion from MT to NT or climate change from 2013 to 2032. PMID- 30025046 TI - Implications of Observed and Simulated Soil Carbon Sequestration for Management Options in Corn-based Rotations. AB - Managing cropping systems to sequester soil organic C (SOC) improves soil health and resilience to changing climate. Perennial crops, no-till planting, manure, and cover crops can add SOC; however, their impacts have not been well documented in the northeastern United States. Our objectives were (i) to monitor SOC from a bioenergy cropping study in Pennsylvania that included a corn ( L.)-soybean [ (L.) Merr.]-alfalfa ( L.) rotation, switchgrass ( L.), and reed canarygrass ( L.); (ii) to use the CQESTR model to predict SOC sequestration in the bioenergy crops (with and without projected climate change); and (iii) to use CQESTR to simulate influence of tillage, manure, cover cropping, and corn stover removal in typical dairy forage (silage corn-alfalfa) or grain corn-soybean rotations. Over 8 yr, measured SOC increased 0.4, 1.1, and 0.8 Mg C ha yr in the bioenergy rotation, reed canarygrass, and switchgrass, respectively. Simulated and measured data were significantly correlated ( < 0.001) at all depths. Predicted sequestration (8-14 Mg C ha over 40 yr) in dairy forage rotations was much larger than with corn-soybean rotations (-4.0-0.6 Mg C ha over 40 yr), due to multiple years of perennial alfalfa. No-till increased sequestration in the simulated dairy forage rotation and prevented a net loss of C in corn-soybean rotations. Simulations indicated limited impact of cover crops and manure on long-term SOC sequestration. The low solids content of liquid dairy manure is the likely reason for the less-than-expected impact of manure. Overall, simulations suggest that inclusion of alfalfa provides the greatest potential for SOC sequestration with a typical Pennsylvania crop rotation. PMID- 30025047 TI - Evaluating Changes in Soil Organic Matter with Climate Using CENTURY in England and Wales. AB - Soil organic C (SOC) dynamics are complex, and models have been developed for predicting future changes, validated using only individual site data. In this study, we used the CENTURY model to predict changes in SOC between 1978 and 2000 using input weather data for 1978 to 2000 from the UK Meteorological Office and soil property input data derived from the National Soil Inventory (NSI). The predicted changes in SOC from the model simulation were validated using the resampled NSI data for the period 1994 to 2000. The modeling results indicate that CENTURY gave unacceptable predictions of change for three specific soil types. When these were omitted from the accuracy assessment, model predictions were statistically acceptable for all ecosystem types with model efficiency (ME) decreasing in the order: seminatural grassland (ME = 0.63) > woodland (ME = 0.27) > arable (ME = 0.08) > managed grassland (ME = 0.02). When comparing the overall measured rates of change, CENTURY correctly predicted the direction but underpredicted the magnitude of change. Once this utility was established, CENTURY was used to predict nation-level climate change-induced changes in SOC with the UKCIP02 (UK Climate Impacts Program of 2002) scenarios for the 2020s, 2050s, and 2080s, each of which comprise four emissions scenarios. The modeling predictions suggest that the predicted changes between scenarios were small. However, within that, the greatest decrease (of 1.54% SOC) will be in seminatural grassland under the high emissions scenario. The future predicted pattern of change in SOC is greater in managed grassland (reduction of 0.27-0.39% SOC) than arable land (reduction of 0.03-0.05% SOC). PMID- 30025049 TI - Simulating Soil Organic Carbon Responses to Cropping Intensity, Tillage, and Climate Change in Pacific Northwest Dryland. AB - Managing dryland cropping systems to increase soil organic C (SOC) under changing climate is challenging after decades of winter wheat ( L.)-fallow and moldboard plow tillage (W-F/MP). The objective was to use CQESTR, a process-based C model, and SOC data collected in 2004, 2008, and 2012 to predict the best management to increase SOC under changing climate in four cropping systems, which included continuous wheat under no tillage (W-W/NT), wheat and sorghum * sudangrass [ (L.) Moench. * L.] under no tillage, wheat-fallow under sweep tillage, and W-F/MP. Since future yields and climate are uncertain, 20 scenarios for each cropping system were simulated with four climate projections and five crop yield scenarios (current crop yields, and 10 or 30% greater or lesser yields). Measured and simulated SOC were significantly ( < 0.0001) correlated ( = 0.98) at all soil depths. Predicted SOC changes ranged from -12.03 to 2.56 Mg C ha in the 1-m soil depth for W-F/MP and W-W/NT, respectively, during the 2012 to 2052 predictive period. Only W-W/NT sequestered SOC at a rate of 0.06 Mg C ha yr under current crop yields and climate. Under climate change and yield scenarios, W-W/NT lost SOC except with a 30% wheat yield increase for 40 yr. Predicted SOC increases in W-W/NT were 0.71, 1.16, and 0.88 Mg C ha under the Oregon Climate Assessment Reports for low emissions and high emissions and the Regional Climate Model version 3 with boundary conditions from the Third Generation Coupled Global Climate Model, respectively, with 30% yield increases. Continuous no-till cropping would increase SOC and improve soil health and resiliency to lessen the impact of extreme weather. PMID- 30025048 TI - Soil Carbon Pools in Dryland Agroecosystems as Affected by Several Years of Drought. AB - No-till and increased cropping intensity (CI) can increase yield and soil organic C (SOC) in the US Great Plains compared with traditional wheat ( L.)-fallow management. However, gains in SOC and other C pools may not be permanent. Increasing frequency of drought may reduce C inputs and potentially reverse gains accrued during wetter periods. This study examined the effect of drought on the persistence of SOC with two objectives: (i) to determine soil C pools (0-20 cm) after 24 yr in no-till as influenced by potential evapotranspiration (PET), landscape position (slope), and CI; and (ii) to compare the size of the C pools after the first 12 yr (wet) versus the subsequent 12 yr, notable for frequent droughts. Rotations were wheat-corn ( L.)-fallow (WCF), continuous cropping (CC), and a grass Conservation Reserve Program mixture planted across slopes at three sites in Colorado with similar precipitation but increasing PET. After 24 yr, water-soluble organic C increased with CI from WCF to CC to grass with 250, 340, and 440 kg C ha, respectively. Soil microbial biomass C also increased with CI 1500, 1660, and 2135 kg C ha for WCF, CC, and grass, respectively. The particulate organic matter C pool had a three-way interaction with PET, slope, and CI. Overall, between Years 12 and 24, SOC increased in grass by 16.9%, with a rate of 425 kg C ha yr sequestration compared with 10.5 and 1.4% for the WCF and CC systems, respectively. PMID- 30025050 TI - Controls of Chloride Loading and Impairment at the River Network Scale in New England. AB - Chloride contamination of rivers due to nonpoint sources is increasing throughout developed temperate regions due to road salt application in winter. We developed a river-network model of chloride loading to watersheds to estimate road salt application rates and investigated the meteorological factors that control riverine impairment by chloride at concentrations above thresholds protective of aquatic organisms. Chloride loading from road salt was simulated in the Merrimack River watershed in New Hampshire, which has gradients in development density. After calibration to a regional network of stream chloride data, the model captured the distribution of regional discharge and chloride observations with efficiencies of 93 and 75%, respectively. The estimate of road salt application is within uncertainties of inventoried estimates of road salt loading and is 122 to 214% greater than recommended targets. Model predictions of chloride showed seasonal variation in chloride concentrations despite a large groundwater storage pool. Interannual variation of mean summer chloride concentration near the outlet varied up to 18%, and the total river length exceeding impairment thresholds varied 12%. Annual snowfall, which drives road salt loading, correlated with chloride impairment only in headwater streams, whereas concentration variability at the outlet was driven primarily by dilution from clean runoff-draining undeveloped forested areas of the watershed. The role of summer meteorology complicates the protection of freshwater systems from chloride contamination. PMID- 30025051 TI - Projecting Soil Organic Carbon Distribution in Central Chile under Future Climate Scenarios. AB - Soil organic C (SOC) is the largest terrestrial C pool, and it influences diverse soil properties and processes in a landscape. At global scales, SOC is related to climate; as climate changes, we expect that SOC will change at broad scales as well, but how SOC will respond to climate change in diverse environments is complex and highly uncertain. To evaluate the potential impact of predicted changes in temperature and precipitation across central Chile, we first estimated current SOC content using pedon descriptions and environmental variables (temperature, rainfall, land use, topography, soil types, and geology) as predictors. A random forest statistical model was used to predict SOC content by pedon data. Maps were created for six standard depths of the GlobalSoilMap project. Results showed mean SOC of 54 g kg at a depth interval of 0 to 5 cm, 51 g kg at 5 to 15 cm, 42 g kg at 15 to 30 cm, 29 g kg at 30 to 60 cm, 17 g kg at 60 to 100 cm, and 11 g kg at 100 to 200 cm. Model validation, withholding 25% of pedons, showed values of 0.70, 0.73, 0.75, 0.65, 0.56, and 0.29 for six depths, respectively. Two future temperature and precipitation for climate change scenarios, representative concentration pathways RCP4.5 and RCP8.5 from the NASA GISS-E2-R models, were considered in predicting SOC in 2050 and 2080. We found that central Chile would experience a loss of SOC in the depth range of 0 to 30 cm, averaging 9.7% for RCP4.5 and 12.9% for the RCP8.5 scenarios by the year 2050, with additional decreases of 8% in the RCP4.5 scenario and 16.5% under RCP8.5 by 2080. PMID- 30025052 TI - Greater Impacts of Incubation Temperature and Moisture on Carbon and Nitrogen Cycling in Poultry Relative to Horse Manure-based Soil Amendments. AB - Manure-based soil amendments (MBSAs) must be managed optimally to maximize N concentration and availability while minimizing environmental impacts (e.g., greenhouse gas [GHG]) emissions. We conducted an 83-d incubation study to determine the effects of different moisture (60 or 120% of water-holding capacity [WHC]) and temperature (4 or 20 degrees C) conditions during the decomposition of MBSAs. We measured CO, CH, and NO emissions and total C, total N, NH, and NO during the decomposition of chicken MBSA and two understudied MBSAs (turkey and horse). Total N decreased by 38 to 50% after 83 d in poultry MBSAs incubated at 20 degrees C and 120% WHC, whereas NH concentration peaked at 30 d. In contrast, poultry MBSAs incubated at 60% WHC or 4 degrees C had limited N losses but higher CO and/or NO emissions. Horse MBSA incubated for 83 d at 20 degrees C and 60% WHC had two- to threefold higher C losses, 53 to 68% higher total N, and two to three orders of magnitude higher NO concentrations than at wetter and/or colder incubation conditions. Horse MBSA incubated at 20 degrees C and 60% WHC had 13- to 130-fold (CH) and 4- to 70-fold (NO) higher emissions than horse MBSA incubated at 4 degrees C. In contrast, CH emissions peaked at 120% WHC and 20 degrees C. Overall, incubating horse MBSA at 20 degrees C and 60% WHC minimized tradeoffs between maximizing N concentration and availability and minimizing GHG emissions during decomposition, whereas we found no ideal decomposition conditions for poultry MBSAs. PMID- 30025053 TI - Celebrating the 350th Anniversary of Phosphorus Discovery: A Conundrum of Deficiency and Excess. AB - 2019 will be the 350th anniversary of the discovery of phosphorus (P) by the alchemist Henning Brandt. This perspective traces the historical threads that P has weaved through the fabric of our society and identifies challenges to improve P stewardship in the future and for our future. A century after Brandt's discovery, P was identified in bone ash, which became the primary source of P until guano and ultimately rock P was mined to provide the various mineral formulations used today. Owing to limited supplies, a strategic shift in resource management ethics-from exploiting to conserving P resources-is needed. In agriculture, remedial strategies should consider when conservation practices can transition from P sinks to sources; however, a broader, long-term strategy for P stewardship is needed. This must include educing P loss in food and other wastes, ecovering P from waste streams, eusing P generated beneficial by-products, and estructuring production systems. A key action to enact such changes will be collaboration across all sectors of society and the supply chain, from field to fork and beyond. As this will likely increase the cost of food, fiber, and feed production, it will require an innovative mix of public and private initiatives. PMID- 30025054 TI - Speciation of Phosphorus from Agricultural Muck Soils to Stream and Lake Sediments. AB - The nature and management of agricultural soils can influence the forms of legacy P present in affected sediments; however, few studies have specifically characterized P in sediments affected by polder agriculture. In this study, the speciation of P as it flows from the muck soils of the Holland Marsh to the sediments of the West Holland River and Lake Simcoe, Ontario, Canada, was investigated. The distribution of P fractions and the characterization of organic P were analyzed by the sequential fractionation method and solution P nuclear magnetic resonance spectroscopy, respectively. Organic P was the predominant P form (~58% of total P) in muck soils, whereas the redox-sensitive P fraction was predominant in surface stream sediments rich in organic matter (~41-48% of total P), despite these sediments exhibiting near-neutral pH and high concentrations of both Ca and P. The proportion of relatively recalcitrant organic P forms was much greater in the muck soils than that exhibited by both stream and lake sediments. The decreasing proportion of recalcitrant organic P forms in sediments downstream from the Holland Marsh indicated the potential for faster organic P cycling. Our findings support the notion that diesters and pyrophosphate should be monitored, in addition to loosely bound inorganic P, due to their potential impact on water quality. The unique environment of the streams and lake area is considered to be particularly vulnerable to excessive fertilizer P use in adjacent croplands. PMID- 30025055 TI - Assessing the Impact of Non-Urea Ruminant Urine Nitrogen Compounds on Urine Patch Nitrous Oxide Emissions. AB - Urea, the dominant form of N in ruminant urine, degrades in soil to produce NO emissions. However, the fate of non-urea urine N compounds (NUNCs) in soil and their contribution to urine patch NO emissions remain unclear. This study evaluated five NUNCs: allantoin (10%), creatinine (3%), creatine (3%), uric acid (1%), and (hypo)xanthine (0.6%), where numbers in parentheses represent the average percentage of total urine N. The fates of NUNCs in a pasture soil were determined using N-labeled NUNCs in a laboratory trial. Two NUNCs, hypoxanthine and creatine, were added to the soil with perennial ryegrass ( L.) present and sampled over time for soil inorganic N, NO emissions, and plant N dynamics. The N enrichments of soil inorganic N and plant N were significantly increased within 24 h of NUNC application, indicating rapid microbial degradation and plant uptake of NUNCs in pasture soil. An autumn field trial was also conducted to evaluate the in situ impact of varying concentrations of NUNCs on urine patch NO emissions. Increasing the proportion of urine N excreted as NUNCs did not alter the urine patch NO emission factor, soil inorganic N concentrations, or plant N uptake. It is concluded that NUNCs rapidly degrade in pasture soil and that an increased ruminant excretion of urine N as NUNCs does not significantly alter the urine patch NO emission factor. PMID- 30025056 TI - Soil Carbon Response to Projected Climate Change in the US Western Corn Belt. AB - The western US Corn Belt is projected to experience major changes in growing conditions due to climate change over the next 50 to 100 yr. Projected changes include increases in growing season length, number of high temperature stress days and warm nights, and precipitation, with more heavy rainfall events. The impact these changes will have on soil organic carbon (SOC) needs to be estimated and adaptive changes in management developed to sustain soil health and system services. The process-based model CQESTR was used to model changes in SOC stocks (0-30 cm) of continuous corn ( L.) and a corn-soybean [ (L.) Merr.] rotation under disk, chisel, ridge, and no-tillage using projected growing season conditions for the next 50 yr. Input for the model was based on management and harvest records from a long-term tillage study (1986-2015) in eastern Nebraska, and model output was validated using measured changes in SOC from 1999 to 2011 in the study. The validated model was used to estimate changes in SOC over 17 yr under climatic conditions projected for 2065 under two scenarios: (i) crop yields increasing at the observed rate from 1971 to 2016 or (ii) crop yields reduced due to negative effects of increasing temperature. CQESTR estimates of SOC agreed well with measured SOC ( = 0.70, < 0.0001). Validated model simulated changes in SOC under projected climate change differed among the three soil depths (0-7.5, 7.5-15, and 15-30 cm). Summed over the 0- to 30-cm depth, there were significant three-way interactions of year * rotation * yield ( = 0.014) and year * tillage * yield ( < 0.001). As yield increased, SOC increased under no-tillage continuous corn but was unchanged under no-tillage corn-soybean and ridge tillage regardless of cropping system. Under chisel and disk tillage, SOC declined regardless of cropping system. With declining yields SOC decreased regardless of tillage or cropping system. These results highlight the interaction between genetics and management in maintaining yield trends and soil C. PMID- 30025057 TI - An Integrated Approach to Identify Critical Source Areas of Agricultural Nonpoint Source Pollution at the Watershed Scale. AB - Nonpoint sources are difficult to control because their nutrient contribution from different parts of a watershed can vary substantially. Identifying critical source areas of nutrient loss is an important step in watershed pollution mitigation programs. This study sought to use an integrated index model to differentiate between subbasins that serve as critical source areas of N and P nonpoint sources of pollution in China's Tiaoxi watershed. In contrast with previous N and P indices, multiple sources of pollution (i.e., agronomic activity, domestic wastewater, livestock farming, and aquaculture) were considered. Nitrogen and P source factors (i.e., N and P annual export loads) and transport factors were multiplied to determine the overall risk of nutrient loss in the integrated index model. Critical source areas were identified by a higher nutrient loss index. Of the 92 subbasins within the Tiaoxi watershed, 13 were determined to be critical sources for N, 10 for P, and seven for both N and P. Critical source area identification corresponds well with water quality data from the subbasins. The results show the potential use of the integrated index model for prioritizing and targeting watershed pollution mitigation activities at the subbasin level. PMID- 30025058 TI - Long-term Trends in Corn Yields and Soil Carbon under Diversified Crop Rotations. AB - Agricultural practices such as including perennial alfalfa ( L.), winter wheat ( L.), or red clover ( L.) in corn ( L.) rotations can provide higher crop yields and increase soil organic C (SOC) over time. How well process-based biogeochemical models such as DeNitrification-DeComposition (DNDC) capture the beneficial effects of diversified cropping systems is unclear. To calibrate and validate DNDC for simulation of observed trends in corn yield and SOC, we used long-term trials: continuous corn (CC) and corn-oats ( L.)-alfalfa-alfalfa (COAA) for Woodslee, ON, 1959 to 2015; and CC, corn-corn-soybean [ (L.) Merr.]-soybean (CCSS), corn-corn-soybean-winter wheat (CCSW), corn-corn-soybean-winter wheat + red clover (CCSW+Rc), and corn-corn-alfalfa-alfalfa (CCAA) for Elora, ON, 1981 to 2015. Yield and SOC under 21st century conditions were projected under future climate scenarios from 2016 to 2100. The DNDC model was calibrated to improve crop N stress and was revised to estimate changes in water availability as a function of soil properties. This improved yield estimates for diversified rotations at Elora (mean absolute prediction error [MAPE] decreased from 13.4 15.5 to 10.9-14.6%) with lower errors for the three most diverse rotations. Significant improvements in yield estimates were also simulated at Woodslee for COAA, with MAPE decreasing from 24.0 to 16.6%. Predicted and observed SOC were in agreement for simpler rotations (CC or CCSS) at both sites (53.8 and 53.3 Mg C ha for Elora, 52.0 and 51.4 Mg C ha for Woodslee). Predicted SOC increased due to rotation diversification and was close to observed values (58.4 and 59 Mg C ha for Elora, 63 and 61.1 Mg C ha for Woodslee). Under future climate scenarios the diversified rotations mitigated crop water stress resulting in trends of higher yields and SOC content in comparison to simpler rotations. PMID- 30025059 TI - Ammonia Emissions from Subalpine Forest and Mountain Grassland Soils in Rocky Mountain National Park. AB - Atmospheric deposition of NH and NH contributes to eutrophication within sensitive subalpine ecosystems of Rocky Mountain National Park (RMNP) in the United States. However, little is known about the local contribution of NH from soils within the park. Thus, the goal of this study was to quantify and compare NH emissions from intact soil cores sampled from a subalpine grassland and forest within RMNP. Cores were collected at 2-wk intervals from 20 June 2011 to 12 Sept. 2011 and transferred to a laboratory chamber system for NH flux measurements. Additionally, N wet deposition was monitored at the sampling location to investigate possible impacts on NH soil emissions. The average quantifiable NH emissions (with SDs) from intact soil cores analyzed in the laboratory (23 degrees C) were 0.42 +/- 0.30 mg NH-N m d for grassland soil and 0.21 +/- 0.03 mg NH-N m d for forest soil ( < 0.001). A mechanistic model was developed to estimate the impact of temperature on soil emissions using the chamber data and field-site air temperatures. Average estimated NH emissions from the field site over the study period were 0.21 and 0.082 mg NH-N m d for grasslands and forests, respectively. Ammonium wet deposition was not correlated to short term reemission of NH based on N isotope analysis. This work provides new information on the magnitude of NH emissions from native subalpine soils, indicating that natural emissions are not likely major sources of NH in the RMNP airshed. PMID- 30025060 TI - Perennialization and Cover Cropping Mitigate Soil Carbon Loss from Residue Harvesting. AB - While the US Midwest is expected to serve as a primary feedstock source for cellulosic biofuel production, the impacts of residue harvesting on soil organic carbon (SOC) may greatly limit sustainable production capacity. However, viable feedstock production could be realized through adoption of management practices and cropping systems that offset residue-harvest-induced SOC losses. Sequestration of SOC can be enhanced by increasing the duration of crop soil cover through cover or double cropping or cultivation of dedicated perennials. However, assessing the efficacy of such options across sites and over long periods is experimentally challenging. Hence, we use the Environmental Productivity Integrated Climate (EPIC) model to provide such an assessment. Model data integration was used to calibrate and evaluate model suitability, which exhibited reasonable effectiveness through of 0.97 and 0.63 for SOC stock and yield, respectively. Long-term simulations indicate considerable capacity for offsetting SOC loss. Incorporating rye ( L.) into continuous corn ( L.) and corn soybean [ (L.) Merr.] systems offset the SOC losses induced by harvesting 21.2 and 38.3% of available stover, respectively. Similarly, converting 20.4% of corn soybean land to miscanthus ( * J.M. Greef & Deuter ex Hodkinson & Renvoize) or 27.5% of land to switchgrass ( L.) offset the SOC impacts of harvesting 60% of stover from the remaining corn-soybean lands. These responses indicate that adoption of such measures would sizably affect the life cycle consequences of residue-derived biofuels and expand estimates of sustainable cellulosic feedstock production capacity from the US Midwest. PMID- 30025061 TI - CQESTR-Simulated Response of Soil Organic Carbon to Management, Yield, and Climate Change in the Northern Great Plains Region. AB - Traditional dryland crop management includes fallow and intensive tillage, which have reduced soil organic carbon (SOC) over the past century, raising concerns regarding soil health and sustainability. The objectives of this study were: (i) to use CQESTR, a process-based C model, to simulate SOC dynamics from 2006 to 2011 and to predict relative SOC trends in cropping sequences that included barley ( L.), pea ( L.), and fallow under conventional tillage or no-till, and N fertilization rates through 2045; and (ii) to identify best dryland cropping systems to increase SOC and reduce CO emissions under projected climate change in eastern Montana. Cropping sequences were conventional-till barley-fallow (CTB-F), no-till barley-fallow (NTB-F), no-till continuous barley (NTCB), and no-till barley-pea (NTB-P), with 0 and 80 kg N ha applied to barley. Under current crop production, climatic conditions, and averaged N rates, SOC at the 0- to 10-cm depth was predicted to increase by 1.74, 1.79, 2.96, and 4.57 Mg C ha by 2045 for CTB-F, NTB-F, NTB-P, and NTCB, respectively. When projected climate change and the current positive US barley yield trend were accounted for in the simulations, SOC accretion was projected to increase by 0.69 to 0.92 Mg C ha and 0.41 to 0.47 Mg C ha, respectively. According to the model simulations, adoption of NT, elimination of fallow years, and N fertilizer management will likely have the greatest impact on SOC stocks in the top soil as of 2045 in the Northern Great Plains. PMID- 30025062 TI - Long-term Cropping Effects on Partitioning of Water Flow and Nitrate Loss between Surface Runoff and Tile Drainage. AB - Surface runoff and tile drainage are the main pathways for water movement and entry of agricultural nitrate into water resources. The objective of this 5-yr study was to characterize the partitioning of water flow and nitrate loss between these pathways for a humid-temperate Brookston clay loam soil under 54 to 59 yr of consistent cropping and fertilization. Cropping treatments included monoculture corn ( L., MC), continuous bluegrass ( L.) sod (CS), and a corn-oat alfalfa ( L.)-alfalfa rotation (RC-RO-RA1-RA2). Fertilization treatments included annual fertilizer addition (F) and no fertilizer addition (NF). Tile drainage and surface runoff occurred primarily during the nongrowing season (November-April), and they were highly correlated with the mean saturated hydraulic conductivity of the near-surface soil profile. Tile drainage accounted for 69 to 90% of cumulative water flow and 79 to 96% of cumulative nitrate loss from fertilized rotation and CS, whereas surface runoff accounted for the majority of the nitrate losses in MC (i.e., 75-93% of water flow and 65-96% of nitrate loss). Cumulative nitrate losses were highest in the RC-F (152 kg N ha), RC-NF (101 kg N ha), RA2-F (121 kg N ha), and RA2-NF (75 kg N ha) plots, and these high losses are attributed to N mineralization from the plowed alfalfa and fertilization (if applicable). Fertilization increased cumulative nitrate loss in tile drainage from all treatments, whereas no fertilization increased cumulative nitrate loss in surface runoff from the rotation. Cropping system and fertilization on clay loam soil changed how water flow and nitrate loss were partitioned between tile drainage and surface runoff. PMID- 30025063 TI - Sodium Persulfate and Potassium Permanganate Inhibit Methanogens and Methanogenesis in Stored Liquid Dairy Manure. AB - Stored liquid dairy manure is a hotspot for methane (CH) emission, thus effective mitigation strategies are required. We assessed sodium persulfate (NaSO), potassium permanganate (KMnO), and sodium hypochlorite (NaOCl) for impacts on the abundance of microbial communities and CH production in liquid dairy manure. Liquid dairy manure treated with different rates (1, 3, 6, and 9 g or mL L slurry) of these chemicals or their combinations were incubated under anoxic conditions at 22.5 +/- 1.3 degrees C for 120 d. Untreated and sodium 2 bromoethanesulfonate (BES)-treated manures were included as negative and positive controls, respectively, whereas sulfuric acid (HSO)-treated manure was used as a reference. Quantitative real-time polymerase chain reaction was used to quantify the abundances of bacteria and methanogens on Days 0, 60, and 120. Headspace CH/CO ratios were used as a proxy to determine CH production. Unlike bacterial abundance, methanogen abundance and CH/CO ratios varied with treatments. Addition of 1 to 9 g L slurry of NaSO and KMnO reduced methanogen abundance (up to ~28%) and peak CH/CO ratios (up to 92-fold). Except at the lowest rate, chemical combinations also reduced the abundance of methanogens (up to ~17%) and CH/CO ratios (up to ninefold), although no impacts were observed when 3% NaOCl was used alone. With slurry acidification, the ratios reduced up to twofold, whereas methanogen abundance was unaffected. Results suggest that NaSO and KMnO may offer alternative options to reduce CH emission from stored liquid dairy manure, but this warrants further assessment at larger scales for environmental impacts and characteristics of the treated manure. PMID- 30025064 TI - Climate Change Impacts on Yields and Soil Carbon in Row Crop Dryland Agriculture. AB - Dryland agroecosystems could be a sizable sink for atmospheric carbon (C) due to their spatial extent and level of degradation, providing climate change mitigation. We examined productivity and soil C dynamics under two climate change scenarios (moderate warming, representative concentration pathway [RCP] 4.5; and high warming, RCP 8.5), using long-term experimental data and the DayCent process based model for three sites with varying climates and soil conditions in the US High Plains. Each site included a no-till cropping intensity gradient introduced in 1985, with treatments ranging from wheat-fallow ( L.) to continuous annual cropping and perennial grass. Simulations were extended to 2100 using data from 16 global circulation models to estimate uncertainty. Simulated yields declined for all crops (up to 50% for wheat), with small changes after 2050 under RCP 4.5 and continued losses to 2100 under RCP 8.5. Of the cropped systems, continuous cropping had the highest average productivity and soil C sequestration rates (78.1 kg C ha yr from 2015 to 2045 under RCP 4.5). Any increase in soil C for cropped rotations was realized by 2050, but grassland treatments increased soil C (up to 69%) through 2100, even under RCP 8.5. Our simulations indicate that reduced frequency of summer fallow can both increase annualized yields and store more soil C. As evapotranspiration is likely to increase, reducing fallow periods without live vegetation from dryland agricultural rotations may enhance the resilience of these systems to climate change while also increasing soil C storage and mitigating carbon dioxide emissions. PMID- 30025066 TI - Mapping Soil Organic Carbon and Organic Matter Fractions by Geographically Weighted Regression. AB - The soil organic matter (SOM) content and dynamic are related to vegetation cover, climate, relief, and geology; these factors have strong variation in space in the southeastern of Brazil. The objective of the study was to compare and evaluate performance of classical multiple linear regressions (MLR) and geographically weighted regression (GWR) models to predict soil organic carbon (SOC) and chemical fractions of organic matter in the Brazilian southeastern mountainous region. The regression models were fitted based on SOC and chemical fractions of SOM. The points ( = 89) were selected by pedologist's experience along transects and toposequences. The covariates were also selected using the empirical knowledge of pedologists when choosing variables that drive soil carbon content and its dynamics. Geology map, legacy soils map, terrain attributes derived from digital elevation model, and remote sensing indices derived from RapidEye sensor bands were used as covariates. In all MLR models (except for fulvic acid fraction [FAF]), the legacy soil map was selected as a covariate by the stepwise approach. The geology map was not selected as important covariate to predict FAF and humin (HUM). At least one variable derived from remote sensing was selected by the adjusted models. For the prediction of the SOC, HUM, and FAF, the GWR models had the highest performance. The MLR models extrapolated the results, especially for SOC. The relationships among SOC, SOM fractions, and environmental covariates were affected by local landscape variability, and the GWR model was better at modeling. PMID- 30025065 TI - Methylmercury Dynamics in Upper Sacramento Valley Rice Fields with Low Background Soil Mercury Levels. AB - Few studies have considered how methylmercury (MeHg, a toxic form of Hg produced in anaerobic soils) production in rice ( L.) fields can affect water quality, and little is known about MeHg dynamics in rice fields. Surface water MeHg and total Hg (THg) imports, exports, and storage were studied in two commercial rice fields in the Sacramento Valley, California, where soil THg was low (25 and 57 ng g). The median concentration of MeHg in drainage water exiting the fields was 0.17 ng g (range: <0.007-2.1 ng g). Compared with irrigation water, drainage water had similar MeHg concentrations, and lower THg concentrations during the growing season. Significantly elevated drainage water MeHg and THg concentrations were observed in the fallow season compared with the growing season. An analysis of surface water loads indicates that fields were net importers of both MeHg (76-110 ng m) and THg (1947-7224 ng m) during the growing season, and net exporters of MeHg (35-200 ng m) and THg (248-6496 ng m) during the fallow season. At harvest, 190 to 700 ng MeHg m and 1400 to 1700 ng THg m were removed from fields in rice grain. Rice straw, which contained 120 to 180 ng MeHg m and 7000-10,500 ng m THg was incorporated into the soil. These results indicate that efforts to reduce MeHg and THg exports in rice drainage water should focus on the fallow season. Substantial amounts of MeHg and THg were stored in plants, and these pools should be considered in future studies. PMID- 30025067 TI - Impact of Flue Gas Desulfurization Gypsum and Manure Application on Transfer of Potentially Toxic Elements to Plants, Soil, and Runoff. AB - There are concerns regarding the fate of nutrients from surface application of animal manure. One approach to reduce losses of P is to treat manure with industrial byproducts such as flue gas desulfurization (FGD) gypsum. However, concerns regarding potentially toxic elements contributed to the environment have arisen based on previous element-rich forms of FGD gypsum that included fly ash, whereas "new" FGD gypsum without fly ash is much lower in contaminants. This study examined the impact of FGD gypsum application on soil, plants, and runoff when applied alone or with poultry litter (PL) to soil. The study consisted of a plant response study (four rates of FGD gypsum of 0, 2.2, 4.4, and 8.9 Mg ha and four rates of PL of 0, 4.4, 8.9, and 13.4 Mg ha) and a rainfall simulation study (3.4 Mg PL ha with four rates of FGD gypsum of 0, 2.2, 4.4, and 8.9 Mg ha and controls). Plant, soil, and runoff samples were analyzed for As, Ba, Be, Ca, Cd, Ba, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, Sb, Se, Tl, V, and Zn. Results indicated that FGD gypsum application would not result in increased potentially toxic elements in plants, soil, or runoff. In addition, the application of FGD gypsum significantly reduced P, As, and Fe concentrations in runoff, indicating that FGD gypsum can reduce the negative impact of manure surface application on surface water degradation. PMID- 30025068 TI - Building an Open Science Framework to Model Soil Organic Carbon. AB - As funding agencies embrace open science principles that encourage sharing data and computer code developed to produce research outputs, we must respond with new modes of publication. Furthermore, as we address the expanding reproducibility crisis in the sciences, we must work to release research materials in ways that enable reproducibility-publishing data, computer code, and research products in addition to the traditional journal article. Toward addressing these needs, we present an example framework to model and map soil organic carbon (SOC) in the cereal grains production region of the northwestern United States. Primarily associated with soil organic matter, SOC relates to many soil properties that influence resiliency and soil health for agriculture. It is also critical for understanding soil-atmospheric C flux, a significant part of the overall C budget of the Earth. The technique for modeling soil properties uses seven categories of environmental input data to make predictions: known soil attributes, climatic values, organisms present, relief, parent material, age, and spatial location. We gather data representing these categories from various public sources. The map is produced using a random forest statistical model with inputs to predict SOC content on a 30-m spatial grid. All modeling components including input data, metadata, computer code, and output products are made freely available under an explicit open-source license. In this way, reproducibility is supported, the methods and code released are available to be reused by other researchers, and the research products are open to critical review and improvement. PMID- 30025069 TI - Iron Oxides Minimize Arsenic Mobility in Soil Material Saturated with Saline Wastewater. AB - The soil material in constructed wetlands is effective in retaining Se from flue gas desulfurization (FGD) wastewater (WW), but reducing conditions can enhance native-soil As mobility. A laboratory-based soil column experiment was performed to assess the effectiveness of ferrihydrite (Fh) in minimizing the mobility of native-soil As in water-saturated soil material. A saline FGD WW mixture (i.e., influent) was delivered to columns of untreated and Fh-treated soil for 60 d. One untreated column and one Fh-treated column were then subjected to drying, followed by an additional 30 d of influent delivery. Although the influent was low in As (~1 MUg L) and the soil As level was normal, the total dissolved As concentration of effluent from the untreated columns increased with time, from ~1 MUg L to a maximum of ~27 MUg L. In contrast, effluent from the Fh-treated columns remained low in As (i.e., <5 MUg L). The strong correlation between total dissolved Fe and As in the effluent suggested that reductive dissolution of native-soil Fe minerals was responsible for releasing As into solution. Results from X-ray absorption spectroscopy showed newly precipitated Fe minerals in the Fh-treated soil, and the remaining As was mainly As(V) species in both the untreated and Fh-treated soils. Thus, native-soil As mobilized under saturated conditions can be sequestered by adding poorly crystalline Fe oxides to soil prior to saturation. Furthermore, results obtained by drying and rewetting the columns showed that saturated conditions must be maintained to minimize the remobilization of sequestered As and retained Se. PMID- 30025070 TI - Selective Early Glial Reactivity in the Visual Pathway Precedes Axonal Loss, Following Short-Term Cerebrospinal Fluid Pressure Reduction. AB - Purpose: To examine the early glial reactivity and neuron damage in response to short-term cerebrospinal fluid pressure (CSFp) reduction, as compared with intraocular pressure (IOP) elevation. Methods: The experiment included 54 male Sprague-Dawley rats with elevated translaminar cribrosa pressure difference (TLPD), defined as IOP minus CSFp. These rats underwent either continuous CSF drainage for 6 hours (n = 18), or unilateral IOP elevation to 40 mm Hg for 6 hours (n = 18). For control, 18 normal rats were anesthetized for 6 hours. Orthograde axonal transport was examined by intravitreal injection of 3% rhodamine-beta-isothiocyanate. We also used transmission electron microscopy to display the ultrastructural features of retinal ganglion cell axons in the optic nerve head. Early glial reactivity in the retina, lateral geniculate nucleus (LGN), and superior colliculus (SC) was detected by immunostaining and Western blot for the glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS). We also observed the glial reactivity in the inferior colliculus and hippocampus to rule out possible influences of CSF dynamics and composition. Results: Anterograde staining with 3% rhodamine-beta-isothiocyanate revealed decreased fluorescence intensity of the SC and LGN projected from both lower CSFp and higher IOP eyes. Transmission electron microscopy showed loss of axons from the optic nerve head in the high-IOP group, but not in the low-CSFp group. Compared with the anesthesia control group, GFAP expression was significantly increased in the retina, LGN, and SC, whereas GS expression was only increased in the retina following CSFp reduction. However, their expressions were not significantly elevated in the inferior colliculus and hippocampus. In the high IOP group, expressions of GFAP and GS were significantly increased in the retina, LGN, and SC. Conclusions: Visual system neurons may be much more sensitive than other nervous tissues. Following short-term CSFp reduction, early glial reactivity may precede axonal loss. Changes of translaminar cribrosa pressure difference in both experimental low-CSFp and high-IOP groups induce selective early glial reactivity. The neuron damage from abnormally low CSFp may be pathogenetically similar to high IOP. PMID- 30025071 TI - Visual Performance as a Function of Luminance in Glaucoma: The De Vries-Rose, Weber's, and Ferry-Porter's Law. AB - Purpose: To determine whether the De Vries-Rose, Weber's, and Ferry-Porter's law, which describe visual performance as a function of luminance, also hold in patients with glaucoma. Methods: A case-control study with 19 glaucoma patients and 45 controls, all with normal visual acuity. We measured foveal and peripheral contrast sensitivity (CS) using static perimetry and foveal and peripheral critical fusion frequency (CFF; stimulus diameter 1 degrees ) as a function of luminance (0.02 to 200 cd/m2). ANOVA was used to analyze the effect of glaucoma and luminance on CS and CFF; analyses were adjusted for age and sex. Results: Foveally, logCS was proportional to log luminance at lower luminances (de Vries Rose) and saturated at higher luminances (Weber); glaucoma patients had a 0.4 log unit lower logCS than controls (P < 0.001), independent of luminance. Peripherally, the difference was more pronounced at lower luminances (P = 0.007). CFF was linearly related to log luminance (Ferry-Porter). Glaucoma patients had a lower CFF compared with controls (P < 0.001), with a smaller slope of the CFF versus log luminance curve, for both the fovea (6.8 vs. 8.7 Hz/log unit; P < 0.001) and the periphery (2.5 vs. 3.4 Hz/log unit; P = 0.012). Conclusions: Even in apparently intact areas of the visual field, visual performance is worse in glaucoma patients than in healthy subjects for a wide range of luminances, without a clear luminance dependency that is consistent across the various experiments. This indicates impaired signal processing downstream in the retina and beyond, rather than an impaired light adaptation in the strictest sense. PMID- 30025072 TI - Aldosterone Exposure Causes Increased Retinal Edema and Severe Retinopathy Following Laser-Induced Retinal Vein Occlusion in Mice. AB - Purpose: To determine the effects of aldosterone exposure on retinal edema and retinopathy in a mouse model of retinal vein occlusion (RVO). Methods: RVO was induced immediately following intravenous injection of Rose bengal (66 mg/kg) using a 532-nm wavelength laser to place three to seven applications at 80 mW and 50-MUm spot size directed at the superior retinal vein one disc diameter away from the nerve. Negative control consisted of placing an equal number of laser spots without targeting the vein. Male and female C57BL/6J mice aged 7 to 9 months with confirmed absence of Crb1rd8 were used. Aldosterone pellets releasing a daily dose of 0.83 MUg/day were implanted subcutaneously 4 weeks prior to RVO. Retinal imaging by optical coherence tomography (OCT) was performed using a Micron IV rodent imaging system. Retinas were analyzed by immunohistochemistry using standard techniques. Retinal imaging and tissue analysis were performed 2, 4, and 7 days following RVO. Comparisons were made using Student's t-test, ANOVA, and Pearson's chi2. Results: RVO caused retinal edema in the form of cystic spaces and retinal thickening detectable by both OCT and histology. RVO also caused Muller glia (MG) dysfunction manifest as upregulated glial fibrillary acidic protein (GFAP) and altered localization of aquaporin 4 (AQP4) and Kir4.1. Treatment with aldosterone caused a significant increase in retinal edema and more severe retinopathy manifest as retinal whitening and extensive intraretinal hemorrhage. MG dysfunction was more severe and persistent in aldosterone-treated mice. Finally, aldosterone greatly increased the number of infiltrating mononuclear phagocytes following RVO. Conclusions: Systemic aldosterone exposure causes a more severe RVO phenotype manifest as increased severity and duration of retinal edema and more severe retinopathy. The effects of aldosterone may be mediated by MG dysfunction and increased infiltration of mononuclear phagocytes. This suggests that small increases in aldosterone levels may be a risk factor for severe RVO. PMID- 30025073 TI - Dynamic Changes in Schlemm Canal and Iridocorneal Angle Morphology During Accommodation in Children With Healthy Eyes: A Cross-Sectional Cohort Study. AB - Purpose: The purpose of this study was to explore changes in Schlemm canal (SC), trabecular meshwork (TM), and iridocorneal angle (ICA) morphology during accommodative effort in children and young adults. Methods: We acquired anterior segment optical coherence tomography images (AS-OCT) of the ICA and ciliary muscle (CM) of both eyes of 50 children age 4 to 16 years with healthy eyes, at two levels of accommodation: 2.5 and 15 diopters (D). Semiautomated nasal ICA measurements were as follows: angle opening distance at 500/750 MUm (AOD-500, 750), trabecular iris space area at 500/750 MUm (TISA-500, -750), and trabecular iris angle at 500/750 MUm (TIA-500, -750). Manual measurements were as follows: anteroposterior and radial SC diameter (SC-APD, SC-RD), cross-sectional area of SC (SC-CSA) and TM height (TMH), TM length (TML), and TM density (TMD). CM width was measured at 1, 2, and 3 mm from the scleral spur (CM-1, CM-2, CM-3). For each parameter, a three-level random-effects model was fitted to estimate differences between the two levels of accommodation. Results: With accommodative effort, SC diameters and CSA increase significantly, as do TM length and iridocorneal angle parameters. With increasing age, SC dimensions reduce. Angle parameters are smaller in eyes with greater spherical equivalent (hypermetropia). Conclusions: AS-OCT can be used to visualize dynamic morphologic changes in outflow structures with physiologic accommodation. The increase in SC dimensions with accommodative effort may contribute to the regulation of IOP in children. PMID- 30025074 TI - Defined Conditions for Differentiation of Functional Retinal Ganglion Cells From Human Pluripotent Stem Cells. AB - Purpose: We aimed to establish an efficient method for retinal ganglion cell (RGC) differentiation from human pluripotent stem cells (hPSCs) using defined factors. Methods: To define the contribution of specific signal pathways to RGC development and optimize the differentiation of hPSCs toward RGCs, we examined RGC differentiation in three stages: (1) eye field progenitors expressing the eye field transcription factors (EFTFs), (2) RGC progenitors expressing MATH5, and (3) RGCs expressing BRN3B and ISLET1. By monitoring the condition that elicited the highest yield of cells expressing stage-specific markers, we determined the optimal concentrations and combinations of signaling pathways required for efficient generation of RGCs from hPSCs. Results: Precise modulation of signaling pathways, including Wnt, insulin growth factor-1, and fibroblast growth factor, in combination with mechanical isolation of neural rosette cell clusters significantly enriched RX and PAX6 double-positive eye field progenitors from hPSCs by day 12. Furthermore, Notch signal inhibition facilitated differentiation into MATH5-positive progenitors at 90% efficiency by day 20, and these cells further differentiated to BRN3B and ISLET1 double-positive RGCs at 45% efficiency by day 40. RGCs differentiated via this method were functional as exemplified by their ability to generate action potentials, express microfilament components on neuronal processes, and exhibit axonal transportation of mitochondria. Conclusions: This protocol offers highly defined culture conditions for RGC differentiation from hPSCs and in vitro disease model and cell source for transplantation for diseases related to RGCs. PMID- 30025075 TI - Irreversible Photoreceptors and RPE Cells Damage by Intravenous Sodium Iodate in Mice Is Related to Macrophage Accumulation. AB - Purpose: To determine the mechanism causing degeneration of the retinal pigment epithelium (RPE) and photoreceptors in mice after an intravenous injection of sodium iodate (NaIO3). Methods: The time-dependent changes in NaIO3-induced retinal degeneration were determined by analyzing the retinal morphology by optical coherence tomographic (OCT) images, histological sections of the retina, physiology of the retina by electroretinography (ERG), and retinal blood flow by laser speckle flowgraphy. In addition, the expression of the genes associated with age-related macular degeneration in humans was assessed in the NaIO3-treated mice by RT-PCR. We also investigated whether macrophages were involved in the NaIO3-induced retinal degeneration. Results: The intravenous injection of 20 mg/kg NaIO3 altered the morphology of the RPE cells and the ERGs transiently. With 40 mg/kg of NaIO3, the degeneration of the RPE cells was still present at 28 days. Aggregated melanin granules were surrounded by zonula occludens protein 1 (ZO-1)-positive cells. In addition, 40 mg/kg of NaIO3 led to a reduction in the amplitudes of the a- and b-waves of the dark-adapted ERGs. Histological studies showed that macrophages had infiltrated the retina and were present around the altered RPE cells. Depletion of the macrophages by a prior injection of clodronate liposomes prevented the damage of the outer retina after the NaIO3 injection but not the RPE. Conclusions: The NaIO3-induced retinal damage was reversible at low concentrations but permanent at high concentrations of NaIO3. The accumulation of macrophages around the RPE cells caused the photoreceptor cell death. PMID- 30025077 TI - Genipin-Crosslinked Donor Sclera for Posterior Scleral Contraction/Reinforcement to Fight Progressive Myopia. AB - Purpose: Myopia has become a global public health problem, particularly in East Asia where myopic retinopathy has become one of the leading causes of blindness and visual impairment in the elderly population. The purpose of this study was to evaluate the efficacy of posterior scleral contraction/reinforcement (PSCR) surgery on controlling the progressive elongation of axial length of highly myopic eyes in young patients. Methods: This is a prospective self-controlled interventional case series. Forty young patients (<18-years old) with progressive high myopia received PSCR with a genipin-crosslinked donor scleral strip for one eye and the fellow eye served as concurrent control without surgery. The main outcome measurement was the change of axial length over 2 to 3 years of follow up. Results: Immediately after the surgery, axial length was shortened and subsequently increased by 0.32 mm over the follow-up period. In contrast, axial length of the fellow eyes increased by 0.82 mm over the same period (P < 0.001, paired t-test). PSCR delayed axial elongation in eyes with or without staphyloma. No significant change of visual acuity, cornea refractive power, or retina thickness was noted between the surgery and fellow eyes. None of the patients lost visual acuity compared with the baseline. The procedure was well tolerated with only temporary corneal refractive axis shifts that recovered by the 6-month postsurgical visit. Conclusions: PSCR with genipin-crosslinked sclera is safe and effective to restrain eye globe elongation in young patients within a 2- to 3 year follow-up period. PMID- 30025076 TI - Safety and Feasibility of Intrastromal Injection of Cultivated Human Corneal Stromal Keratocytes as Cell-Based Therapy for Corneal Opacities. AB - Purpose: To evaluate the safety and feasibility of intrastromal injection of human corneal stromal keratocytes (CSKs) and its therapeutic effect on a rodent early corneal opacity model. Methods: Twelve research-grade donor corneas were used in primary culture to generate quiescent CSKs and activated stromal fibroblasts (SFs). Single and repeated intrastromal injections of 2 to 4 * 104 cells to rat normal corneas (n = 52) or corneas with early opacities induced by irregular phototherapeutic keratectomy (n = 16) were performed, followed by weekly examination of corneal response under slit-lamp biomicroscopy and in vivo confocal microscopy with evaluation of haze level and stromal reflectivity, and corneal thickness using anterior segment optical coherence tomography (AS-OCT). Time-lapse tracing of Molday ION-labelled cells was conducted using Spectralis OCT and label intensity was measured. Corneas were collected at time intervals for marker expression by immunofluorescence, cell viability, and apoptosis assays. Results: Injected CSKs showed proper marker expression with negligible SF related features and inflammation, hence maintaining corneal clarity and stability. The time-dependent loss of injected cells was recovered by repeated injection, achieving an extended expression of human proteoglycans inside rat stroma. In the early corneal opacity model, intrastromal CSK injection reduced stromal reflectivity and thickness, resulting in recovery of corneal clarity, whereas noninjected corneas were thicker and had haze progression. Conclusions: We demonstrated the safety, feasibility, and therapeutic efficacy of intrastromal CSK injection. The cultivated CSKs can be a reliable cell source for potential cell-based therapy for corneal opacities. PMID- 30025078 TI - Relationship Between Foveal Cone Structure and Visual Acuity Measured With Adaptive Optics Scanning Laser Ophthalmoscopy in Retinal Degeneration. AB - Purpose: To evaluate foveal function in patients with inherited retinal degenerations (IRD) by measuring visual acuity (VA) after correction of higher order aberrations. Methods: Adaptive optics scanning laser ophthalmoscopy (AOSLO) was used to image cones in 4 healthy subjects and 15 patients with IRD. The 840 nm scanning laser delivered an "E" optotype to measure AOSLO-mediated VA (AOSLO VA). Cone spacing was measured at the preferred retinal locus by two independent graders and the percentage of cones below the average density of 47 age-similar healthy subjects was computed. Cone spacing was correlated with best-corrected VA measured with the Early Treatment of Diabetic Retinopathy Study protocol (ETDRS VA), AOSLO-VA, and foveal sensitivity. Results: ETDRS-VA significantly correlated with AOSLO-VA (rho = 0.79, 95% confidence interval [CI] 0.5-0.9). Cone spacing correlated with AOSLO-VA (rho = 0.54, 95% CI 0.02-0.7), and negatively correlated with ETDRS letters read (rho = -0.64, 95% CI -0.8 to -0.2). AOSLO-VA remained >=20/20 until cones decreased to 40.2% (CI 31.1-45.5) below normal. Similarly, ETDRS-VA remained >=20/20 until cones were 42.0% (95% CI 36.5-46.1) below normal. Cone spacing z scores negatively correlated with foveal sensitivity (rho = -0.79, 95% CI -0.9 to -0.4) and foveal sensitivity was >=35 dB until cones were 43.1% (95% CI 39.3-46.6) below average. Conclusions: VA and foveal cone spacing were weakly correlated until cones were reduced by 40% to 43% below normal. The relationship suggests that VA is an insensitive measure of foveal cone survival; cone spacing may be a more sensitive measure of cone loss. PMID- 30025079 TI - SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets. AB - Purpose: Oxygen-induced retinopathy (OIR) is the most widely used model for ischemic retinopathies such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), and retinal vein occlusion (RVO). The purpose of this study was to perform the most comprehensive characterization of OIR by a recently developed technique, sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics. Methods: Control and OIR retina samples collected from various time points were subjected to SWATH-MS and detailed data analysis. Immunohistochemistry from mouse retinas as well as neovascular membranes from human PDR and RVO patients were used for the detection of the localization of the proteins showing altered expression in the retina and to address their relevance to human ischemic retinopathies. Results: We report the most extensive proteomic profiling of OIR to date by quantifying almost 3000 unique proteins and their expression differences between control and OIR retinas. Crystallins were the most prominent proteins induced by hypoxia in the retina, while angiogenesis related proteins such as Filamin A and nonmuscle myosin IIA stand out at the peak of angiogenesis. Majority of the changes in protein expression return to normal at P42, but there is evidence to suggest that proteins involved in neurotransmission remain at reduced level. Conclusions: The results reveal new potential therapeutic targets to address hypoxia-induced pathological angiogenesis taking place in number of retinal diseases. The extensive proteomic profiling combined with pathway analysis also identifies novel molecular networks that could contribute to the pathogenesis of retinal diseases. PMID- 30025080 TI - The Impact of Intraocular Pressure Elevation on Optic Nerve Head and Choroidal Blood Flow. AB - Purpose: To use laser speckle flowgraphy (LSFG) to assess blood flow (BF) in the optic nerve head (ONH) tissue and choroid during elevated intraocular pressure (IOP). Methods: This prospective study included 20 eyes of 20 healthy volunteers. The testing protocol had a baseline phase, two elevated IOP phases (+10 and +20 mm Hg), and a recovery phase. IOP was elevated by pushing against the eyelid with a novel tubular device attached to the LSFG apparatus. Measurement parameters in each phase included: LSFG-derived mean blur rate (MBR) and flow acceleration index (FAI); systemic parameters, and IOP. The % change against baseline was calculated for each phase. The protocol was repeated five times to calculate the coefficient of variation (CV) for % change MBR and to determine the effect of mydriasis on % change MBR. We compared % change MBR and FAI and evaluated the relationship between % change ocular perfusion pressure (OPP) and MBR in the choroid and ONH tissue. Results: The % change MBR was highly reproducible (CV: 6.1-8.7%) and not affected by mydriasis (P = 0.57-0.96). The % change MBR and FAI were higher in the ONH tissue than choroid during IOP elevation (P = 0.04). The % change OPP and MBR showed positive linear correlations and two-segmental linear correlations in the choroid and ONH tissue, respectively (P < 0.01). Conclusion: Hemodynamics during IOP elevation differ in the choroid and ONH tissue. LSFG enables highly reproducible assessment of the dynamic autoregulation of ocular BF in the ONH tissue. PMID- 30025082 TI - Keratocyte Density Is Reduced and Related to Corneal Nerve Damage in Diabetic Neuropathy. AB - Purpose: The purpose of this study was to assess the relationship between corneal keratocyte density (KD) and corneal nerve damage in patients with and without diabetic peripheral neuropathy. Methods: Eighty-six patients with type 1 and type 2 diabetes and 21 age-matched control subjects underwent assessment of the neuropathy disability score, quantitative sensory testing, electrophysiology, and corneal confocal microscopy and were divided into those without (DN-) (n = 22) and with (DN+) (n = 64) diabetic neuropathy. Corneal sub-basal nerve parameters and KD in the anterior, mid, and posterior stroma were quantified. Results: Anterior, mid, and posterior stromal KD were significantly reduced in DN- (P = 0.02, P = 0.009, P = 0.01, respectively) and DN+ (all P < 0.0001) subjects compared to controls. Corneal nerve branch density (CNBD) (P < 0.0001, P < 0.0001) and corneal nerve fiber length (CNFL) (P = 0.03, P < 0.0001) were significantly reduced in DN- and DN+ subjects, respectively, and corneal nerve fiber density (CNFD) (P < 0.0001) was significantly reduced only in DN+ subjects compared to controls. Anterior, mid, and posterior stromal KD correlated significantly with CNFD (P = 0.008, P = 0.005, P = 0.01), CNBD (P = 0.01, P = 0.006, P = 0.001), and CNFL (P = 0.04, P = 0.008, P = 0.003), respectively. Conclusions: This study demonstrates a reduction in anterior, mid, and posterior KD, which is associated with corneal sub-basal plexus nerve damage in patients with diabetes. PMID- 30025083 TI - Wnt5a Contributes to the Differentiation of Human Embryonic Stem Cells into Lentoid Bodies Through the Noncanonical Wnt/JNK Signaling Pathway. AB - Purpose: Recent work has indicated that Wnt5a has a critical role in embryonic development. We investigate whether the Wnt5a-activated noncanonical Wnt pathway is capable of promoting embryonic lens differentiation. Methods: A "three-stage" protocol was used to induce lens differentiation of human embryonic stem cells (hESCs) in vitro, and Wnt5a levels were modified by addition of exogenous protein and RNA interference. SP600125 was adopted to inhibit JNK cascades. The number and size of lentoid bodies obtained were measured, and quantitative RT-PCR, Western blotting, and immunofluorescence were used to detect gene and protein expression. Results: The quantity and size of lentoid bodies generated were significantly increased by addition of exogenous Wnt5a. Moreover, expression of lens-specific genes, including CRYAA, CRYAB, BFSP1, and MIP, and the lens fiber differentiation regulator PROX1 were prominently increased. We also observed activation of noncanonical Wnt signaling via upregulation of Dvl2, Rac1, and JNK. When Wnt5a-knockdown hESCs were induced to differentiate, fewer and smaller lentoid bodies resulted. In addition, expression of genes specific to lens was decreased and noncanonical Wnt/JNK pathway activity was downregulated. Accordingly, inhibition of JNK cascade suppressed the formation of lentoid bodies as well, consistent with that of Wnt5a-knockdown group. Conclusions: Wnt5a can promote the differentiation of hESCs into lentoid bodies through the noncanonical Wnt/JNK signaling pathway, thereby contributing to the study of human lens development and moreover the underlying etiology congenital cataracts. PMID- 30025081 TI - A Cross-Sectional and Longitudinal Study of Retinal Sensitivity in RPE65 Associated Leber Congenital Amaurosis. AB - Purpose: RPE65-associated Leber congenital amaurosis (RPE65-LCA) is an early onset severe retinal dystrophy associated with progressive visual field loss. Phase I/II and III gene therapy trials have identified improved retinal sensitivity but little is known about the natural history of retinal sensitivity in RPE65-LCA. Methods: A total of 19 subjects (aged 9 to 23 years) undertook monocular full-field static perimetry of which 13 subjects were monitored longitudinally. Retinal sensitivity was measured as mean sensitivity (MS) and volumetrically quantified (in decibel-steradian) using visual field modeling and analysis software for the total (VTOT), central 30 degrees (V30) and central 15 degrees (V15) visual field. Correlation was evaluated between retinal sensitivity and age, best-corrected visual acuity (BCVA), contrast sensitivity, vision-related quality of life, and genotype. Test-retest reliability was also investigated. Results: V30 was identified to have a strong, weak, and moderate correlation with age, BCVA and contrast sensitivity respectively. Furthermore, V30 was identified as having a weak linear relationship with the mobility and independence domains of the vision-related quality of life questionnaire. Longitudinal analysis demonstrated a slow loss of retinal sensitivity in this cohort. Subjects with at least one RPE65 nonsense variant appeared to show greater progressive loss of retinal sensitivity in the second decade of life than those without. Conclusions: Volumetric assessment of central 30 degrees visual field sensitivity, V30, is a useful independent measure of retinal function and, in our data, represented the best metric to monitor deterioration of retinal sensitivity in RPE65-LCA. Furthermore, functional correlation with genotype may enable more informed prognostic counseling. (ClinicalTrials.gov number, NCT02714816.) PMID- 30025085 TI - 0.005% Preservative-Free Latanoprost Induces Dry Eye-Like Ocular Surface Damage via Promotion of Inflammation in Mice. AB - Purpose: To investigate the side effects of preservative-free 0.005% latanoprost on the murine ocular surface. Methods: We applied 0.005% latanoprost or vehicle in mice in two patterns for 14 to 28 days. Tear production was measured by phenol red cotton test, and corneal epithelial barrier function was assessed by Oregon green-dextran (OGD) staining. Periodic acid-Schiff (PAS) staining was used to quantify conjunctival goblet cells (GCs). The expression of matrix metalloproteinase (MMP)-3 and -9, occludin-1 and zonula occludens (ZO)-1 in corneal epithelium was assessed by immunofluorescent staining and/or quantitative real-time PCR (qRT-PCR). Inflammation in conjunctiva was assessed by activation of P38 and NF-kappaB, infiltration of CD4+ T cells, and production inflammatory cytokines including TNF-alpha, IL-1beta, IFN-gamma, IL-17A, and IL-13. Apoptosis in ocular surface was assessed by TUNEL and immunofluorescent staining for activated caspase-3 and -8. Cell viability assay was performed in human corneal epithelial cells. Results: Topical latanoprost treatment decreased tear production, induced conjunctival GC loss, disrupted the corneal epithelial barrier, and promoted cell apoptosis in the ocular surface. Topical latanoprost treatment increased the expression of MMP-3 and -9, and decreased the expression of ZO-1 and occludin-1 in the corneal epithelium. Topical application of latanoprost promoted activation of P38-NF-kappaB signaling and production of TNF alpha and IL-1beta in conjunctiva. Topical application of latanoprost increased CD4+ T cells infiltration, with increased production of IFN-gamma and IL-17A and decreased production of IL-13 in conjunctiva. Conclusion: 0.005% latanoprost induced dry eye-like ocular surface damage via promotion of inflammation in mice. PMID- 30025084 TI - Aldose Reductase Inhibition Prevents Development of Posterior Capsular Opacification in an In Vivo Model of Cataract Surgery. AB - Purpose: Cataract surgery is a procedure by which the lens fiber cell mass is removed from its capsular bag and replaced with a synthetic intraocular lens. Postoperatively, remnant lens epithelial cells can undergo an aberrant wound healing response characterized by an epithelial-to-mesenchymal transition (EMT), leading to posterior capsular opacification (PCO). Aldose reductase (AR) inhibition has been shown to decrease EMT markers in cell culture models. In this study, we aim to demonstrate that AR inhibition can attenuate induction of EMT markers in an in vivo model of cataract surgery. Methods: A modified extracapsular lens extraction (ECLE) was performed on C57BL/6 wildtype, AR overexpression (AR-Tg), and AR knockout mice. Immunofluorescent staining for the myofibroblast marker alpha-smooth muscle actin (alpha-SMA), epithelial marker E cadherin, and lens fiber cell markers alphaA-crystallin and Aquaporin 0 was used to characterize postoperative PCO. Quantitative reverse transcription PCR (qRT PCR) was employed to quantify postoperative changes in alpha-SMA, vimentin, fibronectin, and E-cadherin. In a separate experiment, the AR inhibitor Sorbinil was applied postoperatively and qRT-PCR was used to assess changes in EMT markers. Results: Genetic AR knockout reduced ECLE-induced upregulation of alpha SMA and downregulation of E-cadherin. These immunofluorescent changes were mirrored quantitatively in changes in mRNA levels. Similarly, Sorbinil blocked characteristic postoperative EMT changes in AR-Tg mice. Interestingly, genetic AR knockout did not prevent postoperative induction of the lens fiber cell markers alphaA-crystallin and Aquaporin 0. Conclusions: AR inhibition prevents the postoperative changes in EMT markers characteristic of PCO yet preserves the postoperative induction of lens fiber cell markers. PMID- 30025086 TI - Psychometric Analysis of the SPEED Questionnaire and CLDEQ-8. AB - Purpose: This study reports on the ability of the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire to detect dry eye (DE) symptoms in contact lens (CL) and non-CL wearers. Methods: The SPEED questionnaire was administered to all subjects while the Contact Lens Dry Eye Questionnaire-8 (CLDEQ-8) was only administered to CL wearers. Tear meniscus heights (TMH) were measured, and the phenol red thread (PRT) test was conducted. These tests along with self-reported DE were used to identify subjects with dry eye disease (DED). Rasch analysis was performed to evaluate the questionnaires for measurement precision and unidimensionality, and the scores from these Rasch analyses were used to understand their ability to predict measures of DED. Results: We enrolled 284 subjects (150 CL and 134 non-CL wearers). Mean subject age was 39.4 +/- 14.2 years. Rasch analysis yielded a multidimensional short form of the SPEED questionnaire (8-items) and a unidimensional short form of the CLDEQ-8 (4-item). Scores from both questionnaires were significantly associated with self-reported DE in CL and non-CL wearers. Scores of the 8-item SPEED questionnaire were associated with DED status in non-CL wearers but not in CL wearers while 4-item CLDEQ scores were associated with DED status in CL wearers. TMH or PRT were not associated with either questionnaire in CL or non-CL wearers. Conclusions: The 8 item SPEED questionnaire demonstrated adequate measurement precision with evidence of quantifying multiple symptoms categories while the 4-item CLDEQ-8 primarily quantified DE symptoms. Questionnaire scores were associated with self reported DE, which suggests that they may have utility in both populations analyzed. PMID- 30025087 TI - Retinopathy of Prematurity Trends in Taiwan: A 10-Year Nationwide Population Study. AB - Purpose: To investigate the 10-year epidemiology and risk factors of retinopathy of prematurity (ROP) in Taiwan using the National Health Insurance Research Database. Methods: All premature infants (n = 34,192) from 2002 to 2011 were screened, and those with length of stay (LOS) longer than 28 days who survived after the initial discharge were enrolled (n = 11,180). The annual incidence of ROP and the risk factors associated with it were analyzed. Results: A total of 4096 ROP infants, 36.6% of premature babies with LOS longer than 28 days, were identified. The numbers of newborns, premature infants, and cases with ROP decreased over time, but the proportion of extremely low birth weight infants increased over time (P < 0.01 for test of trend in number). Also, the proportion of ROP infants receiving treatment increased over time (P < 0.01 for test of trend in number). However, the incidence of ROP was steady throughout the study period. Multivariable analysis revealed that low birth weight, male sex (odds ratio [OR] = 1.12, P = 0.007), and multiparity (OR = 1.17, P = 0.002) were positively associated with ROP, whereas necrotizing enterocolitis (OR = 0.72, P = 0.002) had a negative association with ROP. Conclusions: The average incidence of ROP from 2002 to 2011 in Taiwan showed no significant change over the 10-year period. Proportion of treatment-requiring ROP increased. Low birth weight, multiparity, and male sex were independent risk factors of ROP. PMID- 30025089 TI - 3-Hydroxypyruvate Destabilizes Hypoxia Inducible Factor and Induces Angiostasis. AB - Purpose: Transcriptional analysis of retina protected by hypoxia-inducible factor (HIF) stabilization demonstrates an increase in genes associated with aerobic glycolysis. We hypothesized that since protection is associated with a change in metabolism, oxygen-induced metabolites might transduce oxygen toxicity. We used global metabolic profiling to identify retinal metabolites increased in hyperoxia compared to normoxia. Methods: Untargeted gas chromatography mass spectroscopy (GC-MS) was performed on both mouse retina samples collected in hyperoxia and on primary human retinal endothelial cells, each with and without HIF stabilization. After identifying 3-hydropxypyruvate (3OH-pyruvate) as a unique hyperoxic metabolite, endothelial cells in culture and choroidal explants were challenged with 3OH-pyruvate in order to determine how this glycolytic intermediate was metabolized, and whether it had an effect on angiogenesis. Results: 3OH-pyruvate was one of five metabolites at least 2.0-fold elevated in hyperoxia with a P value < 0.1. Once metabolized by endothelial cells, 3OH-pyruvate led to a 20-fold increase in 3-phosphoglycerate and a 4-fold increase in serine when cells were treated with Roxadustat to induce HIF stabilization. 3OH-pyruvate, but not pyruvate, destabilized HIF in endothelial cells with an increase in proline hydroxylation. 3OH-pyruvate was angiostatic in choroidal explant assays. Conclusions: 3OH-pyruvate is a unique metabolite induced by hyperoxia that destabilizes HIF at least in part by a canonical pathway. 3OH-pyruvate induces angiostasis in vitro. HIF stabilization increases serine biosynthesis in vitro and in vivo. PMID- 30025088 TI - Ascorbate Suppresses VEGF Expression in Retinal Pigment Epithelial Cells. AB - Purpose: To investigate the impact of ascorbate, via DNA hydroxymethylation, on VEGF expression in retinal pigment epithelial (RPE) cells. Methods: Dot-blot and hydroxymethylated DNA immunoprecipitation sequencing were applied to evaluate the impact of ascorbate on DNA hydroxymethylation in ARPE-19 cells. RNA sequencing (RNA-seq) was carried out to analyze the transcriptome. Quantitative RT-PCR and ELISA were conducted to examine the transcription and secretion of VEGF from cultured cells. Primary human fetal RPE cells and RPE-J cells were used to verify the effect of ascorbate on VEGF expression. ELISA was used to measure VEGF in the vitreous humor of Gulo-/- mice, which, like humans, cannot synthesize ascorbate de novo. Results: Treatment with ascorbate (50 MUM) promoted 5 hydroxymethycytosine (5hmC) generation and changed the genome-wide profiles of 5hmC in ARPE-19 cells. Ascorbate also caused a dramatic shift in the transcriptome-3186 differential transcripts, of which 69.3% are correlated with altered 5hmC in promoters or gene bodies. One of the most downregulated genes was VEGFA, which encodes the VEGF protein. The suppression of VEGF by ascorbate is independent of hypoxia-inducible factor 1-alpha (HIF-1alpha) but correlates with increased 5hmC in the gene body. The decreased transcription and secretion of VEGF by ascorbate were verified in primary human fetal RPE cells. Furthermore, adding ascorbate in the diet for Gulo-/- mice resulted in decreased levels of VEGF in the RPE/choroid and vitreous humor. Conclusions: Ascorbate inhibits VEGF expression in RPE cells likely via DNA hydroxymethylation. Thus, ascorbate could be implicated in the prevention or treatment of diseases such as age-related macular degeneration (AMD). PMID- 30025091 TI - Parapapillary Beta Zone and Gamma Zone in a Healthy Population: The Beijing Eye Study 2011. AB - Purpose: To assess prevalence and size of the parapapillary beta zone and gamma zone in a healthy population. Methods: Within the population-based Beijing Eye Study, individuals without retinal or optic nerve disease were selected. Using optical coherence tomography (OCT), we measured the parapapillary beta zone (defined by presence of Bruch's membrane and absence of RPE) and gamma zone (region between Bruch's membrane end and optic disc border). Results: The study included 723 individuals (mean age: 59.5 +/- 7.6 years; range: 50-90 years). The beta zone was detected in 525 eyes (72.6%; 95% confidence interval [CI]: 69.4, 75.9). A larger maximum width of the beta zone (mean: 253 +/- 225 MUm) was associated (multivariate analysis; regression coefficient r2: 0.36) with older age (P < 0.001; standardized regression coefficient beta: 0.28), thinner temporal parapapillary choroidal thickness (P < 0.001; beta: -0.21), longer axial length (P < 0.001; beta: 0.14), longer vertical Bruch's membrane opening (BMO) length (P < 0.001; beta: 0.32), shorter horizontal BMO length (P = 0.003; beta: -0.12), and more pronounced vertical optic disc rotation of (P < 0.001; beta: 0.15). The gamma zone was detected in 190 eyes (26.3 +/- 1.6%; 95% CI: 23.1, 29.5). A larger maximal width of the gamma zone (mean: 86 +/- 187 MUm) was (r2: 0.49) associated with longer axial length (P < 0.001; beta: 0.46), thinner central corneal thickness (P < 0.001; beta: 0.10), thinner temporal parapapillary choroidal thickness (P < 0.001; beta: -0.11), longer vertical (P < 0.001; beta: 0.15), and horizontal (P = 0.02; beta: 0.08) BMO length, and more pronounced vertical rotation of optic disc (P < 0.001; beta: 0.32). Conclusions: As measured by OCT in this healthy adult Chinese population, the gamma zone was mainly associated with longer axial length but not with age, while the beta zone was correlated mainly with older age and also with axial length. Both zones were largest in the temporal parapapillary region and smallest in the nasal region. PMID- 30025090 TI - Retinal Basal Laminar Deposits in Complement fH/fP Mouse Model of Dense Deposit Disease. AB - Purpose: Dense deposit disease (DDD) is caused by dysregulation of the alternative pathway of the complement cascade and characterized by electron-dense deposits in the kidney glomerular basement membrane (GBM) and drusen in Bruch's membrane (BrM). Complement factor H (fH) and factor properdin (fP) regulate complement activation; fH inhibits alternative pathway (AP) activation, whereas fP promotes it. We report pathologic changes in eyes of an fH and fP double mutant mouse, which we previously showed have dense deposits in the GBM and early mortality from nephropathy. Methods: fHm/m, fP-/-, and fHm/m/fP-/- mice were generated on a C57BL/6-129J background. Fundus imaging at 8 weeks of age was followed by analysis via light and electron microscopy. Retinal function was assessed by electroretinography (ERG). Complement levels and localization were tested by immunohistochemistry and ELISA. Retinas of fHm/m/fP-/- mice treated with intraperitoneal injections of an anti-C5 antibody were compared to those of age- and genotype-matched mice injected with an isotype control antibody. Results: fHm/m/fP-/- mice suffered early-onset retinal hypopigmented spots detected using in vivo retinal photography, and histologic examination showed basal laminar deposits (BLamD), degeneration of the photoreceptors, and RPE vacuolization. ERG showed diminished retinal function. The anti-C5 antibody was retina-protective. Conclusions: This unique mouse represents a new model of complement-mediated rapid-onset DDD, and could be useful in exploring the pathologic changes associated with BLamD in age-related macular degeneration. PMID- 30025092 TI - Quantity of Intraretinal Hyperreflective Foci in Patients With Intermediate Age Related Macular Degeneration Correlates With 1-Year Progression. AB - Purpose: The purpose of this study was to evaluate the correlation between quantity of intraretinal hyperreflective foci (HRF) in the eye with intermediate AMD and progression to late AMD. Methods: Volume optical coherence tomography (OCT) scans from 114 eyes of 114 patients were retrospectively reviewed. HRF were assessed both qualitatively and quantitatively. Five sequential en face slabs from midretina were thresholded to isolate the HRF. These five slabs were recombined, and HRF area was measured in the whole 6 * 6-mm image (HRFTOT) and within the central 3-mm (HRF3mm) and 5-mm (HRF5mm) regions. These measurements were correlated with the development of late AMD (defined as choroidal neovascularization [CNV] and/or complete RPE and photoreceptor atrophy [cRORA]) after 1 year of follow-up. Results: HRF area in all three regions showed significant correlations with progression to late AMD: R = 0.610 for HRF3mm, R = 0.622 for HRF5mm, and R = 0.614 for HRFTOT (all P < 0.001). Correlations remained significant with progression to cRORA alone, though not for progression to CNV alone. While qualitative assessment of HRF (i.e., presence of HRF: yes or no) also showed a significant correlation with progression to late AMD (R = 0.454, P < 0.001) and atrophy alone (R = 0.445, P < 0.001), they were weaker than by HRF quantification. Conclusions: The area of HRF from en face OCT in eyes with intermediate AMD correlates with the 1-year risk of progression to late AMD, and in particular with the development of atrophy. PMID- 30025093 TI - Increased Inner Retinal Layer Reflectivity in Eyes With Acute CRVO Correlates With Worse Visual Outcomes at 12 Months. AB - Purpose: To determine if inner retinal layer reflectivity in eyes with acute central retinal vein occlusion (CRVO) correlates with visual acuity at 12 months. Methods: Macular optical coherence tomography (OCT) scans were obtained from 22 eyes of 22 patients with acute CRVO. Optical intensity ratios (OIRs), defined as the mean OCT reflectivity of the inner retinal layers normalized to the mean reflectivity of the RPE, were measured from the presenting and 1-month OCT image by both manual measurements of grayscale B-scans and custom algorithmic measurement of raw OCT volume data. OIRs were assessed for association with final visual outcome. Cohort subgroup division for analysis was determined statistically. Results: Eyes with poorer final visual acuity (>=20/70) at 1 year were more likely to have a higher ganglion cell layer OIR than eyes with better final visual acuity (<20/70) at 1 month (manually: 0.591 to 0.735, P = 0.006, algorithmically: 0.663 to 0.799, P = 0.014). At 1 month, eyes with a poorer final visual acuity demonstrated a higher variance of OIR measurements (algorithmically: 0.087 vs. 0.160, P = 0.002) per scan than eyes with better final visual acuity. Conclusions: In acute CRVO, ganglion cell layer changes at 1 month, including increased reflectivity and increased heterogeneity of reflectivity signal as expressed as OIR and OIR variance, were associated with a poorer visual prognosis at 1 year. Technique calibration with larger sample sizes and automated integration into OCT platforms will be necessary to determine if OIR can be a clinically useful prognostic tool. PMID- 30025095 TI - Hyperreflective Foci Number Correlates with Choroidal Neovascularization Activity in Angioid Streaks. AB - Purpose: To assess the changes in hyperreflective foci (HF) by means of spectral domain optical coherence tomography (SD-OCT) in patients undergoing anti-VEGF treatment for subfoveal choroidal neovascularization (CNV) secondary to angioid streaks (AS). Methods: Fifteen eyes with diagnosis of AS-related CNV (8 males) and 15 control eyes with uncomplicated AS were consecutively recruited. Patients and controls underwent complete ophthalmologic examination and SD-OCT. Patients were subjected to a pro re nata treatment regimen, including monthly examinations and intravitreal aflibercept injection in case of fluid detection on SD-OCT. HF were measured on horizontal scans of the six-line radial SD-OCT, in the fovea and parafovea and the subdivided as retinal or choroidal. Specifically, HF were analyzed at the following time points: baseline, dry on SD-OCT, 1 month before its reactivation, and the time of CNV reactivation. Results: HF numbers resulted higher in all CNV phases with respect to controls, except during inactive phase. Moreover, foveal and parafoveal HF were found significantly increased in active, prereactive, and reactive phases when compared with inactive phase (P < 0.05). A similar trend was detected for choroidal HF. Interestingly, a subanalysis revealed that only foveal choroidal HF are significantly higher in a prereactive phase if compared with an inactive phase (P = 0.03). Our correlational analysis unveiled negative associations between intraretinal HF numbers and logMAR best corrected visual acuity. Conclusions: Our findings suggest that HF represent useful markers to monitor CNV activity. Choroidal HF appear already increased in the fovea 1 month before CNV reactivation. Validation of our results might lead to earlier anti-VEGF reinjection and possibly better visual outcomes. PMID- 30025094 TI - Inhibition of Human Corneal Myofibroblast Formation. AB - Purpose: Transforming growth factor-beta (TGF-beta) isoform 1 (T1) is involved in corneal fibrotic wound healing by stimulating myofibroblast transformation and altering fibrotic gene expression. In this study, two specific inhibitors were used to dissect the relationship between myofibroblast generation and the TGF beta/Smad- or TGF-beta/p38-signaling pathway in human corneal fibroblasts (HCF). Methods: In HCF, Trx-SARA (Smad-pathway inhibitor) was used to block the TGF beta/Smad-signaling pathway, and the p38 inhibitor (p38inh, SB202190) was used to inhibit p38MAPK, thus blocking the TGF-beta/p38-signaling pathway. HCF +/- Trx SARA or Trx-GA (SARA control) were serum starved overnight in Eagle's minimum essential medium (EMEM) +/- p38inh, grown in EMEM +/- T1 +/- p38inh for 24 hours, and then processed for indirect-immunofluorescence, Western blot, or quantitative real-time polymerase chain reaction to examine alpha-smooth muscle actin (alphaSMA) and other fibrotic genes, such as fibronectin, thrombospondin1, and type III collagen. In addition, the morphology and the effect of p38inh on myofibroblast phenotype after myofibroblast formation were examined. Results: We observed that Trx-SARA had little effect on alphaSMA expression, indicating that blocking the Smad pathway did not significantly inhibit myofibroblast formation. However, p38inh did significantly inhibit alphaSMA and other fibrotic genes, thus efficiently preventing the transition of HCFs to myofibroblasts. In addition, morphology changed and alphaSMA decreased in myofibroblasts exposed to p38inh medium, as compared with controls. Conclusions: HCF transition to myofibroblasts was mainly through the p38 pathway. Therefore, blocking the p38 pathway may be a potential therapeutic tool for human corneal fibrosis prevention/treatment, because it controls myofibroblast formation in human corneal cells, while leaving other functions of T1 unaffected. PMID- 30025096 TI - Anatomic Evidence for Information Exchange between Primary Afferent Sensory Neurons Innervating the Anterior Eye Chamber and the Dura Mater in Rat. AB - Purpose: Our previous studies suggested that mechanosensitive trigeminal ganglion (TG) nerve endings innervating the inner wall of the anterior eye chamber (IWAEC) might play a role in baroreception of the IOP. It has been reported that mechanosensitive TG nerve endings also innervate the dura mater. An acute IOP elevation evokes eye pain accompanied by an ipsilateral headache, suggesting that information exchange may occur between the primary afferent neurons (PANs) innervating the IWAEC and the dura mater. To verify the information exchange between PANs of the two locations, we investigated the anatomic connection between them. Methods: Non-trans-synaptic tracers, 1,1'-dilinoleyl-3,3,3',3' tetramethylindo-carbocyanine, 4-chlorobenzenesulfonate (FAST Dil) and cholera toxin subunit-B with a 488-nm fluorescent tag (CTB-488), were applied to the dura of the anterior cranial fossa (DACF) and the anterior eye chamber (AEC) to label the PANs. A trans-synaptic tracer, GFP-expressing pseudorabies virus (PRV152), was injected into the AEC while FAST Dil was applied to the DACF to explore the connection between PANs. Fluorescent localization in the TG was studied with a confocal fluorescent microscope. Results: Nine days after rats were treated with CTB-488 in the AEC and FAST Dil on the DACF, FAST Dil-labeled (red), and CTB-488 labeled (green) TG neurons were observed in the medial part of the TG, while double-labeled neurons were absent. If PRV152 was used to substitute CTB-488, then FAST Dil (red) and PRV152 (green) double-labeled TG neurons and axons were observed 3 days later. Conclusions: Our results indicate that synapses exist between PANs of the IWAEC and the DACF, providing anatomic evidence for information exchange between them. PMID- 30025097 TI - Distribution and Trends in Corneal Thickness Parameters in a Large Population Based Multicenter Study of Young Chinese Adults. AB - Purpose: The purpose of this study was to characterize corneal thickness from multiple regions and determine accurate reference values in young adults for diagnosis and treatment. Methods: This cross-sectional observational study was conducted from January 2008 through October 2016 using examiner-blinded clinical measurements and included 37,375 healthy eyes from young adults who exhibited normal corneal morphology, had no history of eye surgery or trauma, had stopped wearing soft contact lenses for >=2 weeks (rigid contact lenses for >=4 weeks), and had undergone topographies of both eyes on same day. Keratoconus and subclinical keratoconus were excluded. This multicenter study was conducted in four provinces of China: Tianjin, Shandong, Hubei, and Xinjiang. Results: Central corneal, corneal vertex, and thinnest corneal thicknesses were higher in eyes from Hubei than other provinces. The left eye was thicker than the right in patients from Shandong, Tianjin, and Hubei, but not Xinjiang. Overall corneal thickness was higher in eyes from Hubei than from other provinces. Changing trend of the whole-cornea thickness in eyes from Xinjiang differed from eyes from other provinces. Trends in maximum and minimum axial for change of corneal thickness were similar between eyes from Hubei and Xinjiang and between Shandong and Tianjin. Conclusions: Corneal thickness differs among eyes from different regions. Corneal thickness parameters are influenced by ethnicity and geographical location, as increasing proximity to the equator was related to increasing corneal thickness. Design of refractive surgery and diagnosis of related diseases in patients of a certain area should be based on reference values from its population. PMID- 30025098 TI - Surgical Removal of Internal Limiting Membrane and Layering of AAV Vector on the Retina Under Air Enhances Gene Transfection in a Nonhuman Primate. AB - Purpose: To determine if the surgical removal of the internal limiting membrane (ILM) in nonhuman primates (NHPs) will result in safe and effective transfection of adeno-associated viral (AAV2) vectors using green fluorescent protein (GFP) as a reporter. Methods: Six Macaca fascicularis NHP eyes underwent vitrectomy, ILM peel with layering of 1.7 * 1013 genome copies per milliliter of AAV2-GFP under air. Four control eyes underwent only vitrectomy and pooling under air. The intensity and area transfected was quantified in vivo with fundus autofluorescence (FAF) imaging. NHPs were euthanized 16 weeks postsurgery and immunohistochemical analysis assessed GFP expression at the cellular level. Results: There was a larger area of fluorescence in ILM peeled eyes then in non ILM peeled eyes (50.7 [33.1-58.4] pixel2 versus 5.1 [0.6-7.6] pixel2, P < 0.01). The intensity of fluorescence was also higher in ILM peeled eyes (10.3 [2.2-18.5] vs. 1.9 [0.6-4.4], P = 0.05). Non-ILM peeled eyes displayed fluorescence confined to the foveal center. Histological sections showed colocalization in the Muller cell layer, ganglion cell layer, and photoreceptor cell layer in the ILM peeled eyes. In non-ILM peeled eyes GFP expression was only in the ganglion cell layer in three eyes and was confined to the immediate vicinity of the fovea. Conclusions: ILM appears to be the predominate barrier to AAV transfection. An efficacious and safe method of AAV2 gene delivery, taking into account the potential need for repeat treatments, appears to be the surgical removal of ILM and layering of AAV under air.v. PMID- 30025099 TI - Tear Film Proteomics Reveal Important Differences Between Patients With and Without Ocular GvHD After Allogeneic Hematopoietic Cell Transplantation. AB - Purpose: To date, no biomarkers for ocular graft versus host disease (GvHD), a frequent complication following allogeneic hematopoietic cell transplantation (HCT), exist. In this prospective study, we evaluated the potential of human tear proteins as biomarkers for ocular GvHD. Methods: Tears from 10 patients with moderate-to-severe ocular GvHD were compared to 10 patients without ocular GvHD. After a full ocular surface clinical examination, tears were collected onto Schirmer strips and protein composition was analyzed by liquid chromatography tandem mass spectrometry. Statistical evaluation was performed using the Mann Whitney U test to compare means and the false discovery rate method to adjust for multiple comparisons. Functional annotation of differentially expressed proteins was done with the PANTHER classification system. Results: We identified 282 proteins in tryptic digests of Schirmer strips; 79 proteins were significantly differentially expressed between the two groups, from which 54 were up- and 25 downregulated. The most upregulated proteins were classified as nucleic acid binding and cytoskeletal proteins, while the most extensively downregulated proteins belong to an array of classes including transfer and receptor proteins, enzyme modulators, and hydrolases. In addition to proteins already confirmed as differentially expressed in dry eye disease, we report changes in 36 novel proteins. Conclusions: This study reports the proteomic profile of tears in ocular GvHD for the first time and identifies a number of unique differentially expressed proteins. Further studies with a higher number of participants are necessary to confirm these results and to evaluate the reliability of these expression patterns in longitudinal studies. PMID- 30025100 TI - Significant Relationship of Visual Field Sensitivity in Central 10 degrees to Thickness of Retinal Layers in Retinitis Pigmentosa. AB - Purpose: To determine the relationship between the sensitivity of the retina in the central 10 degrees and the thickness of the retinal layers in patients with retinitis pigmentosa (RP). Methods: Fifty-two RP patients were studied. All of the patients had been examined by the Humphrey Field Analyzer 10-2 program (HFA10 2) and spectral-domain optical coherence tomography (SD-OCT). The thicknesses of the photoreceptor outer segment (OS), outer nuclear layer (ONL), inner nuclear layer (INL), and the retinal nerve fiber layer (RNFL) were measured at 1 degrees , 3 degrees , 5 degrees , 7 degrees , and 9 degrees from the fovea. The same measurements were made on the SD-OCT images of 40 healthy subjects and used as controls. The relationships between the retinal sensitivities and retinal layer thicknesses were determined. Results: The thicknesses of the OS and ONL and their product were significantly and positively correlated with the retinal sensitivities. The thickness of the INL was significantly and negatively correlated with the sensitivity. The strongest correlation with the sensitivity was with the OS thickness (marginal R2 [mR2] = 0.525, P < 0.001), followed by the product of the OS and ONL thicknesses (mR2 = 0.420, P < 0.001), ONL thickness (mR2 = 0.416, P < 0.001), and the INL thickness (mR2 = 0.014, P = 0.044). The thickness of the RNFL was not correlated with the sensitivity (mR2 = 0.005, P = 0.331). Conclusions: In contrast to previous reports, the thickness of the OS reflected the retinal sensitivity better than the product of OS and ONL. PMID- 30025101 TI - Characterization and Regulation of Gap Junctions in Porcine Ciliary Epithelium. AB - Purpose: Gap junctions provide a conduit between the intracellular fluids of the pigmented (PE) and non-pigmented (NPE) ciliary epithelial cells, and are therefore critical in the secretion of the aqueous humor (AH). However, opinions differ concerning the connexin (Cx) composition of the gap junctions. Therefore, we aimed to characterize the expression of Cx in the porcine ciliary epithelium (CE), a favorable model for humans; and determine the contribution of the highest expressed Cx to AH secretion. Methods: Freshly-harvested porcine CE cells were used. The mRNA and protein expressions of gap junctions were assessed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting (WB), respectively. The relative gene expressions of various Cx were determined by quantitative PCR. The gap junction permeability of isolated PE-NPE cell couplets was evaluated by Lucifer Yellow dye transfer. Results: Using RT-PCR and WB, Cx43, Cx45, Cx47, Cx50, and Cx60 were present in porcine CE, with Cx43 being the most abundant isoform, having over 200-fold higher expression than other Cx. Cx43 was primarily localized in the PE-NPE interface and the basolateral membranes of PE cells. Knockdown of Cx43 by siRNA significantly reduced gene and protein expressions, resulting in reduction of transcellular fluid flow by 90%. Conclusions: Cx43 was found to be the major component of gap junctions in porcine CE. Consistent with results from a bovine model, our results support the important role of Cx43 in mediating AH secretion. This finding may shed light on the development of a novel ocular hypotensive agent. PMID- 30025102 TI - Ocular Biomarkers of Alzheimer's Disease: The Role of Anterior Eye and Potential Future Directions. AB - Globally, Alzheimer's disease (AD) is a growing health and economic challenge that has no effective cure. Recent clinical trials indicate that preclinical treatment may be required but a routine screening tool for AD has been elusive. Hence, a simple, yet sensitive biomarker for preclinical AD, when the disease is most likely to be amenable to treatment, is lacking. Due to several features, the eye has been explored for this purpose and, among the ocular tissues, the retina has received the most attention. Currently, major works investigating the potential AD diagnosis by detecting amyloid-beta (Abeta) signatures in the retinal tissue are underway, while the anterior eye is more accessible for in vivo imaging and examination. This report provides a concise review of current literature on the anterior eye components, including the crystalline lens, cornea, and aqueous humor, in AD. We also discuss the potential for assessment of the corneal nerve structure and regeneration as well as conjunctival tissue for AD-related alterations. The crystalline lens has received considerable attention, but further research is required to confirm whether Abeta accumulates in the lens and whether it mirrors brain neuropathologic changes, particularly in preclinical AD. The rich corneal neural network and conjunctival vasculature also merit exploration in future studies to shed light on their potential association with AD pathologic changes. PMID- 30025103 TI - Activation of the EGF Receptor by Histamine Receptor Subtypes Stimulates Mucin Secretion in Conjunctival Goblet Cells. AB - Purpose: The purpose of this study was to determine if histamine receptors interact with the epidermal growth factor receptor (EGFR) in cultured rat conjunctival goblet cells. Methods: Goblet cells from rat conjunctiva were grown in organ culture. First-passage goblet cells were used in all experiments. Phosphorylated (active) and total EGFR, AKT, and extracellular signal-regulated kinase (ERK)1/2 were measured by Western blot analysis. Cells were preincubated with the EGFR antagonist AG1478 for 30 minutes or small interfering RNA specific to the EGFR for 3 days prior to stimulation with histamine or agonists specific for histamine receptor subtypes for 2 hours. Goblet cell secretion was measured using an enzyme-linked lectin assay. Goblet cells were incubated for 1 hour with the calcium indicator molecule fura-2/AM, and intracellular [Ca2+] ([Ca2+]i) was determined. Data were collected in real time and presented as the actual [Ca2+]i with time and as the change in peak [Ca2+]i. Results: Histamine increased the phosphorylation of the EGFR. Mucin secretion and increase in [Ca2+]i stimulated by histamine, and agonists specific for each histamine receptor subtype were blocked by inhibition of the EGFR. Increase in [Ca2+]i stimulated by histamine and specific agonists for each histamine receptor was also inhibited by TAPI-1, a matrix metalloproteinase (MMP) inhibitor. The histamine-stimulated increase in activation of AKT, but not ERK1/2, was blocked by AG1478. Conclusions: In conjunctival goblet cells, histamine, using all four receptor subtypes, transactivates the EGFR via an MMP. This in turn phosphorylates AKT to increase [Ca2+]i and stimulate mucin secretion. PMID- 30025105 TI - A Perspective of AMD Through the Eyes of Immunology. AB - Despite strong genetic associations, compelling human histological data and numerous hypotheses generated with supportive animal data, the mechanisms of inflammation or inflammatory control of cell health during progression of age related macular degeneration arguably remain elusive. This perspective delivers a view that maintaining tissue health requires active immune cellular and tissue pathways, but when responses are perturbed or exaggerated, chronic inflammation is destructive. There are potential pathways and processes to enable understanding and determine how potential causative factors including altered cellular metabolism, senescence, oxidative stress disrupt tissue homeostasis are engaged. Establishing differences in the immune phenotype between normal aging and AMD, and how the inter-relatedness of these triggers contribute to pathobiology is integral for future therapeutic success. PMID- 30025104 TI - Patterns of Fundus Autofluorescence Lifetimes In Eyes of Individuals With Nonexudative Age-Related Macular Degeneration. AB - Purpose: To investigate fundus autofluorescence (FAF) lifetimes in patients with nonexudative AMD. Methods: A total of 150 eyes of 110 patients (mean age: 73.2 +/ 10.7 years) with nonexudative AMD, as well as a healthy group of 57 eyes in 38 subjects (mean age: 66.5 +/- 8.7 years), were included. Investigations were conducted at the University Eye Clinic in Jena, Germany, as well as the Moran Eye Center in Salt Lake City, Utah, USA, using the Heidelberg Engineering Spectralis based fluorescence lifetime imaging ophthalmoscope (FLIO). A 30 degrees retinal field centered at the fovea was investigated. FAF decays were detected in short (498-560 nm) and long (560-720 nm, LSC) spectral channels. The mean fluorescence lifetimes (taum) were calculated. Optical coherence tomography scans and fundus photographs were also recorded. Results: In patients with nonexudative AMD, FLIO shows a ring-shaped pattern of prolonged taum in the LSC. This pattern occurs in all patients with AMD (including very early stages) and in one-third of the healthy controls. FAF lifetimes were longer with more advanced stages. The presence of drusen is associated with prolonged taum when compared with the healthy fundus, but drusen identification is difficult with FLIO only. Conclusions: FLIO detects a clear pattern of changes within the fundus, which appears to be AMD-associated. These changes are already visible in early AMD stages and not masked by the presence of other coexisting retinal diseases. These findings may be useful for the early diagnosis of AMD and to distinguish AMD from other retinal diseases. PMID- 30025106 TI - The Proteomic Landscape in the Vitreous of Patients With Age-Related and Diabetic Retinal Disease. AB - Purpose: In contrast to neovascular AMD (nAMD), no treatment option exists for dry AMD. Hence, the identification of specific biomarkers is required to facilitate diagnosis and therapy of dry AMD. Methods: The proteome of 34 vitreous humor samples (dry AMD: n = 6; nAMD: n = 10; proliferative diabetic retinopathy [PDR]: n = 9; epiretinal membrane [ERM]: n = 9) was analyzed by liquid chromatography coupled mass spectrometry. Then, label-free relative quantification of dry AMD, nAMD, and PDR relative to ERM, which was defined as the reference group, was performed. Application of a bioinformatics pipeline further analyzed the vitreous proteome by cluster and gene set enrichment analysis. A selection of differentially regulated proteins was validated by ELISA. Results: A total of 677 proteins were identified in the vitreous of the four patient groups and quantified relatively to ERM. Different clusters of regulated proteins for each patient group were identified and showed characteristic enrichment of specific pathways including "oxidative stress" for dry AMD, "focal adhesion" for nAMD, and "complement and coagulation cascade" for PDR patients. We identified cholinesterase (CHLE) to be specifically upregulated in dry AMD and ribonuclease (pancreatic; RNAS1) together with serine carboxypeptidase (probable; CPVL) to be upregulated in both forms of AMD. Conclusions: The described pathways specific for the different patient groups and the identification of characteristic differentially regulated proteins provide a first step toward the definition of biomarkers for dry AMD. The presented data will facilitate the investigation of mechanistic connections of proteins to the respective disease. PMID- 30025107 TI - Multimodal Imaging of Nonneovascular Age-Related Macular Degeneration. AB - Nonneovascular (dry) AMD is a retinal disease with potential for significant central visual impairment. The hallmarks of this disease are macular drusen, RPE alterations, and geographic atrophy (GA). Classification schemes for nonneovascular AMD have evolved over the years as major advances in retinal imaging have enabled a greater understanding of disease pathophysiology. The original classifications of nonneovascular AMD were based on color fundus photography (CFP), while more modern schemes rely on a multimodal imaging approach. Effective diagnosis and management of nonneovascular AMD requires a thorough understanding of its multimodal imaging features as detailed in this review. Future imaging modalities and imaging biomarkers that may aid in diagnosis and management are also discussed. PMID- 30025108 TI - Perspective on AMD Pathobiology: A Bioenergetic Crisis in the RPE. AB - AMD is the leading cause of blindness in developed countries. The dry form of AMD, also known as atrophic AMD, is characterized by the death of RPE and photoreceptors. Currently, there are no treatments for this form of the disease due in part to our incomplete understanding of the mechanism causing AMD. Strong experimental evidence from studies of human donors with AMD supports the emerging hypothesis that defects in RPE mitochondria drive AMD pathology. These studies, using different experimental methods, have shown disrupted RPE mitochondrial architecture and decreased mitochondrial number and mass, altered content of multiple mitochondrial proteins, increased mitochondrial DNA damage that correlates with disease severity, and defects in bioenergetics for primary RPE cultures from AMD donors. Herein, we discuss a model of metabolic uncoupling that alters bioenergetics in the diseased retina and drives AMD pathology. These data provide the rationale for targeting the mitochondria in the RPE as the most efficacious intervention strategy if administered early, before vision loss and cell death. PMID- 30025109 TI - Stem Cell Treatment for Age-Related Macular Degeneration: the Challenges. PMID- 30025110 TI - MyD88 Deficiency Protects Against Dry Eye-Induced Damage. AB - Purpose: Dry eye disease (DED) is a multifactorial disease associated with ocular surface inflammation. Toll-like receptors (TLRs) are integral in the initiation of inflammatory signaling. Therefore, we evaluated the effect of TLR-deficiency on dry eye-related ocular surface damage and inflammation using a mouse model of experimental dry eye (EDE). Methods: C57BL/6 wild-type (WT), MyD88-/-, and IL-1R /- mice were exposed to EDE conditions for 5 days. Tear production was measured by phenol red thread test and ocular surface damage assessed with fluorescein staining. Corneal homogenates were obtained for matrix metalloproteinase (MMP) and cytokine expression analysis by Luminex assay and quantitative PCR. In addition, whole eyes and eyelids were dissected and goblet cells and Meibomian glands were imaged, respectively. Results: Following 5 days of EDE, WT mice had extensive ocular surface staining, while MyD88-/- mice had no increased staining above non-EDE conditions. Similarly, MyD88-/- mice did not have increased corneal MMP-2, 3, or 8 concentrations, as seen with WT mice. MyD88-deficiency also resulted in decreased corneal cytokine levels. In addition, MyD88-/- mice had significantly lower conjunctival goblet cell counts compared with both WT (EDE) and IL-1R-/- (non-EDE) mice. However, there was no difference in Meibomian gland morphology between WT, IL-1R-/-, and MyD88-/- mice. Conclusions: These studies demonstrate the importance of TLR signaling in dry eye development. Mice lacking TLR signaling, MyD88-/-, were protected from EDE-induced ocular surface damage and inflammatory mediator expression, warranting further investigation into TLR inhibition as a potential therapeutic for DED. PMID- 30025111 TI - VIP Regulates Morphology and F-Actin Distribution of Schlemm's Canal in a Chronic Intraocular Pressure Hypertension Model via the VPAC2 Receptor. AB - Purpose: To investigate the roles of vasoactive intestinal peptides (VIPs) in regulating the morphology and F-actin distribution of Schlemm's canal (SC) of rat eyes. Methods: Chronic intraocular pressure (IOP) hypertension models with episcleral venous cauterization (EVC) were treated with topical VIP or PG99-465 (vasoactive intestinal peptide receptors 2 [VPAC2] antagonist). IOPs were measured with Tono-Pen, and the SC parameters, including the cross-section area, circumference, and length, were statistically evaluated by hematoxylin-eosin and CD31 immunohistochemical staining. Immunofluorescence was performed to detect the distribution of F-actin in the SC. Moreover, the distribution of filamentous actin (F-actin) and globular actin (G-actin) in human umbilical vein endothelial cells (HUVECs) was studied under a pressure system by immunofluorescence and Western blotting. Results: Increased expressions of VIP and VPAC2 receptors, as well as a disordered distribution of F-actin were found in SC endothelial cells (SCEs) in the EVC model. Moreover, topical VIP maintained the normal distribution of F-actin in SCEs, expanded the collapsed SC, and induced a significant decrease in IOP in the EVC model. In in vitro HUVECs, the F-actin/G-actin ratio increased significantly under stress stimulation for 30 minutes. A total of 50 MUM VIP helped maintain the normal F-actin/G-actin ratio of HUVECs against stress stimulation. Conclusions: VIP regulates the distribution of F-actin in SCEs via the VPAC2 receptor in order to induce a decrease in IOP. VIP may represent a new target for antiglaucoma drugs. PMID- 30025112 TI - The Interactions Between Bright Light and Competing Defocus During Emmetropization in Chicks. AB - Purpose: The environment comprises multiple optical signals that affect eye growth. We aimed to determine if the inhibitory effects of myopic defocus and bright light (BL) against myopia are additive in the presence of the myopia-genic hyperopic defocus. Methods: In experiment 1, three groups of 24 chicks each were fitted with the following multizone dual-power lenses (pl): pl/-10 D (50:50 area), +10/-10 D (50:50 area), and +10/-10 D (33:67 area) monocularly for 6 days. Half of each group were raised under normal illumination of 500 lux, 12/12-hour light/dark cycle, whereas the remainder were exposed to 6-hour BL of 40 klx and 6 hour 500 lux during the light cycle. In experiment 2, 38 chicks wore +10/-10 D (33:67 area) lenses monocularly for 8 days and were exposed to one of four light intensities for 6 hours per day-500 lux, 10 klx, 20 klx, or 40 klx-and received 500 lux for the remainder of the light cycle. Results: In experiment 1, interocular difference in refractions after 6 days for the three groups were -3.6 D, +2.0 D, and -4.2 D, respectively, under normal light and were -0.9 D, +4.2 D, and +0.67 D under BL, manifesting as a shorter anterior segment and vitreous chamber. In experiment 2, the effect of BL increased with light intensity in the +10/-10 D (33:67) group, with a significant difference in refraction between the 10 klx and 20 klx groups (interocular difference -2.75 +/- 2.76 D vs. 1.70 +/- 2.40 D, P < 0.01), but plateaued between 20 klx and 40 klx (1.70 +/- 2.40 D vs. 1.70 +/- 0.35 D, P > 0.05). Conclusions: The protective effects of myopic defocus and BL against experimental myopia were additive. The inhibitory effect of BL against myopia was dose dependent at 10 klx and above but plateaued at 20 klx. PMID- 30025113 TI - Characterization of Human iPSC-RPE on a Prosthetic Bruch's Membrane Manufactured From Silk Fibroin. AB - Purpose: RPE cell transplantation as a potential treatment for AMD has been extensively investigated; however, in AMD, ultrastructural damage affects both the RPE and its underlying matrix support, the Bruch's membrane (BrM). An RPE monolayer supported by a surrogate scaffold could thus provide a more effective approach to cell-based therapy for AMD. Toward this goal, we aimed to establish a functional human induced pluripotent stem cell-derived (hiPSC)-RPE monolayer on a Bombyx mori silk fibroin (BMSF) scaffold. Methods: RPE differentiated from five distinct hiPSC lines were cultured on BMSF membrane coated with extracellular matrix (ECM, COL1), and either regular tissue culture plastic or Transwell coated with ECM (LAM-TCP). Morphologic, gene and protein expression, and functional characteristics of the hiPSC-RPE cultured on different membranes were compared in longitudinal experiments spanning 1 day to >=3 months. Results: The hiPSC-RPE monolayers on ECM-coated BMSF and TCP could be maintained in culture for >=3 months and displayed RPE-characteristic morphology, pigmentation, polarity, and expression of RPE signature genes and proteins. Furthermore, hiPSC-RPE on both ECM-coated BMSF and TCP displayed robust expression and secretion of several basement membrane proteins. Importantly, hiPSC-RPE cells on COL1-BMSF and LAM-TCP showed similar efficacy in the phagocytosis and degradation of photoreceptor outer segments. Conclusions: A biomaterial scaffold manufactured from silk fibroin supports the maturation and long-term survival of a functional hiPSC-RPE monolayer. This has significant implications for both in vitro disease modeling and in vivo cell replacement therapy. PMID- 30025114 TI - Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1. AB - Purpose: RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs' endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. Methods: FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. Results: FECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P < 0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients. Conclusions: FECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD. PMID- 30025117 TI - Potential Role of Zinc Dyshomeostasis in Matrix Metalloproteinase-2 and -9 Activation and Photoreceptor Cell Death in Experimental Retinal Detachment. AB - Purpose: We investigated whether zinc dyshomeostasis, a known mechanism of cell death in acute brain injury, contributes to the activation of matrix metalloproteinases (MMPs) and photoreceptor cell death in experimental retinal detachment (RD). Methods: RD was induced in mice by subretinal injection of 1:1 mixture of balanced salt solution and 1% sodium hyaluronate. On days 1 and 3 post RD, eyeballs were sectioned and examined for cell death (TUNEL staining), the degree of hypoxic insult (Hypoxyprobe staining), free zinc levels (TFL-Zn staining), and MMP-2 and -9 activity (gelatin zymography). In addition, we examined whether modulating extracellular zinc concentration or MMP activation in subretinal fluid affected photoreceptor cell death in RD. These changes were further examined in primary retinal cell and photoreceptor-derived cell (661W) cultures. Results: Photoreceptor cell death peaked on day 3 post RD. Intracellular zinc markedly decreased on day 1 post RD, and subsequently accumulated on day 3. MMP-2 and -9 activity showed a concurrent increase in detached retinas. Detached retinas stained with Hypoxyprobe showed strongly positive cells, especially in the photoreceptor layer. Subretinal injection of a zinc-chelator (CaEDTA) or MMP inhibitor (GM6001, minocycline) at the time of RD significantly attenuated photoreceptor cell death in RD. Similar findings were confirmed in oxygen-glucose-deprived or zinc-exposed cell cultures. Conclusions: Upon RD, hypoxic retinal cells in deep layers underwent zinc dyshomeostasis, MMP activation, and ultimately death. These findings provide new insight into the possible mechanism of photoreceptor death in RD, and as such may prove useful in crafting protective measures for photoreceptor cells. PMID- 30025115 TI - Analysis of Anatomic and Functional Measures in X-Linked Retinoschisis. AB - Purpose: To examine the symmetry of structural and functional parameters between eyes in patients with X-linked retinoschisis (XLRS), as well as changes in visual acuity and electrophysiology over time. Methods: This is a single-center observational study of 120 males with XLRS who were evaluated at the National Eye Institute. Examinations included best-corrected visual acuity for all participants, as well as ERG recording and optical coherence tomography (OCT) on a subset of participants. Statistical analyses were performed using nonparametric Spearman correlations and linear regression. Results: Our analyses demonstrated a statistically significant correlation of structural and functional measures between the two eyes of XLRS patients for all parameters. OCT central macular thickness (n = 78; Spearman r = 0.83, P < 0.0001) and ERG b/a ratio (n = 78; Spearman r = 0.82, P < 0.0001) were the most strongly correlated between a participant's eyes, whereas visual acuity was less strongly correlated (n = 120; Spearman r = 0.47, P < 0.0001). Stability of visual acuity was observed with an average change of less than one letter (n = 74; OD -0.66 and OS -0.70 letters) in a mean follow-up time of 6.8 years. There was no statistically significant change in the ERG b/a ratio within eyes over time. Conclusions: Although a broad spectrum of clinical phenotypes is observed across individuals with XLRS, our study demonstrates a significant correlation of structural and functional findings between the two eyes and stability of measures of acuity and ERG parameters over time. These results highlight the utility of the fellow eye as a useful reference for monocular interventional trials. PMID- 30025116 TI - Spatial Patterns and Age-Related Changes of the Collagen Crimp in the Human Cornea and Sclera. AB - Purpose: Collagen is the main load-bearing component of the eye, and collagen crimp is a critical determinant of tissue mechanical behavior. We test the hypothesis that collagen crimp morphology varies over the human cornea and sclera and with age. Methods: We analyzed 42 axial whole-globe sections from 20 normal eyes of 20 human donors, ranging in age from 0.08 (1 month) to 97 years. The sections were imaged using polarized light microscopy to obtain MUm-scale fiber bundle/lamellae orientation from two corneal and six scleral regions. Crimp morphology was quantified through waviness, tortuosity, and amplitude. Results: Whole-globe median waviness, tortuosity, and amplitude were 0.127 radians, 1.002, and 0.273 MUm, respectively. These parameters, however, were not uniform over the globe, instead exhibiting distinct, consistent patterns. All crimp parameters decreased significantly with age, with significantly different age-related decreases between regions. The crimp morphology of the limbus changed the most drastically with age, such that it had the largest crimp in neonates, and among the smallest in the elderly. Conclusions: Age-related decreases in crimp parameters are likely one of the mechanisms underlying age-related stiffening of the sclera and cornea, potentially influencing sensitivity to IOP. Further work is needed to determine the biomechanical implications of the crimp patterns observed. The comparatively large changes in the crimp morphology of the limbus, especially in the early years of life, suggest that crimp in this region may play a role in eye development, although the exact nature of this is unclear. PMID- 30025118 TI - Axial Scaling Is Independent of Ocular Magnification in OCT Images. PMID- 30025119 TI - microRNA Profiling in Glaucoma Eyes With Varying Degrees of Optic Neuropathy by Using Next-Generation Sequencing. AB - Purpose: To explore the microRNA (miRNA) profile and its putative role in glaucomatous optic neuropathy by using next-generation sequencing. Methods: Aqueous humor (AH) samples were collected from 19 primary open-angle glaucoma (POAG) eyes and 17 cataract eyes before surgery. Next-generation sequencing was performed for RNA samples extracted from 18 AH samples, and the bioinformatics approach was applied for samples with adequate clean data output. The other 18 samples were used for quantitative PCR validation of sequencing results. Results: In total, 12 (six POAG and six cataract controls) samples with sufficient clean data output after sequencing were used for further data analysis. Four hundred sixty-six and 480 mature miRNAs were detected in the POAG and cataract control groups, respectively. Among them, 164 miRNAs were detected in all POAG samples, and 96 miRNAs were detected in all cataract control samples. Furthermore, 88 miRNAs were identified as differently expressed between POAG and cataract control eyes. In addition, 16 miRNAs were differently expressed between POAG eyes with severe visual field damage and eyes with moderate visual field damage. This differential expression was predicted to regulate thiamine metabolism, purine metabolism, and transcriptional misregulation. Relative expression patterns of hsa-miR-184, hsa-miR-486-5p, and hsa-miR-93-5p were confirmed by quantitative PCR. Conclusions: This study comprehensively demonstrated the miRNA expression profile in the AH of POAG eyes, especially the differential expression of miRNA in eyes with varying degrees of visual field damage, which, together with the underlying miRNA-related pathways, indicate new targets for the pathogenesis and progression of POAG. PMID- 30025120 TI - Directed Differentiation of Human Corneal Endothelial Cells From Human Embryonic Stem Cells by Using Cell-Conditioned Culture Media. AB - Purpose: A shortage of human corneal endothelial cells (HCEC) for transplant and current methods of differentiation induction require chemical compounds, which might cast further influences after differentiation induction. Therefore, we developed a simple and straightforward approach to endothelial cell differentiation from human embryonic stem cells (hESC). Methods: HESC are used to differentiate into HCEC by employing a two-stage method, which involves the application of two different types of conditioned culture medium, human corneal stromal cell-conditioned medium (HCSC-CM) and lens epithelial cell (LEC) plus HCSC-CM (LEC-CM+HCEC-CM). In brief, hESCs were treated with different conditioned media to induce directed endothelial differentiation. Results: In the presence of conditioned culture medium, embryonic stem cells differentiate first under the control of periocular mesenchymal precursors (POMPs). Consequently, the expression of several POMP markers was observed. Following this first stage differentiation, POMPs were further directed to differentiate into corneal endothelial cell (CEC)-like cells in the presence of the second-conditioned culture medium. The differentiation of POMPs into CEC-like cells is regulated by a TGFbeta-2/FOXC1 signaling pathway that is activated by the factors present in the conditioned culture medium. Conclusions: HCEC-like cells could be differentiated from hESC by simply using a two-step, preconditioned, medium mediated approach, which could significantly minimize the workload to generate HCEC for potential clinical use. This research may provide an ideal cell source for corneal regenerative medicine and clinical treatment for corneal diseases in the future. PMID- 30025121 TI - Fluorescein Leakage and Optical Coherence Tomography Features of Choroidal Neovascularization Secondary to Pathologic Myopia. AB - Purpose: We compare the fluorescein angiography (FA) patterns with morphologic alterations detectable on spectral-domain OCT (SD-OCT) in myopic choroidal neovascularization (mCNV) and evaluate whether they influence the effects of intravitreal ranibizumab (IVRI) in an as-needed (PRN) regimen. Methods: The 49 patients enrolled in this prospective case series underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA), FA, and SD-OCT assessment. The main outcome measure was correlation between FA patterns and SD-OCT features. Secondary outcomes were changes in BCVA and central macular thickness (CMT), and characterization of subretinal hyperreflective exudation (SHE). Results: Three main patterns were identified on the FA: no (5%), minimal (35%), and profuse (59%) leakage CNV. Comparison between minimal versus profuse leakage CNV subtypes revealed no difference regarding baseline and final BCVA, CNV area, choroidal thickness, final CMT, and proportion of intraretinal cysts, subretinal fluid, and external limiting membrane (ELM) interruption; however, the minimal leakage CNV subgroup revealed a lower percentage of SHE (P = 0.0039), required fewer IVRI (P = 0.003), and showed a baseline smaller CMT (P = 0.004). Patients presenting with SHE showed a similar baseline BCVA to those without exudation, but displayed greater final BCVA improvement. CMT was greater at the baseline and the reduction also was more marked. CNV area achieved a significant reduction only in eyes with SHE. ELM interruption was present in all cases compared to 86.3% of eyes without SHE. Lastly, the eyes with SHE required more injections (P = 0.04). Conclusions: Different patterns of mCNV may be identified in FA and they correlate with specific SD-OCT alterations. Moreover, the type of FA leakage may assist in identifying more active mCNV. PMID- 30025122 TI - Grade of Cataract and Its Influence on Measurement of Macular Pigment Optical Density Using Autofluorescence Imaging. AB - Purpose: To evaluate the influence of cataracts on measuring macular pigment optical density (MPOD) using a dual-wavelength confocal scanning autofluorescence imaging technique and to establish methods to compensate for the influence of cataracts. Methods: This prospective case series comprised 100 eyes that underwent cataract surgery. Cataracts were graded based on the World Health Organization classification. MPOD levels were measured with the MPOD module of the Spectralis MultiColor instrument (Spectralis-MP), pre- and postoperatively. We investigated the relationship between change in MPOD values and age, cataract grade, and quality of autofluorescence images. Local MPOD levels were evaluated for four strategically chosen eccentricities within the macular region, and the total MPOD volume was evaluated within 8.98 degrees eccentricity from the center. Results: MPOD levels could be obtained in 67 eyes before surgery. Local and volume MPOD levels were higher postoperatively relative to preoperatively in all eyes. The mean ratio of local MPOD levels after and before surgery (correction factor, CF) ranged from 1.42 to 1.77, with larger CFs required for eccentricities closer to the foveal center. The CF for the MPOD volume was 1.31. Age, grade of nuclear cataract (NUC), posterior subcapsular opacity, and image quality index (IQI) significantly contributed to CFs. For example, regression equation for CF at 0.23 degrees = 0.17 + 0.16 * IQI + 0.29 * NUC grade + 0.01 * age (P < 0.001). Conclusions: Cataracts affected MPOD measurements with the Spectralis-MP, but corrected MPOD results could be obtained via regression equations. PMID- 30025123 TI - Systemic 7,8-Dihydroxyflavone Treatment Protects Immature Retinas Against Hypoxic Ischemic Injury via Muller Glia Regeneration and MAPK/ERK Activation. AB - Purpose: Perinatal hypoxic-ischemic (HI) injury causes significant damages in the immature retina. The brain-derived neurotrophic factor is well known for its neuroprotective role but has limited clinical applications. A selective agonist of tyrosine kinase receptor B, 7,8-dihydroxyflavone (DHF), is a powerful therapeutic tool, when administered systemically. However, it remains unclear whether DHF treatment can protect the immature retinas against HI injury. Methods: Postnatal (P) day 7 rat pups were intraperitoneally injected with DHF or vehicle 2 hours before and 18 hours after being subjected to HI injury. The outcomes were assessed at various timepoints after injury by electroretinography and histologic examinations. Neurogenesis was assessed by double-labeling of retinal sections with 5-bromo-2'-deoxyuridine and different neuronal markers. Results: At P8, 24-hours postinjury, brain-derived neurotrophic factor mRNA levels in the retina decreased significantly. DHF treatment partially protected immature retinas at both histologic and functional levels between P14 and P30 but did not prevent apoptosis, inflammation, or damage of the blood-retinal barrier (BRB) at P8. On the other hand, DHF treatment promoted the survival of proliferating inner retinal cells, including Muller glia, and enhanced their transdifferentiation to bipolar cells at P17. Moreover, DHF treatment rescued the levels of extracellular signal-regulated kinase (ERK) phosphorylation, which were significantly decreased after injury. The neuroprotective effects of DHF were markedly eliminated by inhibition of ERK phosphorylation. Conclusions: Early systemic DHF treatment has neuroprotective effects against HI injury in immature retinas, possibly via promoting neurogenesis through the tyrosine kinase receptor B/ERK signaling pathway. : Chinese Abstract. PMID- 30025124 TI - Trichostatin A Ameliorates Conjunctival Fibrosis in a Rat Trabeculectomy Model. AB - Purpose: To investigate whether histone deacetylase (HDAC) activity is associated with postoperative scarring and to evaluate the effect of HDAC inhibition by topical trichostatin A (TSA) on conjunctival fibrosis after trabeculectomy in a rat model. Methods: Trabeculectomy was performed on the left eye of Sprague Dawley rats. In the first experiment, adenoviruses HDAC 1, HDAC 2, and green fluorescent protein were added to the subconjunctival space during trabeculectomy. Expression of alpha-smooth muscle actin (alpha-SMA) was evaluated. In the second experiment, rats undergoing trabeculectomy were randomized into control, vehicle control, steroid, 500 nmol/L TSA, and 1 MUmol/L TSA groups. On postoperative day 14, bleb vascularity, toxic effect of topical TSA on corneal epithelium, expression of alpha-SMA, transforming growth factor (TGF)-beta1, and phosphorylated-Smad2/3 and the infiltration of CD45+ cells were determined. Masson's trichrome staining and immunofluorescence staining for alpha SMA and CD45 were also performed. Results: Overexpression of HDAC1 contributed to accelerated conjunctival fibrosis after trabeculectomy. HDAC inhibition by topical administration of 1 MUmol/L TSA significantly decreased bleb vascularity, leukocyte infiltration, and expression of alpha-SMA and TGF-beta1 in the conjunctiva. Its effectiveness on conjunctival fibrosis was comparable to that of topical steroid. Masson's trichrome staining showed decreased collagen deposition in the bleb tissues of steroid and 1 MUmol/L TSA treatment groups. Topical TSA did not have any toxic effect on the corneal epithelium. Conclusions: HDAC activity is involved in postoperative conjunctival fibrosis. HDAC inhibition by topical administration of TSA eye drops is a safe and effective therapeutic modality to modulate wound healing after trabeculectomy. PMID- 30025126 TI - The Contribution of Sulfated Glycosaminoglycans to the Inflation Response of the Human Optic Nerve Head. AB - Purpose: In this study, we measured the effect of the removal of sulfated glycosaminoglycans (sGAGs) on the pressure-induced strains of the human lamina cribrosa (LC). Methods: We applied an ex vivo inflation method to measure the three-dimensional (3D) deformation response of six human LCs to pressure, before and after the degradation of chondroitin and dermatan sulfates. The experiment used a laser-scanning microscope (LSM) to acquire the second harmonic generation (SHG) signal of the collagen structure in the LC. Digital volume correlation (DVC) was used to calculate the deformation in the LC after a change in pressure from 5 to 45 mm Hg. Results: The average strains between 5 and 45 mm Hg in the LC decreased significantly after sGAG degradation (P <= 0.03), with the greatest change occurring in regions of previously high strain (P <= 0.003) and the peripheral regions of the LC (P <= 0.02). The stiffening effect was greater in the LC of middle-aged (42-49 years) donors compared with those of older (64-88 years) donors (P < 0.0001). Conclusions: The LC experienced less strain at the same pressures after most sGAGs were removed. These results suggest that the natural decrease in sGAGs within the LC with age may contribute to the stiffer inflation response of older LC to IOP. Likewise, the increase in the amount of sGAGs observed in the LC of glaucomatous eyes, may contribute to a more compliant LC, which may affect the susceptibility and progression of axon damage. PMID- 30025127 TI - Effects of Topical Mucolytic Agents on the Tears and Ocular Surface: A Plausible Animal Model of Mucin-Deficient Dry Eye. AB - Purpose: A topical mucolytic agent, N-acetylcysteine (NAC), has been used to create an animal model without the intestinal mucus layer. In this study, we investigated the effects of topical NAC on the tears and ocular surface. Methods: NAC-treated models were established by topically administering 10% NAC four times daily for 5 days in male Sprague-Dawley rats. Clinical parameters and the expression of mucin proteins and genes were evaluated. Alterations in the conjunctival epithelium and goblet cells were observed. Results: The NAC group showed significant decreases in tear secretion, corneal wetting ability, tear MUC5AC concentration, and conjunctival goblet cell numbers as compared with the control group (all P < 0.01). In addition, significant increases in corneal fluorescein score and rose bengal scores were observed in the NAC group versus in the control group (P < 0.05 and P < 0.01, respectively). Hematoxylin and eosin (H&E) staining and scanning electron microscopy clearly showed damage in the epithelial cell layer and microvilli of the NAC group. Although there was no significant difference in MUC16 gene expression, the MUC16 concentration of the tear film and ocular surface tissue was significantly increased in the NAC group versus in the control group (P < 0.01 and P < 0.05, respectively). Five-day treatment with 3% diquafosol had minimal therapeutic effect in NAC-treated rat eyes. Conclusions: Topical administration of 10% NAC induced ocular surface damage and tear film instability by prompting MUC16 disruption and release from the ocular surface. This animal model could be used to study dry eye disease, especially the mucin-deficiency subtype. PMID- 30025125 TI - D-cis-Diltiazem Can Produce Oxidative Stress in Healthy Depolarized Rods In Vivo. AB - Purpose: New perspectives are needed to understand decades of contradictory reports on the neuroprotective effects of the Cav1.2 L-type calcium channel blocker d-cis-diltiazem in retinitis pigmentosa (RP) models. Here, we address, in vivo, the following two knowledge gaps regarding d-cis-diltiazem's actions in the murine outer retina: (1) do normal mouse rods contain d-cis-diltiazem-insensitive Cav1.2 L-type calcium channels? (2) Can d-cis-diltiazem modify the normal rod redox environment? Methods: First, transretinal Cav1.2 L-type calcium channels were noninvasively mapped with manganese-enhanced magnetic resonance imaging (MRI) following agonist Bay K 8644 in C57BL/6 (B6) and in Cav1.2 L-type calcium channel BAY K 8644-insensitive mutant B6 mice. Second, d-cis-diltiazem-treated oxidative stress-vulnerable (B6) or -resistant [129S6 (S6)] mice were examined in vivo (QUEnch-assiSTed [QUEST] MRI) and in whole retina ex vivo (lucigenin). Retinal thickness was measured using MRI. Results: The following results were observed: (1) manganese uptake patterns in BAY K 8644-treated controls and mutant mice identified in vivo Cav1.2 L-type calcium channels in inner and outer retina; and (2) d-cis-diltiazem induced rod oxidative stress in dark-adapted B6 mice but not in light-adapted B6 mice or dark-adapted S6 mice (QUEST MRI). Oxidative stress in vivo was limited to inferior outer retina in dark-adapted B6 mice approximately 1-hour post d-cis-diltiazem. By approximately 4 hours post, only superior outer retina oxidative stress was observed and whole retinal superoxide production was supernormal. All groups had unremarkable retinal thicknesses. Conclusions: D-cis-diltiazem's unexpectedly complex spatiotemporal outer retinal oxidative stress pattern in vivo was dependent on genetic background and rod membrane depolarization, but not apparently dependent on Cav1.2 L-type calcium channels, providing a potential rationale for contradictory results in different RP models. PMID- 30025128 TI - Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) of Macular Pigment. AB - Purpose: To describe different patterns of macular pigment (MP) seen in fluorescence lifetime imaging ophthalmoscopy (FLIO) and to analyze ex vivo fluorescence characteristics of carotenoids. Methods: A total of 31 eyes of young healthy subjects, 4 eyes from patients with albinism, 36 eyes with macular telangiectasia type 2 (MacTel), 24 eyes with retinitis pigmentosa, and 1 eye with a macular hole were included in this clinic-based, cross-sectional study. All subjects underwent Heidelberg Engineering FLIO and MP measurements (dual wavelength autofluorescence). Fundus autofluorescence (FAF) lifetimes of a 30 degrees retinal field were detected in two spectral channels (SSC: 498-560 nm; LSC: 560-720 nm), and amplitude-weighted mean fluorescence lifetimes (taum) were calculated. Additionally, autofluorescence lifetimes of known dilutions of lutein and zeaxanthin were measured in a cuvette in free- and protein-associated states. Results: MP shows a significant inverse correlation to foveal FAF lifetimes measured with FLIO (SSC: r = -0.608; P < 0.001). Different distribution patterns can be assigned to specific disease-related changes. Two patients with albinism, who did not have MP, were found to be missing short FAF lifetimes. In solvent, lutein and zeaxanthin show very short autofluorescence lifetimes (~50-60 ps; SSC), as do their respective binding proteins (~40-50 ps; SSC). When combining carotenoids with their specific binding proteins, the decay times shift to longer means (~70-90 ps; SSC). Conclusions: This study expands upon previous findings of an impact of MP on short FAF lifetimes by describing ex vivo autofluorescence lifetimes of carotenoids and different in vivo autofluorescence patterns that can be associated with certain diseases. PMID- 30025129 TI - Deep Learning for Predicting Refractive Error From Retinal Fundus Images. AB - Purpose: We evaluate how deep learning can be applied to extract novel information such as refractive error from retinal fundus imaging. Methods: Retinal fundus images used in this study were 45- and 30-degree field of view images from the UK Biobank and Age-Related Eye Disease Study (AREDS) clinical trials, respectively. Refractive error was measured by autorefraction in UK Biobank and subjective refraction in AREDS. We trained a deep learning algorithm to predict refractive error from a total of 226,870 images and validated it on 24,007 UK Biobank and 15,750 AREDS images. Our model used the "attention" method to identify features that are correlated with refractive error. Results: The resulting algorithm had a mean absolute error (MAE) of 0.56 diopters (95% confidence interval [CI]: 0.55-0.56) for estimating spherical equivalent on the UK Biobank data set and 0.91 diopters (95% CI: 0.89-0.93) for the AREDS data set. The baseline expected MAE (obtained by simply predicting the mean of this population) was 1.81 diopters (95% CI: 1.79-1.84) for UK Biobank and 1.63 (95% CI: 1.60-1.67) for AREDS. Attention maps suggested that the foveal region was one of the most important areas used by the algorithm to make this prediction, though other regions also contribute to the prediction. Conclusions: To our knowledge, the ability to estimate refractive error with high accuracy from retinal fundus photos has not been previously known and demonstrates that deep learning can be applied to make novel predictions from medical images. PMID- 30025130 TI - Phenotype Variations Caused by Mutations in the RP1L1 Gene in a Large Mainly German Cohort. AB - Purpose: Mutations in the retinitis pigmentosa-1-like-1 (RP1L1) gene are the major cause of autosomal dominant occult macular dystrophy (OCMD), while recessive mutations have been linked to autosomal recessive retinitis pigmentosa (arRP). We present the clinical phenotype of a large German OCMD cohort, as well as four RP patients. Methods: A total of 42 OCMD patients (27 families) and 4 arRP patients (3 families) with genetically confirmed mutations in RP1L1 were included. Genomic DNA was analyzed by targeted analysis of the c.133C>T;p.R45W mutation for all RP or macular dystrophy-related genes. All patients underwent ophthalmologic examination including psychophysical tests, electrophysiology, fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT). Follow-up time was up to 12 years. Results: In 25 OCMD index patients genomic testing revealed the heterozygous mutation c.133C>T;p.R45W in RP1L1; one patient was homozygous for the mutation. Two OCMD patients displayed the variants c.3599G>A;p.G1200D and c.2849G>A;p.R950H, respectively, in a heterozygous state. All OCMD patients showed characteristic clinical findings and typical microstructural photoreceptor changes. Two arRP patients displayed the novel homozygous mutations c.3022C>T;p.Q1008* and c.1107G>A;p.W369*, respectively, while two RP-siblings carried the two heterozygous mutations c.455G>A;p.R152Q and c.5959C>T;p.Q1987*, the first also being novel. All arRP cases were mild with disease onset ~30 years and preserved ERG-responses. Conclusions: OCMD phenotype showed consistent clinical findings including classical microstructural changes on SD-OCT. An important hallmark of RP1L1-related OCMD is the dominant family history with reduced penetrance. Furthermore, novel mutations in association with arRP were identified, outlining the complexity of the protein. PMID- 30025132 TI - Macular Features on Spectral-Domain Optical Coherence Tomography Imaging Associated With Visual Acuity in Coats' Disease. AB - Purpose: To investigate the association between macular features on spectral domain optical coherence tomography (SD-OCT) and visual acuity (VA) in Coats' disease. Methods: Thirty-nine eyes (39 patients) with SD-OCT from January 1, 2008 to December 31, 2016 were reviewed for SD-OCT features. Central subfield (CSF) SD OCT findings were analyzed relative to VA (logarithm of the minimum angle of resolution) at baseline and final visit (when follow-up >= 6 months) and across visits. Results: Mean VA +/- standard deviation at baseline (37 eyes) was 0.92 +/ 0.82. SD-OCT features associated with worse VA included, for treatment-naive eyes (n = 21), outer retinal atrophy (ORA) (1.18 +/- 0.34 with versus 0.20 +/- 0.30 without, P = 0.005), subretinal fluid (SRF) (1.80 +/- 0.63 vs. 0.63 +/- 0.50, P = 0.008), bright hyperreflectivities (1.23 +/- 0.68 vs. 0.52 +/- 0.53, P = 0.02), thicker foveal subretinal space (r2 = 0.32, P = 0.01), and CSF (r2 = 0.39, P = 0.007); and for previously treated eyes (n = 16), a compact hyperreflective structure (1.60 +/- 0.88 vs. 0.56 +/- 0.64, P = 0.02) and ORA (1.34 +/- 0.86 vs. 0.30 +/- 0.44, P = 0.01). At final follow-up (n = 22), mean VA was 0.81 +/- 0.83. Eyes with final VA <20/200 (n = 6, vs. >20/60, n = 11) more commonly had a compact hyperreflective structure and ORA at baseline and final visit (P < 0.05). Mean change in VA from baseline (n = 20) was -0.20 +/- 0.59. Mean improvement in VA (range, -0.525 to -1.127) occurred in eyes with baseline SRF (P = 0.02) and bright hyperreflectivities (P = 0.03). Changes in thickness that correlated with change in VA included those for the foveal subretinal space (r2 = 0.52, P < 0.001) and CSF (r2 = 0.26, P = 0.045). Conclusions: A compact hyperreflective structure (fibrosis) and ORA were associated with poor final VA while SRF, bright hyperreflectivities (exudation), and foveal subretinal thickness were associated with VA improvement post treatment. PMID- 30025131 TI - Aqp0a Regulates Suture Stability in the Zebrafish Lens. AB - Purpose: To investigate the roles of Aquaporin 0a (Aqp0a) and Aqp0b in zebrafish lens development and transparency. Methods: CRISPR/Cas9 gene editing was used to generate loss-of-function deletions in zebrafish aqp0a and/or aqp0b. Wild type (WT), single mutant, and double mutant lenses were analyzed from embryonic to adult stages. Lens transparency, morphology, and growth were assessed. Immunohistochemistry was used to map protein localization as well as to assess tissue organization and distribution of cell nuclei. Results: aqp0a-/- and/or aqp0b-/- cause embryonic cataracts with variable penetrance. While lenses of single mutants of either gene recover transparency in juveniles, double mutants consistently form dense cataracts that persist in adults, indicating partially redundant functions. Double mutants also reveal redundant Aqp0 functions in lens growth. The nucleus of WT lenses moves from the anterior pole to the lens center with age. In aqp0a-/- mutants, the nucleus fails to centralize as it does in WT or aqp0b-/- lenses, and in double mutant lenses there is no consistent lens nuclear position. In addition, the anterior sutures of aqp0a-/-, but not aqp0b-/- mutants, are unstable resulting in failure of suture maintenance at older stages and anterior polar opacity. Conclusions. Zebrafish Aqp0s have partially redundant functions, but only Aqp0a promotes suture stability, which directs the lens nucleus to centralize, failure of which results in anterior polar opacity. These studies support the hypothesis that the two Aqp0s subfunctionalized during fish evolution and that Aqp0-dependent maintenance of the anterior suture is essential for lens transparency. PMID- 30025133 TI - Projection-Resolved OCT Angiography of Microvascular Changes in Paracentral Acute Middle Maculopathy and Acute Macular Neuroretinopathy. AB - Purpose: To identify the microvascular changes associated with paracentral acute middle maculopathy (PAMM) and acute macular neuroretinopathy (AMN) and to improve our understanding of the relevant involvement of the three retinal capillary plexuses using projection-resolved optical coherence tomography angiography (PR OCTA). Methods: This was a retrospective study of 18 eyes with AMN or PAMM imaged with OCTA. We used cross-sectional PR-OCTA to localize reduced flow signal to the superficial (SCP), middle (MCP), or deep capillary plexus (DCP) or choriocapillaris that corresponded to inner retinal PAMM or outer retinal AMN lesions on OCT. Results: Five eyes with AMN showed outer retinal disruption on OCT associated with reduced DCP flow signal. All three eyes with AMN and follow up had recovery of DCP flow. Thirteen eyes with PAMM showed middle retinal disruption on OCT associated with reduced flow signal in both the MCP and DCP. Of these, five also had reduced flow signal in the SCP. All 10 eyes with PAMM and follow-up showed variable recovery of flow signal in one or more plexuses. PAMM reperfusion was primarily arterial in nature. Three eyes with PAMM and no evidence of MCP reperfusion experienced severe thinning of the inner nuclear layer (INL), while seven eyes with robust MCP flow signal recovery showed relative preservation of INL thickness. Conclusions: Using PR-OCTA, we found that AMN was associated with reduced DCP flow signal, while PAMM was associated with reduced MCP and DCP flow signal and occasionally the SCP. The MCP appears to be important in sustaining INL thickness in these eyes. PMID- 30025134 TI - New Human Organotypic Corneal Tissue Model for Ophthalmic Drug Delivery Studies. AB - Purpose: The purpose of the current work was to develop a physiologically relevant, in vitro human three-dimensional (3D) corneal epithelial tissue model for use in ophthalmic drug development. Methods: Normal human corneal epithelial cells were cultured at the air-liquid interface to produce the 3D corneal tissue model. Corneal barrier was determined by measuring transepithelial electrical resistance (TEER). Quantitative PCR arrays were utilized to investigate expression of 84 phase I/II metabolizing enzymes and 84 drug transporter genes. Permeability was evaluated using model compounds with a wide range of hydrophobicity, molecular weight, and excipients. Finally, different formulations of latanoprost and bimatoprost were administered and drug absorption and tissue viability and integrity were investigated. Results: Histologic assessment and TEER of the corneal tissue model revealed tissue structure, thickness, and barrier formation (1000 +/- 146 Omega.cm2) comparable to native human corneal epithelium. The 3D corneal tissue expressed tight junctions, mucins, and key corneal epithelial detoxification enzymes. Drug-metabolizing enzyme and transporter gene expression in 3D corneal tissue and excised human corneal epithelium were highly correlated (r2 = 0.87). Coefficients of permeation for model drugs in the tissue model and excised rabbit corneas also showed a high correlation (r2 = 0.94). As expected, latanoprost and bimatoprost free acids had much lower permeability (Papp = 1.2 * 10-6 and 1.9 * 10-6) than the corresponding prodrugs (Papp = 2.5 * 10-5 and 5.6 * 10-5), respectively. The presence of 0.02% benzalkonium chloride in ophthalmic formulations significantly affected tissue barrier and viability. Conclusions: The newly developed 3D corneal tissue model appears to be very useful for evaluation of corneal drug permeability and safety during ophthalmic drug development. PMID- 30025135 TI - Brain-Derived Neurotrophic Factor in Patients With Age-Related Macular Degeneration and Its Correlation With Retinal Layer Thicknesses. AB - Purpose: To determine brain-derived neurotrophic factor (BDNF) levels in serum and aqueous humor (AH) and to assess the relationship between BDNF levels and retinal layer thicknesses in age-related macular degeneration (AMD). Methods: A total of 48 AMD patients (AMD group) that was composed of twenty-three nonexudative and 25 exudative patients and 26 control subjects (control group) were included in the study. Serum and AH BDNF levels were assessed by ELISA method. Retinal layer thicknesses were calculated by segmentation analysis of optical coherence tomography. Results: The mean BDNF levels in AH were found to be significantly lower in both the nonexudative and exudative AMD groups than in the control group (P = 0.003 and P < 0.001, respectively). Optical coherence tomography segmentation analysis revealed that the total average retina pigment epithelium thickness was statistically significantly thinner in the nonexudative AMD group compared with the exudative AMD and control groups (P = 0.001 and P = 0.040, respectively). The total average outer nuclear layer (ONL) thicknesses of nonexudative and exudative AMD cases were reduced compared to control group; however, the decrement was statistically significant only in the nonexudative AMD group (P = 0.009). In the correlation analysis of BDNF levels with retinal layer thicknesses, statistically significant correlations exist between BDNF levels of AH with ONL thicknesses in cases of AMD and with retina pigment epithelium thicknesses in the nonexudative AMD group. Conclusions: BDNF concentrations in AH decreased in the AMD group and this decrease correlates with outer retinal layer thicknesses. Low BDNF levels detected in the AMD group may be insufficient to protect the photoreceptors, resulting in thinning of ONL. PMID- 30025136 TI - PEDF Reduces the Severity of Herpetic Simplex Keratitis in Mice. AB - Purpose: The purpose of this study was to explore the effects of pigment epithelium derived factor (PEDF) and PEDF-derived peptides Mer44 and Mer34 on the severity of herpetic simplex keratitis (HSK) in mice. Methods: Adult C57BL/6 mice were infected ocularly with the herpes simplex virus type 1 (HSV-1, McKrae strain) and injected subconjunctivally with PEDF, Mer44, or Mer34. Corneal nerve degeneration, neovascularization, sensitivity, neutrophils, macrophages and CD4+ T-cell infiltration, virus contents, and expressions of VEGF, PEDF, and proinflammatory factors were evaluated during acute period. The direct inhibitory effect of PEDF on HSV-1 replication was further evaluated in cultured monkey Vero cells. Results: Following HSV-1 infection, corneal PEDF expression decreased at 3 and 7 days postinfection (dpi) but increased at 15 dpi, and returned to the similar level of normal mice at 45 dpi, which was accompanied with the progress of corneal nerve degeneration and neovascularization. Exogenous PEDF application attenuated corneal nerve degeneration and neovascularization and improved the impaired corneal sensitivity. Moreover, PEDF attenuated the neutrophils, but not macrophage or CD4+ T-cell infiltration, with the reduced expressions of IL-1beta, IL-6, TNF-alpha, and VEGF. In addition, PEDF inhibited the replication of HSV-1 both in vitro and in mice. Mer44 attenuated corneal nerve degeneration more significantly than Mer34, whereas Mer34 inhibited corneal neovascularization. Conclusions: PEDF and its derived peptides reduce the severity of herpetic simplex keratitis in mice, representing the potential therapeutic approach to control HSK lesions. PMID- 30025137 TI - Effects of Corneal Hydration on Brillouin Microscopy In Vivo. AB - Purpose: To investigate how corneal hydration affects the Brillouin frequency of corneal stroma. Methods: From a simple analytical model considering the volume fraction of water in corneal stroma, we derived the dependence of Brillouin frequency on hydration and hydration-induced corneal thickness variation. The Brillouin frequencies of fresh ex vivo porcine corneas were measured as their hydration was varied in dextran solution and water. Healthy volunteers (8 eyes) were scanned in vivo repeatedly over the course of 9 hours, and the diurnal variations of Brillouin frequency and central corneal thickness (CCT) were measured. Results: The measured dependence of Brillouin frequency on hydration, both ex vivo and in vivo, agreed well with the theoretical prediction. The Brillouin frequencies of human corneas scanned immediately after waking were on average ~25 MHz lower than their daytime average values. For stabilized corneas, the typical variation of Brillouin frequency was +/- 7.2 MHz. With respect to CCT increase or swelling, the Brillouin frequency decreased with a slope of -1.06 MHz/MUm in vivo. Conclusions: The ex vivo and in vivo data agree with our theoretical model and support that the effect of corneal hydration on Brillouin frequency comes predominantly from the dependence of the tissue compressibility on the water. Corneal hydration correlates negatively with the Brillouin frequency. During daytime activities, the influence of physiological hydration changes in human corneas is < +/- 10 MHz. The sensitivity to hydration may potentially be useful in detecting abnormal hydration change in patients with endothelial disorders. PMID- 30025138 TI - Genotype and Phenotype Spectrum of FRMD7-Associated Infantile Nystagmus Syndrome. AB - Purpose: We investigate the genotype and phenotype spectrum of FRMD7-associated infantile nystagmus syndrome in Korean probands. Methods: A total of 37 patients with infantile nystagmus syndrome were recruited prospectively for genetic analysis. We performed polymerase chain reaction (PCR)-based direct sequencing and haplotype analysis for FRMD7. Detailed ophthalmic examinations and eye movement recordings were compared between FRMD7 and non-FRMD7 groups. Results: In 13 (35%) of 37 patients, five different mutations of FRMD7 were detected: start codon mutation c.1A>G, splice site mutation c.162+6T>C, and three missense mutations (c.575A>C, c.722A>G, and c.875T>C). The latter mutation was identified in seven unrelated patients, and always was accompanied with two single nucleotide polymorphisms of exon 12 (rs6637934, rs5977623). Compared to non-FRMD7 groups, a cup-to-disc ratio was significantly decreased in FRMD7 groups (P < 0.001), and a disc-macula distance to disc diameter ratio markedly increased in the FRMD7 group (P = 0.015). Most patients in the FRMD7 group had at least two types of the nystagmus waveforms, and the most common type was unidirectional jerk nystagmus (75%), such as pure jerk and jerk with extended foveation, followed by pendular (25%), bidirectional jerk (19%), and dual jerk (6%) nystagmus. No significant differences were observed between FRMD7 and non-FRMD7 groups in terms of the nystagmus waveform, presence of periodic alternating nystagmus, and mean foveation time. Conclusions: We identified five FRMD7 mutations in 35% of our infantile nystagmus syndrome cohort, expanding its mutational spectrum. The missense mutation c.875T>C may be a common mutation arisen from the founder effect in Korea. Optic nerve dysplasia associated with FRMD7 mutations suggests that the abnormal development of afferent visual systems may affect neural circuitry within the oculomotor system. PMID- 30025139 TI - YAP/TAZ Are Essential for TGF-beta2-Mediated Conjunctival Fibrosis. AB - Purpose: To investigate the roles of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), the major effector molecules of the Hippo pathway, in TGF-beta2-mediated conjunctival fibrosis. Methods: Primary human conjunctival fibroblasts were treated with TGF-beta2. The expression of YAP/TAZ was examined by Western blot analyses and immunocytochemistry. The expression of fibrotic proteins and genes were evaluated by Western blot analyses and quantitative real-time PCR, respectively. The effects of YAP/TAZ on fibrotic changes were examined by knockdown experiments and the YAP/TAZ inhibitor, verteporfin. Results: TGF-beta2 stabilized YAP/TAZ and subsequently activated Smad2/3, which led to the transcription of fibrotic genes in human primary conjunctival fibroblasts. These fibrotic genes were differently regulated by YAP/TAZ. Notably, alpha-smooth muscle actin, fibronectin, collagen I, and collagen IV were primarily regulated by YAP. In contrast, CCN family proteins (CTGF and CYR61) depended on both YAP and TAZ. Mechanistically, YAP/TAZ were located in close proximity to Smad2/3, and in particular, YAP was required for TGF-beta2-mediated phosphorylation and the nuclear translocation of Smad2/3. Furthermore, a YAP/TAZ inhibitor markedly suppressed TGF-beta2-mediated fibrotic changes in conjunctival fibroblasts. Conclusions: YAP/TAZ acted as a molecular hub of TGF-beta2 signaling in a cellular model of conjunctival fibrosis. Moreover, verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects by suppressing TGF-beta2-YAP/TAZ-Smad signaling. Our study highlights YAP/TAZ as essential regulators of conjunctival fibrosis and shows that inhibition of YAP/TAZ might potentially improve the outcomes of glaucoma filtration surgery. PMID- 30025140 TI - A Novel Tree Shrew (Tupaia belangeri) Model of Glaucoma. AB - Purpose: Primates and rodents are used widely as animal models of glaucoma, but each has significant limitations. Researchers need additional animal models that closely resemble the relevant anatomy and pathologic features of the human disease to more quickly advance research. We validate a novel glaucoma animal model in tree shrews (Tupaia belangeri). Methods: Experimental glaucoma was induced in adult tree shrews (n = 8) by injecting 50 MUL of a 25 mg/mL ferromagnetic bead solution into the anterior chamber. Beads were directed into the iridocorneal angle with a magnet to impede aqueous outflow. Animals were followed for 3 months with weekly IOP measurements and biweekly spectral domain optical coherence tomography (SD-OCT) images of the optic nerve head. Histopathology of the optic nerve and optic nerve axon counts were completed at the end of the study. Results: The 12-week average mean IOP was 22.7 +/- 3.6 and 8.6 +/- 2.9 mm Hg in the treated and control eyes, respectively. Longitudinal analysis showed significant retinal nerve fiber layer (RNFL) thinning throughout the study. Axon counts were significantly reduced (59.7%) in treated versus control eyes. SD-OCT imaging showed cupping and posterior displacement of the lamina cribrosa in glaucomatous eyes. RNFL thickness and optic nerve axon counts were reduced consistent with IOP elevation. Optic nerves demonstrated histopathology consistent with glaucomatous optic neuropathy. Conclusions: Tree shrews with experimental glaucoma show key pathologic characteristics of the human disease. The tree shrew model of glaucoma has the potential to help researchers accelerate our understanding of glaucoma pathophysiology. PMID- 30025141 TI - Optic Nerve Sheath Tethering in Adduction Occurs in Esotropia and Hypertropia, But Not in Exotropia. AB - Purpose: Repetitive strain to the optic nerve (ON) due to tethering in adduction has been recently proposed as an intraocular pressure-independent mechanism of optic neuropathy in primary open-angle glaucoma. Since strabismus may alter adduction, we investigated whether gaze-related ON straightening and associated globe translation differ in horizontal and vertical strabismus. Methods: High resolution orbital magnetic resonance imaging was obtained in 2-mm thick quasi coronal planes using surface coils in 25 subjects (49 orbits) with esotropia (ET, 19 +/- 3.6Delta SEM), 11 (15 orbits) with exotropia (XT, 33.7 +/- 7.3Delta), 7 (12 orbits) with hypertropia (HT, 14.6 +/- 3.2Delta), and 31 normal controls (62 orbits) in target-controlled central gaze, and in maximum attainable abduction and adduction. Area centroids were used to determine ON path sinuosity and globe positions. Results: Adduction angles achieved in ET (30.6 degrees +/- 0.9 degrees ) and HT (27.2 degrees +/- 2.3 degrees ) did not significantly differ from normal (28.3 degrees +/- 0.7 degrees ), but significantly less adduction was achieved in XT (19.0 degrees +/- 2.5 degrees , P = 0.005). ON sheath tethering in adduction occurred in ET and HT similarly to normal, but did not in XT. The globe translated significantly less than normal, nasally in adduction in XT and temporally in abduction in ET and HT (P < 0.02, for all). Globe retraction did not occur during abduction or adduction in any group. Conclusions: Similar to normal subjects, the ON and sheath become tethered without globe retraction in ET and HT. In XT, adduction tethering does not occur, possibly due to limited adduction angle. Thus, therapeutic limitation of adduction could be considered as a possible treatment for ON sheath tethering. PMID- 30025143 TI - Outer Plexiform Layer Elevations as a Marker for Prior Ocular Attacks in Patients With Behcet's Disease. AB - Purpose: Patients with Behcet's disease frequently have abnormal focal outer plexiform layer (OPL) bumps, which compress the inner nuclear layer. This study investigates the clinical relevance of these OPL elevations in Behcet's disease patients. Methods: Thirty-one consecutive patients (59 eyes) with Behcet's disease in remission and with available optical coherence tomography (OCT) images were included. The number of OPL bumps was counted using spectral-domain OCT images. The relationships between the number of bumps and visual acuity (VA), retinal thickness, choroidal thickness, disease duration, number of prior ocular attacks, and photoreceptor layer status (including external limiting membrane [ELM] and ellipsoid zone [EZ] continuity) were examined. Results: Eyes with more severe EZ or ELM disruptions had lower VA, more ocular attacks, and thinner retinas. Additionally, EZ line and ELM line status were significantly correlated with the number of OPL elevations. Eyes with OPL elevations had poorer VA, longer disease duration, more ocular attacks, and thinner retinas than those without OPL elevations. Additionally, the number of OPL elevations was strongly correlated with the number of ocular attacks in eyes with a preserved photoreceptor layer (R = 0.720, P < 0.0001). Conclusions: The number of OPL elevations was associated with the number of prior ocular attacks in eyes with preserved photoreceptor layers. Therefore, OPL elevations may be a marker of prior posterior ocular attacks, which is important when determining how best to manage Behcet's uveitis. PMID- 30025142 TI - A Subset of Palisade Endings Only in the Medial and Inferior Rectus Muscle in Monkey Contain Calretinin. AB - Purpose: To further chemically characterize palisade endings in extraocular muscles in rhesus monkeys. Methods: Extraocular muscles of three rhesus monkeys were studied for expression of the calcium-binding protein calretinin (CR) in palisade endings and multiple endings. The complete innervation was visualized with antibodies against the synaptosomal-associated protein of 25 kDa and combined with immunofluorescence for CR. Six rhesus monkeys received tracer injections of choleratoxin subunit B or wheat germ agglutinin into either the belly or distal myotendinous junction of the medial or inferior rectus muscle to allow retrograde tracing in the C-group of the oculomotor nucleus. Double immunofluorescence methods were used to study the CR content in retrogradely labeled neurons in the C-group. Results: A subgroup of palisade and multiple endings was found to express CR, only in the medial and inferior rectus muscle. In contrast, the en plaque endings lacked CR. Accordingly, within the tracer labeled neurons of the C-group, a subgroup expressed CR. Conclusions: The study indicates that two different neuron populations targeting nontwitch muscle fibers are present within the C-group for inferior rectus and medial rectus, respectively, one expressing CR, one lacking CR. It is possible that the CR negative neurons represent the basic population for all extraocular muscles, whereas the CR-positive neurons giving rise to CR-positive palisade endings represent a specialized, perhaps more excitable type of nerve ending in the medial and inferior rectus muscles, being more active in vergence. The malfunction of this CR-positive population of neurons that target nontwitch muscle fibers could play a significant role in strabismus. PMID- 30025144 TI - The Relationship Between Blue-Fundus Autofluorescence and Optical Coherence Tomography in Eyes With Lamellar Macular Holes. AB - Purpose: The purpose of this study was to evaluate the relationship between blue fundus autofluorescence (B-FAF) and optical coherence tomography (OCT) in eyes with lamellar macular holes (LMHs). Methods: this was a multicenter, observational case series. Ninety-two eyes with LMH associated with the standard epiretinal membrane (ERM) or lamellar hole-associated epiretinal proliferation (LHEP) were evaluated. The eyes must also present an area of increased autofluorescence on B-FAF. Results: The ERM-alone group and the LHEP group differed with respect to the following variables: logarithm of the minimum angle of resolution best-corrected visual acuity (0.13 +/- 0.13 vs. 0.25 +/- 0.17; P < 0.001), central foveal thickness (218.74 +/- 52.4 MUm vs. 187.28 +/- 50.29 MUm; P = 0.008), FAF diameter (400.78 +/- 189.36 MUm vs. 503.37 +/- 214.25 MUm; P = 0.014), outer plexiform layer (OPL) diameter (382.10 +/- 157.34 MUm vs. 550.79 +/ 228.05 MUm; P = 0.0001), and disruption of external limiting membrane and ellipsoid zone, which was noted in only 1 and 3 eyes with ERM alone, respectively, and in 18 and 23 eyes with LHEP, respectively (P < 0.0001 for both observations). No difference was found for diameters measured at the level of the inner limiting membrane and schisis/cavitation. In both the ERM-alone group and the LHEP group, a strong correlation was found between the diameters measured on B-FAF and diameters measured at the OPL level on OCT images (P < 0.0001 for both groups). Conclusions: In eyes with LMHs, a strong correlation exists between the diameters of the holes measured with B-FAF and those measured at the OPL level with OCT. This may indicate that the loss or displacement of retinal cells containing macular pigment at the OPL level, specifically photoreceptors and/or Muller cells, is involved in this vitreomaculopathy. PMID- 30025146 TI - Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome. AB - Purpose: To determine the efficacy of trabodenoson, an adenosine mimetic with highly selective adenosine A1 receptor binding properties, in a preclinical mouse model for dry-eye disease. Methods: Dry-eye disease was induced in adult male C57BL/6 mice using a combination of desiccating environment and transdermal administration of scopolamine. Mice were treated concurrently and twice daily with either vehicle, 6% trabodenoson, or 0.05% cyclosporine (Restasis). Efficacy (P < 0.05 versus vehicle) was determined by clinical assessment of dry-eye symptoms using corneal fluorescein staining and tear volumes and histopathologically by quantifying lacrimal gland pathology and conjunctival goblet cells. Results: Twice-daily topical (ocular) administration of trabodenoson increased tear levels and reduced corneal fluorescein staining (P < 0.05) as compared with vehicle-treated eyes in a mouse model of dry-eye disease. Furthermore, significant infiltration of immune cells in the lacrimal gland and reduced number of mucin-producing conjunctival goblet cells were noted in both untreated and vehicle-treated eyes. Comparatively, trabodenoson treatment significantly reduced lacrimal gland infiltration and increased the number of goblet cells (P < 0.05 for both versus vehicle). These trabodenoson-related effects on lacrimal gland pathology and goblet cells were similar to or better than the effects observed with cyclosporine treatment. Conclusions: Topical ocular delivery of trabodenoson significantly improves the clinical and histopathological signs associated with dry-eye disease in mice. This improvement appears to be related to anti-inflammatory effects from targeting adenosine signaling and represents a novel therapeutic approach to develop for the management of dry-eye disease. PMID- 30025145 TI - Tumor Necrosis Factor Inhibition in the Acute Management of Traumatic Optic Neuropathy. AB - Purpose: To determine the effectiveness of etanercept, a tumor necrosis factor (TNF) inhibitor, in conferring neuroprotection to retinal ganglion cells (RGCs) and improving visual outcomes after optic nerve trauma with either optic nerve crush (ONC) or sonication-induced traumatic optic neuropathy (SI-TON) in mice. Methods: Mouse optic nerves were unilaterally subjected to ONC (n = 20) or SI-TON (n = 20). TNF expression was evaluated by using immunohistochemistry and quantitative RT-PCR (qRT-PCR) in optic nerves harvested 6 and 24 hours post ONC (n = 10) and SI-TON (n = 10). Mice in each injury group received daily subcutaneous injections of either etanercept (10 mg/kg of body weight; five mice) or vehicle (five mice) for 7 days. Pattern electroretinograms were performed on all mice at 1 and 2 weeks after injury. ONC mice were killed at 2 weeks after injury, while SI-TON mice were euthanized at 4 weeks after injury. Whole retina flat-mounts were used for RGC quantification. Results: Immunohistochemistry and qRT-PCR showed upregulation of TNF protein and gene expression within 24 hours after injury. In both models, etanercept use immediately following optic nerve injury led to higher RGC survival when compared to controls, which was comparable between the two models (24.23% in ONC versus 20.42% in SI-TON). In both models, 1 and 2 weeks post injury, mice treated with etanercept had significantly higher a wave amplitudes than untreated injured controls. Conclusions: Treatment with etanercept significantly reduced retinal damage and improved visual function in both animal models of TON. These findings suggest that reducing TNF activity in injured optic nerves constitutes an effective therapeutic approach in an acute setting. PMID- 30025147 TI - Non-occupational exposure to asbestos is the main cause of malignant mesothelioma in women in North Jutland, Denmark. AB - Objectives Diffuse malignant mesothelioma (MM) is mainly caused by asbestos inhalation. The malignancy is rare among women and studies of the prevalence and causative role of non-occupational asbestos exposure among women with MM are scarce. This observational study aimed to elucidate the asbestos exposure patterns among women with MM. Methods All histological and cytological specimens from women diagnosed with MM between 1974-2015 at the Institute of Pathology, Aalborg University Hospital in Denmark, were re-evaluated. Occupational and habitation information were obtained from Danish registries and medical journals based on record linkage via the unique person ID. The number of MM cases in each parish in the region of North Jutland was determined and the incidence density in parishes was used to calculate the spatial relative risk (RR) of MM among women. Results Diagnosis of MM was confirmed in 91 women. Exposure types were classified as occupational (9%), domestic (10%), environmental (22%), combination of domestic and environmental (34%) and unknown (25%). Twenty continuous parishes formed a MM "hotspot" around the asbestos-consuming industries in the city of Aalborg. Of these, the maximum RR was found in a parish housing an asbestos factory [RR 10.5, 95% confidence interval (CI) 5.5-19.4, environmental exposure in particular RR 2.9, 95% CI 0.7-6.1]. Conclusion Non-occupational asbestos exposure is the main cause of MM and may account for up to 66% of MM cases among women in North Jutland, Denmark. PMID- 30025148 TI - The signal metabolite trehalose-6-phosphate inhibits the sucrolytic activity of sucrose synthase from developing castor beans. AB - In plants, trehalose 6-phosphate (T6P) is a key signaling metabolite that functions as both a signal and negative feedback regulator of sucrose levels. The mode of action by which T6P senses and regulates sucrose is not fully understood. Here, we demonstrate that the sucrolytic activity of RcSUS1, the dominant sucrose synthase isozyme expressed in developing castor beans, is allosterically inhibited by T6P. The feedback inhibition of SUS by T6P may contribute to the control of sink strength and sucrolytic flux in heterotrophic plant tissues. PMID- 30025149 TI - Starch biosynthesis by AGPase, but not starch degradation by BAM1/3 and SEX1, is rate-limiting for CO2 -regulated stomatal movements under short-day conditions. AB - Starch in guard cells functions in osmoregulation during stomatal movements. Starch metabolism is controlled by the circadian clock. We investigated the role of starch metabolism in stomatal responses to CO2 under different photoperiodic conditions. Guard cell starch levels correlate with low/high [CO2 ] exposure. Starch biosynthesis-deficient AGPase (ADG1) mutants but, unexpectedly, not the starch degradation-deficient BAM1, BAM3, and SEX1 mutants alone, are rate limiting for stomatal conductance responses to [CO2 ]-shifts. Interestingly, AGPase is rate-limiting solely under short- but not long-day conditions. These findings suggest a model of enhanced AGPase activity in guard cells under short days such that starch biosynthesis becomes rate-limiting for CO2 -induced stomatal closing. PMID- 30025150 TI - Ag Nanoparticles Connected to the Surface of TiO2 Electrostatically for Antibacterial Photoinactivation Studies. AB - Supported silver nanoparticles (Ag NPs) were prepared by chemical reduction method with a sol-gel method. The structure, morphology, and interconnectivity of Ag/TiO2 nanocomposites (NCs) were analyzed using different instrumental techniques. Transmission electron microscopy reveals the Ag NPs have uniformly distributed and anchored on the surface of TiO2 . The reduction in electron-hole recombination was measured by Photoluminescence measurements lead, to an increased photocatalytic inactivation of bacteria. Increase in the amount of Ag NPs on TiO2 resulted in a slight decrease in optical band gap energy of TiO2 . The effect of Ag NPs content on the photocatalytic properties of TiO2 for inhibition of bacteria in visible light irradiation was studied. Furthermore, the antibacterial activity of Ag/TiO2 NCs in the presence of UVA light was studied against gram-positive Staphylococcus aureus and gram-negative Escherichia coli bacterial strain by plate count method. Lower values of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the catalysts were observed and used to determine the tolerance factor which is shown bactericidal nature of the NCs. Subsequently, time-killing assay of Ag/TiO2 NCs was shown dynamics of antimicrobial activity. These multifold antibacterial studies exhibited potent antibacterial nature of the NCs and employed in the wider range of biomedical fields. PMID- 30025151 TI - The Lieber-DeCarli Diet-A Flagship Model for Experimental Alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. Understanding the pathophysiology and successful treatment for ALD is closely associated with the suitability of the animal model, which fully reflects all aspects of the pathogenesis and typical histological findings. This study reviews one of the most widely used experimental models of ALD in rodents-the Lieber-DeCarli (LDC) liquid diet. It is an easy, accurate, reliable, and inexpensive model to study the pathogenesis of early stages of ALD. Here, we discuss the historical background and provide an overview of the advantages and disadvantages of the classical LDC as well as modified "second-hit" models. We also provide a comprehensive protocol for the application of the LDC diet to perform it successfully, reliably, and reproducibly in mice. PMID- 30025152 TI - A Clinical Trial with Combined Transcranial Direct Current Stimulation and Attentional Bias Modification in Alcohol-Dependent Patients. AB - BACKGROUND: Modifying attentional processes with attentional bias modification (ABM) might be a relevant add-on to treatment in addiction. This study investigated whether influencing cortical plasticity with transcranial direct current stimulation (tDCS) could increase training effects. tDCS could also help alcohol-dependent patients to overcome craving and reduce relapse, independent of training. These approaches were combined to investigate effects in the treatment of alcoholism. METHODS: Ninety-eight patients (analytical sample = 83) were randomly assigned to 4 groups in a 2-by-2 factorial design. Patients received 4 sessions of ABM (control or real training) combined with 2 mA tDCS (active: 20 minutes or sham: 30 seconds) over the left dorsolateral prefrontal cortex. Alcohol bias and craving were assessed, and treatment outcome was measured as relapse after 1 year. RESULTS: Attentional bias scores indicated that during the training only the group with active tDCS and real ABM displayed an overall avoidance bias (p < 0.05). From pre- to postassessment, there were no main or interaction effects of tDCS and ABM on the bias scores, craving, or relapse (p > 0.2). However, effects on relapse after active tDCS were in the expected direction. CONCLUSIONS: There was no evidence of a beneficial effect of tDCS or ABM or the combination. Whether the absence of effect was due to issues with the outcome measurements (e.g., lack of craving, high dropout, and unreliable measurements) or aspects of the intervention should be further investigated. PMID- 30025153 TI - Phenobarbital-induced phosphorylation converts nuclear receptor RORalpha from a repressor to an activator of the estrogen sulfotransferase gene Sult1e1 in mouse livers. AB - The estrogen sulfotransferase SULT1E1 sulfates and inactivates estrogen, which is reactivated via desulfation by steroid sulfatase, thus regulating estrogen homeostasis. Phenobarbital (PB), a clinical sedative, activates Sult1e1 gene transcription in mouse livers. Here, the molecular mechanism by which the nuclear receptors CAR, which is targeted by PB, and RORalpha communicate through phosphorylation to regulate Sult1e1 activation has been studied. RORalpha, a basal activity repressor of the Sult1e1 promoter, becomes phosphorylated at serine 100 and converts to an activator of the Sult1e1 promoter in response to PB. CAR regulates both the RORalpha phosphorylation and conversion. Our findings suggest that PB signals CAR to communicate with RORalpha via serine 100 phosphorylation, converting RORalpha from transcription repressor to activator of the Sult1e1 gene and inducing SULT1E1 expression in mouse livers. PMID- 30025154 TI - Interventions for increasing the use of shared decision making by healthcare professionals. AB - BACKGROUND: Shared decision making (SDM) is a process by which a healthcare choice is made by the patient, significant others, or both with one or more healthcare professionals. However, it has not yet been widely adopted in practice. This is the second update of this Cochrane review. OBJECTIVES: To determine the effectiveness of interventions for increasing the use of SDM by healthcare professionals. We considered interventions targeting patients, interventions targeting healthcare professionals, and interventions targeting both. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and five other databases on 15 June 2017. We also searched two clinical trials registries and proceedings of relevant conferences. We checked reference lists and contacted study authors to identify additional studies. SELECTION CRITERIA: Randomized and non-randomized trials, controlled before-after studies and interrupted time series studies evaluating interventions for increasing the use of SDM in which the primary outcomes were evaluated using observer-based or patient-reported measures. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 87 studies (45,641 patients and 3113 healthcare professionals) conducted mainly in the USA, Germany, Canada and the Netherlands. Risk of bias was high or unclear for protection against contamination, low for differences in the baseline characteristics of patients, and unclear for other domains.Forty-four studies evaluated interventions targeting patients. They included decision aids, patient activation, question prompt lists and training for patients among others and were administered alone (single intervention) or in combination (multifaceted intervention). The certainty of the evidence was very low. It is uncertain if interventions targeting patients when compared with usual care increase SDM whether measured by observation (standardized mean difference (SMD) 0.54, 95% confidence interval (CI) -0.13 to 1.22; 4 studies; N = 424) or reported by patients (SMD 0.32, 95% CI 0.16 to 0.48; 9 studies; N = 1386; risk difference (RD) -0.09, 95% CI -0.19 to 0.01; 6 studies; N = 754), reduce decision regret (SMD -0.10, 95% CI -0.39 to 0.19; 1 study; N = 212), improve physical (SMD 0.00, 95% CI -0.36 to 0.36; 1 study; N = 116) or mental health-related quality of life (QOL) (SMD 0.10, 95% CI 0.26 to 0.46; 1 study; N = 116), affect consultation length (SMD 0.10, 95% CI 0.39 to 0.58; 2 studies; N = 224) or cost (SMD 0.82, 95% CI 0.42 to 1.22; 1 study; N = 105).It is uncertain if interventions targeting patients when compared with interventions of the same type increase SDM whether measured by observation (SMD 0.88, 95% CI 0.39 to 1.37; 3 studies; N = 271) or reported by patients (SMD 0.03, 95% CI -0.18 to 0.24; 11 studies; N = 1906); (RD 0.03, 95% CI -0.02 to 0.08; 10 studies; N = 2272); affect consultation length (SMD -0.65, 95% CI -1.29 to -0.00; 1 study; N = 39) or costs. No data were reported for decision regret, physical or mental health-related QOL.Fifteen studies evaluated interventions targeting healthcare professionals. They included educational meetings, educational material, educational outreach visits and reminders among others. The certainty of evidence is very low. It is uncertain if these interventions when compared with usual care increase SDM whether measured by observation (SMD 0.70, 95% CI 0.21 to 1.19; 6 studies; N = 479) or reported by patients (SMD 0.03, 95% CI -0.15 to 0.20; 5 studies; N = 5772); (RD 0.01, 95%C: -0.03 to 0.06; 2 studies; N = 6303); reduce decision regret (SMD 0.29, 95% CI 0.07 to 0.51; 1 study; N = 326), affect consultation length (SMD 0.51, 95% CI 0.21 to 0.81; 1 study, N = 175), cost (no data available) or physical health-related QOL (SMD 0.16, 95% CI 0.05 to 0.36; 1 study; N = 359). Mental health-related QOL may slightly improve (SMD 0.28, 95% CI 0.07 to 0.49; 1 study, N = 359; low-certainty evidence).It is uncertain if interventions targeting healthcare professionals compared to interventions of the same type increase SDM whether measured by observation (SMD 0.30, 95% CI -1.19 to 0.59; 1 study; N = 20) or reported by patients (SMD 0.24, 95% CI -0.10 to 0.58; 2 studies; N = 1459) as the certainty of the evidence is very low. There was insufficient information to determine the effect on decision regret, physical or mental health-related QOL, consultation length or costs.Twenty-eight studies targeted both patients and healthcare professionals. The interventions used a combination of patient-mediated and healthcare professional directed interventions. Based on low certainty evidence, it is uncertain whether these interventions, when compared with usual care, increase SDM whether measured by observation (SMD 1.10, 95% CI 0.42 to 1.79; 6 studies; N = 1270) or reported by patients (SMD 0.13, 95% CI -0.02 to 0.28; 7 studies; N = 1479); (RD -0.01, 95% CI -0.20 to 0.19; 2 studies; N = 266); improve physical (SMD 0.08, -0.37 to 0.54; 1 study; N = 75) or mental health-related QOL (SMD 0.01, -0.44 to 0.46; 1 study; N = 75), affect consultation length (SMD 3.72, 95% CI 3.44 to 4.01; 1 study; N = 36) or costs (no data available) and may make little or no difference to decision regret (SMD 0.13, 95% CI -0.08 to 0.33; 1 study; low-certainty evidence).It is uncertain whether interventions targeting both patients and healthcare professionals compared to interventions of the same type increase SDM whether measured by observation (SMD -0.29, 95% CI -1.17 to 0.60; 1 study; N = 20); (RD -0.04, 95% CI -0.13 to 0.04; 1 study; N = 134) or reported by patients (SMD 0.00, 95% CI -0.32 to 0.32; 1 study; N = 150 ) as the certainty of the evidence was very low. There was insuffient information to determine the effects on decision regret, physical or mental health-related quality of life, or consultation length or costs. AUTHORS' CONCLUSIONS: It is uncertain whether any interventions for increasing the use of SDM by healthcare professionals are effective because the certainty of the evidence is low or very low. PMID- 30025155 TI - ActRIIB blockade does not limit ATP supply in mouse skeletal muscle in vivo. AB - INTRODUCTION: Postnatal activin/myostatin type IIB receptor (ActRIIB) blockade increases skeletal muscle mass and strength, but also increases muscle fatigability and impairs oxidative metabolism. The aim of this study was to determine in vivo whether this increased fatigability is due to energy supply limitation. METHODS: The impact of 8-week ActRIIB blockade with soluble receptor (sActRIIB-Fc) upon muscle function and ATP fluxes was investigated noninvasively using multimodal magnetic resonance and indirect calorimetry measurements in wild type mice. RESULTS: ActRIIB blockade reduced (-41%) the muscle apparent mitochondrial capacity and increased (+11%) the basal body energy expenditure. During a fatiguing exercise, ActRIIB blockade decreased both oxidative ATP production rate (-32%) and fatigue resistance (-36%) but these changes affected neither the total ATP production rate nor the contractile ATP cost. DISCUSSION: These findings demonstrate that the increased fatigability following ActRIIB blockade is not due to limitation in energy supply and/or disturbance in contractile ATP cost. This article is protected by copyright. All rights reserved. PMID- 30025156 TI - Noncanonical functions of microRNA pathway enzymes - Drosha, DGCR8, Dicer and Ago proteins. AB - MicroRNAs (miRNAs) are small regulatory noncoding RNAs that are generated in the canonical RNA interference (RNAi) pathway. Drosha, DiGeorge syndrome critical region 8 (DGCR8) and Dicer are key players in miRNA biogenesis. Argonaute (Ago) proteins bind to miRNAs and are guided by them to find messenger RNA targets and carry out post-transcriptional silencing of protein-coding genes. Recently, emerging evidence suggests that RNAi factors have a range of noncanonical functions that are beyond miRNA biogenesis. These functions pertain to various biological processes, such as development, transcriptional regulation, RNA processing and maintenance of genome integrity. Here, we review recent literature reporting miRNA-independent, noncanonical functions of Drosha, DGCR8, Dicer and Ago proteins and discuss the importance of these functions. PMID- 30025157 TI - Childbirth experiences related to obstetric violence in public health units in Quito, Ecuador. AB - OBJECTIVE: To explore women's experiences of obstetric violence related to childbirth in Ecuador. METHODS: The present cross-sectional descriptive study combined qualitative and quantitative elements of women's childbirth experience in Quito, Ecuador, between July 1, 2016, and July 1, 2017. Women who delivered in public health units providing different levels of care completed a survey of 32 questions, divided into six dimensions of obstetric violence. RESULTS: Overall, 388 women completed the survey, of whom 259 (66.8%) delivered vaginally and 129 (33.2%) delivered by cesarean. Among 120 women who delivered for the first time, 62 (51.7%) had an episiotomy. At the second stage of labor, uterine fundus pressure (Kristeller maneuver) was performed for 49 (19.4%) of 252 women. Overall, 196 (50.5%) women reported that they were not allowed to engage in early attachment, and 135 (34.8%) reported that they did not receive support for the initiation of breastfeeding. CONCLUSION: Various forms of obstetric violence are occurring in the public health services of Quito, despite World Health Organization recognition of the need for perinatal care at the highest level. Programs designed to prevent and diminish obstetric violence are urgently required. PMID- 30025159 TI - Scaling of the corpus callosum in wild and domestic canids: Insights into the domesticated brain. AB - All domesticated mammals exhibit marked reductions in overall brain size, however, it is unknown whether the corpus callosum (CC), an integral white matter fiber pathway for interhemispheric cortical communication, is affected by domestication differentially or strictly in coordination with changes in brain size. To answer this question, we used quantitative magnetic resonance imaging to compare the midsagittal cross-sectional areas of the CC in 35 carnivore species, including eight wild canids and 13 domestic dogs. We segmented rostro-caudal regions of interest for the CC and evaluated correlations with brain mass. The results of this study indicate that under the influence of domestication in canids, the CC scales to brain size in an allometric relationship that is similar to that of wild canids and other carnivores, with relatively high correlation coefficients observed for all regions, except the rostrum. These results indicate that architectural and energetic considerations are likely to tightly constrain variation in caudal components of the CC relative to overall brain size, however fibers passing through the rostrum, putatively connecting prefrontal cortex, are less constrained and therefore may contribute more toward species-specific differences in connectivity. Given the species diversity of the Canidae and the resurgence of interest in the brain of the domestic dog, further studies aimed at characterizing the neural architecture in domesticated species is likely to provide new insights into the effects of domestication, or artificial selection, on the brain. PMID- 30025158 TI - Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. AB - Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption. PMID- 30025160 TI - Malt1 self-cleavage is critical for regulatory T cell homeostasis and anti-tumor immunity in mice. AB - Mucosa-associated lymphoid tissue 1 (Malt1) regulates immune cell function by mediating the activation of nuclear factor kappaB (NF-kappaB) signaling through both its adaptor and proteolytic function. Malt1 is also a target of its own protease activity and this self-cleavage further contributes to NF-kappaB activity. Until now, the functional distinction between Malt1 self-cleavage and its general protease function in regulating NF-kappaB signaling and immune activation remained unclear. Here we demonstrate, using a new mouse model, the importance of Malt1 self-cleavage in regulating expression of NF-kappaB target genes and subsequent T cell activation. Significantly, we further establish that Treg homeostasis is critically linked to Malt1 function via a Treg intrinsic and extrinsic mechanism. TCR-mediated Malt1 proteolytic activity and self-cleavage was found to drive Il2 expression in conventional CD4+ T cells, thereby regulating Il2 availability for Treg homeostasis. Remarkably, the loss of Malt1 mediated self-cleavage alone was sufficient to cause a significant Treg deficit resulting in increased anti-tumor immune reactivity without associated autoimmunity complications. These results establish for the first time that inhibition of MALT1 proteolytic activity could be a viable therapeutic strategy to augment anti-tumor immunity. PMID- 30025161 TI - Two Novel Methods for Enhancing Postmortem Fingerprint Recovery from Mummified Remains. AB - Postmortem fingerprint collection is a routine part of many forensic death investigations. Although the production of postmortem prints is usually straight forward, several obstacles and scenarios can make the collection difficult. A common challenge occurs when finger pads are mummified. Several current techniques allow for softening and rehydration of mummified finger pads; however, despite the employment of such techniques, the production of adequate postmortem fingerprints can remain elusive. The authors present two techniques that can improve the chances of obtaining suitable fingerprints from mummified remains. The "baby powder method" involves applying a cornstarch-based powder, such as baby powder, onto the darkened and mummified finger pads, to allow better visualization of the fingerprint detail. The "transillumination method" involves carefully dissecting away the tissues underlying the finger pad, followed by placement of a bright light source underneath the finger pad, such that the finger ridge pattern is illuminated. PMID- 30025162 TI - Sarcomeric disorganization and nemaline bodies in muscle biopsies of patients with EXOSC3-related type 1 pontocerebellar hypoplasia. AB - INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date no distinct features have been identified. METHODS: Clinical data and muscle biopsy findings of three unrelated patients with EXOSC3 mutations are described. RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harbouring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening and small nemaline bodies. DISCUSSION: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. This article is protected by copyright. All rights reserved. PMID- 30025163 TI - Origin of Equisetum: Evolution of horsetails (Equisetales) within the major euphyllophyte clade Sphenopsida. AB - PREMISE OF THE STUDY: Equisetum is the sole living representative of Sphenopsida, a clade with impressive species richness, a long fossil history dating back to the Devonian, and obscure relationships with other living pteridophytes. Based on molecular data, the crown group age of Equisetum is mid-Paleogene, although fossils with possible crown synapomorphies appear in the Triassic. The most widely circulated hypothesis states that the lineage of Equisetum derives from calamitaceans, but no comprehensive phylogenetic studies support the claim. Using a combined approach, we provide a comprehensive phylogenetic analysis of Equisetales, with special emphasis on the origin of genus Equisetum. METHODS: We performed parsimony phylogenetic analyses to address relationships of 43 equisetalean species (15 extant, 28 extinct) using a combination of morphological and molecular characters. KEY RESULTS: We recovered Equisetaceae + Neocalamites as sister to Calamitaceae + a clade of Angaran and Gondwanan horsetails, with the four groups forming a clade that is sister to Archaeocalamitaceae. The estimated age for the Equisetum crown group is mid-Mesozoic. CONCLUSIONS: Modern horsetails are not nested within calamitaceans; instead, both groups have explored independent evolutionary trajectories since the Carboniferous. Diverse fossil taxon sampling helps to shed light on the position and relationships of equisetalean lineages, of which only a tiny remnant is present within the extant flora. Understanding these relationships and early character configurations of ancient plant clades as Equisetales provide useful tests of hypotheses about overall phylogenetic relationships of euphyllophytes and foundations for future tests of molecular dates with paleontological data. PMID- 30025164 TI - Following disease progression in motor neuron disorders with 3 motor unit number estimation methods. AB - INTRODUCTION: The objective of this study was to evaluate a recently developed motor unit number estimation (MUNE) method, MScanFit MUNE (MScan), as a measure of disease progression in amyotrophic lateral sclerosis (ALS) compared with compound muscle action potential (CMAP) amplitude and 2 traditional MUNE methods. METHODS: ALS patients were evaluated clinically using the ALS Functional Rating Scale-Revised (ALSFRS-R). MScan, multiple-point stimulation MUNE (MPS), and motor unit number index (MUNIX) were performed in the abductor pollicis brevis (APB) muscle at baseline (27 patients), 4 months (23 patients), and 8 months (16 patients). RESULTS: Of the 5 measures, MScan registered the largest decline (8.7% per month), compared with MPS (3.4%), MUNIX (4.8%), CMAP amplitude (2.0%), and ALSFRS-R (1.9%). Only MScan and ALSFRS-R registered significant decrements over 4 and 8 months. DISCUSSION: MScan may be useful as a sensitive, objective tool for quantifying motor unit loss in ALS. Muscle Nerve, 2018. PMID- 30025165 TI - Range expansion of tropical pyrosomes in the northeast Pacific Ocean. PMID- 30025166 TI - Contribution to the Development of Guidelines in the Analysis of Biological Evidence in Sexual Assault Investigations. AB - This investigation intends to study materials and techniques used for biological evidence collection in sexual assault cases and is divided into two stages: in stage one, methods for biological evidence collection (the single swab (including three variants) and the "double swab technique") were compared; in stage two, swabs' component material was compared. The sampling was composed of 42 heterosexual couples who provided mock samples. The collection methods in which the whole swab is covered by evidence presented significantly better outcomes (p < 0.001), such as the "double swab technique." Additionally, nylon swabs proved to present significantly better features regarding the capacity of sample elution, providing significantly higher amounts of DNA (p <= 0.034). This study provides guidelines for better collection of biological evidence regarding the collection method using a swab and the proper swab material to utilize. PMID- 30025167 TI - Simultaneous electrokinetic and hydrodynamic injection and sequential stacking featuring sweeping for signal amplification following MEKC during the analysis of rapamycin (sirolimus) in serum samples. AB - Simultaneous electrokinetic and hydrodynamic injection of rapamycin (sirolimus) with off-line and online sample preconcentration techniques and using MEKC has been studied. Compared to conventional hydrodynamic injection, a 168-fold improvement in the signal was obtained with a combination of simultaneous electrokinetic and hydrodynamic injectionand field enhanced sample injection in conjunction with a sweeping technique called sequential stacking featuring sweeping. However, the coupling of the developed electrophoretic method and solid phase microextraction allowed the signal intensity to increase more than 231 times. In this approach, the injection of the sample at negative polarity (anode at the detector end) into the capillary and the MEKC separation was achieved within 5 min using an electrolyte (composed of 10 mM sodium tetraborate and 40 mM SDS) when ultraviolet (UV) detection was performed at 280 nm. Thus, by combining the application of the sequential stacking featuring sweeping supported by the solid-phase microextraction clean-up procedure, the detection limit (LOD) for rapamycin in a serum sample was significantly decreased, and was set at 25 ng/mL. The proposed combined simultaneous electrokinetic and hydrodynamic injection with field enhanced sample injection -sweeping technique following MEKC separation of sirolimus in human serum could be an effective tool in biomedical and clinical applications. PMID- 30025169 TI - Flow force augmented 3D suspended polymeric microfluidic (SPMF3 ) platform. AB - Detection and study of bioelements using microfluidic systems has been of great interest in the biodiagnostics field. Microcantilevers are the most used systems in biodetection due to their implementation simplicity which have been used for a wide variety of applications ranging from cellular to molecular diagnosis. However, increasing further the sensitivity of the microcantilever systems have a great effect on the cantilever based sensing for chemical and bio applications. In order to improve further the performance of microcantilevers, a flow force augmented 3D suspended microchannel is proposed using which microparticles can be conveyed through a microchannel inside the microcantilever to the detection area. This innovative microchannel design addresses the low sensitivity issue by increasing its sensitivity up to 5 times than the earlier reported similar microsystems. Moreover, fabricating this microsystem out of Polydimethylsiloxane (PDMS) would eliminate external exciter dependency in many detection applications such as biodiagnostics. In this study, the designed microsystem has been analyzed theoretically, simulated and tested. Moreover, the microsystem has been fabricated and tested under different conditions, the results of which have been compared with simulation results. Finally, its innovative fabrication process and issues are reported and discussed. PMID- 30025170 TI - A closer look at Verogen's ForenseqTM DNA Signature Prep kit autosomal and Y-STR data for streamlined analysis of routine reference samples. AB - Massively parallel sequencing (MPS) provides forensic DNA laboratories an option to overcome the limitations associated with CE and current STR assays. Verogen's MPS ForenseqTM DNA Signature kit concomitantly amplifies 27 autosomal, 7 X-, and 24 Y-STRs. In addition, 94 identity, 56 ancestry, and 22 phenotypic-informative SNPs are included for a total of over 200 markers in one multiplex. An internal validation of this platform was conducted using reference samples to investigate whether the ForenseqTM DNA Signature Prep kit, specifically primer panel B, has the capability to provide consistent and accurate typing/sequencing data. The data presented in this report is limited to that corresponding to autosomal and Y STRs. Results suggest that the system can consistently generate accurate genotyping data when up to 40 high-quality, high-quantity (i.e. 1 ng) single source samples are pooled into a sequencing reaction. The results generated were used to determine appropriate analysis parameters and thresholds for streamlined data interpretation of reference samples. PMID- 30025168 TI - Intracerebral microdialysis of adenosine and adenosine monophosphate - a systematic review and meta-regression analysis of baseline concentrations. AB - Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies. We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and adenosine monophosphate in microdialysates. We performed a meta-regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area and anaesthesia versus freely behaving, on the adenosine concentration. Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline adenosine monophosphate concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p <= 0.001), but not of probe membrane surface, species, or brain area (p >= 0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, for example, post-surgical recovery time, could not be analysed because of a lack of reported data. This study shows that meta-regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve. PMID- 30025171 TI - A Chinese family with periodontal Ehlers-Danlos syndrome associated with missense mutation in the C1R gene. AB - AIM: We report a rare case of the periodontal Ehlers-Danlos syndrome (pEDS) associated with severe periodontitis and tooth loss in a Chinese family. MATERIAL AND METHODS: The proband complained of gingival bleeding and mobility, which were also reported in his mother, and maternal uncle and his maternal grandmother and great-grandfather in the past. All family members underwent oral, physical, dermatological, and genetic examinations. RESULTS: Oral manifestation of family members affected with pEDS presented severe periodontitis with multiple or total tooth loss. The proband displayed unique clinical manifestations including a characteristic facial appearance and thin, translucent skin with easily visible venous patterns on feet. Whole-exome sequencing identified missense mutation c.265T>C in C1R in all affected family members tested and frameshift mutation c.1322delG in COL3A1 in the proband alone. None of the unaffected members showed any marked oral, physical, dermatological, or genetic findings. CONCLUSION: We reported an extremely rare case of pEDS with a missense mutation in C1R in a Chinese family, with coexistence C1R and COL3A1 mutations in the proband who was suspected to suffer from vascular EDS as well. To our knowledge, this is the first case of coexistence of two forms of EDS in a single individual. PMID- 30025172 TI - Testosterone undecanoate and testosterone enanthate injections are both effective and safe in transmen over 5 years of administration. AB - OBJECTIVE: To retrospectively evaluate and compare safety and efficacy of short and long-acting testosterone (T) parenteral formulations over 5 years in transmen. DESIGN AND METHODS: Fifty transmen between 21 and 42 years of age were enrolled. Twenty-five received T undecanoate 1000 mg IM (weeks 0 and 6 then every 12-16 weeks), and 25 received T enanthate 250 mg IM (every 3-4 weeks). Hormonal and biochemical parameters, anthropometric characteristics and blood pressure were assessed at baseline and then every 12 months. Body composition was evaluated at baseline and then after 1, 3 and 5 years of T treatment. Global satisfaction was assessed at baseline and after 1 and 5 years. RESULTS: Both T formulations led to amenorrhoea in all subjects within 1 year of T administration. Both T treatments led to a similar increase in haemoglobin and haematocrit which always remained within the physiological range. T administration was associated with an increase in total cholesterol, low-density lipoprotein cholesterol and triglycerides and a slight reduction in high-density lipoprotein cholesterol. Coagulative and glucidic profiles and blood pressure did not change significantly in either group. Body weight and BMI showed a slight but not significant increase in both groups, while lean mass rose significantly in both groups. Global satisfaction was increased at years 1 and 5 in both groups. CONCLUSIONS: Preliminary results from this pilot study suggest that administration of either TU or TE for 5 years in young transmen is both effective and safe. Our study presents the longest follow-up published so far reporting no adverse events and these data are consistent with previous reports with a shorter follow-up. PMID- 30025173 TI - Evaluation of mitochondrial respiratory function in rat cardiomyocytes under different glucose conditions, using an extracellular flux analysis method. AB - We studied the effect of glucose supply on mitochondrial respiratory function (MRF) of neonatal rat cardiomyocytes, using a novel extracellular flux analysis. Fundamental respiratory parameters regarding oxygen consumption rate in mitochondria showed glucose concentration-dependent changes, where a significant increase or decrease in these parameters was observed to be associated with glucose concentrations ranging between 10% and 1000% of the concentration used in standard medium (3151 mg/L), respectively. By contrast, the extracellular acidification rate, a parameter of anaerobic activity, was shown to decrease under low-glucose conditions, whereas it increased after inhibiting complex V (ATP synthase) under the same glucose conditions. These findings provide a beneficial basis for various experimental studies on mitochondrial metabolism in cardiomyocytes. PMID- 30025174 TI - Advanced mare age impairs the ability of in vitro-matured oocytes to correctly align chromosomes on the metaphase plate. AB - BACKGROUND: Advanced mare age is associated with declining fertility and an increased risk of early pregnancy loss. Compromised oocyte quality is probably the primary reason for reduced fertility, but the defects predisposing to embryonic death are unknown. In women, advanced age predisposes to chromosome segregation errors during meiosis, which lead to embryonic aneuploidy and a heightened risk of miscarriage. OBJECTIVES: To evaluate the effect of advanced mare age on chromosome alignment and meiotic spindle morphology in in vitro matured (IVM) oocytes. STUDY DESIGN: Morphometric and morphological analysis. METHODS: To investigate differences in spindle organisation and chromosome alignment between young and old mares, oocytes collected from slaughtered mares were divided into two groups depending on mare age (young, <=14 years and old, >=16 years), IVM and stained to visualise chromatin and alpha-tubulin. Spindle morphology, morphometry and chromosome (mis)alignment were evaluated by confocal microscopy and 3D image analysis. RESULTS: Oocytes from old mares showed a higher incidence of chromosome misalignment (47.4% vs. 4.5%; P<0.001) and a thicker metaphase plate (mean +/- s.d.: 5.8 +/- 1.0 MUm vs. 4.9 +/- 0.9 MUm; P = 0.04) than oocytes from young mares. Although no differences in spindle morphometry were detected between old and young mares, an increased major spindle axis length was associated with chromosome misalignment (mean +/- s.d.: 25.3 +/- 6.1 MUm vs. 20.8 +/- 3.3 MUm; P = 0.01) irrespective of age. MAIN LIMITATIONS: The oocytes were IVM and may not exactly reflect chromosome misalignment in vivo. CONCLUSIONS: Advanced mare age predisposes to chromosome misalignment on the metaphase II spindle of IVM oocytes. The compromised ability to correctly align chromosomes presumably predisposes to aneuploidy in resulting embryos and thereby contributes to the age-related decline in fertility and increased incidence of early pregnancy loss. The Summary is available in Portuguese - see Supporting Information. PMID- 30025176 TI - Morphology and Phylogeny of Four New Vorticella Species (Ciliophora: Peritrichia) from Coastal Waters of Southern China. AB - Four new species of Vorticella, V. parachiangi sp. n., V. scapiformis sp. n., V. sphaeroidalis sp. n., and V. paralima sp. n., were isolated from coastal brackish waters of southern China. Their morphology, infraciliature, and silverline system were investigated based on observations of specimens both in vivo and following silver staining. Vorticella parachiangi sp. n. is distinguished by: a J-shaped macronucleus; a single dorsally located contractile vacuole; a two-rowed infundibular polykinetid 3, in which row 1 is shorter than row 2; 21-31 silverlines between peristome and aboral trochal band, 6-11 between aboral trochal band and scopula. Vorticella scapiformis sp. n. is characterized by its conspicuously thin and irregularly edged peristomial lip; a J-shaped macronucleus; a single, ventrally located contractile vacuole; row 1 of the infundibular polykinetid 3 proximally shortened; 18-25 silverlines between peristome and aboral trochal band, 8-12 between aboral trochal band and scopula. Vorticella sphaeroidalis sp. n. can be identified by its small, sub-spherical zooid; a C-shaped macronucleus; a ventrally located contractile vacuole; an aboral trochal band adjacent to the scopula; 16-18 silverlines between persitome and aboral trochal band, two between aboral trochal band and scopula. Vorticella paralima sp. n. can be identified by its ovoidal zooid; a J-shaped macronucleus; a dorsally positioned contractile vacuole; rows 1 and 2 of the infundibular polykinetid 3 proximally shortened; 26-35 silverlines from peristome to aboral trochal band, and 7-13 from aboral trochal band to scopula. The SSU rDNA genes of these four species were sequenced and their phylogeny was analyzed. PMID- 30025175 TI - Crowdsourcing Trauma: Psychopathology in a Trauma-Exposed Sample Recruited via Mechanical Turk. AB - Although crowdsourcing websites like Amazon's Mechanical Turk (MTurk) allow researchers to conduct research efficiently, it is unclear if MTurk and traditionally recruited samples are comparable when assessing the sequela of traumatic events. We compared the responses to validated self-report measures of posttraumatic stress disorder (PTSD) and related constructs that were given by 822 participants recruited via MTurk and had experienced a DSM-5 Criterion A traumatic event to responses obtained in recent samples of participants recruited via traditional methods. Results suggested that the rate of PTSD in the present sample (19.8%) was statistically higher than that found in a recent systematic review of studies that used only traditional recruitment methods. The severity of PTSD reported in the MTurk sample was significantly greater than that reported in a college sample, d = 0.24, and significantly less than that reported in a veteran sample, d = 0.90. The factor structure of PTSD found in the MTurk sample was consistent with prevailing models of PTSD. Findings indicate that crowdsourcing may improve access to this hard-to-reach population. PMID- 30025177 TI - Low-dose Magnesium Sulfate Versus High Dose in the Early Management of Rapid Atrial Fibrillation: Randomized Controlled Double-blind Study (LOMAGHI Study). AB - OBJECTIVES: We aim to determine the benefit of two different doses magnesium sulfate (MgSO4 ) compared to placebo in rate control of rapid atrial fibrillation (AF) managed in the emergency department (ED). METHODS: We undertook a randomized, controlled, double-blind clinical trial in three university hospital EDs between August 2009 and December 2014. Patients > 18 years with rapid AF (>120 beats/min) were enrolled and randomized to 9 g of intravenous MgSO4 (high dose group, n = 153), 4.5 g of intravenous MgSO4 (low-dose group, n = 148), or serum saline infusion (placebo group, n = 149), given in addition to atrioventricular (AV) nodal blocking agents. The primary outcome was the reduction of baseline ventricular rate (VR) to 90 beats/min or less or reduction of VR by 20% or greater from baseline (therapeutic response). Secondary outcome included resolution time (defined as the elapsed time from start of treatment to therapeutic response), sinus rhythm conversion rate, and adverse events within the first 24 hours. RESULTS: At 4 hours, therapeutic response rate was higher in low- and high-MgSO4 groups compared to placebo group; the absolute differences were, respectively, 20.5% (risk ratio [RR] = 2.31, 95% confidence interval [CI] = 1.45-3.69) and +15.8% (RR = 1.89, 95% CI = 1.20-2.99). At 24 hours, compared to placebo group, therapeutic response difference was +14.1% (RR = 9.74, 95% CI = 2.87-17.05) with low-dose MgSO4 and +10.3% (RR = 3.22, 95% CI = 1.45-7.17) with high-dose MgSO4 . The lowest resolution time was observed in the low-dose MgSO4 group (5.2 +/- 2 hours) compared to 6.1 +/- 1.9 hours in the high-dose MgSO4 group and 8.4 +/- 2.5 hours in the placebo group. Rhythm control rate at 24 hours was significantly higher in the low-dose MgSO4 group (22.9%) compared to the high dose MgSO4 group (13.0%, p = 0.03) and the placebo group (10.7%). Adverse effects were minor and significantly more frequent with high-dose MgSO4 . CONCLUSIONS: Intravenous MgSO4 appears to have a synergistic effect when combined with other AV nodal blockers resulting in improved rate control. Similar efficacy was observed with 4.5 and 9 g of MgSO4 but a dose of 9 g was associated with more side effects. PMID- 30025178 TI - Pushing Hard: The Mandate to Improve Care of Pediatric Cardiopulmonary Arrest. PMID- 30025179 TI - Asian children living in Australia have a different profile of allergy and anaphylaxis than Australian-born children: A State-wide survey. AB - BACKGROUND: Asian children born in Australia have higher rates of eczema and nut allergy than non-Asian children. However, it is not known whether this country of birth differential exists for other allergies or anaphylaxis risk. OBJECTIVE: We investigated the influence of maternal and child's country of birth on the prevalence of parent-reported eczema, asthma, food allergy and being diagnosed by a doctor as being "at risk of anaphylaxis." METHODS: We assessed the relationship between mother and child country of birth and allergies using the 2010 School Entrant Health Questionnaire, completed for 57 005 5-year old children (85.8% response rate) in Victoria, Australia. Analyses were conducted using logistic regression with results presented as odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: Children born in Australia to Asian-born mothers were more likely to have parent-reported food allergy (OR 2.33, 95%CI 1.96-2.77) and eczema (OR 2.04, 95%CI 1.73-2.41), but not more likely to have asthma (OR 0.87, 95% CI 0.74-1.02) than non-Asian children. By contrast, children born in Asia who subsequently migrated to Australia had a lower risk of food allergy (OR 0.33, 95%CI 0.20-0.55), eczema (OR 0.37, 95%CI 0.24-0.57) and asthma (OR 0.29, 95% CI 0.21-0.40). Patterns of anaphylaxis risk differed depending on the trigger. Compared with Australian-born non-Asian children, Australian-born Asian children were more likely to be diagnosed as being at risk of both food-induced and non food-induced anaphylaxis. For children born in Asia, risk was lower for anaphylaxis to milk, peanut and tree nuts compared to non-Asian children, but higher for soy, wheat and non-food triggers. CONCLUSIONS AND CLINICAL RELEVANCE: Patterns of allergy/anaphylaxis risk and their triggers differed according to both ethnicity and country of birth, suggesting a gene-environment factor is in play. The difference in patterns for asthma compared with other atopic diseases is surprising and warrants further exploration. PMID- 30025180 TI - Predictors of Posttraumatic Stress Disorder, Anxiety Disorders, Depressive Disorders, and Any Mental Health Condition Among U.S. Soldiers and Marines, 2001 2011. AB - Understanding mental health disorder diagnosis and treatment seeking among active duty military personnel is a topic with both clinical and policy implications. It has been well documented in military populations that individual-level military experience, including deployment history and combat exposure, influences mental health outcomes, but the impact of unit-level factors is less well understood. In the current study, we used administrative longitudinal data to examine a comprehensive set of unit- and individual-level predictors of posttraumatic stress disorder (PTSD), non-PTSD anxiety disorders, depressive disorders, and overall mental health diagnoses among Army and Marines Corps personnel. Using Cox survival models for time-dependent variables, we analyzed time from military accession (between January 1, 2001 and December 31, 2011) until first mental health diagnosis for 773,359 soldiers and 332,093 Marines. Prior diagnosis of a substance abuse disorder during one's military career, hazard ratios (HRs) = 1.68 3.10, and cumulative time spent deployed, HRs = 1.11-2.04, were the most predictive risk factors for all outcomes. Male sex, HRs = 0.35-0.57, and officer rank, HRs = 0.13-0.23, were the most protective factors. Unit-level rate of high deployment stress was a small but significant predictor of all outcomes after controlling for individual-level deployment history and other predictors, HRs = 1.01-1.05. Findings suggest both unit- and individual-level risk and protective factors of mental health diagnoses associated with treatment seeking. Clinical, including mental health assessment and management, and policy implications related to the military environment and the individual as it relates to mental health disorders are discussed. PMID- 30025181 TI - One-Dimensional Arsenic Allotropes: Polymerization of Yellow Arsenic Inside Single-Wall Carbon Nanotubes. AB - The pnictogen nanomaterials, including phosphorene and arsenene, display remarkable electronic and chemical properties. Yet, the structural diversity of these main group elements is still poorly explored. Here we fill single-wall carbon nanotubes with elemental arsenic from the vapor phase. Using electron microscopy, we find chains of highly reactive As4 molecules as well as two new one-dimensional allotropes of arsenic: a single-stranded zig-zag chain and a double-stranded zig-zag ladder. These linear structures are important intermediates between the gas-phase clusters of arsenic and the extended sheets of arsenene. Raman spectroscopy indicates weak electronic interaction between the arsenic and the nanotubes which implies that the formation of the new allotropes is driven primarily by the geometry of the confinement. The relative stabilities of the new arsenic structures are estimated computationally. Band-gap calculations predict that the insulating As4 chains become semiconducting, once converted to the zig-zag ladder, and form a fully metallic allotrope of arsenic as the zig-zag chain. PMID- 30025182 TI - Longitudinal associations between weather, season, and mode of commuting to school among Spanish youths. AB - AIM: To study the associations of weather conditions with the travel mode choice for commuting to and from school. METHODS: A total of 6979 Spanish youths aged 7 to 18 years old (80% adolescents aged 12-18 years old, 51% male) completed a 5 day survey of mode of commuting to school in autumn, winter, and spring. Weather data from the nearest weather station to each school were registered. We used Google MapsTM to calculate the distance from home to school. Multilevel logistic regression models were used to estimate odds of active travel based on weather and season. RESULTS: We analyzed a total of 163 846 discrete journeys. In winter, children (aged 7 to 11 years old) were less likely to choose an active mode of commuting to school (OR: 0.72, 95% CI: 0.59-0.89, P = 0.003). In spring, adolescents were more likely to choose an active mode of commuting to school (OR: 1.43, 95% CI: 1.19-1.73, P < 0.001). With higher mean temperatures, adolescents were more likely to choose an active mode of commuting from school (OR: 1.02, 95% CI: 1.00-1.04, P = 0.029). CONCLUSION: Certain weather conditions seem to influence the travel mode choice for commuting to and from school in youth, including season and temperature. PMID- 30025183 TI - A review of plasticity induced by auditory and visual tetanic stimulation in humans. AB - Long-term potentiation is a form of synaptic plasticity thought to play an important role in learning and memory. Recently noninvasive methods have been developed to induce and measure activity similar to long-term potentiation in humans. Sensory tetani (trains of quickly repeating auditory or visual stimuli) alter the electroencephalogram in a manner similar to electrical stimulation that results in long-term potentiation. This review briefly covers the development of long-term potentiation research before focusing on in vivo human studies that produce long-term potentiation-like effects using auditory and visual stimulation. Similarities and differences between traditional (animal and brain tissue) long-term potentiation studies and human sensory tetanization studies will be discussed, as well as implications for perceptual learning. Although evidence for functional consequences of sensory tetanization remains scarce, studies involving clinical populations indicate that sensory induced plasticity paradigms may be developed into diagnostic and research tools in clinical settings. Individual differences in the effects of sensory tetanization are not well-understood and provide an interesting avenue for future research. Differences in effects found between research groups that have emerged as the field has progressed are also yet to be resolved. PMID- 30025185 TI - Genome-Based Identification of a Plant-Associated Marine Bacterium as a Rich Natural Product Source. AB - The large number of sequenced bacterial genomes provides the opportunity to bioinformatically identify rich natural product sources among previously neglected microbial groups. Testing this discovery strategy, unusually high biosynthetic potential was suggested for the Oceanospirillales member Gynuella sunshinyii, a Gram-negative marine bacterium from the rhizosphere of the halophilic plant Carex scabrifolia. Its genome contains numerous unusual biosynthetic gene clusters for diverse types of metabolites. Genome-guided isolation yielded representatives of four different natural product classes, of which only alteramide A was known. Cytotoxic lacunalides were identified as products of a giant trans-acyltransferase polyketide synthase gene cluster, one of six present in this strain. Cytological profiling against HeLa cells suggested that lacunalide A disrupts CDK signaling in the cell cycle. In addition, chemical studies on model compounds were conducted, suggesting the structurally unusual ergoynes as products of a conjugated diyne-thiourea cyclization reaction. PMID- 30025186 TI - Successful control of hidradenitis suppurativa with verapamil: a case report. AB - An inappropriate immunologic response has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Adalimumab was the first TNF-alpha inhibitor approved for moderate to severe HS. We report on a case of HS (Hurley stage 2) in a 39-year-old man, who had received fusidic acid and isotretinoin treatments without evident benefit during the last 8 years. The patient noticed a reduction in the number of lesions and quality of life (DLQI from 27 to 6) in the 2 months following verapamil initiation for cluster headache. When verapamil was stopped, the lesions recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred. Verapamil has been shown to inhibit TNF-alpha and IL-1beta in vitro and in vivo. We hypothesize that verapamil inhibits the inflammatory process through the TNF-alpha/IL-1 pathway involved in the HS physiopathology. Compared to biologic agents as anti-TNF-alpha (adalimumab) and anti-IL1 (anakinra), verapamil is safer and cheaper. Given its possible role on TNF-alpha/IL-1, verapamil may represent an alternative therapeutic option in mild and moderate HS. PMID- 30025184 TI - Synthesis and Characterization of Self-Assembled Chiral FeII 2 L3 Cages. AB - We present here the synthesis of chiral BINOL-derived (BINOL=1,1'-bi-2-naphthol) bisamine and bispyridine-aldehyde building blocks that can be used for the self assembly of novel chiral FeII 2 L3 cages when mixed with an iron(II) precursor. The properties of a series of chiral cages were studied by NMR and circular dichroism (CD) spectroscopy, cold-spray ionization MS, and molecular modeling. Upon formation of the M2 L3 cages, the iron corners can adopt various isomeric forms: mer, fac-Delta, or fac-Lambda. We found that the coordination geometry around the metal centers in R-Cages 1 and 2 were influenced by the chiral BINOL backbone only to a limited extent, as a mixture of cages was formed with fac and mer configurations at the iron corners. However, single cage species (fac-RR-Cage and fac-RS-Cage) that are enantiopure and highly symmetric were obtained by generating these chiral M2 L3 cages by using the bispyridine-aldehyde building blocks in combination with chiral amine moieties to form pyridylimine ligands for coordination to iron. Next to consistent NMR spectra, the CD spectra confirm the configurations fac-(Lambda,Lambda) and fac-(Delta,Delta) corresponding to RR- and RS-Cage, respectively. PMID- 30025188 TI - Isolated Collagen Mimetic Peptide Assemblies Have Stable Triple-Helix Structures. AB - The origin of the triple-helix structure and high stability of collagen has been debated for many years. As models of the triple helix and building blocks for new biomaterials, collagen mimetic peptide (CMP) assemblies have been deeply studied in the condensed phase. In particular, it was found that hydroxylation of proline, an abundant post-translational modification in collagen, increases its stability. Two main hypotheses emerged to account for this behavior: 1) intra helix stereoelectronic effects, and 2) the role of water molecules H-bound to hydroxyproline side-chains. However, in condensed-phase investigations, the influence of water cannot be fully removed. Therefore, we employed a combination of tandem ion mobility and mass spectrometries to assess the structure and stability of CMP assemblies in the gas phase. These results show a conservation of the structure and stability properties of triple helix models in the absence of solvent, supporting an important role of stereoelectronic effects. Moreover, evidence that small triple helix assemblies with controlled stoichiometry can be studied in the gas phase is given, which opens new perspectives in the understanding of the first steps of collagen fiber growth. PMID- 30025189 TI - Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein Interactions. AB - The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small-molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization. PMID- 30025187 TI - Insulin resistance disrupts cell integrity, mitochondrial function, and inflammatory signaling in lymphatic endothelium. AB - OBJECTIVE: Lymphatic vessel dysfunction and increased lymph leakage have been directly associated with several metabolic diseases. However, the underlying cellular mechanisms causing lymphatic dysfunction have not been determined. Aberrant insulin signaling affects the metabolic function of cells and consequently impairs tissue function. We hypothesized that insulin resistance in LECs decreases eNOS activity, disrupts barrier integrity increases permeability, and activates mitochondrial dysfunction and pro-inflammatory signaling pathways. METHODS: LECs were treated with insulin and/or glucose to determine the mechanisms leading to insulin resistance. RESULTS: Acute insulin treatment increased eNOS phosphorylation and NO production in LECs via activation of the PI3K/Akt signaling pathway. Prolonged hyperglycemia and hyperinsulinemia induced insulin resistance in LECs. Insulin-resistant LECs produced less NO due to a decrease in eNOS phosphorylation and showed a significant decrease in impedance across an LEC monolayer that was associated with disruption in the adherence junctional proteins. Additionally, insulin resistance in LECs impaired mitochondrial function by decreasing basal-, maximal-, and ATP-linked OCRs and activated NF-kappaB nuclear translocation coupled with increased pro-inflammatory signaling. CONCLUSION: Our data provide the first evidence that insulin resistance disrupts endothelial barrier integrity, decreases eNOS phosphorylation and mitochondrial function, and activates inflammation in LECs. PMID- 30025191 TI - Effects of Temperature on the Shape and Symmetry of Molecules and Solids. AB - Despite its undeniable problems from a philosophical point of view, the concept of molecular structure, with attributes such as shape and symmetry, directly borrowed from the description of macroscopic objects, is nowadays central to most of the chemical sciences. Descriptions such as "the tetrahedral carbon atom" or "octahedral coordination complexes" are widely used as much in elementary textbooks as in the most up-to-date research articles. The definition of molecular shape is, however, not as simple as it might seem at first sight. Molecules don't behave as macroscopic objects do, and the arrangement of atoms within a molecule changes continuously due to the incessant motion of its constituent particles, nuclei, and electrons. How are molecular shape and symmetry affected by this thermal motion? In this Minireview, we introduce the language of continuous symmetry measures as a new tool to quantitatively describe the effects of temperature on molecular shape and symmetry, enriching in this way the set of molecular descriptors that might be used in the establishment of new empirical structure-property relations, of great interest in concomitant areas such as medicinal chemistry or materials science. PMID- 30025190 TI - Recommendations on the environment for hospitalised newborn infants from the French neonatal society: rationale, methods and first recommendation on neonatal intensive care unit design. AB - AIM: Hospitalised newborn infants may be stressed due to inappropriate sensory stimuli and early separation from their families, that can negatively impact their neurodevelopment. The French Group of Reflection and Evaluation of the Environment of Newborns (GREEN) issues guidelines based on environmental neonatology and family-centred care. The first recommendation focuses on private family rooms versus large shared rooms. METHODS: These guidelines are based on a systematic evaluation of the literature providing different grades of evidence. Internal and external reviews by multidisciplinary experts examined the scientific evidence of all recommendations. The literature search was performed for the period January 1, 2000 to January 1, 2016 with the keywords 'single room' or 'private room' and 'neonatal intensive care unit'. RESULTS: A total of 25 studies were retained. Most studies reported a positive impact of private rooms on the health of newborn infants and satisfaction of families. Private rooms could lead to sensory deprivation if there is low parental involvement with limited presence and to reduced interaction among caregivers. CONCLUSION: We recommend that neonatal units should mostly have private rooms. With this architectural design, we recommend supporting the staff's needs for changes in the organisation and philosophy of care and to provide improved family support. PMID- 30025192 TI - Visible Light Mediated Aryl Migration by Homolytic C-N Cleavage of Aryl Amines. AB - The photocatalytic preparation of aminoalkylated heteroarenes from haloalkylamides via a 1,4-aryl migration from nitrogen to carbon, conceptually analogous to a radical Smiles rearrangement, is reported. This method enables the substitution of amino groups in heteroaromatic compounds with aminoalkyl motifs under mild, iridium(III)-mediated photoredox conditions. It provides rapid access to thienoazepinone, a pharmacophore present in multiple drug candidates for potential treatment of different conditions, including inflammation and psychotic disorders. PMID- 30025193 TI - An On-Tissue Paterno-Buchi Reaction for Localization of Carbon-Carbon Double Bonds in Phospholipids and Glycolipids by Matrix-Assisted Laser-Desorption Ionization Mass-Spectrometry Imaging. AB - Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) visualizes the distribution of phospho- and glycolipids in tissue sections. However, C=C double-bond (db) positional isomers generally cannot be distinguished. Now an on-tissue Paterno-Buchi (PB) derivatization procedure that exploits benzaldehyde as a MALDI-MSI-compatible reagent is introduced. Laser induced postionization (MALDI-2) was used to boost the yields of protonated PB products. Collision-induced dissociation of these species generated characteristic ion pairs, indicative of C=C position, for numerous singly and polyunsaturated phospholipids and glycosphingolipids in mouse brain tissue. Several db-positional isomers of phosphatidylcholine and phosphatidylserine species were expressed with highly differential levels in the white and gray matter areas of cerebellum. Our PB-MALDI-MS/MS procedure could help to better understand the physiological role of these db-positional isomers. PMID- 30025194 TI - A Multifunctional Dye-doped Liquid Crystal Polymer Actuator: Light-Guided Transportation, Turning in Locomotion, and Autonomous Motion. AB - A strip of a liquid crystal elastomer doped with a near-infrared dye with one side crosslinked monodomain and the other crosslinked polydomain along the thickness behaves like a multifunctional photoactuator without the need for a support. A flat strip with two ends fixed on substrate surface forms a moving bump under laser scanning, which can be used as light-fueled conveyor to transport an object. Cutting off and laser scanning the bump with two free ends makes a soft and flexible millimeter-scale crawler that can not only move straight and climb an inclined surface, but also undergo light-guided turning to right or left as a result of combined out-of-plane and in-plane actuation. Based on the self-shadowing mechanism, with one end of the strip fixed on substrate surface, it can execute a variety of autonomous arm-like movements under constant laser illumination, such as bending-unbending and twisting, depending on the laser incident angles with respect to the strip actuator. PMID- 30025195 TI - Sigmoid volvulus: effects of high altitude. PMID- 30025196 TI - Direct Access to Medium-Chain alpha,omega-Dicarboxylic Acids by Using a Baeyer Villiger Monooxygenase of Abnormal Regioselectivity. AB - Baeyer-Villiger monooxygenases (BVMOs) are versatile biocatalysts in organic synthesis that can generate esters or lactones by inserting a single oxygen atom adjacent to a carbonyl moiety. The regioselectivity of BVMOs is essential in determining the ratio of two regioisomers for converting asymmetric ketones. Herein, we report a novel BVMO from Pseudomonas aeruginosa (PaBVMO); this has been exploited for the direct synthesis of medium-chain alpha,omega-dicarboxylic acids through a Baeyer-Villiger oxidation-hydrolysis cascade. PaBVMO displayed the highest abnormal regioselectivity toward a variety of long-chain aliphatic keto acids (C16 -C20 ) to date, affording dicarboxylic monoesters with a ratio of up to 95 %. Upon chemical hydrolysis, alpha,omega-dicarboxylic acids and fatty alcohols are readily obtained without further treatment; this significantly reduces the synthetic steps of alpha,omega-dicarboxylic acids from renewable oils and fats. PMID- 30025197 TI - Leveraging gamma-Glutamyl Transferase To Direct Cytotoxicity of Copper Dithiocarbamates against Prostate Cancer Cells. AB - A prodrug approach is presented to direct copper-dependent cytotoxicity to prostate cancer cells. The prochelator GGTDTC requires activation by gamma glutamyl transferase (GGT) to release the metal chelator diethyldithiocarbamate from a linker that masks its thiol reactivity and metal binding properties. In vitro studies demonstrated successful masking of copper binding as well as clean liberation of the chelator by GGT. GGTDTC was stable to non-specific degradation when incubated with a series of prostate cancer and normal cell lines, with selective release of diethyldithiocarbamate only occurring in cells with measurable GGT activity. The antiproliferative efficacy of the prochelator correlated with cellular GGT activity, with 24 h inhibitory concentrations ranging from 800 nm in prostate cancer lines 22Rv1 and LNCaP to over 15 MUm in normal prostate PWR-1E cells. These findings underscore a new strategy to leverage the amplified copper metabolism of prostate cancer by conditional activation of a metal-binding pharmacophore. PMID- 30025198 TI - Regression of hepatocellular adenoma after bariatric surgery in severe obese patients. AB - BACKGROUND & AIM: Obesity and metabolic syndrome are increasingly recognized as risk factors for hepatocellular adenomas (HCA). There is still sparse evidence whether weight loss or bariatric surgery could induce HCA regression in these patients. In this brief report we describe the effect of weight loss on HCA regression in severe obese patients that had undergone bariatric surgery in our centre. METHODS: We performed an Electronic Patient Database search and included all patients who underwent bariatric surgery in our bariatric referral centre and had an ICD-10 code of benign neoplasm of liver in our centre from (2006-2017). All imaging studies of eligible patients were re-evaluated by the study radiologist. Primary outcome was change in maximal diameter of HCA. RESULTS: Six of 11 eligible patients were excluded because their lesions were classified as probable focal nodular hyperplasia and two were lost to follow-up. Finally, three women with solitary (n = 1) or multiple HCA (n = 2) and a body mass index (BMI) ranging between 39 and 50 kg/m2 were included. In two patients, HCA completely regressed in 1-2 years following bariatric surgery, after BMI reductions of 36% 48%. The third patient showed a reduction of >50% in diameter of the largest HCA in 2.5 years after bariatric surgery (31% BMI reduction), with complete resolution of smaller HCA. CONCLUSIONS: Bariatric induced weight loss results in significant regression of HCA in severe obese women, which emphasizes the role of overweight in HCA pathophysiology. PMID- 30025199 TI - Use of 5alpha-reductase inhibitors for benign prostate hypertrophy and risk of high grade prostate cancer: a French population-based study. AB - OBJECTIVE: To assess the association between 5alpha-reductase inhibitor (5-ARI) use and high grade (Gleason score 8-10) prostate cancer. PATIENTS AND METHODS: We conducted a population-based nested matched case-control study using the French national health insurance database linked to data from all pathology laboratories in Brittany, France. Among 74 596 patients with >=1 drug reimbursement for symptomatic benign prostate hypertrophy (BPH) between 1 January 2010 and 31 December 2011, 767 incident prostate cancer cases between 1 January 2012 and 31 December 2013 were matched according to age and delay between the first observed delivery of drug for BPH (5-ARIs, alpha-blockers or phytotherapy) and diagnostic date of the case to five control patients, using an incidence density sampling design. RESULTS: A total of 963 patients (153 cases, 810 controls) had been exposed to 5-ARIs. A significant heterogeneity (P = 0.005) was detected across cancer grades when estimating the association between prostate cancer and long term (>=2 years) 5-ARI use vs no 5-ARI exposure: adjusted conditional odds ratio 1.76 (95% confidence interval [CI] 0.97-3.21) for Gleason score >=8 and 0.64 (95% CI 0.44-0.93) for Gleason score < 8. CONCLUSION: Our results indicate an increased risk of high grade and a decreased risk of low grade prostate cancer associated with 5-ARI use. Patients treated for >2 years with 5-ARIs should be informed about the increased risk of development of high grade disease. PMID- 30025200 TI - Hepatitis B virus infection and risk of non-alcoholic fatty liver disease: A population-based cohort study. AB - BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD) has been studied extensively, the potential risk factors for NAFLD among chronic hepatitis B (CHB) patients have not been fully known. METHODS: A population-based cohort of adult CHB patients without a history of alcohol drinking or NAFLD were recruited and followed up from October 2012 to January 2015 in Jiangsu province, China. Using Cox proportional hazards regression model, potential risk factors including viral and metabolic factors for NAFLD were evaluated. RESULTS: Two thousand three hundred and ninety-three adult CHB patients (mean age 50.7 +/- 13.2 years) were included in the cohort. With 4429 person-years of follow-up, 283 individuals progressed to NAFLD with an incidence rate of 63.89/1000 person-years. Overweight and obese CHB patients had an increased risk of NAFLD (overweight adjusted hazard ratio [HR], 3.10; 95% CI, 2.29-4.18; obese HR, 8.52; 95%CI, 5.93-12.25) compared to normal weight carriers. The incidence of NAFLD was associated with concurrent type 2 diabetes mellitus (DM) (HR, 1.88; 95%CI, 1.15-3.08). However, no associations between viral factors with NAFLD incidence rate were identified. In a subgroup of participants with concurrent type 2 DM, detectable HBV DNA levels were negatively associated with the development of NAFLD (HR, 0.37; 95%CI, 0.14 0.98). There was super-multiplicative interaction between BMI and gender with respect to incidence of NAFLD, with an ROR of 2.08 (95%CI, 1.02-4.23). CONCLUSION: Metabolic factors play an important role in the presence of NAFLD among Chinese CHB patients. However, viral replication factors are not related to NAFLD except among those with concurrent type 2 DM. PMID- 30025201 TI - Aggregation-Induced Emission with Long-Lived Room-Temperature Phosphorescence from Methylene-Linked Organic Donor-Acceptor Structures. AB - Aggregation-caused quenching (ACQ), where excited-state and/or ground-state electronic structures are altered to exhibit an increased proclivity for non radiative decay for the aggregates, is largely responsible for the lack of fluorescence and phosphorescence in molecular solids in general. Here we show that ACQ could be effectively circumvented by constructing an aromatic system with a methylene-linker, where the system exhibits typical aggregation-induced emission (AIE) with long-lived room-temperature phosphorescence, since the tetrahedral structure in the solid state may significantly reduce strong intermolecular interactions contributing to ACQ. PMID- 30025202 TI - Identification and biological evaluation of glycol diaryl ethers as novel anti cancer agents through structure-based optimization of crizotinib. AB - Crizotinib, a drug for anaplastic lymphoma kinase (ALK) positive and c-ros oncogene 1 receptor tyrosine kinase (ROS1) positive non-small cell lung cancer (NSCLC), was structurally optimized via a strategy of structure-based fragment replacing. Computational study showed it was beneficial for interaction of crizotinib and ALK to increase the distance between pyridyl ring and phenyl ring in crizotinib, and thus, a series of novel glycol diaryl ethers were synthesized. The in vitro anti-tumor activity of synthesized compounds was studied in NSCLC cell line H2228 and neurobalstoma cell line SH-SY5Y. Among the synthesized compounds, 9e exhibits stronger anti-cancer activity than crizotinib toward H2228 cell line with an IC50 value of 0.22 MUM. Molecular docking indicated that a longer chain between pyridyl ring and phenyl ring enabled molecule to have new interaction with a neighboring small hydrophobic pocket. PMID- 30025203 TI - Self-Assembly of Water-Soluble Platinum(II)-Based Metallacalixarenes and Tuning Their Conformational Interconversion via Synergistic Effects between Solvents and Anions. AB - The aqueous self-assembly of the flexible ligand L bis(1H-benz[d]imidazole-1 yl)methane and cis-coordinated PtII precursors [(en)Pt2+ , (tmeda)Pt2+ , en=ethylenediamine, tmeda=N,N,N',N'-tetramethylethylenediamine)] led to the formation of the metallacalixarenes with full alternative conformations (e.g., two novel water-soluble metallacalixarenes [M2 L2 ]4+ and [M3 L3 ]6+ with D2 and D3 symmetry, respectively). Their molecular structures were determined by single crystal X-ray analyses in solid state. The two metallacalixarenes present different cavity sizes and the [M3 L3 ]6+ cavity encapsulates one NO3 - . NOESY NMR revealed that the conformational interconversion between 1,3-alternate conformer in methanol and cone conformer in DMSO was tuned via the synergistic effect between solvent and anion. Guest encapsulation is also discussed. PMID- 30025204 TI - Revisiting the Vibrational and Optical Properties of P3HT: A Combined Experimental and Theoretical Study. AB - We demonstrate that DFT-based calculations can provide straightforward means to analyze the effect of aggregation on the optical properties of regioregular P3HT oligomers of different lengths (up to 20-mers) and of bioligomers of 8-mers in two different conformations. Our conclusions substantially differ from those obtained previously by applying the exciton model. Indeed, analysis of Huang-Rhys factors has evidenced that two vibrational modes, a collective mode and an effective mode, are combined in the vibronic structure of the absorption spectrum of oligothiophene. Computed spectra match perfectly their experimental counterparts provided we consider that the oligomer and at least the five lowest excited states of bioligomers behave as absorbers, and that both oligomer and bioligomer contribute to the emission spectra. Study of the nature of the Franck Condon excitation and optimization of the five lowest excited singlet states indicate that high (hot) excited states of the bioligomer may play an important role in the initiation of charge separation and highlight the importance to take into account the relaxation processes in the theoretical modeling of emission properties. PMID- 30025205 TI - Boosting the Heavy Atom Effect by Cavitand Encapsulation: Room Temperature Phosphorescence of Pyrene in the Presence of Oxygen. AB - A deep cavitand is used to encapsulate the aromatic molecule pyrene in its interior while also binding Tl+ ions with its terminal carboxylates. Steady-state and time-resolved spectroscopic experiments, along with quantum yield measurements, quantify the enhancements of intersystem crossing and room temperature phosphorescence due to cavitand encapsulation. These results are compared to those obtained for pyrene contained in sodium dodecyl sulfate micelles, which is the usual system used to generate room temperature phosphorescence. The combination of selective binding and strong Tl+ recognition by the cavitand enhances the intersystem crossing and decreases the phosphorescence radiative lifetime from ~30 to 0.23 s. The cavitand also decreases the rate of O2 quenching by a factor of 100. Together, these factors can boost the room temperature phosphorescence signal by several orders of magnitude, allowing it to be detected in water without O2 removal. Host:guest recognition provides a route to molecular-scale triplet emitters that can function under ambient conditions. PMID- 30025206 TI - Construction of Small-Sized, Robust, and Reduction-Responsive Polypeptide Micelles for High Loading and Targeted Delivery of Chemotherapeutics. AB - Polypeptide micelles, though having been proved to be an appealing nanoplatform for cancer chemotherapy, are met with issues like inefficient drug encapsulation, gradual drug release, and low tumor cell selectivity and uptake. Here, we report on cRGD-decorated, small-sized, robust, and reduction-responsive polytyrosine micelles (cRGD-rPTM) based on poly(ethylene glycol)- b-poly(l-tyrosine)-lipoic acid (PEG- b-PTyr-LA) conjugate for high loading and targeted delivery of doxorubicin (Dox). Notably, cRGD-rPTM exhibited efficient loading of Dox, giving cRGD-rPTM-Dox with a drug loading content (DLC) of 18.5 wt % and a small size of 45 nm at a theoretical DLC of 20 wt %. cRGD-rPTM-Dox displayed reduction triggered drug release, high selectivity and superior antiproliferative activity toward alphavbeta3 integrin positive MDA-MB-231 breast cancer cells (IC50 = 1.5 MUg/mL) to both nontargeted rPTM-Dox and clinical liposomal formulation (LP-Dox). cRGD-rPTM-Dox demonstrated a prolonged circulation time compared with the noncrosslinked cRGD-PTM-Dox control and significantly better accumulation in MDA MB-231 breast tumor xenografts than nontargeted rPTM-Dox. Moreover, cRGD-rPTM-Dox at 6 mg Dox equiv/kg could remarkably suppress growth of MDA-MB-231 human breast tumor without inducing obvious side effects, outperforming both rPTM-Dox and LP Dox. These reduction-responsive multifunctional polytyrosine micelles appear to be a viable and versatile nanoplatform for targeted chemotherapy. PMID- 30025207 TI - General Synthesis of Unsymmetrical 3,3'-(Aza)diindolylmethane Derivatives. AB - Diindolylmethane (DIM) and its derivatives have recently been in the focus of interest due to their significant biological activities, specifically in cancer prevention and therapy. Molecular targets of DIM have been identified, e.g., the immunostimulatory G protein-coupled receptor GPR84. However, most of the reported and investigated DIM derivatives are symmetrical because general methods for obtaining unsymmetrical DIMs have been lacking. To optimize the interaction of DIM derivatives with their protein targets, unsymmetrical substitution is required. In the present study we developed a new, mild and efficient access to unsymmetrically substituted 3,3'-DIMs by reaction of (3 indolylmethyl)trimethylammonium iodides with a wide range of substituted indole derivatives. 7-Azaindole also led to the 3,3'-connected DIM analogue, while 4- and 5-azaindoles reacted at the N1-nitrogen atom as confirmed by X-ray crystallography. The reactions were performed in water without the requirement of a catalyst or other additives. Wide substrate scope, operational simplicity, environmentally benign workup, and high yields are further advantages of the new method. The synthetic protocol proved to be suitable for upscaling to yield gram amounts for pharmacological studies. This procedure will allow the preparation of a broad range of novel, unsymmetrical DIM derivatives to exploit their potential as novel drugs. PMID- 30025208 TI - Binding Modes of a Glycopeptidomimetic Molecule on Abeta Protofibrils: Implication for Its Inhibition Mechanism. AB - We recently reported that a glycopeptidomimetic molecule significantly delays the fibrillization process of Abeta42 peptide involved in Alzheimer's disease. However, the binding mode of this compound, named 3beta, was not determined at the atomic scale, hindering our understanding of its mechanism of action and impeding structure-based design of new inhibitors. In the present study, we performed molecular docking calculations and molecular dynamics simulations to investigate the most probable structures of 3beta complexed with Abeta protofibrils. Our results show that 3beta preferentially binds to an area of the protofibril surface that coincides with the protofibril dimerization interface observed in the solid-state NMR structure 5KK3 from the PDB. Based on these observations, we propose a model of the inhibition mechanism of Abeta fibrillization by compound 3beta. PMID- 30025209 TI - Structural Analysis of the Bacterial Effector AvrA Identifies a Critical Helix Involved in Substrate Recognition. AB - Bacterial effector proteins are essential for the infection and proliferation of pathogenic bacteria through manipulation of host immune response pathways. AvrA is a Salmonella effector that belongs to the YopJ family of acetyltransferases, which suppresses c-JUN N-terminal kinase (JNK) signaling in mammals through acetylation of mitogen-activated receptor kinase kinases 4 and 7 (MKK4/7). Interestingly, there are two paralogues of AvrA that differ by only a single internal leucine residue, which when absent (AvrADeltaL140) abrogates the ability to suppress JNK signaling. Here, we present the first crystal structure of a bacterial effector from an animal pathogen, AvrADeltaL140, accompanied by a thorough biophysical characterization of both AvrA variants. The structure in complex with inositol hexaphosphate and coenzyme A reveals two closely associated domains consisting of a catalytic core that resembles the CE clan peptidases and a wedge-shaped regulatory region that mediates cofactor and substrate binding. The loss of the putative function of AvrADeltaL140 is due to its inability to interact with MKK4/7, which ultimately arises from an altered conformation of a critical helix adjacent to the active site that harbors L140. These results provide general insights into substrate recognition across the YopJ family of acetyltransferases. PMID- 30025210 TI - Designing inhaled protein therapeutics for topical lung delivery: what are the next steps? PMID- 30025211 TI - Reply to Rajchgot et al.: Combination Nintedanib and Pirfenidone for Treatment of Idiopathic Pulmonary Fibrosis. PMID- 30025212 TI - Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs. AB - INTRODUCTION: The major challenge of first pass metabolism in oral drug delivery can be surmounted by directing delivery toward intestinal lymphatic system (ILS). ILS circumvents the liver and transports drug directly into systemic circulation via thoracic duct. Lipid and polymeric nanoparticles are transported into ILS through lacteal and Peyer's patches. Moreover, surface modification of nanoparticles with ligand which is specific for Peyer's patches enhances the uptake of drugs into ILS. Bioavailability enhancement by lymphatic uptake is an advantageous approach adopted by scientists today. Therefore, it is important to understand clear insight of ILS in targeted drug delivery and challenges involved in it. Areas covered: Current review includes an overview of ILS, factors governing lymphatic transport of nanoparticles and absorption mechanism of lipid and polymeric nanoparticles into ILS. Various ligands used to target Peyer's patch and their conjugation strategies to nanoparticles are explained in detail. In vitro and in vivo models used to assess intestinal lymphatic transport of molecules are discussed further. Expert opinion: Although ILS offers a versatile pathway for nanotechnology based targeted drug delivery, extensive investigations on validation of the lymphatic transport models and on the strategies for gastric protection of targeted nanocarriers have to be perceived in for excellent performance of ILS in oral drug delivery. PMID- 30025213 TI - Combination Nintedanib and Pirfenidone for Treatment of Idiopathic Pulmonary Fibrosis. PMID- 30025214 TI - Abuse of immediate-release opioids and current approaches to reduce misuse, abuse, and diversion. AB - Deaths from opioid overdoses have increased dramatically over the past few years. Given that immediate-release (IR) opioids account for most of the U.S. market share, and that abusers generally prefer IR opioids over extended-release (ER) opioids, it is not surprising that rates of abuse are higher for IR than ER opioids. IR opioids are widely prescribed, often without consideration for risks of abuse, misuse, and diversion. Prescription opioid abuse and misuse often begins through oral administration and progresses into non-oral routes (e.g. snorting, injecting) as abusers gain more experience; non-oral routes carry heightened safety concerns. Current approaches used for reducing opioid abuse include U.S. Food and Drug Administration regulations, state legislation, insurance company policies, the use of multimodal analgesic therapy, patient risk assessment and monitoring, limiting access to opioids by reducing IR opioid prescription quantity and length, prescription drug monitoring programs, patient education on proper disposal of unused medication and risks of diversion, as well as abuse-deterrent formulations. Albeit, most abuse-deterrent formulations have focused on ways to prevent the circumvention of ER characteristics rather than placing obstacles to abuse of IR opioid formulations. Reducing opioid abuse requires the combined efforts of multiple stakeholders, including prescribing clinicians, patients, pharmacists, nurses, insurance companies, government agencies, and pharmaceutical companies. PMID- 30025216 TI - Silica nanoparticles on the oral delivery of insulin. AB - INTRODUCTION: When intravenous or subcutaneous administration of insulin, various side effects or possible risks have been reported. Oral administration of insulin has significant advantages of convenience, painless and mimetic endogenous insulin pathway, and thus it presents patients compliance, protects pancreatic beta cells and lessens adverse effects caused by long-term injection. This challenging oral delivery of insulin can be achieved by promising silica nanoparticles (SNs), especially mesoporous silica nanoparticles (MSNs), with controllable morphology and high loading efficiency. This review presents the synthesis and physiological behaviors of SNs such as in vivo and in vitro degradation, absorption, distribution, and excretion, as well as preparations of oral insulin based on SNs. As well, this review will provide insights for innovative oral delivery of SNs and insulin. Areas covered: Promising SNs and MSNs have gained interests for application in oral drug delivery of insulin. Expert opinion: After synthesis under proper conditions and methods, promising SNs with controllable structure and suitable stability can be synthesized. By improving permeability and penetration, achieving controlled release and adjusting physiological processes, functionalization on SNs by active groups, molecules, or polymers is necessary for oral delivery of insulin. PMID- 30025215 TI - MUC5B Promoter Polymorphism and Development of Acute Respiratory Distress Syndrome. PMID- 30025217 TI - Self-Perceived Poor/Fair Health, Frequent Mental Distress, and Health Insurance Status Among Working-Aged US Adults. AB - We examined associations of health insurance status with self-perceived poor/fair health and frequent mental distress (FMD) among working-aged US adults from 42 states and the District of Columbia using data from the 2014 Behavioral Risk Factor Surveillance System. After multiple-variable adjustment, compared with adequately insured adults, underinsured and never insured adults were 39% and 59% more likely to report poor/fair health, respectively, and 38% more likely to report FMD. Compared with working-aged adults with employer-based insurance, adults with Medicaid/Medicare or other public insurance coverage were 28% and 13% more likely to report poor/fair health, respectively, and 15% more likely to report FMD. Increasing insurance coverage and reducing cost barriers to care may improve general and mental health. PMID- 30025218 TI - HUD Housing Assistance and Levels of Physical Activity Among Low-Income Adults. AB - INTRODUCTION: Receipt of housing assistance from the US Department of Housing and Urban Development (HUD) is associated with improved health among adults and lower rates of unmet medical need among adults and young children. However, it is unclear whether HUD housing assistance is associated with healthier behaviors. The objective of our study was to assess whether participation in HUD housing assistance programs is associated with increased physical activity among low income adults. METHODS: In 2017, we pooled cross-sectional data from the 2004 2012 National Health Interview Survey (NHIS) linked to administrative records of HUD housing assistance participation. Our primary sample was low-income adults (aged >=18; <200% of federal poverty level). Using multivariate logistic regression, we calculated the odds of being physically active (>=150 min/week of moderate-intensity activity or equivalent combination of moderate- and vigorous intensity activity) among current HUD housing assistance residents compared with a control group of future residents (adults who would receive assistance within the next 2 years). In a secondary analyses, we examined neighborhood socioeconomic status as a modifier and conducted a subanalysis among nonsenior adults (aged <65). RESULTS: Among all low-income adults, the adjusted odds of being physically active were similar for current and future residents (odds ratio =1.17; 95% confidence interval, 0.95-1.46). Among nonseniors, current residents were more likely to be physically active than future residents (odds ratio = 1.47; 95% confidence interval, 1.10-1.97). Associations did not differ by neighborhood socioeconomic status. CONCLUSION: Receiving HUD housing assistance is associated with being physically active among nonsenior low-income adults. PMID- 30025219 TI - Localization of calreticulin and calcium ions in mycorrhizal roots of Medicago truncatula in response to aluminum stress. AB - Aluminum (Al) toxicity limits growth and symbiotic interactions of plants. Calcium plays essential roles in abiotic stresses and legume-Rhizobium symbiosis, but the sites and mechanism of Ca2+ mobilization during mycorrhizae have not been analyzed. In this study, the changes of cytoplasmic Ca2+ and calreticulin (CRT) in Medicago truncatula mycorrhizal (MR) and non-mycorrizal (NM) roots under short Al stress [50 MUM AlCl3 pH 4.3 for 3 h] were analyzed. Free Ca2+ ions were detected cytochemically by their reaction with potassium pyroantimonate and anti CRT antibody was used to locate this protein in Medicago roots by immunocytochemical methods. In MR and NM roots, Al induced accumulation of CRT and free Ca2+. Similar calcium and CRT distribution in the MR were found at the surface of fungal structures (arbuscules and intercellular hyphae), cell wall and in plasmodesmata, and in plant and fungal intracellular compartments. Additionally, degenerated arbuscules were associated with intense Ca2+ and CRT accumulation. In NM roots, Ca2+ and CRT epitopes were observed in the stele, near wall of cortex and endodermis. The present study provides new insight into Ca2+ storage and mobilization in mycorrhizae symbiosis. The colocalization of CRT and Ca2+ suggests that CRT is essential for calcium mobilization for normal mycorrhiza development and response to Al stress. PMID- 30025220 TI - Genome-wide sequence and expressional analysis of autophagy Gene family in bread wheat (Triticum aestivum L.). AB - Autophagy, a highly conserved intracellular degradation system, is regarded to be responsible for self-defense and protect cells from abiotic stress. Extensive studies have demonstrated that autophagy plays a crucial role in regulating plant growth and development as well as in response to diverse stresses. However, little is known about autophagy-associated genes (ATGs) in wheat, especially those involved in the regulatory network of stress processes. In this study, a total of 108 putative wheat ATGs (TaATG) were obtained based on a genome-wide search approach. Phylogenetic analysis classified them into 13 subfamilies, of which the TaAtg16 subfamily consisted of 29 members, ranking it the largest subfamily. The conserved motif compositions as well as their exon-intron structures were systematically analyzed and strongly supported the classification. The homoeologous genes tended to have similar gene features during wheat polyploidization. Furthermore, a total of 114 putative cis-elements were found, and those related to hormone, stress, and light responsiveness were abundantly presented in the promoter regions. Co-expression network analysis revealed that orthologous VAMP727 was the hub node of the whole network, and complex interactions were also found. Finally, the expression profiles of TaATGs among different tissues and under abiotic stresses were investigated to identify tissue-specific or stress-responsive candidates, and then 14 were validated by wet-lab analysis. Results showed that the TaAtg8 subfamily played a crucial role in tissue autophagy and stress defense, which could be considered as processes that are candidates for further functional study. This was the first study to comprehensively investigate the ATG family in wheat, which ultimately provided important clues for further functional analysis and also took a step toward uncovering the evolutionary mechanism of ATG genes in wheat and beyond. PMID- 30025221 TI - Autonomic nervous system depression at term in neurologically normal premature infants. AB - BACKGROUND: Premature infants are vulnerable to destructive brain injury and disturbed neurological development. Prematurity may alter maturation of the central autonomic nervous system (ANS). AIMS: To compare ANS function (using heart rate variability; HRV) between preterm infants with normal neuroimaging at term equivalent age and low-risk term controls. Study design, subjects. We performed a case-control study of preterm infants born <=28 weeks gestational age that had normal brain imaging and archived continuous EKG data at term equivalent age. We documented other factors thought to influence ANS maturation (e.g. infection, ventilation days, and postnatal steroids). Controls were low-risk term gestational age newborns from uncomplicated pregnancies/deliveries. We characterized HRV metrics using frequency-(Welch periodogram) and time-domain (detrended fluctuation) analyses. Sympathetic tone was characterized by alpha1, root mean square analysis (RMS1 and RMS2), low-frequency (LF) power, and normalized LF (nLF) and parasympathetic tone was characterized by high-frequency (HF) power and normalized HF (nHF). alpha2 characterized ultraslow changes in heart rate. We used ANCOVA to compare HRV metrics between groups. Outcome measures, results. HRV from 26 preterm infants were compared to 55 controls. Analyzed HRV data for preterm infants were recorded at median (range) gestational age of 39 (36-39) weeks and for controls at 39 (37-41) weeks gestational age. alpha1, RMS2, LF and HF were significantly higher in control infants and remained significant after controlling for infection, ventilator days, and postnatal steroids (P < .005). CONCLUSIONS: Autonomic maturation is impaired in a premature extrauterine environment. In the absence of destructive brain injury, our data suggest an important role for disturbed programming in this impaired autonomic development. PMID- 30025222 TI - Does antibiotic choice for the treatment of suspected late-onset sepsis in premature infants determine the risk of developing necrotising enterocolitis? A systematic review. AB - BACKGROUND: Necrotising enterocolitis (NEC) is a significant cause of infant morbidity and mortality, disproportionately affecting those of extreme prematurity and/or very low birth weight. A number of risk factors have been identified, including an association between the use of antibiotics, and the subsequent development of NEC. AIM: This review sought to address whether the choice of antibiotic(s) used to treat infants with suspected late-onset sepsis (LOS) influences the risk of developing NEC. METHODS: A systematic review was performed across Web of Knowledge, Cochrane Library, Ovid Medline, EMBASE and CINAHL databases, up to February 2018, assessing the primary outcome of NEC occurrence, as extracted directly from the published articles. Studies were included if they were randomised control trials (or featured adequate adjustment for confounders); included clear criteria for defining LOS/NEC; and assessed occurrence of NEC in premature infants treated for LOS with intravenous antibiotics. Studies were excluded if non-original, not exclusively featuring premature infants, or where treatment was given for early-onset sepsis only. FINDINGS: 2291 titles and abstracts were identified, of which one study (81 subjects) was suitable for analysis, following screening against eligibility criteria. This suggested a decreased risk of developing definite NEC following treatment with a vancomycin/aztreonam combination, versus a vancomycin/gentamicin regimen (OR = 0.08, 95%CI = 0.00-1.45). CONCLUSION: This systematic review identified one study where the occurrence of NEC was reported in the context of comparing different antibiotic regimens for late onset sepsis and highlights that the type of antibiotic used to treat LOS in preterm infants might be a determinant of the risk of developing NEC. Although it is known that different antibiotic combinations impact the enteric microbiome and that antibiotic exposure is a risk factor for NEC, there is a paucity of well-designed studies that look at the relationship between NEC risk and specific antibiotic exposures. PMID- 30025223 TI - Contact-independent suppressive activity of regulatory T cells is associated with telomerase inhibition, telomere shortening and target lymphocyte apoptosis. AB - Regulatory T cells (Tregs) play a fundamental role in the maintenance of immunological tolerance by suppressing effector target T, B and NK lymphocytes. Contact-dependent suppression mechanisms have been well-studied, though contact independent Treg activity is not fully understood. In the present study, we showed that human native Tregs, as well as induced ex vivo Tregs, can cause in vitro telomere-dependent senescence in target T, B and NK cells in a contact independent manner. The co-cultivation of target cells with Tregs separated through porous membranes induced alternative splicing of the telomerase catalytic subunit hTERT (human Telomerase Reverse Transcriptase), which suppressed telomerase activity. Induction of the hTERT splicing variant was associated with increased expression of the apoptotic endonuclease EndoG, a splicing regulator. Inhibited telomerase in target cells co-cultivated with Tregs for a long period of time led to a decrease in their telomere lengths, cell cycle arrest, conversion of the target cells to replicative senescence and apoptotic death. Induced Tregs showed the ability to up-regulate EndoG expression, TERT alternative splicing and telomerase inhibition in mouse T, B and NK cells after in vivo administration. The results of the present study describe a novel mechanism of contact-independent Treg cell suppression that induces telomerase inhibition through the EndoG-provoked alternative splicing of hTERT and converts cells to senescence and apoptosis phenotypes. PMID- 30025224 TI - Obesity influences white matter integrity in schizophrenia. AB - BACKGROUND: White matter (WM) alterations have been consistently described in patients with schizophrenia and correlated with the severity of psychotic symptoms and cognitive impairment. Obesity has been reported in over 40% of patients with schizophrenia and has been associated with cognitive deficits, cardiovascular diseases, metabolic alterations, and overall mortality. Moreover, studies among healthy subjects and subjects at risk for psychosis reported an influence of Body Mass Index (BMI) on structural connectivity. We therefore hypothesized that obesity and overweight could further disrupt WM integrity of patients affected by schizophrenia. METHODS: Eighty-eight schizophrenia patients were evaluated for BMI. We divided the sample in overweight/obese and normal weight groups. We then performed whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA). RESULTS: A significant difference between the two groups was observed: normal weight patients showed higher AD and a higher FA trend compared to obese patients in several fibers' tracts including longitudinal fasciculus, uncinate fasciculus, corona radiata, thalamic radiation, fronto occipital fasciculus, cingulum and corpus callosum. CONCLUSIONS: Elevated BMI might contribute to WM disruption of schizophrenia by hampering structural connectivity in critical cortico-limbic networks, known to play a crucial role in neurocognitive functioning, emotional processing and psychopathology whose dysfunction are prominent features of the disorder. PMID- 30025226 TI - Chemical characterization and relative toxicity assessment of disinfection byproduct mixtures in a large drinking water supply network. AB - In order to reduce the formation of disinfection by-products (DBPs) during potabilization of water it is necessary to explore the potential of the source water and the applied treatment to generate these chemicals. This is actually more challenging in large drinking water networks that use different source waters to satisfy drinking water demand. In this regard, this work investigated the formation of DBPs in water matrices that are commonly supplied to the city of Barcelona and its metropolitan area. The regulated trihalomethanes and haloacetic acids were the most abundant DBP classes in these waters, followed by haloacetamides and haloacetonitriles or trihalogenated acetaldehydes (THALs). On the contrary, the formation potential of iodo-DBPs was minor. Mixing of drinking water treatment plant finished waters with desalinated water decreased the overall DBP formation potential of the water but resulted in the increased formation of brominated DBPs after long chlorine contact time. The formation of most DBPs was enhanced at high water temperatures (except for Br-THALs) and increasing residence times. Potential cytotoxicity and genotoxicity of the DBP mixtures were mainly attributed to the presence of nitrogen-containing DBPs and HAAs. PMID- 30025225 TI - Tetrameric and polymeric silver complexes of the omeprazole scaffold; synthesis, structure, in vitro and in vivo antimicrobial activities and DNA interaction. AB - Two complexes [AgI(pmtbH)]4 (1) and {[Ag4(pmtbH)4(NO3)4.2X}n (2) (where pmtbH is 2-[(2-pyridinylmethyl)thio]-1H-benzimidazole and X is H2O or MeOH) were synthesised and structurally characterised. Complex 2 showed therapeutic potential against Candida albicans, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa but complex 1 did not show significant activity in vitro. Further in vivo studies using larvae of the insect Galleria mellonella indicated that complex 2 significantly stimulates the immune system and that pre-treatment with the complex offers appreciable protection against all three bacteria. Real time flow cytometry data support the observed antimicrobial profile of complex 2 and suggest the antimicrobial response may be linked to a form of bacterial programmed cell death (PCD). Complex 2 was found to interact with DNA in the bacterial and fungal cells but it did not cleave plasmid DNA isolated from the three bacteria. PMID- 30025227 TI - A multimodal rehabilitation program for patients with ICU acquired weakness improves ventilator weaning and discharge home. AB - PURPOSE: To compare the effects of adding a progressive multimodal rehabilitation program to usual care (MRP + UC) versus UC alone on 1) functional mobility, strength, endurance and 2) ventilator weaning and discharge status of patients with ICU-acquired weakness (ICUAW) receiving prolonged mechanical ventilation (PMV). METHODS: Randomized pilot trial of an individualized MRP + UC versus UC in middle-aged and older ICU survivors with ICUAW receiving PMV. Outcomes compare changes in strength, mobility, weaning success and discharge home from a long term acute care hospital (LTACH) between the groups. RESULTS: Eighteen males and 14 females (age 60.3 +/- 11.9 years) who received PMV for >=14 days were enrolled. Despite no significant differences between groups in the changes in handgrip, gait speed, short physical performance battery or 6-min walk distance after treatment, the MRP + UC group had greater weaning success (87% vs. 41%, p < 0.01), and more patients discharged home than UC (53 vs. 12%, p = 0.05). Post hoc analyses, combining patients based on successful weaning or discharge home, demonstrated significant improvements in strength, ambulation and mobility. CONCLUSION: The addition of an MRP that improves strength, physical function and mobility to usual physical therapy in LTACH patients with ICUAW is associated with greater weaning success and discharge home than UC alone. PMID- 30025228 TI - Off-Target and Tumor-Specific Accumulation of Monocytes, Macrophages and Myeloid Derived Suppressor Cells after Systemic Injection. AB - Solid tumors frequently coexist with a degree of local chronic inflammation. Recruited myeloid cells can therefore be considered as interesting vehicles for tumor-targeted delivery of therapeutic agents. Using in vivo imaging, the short term accumulation of systemically injected monocytes, macrophages and myeloid derived suppressor cells (MDSCs) was compared in mice bearing fat pad mammary carcinomas. Monocytes and macrophages demonstrated almost identical in vivo and ex vivo distribution patterns with maximal tumor-associated accumulation seen 48 hours after injection that remained stable over the 4-day follow-up period. However, a substantial accumulation of both cell types was also seen in the liver, spleen and lungs albeit decreasing over time in all three locations. The MDSCs exhibited a similar distribution pattern as the monocytes and macrophages, but demonstrated a better relative on-target fraction over time. Overall, our findings highlight off-target cell accumulation as a major obstacle in the use of myeloid cells as vehicles for therapeutic tumor-targeted agents and indicate that their short-term on-target accumulation is mainly of nonspecific nature. PMID- 30025230 TI - Clinical outcomes of adolescents and young adults with advanced solid tumours participating in phase I trials. AB - BACKGROUND: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. AIM: To study the outcome of AYA patients in phase I clinical trials. METHODS: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. RESULTS: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. CONCLUSION: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options. PMID- 30025229 TI - ETV7-Mediated DNAJC15 Repression Leads to Doxorubicin Resistance in Breast Cancer Cells. AB - Breast cancer treatment often includes Doxorubicin as adjuvant as well as neoadjuvant chemotherapy. Despite its cytotoxicity, cells can develop drug resistance to Doxorubicin. Uncovering pathways and mechanisms involved in drug resistance is an urgent and critical aim for breast cancer research oriented to improve treatment efficacy. Here we show that Doxorubicin and other chemotherapeutic drugs induce the expression of ETV7, a transcriptional repressor member of ETS family of transcription factors. The ETV7 expression led to DNAJC15 down-regulation, a co-chaperone protein whose low expression was previously associated with drug resistance in breast and ovarian cancer. There was a corresponding reduction in Doxorubicin sensitivity of MCF7 and MDA-MB-231 breast cancer cells. We identified the binding site for ETV7 within DNAJC15 promoter and we also found that DNA methylation may be a factor in ETV7-mediated DNAJC15 transcriptional repression. These findings of an inverse correlation between ETV7 and DNAJC15 expression in MCF7 cells in terms of Doxorubicin resistance, correlated well with treatment responses of breast cancer patients with recurrent disease, based on our analyses of reported genome-wide expression arrays. Moreover, we demonstrated that ETV7-mediated Doxorubicin-resistance involves increased Doxorubicin efflux via nuclear pumps, which could be rescued in part by DNAJC15 up-regulation. With this study, we propose a novel role for ETV7 in breast cancer, and we identify DNAJC15 as a new target gene responsible for ETV7 mediated Doxorubicin-resistance. A better understanding of the opposing impacts of Doxorubicin could improve the design of combinatorial adjuvant regimens with the aim of avoiding resistance and relapse. PMID- 30025231 TI - Uterine morcellation and survival in uterine sarcomas. AB - BACKGROUND: There is concern but no solid evidence that morcellation during laparoscopic or vaginal hysterectomy may cause abdominal spread and thereby impaired prognosis of incidental uterine sarcomas. OBJECTIVE: Our purpose was to compare survival among patients with uterine sarcomas who underwent hysterectomy with or without morcellation to test the hypothesis that morcellation impairs prognosis. STUDY DESIGN: We identified all women in Norway diagnosed with uterine sarcoma between 1953 and 2012 through national registries and retrieved data on surgical technique and morcellation by evaluation of patient files. Patients were categorised into abdominal, laparoscopic or vaginal hysterectomy with or without morcellation. Vaginal and laparoscopic hysterectomies were introduced in 1991; our main comparison is from 1991 to 2012. We compared age-adjusted disease specific survival of sarcoma patients treated with or without morcellation and calculated age-adjusted hazard ratios (HRs) and subdistribution HR (accounting for competing risk) with 95% confidence intervals (CIs). RESULTS: Among 1367 patients with uterine sarcoma between 1953 and 2012 in Norway, 653 were diagnosed after 1991, and 23 of these patients (3.5%) underwent morcellation. Uterine sarcoma prevalence was 3.6 per 1000 laparoscopic hysterectomies. Mean follow-up was 6.0 years in the morcellated group and 6.9 years in the non-morcellated group. The risk of dying from uterine sarcoma after morcellation was 1.5 per 1000 procedures. Sarcoma mortality was higher in the morcellated group than in the non morcellated group (age-adjusted HR 1.90, CI 1.05-3.44; multivariate HR, 2.50, 95% CI 0.57-10.9). Age-adjusted 10-year uterine sarcoma survival was 32.2% for women treated with morcellation compared with 57.2% for non-morcellated group (difference 25.5%; CI -55.7 to 18.1). All-cause 10-year survival was 32.2% in the morcellated group and 44.1% in the non-morcellated group (difference 11.9%; CI 40.9 to 32.7). CONCLUSION: Our results strengthen the evidence that morcellation during hysterectomy in patients with incidental uterine sarcoma may cause impaired survival. These results can guide shared decision-making in clinical practice. PMID- 30025232 TI - Structure and Development of the Auxospore in Ardissonea crystallina (C. Agardh) Grunow Demonstrates Another Way for a Centric to Look Like a Pennate. AB - Reproductive development in Ardissonea crystallina revealed a unique mode of enlargement involving a combination of novel and known structures. In light microscopy, auxospores of this elongated polar centric diatom were superficially similar to the auxospores of pennates. With SEM we found three different components in the auxospore wall. In the youngest, nearly spherical cell-stage, the wall consisted only of a delicate veil containing minute siliceous spherules. Incunabular elements developed underneath this layer. Second, a previously unknown form of specifically modified incunabular scales shaped the subsequent ellipsoidal-capsule auxospore stage. Third, there was a clear contribution of scales to the development of scaly transverse perizonial bands (or scaly bands, for brevity). Such bands, although noted by previous researchers, have not been fully appreciated for the evolutionary information they may convey: possibly common among polar centrics but not pennates. Finally, we propose maintaining the term transverse perizonium to refer to these bands in polar diatoms, but to introduce the differentiation of scaly bands described here from pinnate bands (currently known as typical of pennates). Further research into band types among polar centrics may provide new insights into the relationship between the groups within polar centrics that are currently unresolved by molecular methods. PMID- 30025233 TI - Pets enhance antidepressant pharmacotherapy effects in patients with treatment resistant major depressive disorder. AB - Treatment resistant major depressive disorder (TR-MDD) is a severe disease, with very low remission rates. The resistance to pharmacotherapy leads to the search of non-pharmacological alternative approaches. Animal therapy has been used in patients with psychiatric conditions and the results have been promising. However, there have been no studies in TR-MDD patients with pet adoption. This study assessed the impact of TR-MDD patients adopting a pet. Eighty patients were suggested to adopt a pet, and 33 accepted the challenge. Other 33 patients constituted the control group (did not accept the suggestion of pet adoption and did not already have a pet). All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline, 4, 8 and 12 weeks for depressive symptoms using HAMD17 and GAF. Results show that the pet group had an improvement in HAMD17 and GAF scores as well as higher response and remission rates compared to the control group, where no patient responded or remitted. Therefore, pets can be used as an effective adjuvant to pharmacotherapy with regular medical appointments. PMID- 30025234 TI - Factorial integrity and validation of the Eating Pathology Symptoms Inventory (EPSI). AB - The Eating Pathology Symptoms Inventory (EPSI) is a 45-item self-report measure of eating pathology designed to be sensitive in assessing symptoms among diverse populations of individuals with disordered eating. The current study represents the first external validation of the EPSI as well as the first to examine the factor structure in an outpatient eating disorder clinic sample. We conducted an exploratory factor analysis in three separate samples: an outpatient clinic sample (n = 284), a college sample (n = 296), and a community sample (n = 341) and compared the observed factor structures to the original 8-factor solution proposed by Forbush et al. (2013). We also investigated whether the subscales correlated with the Eating Disorder Examination Questionnaire (EDE-Q) and a clinical impairment measure among the outpatient clinic sample. Results suggested between 7 and 8 factors for each of the three samples. Our findings largely replicated those of the original EPSI development study, excepting some deviations in the Muscle Building, Cognitive Restraint, and Excessive Exercise subscales. However, confirmatory factor analysis and exploratory structural equation modeling produced poor model fit, which may be related to the item heterogeneity within many of the subscales. Finally, eating disorder attitudes and behaviors assessed by the EPSI were significantly correlated with the EDE-Q and with clinical impairment. Overall, our results highlight both strengths and limitations of the EPSI. Findings provide preliminary support for the use of the EPSI among research with diverse populations, and present several avenues for future research for enhancing clinical utility. PMID- 30025236 TI - Resting state fMRI reveals the altered synchronization of BOLD signals in essential tremor. AB - Essential tremor (ET) is one of the most common movement disorders in humans. Nevertheless, there remain several controversies surrounding ET, such as whether it is a disorder of abnormal neuronal oscillations within the tremor network. In this work, the resting-state fMRI data were collected from 17 ET patients and 17 age- and gender-matched healthy controls. First, using FOur-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) the abnormal synchronization of fMRI signals in ET patients were investigated. Then, global functional connectivity intensity (gFCI) and density (gFCD) were analyzed in the regions exhibiting significant FOCA differences. Compared with healthy controls, patients with ET showed the increased FOCA values found in the bilateral cuneus, the left lingual gyrus, the left paracentral lobule, the right middle temporal gyrus, the bilateral precentral gyrus, the right postcentral gyrus, the pallidum and putamen. Decreased FOCA values in ET patients were located in the frontal gyrus, the bilateral anterior cingulate and the medial dorsal nucleus of right thalamus. In ET patients, significant changes in gFCI and gFCD were located in the cuneus, the middle temporal gyrus and the middle frontal gyrus. Changes in gFCI were also found in the medial frontal gyrus and thalamus in addition to changes in gFCD in the precentral gyrus. Our results provided further evidence that ET might present with abnormal spontaneous activity in the tremor network, including motor-related cotex, basal ganglia and thalamus, as well as distributed non-motor areas. This work also demonstrated that FOCA and functional connectivity have the potential to provide important insight into the pathophysiological mechanism of ET. PMID- 30025235 TI - Toe dystonia in Parkinson's disease: Impact of subthalamic nucleus deep brain stimulation. AB - BACKGROUND: Off state toe dystonia (TD) is a symptom frequently encountered in Parkinson's disease (PD), but little is known about its evolution after subthalamic nucleus deep brain stimulation (STN-DBS). OBJECTIVE: To analyze the prevalence and the evolution of TD in PD patients candidate to STN-DBS. METHODS: Individual data of consecutive 130 PD patients who underwent STN-DBS between 2010 and 2015 were collected. RESULTS: Data were successfully collected in 95 patients. TD affect 45.3% of the patients in our cohort. TD was present in 32.7% of patients before surgery and was alleviated by STN-DBS in 48% of the cases. Motor improvement provided by STN-DBS, levodopa-equivalent treatment diminution after surgery, disease duration or age at the time of surgery were not predictive of TD evolution. A younger age at PD diagnosis was significantly associated with TD resolution. CONCLUSION: STN-DBS is partially efficient for TD but its evolution seems independent of significant predictive factors. PMID- 30025237 TI - The application of an integrated biogeochemical model to simulate dynamics of vegetation, hydrology and nutrients in soil and streamwater following a whole tree harvest of a northern hardwood forest. AB - Understanding the impacts of clear-cutting is critical to inform sustainable forest management associated with net primary productivity and nutrient availability over the long-term. Few studies have rigorously tested model simulations against field measurements which would provide more confidence in efforts to quantify logging impacts over the long-term. The biogeochemical model, PnET-BGC has been used to simulate forest production and stream chemistry at the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA. Previous versions of PnET-BGC could accurately simulate the longer-term biogeochemical response to harvesting, but were unable to reproduce the marked changes in stream NO3- immediately after clear-cutting which is an important impact of forest harvesting. Moreover, the dynamics of nutrients in major pools including mineralization and plant uptake were poorly predicted. In this study, the model was modified and parametrized allowing for a lower decomposition rate during the earlier years after the clear-cut and increased NH4+ plant uptake with the regrowth of new vegetation to adequately reproduce hydrology, aboveground forest biomass, and soil solution and stream water chemistry in response to a whole-tree harvest of a northern hardwood forest watershed (W5) at the HBEF. Modeled soil solution and stream water chemistry successfully captured the rapid recovery of leaching nutrients to pre-cut levels within four years after the treatment. The model simulated a substantial increase in aboveground net primary productivity (NPP) from around 36% to 97% of pre-cut aboveground values within years 2 to 4 of the cut, which closely reproduced the measured values. The projected accumulation of aboveground biomass 70 years following the harvest was almost 190 t ha-1, which is close to the pre-cut measured value. A first-order sensitivity analysis showed greater sensitivity of projections of the model outputs for the mature forest than the strongly aggrading forest. PMID- 30025238 TI - Hydro-biogeochemical processes and their implications for Ulva prolifera blooms and expansion in the world's largest green tide occurrence region (Yellow Sea, China). AB - The hydro-biogeochemical processes in the world's largest area of green tide occurrence, off the Jiangsu coast in the Yellow Sea, are investigated in the summer, and their implications for Ulva prolifera blooms are discussed. The results show that the offshore transport of coastal water and the inshore upwelling of offshore bottom water both occur off the Jiangsu coast, and the upwelling position is consistent with the 20- to 30-m isobath off the Subei Shoal. The upwelling results in nutrient supplementation off the shoal, where a rapid decrease in the suspended particulate matter content contributes to good light conditions. As a result, a high-value area of phytoplankton is formed within the 20- to 30-m isobath. Eutrophication in the shoal has provided nutrients for the frequent occurrence of Ulva prolifera in recent years, whereas the upwelling area off the shoal has served as a "service station" or "courier station" for floating Ulva prolifera and promoted the species' propagation. The propagation of Ulva prolifera in the upwelling area and its blooms within the Subei Shoal can have a spatially synergistic effect, leading to its large-scale development. Our findings reveal the mechanisms that trigger the world's largest green tides from the perspective of physical-biogeochemical interactions. PMID- 30025240 TI - Characterization and carcinogenic risk assessment of polycyclic aromatic and nitro-polycyclic aromatic hydrocarbons in exhaust emission from gasoline passenger cars using on-road measurements in Beijing, China. AB - The polycyclic aromatic hydrocarbon (PAH) and nitro-polycyclic aromatic hydrocarbon (NPAH) emissions from 16 gasoline passenger cars, encompassing five emission standards and two driving conditions, were tested using a portable emission measurement system (PEMS) in Beijing under on-road conditions. In total, 16 PAHs and 9 NPAHs were quantified in both the gaseous and particulate phases by high-performance liquid chromatography (HPLC). The results indicated that lower PAH and NPAH emissions were observed with improved emission standards, especially for China 3 to China 5 vehicles (P < 0.05). Higher emission factors (EFs) were detected on nonhighway roads than on highway roads due to incomplete combustion. Although most PAHs and NPAHs were in the gas-phase, the TEQBaP of the particulate phase PAHs was 4.2 times higher than that of the gas-phase PAHs, whereas the opposite pattern was observed for NPAHs. The TEQBaP EFs on nonhighway roads were 1.0-2.3 times higher than those on highway roads. The results of this study will be valuable for estimating the emissions and performing carcinogenic risk assessment of PAHs and NPAHs from urban gasoline passenger cars on roads. Formulating more stringent regulations and emission control technologies for PAHs and NPAHs is important. PMID- 30025239 TI - Nitrogen removal rates in a frigid high-altitude river estimated by measuring dissolved N2 and N2O. AB - Rivers are important sites of both nitrogen removal and emission of nitrous oxide (N2O), a powerful greenhouse gas. Previous measurements have focused on nitrogen rich temperate rivers, with cold, low-nitrogen river systems at high-altitude receiving less attention. Here, nitrogen removal rates were estimated by directly measuring dissolved N2 and N2O of the Yellow River in its source region of the Tibetan Plateau, a frigid high-altitude environment. We measured the dissolved N2 and N2O using N2:Ar ratio method and headspace equilibrium technique, respectively. Dissolved N2 in the river water ranged from 337 to 513 MUmol N2 L 1, and dissolved N2O ranged from 10.4 to 15.4 nmol N2O L-1. Excess dissolved N2 (?N2) ranged from -8.6 to 10.5 MUmol N2 L-1, while excess dissolved N2O (?N2O) ranged from 2.1 to 8.3 nmol N2O L-1; they were relatively low compared with most other rivers in the world. However, N2 removal fraction (?N2/DIN, average 21.6%) and EF5r values (N2O - N/NO3 - N, range 1.6 * 10-4-5.0 * 10-2) were comparable with many other rivers despite the high altitude for the Yellow River source region. Furthermore, the EF5r values increased with altitude. Estimated fluxes of N2 and N2O to the atmosphere from the river surface ranged from -67.5 to 93.5 mmol N m-2 d-1 and from 4.8 to 93.8 MUmol N m-2 d-1, respectively, and the nitrogen removal from rivers was estimated to be 1.87 * 107 kg N yr-1 for the Yellow River source region. This is the first report of nitrogen removal for a frigid high-altitude river; the results suggest that N removal and N2O emission from cold high-altitude rivers should be considered in the global nitrogen budget. PMID- 30025241 TI - Replacing calcium with ammonium counterion in lignosulfonates from paper mills affects their molecular properties and bioactivity. AB - Lignosulfonates are important by-products of the paper industry and may be transformed into different commodities. We studied the molecular properties of ammonium (LS-AM) and calcium Lignosulfonates (LS-C) and evaluated their bioactivity towards the early development of maize plantlets. The FT-IR, 13C NMR and 1H-13C-HSQC-NMR spectra showed that the two lignosulfonates varied in hydroxyl, sulfonate and phenolic content, while DOSY-NMR spectroscopy suggested a similar diffusivity. High Performance Size Exclusion Chromatography (HPSEC) was used to simulate the effects of root-exuded acids and describe the conformational dynamics of both LS substrates in acidic aqueous solutions. This technique showed that LS-C was stabilized by the divalent Ca2+ counterion, thus showing a greater conformational stability than LS-AM, whose components could not be as efficiently aggregated by the monovalent NH4+ counter-ion. The plant bioassays revealed that LS-AM enhanced the elongation of the root system, whereas LS-C significantly increased both total and shoot plant weights. We concluded that the lignosulfonate bioactivity on plant growth depended on the applied concentrations, their molecular properties and conformational stability. PMID- 30025242 TI - Iodine distribution and cycling in a beech (Fagus sylvatica) temperate forest. AB - Radioiodine is of health concerns in case of nuclear events. Possible pathways and rates of flow are essential information for risk assessment. Forest ecosystems could influence the global cycle of long-lived radioiodine isotope (129I) with transfer processes similar to stable isotope (127I). Understanding iodine cycling in forest involves study of the ecosystem as a whole. In this context, we determined the 127I contents and distribution in soil, tree compartments and atmospheric inputs during a three years in situ monitoring of a temperate beech forest stand. The iodine cycle was first characterized in terms of stocks by measuring its concentrations in: tree, litterfall, humus, soil, rainfall, throughfall, stemflow and soil solutions. Main annual fluxes (requirement, uptake and internal transfers) and forest input-output budget were also estimated using conceptual model calculations. Our findings show that: (i) soil is the main I reservoir accounting for about 99.9% of ecosystem total stock; (ii) iodine uptake by tree represents a minor fraction of the available pool in soil (<0.2%); (iii) iodine allocation between tree compartments involves low immobilization in wood and restricted location in the roots; (iv) translocation of excess iodine towards senescing foliage appears as an elimination process for trees, and (v) litterfall is a major pathway in the I biological cycling. In our soil conditions, the input - output budget shows that the ecosystem behaves as a potential source of I for groundwater. PMID- 30025243 TI - Concentrations of vanadium in urine and seminal plasma in relation to semen quality parameters, spermatozoa DNA damage and serum hormone levels. AB - Widespread human exposure to vanadium has been well documented. Vanadium exposure was reported to induce male reproductive toxicity in toxicological studies, yet human epidemiologic studies are lacking. Here we determined the associations between environmental exposure to vanadium and semen quality, spermatozoa DNA damage and serum reproductive hormones. Concentrations of vanadium in seminal plasma and repeated urine samples were determined among 764 men recruited from a reproductive medicine centre. Associations of vanadium concentrations with semen quality parameters (n = 764), DNA integrity measures (n = 404) and serum reproductive hormones (n = 381) were assessed by logistic or linear regression models with adjustment for potential confounders. Significant positive dose response relationships were observed between vanadium concentrations in seminal plasma and tail length and serum estradiol, as well as odds ratios for a below reference-value sperm concentration; whereas inverse relationships between seminal plasma vanadium with total testosterone (T) and free T (all p values for trends <0.05) were observed. These relationships were maintained after adjusting for seminal plasma concentrations of other elements (i.e., arsenic, cadmium, copper, selenium, or tin). No significant associations was revealed between urinary vanadium concentrations and semen quality, spermatozoa DNA integrity and reproductive hormones. Our findings suggested that elevated vanadium exposure may be adversely associated with male reproductive health, and that seminal plasma vanadium may be a more direct exposure biomarker for the male reproductive system than urinary vanadium. PMID- 30025244 TI - Performance prediction of an aerobic granular SBR using modular multilayer artificial neural networks. AB - Aerobic granulation is a complex process that, while proven to be more effective than conventional treatment methods, has been a challenge to control and maintain stable operation. This work presents a static data-driven model to predict the key performance indicators of the aerobic granulation process. The first sub model receives influent characteristics and granular sludge properties. These predicted parameters then become the input for the second sub-model, predicting the effluent characteristics. The model was developed with a dataset of 2600 observations and evaluated with an unseen dataset of 286 observations. The prediction R2 and RMSE were >99% and <5% respectively for all predicted parameters. The results of this paper show the effectiveness of data-driven models for simulating the complex aerobic granulation process, providing a great tool to help in predicting the behaviour, and anticipating failures in aerobic granular reactors. PMID- 30025245 TI - Engineering innervated secretory epithelial organoids by magnetic three dimensional bioprinting for stimulating epithelial growth in salivary glands. AB - Current saliva-based stimulation therapies for radiotherapy-induced xerostomia are not fully effective due to the presence of damaged secretory epithelia and nerves in the salivary gland (SG). Hence, three-dimensional bio-engineered organoids are essential to regenerate the damaged SG. Herein, a recently validated three-dimensional (3D) biofabrication system, the magnetic 3D bioprinting (M3DB), is tested to generate innervated secretory epithelial organoids from a neural crest-derived mesenchymal stem cell, the human dental pulp stem cell (hDPSC). Cells are tagged with magnetic nanoparticles (MNP) and spatially arranged with magnet dots to generate 3D spheroids. Next, a SG epithelial differentiation stage was completed with fibroblast growth factor 10 (4-400 ng/ml) to recapitulate SG epithelial morphogenesis and neurogenesis. The SG organoids were then transplanted into ex vivo model to evaluate their epithelial growth and innervation. M3DB-formed spheroids exhibited both high cell viability rate (>90%) and stable ATP intracellular activity compared to MNP-free spheroids. After differentiation, spheroids expressed SG epithelial compartments including secretory epithelial, ductal, myoepithelial, and neuronal. Fabricated organoids also produced salivary alpha-amylase upon FGF10 stimulation, and intracellular calcium mobilization and trans-epithelial resistance was elicited upon neurostimulation with different neurotransmitters. After transplantation, the SG-like organoids significantly stimulated epithelial and neuronal growth in damaged SG. It is the first time bio-functional innervated SG-like organoids are bioprinted. Thus, this is an important step towards SG regeneration and the treatment of radiotherapy-induced xerostomia. PMID- 30025246 TI - Designed trimer-mimetic TNF superfamily ligands on self-assembling nanocages. AB - Presentation of an endogenous bioactive ligand in its native form is a key factor in controlling and determining its bioactivity, stability, and therapeutic efficacy. In this study, we developed a novel strategy for presenting trimeric ligands on nanocages by designing, optimizing and testing based on the rational design, high-resolution structural analysis and agonistic activity assays in vitro and in vivo. We successfully designed a nanocage that presents the TNF superfamily member, TRAIL (TNF-related apoptosis-inducing ligand) in its native like trimeric structure. The native structure of TRAIL complexes was mimicked on the resulting trimeric TRAIL-presenting nanocages (TTPNs) by inserting sufficient spacing, determined from three-dimensional structural models, to provide optimal access to the corresponding receptors. The efficacy of TTPNs as an anti-tumor agent was confirmed in preclinical studies, which revealed up to 330-fold increased affinity, 62.5-fold enhanced apoptotic activity, and improved pharmacokinetic characteristics and stability compared with the monomeric form of TRAIL (mTRAIL). In this latter context, TTPNs exhibited greater than 90% stability over 1 mo, whereas ~50% of mTRAIL aggregated within 2 d. Consistent with their enhanced stability and ultra-high affinity for the TRAIL receptor, TTPNs effectively induced apoptosis of tumor cells in vivo, leading to effective inhibition of tumor growth. Although TRAIL was used here as a proof-of-concept, all members of the TNF superfamily share the TNF homology domain (THD) and have similar distances between ecto-domain C-termini. Thus, other TNF superfamily ligands could be genetically substituted for the TRAIL ligand on the surface of this biomimetic delivery platform. PMID- 30025247 TI - Receptor mediated transcytosis in biological barrier: The influence of receptor character and their ligand density on the transmembrane pathway of active targeting nanocarriers. AB - Active-targeting nanocarriers can significantly improve the transcytosis of poorly water-soluble or bio-macromolecular drugs across biological barrier. However, reasons for the improvement are not understood enough, which hampered the reasonable design of active targeting nanocarriers. To illustrate how different factors influence the transport of active-targeting nanocarriers, we established ligand-decorated micelles targeting different receptors to study how the decorations influence the transcytosis of the micelles by comparing the endocytosis, transport pathway and exocytosis process. Three different kinds of receptors, Neonatal Fc receptor (FcRn), transferrin receptor (TfR) and alphavbeta3 integrin were selected. They presented three different transport pathways, mainly mediating transcytosis, recycling pathway and cell binding, respectively. Their corresponding ligand FcBP, 7pep and c(RGDfK) decorated micelles with different ligand densities were prepared first. Then the effects of receptor and ligand density on the transcytosis across biological barrier were investigated. The results showed that the uptake rate of active micelles was higher than passive micelles and an optimum ligand density with most endocytosis appeared in all functional micelles. Transport pathway study showed 7pep decorated micelles were transferred into apical recycling endosome (ARE) and exocytosed to apical plasma membrane in a ligand depended way. c(RGDfK) decorated micelles were transferred through common recycling endosome (CRE) and Golgi complex to basolateral plasma membrane instead of ARE. While FcBP decorated micelles took both the recycling pathway and transcytosis through CRE, but not Golgi complex. Proper ligand density, not the higher the better, led the most uptake. Also the apical to basolateral transcytosis ratio may not be in accordance with the uptake. Among all the itineraries, transcytosis through CRE is the best itinerary for transcytosis. So, in the design of active targeting nanocarriers to overcome biological barrier, receptor character should be considered priorly, and then ligand density should be optimized. PMID- 30025249 TI - Mannitol-fermenting methicillin-resistant staphylococci (MRS) in pig abattoirs in Cameroon and South Africa: A serious food safety threat. AB - Food animals can be reservoirs of methicillin-resistant staphylococci (MRS) and are involved in their zoonotic transmission through the food chain. In Africa, there is a dearth of information about the food safety issues associated with their dissemination in the farm-to-plate continuum. This study sought to determine and compare the carriage, antimicrobial resistance profiles and clonal relatedness of circulating MRS strains among pigs and exposed workers in Cameroon and South Africa. A total of 288 nasal and rectal pooled samples collected from 432 pigs as well as nasal and hand swabs from 82 humans were cultured on mannitol salt agar supplemented with 6 mg/l cefoxitin. Presumptive MRS were screened for methicillin resistance using the cefoxitin disc test and confirmed with the VITEK 2 system. Selected isolates underwent genomic fingerprinting via REP-PCR. Univariate and multivariate logistic regression analyses were performed to identify risk factors for MRS carriage in humans from a questionnaire survey among slaughterhouse workers. Overall, 75% and 70% of nasal and rectal pooled samples were respectively positive for MRS. The MRS prevalence in all pooled pig samples from Cameroon was higher than that of South Africa. MRS prevalence of carriage (nasal and hand) was higher in Cameroonian exposed workers compared to those from South Africa, with high statistical significance. Nasal MRS colonization was highly statistically associated with hand MRS (31.58% vs 86.21%; p = 0.000; OR = 13.54; 95% CI 3.99-45.95; p = 0.015). Recent antibiotic use, previous hospitalization, occupation of relatives, years in the employment and contact with poultry were the main risk factors identified in the emergence and spread of MRS. MRS are emerging as serious foodborne pathogens and present a food safety threat. There is an urgent need to implement stringent and effective prevention and containment measures to curb antibiotic resistance in the farm-to plate continuum in Cameroon and South Africa. PMID- 30025248 TI - Comparative proteomic analysis of Escherichia coli O157:H7 following ohmic and water bath heating by capillary-HPLC-MS/MS. AB - Escherichia coli O157:H7 is an important food-borne pathogenic microorganism that has been used as a model organism for studying microbial inactivation effects and inactivation mechanism in various sterilization technologies. The objective of this study was to investigate the effects of high voltage short time ohmic- (HVST), low voltage long time ohmic- (LVLT), and water bath- (WB) heating on inactivation and proteome changes of E. coli O157:H7 cells at the same endpoint temperature of 72 degrees C, and to analyze whether a non-thermal death effect existed in ohmic heating. The inactivation effect of E. coli cells after HVST was comparable to WB, and the largest inactivation was observed after LVLT. There was lower intracellular protein content detected in LVLT and HVST samples than those of WB (P < 0.05). Quantitative proteomic profiles using capillary-HPLC-MS/MS technology identified 2626 proteins, among them, a total of 142 (62 up-regulated and 80 down-regulated), 129 (37 up-regulated and 92 down-regulated), and 61 (20 up-regulated and 41 down-regulated) differential proteins were obtained by comparisons of HVST vs. CT (control), LVLT vs. CT, and WB vs. CT samples, respectively, and revealing a strongest cell response to HVST followed by LVLT and WB. Compared with WB samples, more protein changes in HVST and LVLT samples were mainly attributed to the leakage of intracellular proteins due to the damage of cell membrane by current of ohmic heating. Bioinformatics analysis indicated that the differential proteins were mainly involved in transcription, translation, cell wall and membrane biogenesis, amino acid, carbohydrate, and lipid metabolism. KEGG enrichment analysis indicated that the ribosome, terpenoid backbone biosynthesis, glycerophospholipid metabolism, ABC transporters, and folate biosynthesis were significantly enriched. Overall, the application of both HVST and LVLT treatments had the potential to inactivate E. coli cells, especially HVST with a shorter heating time, and the results in this study presented an important step toward understanding the response of E. coli cells to ohmic heating on proteome level. PMID- 30025250 TI - The population-based incidence and mortality of biliary tract cancer in Sweden. AB - BACKGROUND: The incidence trends of biliary tract cancer need to be established. This study investigated the incidence and mortality of biliary tract cancer in Sweden in 1970-2010. METHODS: Sex-specific biliary tract cancer incidence and mortality rates were evaluated using data from the Swedish Cancer Register, Patient Register and Causes of Death Register. Case registration was separate for each register. Gallbladder cancer and cancers of the extra-hepatic bile ducts were analyzed separately. Standardized incidence rates were calculated and joinpoint regression was used to calculate annual percent changes (APC) with 95% Confidence Intervals (CIs). RESULTS: The incidence of non-gallbladder extra hepatic cancers assessed from the Cancer Register decreased in men and women from the mid 1980's (APC: -4.0, 95% CI -5.3 - -2.7 and APC -6.3, 95% CI -7.7 - -4.8, respectively), whereas the mortality of non-gallbladder extra-hepatic cancers rather increased until 1990 (APC: 2.1, 95% CI 1.4-2.8 and APC 2.7, 95% CI 1.3 4.1, in men and women respectively). Notably, the mortality rate was greater than the incidence rate as assessed from the Cancer Register from the early 1990's and onwards. The incidence of non-gallbladder extra-hepatic cancers derived from the Patient Register also increased over time. Gallbladder cancer incidence and mortality rates generally decreased. However, incidence rates assessed from the Patient Register decreased to a lesser extent. CONCLUSIONS: The incidence of gallbladder cancer seems to have decreased over the past decades in Sweden. The incidence trends for extra-hepatic tumors other than gallbladder cancer may however be obscured by under-reporting. PMID- 30025251 TI - Incidence of childhood cancer in Costa Rica, 2000-2014: An international perspective. AB - BACKGROUND: Estimating childhood cancer incidence globally is hampered by a lack of reliable data from low- and middle-income countries. Costa Rica is one of the few middle-income countries (MIC) with a long-term high quality nationwide population-based cancer registry. METHODS: Data on incident cancers in children aged under 15 years reported to the Costa Rica National Cancer Registry between 2000 and 2014 were analyzed by diagnostic group, age, sex, and geographical region and compared with incidence data for Hispanic and Non-Hispanic White (NHW) children in California, USA. RESULTS: During the 15-year period, 2396 cases of childhood cancer were reported in Costa Rica, resulting in an overall age standardized incidence rate (ASR) of 140/million. Most frequent cancer types were leukemias (40.5%), malignant central nervous system (CNS) tumors (13.9%), and lymphomas (12.7%). The observed ASR of lymphoid leukemia (46.9/million) ranked high globally. Low rates were found for most solid tumors including malignant CNS tumors, sympathetic nervous system tumors, and soft tissue sarcomas. There was almost no change in incidence rates over time, while geographical variations were observed within Costa Rica. The overall cancer rate in Costa Rica was lower compared to NHW (176.1/million) and Hispanic (161.7/million) children in California. CONCLUSION: Based on the longstanding registration system, the childhood cancer incidence rates were similar to those observed in other Latin American countries. While a degree of under-ascertainment of cases cannot be excluded, the markedly high leukemia rates, in particular of the lymphoid sub type deserves further study in this population. PMID- 30025253 TI - Posttraumatic stress disorder and positive memories: Clinical considerations. AB - Encoding and retrieval difficulties, and avoidance of both traumatic and positive memories, are associated with posttraumatic stress disorder (PTSD) symptoms. However, most PTSD research and clinical work has solely examined the role of traumatic memories in the maintenance/resolution of PTSD symptoms. This review provides a comprehensive discussion of the literature on positive memories and PTSD. First, we review theories and evidence on the relations between trauma, PTSD, and memory processes (particularly positive memories). Next, we propose a conceptual model that integrates evidence from experimental and positive/memory based intervention research and highlights hypothesized mechanisms underlying the potential effectiveness of targeting positive memories in PTSD interventions. Specifically, we discuss how targeting positive memories could (1) increase positive affect and reduce negative affect, (2) correct negative cognitions, (3) increase specificity of retrieving autobiographical memories, and (4) be effectively integrated/sequenced with and enhance the effects of trauma-focused interventions. Lastly, we suggest clinical research avenues for investigating the relations between positive memories and PTSD, to possibly alter the current PTSD intervention paradigm focused only on traumatic memories. Overall, our proposed model drawing from experimental and intervention research, and outlining potential effects of targeting positive memories to reduce PTSD severity, needs further empirical investigation. PMID- 30025252 TI - MK-2206, an allosteric inhibitor of AKT, stimulates LDLR expression and LDL uptake: A potential hypocholesterolemic agent. AB - BACKGROUND AND AIMS: Induction of low-density lipoprotein receptor (LDLR) plays a significant role in reduction of plasma LDL-cholesterol (LDL-C) levels. Therefore, strategies that enhance the protein level of LDLR provide an attractive therapeutic target for the treatment of hypercholesterolemia. With this aim in mind, we concentrated our effort on studying the role of AKT kinase in regulation of LDLR levels and proceeded to examine the effect of MK-2206, an allosteric and highly selective AKT inhibitor, on LDLR expression. METHODS: Cultured human hepatoma cells were used to examine the effect of MK-2206 on the proteolytic processing of sterol regulatory element-binding protein-2 (SREBP-2), the expression of LDLR and cellular internalization of LDL. We also examined the effect of MK-2206 on LDLR levels in primary human hepatocytes. RESULTS: MK-2206 induced the proteolytic processing of SREBP-2, upregulated LDLR expression and stimulated LDL uptake. In contrast to statins, induction of LDLR levels by MK 2206 did not rely on 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition. As a result, cotreatment of cells with MK-2206 and mevastatin potentiated the impact of mevastatin on LDLR. Importantly, MK-2206 stimulated the expression of LDLR by primary human hepatocytes. CONCLUSIONS: MK-2206 is a novel LDLR-inducing agent that, either alone or in combination with statins, exerts a stimulating effect on cellular LDL uptake. PMID- 30025254 TI - Mental imagery in dentistry: Phenomenology and role in dental anxiety. AB - Dental anxiety is a prevalent problem with marked psychological, physical and public health implications. Based on cognitive theory and evidence, we hypothesized that vivid, sensory image-based cognitions play a role in dental anxiety. A quantitative online survey (N = 306) and qualitative semi-structured interviews (N = 18) found that vivid sensory images were common irrespective of dental anxiety levels, but that their content, associated distress and responses varied. Participants reporting higher anxiety experienced intense and intrusive fear-provoking dental imagery focusing on unpleasant sensations, which were associated with the intrusive recollection of negative past experiences and avoidance of dentistry. Participants with lower anxiety ratings, reported images that were less distressing and centered around reassuring aspects and positive appointment outcomes, potentially acting as protective factors against dental anxiety and facilitating appointment attendance. The inclusion of components aimed at reducing intrusive memories and dental imagery rescripting may help improve interventions for dental anxiety. PMID- 30025255 TI - Adaptive treatment strategies for children and adolescents with Obsessive Compulsive Disorder: A sequential multiple assignment randomized trial. AB - OBJECTIVE: This sequential multiple assignment randomized trial (SMART) tested the effect of beginning treatment of childhood OCD with fluoxetine (FLX) or group cognitive-behavioral therapy (GCBT) accounting for treatment failures over time. METHODS: A two-stage, 28-week SMART was conducted with 83 children and adolescents with OCD. Participants were randomly allocated to GCBT or FLX for 14 weeks. Responders to the initial treatment remained in the same regimen for additional 14 weeks. Non-responders, defined by less than 50% reduction in baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, were re randomized to either switch to or add the other treatment. Assessments were performed at baseline, 7, 14, 21, and 28 weeks. RESULTS: Among the 43 children randomized to FLX who completed the first stage, 15 (41.7%) responded to treatment and 21 non-responders were randomized to switch to (N = 9) or add GCBT (N = 12). Among the 40 children randomized to GCBT who completed the first stage, 18 (51.4%) responded to treatment and 17 non-responders were randomized to switch to (N = 9) or add FLX (N = 8). Primary analysis showed that significant improvement occurred in children initially treated with either FLX or GCBT. Each time point was statistically significant, showing a linear trend of symptom reduction. Effect sizes were large within (0.76-0.78) and small between (-0.05) groups. CONCLUSIONS: Fluoxetine and GCBT are similarly effective initial treatments for childhood OCD considering treatment failures over time. Consequently, provision of treatment for childhood OCD could be tailored according to the availability of local resources. PMID- 30025256 TI - Social orienting predicts implicit false belief understanding in preschoolers. AB - According to the social motivation theory, orienting toward social elements of the environment should be related to sociocognitive abilities, such as theory of mind (ToM), in both typically developing children and children with autism spectrum disorder. The objective of the current study was to assess whether social orienting skills predict ToM abilities in preschoolers by using two social orienting tasks (biological motion and face preference) and an implicit false belief task. A total of 38 children, aged 2-4 years, participated in this study. As expected, participants showed a social preference on both tasks measuring social orienting. More importantly, children's performance on the face preference task predicted their performance on the false belief task, providing the first evidence for a link between social motivation and ToM in preschoolers. PMID- 30025257 TI - Promoting children's learning and transfer across informal science, technology, engineering, and mathematics learning experiences. AB - This study investigated ways to support young children's science, technology, engineering, and mathematics (STEM) learning and transfer of knowledge across informal learning experiences in a museum. Participants were 64 4- to 8-year-old children (Mage = 6.55 years, SD = 1.44) and their parents. Families were observed working together to solve one engineering problem, and then immediately afterward children worked on their own to solve a second engineering problem. At the outset of the problem-solving activities, families were randomly assigned to receive engineering instructions, transfer instructions, both engineering and transfer instructions, or no instructions. Families who received engineering instructions either alone or in combination with the transfer instructions-demonstrated greater understanding and use of the engineering principle of bracing compared with those who received only transfer instructions. Moreover, older children who received both engineering and transfer instructions were more successful when working on their own to solve a perceptually different engineering problem compared with older children who received only one set of instructions or no instructions. Implications of the work for developmental and learning science research and informal education practice are discussed. PMID- 30025258 TI - Modulating the masters: chemical tools to dissect CBP and p300 function. AB - Dysregulation of transcription is found in nearly every human disease, and as a result there has been intense interest in developing new therapeutics that target regulators of transcription. CREB binding protein (CBP) and its paralogue p300 are attractive targets due to their function as 'master coactivators'. Although inhibitors of several CBP/p300 domains have been identified, the selectivity of many of these compounds has remained underexplored. Here, we review recent successes in the development of chemical tools targeting several CBP/p300 domains with selectivity acceptable for use as chemical probes. Additionally, we highlight recent studies which have used these probes to expand our understanding of interdomain interactions and differential coactivator usage. PMID- 30025259 TI - Biodegradation of di-butyl phthalate (DBP) by a novel endophytic bacterium Bacillus subtilis and its bioaugmentation for removing DBP from vegetation slurry. AB - Di-butyl phthalate (DBP) is a widely used plasticizer, recalcitrant and hazardous organic compound with high detection frequencies and concentrations in water and soil that pose a great threat to human health. A novel endphytic bacterium strain N-1 capable of efficiently degrading DBP and utilizing it as sole carbon source was isolated from Ageratum conyzoides. This bacterium was identified as Bacillus subtilis based on its morphological characteristics and 16S rDNA sequence analysis. Under the optimal culture conditions (pH 7.0, 30 degrees C), degradation percentage of DBP (12.5-100 mg/L) was up to 95% within five days, and its biodegradation half-life was less than 7.23 h. Degradation percentage of high DBP concentration (200 mg/L) was relatively lower (89%) with half-life of 56.8 h. DBP was degraded by Bacillus subtilis N-1 into mono-butyl phthalate and phthalic acid as evidenced by GC-MS analysis. Bioaugmentation of Youngia japonica plant slurry with strain N-1 greatly accelerated DBP dissipation with 97.5% removal percentage (higher by 47% than non-inoculation). The results highlighted that strain N-1 has great potential for bioremediation by plant-endophyte partnerships and for lowering PAE accumulation in crops. PMID- 30025260 TI - Life cycle assessment and water footprint evaluation of crude steel production: A case study in China. AB - China, as the world's largest crude steel producer, is suffering from water scarcity and pollution. However, only a few systematic analyses on the environmental burdens and improvements of China's crude steel production have been conducted. Therefore, it is important for research to be done how China's steel industry can be improved in environment management. To help decision-makers understand this, a life cycle water footprint analysis including gray and blue water was performed based on the methodology prescribed in the ISO 14046 standard. A life cycle assessment was also conducted to improve the environmental performance of the steel industry. Results of these assessments revealed that gray water footprint, which is mainly derived from aquatic eutrophication, carcinogens, and non-carcinogens, is higher than blue water footprint. Optimizing indirect processes, including iron ore mining, magnesium oxide production, transportation, and electricity generation, played dominant roles in the reduction of gray water footprint. Furthermore, COD, Cr (VI), phosphate, BOD5, Hg, As, nitrogen oxides, particulates, and sulfur dioxide were the key substances for environmental improvements. The underestimation of direct water footprint showed the importance and urgency of implementing scientific and adequate monitoring indicators. Meanwhile, the environmental burden can be reduced by adopting a reasonable location of the steel industry on the basis of regional water resources and actual transportation status, improving the efficiency of raw material consumption, and optimizing the power structure. PMID- 30025261 TI - Carbon-nitrogen removal in a structured-bed reactor (SBRRIA) treating sewage: Operating conditions and metabolic perspectives. AB - The present study evaluated the efficiency of a structured-bed reactor subjected to recirculation and intermittent aeration (SBRRIA) to promote nitrogen and carbon removal from domestic sewage. The intermittent aeration and the recycling rate of 3 keeps the desired mixing degree inside the SBRRIA. Four different operational conditions were tested by varying the hydraulic retention time (HRT) from 12 to 8 h and aerated and non-aerated periods (A/NA) from 2 h/1 h and 3 h/1 h. At the THD of 8 h and A/NA of 2 h/1 h there was a decrease in the nitrification process (77.5%) due to the increase of organic matter availability, affecting the total-N removal performance. However, by increasing the aerated period from 2 h to 3 h, the nitrification efficiency rose to 91.1%, reaching a total-N removal efficiency of 79%. The system reached a maximum total-N loading removed of 0.117 kgN.m-3.d-1 by applying an HRT of 8 h and an intermittent aeration cycle of 3 h, aerated and 1 h non-aerated. The simultaneous nitrification and denitrification (SND) process was related to a complex interplay among microorganisms affiliated mostly to Acidovorax sp., Comamonas sp., Dechloromonas sp., Hydrogenophaga sp., Mycobacterium sp., Rhodobacter sp., and Steroidobacter sp. PMID- 30025262 TI - Neuroanatomical characterization of perineuronal net components in the human cochlear nucleus and superior olivary complex. AB - The human auditory brainstem, especially the cochlear nucleus (CN) and the superior olivary complex (SOC) are characterized by a high density of neurons associated with perineuronal nets (PNs). PNs build a specific form of extracellular matrix surrounding the neuronal somata, proximal dendrites and axon initial segments. They restrict synaptic plasticity and control high-frequency synaptic activity, a prominent characteristic of neurons of the auditory brainstem. The distribution of PNs within the auditory brainstem has been investigated in a number of mammalian species. However, much less is known regarding PNs in the human auditory brainstem. The present study aimed at the immunohistochemical identification of PNs in the cochlear nucleus (CN) and superior olivary complex (SOC) in the human brainstem. We focused on the complex nature and molecular variability of PNs in the CN and SOC by using specific antibodies against the main PN components (aggrecan, brevican, neurocan and hyaluronan and proteoglycan link protein 1). Virtually all subnuclei within the ventral CN and SOC were found to be associated with PNs. Direct comparison between gerbil and human yielded similar fine structure of PNs and confirmed the typical tight interdigitation of PNs with synaptic terminals in both species. Noticeably, an elaborate combination of immunohistochemical labelings clearly supports the still debated existence of the medial nucleus of trapezoid body (MNTB) in the human brain. In conclusion, the present study demonstrates that PNs form a prominent extracellular structure on CN and SOC neurons in the human brain, potentially stabilizing synaptic contacts, which is in agreement with many other mammalian species. PMID- 30025263 TI - Extending the Rational Method for assessing and developing sustainable urban drainage systems. AB - Onsite runoff control is considered an important part of sustainable urban drainage schemes, but estimating the maximum runoff flow rate from a catchment with onsite runoff controls remains controversial. Runoff controls complicate the issue by dividing the catchment into several subcatchments that feed into individual runoff controls, which dynamically regulate the catchment imperviousness. Rational Method (RM) is the most-employed technique to determine maximum flow rates for designing urban drainage infrastructures, but it cannot handle such conditions. Nonetheless, it has advantages over alternative methods in terms of principle from the urban drainage design perspective. This work develops Rational Method Prime (RMP) that follows the basic principle of RM but instead recalculates catchment variables by taking into account runoff control effects and evaluates runoff control efficiencies by using two indices. RMP has three merits: (1) providing an integrated response of the whole catchment with runoff controls; (2) interpreting runoff control effects by plotting runoff flow rate-rainfall duration curves; (3) connecting the design of runoff controls and storm sewers that are based on different design principles and rainfall statistics. Case study results showed that runoff controls reduced peak flow rates by 5.83-91.6%, corresponding to reduction factors for return period of maximum flow rate from 0.04 to 0.76. Indeed, the original RM is based on four assumptions, which also cause its weakness, and there have been current methods to address 3 of them. RMP contributes to addressing the last assumption (i.e. constant catchment imperviousness), which finally allowing the evolution from RM 1.0 to 2.0. PMID- 30025264 TI - Comparing the mechanisms of ZVI and Fe3O4 for promoting waste-activated sludge digestion. AB - Anaerobic digestion is one of the most promising technologies to stabilize waste activated sludge (WAS) and recover energy. However, the low efficiency of anaerobic digestion of WAS constrains its application. Supplementing zero valent iron (ZVI) and Fe3O4 in digesters could improve the sludge digestion performance, which has recently been extensively studied. However, the mechanisms behind this improvement remain unclear. In this study, the effects of ZVI and Fe3O4 on the four stages of anaerobic digestion of WAS (solubilization, hydrolysis, acidification and methanogenesis) were investigated. Results showed that ZVI had only a slight effect on the solubilization, hydrolysis and acidification processes, while ZVI significantly promoted the hydrogenotrophic methanogenesis, increasing methane production by 70%. Further investigation indicated that coenzyme F420 activity in the ZVI added reactor was 32.3% higher than in the blank. These results indicate that ZVI promoted anaerobic digestion of WAS through promoting hydrogenotrophic methanogenesis. On the other hand, Fe3O4 obviously promoted the solubilization, hydrolysis and acidification of sludge. Vast Fe2+ was detected in the aqueous phase of the Fe3O4 digester which was a result of dissimilatory iron reduction that can utilize complicated matter as a substrate. This was in agreement with the acceleration of the solubilization, hydrolysis and acidification of the sludge. However, the acetoclastic and hydrogenotrophic methanogenesis with Fe3O4 decreased by 27% and 22% compared to the Fe3O4-free digester, respectively. Further study indicated that Fe3O4 competed with CH3?S?CoM for electrons and thus inhibited the methanogenesis process. PMID- 30025265 TI - Complete dechlorination and mineralization of pentachlorophenol (PCP) in a hydrogen-based membrane biofilm reactor (MBfR). AB - Complete biodegradation and mineralization of pentachlorophenol (PCP), a priority pollutant in water, is challenging for water treatment. In this study, a hydrogen (H2)-based membrane biofilm reactor (MBfR) was applied to treat PCP, along with nitrate and sulfate, which often coexist in contaminated groundwater. Throughout 120-days of continuous operation, almost 100% of up to 10 mg/L PCP was removed with minimal intermediate accumulation and in parallel with complete denitrification of 20 mg-N/L nitrate. PCP initially was reductively dechlorinated to phenol, which was then mineralized to CO2 through pathways that began with aerobic activation via monooxygenation by Xanthobacter and anaerobic activation via carboxylation by Azospira and Thauera. Sulfur cycling induced by SO42- reduction affected the microbial community: The dominant bacteria became sulfate reducers Desulfomicrobium, sulfur-oxidizers Sulfuritalea and Flavobacterium. This study provides insights and a promising technology for bioremediation of water contaminated with PCP, nitrate, and sulfate. PMID- 30025266 TI - High-silica zeolites for adsorption of organic micro-pollutants in water treatment: A review. AB - High-silica zeolites have been found to be effective adsorbents for the removal of organic micro-pollutants (OMPs) from impaired water, including various pharmaceuticals, personal care products, industrial chemicals, etc. In this review, the properties and fundamentals of high-silica zeolites are summarised. Recent research on mechanisms and efficiencies of OMP adsorption by high-silica zeolites are reviewed to assess the potential opportunities and challenges for the application of high-silica zeolites for OMP adsorption in water treatment. It is concluded that the adsorption capacities are well-related to surface hydrophobicity/hydrophilicity and structural features, e.g. micropore volume and pore size of high-silica zeolites, as well as the properties of OMPs. By using high-silica zeolites, the undesired competitive adsorption of background organic matter (BOM) in natural water could potentially be prevented. In addition, oxidative regeneration could be applied on-site to restore the adsorption capacity of zeolites for OMPs and prevent the toxic residues from re-entering the environment. PMID- 30025267 TI - In situ measurement of perfluoroalkyl substances in aquatic systems using diffusive gradients in thin-films technique. AB - To better understand the environmental impact of ubiquitous perfluoroalkyl substances (PFASs) in waters, reliable and robust measurement techniques are needed. As one of the most widely used passive sampling approaches, diffusive gradients in thin-films (DGT) is not only easy to handle but also provides time weighted analyte concentrations. Based on DGT with XAD18 as a binding agent, we developed a new methodology to measure two frequently detected PFASs in surface waters and wastewaters, i.e. perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Their diffusion coefficients in the diffusive gel, measured using an independent diffusion cell, were 4.37 * 10-6 and 5.08 * 10-6 cm2 s-1 at 25 degrees C, respectively. DGT had a high capacity for PFOA and PFOS at 196 and 246 MUg per gel disk, suggesting the DGT sampler was suitable for deployment of several weeks. Time-integrated concentrations of PFOA and PFOS in a natural lake and river, and a municipal wastewater treatment plant effluent using DGT samplers deployed in situ for 12-33 d were comparable to those measured by a solid-phase extraction method coupled with high-frequency grab sampling. This study demonstrates that DGT is an effective tool for in situ monitoring of PFASs in natural waters and wastewaters. PMID- 30025268 TI - French validation of the modified-falls efficacy scale (M-FES Fr). AB - INTRODUCTION: Among the tools assessing fall related self-efficacy, the Modified Falls Efficacy Scale (M-FES) seems to be a comprehensive and sensitive scale. However, no validated French version exists to this day. OBJECTIVE: This study aims to translate the M-FES and validate this French translation (M-FES Fr). METHOD: The validation steps used to translate and validate the M-FES Fr were i) forward - backward translation, ii) examination of the internal structure and reliability, iii) evaluation of the convergent validity. In this study, 310 French-speaking older adults (56 geriatric patients and 254 community-dwelling older adults) completed the M-FES Fr. Among the community-dwelling older adults, 67 fallers and 70 non-fallers were also asked to complete questionnaires related to variables such as health, fear of falling, and physical activity levels. RESULTS: A two-factor solution (indoor vs outdoor activities) was suggested, which accounted for 68.1% of the total variance. Reliability estimates for both factors were good (Cronbach alpha > 0.94, ICC > .93). Significant differences between geriatric patients and community-dwelling older adults and between fallers and non-fallers were highlighted. Furthermore, the M-FES Fr scores were significantly linked to various risk factors for falling. CONCLUSION: The M-FES Fr has psychometric properties which are similar to those found in the original version, including reliability and validity. This questionnaire will enable French-speaking researchers and health professionals to work with the same concepts as those used in other languages. Notably, the M-FES Fr could be used in the development and evaluation of intervention strategies in the prevention of falls. PMID- 30025269 TI - Impact of education and electronic decision support tool on the practice of heparin-induced thrombocytopenia testing: An experience of a teaching community hospital. PMID- 30025270 TI - On engagement with anthropology: A critical evaluation of skeletal and developmental abnormalities in the Atacama preterm baby and issues of forensic and bioarchaeological research ethics. Response to Bhattacharya et al. "Whole genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia" in Genome Research, 2018, 28: 423-431. Doi: 10.1101/gr.223693.117. AB - Here we evaluate Bhattacharya et al.'s (2018) recent paper "Whole-genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia" published in Genome Research. In this short report, we examine the hypothesis that the so-called "Atacama skeleton" has skeletal abnormalities indicative of dysplasia, critique the validity of the interpretations of disease based on genomic analyses, and comment on the ethics of research on this partially mummified human foetus. The current paper acts as a case study of the importance of using an anthropological approach for aDNA research on human remains. A critical evaluation of the ethically controversial paper by Bhattacharya et al. highlights how an understanding of skeletal biological processes, including normal and abnormal growth and development, taphonomic processes, environmental context, and close attention to ethical issues of dealing with human remains, is vital to scientific interpretations. To this end, close collaboration with palaeopathologists and local archaeologists through appropriate peer-reviewed journals will add to the rigour of scientific interpretation and circumvent misinterpretation. PMID- 30025271 TI - Learning to activate logic rules for textual reasoning. AB - Most current textual reasoning models cannotlearn human-like reasoning process, and thus lack interpretability and logical accuracy. To help address this issue, we propose a novel reasoning model which learns to activate logic rules explicitly via deep reinforcement learning. It takes the form of Memory Networks but features a special memory that stores relational tuples, mimicking the "Image Schema" in human cognitive activities. We redefine textual reasoning as a sequential decision-making process modifying or retrieving from the memory, where logic rules serve as state-transition functions. Activating logic rules for reasoning involves two problems: variable binding and relation activating, and this is a first step to solve them jointly. Our model achieves an average error rate of 0.7% on bAbI-20, a widely-used synthetic reasoning benchmark, using less than 1k training samples and no supporting facts. PMID- 30025272 TI - Effect of inhibitory spike-timing-dependent plasticity on fast sparsely synchronized rhythms in a small-world neuronal network. AB - We consider the Watts-Strogatz small-world network (SWN) consisting of inhibitory fast spiking Izhikevich interneurons. This inhibitory neuronal population has adaptive dynamic synaptic strengths governed by the inhibitory spike-timing dependent plasticity (iSTDP). In previous works without iSTDP, fast sparsely synchronized rhythms, associated with diverse cognitive functions, were found to appear in a range of large noise intensities for fixed strong synaptic inhibition strengths. Here, we investigate the effect of iSTDP on fast sparse synchronization (FSS) by varying the noise intensity D. We employ an asymmetric anti-Hebbian time window for the iSTDP update rule [which is in contrast to the Hebbian time window for the excitatory STDP (eSTDP)]. Depending on values of D, population-averaged values of saturated synaptic inhibition strengths are potentiated [long-term potentiation (LTP)] or depressed [long-term depression (LTD)] in comparison with the initial mean value, and dispersions from the mean values of LTP/LTD are much increased when compared with the initial dispersion, independently of D. In most cases of LTD where the effect of mean LTD is dominant in comparison with the effect of dispersion, good synchronization (with higher spiking measure) is found to get better via LTD, while bad synchronization (with lower spiking measure) is found to get worse via LTP. This kind of Matthew effect in inhibitory synaptic plasticity is in contrast to that in excitatory synaptic plasticity where good (bad) synchronization gets better (worse) via LTP (LTD). Emergences of LTD and LTP of synaptic inhibition strengths are intensively investigated via a microscopic method based on the distributions of time delays between the pre- and the post-synaptic spike times. Furthermore, we also investigate the effects of network architecture on FSS by changing the rewiring probability p of the SWN in the presence of iSTDP. PMID- 30025273 TI - Treatment of the breast cancer by using low frequency electromagnetic fields and Mn(II) complex of a Schiff base derived from the pyridoxal. AB - The breast cancer is the most common type of cancer in women. In this project, the breast cancer was transplanted in vivo with the TUBO cells. Then, the cancerous mice were treated by radiation of low frequency electromagnetic fields and injection of the Mn(II) complex of the N,N'-dipyridoxyl(1,2-diaminobenzene) Schiff base. Three different concentrations of the Mn(II) complex were used. Cytotoxicity and morphological alterations caused by the Mn(II) complex in the TUBO breast cancer cell line have been evaluated. Apoptotic properties of the Mn(II) complex was studied using the flow cytometry. The Mn(II) complex has a cytotoxic effect on cancer cells. Also, both of the Mn(II) complex and low frequency electromagnetic field induced apoptosis, which was confirmed by flow cytometry. Both of them result in considerable changes in the treated tissues such as decrease of the tumor mass, induction of apoptosis and decrease in number of the blood vessels. PMID- 30025274 TI - Global analysis of metastatic breast cancer policy gaps and advocacy efforts across the patient journey. AB - Metastatic breast cancer (mBC) is an area with high unmet need across the world. Despite significant progress to meet patient need, current breast cancer (BC) policies fail to recognize the unique challenges of patients who are further along the cancer patient journey. This analysis aims to understand BC/mBC policy development at a global level and identify opportunities for further development. A comprehensive analysis of National Cancer Control Plans (NCCPs) policies and programs was conducted across 16 countries, which represent a diverse range of healthcare systems, economies and geographic regions. Examples of promising practices, implemented or initiated by civil society, are provided to demonstrate successful methods to address the identified policy gaps. The analysis finds that disparities in BC policy development exist across and within countries. Progress in BC policy is fragmented and skewed towards the early part of the patient journey e.g. awareness and stakeholder education, with key gaps remaining in diagnosis and patient identification. In addition, access to innovative mBC treatments, ongoing support and palliative care remain a challenge, while care coordination is limited due to inefficient referrals. Although government and policymaker action is fundamental, collaboration between different stakeholders is imperative to address unmet needs of BC/mBC patients alike. Policy initiatives and promising practices that demonstrate successful multi-stakeholder engagement can be replicated or used to inform further advocacy and policy development with the aim to address patient unmet needs. PMID- 30025275 TI - Correlation between crestal alveolar bone loss with intracanal bacteria and apical lesion area in necrotic teeth. AB - OBJECTIVE: This study aimed to analyze the correlation between crestal alveolar bone loss with the presence of some bacterial species in root canals and the apical lesion area of necrotic teeth. DESIGN: Data from 20 patients with diagnosis of pulp necrosis and acute apical abscesses, without active periodontal diseases, were evaluated. Patients with history of antibiotic usage three months prior to the study, with exposed pulp cavity, and with probing depth >3 mm were not included. The root size, the distance between the bone crest to the tooth apex in the mesial and distal surfaces, and the apical lesion area were measured from standard periapical radiographies by a calibrated examiner. Root canal samples were collected using sterilized paper points. In multirooted teeth, the largest root canal was sampled. Culture, microbial isolation and identification by phenotypic methods were performed. Spearman correlation and exact Fischer test were calculated between higher/lower existing bone crests, according to the median and the presence of specific bacteria. RESULTS: No statistically significant differences were found between occurrence of pathogenic bacteria, such as Porphyromonas gingivalis, Porphyromonas endodontalis, and Prevotella intermedia, and groups with higher/lower degree of bone loss (p > 0.05). A negative significant correlation was found between Parvimonas micra and periodontal bone loss (p = 0.02). Additionally, no statistically significant association was found between crestal bone loss and the apical lesion area. CONCLUSIONS: It was concluded that, in patients without active periodontitis, the presence of pathogenic bacteria in the root canal was not correlated with periodontal bone loss. PMID- 30025276 TI - Expediting assessments of database performance for streams of respiratory parameters. AB - A new methodology is proposed to compare database performance for streams of patient respiratory data from patients in an intensive care unit. New metrics are proposed through which databases may be compared both for this and similar streaming applications in the domain of the Internet of Things. Studies are reported using simulated patient data for four freely available databases. The statistical technique of non-parametric bootstrapping is used to minimise the total running time of the tests. We report mean values and bias corrected and accelerated confidence intervals for each metric and use these to compare the databases. We find that, among the four databases tested, ScaleDB is an optimum database technology when handling between 200 and 800 patients in this application, while PostgreSQL performs best outside of this range. Comparing the non-parametric bootstrapping method to a complete set of tests shows that the two approaches give results differing by a few percent. PMID- 30025277 TI - Systematic review and meta-analysis of observational studies to understand the prevalence of restless legs syndrome in multiple sclerosis: an update. AB - OBJECTIVE: Multiple sclerosis (MS) is related to the demyelination of intracranial nerves at multiple sites, while restless legs syndrome (RLS) appears to be caused by dysfunction of the dopaminergic system. Since RLS prevalence is higher among MS patients than in the general population, we carried out an updated meta-analysis to understand whether the two diseases might be associated. METHOD: Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases were searched for observational and case-controlled studies of RLS prevalence in MS. Eligible studies were meta analyzed using Stata 12.0. RESULTS: Pooled RLS prevalence among MS patients of various ethnicities was 26%, and prevalence was lower in Asia (20%) than outside Asia (27%). Prevalence was higher among cross-sectional studies (30%) than among case-control studies (23%). RLS prevalence was higher among female than male MS patients (26% vs. 17%), and it was higher among MS patients than among healthy controls (OR 3.96, 95%CI 3.29-4.77, p < 0.001). CONCLUSION: Our meta-analysis updates the most recent meta-analysis in 2013 and provides perhaps the first reliable pooled estimate of RLS prevalence in MS. The available evidence strongly suggests that RLS risk is higher among MS patients than healthy controls. PMID- 30025278 TI - Outcomes and mutational analysis of patients with lower-risk non-del5q myelodysplastic syndrome treated with antithymocyte globulin with or without ciclosporine A. AB - Immunosuppressive treatment is a disease-modifying therapy for lower-risk myelodysplastic syndromes (MDS). However, IST is relatively rarely used and long term outcomes of patients are seldom reported. We retrospectively studied outcomes of 20 patients with lower-risk non del 5q MDS with transfusion dependency, with horse or rabbit antithymocyte globulin +/- ciclosporine A, and frontline eltrombopag in two of them. IPSS-R was low, intermediate and high in 30%, 55% and 10% of the patients, respectively. Fifty-five percent of the patients had hypocellular bone marrow (BM). Baseline mutations were detected in 31.5% of the patients and were more frequent in patients with normo/hypercellular MDS than in patients with hypocellular MDS. Transfusion independence rate for both red blood cells (RBC) and platelets was achieved in 45% of patients. RBC transfusion duration <=6 months, B-cell counts >0.2 G/L and, marginally, BM blasts <=2% were associated with higher transfusion independence rate. Age and cellularity did not influence the response rate. Median transfusion independence duration was 53 months. Cumulative incidence of progression to a more aggressive myeloid disease was 0 in patients without baseline mutations and 33% in patients with baseline mutations (P = .008). Median progression-free and overall survival after treatment onset and median overall survival after loss of transfusion independence were 45.5 months, 68 months and not reached, respectively. In conclusion, antithymocyte globulin +/- ciclosporine A results in durable responses in MDS, irrespective of age, in patients with lower-risk disease without B-cell lymphopenia and treated early in the course of the disease. PMID- 30025279 TI - Revising flow cytometric mini-panel for diagnosing low-grade myelodysplastic syndromes: Introducing a parameter quantifying CD33 expression on CD34+ cells. AB - Diagnosis of myelodysplastic syndromes (MDS) is not straightforward when objective data, such as blast excess and abnormal cytogenetics, are lacking. Expert laboratories use flow cytometry (FCM) to help diagnose MDS. However, most of FCM protocols for MDS are complex, requiring a high level of expertise and high cost. We have reported a FCM mini-panel consisting of four FCM parameters (so-called Ogata score), which is simple to conduct and inexpensive. In this paper, to refine this mini-panel, we have introduced a new FCM parameter, which quantifies CD33 expression on CD34+ cells (called Granulocyte/CD34 cell CD33 ratio). Bone marrow cells from MDS without blast excess (low-grade MDS) and controls were stained with CD34, CD45, and CD33 and analyzed for five parameters ("Granulocyte/CD34 cell CD33 ratio" plus four parameters in the Ogata score). By a multivariate logistic regression model, only three parameters, including "Granulocyte/CD34 cell CD33 ratio" had statistically significant power for diagnosing low-grade MDS. Based on the results, we constructed a new scoring system, which showed approximately 50% sensitivity and more than 95% specificity in diagnosing low-grade MDS. Our revised mini-panel is suitable for screening samples suspected for MDS and provides a basis for further improvement in diagnostic FCM protocols for MDS. PMID- 30025280 TI - Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms. AB - BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing. METHODS: A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug. FINDINGS: Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively. INTERPRETATIONS: LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a >=50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score. PMID- 30025281 TI - Resolving the matrilineal relationship of seven Late Bronze Age individuals from Stillfried, Austria. AB - In 1976 human remains of seven individuals were discovered in a storage pit located within the Late Bronze Age (9th century B.C.) settlement Stillfried an der March, Austria. In contrast to the common funeral rite of cremation typical for the Urnfield culture (1300-800 B.C.) the individuals' skeletal remains were found outstandingly preserved (Figure S1). As a result, the burial was subject to various investigations, including two conflicting genealogical pedigree reconstructions, one of which was favoured by later geological fingerprinting. We performed mitochondrial (mt)DNA testing in order to genetically characterize the remains and shed light into the matrilineal relationship of the seven individuals that were earlier anthropologically identified as three adults (two women and a man) and four subadults (one female and three males). MtDNA was analysed using Primer Extension Capture and Massively Parallel Sequencing. The results were by and large in conflict with both pedigree models but confirmed some of the details that were elaborated in previous studies. Whereas both pedigree models suggested that all children were related to one or both females, mtDNA analyses revealed that only one subadult male resulted in the same mitotype as one adult female. All other children yielded different mitotypes indicating that they were maternally unrelated to the two females and between each other. PMID- 30025282 TI - Psychosocial determinants of depression in the community of the elderly with cardiovascular disease. AB - The co-morbidity of cardiovascular disease (CVD) and depression is quite frequent in old people, and some potential biological and behavioural mechanisms linking them have been reported. Yet the impact of psychosocial factors on depression in the elderly with CVD remains unclear. This study aimed to analyze the psychosocial determinants of depression in the elderly with CVD. Using the Geriatric Mental Status-Automated Geriatric Examination for Computer Assisted Taxonomy, a community-based household survey was performed in 2,199 elderly people from the Anhui cohort third-wave survey from 2007 to 2009 and an extended study in Hubei from 2010 to 2011. Multiple logistic regression analyses were employed to assess the influence of psychosocial factors on depression. Among them, the prevalence of depression was 4.77%. Three factors were associated with depression in elderly in the community: self-assessed physical health status, anything else severely upsetting and unpleasantness with relatives, friends, or neighbors. In particular, associations of psychosocial factors with depression were more evident in individuals with CVD. This study confirms several psychosocial determinants of depression and the impact of CVD on the associations among the elderly, which provides some clues for interventional strategies of late-life depression. PMID- 30025284 TI - The prevalence of diagnosed obsessive compulsive disorder and associated comorbidities: A population-based Canadian study. AB - The objective of this study was to provide epidemiological data regarding obsessive compulsive disorder (OCD) in Canada, and examine related conditions, childhood experiences and healthcare utilization. A Statistics Canada population based health survey was utilized (N = 25,097). The prevalence of diagnosed OCD in Canada was 0.93% (95% CI 0.75-1.11). People with OCD were younger and more likely to have lower incomes. They were more likely to have mood disorders including depression and bipolar disorder (both diagnosed conditions and by screening), and generalized anxiety disorder. The diagnosis of OCD was also associated with alcohol dependence and substance abuse and dependence. Negative childhood experiences were more common in people with OCD, with 72.33%(95% CI 62.25% 82.41%) of people with OCD having experienced some form of childhood maltreatment. Healthcare utilization was more frequent in people with OCD, but they were also more likely to desire help but feel as if they did not receive it. The higher proportion of people with OCD reporting not receiving the care they needed may reveal a crucial gap in treatment and available resources. PMID- 30025283 TI - Internet addiction in Tibetan and Han Chinese middle school students: prevalence, demographics and quality of life. AB - Internet addiction (IA) is common amongst young people, but no data on IA are available in Tibetan middle school students in China. This study compared the prevalence of IA between Tibetan and Han Chinese middle school students, and examined its association with quality of life. The study was conducted in two middle schools in the Tibetan area of Qinghai province and two Han Chinese middle schools in Anhui province, China. Internet addiction, depressive symptoms and quality of life were measured using standardized instruments. Totally, 1,385 students completed the assessments. The overall prevalence of IA was 14.1%; 15.9% in Tibetan students and 12.0% in Han students. After controlling for the covariates, the prevalence of IA was significantly higher in Tibetan students than in Han students (OR = 3.5, p < 0.001). More severe depressive symptoms, religious beliefs and male gender were positively associated with IA, while good family relationship was negatively associated with IA. Internet addiction was also associated with significantly lower QOL in physical, psychological and environmental domains. Internet addiction appears to be common in Chinese middle school students, particularly amongst Tibetan Chinese students. Considering its negative impact on quality of life, appropriate educational programs and preventive measures for IA should be urgently developed. PMID- 30025285 TI - Loneliness and depression symptoms among the elderly in nursing homes: A moderated mediation model of resilience and social support. AB - Loneliness has been identified as a risk factor for depressive symptoms. Resilience and social support have been regarded as underlying protective factors. Little is known about the complex relations among these factors in the nursing home elderly. This study aimed to assess the prevalence of depressive symptoms, explore whether resilience mediated the association between loneliness and depressive symptoms, and investigate whether social support moderated the indirect or direct effect of mediation model. A total of 323 nursing home elderly were recruited in Jinan City, China. Loneliness, resilience, social support and depressive symptoms were measured. Results shown the association between loneliness and depressive symptoms was partially mediated by resilience. Besides, the indirect effect of the mediation model was moderated by social support. When the level of social support was higher, the indirect effect of loneliness on depressive symptoms through resilience was weaker. The incidence of depressive symptoms among the nursing home elderly could not be neglected. The findings suggest that interventions, such as improving resilience and social support, may help break the link between loneliness and depressive symptoms among the elderly in nursing homes. PMID- 30025287 TI - Sleep, low self-control, and deviance: Direct and indirect links across immigrant groups and socioeconomic strata. AB - Sleep functioning is concurrently and longitudinally associated with norm violating behaviors; however, the specific correlates contributing to these links remain unknown. Moreover, despite known mean-level differences in sleep functioning across immigrant and non-immigrant youth as well as socioeconomic strata, it is largely unknown whether links between sleep and norm-violating behaviors vary across groups. The current study tested the direct effects of sleep problems and sleep quantity on measures of deviance, as well as the indirect links via low self-control. It also tested moderating effects by immigrant and SES groups, indicated by parental education, on the associations and mean-level differences in sleep functioning. Results from structural equation models based on cross-sectional data from a national probability sample of Swiss adolescents (N = 6,866) provided evidence of both direct as well as indirect links between sleep and deviance, via low self-control. Despite mean-level differences, the tested links were invariant across immigrant and SES groups, with one modest exception in the magnitude of effect. PMID- 30025286 TI - Characterization of mouse pericardial fat: regulation by PAPP-A. AB - Although implicated in cardiovascular disease, little is known about the fat surrounding the heart. In humans, epicardial fat is the visceral fat depot of the heart, which directly contacts the myocardium. This strategically placed fat depot is thought to produce bioactive molecules that could affect cardiac function. A major limitation in understanding the biology of epicardial fat is its restricted access in humans and its seeming absence in commonly-used experimental animal models. Although laboratory mice do not have epicardial fat per se, they do have a fat depot around the heart. In this study, we found that mouse pericardial fat has the molecular signature, small adipocyte size, and resistance to differentiation consistent with visceral fat. In addition, we show that mouse pericardial fat is regulated by pregnancy-associated plasma protein-A (PAPP-A), a key modulator of local insulin-like growth factor bioavailability. PAPP-A is highly expressed in mouse pericardial fat at levels equivalent to those in mesenteric visceral fat and 10-fold higher than in subcutaneous inguinal fat (P = .0003). Cultured pre-adipocytes isolated from pericardial fat show 2-fold increased PAPP-A secretion compared to pre-adipocytes isolated from inguinal fat. Furthermore, PAPP-A knock-out mice fed a high fat diet for 20 weeks have significantly reduced pericardial fat (by 60%; P < .0001) compared to wild-type littermates. There was no significant difference in inguinal fat between wild type and PAPP-A knock-out mice. These data characterize a new mouse model of visceral-like pericardial fat and lay a foundation for understanding its role in human heart disease. PMID- 30025288 TI - The influence of junior coaches on club members in the Start2Finish Running & Reading Club: A qualitative study. AB - INTRODUCTION: This study's purpose was to explore youth leaders' involvement and influence on younger program participants in a physical-activity-based positive youth development program (PA-PYD). METHODS: A case study was conducted where 16 youth leaders (8 males, 8 females, Mage = 13.37, SD = 1.36) and 15 program participants (8 males, 7 females, Mage = 10.53, SD = 1.12) from four sites of a PA-PYD program in Canada participated in one-on-one semi-structured interviews regarding their program experiences. A deductive-inductive thematic analysis was conducted. RESULTS: Five themes were identified: (a) learning and building skills, (b) receiving support, (c) enjoyment, (d) relatability, and (e) challenges faced. Program participants shared several ways in which the youth leaders they interacted with had a positive influence on their personal experiences. The youth leaders' perceptions largely aligned with those of the program participants. CONCLUSIONS: This study provides insight into the value that youth leaders can bring to youth programming. PMID- 30025289 TI - Binding interaction of phenazinium-based cationic photosensitizers with human hemoglobin: Exploring the effects of pH and chemical structure. AB - The present study demonstrates a spectroscopic study on the interaction of two phenazinium-based cationic photosensitizers, namely, phenosafranin (PSF) and safranin-O (SO) with human hemoglobin (Hb) with particular emphasis on exploring the effects of pH and chemical structures of the dye molecules on the binding phenomenon. The protein (Hb) undergoes complex conformational transitions depending on the medium pH. The dye molecules exhibit a prominent fluorescence quenching following interaction with Hb under various experimental conditions (pH 3.5, 7.4, and 9.0). Our combined steady-state and time-resolved spectroscopic results provide persuasive evidence for static quenching mechanism showing that the dye:Hb interaction proceeds through ground-state complex formation. The meticulous investigations on the pH-dependence of the interaction of the dye molecules with the protein reveal a relatively strong binding of PSF as well as SO with Hb at physiological pH and alkaline pH, while the binding is weaker at acidic pH at which Hb predominantly exists as monomeric units. The binding constant for PSF:Hb interaction is K(PSF:Hb) = (1.09 +/- 0.06) * 106 M-1 and that of SO:Hb interaction is K(SO:Hb) = (1.34 +/- 0.07) * 105 M-1 at pH 7.4. However, at pH 3.5, the binding constant values are K(PSF:Hb) = (3.58 +/- 0.18) * 104 M-1 and K(SO:Hb) = (4.29 +/- 0.22) * 104 M-1 and at pH 9.0, the values are K(PSF:Hb) = (8.08 +/- 0.40) * 104 M-1 and K(SO:Hb) = (5.07 +/- 0.25) * 104 M-1. This depicts a much stronger binding interaction of the dyes with the native Hb at pH 7.4 compared to those at pH 3.5 and 9.0. Our results also unveil the effect of chemical structures of the dyes on the interaction phenomenon in the sense that the binding constant of PSF with Hb is found to be higher than that of SO at pH 7.4 and pH 9.0. The present study also focuses on exploring such important aspects of the interaction phenomena as the effect of binding of the dyes on the protein conformation by circular dichroism spectroscopy and probable binding location of the dyes within the protein scaffolds via micropolarity measurements and molecular docking simulation. PMID- 30025290 TI - Partitioning of absorbed light energy within photosystem II in barley can be affected by chloroplast movement. AB - Plants have developed many ways to protect reaction centres of photosystems against overexcitation. One of the mechanisms involves reduction of the leaf absorption cross-section by light-induced chloroplast avoidance reaction. Decrease in the probability of photon absorption by the pigments bound within photosystem II (PSII) complexes leads to the increase in quantum yield of PSII photochemistry (PhiPSII). On the other hand, the decrease of PSII excitation probability causes reduction of chlorophyll a fluorescence intensity which is manifested as the apparent increase of determined quantum yield of regulated light-induced non-photochemical quenching (PhiNPQ). Absorption of different light intensity by phototropins led to the different chloroplast distribution within barley leaves, estimated by measurement of the leaf transmittance. Due to a weak blue light used for transmittance measurements, leaves exposed to actinic light with wavelengths longer than 520 nm undergo chloroplast accumulation reaction, in contrast with leaves exposed to light with shorter wavelengths, that showed a different extent of chloroplast avoidance reaction. Based on the PhiNPQ action spectra measured simultaneously with the transmittance, the influence of different chloroplast distribution on PhiNPQ was assessed. The analysis of results showed that decrease in the leaf absorption cross-section due to increasing part of chloroplasts reaching profile position significantly affected the partitioning of excitation energy within PSII and such rearrangement also distorted measured PhiNPQ and cannot be neglected in its interpretation. When the majority of chloroplasts reached profile position, the photoprotective effect appeared to be the most prominent for strong blue light that has the highest absorption in the upper leaf layers in comparison with green or red ones. PMID- 30025291 TI - Lifestyle activities in mid-life contribute to cognitive reserve in late-life, independent of education, occupation, and late-life activities. AB - This study tested the hypothesis that mid-life intellectual, physical, and social activities contribute to cognitive reserve (CR). Two hundred five individuals (196 with magnetic resonance imaging) aged 66-88 years from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.com) were studied, with cognitive ability and structural brain health measured as fluid IQ and total gray matter volume, respectively. Mid-life activities (MAs) were measured using the Lifetime of Experiences Questionnaire. Multivariable linear regression found that MAs made a unique contribution to late-life cognitive ability independent of education, occupation, and late-life activities. Crucially, MAs moderated the relationship between late-life cognitive ability and brain health, with the cognitive ability of people with higher MA less dependent on their brain structure, consistent with the concept of CR. In conclusion, MAs contribute uniquely to CR. The modifiability of these activities has implications for public health initiatives aimed at dementia prevention. PMID- 30025292 TI - Quantitative imaging of clathrin-mediated endocytosis. AB - Clathrin-mediated endocytosis is a process by which eukaryotic cells bend a small region of their plasma membrane to form a transport vesicle that carries specific cargo molecules into the cell. Endocytosis controls the composition of the plasma membrane, imports nutrients and regulates many signalling pathways. The roles of most of the proteins involved in endocytosis have been thoroughly characterised. However, how these proteins cooperate in the cell to drive the endocytic process is not well understood. Microscopy methods have been instrumental in describing the dynamics and the molecular mechanism of endocytosis. Here, we will review the challenges and the recent advances in visualising the endocytic machinery and we will reflect on how the integration of current imaging technologies can lead us toward a quantitative understanding of the molecular mechanisms of endocytosis. PMID- 30025293 TI - Different resolution techniques for management of overlapped spectra: Application for the determination of novel co-formulated hypoglycemic drugs in their combined pharmaceutical dosage form. AB - To maintain intensive glucose control early in the type II diabetes mellitus process, novel combinations of canagliflozin/metformin (CAG/MEF) and empagliflozin/linagliptin (EMG/LIG) offer particular treatment benefits. In this study, sensitive and precise spectrophotometric methods were developed for the determination of such hypoglycemic drug combinations in bulk powder and in pharmaceutical dosage form without prior separation. The first method was ratio difference coupled with modified isosbestic point technique where the amplitude difference between 239 and 291 nm on the ratio spectrum of CAG obtained using 4 MUg/ml of MEF as divisor was used for determination of CAG. On the other hand, MEF was estimated using a modified isosbestic spectrophotometric method, where the total concentration of CAG and MEF in mixture could be calculated at 250 nm (isosbestic point) after multiplication by a correction factor. Then concentration of MEF could be calculated by subtraction. The second method was ratio subtraction coupled with extended ratio subtraction, where EMG was determined at 225 nm by subtraction of plateau values from the ratio spectrum followed by multiplication with the spectrum of 6.5 MUg/ml of LIG (divisor). Then, an extension of the normal ratio subtraction method was performed in order to determine LIG at 226 nm. Linearity was obtained over 5-30, 2.5-16, 2.5-16 and 1.25-8 MUg/ml for CAG, MEF, EMG and LIG, respectively. The developed methods were successfully applied for the determination of studied drugs in tablets. Validation parameters were found to be within acceptance limits, thus confirming methods accuracy and selectivity. The obtained results were statistically compared with the reported one showing no significant difference in terms of accuracy and precision. The methods could be applied for routine analysis of the cited drugs in quality control laboratories. PMID- 30025294 TI - Dispersion analysis of sodium dichromate dihydrate Na2Cr2O7.2H2O single crystal. AB - A single crystal of monoclinic sodium dichromate dihydrate was investigated by FTIR-spectroscopy in the spectral region of 4000-80 cm-1. On the measured reflection spectra dispersion analysis was performed to gain the oscillator parameters of the transition dipole moments of Na2Cr2O7.2H2O and by that the dielectric tensor function. The gained oscillator parameters were verified by forward-calculation of spectra using different crystal faces. PMID- 30025295 TI - Epi-nutrients in the oviductal environment: Folate levels and differential gene expression of its receptors and transporters in the bovine oviduct. AB - Recent studies have demonstrated that the oviductal environment plays an active role in modulating the epigenetic marks of the preimplantation embryo genome, but the molecular factors that mediate this epigenetic effect are unknown. Folate is a well-known epi-nutrient that can impact on cell epigenetic machinery during embryonic and fetal development. However, the study of this epi-nutrient in the oviduct is still limited. The present study was conducted to confirm the presence and physiological concentration of folate in bovine oviductal fluid (OF) and to determine if bovine oviduct epithelial cells (BOECs) are able to regulate the uptake of this micronutrient. Samples of OF from ipsi- and contralateral oviducts were collected at different stages of the estrous cycle and folate levels were determined using a competitive receptor binding immunoassay. In addition, gene expression of folate receptors (FOLR1, FOLR2) and transporters (SLC19A1, SLC46A1) were analyzed in BOECs from ampulla and isthmus regions during different stages of the estrous cycle using RT-qPCR. In vitro culture assays were also performed to evaluate whether expression of these genes responds to hormonal stimulation. Our results demonstrated presence of folate in the OF, showing changes of its concentration in the ipsilateral oviduct during the estrous cycle and significantly lower levels at the postovulatory stage. Moreover, gene expression of folate receptors and transporters was detected in BOECs, showing regional and cycle-dependent changes. In particular, differential expression of FOLR1 mRNA was observed in BOECs from the isthmus region, reaching significantly higher levels during the postovulatory stage. Under in vitro culture conditions, gene expression of folate receptors and transporters was maintained in BOEC explants and a particular susceptibility to steroid hormone stimulation was observed. In conclusion, the present study confirms the presence of folate in the bovine oviduct and proves the existence of a fine-tuned regulation of the expression of its receptors and transporters, highlighting the importance to expand the knowledge about this epi-nutrient in the oviductal context. PMID- 30025296 TI - Effect of dietary energy restriction and subsequent compensatory feeding on testicular transcriptome in developing rams. AB - Nutritional intake and reproductive allocation are strongly associated and dietary energy restriction (ER) or surpluses can affect reproductive capacity. The objective of this study was to investigate the effect of energy levels on sheep testicular development. Three-month old Hu sheep were assigned to four groups, and fed diets containing different levels of energy (Control, maintenance energy; ER1, 85% maintenance energy; ER2, 70% maintenance energy; ER3, 55% maintenance energy). Two months later, half the sheep in each group were euthanized, whereas the remaining sheep were euthanized after a further 3 months feeding on a compensatory energy diet. The testicular weight and reproductive hormone levels of the Hu sheep were investigated. Differences in the testes of ER3 and control group sheep were investigated at the transcriptional level using high-throughput sequencing. The results showed that the testicular weights had decreased in the energy-restricted rams compared with the controls, and that the testosterone concentration in ER3 group rams was significantly lower than that in other compared groups (P < 0.05). After the period of compensatory feeding, however, ER3 sheep testicular weight and testosterone concentrations were similar to those of the control group sheep. In addition, the RNA sequencing results revealed that 81 genes were upregulated and 180 genes were downregulated in the ER3 group compared with the control group. Moreover, based on the enriched steroidogenesis, meiosis and kinases pathways, a number of candidate genes potentially involved in the regulation of testicular development or reproduction of Hu sheep, including CYP11A1, ALDH3B1, FDFT1, WNT2, PGR and INSR, were screened. Quantitative real-time polymerase chain reaction analysis results correlated well with the sequencing data. Taken together, this study provides a first insight into the development of the testis with dietary energy restriction in sheep and shows that these changes are associated with alterations in transcriptomic. The sheep testis mRNA database were extended in this study will provides novel candidate regulators for future genetic and molecular studies on sheep testicular development associated with energy restriction, which will contribute to improving the reproductive performance of sheep. PMID- 30025297 TI - Fluorescence polarization immunoassay of colchicine. AB - In this study, a fluorescence polarization immunoassay (FPIA) technique was developed to determine colchicine (COL), an alkaloid of noxious plants of the order Liliales that is used in a number of medications to treat gout. An optimal combination of the polyclonal antibody and the antigen labelled with fluorescein isothiocyanate (FITC) was selected. Conditions for the competitive interaction of the antigen in the tested samples and its fluorophore conjugate (COL-FITC) with anti-COL antibodies were optimised, and the analytical characteristics of the assay were determined. The developed FPIA was characterised by a detection limit of 1.8 ng/mL and a detectable analyte concentration range of 4.1-74.3 ng/mL. The duration of the analysis was 10 min. The applicability of the developed FPIA for quality control of ready-made drug formulations and for the estimation of COL content in various matrices (urine, milk), with recovery values ranging from 79 to 108%, was demonstrated. PMID- 30025298 TI - Development and validation of a simple chromatographic method for simultaneous determination of clindamycin phosphate and rifampicin in skin permeation studies. AB - Rifampicin (RIF) and clindamycin phosphate (CDM) are the main drugs currently used in combination to treat severe infectious diseases in hair follicles. This work describes a simple, rapid and sensitive method for simultaneous analysis of RIF and CDM in the different skin layers using high performance liquid chromatography (HPLC). The efficient chromatographic separation of CDM and RIF was succeeded using a C18 column (150 mm x 4.6 mm, 5 MUm) with gradient elution using a mobile phase composed of 0.01 M phosphoric acid and methanol at a flow rate of 1 mL min-1. Determinations were performed using UV-vis detector at 200 nm and 238 nm for CDM and RIF, respectively. The method was precise, accurate and linear (r2 > 0.999) with regression curve in the concentration range from 0.5 to 20.0 MUg mL-1 and recovery rates from the skin layers higher than 85%. The retention times for CDM and RIF were approximately 7.4 and 12.2 min, respectively. The presence of skin components did not interfere with the analysis. The validated method was therefore appropriate for quantification of both CDM and RIF and thus may be feasible to be used in skin permeation studies. PMID- 30025299 TI - Comparison against current standards of a DNA aptamer for the label-free quantification of tobramycin in human sera employed for therapeutic drug monitoring. AB - The use of DNA aptamers in biosensors for the quantification of pharmaceuticals in the clinics would help to overcome the limitations of antibody-based detection for small molecules. The interest for such systems is proven by the ever increasing number of aptamer-based solutions for analytics proposed in the literature as proof-of-concept demonstrators. Despite such diversity, these platforms often lack a comparative assessment of their performances against the current standard of practice in the clinics when using real samples. We employed an aptamer against tobramycin discovered in our laboratory to quantify through surface plasmon resonance the concentration of the antibiotic in clinical samples obtained from patients treated with tobramycin and undergoing therapeutic drug monitoring. We then compared the performances of our detection strategy against the current standard of practice. Our results show how, using adequate calibration and matrix complexity reduction, DNA aptamer-based direct assays can assess clinically relevant concentrations of small molecules in patient serum and with good correlation to current standards used in the clinics. PMID- 30025300 TI - Co-activation patterns of gastrocnemius and quadriceps femoris in controlling the knee joint during walking. AB - Muscular co-activation is a well-known mechanism for lower limb joint stabilization in both healthy and pathological individuals. This muscular feature appears particularly important for the knee joint, not only during challenging motor tasks such as cutting and landing but also during walking, due to knee cyclic loading. Gastrocnemius acts on the knee joint with a flexor activity and co-activations with quadriceps muscles lead to greater knee ligament strain with respect to an isolated burst of either muscle. Thus, this study aimed to assess possible co-activations between gastrocnemius and quadriceps muscles during walking. Five co-activation periods were assessed: during early stance (identified in 5.7 +/- 5.1% of total strides), early and late foot-contact (88.9 +/- 8.9% and 8.9 +/- 8.2%), push-off (23.9 +/- 12.2%) and late swing (29.0 +/- 16.1%). Outcomes showed that late foot-contact and swing co-activations could deserve particular attention: in both cases the knee joint was close to the full extension (around 3.5 degrees and 6 degrees , respectively) and thus, considering also the anterior tibia translation due to the quadriceps activity, the simultaneous gastrocnemius burst could lead to an enhanced knee ligaments elongation. Findings of this study represent the first attempt to provide a reference knee joint co-activation framework, useful also for further evaluation in cohorts with knee failures. PMID- 30025301 TI - Neglected children with severe obesity have a right to health: Is foster home an alternative?-A qualitative study. AB - OBJECTIVE: To explore key person's perspectives of foster home placement or notification of risk of harm to Social Services of children with severe obesity. METHODS: This case study research was performed in the southwest of Sweden and based on interviews with nine informants: a foster home youth, two foster parents, a social worker, two hospital social workers, a pediatric physician, a pediatric nurse, and a psychologist. Content analysis was used for narrative evaluations, within- and cross case analyses and displays. RESULTS: Positive health outcomes of the foster home placement were described as a healthy and normalized weight status, a physically and socially active life, and an optimistic outlook on the future. The foster parents made no major changes in their family routines, but applied an authoritative parenting style regarding limit setting about sweets and food portions and supporting physical activity. The professionals described children with severe obesity as having suffered parental as well as societal neglect. Their biological parents lacked the ability to undertake necessary lifestyle changes. Neglected investigations into learning disabilities and neuropsychiatric disorders were seen in the school and healthcare sector, and better collaboration with the Social Services after a report of harm might be a potential for future improvements. Rival discourses were underlying the (in) decision regarding foster home placement. CONCLUSION: A child's right to health was a strong discourse for acting when a child was at risk for harm, but parental rights are strong when relocation to a foster home is judged to be necessary. PMID- 30025302 TI - The interplay of gender, parental behaviors, and child maltreatment in relation to psychopathic traits. AB - Many studies have reported an effect of childhood maltreatment and parenting behavior with the future development of psychopathic traits. However, there is a limited amount of research on parenting behavior and adult psychopathic traits as possible identifiers of childhood maltreatment. The aim of this study is three fold (1) identify specific parenting behaviors and adult psychopathic traits that predict forms of childhood maltreatment, (2) explore gender differences, and (3) expand on other studies on psychopathy by focusing on a representative sample of the community. There are significant associations between recalled childhood maltreatment and parenting behavior, and psychopathic traits. Parental rejection was the most recurrent predictor of childhood maltreatment with a significant positive relation to almost all its forms. Paternal overprotection was positively associated with sexual abuse, while the opposite was true for maternal overprotection. Psychopathic traits displayed in adulthood were also strong indicators of childhood maltreatment; females with high levels of boldness were more likely to have experienced sexual abuse in childhood, and those high in disinhibition were more likely to have experienced physical neglect and sexual abuse. While males were generally higher in terms of psychopathic traits, females reported more childhood abuse and negative parental behaviors. These findings provide support for using parenting behavior and psychopathic traits as markers of childhood maltreatment. PMID- 30025304 TI - Mediating effects of parental psychological distress and individual-level social capital on the association between child poverty and maltreatment in Japan. AB - Child poverty is well known as a major risk factor for child maltreatment. However, it is not known whether parental psychological distress and individual level social capital mediate the association. We examined the mediation effect of these two factors on the association between child poverty and maltreatment. In the Adachi Child Health Impact of Living Difficulty (A-CHILD) Study, a questionnaire was administered to all caregivers of first-grade children in every public elementary school in Adachi City between July and November 2015, and valid responses were used for analysis (N = 3944). Logistic and Poisson regression analyses were employed to examine the association between child poverty and maltreatment. Child poverty was defined in this study as meeting one of these criteria: 1) household income less than 3 million yen; 2) deprivation of specific material items that children or the household requires, or 3) experience of being unable to pay for lifeline utilities. Child maltreatment (physical abuse, neglect, and psychological abuse) was answered by parents. We confirmed a robust association between child poverty and maltreatment. Mediation analysis indicated that parental psychological distress mediated more than 60% of the association between child poverty on physical abuse and psychological abuse, while individual level social capital mediated only 10% of the association with any type of maltreatment. In addition, structural equation modeling analysis revealed that the association was mediated by both parental psychological distress and social capital simultaneously. The findings suggest that supporting parental psychological distress may be an effective intervention to remedy the negative impact of child poverty on maltreatment. PMID- 30025303 TI - Reasons for placement decisions in a case of suspected child abuse: The role of reasoning, work experience and attitudes in decision-making. AB - Child welfare and child protection workers regularly make placement decisions in child abuse cases, but how they reach these decisions is not well understood. This study focuses on workers' rationales. The aim was to investigate the kinds of arguments provided in placement decisions and whether these arguments were predictors for the decision, in addition to the decision-makers' risk assessment, work experience and attitudes towards placement. The sample consisted of 214 professionals and 381 students from the Netherlands. The participants were presented with a vignette describing a case of alleged child abuse and were asked to determine whether the abuse was substantiated, to assess risks and to recommend an intervention. The participants' placement attitudes were assessed using a structured questionnaire. We found that the participants provided a wide range of arguments, but that core arguments - such as the suspected abuse, parenting and parent-child interaction - were often missing. Regression analyses showed that the higher the perceived danger to the child and the more positive the participants' attitudes towards placement, the more likely the participants would be to propose placing the child in care. Arguments related to the severity of the problems (i.e., suspected abuse, parenting and the child's development) as well as the parents' perceived cooperation also influenced placement decisions. The findings indicate trends in the decision-making process, in the sense that participants who decided to place the child out-of-home emphasized different arguments and had different attitudes towards out-of-home placement than those who did not. We discuss the implications of our findings. PMID- 30025306 TI - The intertwined effect of lack of emotional warmth and child abuse and neglect on common mental disorders in adolescence. AB - Adolescence is a vulnerable period for mental health problems. Although child abuse and neglect (CAN) are known risk factors for some of them, it is not clear if the negative consequences on mental health also occur in families where CAN and a warm parent-child relationship coexist. The aim of this study is to explore this gap and investigate the effects of different types of CAN according to levels of warmth in the parent-child relationship on common mental disorders (CMD) in adolescence. This is a cross-sectional study encompassing 487 adolescents attending the ninth grade at 2 public and 4 private schools in Rio de Janeiro, Brazil. CAN was measured by the Child Trauma Questionnaire (CTQ), CMD by the General Health Questionnaire (GHQ-12) and the level of warmth in the parent child relationship were recalled using short Egna Minnen Betraffande Uppfostran (s-EMBU-23). The adjusted separate effects of different types of CAN and a low level of warmth in the parent-child relationship, and both in tandem, were estimated using multivariate linear regression models. Results indicated that emotional abuse and neglect, physical abuse and neglect, and a low level of warmth in the parent-child relationship are important risk factors for CMD in adolescence. Nevertheless, in families where CAN coexist with a warm and affectionate parent-child relationship, the negative effects of CAN on mental health are attenuated. Evidence indicates that actions to prevent or interrupt CAN and improving parental practices could be effective strategies to reduce CMD in adolescence. PMID- 30025305 TI - Media portrayal of a hidden problem: An analysis of Hong Kong newspaper coverage of child maltreatment in 2016. AB - The news media plays a vital role in providing child protection information and resources, shaping the public's understanding and perceptions of child maltreatment, and exposing system failures and setting policy agendas. To date, little is known about how child maltreatment is portrayed in the media in societies where these issues remain largely hidden and under-recognized. The purpose of the present study was to systematically examine newspaper coverage on child abuse and neglect in Hong Kong in order to assess how child maltreatment is currently presented and framed within public discourse. A total of 579 newspaper reports relevant to child maltreatment from four local newspapers in 2016 were reviewed. Similar to prior findings, cases involving sexual abuse received disproportionately more attention compared with other maltreatment types. The vast majority of news reports focused on specific cases or events, and seldom discussed child maltreatment as a broader social issue. Differences in reporting style and media framing were also compared by newspaper credibility, and for free versus paid newspapers. As a mass communication tool, more guidelines are needed to formulate public messages about child maltreatment that can improve individual, community, and structural capacities to prevent, identify, and respond to children who are victimized by abuse and neglect. This is especially important in jurisdictions where no mandatory reporting framework exists to help identify vulnerable children, and where the majority of child maltreatment is brought to the attention of authorities by families and those living within the child's community. PMID- 30025307 TI - The effects of individual- and national-level factors on attitudes toward child maltreatment. AB - Knowledge is lacking regarding the extent to which national norms and policies designed to protect minors influence individual attitudes toward child maltreatment. Relying on the tenets of cultural sociology, we examine whether the orientation of a nation influences individual attitudes toward child maltreatment. Specifically, nations with greater economic and political stability tolerate more self-expressive values, focusing on individual autonomy and enhancing quality of life. Conversely, nations with a survivalist orientation, often characterized by greater economic uncertainty, are less supportive of behaviors that may result in further instability. The current study builds on extant research by investigating the effects of national norms and policies and individual-level attitudes and characteristics on individual attitudes toward child maltreatment (N = 66,391) in 53 developing and developed nations. We analyze data from the World Values Survey using Hierarchical Generalized Linear Modeling. Overall, countries with a greater survivalist orientation appear less tolerant of child maltreatment. Moreover, greater support for violence in general at both the national- and individual-level are associated with more supportive attitudes toward child maltreatment. Policy implications and legislative reform are discussed. PMID- 30025308 TI - Parenting intervention effects on reunification: A randomized trial of PMTO in foster care. AB - Evidence-supported parenting interventions (ESPIs) have expanded into child welfare because a growing research base has demonstrated positive results among children with serious emotional and behavioral problems. Despite a clear federal policy emphasis on reunification, few randomized trials have tested ESPIs with biological families of children in foster care; even fewer studies have investigated the distal outcomes of ESPIs. The aim of the current study was to examine the effects of Parent Management Training, Oregon (PMTO) model on reunification. Children in foster care with emotional and behavioral problems were randomized to in-home PMTO (n = 461) or services as usual (SAU) (n = 457). Cox regression models tested whether children in the PMTO group achieved higher rates of reunification. We applied life tables data for integrals calculations to estimate days saved in foster care. Analyses were conducted as intent-to-treat (ITT), and per protocol analysis (PPA). ITT results showed reunification rates were 6.9% higher for the PMTO group (62.7%) than the SAU group (55.8%) with 151 days saved per typical child. PPA indicated that intervention completion strengthened effects as PMTO completers' reunification rates (69.5%) were 13.7% higher than the SAU group (55.8%), and were 15.3% higher than non-completers (54.2%). Days saved were also greater for completers as compared to the SAU group (299 days) and non-completers (358 days). Overall, findings suggest that an in home parenting intervention positively affected reunification as delivered to biological parents of children and youth in foster care with serious emotional and behavioral problems. Implications and future considerations for research are discussed. PMID- 30025309 TI - Trends in the prevalence of psychological distress and the use of mental health services from 2007 to 2016 in Japan. AB - BACKGROUND: Little is known regarding trends of psychological distress and use of mental health services in Japan during recent years. METHODS: This study examined trends in severe and moderate psychological distress and the use of mental health services among adults (>=18 years old), using the Comprehensive Survey of Living Conditions in Japan from 2007, 2010, 2013, and 2016 (Total N = 2,159,005, all survey years combined). We defined a score of >=13 on Kessler Psychological Distress Scale (K6) as severe distress and a K6 score between 5 and 12 as moderate distress. Age- and sex-specific trends of psychological distress and the use of mental health services were also examined. RESULTS: As compared with 2007, those with severe distress slightly increased in 2016 (4.01%-4.15%, p = 0.02) while those with moderate distress remained mostly unchanged (24.61%-24.69%, p = 0.61). The use of mental health services steadily increased in this decade for both with severe distress (11.95%-15.76%, p < 0.01) and with moderate distress (2.60%-3.56%, p < 0.01). The prevalence of severe distress among women aged 25-29 years old was highest in 2016 among all the age groups although the use of mental health services was not particularly high among women in this age group. LIMITATIONS: Cross-sectional nature of the data did not allow us to examine the causal relationship between psychological distress and the use of mental health services. CONCLUSIONS: In spite of an observed increase in the use of mental health services, the prevalence of psychological distress slightly increased. Further studies are necessary to identify sources of treatment gap especially for vulnerable demographic subgroups. PMID- 30025310 TI - Depression management interests among Alaska Native and American Indian adults in primary care. AB - BACKGROUND: Depression remains the second leading cause of disability worldwide. Symptoms of depression are expressed and experienced differently across cultural groups, impacting treatment decisions. Patient preferences predict service utilization, treatment selection and persistence, as well as health outcomes for medical and behavioral health conditions, including depression. We identified depression management preferences of Alaska Native and American Indian (AN/AI) people who receive care within a comprehensive, integrated, tribally owned and operated healthcare facility in Anchorage, Alaska. METHODS: Adult AN/AI patients who screened positive for depression (10 or greater on the Patient Health Questionnaire - 9 (PHQ-9)) completed a culturally-tailored decision-support tool to assess their depression management interests. RESULTS: The 125 eligible patients, who screened positive for depression, preferred counseling and medications to peer support groups, herbal remedies, and spiritual support. Those 18-39 years of age were more likely to prefer medications and less likely to prefer spirituality and peer support than those 40 years of age and older. Patients with moderate and severe depression were more likely to prefer exercise, healthy eating, and stress reduction than individuals with mild depression. LIMITATIONS: Women comprised 78% of the sample. Responses may not adequately represent the views of men. CONCLUSIONS: Counseling and medications should consistently be made available earlier in the course of depression management. Patient interest in exercise, stress reduction, and healthy eating to manage depression, especially among those with moderate and severe depression, offers opportunity for additional collaboration in an integrated care setting. PMID- 30025311 TI - Association between irritability and suicide-related outcomes across the life course. Systematic review of both community and clinical studies. AB - BACKGROUND: Irritability is gaining considerable attention as a risk factor for suicide-related outcomes (suicide mortality, attempt, and ideation). However, the evidence of this association is scant. We conducted a systematic review of the evidence regarding the associations between irritability and suicide-related outcomes across the life-course. METHODS: We conducted a systematic search on Medline and PsycINFO (up to January 2018) for original articles published in English investigating the association between irritability and suicide-related outcomes. Two researchers independently screened the articles, assessed the quality of the evidence (New-Castle-Ottawa Scale) and extracted study characteristics. RESULTS: Thirty-nine studies were retrieved, most were of low/medium quality. Twelve assessed irritability in childhood/adolescence (6 in community samples, 6 in clinical samples) and 27 in adulthood (7 in community samples, 20 in clinical samples). In both childhood/adolescence and adult samples, most community-based studies reported a positive association between irritability and suicidal ideation and/or attempt, while clinical studies reported mixed findings. More specifically, in clinical studies, the association of irritability with suicide-related outcomes (i) was not supported among adult depressed patients, (ii) findings were inconsistent in adult bipolar patients, (iii) for inpatients/outpatients with various psychiatric disorders/conditions, association was observed in adulthood but not in childhood/adolescence. LIMITATIONS: Differences in methodology and definition/measurement of irritability limited the comparability of included studies. CONCLUSIONS: Although irritability has been proposed as a promising transdiagnostic factor associated with suicide-related outcomes, the absence of consensus in the definition of irritability (vs anger or reactive/impulsive aggression), the poor methodological quality, and the lack of developmental considerations mitigate the conclusions. PMID- 30025312 TI - Orbitofrontal connectivity is associated with depression and anxiety in marijuana using adolescents. AB - BACKGROUND: Prevalence of marijuana (MJ) use among adolescents has been on the rise. MJ use has been reported to impact several brain regions, including frontal regions such as the orbitofrontal cortex (OFC). The OFC is involved in emotion regulation and processing and has been associated with symptoms of depression and anxiety. Therefore, we hypothesized that adolescent MJ users would show disruptions in OFC connectivity compared with healthy adolescents (HC) which would be associated with symptoms of mood and anxiety. METHODS: 43 MJ-using and 31 HC adolescents completed clinical measures including the Hamilton Anxiety Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D). Resting-state functional magnetic resonance imaging data was also acquired for all participants. RESULTS: In MJ users, increased depressive symptoms were associated with increased connectivity between the left OFC and left parietal regions. In contrast, lower ratings of anxiety were associated with increased connectivity between right and left OFC and right occipital and temporal regions. These findings indicate significant differences in OFC connectivity in MJ-using adolescents, which correlated with mood/anxiety. LIMITATIONS: Future studies with an increased number of female participants is required to address potential sex differences in connectivity patterns related to symptoms of depression and anxiety. CONCLUSIONS: This study highlights the association between OFC connectivity, MJ use, and symptoms of depression and anxiety in adolescents. These findings provide further insight into understanding the neural correlates that modulate the relationship between comorbid MJ use and mood disorders and could potentially help us better develop preventive and treatment measures. PMID- 30025313 TI - Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders. AB - BACKGROUND: Previous studies have shown that individuals with mood disorders have a higher prevalence of both hypercortisolemia and insulin resistance. Insulin resistance is posited to contribute to the cognitive deficits observed in individuals who have depression. However, the mechanistic relationship between cortisol and insulin within the central nervous system remains to be further elucidated. This study aimed to evaluate the effects of the antiglucocorticoid agent, mifepristone, on metabolic function and cognitive performance in individuals receiving treatment for depressive disorders who were euthymic at baseline. METHODS: Participants were administered a 600 mg/day dose of mifepristone for 28 days. Oral glucose tolerance tests (OGTTs) and cognitive assessments measuring verbal memory and executive functioning were administered at baseline and after 28 days of treatment. RESULTS: Improvements in attention and verbal learning were associated with reduction of fasting plasma glucose (FPG) in response to mifepristone treatment. LIMITATIONS: Limitations include the open-label design of this study and a small sample size. CONCLUSIONS: The findings from this study suggest that improvement in fasting plasma glucose levels, upon administration of mifepristone, is associated with the improvement in early input of verbal information. Further studies are warranted in order to better evaluate the use of mifepristone or other antiglucocorticoid agents in treatment of mood disorders characterized by metabolic dysfunction. PMID- 30025314 TI - The effects of algal extracellular substances on algal growth, metabolism and long-term medium recycle, and inhibition alleviation through ultrasonication. AB - The algal extracellular substances (AESs), mainly excreted in the lag and stationary phases, inhibited the algal growth and culture recycle. The AESs consisted of protein-like substances and saccharides, which restrained the algal lipid and protein biosynthesis. Moreover, the increasing reactive oxygen species and anti-oxidative enzymes caused by AESs led to the oxidative damage and suppressed the cell activity. The AESs affected the cells through two possible ways: one is the AESs adhered to the cell surfaces; another is the cells yielded signal molecules in response to the AESs. Fortunately, the ultrasound degraded the AESs into small molecules, which clearly alleviated the limitation and recovered the algal biomass and metabolism. This study demonstrated that ultrasonication is a promising way to alleviate the AESs, which facilitating the medium recycle for long-term continuous microalgae production. PMID- 30025315 TI - A new process for simultaneous nitrogen removal and phosphorus recovery using an anammox expanded bed reactor. AB - Phosphorus recovery from wastewater is an important approach for sustainable phosphorus use. In this work, a process combining anammox and hydroxyapatite (HAP) precipitation in an expanded bed reactor for simultaneous nitrogen removal and phosphorus recovery was developed by applying specific Ca/P ratio and pH control. A high phosphorus removal rate (0.14 +/- 0.01 kg-P/m3/d) was obtained while a stable nitrogen removal efficiency (87.4 +/- 2.9%) maintained with an effluent recirculation system applied. Average 13.4% phosphorus (30.7% in P2O5) accumulation in the dry sludge and a Ca/P ratio very close to HAP was observed by quantitative elemental analysis. In this work, different analysis revealed the two layers structure with anammox biofilm attached to inorganic core of the granules. Different spectral analysis determined the major phase of the inorganic content as hydroxyapatite. With proper Ca/P ratio and pH control, anammox expanded bed reactor was transformed into an efficient process to simultaneously remove nitrogen and recover phosphorus. PMID- 30025316 TI - Reduction of Gibbs free energy and enhancement of Methanosaeta by bicarbonate to promote anaerobic syntrophic butyrate oxidation. AB - Bicarbonate (HCO3-) has been extensively researched as a buffer in anaerobic digestion. The effect of HCO3- concentration on syntrophic butyrate oxidation process was evaluated by batch culturing of anaerobic activated sludge, and the mechanism was further revealed by the changes of Gibbs free energy (DeltaG) and the interspecies transfers of electron and proton. The results showed that butyrate degradation rate was enhanced by 32.07% when the supplement of HCO3- increased from 0 to 0.20 mol/L. However, methane production and acetate degradation were strongly inhibited by HCO3- more than 0.10 mol/L. More function of HCO3- was found as 1) decreasing the DeltaG of syntrophic methanogenesis of butyrate while increasing the DeltaG of methanogenesis of acetate, 2) enriching M. harundinacea and M. concilii, 3) increasing the diffusion rate of protons between the syntrophic consortia. This work would increase the anaerobic digestion efficiency by enhancing the interaction of the syntrophic consortia. PMID- 30025317 TI - Effects of hydraulic retention time on process performance of anaerobic side stream reactor coupled membrane bioreactors: Kinetic model, sludge reduction mechanism and microbial community structures. AB - An anoxic/oxic membrane bioreactor (AO-MBR) and three anaerobic side-stream reactor (ASSR) coupled MBRs (ASSR-MBR) were operated to investigate the effects of hydraulic retention time of ASSR (HRTA) and to elucidate sludge reduction mechanisms in ASSR-MBRs. Increasing HRTA from 3.3 to 6.6 h improved nitrogen removal, and enhanced sludge reduction from 8.0% to 40.9% in ASSR-MBR. The sludge decay coefficient was 0.0221 d-1 in MBRs, and 0.0231-0.0345 d-1 in ASSRs. The measured lysis rate coefficient of heterotrophic biomass was 0.083-0.112 d-1 in MBRs and 0.079-0.111 d-1 in ASSRs. The hydrolysis rate coefficient of inactive particulate organic matters (POMs) in ASSRs significantly exceeded that in the MBR. At HRTA of 6.6 h, POMs hydrolysis in ASSR (38.6%) is the dominant route of sludge reduction, and cell lysis occurred principally in aerobic tanks. Illumina MiSeq sequencing showed ASSR-MBRs enriched hydrolytic and fermentative bacteria, and confirmed that anaerobic hydrolysis contributed most to sludge reduction. PMID- 30025319 TI - Binding and hydrolysis properties of engineered cellobiohydrolases and endoglucanases. AB - Because cellulase was the main enzyme used in bioconversion of lignocellulose, it was a valid way to reduce the hydrolysis cost by increasing the adsorption and hydrolysis efficiency of cellulase. In this study, modified cellobiohydrolases (CBHs) and endoglucanases (EGs) were constructed. Two engineered cellulases CBH TrCBMV27E,P30D,Link1 and EG-TrCBMV27E,P30D,Link1 well-performed during hydrolysis. Compared to wild-type enzymes, EG-TrCBMV27E,P30D,Link1 had relatively less adsorption ability to lignin and greater affinity to cellulose, especially Avicel. However, for CBH-TrCBMV27E,P30D,Link1, the hydrolysis manner was changed and in favor to hydrolysis process, although the adsorption properties were unexpected. It suggested that various binding conformations of polysaccharide on CBMs hypothetically resulted in different functions of CBMs, including binding ability, processive and digestive properties on fiber surface. Fusion of T. r CBMV27E,P30D,Link1 to cellulase, both CBH and EG, gave the destruction ability of enzyme and increased the accessible surface of substrate to cellulase, enhanced the adsorption and hydrolysis efficiency of cellulase. PMID- 30025318 TI - Ethylenediamine pretreatment of corn stover facilitates high gravity fermentation with low enzyme loading. AB - This work investigated the effect of ethylenediamine pretreatment on reducing enzyme loading in high gravity fermentation. At optimal conditions of ethylenediamine pretreatment, 85.5% lignin was removed. Enzyme adsorption analysis using a fluorescent cellulose-binding protein showed 35.2% increase of productive adsorption of enzymes to ethylenediamine pretreated biomass, which was caused by high delignification and dramatically increased surface roughness and porosity. In SScF at 15% glucan loading, up to 82.2 g/L ethanol was achieved with a relatively low enzyme loading of 3.6 FPU/g dry matter. It suggested that the remarkably high digestibility of EDA pretreated corn stover could effectively reduce the enzyme loading in the high gravity fermentation of cellulosic ethanol. PMID- 30025320 TI - Phosphoric acid-activated wood biochar for catalytic conversion of starch-rich food waste into glucose and 5-hydroxymethylfurfural. AB - The catalytic activity of engineered biochar was scrutinized for generation of glucose and hydroxymethylfurfural (HMF) from starch-rich food waste (bread, rice, and spaghetti). The biochar catalysts were synthesized by chemical activation of pinewood sawdust with phosphoric acid at 400-600 degrees C. Higher activation temperatures enhanced the development of porosity and acidity (characterized by COPO3 and CPO3 surface groups), which imparted higher catalytic activity of H3PO4 activated biochar towards starch hydrolysis and fructose dehydration. Positive correlations were observed between HMF selectivity and ratio of mesopore to micropore volume, and between fructose conversion and total acid density. High yields of glucose (86.5 Cmol% at 150 degrees C, 20 min) and HMF (30.2 Cmol% at 180 degrees C, 20 min) were produced from rice starch and bread waste, respectively, over H3PO4-activated biochar. These results highlighted the potential of biochar catalyst in biorefinery as an emerging application of engineered biochar. PMID- 30025321 TI - Arundo donax L. can substitute traditional energy crops for more efficient, environmentally-friendly production of biogas: A Life Cycle Assessment approach. AB - Maize silage contributes to biogas production in Lombardy Region (400 anaerobic digestion plants) employing 47,000 Ha (Production Model - PM1). Reducing the area devoted to this energy crop is a goal to free soil for food production. Double cropping (PM2) and Arundo donax L. (PM3) have been proposed and tested to measure the impacts for the three Production Models by Life Cycle Assessment (LCA). The impact category related to Climate Change remained stable for PM2 while it decreased by 17% for Arundo donax L. (PM3) in comparison with PM1. Impact categories related to nutrient management (acidification, particulate matter eutrophication) showed an increase in the range of 3-5% for PM2 in comparison with PM1, while Arundo donax L. allowed the same impact categories to be reduced by 31%, 24%, 17% and 33%, respectively. PMID- 30025322 TI - Silicon carbide foam supported ZSM-5 composite catalyst for microwave-assisted pyrolysis of biomass. AB - Considering a series of issues facing the application of catalysts in large scale catalytic fast pyrolysis systems, a novel composite catalyst of ZSM-5 coatings on SiC foam supports was developed and tested for ex-situ catalytic upgrading of the pyrolytic vapors. Different configurations of catalysts placement were compared and the results showed the composite catalyst could significantly improve the bio oil quality without significantly reducing the yield. The effect of catalyst to biomass ratio on the product yields and bio-oil composition was studied and the results showed that increasing catalyst to biomass ratio could improve the quality of bio-oil at the cost of its yield. In addition, the composite catalyst can maintain its activity until a catalyst to biomass ratio of 1/10, outperforming ZSM-5 in other configurations reported in literature. Furthermore, the composite catalysts could be regenerated and reused while well preserving its material properties and catalytic activity after seven reaction-regeneration cycles. PMID- 30025323 TI - Effect of tetracycline on ammonia and carbon removal by the facultative bacteria in the anaerobic digester of a sewage treatment plant. AB - This study was conducted to see the effect of tetracycline on nitrogen assimilation and carbon removal in an anaerobic digester of a sewage plant. Samples of sewage were collected from an anaerobic digester sludge. Consortium of nitrogen assimilating bacteria were isolated from the sample and its ability to assimilate ammonia at different concentrations of tetracycline was measured along with carbon removal. The results indicate that while high concentrations of tetracycline of more than 100 mg/L delayed the growth of the bacteria, the resistant bacteria grew after a lag period and the removal of nitrogen and carbon was unaffected even at the highest tetracycline concentration of 250 mg/L tested in this study. PMID- 30025324 TI - The potential of microalgae biorefineries in Belgium and India: An environmental techno-economic assessment. AB - This study performs an environmental techno-economic assessment (ETEA) for multiple microalgae biorefinery concepts at different locations, those being Belgium and India. The ETEA methodology, which integrates aspects of the TEA and LCA methodologies and provides a clear framework for an integrated assessment model, has been proposed and discussed. The scenario in India has a higher profitability with a NPV of ?40 million over a period of 10 years, while the environmental impact in Belgium is lower. The inclusion of a medium recycling step provides the best scenario from both perspectives. The crucial parameters for feasibility are the beta-carotene price and content, the upstream environmental impact of electricity and the maximum biomass concentration during cultivation. The identification of these parameters by the ETEA guides future technology developments and shortens the time-to-market for microalgal-based biorefineries. PMID- 30025325 TI - Novel insights into scalability of biosurfactant combined microwave disintegration of sludge at alkali pH for achieving profitable bioenergy recovery and net profit. AB - In the present study, a novel alkali rhamnolipid combined microwave disintegration (ARMD) was employed to achieve net energy production, increased liquefaction and to increase the amenability of sludge towards biomethanation. Additionally, biosurfactant rhamnolipid under alkali conditions enhances the liquefaction at alkali pH of 10 with a maximal liquefaction of 55% with reduced energy consumption (1620 kJ/kg TS) than RMD (45.7% and 3240 kJ/kg TS specific energy) and MD (33.7% and 6480 kJ/kg TS specific energy). A higher biomethane production of 379 mL/g COD was achieved for ARMD when compared to RMD (329 mL/g COD) and MD (239 mL/g COD). The scalable studies imply that the ARMD demands input energy of -282.27 kWh. A net yield of (0.39 USD/ton) was probably achieved via novel ARMD technique indicating its suitability at large scale execution when compared to RMD (net cost -31.34 USD/ton) and MD (-84.23 net cost USD/ton), respectively. PMID- 30025326 TI - A novel 3D yttrium based-graphene oxide-sodium alginate hydrogel for remarkable adsorption of fluoride from water. AB - 3D macrostructure adsorbents have attracted great attention in water treatment recently. A series of novel 3D yttrium-based graphene oxide-sodium alginate hydrogels were prepared by sol-gel process for removal of fluoride. The hydrogels displayed a 3D network porous and amorphous structure composed of 2D sheets, with the uniform dispersion of Y(III) onto the gels. The hydrogel Y-GO-SA1.0 was selected as the optimized adsorbent for the fluoride removal due to its best adsorption performance. The adsorption experiments revealed that the maximum adsorption of fluoride occurred at pH 4. The adsorption equilibrium could be achieved within 24 h at both pH 6.5 and optimal pH 4. Based on Langmuir isotherm model, the maximum adsorption capacity of fluoride was 288.96 mg/g at pH 4.0, much higher than many other reported adsorbents. The adsorption was retarded obviously by the presence of phosphate anions. The regenerated hydrogels maintained high adsorption level for fluoride, which could be easily recycled in operation. Furthermore, the column study exhibited that the hydrogel could be used as column packing for effective removal of fluoride via continuous filtration. The column adsorption data was well described by the Thomas model, with the value of q0 much lower than that for batch adsorption experiment under the same initial F- concentration. Finally, the uptake of F- was associated with the release of -OH groups bonded to Y(III) on the gels. These results imply that the present 3D hydrogels can be potentially applied for the treatment of fluoride containing water. PMID- 30025327 TI - Amorphous carbon layer: An effective assistant for realizing near-infrared activated photocatalysis. AB - Carbon quantum dots (CQDs) were considered as desirable up-conversion luminescent materials. However, the reason leading to their up-conversion luminescence was not clear. In this paper, CQDs decorated ZnSn(OH)6 was successfully synthesized by facile in situ hydrothermal method. Under NIR light irradiation, ciprofloxacin degradation efficiency of sample was 37.4%. Subsequently, reasons for the up conversion effect of CQDs were investigated to some extent. An amorphous carbon layer around CQDs was observed in composite (ZnSn(OH)6@CQDs@C) by HR-TEM and elemental mapping images. To study the effect of amorphous carbon layer on up conversion performance, individual CQDs decorated ZnSn(OH)6 (ZnSn(OH)6@CQDs) was also fabricated by compositely coating. ZnSn(OH)6@CQDs had no up-conversion luminescence under 980 nm laser light excitation and its photocatalytic activity was negligible, implying amorphous carbon layer played a crucial role for realizing of up-conversion luminescence. A comparison of the FTIR spectra of two composites, ZnSn(OH)6@CQDs@C sample revealed greatly enhanced surface oxidation degree, polarity and hydrophilicity. Surface state of ZnSn(OH)6@CQDs@C composite was controlled by adjusting hydrothermal time, and the results confirmed that up conversion performance had a close relationship with surface states of samples. This work could provide a new insight into understanding the up-conversion effect of CQDs. PMID- 30025328 TI - Thermodynamic modeling of the essential physicochemical interactions between the pore solution and the cement hydrates in chloride-contaminated cement-based materials. AB - The chloride transport properties of cement-based materials are determined via the physicochemical interactions between the pore solution and the cement hydrates. Herein, a thermodynamic model based on surface complexation reactions and dissolution/precipitation reactions was established to investigate the essential physicochemical interactions. The effects of chloride concentration, temperature, and saturation degree (the ratio of water volume to pore volume) on the physicochemical interactions were studied in detail using the resulting thermodynamic model. The published experimental results indicate that the resulting thermodynamic model accurately reflects the adsorption capacity of cement hydrates for chloride ions. Thus, this thermodynamic model can be coupled to the transport equations to achieve the durable designs for new reinforced concrete structures (RCSs) or to predict the service life of existing RCSs. It can also optimize corrosion control strategies for RCSs based on the thermodynamics and kinetics of the material. PMID- 30025329 TI - Core-shell structured ZnCo2O4@ZnWO4 nanowire arrays on nickel foam for advanced asymmetric supercapacitors. AB - One of the most effective tactics to promote the electrochemical performance of supercapacitors is to design and synthesize hybrid binder-free electrodes with core-shell structures. In this work, hierarchical ZnCo2O4@ZnWO4 core-shell nanowire arrays grown on nickel foam are successfully fabricated via a facile two step hydrothermal route and subsequent thermal treatment. The ZnCo2O4 nanowire arrays supported on nickel foam serve as the backbone for anchoring ZnWO4 nanosheets. When tested as binder-free electrodes for supercapacitors, the as prepared ZnCo2O4@ZnWO4 hybrid electrode exhibits an ultrahigh specific areal capacitance of 13.4 F cm-2 at a current density of 4 mA cm-2 and superb cycling stability (98.5% retention after 5000 continuous cycles at a current density of 100 mA cm-2). Furthermore, an asymmetric supercapacitor based on ZnCo2O4@ZnWO4//active carbon is successfully designed. The as-designed asymmetric supercapacitor can achieve a maximum energy density of 24 Wh kg-1 at a power density of 400 W kg-1. Moreover, two as-prepared asymmetric supercapacitor devices in a series connection are able to light up a white light-emitting diode over 30 min. The outstanding electrochemical properties of the hybrid electrode demonstrate that it holds great potential for next generation energy storage applications. PMID- 30025330 TI - Gas sensor based on samarium oxide loaded mulberry-shaped tin oxide for highly selective and sub ppm-level acetone detection. AB - Mulberry-shaped tin oxide (SnO2) hierarchical architectures and samarium oxide (Sm2O3) loaded tin oxide with different amounts (0.5, 1, 2.5, and 4 mol% Sm2O3) were successfully synthesized by facile hydrothermal synthesis method and simple isometric impregnation method. The gas sensing performance of the sensors based on pure SnO2 and Sm2O3 loaded SnO2 materials were systematically investigated. The results indicated that Sm2O3 loading considerably affected the improvement of the sensing performance of the SnO2 sensor. The 2.5 mol% Sm2O3/SnO2 exhibited the highest response (41.14) to 100 ppm acetone, the response was 2.29 times higher than that of pure SnO2 (18). In addition, with 2.5 mol% Sm2O3 loading, the low detection threshold of the sensor dropped from 500 ppb to 100 ppb. The enhanced gas sensing performance was mainly bacause of the increased oxygen vacancies created by the substitution of samarium in the SnO2 lattice, which enhanced the adsorption of oxygen and the exceptional catalytic effect of Sm2O3. PMID- 30025331 TI - Dandelion-like nickel/cobalt metal-organic framework based electrode materials for high performance supercapacitors. AB - Metal-organic frameworks (MOFs), serving as a promising electrode material in the supercapacitors, have attracted tremendous interests in recent years. Here, through modifying the molar ratio of the Ni2+ and Co2+, we have successfully fabricated Ni-MOF and Ni/Co-MOF by a facile hydrothermal method. The Ni/Co-MOF with a dandelion-like hollow structure shows an excellent specific capacitance of 758 F g-1 at 1 A g-1 in the three-electrode system. Comparing with Ni-MOF, the obtained Ni/Co-MOF has a better rate capacitance (89% retention at 10 A g-1) and cycling life (75% retention after 5000 circulations). Besides, the assembled asymmetric supercapacitor based on Ni/Co-MOF and active carbon exhibits a high specific energy density of 20.9 W h kg-1 at the power density of 800 W kg-1. All these results demonstrate that the mixed-metal strategy is an effective way to optimize the morphology and improve the electrochemical property of the MOFs. PMID- 30025333 TI - Quantitative and qualitative analysis of ictal vocalization in focal epilepsy syndromes. AB - PURPOSE: To investigate the frequency, localizing significance, and intensity characteristics of ictal vocalization in different focal epilepsy syndromes. METHODS: Up to four consecutive focal seizures were evaluated in 277 patients with lesional focal epilepsy, excluding isolated auras and subclinical EEG seizure patterns. Vocalization was considered to be present if observed in at least one of the analyzed seizures and not being of speech quality. Intensity features of ictal vocalization were analyzed in a subsample of 17 patients with temporal and 19 with extratemporal epilepsy syndrome. RESULTS: Ictal vocalization was observed in 37% of the patients (102/277) with similar frequency amongst different focal epilepsy syndromes. Localizing significance was found for its co occurrence with ictal automatisms, which identified patients with temporal seizure onset with a sensitivity of 92% and specificity of 70%. Quantitative analysis of vocalization intensity allowed to distinguish seizures of frontal from temporal lobe origin based on the intensity range (p = 0.0003), intensity variation (p < 0.0001), as well as the intensity increase rate at the beginning of the vocalization (p = 0.003), which were significantly higher in frontal lobe seizures. No significant difference was found for mean intensity and mean vocalization duration. CONCLUSIONS: Although ictal vocalization is similarly common in different focal epilepsies, it shows localizing significance when taken into account the co-occurring seizure semiology. It especially increases the localizing value of automatisms, predicting a temporal seizure onset with a sensitivity of 92% and specificity of 70%. Quantitative parameters of the intensity dynamic objectively distinguished frontal lobe seizures, establishing an observer independent tool for semiological seizure evaluation. PMID- 30025332 TI - Improvement of catalytic activity over Mn-modified CeZrOx catalysts for the selective catalytic reduction of NO with NH3. AB - A series of MnCeZrOx mixed oxide catalysts were facilely synthesized using the impregnation-NH3.H2O coprecipitation method and tested for selective catalytic reduction (SCR) of NO with NH3. Doping manganese significantly improved the catalytic activity and the best performing SCR catalyst, Mn0.25Ce0.5Zr0.25Ox, was shown to achieve NO conversion > 80% in the temperature range (60-350 degrees C), with the denitration effect up to 50% at room temperature (conditions: [NO] = [NH3] = 500 ppm, [O2] = 5 vol%, He as balance, flow rate = 100 mL/min, GHSV = 40, 000 h-1). Characterization of the catalyst using BET, XRD, XPS, H2-TPR, and in-situ FTIR proved that the improved SCR activity may be attributed to the large surface area, great reduction ability and increased amount of surface adsorbed oxygen afforded by the introduction of manganese. The SCR reaction mechanisms were also investigated by analyzing in-situ FTIR spectra and the SCR reaction pathway over the Mn0.25Ce0.5Zr0.25Ox catalyst was shown to mostly follow the E-R mechanism. PMID- 30025334 TI - Praxis-induced myoclonia: From the neurophysiologist to the patient perspective. AB - PURPOSE: To characterize semiology and EEG features of praxis-induced (PI) myoclonia and to describe the subjective perception of juvenile myoclonic epilepsy (JME) patients with this reflex trait. METHODS: Patients with JME who presented myoclonia during a Video-EEG Neuropsychological Protocol were selected. We analyzed the semiology of upper limbs myoclonia and the ictal EEG patterns on Video-EEG. We explored the subjective aspects of PI by performing a semi structured interview to each patient. RESULTS: 15 patients experienced 59 upper limbs myoclonia. Jerks were more frequently asymmetric or unilateral (32/59); a bilaterally symmetric pattern of all myoclonia was observed in only five patients. Ictal pattern was polyspike-wave (PSW) in 31/59 myoclonic seizures and spike-and-wave (SW) in 28/59. Six patients started perceiving myoclonia while learning a new skill or practicing a previously learned skill in a more stressful context. For most patients, PI-myoclonia were a source of anxiety. PI persisted despite antiepileptic medications in 10 patients. CONCLUSIONS: Electroclinical features of PI-myoclonia were more heterogeneous than traditionally described. Ictal pattern of SW was almost as frequent as classical PSW. Patients described the influence of learning new skills and anxiety on PI. Their subjective perception let us understand the impact of this reflex trait. PMID- 30025335 TI - Morel-Lavallee lesion in a 12-month-old child: A case report and literature review. AB - INTRODUCTION: The Morel-Lavallee lesion is an infrequently described, post traumatic closed de-gloving wound that results from separation of the skin and subcutaneous tissues from the underlying deep fascia as a result of shearing forces that tear perforating vessels and lymphatics. This condition is rare in children and to our knowledge it represents the youngest case of Morel-Lavallee lesion yet reported. PRESENTATION OF CASE: We report on a twelve-month-old girl who presented after a motor vehicle accident with a tender fluctuant mass of the back and buttocks. Computed tomography revealed a large but discrete fluid collection between the subcutaneous fat and the deep fascial planes, extending from the posterior thoracic paraspinal soft tissues to the right gluteal region. A diagnosis of Morel-Lavallee lesion was made. This patient was managed with serial ultrasound-guided percutaneous drainage and compression bandages. The patient did well and was subsequently discharged. There was no recurrence of the lesion on follow-up. DISCUSSION: The Morel-Lavallee lesion is a rare consequence of abrupt high impact trauma. There is no accepted management approach and a variety of conservative as well as surgical options exist. Goals of management include drainage, debridement and meticulous dead space management to prevent recurrence. CONCLUSION: The Morel-Lavallee lesion is a rare finding in children involved in high impact trauma and prompt intervention is crucial to prevent complications. Image-guided drainage is a rational management approach with excellent outcomes. PMID- 30025336 TI - Controversial case: Revascularization of a popliteal vascular injury of poor prognosis. AB - INTRODUCTION: Popliteal injuries are significant health risk that could induce permanent functional impairment, limb loss, and in some cases death. Currently, there is a controversy about the required treatment between amputation and a limb salvage surgery, which in some cases could cause more prominent functional impairment than the amputation. Different indicators help to predict, in some extent, the risk of amputation, however most of them were described two decades ago. PRESENTATION OF CASE: A patient with a prolonged hot ischemia and in critical conditions, which had no favorable clinical indicators for revascularization is shown and discussed. By means of intraoperative analysis, it was decided to perform a revascularization for limb salvage, progressing with a positive outcome. DISCUSSION: Advancements in medical and vascular surgery, such as osteovascularized grafts, the use of flaps to cover large defects, the Ilizarov method for bone elongation and stabilization, the use of growth factors, negative pressure therapy, and the use of extracellular matrix, the improvements of intensive care units (ICU), among others, make necessary to revisit and reevaluate these indicators. The accuracy of these indicators has dropped significantly, and currently the medical evaluation cannot longer only depend on them. CONCLUSION: Our results suggest the need to revisit and improve the predicting indicators scores for amputation prognosis that should include a preoperative and transoperative analysis. PMID- 30025337 TI - Stent graft placement for an incidental finding of hepatic artery pseudoaneurysm post hepatectomy, a case report and literature review. AB - INTRODUCTION: Hepatic artery pseudoaneurysm is usually iatrogenic, with bleeding occurring early or late postoperatively. CASE PRESENTATION: A 61-year-old man with pseudoaneurysm of the common hepatic artery post hepatectomy treated with a stent-graft. The patient was asymptomatic and the pseudoaneurysm appeared incidentally on follow-up. Selective catheterization of the common hepatic artery showed a pseudo-aneurysm close to its origin. Covered stent was deployed in the main hepatic artery. Completion angiography showed no residual spasm and adequate patency of the common hepatic artery, with complete exclusion of the pseudoaneurysm. DISCUSSION: Using stentgraft for pseudoaneurysm management has multiple advantages when compared to other traditional techniques. However, stent placement has its own complications. CONCLUSION: Stent graft placement post hepatic artery pseudo-aneurysm is safe and effective; however its complications should be evaluated with multidisciplinary team. PMID- 30025338 TI - Thermal and non-thermal health effects of low intensity non-ionizing radiation: An international perspective. AB - Exposure to low frequency and radiofrequency electromagnetic fields at low intensities poses a significant health hazard that has not been adequately addressed by national and international organizations such as the World Health Organization. There is strong evidence that excessive exposure to mobile phone frequencies over long periods of time increases the risk of brain cancer both in humans and animals. The mechanism(s) responsible include induction of reactive oxygen species, gene expression alteration and DNA damage through both epigenetic and genetic processes. In vivo and in vitro studies demonstrate adverse effects on male and female reproduction, almost certainly due to generation of reactive oxygen species. There is increasing evidence the exposures can result in neurobehavioral decrements and that some individuals develop a syndrome of "electro-hypersensitivity" or "microwave illness", which is one of several syndromes commonly categorized as "idiopathic environmental intolerance". While the symptoms are non-specific, new biochemical indicators and imaging techniques allow diagnosis that excludes the symptoms as being only psychosomatic. Unfortunately standards set by most national and international bodies are not protective of human health. This is a particular concern in children, given the rapid expansion of use of wireless technologies, the greater susceptibility of the developing nervous system, the hyperconductivity of their brain tissue, the greater penetration of radiofrequency radiation relative to head size and their potential for a longer lifetime exposure. PMID- 30025339 TI - The dynamic role of pH in microbial reduction of uranium(VI) in the presence of bicarbonate. AB - The negative effect of carbonate on the rate and extent of bioreduction of aqueous U(VI) has been commonly reported. The solution pH is a key chemical factor controlling U(VI)aq species and the Gibbs free energy of reaction. Therefore, it is interesting to study whether the negative effect can be diminished under specific pH conditions. Experiments were conducted using Shewanella putrefaciens under anaerobic conditions with varying pH values (4-9) and bicarbonate concentrations ( [Formula: see text] , 0-50 mmol/L). The results showed a clear correlation between the pH-bioreduction edges of U(VI)aq and the [Formula: see text] . The specific pH at which the maximum bioreduction occurred (pHmbr) shifted from slightly basic to acidic pH (~7.5-~6.0) as the [Formula: see text] increased (2-50 mmol/L). At [Formula: see text] = 0, however, no pHmbr was observed in terms of increasing bioreduction with pH (~100%, pH > 7). In the presence of [Formula: see text] , significant bioreduction was observed at pHmbr (~100% at 2-30 mmol/L [Formula: see text] , 93.7% at 50 mmol/L [Formula: see text] ), which is in contrast to the previously reported infeasibility of bioreduction at high [Formula: see text] . The pH-bioreduction edges were almost comparable to the pH-biosorption edges of U(VI)aq on heat-killed cells, revealing that biosorption is favorable for bioreduction. The end product of U(VI)aq bioreduction was characterized as insoluble nanobiogenic uraninite by HRTEM. The redox potentials of the master complex species of U(VI)aq, such as [Formula: see text] , [Formula: see text] , and [Formula: see text] , were calculated to obtain insights into the thermodynamic reduction mechanism. The observed dynamic role of pH in bioreduction suggests the potential for bioremediation of uranium contaminated groundwater containing high carbonate concentrations. PMID- 30025340 TI - Emission factors of particulate and gaseous compounds from a large cargo vessel operated under real-world conditions. AB - On-board emissions measurements were performed on a Handysize-class bulk carrier operating under real-world conditions. Emission factors (EFs) were determined for criteria pollutants such as NOx, CO, total hydrocarbons (THC), and PM; PM composition, including organic and elemental carbon (OC and EC), inorganic species, and a variety of organic compounds and VOC species (including alkanes, alkenes, single-ring aromatics, and oxygenated VOCs) were also analyzed. To investigate the impacts of engine type, fuel, and operating conditions on emissions, measurements were conducted on one main and one auxiliary engines using low- and high-sulfur fuels (LSF and HSF) under actual operating conditions, including at-berth, maneuvering, and cruising at different engine loads. OC was the most abundant PM component (contributing 45-65%), followed by sulfate (2-15%) and EC (1-20%). Compounds with 3 or 4 aromatic rings, including phenanthrene, fluoranthene, pyrene, and benzo[b+k]fluoranthene, dominated the particulate polycyclic aromatic hydrocarbons (PAHs) emitted from the ship, accounting for 69 89% of the total PAHs. Single-ring aromatics constituted 50-78% of the emitted VOCs and were dominated by toluene. In this study, switching from HSF (1.12% S) to LSF (0.38% S) reduced emitted PM by 12%, OC by 20%, sulfate by 71%, and particulate PAHs by 94%, but caused an increase in single-ring aromatics. The power-based EFs generally decreased with increasing engine loads. However, decreasing the ship engine load also reduced the vessel speed and, thus, decreased emissions over a given voyage distance. Herein, a Vessel Speed Reduction (VSR) from 11 to 8-9 knots decreased NOx and PM emissions by approximately 33% and 36%, respectively, and OC, EC, sulfate, and particulate PAHs in PM emissions by 34%, 83%, 29%, and 11%. These data can be used to minimize uncertainty in the emission factors used in ship emissions calculations. PMID- 30025342 TI - Occurrence of halogenated natural products in highly consumed fish from polluted and unpolluted tropical bays in SE Brazil. AB - Natural compounds from the metabolism of marine organisms have been detected at high concentrations in environmental samples which are not the producers of these compounds. These natural substances are known as halogenated natural products (HNPs). HNPs are possibly toxic halogenated compounds analogous to POPs that may bioaccumulate and biomagnify along the food web and pose a further risk to human and environmental health. The present study analyzed the occurrence of HNPs in the edible muscle of the three most consumed commercial fish species in the state of Rio de Janeiro: sardine (Sardinella brasiliensis), whitemouth croaker (Micropogonias furnieri) and mullet (Mugil liza) from the highly polluted Guanabara Bay (GB) and the less polluted Ilha Grande Bay (IGB). The analytical steps included Soxhlet extraction, clean-up step and injection in a gas chromatography system coupled to a mass spectrometer operated in the electron capture negative ion mode (GC/ECNI-MS). The compounds 2,4,6-TBP, 2,4,6-TBA, MHC 1, Q1, 6-MeO-BDE 47 and 2'-MeO-BDE 68 were found in the analyzed fish from both studied areas. Q1, 6-MeO-BDE 47 and 2'-MeO-BDE 68 showed the highest concentrations in samples. Q1 concentrations in the sardines from IGB were higher than the sardines from GB (p < 0.05) and higher than the other IGB species (p < 0.05). The differences found among the species may be related to their characteristic habitat and diet. It is noteworthy that most of these compounds do not have any toxicological reference value. Moreover, the HNPs are being detected in species of low trophic level and since this study has worked only with commercial species, these fish may be considered as a source for human exposure to these natural compounds. PMID- 30025341 TI - Predicting monthly high-resolution PM2.5 concentrations with random forest model in the North China Plain. AB - Exposure to fine particulate matter (PM2.5) remains a worldwide public health issue. However, epidemiological studies on the chronic health impacts of PM2.5 in the developing countries are hindered by the lack of monitoring data. Despite the recent development of using satellite remote sensing to predict ground-level PM2.5 concentrations in China, methods for generating reliable historical PM2.5 exposure, especially prior to the construction of PM2.5 monitoring network in 2013, are still very rare. In this study, a high-performance machine-learning model was developed directly at monthly level to estimate PM2.5 levels in North China Plain. We developed a random forest model using the latest Multi-angle implementation of atmospheric correction (MAIAC) aerosol optical depth (AOD), meteorological parameters, land cover and ground PM2.5 measurements from 2013 to 2015. A multiple imputation method was applied to fill the missing values of AOD. We used 10-fold cross-validation (CV) to evaluate model performance and a separate time period, January 2016 to December 2016, was used to validate our model's capability of predicting historical PM2.5 concentrations. The overall model CV R2 and relative prediction error (RPE) were 0.88 and 18.7%, respectively. Validation results beyond the modeling period (2013-2015) shown that this model can accurately predict historical PM2.5 concentrations at the monthly (R2 = 0.74, RPE = 27.6%), seasonal (R2 = 0.78, RPE = 21.2%) and annual (R2 = 0.76, RPE = 16.9%) level. The annual mean predicted PM2.5 concentration from 2013 to 2016 in our study domain was 67.7 MUg/m3 and Southern Hebei, Western Shandong and Northern Henan were the most polluted areas. Using this computationally efficient, monthly and high-resolution model, we can provide reliable historical PM2.5 concentrations for epidemiological studies on PM2.5 health effects in China. PMID- 30025343 TI - Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as potent anticancer agents with CDK9 inhibitory activity. AB - New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC50 = 0.63-1.32 MUM) relative to sorafenib (IC50 = 0.76 MUM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C). PMID- 30025344 TI - Novel indolo-sophoridinic scaffold as Topo I inhibitors: Design, synthesis and biological evaluation as anticancer agents. AB - Based on the mechanism of action, novel scaffolds as Topo I inhibitors bearing indole and sophoridinine were designed. Preliminary docking study revealed that some molecules among the designed series possessed promising Topo I inhibitor properties. Subsequently, thirty new compounds were synthesized and characterized by 1H NMR, 13C NMR, and Mass spectral analyses. The compounds were then screened for their antiproliferative and enzymatic inhibitory activities. The results affirmed the consistency between docking and activities and the rationality of the design strategy. Furthermore, compound 10b was chosen as a representative compound to test its anticancer effects in vitro and in vivo. The results showed that 10b caused prominent S phase cell cycle arrest and significantly suppressed tumor growth in HepG2 cell derived mouse model. These findings present a promising series of lead molecules which can serve as potential Topo I inhibitors for the treatment of cancer and a theoretical basis for structural modifications. PMID- 30025345 TI - Novel curcumin analogue hybrids: Synthesis and anticancer activity. AB - In this study, twenty curcumin analogue hybrids as potential anticancer agents through regulation protein of TrxR were designed and synthesized. Results of anticancer activity showed that 5,7-dimethoxy-3-(3-(2-((1E, 4E)-3-oxo-5-(pyridin 2-yl)penta-1,4-dien-1- yl)phenoxy)propoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen 4-one (compound 7d) could induce gastric cancer cells apoptosis by arresting cell cycle, break mitochondria function and inhibit TrxR activity. Meanwhile, western blot revealed that this compound could dramatically up expression of Bax/Bcl-2 ratio and high expression of TrxR oxidation. These results preliminarily show that the important role of ROS mediated activation of ASK1/MAPK signaling pathways by this title compound. PMID- 30025346 TI - Biological activity of doubly modified salinomycin analogs - Evaluation in vitro and ex vivo. AB - The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic drugs cisplatin and doxorubicin in the LoVo/DX multi-drug resistant cell line. All analogs were tested against primary acute lymphoblastic leukemia cells in standard cell viability assays; three were more potent than salinomycin. Further studies revealed that selected analogs induced characteristics of apoptotic cell death and increased expression of p53. Additionally, using an ex vivo model of breast tumor, tumor cell viability significantly decreased after treatment with salinomycin or its double-modified derivative (3a) in a time-dependent manner. The present findings indicate that double-modified salinomycin derivatives constitute promising lead compounds for targeting various types of cancer. PMID- 30025347 TI - Synthesis and evaluation of the cytotoxic activity of Furanaphthoquinones tethered to 1H-1,2,3-triazoles in Caco-2, Calu-3, MDA-MB231 cells. AB - Naphthoquinones and 1,2,3-triazoles are structural pharmacophore that is known to impart several cancer cells. This work shows a synthetic methodology to obtain hybrid molecules involving naphthoquinone and triazol scaffold as multiple ligands. A simple and efficient synthetic route was used to prepare a series of sixteen compounds being eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3 dihydronaphtho[1,2 b]furan-4,5-diones and eight 2-(1-aryl-1H-1,2,3-triazol-4-yl) 2,3-dihydronaphtho[2,3-b]furan-4,9-diones. These compounds were tested in MDA MB231, Caco-2 and Calu-3 human cancer cells, and among them 7a was the most selective compound on Caco-2 cells, the most sensitized cell line in this study. In silico study suggest that the blockage of topoisomerase I and IIalpha may be one of the mechanisms of action responsible for the cytotoxic effect of 7a in Caco-2 cells. PMID- 30025349 TI - Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold. AB - Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling. PMID- 30025350 TI - Design, synthesis and screening of 1, 2, 4-triazinone derivatives as potential antitumor agents with apoptosis inducing activity on MCF-7 breast cancer cell line. AB - Some triazinone derivatives are designed and synthesized as potential antitumor agents. Triazinone derivatives 4c, 5e and 7c show potent anticancer activity over MCF-7 breast cancer cells higher than podophyllotoxin (podo) by approximate 6 fold. DNA flow cytometry analysis for the compounds 3c, 4c, 5e, 6c and 7c show a potent inhibitory activity of cell proliferation and cell cycle arrest at G2/M phase. Compounds 4c, 5e and 7c exhibit low to moderate beta-tubulin polymerization inhibition percentage. Meanwhile, compound 6c displayed excellent beta-tubulin percentage of polymerization inhibition equivalent to that exhibited by podo. In addition, compounds 4c, 5e and 7c show strong topoisomerase (topo) II inhibitory activity in nano-molar concentration, compared to known topo inhibitor as etoposide. Finally, apoptotic inducing activity over MCF-7 of compounds 4c, 5e, 6c and 7c is due to up-regulation of p53, increased Bax/Bcl-2 ratio and caspase3/7 levels 2-fold higher than podo. PMID- 30025348 TI - Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease. AB - In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (sigma1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2 carboxamide (18) is highlighted due to its interesting biological profile in sigma1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and sigma1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs. PMID- 30025351 TI - Design, synthesis and antimicrobial evaluation of propylene-tethered ciprofloxacin-isatin hybrids. AB - Twelve novel propylene-tethered ciprofloxacin-isatin hybrids 3a-f and 4a-f were designed, synthesized and characterized by MS, HRMS, 1H NMR and 13C NMR. All hybrids were evaluated for their in vitro antimicrobial activities against representative Gram-positive, Gram-negative and mycobacterial pathogens, cytotoxicity in VERO cell line as well as metabolic stability and in vivo pharmacokinetic (PK) properties. The preliminary results indicated that all mono isatin-ciprofloxacin hybrids exhibited excellent antibacterial activities with MIC ranging from <=0.03 to 0.5 MUg/mL against most of the tested strains. In particular, ciprofloxacin-isatin hybrid 3d was highly potent against all tested Gram-positive and Gram-negative strains including clinically important drug resistant pathogens, which was comparable to or more potent than the parent ciprofloxacin and reference levofloxacin. Whereas, conjugate 3b (MIC: 0.10 and 0.5 MUg/mL) was 4- and 8-fold more active than ciprofloxacin (MIC: 0.78 MUg/mL) and rifampicin (MIC: 0.39 MUg/mL) against MTB H37Rv, and 4->256 times more potent than the three references ciprofloxacin (MIC: 2.0 MUg/mL), rifampicin (MIC: 32 MUg/mL) and isoniazid (>128 MUg/mL) against MDR-TB. Both hybrid 3b and 3d with low cytotoxicity (CC50: 64 and 256 MUg/mL) also showed acceptable metabolic stability and in vivo PK properties, could act as leads for further optimization. PMID- 30025353 TI - Quantifying drivers' visual perception to analyze accident-prone locations on two lane mountain highways. AB - Owing to constrained topography and road geometry, mountainous highways are subjected to frequent traffic accidents, and these crashes have relatively high mortality rates. In middle and high mountains, most roads are two-lane highways. Most two-lane mountain highways are located in rural areas in China, where traffic volume is relatively small; namely, traffic accidents are mainly related to the design of roads, rather than the impact of traffic flow. Previous studies primarily focused on the relationship between actual road geometry and traffic safety. However, some scholars put forward that there was a significant discrepancy between actual and visual perceived information. Drivers greatly depend on what they perceived by their vision to determine driving behavior. Thus, in this paper drivers' visual lane model was established to quantify drivers' visual perception. To further explore drivers' perception of horizontal and vertical alignments, the visual lane model was projected onto horizontal and vertical planes in drivers' vision respectively. The length and curvature of the visual curve were extracted as shape parameters of drivers' visual lane models. Real vehicle driving tests were conducted on typical two-lane mountain highway sections of G318 in Tibet, China. Then the differences of visual perception at black spots and accident-free locations were analyzed and compared. In horizontal and vertical projections of visual lane model, there were 9 shape parameters have significant differences between accident-prone and accident-free locations. A probabilistic neural network (PNN) was formed to identify accident-prone locations on two-lane mountain highways. This study will lay a foundation for the improvement of traffic safety on mountain highways based on the quantification of drivers' visual perception, during the phase of both road design and reconstruction, and can also make a contribution to the automatic driving technique. PMID- 30025354 TI - Health and safety practitioners' health and wellbeing - The link with safety climate and job demand-control-support. AB - BACKGROUND/AIMS: Health and Safety Practitioners (HSPs), as frontline professionals advocating for health and safety (HS) working conditions, have crucial roles for the wellbeing of employees. However, research studying HSPs psychosocial working conditions - i.e. job demands, control and support (JDCS) -, safety climate (SC) and their impact on HSPs health and wellbeing is scarce. This novel study aims to examine the link of JDCS and SC with HSPs' health, wellbeing and efficacy. METHODS: A web-survey was completed by 879 HSPs, members of the Institution of Occupational Safety and Health (IOSH) in Ireland and the UK. Multiple linear regression analysis was used to determine the association between JDCS, SC and general health (GHQ12), mental wellbeing (WEMWBS) and efficacy. RESULTS: After adjusting for age, gender and years of experience, job demands were significantly associated with HSPs health (beta = 0.40; p = 0.00) and mental wellbeing (beta=-0.29; p = 0.00). Positive significant independent associations were also found between job control, support, SC and HSPs health, mental wellbeing as well as efficacy. In a final model, all psychosocial working conditions and SC were significantly associated with health and mental-wellbeing of HSPs. CONCLUSION: This study showed that psychosocial working conditions and SC can affect HSPs health and wellbeing - associations rarely previously recorded. The link of safety climate with HSPs efficacy, with contribution of job control and support, reveals possible further impacts of SC on safety performance. The findings highlight the importance of HSPs working conditions while reflecting on the wider impact on OHS in organisations, its workforce and stakeholders. PMID- 30025352 TI - Co-oxidation of As(III) and Fe(II) by oxygen through complexation between As(III) and Fe(II)/Fe(III) species. AB - Previous studies have shown that the oxidation of Fe(II) by molecular oxygen can lead to the co-oxidation of As(III) at neutral pH. However, the mechanism of As(III) oxidation in the presence of Fe(II) with respect to the interaction between As(III) and Fe(II) is still unclear. In this work, we examined the oxidation of As(III) in the presence of Fe(II) in air-saturated water, which is affected by pH, co-existing phosphate, and scavengers (tert-butanol, superoxide dismutase, catalase and dimethylsulfoxide). Results confirm that the formation of the Fe(II)-As(III) complex (formation constant, KFe(II)-As(III) = 103.86 M-1) plays an extremely important role in the initial stage of As(III) oxidation at pH 7.25. The oxidation of Fe(II)-As(III) promotes the production of H2O2 and colloidal ferric hydroxide. H2O2 reacts with the Fe(II)-As(III) complex through oxidizing Fe(II) to Fe(IV), which then causes the partial oxidation (ca. 50%) of As(III). The other part of As(III) oxidation by H2O2 occurs, in the form of Fe(III)-As(III) complex, through direct electron transfer from As(III) to H2O2 but not through Fe(IV). This work provides new mechanistic insight into arsenic and iron redox chemistry in the environment and furthers our understanding of Fenton reactions at neutral pH. PMID- 30025355 TI - Cortical phase locking to accelerated speech in blind and sighted listeners prior to and after training. AB - Cross-correlation of magnetoencephalography (MEG) with time courses derived from the speech signal has shown differences in phase-locking between blind subjects able to comprehend accelerated speech and sighted controls. The present training study contributes to disentangle the effects of blindness and training. Both subject groups (baseline: n = 16 blind, 13 sighted; trained: 10 blind, 3 sighted) were able to enhance speech comprehension up to ca. 18 syllables per second. MEG responses phase-locked to syllable onsets were captured in five pre-defined source locations comprising left and right auditory cortex (A1), right visual cortex (V1), left inferior frontal gyrus (IFG) and left pre-supplementary motor area. Phase locking in A1 was consistently increased while V1 showed opposite training effects in blind and sighted subjects. Also the IFG showed some group differences indicating enhanced top-down strategies in sighted subjects while blind subjects may have a more fine-grained bottom-up resolution for accelerated speech. PMID- 30025356 TI - Anxiety-associated behavior and genotoxicity found in adult Danio rerio exposed to tebuconazole-based commercial product. AB - The effects of different concentrations of commercial product based on tebuconazole, on adults of Danio rerio, were evaluated through novel tank diving test and micronucleus and comet assay tests. A total of 320 adult D. rerio were divided into eight tanks and exposed to concentrations of 0; 100; 200 and 300 MUg/L the commercial product based on tebuconazole, with their respective replicates at 24, 72 and 96 h. The results showed a behavioral deviation of zebrafish and a significant (p < 0.05) increase in DNA damage as a function of exposed time and different concentrations of the commercial product in relation to the negative control. The results obtained in this study allow to conclude that tebuconazole has effects on adults of Danio rerio, inducing genotoxicity and mutagenicity, as well as altering neurological functions related to the change in the behavior of adults. PMID- 30025357 TI - The use of liver slices from the Cape vulture (Gyps coprotheres) to better understand the role of liver toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) in vultures. AB - Diclofenac, a non-steroidal anti-inflammatory drug (NSAID) was responsible for the death of millions of vultures on the Asian subcontinent, following the consumption of diclofenac contaminated carcasses. The aim of this research was to establish if liver slices could serve as an alternate means of predicting the toxicity of NSAIDs in Gyps vultures. The Cape vulture liver slices was prepared and incubated with four NSAIDs for 6 h. A percent clearance of 1.0 +/- 0.253, 0.58 +/- 0.153, 0.961 +/- 0.312 and 1.242 +/- 0.406 (%/h*g) was attained for diclofenac, carprofen, ketoprofen and meloxicam respectively. Both meloxicam and diclofenac exerted toxic effects on the hepatic cells. Protein content indicated that the vulture tissue had lower enzyme levels than expected for an animal of its size. The poor distinction between the ex vivo hepatic percent clearance of meloxicam and diclofenac indicates that liver slices is not an ideal model to investigate NSAIDs toxicity in Cape vulture. PMID- 30025358 TI - Plasma concentration of Retinol Binding Protein 4 (RBP4) in relation to nutritional status and kidney function in older population of PolSenior Study. AB - PURPOSE: The aim of the study was to assess plasma RBP4 concentration in elderly subjects in relation to nutritional status and kidney function in the population of the PolSenior Study. MATERIAL AND METHODS: We assessed RBP4, glucose, insulin, albumin, lipid profile, C-reactive protein, (hsCRP) and creatinine concentrations in 2614 PolSenior Study participants (1235 women and 1379 men). The study group was divided based on BMI and HOMA-IR values, and the occurrence of diabetes. RESULTS: Plasma RBP4 concentration was similar in normal weight, overweight, and obese subgroups, both in women (40.4 vs 40.8 vs 41.8 ng/ml, respectively), and men (41.2 vs 40.3 vs 42.9 ng/ml, respectively). Similar values were found in subjects with HOMA-IR <2.5; >=2.5 and diabetes, while those with decreased eGFR (<60 ml/min/1.73 m2) were characterized by increased RBP4 levels [46.0 (32.0 64.8) vs 39.4 (28.2-54.9) ng/ml; p < 0.001]. Plasma RBP4 level variability was explained by: age, waist circumference or BMI, and eGFR, but not HOMA-IR and/or hsCRP. The standardized coefficients beta (slopes) for BMI and waist circumference were similar. CONCLUSIONS: The results revealed that in older subjects, circulating RBP4 levels are mostly affected by kidney function and modestly by age, gender, and nutritional status, but not insulin resistance. PMID- 30025359 TI - Bi2Zr2O7 nanoparticles synthesized by soft-templated sol-gel methods for visible light-driven catalytic degradation of tetracycline. AB - Tetracycline (TC), an antibiotic, is persistent in nature and frequently detected in water and sediments. Visible-light-driven photocatalyst for TC degradation is a promising environmental-friendly technology. Bi2Zr2O7, an effective photocatalyst, but no studies on its photodegradation of TC could be found in literature. In this study, Bi2Zr2O7 was synthesized by three soft templated sol gel methods. Three synthesized Bi2Zr2O7 catalysts have different structures, morphologies and band gaps. The Bi2Zr2O7 nanoparticles synthesized with citric acid as the template (BZO-3) had a larger specific surface area (30.7 m2/g) and a narrower band gap (2.39 eV), and exhibited a better performance for TC degradation under visible light with an efficiency of up to 81.3%. They also exhibited good stability and reusability in recycled experiments. A reaction mechanism of TC degradation by these photocatalyst was proposed. The enhanced photocatalytic performance was mainly due to photogenerated holes of reactive species and TC was mainly degraded on the surface of the photocatalyst. Pathways of TC photodegradation were derived from the result of analyses of the reaction intermediates. In conclusion, Bi2Zr2O7 nanoparticles were found effective as photocatalyst for TC photodegradation by visible light. PMID- 30025360 TI - Degradation of norfloxacin in aqueous solution by atmospheric-pressure non thermal plasma: Mechanism and degradation pathways. AB - Norfloxacin is a synthetic antibiotics drug which is widely used in the treatment of infectious diseases and also often carelessly released into natural environment resulting in antibiotics-contaminated wastewater. In this work, we employed atmospheric-pressure non-thermal dielectric barrier discharge (DBD) to treat norfloxacin-contaminated water and investigated the degradation efficiency and mechanism for the plasma treatments under different conditions with varied working gas atmospheres. Our results showed that the DBD efficiency for norfloxacin degradation depended on reactive oxygen/nitrogen species (RONS) produced in the plasma treatment, while the plasma-induced hydroxyl radical played a critical role in the norfloxacin degradation. For O2-DBD, except for the contribution from reactive oxygen species (ROS), ozone could also play an important role. For N2-DBD, reactive nitrogen species (RNS) could work synergistically with H2O2 to enhance the degradation effect. We also checked the plasma activated liquid (PAL) effect and analyzed the degradation products so that the degradation mechanism and pathways could be elucidated. This work may therefore provide the guidance for effective and feasible application of low temperature plasma technology in treatment of antibiotics-contaminated wastewater. PMID- 30025361 TI - Eichhornia crassipes mediated copper phytoremediation and its success using catfish bioassay. AB - Copper (Cu) pollution in aquaculture ponds poses substantial ecological threats. Most phytoremediation studies deal with the efforts of removing Cu from water, but seldom, such endeavors are validated by suitable bioassays. The present study undertook a two-pronged effort to remediate Cu by phytoextraction with an aquatic macrophyte, Eichhornia crassipes, and establish the efficacy of such endeavors by Clarias batrachus bioassay. For phytoextraction trials, E. crassipes was exposed to Cu concentration 0, 5, 10, 15 and 20 mg L-1 in Hoagland solution for 21 days. The highest uptake of 2168 MUg g-1 dw was at 10 mg L-1 Cu exposure, and efficient root to leaf translocation was seen for 5-10 mg Cu L-1. For these doses, there was 55-57% decline in Cu from test waters. We evaluated morphological, physiological and biochemical response of plants towards Cu stress to gauge its phytomediation capacity. For bioassays, fish were reared for 7 days in phytoremediated Cu doses of 5 and 10 mg L-1. The accumulation of Cu followed the pattern: kidney > liver > gill > muscle. Fish muscle accumulated 21.8-27.0 MUg Cu g-1 dw after 7 d, however, for E. crassipes remediated doses, muscle accumulated 8.2-10.9 MUg Cu g-1 dw, which was within the safe levels of Cu in edible tissues. Metal doses declined protein contents and augmented malondialdehyde, superoxide dismutase, catalase and peroxidase concentrations in tissues. Although their concentrations in remediated groups failed to reach the levels of control fish, significant recovery in these parameters were observed. The results pointed towards the efficacy of Cu phytoextration by E. crassipes. PMID- 30025363 TI - Assessment of the effects of graphene exposure in Danio rerio: A molecular, biochemical and histological approach to investigating mechanisms of toxicity. AB - Graphene has been shown to induce toxicity in mammals and marine crustaceans; however, information regarding oxidative stress in fish is scarce. The aim of this study was to evaluate the mechanism of graphene toxicity in different tissues of Danio rerio, considering different parameters of stress. Animals were injected intraperitoneally (i.p.) with 10 MUL of suspensions containing different graphene concentrations (5 and 50 mg/L); the gills, intestine, muscle and brain were analysed 48 h later. There was no significant difference in the expression of the gclc (glutamate cysteine ligase catalytic subunit) and nrf2 (nuclear factor (erythroid-derived 2)-like 2) genes after exposure. In contrast, glutamate cysteine ligase (GCL) and glutathione-S-transferase (GST) activities were modulated and the glutathione (GSH) concentration was reduced in different tissues and at different concentrations. Lipid damage was observed in the gills. Histological analyses were performed to observe if the exposure could induce pathological damage in these tissues. The results showed pathological effects in all tissues, excluding the intestine, after exposure to both concentrations. Overall, these results indicate that graphene induces different grades of toxicological effects that are dependent on the analysed organ, with distinct pathological effects on some and oxidative effects on others. However, the brain and gills seem to be the primary target organs for graphene toxicity. PMID- 30025362 TI - Removal of contaminants of emerging concern (CECs) and antibiotic resistant bacteria in urban wastewater using UVA/TiO2/H2O2 photocatalysis. AB - The dispersion of pollutants and proliferation of antibiotic resistant bacteria in the aquatic environment are an emerging health concern worldwide. In this sense, it is essential to develop new technologies to increase the quality of wastewater treatment, which is spread throughout the environment. The present study has demonstrated evidence of the existence of antibiotic and mercury resistant bacteria in the aquatic environment. The application of heterogeneous photocatalysis with UVA/TiO2 P25 slurry (200 mg L-1), UVA/TiO2-immobilized, and UVA/TiO2-immobilized/H2O2 were evaluated for the simultaneous elimination of a mixture of contaminants of emerging concern (acetamiprid (ACP), imazalil (IMZ) and bisphenol A (BPA)) and inactivation of antibiotic and mercury-resistant bacteria (Pseudomonas aeruginosa and Bacillus subtilis). UVA/TiO2 immobilized/H2O2 increased the inactivation and elimination of the contaminants. After the combined treatment, the mixture of BPA, IMZ and ACP decreased 62%, 21% and <5%, respectively, after 300 min at 13.10 kJ L-1 of accumulated UV energy. The Pseudomonas aeruginosa strain was inactivated after 120 min using 5.24 kJ L-1 of accumulated UV energy, whereas the Bacillus subtilis strain was shown to be extremely resistant, with a capacity to develop mechanisms to avoid the oxidation process. PMID- 30025364 TI - Featured structure-activity relationships for some tri- and tetrachlorobiphenyls in human CYP2E1-activated mutagenicity - Impact of the extent of ortho chlorination. AB - Polychlorinated biphenyls (PCBs) as a group of persistent organic pollutants are confirmed human carcinogens; however, their mutagenicity remains mostly unknown. We have reported the mutagenicity of some PCBs with one to four chlorines in mammalian cells expressing human CYP2E1. To further explore the structural requirements for the mutagenicity of PCBs, eight tri- and tetrachlorobiphenyls untested before were investigated for the induction of gene mutations and micronuclei in a V79-derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1), with SULT1A1 activity inhibited by pentachlorophenol, a potent SULT1 inhibitor. 2,2',6-Tri-, 2,3',6 tri, 2,4',6-tri-, and 2,2',5-trichlorobiphenyls (PCBs 19, 27, 32, and 18, respectively) induced micronuclei and gene mutations in V79-hCYP2E1-hSULT1A1 cells, at potencies slightly higher than 2,6-dichlorobiphenyl, but one order of magnitude below that by 2,3,3'- and 2,3,4'-trichlorobiphenyls as reported recently; in the parental V79-Mz cells, they were nonmutagenic and weak in micronuclei induction. Among the four tetrachlorobiphenyls with varying number of ortho chlorines, 2,3,3',4'-tetrachlorobiphenyl (PCB 56) induced both micronuclei and gene mutations in V79-hCYP2E1-hSULT1A1 cells with a potency greater than the above compounds; however, 2,2',3,3'-tetrachlorobiphenyl was equivocal and 2,2',3,6'-tetra- and 2,2',6,6'-tetrachlorobiphenyls inactive in V79-hCYP2E1 hSULT1A1 cells. Immunofluorescent staining of micronuclei formed by PCBs 32 and 56 in V79-hCYP2E1-hSULT1A1 cells with centromere protein B antibodies indicated that they were predominantly whole chromosomes, implying aneugenic potentials. This study suggests that tri- and tetrachlorobiphenyls with a single ortho chlorine can be most mutagenic under activation by human CYP2E1, and greater numbers of ortho chlorines may cause a drastic decline in the activity, especially for tetrachlorobiphenyls. PMID- 30025365 TI - Towards sustainable removal of methylthioninium chloride by using adsorption electroradical regeneration. AB - The current need for effective regeneration processes to be used in valorization of spent adsorbent demands the research of novel alternative techniques such as application of Advances Oxidation Processes. In this sense, the recent application of electroradical (ER) processes turned out to be very promising in terms of the drugs degradation from different environments. Thus, in this study, harnessing of a low cost natural adsorbent, Tunisian bentonite (BE), was evaluated for the removal of a model drug such as methylthioninium chloride (MC), and then its regeneration by ER processes was demonstrated. Initially, the BE was characterized and the adsorption of the MC was studied. This process followed a pseudo-first order kinetic and Langmuir isotherm fitted well to data reaching uptake values around 145-155 mg g-1. After that, BE regeneration by an ER process such as electro-Fenton process was ascertained. Due to the high buffering capacity of the BE, the addition of citric acid (1 mM) was necessary in order to assure the acidic medium to favor the oxidation reaction. By operating under optimized experimental conditions (current intensity 300 mA, pH 3, Fe2+ (1 mM) and citric acid (1 mM)) near complete adsorbent regeneration was achieved after 300 min of treatment and the pseudo-first-order model fitted well the degradation data. Furthermore, the adsorbent was efficiently used in successive cycles of adsorption-regeneration without operational problems that proved the efficiency of this technology. From the obtained results, a side-by-side configuration was designed and simulated, confirming the viability of the design at large scale. PMID- 30025367 TI - Monitoring the stress resistance of Pennisetum purpureum in Pb (II) contaminated soil bioaugmented with Enterobacter cloacae as defence strategy. AB - Lead (Pb) is reported to have negative effects on the biogeochemical behaviour of the plant growth. In recent years, the significance of rhizoremediation of heavy metals has been of great focus aiding in the development rates of plants under stressed conditions. The present study evaluated the physio-biochemical response of Pennisetum purpureum to different concentrations of Pb (II) viz., 0, 50, 100 and 150 mg kg-1 in the form of lead (II) nitrate. The pre-characterized PGPR strain, Enterobacter cloacae - KU598849 was used to augment the plants. After Pb exposure for 45 d, parameters such as plant growth, lead accumulation, H2O2 content, MDA content, protein, proline content and antioxidant enzymatic activities were quantified. Results illustrated that increasing Pb concentration reduced the early growth, metal accumulation, protein content and affected physio biochemical changes by causing oxidative damage in plants. Upon augmentation of the bacterial inoculum, the plants significantly resisted the toxic effects of Pb. Increased Pb bioaccumulation pattern was recorded in roots than shoots, were highest uptake was found to be 72 mg kg-1 dry weight when exposed to 150 mg kg-1 Pb concentration. Lead supplementation increased the activities of malonylaldehyde (MDA), superoxide dismutase (SOD), peroxidase (POX), ascorbate peroxidase (APX) and catalase (CAT) in P. purpureum. Bacterial bioaugmentation resulted in the reduction of the oxidative stress aided with reduced antioxidant enzyme activities indicating the minimization of the damages under stress. PMID- 30025366 TI - Amendment of soil by biochars and activated carbons to reduce chlordecone bioavailability in piglets. AB - Chlordecone (Kepone or CLD) is a highly persistent pesticide formerly used in French West Indies. Nowadays high levels of this pesticide are still found in soils which represent a subsequent source of contamination for outdoor-reared animals. In that context, sequestering matrices like biochars or activated carbons (ACs) are believed to efficiently decrease the bioavailability of such compounds when added to contaminated soils. The present study intends to test the respective efficiency of soil amendment strategies using commercial ACs or biochars (obtained by a 500 degrees C or 700 degrees C pyrolysis of 4 distinct type of wood). This study involved three experimental steps. The first one characterized specific surface areas of biochars and ACs. The second one assessed CLD-availability of contaminated artificial soils (50 MUg g-1 of Dry Matter) amended with 5% of biochar or AC (mass basis). The third one assessed CLD bioavailability of those artificial soils through an in vivo assay. To limit ethically the number of animals, selections of the most promising media were performed between each experimental steps. Forty four castrated male 40-day-old piglets were exposed during 10 day by amended artificial soils according to their group (n = 4). Only treatment groups exposed through amended soil with AC presented a significant decrease of concentrations of CLD in liver and adipose tissue in comparison with the control group (p < 0.001). A non-significant decrease was obtained by amending artificial soil with biochars. This decrease was particularly high for a coconut shell activated carbon were relative bioavailability was found lower than 3.2% for both tissues. This study leads to conclude that AC introduced in CLD contaminated soil should strongly reduce CLD bioavailability. PMID- 30025368 TI - The combined toxicity of UV/chlorinated products from binary ibuprofen (IBP) and tyrosine (Tyr) on Escherichia coli: Emphasis on their occurrence and underlying mechanism. AB - In this study, the combined toxicity of UV/chlorinated products on Escherichia coli (E. coli) was investigated when ibuprofen (IBP) and tyrosine (Tyr) were used as two precursors. The median-effect equation and combined index (CI)-isobologram equation were used to evaluate the combined toxicity of UV/chlorinated products. Results revealed that the UV/chlorinated products originated from binary Tyr and IBP showed a synergism in toxicity on Escherichia coli at low concentration level while it turned into a clear antagonism effect above a fa value of 0.2 in the toxicity trial. The combined toxic effects on E. coli were determined by both the potential toxicity mode of specific disinfection byproducts (DBPs) and the complicated interaction caused by Tyr and IBP. The addition of IBP decreased the yield of N-DBPs generated from Tyr, which dominated the effect of combined toxicity. Even though the antagonism predominated in toxicity effect on E. coli, the synergistic toxicity at low dose levels should be getting attention, which was more close to the natural concentration of N-DBPs in waters. PMID- 30025369 TI - Assessment of the committed effective dose due to the 210Po intake from fish consumption for the Arabian Gulf population. AB - This study aims to assess the committed effective dose due to the intake of 210Po from the consumption of fish in Arabian Gulf countries. Twenty different kinds of fish, which represent the most common fish species consumed in the Arabian Gulf countries, were analyzed using alpha spectrometer technique. 210Po activity concentrations in fish samples were found to vary over a wide range from 0.1 to 14.7 Bq kg-1 fresh weight. This variation of 210Po concentrations between various type of fish samples might be attributed to the feeding type pattern and the size of fish. The annual committed effective dose due to ingestion of 210Po in fish species for adults in the Arabian Gulf countries was estimated and found to vary from 38 MUSv in Bahrain to 85 MUSv in Oman with an average value of 59 MUSv. These values are considered relatively high compared to those reported in some other regions. However, it is still much lower than the world average ingestion dose due to natural radiation sources. PMID- 30025370 TI - Electrochemical activation of sulfate by BDD anode in basic medium for efficient removal of organic pollutants. AB - Electrochemical advanced oxidation processes (EAOPs) based on hydroxyl radicals (OH) have some limitations when they are applied to real wastewater treatment, such like strict requirements on pH (acidic electrolyte) and high energy consumption. Compared to OH, Sulfate radicals (SO4-) have high redox potential in wider range of pH (2-9). In this study, SO4- were efficiently produced by electrochemical activation of SO42- at boron doped diamond (BDD) anode. The degradation rate of 2,4-DCP (k = 0.828 +/- 0.05 h-1) in the presence of Na2SO4 was approximately 4 times than that without Na2SO4 (k = 0.219 +/- 0.01 h-1), indicating that SO4- exhibited higher reactivity than OH at initial pH = 9. Moreover, the amount of O2 decreased by 65% after 100 min during electro oxidation of 2,4-DCP and the specific energy consumption per unit TOC (ECTOC) was reduced by 70% when the concentration of Na2SO4 increased from 0.01 to 0.1 M. The impact of sulfate ions in the electrochemical advanced oxidation were investigated. Electron spin resonance (ESR) measurements were conducted to identify the formation of SO4-. Electrolysis of 2,4-DCP with specific radical scavengers (ethanol and tert-Butanol) were conducted and the results revealed that SO4- were mainly produced by one-electron loss of sulfate at basic condition. Electro-generation persulfate was measured and participation of non radical activation of persulfate was investigated. O2 production was quantified and we found electrochemical activation of sulfate could inhibit water dissociation. Taken all findings, a mechanism of electrochemical activation of sulfate at BDD anode was summarized. This technology eliminates the requirement for pH adjustment for wastewater treatment and makes EAOPs more effective and economic as well. PMID- 30025371 TI - Myocardial infarction in a patient with multiple sclerosis after receiving natalizumab. AB - Natalizumab is among the most effective drugs for controlling multiple sclerosis (MS). The most important side effect of this drug is progressive multifocal leukoencephalopathy, although some other complications are increasingly reported in literature such as meningitis and encephalitis. Here, a patient with MS who has suffered from myocardial infarction (MI) after the injection of natalizumab is introduced. PMID- 30025372 TI - MICA-129 A/G dimorphism, its relation to soluble mica plasma level and spontaneous preterm birth: A case-control study. AB - The aim of this case- control study was to investigate the association between preterm birth (PTB), MICA-129 A/G dimorphism and sMICA levels. Fifty pregnant women with singleton pregnancy and previous PTB, or clinic diagnostic of threatened preterm labor in the actual pregnancy, or cervical length less than 25 mm and 50 healthy pregnant women were enrolled. DNA was extracted for genotyping for MICA-129 A/G by real-time PCR and sMICA plasma level was quantified by sandwich ELISA assay. Clinical and socioeconomic characteristics, results of TaqMan(r) genotyping and ELISA quantification were compared between the groups using qui-square, Fisher's exact or Mann-Whitney test. A binary logistic regression model was used to predict PTB. The correlation between MICA-129 A/G genotypes and sMICA levels was investigated. There were not statistically significant differences between MICA-129 A/G polymorphism and sMICA plasma level.There was found a correlation between MICA-129 val/val genotype and higher levels of sMICA (rho: -0.342; p:0.001). The presence of MICA-129 val/val genotype may be influencing sMICA expression. PMID- 30025373 TI - Thymus essential oil extraction, characterization and incorporation in phospholipid vesicles for the antioxidant/antibacterial treatment of oral cavity diseases. AB - The aim of the work was to extract, characterize, and formulate Thymus capitatus (Tymbra capitata) essential oil in phospholipid vesicles: liposomes, glycerosomes and Penetration Enhancer-containing Vesicles (PEVs). The steam-distilled essential oil was mainly composed of carvacrol. The oil was mixed with lecithin and water to produce liposomes, or different ratios of water/glycerol or water/propylene glycol (PG) to produce glycerosomes and PG-PEVs, respectively. Cryo-TEM showed the formation of unilamellar, spherical vesicles, and light scattering disclosed that their size increased in the presence of glycerol or PG, which improved long-term stability. The formulations were highly biocompatible, and capable of counteracting oxidative stress and favouring wound repair in keratinocytes, thanks to enhanced uptake. The antibacterial activity of the oil was demonstrated against cariogenic Streptococcus mutans, Lactobacillus acidophilus, and commensal Streptococcus sanguinis. The combination of antioxidant and antibacterial activities of Thymus essential oil formulations may be useful for the treatment of oral cavity diseases. PMID- 30025374 TI - Beta-carotene-bound albumin nanoparticles modified with chlorin e6 for breast tumor ablation based on photodynamic therapy. AB - Chlorin e6 (Ce6) has attracted considerable interest as a promising second generation photosensitizer for photodynamic therapy (PDT). However, the in vivo availability of Ce6 is significantly restricted by its low water solubility and poor ability to target tumors. We sought to overcome the limitations of Ce6 by using albumin nanoparticles with nabTM (nanoparticle albumin-bound) technology. The fabricated albumin nanoparticles consisted of bovine serum albumin (BSA), Ce6 BSA, and beta-carotene as a carrier, photosensitizing agent, and cross-linker, respectively. These albumin nanoparticles (Ce6-BSA-BC-NPs) did not include any toxic chemotherapeutics but instead contained naturally safe beta-carotene and Ce6, which was activated only upon irradiation with 660-nm laser light. Ce6-BSA BC-NPs were ~120 nm in size and spherical, similar to Abraxane(r), and showed good physicochemical stability. The nanoparticles showed significant cytotoxicity toward 4T1 cells as evaluated by MTT, Live/Dead, and TUNEL assays. In particular, results of the TUNEL assay demonstrated that cell death induced by Ce6-BSA-BC-NPs and light irradiation (660 nm) occurred through the apoptotic pathway. Ce6-BSA-BC NPs displayed a remarkably enhanced tumor suppression effect when irradiated by 660-nm light compared with free Ce6 (tumor volume 90 +/- 39 versus 487 +/- 69 mm3 respectively). Overall, this improved in vivo antitumor efficacy seemed to be due to the targetability of albumin nanoparticles. We believe that our Ce6-BSA-BC-NPs with PDT offer a promising new potential therapeutic platform for breast cancer treatment. PMID- 30025375 TI - Volume expansion of erythrocytes is not the only mechanism responsible for the protection by arginine-based surfactants against hypotonic hemolysis. AB - A novel arginine-based cationic surfactant Nalpha-benzoyl-arginine dodecylamide (Bz-Arg-NHC12) was synthesized in our laboratory. In this paper we study the interaction of Bz-Arg-NHC12 with sheep and human red blood cells (SRBC and HRBC respectively) due to their different membrane physicochemical/biophysical properties. SRBC demonstrated to be slightly more resistant than HRBC to the hemolytic effect of the surfactant, being the micellar structure responsible for the hemolytic effect in both cases. Moreover, besides the hemolytic effect, a dual behavior was observed for the surfactant studied: Bz-Arg-NHC12 was also able to protect red blood cells against hypotonic lysis for HRBC in a wide range of surfactant concentrations. However, the degree of protection showed for SRBC was about 50% lower than for HBRC. In this regard, a remarkable volume expansion was evidenced only for SRBC treated with Bz-Arg-NHC12, although no correlation with the antihemolytic potency (pAH) was found. On the contrary, our surfactant showed a greater pAH when human erythrocytes were submitted to hypotonic stress, with a low volume expansion, showing a higher amount of solubilized phospholipids in the supernatant when compared with SRBC behavior. Surface plasmon resonance measurements show the molecular interaction of the surfactant with lipid bilayers from HRBC and SRBC lipids, demonstrating that in the latter neither microvesicle release or lipid extraction occurred. Our results demonstrate that the volume expansion of erythrocytes is not the only mechanism responsible for the protection by surfactants against hypotonic hemolysis: volume expansion could be compensated via microvesicle release or by the extraction of membrane components upon collisions between red blood cells and surfactant aggregates depending on the membrane composition. PMID- 30025376 TI - Dual temperature and pH responsive nanofiber formulations prepared by electrospinning. AB - We report a dual-responsive drug delivery system prepared by electrospinning. Blend fibers of poly(N-vinylcaprolactam) (PNVCL) and ethyl cellulose (EC) were first prepared, with the aim of developing thermoresponsive sustained release formulations. Eudragit L100-based fibers were then generated to yield pH sensitive materials. Attempts to produce three-polymer fibers of EC, PNVCL and Eudragit were unsuccessful, and therefore hybrid mats containing two fiber populations (one made of PNVCL/EC, one comprising Eudragit) were instead fabricated by twin-jet electrospinning. Analogous drug-loaded versions of all the formulations were also prepared containing ketoprofen (KET). The fibers were largely smooth and homogeneous, and the addition of KET did not affect their morphology. The PNVCL-containing fiber mats changed from being hydrophilic to hydrophobic when the temperature was increased through the lower critical solution temperature of 33 degrees C. In vitro drug release profiles showed that the hybrid fiber mats were able to combine the properties of the three polymers, exhibiting both pH-sensitive and thermosensitive properties with sustained release. In addition, they were found to be nontoxic and suitable for cell growth. This study therefore demonstrates that PNVCL/EC/KET-Eudragit/KET multicomponent fiber mats comprise effective and biocompatible materials for targeted drug delivery. PMID- 30025377 TI - Hyaluronan magnetic nanoparticle for mitoxantrone delivery toward CD44-positive cancer cells. AB - Hyaluronic acid (HA) is increasingly investigated for biomedical applications such as regenerative medicine, aesthetic medicine, and drug delivery. Accordingly, conjugation of HA to PEGylated MNPs could increase the active targeting ability of nano-drug carriers toward CD44 receptors and be useful in a clinical setting such as drug delivery. So, we chemically conjugated mitoxantrone (MTX) to HA-PEGylated MNPs to use concurrent advantages such as prolong the circulation time, decrease the side effects and delivery toward special tumor cells. Size of the Fe3O4-DPA-PEG-HA-MTX NPs was determined ~200 nm utilizing FESEM and DLS. Stability analysis confirmed that prepared MNPs were stable in physiological conditions even after 8 days and only 47.3% of MTX was liberated from nanocarriers, in the event that, acidic condition and also presence of protease enzyme accelerated the amount of MTX release to 100% after 8 days of incubation. The in vitro cytotoxicity analysis by MTT assay revealed that viable cell numbers were reduced by 32% when MTX-HA-MNPs were applied against MDA-MB-231 cell lines, while they showed significant decreased cellular cytotoxic effects on cell viability in the MCF-7 cell lines which express lower levels of CD44 receptor at the cell surface. Also, results of flow cytometry analysis following 24 h exposure confirmed that MTX-HA-MNPs have significant induction of apoptosis in MDA-MB-231 cell lines (70.3%) which contains high levels of CD44 expression, whereas there was little effect on the induction of apoptosis in MCF-7 cell lines (5%). The obtained binding models through molecular docking simulation related to each single moieties of prepared MNPs clearly confirmed that MTX-HA-MNPs can easily be bonded to the CD44 receptor with more affinity value in comparison to HA ligand, and so conjugation of HA to MNPs can be a good way for MTX delivery toward special tumor cells or tissues. PMID- 30025378 TI - Differences in pain and function between adolescent athletes and physically active non-athletes with patellofemoral pain. AB - OBJECTIVES: To investigate pain level and function limitation in adolescent athletes and physically active non-athletes with PFP. DESIGN: Cross-sectional study. SETTING: Adolescent athletes were recruited at a sport center complex. Adolescent non-athletes were recruited from upper secondary schools. PARTICIPANTS: 108 adolescents diagnosed with PFP: 42 adolescent athletes and 66 adolescent non-athletes. MAIN OUTCOME MEASURES: To evaluate the level of pain, a visual analog scale (VAS) was used and to evaluate the overall function, the Knee Outcome in Osteoarthritis Survey (KOOS) was used. RESULTS: The adolescent athletes scored significantly higher in the VAS (Mean difference = 0.97 (95% CI = 0.35; 1.60) p = 0.003) compared to adolescent non-athletes. Adolescent athletes scored lower in the KOOS - Symptoms, Pain, Knee-related quality of life and Sport and recreation dimensions - than the non-athletes, however, the minimally clinically important difference was not achieved in Pain dimension. There was no significant difference in the Activities of daily living dimension of the KOOS. CONCLUSIONS: Adolescent athletes presented higher levels of pain and lower physical function status compared with physically active non-athletes. This provides an important insight to the management of PFP in adolescent athletes as worst functional status is linked with poor prognosis in patients with PFP. PMID- 30025379 TI - Scapular muscles weakness in subjects with traumatic anterior glenohumeral instability. AB - OBJECTIVE: To investigate possible alterations on scapular muscle strength in subjects with traumatic anterior glenohumeral instability. DESIGN: Cross sectional study. SETTING: Laboratory setting. PARTICIPANTS: Fifty-two subjects of both sexes: 26 healthy and 26 with traumatic anterior glenohumeral instability. MAIN OUTCOME MEASURES: Subjects performed maximal isometric and concentric isokinetic contractions of shoulder protraction and retraction in scapular and sagittal planes, at slow (12.2 cm/s) and fast (36.6 cm/s) speeds. RESULTS: Subjects with glenohumeral instability presented lower peak force of protraction and retraction during isometric and fast speed tests in the scapular plane; and of isometric protraction in the sagittal plane. CONCLUSIONS: People with traumatic anterior glenohumeral instability present muscle weakness of scapular protractors and retractors. Considering the importance of the scapulothoracic muscles for the dynamic stability of the glenohumeral joint, strengthening of these muscles is recommended for rehabilitation of traumatic anterior glenohumeral instability. PMID- 30025380 TI - Fate and effects of sediment-associated triclosan in subtropical freshwater microcosms. AB - Triclosan (TCS) is an antibacterial agent that is commonly used in personal care products. Because of its sediment-binding properties, TCS exposure presents a potential threat to sediment-dwelling aquatic organisms. Currently our knowledge of the fate and effects of sediment-associated TCS in aquatic systems is limited. To understand the impact of sediment-associated TCS, we used microcosms to assess effects of TCS exposure on a diverse range of organisms selected to mimic a subtropical community, with an exposure period of 28 days. We included the oligochaete freshwater worm Limnodrilus hoffmeisteri to evaluate the interaction between sediment-associated TCS and sediment-dwelling organisms, including potential loss of TCS from the sediment due to biological activity and bioaccumulation. Benthic macroinvertebrate presence significantly increased the TCS levels from 0.013 +/- 0.007 MUg/L to 0.613 +/- 0.030 MUg/L in the overlying water through biological activity, posing a potential additional risk to pelagic species, but it did not result in a significant reduction of the sediment concentration. Furthermore, worms accumulated TCS with estimated Biota-Sediment Accumulation-Factors (BSAFs) ranging between 0.38-3.55. Other than for algae, TCS at environmental concentrations did not affect the survival of the introduced organisms, including the L. hoffmeisteri. Our results demonstrate that, although TCS at currently detected maximum concentration may not have observable toxic effects on the benthic macroinvertebrates in the short term, it can lead to bioaccumulation in worms. PMID- 30025382 TI - Rural - urban differences in determinants of patient satisfaction with primary care. AB - In light of the rising regional inequalities in primary care provider supply, to ensure equitable access is a pressing issue in health policy. Most policy approaches fall short in considering the patient perspective when defining shortage areas. As a consequence, implementations of new service delivery models might fail to be responsive to patients' expectations. To explore regional differences in the relative importance of structure and process attributes as drivers of patient satisfaction with local primary care, we collected data from residents of three objectively well-supplied urban and six objectively worse supplied rural areas in Germany and tested a multi-group structural equation model. The results suggest that the relative importance of care attributes is different among the regional conditions rural and urban. Regardless of regional constraints, the strongest determinants of satisfaction are not related to structural aspects but are concerned with the quality of the doctor-patient relationship. A lack of available choices and a higher tolerance in terms of distances provide possible explanations for the results. The high importance rural residents attribute to the interpersonal relation should not be neglected in the re-organization of traditional service delivery in rural areas. PMID- 30025383 TI - "Like you failed at life": Debt, health and neoliberal subjectivity. AB - The need to more explicitly incorporate political economy and neoliberalism into research on social inequalities in health has been acknowledged across disciplines. This paper explores neoliberalism as it relates to consumer financial debt and internalized feelings of personal responsibility and failure for adults in Boston, Massachusetts. Using data from a mixed-methods study (n = 286), findings show that endorsing a neoliberalized view of personal debt as failure is associated with significantly worse health across a range of measures, including blood pressure, adiposity, self-reported physical and emotional symptoms, depression, anxiety, and perceived stress, even when controlling for several socio-demographic confounders. Results are discussed within the context of both neoliberal economic policies that funnel consumers into chronic debt and neoliberal sociocultural ideologies that promote self-judgments of indebtedness as personal failure. Findings highlight the importance of neoliberalism as an important contemporary social determinant of health and suggest new directions for research to explore. PMID- 30025381 TI - Transchem project - Part II: Transgenerational effects of long-term exposure to pendimethalin at environmental concentrations on the early development and viral pathogen susceptibility of rainbow trout (Oncorhynchus mykiss). AB - In the Transchem project, rainbow trout genitors were exposed to environmental concentrations of pendimethalin over a period of 18 months and two new first generations of offspring, F1_2013 and F1_2014, were obtained. We investigated the impact of direct chemical exposure on juveniles as well as the potential cumulative transgenerational and direct effects on the larval development and on the pathogen susceptibility of offspring. Depending on the chemical treatment or not of the adults, their offspring were distributed in the tanks of our experimental system, in two batches i.e. juveniles from the control genitors (G-) and others from the contaminated ones (G+), and then, half of the tanks were exposed daily to pendimethalin (Off+) while the others were used as controls (Off ). Viral challenges were performed on the offspring, before and after three months of direct chemical exposure, with strains of infectious hematopoietic necrosis virus (IHNV), viral haemorrhagic septicemia virus (VHSV) and sleeping disease alphavirus (SDV). Direct and transgenerational macroscopic effects were observed on offspring, with a percentage of abnormalities in offspring derived from the genitors exposed to pendimethalin (G+) significantly higher compared to those from the genitors from non-exposed group (G-). Before the direct chemical exposure, similar kinetics of mortality was observed between the offspring from the contaminated or control genitors after VHSV infection. With IHNV, the G+ group died in a slightly larger proportion compared to the G- group and seroconversion was greater for the G- group. For the SDV challenge, the mortality was delayed for the G+ offspring compared to the G- and seroconversion reached 65% in the G+ group compared to 45% in the G-, with similar antibody titres. After three months of direct chemical exposure, kinetics of mortality induced by IHNV infection were similar for all groups studied. Infection with SDV resulted in a cumulative mortality of 40% for the G- groups (Off- and Off+), significantly higher than those observed from the contaminated genitors G+. Proportion of seropositivity for SDV varied from 24 to 47% depending on the group, with very low quantities of secreted antibodies. Lastly, the direct exposure of offspring could impact the capacity of fish to adapt their haematological parameters to environmental and physiological changes, and underlines the potential toxic effects on the next generations. PMID- 30025384 TI - Regulatory effects of chrysophanol, a bioactive compound of AST2017-01 in a mouse model of 2,4-dinitrofluorobenzene-induced atopic dermatitis. AB - The aim of this study is to determine whether AST2017-01 which consists of Rumex crispus and Cordyceps militaris would improve atopic dermatitis (AD). We analyzed anti-AD effects of AST2017-01 and chrysophanol, a bioactive compound of AST2017 01, using a 2,4-dinitrofluorobenzene-induced AD murine model. AST2017-01 and chrysophanol relieved clinical severity in AD-like skin lesions and significantly decreased scratching behavior. The thickness of epidermis and infiltration of inflammatory cells in AD-like skin lesions were reduced by AST2017-01 or chrysophanol. AST2017-01 and chrysophanol significantly suppressed the levels of histamine, immunoglobulin E, thymic stromal lymphopoietin (TSLP), interleukin (IL)-4, IL-6, and tumor necrosis factor-alpha in serum of AD mice. The protein levels of TSLP, intercellular adhesion molecule-1, and macrophage inflammatory protein 2 were significantly inhibited in the skin lesions. The mRNA expressions of TSLP, thymus and activation-regulated chemokine/CCL17, and C-C chemokine receptor 3 were inhibited in the skin lesions by AST2017-01 or chrysophanol. In addition, AST2017-01 and chrysophanol significantly suppressed the expressions and activities of caspase-1 in the skin lesions. Taken together, these results suggest that AST2017-01 has beneficial effects on AD and may be used as a health functional food in AD. PMID- 30025385 TI - Predictors of Pathological Complete Response in Women with Clinical Complete Response to Neoadjuvant Chemotherapy in Breast Carcinoma. AB - OBJECTIVE: There is insufficient information on predictors of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast carcinoma that also presented clinical complete response (cCR) evaluated in breast, axilla and breast and axilla. METHODS: This retrospective study included 310 women with breast carcinoma who received NAC from 1/1/13 to 12/31/15 with follow-up until 8/31/16. The factors analyzed to predict pCR and cCR were menopausal status, Ki67, estrogen receptor, histologic grade, molecular subtype, tumor size, axilla status, and stage. RESULTS: The cCR/pCR rates were 53.2/16.5% (breast), 76.3/36.8% (axilla) and 50.6/13.9% (breast and axilla). Molecular subtype and HER2-positive were independent predictors to confirm pCR in women with cCR, mainly triple negative (TN) in breast (OR 22.81, 95% CI 7.13-72.96) and breast and axilla (OR 36.06, 95% CI 8.77-148.26), but not in axilla. Ki67 >=50% expression was predictor of cCR in breast (OR 2.00, 95% CI 1.31-3.06) and breast and axilla (OR 1.67, 95% CI 1.10-1.45). CONCLUSION: TN subtype and HER2-positive were the main independent predictors of pCR in women who also had cCR to NAC in breast and breast and axilla, but none was predictor in axilla. The Ki67 >=50% was the independent predictor of cCR in breast and breast and axilla. PMID- 30025386 TI - Comparative Cytogenetics of Omophoita abbreviata and O. aequinoctialis (Coleoptera, Chrysomelidae, Alticini) from the Adolpho Ducke Forest Reserve in Brazilian Amazonia: Intrapopulation Variation in Karyotypes. AB - The chromosomes of 2 flea beetle species from central Amazonia, Omophoita abbreviata and O. aequinoctialis (Alticini), were investigated through analysis of meiotic and mitotic cells. These species belong to the subtribe Oedionychina, a taxon that has unique cytogenetic features, such as giant sex chromosomes which are aligned at a distance during meiosis I (asynaptic). O. abbreviata and O. aequinoctialis have a meiotic formula of 10II + X + y, which is predominant in this subtribe. While the species of the genus Omophoita possess a relatively stable karyotype, a typical feature for Oedionychina, the present study identified inter- and intrapopulational variation in chromosome morphology, constitutive heterochromatin, and the presence and number of B chromosomes in O. aequinoctialis. In addition, FISH mapping of telomeric sequences revealed signals in the collochores, raising several questions on the chromosomal evolution in this group. PMID- 30025387 TI - MicroRNA-16 Promotes Ovarian Granulosa Cell Proliferation and Suppresses Apoptosis Through Targeting PDCD4 in Polycystic Ovarian Syndrome. AB - BACKGROUND/AIMS: Several miRNAs have been reported to be involved in the pathogenesis of polycystic ovarian syndrome (PCOS). However, the biological roles of miR-16 and its molecular mechanisms in PCOS development remain to be elucidated. METHODS: qRT-PCR was performed to detect the expression levels of miR 16 and programmed cell death protein 4 (PDCD4). GCs proliferation, cell cycle distribution and apoptosis were examined by MTT assay and flow cytometry analysis. Luciferase reporter assay and RIP assay were applied to confirm the regulatory relationship between miR-16 and PDCD4. Western blot was applied to measure the protein levels of PDCD4, PCNA and caspase-3. ELISA kits were used to determine the serum levels of steroids. RESULTS: miR-16 expression was down regulated in ovarian cortex tissues and serums of PCOS patients. PDCD4 expression was up-regulated in ovarian cortex tissues of PCOS patients. miR-16 overexpression facilitated cell proliferation, induced cell cycle progression, and inhibited apoptosis in GCs. Moreover, PDCD4 was a direct target of miR-16. Also, enforced expression of PDCD4 abated the effects of miR-16 on GCs growth and apoptosis. Additionally, testosterone resulted in a decrease of miR-16 expression and an increase of PDCD4 expression, thus blocking cell growth and enhanced apoptosis in GCs. Furthermore, miR-16 overexpression alleviated PCOS in vivo by regulating PDCD4. CONCLUSIONS: miR-16 promoted ovarian GCs proliferation and inhibited apoptosis through directly targeting PDCD4 in PCOS, contributing to a better understanding of the molecular mechanism of GCs dysregulation and providing a promising target in PCOS. PMID- 30025389 TI - Identifying prognostic factors for well-differentiated metastatic pancreatic neuroendocrine tumours (pNETs): A retrospective international multicenter cohort study. AB -
Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicenter, retrospective cohort study we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological, and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62% and 34%, respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status >=2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkaline phosphatase, and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status >=2, synchronous metastases, Ki-67 >=10%, and high alkaline phosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs.
. PMID- 30025388 TI - Activation of Cyclooxygenase-2 by ATF4 During Endoplasmic Reticulum Stress Regulates Kidney Podocyte Autophagy Induced by Lupus Nephritis. AB - BACKGROUND/AIMS: Autophagy plays an essential role in lupus nephritis (LN) induced kidney injury, although the mechanism of action remains obscure. We investigated the role of cyclooxygenase-2 (COX-2) and the ATF4 endoplasmic reticulum (ER) stress pathway in LN-induced podocyte autophagy. METHODS: We evaluated podocyte autophagy in a mouse model of LN. Protein levels of COX-2 and ATF4, and markers of autophagy, were evaluated by immunofluorescence and western blotting. To evaluate apoptosis, levels of PGE2 were measured by enzyme-linked immunosorbent assay. RESULTS: LN induced kidney damage and dysfunction, which was associated with podocyte autophagy. COX-2 and the ATF4 ER stress pathway were induced by LN in cultured podocytes. Inhibition of COX-2 inhibited LN-induced autophagy in podocytes. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and LN-induced autophagy, suggesting that ER stress is required for LN-induced kidney autophagy. Furthermore, LN activated ATF4 and induced its nuclear translocation. Knockdown of ATF4 inhibited LN-induced COX-2 overexpression. CONCLUSIONS: Our study suggests a novel molecular mechanism by which COX2 overexpression, induced by the ATF4 ER stress pathway, contributes to LN-induced kidney autophagy and injury. These data demonstrate that COX-2 may be a potential therapeutic target against LN-induced nephropathy. PMID- 30025390 TI - SIRT1 Involved in the Regulation of Alternative Splicing Affects the DNA Damage Response in Neural Stem Cells. AB - BACKGROUND/AIMS: Alternative splicing and DNA damage exhibit cross-regulation, with not only DNA damage inducing changes in alternative splicing, but alternative splicing itself possibly modulating the DNA damage response (DDR). Sirt1, a prominent anti-aging player, plays pivotal roles in the DDR. However, few studies have examined alternative splicing with DNA damage in neural stem cells (NSCs) and, in essence, nothing is known about whether SIRT1 regulates alternative splicing. Hence, we investigated the potential involvement of Sirt1 mediated alternative splicing in the NSC DDR. METHODS: Genome-wide alternative splicing profiling was performed upon DNA damage induction and SIRT1 deletion. RESULTS: DNA damage caused genome-wide changes in alternative splicing in adult NSCs and Sirt1 deficiency dramatically altered DDR-related alternative splicing. In particular, extensive alternative splicing changes in DDR-related processes such as cell cycle control and DNA damage repair were observed; these processes were dramatically influenced by Sirt1 deficiency. Phenotypically, Sirt1 deficiency altered the proliferation and DNA repair of adult NSCs, possibly by regulating alternative splicing. CONCLUSION: SIRT1 helps to regulate alternative splicing, which itself affects the DDR of NSCs. Our findings provide novel insight into the mechanisms underlying the DDR in stem cells. PMID- 30025391 TI - Method Used for Tumor Bed Closure (Suture vs. Sealant), Ischemia Time and Duration of Surgery are Independent Predictors of Post-Nephron Sparing Surgery Acute Kidney Injury. AB - INTRODUCTION: The aim of our study was to examine the influence of tumor complexity and operative variables on the degree and rate of post-nephron sparing surgery (NSS) acute kidney injury (AKI). METHODS: We retrospectively reviewed the records of 477 patients who underwent NSS for enhancing renal masses in our institution. AKI was determined using the latest definition by AKIN and RIFLE criteria. Serum creatinine was assessed daily starting from day 1 post-surgery and until discharge (usually on postoperative day 3). Estimated glomerular filtration was determined using the Modification of Diet in Renal Disease equation. RESULTS: Overall, 191 patients (40%) developed postoperative AKI, and most of them (88%) were grade 1. Multivariate analysis revealed that the most significant and independent variables associated with AKI were operation time (p = 0.02), ischemia time (p = 0.02), and the use of tissue adhesive for tumor bed closure (p = 0.02). Other important factors (by univariate analysis) were the need for blood transfusion (p = 0.003) and estimated blood loss (p = 0.007). CONCLUSIONS: Operative time, ischemia, and tumor bed closure method are independent predictors of post-NSS AKI. Efforts should be made to limit prolonged ischemia and to reduce viable parenchymal loss. Further studies concerning the functional impact of AKI in these patients will be required. PMID- 30025392 TI - Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Diabetes mellitus is a possible risk factor for the development of idiopathic pulmonary fibrosis (IPF), yet the effect of antidiabetic therapy on the course of IPF is unknown. OBJECTIVES: This post hoc analysis assessed the effect of metformin on clinically relevant outcomes in patients with IPF. METHODS: For the primary analysis, patients randomized to placebo (n = 624) in 3 phase 3, double-blind, controlled trials of pirfenidone (CAPACITY [NCT00287716 and NCT00287729]; ASCEND [NCT01366209]) were categorized by baseline metformin use. The primary outcome was disease progression (forced vital capacity [FVC] decline >=10%, 6-min walking distance [6MWD] decline >=50 m, or death). Other outcomes included mortality, hospitalization, FVC decline (>=10 and >=5%), and 6MWD decline. Outcomes were also assessed in patients with diabetes and/or hyperglycemia (impaired glucose tolerance [IGT] and diabetes population [IGT diabetes population]) and all patients included in the 3 studies (intention-to treat [ITT] population). RESULTS: Overall, 71 (11.4%) patients were metformin users and 553 (88.6%) were nonmetformin users. Baseline data were similar between groups, except for a higher percentage of males (84.5 vs. 73.2%) and a history of diabetes (98.6 vs. 11.6%) in metformin users versus nonmetformin users. The unadjusted 1-year analyses demonstrated no significant differences in disease progression or other outcomes. A higher proportion of metformin users compared with nonmetformin users had a relative FVC decline of >=5% (63.4 vs. 50.6%, p = 0.043). Results were similar for the IGT-diabetes population and for the ITT population. Multivariable analyses yielded similar results. CONCLUSIONS: Metformin has no effect on clinically relevant outcomes in patients with IPF. PMID- 30025393 TI - Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia. AB - BACKGROUND/AIMS: Y+LAT1 protein, encoded by the SLC7A7 gene (a member of the SLC7 family), forms the cationic amino acid transport system y+L (system y+L). This system transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response. METHODS: We analyzed the role of the SLC7A7 gene in the cellular activities of Jurkat cells, specifically the cell cycle and cell proliferation, apoptosis, migration, and invasion. Cell proliferation was assessed using the Cell Counting Kit-8. Apoptosis and the cell cycle were determined with a FACSCalibur flow cytometer. A Transwell chamber was used to measure cell invasion and migration. RESULTS: The proliferative ability of Jurkat cells was not significantly altered by transfection with SLC7A7 overexpression vectors. However, SLC7A7 overexpression significantly decreased the percentage of apoptotic Jurkat cells (P = 0.007) but significantly increased the proportion of G1 phase cells (P = 0.029) and cell migration (P < 0.001) and invasion (P < 0.001). Knockdown of SLC7A7 increased the cell apoptosis rate (P = 0.006) but decreased the G1 phase ratio (P = 0.002) and cell migration (P < 0.001) and invasion (P < 0.001). CONCLUSIONS: SLC7A7 plays a significant role in the pathogenesis of T-cell acute lymphoblastic leukemia. PMID- 30025394 TI - Presentation, Evaluation, Management, and Outcomes of Acute Stroke in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis. AB - AIMS: We performed a systematic review to evaluate stroke presentation, evaluation, management, and outcomes among studies conducted in low- and middle income countries (LMIC). METHODS: We searched MEDLINE (Ovid), Embase (Elsevier), and the Global Health (EBSCOhost) databases between January 2005 and June 2017 for studies conducted in LMICs defined by the World Bank. We pooled prevalence estimates using an inverse-variance weighting method and stratified by the country income group. RESULTS: The search identified 36 hospital-based studies (64,256 participants) in LMICs. Mean (SD) age ranged from 51 (14) to 72 (12) years, and 29-56% of patients were women. Hypertension was the most commonly reported risk factor (64% [95% CI 59-69]). In settings where MRI was not used, head CT scans were reported among 90% patients (95% CI 79-97). Overall, 3% (95% CI 2-4) of patients were treated with tissue plasminogen activator, and 78% (95% CI 66-88) were treated with antiplatelet therapy. Overall, the rate of in hospital mortality was 14% (95% CI 10-19), and the rate of in-hospital pneumonia was 17% (95% CI 14-20). CONCLUSIONS: Our review revealed the low use of evidence based practices for acute stroke care in LMIC. The true use in hospitals that do not conduct this research is probably even lower. Strategies to evaluate and improve health system performance for acute stroke care, including implantation of stroke units and making thrombolysis more available and affordable are needed in LMIC. Registration in Prospero: CRD42017069325. PMID- 30025396 TI - Role of FGF-2 Transfected Bone Marrow Mesenchymal Stem Cells in Engineered Bone Tissue for Repair of Avascular Necrosis of Femoral Head in Rabbits. AB - BACKGROUND/AIMS: Avascular necrosis of the femoral head (ANFH) is the focus and difficulty of orthopedic diseases. Recently, tissue engineering bone for this disease has shown a good therapeutic effect. The aim of the present study was to investigate the therapeutic effect of basic fibroblast growth factor (FGF-2) as cytokines transfected bone marrow mesenchymal stem cells (BMSCs) in constructing tissue-engineered bone for avascular necrosis of the femoral head. METHODS: The FGF-2 gene overexpressed lentivirus-transfected rBMSCs with xenogeneic antigen extracted cancellous bone (XACB) to construct tissue engineered bone, and the model of early avascular necrosis of the femoral head was established by lipopolysaccharide (LPS) combined with hormone. The models were randomly divided into five groups: A (control), B (XACB), C (XACB+rBMSCs), D (XACB+rBMSCs+Lv-GFP), and E (XACB+rBMSCs+Lv-FGF-2/GFP) groups. The therapeutic effect of the tissue engineered bone for the avascular necrosis of the femoral head was evaluated by gross anatomy, X-ray examination, immunohistochemistry and H&E staining. RESULTS: The FGF-2 gene was transfected into rBMSCs (Multiplicity of infection [MOI] = 100) by lentivirus, and its efficiency was above 95%. The rBMSCs were successfully transfected overexpressing FGF-2 by qPCR and western blot. After tissue engineering bone implantation, X-ray examination and gross specimen observation revealed that the repair area in the E group was > 80% at six weeks, the defect was completely repaired at 12 weeks, and osteogenesis was stronger, when compared with the other groups. For the X-ray score, vascular area density and new bone formation area were higher, when compared with the other groups, and the difference was statistically significant (P< 0.05). CONCLUSION: FGF-2 gene overexpression lentivirus transfection BMSCs combined with XACB to construct tissue engineered bone can effectively promote vascular regeneration, and improve the repair effect of avascular necrosis of the femoral head. PMID- 30025395 TI - Midazolam Enhances Mutant Huntingtin Protein Accumulation via Impairment of Autophagic Degradation In Vitro. AB - BACKGROUND/AIMS: Autophagy is a well-known pathway to "clean" the misfolded mutant huntingtin protein (mHtt), which plays a considerable role in polyglutamine diseases. To date, there have been few studies of the choice of anesthetic during surgery in patients with polyglutamine diseases and evaluation of the effects and underlying mechanisms of anesthetics in these patients. METHODS: GFP-Htt (Q74)-PC12 cells, which stably express green fluorescent protein tagged Htt protein containing 74 glutamine repeating units, were used throughout this study. Cells were treated with 15 MUM midazolam and 100 mM trehalose (positive control), and the induction of autophagy and autophagic degradation were assessed by detecting changes in autophagy-related proteins and substrates, and cell viability was assessed using the MTT assay. Overexpression of cathepsin D by plasmid transfection was used to restore midazolam-impaired autophagic degradation. RESULTS: Midazolam increased intracellular mHtt levels in a time- and dose-dependent manner. Additionally, enhancing or blocking autophagic flux by trehalose or chloroquine could decrease or increase midazolam-induced mHtt elevation, respectively. Midazolam induced autophagy in the mTOR-dependent signaling pathway, but autophagic degradation was impaired, with a continuous rise in p62 and LC3 II levels and decrease in cathepsin D. However, overexpression of cathepsin D reversed the effects of midazolam. Midazolam led to a 20% decrease in GFP-Htt (Q74)-PC12 cell viability, which could be abrogated by overexpression of cathepsin D. CONCLUSIONS: Midazolam increased mHtt levels and decreased Htt (Q74)-PC12 cell viability via impairment of autophagic degradation, which could be restored by overexpression of cathepsin D. PMID- 30025397 TI - Beneficial Effects of Bushen Formula Combined with Enticavir on Chronic Hepatitis B Patients with Suboptimal Response to Enticavir by Regulating B-Cell Differentiation. AB - BACKGROUND/AIMS: To investigate the clinical effects of the combination therapy with Bushen Formula (BSF) plus enticavir (ETV) on chronic hepatitis B (CHB) patients with suboptimal response to ETV and explore the regulatory mechanisms of BSF on B cells-mediated humoral immunity. METHODS: Sixty-four HBeAg-positive CHB patients with suboptimal response to ETV were enrolled, and were randomly assigned into control group (C-Group, placebo combined with ETV for 12 months) or treatment group (T-Group, BSF combined with ETV for 12 months). Serum samples from 57 treatment-naive CHB patients and 15 healthy controls were collected. Serum HBV DNA levels were evaluated by real-time PCR. Characteristics of peripheral blood B-cell subtypes were analyzed by flow cytometry. Serum HBV markers and B cell-activating factor (BAFF) levels were detected by ELISA. Chinese medicine symptom complex score was evaluated and recorded. RESULTS: After treatment, the rates of patients with a reduction of HBsAg > 0.5 log10 IU/ml or 1.0 log10 IU/ml and the rates of HBeAg clearance in T-Group were all higher than those in C-group, with no significant intergroup difference. Only in T-Group, Chinese medicine symptom complex score and the frequency of total B cells were significantly decreased, and the frequencies of Bm1, CD24+CD27-switched B cells and plasma cells were markedly increased after treatment compared with those before treatment. Compared with healthy controls, serum BAFF levels in treatment naive CHB patients were increased, and there was a significant positive correlation between serum BAFF and HBsAg levels. However, serum BAFF levels did not differ after treatment in T-Group and C-Group. CONCLUSIONS: The combination therapy with BSF plus ETV promotes the reduction of HBsAg level and the clearance of HBeAg in CHB patients with partial response to ETV through regulating the differentiation of B-cell subsets. PMID- 30025398 TI - Circulating Tumor Cells Correlate with Clinicopathological Features and Outcomes in Differentiated Thyroid Cancer. AB - BACKGROUND/AIMS: As biomarkers, circulating tumor cells (CTCs) from solid tumors can predict metastases and prognoses, and help monitor treatment efficacy. However, conventional CellSearch methods have low sensitivity to differentiated thyroid cancer (DTC) CTCs. In this study, for the first time, we used negative enriching (NE) immunofluorescence-in situ hybridization (iFISH) of chromosome 8 to capture and identify CTCs in DTC patients; and investigated how CTCs correlate with clinicopathological factors and prognosis in DTC patients with distant metastases (DM). METHODS: In this prospective study, we enrolled 72 patients with DTC before they underwent 131I treatment, and 30 healthy controls (HC). Their CTCs were measured in 7.5 ml peripheral blood using the NE-iFISH technique. CTC was defined by the aneuploidy. RESULTS: We detected CTCs in 62 (86.1%) of the 72 subjects with DTC. The mean number of CTCs in patients with DTC with DM (DM+) was significantly higher than in the HC group (P< 0.001) and DTC patients without DM (DM-; P=0.0016). We found CTCs >= 5 was significantly associated with DM+ DTC (P=0.009; sensitivity: 64.3%; specificity: 83.8%); CTCs >= 7 was related to poor response to 131I treatment (sensitivity: 73.7 %; specificity: 69.6 %), and was also associated with worse prognosis in DM+ DTC (P< 0.001). CONCLUSION: We found CTCs >= 5 to be a potential predictive index for DM+ DTC; and CTCs >=7 as a possible indicator of poor response to 131I treatment and worse prognosis in DM+ DTC. PMID- 30025399 TI - Comparative Study between Silodosin and Tamsulosin in Expectant Therapy of Distal Ureteral Stones. AB - OBJECTIVE: To compare the efficacy and safety of silodosin against tamsulosin as medical expulsion therapeutic agent in stone lower 1/3rd ureter. PATIENTS AND METHODS: One hundred fifty patients divided equally into 2 groups I and II received silodosin 8 mg and tamsulosin 0.4 mg respectively. Patients aged 18 years or older having single unilateral stone 10 mm or less were included in the study. Patients with bilateral or multiple stones, marked hydronephrosis, previous open or endoscopic surgery and having urinary infection were excluded. Patients were followed weekly for 4 weeks by ultrasonography, plain radiography of the urinary tract and CT of the urinary tract when indicated. RESULTS: Silodosin showed better results against tamsulosin as stone expulsion rate in silodosin and tamsulosin groups was 82.4 and 61.5% respectively with significant difference (p = 0.007). Also, the stone expulsion time was significantly lower in silodosin against tamsulosin groups as it was 9.4 +/- 3.8 vs. 12.7 +/- 5.1 days in group I and II respectively (p = 0.001). The adverse effects were comparable with non-significant more retrograde ejaculation in the silodosin group. CONCLUSION: Silodosin showed better efficacy in the stone expulsion rate and time with comparable safety of both drugs, with nonsignificant more retrograde ejaculation in silodosin. PMID- 30025400 TI - Reply to the Letter by Van Den Eede and Van der Feltz-Cornelis Related to Our Paper "Management of Functional Somatic Syndromes and Bodily Distress". PMID- 30025402 TI - Biomarker Discovery by Mass Spectrometry in Cerebrospinal Fluid and Plasma after Global Hypoxia-Ischemia in Newborn Piglets. AB - BACKGROUND: Biomarkers may qualify diagnosis, treatment allocation, and prognostication in neonatal encephalopathy. Biomarker development is challenged by competing etiologies, inter-individual genetic variability, and a lack of specific neonatal markers. To address these challenges, we used a standardized neonatal hypoxic-ischemic (HI) encephalopathy model with pre- and post-HI sampling of cerebrospinal fluid (CSF) and plasma. OBJECTIVES: The study aimed to identify novel candidate protein biomarkers of HI encephalopathy in a newborn piglet model in CSF and plasma. METHODS: FiO2 was lowered to 4% in 6 newborn piglets, then adjusted over a 45-min period keeping the amplitude integrated-EEG < 7 uV to induce HI encephalopathy. CSF and plasma was sampled pre-HI and 2 h after HI, protein levels were then analyzed by mass spectrometry. RESULTS: Protein levels after HI changed significantly for 18 CSF proteins and 37 plasma proteins. CSF and plasma data showed distinct information, although peptidyl prolyl cis-trans isomerase A had elevated levels in both fluids. HI regulation involved functional groups such as the antioxidant system, cell proliferation, cell structure, and apoptosis. S100-A8, which increased the most in CSF (9.5 fold), is known to be involved in inflammatory and immune response and to be highly regulated during injury. In plasma, increased proteins included FABP1 (31.8 fold) and proteins with antioxidant (SOD1, GPX3) and lectin function (REG3A, LGALS3). CONCLUSIONS: In this exploratory study, we have identified candidate biomarkers for HI in CSF and plasma, many not previously associated with HI. Identified proteins are promising candidates for further validation in time series experiments and clinical studies. PMID- 30025401 TI - The Gut Microbiota and Healthy Aging: A Mini-Review. AB - The gut microbiota shows a wide inter-individual variation, but its within individual variation is relatively stable over time. A functional core microbiome, provided by abundant bacterial taxa, seems to be common to various human hosts regardless of their gender, geographic location, and age. With advancing chronological age, the gut microbiota becomes more diverse and variable. However, when measures of biological age are used with adjustment for chronological age, overall richness decreases, while a certain group of bacteria associated with frailty increases. This highlights the importance of considering biological or functional measures of aging. Studies using model organisms indicate that age-related gut dysbiosis may contribute to unhealthy aging and reduced longevity. The gut microbiome depends on the host nutrient signaling pathways for its beneficial effects on host health and lifespan, and gut dysbiosis disrupting the interdependence may diminish the beneficial effects or even have reverse effects. Gut dysbiosis can trigger the innate immune response and chronic low-grade inflammation, leading to many age-related degenerative pathologies and unhealthy aging. The gut microbiota communicates with the host through various biomolecules, nutrient signaling-independent pathways, and epigenetic mechanisms. Disturbance of these communications by age-related gut dysbiosis can affect the host health and lifespan. This may explain the impact of the gut microbiome on health and aging. PMID- 30025404 TI - Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is a common and devastating microvascular complication of diabetes and a major cause of acquired blindness in young adults. Advanced glycation end products (AGEs) accumulated under hyperglycemic conditions are thought to play an important role in the pathogenesis of DR. AGEs can exert their deleterious effects by acting directly to induce aberrant crosslinking of extracellular matrix proteins, to increase vascular stiffness, altering vascular structure and function. Moreover, AGEs binding to the receptor for AGEs (RAGE) evokes intensive intracellular signaling cascades that leading to endothelial dysfunction, elaboration of key proinflammatory cytokines and proangiogenic factors, mediating pericyte apoptosis, vascular inflammation and angiogenesis, as well as breakdown of the inner blood-retinal barrier (BRB), the end result of all these events is damage to the neural and vascular components of the retina. Elucidation of AGE-induced mechanisms will help in the understanding of the complex cellular and molecular pathogenesis associated with DR. Novel anti-AGEs agents or AGE crosslink "breakers" are being investigated, it is hoped that in next few years, some of these promising therapies will be successfully applied in clinical context, aiming to reduce the major economical and medical burden caused by DR. PMID- 30025403 TI - Chemoprevention with Enalapril and Aspirin in Men1(+/T) Knockout Mouse Model. AB - Pancreatic neuroendocrine neoplasias (pNEN) are the most common cause of death in adult patients with multiple endocrine neoplasia type 1 (MEN1). So far, only few chemopreventive strategies (e.g., with somatostatin analogues) have been evaluated for MEN1 associated pNENs. In this experimental study on 75 Men1(+/T) knockout mice, the effect of aspirin (n = 25) and an inhibitor of angiotensin-I converting enzyme (enalapril, n = 25) compared to controls (n = 25) were evaluated as single chemopreventive strategies for pNENs after 6, 9, 12, 15, and 18 months. After each study period, mice were sacrificed and the resected pancreata were evaluated by histopathological analysis, immunostaining, and real time PCR. PNEN size and number was measured. Aspirin and enalapril lead to a pNEN size reduction of 80% (167,518 vs. 838,876 um2, p < 0.001) and 79% (174,758 vs. 838,876 um2, p < 0.001) compared to controls. Furthermore, aspirin and enalapril treatment resulted in a significant reduction of the number of pNENs by 33%, (p = 0.04) and 41% (p = 0.002) respectively. The apoptosis marker caspase 3 revealed a higher positive expression in pNEN of treated Men1(+/T) mice. Immunostaining of VEGF in pNEN detected a downregulation of its expression in treated Men1(+/T) mice compared to the control group. REL A transcript was significantly downregulated in 18-months treated enalapril Men1(+/T) mice, but not in aspirin treated Men1(+/T) mice. There was no significant difference in the Ki-67 index. Using a transgenic mouse model that imitates human MEN1, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents that aid in the progression of pNENs. PMID- 30025405 TI - Reversal of Dopamine Supersensitivity as a Mechanism of Action of Clozapine. PMID- 30025406 TI - Subclinical Hypothyroidism Impact on the Characteristics of Patients with Polycystic Ovary Syndrome. A Meta-Analysis of Observational Studies. AB - BACKGROUND/AIMS: Definitive polycystic ovary syndrome (PCOS) diagnosis should exclude thyroid dysfunctions. The purpose of the study is to examine the impact of subclinical hypothyroidism on the characteristics of PCOS patients. METHODS: A meta-analysis of the published observational studies was conducted. Medline, Scopus, and Cochrane database search was performed to identify the studies that compared euthyroid PCOS and subclinical hypothyroidism (SCH)-PCOS patients. A total of 9 studies were selected, totalizing the inclusion of 1,537 euthyroid PCOS and 301 SCH-PCOS. The data were expressed as raw mean difference and standard error, using the random-effects model. Heterogeneity among studies was examined using the Cochran's test (Q) and I2 statistics. RESULTS: Anthropometrical parameters were similar in both groups. Total cholesterol (TC) and triglyceride (TG) were higher in SCH-PCOS (p = 0.036 and p = 0.012). High density lipoprotein cholesterol was lower in the SCH-PCOS group (p = 0.018). Fasting glucose was lower in euthyroid PCOS (p = 0.022). All androgen levels were similar in both group (p > 0.05 for all). CONCLUSION: TC, TG and fasting glucose were higher in SCH-PCOS patients. Because of the heterogeneity among studies, some summarized results should be interpreted with caution. Consistent data for future studies addressing PCOS diagnosis are provided. PMID- 30025408 TI - Perinatal Anemia is Associated with Neonatal and Neurodevelopmental Outcomes in Infants with Moderate to Severe Perinatal Asphyxia. AB - BACKGROUND: Perinatal anemia may cause perinatal asphyxia. Its pathophysiology and neurodevelopmental effects are theoretically different from other causes of perinatal asphyxia. OBJECTIVE: The study aimed to determine whether perinatal anemia results in different short-term and long-term outcomes than other causes of perinatal asphyxia treated with therapeutic hypothermia. METHODS: We retrospectively included infants with moderate to severe hypoxic-ischemic encephalopathy, born between May 2009 and October 2015. During follow-up, we assessed cognitive and motor development at 2-3 years of age, using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III). Neurodevelopmental outcome (NDO) was classified as abnormal in case of cerebral palsy with Gross Motor Function Classification System >=III and/or a BSID-III composite score < 85. Outcomes of infants with perinatal anemia (initial hemoglobin < 7 mmol/L) were compared to infants born with perinatal asphyxia due to other causes. RESULTS: In total, 111 infants were included of whom 30 infants (27%) died during the neonatal period. Infants with anemia (n = 23) had a higher mortality risk, OR 3.33, 95% CI 1.27-8.72, p = 0.01. None of the surviving infants with anemia (n = 12) had an abnormal NDO, in contrast to 26/69 (38%) with neurodevelopmental impairments, particularly motor problems, in the non-anemic group, p < 0.01. CONCLUSIONS: Perinatal anemia causing moderate to severe perinatal asphyxia is associated with a higher risk for neonatal mortality. All survivors with perinatal anemia, however, showed a normal NDO in contrast to children who were born asphyxiated due to other causes. The underlying pathophysiological mechanism for the favorable NDO in the perinatal anemia group needs further elucidation. PMID- 30025407 TI - Identification of the C-Reactive Protein Interaction Network Using a Bioinformatics Approach Provides Insights into the Molecular Pathogenesis of Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: C reactive protein (CRP) levels are elevated in many diseases, including malignant tumors and cardiovascular disorders. In this study, the protein interaction network for CRP was evaluated to determine the importance of CRP and its interacting proteins in the molecular pathogenesis of hepatocellular carcinoma (HCC). METHODS: Isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometry were used to identify CRP interacting proteins in SMMC7721 cells. Moreover, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to evaluate enriched genes and pathways for differentially expressed genes using DAVID and WebGestalt. Co-immunoprecipitation and western blot analyses were employed to assess interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1. RESULTS: In total, 52 proteins that interact with CRP were identified. A GO analysis suggested that most of the interacting proteins were involved in CRP complexes and regulated metabolic processes. A KEGG pathway analysis suggested that most CRP-interacting proteins contribute to the TRAIL signaling pathway, Class I PI3K/Akt signaling pathway, plasma membrane estrogen receptor signaling, Nectin adhesion pathway, and S1P1 pathway. Immunoprecipitation and western blot analyses revealed interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1. CONCLUSIONS: iTRAQ based proteomic profiling revealed the network of CRP interacting proteins. This network may activate the PI3K/Akt signaling pathway, thereby contributing to the pathogenesis of HCC. PMID- 30025409 TI - Rapamycin Reduces Podocyte Apoptosis and is Involved in Autophagy and mTOR/ P70S6K/4EBP1 Signaling. AB - BACKGROUND/AIMS: The purpose of this study was to investigate the impact of rapamycin (RAP) on autophagy in podocytes and the therapeutic effects of RAP on idiopathic membranous nephropathy (IMN). METHODS: We established an in vitro model of IMN by preconditioning mouse podocytes with puromycin aminonucleoside (PAN). A Cell Counting Kit-8 was used to detect the proliferation of each group of podocytes. Podocyte apoptosis was analyzed by flow cytometry via annexin V/propidium iodide dual staining. Subsequently, we observed the number of autophagosomes by transmission electron microscopy. Western blotting was used to detect the levels of LC3, mTOR, p-mTOR, 4EBP1, p-4EBP1, P70S6K, and p-P70S6K in each group. RESULTS: The number of podocytes in the PAN + 100 ng/mL RAP group, PAN + 200 ng/mL RAP group, and PAN + 300 ng/mL RAP group was significantly increased (P < 0.01). The apoptotic rate of podocytes was significantly different between the PAN group and the PAN + RAP group (P < 0.001). There were fewer autophagic corpuscles in the PAN group and more autophagosomes were observed in the PAN + RAP group. LC3 protein expression was down-regulated in the PAN group, while its expression was up-regulated in the PAN + RAP group. In the PAN group, the levels of phosphorylated mTOR, 4EBP1, and P70S6K were increased, while in the PAN + RAP group, protein phosphorylation was reduced. CONCLUSIONS: RAP can effectively inhibit the mTOR/P70S6K/4EBP1 signaling pathway, and activate podocyte autophagy, consequently reducing podocyte apoptosis. Therefore, RAP could be used for the treatment of idiopathic membranous nephropathy. PMID- 30025411 TI - Establishment and Characterization of a Novel Cell Line Derived from a Small Cell Neuroendocrine Carcinoma of the Anal Canal. AB - BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are biologically aggressive tumors, associated with a very poor survival. Due to their rarity, our knowledge on GEP-NEC biology is very limited. The aim of this study was to establish a GEP-NEC cell line model that might contribute to a better understanding of this rare malignant disease to further develop novel therapeutic approaches in preclinical studies. METHODS: Small cell neuroendocrine cancer cell line NEC-DUE3 was derived from a lymph node metastasis of a neuroendocrine carcinoma (NEC) located at the anal canal. Morphological characteristics and the expression of neuroendocrine markers were comprehensively investigated. For genetic profiling, NEC-DUE3 cells were analyzed by DNA fingerprinting. Chromosomal aberrations were mapped by array comparative genomic hybridization. NEC-DUE3 cell tumorigenicity was evaluated in vivo and the sensitivity to chemotherapeutic agents was assessed in vitro. RESULTS: NEC-DUE3 cells were characterized by the expression of molecular markers that are commonly observed in GEP-NECs, were sensitive to treatment with cisplatin, and able to form tumors in immunodeficient mice. CONCLUSION: We established and characterized the first small cell GEP-NEC cell line that may serve as a valuable tool to create a better understanding of the biology of these rare tumors and to develop novel treatment strategies. PMID- 30025410 TI - MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity. AB - BACKGROUND/AIMS: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. METHODS: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. RESULTS: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3' untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. CONCLUSIONS: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity. PMID- 30025413 TI - Access to Treatment for Hepatitis B Virus Infection - Worldwide, 2016. AB - Worldwide, an estimated 257 million persons are living with chronic hepatitis B virus (HBV) infection (1). To achieve the World Health Organization (WHO) goals for elimination of HBV infection worldwide by 2030, defined by WHO as 90% reduction in incidence and 65% reduction in mortality, access to treatment will be crucial. WHO estimated the care cascade* for HBV infection, globally and by WHO Region. The patent and licensing status of entecavir and tenofovir, two WHO recommended medicines for HBV treatment, were examined using the Medicines Patent Pool MedsPaL? database. The international price of tenofovir was estimated using WHO's global price reporting mechanism (GPRM), and for entecavir from a published study (2). In 2016, among the estimated 257 million persons infected with HBV worldwide, approximately 27 million (10.5%) were aware of their infection, an estimated 4.5 million (16.7%) of whom were on treatment. In 2017, all low- and middle-income countries (LMICs) could legally procure generic entecavir, and all but two LMICs could legally procure generic tenofovir. The median price of WHO prequalified generic tenofovir on the international market fell from $208 per year in 2004 to $32 per year in 2016. In 2015, the lowest reported price of entecavir was $427 per year of treatment (2). Increased availability of generic antivirals effective in treating chronic HBV infection has likely improved access to treatment. Taking advantage of reductions in price of antivirals active against HBV infection could further increase access to treatment. Regular analysis of the hepatitis B treatment care cascade can assist in monitoring progress toward HBV elimination goals. PMID- 30025412 TI - Monocrotaline Suppresses RANKL-Induced Osteoclastogenesis In Vitro and Prevents LPS-Induced Bone Loss In Vivo. AB - BACKGROUND/AIMS: Extensive osteoclast formation plays a critical role in bone diseases, including rheumatoid arthritis, periodontitis and the aseptic loosening of orthopedic implants. Thus, identification of agents that can suppress osteoclast formation and bone resorption is important for the treatment of these diseases. Monocrotaline (Mon), the major bioactive component of crotalaria sessiliflora has been investigated for its anti-cancer activities. However, the effect of Mon on osteoclast formation and osteolysis is not known. METHODS: The bone marrow macrophages (BMMs) were cultured with M-CSF and RANKL followed by Mon treatment. Then the effects of Mon on osteoclast differentiation were evaluated by counting TRAP (+) multinucleated cells. Moreover, effects of Mon on hydroxyapatite resorption activity of mature osteoclast were studied through resorption areas measurement. The involved potential signaling pathways were analyzed by performed Western blotting and quantitative real-time PCR examination. Further, we established a mouse calvarial osteolysis model to measure the osteolysis suppressing effect of Mon in vivo. RESULTS: In this study, we show that Mon can inhibit RANKL-induced osteoclast formation and function in a dose-dependent manner. Mon inhibits the expression of osteoclast marker genes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Furthermore, Mon inhibits RANKL-induced the activation of p38 and JNK. Consistent with in vitro results, Mon exhibits protective effects in an in vivo mouse model of LPS induced calvarial osteolysis. CONCLUSION: Taken together our data demonstrate that Mon may be a potential prophylactic anti-osteoclastic agent for the treatment of osteolytic diseases caused by excessive osteoclast formation and function. PMID- 30025414 TI - Colon cleansing efficacy and safety with 1 L NER1006 versus 2 L polyethylene glycol + ascorbate: a randomized phase 3 trial. AB - BACKGROUND: Polyethylene glycol (PEG)-based bowel preparations are effective cleansers but many require high-volume intake. This phase 3, randomized, blinded, multicenter, parallel-group, central reader-assessed study assessed the 1 L PEG NER1006 bowel preparation vs. standard 2 L PEG with ascorbate (2LPEG). METHODS: Patients undergoing colonoscopy were randomized (1:1:1) to receive NER1006, as an evening/morning (N2D) or morning-only (N1D) regimen, or evening/morning 2LPEG. Cleansing was assessed using the Harefield Cleansing Scale (HCS) and the Boston Bowel Preparation Scale (BBPS). Primary end points were overall bowel cleansing success and high-quality cleansing in the right colon. Modified full analysis set (mFAS) and per protocol (PP) analyses were performed. Mean cleansing scores were analyzed post hoc. RESULTS: Of 849 randomized patients, efficacy was analyzed in the following patient numbers (mFAS/PP): total n = 822/670; N2D n = 275/220; N1D n = 275/218; 2LPEG n = 272/232. mFAS established noninferiority. PP showed superiority for N2D on overall success (97.3 % vs. 92.2 %; P = 0.014), and for N2D and N1D on right colon high-quality cleansing (N2D 32.3 % vs. 15.9 %, P < 0.001; N1D 34.4 % vs. 15.9 %, P < 0.001) vs. 2LPEG. Using HCS, N2D and N1D attained superior segmental high-quality cleansing (P <= 0.003 per segment). N2D showed superior mean segmental HCS scores (P <= 0.007 per segment). Both N2D and N1D achieved superior mean overall (P < 0.001 and P = 0.006) and right colon BBPS scores (P < 0.001 and P = 0.013). N2D demonstrated superior right colon polyp detection (P = 0.024). Adherence, tolerability, and safety were comparable between treatments. CONCLUSIONS: NER1006 is the first low-volume preparation to demonstrate superior colon cleansing efficacy vs. standard 2LPEG with ascorbate, with comparable safety and tolerability. European Clinical Trials Database (EudraCT)2014-002185-78TRIAL REGISTRATION: Multicenter, randomized, parallel group, phase 3 trial 2014-002185-78 at https://eudract.ema.europa.eu/. PMID- 30025415 TI - Colon cleansing efficacy and safety with 1 L NER1006 versus sodium picosulfate with magnesium citrate: a randomized phase 3 trial. AB - BACKGROUND: Polyethylene glycol (PEG) bowel preparations are widely used for precolonoscopy bowel cleansing. This phase 3 trial assessed the efficacy, safety, and tolerability of the novel 1 L PEG-based NER1006 vs. sodium picosulfate plus magnesium citrate (SP + MC) in day-before dosing. METHODS: Patients requiring colonoscopy were randomized (1 : 1) to receive NER1006 or SP + MC. Cleansing was assessed on the Harefield Cleansing Scale (HCS) and Boston Bowel Preparation Scale (BBPS) using central readers. Two primary end points were assessed: overall colon cleansing success and high-quality cleansing of the right colon. Intention to-treat (modified full analysis set [mFAS]) and per protocol (PP) analyses were performed. RESULTS: Of 515 patients, efficacy was analyzed in 501 (NER1006, n = 250; SP + MC, n = 251) and 379 patients (NER1006, n = 172; SP + MC, n = 207) in the mFAS and PP analyses, respectively. Non-inferiority of NER1006 vs. SP + MC was established in the mFAS for both overall cleansing (62.0 % vs. 53.8 %; P = 0.04) and high-quality cleansing in the right colon (4.4 % vs. 1.2 %; P = 0.03). Superiority of NER1006 was demonstrated using HCS in the PP set for overall cleansing success (68.0 % vs. 57.5 %; P = 0.02) and right colon high-quality cleansing (5.2 % vs. 1.0 %; P = 0.02) and using BBPS in the mFAS for overall cleansing success (58.4 % vs. 45.8 %; P = 0.003) and right colon high-quality cleansing (4.0 % vs. 0.8 %; P = 0.02). Mean segmental scores for 4/5 segments were higher with NER1006 (P <= 0.04). Both treatments were well tolerated, with more mild adverse events for NER1006 (17.0 % vs. 10.0 %; P = 0.03). CONCLUSIONS: Colon cleansing with NER1006 vs. SP + MC was non-inferior (mFAS) and superior (PP), with acceptable safety.European Clinical Trials Database (EudraCT)2014 002186-30TRIAL REGISTRATION: Multicenter, randomized, parallel group, phase 3 study 2014-002186-30 at https://eudract.ema.europa.eu/. PMID- 30025416 TI - [Neuro-otology counseling for patients with chronic tinnitus]. AB - The diagnosis and treatment of tinnitus requires professional competence in neuro otology and also an appropriate and comprehensible clarification for the individual patient.According to the Tinnitus-Guidelines of 2015 the counselling by the physician in charge is essential regarding the individual aetiopathogenesis, as well as the patient's individual coping mechanism with tinnitus, the prognosis, exacerbating factors and also as to the damaging impact on the ear.Therefore the therapeutic aim is to depathologize the symptom tinnitus and to provide an explanation and a context in the contemporary approved and scientific conception.The requirements of the guidelines are necessary and reasonable, however it is often very difficult to implement this in the daily routine in a doctor's practice, especially in the outpatient medical care.Subsequently we are going to present a four-to-five step-model to communicate the most important issues - analogous the guidelines and coherent for the outpatient or clinic patient in the one-to-one or group medical counselling. This furthermore addresses aspects of mental health.For that diagnosis as well as evaluation the mini-tinnitus-questionnaire (Mini-TF12) is available. It can be filled out and interpreted via homepage of the German Tinnitus-Liga (DTL) without charge. PMID- 30025417 TI - Step-Down Task Identifies Differences in Ankle Biomechanics Across Functional Activities. AB - Currently, there is no clinical exam to evaluate ankle frontal plane kinematics. The purpose of this study was to determine whether individuals identified as "lateral" landing during a video-recorded step-down task have differences in ankle inversion as measured with 3-dimensional motion capture during walking, step-down, and jump-landing tasks compared to individuals identified as "non lateral". Fifty-seven recreationally active adults completed the descriptive laboratory study. During walking, step-down, and jump-landing tasks, participants had their ankle frontal plane kinematics measured using a 3-dimensional motion capture system. In addition, during the step-down task, participants had a posterior view video of their foot recorded using a commercial camera. Following testing, a blinded-investigator scored the step-down video of all participants by classifying them as "lateral" landing or "non-lateral" landing. Ankle frontal plane kinematics during the walking, step-down, and jump-landing tasks were compared between the two groups (lateral (N=24) and non-lateral (N=33) using a binary logistic regression and time-series confidence interval analysis. During walking, stepping-down, and jump-landing, the lateral group had significantly more inversion at initial contact and during various other phases specific to each task. This study found that a clinical screening tool could identify individuals who have significantly more inversion during three tasks. PMID- 30025418 TI - Musculoskeletal Outcomes from Chronic High-Speed, High-Impulse Resistance Exercise. AB - While bones and muscles adapt to mechanical loading, it appears that very specific types of stimuli must be applied to achieve osteogenesis. Our study assessed musculoskeletal outcomes to 30 training sessions on an Inertial Exercise Trainer (Newnan, GA). Subjects (n=13) performed workouts with their left leg, while their right served as an untreated control. Workouts entailed three 60-s sets each of knee extension, hip extension and calf press exercises, separated by 90-s rests. Before and after the 30 training sessions, subjects underwent strength tests (knee and ankle extensors of both legs), DEXA scans (hip, knee and ankles of both legs), and blood draws. After 30 training sessions 2*2 ANOVAs showed left leg peak torques rose significantly. 2*2 ANCOVAs, with bone scan area as a covariate, showed significant left leg calcaneal bone mineral content (+29%) and density (+33%) increases after 30 training sessions. A significant decline in C-terminal telopeptides of type I collagen, a blood marker of bone resorption, also occurred after 30 training sessions. The Inertial Exercise Trainer's large volume of training session repetitions elicited high peak force, peak acceleration and impulses that likely provided a mechanical loading stimulus that evoked calcaneal accretion. PMID- 30025419 TI - Validity of the RSA-RANDOM Test for Young Soccer Players. AB - The present study aimed to examine the reliability, usefulness, responsiveness, age-related differences and construct validity of a novel decision-making RSA test (RSA-RANDOM test) in young soccer players. Twenty-five young male soccer players performed the RSA-RANDOM test on 2 occasions separated by 5-7 days to assess test-retest reliability and determine a priori usefulness. Furthermore, the same players executed the RSA-RANDOM test 4 times throughout the season to analyse responsiveness. Forty-five players (U-13 to U-17) were evaluated in such test to examine age-related differences. Finally, 9 players were used to determine the construct validity of the test. Reliability scores showed a high intraclass correlation coefficient (ICC=0.88 to 0.90) and low coefficient of variation (CV=1.0-1.2%). The responsiveness of the RSA-RANDOM test was good, as the typical short- (1.2-1.9%), mid- (1.4-2.4%) and long-term (2.3-3.2%) changes in RSA-RANDOM performance were higher than the CV. Age-related differences analysis showed better RSA-RANDOM performance as age increased in young soccer players. Low (r=-0.50) to moderate (r=-0.75) relationships were found between the RSA-RANDOM test variables (RSA best and mean times) with high-intensity and total distance covered, respectively. A novel decision-making RSA test (RSA-RANDOM) has shown to be reliable and valid in young soccer players. PMID- 30025420 TI - Inertial Sensors are a Valid Tool to Detect and Consistently Quantify Jumping. AB - Considering the large and repetitive loads associated with jumping in team sports, automatic detection and quantification of jumping may show promise in reducing injury risks. The aim of this study was to validate commercially available inertial-movement analysis software to detect and quantify jumping in team sports. In addition, the test-retest reliability of the software to quantify jumping was assessed. Seventy-six healthy male participants completed a team sport circuit six times containing seven common movements (including three countermovement and two single-leg jumps) whilst wearing an inertial sensor (Catapult Sports, Australia). Jump detection accuracy was assessed by comparing the known number of jumps to the number recorded by the inertial movement analysis software. A further 27 participants separately performed countermovement and single-leg jumps at 33%, 66% and 100% of maximal jump height over two sessions. Jump height quantification accuracy was assessed by comparing criterion three-dimensional motion analysis-derived heights to that recorded by the inertial movement analysis software. Test-retest reliability was assessed by comparing recorded jump heights between both testing sessions. Catapult's inertial movement analysis software displayed excellent jump detection accuracy (96.9%) and test-retest jump height quantification reliability (ICC: 0.86 [countermovement jump], 0.88 [single-leg jump]). However, significant mean bias ( 2.74 cm [95% LoA -10.44 - 4.96]) was observed for jump height quantification. Overall, Catapult's inertial movement analysis software appears to be a suitable method of automatically detecting jumping in team sports, and although reliable, caution is advised when using the IMA software to quantify jump height. PMID- 30025421 TI - [Effort-Reward Imbalance in the Emergency Rescue Service - A Cross-Sectional Study on Prevalence and Influencing Factors among Full-Time Emergency Service Employees]. AB - INTRODUCTION: The emergency service is a challenging field of activity. The Effort-Reward Imbalance model explains on the basis of the ratio between reward/effort the appearance of occupational stress. For the first time, this study examines the extent of Effort-Reward Imbalance in rescue services in Germany. METHODS: Full-time emergency service employees of a German Red Cross District Association were consulted. N=82 employees (78.8%) participated (M age=37.78 years, 73.2% male). In addition to the Effort-Reward-Imbalance Questionnaire, the study included other tools to measure anxiety, depression, health, social support, bullying and optimism of the employees. RESULTS: N=58 persons (70.7%) reported an effort-reward imbalance. The existence of an Effort Reward Imbalance was related to older age, lower education, higher professional qualification (working as a paramedic) and existing partnership. Persons with an effort-reward imbalance reported poorer health and lower social support. DISCUSSION: The high number of persons with Effort-Reward Imbalance in emergency services in Germany coincides with international studies. CONCLUSION: The results demonstrates the need for preventive support and further research. PMID- 30025422 TI - [Genetics of Posttraumatic Stress Disorder (PTSD)]. AB - Post-traumatic stress disorder (PTSD) is a mental disorder following a severe traumatic experience and is characterized by high rates of comorbidity with related psychiatric disorders. However, even for individuals experiencing the same trauma, there is considerable inter-individual variability in the risk of PTSD, and this is largely thought to be determined by biological processes, such as genetic predisposition and epigenetic mechanism. In this review we will summarize recent research on genetics of PTSD, primarily focusing on candidate gene-association studies, targeting on functional genetic variants in the monoaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis. In addition, results from recent genome-wide association studies (GWAS) will be reported and we will highlight the interplay of genetic factors with environmental factors, based on evidence from gene-environment interaction analysis and studies on the epigenetic regulation of PTSD. Finally, we will provide a brief outlook towards the potential and perspectives of pharmaco genetic studies. PMID- 30025423 TI - [Pain During the Night]. PMID- 30025424 TI - [Diffractive Multifocal Intraocular Lenses in Strabismus, Amblyopia and Anisometropia - a Case for an Expert Opinion]. PMID- 30025425 TI - [Intermittent Low Frequency Hearing Loss after Repeated Use of Moxifloxacin Eye Drops]. PMID- 30025426 TI - [Innovative Teaching Methods: Wet Lab-based Ophthalmosurgical Education for Medical Students]. AB - BACKGROUND: An increased demand for young physicians in Germany is causing increased competition to attract the best minds, even during their undergraduate studies. Therefore, it is the task of the university hospitals to offer their students the best possible courses in order to arouse interest in the relevant subject area. We therefore examined the impact of an ophthalmosurgical wet lab on teaching undergraduate medical students. MATERIAL/METHODS: Undergraduate medical students were offered voluntary participation in the ophthalmosurgical wet lab during an ophthalmology block week. At the beginning and at the end of the week, as well as at the end of the wet lab, the students answered questionnaires with questions about the interest in the field of ophthalmology and the specific assessment of the wet lab. RESULTS: The interest of the students in ophthalmology was increased by the block week and additionally by the wet lab. The wet lab enriched the block week and was rated as very good by the participants. The overall rating of the block week was significantly better among participants in the wet lab than in the group without wet lab participation. The wet lab gave the students great pleasure, enabled them to apply the acquired knowledge, gain valuable insights into ophthalmology, and was easily implemented. CONCLUSION: The integration of a wet lab into the block week was evaluated very positively by the students and gives them a valuable insight into the field of ophthalmology. PMID- 30025427 TI - High-Risk Drinking in the Elderly. PMID- 30025429 TI - Virtual screening using ligand-based pharmacophores for inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1). AB - Human tyrosyl-DNA phosphodiesterase (hTdp1) inhibitors have become a major area of drug research and structure-based design since they have been shown to work synergistically with camptothecin (CPT) and selectively in cancer cells. The pharmacophore features of 14hTdp1 inhibitors were used as a filter to screen the ChemNavigator iResearch Library of about 27 million purchasable samples. Docking of the inhibitors and hits obtained from virtual screening was performed into a structural model of hTdp1 based on a high resolution X-ray crystal structure of human Tdp1 in complex with vanadate, DNA and a human topoisomerase I (Top1) derived peptide (PDB code: 1NOP). We present and discuss in some detail 46 compounds matching the three-dimensional arrangement of the pharmacophoric features. The presented novel chemotypes may provide new scaffolds for developing inhibitors of Tdp1. PMID- 30025430 TI - Morphology and ultrastructure of the organ of Bellonci in the marine amphipod Gammarus setosus. AB - The three-dimensional structure of the organ of Bellonci in the marine amphipod Gammarus setosus and the relationship between its sensory cells and concretion are described using light, transmission, and scanning electron microscopy, with chemical treatment for cell lysis, calcium chelation, glycogen staining, and lanthanum labelling. The organ is encapsulated and has three units called fuselli. Each is enclosed by two fusellar cells which generate and release calcium granule strands into the cores of the fusellar concretions, which are united in the center of the organ. The surface of each fusellus is traversed by spiral dendrites entering dorsally and ending ventrally. The spiral dendrites arise from sensory neurons contained in a palm-shaped ganglion in the center of the capsule, beyond which they are twisted like a rope before reaching the concretion. The spiral dendrites are linked in pairs by gap and tight junctions and each gives origin to two pairs of 9+0 sensory cilia 30 MUm apart. The ciliary distal segments give rise to long tubules which are in contact with the calcium granule strands. The ciliary proximal segments are expanded by many long mitochondria which interdigitate with the branched striated ciliary rootlets. The concretion is suspended in the capsule cavity by axons originating from four neurons of a remote mechanoreceptor. The structure of the organ suggests that it is a sensory organ involved in the reception and integration of a variety of stimuli. PMID- 30025428 TI - The Relationship between Aortic Knob Width and Metabolic Syndrome. AB - Background: Both aortic knob width and metabolic syndrome are suggested to be related to atherosclerosis and cardiovascular diseases. However, the association between aortic knob width and metabolic syndrome is unknown. This study aimed to explore this relationship. METHODS: Participants were 3,705 Korean adults aged 18 79 years who visited the health promotion center of a general hospital. Data on chest radiography, physical measurements, medical and social history, and blood tests were collected. We defined metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria. A single reviewer measured aortic knob width on chest radiography. RESULTS: Aortic knob width was significantly correlated with age; body mass index; waist circumference; systolic and diastolic blood pressures; total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting glucose, glycated hemoglobin, insulin, and uric acid levels; and homeostatic model assessment of insulin resistance values. Aortic knob width significantly increased as the number of metabolic syndrome components increased. Moreover, metabolic syndrome component values tended to increase across the quartile groups of aortic knob width after adjusting for age, exercise, smoking status, and alcohol use. Through receiver operating characteristic curve analysis, we determined the clinically useful cutoff value for aortic knob width to be 30.47 mm in premenopausal women. CONCLUSION: Aortic knob width was found to be significantly related to metabolic syndrome and its individual components. PMID- 30025431 TI - Immunocytochemical study of crustacean hyperglycemic hormone in the eyestalks of the prawn Palaemon serratus (Pennant) and some other Palaemonidae, in relation to variations in the blood glucose level. AB - With the use of rabbit antisera against crustacean hyperglycemic hormone (CHH), it is possible to describe a distinct immunopositive reaction in a group of neurosecretory cells in the medulla terminalis ganglionic X-organ2 (MTGX2 ), in the MTGX-sinus gland tract, and in a considerable part of the sinus gland from several species of prawns belonging to the Palaemonidae. By introductory studies on the CHH system in Palaemon serratus, we can postulate a sequence in the activity cycle of the CHH-producing cells on the basis of differences in staining intensity of the immunoreaction and such morphometric parameters as cellular and nuclear diameter. By studying the CHH-producing system in combination with variations in the glucose level of the blood, an "inverse relationship" is observed between the number of immunoreactive cells and the blood glucose level during different periods of the year as well as during different stages of the molting cycle. A "shift in phase" of this correlation during the diurnal cycle suggests that several rhythmical phenomena may play a role in the regulation of glycemia in Crustacea. PMID- 30025432 TI - Morphology of male sex organs and insemination in the grasshopper Taeniopoda eques (Burmeister). AB - The functional morphology of the male genitalia and the insemination process of Taeniopoda eques were examined using scanning electron microscopy and dissections of mating pairs. Male accessory glands consist of 17 separate tubules belonging to eight categories. Males attach to females via a genital locking mechanism, with special motions of the four aedeagal valves aiding in insertion of the aedeagus. The male passes a series of spermatophores. Each is emptied of its spermatodesm contents, then extracted from the male and female genital tracts through motions of the aedeagal valves, while the pair remain in copulo. This allows the male to keep a strong hold on the female, presumably preventing usurpation by other males, while filling the spermatheca with sperm. PMID- 30025433 TI - Mechanics of blood-feeding in black flies (Diptera, simuliidae). AB - The structure and interrelationships of the mouthparts and of the food canal and its accessory cephalic structures of the females of Simulium venustum are described through microscopic observations. The mouthparts that enter the would during feeding are the mandibles, maxillary laciniae, hypopharynx, and labrum and collectively form a "syntrophium." The labium and labellar lobes, which do not enter the wound, ensheathe the syntrophium distally and must be retracted to allow biting. We present an interpretation of mouthpart function during biting that emphasizes how biting steps are accomplished and what sensory structures are used to monitor the process. Four phases of biting are identified: (1) initial penetration of the skin effected by the mandibles; (2) consolidation of mouthpart position involving anchoring the syntrophium into the wound by means of the barbed laciniae; (3) diet sampling and active feeding-food (blood) is pumped by three groups of muscles forming two functional pumps, one located in the cibarium, the other in the pharynx. These pumps are separated from each other and from surrounding regions of the food canal by valve muscles making the pumping process a complex and highly coordinated series of muscular contractions; and (4) mouthpart disengagement involving removal of the laciniae, thus releasing the syntrophium from the wound. PMID- 30025434 TI - Mesodermal organogenesis in the embryo of the primitive moth, Neomicropteryx nipponensis Issiki (Lepidoptera, Micropterygidae). AB - The formation of somites, coelomic sacs, splanchnic mesoderm, fat bodies, circular system, gonads, and musculature in the embryo of the primitive moth, Neomicropteryx nipponensis Issiki, is described. The following paired somites are formed: the labral, antennal, intercalary, mandibular, maxillary, labial, three thoracic, and 11 abdominal. Small but distinct coelomic cavities appear in all these somites. Labral somites differentiate into the labral muscles, stomodaeal muscles, and dorsal dilator muscles of the pharynx. Antennal somites differentiate into the antennal muscles, aorta, and the ventral dilator muscles of the pharynx. Intercalary somites are short-lived, disintegrating to liberate many free cells into the yolk. The suboesophageal body is not formed. Mandibular somites differentiate into the mandibular flexor and extensor muscles. Maxillary and labial somites differentiate into the splanchnic mesoderm, fat bodies, and into muscles of the maxillolabial region. Three pairs of thoracic and ten pairs of abdominal somites split into the splanchric and somatic mesoderm. The 11th abdominal somites merge into the proctodaeal mesoderm, and differentiate into the musculature of the hindgut. The heart is formed by the fusion of the cardioblasts derived from the first thoracic to the tenth abdominal segment. The aorta arises from the antennal median mesoderm. Blood cells are derived from the median mesodermal cells of the maxillary to the tenth abdominal segment. Germ cells appear at the mediodorsal corner of each somite in the fifth abdominal segment. They become enclosed with a mesodermal sheath to form a pair of rudimentary gonads in this segment. Major muscles in the head, thorax, and abdomen of the fully grown embryo are described. PMID- 30025435 TI - Light microscopy of the medial wall of the cerebral cortex of the lizard Psammodromus algirus. AB - The telencephalic medial wall of the lizard Psammodromus algirus was studied using Golgi and conventional light microscopic techniques. The area is formed by two different cytological fields-medial cortex and dorsomedial cortex. These two cortices possess three layers dorsoventrally: a superficial plexiform layer, a cellular layer, and a deep plexiform layer. The alveus, a deep fiber system, runs adjacent to the ependyma. Four classes of neurons are found in the cellular layer of the medial cortex on the basis of soma shape, dendritic pattern, and position in the layer: horizontal, double pyramidal, and candelabra cells. Solitary cells are present in the superficial and deep plexiform layers of the medial cortex. Those of the superficial plexiform layer are stellate cells. Horizontal and vertical cells are found in the deep plexiform layer. Double pyramidal cells are the most frequently impregnated in the cellular layer of the dorsomedial cortex. In addition, candelabra cells are present at the lateral end of the layer. Two cell types are found in the deep plexiform layer of the dorsomedial cortex: solitary pyramidal cells and, among the fibers of the alveus, horizontal cells. Ependymal tanycytes line the ventricular surface, and protoplasmic astrocytes are found in the plexiform layers of both medial and dorsomedial cortices. PMID- 30025436 TI - Morphology and growth of lepidosirenid lungfish tooth plates (Pisces: Dipnoi). AB - The structure of the tooth plates of Protopterus and Lepidosiren was investigated to determine the causes and consequences of postlarval shape change. During growth, the basal area of the tooth plates increases, some cusps become more prominent, and shearing surfaces are sharpened. The jaw articulation restricts the range of movements of the lower jaw, and causes the tooth plates to occlude precisely; the resulting wear patterns are regular. The tooth plates are composed of enamel, trabecular dentine, and petrodentine. A petrodentine column forms the core of a tooth plate; it is flanked by trabecular dentine. Microhardness measurements show that trabecular dentine is comparable in hardness to mammalian dentine, whereas the petrodentine is comparable to enamel. The location and differential wear of these tissues produce the prominent cusps and self-sharpened blades of the adult tooth plates. PMID- 30025437 TI - Models of tongue movement in the walrus (Odobenus rosmarus). AB - Three hypothetical models of tongue movement of the walrus during suction feeding are examined. These models encompass the entire range of simple tongue retraction movements possible by examining 1) movement of the tongue directly to the rear following the curvature of the palate, 2) to the rear and ventrally in a straight line, and 3) ventrally in a straight line. The percent of muscular force available from the hyoglossus, genioglossus, and styloglossus that could be applied toward retraction as predicted by each model is calculated. The resistance that the tongue would provide during retraction is calculated using projected tongue areas and is combined with the above data from the muscles to provide an estimate of the percent of the total available force that is needed to retract the tongue for each model. A separate examination of the direction of tongue-induced wear striations on the palatal and lingual aspects of the teeth is used to help support or reject the three models. The model where the tongue is moved directly to the rear is supported by studies of both muscle force and tooth wear. In the mammalian groups that were compared to the walrus, there is a great deal of interspecific variation in movements of the tongue during suction feeding; no two groups can be considered to have identical stereotyped tongue movements. PMID- 30025438 TI - Mechanisms of hind foot reversal in climbing mammals. AB - Many climbing mammals are able to reverse normal hind foot posture to effect the grip necessary to descend headfirst or to hang upside down. Such hind foot reversal is known in sciurids, procyonids, felids, viverrids, tupaiids, prosimians, and marsupials. The joint movements involved, however, have never been documented unequivocally although various interpretations (some contradictory) have been made. We report here radiographic data from species of the genera Didelphis, Felis, Nasua, Nycticebus, Potos, Sciurus, and Tupaia. In the six eutherians studied, three joints are involved, and there is a common pattern in the mechanism: crurotalar plantarflexion, subtalar inversion, and transverse tarsal supination. Hind foot reversal represents the development of an unusual degree of excursion at these joints, rather than the appearance of any new type of movement. In Didelphis the mechanism is quite different: a bicondylar, spiral tibiotalar joint is the principal site of inversion/abduction movements. This specialization is characteristic of didelphids and phalangerids, and occurs in the extinct multituberculates as well; it is not found in macropodids (which are like eutherians in crurotalar joint structure) or other marsupial families. This diversity in pedal structure and function is evidently the result of parallel evolution from the type of tibiotalar joint of cynodonts and early mammals. In Morganucodon the bulbous, hemispheroidal proximal surface of the talus bears two tibial facets. These facets are represented in didelphids and multituberculates as sulci, whereas in macropodids and eutherians they developed as the proximal and medial surfaces of the talar trochlea. Among living mammals, the primitive hemispheroidal joint is retained among monotremes as a ball and socket joint. PMID- 30025439 TI - Morphology and histology of the alimentary tracts of ambassidae (Cuvier) (Teleostei) in relation to feeding. AB - The gross morphology and histology of the alimentary tracts of three species of glassy perchlet; Ambassis productus, A. natalensis, and A. gymnocephalus from estuaries on the southeast coast of Africa were investigated. The anatomy of the digestive tracts in all three species was found to be similar. Well-developed dentition and pharyngeal teeth together with a distensible stomach and a low relative gut length (RGL) suggest a predatory and carnivorous habit for all three species. The relative gut lengths of Ambassis species from different estuarine systems are compared.. Differences in RGL for A. productus and A. natalensis from the Kosi and St Lucia systems with fish from Mdloti estuary are discussed. It is suggested that decreased RGL for fish at Mdloti is attributable to decreased food availability and not to a lack in the calorific content of their diet. Histological investigation revealed the presence of the following regions: a pharynx; an oesophagus; a stomach differentiated into cardiac and pyloric regions; a duodenum or upper intestine; an ileum or lower intestine; and a rectum. Pyloric and rectal sphincters are present. The tunics of the above regions are described. The epithelium of the oesophagus contains taste buds and numerous mucus cells, and varies from stratified anteriorly to simple columnar posteriorly. The muscularis comprises dorsally and ventrally located inner muscle bundles and an outer circular layer. Both layers consist of striated fibres. Gastric glands are present in the mucosa of the cardiac stomach but are absent in the pylorus. Columnar absorbing cells and goblet cells are present in the epithelium of the upper and lower intestine. The rectum is distinguished from the intestine by the proliferation of mucous-secreting cells which are thought to aid defecation. PMID- 30025441 TI - Effects of aspirin resistance and mean platelet volume on vascular access failure in hemodialysis patients. AB - Background/Aims: Maintaining the patency of vascular access (VA) in hemodialysis (HD) patients is important and can be life-saving. We investigated the effects of aspirin resistance and mean platelet volume (MPV) on VA failure in HD patients. Methods: We enrolled 163 patients on maintenance HD. VA failure was defined as thrombosis or a decrease of > 50% of the normal vessel diameter, as revealed by angiography. Results: Aspirin resistance was observed in 17 of 109 patients in whom this parameter was measured, and was not significantly associated with VA failure (p = 0.051). The mean MPV was 9.15 +/- 0.05 fL. The 163 patients were grouped by the median MPV value (9.08 fL) at baseline; patients with higher MPVs (n = 82) had lower platelet counts (p = 0.002) and albumin levels (p = 0.009). During 34 months of follow-up, 65 VA failures (39.9%) occurred. The Kaplan-Meier curve revealed significant differences between the two groups in terms of cumulative VA failure (54.1% vs. 35.3%, p = 0.018). On multivariate analysis, the MPV (hazard ratio [HR], 1.794; 95% confidence interval [CI], 1.066 to 3.020; p = 0.028), platelet count (HR, 1.003; 95% CI, 1.001 to 1.006; p = 0.01), and smoking status (HR, 1.894; 95% CI, 1.019 to 3.519; p = 0.043) independently predicted VA failure. Conclusions: A high MPV was associated with an increased risk of VA failure, whereas aspirin resistance showed only a weak association. The MPV may predict VA survival in HD patients. PMID- 30025442 TI - Chilaiditi syndrome. PMID- 30025440 TI - Cell type-specific effects of Notch signaling activation on intervertebral discs: Implications for intervertebral disc degeneration. AB - Intervertebral disc (IVD) degeneration is the major cause of back pain. Notch signaling is activated in annulus fibrosus (AF) and nucleus pulposus (NP) tissues of degenerated IVDs, and induced by IL1-beta and TNF-alpha in NP cells. However, the role of Notch activatin in the pathogenesis of IVD degeneration is largely unknown. In this study, we overexpressed the Notch1 intracellular domain (NICD1) in AF, NP, and chondrogenic ATDC5 cells via adenoviruses. Overexpression of NICD1 activated transcription of Notch signaling target genes in AF, NP, and ATDC5 cells, and caused cell type-specific effects on expression of matrix anabolic and catabolic genes. Activation of Notch signaling promoted expression of matrix catabolic genes and inhibited expression of matrix anabolic genes in both AF and ATDC5 cells, whereas its activation suppressed expression of matrix catabolic genes (including Mmp3, Mmp13, Adamts4, and Adamts5) and attenuated TNF-alpha and inflammatory macrophage-induced Mmp13 expression in NP cells. Consistently, sustained activation of Notch1 signaling in postnatal IVDs in mice severely disrupted growth plate and endplate cartilage tissues, but did not overly affect NP tissues. Together, these data indicated that activation of Notch signaling exerted differential and cell type-specific effects in intervertebral discs, and specific Notch signaling regulation may be considered during the treatment of IVD degeneration. PMID- 30025444 TI - Feasibility of Selective Neck Irradiation with Lower Elective Radiation Dose in Treating Nasopharynx Cancer Patients. AB - Purpose: This study aimed to report the clinical outcomes following selective neck irradiation (SNI) with lower elective radiation therapy (RT) dose in treating nasopharyngeal cancer (NPC) patients. Methods and Materials: A total of 347 NPC patients received definitive RT according to our SNI policy and were retrospectively analyzed. The clinical target volumes (CTVs) were subdivided into CTV at high risk (CTV-HR) and CTV at low risk (CTV-LR). The typical doses to gross tumor volume (GTV), CTV-HR, and CTV-LR were 68.4-70.0 Gy, 54.0-60.0 Gy, and 36.0 Gy. Results: With the median follow-up of 68.1 months (range, 2.3 to 197.1 months), the 5-year rates of loco-regional control and progression-free survival in all the patients were 85.0% and 70.8%, respectively. Thirty patients developed regional failure and the regional control rates at 3 and 5 years were 92.6% and 91.4%, respectively. The sites of regional failure in relation to the target volume were exclusively inside GTV/CTV-HR in 20, in- and outside GTV/CTV-HR in three, and exclusively outside GTV/CTV-HR in seven, which were 5.7%, 0.9%, and 2.0% of total patients, respectively. Conclusion: The clinical outcomes by the current SNI policy were feasible and comparable to those following classic elective nodal irradiation policy. PMID- 30025443 TI - Comparison of Efficacy of Pembrolizumab between Epstein-Barr Virus-Positive and Negative Relapsed or Refractory Non-Hodgkin Lymphomas. AB - Purpose: Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and PD1 ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), real-world data about the efficacy of pembrolizumab in NHL patients are limited. Materials and methods: We analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)-positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression. Results: Seven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV negative subtypes did not respond such as diffuse large B-cell lymphoma and T lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%). Conclusion: Pembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL. PMID- 30025445 TI - Correlation of Androgen Deprivation Therapy with Cognitive Dysfunction in Patients with Prostate Cancer: A Nationwide Population-Based Study Using the National Health Insurance Service Database. AB - Purpose: The purpose of this study was to evaluate the association of androgen deprivation therapy (ADT) with cognitive dysfunction. Material and Methods: Using the National Health Insurance Service database of the entire Korean adult prostate cancer population (n=236,391), data on ADT and cognitive dysfunction between 2008 and 2015 were analyzed. We excluded patients previously diagnosed with cognitive dysfunction, dementia, or a cerebral event history. We tested the effect of ADT on the risk of cognitive dysfunction using propensity score-matched Cox proportional hazards regression models and Kaplan-Meier survival analysis. Our final cohort comprised of 35,401 individuals with prostate cancer, including 24,567 men (70.6%) who underwent ADT. Results: During a mean follow-up period of 4.1 years, 4,741 patients were newly diagnosed with cognitive dysfunction. A statistically significant association was found between ADT and the risk of cognitive dysfunction (hazard ratio, 1.169; p=0.002). Meanwhile, age (>=70 years), diabetes, hypertension, cardiovascular history, and peripheral vascular disease were identified as factors that contribute to the increased risk of cognitive dysfunction. In contrast, the use of statins and aspirin was associated with a lower risk of cognitive dysfunction. Kaplan-Meier analysis demonstrated that patients aged 70 years or older who underwent ADT had the lowest cumulative probability of remaining cognitive dysfunction-free (log-rank p < 0.001). Conclusion: Our results revealed an association between the use of ADT for the treatment of prostate cancer and an increased risk of cognitive dysfunction in a nationwide population-based study. This finding should be further evaluated in prospective studies. PMID- 30025446 TI - Upregulation of PITX2 Promotes Letrozole Resistance via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells. AB - Purpose: Although the interferon alpha (IFNalpha) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa. Materials and methods: PITX2 expression was assessed in BCa tissues using quantitative RT-PCR (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels. Results: PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFNalpha signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFNalpha-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozole-elicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFNalpha-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment. Conclusion: These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa. PMID- 30025447 TI - Antimicrobial Magnesium Hydroxide Nanoparticles As an Alternative to Cu Biocide for Crop Protection. AB - In agriculture, prolonged use of copper biocides increases the risk of development of Cu resistance and its accumulation in soil, demanding an alternative. In this paper, we report antimicrobial magnesium hydroxide nanoparticles (NPs) as an alternative to Cu biocides with low cytotoxicity. To improved bioavailability, Mg hydroxide NPs were synthesized followed by coating with water-soluble capping agents, trisodium citrate (zeta potential, xi = -22 mV) or betaine (xi = +35 mV). Electron microscopy study confirmed the formation of ~10-nm-sized cubical NPs with citrate and ~100-nm-sized lamellar NPs with betaine. As-synthesized Mg hydroxide NPs inhibited bacterial growth of X. alfalfae, P. syringae, and E. coli within 4 h. Significant bacterial growth inhibition and killing were observed at 24 h post-treatment. Phytotoxicity studies on tomato plants showed no significant tissue injury. Therefore, Mg hydroxide NPs have the potential to serve as a Cu alternative. PMID- 30025448 TI - Associated Detection of Superoxide Anion and Mercury(II) under Chronic Mercury Exposure in Cells and Mice Models via a Three-Channel Fluorescent Probe. AB - As a cytotoxic heavy metal ion, mercury(II) ion (Hg2+) induces severe oxidative stress and further results in physiological dysfunction. Although mercury poisoning can be treated with many drugs, such as sodium selenite, the therapeutic effect is relatively poor, and it seems that the damage to human health continues. However, the interpretation for the pathogenesis has not been clarified yet. We supposed that the reason is attributed to Hg2+-caused intracellular oxidative stress. To confirm our hypothesis, we strived to design a three-channel ratio fluorescent probe, HCy-SeH, for superoxide anion (O2*-) and Hg2+ combined detection. O2*- is a vital precursor for other reactive oxygen species (ROS), which is involved in many physiological and pathological processes. However, until now there is no efficient chemical tool for O2*- and Hg2+ combined detection in cells and in vivo. The fluorescence response of our probe is initiated by a hydrogen abstraction reaction from the hydrocyanine fluorophore moiety. Once oxidized by O2*-, HCy-SeH recovers its pi-conjugated system back to a heptamethine cyanine derivative, Cy-SeH. Cy-SeH coexists with its conjugate base, Cy?Se. One emits red fluorescence, and the other one emits green fluorescence. The response unit, -SeH, can trap Hg2+ via a Se-Hg antagonism reaction to afford an orange-emitting final product, Keto-Cy. The probe offers high selectivity and sensitivity toward O2*- and Hg2+. When applied for O2*- and Hg2+ detection in HEK 293 cells, the imaging results indicate that our probe can provide a combined response for O2*- and Hg2+ in real time and in situ. Flow cytometry analysis is well-consistent with the results from fluorescence imaging. When applied to image O2*- and Hg2+ in mice models, we find that Hg2+ dominantly accumulates in the kidney and induces a burst of O2*-. We confirm that chronic mercurialism can cause severe oxidative damage and renal fibrosis. HCy-SeH further provides a new information that, even when intracellular Hg2+ has been antagonized, the outbreak of O2*- caused by mercury poisoning still lasts. PMID- 30025450 TI - Metal-Organic Gels of Catechol-Based Ligands with Ni(II) Acetate for Dye Adsorption. AB - Metal organic gels (MOGs) are a class of supramolecular complexes, which have attracted widespread interest because of the coupled advantages of inorganic and organic building blocks. A new compound terminated with catechol was synthesized. This new compound can be used to coordinate with Ni2+ to form MOGs. These MOGs show favorable viscoelasticity and wormhole-shaped porous structures, which were confirmed by transmission electron microscope and scanning electronic microscope images. Taking the benefits of porosity into account, the xerogel could serve as an adsorbent to adsorb dye molecules from the aqueous media. The experimental results indicate that xerogels possess good adsorption effect both on anionic and cationic dyes. Exhaustive research has been performed on the adsorption kinetics and isotherms, revealing that the adsorption process accords with the pseudo second-order model and the Langmuir model. PMID- 30025449 TI - Near Infrared Light Triggered Cucurbit[7]uril-Stabilized Gold Nanostars as a Supramolecular Nanoplatform for Combination Treatment of Cancer. AB - Developing a spatiotemporal-controlled platform with feasible synthesis and multifunctionality is highly desirable in the field of nanomedicine. Here, we present a near-infrared (NIR)-light-triggered approach to control the supramolecular assembly system for drug release and achieve synergistic chemo photothermal therapy for cancer. A cucurbit[7]uril (CB[7]) stabilized gold nanostar (GNS) platform is designed to encapsulate the anticancer drug camptothecin (CPT) via host-guest chemistry. Importantly, CB[7] behaves not only as a surfactant to improve the stability of GNS in the aqueous solution but also as the cage for intermolecular assembly of CPT molecules. Moreover, without the competitive complexation, the drug release could be stimulated under NIR light irradiation. Synergistic treatment of cancer can be achieved by combining chemotherapy with the photothermal effect of GNS. This work develops a NIR-light triggered cucurbituril-based drug-release approach that opens the door for remote control of drug release in the supramolecular assembly system. PMID- 30025451 TI - Potassium Iodide-Promoted One-Pot Synthesis of Fluoroalkylated Quinoxalines via a Tandem Michael Addition/Azidation/Cycloamination Approach. AB - Fluoroalkylated quinoxlines with various groups were efficiently synthesized via a one-pot tandem Michael addition/azidation/cycloamination process. Under the mild and metal-free conditions, a bis-imine intermediate (4a) was detected and isolated for the first time. KI played a crucial role in this reaction. The mechanism was described. PMID- 30025452 TI - Multiparameter Phenotypic Profiling in MCF-7 Cells for Assessing the Toxicity and Estrogenic Activity of Whole Environmental Water. AB - Multi-parameter phenotypic profiling of small molecules is a powerful approach to their toxicity assessment and identifying potential mechanisms of actions. The present study demonstrates the application of image-based multi-parameter phenotypic profiling in MCF-7 cells to assess the overall toxicity and estrogenic activity of whole environmental water. Phenotypic profiling of 30 reference compounds and their complex mixtures was evaluated to investigate the cellular morphological outcomes to targeted biological pathways. Overall toxicity and estrogenic activity of environmental water samples were then evaluated by phenotypic analysis comparing with conventional bioassays and chemical analysis by multivariate analysis. The phenotypic analysis for reference compounds demonstrated that size and structure of cells related to biological processes like cell growth, death, and communication. The phenotypic alteration and nuclei intensity were selected as potential biomarkers to evaluate overall toxicity and estrogenic activities, respectively. The phenotypic profiles were associated with the chemical structure profiles in environmental water samples. Since the phenotypic parameters revealed multiple toxicity endpoints, it could provide more information that is relevant to assessing the toxicity of environmental water samples in compare with conventional bioassays. In conclusion, the image-based multi-parameters phenotypic analysis with MCF-7 cells provides a rapid and information-rich tool for toxicity evaluation and identification in whole water samples. PMID- 30025454 TI - Exploring Acetylene Chemistry: A Transition Metal-Free Route to Dienyl 6,8 Dioxabicyclo[3.2.1]octanes from Ketones and Acetylenes. AB - Dienyl derivatives of 6,8-dioxabicyclo[3.2.1]octanes, closely related to naturally abundant molecules, have been synthesized from 2-acetyl-3,4 dihydropyrans (readily available from ketones and acetylene in two steps), which further add to aryl(hetaryl)acetylenes in the KOBut/DMSO superbase system (105 degrees C, 1.5 h) to stereoselectively give the corresponding E-styryl adducts. The latter undergo ring closure (NH4Cl/H2O, acetonitrile, reflux, 8 h) to form the 6,8-dioxabicyclo[3.2.1]octane core decorated with the (1 Z,3 E)-diene substituent. PMID- 30025455 TI - Achieving Ultrahigh Breakdown Strength and Energy Storage Performance through Periodic Interface Modification in SrTiO3 Thin Film. AB - A periodic layer structure consisting of sol-gel-derived SrTiO3 and anodized Al2O3 has been designed and fabricated by interface engineering. Utilizing the anodized Al2O3 to be the blocking layer, not only the local high electric field around the hole and crack defects could be significantly reduced but also, and equally important, the blocking layer undertaking higher electric field could effectively decrease the breakdown probability of a SrTiO3 layer based on the finite element analysis. As the sample has been modified, the barrier height of the charge carrier was increased through fitting the conductance activation energy ( Hc). In addition, the space charge-limited conductance mechanism was almost eliminated according to the fitted results in the ln E-ln J diagram, indicating that most of the charge carrier released from traps were blocked or isolated by the Al2O3 layer. As a result of the periodic interface modification, the leakage current was decreased 2 orders of magnitude and the breakdown strength was enhanced from 144.13 to 754.23 MV m-1. More importantly, the ultimate energy density is up to 39.49 J cm-3, which is 1505% greater than the sample without interface modification. PMID- 30025453 TI - Physiological Relevance of the Antiproliferative and Estrogenic Effects of Dietary Polyphenol Aglycones versus Their Phase-II Metabolites on Breast Cancer Cells: A Call of Caution. AB - While preclinical studies suggest the breast cancer (BC) chemopreventive effects of dietary polyphenols, the human evidence is still very weak. The huge existing in vitro-in vivo gap is mainly due to the plethora of potential effects reported by in vitro studies that usually assay polyphenols as occurring in the food (beverages, extracts, foods) and/or derived aglycone metabolites with doubtful physiological relevance. Since phase-II metabolites can reach systemic tissues such as malignant breast tumors, we aimed here to compare for the first time the antiproliferative and estrogenic/antiestrogenic effects of dietary polyphenols and microbiota-derived metabolites (i.e., resveratrol, dihydroresveratrol, urolithins (A, B, and Isourolithin A), and the flavanone hesperetin), with those effects exerted by their physiologically relevant glucuronides and sulfates on human BC cell lines (MDA-MB-231 and MCF-7). Results showed that aglycones exerted dose-dependent antiproliferative and estrogenic/antiestrogenic activities, but both their glucuronide and sulfate conjugates lacked these activities. In addition, aglycones underwent phase-II metabolism in BC cells, mainly via sulfation, which determined the cell-dependent differences in the effects observed. Therefore, phase-II metabolism limits the antiproliferative, estrogenic, and antiestrogenic activities of dietary polyphenols on BC cells. Likewise, as a call of caution, enthusiasm should be limited for publishing effects that are not physiologically relevant. PMID- 30025457 TI - Metal Free C-H Functionalization Enabled Diastereoselective Multicomponent Reaction of N-Heterocycles to Fused Heteropolycycles. AB - A novel C-H functionalization enabled multicomponent reaction involving N heterocycles, dinucleophile, and dipolarophile has been developed. Direct alpha- and more challenging beta-C(sp3)-H functionalization of aliphatic N-heterocycles was achieved without the use of metallic reagents and oxidants under either conventional or microwave aided heating conditions. In a single operation, up to five carbon-carbon and carbon-heteroatom bonds are formed in a highly diastereoselective manner, providing the expeditious access to the complex heteropolycycles. PMID- 30025456 TI - Self-Template Etching Synthesis of Urchin-Like Fe3O4 Microspheres for Enhanced Heavy Metal Ions Removal. AB - Hierachical Fe3O4 microspheres with superparamagnetic properties are attractive for their superior structural, water-dispersible, and magnetic separation merits. Here self-template etching route was developed to create optimal porous structure in superparamagnetic Fe3O4 microspheres by using the oxalic acid (H2C2O4) as etching agent. A plausible formation mechanism of the urchin-like Fe3O4 microspheres was proposed based on systematic investigation of the etching process, which involved two stages including pore-forming step based on size selective etching and pore-expanding step based on further etching. The as synthesized Fe3O4 microspheres exhibited urchin-like structure with specific surface area and pore-size tunable, water-dispersible, and superparamagnetic properties. The optimal urchin-like Fe3O4 microspheres demonstrated superior performance including fast magnetic separation and high removal capabilities for the heavy metals ions like Pb2+ (112.8 mg g-1) and Cr(VI) (68.7 mg g-1). This work will shed new light on the synthesis of urchin-like microspheres for superior performance. PMID- 30025458 TI - The Familial alpha-Synuclein A53E Mutation Enhances Cell Death in Response to Environmental Toxins Due to a Larger Population of Oligomers. AB - Amyloid formation of alpha-synuclein (alpha-Syn) and its familial mutations are directly linked with Parkinson's disease (PD) pathogenesis. Recently, a new familial alpha-Syn mutation (A53E) was discovered, associated with an early onset aggressive form of PD, which delays alpha-Syn aggregation. When we overexpressed wild-type (WT) and A53E proteins in cells, showed neither toxicity nor aggregate formation, suggesting merely overexpression may not recapitulate the PD phenotype in cell models. We hypothesized that cells expressing the A53E mutant might possess enhanced susceptibility to PD-associated toxicants compared to that of the WT. When cells were treated with PD toxicants (dopamine and rotenone), cells expressing A53E showed more susceptibility to cell death along with compromised mitochondrial potential and an increased production of reactive oxygen species. The higher toxicity of A53E could be due to more oligomers being formed in cells as confirmed by a dot blot assay using amyloid specific OC and A11 antibody and using an in vitro aggregation study. The cellular model presented here suggests that along with familial mutation, environmental and other cellular factors might play a crucial role in dictating PD pathogenesis. PMID- 30025459 TI - Development and Validation of an Ultra-Sensitive UHPLC-MS/MS Method for Neonicotinoid Analysis in Milk. AB - A very sensitive ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the quantitation of the most common neonicotinoids (thiamethoxam, clothianidin, imidacloprid, acetamiprid, and thiacloprid) at trace levels in milk. Using fast and selective liquid-liquid extraction (LLE) starting from 0.5 mL of milk, lowest limits of quantitation (LLOQ) equal or lower than 10 pg/mL for all analytes were achieved. Precision and accuracy were evaluated at four different concentrations (5, 10, 500, and 10000 pg/mL) and ranged between 2 and 16% (RSD) and 77-125%, respectively. Extraction recoveries and matrix effects ranged between 64 and 76% and 88-98%, respectively. The method was applied to measure neonicotinoid levels in a series of conventional and organic Swiss milks as well as in human breast milk and commercial powdered milk. More than 90% of the samples tested positive for at least one neonicotinoid. However, all animal samples were far below the maximum residue limits authorized for human consumption with average total neonicotinoid levels of 16.1 +/- 13.1 pg/mL. Human breast milks and powdered milks contained similar amounts of neonicotinoids. Taken together, our results demonstrate the high prevalence of neonicotinoids in milk from all origins, albeit at levels considered to be safe for human consumption. PMID- 30025461 TI - In This Issue, Volume 13, Issue 7. PMID- 30025460 TI - Langmuir-Blodgett Deposition of Graphene Oxide-Identifying Marangoni Flow as a Process that Fundamentally Limits Deposition Control. AB - Langmuir-Blodgett deposition is a popular route to produce thin films of graphene oxide for applications such as transparent conductors and biosensors. Unfortunately, film morphologies vary from sample to sample, often with undesirable characteristics such as folded sheets and patchwise depositions. In conventional Langmuir-Blodgett deposition of graphene oxide, alcohol (typically methanol) is used to spread the graphene oxide sheets onto an air-water interface before deposition onto substrates. Here we show that methanol gives rise to Marangoni flow, which fundamentally limits control over Langmuir-Blodgett depositions of graphene oxide. We directly identified the presence of Marangoni flow by using photography, and we evaluated depositions with atomic force microscopy and scanning electron microscopy. The disruptive effect of Marangoni flow was demonstrated by comparing conventional Langmuir-Blodgett depositions to depositions where Marangoni flow was suppressed by a surfactant. Because methanol is the standard spreading solvent for conventional Langmuir-Blodgett deposition of graphene oxide, Marangoni flow is a general problem and may partly explain the wide variety of undesirable film morphologies reported in the literature. PMID- 30025462 TI - Special Issue on Sensors in Biology. PMID- 30025463 TI - In Memoriam: Roger Tsien (1952-2016). AB - The discovery of green fluorescent protein (GFP) and its development into a genetic tag for monitoring cell fate was transformative for bioscience, and in 2008 the Nobel Prize in Chemistry was awarded to Osamu Shimomura, Martin Chalfie, and Roger Tsien for their discoveries. Roger Tsien's development of GFP into an expansive color palette of fluorescent protein tags allowed for the revolutionary ability to monitor different biological processes simultaneously and paved the way for chemical biologists to see into cells like never before. ACS Chemical Biology collected memories from his colleagues, trainees, friends, and family that portray a creative, incisive, and endlessly curious scientist who is deeply missed. This special issue on biological sensing and imaging would not have been possible without his discoveries and is dedicated to his memory. PMID- 30025465 TI - Chemistry Takes a Bath: Reactions in Aqueous Media. PMID- 30025467 TI - Employers' views of the "Healthy Hub Roadshow": a workplace HIV testing intervention in England. AB - We explored employer uptake and perceptions of workplace human immunodeficiency virus (HIV) testing delivered to employees as part of Healthy Hub Roadshow, a multi-component general health check. Intervention included health checks with tailored advice delivered to 776 employees at 20 events hosted by 11 different workplaces (29 approached, 38% employer uptake). Delivery partners were third sector organisations with significant expertise in HIV testing and support. Health checks included optional HIV test (using 4th generation Insti finger prick rapid tests), Body Mass Index (BMI), blood glucose, blood pressure, and cholesterol. Mixed-methods evaluation included post-event online survey and qualitative interviews with participating employers. Declining employers were invited to complete an online feedback survey. Workplace HIV testing was positively received by all participating organisations, although 78% (14/18) of declining organisations did not provide their reasons for non-participation. Factors of importance to employers included the perceived trustworthiness of delivery partners, being able to provide engaging opportunities for employee health, offering HIV testing as part of a wider health check, and having visible top-level managerial support. Concerns about hosting the events were rare and related to having limited budgets for future events, and the potential loss of productivity related to attendance during work time. Employers indicated that they would not actively seek out workplace HIV testing as part of health promotion efforts, but they were highly receptive to its inclusion in workplace health and wellbeing provision by credible external delivery partners. In conclusion, workplaces are an untapped arena for HIV awareness raising and testing in the UK. Employers should be encouraged and supported to offer opt-in HIV testing as part of a wider workplace health and wellbeing provision for employees. PMID- 30025466 TI - Adaptive Memory: Survival Processing and Social Isolation. AB - Social isolation was examined to assess its potential influence on the survival processing effect, which shows that individuals are more likely to remember something when it is processed with regard to their survival. Participants imagined being stranded in the grasslands, going on a space mission, or moving to a foreign land while alone or with a group of friends and rated a list of words for their relevance to the assigned scenario. An incidental memory test showed the typical survival processing effect on recall memory, with a significant interaction showing that the effect occurred in the isolated condition but not in the group condition. A second experiment examined rates of recognition for an isolated and group condition for the grasslands and moving scenarios and found a marginally significant effect of isolation in addition to the typical survival processing effect. Further, in both experiments, the perceived isolation of the isolated and group survival grasslands scenarios was significantly higher than the other conditions. The results are discussed with regard to the self-reference effect and the object-function account of the survival processing effect. PMID- 30025468 TI - Discourses Reproducing Gender Inequities in Hospice Palliative Home Care. AB - Background As home is a site where gendered attitudes, beliefs, and practices are reproduced, it is imperative that policies and practices promote gender equity in end-of-life care at home. Purpose The purpose of this study was to critically analyze gender relations in the sociopolitical context of hospice palliative home care. Methods Using a critical feminist perspective, we examined gender relations between and among clients with cancer, their family caregivers, and nurses in hospice palliative home care. Ethnographic methods of in-depth interviews (n = 25), observations of home visits (n = 9), and review of documents (n = 12) were employed to expose gender (in)equities. Findings This critical analysis sheds light on institutional discourses that reproduce gender inequities: discourses of difference and denial; discourses of individuality, autonomy, and choice; and discourses of efficiency, objectivity, and rationality. Although gender was discounted, these neoliberal discourses reinforced traditional gender relations. Discussion Neoliberal discourses frame health and health-care experiences as resulting primarily from individual behaviors and biomedical factors, permitting health-care providers and policy makers to overlook power relations and the sociopolitical forces that obscure gender inequities. A critical perspective is needed to consider how social structures significantly shape everyday gendered experiences in hospice palliative home care. PMID- 30025469 TI - Health care utilization and spending among privately insured children with medical complexity. AB - Children with medical complexity have high health service utilization and health expenditures that can impose significant financial burdens. This study examined these issues for families with children enrolled in US private health plans. Using IBM Watson/Truven AnalyticsSM MarketScan(r) commercial claims and encounters data (2012-2014), we analyzed through regression models, the differences in health care utilization and spending of disaggregated health care services by health plan types and children's medical complexity levels. Children in consumer-driven and high-deductible plans had much higher out-of-pocket spending and cost shares than those in health maintenance organizations and preferred provider organizations (PPOs). Children with complex chronic conditions had higher service utilization and out-of-pocket expenditures while having lower cost shares on various categories of services than those without any chronic condition. Compared to families covered by PPOs, those with high-deductible or consumer-driven plans were 2.7 and 1.7 times more likely to spend over US$1000 out of pocket on their children's medical care, respectively. Families with higher complexity levels were more likely to experience financial burdens from expenditures on children's medical services. In conclusion, policymakers and families with children need to be cognizant of the significant financial burdens that can arise from children's complex medical needs and health plan demand-side cost sharing. PMID- 30025470 TI - Effect of Supplemental Oxygen on Blood Pressure in Obstructive Sleep Apnea (SOX): A Randomised, CPAP Withdrawal Trial. AB - RATIONALE: Obstructive sleep apnoea (OSA) is associated with systemic hypertension. Either overnight intermittent hypoxia, or the recurrent arousals that occur in OSA, could cause the daytime increases in blood pressure (BP). OBJECTIVES: To establish the role of intermittent hypoxia in the increased morning BP in patients with OSA. METHODS: Randomised, double-blinded, cross-over trial assessing the effects of overnight supplemental oxygen versus air (sham) on morning BP, following continuous positive airway pressure (CPAP) withdrawal in patients with moderate to severe OSA. The primary outcome was the change in home morning BP following CPAP withdrawal for 14 nights, oxygen versus air. Secondary outcomes included oxygen desaturation index (ODI), apnoea hypopnoea index (AHI), subjective (Epworth sleepiness score) and objective (Oxford sleep resistance test) sleepiness. MEASUREMENTS AND MAIN RESULTS: Supplemental oxygen virtually abolished the BP rise following CPAP withdrawal and, compared to air, significantly reduced the rise in mean systolic BP (-6.6mmHg; 95% confidence interval or CI -11.3 to -1.9; p=0.008), mean diastolic BP (-4.6mmHg; 95% CI -7.8 to -1.5; p=0.006), and median ODI (-23.8/h; interquartile range -31.0, -16.3; p<0.001), following CPAP withdrawal. There was no significant difference, oxygen versus air, in AHI, subjective or objective sleepiness. CONCLUSIONS: Supplemental oxygen virtually abolished the rise in morning BP during CPAP withdrawal. Supplemental oxygen substantially reduced intermittent hypoxia, but had a minimal effect on markers of arousal (including AHI), subjective or objective sleepiness. Therefore intermittent hypoxia, and not recurrent arousals, appears to be the dominant cause of daytime increases in BP in OSA. Clinical trial registration available at www.isrctn.com, ID ISRCTN 17987510. PMID- 30025471 TI - Associations of Anthropometric Characteristics, Dietary Habits, and Aerobic Capacity With Cardiovascular Risk Factors of Health-Science Students. AB - The aim of this cross-sectional study was to study the relative importance of dietary habits and aerobic capacity in parameters related to cardiovascular risk in 271 female and 95 male health-science students (mean age = 19.1 +/- 1.4 years). In females, fatty-meat consumption predicted triglycerides (beta = .649, p < .001) and high-density lipoprotein (HDL; beta = -.242, p = .001) and low density lipoprotein (LDL; beta = .373, p < .001) cholesterol levels. Consumption of nuts, legumes, and complex carbohydrates predicted triglyceride (beta = -.099, p = .074), HDL (beta = .231, p = .001), and LDL (beta = -.155, p = .025) levels, respectively. Aerobic capacity (beta = -.245, p < .001) and fatty-meat intake (beta = .230, p < .001) predicted diastolic blood pressure (BP); body mass index (BMI) predicted systolic BP (beta = .340, p < .001). In males, body fat percentage was the strongest predictor of triglycerides (beta = .348, p = .004), cholesterol (beta = .366, p = .006), HDL (beta = -.378, p = .004), and LDL (beta = .271, p = .043) levels. Aerobic capacity (beta = -.263, p = .013) and fatty meat consumption (beta = .334, p = .005) independently predicted triglyceride levels. Nut (beta = -.286, p = .013) and fatty-meat intake (beta = .361, p = .002) predicted systolic BP, while BMI predicted diastolic BP (beta = .209, p = .045). As health sciences students, these participants are future health professionals; targeting such populations is important for chronic disease prevention. PMID- 30025472 TI - Clinical Course and Complications of Catheter and Non-Catheter-Related Upper Extremity Deep Vein Thrombosis in Patients with Cancer. AB - Patients with cancer have an increased risk of venous thromboembolism. Upper extremity venous system is a peculiar site, and little is known about the clinical course in patients with cancer. Electronic medical records were searched for patients with cancer with a diagnosis of upper extremity venous thrombosis. Individual patient data were reviewed. Eighty-seven patients were identified, and the median age was 52.4. The most common underlying malignancies were breast (23.0%), colorectal (18.4%), and gastroesophageal (18.4%). Median time from cancer diagnosis to upper extremity venous thromboembolism (UEDVT) was 3.44 months. Subclavian vein was the most common involved site (56.3%) and 54.0% patients had a central venous catheter; 50.6% of patients developed a complication; pulmonary embolism (PE) in 9.2%, superior vena cava (SVC) syndrome in 14.9%, and 26.4% had postthrombotic syndrome. In patients with isolated single vein thrombosis, complications were higher in the subset with internal jugular vein involvement compared to other sites (68.2% vs 52.2%) as were complications in patients with non-catheter-related thrombosis compared to patients with a central venous catheter in place (55% vs 27.7%). Median overall survival from time of cancer and UEDVT diagnoses was 29.6 and 13.25 months, respectively. In conclusion, UEDVT is an uncommon event. Around 50% developed a complication including PE, SVC or postthrombotic syndromes. Larger studies are needed to better identify risks associated with thrombosis and the best therapeutic approach and duration in this unique subset of patients with cancer. PMID- 30025473 TI - Relationship between cardiovascular diseases and circulating cell-free nucleic acids in human plasma. AB - Cardiovascular diseases (CVDs) are the main cause of human morbidity and mortality worldwide. Early diagnosis could improve the efficiency of treatments. New biomarkers are needed for the identification of high-risk populations in order to make accurate diagnosis and therapy monitoring. Circulating cell-free nucleic acids (cf-NAs) offer a promising new noninvasive tool. These have a role in the regulation of normal physiological functions and in the development of pathological alterations. There is extended research on the clinical application and utilization of cell-free genomic DNA, mtDNA, mRNA, miRNA and long noncoding RNA in CVDs. These molecules could serve as components of new generation therapeutics. Our review focuses on the role of cf-NAs in the pathogenesis of CVDs and we are discussing also possible diagnostic applications and therapeutic implications. PMID- 30025474 TI - Early detection of dementia: The knowledge and attitudes of primary care physicians in Hong Kong. AB - Background Dementia affects people worldwide and its prevalence is growing. Early detection of dementia by primary care physicians can be beneficial; thus, their knowledge and attitudes about this issue are important. Objective To assess primary care physicians' knowledge and attitudes about the early detection of dementia in Hong Kong. Methods This was a mixed methods (qualitative and quantitative) study. Four focus groups with a purposive sample of 31 primary care physicians were interviewed, and a questionnaire-survey was completed and returned by 437 primary care physicians. Results Participants all agreed that the early detection of dementia would benefit patients and primary care physicians should be capable of making such diagnoses. Confidence in making an early diagnosis varied; physicians tended to overlook symptoms in the early stages. All agreed that more training is needed at the post-graduate level of medical education. Conclusions Participants had positive attitudes towards early detection of dementia; however, their confidence and ability to make an early diagnosis varied. PMID- 30025475 TI - Ertugliflozin for treatment of patients with Type 2 diabetes mellitus. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a growing and serious global health problem. Inhibition of the sodium--glucosecotransporter-2 (SGLT2) can increase urinary glucose excretion and decrease plasma glucose levels in an insulin-independent manner. Ertugliflozin is a highly selective inhibitor of SGLT2, and was approved in the US for the treatment of adults with T2DM. Areas covered: In this paper, the mechanism of action, pharmacokinetics, clinical efficacy, safety, etc., of ertugliflozin have been introduced. Expert commentary: Ertugliflozin offers a novel, therapeutic approach to T2DM. Advantages of ertugliflozin include reduction in glycated hemoglobin, weight loss and blood pressure lowering with a low risk of hypoglycemia. The main adverse effects likely to be seen are genital fungal infections. Studies show that there is no increased risk of cardiovascular disease, but studies focusing on longer duration outcome are still essential. PMID- 30025476 TI - Necitumumab: a new option for first-line treatment of squamous cell lung cancer. AB - INTRODUCTION: First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target. Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration. The phase III SQUIRE trial was a randomized study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone for first-line stage IV squamous NSCLC, showing a higher overall survival and better disease control with the addition of necitumumab. Despite the good results, the lack of robust predictive biomarkers makes the selection of the patients who will benefit the most complex. Expert opinion: Necitumumab plus cisplatin-gemcitabine is a first-line treatment option in SCC that improves overall survival and preserves the patient's quality of life with a manageable toxicity profile. PMID- 30025477 TI - Compound Heterozygosity for Hb Adana (HBA2: c.179G>A) and the alpha3.7/alphaalpha Thalassemia Deletion in Greece: Clinical Phenotype and Genetic Counseling. AB - Hb Adana (HBA2: c.179G>A) is found worldwide but is extremely rare and carriers are asymptomatic, with red cell indices similar to alpha+-thalassemia (alpha+ thal) carriers. First line screening tests are unable to detect the unstable hemoglobin (Hb). Coinheritance with the alpha-thal (-alpha3.7) deletion is herein presented and the challenges involving genetic counseling of couples carrying the mutations are discussed. PMID- 30025478 TI - Exploring the Relationships Between Patient Room Layout and Patient Satisfaction. AB - This retrospective, exploratory study examined 8,366 patient responses to surveys on patient satisfaction and patient room spatial layout in a large academic teaching hospital consisting of 17 nursing units and 382 patient rooms. This study included four spatial measures: average distance to the nurse station, room handedness, location of bed, and location of first encounter-and explored their statistical associations with two types of patient satisfaction surveys (Hospital Consumer Assessment of the Healthcare Provider and Systems and third party). The study had two phases: a preliminary study of 3,751 patient respondents in a limited diagnosis-related group (DRG) over 5 years and a general study of 4,615 patient respondents with a broader range of DRG's over 2 different years from the preliminary study. Findings indicated statistically significant relationships between all four spatial layout measures and specific survey questions pertaining to perception of nursing, physician, individual care, and overall room environment. Results emphasize the importance of hospital design-and spatial layout in particular-on patient satisfaction. PMID- 30025479 TI - Role of osteopontin as a predictive biomarker for anti-EGFR therapy in triple negative breast cancer. AB - OBJECTIVE: Effective targeted therapies for patients with triple-negative breast cancer (TNBC) present an unmet clinical need. There is evidence that TNBCs often have increased expression of the epidermal growth factor receptor (EGFR) and of osteopontin (OPN). OPN-mediated signaling can activate EGFR-dependent signaling pathways. Here, we assessed OPN as a potential predictive biomarker for response to anti-EGFR therapy in TNBC. RESEARCH DESIGN AND METHODS: Using two different TNBC cell lines, MDA-MB-468 and MDA-MB-231, we investigated the impact of stable expression of OPN on efficacy of the EGFR inhibitor erlotinib in vitro. RESULTS: We observed that breast cancer cells engineered to overexpress OPN are more sensitive to growth inhibition by erlotinib than control cells. The level of response was related to the level of OPN expression, possibly due to increased phosphorylation status of EGFR Tyr1068. CONCLUSIONS: These results indicate that OPN expression levels are related to sensitivity of TNBC cells to growth inhibition by erlotinib. OPN thus is a promising predictive biomarker for anti EGFR therapy in breast cancer. PMID- 30025480 TI - Cytogenotoxic effects of venlafaxine hydrochloride on cultured human peripheral blood lymphocytes. AB - The potential genotoxic effect of venlafaxine hydrochloride (venlafaxine), an antidepressant drug-active ingredient, was investigated by using in vitro chromosome aberrations (CAs) and cytokinesis-block micronucleus (CBMN) assays in human peripheral blood lymphocytes (PBLs). Mitotic index (MI) and cytokinesis block proliferation index (CBPI) were also calculated to determine the cytotoxicity of this active drug. For this aim, the human PBLs were treated with 25, 50, and 100 ug/ml venlafaxine for 24 h and 48 h. The results of this study showed that venlafaxine significantly induced the formation of structural CA and MN for all concentrations (25, 50, and 100 ug/ml) and treatment periods (24 h and 48 h) when compared with the negative and the solvent control (except 25 ug/ml at 48 h for MN). In addition, the increases in the percentage of structural CA and MN were concentration-dependent for both treatment times. With regard to cell cycle kinetics, venlafaxine significantly decreased the MI at all concentrations, and also CBPI at the higher concentrations for both treatment times as compared to the control groups. The present results indicate for the first time that venlafaxine had significant clastogenic and cytotoxic effects at the tested concentrations (25, 50, and 100 ug/ml) in the human PBLs, in vitro; therefore, its excessive and careless use may pose a potential risk to human health. PMID- 30025481 TI - Mathematical structural descriptors and mutagenicity assessment: a study with congeneric and diverse datasets$. AB - Quantitative bioactivity and toxicity assessment of chemical compounds plays a central role in drug discovery as it saves a substantial amount of resources. To this end, high-performance computing has enabled researchers and practitioners to leverage hundreds, or even thousands, of computed molecular descriptors for the activity prediction of candidate compounds. In this paper, we evaluate the utility of two large groups of chemical descriptors by such predictive modelling, as well as chemical structure discovery, through empirical analysis. We use a suite of commercially available and in-house software to calculate molecular descriptors for two sets of chemical mutagens - a homogeneous set of 95 amines, and a diverse set of 508 chemicals. Using calculated descriptors, we model the mutagenic activity of these compounds using a number of methods from the statistics and machine-learning literature, and use robust principal component analysis to investigate the low-dimensional subspaces that characterize these chemicals. Our results suggest that combining different sets of descriptors is likely to result in a better predictive model - but that depends on the compounds being modelled and the modelling technique being used. PMID- 30025482 TI - Assessing effects of inhaled antibiotics in adults with non-cystic fibrosis bronchiectasis--experiences from recent clinical trials. AB - INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) results from a permanent and progressive destruction of the airways leading to poor lung function. NCFB is characterized by recurrent lung infection, sputum production, and cough, often requiring long-term antibiotic therapy and hospitalization. At present, there are no approved therapies available. Clinical trials of inhaled antibiotics have shown promise against sputum bacterial load, but mixed results on clinical outcomes. Areas covered: The objective of this review is to provide an overview of NCFB and critically evaluate the evidence supporting the outcome measures used in recent clinical trials of inhaled antibiotics. These include quantitative changes in bacterial load, sputum purulence and yield, inflammatory markers, and lung function, as well as clinical changes in exacerbations, exacerbation frequency, hospitalizations, and health-related quality of life. Expert commentary: Recently completed large trials of inhaled antibiotics in NCFB did not consistently meet pre-specified end points, suggesting that we have not yet found the best enrollment criteria or outcome measures to evaluate efficacy, although reduced exacerbation frequency may be clinically most meaningful. Future trials may focus on specific patient populations at high risk with new information obtained through analyses of large international patient registries. ABBREVIATIONS: 6-MWT: Six-Minute Walk Test; AIR-BX: Aztreonam for Inhalation Solution in Patients with Non-Cystic Fibrosis Bronchiectasis trial; BSI: Bronchiectasis Severity Index; CAT: COPD Assessment Test; CF: Cystic Fibrosis; CFTR: Cystic Fibrosis Transmembrane Conductance Regulator; CFU: Colony-Forming Units; COPD: Chronic Obstructive Pulmonary Disease; CRP: C-Reactive Protein; DPI: Dry Powder for Inhalation; EMA: European Medicines Agency; ERS: European Respiratory Society; FACED: FEV1, Age, Chronic colonization by P. aeruginosa, Extension of bronchiectasis and Dyspnea; FDA: US Food and Drug Administration; FEV1: Forced Expiration in 1 s; FVC: Forced Vital Capacity; HFCC: High-Frequency Chest Compression; HRCT: High-Resolution Computed Tomography; HRQoL: Health Related Quality of Life; LCQ: Leicester Cough Questionnaire; MID: Minimal Important Difference; NCFB: Non-Cystic Fibrosis Bronchiectasis; NTM: Nontuberculous Mycobacteria; ORBIT: Once-daily Respiratory Bronchiectasis Inhalation Treatment trial; PRO: Patient-Reported Outcomes; QoL-B: Quality of Life-Bronchiectasis; SGRQ: St. George's Respiratory Questionnaire; SWT: Shuttle Walk Test; TORCH: Towards a Revolution in COPD Health trial; UPLIFT: Understanding Potential Long-term Impacts on Function with Tiotropium trial. PMID- 30025483 TI - Usefulness of zebrafish in evaluating drug-induced teratogenicity in cardiovascular system. AB - To confirm the usefulness of zebrafish for evaluating the teratogenic potential of drug candidates, the effect of O-ethylhydroxylamine hydrochloride (OHY), which induces mutagenesis by methylation, was evaluated in teratogenicity studies in rats and zebrafish. In the rat teratogenicity study, OHY-induced cardiovascular malformations such as increased abnormal vascular structures and ventricular septal defects. In the teratogenicity study using zebrafish-injected microspheres and green fluorescent protein-expressing Tg zebrafish (flk1:EGFP), OHY exposure was associated with the loss or malformation of the mandibular arch, opercular artery, and fourth branchial arch. These results suggested that OHY-induced external malformations in zebrafish eleutheroembryos adequately reflect OHY's teratogenicity in rat fetuses. Moreover, the zebrafish teratogenicity study incorporating vascular morphological examinations, including those of blood vessels in the heart, head and trunk, is an easy and reliable screening method to detect potential drug-induced teratogenicity and phenotypic characteristics. PMID- 30025484 TI - Modified Camitz opponensplasty for treatment of severe carpal tunnel syndrome. PMID- 30025485 TI - Advances in stem cell therapy for amyotrophic lateral sclerosis. AB - INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies. Areas covered: This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies. Expert opinion: While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic. PMID- 30025486 TI - Comparative efficacy and safety between ablative therapies or surgery for small hepatocellular carcinoma: a network meta-analysis. AB - BACKGROUND: Major treatments for small hepatocellular carcinoma (SHCC) include percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), radiofrequency ablation (RFA), or surgical resection (SR). We aimed to compare these therapies concerning with effectiveness and safety. METHODS: Cochrane Library, PubMed, and Embase were searched for randomized controlled studies (RCTs) from inception to 30 April 2017. Odds ratios (OR) for proportion dead (PD), local recurrence (LR) and adverse events (AEs). RESULTS: Fourteen RCTs were identified. Compared with SR, PEI (OR 2.79, CrI 1.25, 6.45, p < 0.01) provided a significantly increased risk of PD. Similarly, PEI (OR 4.29, CrI 1.18, 18.35, p < 0.01) yielded more LR than SR. Also, SR significantly conferred more AEs than RFA (OR 0.10; CrI 0.02, 0.35, p < 0.01), PEI (OR 0.06; CrI 0.01, 0.31, p < 0.01). Besides, RFA conferred the highest efficacy for survival, time to recurrence, and new development of HCC. CONCLUSIONS: SR was superior to PEI. Although SR achieved highest cumulative ranking probabilities in clinical efficacy, it obtained a low benefit-to-risk ratio for patients. RFA was superior to the other ablative therapies. For tumor sizes > 2 cm or <= 2 cm in diameter, SR conferred non significant effects compared with other therapies for SHCC. PMID- 30025487 TI - Correlations between the proportion of type III female genital mutilations in the series and adverse obstetric outcomes: a short meta-analysis. AB - BACKGROUND: Authors have reported that evidence on health harms of female genital mutilation is poor. AIM: Meta-analyzing prospective studies on adverse obstetric outcomes according to the severity of female genital mutilation. METHOD: Prospective studies were already acknowledged in previous meta-analyses and used for calculations. The proportions of type III female genital mutilation were extracted by full-texts, along with the proportions of adverse obstetric outcomes. Assuming random models, the proportions were encoded for meta-analysis and weighted for the inverse of the variance. Nonparametric correlations among weighted proportions of type III female genital mutilation and weighted proportions of obstetric outcomes were built. Analyzable obstetric outcome were: cesarean section, instrumental delivery, episiotomy, post-partum hemorrhage, low Apgar score - need of resuscitation. RESULTS: Meta-analyzable series are few and heterogeneous. There is a trend of direct correlation among the proportion of type III female genital mutilations in the series and the proportion of cesarean section, instrumental deliveries, post-partum hemorrhage and low Apgar scores at birth or need of neonatal resuscitation. The significance was reached for the post-partum hemorrhage and for the fetal adverse outcome. CONCLUSION: It should be retained that type III female genital mutilation is likely to be a serious concern for birth. PMID- 30025489 TI - Sri Lanka and the possibilities of achieving universal health coverage in a poor country. AB - Sri Lanka has been lauded for providing good health coverage at a low cost despite having a modest per capita income. This article identifies the unique historical factors that enabled Sri Lanka to achieve near universal coverage, but it also discusses how this achievement is now being undermined by inadequate government investment in health services, the burdens of non-communicable diseases, and the growing privatisation of health services. In doing so, the article highlights the challenges of achieving and maintaining universal health coverage in a relatively low income country with a health system designed to treat infectious diseases and provide child and maternal health services as the country undergoes an epidemiological transition from infectious to non communicable diseases. Using updated information on developments in the Sri Lankan health system, this article argues, in contrast with earlier publications, that Sri Lanka is no longer providing good health at a low cost. It shows that Sri Lanka's low investment in health is detrimental and not an asset to achieving good health. The article also questions the possibilities of providing coverage for noncommunicable diseases at a low cost. The article has four main sections. The first details Sri Lanka's accomplishments in moving toward universal health coverage. The second identifies the factors enabling Sri Lanka to do so. The third describes the equity and access challenges the health system now confronts. The fourth assesses what the Sri Lankan experience suggests about the requirements for universal health coverage when providing health services for treating non-communicable diseases becomes an important consideration. PMID- 30025488 TI - Reduced peripheral blood regulatory B cell levels are not associated with the Expanded Disability Status Scale score in multiple sclerosis. AB - Objective To investigate levels of regulatory B (Breg) cells, plasma cells, and memory B cells in the peripheral blood, and interleukin (IL)-10 in the serum of multiple sclerosis (MS) patients, and to determine the correlation between Breg cell levels and the Expanded Disability Status Scale (EDSS) score. Methods Levels of Breg cells, plasma cells, and memory B cells in the peripheral blood of 12 MS patients were measured using flow cytometry. IL-10 serum levels were measured by enzyme-linked immunosorbent assay. The correlation between Breg cell levels and MS EDSS score was measured using Pearson's correlation coefficient. Results Compared with healthy controls, MS patients had decreased levels of CD19+CD24hiCD38hi Breg cells in their peripheral blood and reduced serum levels of IL-10; however, the ratios of CD19+CD27hiCD38hi plasma cells and CD19+CD27+CD24hi memory B cells to total B cells did not differ significantly between healthy controls and MS patients. CD19+CD24hiCD38hi Breg cell levels in the peripheral blood of MS patients were not significantly correlated with MS EDSS score. Conclusion Peripheral blood CD19+CD24hiCD38hi Breg cell levels and serum IL-10 levels were reduced in MS patients compared with controls, but Breg cell levels were not correlated with MS EDSS score. PMID- 30025491 TI - Comparing the effect of the subcategories of atypical antipsychotic medications on cognition in schizophrenia using a meta-analytic approach. AB - OBJECTIVES: The aim of this study was to compare the two most commonly prescribed classes of atypical antipsychotic medications (i.e., -pines and -dones) with regard to their effects on cognition in patients with schizophrenia. DATA SOURCES: Ovid Technologies web-based software was used to search the Medline and PsycINFO computerized databases to identify articles that met the inclusion criteria. REVIEW METHODS: The search was limited to papers published after 1990, written in English, employing human subjects, using atypical antipsychotics, using a within-subjects design or control group of patients with schizophrenia for comparisons, using participants aged from 18-65, and employing standardized neuropsychological measures. RESULTS: A total of 996 eligible studies were identified, and of these 19 were finally analyzed. Nine domains of cognitive functioning were assessed. The two groups of agents produced equivalent overall effects (-dones = .254 versus -pines = .202). The -pines were found to improve the domains of attention/working memory, executive functioning, fluency, nonverbal memory, processing speed, and verbal memory, each with a significant, small effect size. The -dones were found to improve attention/working memory, executive functioning, motor function, nonverbal memory, processing speed, and verbal memory, each with a significant, small effect size. Failsafe N was robust for all of the domains for the -pines, but only for the verbal memory domain for the -dones, suggesting that the significant findings for the other domains with the -dones are more tenuous. CONCLUSION: The results indicate that the agents were largely equivalent and that there was no clear evidence that the pattern of cognitive effects differed as a result of the agent applied. The effects themselves, while statistically significant, were small, indicating that some or all of the differences may be attributable to practice effects on the instruments employed. PMID- 30025490 TI - Antitumor Effects of DC Vaccine With ALA-PDT-Induced Immunogenic Apoptotic Cells for Skin Squamous Cell Carcinoma in Mice. AB - Targeted immunotherapy using dendritic cell vaccine has been employed for the treatment of solid tumors. Topical 5-aminolevulinic acid-mediated photodynamic therapy, an established approach for topical cancers, can induce an effective antitumor immune response. We have previously shown that 5-aminolevulinic acid mediated photodynamic therapy-induced tumor lysates could considerably enhance antigen-presenting capacity of ex vivo-generated dendritic cells. The current study further demonstrates that 5-aminolevulinic acid-mediated photodynamic therapy dendritic cell vaccine can induce immune responses against cancers. Dendritic cells pulsed by photodynamic therapy-treated skin squamous cell carcinoma cells inhibited squamous cell carcinoma to a greater extent than tumor lysates treated by photodynamic therapy alone or dendritic cells pulsed by freeze thawed treated tumor cells. Immunohistochemistry showed that photodynamic therapy dendritic cell vaccine could increase the activity of CD4+ and CD8+ T cells in the tumor implantation sites. Flow cytometry assays showed that CD4+ and CD8+ T cells in the spleens of photodynamic therapy dendritic cell vaccine immunized mice increased significantly. Furthermore, we observed increased amounts of interleukin 12 and Interferon gamma (IFN-gamma) and decreased amounts of interleukin 10 in the splenocytes and peripheral blood of photodynamic therapy dendritic cell vaccine immunized mice by enzyme linked immunosorbent assay (ELISA). Taken together, our findings suggest that photodynamic therapy dendritic cell vaccination is an effective prophylactic therapy for squamous cell carcinoma. PMID- 30025492 TI - Vinorelbine's anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: hypotheses with implications for chemo-immunotherapy of advanced cancers and pediatric gliomas. AB - Vinorelbine is a very potent chemotherapeutic agent which is used to treat a number of cancers including breast and non-small cell lung tumors. Vinorelbine mainly acts via blocking microtubules and induces a specific type of cell death called 'mitotic catastrophe/apoptosis' subsequent to mitotic slippage, which is the failure of cells to stay in a mitotic arrested state and replicating their DNA without cytokinesis. Glial tumor cells are especially sensitive to mitotic slippage. In recent years, vinorelbine demonstrated potency in pediatric optic and pontine gliomas. In this manuscript, we propose that vinorelbine's anti-tumor actions involve mitotic apoptosis, autophagy and inflammation. Intravenous infusion of vinorelbine induces a peculiar severe pain in the tumor site and patients with highly vascularized, oedematous and necrotic tumors are particularly vulnerable to this pain. Severe pain is a sign of robust inflammation and anti-inflammatory agents are used in treatment of this side effect. However, no one has questioned whether inflammation contributes to anti tumor effects of vinorelbine, despite the existing data that vinorelbine induces Toll-Like Receptor-4 (TLR4), cytokines and cell death in endothelial cells especially under hypoxia. Robust inflammation may contribute to tumor necrosis such as seen during immunotherapy with lipopolysaccharides (LPS). Evidence also emerges that enhanced cyclooxygenase activity may increase cancer cell death in certain contexts. There are data indicating that non-steroidal anti-inflammatory drugs (NSAIDs) could block anti-tumor efficacy of taxanes, which also work mainly via anti-microtubule actions. Further, combining vinorelbine with immunostimulant cytokines provided encouraging results in far advanced melanoma and renal cell carcinoma, which are highly antigenic tumors. Vinorelbine also showed potential in treatment of inflammatory breast cancer. Finally, pontine gliomas - where partial activity of vinorelbine is shown by some studies - are also tumors which partially respond to immune stimulation. Animal experiments shall be conducted whether TLR4-activating molecules or immune-checkpoint inhibitors could augment anti-tumor actions of vinorelbine. Noteworthy, TLR4-activation seems as the most promising way of cancer immunotherapy, as a high percentage of molecules which demonstrated clinical benefits in cancer treatment are activators of TLR4, including BCG vaccine, monophosphoryl lipid A and picibanil (OKT-432). The provided data would be meaningful for the oncological practice. PMID- 30025493 TI - Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy. AB - : Flavokawain B (FKB), a natural kava chalcone, displays potent antitumor activity in various types of cancer. The mechanism of action, however, remains unclear. Here, we evaluated the efficacy of FKB in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its inhibitory effects in cancer. Approximately 60% of GBM cells became senescent after treatment with FKB as assessed in the senescence-associated (SA)-GLB1/SA-beta galactosidase assay. The cellular process of autophagy potentially contributed to the establishment of senescence. Transmission electron microscopy revealed the formation of autophagic vesicles under FKB treatment, and MAP1LC3B (microtubule associated protein 1 light chain 3 beta)-II was increased. Transfection of ATG5 or ATG7 small interfering RNAs (siRNAs) inhibited FKB-induced autophagy in U251 cells. Western blot revealed that molecular components of the endoplasmic reticulum stress pathway were activated, including ATF4 (activating transcription factor 4) and DDIT3 (DNA damage inducible transcript 3), while levels of TRIB3 (tribbles pseudokinase 3) increased. In addition, based on the phosphorylation status, the AKT-MTOR-RPS6KB1 pathway was inhibited, which induced autophagy in GBM cells. Inhibition of autophagy by autophagy inhibitors 3-methyladenine and chloroquine or knockdown of ATG5 or ATG7 caused FKB-treated U251 cells to switch from senescence to apoptosis. Finally, knockdown of ATG5 or treatment with chloroquine in combination with FKB, significantly inhibited tumor growth in vivo. Our results demonstrated that FKB induced protective autophagy through the ATF4-DDIT3-TRIB3-AKT-MTOR-RPS6KB1 signaling pathway in GBM cells, indicating that the combination treatment of FKB with autophagy inhibitors may potentially be an effective therapeutic strategy for GBM. ABBREVIATIONS: 3-MA: 3-methyladenine; 4 PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; ATG: autophagy related; CASP3: caspase 3; CCK-8: cell counting kit-8; CDKN1A: cyclin-dependent kinase inhibitor 1A; CQ: chloroquine; DDIT3: DNA damage inducible transcript 3; DMEM: Dulbecco's modified Eagle's medium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; FKB: flavokawain B; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBM: glioblastoma multiforme; GFP: green fluorescent protein; HSPA5: heat shock protein family A (Hsp70) member 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase; 1RPS6KB1: ribosomal protein S6 kinase B1; SA-GLB1: senescence-associated galactosidase beta 1; siRNA: short interfering RNA; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TRIB3: tribbles pseudokinase 3; TUNEL: deoxynucleotidyl transferase-mediated dUTP nick-end labeling. PMID- 30025494 TI - Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis. AB - Macroautophagy/autophagy is considered as an evolutionarily conserved cellular catabolic process. In this study, we aimed to elucidate the role of autophagy in vascular smooth muscle cells (SMCs) on atherosclerosis. SMCs cultured from mice with SMC-specific deletion of the essential autophagy gene atg7 (Atg7cKO) showed reduced serum-induced cell growth, increased cell death, and decreased cell proliferation rate. Furthermore, 7-ketocholestrerol enhanced apoptosis and the expression of CCL2 (chemokine [C-C motif] ligand 2) with the activation of TRP53, the mouse ortholog of human and rat TP53, in SMCs from Atg7cKO mice. In addition, Atg7cKO mice crossed with Apoe (apolipoprotein E)-deficient mice (apoeKO; Atg7cKO:apoeKO) showed reduced medial cellularity and increased TUNEL-positive cells in the descending aorta at 10 weeks of age. Intriguingly, Atg7cKO: apoeKO mice fed a Western diet containing 1.25% cholesterol for 14 weeks showed a reduced survival rate. Autopsy of the mice demonstrated the presence of aortic rupture. Analysis of the descending aorta in Atg7cKO:apoeKO mice showed increased plaque area, increased TUNEL-positive area, decreased SMC-positive area, accumulation of macrophages in the media, and adventitia and perivascular tissue, increased CCL2 expression in SMCs in the vascular wall, medial disruption, and aneurysm formation. In conclusion, our data suggest that defective autophagy in SMCs enhances atherosclerotic changes with outward arterial remodeling. PMID- 30025495 TI - Nanog Expression and Proliferation Indices in Canine Cutaneous Mast Cell Tumors. AB - Mast cell tumors are one of the most frequent skin tumors in dogs. Treatment decisions often depend on a wide range of clinical information and the main criteria for prognostic formulation are histological grade, mitotic count, Ki67 index, and KIT immunostaining pattern. NANOG is a pluripotency factor expressed by normal and cancer stem cells, which is a prognostic marker and a potential therapeutic target for several human tumors. In the present study, mast cell tumor samples from 41 dogs were evaluated for NANOG and Ki67 by immunohistochemistry. All samples were positive for NANOG but its expression was not correlated with Ki67 index and no significant differences were found with respect to histopathological grades, disease-related mortality, or survival. Our results suggest that, although related to pluripotency, NANOG expression does not correlate with proliferative activity, and is not a reliable prognostic factor for canine cutaneous mast cell tumors. PMID- 30025496 TI - Violence, abuse and discrimination: key factors militating against control of HIV/AIDS among the LGBTI sector. AB - The Lesbian, Gay, Bisexual, Transgender and Intersex (LGBTI) South Africans continue to face considerable challenges, including societal stigma, homophobic violence (particularly corrective rape), and high rates of sexually transmitted diseases and infections (particularly Human Immunodeficiency Virus (HIV)/AIDS) even when discrimination based on sexual orientation was outlawed by South African's post-apartheid constitution. This study was conducted to ascertain violence, abuse and discrimination against the LGBTI sector as key factors that hinder the smooth implementation of HIV/AIDS programme among sexually minority (LGBTI) group in Walter Sisulu University, South Africa. The self-structured questionnaire was used to collect data. The study involved 3048 purposively selected participants (1285 male and 1763 female) aged 17-38 years. About 70.5% of the participants witnessed physical attack as a form of violence against people in same-gender relationship; 47.7% disagreed that violent targeted at this sexually minority group is justified. The LGBTI face challenges which include verbal insults (937, 32.4%), bullying (532, 18.4%) and name-calling (1389, 48%). Discrimination against members of the LGBTI sector was witnessed in various forms: non-acceptance (981, 33.9%), disapproval of act of homosexuals (1308, 45.2) and denial of rights (327, 11.3). Violence, abuse and discrimination which constitute stigmatisation among the LGBTI sector are received with mix feeling. Some respondents justified the use of one or more of these key elements of stigmatisation against the LGBTI (6.6%, supports violence), others condemned these acts of stigmatisation (28.8%), against discrimination). Social stigma which resulted from violence, abuse and discrimination exist in this institution and is responsible for the unwillingness of disclosure of sexual orientation among the LGBTI members. An enabling environment should be created where the LGBTI members could come out freely to access programmes targeted at the prevention and control of HIV/AIDS. PMID- 30025499 TI - A novel measure of drug benefit-risk assessment based on Scale Loss Score. AB - Quantitative methods have been proposed to assess and compare the benefit-risk balance of treatments. Among them, multicriteria decision analysis (MCDA) is a popular decision tool as it permits to summarise the benefits and the risks of a drug in a single utility score, accounting for the preferences of the decision makers. However, the utility score is often derived using a linear model which might lead to counter-intuitive conclusions; for example, drugs with no benefit or extreme risk could be recommended. Moreover, it assumes that the relative importance of benefits against risks is constant for all levels of benefit or risk, which might not hold for all drugs. We propose Scale Loss Score (SLoS) as a new tool for the benefit-risk assessment, which offers the same advantages as the linear multicriteria decision analysis utility score but has, in addition, desirable properties permitting to avoid recommendations of non-effective or extremely unsafe treatments, and to tolerate larger increases in risk for a given increase in benefit when the amount of benefit is small than when it is high. We present an application to a real case study on telithromycin in Community Acquired Pneumonia and Acute Bacterial Sinusitis, and we investigated the patterns of behaviour of Scale Loss Score, as compared to the linear multicriteria decision analysis, in a comprehensive simulation study. PMID- 30025498 TI - Moral Judgment and Empathic/Deontological Guilt. AB - Background People often make complicated decisions to help or to punish perfect strangers. Harming someone or breaking some moral imperative is usually linked to feeling guilt, and several researches suggested the existence of two different kinds of guilt: altruistic/empathic and deontological. Aim Our study aimed to investigate the decision-making processes in moral and nonmoral judgments and assess how specific situations in which the subject is close to the victim or flanked by an authority can influence his decisions. Methods We used three different moral conditions: Empathic Moral (the decision has made while physically close to the potential victims), Deontological Moral (the decision has made while flanked by an "authority"), and Standard Moral (without any influence); a fourth condition is represented by Nonmoral dilemmas (the subject must make a choice between two different things and this does not cause any harm or victims). Previously, a pilot study was carried out for validating the experimental stories to be used in the main study. Results We observed a higher number of utilitarian/positive responses when individuals had to respond to Empathic Moral condition, with respect to Deontological Moral and Nonmoral dilemmas. Moreover, looking at the time needed to read the dilemma, under empathic guilt condition, people tended to be slower in reading the dilemmas than in other conditions and this both in case of positive and negative responses. No significant differences in time needed to effectively respond emerged. Conclusions These findings suggested that be physically close to potential victims or be flanked by an "authority" differentially influence the decision making processes in moral judgment, inducing slower decisions and more utilitarian answers, particularly in the scenario of physical proximity. PMID- 30025500 TI - Semiparametric analysis of correlated and interval-censored event-history data. AB - We propose a semiparametric multi-state frailty model to analyze clustered event history data subject to interval censoring. The proposed model is motivated by an attempt to study the life course of dental caries at the tooth level, taking into account the multiplicity of caries states and the intra-oral clustering of observations made at periodic time points. Of particular interest is the study of the intra-oral distribution of processes leading to carious lesions, and whether this distribution varies with gender. The model assumes, in view of the covariate profile, a proportionality of the transition intensities conditional on subject level frailties, coupled with a linear spline approximation of the log baseline intensities. The model estimation is conducted using a penalized likelihood where the smoothing parameters are estimated as reciprocal variance components under a mixed-model representation. A Bayesian method is proposed to predict tooth-level caries transition probabilities, which can be used for tailoring tooth-level caries treatment and prevention plans. Intensive simulation studies indicate that the model fitting and prediction perform reasonably well under realistic sample sizes. The practical utility of the methods is illustrated using data from a longitudinal study on oral health among children from low-income families residing in the city of Detroit, Michigan. PMID- 30025501 TI - Poor in vivo efficacy of caspofungin, micafungin and amphotericin B against wild type Candida krusei clinical isolates does not correlate with in vitro susceptibility results. AB - We determined micafungin, caspofungin and amphotericin B (AMB) minimum inhibitory concentration (MICs) and killing rates in RPMI-1640 and in RPMI-1640 with 50% serum against three Candida krusei bloodstream isolates. MIC ranges in RPMI-1640 were 0.125-0.25, 0.25 and 0.125-0.5 mg/L, in RPMI-1640 with 50% serum, MICs were 64-128-, 8- and 4-16-fold higher, respectively. In RPMI-1640 micafungin and caspofungin at 1, 4, 16 and 32 mg/L as well as AMB at 2 mg/L were fungicidal against all isolates in <=3.96, <=4.42 and 14.96 h, respectively. In RPMI-1640 with 50% serum, caspofungin was fungicidal for all isolates only at 32 mg/L, micafungin and AMB were fungistatic. In neutropenic mice, 5 mg/kg caspofungin and 1 mg/kg AMB were ineffective against two of the three isolates. Thus, in vivo efficacy of echinocandins and AMB is weak or absent against C. krusei. Prescribers treating C. krusei infections with echinocandins should watch out for clinical resistance and therapeutic failure. PMID- 30025502 TI - Microfinance and health interventions: Factors influencing loan repayment success with young men in Dar es Salaam, Tanzania. AB - Poverty is associated with numerous poor health outcomes. Youth unemployment in Tanzania is approximately 13.7%, and concentrates in urban areas. These youth lack relevant job skills and access to financial capital. Microfinance continues to be implemented globally to address poverty, and increasingly has been linked to health interventions. Men less frequently are recipients of microfinance loans. We offered microcredit to young men in an area of Dar es Salaam with high poverty as part of a randomised controlled-trial to assess the efficacy of a microfinance and health leadership intervention in preventing STI acquisition. We used mixed methods to understand predictors of successful loan repayment. Our qualitative sub-study showed that leader influence, prior business experience, personal motivation, and planning facilitated repayment. Using a modified Poisson approach, our quantitative analysis showed that successful repayment was associated with business experience, education, increasing number of children, community of residence, percentage of network members trained in business, and repayment success of peer leaders. Our results suggest that enforcing group accountability and repayment rules, offering ongoing training, and using successful entrepreneurs as role models could increase repayment success in similar populations. These strategies could provide financial opportunity for men while minimising risk for microfinance institutions. PMID- 30025503 TI - Characterization of Wolbachia enhancing domain in mosquitoes with imperfect maternal transmission. AB - A novel method to reduce the burden of dengue is to seed wild mosquitoes with Wolbachia-infected mosquitoes in dengue-endemic areas. Concerns in current mathematical models are to locate the Wolbachia introduction threshold. Our recent findings manifest that the threshold is highly dependent on the initial population size once Wolbachia infection alters the logistic control death rate of infected females. However, counting mosquitoes is beyond the realms of possibility. A plausible method is to monitor the infection frequency. We propose the concept of Wolbachia enhancing domain in which the infection frequency keeps increasing. A detailed description of the domain is presented. Our results suggest that both the initial population size and the infection frequency should be taken into account for optimal release strategies. Both Wolbachia fixation and extinction permit the oscillation of the infection frequency. PMID- 30025504 TI - Organ donation - Letter to the editor. PMID- 30025505 TI - Intergenerational differences in the personal and professional values of nurses. AB - OBJECTIVES:: This study was conducted descriptively for the purpose of determining the differences in the personal and professional values of nurses according to their generation. METHODS:: The study was planned according to the descriptive research method. The population of the research consisted of nurses carrying out their duties in Istanbul, and the sample consisted of 718 nurses. The number of nurses to be included in the sample was determined by stratified sampling, and the nurses to be included in the sample were determined through random sampling. The data were collected using an information form, the Value Preferences Scale, Professional Value Order of Priority Scale, and the Nurses' Professional Values Scale. ETHICAL CONSIDERATIONS:: Ethics committee approval for the study was received from the Ethics Committee Presidency of the I.U. Cerrahpasa Medical Faculty of Clinical Studies. The study began after the participants were informed that they could decide to withdraw from the study at any time during the data collection process. In order to use the Nurses Professional Values Scale, written permission was received from Nuray Sahin Orak. FINDINGS:: The primary value preference is social value for nurses from the Baby Boomers generation, Y and Z generations, and political value for nurses from X generation. It is the nurses from every generation who prioritized human dignity among professional values, which is follow by activation and responsibility. It is determined that a great majority of nurses from the Baby Boomers generation, X, Y, and Z generations prioritized human dignity among professional values, which was followed by the values of equality, justice, and freedom. CONCLUSION:: These results indicate that nurses from all generations agree on the professional values required by their profession and thus carry out their duties in accordance with the ethical principles and the values of their profession. PMID- 30025506 TI - Prolonged sitting increases the risk of gallstone disease regardless of physical activity: a cohort study. AB - OBJECTIVES: We aimed to examine the relationship between sitting time and the development of ultrasonography-diagnosed gallstone disease (GSD) in young and middle-aged Korean men and women. MATERIAL AND METHODS: We conducted a cohort study of 147,237 participants without GSD at baseline who underwent a health checkup examination between 2011 and 2015 and were followed annually or biennially until December 2016. Sitting time and physical activity were measured using the validated Korean version of the international physical activity questionnaire short form. GSD was defined as either having had a cholecystectomy or having gallstones based on ultrasound. RESULTS: During 486,376 person-years of follow-up, 2382 incident GSD cases were identified. Both prolonged sitting time and inactive physical activity had a significant independent association with the increased risk of GSD. The multivariate-adjusted hazard ratios (95% confidence interval for GSD comparing sitting times of 5-9 and >=10 h/day with the sitting time of <5 h/day were 1.08 (0.97-1.21) and 1.15 (1.02-1.29), respectively (p for trend = .023). The multivariate-adjusted hazard ratios (95% CIs) for GSD in both the inactive and the minimally active groups compared with HEPA group were 1.22 (1.08-1.38) and 1.13 (0.99-1.28, respectively (p for trend = .001). CONCLUSION: This study demonstrated that sitting time may be associated with GSD risk regardless of physical activity. The findings of this study suggest that both increasing participation in physical activity and reducing sitting time may be independently important in reducing the risk of GSD. PMID- 30025510 TI - Prevalence of urinary incontinence in high-impact sports athletes and their association with knowledge, attitude and practice about this dysfunction. AB - OBJECTIVE: To evaluate the prevalence of urinary incontinence (UI) in female athletes practising high-impact sports and its association with knowledge, attitude and practice (KAP). DESIGN: Observational study. METHODS: A semi structured evaluation form, KAP survey and the International Consultation on Incontinence Questionnaire - Short Form were used. Univariate and multivariate analyses were performed to verify the association of UI with KAP, sociodemographic, gynaecological and sports-related variables, with significant variables remaining in the model (p < .05), through a stepwise strategy. RESULTS: The prevalence of UI in 118 athletes was 82 (70%), of which 19 (23%) had pure stress UI, 19 (23%) had pure urgency UI and 44 (54%) had mixed UI; with 50 (61%) athletes losing urine during training and 37 (45%) during competitions. Regarding the KAP survey, 37 athletes (31%) demonstrated adequate knowledge, 63 (53%) adequate attitude and zero adequate practice. In the multivariate analysis, a sports practice time of over 8 years and dyspareunia presented significant values, with odds ratios (OR) of 2.66 and 2.99, respectively. Knowledge was significantly associated with UI (OR 0.43). UI had a slight impact on QOL. CONCLUSIONS: There is a high prevalence of UI yet low levels of adequate knowledge and practice regarding the occurrence of UI in sports, with sports practice time over 8 years and dyspareunia factors predisposing female athletes to UI by 2.7 and 3 times, respectively. Athletes with adequate knowledge were 57% less likely to develop UI. PMID- 30025511 TI - Syndemics and HIV-related sexual risk among men who have sex with men in India: influences of stigma and resilience. AB - Using syndemics theory as a framework, we explored the experience of men who have sex with men in India in relation to four syndemic conditions (depression, alcohol use, internalised homonegativity and violence victimisation) and to understand their resilience resources. Five focus groups were conducted among a purposive sample of diverse men along with seven key informant interviews with HIV service providers. Participants' narratives suggested various pathways by which syndemic conditions interact with one another to sequentially or concurrently increase HIV risk. Experiences of discrimination and violence from a range of perpetrators (family, ruffians and police) contributed to internalised homonegativity and/or depression, which in turn led some men to use alcohol as a coping strategy. Stigma related to same-sex sexuality, gender non-conformity and sex work contributed to the production of one or more syndemic conditions. While rejection by family and male regular partners contributed to depression/alcohol use, support from family, regular partners and peers served as resources of resilience. In India, HIV prevention and health promotion efforts among men who have sex with men could be strengthened by multi-level multi-component interventions to reduce intersectional/intersecting stigma, address syndemic conditions and foster resilience - especially by promoting family acceptance and peer support. PMID- 30025512 TI - Rendering visible the previously invisible in health care: the ageing LGBTI communities. PMID- 30025513 TI - Differences in management and outcomes for men and women with ST-elevation myocardial infarction. AB - OBJECTIVE: To examine whether there are sex differences in the characteristics, management, and clinical outcomes of patients with an ST-elevation myocardial infarction (STEMI). Design, setting: Cohort study; analysis of data collected prospectively by the CONCORDANCE acute coronary syndrome registry from 41 Australian hospitals between February 2009 and May 2016. PARTICIPANTS: 2898 patients (2183 men, 715 women) with STEMI. MAIN OUTCOME MEASURES: Rates of revascularisation (percutaneous coronary intervention [PCI], thrombolysis, coronary artery bypass grafting [CABG]), adjusted for GRACE risk score quartile. SECONDARY OUTCOMES: timely vascularisation rates; major adverse cardiac event rates; clinical outcomes and preventive treatments at discharge. RESULTS: The mean age of women with STEMI at presentation was 66.6 years (SD, 14.5 years), of men, 60.5 years (SD, 12.5 years). The proportions of women with hypertension, diabetes, prior stroke, chronic kidney disease, chronic heart failure, or dementia were larger than those of men; fewer women had histories of previous coronary artery disease or myocardial infarction, or of prior PCI or CABG. Women were less likely to have undergone coronary angiography (odds ratio, adjusted for GRACE score quartile [aOR], 0.53; 95% CI, 0.41-0.69) or revascularisation (aOR, 0.42; 95% CI, 0.34-0.52); they were less likely to have received timely revascularisation (aOR, 0.72; 95% CI, 0.63-0.83) or primary PCI (aOR, 0.76; 95% CI, 0.61-0.95). Six months after admission, the rates of major adverse cardiovascular events (aOR, 2.68; 95% CI, 1.76-4.09) and mortality (aOR, 2.17; 95% CI, 1.24-3.80) were higher for women. At discharge, significantly fewer women than men received beta-blockers, statins, and referrals to cardiac rehabilitation. CONCLUSION: Women with STEMI are less likely to receive invasive management, revascularisation, or preventive medication at discharge. The reasons for these persistent differences in care require investigation. PMID- 30025514 TI - Delays in primary percutaneous coronary treatment for patients with ST-elevation myocardial infarction. PMID- 30025515 TI - Translation and validation of the PACIC+ questionnaire: the Thai version. AB - BACKGROUND: The number of patients with chronic illness is increasing worldwide. These patients usually receive care from a primary care facility. The Patient Assessment of Chronic Illness Care (PACIC) is a tool that is increasingly used in several countries to measure how the patients perceive the care they receive. The goal of this validation study is to provide and validate an extended version of the tool, the PACIC+ questionnaire, in Thailand. METHODS: In this observational validation study, patients with type 2 diabetes from the outpatient clinic at a university hospital in Thailand completed the PACIC+ at the clinic. For follow up, they received the questionnaire per mail after four weeks. The Thai PACIC+ comprises 26 items, which map onto 5 subscales and a summary score related to the Chronic Care Model (CCM) and 5 subscales and a summary score related to the 5A model, a counseling model for behavioral changes. Data-analysis focused on the use of most extreme answering categories (> 15%), internal consistency (Cronbach's alpha), and test-retest reliability. An exploratory factor analysis (EFA) was performed for the CCM and the 5A model separately to examine the factor structure. RESULTS: A total of 151 patients participated. The average age of the sample was 63 +/- 9 years (range 29-86 years). Fifty-three percent of the respondents were female. In the Delivery System subscale, 20% of patients reported the highest possible value; in all other subscales, relative frequencies of the most extreme categories did not exceed 15%. Cronbach's alpha per subscale varied from 0.58 to 0.81, while that of the summary scores were 0.89 and 0.91. The mean difference from the test-retest varied from - 0.06 to 0.17 across subscales. The Kaiser-Meyer-Olkin criterion for sampling adequacy (KMO) was good for both models as well as the Bartlett's test for sphericity p. While the factor loadings in rotated factor solution showed good concordance with the CCM, concordance was not as good for the 5A model, especially for the subscales "Assess" and "Advice". CONCLUSION: A validated Thai version of the PACIC+ is now available to measure how the patients perceive the care they receive. PMID- 30025516 TI - Intraoperative hyperglycemia is independently associated with infectious complications after non-cardiac surgery. AB - BACKGROUND: Perioperative hyperglycemia and its associated increase in morbidity and mortality have been well studied in the critical care and cardiac surgery literature. However, there is little data regarding the impact of intraoperative hyperglycemia on post-operative infectious complications in non-cardiac surgery. METHODS: All National Surgery Quality Improvement Program patients undergoing general, vascular, and urological surgery at our tertiary care center were reviewed. After integrating intraoperative glucose measurements from our intraoperative electronic health record, we categorized patients as experiencing mild (8.3-11.0 mmol/L), moderate (11.1-16.6 mmol/L), and severe (>= 16.7 mmol/L) intraoperative hyperglycemia. Using multiple logistic regression to adjust for patient comorbidities and surgical factors, we evaluated the association of hyperglycemia with the primary outcome of postoperative surgical site infection, pneumonia, urinary tract infection, or sepsis within 30 days. RESULTS: Of 13,954 patients reviewed, 3150 patients met inclusion criteria and had an intraoperative glucose measurement. 49% (n = 1531) of patients experienced hyperglycemia and 15% (n = 482) patients experienced an infectious complication. Patients with mild (adjusted odds ratio 1.30, 95% confidence interval [1.01 to 1.68], p-value = 0.04) and moderate hyperglycemia (adjusted odds ratio 1.57, 95% confidence interval [1.08-2.28], p-value = 0.02) had a statistically significant risk adjusted increase in infectious complications. The model c-statistic was 0.72 [95% confidence interval 0.69-0.74]. CONCLUSIONS: This is one of the first studies to demonstrate an independent relationship between intraoperative hyperglycemia and postoperative infectious complications. Future studies are needed to evaluate a causal relationship and impact of treatment. PMID- 30025517 TI - Postoperative complications with neuromuscular blocking drugs and/or reversal agents in obstructive sleep apnea patients: a systematic review. AB - BACKGROUND: Neuromuscular blocking drugs (NMBD) are administered intra operatively to facilitate intubation and to achieve muscle relaxation for surgical procedures. Incomplete reversal of NMBD can lead to adverse events in the postoperative period. Patients with obstructive sleep apnea (OSA) may be at higher risk of complications related to the use of NMBD. The objectives of this systematic review were to determine whether: 1) OSA patients are at higher risk of postoperative complications from the use of NMBD than non-OSA patients, and 2) the choice of NMBD reversal agent affects the risk of postoperative complications in OSA patients. METHODS: A literature search of multiple databases was conducted up to April 2017. The inclusion criteria were: (1) adult surgical patients (>=18 years old) with OSA diagnosed by polysomnography, or history, or suspected by screening questionnaire; (2) patients who were given NMBD and/or NMBD reversal agents intraoperatively; (3) reports on postoperative adverse events, particularly respiratory events were available; (4) published studies were in English; and (5) RCTs or observational cohort studies. The quality of evidence was determined by the Oxford Center for Evidence Based Medicine levels of evidence. RESULTS: Out of 4123 studies, five studies (2 RCTs and 3 observational studies) including 1126 patients were deemed eligible. These studies were heterogeneous precluding a meta-analysis of the results. Two of three studies (1 RCT, 2 observational studies) reported that OSA patients given NMBD may be at higher risk of developing postoperative pulmonary complications (PPCs) like hypoxemia, residual neuromuscular blockade or respiratory failure compared to non OSA patients. Two studies (1 RCT, 1 observational study) reported that OSA patients who were reversed with sugammadex vs. neostigmine had less PPCs and chest radiographic changes, but the quality of the included studies was Oxford level of evidence: low to moderate. CONCLUSIONS: OSA patients who receive intraoperative NMBD may be at higher risk for postoperative hypoxemia, respiratory failure and residual neuromuscular blockade compared to non-OSA patients. There is some, albeit very limited evidence that NMBD reversal with sugammadex may be associated with less PPCs than neostigmine in patients with OSA. More high-quality studies are needed. PMID- 30025518 TI - Erythrocyte DHA and AA in infancy is not associated with developmental status and cognitive functioning five years later in Nepalese children. AB - BACKGROUND: Long chain polyunsaturated fatty acids (LCPUFA) especially docosahexaenoic acid (DHA) and arachidonic acid (AA) are crucial for normal brain development in utero and in early infancy. Data on fatty acid status and cognitive development in infants and children from low-income countries are scarce. METHODS: We examined the association between the DHA and AA status in infancy (n = 320) and developmental status and cognitive functioning five years later. At five years of age, we measured development by the Ages and Stages Questionnaire 3rd. ed. (ASQ-3) and cognitive functioning by subtests from the neuropsychological test battery NEPSY II. In addition, infant fatty acid composition in red blood cells (RBC) was analyzed. In multiple linear and logistic regression models, we estimated the associations between DHA and AA status in infancy and scores on the ASQ-3 and the NEPSY II subtests. RESULTS: There were no notable associations between infant AA and DHA status, and the scores on the ASQ-3 and the NEPSY II subtests five years later. It should be noted that we found better than expected concentrations of erythrocyte DHA and AA among the infants, and the ASQ scores were left-skewed, which limited the ability to identify associations. CONCLUSION: DHA and AA status in infancy is seemingly not related to neurodevelopment measured 5 years later in this peri-urban population from Nepal. PMID- 30025520 TI - Patient discourse on chronic kidney disease monitoring: a qualitative study at a Veterans Affairs Renal Clinic. AB - BACKGROUND: Knowing how chronic kidney disease (CKD) patients talk about their encounters with providers (i.e., their discourse) can inform the important clinical goal of engaging patients in their chronic disease self-management. The aim of this study was to analyze patient discourse on ongoing CKD monitoring encounters for health communication strategies that motivate patient engagement. METHODS: Passages regarding CKD monitoring from 6 focus group transcripts on self management with a total of 30 participants age >= 70 years from the Atlanta Veterans Affairs Renal Clinic across three different CKD trajectories (stable, linear decline, and non-linear) were extracted. These passages were examined using three-stage critical discourse analysis (description, interpretation, explanation) for recurring patterns across groups. RESULTS: Focus group participants were an average age of 75.1, 96.7% male, and 60% Black. Passages relating to CKD monitoring (n = 55) yielded predominantly negative communication themes. Perceived negative communication was characterized through a patient discourse of unequal exchange, whereby engaged patients would provide bodily fluids and time for appointments and continued to wait for meaningful, contextualized monitoring information from providers and/or disengaged providers who withheld that information. However, some encounters were depicted as helpful. Perceived positive communication was characterized by a patient discourse of kidney protection, whereby patients and providers collaborate in the mutual goal of preserving kidney function. CONCLUSIONS: Patient perceived an unequal exchange in CKD monitoring encounters. This perception appears rooted in a lack of easily understandable information. By accessing the positive discourse of protecting the kidneys (e.g., through eGFR level) vs. the discourse of damage (e.g., serum creatinine level), healthcare professionals can clarify the purpose of monitoring and in ways that motivate patient engagement in self-management. Patients being monitored for CKD progression may best be supported through messaging that conceptualizes monitoring as kidney protection and provides concrete contextualized information at each monitoring encounter. PMID- 30025519 TI - A prospective randomized comparison of the minimally invasive direct anterior and the transgluteal approach for primary total hip arthroplasty. AB - BACKGROUND: The presented prospective randomized controlled single-centre study compares the clinical outcome up to 12 months after total hip arthroplasty using a minimally invasive single-incision direct anterior (DAA) and a direct transgluteal lateral approach. METHODS: A total of 123 arthroplasties were evaluated utilizing the Harris Hip Score (HHS), the extra short musculoskeletal functional assessment questionnaire (XSFMA), the Short Form 36 (SF-36) health survey, a StepwatchTM Activity Monitor (SAM), and a timed 25 m foot walk (T25 FW). Postoperative x-ray images after THA were reviewed to determine inclination and stem positioning. RESULTS: At final follow-up, the XSFMA functional index scores were 10.3 (anterior) and 15.08 (lateral) while the bother index summed up to a score of 15.8 (anterior) and 21.66 (lateral) respectively, thus only differing significantly for the functional index (p = 0.040 and p = 0.056). The SF-36 physical component score (PCS) was 47.49 (anterior) and 42.91 (lateral) while the mental component score (MCS) summed up to 55.0 (anterior) and 56.23 (lateral) with a significant difference evident for the PCS (p = 0.017; p = 0.714). Patients undergoing THA through a DAA undertook a mean of 6402 cycles per day while those who had undergone THA through a transgluteal approach undertook a mean of 5340 cycles per day (p = 0.012). Furthermore, the obtained outcome for the T25-FW with 18.4 s (anterior) and 19.75 s (lateral) and the maximum walking distance (5932 m and 5125 m) differed significantly (p = 0.046 and p = 0.045). The average HHS showed no significant difference equaling 92.4 points in the anterior group and 91.43 in the lateral group (p = 0.477). The radiographic analysis revealed an average cup inclination of 38.6 degrees (anterior) and 40.28 degrees (lateral) without signs of migration. CONCLUSION: In summary, our outcomes show that after 1 year THA through the direct anterior approach results in a higher patient activity compared to THA utilizing a transgluteal lateral approach while no differences regarding hip function are evident. TRIAL REGISTRATION: DRKS00014808 (German Clinical Trial Register DRKS); date of registration: 31.05.2018. PMID- 30025521 TI - Risk factors of perioperative complications for posterior spinal fusion in degenerative scoliosis patients: a retrospective study. AB - BACKGROUNDS: Rare study has been conducted to detect risk factors of perioperative complications, which are closely related to preoperative status of the patients and surgical stress. The aim of this study is to detect these relationships in degenerative scoliosis (DS) patients. METHODS: Perioperative complications of 226 cases with DS (56 males and 170 females; 65.5 +/- 8.1 years old), who accepted posterior fusion in our hospital from January, 2013 to July, 2017, were retrospectively reviewed. Potential risk factors were first compared between patients with or without perioperative complications using student t test or Chi-squared test. Then, the unevenly distributed variables between the two groups were analyzed with binary logistic regression model. RESULTS: All patients separately underwent decompression with short limited instrumentation (116, 51.3%) or with long instrumentation for correction (110, 48.7%). The mean operation duration (OD) was 216.9 +/- 64.2 min and the average amount of bleeding was 587.4 +/- 357.2 ml. 44 cases (19.5%)suffered from the complications during the perioperative phase, including incision complications (5.3%), urinary infection (3.5%), dura tears/cerebrospinal fluid (CSF) leakages (3.5%) and new neurological deficits (2.7%). Hospital stay was significantly extended for the complications (p < 0.001). Univariate analysis showed that OD (p < 0.001), bleeding (p = 0.014), American Standards Association (ASA) grade > 2 (p = 0.011) and RBC transfusion>=4 U(p = 0.028) were associated with these complications. Multivariate logistic regressions revealed that only ASA grade > 2(p = 0.011, Odds Ratio[OR] = 4.104, 95% Confidence Interval[CI] = 1.413~ 11.917) and OD (p = 0.013, OR = 2.697, 95% CI = 1.233~ 5.899) were the independent risk factors. CONCLUSIONS: The high morbidity of perioperative complications for posterior spinal fusion would significantly extend hospital stay of DS patients. It was independently related to higher ASA grade and longer OD. PMID- 30025522 TI - The effects of magnesium and vitamin E co-supplementation on parameters of glucose homeostasis and lipid profiles in patients with gestational diabetes. AB - BACKGROUND: Magnesium and vitamin E are known to exert multiple beneficial effects, such as anti-glycemic and anti-lipidemic properties. The aim of this study was to determine the effects of magnesium and vitamin E co-supplementation on metabolic status of women with gestational diabetes (GDM). METHODS: This randomized, double-blinded, placebo-controlled trial was conducted among 60 subjects diagnosed with GDM, aged 18-40 years. Subjects were randomly allocated into two groups to receive 250 mg/day magnesium oxide plus 400 IU/day vitamin E supplements or placebo (n = 30 each group) for 6 weeks. Participants' blood samples were taken to determine their metabolic profiles. RESULTS: Subjects who received magnesium plus vitamin E supplements had significantly lower fasting plasma glucose (beta - 5.20 mg/dL; 95% CI, - 7.88, - 2.52; P = 0.002), serum insulin levels (beta - 2.93 MUIU/mL; 95% CI, - 5.68, - 0.18; P = 0.02) and homeostasis model of assessment-insulin resistance (beta - 0.78; 95% CI, - 1.42, 0.14; P = 0.01), and higher quantitative insulin sensitivity check index (beta 0.01; 95% CI, 0.005, 0.02; P = 0.002) compared with placebo. In addition, magnesium plus vitamin E supplementation resulted in a significant reduction in serum triglycerides (beta - 50.31 mg/dL; 95% CI, - 67.58, - 33.04; P < 0.001), VLDL- (beta - 10.06 mg/dL; 95% CI, - 13.51, - 6.60; P < 0.001), total- (beta - 26.10 mg/dL; 95% CI, - 41.88, - 10.33; P = 0.004), LDL- (beta - 15.20 mg/dL; 95% CI, - 29.50, - 0.91; P = 0.03) and total-/HDL-cholesterol ratio (beta - 0.46; 95% CI, - 0.72, - 0.19; P < 0.001) compared with placebo. Magnesium and vitamin E co supplementation did not affect HDL-cholesterol levels. CONCLUSIONS: Overall, magnesium and vitamin E co-supplementation for 6 weeks in women with GDM significantly improved glycemic control and lipid profiles, except for HDL cholesterol levels. CLINICAL TRIAL REGISTRATION NUMBER: http://www.irct.ir : IRCT20170513033941N24. PMID- 30025523 TI - A multi-band double-inversion radial fast spin-echo technique for T2 cardiovascular magnetic resonance mapping of the heart. AB - BACKGROUND: Double inversion recovery (DIR) fast spin-echo (FSE) cardiovascular magnetic resonance (CMR) sequences are used clinically for black-blood T2 weighted imaging. However, these sequences suffer from slice inefficiency due to the non-selective inversion pulses. We propose a multi-band (MB) encoded DIR radial FSE (MB-DIR-RADFSE) technique to simultaneously excite two slices. This sequence has improved signal-to-noise ratio per unit time compared to a single slice excitation. It is also motion robust and enables the reconstruction of high resolution black-blood T2-weighted images and T2 maps for the excited slices. METHODS: Hadamard encoded MB pulses were used in MB-DIR-RADFSE to simultaneously excite two slices. A principal component based iterative reconstruction was used to jointly reconstruct black-blood T2-weighted images and T2 maps. Phantom and in vivo experiments were performed to evaluate T2 mapping performance and results were compared to a T2-prepared balanced steady state free precession (bSSFP) method. The inter-segment variability of the T2 maps were assessed using data acquired on healthy subjects. A reproducibility study was performed to evaluate reproducibility of the proposed technique. RESULTS: Phantom experiments show that the T2 values estimated from MB-DIR-RADFSE are comparable to the spin-echo based reference, while T2-prepared bSSFP over-estimated T2 values. The relative contrast of the black-blood images from the multi-band scheme was comparable to those from a single slice acquisition. The myocardial segment analysis on 8 healthy subjects indicated a significant difference (p-value < 0.01) in the T2 estimates from the apical slice when compared to the mid-ventricular slice. The mean T2 estimate from 12 subjects obtained using T2-prepared bSSFP was significantly higher (p-value = 0.012) compared to MB-DIR-RADFSE, consistent with the phantom results. The Bland-Altman analysis showed excellent reproducibility between the MB-DIR-RADFSE measurements, with a mean T2 difference of 0.12 ms and coefficient of reproducibility of 2.07 in 15 clinical subjects. The utility of this technique is demonstrated in two subjects where the T2 maps show elevated values in regions of pathology. CONCLUSIONS: The use of multi-band pulses for excitation improves the slice efficiency of the double inversion fast spin-echo pulse sequence. The use of a radial trajectory and a joint reconstruction framework allows reconstruction of TE images and T2 maps for the excited slices. PMID- 30025525 TI - Validity and reliability of the patient assessment on chronic illness care (PACIC) questionnaire: the Malay version. AB - BACKGROUND: Majority of patients with chronic illnesses such as diabetes, receive care at primary care setting. Efforts have been made to restructure diabetes care in the Malaysian primary care setting in accordance with the Chronic Care Model (CCM). The Patient Assessment on Chronic Illness Care (PACIC) is a validated self report tool to measure the extent to which patients with chronic illness receive care that aligns with the CCM. To date, no validated tool is available to evaluate healthcare delivery based on the CCM in the Malay language. Thus, the study aimed to translate the PACIC into the Malay language and validate the questionnaire among patients with diabetes in the Malaysian public primary care setting. METHODS: The English version of the PACIC questionnaire is a 20-item scale measuring five key components, which are patient activation, decision support, goal setting, problem solving and follow-up care. The PACIC underwent forward - backward translation and cross cultural adaptation process to produce the PACIC-Malay version (PACIC-M). Reliability was tested using internal consistencies and test-retest reliability analyses, while construct validity was tested using the exploratory factor analysis (EFA). RESULTS: The content of PACIC M and the original version were conceptually equivalent. Overall, the internal consistency by Cronbach's alpha was .94 and the intra-class correlation coefficient was .93. One item was deleted (item 1) when the factor loading was < 0.4. The factor analyses using promax identified three components ('Goal Setting/Tailoring and Problem solving/Contextual', 'follow-up/coordination' and 'patient activation and delivery system design/ decision support'); explaining 61.2% of the variation. The Kaiser-Meyer-Olkin (KMO) was 0.93 and Bartlett's test of sphericity was p = .000. Therefore, the final version of the PACIC-M consisted of 19 items, framed within three components. CONCLUSION: The findings demonstrated that the PACIC-M measured different dimensions from the English version of PACIC. It is however; highly reliable and valid to be used in assessing three CCM model subscales. Further confirmatory factor analysis of PACIC-M should be conducted to confirm this new model. PMID- 30025526 TI - Reconstruction of iliac crest defect after autogenous harvest with bone cement and screws reduces donor site pain. AB - BACKGROUND: The iliac crest is the most common autogenous bone graft donor site, although associated with postoperative pain, functional disability, cosmesis, morphology and surgical satisfaction. We assessed each aspect above by comparing iliac crest reconstruction with bone cement and screws following harvest with no reconstruction. METHODS: We evaluated patients who underwent large iliac crest harvesting, including ten patients who underwent iliac crest defect reconstruction with bone cement and cancellous screws (R group) and ten randomly matched patients without reconstruction (NR group) were evaluated prospectively in the same period. Local pain, cosmesis and other complications were assessed postoperatively at 1 week, 6 weeks, 3 months and 6 months. RESULTS: Pain, cosmesis and satisfaction of patients significantly differed between the two groups. The R group exhibited less complications and lower pain visual analogue scores at postoperative 1 week (p < 0.001), 6 weeks (p < 0.001) and 3 months (p < 0.01) but not at 6 months, at which time patients reported almost no pain. One patient reported pain for more than 1 year in the NR group. The R group exhibited better cosmesis, morphology and satisfaction than the NR group. In the NR group, one patient suffered pain when sitting up and another when wearing a belt. CONCLUSION: Postoperative pain can be reduced and cosmesis can be improved through reconstructing the iliac crest defects after autogenous harvesting with bone cement and cancellous screws. The technique is simple, safe and easy to implement. PMID- 30025524 TI - The association of depression and all-cause and cause-specific mortality: an umbrella review of systematic reviews and meta-analyses. AB - BACKGROUND: Depression is a prevalent and disabling mental disorder that frequently co-occurs with a wide range of chronic conditions. Evidence has suggested that depression could be associated with excess all-cause mortality across different settings and populations, although the causality of these associations remains unclear. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, PsycINFO, and Embase electronic databases were searched through January 20, 2018. Systematic reviews and meta-analyses that investigated associations of depression and all-cause and cause-specific mortality were selected for the review. The evidence was graded as convincing, highly suggestive, suggestive, or weak based on quantitative criteria that included an assessment of heterogeneity, 95% prediction intervals, small-study effects, and excess significance bias. RESULTS: A total of 26 references providing 2 systematic reviews and data for 17 meta analytic estimates met inclusion criteria (19 of them on all-cause mortality); data from 246 unique studies (N = 3,825,380) were synthesized. All 17 associations had P < 0.05 per random effects summary effects, but none of them met criteria for convincing evidence. Associations of depression and all-cause mortality in patients after acute myocardial infarction, in individuals with heart failure, in cancer patients as well as in samples from mixed settings met criteria for highly suggestive evidence. However, none of the associations remained supported by highly suggestive evidence in sensitivity analyses that considered studies employing structured diagnostic interviews. In addition, associations of depression and all-cause mortality in cancer and post-acute myocardial infarction samples were supported only by suggestive evidence when studies that tried to adjust for potential confounders were considered. CONCLUSIONS: Even though associations between depression and mortality have nominally significant results in all assessed settings and populations, the evidence becomes weaker when focusing on studies that used structured interviews and those that tried to adjust for potential confounders. A causal effect of depression on all-cause and cause-specific mortality remains unproven, and thus interventions targeting depression are not expected to result in lower mortality rates at least based on current evidence from observational studies. PMID- 30025527 TI - Arthroscopic debridement of anterior ankle impingement in patients with chronic lateral ankle instability. AB - BACKGROUND: The aim of this study was to determine the functional and radiological outcomes of arthroscopic treatment of anterior ankle impingement (AAI) in patients with chronic lateral ankle instability (CAI). METHODS: All patients with CAI between June 2012 and May 2015 were invited to participate in this investigation. All of them accepted open modified Brostrom repair of lateral ankle ligaments and were divided into two groups: AAI group (with anterior ankle impingement) and pure CAI group (without anterior ankle impingement). All of them were followed up using American Orthopaedic Foot and Ankle Society Score (AOFAS), Karlsson Ankle Functional Score and Tegner activity score. Ankle dorsiflexion was also examined. X-ray examination was applied to investigate anterior tibiotalar osteophytes. RESULTS: Finally, a total of 60 patients were followed up at a mean of 37 +/- 10 months, including 22 patients in the AAI group and 38 patients in the pure CAI group. Preoperatively, the AAI group had significant lower AOFAS score (62.9 +/- 11.7 vs 72.9 +/- 11.1; p = 0.002) and Tegner activity score (1.5 +/- 0.8 vs 2.1 +/- 1.0; p = 0.04) respectively when compared with the pure CAI group. The ankle dorsiflexion of the AAI group (13 +/- 2.1) was also significantly lower than that of the pure CAI group (26.2 +/- 2.1) (p = 0.001). However, there was no significant difference in the AOFAS score or the Karlsson score or the Tegner score or the Ankle dorsiflexion between the two groups postoperatively. The postoperative X-ray images demonstrated complete osteophyte resection in all patients, and no recurrence of osteophyte. CONCLUSION: The functional outcome scores and dorsiflexion had significantly improved postoperatively. Combined treatment of chronic ankle instability and anterior ankle impingement produced satisfactory surgical outcomes in patients with CAI accompanied by anterior ankle impingement symptom. PMID- 30025528 TI - Factors contributing to patient safety incidents in primary care: a descriptive analysis of patient safety incidents in a French study using CADYA (categorization of errors in primary care). AB - BACKGROUND: Patient safety incidents (PSIs) frequently occur in primary care and are often considered to be preventable. Better knowledge of factors contributing to PSIs is required to build safer care. The aim of this work was to describe the underlying factors, specifically the human factors, that are associated with PSIs in primary care using CADYA ("CAtegorisation des DYsfonctionnements en Ambulatoire" or "Categorization of Errors in Primary Care"). METHODS: We followed a mixed method with content analysis and coding in CADYA of PSIs reported in the ESPRIT study, a French cross-sectional survey of primary care. For each incident, a main contributing factor (MD) and, if applicable, a secondary contributing factor (SD) were identified. Several descriptive keywords from an incremental glossary have been suggested to describe each identified human factor (attitudes or behaviours). A descriptive statistical analysis was then conducted. RESULTS: Among the 482 PSIs reported in the ESPRIT study, from 13,438 acts reported by 127 participating general practitioners (GPs), we identified 590 contributing factors (482 MDs and 178 SDs). Overall, 35% were related to the care process, 30% to human factors, 22% to the healthcare environment and 13% to technical factors. The contributing factors, in decreasing order of frequency, were communication errors (13.7%), human factors related to healthcare providers (12.9%) and human factors related to patients (12.9%). The human factors were mainly related to 'lack of attention', 'stress', 'anger' and 'fatigue'. CONCLUSIONS: Our results tend to prove that human factors are often involved in PSIs in primary care, with GPs and patients being equally responsible. Beyond the identification of communication errors, often found in other international research, we have described the attitudes and behaviours contributing to unsafe care. Further research exploring the links between working conditions and human factors is required. PMID- 30025529 TI - Biomechanical evaluation of an arthroscopic transosseous repair as a revision option for failed rotator cuff surgery. AB - BACKGROUND: The number of revision rotator cuff cases is increasing. The literature is lacking guidance or biomechanical evaluation for fixation strength in a revision case scenario. Therefore, the aim of the study was to provide biomechanical data investigating primary fixation strength of a transosseous technique after anchor pullout failure of a single row reconstruction. It was hypothesized that an arthroscopic transosseous repair system as a procedure for rotator cuff revisions is providing equivalent stability compared to a primary single row suture anchor fixation due to change of fixation site. METHODS: Eight matched pairs (n = 16) of fresh frozen human shoulders were tested. The paired specimen shoulders were randomly divided into two repair groups (A single row and B primary transosseous repair). The potted specimens were mounted onto the Servohydraulic test system. Both groups were tested under cyclic loading followed by load to failure testing. Suture anchor repair shoulders (group A) that were tested to failure underwent a revision transosseous repair and were subsequently tested again using the same setup and protocol (group C). RESULTS: The mean native footprint areas did not show a significant difference between groups. The reconstructed footprint area showed a significantly greater coverage in favor of the transosseous repair. Ultimate load to failure of reconstructions with the primary anchor fixation (344.73 N +/- 63.19) and the primary transosseous device (375.36 N +/- 70.27) was not significantly higher compared to the revision repair (332.19 N +/- 119.01 p = 0.45, p = 0.53). CONCLUSION: The tested transosseous anchor device is a suitable option to widely used suture anchors, providing equivalent fixation properties even in a revision case scenario. LEVEL OF EVIDENCE: Basic Science Study, Biomechanics. PMID- 30025531 TI - Improving results in rat fracture models: enhancing the efficacy of biomechanical testing by a modification of the experimental setup. AB - BACKGROUND: Animal fracture models, primarily performed in rats, are crucial to investigate normal and pathological bone healing. However, results of biomechanical testing representing a major outcome measure show high standard deviations often precluding statistical significance. Therefore, the aim of our study was a systematical examination of biomechanical characteristics of rat femurs during three-point bending. Furthermore, we tried to reduce variation of results by individually adapting the span of bearing and loading areas to the bone's length. METHODS: We examined 40 paired femurs of male Wistar-rats by DXA (BMD and BMC of the whole femur) and pQCT-scans at the levels of bearing and loading areas of the subsequent biomechanical three-point bending test. Individual adjustment of bearing and loading bars was done respecting the length of each specimen. Subgroups of light (< 400 g, n = 22) and heavy (> 400 g, n = 18) animals were formed and analysed separately. We furthermore compared the results of the individualised bending-setting to 20 femurs tested with a fix span of 15 mm. RESULTS: Femurs showed a length range of 34 to 46 mm. The failure loads ranged from 116 to 251 N (mean 175.4 +/- 45.2 N; heavy animals mean 221 +/- 18.9 N; light animals mean 138.1 +/- 16.4 N) and stiffness ranged from 185 N/mm to 426 N/mm (mean 315.6 +/- 63 N/mm; heavy animals mean 358.1 +/- 34.64 N/mm; light animals mean 280.8 +/- 59.85 N/mm). The correlation of densitometric techniques and failure loads was high (DXA R2 = 0.89 and pQCT R2 = 0.88). In comparison to femurs tested with a fix span, individual adaptation of biomechanical testing homogenized our data significantly. Most notably, the standard deviation of failure loads (221 +/- 18.95 N individualized setting vs. 205.5 +/- 30.36 N fixed) and stiffness (358.1 +/- 34.64 N/mm individualized setting vs. 498.5 +/- 104.8 N/mm fixed) was reduced by at least one third. CONCLUSIONS: Total variation observed in any trait reflects biological and methodological variation. Precision of the method hence affects the statistical power of the study. By simply adapting the setting of the biomechanical testing, interindividual variation could be reduced, which improves the precision of the method significantly. PMID- 30025530 TI - The CANadian Pediatric Weight management Registry (CANPWR): lessons learned from developing and initiating a national, multi-centre study embedded in pediatric clinical practice. AB - BACKGROUND: There is increasing recognition of the value of "real-world evidence" in evaluating health care services. Registry-based, observational studies conducted in clinical settings represent a relevant model to achieve this directive. Starting in 2010, we undertook a longitudinal, observational study (the CANadian Pediatric Weight management Registry [CANPWR]), which is embedded in 10 multidisciplinary, pediatric weight management clinics across Canada. The objective of this paper was to share the lessons our team learned from this multi centre project. METHODS: Data sources included a retrospective review of minutes from 120 teleconferences with research staff and investigators, notes taken during clinical site visits made by project leaders, information from quality control processes to ensure data accuracy and completeness, and a study-specific survey that was sent to all sites to solicit feedback from research team members (n = 9). Through an iterative process, the writing group identified key themes that surfaced during review of these information sources and final lessons learned were developed. RESULTS: Several key lessons emerged from our research, including the (1) value of pilot studies and central research coordination, (2) need for effective and regular communication, (3) importance of consensus on determining outcome measures, (4) challenge of embedding research within clinical practice, and (5) difficulty in recruiting and retaining participants. The sites were, in spite of these challenges, enthusiastic about the benefits of participating in multi-centre collaborative studies. CONCLUSION: Despite some challenges, multi-centre observational studies embedded in pediatric weight management clinics are feasible and can contribute important, practical insights into the effectiveness of health services for managing pediatric obesity in real world settings. PMID- 30025532 TI - The efficiency of electronic list-based multidisciplinary team meetings in management of gastrointestinal malignancy: a single-center experience in Southern China. AB - BACKGROUND: The multidisciplinary team (MDT) discussion has earned increasing popularity for the delivery of cancer care. However, MDT meeting (MDTM) is time and resource intensive, and some efforts to optimize discussion processes are required. This study aims to investigate the efficiency of electronic list-based MDTM in treatment of gastrointestinal (GI) malignancy. METHODS: Between January 2015 and December 2016, patients with GI cancers were retrospectively reviewed. Patients permitting an MDTM with our novel technique (eMDT group) were compared with those undergoing a traditional discussion (cMDT group). The efficiency of MDT working, including time cost per meeting or case and overall number of reviewed cases, was checked, with accuracy of clinical staging and other outcomes explored meanwhile. RESULTS: Three thousand six hundred seventy-four patients were included, with 2156 (58.7%) and 1518 (41.3%) cases for eMDT and cMDT groups, respectively. Comparisons in age (P = 0.529), gender (P = 0.844), cancer type (P = 0.218), treatment plan (P = 0.737), and pathological stage (P = 0.098) were not significant between groups. However, the average time cost in both each meeting (149.4 vs. 205.1 min; P < 0.001) and each case (3.1 vs. 6.2 min; P < 0.001) was markedly reduced. Besides, this novel technique was associated with improved accuracy of clinical staging (P = 0.070) and reduced hospital stay (P < 0.001) compared with the traditional approach, with similar incidence of complications observed (P = 0.243). CONCLUSIONS: The MDT working based on an intelligent checklist could save considerable time while not affecting treatment of GI malignancies. The improved efficiency also earns an increased capacity of hospital admission and in-patient care. PMID- 30025533 TI - Do site and type of metastasis in breast cancer show a changing pattern with increased age? A cross comparison of clinicopathological characteristics between age groups. AB - BACKGROUND: In here, we evaluated pattern of metastasis and cross-compared clinicopathological features between different age groups with breast cancer (BC). METHODS: This study was conducted in the Shiraz Breast Cancer Registry (largest BC registry in Iran). Patients were classified as < 30 years old (group 1), 30-60 years old (group 2), and > 60 years old (group 3). The three age groups were compared regarding clinical and baseline characteristics. RESULTS: Overall, 564 individuals entered group 1, 4519 group 2, and 670 group 3. Group 1 had lower rates of tumor necrosis (p < 0.001), higher lymphatic or vascular invasion (p = 0.002), estrogen receptor-negative individuals, and HER2-positive individuals (p <= 0.001). Younger groups had more stage 3 BC (31.1, 25.6, and 19.7% for groups 1, 2, and 3, respectively) (p = 0.016), grade 3 BC (27.4, 20.6, and 16.5% for groups 1, 2, and 3, respectively) (p = 0.001), and grade 3 nucleus (43.1, 34.5, and 27.6% for groups 1, 2, and 3, respectively) (p < 0.001). Group 1 had higher rates of regional metastasis (4.7 vs. 1.5 and 2.1% for groups 2 and 3, respectively). Younger individuals had higher rates of brain metastasis (13.3, 5.4, and 1.1% for groups 1, 2, and 3, respectively). Moreover, those > 60 years old had more lung metastasis (33 vs. 12.6 and 6.7% for groups 2 and 1, respectively) (p < 0.001). Younger groups had more < 5-year recurrence (16.3, 11.7, and 8.9%, for groups 1, 2, and 3, respectively) (p = 0.023). CONCLUSION: Pattern and site of recurrence changes according to age in BC. This brings up the question whether age is an independent predictor of organ of metastasis or is site of metastasis the result of other clinicopathological determinants which differ between age groups. PMID- 30025535 TI - Correction to: Effectiveness and acceptance of a web-based depression intervention during waiting time for outpatient psychotherapy: study protocol for a randomized controlled trial. AB - Following publication of the original article [1], the author reported the errors in the figure and in text reference in the published article. These errors are detailed below. The original article has been corrected. PMID- 30025534 TI - The impact of a prescription review and prescriber feedback system on prescribing practices in primary care clinics: a cluster randomised trial. AB - BACKGROUND: To evaluate the effectiveness of a structured prescription review and prescriber feedback program in reducing prescribing errors in government primary care clinics within an administrative region in Malaysia. METHODS: This was a three group, pragmatic, cluster randomised trial. In phase 1, we randomised 51 clinics to a full intervention group (prescription review and league tables plus authorised feedback letter), a partial intervention group (prescription review and league tables), and a control group (prescription review only). Prescribers in these clinics were the target of our intervention. Prescription reviews were performed by pharmacists; 20 handwritten prescriptions per prescriber were consecutively screened on a random day each month, and errors identified were recorded in a standardised data collection form. Prescribing performance feedback was conducted at the completion of each prescription review cycle. League tables benchmark prescribing errors across clinics and individual prescribers, while the authorised feedback letter detailed prescribing performance based on a rating scale. In phase 2, all clinics received the full intervention. Pharmacists were trained on data collection, and all data were audited by researchers as an implementation fidelity strategy. The primary outcome, percentage of prescriptions with at least one error, was displayed in p-charts to enable group comparison. RESULTS: A total of 32,200 prescriptions were reviewed. In the full intervention group, error reduction occurred gradually and was sustained throughout the 8-month study period. The process mean error rate of 40.7% (95% CI 27.4, 29.5%) in phase 1 reduced to 28.4% (95% CI 27.4, 29.5%) in phase 2. In the partial intervention group, error reduction was not well sustained and showed a seasonal pattern with larger process variability. The phase 1 error rate averaging 57.9% (95% CI 56.5, 59.3%) reduced to 44.8% (95% CI 43.3, 46.4%) in phase 2. There was no evidence of improvement in the control group, with phase 1 and phase 2 error rates averaging 41.1% (95% CI 39.6, 42.6%) and 39.3% (95% CI 37.8, 40.9%) respectively. CONCLUSIONS: The rate of prescribing errors in primary care settings is high, and routine prescriber feedback comprising league tables and a feedback letter can effectively reduce prescribing errors. TRIAL REGISTRATION: National Medical Research Register: NMRR-12-108-11,289 (5th March 2012). PMID- 30025536 TI - Correction to: Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer. AB - After publication of the original article [1], the authors found that Fig. 3 contained an incorrect version of Fig. 3c. This does not affect the Figure legend, results and conclusions of the article. PMID- 30025537 TI - How well do public sector primary care providers function as medical generalists in Cape Town: a descriptive survey. AB - BACKGROUND: Effective primary health care requires a workforce of competent medical generalists. In South Africa nurses are the main primary care providers, supported by doctors. Medical generalists should practice person-centred care for patients of all ages, with a wide variety of undifferentiated conditions and should support continuity and co-ordination of care. The aim of this study was to assess the ability of primary care providers to function as medical generalists in the Tygerberg sub-district of the Cape Town Metropole. METHODS: A randomly selected adult consultation was audio-recorded from each primary care provider in the sub-district. A validated local assessment tool based on the Calgary Cambridge guide was used to score 16 skills from each consultation. Consultations were also coded for reasons for encounter, diagnoses and complexity. The coders inter- and intra-rater reliability was evaluated. Analysis described the consultation skills and compared doctors with nurses. RESULTS: 45 practitioners participated (response rate 85%) with 20 nurses and 25 doctors. Nurses were older and more experienced than the doctors. Doctors saw more complicated patients. Good inter- and intra-rater reliability was shown for the coder with an intra class correlation coefficient of 0.84 (95% CI 0.045-0.996) and 0.99 (95% CI 0.984 0.998) respectively. The overall median consultation score was 25.0% (IQR 18.8 34.4). The median consultation score for nurses was 21.6% (95% CL 16.7-28.1) and for doctors was 26.7% (95% CL 23.3-34.4) (p = 0.17). There was no difference in score with the complexity of the consultation. Ten of the 16 skills were not performed in more than half of the consultations. Six of the 16 skills were partly or fully performed in more than half of the consultations and these included the more biomedical skills. CONCLUSION: Practitioners did not demonstrate a person-centred approach to the consultation and lacked many of the skills required of a medical generalist. Doctors and nurses were not significantly different. Improving medical generalism may require attention to how access to care is organised as well as to training programmes. PMID- 30025538 TI - A clarion call to the community of current and potential journal reviewers. PMID- 30025540 TI - Level of participation in physical therapy or an internet-based exercise training program: associations with outcomes for patients with knee osteoarthritis. AB - BACKGROUND: To examine whether number of physical therapy (PT) visits or amount of use of an internet-based exercise training (IBET) program is associated with differential improvement in outcomes for participants with knee osteoarthritis (OA). METHODS: A secondary analysis was performed using data from participants in 2 arms of a randomized control trial for individuals with symptomatic knee OA: PT (N = 135) or IBET (N = 124). We examined associations of number of PT visits attended (up to 8) or number of days the IBET website was accessed during the initial 4-month study period with changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total, pain and function subscales, as well as a 2-min Step Test, at 4-month and 12-month follow-up. RESULTS: Participants with more PT visits experienced greater improvement in WOMAC total score (estimate per additional visit = - 1.18, CI 95% = - 1.91, 0.46, p < 0.001) and function subscore (estimate = - 0.80, CI 95% = - 1.33, - 0.28, p < 0.001) across follow-up periods. For WOMAC pain subscale, the association with number of PT visits varied significantly between 4- and 12-month follow-up, with a stronger relationship at 4-months. There was a non-significant trend for more PT visits to be associated with greater improvement in 2-min Step Test. More frequent use of the IBET website was not associated with greater improvement for any outcome, at either time point. CONCLUSION: Increased number of PT visits was associated with improved outcomes, and some of this benefit persisted 8 months after PT ended. This provides guidance for PT clinical practice and policies. TRIAL REGISTRATION: NCT02312713 , posted 9/25/2015. PMID- 30025539 TI - Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? AB - BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin. PMID- 30025541 TI - Incomplete cellular reprogramming of colorectal cancer cells elicits an epithelial/mesenchymal hybrid phenotype. AB - BACKGROUND: Induced pluripotency in cancer cells by ectopic expression of pluripotency-regulating factors may be used for disease modeling of cancers. MicroRNAs (miRNAs) are negative regulators of gene expression that play important role in reprogramming somatic cells. However, studies on the miRNA expression profile and the expression patterns of the mesenchymal-epithelial transition (MET)/epithelial-mesenchymal transition (EMT) genes in induced pluripotent cancer (iPC) cells are lacking. METHODS: iPC clones were generated from two colorectal cancer (CRC) cell lines by retroviral transduction of the Yamanaka factors. The iPC clones obtained were characterized by morphology, expression of pluripotency markers and the ability to undergo in vitro tri-lineage differentiation. Genome wide miRNA profiles of the iPC cells were obtained by microarray analysis and bioinformatics interrogation. Gene expression was done by real-time RT-PCR and immuno-staining; MET/EMT protein levels were determined by western blot analysis. RESULTS: The CRC-iPC cells showed embryonic stem cell-like features and tri lineage differentiation abilities. The spontaneously-differentiated post-iPC cells obtained were highly similar to the parental CRC cells. However, down regulated pluripotency gene expression and failure to form teratoma indicated that the CRC-iPC cells had only attained partial pluripotency. The CRC-iPC cells shared similarities in the genome-wide miRNA expression profiles of both cancer and pluripotent embryonic stem cells. One hundred and two differentially expressed miRNAs were identified in the CRC-iPC cells, which were predicted by bioinformatics analysis be closely involved in regulating cellular pluripotency and the expression of the MET/EMT genes, possibly via the phosphatidylinositol-3 kinases-protein kinase B (PI3K-Akt) and transforming growth factor beta (TGF beta) signaling pathways. Irregular and inconsistent expression patterns of the EMT vimentin and Snai1 and MET E-cadherin and occludin proteins were observed in the four CRC-iPC clones analyzed, which suggested an epithelial/mesenchymal hybrid phenotype in the partially reprogrammed CRC cells. MET/EMT gene expression was also generally reversed on re-differentiation, also suggesting epigenetic regulation. CONCLUSIONS: Our data support the elite model for cancer cell reprogramming in which only a selected subset of cancer may be fully reprogrammed; partial cancer cell reprogramming may also elicit an epithelial mesenchymal mixed phenotype, and highlight opportunities and challenges in cancer cell-reprogramming. PMID- 30025543 TI - Patient-Oriented Research Competencies in Health (PORCH) for patients, healthcare providers, decision-makers and researchers: protocol of a scoping review. AB - BACKGROUND: Patient-Oriented Research (POR) is a Canadian initiative for health research that refers to research processes informed by full and active patient involvement in all aspects of the research. Ideally, POR results in a wide dissemination of the research findings and the uptake of such findings in both clinical practice and health policy. The Canadian Institute for Health Research (CIHR) identifies four stakeholder groups that are involved in POR who are envisioned to take on a collaborative role in enacting this approach to research. Those stakeholder groups are patients, researchers, health care providers and healthcare decision-makers. To achieve collaboration among stakeholders in POR, tools, resources, education/training and capacity building are required for each stakeholder group engaged in this work. Therefore, this review focuses on understanding and articulating competencies needed by participants to engage in POR. The aim is to summarize existing knowledge on discrete POR competencies for the four stakeholder groups; to support collaboration among them for uptake and strengthening of POR; and to inform policy, education and future research. Accordingly, our research question is 'What are the POR core competencies needed by patients, researchers, healthcare providers, and decision-makers?' The main objectives are to (1) systematically explore the academic and grey literature on competencies needed for these stakeholder groups to engage in POR; (2) map the eligible publications and research gaps in this area; (3) gain knowledge to support collaboration among stakeholders; and (4) provide recommendations for further research to use competencies that emerge in developing stakeholder groups' readiness to conduct POR. METHODS/DESIGN: We will use a methodologically rigorous scoping review approach including formulation of the research question and development of the protocol; screening and identification of the literature; selection of relevant studies; data extraction; and collation, summary and report of the results. Our eligibility criteria include elements of population (patients, researchers, healthcare providers and decision-makers); concept (competencies: knowledge, skills, attitudes; and POR); context (level of involvement in research, settings, funding sources); study design (sample, stakeholder group, methodology, grey literature, theoretical framework); outcomes (primary: relevant to decision-making/policy and practice; and secondary: relevant to education and research); language (English, French); and timing (1990 2017). Registration with PROSPERO is not eligible for scoping reviews; so, it has not been registered. DISCUSSION: Research on core competencies required to enact POR is in its infancy. In this review, we can articulate what is known and thought about competencies (knowledge, skills and attitudes) needed by individuals on POR research teams and ultimately provide knowledge that could impact research, practice, education and policy. Identification of competencies can contribute to design of healthcare professionals' basic and ongoing educational programmes, patient training in research, and professional development activities for health care providers and decision-makers. In addition, knowledge of core competencies can permit individuals to evaluate their own readiness to enter POR research teams. PMID- 30025546 TI - Dietary supplementation of essential oils in dairy cows: evidence for stimulatory effects on nutrient absorption. AB - Results of recent in vitro experiments suggest that essential oils (EO) may not only influence ruminal fermentation but also modulate the absorption of cations like Na+, Ca2+ and NH4 + across ruminal epithelia of cattle and sheep through direct interaction with epithelial transport proteins, such as those of the transient receptor potential family. The aim of the current study was to examine this hypothesis by testing the effect of a blend of essential oils (BEO) on cation status and feed efficiency in lactating dairy cows. In the experiment, 72 dairy cows in mid-to-end lactation were divided into two groups of 36 animals each and fed the same mixed ration with or without addition of BEO in a 2*2 cross over design. Feed intake, milk yield and composition, plasma and urine samples were monitored. Feeding BEO elevated milk yield, milk fat and protein yield as well as feed efficiency, whereas urea levels in plasma and milk decreased. In addition, plasma calcium levels increased significantly upon BEO supplementation, supporting the hypothesis that enhanced cation absorption might contribute to the beneficial effects of these EO. PMID- 30025544 TI - Whole-body clearing, staining and screening of calcium deposits in the mdx mouse model of Duchenne muscular dystrophy. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal, X-linked genetic disorder. Although DMD is the most common form of muscular dystrophy, only two FDA-approved drugs were developed to delay its progression. In order to assess therapies for treating DMD, several murine models have recently been introduced. As the wide variety of murine models enlighten mechanisms underlying DMD pathology, the question on how to monitor the progression of the disease within the entire musculoskeletal system still remains to be answered. One considerable approach to monitor such progression is histological evaluation of calcium deposits within muscle biopsies. Although accurate, histology is limited to small tissue area and cannot be utilized to evaluate systemic progression of DMD. Therefore, we aimed to develop a methodology suitable for rapid and high resolution screening of calcium deposits within the entire murine organism. METHODS: Procedures were performed on adult male C57BL/10-mdx and adult male C57BL mice. Animals were sacrificed, perfused, paraformaldehyde-fixed, and subjected to whole-body clearing using optimized perfusion-based CUBIC protocol. Next, cleared organisms were stained with alizarin red S to visualize calcium deposits and subjected to imaging. RESULTS: Study revealed presence of calcium deposits within degenerated muscles of the entire C57BL/10-mdx mouse organism. Calcified deposits were observed within skeletal muscles of the forelimb, diaphragm, lumbar region, pelvic region, and hindlimb. Calcified deposits found in quadriceps femoris, triceps brachii, and spinalis pars lumborum were characterized. Analysis of cumulative frequency distribution showed different distribution characteristics of calcified deposits in quadriceps femoris muscle in comparison to triceps brachii and spinalis pars lumborum muscles (p < 0.001) and quadriceps femoris vs spinalis pars lumborum (p < 0.001). Differences between the number of calcified deposits in selected muscles, their volume, and average volume were statistically significant. CONCLUSIONS: In aggregate, we present new methodology to monitor calcium deposits in situ in the mouse model of Duchenne muscular dystrophy. Sample imaging with the presented setup is feasible and applicable for whole-organ/body imaging. Accompanied by the development of custom made LSFM apparatus, it allows targeted and precise characterization of calcium deposits in cleared muscles. Hence, presented approach might be broadly utilized to monitor degree to which muscles of the entire organism are affected by the necrosis and how is it altered by the treatment or physical activity of the animal. We believe that this would be a valuable tool for studying organs alternations in a wide group of animal models of muscle dystrophy and bone oriented diseases. PMID- 30025542 TI - Identifying the etiology and pathophysiology underlying stunting and environmental enteropathy: study protocol of the AFRIBIOTA project. AB - BACKGROUND: Globally one out of four children under 5 years is affected by linear growth delay (stunting). This syndrome has severe long-term sequelae including increased risk of illness and mortality and delayed psychomotor development. Stunting is a syndrome that is linked to poor nutrition and repeated infections. To date, the treatment of stunted children is challenging as the underlying etiology and pathophysiological mechanisms remain elusive. We hypothesize that pediatric environmental enteropathy (PEE), a chronic inflammation of the small intestine, plays a major role in the pathophysiology of stunting, failure of nutritional interventions and diminished response to oral vaccines, potentially via changes in the composition of the pro- and eukaryotic intestinal communities. The main objective of AFRIBIOTA is to describe the intestinal dysbiosis observed in the context of stunting and to link it to PEE. Secondary objectives include the identification of the broader socio-economic environment and biological and environmental risk factors for stunting and PEE as well as the testing of a set of easy-to-use candidate biomarkers for PEE. We also assess host outcomes including mucosal and systemic immunity and psychomotor development. This article describes the rationale and study protocol of the AFRIBIOTA project. METHODS: AFRIBIOTA is a case-control study for stunting recruiting children in Bangui, Central African Republic and in Antananarivo, Madagascar. In each country, 460 children aged 2-5 years with no overt signs of gastrointestinal disease are recruited (260 with no growth delay, 100 moderately stunted and 100 severely stunted). We compare the intestinal microbiota composition (gastric and small intestinal aspirates; feces), the mucosal and systemic immune status and the psychomotor development of children with stunting and/or PEE compared to non stunted controls. We also perform anthropological and epidemiological investigations of the children's broader living conditions and assess risk factors using a standardized questionnaire. DISCUSSION: To date, the pathophysiology and risk factors of stunting and PEE have been insufficiently investigated. AFRIBIOTA will add new insights into the pathophysiology underlying stunting and PEE and in doing so will enable implementation of new biomarkers and design of evidence-based treatment strategies for these two syndromes. PMID- 30025547 TI - Cultural engagement and cognitive reserve: museum attendance and dementia incidence over a 10-year period. AB - SummaryTheories of cognitive reserve, disuse syndrome and stress have suggested that activities that are mentally engaging, enjoyable and socially interactive could be protective against the development of dementia. Using data from the English Longitudinal Study of Ageing, this study shows that for adults aged 50 and older visiting museums every few months or more was associated with a lower incidence rate of dementia over a 10-year follow-up period compared with less frequent visiting. This association was independent of demographics, socioeconomic status, health-related variables including sensory impairment, depression, vascular conditions and other forms of community engagement. Visiting museums may be a promising psychosocial activity to support the prevention of dementia.Declaration of interestNone. PMID- 30025548 TI - ASSESSING THE VALUE OF INNOVATIVE MEDICAL DEVICES AND DIAGNOSTICS: THE IMPORTANCE OF CLEAR AND RELEVANT CLAIMS OF BENEFIT. AB - OBJECTIVES: Large numbers of new medical devices and diagnostics are developed and health services need to identify which ones offer real advantages. The National Institute for Health and Care Excellence (NICE) has introduced a system for assessing technologies that are often notified by companies, based on claims made for their benefits to patients, the National Health Service, and the environment. METHODS: Detailed scrutiny of claims made for the benefits of products and the corresponding evidence, seeking associations between these and the selection of products for full evaluation to produce NICE guidance. RESULTS: Between 2009 and 2015 a NICE committee considered 169 technologies, of which it selected 74 (44 percent) for full evaluation, based on the claims of benefit and the evidence available. An average of 7.5 claims were made per technology; the total number did not influence selection but presence of studies supporting all the claims (p < .001) or any of the claims (p < .05) had a positive influence, as did claims for quicker patient recovery (p < .001). A greater number of studies to support the claims made selection more likely (p < .001), as did cohort studies (p < .05) and surveys (p < .05) but, unexpectedly, not randomized trials. The Medical Device Directive class had no influence. CONCLUSIONS: This study presents categories of claims that may be useful to those developing new products and to others engaged in health technology assessment. It illustrates the importance of relevant evidence and of having a clear vision of the place of new products in care pathways from an early stage. PMID- 30025549 TI - Against the Stream: lowering the age of sexual consent. AB - Lowering the legal age of sexual consent would decriminalise a large number of 'underage' young people engaging in sexual intercourse. The arguments against such a change in the law are summarised and shown to lack validity.Declaration of interestNone. PMID- 30025550 TI - Accurate recording of personality disorder in clinical practice. AB - SummaryDisturbances of personality are recorded very poorly in official statistics, but there are signs that this is changing. For many years, personality disorder has been either regarded as a secondary diagnosis that can be forgotten in the presence of another mental disorder, or avoided as the diagnosis gives the impression of untreatability or stigma. What is now abundantly clear is that under-diagnosis of personality disorder represents a disservice to patients and practitioners. It prevents a proper understanding of the longitudinal course of psychiatric disorder and an appreciation of some of the positive aspects of abnormal personality that can be used in treatment. We must no longer bury personality disorder, ostrich-like, in the diagnostic sand. It is there for the asking and needs to be embraced honestly and without fear if we are to improve the management of psychiatric patients.Declaration of interestNone. PMID- 30025551 TI - Plastic pollution and potential solutions. AB - A review is presented of the manufacture and use of different types of plastic, and the effects of pollution by these materials on animal, human and environmental health, insofar as this is known. Since 2004, the world has made as much plastic as it did in the previous half century, and it has been reckoned that the total mass of virgin plastics ever made amounts to 8.3 billion tonnes, mainly derived from natural gas and crude oil, used as chemical feedstocks and fuel sources. Between 1950 and 2015, a total of 6.3 billion tonnes of primary and secondary (recycled) plastic waste was generated, of which around 9% has been recycled, and 12% incinerated, with the remaining 79% either being stored in landfills or having been released directly into the natural environment. In 2015, 407 million tonnes (Mt) of plastic was produced, of which 164 Mt was consumed by packaging (36% of the total). Although quoted values vary, packaging probably accounts for around one third of all plastics used, of which approximately 40% goes to landfill, while 32% escapes the collection system. It has been deduced that around 9 Mt of plastic entered the oceans in 2010, as a result of mismanaged waste, along with up to 0.5 Mt each of microplastics from washing synthetic textiles, and from the abrasion of tyres on road surfaces. However, the amount of plastics actually measured in the oceans represents less than 1% of the (at least) 150 Mt reckoned to have been released into the oceans over time. Plastic accounts for around 10% by mass of municipal waste, but up to 85% of marine debris items - most of which arrive from land-based sources. Geographically, the five heaviest plastic polluters are P. R. China, Indonesia, Philippines, Vietnam and Sri Lanka, which between them contribute 56% of global plastic waste. Larger, primary plastic items can undergo progressive fragmentation to yield a greater number of increasingly smaller 'secondary' microplastic particles, thus increasing the overall surface area of the plastic material, which enhances its ability to absorb, and concentrate, persistent organic pollutants (POPs) such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), with the potential to transfer them to the tissues of animals that ingest the microplastic particles, particularly in marine environments. Although fears that such microparticles and their toxins may be passed via food webs to humans are not as yet substantiated, the direct ingestion of microplastics by humans via drinking water is a distinct possibility - since 92% of samples taken in the USA and 72% in Europe showed their presence - although any consequent health effects are as yet unclear. Foodstuffs may also become contaminated by microplastics from the air, although any consequent health effects are also unknown. In regard to such airborne sources, it is noteworthy that small plastic particles have been found in human lung tissue, which might prove an adverse health issue under given circumstances. It is also very striking that microplastics have been detected in mountain soils in Switzerland, which are most likely windborne in origin. Arctic ice core samples too have revealed the presence of microplastics, which were most likely carried on ocean currents from the Pacific garbage patch, and from local pollution from shipping and fishing. Thus, sea ice traps large amounts of microplastics and transports them across the Arctic Ocean, but these particles will be released into the global environment when the ice melts, particularly under the influence of a rising mean global temperature. While there is a growing emphasis toward the substitution of petrochemically derived plastics by bioplastics, controversy has arisen in regard to how biodegradable the latter actually are in the open environment, and they presently only account for 0.5% of the total mass of plastics manufactured globally. Since the majority of bioplastics are made from sugar and starch materials, to expand their use significantly raises the prospect of competition between growing crops to supply food or plastics, similarly to the diversion of food crops for the manufacture of primary biofuels. The use of oxo-plastics, which contain additives that assist the material to degrade, is also a matter of concern, since it is claimed that they merely fragment and add to the environmental burden of microplastics; hence, the European Union has moved to restrict their use. Since 6% of the current global oil (including natural gas liquids, NGLs) production is used to manufacture plastic commodities - predicted to rise to 20% by 2050 - the current approaches for the manufacture and use of plastics (including their end-use) demand immediate revision. More extensive collection and recycling of plastic items at the end of their life, for re-use in new production, to offset the use of virgin plastic, is a critical aspect both for reducing the amount of plastic waste entering the environment, and in improving the efficiency of fossil resource use. This is central to the ideology underpinning the circular economy, which has common elements with permaculture, the latter being a regenerative design system based on 'nature as teacher', which could help optimise the use of resources in town and city environments, while minimising and repurposing 'waste'. Thus, food might be produced more on the local than the global scale, with smaller inputs of fuels (including transportation fuels for importing and distributing food), water and fertilisers, and with a marked reduction in the use of plastic packaging. Such an approach, adopted by billions of individuals, could prove of immense significance in ensuring future food security, and in reducing waste and pollution - of all kinds. PMID- 30025552 TI - Occam's razor: from Ockham's via moderna to modern data science. AB - The principle of parsimony, also known as 'Occam's razor', is a heuristic dictum that is thoroughly familiar to virtually all practitioners of science: Aristotle, Newton, and many others have enunciated it in some form or other. Even though the principle is not difficult to comprehend as a general heuristic guideline, it has proved surprisingly resistant to being put on a rigorous footing - a difficulty that has become more pressing and topical with the 'big data' explosion. We review the significance of Occam's razor in the philosophical and theological writings of William of Ockham, and survey modern developments of parsimony in data science. PMID- 30025545 TI - Voltage sensing mechanism in skeletal muscle excitation-contraction coupling: coming of age or midlife crisis? AB - The process by which muscle fiber electrical depolarization is linked to activation of muscle contraction is known as excitation-contraction coupling (ECC). Our understanding of ECC has increased enormously since the early scientific descriptions of the phenomenon of electrical activation of muscle contraction by Galvani that date back to the end of the eighteenth century. Major advances in electrical and optical measurements, including muscle fiber voltage clamp to reveal membrane electrical properties, in conjunction with the development of electron microscopy to unveil structural details provided an elegant view of ECC in skeletal muscle during the last century. This surge of knowledge on structural and biophysical aspects of the skeletal muscle was followed by breakthroughs in biochemistry and molecular biology, which allowed for the isolation, purification, and DNA sequencing of the muscle fiber membrane calcium channel/transverse tubule (TT) membrane voltage sensor (Cav1.1) for ECC and of the muscle ryanodine receptor/sarcoplasmic reticulum Ca2+ release channel (RyR1), two essential players of ECC in skeletal muscle. In regard to the process of voltage sensing for controlling calcium release, numerous studies support the concept that the TT Cav1.1 channel is the voltage sensor for ECC, as well as also being a Ca2+ channel in the TT membrane. In this review, we present early and recent findings that support and define the role of Cav1.1 as a voltage sensor for ECC. PMID- 30025553 TI - Repeatability and Reproducibility of Quantitative Assessment of the Retinal Microvasculature Using Optical Coherence Tomography Angiography Based on Optical Microangiography. AB - OBJECTIVE: The aim of this study was to determine the repeatability and reproducibility of optical coherence tomography angiography (OCTA) based on optical microangiography (OMAG) measurements of macular vessels in normal eyes. METHODS: In this prospective cohort study, 40 eyes of 40 healthy volunteers underwent repeated OCTA (Cirrus HD-OCT 5000 angiography system, Carl Zeiss Meditec, Inc.) scans on two separate visit days. On each visit day, the eyes were scanned three times. The following parameters were used to quantitatively describe the OCTA images of the superficial vascular network: vessel area density (VAD), vessel skeleton density (VSD), vessel diameter index (VDI), vessel perimeter index (VPI), vessel complexity index (VCI), flux, and foveal avascular zone (FAZ). Coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for evaluating intravisit and intervisit repeatability, as well as interobserver reproducibility. RESULTS: The measurements showed high repeatability [CVs ? 4.2% (intravisit) and ? 4.6% (intervisit)] and interobserver reproducibility (ICCs ? 0.923) for all parameters. CONCLUSION: This study demonstrated good repeatability and reproducibility of OCTA based on OMAG for the measurement of superficial vessel parameters in normal eyes. PMID- 30025554 TI - An Experimental Study on the Optimal Timing for the Repair of Incomplete Facial Paralysis by Hypoglossal-facial 'Side'-to-side Neurorrhaphy in Rats. AB - OBJECTIVE: To investigate the optimal timing for the repair of persistent incomplete facial paralysis by hypoglossal-facial 'side'-to-side neurorrhaphy in rats. METHODS: A total of 30 adult rats with crushed and bulldog-clamped facial nerve injury were randomly divided into 5 groups (n = 6 each) that were subjected to injury without nerve repair or with immediate repair, 2-week-delayed repair, 4 week-delayed repair, or 8-week-delayed repair. Three months later, the effects of repair in each rat were evaluated by facial symmetry assessment, electrophysiological examination, retrograde labeling, and axon regeneration measurement. RESULTS: At 3 months after injury, the alpha angle significantly increased in the group of rats with 4-week-delayed repair compared with the other four groups. Upon stimulation of the facial nerve or Pre degenerated nerve, the muscle action potentials MAPs were recorded in the whisker pad muscle, and the MAP amplitude and area under the curve in the 4-week-delayed repair group were significantly augmented at 3 months post-injury. Similarly, the number of retrograde-labeled motor neurons in the facial and hypoglossal nuclei was quantified to be significantly greater in the 4-week-delayed repair group than in the other groups, and a large number of regenerated axons was also observed. CONCLUSION: The results of this study demonstrated that hemiHN-FN neurorrhaphy performed 4 weeks after facial nerve injury was most effective in terms of the functional recovery of axonal regeneration and activation of facial muscles. PMID- 30025555 TI - Prevalence of Undernutrition and Related Dietary Factors among People Aged 75 Years or Older in China during 2010-2012. AB - OBJECTIVE: Undernutrition is highly prevalent among older people. The aim of this study was to estimate the prevalence of undernutrition in elderly Chinese residents and explore the relationship between undernutrition and dietary factors. METHODS: Data were collected from 2,552 elderly people aged 75 years and over from the Chinese Nutrition and Health Surveillance during 2010-2012 using questionnaires, anthropometric measurement, and individual consecutive 3-day 24 hour dietary records. RESULTS: The present study showed that 10.5% of participants had undernutrition. The prevalence was higher among the population living in rural areas, those living in the South region, those who smoked, and those with low income levels. Most participants failed to meet the Chinese Dietary Reference Intakes for energy (66.1%) and protein (72.1%). When comparing quartiles of food intake, high rice consumption [odds ratio (OR) = 2.44, 95% confidence interval (CI): 1.35-4.40)], animal oil intake (OR = 1.60, 95% CI: 1.18 2.17), and high fat intake from animal sources (OR = 1.56, 95% CI: 1.06-2.31) were positively associated with underweight whereas high wheat consumption (OR = 0.44, 95% CI: 0.26-0.74), a proper proportion (24%-32%) of energy intake from fat (OR = 0.54, 95% CI: 0.35-0.83), and high fat intake from plant sources (OR = 0.67, 95% CI: 0.46-0.99) were inversely related. CONCLUSION: The prevalence of undernutrition was high among elderly Chinese people, especially in rural areas. Dietary factors, such as high consumption of rice, were associated with undernutrition. PMID- 30025556 TI - Association of Dietary Carotenoids Intake with Skeletal Fluorosis in the Coal burning Fluorosis Area of Guizhou Province. AB - OBJECTIVE: To explore whether the intake of dietary carotenoids could protect against skeletal fluorosis in Guizhou province in which coal-burning fluorosis is endemic. METHODS: A case-control study of 196 patients with skeletal fluorosis and 196 age and gender-matched controls was conducted in Zhijin, Guizhou Province. Face-to-face interviews were conducted to assess habitual dietary intake using a 75-item food frequency questionnaire and various covariates with structured questionnaires. Urinary fluoride was measured using an ion-selective electrode method. The genotype of superoxide dismutase 2 (SOD2) rs11968525 was detected by TaqMan method. RESULTS: We observed significant dose-dependent inverse associations of skeletal fluorosis with intake of beta-carotene, lutein/zeaxanthin, lycopene, and total carotenoids (P-trend = 0.002 to 0.018), whereas alpha-carotene and beta-cryptoxanthin intakes were not found to be related to skeletal fluorosis, after adjustment for potential confounders. The adjusted ORs and 95% CI of skeletal fluorosis for the highest versus lowest quartile were 0.30 (0.10, 0.86) for beta-carotene, 0.23 (0.08, 0.66) for lycopene, 0.26 (0.10, 0.75) for lutein/zeaxanthin and 0.34 (0.14, 0.74) for total carotenoids (all P-trend < 0.05). Stratified analyses showed that the protective effects of lutein/zeaxanthin and total carotenoids on skeletal fluorosis were more evident for individuals with the AG+AA genotypes of SOD2 (rs11968525). CONCLUSION: Increased intakes of beta-carotene, lutein/zeaxanthin, lycopene, and total carotenoids are independently associated with a lower risk of coal-burning skeletal fluorosis. SOD2 (rs11968525) polymorphisms might modify the inverse associations between dietary carotenoids and skeletal fluorosis. PMID- 30025557 TI - Risk of Active Pulmonary Tuberculosis among Patients with Coal Workers'Pneumoconiosis: A Case-control Study in China. AB - The aim of this study was to estimate the association between occupational, environmental, behavioral risk factors, and active pulmonary tuberculosis (PTB) among coal workers' pneumoconiosis (CWP) patients. A matched case-control study was conducted in 86 CWP patients with active PTB and 86 CWP controls without TB. A standardized questionnaire was used for risk factors assessment. Conditioned logistic regression analysis was used to identify associations between the risk factors and active PTB among CWP patients. The results showed that the stage of CWP, poor workplace ventilation, family history of TB, and exposure to TB were independent risk factors for active PTB in patients with CWP with which recommendations for improving work environments, and for case finding activities in patients with CWP could be made. PMID- 30025558 TI - Association between IgG N-glycans and Nonalcoholic Fatty Liver Disease in Han Chinese. AB - Nonalcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. Immunoglobulin G (IgG) N-glycans are associated with risk factors for NAFLD, such as obesity and diabetes. A cross-sectional study involving 500 Han Chinese adults recruited from a community in Beijing was carried out to explore the association between IgG N-glycans and NAFLD. IgG N-glycosylation was significantly associated with NAFLD, with the disease showing a negative correlation with galactosylation (GP14, GP14n, and G2n), positive correlation with fucosylation (FBG2n/G2n), and positive correlation with bisecting N acetylglucosamine (GlcNAc) [FBG2n/FG2n and FBG2n/(FG2n+FBG2n)], after controlling age, gender, and prevalence of obesity, type 2 diabetes mellitus, hypertension, and hyperlipidemia. In other words, the present study showed a possible association between NAFLD and the loss of galactose and elevations of fucose and bisecting GlcNAc. Aberrant IgG glycosylation might therefore be a potential biomarker for the primary or secondary prevention of NAFLD. PMID- 30025559 TI - A Retrospective Study of Culture-confirmed Mycobacterial Infection among Hospitalized HIV-infected Patients in Beijing, China. AB - A retrospective analysis was performed in two major HIV/AIDS referral hospitals in Beijing to evaluate the prevalence of Mycobacterium tuberculosis (MTB) and non tuberculous mycobacterial (NTM) infections in HIV-infected patients. A total of 627 patients' data were reviewed, and 102 (16.3%) patients were diagnosed with culture-confirmed mycobacterial infection, including 84 with MTB, 16 with NTM, and 2 with both MTB and NTM. The most frequent clinical complication by mycobacterial infection was pulmonary infection (48/102, 47.1%). The overall rates of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR TB) were 11.9% and 3.4%, respectively. This study underlines the urgent need to intensify screening for mycobacteria coinfection with HIV and to prevent the spread of drug-resistant TB among HIV-infected patients. PMID- 30025561 TI - MMP Inhibitor Ilomastat Improves Survival of Mice Exposed to gamma-Irradiation. AB - There is still a need for better protection against or mitigation of the effects of ionizing radiation following conventional radiotherapy or accidental exposure. The objective of our current study was to investigate the possible roles of matrix metalloproteinase inhibitor, ilomastat, in the protection of mice from total body radiation (TBI), and the underlying protective mechanisms. Ilomastat treatment increased the survival of mice after TBI. Ilomastat pretreatment promoted recovery of hematological and immunological cells in mice after 6 Gy gamma-ray TBI. Our findings suggest the potential of ilomastat to protect against or mitigate the effects of radiation. PMID- 30025560 TI - Validation of the China-PAR Equations for Cardio-cerebrovascular Risk Prediction in the Inner Mongolian Population. AB - The objective of this study was to evaluate the usefulness of the China-PAR equations in predicting the 10-year risk of cardiovascular disease (CVD) in the Inner Mongolians population. A population-based, prospective cohort of 2,589 Mongolians were followed up from 2003 to 2012. Participants were categorized into 4 subgroups according to their 10-year CVD risks calculated using the China-PAR equations: < 5%, 5%-9.9%, 10%-19.9%, and ? 20%. The China-PAR equations discriminated well with good C statistics (range, 0.76-0.86). The adjusted hazard ratios for CVD showed an increasing trend among the 4 subgroups (P for trend < 0.01). However, the China-PAR equations underestimated the 10-year CVD risk in Mongolians, and the calibration was unsatisfactory (Hosmer-Lemeshow chi2 = 19.98, P < 0.01 for men, chi2 = 46.58, P < 0.001 for women). The performance of the China-PAR equations warrants further validation in other ethnic groups in China. PMID- 30025562 TI - Association between the HOTAIR Polymorphism and Susceptibility to Lead Poisoning in a Chinese Population. AB - This study explored the association between the lncRNA HOTAIR polymorphism and susceptibility to lead poisoning in a Chinese population. We speculated that lead poisoning caused elevated levels of oxidative stress, which, in turn, activate the HOTAIR gene to cause apoptosis. Three lncRNA HOTAIR tagSNPs (rs7958904, rs4759314, and rs874945) were genotyped by TaqMan genotyping technology in 113 lead-sensitive and 113 lead-resistant Chinese workers exposed to lead. Rs7958904 was significantly associated with susceptibility to lead poisoning (P = 0.047). The rs7958904 G allele had a protective effect compared with the C allele and reduced the risk of lead poisoning (P = 0.016). Rs7958904 may act as a potential biomarker for predicting the risk of lead poisoning and distinguishing lead sensitive individuals from lead-resistant individuals. PMID- 30025563 TI - Emerging New Phylogenetic Groups of Rabies Virus in Chinese Ferret Badgers. AB - Chinese ferret badger (FB)-transmitted rabies is a serious threat to public health in southeast China. Although mostly associated with dogs, the rabies virus (RABV) presents genetic diversity and has a significantly wide host range in China. Instead of the dog- and wildlife-associated China II lineage in the past decades, the China I lineage has become the main epidemic group hosted and transmitted by dogs. In this study, four new lineages, including 43 RABVs from FBs, have been classified within the dog-dominated China I lineage since 2014. FB RABVs have been previously categorized in the China II lineage. Moreover, FB hosted viruses seem to have become the main independent FB-associated clade in the phylogenetic tree. This claim suggests that the increasing genetic diversity of RABVs in FBs is a result of the selective pressure from coexisting dog rabies. FB transmission has become complicated and serious with the coexistence of dog rabies. Therefore, apart from targeting FB rabies, priority should be provided by the appropriate state agencies to perform mass immunization of dog against rabies. PMID- 30025564 TI - Facile Synthesis of the Magnetic Metal Organic Framework Fe3O4@UiO-66-NH2 for Separation of Strontium. AB - A magnetic metal organic framework (MMOF) was synthesized and used to separate Sr2+ in aqueous solution. The shape and structure of prepared Fe3O4@UiO-66-NH2 were characterized, and the absorbed concentration of strontium was determined through inductively coupled plasma mass spectrometry. The results indicated that Fe3O4 and UiO-66-NH2 combined through chemical bonding. The experimental adsorption results for separation of Sr2+ in aqueous solution indicated that the adsorption of Sr2+ to Fe3O4@UiO-66-NH2 increased drastically from pH 11 to pH 13. The adsorption isotherm model indicated that the adsorption of Sr2+ conformed to the Freundlich isotherm model (R2 = 0.9919). The MMOF thus inherited the superior qualities of magnetic composites and metal organic frameworks, and can easily be separated under an external magnetic field. This MMOF thus has potential applications as a magnetic adsorbent for low level radionuclide 90Sr. PMID- 30025565 TI - Introduction to the Paul Joyce special issue. PMID- 30025566 TI - The application of low-altitude near-infrared aerial photography for detecting clandestine burials using a UAV and low-cost unmodified digital camera. AB - Aerial photography and remote sensing has been carried out in the past by numerous different platforms, utilizing imaging from across the electromagnetic (EM) spectrum to gain information about the earth. These techniques have additionally been found effective when locating mass graves and single clandestine graves created by perpetrators when concealing homicide victims. Applications for performing aerial photography and remote sensing are costly and therefore usually overlooked by police investigators, resulting in employing more contemporary geophysical methods for locating burials. Recent advances in technology however have seen the development of small Unmanned Aerial Vehicles (UAVs) for aerial photography which can be executed at low altitude and controlled remotely from the surface. This development has introduced low-cost approaches in detecting surface features, commonly utilised in the archaeological field for its accuracy in detecting anomalies, particularly when using near infrared (NIR) photography. NIR aerial images have been shown to expose cropmarks of historical value which are unnoticeable in conventional colour photography, deriving from the visual area of the EM spectrum. However, little attempt has been made to investigate the practice of NIR photography to detect clandestine graves using low-cost aerial platforms in the form of UAVs. This paper considers adopting a low-cost and non-invasive approach to detect clandestine graves through the implementation of a small UAV and an unmodified GoPro camera fixed with a near-infrared filter. The results presented here have recognised real-time suitability for using UAVs as an aerial photographic platform in the forensic archaeological field as well as noting the advantage of NIR photography as an ongoing technique for discriminating recent graves from their surroundings. PMID- 30025567 TI - The current state and future directions of skeletal toxicology: Forensic and humanitarian implications of a proposed model for the in vivo incorporation of drugs into the human skeleton. AB - At present, the inability to meaningfully and reliably conduct toxicological testing on human skeletal material represents a significant gap in forensic practice, especially in a time when the U.S. has declared opioid use a public health emergency and chemical weapon use in both mass and isolated attacks is prevalent in international news. In recent years, an increasing number of case studies and experiments have been published in an attempt to fill this knowledge gap. These papers are reviewed, and their valuable and pertinent findings discussed. However, the lack of an established model for the incorporation of drugs of forensic interest into bone has limited interpretation of results and delayed adoption of skeletal toxicology methods into accepted forensic practice. A model for the in vivo incorporation of drugs of forensic interest into bone tissue is proposed herein. This model is derived from known pathways for in vivo incorporation of compounds and analytes not of traditional forensic interest into bone tissue and is based on principles of ionic exchange, adsorption, and substitution. Testing and understanding these pathways may better guide skeletal toxicological experimentation, resulting in methods more tailored to human bone as a unique, largely inorganic matrix, as well as in increased interpretability of results. Further, the proposed model suggests possible novel applications for the field of skeletal toxicology on the humanitarian stage. Indeed, based on their chemical properties, chemical weapon nerve agents should be investigated as xenobiotics that may incorporate into the human skeleton at relatively elevated levels. If nerve agents can be isolated from skeletal remains, the field of skeletal toxicology may be able to offer important contributions to human rights investigations of mass graves. PMID- 30025568 TI - Commercial cannabis consumer products part 2: HPLC-DAD quantitative analysis of cannabis cannabinoids. AB - Quantitative analysis for the cannabis cannabinoids such as cannabidiol and Delta9-tetrahydrocannabinol in commercial products is necessary for evaluating label information, and assessing dosages and exposures when the products are consumed. Herein is presented a broadly applicable HPLC-DAD method for the determination of cannabis cannabinoids in commercial consumer products and traditional plant-related substances. The current method provides chromatographic resolution of 11 cannabinoids using a commercial, mixed C18-aromatic functionality stationary phase. The method uses 95% or pure ethanol for extraction, and certain modifications which address specific matrix types are detailed herein. Extensive method validation including precision and accuracy was conducted for five cannabinoids of primary interest (CBD, Delta9-THC, CBDA, THCA, and CBN). UV detection provided excellent sensitivity with limits of quantitation (LOQs) of 10MUg/g across cannabinoids. The method was applied to about 60 commercial products representing diverse product types and a broad range of cannabinoids amounts (0.01-350mg/g). PMID- 30025569 TI - Accuracy of clinical methods of age estimation based on permanent teeth present as erupted: A study on the coastal population of India. AB - INTRODUCTION: The role of age estimation in paediatric dentistry has been well documented with an onus being placed for the development of methods independent of radiographic analysis. The study was done to evaluate the accuracy of previously established clinical methods of age estimation in Indian children and to derive new methods for use in an Indian subpopulation. MATERIALS AND METHODS: Foti's clinical method of age estimation based on the eruption status of permanent teeth was tested for accuracy in a sample comprising 1000 children within the age group of 6-14 years encompassing five different southern states of India. A comparative evaluation of Foti's methods and new regressive models developed for an Indian subpopulation was conducted in a sample size comprising 100 children reporting to the department of pedodontics, A.B. Shetty Memorial Institute of Dental Sciences, Mangalore. RESULTS: Statistical analysis revealed greater correlation between chronological and estimated dental age using the newer formulae as compared to the original formulae. CONCLUSION: Hence it is derived that the new population specific methods can help ascertain an individual's age with relative accuracy, even in the absence of radiographs, and hence can be of considerable importance in a rural setup. PMID- 30025570 TI - Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. AB - BACKGROUND: Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. The degree to which gaps in medication use and dosing persist in contemporary outpatient practice is unclear. OBJECTIVES: This study sought to characterize patterns and factors associated with use and dose of HFrEF medications in current practice. METHODS: The CHAMP-HF (Change the Management of Patients with Heart Failure) registry included outpatients in the United States with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA). Patient-level factors associated with medication use were examined. RESULTS: Overall, 3,518 patients from 150 primary care and cardiology practices were included. Mean age was 66 +/- 13 years, 29% were female, and mean EF was 29 +/- 8%. Among eligible patients, 27%, 33%, and 67% were not prescribed ACEI/ARB/ARNI, beta-blocker, and MRA therapy, respectively. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (17%), ARNI (14%), and beta-blocker (28%), whereas most patients were receiving target doses of MRA therapy (77%). Among patients eligible for all classes of medication, 1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, and MRA. In adjusted models, older age, lower blood pressure, more severe functional class, renal insufficiency, and recent HF hospitalization generally favored lower medication utilization or dose. Social and economic characteristics were not independently associated with medication use or dose. CONCLUSIONS: In this contemporary outpatient HFrEF registry, significant gaps in use and dose of guideline-directed medical therapy remain. Multiple clinical factors were associated with medication use and dose prescribed. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy. PMID- 30025571 TI - Are Guidelines Merely Suggestions? PMID- 30025573 TI - Will Transcatheter Replacement Become the New Default Therapy When Bioprosthetic Valves Fail? PMID- 30025572 TI - Transcatheter Aortic Valve Replacement of Failed Surgically Implanted Bioprostheses: The STS/ACC Registry. AB - BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) has been shown to be feasible, yet the safety and efficacy in relation to native valve (NV) TAVR are not known. OBJECTIVES: This study sought to evaluate the safety and effectiveness of ViV TAVR for failed surgical aortic valve replacement (SAVR) by comparing it with the benchmark of NV TAVR. METHODS: Patients who underwent ViV-TAVR (n = 1,150) were matched 1:2 (on sex, high or extreme risk, hostile chest or porcelain aorta, 5-m-walk time, and Society of Thoracic Surgeons Predicted Risk of Mortality for reoperation) to patients undergoing NV-TAVR (n = 2,259). Baseline characteristics, procedural data, and in-hospital outcomes were obtained from the Transcatheter Valve Therapy Registry. The 30-day and 1-year outcomes were obtained from linked Medicare administrative claims data. RESULTS: Unadjusted analysis revealed lower 30-day mortality (2.9% vs. 4.8%; p < 0.001), stroke (1.7% vs. 3.0%; p = 0.003), and heart failure hospitalizations (2.4% vs. 4.6%; p < 0.001) in the ViV-TAVR compared with NV-TAVR group. Adjusted analysis revealed lower 30-day mortality (hazard ratio: 0.503; 95% confidence interval: 0.302 to 0.839; p = 0.008), lower 1-year mortality (hazard ratio: 0.653; 95% confidence interval: 0.505 to 0.844; p = 0.001), and hospitalization for heart failure (hazard ratio: 0.685; 95% confidence interval: 0.500 to 0.939; p = 0.019) in the ViV-TAVR group. Patients in the ViV-TAVR group had higher post-TAVR mean gradient (16 vs. 9 mm Hg; p < 0.001), but less moderate or severe aortic regurgitation (3.5% vs. 6.6%; p < 0.001). Post-TAVR gradients were highest in small SAVRs and stenotic SAVRs. CONCLUSIONS: Comparison with the benchmark NV TAVR shows ViV-TAVR to be a safe and effective procedure in patients with failed SAVR who are at high risk for repeat surgery. PMID- 30025575 TI - Minimizing Stroke and Mortality Risks in Coronary Revascularization. PMID- 30025574 TI - Stroke Rates Following Surgical Versus Percutaneous Coronary Revascularization. AB - BACKGROUND: Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used for coronary revascularization in patients with multivessel and left main coronary artery disease. Stroke is among the most feared complications of revascularization. Due to its infrequency, studies with large numbers of patients are required to detect differences in stroke rates between CABG and PCI. OBJECTIVES: This study sought to compare rates of stroke after CABG and PCI and the impact of procedural stroke on long-term mortality. METHODS: We performed a collaborative individual patient-data pooled analysis of 11 randomized clinical trials comparing CABG with PCI using stents; ERACI II (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Patients With Multiple Vessel Disease) (n = 450), ARTS (Arterial Revascularization Therapy Study) (n = 1,205), MASS II (Medicine, Angioplasty, or Surgery Study) (n = 408), SoS (Stent or Surgery) trial (n = 988), SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial (n = 1,800), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial (n = 600), FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900), VA CARDS (Coronary Artery Revascularization in Diabetes) (n = 198), BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease) (n = 880), NOBLE (Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis) trial (n = 1,184), and EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial (n = 1,905). The 30-day and 5 year stroke rates were compared between CABG and PCI using a random effects Cox proportional hazards model, stratified by trial. The impact of stroke on 5-year mortality was explored. RESULTS: The analysis included 11,518 patients randomly assigned to PCI (n = 5,753) or CABG (n = 5,765) with a mean follow-up of 3.8 +/- 1.4 years during which a total of 293 strokes occurred. At 30 days, the rate of stroke was 0.4% after PCI and 1.1% after CABG (hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.20 to 0.53; p < 0.001). At 5-year follow-up, stroke remained significantly lower after PCI than after CABG (2.6% vs. 3.2%; HR: 0.77; 95% CI: 0.61 to 0.97; p = 0.027). Rates of stroke between 31 days and 5 years were comparable: 2.2% after PCI versus 2.1% after CABG (HR: 1.05; 95% CI: 0.80 to 1.38; p = 0.72). No significant interactions between treatment and baseline clinical or angiographic variables for the 5-year rate of stroke were present, except for diabetic patients (PCI: 2.6% vs. CABG: 4.9%) and nondiabetic patients (PCI: 2.6% vs. CABG: 2.4%) (p for interaction = 0.004). Patients who experienced a stroke within 30 days of the procedure had significantly higher 5-year mortality versus those without a stroke, both after PCI (45.7% vs. 11.1%, p < 0.001) and CABG (41.5% vs. 8.9%, p < 0.001). CONCLUSIONS: This individual patient data pooled analysis demonstrates that 5-year stroke rates are significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the 30 day post-procedural period but a similar risk of stroke between 31 days and 5 years. The greater risk of stroke after CABG compared with PCI was confined to patients with multivessel disease and diabetes. Five-year mortality was markedly higher for patients experiencing a stroke within 30 days after revascularization. PMID- 30025576 TI - Ventricular Assist Device Support as a Bridge to Transplantation in Pediatric Patients. AB - BACKGROUND: Pediatric ventricular assist device (VAD) use has evolved dramatically over the last 2 decades. OBJECTIVES: This study sought to describe the evolution of VAD support to heart transplantation (HTx) in children in a large international multicenter cohort. METHODS: Using data from the Pediatric Heart Transplant Study, comparisons were made between children (<18 years) supported to HTx (January 1, 1993 to December 31, 2015) with VAD or extracorporeal membrane oxygenation (ECMO) to VAD support. RESULTS: Of 7,135 listed patients, 5,145 underwent HTx; 995 (19.3%) were supported by a VAD (113 with congenital heart disease [CHD]). Patients with a VAD as their first device (n = 821) were older, larger, and more likely to have cardiomyopathy (80%) than patients transitioned from ECMO to VAD (n = 164). In the VAD-only cohort, 79% underwent HTx and 14% died, compared with 69% and 24% in the ECMO-to-VAD cohort, respectively. Patients with cardiomyopathy achieved HTx 84% of the time, with a 9% waitlist mortality rate compared with 55% and 36%, respectively, for CHD. Among VAD-treated patients, 79% were age >10 years in the earliest era, a percentage decreasing to 34% more recently, though neonates still represent <1%. Overall, survival at 2 and 20 years showed no difference between VAD and no support (2 years: 75% vs. 80%; 20 years: 55% vs. 54%). Post-HTx outcomes were better for durable versus temporary VADs (p < 0.01) and for continuous versus pulsatile VADs (p < 0.01) from 2005 onward; timing of VAD had no impact on post HTx survival (p = 0.65). CONCLUSIONS: For one-quarter of a century, major advances have occurred in mechanical support technology for children, thereby expanding the capability to bridge to HTx without compromising post-HTx outcomes. Significant challenges remain, especially for neonates and patients with CHD, but ongoing innovation portends improved methods of support during the next decade. PMID- 30025577 TI - Pediatric Ventricular Assist Devices: A Quarter-Century of Support, Yet So Far to Go. PMID- 30025578 TI - Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy. AB - BACKGROUND: Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants. OBJECTIVES: This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test. METHODS: WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice altering variants. RESULTS: The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing. CONCLUSIONS: WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families. PMID- 30025579 TI - Genome Sequencing in Hypertrophic Cardiomyopathy. PMID- 30025581 TI - RESPONSE: What Will Echocardiography Look Like in the Future? PMID- 30025582 TI - Stroke Prophylaxis After a New Emergency Department Diagnosis of Atrial Fibrillation. PMID- 30025583 TI - A Call for Standardization in Left Atrial Appendage Occlusion. PMID- 30025584 TI - Suboptimal Device Implantation May Increase the Occurrence of Device Thrombosis After Left Atrial Appendage Occlusion. PMID- 30025585 TI - Reply: Device-Related Thrombus After Percutaneous Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation. PMID- 30025580 TI - Coronary Calcium Score and Cardiovascular Risk. AB - Coronary artery calcium (CAC) is a highly specific feature of coronary atherosclerosis. On the basis of single-center and multicenter clinical and population-based studies with short-term and long-term outcomes data (up to 15 year follow-up), CAC scoring has emerged as a widely available, consistent, and reproducible means of assessing risk for major cardiovascular outcomes, especially useful in asymptomatic people for planning primary prevention interventions such as statins and aspirin. CAC testing in asymptomatic populations is cost effective across a broad range of baseline risk. This review summarizes evidence concerning CAC, including its pathobiology, modalities for detection, predictive role, use in prediction scoring algorithms, CAC progression, evidence that CAC changes the clinical approach to the patient and patient behavior, novel applications of CAC, future directions in scoring CAC scans, and new CAC guidelines. PMID- 30025586 TI - Development and In-Hospital Mortality of Transcatheter and Surgical Aortic Valve Replacement in 2015 in Germany. PMID- 30025587 TI - Combining individual patient data from multiple trials require specific modelling techniques in order to provide accurate predictions. PMID- 30025588 TI - Reply to: Combining individual patient data from multiple trials require specific modelling techniques in order to provide accurate predictions. PMID- 30025589 TI - The "do's and don'ts" of head up CPR: Lessons learned from the animal laboratory. PMID- 30025590 TI - How confident are general practitioners in interpreting neuroradiology reports? AB - AIM: To determine the level of confidence general practitioners (GPs) have in radiology reports provided by neuroradiologists and to elicit the preferences of GPs regarding report format and level of detail. MATERIALS AND METHODS: Electronic surveys comprising anonymised neuroradiology reports were sent to GP practices served by a tertiary neuroscience centre. After reviewing the reports, GPs were asked to complete a two-part questionnaire. Firstly, GPs indicated their level of confidence, using a five-tiered Likert scale, in their understanding of: (a) the body of text; (b) the meaning of the report; and (c) the significance of the report. Secondly, GPs provided free-text suggestions for improving the report and highlighted any phrases that they did not understand. RESULTS: One hundred GPs responded from a group of 439 that received a survey (response rate 23%). Although the majority of GPs were fairly confident in their understanding of reports, fewer than one-third of GPs were entirely confident. Approximately 10% of GPs were not confident at all in their understanding of the reports. Causes of confusion included the use of detailed anatomy, acronyms, radiological terminology, and a lack of a conclusion and an action plan. CONCLUSION: General practice is a time-sensitive discipline that demands clear communication. In neuroradiology reports, GPs do not find detailed anatomy, acronyms, or radiological terminology helpful. Rather, GPs want a clear conclusion and action plan. PMID- 30025592 TI - [Pilomatricoma: Correlation between dermatopathology and dermatoscopy]. PMID- 30025591 TI - Fate of petroleum hydrocarbons in bioturbated pristine sediments from Caleta Valdes (Patagonia Argentina): An ex situ bioassay. AB - Petroleum can pollute pristine shorelines as a consequence of accidental spills or chronic leaks. In this study, the fate of petroleum hydrocarbons in soft pristine sediment of Caleta Valdes (Argentina) subject to ex situ simulated oil pollution was assessed. Sedimentary columns were exposed to medium and high concentrations of Escalante Crude Oil (ECO) and incubated in the laboratory during 30 days. Levels of aliphatic hydrocarbons at different depths of the sedimentary column were determined by gas chromatography. Oil penetration was limited to the first three centimetres in both treatments, and under this depth, hydrocarbons were clearly biogenic (terrestrial plants) as in the whole sedimentary column of the control assay. Bioturbation by macrobenthic infauna was strongly impacted by oil pollution which resulted in reduced sediment oxygenation and low burial of petroleum hydrocarbons. This may partly explain the limited hydrocarbon biodegradation observed, as indicated by the relatively high values of the ratios nC17/pristane, nC18/phytane, and total resolved aliphatic hydrocarbons/unresolved complex mixture. Correspondingly, at the end of the experiment the most probable number of hydrocarbon-degrading bacteria reached ~ 103 MPN g-1 dry weight. These values were lower than those found in chronically polluted coastal sediments, reflecting a low activity level of the oil-degrading community. The results highlight the low attenuation capacities of Caleta Valdes pristine sediments to recover its original characteristics in a short time period if an oil spill occurs. In this work, we present a novel and integrative tool to evaluate the fate of petroleum hydrocarbons and their potential damage on pristine sediments. PMID- 30025593 TI - CD3-positive diffuse large B-cell lymphoma relapses as CD3-negative large B-cell lymphoma: Loss of aberrant antigen expression in B-cell lymphoma after chemotherapy. AB - Aberrant expression of CD3 on diffuse large B-cell lymphoma (DLBCL) is rare, and its mechanism and biological significance are currently unclear. Herein we report a case of Epstein-Barr virus-negative, CD3-positive DLBCL in a 53 year-old male, who had a remote history of renal transplantation. After standard chemotherapy, the patient was in clinical remission. He relapsed three years later, but at this time with apparent loss of CD3 expression. PCR-based IGK gene rearrangement studies demonstrated clonal amplicons with an identical nucleotide size between the primary and secondary DLBCL, confirming the clonal relationship despite their phenotypic differences. To our knowledge, this is the first case of CD3-positive DLBCL that demonstrated a loss of aberrant CD3 on relapse. The chronologic change in phenotype seen in this case suggests that the source of the patient's lymphoma relapse may arise from either a quiescent subclone without CD3 expression, or from an upstream neoplastic precursor cell. PMID- 30025594 TI - Therapeutic management of peritoneal ascitic sarcomatosis by Ruta graveolens: A study in experimental mice. AB - RELEVANCE: Malignant peritoneal sarcomatosis related ascitic formation often leads to grave consequences but the therapeutic management of the fatal pathophysiological condition remains a rarely discussed issue. The present study investigates the anti-neoplastic activity of the plant alkaloid from Ruta graveolens on ascitic Sarcoma-180 bearing mice as a model of human malignant peritoneal ascites. MATERIALS AND METHODS: The efficacy of the loco-regional administration of Ruta graveolens on tumour cells was explored with cytopathological and cytotoxicological studies, along with the expressional modulation vital regulatory molecules viz. Chk2, c-Myc, CD95 and Aurora kinase. RESULTS: The study revealed a series of anti-neoplastic events exerted by Ruta graveolens that included the boosting of anti-tumour immunity, generation of tumour cell cytotoxicity and disruption of cellular energetics which lead to the induction of apoptosis and simultaneous impairment of cell division in tumour cells. Expressional decline of c-Myc oncoproteins and mitosis promoter Aurora kinase A together with up regulation of vital tumour suppressor Chk-2 and apoptosis inducer CD 95 in ascitic tumour cells was also found to be associated with Ruta administration. CONCLUSION: Our observations revealed that loco regional Ruta administration resulted in the anti-neoplastic effect on peritoneal sarcoma related ascites and the alteration of vital regulatory molecules which depicted the therapeutic utility of Ruta in the management of peritoneal malignant ascites. PMID- 30025595 TI - The diatoms test in veterinary medicine: A pilot study on cetaceans and sea turtles. AB - Fishing activities are considered one of the most relevant threats for cetaceans and sea turtles conservation since these animals are sometimes found dead entangled in fishing gears. Currently, postmortem diagnosis is based mainly on the presence of nets and lines on the body and the related marks and injuries evident at gross examination. A more detailed and objective evidence is needed to clarify doubts cases and the diatoms technique, used in forensic human medicine, could support drowning diagnosis also in this field. Diatoms' investigation was implemented to be applied in marine vertebrate on 8 striped (Stenella coeruleoalba) and 1 bottlenose (Tursiops truncatus) dolphins and 5 sea turtles (Caretta caretta) stranded along the Italian coastlines with a likely cause of death hypothized on necropsies carried out by veterinary pathologists. Diatoms were microscopically searched in the bone marrow collected from long bones implementing protocols used in human medicine and their presence was observed in 4 cetaceans and 2 sea turtles. Despite a clear relation between diatoms' presence and amount and the likely cause of death was not proved due to the poor number of samples, the higher burden of diatoms was found in 3 animals deemed to be death for the interaction with human activity. Despite more studied are necessary to identify the possible relation between the cause of death and diatoms' findings, the present study implemented this technique to be adapted to marine animals, confirming its possible application also in veterinary forensic medicine. PMID- 30025603 TI - Biomechanical evaluation of Chinese customized three-dimensionally printed total temporomandibular joint prostheses: A finite element analysis. AB - PURPOSE: This work aims to evaluate the biomechanical behavior of Chinese customized three-dimensional (3D)-printing total temporomandibular joint (TMJ) prostheses by means of finite element analysis. METHODS: A 3D model was established by Mimics 18.0, then output in a stereolithography (STL) format. Two models were established to investigate the strain behaviors of an intact mandible and a one-side implanted mandible respectively. Hypermesh and LS-DYNA software were used to establish computer-aided engineering finite element models. The stress distribution on the custom-made total TMJ prosthesis and the strain distribution on the mandible were analyzed by loading maximal masticatory force. RESULTS: The maximum stress on the surface of the ultra-high-molecular weight polyethylene was 19.61 MPa. With respect to the mandibular component, the maximum stress in the mandibular component was located at the anterior and posterior surface of the condylar neck, reaching 170.01 MPa. The peak von Mises stress was observed on the topside screw of the mandible, which was found to be 236.08 MPa. For the intact model, it was observed that the strain distribution was basically symmetrical. For the model with the prosthesis, the curve of strain distribution was fundamentally consistent with that in the intact mandible, except for the last 24 mm along the control line. A prominent strain decrease between 41.4% and 58.3% was observed in this area. CONCLUSIONS: Chinese customized 3D-printed total TMJ prostheses exhibit uniform stress distribution without changing the behavior of the opposite side natural joint. Furthermore, the prostheses have a great potential to be improved in design and materials with a promising future. PMID- 30025605 TI - Standardized irrigation technique reduces intraabdominal abscess after appendectomy. AB - PURPOSE: The utility of irrigation at the time of appendectomy for acute appendicitis has been debated, with recent studies showing no benefit to irrigation. In our practice, two techniques have been used; one in which irrigation was at the discretion of the surgeon, and one in which irrigation was standardized. The standardized irrigation technique involved large volume (3-12 l) irrigation in small, focused, directed aliquots to achieve optimal dilution. We sought to retrospectively assess whether the standardized large volume irrigation technique was associated with measurably reduced intraabdominal infection. We hypothesized that there would be no difference in intraabdominal infection rate. METHODS: Medical records for cases of appendectomies performed for acute appendicitis, years 2007 through 2017, were reviewed (n = 432). Rate of subsequent abdominal infection was compared between patients who underwent the standardized large volume irrigation technique compared to those who did not using Fisher's exact test; p < 0.05 was considered significant. RESULTS: For patients that underwent the standardized large volume irrigation technique there were no (0/140) subsequent abdominal infections within the study period, compared with a rate of 6.2% (18/292) for all other patients (p value 0.001). Among cases that had a perforated appendix (n = 105), the rates were 0% (0/31) compared to 18.9% (14/74; p value 0.009). CONCLUSIONS: Utilization of a standardized large volume irrigation technique with the objective of serial dilution is associated with a significantly lower rate of subsequent abdominal infection, even among cases with a perforated appendix. Prospective studies are needed to evaluate this technique. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Treatment study. PMID- 30025604 TI - Rethinking Pharmacological Nomenclature. AB - Pharmacological nomenclature has been continuously developed over the last century and taught to generations of medical, pharmacy, and science students. Many pharmacological terms coined decades ago remain in textbooks and the scientific literature. With the advancement in the field and the identification of molecular drug targets, rethinking the pharmacological terms in the context of these new findings has become imperative. Some examples of such terms are antihistamine, beta blocker, calcium antagonist, disease-modifying antirheumatic drug (DMARD), and non-steroidal anti-inflammatory drug (NSAID). This opinion article is an attempt to generate discussion in the community that the better way forward to name/rename pharmacological terms would be according to their mechanism of action. A mechanism-based nomenclature provides important information about therapeutic and adverse effects of drugs. Abbreviations for drug classes have also been suggested. A parsimonious, practical, and mechanism oriented pharmacological nomenclature will ultimately improve quality and safety of drug therapy. PMID- 30025606 TI - Detecting chimerism contributes to diagnosis of graft versus host disease after orthotopic liver transplantation. PMID- 30025607 TI - Outcomes of venopulmonary arterial extracorporeal life support as temporary right ventricular support after left ventricular assist implantation. AB - OBJECTIVES: We report our experience with temporary postoperative venopulmonary arterial extracorporeal life support as short-term right ventricular support in patients with biventricular failure undergoing HeartWare (HeartWare Inc, Framingham, Mass) left ventricular assist device implantation and compared these outcomes with isolated left ventricular assist device support and long-term biventricular assist device support. METHODS: A total of 112 consecutive patients were studied, 75 with the isolated HeartWare left ventricular assist device, 23 with a concomitant left ventricular assist device and venopulmonary arterial extracorporeal life support, and 14 with durable biventricular assist device support. The decision concerning short-term or durable biventricular support was based on the clinical characteristics, echocardiography, and hemodynamic profile. RESULTS: Patients who required venopulmonary arterial extracorporeal life support after left ventricular assist device insertion required the greatest support preoperatively and were more likely to have Interagency Registry for Mechanical Assisted Circulatory Support level 1 (left ventricular assist device 19%, venopulmonary arterial extracorporeal life support 48%, biventricular assist device 57%, P < .001). They were more likely to require preoperative mechanical support (left ventricular assist device 9%, venopulmonary arterial extracorporeal life support 43%, and biventricular assist device 29%, P < .001) or preoperative ventilation (9%, 38%, and 21%, respectively, P < .05). Preoperative echocardiographic and hemodynamic parameters were more similar to those requiring isolated left ventricular assist device, with patients requiring durable biventricular assist device support more likely to have elevated right atrial pressure (left ventricular assist device 14.3 +/- 6.7 vs venopulmonary arterial extracorporeal life support 13.6 +/- 4.8 vs biventricular assist device 18.7 +/- 6.0 mm Hg, P < .05); right atrial/pulmonary capillary wedge pressure ratio (0.53 +/- 0.23 vs 0.51 +/- 0.17, vs 0.69 +/- 0.22, respectively, P < .02); and tricuspid regurgitation grade (1.7 +/- 1.5 vs 1.7 +/- 1.6 vs 2.8 +/- 1.6, respectively, P < .01). One-year survival was 84% for those with an isolated left ventricular assist device compared with 62% for those with venopulmonary arterial extracorporeal life support and 64.3% for biventricular assist device. CONCLUSIONS: In critically unwell patients requiring temporary biventricular support, planned venopulmonary arterial extracorporeal life support provides acceptable outcomes, similar to durable biventricular assist device support. Requirement for venopulmonary arterial extracorporeal life support is more determined by the level of preoperative acuity than echocardiographic or hemodynamic parameters. PMID- 30025608 TI - Enantiomeric ratios: Why so many notations? AB - The correct quantification of enantiomers is pivotal in a variety of fields, such as pharmacokinetic studies, enantioselective syntheses, chemical characterization of natural products, authentication of fragrance and food, biodegradation behavior, accurate evaluation of environmental risk, and it can also provide information for sentencing guidance in forensic field. Enantioselective chromatography is the first choice to assess the composition of an enantiomeric mixture. Different notations have been used to express the measured enantiomeric ratios, which compromise the results and represent a challenge for data comparison. This manuscript critically discusses the currently used notations and exemplifies with applications in different fields indicating the advantages and disadvantages of one of the adopted systems. In order to simplify the notations, the use of enantiomeric ratio (e.r.%) as standardization for nonchiroptical methods is proposed. PMID- 30025609 TI - Contemporary theory of enantioseparations in capillary electrophoresis. AB - The first separation of enantiomers in capillary electrophoresis (CE) counts slightly longer than three decades. Fast development of the practice and theory of chiral CE occurred in the past 30 years and today one can consider this technology to have a solid and mature theoretical background. The goal of the present review is not only to summarize the history and contemporary theory of enantioseparations by using CE but also to present the authors personal view where shall we head to with this attractive technology not only from the viewpoint of separation of enantiomers but also for better understanding the mechanisms of non-covalent (enantioselective) interactions in chemistry, biology, medicine and related disciplines. PMID- 30025610 TI - Numerical correction for asymmetrical peak profiles for moment analysis of chromatographic behavior. AB - A numerical correction method is proposed for the moment analysis of some properties of chromatographic columns, even when the profiles of their elution peaks exhibit some asymmetry. Information on the retention equilibrium and the mass transfer kinetics of a C18-silica gel packing material is derived by the moment analysis from the experimental data obtained under three different sets of conditions: (1) the tailing peaks eluted from the column used; they are not corrected by the numerical method; (2) the same peaks are corrected by the numerical method, which provides the information on the column radial heterogeneity and on the efficiency at its center; and (3) symmetrical peaks having nearly Gaussian profiles eluted from another column packed with the same material; these peaks are not corrected by the numerical method. The analytical results obtained under the three different conditions are compared. The results demonstrate that the numerical correction method allows the determination of the information on the chromatographic behavior of columns from asymmetrical peak profiles, i.e., column efficiency at radial center, order of the polynomial functions for representing the radial distributions of mobile phase flow velocity and column efficiency, ratio of the flow velocity near the wall to that at the column center, and ratio of the column efficiency near the wall to that at the column center. PMID- 30025611 TI - Dynamically modified C18 silica monolithic column for the rapid determinations of lead, cadmium and mercury ions by reversed-phase high-performance liquid chromatography. AB - In this article, a new reversed-phase high-performance liquid chromatography (RP HPLC) method for the rapid, selective and sequential separation of toxic heavy metal ions namely, Pb2+, Hg2+, and Cd2+ is reported. For this RP-HPLC method, a C18 silica monolith column (Chromolith RP-18e, 100 * 4.6 mm) has been surface modified using a laboratory-synthesized amphiphilic organic ligand namely, 1,5 dioctanoyl-1,5-diphenylcarbazide (DODPC), which acts an ion-selective receptor, for the separation of the target analytes. The eluted metal ions were subjected to post-column derivatization reaction with 4-(2-pyridylazo) resorcinol (PAR) prior to their detection using a UV-vis detector (at 520 nm). The post-column reagent (PAR; 4.7 * 10-4 M; pH 9.0; 1.5 mL/min) was mixed with the column eluate through an ingeniously designed T-connector. An ultra-fast separation of Pb2+, Cd2+, and Hg2+ ions with a retention time of 1.67, 1.88 and 3.62 min, respectively was achieved, using 0.0526 mmol of DODPC coated C18 monolithic column along with tartaric acid solution (1.0 * 10-2 M; pH 4.0; 1.0 mL/min), as the isocratic eluent (mobile phase). The chromatographic parameters such as linearity, accuracy, recovery, limits of detection and quantification were validated to achieve superior analytical results. The influence of various analytical parameters such as nature of mobile phase and its concentration, solution pH, flow rate, post-column reagent and its concentration were studied and optimized. The studies revealed a lower detection limits of 0.075, 0.090 and 0.120 MUg/L, and a quantification limits of 0.225, 0.270 and 0.450 MUg/L, for Pb2+, Cd2+ and Hg2+ ions, respectively. A linear signal response in the concentration range of 0.05-50.0 MUg/mL, was observed for the target metal ions, with an average r2 value of 0.9994. The method was selective for the target metal ions, with excellent data reliability and reproducibility that accounts for an average recovery value of 99.76%, with a relative standard deviation of <=1.83%. PMID- 30025612 TI - Effect of the combined use of gamma-cyclodextrin and a chiral ionic liquid on the enantiomeric separation of homocysteine by capillary electrophoresis. AB - The enantioseparation of the non-protein amino acid homocysteine by CE was investigated in this article using eleven neutral CDs and five chiral ionic liquids as chiral selectors. Using a previous derivatization step with FMOC and the subsequent separation under neutral conditions, homocysteine enantiomers were only separated when gamma-CD or (R)-N,N,N-trimethyl-2-aminobutanol bis(trifluoromethane-sulfon)imidate (EtCholNTf2) were employed as sole chiral selectors in the separation buffer. On the one hand, gamma-CD gave rise to the enantiomeric separation in 10min with a resolution value of 1.9, whereas EtCholNTf2 let to obtain a resolution value of 1.4 in more than 50min. Then, the evaluation of the combined use of both selectors was also carried out, resulting in a considerable increase in the Rs. The best enantioseparation for homocysteine was obtained when 10mM EtCholNTf2 was added to 50mM phosphate buffer (pH 7.0) containing 2mM gamma-CD. In an attempt to discriminate specific chiral cation effect from the salt effect, the influence of adding LiNTf2 to the separation medium was also evaluated, resulting in lower resolution values for homocysteine when compared to those achieved with the addition of EtCholNTf2, indicating a synergistic effect between EtCholNTf2 and gamma-CD. Interestingly, the enantiomer migration order changed depending on the use of a single chiral selector or dual systems. When EtCholNTf2 or gamma-CD were employed as sole chiral selectors, D enantiomer was the first-migrating enantiomer. However, an inversion in the migration order was observed when both selectors were combined in a dual system being the L-enantiomer the first-migrating one. PMID- 30025613 TI - Characterization of radial and axial heterogeneities of chromatographic columns by flow reversal. AB - The impact of the column length (5, 10, and 15 cm) and packing mode (constant pressure and constant flow rate up to 15,000 psi) on the radial and axial heterogeneities of 3.0 mm i.d. research prototype columns packed with the same batch of 2.4 MUm BEH-C18 particles was investigated by the flow reversal technique. The data were gathered for a non-retained marker (uracil, acetonitrile/water eluent mixture, 80/20, v/v, flow rate 0.5 mL/min, T = 297 K) and revealed that the radial heterogeneity of the packed bed, characterized by the center-to-wall relative velocity bias (omegabeta) and its length scale, is nearly independent on the packing mode: the velocity biases extend over a same length scale estimated at 154 MUm while omegabeta is in between 4% and 6% for all columns. Secondly, the data revealed that the column length has a slight impact on omegabeta: assuming a two-region (wall and center regions) stochastic model of transcolumn eddy dispersion, omegabeta increases from 4.6% to 5.1% and to 6.1% for 5, 10, and 15 cm long columns, respectively, when packed at constant flow rate. For columns packed at constant pressure, omegabeta increases from 5.0% to 5.2% and to 5.6%, respectively. Finally, it is found that all columns are axially heterogeneous: the bottom half, which is packed first (column inlet), is slightly more uniform than the top half (column outlet) which is packed last. Overall, the results of the flow reversal experiments corroborate recent observations (130 MUm thick wall region and omegabeta = 5.0%) based on flow simulations in a focused ion-beam scanning electron microscopy (FIB-SEM) based 3D reconstruction from a 2.1 mm * 50 mm column packed with 2 MUm BEH-C18 particles. PMID- 30025614 TI - Improved delay-dependent stability result for neural networks with time-varying delays. AB - This paper is concerned with a new Lyapunov-Krasovskii functional (LKF) approach to the stability for neural networks with time-varying delays. The LKF has two features: First, it can make full use of the information of the activation function. Second, it employs the information of the maximal delayed state as well as the instant state and the delayed state. When estimating the derivative of the LKF we employ a new technique that has two characteristics: One is that Wirtinger based integral inequality and an extended reciprocally convex inequality are jointly employed; the other is that the information of the activation function is used as much as we can. Based on Lyapunov stability theory, a new stability result is obtained. Finally, three examples are given to illustrate the stability result is less conservative than some recently reported ones. PMID- 30025615 TI - Patient preferences for the delivery of cardiac rehabilitation. AB - OBJECTIVE: To elicit patients' preferences for cardiac rehabilitation(CR). METHODS: A Discrete Choice Experiment was used to quantify patients' preferences for the delivery of CR. This survey-based method elicited the relative importance of different characteristics of a program. RESULTS: 200 in-patients eligible to attend CR completed the survey. Over half of the patients strongly preferred a centre-based compared to a home-based program. Many but not all preferred a program starting within two rather than six weeks of discharge and exercise delivered in a group rather than individual setting, with exercise via the internet using telehealth strongly disliked. Some respondents preferred lifestyle information delivered one-to-one by a health professional, and there was an overall preference against delivery by smart phone Apps. Some preferred a program out of rather than within working hours and a shorter program (four weeks compared to eight weeks). CONCLUSIONS: This study provides further insight into patient preferences for a CR program. Although the strongest preferences were for centre-based programs with healthcare professionals facilitating exercise classes and one-on-one education, it is important to offer flexible delivery as one approach will not suit everyone. PRACTICE IMPLICATIONS: There is the potential to improve CR programs by focusing on patient preferences. PMID- 30025616 TI - Comment to: "Transcutaneous stimulation of the posterior tibial nerve for treating refractory urge incontinence of idiopathic and neurogenic origin". PMID- 30025617 TI - Long-term safety and efficacy of mirabegron and solifenacin in combination compared with monotherapy in patients with overactive bladder: SYNERGY II study. PMID- 30025618 TI - Heterocellular molecular contacts in the mammalian stem cell niche. AB - Adult tissue homeostasis and repair relies on prompt and appropriate intervention by tissue-specific adult stem cells (SCs). SCs have the ability to self-renew; upon appropriate stimulation, they proliferate and give rise to specialized cells. An array of environmental signals is important for maintenance of the SC pool and SC survival, behavior, and fate. Within this special microenvironment, commonly known as the stem cell niche (SCN), SC behavior and fate are regulated by soluble molecules and direct molecular contacts via adhesion molecules providing connections to local supporting cells and the extracellular matrix. Besides the extensively discussed array of soluble molecules, the expression of adhesion molecules and molecular contacts is another fundamental mechanism regulating niche occupancy and SC mobilization upon activation. Some adhesion molecules are differentially expressed and have tissue-specific consequences, likely reflecting the structural differences in niche composition and design, especially the presence or absence of a stromal counterpart. However, the distribution and identity of intercellular molecular contacts for adhesion and adhesion-mediated signaling within stromal and non-stromal SCN have not been thoroughly studied. This review highlights common details or significant differences in cell-to-cell contacts within representative stromal and non stromal niches that could unveil new standpoints for stem cell biology and therapy. PMID- 30025619 TI - Surgical site infection incidence and risk factors in knee arthroplasty: A 9-year prospective cohort study at a university teaching hospital in Spain. AB - BACKGROUND: Surgical site infection (SSI) is one of the complications posed by knee replacement surgery. Hospital-based infection surveillance systems may provide indicators of improvement and allow the characterization of risk factors critical to reduce infection. The aims of this study were to compare the incidence of SSI in our center with rates in the Madrid Region, Spain, and the United States, and to evaluate any possible SSI-related risk factor in knee replacement surgery. METHODS: All patients who underwent knee replacement surgery at a tertiary hospital in 2008-2016 were included. SSI was defined according to Centers for Disease Control and Prevention criteria. Infection rate was calculated. The association between risk factors and SSI incidence was assessed by reference to odds ratio (OR) with multivariate analysis. RESULTS: The study population (n = 1969) had a global SSI risk of 1.0%. We found a declining trend in the follow-up period, from an SSI risk of 1.8% in 2009 to 0.4% in 2016. Independent risk factors included hair removal (OR: 3.09, 95% confidence interval [CI]: 1.27-7.50) and National Healthcare Safety Network risk index >= 2 (OR: 9.37, 95% CI: 2.90-30.26). CONCLUSION: This study identified risk factors that showed the necessity to strictly comply with wound decontamination and patient preparation protocols, reduce surgery duration, and identify patients who require comprehensive monitoring. PMID- 30025620 TI - Predicting the future burden of NAFLD and NASH. PMID- 30025621 TI - Nrf2-mediated metabolic reprogramming of tolerogenic dendritic cells is protective against aplastic anemia. AB - Aplastic anemia (AA) is a rare disease characterized by immune-mediated suppression of bone marrow (BM) function resulting in progressive pancytopenia. Stem cell transplant and immunosuppressive therapies remain the major treatment choices for AA patients with limited benefit and undesired side effects. Here, we report for the first time the therapeutic utility of Nrf2-induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in the suppression of AA in mice. CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-beta and suppression of TNFalpha, IFN-gamma, and IL-12 levels in Nrf2+/+ but not Nrf2-/- DCs. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Although immature and LPS-induced (mature) Nrf2+/+ and Nrf2-/- DCs exhibited similar patterns of oxidative phosphorylation (OXPHOS) and glycolysis, only Nrf2+/+ DCs partially restored OXPHOS and reduced glycolysis during CDDO-DFPA-induced Nrf2 activation. These results were further confirmed by altered glucose uptake and lactate production. We observed significantly enhanced HO-1 and reduced iNOS/NO production in Nrf2+/+ compared to Nrf2-/- DCs, suggesting Nrf2-dependent TolDC induction is linked to suppression of the inhibitory effect of NO on OXPHOS. Furthermore, Nrf2-/- DCs demonstrated higher antigen-specific T cell proliferation. Lastly, TolDC administration improved hematopoiesis and survival in AA murine model, with decreased Th17 and increased Treg cells. Concomitantly, immunohistochemical analysis of AA patient BM biopsies displayed higher DCs, T cells, and iNOS expression accompanied with lower Nrf2 and HO-1 expression when compared to normal subjects. These results provide new insight into the therapeutic utility of metabolically reprogrammed TolDCs by CDDO-DFPA induced Nrf2 signaling in the treatment of AA. PMID- 30025622 TI - Vocal Fold Paresis: Incidence, and the Relationship between Voice Handicap Index and Laryngeal EMG Findings. AB - OBJECTIVE: To determine whether there is a correlation between Voice Handicap Index 10 (VHI-10) and degree of vocal fold paresis as determined by laryngeal EMG. Secondary objective was to determine the incidence of vocal fold paresis in a tertiary laryngology practice. METHODS: A retrospective chart review of all new voice patients seen by the senior author (RTS) from January 1, 2016 to December 31, 2017. Subjects completed VHI at their initial visit. Patients were examined with flexible and rigid laryngoscopy and videostroboscopy and referred for laryngeal electromyography (LEMG) if neuromuscular weakness was suspected. LEMG was used to identify the affected nerves and to quantify subjectively the degree of paresis. Patients who did not complete LEMG and or handicap index were excluded from the correlation analysis. The prevalence of vocal fold paresis was determined by reviewing the records of each subject. The number of patients diagnosed clinically with paresis or paralysis and referred for LEMG was documented. RESULTS: The subjects, who had paresis confirmed on LEMG (n = 210) were grouped according to the nerves involved and by the degree of paresis. The unilateral superior laryngeal nerve and ipsilateral recurrent laryngeal nerve paresis group (n = 29) had a reasonably even distribution of patients in each sub group (n = 11; 12; 6) and was analyzed for correlation. There was a strong positive correlation between the degree of paresis and the VHI score (r = 0.59, P < 0.001). Other groups did not have an even distribution among sub-groups and could not be to be analyzed for correlation. The senior author examined 344 new voice patients during years of 2016 and 2017. Based on laryngoscopy, 335 patients were referred for LEMG (97.4%). Two hundred thirty-seven patients had LEMG performed, and 234 patients confirmed to have vocal fold paresis were confirmed (98.7%.). The incidence of vocal fold paresis in subjects who underwent LEMG or who had normal motion during laryngoscopy was 95.1% (234 out of 246). The incidence in the 98 subjects who did not complete the recommended LEMG is unknown. CONCLUSION: The unilateral superior laryngeal nerve with ipsilateral recurrent laryngeal nerve paresis was the only group that allowed for analysis whether patient's perception of their voice problem as measured VHI-10 correlated with increasing degree of vocal fold paresis. A strong significant positive correlation in this group was identified. Additional studies with a larger patient cohort are recommended. PMID- 30025623 TI - Treatment Effectiveness of Novafon Local Vibration Voice Therapy for Dysphonia Treatment. AB - BACKGROUND: The objective of this study was to explore the effectiveness of the five-week Novafon local vibration voice therapy (NLVVT) program with and without Novafon local vibration for dysphonia treatment. METHODS: Twenty-two voice disordered subjects were divided into two groups. The intervention group (IG) performed the NLVVT program and the control group (CG) had the same voice exercises of this program without local vibration. RESULTS: After NLVVT, the IG showed significantly high results in all parameters of acoustics, multiparametric indices, and self-evaluation (all P values < 0.01). The CG revealed mostly much significantly lower results (P values < 0.05) or nonsignificant results for these parameters after the treatment. The intergroup comparison under consideration before and after NLVVT showed a large and significant treatment effect in voice quality (ie, narrowband spectrograms, and Acoustic Voice Quality Index), in which the IG had better treatment results. The aerodynamic measurement showed no significant changes for both groups after NLVVT (P value > 0.05). CONCLUSION: After the NLVVT program both groups showed significant improvements of various voice measurements, in which the IG revealed better treatment results than the CG. However, next to voice exercises an extra benefit for local vibration with the Novafon appliance was assessed in voice quality. PMID- 30025624 TI - The causes and evolutionary consequences of variation in female mate choice in insects: the effects of individual state, genotypes and environments. AB - Sexual selection generally involves males evolving secondary sexual characters that satisfy the mating preferences of females. Behavioral ecologists have spent considerable research effort on identifying how variation in sexually-selected traits in insects is maintained among males at the expense of investigating the proximate and ultimate causes of variation in female mating preferences for those male traits. The past decade has witnessed improved effort in redressing this bias in insects with researchers identifying a host of factors intrinsic and extrinsic to the female as mediating flexibility in female mating behavior. Evidence is mounting that a female's social environment, whether experienced during development or as an adult, is key to shaping her mating preferences. Others have extended these observations to show that the genetic identity of the conspecific individuals comprising the social environment can have profound effects on female mating preferences via indirect genetic effects (IGEs), or through interspecific indirect genetic effects (IIGEs) if the genotype of heterospecifics influences plasticity in mating preferences. Considerably more work is needed to not only expand our list of mediating intrinsic and extrinsic factors but also to identify how their interaction influences individual variation in male and female mating preferences. PMID- 30025627 TI - Erratum to "Retinal perception and ecological significance of color vision in insects" [Curr. Opin. Insect Sci. 24 (2017) 75-83]. PMID- 30025628 TI - Corrigendum to "Genomics of interaction between the brown planthopper and rice" [Curr. Opin. Insect Sci. 19 (2017) 82-87]. PMID- 30025626 TI - The genomics of insecticide resistance: insights from recent studies in African malaria vectors. AB - Over 80% of the world's population is at risk from arthropod-vectored diseases, and arthropod crop pests are a significant threat to food security. Insecticides are our front-line response for controlling these disease vectors and pests, and consequently the increasing prevalence of insecticide resistance is of global concern. Here we provide a brief overview of how genomics can be used to implement effective insecticide resistance management (IRM), with a focus on recent advances in the study of Anopheles gambiae, the major vector of malaria in Africa. These advances unlock the potential for a predictive form of IRM, allowing tractable feedback for stakeholders, where the latest field data and well parameterised models can maximise the lifetime and effectiveness of available insecticides. PMID- 30025625 TI - An overview of functional genomic tools in deciphering insecticide resistance. AB - In this short review, we highlight three functional genomic technologies that have recently been contributing to the understanding of the molecular mechanisms underpinning insecticide resistance: the GAL4/UAS system, a molecular tool used to express genes of interest in a spatiotemporal controlled manner; the RNAi system, which is used to knock-down gene expression; and the most recently developed gene editing tool, CRISPR/Cas9, which can be used to knock-out and knock-in sequences of interest. PMID- 30025629 TI - Dispersal strategies in terrestrial insects. AB - Terrestrial insects frequently disperse and/or migrate, either through their own self-directed actions or via other vehicles. Here, the following recent advances in the study of insect dispersal are highlighted: (1) components of classic hypotheses (marginal value theorem and inbreeding avoidance via sex-specific dispersal) have found varying degrees of recent support; (2) modern genetic tools have uncovered several candidate dispersal genes; (3) dispersal syndromes vary in their genetic and/or physiological constraints; and (4) common laboratory techniques may not accurately reflect dispersal in the field. A common theme is the tendency for breakthroughs to be concentrated in species with extremely well defined dispersal phenotypes (e.g., long-distance migrants, wing polymorphic insects), suggesting the need for increased focus on species exhibiting less self directed modes of dispersal. PMID- 30025630 TI - Plasticity in a changing world: behavioural responses to human perturbations. AB - Most insect species are affected by Human Induced Rapid Environmental Changes (HIREC). Multiple responses to HIREC are observed in insects, such as modifications of their morphology, physiology, behavioural strategies or phenology. Most of the responses involve phenotypic plasticity rather than genetic evolution. Here, we review the involvement of behavioural plasticity in foraging, reproduction, habitat choice and dispersal; and how behavioural plasticity modifies social behaviour and inter-specific interactions. Although important, behavioural plasticity is rarely sufficient to cope with HIREC. An increasing number of studies find species to respond maladaptively or insufficiently to various anthropogenic disturbances, and less often is large degree of plasticity linked to success. PMID- 30025631 TI - Could increased understanding of foraging behavior help to predict the success of biological control? AB - Importation biological control, the introduction of a specialist natural enemy from the region of origin of an invasive pest or weed, has been practiced for more than 100 years and has provided some iconic success stories, but also a number of failures. To improve both the success and safety of biological control in the future it is important to consider all opportunities that can help to transform biological control into a more predictive science. Once established, whether or not an imported natural enemy can reduce the abundance and distribution of an invasive host, likely depends on a suite of life history and behavioral traits that include phenological synchronization and foraging efficiency among many others. One key aspect of foraging efficiency is how individuals respond to the patchy distribution of hosts in a spatially fragmented environment when facing potential competition and predation risk. Another is what distributions of natural enemy foraging effort lead to the greatest temporal reduction in mean host density among patches. Here we explore the current theoretical framework for natural enemy foraging behavior and find some evidence that a weak resource dilution distribution of natural enemies among patches might be an important trait for improving the success of importation biological control. PMID- 30025632 TI - Lessons from the multitudes: insights from polyembryonic wasps for behavioral ecology. AB - Even for parasitic Hymenoptera, polyembryonic wasps are unusual creatures. Two features in particular, allow for novel exploration of major questions in behavioral ecology: the production of multiple offspring per egg and, in some species, the production of a soldier caste. Because final brood sizes of polyembryonic species are not constrained by trade-offs between current and future parental reproductive effort, we can clearly examine the selective forces at play that drive the balance between the number of offspring and their body size. Polyembryony also provides excellent opportunities to compare the performance of identical genotypes under different environmental conditions. Finally, polyembryonic species can provide unique tests of how genetic conflicts at multiple levels are resolved. PMID- 30025633 TI - Nutritional ecology and foraging theory. AB - Historically, two fields of research have developed theory around foraging and feeding that have influenced biology more broadly, optimal foraging theory and nutritional ecology. While these fields have developed largely in parallel, they are complementary with each offering particular strengths. Here we show how an approach developed in the study of insect nutrition, called nutritional geometry, has provided a framework for incorporating key aspects of optimal foraging theory into nutritional ecology. This synthesis provides a basis for integrating with foraging and feeding the many facets of biology that are linked to nutrition and is now influencing diverse areas of the biological and biomedical sciences. PMID- 30025634 TI - Insect personality: what can we learn from metamorphosis? AB - Ontogeny of animal personality is still an open question. Testing whether personality traits correlated with state variables (e.g. metabolic rate, hormones) and/or life history traits, and which ones are involved, requires more empirical studies. Insects with metamorphosis represent a good opportunity to tackle this question. Because of the various degrees of internal (physiological, nervous) and environmental changes linked to metamorphosis they allow testing whether these modifications drive consistency in personality traits between immature and adult stages. In this review, we establish general predictions for the effects of metamorphosis on personality in insects with complete or incomplete metamorphosis and suffering from a strong or weak niche shift after metamorphosis. We then reviewed the still rare empirical literature and discuss future research axes. PMID- 30025635 TI - Comparative analysis of behavioural traits in insects. AB - Comparative studies of insect behaviour based on evolutionary trees are currently blossoming, because of the increasing ease of phylogeny estimation, the availability of new trait data to analyze, and a vast and growing array of statistical techniques for exploring data and testing hypotheses. These studies address not only the selective forces and constraints on insect behaviour, which are the realm of traditional behavioural ecology, but also their ecological and evolutionary consequences. Recent studies have significantly increased our understanding of foraging behaviour, interspecific interactions, locomotion and dispersal, communication and signalling, mate choice and sexual selection, parental care and the evolution of sociality. The curating of trait data remains a significant challenge to maximize the future potential of insect comparative studies. PMID- 30025636 TI - Harnessing model organisms to study insecticide resistance. AB - The vinegar fly, Drosophila melanogaster, has made an enormous contribution to our understanding of insecticide targets, metabolism and transport. This contribution has been enabled by the unmatched capacity to manipulate genes in D. melanogaster and the fact that lessons learn in this system have been applicable to pests, because of the evolutionary conservation of key genes, particularly those encoding targets. With the advent of the CRISPR-Cas9 gene editing technology, genes can now be manipulated in pest species, but this review points to advantages that are likely to keep D. melanogaster at the forefront of insecticide research. PMID- 30025637 TI - Insect cuticle: a critical determinant of insecticide resistance. AB - Intense use of insecticides has resulted in the selection of extreme levels of resistance in insect populations. Therefore understanding the molecular basis of insecticide resistance mechanisms becomes critical. Penetration resistance refers to modifications in the cuticle that will eventually slow down the penetration of insecticide molecules within insects' body. So far, two mechanisms of penetration resistance have been described, the cuticle thickening and the altering of cuticle composition. Cuticular modifications are attributed to the over expression of diversified genes or proteins, which belong to structural components (cuticular proteins mainly), enzymes that catalyze enzymatic reactions (CYP4G16 and laccase 2) or ABC transporters that promote cuticular translocation. In the present review we summarize recent studies and discuss future perspectives. PMID- 30025638 TI - Adaptive learning in non-social insects: from theory to field work, and back. AB - We review the evidence that learning affects fitness in non-social insects. Early accounts date back from the 1970s and were based on field-based observational and experimental work, yet exploration of the ways in which various forms of learning increase fitness remains limited in non-social insects. We highlight the concerns that arise when artificial laboratory settings, which do not take the ecology of the species into account, are used to estimate fitness benefits of learning. We argue that ecologically-relevant experimental designs are most useful to provide fitness estimates of learning, that is, designs that include: firstly, offspring of wild-caught animals producing newly established stocks under relevant breeding conditions, combined with common-garden and reciprocal transplant experiments; secondly, the spatio-temporal dynamics of key ecological resources; and thirdly, the natural behaviours of the animals while searching for, and probing, resources. Finally, we provide guidelines for the study of fitness-learning relationships in an eco-evolutionary framework. PMID- 30025640 TI - Regulating resistance: CncC:Maf, antioxidant response elements and the overexpression of detoxification genes in insecticide resistance. AB - Although genetic and genomic tools have greatly furthered our understanding of resistance-associated mutations in molecular target sites of insecticides, the genomic basis of transcriptional regulation of detoxification loci in insect pests and vectors remains relatively unexplored. Recent work using RNAi, reporter assays and comparative genomics are beginning to reveal the molecular architecture of this response, identifying critical transcription factors and their binding sites. Central to this is the insect ortholog of the mammalian transcription factor Nrf2, Cap 'n' Collar isoform-C (CncC) which as a heterodimer with Maf-S regulates the transcription of phase I, II and III detoxification loci in a range of insects, with CncC knockdown or upregulation directly affecting phenotypic resistance. CncC:Maf binds to specific antioxidant response element sequences upstream of detoxification genes to initiate transcription. Recent work is now identifying these binding sites for resistance-associated loci and, coupled with genome sequence data and reporter assays, enabling identification of polymorphisms in the CncC:Maf binding site which regulate the insecticide resistance phenotype. PMID- 30025639 TI - Copy number variation (CNV) and insecticide resistance in mosquitoes: evolving knowledge or an evolving problem? AB - Copy number variation (CNV) in insect genomes is a rich source of potentially adaptive polymorphism which may help overcome the constraints of purifying selection on conserved genes and/or permit elevated transcription. Classic studies of amplified esterases and acetylcholinesterase duplication in Culex pipiens quantified evolutionary dynamics of CNV driven by insecticidal selection. A more complex and potentially medically impactful form of CNV is found in Anopheles gambiae, with both heterogeneous duplications and homogeneous amplifications strongly linked with insecticide resistance. Metabolic gene amplification, revealed by shotgun sequencing, appears common in Aedes aegypti, but poorly understood in other mosquito species. Many methodologies have been used to detect CNV in mosquitoes, but relatively few can detect both duplications and amplifications, and contrasting methods should be combined. Genome scans for CNV have been rare to date in mosquitoes, but offer immense potential to determine the overall role of CNV as a component of resistance mechanisms. PMID- 30025641 TI - Rethinking biological control programs as planned invasions. AB - Biological control of pests with their natural enemies essentially consists of planned invasions, with the opportunity to select both the invader and the invaded environment. Recent advances in invasion science link 'intrinsic invasion factors' (life history and behavioral traits) with invader success; connect 'extrinsic invasion factors' (abiotic and biotic aspects of the invaded environment) with environmental invasibility; and demonstrate that their interaction leads not only to ecologically driven variability but also to rapid evolutionary change in biocontrol systems. However, current theory and empirical evidence from invasion science have not yet been extensively adopted into biological control research and practice. PMID- 30025642 TI - The role of glutathione S-transferases (GSTs) in insecticide resistance in crop pests and disease vectors. AB - Insecticide resistance seriously threatens efficient arthropod pest management. Arthropod glutathione S-transferases (GSTs) confer resistance via direct metabolism or sequestration of chemicals, but also indirectly by providing protection against oxidative stress induced by insecticide exposure. To date, GST activity has been associated with resistance to all main classes of insecticides. However, recent advances in genome and transcriptome sequencing, together with modern genetic, functional and biochemical techniques, facilitate the unraveling of specific GST-mediated resistance mechanisms. Recently, the role of a number of GSTs (BdGSTe2, BdGSTe4, AfGSTe2) has been validated by (reverse) genetic methods in vivo, while a number of GSTs (BmGSTu2, TuGSTd05, AfGSTe2) have now been shown to metabolize insecticides in vitro. PMID- 30025643 TI - Editorial overview: Pests and resistance: Resistance to pesticides in arthropod crop pests and disease vectors: mechanisms, models and tools. PMID- 30025644 TI - Editorial overview: Behavioural ecology: Behavioural ecology of insects: current research and potential applications. PMID- 30025645 TI - Authors' Reply. PMID- 30025646 TI - Reply to "Development of a Point-of-Care Cardiovascular Ultrasound Program for Preclinical Medical Students". PMID- 30025647 TI - Authors' Reply. PMID- 30025648 TI - Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials. AB - BACKGROUND AND AIMS: Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]). METHODS: Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg) every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients received background maximally tolerated statin therapy. RESULTS: Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, have had prior myocardial infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C; primary endpoint; p < 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection site reactions versus controls. CONCLUSIONS: Alirocumab is generally well tolerated and effective with a similar safety profile in high-risk patients with or without prior revascularization (PCI/CABG). PMID- 30025649 TI - First data on cardiac mapping and outcome of pulmonary vein isolation using a novel ablation catheter with tip mini electrodes. AB - AIMS: Pulmonary vein isolation (PVI) is a standard treatment of atrial fibrillation (AF). AF recurrence after PVI occurs in a substantial number of cases. A novel ablation catheter equipped with mini-electrodes (ME) may facilitate PVI. Our study evaluated outcome after PVI with the ME catheter compared to a standard catheter. METHODS: Patients undergoing PVI with the ME catheter were compared to a control group ablated with a standard contact force sensing catheter. Freedom of AF after 12 months was the study endpoint. Additionally, low voltage areas (LVA) <0.5 mV were identified with a circular mapping catheter (CMC) and the ablation catheter in each group. LVA were compared between the maps obtained with the CMC and the ME or standard catheter, respectively. RESULTS: A total of 110 patients underwent PVI with ME catheter (n = 59) or the standard catheter (n = 51). Procedure duration (117.4 +/- 43 vs. 103.1 +/- 32.8 min, p = 0.15), radiation dose (1135.6 +/- 1125.7 vs. 1078.8 +/- 951.4 MUGy/m2, p = 0.91), incidence of complications and 12-month success rate (64.4 vs 72.5%, p = 0.36) were not significantly different between the groups. LVA were significantly smaller when obtained with the standard catheter compared to the CMC (14 +/- 13 vs. 58.5 +/- 22.1 cm2, p < 0.001), while no such difference was seen for mapping with the ME compared to the CMC (37 +/- 30.3 vs. 33.4 +/- 39 cm2, p = 0.4). CONCLUSION: Clinical outcomes are comparable between ME catheter and a standard contact force sensing catheter. Furthermore, better LVA detection points to improved mapping capabilities of the ME catheter. PMID- 30025650 TI - Coupling interval variability: A new diagnostic method for distinguishing left from right ventricular outflow tract origin in idiopathic outflow tract premature ventricular contractions patients with precordial R/S transition at lead V3. AB - BACKGROUND: To distinguish left ventricular outflow tract (LVOT) from right ventricular outflow tract (RVOT) origin in idiopathic outflow tract premature ventricular contractions (IOT-PVCs) patients with precordial R/S transition at lead V3 is still a challenge. We sought to develop a new electrocardiography (ECG) method for distinguishing LVOT from RVOT origin in IOT-PVCs patients with precordial R/S transition at lead V3. METHODS: We analyzed the surface 12-lead ECG characteristics and the difference of coupling interval variability (CIV) of PVCs between distinct origin sites in a retrospective cohort of IOT-PVCs patients with precordial R/S transition at lead V3 who underwent successful radiofrequency catheter ablation (RFCA) to develop a new diagnostic method, then validated it in a prospective cohort. RESULTS: A total of 196 consecutive patients (41 +/- 15 years, 36.7% male) underwent RFCA of IOT-PVCs between January 2014 and August 2016. Among them, 68 patients (34.7%, 23 male) with precordial R/S transition at lead V3 constituted the retrospective cohort. Based on the areas under the receiver operating characteristic curves (AUCs), a CIV > 100 ms with the largest value of AUC was selected to develop a new diagnostic method with a specificity of 93.9% and an accuracy of 92.6%. It correctly identified the origin site of 38 from 41 patients in the prospective cohort, demonstrating a 96.8% specificity and 92.7% accuracy. CONCLUSIONS: We presented a new simple method, a CIV > 100 ms which could reliably distinguish LVOT from RVOT origin in IOT-PVCs patients with precordial R/S transition at lead V3. PMID- 30025651 TI - SNX17 produces anti-arrhythmic effects by preserving functional SERCA2a protein in myocardial infarction. AB - BACKGROUND: Sorting nexin 17 (SNX17) is a critical cytoplasmic adaptor protein that regulates endosomal trafficking of membrane proteins to determine their recycling and/or degradation. The potential role of SNX17 in cardiovascular pathophysiology has not been reported. METHODS AND RESULTS: Cardiac arrhythmias were monitored using standard limb lead II electrocardiograph, and cardiac performances were determined by echocardiography in a rat model of myocardial infarction (MI) created by left anterior descending coronary artery ligation. We found that SNX17 was substantially downregulated in ischemic myocardium. The downregulation contributed to the cardiac electrical disturbances and contractile dysfunction as SNX17 replacement mitigated the detrimental alterations of MI hearts. Specifically, silence of SNX17 expression using RNA interference caused intracellular Ca2+ overload as revealed by the abnormal rise of resting [Ca2+]i and deceleration of Ca2+ decay, whereas SNX17 overexpression using vectors elicited the opposite effects. Moreover, the protein level of SERCA2a was significantly decreased by silencing SNX17. Immunohistochemistry indicated that SNX17 and SERCA2a were co-localized, and co-immunoprecipitation revealed the binding between the phox-homology domain of SNX17 and SERCA2a protein. Furthermore, lysosome inhibitor chloroquine prevented SNX17 silencing-induced reduction of SERCA2a protein level. CONCLUSION: Abnormal downregulation of SNX17 contributes to ischemic damages of cardiac electrophysiology and contractile function. SNX17 is an endogenous anti-arrhythmic factor acting by preserving functional SERCA2a protein in MI thereby offering a new strategy for the management of MI to alleviate ischemic myocardial injuries. PMID- 30025652 TI - Corrigendum to "Letter to correlation between pulmonary artery pressure and thoracic impedance: Insights from dailymonitoring through an implanted device in chronic heart failure" [Int. J. Cardiol. 245 (2017) 196-200]. PMID- 30025653 TI - The definition of left bundle branch block influences the response to cardiac resynchronization therapy. AB - BACKGROUND: CRT has been proven to achieve most benefit in patients with left bundle branch block morphology (LBBB). However, ECG criteria to define LBBB significantly differ from each other. Objective of the study was to evaluate the impact of different ECG criteria for LBBB definition on survival, hospitalization for heart failure and reverse remodelling in patients who received cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Three-hundred-sixteen consecutive patients were included in the analysis. Six different classifications were assessed in baseline ECGs of patients who received a CRT device: a QRS duration of >=150 ms and LBBB according to AHA/ACC/HRS, ESC 2006, ESC 2009, ESC 2013 and the classification proposed by Strauss and colleagues. In univariate analysis, the ESC 2009 and 2013 and the Strauss classifications were significantly associated with a reduction in cumulative probability for heart failure (HF) and mortality (HR 0.60, 95%CI 0.42-0.86, HR 0.61, 95% CI 0.43-0.87 and HR 0.57, 95% CI 0.40-0.80, respectively). In multivariate analysis, the association with the combined endpoint was confirmed only for ESC 2009 and 2013 classifications and for Strauss. Moreover, the cumulative probability of all cause death and HF hospitalizations was higher in patients who were negative for all the 5 LBBB classifications. CONCLUSIONS: This study shows that the strength of the association of LBBB to outcome in CRT depends on the ECG classifications used to define LBBB, the simplest criteria (ESC 2009 and 2013) providing the best association with clinical endpoints in CRT. PMID- 30025654 TI - A closer look into the complexity of our practice: Outcome research for transvenous temporary cardiac pacing. PMID- 30025655 TI - The Heart SentinelTM app for detection and automatic alerting in cardiac arrest during outdoor sports: Field tests and ventricular fibrillation simulation results. PMID- 30025656 TI - Pulmonary artery catheterization use and mortality in hospitalizations with HFrEF and HFpEF: A nationally representative trend analysis from 2005 to 2014. AB - BACKGROUND: The aim of our study was to analyze the trends in use of pulmonary artery catheterization (PAC) in heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and adjusted mortality from 2005 to 2014 using National Inpatient Sample (NIS) database. METHODS: The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes were used to identify patients with HFrEF and HFpEF from the National Inpatient Sample database. RESULTS: We identified a total of 3,225,529 hospitalizations with HFrEF and 3,419,834 hospitalizations with HFpEF. Per 1000 hospitalizations, use of PAC declined from 2005 to 2010 in both HFrEF (12.9 to 7.9, Ptrend < 0.001) and HFpEF (12.9 to 5.5, Ptrend < 0.001). However, from 2010 to 2014, the use of PAC per 1000 hospitalizations increased in both HFrEF (7.9 to 9.7, Ptrend < 0.001) and HFpEF (5.5 to 6.7, Ptrend < 0.001). We noted a temporal decline in risk-adjusted mortality during the study period for HFrEF (odds ratio, 3.93 in 2005-06 to 2.7 in 2013-14, Ptrend < 0.001) and HFpEF (odd ratio, 2.72 in 2005-06 to 2.62 in 2013 14, Ptrend < 0.001). The length of stay and cost were significantly higher with PAC use in both HFrEF and HFpEF. CONCLUSION: The use of PAC declined from 2005 to 2010 in both HFrEF and HFpEF but has since increased from 2010 to 2014 in both HFrEF and HFpEF. There is also a temporal decline in excess mortality associated with PAC use in both HFrEF and HFpEF from 2005 to 2014. PMID- 30025657 TI - Sex differences in stroke and major adverse clinical events in patients with atrial fibrillation: A systematic review and meta-analysis of 993,600 patients. AB - BACKGROUND: Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia, which is associated with an increased risk of stroke. Several studies have suggested that female AF patients could have a greater risk for stroke and thromboembolic events (TE). METHODS: A systematic literature review update and meta-analysis was conducted using Pubmed. The search used the terms "atrial fibrillation", "gender", "sex", "female", "women", "stroke", "thromboembolism". Main aim of the study was to compare and male AF patients for occurrence of stroke and TE. Secondary outcomes were: major bleeding, cardiovascular (CV) death and all-cause death. RESULTS: Forty-four studies were included in the analysis including 993,603 patients (48.9% women). After pooling the data, there was a higher risk of stroke for women vs. male AF patients (hazard ratio [HR]: 1.24; 95% confidence intervals [CIs]: 1.14-1.36). Overall, TE risk was not different between female and male patients, despite sensitivity analysis left some uncertainties. No sex differences were found for major bleeding, CV death and all cause death. A significant relationship between increasing age and the difference in stroke risk between female and male AF patients was found (Delta HR: 1.01; 95% CI: 1.00-1.03 for each year of age increase). CONCLUSIONS: Female patients with AF are at increased risk of stroke compared to men. A significant relationship between increasing age and stroke risk in women compared to men was found, most evident at age > 65 years. Female sex may act as a stroke risk modifier, particularly in elderly and very elderly AF subjects, conferring a significant increase in stroke risk. PMID- 30025658 TI - Epidemiology, patterns of care and mortality for patients with hemodynamically unstable acute symptomatic pulmonary embolism. AB - BACKGROUND: Limited information exists about the epidemiology, management and outcomes of hemodynamically unstable patients with acute pulmonary embolism (PE). We aimed to evaluate the prevalence and outcomes of unstable PE, and to assess the acute management in routine clinical practice. METHODS: This study included 34,380 patients from the RIETE registry with PE between 2001 and 2016. Primary outcomes included all-cause and PE-specific 30-day mortality. We used multivariable adjustments to calculate hazard ratios among unstable patients who did and did not receive reperfusion. RESULTS: Overall, 1207 patients (3.5%) presented with hemodynamic instability. All-cause 30-day mortality was 14% and 5.4% in those with versus those without hemodynamic instability (P < 0.001). Two hundred and thirty eight (20%) unstable patients received reperfusion therapy. After multivariable adjustment, reperfusion therapy was associated with non significantly reduced 30-day all-cause mortality (hazard ratio [HR] 0.71; 95% CI, 0.45 to 1.10; P = 0.12), and significantly reduced 30-day PE-related mortality (HR 0.56; 95% CI, 0.31 to 0.99; P = 0.04). When limiting the adjusted analyses to unstable patients with right ventricular dysfunction, the difference was significant for both all-cause (HR 0.65; 95% CI, 0.42 to 1.00; P = 0.05) and PE related mortality (HR 0.52; 95% CI, 0.30 to 0.92; P = 0.02). CONCLUSIONS: In a multinational registry of patients with PE, prevalence of hemodynamic instability was 3.5%, with high associated 30-day mortality rates. Although use of reperfusion was associated with lower mortality rates, particularly in patients with right ventricular dysfunction, it was used in only a fifth of patients. PMID- 30025659 TI - Bioresorbable vascular scaffolds for complex chronic total occlusions. AB - PURPOSE: This analysis of a consecutive series of bioresorbable vascular scaffolds (BVS) implanted for complex chronic total occlusions (CTOs) was done to evaluate the potential of this device to avoid a permanent full metal jacket with drug-eluting stents. PATIENTS: We analyzed 52 young patients (50.8 +/- 8.3 years) for the BVS group, and additionally we followed a subgroup of 17 patients where DES were combined with BVS mainly because severe calcification at the lesion site (hybrid group). RESULTS: BVS were successfully implanted in 69 of 70 patients. An average of 3.17 BVS were used per lesion in the BVS group, with a CTO length of 28 +/- 20 mm, and a reference diameter of 2.92 +/- 0.34 mm, 69% were J-CTO >= 2. The retrograde approach was used in 38%. The device length was 79 +/- 25 mm with 3.65 +/- 0.34 mm final balloon diameter. In the hybrid group BVS was used to cover the distal segment beyond the actual occlusion predominantly in LAD lesions. Patients were discharged with dual antiplatelet therapy prescribed for 12 months. At 12 months, no patient had died or experienced an acute myocardial infarction. Angiography or MSCT follow-up available in 67% showed no reocclusion within 12 months. The target revascularization was 7% at 12 months. Two patients experienced a late non-acute reocclusion at 17 and 19 months. CONCLUSIONS: The implantation of BVS for long complex CTOs was feasible with no stent thrombosis despite the high complexity of lesions and multiple BVS implanted. The lack of mechanical strength may lead to the need for focal reintervention, but still the long-term burden of full metal jacketed vessels could be avoided. PMID- 30025660 TI - Endovascular Therapy for Acute Ischemic Stroke: A Comprehensive Review of Current Status. AB - Stroke remains among the leading causes of disability and death worldwide. Fibrinolytic therapy is associated with poor patency and functional outcomes. Recently, multiple randomized trials have been published that have consolidated the role of endovascular therapy for ischemic stroke due to large vessel occlusion in the anterior cerebral circulation. This manuscript reviews the current understanding of the endovascular management of acute stroke including technical aspects and current evidence base. PMID- 30025661 TI - Transfusion Medicine in a Multidisciplinary Approach to Morbidly Adherent Placenta: Preparing for and Preventing the Worst. AB - The increasing incidence of placenta accreta has paralleled the rise in its greatest risk factor: cesarean delivery. In placenta accreta, the abnormal invasion of the chorionic villi into the myometrium prevents separation of the placenta at delivery, and the myometrium is unable to contract to prevent hemorrhage. Spontaneous uterine rupture and hemoperitoneum may also occur in the setting of placenta percreta. The average blood loss during a delivery complicated by placenta accreta is 2 to 5 L, compared to less than 0.5 L for a normal spontaneous vaginal delivery and less than 1 L for a cesarean delivery. Transfusion support for these patients, including preoperative blood component planning, is challenging for the transfusion service, and there is no consensus on how transfusion services should prepare for such cases. Herein, we review the value of a multidisciplinary approach in minimizing and supporting maternal hemorrhage in placenta accreta, predictors of hemorrhage, blood product preparation, potential strategies to limit blood loss, and intraoperative management considerations. We also highlight future opportunities and challenges in this unique group of patients. PMID- 30025662 TI - On-Treatment Platelet Reactivity is a Predictor of Adverse Events in Peripheral Artery Disease Patients Undergoing Percutaneous Angioplasty. AB - OBJECTIVES: Few data are available on the association between a different entity of platelet inhibition on antiplatelet treatment and clinical outcomes in patients with peripheral artery disease (PAD). The aim of this study was to evaluate the degree of on-treatment platelet reactivity, and its association with ischaemic and haemorrhagic adverse events at follow up in PAD patients undergoing percutaneous transluminal angioplasty (PTA). METHODS: In this observational, prospective, single centre study, 177 consecutive patients with PAD undergoing PTA were enrolled, and treated with dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. Platelet function was assessed on blood samples obtained within 24 h from PTA by light transmission aggregometry (LTA) using arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists of platelet aggregation. High on treatment platelet reactivity (HPR) was defined by LTA >= 20% if induced by AA, and LTA >= 70% if induced by ADP. Follow up was performed to record outcomes (death, major amputation, target vessel re-intervention, acute myocardial infarction and/or myocardial revascularisation, stroke/TIA, and bleeding). RESULTS: HPR by AA and HPR by ADP were found in 45% and 32% of patients, respectively. During follow up (median duration 23 months) 23 deaths (13%) were recorded; 27 patients (17.5%) underwent target limb revascularisation (TLR), two (1.3%) amputation, and six (3.9%) myocardial revascularisation. Twenty-four patients (15.6%) experienced minor bleeding. On multivariable analysis, HPR by AA and HPR by ADP were independent predictors of death [HR 3.8 (1.2-11.7), p = .023 and HR 4.8 (1.6-14.5), p = .006, respectively]. The median value of LTA by ADP was significantly lower in patients with bleeding complications than in those without [26.5% (22-39.2) vs. 62% (44.5-74), p < .001). LTA by ADP <= 41% was independently associated with bleeding HR 14.6 (2.6-24.0), p = .001] on multivariable analysis. CONCLUSIONS: In this study a high prevalence of on clopidogrel and aspirin high platelet reactivity was found, which was significantly associated with the risk of death. Conversely, a low on-clopidogrel platelet reactivity was associated with a higher risk of bleeding. These results document that the entity of platelet inhibition is associated with both thrombotic and bleeding complications in PAD patients. PMID- 30025663 TI - Using the Electronic Medical Record to Improve Preoperative Identification of Patients at Risk for Obstructive Sleep Apnea. AB - PURPOSE: Obstructive sleep apnea (OSA) is a breathing disorder found in surgical patients and associated with complications in the postoperative period. The implementation of a preoperative universal screening process using the STOP-BANG questionnaire to identify patients at high risk for OSA provides opportunities for improved management. DESIGN: A pre-post design was used to evaluate screening compliance rates. METHODS: This initiative included staff education, which included the process for evaluating and documenting STOP-BANG scores. The data were collected via a chart review of the electronic medical record (EMR). FINDINGS: The rate of screening for OSA doubled after implementation of this initiative, and compliance with STOP-BANG questionnaire screening was 66.1%. High risk designation in the EMR was 73.0%. Nearly half of the patients screened were found to be at high risk for OSA. CONCLUSIONS: Implementation of a universal screening initiative for patients and design for the EMR improves compliance with screening and identification of patients at high risk for OSA. PMID- 30025664 TI - Perioperative Considerations for Patients Diagnosed With Pulmonary Hypertension Undergoing Noncardiac Surgery. AB - The prevalence of pulmonary hypertension (PH) has risen in adults of all races, genders, and ethnicities. PH is a fatal disease that presents many challenges to the perioperative health care team. Through increased knowledge of PH pathophysiological changes and anesthesia medications' effect on PH, perioperative health care teams can conduct a detailed preoperative evaluation to determine appropriate therapies to administer. This will assist the perioperative health care team in reducing the pulmonary vascular resistance, optimizing the matching of right ventricle and pulmonary circulations, and reduce the incidence of intraoperative and postoperative complications. PMID- 30025665 TI - The Impact of Music Therapy in the Postoperative Setting on Overall Patient Satisfaction Using Validated Outcome Scores. AB - PURPOSE: Previous studies have examined music therapy (MT) as a potential modality to relieve negative postoperative symptoms such as pain. This randomized control trial examined the use of MT on patient satisfaction in the postanesthesia care unit. DESIGN: Fifty patients undergoing outpatient orthopaedic surgery were enrolled and randomized into two groups, those receiving MT postoperatively and a control group who did not. METHODS: After hospital discharge, subjects were assessed with two validated outcome measurements for overall patient satisfaction, the visual analog satisfaction scale and the Patient Judgment of Hospital Quality survey. FINDINGS: The results showed no statistically significant differences between the MT and control group on the Patient Judgment of Hospital Quality survey (MT = 3.42, standard therapy = 3.41, P = .94) and the visual analog satisfaction scale (MT = 91.20, standard therapy = 91.65, P = .88). CONCLUSIONS: MT given in the postoperative setting has no impact on overall patient satisfaction. PMID- 30025666 TI - Experimental Studies of Evolutionary Dynamics in Microbes. AB - Evolutionary dynamics in laboratory microbial evolution experiments can be surprisingly complex. In the past two decades, observations of these dynamics have challenged simple models of adaptation and have shown that clonal interference, hitchhiking, ecological diversification, and contingency are widespread. In recent years, advances in high-throughput strain maintenance and phenotypic assays, the dramatically reduced cost of genome sequencing, and emerging methods for lineage barcoding have made it possible to observe evolutionary dynamics at unprecedented resolution. These new methods can now begin to provide detailed measurements of key aspects of fitness landscapes and of evolutionary outcomes across a range of systems. These measurements can highlight challenges to existing theoretical models and guide new theoretical work towards the complications that are most widely important. PMID- 30025667 TI - An Assessment of Public Preferences for Newborn Screening Using Best-Worst Scaling. AB - OBJECTIVE: To identify and quantify public preferences for attributes of newborn screening conditions. STUDY DESIGN: We conducted an online national survey of the public (n = 502) to evaluate preferences for attributes of candidate newborn screening conditions. Respondents were presented with hypothetical condition profiles that were defined using 10 attributes with 2-6 levels per attribute. Participants indicated whether they would recommend screening for a condition and which condition attributes were most and least important when making this decision (best-worst scaling). Difference scores were calculated and stratified by condition recommendation (recommend or not recommend for screening). Regression analyses were used to evaluate the effect of attributes on choice to screen or not screen. RESULTS: The number of babies diagnosed was important to those who would recommend newborn screening for a profile, and age at which the treatment would start was important to those who would not recommend newborn screening. Cost was considered to be a key attribute, and treatment effectiveness and impact of making the diagnosis through newborn screening were of low importance for both groups. CONCLUSION: Public preferences identified through survey methods that provide an adequate baseline understanding of newborn screening can be used to inform newborn screening decisions. PMID- 30025668 TI - A Girl with Delayed Puberty and Bumpy Lips. PMID- 30025670 TI - Can Real World Evidence on Body Mass Index Trajectories Inform Clinical Practice? PMID- 30025669 TI - Clinical Characteristics and Risk Factors for Developing Pulmonary Hypertension in Children with Down Syndrome. AB - OBJECTIVES: To determine the incidence, characteristics of, and risk factors contributing to the development of pulmonary hypertension in children with Down syndrome. STUDY DESIGN: This retrospective, review of a large cohort (n = 1242) of children with Down syndrome receiving care at a specialized referral center evaluated clinical data and serial echocardiograms from a clinic database and electronic medical records. Pulmonary hypertension characteristics and comorbidities were reviewed. Pulmonary hypertension was considered transient if echocardiographic evidence of pulmonary hypertension resolved without recurrence, persistent if no resolution, and recurrent if evidence of pulmonary hypertension returned after a period of resolution. RESULTS: The incidence of pulmonary hypertension in children with Down syndrome was 28% (n = 346). Median age at initial diagnosis was 5 days (range: 0-7067 days). Pulmonary hypertension was differentiated into transient (70%), persistent (15%), and recurrent (15%) disease. Median duration of transient pulmonary hypertension was 8 months (range: 0.1-130.2 months). Median age at recurrence was 2.5 years (range 0.2-11.5 years). Initial pulmonary hypertension diagnosis was classified as World Health Organization group I disease in 82%, with 45% associated with congenital heart disease (CHD), and 38% persistent pulmonary hypertension of the newborn (PPHN). The pulmonary hypertension recurrence rate was significant and similar for both those with initial PPHN (12%) and non-PPHN (16%). A majority (87%) of patients with recurrent pulmonary hypertension were classified as World Health Organization group III. Frequently identified comorbid conditions included CHD, obstructive sleep apnea, intermittent hypoxia, and recurrent pneumonia. CONCLUSIONS: Pulmonary hypertension is common in children with Down syndrome, is typically transient, and related to CHD or PPHN but can recur in the setting of respiratory disease such as obstructive sleep apnea, intermittent hypoxia, and recurrent pneumonia. PMID- 30025671 TI - Morning Glory Disc Anomaly in a Child with Esotropia. PMID- 30025673 TI - The Complexities of Ascertaining Public Preferences for Newborn Screening Policies. PMID- 30025672 TI - Predicting Enrollment in Multidisciplinary Clinical Care for Pediatric Weight Management. AB - OBJECTIVES: To characterize the children who were referred, determine the proportion of referred children who enrolled, and examine factors associated with enrollment in multidisciplinary clinical care for pediatric weight management. STUDY DESIGN: This cross-sectional study included the population of children (2 17 years of age; body mass index of >=85th percentile) referred to 1 of 3 hospital-based multidisciplinary weight management clinics in Alberta, Canada, from April 2013 to April 2016. Referral and enrollment data were obtained from Alberta Health Services databases. Bivariate and multivariable logistic regression models were used to determine the independent and combined effects of predictors of enrollment. RESULTS: Of the 2014 children (51.8% male; mean body mass index z-score: 3.42 +/- 0.03) referred to multidisciplinary clinical care, 757 (37.6%) enrolled in care. Most referred children had severe obesity and were referred by physicians. Several factors independently predicted enrollment; however, in our most parsimonious multivariable model, only the time gap (OR, 0.94; 95% CI, 0.88-0.99; P = .03) between the attendance date of the orientation session and the booking date of initial appointment predicted enrollment for all children. Body mass index z-score (OR, 0.81; 95% CI, 0.67-0.98; P = .03) and time gap (OR, 0.92; 95% CI, 0.85-0.99; P = .02) predicted enrollment in children with severe obesity exclusively. CONCLUSIONS: Fewer than 40% of referred children enrolled in multidisciplinary clinical care. Reducing the duration of enrollment and providing additional support for treatment initiation to children with severe obesity may enhance treatment uptake for pediatric weight management. PMID- 30025674 TI - Constipation Burden in Children with Autism Spectrum Disorder: Emergency Department and Healthcare Use. PMID- 30025675 TI - Paradoxical adaptation of successful movements: The crucial role of internal error signals. AB - Visuo-motor adaptation has been classically studied using movements aimed at visual targets with visual feedback. In this type of experimental design, the respective roles of the different error signals cannot be fully disentangled. Here, we show that visuo-motor adaptation occurs despite the terminal success of the action and the compensation of the external error by a jump of the visual target. By using three grasping task conditions we manipulated the retinal error signal between the seen hand and the target (external error) and the conflict between the hand's visual reafference and either the proprioceptive or the efference copy signal (internal error), in order to estimate their respective roles in prism adaptation. In all conditions, subjects were asked to rapidly grasp an object. In the classical 'Prism' condition the object was stationary, which provided both external and internal errors. In the 'Prism & Jump' condition, at movement onset the object was suddenly displaced (jump) toward its virtual image location (visually displaced by the prism) which also corresponded to the location where the movement was planned to and executed through prisms. This jump therefore cancelled the external error (between the seen target and the seen hand), whereas the internal error (between the seen hand and the expected visual reafference of the hand, or between the seen hand and the hand felt by proprioception) was unchanged (because it is independent of the presence of the goal). In the 'Jump' condition, the movement was planned and executed without prismatic goggles and consequently with no internal error (no difference between where the hand visual reafference is expected to be and where it actually is), but the object was suddenly displaced at movement onset by a displacement equivalent to a prism shift which provided an external error. The 'Prism' and 'Prism & Jump' conditions exhibited similar aftereffects, whereas no aftereffect was observed in the 'Jump' condition. These results suggest that successful actions can be subjected to adaptation and that internal error is the only signal necessary to elicit true visuomotor adaptation characterized by context independent generalization. PMID- 30025676 TI - Process evaluation of the midwifery initiated oral health-dental service program: Perceptions of midwives in Greater Western Sydney, Australia. AB - BACKGROUND: Despite links between poor maternal oral health, adverse pregnancy outcomes and early childhood decay there is limited emphasis on maternal oral health in Australia. To address this, the Midwifery Initiated Oral Health Dental Service (MIOH-DS) program was developed in collaboration with the Australian College of Midwives. AIMS: To undertake a process evaluation and explore perceptions of midwives involved in the MIOH-DS program to determine its practicability, acceptability and feasibility if it were to be up-scaled and implemented into clinical practice. METHODS: Qualitative content analysis was undertaken on data from three focus groups with 21 midwives. FINDINGS: Midwives generally found the MIOH-DS to be acceptable and feasible with potential for widespread scalability. The trust women had in midwives was an important factor in gaining women's attention about oral health in pregnancy. The program assisted in increasing midwives' knowledge and awareness, though some felt it was outside their scope of practice. The oral health assessment tool was acceptable to midwives but some concerns were expressed about undertaking a visual oral inspection. Most midwives stated they were now confident with referring individuals to a dentist. Significant barriers to widespread implementation included the cost of dental care and the continued lack of awareness and misconceptions pregnant women had towards oral health. CONCLUSION: Midwives found the MIOH-DS to be acceptable and feasible which are two important barriers to potential implementation at scale. Misconceptions over the importance of oral health by women and cost of accessing dental services still need resolving. PMID- 30025677 TI - Midwives' personal use of complementary and alternative medicine (CAM) influences their recommendations to women experiencing a post-date pregnancy. PMID- 30025678 TI - Prior antibiotic exposure and risk of type 2 diabetes among Veterans. AB - BACKGROUND: Exposure to antibiotics may increase the risk of type 2 diabetes. Veterans are at increased risk for diabetes and for exposure to antibiotics. OBJECTIVE: To determine the impact of antibiotic exposure for risk of diabetes. DESIGN: Retrospective cohort study. PARTICIPANTS: Veterans at the New York Harbor Healthcare System enrolled in primary care, 2004-2014, with >=2 glycosylated hemoglobin test results <6.5%. MAIN MEASURES: The primary exposure was any antimicrobial prescribed >6 months prior to the date of diabetes diagnosis, loss to follow-up, death, or the end of the study, measured as the number of courses of antimicrobial prescriptions filled and the mean daily dose (MDD). The primary outcome was incident diagnosis of diabetes through 2014, defined >=2 ICD-9 codes for diabetes or >=2 prescriptions of diabetes medications, other than metformin. Cox proportional hazards regression was used to model antimicrobial medications, demographic and anthropometric measures, and comorbid cardiovascular conditions to incident diabetes. Models incorporated time varying covariates of antimicrobial medication and MDD to analyze associations by antimicrobial class. KEY RESULTS: Among 14,361 Veterans, 9922 (69.1%) were prescribed any antimicrobial medication during the study period. 1413 (9.8%) individuals developed type 2 diabetes. Increased risk of diabetes was associated with >1 prescription (HR 1.13 [1.01-1.26]) compared to none. Time varying analysis of the total number of cumulative courses prescribed showed increased diabetes risk for cephalosporin (HR 1.17 [1.04-1.31]), macrolide (HR 1.08 [1.03-1.13]) and penicillin (HR 1.05 [1.02-1.07]). MDD showed increased risk per 100-unit (mg) increase in antibiotic exposure from (HR 1.05 [1.02-1.08]) for sulfonamide to (HR 1.70 [1.51-1.92]) for cephalosporin. CONCLUSION: Any and repeated exposure to certain antibiotics may increase diabetes risk among Veterans. Results from this study add to the growing evidence suggesting that antibiotic exposure increases risk for diabetes. Antibiotic stewardship may be enhanced by better understanding this risk, and may lower the incidence of diabetes in populations at risk. PMID- 30025679 TI - Corticosteroids in Adult Cardiac Surgery-Yet Another Paper. PMID- 30025680 TI - Treatment for HIV prevention, one couple at a time. PMID- 30025682 TI - Palliative care as an essential component of the HIV care continuum. AB - Although antiretroviral therapy has reduced mortality among people with HIV, inadequate treatment coverage, ageing, and the increasing incidence of organ failure and malignancies mean that high-quality care should include care at the end of life. This Review summarises the epidemiology of HIV in relation to mortality, and the symptoms and concerns of people with AIDS and those living with HIV who have either related or unrelated advanced comorbidities. In response to the evidence of a need for palliative care, the principles and practice of palliative care are described, and the evidence for its effectiveness and cost effectiveness is appraised. The core practices of palliative care offer a mechanism to enhance the person-centred nature of HIV care; I identify the gaps in this type of care, and present evidence for effective models of care to address these. I detail the policies that prompt governments and health systems to respond to the palliative care needs of their population. Finally, I conclude this Review with evidence-based recommendations to improve the delivery of, and access to, high-quality HIV care until the end of life, reducing unnecessary suffering while optimising person-centred outcomes. PMID- 30025681 TI - Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. AB - BACKGROUND: Evidence on viral load and HIV transmission risk in HIV serodiscordant male homosexual couples is limited to one published study. We calculated transmission rates in couples reporting condomless anal intercourse (CLAI), when HIV-positive partners were virally suppressed, and daily pre exposure prophylaxis (PrEP) was not used by HIV-negative partners. METHODS: In the Opposites Attract observational cohort study, serodiscordant male homosexual couples were recruited from 13 clinics in Australia, one in Brazil, and one in Thailand. At study visits, HIV-negative partners provided information on sexual behaviour and were tested for HIV and sexually transmitted infections; HIV positive partners had HIV viral load tests, CD4 cell count, and sexually transmitted infection tests done. Viral suppression was defined as less than 200 copies per mL. Linked within-couple HIV transmissions were identified with phylogenetic analysis. Incidence was calculated per couple-year of follow-up, focusing on periods with CLAI, no use of daily PrEP, and viral suppression. One sided upper 95% CI limits for HIV transmission rates were calculated with exact Poisson methods. FINDINGS: From May 8, 2012, to March 31, 2016, in Australia, and May 7, 2014, to March 31, 2016, in Brazil and Thailand, 358 couples were enrolled. 343 couples had at least one follow-up visit and were followed up for 588.4 couple-years. 258 (75%) of 343 HIV-positive partners had viral loads consistently less than 200 copies per mL and 115 (34%) of 343 HIV-negative partners used daily PrEP during follow-up. 253 (74%) of 343 couples reported within-couple CLAI during follow-up, with a total of 16 800 CLAI acts. Three new HIV infections occurred but none were phylogenetically linked. There were 232.2 couple-years of follow-up and 12 447 CLAI acts in periods when CLAI was reported, HIV-positive partners were virally suppressed, and HIV-negative partners did not use daily PrEP, resulting in an upper CI limit of 1.59 per 100 couple-years of follow-up for transmission rate. INTERPRETATION: HIV treatment as prevention is effective in men who have sex with men. Increasing HIV testing and linking to immediate treatment is an important strategy in HIV prevention in homosexual men. FUNDING: National Health and Medical Research Council; amfAR, The Foundation for AIDS Research; ViiV Healthcare; and Gilead Sciences. PMID- 30025683 TI - Management of Arrhythmias and Cardiac Implantable Electronic Devices in Patients With Left Ventricular Assist Devices. AB - For patients with end-stage heart failure, the use of mechanical circulatory support has increased in the last decade due to improved outcomes with durable left ventricular assist devices. The management of these complex patients requires coordinated care by a multidisciplinary team including cardiac electrophysiologists because atrial and ventricular arrhythmias are prevalent in this population. There have been an increasing number of studies that attempt to address issues regarding arrhythmia management in patients with left ventricular assist devices. The purpose of this review is to provide electrophysiologists with an evidence-based approach to manage a broad spectrum of arrhythmia issues in these patients. PMID- 30025684 TI - Guidance for Optimal Site Selection of a Leadless Left Ventricular Endocardial Electrode Improves Acute Hemodynamic Response and Chronic Remodeling. AB - OBJECTIVES: This study hypothesized that guided implants, in which the optimal left ventricular endocardial (LVENDO) pacing location was identified and targeted, would improve acute markers of contractility and chronic markers of cardiac resynchronization (CRT) response. BACKGROUND: Biventricular endocardial (BiVENDO) pacing may offer a potential benefit over standard CRT; however, the optimal LVENDO pacing site is highly variable. Indiscriminately delivered BiVENDO pacing is associated with a reverse remodeling response rate of between 40% and 60%. METHODS: Registry of centers implanting a wireless, LVENDO pacing system (WiSE-CRT System, EBR Systems, Sunnyvale, California); John Radcliffe Hospital (Oxford, United Kingdom), Guy's and St. Thomas' Hospital (London, United Kingdom), and The James Cook University Hospital (Middlesbrough, United Kingdom). Centers used a combination of preprocedural imaging and electroanatomical mapping the identify the optimal LVENDO site. RESULTS: A total of 26 patients across the 3 centers underwent a guided implant. Patients were predominantly male with a mean age of 68.8 +/- 8.4 years, the mean LV ejection fraction was 34.2 +/- 7.8%. The mean QRS duration was 163.8 +/- 26.7 ms, and 30.8% of patients had an ischemic etiology. It proved technically feasible to selectively target and deploy the pacing electrode in a chosen endocardial segment in almost all cases, with a similar complication rate to that observed during indiscriminate BiVENDO. Ninety percent of patients met the definition of echocardiographic responder. Reverse remodeling was observed in 71%. CONCLUSIONS: Guided endocardial implants were associated with a higher degree of chronic LV remodeling compared with historical nonguided approaches. PMID- 30025685 TI - Left Ventricular Endocardial Cardiac Resynchronization Therapy Is Here, But Where Should We Place the Lead? PMID- 30025686 TI - Use of Programmed Ventricular Extrastimulus During Supraventricular Tachycardia to Differentiate Atrioventricular Nodal Re-Entrant Tachycardia From Atrioventricular Re-Entrant Tachycardia. AB - OBJECTIVES: This study hypothesized that early coupled ventricular extrastimuli (V2) stimulation might yield a more robust differentiation between atrioventricular nodal re-entrant tachycardia (AVNRT) and atrioventricular re entrant tachycardia (AVRT). BACKGROUND: Programmed V2 during supraventricular tachycardia are useful to differentiate AVNRT from AVRT by subtracting the ventriculoatrial (VA) interval from the stimulus to atrial depolarization (stimulus atrial [SA]) interval, but all such maneuvers have limitations. METHODS: Patients with either AVNRT or AVRT were investigated. The entire tachycardia cycle length (TCL) was scanned with V2 delivered from the right ventricular apex. The SA-VA difference was calculated with V2 clearly resetting the tachycardia. The prematurity of V2 was calculated by dividing the coupling interval (CI) by the TCL. RESULTS: A total of 210 patients (102 with AVNRT) were included. The SA-VA difference was >70 ms in all AVNRT patients and was <70 ms in all AVRT patients with right and septal accessory pathways (APs), except for those with decremental APs, in whom there was an overlap between AVNRT and AVRT with left APs. However, a SA-VA difference >110 ms with a CI/TCL of <65% distinguished AVNRT from AVRT using the left AP, with sensitivity and specificity of 87% and 100%, respectively. Ventricular overdrive pacing resulted in tachycardia termination or AV dissociation in 28% of patients compared with 15% of patients using the V2 technique (p = 0.008). CONCLUSIONS: A SA-VA of >70 ms using the V2 technique differentiated AVNRT from AVRT using septal and right APs. Use of the V2 technique with a short CI differentiated AVNRT from AVRT using left APs. The V2 technique less frequently resulted in tachycardia termination compared with ventricular entrainment. PMID- 30025688 TI - One Size Doesn't Fit All: A Closer Look at the Effects of Multipoint Pacing in Cardiac Resynchronization Therapy. PMID- 30025687 TI - Pressure-Volume Loop Analysis of Multipoint Pacing With a Quadripolar Left Ventricular Lead in Cardiac Resynchronization Therapy. AB - OBJECTIVES: This study aimed to compare multipoint pacing (MPP) to optimal biventricular pacing with a quadripolar left ventricular (LV) lead and find factors associated with hemodynamic response to MPP. BACKGROUND: MPP with a quadripolar LV lead may increase response to cardiac resynchronization therapy. METHODS: Heart failure patients with a left bundle branch block underwent cardiac resynchronization therapy implantation. Q to LV sensing interval divided by the intrinsic QRS duration was measured. Invasive pressure-volume loops were assessed during 4 biventricular pacing settings and 3 MPP settings, using 4 atrioventricular delays. Hemodynamic response was defined as change in stroke work (Delta%SW) compared with baseline measurements during intrinsic conduction. Delta%SW of MPP was compared with conventional biventricular pacing using the distal electrode and the electrode with highest Delta%SW (BIV-OPT). RESULTS: Forty-three patients were analyzed (age 66 +/- 10 years, 63% men, 30% ischemic cardiomyopathy, LV ejection fraction 29 +/- 8%, and QRS duration 175 +/- 13 ms). Q to local LV sensing interval corrected for QRS duration was 84 +/- 8%, and variation between LV electrodes was 9 +/- 5%. Compared with conventional biventricular pacing using the distal electrode, MPP showed a significant higher increase of SW (Delta%SW +15 +/- 35%; p < 0.05) with a large interindividual variation. There was no significant difference in Delta%SW with MPP compared with BIV-OPT (-5 +/- 24%; p = 0.19). Male sex and low LV ejection fraction were associated with increase in Delta%SW due to MPP versus BIV-OPT in multivariate analysis, while ischemic cardiomyopathy was only associated in univariate analysis. CONCLUSIONS: Optimization of the pacing site of a quadripolar LV lead is more important than to program MPP. However, specific subgroups (i.e., especially men) may benefit substantially from MPP. PMID- 30025690 TI - Longer Duration Versus Increasing Power During Radiofrequency Ablation Yields Different Ablation Lesion Characteristics. AB - OBJECTIVES: The goal of this study was to characterize differences in ablation lesions with varying radiofrequency ablation (RFA) power and time. BACKGROUND: Increasing power delivery or prolonging duration can improve the efficacy of RFA. However, the extent to which ablation lesion characteristics change, based on varying degrees of power and duration, is unknown. METHODS: An ex vivo model consisting of viable bovine myocardium in a circulating warmed saline bath was used. An open irrigated RFA catheter was positioned with 10 g of force in the perpendicular position, and RFA was delivered at powers of 20, 30, 40, and 50 W and for various time intervals, up to a total of 90 s, at each power. An in vivo porcine thigh preparation model was used to perform RFA at 50 W for 5 s and 20 W for 30 s. Lesion volumes were analyzed. RESULTS: Greater power delivery and longer radiofrequency time increased ablation lesion size. However, compared with a proportional change in radiofrequency duration, the same proportional increase in power produced a significantly larger lesion volume (p < 0.01). For in vivo models, 50 W/5 s ablation lesions yielded similar volumes but significantly less depth than 20 W/30 s ablation lesions. Peak temperatures were not significantly different at 2 and 4 mm with 50 W/5 s versus 20 W/30 s. CONCLUSIONS: Varying power and duration will confer different ablation lesion characteristics that can be tailored according to the substrate/anatomy that is being ablated. This phenomenon has important implications during catheter ablation. PMID- 30025691 TI - Slow and Steady Doesn't Always Win the Race. PMID- 30025689 TI - Thoracoscopic Left Atrial Appendage Clipping: A Multicenter Cohort Analysis. AB - OBJECTIVES: This study sought to document the closure rate, safety, and stroke rate after thoracoscopic left atrial appendage (LAA) clipping. BACKGROUND: The LAA is the main source of stroke in patients with atrial fibrillation, and thoracoscopic clipping may provide a durable and safe closure technique. METHODS: The investigators studied consecutive patients undergoing clipping as part of a thoracoscopic maze procedure in 4 referral centers (the Netherlands and the United States) from 2012 to 2016. Completeness of LAA closure was assessed by either computed tomography (n = 100) or transesophageal echocardiography (n = 122). The primary outcome was complete LAA closure (absence of residual LAA flow and pouch <10 mm). The secondary outcomes were 30-day complications; the composite of ischemic stroke, hemorrhagic stroke, or transient ischemic attack; and all-cause mortality. RESULTS: A total of 222 patients were included, with a mean age of 66 +/- 9 years, and 68.5% were male. The mean CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65 to 74 years, sex category [female]) score was 2.3 +/- 1.0. Complete LAA closure was achieved in 95.0% of patients. There were no intraoperative or clip-related complications, and the overall 30-day freedom from any complication rate was 96.4%. The freedom from cerebrovascular events after surgery was 99.1% after median follow-up of 20 months (interquartile range: 14 to 25 months; 369 patient years of follow-up), and overall survival was 98.6%. The observed rate of cerebrovascular events after LAA clipping was low (0.5 per 100 patient-years). CONCLUSIONS: LAA clipping during thoracoscopic ablation is a feasible and safe technique for closure of the LAA in patients with atrial fibrillation. The lower than expected rate of cerebrovascular events after deployment was likely multifactorial, including not only LAA closure, but also the effect of oral anticoagulation and rhythm control. PMID- 30025692 TI - Prognostic Value of Noninducibility on Outcomes of Ventricular Tachycardia Ablation: A VANISH Substudy. AB - OBJECTIVES: This study sought to evaluate the predictive value of noninducibility on long-term outcomes. BACKGROUND: The traditional endpoint for catheter ablation of ventricular tachycardia (VT) is noninducibility of VT by programmed stimulation; however, the definition of inducibility remains variable and its prognostic value limited by nonstandardized periprocedural antiarrhythmic drug therapy and implantable cardioverter-defibrillator programming in prior observational studies. The VANISH trial randomized patients with prior myocardial infarction and VT to ablation (with an endpoint of noninducibility of VT >=300 ms after ablation) versus antiarrhythmic drug escalation. METHODS: Patients enrolled in the VANISH study randomized to catheter ablation were included. The relationship between post-ablation inducibility and the primary composite endpoint (death, VT storm >30 days, or appropriate implantable cardioverter defibrillator shock >30 days) was assessed using a time-to-event analysis, adjusting for other clinical and procedural characteristics. RESULTS: A total of 129 patients from the ablation arm were included in the primary analysis, of which 51 were noninducible post-ablation compared with 78 who had inducible VT or in whom inducibility testing was not performed. There were no significant baseline characteristic or procedural differences except for increased implantable cardioverter-defibrillator shocks before randomization in the noninducible group. In multivariate analysis, inducibility significantly increased the risk of death, appropriate shock, or VT storm after 30 days (HR: 1.87; p = 0.017). CONCLUSIONS: Inducibility of any VT post-ablation was associated with an increased risk of the composite endpoint in the VANISH trial. A randomized trial is required to confirm whether more aggressive ablation targeting faster induced VTs (<300 ms) can improve outcomes. PMID- 30025693 TI - Novel Electrocardiographic Criteria for Real-Time Assessment of Anterior Mitral Line Block: "V1 Jump" and "V1 Delay". AB - OBJECTIVES: This study hypothesized that P-wave morphology and timing under left atrial appendage (LAA) pacing change characteristically immediately upon anterior mitral line (AML) block. BACKGROUND: Perimitral flutter commonly occurs following ablation of atrial fibrillation and can be cured by an AML. However, confirmation of bidirectional block can be challenging, especially in severely fibrotic atria. METHODS: The study analyzed 129 consecutive patients (66 +/- 8 years, 64% men) who developed perimitral flutter after atrial fibrillation ablation. We designed electrocardiography criteria in a retrospective cohort (n = 76) and analyzed them in a validation cohort (n = 53). RESULTS: Bidirectional AML block was achieved in 110 (85%) patients. For ablation performed during LAA pacing without flutter (n = 52), we found a characteristic immediate V1 jump (increase in LAA stimulus to P wave peak interval in lead V1) as a real-time marker of AML block (V1 jump >=30 ms: sensitivity 95%, specificity 100%, positive predictive value 100%, negative predictive value 88%). As V1 jump is not applicable when block coincides with termination of flutter, absolute V1 delay was used as a criterion applicable in all cases (n = 129) with a delay of 203 ms indicating successful block (sensitivity 92%, specificity 84%, positive predictive value 90%, negative predictive value 87%). Furthermore, an initial negative P-wave portion in the inferior leads was observed, which was attenuated in case of additional cavotricuspid isthmus ablation. Computational P-wave simulations provide mechanistic confirmation of these findings for diverse ablation scenarios (pulmonary vein isolation +/- AML +/- roof line +/- cavotricuspid isthmus ablation). CONCLUSIONS: V1 jump and V1 delay are novel real-time electrocardiography criteria allowing fast and straightforward assessment of AML block during ablation for perimitral flutter. PMID- 30025694 TI - Mitral Isthmus Ablation for Atrial Fibrillation: How and When, If Ever? PMID- 30025695 TI - Value of Regular Defibrillation Threshold Testing After Extracardiac Implantable Cardioverter Defibrillator Placement in Small Children During Mid-Term Follow-Up. AB - OBJECTIVES: The purpose of this study was to analyze course of defibrillation threshold (DFT) with growth. BACKGROUND: Data on regular DFT testing after extracardiac implantable cardioverter-defibrillator (ICD) placement in infants and small children is still limited. METHODS: An extracardiac ICD was placed in 23 pediatric patients (median age 6.1 years; median body weight 21 kg, median length 120 cm). The defibrillator lead was tunneled pleurally, and the device was placed as "active can" in the right upper abdomen or in a horizontal position between the diaphragm and the pericardium, respectively. DFT was verified intraoperatively, 3 months later, and every 12 months thereafter. The aim was to achieve DFT <15 J allowing ICD programming with a double safety margin above DFT. RESULTS: In all 23 patients, an intraoperative DFT <15 J could be accomplished. Serial DFT testing showed an increase from a median DFT of 10 J intraoperatively to 15 J after 1 year. During mean follow-up of 2.0 years, a significant correlation between DFT and body length, but not body weight, was observed. In 4 of 23 (17%) patients, surgical revision was required because of a DFT increase >20 J during regular DFT testing. No complications regarding DFT testing were noted. CONCLUSIONS: After extracardiac ICD placement in infants and small children, DFT increase related to body length was evident during mid-term follow up. Routine serial DFT testing was a safe procedure and identified a significant DFT increase in 4 of 23 patients. Serial DFT testing during follow-up in these patients is recommended. PMID- 30025697 TI - Clinical Trials in Atrial Fibrillation: Lessons From the Box Score. PMID- 30025696 TI - The Current Landscape of Atrial Fibrillation and Atrial Flutter Clinical Trials: A Report of 348 Studies Registered With ClinicalTrials.gov. AB - OBJECTIVES: This analysis sought to systematically characterize trial-level patterns in atrial fibrillation/atrial flutter (AF/AFL) by using the ClinicalTrials.gov database. BACKGROUND: Despite an abundance of clinical trials in this field, there is a lack of high-level evidence guiding management of AF/AFL. METHODS: We queried all closed, phase II to IV interventional trials registered in the ClinicalTrials.gov database through October 2016 that enrolled patients known to have AF/AFL. Published trials were evaluated for methodological quality, using the 3-item Jadad scale (range: 0 to 5, where 5 = highest quality). RESULTS: The initial search yielded 465 uniquely registered studies, of which 348 directly studied AF/AFL. Of those studies, 173 (50%) were published, enrolling a median of 190 patients from a median of 15 sites. The volume of published trials increased over time (7% prior to 2008 vs. 41% from 2014 to 2016; p < 0.001 for trend). Of the completed trials, 29% remain unpublished. Industry sources accounted for most funding (54%). Recurrence of AF/AFL was the most common endpoint (45%), whereas rates of primary clinical endpoints were low (13%). The mean Jadad score of published trials of pharmacological approaches (n = 112) was 4.0 +/- 1.4. Of the 61 AF/AFL trials involving ablation or device therapies, 69% were randomized, 28% were single-arm studies, and patient, proceduralist, and event-ascertainment blinding was used in 16%, 4%, and 44%, respectively. CONCLUSIONS: Contemporary trials of AF/AFL are often multicenter and modest in size. The primary study endpoint is commonly recurrence of arrhythmia, even in high-quality and late-phase trials. Although methodological quality is high in trials of pharmacologic approaches, trials of AF/AFL ablation and device therapies variably employ randomization and blinding. PMID- 30025699 TI - Management of Peridevice Leak Following Left Atrial Appendage Occlusion. PMID- 30025698 TI - Effect of Charge Delivery on Thromboembolism During Radiofrequency Ablation in Canines. AB - OBJECTIVES: This study investigated whether delivering negative charge to catheter tips reduces thromboembolism during catheter ablation. BACKGROUND: Radiofrequency (RF) ablation prevents atrial fibrillation that can cause stroke or death. However, ablation itself can cause stroke (2%) or silent ischemia (2% to 41%), possibly via particulate debris that embolizes after coagulum adherence to catheter surfaces. Coagulum formation on RF catheters can be prevented by applying negative charge, but it is unknown if charge reduces peripheral thromboembolism. METHODS: Paired (Charge ON vs. OFF) endocardial RF ablations were performed in 9 canines using nonirrigated RF catheters. Continuous negative charge was delivered via -100 MUA of DC current applied to ablation catheter electrodes. Intracardiac echocardiography was used to navigate the catheter and to monitor coagulum formation. In a subset of 5 canines, microemboli flowing through polyester tubing between the femoral artery and vein (extracorporeal loop) were monitored with bubble counters and inline filter fabric. After each ablation, catheter-tip coagulum and blood particles deposited on the filters were quantified using photography and imaging software (ImageJ, U.S. National Institutes of Health, Bethesda, Maryland). RESULTS: Negative charge significantly decreased the extracorporeal loop median filter area covered by particles (n = 19 pairs) by 10.2 mm2 (p = 0.03), and decreased median filter particles by 349 (p = 0.03). Negative charge also decreased the percentage of the catheter tip surface area covered by coagulum (n = 39 pairs) by 7.2% (p = 0.03). CONCLUSIONS: Negative charge delivery to ablation catheter tips during RF ablation can reduce particulate embolization material in an extracorporeal loop, and potentially reduce thromboembolic risk associated with RF ablation. PMID- 30025701 TI - Association of Body Mass Index With Intracardiac Left Atrial Voltage in Patients With Atrial Fibrillation. PMID- 30025700 TI - A Case With Pulmonary Vein Stenosis and Obstruction After Pulmonary Vein Isolation: A Multimodality Approach. PMID- 30025702 TI - End-Stage Renal Disease and Arrhythmic Death. PMID- 30025703 TI - Reply: End-Stage Renal Disease and Arrhythmic Death. PMID- 30025704 TI - Inhibiting Growth of Clostridioides difficile by Restoring Valerate, Produced by the Intestinal Microbiota. AB - BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is effective for treating recurrent Clostridioides difficile infection (CDI), but there are concerns about its long-term safety. Understanding the mechanisms of the effects of FMT could help us design safer, targeted therapies. We aimed to identify microbial metabolites that are important for C difficile growth. METHODS: We used a CDI chemostat model as a tool to study the effects of FMT in vitro. The following analyses were performed: C difficile plate counts, 16S rRNA gene sequencing, proton nuclear magnetic resonance spectroscopy, and ultra-performance liquid chromatography and mass spectrometry bile acid profiling. FMT mixtures were prepared using fresh fecal samples provided by donors enrolled in an FMT program in the United Kingdom. Results from chemostat experiments were validated using human stool samples, C difficile batch cultures, and C57BL/6 mice with CDI. Human stool samples were collected from 16 patients with recurrent CDI and healthy donors (n = 5) participating in an FMT trial in Canada. RESULTS: In the CDI chemostat model, clindamycin decreased valerate and deoxycholic acid concentrations and increased C difficile total viable counts and valerate precursors, taurocholic acid, and succinate concentrations. After we stopped adding clindamycin, levels of bile acids and succinate recovered, whereas levels of valerate and valerate precursors did not. In the CDI chemostat model, FMT increased valerate concentrations and decreased C difficile total viable counts (94% decrease), spore counts (86% decrease), and valerate precursor concentrations; concentrations of bile acids were unchanged. In stool samples from patients with CDI, valerate was depleted before FMT but restored after FMT. Clostridioides difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid was required for germination but had no effect on vegetative growth. Clostridioides difficile total viable counts were decreased by 95% in mice with CDI given glycerol trivalerate compared with phosphate buffered saline. CONCLUSIONS: We identified valerate as a metabolite that is depleted with clindamycin and only recovered with FMT. Valerate is a target for a rationally designed recurrent CDI therapy. PMID- 30025705 TI - New Onset Villous Atrophy in a Patient With Celiac Disease. PMID- 30025706 TI - Long-term follow-up in adults with coeliac disease: Predictors and effect on health outcomes. AB - INTRODUCTION: Guidelines recommend regular follow-up in coeliac disease, but effect of this on long-term outcomes remains unclear. AIMS: To evaluate predictors and significance of long-term follow-up. METHODS: 677 previously diagnosed coeliac patients were recruited for a nationwide health survey. Medical data were gathered through interviews and patient records. Current symptoms and quality of life were assessed by validated questionnaires and blood samples were drawn for serology. All variables were compared between patients with and without long-term (>2 years) follow-up. RESULTS: 15% had long-term follow-up, median duration 10 years. Predictors (p < 0.05) for the follow-up were immunological (35% vs. 24%) and circulatory (20% vs. 12%) comorbidities, whereas it was less common in subjects with musculoskeletal (23% vs. 34%) comorbidity and those not belonging to any at-risk group (16% vs. 27%). Patients with or without follow-up had comparable age, adherence and ability to manage a gluten-free diet and frequency of seropositivity. Also questionnaire scores paralleled, but those without follow-up reported more overall symptoms (16% vs. 26%). Most patients wished for follow-up. CONCLUSION: Only a minority of patients had regular follow up. However, patients with and without the follow-up were comparable in most long term outcomes, indicating that it might not be always necessary. The results call for more personalized follow-up policies in coeliac disease. PMID- 30025707 TI - The Added Value of Qualitative Methodologies for Studying Emotional Disclosure About Pain. PMID- 30025708 TI - A hypothetical new role for single-stranded DNA binding proteins in the immune system. AB - The breadth of the host range of single-stranded DNA (ssDNA) viruses is roughly comparable to the host range of double-stranded DNA viruses (dsDNA). Yet, general ssDNA sensing receptors that activate the immune system have not been unequivocally identified while numerous dsDNA sensing receptors are known. Here, we hypothesize that some of the Single-Stranded DNA Binding (SSB) proteins may act as receptors that detect single-stranded DNA from pathogens and activate the innate immune system. As the first test of our hypothesis, we checked whether human genes that are known to bind to ssDNA are potentially interferon-regulated. Out of the 102 human genes that are known to have ssDNA binding ability 23 genes show a more than two-fold increase in gene expression upon interferon treatment. Single-stranded DNA viruses are pathogens of not only animals but also of plants and protozoans. We used this information to further prioritize our candidate list to ssDNA binding genes that are common between the model plant Arabidopsis thaliana and humans. Based on these strategies, we shortlist several promising candidate genes including the HMGB1 gene which could act as a ssDNA sensor that activates the immune system. Agreeably though we cannot establish a definitive role for these genes as ssDNA sensors of the immune system as yet, our preliminary analysis suggests the potential existence of ssDNA binding protein like receptors (SLR's) that are worth investigating further. PMID- 30025709 TI - Procyanidin B2 protects rats from paraquat-induced acute lung injury by inhibiting NLRP3 inflammasome activation. AB - Paraquat is a commonly used heterocyclic herbicide and has high toxicity by causing acute lung injury. There is no effective treatment for paraquat poisoning. We evaluated the effects of procyanidin B2, a natural dietary phytochemical, on paraquat-induced lung injury in rats. Paraquat was used to induce acute lung injury of rats, which were administered with procyanidin B2. The lung injury was evaluated by measuring the lung/body weight ratio, the histology and PMNs count. The oxidative stress was assessed by detecting ROS mediated indices in the BALF. The expression of IL-1beta and IL-18 were detected by RT-PCR and ELISA. The levels of NLRP3 inflammasome components including NLRP3, ASC and caspase-1 were detected by western blot. The lung injury in the paraquat induced models in NLRP3 gene silenced animals was compared with the same lung injury model treated with procyanidin B2. Administration of procyanidin B2 significantly reduced paraquat-induced lung injury with lower BALF PMNs count, MPO activity, MDA level and elevated SOD activity. Procyanidin B2 suppressed expression of IL-1beta and IL-18 at both RNA and protein levels, similar to the NLRP3 gene silenced rats. Compared to paraquat-induced group, procyanidin B2 showed remarkably decreased NLRP3, ASC and caspase-1 signals in the lung tissues in a dose-dependent manner. Procyanidin B2 significantly suppressed the activation of NLRP3 inflammasome in the lung tissue induced by paraquat in the rat model. This finding revealed a novel mechanism by which procyanidin B2 exerts anti-inflammatory effects and their clinical benefits in health. PMID- 30025710 TI - Immunoglobulin heavy chain variable region analysis in dairy goats. AB - Based on the goat genome database, we have annotated the genomic organization of the goat immunoglobulin heavy chain variable region. The goat IgH locus is present on seven genome scaffolds, and contains ten VH, three DH and six JH segments. After the exclusion of three shorter segments, the VH genes were divided into two gene families based on sequence similarity. By analyzing the IgH cDNA sequences, we further identified that VH2 (54.2%), DH1 (61.7%) and JH1 (60.5%) segments were most frequently utilized in the expression of the immunoglobulin variable region, and that point mutations introduced by somatic hypermutation were the major mutation present in these expressed variable region. Compared with human and horses, DH-DH fusion occurred at a higher frequency in goat V(D)J recombination. These results provided variable insights into goat immunoglobulin heavy chain variable region genome loci and repertoire diversity. PMID- 30025712 TI - The Benefit of an Enhanced Recovery Program for Living Kidney Donors. AB - In our efforts to continue to evolve the care of living kidney donors, the application of enhanced recovery after surgery guidelines appears to offer expedited recovery and decrease the incidence of readmission. PMID- 30025711 TI - Genomic Characterization of Testicular Germ Cell Tumors Relapsing After Chemotherapy. AB - BACKGROUND: Although both seminomatous and nonseminomatous testicular germ cell tumors (TGCTs) have favorable outcomes with chemotherapy, a subset is chemorefractory, and novel therapeutic options are needed. OBJECTIVE: To molecularly characterize chemotherapy-refractory TGCTs. DESIGN, SETTING, AND PARTICIPANTS: Archival tissues from 107 chemotherapy-treated and relapsed TGCT patients (23 seminomas; 84 nonseminomas) underwent hybrid-capture-based genomic profiling to evaluate four classes of genomic alterations (GAs). Tumor mutational burden (TMB) and microsatellite instability (MSI) were also measured. INTERVENTION: Genomic profiling on tumor samples from chemotherapy-refractory TGCTs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive analyses and differences between seminoma and nonseminoma subgroups were reported. RESULTS AND LIMITATIONS: The mean GA/tumor was 2.9 for seminomas and 4.0 for nonseminomas (p=0.04). KRAS alterations (mainly amplifications) were the most common GAs at the single-gene level (47.8% of seminomas and 51.2% of nonseminomas). RAS-RAF pathway (56.5% vs 52.3%) and cell-cycle pathway (52.2% vs 56.0%) were the most common GA classes in seminomas and nonseminomas, respectively. Receptor tyrosine kinase pathway and PI3K pathway GAs were more frequent in seminomas (p=0.02). Median TMB was 1.8 mutations/Mb for seminomas and 2.7 mutations/Mb for nonseminomas (p=0.098), and MSI-high status was found in one nonseminoma only (1.2%). A lack of clinical outcome correlation is a limitation of the present analyses. CONCLUSIONS: In chemotherapy-refractory TGCTs, trials with agents targeting the KRAS pathway may be pursued due to the high frequency of KRAS GAs. Overall, the GAs found in refractory seminomas and nonseminomas differ significantly. Considering the frequency of high TMB or MSI-high status, immunotherapy may benefit a small subset of nonseminomas. PATIENT SUMMARY: Testicular cancers that are resistant to or relapse after standard chemotherapy may harbor genomic alterations that are potentially druggable, particularly in the clinical trial setting, and genomic profiling can guide clinical research and disclose therapeutic opportunities for these patients. PMID- 30025713 TI - A Phase 2 Randomized Trial To Evaluate Different Dose Regimens of Low-intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction: Clinical Trial Update. AB - Preliminary results from our study provide further evidence that low-intensity extracorporeal shockwave therapy is a safe and effective treatment modality for erectile dysfunction. Our treatment protocol with shockwaves given to men over 2 wk had the most robust effect. PMID- 30025714 TI - Minimal change in physical activity after lower limb joint arthroplasty, but the outcome measure may be contributing to the problem: a systematic review and meta analysis. AB - BACKGROUND: The literature pertaining to changes in physical activity (PA) in people who have undergone lower limb arthroplasty is controversial, but it is unknown whether this is due to participant characteristics or how physical activity is measured. OBJECTIVES: To determine whether PA changes after total knee or hip arthroplasty and what explains contradictory results between different published studies. DATA SOURCES: Five online databases were searched for keywords and MeSH headings. Reference lists were also hand-searched. STUDY SELECTION: Cohort studies and the control groups of clinical trials that examined PA levels prior to total arthroplasty as well as 6- and/or 12-month post operative included. PA could be measured using accelerometery, pedometery or patient reported outcomes. DATA EXTRACTION: PA outcomes were categorised into frequency, intensity, duration and type. Meta-analysis was performed when possible. RESULTS: Eleven studies, examining 277 individuals with THA and 406 people with TKA were included. Studies differed in the outcome measure reported, device used and placement of accelerometers. When measured as steps per day, pooled data revealed a small increase in the frequency of PA at 12 months post TKA (SMD 0.44 [0.2, 0.67] I2=0%) and moderate increase in individuals post-THA (SMD 0.65 [0.32, 0.97] I2=0%). Pooled evidence indicated no change in PA duration when measured as time spent active (SMD 0.05 [-0.42, 0.52] I2=46%) or proportion of time spent active (SMD 0.5 [-0.17, 1.16] I2=75%) 6-months post-TKA. Data examining PA duration, intensity and type at 12-months could not be pooled. CONCLUSION: The true nature of changes in PA post-surgery remains largely unclear. While frequency of PA may increase, the balance of evidence indicates that PA does not substantially increase post total joint arthroplasty. Improvements in the consistency of device type, placement and outcome measure would substantially assist in improving knowledge in this area. TRIAL REGISTRATION: CRD42015029686. PMID- 30025715 TI - Development of ProFibro - a mobile application to promote self-care in patients with fibromyalgia. AB - Fibromyalgia is a rheumatic syndrome characterised by chronic widespread pain, often associated with fatigue, unrefreshed sleep and cognitive problems. Effective management of fibromyalgia requires a proactive approach in which the patient takes responsibility for self-care. The purpose of this research was to develop an application (app) for promoting self-care as a complementary Mobile Health resource to physical therapy in the management of fibromyalgia. The app was developed in five stages, according to the prototyping paradigm. In Stage 1, an expert panel of five physical therapists, five patients with fibromyalgia, a digital interface designer and a programmer analysed the requirements and content, and set the software objectives. In Stage 2, the designer created the screen layouts. In Stage 3, the programmer developed the prototype for the Android operating system (Google Inc., Mountain View, CA, USA). In Stage 4, the prototype was pilot tested regarding its quality of use by 10 patients with fibromyalgia. Finally, in Stage 5, the designer improved the interface and the programmer built the final product. This article describes the development of ProFibro, the first free mobile app in Brazilian Portuguese for fibromyalgia. Its functions are patient education through animation, self-monitoring, sleep strategies, scheduling, graded exercise programme, practice of gratitude, family adjustments and hints through notifications. PMID- 30025716 TI - Impact of pain in overweight to morbidly obese women: preliminary findings of a cross-sectional study. AB - OBJECTIVES: To evaluate the effect of body mass index (BMI) on the prevalence, intensity and interference of pain in women, and how it affects quality of life and level of physical activity; and to determine independent predictors of pain intensity. DESIGN: Cross-sectional observational study. SETTINGS: Obesity treatment clinic, community and university laboratory. PARTICIPANTS: Seventy three of 133 women aged 25-75 years reported the presence of pain for at least 2 weeks and were categorised according to BMI (normal weight, overweight, obese or morbidly obese). MAIN OUTCOME MEASURES: BMI and questionnaires [McGill Pain Questionnaire (MPQ), Brief Pain Inventory (BPI), Short-Form Health Survey-36 (SF 36) and Baecke Physical Activity Questionnaire]. RESULTS: Pain intensity was 3 and 4.5 times higher in the MPQ and BPI, respectively, in morbidly obese women compared with women of normal weight. Morbidly obese women had 10.7 times higher pain interference and lower scores on the SF-36 domains of physical function and role function-physical compared with women of normal weight. Obese and morbidly obese women had less pain relief from treatment. Regression analysis showed that high BMI and low level of physical activity contributed to the intensity of pain, and these variables explained 16% of the variance of pain intensity. CONCLUSIONS: This study found that the prevalence and intensity of pain are greater in morbidly obese women than women of normal weight, and pain is negatively associated with physical activity. The causal inter-relationships between pain, obesity and physical activity are complex and require further study. PMID- 30025717 TI - Effects of ovarian fluid, venom and egg surface characteristics of Tetrastichus brontispae (Hymenoptera: Eulophidae) on the immune response of Octodonta nipae (Coleoptera: Chrysomelidae). AB - Although the importance of parasitoids as biocontrol agents has long been recognized, systematic studies of the physiological mechanisms are scarce, especially in those parasitoids that are able to successfully invade their hosts by activating host immune responses. This study explored this phenomenon by investigating the effects of ovarian fluid, venom and egg surface characteristics of Tetrastichus brontispae (Hymenoptera: Eulophidae) on host immunity. The results showed that the injection of venom alone induced higher phenoloxidase activity, while a mixture of ovarian plus venom fluids provoked higher granulocyte and plasmatocyte spreading ratios, highlighting the role that egg surface characteristics may play in successful parasitism. After thorough investigation, the presence of a hemomucin homologue was documented on the egg surface (which was named Tetrastichus brontispae adipocyte plasma membrane associated protein-like, TbAPMAP-like), while the absence of polydnaviruses, fibrous layers and virus-like filaments was confirmed. The higher encapsulation index of eggs incubated with TbAPMAP-like polyclonal antibody demonstrated the protection of the protein against encapsulation. These results contribute to our understanding of the mechanisms used by endoparasitoids to evade encapsulation during the early parasitism stage while enriching our knowledge of local active regulatory mechanisms. It is likely that this is the first study to determine the egg protective properties of TbAPMAP-like in host-parasite systems. PMID- 30025718 TI - Acth-induced model of depression resistant to tricyclic antidepressants: Neuroendocrine and behavioral changes and influence of long-term magnesium administration. AB - Magnesium (Mg), is not only a modulator of the glutamatergic NMDA receptors' affinity, it also prevents HPA axis hyperactivity, thus possibly being implicated in neurobiological features of mood disorders. Further uncovering of molecular mechanisms underlying magnesium's proposed effects is needed due to the recent shift in research of treatment resistant depression (TRD) towards glutamatergic pathways. Here, we applied Mg via drinking water for 28 days (50 mg/kg/day), in ACTH-treated rats, an established animal model of depression resistant to tricyclic antidepressants. Using this model in male rats we measured (1) changes in hippocampal neurogenesis and behavioral alterations, (2) adrenal hormones response to acute stress challenge and (3) levels of biometals involved in regulation of monoamines turnover in rat prefrontal cortex. Our results support beneficial behavioral impact of Mg in TRD model together with increased hippocampal neurogenesis and BDNF expression. Furthermore, Mg prevented ACTH induced disruption in HPA axis function, by normalizing the levels of plasma ACTH, corticosterone and interleukin-6, and by increasing the peripheral release of adrenaline, noradrenaline and serotonin after the acute stress challenge. Finally, the influence on copper/zinc ratio suggested probable magnesium's involvement in monoamine turnover in PFC. Our findings provide further insights into the possible pathways implicated in the behavioral modulation effects of Mg, as well as its central and peripheral effects in ACTH-induced TRD model. Thus, further investigation of molecular signaling related to the glutamatergic transmission and role of Mg, could reveal prospects to novel treatment strategies that could be of particular importance for patients suffering from TRD. PMID- 30025719 TI - Minimally invasive decompression in patients with degenerative spondylolisthesis associated with lumbar spinal stenosis. Report of a surgical series and review of the literature. AB - We reported the results of minimally invasive spinal decompression (MISD) in patients with degenerative spondylolisthesis (DS) associated with lumbar spinal stenosis (LSS) and performed a literature review in order to evaluate the clinical and radiological outcomes, the complications and reoperation rate of MISD procedures in these patients. Data of 28 patients submitted to MISD for DS associated to LSS were reviewed. We evaluated the Visual Analogue Scale (VAS) both for low back pain (LBP) and legs pain, the Oswestry Disability Index (ODI) and the degree of the slippage. A PubMed search of the English literature was conducted. Only papers with more than 10 patients and reporting explicitly data of patients with DS were included in the analysis. We found a statistically significant improvement of LBP, legs pain and ODI in our series. The degree of slippage was stable at follow-up (FU) with no need of reoperation. No major complications occurred. In our literature review, we were able to analyze the differences in ODI in 156 patients and the differences in Japanese Orthopedic Association (JOA) score in 218 patients. We observed a statistically significant improvement of ODI and JOA score at FU compared to pre-operative. The percentage of slippage, evaluated in 283 patients, was unchanged at FU compared to pre operative. The overall complication rate was 1.6%. The overall reoperation rate was 4.5%. MISD procedures are safe and effective in patients with DS associated to LSS and are associated to low morbidity and significant improvement of disability without progression of slippage. PMID- 30025720 TI - Intracranial plasmacytoma presenting as glioblastoma multiforme. PMID- 30025721 TI - Difficulties in the diagnosis of four repeats (4R) tauopathic parkinsonian syndromes. AB - Corticobasal Degeneration Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) are types of four repeats (4R) tauopathies, which are associated to parkinsonian syndromes. The aim of the work is to analyze cases of patients of the Department of Neurology, overlapping of syndromes related to both pathologies and to show that most likely CBS and PSP are not lineary related to their commonly associated syndromes i.e. adequately corticobasal syndromes and progressive supranuclear palsy syndromes. In the context of each patient factors in favor of most likely CBS, PSP or both diseases are discussed and analyzed using contemporary criteria. This work discusses multidimensional aspect of the examination of five patient aged 64 to 83 - 4 females and 1 male with 4R tauopathies and difficulties in distinguishing both diseases. The duration of the disease varied from 1 to 5 years. Each patient after neurological examination was assessed using magnetic resonance imaging (MRI) and psychological test. Examination of all patients was extended using single photon emission computer tomography (SPECT) to reveal the usefulness of this tool in differentiation of diseases was done. The outcome of this examination was verified with prior clinical manifestation of patients and morphological abnormalities in magnetic resonance imaging. Autopsies were not conducted. PMID- 30025722 TI - Application of peripheral nerve conduits in clinical practice: A literature review. AB - Understanding the pathomechanisms behind peripheral nerve damage and learning the course of regeneration seem to be crucial for selecting the appropriate methods of treatment. Autografts are currently the gold standard procedure in nerve reconstruction. However, due to the frequency of complications resulting from autografting and a desire to create a better environment for the regeneration of the damaged nerve, artificial conduits have become an approved alternative treatment method. The aim of this mini-review is to present the nerve scaffolds that have been applied in clinical practice to date, and the potential directions of developments in nerve conduit bioengineering. Articles regarding construction and characterization of nerve conduits were used as the theoretical background. All papers, available in PubMed database since 2000, presenting results of application of artificial nerve conduits in clinical trials were included into this mini-review. Fourteen studies including <=10 patients and 10 trials conducted on >10 patients were analyzed as well as 24 papers focused on artificial nerve conduits per se. Taking into consideration the experiences of the authors investigating nerve conduits in clinical trials, it is essential to point out the emergence of bioresorbable scaffolds, which in the future may significantly change the treatment of peripheral nerve injuries. Also worth mentioning among the advanced conduits are hybrid conduits, which combine several modifications of a synthetic material to provide the optimal regeneration of a damaged nerve. PMID- 30025723 TI - [Early onset rhabdomyolysis and acute renal failure associated with the administration of daptomycin. A Case report and literature review]. PMID- 30025724 TI - Perceptions of plain cigarette packaging among smokers and non-smokers in Andalusia (Spain). AB - OBJECTIVES: Each year tobacco is responsible for 650,000 deaths in Europe and 55,000 in Spain. With tobacco advertising and promotion banned in Spain and most of Europe, the last bastion of marketing is the packaging. Plain tobacco packaging -which involves packs having a standardised appearance- has been proposed to counter this. The objective of this study is to research perceptions arising from the plain packaging of tobacco products. METHODS: We employed a qualitative research methodology -focus groups- with smokers and non-smokers in in two medium-sized Andalusian towns (Spain). RESULTS: Results show the importance of plain cigarette packaging as a form of promotion, particularly among women and young people, how pack colour influences product perceptions, and how removing full branding increases the salience of the warnings. CONCLUSIONS: Plain packaging, combined with pictorial health warnings, may reduce the capacity of packaging to be distinctive and a badge product. Altering pack design in such a way would make it more difficult for tobacco companies to create a favourable image of their brands and may help to reinforce the ability of the population to protect themselves from the dangers of smoking. PMID- 30025725 TI - Angiography Alone Versus Angiography Plus Optical Coherence Tomography to Guide Percutaneous Coronary Intervention: Outcomes From the Pan-London PCI Cohort. AB - OBJECTIVES: This study aimed to determine the effect on long-term survival of using optical coherence tomography (OCT) during percutaneous coronary intervention (PCI). BACKGROUND: Angiographic guidance for PCI has substantial limitations. The superior spatial resolution of OCT could translate into meaningful clinical benefits, although limited data exist to date about their effect on clinical endpoints. METHODS: This was a cohort study based on the Pan London (United Kingdom) PCI registry, which includes 123,764 patients who underwent PCI in National Health Service hospitals in London between 2005 and 2015. Patients undergoing primary PCI or pressure wire use were excluded leaving 87,166 patients in the study. The primary endpoint was all-cause mortality at a median of 4.8 years. RESULTS: OCT was used in 1,149 (1.3%) patients, intravascular ultrasound (IVUS) was used in 10,971 (12.6%) patients, and angiography alone in the remaining 75,046 patients. Overall OCT rates increased over time (p < 0.0001), with variation in rates between centers (p = 0.002). The mean stent length was shortest in the angiography-guided group, longer in the IVUS-guided group, and longest in the OCT-guided group. OCT-guided procedures were associated with greater procedural success rates and reduced in-hospital MACE rates. A significant difference in mortality was observed between patients who underwent OCT-guided PCI (7.7%) compared with patients who underwent either IVUS-guided (12.2%) or angiography-guided (15.7%; p < 0.0001) PCI, with differences seen for both elective (p < 0.0001) and acute coronary syndrome subgroups (p = 0.0024). Overall this difference persisted after multivariate Cox analysis (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.26 to 0.81; p = 0.001) and propensity matching (hazard ratio: 0.39; 95% CI: 0.21 to 0.77; p = 0.0008; OCT vs. angiography-alone cohort), with no difference in matched OCT and IVUS cohorts (HR: 0.88; 95% CI: 0.61 to 1.38; p = 0.43). CONCLUSIONS: In this large observational study, OCT-guided PCI was associated with improved procedural outcomes, in-hospital events, and long-term survival compared with standard angiography-guided PCI. PMID- 30025726 TI - Will Optical Coherence Tomography Become the Standard Imaging Tool for Percutaneous Coronary Intervention Guidance? PMID- 30025727 TI - Neoatherosclerosis in Patients With Coronary Stent Thrombosis: Findings From Optical Coherence Tomography Imaging (A Report of the PRESTIGE Consortium). AB - OBJECTIVES: The purpose of this study was to assess neoatherosclerosis in a registry of prospectively enrolled patients presenting with stent thrombosis using optical coherence tomography. BACKGROUND: In-stent neoatherosclerosis was recently identified as a novel disease manifestation of atherosclerosis after coronary stent implantation. METHODS: Angiography and intravascular optical coherence tomography were used to investigate etiologic factors of neoatherosclerosis in patients presenting with stent thrombosis >1 year after implantation (very late stent thrombosis [VLST]). Clinical data were collected according to a standardized protocol. Optical coherence tomographic acquisitions were analyzed in a core laboratory. Cox regression analysis was performed to identify factors associated with the formation of neoatherosclerosis and plaque rupture as a function of time. RESULTS: Optical coherence tomography was performed in 134 patients presenting with VLST. A total of 58 lesions in 58 patients with neoatherosclerosis were compared with 76 lesions in 76 patients without neoatherosclerosis. Baseline characteristics were similar between groups. In-stent plaque rupture was the most frequent cause (31%) in all patients presenting with VLST. In patients with neoatherosclerosis, in-stent plaque rupture was identified as the cause of VLST in 40 cases (69%), whereas uncovered stent struts (n = 22 [29%]) was the most frequent cause in patients without neoatherosclerosis. Macrophage infiltration was significantly more frequent in optical coherence tomographic frames with plaque rupture compared with those without (50.2% vs. 22.2%; p < 0.0001), whereas calcification was more often observed in frames without plaque rupture (17.2% vs. 4%; p < 0.0001). Implantation of a drug-eluting stent was significantly associated with the formation of neoatherosclerosis (p = 0.02), whereas previous myocardial infarction on index percutaneous coronary intervention was identified as a significant risk factor for plaque rupture in patients with neoatherosclerosis (p = 0.003). No significant difference was observed in thrombus composition between patients with or without neoatherosclerosis. CONCLUSIONS: Neoatherosclerosis was frequently observed in patients with VLST. Implantation of a drug-eluting stent was significantly associated with neoatherosclerosis formation. In-stent plaque rupture was the prevailing pathological mechanism and often occurred in patients with neoatherosclerosis and previous myocardial infarction at index percutaneous coronary intervention. Increased macrophage infiltration heralded plaque vulnerability in our study and might serve as an important indicator. PMID- 30025728 TI - In-Stent Neoatherosclerosis and Very Late Stent Thrombosis: An Endless Fight Against Atherosclerosis. PMID- 30025730 TI - Post-Percutaneous Coronary Intervention Discharge Against Medical Advice: Infrequent But Deadly. PMID- 30025729 TI - Discharge Against Medical Advice After Percutaneous Coronary Intervention in the United States. AB - OBJECTIVES: This study aimed to evaluate discharge against medical advice (DAMA) in percutaneous coronary intervention (PCI) and how DAMA affects readmissions. BACKGROUND: DAMA is infrequent but associated with poor patient outcomes. DAMA in the context of PCI has not been described in the published reports. METHODS: The authors analyzed patients in the Nationwide Readmission Database between 2010 and 2014 with a PCI procedure who were either discharged home or against medical advice. The primary endpoint was all-cause 30-day readmissions and their causes. Descriptive statistics were used to compare DAMA with patients discharged home, and multiple logistic regressions were used to determine patient characteristics associated with DAMA and readmission. RESULTS: Among the 2,021,104 patients in the analysis, the proportion of patients who DAMA was 0.5% (n = 10,049). The 30 day readmission rate for patients who were DAMA and those discharged home was 16.8% and 8.5%, respectively (p < 0.001). Important predictors of DAMA included diagnosis of acute myocardial infarction (odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.25 to 1.51; p < 0.001), smoking (OR: 1.71; 95% CI: 1.57 to 1.86; p < 0.001), drug abuse (OR: 1.82; 95% CI: 1.60 to 2.06; p < 0.001), and alcohol misuse (OR: 1.53; 95% CI: 1.32 to 1.78; p < 0.001). DAMA was the strongest predictor for readmission (OR: 1.89; 95% CI: 1.71 to 2.08; p < 0.001). DAMA patients were more likely to have neuropsychiatric reasons for noncardiac causes of readmission (8.3% vs. 2.4%) and acute myocardial infarction for cardiac causes of readmission (39.4% vs. 19.5%) compared with patients discharged home. CONCLUSIONS: DAMA occurs in approximately 0.5% of patients following PCI and is strongly associated with readmission within 30 days. Interventions should be developed to reduce DAMA in high-risk groups and initiate interventions to avoid complications and readmission when it occurs. PMID- 30025731 TI - The SAVI-TF Registry: 1-Year Outcomes of the European Post-Market Registry Using the ACURATE neo Transcatheter Heart Valve Under Real-World Conditions in 1,000 Patients. AB - OBJECTIVES: The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions. BACKGROUND: The self-expanding, supra-annular ACURATE neo prosthesis is a transcatheter heart valve that gained the Conformite Europeene mark in 2014, but only limited clinical data are available so far. METHODS: This prospective, multicenter registry enrolled 1,000 patients at 25 European centers who were followed for 1 year post-procedure. RESULTS: Mean patient age was 81.1 +/- 5.2 years; mean logistic European System for Cardiac Operative Risk Evaluation I score, European System for Cardiac Operative Risk Evaluation II score, and Society of Thoracic Surgeons score were 18.1 +/- 12.5%, 6.6 +/- 7.5%, and 6.0 +/- 5.6%, respectively. At 1 year, 8.0% (95% confidence interval [CI]: 6.3% to 9.7%) of patients had died, 2.3% (95% CI: 1.3% to 3.2%) had disabling strokes, and 9.9% (95% CI: 8.1% to 11.8%) had permanent pacemaker implantations. Through 1 year, 5 reinterventions (0.5%; 95% CI: 0.1% to 1.0%) were performed: 3 valve-in-valve and 2 surgical aortic valve replacements. Mean effective orifice area was 1.84 +/- 0.43 cm2, mean gradient was 7.3 +/- 3.7 mm Hg, and greater than mild paravalvular leakage was observed in 3.6% of patients. CONCLUSIONS: Transfemoral implantation of the ACURATE neo prosthesis resulted in favorable 1-year clinical and echocardiographic outcomes with very low mortality and new pacemaker rates. PMID- 30025732 TI - Contemporary Trends and Comparative Outcomes With Adjunctive Inferior Vena Cava Filter Placement in Patients Undergoing Catheter-Directed Thrombolysis for Deep Vein Thrombosis in the United States: Insights From the National Inpatient Sample. AB - OBJECTIVES: The aim of this study was to investigate the contemporary trends and comparative effectiveness of adjunctive inferior vena cava filter (IVCF) placement in patients undergoing catheter-directed thrombolysis (CDT) for treatment of proximal lower extremity or caval deep vein thrombosis. BACKGROUND: CDT is being increasingly used in the management of proximal deep vein thrombosis. Although a significant number of patients treated with CDT undergo adjunctive IVCF placement, the benefit of this practice remains unknown. METHODS: The National Inpatient Sample database was used to identify all patients with proximal or caval deep vein thrombosis who underwent CDT (with and without adjunctive IVCF placement) in the United States between January 2005 and December 2013. A propensity score-matching algorithm was then used to derive 2 matched groups of patients (IVCF and no IVCF) for comparative outcomes (mortality and major and minor bleeding) and resource use analysis. RESULTS: Of the 7,119 patients treated with CDT, 2,421 (34%) received IVCFs. There was no significant difference in in-hospital mortality (0.7% vs 1.0%; p = 0.20), procedure-related hemorrhage (1.4% vs. 1.0%; p = 0.23), or intracranial hemorrhage (0.7% vs. 0.6%; p = 0.70) between the IVCF (n = 2,259) and no-IVCF (n = 2,259) groups, respectively. Patients undergoing IVCF placement had higher rates of hematoma (3.4% vs 2.1%; p = 0.009), higher in-hospital charges ($104,049 +/- 75,572 vs. $92,881 +/- 80,194; p < 0.001) and increased length of stay (7.3 +/- 5.6 days vs. 6.9 +/- 6.9 days; p = 0.046) compared with the no-IVCF group. CONCLUSIONS: This nationwide observational study suggests that one-third of all patients undergoing CDT receive IVCFs. IVCF use was not associated with a decrease in in-hospital mortality but was associated with higher inpatient charges and longer length of stay. PMID- 30025733 TI - Inferior Vena Cava Filter Placement With Catheter-Directed Lysis: How Did We Get to This Point? PMID- 30025736 TI - Early Angiography Use in Patients With Non-ST-Segment Elevation Myocardial Infarction in the United States: Focus on Elderly Patients. PMID- 30025735 TI - The OPTALYSE PE Trial: Another Step Toward Understanding the Truth About Catheter Directed Thrombolysis for Submassive Pulmonary Embolism. PMID- 30025734 TI - A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. AB - OBJECTIVES: The aim of this study was to determine the lowest optimal tissue plasminogen activator (tPA) dose and delivery duration using ultrasound facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk (submassive) pulmonary embolism. BACKGROUND: Previous trials of USCDT used tPA over 12 to 24 h at doses of 20 to 24 mg for acute pulmonary embolism. METHODS: Hemodynamically stable adults with acute intermediate-risk pulmonary embolism documented by computed tomographic angiography were randomized into this prospective multicenter, parallel-group trial. Patients received treatment with 1 of 4 USCDT regimens. The tPA dose ranged from 4 to 12 mg per lung and infusion duration from 2 to 6 h. The primary efficacy endpoint was reduction in right ventricular-to-left ventricular diameter ratio by computed tomographic angiography. A major secondary endpoint was embolic burden by refined modified Miller score, measured on computed tomographic angiography 48 h after initiation of USCDT. RESULTS: One hundred one patients were randomized, and improvements in right ventricular-to-left ventricular diameter ratio were as follows: arm 1 (4 mg/lung/2 h), 0.40 (24%; p = 0.0001); arm 2 (4 mg/lung/4 h), 0.35 (22.6%; p = 0.0001); arm 3 (6 mg/lung/6 h), 0.42 (26.3%; p = 0.0001); and arm 4 (12 mg/lung/6 h), 0.48 (25.5%; p = 0.0001). Improvement in refined modified Miller score was also seen in all groups. Four patients experienced major bleeding (4%). Of 2 intracranial hemorrhage events, 1 was attributed to tPA delivered by USCDT. CONCLUSIONS: Treatment with USCDT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline. The major bleeding rate was low, but 1 intracranial hemorrhage event due to tPA delivered by USCDT did occur. PMID- 30025738 TI - Don't Leave the Back Door Open. PMID- 30025737 TI - Does Late Lumen Loss Represent a Measure of the Efficacy of Bioresorbable Scaffolds? PMID- 30025739 TI - Reply: Don't Leave the Back Door Open. PMID- 30025740 TI - Coronary Artery Intraplaque Microvessels by Optical Coherence Tomography Correlate With Vulnerable Plaque and Predict Clinical Outcomes in Patients With Ischemic Angina. PMID- 30025741 TI - Tinnitus perception in patients after vagal nerve stimulator implantation for epilepsy. AB - PURPOSE: Vagal nerve stimulation in conjunction with sound therapy has been proposed as a treatment for subjective tinnitus. The purpose of this study is to retrospectively review the effect of VNS on perception of tinnitus in epilepsy patients. We explore the incidence of tinnitus and its perceived reduction in patients requiring implantation of VNS for medically refractory seizures. MATERIALS AND METHODS: A phone survey was conducted in adult patients with prior VNS implantation. A questionnaire including the visual analog scale (VAS) of tinnitus loudness was used to determine the presence and severity of tinnitus. RESULTS: Out of the 56 patients who had completed the phone survey, 20 (35%) reported the presence of pre-operative tinnitus. The tinnitus positive group was significantly older (p = 0.019). Of the 20 pre-operative tinnitus positive patients, all patients continued to have tinnitus post-operatively. Four (20%) noted no changes in VAS of tinnitus loudness while 16 (80%) had at least a one point decrease. The mean difference between pre- and post-operative VAS of loudness was 2.05, with a standard deviation of 1.84 and this was statistically significant (p < 0.001). CONCLUSIONS: In this study, we evaluate the potential of vagal nerve stimulation to alter the perception of tinnitus in patients with refractory epilepsy. Eighty percent of patients noted some level of subjective tinnitus improvement after VNS implantation. Given this finding, there may be a potential additional benefit to the use of VNS in patients with epilepsy. PMID- 30025742 TI - Prevalence and incidence of clinically significant patulous Eustachian tube: A population-based study using the Korean National Health Insurance Claims Database. AB - OBJECTIVES: The aim of this study is to estimate the entire population-based prevalence and incidence of Patulous Eustachian tube (PET) using the Korean National Health Insurance (NHI) claims database. The annual trends of prevalence and incidence of PET were also investigated. METHODS: Retrospective analysis of PET patients was performed between 2010 and 2016, from the NHI claims database. PET patients were defined as those who had at least one service claim with a primary diagnosis under an ICD-10-based PET code (H69.0). RESULTS: During the study period, there were 20,533 new PET patients in Korea. In 2016 there were 4482 incident cases, and the standardized annual incidence rate was 8.8 per 100,000 persons. The standardized annual prevalence rate increased significantly from 7.2 per 100,000 persons in 2010 to 10.3 per 100,000 persons in 2016. The prevalence increased significantly on annual basis, whereas the incidence rate fluctuated over time. Interestingly, the incidence and prevalence of PET in women was almost twice as high as that in men, and peaked in their 20s. CONCLUSIONS: This study demonstrated the substantial annual increase of the NHI claims with PET code (H69.0) in Korea from 2010 to 2016. Statistical results based on the NHI claims, we confirmed the high prevalence and incidence rates of clinically significant PET in women than in men. This study only covered patient using the medical service for PET and missed PET sufferers not seeking medical service. However, this study can provide basic epidemiological information on clinically significant PET. PMID- 30025743 TI - Utilizing prestin as a predictive marker for the early detection of outer hair cell damage. AB - PURPOSE: To evaluate prestin as a biomarker for the identification of early ototoxicity. MATERIALS AND METHODS: Rats (n = 47) were randomly assigned to five groups: low-dose (LAG) or high-dose (HAG) amikacin (200 and 600 mg/kg/day, respectively, for 10 days), low-dose (LCIS)or high-dose (HCIS) cisplatin (single doses of 5 and 15 mg/kg, respectively, for 3 days), and control (n = 8). At the end of the experiment, measurement of distortion product-evoked otoacoustic emissions (DPOAE) were performed to evaluate hearing, then blood samples and both ear tissues were collected under anesthesia. Prestin levels were determined by ELISA. Cochlear damage was evaluated histologically using a 4-point scoring system. RESULTS: The mean serum prestin levels were 377.0 +/- 135.3, 411.3 +/- 73.1, 512.6 +/- 106.0, 455.0 +/- 74.2 and 555.3 +/- 47.9 pg/ml for control, LCIS, HCIS, LAG and HAG groups, respectively. There was significant difference between prestin levels of Control-LCIS-HCIS groups (p = 0.031) and prestin levels of Control-LAG-HAG groups (p = 0.003). There were also significant differences in prestin levels between the low- and high-dose cisplatin and amikacin groups (p = 0.028 and p = 0.011, respectively). Each group had significantly lower DPOAE results at 4, 6 and 8 kHz than control groups (p < 0.001). The LAG, HAG, LCIS and HCIS groups had significantly higher cochlear damage scores than the control group (p < 0.05). CONCLUSIONS: Higher doses of cisplatin and amikacin were associated with the greatest increases in serum prestin level and cochlear damage score. The results of this study suggest that prestin is a promising early indicator of cochlear damage. PMID- 30025744 TI - Enhanced visualization of the surgical field in pediatric direct laryngoscopy using a three-dimensional endoscopic system. AB - BACKGROUND: Direct laryngoscopy and rigid bronchoscopy are currently performed using 2-dimensional endoscopic systems. Our objective was to determine whether a 3-dimensional endoscopic system can enhance visualization of the surgical field in pediatric direct laryngoscopy and rigid bronchoscopy. METHODS: A prospective cohort study was conducted. Thirty three children who underwent direct laryngoscopies in a tertiary referral children's hospital were enrolled. Direct laryngoscopy was performed using both 2- and 3-dimensional endoscopic systems, after which the surgeons scored the quality of the images obtained with each system on a scale from 1 (low) to 5 (high). Comparison of the scores obtained with the 2 endoscopic systems was performed. RESULTS: The 33 study children (mean age 2.3 years, M:F ratio 1:1.6) underwent 47 direct laryngoscopies. The mean score for visualization of the glottis was 4.8 for the three-dimensional system compared to 4.0 for the two-dimensional system (P = .025), 4.7 vs. 3.8, respectively, (P = .019) for the subglottis, and 4.6 vs. 3.9, respectively (P = .031) for visualization of the proximal trachea. The mean score for visualization of the distal trachea was 3.0 vs. 3.7, respectively (P = .020). In a child with recurrent type 3 laryngotracheal cleft a residual tracheo-esophageal fistula could not be detected using the 2D system, but was immediately detected using the 3D system. CONCLUSIONS: Visualization of the glottis, subglottis and proximal trachea during direct laryngoscopy using a 3-dimensional endoscopic system was rated by the surgeons as being superior to the conventional 2-dimensional technique. Further outcome studies that will demonstrate the clinical advantage of the 3D technology are highly required. LEVEL OF EVIDENCE: 2b. PMID- 30025745 TI - Trimodal prehabilitation for colorectal surgery attenuates post-surgical losses in lean body mass: A pooled analysis of randomized controlled trials. AB - BACKGROUND & AIMS: Preservation of lean body mass is an important cancer care objective. The capacity for prehabilitation interventions to modulate the lean body mass (LBM) of colorectal cancer patients before and after surgery is unknown. METHODS: A pooled analysis of two randomized controlled trials of trimodal prehabilitation vs. trimodal rehabilitation at a single university affiliated tertiary center employing Enhanced Recovery After Surgery (ERAS) care was conducted. The prehabilitation interventions included exercise, nutrition, and anxiety-reduction elements that began approximately four weeks before surgery and continued for eight weeks after surgery. The rehabilitation interventions were identical to the prehabilitation interventions but were initiated only after surgery. Body composition, measured using multifrequency bioelectrical impedance analysis, was recorded at baseline, pre-surgery, 4 and 8 weeks after surgery. The primary outcome was change in LBM before and after colorectal surgery for cancer. A mixed effects regression model was used to estimate changes in body mass and body composition over time controlling for age, sex, baseline body mass index (BMI), baseline six-minute walk test (6MWT), and postoperative compliance to the interventions. NCT02586701 &NCT01356264. RESULTS: Pooled data included 76 patients who followed prehabilitation and 63 patients who followed rehabilitation (n = 139). Neither group experienced changes in preoperative LBM. Compared to rehabilitated patients, prehabilitated patients had significantly more absolute and relative LBM at four and eight-weeks post-surgery in models controlling for age, sex, baseline BMI, baseline 6MWT, and compliance to the postoperative intervention. CONCLUSION: Trimodal prehabilitation attenuated the post-surgical LBM loss compared to the loss observed in patients who received the rehabilitation intervention. Patients who receive neither intervention (i.e., standard of care) would be likely to lose more LBM. Offering a prehabilitation program to colorectal cancer patients awaiting resection is a useful strategy to mitigate the impact of the surgical stress response on lean tissue in an ERAS setting, and, in turn, might have a positive impact on the cancer care course. CLINICAL TRIAL REGISTRATION: NCT02586701 &NCT01356264 (clinicaltrials.gov). PMID- 30025746 TI - Potato consumption is prospectively associated with risk of hypertension: An 11.3 year longitudinal cohort study. AB - BACKGROUND & AIMS: Government has popularized potatoes as the staple food in China. Potatoes as a potassium-rich food show high glycemic responses after consumption. Whether potato consumption is prospectively linked with the risk of hypertension remains unclear in oriental populations. In this study, we aimed to investigate the association of potato consumption with the risk of hypertension among Chinese people. METHODS: A total of 11,763 adults (>=20 years old) who were free of hypertension at baseline were enrolled from China Health and Nutrition Survey (CHNS) Cohort study in 1989-2011. Participants were excluded if they were <20 years old, identified to be pregnant, and previously diagnosed with hypertension, cancers, infarction, apoplexy and diabetes at baseline. Cox proportional hazards regression models were used to estimate the associations after adjusting for potential confounders. RESULTS: During average 11.3 years of follow-up, 4033 incident cases of hypertension were ascertained. People who consumed more amounts of total potatoes, stir-fried potatoes, and non stir-fried potatoes had higher risk of hypertension (P for trend = 0.1225, 0.2168 and 0.0456, respectively). Multivariable hazard ratios (HRs) for increased consumption of total potatoes were 1.402 (95% confidence interval [CI], 1.270 1.548), 1.198 (95% CI, 1.014-1.415), and 1.120 (95% CI, 0.929-1.349) compared with non-consumers. However, the participants with higher intake of potato consumption were inclined to have lower risk of hypertension when excluding the non-consumers of total potatoes or stir-fried potatoes (P for trend = 0.0271 and 0.0001). In addition, a positive association of sweet potatoes intake with hypertension risk was only found in urban residents (P for trend = 0.0239). CONCLUSIONS: Our results showed that potato consumption was prospectively associated with hypertension in Chinese population. As the urbanization process continues along with the transition to Western-style diets, more consideration should be taken before the formulation of potato popularization is promoted in China. PMID- 30025747 TI - Acute stress enhances pupillary responses to erotic nudes: Evidence for differential effects of sympathetic activation and cortisol. AB - Chronic stress attenuates reproductive behavior in many species, but evidence regarding the impact of acute stress on human sexual arousability is insufficient. Stressor-specific effects might result from divergent roles of both stress response systems. Social self-threat, linked to affiliation-oriented coping, might also influence sexual responsivity. To investigate stress-induced modulation of the processing of sexual cues and its relationship with cortisol, 58 participants underwent either a predominantly sympathetic stressor (3 min sustained handgrip) or similar control procedure. In both conditions, half of the sample was monitored by an opposite-sex person (social evaluation). Pupillary responses to erotic nudes were recorded and dissociated into fast and slow PCA components. Physically stressed participants showed enhanced (slow) dilation to explicit pictures. Cortisol levels after stress negatively predicted rapid responses to opposite-sex and (marginally) explicit stimuli. Our results suggest that acute sympathetic stress exposure facilitates cognitive sexual processing, whereas subsequent HPA-axis activation may induce counteracting effects. PMID- 30025748 TI - Selective vs stepwise removal of deep carious lesions in primary molars: 12 Months results of a randomized controlled pilot trial. AB - OBJECTIVES: For deep carious lesions, selective or stepwise carious tissue removal (SE, SW) seem advantageous compared with non-selective removal. For primary molars, there is insufficient evidence comparing SE against SW. This randomized pilot trial compared SE and SW over 12 months. METHODS: A two-arm superiority trial was conducted comparing SE and SW in primary molars with deep lesions but without pulpal symptoms. We recruited 74 children (one molar/child) aged 3-9 years. In both groups, peripheral carious tissue removal was performed at T1 to hard dentin. In proximity to the pulp, leathery dentin was left followed by an adhesive compomer restoration. Blinded re-examination was performed after six months (T2). Molars allocated to SW were re-entered, removal to firm dentin carried out pulpo-proximally, and again restored. After another 6 months, all molars were re-examined (T3). Our primary outcome was success, defined as no restorative/endodontic complications (including pulp exposure) leading to reinterventions. Secondary outcomes included total treatment and opportunity costs. Patients', dentists' and parents' subjective assessments were recorded. This trial was registered (ClinicalTrials.gov/NCT02232828). RESULTS: After 12 months a total of 72 children (36 SE, 36 SW) were analyzed. Three failures occurred (2 exposures in SW, 1 pulpal complication leading to extraction in SE) (p > 0.05). The subjective evaluation by patients, parents or dentists did not differ significantly. Combined treatment and opportunity costs were significantly higher in SW (mean;SD: 186;61 Euro) than SE (100;59) (p < 0.001). CONCLUSIONS: The significantly increased costs for performing SW instead of SE in deep carious lesions in primary molars may not be justified. CLINICAL SIGNIFICANCE: For primary molars with deep lesions, but vital pulps, SE was less costly at similar efficacy compared with SW. Dentists' decision-making should consider this alongside further clinical aspects. PMID- 30025749 TI - Is mortality in elderly septic patients as high as expected? Long-term mortality in a surgical sample cohort. AB - PURPOSE: To determine the differences in short- and long-term mortality in elderly septic patients with multiorgan dysfunction syndrome and establish the factors related to non-survival. MATERIALS AND METHODS: A retrospective cohort study was made of 206 patients over 65 years of age with septic and septic shock criteria admitted to the ICU of Rio Hortega Hospital between January 2011 and February 2017. Study variables were obtained from electronic database records. RESULTS: A total of 206 patients were included, divided into three groups of age (65-74, 75-85, >85 years). There were no significant differences in mortality according to age group after 28 days, 90 days or one year (28.6%, 32.1% and 45.2% in the 65-74 years age group; 32.5%, 38.6% and 45.8% in the 75-85 years age group, 41%, 48.7% and 56.4% in the >85 years age group). The factors related to mortality were: chronic heart failure, non-haematological cancer, liver dysfunction and central nervous system dysfunction. CONCLUSIONS: The results indicate that there is no significant difference in mortality among the different age groups. About 50% of the elderly patients survive a septic process. There is a close relationship between the number of affected organs and days of dysfunction, the use of interventional techniques and long-term mortality. PMID- 30025750 TI - miR-128 targets the CC chemokine ligand 18 gene (CCL18) in cutaneous malignant melanoma progression. AB - BACKGROUND: The CC chemokine ligand 18 (CCL18) has a higher expression in some tumors, while the CCL18 level can be a marker of tumor progression and prognosis. We previously reported that the expression of CCL18 gene was dramatically up regulated in cutaneous malignant melanoma (CMM) and its expression levels were correlated with tumor thickness. OBJECTIVE: To investigate miRNAs which could target the CCL18 gene so as to mediate CMM development and improvement. METHODS: The expression of miR-128 and CCL18 in CMM were measured by qRT-PCR. The interaction of miR-128 with CCL18 3'UTR was verified by Luciferase reporter gene assay. The changes in expression of CCL18 after miR-128 mimic transfection of A375 melanoma cells were determined by both qRT-PCR and Western-bloting. Cell viability was accessed by CCK8-assay. Flow cytometry was employed to detect the incidence of apoptosis. Clonogenic assay was used to detect the ability of colony formation. Cell migration was evaluated by Transwell migration study. The protein levels of epithelial-mesenchymal transition (EMT), such as E-cadherin, N-cadherin and beta-catenin were analyzed by Western-bloting. RESULTS: The expression of miR 128 had negative relevance with CCL18 in CMM. miR-128 could interact with CCL18 3'UTR. Transfected miR-128 mimic significantly reduced CCL18 expression and this impairment of CCL18 gene promoted apoptosis, inhibited migration and colony formation of A375 melanoma cells. Furthermore, the relative expression of N cadherin was decreased. CONCLUSION: CCL18 is a target gene of miR-128. Overexpression of miR-128 inhibits the oncogenic effect of CCL18. PMID- 30025751 TI - Dose reduction of high-dose first-generation antipsychotics or switch to ziprasidone in long-stay patients with schizophrenia: A 1-year double-blind randomized clinical trial. AB - Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms and side effects. We investigated in a randomized double-blind trial whether a dose-reduction strategy to achieve an adequate dose of a FGA (5 mg/day haloperidol equivalents, n = 24) or switching to ziprasidone (160 mg/day, n = 24) in treatment resistant patients would decrease negative symptoms after 1 year of treatment. We found that negative symptoms did not change significantly in either condition. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference between conditions in favour of FGA dose reduction. Relapse and treatment failure, defined as a prolonged or repeated relapse, occurred more often with ziprasidone than with FGA (45.8% versus 20.8%, and 25.0% versus 16.7%, respectively). Treatment with ziprasidone was superior for extrapyramidal symptoms. Our study establishes that lowering high FGA doses to an equivalent of 5 mg/day haloperidol or switching to ziprasidone is feasible in the vast majority of patients but does not improve negative or other symptoms. Neither FGA dose reduction nor switching to ziprasidone is an adequate alternative to clozapine for long-stay patients with severe treatment resistant schizophrenia. PMID- 30025753 TI - Increased glycine levels in cerebrospinal fluid of patients with multiple sclerosis. PMID- 30025752 TI - Circulating lncRNA XLOC_009167 serves as a diagnostic biomarker to predict lung cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have been proven to be involved in carcinogenesis and to be released into peripheral blood. Our objective was to develop a circulating lncRNA as a novel biomarker to predict lung cancer. METHODS: We analyzed the lncRNA expression profile in lung cancer patients by lncRNA array and identified lncRNA XLOC_009167 as a circulating biomarker using qRT-PCR in whole blood of lung cancer patients. The diagnostic value of was analyzed by area under curve (AUC) and the receiver operating characteristic (ROC) test. RESULTS: LncRNA XLOC_009167 was screened as a candidate biomarker for lung cancer and was up-regulated in both lung cancer tissues and cell lines. Notably, lncRNA XLOC_009167 in whole blood of lung cancer patients was highly expressed as compared with that in healthy controls or in patients with pneumonia. The values of AUC of lung cancer vs. healthy controls, and that of lung cancer vs. pneumonia were 0.7398 (95%CI = 0.6493 to 0.8303) and 0.7005 (95%CI = 0.5771 to 0.8240), respectively. Intriguingly, the ROC showed lncRNA XLOC_009167 was a better diagnostic potential compared to the traditional biomarkers (CYFR21-1, NSE and CA72-4), and the circulating lncRNA XLOC_009167 was found to be stable in whole blood under different conditions. CONCLUSIONS: LncRNA XLOC_009167 could serve as a novel diagnostic biomarker to distinguish lung cancer from benign lung disease and healthy controls. PMID- 30025754 TI - Age and sex differences in the relationship between neutrophil-to-lymphocyte ratio and chronic kidney disease among an adult population in Taiwan. AB - BACKGROUND: This study investigated the association between systemic inflammation and chronic kidney disease (CKD), and whether this association changes with aging in adults, by using neutrophil-to-lymphocyte ratio (NLR) as an inflammation marker. MATERIALS AND METHODS: A total of 2954 adults (1815 men and 1139 women) who attended a health examination at a medical center in central Taiwan were included for the final cross-sectional analysis. RESULTS: Compared with participants aged <60 years, participants aged >=60 years had a markedly higher prevalence rate of CKD in both men (7.6% vs. 37.8%, p < .001) and women (3.8% vs. 28.0%, p < .001). In men aged <60 years, multivariable logistic regression analysis revealed that, after adjusting for conventional CKD risk factors, higher NLR (per 1 unit increment) was independently associated with higher risk of CKD [adjusted OR = 1.48 (95% C.I.: 1.10 to 1.99, p = .009)]. There was no such association in both men and women aged ?60 years, and woman aged <60 years. CONCLUSIONS: Our study showed a differential effect that aging has on the relationship between NLR and CKD in men but not in women. Being inexpensive and readily available, NLR may potentially be used for CKD risk assessment in men younger than 60 years of age. PMID- 30025755 TI - Pediatric reference intervals for calculated LDL cholesterol, non-HDL cholesterol, and remnant cholesterol in the healthy CALIPER cohort. AB - OBJECTIVES: Increased prevalence of pediatric obesity and associated co morbidities has heightened the concern for cardiovascular disease (CVD) risk later in life. Although the fasting lipid profile is traditionally used to assess CVD risk, the non-fasting lipid profile may simplify lipid testing and better predict CVD risk. Unfortunately, non-fasting lipid reference values are limited, particularly for children. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) has recruited thousands of healthy pediatric subjects to develop a pediatric reference interval database. Here, CALIPER reports pediatric reference intervals for non-fasting calculated low-density lipoprotein cholesterol (LDLc), non-high-density lipoprotein cholesterol (non HDLc) and remnant cholesterol. METHODS: Non-fasting serum samples from the CALIPER cohort of community children and adolescents were previously analyzed for HDLc, total cholesterol, and triglycerides. These values were used to calculate LDLc, non-HDLc, and remnant cholesterol and subsequently establish reference intervals with corresponding 90% confidence intervals according to CLSI EP28-A3c guidelines. Reference intervals were also calculated using alternative statistical methods highlighted in recent literature. RESULTS: All three lipid parameters required an age partition at 1 year due to wider reference intervals in the first year of life. LDLc and non-HDLc required sex partitioning for subjects 1-<10 years. Non-HDLc upper reference limit was higher than the 2011 National Heart, Lung, and Blood Institute (NHLBII) pediatric recommended cut offs, suggesting elevated atherogenic lipoproteins in a proportion of apparently healthy pediatric subjects. The LDLc upper reference limit (10-<19 year partition) was the same as the NHLBI cut-off, potentially due to lower calculated LDLc values in the non-fasting state. CONCLUSIONS: With the increased use of non fasting lipid profiles, age- and sex-specific reference intervals and appropriate clinical decision limits are necessary for pediatric lipid monitoring. Our data supports the notion that appropriate decision limits, rather than reference intervals, should be used to interpret lipid levels in children as there is a high prevalence of hyperlipidemia in the apparently healthy pediatric population. PMID- 30025756 TI - Clinical evaluation of hepatitis B core-related antigen in chronic hepatitis B and hepatocellular carcinoma patients. AB - BACKGROUND: Hepatitis B core-related antigen (HBcrAg) has been revealed as an important marker of Hepatitis B virus (HBV) infection recently. We aimed to evaluate the HBcrAg assay for indication of HBV loads in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) patients and assess the association between HBcrAg/cccDNA and HCC recurrence. METHODS: HBcrAg was measured by chemiluminescence enzyme immunoassay. Intrahepatic covalently closed circular DNA (cccDNA) was measured by real-time PCR with TaqMan fluorescent probes based on liver specimens from 89 HCC patients. RESULTS: HBcrAg correlated positively with HBV DNA irrespective of HBeAg status. Both HBcrAg and HBV DNA were associated with cccDNA in patients with elevated serum HBV DNA (>4 log IU/mL). In patients with non-elevated HBV DNA (<=4 log IU/mL), no relationship between HBV DNA and cccDNA was observed, but we still documented a modest correlation between HBcrAg and cccDNA. Finally, the recurrence-free survival rates were significantly lower in HCC patients with high intrahepatic cccDNA and serum HBcrAg levels than those with low cccDNA/HBcrAg levels (p = 0.035, p = 0.003 respectively). CONCLUSIONS: HBcrAg not only can serve as a biomarker to assess HBV loads in patients as well as provide a good method for monitoring cccDNA in HCC, but also can be used as a good prognostic predictor for HCC patients. PMID- 30025757 TI - Patients with abdominal-based free flap breast reconstruction a decade after surgery: A comprehensive long-term follow-up study. AB - BACKGROUND: Abdominal-based free flap has increasingly become the gold standard for breast reconstruction, however long-term evidence of the aesthetic outcome and quality of life is lacking. The present study aims to gain an overview of patients with abdominal-based free flap breast reconstructions in a long-term perspective. METHODS: Seventy-five patients who received abdominal-based free flap breast reconstructions between 2000-2007 in Uppsala, Sweden were invited back for photographs, 3D imaging and questionnaires. A retrospective chart review was conducted. Patient satisfaction with appearance and quality of life were assessed using the Breast-Q questionnaire. A layman panel and a professional panel rated the aesthetic appearance of the reconstructed breast from photographs and 3D images. RESULTS: Fifty-five patients participated with a mean age of 52 +/ 8 years at the time of reconstruction and a mean follow-up time of 11.4 +/- 1.8 years completed the study. The majority of the patients had received unilateral (85%), delayed reconstructions (73%) with prior radiation (55%). There were 53 patients with DIEP flaps, one with free TRAM flap and one with SIEA flap. Breast Q scores in the cohort were comparable to normative values of women without breast cancer (p < 0.001). There was a high level of agreement for the aesthetic results of the reconstructions between patient, professionals and layman panels (0.89 ICC, 95% CI: 0.83 - 0.93). CONCLUSION: Abdominal-based free flap reconstructions were effective in achieving a lasting positive aesthetic result and a high quality of life in patients a decade after surgery. PMID- 30025758 TI - A comparison of patient satisfaction (using the BREAST-Q questionnaire) with bilateral breast reconstruction following risk-reducing or therapeutic mastectomy. AB - INTRODUCTION: Patients undergoing mastectomy and immediate breast reconstruction for cancer may be expected to have different perceptions of long-term outcomes compared with those who have this operation prophylactically. METHODS: Patients who underwent bilateral mastectomy and breast reconstruction from 2008 to 2014 at the Cambridge Breast Unit were identified from a prospective register and their notes were audited. They were classified according to their indication for surgery as follows: bilaterally therapeutic, bilaterally risk-reducing or combination. The BREAST-QTM questionnaire was posted to participants using the 'total Dillman method'. Q-SCORE software was utilised to analyse patient satisfaction scores. RESULTS: Sixty-five (58%) responses were received, of which 8 were excluded, leaving 57 usable for the study. The therapeutic group had higher patient satisfaction than the risk-reducing group across most domains including breast, outcome, psychosocial, sexual, physical and information. The combination group scored lower and BRCA gene mutation-positive patients scored the lowest. Physical well-being was maintained across all groups but psychosocial/sexual well-being varied. Good psychosocial well-being was linked to a higher satisfaction with the outcome in the combination and risk-reducing groups. CONCLUSION: This study highlights the need for clinicians to take into account the indication for surgery as a major psychological factor in patients' perception of self and experience of surgery. It demonstrates that bilateral immediate reconstruction patients report similar physical symptoms irrespective of indication for mastectomy, but the decision-making process in terms of risk balancing and diagnosis influences satisfaction with self and surgery. It underlines the importance of preoperative management of expectations for patients undergoing risk-reducing procedures. PMID- 30025759 TI - Refining strategies to drive cognitive gains through transcranial electrical stimulation. PMID- 30025760 TI - Cytokines in cerebrospinal fluid of patients with schizophrenia spectrum disorders: New data and an updated meta-analysis. AB - Few studies have been conducted examining cytokines in cerebrospinal fluid of patients compared to healthy volunteers. The goals of this study were: 1) to report original data detailing cytokine levels in the cerebrospinal fluid (CSF) of 10 patients with a schizophrenia spectrum disorder (SSD) diagnosis and 10 healthy controls and 2) to conduct a meta-analysis of the available data on cytokine levels in the CSF of patients with SSD compared to healthy controls, including our new data. Cytokine concentrations were measured using the Q-plex Human Cytokine Screen array in CSF of 10 patients with SSD and 10 healthy volunteers. For the meta-analysis, an electronic PubMed and Google Scholar search without restrictions was conducted for articles that reported on cytokine levels in CSF in patients with an SSD compared to healthy controls. Our original data revealed statistically significant increases in levels of interleukin-8 (IL-8) and interleukin-1 beta (IL-1beta) in the CSF of patients with an SSD compared to healthy volunteers. Our meta-analysis showed statistically significant increases in interleukin-6 (IL-6) and IL-8 in patients compared to healthy volunteers. Effect sizes between treated and untreated patients for IL-6 were of similar magnitude. However, IL-6 levels were higher in early stage schizophrenia patients compared to chronic schizophrenia patients. Studies with larger sample sizes, comprehensive assessments and ideally in the context of a randomized controlled intervention to minimize the impact of confounding factors are needed to fully understand the role of cytokines and inflammatory markers in the pathophysiology and treatment of schizophrenia. PMID- 30025761 TI - Treatment outcomes of locally advanced cervical cancer by histopathological types in a single institution: A propensity score matching study. AB - BACKGROUND: In the current National Comprehensive Cancer Network (NCCN) guidelines, the standard treatment methods revealed no difference between locally advanced cervical (LAC) adenocarcinoma/adenosquamous carcinoma (AC/ASC) and LAC squamous cell carcinoma (SCC). The aim of this study was to compare the treatment outcomes of LAC AC/ASC with LAC SCC through the propensity score matching (PSM) analysis. METHODS: This retrospective study enrolled 181 LAC cancer patients who were treated with intensity modulated radiotherapy/volumetric modulated arc therapy and concurrent weekly cisplatin 30-40 mg/m2. In total, there were 151 LAC SCC patients and 30 LAC AC/ASC patients. The endpoints were overall survival (OS), disease-free survival (DFS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS). A 1:1 ratio PSM analysis was performed using the nearest neighbor method with a caliper of 0.20. Treatment outcomes were compared between 30 matched LAC SCC patients and 30 LAC AC/ASC patients. RESULTS: Before a 1:1 ratio PSM, the 5-year OS, DFS, LRFFS, and DMFS in the LAC SCC group were 78.6%, 71.3%, 88.2%, and 76.2%, respectively. After a 1:1 ratio PSM, the 5-year OS, DFS, LRFFS, and DMFS in the LAC AC/ASC group were 46.0%, 43.3%, 70.0%, and 45.4%, respectively, which were all significantly inferior than the rates of 90.0%, 75.8%, 96.6%, and 78.8% in the matched LAC SCC group, respectively (p < 0.05). CONCLUSION: LAC AC/ASC carries a poorer prognosis than LAC SCC. LAC AC/ASC needs more aggressive treatment in order to achieve higher OS and DFS. PMID- 30025762 TI - Systematic overexpression study to find target enzymes enhancing production of terpenes in Synechocystis PCC 6803, using isoprene as a model compound. AB - Of the two natural metabolic pathways for making terpenoids, biotechnological utilization of the mevalonate (MVA) pathway has enabled commercial production of valuable compounds, while the more recently discovered but stoichiometrically more efficient methylerythritol phosphate (MEP) pathway is underdeveloped. We conducted a study on the overexpression of each enzyme in the MEP pathway in the unicellular cyanobacterium Synechocystis sp. PCC 6803, to identify potential targets for increasing flux towards terpenoid production, using isoprene as a reporter molecule. Results showed that the enzymes Ipi, Dxs and IspD had the biggest impact on isoprene production. By combining and creating operons out of those genes, isoprene production was increased 2-fold compared to the base strain. A genome-scale model was used to identify targets upstream of the MEP pathway that could redirect flux towards terpenoids. A total of ten reactions from the Calvin-Benson-Bassham cycle, lower glycolysis and co-factor synthesis pathways were probed for their effect on isoprene synthesis by co-expressing them with the MEP enzymes, resulting in a 60% increase in production from the best strain. Lastly, we studied two isoprene synthases with the highest reported catalytic rates. Only by expressing them together with Dxs and Ipi could we get stable strains that produced 2.8 mg/g isoprene per dry cell weight, a 40-fold improvement compared to the initial strain. PMID- 30025763 TI - Dynamic modeling of subcellular phenylpropanoid metabolism in Arabidopsis lignifying cells. AB - Lignin is a polymer that significantly inhibits saccharification of plant feedstocks. Adjusting the composition or reducing the total lignin content have both been demonstrated to result in an increase in sugar yield from biomass. However, because lignin is essential for plant growth, it cannot be manipulated with impunity. Thus, it is important to understand the control of carbon flux towards lignin biosynthesis such that optimal modifications to it can be made precisely. Phenylalanine (Phe) is the common precursor for all lignin subunits and it is commonly accepted that all biosynthetic steps, spanning multiple subcellular compartments, are known, yet an in vivo model of how flux towards lignin is controlled is lacking. To address this deficiency, we formulated and parameterized a kinetic model based on data from feeding Arabidopsis thaliana basal lignifying stems with ring labeled [13C6]-Phe. Several candidate models were compared by an information theoretic approach to select the one that best matched the experimental observations. Here we present a dynamic model of phenylpropanoid metabolism across several subcellular compartments that describes the allocation of carbon towards lignin biosynthesis in wild-type Arabidopsis stems. Flux control coefficients for the enzymes in the pathway starting from arogenate dehydratase through 4-coumarate: CoA ligase were calculated and show that the plastidial cationic amino-acid transporter has the highest impact on flux. PMID- 30025764 TI - Pharmacy Education in Saudi Arabia: The Current Status. PMID- 30025765 TI - Promoting a growth mindset in pharmacy educators and students. AB - COMMENTARY: Mindsets are implicit theories that influence how individuals think, act, and respond. Those with a fixed mindset tend to resist learning opportunities; those with a growth mindset embrace learning opportunities. It is important that pharmacy educators work to shift the mindsets of their students toward a growth mindset in order to promote resilience, improve personal outcomes, and enhance attitudes toward learning. Mindsets are not static, and with persistence and effort, can be modified. IMPLICATIONS: Pharmacy educators can do much to influence the mindsets of their learners, and with purposeful effort, can help cultivate an environment that enhances a learner's growth mindset. If an educator is not deliberate, fixed mindsets can be inadvertently promoted to learners, which can result in diminished learning experiences for both student and educator. This commentary will inform pharmacy educators about mindsets and present several teaching and precepting techniques that can help promote a growth mindset among themselves and their learners. PMID- 30025766 TI - Pharmacy resident teaching and learning curriculum program outcomes: Student performance and quality assessment. AB - INTRODUCTION: The purpose of this study was to assess: (1) student performance on topics taught by first and second year postgraduate pharmacy residents and (2) the quality of learning objectives and multiple choice questions prepared by pharmacy residents. METHODS: Using a retrospective cohort design, residents and students who taught or were enrolled, respectively, in the Medication Therapy Management course in years 2010 to 2012 were participants in this study. Student performance was assessed using scores earned on the individual readiness assurance tests (iRATs), team readiness assurance tests (tRATs), and course examinations. To assess the quality of the learning objectives and multiple choice questions written by pharmacy residents, criteria were established by the authors. Each learning objective and multiple choice question was then evaluated independently by two authors to determine if these criteria were met. RESULTS: Statistical differences were observed in student performance across all content areas among the three years for iRAT, tRAT, and course examination scores, with the exception of the heart failure course examination (p = 0.05; all other p values < 0.05). A total of 20 (42%) learning objectives met all quality review criteria, while 73 (79%) of the multiple-choice questions met all quality review criteria. DISCUSSION AND CONCLUSIONS: Student performance varied significantly depending on the content, but the overall impact of resident instructors on student course performance was not educationally significant. Teaching and learning curriculum programs should focus on teaching residents to create quality learning objectives that help students focus on learning the most important course content. PMID- 30025767 TI - Identifying student learning competencies for urban underserved practice using a Delphi process. AB - INTRODUCTION: The pharmacy profession has a growing opportunity to provide high quality patient care to urban underserved patients. The Accreditation Council for Pharmacy Education (ACPE) has also recognized the necessity of training pharmacy students to care for underserved patients within Standard 3.5 in Standards 2016. Despite this recognized need to train students to care for urban underserved patients, there is limited literature to guide schools and colleges of pharmacy in developing learning activities and curricula to meet this need. METHODS: This study utilized a three-round modified Delphi process to develop learning competencies. Participation was solicited from pharmacy practice faculty members of the American Association of Colleges of Pharmacy (AACP) Health Disparities and Cultural Competency Special Interest Group (SIG). This study used a proportion of experts rating agree or strongly agree at 80% to determine consensus. RESULTS: The expert pool had a combined 235 years of pharmacy practice experience in urban underserved settings. Ten learning competencies were developed and finalized: Identified learning competencies related to the development of pharmaceutical and social knowledge base; development of pharmaceutical care and social skills; and building awareness of benefits and disadvantages of working with urban underserved patient populations. DISCUSSION: The learning competencies described in this study provide schools and colleges of pharmacy a tool to help guide learning activity and curricular development to educate students to provide high quality and compassionate care to urban underserved patients. CONCLUSIONS: This study is the first description of practice-based student learning competencies for urban underserved pharmacy practice in the literature. PMID- 30025768 TI - Examining the relationship between prerequisite grades and types of academic performance in pharmacy school. AB - PURPOSE: To investigate relationships between different prerequisite course grades and grade point average (GPA) of different types of academic performance in a Canadian entry-to-practice pharmacy program while controlling for important demographic variables. METHODS: Data from eight years of recently admitted students (2007-2014) were used to conduct a series of multiple linear regression analyses to assess relationships between prerequisite course GPA and eight different pharmacy school academic performance variables including: GPA in each of the first three years of the program, overall Y1-Y3 GPA, and GPA in pharmaceutical science, clinical science, clinical practice, and behavioral, social, and administrative (BSA) science courses. Demographic predictor variables including gender, mature status, and whether students attended ranked versus non ranked universities were included as control variables. RESULTS: Analysis reveals that Biology and Biochemistry prerequisite GPA consistently predicts all eight academic performance variables while prerequisite English GPA was found to predict only clinical practice and BSA GPA. Being female and attending ranked universities were revealed as positively associated with most types of performance. Being classified as a mature student generally predicted lower academic performance. CONCLUSIONS: The consistent relationship between biology based prerequisites and academic performance warrants consideration for increasing their weight in admissions GPA calculations. The fact that the set of prerequisites and demographic variables are weaker predictors of clinical practice and BSA performance than pharmaceutical science performance provides empirical support for recent moves to include non-traditional admission criteria. PMID- 30025769 TI - Allocation of faculty and curricular time to the teaching of transitions of care concepts by colleges of pharmacy. AB - INTRODUCTION: To determine the allocation of faculty and curricular time to the teaching of transitions of care (ToC) concepts by colleges of pharmacy (COPs) to equip students with the necessary skills for the provision of these services. METHODS: A novel 15-question anonymous electronic survey was sent to 136 pharmacy practice chairpersons. RESULTS: Response rate was 26.5% (n = 36). Of these, 47% employed ToC faculty while 44% are not actively recruiting for that position in the foreseeable future. Median total curriculum hours dedicated to teaching ToC was four (interquartile range two to 10 hours). Medication reconciliation skills were taught didactically and via interactive lab sessions by 53% of respondents. Only 11% offered an interdisciplinary ToC program. A significant association between not having ToC faculty and lack of implementation of ToC concepts within a pharmacy curriculum (p = 0.02, Fisher's Exact) and practice site (p = 0.045, Pearson's) was observed. Barriers to adopting ToC within the curriculum (e.g., uncertainty of placement within curriculum, resistance by faculty and administrators) and at a practice site (e.g., inadequate infrastructure to accommodate ToC delivery, ToC faculty unavailability and resistance by other health care providers) were reported. DISCUSSION AND CONCLUSIONS: This study demonstrated that COPs devote curricular time to ToC activities and involve dedicated faculty in the provision of these services. Several barriers to employing ToC faculty and planning additional time in the curriculum for teaching these skills were identified. Future research should determine the best methods for training students to ensure competence in performing ToC tasks. PMID- 30025770 TI - Student pharmacist perceptions of participation in hands-on naloxone counseling. AB - BACKGROUND AND PURPOSE: Opioid overdose is a leading cause of death across the United States. Rho Chi Pharmacy Honor Society students at the University of Kentucky initiated a project to provide fellow students a volunteer opportunity to educate at-risk patients about naloxone using a physician-approved protocol. The goal was to improve student counseling skills by allowing them to apply knowledge learned during didactic and simulated training. EDUCATIONAL ACTIVITY AND SETTING: Third and fourth year pharmacy students at the University of Kentucky voluntarily provided opioid overdose and naloxone counseling to patients at the health department and other locations. Students who counseled at the health department were asked to complete an Institutional Review Board (IRB) approved, anonymous, electronic survey at the end to gauge their perceptions of the experience. FINDINGS: Thirty-five of forty-five participating students responded to the survey, indicating a 78% response rate. The results suggested that student comfort with naloxone counseling increased after real-world counseling, compared with their perceived comfort levels entering the experience. The majority of the respondents (77%, n = 27) reported a change in their personal views on drug addiction and the associated patient population. Ninety-one percent (n = 32) of students plan to pursue certification to dispense naloxone as part of their future pharmacy practice. Most (94%, n = 33) perceived the counseling experience as practical application of their didactic education. DISCUSSION AND CONCLUSIONS: As opioid addiction and accidental overdose plagues the nation, pharmacists are prepared to lead the battle against this disease. Pharmacy education and hands-on opportunities provide students with the practical knowledge and skills necessary to have impact on their patients and the opioid epidemic. PMID- 30025771 TI - Implementation and assessment of a naloxone-training program for first-year student pharmacists. AB - BACKGROUND AND PURPOSE: Develop a naloxone training activity and assess the activity's impact on increasing student pharmacist knowledge and confidence to counsel about management of opioid overdose and naloxone administration. EDUCATIONAL ACTIVITY AND SETTING: First-year student pharmacists participated in a naloxone training activity in an abilities laboratory course. The students completed pre-lab questions, received a brief lecture about responding to an opioid overdose, and then practiced counseling and administering intranasal and intramuscular naloxone using training kits. An Objective Structured Clinical Examination (OSCE) was conducted to assess students' ability to counsel on intranasal naloxone use in response to opioid overdose. Students completed self assessments about their confidence in counseling patients about management of opioid overdose and naloxone administration following the OSCE and at course end. FINDINGS: 158 students participated and the average OSCE score was 82%. In the post-encounter self-assessment, 93% of students agreed or completely agreed that the OSCE improved their confidence in counseling about management of an opioid overdose and intranasal naloxone administration. Fifty-nine students completed the end-of-course survey and >90% of respondents reported they were somewhat or very confident in their ability to administer intranasal or intramuscular naloxone, recognize the opioid overdose symptoms, and counsel about intranasal naloxone use. Confidence in counseling about use of intramuscular naloxone was slightly lower. SUMMARY: Further study of training programs to increase future healthcare professionals' ability to respond to opioid overdoses is warranted. Incorporation of a short training activity can increase student pharmacists' knowledge and confidence in counseling patients about opioid overdose and naloxone administration. PMID- 30025772 TI - Progressive disclosure cases: The design and evaluation of use in multiple therapeutics courses. AB - BACKGROUND AND PURPOSE: Case-based learning is used frequently throughout pharmacy education. Although beneficial, stand-alone cases may result in segmented learning that does not simulate realistic longitudinal patient care. We report the development, implementation, and evaluation of a longitudinal progressive disclosure case surrounding a single patient spanning two different therapeutics courses. EDUCATIONAL ACTIVITY AND SETTING: A patient case was developed surrounding topics in two third professional year therapeutics courses occurring sequentially in the same semester. Changes to the patient's status were provided to students longitudinally via "disclosures." Students were assessed via quizzes and written assessment and plans. Students completed four perceptions of confidence surveys via a four-point Likert Scale. Surveys included questions surrounding confidence in areas of the pharmacists' patient care process (PPCP) before and after courses utilizing the progressive disclosure case. Case assessment grades were used to evaluate the impact on student performance on course examinations. Students also completed a survey on final perceptions of the activity. FINDINGS: Seventy students were enrolled in the two courses participating in the progressive disclosure case and there were 50 (71.4%) matched, completed surveys completed for analysis. Significant improvements were seen in several questions surrounding confidence in the areas of the PPCP between the beginning and conclusion of courses that contained the progressive disclosure case. No correlation between case activity grades and examination performance was found. DISCUSSION AND CONCLUSION: Overall, student confidence in patient care skills associated with information collection, assessment, plan design, and monitoring improved with the use of progressive disclosure cases within two sequential therapeutics courses. PMID- 30025773 TI - Simulated patient cases using DecisionSimTM improves student performance and satisfaction in pharmacotherapeutics education. AB - BACKGROUND AND PURPOSE: Pharmacy education is continuously evolving and incorporation of technology is more prevalent. Computer-based patient cases are being utilised to illustrate complex concepts and develop clinical decision making skills by enabling deliberate practice and continued feedback to scaffold student learning. Simulations are received positively by students but there is limited information on the benefit to student performance. The study aim was to determine the benefits of computer-based cases for oncology therapeutics in terms of student satisfaction and performance. EDUCATIONAL ACTIVITY AND SETTING: Computer based oncology cases were designed using DecisionSimTM technology and introduced to final year pharmacy students. Student satisfaction was measured using a questionnaire with a 5-point Likert scale (1 strongly agree to 5 strongly disagree), and an option for open-ended comments. Performance was measured using results of assessment items in the oncology course compared to a similar course (psychiatric/neurology). FINDINGS: Students found the simulated oncology cases engaged them in learning (median 1.5), had a role in therapeutics education (median 1), and developed decision making skills (median 1). Thematic analysis of open comments suggested it was most beneficial as a self-directed study tool. The students performed significantly higher (p < 0.05) in the oncology end of semester exam (78.6 +/- 8.6) compared to psychiatric/neurology (70.7 +/- 9.6). SUMMARY: A computer-based simulation for oncology pharmacotherapeutics can engage students and develop decision making skills. DecisionSimTM enhanced both student satisfaction and performance in management of oncology cases, and is a beneficial educational tool for teaching complex therapeutic topics to pharmacy students. PMID- 30025774 TI - Massive open online courses in U.S. healthcare education: Practical considerations and lessons learned from implementation. AB - BACKGROUND AND PURPOSE: Massive Open Online Courses (MOOCs) offer an innovative approach to pharmacy education and are expected to challenge traditional pedagogy and foundational knowledge acquisition practices. A survey of the literature reveals no current publications describing implementation of MOOCs in pharmacy education and limited information about MOOC implementation in other healthcare disciplines in the United States. EDUCATIONAL ACTIVITY AND SETTING: A few colleges of pharmacy (COPs) and other health professions' educational programs have recently started offering MOOCs. FINDINGS: Herein we provide an overview of MOOCs and describe the early implementation stages of MOOCs being conducted at two COPs, an interprofessional MOOC, and a variety of MOOCs offered by a public health program. This overview and the four case studies on MOOC implementation in healthcare education provide practical information about course development, descriptions of selected course engagement outcomes, insight into lessons learned by the institutions, and practical considerations for development of future MOOCs. DISCUSSION: MOOCs prompt diversification of models of teaching and learning, transformation of pedagogical frameworks, and innovation in the scholarship of teaching and learning. SUMMARY: MOOCs offer exciting opportunities to distribute knowledge on a massive and global scale to a diverse population of learners. PMID- 30025775 TI - Performance and retention of basic life support skills improve with a peer-led training program. AB - BACKGROUND AND PURPOSE: Pharmacy students' performance and retention of Basic Life Support (BLS) skills were evaluated 120 days after completion of a peer-led BLS training program. EDUCATIONAL ACTIVITY AND SETTING: This was a single-center, parallel group, observational study. Doctor of pharmacy (PharmD) students in their third professional year completed a peer-led BLS training program (n = 148) and participated in a high-fidelity mannequin simulation activity 120 days later. Students were randomly assigned to rapid response teams (n = 24) of five to six members and the American Heart Association's standardized form for BLS assessment was used to assess BLS skills performance. The performance of skills was compared to that of students two years prior to the implementation of the peer-led BLS program. FINDINGS AND DISCUSSION: Students who received peer-led BLS training demonstrated retention of BLS skills 120 days after the BLS training program. The teams also displayed significant improvement of the skills evaluated when compared to student teams prior to implementation of the peer-led training (n = 22). Improvement was demonstrated for assessment of responsiveness (96% vs. 41%, p < 0.001), assessment for breathing (100% vs. 32%, p < 0.001), assessment for pulse (96% vs. 36%, p < 0.001), and administration of appropriate ventilation (100% vs. 32%, p < 0.001). Numerical superiority was exhibited for high-quality cardiopulmonary resuscitation (CPR) initiation by teams who received peer-led training (100% vs. 86%, p = 0.101). SUMMARY: Students who received peer-led BLS training demonstrated significant improvement in BLS skills performance and retention 120 days after the training program. Data suggests that peer-led BLS training can improve student BLS skills performance and retention. PMID- 30025776 TI - Virtual simulation to personalize student learning in a required pharmacy course. AB - BACKGROUND AND PURPOSE: Virtual simulation is used to provide a realistic and safe environment for student pharmacists to learn and practice a variety of skills in the didactic and experiential settings. EDUCATION ACTIVITY AND SETTING: The simulation program, MyDispense, that is used to teach medication dispensing in the outpatient setting was incorporated into a 2-credit hour required first year pharmacy practice skills course. A total of 30 optional and 16 required exercises were completed by students. FINDINGS: There was a total of 2,457 attempts (mean = 28.9 attempts per student) at optional practice exercises and students completed an average of 16.6 +/- 7.9 (range 1-30). While variation in the number of optional practice exercises completed was observed between students with varying levels of pharmacy experience, the difference was not statistically significant. A component of the final exam utilized the virtual simulation program and all students passed this portion of the exam based on a minimum requirement of 70.0% (mean 92.9%, range 74.5-100%). DISCUSSION: Students generally identified that the use of virtual simulation was an effective tool to learn medication dispensing skills in a classroom setting. Furthermore, this created an opportunity for pharmacy practice residents to develop teaching skills. The biggest barrier to implementation was the amount of time required to create and test each exercise. SUMMARY: The virtual simulation program allowed students to self-identify the amount of practice they thought was necessary in order to gain specific skills related to medication dispensing. PMID- 30025777 TI - Counseling our aging population: A training program for pharmacy students on hearing loss. AB - BACKGROUND AND PURPOSE: Hearing loss affects approximately one-third of adults age 61-70 and >80% of those older than 85 years. This can impede the ability to hear medication administration instructions, leading to poor adherence and unnecessary disease progression and complications. The study purpose was to educate students on hearing loss and identify program impact. EDUCATIONAL ACTIVITY AND SETTING: An online program for advanced pharmacy practice experience (APPE) students was developed to train students how to counsel patients with hearing loss to improve medication understanding and adherence. The purpose of the training program was to provide background on hearing loss, increase understanding of the impact hearing loss, and to prepare students to counsel this population. A link from SurveyMonkey was provided upon training program completion. FINDINGS: Ninety-two students completed the survey. Prior to training, < 20% (18.5%) were comfortable interacting with patients with hearing impairment, despite ~50% of these students completing more than three APPEs with direct patient care. The majority (88%) recognized that hearing loss contributes to poor medication adherence. More than 80% believed that the training program improved their understanding of the psychological consequences of hearing loss and ability to counsel patients with hearing loss. Over 70% agreed that the training program made them feel more prepared to counsel patients with hearing loss. DISCUSSION AND SUMMARY: It is crucial to prepare students to better understand this population in order to meet their needs. This program enhanced students' knowledge of hearing loss and increased their understanding of communication barriers. PMID- 30025778 TI - Impact of student to student peer mentoring program in first year of pharmacy program. AB - BACKGROUND AND PURPOSE: Mentoring programs, a practical tool commonly used by universities, can serve to help new students adapt to challenging college life. Peer mentorship offers the potential for professional development of student pharmacists. EDUCATIONAL ACTIVITY AND SETTING: The Raabe College of Pharmacy at Ohio Northern University implemented a peer mentoring program in 2014. This study evaluates the impact of that program on new student pharmacists. A post-program survey was completed evaluating students' career perception, emotional stability, academic success, and student perception of the program's influence on these areas. FINDINGS: The results indicated that 71.7% of respondents found the mentoring program helpful in their transition to college, and that 60.4% of respondents would "somewhat likely" or "extremely likely" stay active in the mentoring program. DISCUSSION: Peer mentorship may serve as a tool to assist student acclimation to the expectations of a professional degree program. SUMMARY: It was concluded that the pharmacy mentorship program at the Raabe College of Pharmacy at Ohio Northern is making a positive impact on first-year students by engaging them in the pharmacy program and aiding their transition from high school to college. PMID- 30025779 TI - Supporting formative peer review of clinical teaching through a focus on process. AB - BACKGROUND: The professional need for development of clinical faculty is clear. Previous scholarship provides insight into the formative potential of peer review in both didactic and experiential settings. Less information exists on a comprehensive peer review process (PRP) designed to support faculty change. EDUCATIONAL ACTIVITY AND SETTING: A clinical faculty PRP was developed and implemented based on input from the literature, stakeholders, and field experts. The process included: 1) self-reflective pre-work, 2) a peer-observation component, 3) self-reflective post-work, and 4) creation of a specific action plan via meeting with an educational expert. The process was assessed by collecting evaluative data from peer reviewer and clinical faculty participants. FINDINGS: Eight of 26 faculty members participated in a pilot of the PRP and formed four clinical faculty-peer dyads. When surveyed, all participants unanimously reported that they would participate in the PRP again. Aspects perceived among most helpful to clinical teaching included peer observation, self reflection, and meeting with an educational expert. Challenges related to the process included anxiety of peer observation, burden of pre-work, and logistics of scheduling meetings. DISCUSSION: While instruments are important in guiding and documenting the evaluation of clinical teaching during an observation period, this initiative focused on the process supporting the observation and evaluation, in order to optimize the formative feedback received by participating faculty and encourage professional development actions. SUMMARY: A PRP that incorporates preparation, reflective practice, and a meeting with an educational expert may support meaningful faculty development in the area of clinical teaching. PMID- 30025780 TI - Comparing student self-assessments of global communication with trained faculty and standardized patient assessments. AB - BACKGROUND AND PURPOSE: Assess the reliability of first year pharmacy student assessments completed by faculty members in comparison with a standardized patient (SP), and student self-assessments during a structured educational module on communication. EDUCATIONAL ACTIVITY AND SETTING: Pharmacy students completed four stations focused on communication with an SP. During each encounter, students completed a self-assessment and were evaluated by a faculty member and a trained SP. A five point Likert scale was used to evaluate student performance. Faculty assessments were compared against all others. A Pearson correlation coefficient for total scores was used and a Cohen's kappa was used to compare inter-rater reliability. Agreement and correlation was performed with student results categorized into poor, adequate, and exceptional performance based on faculty evaluation. FINDINGS: Twenty-four students participated. In all stations, student self-assessments were graded higher than corresponding faculty and SP assessments. Agreement between faculty, SP, and self-assessment was fair to slight (k < 0.4) for all comparisons but only significant (p < 0.05) between the faculty and self-assessment. After categorization, there was a small, non significant correlation between faculty and self-assessment (r = 0.13, p = 0.21) and moderate and significant correlation between faculty and SP (r = 0.32, p = 0.001). Categorized inter-rater agreement was fair for all comparisons (k < 0.2) and only significant (p < 0.05) between faculty and SP assessment. DISCUSSION: Pharmacy students in their first professional year assess their communication skills more positively than other evaluators. Further instruction for students and reflection may be required to build understanding of global assessment in communication. SUMMARY: There is high incongruity between student self-assessment and faculty appraisal. PMID- 30025781 TI - Evaluation of multidisciplinary and pharmacy-only student-run clinics on student's perceptions of interprofessional roles. AB - BACKGROUND AND PURPOSE: To determine how participation in multidisciplinary training workshops and student-run clinics impacts students' perceptions of the role of other health professions. Student perceptions from pharmacy-only versus multidisciplinary smoking cessation clinics were also compared. EDUCATION ACTIVITY AND SETTING: Students from pharmacy, osteopathic medicine, physician assistant, and clinical psychology programs participated in two multidisciplinary smoking cessation training sessions, then provided smoking cessation services to the underserved population in either a multidisciplinary or pharmacy-only student run smoking cessation clinic. Students completed a survey regarding the roles of other healthcare professionals prior to the workshops, after the workshops, and after the smoking cessation clinic. FINDINGS: Fifty-six students attended both smoking cessation training sessions and showed statistically significant increases in familiarity and confidence related to smoking cessation after the training workshops. Forty-two students participated in the ten smoking cessations clinics, which included six multidisciplinary clinics and four pharmacy-only clinics. A statistically significant improvement was seen between the pre workshop survey and post-clinic survey regarding the students' perception of the roles of other healthcare providers in a smoking cessation clinic. Students who participated within the multidisciplinary smoking cessation clinics experienced a significantly greater impact on their perceptions of other healthcare providers than students who participated in the pharmacy-only clinics. SUMMARY: Student participation in a student-run free clinic is an effective method to increase role awareness of other health professional students in an underserved setting. PMID- 30025782 TI - Learning organic chemistry day by day: The best choice of the best pharmacy students. AB - BACKGROUND AND PURPOSE: During over ten years of experience in teaching organic chemistry at the Department of Pharmacy we have tried to answer the following question: why do most students tend to take the exam one, two, or more years after the end of the course they have attended? Several reasons could justify this delay, but three seem to be the most common drawbacks for our students: a) time needed for the comprehension of the arguments; b) the number of mandatory exams to pass before organic chemistry; c) lack of a self-evaluation method. EDUCATIONAL ACTIVITY AND SETTING: To increase the number of students in the exam sessions of the semester just after the course we have proposed two strategies: 1) a systematic, but stressless, approach by which homework and everyday life examples concerning organic chemistry are used to increase the sense of responsibility in studying; 2) the modification of the number of mandatory exams required for organic chemistry. FINDINGS: The rate of successful students in the exam sessions at the end of the course increased from 38.3 up to 61.3%. Interestingly, the highest scores tend to be obtained by students in the first session available just after the conclusion of the course. DISCUSSION AND SUMMARY: The combined effect of Strategy 1 and Strategy 2 seems to be effective in promoting the learning of organic chemistry and points out that the best performances tend to be associated with students which follow organized studying. PMID- 30025783 TI - More than I expected: Reflections on being observed and reviewed as a pharmacy teacher. AB - PURPOSE: Reflection is an important skill development for teachers in order for their improvement in teaching style and practice. One of the ways in which teachers can reflect on their teaching is through peer observation and review. DESCRIPTION: The article describes the process of peer observation and review by three academic teachers from three different disciplines at an Australian university. This process was utilized to assist and enhance the teaching practice of a pharmacy educator, whom has been teaching for > 15 years. Using Brookfield's reflective model through the "eyes" of the four "lenses," the pharmacy educator describes what she has learned and wisdom gained through this reflective practice process. ANALYSIS: The peer observation and review process involved elements including (i) a group verbal feedback and (ii) a written report outlining some strategies that could be utilized to improve teaching practice. Both were considered valuable and the method for providing "sandwiched" feedback utilized verbal and non-verbal cues. CONCLUSIONS: Peer observation is a time consuming exercise that requires valuable time. However, the value that generates from such practices and the insights gained through this process far outweighs time spent. Providing feedback in a safe learning environment and "sandwiching" the positive and negative comments can be an effective process. IMPLICATIONS: The value of reflecting on one's teaching practice can allow teachers to develop and improve their teaching style. Universities and colleges that support this type of reflective practice are likely to generate better teachers who will engage students to enhance their learning. PMID- 30025784 TI - Thematic analysis of qualitative research data: Is it as easy as it sounds? AB - ISSUE: We are seeing the use of qualitative research methods more regularly in health professions education as well as pharmacy education. Often, the term "thematic analysis" is used in research studies and subsequently labeled as qualitative research, but saying that one did this type of analysis does not necessarily equate with a rigorous qualitative study. This methodology review will outline how to perform rigorous thematic analyses on qualitative data to draw interpretations from the data. METHODOLOGICAL LITERATURE REVIEW: Despite not having an analysis guidebook that fits every research situation, there are general steps that you can take to make sure that your thematic analysis is systematic and thorough. A model of qualitative data analysis can be outlined in five steps: compiling, disassembling, reassembling, interpreting, and concluding. MY RECOMMENDATIONS AND THEIR APPLICATIONS: Nine practical recommendations are provided to help researchers implement rigorous thematic analyses. POTENTIAL IMPACT: As researchers become comfortable in properly using qualitative research methods, the standards for publication will be elevated. By using these rigorous standards for thematic analysis and making them explicitly known in your data process, your findings will be more valuable. PMID- 30025785 TI - Skin autofluorescence: Correlation with measures of diabetic sensorimotor neuropathy. AB - OBJECTIVE: Advanced glycation end products (AGE) contribute to the development of diabetes complications. Their accumulation in skin can be non-invasively assessed by measurement of skin autofluorescence (SAF). Our study investigated whether SAF correlates with measures of diabetic peripheral neuropathy (DPN). METHODS: In a multi-center study (8 centers), 497 consecutive individuals with diabetes mellitus were investigated. Forearm SAF was measured using the AGE Reader (Groningen, The Netherlands). DPN was assessed using the Toronto Clinical Neuropathy Score (TCNS), the Neuropathy Symptoms Score (NSS) and the Neuropathy Disability Score (NDS). RESULTS (MEAN +/- SD): According to the TCNS, SAF (arbitrary units - AU) was increased in individuals with DPN (TCNS > 5): 2.59 +/- 0.56 AU compared with those without DPN (TCNS <= 5): 2.45 +/- 0.53 AU, (p = 0.04) and significantly increased with the severity of DPN (p = 0.028). Higher SAF was detected in individuals with neuropathic deficits (NDS > 2): 2.58 +/- 0.56 AU vs. those without deficits (NDS <= 2): 2.45 +/- 0.53 AU, (p = 0.009) as well as in individuals with symptoms (NSS > 2): 2.54 +/- 0.56 AU vs. those without symptoms (NSS <= 2): 2.40 +/- 0.47 AU, (p = 0.022). CONCLUSIONS: Accumulation of AGE in skin is increased in individuals with DPN and progresses with the severity of DPN. Therefore, SAF measurement, an easy-to-use, quick and non-invasive method, might help in identifying subjects at high risk for having DPN. PMID- 30025786 TI - Serum levels of chemokines IP-10, IL-8 and SDF-1 serve as good biomarkers for diabetes-tuberculosis nexus. AB - BACKGROUND: Inflammation has long been identified as an essential component of both Type-2 diabetes and tuberculosis. Chemokines are low molecular weight proteins which play an important role in both inflammation (diabetes) and immunity (tuberculosis). METHODS: In this study, we measured the serum levels of IP-10, IL-8 and SDF-1 in subjects with Normal Glucose Tolerance (NGT-TB- = 108; NGT-TB+ = 200), Pre-Diabetes (PDM-TB- = 118; PDM-TB+ = 105), Newly Diagnosed Diabetes (NDM-TB- = 105; NDM-TB+ = 63) and Known Diabetes (KDM-TB- = 131; KDM-TB+ = 108), by ELISA. Along with chemokines pro-inflammatory cytokines TNF-alpha and IL-6 were also measured in these groups. RESULTS: While IP-10 levels were significantly reduced in TB+ subjects in all the sub-groups, IL-8 levels were significantly reduced in NDM-TB+ and increased in KDM-TB+ subjects. SDF-1 levels were significantly elevated in TB+ subjects in all the subgroups, except for KDM TB+. CONCLUSION: Altered serum chemokine levels can alter anti-TB immunity in diabetes patients and can fuel DM-TB nexus. PMID- 30025787 TI - Influence of sex and estrous cycle on blood glucose levels, body weight gain, and depressive-like behavior in streptozotocin-induced diabetic rats. AB - Depression is the most common psychiatric disorder in diabetic patients, showing higher rates in women than in men. This comorbidity has been studied in rodents using the streptozotocin (STZ)-induced diabetes (DM) model, consistently reporting a depressive-like profile in males. Few articles have examined these disturbances in females (ovariectomized or combined with male rats) yielding controversial results. This work was aimed to study whether there are sex differences in the depressive-like profile of STZ-treated male and naturally cycling female Wistar rats. We also analyzed the possible influence of the estrous cycle in females. DM was induced by injecting STZ (50 mg/kg, i.p.) in 2 consecutive days. Ten days later, the depressive-like profile was assessed in the Forced-Swim Test (FST). Locomotion and motor coordination were also evaluated. Body weight and blood glucose levels were registered at the beginning and at the end of the experiment; the estrous cycle, food and water intake were daily monitored. All diabetic subjects showed increased blood glucose levels, polyphagia, polydipsia and decreased body weight as compared to controls, but males were more susceptible to STZ-treatment than females pooled in all phases of the estrous cycle. After treatment with STZ, males and females in proestrus/estrus (P/E) exhibited a depressive-like profile in the FST (increased immobility and reduced swimming); females in metestrus/diestrus were unaffected. The only sex difference observed was a more pronounced reduced swimming in STZ treated P/E females compared with hyperglycemic males. No changes in locomotion or motor coordination were found. This work emphasizes estrous cycle differences in STZ-treated rats, and in the resultant depressive-like profile. It also supports clinical evidences made in women with DM and stresses the importance of studying STZ-treated naturally cycling females and their estrous cycle phases. PMID- 30025788 TI - Mathematical assessment of the role of Dengvaxia vaccine on the transmission dynamics of dengue serotypes. AB - A new mathematical model is designed and used to assess the impact of the newly released Dengvaxia vaccine on the transmission dynamics of two co-circulating dengue strains (where strain 1 consists of dengue serotypes 1, 3 and 4; and strain 2 consists of dengue serotype 2). It is shown that the model exhibits the phenomenon of backward bifurcation when the disease-induced mortality in the host population exceeds a certain threshold value or if the vaccine does not provide perfect protection against infection with the two strains. In the absence of backward bifurcation, the disease-free equilibrium of the model is shown to be globally-asymptotically stable whenever the associated reproduction number is less than unity. It is shown that the community-wide use of the vaccine could induce positive, negative or no population-level impact, depending on the sign of a certain epidemiological threshold quantity (known as the vaccine impact factor). Simulations of the model, using data from Oaxaca, Mexico, show that, although the community-wide use of the vaccine will significantly reduce dengue burden in the community, it is unable to lead to the elimination of the two dengue strains. It is further shown that the use of Dengvaxia vaccine in dengue naive populations may induce increased risk of severe disease in these populations. PMID- 30025789 TI - Fast and slow thinking: Electrophysiological evidence for early conflict sensitivity. AB - Popular dual process models have characterized reasoning as an interplay between fast, intuitive (System 1) and slow, deliberate (System 2) processes, but the precise nature of the interaction between the two systems is much debated. Here we relied on the temporal resolution of electroencephalogram (EEG) recordings to decide between different models. We adopted base-rate problems in which an intuitively cued stereotypical response was either congruent or incongruent with the correct response that was cued by the base-rates. Results showed that solving problems in which the base-rates and stereotypical description cued conflicting responses resulted in an increased centro-parietal N2 and frontal P3. This early conflict sensitivity suggests that the critical base-rates can be processed fast without slow and deliberate System 2 reflection. Findings validate prior EEG work and support recent hybrid dual process models in which the fast System 1 is processing both heuristic belief-based responses (e.g., stereotypes) and elementary logico-mathematical principles (e.g., base-rates). PMID- 30025790 TI - Comparing adaptation in emotional and non-emotional conflict in patients with schizophrenia and borderline personality disorder. AB - Research on conflict adaptation suggests that complex networks are involved in the detection and resolution of conflicts. These networks are believed to be different depending on whether the conflict occurs in emotional or non-emotional contexts. In addition, the adaptation to both types of conflict also seems to have different neural bases. The main aim of the present study was to compare conflict adaptation in two clinical groups - patients with schizophrenia (SZ) and patients with borderline personality disorder (BPD) - and a healthy control group during emotional and non-emotional versions of a facial Stroop task. We considered that the neural impairment and neuropsychological profile of these populations would be interesting to examine the above-mentioned mechanisms. Results showed that the performance was worse with incongruent compared to congruent stimuli in both task contexts. The Stroop effect was more marked in both clinical groups and greater in the SZ group. By contrast, the Gratton effect was clearly present in the SZ group, but was inverted in the BPD group mainly in the emotional task. Specifically, participants with BDP had a higher error rate in the current incongruent trial when the previous trial was incongruent in the emotional task. These results suggest that SZ and BDP groups have different patterns of conflict adaptation. Results are discussed according to the clinical characteristics and neural systems affected in each of these psychopathological disorders. PMID- 30025791 TI - Anterior chamber parameters in early and advanced keratoconus. A meridian by meridian analysis. AB - PURPOSE: To explore anterior segment changes with keratoconus onset and progression to determine whether structural changes are predominantly corneal, limbal or both. To investigate these changes in different corneal meridians. METHOD: Eighty-four eyes with keratoconus and 49 healthy eyes were included in the study. Eyes with keratoconus were divided in two groups according to the Amsler-Krumeich classification: stage I and stages II-IV. Scheimpflug images at three different meridians were used to evaluate the following parameters: anterior chamber depth from the endothelium (ACD_end) and corneal thickness (CT) (software provided), anterior chamber depth (ACD) and sagittal depth (SAGT) from the epithelium, and distance from the end point of SAGT to the anterior surface of the lens (DL) (measured manually), and [ACD - CT] and [SAGT - CT] (calculated). Changes in these parameters with ocular condition and meridian were analysed. RESULTS: Statistically significant larger values were found of ACD (p = 0.012) and DL (p = 0.016) with keratoconus onset and progression, with no differences in SAGT values. Besides, [ACD - CT] and [SAGT - CT] were significantly larger in keratoconus eyes (p < 0.001 and p = 0.003, respectively). Significant differences (all p < 0.001) were found in SAGT, [SAGT - CT] and DL among meridians. Changes in these parameters with keratoconus onset and progression were similar in all meridians. CONCLUSION: Considering the results from the three meridians under investigation, it may be concluded that keratoconus onset has an impact on the anterior segment as a whole and not only on corneal structures. The DL distance is a useful parameter to describe limbal changes in keratoconus. PMID- 30025792 TI - Metabolomic and glycomic findings in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is a stressor-related disorder that develops in a subset of individuals exposed to a traumatic experience. Factors associated with vulnerability to PTSD are still not fully understood. PTSD is frequently comorbid with various psychiatric and somatic disorders, moderate response to treatment and remission rates. The term "theranostics" combines diagnosis, prognosis, and therapy and offers targeted therapy based on specific analyses. Theranostics, combined with novel techniques and approaches called "omics", which integrate genomics, transcriptomic, proteomics and metabolomics, might improve knowledge about biological underpinning of PTSD, and offer novel therapeutic strategies. The focus of this review is on metabolomic and glycomic data in PTSD. Metabolomics evaluates changes in the metabolome of an organism by exploring the set of small molecules (metabolites), while glycomics studies the glycome, a complete repertoire of glycan structures with their functional roles in biological systems. Both metabolome and glycome reflect the physiological and pathological conditions in individuals. Only a few studies evaluated metabolic and glycomic changes in patients with PTSD. The metabolomics studies in PTSD patients uncovered different metabolites that might be associated with psychopathological alterations in PTSD. The glycomics study in PTSD patients determined nine N-glycan structures and found accelerated and premature aging in traumatized subjects and subjects with PTSD based on a GlycoAge index. Therefore, further larger studies and replications are needed. Better understanding of the biological basis of PTSD, including metabolomic and glycomic data, and their integration with other "omics" approaches, might identify new molecular targets and might provide improved therapeutic approaches. PMID- 30025793 TI - Effect of age onset on schizophrenia-like phenotypes and underlying mechanisms in model mice. AB - In humans, schizophrenia with onset in adolescence or adult has distinct features. To understand whether schizophrenia with either adolescence- or adult onset have distinct phenotypes and cellular mechanisms in schizophrenia model mice, we altered Nrg1 signaling during either adolescence or adult mice via injection of anti-Nrg1 antibodies. We found that in either early-onset schizophrenia (EOS)- or late-onset schizophrenia (LOS)-like mice, certain behavior phenotypes are shared including hyperlocomotion, impaired working memory and impaired fear conditioning. Anxiety appears to be largely unaffected. In vitro electrophysiology in brain slices showed altered excitation/inhibition balance in EOS-like mice towards enhanced synaptic excitation, but intrinsic excitability of the fast-spiking GABAergic neurons was elevated in the LOS-like mice. Thus, although schizophrenia-like main phenotypes appear to be preserved in both age onset model mice, there are distinct differences in cellular mechanisms between them. We suggest that these differences are important for more precise diagnosis and more effective treatment of schizophrenia. PMID- 30025794 TI - Knockdown of CLC-3 in the hippocampal CA1 impairs contextual fear memory. AB - Previous studies support a critical role of hippocampus in contextual fear memory. Structural and functional alterations of hippocampus occur frequently in posttraumatic stress disorders (PTSD). Recent reports reveal that knockout of CLC 3, a member of the CLC family of anion channels and transporters, leads to neuronal degeneration and loss of hippocampus. However, the role of CLC-3 in contextual fear memory remains unknown. Using adenovirus and adeno-associated virus gene transfer to knockdown CLC-3 in hippocampal CA1, we investigate the role of CLC-3 in contextual fear memory. CLC-3 expression is increased in hippocampal CA1 after formation of long-term contextual fear memory. Knockdown of CLC-3 by adenovirus infusion in hippocampal CA1 significantly attenuates the contextual fear memory, reduces spine density, induces defects of excitatory synaptic ultrastructure showed by the decreased PSD length, PSD thickness and active zone length, and impairs L-LTP induction and maintenance. Knockdown of CLC 3 also induces the synaptic NMDAR subunit composition to an increased GluN2A/GluN2B ratio pattern and reduces the activity of CaMKII-alpha. Furthermore, selectively knockdown of CLC-3 in excitatory neurons by adeno associated virus driven from CaMKII-alpha promoter is sufficient to impair long term contextual fear memory. These findings highlight that CLC-3 in hippocampal CA1 is necessary for contextual fear memory. PMID- 30025795 TI - Scale-up of continuous multicolumn chromatography for the protein a capture step: From bench to clinical manufacturing. AB - The awareness about implementing continuous processing for biopharmaceutical products has significantly increased throughout the recent years not only at developmental scale but also for phase I supply in clinical trial manufacturing. In this study, we focused on upscaling continuous protein A chromatography from lab to pilot scale using the CadenceTM BioSMB PD and the CadenceTM BioSMB Process 80 system, respectively. Additionally, we evaluated hardware and software capability whilst running the system for 10 days non-stop using feed from a perfusion bioreactor. In terms of product quality and removal of impurities, comparable data was obtained regarding lab scale and production scale. Compared to batch mode, productivity was increased by 400 to 500%. Furthermore, the system worked accurately during the whole trial, proving its potential for the implementation into a hybrid or an end-to-end continuous process. PMID- 30025796 TI - Life after a gastrectomy: Experience of patients with gastric cancer. AB - OBJECTIVE: To describe the experience of patients with gastric cancer who have undergone gastrectomy. METHOD: Qualitative study with 17 adults who underwent total gastrectomy in a cancer care centre in Bogota, Colombia. The approach was phenomenological using the analysis proposed by Colaizzi. Descriptive codes, nominal codes and categories were identified as central issues. In-depth interviews were used and theoretical saturation sampling. RESULT: From 165 descriptive codes, 27 nominal codes emerged that make up 6 subjects that describe the experience of the person who has undergone total gastrectomy: 1) a new opportunity, 2) a foreign body, 3) yearning to feel useful, 4) understanding other treatments, 5) sensing discomfort and symptoms, and 6) eating what I can. CONCLUSIONS: The patient who has undergone total gastrectomy faces an experience as a cancer survivor that involves understanding how to manage physical discomfort, adaptation to diet, economic difficulty and unemployment. Viewing the experience as a new opportunity, and the requirements of other treatments implies having a social, emotional and spiritual support network. It is essential to consolidate monitoring programmes for survivors that respond in a timely manner to their needs. PMID- 30025797 TI - The use of home non-invasive ventilation and the reduction of inhospital mortality of patients with respiratory failure. AB - OBJECTIVES: To establish the relationship between the use of home non-invasive ventilation (NIV) and inhospital mortality in people admitted due to exacerbation of their respiratory disease. METHODS: Retrospective cohort study with 191 cases of patients attended at the emergency department of the Reina Sofia General University Hospital in Murcia due to ARF of any cause and who required NIV as supportive treatment. RESULTS: Mortality among patients using NIV as routine home treatment was 6.45%, compared to 20.1% among those who did not use it (P<.05). CONCLUSIONS: routine domiciliary treatment with NIV has been shown to be a protective factor against inpatient hospital mortality for patients who underwent NIV during their admission, through the emergency department, for acute respiratory failure or acute chronic disease, regardless of the triggering pathology. PMID- 30025798 TI - Isolation of a divergent strain of Rickettsia japonica from Dew's Australian bat Argasid ticks (Argas (Carios) dewae) in Victoria, Australia. AB - A divergent strain of Rickettsia japonica was isolated from a Dew's Australian bat argasid tick, Argas (Carios) dewae, collected in southern Victoria, Australia and a full-genome analysis along with sequencing of 5 core gene fragments was undertaken. This isolate was designated Rickettsia japonica str. argasii (ATCC VR 1665, CSUR R179). PMID- 30025800 TI - The Reply. PMID- 30025799 TI - Lutescins A and B, two new ellagitannins from the twigs of Trigonostemon lutescens and their antiproliferative activity. AB - Two new ellagitannins, lutescins A and B (1-2), along with eight known compounds (3-10), were isolated from the twigs of Trigonostemon lutescens. Their structures were elucidated by extensive spectroscopic analyses as well as by comparison with literature data. Compounds 1 and 2 are the first examples of ellagitannins reported in Trigonostemon Genus, and their structures featured a hexahydroxydiphenoyl (HHDP) moiety less often as R configurations in natural products. In addition, all isolated compounds were tested for their inhibitory effects against HeLa, HCT116 and HepG2 cancer cell lines. Compounds 1, 2, 5 showed potent antiproliferative activity, compared with the positive control Cisplatin. PMID- 30025801 TI - Reply to "Work-up for mitochondrial small fiber neuropathy requires application of skin biopsies". PMID- 30025802 TI - Work-up for mitochondrial small fiber neuropathy requires application of skin biopsies. PMID- 30025804 TI - Deep learning for detection of focal epileptiform discharges from scalp EEG recordings. AB - OBJECTIVE: Visual assessment of the EEG still outperforms current computer algorithms in detecting epileptiform discharges. Deep learning is a promising novel approach, being able to learn from large datasets. Here, we show pilot results of detecting epileptiform discharges using deep neural networks. METHODS: We selected 50 EEGs from focal epilepsy patients. All epileptiform discharges (n = 1815) were annotated by an experienced neurophysiologist and extracted as 2 s epochs. In addition, 50 normal EEGs were divided into 2 s epochs. All epochs were divided into a training (n = 41,381) and test (n = 8775) set. We implemented several combinations of convolutional and recurrent neural networks, providing the probability for the presence of epileptiform discharges. The network with the largest area under the ROC curve (AUC) in the test set was validated on seven independent EEGs with focal epileptiform discharges and twelve normal EEGs. RESULTS: The final network had an AUC of 0.94 for the test set. Validation allowed detection of epileptiform discharges with 47.4% sensitivity and 98.0% specificity (FPR: 0.6/min). For the normal EEGs in the validation set, the specificity was 99.9% (FPR: 0.03/min). CONCLUSIONS: Deep neural networks can accurately detect epileptiform discharges from scalp EEG recordings. SIGNIFICANCE: Deep learning may result in a fundamental shift in clinical EEG analysis. PMID- 30025803 TI - Reply to "Clinical practice guidelines or clinical research guidelines?" PMID- 30025805 TI - Definition: Dual-tasking and multitasking. PMID- 30025807 TI - Improving management of neonatal infections. PMID- 30025809 TI - Acute rheumatic fever. AB - Acute rheumatic fever is caused by an autoimmune response to throat infection with Streptococcus pyogenes. Cardiac involvement during acute rheumatic fever can result in rheumatic heart disease, which can cause heart failure and premature mortality. Poverty and household overcrowding are associated with an increased prevalence of acute rheumatic fever and rheumatic heart disease, both of which remain a public health problem in many low-income countries. Control efforts are hampered by the scarcity of accurate data on disease burden, and effective approaches to diagnosis, prevention, and treatment. The diagnosis of acute rheumatic fever is entirely clinical, without any laboratory gold standard, and no treatments have been shown to reduce progression to rheumatic heart disease. Prevention mainly relies on the prompt recognition and treatment of streptococcal pharyngitis, and avoidance of recurrent infection using long-term antibiotics. But evidence for the effectiveness of either approach is not strong. High-quality research is urgently needed to guide efforts to reduce acute rheumatic fever incidence and prevent progression to rheumatic heart disease. PMID- 30025811 TI - The role of ASCT2 in cancer: A review. AB - Reorganization of cellular metabolism is one of the hallmarks of cancer and many tumors show high glucose uptake and glutamine addiction. Glutamine is imported by the SLC family transporters from the microenvironment, and ASCT2 (encoded by the SLC1A5 gene) is recognized as a primary transporter. Of note, ASCT2 is overexpressed in different cancers and is closely related to poor prognosis. Nonetheless, the mechanisms regulating ASCT2 activity has not been elucidated. Moreover, several inhibitors of ASCT2 have emerged and shown a surprising antitumor effect. In conclusion, this review describes the function, regulatory mechanism, and inhibitors of ASCT2 in cancer, suggesting that high expression of ASCT2 is a promising prognostic marker and a potential drug target. PMID- 30025810 TI - Viral gastroenteritis. AB - Enteric viruses, particularly rotaviruses and noroviruses, are a leading cause of gastroenteritis worldwide. Rotaviruses primarily affect young children, accounting for almost 40% of hospital admissions for diarrhoea and 200 000 deaths worldwide, with the majority of deaths occurring in developing countries. Two vaccines against rotavirus were licensed in 2006 and have been implemented in 95 countries as of April, 2018. Data from eight high-income and middle-income countries showed a 49-89% decline in rotavirus-associated hospital admissions and a 17-55% decline in all-cause gastroenteritis-associated hospital admissions among children younger than 5 years, within 2 years of vaccine introduction. Noroviruses affect people of all ages, and are a leading cause of foodborne disease and outbreaks of gastroenteritis worldwide. Prevention of norovirus infection relies on frequent hand hygiene, limiting contact with people who are infected with the virus, and disinfection of contaminated environmental surfaces. Norovirus vaccine candidates are in clinical trials; whether vaccines will provide durable protection against the range of genetically and antigenically diverse norovirus strains remains unknown. Treatment of viral gastroenteritis is based primarily on replacement of fluid and electrolytes. PMID- 30025808 TI - Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study. AB - BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95.4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13.2 (95% credible interval [CrI] 11.2-15.6) per 1000 livebirths and of viral infections was 10.1 (9.4-11.6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5.4, 95% CrI 4.8-6.3 episodes per 1000 livebirths), followed by Ureaplasma spp (2.4, 1.6-3.2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation. PMID- 30025812 TI - Unravelling the intravenous and in situ vasopressin effects on the urinary bladder in anesthetized female rats: More than one vasopressin receptor subtype involved? AB - Urinary bladder dysfunctions show high prevalence in women. We focused to investigate the intravenous and in situ (topic) vasopressin effects on the bladder and also to characterize the vasopressin receptor subtypes in the bladder. Adult female Wistar rats anesthetized with isoflurane underwent to the cannulation of the femoral artery and vein, and also urinary bladder for mean arterial pressure, heart rate and intravesical pressure (IP) recordings, respectively. Doppler flow probe was placed around the renal artery for blood flow measurement. After baseline recordings, intravenous injection of saline or vasopressin at different doses (0.25, 0.5, 1.0 ng/ml/kg of b.w.); or 0.1 ml of saline or 0.1 ml of vasopressin at different doses (0.25, 0.5, 1.0 ng/ml) was randomly dropped on the bladder. In another group of rats, the UB was harvest for gene expression by qPCR and also for protein expression by Western blotting of the vasopressin receptor subtypes. We observed that either intravenous or in situ vasopressin evoked a huge increase in the IP in a dose-dependent manner compared to saline, whilst no differences were observed in the cardiovascular parameters. The genes and the protein expression of V1a, V1b and V2 vasopressin receptors subtypes were found in the bladder. Intravenous injection of V1a or V2 receptor antagonist evoked a huge fall in IP and 30 min later, i.v or in situ vasopressin evoked responses on IP were significantly attenuated. Therefore, intravenous or in situ vasopressin increases the IP due to binding in V1a or V2 receptors localized in the bladder. PMID- 30025813 TI - Inhibition of microRNA-505 suppressed MPP+ -induced cytotoxicity of SHSY5Y cells in an in vitro Parkinson's disease model. AB - Parkinson's disease (PD) is a progressive and incurable neurodegenerative disorder. In this study, we utilized SHSY5Y cells an in vitro PD model to study the biological function of microRNA-505 (miR-505) in 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity. SHSY5Y cells were treated with MPP+ to induce PD associated cell death and cytotoxicity. MiR-505 was found to be upregulated by MPP+ . Lentiviral transduction mediated miR-505 downregulation protected SHSY5Y cells from MPP+ -induced cell death, whereas miR-505 upregulation had no effect on MPP+ -induced SHSY5Y cell death. MiR-505 downregulation also ameliorated MPP+ induced cytotoxicity, by preserving MMP and reducing LDH level, caspase-3 and reactive oxygen species activities. Possible downstream target of miR-505, neural proliferation, differentiation and control 1 (NPDC1) was confirmed to be the downstream target of miR-505 in SHSY5Y cells. In addition, NPDC1 knockdown was shown to reverse the protection of miR-505-downregulation on MPP+ -induced cytotoxicity. Thus, our study demonstrated that miR-505, by inversely regulating NPDC1 may have a functional role in regulating human Parkinson's disease. PMID- 30025814 TI - Characterisation and antidiabetic utility of a novel hybrid peptide, exendin 4/gastrin/xenin-8-Gln. AB - Enteroendocrine derived hormones such as glucagon-like-peptide-1 (GLP-1), glucose dependent insulinotropic polypeptide (GIP), gastrin and xenin are known to exert complementary beneficial metabolic effects in diabetes. This study has assessed the biological activity and therapeutic utility of a novel GLP-1/gastrin/xenin hybrid peptide, namely exendin-4/gastrin/xenin-8-Gln hybrid, both alone and in combination with the stable GIP mimetic, (DAla2)GIP. Exendin-4/gastrin/xenin-8 Gln increased in vitro insulin secretion to a similar or superior extent, as the parent peptides. Insulinotropic effects were mainly linked to modulation of GLP-1 and neurotensin receptors. Exendin-4/gastrin/xenin-8-Gln also augmented the insulinotropic actions of (DAla2)GIP. Acute administration of exendin 4/gastrin/xenin-8-Gln in mice induced significant appetite suppressive, glucose lowering and insulin secretory effects, with a duration of biological action beyond 8 h. Twice daily administration of exendin-4, exendin-4/gastrin/xenin-8 Gln, either alone or in combination with (DAla2)GIP, reduced circulating glucose, increased plasma insulin as well as improving glucose tolerance, insulin sensitivity and metabolic response to GIP in high fat fed mice. Body weight, food intake, circulating glucagon and amylase activity were unaltered. All hybrid peptide treated high fat mice exhibited marked reductions in LDL-cholesterol and body fat mass. Energy expenditure and locomotor activity were increased in mice treated with exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP. Interestingly, exendin-4 and exendin-4/gastrin/xenin-8-Gln treatment, but not exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP, reduced pancreatic islet and beta-cell area when compared to high fat controls. These studies confirm that unimolecular multi-agonist peptide hormones exert beneficial metabolic effects in diabetes, highlighting their potential as novel treatment strategies. PMID- 30025815 TI - Effects of hypoxia exposure on apoptosis and expression of membrane steroid receptors, ZIP9, mPRalpha, and GPER in Atlantic croaker ovaries. AB - Hypoxia exposure causes endocrine disruption in croaker resulting in impairment of ovarian growth and oocyte development, but the effects of hypoxia on non classical steroid actions in fish ovaries in vivo remain largely unknown. Membrane androgen receptor (ZIP9) enhances apoptosis of cultured Atlantic croaker ovarian follicle cells via upregulation of p53 and Bax, and increased caspase 3 activity through non-classical steroid signaling. Conversely, apoptosis is inhibited in these cells by non-classical steroid mechanisms through membrane progestin receptor alpha (mPRalpha) and G protein-coupled estrogen receptor (GPER). Apoptosis and the expression of ZIP9, mPRalpha, and GPER were investigated in ovaries of croakers that had been exposed to normoxia (7.0 mg DO/L) or hypoxia (2.0 mg DO/L) for 6 weeks during their period of gonadal recrudescence. The proportion of tertiary yolk stage oocytes was decreased, and the proportions of atretic and apoptotic ovarian follicles were increased in ovaries from hypoxia-exposed fish compared to controls. Ovarian expression of all three receptors was altered after hypoxia exposure. Expression of mPRalpha and GPER mRNA and protein levels were decreased after hypoxia exposure, consistent with a decline in anti-apoptosis. In contrast, ZIP9 mRNA and protein levels were upregulated 4-fold in hypoxia-exposed fish compared to normoxic controls. The enhanced apoptosis in ovaries of hypoxia-exposed fish was associated with increased caspase-3/7 activity and elevated expression of the pro-apoptotic genes, Bax and p53. The finding that ZIP9 expression was increased in ovaries of croaker exposed to hypoxia provides in vivo evidence supporting ZIP9's proposed function in mediating ovarian follicle cell apoptosis. PMID- 30025816 TI - Current status of the megabenthic community in coastal Fukushima Prefecture, Japan, in the wake of the Great East Japan Earthquake. AB - We conducted fisheries-independent bottom-trawl surveys along the coast of Fukushima, Japan, from 2013 to 2017 to study the megabenthic community structure after the 2011 earthquake, tsunami, and nuclear disaster. Although we observed no substantial changes in biodiversity, total abundance and biomass fluctuated among years, primarily because of temporary increases in the abundance or biomass of small shrimp and squid, or variations in abundance or biomass of mid-sized fishes (i.e. puffers and flatfishes) and large elasmobranchs. Echinoderm abundance and biomass decreased in all areas. Crustacean abundance and biomass were extremely low in the central and southern offshore transects. Our results suggest that there has been no recognizable recovery in the megabenthic community, and megabenthic species off the coast of Fukushima might have been experiencing reproductive or recruitment failure. Further research is needed to reveal the causal factors behind changes in these megabenthic communities. PMID- 30025817 TI - Mutation analysis at 17 Y-STR loci (Yfiler) in father-son pairs of male pedigrees from Pakistan. PMID- 30025818 TI - Systemic lupus erythematosus-myasthenia gravis overlap syndrome: Presentation and treatment depend on prior thymectomy. AB - In this study, we investigated four patients who met the diagnostic criteria for overlapping systemic lupus erythematosus (SLE) and myasthenia gravis (MG) but responded differently to treatment. All patients were acetylcholine receptor (AChR) and antinuclear antibody positive at the time of SLE diagnosis. Two patients presented with SLE who have been effectively treated with cholinesterase inhibitors for MG. These patients developed SLE with photosensitivity, rash, and arthritis post thymectomy, which had been performed 29 years and 40 years earlier, respectively. Two other patients were found to have AChR antibodies and MG in the context on new-onset SLE. These subjects were responsive to hydroxychloroquine and immunosuppression but failed cholinesterase inhibitors. The evolution of these cases is relevant for the role of thymus in lupus pathogenesis during aging and for treatment selection in SLE-MG overlap patients. PMID- 30025819 TI - Effects of HLA status and HER2 status on outcomes in breast cancer patients at risk for recurrence - Implications for vaccine trial design. AB - Immunotherapy, using peptide-based cancer vaccines is being studied to assess its potential in breast cancer. Trials of HLA-restricted peptide vaccines have been difficult to enroll given HLA subtype restrictions. It is necessary to determine the prognostic significance of HLA-status in breast cancer if patients who are ineligible to receive a vaccine due to their HLA-status are used as controls. The impact of targeted tumor associated antigen expression, when it effects eligibility is also important. We examined control patients from two randomized phase II trials that tested HER2-peptide vaccines to determine the effect of HLA A2 status and HER2 expression on disease-free survival. The analysis showed that HLA-A2-status does not affect disease-free survival, regardless of HER2 expression suggesting that HLA-A2 negative patients can be used as control patients. Additionally, HER2 over-expression was associated with a better disease free survival in this population, underscoring the need for additional therapies in HER2 low-expressing breast cancer. ClinicalTrials.gov Identifier: NCT00524277. PMID- 30025820 TI - Prioritizing the integration of geriatric oncology and palliative care. PMID- 30025821 TI - Immunotherapy and targeted therapies in older patients with advanced melanoma; Young International Society of Geriatric Oncology review paper. AB - Malignant melanoma is an aggressive cancer associated with a poor prognosis in patients with metastatic disease. As in many other cancers, the incidence of melanoma rises with age; and combined with the longer life expectancy, this led to an increasing prevalence of melanoma in the older population. Recently, immune checkpoint inhibitors significantly improved the treatment of melanoma given their efficacy and tolerability profile. Two major classes of agents include the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, such as ipilimumab, and the anti-programmed death-ligand 1 (PD-1) inhibitors, such as nivolumab and pembrolizumab. Treatment of metastatic disease with immune checkpoint inhibitors demonstrated improved efficacy and better safety profiles compared to cytotoxic drugs and appears to be an attractive treatment option. Nevertheless, there is a need for tools designed to better predict which older patients will benefit from its use and who will experience toxicities related to the treatment. Current data do not show a major increase in toxicity rates in older patients. However, patients above 75 are often under-represented and those who are included are not representative of the general population of older patients, thereby also stressing the need for real-life data. Ongoing research is aiming at maximizing the potential treatment efficacy and developing novel immune targeting modalities. Future studies should include older patients and assess geriatric domains in these older patients to better guide decision-making. This review discusses published clinical trials and where known, the efficacy and toxicity in older patients. Moreover, the clinical implications and future perspectives are discussed, with current recommendations for older patients, management of toxicities, and a proposal for an initial approach to the treatment of older patients with metastatic melanoma. PMID- 30025822 TI - Radiosensitization by the PARP inhibitor olaparib in BRCA1-proficient and deficient high-grade serous ovarian carcinomas. AB - OBJECTIVE: Approximately 15-25% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1/2 mutations. Inhibition of Poly (ADP-ribose) polymerase (PARP) is synthetically lethal to cells and tumors with BRCA1/2 mutation. Our goal was to investigate the radiosensitizing effects of PARP inhibitor olaparib in HGSOC with different BRCA1 status. METHODS: The radiosensitizing effects of olaparib were tested on BRCA1-proficient and deficient HGSOC by clonogenic survival and tumor growth assays. The effects of olaparib and radiation on DNA damage, PARP activity, and apoptosis were determined. RESULTS: BRCA1-deficient HGSOC cells were more sensitive to RT alone and exhibited significantly higher levels of olaparib-mediated radiosensitization compared to BRCA1-proficient cells. Furthermore, when combined with RT, olaparib inhibited DNA damage repair and PARP1 activity, increased apoptosis, decreased growth of HGSOC xenografts and increased overall host survival. The growth-inhibitory effects of the combined olaparib and RT treatment were more pronounced in mice bearing BRCA1-deficient tumors compared to BRCA1-proficient tumors. CONCLUSIONS: These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in HGSOC, particularly in tumors with BRCA1 deficiencies. PMID- 30025823 TI - Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction. AB - Tumor metastasis is the primary factor causing death of cancer patients and it is a study emphasis in cancer treatment to suppress tumor metastasis by inhibiting glycolysis, which is the main way of energy supply for cell mobility in tumor. In the present study, we aimed to explore the effect of quercetin, a bioactive flavonoid, on tumor metastasis and cell glycolysis and its related functionary mechanism in breast cancer progression. Firstly, trans-well invasion assay and wound healing assay indicated that quercetin effectively suppressed cell mobility. The corresponding western blot revealed that quercetin treatment down regulated the expression of cell migration marker proteins, such as matrix metalloproteinase 2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF). The further experiments exhibited that quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the production of lactic acid, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA). The above results revealed that quercetin might inhibit glycolysis to limit the migration of tumor cells by reducing the acidity of the tumor microenvironment. Moreover, our further investigation showed that quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway. At the same time, the application of autophagy inhibitor 3-MA and Akt-mTOR pathway inducer IGF-1 further demonstrated that quercetin exerted inhibiting effect on cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction. At last, the in vivo experiments also showed that quercetin treatment could suppress tumor growth and metastasis, inhibit glycolysis and induce autophagy through the inhibition of p-AKT/AKT. Taken together, we firstly revealed that quercetin suppressed the progression of breast cancer by inhibiting cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction and may provide a potential therapeutic target for breast cancer treatment. PMID- 30025824 TI - Glucocorticoid receptor inhibit the activity of NF-kappaB through p38 signaling pathway in spinal cord in the spared nerve injury rats. AB - AIMS: The glucocorticoid receptors (GRs) are an active regulator in inflammatory responses. The inflammatory reaction plays an important role in neuropathic pain, but the underlying mechanisms that GR regulates the inflammatory responses in neuropathic pain are still unknown. The activation of GRs has been shown to participate in the p38MAPK-mediated suppression of transcription activation. An unanswered question is whether GRs take part in inflammatory responses in neuropathic pain through p38MAPK signaling pathway. MAIN METHODS: The spared nerve injury (SNI) in rats was used as a model of neuropathic pain. Pain sensitivity was tested by von Frey filaments. The expression of GR, p-p38 and NF kappaB were detected by Western blot and immunofluorescence. Elisa was used to examine the expression of IL-6 and TNF-alpha. KEY FINDINGS: Nerve injury led to p38 activation and GR expression decline in spinal cord of SNI rats. Intrathecal injection of the p38MAPK antagonist SB203580 activated GR and decreased NF kappaB, resulting in pain relief since 3 days post-operation in SNI rats. Moreover, Intrathecal injection of the GR antagonist RU38486 counteracted the effect of SB203580 on NF-kappaB expression along with the release of IL-6 and TNF alpha. On the contrary, activation of the GR by intrathecal administration of dexamethasone, a GR agonist, inhibited the expression of NF-kappaB and the release of IL-6 and TNF-alpha, resulting in pain relief. SIGNIFICANCE: Activation of p38MAPK in spinal cord could downregulate the GR expression and thereby activate NF-kappaB, thus promoting the release of IL-6 and TNF-alpha and participating in the development of neuropathic pain. PMID- 30025825 TI - ECIS based wounding and reorganization of cardiomyocytes and fibroblasts in co cultures. AB - The crosstalk of two major heart cell groups, cardiomyocytes and fibroblasts, relies on direct electromechanical cellular coupling as well as indirect mechanical signal transmission through the surrounding viscoelastic extracellular matrix. Upon injury of cardiac tissue, this communication becomes unbalanced: fibrosis is initiated leading to increased collagen deposition, accompanied by an activation of fibroblasts - the key players of fibrosis. They undergo a reorganization or partial transformation to myofibroblasts during this process, which precedes scar formation within the infarcted heart in vivo. Here, we induce wound formation in an in vitro system as a model for these fibrotic conditions: we assessed the dynamics of wound healing in co-cultures of fibroblasts and myocytes upon targeted wound initiation using Electric Cell Substrate Impedance Sensing (ECIS) under optical control. We discovered distinct wound closure dynamics for mono- and co-cultures of myocytes and fibroblasts and observed a cessation of the contractile behavior for recovering cardiomyocyte cultures. We furthermore identified a change of cellular impedance for recovering fibroblasts and the presence of alpha-SMA, suggesting a partial transformation into myofibroblasts. This was concomitant with a modulation of connectivity, cell substrate dynamics and membrane capacitance of all wounded cell cultures. Qualitatively, connexin 43 observation confirmed the ECIS trend found for cell cell connectivity. Finally, we were able to validate the ECIS based wounding approach against an ECIS based barrier assay - the so-called electric fence. In particular the cell-cell connectivity and thus cell layer integrity dominates the healing dynamics within the two intrinsically different assays. PMID- 30025826 TI - Early Stage Melanoma and Hematopoietic Stem Cell Transplantation Outcomes. PMID- 30025827 TI - Less painful and effective intralesional injection method for lichen simplex chronicus. PMID- 30025828 TI - Femoral artery ultrasound for improving the detection of atherosclerosis in psoriasis. PMID- 30025829 TI - Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. AB - BACKGROUND: Bullous disorders associated with anti-programmed cell death 1 (PD 1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established. OBJECTIVE: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy. METHODS: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018. RESULTS: We identified 9 of 853 patients who developed bullous eruptions (~1%) that were treated with an-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSIONS: Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents. PMID- 30025830 TI - The limits of aggressive surgical cytoreduction. PMID- 30025831 TI - Reply. PMID- 30025832 TI - Identification of altered microRNAs in serum of a mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, whose hallmark is the loss of dopamine terminals in the substantia nigra pars compacta (SNpc). PD is usually diagnosed after the appearance of motor symptoms, when about 70% of neurons in the SNpc have already been lost. Because of that, it is important to search for new methods that aid in the early diagnosis of PD. In recent years, microRNAs (miRs) have emerged as potential biomarkers for a variety of diseases and hold the potential to be used to aid in the diagnosis of PD. Therefore, the aim of this study was to characterize if specific miRs are differentially expressed in serum in a mouse model of PD. To induce PD-like damage, mice were subcutaneously injected with 25 mg/kg of 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine hydrochloride (MPTP) by administering 10 doses over a period of 5 weeks, with 3.5 days between doses. Expression of 71 different microRNAs was quantified in serum separated from blood collected at day 35, using next-generation sequencing. Histological analysis and quantification of neurotransmitters were performed to confirm dopaminergic neurodegeneration. Chronic MPTP treatment induced loss of dopaminergic terminals in the SNpc and caudate putamen, confirmed by a decrease in the number of tyrosine hydroxylase and dopamine transporter positive cells. In addition, MPTP decreased the concentration of dopamine and its metabolites in the SNpc, simulating the damage observed in PD. From the 71 miRs analyzed, only 4 were differentially expressed after MPTP treatment. Serum levels of miR19b, miR124, miR126a and miR133b were significantly decreased in MPTP-treated mice compared to control. These data suggest that specific miRs are downregulated in a pre-clinical model of PD and hold the potential to be used as biomarkers to aid in the diagnosis of this disease. Further experiments need to be conducted to validate the use of these miRs as biomarkers of PD in additional pre-clinical models as well as in samples from patients diagnosed with PD. PMID- 30025833 TI - Astrocyte activation and reactive gliosis-A new target in stroke? AB - Stroke is an acute insult to the central nervous system (CNS) that triggers a sequence of responses in the acute, subacute as well as later stages, with prominent involvement of astrocytes. Astrocyte activation and reactive gliosis in the acute stage of stroke limit the tissue damage and contribute to the restoration of homeostasis. Astrocytes also control many aspects of neural plasticity that is the basis for functional recovery. Here, we discuss the concept of intermediate filaments (nanofilaments) and the complement system as two handles on the astrocyte responses to injury that both present attractive opportunities for novel treatment strategies modulating astrocyte functions and reactive gliosis. PMID- 30025834 TI - Isavuconazole is highly active in vitro against Candida species isolates but shows trailing effect. AB - OBJECTIVES: Isavuconazole is a triazole previously shown to have potent in vitro activity against Aspergillus spp., Mucorales and Candida spp. Unlike other azoles, it is unclear whether isavuconazole induces a trailing effect. We studied isavuconazole MICs for a large collection of Candida isolates from blood samples and determined the extent of the trailing effect when using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) E.Def 7.3.1 method. METHODS: A total of 762 molecularly identified Candida isolates from blood samples of 743 patients admitted to hospital (January 2007 to September 2017) were evaluated and further tested for in vitro susceptibility to isavuconazole following the EUCAST E.Def 7.3.1 test method. RESULTS: C. albicans showed the highest susceptibility, followed by C. parapsilosis and C. tropicalis (geometric mean MIC 0.0029 vs. 0.0049/0.0052, respectively; p <0.001). In contrast, C. glabrata and C. krusei had significantly higher MIC values (geometric mean MIC 0.171 vs. 0.117, respectively). Isavuconazole MIC distributions were not truncated at the lowest concentration tested except for C. albicans. Overall, the mean percentage of trailing was 13.6%, but differences among species were observed: C. glabrata, C. albicans and C. tropicalis exhibited higher trailing compared to C. parapsilosis and non-Candida yeasts (p <0.001). The percentage of non-wild-type C. albicans (considering the heavy trailer isolates as wild type), C. parapsilosis and C. glabrata isolates were 1.1% (4/357), 1.5% (3/201) and 1.1% (1/86), respectively. CONCLUSIONS: Isavuconazole showed high in vitro activity against Candida spp., particularly against C. albicans. A trailing effect is commonly observed with isavuconazole, particularly with C. glabrata. PMID- 30025835 TI - Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model. AB - OBJECTIVES: Streptococcus pyogenes causes life-threatening invasive infections including necrotizing fasciitis (NF). Current treatment guidelines recommend the use of a cell-wall-active antibiotic combined with a protein synthesis inhibitor and surgical debridement in NF patients. Adjunctive therapy with intravenous immunoglobulin (IVIG) has been proposed for superantigen-associated streptococcal toxic shock syndrome. So far, benefits of IVIG treatment remain unclear and prospective clinical studies are scarce. Thus, we aimed to assess the effects of IVIG on virulence factor activity in vitro, ex vivo in patients and in vivo in a NF mouse model. METHODS: We investigated the effect of IVIG on the activity of the virulence factors streptolysin O (SLO), streptodornase 1 (Sda1), S. pyogenes cell envelope protease and streptococcal pyrogenic exotoxin B in vitro and ex vivo in patient sera. Additionally, we assessed the influence of IVIG on the clinical outcome in a murine NF model. RESULTS: In vitro, IVIG inhibited various streptococcal virulence factors. Further, IVIG treatment of group A Streptococcus infected mice led to a reduced skin lesion size (median (interquartile range) day 3 intraperitoneal administration: 12 mm2 (9-14.5) vs. 4 mm2 (0.8-10.5), subcutaneous: 10.3 mm2 (6.9-18.6) vs. 0.5 mm2 (0.1-6.8)) and lower SLO activity. After treatment with IVIG, patient sera showed an elevated titre of specific SLO (7/9) and Sda1 (5/9) antibodies, reducing SLO and Sda1 activity. CONCLUSIONS: The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human sera suggest that IVIG may be beneficial in invasive group A Streptococcus infections such as NF in addition to streptococcal toxic shock syndrome. PMID- 30025836 TI - Re: 'Are third-generation cephalosporins associated with a better prognosis than amoxicillin-clavulanate in patients hospitalized in the medical ward for community-onset pneumonia?' by Batard, et al. PMID- 30025837 TI - User perspectives on orthoses for thumb carpometacarpal osteoarthritis. AB - STUDY DESIGN: Qualitative and interpretive description. INTRODUCTION: Orthoses are often the first-choice treatment for thumb carpometacarpal osteoarthritis (CMCOA). It is unknown to what extent the orthoses are used in the way intended by health professionals and why patients continue using the orthoses despite minimal pain reduction. PURPOSE OF THE STUDY: The purpose of this study is to investigate user perspectives and experiences with 2 types of CMCOA orthoses. METHODS: Semistructured interviews were conducted with 16 individuals with CMCOA who used the Push-Ortho-Thumb-Brace-CMC (Nea International BV, Netherlands) and a custom-made orthosis. The data were analyzed using the phenomenological and the framework approach. RESULTS: Four men and 12 women participated (mean age, 57 years; half of whom were employed). Five central phenomena were identified, explaining the essence of the relation between user and orthosis: the orthosis as stabilizer, tool, healer, preventer, and nuisance. Users mentioned better appearance and the ability to do a variety of activities as advantages of the Push-Ortho-Thumb-Brace-CMC and better support and the ability to do strenuous activities as advantages of the custom-made orthosis. The central phenomena were related to the users' understanding of the disease process and the working mechanism of the orthoses and affected the patterns of usage and orthosis preference. DISCUSSION: It is recommended that the provider recognizes user perspectives and discusses the disease process of CMCOA along with the working mechanism of the orthosis to support therapy adherence. CONCLUSIONS: There is a wide variety in usage patterns of the CMCOA orthoses, which are influenced by different user perspectives. PMID- 30025838 TI - Shape-texture-identification-STI-A test for tactile gnosis: Concurrent validity of STI2. AB - STUDY DESIGN: Cross-sectional study. INTRODUCTION: The shape-texture identification (STI) test (Ossur Nordic AB, Sweden) is used to evaluate one aspect of tactile gnosis in nerve disorders, and it has proven good methodological properties. PURPOSE OF THE STUDY: A new version of the STI test was recently introduced-STI2 (www.sensory-test.com). The purpose of this study was to test the concurrent validity in STI2. METHODS: Using a cross-sectional design, this methodological study compared STI2 to the original version based on 2 cohorts; 1 including 20 persons (1 affected finger and corresponding finger on in opposite hand) with affected sensibility after hand injuries and 1 healthy group including 20 persons (digits II and V in both hands). The agreement between the 2 versions of the instrument was calculated statistically by a percentage comparison of the test results and weighted kappa. RESULTS: The 112 tested fingers showed a complete agreement, or 1-point accepted deviation, between the 2 tests in 92% with weighted kappa of 0.74 and 95% confidence interval of 0.63 0.89. The result showed that there is no significant deviation between the 2 versions of the test. DISCUSSION: The use of standardizes and evidence based assessment tools in clinical practice is paramount for a patient centered healthcare. Previous research has shown good psychometric proprties in the STI test. This study contributes to the scientific evidence of the instrument. CONCLUSION: As the new STI2 proved good agreement within the accepted deviation, we conclude that there is evidence to use the new STI2 test in assessment of tactile gnosis. PMID- 30025839 TI - The interaction between pain and movement. AB - STUDY DESIGN: Clinical commentary. INTRODUCTION/PURPOSE: Pain and movement are universally relevant phenomena that influence human experiences in readily observable ways. Improved understanding of pain-movement relationships can guide medical and rehabilitative approaches to recovery and decrease risk of dysfunctional long-term consequences of otherwise normal neuromuscular responses. Therefore, the overall intent of this article is to elucidate the relationships between pain and movement as they relate to clinical decision making. CONCLUSIONS: Motor output is highly adaptable, can be influenced by multiple mechanisms at various levels along the nervous system, and may vary between individuals despite similar diagnoses. Therefore, interventions need to be individualized and consider both the types of motor response observed (ie, whether the response is protective or maladaptive), and the patient's acute physical activity tolerance when prescribing exercise/movement. PMID- 30025840 TI - Response letter to the role of proprioception of lateral elbow tendinopathy. PMID- 30025841 TI - The validity and reliability of DrGoniometer, a smartphone application, for measuring forearm supination. AB - STUDY DESIGN: Clinical measurement (reliability and validity) study. INTRODUCTION: Forearm supination is important in many daily activities and is thus measured by therapists and researchers usually with a universal goniometer. DrGoniometer, a SmartPhone application, has been validated for other joint angles in the body. PURPOSE OF THE STUDY: To establish the reliability and validity of DrGoniometer (CDM S.r.L, Cagliari, Italy) for measuring forearm supination in healthy populations and those with forearm fractures. METHODS: Participants had sustained a distal radius fracture that was treated non-surgically. Forearm supination of the participant's fractured (n = 30) and healthy forearm (n = 30) was measured using DrGoniometer and the universal goniometer by two assessors. The assessors were blinded to each other's measurements and their own previous measurements. Reliability was established by calculating Intra-class Correlation Coefficients, standard error of measurement and minimal detectable change. The validity of DrGoniometer was established against the universal goniometer using Pearson's correlation co-efficient. RESULTS: Intra-rater reliability of both DrGoniometer and the universal goniometer was high for both fractured and healthy forearms (ICCs ranged from 0.74-0.88). Inter-rater reliability of both DrGoniometer and the universal goniometer was also high in the fractured forearm group (0.76 and 0.72 respectively), but low in the healthy forearm group (0.34 and 0.42 respectively). Correlation between the tools was excellent across the fractured and healthy forearm groups (0.94 and 0.93 respectively). DISCUSSION: Both goniometers demonstrated good-to-excellent intrarater and iner-rater reliability except in the healthy forearm group where both goniometers demonstrated poor inter-rater reliability which could be due to assessor instructions. The speed the photo can be taken and the digital record obtained are valuable aspects of DrGoniometer. CONCLUSION: DrGoniometer is a valid, alternate tool for measuring forearm supination. PMID- 30025842 TI - Short functional dynamic orthosis for proximal interphalangeal joint extension deficit. Crest design. AB - This author provides instruction in the fabrication of a cost-effective dynamic proximal interphalangeal (PIP) extension orthosis. The device allows PIP flexion for activities of daily living and promotes PIP extension-Kristin Valdes, OTD, OT, CHT, Practice Forum Editor. PMID- 30025843 TI - Combined effects of botulinum toxin type A and repetitive transcranial magnetic stimulation with intensive motor training immediately after injection in a patient with chronic stroke: A case report. AB - STUDY DESIGN: Single case report. INTRODUCTION: A previous study clarified that spasticity and motor function were improved by combined treatment with botulinum toxin type A (BTX) injection and 1-Hz repetitive transcranial magnetic stimulation (rTMS) with intensive motor training at 4 weeks after injection. However, it is not clear whether 1-Hz rTMS with intensive motor training immediately after BTX injection also improves spasticity and motor function in stroke patients. PURPOSE OF THE CASE REPORT: The purpose of this case report is to test the short- and long-term effects of BTX injection and rTMS with intensive motor training on the spasticity, motor function, and usefulness of the paretic hand in a stroke patient. METHODS: A 64-year-old male, who suffered from a right cerebral hemorrhage 53 months previously, participated in the present study. BTX was injected into the spastic muscles of the affected upper limb. He then received the new protocol for a total of 24 sessions. The Modified Ashworth Scale (MAS), Fugl-Meyer Assessment (FMA), and Motor Activity Log, consisting of the amount of use and quality of movement scales, were assessed before and immediately after BTX injection, at discharge, and monthly for up to 5 months after discharge. RESULTS: For the short-term effects of the therapy, the MAS scores of the elbow and wrist, FMA score, and quality of movement score improved. For the long-term effects of the therapy, the MAS score of the fingers, FMA score, and amount of use score improved for up to 5 months after discharge. CONCLUSIONS: The present case report showed the improvement of all assessments performed in the short and/or long term and suggest the possibility of shortening the intervention period of combined therapy of BTX and rTMS with intensive motor training. PMID- 30025844 TI - Efficacy of orthotic devices for increased active proximal interphalangeal extension joint range of motion: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION/PURPOSE OF THE STUDY: To determine the efficacy of orthotic devices for increased active proximal interphalangeal (PIP) joint range of motion and optimal wearing schedule of the devices to guide clinical practice. The secondary purpose is to capture the outcome measures used by the authors. The final purpose was to determine if recent studies addressed patient satisfaction and adherence in the orthotic management of a PIP joint injury. METHODS: A comprehensive literature search was conducted using the search terms splint, orthotic device, hand orthotic, brace, proximal interphalangeal joint, occupational therapy, and physical therapy using PubMed, CINAHL, MEDLINE, and ProQuest. The following data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines: background statement, objectives, data sources, study eligibility criteria, participants, and interventions, study appraisal and synthesis methods, results, limitations, conclusions, and implications of key findings. RESULTS: Best results were achieved when the PIP orthoses were worn for a longer duration especially for the treatment of extension deficits. DISCUSSION: Studies that provided a wearing schedule of a minimum of 6 hours obtained the greatest improvements in extension deficits of the PIP joint. CONCLUSION: Recommended orthotic dosage to treat PIP joint injury is at least 6 hours a day for 8-17 weeks. PMID- 30025845 TI - Inflammation induced preterm labor and birth. AB - Preterm birth which occurs before 37 weeks gestation is one of the most common obstetrical complication in humans. After many studies, it appears that "not one answer fits all" regarding the risk factors, causes and the treatments for this syndrome. However, it is becoming more evident that one of the major risk factors is inflammation and/or infection in the fetoplacental unit. In animal models (usually consisting of mice injected with lipopolysaccharide at 14 days of gestation), IL-22 and IL-6 have been identified as factors related to preterm birth. There are some clinical tests available to determine the risk for preterm labor and delivery, which can be identified before, during early, or at mid gestation. However, treatment of preterm birth with antibiotics so far has not been "curable" and studies using anti-inflammatory treatments are not readily available. More studies regarding causes and treatments for preterm labor and delivery in humans are necessary to prevent neonatal deaths and/or developmental abnormalities associated with this common syndrome. PMID- 30025846 TI - Colon and rectal surgery surgical site infection reduction bundle: To improve is to change. AB - BACKGROUND: Despite the introduction of the Surgical Care Improvement Project, surgical site infections remain a source of morbidity. The aim of this study was to determine the value of implementing a colorectal bundle on SSI rates. METHODS: Between 2011 and 2016 a total of 1351 patients underwent colorectal operations. Patients were grouped into pre-implementation (Group A, January 1, 2011-December 31, 2012), implementation (Group B, January 1, 2013-December 31, 2014) and post implementation (Group C, January 1, 2015-December 31, 2016). Primary endpoints were superficial SSI, deep SSI, wound separation and total SSI. RESULTS: After the bundle was implemented, there was a significant reduction in superficial (6.6%-4%, p < 0.05), deep (3.7%-1.1%, p < 0.05), and total SSI rates (10.9%-4.7%, p < 0.05). Comparing Group A to Group C there was a decrease in total SSI (9.4% 4.7%, p < 0.05). CONCLUSION: Implementation of the bundle resulted in a reduction in overall SSI rates particularly as compliance increased. This study offers evidence that small changes can lead to significant decreases in surgical site infections. PMID- 30025848 TI - Techniques in Septoplasty: Traditional Versus Endoscopic Approaches. AB - This article provides a review of modern techniques in the surgical management of the deviated septum with emphasis on the comparison of traditional versus endoscopic septoplasty approaches. Relevant anatomy and physiology of the nasal septum are discussed. A brief history of the evolution of the surgical approaches for the correction of a deviated septum is provided. Traditional and endoscopic septoplasty techniques are reviewed; the indications, advantages, and limitations of each approach are highlighted. Potential complications of septoplasty, with a focus on prevention and management, are also discussed. PMID- 30025849 TI - Risk of Alzheimer's disease with metal concentrations in whole blood and urine: A case-control study using propensity score matching. AB - Environmental exposure to heavy metals is suspected to result in neuropathology damage and cognitive impairment. We aimed to explore the association of Alzheimer's disease (AD) risk with the internal dose of heavy metals by constructing a hospital-based case-control study and using propensity-score matching methods. We investigated 170 patients with AD and 264 controls from the Department of Neurology and Family Medicine, China Medical University Hospital in Taiwan. All patients with AD received clinical neuropsychological examination and cognitive-function assessments, including the mini-mental status examination and clinical dementia rating scale. We also constructed a propensity-score-matched population of 82 patients with AD and 82 controls by matching age, gender, education, and AD-related comorbidity. Blood levels with cadmium, lead, mercury, selenium, and urinary arsenic profile were measured. Logistic regression models and 95% confidence intervals (CIs) were applied to estimate AD risk. After stratification by respective quartile cutoffs of heavy metals, the AD risk of study participants with high urinary inorganic arsenic (InAs%) or low dimethylarsinic acid (DMA%) significantly increased (p < 0.05), as similarly found in the propensity-score-matched population. In addition, people with a low median level of selenium and high median level of InAs%, or/and a low median level of DMA% had approximately two- to threefold significant AD risk. Urinary arsenic profiles may be associated with increased AD risk. Repeat measurements of heavy metals with large sample size and the surveying of potential exposure sources are recommended in future studies. PMID- 30025847 TI - Analytical approaches for myocardial fibrillation signals. AB - Atrial and ventricular fibrillation are complex arrhythmias, and their underlying mechanisms remain widely debated and incompletely understood. This is partly because the electrical signals recorded during myocardial fibrillation are themselves complex and difficult to interpret with simple analytical tools. There are currently a number of analytical approaches to handle fibrillation data. Some of these techniques focus on mapping putative drivers of myocardial fibrillation, such as dominant frequency, organizational index, Shannon entropy and phase mapping. Other techniques focus on mapping the underlying myocardial substrate sustaining fibrillation, such as voltage mapping and complex fractionated electrogram mapping. In this review, we discuss these techniques, their application and their limitations, with reference to our experimental and clinical data. We also describe novel tools including a new algorithm to map microreentrant circuits sustaining fibrillation. PMID- 30025850 TI - Comparative study of anti-VEGF Ranibizumab and Interleukin-6 receptor antagonist Tocilizumab in Adjuvant-induced Arthritis. AB - Although the precise etiology of Rheumatoid arthritis (RA) remains obscure, heightened immune response is thought to play a vital role in provoking joint inflammation and bone erosion. This study aims at comparatively evaluating the effects of two monoclonal antibodies Ranibizumab (RANI) as anti-VEGF antibody and Tocilizumab (TCZ) as interleukin-6 receptor (IL-6R) antagonist, against adjuvant induced arthritis in rats. CFA-induced arthritic rats were treated for three consecutive weeks with Methotrexate (MTX), TCZ and RANI monotherapy. Clinical assessment of RA, bone erosion, inflammatory, angiogenic and apoptotic markers were determined to assess the anti-arthritic effect. Liver enzymes and histopathological examination of liver and spleen were assessed to evaluate the toxicity profile of the tested therapeutic agents. MTX, TCZ and RANI monotherapy significantly enhanced the anti-arthritic parameters in comparison with the Complete Freund's Adjuvant (CFA)-induced arthritic rats through significant reduction of ankle and paw swelling. Also, they significantly reduced inflammatory, angiogenic and apoptotic markers. Importantly, Ranibizumab showed better effect than the standard anti-rheumatic drugs Methotrexate (MTX) or Tocilizumab (TCZ) in bone protection and cartilage health; hence proves to be a promising new therapeutic agent for RA. PMID- 30025852 TI - Neural mechanisms of the EEG alpha-BOLD anticorrelation. AB - An experimentally tested neural field theory of the corticothalamic system is used to model brain activity and resulting experimental EEG data, and to elucidate the neural mechanisms and physiological basis of alpha-BOLD anticorrelation observed in concurrent EEG and fMRI measurements. Several studies have proposed that the anticorrelation originates from a causal link between changes in the alpha power and BOLD signal. However, the results in this study reveal that fluctuations in alpha and BOLD power do not generate one another but instead respectively result from high- and low-frequency components of the same underlying cortical activity, and that they are inversely correlated via variations in the strengths of corticothalamic and intrathalamic feedback, thereby explaining their anticorrelation. PMID- 30025853 TI - From relief to surprise: Dual control of epistemic curiosity in the human brain. AB - Epistemic curiosity (EC) is a cornerstone of human cognition that contributes to the actualization of our cognitive potential by stimulating a myriad of information-seeking behaviors. Yet, its fundamental relationship with uncertainty remains poorly understood, which limits our ability to predict within- and between-individual variability in the willingness to acquire knowledge. Here, a two-step stochastic trivia quiz designed to induce curiosity and manipulate answer uncertainty provided behavioral and neural evidence for an integrative model of EC inspired from predictive coding. More precisely, our behavioral data indicated an inverse relationship between average surprise elicited by previous trivia items and EC levels, which depended upon hemodynamic activity in the rostrolateral prefrontal cortex from one trial to another and from one individual to another. Complementary, the relief of acute curiosity recruited the ventral striatum when knowledge delivery was unpredictable. Taken together, our results account for the temporal evolution of EC over time, as well as for the interplay of EC, prior knowledge and surprise in controlling memory gain. PMID- 30025851 TI - Probabilistic functional tractography of the human cortex revisited. AB - In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human. PMID- 30025854 TI - The connectivity signature of co-speech gesture integration: The superior temporal sulcus modulates connectivity between areas related to visual gesture and auditory speech processing. AB - Humans integrate information communicated by speech and gestures. Functional magnetic resonance imaging (fMRI) studies suggest that the posterior superior temporal sulcus (STS) and adjacent gyri are relevant for multisensory integration. However, a connectivity model representing this essential combinatory process is still missing. Here, we used dynamic causal modeling for fMRI to analyze the effective connectivity pattern between middle temporal gyrus (MTG), occipital cortex (OC) and STS associated with auditory verbal, visual gesture-related, and integrative processing, respectively, to unveil the neural mechanisms underlying integration of intrinsically meaningful gestures (e.g., "Thumbs-up gesture") and corresponding speech. 20 participants were presented videos of an actor either performing intrinsic meaningful gestures in the context of German or Russian sentences, or speaking a German sentence without gesture, while performing a content judgment task. The connectivity analyses resulted in a winning model that included bidirectional intrinsic connectivity between all areas. Furthermore, the model included modulations of both connections to the STS (OC->STS; MTG->STS), and non-linear modulatory effects of the STS on bidirectional connections between MTG and OC. Coupling strength in the occipital pathway (OC->STS) correlated with gesture related advantages in task performance, whereas the temporal pathway (MTG->STS) correlated with performance in the speech only condition. Coupling between MTG and OC correlated negatively with subsequent memory performance for sentences of the Gesture-German condition. Our model provides a first step towards a better understanding of speech-gesture integration on network level. It corroborates the importance of the STS during audio-visual integration by showing that this region inhibits direct auditory visual coupling. PMID- 30025855 TI - Transcriptional regulation of FeS biogenesis genes: A possible shield against arsenate toxicity activated by Yap1. AB - In the eukaryotic model yeast Saccharomyces cerevisiae, arsenic (As) detoxification is regulated by two transcriptional factors, Yap8 and Yap1. Yap8 specifically controls As extrusion from the cell, whether Yap1 avoids arsenic induced oxidative damages. Accordingly, cells lacking both Yap1 and Yap8 are more sensitive to arsenate than cells lacking each regulator individually. Strikingly enough, the same sensitivity pattern was observed under anoxia, suggesting that Yap1 role in As detoxification might not be restricted to the regulation of the oxidative stress response. This finding prompted us to study the transcriptomic profile of wild-type and yap1 mutant cells exposed to arsenate. Interestingly, we found that, under such conditions, several genes involved in the biogenesis of FeS proteins were upregulated in a Yap1-dependent way. In line with this observation, arsenate treatment decreases the activity of the mitochondrial aconitase, Aco1, an FeS cluster-containing enzyme, this effect being even more pronounced in the yap1 mutant. Reinforcing the relevance of FeS cluster biogenesis in arsenate detoxification, the overexpression of several ISC and CIA machinery genes alleviates the deleterious effect of arsenate caused by the absence of Yap1 and Yap8. Altogether our data suggest that the upregulation of FeS biogenesis genes regulated by Yap1 might work as a cellular shield against arsenate toxicity. PMID- 30025856 TI - Cyclooxygenases and lipoxygenases are used by the fungus Podospora anserina to repel nematodes. AB - : Oxylipins are secondary messengers used universally in the living world for communication and defense. The paradigm is that they are produced enzymatically for the eicosanoids and non-enzymatically for the isoprostanoids. They are supposed to be degraded into volatile organic compounds (VOCs) and to participate in aroma production. Some such chemicals composed of eight carbons are also envisoned as alternatives to fossil fuels. In fungi, oxylipins have been mostly studied in Aspergilli and shown to be involved in signalling asexual versus sexual development, mycotoxin production and interaction with the host for pathogenic species. Through targeted gene deletions of genes encoding oxylipin producing enzymes and chemical analysis of oxylipins and volatile organic compounds, we show that in the distantly-related ascomycete Podospora anserina, isoprostanoids are likely produced enzymatically. We show the disappearance in the mutants lacking lipoxygenases and cyclooxygenases of the production of 10 hydroxy-octadecadienoic acid and that of 1-octen-3-ol, a common volatile compound. Importantly, this was correlated with the inability of the mutants to repel nematodes as efficiently as the wild type. Overall, our data show that in this fungus, oxylipins are not involved in signalling development but may rather be used directly or as precursors in the production of odors against potential agressors. SIGNIFICANCE: We analyzse the role in inter-kingdom communication of lipoxygenase (lox) and cyclooxygenase (cox) genes in the model fungus Podospora anserina. Through chemical analysis we define the oxylipins and volatile organic compounds (VOCs)produce by wild type and mutants for cox and lox genes, We show that the COX and LOX genes are required for the production of some eight carbon VOCs. We show that COX and LOX genes are involved in the production of chemicals repelling nematodes. This role is very different from the ones previously evidenced in other fungi. PMID- 30025857 TI - The oligomeric assembly of the phosphodiesterase-5 is a mixture of dimers and tetramers: A putative role in the regulation of function. AB - BACKGROUND: Phosphodiesterases (PDEs) are a superfamily of evolutionary conserved cyclic nucleotides (cAMP/cGMP) hydrolysing enzymes, components of transduction pathways regulating crucial aspects of cell life. PDE5, one of these families, is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Despite its medical relevance, PDE5 macromolecular structure has only been solved for the isolated regulatory and catalytic domains. The definition of the quaternary structure of the full length PDE5 (MmPDE5A1), produced in large amounts in the yeast Kluyveromyces lactis, could greatly enhance the knowledge on its assembly/allosteric regulation and the development of new inhibitors for clinical-therapeutic applications. METHODS: Small-angle X ray scattering (SAXS), analytical ultracentrifugation (AUC), size exclusion chromatography (SEC), native polyacrylamide gel electrophoresis (PAGE) and western blot (WB) were used to assess the assembly of PDE5A1. RESULTS: The full length MmPDE5A1 isoform is a mixture of dimers and tetramers in solution. We also report data showing that dimers and tetramers also coexist in vivo in platelets, blood components naturally containing high levels of PDE5. CONCLUSIONS: This is the first time that structural studies on the full length protein evidenced the assembly of PDE5 in tetramers in addition to the expected dimers. GENERAL SIGNIFICANCE: The assembly of PDE5 in tetramers in platelets, beside the dimers, opens the possibility to alternative assembly/allosteric regulation of this enzyme, as component of large signaling complexes, in all cellular districts in which PDE5 is present. PMID- 30025858 TI - Conformational response to charge clustering in synthetic intrinsically disordered proteins. AB - BACKGROUND: Recent theoretical and computational studies have shown that the charge content and, most importantly, the linear distribution of opposite charges are major determinants of conformational properties of intrinsically disordered proteins (IDPs). Charge segregation in a sequence can be measured through kappa, which represents a normalized measure of charge asymmetry. A strong inverse correlation between kappa and radius of gyration has been previously demonstrated for two independent sets of permutated IDP sequences. METHODS: We used two well characterized IDPs, namely measles virus NTAIL and Hendra virus PNT4, sharing a very similar fraction of charged residues and net charge per residue, but differing in proline (Pro) content. For each protein, we have rationally designed a low- and a high-kappa variant endowed with the highest and the lowest kappa values compatible with their natural amino acid composition. Then, the conformational properties of wild-type and kappa-variants have been assessed by biochemical and biophysical techniques. RESULTS: We confirmed a direct correlation between kappa and protein compaction. The analysis of our original data along with those available from the literature suggests that Pro content may affects the responsiveness to charge clustering. CONCLUSIONS: Charge clustering promotes IDP compaction, but the extent of its effects depends on the sequence context. Proline residues seem to play a role contrasting compaction. GENERAL SIGNIFICANCE: These results contribute to the identification of sequence determinants of IDP conformational properties. They may also serve as an asset for rational design of non-natural IDPs with tunable degree of compactness. PMID- 30025859 TI - Function of C-terminal peptides on enzymatic and interfacial adsorption properties of lipase from Gibberella zeae. AB - BACKGROUND: The crystal structure of lipase from Gibberella zeae (GZEL) indicates that its C-terminal extension is composed of a loop and a alpha-helix. This structure is unique, possibly providing novel evidence on lipase mechanisms. METHODS: Two C-terminally truncated mutants (GZEL-Delta(alpha-helix) and GZEL Delta(alpha-helix+loop)) were constructed. The role of these secondary structure segments on enzymatic activities and interfacial binding properties of GZEL was investigated by using conventional pH-stat method and monomolecular film techniques. In addition, inactive variants (Ser144Ala) of wild-type GZEL and two truncated mutants were constructed and produced specifically for interfacial binding experiments. RESULTS: Compared to the wild-type GZEL, lipase and phospholipase activities were significantly decreased in the two mutants. Deletion of the alpha-helix had great influence on the lipase activity of GZEL, resulting in residual 7.3% activity; the additional deletion of the loop led to 8.1% lipase activity. As for the phospholipase function, residual activities of 63.0% and 35.4% were maintained for GZEL-Delta(alpha-helix) and GZEL-Delta(alpha helix+loop), respectively. Findings obtained with monomolecular film experiments further indicated that the reduction in phospholipase activity occurred with the anionic phospholipid as substrate, but was not seen with zwitterionic phospholipid. Results of the maximum insertion pressure, synergy factor and binding kinetic parameters documented that the alpha-helix structure of GZEL strongly influence the binding and insertion of enzyme to the phospholipid monolayer. Moreover, the interfacial binding function of alpha-helix was partly conformed by connecting to the C-terminal of Aspergillus oryzae lipase. GENERAL SIGNIFICANCE: Our results provide important information on the understanding of the structure-function relationship of GZEL. PMID- 30025860 TI - Maternal High-fat Diet Programs Offspring Emotional Behavior in Adulthood. AB - Prenatal exposure to high-fat diet (HFD) might predispose offspring to develop metabolic and mental disorders later in life. Insight into the molecular and behavioral consequences of maternal HFD on offspring is sparse but may involve both neuroinflammation and a dysregulated neuroendocrine stress axis. Thus, the aim of this work was to: (i) investigate the influence of maternal HFD on memory, anxiety and depression-like behavior in adult offspring and (ii) identify possible biological biomarkers related to neuroinflammation and stress responses. Seven-week-old, female Sprague-Dawley rats received a control diet or a HFD eight weeks prior to conception and during gestation and lactation. We investigated the phenotype of the offspring in the in elevated plus maze, forced swim test, novel object recognition and open field test. Furthermore, hippocampal gene expression related to neuroinflammation and the stress axis was quantitated by real-time qPCR. We found that maternal HFD led to an anxiogenic offspring phenotype in the elevated plus maze, independent of sex. This behavioral alteration was accompanied by significantly higher mRNA levels of the hippocampal pro inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) mRNA and monocyte chemoattractant protein-1 (MCP-1), both of which correlated with degree of behavioral change. Maternal exposure to HFD increased the offspring's levels of hippocampal, corticosteroid releasing hormone receptor 2 (CRHR2) and kynurenine mono oxygenase (KMO) mRNA, whereas kynurenine aminotransferase I (KAT1) mRNA levels were decreased. The present results suggest that neuroinflammatory and stress axis pathways in the hippocampus may contribute to anxiogenic effects of maternal HFD in offspring. PMID- 30025861 TI - Expression Profiles of Metallothionein I/II and Megalin in Cuprizone Model of De- and Remyelination. AB - Copper chelator cuprizone (CPZ) is neurotoxicant, which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. To explore the participation of metallothioneins (MTs) in these processes, in this study we analyzed the expression profiles of MT-I/II and their receptor megalin (low density lipoprotein receptor related protein-2) in the brain of mice subjected to different protocols of CPZ feeding. Experiments were performed in female C57BL/6 mice fed with 0.25% CPZ during 1, 3 and 5 weeks. They were sacrificed immediately after feeding with CPZ or 2 weeks after the withdrawal of CPZ. The data showed that CPZ-induced demyelination was followed by high astrogliosis and enhanced expression of MTs and megalin in white (corpus callosum and internal capsule) and gray matter of the brain (cortex, hippocampus, and cerebellum). Moreover, in numerous cortical neurons and progenitor cells the signs of MT/megalin interactions and Akt1 phosphorylation was found supporting the hypothesis that MTs secreted from the astrocytes might directly affect the neuronal differentiation and survival. Furthermore, in mice treated with CPZ for 5 weeks the prominent MTs and megalin immunoreactivities were found on several neural stem cells and oligodendrocyte progenitors in subgranular zone of dentate gyrus and subventricular zone of lateral ventricles pointing to high modulatory effect of MTs on adult neuro- and oligodendrogenesis. The data show that MT I/II perform important cytoprotective and growth-regulating functions in remyelinating processes activated after toxic demyelinating insults. PMID- 30025862 TI - Contribution of Visual Motion Cues from a Held Tool to Kinesthesia. AB - Incorporation of a tool into the body schema is well established. Here, we assessed whether visual signals originating from the tool provide relevant cues for the perception of arm movements, as would signals originating from the arm holding it. Kinesthetic illusions were investigated by passively moving one arm (via a robotized manipulandum) and therefore the tool (a rake), using the mirror paradigm, with the reflected part being limited to the tool, the arm, or both. Illusory movements concerned the other arm, remaining static and hidden behind the mirror. In Experiments 1 and 3, participants held the same tools in their hands. Results showed that seeing the displacement of the reflected tool in the mirror induced kinesthetic mirror illusions in the hidden arm, similarly to seeing the reflected arm itself, though slightly reduced in terms of strength and occurrence frequency. In Experiment 2, participants held either the same objects in their hands (the rakes) or different ones (a rake, the image of which was reflected in the mirror, and a ball in the other hand). Results showed that mirror vision of the moving tool was not sufficient for mirror illusions to occur, the same tool in the two hands being an essential condition. Finally, in Experiment 3, we showed that neither prior practice nor active tool use was necessary for the tool mirror illusion to occur. Altogether, these results demonstrate that the visual cues originating from the held-tool are integrated for sensing arm movement. PMID- 30025865 TI - Implication of C-type lectin receptor langerin and keratan sulfate disaccharide in emphysema. AB - Glycosylation is profoundly involved in various diseases, and interactions between glycan binding proteins and their sugar ligands are plausible drug targets. Keratan sulfate (KS), a glycosaminoglycan, is downregulated in lungs by cigarette smoking, suggesting that KS is involved in smoking-related diseases, such as chronic obstructive pulmonary disease (COPD). We found that a highly sulfated KS disaccharide, L4, suppresses lung inflammation and is effective against COPD and its exacerbation in mouse models. Its anti-inflammatory activity was comparable to that of a steroid. As a possible mechanism, langerin, a C-type lectin receptor (CLR) expressed in dendritic cells, was suggested to function as an L4 receptor. Oligomeric L4 derivatives were chemically designed to create new ligands with higher affinity and activity. The synthetic L4 oligomers bound to langerin with over 1000-fold higher affinity than the L4 monomer, suggesting that these compounds are effective drug candidates against COPD and inflammatory diseases. PMID- 30025864 TI - IL-10 induces an immune repressor pathway in sepsis by promoting S100A9 nuclear localization and MDSC development. AB - The myeloid-related protein S100A9 reprograms Gr1+CD11b+ myeloid precursors into myeloid-derived suppressor cells (MDSCs) during murine sepsis. Here, we show that the immunosuppressive cytokine IL-10 supports S100A9 expression and its nuclear localization in MDSCs to function as immune repressors. To support this new concept, we showed that antibody mediated IL-10 blockade in wild-type mice after sepsis induction inhibited MDSC expansion during late sepsis, and that ectopic expression of S100A9 in Gr1+CD11b+ cells from S100A9 knockout mice switched them into the MDSC phenotype only in the presence of IL-10. Knockdown of S100A9 in MDSCs from wild-type mice with late sepsis confirmed our findings in the S100A9 knockout mice. We also found that while both IL-6 and IL-10 can activate S100A9 expression in naive Gr1+CD11b+ cells, only IL-10 can induce S100A9 nuclear localization. These results support that IL-10 drives the molecular path that generates MDSCs and enhances immunosuppression during late sepsis, and inform that targeting this immune repressor path may improve sepsis survival in mice. PMID- 30025863 TI - HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice. AB - Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. This underlines the need of new therapeutic approaches to improve cognition in treated schizophrenia patients. Our previous findings suggested that upregulation of histone deacetylase 2 (HDAC2) expression upon chronic antipsychotic treatment may lead to negative effects on cognition and cortical synaptic structure. Here we tested different phenotypes of psychosis, synaptic plasticity, cognition and antipsychotic drug action in HDAC2 conditional knockout (HDAC2-cKO) mice and controls. Conditional depletion of HDAC2 function in glutamatergic pyramidal neurons led to a protective phenotype against behavior models induced by psychedelic and dissociative drugs, such as DOI and MK801, respectively. Immunoreactivity toward synaptophysin, which labels presynaptic terminals of functional synapses, was decreased in the frontal cortex of control mice chronically treated with clozapine - an opposite effect occurred in HDAC2-cKO mice. Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients. PMID- 30025866 TI - Localized Inflammatory Myofibroblastic Tumor Involving the Genitourinary System: Adolescent Case Series and Review. AB - We describe four adolescent cases of inflammatory myofibroblastic tumor involving the genitourinary system. Two patients with masses of the urinary bladder presented with gross hematuria. The third patient presented with left flank pain and a mass encasing the left ureter causing hydronephrosis. The fourth patient presented with a painless, growing palpable mass of the left hemiscrotum. Currently, no standards exist for the management of inflammatory myofibroblastic tumors. Herein, we discuss the work-up and treatment approaches taken in each case. PMID- 30025868 TI - Impact of Resident Overnight Duty Hour Changes on Obstetrical Outcomes: A Population-Based Cohort Study. AB - OBJECTIVE: To determine whether obstetrical patient outcomes have changed following the introduction of restricted resident work hours. METHODS: A population-based retrospective cohort study of the effects of restricted duty hours for residents in July 2013 at three academic hospitals in Toronto, ON using linked health care databases. The study included 6763 deliveries in the 2 years pre-exposure and 5548 deliveries in the 2 years post-exposure. RESULTS: The primary outcome, planned prior to data collection, was a composite index of 29 maternal/fetal outcomes including maternal transfusion/postpartum hemorrhage, maternal infection, fetal mortality, NICU admissions, and surgical/obstetrical complications. There were seven secondary outcomes analysed: NICU admissions; neonatal death; maternal transfusion or postpartum hemorrhage; maternal infection; and three composite measures. A generalized estimating equation model, clustered by institution, was utilized to assess for differences post intervention. We found no significant differences in baseline demographics between groups. After the implementation of duty hour restrictions, no significant difference was seen in the primary outcome. However, an increased incidence of composite maternal surgical/obstetrical outcomes (OR 1.191; 95% CI 1.037-1.367, P = 0.013) and transfusion/postpartum hemorrhage (OR 1.232; 95% CI 1.074-1.413, P = 0.003) was found. There were no significant differences in other secondary outcomes. CONCLUSION: Since the implementation of resident duty hour restrictions, there was no overall change in patient outcomes. However, there was an increase in surgical/obstetrical complications and transfusion/postpartum hemorrhage. This suggests that duty hour restrictions may not be beneficial to patient outcomes. It highlights the need to further investigate the clinical impact of a change in resident duty hours. PMID- 30025867 TI - Enhanced First Trimester Aneuploidy Screening with Placental Growth Factor and Alpha Feto-Protein: Detection of Trisomies 18 and 13. AB - OBJECTIVES: To assess the performance of first trimester combined screening (FTS) when enhanced with placental growth factor and alpha feto-protein in the detection of trisomies 18 and 13. METHODS: A retrospective case-control study. Marker parameters were derived using frozen serum samples. Multivariate Gaussian modelling predicted the detection rate (DR) and false-positive rate (FPR) for trisomies 18 and 13 with FTS and enhanced first trimester screening (eFTS) using the risk of trisomy 21 alone and an additional risk cut-off for trisomy 18, or trisomies 18 or 13. RESULTS: There were 83 trisomy 18, 22 trisomy 13, and 588 controls. The median placental growth factor levels in trisomies 18 and 13 were 0.75 and 0.65 multiple of the median of controls, respectively (both P < 0.0001). There were no statistically significant differences in alpha feto-protein levels. Modelling predicts that using a trisomy 21 risk cut-off alone, at FPR of 3%, eFTS increases the DR for trisomies 18 and 13 by 0.6-0.8% compared with FTS. Additionally using a trisomy 18 risk cut-off, at an extra FPR of 0.2%, eFTS increased the DR by 0.6-0.9% over FTS; using a trisomy 18 or 13 risk cut-off did not further increase detection for FTS or eFTS. The increase in DR was greater at higher FPR. CONCLUSION: eFTS increases the detection of trisomies 18 and 13 to a small extent. PMID- 30025869 TI - Understanding and Practising Safe Electrosurgery in the Operating Room. PMID- 30025870 TI - Survey of Canadian PGY-4 and PGY-5 Obstetrics and Gynaecology Residents on Knowledge of and Exposure to Premature Ovarian Insufficiency. AB - OBJECTIVES: (1) To determine exposure to and general knowledge on premature ovarian insufficiency (POI) among Canadian senior obstetrics and gynaecology residents. (2) To identify opportunity to improve trainee exposure to POI. METHODS: Canadian PGY-4 and PGY-5 obstetrics and gynaecology residents were approached to complete an electronic survey. The questions in the survey included the basic POI knowledge, previous exposure to POI, and comfort level in managing POI patients. Data from the survey was summarized descriptively and compared between two trainee groups (PGY-4 and PGY-5) using chi-square or Fisher exact tests. RESULTS: Responses were received from trainees in all Canadian residency programs with an overall response rate of 45% (95/210 residents). Most respondents (79%, 75/95 residents) identified correct age for POI diagnosis, and 65% (62/95 residents) recognized the most common aetiology. A majority (99%, 92/93 residents) would prescribe hormone therapy for POI patients. Most trainees (62%, 59/95 residents) lack access to a POI clinic at their centre and 63% (59/94 residents) have seen less than six POI patients during residency training. Most feel somewhat comfortable managing POI patients (67%, 64/95 residents), but 22% (21/95 residents) feel totally uncomfortable with a majority of respondents (83%, 78/94 residents), indicating they would benefit from additional training. Compared with PGY-4 residents, the proportion of trainees who could identify the correct age for diagnosis of POI was significantly higher in PGY-5 residents (89% vs. 70%, P = 0.024). CONCLUSION: Many senior obstetrics and gynaecology residents in Canada lack knowledge around POI, and most indicate need for further exposure to POI during residency training. We identified an opportunity for improved POI curricula. PMID- 30025871 TI - Tooth fractures in the Krapina Neandertals. AB - Dental fractures can be produced during life or post-mortem. Ante-mortem chipping may be indicative of different uses of the dentition in masticatory and non masticatory activities related to variable diets and behaviors. The Krapina collection (Croatia, 130,000 years BP), thanks to the large number of teeth (293 teeth and tooth fragments) within it, offers an excellent sample to investigate dental fractures systematically. Recorded were the distribution, position and severity of the ante-mortem fractures according to standardized methods. High frequencies of teeth with chipping in both Krapina adults and subadults suggest that the permanent and deciduous dentition were heavily subjected to mechanical stress. This is particularly evident when the frequencies of chipping are compared with those in modern humans (Upper Paleolithic and historic samples) that we analysed using the same methods. The distribution of chipping in the Krapina sample (anterior teeth are more affected) and its position (labial) suggest a systematic use of the anterior teeth for non-masticatory tasks. PMID- 30025872 TI - Biomechanical implications of the onset of walking. AB - Changes in long bone strength associated with the onset of bipedal walking in humans have been previously documented in a longitudinal growth sample. However, it is unclear if this transition can be detected using archaeological, cross sectional data, which likely encompass more cultural and biological variation than a single dataset of living children. Focusing on variation in cross sectional polar second moment of area, we evaluate the ratios of femoral, tibial, and humeral strength in seven temporally diverse samples of individuals from birth to the age of eighteen years (n = 501), with subsequent comparisons to immature Late Pleistocene fossils. Using these samples, we determine whether changes related to the developmental onset of bipedality can be detected in a large, multi-population sample, test for differences in long bone strength ratios among Holocene groups that may indicate developmental differences in the onset of walking, and determine whether immature Late Pleistocene samples follow the same patterns as modern humans. Despite great variation within the Holocene sample, clear changes in these ratios are apparent around the age of the onset of walking. Humeral-to-femoral strength increases briefly prior to the age of one, with a sharp decline in relative humeral strength thereafter until age four. A similar pattern is apparent in the ratio of humeral/tibial and femoral/tibial strength. While the general pattern is consistent across all human groups sampled, these ratios vary by skeletal population, which seems to be closely related to variation in tibial length among samples. Although the extremely small fossil sample makes differences difficult to interpret, Neandertals also differ from both Late Pleistocene and Holocene modern humans in their strength ratios. Further research in this area may provide additional information about the skeletal impact of the onset of walking in the past and in additional fossil taxa. PMID- 30025874 TI - Hydrocephalus and intracranial hypertension in a woman from Ecuador. PMID- 30025873 TI - Transchem project - Part I: Impact of long-term exposure to pendimethalin on the health status of rainbow trout (Oncorhynchus mykiss L.) genitors. AB - Pendimethalin is a herbicide active substance commonly used in terrestrial agricultural systems and is thus detected at high concentrations in the surface water of several European countries. Previous studies reported several histopathological changes, enzymatic antioxidant modulation and immunity disturbance in fish exposed to this pesticide. The objective of this work was to investigate the direct effects of long-term exposure to environmental concentrations of pendimethalin over a period of 18 months in rainbow trout (Oncorhynchus mykiss) genitors. To do so, an experimental system consisting of eight similar 400 L tanks with a flow-through of fresh river water was used to perform daily chemical contamination. Fish were exposed to 850 ng/L for one hour and the pendimethalin concentration was then gradually diluted during the day to maintain optimal conditions for the fish throughout the experiment and to achieve a mean theoretical exposure level of around 100 ng L-1 per day. Every November, males and females were stripped to collect eggs and sperm and two new first generations of offspring were obtained. Kinetic sampling revealed differences in immune system parameters and antioxidative defences in the contaminated trout compared to the controls, due to pesticide exposure combined with seasonal changes related to gamete maturation. Moreover, reproductive capacity was significantly affected by exposure to the herbicide; a time lag of more than five weeks was observed for egg maturation in contaminated females and high bioconcentrations of pendimethalin were measured in eggs and sperm. Chemical transfer from genitors to offspring via gametes may affect embryo development and negatively impact the early stages of development. PMID- 30025875 TI - Egr-1 transactivates WNT5A gene expression to inhibit glucose-induced beta-cell proliferation. AB - Selective beta-cell loss is a characteristic of type 2 diabetes mellitus (T2DM). Inhibition of glucose-stimulated beta-cell proliferation is one of the in vivo results of the lipotoxicity of saturated fatty acids (SFAs). However, the mechanism by which lipotoxicity inhibits beta-cell proliferation is still unclear. In this study, we found palmitate, a saturated fatty acid, inhibited the beta-cell proliferation induced by high glucose through the induction of Wnt5a expression in vitro and in vivo. We also found that Wnt5a was both sufficient and necessary for inhibition of beta-cell proliferation. Additionally, Egr-1, but not NF-kappaB, FOXO1, Smad2, Smad3, SP1 or SP3 mediated the expression of Wnt5a. Deletion and site-directed mutagenesis of the WNT5A promoter revealed that activation of WNT5A gene transcription depends primarily on a putative Egr binding sequence between nucleotides -52 to -44, upstream of the transcription start site. Furthermore, Egr-1 bound directly to this sequence in response to palmitate treatment, both in vitro and in vivo. Moreover, after mice islets were treated with Egr inhibitors, the expression of Wnt5a decreased significantly and the glucose-induced beta-cell proliferation inhibited by palmitate was resumed. These findings establish Wnt5a as an Egr-1 target gene in beta-cells, uncovering a novel Egr-1/Wnt5a pathway by which saturated free fatty acids block glucose induced beta-cell proliferation. Our study lends support for the potential of Egr 1 inhibitors or Wnt5a antibodies as therapeutics for the treatment of T2DM. PMID- 30025876 TI - YAP transcriptionally regulates ErbB2 to promote liver cell proliferation. AB - The Hippo signaling pathway is implicated in regulation of liver size and dysregulation of this pathway contributes to tumorigenesis. The transcriptional targets and downstream pathways of the Hippo pathway effector YAP that contribute to liver growth have yet to be well-characterized. We examined the liver transcriptome in response to YAP overexpression and identify the ErbB signaling pathway as a mediator of cell growth downstream of YAP. ErbB2 is transcriptionally regulated by YAP in both the mouse liver and in HepG2 human hepatoma cells. Knockdown of YAP or pharmacological inhibition with verteporfin reduced ERBB2 levels in HepG2 cells. Analysis of ChIP-seq data revealed enrichment of the transcription factor TEAD4 at the ERBB2 promoter. Using luciferase reporter and chromatin immunoprecipitation assays, we show that YAP and TEAD4 directly bind to and activate a regulatory element in the ErbB2 promoter in both the mouse liver and HepG2 cells. Functionally, knockdown of YAP reduced EGF-induced ERBB2-mediated HepG2 cell proliferation and PI3K/AKT activation. Our findings highlight a mechanism by which YAP exerts its effects on liver cell proliferation through the ErbB signaling pathway by directly regulating the transcription of ErbB2. PMID- 30025877 TI - Severe imported falciparum malaria - Clinical and drug supply challenges. PMID- 30025878 TI - Caspase-2 is a negative regulator of necroptosis. AB - The role of caspase-2 in cell death regulation remains largely unknown. In this study we have analyzed the involvement of caspase-2 in RIPK1-regulated necrosis (necroptosis) in human ovarian carcinoma cells. We show that these cells undergo necroptosis upon treatment with the DNA damaging drug cisplatin in combination with the pan-caspase inhibitor zVAD-fmk. Downregulation of caspase-2 leads to an increase of necroptosis in CAOV-4 cells. Interestingly, an association of caspase 2 to the necrosome complex was not detected. Importantly, downregulation of caspase-2 with shRNA or CRISPR/Cas9 system led to an enhanced phosphorylation of RIPK1 and MLKL. Taken together, our data strongly indicate that caspase-2 negatively regulates necroptotic cell death, which might play an important role in further therapeutic applications. PMID- 30025879 TI - A Case of Fulminant Lymphocytic Myocarditis Responsive to Immunosuppression. PMID- 30025880 TI - Workplace Factors Associated With Neck Pain Experienced by Computer Users: A Systematic Review. AB - INTRODUCTION: The purpose of this systematic review was to examine literature on workplace factors associated with neck pain or symptoms in computer users performing clerical functions. METHODS: A systematic search of the Cochrane, Medline, CINAHL, and EMBASE databases was conducted for observational and experimental studies published since 2000. This review applied the case definition of The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. RESULTS: Seven hundred twenty-nine studies were identified. Seven hundred and two studies were excluded. Twenty-seven studies fulfilled inclusion criteria and were assessed for risk of bias. Cross-sectional studies were commonly at risk from nonresponse bias and lack of adequate case definitions. Experimental studies were mostly at risk of bias due to confounding and participant recruitment methods. CONCLUSIONS: Neck pain was not significantly associated with high job demands, low skill discretion, low decision authority, or low peer support. However, when these variables were combined with increased duration of computing tasks, or ergonomic demands, they reached significance. Supervisor support was found to be the only significant buffer capable of preventing these variables reaching significance in female office workers. PMID- 30025881 TI - Corrigendum re: "A Larger Prospective Study is Needed when Judging Robotic Radical Nephrectomy" [Eur Urol 2018;74:123-9]. PMID- 30025882 TI - Neoadjuvant Chemotherapy Reinforces Antitumour T cell Response in Urothelial Urinary Bladder Cancer. AB - Evidence indicates that neoadjuvant chemotherapy (NAC) may promote antitumour immune responses by activating T cells. The tumour-draining sentinel node (SN) is a key site to study tumour-specific T cell activation, being the primary immunological barrier against the tumour. In this prospective study, we set out to elucidate the effects of NAC on T cell subsets in the SNs of patients with muscle-invasive urothelial bladder cancer. We found that CD8+ effector T (Teff) cell exhaustion was reduced after NAC treatment, while cytotoxicity was increased. Additionally, in complete responders (CR patients), these cells were functionally committed effectors, as displayed by epigenetic analysis. In CD4+ Teffs, NAC treatment was associated with increased clonal expansion of tumour specific SN-derived cells, as demonstrated by a specific cell reactivity assay. In contrast, we observed an attenuating effect of NAC on regulatory T cells (Tregs) with a dose-dependent decrease in Treg frequency and reduced effector molecule expression in the remaining Tregs. In addition, multicolour flow cytometry analysis revealed that CR patients had higher Teff to activated Treg ratio, promoting antitumoural T cell activation. These results suggest that NAC reinforces the antitumour immune response by activating the effector arm of the T cell compartment and diminishing the influence of suppressive Tregs. PATIENT SUMMARY: In this report, we analysed the effect of chemotherapy on immune cell subsets of 40 patients with advanced bladder cancer. We found that chemotherapy has a positive effect on immune effector T cells, whereas an opposite, diminishing effect was observed for immune-suppressive regulatory T cells. We conclude that chemotherapy reinforces the antitumour immune response in bladder cancer patients. PMID- 30025883 TI - Linking perceived discrimination during adolescence to health during mid adulthood: Self-esteem and risk-behavior mechanisms. AB - RATIONALE: The literature on the effect of perceived discrimination on health has three gaps. First, the long-term relationship between perceived discrimination and health is underexplored. Second, the mechanisms through which perceived discrimination affects health remain unclear. Third, most studies focus on racial/ethnic discrimination, and other aspects of discrimination are overlooked. OBJECTIVE: This study aims to fill these gaps by testing a research framework that links the discriminatory experience during adolescence to an individual's health during mid-adulthood via self-esteem and risk behaviors at early adulthood. METHOD: Structural equation modeling is applied to the National Longitudinal Survey of Youth, 1979 Cohort (N = 6478). RESULTS: The discriminatory experience during adolescence imposes an adverse impact on health during mid adulthood even after accounting for other potential covariates, a detrimental effect lasting for over 30 years. In addition, while perceived discrimination reduces self-esteem at early adulthood, it affects only mental health during mid adulthood, rather than general health. Finally, the discriminatory experience promotes risk behaviors at early adulthood and the risk behaviors subsequently compromise health during mid-adulthood. CONCLUSIONS: Using a life course perspective, we find that the effect of perceived discrimination is more profound than the literature suggested and that risk behaviors may account for approximately 17% of the total effect of perceived discrimination on health. Our findings highlight the importance of early interventions in coping with perceived discrimination during adolescence. PMID- 30025884 TI - Workflow process mapping to characterize office-based primary care medication use and safety: A conceptual approach. AB - BACKGROUND: We developed the PCMedSafety conceptual framework to illustrate primary care medication safety transformation opportunities. PCMedSafety demonstrates the interrelationship between the practice-level primary care delivery system, medication workflow processes for common medication-related activities, and medication use and safety outcomes. This framework was used to conceptualize a workflow process mapping approach to characterize and evaluate the safety of medication-related activities performed in primary care practices. OBJECTIVES: In this article, we conceptually describe how workflow process mapping of primary care medication-related activities can be used to: (1) understand and characterize common office-based primary care medication-related workflows, and (2) identify medication-related workflow process gaps and deviations and their impact on medication use and safety within office-based primary care. METHODS: Workflow process mapping of primary care medication related activities consists of 9 major steps, including: (1) identification of a primary care practice, (2) establishment of a workflow mapping team, (3) selection of medication-related activities, (4) development of ideal-state workflow process map(s), (5) selection of data elements and development of data collection form(s), (6) development of a workflow observation schedule, (7) completion of direct workflow observations, (8) development of observed workflow process map(s), and (9) data analysis to identify medication safety workflow gaps and deviations. CONCLUSION: The medication workflow process mapping approach illustrated in this article can be used by primary care executive leadership, clinician leaders, primary care providers, and clinical pharmacists to identify, resolve, and prevent medication safety concerns within a primary care practices. Workflow gaps and deviations identified through workflow process mapping can be used to inform practice-specific opportunities for: (1) team-based primary care redesign to integrate clinical pharmacists into the expanded primary care team; (2) workforce development, including staff/provider training and role delegation for common primary care medication-related activities; and (3) improvements in workflow efficiency and consistency to reduce preventable medication errors. PMID- 30025885 TI - Superensemble forecast of respiratory syncytial virus outbreaks at national, regional, and state levels in the United States. AB - Respiratory syncytial virus (RSV) infections peak during the winter months in the United States, yet the timing, intensity, and onset of these outbreaks vary each year. An RSV vaccine is on the cusp of being released; precise models and accurate forecasts of RSV epidemics may prove vital for planning where and when the vaccine should be deployed. Accurate forecasts with sufficient spatial and temporal resolution could also be used to support the prevention or treatment of RSV infections. Previously, we developed and validated an RSV forecast system at the regional scale in the United States. This model-inference system had considerable forecast skill, relative to the historical expectance, for outbreak peak intensity, total outbreak size, and onset, but only marginal skill for predicting the timing of the outbreak peak. Here, we use a superensemble approach to combine three forecasting methods for RSV prediction in the US at three different spatial resolutions: national, regional, and state. At the regional and state levels, we find a substantial improvement of forecast skill, relative to historical expectance, for peak intensity, timing, and onset outbreak up to two months in advance of the predicted outbreak peak. Moreover, due to the greater variability of RSV outbreaks at finer spatial scales, we find that improvement of forecast skill at the state level exceeds that at the regional and national levels. Such finer scale superensemble forecasts may be more relevant for effecting local-scale interventions, particularly in communities with a high burden of RSV infection. PMID- 30025886 TI - Sports and cardiac arrhytmias. PMID- 30025887 TI - Linker histones and chromatin remodelling complexes maintain genome stability and control cellular ageing. AB - Linker histones are major players in chromatin organization and per se are essential players in genome homeostasis. As the fifth class of histone proteins the linker histones not only interact with DNA and core histones but also with other chromatin proteins. These interactions prove to be essential for the higher levels of chromatin organization like chromatin loops, transcription factories and chromosome territories. Our recent results have proved that Saccharomyces cerevisiae linker histone - Hho1p, physically interacts with the actin-related protein 4 (Arp4) and that the abrogation of this interaction through the deletion of the gene for the linker histone in arp4 mutant cells leads to global changes in chromatin compaction. Here, we show that the healthy interaction between the yeast linker histone and Arp4p is critical for maintaining genome stability and for controlling cellular sensitivity to different types of stress. The abolished interaction between the linker histone and Arp4p leads the mutant yeast cells to premature ageing phenotypes. Cells die young and are more sensitive to stress. These results unambiguously prove the role of linker histones and chromatin remodelling in ageing by their cooperation in pertaining higher-order chromatin compaction and thus maintaining genome stability. PMID- 30025888 TI - Recent advances on biogranules formation in dark hydrogen fermentation system: Mechanism of formation and microbial characteristics. AB - Hydrogen producing granules (HPGs) are most promising biological methods used to treat organic rich wastes and generate clean hydrogen energy. This review provides information regarding types of immobilization, supporting materials and microbiome involved on HPG formation and its performances. In this review, importance has been given to three kinds of immobilization techniques such as adsorption, encapsulation, and entrapment. The HPG, characteristics and types of organic and inorganic supporting materials followed for enhancing hydrogen yield were also discussed. This review also considers the applications of HPG for sustainable and high rate hydrogen production. A detailed discussion on insight of key mechanism for HPGs formation and its performances for stable operation of high rate hydrogen production system are also provided. PMID- 30025889 TI - Photobiomodulation therapy on bothrops snake venom-induced local pathological effects: A systematic review. AB - Bothrops snakebite treatment is antivenom therapy, which is ineffective in neutralizing the severe local effects caused by these envenomations. There are evidence that photobiomodulation therapy (PBMT) has emerged as a promising tool to counteract the venom-induced local effects. The purpose was to write a narrative review of the literature about PBMT as a treatment for Bothrops snakebites. We reviewed articles indexed in PubMed, SCOPUS and Scientif Direct database with filter application. Included studies had to investigate local effects induced by Bothrops snake venom in any animal model using any type of photobiomodulation irradiation and at least one quantitative measure of local effects of Bothrops envenomation. Sixteen studies were selected from 54 original articles targeted PBMT (low-level laser or light emitting diode) as a complementary tool for local effects treatment induced by snakebites, and all its assessments. Articles were critically assessed by two independent raters with a structured tool for rating the research quality. PBMT demonstrate to be a promising tool for local treatment effects caused by snakebite by reducing local edema, hyperalgesia, leukocyte influx and myonecrosis and accelerating tissue regeneration related to myotoxicity. However, the mechanism is not well understood and additional studies are needed. PMID- 30025890 TI - Multimorbidity and polypharmacy among elderly people followed in general practices in Germany. PMID- 30025891 TI - Short- and long-term prognostic role of diastolic blood pressure in intermediate high risk patients with acute pulmonary embolism. PMID- 30025892 TI - A new model to study cell-to-cell transfer of alphaSynuclein in vivo. AB - Parkinson's disease (PD) compromises motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta. At the histopathological level, PD is characterized by the accumulation of Lewy bodies, large protein inclusions containing aggregated alphaSynuclein (alphaSyn). The progression of PD involves the spreading of alphaSyn misfolding through the brain mediated by a prion-like mechanism, where the protein is transferred between cells. Here we report that alphaSyn internalization is a dynamic process, where the protein transits through different sub-cellular compartments. Importantly, cells incorporating alphaSyn develop larger protein-like inclusions when compared to alphaSyn producing cells. We developed a new tool to monitor cell-to-cell transfer of alphaSyn in vivo using an adeno-associated viral (AAV) vector expressing alphaSyn fused to a red fluorescent protein in addition to soluble EGFP to label donor cells. Intra-nigral delivery of this reporter AAV construct allowed the visualization of alphaSyn incorporation into surrounding neurons. This work provides a new tool to study alphaSyn cell-to-cell transfer in vivo and may open new opportunities to study PD pathogenesis. PMID- 30025894 TI - FoxO1 expression in osteoblasts modulates bone formation through resistance to oxidative stress in mice. AB - Accumulation of reactive oxygen species (ROS) induced by oxidative stress (OS) affects cell survival, cell function and even results in cell death. As a major transcription factor of forkhead O (FoxOs) family, FoxO1 orchestrates multiple osteoblastic biological processes, thus regulating osteoblast physiology and bone metabolism. However, the outcome of osteoblast behaviors varies under different physiological and pathological conditions. Also, the underlying impact of FoxO1 on oxidative stress and further on bone metabolism still remains unclear. In this study, using osteoblast-specific FoxO1 knockout (FoxO1OB-/-) mice, we investigated the potential roles of FoxO1 on bone formation and osteoblast bioactivity under physiological condition. We show herein that FoxO1-knockout decreased bone volume and bone formation rate in FoxO1OB-/- mice, which might be related to the decreased osteoblasts number. We also found that FoxO1-knockout increased apoptosis-related caspase-3 activity of osteoblasts, and inhibited the expression of osteogenic phenotypic markers (i.e. Runx2, Osx, ALP and OPN), leading to reduced osteoblasts differentiation. The alterations of bone formation and osteoblasts bioactivity were further testified to be linked to the elevated intracellular oxidative stress levels in FoxO1-deficient osteoblasts. Besides, administration of the antioxidant N-acetyl-l-cysteine (NAC) normalized the increased ROS levels in FoxO1-deficient osteoblasts, restoring the decreased osteoblasts differentiation, suppressing apoptosis-related caspase-3 activity, and promoting the expression of osteogenic markers in FoxO1-deficient osteoblasts. These results together illustrated that as a major regulator in redox homeostasis and osteoblast physiology, FoxO1 provides a favorable intracellular environment for osteoblast functions by defensing against the adverse effects of oxidative stress. PMID- 30025893 TI - Glucocorticoid-induced CREB activation and myostatin expression in C2C12 myotubes involves phosphodiesterase-3/4 signaling. AB - Muscle atrophy in metabolic conditions like chronic kidney disease (CKD) and diabetes are associated with glucocorticoid production, dysfunctional insulin/Akt/FoxO3 signaling and increased myostatin expression. We recently found that CREB, a transcription factor proposed to regulate myostatin expression, is highly phosphorylated in some wasting conditions. Based on a novel Akt-PDE3/4 signaling paradigm, we hypothesized that reduced Akt signaling contributes to CREB activation and myostatin expression. C2C12 myotubes were incubated with dexamethasone (Dex), an atrophy-inducing synthetic glucocorticoid. Akt/CREB signaling and myostatin expression were evaluated by immunoblot and qPCR analyses. Inhibitors of Akt, phosphodiesterase (PDE)-3/4, and protein kinase A (PKA) signaling were used to test our hypothesis. Incubating myotubes with Dex for 3-24 h inhibited Akt phosphorylation and enhanced CREB phosphorylation as well as myostatin mRNA and protein. Inhibition of PI3K/Akt signaling with LY294002 similarly increased CREB phosphorylation. Isobutyl-methylxanthine (IBMX, a pan PDE inhibitor), milrinone (PDE3 inhibitor) and rolipram (PDE4 inhibitor) augmented CREB phosphorylation and myostatin expression. Inhibition of protein kinase A by PKI reverted Dex- or IBMX-induced CREB phosphorylation and myostatin expression. Our study provides evidence supporting a newly identified mechanism by which a glucocorticoid-related reduction in Akt signaling contributes to myostatin expression via CREB activation. PMID- 30025895 TI - Corrigendum to "FoxO3a-mediated autophagy is down-regulated in the laforin deficient mice, an animal model for Lafora progressive myoclonus epilepsy" [Biochem. Biophys. Res. Commun. 474 (2) (2016) 321-327]. PMID- 30025896 TI - Auriculasin from Flemingia philippinensis roots shows good therapeutic indexes on hyperactive behavior in zebrafish. AB - Previously, period1b-/- zebrafish mutants were used to establish an attention deficit hyperactivity disorder (ADHD) model, in which hyperactive behavior was found to be a typical characteristic of ADHD due to down-regulated dopamine levels. Here, we used five prenylated isoflavones from Flemingia philippinensis roots to study their therapeutic effects on hyperactivity behavior in period1b-/- zebrafish. Results of locomotor activity assay showed that auriculasin, one of the prenylated isoflavones, significantly reduced the hyperactivity behavior in period1b-/- zebrafish. Hormone measurement results showed that auriculasin increased melatonin and dopamine content. Results of quantitative real-time polymerase chain reaction showed that auriculasin down-regulated the expression of mao but up-regulated the expression of th and per1b. Thus, auriculasin demonstrated a potential biological effect on dopamine activity to inhibit hyperactivity behavior in the ADHD zebrafish model by regulating circadian clock gene per1b. PMID- 30025897 TI - NGS-identified circulating miR-375 as a potential regulating component of myocardial infarction associated network. AB - Acute myocardial infarction (MI), the most severe type of coronary heart disease, is a leading cause of disability and mortality worldwide. In order to investigate the involvement of miRNAs in the pathologic processes related to MI, we performed the analysis of circulating miRNAs - stable short noncoding RNA molecules - in the peripheral blood plasma of MI patients compared to healthy controls (all persons were men and lived in European Russia) using next generation sequencing. We observed 20 miRNAs, which levels in plasma more than two-fold differed in MI patients (p < 0.05). Among them miR-208b and miR-375 passed threshold for multiple corrections (FC = 49.2, FDR-adjusted p-value = 0.0078 and FC = -6.4, FDR adjusted p-value = 0.00076, respectively); these data were then validated using RT-qPCR (FC = 5.3, p-value = 0.028 and FC = -2.1, p-value = 0.0039, respectively). While for miR-208b we reidentified earlier observations, miR-375 was found to be associated with MI for the first time. To investigate the reasons for which miR-375 holds a special place among circulating miRNAs in MI, enrichment and network analyses of miR-375 target genes and their interactions were carried out. PIK3CA and TP53 genes, regulated by miR-375, were identified as the key players of MI disease module. PMID- 30025898 TI - 'Parents are the best prevention'? Troubling assumptions in cannabis policy and prevention discourses in the context of legalization in Canada. AB - BACKGROUND: Canada has announced that it will legalize cannabis on October 17, 2018, and as a result of this impending drug law reform the need to develop prevention resources and drug education - in schools, in public health, and for parents - has emerged as a public concern and a policy priority. Set against this context, the aim of our paper is to amplify the parent perspective on preventing problematic adolescent cannabis use, but also to interrogate the idea of 'parents as the best prevention' that has taken hold in discussions about the potential consequences of legalization for youth. METHODS: In 2016 we undertook an exploratory, qualitative interview study in Vancouver, British Columbia (n = 16) with parents of adolescents who had used cannabis. Building on our past research developing educator-led resources to support an open dialogue about cannabis in the classroom, in this study we asked parents about the supports and resources they needed to inform their discussions about cannabis with their adolescent children, as well the challenges they faced in responding to cannabis use when they believed it had become problematic. FINDINGS: Across the interviews, parents mobilized discourses of risk and responsibility for preventing problematic cannabis use that appeared to reinstate individualizing accounts of substance use. Many echoed normative ideas about health, the risks of cannabis use, and 'good' parenting, sidestepping social inequities around drug use, and thus implicating parents and families as solely responsible for preventing adolescent drug use. CONCLUSION: Our analysis suggests how parents have been largely disempowered and unsupported when it comes to addressing adolescent drug use in the family context. Even as they expressed their awareness that formal supports and resources to assist them were lacking, parents also assigned blame to themselves - or to other parents - for 'failing' to prevent problematic cannabis use. PMID- 30025899 TI - Problematisation and regulation: Bodies, risk, and recovery within the context of Neonatal Abstinence Syndrome. AB - BACKGROUND: Neonatal Abstinence Syndrome (NAS) is an anticipated effect of maternal drug use during pregnancy. Yet it remains a contested area of policy and practice. In this paper, we contribute to ongoing debates about the way NAS is understood and responded to, through different treatment regimes, or logics of care. Our analysis examines the role of risk and recovery discourses, and the way in which the bodies of women and babies are conceptualised within these. METHODS: Qualitative interviews with 16 parents (9 mothers, 7 fathers) and four focus groups with 27 health and social care professionals based in Scotland. All the mothers were prescribed opioid replacement therapy and parents were interviewed after their baby was born. Data collection explored understandings about the causes and consequences of NAS and experiences of preparing for, and caring for, a baby with NAS. Data were analysed using a narrative and discursive approach. RESULTS: Parent and professional accounts simultaneously upheld and subverted logics of care which govern maternal drug use and the assessment and care of mother and baby. Despite acknowledging the unpredictability of NAS symptoms and the inability of the women who are opioid-dependent to prevent NAS, logics of care centred on 'proving' risk and recovery. Strategies appealed to the need for caution, intervening and control, and obscured alternative logics of care that focus on improving support for mother-infant dyads and the family as a whole. CONCLUSION: Differing notions of risk and recovery that govern maternal drug use, child welfare and family life both compel and trouble all logics of care. The contentious nature of NAS reflects wider socio-political and moral agendas that ultimately have little to do with meeting the needs of mothers and babies. Fundamental changes in the principles, quality and delivery of care could improve outcomes for families affected by NAS. PMID- 30025900 TI - Recent advances in peptidomimetics antagonists targeting estrogen receptor alpha coactivator interaction in cancer therapy. AB - Estrogen receptor alpha (ERalpha) is a crucial target for ERalpha positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERalpha. However, significant percentage of patients developed cancer relapse with drug-resistance. ERalpha peptidomimetic modulators have been considered as promising treatments for drug resistant breast cancers as they are targeting ERalpha-coactivator interacting interface instead of the ligand binding pocket of ERalpha. Herein, we reviewed the recent development of ERalpha peptidomimetics antagonists. PMID- 30025901 TI - Expanding chemical space of DNA-binding molecules with three base-binding units. AB - A new molecule NC3-3 designed to expand chemical space of parent molecule NCD by adding the third base-binding unit was reported. NC3-3 bound to the G-G mismatch in the 5'-CGG-3'/5'-CGG-3' motif but not to that in 5'-GGC-3'/5'-GGC-3'. This binding selectivity is similar to that reported for NCD. Fluorimetric screening of NCD and NC3-3 to dsDNA library containing yGw/xGz motifs showed that NC3-3 still kept the sequence selectivity as we observed for NCD-binding. The third naphthyridine heterocycle in NC3-3 affected the mode of the binding, but a little effect on the sequence selectivity. PMID- 30025902 TI - New lead elements for histamine H3 receptor ligands in the pyrrolo[2,3 d]pyrimidine class. AB - This work describes the microwave assisted synthesis of twelve novel histamine H3 receptor ligands. They display pyrrolo[2,3-d]pyrimidine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for H3R and H4R binding affinities in radioligand displacement assays and the most potent compounds were evaluated for H3R binding properties in vitro and in docking studies. The combination of a rigidized H3R warhead and the pyrrolo[2,3 d]pyrimidine scaffold resulted in selective activity at the H3 receptor with a pKi value of 6.90 for the most potent compound. A bipiperidine warhead displayed higher affinity than a piperazine or morpholine motif, while a naphthyl moiety in the arbitrary region increased affinity compared to a phenyl derivative. The compounds can be starting points for novel, simply synthesized histamine H3 receptor ligands. PMID- 30025903 TI - Microbiology and clinical characteristics of viridans group streptococci in patients with cancer. AB - This study assessed the microbiology, clinical syndromes, and outcomes of oncologic patients with viridans group streptococci isolated from blood cultures between January 1st, 2013 and December 31st, 2016 in a referral hospital in Mexico using the Bruker MALDI Biotyper. Antimicrobial sensitivity was determined using BD Phoenix 100 according to CLSI M100 standards. Clinical information was obtained from medical records and descriptive analysis was performed. Forty-three patients were included, 22 females and 21 males, aged 42 +/- 17 years. Twenty (46.5%) patients had hematological cancer and 23 (53.5%) a solid malignancy. The viridans group streptococci isolated were Streptococcus mitis, 20 (46.5%); Streptococcus anginosus, 14 (32.6%); Streptococcus sanguinis, 7 (16.3%); and Streptococcus salivarius, 2 (4.7%). The main risk factors were pyrimidine antagonist chemotherapy in 22 (51.2%) and neutropenia in 19 (44.2%) cases, respectively. Central line associated bloodstream infection was diagnosed in 18 (41.9%) cases. Septic shock occurred in 20.9% of patients, with an overall mortality of 18.6%. Only four S. mitis revealed penicillin-resistance. Our results are similar to those of other series, identifying these bacteria as emerging pathogens with significant morbidity and mortality in oncologic patients. The MALDI-TOF system increased the rate of viridans group streptococci isolation in this population. PMID- 30025904 TI - Fungal biofilms in the hemodialysis environment. AB - Hemodialysis, which is a kidney failure treatment that uses hemodialysis machine, dialyzer, dialysis solution, catheters, and needles, favors biofilm formation. This study evaluates whether Aspergillus, Candida, and Fusarium can form biofilm in dialysis fluids. Biofilms were grown in 96-well microplates containing solutions (acid and basic) consisting of dialysate, dialysate per se, or dialysate plus glucose as culture medium. The biofilms were incubated at 30 degrees C for 72 h, quantified by the violet crystal methodology, and visualized by transmission electron microscopy. All the fungi formed biomass in all the tested solutions. However, Bonferroni analysis revealed that the dialysate facilitated Aspergillus biomass development, whereas the dialysate and dialysate with glucose provided similar Fusarium oxysporum biomass development. Candida parapsilosis development was favored in biofilms grown in basic electrolytic solution. Electron micrographs of biofilms that grew on catheters after 72 h showed that Aspergillus formed abundant hyphae; the extracellular matrix was visible on the surface of some hyphae when Aspergillus was grown in the dialysate. A multilayered hyphal structure emerged when F. oxysporum biofilms were incubated in the dialysate with glucose. C. parapsilosis biofilm growth in basic solution elicited a dense network of yeasts and pseudohyphae as well as the extracellular matrix; the biofilm was attached across the catheter length. This study may contribute to the formulation of new strategies to monitor biofilm formation and to increase knowledge associated with fungal biofilms in the dialysis environment. PMID- 30025905 TI - Modifying effects of delta-Aminolevulinate dehydratase polymorphism on blood lead levels and ALAD activity. AB - Lead is an environmental hazard with great public health concern and has been known to inhibit delta-aminolevulinate dehydratase (ALAD) activity involved in the heme biosynthetic pathway. The study aimed to investigate the influence of ALAD polymorphism (G177C) on retention of Pb-B levels and ALAD activity on occupationally exposed lead workers. In the present study, we enrolled 561 lead exposed and 317 non-occupationally exposed subjects and performed a comprehensive analysis of Pb-B levels along with ALAD activity and genotyping. The frequency of ALAD variants observed in the total subjects (n = 878) was 70.04% for ALAD 1-1, 27.44% for heterozygous ALAD 1-2 and 2.5% for homozygous mutant ALAD 2-2. Our study revealed that ALAD 1-2 carriers presented higher Pb-B levels compared to wild type ALAD 1-1 carriers. Further, a significant difference was observed in the activity of ALAD between ALAD 1-2/ 2-2 and ALAD 1-1 carriers of non occupationally exposed group indicating that the polymorphic nature of the enzyme may contribute to altered activity of ALAD irrespective of lead exposure. Hence, ALAD 2 allele might contribute to increased susceptibility to high Pb-B retention, and genotyping of ALAD in lead exposed subjects might be used as a prediction marker to impede tissue/organ damage due to lead toxicity. PMID- 30025906 TI - Niemann-Pick Disease Type B: A Rare Cause of Lung Cysts. PMID- 30025907 TI - New approaches to allergen immunotherapy. AB - OBJECTIVE: New insights into mechanisms should enable strategic improvement of allergen immunotherapy, aiming to make it safer, faster, more effective, and able to induce long-term tolerance. We review novel approaches with potential to translate into clinical use. DATA SOURCES: Database searches were conducted in PubMed, Scopus, and Google Scholar. STUDY SELECTIONS: Search terms were based on current and novel approaches in immunotherapy. Literature was selected primarily from recent randomized double-blinded placebo-controlled trials and meta analyses. RESULTS: Alum, microcrystalline tyrosine, and calcium phosphate are adjuvants in current use. Toll-like receptor-4 agonists combined with allergen have potential to shorten duration of treatment. Other novel adjuvants, nanoparticles, and virus-like particles in combination with allergen have shown early promise. Omalizumab lessens systemic side effects but does not improve efficacy. Intralymphatic immunotherapy for aeroallergens, epicutaneous immunotherapy for food allergens, and use of modified allergens (allergoids), recombinant allergens (and hypoallergenic variants), and T- and B-cell peptide approaches have shown evidence of efficacy and permitted shortened courses but have only rarely been compared with conventional extracts. CONCLUSION: Novel routes of immunotherapy, use of modified allergens, and combination of allergens with immunostimulatory adjuvants or immune modifiers have been developed to augment downregulation of T-helper cell type 2 immunity and/or induce "protective" blocking antibodies. Although these strategies have permitted shortened courses, confirmatory phase 3 trials are required to confirm efficacy and safety and head-to-head trials are required for comparative efficacy. Currently, subcutaneous and sublingual immunotherapies using in-house standardized crude extracts remain the only approaches proved to induce long-term tolerance. PMID- 30025908 TI - Allergy to ginger with cysteine proteinase GP-I as the relevant allergen. PMID- 30025909 TI - Evaluation of the manufacturer-dependent differences in specific immunoglobulin E results for indoor allergens. AB - BACKGROUND: Even though allergies are an important health issue, the detected amount of allergen-specific IgE (sIgE) has differed widely between manufacturers in the past, and even as recently as this year. These discrepancies hinder diagnostics and can even impact allergen immunotherapy. OBJECTIVE: The aim of this study was to evaluate the development and status quo of the quality of in vitro diagnostic testing for house dust mites (HDM) and cat epithelium, 2 important indoor allergen sources. METHODS: We analyzed data on the allergen sources European HDM, American HDM, and cat epithelium, which were collected by the Society for Promoting Quality Assurance in Medical Laboratories (INSTAND e.V.) during 7 years as part of External Quality Assessment schemes (EQAs). A pseudoanonymized comparison was made of the semiquantitative data and allergen class results of the 4 main suppliers of in vitro diagnostic sIgE tests. Coefficients of variation (CV) were determined in order to evaluate interlaboratory comparability. RESULTS: In vitro allergy diagnostic testing for the major allergen sources HDM and cat epithelium still reveals manufacturer dependent differences. Despite this, a cautious trend was found towards an alignment of the results and interlaboratory comparability, with the exception of 1 supplier. CONCLUSION: Even though these results are promising, future EQAs have to be closely monitored to ensure this positive trend is not just a snapshot. PMID- 30025910 TI - An Economic Evaluation of Immediate Verses Non-immediate Activation of Emergency Medical Services After Epinephrine Use for Peanut-induced Anaphlaxis. AB - BACKGROUND: Layperson food allergy management plans commonly stipulate that if epinephrine is used to "immediately call 911 and seek care in the nearest medical facility" for observation. OBJECTIVE: To evaluate the cost-effectiveness of this strategy, versus a watchful waiting approach before activating emergency medical services (EMS). METHODS: We performed a cost-effectiveness analysis using Markov modeling simulated over a 20-year horizon comparing activating EMS immediately after epinephrine use for allergic reactions to peanut vs. a "wait and see" approach in which EMS was only activated if symptoms of the reaction did not promptly resolve after treatment. The base-case model assumed a 10-fold increased fatality risk with delayed EMS activation. RESULTS: The fatality risk associated with early EMS use was minimal, with a per-patient fatality rate over a 20-year horizon of 1.2 * 10-6, vs. 1.9 * 10-6 for a "wait and see" approach. The incremental cost per life-year saved was $142,943,447 for early EMS vs "wait and see," with the cost per death prevented reaching $1,349,335,651 as the simulation concluded. Cost of early EMS activation rose to $321,625,534 per lifeyear saved ($3,035,454,848 per death prevented) if a 5-fold increase in fatality risk was assumed, and was $12,997,173 per life-year saved ($122,689,936 per death prevented) if a 100-fold increase in fatality risk was assumed. CONCLUSION: Medical observation of a treated and promptly resolved peanut allergic reaction has minimal benefit and excessive costs. Immediately activating EMS after using epinephrine for a peanut allergic reaction in this context is not cost-effective. PMID- 30025911 TI - Patient burden and quality of life in atopic dermatitis in US adults: A population-based cross-sectional study. AB - BACKGROUND: The patient burden and quality of life (QOL) impact of atopic dermatitis (AD) in the United States population is not well established. OBJECTIVE: To elucidate the patient burden of AD in the US population. METHODS: A cross-sectional, population-based study of 602 adults was performed. Atopic dermatitis was determined using modified UK Diagnostic Criteria for AD. Its severity was assessed using self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring AD (PO-SCORAD), PO-SCORAD-itch, and sleep. Quality of life was assessed using short-form (SF-)12 mental and physical health scores and Dermatology Life Quality Index (DLQI). RESULTS: Adults with AD reported higher proportions of having only fair/poor overall health (25.8% vs. 15.8%), being somewhat/very dissatisfied with life (16.7% vs 11.4%), lower weighted mean (standard deviation [SD]) SF-12 mental (45.9 [9.9] vs 50.9 [9.2]) and physical health subscores (53.0 [2.5] vs 53.5 [2.3]) and higher DLQI (4.9 [6.5] vs 1.1 [2.8]). In multivariable regression models adjusting for sociodemographics and multiple comorbid health disorders, significant stepwise decreases by AD severity (self-reported, POEM, PO-SCORAD) of overall health, life satisfaction, SF-12 mental health, and increases of DLQI scores were seen. The SF 12 physical health scores were only associated with moderate AD. Concurrently, severe PO-SCORAD, POEM, or PO-SCORAD-itch was associated with very low mean SF-12 mental health (34.7) and high DLQI scores (24.7). Atopic dermatitis commonly limited lifestyle (51.3%), led to avoidance of social interaction (39.1%), and impacted activities (43.3%). The most burdensome AD symptoms were itch (54.4%), excessive dryness/scaling (19.6%), and red/inflamed skin (7.2%). CONCLUSION: These data support the heavy burden that AD places on patients, particularly those with moderate and severe AD. PMID- 30025912 TI - Search for the optimal antimicrobial therapy of Clostridium difficile infection. PMID- 30025913 TI - Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis. AB - BACKGROUND: Several new treatments for Clostridium difficile infections have been investigated. We aimed to compare and rank treatments for non-multiply recurrent infections with C difficile in adults. METHODS: We did a random effects network meta-analysis within a frequentist setting to obtain direct and indirect comparisons of trials. We searched MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for published and unpublished trials from the creation of these databases until June 30, 2017. We included randomised controlled trials of treatments for non-multiply recurrent infections with confirmed C difficile in adults (at least 18 years) that reported both primary cure and recurrence rates, and we used the Cochrane Risk of Bias tool to appraise trial methods. For our analysis, we extracted the total numbers of patients with primary cure and recurrence from published and unpublished reports. The primary outcome was sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death. FINDINGS: Of 23 004 studies screened, 24 trials, which comprised 5361 patients and 13 different treatments, were included in the analysis. The overall quality of evidence was rated as moderate to low. For sustained symptomatic cure, fidaxomicin (odds ratio 0.67, 95% CI 0.55-0.82) and teicoplanin (0.37, 0.14-0.94) were significantly better than vancomycin. Teicoplanin (0.27, 0.10-0.70), ridinilazole (0.41, 0.19-0.88), fidaxomicin (0.49, 0.35-0.68), surotomycin (0.66, 0.45-0.97), and vancomycin (0.73, 0.56-0.95) were better than metronidazole. Bacitracin was inferior to teicoplanin (0.22, 0.06-0.77) and fidaxomicin (0.40, 0.17-0.94), and tolevamer was inferior to all drugs except for LFF571 (0.50, 0.18 1.39) and bacitracin (0.67, 0.28-1.58). Global heterogeneity of the entire network was low (Cochran's Q=15.70; p=0.47). INTERPRETATION: Among the treatments for non-multiply recurrent infections by C difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C difficile. FUNDING: None. PMID- 30025914 TI - Comprehension and perceptions of study participants upon receiving perfluoroalkyl substance exposure biomarker results. AB - BACKGROUND: Measurement of environmental biomarkers in biomedia is increasingly used as a method of exposure characterization in human population studies. Reporting the results of biomarker measurements back to study participants has been controversial, including questions of ethics and whether the study participants would want to receive and would understand the results. METHODS: Recently we mailed individual measurements of two serum biomarkers, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) to participants in three exposure studies of persons living in the Ohio River Valley, of whom 60 were parents of children who had been sampled. Many had serum concentrations of PFOA above the US population 95th percentile value. Reporting forms used in the three studies were somewhat different (either tables or charts for comparison to US population values) and varied in complexity. With all reports, we included information about concentrations of PFOA and PFOS in the general population, and a survey designed to ascertain the opinions of the study participants about the information they received. RESULTS: Approximately 33% (273/821) returned the survey, and of those, 96% reported that they were pleased that we had sent them the report. Most (86%) responded that the results were easy to understand and the enclosed fact sheet was helpful in answering questions (87%). Regarding the amount of information, most felt that we provided the "right amount" (78%) but some "too much" (7%) and some "too little" (15%). The majority (53%) were surprised at their serum concentrations. Of those with serum values > 13.0 ng/mL, 74% responded that they thought their serum concentration was "high", but only 22% of those with serum concentrations <=5.6 responded that their concentration was "low". Surprisingly, many talked to no one about their levels; those who did were most likely to discuss the report with family members. CONCLUSIONS: Reporting back individual environmental biomarker results is generally well received by study participants, and those with high concentrations perceived them to be high. Questions remain as to why study participants did not discuss their results with others. PMID- 30025915 TI - Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells. AB - Pituitary corticotroph tumors lead to excess adrenocorticotrophic hormone (ACTH) secretion, resulting in Cushing's disease (CD), which is associated with significant mortality. Standard treatments include neurosurgery, radiotherapy and medical therapy. Both surgery and radiotherapy have undesirable complications and high recurrence rates. At present, there is only one medical option available that targets pituitary adenoma and ACTH secretion, the drug pasireotide. However, hyperglycemia is common during pasireotide treatment. In addition, some patients have discontinued pasireotide treatment because of hyperglycemia-related adverse events or uncontrolled diabetes. New medical treatments directly targeting the corticotroph cells and suppressing ACTH secretion are urgently required. Metformin is a commonly used antidiabetic drug that has been widely used to control the hyperglycemia that occurs in patients with CD, which is secondary to both cortisol excess and pasireotide treatment. Recent studies suggest that metformin has direct anticancer activities against many tumor cell lines. In the present study, we investigated whether metformin exerts an anti-tumor effect by directly targeting pituitary corticotroph tumors and exploring the underlying mechanisms. Using the mouse corticotroph tumor cells, AtT20 cells, we report that metformin inhibited cell proliferation, promoted cell apoptosis and decreased ACTH secretion but did not block the cell cycle in cells. The apoptosis induced by metformin was accompanied by increased caspase-3 activity. Meanwhile, metformin down-regulated the anti-apoptotic protein B cell lymphoma 2 (Bcl-2) but up-regulated the pro-apoptotic protein Bcl2-associated X (BAX), which suggests the involvement of the mitochondrial-mediated apoptosis pathway. Furthermore, metformin promoted AMP-activated protein kinase (AMPK) phosphorylation but inhibited insulin-like growth factor-1 receptor (IGF-1R) expression, protein kinase B (PKB/AKT) phosphorylation and mammalian target of rapamycin (mTOR) phosphorylation. Finally, the IGF-1R inhibitor picropodophyllin (PPP) significantly inhibited the cell proliferation of AtT20 cells. We conclude that metformin inhibits cell proliferation and induces apoptosis in AtT20 cells by activating AMPK/mTOR and inhibiting IGF-1R/AKT/mTOR signaling pathways. Metformin may have direct antitumor activity against pituitary corticotroph tumors. PMID- 30025916 TI - Greater loss of horizontal force after a repeated-sprint test in footballers with a previous hamstring injury. AB - OBJECTIVES: To quantify changes in running kinetics and kinematics during a repeated-sprint test in football players, and explore the sensitivity and specificity with which these variables can identify previous hamstring injury. DESIGN: 20 Western Australia State League footballers with previous unilateral hamstring injury and 20 players without completed a 10*6-s repeated-sprint test on a non-motorised treadmill dynamometer. METHODS: Changes in horizontal force, vertical force, contact time and flight time were compared between previously injured and uninjured legs of participants. RESULTS: Mean horizontal force production of the previously injured leg in the injured group was 13% lower (p=0.001), and this magnitude of change was used to identify the injured legs within the cohort with 77% specificity and 85% sensitivity. Furthermore, the area under the Receiver Operating Characteristics curve (0.846) demonstrated that the between-leg difference in mean horizontal force was a good instrument for identifying previous hamstring injury. CONCLUSIONS: There is a greater fatigued induced change in mean horizontal force during a repeated-sprint test in legs with previous hamstring injury than the non-injured legs of the injured players or the legs of uninjured players. Such asymmetry may contribute to impaired performance in football players returning from hamstring injury and also to the high rate of hamstring re-injury. Rehabilitation and return-to-play strategies should emphasise a reduction in asymmetry, particularly during repeated high intensity efforts. Furthermore, binary regression and Receiver Operating Characteristic analyses suggest that changes in mean horizontal force could be used to assess risk of hamstring injury, re-injury and/or return to play. PMID- 30025917 TI - Predicting postoperative pain and analgesia in children after urological outpatient procedures: Is it clear? PMID- 30025918 TI - Demonstration of P-selectin expression and potential function in human corneal epithelial cells. AB - In response to an unexpected observation of apparent localisation by immunocytochemistry, we have investigated the potential expression and function of P-selectin (CD62P) in human corneal epithelial cells. The SV40 immortalised cell line, HCE-T (validated by STR profiling), along with multiple donor corneal limbal tissue samples, were examined for P-selectin expression using a combination of immunocytochemistry, Western blotting, RT-PCR and immunohistochemistry. Potential expression of the major ligand for P-selectin (P selectin glycoprotein ligand-1; PSGL-1; CD162) was also examined by immunocytochemistry and RT-PCR. A selective inhibitor of P-selectin-PSGL-1 binding (KF38789) was subsequently tested for effects on HCE-T cells using a cell culture gap-closure assay. HCE-T cells as well as primary epithelial cultures derived from donor corneal-limbal tissue, displayed positive immunostaining for P selectin. Staining was particularly evident at cell-cell boundaries and at the outer edge of expanding epithelial islands. P-selectin expression was confirmed by Western blotting and RT-PCR (validated by product sequencing), as well as by immunohistochemistry performed on serial sections of corneal-limbal tissue stained for P-selectin, keratin 3 and p63. PSGL-1 was detected by RT-PCR and immunocytochemistry in both corneal epithelial cells as well as human limbal fibroblasts (HLF). KF38789 (5 MUM) significantly reduced closure of a 500-MUm gap between confluent sheets of HCE-T cells over an 8-hr period (by ~40%, p < 0.01; paired two-tailed T test), but had no effect on culture gap-closure by either HLF or murine 3T3 fibroblasts. These results provide evidence of P-selectin expression in human corneal epithelial cells and suggest a potential role for this glycoprotein in facilitating the net movement of confluent sheets of human corneal epithelial cells. PMID- 30025919 TI - Vasoactivity of retinal veins: A potential involvement of endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion (RVO). AB - PURPOSE: Whilst the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors. Therefore, we studied the influence of ET-1 on the retinal veins in hypertensive rats. METHODS: We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). To determine whether ET-1 was associated with the blood flow in eyes of SHRs, the chorioretinal blood flow in the rats was assessed using laser speckle flowgraphy (LSFG-Micro, Softcare, Fukuoka, Japan) before and after an intravenous injection of ET-1 under general anesthesia. In addition, retinas from SHRs and age-matched normotensive Wistar-Kyoto rats (WKYs) were removed, and retinal sections were immunostained for the ET-A and ET-B receptors. The protein levels of both ET-1 receptors and hypoxia-inducible factor 1 (HIF-1) in the retinal tissues were also determined by western blot analysis. RESULTS: One of the retinal veins became exceptionally constricted and was nearly occluded, and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the injection of ET-1. Immunoreactivity to ET-A receptor was higher in SHR retinas than in WKY retinas. The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas. CONCLUSIONS: An increase of ET-1 in circulating blood leads to the local constriction of retinal veins and this effect is accentuated in hypertensive rats by an upregulation of ET-A receptor. It is plausible that such a constriction of retinal veins increases retinal venous pressure, and may even contribute to the pathogenesis of RVO. PMID- 30025920 TI - Cannabinoid type 2 receptors mediate a cell type-specific self-inhibition in cortical neurons. AB - Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB1R and CB2R). In the central nervous system endocannabinoids are produced in an activity-dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell-autonomous slow self-inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long-lasting hyperpolarization of the membrane potential, rendering the cells less excitable. Different endocannabinoid receptors and effector mechanisms have been described underlying SSI in different cell types and brain areas. Here, we investigate SSI in neurons of layer 2/3 in the somatosensory cortex. High-frequency bursts of action potentials induced SSI in pyramidal cells (PC) and regular spiking non-pyramidal cells (RSNPC), but not in fast-spiking interneurons (FS). In RSNPCs the hyperpolarization was accompanied by a change in input resistance due to the activation of G protein-coupled inward-rectifying K+ (GIRK) channels. A CB2R specific agonist induced the long-lasting hyperpolarization, whereas preincubation with a CB2R-specific inverse agonist suppressed SSI. Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB1R-deficient but abolished in CB2R-deficient mice. Taken together, we describe an additional SSI mechanism in which the activity-induced release of endocannabinoids activates GIRK channels via CB2Rs. These findings expand our knowledge about cell type-specific differential neuronal cannabinoid receptor signaling and suggest CB2R-selective compounds as potential therapeutic approaches. PMID- 30025921 TI - Species specificity of rat and human alpha7 nicotinic acetylcholine receptors towards different classes of peptide and protein antagonists. AB - Peptide and protein neurotoxins, such as alpha-conotoxins from Cone snails and alpha-neurotoxins from snake venoms, are excellent tools to identify distinct nicotinic acetylcholine receptor (nAChR) subtypes. Here we compared the rat/human species specificity of alpha7 nAChR towards peptide and protein neurotoxins and found that alpha-conotoxin analogues [K11A]TxIB and [H5D]RegIIA are much more potent on the rat versus human alpha7 receptor expressed in Xenopus oocytes. In the hope to determine the key residue responsible for the difference in alpha conotoxin analogues affinities, ten single mutants of rat alpha7 nAChR were obtained because there are 10 differences in the extracellular ligand-binding domains of these species, and only K185R mutation decreased the affinity for alpha-conotoxins [K11A]TxIB and [H5D]RegIIA, down to their low affinities for human alpha7 nAChR. On the other hand, the reverse mutation R185K in human alpha7 nAChR resulted in the greatest increase in the affinity for both conotoxins, while a double mutation halpha7[S183N, R185K] made the potency of the receptor for them as high as that of rat alpha7 nAChR. The effects of mutations at position 185 were investigated also with some other alpha-conotoxins and cobra venom alpha-cobratoxin and found to have similar but much less pronounced effects on their species specificity. Molecular modeling provided possible explanation for the high species selectivity of [K11A]TxIB and [H5D]RegIIA towards alpha7 nAChR, opening the new way for design of their analogues with improved affinity to the human receptor. PMID- 30025922 TI - Prevalence of and Risk Factors for Colorectal Neoplasia in Asymptomatic Young Adults (20-39 Years Old). AB - BACKGROUND & AIMS: The incidence of colorectal cancer is increasing among persons 50 years old or younger. However, data on the epidemiology of young-onset colorectal neoplasia (CRN) are limited. Although some studies have investigated the epidemiology of CRN in persons younger than 50 years, most have focused on persons 40 years or older. We evaluated the prevalence of and risk factors for CRN in adults younger than 40 years. METHODS: We performed a cross-sectional analysis of 72,356 asymptomatic individuals, 20-39 years old, who underwent colonoscopies as participants in the Kangbuk Samsung Health Study in South Korea, from August 2004 through December 2015. Data on medical history and health related behavior were collected from self-administered questionnaires. Patients were divided into groups based on age (20-29 years, n = 7340 or 30-39 years, n = 65,016), and chi2 tests were used to compare categorical variables between groups. A multivariate logistic regression model was used to assess the risk factors for overall and advanced CRN. RESULTS: The prevalence of overall CRN in group of 20-29 years was 5.9% and in the group of 30-39 years was 9.5% (P < .001); prevalence values for advanced CRN were 0.6% and 0.9%, respectively (P = .005). In the group of 30-39 years, age, smoking, alcohol intake, obesity, and abdominal obesity were independent risk factors for overall and advanced CRN. Additionally, male sex and metabolic syndrome were independent risk factors for overall CRN, whereas regular exercise reduced risk of overall CRN. Even in the 20 29 years group, obesity, abdominal obesity, and increased levels of triglycerides were independent risk factors for overall and advanced CRN, whereas age, increased blood pressure, and increased fasting blood glucose level were independent risk factors for overall CRN. CONCLUSION: In a retrospective analysis of 72,356 asymptomatic persons under 40 years of age evaluated by colonoscopy in Korea, we found modifiable factors, such as smoking, alcohol intake, obesity, and metabolic syndrome, to be significant risk factors for CRN-even in persons of 20 39 years old. Colorectal cancer screening strategies should consider these risk factors. PMID- 30025923 TI - Reply: Prophylactic placement of permanent synthetic mesh at the time of ostomy closure prevents formation of incisional hernias. PMID- 30025924 TI - Robotic surgery or enhanced recovery programs or both? And in which order? PMID- 30025925 TI - Reply to "Nodal skip metastasis may undermine the predictive power of topographic pN classification in esophageal squamous cell carcinoma". PMID- 30025926 TI - Genome-wide identification, and phylogenetic and expression profiling analyses of CaM and CML genes in Brassica rapa and Brassica oleracea. AB - Calmodulin (CaM) and calmodulin-like (CML) proteins are two kinds of calcium (Ca2+)-sensing proteins that are involved in Ca2+-signaling processes. B. rapa and B. oleracea are two of three diploid Brassica species that have undergone recent additional Brassiceae-lineage-specific whole-genome triplication events. To elucidate the expansion, evolution, expression pattern and interaction network of these Ca2+ sensors in B. rapa and B. oleracea, we conducted a comparative syntenic study on a genome-wide level using Arabidopsis thaliana. In total, 80 and 79 CaM/CML genes were identified in B. rapa and B. oleracea, respectively. The CaM/CML genes have expanded throughout the whole genomes of B. rapa and B. oleracea by whole-genome and tandem duplication events. The CaMs/CMLs of B. rapa and B. oleracea can be classified into nine subgroups based on their A. thaliana orthologs. Expression data from various tissues revealed that a large portion of CaM/CML genes exhibited patterns of differential and tissue-specific expression. The expression levels among duplicated paralogs in different subgenomes demonstrated the expression divergence of these genes in B. rapa and B. oleracea. The differential expressions of duplicated CaM and CML genes in B. rapa indicated that their functional differentiation occurred after polyploidization. The construction of interaction network and GO enrichment analysis of genes in this network revealed Br/BoCaMs/CMLs involving biological processes. This work will promote a better understanding of Ca2+ sensors and Ca2+-signaling pathways in B. rapa and B. oleracea. PMID- 30025927 TI - Transcriptomic analysis of high-throughput sequencing about circRNA, lncRNA and mRNA in bladder cancer. AB - An increasing number of studies have revealed that long noncoding RNA (lncRNA) and circular RNA (circRNA) participate in the carcinogenesis and progression of tumors. However, most of these noncoding RNAs are of unknown function or without annotation. We carried out high-throughput sequencing to investigate the differential expression of lncRNAs and circRNAs and their biological functions in four coupled bladder cancer and adjacent noncancerous tissues. We identified significant differentially expressed transcripts and genes and acquired their annotations from the RefSeq and circBase databases, then confirmed the expression of randomly selected RNAs with quantitative real-time PCR. We also constructed a coding-noncoding co-expression (CNC) network and a competing endogenous RNA (ceRNA) network to predict the functions of these RNAs using well-studied protein coding mRNA. Compared with adjacent tissues, 56 lncRNAs, 34 circRNAs and 467 protein-coding mRNAs were upregulated while 32 lncRNAs, 84 circRNAs and 326 protein-coding mRNAs were downregulated in cancer tissues. Co-expression analysis showed that expression of LINC00885 were correlated with GATA3 expression. The ceRNA network indicated that lncRNA MIR194-2HG, AATBC and circRNA PGM5 could harbor bladder cancer-related microRNA (miRNA) recognition elements. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to ascertain the biological function of significantly dysregulated genes. Cell cycle and cell division pathways related to proliferation and apoptosis were obvious in enriched terms. Comprehensive analysis indicated that the dysregulated lncRNAs and circRNAs could participate in the genesis and progression of bladder cancer. Our approach may therefore be valuable for detecting novel transcripts, discovering new biomarkers for bladder cancer and expounding the pathogenic mechanisms of this disease. PMID- 30025928 TI - Inventory of ABC proteins and their putative role in salt and drug tolerance in Debaryomyces hansenii. AB - ATP-binding cassette (ABC) is one of the largest superfamily of proteins, which are ubiquitously present, performing variety of cellular functions. These proteins as drug transporters have been enticing substantial consideration because of their clinical importance. The present study focuses on genome wide identification of ABC proteins of an important halotolerant yeast Debaryomyces hansenii and explores their role in salt and drug tolerance. Our bioinformatics analysis identified a total of 30 putative ABC protein-coding genes whose expression at transcript level was confirmed by qRT-PCR. Our comparative phylogenetic analysis of nucleotide binding domains of D. hansenii and topology prediction categorized these proteins into six subfamilies; ABCB/MDR, ABCC/MRP, ABCD/ALDP, ABCF/YEF3, ABCE/RLI, and ABCG/PDR based on the nomenclature adopted by the Human Genome Organization (HUGO). Further, our transmembrane domain (TMD) predictions suggest that out of 30 ABC proteins, only 22 proteins possess either two or one TMD and hence are considered as membrane localized ABC proteins. Notably, our transcriptional dynamics of ABC proteins encoding genes following D. hansenii cells treatment with different salts and drugs concentrations illustrated variable transcriptional response of some of the genes, pointing to their role in salt and drug tolerance. This study first time provides a comprehensive inventory of the ABC proteins of a haploid D. hansenii which will be helpful for exploring their functional relevance. PMID- 30025929 TI - Safety and effectiveness of combined scoring balloon and paclitaxel-coated balloon angioplasty for stenosis in the hemodialysis access circuit. AB - PURPOSE: To evaluate the safety and effectiveness of combined scoring balloon (SB) and paclitaxel-coated balloon (PCB) angioplasty for stenosis in the dysfunctional hemodialysis access circuit. MATERIAL AND METHODS: Patients were referred from outpatient dialysis centers by their nephrologists because of dysfunctional dialysis access circuit. Fistulogram/graftogram was performed by experienced interventional radiologists. Those with in-stent stenosis, stent edge stenosis or vessel diameter at the culprit segment larger than 6mm were excluded. Angioplasty of the stenotic segment was performed with SB and followed by PCB. All study outcomes were defined according to the Society of Interventional Radiology technology assessment committee reporting standards for percutaneous interventional procedures in dialysis access circuit. RESULTS: A total of 23 patients received combined SB/PCB angioplasty for stenosis of hemodialysis access circuit which included 15 fistulas and 8 grafts. There were 10 men and 13 women with a mean age of 63.3+/-2.7 (SD) years (range: 37-85years). The technical success and clinical success rates were both 100%. There were no complications during or after the procedures. The target lesion primary patency rates at 3, 6 and 12months were 91.3%, 69.6%, and 45.2%, respectively and the estimated median target lesion restenosis (TLR) free duration was 11.0months (95% confidence interval [CI]: 5.1-16.9months). In patients with a recurrent stenosis, the median TLR-free duration of combined angioplasty was significantly higher than that of prior angioplasty with plain balloon (10.2months [95% CI: 6.4-14.0months] vs. 4.2months [95%CI: 2.1-6.4months]) (P=0.047). The mean TLR-free duration was significantly higher in patients with a juxta-anastomotic stenosis than those with non-juxta-anastomotic lesion (21.3months [95% CI: 14.7-28.0months] vs. 8.2months [95% CI: 5.1-11.4months]) (P=0.004). CONCLUSION: Combined SB/PCB angioplasty is safe and effective for the hemodialysis access stenosis. PMID- 30025930 TI - Tibolone is not an oestrogen but a mixture of a strong progestin and two weak oestrogens: Comment on a paper by Johanna Simin et al, European Journal of Cancer 2017; 84:60-68. PMID- 30025931 TI - How Well Do We Represent Ourselves? A Student-Centric Analysis of Radiology Residency Website Content. PMID- 30025932 TI - Utility of the Hybrid Operating Room for Lead Extraction: Initial Experience in a Single Center. PMID- 30025934 TI - The difficile in Clostridium difficile infection. PMID- 30025933 TI - WITHDRAWN: Long-term outcomes of surgical intervention in patients with end-stage hepatic alveolar echinococcosis. AB - This article has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 30025935 TI - Taste Alterations During Treatment With Protein Kinase Inhibitors: A Pilot Study. PMID- 30025936 TI - Cultural Factors Influencing Advance Care Planning in Progressive, Incurable Disease: A Systematic Review With Narrative Synthesis. AB - CONTEXT: Advance care planning (ACP) can improve end-of-life outcomes, but low uptake indicates it is less acceptable to patients of some cultural backgrounds. OBJECTIVES: The objectives of this study were to explore how cultural factors influence ACP for patients with progressive, incurable disease and how ACP might be made cross-culturally appropriate. METHOD: We conducted a systematic literature review using narrative synthesis. Protocol was registered prospectively (PROSPERO CRD42017060441). Key words and subject headings of six databases (AMED, PsycINFO, Embase, Ovid MEDLINE, CINAHL, and Cochrane) were searched without time restrictions. Eligible studies reported original research published in full that included adult participants with progressive, incurable disease or their formal or informal caregivers. Study quality was assessed using the Mixed Methods Appraisal Tool. RESULTS: Eight hundred and eighteen studies were screened. Twenty-seven were included: 20 quantitative, four qualitative, and three mixed methods. Most (20/30) studies were conducted in the U.S., where nonwhite ethnicity was associated with lower acceptability of formal, documented ACP processes. Cultural factors affecting ACP acceptability included religiosity, trust in the health care system, patient and clinician comfort discussing death, and patient attitudes regarding decision-making. Informal, communication-focused approaches to ACP appear more cross-culturally acceptable than formal processes. Clinician education in cultural competence is recommended. Study limitations included use of unvalidated tools and convenience samples and lack of reflexivity. CONCLUSION: Many interconnected cultural factors influence the acceptability of ACP in progressive, incurable disease, although specific mechanisms remain unclear. A communication-focused approach to ACP may better meet the needs of culturally diverse populations. PMID- 30025937 TI - Quality of Communication and Trust in Patients With Serious Illness: An Exploratory Study of the Relationships of Race/Ethnicity, Socioeconomic Status, and Religiosity. AB - CONTEXT: Better understanding of clinicians' skill communicating with their patients and of patients' trust in clinicians is necessary to develop culturally sensitive palliative care interventions. Race/ethnicity, socioeconomic status, and religiosity have been documented as factors influencing quality of communication and trust. OBJECTIVES: The objective of this study was to explore associations of seriously ill patients' race/ethnicity, socioeconomic status, and religiosity with patients' ratings of the quality of clinicians' communication and trust in clinicians. METHODS: An observational analysis was performed using baseline data from a multicenter cluster-randomized trial of a communication intervention. We enrolled consecutive patients with chronic, life-limiting illnesses (n = 537) cared for by primary and specialty care clinicians (n = 128) between 2014 and 2016 in outpatient clinics in Seattle, Washington. We assessed patient demographics (age, gender, race/ethnicity, education, income, and self rated health status), Duke University Religion Index, Quality of Communication Scale, and Wake Forest Physician Trust Scale. We used probit and linear regression and path analyses to examine associations. RESULTS: Patients providing higher ratings of clinician communication included those belonging to racial/ethnic minority groups (P = 0.001), those with lower income (P = 0.008), and those with high religiosity/spirituality (P = 0.004). Higher trust in clinicians was associated with minority status (P = 0.018), lower education (P = 0.019), and clinician skill in communication (P < 0.001). CONCLUSION: Contrary to prior studies, racial/ethnic minorities and patients with lower income rated communication higher and reported higher trust in their clinicians than white and higher income patients. More research is needed to identify and understand factors associated with quality communication and trust between seriously ill patients and clinicians to guide development of patient-centered palliative care communication interventions. PMID- 30025938 TI - Terminally Ill Cancer Patients' Concordance Between Preferred Life-Sustaining Treatment States in Their Last Six Months of Life and Received Life-Sustaining Treatment States in Their Last Month: An Observational Study. AB - CONTEXT/OBJECTIVE: The extent to which patients' preferences for end-of-life (EOL) care are honored may be distorted if preferences are measured long before death, a common approach of existing research. We examined the concordance between cancer patients' states of life-sustaining treatments (LSTs) received in their last month and LST preference states assessed longitudinally over their last six months. METHODS: We examined states of preferred and received LSTs (cardiopulmonary resuscitation, intensive care unit care, chest compression, intubation with mechanical ventilation, intravenous nutrition, and nasogastric tube feeding) in 271 cancer patients' last six months by a transition model with hidden Markov modeling (HMM). The extent of concordance was measured by a percentage and a kappa value. RESULTS: HMM identified four LST preference states: life-sustaining preferring, comfort preferring, uncertain, and nutrition preferring. HMM identified four LST states received in patients' last month: generally received LSTs, LSTs uniformly withheld, selectively received LSTs, and received intravenous nutrition only. LSTs received concurred poorly with patients' preferences estimated right before death (39.5% and kappa value: 0.06 [95% CI: -0.02, 0.13]). Patients in the life-sustaining-preferring, uncertain, and nutrition-preferring states primarily received no LSTs, and patients in three of four states received intravenous nutrition against their preferences. Concordance was strongest for comfort-preferring patients. CONCLUSIONS: Concordance was poor between patients' preferred and received LST states. Interventions are needed to clarify patients' EOL care goals and to facilitate their understanding about LST's ineffectiveness in prolonging life at EOL. Such interventions might increase patients' comfort preference and ensure concordance between their preferred and received EOL care. PMID- 30025940 TI - Cryotherapy Relieves Pain and Edema After Inguinal Hernioplasty in Males With End Stage Renal Disease: A Prospective Randomized Study. AB - CONTEXT: Tension-free hernioplasty under local anesthetic infiltration is a reasonable choice for end-stage renal disease patients with hernia. OBJECTIVES: The purpose of the study was to investigate the feasibility of cryotherapy after hernioplasty surgery to relieve pain and scrotal edema. METHODS: This was a prospective, randomized, and controlled trial held in a large integrated health care facility in South China. One hundred sixty-nine male patients on hemodialysis and scheduled for hernioplasty were enrolled between March 2013 and February 2017. The participants were divided into an intervention group and a control group. In the intervention group, ice packs were applied after surgery. Demographic information, vital signs, pain score, opioid consumption, wound inflammation, scrotal edema, and patient satisfaction were compared between the two groups. The primary outcome was pain score. RESULTS: Cryotherapy-treated patients required less opioid consumption (5.95 vs. 15.29 mg; P < 0.05), reported lower pain scores from 30 minutes to 48 hours after operation (P < 0.05), less wound inflammation (11.90 vs. 32.94%; P < 0.05), lower incidence of scrotal edema in the first and second days (P < 0.05), and higher patient satisfaction (8.95 vs. 6.50 cm; P < 0.05), with stable vital signs throughout the monitoring period (P > 0.05). CONCLUSION: Owing to its favorable cost, convenience, and low frequency of adverse effects, cryotherapy is useful for end-stage renal disease populations after hernioplasty to relieve pain and scrotal edema. PMID- 30025941 TI - Computerized Residency Interview Scheduling: A Randomized Controlled Trial of Categorical General Surgery Applicants. AB - OBJECTIVE: Scheduling interviews can be stressful and time-intensive for general surgery applicants and program coordinators. The objectives of this study were to determine whether computerized scheduling program (CSP) would decrease time to schedule interviews, reduce workload for residency coordinators, and improve applicant satisfaction. DESIGN: A prospective randomized controlled trial of 2 interview-scheduling methods was conducted. All categorical general surgery applicants selected to interview for the 2017 match were randomized to either standard e-mail/phone scheduling or CSP using InterviewBroker. Time required to schedule an interview, number of communications, reschedules, withdrawals, and cancellations were all recorded. Additionally, applicants completed a voluntary, anonymous 9-question paper survey on their interview date. The program director and interviewers were blinded to the experimental groups. SETTING: A single general surgery residency program. PARTICIPANTS: Participants in the study included all categorical general surgery applicants selected for an interview in the 2017 match cycle (N = 62 standard group, N = 62 CSP group). RESULTS: The CSP group took less time to schedule interviews (9 minutes vs. 80 minutes; p < 0.01), had fewer e-mail/phone communications (3 vs. 1; p < 0.01), and more total rescheduling events (26 vs. 4; p = 0.03) when compared to the standard group. Survey responses showed that 55% of applicants used CSPs at 5 or fewer other programs. The CSP group reported increased overall satisfaction (80% vs. 56% very satisfied; p = 0.02) and access to preferred interview dates (80% vs. 53% very satisfied; p = 0.02). Overall, 77% of applicants responded that CSPs should be widely adopted among general surgery residency programs. CONCLUSIONS: CSPs expedited interview scheduling, decreased workload for program coordinators, and improved general surgery applicant satisfaction. However, despite the benefits of CSPs for programs and applicants, CSP use is not widespread among general surgery residency programs. Adoption of CSPs by all programs could greatly improve interview-scheduling processes for applicants and programs. PMID- 30025939 TI - Advance Care Planning With Patients Who Have End-Stage Kidney Disease: A Systematic Realist Review. AB - CONTEXT: Patients with end-stage kidney disease have a high mortality rate and disease burden. Despite this, many do not speak with health care professionals about end-of-life issues. Advance care planning is recommended in this context but is complex and challenging. We carried out a realist review to identify factors affecting its implementation. OBJECTIVES: The objectives of this study are 1) to identify implementation theories; 2) to identify factors that help or hinder implementation; and 3) to develop theory on how the intervention may work. METHODS: We carried out a systematic realist review, searching seven electronic databases: Medline, Embase, CINAHL, PsycINFO, Cochrane Library, Google Scholar, and ScienceDirect. RESULTS: Sixty-two papers were included in the review. CONCLUSION: We identified two intervention stages-1) training for health care professionals that addresses concerns, optimizes skills, and clarifies processes and 2) use of documentation and processes that are simple, individually tailored, culturally appropriate, and involve surrogates. These processes work as patients develop trust in professionals, participate in discussions, and clarify values and beliefs about their condition. This leads to greater congruence between patients and surrogates; increased quality of communication between patients and professionals; and increased completion of advance directives. Advance care planning is hindered by lack of training; administrative complexities; pressures of routine care; patients overestimating life expectancy; and when patients, family, and/or clinical staff are reluctant to initiate discussions. It is more likely to succeed where organizations treat it as core business; when the process is culturally appropriate and takes account of patient perceptions; and when patients are willing to consider death and dying with suitably trained staff. PMID- 30025942 TI - Correction to Lancet Glob Health 2018; 6: e820-21. PMID- 30025943 TI - ARID1A mutant ovarian clear cell carcinoma: A clear target for synthetic lethal strategies. AB - SWI/SNF chromatin remodeling complexes play an important role in the epigenetic regulation of chromatin structure and gene transcription. Mutual exclusive subunits in the SWI/SNF complex include the DNA targeting members ARID1A and ARID1B as well as the ATPases SMARCA2 and SMARCA4. SWI/SNF complexes are mutated across many cancer types. The highest mutation incidence is found in ARID1A, primarily consisting of deleterious mutations. Current advances have reported synthetic lethal interactions with the loss of ARID1A in several cancer types. In this review, we discuss targets that are only important for tumor growth in an ARID1A mutant context. We focus on synthetic lethal strategies with ARID1A loss in ovarian clear cell carcinoma, a cancer with the highest ARID1A mutation incidence (46-57%). ARID1A directed lethal strategies that can be exploited clinically include targeting of the DNA repair proteins PARP and ATR, and the epigenetic factors EZH2, HDAC2, HDAC6 and BRD2. PMID- 30025944 TI - Sex and Race Differences in Pain Sensitization among Patients with Chronic Low Back Pain. AB - Growing evidence suggests that chronic low back pain (CLBP) is associated with pain sensitization, and that there are sex and race disparities in CLBP. Given the sex and race differences in pain sensitization, this has been hypothesized as a mechanism contributing to the sex and race disparities in CLBP. This study examined sex and race differences in pain sensitization among patients with CLBP, as well as the role of catastrophizing as a potential mediator of those differences. The study found that compared with men, women required less pressure to produce deep muscle pain and rated mechanical punctate pain as more painful. Compared with non-Hispanic white patients, black patients demonstrated greater pain sensitivity for measures of deep muscle hyperalgesia and mechanical punctate pain. Furthermore, catastrophizing partially mediated the race differences in deep muscle pain such that black participants endorsed greater pain catastrophizing, which partially accounted for their increased sensitivity to, and temporal summation of, deep muscle pain. Taken together, these results support the need to further examine the role of catastrophizing and pain sensitization in the context of sex and race disparities in the experience of CLBP. PERSPECTIVE: This study identifies sex and race differences in pain sensitization among patients with CLBP. Further, it recognizes the role of catastrophizing as a contributor to such race differences. More research is needed to further dissect these complex relationships. PMID- 30025945 TI - [Burnout in anesthesiology]. AB - BACKGROUND AND OBJECTIVES: Burnout is a chronic condition caused by high levels of stress and anesthesiology is a stressful medical specialty with more vulnerability to burnout. The aim of this study is to review the characteristics and impact of burnout in anesthesiology. CONTENTS: In this review, the stressors and risk factors, manifestations, assessment, complications, management and prevention of burnout as well as the inconsistent research found in the state-of art are approached. CONCLUSIONS: Anesthesiologists are in a high-risk group to develop burnout, with different manifestations and consequences such as suicide or medical errors. Although there is no specific treatment yet, there are a lot of helpful measures to cope this condition. Prevention is considered an important step in order to reduce the prevalence of burnout. PMID- 30025947 TI - [The role of videolaryngoscope in endotracheal intubation training programs]. AB - BACKGROUND: Macintosh laryngoscopes are widely used for endotracheal intubation training of medical students and paramedics whereas there are studies in the literature that supports videolaryngoscopes are superior in endotracheal intubation training. Our aim is to compare the endotracheal intubation time and success rates of videolaryngoscopes and Macintosh laryngoscopes during endotracheal intubation training and to determine the endotracheal intubation performance of the students when they have to use an endotracheal intubation device other than they have used during their education. METHODS: Endotracheal intubation was performed on a human manikin owing a standard respiratory tract by Macintosh laryngoscopes and C-MAC(r) videolaryngoscope (Karl Storz, Tuttligen, Germany). Eighty paramedic students were randomly allocated to four groups. At the first week of the study 10 endotracheal intubation trials were performed where, Group-MM and Group-MV used Macintosh laryngoscopes; Group-VV and Group-VM used videolaryngoscopes. Four weeks later all groups performed another 10 endotracheal intubation trial where Macintosh laryngoscopes was used in Group-MM and Group-VM and videolaryngoscopes used in Group-VV and Group-MV. RESULTS: Success rates increased in the last 10 endotracheal intubation attempt in groups MM, VV and MV (p=0.011; p=0.021, p=0.290 respectively) whereas a decrease was observed in group-VM (p=0.008). CONCLUSIONS: The success rate of endotracheal intubation decreases in paramedic students who used VL during endotracheal intubation education and had to use Macintosh laryngoscopes later. Therefore we believe that solely videolaryngoscopes is not enough in endotracheal intubation training programs. PMID- 30025946 TI - [Relationship between cigarette smoking and the carbon monoxide concentration in the exhaled breath with perioperative respiratory complications]. AB - BACKGROUND: The purpose of the current study was to determine the effects of preoperative cigarette smoking and the carbon monoxide level in the exhaled breath on perioperative respiratory complications in patients undergoing elective laparoscopic cholecystectomies. METHODS: One hundred and fifty two patients (smokers, Group S and non-smokers, Group NS), who underwent laparoscopic cholecystectomies under general anesthesia, were studied. Patients completed the Fagerstrom Test for Nicotine Dependence. The preoperative carbon monoxide level in the exhaled breath levels were determined using the piCO+Smokerlyzer 12h before surgery. Respiratory complications were recorded during induction of anesthesia, intraoperatively, during extubation, and in the recovery room. RESULTS: Statistically significant increases were noted in group S with respect to the incidence of hypoxia during induction of anesthesia, intraoperative bronchospasm, bronchodilator treatment intraoperatively, and bronchospasm during extubation. The carbon monoxide level in the exhaled breath and the Fagerstrom Test for Nicotine Dependence, and number of cigarettes smoked 12h preoperatively were designated as covariates in the regression model. Logistic regression analysis of anesthetic induction showed that a 1 unit increase in the carbon monoxide level in the exhaled breath level was associated with a 1.16 fold increase in the risk of hypoxia (OR=1.16; 95% CI 1.01-1.34; p=0.038). Logistic regression analysis of the intraoperative course showed that a 1 unit increase in the number of cigarettes smoked 12h preoperatively was associated with a 1.16 fold increase in the risk of bronchospasm (OR=1.16; 95% CI 1.04-1.30; p=0.007). While in the recovery room, a 1 unit increase in the Fagerstrom Test for Nicotine Dependence score resulted in a 1.73 fold increase in the risk of bronchospasm (OR=1.73; 95% CI 1.04-2.88; p=0.036). CONCLUSIONS: Cigarette smoking was shown to increase the incidence of intraoperative respiratory complications while under general anesthesia. Moreover, the estimated preoperative carbon monoxide level in the exhaled breath level may serve as an indicator of the potential risk of perioperative respiratory complications. PMID- 30025948 TI - Ultrasound for identifying the cricothyroid membrane prior to the anticipated difficult airway. AB - BACKGROUND: Prior to the anticipated difficult airway, the emergency physician commonly palpates the neck to identify the presumed location of the cricothyroid membrane (CTM). In the event of a "cannot-intubate, cannot-oxygenate" airway, precise CTM localization is vital to the success of a cricothyrotomy and hence, the patient's survival. OBJECTIVE: This narrative review will summarize the prospective studies evaluating CTM identification. It will demonstrate the inaccuracy of the classically used landmark palpation technique. It will then describe the use of ultrasound (US) as a superior tool for CTM identification, illustrate the technique itself, and propose its implementation in the pre intubation checklist for the anticipated difficult airway. DISCUSSION: Evidence demonstrates that physicians are not sufficiently accurate in palpating the CTM in both cadavers and volunteers in a stable non-emergent setting. In preparing for a real-time intubation, this fine motor task would be more difficult to achieve. Moreover, this particular patient group may often exhibit difficult airway features. US has been demonstrated to be superior for locating the CTM than landmark palpation across body habitus, gender, and failed airway simulations. This technique carries a short learning curve even without prior airway US experience, along with a high retention rate. An illustrative tutorial is provided. CONCLUSION: Emergency physicians may apply this US technique for CTM localization in preparation for an anticipated difficult airway. However, since this technique takes longer than landmark palpation, using US is not recommended once already in the midst of a failed airway situation. PMID- 30025949 TI - Effect of hypertension across the age group on survival outcomes in out-of hospital cardiac arrest. AB - OBJECTIVE: There are few studies on the effects hypertension has on survival outcomes in out-of-hospital-cardiac arrest (OHCA) patients, although hypertension is a major risk factor for the incidence of cardiac arrest. This study aims to investigate whether hypertension is associated with survival outcomes in cardiac arrest patients across age groups. METHODS: This study was conducted using the national cardiac arrest registry of OHCA patients who survived to hospital admission from 2012 to 2016. The clinical histories of hypertension were obtained from patients' medical records. The endpoint was cerebral performance category (CPC) 1 and 2 (good CPC) and survival to discharge. Multivariable logistic regression analysis was performed on the data collected. The final model with an interaction term was evaluated to compare the effects of hypertension across age groups. RESULTS: A total 11,610 patients (61.0% hypertensive patients and 39.0% non-hypertensive patients) were included. The group over 80 years old with hypertension were more likely to have good neurologic recovery (AOR 2.53 [1.43 4.50]) and those under 65 years old with hypertension were more likely to survive to hospital discharge with statistical significance (AOR 1.19 [1.04-1.35]). CONCLUSIONS: Hypertension does not imply poor survival outcomes independently for all ages, as those over 80 years of age can have rather good neurological outcomes. PMID- 30025950 TI - Relevance of opioid guidelines in the emergency room (ROGER). PMID- 30025951 TI - Pain management of renal colic in the emergency department with intravenous lidocaine. AB - OBJECTIVE: To describe our experience with intravenous lidocaine (IVL) to manage pain of renal colic origin in the emergency department (ED). METHODS: A retrospective analysis of all patients presenting with pain of renal colic origin from the periods of 2014 to 2017 by using the ED electronic medical record database (AllscriptsTM). RESULTS: Forty-four patients received IVL for renal colic over a three-year period. The average dose of IVL as a primary analgesic was 117.2 mg, and as a rescue was 108 mg. Administration of IVL resulted in a decrease in overall pain score by 6.3 points (numerical rating scale), by 7.4 points when IVL was used as a primary analgesic, and by 5.2 points when IVL was given as a rescue. There were no documented adverse effects. CONCLUSION: Intravenous lidocaine has a potential of being used for patients presenting to the ED with a pain of renal colic origin as a primary analgesic or as a rescue. Although promising, this therapy will need to be studied in prospective randomized fashion and larger patients' population with underlying cardiac disease before it can be recommended for broad use in the ED. PMID- 30025952 TI - Esmolol does not affect circulation negatively during resuscitation a randomized, controlled, experimental study. PMID- 30025953 TI - Impact of comorbidities on fatigue in rheumatoid arthritis patients: Results from a nurse-led program for comorbidities management (COMEDRA). AB - OBJECTIVES: To analyze the factors associated with fatigue focusing on comorbidities in a large cohort of rheumatoid arthritis (RA). METHODS: Cross sectional analyses were performed on RA patients from the French COMEDRA cohort study, a nurse-led program for comorbidities management. Fatigue was assessed using Question 3 of the Rheumatoid Arthritis Impact of Disease (RAID) score on a 0-10 numerical rating scale (NRS). Fatigue was defined as acceptable if <= 2, moderate if 3 or 4, or severe if >= 5 out of 10. Using univariate and multivariate models, the relationship between fatigue and demographics, social, disease characteristics, comorbidities (cardiovascular, infections, cancer, pulmonary, osteoporosis, and psychiatric disorders), physical activity, quality of life, and treatments was investigated. RESULTS: In total, 962 patients were analyzed. The mean fatigue score was 3.8 +/- 2.7, 40% of patients reported severe fatigue. Patients had an average of 1.8 additional morbid conditions, with anxiety/depression the most common (52%). In univariate analysis, severe fatigue was more frequent in women, in patients not working, and in those with less physical activity. It was associated with disease duration and activity, mHAQ, pain, sleeping and emotional difficulties. Severe fatigue correlated with Multimorbidity index assessing the number of morbid conditions and was associated with obesity, hypertension, COPD, and anxiety/depression. In multivariate models, the risk of severe fatigue was associated with female gender, disease activity, mHAQ, current treatment with NSAIDs and biologics, multimorbidity, obesity and anxiety/depression. CONCLUSIONS: Assessment of comorbidities, psychological health and physical activity should be taken into account in order to address frequent RA-related severe fatigue. PMID- 30025954 TI - Determinants of daily pain trajectories and relationship with pain acceptability in hip and knee osteoarthritis. A national prospective cohort study on 886 patients. AB - OBJECTIVES: To study daily pain trajectories (DPT) in patients with knee (KOA) and hip osteoarthritis (HOA) over a one-month period and identify relationships with patients characteristics and acceptability. METHODS: This prospective, multicenter cohort study was conducted in France by 602 GPs, on outpatients, with painful KOA or HOA. Patients were asked to fill-in a 28-days daily pain diary. DPT were determined by the difference between daily pain and mean pain over 28 days. Pain peaks were defined as an increase of more than 1 point above the mean for up to three consecutive days. The number of pain peaks over the 28 day period allowed classifying the patient's pain trajectory as either "stable" or "unstable". A logistic regression model was used to identify predicting factors associated with stable pain profile. RESULTS: Overall, 1645 patients were included and 886 were analyzed, (56% women, 67.8 years, BMI 27.6 kg/m2, pain 6.0, KOA 71.3%). At one month, stable DPT was found in 59.5% of the patients whatever OA location. In HOA, a shorter duration of disease and pain, a greater disability and in KOA, a more recent disease, morning stiffness >= 15 minutes and flare-up were independent factors associated with "stable" DPT. At one month, acceptable pain state was more frequent (65.4%) in patients with stable profiles. CONCLUSION: In lower limb OA, pain is mostly stable over a 28-days period. Pain is better accepted when stable, with different determining factors according location. DPT should be considered when establishing HOA and KOA management. PMID- 30025955 TI - Joint manifestations can provide diagnostic clues in Morquio syndrome. Comment on: "Mucopolysaccharidoses seen in adults in rheumatology" by Mitrovic et al., Joint Bone Spine 2017;84:663-70. PMID- 30025956 TI - Association between gout and cardiovascular disease risk: A nation-wide case control study. PMID- 30025957 TI - Serum and urinary macrophage migration inhibitory factor (MIF) in primary Sjogren's syndrome. PMID- 30025958 TI - Obstacles and motivations to influenza and pneumococcal vaccination in patients with rheumatoid arthritis. A qualitative study. Comment on: "Pneumococcal and influenza vaccination rates in patients treated with corticosteroids and/or immunosuppressive therapies for systemic auto-immune diseases: A cross-sectional study" by Assala et al., Joint Bone Spine 2017;84:365-6. PMID- 30025959 TI - Non-pharmacologic measures for gout management in the prospective GOSPEL cohort: Physicians' practice and patients' compliance profiles. AB - OBJECTIVES: Gout management includes non-pharmacological measures (NPM). The main objective of this study was to describe the NPM proposed by physicians and their implementation by patients after 3-6 months. The secondary objective was to identify NPM compliance profiles among these patients. METHODS: Ancillary observational study using the GOSPEL French cohort of 1003 patients with gout, based on questionnaires for physicians and patients at inclusion and then after 3 6 months. Patients were included by a representative sample of 398 general practitioners (GP) and 109 private-practice rheumatologists. Modifiable risk factors of hyperuricemia and proposed NPM were compared. Patient compliance profiles were identified by multiple correspondence and hierarchical clustering analysis. RESULTS: The study included 630 patients: 80.7% were obese or overweight, 51% reported excessive alcohol consumption. Physicians identified fewer modifiable risk factors than their real prevalence in the cohort. Physicians proposed NPM to 57% of patients, particularly diet modifications (46.4%). Increasing physical activity (P < 0.0001) was the best followed NPM. The physician's influence in the decision of starting NPM was more frequent among GPs' patients (P = 0.01). Three patients' compliance profiles were identified. "Very good responders" (55.8%) implemented all the proposed NPM. "Good responders" (12.7%) had a more severe disease and followed the proposed NPM, but for alcohol consumption. "Bad responders" (31.5%) did not modify their life style: these were older patients with a very recent gout diagnosis. CONCLUSION: More personalized care about NPM requires adapting the practitioner's approach to patients' compliance profiles, especially elderly patients with recent gout. PMID- 30025960 TI - Is fat that bad in rheumatoid arthritis? PMID- 30025961 TI - The popliteal groove region: A new target for the detection of monosodium urate crystal deposits in patients with gout. An ultrasound study. AB - OBJECTIVES: To determine the prevalence of the ultrasound findings indicating monosodium urate crystal deposits at the popliteal groove region in patients with gout; to evaluate the diagnostic accuracy of ultrasound in detecting monosodium urate crystal deposits at the popliteal groove region, patellar tendon and the knee hyaline cartilage; to investigate the correlation between the ultrasound findings at the popliteal groove region and the clinical features. METHODS: Bilateral ultrasound assessment of the popliteal groove region, patellar tendon and femoral condyles' hyaline cartilage was performed on 47 consecutive patients with gout and 37 controls. The ultrasound findings indicating monosodium urate crystals (aggregates, tophi and "double-contour" sign) were identified according to the Outcome Measures in Rheumatology definitions. RESULTS: One or more ultrasound abnormalities (aggregates and/or tophi) were found in at least one popliteal groove region in 23 out of 47 patients with gout (48.9%) and in 4 out of 37 controls (10.8%) (P < 0.001). Sensitivity, specificity and diagnostic odds ratio of the ultrasound findings at the popliteal groove region, patellar tendon and at the femoral condyles' hyaline cartilage were 0.49/0.89/7.9, 0.62/0.81/6.9 and 0.30/1.0/32.0, respectively. There was a significant correlation between the ultrasound findings at the popliteal groove region and history of knee inflammatory involvement (P < 0.001, V = 0.644) and number of gouty "attacks" in the previous year (P = 0.012, V = 0.434). CONCLUSIONS: This study provides new insights into the ultrasound assessment of patients with gout, highlighting the clinical relevance of the popliteal groove region as an area of collection of otherwise undetectable monosodium urate crystals. PMID- 30025962 TI - Serum retinol binding protein 4 is associated with insulin resistance in patients with early and untreated rheumatoid arthritis. AB - OBJECTIVE: Retinol-binding protein 4 (RBP4), systemic inflammation and insulin resistance(IR) are linked, yet the determinants of RBP4 and its impact on IR in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to explore the prevalence of IR in RA and investigate whether the serum levels of RBP4 were associated with IR in patients with RA. METHODS: In this study, 403 individuals with newly diagnosed and untreated RA were consecutively recruited. We calculated the Disease Activity Score assessed using 28-joint counts for swelling and tenderness (DAS28). Levels of serum RBP4, interleukin-6 (IL-6) and tumor necrosis factor (TNF) alpha were tested. IR was defined as Homeostasis model assessment for insulin resistance (HOMA-IR) index greater than or equal 2.40. RESULTS: In those 403 patients, 68 (16.9%) were male and the median age was 43 years (IQR, 36-52). There was an evidently positive correlation between increased serum levels of RBP4 and increasing severity of RA (DAS-28) (r = 0.403, P < 0.001). Furthermore, a modest positive correlation between levels of serum RBP4 and HOMA-IR score (r = 0.251; P < 0.0001) was found. Eighty-five patients (21.1%) in patients with RA were defined as IR (HOMA-IR>=2.40), which was significantly higher than in normal cases (4.7%). In the patients with IR, serum levels of RBP4 were higher when compared with those in patients free-IR [P < 0.001). The IR distribution across the quartiles of RBP4 ranged between 5.0% (first quartile) to 39.0% (fourth quartile), P for trend<0.001. For each 1unit increase of RBP4, the unadjusted and adjusted risk of IR increased by 8% (OR: 1.08; 95% CI, 1.05-1.11, P < 0.001) and 5% (1.05; 1.02-1.09, P = 0.001), respectively. When RBP4 was added to the model containing established significant risk factors, AUROC (standard error) was increased from 0.768 (0.025) to 0.807(0.021). A significant difference in the AUC between the established risk factors alone and the addition of RBP4 was observed (difference, 0.039[0.004]; P = 0.02). CONCLUSION: Elevated serum levels of RBP4 were associated with increased risk of IR and might be useful in identifying RA at risk for IR and/or impaired glucose tolerance for early prevention strategies, especially in obese and women patients. PMID- 30025963 TI - Transplanted neural-like cells improve memory and Alzheimer-like pathology in a rat model. AB - BACKGROUND AIMS: Degeneration of the central nerve system, particularly in Alzheimer's disease, is a burden on society, and despite years of research, there is no effective treatment. Cell therapy appears to be an option that is of growing interest in neural studies. The main aim of this study was to investigate the histological and physiological effects of transplantation the neuron-like cell (NLC)-derived mouse embryonic stem cells (mESCs) on the repair of brain lesions in an Alzheimer's animal model (AM) in rats. METHODS: Behavioral experiments were conducted in the light hours in a Y-shaped maze device. Animals were randomly divided into five groups, with seven rats per group. The nucleus basalis of Meynert (NBM) was destroyed bilaterally with an electrical lesion (0.5 mA for 3 s). One week after the bilateral lesion of the NBM, the differentiated NLCs (0.1 mL) were injected with stereotaxic surgery using a Hamilton syringe at NBM coordinates, and behavioral and histological tests were performed by the Y maze task and hematoxylin and eosin staining after five weeks of the lesion. Also, differentiated cells detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis and fluorescent immunostaining. RESULTS: The expression of neuronal markers including Nestin, Map2, NF-H, Tuj-1, GFAP and Olig-2 was surveyed by using the immunocytochemistry and qRT-PCR methods, and the results confirmed that the genes in question were expressed significantly more compared than the control sample. Five weeks after the cell transplantation in the AM, morphological and physiological investigation during the determination period confirmed improved disease state in the tested models. CONCLUSIONS: It should be noted that by improving the neuronal connectivity in AM rat brains, the transplanted NLCs rescue Alzheimer's cognition. This research has presented some preclinical evidence that showed NLCs transplantation can be used for AM treatment. PMID- 30025964 TI - Effect of edible pectin-fish gelatin films containing the olive antioxidants hydroxytyrosol and 3,4-dihydroxyphenylglycol on beef meat during refrigerated storage. AB - The objective of this research was to evaluate the effect of the addition of two antioxidants naturally present in olives, hydroxytyrosol (HT) and 3,4 dihydroxyphenylglycol (DHPG), to a pectin-fish gelatin edible film on the preservation of raw beef meat during refrigerated storage. A new composite film that included beeswax was also prepared, resulting in a reduction in the film's oxygen permeability. Results showed that the meat samples wrapped with film containing antioxidants reduced the formation of oxidation products in the form of thiobarbituric acid reaction substances (TBARS) compared with control film without antioxidants. HT added at 0.5% to the film with beeswax suppressed the lipid oxidation of beef meat during 7 days of storage at 4 degrees C, possibly by the combined effect of acting as an oxygen barrier and the specific antioxidant activity. The interference of plasticizer agents (glycerol and sorbitol) incorporated to the film on the TBARS method was showed for the first time. PMID- 30025965 TI - Identification of Malassezia species by MALDI-TOF MS after expansion of database. AB - The taxonomy of Malassezia species is evolving with introduction of molecular techniques, and difficulty is faced to identify the species by phenotypic methods. Among 15 known Malassezia species, the present Bruker database could identify only 2 species. The present study was aimed to improve Matrix -assisted laser desorption ionization time-flight mass spectrometry (MALDI-TOF MS) based identification of Malassezia species. A total of 88 isolates (DNA sequencing confirmed) for database preparation and, for the validation of database, 190 isolates confirmed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) were used. The main spectrum profile dendrogram showed the sufficient discrimination between all the species by MALDI-TOF MS. The updated Malassezia database could identify 94.7% and 5.3% strains to the species and genus level, respectively. MALDI-TOF MS is a significantly reliable technique, and results were comparable with PCR-RFLP with kappa value 0.9. In conclusion, MALDI-TOF MS could be a possible alternative tool to other molecular methods for rapid and accurate identification of Malassezia species. PMID- 30025966 TI - Multidrug-resistant CTX-M-15-producing Klebsiella pneumoniae ST231 associated with infection and persistent colonization of dog. AB - Extended spectrum beta-lactamase (ESBL)-producing bacterial infections in veterinary medicine are a clinical and epidemiological challenge. We report a case of CTX-M-15-producing Klebsiella pneumoniae infection followed by persistent colonization, in a dog presenting with bilateral purulent nasal discharge and dyspnea. In this regard, 5 broad-spectrum cephalosporin-resistant K. pneumoniae isolates were recovered from infection and surveillance cultures, collected during 1 year and eight months study. Genomic analysis of a representative clone of K. pneumoniae (KpPB76) revealed the presence of the human-associated lineage ST231, whereas resistome data confirmed the presence of genes conferring resistance to aminoglycosides, beta-lactams, fluoroquinolones, fosfomycin, phenicols, sulfonamides, tetracyclines and trimethoprim. In the absence of therapeutic options, meropenem therapy was used, contributing to the control of infection during persistent carriage of K. pneumoniae CTX-M-15/ST231. Persistent colonization of companion animals with ESBL-producing bacteria could be result from a variety of situations, including multi introduction from the owner or household family members to pets, or from environmental exposure; whereas colonized animals may serve as an important source for the spread of ESBL producing strains in the human-animal interface. PMID- 30025967 TI - Failure of a multiplex polymerase chain reaction assay to detect IMP-27 in a clinical isolate of Morganella morganii. AB - A case of an IMP-27-positive Morganella morganii isolate is reported, where the carbapenemase enzyme was demonstrated by whole genome sequencing. Carbapenemase detection using a multiplex PCR assay was negative due to mutations in the primer binding site. This case serves to illustrate the limitations of multiplex PCR for carbapenemase detection. PMID- 30025968 TI - Development of colorimetric sensor array for diagnosis of tuberculosis through detection of urinary volatile organic compounds. AB - BACKGROUND: Top priorities for tuberculosis control and elimination include a simple, low-cost screening test using sputum and a non-sputum-based test in patients that do not produce sputum. The aim of this study was to evaluate the performance of a colorimetric sensor array (CSA) test, for analysis of volatile organic compounds in urine, in the diagnosis of pulmonary TB. MATERIAL AND METHODS: Urine samples were collected from individuals suspected of having pulmonary TB in Western Kenya. Reference methods included MGIT culture and/or Xpert MTB/RIF nucleic acid amplification test on sputa. Fresh urine samples were tested with the CSA, with acid and base and without an additive. The CSA were digitally imaged, and the resulting colorimetric response patterns were used for chemometric analysis. Sensitivity, specificity, and negative (NPV) and positive predictive (PPV) values were determined for HIV-positive and HIV-negative patients. RESULTS: In HIV-negative patients, the highest accuracy was obtained in urine samples pre-treated with a base, yielding a sensitivity, specificity, PPV, and NPV of 78.3% (65/83), 69.2% (54/78), 73.0% (n/89) and 75.0% (n/72). The highest sensitivity of 79.5% was achieved using sensor data from all three test conditions at a specificity of 65.4%. In HIV-positive subjects, the sensor performance was substantially lower with sensitivity, specificity, PPV, and NPV ranging from 48.3% to 62.3%, 54.1% to 74.0%, 55.9% to 64.2%, and 60.6% to 64.9%, respectively. CONCLUSION: The CSA fingerprint of urine headspace volatiles showed moderate accuracy in diagnosing TB in HIV-negative patients, but the sensor performance dropped substantially in HIV-coinfected patients. Further development of TB-responsive CSA indicators may improve the accuracy of CSA urine assay. PMID- 30025969 TI - Prospective evaluation of vancomycin pharmacokinetics in a heterogeneous critically ill population. AB - Rich pharmacokinetic data on vancomycin in critically ill patients are lacking. The purpose of this study was to evaluate the pharmacokinetics of vancomycin in this population using rich pharmacokinetic sampling. Nineteen critically ill patients received individualized vancomycin doses by intermittent infusion to achieve target trough concentrations (15-20 mg/L). Blood samples were collected following the third or later dose of vancomycin. Serial blood samples were collected at 30 min following initiation of the vancomycin infusion; at the end of the infusion; serially at 60, 120, 300, and 480 min after the infusion finished; and immediately prior to the next dose. Vancomycin concentration-time profiles at steady state were fit to a noncompartmental model to determine the pharmacokinetic parameters. Vancomycin trough concentration was correlated to AUC0-24 (r = 0.83, P < 0.001). Total body weight was a predictor of volume of distribution (r = 0.43, P = 0.03). Age, serum creatinine, and creatinine clearance (CrCl) were found to be predictors for vancomycin clearance (r = -0.67, -0.52, and, 0.72, respectively). CrCl was the best predictor of vancomycin systemic clearance, and addition of other variables to a multivariate model failed to improve model fit. Vancomycin trough concentration may not be an adequate surrogate of AUC0-24. Additional research is needed to determine dosing strategies to optimize AUC0-24 while limiting toxicity. PMID- 30025970 TI - Mycobacterium avium complex bacteria remain viable in sputum during storage and refrigeration. AB - Diagnostic mycobacteriology often involves shipping of samples to centralized laboratories. Using two quantitative culture techniques, we show that 7 days storage of sputum samples at room temperature or 4 degrees C does not affect the number of viable Mycobacterium avium complex bacteria. Storage at room temperature increases the chance of contamination. PMID- 30025971 TI - Incubation time and culture media impact success of identification of Nocardia spp. by MALDI-ToF mass spectrometry. AB - Identification of Nocardia can be challenging, even by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF MS). We examined the impact of incubation duration, culture media and bead-beading on identification success. When isolates were grown for 3 days on SAB (Saboround dextrose agar), then extracted using a bead-beating, ethanol/formic acid (EtOH/FA) procedure, MALDI-ToF MS correctly identified 36.4% to species level. By contrast, 80.9% of isolates were correctly identified to species level when processed with the standard EtOH/FA extraction from Columbia blood agar (CBA) cultures incubated until colonies first appeared. Excluding rare species, the latter approach correctly identified 93.0% of isolates of commonly-encountered Nocardia species when additional database entries were included to expand representation of select species. We demonstrate that while bead-beating has little impact on identification success by MALDI-ToF MS, analysis of early growth is crucial. Additionally, culture media that promotes quick growth of Nocardia (e.g. CBA) is recommended. PMID- 30025972 TI - The stability of antimycobacterial drugs in media used for drug susceptibility testing. AB - The emergence of drug-resistant tuberculosis and disease caused by nontuberculous mycobacteria has increased the need for accurate drug susceptibility testing of mycobacteria. The stability of the tested drugs in relevant test media have been understudied. We assessed the stability of isoniazid, rifampicin, clarithromycin, linezolid and amikacin in Middlebrook 7H9 medium and that of clarithromycin, amikacin and cefoxitin in the cation-adjusted Mueller Hinton broth. We used ultra performance liquid chromatography (UPLC) methods for rifampicin and isoniazid and a microbiological assay for rifampicin, clarithromycin, amikacin, cefoxitin and linezolid. Rifampicin and isoniazid concentrations in Middlebrook 7H9 medium had decreased by 92% and 54% after 7 days. The microbiological assay revealed decreases in drug concentration of >=75% (rifampicin, clarithromycin, cefoxitin) and 60% (linezolid) after 14 days. With the exception of amikacin, all antimycobacterial drugs were unstable during 14 days of incubation in the preferred media for DST. Drug stability may influence minimum inhibitory concentration measurements. PMID- 30025973 TI - Availability of NHS-biotin labeling to identify free protein lysine revealed by experiment and MD simulation. AB - It is known that the crystallizability of protein molecules may be improved by replacing their surface lysine residues with other residue types. Here an experimental method to identify surface lysine residues by NHS-biotin chemical modification combined with MALDI-TOF MS was proposed and was evaluated using PH1033 protein from Pyrococcus horikoshii. Interestingly, the biotinylation experiment with a protein-reagent molar ratio of 1:1 revealed that only seven of twenty-two lysine residues in the protein comprising 144 residues were labeled. To investigate the result, we analyzed structures from a molecular-dynamics simulation mimicking the experiment. A logistic regression analysis revealed that the biotinylation was significantly correlated with four factors relevant to the local environment of lysine residues: the solvent accessibility, the electrostatic energy, the number of hydrogen bonds, and the estimated pKa value. This result is overall in agreement with that from the same analysis on the crystal structure. However, reflecting the flexibility of the protein molecule in solution state, the factors except for the electrostatic energy were highly variable in the MD structures depending upon the protonation state of Tyr87. The present procedure of biotin-labeling can avoid lysine residues with extensive intramolecular interactions that are incompatible with the rational design of protein crystals. PMID- 30025974 TI - Homologous ELISA for measurement of medroxyprogesterone acetate in serum. AB - In order to develop ELISA for medroxyprogesterone acetate, medroxyprogesterone acetate-3-carboxymethyloxime (MPA-3-CMO) was coupled to bovine serum albumin (BSA) for immunogen preparation and to horseradish peroxidase (HRP) for enzyme conjugate preparation by N-hydroxysuccinimide mediated carbodiimide reaction. The immunogen was used to raise the antiserum in New Zealand white rabbit. The immunoreactivity of MPA-3-CMO-BSA-antibody and MPA-3-CMO-HRP enzyme conjugate was checked by checkerboard assay. The MPA-3-CMO-HRP enzyme conjugate and MPA-3-CMO BSA-antibody were used for further development, standardization and validation of the assay. Sensitivity, ED50 and affinity of the assay were found to be 0.114 ng/mL, 2.75 ng/mL and 9.9 * 10-8 L/mol respectively. The % cross-reaction of analogous steroids with MPA-3-CMO-BSA-antibody was less than 0.025%. The recovery of the exogenously spiked MPA serum pools were in the range of 96.83-105.47%. The intra- and inter-assay coefficients of variation was less than 7.02%. The correlation coefficient of the serum level of MPA measured by the developed assay with the commercially available kit was found to be 0.95 (n = 37). This developed ELISA was further validated by measuring serum level of MPA in rat after administering them different doses of MPA intramuscularly. PMID- 30025975 TI - Anterior nucleus of thalamus stimulation inhibited abnormal mossy fiber sprouting in kainic acid-induced epileptic rats. AB - BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has demonstrated antiepileptic efficacy, especially for mesial temporal lobe epilepsy (MTLE). Mossy fiber sprouting (MFS) is involved in the pathogenesis of MTLE, and Sema-3A and GAP-43 are pivotal regulators of MFS. This study investigated the effects of ANT-DBS on MFS and expression levels of Sema-3A and GAP-43 as a possible mechanism for seizure suppression. METHODS: Adult male Sprague-Dawley rats were randomly divided into four groups: (1) control (saline injection), (2) KA (kainic acid injection), (3) KA + Sham-DBS (electrode implantation without stimulation), and (4) KA + DBS (electrode implantation with stimulation). Video electroencephalography (EEG) was used to ensure model establishment and monitor seizure frequency, latency, and severity (Racine stage). Chronic ANT stimulation was conducted for 35 days in the KA + DBS group, and MFS compared to the other groups by quantitative Timm staining. Sema-3A and GAP-43 expression levels in the hippocampal formation were evaluated in all groups with western blot. RESULTS: The latency period was significantly prolonged and spontaneous seizure frequency reduced in the KA + DBS group compared to KA and KA + Sham-DBS groups. Staining scores for MFS in CA3 and dentate gyrus (DG) were significantly lower in the KA + DBS group. The KA + DBS group also exhibited decreased GAP-43 expression and increased Sema-3A expression compared to KA and KA + Sham-DBS groups. CONCLUSION: These results suggest that ANT-DBS extends the latent period following epileptogenic stimulation by impeding MFS through modulation of GAP-43 and Sema-3A expression. PMID- 30025976 TI - Critical role of Erythrocyte Binding-Like protein of the rodent malaria parasite Plasmodium yoelii to establish an irreversible connection with the erythrocyte during invasion. AB - Plasmodium malaria parasites multiply within erythrocytes and possess a repertoire of proteins whose function is to recognize and invade these vertebrate host cells. One such protein involved in erythrocyte invasion is the micronemal protein, Erythrocyte Binding-Like (EBL), which has been studied as a potential target of vaccine development in Plasmodium vivax (PvDBP) and Plasmodium falciparum (EBA-175). In the rodent malaria parasite model Plasmodium yoelii, specific substitutions in the EBL regions responsible for intracellular trafficking (17XL parasite line) or receptor recognition (17X1.1pp. parasite line), paradoxically increase invasion ability and virulence rather than abolish EBL function. Attempts to disrupt the ebl gene locus in the 17XL and 17XNL lines were unsuccessful, suggesting EBL essentiality. To understand the mechanisms behind these potentially conflicting outcomes, we generated 17XL-based transfectants in which ebl expression is suppressed with anhydrotetracycline (ATc) and investigated merozoite behavior during erythrocyte invasion. In the absence of ATc, EBL was secreted to the merozoite surface, whereas following ATc administration parasitemia was negligible in vivo. Merozoites lacking EBL were unable to invade erythrocytes in vitro, indicating that EBL has a critical role for erythrocyte invasion. Quantitative time-lapse imaging revealed that with ATc administration a significant number of merozoites were detached from the erythrocyte after the erythrocyte deformation event and no echinocytosis was observed, indicating that EBL is required for merozoites to establish an irreversible connection with erythrocytes during invasion. PMID- 30025977 TI - Antibiotic Scars Left on the Gut Microbiota from the Stringent Response. AB - Current research is primarily focused on compositional shifts and alterations in the metabolic status of the gut microbiota to elucidate the damage caused by antibiotics. However, the impact of the stringent response, which is governed by a global gene regulatory system conserved in most gut bacteria, should not be overlooked. PMID- 30025978 TI - Changes in Patient-reported Swallow Function in the Long Term After Chemoradiotherapy for Oropharyngeal Carcinoma. AB - AIMS: To assess long-term patient-reported swallow function after chemoradiotherapy for oropharyngeal carcinoma and to evaluate the frequency of deterioration/improvement over years. MATERIALS AND METHODS: Fifty-nine patients with oropharyngeal carcinoma treated with parotid-sparing intensity-modulated radiotherapy and concurrent chemotherapy between 2010 and 2012 had previously completed the MD Anderson Dysphagia Inventory (MDADI) at a median of 34 months (range 24-59) after treatment. An MDADI was posted to 55 alive and disease-free patients after a 30 month interval; 52/55 replies were received, a median of 64 months (range 52-88) after treatment; 27/52 (52%) had been managed with a prophylactic gastrostomy. A 10 point or greater change in the MDADI scores was defined as clinically significant. RESULTS: Overall, in the whole cohort, patient reported swallow function showed a small absolute improvement in MDADI composite score on the second MDADI questionnaire (>5 years after treatment) compared with the first MDADI (>2 years after treatment); mean 68.0 (standard deviation 19.3) versus 64.0 (standard deviation 16.3), P = 0.021. Using the composite score, swallow function was stable over time in 29/52 (56%) patients; a clinically significant improvement in swallow function over time was noted in 17/52 (33%) patients; conversely 6/52 (12%) patients experienced a clinically significant deterioration with time. Abnormality of pre-treatment diet and a prophylactic gastrostomy correlated with an inferior MDADI composite score on the later questionnaire (P = 0.029 and P = 0.044, respectively). CONCLUSIONS: Long-term dysphagia is prevalent >5 years after treatment. Although long-term swallow function is stable in most patients, it is not static in a minority. On MDADI composite summary scores, 33% of patients experienced an improvement, whereas 12% deteriorated with time. Further investigation is needed to determine underlying mechanisms behind these divergent outcomes. PMID- 30025979 TI - Antigen conjugated nanoparticles reprogrammed the tumor-conditioned macrophages toward pro-immunogenic type through regulation of NADPH oxidase and p38MAPK. AB - Tumor associated macrophages (TAMs) are pertinent to cancer cell growth in the tumor microenvironment. Indeed, TAMs differentiate from monocytes (MPhi) due to specific growth factors present in the tumor microenvironment. TAMs show mostly an M2-like phenotype is due to the absence of pro-inflammatory signals and supply fuel to tumor growth. Several attempts have been taken to switch TAMs into a pro immunogenic type. To address context, we used a tumor microenvironment by in vitro coculturing human blood MPhi with cancer cell conditioned media (TC-MPhi). We showed that the antigen cobalt oxide nanoparticles (Ag-NPs) can reprogram TC MPhi to pro-immunogenic type to build up an antitumor immune response. Our results demonstrate that NPs-Ag induced a marked activation of NADPH oxidase in TC-MPhi, likely through stimulation of ROS linked to activation of p38 MAPK. These activated p38 MAPK up-regulated the IFN-gamma, TNF-alpha and initial IL-12 production, in turn, the activation of IFN-gamma prolonged IL-12 production. PMID- 30025980 TI - The reliability and validity of rapid transcranial magnetic stimulation mapping. AB - BACKGROUND: Traditional transcranial magnetic stimulation mapping involves systematically delivering stimuli over a predefined grid. The pseudorandom walk method seeks to improve map acquisition times by abandoning the grid in favour of delivering stimuli randomly over a given area. OBJECTIVES: To i) determine the minimum interstimulus interval (ISI) required for reliable mapping outcomes within and between sessions using the pseudorandom walk method and ii) assess the validity of the pseudorandom walk method by testing its equivalence with traditional mapping. METHODS: Maps collected using the pseudorandom walk method at four ISIs (4, 3, 2, and 1s) were compared to maps collected using traditional mapping in twenty healthy individuals. Outcomes included map area, volume, centre of gravity, mean MEP amplitude, and number of discrete peaks. RESULTS AND CONCLUSIONS: The pseudorandom walk method was valid and reliable with a 2-second ISI for all outcomes except number of discrete peaks, which was less reliable than other measures. PMID- 30025981 TI - Theory of turbid microalgae cultures. AB - Microalgae can be cultivated in closed or open photobioreactors (PBR). In these systems, light rapidly decreases as it passes through the culture due to the turbidity of the medium. Thus, microalgae experiment different light intensities depending on their position in the medium. In this paper, we study theoretically how the growth rate of microalgae is affected by different factors; incident light intensity, form of the PBR, microalgae population density, turbidity of non microalgae components, and light path-length of the reactor. We show that for different types of PBR the average growth rate is completely determined by the incident light intensity and the optical depth. In the case of vertical cylindrical PBRs illuminated from above (e.g. race-way or panel-type reactors), we described (and we prove under general assumptions) in details the dependence of the AGR on the aforementioned factors. Finally, we discuss some implications of our analysis; the occurrence of the Allee effect, if light ostensibly limits or inhibits the growth rate in outdoor cultures, and how the geometry of the PBR affects microalgae growth rate and productivity. PMID- 30025982 TI - Rab GTPase Function in Endosome and Lysosome Biogenesis. AB - Eukaryotic cells maintain a highly organized endolysosomal system. This system regulates the protein and lipid content of the plasma membrane, it participates in the intracellular quality control machinery and is needed for the efficient removal of damaged organelles. This complex network comprises an endosomal membrane system that feeds into the lysosomes, yet also allows recycling of membrane proteins, and probably lipids. Moreover, lysosomal degradation provides the cell with macromolecules for further growth. In this review, we focus primarily on the role of the small Rab GTPases Rab5 and Rab7 as organelle markers and interactors of multiple effectors on endosomes and lysosomes and highlight their role in membrane dynamics, particularly fusion along the endolysosomal pathway. PMID- 30025983 TI - Clinical deterioration of ward patients in the presence of antecedents: A systematic review and narrative synthesis. AB - AIM: The aim of this review was to identify and synthesise published accounts of recognising and responding to patient deterioration in the presence of deterioration antecedents. DESIGN: The systematic review canvassed four electronic databases/search engines for studies of adult ward patients who had altered physiological parameters before developing major adverse events. SYNTHESIS METHODS: The findings were synthesised using a narrative approach. RESULTS: Clinical deterioration can be missed by nurses, even with adequate charting. Delays in recognising and responding to patient deterioration remains an international patient safety concern, and strategies to enhance recognition of patient deterioration have not achieved consistent improvements. The lack of significant and sustained improvement through targeted training suggests the problem may be rooted in human behaviour and local ward culture. Nurses play a pivotal role in recognising and responding to patient deterioration; however, patient records do not facilitate tracking of all nurse decisions and actions, and any undocumented care cannot be easily captured by auditing processes. CONCLUSION: Failure to recognise clinical deterioration was evident even with adequate charting. It is not clear if nurses do not recognise clinical deterioration because they failed to interpret the signs of deterioration or they made a conscious decision not to escalate based on their clinical judgement or they lacked attention at the time of the event. Whatever the reason, focus is warranted for nurses' decision-making after the recording of clinical deterioration signs and the role of human factors in delayed recognition, before maximum benefit of any strategy can be achieved. PMID- 30025984 TI - Molecular cloning and functional characterization of duck DDX41. AB - DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41), a receptor belonging to DExD/H box helicase family, acts as an intracellular DNA sensor and induces type I IFN production in mammals and fish. However, the function of avian DDX41 in innate immune response is still unknown. In this study, the full-length duck DDX41 (duDDX41) cDNA sequence was cloned for the first time and encoded a putative protein of 618 amino acid residues which showed the high sequence similarity with both zebra finch and chicken DDX41s. The duDDX41 mRNA was widely distributed in all tested tissues, especially the cerebrum, cerebellum, and liver. Overexpression of duDDX41 triggered the activation of transcription factors IRF1 and NF-kappaB, as well as IFN-beta expression in DEFs. The DEADc domain of duDDX41 played an extremely vital role in duck type I IFN signaling pathway. Knockdown of duDDX41 by siRNA silencing dramatically decreased IFN-beta expression stimulated by poly(dA:dT) or duck enteritis virus (DEV). In addition, the replication of DEV was significantly inhibited in duDDX41-expressed DEFs and was enhanced in DDX41 knockdown DEFs. These results suggest that DDX41 is an important cytosolic DNA sensor and plays a crucial role in duck antiviral innate immune response. PMID- 30025985 TI - A rapid PCR-based method to discriminate Macrococcus caseolyticus and Macrococcus canis from closely-related Staphylococcus species based on the ctaC gene sequence. AB - Our method exploits the amplification of the cytochrome c oxidase subunit II (ctaC) gene for the screening of Macrococcus caseolyticus and Macrococcus canis in complex microbial communities, and discriminating these species from strains of their sister genus Staphylococcus. Thirteen novel strains of these species were isolated using this approach. PMID- 30025986 TI - Topical insulin in neurotrophic keratopathy after resection of acoustic neuroma. AB - CASE REPORT: A patient with a history of surgical resection of an acoustic neuroma presented with involvement of both the left facial nerve and the left trigeminal nerve. She initially consulted for exposure keratitis, but two weeks later presented with an infectious keratitis. After taking the corneal sample, she presented with persistent epithelial defect, which did not respond to medical management. Topical insulin was indicated, and a decrease in the area of the lesion was seen in the following 5 days. A therapeutic contact lens was also placed at that time and finally, two weeks after the initiation of insulin, the epithelial defect completely closed. DISCUSSION: This was a complex case due to the confluence of facial paralysis, neurotrophic keratitis, and infectious keratitis, which finally had a successful outcome. Topical insulin can be an effective adjuvant therapy in cases of neurotrophic ulcers that do not respond to standard therapy. PMID- 30025987 TI - Visual outcomes, spectacle independence and satisfaction after diffractive trifocal intraocular lens implantation. AB - PURPOSE: To investigate visual outcomes, spectacle independence, and patient satisfaction after trifocal intraocular lens implantation. METHODS: A retrospective study conducted on 5,186 patients who underwent phacoemulsification and were implanted with a diffractive trifocal intraocular lens (FineVision Micro F, PhysIOL SA, Liege, Belgium). RESULTS: The mean pre-operative keratometry was 43.61+/-1.55 D, and mean keratometric cylinder was -0.86+/-0.66 D. At 3 months post-operatively, values changed to 43.59+/-1.56 and -0.71+/-0.46 D, respectively. Mean sphere varied from 2.04+/-2.60 to 0.14+/-0.38 D, and mean spherical equivalent from 1.64+/-2.61 to -0.05+/-0.36 D. More than 60% of the patients achieved better corrected distance visual acuity. The majority had a final residual refractive error (predictability) lower than 1 D (99.1%), with 14.3% needing optical adjustment (bioptics). Posterior capsulotomy was performed in 2.2%, and the lens was replaced in 5 patients. A high percentage of patients were satisfied in terms of vision and spectacle independence at all distances. Although 2% referred to worsening of night vision quality, only 2% were not very satisfied and 20 patients were dissatisfied. The causes were: blurred vision (7 cases), spectacle dependence (10), dysphotopsia (7), and dry eye (4). CONCLUSIONS: The implantation of this model provided good visual performance in all distances, as well as high levels of spectacle independence and satisfaction. PMID- 30025988 TI - Infrared meibography and molecular assessment of p63 gene mutations in a Mexican patient with EEC syndrome. AB - OBJECTIVE: To report the finding of infrared meibography in a Mexican patient with EEC syndrome (Ectrodactyly-ectodermal dysplasia-cleft syndrome) confirmed by molecular analysis of the p63 gene. CLINICAL CASE: A 31 year-old male patient was seen due to a history of progressive visual loss in both eyes associated with long-term photophobia. The patient was born with cleft lip and palate, ectrodactyly of right hand, and afterwards, displayed nail dysplasia, anodontia and alopecia, with which ectodermal dysplasia was diagnosed. The ophthalmological findings were limited to the adnexa and the ocular surface. In vivo infrared meibography showed total absence of Meibomian glands in the lower eyelids and severe deficiency in the upper eyelids. In addition, it was shown that the patient was a heterozygous carrier of a missense mutation R304W (C -> T) in exon 8 of the p63 gene. DISCUSSION: The R304W mutation in the p63 gene region is definitely related to characteristics such as the absence of Meibomian glands. PMID- 30025989 TI - Nutritional supplements with omega 3 in retinal disease: Relationship between volume and concentration in commercial products. AB - OBJECTIVE: To analyse the morphometric characteristics and the concentration of (docosahexaenoic acid) DHA and eicosapentaenoic acid (EPA) of the different nutritional supplements with omega 3 available on the market for retinal disease. MATERIAL AND METHODS: A double-blind study was conducted with a single observer, of the different omega 3 supplementation tablets sample marketed in Spain. The length of the tablet, the concentration of omega 3 in total, as well as DHA and EPA were studied separately using the amount provided by the manufacturer and the volume of the capsule calculated from the development of a specific formula for it. RESULTS: A total of 10 different nutritional supplements were included. The mean of total omega 3, DHA and EPA was 383.10+/-160.90, 210.72+/-93.3, and 112.34+/-140.98mg, respectively. The mean size of the capsules was 14.77+/ 0.19*8.13+/-0.09mm The smallest sized capsule was that of Oftan macula omega(r) (Esteve, Barcelona, Spain). Brudymacula(r) (Brudylab, Barcelona, Spain) and Brudyretina 1.5 g(r) (Brudylab, Barcelona, Spain) tablets contained more DHA, with Nutrof omega(r) (Thea Laboratories, Barcelona, Spain) having the lowest concentration of omega 3, DHA and EPA, per tablet. CONCLUSION: There are significant differences in size, volume, quantity, and concentration of omega 3 and its derivatives, between different commercial preparations. Only the knowledge of the characteristics of the nutritional supplements will enable us to provide a more personalised indication of their use for our patients. PMID- 30025990 TI - Ocular external myiasis. A series of cases due to larvae Oestrus ovis in Navarra, Spain. AB - OBJECTIVE: To report a case series of external ophthalmomyiasis in a region of Spain together with its common epidemiological factors and treatment. MATERIAL AND METHODS: A presentation is made of four clinical cases of patients with external ocular myiasis caused by Oestrus ovis larvae. RESULTS: Ocular myiasis is a parasitic infection by larval stages of flies. It can affect the ocular globe externally and / or internally, with the former being the most frequently found condition. The organism that mainly affects the eyes is the Oestrus ovis larvae. CONCLUSION: Ocular external myiasis is a rare condition that occasionally can occur in humans. In this case series, a common risk factor for infection is established: the previous exposure to livestock and / or agricultural activity. An adequate diagnosis and treatment could avoid the transition from external to internal form, as well as its complications. PMID- 30025993 TI - [Adaptation of platelet concentrates delivery to HAS/ANSM requirements evolution in EFS Grand-Est]. AB - Evolution of French HAS/ANSM guidelines in 2015 about optimal platelet transfusion dose for patients brought us to review about our practices for platelet concentrates delivery in EFS Grand-Est region. In addition, pathogen inactivation in platelet concentrates has been implemented all over the country and transfusion centers have merged. All these changes required harmonization. In this context, our major issue was to answer patient's requirements, according to the new guidelines keeping in mind the cost effectiveness on public finances. We report here on the changes in our practices and their impacts. PMID- 30025991 TI - Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease. AB - This 52-week, phase I/II double-blind, randomized, placebo-controlled study investigated the novel use of clenbuterol in late-onset Pompe disease (LOPD) stably treated with ERT. Eleven of thirteen participants completed the study. No serious adverse events were related to clenbuterol, and transient minor adverse events included mild elevations of creatine kinase, muscle spasms, and tremors. At week 52, the 6-min walk test distance increased by a mean of 16 m (p = 0.08), or a mean of 3% of predicted performance (p = 0.03), and the maximum inspiratory pressure increased 8% (p = 0.003) for the clenbuterol group. The quick motor function test score improved by a mean of seven points (p = 0.007); and the gait, stairs, gower, chair test improved by a mean of two points (p = 0.004). Clenbuterol decreased glycogen content in the vastus lateralis by 50% at week 52. Transcriptome analysis revealed more normal muscle gene expression for 38 of 44 genes related to Pompe disease following clenbuterol. The placebo group demonstrated no significant changes over the course of the study. This study provides initial evidence for safety and efficacy of adjunctive clenbuterol in patients with LOPD (NCT01942590). PMID- 30025992 TI - lncRNA PFAR Promotes Lung Fibroblast Activation and Fibrosis by Targeting miR-138 to Regulate the YAP1-Twist Axis. AB - Long non-coding RNAs (lncRNAs) have been reported to be involved in various pathophysiological processes in many diseases. However, the role and mechanism of lncRNAs in idiopathic pulmonary fibrosis (IPF) have not been explicitly delineated. In the present study, we reported that lncRNA NONMMUT065582, designated pulmonary fibrosis-associated RNA (PFAR), is upregulated in the lungs of mice with lung fibrosis as well as in fibrotic lung fibroblasts. Overexpression of PFAR promoted fibrogenesis through modulation of miR-138, whereas knockdown of PFAR attenuated TGF-beta1-induced fibrogenesis in lung fibroblasts. In addition, knockdown of miR-138 promoted fibrogenesis by targeting regulation of yes-associated protein 1 (YAP1), whereas enhanced expression of miR 138 attenuated fibrogenesis in lung fibroblasts. Mechanistically, PFAR acted as competing endogenous RNA (ceRNA) of miR-138: forced expression of PFAR reduced the expression and activity of miR-138 to activate YAP1 and promote fibrogenesis in lung fibroblasts, whereas loss of YAP1 abrogated the pro-fibrotic effect of PFAR. More importantly, PFAR silencing alleviated BLM-induced lung fibrosis in mice. Taken together, the results of our study identified lncRNA PFAR as a new pro-fibrotic molecule that acts as a ceRNA of miR-138 during lung fibrosis and demonstrated PFAR as a novel therapeutic target for the prevention and treatment of lung fibrosis. PMID- 30025994 TI - The reliability of motor evoked potentials to predict dorsiflexion injuries during lumbosacral deformity surgery: importance of multiple myotomal monitoring. AB - STUDY DESIGN: Case-control analysis of transcranial motor evoked potential (MEP) responses and clinical outcome. OBJECTIVE: To determine the sensitivity and specificity of MEPs to predict isolated nerve root injury causing dorsiflexion weakness in selected patients having complex lumbar spine surgery. SUMMARY OF BACKGROUND DATA: The surgical correction of distal lumbar spine deformity involves significant risk for damage to neural structures that control muscles of ankle and toe dorsiflexion. Procedures often include vertebral translation, interbody fusion, and posterior-based osteotomies. The benefit of using MEP monitoring to predict dorsiflexion weakness has not been well-established. The purpose of this paper is to describe the relationship between neural complications from lumbar surgery and intraoperative MEP changes. METHODS: Included were 542 neurologically intact patients who underwent posterior spinal fusion for the correction of distal lumbar deformity. Two myotomes, including tibialis anterior (TA) and extensor hallucis longus (EHL), were monitored. MEP and free-running electromyography data were assessed in each patient. Cases of new dorsiflexion weakness noted postoperatively were identified. Data in case and control patients were compared. There was no direct funding for this work. The Department of Anesthesiology and Perioperative Care provides salary support for authors one and six. Authors two and three report employment in the field of intraoperative neurophysiological monitoring as a study-specific conflict of interest. RESULTS: Twenty-five patients (cases) developed dorsiflexion weakness. MEP amplitude decreased in the injured myotomes by an average of 65 +/- 21% (TA) and 60+/-26% (EHL), which was significantly greater than the contralateral uninjured side or for control subjects. (p < .01) Receiver operator characteristic (ROC) curves showed high sensitivity, specificity, and predictive value for changes in MEP amplitude using either the TA or EHL. Analysis of MEP changes to either TA or EHL yielded a superior ROC curve. Net reclassification improvement analysis showed assessing MEP changes to both TA and EHL improved the predictability of injury. CONCLUSIONS: The use of MEP amplitude change is highly sensitive and specific to predict a new postoperative dorsiflexion injury. Monitoring two myotomes (both TA and EHL) is superior to relying on MEP changes from a single myotome. Electromyography activity was less accurate but compliments MEP use. Additional studies are needed to define optimal intraoperative MEP warning thresholds. PMID- 30025995 TI - Digital biomarkers of spine and musculoskeletal disease from accelerometers: Defining phenotypes of free-living physical activity in knee osteoarthritis and lumbar spinal stenosis. AB - BACKGROUND CONTEXT: Lumbar spinal stenosis (LSS) and knee osteoarthritis (OA) are 2 of the leading causes of disability worldwide. In order to provide disease specific prescriptions for physical activity, there is a clear need to better understand physical activity in daily life (performance) in these populations. PURPOSE: To discover performance phenotypes for LSS and OA by applying novel analytical methods to accelerometry data. Specific objectives include the following: (1) to identify characteristic features (phenotypes) of free-living physical activity unique to individuals with LSS and OA, and (2) to determine which features can best differentiate between these conditions. STUDY DESIGN AND SETTING: Leveraging data from 3 existing cross-sectional cohorts, accelerometry signal feature characterization and selection were performed in a computational laboratory. PATIENT SAMPLE: Data from a total of 4,028 individuals were analyzed from the following 3 datasets: LSS Accelerometry Database (n=75); OA Initiative (n=1950); and the 2003 to 2004 National Health and Nutrition Examination Survey (pain-free controls, n=2003). METHODS: In order to characterize the accelerometry signals, data were examined using (1) standard intervals for counts/minute from Freedson et al. and (2) the physical performance intervals for mobility-limited pain populations. From this, 42 novel accelerometry features were defined and evaluated for significance in discriminating between the groups (LSS, OA, and controls) in order to then determine which sparse set of features best differentiates between the groups. These sparse sets of features defined the performance phenotypes. OUTCOME MEASURES: Accelerometry features and their ability to differentiate between individuals with LSS, OA, and controls. RESULTS: Given age and gender, classification rates were at least 80% accurate (pairwise) between diseased and pain-free populations (LSS vs. controls and OA vs. controls). The most important features to distinguish between disease groups corresponded to measures in the light and sedentary activity intervals. The more subtle classification between diseased populations (LSS vs. OA) was 72% accurate, with light and moderate activity providing the prominent distinguishing features. CONCLUSIONS: We describe the discovery of performance phenotypes of LSS and OA from accelerometry data, revealed through a novel set of features that characterize daily patterns of movement in people with LSS and OA. These performance phenotypes provide a new method for analyzing free-living physical activity (performance) in LSS and OA, and provide the groundwork for more personalized approaches to measuring and improving function. PMID- 30025996 TI - Severe hyperkyphosis reduces the aerobic capacity and maximal exercise tolerance in patients with Scheuermann disease. AB - BACKGROUND CONTEXT: The evaluation of ventilatory functional restrictions during a maximal exercise tolerance test in patients with Scheuermann disease has never been described. PURPOSE: This study evaluated the respiratory functional capacity of patients with Scheuermann disease compared to healthy adolescents matched in age. STUDY DESIGN/SETTING: Prospective comparative study. PATIENTS SAMPLE: Forty one consecutive adolescents with Scheuermann hyperkyphosis (SK) and 20 healthy controls matched in age were included in the study. OUTCOME MEASURES: Basal spirometry and dynamic ventilatory parameters were measured during a maximal cardiopulmonary exercise tolerance test. Heart rate, oxygen saturation (SatO2), maximum oxygen uptake (VO2 max), quotient between ventilation and volume of exhaled carbon dioxide (VE/CO2), respiratory exchange rate (RER), ventilatory capacity at maximal exercise (VEmax), and test duration were recorded at initium and at maximal exercise. METHODS: The exercise tolerance test (ETT) was completed to exhaustion using a standard Bruce protocol on a ramp treadmill. Comparisons of quantitative variables between SK and control group were analyzed by statistical nonparametric test. The correlations between the magnitude of the thoracic kyphosis and both the VO2 max/kg and VEmax of the SK group were also analyzed. No funds were required. The authors have no conflicts of interests. RESULTS: Patients with SK started the test with a higher heart rate (p<.01) and reached exhaustion with a lower heart rate (p<.05) than healthy controls. At maximal exercise, the SatO2 was declined in Scheuermann patients compared to healthy subjects (p<.05). The maximal aerobic power (VO2max) was greater in healthy controls than in hyperkyphotic patients (50.0+/-6.7 vs. 43.4+/-11.3 mL/kg/min; p<.05). There was an inverse correlation between the increase in the magnitude of thoracic kyphosis and the deterioration of the maximal aerobic power. VO2max and VEmax were severely deteriorated in patients with more than 75 degrees kyphosis. Patients with >75 degrees thoracic kyphosis also showed an impairment in their cardiovascular efficiency as measured by the heart rate/VO2 quotient. The limited tolerance to the exercise in SK patients was reflected by a shorter duration of the exercise test and a lower energy cost measured in METS (metabolic equivalents) as compared to healthy controls. CONCLUSIONS: Patients with severe hyperkyphosis (>75 degrees ) show significant respiratory inefficiency together with a lower ventilation capacity and lower VO2max. There is an inverse correlation between the increase in the magnitude of thoracic kyphosis and the deterioration of the maximal aerobic power. PMID- 30025997 TI - Trigger Point Manual Therapy for the Treatment of Chronic Noncancer Pain in Adults: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To determine the effectiveness of trigger point manual therapy (TPMT) for reducing chronic noncancer pain and associated problems in adults, by analyzing all relevant randomized controlled trials (RCTs). DATA SOURCES: We searched databases and clinical trials registers from their inception to May 2017. STUDY SELECTION: We included RCTs in any language that recruited patients older than 18, with pain of 3 months' duration or more. We assessed pain, function, and patient-reported improvement as outcomes. DATA EXTRACTION: Two authors independently extracted and verified data. Meta-analysis was completed where possible, otherwise data were synthesized narratively. DATA SYNTHESIS: We combined all data using a random-effects model and assessed the quality of evidence using GRADE. A total of 19 trials (involving 1047 participants) met inclusion criteria, representing TPMT treatment of musculoskeletal, pelvic, and facial pain. No effect was found for short-term pain relief (mean standardized difference -0.53; 95% confidence interval [CI], -1.08 to 0.02). One small study showed a longer-term benefit for pain (mean standardized difference -2.00; 95% CI, -3.40 to -0.60) but with low confidence in the effect. Significant gains emerged for function (mean standardized difference -0.77; 95% CI, -1.27 to -0.26) and in patient global response (odds ratio 3.79; 95% CI, 1.86-7.71) from 4 studies, but not for health-related quality of life. CONCLUSIONS: Evidence for TPMT for chronic noncancer pain is weak and it cannot currently be recommended. PMID- 30025998 TI - Molecular identification of Candida auris by PCR amplification of species specific GPI protein-encoding genes. AB - The emerging multidrug-resistant pathogenic yeast Candida auris causes life threatening invasive infections and shows a capacity for hospital transmission that is uncommon in other Candida species. Rapid and accurate diagnosis of C. auris infections is crucial; however, the fungus is frequently misidentified. Here, we present a rapid and easily applicable PCR assay for reliable identification of C. auris by designing primers from unique GPI protein-encoding genes. Specificity of the used primers for C. auris was verified with a panel of 19 different Candida species including the clinically most relevant and phylogenetically closely related species. Efficacy of the PCR approach was validated by correctly identifying 112 C. auris isolates from an outbreak in a Spanish hospital, 20% of which were not reliably identified by MALDI-TOF MS, and 27 genotypically diverse C. auris isolates originating from hospitals in various countries, in a test that included (blind) negative controls. By employing two GPI protein primer pairs in a single PCR, a double screening can be performed, which enhances the robustness of the PCR assay and avoids potential false negatives due to recent evolutionary events, as was observed for two isolates. Our PCR method, which is based on the uniqueness of selected GPI protein-encoding genes, is useful for easy, low-cost, and accurate identification of C. auris infections in a clinical setting. PMID- 30025999 TI - Claudin-4 Expression Is Associated With Disease-Free Survival in Breast Carcinoma in-Situ: Mean Follow-up of 8.2 Years. AB - INTRODUCTION: Claudins are tight junctions associated with breast cancer prognosis. The claudin-low intrinsic subtype of invasive carcinoma is associated with high-grade carcinoma, low junction molecule expression, and worse response to chemotherapy. However, it is not known whether the expression of claudins may provide clues as to carcinoma-in-situ (CIS) prognosis. The aim of this study was evaluate claudin-4 expression in CIS and its association with disease-free survival and histologic type of local recurrence (in situ or invasive). METHODS: A tissue microarray block, constructed from 137 pure CIS paraffin blocks, was submitted to immunohistochemical staining for claudin-4, beta-catenin, E cadherin, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. A claudin-4 score categorized samples as claudin-4-low or high. Clinical and treatment data were obtained from medical records. RESULTS: Claudin-4 expression was evaluated in 86 samples; 88.4% were high and 11.6% low. Mean follow-up was 98.4 months, and the local recurrence rate was 10.4%. There was a significant difference in disease-free survival between claudin-4-high and low (4.9 and 1.9 years, respectively, P = .02); however, there was no difference between them in histologic type of recurrence (invasive or in situ) (P = .44). CONCLUSION: In our samples, high claudin-4 expression in CIS was more frequent than low expression. Claudin-4-low expression had a worse prognosis in CIS (inferior disease-free survival), but it was similar to high claudin-4 in histologic type of local recurrence. PMID- 30026001 TI - PARP inhibitors and quality of life in ovarian cancer. PMID- 30026000 TI - Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial. AB - BACKGROUND: Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL. METHODS: The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European QOL five dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3-4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274. FINDINGS: Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25.0-25.6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0.838 [0.0097] in the niraparib group vs 0.834 [0.0173] in the placebo group in the gBRCAmut cohort; and 0.833 [0.0077] in the niraparib group vs 0.815 [0.0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects. INTERPRETATION: These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo. FUNDING: TESARO. PMID- 30026002 TI - Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial. AB - BACKGROUND: In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. METHODS: In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6-12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. FINDINGS: The adjusted average mean change from baseline over the first 12 months in TOI was -2.90 (95% CI -4.13 to -1.67) with olaparib and -2.87 (-4.64 to -1.10) with placebo (estimated difference -0.03; 95% CI -2.19 to 2.13; p=0.98). Mean QAPFS (13.96 [SD 10.96] vs 7.28 [5.22] months; difference 6.68, 95% CI 4.98-8.54) and mean duration of TWiST (15.03 [SD 12.79] vs 7.70 [6.42] months; difference 7.33, 95% CI 4.70-8.96) were significantly longer with olaparib than with placebo. INTERPRETATION: Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies. FUNDING: AstraZeneca. PMID- 30026003 TI - Beware biofilm! Dry biofilms containing bacterial pathogens on multiple healthcare surfaces; a multi-centre study. AB - BACKGROUND: Wet biofilms associated with medical devices have been widely studied and their link with healthcare-associated infections (HCAIs) is well recognized. Little attention has been paid to the presence of dry biofilms on environmental surfaces in healthcare settings. AIM: To investigate the occurrence, prevalence, and diversity of dry biofilms on hospital surfaces. METHODS: Sixty-one terminally cleaned items were received from three different UK hospitals. The presence of dry biofilm was investigated using culture-based methods and scanning electron microscopy (SEM). Bacterial diversity within biofilms was investigated using ribosomal RNA intergenic spacer analysis (RISA)-polymerase chain reaction and next-generation sequencing. FINDINGS: Multi-species dry biofilms were recovered from 95% of 61 samples. Abundance and complexity of dry biofilms were confirmed by SEM. All biofilms harboured Gram-positive bacteria including pathogens associated with HCAI; 58% of samples grew meticillin-resistant Staphylococcus aureus. Dry biofilms had similar physical composition regardless of the type of items sampled or the ward from which the samples originated. There were differences observed in the dominance of particular species: dry biofilms from two hospitals contained mostly staphylococcal DNA, whereas more Bacillus spp. DNA was found on surfaces from the third hospital. CONCLUSION: The presence of dry biofilms harbouring bacterial pathogens is virtually universal on commonly used items in healthcare settings. The role of dry biofilms in spreading HCAIs may be underestimated. The risk may be further exacerbated by inefficient cleaning and disinfection practices for hospital surfaces. PMID- 30026005 TI - Verification of Cepheid Xpert Xpress Flu/RSV assay for use with gargle samples, sputa and endotracheal secretions. PMID- 30026004 TI - Risk factors for early onset prosthetic valve endocarditis: a case-control study. AB - BACKGROUND: Early onset prosthetic valve endocarditis (EO-PVE) is an infrequent complication of cardiac valve surgery. It is considered a healthcare-associated infection due to contamination of the prosthesis during the implant or in the early postoperative period. AIM: To evaluate which factors may be related to the acquisition of EO-PVE. METHODS: A nested case-control study was conducted from 2006 to 2016. Cases were patients who had definite prosthetic endocarditis by the modified Duke criteria up to 12 months of heart valve replacement. Cases and controls were matched by age, gender, date and type of surgery. FINDINGS: There were 26 cases and 78 controls, in 2496 valve surgeries. The median incidence of EO-PVE was 1.1%. Risk factors identified during surgery were: use of >=2 cryoprecipitate units (odds ratio (OR): 5.95; 95% confidence interval (CI): 1.31 27.0) and >=2 plasma units (OR: 2.73; 95% CI: 1.0-7.5). In the postoperative period, associated factors were bloodstream infection (OR: 14.00; CI: 1.49 131.77), pneumonia (4.38; 1.21-15.84), any infection (4.46; 1.63-12.21), central line for >=2 weeks (5.33; 2.06-13.78), presence of dialysis catheter (3.22; 1.15 9.03), and new open chest surgery (3.89; 1.28-11.78). Mortality at 12 months was 34.6% in cases and 6.4% in controls (OR: 7.73; CI: 2.3-26.06). CONCLUSION: Cases had more infections, invasive procedures and surgical re-interventions in the early postoperative period, which favoured contamination of the newly implanted prosthesis. A preventive approach, with reinforcement of infection control practices, may curb the incidence of this condition. PMID- 30026007 TI - Fatal infection with Elisabethkingia miricola after lung transplantation. PMID- 30026006 TI - The local hospital milieu and healthcare-associated vancomycin-resistant enterococcus acquisition. AB - BACKGROUND: Vancomycin-resistant enterococcus (VRE) causes 4% of all healthcare associated infections in the USA. The process by which the local hospital milieu contributes to VRE acquisition is not fully understood. AIM: To determine the importance of specific factors within the local hospital environment for healthcare-associated VRE acquisition. METHODS: This retrospective cohort study included patients admitted to six intensive care units at an academic medical centre from January 2012 to December 2016 with negative rectal VRE cultures on admission. VRE acquisition was defined as a positive surveillance swab performed at any time after the initial negative swab during the index hospitalization. The exposures of interest were VRE colonization pressure, VRE importation pressure, and use of vancomycin. Multivariable Cox proportional hazards modelling was performed, with patients followed until VRE acquisition, death, or for up to 30 days. FINDINGS: Of 8485 patients who were initially VRE negative, 161 patients acquired VRE. On univariate analysis, patients with VRE acquisition were more likely to have received vancomycin, to have had a neighbouring patient who received vancomycin, to have high VRE importation pressure, or to have high VRE colonization pressure. On multivariable analysis, only high VRE colonization pressure was an independent predictor of VRE acquisition (adjusted hazard ratio: 1.79; 95% confidence interval: 1.19-2.70). CONCLUSION: VRE colonization pressure was the most important risk factor for healthcare-associated VRE acquisition, regardless of VRE importation pressure. Interventions seeking to reduce VRE acquisition should focus on minimizing transmission between patients with known VRE and the local hospital environment. PMID- 30026008 TI - Efficacy of sodium hypochlorite against multidrug-resistant Gram-negative bacteria. AB - BACKGROUND: Increased antimicrobial resistance has been observed among many bacteria leading to treatment failures in human and veterinary medicine. Disinfection is a prerequisite for infection control and prevention in healthcare settings. Chlorine compounds are cost-effective and accessible worldwide. AIM: To determine the efficacy of sodium hypochlorite (NaOCl) against multidrug-resistant Gram-negative bacteria (MDR-GNB). METHODS: Minimum inhibitory concentrations (MICs) were determined using broth macro-dilution. Bactericidal efficacy was measured by qualitative and quantitative suspension tests followed by practical tests without mechanical action on stainless steel carriers. The guidelines of the German Association for Applied Hygiene were followed. FINDINGS: Results varied remarkably depending on the method. MICs were 0.1% or 0.2% NaOCl. Qualitative suspension tests revealed up to 500-fold lower bactericidal concentrations. Pseudomonas aeruginosa (P = 0.0025) was significantly less susceptible in these tests whereas quantitative suspension tests revealed no significant differences between strains (P > 0.05). Practical tests determined bactericidal concentrations of 0.8-0.32% NaOCl at 1 min of contact and even lower concentrations for longer contact times. At 1 min, five Klebsiella were significantly less susceptible (P = 0.0124), whereas the lower susceptibility of P. aeruginosa was not confirmed. Organic load inhibited bactericidal activity significantly, whereas contact time had a marginal effect. Differing test results underline that MIC determination and qualitative suspension tests may be insufficient approaches to evaluate bacterial susceptibility or resistance. CONCLUSION: NaOCl efficiently reduced Pseudomonas aeruginosa, Acinetobacter spp., and Klebsiella spp., most notably in the absence of organic matter. Strain- and species-specific differences in susceptibility were noticed, but in general MDR GNB revealed no higher tolerance to NaOCl. PMID- 30026009 TI - Leukaemia risk associated with low-dose radiation. PMID- 30026011 TI - Chronic exposure to cannabinoids before an emotional trauma may have negative effects on emotional function. AB - Chronic direct activation of cannabinoid CB1 receptors (CB1r) may lead to downregulation of CB1r which may in turn result in a depression-like phenotype in certain individuals. We examined the effects of chronic cannabinoid receptor activation before exposure to an emotional traumatic event on CB1r expression in the basolateral amygdala (BLA) and CA1 and on protracted anxiety- and depression like behaviors. We used exposure to severe shock and situational reminders (SRs) in an inhibitory apparatus as a model for emotional trauma. Chronic treatment with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg, i.p.) before shock exposure had differential effects on depression- and anxiety-like behavioral measures depending on withdrawal periods. In the 24 hrs withdrawal condition, WIN55,212-2 enhanced fear retrieval and impaired extinction, increased anhedonia and despair, but had a therapeutic effect in the startle test. In the 10 days withdrawal condition, WIN55,212-2 enhanced fear retrieval and impaired extinction without preventing the shock/SR-induced negative effects on anhedonia or startle response, but had a therapeutic effect in the despair test. Chronic treatment with WIN55,212-2 was found to down regulate CB1r protein levels in the BLA in the 10 days withdrawal condition, and to upregulate CB1r protein levels in the 24 hrs condition. In the CA1, rats chronically injected with vehicle or WIN55,212-2 demonstrated downregulation of CB1r protein levels. Chronic exposure to cannabinoids prior to an emotional trauma may have deleterious effects on emotional function suggesting that direct CB1/2 receptor activation may not be an optimal way to manipulate the endocannabinoid system in stressful individuals. PMID- 30026012 TI - Outcomes of pancreatic adenocarcinoma that was not resected because of isolated para-aortic lymph node involvement. AB - PURPOSE: Survival appears to be poor in cases of pancreatic ductal adenocarcinoma (PDAC) with para-aortic lymph node involvement (PALN+). However, resection is still performed in these cases because the prognostic impact of PALN+remains controversial. METHODS: PALN+was intraoperatively found in 14 patients (4.8%) with resectable PDAC who consequently did not undergo pancreatectomy. RESULTS: The median overall survival time after laparotomy was 21 months. The 1- and 3 year overall survival rates were 58.3% and 25%, respectively. CONCLUSIONS: We support the advisability of reconsidering pancreatectomy in patients with intraoperatively detected PALN+because the reported survival of such patients who undergo pancreatectomy is poorer than the survival observed for patients in our series. PMID- 30026010 TI - Leukaemia and myeloid malignancy among people exposed to low doses (<100 mSv) of ionising radiation during childhood: a pooled analysis of nine historical cohort studies. AB - BACKGROUND: Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (<100 mSv) radiation is less certain, although this is the dose range most relevant to the general population. We aimed to estimate the risk of leukaemia associated with low-dose radiation exposure in childhood (age <21 years). METHODS: In this analysis of historical cohort studies, we pooled eligible cohorts reported up to June 30, 2014. We evaluated leukaemia and myeloid malignancy outcomes in these cohorts with the relevant International Classification of Diseases and International Classification of Diseases for Oncology definitions. The cohorts included had not been treated for malignant disease, had reported at least five cases of the relevant haematopoietic neoplasms, and estimated individual active bone marrow (ABM) doses. We restricted analysis to individuals who were younger than 21 years at first irradiation who had mean cumulative ABM doses of less than 100 mSv. Dose response models were fitted by use of Poisson regression. The data were received in fully anonymised form by the statistical analyst. FINDINGS: We identified nine eligible cohorts from Canada, France, Japan, Sweden, the UK, and the USA, including 262 573 people who had been exposed to less than 100 mSv enrolled between June 4, 1915, and Dec 31, 2004. Mean follow-up was 19.63 years (SD 17.75) and mean cumulative ABM dose was 19.6 mSv (SD 22.7). 154 myeloid malignancies were identified (which included 79 acute myeloid leukaemias, eight myelodysplastic syndromes, and 36 chronic myeloid leukaemias, in addition to other unspecified myeloid malignancies) and 40 acute lymphoblastic leukaemias, with 221 leukaemias (including otherwise unclassified leukaemias but excluding chronic lymphocytic leukaemia) identified overall. The fitted relative risks at 100 mSv were 3.09 (95% CI 1.41-5.92; ptrend=0.008) for acute myeloid leukaemia and myelodysplastic syndromes combined, 2.56 (1.09-5.06; ptrend=0.033) for acute myeloid leukaemia, and 5.66 (1.35-19.71; ptrend=0.023) for acute lymphoblastic leukaemia. There was no clear dose-response for chronic myeloid leukaemia, which had a relative risk at 100 mSv of 0.36 (0.00-2.36; ptrend=0.394). There were few indications of between-cohort heterogeneity or departure from linearity. For acute myeloid leukaemia and myelodysplastic syndromes combined and for acute lymphoblastic leukaemia, the dose-responses remained significant for doses of less than 50 mSv. Excess absolute risks at 100 mSv were in the range of 0.1-0.4 cases or deaths per 10 000 person-years. INTERPRETATION: The risks of acute myeloid leukaemia and acute lymphoblastic leukaemia were significantly increased after cumulative doses of ionising radiation of less than 100 mSv in childhood or adolescence, with an excess risk also apparent for cumulative radiation doses of less than 50 mSv for some endpoints. These findings support an increased risk of leukaemia associated with low-dose exposure to radiation and imply that the current system of radiological protection is prudent and not overly protective. FUNDING: National Cancer Institute Intramural Research Program, National Cancer Institute, and US National Institutes for Health. PMID- 30026013 TI - A rare case of child abuse from early modern Lithuania. AB - The aim of this article was to describe the outcome of a probable case of physical abuse in the remains of a child dating from the 16th-18th centuries CE. The skeleton of a subadult was recovered during archaeological excavations carried out in the village of Uzubaliai, located in Alytus in southern Lithuania, and subsequently curated in the Faculty of Medicine at Vilnius University. The bones of this child were observed macroscopically and then submitted for radiological investigation. In order to speculate on the presence of abuse, features such as the presence, quantity, and type of injuries were considered. Stages of healing and the occurrence of additional nonspecific stress markers, such as linear enamel hypoplasia or Harris lines, were also recorded. The remains revealed the presence of lesions showing three stages of healing, including antemortem and perimortem fractures. Periosteal reactions were also observed on many of the bones. Traumas with high specificity for abuse, such as rib and scapular fractures, were assessed. Finally, endocranial new bone formation was also noted as a possible sign of neglect. The pattern of observed injuries showed evidence that was compatible with a case of physical abuse. PMID- 30026014 TI - Structural remodeling and conduction velocity dynamics in the human left atrium: Relationship with reentrant mechanisms sustaining atrial fibrillation. AB - BACKGROUND: Rate-dependent conduction velocity (CV) slowing is associated with atrial fibrillation (AF) initiation and reentrant mechanisms. OBJECTIVE: The purpose of this study was to assess the relationship between bipolar voltage, CV dynamics, and AF drivers. METHODS: Patients undergoing catheter ablation for persistent AF (<24 months) were enrolled. Unipolar electrograms were recorded with a 64-pole basket catheter during atrial pacing at 4 pacing intervals (PIs) during sinus rhythm. CVs were measured between pole pairs along the wavefront path and correlated with underlying bipolar voltage. CV dynamics within low voltage zones (LVZs <0.5 mV) were compared to those of non-LVZs (>=0.5 mV) and were correlated to driver sites mapped using CARTOFINDER (Biosense Webster). RESULTS: Eighteen patients were included (age 62 +/- 10 years). Mean CV at 600 ms was 1.59 +/- 0.13 m/s in non-LVZs vs 0.98 +/- 0.23 m/s in LVZs (P <.001). CV decreased incrementally over all 4 PIs in LVZs, whereas in non-LVZs a substantial decrease in CV was only seen between PIs 300-250 ms (0.59 +/- 0.09 m/s; P <.001). Rate-dependent CV slowing sites measurements, defined as exhibiting CV reduction >=20% more than the mean CV reduction seen between PIs 600-250 ms for that voltage zone, were predominantly in LVZs (0.2-0.5 mV; 75.6% +/- 15.5%; P <.001). Confirmed rotational drivers were mapped to these sites in 94.1% of cases (sensitivity 94.1%, 95% CI 71.3%-99.9%; specificity 77.9%, 95% CI 74.9%-80.7%). CONCLUSION: CV dynamics are determined largely by the extent of remodeling. Rate dependent CV slowing sites are predominantly confined to LVZs (0.2-0.5 mV), and the resultant CV heterogeneity may promote driver formation in AF. PMID- 30026015 TI - Cryoballoon or contact force-guided radiofrequency catheter ablation for persistent atrial fibrillation: Different strategies with similar results. PMID- 30026016 TI - Effect of bipolar electrode orientation on local electrogram properties. AB - BACKGROUND: The direct effect of bipolar orientation on electrograms (EGMs) remains unknown. OBJECTIVE: The purpose of this study was to examine the variation of EGMs with diagonally orthogonal bipoles. METHODS: The HD-32 Grid catheter (Abbott, Minneapolis, MN) can assess the effect of bipolar orientation while keeping the interelectrode distance and center unchanged. Seven sheep with anterior myocardial infarction were analyzed using diagonally orthogonal electrode pairs across splines by comparing local EGMs from each pair of opposing electrodes {eg. A1-B3 (southeast direction [SE]) vs A3-B1 (northeast direction [NE])}. RESULTS: A total of 4084 EGMs (1 in each direction) were analyzed for 2042 sites (544 in the infarcted area, 488 in the border area, and 1010 in the normal area). The higher and lower voltages measured using each pair of opposing electrodes significantly differed (1.10 mV [0.43-2.56 mV] vs 0.69 mV [0.28-1.58 mV]; P < .0001), and the median variation was 0.28 mV (0.11-0.80 mV) (31.7% [16.0%-48.9%]). The voltage variation was maximized to 48.7% (37.7%-61.6%) (P < .0001) on sites where the activation wavefront was perpendicular to the one bipolar direction and parallel to the other. A total of 594 of 719 (82.6%) sites with the voltage <0.5 mV and 539 of 699 (77.1%) sites with the voltage >1.5 mV in NE stayed in the same voltage range as those in SE. However, only 348 of 624 (55.8%) sites with the voltage 0.5-1.5 mV in NE stayed in the same range as those in SE. Local ventricular abnormal activities (LAVAs) were detected in 592 of 2042 (29.0%) sites in total, frequently distributed in the border area. A total of 177 (29.9%) LAVAs were missed in one direction and 180 (30.4%) in the other. When 415 (70.1%) LAVAs detected in NE are defined as the reference, 235 of 415 (56.6%) matched with those detected in SE. CONCLUSION: The bipolar voltage and distribution of LAVAs may differ significantly between diagonally orthogonal bipolar pairs at any given site. PMID- 30026018 TI - Annotation resource of tandem repeat-containing secretory proteins in sixty fungi. AB - Fungal secretory proteins that interact with host plants are regarded as effectors. Because fungal effectors rarely contain conserved sequence features, identification and annotation of fungal effectors from predicted secretory proteins are difficult using outward comparison methods such as BLAST or hidden Markov model. In desire of more sequence features to prioritize research interests of fungal secretory proteins, this study developed a pipeline to identify tandem repeat (TR) domain within putative secretory proteins and tested a hypothesis that at least one type of TR domain in non-orthologous secretory proteins has emerged from convergent evolution for plant pathogenicity. There were 2804 types of TR domains and a total of 2925 TR-containing secretory proteins found from 60 fungi. There was no conserved type of TR domain shared only by plant pathogens, indicating functional divergence for different types of TR domain and TR-containing secretory proteins. The annotation resource of putative fungal TR-containing secretory proteins provides new sequence features that will be useful for the community interested in fungal effector biology. PMID- 30026017 TI - Increased rates of 25-hydroxy vitamin D testing: Dissecting a modern epidemic. AB - INTRODUCTION: Laboratories have noted marked increases in the analysis of 25 hydroxy vitamin D (25(OH)D) in recent decades. Our objectives were to describe the annual number of 25(OH)D tests, examine the characteristics of those tested and those ordering them, and determine the proportion of potentially unnecessary tests in Manitoba. METHODS: Manitoba residents who were tested between 2006/7 and 2012/13 had their data anonymously linked to Manitoba Centre for Health Policy comprehensive administrative datasets. Patient and physician characteristics, location of residence, and 25(OH)D concentrations were determined. Descriptive statistics and multivariable regression models were utilized. RESULTS: There was a quadrupling in testing from 2006 to 2013, with >20,000 tests performed in 2012/13. The median annual number of tests was one per patient; the maximum was >10 tests per year. Adult females had twice the number of tests compared to males (p < 0.001). There was a rise in 25(OH)D concentrations over time with hypervitaminosis D increasing disproportionately (2006/7 to 212/13 (0% vs. 0.15%, p < 0.001)). Apparently unnecessary testing rose by 1/3 over time, frequently ordered by Family Medicine practitioners. A revised 25(OH)D requisition resulted in striking reduction of 25(OH)D requests (~80%). DISCUSSION: Manitoba noted a rapid increase in testing, and rise in 25(OH)D concentrations with levels that may be associated with toxicities; both have been reported in other jurisdictions. There appeared to a striking rise in 'unnecessary' tests. We similarly report the benefit of the implementation of a mandatory requisition specifying eligibility criteria for 25(OH)D and education about appropriate testing. PMID- 30026019 TI - Result of A1 pulley reconstruction after closed rupture of the thumb pulleys during childbirth. AB - Closed rupture of the thumb flexor tendon pulleys is rare. Although anatomical and biomechanical studies have exposed the roles played by the pulleys in flexor pollicis longus (FPL) function, no standardized surgical management has yet been defined, in contrast to situations where pulley reconstruction is required in the fingers. We describe a case of rupture of the three pulleys in the thumb that probably occurred after violent thumb grasp during childbirth in the absence of any other trauma. We reconstructed the A1 pulley only using an extensor retinaculum graft because no remnants of the native pulleys were present. PMID- 30026020 TI - Melatonin synthesis and clock gene regulation in the pineal organ of teleost fish compared to mammals: Similarities and differences. AB - The pineal organ of all vertebrates synthesizes and secretes melatonin in a rhythmic manner due to the circadian rhythm in the activity of arylalkylamine N acetyltransferase (AANAT) - the rate-limiting enzyme in melatonin synthesis pathway. Nighttime increase in AANAT activity and melatonin synthesis depends on increased expression of aanat gene (a clock-controlled gene) and/or post translation modification of AANAT protein. In mammalian and avian species, only one aanat gene is expressed. However, three aanat genes (aanat1a, aanat1b, and aanat2) are reported in fish species. While aanat1a and aanat1b genes are expressed in the fish retina, the nervous system and other peripheral tissues, aanat2 gene is expressed exclusively in the fish pineal organ. Clock genes form molecular components of the clockwork, which regulates clock-controlled genes like aanat gene. All core clock genes (i.e., clock, bmal1, per1, per2, per3, cry1 and cry2) and aanat2 gene (a clock-controlled gene) are expressed in the pineal organ of several fish species. There is a large body of information on regulation of clock genes, aanat gene and melatonin synthesis in the mammalian pineal gland. However, the information available on clock genes, aanat genes and melatonin synthesis in photoreceptive pineal organ of teleosts is fragmentary and not well documented. Therefore, we have reviewed published information on rhythmic expression of clock genes, aanat genes as well as synthesis of melatonin, and their regulation by photoperiod and temperature in teleostean pineal organ as compared to mammalian pineal gland. A critical analysis of the literature suggests that in contrast to the mammalian pineal gland, the pineal organ of teleosts (except salmonids) possesses a well developed indigenous clock composed of clock genes for regulation of rhythmic expression of aanat2 gene and melatonin synthesis. Further, the fish pineal organ also possesses essential molecular components for responding to light and temperature directly. The fish pineal organ seems to act as a potential master biological clock in most of the teleosts. PMID- 30026021 TI - Assessing puberty in ex situ male cheetahs (Acinonyx jubatus) via fecal hormone metabolites and body weights. AB - Cheetahs are one of the most heavily studied felid species, with numerous publications on health, disease, and reproductive physiology produced over the last 30 years. Despite this relatively long history of research, there is a paucity of crucial biological data, such as pubertal onset, which has direct and significant applications to improved management of ex situ cheetah populations. This study aimed to determine age of pubertal onset in ex situ male cheetahs using non-invasive fecal steroid hormone monitoring and body weights. Fecal samples from 12 male cheetahs from four institutions were collected 2-3 times weekly from 1 to 42 months of age. Fecal androgen and glucocorticoid metabolites were analyzed using enzyme immunoassays previously validated for use with cheetah feces. Animal body weights were recorded monthly. Fecal hormone and body weight data were analyzed using generalized linear mixed models. Androgen concentrations exhibited an increase to levels similar to those observed in adult males by 18-24 months of age, and males attained adult body weights by 21 months of age. Based on these weight data and the initial increase in androgens toward adult concentrations, males were considered pubertal from 18 to 24 months of age. Glucocorticoid concentrations and amplitude of concentration over baseline were also increased during this period. Knowledge about the physiological changes associated with puberty is useful for management and improving reproductive success of cheetah populations under human care, particularly for determining timing of litter separation from dam, littermate dispersal and when to introduce potential breeding pairs. PMID- 30026022 TI - The endocannabinoid system in mental disorders: Evidence from human brain studies. AB - Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CB1 receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders. PMID- 30026023 TI - Differential effects of apoE and apoJ mimetic peptides on the action of an anti Abeta scFv in 3xTg-AD mice. AB - Anti-Abeta immunotherapy has emerged as a promising approach to treat Alzheimer's disease (AD). The single-chain variable fragment scFv-h3D6 is an anti-Abeta antibody fragment that lacks the Fc region, which is associated with the induction of microglial reactivity by the full-length monoclonal antibody bapineuzumab. ScFv-h3D6 was previously shown to restore the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ) in a triple-transgenic-AD (3xTg-AD) mouse model. Since apoE and apoJ play an important role in the development of AD, we aimed to study the in vivo effect of the combined therapy of scFv-h3D6 with apoE and apoJ mimetic peptides (MPs). Four-and-a-half-month-old 3xTg-AD mice were treated for six weeks with scFv-h3D6, apoE-MP, apoJ-MP, or a combination of scFv-h3D6 with each of the MPs, or a vehicle, and then the results were compared to non-transgenic mice. Magnetic Resonance Imaging showed a general tendency of the different treatments to protect against the reduction in brain volume. Abeta burden decreased after treatment with scFv-h3D6, apoE-MP, or apoJ MP, but the effect was not as evident with the combined therapies. In terms of glial reactivity, apoE-MP showed a potent anti-inflammatory effect that was eased by the presence of scFv-h3D6, whereas the combination of apoJ-MP and scFv-h3D6 was not detrimental. ScFv-h3D6 alone did not induce microglial reactivity, as full-length antibodies do; rather, it reduced it. Endogenous apoE and apoJ levels were decreased by scFv-h3D6, but the MPs lead to a simultaneous increase of both apolipoproteins. While apoE-MP and apoJ-MP demonstrated different effects in the combined therapies with scFv-h3D6, they did not improve the overall protective effect of scFv-h3D6 in reducing the Abeta burden, apolipoproteins levels or microglial reactivity. PMID- 30026024 TI - Assessment of insecticide resistance in primary dengue vector, Aedes aegypti (Linn.) from Northern Districts of West Bengal, India. AB - Aedes mosquitoes are the major vectors transmitting several arboviral diseases such as dengue, zika and chikungunya worldwide. Northern districts of West Bengal is home to several epidemics vectored by mosquito including dengue infections, proper control of which depends on efficient vector control. However the onset of insecticide resistance has resulted in failure of vector control approaches. This study was carried out to unveil the level of insecticide resistance prevailing among the primary dengue vector in this dengue endemic region of India. It was observed that, field caught populations of Ae. aegypti were moderately to severely resistant to majority of the insecticide classes tested, i.e. Organochlorine (DDT), Organophosphates (temephos, malathion), Synthetic Pyrethroids (deltamethrin, lambdacyhalothrin and permethrin) and carbamate (propoxur). In majority of the populations, metabolic detoxification seemed to play the underlying role behind the development of insecticide resistance. This study seems to be the first report revealing the pattern of insecticide resistance in Ae. aegypti from Northern West Bengal. Efficient disease management in this region can only be achieved through proper insecticide resistance management. This study may help the concerned authorities in the formulation of an effective vector control strategy throughout this region incorporating the knowledge gained through this study. PMID- 30026026 TI - Association of ibuprofen at the polar/apolar interface of lipid membranes. AB - Ibuprofen is a non-steroidal anti-inflammatory drug widely used to treat inflammatory diseases, and for its analgesic and antipyretic activity. Although operating as a protein inhibitor, it is also known to interact with lipid membranes. We combined calorimetry, electron spin resonance, attenuated total reflectance-Fourier transform infrared and molecular docking to characterize the interaction of ibuprofen with dimyristyolphosphatidylcholine (DMPC) bilayers, as a function of temperature and drug concentration. At increasing concentration, ibuprofen first perturbs and then suppresses the DMPC pre-transition, stabilizes the fluid state, and favours gel-fluid phase coexistence. The drug decreases the molecular packing of the polar heads and of the first methylene segments of lipid membranes in the gel phase, whereas it leaves unperturbed the chain flexibility in the liquid-crystalline phase. The action of ibuprofen also leads to a higher degree of hydration of the bilayer polar heads and favours hydrogen bond formation with solvent molecules. The overall results reveal that ibuprofen affects a number of key molecular properties of DMPC bilayers by binding through non-specific interactions at the polar/apolar interface. PMID- 30026025 TI - Diversity of structures, catalytic mechanisms and processes of cofactor biosynthesis of tryptophylquinone-bearing enzymes. AB - Tryptophyquinone-bearing enzymes contain protein-derived cofactors formed by posttranslational modifications of Trp residues. Tryptophan tryptophylquinone (TTQ) is comprised of a di-oxygenated Trp residue, which is cross-linked to another Trp residue. Cysteine tryptophylquinone (CTQ) is comprised of a di oxygenated Trp residue, which is cross-linked to a Cys residue. Despite the similarity of these cofactors, it has become evident in recent years that the overall structures of the enzymes that possess these cofactors vary, and that the gene clusters that encode the enzymes are quite diverse. While it had been long assumed that all tryptophylquinone enzymes were dehydrogenases, recently discovered classes of these enzymes are oxidases. A common feature of enzymes that have these cofactors is that the posttranslational modifications that form the mature cofactors are catalyzed by a modifying enzyme. However, it is now clear that modifying enzymes are different for different tryptophylquinone enzymes. For methylamine dehydrogenase a di-heme enzyme, MauG, is needed to catalyze TTQ biosynthesis. However, no gene similar to mauG is present in the gene clusters that encode the other enzymes, and the recently characterized family of CTQ-dependent oxidases, termed LodA-like proteins, require a flavoenzyme for cofactor biosynthesis. PMID- 30026027 TI - Cold atmospheric-pressure nitrogen plasma induces the production of reactive nitrogen species and cell death by increasing intracellular calcium in HEK293T cells. AB - Cold atmospheric-pressure plasma (CAP) has been emerging as a promising tool for cancer therapy in recent times. In this study, we used a CAP device with nitrogen gas (N2CAP) and investigated the effect of the N2CAP on the viability of cultured cells. Moreover, we investigated whether N2CAP-produced hydrogen peroxide (H2O2) in the medium is involved in N2CAP-induced cell death. Here, we found that the N2CAP irradiation inhibited cell proliferation in the human embryonic kidney cell line HEK293T and that the N2CAP induced cell death in an irradiation time- and distance-dependent manner. Furthermore, the N2CAP and H2O2 increased intracellular calcium levels and induced caspase-3/7 activation in HEK293T cells. The N2CAP irradiation induced a time-dependent production of H2O2 and nitrite/nitrate in PBS or culture medium. However, the amount of H2O2 in the solution after N2CAP irradiation was too low to induce cell death. Interestingly, carboxy-PTIO, a nitric oxide scavenger, or BAPTA-AM, a cell-permeable calcium chelator, inhibited N2CAP-induced morphological change and cell death. These results suggest that the production of reactive nitrogen species and the increase in intracellular calcium were involved in the N2CAP-induced cell death. PMID- 30026028 TI - Therapeutic Role of Sphingosine-1-Phosphate Receptor 2 in the Progression of Esophageal Adenocarcinoma. AB - This commentary highlights the article by Liu et al that provides novel mechanistic insights in how conjugated bile acids promote invasive growth of esophageal adenocarcinoma. PMID- 30026029 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 30026030 TI - Oocyte-specific deletion of Gsalpha induces oxidative stress and deteriorates oocyte quality in mice. AB - The stimulatory heterotrimeric Gs protein alpha subunit (Gsalpha) is a ubiquitous guanine nucleotide-binding protein that regulates the intracellular cAMP signaling pathway and consequently participates in a wide range of biological events. In the reproductive system, despite Gsalpha being associated with oocyte meiotic arrest in vitro, the exact role of Gsalpha in female fertility in vivo remains largely unknown. Here, we generated oocyte-specific Gsalpha knockout mice by using the Cre/LoxP system. We observed that the deletion of Gsalpha caused complete female infertility. Exclusion of post-implantation abnormalities, oogenesis, fertilization, and early embryo development was subsequently monitored; meiosis in Gsalpha-deficient oocytes precociously resumed in only 43% of antral follicles from mutant mice, indicating that alteration of meiotic pause was not the key factor in infertility. Ovulation process and number were normal, but the rate of morphological abnormal oocytes was apparently increased; spindle organization, fertilization, and early embryo development were impaired. Furthermore, the level of ROS (reactive oxygen species) and the mitochondrial aggregation increased, and antioxidant glutathione (GSH) content, ATP level, mtDNA copy number, and mitochondrial membrane potential decreased in Gsalpha deficient oocytes. GV oocytes from mutant mice showed early-stage apoptosis. Meanwhile, the Gsalpha knockout-induced decline in oocyte quality and low developmental potential was partially rescued by antioxidant supplementation. To sum up, our results are the first to reveal that the profile of Gsalpha oocyte specific deletion caused female infertility in vivo, and oxidative stress plays an important role in this event. PMID- 30026031 TI - Role of alpha-Dystrobrevin in the differentiation process of HL-60 cells. AB - The alpha-Dystrobrevin gene encodes at least five different protein isoforms, expressed in diverse tissues. The alpha-Dystrobrevin-1 isoform (alpha-Db-1) is a member of the cytoplasmic dystrophin-associated protein complex, which has a C terminal extension comprising at least three tyrosine residues susceptible to phosphorylation in vivo. We previously described alpha-Db in stem-progenitor cells and blood neutrophils as playing a scaffolding role and, in association with kinesin and microtubules, alpha-Db promotes platelet-granule trafficking. Additionally, the microtubules must establish a balanced interaction with the lamina A/C network for appropriate nuclear morphology. Considering that the most outstanding feature during neutrophil differentiation is nuclei lobulation, we hypothesized that alpha-Db might possess a pivotal function during the neutrophil differentiation process. Western Blot (WB) and confocal microscope assays evidenced a differential pattern expression and a subcellular redistribution of alpha-Db in neutrophils derived from HL-60 cells. At the end of the differentiation process, we detected an important diminution in the expression of tubulin, kinesin, and alpha-Db-1. Knockdown of alpha-Db prevented nuclei lobulation, increased Lamin A/C and syne1 expression and augmented the roughness of derived neutrophil membrane and disturbed filopodia assembly. Our results suggest that HL-60 cells undergo extensive cytoskeletal reorganization including alpha-Db in order to possess lobulated nuclei when they further differentiate into neutrophils. PMID- 30026032 TI - Prevalence of middle ear abnormalities from otitis media in relation with pneumococcal vaccine use in the Inuit population of Nunavik, province of Quebec, Canada. AB - BACKGROUND: Otitis media (OM) constitutes an important public health problem in the Inuit population of Nunavik, Northern Quebec. One of the objectives of the childhood pneumococcal vaccination program is to reduce OM burden. The program was implemented in 2002, and 7-, 10-, and 13-valent conjugate vaccines were used sequentially, with doses offered at 2, 4, 6 and 12-18 months, respectively. OBJECTIVE: To assess the prevalence of middle ear abnormalities at age 5 years in relation with exposure to different pneumococcal conjugate vaccines. METHODS: Immunization cards and audiology screening tests at age 5 years of children born in 1994-2010 were reviewed. Children were classified according to the vaccine schedule recommended for their birth cohort or to the vaccines they actually received. Log-linked binomial regression models were used to assess the relative abnormalities risk according to different vaccination schedules. RESULTS: Among 3517 children with complete documentation, the prevalences of minor and major abnormalities were 29% and 18%, respectively. Minor abnormalities frequency was higher in unvaccinated children (34%) and lower in children vaccinated with PCV7 (22%), PCV7 + PCV10 (17%), PCV10 (15%) and PCV10 + PCV13 (18%). No substantial differences among vaccine schedules were observed for major abnormalities. CONCLUSIONS: Pneumococcal conjugate vaccination was associated with a decreased frequency of middle ear abnormalities although no effect was seen for major abnormalities which may be trigger by OM with early onset. Clinicaltrials.gov registration number: NCT01694329. PMID- 30026033 TI - Vaccination status of children aged 1-4 years in Afghanistan and associated factors, 2015. AB - BACKGROUND: Childhood mortality in Afghanistan fell by half between 1990 and 2015, due in part to the government's commitment to improving pediatric immunization services. Although progress has been made, immunization coverage has nonetheless remained low with only 65% of children receiving the third dose of Diphtheria-Pertussis-Tetanus (DPT3) based on WHO estimates. This study aims to calculate the proportion of Afghan children aged 1-4 years who were fully vaccinated, under-vaccinated, or non-vaccinated with government-recommended Expanded Program on Immunization vaccines and identify predictors related to the family's sociodemographic status and maternal autonomy. METHODS: Data from the 2015 Afghanistan Demographic and Health Survey was used to calculate the proportion of children who were fully vaccinated (i.e. received all recommended vaccines), under-vaccinated (i.e. received some, but not all), and non-vaccinated (i.e. did not receive any vaccines) according to WHO guidelines. A multivariable multinomial logistic regression model generated odds ratios for under-vaccination and non-vaccination versus full vaccination, and examined associations between independent factors and full vaccination status. RESULTS: We found 40.6% of Afghan children age 1-4 were fully vaccinated, 42.4% under-vaccinated, and 17% non-vaccinated. Large disparities characterized immunization coverage among provinces and between urban and rural regions. Birthing in a government institution (vs. non-institutional setting), a higher number of antenatal care visits, and a visit to a health facility in the past 12 months were all associated with increased odds of full immunization. Factors related to maternal autonomy including maternal decision-making and maternal attitudes towards beating were also significantly associated with vaccination status. CONCLUSION: Approximately 60% of children in Afghanistan are under-vaccinated or non vaccinated, leaving millions of children unnecessarily at risk for vaccine preventable diseases. Engagement with community and religious leaders to create programs that increase women's autonomy and expand access to institutional delivery could lead to downstream increases in childhood vaccination coverage. PMID- 30026035 TI - Inhibition of astrocytic adenosine receptor A2A attenuates microglial activation in a mouse model of Sandhoff disease. AB - Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces beta-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb-/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb-/- mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A2A receptor in the cerebral cortices of Hexb-/- mice at the later inflammatory phase. In cultured astrocytes, expression of A2A receptor could be induced by astrocyte defined medium, and then the activation of the A2A receptor induced ccl2 expression. In Hexb-/- mice, inhibition of the A2A receptor antagonized by istradefylline decreased the number of activated microglial cells and inflammatory cytokines/chemokines at 13 weeks. Thus, the astrocytic A2A receptor is an important sensor that regulates microglial activation in the late phase of inflammation. PMID- 30026034 TI - Cerium oxide nanoparticles as potential antibiotic adjuvant. Effects of CeO2 nanoparticles on bacterial outer membrane permeability. AB - BACKGROUND: Therapeutic options against Multi Drug Resistant (MDR) pathogens are limited and the overall strategy would be the development of adjuvants able to enhance the activity of therapeutically available antibiotics. Non-specific outer membrane permeabilizer, like metal-oxide nanoparticles, can be used to increase the activity of antibiotics in drug-resistant pathogens. The study aims to investigate the effect of cerium oxide nanoparticles (CeO2 NPs) on bacterial outer membrane permeability and their application in increasing the antibacterial activity of antibiotics against MDR pathogens. METHODS: The ability of CeO2 NPs to permeabilize Gram-negative bacterial outer membrane was investigated by calcein-loaded liposomes. The extent of the damage was evaluated using lipid vesicles loaded with FITC-dextran probes. The effect on bacterial outer membrane was evaluated by measuring the coefficient of permeability at increasing concentrations of CeO2 NPs. The interaction between CeO2 NPs and beta-lactams was evaluated by chequerboard assay against a Klebsiella pneumoniae clinical isolate expressing high levels of resistance against those antibiotics. RESULTS: Calcein leakage increases as NPs concentrations increase while no leakage was observed in FITC-dextran loaded liposomes. In Escherichia coli the outer membrane permeability coefficient increases in presence of CeO2 NPs. The antibacterial activity of beta-lactam antibiotics against K. pneumoniae was enhanced when combined with NPs. CONCLUSIONS: CeO2 NPs increases the effectiveness of antimicrobials which activity is compromised by drug resistance mechanisms. The synergistic effect is the result of the interaction of NPs with the bacterial outer membrane. The low toxicity of CeO2 NPs makes them attractive as antibiotic adjuvants against MDR pathogens. PMID- 30026036 TI - Deep brain stimulation does not enhance neuroinflammation in multiple system atrophy. AB - Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of alpha-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of alpha-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression. PMID- 30026037 TI - The clinical significance of PINX1 expression in papillary thyroid carcinoma. AB - PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) is a telomerase inhibitor located on human chromosome 8p23 and also acts as a tumor suppressor in several types of cancers, including breast, gastric, ovarian, and bladder cancer. However, the role of PINX1 expression in papillary thyroid carcinoma (PTC) has not been defined. Therefore, we investigated the role of PINX1 expression in PTC by analyzing the correlation between PINX1 expression and various clinicopathological factors. Immunohistochemistry for PINX1 was performed using a tissue microarray of samples taken from the 160 patients with PTC. We also assessed mRNA and protein expression for PINX1 via quantitative real-time polymerase chain reaction and immunohistochemical analysis. Positive staining for PINX1 was found in 16.3% of PTC cases. PINX1 expression was significantly associated with tumor size, lymph node metastasis, telomerase reverse transcriptase, promoter mutation and recurrence. PINX1 mRNA expression was more pronounced in the recurrent group than in the nonrecurrent group. In addition, results of the binary logistic regression model showed that PINX1 protein expression had a significant influence on recurrence. We concluded that PINX1 expression was associated with several clinicopathological factors and had a significant influence on recurrence in patients with PTC. Therefore, PINX1 expression could be a useful prognostic marker in PTC patients. PMID- 30026038 TI - Outcomes of developmental exposure to total particulate matter from cigarette smoke in zebrafish (Danio rerio). AB - The effects of prenatal exposure to cigarette smoke remain a subject of major interest, especially as it relates to neural development and adverse behavioral outcomes. Several studies have investigated the developmental toxicity of cigarette smoke components in a zebrafish model, showing that developmental exposure to total particulate matter (TPM; particulate phase of cigarette smoke) leads to adverse physiological aberrations and locomotor hyperactivity. Thus, the current study examines whether developmental TPM exposure of zebrafish embryos/larvae (F0) leads to physiological and behavioral alterations, and whether adverse effects are observed in adult fish and the next generation (F1; i.e. F0 offspring). We also examine whether behavioral effects are associated with changes in neural development, stress response, neurotransmitters, and bioenergetics. We demonstrate that TPM exposure during F0 development increased the incidence of deformities in F0 larvae, but F1 larvae did not exhibit any deformities. TPM exposure also resulted in swimming hyperactivity in F0 larvae and several behavioral changes were noted in F0 fish when they grew into adulthood. These behavioral changes were generally not associated with changes in markers of neural development in larvae, stress response in F0 adults, and concentration of neurotransmitters (acetylcholine, dopamine, and serotonin) in F0 adult brain. There were also no changes in F0 or F1 embryonic oxygen consumption rate (OCR; marker of bioenergetics and mitochondrial health); however, the OCR in the brain of F0 males was reduced with TPM. We conclude that developmental exposure to TPM affects larval physiology and induces hyperactive swimming behavior, but these effects do not persist in F1 larvae. Moreover, developmental TPM exposure leads to long-lasting sex-specific behavioral outcomes in the F0 adult fish. PMID- 30026039 TI - Construction of a series of intermediates in the beta-oxidation pathway from THA to EPA via DHA in free acid form. AB - beta-Oxidation of most fatty acids occurs in the mitochondria. However, beta oxidation for omega-3 polyunsaturated fatty acids (PUFAs) is distinct from abundant fatty acids and occurs in the peroxisomes. Since little is known about peroxisomal beta-oxidation, here we report the synthesis of proposed intermediates of omega-3 PUFA beta-oxidation steps in free fatty acid form having a conjugated double bond, a beta-hydroxyl group, a beta-olefin and a beta carbonyl group. These fatty acids can serve as authentic samples for biological experiments. PMID- 30026041 TI - Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition. AB - Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates. PMID- 30026040 TI - Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists. AB - Activation of the nuclear farnesoid X receptor (FXR) which acts as cellular bile acid sensor has been validated as therapeutic strategy to counter liver disorders such as non-alcoholic steatohepatitis by the clinical efficacy of obeticholic acid. FXR antagonism, in contrast, is less well studied and potent small molecule FXR antagonists are rare. Here we report the systematic optimization of a novel class of FXR antagonists towards low nanomolar potency. The most optimized compound antagonizes baseline and agonist induced FXR activity in a full length FXR reporter gene assay and represses intrinsic expression of FXR regulated genes in hepatoma cells. With this activity and a favorable toxicity-, stability- and selectivity-profile it appears suitable to further study FXR antagonism in vitro and in vivo. PMID- 30026042 TI - Structure-guided engineering of TGF-betas for the development of novel inhibitors and probing mechanism. AB - The increasing availability of detailed structural information on many biological systems provides an avenue for manipulation of these structures, either for probing mechanism or for developing novel therapeutic agents for treating disease. This has been accompanied by the advent of several powerful new methods, such as the ability to incorporate non-natural amino acids or perform fragment screening, increasing the capacity to leverage this new structural information to aid in these pursuits. The abundance of structural information also provides new opportunities for protein engineering, which may become more and more relevant as treatment of diseases using gene therapy approaches become increasingly common. This is illustrated by example with the TGF-beta family of proteins, for which there is ample structural information, yet no approved inhibitors for treating diseases, such as cancer and fibrosis that are promoted by excessive TGF-beta signaling. The results presented demonstrate that through several relatively simple modifications, primarily involving the removal of an alpha-helix and replacement of it with a flexible loop, it is possible to alter TGF-betas from being potent signaling proteins into inhibitors of TGF-beta signaling. The engineered TGF-betas have improved specificity relative to kinase inhibitors and a much smaller size compared to monoclonal antibodies, and thus may prove successful as either as an injected therapeutic or as a gene therapy-based therapeutic, where other classes of inhibitors have failed. PMID- 30026043 TI - Copeptin and Estimated Insulin Sensitivity in Adults With and Without Type 1 Diabetes: The CACTI Study. AB - OBJECTIVES: Copeptin, a surrogate marker for vasopressin, is elevated in participants with insulin resistance (IR) and type 2 diabetes. Whereas adults with type 1 diabetes also demonstrate elevated copeptin concentrations and IR compared to controls without diabetes, the relationship between copeptin and IR in type 1 diabetes is unclear. METHODS: Participants with (n=209) and without (n=244) type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, vitals, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, glycated hemoglobin and lipid panels. Estimated insulin sensitivity (eIS) was calculated by validated equations in participants with and without type 1 diabetes. The relationships among copeptin, IR, waist circumference (WC) and body mass index (BMI) were examined with unadjusted and adjusted linear regression models. RESULTS: Copeptin was correlated with eIS (R=-0.17, R2=0.029), WC (R=0.16, R2=0.026) and BMI (R=0.22, R2=0.048) for type 1 diabetes and with eIS (R=-0.37, R2=0.14), WC (R=0.40, R2=0.16) and BMI (R=0.25, R2=0.063) in non-type 1 diabetes. In multivariable analysis, copeptin correlated with total cholesterol (beta+/-SE: 0.12+/-0.04, p=0.008) and low-density lipoprotein (beta+/-SE: -0.11+/-0.04, p=0.01) in type 1 diabetes. In non-type 1 diabetes, copeptin was associated with WC (beta+/-SE: 0.14+/-0.04, p=0.0024), BMI (beta+/-SE: 0.13+/-0.04, p=0.007) and eIS (beta+/-SE: -0.14+/-0.04, p=0.0013). CONCLUSIONS: Copeptin does not correlate with markers of IR in type 1 diabetes but strongly correlates in non-type 1 diabetes. Thus, elevated vasopressin activity and IR appear to be independent risk factors for vascular complications in type 1 diabetes. PMID- 30026044 TI - Association Between Elevated C-Reactive Protein Levels and Prediabetes in Adults, Particularly Impaired Glucose Tolerance. AB - OBJECTIVES: Prediabetes is a precursor of diabetes and increases the risk for cardiovascular disease. A high C-reactive protein (CRP) level is a risk factor for diabetes, and individuals with prediabetes have higher CRP levels than those with normal glucose tolerance. In addition, systemic inflammation may play a role in the early-phase deterioration of glucose metabolism. We examined the association between serum CRP levels and prediabetes. METHODS: Overall, 4,101 subjects without diabetes underwent oral glucose tolerance tests. Levels of serum CRP were divided into quartiles; the lowest quartile was used as the reference when calculating odds ratios (ORs) and confidence intervals. Isolated fasting glucose, isolated glucose tolerance and elevated glycated hemoglobin levels (i.e. between 42 and 47 mmol/mol [6.0% to 6.4%]) were indicative of prediabetes. RESULTS: In the multiple logistic regression analysis, the ORs (95% confidence intervals) for impaired glucose tolerance, impaired fasting glucose and elevated glycated hemoglobin levels corresponding to the highest quartile of CRP levels were 1.67 (1.31 to 2.14); 1.62 (1.15 to 2.28); and 1.47 (1.14 to 1.90), respectively. In the stratified analysis, the ORs for impaired glucose tolerance were consistently higher in the uppermost quartile than in the reference quartile in both the presence and absence of hypertension or dyslipidemia. In contrast, the ORs for impaired fasting glucose in the uppermost quartile were higher only in the presence of hypertension and dyslipidemia, and the OR for elevated glycated hemoglobin levels in the uppermost quartile was higher only in the presence of hypertension. CONCLUSIONS: Elevated serum CRP levels are associated with prediabetes, particularly impaired glucose tolerance. PMID- 30026045 TI - Perceptions by Adult Patients with Type 1 and 2 Diabetes of Current and Advanced Technologies of Blood Glucose Monitoring: A Prospective Study. AB - OBJECTIVE: Intensive self-monitoring of blood glucose levels by patients with diabetes achieves optimal glucose control, hence reducing the likelihood of complications. METHODS: This is a prospective, cross-sectional study targeting adults with diabetes through community pharmacies and patient groups in Central and West London over a period of 10 weeks. RESULTS: In all, 195 adults with diabetes were included in the analysis of the results. When monitoring adherence was examined, 43.4% (n=33/76) of participants with type 1 diabetes reported that their health care professionals had asked them to monitor their blood glucose levels between 3 and 4 times per day; however, 10% of this group was not following their health-care professionals' directions. Participants with type 2 diabetes were asked the same question; 42.9% (n=51/119) were asked to monitor their blood glucose between 3 and 4 times a day, but only 2.5% (n=3/119) were following their health-care professionals' directions. When questioned about their reasons for poor adherence, the cohort indicated that it was due to the painful (29.2%, n=57/195), uncomfortable (33.8%, n=66/195) or inconvenient (36.9%, n=72/195) nature of testing. In addition, 75.3% (n=147/195) of the participants expressed their desire for a noninvasive monitoring device, and 74.3% (n=145/195) said they would be satisfied to use one of the preselected advanced technologies to monitor their blood glucose levels. CONCLUSIONS: The favoured advanced technology, selected by 49.7% (n=97/195) of participants, was the wristband. Statistical significance was seen between the type of diabetes and the device selected; patients with type 1 diabetes preferred contact lenses (p<0.05) and tattoos (p<0.0001), whereas participants with type 2 diabetes preferred earlobe sensors (p<0.0001) and saliva analyzers (p<0.0001). Participants' gender, age and ethnicity also influenced device selection. PMID- 30026046 TI - Population-Level Outcomes With a 2-Step Approach for Gestational Diabetes Screening and Diagnosis: Response to the Letter to the Editor From Dr. Kong. PMID- 30026047 TI - Assessing the Levels of L-Carnitine and Total Antioxidant Capacity in Adults With Newly Diagnosed and Long-Standing Type 2 Diabetes. AB - OBJECTIVES: This study is essentially a correlative study that examines the potential of reduced levels of L-carnitine (LC) when combined with the pathophysiology of type 2 diabetes. The aim of the study was to assess the levels of LC, total antioxidant capacity (TAOC), fasting blood sugar (FBS), triglycerides and cholesterol in people with newly diagnosed and long-standing type 2 diabetes and in healthy controls. METHODS: The study was done in 90 adult subjects, including 30 with newly diagnosed diabetes, 30 with long-standing type 2 diabetes and 30 healthy controls. Plasma samples were used to assay the biochemical parameters. RESULTS: In this study, both groups (newly diagnosed and long-standing type 2 diabetes) were significantly different in baseline characteristics, such as age, height, weight, body mass index, FBS, cholesterol and triglycerides, compared to the healthy controls. Plasma LC levels in patients with newly diagnosed and long-standing type 2 diabetes were significantly lower than in healthy controls (p<0.001). Also, the mean plasma TAOC level in the patients with newly diagnosed and long-standing type 2 diabetes was slightly lower than in the healthy controls. Nevertheless, TAOC levels were not significantly different across all the groups (p=0.87). The plasma LC levels were significantly positive when compared to the plasma TAOC levels (r=0.516), which means that an increase in LC levels is associated with an increase in TAOC levels. However, a negative correlation was observed between LC levels and FBS (r=-0.387), triglycerides (-0.159) and body mass indexes (r=-0.068). This means that a decrease in LC levels is associated with increases in FBS, triglyceride and body mass index levels. CONCLUSIONS: According to the effects of reduced LC levels on the metabolic profiles of patients with long-standing type 2 diabetes, setting the LC content value to prevent diabetes through the use of effective drugs or nutrition containing LC can be useful in managing diabetes. PMID- 30026048 TI - Improving Glycemic Control in Adults and Children With Type 1 Diabetes With the Use of Smartphone-Based Mobile Applications: A Systematic Review. AB - OBJECTIVES: Management of type 1 diabetes is often challenging. Smartphone mobile applications (apps) may provide additional support and help to improve glycemic control and clinical outcomes. The objectives of this study were to examine the literature evaluating the use of mobile apps (stand-alone and text messaging/feedback) in type 1 diabetes and to review top-rated mobile apps applicable to type 1 diabetes. METHODS: Medline, Cochrane and Embase databases were systematically searched to identify studies published from inception to February 2018. Top-rated relevant apps from Google Play Store and Apple App Store were reviewed in July 2017. RESULTS: The literature search yielded 3,462 studies. Of these studies, 9 evaluated the stand-alone apps; 3 showed significant improvement in glycated hemoglobin (A1C) levels (0.5%, p<0.05, 0.57%, p<0.05, and 0.58%, p=0.02); 3 demonstrated improved adherence to glucose monitoring; and 1 study demonstrated a reduction in hypoglycemic events (glucose<3.0 mmol/L) in 6 of 10 participants who completed the study. Also, 5 studies evaluated a mobile app plus text-messaging/feedback system. Only 1 showed a significant reduction in severe hypoglycemic events (mobile app+text, IQR 0.33, 95% CI 0.17 to 0.63; vs. control, IQR 2.29, 95% CI 1.80 to 2.91), while another single study demonstrated a reduction in median glycated hemoglobin levels (0.3%; p<0.001). Most top-rated mobile apps logged parameters relevant to diabetes management, and some provided graphic analysis and set reminders. CONCLUSIONS: This study highlights the need for larger and longer studies to explore the efficacy of apps to optimize outcomes in type 1 diabetes, the populations that would benefit most from these tools and the resources needed to support mobile apps plus text messaging/feedback systems. PMID- 30026049 TI - Detecting mental fatigue from eye-tracking data gathered while watching video: Evaluation in younger and older adults. AB - Health monitoring technology in everyday situations is expected to improve quality of life and support aging populations. Mental fatigue among health indicators of individuals has become important due to its association with cognitive performance and health outcomes, especially in older adults. Previous models using eye-tracking measures allow inference of fatigue during cognitive tasks, such as driving, but they require us to engage in specific cognitive tasks. In addition, previous models were mainly tested by user groups that did not include older adults, although age-related changes in eye-tracking measures have been reported especially in older adults. Here, we propose a model to detect mental fatigue of younger and older adults in natural viewing situations. Our model includes two unique aspects: (i) novel feature sets to better capture fatigue in natural-viewing situations and (ii) an automated feature selection method to select a feature subset enabling the model to be robust to the target's age. To test our model, we collected eye-tracking data from younger and older adults as they watched video clips before and after performing cognitive tasks. Our model improved detection accuracy by up to 13.9% compared with a model based on the previous studies, achieving 91.0% accuracy (chance 50%). PMID- 30026050 TI - Individual determinants of emotional eating: A simultaneous investigation. AB - Emotional eating, the tendency to regulate negative mood through unhealthy food intake, has been widely recognized as one source of today's obesity epidemic. However, empirical evidence suggests that this phenomenon is not universal but subject to psychological, situational, and biological determining factors. To date, little is known about the relative importance of these determinants of emotional eating behavior, as no research has investigated these factors simultaneously. This study aims to close this gap and reports the results of a laboratory experiment with 179 participants from a university environment (mean age = 23.15 years, ranging from 17 to 63 years; 56.98% male), in which real food choice was observed after manipulating participants' mood states (either negative or positive) while simultaneously assessing potential determinants of emotional eating. Binary logistic regression analysis revealed that the biological determinants (e.g., weight status) tend to loose in relative importance while psychological (i.e., restrained eating) and situational (i.e., stress) factors tend to be more relevant in explaining food choice in response to a negative affective state. These results have important implications for both research and public health practice. PMID- 30026052 TI - LncRNA-p23154 promotes the invasion-metastasis potential of oral squamous cell carcinoma by regulating Glut1-mediated glycolysis. AB - The dysregulation of glycolysis has been suggested to lead to alteration of cell drug resistance signals, proliferation and metastasis. Emerging evidence indicates that lncRNAs play a key role in the cellular processes of tumor cells, including glycolysis, growth, and movement. However, the role and potential mechanism of lncRNAs in glycolysis-mediated metastasis has not been explored. In this study, we identified a novel lncRNA lnc-p23154 which is associated with OSCC patient metastasis and the promotion of OSCC cell migration and invasion in vitro and in vivo. Furthermore, we found that lnc-p23154 also participates in OSCC glycolysis by facilitating Glut1 expression. Rescue of lnc-p23154 reversed the suppression of OSCC cell migration and invasion induced by Glut1 knockdown. In addition, lnc-p23154 is mainly located in the nucleus and binds to the promoter region of miR-378a-3p, which represses Glut1 expression by targeting to its 3'UTR directly. Therefore, we concluded that lnc-p23154 may play an important role in Glut1-mediated glycolysis by inhibiting miR-378a-3p transcription and accelerate OSCC metastasis. PMID- 30026053 TI - Relevance of the natural HDAC inhibitor sulforaphane as a chemopreventive agent in urologic tumors. AB - Due to an increased understanding of molecular biology and the genomics of cancer, new and potent agents have been approved by the Food and Drug Administration (FDA) to fight this disease. However, all of these drugs cause severe side effects and resistance inevitably develops, re-activating tumor growth and dissemination. For this reason, patients turn to natural compounds as alternative or complementary treatment options, since it has been found that natural plant products may block, inhibit, or reverse cancer development. The present review focusses on the role of the natural compound sulforaphane (SFN) as an anti-tumor agent in urologic cancer. SFN is a natural compound found in cruciferous vegetables from the Brassicaceae family such as broccoli, cauliflower and cabbage. Several epidemiologic and clinical studies have documented chemopreventive properties of SFN, making it an interesting candidate for additive cancer treatment. SFN shows remarkable anti-tumor effects in vitro and in vivo without exerting toxicity. The review summarizes the current understanding of SFN and provides insights into its molecular mode of action with particular emphasis on epigenetic tumor control. PMID- 30026051 TI - Production, characterization, and epitope mapping of a monoclonal antibody against genotype VII Newcastle disease virus V protein. AB - Newcastle disease virus (NDV) V protein is crucial for viral interferon (IFN) antagonism and virulence, determining its host range restriction. However, little information is available on the B cell epitopes of V protein and the subcellular movement of V protein in the process of NDV infection. In this study, the monoclonal antibody (mAb) clone 3D7 against genotype VII NDV V protein was generated by immunizing mice with a purified recombinant His-tagged carboxyl terminal domain (CTD) region of V protein. Fine epitope mapping analysis and B cell epitope prediction indicated that mAb 3D7 recognized a linear epitope 152RGPAELWK159, which is located in the V protein CTD region. Sequence alignment showed that the mAb clone 3D7-recognized epitope is highly conserved among Class II genotype VII NDV strains, but not among other genotypes, suggesting it could serve as a genetic marker to differentiate NDV genotypes. Furthermore, the movement of V protein during NDV replication in infected cells were determined by using this mAb. It was found that V protein localized around the nucleus during virus replication. The establishment of V protein-specific mAb and identification of its epitope extend our understanding of the antigenic characteristics of V protein and provide a basis for the development of epitope-based diagnostic assays. PMID- 30026055 TI - CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations. AB - Magnesium (Mg2+) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy. The only homozygous mutation reported so far, is responsible for hypomagnesemia associated with a severe neurological phenotype characterized by refractory epilepsy, microcephaly, severe global developmental delay and intellectual disability. Here, we report the second homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy. Thus, we review and discuss the phenotypic spectrum associated with CNNM2 mutations. PMID- 30026054 TI - Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment. AB - Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a 3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk. PMID- 30026056 TI - Prenatal undernutrition attenuates fasting-induced reproductive dysfunction in pre-pubertal male rats. AB - Prenatal undernutrition affects various physiological functions, such as metabolic and reproductive functions, after birth, and such changes are associated with the pathogeneses of certain diseases. It has been hypothesized that these changes are predictive adaptive responses that help individuals to endure similar conditions in the postnatal period. Thus, we evaluated the effects of prenatal undernutrition on the responses of the body weight (BW) regulation system and reproductive functions to fasting in the pre-pubertal period in male rats. Prenatally normally nourished and undernourished rats exhibited similar reductions in BW and visceral fat after 48 h fasting in the pre-pubertal period. Furthermore, these two groups displayed similar fasting-induced patterns of change in their hypothalamic levels of appetite regulatory factors; i.e., neuropeptide Y and pro-opiomelanocortin. These results indicate that prenatal undernutrition had no marked effects on BW regulation in male rats. On the other hand, serum luteinizing hormone and testosterone levels were decreased by 48 h fasting in the prenatally normally nourished rats, whereas the levels of these hormones did not change in the prenatally undernourished rats. However, the hypothalamic mRNA level of kisspeptin 1 (Kiss1), which is a positive regulator of gonadotropin-releasing hormone/gonadotropins, was reduced by fasting in both groups. These results indicate that prenatal undernutrition might attenuate fasting-induced reproductive dysfunction in the postnatal period; however, these changes might not be induced by alterations in the hypothalamic Kiss1 system. Further studies are needed to clarify the mechanisms involved in these changes in reproductive function. PMID- 30026057 TI - Mouse models of maternal immune activation: Mind your caging system! AB - Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools to study neuronal and behavioral dysfunctions in relation to infection-mediated neurodevelopmental disorders. One of the most widely used MIA models is based on gestational administration of poly(I:C) (= polyriboinosinic polyribocytdilic acid), a synthetic analog of double-stranded RNA that induces a cytokine-associated viral-like acute phase response. The effects of poly(I:C) induced MIA on phenotypic changes in the offspring are known to be influenced by various factors, including the precise prenatal timing, genetic background, and immune stimulus intensity. Thus far, however, it has been largely ignored whether differences in the basic type of laboratory housing can similarly affect the outcomes of MIA models. Here, we examined this possibility by comparing the poly(I:C)-based MIA model in two housing systems that are commonly used in preclinical mouse research, namely the open cage (OC) and individually ventilated cage (IVC) systems. Pregnant C57BL6/N mice were kept in OCs or IVCs and treated with a low (1 mg/kg, i.v.) or high (5 mg/kg, i.v.) dose of poly(I:C), or with control vehicle solution. MIA or control treatment was induced on gestation day (GD) 9 or 12, and the resulting offspring were raised and maintained in OCs or IVCs until adulthood for behavioral testing. An additional cohort of dams was used to assess the influence of the different caging systems on poly(I:C)-induced cytokine and stress responses in the maternal plasma. Maternal poly(I:C) administration on GD9 caused a dose-dependent increase in spontaneous abortion in IVCs but not in OCs, whereas MIA in IVC systems during a later gestational time point (GD12) did not affect pregnancy outcomes. Moreover, the precise type of caging system markedly affected maternal cytokines and chemokines at basal states and in response to poly(I:C) and further influenced the maternal levels of the stress hormone, corticosterone. The efficacy of MIA to induce deficits in working memory, social interaction, and sensorimotor gating in the adult offspring was influenced by the different housing conditions, the dosing of poly(I:C), and the precise prenatal timing. Taken together, the present study identifies the basic type of caging system as a novel factor that can confound the outcomes of MIA in mice. Our findings thus urge the need to consider and report the kind of laboratory housing systems used to implement MIA models. Providing this information seems pivotal to yield reproducible results in these models. PMID- 30026058 TI - Two hit induced acute lung injury impairs cognitive function in mice: A potential model to study cross talk between lung and brain. AB - Acute lung injury (ALI), a pulmonary inflammatory disorder, is associated with high morbidity and mortality rates. Interestingly, ALI survivors have been reported for some neurocognitive deterioration at/after discharge. However, the molecular factors behind such extra pulmonary manifestation are not clearly known. The present work was designed to investigate lung-brain cross talk in experimental mice for deciphering primary molecular factors that may be involved in ALI-mediated cognitive impairment. ALI was induced in Balb/c mice by intra tracheal administration of either 0.1 N HCl (2 ml/kg) or LPS (1 mg/kg) as single hits or both agents were administered successively to mimic the 'two hit' model. Interestingly two hit-mediated ALI resulted in exaggerated inflammatory response as reflected by increased pulmonary neutrophils and inflammatory factors (TNF alpha/IL-1beta/IL-6). Additionally, two hits resulted in delayed resolution of lung inflammation and was coupled with persistent decline in memory, as assessed by Morris water maze test. Further, two hits elevate serum levels of TNF-alpha/IL 1beta which was associated with compromised blood brain barrier (BBB), as evident by decreased expression of occludin/claudin-5 and consequent Evans-blue extravasation in hippocampus 1 week post injury. Finally, dexamethasone protects against the two hit mediated cognitive impairment by lowering the pro inflammatory factors (TNF-alpha/IL-1beta) both in lungs and blood. Overall, we report for the first time that 'two hit' mediated ALI cause persistent cognitive impairment in mice partly via up-regulating systemic expression of TNF-alpha/IL 1beta that may disrupt BBB and hence the model may be a useful tool to examine the lung-brain cross-talk at the molecular level for exploring newer therapeutics. PMID- 30026059 TI - A Phase II Clinical Trial of Apatinib in Pretreated Advanced Non-squamous Non small-cell Lung Cancer. AB - OBJECTIVES: Apatinib exhibits broad-spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor-2. This study evaluated the efficacy and safety of apatinib in patients with advanced non-squamous non small-cell lung cancer who were heavily pretreated or not suitable to receive standard second-line chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm phase II clinical trial (ClinicalTrials.govNCT02515435). Patients received 500 or 750 mg apatinib daily until progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was the objective response rate. The secondary endpoints included disease control rate, progression-free survival, overall survival, and side effects. Apatinib administration was allowed beyond disease progression. RESULTS: Between March 2015 and August 2016, 40 patients were enrolled. Among them, 6 (15.0%), 16 (40.0%), and 18 (45.0%) received apatinib as the second-, third-, and fourth-line or beyond treatment, respectively. The mean dosage of apatinib was 477.0 +/- 85.3 mg/day. Thirty-eight patients were available for response evaluation; the objective response rate and disease control rate were 13.2% and 63.2%, respectively. The median progression free survival was 3.06 months (95% confidence interval [CI], 2.20-4.14 months). The median overall survival was 7.69 months (95% CI, 5.36 months to not estimable). The most common treatment-related adverse events were hand-foot-skin reaction (30.0%), proteinuria (27.5%), oral mucositis (22.5%), fatigue (20.0%), and hypertension (17.5%). Nine patients received apatinib after progression, and the median duration of apatinib therapy beyond progression was 5.13 months (95% CI, 4.27-7.82 months). CONCLUSION: Apatinib shows promising efficacy and manageable toxicity in patients with advanced non-squamous non-small-cell lung cancer. Apatinib therapy beyond progression could provide further benefits in specific subpopulations. PMID- 30026060 TI - Global lessons for deinstitutionalisation from the ill-fated transfer of mental health-care users in Gauteng, South Africa. AB - South Africa witnessed a national tragedy between October, 2015, and June, 2016, when the Department of Health in Gauteng province moved 1711 mental health-care users with severe mental illness or severe and profound intellectual disability out of facilities managed by a private company, Life Esidimeni, mainly into the care of non-governmental organisations. The plan was called the Gauteng Mental Health Marathon Project. In a rushed and flawed process, 144 people died, and the whereabouts of another 44 remain unknown. The report of an extensive arbitration process, released in March, 2018, raises important ethical, moral, political, legal, governance, accountability, and clinical issues. The events from the tragedy and findings that were made also serve as lessons for future deinstitutionalisation globally. PMID- 30026061 TI - Neonatal sleep, a genetically-driven rehearsal before the show: an endless encounter with Michel Jouvet. AB - In this short review, I would like to share some personal memories about the insights and achievements of Michel Jouvet in the field of sleep ontogeny. The first time I met Michel Jouvet was in 1972 when he accepted to chair my thesis on sleep, the research work being preformed in Howard Roffwarg's lab in New York. From then on we had many discussions together about the mechanisms and nature of neonatal Paradoxical Sleep, notably its characteristic muscular "twitches". The idea emerged of a genetically programmed pattern of motor activation responsible for this state of "seismic" sleep. Such a pattern would underlie, for example, the facial mimics displayed during sleep in early life, whose function would be to "pre-practice" a specific behavior. Later on, in the 1980's Michel Jouvet had the masterful insight to extend this role of Paradoxical Sleep to the theory of genetic programming for maintaining psychological individualism. Michel Jouvet's scientific curiosity and generosity led to his exceptional accomplishments, and he will remain as an immense figure in the culture of sleep science. PMID- 30026062 TI - Identification of 9-oxo-1,2,3,4,5,6,10,19-octanor-13,17-secoandrost-8(14)-ene 7,17-dioic acid as a metabolite of steroid degradation in Comamonas testosteroni TA441 and the genes involved in the conversion. AB - Comamonas testosteroni TA441 degrades steroid compounds via aromatization of the A-ring to produce 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid (a metabolite with C- and D-rings), which is presumed to be further degraded via beta-oxidation. In elucidating the complete steroid degradation process in C. testosteroni, we isolated 9-oxo-1,2,3,4,5,6,10,19-octanor-13,17-secoandrost-8(14) ene-7,17-dioic acid and several other metabolites containing only C-ring. For conversion of the CoA-ester of this compound, a two-subunit beta -ketoacyl-CoA transferase encoded by ORF1 and ORF2 was shown to be indispensable. ORF1 and ORF2 are located just after tesB, the meta-cleavage enzyme gene in one of the two major steroid degradation gene clusters of strain TA441. Conversion by the CoA transferase leads to cleavage of the remaining C-ring, and the product was suggested to be further degraded by beta-oxidation involving other genes in the cluster. ORF1 and ORF2 are considered orthologues of ipdAB gene in Mycobacterium tuberculosis H37Rv, which is recently reported as the CoA-transferase of 9-oxo 1,2,3,4,5,6,10,19-octanor-13,17-secoandrost-8(14)-ene-7,17-dioic acid (Crowe AM, Casabon I, Brown KL, Liu J, Lian J, Rogalski JC, Hurst TE, Snieckus V, Foster LJ, Eltis LD. 2017. MBio 8). PMID- 30026063 TI - Identification of 4-methyl-5-oxo-octane-1,8-dioic acid and the derivatives as metabolites of steroidal C,D-ring degradation in Comamonas testosteroni TA441. AB - Comamonas testosteroni TA441 degrades steroids via 9,17-dioxo-1,2,3,4,10,19 hexanorandrostan-5-oic acid, which is presumed to be further degraded by beta oxidation. In the beta-oxidation process, Coenzyme A (CoA)-ester of 9-oxo 1,2,3,4,5,6,10,19-octanor-13,17-secoandrost-8(14)-ene-7,17-dioic acid is produced and converted by beta-ketoacyl-CoA-transferase encoded by ORF1 and ORF2 (scdL1L2) to cleave the remaining C-ring. In this study, we isolated and identified 4 methyl-5-oxo-octane-1,8-dioic acid and 4-methyl-5-oxo-3-octene-1,8-dioic acid from the culture of the ORF3 (scdN)-null mutant as metabolites of steroid degradation (ADD and cholic acid analogues; cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid). In addition of these compounds, UHPLC/MS analysis of the culture of the scdN-null mutant revealed significant accumulation of another compound, which was detected as a dominant peak of m/z 155 ([M-CO2]-) accompanied by a small peak of parental ion (m/z 199 [M-]). On the bases of experimental data, this compound was presumed to be 4-methyl-5-oxo-2-octene-1,8 dioic acid, whose CoA-ester was indicated to be converted by scdN-encoded CoA hydratase into the CoA-ester of 3-hydroxy-4-methyl-5-oxooctan-1,7-carboxylic acid. PMID- 30026064 TI - Fatty-acylation target sequence in the ligand-binding domain of vertebrate steroid receptors demarcates evolution from estrogen-related receptors. AB - Present-day nuclear receptors (NRs) responding to adrenal and sex steroids are key regulators of reproduction and growth in mammals, and are thought to have evolved from an ancestral NR most closely related to extant estrogen-related receptors (ERRs). The molecular events (and ligands) that distinguish steroid activated NRs (SRs) from their inferred ancestor, that gave rise to both the ERRs and SRs, remain unknown. We report that target sequences for fatty-acylation (palmitoylation) at a key cysteine residue (corresponding to Cys447 in human estrogen receptor ERalpha) in helix 8 of the ligand-binding domain accurately demarcate SRs from ERRs. Docking studies are consistent with the hypothesis that palmitate embeds into a key groove in the receptor surface. The implications of lipidation, and of potential alternative ligands for the key cysteine residue, for receptor function and the evolution of SRs are discussed. PMID- 30026065 TI - Intra-hospital mortality for community-acquired pneumonia in mainland Portugal between 2000 and 2009. AB - INTRODUCTION: Community-acquired pneumonia (CAP) remains a common and serious infection with wide variability in intra-hospital mortality. METHODS: We performed a retrospective analysis of adult patients admitted with CAP in mainland Portugal between the years 2000 and 2009. RESULTS: The intra-hospital mortality rate was 20.4% with deaths in all age groups. The average age of deceased patients was 79.8 years, significantly higher than surviving patients with 71.3 years. Patients aged 50 or more presented a relative risk of death 4.4 times the risk of patients under this age group. Likewise, in patients aged 65 or more the risk of death was 3.2 times the risk of patients <65 years. Men died more at a younger age than women, the men who died were, on average, 4 years younger than women, 78.1 vs 82.1 years old. Relative risk of death in men was 17% higher than women after adjustment for year of admission and age. CONCLUSION: CAP remains an important cause of hospital mortality in all age groups. PMID- 30026066 TI - Role of interleukin-17 in a murine community-associated methicillin-resistant Staphylococcus aureus pneumonia model. AB - Interleukin (IL)-17 is a key member of the Th17 cytokines and has been reported to be involved in the pathomechanisms underlying various diseases, including infectious diseases. Infections with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) have garnered worldwide attention, and the representative USA300 strain is known to cause pneumonia in healthy people, which can be lethal. However, little is known about the role of IL-17 in CA-MRSA pneumonia. In this study, we investigated the role of IL-17 in a CA-MRSA pneumonia animal model. Mortality was higher and occurred at an earlier stage of infection in the IL-17A-knockout mice than in the wild-type (P < 0.01) and IL 17A/F-knockout mice (P < 0.05); however, no significant difference in the intrapulmonary bacterial counts was observed among the three groups of mice. Moreover, the IL-17A-knockout group showed significantly higher levels of IL-17F and granulocyte-colony stimulating factor (G-CSF) and a significantly higher neutrophil count in the bronchoalveolar lavage fluid than the other groups. These results confirmed that G-CSF expression significantly increased, and significant neutrophilic inflammation occurred under conditions of IL-17A deficiency in the murine CA-MRSA pneumonia model. PMID- 30026067 TI - Transferability of artificial neural networks for clinical document classification across hospitals: A case study on abnormality detection from radiology reports. AB - OBJECTIVE: Application of machine learning techniques for automatic and reliable classification of clinical documents have shown promising results. However, machine learning models require abundant training data specific to each target hospital and may not be able to benefit from available labeled data from each of the hospitals due to data variations. Such training data limitations have presented one of the major obstacles for maximising potential application of machine learning approaches in the healthcare domain. We investigated transferability of artificial neural network models across hospitals from different domains representing various age demographic groups (i.e., children, adults, and mixed) in order to cope with such limitations. MATERIALS AND METHODS: We explored the transferability of artificial neural networks for clinical document classification. Our case study was to detect abnormalities from limb X ray reports obtained from the emergency department (ED) of three hospitals within different domains. Different transfer learning scenarios were investigated in order to employ a source hospital's trained model for addressing a target hospital's abnormality detection problem. RESULTS: A Convolutional Neural Network (CNN) model exhibited the best effectiveness compared to other networks when employing an embedding model trained on a large corpus of clinical documents. Furthermore, CNN models derived from a source hospital outperformed a conventional machine learning approach based on Support Vector Machines (SVM) when applied to a different (target) hospital. These models were further improved by leveraging available training data in target hospitals and outperformed the models that used only the target hospital data with F1-Score of 0.92-0.96 across three hospitals. DISCUSSION: Our transfer learning model used only simple vector representations of documents without any task-specific feature engineering. Transferring the CNN model significantly improved (approx.10% in F1-Score) the state-of-the-art approach for clinical document classification based on a trivial transferred model. In addition, the results showed that transfer learning techniques can further improve a CNN model that is trained only on either a source or target hospital's data. CONCLUSION: Transferring a pre-trained CNN model generated in one hospital to another facilitates application of machine learning approaches that alleviate both hospital-specific feature engineering and training data. PMID- 30026068 TI - Spike detection: The first step towards an ENG-based neuroprosheses. AB - BACKGROUND: Being able to control an upper limb prosthesis by means of the signals recorded from the peripheral nerves is not a trivial task. New generations of neural electrodes are able to record this information but the quality of the signal can make difficult the extraction of the useful information. Several techniques have been adopted both for central and peripheral acquisitions in order to remove the noise and/or enhance the electrical activity generated by the brain or carried by the nerves. NEW METHODS: In this review, common spike detection algorithms have been tested on both real and simulated recordings to verify which is the best choice to be applied in a neuroprosthetics context. In particular, the moving average algorithm (MAA), the non-linear energy operator (NEO) and the wavelet denoising (WD) have been implemented and their performance have been tested by means of the number of the detected real positives (RPs) and false positives (FPs). RESULTS: MAA outperforms the other techniques because it is capable of detecting a high amount of RPs and, compared to NEO, with a reduced number of FPs. COMPARISON WITH EXISTING METHODS: MAA needs only the information of the duration of the action potential while the NEO and the WD require the frequency and/or the shape of the action potentials. CONCLUSIONS: NEO and WD are algorithms requiring information about the signal, not a priori known. MAA, then, seems most suitable for online applications. PMID- 30026069 TI - GraphVar 2.0: A user-friendly toolbox for machine learning on functional connectivity measures. AB - BACKGROUND: We previously presented GraphVar as a user-friendly MATLAB toolbox for comprehensive graph analyses of functional brain connectivity. Here we introduce a comprehensive extension of the toolbox allowing users to seamlessly explore easily customizable decoding models across functional connectivity measures as well as additional features. NEW METHOD: GraphVar 2.0 provides machine learning (ML) model construction, validation and exploration. Machine learning can be performed across any combination of graph measures and additional variables, allowing for a flexibility in neuroimaging applications. RESULTS: In addition to previously integrated functionalities, such as network construction and graph-theoretical analyses of brain connectivity with a high-speed general linear model (GLM), users can now perform customizable ML across connectivity matrices, graph measures and additionally imported variables. The new extension also provides parametric and nonparametric testing of classifier and regressor performance, data export, figure generation and high quality export. COMPARISON WITH EXISTING METHODS: Compared to other existing toolboxes, GraphVar 2.0 offers (1) comprehensive customization, (2) an all-in-one user friendly interface, (3) customizable model design and manual hyperparameter entry, (4) interactive results exploration and data export, (5) automated queue system for modelling multiple outcome variables within the same session, (6) an easy to follow introductory review. CONCLUSIONS: GraphVar 2.0 allows comprehensive, user friendly exploration of encoding (GLM) and decoding (ML) modelling approaches on functional connectivity measures making big data neuroscience readily accessible to a broader audience of neuroimaging investigators. PMID- 30026070 TI - Biophysically based method to deconvolve spatiotemporal neurovascular signals from fMRI data. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) is commonly used to infer hemodynamic changes in the brain after increased neural activity, measuring the blood oxygen level-dependent (BOLD) signal. An important challenge in the analyses of fMRI data is to develop methods that can accurately deconvolve the BOLD signal to extract the driving neural activity and the underlying cerebrovascular effects. NEW METHOD: A biophysically based method is developed, which combines an extensively verified physiological hemodynamic model with a Wiener filter, to deconvolve the BOLD signal. RESULTS: The method is able to simultaneously obtain spatiotemporal images of underlying neurovascular signals, including neural activity, cerebral blood flow, cerebral blood volume, and deoxygenated hemoglobin concentration. The method is tested on simulated data and applied to various experimental data to demonstrate its stability, accuracy, and utility. COMPARISON WITH EXISTING METHODS: The resulting profiles of the deconvolved signals are consistent with measurements reported in the literature, obtained via multiple neuroimaging modalities. CONCLUSIONS: The method provides new testable predictions of the spatiotemporal relations of the deconvolved signals for future studies. This demonstrates the ability of the method to quantify and analyze the neurovascular mechanisms that underlie fMRI, thereby expanding its potential uses. PMID- 30026071 TI - Long-Term Active Surveillance of Screening Detected Subsolid Nodules is a Safe Strategy to Reduce Overtreatment. AB - INTRODUCTION: Lung cancer presenting as subsolid nodule (SSN) can show slow growth, hence treating SSN is controversial. Our aim was to determine the long term outcome of subjects with unresected SSNs in lung cancer screening. METHODS: Since 2005, the Multicenter Italian Lung Detection (MILD) screening trial implemented active surveillance for persistent SSN, as opposed to early resection. Presence of SSNs was related to diagnosis of cancer at the site of SSN, elsewhere in the lung, or in the body. The risk of overall mortality and lung cancer mortality was tested by Cox proportional hazards model. RESULTS: SSNs were found in 16.9% (389 of 2303) of screenees. During 9.3 +/- 1.2 years of follow-up, the hazard ratio of lung cancer diagnosis in subjects with SSN was 6.77 (95% confidence interval: 3.39-13.54), with 73% (22 of 30) of cancers not arising from SSN (median time to diagnosis 52 months from SSN). Lung cancer specific mortality in subjects with SSN was significantly increased (hazard ratio = 3.80; 95% confidence interval: 1.24-11.65) compared to subjects without lung nodules. Lung cancer arising from SSN did not lead to death within the follow-up period. CONCLUSIONS: Subjects with SSN in the MILD cohort showed a high risk of developing lung cancer elsewhere in the lung, with only a minority of cases arising from SSN, and never representing the cause of death. These results show the safety of active surveillance for conservative management of SSN until signs of solid component growth and the need for prolonged follow-up because of high risk of other cancers. PMID- 30026072 TI - Retinoblastoma membrane models and their interactions with porphyrin photosensitisers: An infrared microspectroscopy study. AB - Fourier Transform Infrared (FTIR) microspectroscopy was used to highlight the interactions between two photosensitisers (PS) of different geometries, TPPmOH4 and a glycoconjugated analogous, TPPDegMan, and lipid bilayers modelling retinoblastoma cell membranes. Retinoblastoma is a rare disease occurring in young infants, for whom conservative treatments may present harmful side-effects. Photodynamic therapy (PDT) is expected to induce less side-effects, as the photosensitiser is only activated when the tumour is illuminated. Since efficiency of the treatment relies on photosensitiser penetration in cancer cells, bilayers with three lipid compositions - pure SOPC, SOPC/SOPE/SOPS/Chol (56:23:11:10) and SOPC/SOPE/SOPS/Chol/CL (42:32:9:8:6) - were used as plasma and mitochondria model membranes. FTIR spectra showed that the interaction of the PSs with the lipid bilayers impacted the lipid organization of the latter, causing significant spectral variations. Both studied photosensitisers inserted at the level of lipid hydrophobic chains, increasing chain fluidity and disorder. This was confirmed by surface pressure measurements. Photosensitisers - TPPmOH4 more than TPPDegMan - also interacted with the polar region of the bilayer, forming hydrogen bonds with phosphate groups that induced major shifts of phosphate absorption bands. This difference in PS interaction with moieties in the polar region was more pronounced with the models with complex lipid composition. PMID- 30026073 TI - Ethmoid tumor and oncogenic osteomalacia: Case report and review of the literature. AB - INTRODUCTION: Oncogenic osteomalacia is a very rare disease usually caused by a phosphaturic mesenchymal tumor, particularly the "mixed connective tissue type", secreting FGF-23 hormone. OBJECTIVE: The authors report a case of ethmoid tumor associated with oncogenic osteomalacia and discuss management based on a review of the literature. CASE SUMMARY: A 41-year-old woman with multiple fractures causing major disability was diagnosed with early-onset osteoporosis. CT scan followed by MRI, performed due to the concomitant presence of nasal obstruction, showed a right ethmoid tumor in contact with the dura mater and periorbital tissues, but with no signs of invasion. Endoscopic resection was performed with reconstruction of the defect of the cribriform plate by a nasoseptal flap. Nasal and bone symptoms subsequently resolved. Histological examination revealed a phosphaturic mesenchymal tumor. DISCUSSION: Twelve cases of mesenchymal tumor of the ethmoid sinus associated with oncogenic osteomalacia have been reported to date. FGF-23 assay and whole-body MRI with STIR sequence are useful for the diagnosis. A very favorable outcome is observed after surgical treatment in the majority of cases. PMID- 30026075 TI - Loneliness and cardiovascular reactivity to acute stress in younger adults. AB - Loneliness is connected to poorer health outcomes with stress reactivity proposed as an underlying mechanism. The present study explored whether the relationship between loneliness and cardiovascular reactivity (CVR) varies across acute psychological stress tasks. Eighty-eight healthy younger adults completed a psychometric measure of loneliness and participated in a standardised cardiovascular stress-testing protocol, with a public speaking and a mental arithmetic task. Cardiovascular functioning was assessed before and during the acute stress exposure. Higher levels of loneliness significantly predicted lower total peripheral resistance (TPR) reactivity to the public speaking task but not to the arithmetic challenge. This suggests that the effect of loneliness on cardiovascular reactivity to acute stress may vary by stressor type. These findings are discussed in relation to future research. PMID- 30026074 TI - In vivo singlet molecular oxygen measurements: Sensitive to changes in oxygen saturation during PDT. AB - BACKGROUND: Direct singlet molecular oxygen detection is known to be a valuable tool for understanding photodynamic action. It could become useful for optimizing illumination schedules in photodynamic therapy. The method of time resolved singlet molecular oxygen luminescence detection can give insights into generation of singlet oxygen and its interaction with the environment and therefore possibly allows monitoring the treatments efficacy. Due to high requirements for sensitivity as well as time resolution it has not yet been used in situ. The latest improvements in the detection system make in vivo time resolved singlet molecular oxygen luminescence detection possible. METHODS: In this work, blood vessels in the chicken embryo CAM-model were scanned after injection of the photosensitizer Foslip(r), yielding time resolved singlet molecular oxygen luminescence. A custom-made trifurcated fiber in combination with a dye laser, a photomultiplier tube and a fiber spectrometer was utilized for simultaneous excitation, singlet molecular oxygen luminescence and photosensitizer fluorescence detection. RESULTS: Singlet oxygen luminescence kinetics for mixed venous and arterialized blood in chicken embryos using the CAM-model were recorded. The data analysis resulted in two distinct and distinguishable photosensitizer triplet lifetimes corresponding to the high and low oxygen partial pressures in the oxygen-rich arterialized blood and oxygen-poor mixed venous blood. CONCLUSIONS: The sensitivity of direct singlet molecular oxygen luminescence detection to different oxygen partial pressures could be shown in vivo. Therefore, this study is a first step towards optimizing the illumination conditions of photodynamic treatment in situ by real time monitoring of the oxygen partial pressure within the target tissue. PMID- 30026076 TI - The roles of protein tyrosine phosphatases in bone-resorbing osteoclasts. AB - Maintaining the proper balance between osteoblast-mediated production of bone and its degradation by osteoclasts is essential for health. Osteoclasts are giant phagocytic cells that are formed by fusion of monocyte-macrophage precursor cells; mature osteoclasts adhere to bone tightly and secrete protons and proteases that degrade its matrix. Phosphorylation of tyrosine residues in proteins, which is regulated by the biochemically-antagonistic activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), is central in regulating the production of osteoclasts and their bone-resorbing activity. Here we review the roles of individual PTPs of the classical and dual-specificity sub families that are known to support these processes (SHP2, cyt-PTPe, PTPRO, PTP PEST, CD45) or to inhibit them (SHP1, PTEN, MKP1). Characterizing the functions of PTPs in osteoclasts is essential for complete molecular level understanding of bone resorption and for designing novel therapeutic approaches for treating bone disease. PMID- 30026077 TI - Role of protein phosphatases in the cancer microenvironment. AB - Cancer cells depend on a supportive niche (the tumor microenvironment) that promotes tumor cell survival while protecting the malignant cells from therapeutic challenges and the host's defense systems. Cancer cells and the support cells in the tumor microenvironment communicate via cytokines/chemokines, cell:cell contact, or alterations in the metabolic state of the niche (e.g. hypoxia) that promote growth and survival of the tumor cell, influence metastasis, and defeat immune surveillance. These signaling pathways involve dysregulation of not only protein kinases but also protein phosphatases as normal signal transduction processes require both activation and deactivation. For instance, aberrant receptor signaling can result from constitutive activation of a tyrosine kinase such as FLT3 or inactivation of a tyrosine protein phosphatase such as SHP-2 (PTPN11). Activation of serine/threonine kinases such as AKT and ERK are often observed during the development of drug resistance while genomic and non-genomic suppression of serine/threonine protein phosphatases such as PP2A achieve similar results. It is fairly clear that the various protein phosphatases will impact processes that support drug resistance. Of growing interest is the emerging model whereby the support cells in the tumor microenvironment actually serve as drivers of tumorigenesis. This phenomenon has been most prominently observed in osteoblast cells in leukemic niches. At least one protein phosphatase, PTPN11, has emerged as a critical driver of this process in juvenile myelomonocytic leukemia. This review will cover the role of various serine/threonine and tyrosine protein phosphatases in processes that are central to tumor microenvironment function. PMID- 30026078 TI - Tumor-targeting core-shell structured nanoparticles for drug procedural controlled release and cancer sonodynamic combined therapy. AB - Combination therapy with multiple drugs or/and multiple assistant treatments has become a hot spot in cancer therapy. In this study, a new type of core-shell structured dual-drug delivery system based on poly (lactic-co-glycolic acid) (PLGA, inner cores) and hyaluronic acid (HA, outer shells) was constructed. Firstly, HA was conjugated to PLGA for preparation of HA-PLGA block copolymer. Secondly, 5-amino levulinic acid (ALA) was connected to PLGA through a pH sensitive hydrazone bond for synthesization of PLGA-HBA-ALA. Finally, the core shell structured nanoparticles (HA-PLGA@ART/ALA NPs) were constructed by self assembled method for artemisinin (ART) loading in PLGA cores. In this co-delivery system, ALA and ART can be released in a manner of procedural controlled release. ALA was released from the NPs at first though the pH sensitive hydrazone bond cleavage in order to generate protoporphyrin IX (PpIX) for heme formation. And the increase of heme can effectively improve the curative effect of the subsequent released ART. Furthermore, this system has also shown obvious sonodynaimc activity which can be used for cancer sonodynamic combination therapy. The in vitro and in vivo anticancer results demonstrate that HA PLGA@ART/ALA delivery system could provide a prospective comprehensive treatment strategy for cancer therapy. PMID- 30026079 TI - Plasma membrane-anchorable photosensitizing nanomicelles for lipid raft responsive and light-controllable intracellular drug delivery. AB - The past decade has witnessed a growing number of nanoparticulate drug delivery systems for cancer treatment. However, insufficient cellular uptake by cancer cells and the undesirable endo/lysosomal entrapment of internalized therapeutic drugs remain the "Achilles heel" of many developed nanoagents. Here, we develop a novel lipid raft-responsive and light-controllable polymeric drug for efficient cytosolic delivery of photosensitizers. Conjugating a photosensitizer protoporphyrin IX (PpIX) to a polyethylene glycol-cholesterol polymer affords the amphiphilic drug (denoted as Chol-PEG-PpIX) that forms micelles in aqueous solutions. The Chol-PEG-PpIX with two hydrophobic units (cholesterol and PpIX) showed robust binding to plasma membranes and enabled significant cellular uptake via two pathways: (1) cholesterol moiety triggered the lipid raft-mediated endocytosis of Chol-PEG-PpIX with minimized endo/lysosomal trafficking after internalization; (2) the membrane-bound PpIX acted as a light-controlled trigger and can augment the permeability of plasma membranes upon laser irradiation, allowing the rapid influx of extracellular Chol-PEG-PpIX within 5 min. For systemic drug delivery, Chol-PEG-PpIX was anchored on the surface of liposomes via in situ membrane modification, which substantially avoided nonspecific binding of Chol-PEG-PpIX to red blood cells during circulation. Besides, the Chol PEG-PpIX-anchored liposomes exhibited enhanced in vivo fluorescence, reduced liver uptake, prolonged tumor retention, and effective tumor ablation by photodynamic therapy. This work illustrates a new strategy for direct and efficient cytosolic delivery of photosensitizers, which may hold great promise in cancer therapy. PMID- 30026080 TI - Dexamethasone prodrugs as potent suppressors of the immunostimulatory effects of lipid nanoparticle formulations of nucleic acids. AB - Lipid nanoparticles (LNPs) are playing a leading role in enabling clinical applications of gene therapies based on DNA or RNA polymers. One factor impeding clinical acceptance of LNP therapeutics is that LNP formulations of nucleic acid polymers can be immunostimulatory, necessitating co-administration of potent corticosteroid immunosuppressive agents. Here, we describe the development of hydrophobic prodrugs of a potent corticosteroid, dexamethasone, that can be readily incorporated into LNP systems. We show that the presence of the dexamethasone prodrug LD003 effectively suppresses production of cytokines such as KC-GRO, TNFalpha, IL-1beta and IL-6 following intravenous administration of LNP loaded with immune stimulatory oligodeoxynucleotides containing cytosine guanine dinucleotide motifs. Remarkably, LD003 dose levels corresponding to 0.5 mg/kg dexamethasone achieve a greater immunosuppressive effect than doses of 20 mg/kg of free dexamethasone. Similar immunosuppressive effects are observed for subcutaneously administered LNP-siRNA. Further, the incorporation of low levels of LD003 in LNP containing unmodified mRNA or plasmid DNA significantly reduced pro-inflammatory cytokine levels following intravenous administration. Our results suggest that incorporation of hydrophobic prodrugs such as LD003 into LNP systems could provide a convenient method for avoiding the immunostimulatory consequences of systemic administration of genetic drug formulations. PMID- 30026081 TI - Transdermal insulin delivery using choline-based ionic liquids (CAGE). AB - Transdermal delivery of pharmaceuticals using ionic liquids and deep eutectic solvents (DES) has attracted significant interest due to the inherent tunability of the molecules and their capacity to transport large molecules across the skin. Several key properties of DESs including viscosity, miscibility and possible transport enhancement can be controlled through the choice of ions and their ratio in DES. Herein we investigate the effect of cation/anion ratio using Choline and Geranic acid (CAGE) based DES. We synthesized variants of CAGE by controlling the ratio of Choline to Geranic acid over a range of 1:4 to 2:1. Physicochemical properties including viscosity, conductivity and diffusivity were measured. Effect of CAGE on skin permeability was assessed using insulin in ex vivo porcine skin. Each variant was found to have distinct properties, including interionic interactions, viscosity, and conductivity. In addition, the effect of CAGE on stratum corneum lipids, as assessed by FTIR, was dependent on its composition. Transport enhancement was also composition-dependent, as the variants containing excess geranic acid (1:2 and 1:4, but not geranic acid alone) exhibited higher insulin delivery into the dermis compared to other compositions, demonstrating the importance of investigating the effect of ion ratios on drug delivery. PMID- 30026082 TI - Cell reprogramming approaches in gene- and cell-based therapies for Parkinson's disease. AB - Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta is the pathological hallmark of Parkinson's disease (PD). In PD multiple pathogenic mechanisms initiate and drive this neurodegenerative process, making the development of effective treatments challenging. To date, PD patients are primarily treated with dopaminergic drugs able to temporarily enhance DA levels, therefore relieving motor symptoms. However, the drawbacks of these therapies including the inability to alter disease progression are constantly supporting the search for alternative treatment approaches. Over the past years efforts have been put into the development of new therapeutic strategies based on the delivery of therapeutic genes using viral vectors or transplantation of DA neurons for cell-based DA replacement. Here, past achievements and recent advances in gene- and cell-based therapies for PD are outlined. We discuss how current gene and cell therapy strategies hold great promise for the treatment of PD and how the use of stem cells and recent developments in cellular reprogramming could contribute to open a new avenue in PD therapy. PMID- 30026083 TI - Optical Coherence Tomography Angiography in Intermediate Uveitis. AB - PURPOSE: To investigate the involvement of the retinal and choriocapillaris microvasculature in intermediate uveitis on optical coherence tomography angiography (OCT-A). DESIGN: Case-control study. METHODS: Patients and age matched controls were imaged with swept-source OCT-A. Using ImageJ, superficial and deep retinal vasculature were semi-automatically analyzed for vessel (VD) and skeleton density (SD), vessel diameter index (VDI), and fractal dimension (FD). Choriocapillaris layer was automatically graded for mean signal intensity, signal intensity standard deviation, kurtosis of signal intensity distribution, and flow signal voids. RESULTS: Twenty-nine intermediate uveitis eyes and 30 control eyes were included. Both superficial and deep retinal layers showed significant reduction in all OCT-A parameters (eg, superficial retinal layer: 0.31 vs 0.40 VD, 5.6e-8 vs 6.4e-8 SD, 5.4e6 vs 6.1e6 VDI, and 1.78 vs 1.79 FD, respectively, all P < .05). At the choriocapillaris layer a greater heterogeneity of perfusion with a shift toward a higher proportion of large confluent flow signal voids was present. Also in the absence of macular edema OCT-A parameters were reduced when compared with healthy controls (all parameters except for VDI in the superficial retinal layer and the choriocapillaris kurtosis and flow signal void analyses). CONCLUSIONS: In intermediate uveitis, reduced vascular density and complexity in superficial as well as deep retinal layers and altered choriocapillaris perfusion are present. Moreover, these findings indicate impairment of the macular microvasculature even in the absence of macular edema. The results of our study may aid in the diagnosis as well as the monitoring of intermediate uveitis. PMID- 30026084 TI - Elastin Content and Distribution in Endothelial Keratoplasty Tissue Determines Direction of Scrolling. AB - PURPOSE: Descemet membrane endothelial keratoplasty (DMEK) and pre-Descemet endothelial keratoplasty (PDEK) tissues always scroll with the endothelial cells (EC) outside. We designed a study to understand the reason for this behavior. DESIGN: Experimental study. METHODS: Elastin content in Descemet membrane (DM), pre-Descemet layer (PDL), central and peripheral stroma, sclera, and trabecular meshwork were measured by the Fastin elastin assay kit. Distribution of elastin in DM, PDL, and anterior lens capsule (ALC) were examined by immunohistology. The effect of recombinant elastase enzyme and the effect of complete removal of EC and epithelial cells on the scrolling of DM and ALC, respectively, were studied. RESULTS: PDL showed the highest elastin content among the different tissues studied. Elastin localized as a distinct anterior band in the DM and was uniformly distributed in the PDL demarcating the latter from corneal stroma. Enzymatic treatment of DM with elastase reversed scrolling and corresponded with degradation or disappearance of elastin. Removal of EC did not affect the direction of scrolling. ALC behaved in the same manner with regard to distribution of elastin, scrolling, and removal of epithelial cells. CONCLUSIONS: This pattern of elastin distribution in DM explains why DMEK and PDEK tissues always scroll with the EC outside. This behavior is not influenced by the EC. High elastin content and uniform distribution in the PDL suggest a structural difference from the posterior stroma. PMID- 30026085 TI - Crystal structure of saposin D in an open conformation. AB - Saposins are accessory proteins that aid in the degradation of sphingolipids by hydrolytic enzymes. Their structure usually comprises four alpha-helices arranged in various conformations including an open, V-shaped form that is generally associated with the ability to interact with membranes and/or enzymes to accentuate activity. Saposin D is required by the lysosomal hydrolase, acid ceramidase, which breaks down ceramide into sphingosine and free fatty acid, to display optimal activity. The structure of saposin D was previously determined in an inactive conformation, revealing a monomeric, closed and compact form. Here, we present the crystal structure of the open, V-shaped form of saposin D. The overall shape is similar to the open conformation found in other saposins with slight differences in the angles between the alpha-helices. The structure forms a dimer that serves to stabilize the hydrophobic surface exposed in the open form, which results in an internal, hydrophobic cavity that could be used to carry extracted membrane lipids. PMID- 30026086 TI - Glottic patency during noninvasive ventilation in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Non-invasive ventilation (NIV) provides ventilatory support for patients with respiratory failure. However, the glottis can act as a closing valve, limiting effectiveness of NIV. This study investigates the patency of the glottis during NIV in patients with acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD). METHODS: Electrical activity of the diaphragm, flow, pressure and videolaryngoscopy were acquired. NIV was randomly applied in pressure support (PSV) and neurally adjusted ventilatory assist (NAVA) mode with two levels of support. The angle formed by the vocal cords represented glottis patency. RESULTS: Eight COPD patients with acute exacerbation requiring NIV were included. No differences were found in median glottis angle during inspiration or peak inspiratory effort between PSV and NAVA at low and high support levels. CONCLUSIONS: The present study showed that glottis patency during inspiration in patients with an acute exacerbation of COPD is not affected by mode (PSV or NAVA) or level of assist (5 or 15 cm H2O) during NIV. PMID- 30026087 TI - Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: The role of Keap-1/Nrf-2 and P38-MAPK/NF-kappaB/iNOS signaling pathway. AB - The present study was designed to investigate the potential protective effects of diosmin (DS) and/or sildenafil against bile duct ligation (BDL). In order to achieve this goal, BDL was performed to induce liver cirrhosis, DS (100 mg/kg/day, p.o.) and sildenafil (10 mg/kg, twice daily, p.o.) were administrated alone or in combination 24 h after the surgical operation and lasted for 4 weeks. Liver function biomarkers, fibrotic markers, oxidative stress markers, mRNA expression of NF-kappaB-p65, P38-MAPK, Nrf-2, and Keap-1, as well as protein expression of cytoglobin, NF-kappaB-p65, Nrf-2, iNOS and eNOS were investigated concomitantly with histopathological study. The results revealed that, 4 weeks of BDL induced a significant alteration in liver functions, fibrotic and oxidative stress markers. Furthermore, up-regulation of NF-kappaB-p65, P38-MAPK, Keap-1 and iNOS concomitantly with down-regulation of Nrf-2, cytoglobin and eNOS expressions were observed after BDL. DS and/or sildenafil treatment significantly alleviated the disturbance induced by BDL. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of DS and sildenafil were found to significantly improved liver defects due to BDL as compared to the individual drugs. It can be concluded that, DS and sildenafil exhibit hepatoprotective effects through modulation of Keap-1/Nrf-2 and P38 MAPK/NF-kappaB/iNOS pathway. PMID- 30026088 TI - Antioxidant, anti-inflammatory and synergistic anti-hyperglycemic effects of Malaysian propolis and metformin in streptozotocin-induced diabetic rats. AB - Diabetes mellitus is characterized by hyperglycemia which causes oxidative stress. Propolis has been reported to have antihyperglycemic and antioxidant potentials. The present study therefore examined the anti-hyperglycemic, antioxidant and anti-inflammatory activities of Malaysian propolis (MP) using streptozotocin-induced diabetic rats. Ethanol extract of MP showed in vitro antioxidant (DPPH, FRAP and H2O2 radical scavenging) and alpha-glucosidase inhibition activities. Male Sprague Dawley rats were either treated with distilled water (normal control and diabetic control), MP (300 mg/kg b. w.), metformin (Met) (300 mg/kg b. w.) or both. After four weeks, fasting blood glucose decreased, while body weight change and serum insulin level increased significantly in MP, Met and MP + Met treated diabetic groups compared to diabetic control (DC) group. Furthermore, pancreatic antioxidant enzymes, total antioxidant capacity, interleukin (IL)-10 and proliferating cell nuclear antigen increased, while malondialdehyde, nuclear factor-kappa B (p65), tumor necrosis factor alpha, IL-1beta and cleaved caspase-3 decreased significantly in the treated diabetic groups compared to DC group. Histopathology of the pancreas showed increased islet area and number of beta cells in the treated groups, compared to DC group, with D + MP + Met group comparable to normal control. We conclude that MP has anti-hyperglycemic, antioxidant, anti-inflammatory and antiapoptotic potentials, and exhibits synergistic effect with metformin. PMID- 30026089 TI - Mercury concentrations in seafood and the associated risk in women with high fish consumption from coastal villages of Sonora, Mexico. AB - Mercury concentrations in the ocean have increased considerably since the industrial revolution and will continue to increase in the next 50 years. Therefore, it is important to monitor Hg levels in fish and to evaluate the health risks in populations with high fish consumption. In the present study, a total of 238 samples of commercial fish and shellfish, were analyzed from the Central Gulf of California, Mexico. Concentrations of total Hg in fish ranged from < DL (detection limit) up to 1.22 MUg g-1, with a mean of 0.15 +/- 0.19 MUg g-1, the majority of the samples were lower than the maximum permissible level. To evaluate the risk, a total of 110 food frequency questionnaires were applied to women (16-68 years old) from 15 coastal fishing villages of Sonora. Results indicated a high seafood consumption at these communities (mean = 307 g day-1), and a high hazard risk (HQ = 6.2) due to methyl mercury ingestion. It is recommended to limit seafood consumption in pregnant women to 4 portions of fish per week, preferably of low mercury concentrations so that all the benefits of seafood consumption are obtained without the negative health effects of methyl mercury. PMID- 30026090 TI - Resveratrol inhibits human leiomyoma cell proliferation via crosstalk between integrin alphavbeta3 and IGF-1R. AB - Leiomyomas (myomas) are the most common benign smooth muscle cell tumor of the myometrium. Resveratrol, a stilbene, has been used as an anti-inflammatory and antitumor agent. In the current study, we investigated the inhibitory effect of resveratrol on the proliferation of primary human myoma cell cultures. Resveratrol arrested cell proliferation via integrin alphavbeta3. It also inhibited integrin alphavbeta3 expression and protein accumulation. Concurrently, constitutive AKT phosphorylation in myoma cells was inhibited by resveratrol. Expressions of proapoptotic genes, such as cyclooxygenase (COX)-2, p21 and CDKN2, were induced by resveratrol in myoma cells. On the other hand, expressions of proliferative (anti-apoptotic) genes were either inhibited, as in BCL2, or unchanged, as in cyclin D1 and proliferating cell nuclear antigen (PCNA). The accumulation of insulin-like growth factor (IGF)-1 receptor (IGF-1R) was inhibited by resveratrol in primary myoma cells. IGF-1-induced cell proliferation was inhibited by co-incubation with resveratrol. Therefore, growth modulation of myoma cells occurs via mechanisms dependent on cross-talk between integrin alphavbeta3 and IGF-1R. Our findings suggest that resveratrol can be considered an alternative therapeutic agent for myomas. PMID- 30026091 TI - In vitro systems toxicology-based assessment of the potential modified risk tobacco product CHTP 1.2 for vascular inflammation- and cytotoxicity-associated mechanisms promoting adhesion of monocytic cells to human coronary arterial endothelial cells. AB - Cigarette smoking causes cardiovascular diseases. Heating tobacco instead of burning it reduces the amount of toxic compounds in the aerosol and may exert a reduced impact on health compared with cigarette smoke. Aqueous extract from the aerosol of a potential modified risk tobacco product, the Carbon Heated Tobacco Product (CHTP) 1.2, was compared in vitro with aqueous extract from the smoke of a 3R4F reference cigarette for its impact on the adhesion of monocytic cells to artery endothelial cells. Human coronary artery endothelial cells (HCAEC) were treated for 4 h with conditioned media from human monocytic Mono Mac 6 (MM6) cells exposed to CHTP1.2 or 3R4F extracts for 2 h or directly with those extracts freshly generated. In vitro monocyte-endothelial cell adhesion was measured concomitantly with inflammatory, oxidative stress, cytotoxicity, and death markers. Furthermore, transcriptomics analyses enabled to quantify the level of perturbation in HCAECs, and provide biological interpretation for the underlying molecular changes following exposure to 3R4F or CHTP1.2 extract. Our systems toxicology study demonstrated that approximately 10-15-fold higher concentrations of the CHTP 1.2 aerosol extract were needed to elicit similar effects as the 3R4F smoke extract on cardiovascular disease-relevant inflammation and cytotoxicity related mechanisms and markers investigated in vitro. PMID- 30026092 TI - Preparation of novel tissue acidosis-responsive chitosan drug nanoparticles: Characterization and in vitro release properties of Ca2+ channel blocker nimodipine drug molecules. AB - The pH-responsive intelligent drug release facility of hydrophobically modified chitosan nanoparticles (Chit NPs) (d = 5.2 +/- 1.1 nm) was presented in the case of poorly water soluble Ca2+ channel blocker nimodipine (NIMO) drug molecules. The adequate pH-sensitivity, i.e. the suitable drug carrier properties of the initial hydrophilic Chit were achieved by reductive amination of Chit with hexanal (C6-) and dodecanal (C12-) aldehydes. The successful modifications of the macromolecule were evidenced via FTIR measurements: the band appearing at 1412 cm 1 (CN stretching in aliphatic amines) in the cases of the hydrophobically modified Chit samples shows that the CN bond successfully formed between the Chit and the aldehydes. Hydrophobization of the polymer unambiguously led to lower water contents with lower intermolecular interactions in the prepared hydrogel matrix: the initial hydrophilic Chit has the highest water content (78.6 wt%) and the increasing hydrophobicity of the polymer resulted in decreasing water content (C6-chit.: 74.2 wt% and C12-chit.: 47.1 wt%). Furthermore, it was established that the length of the side chain of the aldehyde influences the pH-dependent solubility properties of the Chit. Transparent homogenous polymer solution was obtained at lower pH, while at higher pH the formation of polymer (nano)particles was determined and the corresponding cut-off pH values showed decreasing tendency with increasing hydrophobic feature (pH = 7.47, 6.73 and 2.49 for initial Chit, C6-chit and C12-chit, respectively). Next the poorly water soluble NIMO drug was encapsulated with the C6-chit with adequate pH-sensitive properties. The polymer stabilized NIMO particles with 10 wt% NIMO content resulted in stable dispersion in aqueous phase, the formation of polymer shell increased in the water solubility/dispersibility of the initial hydrophobic drug. According to the drug release experiments, we clearly confirmed that the encapsulated low crystallinity NIMO drug remained closed in the polymer NPs at normal tissue pH (pH = 7.4, PBS buffer, physiological condition) but at pH < 6.5 which is typical for seriously ischemic brain tissue, 93.6% of the available 0.14 mg/ml NIMO was released into the buffer solution under 8 h release time. According to this in vitro study, the presented pH-sensitive drug carrier system could be useful to selectively target ischemic brain regions characterized by acidosis, to achieve neuroprotection at tissue zones at risk of injury, without any undesirable side effects caused by systemic drug administration. PMID- 30026093 TI - Modulation of antibiotic effect by Fe2(MoO4)3 microstrutures. AB - In this study, we report the antibacterial activity and modulation of antibiotic activity by Fe2(MoO4)3 microstructures obtained by the hydrothermal route without use of surfactants or organic additives. This material was characterized by X-ray diffraction (XRD), Raman spectroscopy and scanning electron microscopy (SEM) images. The XRD pattern showed that the Fe2(MoO4)3 crystallize in a monoclinic structure without secondary phases. Raman spectroscopy confirms the formation of Fe2(MoO4)3. SEM images show that the Fe2(MoO4)3 obtained have ball-of-yarn shaped morphology. In the antibacterial assays, strains of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were assayed by microdilution method to evaluate the antibacterial and modulatory-antibiotic activity with antibiotics as gentamicin, norfloxacin and imipenem. Against all bacteria, the Minimum Inhibitory Concentration (MIC) was Fe2(MoO4)3 >= 1024 MUg/mL. This high MIC result must be associated with the fact of the iron be an essential microelement to the bacterial growth. However, when the Fe2(MoO4)3 was assayed in association with the antibiotics was observed an antagonistic effect demonstrated by an enhance of the MIC. This fact is associated directly with the pro-oxidative properties of metallic oxides. These compounds enhance the production of free radicals, as H2O2 and superoxide ions that can affect the cell structures as cell membrane and cell wall. Other effect is associated with the possible coordination of the metal, performing bonds with the chemical structure of the antibiotics, reducing their activity. Our results indicated that nanocompounds as Fe2(MoO4)3 can not be used as antimicrobial products for clinical usage, neither directly and neither in association with antibiotics. PMID- 30026094 TI - The effect of entomopathogenic fungal culture filtrate on the immune response and haemolymph proteome of the large pine weevil, Hylobius abietis. AB - The large pine weevil Hylobius abietis L. is a major forestry pest in 15 European countries, where it is a threat to 3.4 million hectares of forest. A cellular and proteomic analysis of the effect of culture filtrate of three entomopathogenic fungi (EPF) species on the immune system of H. abietis was performed. Injection with Metarhizium brunneum or Beauvaria bassiana culture filtrate facilitated a significantly increased yeast cell proliferation in larvae. Larvae co-injected with either Beauvaria caledonica or B. bassiana culture filtrate and Candida albicans showed significantly increased mortality. Together these results suggest that EPF culture filtrate has the potential to modulate the insect immune system allowing a subsequent pathogen to proliferate. Injection with EPF culture filtrate was shown to alter the abundance of protease inhibitors, detoxifing enzymes, antimicrobial peptides and proteins involved in reception/detection and development in H. abietis larvae. Larvae injected with B. caledonica culture filtrate displayed significant alterations in abundance of proteins involved in cellulolytic and other metabolic processes in their haemolymph proteome. Screening EPF for their ability to modulate the insect immune response represents a means of assessing EPF for use as biocontrol agents, particularly if the goal is to use them in combination with other control agents. PMID- 30026095 TI - Functional characterization of olfactory receptors in the Oriental fruit fly Bactrocera dorsalis that respond to plant volatiles. AB - The Oriental fruit fly, Bactrocera dorsalis, is a highly destructive pest of various fruits. The reproductive and host-finding behaviors of this species are affected by several plant semiochemicals that are perceived through chemosensory receptors. However, the chemosensory mechanisms by which this perception occurs have not been fully elucidated. We conducted RNA sequencing analysis of the chemosensory organs of B. dorsalis to identify the genes coding for chemosensory receptors. We identified 60 olfactory receptors (ORs), 17 gustatory receptors and 23 ionotropic receptors-including their homologs and variants-from the transcriptome of male antennae and proboscises. We functionally analyzed ten ORs co-expressed with the obligatory co-receptor ORCO in Xenopus oocytes to identify their ligands. We tested 24 compounds including attractants for several Bactrocera species and volatiles from the host fruits of B. dorsalis. We found that BdorOR13a co-expressed with ORCO responded robustly to 1-octen-3-ol. BdorOR82a co-expressed with ORCO responded significantly to geranyl acetate, but responded weakly to farnesenes (a mixture of isomers) and linalyl acetate. These four compounds were subsequently subjected to behavioral bioassays. When each of the aforementioned compound was presented in combination with a sphere model as a visual cue to adult flies, 1-octen-3-ol, geranyl acetate, and farnesenes significantly enhanced landing behavior in mated females, but not in unmated females or males. These results suggest that the ORs characterized in the present study are involved in the perception of plant volatiles that affect host-finding behavior in B. dorsalis. PMID- 30026096 TI - Biosynthesis and characterization of polyhydroxyalkanoate from marine Bacillus cereus MCCB 281 utilizing glycerol as carbon source. AB - Polyhydroxyalkanoates (PHAs) are aliphatic polyesters produced by bacteria from renewable resources which serve as a substitute of synthetic plastics. In the present study isolation, screening, identification of PHA producing bacteria from marine water samples and optimization of process variables for increased PHA production were accomplished. The potent isolate identified as Bacillus cereus MCCB 281 synthesized PHA co-polymer with 13 mol% 3-hydroxyvalerate in presence of glycerol. Process parameters optimized using central composite design for enhanced PHA production showed 1.5 fold higher PHA yield. Cell dry weight of 3.72 +/- 0.04 g L-1, PHA yield 2.54 +/- 0.07 g L-1 and PHA content of 68.27 +/- 1.2% (w/w) was achieved in fermenter at the optimized conditions. Purified polymer was characterized by Fourier-transform infrared spectroscopy, Nuclear magnetic resonance spectroscopy, Gas chromatography-Mass spectrometry, X-ray powder diffraction techniques and molecular weight of PHA was found to be 2.56 * 105 Da. PHA nanoparticles with average particle size 179 nm were synthesized for medical applications and biocompatibility analysis was performed with L929 mouse fibroblast cell line. This is the first report of a moderately halophilic B. cereus, which utilizes glycerol as the sole carbon source for PHA co-polymer production. PMID- 30026097 TI - Effects of epsilon-Poly-l-lysine on the cell wall of Saccharomyces cerevisiae and its involved antimicrobial mechanism. AB - epsilon-Poly-l-lysine (epsilon-PL) is widely used as an antibacterial agent because of its broad antimicrobial spectrum. However, the antimicrobial mechanism of epsilon-PL against Saccharomyces cerevisiae (S. cerevisiae) is only vaguely described. Especially, it is widely accepted that membrane disruption is its main antimicrobial mode of action, but its effect on the cell wall remains unclear. In this study, the effects of epsilon-PL on cell wall of S. cerevisiae were investigated, and the possible action mode of epsilon-PL on the cell wall was discussed. The results showed that epsilon-PL affected significantly the cell wall composition such as beta-1, 3-glucan, mannosylphosphate and chitin, and caused cell wall more fragile. The cell wall permeability was significantly increased. Furthermore, epsilon-PL induced the intracellular accumulation of reactive oxygen species (ROS), as well as lead to DNA fragmentation. These results indicate that epsilon-PL may have a complicated antimicrobial mode of action with multi-target mechanisms against S. cerevisiae cells. PMID- 30026098 TI - Sirt1 alleviates LPS induced inflammation of periodontal ligament fibroblasts via downregulation of TLR4. AB - This study was aimed to investigate the role of Sirt1 in LPS-injured periodontal ligament fibroblast (PDLF), to evaluate potential functions of Sirt1 in the pathogenesis of periodontitis. Sirt1 overexpression significantly increased cell viability, Ki67 positive cell number and PCNA expression in LPS-injured PDLF, and vice versa. Cell apoptosis was significantly decreased, and the release of pro inflammatory cytokines (IL-1alpha, IL-6, IL-8 and TNF-alpha) was significantly reduced when Sirt1 was overexpressed. Sirt1 overexpression down-regulated toll like receptor 4 (TLR4), and inhibited the JNK/NF-kappaB pathways; while knockdown of Sirt1 up-regulated TLR4, and activated JNK/NF-kappaB pathways. To conclude, Sirt1 alleviates inflammation of PDLF induced by LPS through down-regulation of TLR4 and inactivation of JNK/NF-kappaB pathways. PMID- 30026099 TI - Halophilic lipase does forms catalytically active aggregates: Evidence from Marinobacter sp. EMB5 lipase (LipEMB5). AB - Lipases are prone to aggregation due to the presence of hydrophobic surface and corresponding hydrophobic interactions. However, like most lipases, halophilic lipases do not tend to aggregate owing to the presence of charged surface. Conversely, Marinobacter sp. EMB5 produces a unique lipase (LipEMB5) which tends to form functionally active aggregate, despite a presence of 2% (w/v) NaCl in the environment. Gel filtration using Sephacryl S-200 column resulted in elution of lipase in the void volume despite a high salt level, suggesting aggregation behavior. The aggregated form of LipEMB5 (172.35kDa) was shown to have specific activity of 16.3IUmg-1 protein. The disaggregated form (<6kDa) with increased elution volume was also obtained by inclusion of 70% 2-propanol in the elution buffer. It was catalytically less active (0.086IUmg-1 protein specific activity) in comparison to aggregated form. Aggregated and 2-propanol induced disaggregated forms were characterized in terms of DLS, biochemical, morphological, and structural properties. Broadly, the aggregated form showed 24 times more activity with 1000-fold less Km compared to its counterpart. The enzymatic properties were almost observed to be same for both the species. However, better structural integrity in the disaggregated form was observed on the basis of FTIR and CD studies. Overall, the study comes out with a unique halophilic lipase from Marinobacter sp. EMB5 which have a tendency to form active aggregates in high salt laden environment. PMID- 30026100 TI - Development of antibacterial epsilon-polylysine/chitosan hybrid films and the effect on citrus. AB - In this study, the epsilon-polylysine (PL)/chitosan (CS) composite films with the PL concentration of 0%, 1%, 3%, 5% and 7% were prepared via casting method. The Fourier transform infrared (FTIR), scanning electron microscope (SEM), mechanical and antibacterial properties of PL/CS composite films, as well as the effect of PL/CS coatings on citrus were observed. FTIR spectra suggested that there was no strong hydrogen bond between CS and PL. SEM images indicated that the film surface was smooth and the addition of PL to chitosan lead to more holes. The tensile strength was deceasing and the elongation at break of the films was elevating with the increase of PL content. The antibacterial activity against Staphylococcus aureus and Escherichia coli of PL/CS composite films was enhanced with increasing of PL content. Furthermore, it was found that the PL/CS coatings inhibited efficiently the decline of total soluble solids (TSS), ascorbic acid content and reduced the disease incidence of citrus, compared with the control. Also the disease incidence of citrus was decreasing with the increase of PL content. However, the weight loss did not show significant differences between the coated citrus and control during the whole storage period. PMID- 30026101 TI - Compositional and functional investigation of individual and pooled venoms from long-term captive and recently wild-caught Bothrops jararaca snakes. AB - : Intraspecific venom variability has been extensively reported in a number of species and is documented to be the result of several factors. However, current evidence for snake venom variability related to captivity maintenance is controversial. Here we report a compositional and functional investigation of individual and pooled venoms from long-term captive (LTC) and recently wild caught (RWC) B. jararaca snakes. The composition of individual venoms showed a remarkable variability in terms of relative abundance of toxins (evidenced by 1 DE and RP-HPLC), enzymatic activities (proteolytic, PLA2, and LAAO) and coagulant activity, even among captive specimens. Thus, no compositional and functional pattern could be established to assign each individual venom to a specific group. Conversely, pooled venom from LTC and RWC snakes showed no significant differences regarding protein composition (characterized by 1-DE and shotgun proteomics), enzymatic activities (proteolytic, PLA2 and LAAO) and biological function (coagulant, hemorrhagic and lethal activities), except for edematogenic activity, which was more prominent in RWC venom pool. Additionally, both pooled venoms displayed similar immunoreactivity with the bothropic antivenom produced by Instituto Butantan. Taken together, our results highlight the complexity and the high intraspecific variation of B. jararaca venom, that is not influenced at a discernible extent by captivity maintenance. BIOLOGICAL SIGNIFICANCE: Bothrops jararaca snakes are one of the main causes of snakebites in Southeastern Brazil. Due to its medical interest, the venom of this species is the most studied and characterized among Brazilian snakes and captive B. jararaca specimens are maintained for long periods of time in our venom production facility. However, knowledge on the influence of captivity maintenance on B. jararaca venom variability is scarce. In this report, we described a high compositional and functional variability of individual venoms from LTC and RWC B. jararaca snakes, which are not observed between LTC and RWC pooled venoms. This intraspecific variability is more likely to be due to genetic/populational differences rather than "captivity vs wild" conditions. In this regard, data generated by the present work support the use of venom from captive and wild snakes for antivenom production and scientific research. Moreover, the data generated by this study highlight the importance of analyzing individual venom samples in studies involving intraspecific venom variability. PMID- 30026102 TI - Expression levels of myoglobin in muscle and non-muscle tissues of rainbow trout Oncorhynchus mykiss, a hypoxia intolerant species. AB - Myoglobin (Mb) is one of the most intensively studied intracellular respiratory muscle proteins. Since the discovery of the fascinating fact that Mb is not confined only to oxidative muscle tissues but also is co-localized in different non-muscle tissues of cyprinids, hypoxia tolerant cyprinids have been established as the model teleost. Mb both at mRNA and protein levels have been reported in this study for the first time from a number of muscle and non-muscle tissues of rainbow trout Oncorhynchus mykiss, a hypoxia intolerant species. Mb transcript levels were high in the heart and slow skeletal muscle, and were comparatively high in the gonad and gill among the non-muscle tissues. Western-blotting by using anti-rainbow trout Mb peptide rabbit antibody detected Mb protein in the muscles and several non-muscle tissues. By both RNA in situ hybridization and immunofluorescence, Mb was localized in the cardiomyocytes and oxidative muscle fibers. On the other hand, Mb both at mRNA and protein levels was restricted to the lamellar epithelial cells of the gill, epithelial layers of hepato-biliary duct, neurons and endothelial cells of brain, ooplasm of gonad, kidney tubules, endothelial cells, and epithelial layer of intestine. Neuroglobin isoform 1 and 2 mRNAs along with Mb mRNA were localized in the granular layer of cerebellum. Considering the previous data reported for cyprinids, the expression sites of Mb in the muscle and non-muscle tissues of teleost could be universal, where Mb concerted with the other globins might play meaningful physiological roles. PMID- 30026103 TI - In situ monitoring and analysis of enamel demineralisation using synchrotron X ray scattering. AB - : Dental caries is one of the most common chronic diseases that affect human teeth. It often initiates in enamel, undermining its mechanical function and structural integrity. Little is known about the enamel demineralisation process caused by dental caries in terms of the microstructural changes and crystallography of the inorganic mineral phase. To improve the understanding of the carious lesion formation process and to help identify efficient treatments, the evolution of the microstructure at the nano-scale in an artificially induced enamel erosion region was probed using advanced synchrotron small-angle and wide angle X-ray scattering (SAXS and WAXS). This is the first in vitro and time resolved investigation of enamel demineralisation using synchrotron X-ray techniques which allows in situ quantification of the microstructure evolution over time in a simulated carious lesion. The analysis revealed that alongside the reduction of mineral volume, a heterogeneous evolution of hydroxyapatite (HAp) crystallites (in terms of size, preferred orientation and degree of alignment) could be observed. It was also found that the rate and direction of dissolution depends on the crystallographic orientation. Based on these findings, a novel conceptual view of the process is put forward that describes the key structural parameters in establishing high fidelity ultrastructure-based numerical models for the simulation of the enamel demineralisation process. STATEMENT OF SIGNIFICANCE: Hydroxyapatite (HAp) crystallites in the enamel dissolve during dental caries although little is known about the structural-chemical relationships that control the dynamic demineralisation process. For the first time this work investigated the in situ evolution of nano-scale morphology and the spatial distribution of ultrastructural HAp crystallites of human enamel during demineralisation in simulated caries. Advanced synchrotron SAXS and WAXS techniques showed that the heterogeneous evolution of crystallites (size, preferred orientation and degree of alignment) could be attributed to crystallographic-orientation-dependent anisotropic dissolution. Hence we propose a novel conceptual schematic diagram to describe the demineralisation process. These findings have important implications for understanding the detailed mechanisms of enamel demineralisation and provide insight into potential enamel remineralisation that could restore structural integrity and function. PMID- 30026104 TI - Characterization of unusual MgCa particles involved in the formation of foraminifera shells using a novel quantitative cryo SEM/EDS protocol. AB - : Quantifying ion concentrations and mapping their intracellular distributions at high resolution can provide much insight into the formation of biomaterials. The key to achieving this goal is cryo-fixation, where the biological materials, tissues and associated solutions are rapidly frozen and preserved in a vitreous state. We developed a correlative cryo-Scanning Electron Microscopy (SEM)/Energy Dispersive Spectroscopy (EDS) protocol that provides quantitative elemental analysis correlated with spatial imaging of cryo-immobilized specimens. We report the accuracy and sensitivity of the cryo-EDS method, as well as insights we derive on biomineralization pathways in a foraminifer. Foraminifera are marine protozoans that produce Mg-containing calcitic shells and are major calcifying organisms in the oceans. We use the cryo-SEM/EDS correlative method to characterize unusual Mg and Ca-rich particles in the cytoplasm of a benthic foraminifer. The Mg/Ca ratio of these particles is consistently lower than that of seawater, the source solution for these ions. We infer that these particles are involved in Ca ion supply to the shell. We document the internal structure of the MgCa particles, which in some cases include a separate Si rich core phase. This approach to mapping ion distribution in cryo-preserved specimens may have broad applications to other mineralized biomaterials. STATEMENT OF SIGNIFICANCE: Ions are an integral part of life, and some ions play fundamental roles in cell metabolism. Determining the concentrations of ions in cells and between cells, as well as their distributions at high resolution can provide valuable insights into ion uptake, storage, functions and the formation of biomaterials. Here we present a new cryo-SEM/EDS protocol that allows the mapping of different ion distributions in solutions and biological samples that have been cryo-preserved. We demonstrate the value of this novel approach by characterizing a novel biogenic mineral phase rich in Mg found in foraminifera, single celled marine organisms. This method has wide applicability in biology, and especially in understanding the formation and function of mineral-containing hard tissues. PMID- 30026105 TI - Characterization of proteins in different subcellular localizations for Escherichia coli K12. AB - Knowing the comprehensive knowledge about the protein subcellular localization is an important step to understand the function of the proteins. Recent advances in system biology have allowed us to develop more accurate methods for characterizing the proteins at subcellular localization level. In this study, the analysis method was developed to characterize the topological properties and biological properties of the cytoplasmic proteins, inner membrane proteins, outer membrane proteins and periplasmic proteins in Escherichia coli (E. coli). Statistical significant differences were found in all topological properties and biological properties among proteins in different subcellular localizations. In addition, investigation was carried out to analyze the differences in 20 amino acid compositions for four protein categories. We also found that there were significant differences in all of the 20 amino acid compositions. These findings may be helpful for understanding the comprehensive relationship between protein subcellular localization and biological function. PMID- 30026106 TI - Role of MicroRNAs and small RNAs in regulation of developmental processes and agronomic traits in Gossypium species. AB - Small RNAs (sRNAs) are short, non-coding, 17-24 nucleotides long RNA molecules that play vital roles in regulating gene expression in every known organism investigated to date including cotton (Gossypium ssp.). These tiny RNA molecules target diverse categories of genes from different bioliogical and metabolic processes and have been reported in the three domains of life. Small RNAs, including miRNAs, are involved in ovule and fiber development, biotic and abiotic stresses, fertility, and other biochemical processes in cotton species. Also, sRNAs are the critical components in RNA interference pathway. In this article, we have reviewed the research efforts related to the isolation and characterization of miRNAs using molecular and genomic approaches. The progress made in understanding the functional roles of miRNAs in regulation, alteration, and inactivation of fundamental plant processes and traits of importance in cotton are presented here. PMID- 30026108 TI - Vanishing Bile Ducts in the Long Term after Pediatric Hematopoietic Stem Cell Transplantation. AB - There are no structured studies on liver histology after hematopoietic stem cell transplantation (HSCT). We aimed to prospectively describe the clinicopathologic features of liver disease in the long term after HSCT in an observational, longitudinal study of liver histology in a consecutive cohort of children undergoing allogeneic HSCT. First liver biopsy was performed in presence of abnormal liver function tests and repeated per protocol thereafter. A previously reported semiquantitative score evaluating inflammation, cholestasis, and ductopenia (bile ducts-to-portal tracts ratio <= .5) was adopted. Graft-versus host disease (GVHD) was diagnosed according to standard criteria. We evaluated 131 biopsies taken in 50 HSCTs performed in 47 children (mean age, 9.7 +/- 5.2 years). Pre-HSCT chemotherapy was administered in 36 of 50 (72%). GVHD was diagnosed in 17 of 50 (34%). Over time the overall score decreased from a mean of 6 +/- 2.7 to 3.25 +/- .96 (P < .01), inflammation from 1.22 +/- 1.19 to 1 +/- 0 (not significant), and cholestasis from 3.9 +/- 2.08 to 1.5 +/- .58 (P < .01). Ductopenia, found in 113 of 131 biopsies (93%), worsened from .63 +/- .35 to .16 +/- .14 (P < .01). On multivariate analysis severe ductopenia (ratio <= .2) was associated with previous chemotherapy (P = .04), in particular with thiotepa, but not with history of GVHD. Vanishing bile duct syndrome after HSCT may be due to drug-induced liver disease. Longer follow-up will reveal whether these patients are prone to late liver-related morbidity and mortality. PMID- 30026107 TI - Low-Dose Anti-T Lymphoglobulin as Prophylaxis for Graft-versus-Host Disease in Unrelated Donor Transplantations for Acute Leukemias and Myelodysplastic Syndromes. AB - Chronic graft-versus-host disease (cGVHD) is a major complication after stem cell transplantation (HSCT). Several randomized studies already demonstrated that anti T lymphoglobulin (ATLG) is effective in preventing GVHD after myeloablative unrelated and HLA-identical sibling transplants. However, the issue of doses and the potential increase of relapses still remain unsolved. Here we report data on 190 patients with acute leukemia and myelodysplastic syndrome who underwent an unrelated HSCT with low-dose ATLG (15 to 30 mg/kg) given at an earlier timing (days -6 to -2). HSCT was performed from HLA 10/10 (n = 62, 33%), 9/10 (n = 91, 48%), 8/10 (n = 30, 16%), and <8/10 (n = 7, 4%) identical unrelated donor. Peripheral blood was the stem cell source in 42% (n = 80). Median follow-up was 51 months. Grades II to IV and III to IV acute GVHD were 26% and 9%, respectively, and 2-year overall and moderate to severe cGVHD were 23% and 14%, respectively. The 3-year incidences of relapse and nonrelapse mortality were 26% and 18%, respectively. The rates of 3-year overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 60%, 56% and 44%, respectively. Factors such as younger donor, good performance status, and early disease were associated with better outcome in terms of OS, DFS, and GRFS. Our data indicate that doses of ATLG lower that those used in randomized clinical trials can be used for GVHD prevention, even in the adult setting, without clear increases in relapse and infections; these findings need to be further validated by a prospective randomized study. PMID- 30026109 TI - Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of Severe Aplastic Anemia Patients with Infection: A Single-Center Retrospective Study. AB - To assess the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe aplastic anemia (SAA) patients with infection, we conducted a retrospective study on 65 SAA patients with infection who received allo-HSCT from August 2012 to December 2016. All patients received antibacterial and/or antifungal therapy before transplantation. The infection status after initial anti-infection therapy was classified as complete response (CR) (n = 14) or partial response/stable disease (PR/SD) (n = 51) before transplantation. The median times for myeloid engraftment in the PR/SD and CR groups were 10.5 days (range, 7 to 22) and 10 days (range, 8 to 11), with cumulative incidences of 98% and 100%, respectively. With a median follow-up of 788 days (range, 181 to 1758), patients with PR/SD had comparable results for 3-year estimated overall survival (85.4% versus 92.9%, P = .530) and 3-year failure-free survival (82.7% versus 92.9%, P = .458) with 14 patients with CR who received contemporaneous transplantation. In multivariate analysis, poor survival outcomes for the entire cohort was significantly associated with poor pretransplantation performance status. This retrospective study indicated that allo-HSCT may be a feasible therapeutic option for SAA patients with infection. PMID- 30026110 TI - Repurposing Nilotinib for Cytomegalovirus Infection Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Arm, Phase II Trial. AB - Platelet-derived growth factor receptor-alpha (PDGFRa) is a critical receptor for cytomegalovirus (CMV) entry into cells, leading to subsequent infection. This trial tested whether PDGFRa inhibition by nilotinib could prevent CMV infection in patients after allogeneic stem cell transplantation (allo-HSCT). Nilotinib (200 mg/day) was given continuously after engraftment, and plasma CMV DNA levels were monitored weekly. The primary endpoint was successful prophylaxis of CMV infection, defined as plasma CMV DNA copies less than 10,000 copies/mL, no anti CMV treatment initiated, and no clinical CMV disease by day 100. All 37 enrolled recipients and their donors were CMV seropositive. Thirty patients received matched sibling transplants, 15 received nonmyeloablative conditioning regimens, and 15 received antithymocyte globulin as a part of graft-versus-host disease prophylaxis. The median interval from transplantation to nilotinib treatment was 23 days, and the median duration of administration was 76 days. None of the 31 assessable patients had nilotinib-associated grade 3/4 adverse events or nilotinib discontinuation. Twenty-five of 31 assessable patients (80.6%) fulfilled the predefined criteria for successful CMV prophylaxis, and none of them had clinical CMV disease. Only 1 of 6 failed patients developed CMV colitis. Nilotinib is well tolerated in allo-HSCT recipients, and its preliminary efficacy results suggest that blocking CMV entry to prevent CMV infection may warrant further exploration. (ClinicalTrials.gov identifier: NCT01252017.). PMID- 30026111 TI - Human Herpes Virus-6-Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor-Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients. AB - Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P = .049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P = .036), whereas there was no significant difference among the latter 2 groups (P = .889). The development of HHV6 associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication. PMID- 30026112 TI - Laparoscopic Ovarian Cystectomy in a Patient with Situs Inversus Totalis. PMID- 30026113 TI - Bovine serum albumin nanoparticles containing amphotericin B were effective in treating murine cutaneous leishmaniasis and reduced the drug toxicity. AB - Cutaneous leishmaniasis is the most common form of leishmaniasis and the available chemotherapy causes serious side effects, justifying the search for new therapies. This study investigated the antileishmanial activity of bovine serum albumin (BSA) nanoparticles containing amphotericin B (AmB) against Leishmania amazonensis. The antiproliferative activity against promastigotes and amastigotes was assessed and the cytotoxicity was determined and compared to commercial AmB deoxycholate (AmB-D). In vivo antileishmania activity was evaluated in murine cutaneous leishmaniasis model. BSA nanoparticles showed spherical shape, mean size about 180 nm, zeta potential of ~ -45 mV and AmB encapsulation efficiency >95%. AmB-D was effective in promastigote and amastigote forms, while AmB-loaded BSA nanoparticles were more effective against amastigotes than promastigotes. AmB D was more effective than AmB-loaded BSA nanoparticles in both forms, however, the lowest cytotoxicity against macrophages was achieved by AmB-nanoparticles. BALB/c mice treated with AmB-D or AmB-loaded BSA nanoparticles showed a significant decrease in the lesion thickness at the infected footpad. Histopathological analysis after 3 weeks of treatment revealed AmB-D-related toxicity in heart, spleen, lung, liver and kidneys, while treatment with AmB loaded BSA nanoparticles did not reveal tissue toxicity. The antileishmanial efficacy and the reduced toxicity become BSA nanoparticles containing AmB a potential candidate for treating cutaneous leishmaniasis. PMID- 30026114 TI - Trypanocidal activity of tetradentated pyridine-based manganese complexes is not linked to inactivation of superoxide dismutase. AB - Two tetradentated pyridine-based manganese complexes (Cpd2 and Cpd3) were previously reported to inhibit efficiently the growth of Trypanosoma cruzi in vitro and in vivo. Cpd3 was also shown to be a potent inhibitor of trypanosomal iron superoxide dismutase (Fe-SOD) and its trypanocidal activity linked to the inhibition of this enzyme. Here we investigated the anti-trypanosomal activity of the two compounds against bloodstream forms of Trypanosoma brucei. Both compounds displayed potent trypanocidal activity against T. brucei bloodstream forms with minimum inhibitory concentrations (MICs) and 50% growth inhibition (GI50) values of 1 MUM and 0.2-0.3 MUM, respectively. Cpd2 and Cpd3 also showed cytotoxicity against HL-60 cells but based on GI50 values the human cells were 14 and 87 times less sensitive indicating moderate selectivity. In contrast to previous observation, Cpd3 did not inhibit Fe-SOD within trypanosomes and Cpd2 inhibited the enzyme only by 34%. As Fe-SOD together with ornithine decarboxylase play vital roles in the antioxidant defence in bloodstream forms of T. brucei, inhibition of both enzymes should be synergistically. Therefore, the interaction of Cpd2 and Cpd3 with the ornithine decarboxylase inhibitor eflornithine was determined. Both compounds were found in combination with eflornithine to produce only an additive effect. Thus, the observed lack of synergy between Cpd2/Cpd3 and eflornithine can be regarded as further indication that both compounds are not very strong inhibitors of trypanosomal Fe-SOD. Nevertheless, tetradentated pyridine-based manganese complexes are interesting compounds with promising anti trypanosomal activity. PMID- 30026115 TI - Prevalence of free living amoeba in the domestic waters reservoirs in Sfax, Tunisia. AB - Free living amoebas (FLA) are opportunistic pathogen found in different water sources in the environment. The aim of this study was to investigate the prevalence of free living amoeba in different samples of domestic water reserves (DWR) in Sfax region from Tunisia. It was a prospective study dealing with 486 water samples collected from different DWR. After filtration through a cellulose acetate membrane samples were cultured on non-nutrient agar and the FLA were detected and strained with Giesma, Trichrome and red nuclear stain for morphological and morphotypic studies. FLA were found in 62% of samples. The Acanthopodial morphotype was detected in 43%, Polytactic (38%), Monotactic (28%), Fan-shaped (17%), Rugose (11%), Dactilopodial (10%) and Eruptive (9%). These results demonstrate that domestic water reserves are a significant source of the FLA and maintenance of DWR is recommended. PMID- 30026117 TI - Evidence-based tobacco treatment utilization among dual users of cigarettes and E cigarettes. AB - Dual users of e-cigarettes and cigarettes may represent a unique and receptive population for evidence-based tobacco dependence treatment. We measured the frequency of quit attempts during the past year, and the use of evidence-based tobacco dependence treatments (i.e., behavioral and/or pharmacological treatments), among adult smokers who are current e-cigarette users (dual users) compared with those who do not use e-cigarettes (exclusive smokers). Data were analyzed from the 2015 National Health Interview Survey. Multivariate-adjusted regression models were used to examine the correlates of tobacco treatment use among adult smokers, comparing current e-cigarette users with those who did not use e-cigarettes, stratifying by age group, and adjusting for sociodemographic characteristics. Analyses were based on 5415 adult current cigarette smokers. Compared to exclusive smokers, dual users were more likely to report a quit attempt in the past year among adults <65 years: 18-24 years (odds ratio [OR] = 2.25), 25-44 years (OR = 1.60), and 45-64 years (OR = 1.96). With the exception of adults >=65 years, dual users reported low rates of using combination (behavioral and pharmacological) treatments that were not statistically different from exclusive smokers: 18-24 years (0.1% vs. 2.1%, respectively), 25-44 years (4.3% vs. 4.7%), and 45-64 years (3.0% vs. 8.3%). Despite higher likelihood for dual users to make a quit attempt, their use of evidence-based tobacco treatment is low, similar to exclusive smokers. Dual users of cigarettes and e-cigarettes represent a prime target for interventions to expand access and utilization of evidence-based tobacco use treatments. PMID- 30026118 TI - Socioeconomic variation in absolute cardiovascular disease risk and treatment in the Australian population. AB - Cardiovascular disease (CVD), preventable through appropriate management of absolute CVD risk, disproportionately affects socioeconomically disadvantaged individuals. The aim of this study was to estimate absolute and relative socioeconomic inequalities in absolute CVD risk and treatment in the Australian population using cross-sectional representative data on 4751 people aged 45-74 from the 2011-12 Australian Health Survey. Poisson regression was used to calculate prevalence differences (PD) and ratios (PR) for prior CVD, high 5-year absolute risk of a primary CVD event and guideline-recommended medication use, in relation to socioeconomic position (SEP, measured by education). After adjusting for age and sex, the prevalence of high absolute risk of a primary CVD event among those of low, intermediate and high SEP was 12.6%, 10.9% and 7.7% (PD, low vs. high = 5.0 [95% CI: 2.3, 7.7], PR = 1.6 [1.2, 2.2]) and for prior CVD was 10.7%, 9.1% and 6.7% (PD = 4.0 [1.4, 6.6], PR = 1.6 [1.1, 2.2]). The proportions using preventive medication use among those with high primary risk were 21.3%, 19.5% and 29.4% for low, intermediate and high SEP and for prior CVD, were 37.8%, 35.7% and 17.7% (PD = 20.1 [9.7, 30.5], PR = 2.1 [1.3, 3.5]). Proportions at high primary risk and not using medications among those of low, intermediate and high SEP were 10.6%, 8.8% and 4.7% and with prior CVD and not using medications were 8.5%, 6.3% and 4.1%. Findings indicate substantial potential to prevent CVD and reduce inequalities through appropriate management of high absolute risk in the population. PMID- 30026116 TI - Survival Prediction in High-grade Osteosarcoma Using Radiomics of Diagnostic Computed Tomography. AB - The poor 5-year survival rate in high-grade osteosarcoma (HOS) has not been increased significantly over the past 30 years. This work aimed to develop a radiomics nomogram for survival prediction at the time of diagnosis in HOS. In this retrospective study, an initial cohort of 102 HOS patients, diagnosed from January 2008 to March 2011, was used as the training cohort. Radiomics features were extracted from the pretreatment diagnostic computed tomography images. A radiomics signature was constructed with the lasso algorithm; then, a radiomics score was calculated to reflect survival probability by using the radiomics signature for each patient. A radiomics nomogram was developed by incorporating the radiomics score and clinical factors. A clinical model was constructed by using clinical factors only. The models were validated in an independent cohort comprising 48 patients diagnosed from April 2011 to April 2012. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Kaplan-Meier survival analysis was performed. The radiomics nomogram showed better calibration and classification capacity than the clinical model with AUC 0.86 vs. 0.79 for the training cohort, and 0.84 vs. 0.73 for the validation cohort. Decision curve analysis demonstrated the clinical usefulness of the radiomics nomogram. A significant difference (p-value <.05; log-rank test) was observed between the survival curves of the nomogram-predicted survival and non-survival groups. The radiomics nomogram may assist clinicians in tailoring appropriate therapy. PMID- 30026119 TI - Foreclosures and weight gain: Differential associations by longer neighborhood exposure. AB - While home foreclosure can lead to mental and physical health declines in persons experiencing the foreclosure, whether neighborhood foreclosures can affect the health of other residents is debatable. Using a racially/ethnically diverse sample of Chicago metropolitan area residents linked to foreclosure data from 2008 to 2014, we assessed whether exposure to neighborhood foreclosure fillings was associated with changes in objectively measured body mass index (BMI) over time. Using a retrospective longitudinal design, we employed fixed-effects regression models that controlled for individual- and neighborhood-level covariates to test the association of neighborhood foreclosures and BMI in >60,000 individuals and for individuals who did not move during the follow-up period. We also adjusted for the non-linear association of age and BMI and comorbidities and employed a series of sensitivity analysis to test for robustness. In fully adjusted models, a standard-deviation increase in neighborhood foreclosure filings within 500 m was associated with increases in BMI for individuals who did not move (nonmovers) (mean = 0.03 BMI units, 95% confidence interval: 0.01, 0.06). Neighborhood foreclosure rates were not associated with changes in BMI for the full sample. Given the potential deleterious effects of neighborhood foreclosure on individuals with longer exposure to the local vicinity, clarifying the potential health effects of neighborhood foreclosures would help policymakers when planning actions to prevent home losses, predatory home loans, and that aim to more efficiently return foreclosure properties to productive uses. PMID- 30026120 TI - WIND1 induces dynamic metabolomic reprogramming during regeneration in Brassica napus. AB - Plants often display a high competence for regeneration under stress conditions. Signals produced in response to various types of stress serve as critical triggers for de novo organogenesis, but the identity of these signaling molecules underlying cellular reprogramming are largely unknown. We previously identified an AP2/ERF transcription factor, WOUND INDUCED DEDIFFERENTIATION1 (WIND1), as a key regulator involved in wound-induced cellular reprogramming in Arabidopsis. In this study, we found that activation of Arabidopsis WIND1 (AtWIND1) in hypocotyl explants of Brassica napus (B. napus) enhances callus formation and subsequent organ regeneration. Gene expression analyses revealed that AtWIND1 enhances expression of B. napus homologs of ENHANCER OF SHOOT REGENERATION1/DORNROSCHEN (ESR1/DRN), which is a direct target of WIND1 in Arabidopsis. Further, time course hormonal analyses showed that an altered balance of endogenous auxin/cytokinin exists in AtWIND1-activated B. napus explants. Our mass spectrometry analyses, in addition, uncovered dynamic metabolomic reprogramming in AtWIND1-activated explants, including accumulation of several compounds, e.g. proline, gamma aminobutyric acid (GABA), and putrescine, that have historically been utilized as additives to enhance plant cell reprogramming in tissue culture. Our findings thus provide new insights into how WIND1 functions to promote cell reprogramming. PMID- 30026122 TI - A quantitative model of developmental RTK signaling. AB - Receptor tyrosine kinases (RTKs) control a wide range of developmental processes, from the first stages of embryogenesis to postnatal growth and neurocognitive development in the adult. A significant share of our knowledge about RTKs comes from genetic screens in model organisms, which provided numerous examples demonstrating how specific cell fates and morphologies are abolished when RTK activation is either abrogated or significantly reduced. Aberrant activation of such pathways has also been recognized in many forms of cancer. More recently, studies of human developmental syndromes established that excessive activation of RTKs and their downstream signaling effectors, most notably the Ras signaling pathway, can also lead to structural and functional defects. Given that both insufficient and excessive pathway activation can lead to abnormalities, mechanistic analysis of developmental RTK signaling must address quantitative questions about its regulation and function. Patterning events controlled by the RTK Torso in the early Drosophila embryo are well-suited for this purpose. This mini review summarizes current state of knowledge about Torso-dependent Ras activation and discusses its potential to serve as a quantitative model for studying the general principles of Ras signaling in development and disease. PMID- 30026121 TI - Distinct mechanisms for PDGF and FGF signaling in primitive endoderm development. AB - FGF signaling is known to play a critical role in the specification of primitive endoderm (PrE) and epiblast (Epi) from the inner cell mass (ICM) during mouse preimplantation development, but how FGFs synergize with other growth factor signaling pathways is unknown. Because PDGFRalpha signaling has also been implicated in the PrE, we investigated the coordinate functions of PDGFRalpha together with FGFR1 or FGFR2 in PrE development. PrE development was abrogated in Pdgfra; Fgfr1 compound mutants, or significantly reduced in Pdgfra; Fgfr2 or PdgfraPI3K; Fgfr2 compound mutants. We provide evidence that both Fgfr2 and Pdgfra play roles in PrE cell survival while Fgfr1 controls PrE cell specification. Our results suggest a model where FGFR1-engaged ERK1/2 signaling governs PrE specification while PDGFRalpha- and by analogy possibly FGFR2- engaged PI3K signaling regulates PrE survival and positioning in the embryo. Together, these studies indicate how multiple growth factors and signaling pathways can cooperate in preimplantation development. PMID- 30026123 TI - Combining complete chloroplast genome sequences with target loci data and morphology to resolve species limits in Triplostegia (Caprifoliaceae). AB - Species represent the most basic unit of taxonomy. As such, species delimitation represents a crucial issue for biodiversity conservation. Taxonomic practices were revolutionized in the last three decades due to the increasing availability of molecular phylogenetic data. The genus Triplostegia (Caprifoliaceae) traditionally consists of two species, T. glandulifera and T. grandiflora, distinguishable mainly based on quantitative morphological features. In this study, we sequenced nine chloroplast loci (i.e., accD, psbK-psbI, rbcL-accD, rpoB trnC, rps16-trnQ, trnE-trnT, trnF-ndhJ, trnH-psbA, trnS-trnG) and one nuclear locus (ITS) of 16 individuals of Triplostegia representing the entire distribution range of both species recognized. Furthermore, we also obtained whole chloroplast sequences for 11 of the 16 individuals for which silica gel dried leaves were available. Our phylogenetic analyses integrating chloroplast genome sequences and multiple loci data revealed that Triplostegia includes four main clades that largely match geography. Neither T. grandiflora nor T. glandulifera was recovered as monophyletic and no diagnosable differences in leaf, flower, and pollen traits were detected between the two species, indicating the need for a revised species circumscription within Triplostegia. Our study highlights the importance of combining data from different sources while defining species limits. PMID- 30026124 TI - Evidence for mtDNA capture in the jacamar Galbula leucogastra/chalcothorax species-complex and insights on the evolution of white-sand ecosystems in the Amazon basin. AB - Jacamar species occur throughout Amazonia, with most species occupying forested habitats. One species-complex, Galbula leucogastra/chalcothorax, is associated to white sand ecosystems (WSE). Previous studies of WSE bird species recovered shallow genetic structure in mtDNA coupled with signs of gene flow among WSE patches. Here, we characterize diversification of the G. leucogastra/chalcothorax species-complex with dense sampling across its distribution using mitochondrial and genomic (Ultraconserved Elements, UCEs) DNA sequences. We performed concatenated likelihood and Bayesian analysis, as well as a species-tree analysis using *BEAST, to establish the phylogenetic relationships among populations. The mtDNA results recovered at least six geographically-structured lineages, with G. chalcothorax embedded within lineages of G. leucogastra. In contrast, both concatenated and species-tree analyses of UCE data recovered G. chalcothorax as sister to all G. leucogastra lineages. We hypothesize that the mitochondrial genome of one of the G. leucogastra lineage (Madeira) was captured into G. chalcothorax in the past. We discuss how WSE evolution and the coevolution of mtDNA and nuclear genes might have played a role in this apparently rare event. PMID- 30026125 TI - A way forward of alternative methods in China: Implementation of skin corrosivity potential using in vitro reconstructed human epidermis. AB - The purpose of present study was to investigate the applicability of reconstructed human epidermis model to identify skin corrosive UN GHS Categories 1A, 1B/1C and non-corrosive chemicals in China. By using a commercialized reconstructed human epidermis model, China EpiSkinTM which had been proven to be applicable as a stand-alone test method to predict skin irritation in previous study, the predictive capacity of corrosion was assessed with 76 chemicals that included 30 reference chemicals recommended by OECD TG 431 in this study. The latter reference chemicals were tested in three runs, the within-laboratory reproducibility reached 100%, the accuracy was 90% for distinguishing corrosive and non-corrosive chemicals and 80% for sub-categorization (Cat. 1A vs Cat. 1B/1C vs non corrosive). Additional 46 chemicals were also tested, and the overall accuracy for sub-categorization of all 76 tested chemicals was 80.3% with 91.7% sensitivity for Category 1A, 82.1% sensitivity for category 1B/1C and 75% specificity which met all required predictive capacity by OECD. The present study results show that China EpiSkinTM model can be applied to predict sub categorization 1A and 1B/1C of corrosive chemicals. The availability of skin corrosion in vitro test method provides the applicability of in vitro non-animal testing method for chemicals widely used in various industries, and will further support the implementation and promotion of alternative methods in China. PMID- 30026126 TI - DeltaNp63 promotes abnormal epidermal proliferation in arsenical skin cancers. AB - Arsenic is known to perturb epidermal homeostasis and induce abnormal keratinocyte proliferation, leading to skin carcinogenesis. P63 and its isoforms are essential to regulate epidermal homeostasis. This study aimed to investigate the role of p63 isoforms in abnormal epidermal proliferation induced by arsenic. Using arsenic-induced Bowen's disease (As-BD; an intraepidermal carcinoma) as a disease model, we found that in As-BD, the expression of proliferating basal keratinocytes marker cytokeratin 14 (CK14) and N-terminal truncated p63 isoform (DeltaNp63; proliferation regulator) was increased, however, that of the differentiation marker cytokeratin 10 (CK10) and full-length p63 isoform (TAp63; differentiation regulator) was decreased in squamous cells as compared with healthy subjects. These observations were recapitulated in the arsenic-treated skin equivalents (SEs). The SEs showed that arsenic increased epidermal thickness, induced abnormal proliferation, and increased DeltaNp63 expression in squamous cells as compared with the control. Treatment of cultured normal human epidermal keratinocytes (HKCs) with arsenic increased CK14 and ?Np63 expressions, but decreased TAp63 and CK10 expressions. Furthermore, knockdown of DeltaNp63 by RNA interference abrogated arsenic-induced CK14 expression and recovered the reduction of TAp63 and CK10 caused by arsenic. These findings indicated that DeltaNp63 is a pivotal regulator in the abnormal cell proliferation in arsenical cancers. PMID- 30026127 TI - Supercritical carbon dioxide-based technologies for the production of drug nanoparticles/nanocrystals - A comprehensive review. AB - Low drug bioavailability, which is mostly a result of poor aqueous drug solubilities and of inadequate drug dissolution rates, is one of the most significant challenges that pharmaceutical companies are currently facing, since this may limit the therapeutic efficacy of marketed drugs, or even result in the discard of potential highly effective drug candidates during developmental stages. Two of the main approaches that have been implemented in recent years to overcome poor drug solubility/dissolution issues have frequently involved drug particle size reduction (i.e., micronization/nanonization) and/or the modification of some of the physicochemical and structural properties of poorly water soluble drugs. A large number of particle engineering methodologies have been developed, tested, and applied in the synthesis and control of particle size/particle-size distributions, crystallinities, and polymorphic purities of drug micro- and nano-particles/crystals. In recent years pharmaceutical processing using supercritical fluids (SCF), in general, and supercritical carbon dioxide (scCO2), in particular, have attracted a great attention from the pharmaceutical industry. This is mostly due to the several well-known advantageous technical features of these processes, as well as to other increasingly important subjects for the pharmaceutical industry, namely their "green", sustainable, safe and "environmentally-friendly" intrinsic characteristics. In this work, it is presented a comprehensive state-of-the-art review on scCO2-based processes focused on the formation and on the control of the physicochemical, structural and morphological properties of amorphous/crystalline pure drug nanoparticles. It is presented and discussed the most relevant scCO2, scCO2-based fluids and drug physicochemical properties that are pertinent for the development of successful pharmaceutical products, namely those that are critical in the selection of an adequate scCO2-based method to produce pure drug nanoparticles/nanocrystals. scCO2-based nanoparticle formation methodologies are classified in three main families, and in terms of the most important role played by scCO2 in particle formation processes: as a solvent; as an antisolvent or a co-antisolvent; and as a "high mobility" additive (a solute, a co-solute, or a co-solvent). Specific particle formation methods belonging to each one of these families are presented, discussed and compared. Some selected amorphous/crystalline drug nanoparticles that were prepared by these methods are compiled and presented, namely those studied in the last 10-15 years. A special emphasis is given to the formation of drug cocrystals. It is also discussed the fundamental knowledge and the main mechanisms in which the scCO2-based particle formation methods rely on, as well as the current status and urgent needs in terms of reliable experimental data and of robust modeling approaches. Other addressed and discussed topics include the currently available and the most adequate physicochemical, morphological and biological characterization methods required for pure drug nanoparticles/nanocrystals, some of the current nanometrology and regulatory issues associated to the use of these methods, as well as some scale-up, post-processing and pharmaceutical regulatory subjects related to the industrial implementation of these scCO2-based processes. Finally, it is also discussed the current status of these techniques, as well as their future major perspectives and opportunities for industrial implementation in the upcoming years. PMID- 30026128 TI - Empowered with Movement to Prevent Obesity & Weight Regain (EMPOWER): Design and methods. AB - Promoting lasting weight loss among older adults is an important public health challenge. Participation in physical activity aids in weight loss and is important for the maintenance of physical function and quality of life. However, traditional intensive lifestyle interventions place a focus on discrete bouts of structured activity, leaving much of the remainder of the day for sedentary behavior. Structured exercise and weight loss programs often produce short-term weight loss that is typically followed by weight regain, and older adults are more likely to regain weight as fat mass rather than lean mass. Preliminary evidence suggests a focus on day-long movement intended to minimize time spent sitting produces better short-term weight loss and weight maintenance. Herein we describe the design and methods for a three-arm randomized controlled trial comparing mHealth-supported weight loss (WL) + structured exercise (EX); WL + a novel daily movement intervention (SitLess); and WL + EX + SitLess. Older adults (N = 180) will be randomly assigned to one of the three interventions, each comprised of a 6-month intensive phase; a 3-month transition phase; and a 9-month maintenance phase. The primary aim of the study is to determine whether the addition of SitLess to a traditional intensive lifestyle intervention comprised of dietary weight loss and structured exercise produces a larger 18-month reduction in body weight relative to WL + EX and WL + SitLess. PMID- 30026129 TI - Safety and Feasibility of a Nocturnal Heart Rate Elevation-Exploration of a Novel Treatment Concept. AB - BACKGROUND: Diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) are associated with myocardial fibrosis and concentric left ventricular hypertrophy (LVH). In a preclinical model of LVH, we demonstrated that a moderate increase in heart rate can reduce interstitial fibrosis and improve LV compliance. We therefore hypothesized that moderately elevated heart rates can be used to beneficially modify the myocardial substrate in patients with diastolic dysfunction and HFpEF. As a preliminary step to test this hypothesis, we evaluated if patients can tolerate this novel pacemaker-based treatment approach without adverse effects. METHODS AND RESULTS: A pacemaker mediated increase in heart rate to 100 beats/min for 5 hours at night was tested over 4 weeks in 10 patients with diastolic dysfunction. The patients underwent a physical examination, biomarker collection, 6-minute walk test, heart failure questionnaire, and echocardiography before and after the pacing intervention. None of the patients reported any symptoms at night. No arrhythmias were induced. Eight patients completed the protocol. Three patients experienced unanticipated daytime pacing from an interfering pacemaker function. There were no detrimental changes in biomarkers or LV systolic function. CONCLUSIONS: Nocturnal pacing at a rate of 100 beats/min appears to be safe and well tolerated in this small exploratory patient cohort. PMID- 30026130 TI - Increased Urinary Liver-Type Fatty Acid-Binding Protein Level Predicts Worsening Renal Function in Patients With Acute Heart Failure. AB - BACKGROUND: Urinary liver-type fatty acid-binding protein (L-FABP) is a potential biomarker for acute kidney injury, and it in turn increases cardiovascular mortality. We tested whether the urinary L-FABP level predicted short- and mid term outcomes in patients with acute heart failure. METHODS AND RESULTS: We enrolled consecutive patients with acute heart failure, and measured their urinary L-FABP levels before acute treatment. Worsening renal function (WRF), defined as both an absolute increase in the serum creatinine level of >=0.3mg/dL and a >=25% relative increase in its level from baseline, occurred in 37 (26.8%) of 138 patients. Patients with a urinary L-FABP level above the upper normal limit (8.4 ug/g creatinine) (n = 49; 35.5%) were more likely than those with a urinary L-FABP level within normal limits (n = 89; 64.5%) to develop WRF (n = 26 [53.1%] vs n = 11 [12.4%]; P < .001). A urinary L-FABP level above the upper limit was independently associated with WRF (hazard ratio 1.8; P = .01). During 1 year of follow-up, 12 patients (8.7%) died, and urinary L-FABP level had no association with all-cause mortality. There was, however, a tendency toward a higher readmission rate in patients with a urinary L-FABP level above the upper normal limit who survived the index hospitalization (n = 46) than in those without an abnormal L-FABP level (n = 88; n = 13 [28.3%] vs n = 13 [14.8%]; log rank P = .06). CONCLUSIONS: Increased urinary L-FABP level before treatment may predict WRF in patients with acute heart failure. Further investigation is warranted for its predictive ability of adverse outcomes. PMID- 30026131 TI - Chebulinic acid and Boeravinone B act as anti-aging and anti-apoptosis phyto molecules during oxidative stress. AB - INTRODUCTION: Aquatic pollutant Malachite green (MG) induces oxidative stress by producing intracellular H2O2 and associated hydroxyl, hydroxymethyl or hydroperoxide radicals in Saccharomyces cerevisiae. These radicals disturb cellular functions leading to early aging. Exogenous supply of natural antioxidants may play a crucial role as anti-aging by ensuring the cellular survival. METHODS: Protective effect of Chebulinic acid (CA) and Boeravinone B (BB) was biochemically evaluated by measuring the expression levels of antioxidant enzymes. Intracellular oxidants generation, nuclear damage, necrosis, apoptosis, reduction in caspase 3/7 activity studied microscopically, spectrofluorometrically and biochemically along with growth dynamics and relative quantitation of Yap1, Sir2 and Bir1 expression using RT-PCR. RESULTS: Malachite green (MG) showed adverse effect on S. cerevisiae showing 400.83% enhancement in accumulation of intracellular H2O2 and associated hydroxyl, hydroxymethyl or hydroperoxide radicals. Independent supplementation of CA (5 MUg/ml) and BB (3 MUg/ml) significantly reduced the accumulation by 385.78 and 372.68%, respectively. Presence of MG extended the lag phase of growth curve and also reduced colony forming units (CFUs)/ml to 3 * 108 from 15 * 108. Whereas, CA and BB maintained the normal growth curve, CFUs and proved as anti-aging. Elevation in the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) by 241.35, 539.02 and 432.60% was observed after 2 h MG exposure. However, CA and BB significantly reduced the CAT, SOD and GPx activities. Microscopic observation of CA and BB augmented cells revealed protection from H2O2 and associated hydroxyl, hydroxymethyl or hydroperoxide radicals accumulation, nuclear disorganization, morphological distortion, apoptosis and necrosis contrary to MG exposed cells. An enhancement of 112.78% in caspase 3/7 activity was noted in MG exposed cells over control. Both CA and BB supplementation reduced the caspase 3/7 activity by 106.06 and 105.82%, respectively which was almost near normal. MG was found to induce the expression of yeast transcription factor Yap1; while presence of CA and BB restored expression of Yap1. Expression of longevity responsible gene Silent Information Regulator (Sir2) was also found to be reduced during MG exposure. However, CA and BB triggered the expression of Sir2. Similarly, MG lowered the expression of Baculoviral IAP repeat (Bir1) which is the inhibitor of apoptosis while CA and BB aided the over expression of Bir1. CONCLUSIONS: CA and BB supplementation could significantly decrease oxidative stress, enhance cell viability and ultimately protected S. cerevisiae cells form aging. PMID- 30026132 TI - Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment. AB - HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype. PMID- 30026133 TI - Pseudomonas fluorescens tolerance to benzyldimethyldodecyl ammonium chloride: Altered phenotype and cross-resistance. AB - OBJECTIVES: Benzyldimethyldodecyl ammonium chloride (BDMDAC) is a quaternary ammonium compound (QAC) with bactericidal action that is used as an active molecule in detergent formulations. Pseudomonas fluorescens is a Gram-negative bacterium with versatile metabolism that is frequently present in biofilms on industrial surfaces. This work reports P. fluorescens adaptation to BDMDAC and subsequent concurrent reduced susceptibility to the QAC benzalkonium chloride (BAC) and the antimicrobial ciprofloxacin (CIP). METHODS: Stepwise adaptation to increasing concentrations of BDMDAC was easily achieved and caused changes in the bacterial phenotype of P. fluorescens. Adaptation was evaluated through minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determination and was subsequently confirmed by time-kill curves. Biofilm phenotype (biomass and number of cells) was characterised for the adapted and reference strains after treatment with BDMDAC, BAC and CIP. RESULTS: Susceptibility to BAC and CIP was reduced in adapted P. fluorescens. Biofilms developed by the adapted strain had 20% more mass and a higher number of bacteria (2 log). CONCLUSIONS: This study revealed that exposure to sublethal concentrations of BDMDAC may select tolerant strains to that product as well as to related products and unrelated antimicrobial agents. PMID- 30026134 TI - Taurine treatment decreases inflammation and oxidative stress in lungs of adult mice exposed to cigarette smoke. AB - Taurine is the major free amino acid found in mammalian cells and is known to be an antioxidant and membrane-stabilizing agent. This study aimed to evaluate the effects of taurine on oxidative stress and inflammatory response in the lungs of mice exposed to cigarette smoke. Fifty male C57BL/6 mice were divided into 5 groups: control group (CG), vehicle group (VG), taurine group (TG), cigarette smoke group (CSG), and cigarette smoke + taurine group (CSTG). For five consecutive days, CSG and CSTG were exposed to 4 cigarettes 3 times a day. Taurine administration was able to reduce total leukocytes in bronchoalveolar lavage fluid in CSTG compared to CSG. There was an increase in antioxidant superoxide dismutase and catalase activity in CSG compared to that in CG and TG, and a decrease in CSTG compared to CSG. There was an increase in the concentration of TNF and IL-17 in CSG and CSTG compared to CG and TG. There was an increase in the concentration of IL-22 in CSG compared to CG and TG, and a decrease in CSTG compared to CSG. The administration of taurine has been shown to reduce the inflammation and oxidative stress induced by short-term exposure to cigarette smoke. PMID- 30026135 TI - Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges. AB - Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species. PMID- 30026136 TI - Safety assessment of Oryeong-san, a traditional herbal formula: Study of subacute toxicity and influence of cytochrome P450s and UDP-glucuronosyltransferases. AB - Oryeong-san is a traditional herbal formula that is used for the treatment of common genitourinary diseases in Korea and other Asian countries. However, little is known about its safety and influence on drug metabolism. In the present study, we investigated the subacute toxicity of an Oryeong-san water extract (OSWE) in rats and its effects on activities of drug-metabolizing enzymes. Subacute toxicity was modeled in animals exposed to treatment with the extract at multiple doses. Rats were given OSWE by oral gavage at 0, 1000, 2000 and 5000 mg/kg/day for 4 weeks. We checked general observations and investigated any changes of body/organ weight, food consumption, hematology, serum biochemistry, and urinalysis in vivo; and the activities of human microsomal cytochrome P450s (CYP450s) and UDP-glucuronosyltransferase (UGT) isozymes in vitro. We found that OSWE caused no significant toxicological changes at the doses tested. Therefore, the no observed adverse effect level of OSWE was more than 5000 mg/kg/day for male and female rats. OSWE inhibited the activities of CYP2C19 (IC50: 737.69 MUg/mL) and CYP2E1 (IC50: 177.77 MUg/mL). These results indicate that OSWE may be safe with no drug-related toxicity for up to 4 weeks and provide useful information concerning its potential to interact with conventional drugs or other herbal medicines. PMID- 30026137 TI - Parent attitudes toward resident involvement in their child's strabismus surgery. AB - PURPOSE: To explore patterns in parents' understanding and preferences related to ophthalmology resident participation in their child's strabismus surgery. METHODS: Over a 4-week period, a survey was distributed at a suburban, academic eye center to English-speaking parents of children with strabismus who have not previously undergone, or were not being scheduled for, strabismus surgery. RESULTS: All of the 64 eligible parents participated in the survey. For a resident to assist or perform the surgery, 80% and 97% of parents, respectively, indicated it was important or extremely important to be asked permission beforehand; 69% indicated the attending surgeon should ask permission for the resident to perform the surgery, whereas only 11% believed a standard written consent was sufficient. Of the 64 respondents, 77% indicated that they would agree to a resident assisting with their child's operation; 36% would agree to a resident performing the surgery. CONCLUSIONS: Nearly all parents in our study indicated that they would want to be informed of resident involvement by the attending surgeon. The vast majority would consent to having an ophthalmology resident assist in their child's strabismus surgery, and more than one-third would consent to having the resident perform their child's strabismus surgery. Obtaining informed consent prior to resident involvement increases transparency and highlights the importance of ophthalmology residency education. PMID- 30026138 TI - Rapid Ventricular Pacing for Neurovascular Surgery: A Study on Cardiac and Cerebral Effects. AB - BACKGROUND AND OBJECTIVE: Intraoperative rupture of a cerebral aneurysm during neurosurgery can be a devastating event that increases perioperative morbidity and mortality. Rapid ventricular pacing (RVP) is a technique to obtain flow arrest for short periods of time during dissection or rupture of the aneurysm. The objective of this study was to evaluate the neurological and cardiac effects of repetitive periods of RVP during cerebrovascular surgery. METHODS: Data from patients who underwent repetitive RVP during craniotomy for cerebrovascular disorders were retrospectively analyzed from a single-center medical records database (Cegeka Medical Health Care Systems). We compared preoperative and postoperative troponin levels (cTnI) to assess cardiac ischemia. Preoperative and postoperative magnetic resonance imaging (MRI) results were screened for RVP induced infarcts by evaluating diffusion restriction in the hemisphere contralateral to the operated side and the fossa posterior. RESULTS: A total of 37 patients were analyzed. An immediate decrease of systolic arterial blood pressure (<60 mm Hg) was achieved after initiation of RVP. Postoperative MRI did not reveal areas of diffusion restriction. RVP tended to be a predictor of postoperative cTnI increase. Preoperative and postoperative cTnI levels were higher in patients with a subarachnoid hemorrhage compared to patients without one. After 24 hours cTnI jevels normalized to preoperative values. CONCLUSIONS: Systolic arterial blood pressure decreased after RVP but normalized immediately when pacing stopped. MRI of the brain did not show RVP-related ischemia and the limited cTnI level increase normalized to preoperative values. Therefore, RVP during short periods of time seems to be a safe blood pressure-lowering technique for the brain and heart. PMID- 30026139 TI - Usage of Bone Wax to Facilitate Percutaneous Endoscopic Cervical Discectomy Via Anterior Transcorporeal Approach for Cervical Intervertebral Disc Herniation. AB - BACKGROUND: Currently, anterior transdiscal access and posterior interlaminar approach are the main approaches for percutaneous endoscopic cervical discectomy (PECD). To overcome access shortcomings, we previously described a novel anterior endoscopic transcorporeal approach on a migrated cervical disc. We innovatively introduced bone wax into endoscopic surgery to aid hemostasis and facilitate the process of drilling an intracorporeal tunnel. METHODS: Five patients with cervical intervertebral disc herniation (CIDH) were treated by PECD via the anterior transcorporeal approach. During the operation, we marked the punctured tunnel with bone wax containing indigo carmine as a guide and smeared bone wax on the endoscopic burr to aid hemostasis. RESULTS: A satisfactory clinical outcome was observed in all 5 patients postoperatively; pain and neurologic condition were dramatically improved. Surgery-related complications, such as esophageal injury, vascular rupture, hematoma, intervertebral disc infection, or postoperative headache, were not encountered. A computed tomography scan was used to observe the process of bone healing. At 3-month postoperative follow-up, the bone defect within the drilling tunnel had partially shrank and was completely healed at 6 months postoperatively. CONCLUSIONS: The anterior endoscopic transcorporeal approach for PECD is a novel, valuable alternative for the treatment of CIDH. Bone wax could indeed facilitate the operation by guiding the drilling process and instantly controlling the bleeding without obvious interference with bone healing. Long-term follow-up is warranted in further clinical studies. PMID- 30026141 TI - Fifteen Years and 2530 Patients: The Evolution of Instrumentation, Surgical Strategies, and Outcomes in Adolescent Idiopathic Scoliosis in a Single Institution. AB - BACKGROUND: Over the past decade, the surgical treatment of adolescent idiopathic scoliosis (AIS) has established new techniques to reduce curve severity and shifted to include the regular use of pedicle screws. Few studies have focused on this evolving trend in AIS correction surgery. In this study, we investigated how the operative approach, instrumentation, and surgical techniques have changed over the past 15 years and to quantify the related improvements in AIS surgical treatment. METHODS: This is a retrospective review of a prospective AIS registry in a single center. Patient data were reviewed from January 2001 to December 2015. The age and surgical case distribution were recorded for each year. Trends in classification use, instrumentation types, levels of fusion, and surgical approaches were analyzed by year. The major Cobb angles and correction rates were compared between different instrumentations and surgical approaches. RESULTS: A total of 2530 patients with AIS (83.0% female) were included, with a mean age of 15.14 years. Most patients underwent surgery at 14 years of age (473 patients, 18.7%), followed by 15 years of age (468 patients, 18.5%). In our center, the classification of patients with AIS shifted from the King classification to the Lenke classification in 2005. The major baseline Cobb angle of the entire cohort averaged 50.99 degrees and this mean Cobb angle decreased to 14.41 degrees after surgery. The correction rates for the first 3 years (2001-2003) were less than 70%, whereas the correction rates for the rest of the years were all greater than 70%. In addition, significantly higher correction rates were observed in patients with Cobb angles <90 degrees (72.93% vs. 55.61%, P < 0.001). A total of 218 anterior-only surgeries and 109 combined anteroposterior surgeries were performed; the remaining 2205 surgeries were performed with a posterior-only approach. The use of anterior-only and anteroposterior approaches trended to decrease after 2005. The correction rate of anterior-only approaches was significantly greater than posterior-only and anteroposterior approaches (77.86%, 72.51%, and 59.37%, respectively). In patients corrected with a posterior-only approach, the screw-hook hybrid construct was used in 342 patients, whereas the all-pedicle-screw construct was used in 1835 patients. The shift from hybrid to all-screw construct occurred in 2006. In patients with thoracic AIS, the correction rate was significantly higher in the all-screw group (73.26% vs. 67.76%; P < 0.001). CONCLUSIONS: Consistent improvement of major curve correction has been achieved by the spine community over 15 years. After stabilized coronal correction and fewer fusion levels, the next steps in this evolution are the restoration of sagittal profiles, especially the hypokyphosis seen in patients with Lenke 1, the posterior minimally invasive approach, and a fast-track return to activity. PMID- 30026140 TI - Surgical Techniques and Associated Outcomes of Primary Chondrosarcoma of the Spine. AB - BACKGROUND: Only a few case reports and case series exist reporting on primary chondrosarcomas of the spine. The objective of this study was to gain a better understanding of this patient population and surgical techniques used for treatment. METHODS: A systematic literature search was performed in January 2018 querying several scientific databases, per PRISMA guidelines. Surgery type was categorized into en bloc, piecemeal excision, or non-en bloc or piecemeal excision. RESULTS: In total, 34 records and 3 patients were included in the systematic review, yielding 87 patients with primary chondrosarcoma of the spine. The mean age was 41.5 years, with the tumor most commonly arising in adult patients (90.8%, 79/87); most were male (66.7%, 58/87). Those who underwent piecemeal excision had the highest death rate (56.7%, P <= 0.001) and highest rate of recurrence (63.3%, P <= 0.001) compared with en bloc and non-en bloc or piecemeal excision. The calculated reduced relative risk (RR) comparing en bloc with the other surgical techniques for recurrence and mortality was 78.8% (RR, 0.21; P <= 0.001) and 80.7% (RR, 0.19; P<= 0.001), respectively. Survival analysis showed patients with a piecemeal excision had 9.4 times hazards ratio for death compared with en bloc (P = 0.001). CONCLUSIONS: CS is a rare lesion that most commonly presents in adult male patients. En bloc surgical resection was associated with a significant decrease in recurrence, mortality, and increased survival compared with the other surgical techniques. In addition, any surgical technique that involved entering the tumor capsule showed a significantly greater risk for recurrence and death. PMID- 30026142 TI - Effect of the Hybrid Emergency Room System on Functional Outcome in Patients with Severe Traumatic Brain Injury. AB - OBJECTIVE: The timely treatment of severe traumatic brain injury (TBI) is essential for limiting the effects of damage; however, there is no consensus regarding an effective method for early intervention. In August 2011, our hospital launched a novel trauma workflow using the hybrid emergency room (ER), consisting of an interventional radiology-computed tomography (CT) unit installed in the trauma resuscitation room to facilitate early interventions. The aim of this study was to evaluate effects of the hybrid ER system on functional outcomes in patients with severe TBI. METHODS: We conducted a retrospective historical control study of patients with severe TBI (Glasgow Coma Scale score <=8) who received conventional treatment (August 2007-July 2011) or treatment in the hybrid ER (August 2011-July 2015). The primary end point was unfavorable outcome at 6 months after injury (death, vegetative state, or lower severe disability) as evaluated by the Glasgow Outcome Scale-Extended. Secondary end points included time from arrival to the start of CT examination and emergency intracranial operation. Potential confounders were adjusted with multivariable logistic regressions. RESULTS: Among 158 included patients, 88 were in the conventional group and 70 were in the hybrid ER group. After model adjustment, the hybrid ER group was significantly associated with a reduction in unfavorable outcomes. Times to CT examination and intracranial operation were significantly shorter in the hybrid ER group than that in the conventional group. CONCLUSIONS: The hybrid ER system is useful for realizing immediate CT examination and emergency surgery and improving functional outcomes in patients with severe TBI. PMID- 30026143 TI - Experience Using the Pterional Keyhole Approach for the Treatment of Ruptured Intracranial Aneurysms of the Anterior Circulation. AB - BACKGROUND: The pterional keyhole approach is a more recently introduced minimally invasive version of the traditional pterional approach for treating aneurysms of the anterior circulation. METHODS: In this study, we compared operative parameters and clinical outcomes in patients treated with the pterional keyhole approach and historical controls in whom the traditional pterional approach was used. We reviewer records of 356 patients treated with the pterional keyhole approach between 2009 and 2016, along with those of 301 patients treated via the traditional pterional approach at the same period who served as a control group. The clinical manifestations, surgical details, postoperative complications, and modified Rankin Scale scores in the 2 groups were retrospectively compared. RESULTS: There were 408 aneurysms in the study group and 362 aneurysms in the control group. In the pterional keyhole group, the total clipping ratio was 93.6%, leaving a remnant/wrapping rate of 6.37%, compared with 93.9% and 6.08%, respectively, in the standard pterional group. In the patients treated via the keyhole approach, the mean bone flap diameter was 4 * 3 cm, mean blood loss was 204 +/- 100 mL, mean operation time was 160 +/- 57 minutes, and mean length of stay was 8.32 +/- 2.72 days, compared with control group parameters of 5 * 6 cm, 284 +/- 150 mL, 180 +/- 49 minutes, and 11.32 +/- 2.48 days, respectively. At a 6-month follow-up, 71.1% had a favorable outcome, 25.8% had a poor outcome, and the mortality was 3.09%, compared with 68.1%, 29.9% and 1.99%, respectively, in the control group. CONCLUSIONS: The pterional keyhole approach offers shorter operative times, less blood loss, shorter length of stay, and improved cosmesis without sacrificing outcomes compared with traditional pterional craniotomy. PMID- 30026144 TI - Percutaneous Endoscopic Retrieval of Intraspinal Cement Leakage: Technical Note. AB - OBJECTIVE: We sought to preliminarily explore the efficacy and safety of percutaneous endoscopic spinal surgery for epidural cement leakage. We report a case series of patients who underwent percutaneous retrieval of leaked epidural cement and achieved spinal decompression under endoscopy. METHODS: Five patients with neurologic impairment due to epidural cement leakage after percutaneous vertebroplasty were treated with percutaneous endoscopic spinal decompression. Computed tomography reconstruction and 3-dimensional imaging were used to evaluate the extruded material. During follow-up at 3, 6, and 12 months postoperatively, all patients were advised to undergo plain radiograph and computed tomography examinations. RESULTS: The leaked epidural cement was successfully removed in all patients under percutaneous endoscopy through a unilateral or bilateral approach. At the 12-month follow-up, the visual analog scale score of all patients improved. In addition, the neurologic function of each patient improved to at least 1 grade level, as evaluated using the American Spinal Injury Association. According to the modified MacNab criteria, 2 patients had excellent recovery, whereas the other 3 patients had good recovery. CONCLUSIONS: We described a novel and minimally invasive procedure to ameliorate intractable epidural cement extrusion. As an alternative to conventional laminectomy, percutaneous endoscopic retrieval achieved the targeted decompression without damaging the posterior lamina. Moreover, the whole operation was performed under regional anesthesia accompanied with dexmedetomidine sedation, allowed real-time neural function evaluation, and had lower risks of anesthesia-related complications, compared with general anesthesia. PMID- 30026145 TI - Duraplasty Type as a Predictor of Meningitis and Shunting After Chiari I Decompression. AB - BACKGROUND: Expansile duraplasty is frequently performed during Chiari I decompression. Aseptic and bacterial meningitis are possible complications of this procedure. We sought to compare the rates of meningitis and subsequent need for cerebrospinal fluid (CSF) diversion with duraplasty using bovine pericardial (BPC) xenograft and allograft. METHODS: We conducted a retrospective review of 112 patients who underwent Chiari I decompression. All patients underwent duraplasty with either allograft or BPC. Occurrence of postoperative lumbar punctures and associated data were recorded to determine rates of meningitis. Rates of subsequent shunting were also recorded. RESULTS: Overall, 112 patients were included in the study: 30 underwent duraplasty with allograft (27%) and 82 received BPC (73%). A total of 26 patients developed postoperative meningitis (23 cases of chemical meningitis and 3 of bacterial meningitis). Rates of meningitis were higher in patients who received BPC than patients who received allograft (28% vs. 10%, respectively; P = 0.047). The rate of shunting was greater in patients with meningitis compared with patients without meningitis (56.5% vs. 5.75%, respectively; P < 0.0001). Moreover, 13 of the 15 patients (87%) in the BPC cohort who were shunted were found to have meningitis compared with 0 of the 3 shunted patients (0%) in the allograft cohort (P = 0.044). CONCLUSIONS: We found that rates of total meningitis were greater in patients who underwent Chiari I decompression and duraplasty with BPC compared with an allograft. The rate of shunting was significantly higher for patients who developed meningitis after decompression compared with patients without meningitis. PMID- 30026146 TI - Analysis of Unplanned Return to the Operating Room Within 30 Days of Initial Neurosurgery: A 3-Year Experience at a Single Center. AB - OBJECTIVE: The goal of this study was to evaluate the reasons and prognosis of unplanned return to the operating room (URTOR) and to help improve neurosurgical service quality. METHODS: Medical records of URTOR within 30 days of initial surgery were reviewed at a single neurosurgical center for a period of 3 years. Out of 4516 neurosurgeries, 62 URTOR cases were included to analyze patients' age, sex, initial surgery code, seniority of the performed surgeon, interval between the reopening procedures and initial procedures, reason for reopening, prognosis, and complications. RESULTS: The 62 patients underwent 70 URTORs. Out of 1445 primary operations performed by junior surgeons, 40 experienced URTOR, whereas 22 of 3071 craniotomies initially performed by senior surgeons resulted in URTOR. Five patients died in this series. Out of the 54 patients who experienced 1-time URTOR, 3 died, whereas 2 of the 8 patients who experienced 2 time URTOR died. Of 22 URTOR surgeries performed by senior surgeons, 10 took place within 24 hours, compared with 26 out of 48 performed by the junior surgeon. CONCLUSIONS: The main reasons for URTOR after neurosurgery were rebleeding and swelling of the brain. The number of URTORs and time from primary craniotomy to URTOR are not associated with morbidity or mortality. However, the seniority of the surgeon affects the rate of URTOR: surgeons with rich experience in surgery may reduce the chance of a second craniotomy and increase the chance of a good prognosis. PMID- 30026147 TI - Use of Flow Diversion for the Treatment of Distal Circulation Aneurysms: A Multicohort Study. AB - OBJECTIVE: The safety and efficacy of flow diversion for distal circulation aneurysms of the cerebral vasculature has not been well evaluated. The objective of this study was to assess the use of flow diversion for distal circulation aneurysms (defined as at or beyond the M1, P1, and A1 segments of the middle cerebral artery, posterior cerebral artery, and anterior cerebral artery, respectively) in an international multicenter cohort. METHODS: Clinical and radiologic records from all patients undergoing flow diversion treatment of distal circulation aneurysms at 3 academic centers (2 in the USA and 1 in Europe) from 2014 until 2017 were retrospectively reviewed. RESULTS: Forty-six patients (mean age, 58.2 years; 33 women) harboring 46 aneurysms who underwent treatment with either the Pipeline Embolization Device (Medtronic Inc., Dublin, Ireland) or the Flow Re-Direction Endoluminal Device (MicroVention, Tustin, California, USA) were included in these analyses. Thirty-four aneurysms (74%) were located in the anterior circulation and 12 (26%) were located in the posterior circulation. With a mean follow-up of 13.0 months, complete (100%) and near-complete (90%-99%) occlusion was noted in 36 aneurysms (78.2%). Angiographic evidence of side branch or perforator vessel coverage was present in 35 aneurysms (76.1%) but was not associated with failure to occlude at follow-up (P = 0.06). All patients had good functional outcomes after treatment (modified Rankin Scale score 0-2). There were 2 cases (4.3%) of perforator vessel stroke and no hemorrhagic complications. CONCLUSIONS: Flow diversion for aneurysms beyond the circle of Willis has occlusion rates comparable to alternative treatments and low morbidity. The clinical significance of flow limitation through covered side branches requires further investigation. PMID- 30026149 TI - Freehand Technique of an Electromagnetic Navigation System Emitter to Avoid Interference Caused by Metal Neurosurgical Instruments. AB - BACKGROUND: Electromagnetic (EM) navigation has been reported to be a noninvasive and easy-to-use technique. However, the use of metal neurosurgical instruments (e.g., skin hooks, head frames, brain retractors systems) can interfere with the magnetic fields of such systems. We present the freehand technique, a new technique involving the manual manipulation of the emitter of an EM navigation system, which helps to prevent interference caused by metal instruments during surgery. METHODS: The AxiEM Electromagnetic StealthStation Navigation System (Medtronic) was used in this study. The emitter was placed in the sterilized surgical field, which allowed it to be moved freely during surgery. When navigation was necessary during the procedure, the assistant held the emitter at an appropriate angle to the sterile surgical field to avoid interference caused by the metal neurosurgical instruments. RESULTS: During surgery involving metal surgical instruments, all of the functions of the EM navigation system were available throughout the procedure. The accuracy of the navigation system was sufficient to allow craniotomy and intradural manipulation to be conducted. CONCLUSIONS: During the use of EM navigation systems, the freehand technique with the emitter can prevent interference caused by metal instruments. PMID- 30026148 TI - Completely Thrombosed Giant Intracranial Aneurysm with Spontaneous Thrombosis of the Parent Artery: Is It Nature's Divine Intervention and a Self-Cure? AB - BACKGROUND: Although partial thrombosis is common with intracranial aneurysms, complete aneurysmal thrombosis is extremely rare. An even rarer and seldom reported phenomenon is the spontaneous complete occlusion of the parent artery in the presence of a thrombosed aneurysm. Given the unclear natural history of this phenomenon, therapeutic decision making may be rather difficult. Here we report a case of right cavernous carotid artery aneurysm with spontaneous right internal carotid artery (ICA) thrombosis in a 45-year-old man. CASE DESCRIPTION: Our patient presented almost 1 month after an episode of sudden-onset severe holocranial headache associated with vomiting that had resolved completely within 2 days. He was neurologically intact at the time of presentation. A computed tomography (CT) scan done at the time of ictus showed a rounded hyperdensity with the epicenter at the right parasellar region along with nonvisualization of the ipsilateral ICA on CT angiography. Magnetic resonance imaging (MRI) suggested a diagnosis of a completely thrombosed right cavernous segment ICA aneurysm. Intra arterial angiography confirmed a complete ipsilateral ICA thrombosis and a good arterial cross-flow from the left side to the bilateral anterior and middle cerebral artery territories. We started the patient on oral aspirin and a close clinicoradiologic follow-up after having decided against any active intervention. CONCLUSIONS: Spontaneous thrombosis of an intracranial aneurysm and the parent artery is rare, with only a few cases reported in the literature. In the absence of symptoms and adequate collateral circulation, these patients are perhaps best managed conservatively. PMID- 30026150 TI - Radiologic Characteristics and High Risk of Seizures in Infants with Ruptured Intracranial Aneurysms: Case Report and Review of the Literature. AB - OBJECTIVE: To evaluate the parameters related to the high risk of preoperative seizures in infants (1 year or younger) with ruptured intracranial aneurysms. METHODS: Infants with ruptured intracranial aneurysms treated at our institution from January 2012 to January 2018 were retrospectively analyzed. Seventeen similar cases of infant patients with seizures reported in published studies were reviewed. RESULTS: The mean age of the 7 infant patients treated at our institution was 4.1 +/- 3.3 months (range, 28 days to 11 months), with 2 male and 5 female subjects. One patient (14.3%) had an internal carotid artery aneurysm with subarachnoid hemorrhage, and the remaining 6 patients (85.7%) had middle cerebral artery (MCA) aneurysms in the distal arterial region with lobe hemorrhage. Five of the 7 infants (71.4%) had seizures, 4 of whom (4/5, 80.0%) had MCA distal arterial aneurysms with lobe hemorrhage. Management was successful for all patients with aneurysm clipping or resection surgery, and one patient experienced postoperative seizures. Of the 17 reviewed cases of infant patients with seizures, 10 patients (58.8%) exhibited the typical distal arterial aneurysm with lobe hemorrhaging, and 6 (60%) of them had aneurysms in MCA. CONCLUSIONS: Infant patients with ruptured intracranial aneurysms have a high risk of preoperative seizures. The typical radiologic finding of distal arterial aneurysm with lobe hemorrhage was frequently observed in the MCA, and it might be related to the high risk of preoperative seizures in this population. Microsurgical techniques effectively control postoperative seizures in infants with ruptured intracranial aneurysms. PMID- 30026151 TI - Treatment of Partially Thrombosed Intracranial Aneurysms: Single-Center Series and Systematic Review. AB - OBJECTIVE: Partially thrombosed intracranial aneurysms (PTIAs) represent a challenging subgroup of aneurysms, with an organized intraluminal thrombus and a solid mass, in which the optimal therapeutic strategy is discussed controversially because of limited data. We therefore analyzed the results of surgical and endovascular treatment in patients with PTIAs treated in our department and combined the results with a systematic literature review. METHODS: Between January 2006 and October 2016, data from 996 patients with intracranial aneurysms were prospectively entered into a database. Twenty-five consecutive patients harbored PTIAs and were treated in the authors' institution. The degree of aneurysm occlusion, the degree of recurrence, and the necessity of aneurysm retreatment were assessed and analyzed. PubMed was searched for published studies of PTIAs to gain a larger population. Multivariate regression models were performed on the pooled data. RESULTS: Literature data, including the present series, revealed a total of 157 patients. Overall, 64 patients (41%) were treated by clipping, and 93 patients (59%) were treated by endovascular treatment. In the multivariate analysis, surgical treatment of PTIAs was an independent predictor for complete aneurysm occlusion (P < 0.001). In a second multivariate model, endovascular treatment was independently associated with aneurysm recurrence (P < 0.001). In a third multivariate model, endovascular treatment was associated with a higher rate of retreatment (P < 0.001). CONCLUSIONS: In this study, surgical treatment of PTIAs showed superior initial radiologic results and better long term stability than endovascular treatment. Therefore, surgical treatment should be considered in those patients harboring PTIAs who are qualified as suitable surgical candidates after interdisciplinary consensus. PMID- 30026152 TI - Rare Complication of Percutaneous Technique: Intradural Cement Leakage and Its Surgical Treatment. AB - Popularity of percutaneous vertebroplasty and vertebral augmentation to treat vertebral compression fractures is increasing. Cement leakages are relatively common, but intradural cement leakage is rare. Few cases of intradural cement leakage have been reported in the literature, and emergency surgery has been reported to be <1%. A 64-year-old man with osteolytic vertebral compression fracture at L1, caused by a malignant tumor, had undergone a vertebral augmentation by craniocaudal procedure. Neurologic examination after the surgery revealed paralysis in both legs immediately postoperatively. Computed tomographic imaging revealed a large cement leakage into the spinal canal. The patient was referred to our department for emergency management. He was rapidly scheduled for surgical decompression by laminectomy. First, stabilization by a secure posterior short fixation was done. The laminectomy showed that insertion of a needle through the pedicle had breached the dura and had caused intradural cement leakage. As shown in the Supplementary Video, the piece of intradural cement was finally removed after posterior durotomy. This case demonstrates that even if percutaneous vertebroplasty is a relatively safe technique, it should be performed by well-trained physicians and with great care to prevent disabling complications. PMID- 30026153 TI - Who Needs Sleep? An Analysis of Patient Tolerance in Awake Craniotomy. AB - BACKGROUND: Awake craniotomy (AC) is generally a safe and effective procedure; however, a small but not insignificant portion of cases are aborted due to patient intolerance of the awake portion of surgery. There is not yet a firm understanding of what characteristics indicate patient tolerance or failure of AC. METHODS: We retrospectively reviewed a single-surgeon database of patients treated by AC over a 5-year period. Charts were reviewed for demographic, clinical, and operative characteristics, including anesthetic administration during the awake portion of surgery. Statistical analysis was performed to determine which factors predicted patient tolerance or failure. RESULTS: Our study cohort comprised 120 patients with an average age of 56.0 +/- 15.2 years. A majority of patients were male (55.8%). The most common surgical indication was tumor (95.8%), with gliobastoma as the most common diagnosis (43.3%). Male sex predicted surgical tolerance on univariate analysis (P = 0.015). Remifentanil administration was associated with surgical failure on univariate analysis (P = 0.068), and also predicted failure on multivariate analysis (P = 0.030). Preoperative seizure, ketamine administration, and right-sided surgery each predicted patient tolerance, but did not achieve statistical significance. Similarly, respiratory comorbidity was associated with surgical failure, but did not achieve significance. CONCLUSIONS: AC remains an effective treatment option; the majority of patients tolerate the procedure without issue. Male patients have lower rates of surgical failure, whereas remifentanil administration may increase failure rate. PMID- 30026154 TI - Clinical Usefulness of Waiting after Stent Deployment in Mechanical Thrombectomy: Effect of the Clot Integration. AB - BACKGROUND: Pulling a retriever stent after several minutes of waiting time is a popular technique in mechanical thrombectomy with a stent retriever, but little data exist on the actual effects of waiting after stent deployment. METHODS: We conducted a multicenter retrospective study of consecutive 210 patients separated into 2 groups, a waiting after stent deployment group and a nonwaiting group. A comparative analysis was performed in terms of clinical and radiologic outcomes and complications with respect to multiple categories. RESULTS: There were no significant differences in baseline characteristics and clinical outcomes between the 2 groups. However, compared with the nonwaiting group, the waiting group had a higher rate of one-pass procedures, a lower mean number of stent passages, and a shorter procedure time (P = 0.021, 0.014, and 0.004, respectively). The proportion of patients with successful recanalization was also higher in the waiting group (P = 0.038). In multivariate analysis, waiting after stent deployment was a predictive factor for successful recanalization (odds ratio, 1.60; 95% confidence interval, 1.110-2.090; P = 0.02). CONCLUSIONS: Waiting after stent deployment can lead to a more successful recanalization with a smaller number of stent passages and less distal emboli. More randomized controlled trials are needed to support these findings. PMID- 30026155 TI - Comparative Prospective Study of Microvascular Anastomosis Training by Self Learning or with Expert Instruction. AB - BACKGROUND: Young neurosurgeons have little opportunity to receive expert feedback while learning microvascular anastomosis. Our objective was to determine the importance of expert feedback. We compared students who studied anastomosis by self-learning with those who studied it with expert feedback. Our second objective was to determine the efficacy of intensive training by comparing the skills of the students with expert feedback with those of neurosurgeons. METHODS: Twenty-five medical students and 9 neurosurgeons participated. The students were provided with instructional Digital Video Disks (DVDs) and spent 2 weeks practicing gauze fiber microsuturing followed by 6 weeks practicing end-to-side anastomosis using silicone tube. The students assigned to the expert feedback group received weekly feedback through a video call, whereas those in the self learning group did not. After training, the students completed a final practical examination that was recorded on DVD. The DVDs and procedural products were numbered and distributed to 2 blinded independent expert neurosurgeons for grading. The neurosurgeons completed a similar examination, and their performances were also recorded and compared with those of the medical students. RESULTS: Compared with the self-learning group, the expert feedback group showed significantly higher anastomosis scores (P = 0.0261) and a nonsignificant tendency toward slower anastomosis times (P = 0.4188). The expert feedback group also achieved significantly higher anastomosis scores than did the neurosurgeons (P = 0.0055). CONCLUSIONS: Expert feedback improves mastery of microvascular anastomosis. Intensive training with regular expert feedback enables medical students to achieve microvascular anastomosis skills better than those of neurosurgeons. PMID- 30026156 TI - Intractable Hiccups Associated with Chiari Type I Malformation: Case Report and Literature Review. AB - BACKGROUND: The authors report the case of a 34-year-old man who presented with intractable hiccups. The imaging examination showed that the patient was suffering from syringomyelia associated with Chiari type I malformation. CASE DESCRIPTIONS: The patient underwent posterior fossa decompression combined with bilateral tonsillectomy and duroplasty. The intractable hiccups completely resolved 1 week after operation and had not recurred at 2 months after surgery. Postoperative magnetic resonance imaging showed the atrophy of the tonsils of the cerebellum and disappearance of the cavities of the spinal cord. CONCLUSIONS: Intractable hiccups as the main symptoms of Chiari type I malformation are extremely rare in the clinic. Decompression surgery should be an appropriate method to relieve the symptoms. PMID- 30026157 TI - Elevated Serum Fibrinogen Degradation Products on Admission Is a Novel Predictive Factor for Recurrence of Chronic Subdural Hematoma. AB - BACKGROUND: Previous studies reported an association of hematologic parameters, including white blood cells, neutrophil, eosinophils, or coagulation-related factors, with prognosis in cerebrovascular disorders. However, an association of recurrence rate with serum coagulation-related factors (e.g., D-dimer or fibrinogen degradation products [FDP]) in chronic subdural hematoma (CSDH) is unclear. METHODS: Ninety-two patients who experienced first-time CSDH treated with burr-hole hematoma evacuation were included in this study. Laboratory data on admission were used to divide patients into 2 groups: serum FDP >5 MUg/mL or FDP <=5 MUg/mL (within normal range), based on the reference range of our institute. We retrospectively compared the recurrence rate of CSDH within 90 days after the first operation between these groups. Statistical significance was accepted at P < 0.05. RESULTS: Patients with an FDP greater than 5 MUg/mL showed a significantly increased recurrence rate compared with those with a normal FDP (<=5 MUg/mL; 27.3% vs. 10.2%, respectively; P = 0.03). Patients with an FDP greater than 5 MUg/mL also showed a significantly higher recurrence rate within 30 days after the operation (15.2% vs. 3.4%, respectively; P = 0.04), but no difference in the recurrence rate at 31-90 days after the operation (12.1% vs. 6.8%, respectively; P = 0.38). In multivariable analysis, monolayer hematoma (odds ratio, 7.61; P = 0.003) and an FDP >5 MUg/mL (odds ratio, 5.04; P = 0.01) were independent predictive factors for recurrence within 90 days. CONCLUSIONS: Elevated serum FDP on admission is a novel predictive factor for the recurrence of CSDH. These patients require careful follow-up, and recurrence within 30 days after the first operation should be considered. PMID- 30026158 TI - Recurrences of Pituitary Adenomas or Second De Novo Tumors: Comparisons with First Tumors. AB - BACKGROUND: Recurrences of pituitary adenomas are not so rare. METHODS: In the German Registry of Pituitary Tumors, more than 12,000 surgical specimens were collected between 1967 and 2012, of which 312 patients with altogether 334 recurrences (n = 646 specimens) were included in our study. RESULTS: The histopathology of 162 recurrent adenomas could be compared with the original tumor and 37 second recurrences could be compared with the first recurrence. Comparing the proliferation index (Ki-67) of the original and the first recurrent tumor (n = 162), we found an unchanged index in 43 cases (26%), whereas in 69 cases (43%) the index increased and in 50 cases (31%) it decreased. Comparing the first with the second recurrence (n = 37), we found an unchanged index in 8 cases (22%), an increased index in 15 cases (40%), and a decreased index in 14 cases (38%). The third recurrence showed an unchanged index in 1 case (20%), an increased index in 2 cases (40%), and a decreased index in 2 cases (40%). p53 was unchanged in recurrences in 44% of cases, increased in 33%, and decreased in 22%. In 4 cases, adenomas developed into adenomas with strongly increased proliferation (formerly atypical adenomas, now aggressive adenomas) for the first recurrence, and 9 recurrences became aggressive adenomas. A change of tumor type without change of the common transcription factor occurred in 82 cases. CONCLUSIONS: A second independent de novo adenoma was present in 10 cases, probably due to changes of transcription factors. PMID- 30026159 TI - Left Supraorbital Eyebrow Approach for Microscopic Fenestration of a Neuroglial Cyst. AB - Neuroglial cysts (also known as glioependymal cysts) are rare, benign, epithelial lined cystic lesions that can potentially occur anywhere in the neuraxis. They can be intra, or within, a cranial nerve with the former being more common. The frontal lobe is thought to be the most common location. On magnetic resonance imaging, they follow cerebrospinal fluid signal and have smooth nonenhancing borders. This video demonstrates in a step-by-step fashion the technical nuances of the supraorbital keyhole approach through an eyebrow incision, for fenestration and biopsy of a neuroglial cyst within the left optic tract. The patient was a 27-year-old female who had peripheral vision disturbance postpartum. The cyst on magnetic resonance imaging was initially observed, but follow-up Humphrey visual field testing demonstrated worsening of the partial left superior quadrantanopsia. The keyhole supraorbital approach was selected to provide a direct route to the pathology with minimal soft tissue disruption. The patient was discharged on postoperative day 2 without any complications. Follow up at 6 weeks demonstrated near-complete resolution of her quadrantanopsia and good cosmesis with no frontalis palsy. PMID- 30026160 TI - Application of Diffusion Tensor Imaging Cutoff Value to Evaluate the Severity and Postoperative Neurologic Recovery of Cervical Spondylotic Myelopathy. AB - BACKGROUND: Magnetic resonance imaging (MRI) plays an important role in the assessment of spinal cord status for cervical spondylotic myelopathy (CSM). Diffusion tensor imaging (DTI) also is a novel investigation tool with good sensitivity to detect changes in CSM, but it is not routinely used in spinal cord evaluation. METHODS: Sixty-six patients with CSM who required surgical decompression were included. All the patients were divided into 4 subgroups according to Japanese Orthopaedic Association (JOA) recovery rate. A 3.0T MR system was applied to obtain DTI of the spinal cord. Clinical assessment was performed with the JOA scores system. RESULTS: DTI data of 61 patients were available for further analysis in this study. No significant differences in age, sex, cervical curvature, surgical approach, and preoperative JOA score between the 4 subgroups were found (P > 0.05). Significant differences in apparent diffusion coefficient (ADC) (P < 0.0001), mean diffusivity (MD), (P < 0.0001), axial diffusivity (AD) (P = 0.0459), and radial diffusivity (RD) (P < 0.0001) values were found between the 4 groups. The ADC (P < 0.0001), MD (P < 0.0001), AD (P = 0.0434), and RD (P < 0.0001) values were significantly correlated with JOA recovery rate. Cutoff values of ADC, MD, AD, and RD in this study were 1.378*10 3, 1.378*10-3, 2.386*10-3, and 0.894*10-3 mm2/s, respectively. CONCLUSION: DTI was closely related to the severity of CSM, and cutoff values of DTI enabled the surgeons to predict the surgical outcomes in patients with CSM. These evaluation metrics may reflect the pathologic conditions of the spinal cord quantitatively, and potentially evaluate the functional status of spinal cords. PMID- 30026161 TI - Location and Threshold of Electrical Cortical Stimulation for Functional Brain Mapping. AB - BACKGROUND AND OBJECTIVE: Although many studies have investigated functional localization by electrical stimulation, the threshold to identify each area remains controversial. The present study aimed to elucidate the threshold of a cortical stimulation for functional mapping. METHODS: We analyzed data from 17 patients with medically intractable epilepsy who underwent a 50-Hz electrical cortical stimulation for functional mapping between October 2013 and May 2017. The symptoms induced by the stimulation and the thresholds of the stimulation for these responses were evaluated. RESULTS: Motor responses were observed after the stimulation of the primary motor cortex, supplementary motor area, and frontal eye field, and sensory responses after the stimulation of the primary and secondary sensory cortex. Regarding negative responses, language impairment was observed after the stimulation of the anterior, posterior, and basal temporal language areas, negative motor responses after the stimulation of the premotor cortex, posterior parietal cortex, and the pre- supplementary motor area, and an impairment in spatial recognition after the stimulation of the right posterior parietal cortex. Negative or positive auditory symptoms were observed with the stimulation of the posterior superior temporal gyrus. The thresholds for positive phenomena were significantly lower than those for negative phenomena (Mann Whitney U test, P < 0.01), and sensory responses were induced at significantly lower intensities than motor responses (P < 0.01). CONCLUSIONS: Positive and sensory effects are induced by lower intensities than negative and motor responses, respectively. The present results provide not only a practical guide for functional mapping, but also a hierarchal concept of processing in the brain. PMID- 30026162 TI - A Novel Drill Navigation Template Combines Preoperative Simulation in Expansive Open-Door Laminoplasty. AB - OBJECTIVE: To evaluate the effects of preoperative simulation based on patient specific vertebral models, and computer-assisted designed drill navigation templates in expansive open-door laminoplasty (EOLP). METHODS: We retrospectively analyzed 18 consecutive patients who underwent EOLP, 11 patients (45 vertebrae) were treated with traditional EOLP (traditional group) and 7 patients (28 vertebrae) were treated with EOLP aided by the drill navigation template and preoperative simulation (template group). We assessed the operation time, intraoperative blood loss, hospitalization expenses, visual analog scale (VAS), Japanese orthopedic association (JOA), neck disability index (NDI), Pavlov's ratio, laminoplasty opening size (LOS), hinge fracture rate and trough positions. RESULTS: The operation time of template group (98.6 +/- 13.0 minutes) was significantly shorter (P < 0.05) than that of traditional group (125.4 +/- 13.2 minutes). Both groups achieved similar hospitalization expenses and significant improvement in VAS, JOA score, NDI, and Pavlov ratio. The postoperative hinge fracture rate of template group (0%; 0/28) was significantly lower (P < 0.05) than that of traditional group (11.1%, 5/45). In template group, all the troughs (56/56 [100%]; 28/28 on the hinge side and 28/28 on the open side), while in traditional group, only 72.2% (65/90; 31/45 on the hinge side and 34/45 on the hinge side) of the troughs were at the proper hinge position. CONCLUSIONS: Drill navigation template and preoperative simulations in EOLP are technically feasible. With the help of templates and preoperative simulation, shorten operation time, accurate trough positioning, decrease incidence of hinge fracture and could be acquired. This technique should be further studied and affirmed in clinical applications. PMID- 30026163 TI - Long-Term Functional and Oncologic Outcomes of Glioma Surgery with and without Intraoperative Neurophysiologic Monitoring: A Retrospective Cohort Study in a Single Center. AB - OBJECTIVE: To evaluate long-term functional and survival outcomes of patients with glioma after intraoperative neurophysiologic monitoring (IONM) application. METHODS: A total of 856 patients with glioma, who underwent tumor resection between October 2010 and March 2016, were included in this retrospective cohort study. All patients were stratified into IONM (439 patients) and non-IONM groups (417 patients). The primary outcome measured was overall survival (OS), and the secondary outcome measured was rate of late neurologic deficits. Analyses were performed using univariate tests and multivariate logistic regression and Cox proportional hazard model. RESULTS: The 2 cohorts were well balanced with respect to baseline characteristics. Univariate survival analysis showed longer OS in the IONM group than that in the non-IONM group (P = 0.036), especially in patients with high-grade astrocytic tumor (P = 0.034). The IONM group showed a lower rate of neurologic deficits than did the non-IONM group. Multivariate analysis showed that IONM was a favorable factor of OS (odds ratio, 0.776; P = 0.046) and late neurologic function (odds ratio, 0.583; P = 0.039). Dominant hemispheric and eloquent location of glioma had no association with OS. CONCLUSIONS: Application of IONM is beneficial to long-term functional and oncologic outcomes of patients with glioma. PMID- 30026164 TI - Arcuate Foramen: Anatomy, Embryology, Nomenclature, Pathology, and Surgical Considerations. AB - BACKGROUND: The arcuate foramen is an anatomic variant that is thought to arise from ossification of the posterior atlanto-occipital membrane. Owing to potential entrapment of the vertebral artery segment that traverses the foramen, vertebrobasilar ischemia may occur, and the person may experience vertigo, headache, or neck pain. METHODS: We reviewed the literature regarding anatomy (both human and comparative), embryology, nomenclature, pathology, and surgery of the arcuate foramen. RESULTS: Surgically, the presence of an arcuate foramen is important when placing screws into lateral masses of the atlas. In these cases, the screws can damage the V3 segment of the vertebral artery and/or the suboccipital nerve. CONCLUSIONS: It is important to review the current literature on the arcuate foramen to further understand its morphology and clinical relevance. PMID- 30026165 TI - Tenosynovial Giant Cell Tumor of the Clinoid: Rare Condition. AB - BACKGROUND: A tenosynovial giant cell tumor (TGCT) is a rare type of tumor that primarily arises from the tendon sheath, synovium, and bursae. In rare cases, these tumors can affect joints of the head and neck such as the temporomandibular joint. This is the only case to our knowledge of an intracranial TGCT tumor of the clinoid. CASE DESCRIPTION: We present the case of a 25-year-old female with a 2-year history of progressively blurred vision in her left eye without visual field defects. She denied any headaches or symptoms referable to the left eye region. Past medical history was significant for meningitis at 10 months of age. Family history was noncontributory with no history of brain tumors. CONCLUSIONS: A tumor originating from the left anterior clinoid was found intraoperatively and confirmed by histology to be a TGCT. PMID- 30026166 TI - Long-Term Outcome of Gamma Knife Radiosurgery for Brain Cavernoma: Factors Associated with Subsequent De Novo Cavernoma Formation. AB - BACKGROUND: We aimed to evaluate the factors associated with de novo brain cavernoma formations after patients underwent gamma knife radiosurgery (GKRS) and confirmed whether developmental venous anomaly (DVA) presented with a cavernoma and whether the cavernoma was included in the GKRS target location. METHODS: From January 2003 to December 2008, 95 patients underwent radiosurgery for brain cavernoma at our institution. Of these, 15 with multiple cavernomas related to familial cavernoma or with a history of surgical treatment for cavernoma were excluded. A total of 80 patients (44 men and 36 women; average age, 39.4 years) with sporadic cavernoma were retrospectively analyzed by considering the patient characteristics, including sex, age, target volume, radiation dose, clinical symptoms, cavernoma location, radiosurgery complications, and morphology of DVA. RESULTS: The average target volume, mean radiation dose, and mean target percentage were 1019.2 mm3, 13.7 Gy, and 51.1%, respectively. Nineteen patients showed cavernomas associated with DVA; of these, de novo cavernoma formations were noticed in 4 patients at a median of 49.5 months after undergoing GKRS. All de novo cavernomas were related to the presence of DVA and were located near the brainstem or cerebral peduncle. De novo cavernomas occurred when DVAs were not included in the GKRS-target location. CONCLUSIONS: All de novo cavernomas were located near the brainstem or cerebral peduncle, and they occurred in the presence of DVAs. The presence of DVA in the radiosurgery target location might be potentially an important factor associated with de novo cavernoma formation. PMID- 30026167 TI - Intravenous Drug Use Is Novel Predictor of Infectious Intracranial Aneurysms in Patients with Infective Endocarditis. AB - INTRODUCTION: Infectious intracranial aneurysms (IIAs) are a rare but potentially devastating complication of infective endocarditis. The clinical and radiographic findings that predispose patients to IIA remain poorly understood. METHODS: We performed a retrospective review of a prospectively maintained database of consecutive endocarditis patients undergoing catheter-based angiography at a single tertiary-level academic center during the period of July 2013-December 2017. Patient records were reviewed for clinical and radiographic characteristics that may be associated with IIA. Multivariate regression models were used to evaluate the relationship between clinical and radiographic characteristics and presence of IIA on invasive imaging. RESULTS: Of 92 patients included in this analysis, 12 of them with 19 IIAs were discovered. Univariate analysis identified age, male sex, presence of hemorrhage, and history of IV drug use (IVDU) as predictors of IIA presence. After multivariate analysis, only intracranial hemorrhage and IVDU remained as independent predictors of IIA. CONCLUSIONS: Presence of hemorrhage on noninvasive imaging and history of IVDU are independently predictive of IIA presence in patients with infectious endocarditis. Risk stratification using these 2 factors may help identify the most vulnerable populations for IIA formation. PMID- 30026168 TI - Synthesis of breast cancer targeting conjugate of temporin-SHa analog and its effect on pro- and anti-apoptotic protein expression in MCF-7 cells. AB - The frog natural product temporin-SHa (FLSGIVGMLGKLFamide) is a potent antimicrobial peptide, as is the analog [S3K]SHa. By solid-phase synthesis, we prepared temporin-SHa and several temporin-SHa analogs with one or more D-alanine residues incorporated. The natural product and the analog [G10a]SHa were found to be cytotoxic in mammalian cell lines and induce cell death. To achieve selectivity, we conjugated the analog [G10a]SHa with a breast cancer targeting peptide (BCTP). The resulting peptide temporin [G10a]SHa-BCTP conjugate was selectively active against the MCF-7 breast cancer cell line with no cytotoxicity in NIH-3T3 fibroblasts. Unlike the natural product or [G10a]SHa, the conjugated peptide induced apoptosis, downregulating the expression of Bcl-2 and survivin and upregulating Bax and caspase-3. PMID- 30026169 TI - Ethnomedicinal plants and traditional knowledge among three Chin indigenous groups in Natma Taung National Park (Myanmar). AB - ETHNOPHARMACOLOGICAL RELEVANCE: This research describes the ethnomedicinal plants as used by three Chin indigenous groups inhabiting areas at Natma Taung National Park (NTNP) in bio-culturally diverse Myanmar. The aim of this study was (1) to identify wild medicinal species and evaluate their local importance in local peoples' healthcare as well as in protected area conservation; and (2) to compare traditional medicinal plant knowledge among the informants. MATERIALS AND METHODS: A total of 206 Muun, Ng'gah and Daai informants from 20 villages were interviewed using semi-structured questionnaires. Species use-reports were computed to determine plant local importance and the informant consensus factor. Descriptive and the inferential statistics Mann-Whitney U and Kruskal-Wallis tests were employed to evaluate and compare the informants' traditional medicinal knowledge. RESULTS: A total of 75 wild ethnomedicinal taxa in 40 plant families across 16 ICPC-based disease categories were recorded. Species which recorded the highest number of use-reports appeared to play an important role not only in informants' primary healthcare and in park conservation, but also in local livelihood. CONCLUSION: This study presents the diversity of ethnomedicinal plants and their local importance in Chin indigenous peoples' healthcare. This paper also recognizes the value of these plants and the local traditional knowledge for the conservation and management of NTNP. PMID- 30026170 TI - Concentration-dependent plasma protein binding: Expect the unexpected. AB - The unbound fraction of a drug in plasma can profoundly influence both its pharmacokinetics and pharmacodynamics. For most drugs, the unbound fraction is relatively constant across the clinically relevant range of concentrations in a given individual. Nonlinear plasma protein binding involving saturation of binding sites results in increasing unbound fraction as the concentration of the drug increases, a phenomenon that is consistent with the law of mass action and is well recognized. Not widely appreciated is that some drugs undergo atypical concentration-dependent binding to plasma proteins, whereby the unbound fraction decreases with increasing concentration. In this article we review the drugs for which atypical nonlinear plasma protein binding has been reported. For each drug, the evidence for the phenomenon is presented and the proposed mechanism discussed. Also reviewed are the potential implications of atypical nonlinearity in plasma protein binding. Highlighted is the importance of understanding the relationship between unbound fraction and plasma drug concentration during the preclinical and early clinical stages of drug development, and during the routine clinical use of a drug especially if therapeutic drug monitoring is used to assist in optimization of the dosing regimen. The lesson is that the unexpected concentration-dependent behavior that has been observed for a number of drugs should be expected to occur for some other drugs. PMID- 30026171 TI - Ubiquity of the neurotoxin beta-N-methylamino-L-alanine and its isomers confirmed by two different mass spectrometric methods in diverse marine mollusks. AB - In recent years, the neurotoxin beta-N-methylamino-L-alanine (BMAA) has been reported in some marine mollusk species. To further discover BMAA in marine animals, a total of 59 samples belonging to 3 phyla, 22 families, and 43 species, were collected from Dalian, Rongcheng, and Zhoushan cities, China, in April 2017. All samples were quantified by a hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) analysis of underivatized extract, and ten samples were also analyzed by a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis using a precolumn AQC (6-aminoquinolyl-N hydroxysuccinimidyl carbamate)-derivatization method. Results indicated that 48 mollusk samples contained BMAA with concentrations above the limit of detection (0.31 MUg g-1 wet weight), and the isomers of BMAA, beta-amino-N-methylalanine (BAMA) and 2,4-diaminobutyric acid (DAB) were universally present in most samples. However, N-(2-aminoethyl) glycine (AEG) was not found in any sample. Comparison of both analytical methods showed that BMAA and BAMA were not completely separated by the HILIC column although they still could be identified by specific transitions. In contrast the C18 column provided good separation for the AQC-derivatives of BMAA and all of its isomers. Development of analytical methods and stable isotope tracing of BMAA should be carried out in the future. PMID- 30026172 TI - Changes in the structure and function of the brain years after Pre-eclampsia. AB - Pre-eclampsia (PE) is a pregnancy specific syndrome that affects multiple organs including the brain. PE resolves after delivery of the placenta. Nonetheless, PE is a predisposing factor for cardiovascular disorders and hypertension later in life. These conditions are associated with a cognitive decline and dementia later in life. Studies have suggested that there may be long term pathological changes within the brain of the woman after PE/eclampsia and PE may be a risk marker for early cerebrovascular impairment. The aim of this review is to provide an insight into the possible long-term effect of PE and eclampsia on the brain structure and function with the probability of PE being a risk factor for neurodegenerative development. Long term effects of PE include cognitive impairment such as memory loss, attention deficit and motor speed impairment. Also, the pathology of the brain seems to be much affected later in life in women with history of PE/eclampsia. Certain changes in the structure and function of the brain observed among women with history of PE/eclampsia are similar to neurological disease like Alzheimer's disease (AD) and dementia. PMID- 30026174 TI - A novel p38 MAPK gene in the sea cucumber Apostichopus japonicus (Ajp38) is associated with the immune response to pathogenic challenge. AB - The p38 mitogen-activated protein kinase (MAPK), an important component of the MAPK signal cascade, is activated by extracellular stimuli, such as environmental stress and pathogenic infection. To clarify the function of p38 MAPKs in echinoderms, we used transcriptome database mining and rapid amplification of cDNA ends (RACE) to identify a novel p38 MAPK gene in the sea cucumber Apostichopus japonicus (here designated Ajp38). The full-length cDNA of Ajp38 was 2231 bp, including an open reading frame encoding 356 amino acid residues. Our sequence analysis indicated that the predicted Ajp38 protein contained the dual phosphorylation site Thr-Gly-Tyr (TGY) and was similar to the p38 homolog in sea urchins. Quantitative real-time PCR analysis showed that Ajp38 was ubiquitously expressed in all examined tissues of healthy adult A. japonicus, with the highest level of expression identified in the coelomocytes. Ajp38 mRNA expression was significantly upregulated in the coelomocytes 4, 12, and 72 h post in vivo infection with Vibrio splendidus. Our results provide more information about the characteristics and immune functions of the p38 homolog in sea cucumbers. PMID- 30026173 TI - Immunogenicity of extracellular products from an inactivated vaccine against Aeromonas veronii TH0426 in koi, Cyprinus carpio. AB - Aeromonas veronii is a type of human-livestock-aquatic animal pathogen; it is widely found in nature and causes many deaths among aquatic animals. Extracellular products (ECPs) are secreted by the pathogen during growth and reproduction. These products are considered effective protective antigens that can induce the host to produce an immune response. In this study, the ECPs of A.veronii TH0426 were prepared by ultrafiltration, and then the pathogenicity and enzymatic activity of the ECPs were determined. All the groups were injected intraperitoneally, as follows: group one: ECP protein with an equal volume of Freund's adjuvant; group two: ECPs and formalin-killed cells (FKC) of A.veronii combined with an equal volume of Freund's adjuvant (FKC + ECPs); group three: formalin-killed cells (FKC) of A.veronii combined with an equal volume of Freund's adjuvant (FKC); and, group four: sterile PBS as the control group. The expression levels of IgM, IL-1beta, and TNF-alpha and the lysozyme activity in blood were examined at 7, 14, and 21 days after the immunizations. The results show that the ECPs can produce protease, lipase, amylase and hemolyase, and there was no lecithinase, urease, or gelatinase activity. The results indicate that the ECPs were clearly pathogenic to koi fish, and the LD50 dose was 391.6 MUg/fish. Throughout this study, the RPS of the three experimental groups were 75%, 50%, and 70%. This study indicates that the ECPs of A.veronii can effectively enhance the ability of kio fish to resist bacterial invasion. PMID- 30026175 TI - SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines. AB - One of the major challenges in cancer chemotherapy is the development of multidrug resistance phenomenon attributed to the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells. Therefore, re sensitizing MDR cancer cells to chemotherapy by directly inhibiting the activity of ABC transporters has clinical relevance. Unfortunately, previous attempts of developing clinically applicable synthetic inhibitors have failed, mostly due to problems associated with toxicity and unforeseen drug-drug interactions. An alternative approach is by repositioning drugs with known pharmacological properties as modulators of ABCB1 and ABCG2. In this study, we discovered that the transport function of ABCB1 and ABCG2 is strongly inhibited by SIS3, a specific inhibitor of Smad3. More importantly, SIS3 enhances drug-induced apoptosis and resensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic drugs at non-toxic concentrations. These findings are further supported by ATPase assays and by a docking analysis of SIS3 in the drug-binding pockets of ABCB1 and ABCG2. In summary, we revealed an additional action of SIS3 that re-sensitizes MDR cancer cells and a combination therapy with this drug and other chemotherapeutic agents may be beneficial for patients with MDR tumors. PMID- 30026176 TI - Challenges and Potential Opportunities of Mobile Phone Call Detail Records in Health Research: Review. AB - BACKGROUND: Call detail records (CDRs) are collected by mobile network operators in the course of providing their service. CDRs are increasingly being used in research along with other forms of big data and represent an emerging data type with potential for public good. Many jurisdictions have infrastructures for health data research that could benefit from the integration of CDRs with health data. OBJECTIVE: The objective of this study was to review how CDRs have been used in health research and to identify challenges and potential opportunities for their wider use in conjunction with health data. METHODS: A literature review was conducted using structured search terms making use of major search engines. Initially, 4066 items were identified. Following screening, 46 full text articles were included in the qualitative synthesis. Information extracted included research topic area, population of study, datasets used, information governance and ethical considerations, study findings, and data limitations. RESULTS: The majority of published studies were focused on low-income and middle-income countries. Making use of the location element in CDRs, studies often modeled the transmission of infectious diseases or estimated population movement following natural disasters with a view to implementing interventions. CDRs were used in anonymized or aggregated form, and the process of gaining regulatory approvals varied with data provider and by jurisdiction. None included public views on the use of CDRs in health research. CONCLUSIONS: Despite various challenges and limitations, anonymized mobile phone CDRs have been used successfully in health research. The use of aggregated data is a safeguard but also a further limitation. Greater opportunities could be gained if validated anonymized CDRs were integrated with routine health records at an individual level, provided that permissions and safeguards could be put in place. Further work is needed, including gaining public views, to develop an ethically founded framework for the use of CDRs in health research. PMID- 30026177 TI - You Will Know That Despite Being HIV Positive You Are Not Alone: Qualitative Study to Inform Content of a Text Messaging Intervention to Improve Prevention of Mother-to-Child HIV Transmission. AB - BACKGROUND: Prevention of mother-to-child HIV transmission (PMTCT) relies on long term adherence to antiretroviral therapy (ART). Mobile health approaches, such as text messaging (short message service, SMS), may improve adherence in some clinical contexts, but it is unclear what SMS content is desired to improve PMTCT ART adherence. OBJECTIVE: We aimed to explore the SMS content preferences related to engagement in PMTCT care among women, male partners, and health care workers. The message content was used to inform an ongoing randomized trial to enhance the PMTCT-ART adherence. METHODS: We conducted 10 focus group discussions with 87 HIV infected pregnant or postpartum women and semistructured individual interviews with 15 male partners of HIV-infected women and 30 health care workers from HIV and maternal child health clinics in Kenya. All interviews were recorded, translated, and transcribed. We analyzed transcripts using deductive and inductive approaches to characterize women's, partners', and health care workers' perceptions of text message content. RESULTS: All women and male partners, and most health care workers viewed text messages as a useful strategy to improve engagement in PMTCT care. Women desired messages spanning 3 distinct content domains: (1) educational messages on PMTCT and maternal child health, (2) reminder messages regarding clinic visits and adherence, and (3) encouraging messages that provide emotional support. While all groups valued reminder and educational messages, women highlighted emotional support more than the other groups (partners or health care workers). In addition, women felt that encouraging messages would assist with acceptance of their HIV status, support disclosure, improve patient-provider relationship, and provide support for HIV related challenges. All 3 groups valued not only messages to support PMTCT or HIV care but also messages that addressed general maternal child health topics, stressing that both HIV- and maternal child health-related messages should be part of an SMS system for PMTCT. CONCLUSIONS: Women, male partners, and health care workers endorsed SMS text messaging as a strategy to improve PMTCT and maternal child health outcomes. Our results highlight the specific ways in which text messaging can encourage and support HIV-infected women in PMTCT to remain in care, adhere to treatment, and care for themselves and their children. TRIAL REGISTRATION: ClinicalTrials.gov NCT02400671; https://clinicaltrials.gov/ct2/show/NCT02400671 (Archived by WebCite at http://www.webcitation.org/70W7SVIVJ). PMID- 30026179 TI - Leveraging Self-Affirmation to Improve Behavior Change: A Mobile Health App Experiment. AB - BACKGROUND: mHealth interventions can help to improve the physical well-being of participants. Unfortunately, mHealth interventions often have low adherence and high attrition. One possible way to increase adherence is instructing participants to complete self-affirmation exercises. Self-affirmation exercises have been effective in increasing many types of positive behaviors. However, self affirmation exercises often involve extensive essay writing, a task that is not easy to complete on mobile platforms. OBJECTIVE: This study aimed to adapt a self affirmation exercise to a form better suited for delivery through a mobile app targeting healthy eating behaviors, and to test the effect of differing self affirmation doses on adherence to behavior change goals over time. METHODS: We examined how varied self-affirmation doses affected behavior change in an mHealth app targeting healthy eating that participants used for 28 days. We divided participants into the 4 total conditions using a 2*2 factorial design. The first independent variable was whether the participant received an initial self affirmation exercise. The second independent variable was whether the participant received ongoing booster self-affirmations throughout the 28-day study. To examine possible mechanisms through which self-affirmation may cause positive behavior change, we analyzed three aspects of self-affirmation effects in our research. First, we analyzed how adherence was affected by self-affirmation exercises. Second, we analyzed whether self-affirmation exercises reduced attrition rates from the app. Third, we examined a model for self-affirmation behavior change. RESULTS: Analysis of 3556 observations from 127 participants indicated that higher doses of self-affirmation resulted in improved adherence to mHealth intervention goals (coefficient 1.42, SE 0.71, P=.04). This increased adherence did not seem to translate to a decrease in participant attrition (P value range .61-.96), although our definition of attrition was conservative. Finally, we examined the mechanisms by which self-affirmation may have affected intentions of behavior change; we built a model of intention (R2=.39, P<.001), but self-affirmation did not directly affect final intentions (P value range .09 .93). CONCLUSIONS: Self-affirmations can successfully increase adherence to recommended diet and health goals in the context of an mHealth app. However, this increase in adherence does not seem to reduce overall attrition. The self affirmation exercises we developed were simple to implement and had a low cost for both users and developers. While this study focused on an mHealth app for healthy eating, we recommend that other mHealth apps integrate similar self affirmation exercises to examine effectiveness in other behaviors and contexts. PMID- 30026178 TI - Patient-Centered eHealth Interventions for Children, Adolescents, and Adults With Sickle Cell Disease: Systematic Review. AB - BACKGROUND: Sickle cell disease is an inherited blood disorder that affects over 100,000 Americans. Sickle cell disease-related complications lead to significant morbidity and early death. Evidence supporting the feasibility, acceptability, and efficacy of self-management electronic health (eHealth) interventions in chronic diseases is growing; however, the evidence is unclear in sickle cell disease. OBJECTIVE: We systematically evaluated the most recent evidence in the literature to (1) review the different types of technological tools used for self management of sickle cell disease, (2) discover and describe what self-management activities these tools were used for, and (3) assess the efficacy of these technologies in self-management. METHODS: We reviewed literature published between 1995 and 2016 with no language limits. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and other sources. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened titles and abstracts, assessed full-text articles, and extracted data from articles that met inclusion criteria. Eligible studies were original research articles that included texting, mobile phone-based apps, or other eHealth interventions designed to improve self-management in pediatric and adult patients with sickle cell disease. RESULTS: Of 1680 citations, 16 articles met all predefined criteria with a total of 747 study participants. Interventions were text messaging (4/16, 25%), native mobile apps (3/16, 19%), Web-based apps (5/16, 31%), mobile directly observed therapy (2/16, 13%), internet-delivered cognitive behavioral therapy (2/16, 13%), electronic pill bottle (1/16, 6%), or interactive gamification (2/16, 13%). Interventions targeted monitoring or improvement of medication adherence (5/16, 31%); self-management, pain reporting, and symptom reporting (7/16, 44%); stress, coping, sleep, and daily activities reporting (4/16, 25%); cognitive training for memory (1/16, 6%); sickle cell disease and reproductive health knowledge (5/16, 31%); cognitive behavioral therapy (2/16, 13%); and guided relaxation interventions (1/16, 6%). Most studies (11/16, 69%) included older children or adolescents (mean or median age 10-17 years; 11/16, 69%) and 5 included young adults (>=18 years old) (5/16, 31%). Sample size ranged from 11 to 236, with a median of 21 per study: <20 in 6 (38%), >=20 to <50 in 6 (38%), and >50 participants in 4 studies (25%). Most reported improvement in self-management-related outcomes (15/16, 94%), as well as high satisfaction and acceptability of different study interventions (10/16, 63%). CONCLUSIONS: Our systematic review identified eHealth interventions measuring a variety of outcomes, which showed improvement in multiple components of self management of sickle cell disease. Despite the promising feasibility and acceptability of eHealth interventions in improving self-management of sickle cell disease, the evidence overall is modest. Future eHealth intervention studies are needed to evaluate their efficacy, effectiveness, and cost effectiveness in promoting self-management in patients with sickle cell disease using rigorous methods and theoretical frameworks with clearly defined clinical outcomes. PMID- 30026181 TI - Evidence and tips on the use of medication compliance aids. PMID- 30026180 TI - Development of a Web-Based Formative Self-Assessment Tool for Physicians to Practice Breaking Bad News (BRADNET). AB - BACKGROUND: Although most physicians in medical settings have to deliver bad news, the skills of delivering bad news to patients have been given insufficient attention. Delivering bad news is a complex communication task that includes verbal and nonverbal skills, the ability to recognize and respond to patients' emotions and the importance of considering the patient's environment such as culture and social status. How bad news is delivered can have consequences that may affect patients, sometimes over the long term. OBJECTIVE: This project aimed to develop a Web-based formative self-assessment tool for physicians to practice delivering bad news to minimize the deleterious effects of poor way of breaking bad news about a disease, whatever the disease. METHODS: BReaking bAD NEws Tool (BRADNET) items were developed by reviewing existing protocols and recommendations for delivering bad news. We also examined instruments for assessing patient-physician communications and conducted semistructured interviews with patients and physicians. From this step, we selected specific themes and then pooled these themes before consensus was achieved on a good practices communication framework list. Items were then created from this list. To ensure that physicians found BRADNET acceptable, understandable, and relevant to their patients' condition, the tool was refined by a working group of clinicians familiar with delivering bad news. The think-aloud approach was used to explore the impact of the items and messages and why and how these messages could change physicians' relations with patients or how to deliver bad news. Finally, formative self-assessment sessions were constructed according to a double perspective of progression: a chronological progression of the disclosure of the bad news and the growing difficulty of items (difficulty concerning the expected level of self-reflection). RESULTS: The good practices communication framework list comprised 70 specific issues related to breaking bad news pooled into 8 main domains: opening, preparing for the delivery of bad news, communication techniques, consultation content, attention, physician emotional management, shared decision making, and the relationship between the physician and the medical team. After constructing the items from this list, the items were extensively refined to make them more useful to the target audience, and one item was added. BRADNET contains 71 items, each including a question, response options, and a corresponding message, which were divided into 8 domains and assessed with 12 self-assessment sessions. The BRADNET Web-based platform was developed according to the cognitive load theory and the cognitive theory of multimedia learning. CONCLUSIONS: The objective of this Web-based assessment tool was to create a "space" for reflection. It contained items leading to self reflection and messages that introduced recommended communication behaviors. Our approach was innovative as it provided an inexpensive distance-learning self assessment tool that was manageable and less time-consuming for physicians with often overwhelming schedules. PMID- 30026182 TI - RH genotype matching for transfusion support in sickle cell disease. AB - Rh alloimmunization remains a challenge for patients with sickle cell disease (SCD) despite transfusion of serologic Rh C, E, and K antigen-matched red cells. Inheritance of altered RH alleles contributes to the prevalence of Rh antibodies after blood transfusion in patients with SCD and explains approximately one-third of cases. The remainder seem to be stimulated by altered Rh proteins on African American donor red cells. Matching patients with donors on the basis of RH genotype may mitigate Rh alloimmunization, but the feasibility and resources required are not known. We compared RH allele frequencies between patients with SCD (n = 857) and African American donors (n = 587) and showed that RH allele frequencies are similar. Overall, 29% of RHD and 53% of RHCE alleles are altered in patients and African American donors. We modeled RH genotype matching compared with serologic Rh D, C, and E, along with K antigen matching, and found that approximately twice the number of African American donors would be required for RH genotype vs Rh serologic matching at our institution. We demonstrated that African American donor recruitment is necessary to maintain an adequate supply of C-, E-, and K-negative donor units to avoid depleting the Rh-negative (RhD-) blood supply. Our results suggest that prophylactic RH genetic matching for patients with SCD is feasible with a donor pool comprised primarily of African Americans and would optimize the use of our existing minority donor inventory. The current cost of RH genotyping all minority donors and management of the data remain limiting factors. PMID- 30026185 TI - Managing accidental hypothermia: a UK-wide survey of prehospital and search and rescue providers. AB - AIM: The management of hypothermic casualties is a challenge faced by all prehospital and search and rescue (SAR) teams. It is not known how the practice of these diverse teams compare. The aim of this study was to review prehospital hypothermia management across a wide range of SAR providers in the UK. METHODS: A survey of ground ambulances (GAs), air ambulances (AAs), mountain rescue teams (MRTs, including Ministry of Defence), lowland rescue teams (LRTs), cave rescue teams (CRTs), and lifeboats and lifeguard organisations (LLOs) across the UK was conducted between May and November 2017. In total, 189 teams were contacted. Questions investigated packaging methods, temperature measurement and protocols for managing hypothermic casualties. RESULTS: Response rate was 59%, comprising 112 teams from a wide range of organisations. Heavyweight (>3 kg) casualty bags were used by all CRTs, 81% of MRTs, 29% of LRTs, 18% of AAs and 8% of LLOs. Specially designed lightweight (<0.5 kg) blankets or wraps were used by 93% of LRTs, 85% of LLOs, 82% of GAs, 71% of AAs and 50% of MRTs. Bubble wrap was used mainly by AAs, with 35% of AAs reporting its use. Overall, 94% of packaging methods incorporated both insulating and vapour-tight layers. Active warming by heated pads or blankets was used by 65% of AAs, 60% of CRTs, 54% of MRTs, 29% of LRTs and 9% of GAs, with no LLO use. Temperature measurement was reported by all AAs and GAs, 93% of LRTs, 80% of CRTs, 75% of MRTs and 31% of LLOs. The favoured anatomical site for temperature measurement was tympanic. Protocols for packaging hypothermic casualties were reported by 73% of services. CONCLUSIONS: This survey describes current practice in prehospital hypothermia management, comparing the various methods used by different teams, and provides a basis to direct further education and research. PMID- 30026184 TI - Defective TAFI activation in hemophilia A mice is a major contributor to joint bleeding. AB - Joint bleeds are common in congenital hemophilia but rare in acquired hemophilia A (aHA) for reasons unknown. To identify key mechanisms responsible for joint specific bleeding in congenital hemophilia, bleeding phenotypes after joint injury and tail transection were compared in aHA wild-type (WT) mice (receiving an anti-factor VIII [FVIII] antibody) and congenital HA (FVIII-/-) mice. Both aHA and FVIII-/- mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII-/ mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI-/- mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII-/- mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII-/- mice in vivo, consistent with previous in vitro analyses in FVIII-deficient plasma. In contrast, notable TAFI activation was observed in aHA mice, suggesting that TAFI protected aHA joints against bleeding. Pharmacological inhibitors of fibrinolysis revealed that urokinase-type plasminogen activator (uPA)-induced fibrinolysis drove joint bleeding, whereas tissue-type plasminogen activator-mediated fibrinolysis contributed to tail bleeding. These data identify TAFI as an important modifier of hemophilic joint bleeding in aHA by inhibiting uPA-mediated fibrinolysis. Moreover, our data suggest that bleed protection by TAFI was absent in congenital FVIII-/- mice because of severely defective TAFI activation, underscoring the importance of clot protection in addition to clot formation when considering prohemostatic strategies for hemophilic joint bleeding. PMID- 30026183 TI - Platelets kill circulating parasites of all major Plasmodium species in human malaria. AB - Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet-erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodium species studied, particularly mature stages, and was greatest in P vivax patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+ parasites). These PF4+TUNEL+ parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodium species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet-erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria. PMID- 30026186 TI - Gene Birth Contributes to Structural Disorder Encoded by Overlapping Genes. AB - The same nucleotide sequence can encode two protein products in different reading frames. Overlapping gene regions encode higher levels of intrinsic structural disorder (ISD) than nonoverlapping genes (39% vs. 25% in our viral dataset). This might be because of the intrinsic properties of the genetic code, because one member per pair was recently born de novo in a process that favors high ISD, or because high ISD relieves increased evolutionary constraint imposed by dual coding. Here, we quantify the relative contributions of these three alternative hypotheses. We estimate that the recency of de novo gene birth explains [Formula: see text] or more of the elevation in ISD in overlapping regions of viral genes. While the two reading frames within a same-strand overlapping gene pair have markedly different ISD tendencies that must be controlled for, their effects cancel out to make no net contribution to ISD. The remaining elevation of ISD in the older members of overlapping gene pairs, presumed due to the need to alleviate evolutionary constraint, was already present prior to the origin of the overlap. Same-strand overlapping gene birth events can occur in two different frames, favoring high ISD either in the ancestral gene or in the novel gene; surprisingly, most de novo gene birth events contained completely within the body of an ancestral gene favor high ISD in the ancestral gene (23 phylogenetically independent events vs. 1). This can be explained by mutation bias favoring the frame with more start codons and fewer stop codons. PMID- 30026187 TI - Inferring Continuous and Discrete Population Genetic Structure Across Space. AB - A classic problem in population genetics is the characterization of discrete population structure in the presence of continuous patterns of genetic differentiation. Especially when sampling is discontinuous, the use of clustering or assignment methods may incorrectly ascribe differentiation due to continuous processes (e.g., geographic isolation by distance) to discrete processes, such as geographic, ecological, or reproductive barriers between populations. This reflects a shortcoming of current methods for inferring and visualizing population structure when applied to genetic data deriving from geographically distributed populations. Here, we present a statistical framework for the simultaneous inference of continuous and discrete patterns of population structure. The method estimates ancestry proportions for each sample from a set of two-dimensional population layers, and, within each layer, estimates a rate at which relatedness decays with distance. This thereby explicitly addresses the "clines versus clusters" problem in modeling population genetic variation, and remedies some of the overfitting to which nonspatial models are prone. The method produces useful descriptions of structure in genetic relatedness in situations where separated, geographically distributed populations interact, as after a range expansion or secondary contact. We demonstrate the utility of this approach using simulations and by applying it to empirical datasets of poplars and black bears in North America. PMID- 30026189 TI - Secondhand smoke exposure during pregnancy: a cross-sectional analysis of data from Demographic and Health Survey from 30 low-income and middle-income countries. AB - BACKGROUND: Secondhand smoke (SHS) exposure during pregnancy increases the risk of infant stillbirth, congenital malformations, low birth weight and respiratory illnesses. However, little is known about the extent of SHS exposure during pregnancy. We assessed the prevalence of SHS exposure in pregnant women in low income and middle-income countries (LMICs). METHODS: We used Demographic and Health Survey data collected between 2008 and 2013 from 30 LMICs. We estimated weighted country-specific prevalence of SHS exposure among 37 427 pregnant women. We accounted for sampling weights, clustering and stratification in the sampling methods. We also explored associations between sociodemographic variables and SHS exposure in pregnant women using pairwise multinomial regression model. FINDINGS: The prevalence of daily SHS exposure during pregnancy ranged from 6% (95% CI 5% to 7%) (Nigeria) to 73% (95% CI 62% to 81%) (Armenia) and was greater than active tobacco use in pregnancy across all countries studied. Being wealthier, maternal employment, higher education and urban households were associated with lower SHS exposure in full regression models. SHS exposure in pregnant women closely mirrors WHO Global Adult Tobacco Survey male active smoking patterns. Daily SHS exposure accounted for a greater population attributable fraction of stillbirths than active smoking, ranging from 1% of stillbirths (Nigeria) to 14% (Indonesia). INTERPRETATION: We have demonstrated that SHS exposure during pregnancy is far more common than active smoking in LMICs, accounting for more stillbirths than active smoking. Protecting pregnant women from SHS exposure should be a key strategy to improve maternal and child health. PMID- 30026188 TI - NT-PGC-1alpha deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo. AB - Transcriptional coactivator PPAR gamma coactivator (PGC)-1alpha and its splice variant N-terminal (NT)-PGC-1alpha mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature. PGC-1alpha is dispensable for cold-induced BAT thermogenesis as long as NT-PGC 1alpha is present. However, the functional significance of NT-PGC-1alpha in BAT has not been determined. In the present study, we generated NT-PGC-1alpha-/- mice to investigate the effect of NT-PGC-1alpha deficiency on adaptive BAT thermogenesis. At thermoneutrality, NT-PGC-1alpha-/- mice exhibited abnormal BAT phenotype with increased accumulation of large lipid droplets concomitant with marked downregulation of FA oxidation (FAO)-related genes. Consistent with transcriptional changes, mitochondrial FAO was significantly diminished in NT-PGC 1alpha-/- BAT. This alteration, in turn, enhanced glucose utilization within the NT-PGC-1alpha-/- BAT mitochondria. In line with this, NT-PGC-1alpha-/- mice had higher reliance on carbohydrates. In response to cold or beta3-adrenergic receptor agonist, NT-PGC-1alpha-/- mice transiently exhibited lower thermogenesis but reached similar thermogenic capacities as their WT littermates. Collectively, these findings demonstrate that NT-PGC-1alpha is an important contributor to the maintenance of FAO capacity in BAT at thermoneutrality and provide deeper insights into the relative contributions of PGC-1alpha and NT-PGC-1alpha to temperature-regulated BAT remodeling. PMID- 30026190 TI - Presurgery osteoarthritis severity over 10 years in 2 Ontario prospective total knee replacement cohorts: a cohort study. AB - BACKGROUND: It has been suggested that total knee replacement is being performed in people with less-severe osteoarthritis. We aimed to determine whether there were differences in the presurgery profile, symptoms and disability of 2 cohorts who underwent total knee replacement over a 10-year period. METHODS: Patients aged 18-85 years undergoing primary total knee replacement for osteoarthritis at 1 of 4 sites in Toronto and Strathroy, Ontario, were recruited in a cohort study during 2006-2008 (cohort 1) and 2012-2015 (cohort 2). Patients undergoing unicompartmental or revision arthroplasty were excluded. Demographic and health (body mass index [BMI], comorbidity) variables and osteoarthritis severity, as assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the disability component of the Late-Life Function and Disability Instrument (LLFDI-D), were collected before surgery. We calculated proportions, means and standard deviations with 95% confidence intervals (CIs) for all data. We constructed density plots by tertile score for the WOMAC pain and physical function subscales and the LLFDI-D limitation scale. RESULTS: There were 494 patients in cohort 1 and 251 patients in cohort 2. There were no differences in age, sex, education, living status, BMI, comorbidity, pain severity or disability between the cohorts based on overlapping 95% CIs and the density plots. More patients in cohort 1 than in cohort 2 were single (176 [35.6%], 95% CI 32.5% 41.1% v. 63 [25.1%], 95% CI 20.3%-31.0%). Patients in cohort 2 reported less limitation in higher-demand activities than did those in cohort 1 (mean score on LLFDI-D 62.3 [95% CI 60.7-63.9] v. 59.2 [95% CI 58.2-60.2]). INTERPRETATION: The patient profile and reported osteoarthritis severity were similar in 2 cohorts that had total knee replacement over a 10-year period. This suggests that increasing total knee replacement volumes over this period likely were not driven by these factors. PMID- 30026192 TI - Reorganisation costs lives. PMID- 30026191 TI - The influence of patient-clinician ethnocultural and language concordance on continuity and quality of care: a cross-sectional analysis. AB - BACKGROUND: Concordance refers to shared characteristics between a clinician and patient, such as ethnicity or language. The purpose of this study was to examine whether patient-clinician concordance is associated with patient-reported continuity of care (relational, informational and management) and patient reported impacts of care (quality and empowerment). METHODS: This is a secondary analysis of cross-sectional patient surveys that were administered across British Columbia, Manitoba and Quebec using random digit dialling. Participants were adults who spoke English, French, Mandarin, Cantonese or Punjabi and who had visited a primary care clinician in the previous 12 months (n = 3156). Patients self-identified as being of European, Chinese, South Asian and Indigenous descent. Outcome measures included patients' perceptions of continuity, quality and empowerment. Adjusted logistic regression models and odds ratio were generated. RESULTS: More than 64% of non-Indigenous respondents reported ethnocultural concordance. Ethnocultural concordance was associated with higher odds of relational and management continuity. This same pattern held when there was both ethnocultural and language concordance. No association was found between language concordance and any outcome measure. Chinese participants reported lower quality (odds ratio [OR] 0.24, 95% confidence interval [CI] 0.12-0.48), as did South Asian participants (OR 0.17, 95% CI 0.09-0.31) than did participants of European descent. INTERPRETATION: Higher relational and management continuity is more likely with the presence of patient-clinician ethnocultural and language concordance. Lower continuity and quality reported by Chinese and South Asian particpants could indicate important health care disparities. PMID- 30026193 TI - Eosinophils can more than kill. AB - In this issue of JEM, Arnold et al. (https://doi.org/10.1084/jem.20172049) demonstrate that eosinophils suppress mucosal inflammation by directly interacting with pro-inflammatory Th1 cells. This emphasizes the dual role of eosinophils, which can act both as effector cells that control an infection and as immunomodulatory cells that promote immune homeostasis. PMID- 30026194 TI - Understanding when people will report crimes to the police. PMID- 30026195 TI - New pests for old as GMOs bring on substitute pests. PMID- 30026196 TI - Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE. AB - EmrE is a small, homodimeric membrane transporter that exploits the established electrochemical proton gradient across the Escherichia coli inner membrane to export toxic polyaromatic cations, prototypical of the wider small-multidrug resistance transporter family. While prior studies have established many fundamental aspects of the specificity and rate of substrate transport in EmrE, low resolution of available structures has hampered identification of the transport coupling mechanism. Here we present a complete, refined atomic structure of EmrE optimized against available cryo-electron microscopy (cryo-EM) data to delineate the critical interactions by which EmrE regulates its conformation during the transport process. With the model, we conduct molecular dynamics simulations of the transporter in explicit membranes to probe EmrE dynamics under different substrate loading and conformational states, representing different intermediates in the transport cycle. The refined model is stable under extended simulation. The water dynamics in simulation indicate that the hydrogen-bonding networks around a pair of solvent-exposed glutamate residues (E14) depend on the loading state of EmrE. One specific hydrogen bond from a tyrosine (Y60) on one monomer to a glutamate (E14) on the opposite monomer is especially critical, as it locks the protein conformation when the glutamate is deprotonated. The hydrogen bond provided by Y60 lowers the [Formula: see text] of one glutamate relative to the other, suggesting both glutamates should be protonated for the hydrogen bond to break and a substrate-free transition to take place. These findings establish the molecular mechanism for the coupling between proton transfer reactions and protein conformation in this proton-coupled secondary transporter. PMID- 30026197 TI - Rates of cavity filling by liquids. AB - Understanding the fundamental wetting behavior of liquids on surfaces with pores or cavities provides insights into the wetting phenomena associated with rough or patterned surfaces, such as skin and fabrics, as well as the development of everyday products such as ointments and paints, and industrial applications such as enhanced oil recovery and pitting during chemical mechanical polishing. We have studied, both experimentally and theoretically, the dynamics of the transitions from the unfilled/partially filled (Cassie-Baxter) wetting state to the fully filled (Wenzel) wetting state on intrinsically hydrophilic surfaces (intrinsic water contact angle <90 degrees , where the Wenzel state is always the thermodynamically favorable state, while a temporary metastable Cassie-Baxter state can also exist) to determine the variables that control the rates of such transitions. We prepared silicon wafers with cylindrical cavities of different geometries and immersed them in bulk water. With bright-field and confocal fluorescence microscopy, we observed the details of, and the rates associated with, water penetration into the cavities from the bulk. We find that unconnected, reentrant cavities (i.e., cavities that open up below the surface) have the slowest cavity-filling rates, while connected or non-reentrant cavities undergo very rapid transitions. Using these unconnected, reentrant cavities, we identified the variables that affect cavity-filling rates: (i) the intrinsic contact angle, (ii) the concentration of dissolved air in the bulk water phase (i.e., aeration), (iii) the liquid volatility that determines the rate of capillary condensation inside the cavities, and (iv) the presence of surfactants. PMID- 30026198 TI - "Shepherd's crook" neurons drive and synchronize the enhancing and suppressive mechanisms of the midbrain stimulus selection network. AB - The optic tectum (TeO), or superior colliculus, is a multisensory midbrain center that organizes spatially orienting responses to relevant stimuli. To define the stimulus with the highest priority at each moment, a network of reciprocal connections between the TeO and the isthmi promotes competition between concurrent tectal inputs. In the avian midbrain, the neurons mediating enhancement and suppression of tectal inputs are located in separate isthmic nuclei, facilitating the analysis of the neural processes that mediate competition. A specific subset of radial neurons in the intermediate tectal layers relay retinal inputs to the isthmi, but at present it is unclear whether separate neurons innervate individual nuclei or a single neural type sends a common input to several of them. In this study, we used in vitro neural tracing and cell-filling experiments in chickens to show that single neurons innervate, via axon collaterals, the three nuclei that comprise the isthmotectal network. This demonstrates that the input signals representing the strength of the incoming stimuli are simultaneously relayed to the mechanisms promoting both enhancement and suppression of the input signals. By performing in vivo recordings in anesthetized chicks, we also show that this common input generates synchrony between both antagonistic mechanisms, demonstrating that activity enhancement and suppression are closely coordinated. From a computational point of view, these results suggest that these tectal neurons constitute integrative nodes that combine inputs from different sources to drive in parallel several concurrent neural processes, each performing complementary functions within the network through different firing patterns and connectivity. PMID- 30026199 TI - Meat consumption, health, and the environment. AB - Both the global average per capita consumption of meat and the total amount of meat consumed are rising, driven by increasing average individual incomes and by population growth. The consumption of different types of meat and meat products has substantial effects on people's health, and livestock production can have major negative effects on the environment. Here, we explore the evidence base for these assertions and the options policy-makers have should they wish to intervene to affect population meat consumption. We highlight where more research is required and the great importance of integrating insights from the natural and social sciences. PMID- 30026200 TI - Modeling the ecology and evolution of biodiversity: Biogeographical cradles, museums, and graves. AB - Individual processes shaping geographical patterns of biodiversity are increasingly understood, but their complex interactions on broad spatial and temporal scales remain beyond the reach of analytical models and traditional experiments. To meet this challenge, we built a spatially explicit, mechanistic simulation model implementing adaptation, range shifts, fragmentation, speciation, dispersal, competition, and extinction, driven by modeled climates of the past 800,000 years in South America. Experimental topographic smoothing confirmed the impact of climate heterogeneity on diversification. The simulations identified regions and episodes of speciation (cradles), persistence (museums), and extinction (graves). Although the simulations had no target pattern and were not parameterized with empirical data, emerging richness maps closely resembled contemporary maps for major taxa, confirming powerful roles for evolution and diversification driven by topography and climate. PMID- 30026202 TI - Space, still the final frontier. PMID- 30026201 TI - Human influence on the seasonal cycle of tropospheric temperature. AB - We provide scientific evidence that a human-caused signal in the seasonal cycle of tropospheric temperature has emerged from the background noise of natural variability. Satellite data and the anthropogenic "fingerprint" predicted by climate models show common large-scale changes in geographical patterns of seasonal cycle amplitude. These common features include increases in amplitude at mid-latitudes in both hemispheres, amplitude decreases at high latitudes in the Southern Hemisphere, and small changes in the tropics. Simple physical mechanisms explain these features. The model fingerprint of seasonal cycle changes is identifiable with high statistical confidence in five out of six satellite temperature datasets. Our results suggest that attribution studies with the changing seasonal cycle provide powerful evidence for a significant human effect on Earth's climate. PMID- 30026204 TI - Congo rapidly curtails Ebola. PMID- 30026205 TI - A new portal for patient data. PMID- 30026206 TI - Echidnas don't suck-but their ancestors did. PMID- 30026207 TI - 'Frightening' typhoid fever outbreak spreads in Pakistan. PMID- 30026208 TI - Hackers easily fool artificial intelligences. PMID- 30026209 TI - A second chance. PMID- 30026210 TI - A path to clean water. PMID- 30026211 TI - Regulate to reduce chemical mixture risk. PMID- 30026212 TI - Transcriptional control of kidney cancer. PMID- 30026213 TI - The seasonal fingerprint of climate change. PMID- 30026214 TI - Houseplants as home health monitors. PMID- 30026215 TI - Exploring cytoskeletal diversity in neurons. PMID- 30026216 TI - Engage research institutions on research regulatory reform. PMID- 30026217 TI - Bialowieza Forest: A new threat. PMID- 30026218 TI - Preparing junior faculty for success. PMID- 30026219 TI - A closer look at ageism in science. PMID- 30026220 TI - Wallpaper fermions and the nonsymmorphic Dirac insulator. AB - Materials whose gapless surface states are protected by crystal symmetries include mirror topological crystalline insulators and nonsymmorphic hourglass insulators. There exists only a very limited set of possible surface crystal symmetries, captured by the 17 "wallpaper groups." Here we show that a consideration of symmetry-allowed band degeneracies in the wallpaper groups can be used to understand previously described topological crystalline insulators and to predict phenomenologically distinct examples. In particular, the two wallpaper groups with multiple glide lines, pgg and p4g, allow for a topological insulating phase whose surface spectrum consists of only a single, fourfold-degenerate, true Dirac fermion, representing an exception to a symmetry-enhanced fermion-doubling theorem. We theoretically predict the presence of this phase in Sr2Pb3 in space group 127 (P4/mbm). PMID- 30026221 TI - Electrofluorochromism at the single-molecule level. AB - The interplay between the oxidation state and the optical properties of molecules is important for applications in displays, sensors, and molecular-based memories. The fundamental mechanisms occurring at the level of a single molecule have been difficult to probe. We used a scanning tunneling microscope (STM) to characterize and control the fluorescence of a single zinc-phthalocyanine radical cation adsorbed on a sodium chloride-covered gold (111) sample. The neutral and oxidized states of the molecule were identified on the basis of their fluorescence spectra, which revealed very different emission energies and vibronic fingerprints. The emission of the charged molecule was controlled by tuning the thickness of the insulator and the plasmons localized at the apex of the STM tip. In addition, subnanometric variations of the tip position were used to investigate the charging and electroluminescence mechanisms. PMID- 30026222 TI - Cavity-mediated collective spin-exchange interactions in a strontium superradiant laser. AB - Laser-cooled and quantum degenerate atoms are being pursued as quantum simulators and form the basis of today's most precise sensors. A key challenge toward these goals is to understand and control coherent interactions between the atoms. We observe long-range exchange interactions mediated by an optical cavity, which manifest as tunable spin-spin interactions on the pseudo spin-1/2 system composed of the millihertz linewidth clock transition in strontium. This leads to one-axis twisting dynamics, the emergence of a many-body energy gap, and gap protection of the optical coherence against certain sources of decoherence. Our observations will aid in the future design of versatile quantum simulators and the next generation of atomic clocks that use quantum correlations for enhanced metrology. PMID- 30026223 TI - Torsional instability in the single-chain limit of a transition metal trichalcogenide. AB - The scientific bounty resulting from the successful isolation of few to single layers of two-dimensional materials suggests that related new physics resides in the few- to single-chain limit of one-dimensional materials. We report the synthesis of the quasi-one-dimensional transition metal trichalcogenide NbSe3 (niobium triselenide) in the few-chain limit, including the realization of isolated single chains. The chains are encapsulated in protective boron nitride or carbon nanotube sheaths to prevent oxidation and to facilitate characterization. Transmission electron microscopy reveals static and dynamic structural torsional waves not found in bulk NbSe3 crystals. Electronic structure calculations indicate that charge transfer drives the torsional wave instability. Very little covalent bonding is found between the chains and the nanotube sheath, leading to relatively unhindered longitudinal and torsional dynamics for the encapsulated chains. PMID- 30026224 TI - Fault-tolerant detection of a quantum error. AB - A critical component of any quantum error-correcting scheme is detection of errors by using an ancilla system. However, errors occurring in the ancilla can propagate onto the logical qubit, irreversibly corrupting the encoded information. We demonstrate a fault-tolerant error-detection scheme that suppresses spreading of ancilla errors by a factor of 5, while maintaining the assignment fidelity. The same method is used to prevent propagation of ancilla excitations, increasing the logical qubit dephasing time by an order of magnitude. Our approach is hardware-efficient, as it uses a single multilevel transmon ancilla and a cavity-encoded logical qubit, whose interaction is engineered in situ by using an off-resonant sideband drive. The results demonstrate that hardware-efficient approaches that exploit system-specific error models can yield advances toward fault-tolerant quantum computation. PMID- 30026225 TI - Atmospheric new particle formation from sulfuric acid and amines in a Chinese megacity. AB - Atmospheric new particle formation (NPF) is an important global phenomenon that is nevertheless sensitive to ambient conditions. According to both observation and theoretical arguments, NPF usually requires a relatively high sulfuric acid (H2SO4) concentration to promote the formation of new particles and a low preexisting aerosol loading to minimize the sink of new particles. We investigated NPF in Shanghai and were able to observe both precursor vapors (H2SO4) and initial clusters at a molecular level in a megacity. High NPF rates were observed to coincide with several familiar markers suggestive of H2SO4 dimethylamine (DMA)-water (H2O) nucleation, including sulfuric acid dimers and H2SO4-DMA clusters. In a cluster kinetics simulation, the observed concentration of sulfuric acid was high enough to explain the particle growth to ~3 nanometers under the very high condensation sink, whereas the subsequent higher growth rate beyond this size is believed to result from the added contribution of condensing organic species. These findings will help in understanding urban NPF and its air quality and climate effects, as well as in formulating policies to mitigate secondary particle formation in China. PMID- 30026226 TI - Mesophotic coral ecosystems are threatened and ecologically distinct from shallow water reefs. AB - The rapid degradation of coral reefs is one of the most serious biodiversity problems facing our generation. Mesophotic coral reefs (at depths of 30 to 150 meters) have been widely hypothesized to provide refuge from natural and anthropogenic impacts, a promise for the survival of shallow reefs. The potential role of mesophotic reefs as universal refuges is often highlighted in reef conservation research. This hypothesis rests on two assumptions: (i) that there is considerable overlap in species composition and connectivity between shallow and deep populations and (ii) that deep reefs are less susceptible to anthropogenic and natural impacts than their shallower counterparts. Here we present evidence contradicting these assumptions and argue that mesophotic reefs are distinct, impacted, and in as much need of protection as shallow coral reefs. PMID- 30026229 TI - Working science into fundraising. PMID- 30026227 TI - Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. AB - Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of beta thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain-focused CRISPR-Cas9-based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies. PMID- 30026230 TI - Subacromial decompression versus diagnostic arthroscopy for shoulder impingement: randomised, placebo surgery controlled clinical trial. AB - OBJECTIVE: To assess the efficacy of arthroscopic subacromial decompression (ASD) by comparing it with diagnostic arthroscopy, a placebo surgical intervention, and with a non-operative alternative, exercise therapy, in a more pragmatic setting. DESIGN: Multicentre, three group, randomised, double blind, sham controlled trial. SETTING: Orthopaedic departments at three public hospitals in Finland. PARTICIPANTS: 210 patients with symptoms consistent with shoulder impingement syndrome, enrolled from 1 February 2005 with two year follow-up completed by 25 June 2015. INTERVENTIONS: ASD, diagnostic arthroscopy (placebo control), and exercise therapy. MAIN OUTCOME MEASURES: Shoulder pain at rest and on arm activity (visual analogue scale (VAS) from 0 to 100, with 0 denoting no pain), at 24 months. The threshold for minimal clinically important difference was set at 15. RESULTS: In the primary intention to treat analysis (ASD versus diagnostic arthroscopy), no clinically relevant between group differences were seen in the two primary outcomes at 24 months (mean change for ASD 36.0 at rest and 55.4 on activity; for diagnostic arthroscopy 31.4 at rest and 47.5 on activity). The observed mean difference between groups (ASD minus diagnostic arthroscopy) in pain VAS were -4.6 (95% confidence interval -11.3 to 2.1) points (P=0.18) at rest and -9.0 (-18.1 to 0.2) points (P=0.054) on arm activity. No between group differences were seen between the ASD and diagnostic arthroscopy groups in the secondary outcomes or adverse events. In the secondary comparison (ASD versus exercise therapy), statistically significant differences were found in favour of ASD in the two primary outcomes at 24 months in both VAS at rest (-7.5, -14.0 to 1.0, points; P=0.023) and VAS on arm activity (-12.0, -20.9 to -3.2, points; P=0.008), but the mean differences between groups did not exceed the pre specified minimal clinically important difference. Of note, this ASD versus exercise therapy comparison is not only confounded by lack of blinding but also likely to be biased in favour of ASD owing to the selective removal of patients with likely poor outcome from the ASD group, without comparable exclusions from the exercise therapy group. CONCLUSIONS: In this controlled trial involving patients with a shoulder impingement syndrome, arthroscopic subacromial decompression provided no benefit over diagnostic arthroscopy at 24 months. TRIAL REGISTRATION: Clinicaltrials.gov NCT00428870. PMID- 30026228 TI - VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. AB - Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor kappaB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC. PMID- 30026231 TI - Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency. AB - Autotaxin (ATX) is a secreted glycoprotein and the only member of the ectonucleotide pyrophosphatase/phosphodiesterase family that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key responses, such as cell migration, proliferation, and survival, implicating ATX LPA signaling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, called the "pocket" and the "tunnel," respectively. However, the mechanisms in allosteric modulation of ATX's activity as a lysophospholipase D are unclear. Here, using the physiological LPC substrate, a new fluorescent substrate, and diverse ATX inhibitors, we revisited the kinetics and allosteric regulation of the ATX catalytic cycle, dissecting the different steps and pathways leading to LPC hydrolysis. We found that ATX activity is stimulated by LPA and that LPA activates ATX lysophospholipase D activity by binding to the ATX tunnel. A consolidation of all experimental kinetics data yielded a comprehensive catalytic model supported by molecular modeling simulations and suggested a positive feedback mechanism that is regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend the current understanding of ATX hydrolysis in light of the allosteric regulation by ATX-produced LPA species and have implications for the design and application of both orthosteric and allosteric ATX inhibitors. PMID- 30026232 TI - Kruppel-like factor 10 (KLF10) is transactivated by the transcription factor C/EBPbeta and involved in early 3T3-L1 preadipocyte differentiation. AB - Adipose tissue stores energy and plays an important role in energy homeostasis. CCAAT/enhancer-binding protein beta (C/EBPbeta) is an important early transcription factor for 3T3-L1 preadipocyte differentiation, facilitating mitotic clonal expansion (MCE) and transactivating C/EBPalpha and peroxisome proliferator-activated receptor-gamma (PPARgamma) to promote adipogenesis. C/EBPbeta is induced early, but the expression of antimitotic C/EBPalpha and PPARgamma is not induced until ~48 h. The delayed expression of C/EBPalpha and PPARgamma is thought to ensure MCE progression, but the molecular mechanism for this delay remains elusive. Here, we show that the zinc-finger transcription factor Kruppel-like factor 10 (KLF10) is induced after adipogenic induction and that its expression positively correlates with that of C/EBPbeta but inversely correlates with expression of C/EBPalpha and PPARgamma. C/EBPbeta bound to the KLF10 promoter and transactivated its expression during MCE. KLF10 overexpression in 3T3-L1 preadipocyte repressed adipogenesis and decreased C/EBPalpha and PPARgamma expression, whereas siRNA-mediated down-regulation of KLF10 enhanced adipogenesis and increased C/EBPalpha and PPARgamma expression. Luciferase assays revealed an inhibitory effect of KLF10 on C/EBPalpha promoter activity. Using promoter deletion and mutation analysis, we identified a KLF10-binding site within the proximal promoter region of C/EBPalpha. Furthermore, KLF10 interacted with and recruited histone deacetylase 1 (HDAC1) to the C/EBPalpha promoter, decreasing acetylated histone H4 on the C/EBPalpha promoter and inactivating C/EBPalpha transcription. Because C/EBPalpha can transactivate PPARgamma, our results suggest a mechanism by which expression of C/EBPalpha and PPARgamma is delayed via KLF10 expression and shed light on the negative feedback loop for C/EBPbeta-regulated adipogenesis in 3T3-L1 preadipocyte. PMID- 30026233 TI - Characterization of the molecular mechanism of the autophagy-related Atg8-Atg3 protein interaction in Toxoplasma gondii. AB - Toxoplasmosis is caused by an obligate intracellular parasite, the protozoan Toxoplasma gondii Discovery of novel drugs against T. gondii infection could circumvent the toxicity of existing drugs and T. gondii resistance to current treatments. The autophagy-related protein 8 (Atg8)-Atg3 interaction in T. gondii is a promising drug target because of its importance for regulating Atg8 lipidation. We reported previously that TgAtg8 and TgAtg3 interact directly. Here we validated that substitutions of conserved residues of TgAtg8 interacting with the Atg8 family-interacting motif (AIM) in Atg3 disrupt the TgAtg8-TgAtg3 interaction and reduce TgAtg8 lipidation and autophagosome formation. These findings were consistent with results reported previously for Plasmodium Atg8, suggesting functional conservation of Atg8 in Toxoplasma and Plasmodium. Moreover, using peptide and AlphaScreen assays, we identified the AIM sequence in TgAtg3 that binds TgAtg8. We determined that the core TgAtg3 AIM contains a Phe239-Ala240-Asp241-Ile242 (239FADI242) signature distinct from the 105WLLP108 signature in the AIM of Plasmodium Atg3. Furthermore, an alanine-scanning assay revealed that the TgAtg8-TgAtg3 interaction in T. gondii also depends strongly on several residues surrounding the core TgAtg3 AIM, such as Asn238, Asp243, and Cys244 These results indicate that distinct AIMs in Atg3 contribute to differences between Toxoplasma and Plasmodium Atg8-Atg3 interactions. By elucidating critical residues involved in the TgAtg8-TgAtg3 interaction, our work paves the way for the discovery of potential anti-toxoplasmosis drugs. The quantitative and straightforward AlphaScreen assay developed here may enable high throughput screening for small molecules disrupting the TgAtg8-TgAtg3 interaction. PMID- 30026236 TI - A pain in the back. PMID- 30026234 TI - Both reentrant loops of the sodium-coupled glutamate transporters contain molecular determinants of cation selectivity. AB - In the brain, glutamate transporters terminate excitatory neurotransmission by removing this neurotransmitter from the synapse via cotransport with three sodium ions into the surrounding cells. Structural studies have identified the binding sites of the three sodium ions in glutamate transporters. The residue side-chains directly interact with the sodium ions at the Na1 and Na3 sites and are fully conserved from archaeal to eukaryotic glutamate transporters. The Na2 site is formed by three main-chain oxygens on the extracellular reentrant hairpin loop HP2 and one on transmembrane helix 7. A glycine residue on HP2 is located closely to the three main-chain oxygens in all glutamate transporters, except for the astroglial transporter GLT-1, which has a serine residue at that position. Unlike for WT GLT-1, substitution of the serine residue to glycine enables sustained glutamate transport also when sodium is replaced by lithium. Here, using functional and simulation studies, we studied the role of this serine/glycine switch on cation selectivity of substrate transport. Our results indicate that the side-chain oxygen of the serine residues can form a hydrogen bond with a main chain oxygen on transmembrane helix 7. This leads to an expansion of the Na2 site such that water can participate in sodium coordination at Na2. Furthermore, we found other molecular determinants of cation selectivity on the nearby HP1 loop. We conclude that subtle changes in the composition of the two reentrant hairpin loops determine the cation specificity of acidic amino acid transport by glutamate transporters. PMID- 30026235 TI - Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1). AB - JIP1 was first identified as scaffold protein for the MAP kinase JNK and is a cargo protein for the kinesin1 molecular motor. JIP1 plays significant and broad roles in neurons, mainly as a regulator of kinesin1-dependent transport, and is associated with human pathologies such as cancer and Alzheimer disease. JIP1 is specifically recruited by the kinesin-light chain 1 (KLC1) of kinesin1, but the details of this interaction are not yet fully elucidated. Here, using calorimetry, we extensively biochemically characterized the interaction between KLC1 and JIP1. Using various truncated fragments of the tetratricopeptide repeat (TPR) domain of KLC1, we narrowed down its JIP1-binding region and identified seven KLC1 residues critical for JIP1 binding. These isothermal titration calorimetry (ITC)-based binding data enabled us to footprint the JIP1-binding site on KLC1-TPR. This footprint was used to uncover the structural basis for the marginal inhibition of JIP1 binding by the autoinhibitory LFP-acidic motif of KLC1, as well as for the competition between JIP1 and another cargo protein of kinesin1, the W-acidic motif-containing alcadein-alpha. Also, we examined the role of each of these critical residues of KLC1 for JIP1 binding in light of the previously reported crystal structure of the KLC1-TPR:JIP1 complex. Finally, sequence search in eukaryotic genomes identified several proteins, among which is SH2D6, that exhibit a motif similar to the KLC1-binding motif of JIP1. Overall, our extensive biochemical characterization of the KLC:JIP1 interaction, as well as identification of potential KLC1-binding partners, improves the understanding of how this growing family of cargos is recruited to kinesin1 by KLC1. PMID- 30026238 TI - Silencing cuticular pigmentation genes enables RNA FISH in intact insect appendages. AB - Optical imaging of gene expression by fluorescence in situ hybridisation (FISH) in insects is often impeded by their pigmented cuticle. As most chemical bleaching agents are incompatible with FISH, we developed an RNA interference (RNAi)-based method for clearing cuticular pigmentation which enables the use of whole-mount body appendages for RNA FISH (termed RNA-i-FISH). Silencing laccase2 or tyrosine hydroxylase in two leaf beetles species (Chrysomela populi and Phaedon cochleariae) cleared their pigmented cuticle and decreased light absorbance. Subsequently, intact appendages (palps, antennae, legs) from RNAi cleared individuals were used to image the expression and spatial distribution of antisense mRNA of two chemosensory genes encoding gustatory receptor and odorant binding protein. Imaging did not work for RNAi controls because the pigmentation was retained, or for FISH controls (sense mRNA). Several bleaching agents were incompatible with FISH, because of degradation of RNA, lack of clearing efficacy or long incubation times. Overall, silencing pigmentation genes is a significant improvement over bleaching agents, enabling FISH in intact insect appendages. PMID- 30026237 TI - Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose. AB - The high blood-O2 affinity of the bar-headed goose (Anser indicus) is an integral component of the biochemical and physiological adaptations that allow this hypoxia-tolerant species to undertake migratory flights over the Himalayas. The high blood-O2 affinity of this species was originally attributed to a single amino acid substitution of the major hemoglobin (Hb) isoform, HbA, which was thought to destabilize the low-affinity T state, thereby shifting the T-R allosteric equilibrium towards the high-affinity R state. Surprisingly, this mechanistic hypothesis has never been addressed using native proteins purified from blood. Here, we report a detailed analysis of O2 equilibria and kinetics of native major HbA and minor HbD isoforms from bar-headed goose and greylag goose (Anser anser), a strictly lowland species, to identify and characterize the mechanistic basis for the adaptive change in Hb function. We find that HbA and HbD of bar-headed goose have consistently higher O2 affinities than those of the greylag goose. The corresponding Hb isoforms of the two species are equally responsive to physiological allosteric cofactors and have similar Bohr effects. Thermodynamic analyses of O2 equilibrium curves according to the two-state Monod Wyman-Changeaux model revealed higher R-state O2 affinities in the bar-headed goose Hbs, associated with lower O2 dissociation rates, compared with the greylag goose. Conversely, the T state was not destabilized and the T-R allosteric equilibrium was unaltered in bar-headed goose Hbs. The physiological implication of these results is that increased R-state affinity allows for enhanced O2 saturation in the lungs during hypoxia, but without impairing O2 delivery to tissues. PMID- 30026240 TI - How the egg rolls: a morphological analysis of avian egg shape in the context of displacement dynamics. AB - Very little is known about how morphology affects the motion, spatial stability and resulting viability of avian eggs. The limited existing research focuses on the uniquely pyriform egg shapes found in the Alcidae bird family. This unusual shell shape was originally thought to suppress displacement and prevent egg loss on the cliffside nesting habitat of the Uria genus. Unfortunately, these early studies never isolated or quantified the specific morphological features (elongation, asymmetry and conicality) of these pyriform eggs, which limits their applicability to other taxa and has hampered a robust proof of concept. We isolated each feature as an enumerated variable, produced model 3D printed eggs with incremental expressions of a single variable and then with all three features co-varying simultaneously. Recorded motion (egg-rolling) trials were conducted to test the individual and combined effects of each morphological characteristic on displacement over a range of inclines representative of the conditions found in natural habitats. Increasing elongation and asymmetry significantly increased displacement, whereas increased conicality decreased displacement in the single-variable egg models. In the multivariable egg models, only conicality consistently suppressed displacement, while lower levels of asymmetry significantly increased displacement. Our findings broadly support previous studies' assertions of the adaptive value of the pyriform eggs while also providing methodology and comparative data for future analyses of the interactions between nesting habitat, behavior and egg shape, beyond the confines of a handful of focal species. PMID- 30026239 TI - Metabolic rate scaling, ventilation patterns and respiratory water loss in red wood ants: activity drives ventilation changes, metabolic rate drives water loss. AB - Metabolic rate and its relationship with body size is a fundamental determinant of many life history traits and potentially of organismal fitness. Alongside various environmental and physiological factors, the metabolic rate of insects is linked to distinct ventilation patterns. Despite significant attention, however, the precise role of these ventilation patterns remains uncertain. Here, we determined the allometric scaling of metabolic rate and respiratory water loss in the red wood ant, as well as assessing the effect of movement upon metabolic rate and ventilation pattern. Metabolic rate and respiratory water loss are both negatively allometric. We observed both continuous and cyclic ventilation associated with relatively higher and lower metabolic rates, respectively. In wood ants, however, movement not metabolic rate is the primary determinant of which ventilation pattern is performed. Conversely, metabolic rate not ventilation pattern is the primary determinant of respiratory water loss. Our statistical models produced a range of relatively shallow intraspecific scaling exponents between 0.40 and 0.59, emphasising the dependency upon model structure. Previous investigations have revealed substantial variation in morphological allometry among wood ant workers from different nests within a population. Metabolic rate scaling does not exhibit the same variability, suggesting that these two forms of scaling respond to environmental factors in different ways. PMID- 30026241 TI - Bi-directional movement characteristics of Camponotus japonicus ants during nest relocation. AB - Foraging and nest relocation forming a bi-directional traffic of outbound and inbound individuals in one-lane organization are two main activities in an ant's life. In this paper, we conducted an experiment on nest relocation of loaded and unloaded ants, moving back and forth between the old nest and the new one. In the experiment, we observed both uni- and bi-directional traffic flow. The headway speed relationships indicate that the ants showed the same sensitivity to the distance headway in the two types of flow. For bi-directional traffic flow, head on encounters and giving-way behavior between ants moving in opposing directions were a common occurrence. It took one unloaded ant 2.61 s to solve a head-on encounter with another unloaded ant. Compared with unloaded ants, loaded ants had a lower moving speed, but were less likely to be impacted by a head-on encounter. In the observation region, both sudden stop and head-on encounters contained two phases: deceleration and acceleration. Our analysis indicates that the relaxation time in the deceleration process is less than that in the acceleration process. The reduction of movement efficiency of encountering two discontinuous ants is larger than that when encountering two successive ants (0.18). This is owing to the absence of head-on encounters with following ants. The bi-directional traffic of ants under experimental conditions investigated in this study may inform future studies of high-efficiency movement in collective behavior and traffic systems. PMID- 30026242 TI - Neuromuscular control of locomotion is altered by tail autotomy in geckos. AB - Animal locomotion is driven by underlying axial and appendicular musculature. In order for locomotion to be effective, these muscles must be able to rapidly respond to changes in environmental and physiological demands. Although virtually unstudied, muscles must also respond to morphological changes, such as those that occur with tail autotomy in lizards. Tail autotomy in leopard geckos (Eublepharis macularius) results in a 25% loss of caudal mass and significant kinematic alterations to maintain stability. To elucidate how motor control of the locomotor muscles is modulated with these shifts, we used electromyography (EMG) to quantify patterns of in vivo muscle activity in forelimb and hindlimb muscles before and after autotomy. Forelimb muscles (biceps brachii and triceps brachii) exhibited no changes in motor recruitment, consistent with unaltered kinematics after autotomy. The amplitude of activity of propulsive muscles of the hindlimbs (caudofemoralis and gastrocnemius) was significantly reduced and coincided with decreases in the propulsive phases of femur retraction and ankle extension, respectively. The puboischiotibialis did not exhibit these changes, despite significant reductions in femur depression and knee angle, suggesting that the reduction in mass and vertical ground-reaction force by autotomy allows for the maintenance of a more sprawled and stable posture without increasing motor recruitment of the support muscles. These results highlight the significant neuromuscular shifts that occur to accommodate dramatic changes in body size and mass distribution, and illuminate the utility of tail autotomy as a system for studying the neuromuscular control of locomotion. PMID- 30026243 TI - Language Disorders and Problem Behaviors: A Meta-analysis. AB - CONTEXT: A large number of studies have shown a relationship between language disorders and problem behaviors; however, methodological differences have made it difficult to draw conclusions from this literature. OBJECTIVE: To determine the overall impact of language disorders on problem behaviors in children and adolescents between the ages of birth and 18 years and to investigate the role of informant type, age, and type of problem behavior on this relationship. DATA SOURCES: We searched PubMed, EBSCO, and ProQuest. STUDY SELECTION: Studies were included when a group of children with language disorders was compared with a group of typically developing children by using at least 1 measure of problem behavior. DATA EXTRACTION: Effect sizes were derived from all included measures of problem behaviors from each study. RESULTS: We included 47 articles (63 153 participants). Meta-analysis of these studies revealed a difference in ratings of problem behaviors between children with language disorders and typically developing children of moderate size (g = 0.43; 95% confidence interval 0.34 to 0.53; P < .001). Age was entered as a moderator variable, and results showed that the difference in problem behavior ratings increases with child age (increase in g for each additional year in age = 0.06; 95% confidence interval 0.02 to 0.11; P = .004). LIMITATIONS: There was considerable heterogeneity in the measures of problem behaviors used across studies. CONCLUSIONS: Children with language disorders display greater rates of problem behaviors compared with their typically developing peers, and this difference is more pronounced in older children. PMID- 30026244 TI - Trends in Abstaining From Substance Use in Adolescents: 1975-2014. AB - : : media-1vid110.1542/5789654654001PEDS-VA_2017-3498Video Abstract BACKGROUND AND OBJECTIVES: Adolescent substance use is a prevalent modifiable health behavior; understanding long-term trends is essential to inform prevention efforts and public health policy. We investigated changes in the proportion of substance nonuse among adolescents over a 40-year period and associations between abstinence and individual risk and protective factors. METHODS: Data from the nationally representative Monitoring the Future survey, administered 1975-2014, were analyzed to determine the annual proportion of abstinent students. The 2014 Monitoring the Future cohort was analyzed to determine associations between nonuse and risk and protective factors. RESULTS: The prevalence of abstaining seniors between 1976 and 2014 increased fivefold for lifetime abstinence and more than doubled for past 30 days; similar increases were reported by younger students between 1991 and 2014. Trend lines were distinct for alcohol, which increased steadily over the past 38 years; tobacco, which increased dramatically over the past 20 years; and marijuana and illicit drugs, which increased slightly, although not consistently, between 1976 and 2014. In 2014, students that identified as male, African American, or other race and those who reported greater religious commitment were significantly more likely to report lifetime abstinence. Students that lived in single-parent households, spent more evenings out, worked more hours during the school year, and reported lower grades and more truancy had lower abstinence rates. CONCLUSIONS: Abstinence is a realistic choice for a growing proportion of high school students. With the differences in abstinence trends for individual substances, we suggest strategies for advancing prevention efforts. PMID- 30026245 TI - Reorganisation costs much of the increased funding for the NHS. PMID- 30026246 TI - Opioid prescriptions outnumber patients in some parts of the US. PMID- 30026248 TI - Adrenaline after cardiac arrest doubles risk of serious brain damage, finds trial. PMID- 30026249 TI - The Use of the Child Fatality Review Committee to Contribute to a Longitudinal Quality Improvement Project on Safe Sleep. PMID- 30026247 TI - Draxin acts as a molecular rheostat of canonical Wnt signaling to control cranial neural crest EMT. AB - Neural crest cells undergo a spatiotemporally regulated epithelial-to-mesenchymal transition (EMT) that proceeds head to tailward to exit from the neural tube. In this study, we show that the secreted molecule Draxin is expressed in a transient rostrocaudal wave that mirrors this emigration pattern, initiating after neural crest specification and being down-regulated just before delamination. Functional experiments reveal that Draxin regulates the timing of cranial neural crest EMT by transiently inhibiting canonical Wnt signaling. Ectopic maintenance of Draxin in the cranial neural tube blocks full EMT; while cells delaminate, they fail to become mesenchymal and migratory. Loss of Draxin results in premature delamination but also in failure to mesenchymalize. These results suggest that a pulse of intermediate Wnt signaling triggers EMT and is necessary for its completion. Taken together, these data show that transient secreted Draxin mediates proper levels of canonical Wnt signaling required to regulate the precise timing of initiation and completion of cranial neural crest EMT. PMID- 30026250 TI - A Hospital-Based Initiative to Reduce Postdischarge Sudden Unexpected Infant Deaths. AB - BACKGROUND AND OBJECTIVES: Sudden unexpected infant deaths (SUID) most often occur because infants are placed in unsafe sleep environments. Although authors of previous literature have demonstrated that parents who receive comprehensive safe sleep education increase knowledge and intention to place children in safe sleep environments, no studies have demonstrated improved outcomes. We describe the development of a hospital-based newborn SUID risk reduction quality improvement project and its effectiveness in reducing subsequent SUIDs in a community using linked outcome data from local Child Fatality Review Teams. METHODS: Qualitative and quantitative evaluation of a long-term iterative performance improvement intervention for a nursery-based comprehensive safe sleep program in a community teaching hospital. Key themes and exemplary comments were noted. The rate of infant deaths per 1000 births was the primary quantitative outcome. The rate is calculated quarterly and monitored with control charts by using Child Fatality Review data about infant sleep deaths. RESULTS: The average death rate fell from 1.08 infants per 1000 births preintervention to 0.48 infants per 1000 births after complete intervention, and the average number of deaths between deliveries increased from 1 in every 584 deliveries (upper control limit: 3371) to 1 in every 1420 deliveries (upper control limit: 8198). Qualitative observation of nursery providers revealed 3 themes, including routine inclusion of sleep safety information, dissemination of safety information by all staff, and personal commitment to success. CONCLUSIONS: A comprehensive sleep safety culture change can be effectively integrated into a nursery setting over time by using feedback from Child Fatality Review and performance improvement methodology. Repeated messaging and education by the entire nursery staff has the potential to play a role in reducing sleep-related deaths in infants born at their hospital. PMID- 30026251 TI - Birth weight for gestational age and the risk of asthma in childhood and adolescence: a retrospective cohort study. AB - OBJECTIVE: To examine the association between birth weight for gestational age and asthma in childhood and adolescence while controlling for potential confounders and considering smoking as an effect modifier. METHODS: A retrospective cohort of all singleton term births in Nova Scotia, Canada, between 1989 and 1993 was identified in the provincial perinatal database and followed through 2014 by linking with administrative health data. The outcome, asthma, was defined as having one hospitalisation or two physician visits with an International Classification of Diseases code for asthma in a 2-year period. Birth weight was categorised as small (SGA), large (LGA) or appropriate (AGA) for gestational age. Multivariable-adjusted Cox proportional hazards models were used to examine the association between the birth weight for gestational age and asthma and to test for effect modification by maternal smoking in pregnancy. RESULTS: Of the 40 724 cohort children, 10.5% and 11.7% were born SGA and LGA, respectively, and the risk of developing asthma to age 18 years was 30.2%. The adjusted HRs for SGA and LGA (relative to AGA) and asthma were 1.07 (95% CI 1.02 to 1.14) and 0.96 (95% CI 0.91 to 1.02), respectively. Relative to AGA children born to non-smoking mothers, SGA children were not at increased risk of asthma (HR 1.02), whereas both AGA and SGA children born to smoking mothers were at significantly increased risk (HR 1.14 and 1.29, respectively). CONCLUSIONS: Our findings suggest that SGA in term infants is not associated with asthma in childhood in the absence of smoking in pregnancy. PMID- 30026252 TI - Predictive tool for intravenous immunoglobulin resistance of Kawasaki disease in Beijing. AB - OBJECTIVE: To construct a predictive tool for the efficacy of intravenous immunoglobulin (IVIG) therapy in children with Kawasaki disease (KD) in Beijing, China. DESIGN: This was a cohort study. Data set (including clinical profiles and laboratory findings) of children with KD diagnosed between 1 January 2010 and 31 December 2015 was used to analyse the risk factors and construct a scoring system. Data set of children with KD diagnosed between 1 January 2016 and 1 December 2016 was used to validate this model. SETTING: Children's Hospital Capital Institute of Pediatrics and Beijing Children's Hospital. PATIENTS: 2102 children diagnosed with KD. INTERVENTIONS: No. MAIN OUTCOME MEASURES: Responsiveness to IVIG. RESULTS: The predictive tool included C reactive protein >=90 mg/L (3 points), neutrophil percentage >=70% (2.5 points), sodium ion concentration <135 mmol/L (3 points), albumin <35 g/L (2.5 points) and total bilirubin >20 MUmol/L (5 points), which generated an area under the the receiver operating characteristic curve of 0.77 (95% CI 0.71 to 0.82) for the internal validation data set, and 0.69 (95% CI 0.58 to 0.81) and 0.63 (95% CI 0.53 to 0.72) for two external validation data sets, respectively. If a total of >=6 points were considered high-risk for IVIG resistance, sensitivity and specificity were 56% and 79% in the internal verification, and the predictive ability was similar in the external validation. CONCLUSIONS: The predictive tool is helpful in early screening of high-risk IVIG resistance of KD in the Beijing area. Consequently, it will guide the clinician in selecting appropriate individualised regimens for the initial treatment of this disease, which is important for the prevention of coronary complications. PMID- 30026253 TI - Drug monitoring in long-term treatment with adalimumab for juvenile idiopathic arthritis-associated uveitis. AB - OBJECTIVES: Assessing influence of anti-adalimumab (ADA) antibodies (AAA) on serum trough ADA levels and uveitis activity in long-term ADA treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. PATIENTS AND INTERVENTIONS: This prospective observational study included 20 patients from a single centre treated with ADA for active uveitis refractory to conventional disease-modifying antirheumatic drugs. AAA, serum ADA trough levels and uveitis activity were evaluated at regular intervals up to 6 years. RESULTS: AAA were detected in nine patients (45%). Permanent AAA in seven were associated with undetectable ADA trough levels and loss of response (LOR). Transient AAA were detected in four with measurable ADA trough levels and response of uveitis to treatment, followed in two by permanent AAA associated with LOR. Use of concomitant immunosuppression was significantly higher in patients without AAA (p<0.05). CONCLUSIONS: AAA-associated LOR frequently occurs in long-term treatment with ADA for JIA-associated uveitis. Concomitant immunosuppressive therapy significantly reduces the risk of LOR due to AAA. PMID- 30026254 TI - THO Complex-Dependent Posttranscriptional Control Contributes to Vascular Smooth Muscle Cell Fate Decision. AB - RATIONALE: Modulation of vascular smooth muscle cell (VSMC) phenotype plays a fundamental role in vascular development and diseases. Although extensive studies uncovered the roles of transcriptional regulation in VSMC-specific gene expression, how posttranscriptional regulation contributes to VSMC fate decisions remains to be determined. OBJECTIVE: To establish THO complex-dependent VSMC gene expression as a novel regulatory basis controlling VSMC phenotypes. METHODS AND RESULTS: Immunohistochemical staining against THOC2 and THOC5, 2 components of the THO complex, revealed a dramatic reduction in their expression in human arteries undergoing carotid endarterectomy compared with normal internal mammary arteries. Silencing of THOC2 or THOC5 led to dedifferentiation of VSMCs in vitro, characterized by decreased VSMC marker gene expression and increased migration and proliferation. Furthermore, RNA high-throughput sequencing (Seq) revealed that THOC5 silencing closely resembled the gene expression changes induced on PDGF (platelet-derived growth factor)-BB/PDGF-DD treatments in cultured VSMCs. Mechanistically, THOC2 and THOC5 physically interacted with and functionally relied on each other to bind to specific motifs on VSMC marker gene mRNAs. Interestingly, mRNAs that lost THOC2 or THOC5 binding during VSMC dedifferentiation were enriched for genes important for the differentiated VSMC phenotype. Last, THOC5 overexpression in injured rat carotid arteries significantly repressed loss of VSMC marker gene expression and neointima formation. CONCLUSIONS: Our data introduce dynamic binding of THO to VSMC marker gene mRNAs as a novel mechanism contributing to VSMC phenotypic switching and imply THOC5 as a potential intervention node for vascular diseases. PMID- 30026255 TI - Frailty and frailty-related factors are associated with postoperative complications in older patients undergoing elective surgery. PMID- 30026256 TI - Hydrophilic polymer embolic complication during diagnostic cerebral angiography presenting with delayed intracranial hemorrhage: case report and literature review. AB - We report two serial neuroendovascular cases of hydrophilic polymer embolic complications, and highlight a unique case of a routine diagnostic cerebral angiogram that was complicated by delayed intracranial hemorrhage requiring surgical decompression. Histopathology specimens revealed organized intravascular thrombi with foci of non-polarizable, basophilic foreign material. Shavings from the hydrophilic coatings of a standard diagnostic catheter and guidewire share histologic characteristics with this intravascular foreign material, confirming the diagnosis of hydrophilic polymer emboli. While this phenomenon has been described for complex neurointerventional procedures, it is rare with routine diagnostic cerebral angiography. Along with a detailed literature review, these cases provides further evidence that even basic hydrophilic coated catheters and/or wires may contribute to the etiology of iatrogenic emboli in the neurovasculature with the potential for acute and subacute complications, requiring further investigation. PMID- 30026257 TI - Single-cell RNA-seq analysis reveals the progression of human osteoarthritis. AB - OBJECTIVES: Understanding the molecular mechanisms underlying human cartilage degeneration and regeneration is helpful for improving therapeutic strategies for treating osteoarthritis (OA). Here, we report the molecular programmes and lineage progression patterns controlling human OA pathogenesis using single-cell RNA sequencing (scRNA-seq). METHODS: We performed unbiased transcriptome-wide scRNA-seq analysis, computational analysis and histological assays on 1464 chondrocytes from 10 patients with OA undergoing knee arthroplasty surgery. We investigated the relationship between transcriptional programmes of the OA landscape and clinical outcome using severity index and correspondence analysis. RESULTS: We identified seven molecularly defined populations of chondrocytes in the human OA cartilage, including three novel phenotypes with distinct functions. We presented gene expression profiles at different OA stages at single-cell resolution. We found a potential transition among proliferative chondrocytes, prehypertrophic chondrocytes and hypertrophic chondrocytes (HTCs) and defined a new subdivision within HTCs. We revealed novel markers for cartilage progenitor cells (CPCs) and demonstrated a relationship between CPCs and fibrocartilage chondrocytes using computational analysis. Notably, we derived predictive targets with respect to clinical outcomes and clarified the role of different cell types for the early diagnosis and treatment of OA. CONCLUSIONS: Our results provide new insights into chondrocyte taxonomy and present potential clues for effective and functional manipulation of human OA cartilage regeneration that could lead to improved health. PMID- 30026258 TI - Occurrence and regression of BK polyomavirus associated carcinoma: a clinical and next-generation sequencing study. AB - Low-level BK polyomavirus (BKPyV) shedding is seen in at least 10% of seropositive immunocompetent adults. Moreover, BKPyV infection is highly prevalent amongst immunocompromised populations, yet little is known on its relationship with malignancy. We studied a female patient with BKPyV-associated and donor-derived de novo high-grade sarcomatoid urothelial carcinoma developed 8 years after kidney transplantation from a male donor. Through whole-genome sequencing, we discovered integration of genotype IV BKPyV genome into the non coding RNA (ncRNA) intronic region of human chromosome 18. The two breakpoints in the virus genome were located at the non-coding control region (NCCR) and large T antigen (TAg) coding region, respectively. Nevertheless, the TAg was overexpressed. We, therefore, inferred that the BKPyV was clonally integrated into the human genome in the form of concatemers, facilitating the expression of the TAg. The patient presented with multiorgan metastases, which were reduced in size and number throughout the body after removal of the graft and cessation of immunosuppressants. The few remaining lesions located in the liver were identified, through biopsy to be necrotic tumor tissue with TAg detected; additionally, genomic sequencing of the liver mass found Y chromosome. In conclusion, we propose that integration of the BKPyV genome is closely related to oncogenesis in this patient; while oncogenesis occurred when host immunity was impaired, recovery of the patient's native immunity effectively curbed viral replication and eliminated the metastatic lesions. PMID- 30026259 TI - Sex-dependent expression of brain medullary MAP and PI3 kinases in adult sheep with antenatal betamethasone exposure. AB - Antenatal betamethasone (BM) therapy for women in jeopardy of premature delivery accelerates the lung development in preterm infants and reduces infant mortality rates, but may induce early programming events with chronic cardiovascular consequences. In a sheep model of fetal programming, in utero BM-exposed (BMX) offspring as adults exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for the control of heart rate and insulin resistance accompanied by dysregulation of the brain renin-angiotensin (Ang) system (RAS). However, the status of signaling mechanisms in the brain dorsomedial medulla (DMM) of the BMX sheep that comprise both the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) cellular pathways is unknown. Given the importance of these signaling pathways in the actions of Ang peptides as well as baroreflex function and autonomic integration, we applied both a kinase signaling array and associated individual immunoblots of the dorsomedial brain medulla from adult female and male sheep with antenatal BMX. MAPK and PI3K pathways were altered significantly in the BMX sheep in a sex-dependent manner. A protein array for kinases (PathScan(r) Intracellular Signaling Array Kit, Cell Signaling) and subsequent verification by immunoblot revealed that within the DMM, female BMX sheep exhibit lower expression of proteins in the PI3K pathway, while male BMX sheep show greater expression of p-MAPK pathway proteins extracellular signal regulated kinase (ERK) 1/2. We conclude that maladaptive changes in these two kinase pathways in the DMM may contribute to the chronic dysregulation of blood pressure in this model of fetal programming. PMID- 30026260 TI - GDF11 Improves Angiogenic Function of EPCs in Diabetic Limb Ischemia. AB - Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity and rejuvenate the function of multiple organs in old mice, but little is known about the functions of GDF11 in the diabetic rat model of hindlimb ischemia. In this study, we found that systematic replenishment of GDF11 rescues angiogenic function of endothelial progenitor cells (EPCs) and subsequently improves vascularization and increases blood flow in diabetic rats with hindlimb ischemia. Conversely, anti-GDF11 monoclonal antibody treatment caused impairment of vascularization and thus, decreased blood flow. In vitro treatment of EPCs with recombinant GDF11 attenuated EPC dysfunction and apoptosis. Mechanistically, the GDF11-mediated positive effects could be attributed to the activation of the transforming growth factor-beta/Smad2/3 and protein kinase B/hypoxia-inducible factor 1alpha pathways. These findings suggest that GDF11 repletion may enhance EPC resistance to diabetes-induced damage, improve angiogenesis, and thus, increase blood flow. This benefit of GDF11 may lead to a new therapeutic approach for diabetic hindlimb ischemia. PMID- 30026262 TI - Drug Duo Disappoints in Colorectal Cancer. AB - A phase III study determined that the combination of atezolizumab and cobimetinib wasn't more effective than standard therapy in patients with inoperable, locally advanced or metastatic colorectal cancer. The overall survival for patients treated with the combination was 8.9 months, versus 8.5 months for standard-of care regorafenib. Further, only 2.7% of patients responded to the drug duo, versus 2.2% for regorafenib. PMID- 30026261 TI - Effects of hypoxic preconditioning on neuroblastoma tumour oxygenation and metabolic signature in a chick embryo model. AB - Hypoxia episodes and areas in tumours have been associated with metastatic dissemination and poor prognosis. Given the link between tumour tissue oxygen levels and cellular metabolic activity, we hypothesised that the metabolic profile between metastatic and non-metastatic tumours would reveal potential new biomarkers and signalling cues. We have used a previously established chick embryo model for neuroblastoma growth and metastasis, where the metastatic phenotype can be controlled by neuroblastoma cell hypoxic preconditioning (3 days at 1% O2). We measured, with fibre-optic oxygen sensors, the effects of the hypoxic preconditioning on the tumour oxygenation, within tumours formed by SK-N AS cells on the chorioallantoic membrane (CAM) of chick embryos. We found that the difference between the metastatic and non-metastatic intratumoural oxygen levels was small (0.35% O2), with a mean below 1.5% O2 for most tumours. The metabolomic profiling, using NMR spectroscopy, of neuroblastoma cells cultured in normoxia or hypoxia for 3 days, and of the tumours formed by these cells showed that the effects of hypoxia in vitro did not compare with in vivo tumours. One notable difference was the high levels of the glycolytic end-products triggered by hypoxia in vitro, but not by hypoxia preconditioning in tumours, likely due to the very high basal levels of these metabolites in tumours compared with cells. In conclusion, we have identified high levels of ketones (3-hydroxybutyrate), lactate and phosphocholine in hypoxic preconditioned tumours, all known to fuel tumour growth, and we herein point to the poor relevance of in vitro metabolomic experiments for cancer research. PMID- 30026263 TI - New LC-MS/MS method with single-step pretreatment analyzes fat-soluble vitamins in plasma and amniotic fluid. AB - Fat-soluble vitamins (FSVs), A, D, and E, are components of prenatal vitamin care. Previously, limited evidence existed to explain on a molecular level how maternal FSV supplementation affects the fetus during pregnancy. We developed a simplified LC-MS/MS method to simultaneously detect FSVs in maternal plasma (MP) and amniotic fluid (AF); we used this approach to investigate the correlation between FSV levels in these two matrices. With this method, we circumvented frequently used liquid-liquid extraction or solid-phase extraction methods and, instead, used simple protein precipitation with acetonitrile for sample preparation. This method displayed satisfactory linearity, intra- and inter-day imprecision, and accuracy. We validated the consistency with standard reference material 972a and 968f certification. In analysis of MP and AF samples from 50 pregnant women in the second trimester, concentrations of retinol, 25 hydroxyvitamin D3 [25(OH)D3], and alpha-tocopherol (reflecting vitamins A, D, and E, respectively) were lower in AF than in MP. Significant positive correlations existed between MP and AF for 25(OH)D3 (r = 0.667; P < 0.001) and retinol (r = 0.393; P = 0.005), but not for alpha-tocopherol (r = 0.145, P > 0.05). This novel LC-MS/MS method shows prominent applicability for FSV detection and the observed correlations contribute to research on fetal development. PMID- 30026264 TI - Seasonally dependent relationship between insect herbivores and host plant density in Jatropha nana, a tropical perennial herb. AB - The fact that plant spatial aggregation patterns shape insect-herbivore communities in a variety of ways has resulted in a large body of literature on the subject. The landmark resource concentration hypothesis predicts that density of insect herbivores per plant will increase as host plant density increases. I examined this prediction across temporal samplings using Jatropha nana and the associated specialist insect herbivores as a system. Through 12 field samplings, I modelled the effect of host plant density on insect-herbivore loads. The initial samplings (2-3) provided evidence for the resource concentration hypothesis, with insect loads increasing with increasing host plant density, whereas the later samplings (4-5, 7-11) showed the opposite; a resource dilution pattern with a decline of insect loads with increasing host plant density. These patterns also depend on the biology of the herbivores and have important implications on J. nana population dynamics.This article has an associated First Person interview with the first author of the paper. PMID- 30026267 TI - How to use C-reactive protein. AB - A 3-month-old baby is brought to the paediatric emergency department by their parents because of a fever. You decide to check their inflammatory markers. Their C-reactive protein (CRP) level comes back as 20 mg/L. Does this affect whether or not you start antibiotic therapy? Does it influence your decision to admit or discharge the patient? CRP is a commonly used biochemical test and yet its use is constantly debated and challenged. We look at the current evidence and suggest the best way to use this test in clinical practice. PMID- 30026265 TI - Mammalian embryo comparison identifies novel pluripotency genes associated with the naive or primed state. AB - During early mammalian development, transient pools of pluripotent cells emerge that can be immortalised upon stem cell derivation. The pluripotent state, 'naive' or 'primed', depends on the embryonic stage and derivation conditions used. Here we analyse the temporal gene expression patterns of mouse, cattle and porcine embryos at stages that harbour different types of pluripotent cells. We document conserved and divergent traits in gene expression, and identify predictor genes shared across the species that are associated with pluripotent states in vivo and in vitro Amongst these are the pluripotency-linked genes Klf4 and Lin28b The novel genes discovered include naive- (Spic, Scpep1 and Gjb5) and primed-associated (Sema6a and Jakmip2) genes as well as naive to primed transition genes (Dusp6 and Trip6). Both Gjb5 and Dusp6 play a role in pluripotency since their knockdown results in differentiation and downregulation of key pluripotency genes. Our interspecies comparison revealed new insights of pluripotency, pluripotent stem cell identity and a new molecular criterion for distinguishing between pluripotent states in various species, including human. PMID- 30026266 TI - Human trophoblasts are primarily distinguished from somatic cells by differences in the pattern rather than the degree of global CpG methylation. AB - The placenta is a fetal exchange organ connecting mother and baby that facilitates fetal growth in utero DNA methylation is thought to impact placental development and function. Global DNA methylation studies using human placental lysates suggest that the placenta is uniquely hypomethylated compared to somatic tissue lysates, and this hypomethylation is thought to be important in conserving the unique placental gene expression patterns required for successful function. In the placental field, methylation has frequently been examined in tissue lysates, which contain mixed cell types that can confound results. To better understand how DNA methylation influences placentation, DNA from isolated first trimester trophoblast populations underwent reduced representation bisulfite sequencing and was compared to publicly available data of blastocyst-derived and somatic cell populations. First, this revealed that, unlike murine blastocysts, human trophectoderm and inner cell mass samples did not have significantly different levels of global methylation. Second, our work suggests that differences in global CpG methylation between trophoblasts and somatic cells are much smaller than previously reported. Rather, our findings suggest that different patterns of CpG methylation may be more important in epigenetically distinguishing the placenta from somatic cell populations, and these patterns of methylation may contribute to successful placental/trophoblast function. PMID- 30026268 TI - HDL (High-Density Lipoprotein) Metrics and Atherosclerotic Risk in Women. AB - Objective- HDL-C (high-density lipoprotein cholesterol) may not always be cardioprotective in postmenopausal women. HDL particles (HDL-P) via ion-mobility may better reflect the antiatherogenicity of HDL. Objectives were (1) to evaluate associations of HDL-C and ion-mobility HDL-P with carotid intima-media thickness (cIMT) and carotid plaque separately and jointly in women; and (2) to assess interactions by age at and time since menopause. Approach and Results- Analysis included 1380 females from the MESA (Multi-Ethnic Study of Atherosclerosis; age: 61.8+/-10.3; 61% natural-, 21% surgical-, and 18% peri-menopause). Women with unknown or early menopause (age at nonsurgical menopause <=45 years) were excluded. Adjusting for each other, higher HDL-P but not HDL-C was associated with lower cIMT ( P=0.001), whereas higher HDL-C but not HDL-P was associated with greater risk of carotid plaque presence ( P=0.04). Time since menopause significantly modified the association of large but not small HDL-P with cIMT; higher large HDL-P was associated with higher cIMT close to menopause but with lower cIMT later in life. The proatherogenic association reported for HDL-C with carotid plaque was most evident in women with later age at menopause who were >10 years postmenopausal. Conclusions- Elevated HDL-C may not always be cardioprotective in postmenopausal women. The cardioprotective capacity of large HDL-P may adversely compromise close to menopause supporting the importance of assessing how the menopause transition might impact HDL quality and related cardiovascular disease risk later in life. PMID- 30026269 TI - Direct Targeting of the mTOR (Mammalian Target of Rapamycin) Kinase Improves Endothelial Permeability in Drug-Eluting Stents-Brief Report. AB - Objective- Drug-eluting stents eluting canonical mTOR (mammalian target of rapamycin) inhibitors are widely used to treat coronary artery disease but accelerate the development of atherosclerosis within the stent (neoatherosclerosis)-a leading cause of late stent failure. We recently showed that canonical mTOR inhibitors bind FKBP12.6 (12.6-kDa FK506-binding protein 12), displace it from calcium release channels, resulting in activation of PKCalpha (protein kinase Calpha) and dissociation of p-120-catenin (p120) from VE-CAD (vascular endothelial cadherin; promoting endothelial barrier dysfunction [EBD]). However, the relevance of these findings to drug-eluting stents remains unknown. Newer generation direct mTOR kinase inhibitors do not bind FKBP12.6 and offer the potential of improving endothelial barrier function while maintaining antirestenotic efficacy, but their actual effects are unknown. We examined the effects of 2 different pharmacological targeting strategies-canonical mTOR inhibitor everolimus and mTOR kinase inhibitors Torin-2-on EBD after stenting. Approach and Results- Using the rabbit model of stenting and a combination of Evans blue dye, confocal and scanning electron microscopy studies, everolimus eluting stents resulted in long-term EBD compared with bare metal stents. EBD was mitigated by using stents that eluted mTOR kinase inhibitors (Torin-2-eluting stent). At 60 days after stent placement, everolimus-eluting stents demonstrated large areas of Evans blue dye staining and evidence of p120 VE-CAD dissociation consistent with EBD. These findings were absent in bare metal stents and significantly attenuated in Torin-2-eluting stent. As proof of concept of the role of EBD in neoatherosclerosis, 100 days after stenting, animals were fed an enriched cholesterol diet for an additional 30 days. Everolimus-eluting stents demonstrated significantly more macrophage infiltration (consistent with neoatherosclerosis) compared with both bare metal stents and Torin-2-eluting stent. Conclusions- Our results pinpoint interactions between FKBP12.6 and canonical mTOR inhibitors as a major cause of vascular permeability and neoatherosclerosis, which can be overcome by using mTOR kinase inhibitors. Our study suggests further refinement of molecular targeting of the mTOR complex may be a promising strategy (Graphic Abstract). PMID- 30026270 TI - Inhibiting Glycogen Synthase Kinase 3 Reverses Obesity-Induced White Adipose Tissue Inflammation by Regulating Apoptosis Inhibitor of Macrophage/CD5L-Mediated Macrophage Migration. AB - Objective- Obesity-induced inflammation in white adipose tissue, characterized by increased macrophage infiltration and associated with macrophage population shift from anti-inflammatory M2 to proinflammatory M1 macrophages, largely contributes to obesity-induced insulin resistance and influences type 2 diabetes mellitus pathogenesis. GSK3 (glycogen synthase kinase 3), a serine/threonine kinase, has been reported to participate in various cellular processes. We sought to examine the potential mechanism by which GSK3, a serine/threonine kinase implicated in various cellular processes, modulates obesity-induced visceral adipose tissue (VAT) inflammation. Approach and Results- Male C57BL/6J mice were fed a high-fat diet for 10 weeks while being treated with vehicle control or GSK3 inhibitors SB216763 or CHIR99021. RNA-sequencing results using VAT demonstrated that GSK3 inhibitor treatment reversed obesity-specific expression of genes associated with inflammation. Consistently, GSK3 inhibition reduced obesity-induced VAT inflammation as characterized by decreased proinflammatory M1 macrophages but increased anti-inflammatory M2 macrophages in the VAT and reduced circulatory inflammatory monocytes. These anti-inflammatory effects of GSK3 inhibition were found to be driven, at least in part, by inhibiting production of apoptosis inhibitor of macrophage in macrophages via inactivating STAT3 to reduce free fatty acid and chemokine level produced from VAT to suppress the migration/chemotaxis of macrophages and monocytes. Conclusions- Our findings suggest that GSK3 may act as an important regulator of obesity-induced inflammation and characterize the novel role of GSK3 in shifting macrophage polarization and reinforce its therapeutic potential for obesity-induced inflammation and its associated diabetes mellitus. PMID- 30026271 TI - Transcription Factor Zhx2 Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice. AB - Objective- The objective of this study was to determine the basis of resistance to atherosclerosis of inbred mouse strain BALB/cJ. Approach and Results- BALB/cJ mice carry a naturally occurring null mutation of the gene encoding the transcription factor Zhx2, and genetic analyses suggested that this may confer resistance to atherosclerosis. On a hyperlipidemic low-density lipoprotein receptor null background, BALB/cJ mice carrying the mutant allele for Zhx2 exhibited up to a 10-fold reduction in lesion size as compared with an isogenic strain carrying the wild-type allele. Several lines of evidence, including bone marrow transplantation studies, indicate that this effect of Zhx2 is mediated, in part, by monocytes/macrophages although nonbone marrow-derived pathways are clearly involved as well. Both in culture and in atherosclerotic lesions, macrophages from Zhx2 null mice exhibited substantially increased apoptosis. Zhx2 null macrophages were also enriched for M2 markers. Effects of Zhx2 on proliferation and other bone marrow-derived cells, such as lymphocytes, were at most modest. Expression microarray analyses identified >1000 differentially expressed transcripts between Zhx2 wild-type and null macrophages. To identify the global targets of Zhx2, we performed ChIP-seq (chromatin immunoprecipitation sequencing) studies with the macrophage cell line RAW264.7. The ChIP-seq peaks overlapped significantly with gene expression and together suggested roles for transcriptional repression and apoptosis. Conclusions- A mutation of Zhx2 carried in BALB/cJ mice is responsible in large part for its relative resistance to atherosclerosis. Our results indicate that Zhx2 promotes macrophage survival and proinflammatory functions in atherosclerotic lesions, thereby contributing to lesion growth. PMID- 30026273 TI - Calcification Induced by Type I Interferon in Human Aortic Valve Interstitial Cells Is Larger in Males and Blunted by a Janus Kinase Inhibitor. AB - Objective- Calcific aortic valve disease is the most prevalent valvulopathy in Western countries. An unanticipated pathogenetic clue involving IFN (interferon) was disclosed by the finding of constitutive type I IFN activity associated with aortic valve calcification in children with the atypical Singleton-Merten syndrome. On this basis, the role of type I IFN on inflammation and calcification in human aortic valve interstitial cells (AVIC) was examined. Approach and Results- IFN-alpha was weakly proinflammatory but potentiated lipopolysaccharide mediated activation of NF (nuclear factor)-kappaB and the ensuing induction of proinflammatory molecules in human AVIC. Stimulation with IFN-alpha and in combination with lipopolysaccharide promoted osteoblast-like differentiation characterized by increased osteoblastic gene expression, BMP (bone morphogenetic protein)-2 secretion, and ectopic phosphatase activity. Sex differences were observed. Likewise, IFN-alpha treatment of human AVICs in osteogenic medium resulted in increased formation of calcific nodules. Strikingly, IFN-alpha mediated calcification was significantly higher in AVICs from males, and was blocked by tofacitinib, a JAK (Janus kinase) inhibitor, and by a BMP antagonist. A female-specific protective mechanism involving the activation of PI3K-Akt (protein kinase B) pathways and cell survival was disclosed. Females exhibited higher levels of BCL2 in valve cells and tissues and lower annexin V staining on cell stimulation. Conclusions- IFN-alpha acts as a proinflammatory and pro osteogenic cytokine in AVICs, its effects being potentiated by lipopolysaccharide. Results also uncovered sex differences with lower responses in female AVICs and sex-specific mechanisms involving apoptosis. Data point to JAK/STAT (signal transducer and activator of transcription) system as a potential therapeutic target for calcific aortic valve disease. PMID- 30026272 TI - Direct Reprogramming of Fibroblasts Into Smooth Muscle-Like Cells With Defined Transcription Factors-Brief Report. AB - Objective- To identify the transcription factors that could contribute to direct reprogramming of fibroblasts toward smooth muscle cell fate. Approach and Results We screened various combinations of transcription factors, including Myocd (myocardin), Mef2C (myocyte enhancer factor 2C), Mef2B (myocyte enhancer factor 2B), Mkl1 (MKL [megakaryoblastic leukemia]/Myocd-like 1), Gata4 (GATA-binding protein 4), Gata5 (GATA-binding protein 5), Gata6 (GATA-binding protein 6), Ets1 (E26 avian leukemia oncogene 1, 5' domain), and their corresponding carboxyterminal fusions to the transactivation domain of MyoD (myogenic differentiation 1)-indicated by *-for their effects on reprogramming mouse embryonic fibroblasts and human adult dermal fibroblasts to the smooth muscle cell fate as determined by the expression of specific markers. The combination of 3 transcription factors, Myocd (or Myocd*) with Mef2C (or Mef2C*) and Gata6, was the most efficient in enhancing the expression of smooth muscle marker genes and decreasing fibroblast gene expression. Additionally, the derived induced smooth muscle-like cells showed a contractile phenotype in response to carbachol. Conclusions- Combination of Myocd and Gata6 with Mef2C* (MG2*) could sufficiently and efficiently direct differentiation of mouse embryonic and human dermal fibroblasts into induced smooth muscle-like cells, thus opening new opportunities for disease modeling, tissue engineering, and personalized medicine. PMID- 30026275 TI - Liraglutide Reduces Postprandial Hyperlipidemia by Increasing ApoB48 (Apolipoprotein B48) Catabolism and by Reducing ApoB48 Production in Patients With Type 2 Diabetes Mellitus. AB - Objective- Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48). Approach and Results- We performed an in vivo kinetic study with stable isotopes (D8-valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1.2 mg/d). We also evaluated, in mice, the effect of a 1-week liraglutide treatment on postload triglycerides and analysed in vitro on jejunum, the direct effect of liraglutide on the expression of genes involved in the biosynthesis of chylomicron. In diabetic patients, liraglutide treatment induced a dramatic reduction of ApoB48 pool (65+/-38 versus 162+/-87 mg; P=0.005) because of a significant decrease in ApoB48 production rate (3.02+/-1.33 versus 6.14+/ 4.27 mg kg-1 d-1; P=0.009) and a significant increase in ApoB48 fractional catabolic rate (5.12+/-1.35 versus 3.69+/-0.75 pool d-1; P=0.005). One-week treatment with liraglutide significantly reduced postload plasma triglycerides in mice and liraglutide, in vitro, reduced the expression of ApoB48, DGAT1 (diacylglycerol O-acyltransferase 1), and MTP (microsomal transfer protein) genes. Conclusions- We show that treatment with liraglutide induces a significant reduction of the ApoB48 pool because of both a reduction of ApoB48 production and an increase in ApoB48 catabolism. In vitro, liraglutide reduces the expression of genes involved in chylomicron synthesis. These effects might benefit cardiovascular health. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02721888. PMID- 30026276 TI - Medium-Chain Acylcarnitines Are Associated With Cardioembolic Stroke and Stroke Recurrence. AB - Objective- Stroke is a heterogeneous disease with diverse causes, which affect the risk of recurrence. This study aimed to identify novel biomarkers that are clinically relevant to the diagnosis of cardioembolic stroke (CE) and the prediction of stroke recurrence using metabolomics. Approach and Results- We obtained blood samples and clinical data from a consecutively registered, hospital-based acute stroke registry and from healthy controls. Mass-spectrometry based profiling was performed, and several metabolomic signatures were selected for the discrimination of CE and stroke recurrence, coupled with multivariate statistical analysis. Finally, 190 acute ischemic stroke participants (43 CE patients and 147 non-CE patients) and 30 control participants were included. We obtained 29 metabolomics signatures, and of these, 2 medium-chain acylcarnitines (decanoylcarnitine and octanoylcarnitine) were selected as independent discriminants for CE (odds ratio, 2.839; 95% CI, 1.241-6.493 for decanoylcarnitine; odds ratio, 2.839; 95% CI, 1.241-6.493 for octanoylcarnitine). Elevated medium-chain acylcarnitines were also associated with a higher risk of stroke recurrence (hazard ratio, 3.767; 95% CI, 1.276-11.117 for decanoylcarnitine; hazard ratio, 5.519; 95% CI, 1.22-18.781 for octanoylcarnitine). The levels of decanoylcarnitine and octanoylcarnitine were correlated as known surrogate markers of CE. The levels of decanoylcarnitine and octanoylcarnitine were significantly higher in stroke patients with a high-risk potential of cardioembolism than in those with low or intermediate risk. Conclusions- Metabolomics provided an improved understanding of CE pathogenesis and stroke recurrence. We have identified decanoylcarnitine and octanoylcarnitine as novel biomarkers for CE and stroke recurrence. PMID- 30026274 TI - Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure. AB - Objective- Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure. Importantly, alpha-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release in resistance arteries, also requires localization to membrane caveolae. Here, we test whether localization of Panx1 to Cav1 (caveolin-1) promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for blood pressure homeostasis. Approach and Results- We use in vitro VSMC culture models, ex vivo resistance arteries, and a novel inducible VSMC-specific Cav1 knockout mouse to probe interactions between Panx1 and Cav1. We report that Panx1 and Cav1 colocalized on the VSMC plasma membrane of resistance arteries near sympathetic nerves in an adrenergic stimulus-dependent manner. Genetic deletion of Cav1 significantly blunts adrenergic-stimulated ATP release and vasoconstriction, with no direct influence on endothelium-dependent vasodilation or cardiac function. A significant reduction in mean arterial pressure (total=4 mm Hg; night=7 mm Hg) occurred in mice deficient for VSMC Cav1. These animals were resistant to further blood pressure lowering using a Panx1 peptide inhibitor Px1IL2P, which targets an intracellular loop region necessary for channel function. Conclusions- Translocalization of Panx1 to Cav1-enriched caveolae in VSMCs augments the release of purinergic stimuli necessary for proper adrenergic mediated vasoconstriction and blood pressure homeostasis. PMID- 30026277 TI - miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase). AB - Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR 34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a+/+ and Mir34a-/- mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a-/- SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a+/+ cells. Furthermore, unlike in Mir34a+/+ SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a-/- SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC. PMID- 30026279 TI - There has been very little progress in treating or preventing antipsychotic induced tardive dyskinesia. PMID- 30026278 TI - Somatic Editing of Ldlr With Adeno-Associated Viral-CRISPR Is an Efficient Tool for Atherosclerosis Research. AB - Objective- Atherosclerosis studies in Ldlr knockout mice require breeding to homozygosity and congenic status on C57BL6/J background, a process that is both time and resource intensive. We aimed to develop a new method for generating atherosclerosis through somatic deletion of Ldlr in livers of adult mice. Approach and Results- Overexpression of PCSK9 (proprotein convertase subtilisin/kexin type 9) is currently used to study atherosclerosis, which promotes degradation of LDLR (low-density lipoprotein receptor) in the liver. We sought to determine whether CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated 9) could also be used to generate atherosclerosis through genetic disruption of Ldlr in adult mice. We engineered adeno-associated viral (AAV) vectors expressing Staphylococcus aureus Cas9 and a guide RNA targeting the Ldlr gene (AAV-CRISPR). Both male and female mice received either (1) saline, (2) AAV-CRISPR, or (3) AAV-hPCSK9 (human PCSK9)-D374Y. A fourth group of germline Ldlr-KO mice was included for comparison. Mice were placed on a Western diet and followed for 20 weeks to assess plasma lipids, PCSK9 protein levels, atherosclerosis, and editing efficiency. Disruption of Ldlr with AAV CRISPR was robust, resulting in severe hypercholesterolemia and atherosclerotic lesions in the aorta. AAV-hPCSK9 also produced hypercholesterolemia and atherosclerosis as expected. Notable sexual dimorphism was observed, wherein AAV CRISPR was superior for Ldlr removal in male mice, while AAV-hPCSK9 was more effective in female mice. Conclusions- This all-in-one AAV-CRISPR vector targeting Ldlr is an effective and versatile tool to model atherosclerosis with a single injection and provides a useful alternative to the use of germline Ldlr-KO mice. PMID- 30026280 TI - Evaluation of the minimum age for consent to mental health treatment with the minimum age of criminal responsibility in children and adolescents: a global comparison. AB - BACKGROUND: In many countries, a young person who seeks medical care is not authorised to consent to their own assessment and treatment, yet the same child can be tried for a criminal offence. The absence of child and adolescent mental health legislation in most countries exacerbates the issues young people face in independently accessing mental healthcare. Countries with existing legislation rarely define a minimum age for mental health consent (MAMHC). In stark contrast, nearly all 196 nations studied maintain legislation defining a minimum age of criminal responsibility (MACR). OBJECTIVE: This review highlights inconsistent developmental and legal perspectives in defined markers of competency across medical and judicial systems. METHODS: A review of the MAMHC was performed and compared with MACR for the 52 countries for which policy data could be identified through publicly available sources. FINDINGS: Only 18% of countries maintain identifiable mental health policies specific to children's mental health needs. Of those reviewed, only 11 nations maintained a defined MAMHC, with 7 of 11 having a MAMHC 2 years higher than the country's legislated MACR. CONCLUSIONS: With increasing scientific understanding of the influences on child and adolescent decision making, some investment in the evidence-base and reconciliation of the very different approaches to child and adolescent consent is needed. CLINICAL IMPLICATIONS: A more coherent approach to child and adolescent consent across disciplines could help improve the accessibility of services for young people and facilitate mental health professionals and services as well as criminal justice systems deliver optimal care. PMID- 30026281 TI - Rate of avoidable deaths in a Norwegian hospital trust as judged by retrospective chart review. AB - BACKGROUND: The proportion of avoidable hospital deaths is challenging to estimate, but has great implications for quality improvement and health policy. Many studies and monitoring tools are based on selected high-risk populations, which may overestimate the proportion. Mandatory reporting systems, however, under-report. We hypothesise that a review of an unselected sample of hospital deaths will provide an estimate of avoidability in-between the estimates from these methods. METHODS: A retrospective case record review of an unselected population of 1000 consecutive non-psychiatric hospital deaths in a Norwegian hospital trust was conducted. Reviewers evaluated to what degree each death could have been avoided, and identified problems in care. RESULTS: We found 42 (4.2%) of deaths to be at least probably avoidable (more than 50% chance of avoidability). Life expectancy was shortened by at least 1 year among 34 of the 42 patients with an avoidable death. Patients whose death was found to be avoidable were less functionally dependent compared with patients in the non avoidable death group. The surgical department had the greatest proportion of such deaths. Very few of the avoidable deaths were reported to the hospital's report system. CONCLUSIONS: Avoidable hospital deaths occur less frequently than estimated by the national monitoring tool, but much more frequently than reported through mandatory reporting systems. Regular reviews of an unselected sample of hospital deaths are likely to provide a better estimate of the proportion of avoidable deaths than the current methods. PMID- 30026282 TI - Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction - The Randomized SHOCK-COOL Trial. AB - Background -Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock following acute myocardial infarction. The objective of this study was to inves-tigate hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction. Methods -Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary in-tervention without classical indication for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 h or control. The primary endpoint was cardiac power index at 24 h; secondary endpoints included other hemodynamic parameters as well as serial measurements of arterial lactate. Results -No relevant differences were observed for the primary endpoint cardiac power index at 24 h (mild therapeutic hypothermia vs. control: 0.41 [interquartile range 0.31-0.52] vs. 0.36 [inter-quartile range 0.31-0.48] W/m2; p=0.50, median difference -0.025 [95% confidence interval -0.12 to 0.06 W/m2]). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8 and 10 hours were significantly higher in patients in the MTH group with a slower decline (p for interaction 0.03). There were no differences in 30-day mortality: (60 vs. 50%, hazard ratio 1.27 [95% confidence interval 0.55-2.94]; p=0.55). Conclusions -In this randomized trial mild therapeutic hypothermia failed to show a substantial beneficial effect in patients with cardiogenic shock after acute myocardial infarction on cardiac power index at 24 h. Clinical Trial Registration -URL: www.clinicaltrials.gov Unique Identifier: NCT01890317. PMID- 30026283 TI - Reciprocal relations between care-related emotional burden and sleep problems in healthcare professionals: a multicentre international cohort study. AB - OBJECTIVE: To determine whether there are reciprocal relations between care related regret and insomnia severity among healthcare professionals, and whether the use of different coping strategies influences these associations. METHODS: This is a multicentre international cohort study of 151 healthcare professionals working in acute care hospitals and clinics (87.4% female; mean age=30.4+/-8.0 years, 27.2% physicians, 48.3% nurses and 24.5% other professions) between 2014 and 2017. Weekly measures of regret intensity, number of regrets, and use of coping strategies (Regret Coping Scale) and sleep problems (Insomnia Severity Index) were assessed using a web survey. RESULTS: The associations between regret and insomnia severity were bidirectional. In a given week, regret intensity (bregret intensity->sleep=0.26, 95% credible interval (CI) (0.14 to 0.40)) and number of regrets (bnumber of regrets->sleep=0.43, 95% CI (0.07 to 0.53)) were significantly associated with increased insomnia severity the following week. Conversely, insomnia severity in a given week was significantly associated with higher regret intensity (bsleep->regret intensity=0.14, 95% CI (0.11 to 0.30)) and more regrets (bsleep->number of regrets=0.04, 95% CI (0.02 to 0.06)) the week after. The effects of regret on insomnia severity were much stronger than those in the opposite direction. The use of coping strategies, especially if they were maladaptive, modified the strength of these cross-lagged associations. CONCLUSIONS: The present study showed that care-related regret and sleep problems are closely intertwined among healthcare professionals. Given the high prevalence of these issues, our findings call for the implementation of interventions that are specifically designed to help healthcare professionals to reduce their use of maladaptive coping strategies. PMID- 30026284 TI - Meeting the Palliative Care Needs of Maintenance Hemodialysis Patients: Beyond the Math. PMID- 30026285 TI - End of Life, Withdrawal, and Palliative Care Utilization among Patients Receiving Maintenance Hemodialysis Therapy. AB - BACKGROUND AND OBJECTIVES: Withdrawal from maintenance hemodialysis before death has become more common because of high disease and treatment burden. The study objective was to identify patient factors and examine the terminal course associated with hemodialysis withdrawal, and assess patterns of palliative care involvement before death among patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We designed an observational cohort study of adult patients on incident hemodialysis in a midwestern United States tertiary center, from January 2001 to November 2013, with death events through to November 2015. Logistic regression models evaluated associations between patient characteristics and withdrawal status and palliative care service utilization. RESULTS: Among 1226 patients, 536 died and 262 (49% of 536) withdrew. A random sample (10%; 52 out of 536) review of Death Notification Forms revealed 73% sensitivity for withdrawal. Risk factors for withdrawal before death included older age, white race, palliative care consultation within 6 months, hospitalization within 30 days, cerebrovascular disease, and no coronary artery disease. Most withdrawal decisions were made by patients (60%) or a family member (33%; surrogates). The majority withdrew either because of acute medical complications (51%) or failure to thrive/frailty (22%). After withdrawal, median time to death was 7 days (interquartile range, 4-11). In-hospital deaths were less common in the withdrawal group (34% versus 46% nonwithdrawal, P=0.003). A third (34%; 90 out of 262) of those that withdrew received palliative care services. Palliative care consultation in the withdrawal group was associated with longer hemodialysis duration (odds ratio, 1.19 per year; 95% confidence interval, 1.10 to 1.3; P<0.001), hospitalization within 30 days of death (odds ratio, 5.78; 95% confidence interval, 2.62 to 12.73; P<0.001), and death in hospital (odds ratio, 1.92; 95% confidence interval, 1.13 to 3.27; P=0.02). CONCLUSIONS: In this single-center study, the rate of hemodialysis withdrawals were twice the frequency previously described. Acute medical complications and frailty appeared to be driving factors. However, palliative care services were used in only a minority of patients. PMID- 30026286 TI - Association of Inpatient Palliative Care with Health Care Utilization and Postdischarge Outcomes among Medicare Beneficiaries with End Stage Kidney Disease. AB - BACKGROUND AND OBJECTIVES: Palliative care may improve quality of life and reduce the cost of care for patients with chronic illness, but utilization and cost implications of palliative care in ESKD have not been evaluated. We sought to determine the association of inpatient palliative care with health care utilization and postdischarge outcomes in ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In analyses stratified by whether patients died during the index hospitalization, we identified Medicare beneficiaries with ESKD who received inpatient palliative care, ascertained by provider specialty codes, between 2012 and 2013. These patients were matched to hospitalized patients who received usual care using propensity scores. Primary outcomes were length of stay and hospitalization costs. Secondary outcomes were 30-day readmission and hospice enrollment. RESULTS: Inpatient palliative care occurred in <1% of hospitalizations lasting >2 days. Among the decedent cohort (n=1308), inpatient palliative care was associated with a 21% shorter length of stay (-4.2 days; 95% confidence interval, -5.6 to -2.9 days) and 14% lower hospitalization costs ( $10,698; 95% confidence interval, -$17,553 to -$3843) compared with usual care. Among the nondecedent cohort (n=5024), inpatient palliative care was associated with no difference in length of stay (0.4 days; 95% confidence interval, -0.3 to 1.0 days) and 11% higher hospitalization costs ($4275; 95% confidence interval, $1984 to $6567) compared with usual care. In the 30-day postdischarge period, patients who received inpatient palliative care had higher likelihood of hospice enrollment (hazard ratio, 8.3; 95% confidence interval, 6.6 to 10.5) and lower likelihood of rehospitalization (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9). CONCLUSIONS: Among patients with ESKD who died in the hospital, inpatient palliative care was associated with shorter hospitalizations and lower costs. Among those who survived to discharge, inpatient palliative care was associated with no difference in length of stay and higher hospitalization costs but markedly higher hospice use and fewer readmissions after discharge. PMID- 30026287 TI - Long-Term Administration of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND AND OBJECTIVES: In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for >=1 year (mean+/-SD, 4.6+/-2.8; range, 1.1-11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up. RESULTS: Patients treated with tolvaptan had lower eGFR slopes from baseline (mean+/-SD, -2.20+/-2.18 ml/min per 1.73 m2 per year) and from month 1 (mean+/-SD, -1.97+/-2.44 ml/min per 1.73 m2 per year) compared with controls (mean+/-SD, -3.50+/-2.09 ml/min per 1.73 m2 per year; P<0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment. CONCLUSIONS: Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups. PMID- 30026288 TI - OsDER1 Is an ER-Associated Protein Degradation Factor That Responds to ER Stress. AB - Endoplasmic reticulum-associated protein degradation (ERAD) plays an important role in endoplasmic reticulum (ER) quality control. To date, little is known about the retrotranslocation machinery in the plant ERAD pathway. We obtained a DERLIN-like protein (OsDER1) through a SWATH-based quantitative proteomic analysis of ER membrane proteins extracted from ER-stressed rice (Oryza sativa) seeds. OsDER1, a homolog of yeast and mammal DER1, is localized in the ER and accumulates significantly under ER stress. Overexpression or suppression of OsDER1 in rice leads to activation of the unfolded protein response and hypersensitivity to ER stress, and suppression results in floury, shrunken seeds. In addition, the expression levels of polyubiquitinated proteins increased markedly in OsDER1 overexpression or suppression transgenic rice. Coimmunoprecipitation experiments demonstrated that OsDER1 interacted with OsHRD1, OsHRD3, and OsCDC48, the essential components of the canonical ERAD pathway. Furthermore, OsDER1 associated with the signal peptide peptidase, a homolog of a component of the alternative ERAD pathway identified recently in yeast and mammals. Our data suggest that OsDER1 is linked to the ERAD pathway. PMID- 30026290 TI - The ARF7 and ARF19 Transcription Factors Positively Regulate PHOSPHATE STARVATION RESPONSE1 in Arabidopsis Roots. AB - PHOSPHATE STARVATION RESPONSE1 (PHR1) is a key regulatory component of the response to phosphate (Pi) starvation. However, the regulation of PHR1 in this response remains poorly understood. Here, we report that PHR1 is a target of the transcription factors AUXIN RESPONSE FACTOR7 (ARF7) and ARF19 and is positively regulated by auxin signaling in Arabidopsis (Arabidopsis thaliana) roots. PHR1 expression was induced by exogenous auxin and suppressed by auxin transport inhibitors in Arabidopsis roots. In the PHR1 promoter, three auxin-response elements, which are bound directly by ARF7 and ARF19, were shown to be essential for PHR1 expression. The arf7, arf19, and arf7 arf19 mutants showed down regulated expression of PHR1 and downstream Pi starvation-induced genes in roots; they also exhibited defective Pi uptake in roots and overaccumulation of anthocyanin in shoots. The induction of lateral root formation in response to low Pi and to exogenous auxin was decreased in the phr1 mutant, whereas the expression of LATERAL ORGAN BOUNDARIES-DOMAIN16 (LBD16) and LBD29 was not changed significantly. PHR1 acted independently of LBD16 and LBD29 in the regulation of lateral root formation in response to low Pi. Under low-Pi conditions, lateral root impairment in the arf7 arf19 mutant was partially rescued by constitutive expression of PHR1, demonstrating that reduced PHR1 expression contributed to the arf7 arf19 phenotype. In addition to PHR1, other genes encoding MYB-CC members also were targets of ARF7 and ARF19. Our work thus reveals a mechanism coordinating auxin signaling and the PHR1 regulon in Arabidopsis responses to Pi deficiency. PMID- 30026292 TI - Constant structural reorganisation has never improved or transformed healthcare. PMID- 30026289 TI - A Comprehensive Toolkit for Inducible, Cell Type-Specific Gene Expression in Arabidopsis. AB - Understanding the context-specific role of gene function is a key objective of modern biology. To this end, we generated a resource for inducible cell type specific transactivation in Arabidopsis (Arabidopsis thaliana) based on the well established combination of the chimeric GR-LhG4 transcription factor and the synthetic pOp promoter. Harnessing the flexibility of the GreenGate cloning system, we produced a comprehensive set of transgenic lines termed GR-LhG4 driver lines targeting most tissues in the Arabidopsis shoot and root with a strong focus on the indeterminate meristems. When we combined these transgenic lines with effectors under the control of the pOp promoter, we observed tight temporal and spatial control of gene expression. In particular, inducible expression in F1 plants obtained from crosses of driver and effector lines allows for rapid assessment of the cell type-specific impact of an effector with high temporal resolution. Thus, our comprehensive and flexible method is suitable for overcoming the limitations of ubiquitous genetic approaches, the outputs of which often are difficult to interpret due to the widespread existence of compensatory mechanisms and the integration of diverging effects in different cell types. PMID- 30026291 TI - MtNODULE ROOT1 and MtNODULE ROOT2 Are Essential for Indeterminate Nodule Identity. AB - Symbiotic interactions between legume plants and rhizobia result in the formation of nitrogen-fixing nodules, but the molecular actors and the mechanisms allowing for the maintenance of nodule identity are poorly understood. Medicago truncatula NODULE ROOT1 (MtNOOT1), Pisum sativum COCHLEATA1 (PsCOCH1), and Lotus japonicus NOOT-BOP-COCH-LIKE1 (LjNBCL1) are orthologs of Arabidopsis (Arabidopsis thaliana) AtBLADE-ON-PETIOLE1/2 and are members of the NBCL gene family, which has conserved roles in plant development and is essential for indeterminate and determinate nodule identity in legumes. The loss of function of MtNOOT1, PsCOCH1, and LjNBCL1 triggers a partial loss of nodule identity characterized by the development of ectopic roots arising from nodule vascular meristems. Here, we report the identification and characterization of a second gene involved in regulating indeterminate nodule identity in M. truncatula, MtNOOT2MtNOOT2 is the paralog of MtNOOT1 and belongs to a second legume-specific NBCL subclade, the NBCL2 clade. MtNOOT2 expression was induced during early nodule formation, and it was expressed primarily in the nodule central meristem. Mtnoot2 mutants did not present any particular symbiotic phenotype; however, the loss of function of both MtNOOT1 and MtNOOT2 resulted in the complete loss of nodule identity and was accompanied by drastic changes in the expression of symbiotic, defense, and root apical meristem marker genes. Mtnoot1 noot2 double mutants developed only nonfixing root-like structures that were no longer able to host symbiotic rhizobia. This study provides original insights into the molecular basis underlying nodule identity in legumes forming indeterminate nodules. PMID- 30026294 TI - Sequential allogeneic and autologous CAR-T-cell therapy to treat an immune compromised leukemic patient. PMID- 30026295 TI - Physical Activity and Cancer Incidence in Alberta's Tomorrow Project: Results from a Prospective Cohort of 26,538 Participants. AB - Background: Physical activity (PA) has been associated with lower risks of several cancers. We examined the association between total and domain-specific PA and risk of all and site-specific cancer risk.Methods: We analyzed baseline data from Alberta's Tomorrow Project. Specifically, adults ages 35-69 years who completed the Past Year Total Physical Activity Questionnaire were included (n = 26,538). For each activity, participants reported the type, duration, and intensity of PA. Total, recreational, and occupational PA metabolic equivalent hours/week were divided into quartiles. Incident cancer cases up to December 2016 were identified via linkage to the Alberta Cancer Registry. The associations of PA on cancer risk were examined using Cox proportional hazards models.Results: A total of 2,186 participants (8.24%) developed cancer during follow-up from 2001 to 2016. We observed a significant inverse association between total PA and all cancer incidence in the multivariate-adjusted model [HRQ4vQ1 = 0.87; 95% confidence interval (CI): 0.76-0.99] that remained significant in the latency multivariate-adjusted model. Higher recreational PA was associated with a risk decrease for all-cancer in the latency multivariate-adjusted model (HR = 0.84; 95% CI: 0.74-0.96), and showed a linear inverse association with breast cancer. While none of the HR estimates for quartiles of occupational PA and all-cancer reached statistical significance, the model Ptrend was marginally significant in the latency multivariate-adjusted model (P = 0.06).Conclusions: In this cohort of Albertans, higher total PA and recreational PA appears to convey modest protection against the development of all-cancer.Impact: Public health and cancer prevention efforts should focus on encouraging population-level increases in PA. Cancer Epidemiol Biomarkers Prev; 27(8); 945-54. (c)2018 AACR. PMID- 30026293 TI - Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1. AB - Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor pleomorphic adenoma gene 1 (PLAG1) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress PLAG1 through copy number alterations, and PLAG1 expression correlates with prognosis in Wilms tumors. PLAG1 overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings, PLAG1 transactivates insulin-like growth factor 2 (IGF2), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1-IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis. PMID- 30026297 TI - Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales. AB - BACKGROUND: Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. METHODS: We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. RESULTS: Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be -178.8 g (95% CI -225.43 to -134.47 g) in the Danish population and -210.08 g (95% CI -281.97 to -141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age. CONCLUSIONS: CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation. PMID- 30026296 TI - Cancer Site-Specific Disparities in New York, Including the 1945-1965 Birth Cohort's Impact on Liver Cancer Patterns. AB - Background: Analyses of cancer patterns by detailed racial/ethnic groups in the Northeastern United States are outdated.Methods: Using 2008-2014 death data from the populous and diverse New York State, mortality rates and regression-derived ratios with corresponding 95% confidence intervals (CIs) were computed to compare Hispanic, non-Hispanic white (NHW), non-Hispanic black (NHB), Asian populations, and specific Hispanic and NHB subgroups: Puerto Rican, Dominican, South American, Central American, U.S.-born black, and Caribbean-born black. Special analyses on liver cancer mortality, given the higher prevalence of hepatitis C infection among the 1945-1965 birth cohort, were performed.Results: A total of 244,238 cancer-related deaths were analyzed. Mortality rates were highest for U.S.-born blacks and lowest for South Americans and Asians. Minority groups had higher mortality from liver and stomach cancer than NHWs; Hispanics and NHBs also had higher mortality from cervical and prostate cancers. Excess liver cancer mortality among Puerto Rican and U.S.-born black men was observed, particularly for the 1945-1965 birth cohort, with mortality rate ratios of 4.27 (95% CI, 3.82 4.78) and 3.81 (95% CI, 3.45-4.20), respectively.Conclusions: U.S.-born blacks and Puerto Ricans, who share a common disadvantaged socioeconomic profile, bear a disproportionate burden for many cancers, including liver cancer among baby boomers. The relatively favorable cancer profile for Caribbean-born blacks contrasts with their U.S.-born black counterparts, implying that race per se is not an inevitable determinant of higher mortality among NHBs.Impact: Disaggregation by detailed Hispanic and black subgroups in U.S. cancer studies enlightens our understanding of the epidemiology of cancer and is fundamental for cancer prevention and control efforts. Cancer Epidemiol Biomarkers Prev; 27(8); 917-27. (c)2018 AACR. PMID- 30026299 TI - The cells are ambiguous, not the message. PMID- 30026300 TI - PI3K inhibitors and the search for the Holy Grail. PMID- 30026301 TI - HSP90 inhibition without heat shock response. PMID- 30026298 TI - Interferon-alpha-Mediated Activation of T Cells from Healthy and HIV-Infected Individuals Is Suppressed by Delta9-Tetrahydrocannabinol. AB - Patients with HIV routinely use medicinal cannabinoids to treat neuropathic pain, anxiety, and human immunodeficiency virus (HIV)-associated wasting. However, Delta9-tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in cannabis, suppresses T-cell function and secretion of interferons, both critically important in the antiviral immune response. Interferon-alpha (IFNalpha), a key cytokine in T-cell activation and peripheral control of HIV infection, can potentiate responsiveness to interleukin-7 (IL-7), a crucial homeostatic cytokine for peripheral T-cell maintenance. The objective of this investigation was to compare the response of T cells to stimulation by IFNalpha and IL-7 in T cells from healthy and HIV+ donors in the absence and presence of THC. To compare T-cell responses between healthy and HIV+ donors signaling through IFNalpha receptor, IFNalpha-induced expression of IL-7alpha receptor (IL 7Ralpha), cognate signaling through IL-7R, and on IL-7-mediated T-cell proliferation were measured by flow cytometry and real-time quantitative polymerase chain reaction. CD8+ T cells from HIV+ donors showed a diminished response to IFNalpha-induced phosphorylated signal transducer and activator of transcription-1 activation compared with CD8+ T cells from healthy donors, whereas CD4+ T cells from HIV+ donors and healthy donors were comparable. Treatment with IFNalpha promoted IL-7R expression and potentiated IL-7-induced STAT5 phosphorylation to augment IL-7-mediated proliferation by T cells from healthy and HIV+ donors. Finally, HIV+ donors exhibited reduced sensitivity to THC-mediated suppression by IFNalpha- and IL-7-mediated stimulation compared with healthy donors. These results further support THC as being immune suppressive while identifying putatively beneficial aspects of cannabinoid-based therapies in HIV+ patients. PMID- 30026302 TI - XG blood group puzzle solved: what's next? PMID- 30026303 TI - Aberrant T-cell antigen expression in a plasma cell neoplasm. PMID- 30026304 TI - Table of contents. Blood. 2018;131(18):ix-x. PMID- 30026305 TI - Ambiguous lineage leukemia treatment. PMID- 30026306 TI - Adverse respiratory effects of opioids for chronic breathlessness: to what extent can we learn lessons from chronic pain? PMID- 30026308 TI - SPATC1L maintains the integrity of the sperm head-tail junction. AB - Spermatogenesis is a tightly regulated process involving germ cell-specific and germ cell-predominant genes. Here we investigate a novel germ cell-specific gene, Spatc1l (spermatogenesis and centriole associated 1 like). Expression analyses show that SPATC1L is expressed in mouse and human testes. We find that mouse SPATC1L localizes to the neck region in testicular sperm. Moreover, SPATC1L associates with the regulatory subunit of protein kinase A (PKA). Using CRISPR/Cas9-mediated genome engineering, we generate mice lacking SPATC1L. Disruption of Spatc1l in mice leads to male sterility owing to separation of sperm heads from tails. The lack of SPATC1L is associated with a reduction in PKA activity in testicular sperm, and we identify capping protein muscle Z-line beta as a candidate target of phosphorylation by PKA in testis. Taken together, our results implicate the SPATC1L-PKA complex in maintaining the stability of the sperm head-tail junction, thereby revealing a new molecular basis for sperm head tail integrity. PMID- 30026307 TI - Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models. AB - Planar cell polarity (PCP) describes a cell-cell communication process through which individual cells coordinate and align within the plane of a tissue. In this study, we show that overexpression of Fuz, a PCP gene, triggers neuronal apoptosis via the dishevelled/Rac1 GTPase/MEKK1/JNK/caspase signalling axis. Consistent with this finding, endogenous Fuz expression is upregulated in models of polyglutamine (polyQ) diseases and in fibroblasts from spinocerebellar ataxia type 3 (SCA3) patients. The disruption of this upregulation mitigates polyQ induced neurodegeneration in Drosophila We show that the transcriptional regulator Yin Yang 1 (YY1) associates with the Fuz promoter. Overexpression of YY1 promotes the hypermethylation of Fuz promoter, causing transcriptional repression of Fuz Remarkably, YY1 protein is recruited to ATXN3-Q84 aggregates, which reduces the level of functional, soluble YY1, resulting in Fuz transcriptional derepression and induction of neuronal apoptosis. Furthermore, Fuz transcript level is elevated in amyloid beta-peptide, Tau and alpha-synuclein models, implicating its potential involvement in other neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Taken together, this study unveils a generic Fuz-mediated apoptotic cell death pathway in neurodegenerative disorders. PMID- 30026311 TI - How online GP services are tackling safety concerns. PMID- 30026312 TI - New BASHH sexual health advisers and nurses special interest group. PMID- 30026310 TI - A rationale for tRNA modification circuits in the anticodon loop. AB - The numerous post-transcriptional modifications of tRNA play a crucial role in tRNA function. While most modifications are introduced to tRNA independently, several sets of modifications are found to be interconnected such that the presence of one set of modifications drives the formation of another modification. The vast majority of these modification circuits are found in the anticodon loop (ACL) region where the largest variety and highest density of modifications occur compared to the other parts of the tRNA and where there is relatively limited sequence and structural information. We speculate here that the modification circuits in the ACL region arise to enhance enzyme modification specificity by direct or indirect use of the first modification in the circuit as an additional recognition element for the second modification. We also describe the five well-studied modification circuits in the ACL, and outline possible mechanisms by which they may act. The prevalence of these modification circuits in the ACL and the phylogenetic conservation of some of them suggest that a number of other modification circuits will be found in this region in different organisms. PMID- 30026313 TI - HIV/AIDS in the Middle East and North Africa: a positive future. PMID- 30026309 TI - Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. AB - RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between beta2 and beta3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP pocket-binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2 XIAP interaction, and of cellular and in vivoNOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling. PMID- 30026314 TI - A molecular mechanism for Wnt ligand-specific signaling. AB - Wnt signaling is key to many developmental, physiological, and disease processes in which cells seem able to discriminate between multiple Wnt ligands. This selective Wnt recognition or "decoding" capacity has remained enigmatic because Wnt/Frizzled interactions are largely incompatible with monospecific recognition. Gpr124 and Reck enable brain endothelial cells to selectively respond to Wnt7. We show that Reck binds with low micromolar affinity to the intrinsically disordered linker region of Wnt7. Availability of Reck-bound Wnt7 for Frizzled signaling relies on the interaction between Gpr124 and Dishevelled. Through polymerization, Dishevelled recruits Gpr124 and the associated Reck-bound Wnt7 into dynamic Wnt/Frizzled/Lrp5/6 signalosomes, resulting in increased local concentrations of Wnt7 available for Frizzled signaling. This work provides mechanistic insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members. PMID- 30026315 TI - Large-scale ocean deoxygenation during the Paleocene-Eocene Thermal Maximum. AB - The consequences of global warming for fisheries are not well understood, but the geological record demonstrates that carbon cycle perturbations are frequently associated with ocean deoxygenation. Of particular interest is the Paleocene Eocene Thermal Maximum (PETM), where the carbon dioxide input into the atmosphere was similar to the IPCC RCP8.5 emission scenario. Here we present sulfur-isotope data that record a positive 1 per mil excursion during the PETM. Modeling suggests that large parts of the ocean must have become sulfidic. The toxicity of hydrogen sulfide will render two of the largest and least explored ecosystems on Earth, the mesopelagic and bathypelagic zones, uninhabitable by multicellular organisms. This will affect many marine species whose ecozones stretch into the deep ocean. PMID- 30026316 TI - Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. AB - RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1 deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system. PMID- 30026317 TI - Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation. AB - RNA tails play integral roles in the regulation of messenger RNA (mRNA) translation and decay. Guanylation of the poly(A) tail was discovered recently, yet the enzymology and function remain obscure. Here we identify TENT4A (PAPD7) and TENT4B (PAPD5) as the enzymes responsible for mRNA guanylation. Purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues, the most common of which is guanosine. A single guanosine residue is sufficient to impede the deadenylase CCR4-NOT complex, which trims the tail and exposes guanosine at the 3' end. Consistently, depletion of TENT4A and TENT4B leads to a decrease in mRNA half-life and abundance in cells. Thus, TENT4A and TENT4B produce a mixed tail that shields mRNA from rapid deadenylation. Our study unveils the role of mixed tailing and expands the complexity of posttranscriptional gene regulation. PMID- 30026318 TI - Optical skyrmion lattice in evanescent electromagnetic fields. AB - Topological defects play a key role in a variety of physical systems, ranging from high-energy to solid-state physics. A skyrmion is a type of topological defect that has shown promise for applications in the fields of magnetic storage and spintronics. We show that optical skyrmion lattices can be generated using evanescent electromagnetic fields and demonstrate this using surface plasmon polaritons, imaged by phase-resolved near-field optical microscopy. We show how the optical skyrmion lattice exhibits robustness to imperfections while the topological domain walls in the lattice can be continuously tuned, changing the spatial structure of the skyrmions from bubble type to Neel type. Extending the generation of skyrmions to photonic systems provides various possibilities for applications in optical information processing, transfer, and storage. PMID- 30026319 TI - Abrupt cloud clearing of marine stratocumulus in the subtropical southeast Atlantic. AB - We document rapid and abrupt clearings of large portions of the subtropical marine low cloud deck that have implications for the global radiation balance and climate sensitivity. Over the southeast Atlantic, large areas of stratocumulus are quickly eroded, yielding partial or complete clearing along sharp transitions hundreds to thousands of kilometers in length that move westward at 8 to 12 meters per second and travel as far as 1000+ kilometers from the African coast. The westward-moving cloudiness reductions have an annual peak in occurrence in the period from April through June. The cloud erosion boundaries reduce cloud at ~10-kilometer scale in less than 15 minutes, move approximately perpendicular to the mean flow, and are often accompanied by small-scale wave features. Observations suggest that the cloud erosion is caused by atmospheric gravity waves. PMID- 30026320 TI - Towards evidence-based medicine for paediatricians. PMID- 30026322 TI - Constant structural reorganisation is likely to continue. PMID- 30026323 TI - Psychiatrist wins injunction to stop disciplinary proceedings against her. PMID- 30026324 TI - Targeting CCR8 Induces Protective Antitumor Immunity and Enhances Vaccine-Induced Responses in Colon Cancer. AB - CCR8 is a chemokine receptor expressed principally on regulatory T cells (Treg) and is known to be critical for CCR8+ Treg-mediated immunosuppression. Recent studies have demonstrated that CCR8 is uniquely upregulated in human tumor resident Tregs of patients with breast, colon, and lung cancer when compared with normal tissue-resident Tregs. Therefore, CCR8+ tumor-resident Tregs are rational targets for cancer immunotherapy. Here, we demonstrate that mAb therapy targeting CCR8 significantly suppresses tumor growth and improves long-term survival in colorectal tumor mouse models. This antitumor activity correlated with increased tumor-specific T cells, enhanced infiltration of CD4+ and CD8+ T cells, and a significant decrease in the frequency of tumor-resident CD4+CCR8+ Tregs. Tumor specific CD8+ T cells displayed lower expression of exhaustion markers as well as increased functionality upon restimulation. Treatment with anti-CCR8 mAb prevented de novo induction and suppressive function of Tregs without affecting CD8+ T cells. Initial studies explored a combinatorial regimen using anti-CCR8 mAb therapy and a Listeria monocytogenes-based immunotherapy. Anti-CCR8 mAb therapy synergized with L. monocytogenes-based immunotherapy to significantly delay growth of established tumors and to prolong survival. Collectively, these findings identify CCR8 as a promising new target for tumor immunotherapy and provide a strong rationale for further development of this approach, either as a monotherapy or in combination with other immunotherapies.Significance: Inhibition of CCR8 represents a promising new cancer immunotherapy strategy that modulates tumor-resident regulatory T cells to enhance antitumor immunity and prolong patient survival. Cancer Res; 78(18); 5340-8. (c)2018 AACR. PMID- 30026325 TI - Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors. AB - Asparagine (N)-linked glycosylation is a posttranslational modification essential for the function of complex transmembrane proteins. However, targeting glycosylation for cancer therapy has not been feasible due to generalized effects on all glycoproteins. Here, we perform sensitivity screening of 94 lung cancer cell lines using NGI-1, a small-molecule inhibitor of the oligosaccharyltransferase (OST) that partially disrupts N-linked glycosylation, and demonstrate a selective loss of tumor cell viability. This screen revealed NGI-1 sensitivity in just 11 of 94 (12%) cell lines, with a significant correlation between OST and EGFR inhibitors. In EGFR-mutant non-small cell lung cancer with EGFR tyrosine kinase inhibitor (TKI) resistance (PC9-GR, HCC827-GR, and H1975-OR), OST inhibition maintained its ability to induce cell-cycle arrest and a proliferative block. Addition of NGI-1 to EGFR TKI treatment was synthetic lethal in cells resistant to gefitinib, erlotinib, or osimertinib. OST inhibition invariably disrupted EGFR N-linked glycosylation and reduced activation of receptors either with or without the T790M TKI resistance mutation. OST inhibition also dissociated EGFR signaling from other coexpressed receptors like MET via altered receptor compartmentalization. Translation of this approach to preclinical models was accomplished through synthesis and delivery of NGI-1 nanoparticles, confirmation of in vivo activity through molecular imaging, and demonstration of significant tumor growth delay in TKI-resistant HCC827 and H1975 xenografts. This therapeutic strategy breaks from kinase-targeted approaches and validates N-linked glycosylation as an effective target in tumors driven by glycoprotein signaling.Significance:EGFR-mutant NSCLC is incurable despite the marked sensitivity of these tumors to EGFR TKIs. These findings identify N-linked glycosylation, a posttranslational modification common to EGFR and other oncogenic signaling proteins, as an effective therapeutic target that enhances tumor responses for EGFR-mutant NSCLC. Cancer Res; 78(17); 5094-106. (c)2018 AACR. PMID- 30026326 TI - A Rare Missense Variant in TCF7L2 Associates with Colorectal Cancer Risk by Interacting with a GWAS-Identified Regulatory Variant in the MYC Enhancer. AB - Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in TCF7L2 [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69-2.57, P = 5.66 * 10-12] and a previous European GWAS identified 3'-UTR variant in ATF1 (rs11169571, OR = 1.18, 95% CI: 1.13-1.24, P = 1.65 * 10-12). We found a significant interaction between the TCF7L2 missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the MYC enhancer (Pinteraction = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the MYC enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the ATF1 rs11169571 variant significantly correlated with ATF1 expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes NRAS and BRAF were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer.Significance: Exome-wide association analysis identifies a rare missense variant in TCF7L2 and a common regulatory variant in ATF1 as susceptibility factors of colorectal cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/5164/F1.large.jpg Cancer Res; 78(17); 5164-72. (c)2018 AACR. PMID- 30026328 TI - The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors. AB - Radiotherapy amplifies p53 expression in cancer cells with wild-type (wt) p53. Blocking the negative regulators MDM2 and MDMX stabilizes p53 and may therefore potentiate radiotherapy outcomes. In this study, we investigate the efficacy of the novel anti-MDM2/X stapled peptide PM2 alone and in combination with external gamma radiation in vitro and in vivo PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both in vitro and in vivo assays, whereas these effects did not manifest in p53 -/- cells. Biodistribution and autoradiography of 125I-PM2 revealed high and retained uptake homogenously distributed throughout the tumor. In mice carrying wt p53 tumors, PM2 combined with radiotherapy significantly prolonged the median survival by 50%, whereas effects of PM2 therapy on mutant and p53 -/- tumors were negligible. PM2-dependent stabilization of p53 was confirmed with ex vivo immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator in vivo and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control.Significance: These findings contribute advances to cancer radiotherapy by using novel p53-reactivating stapled peptides as radiosensitizers in wild-type p53 cancers. Cancer Res; 78(17); 5084-93. (c)2018 AACR. PMID- 30026327 TI - Loss of XIST in Breast Cancer Activates MSN-c-Met and Reprograms Microglia via Exosomal miRNA to Promote Brain Metastasis. AB - Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long noncoding RNAs in brain metastatic tumors from patients with breast cancer and found that the X-inactive-specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XISThigh cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal transition and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal miRNA-503, which triggered M1-M2 polarization of microglia. This M1 M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XISTlow breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis.Significance: These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XISTlow tumor cells in the brain. Cancer Res; 78(15); 4316-30. (c)2018 AACR. PMID- 30026329 TI - Matrix Stiffening and EGFR Cooperate to Promote the Collective Invasion of Cancer Cells. AB - In squamous cell carcinoma (SCC), tissue invasion by collectively invading cells requires physical forces applied by tumor cells on their surrounding extracellular matrix (ECM). Cancer-related ECM is composed of thick collagen bundles organized by carcinoma-associated fibroblasts (CAF) within the tumor stroma. Here, we show that SCC cell collective invasion is driven by the matrix dependent mechano-sensitization of EGF signaling in cancer cells. Calcium (Ca2+) was a potent intracellular second messenger that drove actomyosin contractility. Tumor-derived matrix stiffness and EGFR signaling triggered increased intracellular Ca2+ through CaV1.1 expression in SCC cells. Blocking L-type calcium channel expression or activity using Ca2+ channel blockers verapamil and diltiazem reduced SCC cell collective invasion both in vitro and in vivo These results identify verapamil and diltiazem, two drugs long used in medical care, as novel therapeutic strategies to block the tumor-promoting activity of the tumor niche.Significance: This work demonstrates that calcium channels blockers verapamil and diltiazem inhibit mechano-sensitization of EGF-dependent cancer cell collective invasion, introducing potential clinical strategies against stromal-dependent collective invasion.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/18/5229/F1.large.jpg Cancer Res; 78(18); 5229-42. (c)2018 AACR. PMID- 30026331 TI - Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis. AB - Regulatory T cells (Treg) are critical mediators of immunosuppression in established tumors, although little is known about their role in restraining immunosurveillance during tumorigenesis. Here, we employ an inducible autochthonous model of melanoma to investigate the earliest Treg and CD8 effector T-cell responses during oncogene-driven tumorigenesis. Induction of oncogenic BRAFV600E and loss of Pten in melanocytes led to localized accumulation of FoxP3+ Tregs, but not CD8 T cells, within 1 week of detectable increases in melanocyte differentiation antigen expression. Melanoma tumorigenesis elicited early expansion of shared tumor/self-antigen-specific, thymically derived Tregs in draining lymph nodes, and induced their subsequent recruitment to sites of tumorigenesis in the skin. Lymph node egress of tumor-activated Tregs was required for their C-C chemokine receptor 4 (Ccr4)-dependent homing to nascent tumor sites. Notably, BRAFV600E signaling controlled expression of Ccr4-cognate chemokines and governed recruitment of Tregs to tumor-induced skin sites. BRAFV600E expression alone in melanocytes resulted in nevus formation and associated Treg recruitment, indicating that BRAFV600E signaling is sufficient to recruit Tregs. Treg depletion liberated immunosurveillance, evidenced by CD8 T cell responses against the tumor/self-antigen gp100, which was concurrent with the formation of microscopic neoplasia. These studies establish a novel role for BRAFV600E as a tumor cell-intrinsic mediator of immune evasion and underscore the critical early role of Treg-mediated suppression during autochthonous tumorigenesis.Significance: This work provides new insights into the mechanisms by which oncogenic pathways impact immune regulation in the nascent tumor microenvironment. Cancer Res; 78(17); 5038-49. (c)2018 AACR. PMID- 30026330 TI - Identification of Metastatic Lymph Nodes in MR Imaging with Faster Region-Based Convolutional Neural Networks. AB - MRI is the gold standard for confirming a pelvic lymph node metastasis diagnosis. Traditionally, medical radiologists have analyzed MRI image features of regional lymph nodes to make diagnostic decisions based on their subjective experience; this diagnosis lacks objectivity and accuracy. This study trained a faster region based convolutional neural network (Faster R-CNN) with 28,080 MRI images of lymph node metastasis, allowing the Faster R-CNN to read those images and to make diagnoses. For clinical verification, 414 cases of rectal cancer at various medical centers were collected, and Faster R-CNN-based diagnoses were compared with radiologist diagnoses using receiver operating characteristic curves (ROC). The area under the Faster R-CNN ROC was 0.912, indicating a more effective and objective diagnosis. The Faster R-CNN diagnosis time was 20 s/case, which was much shorter than the average time (600 s/case) of the radiologist diagnoses.Significance: Faster R-CNN enables accurate and efficient diagnosis of lymph node metastases. Cancer Res; 78(17); 5135-43. (c)2018 AACR. PMID- 30026332 TI - Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow Resident Melanoma CTCs. AB - Systemic metastasis is the major cause of death from melanoma, the most lethal form of skin cancer. Although most patients with melanoma exhibit a substantial gap between onset of primary and metastatic tumors, signaling mechanisms implicated in the period of metastatic latency remain unclear. We hypothesized that melanoma circulating tumor cells (CTC) home to and reside in the bone marrow during the asymptomatic phase of disease progression. Using a strategy to deplete normal cell lineages (Lin-), we isolated CTC-enriched cell populations from the blood of patients with metastatic melanoma, verified by the presence of putative CTCs characterized by melanoma-specific biomarkers and upregulated gene transcripts involved in cell survival and prodevelopment functions. Implantation of Lin- population in NSG mice (CTC-derived xenografts, i.e., CDX), and subsequent transcriptomic analysis of ex vivo bone marrow-resident tumor cells (BMRTC) versus CTC identified protein ubiquitination as a significant regulatory pathway of BMRTC signaling. Selective inhibition of USP7, a key deubiquinating enzyme, arrested BMRTCs in bone marrow locales and decreased systemic micrometastasis. This study provides first-time evidence that the asymptomatic progression of metastatic melanoma can be recapitulated in vivo using patient isolated CTCs. Furthermore, these results suggest that USP7 inhibitors warrant further investigation as a strategy to prevent progression to overt clinical metastasis.Significance: These findings provide insights into mechanism of melanoma recurrence and propose a novel approach to inhibit systematic metastatic disease by targeting bone marrow-resident tumor cells through pharmacological inhibition of USP7.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/18/5349/F1.large.jpg Cancer Res; 78(18); 5349-62. (c)2018 AACR. PMID- 30026333 TI - A 26-Week Randomized Controlled Trial of Semaglutide Once Daily Versus Liraglutide and Placebo in Patients With Type 2 Diabetes Suboptimally Controlled on Diet and Exercise With or Without Metformin. AB - OBJECTIVE: To investigate the efficacy and safety of once-daily semaglutide in comparison with once-daily liraglutide and placebo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, multicenter, double-blind trial involved patients diagnosed with type 2 diabetes with HbA1c 7.0-10.0% (53 86 mmol/mol) and treated with diet and exercise with or without metformin. Patients were randomized 2:2:1 to once-daily semaglutide, liraglutide, or placebo in one of four volume-matched doses (semaglutide 0.05, 0.1, 0.2, or 0.3 mg and liraglutide 0.3, 0.6, 1.2, or 1.8 mg, with both compared within each volume matched dose group). Primary end point was change in HbA1c from baseline to week 26. RESULTS: In total, 705 randomized patients were exposed to trial products. At week 26, a dose-dependent change in HbA1c was observed with semaglutide from 1.1% (0.05 mg) to -1.9% (0.3 mg) and with liraglutide from -0.5% (0.3 mg) to 1.3% (1.8 mg) (all P < 0.001 in favor of volume-matched semaglutide dose). Change with pooled placebo was -0.02% (P < 0.0001 vs. semaglutide). Gastrointestinal (GI) disorders were the most common adverse events (AEs) with semaglutide and liraglutide, occurring in 32.8-54.0% and 21.9-41.5% of patients, respectively. CONCLUSIONS: Once-daily semaglutide at doses up to 0.3 mg/day resulted in greater reductions in HbA1c compared with liraglutide or placebo but with a higher frequency of GI AEs. PMID- 30026336 TI - Comprehensive molecular characterization of a heavy chain deposition disease case. PMID- 30026334 TI - Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). AB - OBJECTIVE: Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to creatinine ratios (ACRs) in the normal range at age 10-16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2-4-year AdDIT study. RESEARCH DESIGN AND METHODS: One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study. RESULTS: After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log rank P < 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08-8.85]) and HbA1c (1.37 [1.10-1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], P = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group (P < 0.05). CONCLUSIONS: ACR at the higher end of the normal range at the age of 10-16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA1c. PMID- 30026337 TI - PD-L1+ tumor-associated macrophages and PD-1+ tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma. AB - Primary testicular lymphoma is a rare and aggressive lymphoid malignancy, most often representing diffuse large B-cell lymphoma histologically. Tumor-associated macrophages and tumor-infiltrating lymphocytes have been associated with survival in diffuse large B-cell lymphoma, but their prognostic impact in primary testicular lymphoma is unknown. Here, we aimed to identify macrophages, their immunophenotypes and association with lymphocytes, and translate the findings into survival of patients with primary testicular lymphoma. We collected clinical data and tumor tissue from 74 primary testicular lymphoma patients, and used multiplex immunohistochemistry and digital image analysis to examine macrophage markers (CD68, CD163, and c-Maf), T-cell markers (CD3, CD4, and CD8), B-cell marker (CD20), and three checkpoint molecules (PD-L1, PD-L2, and PD-1). We demonstrate that a large proportion of macrophages (median 41%, range 0.08-99%) and lymphoma cells (median 34%, range 0.1-100%) express PD-L1. The quantity of PD L1+ CD68+ macrophages correlates positively with the amount of PD-1+ lymphocytes, and a high proportion of either PD-L1+ CD68+ macrophages or PD-1+ CD4+ and PD-1+ CD8+ T cells translates into favorable survival. In contrast, the number of PD L1+lymphoma cells or PD-L1- macrophages do not associate with outcome. In multivariate analyses with IPI, PD-L1+ CD68+ macrophage and PD-1+ lymphocyte contents remain as independent prognostic factors for survival. In conclusion, high PD-L1+ CD68+ macrophage and PD-1+ lymphocyte contents predict favorable survival in patients with primary testicular lymphoma. The findings implicate that the tumor microenvironment and PD-1 - PD-L1 pathway have a significant role in regulating treatment outcome. They also bring new insights to the targeted thera py of primary testicular lymphoma. PMID- 30026339 TI - Endothelial protein C receptor (EPCR) expression marks human fetal liver hematopoietic stem cells. PMID- 30026338 TI - The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2. AB - YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and with YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of three five novel missense variants showed they that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency = 0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype. PMID- 30026340 TI - Niche TWIST1 is critical for maintaining normal hematopoiesis and impeding leukemia progression. AB - Bone marrow microenvironment regulates normal and malignant hematopoiesis, but the underlying molecular mechanisms remain poorly defined. Using a chimeric mice model, we demonstrate that Twist1 deletion in microenvironment results in alteration of multiple niche cells as well as downregulated expression of major hematopoietic stem cell supportive factors. The perturbed microenvironment reduces hematopoietic stem cell homing and retention, impairs hematopoietic stem cell self-renewal and induces myeloid skewing. Nevertheless, it accelerates MLL AF9 leukemia progression, which is partially mediated by Jagged-2 dependent Notch signaling. Our data for the first time demonstrates a pivotal role of TWIST1 in favoring normal hematopoiesis and hampering leukemia development. It also brings new insights into the role of bone marrow niche in driving the development of acute myeloid leukemia, and proposes possible new avenues from the niche angle to improve leukemia treatments. PMID- 30026335 TI - Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial. AB - OBJECTIVE: This 24-week, double-blinded, phase 3 clinical trial (DEPICT-2; ClinicalTrials.gov, NCT02460978) evaluated efficacy and safety of dapagliflozin as adjunct therapy to adjustable insulin in patients with inadequately controlled type 1 diabetes (HbA1c 7.5-10.5%). RESEARCH DESIGN AND METHODS: Patients were randomized 1:1:1 to dapagliflozin 5 mg (n = 271), dapagliflozin 10 mg (n = 270), or placebo (n = 272) plus insulin. Insulin dose was adjusted by investigators according to self-monitored glucose readings, local guidance, and individual circumstances. RESULTS: Baseline characteristics were balanced between treatment groups. At week 24, dapagliflozin significantly decreased HbA1c (primary outcome; difference vs. placebo: dapagliflozin 5 mg -0.37% [95% CI -0.49, -0.26], dapagliflozin 10 mg -0.42% [-0.53, -0.30]), total daily insulin dose (-10.78% [ 13.73, -7.72] and -11.08% [-14.04, -8.02], respectively), and body weight (-3.21% [-3.96, -2.45] and -3.74% [-4.49, -2.99], respectively) (P < 0.0001 for all). Mean interstitial glucose, amplitude of glucose excursion, and percent of readings within target glycemic range (>70 to <=180 mg/dL) versus placebo were significantly improved. More patients receiving dapagliflozin achieved a reduction in HbA1c >=0.5% without severe hypoglycemia compared with placebo. Adverse events were reported for 72.7%, 67.0%, and 63.2% of patients receiving dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. Hypoglycemia, including severe hypoglycemia, was balanced between groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events with dapagliflozin: 2.6%, 2.2%, and 0% for dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. CONCLUSIONS: Dapagliflozin as adjunct therapy to adjustable insulin in patients with type 1 diabetes was well tolerated and improved glycemic control with no increase in hypoglycemia versus placebo but with more DKA events. PMID- 30026341 TI - Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia. Analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group. AB - In standard risk acute promyelocytic leukemia, recent results have shown that ATRA + Arsenic trioxide combinations were at least as effective as classical ATRA + anthracycline based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher risk acute promyelocytic leukemia, and access to arsenic remains limited for frontline treatment of standard risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared for consolidation treatment (after ATRA Chemotherapy induction treatment) arsenic, ATRA and the classical AraC in standard risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher risk APL. Newly diagnosed acute promyelocytic leukemia patients with white blood cells < 10 G/L, after an induction treatment consisting of ATRA plus Idarubicin-AraC, received consolidation chemotherapy with Idarubicin and AraC, arsenic or ATRA. Patients with white blood cells >10G received consolidation chemotherapy with arsenic or without arsenic.795 acute promyelocytic leukemia patients were enrolled in this trial. In Standard risk APL (n= 581), 5-year EFS from randomization was 88.7%, 95.7% and 85.4% in the AraC, arsenic and ATRA consolidation groups, respectively (p=0.0067) and 5 year cumulative incidence of relapse (CIR) was 5.5%, 0% and 8.2%. (p=0.001). In higher risk APL (n=214), 5-year EFS was 85.5% vs 92.1% (p=0.38) in the chemotherapy and chemotherapy+ arsenic groups, respectively and 5-year CIR of 4.6% and 3.5% (p= 0.99) in the chemotherapy and chemotherapy+ arsenic groups. Due to prolonged myelosuppression in the chemotherapy+ arsenic arm, an amendment excluded AraC during consolidation cycles in the chemotherapy+ arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation where we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365). PMID- 30026342 TI - Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI. AB - Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton's tyrosine kinase (Btk) used in the treatment of B cell malignancies. They bind irreversibly to cysteine 481 of Btk, blocking autophosphorylation on tyrosine (Y) 223 and phosphorylation of downstream substrates including phospholipase-gamma2 (PLCgamma2). In the present study, we demonstrate that concentrations of ibrutinib and acalabrutinib that block Btk kinase activity as shown by loss of phosphorylation at Y223 and PLCgamma2 delay but do not block aggregation to a maximally-effective concentration of CRP or collagen. In contrast, 10- 20 fold higher concentrations of ibrutinib or acalabrutinib block platelet aggregation to GPVI agonists. Ex vivo studies on patients treated with ibrutinib, but not acalabrutinib, show a reduction of platelet aggregation to CRP indicating that the clinical dose of ibrutinib but not acalabrutinib is supramaximal for Btk blockade. Unexpectedly, low concentrations of ibrutinib inhibit aggregation to CRP in patients deficient in Btk. The increased bleeding seen with ibrutinib over acalabrutinib is due to off-target actions of ibrutinib that occur because of unfavourable pharmacodynamics. PMID- 30026343 TI - Treatment optimization for Multiple Myeloma: schedule-dependent synergistic cytotoxicity of pomalidomide and carfilzomib in an in vitro and ex-vivo model. AB - Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), significantly enhanced the depth of response and prolonged the survival of Multiple Myeloma (MM) patients, although not all patients respond favourably to treatment. Optimization of treatment schedules and dosages of IMiDs and PIs might lead to improved treatment efficacy. In this study we aimed at exploring the optimal schedule of IMiDs and PIs in both in vitro models, including bone marrow (BM) microenvironment simulation, and an ex-vivo model using patient-derived BM samples. MM cells were exposed to IMiDs and PIs either simultaneously or sequentially. Using the median effect method of Chou Talalay, we evaluated the combination indices for simultaneous and sequential treatment schedules. We demonstrated schedule-dependent synergistic cytotoxicity for the combination of IMiDs and PIs and a maximal apoptosis was observed in IMiDs pre-exposure schedule. The superior activity of this schedule was maintained even in BM microenvironment models, and was further confirmed using patient-derived samples. Our data overall suggest that the administration of IMiDs before PIs can improve treatment efficacy. Clinical trials are needed to investigate the most effective schedule, which could be to start the administration of IMiDs before PIs to increase cells killing. PMID- 30026346 TI - Farm animal welfare matters to all vets. PMID- 30026347 TI - Non-vets would compromise OVs, warns VPHA. PMID- 30026351 TI - Assessing farm assurance schemes in the UK. PMID- 30026353 TI - Using forensics to track pangolin trafficking. AB - Forensic techniques can be used in many criminal cases, but, as Georgina Mills explains, its use in wildlife trafficking is just taking off. PMID- 30026354 TI - Encouraging young children to pursue veterinary careers. PMID- 30026344 TI - The actin cortex at a glance. AB - Precisely controlled cell deformations are key to cell migration, division and tissue morphogenesis, and have been implicated in cell differentiation during development, as well as cancer progression. In animal cells, shape changes are primarily driven by the cellular cortex, a thin actomyosin network that lies directly underneath the plasma membrane. Myosin-generated forces create tension in the cortical network, and gradients in tension lead to cellular deformations. Recent studies have provided important insight into the molecular control of cortical tension by progressively unveiling cortex composition and organization. In this Cell Science at a Glance article and the accompanying poster, we review our current understanding of cortex composition and architecture. We then discuss how the microscopic properties of the cortex control cortical tension. While many open questions remain, it is now clear that cortical tension can be modulated through both cortex composition and organization, providing multiple levels of regulation for this key cellular property during cell and tissue morphogenesis. PMID- 30026355 TI - Schmallenberg virus expands its geographical range in Northern Ireland. PMID- 30026356 TI - Diagnosis by ruling out other diseases or conditions. PMID- 30026358 TI - Over treatment and inadequate trial protocols. PMID- 30026359 TI - Extension of badger culling unfounded and unjustified. PMID- 30026360 TI - We need to talk about the rabbit in the room .... PMID- 30026361 TI - Tracking the history of research on cats and their ailments. PMID- 30026362 TI - Is BVA stifling free-reigning ethical debate? AB - Paul Roger argues that the structure for debating and endorsing new policy decisions at BVA is not fit for purpose, and that this should be reviewed and adapted so that it can meet today's demands. PMID- 30026363 TI - Ignorance - an unwelcome form of bliss. PMID- 30026364 TI - Managing perfectionism. PMID- 30026367 TI - CBMNet: the 'Crossing Biological Membranes' network in industrial biotechnology and bioenergy. AB - The ~1300 academic and industry members of the BBSRC (Biotechnology and Biological Sciences Research Council) Network in Industrial Biotechnology and Bioenergy (NIBB) Crossing Biological Membranes Network (CBMNet) are motivated to explore how knowledge of the roles of biological membranes can be exploited to enhance the productivity of cell factories. Improving existing, and developing new, cell factories requires a deep understanding of the mechanisms by which substances are transported into, within, and out of the cells. Embedding consideration of membrane function into the design of cell factories is crucial for the future of almost all cell-based Industrial Biotechnology and Bioenergy (IBBE) applications. CBMNet provides a forum for: knowledge exchange between academics and companies; developing new interactions in the context of responsible innovation; forming, and then supporting, new multi-disciplinary teams to develop innovative membrane-based solutions to overcome IBBE bottlenecks; and funding consortia to carry out feasibility studies with the target of generating competitive bids for further research funding. More broadly, CBMNet is working with other NIBB to raise the profile of IBBE among policymakers and develop a national strategy for IBBE in the U.K. PMID- 30026369 TI - SNARE dynamics during melanosome maturation. AB - Historically, studies on the maturation and intracellular transport of melanosomes in melanocytes have greatly contributed to elucidating the general mechanisms of intracellular transport in many different types of mammalian cells. During melanosome maturation, melanosome cargoes including melanogenic enzymes (e.g. tyrosinase) are transported from endosomes to immature melanosomes by membrane trafficking, which must require a membrane fusion process likely regulated by SNAREs [soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptors]. In the present study, we review the literature concerning the expression and function of SNAREs (e.g. v-SNARE vesicle-associated membrane protein 7 and t-SNAREs syntaxin-3/13 and synaptosomal-associated protein-23) in melanocytes, especially in regard to the fusion process in which melanosome cargoes are finally delivered to immature melanosomes. We also describe the recent discovery of the SNARE recycling system on mature melanosomes in melanocytes. Such SNARE dynamics, especially the SNARE recycling system, on melanosomes will be useful in understanding as yet unidentified SNARE dynamics on other organelles. PMID- 30026370 TI - Marine glycosaminoglycan-like carbohydrates as potential drug candidates for infectious disease. AB - Glycosaminoglycans (GAGs), present in the extracellular matrix, are exploited by numerous, distinct microbes for cellular attachment, adhesion, invasion and evasion of the host immune system. Glycosaminoglycans, including the widely used, clinical anticoagulant heparin and semi-synthetic analogues thereof, have been reported to inhibit and disrupt interactions between microbial proteins and carbohydrates present on the surface of host cells. However, the anticoagulant properties of unmodified, pharmaceutical heparin preparations preclude their capabilities as therapeutics for infectious disease states. Here, unique Glycosaminoglycan-like saccharides from various, distinct marine species are reported for their potential use as therapeutics against infectious diseases; many of which possess highly attenuated anticoagulant activities, while retaining significant antimicrobial properties. PMID- 30026371 TI - Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically? AB - Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes. PMID- 30026372 TI - Meet the First Authors. PMID- 30026368 TI - Fantastic nuclear envelope herniations and where to find them. AB - Morphological abnormalities of the bounding membranes of the nucleus have long been associated with human diseases from cancer to premature aging to neurodegeneration. Studies over the past few decades support that there are both cell intrinsic and extrinsic factors (e.g. mechanical force) that can lead to nuclear envelope 'herniations', a broad catch-all term that reveals little about the underlying molecular mechanisms that contribute to these morphological defects. While there are many genetic perturbations that could ultimately change nuclear shape, here, we focus on a subset of nuclear envelope herniations that likely arise as a consequence of disrupting physiological nuclear membrane remodeling pathways required to maintain nuclear envelope homeostasis. For example, stalling of the interphase nuclear pore complex (NPC) biogenesis pathway and/or triggering of NPC quality control mechanisms can lead to herniations in budding yeast, which are remarkably similar to those observed in human disease models of early-onset dystonia. By also examining the provenance of nuclear envelope herniations associated with emerging nuclear autophagy and nuclear egress pathways, we will provide a framework to help understand the molecular pathways that contribute to nuclear deformation. PMID- 30026373 TI - A CRISPR Take on Clonal Hematopoiesis. PMID- 30026375 TI - David M. Ryba: Pushing the Field Forward. PMID- 30026376 TI - Jose Jalife: Perseverance Pays Off. PMID- 30026374 TI - Softening the Stressed Giant Titin in Diabetes Mellitus. PMID- 30026377 TI - Leducq Network: Modulating Autophagy to Treat Cardiovascular Disease. PMID- 30026378 TI - Redox Regulation Beyond ROS: Why ROS Should Not Be Measured as Often. PMID- 30026379 TI - Effective Metabolic Approaches for the Energy Starved Failing Heart: Bioenergetic Resiliency via Redundancy or Something Else? PMID- 30026380 TI - Mouse Models of Cardiac Arrhythmias. PMID- 30026381 TI - Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer. AB - With rising incidence rates, endometrial cancer is one of the most common gynecologic malignancies in the United States. Although surgery provides significant survival benefit to early-stage patients, those with advanced or recurrent metastatic disease have a dismal prognosis. Limited treatment options include chemotherapy and radiotherapy. Hence, there is a compelling need for developing molecularly targeted therapy. Here, we show that the polycomb ring finger protein BMI1, also known as a stem cell factor, is significantly overexpressed in endometrial cancer cell lines, endometrial cancer patient tissues as well as in nonendometrioid histologies and associated with poor overall survival. PTC-028, a second-generation inhibitor of BMI1 function, decreases invasion of endometrial cancer cells and potentiates caspase-dependent apoptosis, while normal cells with minimal expression of BMI1 remain unaffected. In an aggressive uterine carcinosarcoma xenograft model, single-agent PTC-028 significantly delayed tumor growth and increased tumor doubling time compared with the standard carboplatin/paclitaxel therapy. Therefore, anti-BMI1 strategies may represent a promising targeted approach in patients with advanced or recurrent endometrial cancer, a population where treatment options are limited. Mol Cancer Ther; 17(10); 2136-43. (c)2018 AACR. PMID- 30026383 TI - Application of Reduced-FOV Diffusion-Weighted Imaging in Evaluation of Normal Pituitary Glands and Pituitary Macroadenomas. AB - BACKGROUND AND PURPOSE: FOV optimized and constrained undistorted single-shot imaging provides relatively high-resolution images with few artifacts. This study evaluated the image quality and value of FOV optimized and constrained undistorted single-shot DWI in the evaluation of normal pituitary glands and pituitary macroadenomas. MATERIALS AND METHODS: Subjects with normal pituitary glands and patients with pituitary macroadenomas underwent FOV optimized and constrained undistorted single-shot and EPI DWI. Two neuroradiologists graded the image quality based on visualization of the pituitary stalk, pituitary gland, and pituitary macroadenoma. Intra- and interobserver agreements were assessed by kappa statistics. Image quality and ADCs were compared between the 2 methods by the paired Wilcoxon signed rank test and t test. Differences in ADC between normal pituitary glands and macroadenomas were analyzed by the independent samples t test. RESULTS: Twenty-eight subjects with normal pituitary glands and 16 patients with macroadenomas were enrolled. Intra- and interobserver agreements for image-quality assessment were moderate to substantial. Relative to EPI DWI, FOV optimized and constrained undistorted single-shot DWI exhibited obviously better image quality both in normal pituitary glands and macroadenomas. There was no significant difference in ADCs of macroadenomas between the 2 methods. Macroadenomas with soft consistency (0.75 +/- 0.14 * 10-3 mm2/s) had significantly lower mean ADC than normal pituitary glands (1.18 +/- 0.19 * 10-3 mm2/s; P < .001). CONCLUSIONS: FOV optimized and constrained undistorted single shot DWI helps acquire high-resolution images of normal pituitary glands and pituitary macroadenomas with relatively few susceptibility artifacts in a clinically feasible scan time. This sequence might be helpful for evaluating the consistency of pituitary macroadenomas. PMID- 30026384 TI - Clinical Value of Vascular Permeability Estimates Using Dynamic Susceptibility Contrast MRI: Improved Diagnostic Performance in Distinguishing Hypervascular Primary CNS Lymphoma from Glioblastoma. AB - BACKGROUND AND PURPOSE: A small subset of primary central nervous system lymphomas exhibits high cerebral blood volume, which is indistinguishable from that in glioblastoma on dynamic susceptibility contrast MR imaging. Our study aimed to test whether estimates of combined perfusion and vascular permeability metrics derived from DSC-MR imaging can improve the diagnostic performance in differentiating hypervascular primary central nervous system lymphoma from glioblastoma. MATERIALS AND METHODS: A total of 119 patients (with 30 primary central nervous system lymphomas and 89 glioblastomas) exhibited hypervascular foci using the reference method of leakage-corrected CBV (reference-normalized CBV). An alternative postprocessing method used the tissue residue function to calculate vascular permeability (extraction fraction), leakage-corrected CBV, cerebral blood flow, and mean transit time. Parameters were compared using Mann Whitney U tests, and the diagnostic performance to distinguish primary central nervous system lymphoma from glioblastoma was calculated using the area under the curve from the receiver operating characteristic curve and was cross-validated with bootstrapping. RESULTS: Hypervascular primary central nervous system lymphoma showed similar leakage-corrected normalized CBV and leakage-corrected CBV compared with glioblastoma (P > .05); however, primary central nervous system lymphoma exhibited a significantly higher extraction fraction (P < .001) and CBF (P = .01) and shorter MTT (P < .001) than glioblastoma. The extraction fraction showed the highest diagnostic performance (the area under the receiver operating characteristic curve [AUC], 0.78; 95% confidence interval, 0.69-0.85) for distinguishing hypervascular primary central nervous system lymphoma from glioblastoma, with a significantly higher performance than both CBV (AUC, 0.53 0.59, largest P = .02) and CBF (AUC, 0.72) and MTT (AUC, 0.71). CONCLUSIONS: Estimation of vascular permeability with DSC-MR imaging further characterizes hypervascular primary central nervous system lymphoma and improves diagnostic performance in glioblastoma differentiation. PMID- 30026382 TI - Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms. AB - Antiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30 mg/kg daily versus regorafenib 10 mg/kg daily for a maximum of 28 days in 10 PDX mouse models. In vivo angiogenesis and glucose uptake were assessed using dynamic contrast-enhanced (DCE)-MRI and [18F]-FDG-PET imaging, respectively. RNA-Seq, RTK assay, and immunoblotting analysis were used to evaluate gene pathway regulation in vivo and in vitro Analysis of TGII demonstrated significant antitumor effects with cabozantinib compared with regorafenib (average TGII 3.202 vs. 48.48, respectively; P = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared with baseline. Gene pathway analysis showed that cabozantinib significantly decreased protein activity involved in glycolysis and upregulated proteins involved in autophagy compared with control, whereas regorafenib did not. The combination of two separate antiautophagy agents, SBI 0206965 and chloroquine, plus cabozantinib increased apoptosis in vitro Cabozantinib demonstrated significant antitumor activity, reduction in tumor vascularity, increased autophagy, and altered cell metabolism compared with regorafenib. Our findings support further evaluation of cabozantinib and combinational approaches targeting autophagy in colorectal cancer. Mol Cancer Ther; 17(10); 2112-22. (c)2018 AACR. PMID- 30026385 TI - The Bone Does Not Predict the Brain in Sturge-Weber Syndrome. AB - BACKGROUND AND PURPOSE: It has been hypothesized that skull marrow signal alteration may represent an early disease manifestation of Sturge-Weber syndrome before development of its intracranial manifestations. We alternatively hypothesized that intraosseous changes are associated with the overlying port wine stain rather than the intracranial stigmata of Sturge-Weber syndrome and hence are not a predictor of brain involvement. MATERIALS AND METHODS: MR imaging of children presenting with port-wine stain and/or Sturge-Weber syndrome between 1998 and 2017 was evaluated by 2 pediatric neuroradiologists for marrow signal abnormality and pial angioma and other Sturge-Weber syndrome features: ocular hemangioma, atrophy, and white matter changes (advanced myelination). Groups were divided into port-wine stain-only (without intracranial Sturge-Weber syndrome features) and Sturge-Weber syndrome (the presence of cerebral pial angioma). The chi2 test was performed to evaluate the association between port-wine stain and bone marrow changes and between osseous change and pial angioma. RESULTS: We reviewed 139 cases: 40 with port-wine stain-only and 99 with Sturge-Weber syndrome with pial angioma. Fifteen of 99 cases of Sturge-Weber syndrome had no port-wine stain. In the port-wine stain-only cohort, 78% had ipsilateral bony changes and 17% had no intraosseous changes. In the Sturge-Weber syndrome cohort, 84/99 had associated port-wine stain, 91% (P < .01) had bony changes ipsilateral to the port-wine stain or had no bone changes in the absence of port-wine stain, and 77% (P = .27) had bony changes ipsilateral to a cerebral pial angioma. Eighty percent of patients with Sturge-Weber syndrome who lacked a port-wine stain also lacked marrow changes. Five patients with bilateral port-wine stain and bilateral marrow changes had only a unilateral pial angioma. CONCLUSIONS: Intraosseous marrow changes are strongly associated with facial port-wine stain; no significant association was found between pial angioma and bone marrow changes. PMID- 30026387 TI - Seven days in medicine: 11-17 July. PMID- 30026386 TI - Vessel Wall Enhancement in Unruptured Intracranial Aneurysms: An Indicator for Higher Risk of Rupture? High-Resolution MR Imaging and Correlated Histologic Findings. AB - BACKGROUND AND PURPOSE: Recent studies have suggested that wall enhancement of unruptured intracranial aneurysms in high-resolution MR imaging might serve as an imaging biomarker for higher risk of rupture. Histologic studies have revealed a possible association among inflammatory processes, degeneration, and destabilization of the aneurysm wall preceding rupture. Understanding the histologic condition underlying aneurysm wall enhancement could be an important step toward assessing the value of this method for risk stratification. We present our observations of aneurysm wall enhancement in MR vessel wall imaging and underlying histologic changes. MATERIALS AND METHODS: We reviewed records of patients with an unruptured middle cerebral artery aneurysm who underwent MR vessel wall imaging before aneurysm clipping. Contrast enhancement of the aneurysm wall was dichotomized into either none/faint or strong. Histologic analysis included myeloperoxidase stain for detection of inflammatory cell invasion and CD34 stain for assessment of neovascularization and vasa vasorum. RESULTS: Thirteen aneurysms were included. Five aneurysms showed strong wall enhancement. Among these, myeloperoxidase staining revealed inflammatory cell infiltration in 4. Three showed neovascularization. In 2 aneurysms, vasa vasorum were present. Seven aneurysms did not show wall enhancement; 1 had only mild enhancement. None of these bore evidence of inflammatory cell invasion or neovascularization, and they all lacked vasa vasorum. CONCLUSIONS: Wall enhancement in MR vessel wall imaging is associated with inflammatory cell invasion, neovascularization, and the presence of vasa vasorum. Enhancement does not occur when histologic signs of inflammation are absent. Our results support the hypothesis that MR vessel wall imaging could provide valuable information for risk stratification. PMID- 30026388 TI - Exome sequencing of an adolescent with nonalcoholic fatty liver disease identifies a clinically actionable case of Wilson disease. AB - Diagnostic whole-exome sequencing has proven highly successful in a range of rare diseases, particularly early-onset genetic conditions. In more common conditions, however, exome sequencing for diagnostic purposes remains the exception. Here we describe a patient initially diagnosed with a common, complex liver disease, nonalcoholic fatty liver disease (NAFLD), who was determined to have Wilson disease (WD) upon research-related exome sequencing. The patient presented as a 14.5-yr-old adolescent with chronically elevated aminotransferases, normal ceruloplasmin, and histologic examination consistent with NAFLD with advanced fibrosis. He was enrolled in a large longitudinal study of patients with NAFLD and was found to have WD by exome sequencing performed 4 yr later. This new diagnosis, confirmed clinically by 24 h urine copper quantification, led to a change in the therapy from lifestyle counseling to directed treatment with d penicillamine, a copper chelating agent. In this case, the likelihood of making the correct diagnosis and thereby choosing the appropriate treatment was increased by exome sequencing and careful interpretation. This example illustrates the utility of exome sequencing diagnostically in more common conditions not currently considered as targets for genome-wide evaluation and adds to a growing body of evidence that patients diagnosed with more common conditions often in fact have rarer genetically determined syndromes that have escaped clinical detection. PMID- 30026390 TI - Our Part in the Evolution of Correctional Mental Health Care. PMID- 30026389 TI - Gut-brain axis biochemical signalling from the gastrointestinal tract to the central nervous system: gut dysbiosis and altered brain function. AB - BACKGROUND: The gut-brain axis facilitates a critical bidirectional link and communication between the brain and the gut. Recent studies have highlighted the significance of interactions in the gut-brain axis, with a particular focus on intestinal functions, the nervous system and the brain. Furthermore, researchers have examined the effects of the gut microbiome on mental health and psychiatric well-being.The present study reviewed published evidence to explore the concept of the gut-brain axis. AIMS: This systematic review investigated the relationship between human brain function and the gut-brain axis. METHODS: To achieve these objectives, peer-reviewed articles on the gut-brain axis were identified in various electronic databases, including PubMed, MEDLINE, CIHAHL, Web of Science and PsycINFO. RESULTS: Data obtained from previous studies showed that the gut brain axis links various peripheral intestinal functions to brain centres through a broad range of processes and pathways, such as endocrine signalling and immune system activation. Researchers have found that the vagus nerve drives bidirectional communication between the various systems in the gut-brain axis. In humans, the signals are transmitted from the liminal environment to the central nervous system. CONCLUSIONS: The communication that occurs in the gut-brain axis can alter brain function and trigger various psychiatric conditions, such as schizophrenia and depression. Thus, elucidation of the gut-brain axis is critical for the management of certain psychiatric and mental disorders. PMID- 30026391 TI - Legislative Advocacy and Forensic Psychiatry Training. AB - Very few residency and fellowship programs offer mandatory or elective rotations in health advocacy. Where there are formal training opportunities, they are commonly didactic or clinical community rotations, where trainees participate in a clinically oriented project with a local community organization. Fewer programs offer specific training opportunities in legislative advocacy and the legislative process. The University of Washington assembled two task forces to advise the general psychiatry residency program on training needs in the areas of (1) Forensic Psychiatry and (2) Advocacy and Public Policy. Both task forces identified, as an aspirational goal, resident involvement in legislative and regulatory processes as means of advocacy. This article describes a model curriculum in legislation developed at the University of Washington that is suitable for trainees at different stages in their professional development (including residents and fellows), and an explanation of how the curriculum supports training in forensic psychiatry. Challenges in creating the elective training opportunity are also discussed. PMID- 30026392 TI - Role of Forensic Psychiatry in Legislative Advocacy. AB - Dr. Piel presents a model curriculum for elective legislative advocacy training of general psychiatry residents at the University of Washington. In this commentary, we discuss the role of the physician as a leader in legislative advocacy and emphasize the need for training in this neglected arena. We highlight the common ground between legislative advocacy and forensic psychiatry and make a case for increased involvement of forensic psychiatrists. PMID- 30026393 TI - Evaluations of Urban Sovereign Citizens' Competency to Stand Trial. AB - There are few studies of sovereign citizens undergoing competency-to-stand-trial evaluations and little has been written about African-American or urban sovereign citizens. In this study, we examined competency-to-stand-trial reports of 36 New York City defendants who declared themselves to be sovereign citizens during their evaluations. All were men and 33 were African American. The majority denied recent or remote histories of psychiatric hospitalizations or substance use. Sixty-nine percent were deemed competent. Compared with those deemed competent, those deemed not competent were significantly more likely to have diagnosed psychotic disorders and to have reported histories of psychiatric hospitalizations. The 36 who declared themselves sovereign citizens were compared with 200 who did not, from a study conducted in the same forensic clinic. The sovereign citizens were significantly more likely to be male, African American, and high school graduates and were significantly less likely to report a history of psychiatric hospitalization or substance use. Compared with the nonsovereign citizens, they were less likely to receive a diagnosis of psychotic or mood disorders during the competency evaluation and were more likely to be deemed competent. Included are suggestions to assist forensic examiners conducting evaluations of these difficult cases. PMID- 30026394 TI - Sovereign Citizens and Competency to Stand Trial. AB - Urban and African-American sovereign citizens represent an underappreciated population of the sovereign citizen movement, who have adapted sovereign citizen beliefs to their own circumstances, overlooking the white supremacist origins of the sovereign citizen movement. The number of African-American sovereign citizens is not known, but though they appear to represent a very small percentage of criminal defendants referred for evaluation of competence to stand trial, they have a disproportionate impact on the court system because of their efforts to stymie the proceedings by asserting sovereign citizen beliefs. As a result, judges are often familiar with sovereign citizen beliefs and have adopted strategies to thwart the impact of sovereign citizens on their courts. Quantitative research on forensic evaluations of sovereign citizens, from all demographic groups, represents a challenge, given the low number of defendants referred for evaluation, but qualitative research on how they came to adopt sovereign citizen beliefs could be fruitful. PMID- 30026395 TI - Female Residents with Psychopathy in a High-Security Italian Hospital. AB - Before its closure on April 1, 2015, the Castiglione delle Stiviere was the only maximum-security hospital in Italy that admitted women. In this context, the investigators examined factors related to psychopathy that were thought to be gender specific. Several prior investigations have reported a significant correlation between psychopathy and borderline personality disorder, a disorder thought to represent the phenotypical expression of psychopathy in women. The purpose of this research was to identify psychopathological and phenotypical gender-specific factors that are associated with psychopathy in women. The data appear consistent with that found in the recent international literature and also highlight the different phenotypical manifestation of psychopathy in the two genders. Whereas in males psychopathy is associated with antisocial personality disorder, in females psychopathy is associated with borderline personality disorder. PMID- 30026396 TI - Clinical, Social, and Neuropsychological Dimensions of the Intersection of Addiction and Criminality. AB - To examine the social cognitive processes underlying the relationship of addiction and criminality, we administered the Addiction Severity Index-CF (ASI CF) and the Iowa Gambling Task (IGT) to 35 participants (11 women) who had been released recently from jail or prison. ASI-CF revealed highest lifetime drug use for alcohol, followed by cannabis, cocaine, and heroin, with an average of 42 lifetime arrests in this ex-offender sample. The men and the women showed similar psychiatric histories marked by depression and anxiety, but the women had more lifetime problems with thinking than did the men, who had higher lifetime problems with hallucinations. On the IGT, participants showed evidence of reward learning across the initial three blocks of 20 trials, but their performance declined over the last 40 trials, suggesting a failure to sustain gains: that is, to learn from feedback in deciding among advantageous and disadvantageous decks of cards. These deficits in motivated decision-making were moderated by current social and psychological factors, as assessed by ASI-CF. These results are discussed in regard to how disturbances in social cognitive processes may underlie the relationship of addiction and criminality. PMID- 30026397 TI - Evaluation of Outcomes for a Skilled Nursing Facility for Persons Who are Difficult to Place. AB - Individuals with serious mental illness, prisoners, and ex-offenders needing skilled nursing facility (SNF)-level care are difficult to place in traditional SNFs. SNFs accepting these historically marginalized individuals may offer them a more appropriate level of care. We compared health services use (emergency room (ER) visits, acute hospitalizations), total number of antipsychotic medications prescribed, and quality-of-life indicators (depressive symptoms, cognition, resident behaviors), before and after admission, among 86 individuals admitted to a Connecticut SNF for persons difficult to place. Residents were racially diverse, primarily male (89%), and 58.4 (+/-12.5) years of age; 56 percent were transferred from state psychiatric facilities. Twelve-month hospitalization rates decreased from 36.5 to 10.6 percent, 27 percent of those taking an antipsychotic medication at admission experienced a reduction in total number of antipsychotics prescribed by six months, and 13 residents transitioned into the community. Quality-of-life indicators did not change between admission and first quarterly assessment. A SNF for persons difficult to place may help prevent hospitalizations, optimize antipsychotic medication use, and serve as an intermediate step into the community. These findings may inform development of an evidence-based model for establishing SNFs in other states for persons who are difficult to place. PMID- 30026398 TI - Response to Disclosure as an Indicator of Competence to Stand Trial. AB - Ethics guidelines recommend that forensic mental health professionals begin in person assessments by explaining the nature and purpose of the examination. To learn whether evaluees have understood and can give consent, forensic practitioners may ask evaluees to paraphrase the explanation. This article explores how a forensic evaluee's disclosure response (DR) reveals substantive information relevant to the purposes of a forensic examination. We examined archival data from 255 reports on competence to stand trial (CST) that a Midwest public sector hospital had previously submitted to courts. We classified each evaluee's DR at one of three levels: DR = yes (accurate paraphrasing), DR = no (inability to paraphrase or provide a relevant response), or DR = other (an intermediate level implying a less-than-accurate response). None of the 28 DR = no evaluees was CST, and only 7 (17%) of the 48 DR = other evaluees were CST. Thus, a CST evaluee who cannot paraphrase an examiner's explanation is likely to be incompetent to stand trial, and an examiner would need to adduce a strong argument to support any opinion to the contrary. PMID- 30026399 TI - Current Regulation of Mobile Mental Health Applications. AB - In recent years, the availability of software that is targeted toward the general public and designed to assist in the diagnosis and treatment of mental illness or to promote general mental health has expanded greatly. Regulation of more traditional health care providers and health care-associated devices is well established by statute, regulatory guidelines, and common law precedents. Applications (apps), in contrast, pose a novel regulatory challenge. This review examines the current regulatory guidelines for psychiatric mobile mental health apps, as well as the current state of case law in the psychiatric mobile mental health realm. PMID- 30026400 TI - The Journey to Find My Grandfather. PMID- 30026401 TI - Involuntary Treatment of Psychosis in Pregnancy. AB - When a patient with acute psychosis refuses antipsychotic medication despite a clear need for treatment, involuntary medication is often considered. When the patient is both pregnant and acutely unwell, an additional layer of analysis enters the picture. This analysis then also includes the health of the mother and fetus, rights of the mother and fetus, and whose rights take precedence when choosing treatment options in event of a conflict. Antipsychotic agents are frequently the medications prescribed as involuntary treatment. Typical and atypical antipsychotic agents are often used in both emergent and nonemergent situations during pregnancy. Despite a lack of randomized, double-blind, controlled, prospective studies in pregnancy, available data regarding the safety of antipsychotic agents in pregnancy are relatively reassuring. At the same time, the risks of untreated psychosis, for both the mother and the fetus, are not negligible. Such cases merit ethics-related and legal analyses. Forensic psychiatrists involved in such cases need to consider the patient's capacity to make medical decisions and be able to discuss the potential risks, benefits, and alternatives with patients and in court, as part of initiation of involuntary treatment. PMID- 30026402 TI - Internet Access for Patients on Psychiatric Units. AB - Millions of Americans rely on Internet access to fulfill everyday needs, yet psychiatric units frequently restrict patients from going online. This article reviews the evolution of legal rights for hospitalized psychiatric patients in the United States over the past 50 years and argues that legal oversight of psychiatric hospitalization has not kept pace with the rise of digital technology. As a result of this discrepancy, Internet access on inpatient psychiatry remains controversial and often varies by institution. This article examines literature on Internet use by psychiatric patients, as well as recent court cases relevant to this topic. Finally, this article addresses clinical considerations surrounding Internet access for psychiatric inpatients and provides recommendations for the development of Internet policies in inpatient psychiatric settings. PMID- 30026403 TI - The Transgender Bathroom Debate at the Intersection of Politics, Law, Ethics, and Science. AB - The debate over whether transgender individuals should be allowed to use the public restrooms (including locker rooms and changing rooms) that correspond to their currently expressed gender rather than their biological sex has been of recent interest nationally. The first state law addressing transgender access to restrooms was in North Carolina in 2016. This law prohibited transgender individuals from using the restroom that corresponded to their gender. The terms used in the bill and other legal documents caused it to be referred to as the "bathroom bill." Shortly thereafter, such bills were proposed in many states. Proponents of the bills identify the need to protect public safety by mandating that individuals use the facility that corresponds to their biological sex. Opponents describe such bills as discriminatory. The debate about these bills incorporates ethics-related, legal, and biological arguments. In this commentary, we review the history of such bills in the United States as well as the ethics related, legal, and evidence-based arguments raised in the debate. PMID- 30026404 TI - The American Academy of Psychiatry and the Law Practice Resource for Prescribing in Corrections. AB - The practice of prescribing in jails and prisons is often different from that in the community. Serious mental illness is common among inmates, and so are co morbidities such as substance use, impulse-control, attention deficit/hyperactivity, and personality disorders. Operational requirements, staffing, and the physical plant of the institution may complicate the provision of treatment according to community standards. Problems related to medication nonadherence, as well as the pursuit of medications for nonmedical reasons, are often seen in these settings and may be managed differently than they are elsewhere. Existing practice resources rarely account for these challenges. Pursuant to a recommendation by the Correctional Committee of the American Academy of Psychiatry and the Law (AAPL), the AAPL Council in May 2015 approved the creation of a task force charged with producing a document on prescribing in correctional facilities.Full Document: Tamburello A, Metzner J, Ferguson E, et al: AAPL practice resource for prescribing in corrections. Journal of the American Academy of Psychiatry and the Law Online Supplement 2018, 46 (2). Available at: http://www.jaapl.org/content/46/2_Supplement. PMID- 30026405 TI - Global quantitative TPA-based proteomics of mouse brain structures reveals significant alterations in expression of proteins involved in neuronal plasticity during aging. AB - Aging is believed to be the result of alterations of protein expression and accumulation of changes in biomolecules. Although there are numerous reports demonstrating changes in protein expression in brain during aging, only few of them describe global changes at the protein level. Here, we present the deepest quantitative proteomic analysis of three brain regions, hippocampus, cortex and cerebellum, in mice aged 1 or 12 months, using the total protein approach technique. In all the brain regions, both in young and middle-aged animals, we quantitatively measured over 5,200 proteins. We found that although the total protein expression in middle-aged brain structures is practically unaffected by aging, there are significant differences between young and middle-aged mice in the expression of some receptors and signaling cascade proteins proven to be significant for learning and memory formation. Our analysis demonstrates that the hippocampus is the most variable structure during natural aging and that the first symptoms of weakening of neuronal plasticity may be observed on protein level in middle-aged animals. PMID- 30026407 TI - Small-diameter vascular graft using co-electrospun composite PCL/PU nanofibers. AB - Small-diameter vascular scaffolds have been developed by a co-electrospinning method using polyethylene terephthalate (PCL) and elastic polytetrafluoroethylene (PU) as biopolymers with long degradation time. Although they possess favorable properties, individually these two polymers do not meet the requirements for the production of synthetic vascular scaffolds. The co-electrospinning method was adopted to develop and mechanically improve the composite PCL/PU vascular scaffolds. The morphological, mechanical and biological properties of these vascular scaffolds were evaluated through scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, compliance, tensile testing and MTT assay. The in vivo study of the vascular scaffolds was performed by implanting them on rat and sheep models. The compliance of the composite vascular scaffolds improved by up to 43% through an increased percentage of PU from 10%-90%. The obtained UTS of the scaffolds at 10%, 25%, 50%, 75% and 90% of PU were 4.7 +/- 0.34, 3.4 +/- 0.6, 4.8 +/- 0.62, 2.2 +/- 0.34 and 4.4 +/- 1.9 MPa, respectively. The results of MTT assays indicated that the cell growth on the scaffolds was augmented when compared to the control, from day one to day seven. Mild edema, mild foreign-body granulomatous reaction and mild fibrosis were observed by pathology test as the side effects in the composite scaffold with 50% PCL. Doppler ultrasound and angiography images confirm that no aneurysm, thrombogenesis, neointimal hyperplasia or occlusion exist, and there is complete patency at the end of an eight month investigation. The fabricated composite vascular scaffolds provide appropriate mechanical and biological properties and clinical requirements, indicating their required potential to be applied as a small-diameter vascular graft. PMID- 30026406 TI - Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2. AB - Cellular senescence is a key driver of ageing, influenced by age-related changes to the regulation of alternative splicing. Hydrogen sulfide (H2S) has similarly been described to influence senescence, but the pathways by which it accomplishes this are unclear.We assessed the effects of the slow release H2S donor Na-GYY4137 (100 ug/ml), and three novel mitochondria-targeted H2S donors AP39, AP123 and RT01 (10 ng/ml) on splicing factor expression, cell proliferation, apoptosis, DNA replication, DNA damage, telomere length and senescence-related secretory complex (SASP) expression in senescent primary human endothelial cells.All H2S donors produced up to a 50% drop in senescent cell load assessed at the biochemical and molecular level. Some changes were noted in the composition of senescence-related secretory complex (SASP); IL8 levels increased by 24% but proliferation was not re-established in the culture as a whole. Telomere length, apoptotic index and the extent of DNA damage were unaffected. Differential effects on splicing factor expression were observed depending on the intracellular targeting of the H2S donors. Na-GYY4137 produced a general 1.9 - 3.2-fold upregulation of splicing factor expression, whereas the mitochondria-targeted donors produced a specific 2.5 and 3.1-fold upregulation of SRSF2 and HNRNPD splicing factors only. Knockdown of SRSF2 or HNRNPD genes in treated cells rendered the cells non responsive to H2S, and increased levels of senescence by up to 25% in untreated cells.Our data suggest that SRSF2 and HNRNPD may be implicated in endothelial cell senescence, and can be targeted by exogenous H2S. These molecules may have potential as moderators of splicing factor expression and senescence phenotypes. PMID- 30026408 TI - [Clinical Practice of Carcinoma of Unknown Primary]. AB - Carcinoma of unknown primary(CUP)is defined as the presence of metastatic cancer documented in the absence of an identifiable primary tumor site. According to this definition, between 1% and 5% of cancer patients are diagnosed with this clinical entity. CUPs are a heterogeneous group of neoplasms with widely varying natural histories and biologic characteristics. In this broad category, there are 5 major diagnoses, as assessed by light microscopy: (1)poorly differentiated neoplasm,(2) well differentiated and moderately differentiated adenocarcinoma,(3)squamous cell carcinoma(4)neuroendocrine tumor, and(5)poorly differentiated carcinoma(with or without features of adenocarcinoma) .It has been reported that the prognosis of patients with CUP is poor. The median survival time(MST)is 6 to 9 months, and less than 25% of the CUP patients are alive 1 year after diagnosis. Previous trials with a variety of chemotherapeutic regimens have produced response rates of less than 50% with negligible benefit in terms of median survival. Platinum -containing regimens have induced higher response rates than those without it in patients with CUP, and platinum is considered a key drug in UPC treatment. PMID- 30026409 TI - [Possibility of Metabolite Biomarkers for Early Detection of Cancer]. AB - Recently, the omics analysis, which comprehensively analyzed the biological molecules such as DNA, RNA, protein and low molecular weight metabolites, has been developed. The metabolome analysis that comprehensively analyzes low molecular weight metabolites is one of the most recent omics analysis, and attracts rising attention. Evaluating the metabolite alterations and clarifying the metabolite profiles in the body will lead to understandings of biological information, and the metabolome analysis has the potential of elucidation of novel pathological conditions and discovery of metabolite biomarkers. In this article, we explain the characteristics of the omics analysis. Regarding the metabolome analysis, its detailed explanations are carried out, and we also introduce our metabolite biomarker research about pancreatic cancer using the metabolome analysis. PMID- 30026410 TI - [MicroRNA in Body Fluids - Development of the Novel Plat Form for Cancer Therapeutics and Diagnosis]. AB - MicroRNAs(miRNAs)are small non-coding RNAs that function in diverse biological processes and are approximately 20-22 nucleotide RNAs that regulate the expression of target genes, mainly at the post-transcriptional level. A number of studies report that miRNAs are involved in homeostatic maintenance such as cell cycle regulation, cell division and apoptosis, and that aberrant expression of miRNAs is often detected in various types of diseases, including cancer. In cancer biology, miRNAs play functional roles in tumor seeding, drug sensitivity, and metastasis. MiRNAs are also secreted through the small vesicles called exosomes, which are endosome-derived vesicles from various cell types including immune and tumor cells. In addition to cellular miRNAs, secreted miRNAs also play important roles in cancer development and metastasis. Therefore, secreted miRNAs in body fluids have been investigated as a promising biomarkers and therapeutic targets for the treatment of cancer patients. In this review, we introduce the current knowledge of miRNA functions in cancer development and discuss the clinical applications of se-miRNAs, eg, as diagnostic markers and therapeutic targets. PMID- 30026411 TI - [Analysis of Fecal Cancer-Specific DNA to Detect Colorectal Neoplasia]. AB - To screen colorectal cancers, fecal occult blood test(FOBT), conducted to detect occult blood present in the feces, has been shown to reduce colorectal cancer mortality in many large-scale colorectal cancer screening programs. However, the sensitivities of FOBT for early-stage colon cancer, colon cancer located at the right colon and colorectal adenoma tend to be low. Additionally, some colorectal cancers which could not detect by repeated FOBT screening are actually existed. Beyond those disadvantages, FOBT is the most promised colorectal cancer screening tool for large-scale cohort. To overcome the weak points of FOBT to screen colorectal tumors, the strategy for capturing and recovering tumor-derived DNA in feces has been developed and applied for clinical usage. In this study, we summarized the series of strategies for capturing and recovering fecal tumor derived DNA to screen colorectal neoplasia. PMID- 30026412 TI - [Research of the Cancer-Odor]. AB - Early detection and resection of cancer is the most effective in the treatment of solid cancer. Development of a new cancer detection method is expected to become a breakthrough to solve various problems for early detection. It has been reported that there is the specific odors of cancer by using bio olfaction such as dogs, and it has been recognized that there is the odors of cancer. Cancer cells acquire malignant traits as a result of metabolic changes originating from genetic mutation. The cancer specific odorous substances may be considered to be the end products of their metabolic changes. Omics researches such as genomics, proteomics, and metabolomics have been extensively performed to comprehensively analyze changes in DNA, RNA, protein, metabolism and its products specific to cancer for the purpose of developing a new cancer detection marker. It is thought that the research on the odor of cancer is also on the line of omics research. It is difficult to identify cancer-specific odorants buried in various environmental substances. However, it is expected that human will be able to acquire the technology, from the fact that they can be recognized by biological olfaction. We are continuing the research with the dream that identification of the odorous substances as a new cancer detection marker and sensor development for it will lead to the happiness of colleagues in the world. PMID- 30026413 TI - [Early Diagnosis of Cancer Using Nematoda C. elegans]. AB - Cancer is the leading cause of death in Japan, and one in two people experience cancer in their lifetime. Early diagnosis of cancer is the most important for increasing survival rate of cancer, which is also expected to contribute to decrease budget impact of cancer, but participation rate of cancer screening is still low in Japan. Currently, people need to take multiple examinations to detect different types of cancer, which increases the cost, time and pain burdens for the examinees. Therefore, it is desirable to develop cheaper, non-invasive, as well as sensitive cancer screening methods that can detect multiple types of cancer at the same time. Most of the existing cancer screening tests including imaging diagnosis depend on artificial devices, which usually require high cost to achieve high sensitivity. We have developed a new technique, N-NOSE, which takes advantage of the good olfaction of nematode C. elegans to detect cancer smell in urine samples. N-NOSEexhibited 95.8% sensitivity and 95.0% specificity on 242 urine samples of 10 cancers types tested including those of early stages. C. elegans is easy to be maintained in a laboratory with low cost. In addition, as C. elegans is a hermaphroditic organism with homogeneous genetic background, they show stable and reproducible behavioral results. Therefore, N-NOSEis expected to offer a reasonable and non-invasive cancer screening method which is suitable for regular health checkup. PMID- 30026414 TI - [Central Nervous System Tumor Additional Therapies for Gliomas]. PMID- 30026415 TI - [I. Cyberknife Stereotactic-Radiotherapy for Gliomas]. PMID- 30026416 TI - [II. Treatment of Glioblastoma with Alternating Electric Fields]. PMID- 30026417 TI - [III. Photodynamic Therapy for Malignant Glioma]. PMID- 30026418 TI - [IV. How Do We Think about Generics of Anti-Cancer Agent - Focusing on Temozolomide Oral Preparation]. PMID- 30026419 TI - [Survey of Anticancer Drug Exposure to Attendant Families in Pediatric Medical Centers]. AB - The occupational exposure to hazardous drugs(HD)has already been investigated; however, the actual exposure of the attendant family members of patients with childhood cancer has remained unknown. Here, we analyzed cyclophosphamide (CPM)exposure in attendant family members and the environment after the administration of CPM to patients with pediatric cancer. CPM of 320(8.39-1,510)ng from infant-families and 0(0-58.4)ng from adolescent-families were detected(p= 0.01). The exposure of infant-families was significantly greater than those of adolescent-families. In addition, CPM were detected in the hot water after bathing the infant, underwear, and sheets. We elucidated that the exposures take place through body fluid and excretions of the children. In the field of childhood cancer, HD exposure measures should be taken according to the age of the child to minimize health damage to medical personnel, family members, and other children who share the room. Nurses are recommended to educate the patients and their family members about preventing exposure to HD in pediatric medical centers. PMID- 30026420 TI - [Experience of Fulvestrant for Hormone Receptor-Positive HER2-Negative Advanced and Metastatic Breast Cancer]. AB - Several cases of hormone receptor-positive HER2-negative advanced and recurrent breast cancer treated with fulvestrant (FUL)were retrospectively investigated to assess the efficacy and safety of the treatment. FUL was administered to a total of 41 patients-33 with recurrent and 8 with Stage IV cancer-from January 2012 to September 2016. The median number of lines that used FUL was 3, the median time to treatment failure(TTF)was 7 months, the overall response rate(RR)was 19.5%, and the clinical benefit rate(CBR)was 53.6%. Our result was similar to those of the FIRST and the FALCON studies, which showed a decrease in RR after the fourth line. With regard to RR, FUL seemed to provide better results at Cthird-lines of treatment. While a shorter TTF was seen in the cases with liver metastases, a longer TTF was seen in the cases with soft tissue metastases. Therefore, it may be helpful to consider the site of metastasis when predicting the effects of FUL. PMID- 30026421 TI - [Analysis of the Patient Factors in the Difference between Adverse Effect Evaluation and Distress Evaluation in Cancer Patients Receiving Chemotherapy]. AB - A safety evaluation of chemotherapy is performed by CTCAE. It is the evaluation by health care workers, and distress evaluation by patient himself is not included in it. Therefore, a health care worker underestimates patients' distress. This study was carried out to identify the patients' characteristics underlying differences between safety evaluation and distress evaluation. The patients who met the criteria were 72 in number. They were divided into 2 groups. Group A(17 patients)included patients who demonstrated difference between safety evaluation and distress evaluation. Group B(55 patients)included patient who did not show difference between safety evaluation and distress evaluation. The patients who visited a hospital were evaluated for QOL, depression screening, CTCAE(safety evaluation), and PRO-CTCAE(distress evaluation). A meaningful difference was observed between depression screening, QOL-ACD(physical status, psychological status, face scale, and total), and the number of items of side effect by PRO-CTCAE through a univariate analysis. A meaningful difference was observed for QOL-ACD(physical)in logistic regression analysis(odds ratio=1.47, p=0.013). It is suggested that having physical distress reflected by the QOL evaluation before chemotherapy results in the difference between safety evaluation and distress evaluation. PMID- 30026422 TI - [Impact of Physician Order Support Duties on de novo Hepatitis Prevention]. AB - "Immunosuppression and hepatitis B measures and guidelines for chemotherapy" were announced in 2009. However, a fulminant case that appeared when the guidelines were not observed was reported, and de novo hepatitis prevention is an urgent problem. The rate of compliance with these guidelines as of January 2014 was 20.4%, but this rose to 34.3%after the alert indication for de novo hepatitis prevention was set on an electronic chart system from June 2014. The rate of compliance increased to 63.9% at a hospital where de novo hepatitis alerts were put on clinical cards in April 2015, but it gradually decreased thereafter. HBV DNA measurement was 100% in compliance with the guidelines from August 2016 when HB antigen, HB antibody, and anti-hepatitis B core antigen measurements were all performed in March 2016 because the pharmacists practiced physician order support duties at that time. This helped to reduce the burden on physicians, and the physician order support duties by the pharmacist were educational. Thus, de novo hepatitis prevention may contribute to safe cancer chemotherapy. PMID- 30026423 TI - [Evaluation of Patient Adherence to Anastrozole Therapy for Breast Cancer]. AB - PURPOSE: There are many reports that describe the effectiveness of aromatase inhibitors as endocrine therapy after breast cancer surgery. However, there are few detailed evaluations of patient adherence to anastrozole(ANA)therapy. Here, we evaluated the adherence to ANA therapy in postoperative patients with primary breast cancer. METHODS: We investigated 102 postoperative patients with primary breast cancer without distant metastasis, who received ANA at JCHO Kyusyu Hospital. We calculated the medication continuation rate and disease-free survival at 5 years from the initiation of medication. The reasons for medication discontinuation and alternative drug therapy after ANA therapy discontinuation were also investigated. Re- sults: The 5-year continuation rate of ANA treatment alone was 79%(81/102). The rate of all patients who continued ANA treatment, including 9 who changed to other drugs, was 88%(90/102). The most frequent ANA discontinuation reasons were progressive disease(8 cases), arthritis(5 cases), and nausea(3 cases). The disease-free survival rate was 92%(94/102), and the overall survival rate was 97%(99/102). CONCLUSION: ANA showed a high continuation rate. Adherence of ANA in postoperative patients with breast cancer was well maintained, even when the treatment was changed to other drugs due to adverse events. PMID- 30026424 TI - [A Case of Advanced Gastric Cancer Treated with Curative Resection after Preoperative Secondary Chemotherapy with Irinotecan after Primary Chemotherapy with Docetaxel, Cisplatin, and S-1]. AB - A 70-year-old man was diagnosed with advanced gastric cancer based on esophagogastroduodenoscopy(EGD). Abdominal computed tomography(CT)showed swelling of the lymph nodes and invasion to the liver and pancreas. The patient was treated using combined docetaxel, cisplatin, and S-1(DCS)chemotherapy. After 2 courses of treatment, the primary tumor and lymph node metastases continued to grow. The patient was treated using secondary chemotherapy with irinotecan (CPT 11). After 1 course of treatment, the primary tumor and regional lymph nodes reduced in size. We performed curative total gastrectomy with D2 lymph node dissection. There has been no recurrence for 15 months after adjuvant chemotherapy with capecitabine and oxaliplatin(CapeOX). Therefore, CPT-11 therapy is a possible option for the management of advanced gastric cancer after DCS therapy. PMID- 30026426 TI - [A Case of Radical Resection after CapeOX Therapy for Locally Advanced Sigmoid Colon Cancer with Anemia and Abscess Formation in a Jehovah's Witness]. AB - The patient-a Jehovah's Witness-was a woman in her 60s, with locally advanced sigmoid colon cancer. She had severe anemia, and a computed tomography scan of her abdomen showed a tumor with abscess formation and perforation that had invaded into the left urinary duct and the left ovary, without distant metastasis. It was difficult to perform curative resections without transfusion; therefore, CapeOX therapy was plannedas the neoadjuvant treatment. After 3 courses of CapeOX therapy, the patient's anemia improved, and the tumor and abscess had shrunk. Subsequently, a sigmoidectomy with D3 lymph node dissection, partial resection of the small intestine, and the left adnexectomy, as a radical surgery, were performed without blood transfusion. In cases of concomitant colon cancer with anemia that are treated with highly invasive surgery, it might be necessary to conduct systematic treatment in order to complete non-transfusion therapy. PMID- 30026425 TI - [Resection of an Advanced Rectal Gastrointestinal Stromal Tumor Following Neoadjuvant Chemotherapy]. AB - A 66-year-old man was referred to our hospital after being diagnosed with a pelvic tumor. A subsequent transperineal biopsy revealed spindle cells with CD34.c-kit(+). An enhanced computed tomography scan showed a giant rectal-derived tumor in the pelvis. The tumor was pressing on the urinary bladder and the prostate, and appeared to invade the posterior wall ofthese organs. The patient was diagnosed with rectal GIST, and neoadjuvant therapy with 400mg/day imatinib was initiated. Three months later, the tumor reduction rate was at 33.6%, and surgery was performed. The operative method applied was pelvic exenteration and ileal conduit, for local R0 resection. The patient has remained recurrence free for 2.5 years since the surgery. PMID- 30026427 TI - [A Case of Rectal Gastrointestinal Stromal Tumor(GIST)Treated with Imatinib Mesylate Neoadjuvant Therapy to Preserve the Anus]. AB - A woman in her 40's who initially presented with anal pain was diagnosed with rectal GIST. A 9 cm tumor extended to near the anus, and curative abdominoperineal tumor resection was required. The patient initially received neoadjuvant therapy with imatinib mesylate. Neoadjuvant chemotherapy for 6 months reduced the tumor to approximately 47% of its original size and permitted anus preserving surgery. The present case suggests that neoadjuvant therapy with imatinib mesylate is useful for large rectal GISTs, from the standpoint of anal function preservation. PMID- 30026428 TI - [A Case of Rectal Cancer and Multiple Liver Metastases Treated Using mFOLFOX and Bevacizumab under Maintenance Dialysis]. AB - A 50s man receiving dialysis for chronic kidney disease due to IgA nephropathy underwent laparoscopic reversal via Hartmann 's procedure for rectal cancer and multiple liver metastases, followed by chemotherapy for the liver metastases. Following a single course of mFOLFOX therapy, bevacizumab was administered for 8 courses, resulting in tumor shrinkage and a decrease in tumor marker levels. The initial doses were 60mg/m2 oxaliplatin and 280(bolus injection)and 1,680mg/m2 (continuous infusion)of 5-FU. Subsequently, these doses were adjusted to be administered every 3 weeks. No serious adverse events other than neutropenia(Grade3 ), anorexia(Grade1 ), and hiccups(Grade1)were noted. PMID- 30026429 TI - [Severe Liver Injury Due to Sinusoidal Obstruction Syndrome Induced by Oxaliplatin in a Patient with Resectable Colorectal Liver Metastases]. AB - A 62-year-old man was diagnosed with liver metastasis of sigmoid colon cancer, which resulted in bowel obstruction. SOX plus bevacizumab therapy was administered to perform hepatectomy, after the artificial anus construction; however, substantial liver dysfunction occurred. Therefore, we only performed primary tumor resection and waited for improvement in liver function. After 2 months, liver function improved and liver metastasis increased. However, another metastasis was not recognized, so hepatectomy was carried out, and R0 resection was performed. The oxaliplatin-induced liver function disorder was reversible; however, preoperative chemotherapy for resectable colorectal liver metastases increases the risk of missing the resection window. It is necessary to carefully examine the tumor type and preoperative liver function. PMID- 30026430 TI - [A Case of Malignant Peritoneal Mesothelioma Treated with Cisplatin and Pemetrexed]. AB - A 65-year-old man was admitted to our hospital complaining of general malaise, anorexia and weight loss. A computed tomography(CT)scan showed massive ascites and multiple peritoneal masses. Although adenocarcinoma was suspected based on the cytology of the ascites, we were unable to determine the site of origin. We next performed a laparoscopy and a biopsy of the tumor on the omentum. The laparoscopy showed small, white, hard nodules that were disseminated throughout the abdominalcavity, and histologicaldiagnosis confirmed malignant peritonealmesothel ioma. The patient was administered chemotherapeutic treatment of cisplatin and pemetrexed. After treatment, the ascites decreased; however, tumor regression was not observed. The patient's performance status gradually decreased, and he died on hospital day 104. Prognosis of malignant peritoneal mesothelioma remains poor, and malignant peritoneal mesothelioma should be considered when diagnosing peritoneal tumors. PMID- 30026431 TI - [A Case of Aggressive Angiomyxoma in a 75-Year-Old Man]. AB - Aggressive angiomyxoma is an uncommon mesenchymal tumor that mostly involves the pelvic and perineal regions in young women.We herein report an extremely rare case of aggressive angiomyxoma in a 75-year-old man. The patient had undergone follow-up for an intraductal papillary mucinous neoplasm.In September 2015, CT detected a tumor measuring 33 mm in diameter around the pelvis, and the tumor showed gradual increase in size.MRI revealed a relatively sharply marginated tumor with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.For treatment and diagnosis, we laparoscopically resected the tumor. Histopathologically, the specimen showed spindle tumor cells within a myxoid background and vascular structures.The tumor was diagnosed as aggressive angiomyxoma, and surgical margins were negative for tumor cells. The patient is currently doing well without any signs of recurrence as of 18 months postoperatively. PMID- 30026432 TI - [A Case of Essential Thrombocythemia with a JAK2V617F Mutation andPolymyalgia Rheumatica]. AB - A patient with polymyalgia rheumatica(PMR)had increasing thrombocytosis. CRP levels, the ESR, and serum interleukin (IL)-6 levels were slightly elevated, and the patient tested negative for RF and anti CCP antibodies. Muscle pain was ameliorated with the administration of corticosteroids. Genetic analysis of the peripheral white blood cells demonstrated the presence of a JAK2V617F mutation. The muscle pain experienced by the patient was considered to be due to essential thrombocythemia( ET)of myeloproliferative neoplasms(MPNs)along with an inflammatory reaction. Unfortunately, the patient died suddenly because of cerebral infarction. PMID- 30026433 TI - [Two Case Reports of Chemotherapy-Induced Radiation Myositis]. AB - Radiation recall is regarded as an acute inflammatory reaction that is triggered by cytotoxic agents within a previously irradiated area, and the most common site is the skin. Gemcitabine-related radiation recall is rare, and most reported cases involving gemcitabine occur in the muscle, unlike those of other chemotherapeutic agents. Here, we report 2 cases of chemotherapy- induced radiation myositis. Combination chemotherapy with gemcitabine and S-1 was performed in both patients after radiation therapy. The irradiation dose to the muscle was quite low compared to the muscle tolerance dose in both cases. To the best of our knowledge, there are no reports on radiation recall with S-1. Therefore, it is unclear whether S-1 is related to myositis in these cases. Although radiation recall with gemcitabine is rare and uncommon, it has the potential to occur in any organ in forms such as myositis or central nervous system necrosis, and careful observation is required for patients who received chemotherapy that includes gemcitabine after radiation therapy. PMID- 30026434 TI - [The Ideal Situation and Problem for Providing of Cancer Information]. AB - More than 60% of cancer patients obtain cancer information from the Internet. However, on the Internet of Japan, there are many inappropriate information about cancer including advertisements for commercial purposes. In search sites, strong Search Engine Optimization are applied, paid advertisements are given priority, and it is difficult for patients without certain medical knowledge to judge whether information is accurate, and patients and families do not receive standard treatment. There is a problem that it is induced to wrong cancer treatment. In order to solve this problem, we believe that multifaceted response in addition to promoting the establishment of a system for creating information by collaboration among medical staff across organizations, promotion of communication between medical professionals and patients, regulation of Internet advertisements of medical institutions by medical law, improvement of the search algorithm on the search site, and improvement of information literacy of the patient are necessary. PMID- 30026435 TI - [Challenges in Healthcare Economics of Today's Cancer Treatment]. AB - Healthcare economics concerns with the way in which to distribute and allocate scarce resources that result in maximized outcome. When the expenditure on cancer medicine was examined using the macro data open to the public, it was found to have increased in parallel with the National Medical Care Expenditure. More specifically, the growth rates of the two showed a similar trend in the five years from 2011 to 2015. However, when looked more closely by excluding the patient share and separating the care settings, the result was different. The expenditure in outpatient care displayed a significant increase, implying the influence of chemotherapy shifting to take place more in the outpatient setting. Current discussion on introducing the concept of cost effectiveness into the fee schedule scheme should be based on multidimensional consideration. PMID- 30026436 TI - [Cost Effectiveness and Health Economics of Immune Checkpoint Inhibitors for Non Small Cell Lung Cancer]. AB - Immune checkpoint inhibitors (ICIs) are available for the treatment of advanced non-small cell lung cancer (NSCLC). ICIs have improved the overall survival of patients with NSCLC; however, their cost effectiveness needs to be evaluated because of the high cost associate with a longer duration of the treatment. Although the cost effectiveness is similar between standard chemotherapy and ICIs in second-line setting, treatment with ICIs in the first-line is expensive. Survival curves have shown a plateau at the tail after treatment with ICIs. These findings suggest that ICIs treatment could result in longer survival or cure, thereby contributing to a reduction in healthcare cost. Currently, there are no definite biomarkers for evaluating cost effectiveness of ICIs, and more reliable biomarkers in addition to PD-L1 are required. PMID- 30026437 TI - [Measuring Financial Toxicity in Japanese Cancer Patients]. AB - Financial toxicity (FT) has a negative impact on quality of life (QOL) and survival of patients with cancer. However, FT has not been well defined and unlike the Common Terminology Criteria for Adverse Events (CTCAE) for physical toxicities, valid methods to quantify FT have not been well established. Hence, further studies into the methods to properly measure and quantify the risks of FT are important. The COmprehensive Score for financial Toxicity (COST) score has been validated as a useful tool for measuring FT among patients with cancer in the US. However, the health insurance system in the US is unique and thus, COST score's feasibility and validity in other countries with public universal health care in place is unknown. Thus, we aimed to evaluate the feasibility of COST questionnaire as a tool to evaluate FT among patients with cancer in a different health care system of Japan where universal public health insurance system exists. We performed a prospective survey to ascertain the feasibility of using COST questionnaire (Japanese version) to evaluate FT in Japanese patients with advanced solid cancer who were receiving chemotherapy. The survey showed some Japanese patients experienced meaningful FT during chemotherapy. PMID- 30026438 TI - [Points of View among Patients and Peer Supporters for"High Cost Medical Care"]. PMID- 30026439 TI - [Hematologic Malignancies/Pediatric Malignancies New Therapeutic Strategy for Hematologic Malignancies]. PMID- 30026440 TI - [I. Recent Progress in Therapies for Acute Myeloid Leukemia]. PMID- 30026441 TI - [II. New Treatment Option for Acute Lymphoblastic Leukemia]. PMID- 30026442 TI - [III. Novel Agents for Peripheral T-Cell Lymphoma]. PMID- 30026443 TI - [IV. Multiple Myeloma - Development of Novel Therapeutic Strategy]. PMID- 30026444 TI - [Retrospective Analysis of Weekly Paclitaxel Chemotherapy for Gemcitabine- and S 1-Resistant Pancreatic Cancer]. AB - Chemotherapy for unresectable pancreatic cancer has moved from using gemcitabine (GEM) and/or S-1 to using 5- fluorouracil plus Leucovorin plus oxaliplatin plus irinotecan (FOLFIRINOX) or GEM and nano albumin-bound paclitaxel (nab- PTA). We administered weekly PTA 80mg/m2 (days 1, 8, 15 every 4 weeks) in 22 patients with both GEM and S-1 resistance before nab-PTX became available through medical insurance in Japan. This regimen was used as a second-line in 3 cases, as the third-line in 14 cases and as a later line in 5 cases. The mean number of chemotherapy courses was 2.7, and the mean dose intensity was 86.1%. Postponement and dose reduction was made in 15 and 5 cases, respectively. The best overall response was 1 PR, 5 SD, 15 PD and 1 NE. The response rate was 4.5%, and disease control rate was 27.3%. The median progression-free survival was 1.7 months, and the median overall survival was 4.6 months. The main adverse events included anorexia, general malaise, and peripheral neurotoxicity and they were tolerable. This study wherein nab-PTX plus GEM was one of the standard therapies, indicated that the PTX alone was effective in pancreatic cancer patients who were resistant to GEM and S-1. PMID- 30026445 TI - [Application of Bevacizumab beyond Progressive Disease in Patients with Lung Cancer Recurrence after Surgery]. AB - BACKGROUND: The benefits of continuing bevacizumab (BEV) beyond progressive disease (PD) in patients with non-small cell lung cancer (NSCLC) remain unclear. We present our experience of continuing chemotherapy with BEV in patients with recurrent NSCLC after surgery. PATIENTS: From January 2010 to December 2016, chemotherapy with BEV was continued beyond PD in 20 patients. These patients included 10 men and 10 women, and their mean age at surgery was 71+/-10 years. Recurrence was observed at 630+/-460 days after surgery. RESULTS: The average number of protocols with BEV was 3+/-1 (1-6). The presented side effects were acceptable. Eight patients died of cancer. The 5-year survival rates after surgery, recurrence, and initiation of BEV were 78.8%, 50.1%, and 34.3%, respectively, and the median survival times were 2,465, 2,017, and 1,120 days, respectively. CONCLUSION: The majority of patients with operable NSCLC had a good performance status. We could detect recurrence early on, before the symptoms appeared, by regular examination. Therefore, these patients had an advantage in that more chemotherapeutic regimens could be administered to them and their prognosis could be improved by the continuation of BEV beyond over PD. PMID- 30026446 TI - [Results of Palliative Stent Insertion for Malignant Colorectal Obstruction]. AB - We compared the utility of self-expandable metallic stents (SEMS) to that of colostomy in palliative care patients with malignant colorectal obstruction. The SEMS-related morbidity and mortality rates were 15.4% and 7.7% in 13 patients, respectively. The median time to first diet was significantly shorter after SEMS insertion than that after colostomy, (2 vs 6 days, respectively, p=0.0102). The postprocedure median length of hospital stay of the palliative care patients without followed chemotherapy was shorter after SEMS insertion than after colostomy (10 vs 23 days, respectively). The median time to chemotherapy administration was shorter after SEMS insertion than after colostomy (13 vs 29 days, respectively); however, this difference was not statistically significant. Insertion of SEMS should be considered as the first-line treatment for palliative care patients with malignant colorectal obstruction. PMID- 30026447 TI - [The Usefulness of a Pamphlet for Preventing Exposure to Antineoplastic Agents at Cancer Patients' Homes and an Awareness Survey for Pharmacists about Providing Information to Cancer Patients about Exposure to Antineoplastic Agents]. AB - As the number of patients undergoing outpatient chemotherapy has increased, there is concern that cancer patients' family members are unknowingly exposed to antineoplastic agents at home through cancer patients' excrement or other secreted materials. In this study, we created a pamphlet that introduces several methods to prevent exposure to antineoplastic agents at home and conducted a questionnaire survey to assess the usefulness of the pamphlet. The results indicated that more than 90% of patients believed that the pamphlet was "useful" or "very useful" for ensuring safety with respect to antineoplastic agents at home. Further, most patients responded that the pamphlet decreased their anxieties about their disease and/or treatment. In order to examine pharmacists' involvement in providing information to cancer patients about exposure to antineoplastic agents, we conducted another questionnaire survey, with pharmacists working at Sapporo-Higashi Tokushukai Hospital and Sapporo Tokushukai Hospital. The results indicated that 41 out of 46 pharmacists practiced medication counseling; however, 39 pharmacists did not provide patients with instructions on ways to prevent exposure to antineoplastic agents at home. Their primary reason was a lack of adequate information to do so. Accordingly, the pamphlet prepared in our study would be an effective way to provide guidance for preventing exposure to antineoplastic agents at home. PMID- 30026448 TI - [Current Status of Oncofertility in Adolescent and Young Adult (AYA) Generation Cancer Patients in Japan - National Survey of Oncologists]. AB - A national survey conducted in 2016 aimed to evaluate the current status and needs of the field of oncofertility and to consider optimized medical delivery systems. A total of 739 oncologists, excluding gynecological and urological specialists, were surveyed. Of these, 99.2% thought that providing information on fertility preservation was important. Of the surveyed oncologists, 48% were affiliated with facilities providing assisted reproductive technology, and 79.3% practiced in university hospitals. Of 238 (32.2%) specialists who provided information on the risk of reproductive damage resulting from treatment in their facility, 163 (44.9%) and 75 (19.9%) practiced in university hospitals (n=363) and non-university hospitals (n= 376), respectively. In contrast, 14.3% and 32.7% of oncologists who practiced in university hospitals and non-university hospitals, respectively, collaborated with local obstetricians and gynecologists. Among oncologists who use a gradually expanding regional oncofertility network, 0.6% practice in university hospitals and 2.7% practice in non-university hospitals. Patients were advised that the risk of infertility was 92.3% and the likelihood of fertility preservation was 66.9%. Furthermore, as an ideal way of providing information on preservation of fertility, 22.9% of oncologists collaborate with local gynecologists, and 26.3% do so at a public cancer and reproductive medical counseling center. In addition, 34.7% and 55.1% of oncologists at university and non-university hospitals, respectively, thought that implementation of a fertility preservation program at a public facility would be desirable. Although most oncologists recognize the importance of providing information on reproductive medicine, the support system for reproductive function and fertility in adolescent and young adult (AYA) generation cancer patients is limited because of the lack of agreement on patient referral. The limited number of referrals in turn limits data collection in the field of oncofertility. Grant: A Health and Labour Sciences Research Grant: H27 Cancer Control-Ippan. PMID- 30026450 TI - [A Case of Drug-Induced Organizing Pneumonia Caused by Dasatinib]. AB - A 52-year-old man with chronic myelogenous leukemia (CML) received dasatinib after the failure of imatinib and nilotinib therapy. Two years after the initiation of dasatinib, he developed shortness of breath that gradually worsened. Chest X-ray and computed tomography scan showed pulmonary infiltrative shadows and bilateral pleural effusion. We performed a transbronchial lung biopsy and diagnosed organizing pneumonia caused by dasatinib treatment. Corticosteroid therapy was initiated after the discontinuation of dasatinib and all his symptoms were significantly improved. Because of the exacerbation of CML, the patient was treated with imatinib and then nilotinib; however, these drugs failed to decrease the leukemic cells. Re - administration of dasatinib in combination with corticosteroid therapy successfully controlled CML without recurrence of organizing pneumonia. PMID- 30026449 TI - [A Case Report of Surgery and Chemotherapy for a Patient with Rapidly Progressing Breast Cancer during Pregnancy]. AB - A 33-year-old woman became aware of a right breast mass at her 28th week of pregnancy. From the biopsy results, we diagnosed her with right breast cancer. At her 33rd week of pregnancy, she underwent modified radical mastectomy (pT2N3aM0, Stage III C, ER-negative, PR-negative, HER2-positive), and she elected to receive adjuvant therapy after the surgery during her pregnancy. She received the first course of EC (epirubicin plus cyclophosphamide) therapy on the 13th postoperative day (35 weeks of gestation) and gave a natural, vaginal delivery at 36 weeks and 5 days of gestation. On the 4th day after birth, the patient noticed a contralateral left breast mass and was diagnosed with left breast cancer, after core needle biopsy. She received 4 courses of EC therapy and is currently undergoing PTX plus HER (paclitaxel plus trastuzumab) therapy. Regarding chemotherapy during pregnancy, we recommend that there is no need to perform artificial preterm birth, because chemotherapy has little influence on children after their second-trimester. After the second-trimester, chemotherapy can be safely performed. PMID- 30026451 TI - [A Case of Consciousness Disorder Induced by the Syndrome of Inappropriate Antidiuretic Hormone Secretion Following Cisplatin and 5-Fluorouracil Chemotherapy in a Patient with Tongue Cancer]. AB - We herein report a case of a consciousness disorder that was induced by the syndrome of inappropriate antidiuretic hormone secretion following cisplatin (CDDP) and 5 -fluorouracil (5-FU) chemotherapy in a patient with tongue cancer. A 72- year-old woman complained of tongue pain and was admitted to our hospital for neoadjuvant chemotherapy, under a diagnosis of tongue squamous cell carcinoma (T4aN2bM0). She was treated with CDDP and 5-FU. On the second day after administration, she complained of nausea and anorexia, and on the third day, she showed impaired consciousness. Laboratory studies revealed that the patient had a serum sodium concentration 112mEq/L, and no dehydration was noted. The patient was diagnosed with SIADH, using the appropriate diagnostic criteria based on serum and urine hypoosmolality. We subsequently discontinued chemotherapy and initiated fluid restriction and sodium supplements. Two days after this treatment, her consciousness level improved, and on the fifth day of treatment, laboratory studies revealed a serum sodium level of 134mEq/ L. PMID- 30026452 TI - [Resection of a Granulocyte Colony-Stimulating Factor-Producing Anaplastic Carcinoma of the Pancreas, Associated with Humoral Hypercalcemia of Malignancy]. AB - We herein report the case of a 65-year-old man who presented with an anaplastic carcinoma of the pancreas, producing granulocyte colony-stimulating factor (G CSF). The patient's laboratory data showed an increase in his serum CA19-9 levels 1 year after he had undergone surgery for transverse colon cancer. Computed tomography (CT) showed a mass in the pancreatic head. Following a diagnosis of primary or metastatic pancreatic cancer, we performed the pancreatoduodenectomy. The postoperative course was uneventful. However, on postoperative day 28, he suffered a disturbance of consciousness and demonstrated hypercalcemia with elevated serum levels of parathyroid hormone-related protein (PTHrP). CT revealed multiple liver metastases and massive ascites. His serum Ca level decreased temporarily, and he subsequently died 58 days after the pancreatoduodenectomy. A pathological examination revealed pleomorphic-type anaplastic carcinoma of the pancreas. Immunohistochemical staining showed the tumor cells to be positive for G-CSF. To the best of our knowledge, there have been no reports of G-CSF producing anaplastic carcinoma of the pancreas associated with humoral hypercalcemia of malignancy. PMID- 30026453 TI - [A Case Describing Treatment with FOLFIRI plus Bevacizumab after a Self Expandable Metallic Stent Placement for Local Recurrence]. AB - A 50-year old male patient chose to have elective surgery for obstructive rectal cancer. Before undergoing surgery, he had a self-expandable metallic stent (SEMS) placed to relieve a colonic obstruction. He was discharged from our hospital after the elective surgery without surgical complications. In our outpatient clinic, he was prescribed UFT/LV for adjuvant chemotherapy. Eight months after surgery, he came back to the hospital complaining of abdominal distension, abdominal pain and constipation. A diagnosis of local recurrence of rectal cancer, peritoneal metastasis and metastatic liver cancer was confirmed. He was admitted to have the bowel obstruction relieved by having a SEMS placed. The procedure was successful in relieving the bowel obstruction and the patient began FOLFIRI plus bevacizumab as chemotherapy. Through this case, we were able to see that SEMS placement can circumvent emergency surgery and prevent the formation of a stoma by relieving a colonic obstruction. A SEMS placement can also lead to positive benefits such as faster treatment and therapy for palliative cases. PMID- 30026454 TI - [Five-Year Survival of Two Patients with Para-Aortic Lymph Node Metastasis Treated with Four FOLFOX6and Four FOLFIRI Courses in Combination with Bevacizumab]. AB - Patients with metastatic colon cancer can be treated with alternating courses of FOLFOX6 and FOLFIRI in order to reduce their adverse events. We report 2 patients with para-aortic lymph node metastasis treated with 4 courses each of FOLFOX6 and FOLFIRI in combination with bevacizumab, which led to a complete response. Case 1: The patient was a 53-year-old woman with transvers colon cancer tub2 pSS, ly3, v2, n4, H0, P0. Case 2: The patient was a 60-year-old woman with upper rectal cancer tub1 pSS, ly3, v3, n4, H0, P0. The administration of tegafur/uracil plus oral Leucovorin was continued for 6 months. Furthermore, only the administration of oral doxifluridine was continued for 4 years. Complete response has been maintained for over 5 years since resection. Four courses each of FOLFOX6 and FOLFIRI in combination with bevacizumab will not only provide a remission rate of 100% but will also be effective radical therapy for patients with para-aortic lymph node metastasis. PMID- 30026455 TI - [A Case of Synchronous Liver Metastasis of Ascending Colon Cancer with Pathological Complete Response to S-1/Oxaliplatin (SOX) and Bevacizumab]. AB - A 77-year-old man was diagnosed with ascending colon cancer with synchronous liver metastasis. Per our policy we first only performed a right hemicolectomy (pSSN2H2M0, stage IV). We then planned S-1 and oxaliplatin (SOX) plus bevacizumab (Bmab) chemotherapy as a neoadjuvant for the resection of liver metastasis. After 4 courses, enhanced CT and EOB-MRI findings showed the liver tumor had significantly decreased in size with no side effects, and we performed a partial liver resection for the S7 lesion. Postoperatively, histopathological analysis revealed only a fibrotic lesion and no cancerous cells in the resected specimen, indicating that chemotherapy had downgraded the tumor to Grade 3. Adjuvant chemotherapy was not continued owing to the patient's refusal, but no recurrence was noted 18 months after the second operation. SOX plus Bmab chemotherapy is, therefore, effective in terms of its anti-tumor effects, tolerance, and accessibility. We believe SOX plus Bmab chemotherapy can be considered as an effective option for cases with synchronous liver metastasis of colon cancer as neoadjuvant chemotherapy for interval liver resection. PMID- 30026456 TI - [A Case of Postoperative Recurrence of Rectal Cancer in Which Desensitization Therapy Was Effective against Oxaliplatin Allergy in L-OHP]. AB - The case involved a 44-year-old man who underwent intersphincteric resection and lateral lymph node dissection for rectal cancer. Pathological diagnosis revealed a well-differentiated adenocarcinoma comprising KRAS wild type, and pT2N0M0 (pathological Stage I). CapeOX (capecitabine plus oxaliplatin[L-OHP]), and bevacizumab therapy was initiated because of local recurrence. Although a partial response (PR) was observed, the therapy was terminated after 6 courses because of the development of hand-foot syndrome. FOLFIRI and cetuximab therapy was initiated after cancer recurrence was observed during a follow up. As the therapeutic efficiency is characterized by stability (stable disease: SD), and the tumor reduction effect observed was not sufficient, we performed an abdominoperineal resection to achieve local control. However, a left hydronephrosis occurred due to the pelvic recurrence, necessitating the emergency hospitalization of the patient. Because resistance to L-OHP was not confirmed, mFOLFOX6 and bevacizumab therapy was introduced in hopes of the effect of the former. As Grade 2 allergy (erythema) appeared immediately after the L-OHP was administered during the 3 courses, treatment was discontinued. We the reinitiated the treatment along with the desensitization therapy from the 4 courses. A total of 27 courses of mFOLFOX6 and bevacizumab therapy were administered until the state of disease progression (progression disease: PD) was determined. PR was defined as the best therapeutic efficiency. In some cases, discontinuation of treatment is necessary as observed in the present case due to the onset of L-OHP allergies, even if the overall effect of the treatment is expected to be good. Our case is essentialas it demonstrates the successfulness of desensitization therapy for L-OHP allergies. PMID- 30026457 TI - [Effect of the Administration Period of Rasburicase in Japanese Adult Hematological Malignancy Patients at High-Risk for Tumor Lysis Syndrome]. AB - Tumor lysis syndrome (TLS) is a life-threatening metabolic complication caused by the rapid breakdown of malignant cells. It is an oncologic emergency and occurs spontaneously after the initiation of chemotherapy for hematological malignancies. Therefore, the management of TLS is important. Rasburicase (RSB) has been shown to be effective for the management of TLS. We retrospectively investigated the optimal administration period of RSB (1 to 7 days) for 38 adult patients with a hematological malignancy who were at high risk for TLS. In all patients, the serum uric acid (sUA) value did not increase beyond the upper limit of normal. Clinical TLS did not occur in any patients. Seven patients were administered a single-dose of RSB and sUA remained within normal limits. These results suggested that single-dose RSB administration was efficacious for Japanese adult patients with hematological malignancies who are at high risk for TLS. PMID- 30026458 TI - [Improvement of Meals for Patients Undergoing Chemotherapy]. PMID- 30026459 TI - The Impact of EGFR Gene Polymorphisms on the Risk of Alzheimer's Disease in a Chinese Han Population: A Case-Controlled Study. AB - BACKGROUND The aim of this study was to investigate the association between polymorphisms of the epidermal growth factor receptor (EGFR) gene with the risk of Alzheimer's disease (AD) in a Chinese Han population. MATERIAL AND METHODS A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to genotype 139 patients with AD and 152 healthy control individuals. The Hardy-Weinberg equilibrium (HWE) was analyzed using the chi squared (chi2) test, and genotype and allele frequencies were compared between the two population groups, using the chi2 test. The odds ratios (ORs) and corresponding 95% confidence intervals (CI) were calculated to express the degree of risk of AD resulting from polymorphisms in the EGFR gene. Linkage disequilibrium among EGFR polymorphisms was analyzed using the Haploview bioinformatics software. RESULTS The CC genotype and C allele frequencies of rs730437 were significantly lower in patients with AD compared with the controls (P=0.037), indicating that rs730437 was associated with a reduced risk of AD (CC vs. AA: OR=0.446, 95% CI=0.207-0.960) (C vs. A: OR=0.702, 95% CI=0.502-0.980). The presence of the TT genotype of rs1468727 significantly reduced the risk of AD (P=0.003; OR=0.333, 95% CI=0.160-0.691), and T allele carriers of rs1468727 had a 0.605-fold increased risk of AD. Haplotype A-C-C was significantly correlated with an increased risk of AD (OR=1.922, 95% CI=1.130-3.269). CONCLUSIONS In a Han Chinese population, EGFR gene polymorphisms, rs730437 and rs1468727 and haplotype A-C-C were shown to be possible protective factors for the development of AD. PMID- 30026460 TI - Perioperative Telemetric Monitoring in Pig-to-Baboon Heterotopic Thoracic Cardiac Xenotransplantation. AB - BACKGROUND Perioperative monitoring and hemodynamic management after heterotopic thoracic cardiac xenotransplantation is challenging due to 2 independently beating hearts. Telemetry allows continuous monitoring of hemodynamic parameters of both the donor and recipient hearts. We describe our experience and report on the validity of a telemetric system during and after surgery. MATERIAL AND METHODS Wireless telemetry transmitters were implanted in 3 baboons receiving porcine donor hearts. Left ventricular pressure and ECG were assessed from the donor heart, whereas aortic pressure and temperature were assessed from the recipient. Telemetric data were validated with invasive blood pressure measurements. RESULTS Telemetric blood pressure was lower than invasive blood pressure. Intraoperatively, the probe in the graft's left ventricle measured negative end-diastolic pressures. Telemetry allowed simple discrimination between donor's and recipient's heart rates. Body temperature was underestimated by telemetry. Telemetric monitoring facilitates recognition of graft arrhythmias and volume demand. CONCLUSIONS In heterotopic thoracic cardiac xenotransplantation, telemetric implants are useful tools to continuously monitor the animals' hemodynamic parameters and to discriminate donor and recipient organs. Accuracy is sufficient for systemic pressure measurement, but perioperative use of left ventricular end-diastolic pressure as a surrogate parameter for graft function is not advisable. Temperature measurements by telemetry do not reflect body core temperature. PMID- 30026461 TI - Successful Laparoscopic Sleeve Gastrectomy in Emergency for a Gastric Gastrointestinal Stomal Tumor (GIST) with Acute Bleeding: A Case Report. AB - BACKGROUND Gastrointestinal stomal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and the stomach is the most commonly involved organ. Complete surgical resection with negative margins is the primary and only potentially curative treatment. Surgeon experience with minimally invasive gastric resections in addition to the tumor size and site has to be considered in the choice of laparoscopic or open surgical approach in order to remove the lesion. CASE REPORT A 67-year-old male patient with an history of gastric ulcer presented 2 days after an esophagogastroduodenoscopy with an incidental finding of a 30-mm gastric submucosal lesion that was not histologically defined (biopsies were taken), chest pain in association with hematemesis, and melena. An initial attempt to achieve endoscopic hemostasis with epinephrine injection was followed by the recurrence of the gastric bleeding until the presentation of hemorrhagic shock. An emergent laparoscopic sleeve gastrectomy was then performed for hemorrhage control. There were no intra- or postoperative major complications and the histological findings led to the diagnosis of a gastrointestinal stromal tumor (GIST). CONCLUSIONS Laparoscopic sleeve gastrectomy is a bariatric surgical treatment of morbid obesity. This report describes the application of a bariatric procedure in a life-threatening situation and illustrates how safe and effective it can be when performed by surgeons with excellent laparoscopic skills. PMID- 30026462 TI - Neuropil contraction in relation to Complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients-a pilot study. AB - A recent report suggested Complement 4 (C4A) gene copy numbers (GCN) as risk factors for schizophrenia. Rodent model showed association of C4 with synaptic pruning suggesting its pathophysiological significance (Sekar, A. et al. (2016)). We, therefore, predicted that C4A GCN would be positively correlated with neuropil contraction in the human brain among schizophrenia patients showing more prominent correlations in ventral regions among young adults and dorsal regions among adolescents since neuromaturation progresses dorsoventrally. Whole-brain, multi-voxel, in vivo phosphorus magnetic resonance spectroscopy (31P MRS) assessed neuropil changes by estimating levels of membrane phospholipid (MPL) precursors and catabolites. Increased MPL catabolites and/or decreased MPL precursors indexed neuropil contraction. Digital droplet PCR-based assay was used to estimate C4A and C4B GCN. We evaluated two independent cohorts (young adult onset early-course schizophrenia (YASZ = 15) and adolescent-onset schizophrenia (AOSZ = 12) patients), and controls matched for each group, n = 22 and 15, respectively. Separate forward stepwise linear regression models with Akaike information Criterion were built for MPL catabolites and precursors. YASZ cohort: Consistent with the rodent model (Sekar, A. et al. 2016)), C4A GCN positively correlated with neuropil contraction (increased pruning/decreased formation) in the inferior frontal cortex and inferior parietal lobule. AOSZ cohort: C4A GCN positively correlated with neuropil contraction in the dorsolateral prefrontal cortex and thalamus. Exploratory analysis of C4B GCN showed positive correlation with neuropil contraction in the cerebellum and superior temporal gyrus among YASZ while AOSZ showed neuropil contraction in the prefrontal and subcortical structures. Thus, C4A and C4B GCN are associated with neuropil contraction in regions often associated with schizophrenia, and may be neuromaturationally dependent. PMID- 30026463 TI - Genetic variants in SEC16B are associated with body composition in black South Africans. AB - OBJECTIVE: The latest genome-wide association studies of obesity-related traits have identified several genetic loci contributing to body composition (BC). These findings have not been robustly replicated in African populations, therefore, this study aimed to assess whether European BC-associated gene loci played a similar role in a South African black population. METHODS: A replication and fine mapping study was performed in participants from the Birth to Twenty cohort (N = 1,926) using the Metabochip. Measurements included body mass index (BMI), waist and hip circumference, waist-to-hip ratio (WHR), total fat mass, total lean mass and percentage fat mass (PFM). RESULTS: SNPs in several gene loci, including SEC16B (Padj < 9.48 * 10-7), NEGR1 (Padj < 1.64 * 10-6), FTO (Padj < 2.91 * 10 5), TMEM18 (Padj < 2.27 * 10-5), and WARS2 (Padj < 3.25 * 10-5) were similarly associated (albeit not at array-wide signficance (P <= 6.7 * 10-7) with various phenotypes including fat mass, PFM, WHR linked to BC in this African cohort, however the associations were driven by different sentinel SNPs. More importantly, DXA-derived BC measures revealed stronger genetic associations than simple anthropometric measures. Association signals generated in this study were shared by European and African populations, as well as unique to this African cohort. Moreover, sophisticated estimates like DXA measures enabled an enhanced characterisation of genetic associations for BC traits. CONCLUSION: Results from this study suggest that in-depth genomic studies in larger African cohorts may reveal novel SNPs for body composition and adiposity, which will provide greater insight into the aetiology of obesity. PMID- 30026464 TI - Hollow-core conjoined-tube negative-curvature fibre with ultralow loss. AB - Countering the optical network 'capacity crunch' calls for a radical development in optical fibres that could simultaneously minimize nonlinearity penalties, chromatic dispersion and maximize signal launch power. Hollow-core fibres (HCF) can break the nonlinear Shannon limit of solid-core fibre and fulfil all above requirements, but its optical performance need to be significantly upgraded before they can be considered for high-capacity telecommunication systems. Here, we report a new HCF with conjoined-tubes in the cladding and a negative-curvature core shape. It exhibits a minimum transmission loss of 2 dB km-1 at 1512 nm and a <16 dB km-1 bandwidth spanning across the O, E, S, C, L telecom bands (1302-1637 nm). The debut of this conjoined-tube HCF, with combined merits of ultralow loss, broad bandwidth, low bending loss, high mode quality and simple structure heralds a new opportunity to fully unleash the potential of HCF in telecommunication applications. PMID- 30026465 TI - Publisher Correction: Operando monitoring the lithium spatial distribution of lithium metal anodes. AB - The original HTML version of this Article omitted to list Zhengcao Li as a corresponding author. Correspondingly, the original PDF version of this Article incorrectly stated that 'Correspondence and requests for materials should be addressed to M.W. (email: m.wagemaker@tudelft.nl)', instead of the correct 'Correspondence and requests for materials should be addressed to Z.L. (email: zcli@tsinghua.edu.cn) or to M.W. (email: m.wagemaker@tudelft.nl)'. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30026466 TI - Gate-controlled quantum dots and superconductivity in planar germanium. AB - Superconductors and semiconductors are crucial platforms in the field of quantum computing. They can be combined to hybrids, bringing together physical properties that enable the discovery of new emergent phenomena and provide novel strategies for quantum control. The involved semiconductor materials, however, suffer from disorder, hyperfine interactions or lack of planar technology. Here we realise an approach that overcomes these issues altogether and integrate gate-defined quantum dots and superconductivity into germanium heterostructures. In our system, heavy holes with mobilities exceeding 500,000 cm2 (Vs)-1 are confined in shallow quantum wells that are directly contacted by annealed aluminium leads. We observe proximity-induced superconductivity in the quantum well and demonstrate electric gate-control of the supercurrent. Germanium therefore has great promise for fast and coherent quantum hardware and, being compatible with standard manufacturing, could become a leading material for quantum information processing. PMID- 30026468 TI - Publisher Correction: Bioprospecting on invasive plant species to prevent seed dispersal. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30026467 TI - FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins. AB - Ferlin proteins participate in such diverse biological events as vesicle fusion in C. elegans, fusion of myoblast membranes to form myotubes, Ca2+-sensing during exocytosis in the hair cells of the inner ear, and Ca2+-dependent membrane repair in skeletal muscle cells. Ferlins are Ca2+-dependent, phospholipid-binding, multi C2 domain-containing proteins with a single transmembrane helix that spans a vesicle membrane. The overall domain composition of the ferlins resembles the proteins involved in exocytosis; therefore, it is thought that they participate in membrane fusion at some level. But if ferlins do fuse membranes, then they are distinct from other known fusion proteins. Here we show that the central FerA domain from dysferlin, myoferlin, and otoferlin is a novel four-helix bundle fold with its own Ca2+-dependent phospholipid-binding activity. Small-angle X-ray scattering (SAXS), spectroscopic, and thermodynamic analysis of the dysferlin, myoferlin, and otoferlin FerA domains, in addition to clinically-defined dysferlin FerA mutations, suggests that the FerA domain interacts with the membrane and that this interaction is enhanced by the presence of Ca2+. PMID- 30026470 TI - Enhanced Corrosion Protection Performance by Organic-Inorganic Materials Containing Thiocarbonyl Compounds. AB - In the present study, the synergistic effect on the corrosion protection properties of Mg alloys subjected to plasma electrolytic oxidation and chemically treated with thiourea as an inhibitor is investigated by surface microstructure analysis, evaluation of the electrochemical performance, and chemical quantum calculations. Physical adsorption of thiourea on the inorganic material surface might be due to physical interaction between thiourea with a low ionization potential serving as an electron donor and the inorganic components with high electron affinities acting as acceptors. The results from potentiodynamic polarization and electrochemical impedance spectroscopy for organic-inorganic coating reveal a clear decrease in the corrosion rate owing to the introduced thiourea. PMID- 30026471 TI - Symbionts and metabolites. PMID- 30026469 TI - Embryonic germ cell extracts erase imprinted genes and improve the efficiency of induced pluripotent stem cells. AB - Patient-specific induced pluripotent stem cells (iPSCs) have the potential to be useful in the treatment of human diseases. While prior studies have reported multiple methods to generate iPSCs, DNA methylation continues to limit the totipotency and reprogramming efficiency of iPSCs. Here, we first show the competency of embryonic germ cells (EGCs) as a reprogramming catalyst capable of effectively promoting reprogramming induced by four defined factors, including Oct4, Sox2, Klf4 and c-Myc. Combining EGC extracts with these four factors resulted in formation of more embryonic stem cell-like colonies than did factors alone. Notably, expression of imprinted genes was higher with combined induction than with factors alone. Moreover, iPSCs derived from the combined inductors tended to have more global hypomethylation. Our research not only provides evidence that EGC extracts could activate DNA demethylation and reprogram imprinted genes, but also establishes a new way to enhance reprogramming of iPSCs, which remains a critical safety concern for potential use of iPSCs in regenerative medicine. PMID- 30026472 TI - Modeling AD. PMID- 30026473 TI - Triggering myelopoiesis. PMID- 30026474 TI - Autophagy & MDSCs. PMID- 30026475 TI - A harmful pairing. PMID- 30026476 TI - TILs show the way. PMID- 30026477 TI - Comment on: Evidence of innate lymphoid cell redundancy in humans. PMID- 30026478 TI - Reply to 'Comment on: Evidence of innate lymphoid cell redundancy in humans'. PMID- 30026479 TI - Natural killer cell specificity for viral infections. AB - Natural killer (NK) cells are lymphocytes that contribute to the early immune responses to viruses. NK cells are innate immune cells that do not express rearranged antigen receptors but sense their environment via receptors for pro inflammatory cytokines, as well as via germline-encoded activating receptors specific for danger or pathogen signals. A group of such activating receptors is stochastically expressed by certain subsets within the NK cell compartment. After engagement of the cognate viral ligand, these receptors contribute to the specific activation and 'preferential' population expansion of defined NK cell subsets, which partially recapitulate some features of adaptive lymphocytes. In this Review, we discuss the numerous modes for the specific recognition of viral antigens and peptides by NK cells and the implications of this for the composition of the NK cell repertoire as well as for the the selection of viral variants. PMID- 30026480 TI - Publisher Correction: Hyperpolarized [1-13C]-acetate Renal Metabolic Clearance Rate Mapping. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30026481 TI - Identification and characterization of known and novel microRNAs in strawberry fruits induced by Botrytis cinerea. AB - MicroRNAs are endogenous small non-coding RNAs that negatively regulate mRNAs, mainly at the post-transcriptional level, and play an important role in resistance response of plants. To date, there are few reports on resistance response of strawberry miRNAs to pathogens. In this study, using high-throughput sequencing, 134 conserved and 35 novel miRNAs were identified in six libraries within the treatment of Botrytis cinerea. A total 497 potential target genes were predicted using Fragaria vesca genome. Most of the differential expressed miRNAs in strawberry fruits were up-regulated in early libraries and down-regulated in late libraries. PIRL, the target gene of miR5290a, showed the opposite expressed trend compared with miR5290 from T1 to T3 libraries, and functional analysis of the PIRL gene shows that it has obvious resistance to B. cinerea in the strawberry fruits with overexpressed PIRL gene. We speculate that miR5290a negatively regulates its target gene PIRL to increase resistance to pathogen infection, and further analysis of PIRL function is meaningful for studying the plant-pathogen relationship and improving strawberry fruit quality and yield. PMID- 30026482 TI - Streptomyces qaidamensis sp. nov., isolated from sand in the Qaidam Basin, China. AB - A novel actinobacterial strain, designated S10T, was isolated from a sand sample collected from the Qaidam Basin in Qinghai province, China. The strain S10T exhibited antibacterial activity against MRSA. The taxonomic position of the strain S10T was determined by a polyphasic approach. There were six copies of 16S rDNA in S10T which were not same exactly (MH257693-MH257698). Phylogenetic analysis of 16S rRNA gene sequences indicated the strain belonging to the genus Streptomyces and it showed high sequence similarities with Streptomyces chartreusis NBRC 12753T (99.31%), Streptomyces phaeoluteigriseus DSM 41896T (99.24%), Streptomyces variegatus NRRL B-16380T (99.17%) and Streptomyces flavovariabilis NRRL B-16367T (99.17%) comparing with MH257693, MH257695, MH257696, MH257697, and MH257698. Similarities with Streptomyces kunmingensis NBRC14463T (98.82%), Streptomyces bungoensis DSM 41781T(98.76%), S. chartreusis NBRC 12753T (98.69%) and S. phaeoluteigriseus DSM 41896T (98.62%) with MH257694. Whole-genome average nucleotide identity (ANI) values between strain S10T and S. chartreusis NBRC 12753T, S. phaeoluteigriseus DSM 41896T, S. variegatus NRRL B 16380T, S. flavovariabilis NRRL B-16367T, S. kunmingensis NBRC 14463T, S. bungoensis DSM 41781T were 83.63%, 82.89%, 92.55%, 92.51%, 79.29, and 82.87%, respectively, suggesting that the strain S10T represented a new species. A phylogenetic analysis comparing the S10T genome with those of 336 other sequenced Streptomyces genomes confirmed its relatedness with Streptomyces variegatus NRRL B-16380T and Streptomyces flavovariabilis NRRL B-16367T. Strain S10T contained LL diaminopimelic acid in the cell wall. The predominant menaquinones were MK-9(H6) and MK-9(H8) and the major fatty acids were iso-C15:0, anteiso-C15:0, iso-C16:0, and anteiso-C17:0. Phospholipids detected were diphosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl choline, three unknown phospholipids, an unknown aminophospholipid and an unknown phosphatidyl glycolipid. On the basis of these genotypic and phenotypic data, it is proposed that isolate S10T (=JCM 31184T =CGMCC 4.7315T) should be classified in the genus Streptomyces as Streptomyces qaidamensis sp. nov. PMID- 30026483 TI - Abrupt events and population synchrony in the dynamics of Bovine Tuberculosis. AB - Disease control strategies can have both intended and unintended effects on the dynamics of infectious diseases. Routine testing for the harmful pathogen Bovine Tuberculosis (bTB) was suspended briefly during the foot and mouth disease epidemic of 2001 in Great Britain. Here we utilize bTB incidence data and mathematical models to demonstrate how a lapse in management can alter epidemiological parameters, including the rate of new infections and duration of infection cycles. Testing interruption shifted the dynamics from annual to 4-year cycles, and created long-lasting shifts in the spatial synchrony of new infections among regions of Great Britain. After annual testing was introduced in some GB regions, new infections have become more de-synchronised, a result also confirmed by a stochastic model. These results demonstrate that abrupt events can synchronise disease dynamics and that changes in the epidemiological parameters can lead to chaotic patterns, which are hard to be quantified, predicted, and controlled. PMID- 30026485 TI - Representation of Multidecadal Sahel Rainfall Variability in 20th Century Reanalyses. AB - Summer rainfall in the Sahel region has exhibited strong multidecadal variability during the 20th century causing dramatic human and socio-economic impacts. Studies have suggested that the variability is linked to the Atlantic multidecadal variability; a spatially persistent pattern of warm/cold sea surface temperatures in the North Atlantic. In the last few years, several promising century-long reanalysis datasets have been made available, opening up for further studies into the dynamics inducing the observed low-frequency rainfall variability in Sahel. We find that although three of the 20th century ECMWF reanalyses show clear multidecadal rainfall variability with extended wet and dry periods, the timing of the multidecadal variability in two of these reanalyses is found to exhibit almost anti-phase features for a large part of the 20th century when compared to observations. The best representation of the multidecadal rainfall variability is found in the ECMWF reanalysis that, unlike the other reanalyses (including NOAA's 20th century), do not assimilate any observations and may well be a critical reason for this mismatch, as discussed herein. This reanalysis, namely ERA-20CM, is thus recommended for future studies on the dynamics driving the multidecadal rainfall variability in Sahel and its linkages to the low-frequency North Atlantic oceanic temperatures. PMID- 30026484 TI - FTY720 restores endothelial cell permeability induced by malaria sera. AB - Increased endothelial cell (EC) permeability in severe Plasmodium falciparum malaria contributes to major complications of severe malaria. This study explored EC permeability in malaria, and evaluated the potential use of FTY720 to restore EC permeability. ECs were incubated with sera from malaria patients (P. vivax, uncomplicated and complicated P. falciparum malaria). Cellular permeability was investigated using a fluorescein isothiocyanate (FITC)-dextran permeability assay. FTY720, an analogue of sphingosine-1-phosphate (S1P), was tested for its potential action in maintaining EC integrity. ECs incubated with sera from malaria patients with complicated P. falciparum showed higher fluorescein leakage compared with ECs incubated with sera from P. vivax (p < 0.001) and uncomplicated P. falciparum (p < 0.001). ECs pretreated with FTY720 before incubation with malaria sera had significantly decreased fluorescein leakage compared with no FTY720 treatment. In addition, FTY720 treatment significantly reduced fluorescein leakage for both uncomplicated (at 45 min) (p = 0.015), and complicated P. falciparum malaria (15 min) (p = 0.043). The permeability increase induced by complicated P. falciparum sera was significantly reversed and prevented by FTY720 in vitro. FTY720 may have clinical applications to protect against endothelial barrier dysfunction in severe P. falciparum malaria. PMID- 30026486 TI - Author Correction: Septicemia due to Streptococcus dysgalactiae subspecies dysgalactiae in vampire bats (Desmodus rotundus). AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30026487 TI - Hyperuniformity with no fine tuning in sheared sedimenting suspensions. AB - Particle suspensions, present in many natural and industrial settings, typically contain aggregates or other microstructures that can complicate macroscopic flow behaviors and damage processing equipment. Recent work found that applying uniform periodic shear near a critical transition can reduce fluctuations in the particle concentration across all length scales, leading to a hyperuniform state. However, this strategy for homogenization requires fine tuning of the strain amplitude. Here we show that in a model of sedimenting particles under periodic shear, there is a well-defined regime at low sedimentation speed where hyperuniform scaling automatically occurs. Our simulations and theoretical arguments show that the homogenization extends up to a finite length scale that diverges as the sedimentation speed approaches zero. PMID- 30026488 TI - Hypothalamic oxidative stress and inflammation, and peripheral glucose homeostasis in Sprague-Dawley rat offspring exposed to maternal and postnatal chocolate and soft drink. AB - BACKGROUND: Predisposition to obesity and type 2 diabetes can arise during foetal development and in early postnatal life caused by imbalances in maternal nutritional overload. We aimed to investigate the effects of maternal and postnatal intake of chocolate and soft drink on hypothalamic anti-oxidative stress markers, inflammation and peripheral glucose homeostasis. METHODS: Pregnant Sprague-Dawley rats were fed ad libitum chow diet only (C) or with chocolate and high sucrose soft drink supplements (S). At birth, litter size was adjusted into 10 male offspring per dam. After weaning at 3 weeks of age, offspring from both dietary groups were assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age. RESULTS: Offspring exposed to maternal S had up-regulated hypothalamic anti-oxidative markers such as SOD2 and catalase at 3 weeks of age as an indication of oxidative stress. However, at 12 weeks of age these anti-oxidative markers tended to decrease while pro-inflammatory markers such as TNF and IL-1beta became up regulated of all offspring exposed to S diet during some point of their life. Thus, despite an increase in anti-oxidative stress response, offspring exposed to maternal S had a reduced ability to counteract hypothalamic inflammation. At the same time point, postnatal S resulted in increased adiposity, reduced glucose tolerance and insulin sensitivity with no effect on body weight. However, at 25 weeks of age, the impaired glucose tolerance was reversible to the response of the control regardless of increased adiposity and body weight pointing towards a compensatory response of the insulin sensitivity or insulin secretion. CONCLUSION: Indications of hypothalamic oxidative stress was observed prior to the inflammatory response in offspring exposed to maternal S. Both maternal and postnatal S induced hypothalamic inflammation prior to increased weight gain and thus contributing to obese phenotype. PMID- 30026489 TI - Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression. AB - The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity-at the level of long-range network activity and task-related firing patterns-may underlie cognitive impairments. PMID- 30026490 TI - Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4. AB - Recent studies suggest the emerging roles of armadillo (ARM) family proteins in tumor progression. However, the functions and underlying mechanisms of ARM members in tumorigenesis and aggressiveness of neuroblastoma (NB) remain to be determined. Herein, we identify armadillo repeat containing 12 (ARMC12) as an ARM member associated with NB progression. ARMC12 promotes the growth and aggressiveness of NB cell lines. Mechanistically, ARMC12 physically interacts with retinoblastoma binding protein 4 (RBBP4) to facilitate the formation and activity of polycomb repressive complex 2, resulting in transcriptional repression of tumor suppressive genes. Blocking the interaction between ARMC12 and RBBP4 by cell-penetrating inhibitory peptide activates the downstream gene expression and suppresses the tumorigenesis and aggressiveness of NB cells. Both ARMC12 and RBBP4 are upregulated in NB tissues, and are associated with unfavorable outcome of patients. These findings suggest the crucial roles of ARMC12 in tumor progression and a potential therapeutic approach for NB. PMID- 30026491 TI - Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo. AB - Norepinephrine is a monoamine neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent false neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug's effect. PMID- 30026492 TI - Contrasting biogeography and diversity patterns between diatoms and haptophytes in the central Pacific Ocean. AB - Diatoms and haptophytes are two major phytoplankton groups, playing pivotal roles in global biogeochemical cycles and marine ecosystems. In general, diatoms have higher growth rates than haptophytes, whereas haptophytes tend to have higher nutrient uptake affinity. However, precise linkages between their ecological traits and geographical distributions remain poorly understood. Herein, we examined the basin-scale variability of the abundance and taxonomic composition of these two phytoplankton groups across 35 sites in the Pacific Ocean using DNA metabarcoding. The diatom community was generally dominated by a few genera at each sample site, whereas the haptophyte community consisted of a large number of genera in most of the sites. The coexistence of various haptophyte genera might be achieved by diversification of their ecophysiological traits such as mixotrophy. On the other hand, the diatom community might experience greater inter-genus competition due to the rapid uptake of nutrients. Our data further supports the notion that their distinct ecological strategies underlie the emergence of contrasting diversity patterns of these phytoplankton groups in the central Pacific at a basin scale. PMID- 30026493 TI - Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq Coupled Receptors. AB - Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell differentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)-dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no effect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR-dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68. PMID- 30026494 TI - Synchronized mesenchymal cell polarization and differentiation shape the formation of the murine trachea and esophagus. AB - Tube morphogenesis is essential for internal-organ development, yet the mechanisms regulating tube shape remain unknown. Here, we show that different mechanisms regulate the length and diameter of the murine trachea. First, we found that trachea development progresses via sequential elongation and expansion processes. This starts with a synchronized radial polarization of smooth muscle (SM) progenitor cells with inward Golgi-apparatus displacement regulates tube elongation, controlled by mesenchymal Wnt5a-Ror2 signaling. This radial polarization directs SM progenitor cell migration toward the epithelium, and the resulting subepithelial morphogenesis supports tube elongation to the anteroposterior axis. This radial polarization also regulates esophageal elongation. Subsequently, cartilage development helps expand the tube diameter, which drives epithelial-cell reshaping to determine the optimal lumen shape for efficient respiration. These findings suggest a strategy in which straight-organ tubulogenesis is driven by subepithelial cell polarization and ring cartilage development. PMID- 30026495 TI - M1-linked ubiquitination by LUBEL is required for inflammatory responses to oral infection in Drosophila. AB - Post-translational modifications such as ubiquitination play a key role in regulation of inflammatory nuclear factor-kappaB (NF-kappaB) signalling. The Drosophila IkappaB kinase gamma (IKKgamma) Kenny is a central regulator of the Drosophila Imd pathway responsible for activation of the NF-kappaB Relish. We found the Drosophila E3 ligase and HOIL-1L interacting protein (HOIP) orthologue linear ubiquitin E3 ligase (LUBEL) to catalyse formation of M1-linked linear ubiquitin (M1-Ub) chains in flies in a signal-dependent manner upon bacterial infection. Upon activation of the Imd pathway, LUBEL modifies Kenny with M1-Ub chains. Interestingly, the LUBEL-mediated M1-Ub chains seem to be targeted both directly to Kenny and to K63-linked ubiquitin chains conjugated to Kenny by DIAP2. This suggests that DIAP2 and LUBEL work together to promote Kenny-mediated activation of Relish. We found LUBEL-mediated M1-Ub chain formation to be required for flies to survive oral infection with Gram-negative bacteria, for activation of Relish-mediated expression of antimicrobial peptide genes and for pathogen clearance during oral infection. Interestingly, LUBEL is not required for mounting an immune response against systemic infection, as Relish-mediated antimicrobial peptide genes can be expressed in the absence of LUBEL during septic injury. Finally, transgenic induction of LUBEL-mediated M1-Ub drives expression of antimicrobial peptide genes and hyperplasia in the midgut in the absence of infection. This suggests that M1-Ub chains are important for Imd signalling and immune responses in the intestinal epithelia, and that enhanced M1 Ub chain formation is able to drive chronic intestinal inflammation in flies. PMID- 30026496 TI - Chronic Electrical Stimulation Promotes the Excitability and Plasticity of ESC derived Neurons following Glutamate-induced Inhibition In vitro. AB - Functional electrical stimulation (FES) is rapidly gaining traction as a therapeutic tool for mediating the repair and recovery of the injured central nervous system (CNS). However, the underlying mechanisms and impact of these stimulation paradigms at a molecular, cellular and network level remain largely unknown. In this study, we used embryonic stem cell (ESC)-derived neuron and glial co-cultures to investigate network maturation following acute administration of L-glutamate, which is a known mediator of excitotoxicity following CNS injury. We then modulated network maturation using chronic low frequency stimulation (LFS) and direct current stimulation (DCS) protocols. We demonstrated that L-glutamate impaired the rate of maturation of ESC-derived neurons and glia immediately and over a week following acute treatment. The administration of chronic LFS and DCS protocols individually following L glutamate infusion significantly promoted the excitability of neurons as well as network synchrony, while the combination of LFS/DCS did not. qRT-PCR analysis revealed that LFS and DCS alone significantly up-regulated the expression of excitability and plasticity-related transcripts encoding N-methyl-D-aspartate (NMDA) receptor subunit (NR2A), brain-derived neurotrophic factor (BDNF) and Ras related protein (RAB3A). In contrast, the simultaneous administration of LFS/DCS down-regulated BDNF and RAB3A expression. Our results demonstrate that LFS and DCS stimulation can modulate network maturation excitability and synchrony following the acute administration of an inhibitory dose of L-glutamate, and upregulate NR2A, BDNF and RAB3A gene expression. Our study also provides a novel framework for investigating the effects of electrical stimulation on neuronal responses and network formation and repair after traumatic brain injury. PMID- 30026497 TI - The Effect of Size Statistics of the Background Texture on Perceived Target Size. AB - We investigated the effect of the size distribution statistics of background elements on the perceived size of a target. We manipulated the first, second, and third order statistics (i.e., mean, variance, and skewness) of the background element size distribution. We used a two-interval forced-choice paradigm to measure perceived target size at different background size distributions. In each trial, a standard disk, or target, was presented in one interval with a textured background and a comparison disk, on a blank background, in the other. The task for the observers was to determine which interval contained a larger disk. We measured the point of subjective equality for the perceived target size with a staircase procedure. The perceived target size decreased with the increment of mean background disk size. The variance and skewness of the background element size did not affect the perceived target size. Our results showed that only the first order statistics of the background modulated the perceived target size, not the higher order statistics. A computational model, in which the visual system extracts size information by averaging the responses of different size channels, whose response is modulated by the size of the background elements, can account for the results. PMID- 30026498 TI - Tuning the structure of the Josephson vortex lattice in Bi2Sr2CaCu2O8+delta single crystals with pancake vortices. AB - In extremely anisotropic cuprate superconductors a lattice of stacks of pancake vortices nucleates when a magnetic field is applied perpendicular to the copper oxide layers, while an orthogonal lattice of highly elliptical Josephson vortices forms when the applied field is parallel to the layers. Under tilted magnetic fields these sublattices can interact in complex ways to form systems of vortex chains and composite vortex lattices. Here we have used high-resolution scanning Hall microscopy (SHM) to map the rich tilted-field vortex phase diagram in an underdoped Bi2Sr2CaCu2O8+delta single crystal. We find that the Josephson vortex lattice spacing has an unexpected non-monotonic dependence on the pancake vortex density reflecting the delicate balance between attractive and repulsive vortex interactions, and actually undergoes a field-driven structural transformation with increasing out-of-plane fields. We also identify particularly stable composite structures composed of vortex chains separated by an integer number of rows of interstitial pancake vortex stacks and are able to establish the precise evolution of vortex-chain phases as the out-of-plane field is increased at small in-plane fields. Our results are in good semi-quantitative agreement with theoretical models and could enable the development of vortex ratchets and lenses based on the interactions between Josephson and pancake vortices. PMID- 30026499 TI - Author Correction: Multivariate EEG analyses support high-resolution tracking of feature-based attentional selection. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30026500 TI - Permafrost Degradation and Subsidence Observations during a Controlled Warming Experiment. AB - Global climate change has resulted in a warmer Arctic, with projections indicating accelerated modifications to permafrost in the near future. The thermal, hydrological, and mechanical physics of permafrost thaw have been hypothesized to couple in a complex fashion but data collection efforts to study these feedbacks in the field have been limited. As a result, laboratory and numerical models have largely outpaced field calibration datasets. We present the design, execution, and initial results from the first decameter-scale controlled thawing experiment, targeting coupled thermal/mechanical response, particularly the temporal sequence of surface subsidence relative to permafrost degradation at depth. The warming test was conducted in Fairbanks, AK, and utilized an array of in-ground heaters to induce thaw of a ~11 * 13 * 1.5 m soil volume over 63 days. The 4-D temperature evolution demonstrated that the depth to permafrost lowered 1 m during the experiment. The resulting thaw-induced surface deformation was ~10 cm as observed using a combination of measurement techniques. Surface deformation occurred over a smaller spatial domain than the full thawed volume, suggesting that gradients in cryotexture and ice content were significant. Our experiment provides the first large field calibration dataset for multiphysics thaw models. PMID- 30026502 TI - Prevalence and determinants of folate deficiency among urban Indian women in the periconception period. AB - Maternal folate insufficiency is of particular concern in developing countries due to its association with various adverse pregnancy outcomes. This study aimed to determine the prevalence of folate deficiency and its determinants among urban Indian women in the periconception period. Serum folate concentrations were measured in 584 women in early pregnancy (11 +/- 3 weeks of gestation) using microbiological assay. Folate deficiency was detected in 24% women and possible deficiency was detected in 21% women. Multigravidity (aOR 1.84, 95% CI 1.16-2.92) and low education (aOR 1.67, 95% CI 1.06-2.62) emerged as determinants of folate deficiency while prenatal folic acid supplementation was favorable in decreasing the odds of folate deficiency (aOR 0.17, 95% CI 0.06-0.43). No association was observed between folate levels and adverse pregnancy outcomes including neural tube defects. The high prevalence of folate deficiency underlines the need for implementation of preconception folic acid supplementation as part of maternal health services in India. PMID- 30026501 TI - A Multifunctional Interlayer for Solution Processed High Performance Indium Oxide Transistors. AB - Multiple functionality of tungsten polyoxometalate (POM) has been achieved applying it as interfacial layer for solution processed high performance In2O3 thin film transistors, which results in overall improvement of device performance. This approach not only reduces off-current of the device by more than two orders of magnitude, but also leads to a threshold voltage reduction, as well as significantly enhances the mobility through facilitated charge injection from the electrode to the active layer. Such a mechanism has been elucidated through morphological and spectroscopic studies. PMID- 30026503 TI - MicroRNA-132 - master regulator of neuronal health? PMID- 30026504 TI - Association of coding and UTR variants in the known regions with wet age-related macular degeneration in Han Chinese population. AB - Age-related macular degeneration (AMD) is the leading cause worldwide of severe visual impairment among people older than 55 years of age. This study aimed to investigate the genetic association between coding and untranslated region (UTR) variants in previously reported loci and exudative age-related macular degeneration (wet AMD) in a Han Chinese population. Using our previously published whole exome sequencing dataset of 349 wet AMD patients and 1253 controls, we searched for associations between coding and UTR variants of the 72 genes located within the 47 reported wet AMD loci regions. From these, 25 variants in 18 of the 72 genes with P < 10 * 10-3 were selected for the first replication of Sequenom mass-array genotyping in 885 wet AMD subjects and 562 controls. Next, four SNPs were selected for further validation by SNaPshot genotyping in a third Chinese cohort with 456 wet AMD subjects and 211 controls. As a result, we identified two new potential coding and UTR variant SNPs (rs189132250 in BBX located in 3q12.1 and rs144351944 in FILIP1L located in 3q12.1) that showed weak associations with wet AMD in the Han Chinese population. These findings provide new information regarding the coding and UTR variants of the known wet AMD loci in the studied Chinese cohort. PMID- 30026506 TI - Probing the coordination and function of Fe4S4 modules in nitrogenase assembly protein NifB. AB - NifB is an essential radical S-adenosylmethionine (SAM) enzyme for nitrogenase cofactor assembly. Previous studies show that NifB couples a putative pair of [Fe4S4] modules (designated K1 and K2) into an [Fe8S9C] cofactor precursor concomitant with radical SAM-dependent carbide insertion through the action of its SAM-binding [Fe4S4] module. However, the coordination and function of the NifB cluster modules remain unknown. Here, we use continuous wave and pulse electron paramagnetic resonance spectroscopy to show that K1- and K2-modules are 3-cysteine-coordinated [Fe4S4] clusters, with a histidine-derived nitrogen serving as the fourth ligand to K1 that is lost upon K1/K2-coupling. Further, we demonstrate that coexistence of SAM/K2-modules is a prerequisite for methyltransfer to K2 and hydrogen abstraction from the K2-associated methyl by a 5'-deoxyadenosyl radical. These results establish an important framework for mechanistic explorations of NifB while highlighting the utility of a synthetic cluster-based reconstitution approach employed herein in functional analyses of iron-sulfur (FeS) enzymes. PMID- 30026507 TI - Endometriosis. AB - Endometriosis is a common inflammatory disease characterized by the presence of tissue outside the uterus that resembles endometrium, mainly on pelvic organs and tissues. It affects ~5-10% of women in their reproductive years - translating to 176 million women worldwide - and is associated with pelvic pain and infertility. Diagnosis is reliably established only through surgical visualization with histological verification, although ovarian endometrioma and deep nodular forms of disease can be detected through ultrasonography and MRI. Retrograde menstruation is regarded as an important origin of the endometrial deposits, but other factors are involved, including a favourable endocrine and metabolic environment, epithelial-mesenchymal transition and altered immunity and inflammatory responses in genetically susceptible women. Current treatments are dictated by the primary indication (infertility or pelvic pain) and are limited to surgery and hormonal treatments and analgesics with many adverse effects that rarely provide long-term relief. Endometriosis substantially affects the quality of life of women and their families and imposes costs on society similar to those of other chronic conditions such as type 2 diabetes mellitus, Crohn's disease and rheumatoid arthritis. Future research must focus on understanding the pathogenesis, identifying disease subtypes, developing non-invasive diagnostic methods and targeting non-hormonal treatments that are acceptable to women who wish to conceive. PMID- 30026505 TI - A novel European H5N8 influenza A virus has increased virulence in ducks but low zoonotic potential. AB - We investigated in a unique setup of animal models and a human lung explant culture biological properties, including zoonotic potential, of a representative 2016 highly pathogenic avian influenza virus (HPAIV) H5N8, clade 2.3.4.4 group B (H5N8B), that spread rapidly in a huge and ongoing outbreak series in Europe and caused high mortality in waterfowl and domestic birds. HPAIV H5N8B showed increased virulence with rapid onset of severe disease and mortality in Pekin ducks due to pronounced neuro- and hepatotropism. Cross-species infection was evaluated in mice, ferrets, and in a human lung explant culture model. While the H5N8B isolate was highly virulent for Balb/c mice, virulence and transmissibility were grossly reduced in ferrets, which was mirrored by marginal replication in human lung cultures infected ex vivo. Our data indicate that the 2016 HPAIV H5N8B is avian-adapted with augmented virulence for waterfowl, but has low zoonotic potential. The here tested combination of animal studies with the inoculation of human explants provides a promising future workflow to evaluate zoonotic potential, mammalian replication competence and avian virulence of HPAIV. PMID- 30026508 TI - Author Correction: Subgenual anterior cingulate cortex controls sadness-induced modulations of cognitive and emotional network hubs. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30026509 TI - Difference of Sagittal Alignment between Adolescents with Symptomatic Lumbar Isthmic Spondylolisthesis and the General Population. AB - This case-control study aimed to investigate differences in the sagittal spinal parameters between the symptomatic spondylolisthesis patients and the general population. Twenty-nine adolescent patients with symptomatic lumbar isthmic spondylolisthesis were included. For each patient, two age-matched, gender matched and BMI-matched controls were enrolled. Comparison analyses detected higher values in the case group for the following parameters: CL (-22.06 +/- 7.552 degrees versus -20.36 +/- 7.016 degrees , P < 0.001), T1 Slope (19.84 +/- 8.708 degrees versus 13.99 +/- 6.537 degrees , P = 0.001), PT (21.54 +/- 9.082 degrees versus 8.87 +/- 7.863 degrees , P < 0.001), PI (64.45 +/- 13.957 degrees versus 43.60 +/- 9.669 degrees , P < 0.001), SS (42.90 +/- 9.183 degrees versus 34.73 +/- 8.265 degrees , P < 0.001), LL (-50.82 +/- 21.596 degrees versus 43.78 +/- 10.356 degrees , P = 0.042), SVA (16.99 +/- 14.625 mm versus 0.32 +/- 31.824 mm, P = 0.009), L5 Slope (33.95 +/- 13.567 degrees versus 19.03 +/- 6.809 degrees , P < 0.001), and L5I (8.90 +/- 6.556 degrees versus 1.29 +/- 6.726 degrees , P < 0.001). Conversely, TS-CL (6.56 +/- 6.716 degrees versus 11.04 +/- 7.085 degrees , P = 0.006), cSVA (11.31 +/- 6.867 mm versus 17.92 +/- 11.832 mm, P = 0.007), and TLK (-2.66 +/- 10.101 degrees versus 2.71 +/- 7.708 degrees , P = 0.007) were smaller in the case group. Slippage percentage was most correlated with PI (r = 0.530, P = 0.003), followed by PT (r = 0.465, P = 0.011) and L5I (r = 0.433, P = 0.019). Results of binary logistic regression showed that the main risk factor of isthmic spondylolisthesis was PI (OR = 1.145, 95%CI = 1.083-1.210, P < 0.001). Further subgroup analysis also showed that PI was the main risk factor of isthmic spondylolisthesis in the female adolescents (OR = 1.237, 95%CI = 1.086-1.493, P = 0.003) and in the male adolescents (OR = 1.523, 95%CI = 1.093 2.123, P = 0.013). PI was the main risk factor for adolescent symptomatic isthmic spondylolisthesis in the Chinese Han adolescents. The greater PI indicated the higher the progressive risk of spondylolisthesis. In these isthmic spondylolisthesis adolescents, the body always inclined forward and lumbar and cervical lordosis increased. PMID- 30026511 TI - Publisher Correction: A globally-distributed alien invasive species poses risks to United States imperiled species. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30026510 TI - The lincRNA MIRAT binds to IQGAP1 and modulates the MAPK pathway in NRAS mutant melanoma. AB - Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules. LncRNAs have been implicated in cancer development and response to different therapeutics and are thus potential treatment targets; however, the majority of their functions and molecular interactions remain unexplored. In this study, we identify a novel cytoplasmic intergenic lincRNA (MIRAT), which is upregulated following prolonged MAPK inhibition in NRAS mutant melanoma and modulates MAPK signaling by binding to the MEK scaffold protein IQGAP1. Collectively, our results present MIRAT's direct modulatory effect on the MAPK pathway and highlight the relevance of cytoplasmic lncRNAs as potential targets in drug resistant cancer. PMID- 30026512 TI - Predictors of Early Onset Multiple Organ Dysfunction in Major Burn Patients with Ventilator Support: Experience from A Mass Casualty Explosion. AB - Organ dysfunction is common in patients with major burns and associated with poor outcomes. The risk factors for early onset multiple organ dysfunction syndrome (MODS) in major burn patients with invasive ventilator support has rarely been evaluated before. In this study, major burn patients with invasive ventilator support from 499 victims suffered in a mass casualty color dust explosion were retrospectively enrolled. The development of early MODS that occurred within 5 days after burn injury was determined and the risk factors associated with early MODS were analyzed. A total of 88 patients from five medical centers were included. Their mean total body surface area (TBSA) was 60.9 +/- 15.8%, and 45 (51.1%) patients had early MODS. Hematologic failure was the most common organ failure (68.6%), followed by respiratory failure (48.9%). Independent clinical factors associated with early MODS included TBSA >=55% (OR: 3.83; 95% CI: 1.29 11.37) and serum albumin level <2.1 g/dL upon admission (OR: 3.43; 95% CI: 1.01 11.57). Patients with early MODS had prolonged ventilator dependence and longer ICU admission than those without early MODS. Our results showed that early MODS in major burn patients with invasive ventilator support is very common and can be predicted early on admission. PMID- 30026513 TI - Involvement of Endothelin 1 in Remote Preconditioning-Induced Cardioprotection through connexin 43 and Akt/GSK-3beta Signaling Pathway. AB - The present study was aimed to explore the role of endothelins in remote preconditioning (RP)-induced myocardial protection in ischemia-reperfusion (IR) injury. RP stimulus was given by subjecting hind limb to four cycles of ischemia and reperfuion (5 minutes each) using blood pressure cuff in male rats. Following RP, hearts were isolated and subjected to 30 minutes of ischemia and 120 minutes of reperfusion on Langendorff apparatus. The extent of myocardial injury was determined by measuring the levels of LDH-1, CK-MB and cardiac troponin T (cTnT) in coronary effluent; caspase-3 activity and Bcl 2 expression in heart (apoptosis); infarct size by triphenyl tetrazolium chloride and contractility parameters including left ventricular developed pressure, dp/dtmax dp/dtmin and heart rate. RP reduced ischemia reperfusion-induced myocardial injury, increased the levels of endothelin 1 (in blood), Akt-P, GSK-3beta-P and P-connexin 43 (in hearts). Pretreatment with ETA receptor antagonist, BQ 123 (1 and 2 mg/kg), ETB receptor antagonist, BQ 788 (1 and 3 mg/kg) and dual inhibitor of ETA and ETB receptor, bonsentan (25 and 50 mg/kg) abolished these effects of RP. However, the effects of bonsentan were more pronounced in comparison to BQ 123 and BQ 788. It is concluded that RP stimulus may release endothelin 1 in the blood, which may activate myocardial ETA and ETB receptors to trigger cardioprotection through connexin 43 and Akt/GSK-3beta pathway. PMID- 30026514 TI - The effects of Jerusalem artichoke and fermented soybean powder mixture supplementation on blood glucose and oxidative stress in subjects with prediabetes or newly diagnosed type 2 diabetes. AB - BACKGROUND/OBJECTIVES: The objective of this study was to evaluate the effect of supplementation with a Jerusalem artichoke and fermented soybean powder mixture on blood glucose and oxidative stress levels. SUBJECTS/METHODS: This randomized, double-blinded, placebo-controlled study was conducted on 60 subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or newly diagnosed type 2 diabetes. The subjects were randomly assigned to either a group that ingested 40 g of a Jerusalem artichoke and fermented soybean powder mixture (19.45 g each) daily or a group that received a placebo for 12 weeks. Paired t test and independent t-test were performed for comparisons within groups and between groups, respectively. RESULTS: Supplementation with the Jerusalem artichoke and fermented soybean powder mixture reduced the levels of fasting glucose (p < 0.001) and FFAs (p = 0.034), glucose at 60 min (p = 0.004), glucose (p = 0.006) areas under the response curve (AUC), homeostasis model assessment insulin resistance (p = 0.018), and the urinary 8-epi-prostaglandin F2alpha (8 epi-PGF2alpha) level (p = 0.028). The changes (Delta) in urinary 8-epi-PGF2alpha, glucose at 60 min, 120 min, and AUC, FFAs at 0 min and AUC were significantly different between the two groups. In addition, Delta glucose at 120 min (r = 0.472, p = 0.027) and the Delta glucose AUC (r = 0.572, p = 0.005) were positively correlated with ? plasma malondialdehyde in the test group. CONCLUSIONS: The consumption of a Jerusalem artichoke and fermented soybean powder mixture for 12 weeks was effective for reducing postprandial glucose and oxidative stress level, particularly 8-epi-PGF2alpha, in subjects with IFG, IGT, or newly diagnosed type 2 diabetes. PMID- 30026515 TI - Impact of honey on dental erosion and adhesion of early bacterial colonizers. AB - The aim was to investigate if honey causes erosion and if salivary pellicle modified with honey, or its components, or the by-product propolis has a protective effect against dental erosion and adhesion of early bacterial colonizers. The tested substances were: 3 types of honey, methylglyoxal (MGO), hydrogen peroxide, propolis. First in the erosion experiment, 120 human enamel specimens were covered with salivary pellicle and modified with the substances. Then they were eroded with 1% citric acid, pH 3.6 for 2 min, before surface hardness was measured. In the microbiological assay, the enamel specimens (n = 126) covered with modified salivary pellicle were contaminated with bacterial suspensions. The antimicrobial activity of each substance and their effect on early bacterial colonizer adhesion and biofilm formation were determined. Despite a low pH, honey did not cause erosion. On the other hand, pellicle modification with the tested solutions did not protect the enamel from erosion. Microbiologically, the 3 honeys inhibited species-specific growth of oral bacteria. Propolis decreased initial attachment of Streptococcus gordonii, while one honey inhibited demineralization of enamel by biofilm. In conclusion, pellicle modification with honey, or its components, or propolis did neither protect against erosion nor promote it. Propolis presented some bacterial adhesion inhibition. PMID- 30026516 TI - Discrimination of histopathologic types of childhood peripheral neuroblastic tumors based on clinical and biological factors. AB - The aim of this study was to discriminate the children malignant peripheral neuroblastic tumors (PNTs) from those with benign histotype ganglioneuroma (GN) based on clinical and biological characteristics in all PNTs. Four hundred and seventy-six patients were included in this study, containing 345 patients for model development and 131 patients for external validation. Multivariate logistic regression analysis was conducted to select potentially useful characteristics for discrimination of histopathology. External validation was performed for model evaluation. Compared with the main characteristics of GN (85/345, 24.6%), those of malignant PNTs (260/345, 75.4%) showed significant differences. Multivariate analysis was performed to further find the characteristics linked to histopathology. The results indicated that for the patients younger than 49 months, the primary site of adrenal and thoracic, the level of serum neuron specific enolase (NSE) > 33 ng/mL, and tumor encasing blood vessels were the extremely important discrimination factors of malignant PNTs. The area under the receiver-operating-characteristic of the discrimination model was 0.96. The accuracy rate, sensitivity and specificity were 93.4%, 96.3% and 83.8%, respectively. Meanwhile, the accuracy rate of the external validation from the 131 patients was 97.0%. Overall, histopathologic type of childhood malignant PNTs can be discriminated based on age, primary site, NSE level and the relationship between primary tumor and blood vessels. PMID- 30026517 TI - Long-range non-diffusive spin transfer in a Hall insulator. AB - We report on optical visualization of spin propagation more than 100 um. We present an electronic system in a new state of aggregation, the magnetofermionic condensate, in which the lowest-energy spin excitations - photoexcited spin triplet magnetoexcitons - freely propagate over long distances, in the order of a millimeter, which implies non-diffusion spin transport. Our results open up a completely new system suitable for spintronic devices. PMID- 30026518 TI - Enzymatic one-step ring contraction for quinolone biosynthesis. AB - The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate. PMID- 30026520 TI - Defence countermeasures. PMID- 30026519 TI - Preparation of Macrometallocycle and Selective Sensor for Copper Ion. AB - Two bis-imidazolium salts 1,8-bis[2'-(N-R-imidazoliumyl)acetylamino]naphthalene chloride (L1H4.Cl2: R = Et; L2H4.Cl2: R = nBu), as well as their four NHC metal complexes [L1H2Ag]Cl (1), [L1Ni] (2), [L2Ni] (3) and [L1H2Hg(HgCl4)] (4) have been synthesized. In each of the cationic moieties of complexes 1 or 4, there is a groove-like 14-membered macrometallocycle, and each macrometallocycle is consisted of one biscarbene ligand L1H2 and one metal ion (silver(I) ion for 1 and mercury(II) ion for 4). Three 6-membered cycles are contained in each molecule of complexes 2 or 3. Additionally, the selective recognition of macrometallocycle 1 for Cu2+ was studied with the methods of fluorescence and ultraviolet spectroscopy, 1H NMR titrations, MS and IR spectra. The experimental results display macrometallocycle 1 can discriminate Cu2+ from other cations effectively. PMID- 30026522 TI - Cancer: Releasing tumour suppressors. PMID- 30026521 TI - Publisher Correction: Mechanism of parkin activation by phosphorylation. AB - In the version of this article initially published, RING2 in the schematic to the left in Fig. 1b was mislabeled as RING0. The error has been corrected in the HTML and PDF versions of the article. PMID- 30026523 TI - Infectious disease: Curbing cholera. PMID- 30026525 TI - Genetic disorders: PI3K inhibitor reverses overgrowth syndrome. PMID- 30026526 TI - Autoimmune disease: A human antibody selectively targets regulatory T cells. PMID- 30026527 TI - Cardiovascular disease: Improving cardiomyocyte contractility. PMID- 30026528 TI - Trends driving clinical trials into large clinical care settings. PMID- 30026524 TI - Targeting the NLRP3 inflammasome in inflammatory diseases. AB - Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1beta (IL-1beta) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules. PMID- 30026529 TI - Anticancer therapy: Metabolic synthetic lethality. PMID- 30026530 TI - Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases. AB - Alternative splicing contributes to phenotypic diversity at multiple biological scales, and its dysregulation is implicated in both ageing and age-associated diseases in human. Cross-tissue variability in splicing further complicates its links to age-associated phenotypes and elucidating these links requires a comprehensive map of age-associated splicing changes across multiple tissues. Here, we generate such a map by analyzing ~8500 RNA-seq samples across 48 tissues in 544 individuals. Employing a stringent model controlling for multiple confounders, we identify 49,869 tissue-specific age-associated splicing events of 7 distinct types. We find that genome-wide splicing profile is a better predictor of biological age than the gene and transcript expression profiles, and furthermore, age-associated splicing provides additional independent contribution to age-associated complex diseases. We show that the age-associated splicing changes may be explained, in part, by concomitant age-associated changes of the upstream splicing factors. Finally, we show that our splicing-based model of age can successfully predict the relative ages of cells in 8 of the 10 paired longitudinal data as well as in 2 sets of cell passage data. Our study presents the first systematic investigation of age-associated splicing changes across tissues, and further strengthening the links between age-associated splicing and age-associated diseases. PMID- 30026531 TI - Faster growth with shorter antigens can explain a VSG hierarchy during African trypanosome infections: a feint attack by parasites. AB - The parasitic African trypanosome, Trypanosoma brucei, evades the adaptive host immune response by a process of antigenic variation that involves the clonal switching of variant surface glycoproteins (VSGs). The VSGs that come to dominate in vivo during an infection are not entirely random, but display a hierarchical order. How this arises is not fully understood. Combining available genetic data with mathematical modelling, we report a VSG-length-dependent hierarchical timing of clonal VSG dominance in a mouse model, consistent with an inverse correlation between VSG length and trypanosome growth-rate. Our analyses indicate that, among parasites switching to new VSGs, those expressing shorter VSGs preferentially accumulate to a detectable level that is sufficient to trigger a targeted immune response. This may be due to the increased metabolic cost of producing longer VSGs. Subsequent elimination of faster-growing parasites then allows slower growing parasites with longer VSGs to accumulate. This interaction between the host and parasite is able to explain the temporal distribution of VSGs observed in vivo. Thus, our findings reveal a length-dependent hierarchy that operates during T. brucei infection. This represents a 'feint attack' diversion tactic utilised by these persistent parasites to out-maneuver the host adaptive immune system. PMID- 30026533 TI - Endometriosis. PMID- 30026534 TI - Subsampling reveals that unbalanced sampling affects STRUCTURE results in a multi species dataset. AB - Studying the genetic population structure of species can reveal important insights into several key evolutionary, historical, demographic, and anthropogenic processes. One of the most important statistical tools for inferring genetic clusters is the program STRUCTURE. Recently, several papers have pointed out that STRUCTURE may show a bias when the sampling design is unbalanced, resulting in spurious joining of underrepresented populations and spurious separation of overrepresented populations. Suggestions to overcome this bias include subsampling and changing the ancestry model, but the performance of these two methods has not yet been tested on actual data. Here, I use a data set of 12 high-alpine plant species to test whether unbalanced sampling affects the STRUCTURE inference of population differentiation between the European Alps and the Carpathians. For four of the 12 species, subsampling of the Alpine populations-to match the sample size between the Alps and the Carpathians resulted in a drastically different clustering than the full data set. On the other hand, STRUCTURE results with the alternative ancestry model were indistinguishable from the results with the default model. Based on these results, the subsampling strategy seems a more viable approach to overcome the bias than the alternative ancestry model. However, subsampling is only possible when there is an a priori expectation of what constitute the main clusters. Though these results do not mean that the use of STRUCTURE should be discarded, it does indicate that users of the software should be cautious about the interpretation of the results when sampling is unbalanced. PMID- 30026532 TI - Genomic inference of the metabolism and evolution of the archaeal phylum Aigarchaeota. AB - Microbes of the phylum Aigarchaeota are widely distributed in geothermal environments, but their physiological and ecological roles are poorly understood. Here we analyze six Aigarchaeota metagenomic bins from two circumneutral hot springs in Tengchong, China, to reveal that they are either strict or facultative anaerobes, and most are chemolithotrophs that can perform sulfide oxidation. Applying comparative genomics to the Thaumarchaeota and Aigarchaeota, we find that they both originated from thermal habitats, sharing 1154 genes with their common ancestor. Horizontal gene transfer played a crucial role in shaping genetic diversity of Aigarchaeota and led to functional partitioning and ecological divergence among sympatric microbes, as several key functional innovations were endowed by Bacteria, including dissimilatory sulfite reduction and possibly carbon monoxide oxidation. Our study expands our knowledge of the possible ecological roles of the Aigarchaeota and clarifies their evolutionary relationship to their sister lineage Thaumarchaeota. PMID- 30026535 TI - Maternal betaine supplementation affects fetal growth and lipid metabolism of high-fat fed mice in a temporal-specific manner. AB - BACKGROUND/OBJECTIVES: Maternal obesity increases the risk of gestational diabetes mellitus (GDM), which results in fetal overgrowth and long-lasting metabolic dysfunctioning in the offspring. Previous studies show that maternal choline supplementation normalizes fetal growth and adiposity of progeny from obese mice. This study examines whether supplementation of betaine, a choline derivative, has positive effects on fetal metabolic outcomes in mouse progeny exposed to maternal obesity and GDM. METHODS: C57BL/6J mice were fed either a high-fat (HF) diet or a control (normal-fat, NF) diet and received either 1% betaine (BS) or control untreated (BC) drinking water 4-6 weeks before timed mating and throughout gestation. Maternal, placental, and fetal samples were collected for metabolite and gene-expression assays. RESULTS: At E12.5, BS prevented fetal and placental overgrowth and downregulated glucose and fatty acid transporters (Glut1 and Fatp1) and the growth-promoting insulin-like growth factor 2 (Igf2) and its receptor Igf1r in the placenta of HF, glucose-intolerant dams (P < 0.05). However, these effects disappeared at E17.5. At E17.5, BS reduced fetal adiposity and prevented liver triglyceride overaccumulation in HF versus NF fetuses (P < 0.05). BS fetal livers had enhanced mRNA expression of microsomal triglyceride transfer protein (Mttp) (P < 0.01), which promotes VLDL synthesis and secretion. Although we previously reported that maternal choline supplementation downregulated mRNA expression of genes involved in de novo lipogenesis in fetal livers, such alterations were not observed with BS, suggesting differential effects of betaine and choline on fetal gene expression. CONCLUSION: We propose a temporal-specific mechanism by which maternal BS influences fetal growth and lipid metabolic outcomes of HF mice during prenatal development. PMID- 30026536 TI - Size dependent effects of Gold Nanoparticles in ISO-induced Hyperthyroid Rats. AB - In this study, we applied different sizes of gold nanoparticles (Au-NPs) to isoproterenol (ISO)-induced hyperthyroid heart disease rats (HHD rats). Single dose of 5, 40, 100 nm Au-NPs were injected intravenously. Cardiac safety tests were evaluated by cardiac marker enzymes in serum and cardiac accumulation of Au NPs were measured by ICP-MS. Our results showed that size-dependent cardiac effects of Au-NPs in ISO-induced hyperthyroid rats. 5 nm Au-NPs had some cardiac protective effect but little accumulation in heart, probably due to smaller size Au-NPs can adapt to whole body easily in vivo. Histological analysis and TUNEL staining showed that Au-NPs can induce pathological alterations including cardiac fibrosis, apoptosis in control groups, however they can protect HHD groups from these harmful effects. Furthermore, transmission electron microscopy and western blotting employed on H9C2 cells showed that autophagy presented in Au-NPs treated cells and that Au-NPs can decrease LC3 II turning to LC3 I and decrease APG7 and caspase 12 in the process in HHD groups, while opposite effects on control groups were presented, which could be an adaptive inflammation reacts. As there are few animal studies about using nanoparticles in the treatment of heart disease, our in vivo and in vitro studies would provide valuable information before they can be considered for clinical use in general. PMID- 30026538 TI - Investigating the Association between Chronic Kidney Disease and Ischaemic Stroke from a Health Examination Database. AB - Stroke has become one of the leading causes of death, with ischaemic stroke as the most common type of stroke occurrence compared to haemorrhagic stroke. Chronic kidney disease(CKD), another important cause of death, shares several traditional cardiovascular riskfactors with ischaemic stroke. Therefore, it is important to examine the existence of shared risk factors in the association between CKD and ischaemic stroke. This study used a health examination database from a medical centre in Taiwan. A generalized linear regression analysis was used to determine the association between CKD and ischaemic stroke. The Maentel Haenszel test was performed to analyse the effect of possible confounding factors on the association between CKD and ischaemic stroke. A prevalence rate study showed that more subjects with CKD suffered from ischaemic stroke than subjects without CKD. Diabetes, hypertension, hypertriglyceridemia, and hypercholesterolemia were associated with increased risks of ischaemic stroke in CKD subjects. There was an inverse association of the odds ratio of ischaemic stroke between CKD and non-CKD patients, which implied that younger subjects with CKD should be made aware of ischaemic stroke prevention. PMID- 30026537 TI - HIV-1 targets L-selectin for adhesion and induces its shedding for viral release. AB - CD4 and chemokine receptors mediate HIV-1 attachment and entry. They are, however, insufficient to explain the preferential viral infection of central memory T cells. Here, we identify L-selectin (CD62L) as a viral adhesion receptor on CD4+ T cells. The binding of viral envelope glycans to L-selectin facilitates HIV entry and infection, and L-selectin expression on central memory CD4+ T cells supports their preferential infection by HIV. Upon infection, the virus downregulates L-selectin expression through shedding, resulting in an apparent loss of central memory CD4+ T cells. Infected effector memory CD4+ T cells, however, remain competent in cytokine production. Surprisingly, inhibition of L selectin shedding markedly reduces HIV-1 infection and suppresses viral release, suggesting that L-selectin shedding is required for HIV-1 release. These findings highlight a critical role for cell surface sheddase in HIV-1 pathogenesis and reveal new antiretroviral strategies based on small molecular inhibitors targeted at metalloproteinases for viral release. PMID- 30026539 TI - Systematic evaluation of error rates and causes in short samples in next generation sequencing. AB - Next-generation sequencing (NGS) is the method of choice when large numbers of sequences have to be obtained. While the technique is widely applied, varying error rates have been observed. We analysed millions of reads obtained after sequencing of one single sequence on an Illumina sequencer. According to our analysis, the index-PCR for sample preparation has no effect on the observed error rate, even though PCR is traditionally seen as one of the major contributors to enhanced error rates in NGS. In addition, we observed very persistent pre-phasing effects although the base calling software corrects for these. Removal of shortened sequences abolished these effects and allowed analysis of the actual mutations. The average error rate determined was 0.24 +/- 0.06% per base and the percentage of mutated sequences was found to be 6.4 +/- 1.24%. Constant regions at the 5'- and 3'-end, e.g., primer binding sites used in in vitro selection procedures seem to have no effect on mutation rates and re sequencing of samples obtains very reproducible results. As phasing effects and other sequencing problems vary between equipment and individual setups, we recommend evaluation of error rates and types to all NGS-users to improve the quality and analysis of NGS data. PMID- 30026540 TI - Novel 2-phenyloxypyrimidine derivative induces apoptosis and autophagy via inhibiting PI3K pathway and activating MAPK/ERK signaling in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality globally. Because most patients are diagnosed at advanced stages of the disease, multi-targeted tyrosine kinase inhibitor sorafenib is the only available drug to show limited effectiveness. Novel and effective therapies are unmet medical need for advanced HCC patients. Given that the aberrant expression and activity of platelet-derived growth factor receptor alpha (PDGFRalpha) are closely associated with the pathogenesis of HCC, here we present the discovery and identification of a novel PDGFRalpha inhibitor, N-(3-((4-(benzofuran-2 yl)pyrimidin-2-yl)oxy)-4-methylphenyl)-4-((4-methylpiperazin-1 yl)methyl)benzamide (E5) after comparison of different derivatives. We found that E5 inhibited proliferation and induced apoptosis in HCC cells. Since the pan caspase inhibitor Z-VAD-FMK partially rescued HCC cells from E5-reduced cell viability, autophagic cell death triggered by E5 was subsequently investigated. E5 could induce the conversion of LC3-I to LC3-II, increase the expression of Atg5 and restore the autophagy flux blocked by chloroquine. Meanwhile, E5 was able to downregulate the PDGFRalpha/PI3K/AKT/mTOR pathway and to activate MAPK/ERK signaling pathway. Taken together, in addition to the possibility of E5 as a valuable drug candidate, the present study further supports the notion that targeted inhibition of PDGFRalpha is a promising therapeutic strategy for HCC. PMID- 30026541 TI - Arrestins as rheostats of GPCR signalling. PMID- 30026542 TI - Native point defects of semiconducting layered Bi2O2Se. AB - Bi2O2Se is an emerging semiconducting, air-stable layered material (Nat. Nanotechnol. 2017, 12, 530; Nano Lett. 2017, 17, 3021), potentially exceeding MoS2 and phosphorene in electron mobility and rivalling typical Van der Waals stacked layered materials in the next-generation high-speed and low-power electronics. Holding the promise of functional versatility, it is arousing rapidly growing interest from various disciplines, including optoelectronics, thermoelectronics and piezoelectronics. In this work, we comprehensively study the electrical properties of the native point defects in Bi2O2Se, as an essential step toward understanding the fundamentals of this material. The defect landscapes dependent on both Fermi energy and the chemical potentials of atomic constituents are investigated. Along with the bulk defect analysis, a complementary inspection of the surface properties, within the simple context of charge neutrality level model, elucidates the observed n-type characteristics of Bi2O2Se based FETs. This work provides important guide to engineer the defects of Bi2O2Se for desired properties, which is key to the successful application of this emerging layered material27. PMID- 30026543 TI - Controls on explosive-effusive volcanic eruption styles. AB - One of the biggest challenges in volcanic hazard assessment is to understand how and why eruptive style changes within the same eruptive period or even from one eruption to the next at a given volcano. This review evaluates the competing processes that lead to explosive and effusive eruptions of silicic magmas. Eruptive style depends on a set of feedback involving interrelated magmatic properties and processes. Foremost of these are magma viscosity, gas loss and external properties such as conduit geometry. Ultimately, these parameters control the speed at which magmas ascend, decompress and outgas en route to the surface, and thus determine eruptive style and evolution. PMID- 30026544 TI - Quantifying the spatial spread of dengue in a non-endemic Brazilian metropolis via transmission chain reconstruction. AB - The ongoing geographical expansion of dengue is inducing an epidemiological transition in many previously transmission-free urban areas, which are now prone to annual epidemics. To analyze the spatiotemporal dynamics of dengue in these settings, we reconstruct transmission chains in Porto Alegre, Brazil, by applying a Bayesian inference model to geo-located dengue cases from 2013 to 2016. We found that transmission clusters expand by linearly increasing their diameter with time, at an average rate of about 600 m month-1. The majority (70.4%, 95% CI: 58.2-79.8%) of individual transmission events occur within a distance of 500 m. Cluster diameter, duration, and epidemic size are proportionally smaller when control interventions were more timely and intense. The results suggest that a large proportion of cases are transmitted via short-distance human movement (<1 km) and a limited contribution of long distance commuting within the city. These results can assist the design of control policies, including insecticide spraying and strategies for active case finding. PMID- 30026545 TI - Structure of the replication regulator Sap1 reveals functionally important interfaces. AB - The mechanism by which specific protein-DNA complexes induce programmed replication fork stalling in the eukaryotic genome remains poorly understood. In order to shed light on this process we carried out structural investigations on the essential fission yeast protein Sap1. Sap1 was identified as a protein involved in mating-type switching in Schizosaccharomyces pombe, and has been shown to be involved in programmed replication fork stalling. Interestingly, Sap1 assumes two different DNA binding modes. At the mating-type locus dimers of Sap1 bind the SAS1 sequence in a head-to-head arrangement, while they bind to replication fork blocking sites at rDNA and Tf2 transposons in a head-to-tail mode. In this study, we have solved the crystal structure of the Sap1 DNA binding domain and we observe that Sap1 molecules interact in the crystal using a head-to tail arrangement that is compatible with DNA binding. We find that Sap1 mutations which alleviate replication-fork blockage at Tf2 transposons in CENP-B mutants map to the head-to-tail interface. Furthermore, several other mutations introduced in this interface are found to be lethal. Our data suggests that essential functions of Sap1 depend on its head-to-tail oligomerization. PMID- 30026546 TI - Interactions of bacteriophage T4 adhesin with selected lipopolysaccharides studied using atomic force microscopy. AB - The interaction between the T4 bacteriophage gp37 adhesin and the bacterial lipopolysaccharide (LPS) is a well-studied system, however, the affinity and strength of the interaction haven't been analyzed so far. Here, we use atomic force microscopy to determine the strength of the interaction between the adhesin and its receptor, namely LPS taken from a wild strain of E. coli B. As negative controls we used LPSs of E. coli O111:B and Hafnia alvei. To study the interaction an AFM tip modified with the gp37 adhesin was used to scan surfaces of mica covered with one of the three different LPSs. Using the correlation between the surface topography images and the tip-surface interaction we could verify the binding between the specific LPS and the tip in contrast to the very weak interaction between the tip and the non-binding LPSs. Using force spectroscopy we could then measure the binding strength by pulling on the AFM tip until it lifted off from the surface. The force necessary to break the interaction between gp37 and LPS from E. coli B, LPS from E. coli O111:B and LPS from H. alvei were measured to be 70 +/- 29 pN, 46 +/- 13 pN and 45 +/- 14 pN, respectively. The latter values are likely partially due to non-specific interaction between the gp37 and the solid surface, as LPS from E. coli O111:B and LPS from H. alvei have been shown to not bind to gp37, which is confirmed by the low correlation between binding and topography for these samples. PMID- 30026548 TI - Large body size constrains dispersal assembly of communities even across short distances. AB - Dispersal limitation has been considered to decrease with body size in animals and to be an important factor limiting community assembly on spatially isolated patches. Here we hypothesize that for flightless bark-dwelling oribatid mites dispersal limitation onto young trees might increase with body size (due to a decrease in aerial dispersal capacities), and it might occur even within a spatially contiguous forest canopy. We suppressed dispersal limitation towards branches from young trees by physically connecting them to branches from old trees and analyzed the impacts on community composition, accounting for branch microhabitat variables. Suppression of dispersal limitation increased community evenness and mean body size of mites on branches from young trees. Across all species, large species body-size corresponds to an abundance increase after suppression of dispersal limitation. Consistently, on no-contact control branches, mite body-sizes were larger on branches from old compared to young trees. Our study suggests that colonization/performance trade-offs might affect community assembly even across seemingly contiguous habitats. Overall, a previously underappreciated factor selecting against large body size in flightless canopy-dwelling invertebrates might be that large bodies makes these invertebrates fall faster and disperse less, not more. PMID- 30026547 TI - Mapping the sensing spots of aerolysin for single oligonucleotides analysis. AB - Nanopore sensing is a powerful single-molecule method for DNA and protein sequencing. Recent studies have demonstrated that aerolysin exhibits a high sensitivity for single-molecule detection. However, the lack of the atomic resolution structure of aerolysin pore has hindered the understanding of its sensing capabilities. Herein, we integrate nanopore experimental results and molecular simulations based on a recent pore structural model to precisely map the sensing spots of this toxin for ssDNA translocation. Rationally probing ssDNA length and composition upon pore translocation provides new important insights for molecular determinants of the aerolysin nanopore. Computational and experimental results reveal two critical sensing spots (R220, K238) generating two constriction points along the pore lumen. Taking advantage of the sensing spots, all four nucleobases, cytosine methylation and oxidation of guanine can be clearly identified in a mixture sample. The results provide evidence for the potential of aerolysin as a nanosensor for DNA sequencing. PMID- 30026549 TI - Arylsulphatase A Pseudodeficiency (ARSA-PD), hypertension and chronic renal disease in Aboriginal Australians. AB - Chronic renal disease (CRD) associated with cardiovascular disease (CVD) and/or type 2 diabetes (T2D) is a significant problem in Aboriginal Australians. Whole exome sequencing data (N = 72) showed enrichment for ClinVar pathogenic variants in gene sets/pathways linking lipoprotein, lipid and glucose metabolism. The top Ingenuity Pathway Analysis canonical pathways were Farsenoid X Receptor and Retinoid Receptor (FXR/RXR; (P = 1.86 * 10-7), Liver X Receptor and Retinoid Receptor (LXR/RXR; P = 2.88 * 10-6), and atherosclerosis signalling (P = 3.80 * 10-6). Top pathways/processes identified using Enrichr included: Reactome 2016 chylomicron-mediated lipid transport (P = 3.55 * 10-7); Wiki 2016 statin (P = 8.29 * 10-8); GO Biological Processes 2017 chylomicron remodelling (P = 1.92 * 10 8). ClinVar arylsulfatase A pseudodeficiency (ARSA-PD) pathogenic variants were common, including the missense variant c.511 G > A (p.Asp171Asn; rs74315466; frequency 0.44) only reported in Polynesians. This variant is in cis with known ARSA-PD 3' regulatory c.*96 A > G (rs6151429; frequency 0.47) and missense c.1055 A > G (p.Asn352Ser; rs2071421; frequency 0.47) variants. These latter two variants are associated with T2D (risk haplotype GG; odds ratio 2.67; 95% CI 2.32 3.08; P = 2.43 * 10-4) in genome-wide association data (N = 402), but are more strongly associated with quantitative traits (DBP, SBP, ACR, eGFR) for hypertension and renal function in non-diabetic than diabetic subgroups. Traits associated with CVD, CRD and T2D in Aboriginal Australians provide novel insight into function of ARSA-PD variants. PMID- 30026550 TI - CTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells. AB - Telomerase elongates the telomeric G-strand to prevent telomere shortening through conventional DNA replication. However, synthesis of the complementary C strand by DNA polymerase alpha is also required to maintain telomere length. Polymerase alpha cannot perform this role without the ssDNA binding complex CST (CTC1-STN1-TEN1). Here we describe the roles of individual CST subunits in telomerase regulation and G-overhang maturation in human colon cancer cells. We show that CTC1-STN1 limits telomerase action to prevent G-overhang overextension. CTC1-/- cells exhibit telomeric DNA damage and growth arrest due to overhang elongation whereas TEN1-/- cells do not. However, TEN1 is essential for C-strand synthesis and TEN1-/- cells exhibit progressive telomere shortening. DNA binding analysis indicates that CTC1-STN1 retains affinity for ssDNA but TEN1 stabilizes binding. We propose CTC1-STN1 binding is sufficient to terminate telomerase action but altered DNA binding dynamics renders CTC1-STN1 unable to properly engage polymerase alpha on the overhang for C-strand synthesis. PMID- 30026551 TI - Identification of dynamic undifferentiated cell states within the male germline. AB - The role of stem cells in tissue maintenance is appreciated and hierarchical models of stem cell self-renewal and differentiation often proposed. Stem cell activity in the male germline is restricted to undifferentiated A-type spermatogonia (Aundiff); however, only a fraction of this population act as stem cells in undisturbed testis and Aundiff hierarchy remains contentious. Through newly developed compound reporter mice, here we define molecular signatures of self-renewing and differentiation-primed adult Aundiff fractions and dissect Aundiff heterogeneity by single-cell analysis. We uncover an unappreciated population within the self-renewing Aundiff fraction marked by expression of embryonic patterning genes and homeodomain transcription factor PDX1. Importantly, we find that PDX1 marks a population with potent stem cell capacity unique to mature, homeostatic testis and demonstrate dynamic interconversion between PDX1+ and PDX1- Aundiff states upon transplant and culture. We conclude that Aundiff exist in a series of dynamic cell states with distinct function and provide evidence that stability of such states is dictated by niche-derived cues. PMID- 30026552 TI - Chromatin remodeling in Drosophila preblastodermic embryo extract. AB - Chromatin is known to undergo extensive remodeling during nuclear reprogramming. However, the factors and mechanisms involved in this remodeling are still poorly understood and current experimental approaches to study it are not best suited for molecular and genetic analyses. Here we report on the use of Drosophila preblastodermic embryo extracts (DREX) in chromatin remodeling experiments. Our results show that incubation of somatic nuclei in DREX induces changes in chromatin organization similar to those associated with nuclear reprogramming, such as rapid binding of the germline specific linker histone dBigH1 variant to somatic chromatin, heterochromatin reorganization, changes in the epigenetic state of chromatin, and nuclear lamin disassembly. These results raise the possibility of using the powerful tools of Drosophila genetics for the analysis of chromatin changes associated with this essential process. PMID- 30026554 TI - Phytolith assemblage analysis for the identification of rice paddy. AB - The rice arable system is of importance to both society and the environment. The emergence of rice paddies was a crucial step in the transition from pre-domestic cultivation to systematic land use and management. However, many aspects of the formation of rice farming systems remain unclear. An important reason is the lack of reliable methods for identifying early rice paddies. One possible means of remedying this knowledge deficit is through analysis of phytolith assemblages, which are closely related to their parent plant communities. In this study, phytolith assemblages from 27 surface soil samples from wild rice fields, 91 surface soil samples from modern rice paddies, and 50 soil samples from non-rice fields were analysed to establish a discriminant function. This discriminant function enabled classification of 89.3% of the samples into appropriate groups. Further, the results suggested that phytolith assemblages can be used to identify rice fields and differentiate between wild rice fields and domesticated rice fields. The method was demonstrated to be an effective way of utilising the large amounts of unidentifiable phytoliths discovered at archaeological sites to provide a modern analogue that may be a valuable key to unlocking the past. PMID- 30026553 TI - Runx1-Stat3 signaling regulates the epithelial stem cells in continuously growing incisors. AB - Rodent incisors grow permanently and the homeostasis of enamel production is maintained by a continuous supply of epithelial progenitors from putative stem cells in the cervical loop. We herein report that Runx1 regulates the Lgr5 expressing epithelial stem cells and their subsequent continuous differentiation into ameloblasts. Mice deficient in epithelial Runx1 demonstrate remarkable shortening of the incisors with underdevelopment of the cervical loop and enamel defects. In this mutant cervical loop, the proliferation of the dental epithelium was significantly disturbed and the expression of Lgr5 and enamel matrix proteins was remarkably downregulated. Interestingly, the expression of Socs3, an inhibitor of Stat3 signaling, was upregulated and Stat3 phosphorylation was suppressed specifically in the mutant cervical loop. The expression of Lgr5 and the enamel matrix protein in the wild-type incisor germs is disturbed by pharmaceutical Stat3 inhibition in vitro., of. Conversely, pharmaceutical activation of Stat3 rescues the defective phenotypes of the Runx1 mutant with upregulated Lgr5 and enamel matrix protein genes. The present results provide the first evidence of the role of Runx1 regulates the Lgr5-expressing epithelial stem cells and differentiation of ameloblast progenitors in the developing incisors. Our study also demonstrates that Stat3 modulates the Runx1-Lgr5 axis in the cervical loop. PMID- 30026556 TI - Novel perspectives in the management of decompensated cirrhosis. AB - The current approaches to the management of patients with decompensated cirrhosis are based on targeted strategies aimed at preventing or treating specific complications of the disease. The improved knowledge of the pathophysiological background of advanced cirrhosis, represented by a sustained systemic inflammation strictly linked to a circulatory dysfunction, provides a novel paradigm for the management of these patients, with the ambitious target of modifying the course of the disease by preventing the onset of complications and multiorgan failure; these interventions will eventually improve patients' quality of life, prolong survival and reduce health-care costs. Besides aetiological treatments, these goals could be achieved by persistently antagonizing key pathophysiological events, such as portal hypertension, abnormal bacterial translocation from the gut, liver damage, systemic inflammation, circulatory dysfunction and altered immunological responses. Interestingly, in addition to strategies based on new therapeutic agents, these targets can be tackled by employing drugs that are already used in patients with cirrhosis for different indications or in other clinical settings, including non-absorbable oral antibiotics, non-selective beta-blockers, human albumin and statins. The scope of the present Review includes reporting updated information on the treatments that promise to influence the course of advanced cirrhosis and thus act as disease modifying agents. PMID- 30026555 TI - A Novel In Vivo Model to Study Impaired Tissue Regeneration Mediated by Cigarette Smoke. AB - Cigarette smoke is associated with several pathologies including chronic respiratory diseases and cancer. In addition, exposure to cigarette smoke is correlated with impaired wound healing, where a significant decrease in the regenerative capacity of smokers is well documented and broadly considered a negative risk factor after trauma or surgery. So far, some in vitro and in vivo models have been described to study how exposure to cigarette smoke diminishes the regenerative potential in different organisms. However, although useful, many of these models are difficult and expensive to implement and do not allow high throughput screening approaches. In order to establish a reliable and accessible model, we have evaluated the effects of cigarette smoke extract (CSE) on zebrafish development and regeneration. In this work, zebrafish embryos and larvae were exposed to low doses of aqueous CSE showing severe developmental abnormalities in a dose-dependent manner. Furthermore, when adult zebrafish were subjected to caudal fin amputation, we observed a significant decrease in the regenerative capacity of animals exposed to CSE. The effect was exacerbated in male and aged fish compared to female or young organisms. The establishment of a zebrafish model to assess the consequences of cigarette smoke and its effects on animal physiology could provide a new tool to study the underlying mechanisms involved in impaired tissue regeneration, and aid the development of novel approaches to treat complications associated with cigarette smoke toxicity. PMID- 30026557 TI - Assessment of the impact of shared brain imaging data on the scientific literature. AB - Data sharing is increasingly recommended as a means of accelerating science by facilitating collaboration, transparency, and reproducibility. While few oppose data sharing philosophically, a range of barriers deter most researchers from implementing it in practice. To justify the significant effort required for sharing data, funding agencies, institutions, and investigators need clear evidence of benefit. Here, using the International Neuroimaging Data-sharing Initiative, we present a case study that provides direct evidence of the impact of open sharing on brain imaging data use and resulting peer-reviewed publications. We demonstrate that openly shared data can increase the scale of scientific studies conducted by data contributors, and can recruit scientists from a broader range of disciplines. These findings dispel the myth that scientific findings using shared data cannot be published in high-impact journals, suggest the transformative power of data sharing for accelerating science, and underscore the need for implementing data sharing universally. PMID- 30026558 TI - Uncertainty Quantification of Extratropical Forest Biomass in CMIP5 Models over the Northern Hemisphere. AB - Simplified representations of processes influencing forest biomass in Earth system models (ESMs) contribute to large uncertainty in projections. We evaluate forest biomass from eight ESMs outputs archived in the Coupled Model Intercomparison Project Phase 5 (CMIP5) using the biomass data synthesized from radar remote sensing and ground-based observations across northern extratropical latitudes. ESMs exhibit large biases in the forest distribution, forest fraction, and mass of carbon pools that contribute to uncertainty in forest total biomass (biases range from -20 Pg C to 135 Pg C). Forest total biomass is primarily positively correlated with precipitation variations, with surface temperature becoming equally important at higher latitudes, in both simulations and observations. Relatively small differences in forest biomass between the pre industrial period and the contemporary period indicate uncertainties in forest biomass were introduced in the pre-industrial model equilibration (spin-up), suggesting parametric or structural model differences are a larger source of uncertainty than differences in transient responses. Our findings emphasize the importance of improved (1) models of carbon allocation to biomass compartments, (2) distribution of vegetation types in models, and (3) reproduction of pre industrial vegetation conditions, in order to reduce the uncertainty in forest biomass simulated by ESMs. PMID- 30026559 TI - Evaluation of Oxford Nanopore's MinION Sequencing Device for Microbial Whole Genome Sequencing Applications. AB - The MinION sequencer (Oxford Nanopore Technologies) is a paradigm shifting device allowing rapid, real time long read sequencing of nucleic acids. Yet external benchmarking of this technologies' capabilities has not been extensively reported, nor has thorough evaluation of its utility for field-based analysis with sub-optimal sample types been described. The aim of this study was to evaluate the capability of the MinION sequencer for bacterial genomic and metagenomic applications, with specific emphasis placed on the quality, yield, and accuracy of generated sequence data. Two independent laboratories at the National Microbiology Laboratory (Public Health Agency of Canada), sequenced a set of microbes in replicate, using the currently available flowcells, sequencing chemistries, and software available at the time of the experiment. Overall sequencing yield and quality improved through the course of this set of experiments. Sequencing alignment accuracy was high reaching 97% for all 2D experiments, though was slightly lower for 1D sequencing (94%). 1D sequencing provided much longer sequences than 2D. Both sequencing chemistries performed equally well in constructing genomic assemblies. There was evidence of barcode cross-over using both the native and PCR barcoding methods. Despite the sub optimal nature of samples sequenced in the field, sequences attributable to B. anthracis the target organism used in this scenario, could none-the-less be detected. Together, this report showcases the rapid advancement in this technology and its utility in the context of genomic sequencing of microbial isolates of importance to public health. PMID- 30026561 TI - Epidemiology of hypertension among Bangladeshi adults using the 2017 ACC/AHA Hypertension Clinical Practice Guidelines and Joint National Committee 7 Guidelines. AB - In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) released updated guidelines on the definition of hypertension, and blood pressure thresholds for initiation of antihypertensive medication. Our objective was to assess the change in prevalence of hypertension, risk factors, and identify populations recommended for treatment among Bangladeshi adults, based on the 2017 ACC/AHA guidelines. Data for this analysis were collected from a population-based nationally representative sample of 1843 Bangladeshi adults, aged >=18 years in 2015. Hypertension was defined based on two definitions: the JNC 7 guidelines (SBP >= 140 or DBP >= 90 mmHg), and the 2017 ACC/AHA guidelines (SBP >= 130 mmHg, or DBP >= 80 mmHg), or a self-reported diagnosis of hypertension. Based on the 2017 ACC/AHA guidelines, the prevalence of hypertension was 40.7% (95% CI: 38.5-43.0). The prevalence of JNC 7 definition of hypertension was 17.9% (95% CI: 16.2-19.7), indicating a 22.8% increase in prevalence. Based on both definitions, urban residents, older adults, adults with low physical activity, obese, abdominally obese, and diabetic adults were more likely to have hypertension. Based on current JNC 7 guidelines, only half of hypertensive adults were aware of having hypertension. Among those aware of their condition, 75% were taking medication based on self-report. Using the 2017 ACC/AHA guidelines, the prevalence of hypertension will more than double in Bangladesh. Newly diagnosed hypertensive adults will be considered high-risk for cardiovascular disease leading to a larger burden on Bangladesh's health system. However, implementation of the ACC/AHA guidelines may improve prevention efforts where lifestyle changes are appropriate. PMID- 30026560 TI - PRMT5-mediated regulation of developmental myelination. AB - Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system. They are derived from differentiation of oligodendrocyte progenitors through a process requiring cell cycle exit and histone modifications. Here we identify the histone arginine methyl-transferase PRMT5, a molecule catalyzing symmetric methylation of histone H4R3, as critical for developmental myelination. PRMT5 pharmacological inhibition, CRISPR/cas9 targeting, or genetic ablation decrease p53-dependent survival and impair differentiation without affecting proliferation. Conditional ablation of Prmt5 in progenitors results in hypomyelination, reduced survival and differentiation. Decreased histone H4R3 symmetric methylation is followed by increased nuclear acetylation of H4K5, and is rescued by pharmacological inhibition of histone acetyltransferases. Data obtained using purified histones further validate the results obtained in mice and in cultured oligodendrocyte progenitors. Together, these results identify PRMT5 as critical for oligodendrocyte differentiation and developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation. PMID- 30026562 TI - Multiple Cold-Water Immersions Attenuate Muscle Damage but not Alter Systemic Inflammation and Muscle Function Recovery: A Parallel Randomized Controlled Trial. AB - The aim of this study was to investigate the effects of multiple cold-water immersions (CWIs) on muscle function, markers of muscle damage, systemic inflammation and ECM degradation following exercise-induced muscle damage (EIMD). Thirty physically active males were randomly assigned to either a control (n = 15) or cold-water immersion (CWI) group (n = 15). The CWI group performed one immersion (10 degrees C for 20 min) at post-exercise and every 24 h for the following 72 h, while the control group remained in a seated position during these corresponding periods. Muscle strength, vertical jump height, muscle thickness, delayed-onset muscle soreness (DOMS), systemic creatine kinase (CK), C reactive protein (CRP), inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) activity were assessed at Pre, Post, 24, 48, 72, 96 and 168 h following EIMD. No significant time * group interaction was obtained for muscle strength, vertical jump height recovery and MMP-2 activity (p > 0.05). At 24 h, muscle thickness from the CWI group returned to baseline and was lower than the control (p = 0.04). DOMS returned to baseline at 168 h for the CWI group (p = 0.109) but not for the control (p = 0.008). At 168 h, CK showed a time-group difference with a greater peak for the control group (p = 0.016). In conclusion, multiple CWIs attenuated muscle damage, but not altered systemic inflammation and muscle function recovery. PMID- 30026563 TI - Response Surface Methodology-Genetic Algorithm Based Medium Optimization, Purification, and Characterization of Cholesterol Oxidase from Streptomyces rimosus. AB - The applicability of the statistical tools coupled with artificial intelligence techniques was tested to optimize the critical medium components for the production of extracellular cholesterol oxidase (COD; an enzyme of commercial interest) from Streptomyces rimosus MTCC 10792. The initial medium component screening was performed using Placket-Burman design with yeast extract, dextrose, starch and ammonium carbonate as significant factors. Response surface methodology (RSM) was attempted to develop a statistical model with a significant coefficient of determination (R2 = 0.89847), followed by model optimization using Genetic Algorithm (GA). RSM-GA based optimization approach predicted that the combination of yeast extract, dextrose, starch and ammonium carbonate at concentrations 0.99, 0.8, 0.1, and 0.05 g/100 ml respectively, has resulted in 3.6 folds increase in COD production (5.41 U/ml) in comparison with the un optimized medium (1.5 U/ml). COD was purified 10.34 folds having specific activity of 12.37 U/mg with molecular mass of 54 kDa. The enzyme was stable at pH 7.0 and 40 degrees C temperature. The apparent Michaelis constant (Km) and Vmax values of COD were 0.043 mM and 2.21 MUmol/min/mg, respectively. This is the first communication reporting RSM-GA based medium optimization, purification and characterization of COD by S. rimosus isolated from the forest soil of eastern India. PMID- 30026564 TI - New dates on dingo bones from Madura Cave provide oldest firm evidence for arrival of the species in Australia. AB - The dingo is the only placental land mammal aside from murids and bats to have made the water crossings to reach Australia prior to European arrival. It is thought that they arrived as a commensal animal with people, some time in the mid Holocene. However, the timing of their arrival is still a subject of major debate with published age estimates varying widely. This is largely because the age estimates for dingo arrival are based on archaeological deposit dates and genetic divergence estimates, rather than on the dingo bones themselves. Currently, estimates vary from between 5000-4000 years ago, for finds from archaeological contexts, and as much as 18,000 based on DNA age estimates. The timing of dingo arrival is important as post arrival they transformed Indigenous societies across mainland Australia and have been implicated in the extinction of a number of animals including the Tasmanian tiger. Here we present the results of direct dating of dingo bones from their oldest known archaeological context, Madura Cave on the Nullarbor Plain. These dates demonstrate that dingoes were in southern Australia by between 3348 and 3081 years ago. We suggest that following their introduction the dingo may have spread extremely rapidly throughout mainland Australia. PMID- 30026565 TI - Microglia permit climbing fiber elimination by promoting GABAergic inhibition in the developing cerebellum. AB - Circuit refinement during postnatal development is finely regulated by neuron neuron interactions. Recent studies suggest participation of microglia in this process but it is unclear how microglia cooperatively act with neuronal mechanisms. To examine roles of microglia, we ablate microglia by microglia selective deletion of colony-stimulating factor 1 receptor (Csf1r) by crossing floxed-Csf1r and Iba1-iCre mice (Csf1r-cKO). In Csf1r-cKO mice, refinement of climbing fiber (CF) to Purkinje cell (PC) innervation after postnatal day 10 (P10)-P12 is severely impaired. However, there is no clear morphological evidence suggesting massive engulfment of CFs by microglia. In Csf1r-cKO mice, inhibitory synaptic transmission is impaired and CF elimination is restored by diazepam, which suggests that impairment of CF elimination is caused by a defect of GABAergic inhibition on PCs, a prerequisite for CF elimination. These results indicate that microglia primarily promote GABAergic inhibition and secondarily facilitate the mechanism for CF elimination inherent in PCs. PMID- 30026566 TI - Global investigation of an engineered nitrogen-fixing Escherichia coli strain reveals regulatory coupling between host and heterologous nitrogen-fixation genes. AB - Transfer of nitrogen fixation (nif) genes from diazotrophs to amenable heterologous hosts is of increasing interest to genetically engineer nitrogen fixation. However, how the non-diazotrophic host maximizes opportunities to fine tune the acquired capacity for nitrogen fixation has not been fully explored. In this study, a global investigation of an engineered nitrogen-fixing Escherichia coli strain EN-01 harboring a heterologous nif island from Pseudomonas stutzeri was performed via transcriptomics and proteomics analyses. A total of 1156 genes and 206 discriminative proteins were found to be significantly altered when cells were incubated under nitrogen-fixation conditions. Pathways for regulation, metabolic flux and oxygen protection to nitrogenase were particularly discussed. An NtrC-dependent regulatory coupling between E. coli nitrogen regulation system and nif genes was established. Additionally, pentose phosphate pathway was proposed to serve as the primary route for glucose catabolism and energy supply to nitrogenase. Meanwhile, HPLC analysis indicated that organic acids produced by EN-01 might have negative effects on nitrogenase activity. This study provides a global view of the complex network underlying the acquired nif genes in the recombinant E. coli and also provides clues for the optimization and redesign of robust nitrogen-fixing organisms to improve nitrogenase efficiency by overcoming regulatory or metabolic obstacles. PMID- 30026568 TI - Detection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies. AB - Liquid biopsyis being integrated into cancer diagnostics with profound therapeutic implications. However, its role in Waldenstrom's Macroglobulinemia (WM) and IgM monoclonal gammopathies is still unclear. In this study, we evaluated the role of peripheral blood (PB) cell-free DNA (cfDNA) in characterizing the mutational status of MYD88 and CXCR4 of patients with IgM monoclonal gammopathies. Paired bone marrow (BM) tumor DNA (tDNA) and PB cfDNA samples from 98 patients (9 MGUS, 45 with WM in remission, 44 with smoldering WM, newly diagnosed or relapsed WM) and 10 controls with non-IgM monoclonal gammopathies were analyzed. Regarding MYD88L265P mutation, 76 patients had paired tDNA and cfDNA informative samples. Among patients with WM in remission, 65% harbored the MYD88L265P mutation, whereas the corresponding percentage among smoldering/newly diagnosed or relapsed WM was 92%. The overall concordance rate was 94% (72/76). For CXCR4 mutations, 65 patients had paired informative tDNA and cfDNA samples. The overall concordance rate was 90% (59/65). All controls had wild-type MYD88 and CXCR4. In conclusion, PB cfDNA is a useful, minimally invasive, cost-effective, and time-effective tool for the identification of the presence of MYD88 and CXCR4 mutations in patients with IgM monoclonal gammopathies avoiding unnecessary BM assessment. PMID- 30026567 TI - A Pilot Randomized Controlled Trial to Explore Cognitive and Emotional Effects of Probiotics in Fibromyalgia. AB - It has recently been found that microbes in the gut may regulate brain processes through the gut microbiota-brain axis, which modulates affection, motivation and higher cognitive functions. According to this finding, the use of probiotics may be a potential treatment to improve physical, psychological and cognitive status in clinical populations with altered microbiota balance such as those with fibromyalgia (FMS). Thus, the aim of the present pilot study with a double-blind, placebo-controlled, randomised design was to test whether a multispecies probiotic may improve cognition, emotional symptoms and functional state in a sample of patients diagnosed with FMS. Pain, impact of FMS, quality of life, anxiety and depressive symptoms were measured during the pre- and post intervention phases; participants also completed two computerised cognitive tasks to assess impulsive choice and decision-making. Finally, urinary cortisol concentration was determined. To our knowledge, this is the first study that explore the effect of a multispecies probiotic in FMS patients. Our results indicated that probiotics improved impulsivity and decision-making in these patients. However, more research is needed to further explore the potential effects of probiotics on other cognitive functions affected in FMS as well as in other clinical populations. PMID- 30026569 TI - Clonal hematopoiesis in patients with multiple myeloma undergoing autologous stem cell transplantation. PMID- 30026570 TI - Molecular remission as a therapeutic objective in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a subtype of acute leukemia characterized by a unique t(15;17) translocation generating the PML/RARA fusion gene and hybrid oncoprotein. Besides its critical role in leukemogenesis, this genetic aberration serves as a disease-specific biomarker for rapid diagnosis and monitoring of minimal residual disease (MRD). Moreover, PML/RARA is specifically targeted by All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two agents that synergistically act to induce degradation of the oncoprotein. Large clinical studies including two randomized trials conducted in newly diagnosed APL patients have shown that the ATRA-ATO combination is superior to conventional ATRA and chemotherapy both in terms of efficacy and safety. Preliminary studies using oral formulations of arsenic and ATRA suggest that oral arsenic is as effective and manageable as intravenous ATO. Following early retrospective studies indicating the prognostic relevance of PML/RARA monitoring, several prospective studies were conducted in large cohorts of APL patients enrolled in clinical trials with the aim of better assessing the prognostic value of longitudinal PCR testing. The results consistently showed that molecular remission (defined as negativization of the PCR test for PML/RARA) correlates with a significantly decreased risk of relapse, whereas persistence of PCR positivity for PML/RARA after consolidation or conversion from negative to positive during follow-up is strongly associated with hematologic relapse. Based on these data, various groups started using pre emptive salvage therapy for patients who persisted PCR-positive after frontline consolidation or converted from negative to positive PCR during follow-up. Finally, several expert panels have recommended that molecular remission should be considered a therapeutic objective in APL, and molecular response has been adopted as a study endpoint in modern clinical trials. PMID- 30026571 TI - Acute lymphoblastic leukemia as a clonally unrelated second primary malignancy after multiple myeloma. AB - Multiple myeloma (MM) patients have an 11-fold increased risk of developing myeloid neoplasms compared to the general population; however, acute lymphoblastic leukemia (ALL) is rarely observed. Given that both MM and the majority of ALL are of B cell origin, this raises the question of whether ALL in patients with MM arises from the same clone. We report 13 cases of B-cell ALL following therapy for MM. The interval from MM diagnosis to ALL onset was 5.4 years (range 3.3-10). The median age at the time of ALL diagnosis was 60 years (range 43-67). MM therapy included immunomodulatory agents in all patients and autologous hematopoietic cell transplantation in 10 (77%) patients preceding ALL diagnosis. ALL genetics showed a normal karyotype, TP53 mutation/deletion, and monosomy 7 or 7q deletion in 5, 3, and 2 cases, respectively. Analysis of paired samples of MM and ALL using whole exome sequencing demonstrated that the malignancies arose from different clones. Thus, ALL as a second primary malignancy following MM is not clonally related but could potentially represent a therapy-related leukemia. PMID- 30026572 TI - Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML. AB - Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous neoplasm in which JAK2 inhibition has demonstrated reductions in inflammatory cytokines and promising clinical activity. We hypothesize that annotation of inflammatory cytokines may uncover mutation-independent cytokine subsets associated with novel CMML prognostic features. A Luminex cytokine profiling assay was utilized to profile cryopreserved peripheral blood plasma from 215 CMML cases from three academic centers, along with center-specific, age-matched plasma controls. Significant differences were observed between CMML patients and healthy controls in 23 out of 45 cytokines including increased cytokine levels in IL-8, IP-10, IL 1RA, TNF-alpha, IL-6, MCP-1/CCL2, hepatocyte growth factor (HGF), M-CSF, VEGF, IL 4, and IL-2RA. Cytokine associations were identified with clinical and genetic features, and Euclidian cluster analysis identified three distinct cluster groups associated with important clinical and genetic features in CMML. CMML patients with decreased IL-10 expression had a poor overall survival when compared to CMML patients with elevated expression of IL-10 (P = 0.017), even when adjusted for ASXL1 mutation and other prognostic features. Incorporating IL-10 with the Mayo Molecular Model statistically improved the prognostic ability of the model. These established cytokines, such as IL-10, as prognostically relevant and represent the first comprehensive study exploring the clinical implications of the CMML inflammatory state. PMID- 30026573 TI - Spectrum and functional validation of PSMB5 mutations in multiple myeloma. AB - Despite an increasing number of approved therapies, multiple myeloma (MM) remains an incurable disease and only a small number of patients achieve prolonged disease control. Some genes have been linked with response to commonly used anti MM compounds, including immunomodulators (IMiDs) and proteasome inhibitors (PIs). In this manuscript, we demonstrate an increased incidence of acquired proteasomal subunit mutations in relapsed MM compared to newly diagnosed disease, underpinning a potential role of point mutations in the clonal evolution of MM. Furthermore, we are first to present and functionally characterize four somatic PSMB5 mutations from primary MM cells identified in a patient under prolonged proteasome inhibition, with three of them affecting the PI-binding pocket S1. We confirm resistance induction through missense mutations not only to Bortezomib, but also, in variable extent, to the next-generation PIs Carfilzomib and Ixazomib. In addition, a negative impact on the proteasome activity is assessed, providing a potential explanation for later therapy-induced eradication of the affected tumor subclones in this patient. PMID- 30026574 TI - A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity. AB - Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance. Finally, we show that pretreatment with either proteasome inhibitors or NEDD8 activating enzyme (NAE) inhibitors can abrogate degradation and maintain levels of CRBN, thereby enhancing sensitivity to IMiDs. These studies therefore demonstrate that CSN9 signalosome complex regulates sensitivity to IMiDs by modulating CRBN expression. PMID- 30026575 TI - Metabolic Phenotyping and Strain Characterisation of Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients Using Rapid Evaporative Ionisation Mass Spectrometry. AB - Rapid evaporative ionisation mass spectrometry (REIMS) is a novel technique for the real-time analysis of biological material. It works by conducting an electrical current through a sample, causing it to rapidly heat and evaporate, with the analyte containing vapour channelled to a mass spectrometer. It was used to characterise the metabolome of 45 Pseudomonas aeruginosa (P. aeruginosa) isolates from cystic fibrosis (CF) patients and compared to 80 non-CF P. aeruginosa. Phospholipids gave the highest signal intensity; 17 rhamnolipids and 18 quorum sensing molecules were detected, demonstrating that REIMS has potential for the study of virulence-related metabolites. P. aeruginosa isolates obtained from respiratory samples showed a higher diversity, which was attributed to the chronic nature of most respiratory infections. The analytical sensitivity of REIMS allowed the detection of a metabolome that could be used to classify individual P. aeruginosa isolates after repeated culturing with 81% accuracy, and an average 83% concordance with multilocus sequence typing. This study underpins the capacities of REIMS as a tool with clinical applications, such as metabolic phenotyping of the important CF pathogen P. aeruginosa, and highlights the potential of metabolic fingerprinting for fine scale characterisation at a sub species level. PMID- 30026576 TI - Neandertal fire-making technology inferred from microwear analysis. AB - Fire use appears to have been relatively common among Neandertals in the Middle Palaeolithic. However, the means by which Neandertals procured their fire-either through the collection of natural fire, or by producing it themselves using tools is still a matter of debate. We present here the first direct artefactual evidence for regular, systematic fire production by Neandertals. From archaeological layers attributed to late Mousterian industries at multiple sites throughout France, primarily to the Mousterian of Acheulean Tradition (MTA) technoculture (ca. 50,000 years BP), we identify using microwear analysis dozens of late Middle Palaeolithic bifacial tools that exhibit macroscopic and microscopic traces suggesting repeated percussion and/or forceful abrasion with a hard mineral material. Both the locations and nature of the polish and associated striations are comparable to those obtained experimentally by obliquely percussing fragments of pyrite (FeS2) against the flat/convex sides of a biface to make fire. The striations within these discrete use zones are always oriented roughly parallel to the longitudinal axis of the tool, allowing us to rule out taphonomic origins for these traces. We therefore suggest that the occasional use of bifaces as 'strike-a-lights' was a technocultural feature shared among the late Neandertals in France. PMID- 30026577 TI - Stable symmetry-protected 3D embedded solitons in Bose-Einstein condensates. AB - Embedded solitons are rare self-localized nonlinear structures that, counterintuitively, survive inside a continuous background of resonant states. While this topic has been widely studied in nonlinear optics, it has received almost no attention in the field of Bose-Einstein condensation. In this work, we consider experimentally realizable Bose-Einstein condensates loaded in one dimensional optical lattices and demonstrate that they support continuous families of stable three-dimensional (3D) embedded solitons. These solitons can exist inside the resonant continuous Bloch bands because they are protected by symmetry. The analysis of the Bogoliubov excitation spectrum as well as the long term evolution after random perturbations proves the robustness of these nonlinear structures against any weak perturbation. This may open up a way for the experimental realization of stable 3D matter-wave embedded solitons as well as for monitoring the gap-soliton to embedded-soliton transition. PMID- 30026578 TI - Collective resonances near zero energy induced by a point defect in bilayer graphene. AB - Intrinsic defects give rise to scattering processes governing the transport properties of mesoscopic systems. We investigate analytically and numerically the local density of states in Bernal stacking bilayer graphene with a point defect. With Bernal stacking structure, there are two types of lattice sites. One corresponds to connected sites, where carbon atoms from each layer stack on top of each other, and the other corresponds to disconnected sites. From our theoretical study, a picture emerges in which the pronounced zero-energy peak in the local density of states does not attribute to zero-energy impurity states associated to two different types of defects but to a collective phenomenon of the low-energy resonant states induced by the defect. To corroborate this description, we numerically show that at small system size N, where N is the number of unit cells, the zero-energy peak near the defect scales as 1/lnN for the quasi-localized zero-energy state and as 1/N for the delocalized zero-energy state. As the system size approaches to the thermodynamic limit, the former zero energy peak becomes a power-law singularity 1/|E| in low energies, while the latter is broadened into a Lorentzian shape. A striking point is that both types of zero-energy peaks decay as 1/r2 away from the defect, manifesting the quasi localized character. Based on our results, we propose a general formula for the local density of states in low-energy and in real space. Our study sheds light on this fundamental problem of defects. PMID- 30026580 TI - Rotating magnetocaloric effect and unusual magnetic features in metallic strongly anisotropic geometrically frustrated TmB4. AB - We have investigated the rotating magnetocaloric effect (R-MCE) of TmB4 - an anisotropic magnetic system with geometrical frustration of Shastry-Sutherland type. The R-MCE was obtained from detailed temperature dependencies of heat capacity in various magnetic fields of a single crystalline sample for crystal axes orientations c || B and c ? B. The received results exhibit rather complex distributions of positive and negative entropy DeltaS(T, B) and temperature DeltaT(T, B) differences below and above TN when the direction of the magnetic field changes between directions c || B and c ? B. The calculated results were confirmed by direct R-MCE measurements which, moreover, show an interesting angular dependence of R-MCE in the ordered phase, which seems to be related with the change of the effective magnetic field along the c axis during sample rotation. Thus, our study presents a new type of magnetic refrigerant with a rather large R-MCE for low temperature magnetic refrigeration, and points to further interesting magnetic features in the ordered phase of this frustrated system. PMID- 30026579 TI - Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. AB - Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases, and other human pathologies. To evaluate the consequences of depletion of mtDNA in the whole animal, we created an inducible mtDNA-depleter mouse expressing, in the polymerase domain of POLG1, a dominant-negative mutation to induce depletion of mtDNA in various tissues. These mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. We demonstrate that ubiquitous depletion of mtDNA in mice leads to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses. Development of skin wrinkle was associated with the significant epidermal hyperplasia, hyperkeratosis, increased expression of matrix metalloproteinases, and decreased expression of matrix metalloproteinase inhibitor TIMP1. We also discovered markedly increased skin inflammation that appears to be a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including IGF1R, KLOTHO, VEGF, and MRPS5. mtDNA-repleter mice showed that, by turning off the mutant POLG1 transgene expression, mitochondrial function, as well as the skin and hair pathology, is reversed to wild-type level. To our knowledge that restoration of mitochondrial functions can reverse the skin and hair pathology is unprecedented. PMID- 30026581 TI - Author Correction: The role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30026582 TI - Non-covalent control of spin-state in metal-organic complex by positioning on N doped graphene. AB - Nitrogen doping of graphene significantly affects its chemical properties, which is particularly important in molecular sensing and electrocatalysis applications. However, detailed insight into interaction between N-dopant and molecules at the atomic scale is currently lacking. Here we demonstrate control over the spin state of a single iron(II) phthalocyanine molecule by its positioning on N-doped graphene. The spin transition was driven by weak intermixing between orbitals with z-component of N-dopant (pz of N-dopant) and molecule (dxz, dyz, dz2) with subsequent reordering of the Fe d-orbitals. The transition was accompanied by an electron density redistribution within the molecule, sensed by atomic force microscopy with CO-functionalized tip. This demonstrates the unique capability of the high-resolution imaging technique to discriminate between different spin states of single molecules. Moreover, we present a method for triggering spin state transitions and tuning the electronic properties of molecules through weak non-covalent interaction with suitably functionalized graphene. PMID- 30026583 TI - A novel high-power all-fiberized flexible spectral filter for high power linearly polarized Raman fiber laser. AB - Power scaling of linearly polarized Raman fiber laser (LPRFL), which has wide application potentials, is mainly limited by the generation of high-order Stokes light. In this paper, we propose a novel flexible spectral filter with all fiberized configuration and high-power handling. Combining with the polarization dependence of Raman gain, the filter could be used to efficiently suppress high order Stokes light in LPRFL and thus help further power scaling. The filter is fabricated by two 45 degrees cross-splice of three pieces of polarization maintaining (PM) passive fibers. The bandwidth and central wavelength of transmission spectrum of the spectral filter could be flexibly tuned through changing the length and temperature of the cross-spliced fiber. The insertion loss of the filter fabricated in the lab is measured to be as low as 0.07 dB. The filter is employed in a LPRFL, and the maximum output power of the LPRFL is increased by 48.7%. PMID- 30026584 TI - Data sharing and the future of science. PMID- 30026585 TI - SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix. AB - SP7/Osterix (OSX) is a master regulatory transcription factor that activates a variety of genes during differentiation of osteoblasts. However, the influence of post-translational modifications on the regulation of its transactivation activity is largely unknown. Here, we report that sirtuins, which are NAD(+) dependent deacylases, regulate lysine deacylation-mediated transactivation of OSX. Germline Sirt7 knockout mice develop severe osteopenia characterized by decreased bone formation and an increase of osteoclasts. Similarly, osteoblast specific Sirt7 knockout mice showed attenuated bone formation. Interaction of SIRT7 with OSX leads to the activation of transactivation by OSX without altering its protein expression. Deacylation of lysine (K) 368 in the C-terminal region of OSX by SIRT7 promote its N-terminal transactivation activity. In addition, SIRT7 mediated deacylation of K368 also facilitates depropionylation of OSX by SIRT1, thereby increasing OSX transactivation activity. In conclusion, our findings suggest that SIRT7 has a critical role in bone formation by regulating acylation of OSX. PMID- 30026587 TI - High health gain patients with asthma: a cross-sectional study analysing national Scottish data sets. AB - Studies have shown that a small proportion of patients have particularly high needs and are responsible for disproportionally high disease burden. Estimates suggest that 2-5% of patients are high users of healthcare for their health gain. Such patients in Scotland are referred to as high health gain (HHG) patients. We wanted to investigate if there were HHG individuals with asthma in Scotland. We analysed data from the Scottish Health Survey (2010-11), and primary and National Health Survey (NHS) secondary healthcare and administrative data sets (2011-12). In all, 1,379,690 (26.0%) and 836,135 (15.8%) people reported to have ever had and currently have symptoms suggestive of asthma, respectively; 369,868 (7.0%) people reported current symptomatic clinician-diagnosed asthma. 310,050 (5.6%) people had clinician-reported-diagnosed asthma; there were 289,120 nurse consultations, 215,610 GP consultations, 9235 accident and emergency visits (0.2% people), 8263 ambulance conveyances (0.2% people), 7744 inpatient episodes (0.1% people), 3600 disability allowance claims (0.1% people), 187 intensive care unit (ICU) episodes and 94 deaths from asthma. From our study a maximum of about 9.4% of asthma patients (n = 29,145), which is 0.5% of the Scottish population, and from the National Review of Asthma Deaths' estimate (10% hospitalised), a minimum of nine people had severe asthma attacks that needed acute hospital attendance/admission. We found that although a high proportion of the Scottish population had symptoms suggestive of asthma and clinician diagnosed asthma, only a small proportion of asthma patients experienced exacerbations that were severe enough to warrant hospital attendance/admission in any given year. Developing risk prediction models to identify these HHG patients has the potential to both improve health outcomes while substantially reducing healthcare expenditure. PMID- 30026586 TI - Substitution of linoleic acid with alpha-linolenic acid or long chain n-3 polyunsaturated fatty acid prevents Western diet induced nonalcoholic steatohepatitis. AB - Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet may increase the risk of nonalcoholic fatty liver disease (NAFLD). This study investigates the impact of substitution of linoleic acid with alpha linolenic acid (ALA) or long chain (LC) n-3 PUFA and hence decreasing n-6:n-3 fatty acid ratio on high fat, high fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were divided into four groups and fed control diet, HFHF diet (n-6:n-3 ratio of 200), HFHF diet with ALA (n-6:n 3 ratio of 2) or HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5) for 24 weeks. Rats fed HFHF diet with n-6:n-3 ratio of 200 resulted in hepatic steatosis, induced glucose intolerance, insulin resistance and oxidative stress accompanied by increase in markers of inflammation, plasma lipids and aminotransferase levels. Histopathological examination of liver further confirmed the establishment of NASH. ALA and LC n-3 PUFA supplementation prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity. Furthermore, n-3 PUFA supplementation attenuated hepatic oxidative stress by restoring antioxidant status, decreased inflammation and preserved hepatic architecture. These finding suggest that decreasing n-6:n-3 ratio prevented HFHF induced NASH by attenuating oxidative stress and inflammation. PMID- 30026588 TI - Adult weight change in relation to visceral fat and liver fat at middle age: The Netherlands epidemiology of obesity study. AB - OBJECTIVE: We aimed to investigate the associations between weight change during adulthood and the amount of abdominal subcutaneous fat, visceral fat, and liver fat at middle age. METHODS: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort of 6671 middle-aged men and women. We calculated the percentage of weight change during adulthood based on body weight at middle age and recalled body weight at age 20. Abdominal subcutaneous and visceral adipose tissue were assessed by magnetic resonance imaging (MRI), in addition to hepatic triglyceride content by 1H-MR spectroscopy in a random subgroup (maximum of n = 2580). With multivariable linear regression analysis, we examined the associations between categories of adult weight change, body mass index (BMI) at age 20 and measures of abdominal adiposity at middle age, adjusted for age, sex, ethnicity, lifestyle factors, menopausal status, parity, use of medication and total body fat at middle age. RESULTS: In 2399 participants (54% women), individuals who gained more than 50% of body weight during adulthood had 1.96 (95% CI: 1.64; 2.33) times more visceral adipose tissue at middle age and 2.39 (95% CI: 1.70, 3.36) times more hepatic triglyceride content than weight maintainers (weight change between -5% and 5%). Associations with abdominal subcutaneous adipose tissue were weaker: participants who gained more than 50% of their body weight had 1.54 (95% CI: 1.38, 1.72) times more abdominal subcutaneous adipose tissue compared with weight maintainers. CONCLUSIONS: In this population based study, adult weight gain was associated with relatively more visceral adipose tissue and hepatic triglyceride content at middle age than abdominal subcutaneous adipose tissue. Overall, our study suggests that weight maintenance during adulthood plays an important role in limiting excess visceral adipose tissue and hepatic triglyceride content at middle age. PMID- 30026589 TI - Causal relationships between adiposity and childhood asthma: bi-directional Mendelian Randomization analysis. AB - BACKGROUND/OBJECTIVES: Obesity and asthma are common chronic diseases and have been reported to be mutually causative. We investigated the causal direction of the relationship between adiposity and asthma using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. SUBJECTS/METHODS: We used data from the Taiwan Children Health Study with 24 body mass index (BMI)-single-nucleotide polymorphisms (SNPs, combined into a weighted allelic score) and 16 asthma-SNPs (combined into two weighted allelic scores, separately for asthma inflammatory and antioxidative genes) to yield genetic IVs for adiposity and asthma, respectively. RESULTS: The weighted allele score for BMI was strongly associated with adiposity (p = 2 * 10-16) and active asthma (p = 0.03). The two-stage least square regression risk ratio (RR) for the effect of BMI on asthma was 1.04 (95% confidence interval: 1.00-1.07, p = 0.03). Although the weighted asthma genetic scores were significantly associated with asthma (p = 8.4 * 10-3), no association was seen for genetically instrumented asthma with BMI using MR. Central obesity was the most accurate predictor of asthma. Adiposity showed higher causal effects on asthma in boys and children with non-atopic asthma. Sensitivity analysis for MR revealed no directional genetic pleiotropy effects. The causal effect RRs of BMI on asthma were 1.04, 1.08, and 1.03 for inverse-variance weighted, MR-Egger regression (slope), and weighted median methods, respectively, all in accordance with the MR estimates. CONCLUSIONS: High adiposity may lead to asthma, whereas the effects of asthma on adiposity accumulation are likely to be small. PMID- 30026590 TI - Adult energy requirements predicted from doubly labeled water. AB - BACKGROUND: Estimating energy requirements forms an integral part of developing diet and activity interventions. Current estimates often rely on a product of physical activity level (PAL) and a resting metabolic rate (RMR) prediction. PAL estimates, however, typically depend on subjective self-reported activity or a clinician's best guess. Energy-requirement models that do not depend on an input of PAL may provide an attractive alternative. METHODS: Total daily energy expenditure (TEE) measured by doubly labeled water (DLW) and a metabolic chamber from 119 subjects obtained from a database of pre-intervention measurements measured at Pennington Biomedical Research Center were used to develop a metabolic ward and free-living models that predict energy requirements. Graded models, including different combinations of input variables consisting of age, height, weight, waist circumference, body composition, and the resting metabolic rate were developed. The newly developed models were validated and compared to three independent databases. RESULTS: Sixty-four different linear and nonlinear regression models were developed. The adjusted R2 for models predicting free living energy requirements ranged from 0.65 with covariates of age, height, and weight to 0.74 in models that included body composition and RMR. Independent validation R2 between actual and predicted TEE varied greatly across studies and between genders with higher coefficients of determination, lower bias, slopes closer to 1, and intercepts closer to zero, associated with inclusion of body composition and RMR covariates. The models were programmed into a user-friendly web-based app available at: http://www.pbrc.edu/research-and faculty/calculators/energy-requirements/ (Video Demo for Reviewers at: https://www.youtube.com/watch?v=5UKjJeQdODQ ) CONCLUSIONS: Energy-requirement equations that do not require knowledge of activity levels and include all available input variables can provide more accurate baseline estimates. The models are clinically accessible through the web-based application. PMID- 30026591 TI - Interactive effects of parenting behavior and regulatory skills in toddlerhood on child weight outcomes. AB - OBJECTIVES: There is limited research investigating whether maternal behaviors exhibited during non-feeding contexts play a role in the development of obesity, and whether this association varies based on children's emerging regulatory skills. The objective of this study was to investigate interactions between maternal behaviors and toddler regulation predicting child BMI z-scores (BMIZ) at 4.5 years. SUBJECTS/METHODS: Infant-mother dyads (n = 108) participated in laboratory visits when the child was 18 months and 4.5 years of age. Maternal interactive behaviors (i.e., positive responsiveness, gentle control) were coded from recordings of free play and clean-up tasks with their toddlers. Toddler regulation was assessed via an observational task, experimenter ratings, and parent ratings. Child and mother length/height and weight measurements were recorded and used to calculate child BMIZ and maternal BMI, respectively. RESULTS: After controlling for covariates, two significant interactions emerged between maternal behaviors and toddler regulation predicting BMIZ at 4.5 years. First, an interaction of positive responsiveness during free play and toddler regulation demonstrated that greater positive responsiveness significantly related to lower child BMIZ for toddlers with poor regulation. Second, an interaction of gentle control during clean-up and toddler regulation indicated that greater gentle control was associated with lower BMIZ for toddlers with lesser regulatory abilities, but higher BMIZ for well-regulated toddlers. No significant main effects emerged for maternal interactive behaviors or toddler regulation. CONCLUSIONS: These results suggest that associations between maternal behaviors and child BMIZ may depend on toddlers' emerging regulatory abilities. Maternal responsiveness during free play and gentle control during clean-up appear to protect against weight gain, especially for toddlers with lower regulatory abilities. However, greater levels of gentle control may have adverse effects on BMIZ for well-regulated toddlers. These results suggest that both parenting and toddler regulation, examined outside feeding contexts, may have important implications for child obesity. PMID- 30026592 TI - How body composition influences hearing status by mid-childhood and mid-life: The Longitudinal Study of Australian Children. AB - BACKGROUND: Hearing loss is a disabling condition whose prevalence rises with age. Obesity-a risk factor common to many non-communicable diseases-now appears to be implicated. We aimed to determine: (1) cross-sectional associations of body composition measures with hearing in mid-childhood and mid-life and (2) its longitudinal associations with 10-year body mass index (BMI) trajectories. METHODS: Design & Participants: There were 1481 11-12-year-old children and 1266 mothers in the population-based cross-sectional CheckPoint study nested within the Longitudinal Study of Australian Children (LSAC). Anthropometry (CheckPoint): BMI, fat/fat-free mass indices, waist-to-height ratio; LSAC wave 2-6-biennial measured BMI. Audiometry (CheckPoint): Mean hearing threshold across 1, 2 and 4 kHz; hearing loss (threshold > 15 dB HL, better ear). ANALYSIS: Latent class models identifying BMI trajectories; linear/logistic regression quantifying associations of body composition/trajectories with hearing threshold/loss. RESULTS: Measures of adiposity, but not fat-free mass, were cross-sectionally associated with hearing. Fat mass index predicted the hearing threshold and loss in children (beta 0.6, 95% confidence interval (CI) 0.3-0.8, P < 0.001;, odds ratio (OR) 1.2, 95% CI 1.0-1.4, P = 0.05) and mothers (beta 0.8, 95% CI 0.5-1.2, P < 0.001; OR 1.2, 95% CI 1.1-1.4, P = 0.003). Concurrent obesity (OR 1.5, 95% CI 1.1-2.1, P = 0.02) and waist-to-height ratio (WHtR) >= 0.6 (OR 1.6, 95% CI 1.2 2.3, P = 0.01) predicted maternal hearing, with similar but attenuated patterns in children. In longitudinal analyses, mothers', but not children's, BMI trajectories predicted hearing (OR for severely obese 3.0, 95% CI 1.4-6.6, P = 0.01). CONCLUSIONS: Concurrent adiposity and decade-long BMI trajectories showed small, but clear, associations with poor hearing in mid-life women, with emergent patterns by mid-childhood. This suggests that obesity may play a role in the rising global burden of hearing loss. Replication and mechanistic and body compositional studies could elucidate possible causal relationships. PMID- 30026593 TI - Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy. AB - Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs. PMID- 30026594 TI - Small molecule activator of Nm23/NDPK as an inhibitor of metastasis. AB - Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E) 3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent. PMID- 30026595 TI - Transcriptome Profiles of Nod Factor-independent Symbiosis in the Tropical Legume Aeschynomene evenia. AB - Nod factors (NF) were assumed to be indispensable for the establishment of a rhizobium-legume symbiosis until the discovery that certain Bradyrhizobium strains interacting with certain Aeschynomene species lack the canonical nodABC genes required for their synthesis. So far, the molecular dialogue between Aeschynomene and its symbionts remains an open question. Here we report a time course transcriptional analysis of Aeschynomene evenia in response to inoculation with Bradyrhizobium ORS278. The NF-independent symbiotic process was monitored at five time points between bacterial infection and nodule maturity. The five time points correspond to three specific events, root infection by crack entry, nodule organogenesis, and the establishment of the nitrogen fixing process. During the third stage, about 80 NCR-like genes and eight symbiotic genes known to be involved in signaling, bacterial infection or nodulation regulation were highly expressed. Comparative gene expression analyses at the five time points also enabled the selection of genes with an expression profile that makes them promising markers to monitor early plant responses to bacteria. Such markers could be used in bioassays to identify the nature of the bacterial signal(s). Our data represent valuable resources for investigation of this Nod factor independent symbiosis. PMID- 30026596 TI - Common and rare variants of WNT16, DKK1 and SOST and their relationship with bone mineral density. AB - Numerous GWAS and candidate gene studies have highlighted the role of the Wnt pathway in bone biology. Our objective has been to study in detail the allelic architecture of three Wnt pathway genes: WNT16, DKK1 and SOST, in the context of osteoporosis. We have resequenced the coding and some regulatory regions of these three genes in two groups with extreme bone mineral density (BMD) (n = ~50, each) from the BARCOS cohort. No interesting novel variants were identified. Thirteen predicted functional variants have been genotyped in the full cohort (n = 1490), and for ten of them (with MAF > 0.01), the association with BMD has been studied. We have found six variants nominally associated with BMD, of which 2 WNT16 variants predicted to be eQTLs for FAM3C (rs55710688, in the Kozak sequence and rs142005327, within a putative enhancer) withstood multiple-testing correction. In addition, two rare variants in functional regions (rs190011371 in WNT16b 3'UTR and rs570754792 in the SOST TATA box) were found only present in three women each, all with BMD below the mean of the cohort. Our results reinforce the higher importance of regulatory versus coding variants in these Wnt pathway genes and open new ways for functional studies of the relevant variants. PMID- 30026597 TI - Soil evaporation and organic matter turnover in the Sub-Taiga and Forest-Steppe of southwest Siberia. AB - Southwest Siberia encompasses the forest-steppe and sub-taiga climatic zones and has historically been utilized for agriculture. Coinciding with predicted changes in climate for the region is the pressure of agricultural development; however, a characterization of the soil water and carbon dynamics is lacking. We assessed current soil water properties and soil organic carbon turnover in forests and grasslands for two sites that span the forest steppe and sub-taiga bioclimatic zones. Soil evaporation was 0.62 +/- 0.17 mm d-1 (mean +/- standard error) in grasslands and 0.45 +/- 0.08 mm d-1 in the forests of the forest-steppe site. Evaporation at the sub-taiga site was 1.80 +/- 1.70 mm d-1 in grasslands and 0.96 +/- 0.05 mm d-1 in forest plots. Evaporation was significantly greater at the sub taiga site than the forest-steppe site. The density of fine roots explained the soil water isotopic patterns between vegetation types and sites. We found soil organic matter turnover to be three times faster in the sub-taiga site than in the forest-steppe site. Our results show that while climate factors, in particular snow levels, between the two sites are drivers for water and carbon cycles, site level hydrology, soil characteristics, and vegetation directly interact to influence the water and carbon dynamics. PMID- 30026598 TI - Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia. AB - Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL 1beta release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1beta release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED50 of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1beta release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ 55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1beta release and microglial activation leading to efficacy in two models of anhedonia in rodents. PMID- 30026599 TI - Increased testicular blood flow maintains oxygen delivery and avoids testicular hypoxia in response to reduced oxygen content in inspired air. AB - Despite a long-standing assertion that mammalian testes operate near hypoxia and increased testicular temperature causes frank hypoxia, we have preliminary evidence that changes are due to hyperthermia per se. The objective was to determine how variations in inspired oxygen concentration affected testicular blood flow, oxygen delivery and extraction, testicular temperature and lactate production. Eight rams were maintained under general anesthesia, with successive decreases in oxygen concentration in inspired air (100, 21 and 13%, respectively). As oxygen concentration decreased from 100 to 13%, there were increases in testicular blood flow (9.6 +/- 1.7 vs 12.9 +/- 1.9 ml/min/100 g of testis, P < 0.05; mean +/- SEM) and conductance (normalized flow; 0.46 +/- 0.07 to 1.28 +/- 0.19 ml/min/mm Hg/100 g testis (P < 0.05). Increased testicular blood flow maintained oxygen delivery and increased testicular temperature by ~1 degrees C; this increase was correlated to increased testicular blood flow (r = 0.35, P < 0.0001). Furthermore, oxygen utilization increased concomitantly and there were no significant differences among oxygen concentrations in blood pH, HCO3- or base excess, and no effects of venous-arterial differences in lactate production. In conclusion, under acute hypoxic conditions, testes maintained oxygen delivery and uptake by increasing blood flow and oxygen extraction, with no evidence of anaerobic metabolism. However, additional studies are needed to determine longer-term responses and potential evidence of anaerobic metabolism at the molecular level. PMID- 30026600 TI - Study of an AC dielectric barrier single micro-discharge filament over a water film. AB - In the last decades, AC powered atmospheric dielectric barrier discharges (DBDs) in air with a liquid electrode have been proposed as a promising plasma technology with versatile applicability in medicine, agriculture and water treatment. The fundamental features of the micro-discharge filaments that make up this type of plasma have, however, not been studied yet in sufficient detail. In order to address this need, we investigated a single DBD micro-discharge filament over a water film in a sphere-to-sphere electrode configuration, by means of ICCD imaging and optical emission spectroscopy. When the water film temporarily acts as the cathode, the plasma duration is remarkably long and shows a clear similarity with a resistive barrier discharge, which we attribute to the resistive nature of the water film and the formation of a cathode fall. As another striking difference to DBD with solid electrodes, a constant glow-like plasma is observed at the water surface during the entire duration of the applied voltage cycle, indicating continuous plasma treatment of the liquid. We propose several elementary mechanisms that might underlie the observed unique behavior, based on the specific features of a water electrode. PMID- 30026601 TI - Automated flow cytometric identification of disease-specific cells by the ECLIPSE algorithm. AB - Multicolor Flow Cytometry (MFC)-based gating allows the selection of cellular (pheno)types based on their unique marker expression. Current manual gating practice is highly subjective and may remove relevant information to preclude discovery of cell populations with specific co-expression of multiple markers. Only multivariate approaches can extract such aspects of cell variability from multi-dimensional MFC data. We describe the novel method ECLIPSE (Elimination of Cells Lying in Patterns Similar to Endogeneity) to identify and characterize aberrant cells present in individuals out of homeostasis. ECLIPSE combines dimensionality reduction by Simultaneous Component Analysis with Kernel Density Estimates. A Difference between Densities (DbD) is used to eliminate cells in responder samples that overlap in marker expression with cells of controls. Thereby, subsequent data analyses focus on the immune response-specific cells, leading to more informative and focused models. To prove the power of ECLIPSE, we applied the method to study two distinct datasets: the in vivo neutrophil response induced by systemic endotoxin challenge and in studying the heterogeneous immune-response of asthmatics. ECLIPSE described the well characterized common response in the LPS challenge insightfully, while identifying slight differences between responders. Also, ECLIPSE enabled characterization of the immune response associated to asthma, where the co expressions between all markers were used to stratify patients according to disease-specific cell profiles. PMID- 30026602 TI - Correction: Superoxide drives progression of Parkin/PINK1-dependent mitophagy following translocation of Parkin to mitochondria. AB - The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information. PMID- 30026604 TI - Publisher Correction: Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma. AB - In the originally published version of this Article, the affiliation details for Dorina Avram incorrectly included "Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, 2015 SW 16th Ave, Gainesville, FL, 32608, USA", instead of "UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA". This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30026603 TI - FoxM1 repression during human aging leads to mitotic decline and aneuploidy driven full senescence. AB - Aneuploidy, an abnormal chromosome number, has been linked to aging and age associated diseases, but the underlying molecular mechanisms remain unknown. Here we show, through direct live-cell imaging of young, middle-aged, and old-aged primary human dermal fibroblasts, that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome mis segregation in elderly mitotic cells correlates with an early senescence associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives G2/M gene expression. FoxM1 induction in elderly and Hutchison-Gilford progeria syndrome fibroblasts prevents aneuploidy and, importantly, ameliorates cellular aging phenotypes. Moreover, we show that senescent fibroblasts isolated from elderly donors' cultures are often aneuploid, and that aneuploidy is a key trigger into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes. PMID- 30026605 TI - Plasmodium falciparum RUVBL3 protein: a novel DNA modifying enzyme and an interacting partner of essential HAT protein MYST. AB - RUVBLs constitute a conserved group of ATPase proteins that play significant role in a variety of cellular processes including transcriptional regulation, cell cycle and DNA damage repair. Three RUVBL homologues, namely, PfRUVBL1, PfRUVBL2 and PfRUVBL3 have been identified in P. falciparum, unlike its eukaryotic counterparts, which have two RUVBL proteins (RUVBL1 & RUVBL2). The present study expands our understanding of PfRUVBL3 protein and thereby basic biology of Plasmodium in general. Here, we have shown that parasite PfRUVBL3 is a true homolog of human/yeast RUVBL2 protein. Our result show that PfRUVBL3 constitutively expresses throughout the stages of intra-erythrocytic cycle (IDC) with varied localization. In addition to ATPase and oligomerization activity, we have for the first time shown that PfRUVBL3 possess DNA cleavage activity which interestingly is dependent on its insertion domain. Furthermore, we have also identified RUVBL3 to be an interacting partner of an essential chromatin remodeling protein PfMYST and together they colocalize with H3K9me1 histone in parasitophorous vacuole during the ring stage of IDC suggesting their potential involvement in chromatin remodeling and gene transcription. PMID- 30026606 TI - Telomere length and survival in primary cutaneous melanoma patients. AB - Telomere repeats at chromosomal ends, critical to genomic integrity, undergo age dependent attrition. Telomere length, a polygenic trait, has been associated with risk of several disorders including cancers. In contrast to association of long telomeres with increased risk of several cancers, including melanoma, emerging reports suggest that short telomeres predict poor survival in patients with different cancers. In this study based on 1019 stage I and II cutaneous melanoma patients, we show an association between the patients with short telomeres and poor melanoma-specific survival (HR 2.05, 95% CI 1.33-3.16) compared to patients with long telomeres. Due to inverse correlation between age and telomere length (r -0.19, P < 0.0001), we stratified the patients into quantiles based on age at diagnosis and also carried out age-matched analysis. The effect of short telomeres on survival was determined by using multivariate Cox regression that included composite genetic risk score computed from genotyping of the patients for telomere-length associated polymorphisms. The effect of decreased telomere length on poor melanoma-specific survival was particularly strong in patients within the age quantile below 30 years (HR 3.82, 95% CI 1.10-13.30) and between 30-40 years (HR 2.69, 95% CI 1.03-7.03). Our study shows that in contrast to increased melanoma risk associated with increased telomere length, decreased telomere length predicts poor survival in melanoma subgroups. PMID- 30026607 TI - Accumulation of myeloid lineage cells is mapping out liver fibrosis post injury: a targetable lesion using Ketanserin. AB - Liver fibrosis is problematic after persistent injury. However, little is known about its response to an acute insult. Accumulation of myeloid lineage cells contributes into the promotion and resolution of inflammation and fibrosis. Using Cre-transgenic mice that specifically mark myeloid lineage cells with EYFP and burn as a model of acute systemic injury, we investigated the role of myeloid lineage cells in the liver after acute injury. Our data show that thermal injury in mice (30% total body surface area) induces fibrosis predominantly around portal venules whereas myeloid cells are enriched throughout the liver. The fibrosis peaks around 1-2 weeks post injury and resolves by week 3. Ablating myeloid cells led to lower fibrosis. Through FACS sorting, we isolated myeloid lineage cells (EYFP +ve cells) from injured animals and from the control uninjured animals and subjected the extracted RNA from these cells to microarray analysis. Microarray analysis revealed an inflammatory signature for EYFP +ve cells isolated from injured animals in comparison with control cells. Moreover, it showed modulation of components of the serotonin (5-HT) pathway in myeloid cells. Antagonizing the 5HT2A/2C receptor decreased fibrosis in thermally injured mice by skewing macrophages away from their pro-fibrotic phenotype. Macrophages conditioned with Ketanserin showed a lower pro-fibrotic phenotype in a co-culture system with mesenchymal cells. There is a spatiotemporal pattern in liver fibrosis post-thermal injury, which is associated with the influx of myeloid cells. Treating mice with a 5HT2A/2C receptor antagonist promotes an anti fibrotic effect, through modulating the phenotype of macrophages. PMID- 30026608 TI - Iridium-catalyzed reductive Ugi-type reactions of tertiary amides. AB - Amides are ubiquitous in the fine chemical, agrochemical and pharmaceutical industries, but are rarely exploited as substrates for homologous amine synthesis. By virtue of their high chemical stability, they are essentially inert to all but the harshest of chemical reagents and to the majority of chemical transformations routinely used in organic synthesis. Accordingly, the development of chemoselective carbon-carbon bond-forming methodologies arising from the functionalization of the amide functionality should find widespread use across academia and industry. We herein present our findings on a series of Ugi-type reactions of tertiary amides enabled by an initial chemoselective iridium catalyzed partial reduction, followed by reaction with isocyanide and (thio)acetic acid or trimethylsilyl azide, thus providing a multicomponent synthesis of alpha-amino (thio)amide or alpha-amino tetrazole derivatives. The reductive Ugi-type reactions are amenable to a broad range of amides and isocyanides, and are applicable to late-stage functionalization of various bioactive molecules and pharmaceutical compounds. PMID- 30026609 TI - Inter-individual differences in contamination profiles as tracer of social group association in stranded sperm whales. AB - Ecological and physiological factors lead to different contamination patterns in individual marine mammals. The objective of the present study was to assess whether variations in contamination profiles are indicative of social structures of young male sperm whales as they might reflect a variation in feeding preferences and/or in utilized feeding grounds. We used a total of 61 variables associated with organic compounds and trace element concentrations measured in muscle, liver, kidney and blubber gained from 24 sperm whales that stranded in the North Sea in January and February 2016. Combining contaminant and genetic data, there is evidence for at least two cohorts with different origin among these stranded sperm whales; one from the Canary Island region and one from the northern part of the Atlantic. While genetic data unravel relatedness and kinship, contamination data integrate over areas, where animals occured during their lifetime. Especially in long-lived animals with a large migratory potential, as sperm whales, contamination data may carry highly relevant information about aggregation through time and space. PMID- 30026610 TI - Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways. AB - Immune responses against gene therapy products limit its therapeutic efficacy and present a safety risk. Identification of agents that blunt immune reactions may aid in developing novel immunomodulatory therapies. Fingolimod (FTY720) is an FDA approved immunomodulatory drug for treating multiple sclerosis that inhibits lymphocyte egress from lymphoid tissues by down regulating sphingosine-1 phosphate receptor (S1PR). Recent studies found that FTY720 inhibits T cell activation (TCA) in a S1PR-independent manner; however, the mechanism is incompletely understood. Here we characterized the effects of FTY720 on human T cell receptor (TCR) signaling pathways. FTY720 inhibited both the TCR-dependent and independent activation of primary human T cells. FTY720 did not affect proximal TCR signaling events as measured by phosphorylation of Lck, ZAP-70 and LAT; however, inhibited PMA/Ionomycin induced distal TCR signaling as measured by IL-2, IFN-gamma release and CD25 expression. FTY720 induced aberrant NFAT1, AP1 and NFkappaB activation which were associated with increased acetylation of histone (H3K9). Phosphorylated FTY720 did not inhibit TCA, and arachidonic acid did not rescue FTY720 mediated inhibition of TCA. These data suggest that FTY720 mediated inhibition of TCA is due to inhibition of distal TCR signaling. Understanding FTY720-mediated inhibition of TCA may aid in developing novel FTY720-based immunomodulatory agents. PMID- 30026611 TI - A Poly(ionic liquid) Gel Electrolyte for Efficient all Solid Electrochemical Double-Layer Capacitor. AB - Polyionic liquid based gels have stimulated significant interest due to their wide applications in flexible electronics, such as wearable electronics, roll-up displays, smart mobile devices and implantable biosensors. Novel supported liquid gel electrolyte using polymerisable ionic liquid and an acrylate monomer, has been developed in this work by entrapping ionic liquid during polymerisation instead of post polymerisation impregnation. The chemically crosslinked polyionic liquid gel electrolyte (PIL) is prepared using 2-hydroxyethylmethacrylate (HEMA) monomer and a polymerisable ionic liquid, 1,4-di(vinylimidazolium)butane bisbromide (DVIMBr) in an ionic liquid (IL- 1-butyl-3 methylimidazolium hexafluorophosphate) as the polymerisation solvent, which resulted in in-situ entrapment of the IL in the gel during polymerisation and crosslinking of the polymer. The supported liquid gel electrolyte (SLG) material was characterised with thermal analysis, infrared spectroscopy, and dynamic mechanical analysis, and was found to be stable with good mechanical properties. The electrochemical analysis showed that these chemically cross-linked PIL gel electrolyte-supported ILs are suitable for solid-state, flexible supercapacitor applications. PMID- 30026612 TI - Comparison between complete genomes of an isolate of Pseudomonas syringae pv. actinidiae from Japan and a New Zealand isolate of the pandemic lineage. AB - The modern pandemic of the bacterial kiwifruit pathogen Pseudomonas syringae pv actinidiae (Psa) is caused by a particular Psa lineage. To better understand the genetic basis of the virulence of this lineage, we compare the completely assembled genome of a pandemic New Zealand strain with that of the Psa type strain first isolated in Japan in 1983. Aligning the two genomes shows numerous translocations, constrained so as to retain the appropriate orientation of the Architecture Imparting Sequences (AIMs). There are several large horizontally acquired regions, some of which include Type I, Type II or Type III restriction systems. The activity of these systems is reflected in the methylation patterns of the two strains. The pandemic strain carries an Integrative Conjugative Element (ICE) located at a tRNA-Lys site. Two other complex elements are also present at tRNA-Lys sites in the genome. These elements are derived from ICE but have now acquired some alternative secretion function. There are numerous types of mobile element in the two genomes. Analysis of these elements reveals no evidence of recombination between the two Psa lineages. PMID- 30026613 TI - Comparison of anal cancer screening strategies including standard anoscopy, anal cytology, and HPV genotyping in HIV-positive men who have sex with men. AB - BACKGROUND: There is no consensus on screening strategy of high-grade intraepithelial neoplasia (HGAIN). Guidelines range from clinical examination with digital anorectal examination followed by standard anoscopy (SA), to anal cytology (Pap)+/- HPV genotyping. We compared screening strategy yields based on Pap, SA, and HPV-16 genotyping alone or in combination in HIV-MSM. METHODS: Pap, SA, and HPV-16 genotyping were performed in all HIV-MSM attending a first anal cancer screening consultation in Paris, France. High-resolution anoscopy, the gold standard to detect HGAIN, was performed in the case of HPV-16 positivity or abnormal cytology. Yield was defined as the number of patients with HGAIN relative to the total number of patients screened. RESULTS: On 212 patients, the complete strategy (SA + Pap + HPV genotyping) yield (12.7%) was significantly higher than that of SA (3.3%, p < 0.001) and HPV-16 alone (6.6%, p < 0.05). Although none of the other strategies were significantly different from the complete strategy, Pap + HPV-16 and Pap + SA had closer yields (about 11%), with OR = 0.83 (95% CI [0.44;1.57]) and 0.87 (95% CI [0.46;1.64]), respectively. CONCLUSIONS: Pap combined with HPV-16 genotyping or SA tended towards higher yields compared to Pap alone, and closer to that of the complete strategy. PMID- 30026614 TI - Feasibility and acceptability of brief behavioral therapy for cancer-related insomnia: effects on insomnia and circadian rhythm during chemotherapy: a phase II randomised multicentre controlled trial. AB - BACKGROUND: This phase II RCT was conducted to determine the feasibility and acceptability of brief behavioral therapy for cancer-related insomnia (BBT-CI) in breast cancer patients undergoing chemotherapy. We also assessed the preliminary effects of BBT-CI on insomnia and circadian rhythm in comparison to a Healthy Eating Education Learning control condition (HEAL). METHODS: Of the 71 participants recruited, 34 were randomised to receive BBT-CI and 37 to receive HEAL. Oncology staff was trained to deliver the intervention in four community clinics affiliated with the NCI. Insomnia was assessed with the Insomnia Severity Index (ISI), and circadian rhythm was assessed using a wrist-worn actiwatch. RESULTS: Community staff interveners delivered 72% of the intervention components, with a recruitment rate of 77% and an adherence rate of 73%, meeting acceptability and feasibility benchmarks. Those randomised to BBT-CI improved their ISI scores by 6.3 points compared to a 2.5-point improvement in those randomised to HEAL (P = 0.041). Actigraphy data indicated that circadian functioning improved in the BBT-CI arm as compared to the HEAL arm at post intervention (all P-values <0.05). CONCLUSIONS: BBT-CI is an acceptable and feasible intervention that can be delivered directly in the community oncology setting by trained staff. The BBT-CI arm experienced significant improvements in insomnia and circadian rhythm as compared to the control condition. PMID- 30026616 TI - Breaking out of the shy silo. PMID- 30026615 TI - Experimental manipulation of incubation period reveals no apparent costs of incubation in house wrens. AB - Fitness costs of incubation ensue whenever the trade-off between incubation and foraging leads to suboptimal incubation or decreased parental body condition. We examined the costs of incubation in a wild population of house wrens, Troglodytes aedon, by experimentally extending or decreasing the incubation period by cross fostering eggs between nests at different stages of incubation (eggs from control nests were cross-fostered at the same stage of incubation). We determined whether parents or offspring bear the costs of incubation by measuring effects on females and offspring within the same breeding season during which the manipulation occurred, but also by evaluating potential trade-offs between current and future reproduction by monitoring return rates of experimental females and recruitment rates of offspring in subsequent breeding seasons. There was no difference in hatching or fledging success across treatments. There was also no effect of incubation duration on female size-corrected mass, and females from different treatments were equally likely to produce a second brood. Nestlings produced by females did not differ in body mass, tarsus length or residual mass. Neither return rates of females, nor the number of offspring recruited, differed across treatments. We conclude, therefore, that although prolonged incubation entails increased energy expenditures, females are able to offset these losses while foraging, thereby mitigating the costs of incubation. This resiliency is more likely to be seen in income breeders, such as house wrens, that retain some ability to recoup energy expended in incubation, than in capital breeders that are constrained by stored energy reserves. PMID- 30026617 TI - Veterinary Medical Ethics. PMID- 30026618 TI - 2017 Annual Report of the Canadian Veterinary Medical Association. PMID- 30026619 TI - Building the antimicrobial stewardship leadership plan for animal health in Canada (workshop, Ottawa, October 3-4, 2017). PMID- 30026620 TI - Compassion does not fatigue! PMID- 30026621 TI - Long-term clinical control of feline pancreatic carcinoma with toceranib phosphate. AB - An 11-year-old, spayed female, domestic shorthair cat was presented with a non resectable abdominal mass diagnosed as carcinomatosis of pancreatic origin. Treatment with toceranib phosphate was started. Abdominal ultrasound approximately 1 year after diagnosis revealed progressive disease. The cat was humanely euthanized approximately 792 days after initial presentation due to progressive clinical signs. PMID- 30026622 TI - Acute cerebrovascular event in a dog with polycythemia vera. AB - A 1-year-old neutered male Labrador retriever mixed breed dog was referred for peracute onset of ataxia and seizures. Hematocrit at presentation was 84%. Magnetic resonance imaging of the brain revealed a lesion in the right caudate nucleus consistent with infarction. Postmortem findings were consistent with polycythemia vera and presumed secondary cerebral infarction. PMID- 30026623 TI - Successful management of proteinuria and systemic hypertension in a dog with renal cell carcinoma with surgery, telmisartan, and amlodipine. AB - An 11-year-old neutered male Yorkshire terrier dog was presented with a 3-week history of hematuria and anorexia. A unilateral renal mass was detected and surgically removed. The renal mass was diagnosed on histopathologic examination as a renal carcinoma. Supportive medical therapy was carried out and persistent systemic hypertension was managed using telmisartan. PMID- 30026624 TI - Internal neurolysis of the maxillary branch of the trigeminal nerve for the treatment of equine trigeminal mediated headshaking syndrome. AB - A 5-year-old Hannovarian warmblood gelding was presented for recurrent headshaking exacerbated with exercise. The horse displayed clinical signs of repetitive vertical head movements, face rubbing on the forelimbs and on the ground, repetitive sneezing, and striking the muzzle with his forelimbs. The clinical signs resulted in a horse that could not be ridden and was dangerous. Clinical signs were most persistent in direct sunlight, but occurred with excitement, exercise, or bridling indoors. A diagnosis of equine trigeminal mediated headshaking syndrome was made. Surgical treatment was performed with a supraorbital approach to the maxillary branch of the trigeminal nerve as it exits the round foramen, where an internal neurolysis (nerve combing) was conducted on both the left and right nerves. Severe headshaking behavior resolved after surgery. The horse displayed face rubbing of the muzzle which began 96 hours after surgery and resolved over 12 days with corticosteroid and vitamin E therapy. The horse became pasture sound and the clinical signs had resolved in the presence of sunlight, but repetitive vertical head movements persisted under saddle which left the horse unpleasant to ride. PMID- 30026625 TI - A pilot study of Coxiella seroprevalence in occupationally exposed individuals in the Peace River region of Alberta and British Columbia. AB - A pilot seroprevalence study was performed among asymptomatic occupationally exposed individuals in June, 2016 in the Peace River region of Alberta and British Columbia. Five of 40 subjects - 3 of 24 small ruminant producers, 1 of 14 abattoir workers, and 1 of 2 veterinarians had evidence of Coxiella exposure. More systematic surveillance and more active promotion of biosecure husbandry methods should be considered. PMID- 30026626 TI - Effect of routine pre-anesthetic laboratory screening on pre-operative anesthesia related decision-making in healthy dogs. AB - The usefulness of pre-anesthetic laboratory screening of healthy veterinary patients is controversial and clear evidence-based guidelines do not exist. The purpose of our study was to determine the influence of preanesthetic laboratory screening on peri-anesthetic plans in canine patients undergoing elective surgery. One hundred medical records were randomly selected between the years 2008 and 2013 and patient information was presented to 5 Diplomates of the American College of Veterinary Anesthesia and Analgesia (ACVAA) for review. They were given pre-anesthetic laboratory screening test results for each patient and asked whether the results would change the way they managed the case from an anesthesia perspective. Peri-operative anesthetic management was altered in 79% of patients based on pre-anesthetic screening results; however, the overall agreement among anesthesiologists was weak with 64% of changes made by only a single anesthesiologist. Pre-anesthetic laboratory screening test results may influence pre-operative anesthesia case management but major discrepancies can occur among ACVAA diplomates. PMID- 30026627 TI - A retrospective analysis of feedlot morbidity and mortality outcomes in calves born to dams with known viral vaccination history. AB - This retrospective analysis aimed to determine the effects of a maternal viral vaccination program (MVVP; Express Verified) on calf health during the feeding period. In low- and high-risk populations, calves born to dams vaccinated pre breeding with program products had improved morbidity and mortality outcomes compared with non-program animals. PMID- 30026628 TI - A longitudinal study describing horse demographics and movements during a competition season in Ontario, Canada. AB - The objective of this study was to describe the demographics and movement patterns of a sample of horses in Ontario, Canada. A convenience sample of 222 owners completed an initial questionnaire to provide demographic information for 570 horses. These horses were enrolled in a longitudinal study to document their movements from May to November 2015 using a monthly questionnaire. The median age of the participating horses was 11 years (IQR: 8 to 16 years). The primary discipline of participating horses included competitive disciplines (63.3%), leisure (33.3%), and racing (3.2%). During the 7-month period, there were 3001 unidirectional movements of horses between facilities. Reasons for travel on/off a facility included attending a competition (38.7%), leisure activities (18.8%), and training (7.5%). The demographic and movement data presented in this study provide insight into the characteristics of a subset of horses in Ontario, and may contribute to outbreak preparedness in the population. PMID- 30026629 TI - Effects of alfaxalone, thiopental, or propofol and diazepam on laryngeal motion in healthy dogs. AB - Laryngeal function is assessed by direct visualization of the larynx under a light plane of anesthesia. This study compared the effects of 3 anesthetic protocols on arytenoid motion in healthy dogs. Eight dogs were randomly assigned to receive alfaxalone, propofol and diazepam, or thiopental. Videolaryngoscopy was performed and still images at maximum inspiration and expiration were used to measure the area and height of the glottal gap. The normalized glottal gap area (NGGA = area in pixels/height2) was calculated. The NGAA change was defined as the difference between NGAA during inspiration and exhalation. Data were analyzed using Mann-Whitney and Kruskal-Wallis tests, P-values < 0.05 were considered statistically significant. No significant difference among induction protocols was found when comparing NGGA change after induction or before recovery. Alfaxalone and propofol/diazepam are useful for evaluation of laryngeal function when administered to effect and a light plane of anesthesia is maintained. PMID- 30026630 TI - Claw disease in the dog: Does your patient have symmetrical lupoid onychodystrophy (SLO)? PMID- 30026631 TI - Let the good times roll: Results of the 2017 CVMA practice owners economic survey. PMID- 30026632 TI - Confidence gained through experience. PMID- 30026633 TI - Dual Photoreactivity of a New Rh2(II,II) Complex for Biological Applications. AB - A new Rh2(II,II) complex containing one dppn (benzo[i]dipyrido[3,2-a:2,3 c]phenazine) ligand with an extended pi-system, cis-H,H [Rh2(OCCH3NH)2(dppn)(CH3CN)2]2+ (2), was synthesized and characterized. The dppn ligand, which serves as a DNA base pair intercalator, chelates to a single Rh center and is positioned trans to the amidato N atoms of the bridging acetamide ligand. This ligand also possesses a low-lying dppn-centered 3pipi* state that is advantageous for the sensitization of singlet oxygen (1O2), which complex 2 produced with a quantum yield, Phi 1O2460, of 0.22(7) with 460 nm excitation. In addition, one equivalent of CH3CN is released from 2 upon irradiation with visible light, generating cis-H,H-[Rh2(OCCH3NH)2(dppn)(H2O)(CH3CN)]2+ in aqueous media with photoinduced ligand exchange quantum yield, PhiLE450, of 0.0033(1). Thermal denaturation and relative viscosity studies are consistent with a pi stacking interaction of 2 with double-stranded DNA together with covalent binding to the duplex upon irradiation with visible light. Therefore, 2 exhibits dual photoreactivity towards DNA, making it potentially useful for photochemotherapy with enhanced activity relative to compounds able to achieve only one mode of cell death upon irradiation. PMID- 30026634 TI - Thermosphere-Ionosphere-Electrodynamics General Circulation Model for the Ionospheric Connection Explorer: TIEGCM-ICON. AB - The NASA Ionospheric Connection explorer (ICON) will study the coupling between the thermosphere and ionosphere at low- and mid-latitudes by measuring the key parameters. The ICON mission will also employ numerical modeling to support the interpretation of the observations, and examine the importance of different vertical coupling mechanisms by conducting numerical experiments. One of these models is the Thermosphere-Ionosphere-Electrodynamics General Circulation Model ICON (TIEGCM-ICON) which will be driven by tidal perturbations derived from ICON observations using the Hough Mode Extension method (HME) and at high latitude by ion convection and auroral particle precipitation patterns from the Assimilative Mapping of Ionospheric Electrodynamics (AMIE). The TIEGCM-ICON will simulate the thermosphere-ionosphere (TI) system during the period of the ICON mission. In this report the TIEGCM-ICON is introduced, and the focus is on examining the effect of the lower boundary on the TI-system to provide some guidance for interpreting future ICON model results. PMID- 30026635 TI - Daytime O/N2 Retrieval Algorithm for the Ionospheric Connection Explorer (ICON). AB - The NASA Ionospheric Connection Explorer Far-Ultraviolet spectrometer, ICON FUV, will measure altitude profiles of the daytime far-ultraviolet (FUV) OI 135.6 nm and N2 Lyman-Birge-Hopfield (LBH) band emissions that are used to determine thermospheric density profiles and state parameters related to thermospheric composition; specifically the thermospheric column O/N2 ratio (symbolized as SigmaO/N2). This paper describes the algorithm concept that has been adapted and updated from one previously applied with success to limb data from the Global Ultraviolet Imager (GUVI) on the NASA Thermosphere Ionosphere Mesosphere Energetics and Dynamics (TIMED) mission. We also describe the requirements that are imposed on the ICON FUV to measure SigmaO/N2 over any 500-km sample in daytime with a precision of better than 8.7%. We present results from orbit simulation testing that demonstrates that the ICON FUV and our thermospheric composition retrieval algorithm can meet these requirements and provide the measurements necessary to address ICON science objectives. PMID- 30026636 TI - Copper Mediated Coupling of 2-(Piperazine)-pyrimidine Iodides with Aryl Thiols using Cu(I)Thiophene-2-carboxylate. AB - A copper-mediated synthesis of diaryl sulfides utilizing Cu(I)-thiophene-2 carboxylate (CuTC) is described. We demonstrate the use of CuTC as a soluble, non basic catalyst in the coupling of aryl iodides and aryl thiols in the synthesis of synthetically advanced diaryl sulfides. This method allows for the successful coupling of challenging substrates including ortho-substituted and heteroaryl iodides and thiols. Additionally, most of the aryl iodide substrates used here contain the privileged piperazine scaffold bound to a pyrimidine, pyridine, or phenyl ring and thus this method allows for the elaboration of complex piperazine scaffolds into molecules of biological interest. The method described here enables the incorporation of late-stage structural diversity into diaryl sulfides containing the piperazine ring, thus enhancing the number and nature of derivatives available for SAR investigation. PMID- 30026637 TI - The Effects of Changes in Kindergarten Entry Age Policies on Educational Achievement. AB - This study explores the effects of state kindergarten-entry-age policies on students' outcomes by exploiting variation in the kindergarten entry cutoff dates enacted by states in the United States over the last 40 years. Using the state average and standard deviation in NAEP test scores in 4th, 8th and 12th grades, we estimate the impacts of state entry-age policies on educational achievement and test score dispersion in the state. The estimation results from the baseline state and time fixed effects model show that a one month earlier cutoff increases average state reading and math scores of 4th graders by 21.7 and 13.6 percent of a standard deviation, respectively. Eighth graders' average score increases in math and science are 12.4 and 24.3 percent of a standard deviation, respectively, while the effect on reading score significantly decreases. We find no effect of kindergarten entry date on educational outcomes in 12th grade. We also find that an earlier kindergarten entry date generally reduces the standard deviation of state test scores. Robustness checks support these findings and suggest no evidence of endogeneity of the policy changes. Our findings provide novel evidence that early school start cutoffs have improved state-level achievement measures over the past 40 years. PMID- 30026638 TI - Evaluation of Methods of Displaying the Real-Time Scattered Radiation Distribution during Fluoroscopically-Guided Interventions for Staff Dose Reduction. AB - 2D and 3D scatter dose display options are evaluated for usefulness and ease of interpretation for real-time feedback to staff to facilitate changes in individual positioning for dose reduction purposes, as well as improving staff consciousness of radiation presence. Room-sized scatter dose 3D matrices are obtained utilizing Monte Carlo simulations in EGSnrc. These distributions are superimposed on either a ceiling-view 2D graphic of the patient and table for reference or a 3D augmented reality (AR) display featuring a real-time video feed of the interventional room. A slice of the scatter dose matrix, at a selectable distance above the floor, is color-coded and superimposed on the computer graphic or AR display. The 3D display obtains depth information from a ceiling mounted Microsoft Kinect camera, which is equipped with a 1080p visual camera, as well as an IR emitter/receiver to generate a depth map of the interventional suite and persons within it. The 3D depth information allows parts of objects above the 2D dose map to pass through the map without being colorized by it so the height perspective of the dose map can be maintained. The 2D and 3D displays incorporate network information from the imaging system to scale the scatter dose with exposure factors and adjust rotation of the distribution to match the gantry. Demonstration images were displayed to neurosurgery interventional staff and survey responses were collected. Results from the survey indicated that scatter distribution displays would be desirable and helpful in managing staff dose. PMID- 30026639 TI - Erratum: Pediatric Portal Interventions. AB - [This corrects the article DOI: 10.1055/s-0038-1642043.]. PMID- 30026640 TI - Changes in antimicrobial resistance levels among Escherichia coli, Salmonella, and Campylobacter in Ontario broiler chickens between 2003 and 2015. AB - Poultry has been identified as a reservoir of foodborne enteric pathogens and antimicrobial resistant bacteria. The objective of this study was to describe and compare antimicrobial resistant isolates from an Ontario broiler chicken farm level baseline project (2003 to 2004) to the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) Ontario abattoir and retail surveillance data from 2003, and to the most recent (2015) CIPARS Ontario chicken surveillance data in order to assess the impact of an industry-wide policy change in antimicrobial use. Ceftiofur resistance (TIO-R) prevalence in Salmonella decreased by 7% on farm between 2003 and 2004 and 2015. During the same timeframe, TIO-R E. coli prevalence decreased significantly by 16%, 11%, and 8% in farm, abattoir, and retail samples, respectively. Gentamicin resistant (GEN-R) E. coli, however, increased by 10% in farm and 15% in retail-derived isolates, and trimethoprim-sulfamethoxazole resistant (TMSm-R) E. coli increased significantly by 20%, 18%, and 5% in farm, abattoir, and retail isolates, respectively. Similarly, ciprofloxacin-resistant (CIP-R) Campylobacter spp. significantly increased in retail isolates by 11% and increased in farm (33%) and abattoir isolates (7%). The decrease in TIO-R Salmonella/E. coli in recent years is consistent with the timing of an industry-led intervention eliminating the preventive use of ceftiofur, a third generation cephalosporin and class of antimicrobials deemed critically important to human medicine. The rise in GEN-R and TMSm-R prevalence is indicative of recent shifts in antimicrobial use. Our study highlights the importance of integrated surveillance in detecting emerging trends and determining the efficacy of interventions to improve food safety. PMID- 30026641 TI - Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. AB - The purpose of this study was to determine the pharmacokinetics of cannabidiol (CBD) in healthy dogs. Thirty, healthy research dogs were assigned to receive 1 of 3 formulations (oral microencapsulated oil beads, oral CBD-infused oil, or CBD infused transdermal cream), at a dose of 75 mg or 150 mg q12h for 6 wk. Serial cannabidiol plasma concentrations were measured over the first 12 h and repeated at 2, 4, and 6 wk. Higher systemic exposures were observed with the oral CBD infused oil formulation and the half-life after a 75-mg and 150-mg dose was 199.7 +/- 55.9 and 127.5 +/- 32.2 min, respectively. Exposure is dose-proportional and the oral CBD-infused oil provides the most favorable pharmacokinetic profile. PMID- 30026642 TI - Does antimicrobial therapy improve outcomes in horses with severe equine asthma and a positive tracheal wash bacterial culture? AB - The objective of this study was to observe the outcomes of adding an antimicrobial treatment to a conventional treatment regime in horses with severe equine asthma in a clinical setting. Eleven client-owned horses with a history consistent with severe equine asthma, increased respiratory effort and nostril flaring, >= 20% neutrophils on bronchoalveolar lavage (BAL), and a positive tracheal wash (TW) bacterial culture were treated with environmental management, corticosteroids, and bronchodilators. Six horses were also treated with an antimicrobial (principal group), while the other 5 were administered saline as a placebo (control group). Treatment with antimicrobials significantly improved the post-treatment clinical score of the principal group compared with the pre treatment score, whereas no significant difference occurred in the control group. The principal group also had significantly less neutrophil myeloperoxidase (MPO) activity post-treatment than pre-treatment, with a median difference of -0.39 units/[protein] in the principal group and a median difference of -0.21 units/[protein] in the controls. There was no difference in MPO activity pre- versus post-treatment in the control group. No differences were noted in the intra-group comparisons of pre- versus post-treatment BAL neutrophil counts, mucus scores, and concentrations of interleukin-8 (IL-8) or tumor necrosis factor alpha (TNF-alpha) in bronchoalveolar lavage fluid (BALF) in either group. There were no differences found in the inter-group comparisons of the principal versus controls for each of the pre- and post-treatment time periods for BAL neutrophil count, mucus score, clinical scores, MPO activity, and IL-8 or TNF-alpha concentrations. The role of airway bacteria in horses with severe equine asthma requires further investigation as antimicrobial therapy improved post-treatment clinical scores and decreased MPO activity in the group of horses studied, but did not affect other measures of airway inflammation. PMID- 30026643 TI - Impact of a trap-neuter-return event on the size of free-roaming cat colonies around barns and stables in Quebec: A randomized controlled trial. AB - The objective of this study was to evaluate the impact of a trap-neuter-return (TNR) event on the size of free-roaming rural cat colonies in Quebec. This prospective randomized, controlled study included 18 cat colonies around barns and stables that were randomly assigned to either a TNR group (10 colonies of 7 to 27 cats; 14.3 cats on average) or a control group (8 colonies of 7 to 26 cats; 14.5 cats on average). The number of cats in each colony was calculated from the images obtained by camera-trapping at: baseline (T0), 7.5 mo (T7), and 12 mo (T12). At baseline, the TNR group was subjected to a TNR event. When taking into account adults only, a significant growth difference was observed in the number of cats between the TNR group and the control group at T7 (P = 0.03). When including kittens as well as adults, a trend towards a lower growth of the TNR group compared to the control group was noted at T7 (P = 0.06). There was no difference in the number of kittens between the 2 groups at T7 (P = 0.49) or at T12 (P = 0.36). There was a trend towards more emigration in the control group at T12 (P = 0.095). Isolated TNR events have a low and temporary impact on colony size in Quebec's rural cat colonies. PMID- 30026644 TI - Cardiac weights and weight ratios as indicators of cardiac lesions in pigs: A study of pig hearts from an Ontario abattoir. AB - Clinically healthy pigs used in research are assumed to have normal cardiac structure and function. Subclinical cardiac abnormalities may adversely affect the responses being measured in these experiments. The gross and histologic lesions observed in hearts collected from a Canadian abattoir between 2012 and 2015 indicated an unexpectedly high prevalence of cardiac abnormalities: 75% (297/396) of the hearts examined had such lesions. The ratios of total heart weight to body weight and of right ventricle weight to body weight were significantly greater for the hearts with lesions than for the hearts with no lesions, which suggests that cardiac remodeling, particularly hypertrophy, had occurred. The large percentage of hearts with cardiac remodeling from asymptomatic market pigs demonstrates an increased probability that subclinical cardiac abnormalities may exist in research pigs, especially those accessed through commercial channels. Researchers should be aware of this likelihood if subclinical cardiac abnormalities could adversely affect their experimental findings. PMID- 30026646 TI - Intraocular pressure measurements in cattle, sheep, and goats with 2 different types of tonometers. AB - The aim of this study was to investigate normal intraocular pressure (IOP) values of cattle, sheep, and goats with a rebound tonometer [TonoVet (TV)] and an applanation tonometer [Tono-Pen AVIA (TPA)] and to determine correction functions for the 2 devices. A total of 60 healthy cattle, sheep, and goats (20 of each) underwent slit-lamp biomicroscopy. Intraocular pressure (IOP) readings were taken from both eyes with the 2 different tonometers and statistically analyzed. For calibration purposes, the IOP was preset on each instrument at 5 to 60 mmHg using 5 mmHg increments in 10 bovine, 8 ovine, and 6 caprine freshly enucleated eyes. Readings were taken with both tonometers at each interval and compared to the manometrically controlled IOP (Mann-Whitney U-test, P <= 0.05; Bland-Altman plot, and regression analysis). The median IOP measurements (min to max) obtained with the TV were 23 mmHg (12 to 40 mmHg), 11 mmHg (7 to 20 mmHg), and 23 mmHg (9 to 37 mmHg) for cattle, sheep, and goats, respectively. Using the TPA, the median IOP measurements were 16 mmHg (8 to 27 mmHg), 10 mmHg (5 to 18 mmHg), and 13 mmHg (4 to 25 mmHg) for cattle, sheep, and goats, respectively. There were statistically significant differences between the readings taken with the TV and the TPA in all species (Wilcoxon-test, P <= 0.05). All measurements obtained with the TV and the TPA during the calibration procedure differed statistically significantly from the manometrically controlled IOP measurements (Mann-Whitney U-test, P <= 0.05). For both instruments, regression formulas were calculated to correct the measurements. Both tonometers can be used effectively to assess intraocular pressure in ruminants, using the specific regression formulas. PMID- 30026645 TI - Effects of a single intravenous bolus injection of alfaxalone on canine splenic volume as determined by computed tomography. AB - The purpose of this study was to evaluate the effects of a single intravenous dose of alfaxalone on canine splenic volume. In 6 adult beagle dogs the splenic volume [mean +/- standard error (SE)] was determined by computed tomography to be 0.17 +/- 0.02 L before alfaxalone administration and 0.24 +/- 0.02 L (P = 0.0091) and 0.23 +/- 0.02 L (P = 0.0268) 15 and 30 min, respectively, after alfaxalone administration. Hematocrits (mean +/- SE) obtained at the same times were, respectively, 46.3% +/- 1.3%, 40.6% +/- 1.3% (P = 0.0015), and 41.7% +/- 1.3% (P = 0.0057). In conclusion, alfaxalone caused relaxation of the canine splenic capsule and an increase in the splenic volume, along with a decrease in the hematocrit in these dogs. PMID- 30026647 TI - The biological characteristics of sheep umbilical cord mesenchymal stem cells. AB - Although mesenchymal stem cells (MSCs) are now regarded as a promising cell resource for tissue repair and regeneration, the optimal source of MSCs has not yet been determined. The objective of this study was to provide a theoretical basis for the clinical application of umbilical cord mesenchymal stem cells (UCMSCs) in the future. Umbilical cord is an easily obtainable tissue resource, which is one reason that it has become a candidate resource for mesenchymal stem cells. In this study, we analyzed the biological characteristics of UCMSCs, such as their multiple differentiation and clone-forming ability, through morphological observation, reverse transcription polymerase chain reaction (RT PCR), growth curve, positive rate test, and immunophenotype. Umbilical cord MSCs were successfully isolated and passaged to 29 generations. The results from RT PCR showed that UCMSCs were positive for CD29, CD44, CD73, but negative for CD34. The expression of the stem cell marker nucleostemin and tenocyte-related markers showed similar positive results with CD44, CD73, and CD90. In addition, UCMSCs can be induced to differentiate into osteoblasts, adipocytes, or chondrocytes. Our study showed that UCMSCs not only have the ability to self-renew, but also have the potential to differentiate into multiple lineages. In general, we concluded that UCMSCs are a reliable source for use in cell therapy. PMID- 30026648 TI - Isolation, culture, and characterization of chicken lung-derived mesenchymal stem cells. AB - Using lung tissues separated from 12-day-old chicken embryos, we attempted to obtain a novel population of stem cells, namely, chicken lung-derived mesenchymal stem cells (LMSCs), which exhibit spindle-like morphology. The results of colony forming assay and population doubling assay demonstrated that LMSCs had enormous colony-forming, self-renewal, and proliferative potential. When appropriately induced, LMSCs could differentiate into osteoblasts, adypocytes, chondrocytes, and neurons; in other words, LMSCs had cross-embryonic layer differentiation potential under corresponding induction conditions. Aside from colony-forming, self-renewal, and multilineage differentiation capabilities, LMSCs were characterized by specific cell phenotypes. The results of immunohistochemistry and flow cytometry demonstrated that LMSCs consistently expressed OCT-4 - a specific gene marker expressed in pluripotent stem cells - and markers associated with MSCs such as CD29, CD73, CD90, and CD105. However, LMSCs lacked hematopoietic cell surface molecules such as CD34 and CD45. Primary LMSCs could be subcultured to passage 24 at most in vitro and karyotype analysis demonstrated that LMSCs possessed genomic stability. These unique characteristics were consistent with the characteristics of MSCs, which had been isolated from other tissues. This provides a foundation for LMSCs as a promising avenue for cellular transplantation therapy, regenerative medicine, and tissue engineering. PMID- 30026649 TI - ACTN3 gene variants as potential phenotype and performance biomarkers in Brazilian sport horses training for eventing in a tropical climate. AB - The aim of this study was to look for mutations in the equine ACTN3 gene and to identify sequence variants that might be associated with the phenotype and performance of Brazilian sport horses training for events in a tropical climate. Among 17 such horses direct DNA sequencing and mutation analysis of the exon 15 and the intron-exon boundaries of ACTN3 revealed 2 new sequence variants in the ACTN3 intron 14-15, designated c.1681-86G > A and c.1681-129delA. Wild type/deletion heterozygotes (A/del) had a lower mean subcutaneous fat layer in the region of the gluteus medius, as measured by ultrasonography, than the del/del homozygotes; the correlation was significant (P = 0.017). This single base-pair deletion in ACTN3 intron 14-15 may have resulted in metabolic changes that led to increased deposition of body fat in the homozygous state. However, neither sequence variant was correlated with the time to fatigue in a test on a high-speed treadmill with an incremental-speed protocol. PMID- 30026650 TI - Effect of piglet separation from dam at birth on colostrum uptake. AB - The objective of this study was to determine whether birth order influences piglet survival because of reduced uptake of maternal antibodies by the piglets born later in large litters. Forty-five litters were serially allocated to one of 2 study groups. The creche group consisted of 18 litters for which the 205 piglets were removed to a warm box to prevent suckling until 4 h after delivery of the first pig, and the control group of 27 litters for which 306 piglets were allowed to suckle from birth. The protein content of piglet blood and sow colostrum was determined with Brix refractometers. Parity, farrowing duration, liveborn litter size, litter size at 12 d, and piglet weight at birth and at 24 h and 12 d of age did not differ between the 2 treatment groups (P > 0.1). There were also no significant differences (P > 0.1) at any time point in weight or in the mean percent protein in plasma between the first 3 and the last 3 piglets born to an individual sow. However, the mean percent protein in plasma was significantly higher in the control group than in the creche group at both 24 h (P <= 0.05) and day 12 (P <= 0.01) postpartum. The lack of differences in plasma protein levels between the first and last pigs born along with the lower percent plasma protein in the piglets that were prevented from suckling immediately after birth militate against the use of this technique as a way to equalize the opportunity for adequate transfer of maternal antibodies. PMID- 30026651 TI - The Effects of Teenage Childbearing on Adult Soft Skills Development. AB - Research examining impacts of teenage childbearing on economic and social outcomes has focused on completed schooling and labor force outcomes. In this paper, we examine outcomes that have remained largely unexplored, soft-skills and personality. We use Add Health data to construct relevant controls for teenage mothers and explore a set of measures that proxy for what is usually deemed in economics as "non-cognitive" or "soft-skill" traits. We find that teenage childbearing increases impulsivity, a trait that has been found to have negative effects on a large set of outcomes and has a negative effect on other personality traits perceived as positive, such as openness to experiences. Our results remain consistent through a set of robustness checks, and we interpret our findings to suggest that adolescence may be a sensitive period for the development of soft skills and that childbearing may interrupt this process. PMID- 30026652 TI - Interaction of Fluorescently Labeled Cadherin G Protein-coupled Receptor with the Cry1Ab Toxin of Bacillus thuringiensis. AB - The Cry1Ab toxin produced by Bacillus thuringiensis binds to a conserved structural motif in the 12th ectodomain module (EC12) of BT-R1, a cadherin G protein-coupled receptor (GPCR) contained in the membrane of midgut epithelial cells of the tobacco hornworm Manduca sexta. Toxin binding transmits a signal into the cells and turns on a multi-step signal transduction pathway, culminating in cell death. Using chromatographically purified Cry1Ab and EC12 proteins, we demonstrated the direct formation of a stable complex between these two proteins in solution and visualized it on a native polyacrylamide gel. Moreover, we generated a fluorescent EC12 probe by converting the 36th residue to cysteine to enable maleimide-mediated conjugation of Alexa-488 fluorescent dye to EC12 by site-directed mutagenesis. In addition, we changed the 44th residue of EC12 to tryptophan, which greatly improved accuracy of protein quantification and traceability. Using the fluorescently labeled EC12 probe for direct and competitive binding assays, we were able to determine binding specificity in solution. These accomplishments will facilitate identification and characterization of the interface sequences for both the Cry1Ab toxin and BT-R1. PMID- 30026653 TI - Financial Integration and Relationship Transitions of Young Adult Cohabiters. AB - Despite increasing rates of pre-marital cohabitation, the majority of research on household financial practices in the United States has focused on married couples. This study explored ways young adult cohabiters (N = 691) financially combined their lives and the associations with subsequent relationship outcomes. Results indicated cohabiters were intertwining credit histories and bank accounts, and acquiring assets such as purchasing homes together. Sharing a mortgage was associated with an increased likelihood of marriage, whereas joint credit card accounts increased the odds of dissolution. Cohabiters with an intent to marry were much more likely to start integrating their finances prior to marriage. This study sheds light on the heterogeneous ways that a recent cohort of young adult couples manages their finances and navigates relationships. PMID- 30026654 TI - Avoiding Exploitation in Phase I Clinical Trials: More than (Un)Just Compensation. PMID- 30026655 TI - The Ethics of Using Complementary Medicine in Pediatric Oncology Trials: Reconciling Challenges. PMID- 30026656 TI - The effects of downscaling method on the variability of simulated watershed response to climate change in five U.S. basins. AB - Simulations of future climate change impacts on water resources are subject to multiple and cascading uncertainties associated with different modeling and methodological choices. A key facet of this uncertainty is the coarse spatial resolution of GCM output compared to the finer-resolution information needed by water managers. To address this issue, it is now common practice to apply spatial downscaling techniques, using either higher-resolution regional climate models or statistical approaches applied to GCM output to develop finer-resolution information for use in water resources impacts assessments. Downscaling, however, can also introduce its own uncertainties into water resources impacts assessments. This study uses watershed simulations in five U.S. basins to quantify the sources of variability in streamflow, nitrogen, phosphorus, and sediment loads associated with the underlying GCM compared to the choice of downscaling method (both statistically and dynamically downscaled GCM output). We also assess the specific, incremental effects of downscaling by comparing watershed simulations based on downscaled and non-downscaled GCM model output. Results show that the underlying GCM and the downscaling method each contribute to the variability of simulated watershed responses. The relative contribution of GCM and downscaling method to the variability of simulated responses varies by watershed and season of the year. Results illustrate the potential implications of one key methodological choice in conducting climate change impacts assessments for water - the selection of downscaled climate change information. PMID- 30026658 TI - An overview of abuse-deterrent opioids and recommendations for practical patient care. AB - Despite advances in the treatment of severe intractable pain, opioids remain a critical and appropriate component of treatment. However, abuse, misuse, and diversion of prescription opioids are significant public health concerns. Opioid abuse-deterrent formulations (ADFs) are one component of an opioid risk management plan to manage patient's pain relief and quality of life while offering some protection against potentially harmful consequences of opioids from misuse and abuse. Opioid ADFs are designed to make manipulation more difficult and administration via non-oral routes less appealing. There are currently nine extended-release and one immediate-release opioid pain medications with US Food and Drug Administration-approved ADF labeling. All use physical/chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence suggests that opioid ADFs decrease rates of abuse and diversion of opioids in the USA; however, some opioid ADFs are not yet commercially available or have not been on the market long enough to undergo post-marketing data analyses. Opioid ADFs along with the use of prescription drug monitoring programs, clinical assessment tools, toxicology testing, and co-prescribing of naloxone are all tools that can be used to reduce opioid abuse. Patient education on the risks of abuse and diversion is vital and includes a discussion of appropriate use of medication and proper storage. Physician assistants and nurse practitioners are on the "front lines" in battling opioid abuse and serve a key role in recognizing and mitigating the risks of prescription opioid diversion, abuse, and misuse (intentional and unintentional) and in identifying patients at risk for abuse while still providing pain relief to patients. PMID- 30026657 TI - Statistical concerns about the study: hypoglycemic and antioxidant effect of Tai chi exercise training in older adults with metabolic syndrome. PMID- 30026659 TI - A molecular and conchological dissection of the "scaly" Georissa of Malaysian Borneo (Gastropoda, Neritimorpha, Hydrocenidae). AB - The Bornean hydrocenids have so far been understudied compared to other non pulmonate snails in this region. In the present study, we review a first group of minute land snail species belonging to the genus Georissa (Gastropoda, Hydrocenidae) from Malaysian Borneo. This group is restricted to the species with conspicuous scale-like sculpture on the shell. Based on materials from recent fieldwork, museums, and personal collections, Malaysian Borneo hydrocenids are more complex and diverse in shell characters than previously anticipated. Here, a molecular, conchological, and biogeographic study of this "scaly group" is presented. We recognise 13 species of which six are new to science, namely Georissa anyiensissp. n., Georissa muluensissp. n., Georissa bauensissp. n., Georissa silaburensissp. n., Georissa kinabatanganensissp. n., and Georissa sepulutensissp. n. PMID- 30026661 TI - A new species of the genus Blaptogonia from the Himalayas with four DNA markers (Coleoptera, Tenebrionidae, Blaptini). AB - A new species of the genus Blaptogonia Medvedev, 1998, B. zhentangasp. n., is described from the southern Himalayas of China. Two fragments of mitochondrial protein-coding genes (COI, Cytb), one fragment of mitochondrial ribosomal RNA gene (16S), and one fragment of nuclear rRNA gene (28SD2) of the new species were obtained. A key to the known species of the genus is presented. PMID- 30026660 TI - The complete mitochondrial genome of Xizicus (Haploxizicus) maculatus revealed by Next-Generation Sequencing and phylogenetic implication (Orthoptera, Meconematinae). AB - Xizicus Gorochov, 1993, the quiet-calling katydid, is a diverse genus with 68 species in world, which includes more than 45 species in China, has undergone numerous taxonomic revisions with contradicting conclusions. In this study the complete mitochondrial genome of Xizicus (Haploxizicus) maculatus collected from Hainan for the first time was sequenced using the Next-Generation Sequencing (NGS) technology. The length of whole mitogenome is 16,358 bp and contains the typical gene arrangement, base composition, and codon usage found in other related species. The overall base composition of the mitochondrial genome is 37.0 % A, 32.2 % T, 20.2 % C, and 10.6 % G. All 13 protein-coding genes (PCGs) began with typical ATN initiation codon. Nine of the 13 PCGs have a complete termination codon, but the remaining four genes (COI, COIII, ND5, and ND4) terminate with an incomplete T. Phylogenetic analyses are carried out based on the concatenated dataset of 13 PCGs and two rRNAs of Tettigoniidae species available in GenBank. Both Bayesian inference and Maximum Likelihood analyses recovered each subfamily as a monophyletic group. Regardless of the position of Lipotactinae, the relationships among the subfamilies of Tettigoniidae were as follows: ((((Tettigoniinae, Bradyporinae) Meconematinae) Conocephalinae) Hexacentrinae). The topological structure of the phylogeny trees showed that the Xizicus (Haploxizicus) maculatus is closer to Xizicus (Xizicus) fascipes than Xizicus (Eoxizicus) howardi. PMID- 30026662 TI - Molecular association and morphological characterisation of Himalopsyche larval types (Trichoptera, Rhyacophilidae). AB - Himalopsyche Banks, 1940 (Trichoptera, Rhyacophilidae) is a genus of caddisflies inhabiting mountain and alpine environments in Central and East Asia and the Nearctic. Of 53 known species, only five species have been described previously in the aquatic larval stage. We perform life stage association using three strategies (GMYC, PTP, and reciprocal monophyly) based on fragments of two molecular markers: the nuclear CAD, and the mitochondrial COI gene. A total of 525 individuals from across the range of Himalopsyche (Himalayas, Hengduan Shan, Tian Shan, South East Asia, Japan, and western North America) was analysed and 32 operational taxonomic units (OTUs) in our dataset delimited. Four distinct larval types of Himalopsyche are uncovered, and these are defined as the phryganea type, japonica type, tibetana type, and gigantea type and a comparative morphological characterisation of the larval types is presented. The larval types differ in a number of traits, most prominently in their gill configuration, as well as in other features such as setal configuration of the pronotum and presence/absence of accessory hooks of the anal prolegs. PMID- 30026663 TI - Hawaiian Philodoria (Lepidoptera, Gracillariidae, Ornixolinae) leaf mining moths on Myrsine (Primulaceae): two new species and biological data. AB - This paper provides new taxonomic and biological data on a complex of gracillariid moths in the endemic genus Philodoria Walsingham, 1907 that are associated with Myrsine (Primulaceae) in the Hawaiian Islands, United States. Two new species, Philodoria kauaulaensis Kobayashi, Johns & Kawahara, sp. n. (host: Myrsine lanaiensis, M. lessertiana, and M. sandwicensis) and P. kolea Kobayashi, Johns & Kawahara, sp. n. (host: M. lessertiana) are described. Biological data are provided for two previously described species that also feed on Myrsine: P. auromagnifica Walsingham, 1907 and P. succedanea Walsingham, 1907. For the first time we detail and illustrate genital structures, immature stages, biology, and host plants of P. auromagnifica and P. succedanea. Philodoria kolea, P. auromagnifica, and P. succedanea occur in sympatry on the island of Hawaii (Big Island), but each species differs in behavioral characters: P. kolea utilizes leaves of seedlings and forms a serpentine mine, whereas the latter two utilize leaves of larger plants, and form linear or serpentine to blotch mines. More broadly, leaf mine forms and diagnostic characteristics of the Myrsine-feeding species complex of Philodoria (as currently known) are reviewed and illustrated. PMID- 30026664 TI - Parasitic wasps related to Prays oleae (Bernard, 1788) (Lepidoptera, Praydidae) in olive orchards in Greece. AB - The olive moth, Prays oleae (Bernard, 1788) (Lepidoptera: Praydidae) is categorised among the most devastating insect pests of olives, whose anthophagous and carpophagous generations can cause yield loss up to 581 and 846 kg of fruit per ha, respectively. In this study, results of the captured parasitoids in olive tree (Olea europaea Linnaeus, 1753) orchards, or infested olive plant material in Crete, Greece, is presented. Five of the six identified species captured in trap devices are related to P. oleae, i.e., Chelonus elaeaphilus Silvestri, 1908, Chelonus pellucens (Nees, 1816), Apanteles xanthostigma (Haliday, 1834), Diadegma armillatum (Gravenhorst, 1829), and Exochus lentipes Gravenhorst, 1829. The species Eupelmus urozonus Dalman, 1820 and Pnigalio mediterraneus Ferriere & Delucchi, 1957 were reared from infested P. oleae leaves. Chelonus pellucens is reported for the first time from Greece. According to the international literature, 59 hymenopterous and dipterous parasitoid species are associated with P. oleae in Europe. PMID- 30026665 TI - Updated checklist of Poa in the Iberian Peninsula and Balearic Islands. AB - Based on our study of 4,845 herbarium sheets of the genus Poa from the area covered by Flora iberica, namely, the Iberian Peninsula and the Balearic Islands, we recognise 24 taxa (17 species, 1 subspecies and 8 varieties), mostly perennials. Most of these taxa have wide global and/or European distributions, while two (P. legionensis and P. minor subsp. nevadensis) are Spanish endemics and two have restricted distributions (P. ligulata, Iberia-North Africa; P. flaccidula, Iberia-North Africa and the Balearic Islands, extending to Provence, France). We have studied the original publications of more than 225 names considered as synonyms, with those more historically cited in Flora iberica taken into account in this paper; a total of 26 are new synonyms. The following names are typified: P. alpina var. involucrata Lange, P. annua var. lanuginosa Sennen, P. minor subsp. nevadensis Nannf., P. paui Font Quer, P. sulcata Lag. and P. trivialis var. flaccida Willk. ex J.J. Rodr. We include P. compressa L. in the flora of Portugal for the first time and present detailed illustrations of three very interesting taxa (P. legionensis, P. minor subsp. nevadensis and P. ligulata). In addition to a general species key, we provide the following information for each taxon: synonyms, types, typification, the most relevant iconography, regional flowering time, regional and general distribution and, as supplementary material, the number of sheets examined and a list of selected materials. PMID- 30026666 TI - Photo images, 3D models and CT scanned data of loaches (Botiidae, Cobitidae and Nemacheilidae) of Japan. AB - Background: Loach is one of the major cypriniform fishes in freshwater habitats of Japan; 35 taxa/clades have, until now, been recognised. Parallel to genetic studies, morphological examinations are needed for further development of loach study, eventually ichthyology and fish biology. Digital archiving, concerning taxonomy, ecology, ethology etc., is one of the progressive challenges for the open science of biology. This paper aimed to online publish photo images, 3D models and CT scanned data of all the known clades of loaches inhabiting Japan (103 individuals in total with several type specimens), contributing to ichthyology and public interest of biodiversity/biology. New information: Photo images, 3D models and CT scanned data of all the known 35 taxa/clades of loaches inhabiting in Japan were online published at http://ffish.asia/loachesOfJapan and http://ffish.asia/loachesOfJapan3D. PMID- 30026667 TI - Earthworms (Oligochaeta: Lumbricidae) of Interior Alaska. AB - Earthworms in the family Lumbricidae in Alaska, which are known from coastal regions, primarily in south-central and south-eastern Alaska, are thought to be entirely non-native and have been shown to negatively impact previously earthworm free ecosystems in study regions outside of Alaska. Despite occasional collections by curious citizens, there had not been a standardised earthworm survey performed in Interior Alaska and no published records exist of earthworms species from this region. Mustard extraction was used to sample six locations that differed in elevation, mostly in the College region of Fairbanks, Alaska. Two of the six locations yielded earthworms. There was no relationship between earthworm abundance and elevation (p = 0.087), although our sample size was small. Our sampling, combined with specimens in the University of Alaska Museum, has documented four exotic species and one presumed native species of lumbricid earthworms in Interior Alaska. PMID- 30026668 TI - A new species of Rhodocybe sect. Rufobrunnea (Entolomataceae, Agaricales) from Italy. AB - Rhodocybe fumanellii is described from Italy as a new species based both on morphological and molecular nrITS/nrLSU data. It belongs in sect. Rufobrunnea and is characterised by massive tricholomatoid basidiomata with reddish-brown tinges, adnate and crowded lamellae, an enlarged stipe base with long rhizomorphs, long sinuose slender cheilocystidia, ellipsoid basidiospores and the presence of caulocystidia. Drawings of the main micromorphological features as well as a colour photograph of fresh basidiomata in situ are provided and its morphological relationships with allied species are discussed. PMID- 30026669 TI - Microfilaria persistent foci during post MDA and the risk assessment of resurgence in India. AB - Background: Pondicherry, a union territory in India, is an endemic district for bancroftian lymphatic filariasis transmitted by Culex quinquefasciatus where eight rounds of mass drug administration (MDA) were completed in 2011 (annually once from 2004 to 2011).The objectives of this study were to conduct a focal survey to assess microfilaria and antigen (Ag) prevalence among young adults and to assess vector infection and infectivity through a focal entomological survey. Methods: Mosquitoes were collected using gravid traps in Sedurapet village of Pondicherry and dissected to enumerate W. bancrofti larvae stage first larval stage (L1), second larval stage (L2), and third larval stage (L3). Microfilarias (Mf) were detected using blood smears collected from inhabitants. Results: A total of 360 individuals from 67 houses were enrolled in this study of which 290 (80.6%) were surveyed for the presence of Mf. Two Mf carriers were detected yielding an overall prevalence of 0.69% and two out of 85 (2.35%) were Mf antigen positive. Of the 2875 mosquitoes collected by gravid trap, Culex quinquefasciatus (93.9%) was the predominant species, followed by Anopheles subpictus (2.3%) and Culex vishnui (3.8%). The density of Cx. quinquefasciatus was 28.1 per trap night. A total of 2429 Cx. quinquefasciatus were dissected and microscopically examined for abdominal conditions (gravid 85%, semi-gravid 9.4%, unfed 3.8%, and fully fed 1.9%) and filarial infection. One mosquito (infection rate equal to 0.04%) was found to harbor a second stage filarial larva, and none of the mosquitoes had infective stage larva. Conclusion: Our results show no reappearance of infection of lymphatic filariasis in Sedurapet village of Pondicherry after MDA, and thus, no further intervention is required in that area for possible resurgence of lymphatic filariasis. However, monitoring should be continued as part of post MDA activities until the endpoint of complete elimination is achieved. We demonstrated that xenomonitoring can be used to monitor the post MDA situation for possible risk of transmission to initiate control measures. PMID- 30026670 TI - Risk Factors for Sepsis Based on Sepsis-3 Criteria after Orthotopic Liver Transplantation. AB - Sepsis is a common complication of solid organ transplant procedures and, in particular, can affect the prognosis of orthotopic liver transplantation (OLT). This retrospective study determined the pre-, peri-, and postoperative risk factors for sepsis after OLT, using as reference the 2016 Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Pre-, peri-, and postoperative clinical data of the sepsis-positive (n = 85) and sepsis-negative (n = 41) groups were analyzed for potential risk factors of OLT-related sepsis. The sepsis-positive patients had a significantly higher rate of dialysis (49.4%), longer time under mechanical ventilation (1.5 d), higher hospitalization costs (0.41 million RMB), and worse survival rate (68.5%), compared with the sepsis negative patients (4.8%, 1 d, 0.30 million RMB, and 73.1%, resp.). The multivariate logistic analysis identified the following as risk factors for OLT related sepsis: preoperative Child-Pugh grade C (OR 10.43; 95% CI 2.081-52.292; P = 0.004), preoperative hypercalcemia (OR 6.372; 95% CI 1.693-23.98; P = 0.006), and perioperative acidosis (OR 6.364; 95% CI 1.196-33.869; P = 0.030). Patients with preoperative Child-Pugh grade C, preoperative hypercalcemia, or perioperative acidosis are at higher risk for developing sepsis after OLT. When any of these problems occur, timely sepsis management should be planned. PMID- 30026671 TI - Predictors of organizational commitment among university nursing Faculty of Kathmandu Valley, Nepal. AB - Background: Increasing work efficiency, improving psychological health, decreasing turnover, turnover intention, and absenteeism may be dependent on organizational commitment of an employee. This study was carried out to identify the predictors of organizational commitment among university nursing faculty within Kathmandu Valley, Nepal. Methods: A cross-sectional analytical study was conducted based on a sample of 197 nursing faculty selected from 18 nursing colleges affiliated to 5 universities in Kathmandu Valley by using a proportionate stratified random sampling technique. Structured questionnaires regarding socio-demographic information, perceived faculty developmental opportunity, job satisfaction, perceived organizational support, and organizational commitment were used for data collection. Double data entry and data cleaning were done by using Epi-data software; and data analysis was carried out with SPSS version 16 software. Binary regression analysis was used to identify the predictors of organizational commitment and the adjusted odds ratio (AOR) was also calculated. Results: The findings of this study showed that a majority of respondents had moderate level of organizational commitment (68%) followed by high level (29%) and low level (3%). This study also revealed that the nursing faculty who had a master's degree in nursing, a permanent appointment, and job satisfaction had a high level of organizational commitment. On the contrary, this study also revealed that the nursing faculty who were in the position of assistant instructor to assistant lecturer level and more than 5 years of work experience within same organization were less likely to have a high level of organizational commitment. Conclusions: Nursing faculty within Kathmandu Valley have a moderate level of organizational commitment. The predictors of organizational commitment are higher education in nursing, position, type of appointment, current organizational tenure, and job satisfaction. Therefore, an organizational authority must pay attention to the modifiable predictors of organizational commitment to enhance organizational commitment of its nursing faculty. This will help to reduce faculty turnover, increase quality of teaching and student's satisfaction. PMID- 30026672 TI - Identification of long non-coding RNA signatures in triple-negative breast cancer. AB - Background: Triple-negative breast cancer (TNBC) is a particular breast cancer subtype with poor prognosis due to its aggressive biological behavior and lack of targets for therapy. This study aimed to explore the expression profile and potential function of lncRNAs in TNBC through bioinformatic methods. Methods: Two microarrays of TNBC were obtained from the Gene Expression Omnibus database. Differentially expressed lncRNAs and mRNAs were screened out and the expressions of top lncRNAs and overlapping lncRNAs were validated using data from The Cancer Genome Atlas database. The co-expression analysis of lncRNAs and mRNAs was conducted using R software and functional enrichment analysis for was performed by Metascape. Kaplan-Meier Plotter was used for survival analysis. Results: A total of 1034 dysregulated lncRNAs were found in the two microarrays, and there were 8 overlapped lncRNAs. Among them, 537 lncRNAs were significantly correlated with 451 protein-coding genes (PCGs). The co-expressed PCGs were mainly enriched in terms including cell division, cell cycle, and protein/DNA binding, and were involved in pathways in cancer and other pathways such as PI3K-Akt, MAPK, ErbB and p53 signaling pathways. Hub-genes in the co-expression network were identified, and 7 of them were associated with relapse-free survival of TNBC (MAGI2-AS3: HR = 0.51; GGTA1P: HR = 0.54; NAP1L2: HR = 0.59; CRABP2: HR = 0.41; SYNPO2: HR = 0.50; MKI67: HR = 2.23; COL4A6: HR = 1.91; all P < 0.05). Conclusions: Numerous lncRNAs were dysregulated in TNBC, and many of them are possibly involved in cancer biology. Several of these lncRNAs were associated with of TNBC prognosis, which can be promising biomarkers. PMID- 30026673 TI - Human blood platelets and viruses: defense mechanism and role in the removal of viral pathogens. AB - Platelets are small non-nucleated cell fragments and the second most abundant cell that play crucial role in managing vascular integrity and regulating hemostasis. Recent finding shows, beyond its hemostatic function platelets also play a main role in fighting against pathogen including viruses. With their receptors, platelet interacts with viral pathogen and this interaction between platelets and viral pathogens result in activation of platelets. Activated platelet releases different molecules that have antiviral activity including kinocidins and other platelet microbicidal peptides. In addition, activated platelet has antiviral role by different mechanism including; phagocytosis of viral pathogen, produce reactive oxygen species and interact with and activate other immune cells. In other side, antiplatelet treatments are one of defending mechanism of viral pathogen. This narrative review summarizes what is known regarding the role of human platelets in fighting viral pathogen. PMID- 30026674 TI - Differential Diagnosis between Low-Grade and High-Grade Astrocytoma Using System A Amino Acid Transport PET Imaging with C-11-MeAIB: A Comparison Study with C-11 Methionine PET Imaging. AB - Introductions: [N-methyl-C-11]alpha-Methylaminoisobutyric acid (MeAIB) is an artificial amino acid radiotracer used for PET study, which is metabolically stable in vivo. In addition, MeAIB is transported by system A neutral amino acid transport, which is observed ubiquitously in all types of mammalian cells. It has already been shown that MeAIB-PET is useful for malignant lymphoma, head and neck cancers, and lung tumors. However, there have been no reports evaluating the usefulness of MeAIB-PET in the diagnosis of brain tumors. The purpose of this study is to investigate the efficacy of system A amino acid transport PET imaging, MeAIB-PET, in clinical brain tumor diagnosis compared to [S-methyl-C-11] L-methionine (MET)-PET. Methods: Thirty-one consecutive patients (male: 16, female: 15), who were suspected of having brain tumors, received both MeAIB-PET and MET-PET within a 2-week interval. All patients were classified into two groups: Group A as a benign group, which included patients who were diagnosed as low-grade astrocytoma, grade II or less, or other low-grade astrocytoma (n=12) and Group B as a malignant group, which included patients who were diagnosed as anaplastic astrocytoma, glioblastoma multiforme (GBM), or recurrent GBM despite prior surgery or chemoradiotherapy (n=19). PET imaging was performed 20 min after the IV injection of MeAIB and MET, respectively. Semiquantitative analyses of MeAIB and MET uptake using SUVmax and tumor-to-contralateral normal brain tissue (T/N) ratio were evaluated to compare these PET images. ROC analyses for the diagnostic accuracy of MeAIB-PET and MET-PET were also calculated. Results: In MeAIB-PET imaging, the SUVmax was 1.20 +/- 1.29 for the benign group and 2.94 +/- 1.22 for the malignant group (p < 0.005), and the T/N ratio was 3.77 +/- 2.39 for the benign group and 16.83 +/- 2.39 for the malignant group (p < 0.001). In MET PET, the SUVmax was 3.01 +/- 0.94 for the benign group and 4.72 +/- 1.61 for the malignant group (p < 0.005), and the T/N ratio was 2.64 +/- 1.40 for the benign group and 3.21 +/- 1.14 for the malignant group (n.s.). For the analysis using the T/N ratio, there was a significant difference between the benign and malignant groups with MeAIB-PET with p < 0.001. The result of ROC analysis using the T/N ratio indicated a better diagnosis accuracy for MeAIB-PET for brain tumors than MET-PET (p < 0.01). Conclusions: MeAIB, a system A amino acid transport-specific radiolabeled agents, could provide better assessments for detecting malignant type brain tumors. In a differential diagnosis between low grade and high-grade astrocytoma, MeAIB-PET is a useful diagnostic imaging tool, especially in evaluations using the T/N ratio. Clinical trial registration: This trial was registered with UMIN000032498. PMID- 30026675 TI - A novel RASA1 mutation causing capillary malformation-arteriovenous malformation (CM-AVM): the first genetic clinical report in East Asia. AB - Capillary malformation-arteriovenous malformation (CM-AVM) is a clinical entity newly identified in 2003 that is caused by mutation of the RASA-1 gene, which encodes the protein p120-RasGAP. To date, most of the clinical reports on CM-AVM in the literature involve samples entirely consisting of Caucasians of European and North American descent, while reports from China or East Asia are few. Here, we describe a genetic clinical report of CM-AVM. Sequencing revealed a novel stop mutation in the RASA-1 gene causing loss of function (LOF) of the RasGAP domain. To our knowledge, this is the first genetic clinical report of a CM-AVM patient in East Asia. This report may extend our understanding and support further studies of CM-AVM in East Asia. PMID- 30026676 TI - Bitter melon extract ameliorates palmitate-induced apoptosis via inhibition of endoplasmic reticulum stress in HepG2 cells and high-fat/high-fructose-diet induced fatty liver. AB - Background: Bitter melon (BM) improves glucose level, lipid homeostasis, and insulin resistance in vivo. However, the preventive mechanism of BM in nonalcoholic fatty liver disease (NAFLD) has not been elucidated yet. Aim & Design: To determine the protective mechanism of bitter melon extract (BME), we performed experiments in vitro and in vivo. BME were treated palmitate (PA) administrated HepG2 cells. C57BL/6J mice were divided into two groups: high fat/high-fructose (HF/HFr) without or with BME supplementation (100 mg/kg body weight). Endoplasmic reticulum (ER) stress, apoptosis, and biochemical markers were then examined by western blot and real-time PCR analyses. Results: BME significantly decreased expression levels of ER-stress markers (including phospho eIF2alpha, CHOP, and phospho-JNK [Jun N-terminal kinases]) in PA-treated HepG2 cells. BME also significantly decreased the activity of cleaved caspase-3 (a well known apoptotic-induced molecule) and DNA fragmentation. The effect of BME on ER stress-mediated apoptosis in vitro was similarly observed in HF/HFr-fed mice in vivo. BME significantly reduced HF/HFr-induced hepatic triglyceride (TG) and serum alanine aminotransferase (ALT) as markers of hepatic damage in mice. In addition, BME ameliorated HF/HFr-induced serum TG and serum-free fatty acids. Conclusion: These data indicate that BME has protective effects against ER stress mediated apoptosis in HepG2 cells as well as in HF/HFr-induced fatty liver of mouse. Therefore, BME might be useful for preventing and treating NAFLD. PMID- 30026677 TI - Quercetin prevents small intestinal damage and enhances intestinal recovery during methotrexate-induced intestinal mucositis of rats. AB - Background: Gastrointestinal mucositis occurs as a consequence of cytotoxic treatment. Quercetin (QCT) is a bioflavonoid that exerts significant antioxidant activity and anti-inflammatory as well as anti-malignancy properties. Objective: To evaluate the effects of oral QCT consumption in preventing intestinal mucosal damage and stimulating intestinal recovery following methotrexate (MTX)-induced intestinal damage in a rat model. Design: Male Sprague-Dawley rats were divided into four groups: Control Group A (CONTR) - rats were treated with 2 cc of saline given by gavage for 6 days. Group B (CONTR-QCT) - rats were treated with QCT (100 mg/kg in 2 ml saline) given by gavage 3 days before and 3 days after intraperitoneal (IP) injection of saline. Group C (MTX) - rats were injected a single dose (25 mg/kg) of MTX IP. Group D (MTX-QCT) rats were treated with QCT (similar to Group B) 3 days before and 3 days after IP MTX injection. Intestinal mucosal parameters (bowel and mucosal weight, mucosal DNA and protein content, and villus height and crypt depth), enterocytes proliferation, and enterocyte apoptosis degree were investigated at sacrifice on the 4th day after MTX or saline injection. Results: Administration of QCT to MTX-treated rats resulted in: (1) significant decrease in intestinal injury score, (2) significant increase in intestinal and mucosal weight in jejunum and ileum, (3) increase on the protein content of the ileum, (4) increase in the villus height in the ileum, (5) increase of crypt depth of jejunum and ileum, and (6) increase in cell proliferation in the jejunum and ileum compared to MTX-nontreated group. Conclusions: Administration of QCT prevents intestinal damage and improves intestinal recovery following MTX-induced intestinal damage in a rat. We surmise that the effect of QCT is based on induction of cell proliferation in the crypt rather than inhibition of apoptosis. PMID- 30026678 TI - Immunomodulatory activity of Lactobacillus plantarum KLDS1.0318 in cyclophosphamide-treated mice. AB - Background: Probiotics in fermented foods have attracted considerable attention lately as treatment options for immune diseases, the incidence of which has been increasing throughout the world. Objective: The objective of the present study was to investigate the immunomodulatory activity of Lactobacillus plantarum (L. plantarum) KLDS1.0318 in cyclophosphamide-treated mice. Design: To investigate the immune-enhancing effects of L. plantarum KLDS1.0318, we used a immunosuppressive model. Ninety female six-week-old BALB/c mice were randomly divided into six groups: normal control (NC) group, model control (MC) group, immunosuppression plus L. plantarum KLDS1.0318 groups with three different doses (KLDS1.0318-L, KLDS1.0318-M, and KLDS1.0318-H), and plus levamisole hydrochloride as positive control (PC) group. Results and discussions: Results showed that the thymus and spleen indexes of the four treatment groups were significantly higher than those of the MC group (2.01+/-0.16) ( p < 0.05). The capacity of lymphocyte proliferation, the activity of natural killer (NK) cell and macrophages phagocytosis were significantly increased ( p < 0.05) in four treatment groups as compared with the MC group (0.327+/-0.022, 62.29+/-0.8, 0.087+/-0.008, respectively). The levels of relative immune factors (IL-2, IL-6, and IFN-gamma) showed similar patterns ( p < 0.05). Conclusions: This study suggested that orally administered L.plantarum KLDS1.0318 may effectively accelerate the recovery of immunosuppressive mice caused by cyclophosphamide (CTX). The immunomodulatory activity of the srtain recommended that L. plantarum KLDS1.0318 could be used as a powerful medicinal treatment against immunosuppression. PMID- 30026681 TI - Ghrelin Ameliorates Traumatic Brain Injury by Down-Regulating bFGF and FGF-BP. AB - Traumatic brain injury (TBI) is a primary cause of disability and mortality. Ghrelin, a gastrointestinal hormone, has been found to have protective effects for the brain, but the molecular mechanism of these neuroprotective effects of ghrelin remains unclear. In this study, an electronic cortical contusion impactor was used to establish a rat TBI model and we investigated the effect of ghrelin on brain repair by neurological severity score and histological examination. An antibody array was employed to uncover the molecular mechanism of ghrelin's neuroprotective effects by determining the alterations of multiple proteins in the brain cortex. As a result, ghrelin attenuated brain injury and promoted brain functional recovery. After TBI, 13 proteins were up-regulated in the brain cortex, while basic fibroblast growth factor (bFGF) and fibroblast growth factor binding protein (FGF-BP) were down-regulated after ghrelin treatment. It is known that bFGF can induce angiogenesis in the brain and accelerate wound healing, which can be further enhanced by FGF-BP. Based on the previous studies, it is hypothesized that the exogenous ghrelin curing TBI might cause the closure of bFGF and FGF-BP functions on wound healing, or ghrelin might exert the neuroprotective effects by competitively inhibiting bFGF/FGF-BP-induced neovascularization. Whether the combinational administration of ghrelin and bFGF/FGF-BP can enhance or weaken the therapeutic effect on TBI requires further research. PMID- 30026679 TI - Non-motor Characterization of the Basal Ganglia: Evidence From Human and Non human Primate Electrophysiology. AB - Although the basal ganglia have been implicated in a growing list of human behaviors, they include some of the least understood nuclei in the brain. For several decades studies have employed numerous methodologies to uncover evidence pointing to the basal ganglia as a hub of both motor and non-motor function. Recently, new electrophysiological characterization of the basal ganglia in humans has become possible through direct access to these deep structures as part of routine neurosurgery. Electrophysiological approaches for identifying non motor function have the potential to unlock a deeper understanding of pathways that may inform clinical interventions and particularly neuromodulation. Various electrophysiological modalities can also be combined to reveal functional connections between the basal ganglia and traditional structures throughout the neocortex that have been linked to non-motor behavior. Several reviews have previously summarized evidence for non-motor function in the basal ganglia stemming from behavioral, clinical, computational, imaging, and non-primate animal studies; in this review, instead we turn to electrophysiological studies of non-human primates and humans. We begin by introducing common electrophysiological methodologies for basal ganglia investigation, and then we discuss studies across numerous non-motor domains-emotion, response inhibition, conflict, decision-making, error-detection and surprise, reward processing, language, and time processing. We discuss the limitations of current approaches and highlight the current state of the information. PMID- 30026680 TI - Contribution of Tau Pathology to Mitochondrial Impairment in Neurodegeneration. AB - Tau is an essential protein that physiologically promotes the assembly and stabilization of microtubules, and participates in neuronal development, axonal transport, and neuronal polarity. However, in a number of neurodegenerative diseases, including Alzheimer's disease (AD), tau undergoes pathological modifications in which soluble tau assembles into insoluble filaments, leading to synaptic failure and neurodegeneration. Mitochondria are responsible for energy supply, detoxification, and communication in brain cells, and important evidence suggests that mitochondrial failure could have a pivotal role in the pathogenesis of AD. In this context, our group and others investigated the negative effects of tau pathology on specific neuronal functions. In particular, we observed that the presence of these tau forms could affect mitochondrial function at three different levels: (i) mitochondrial transport, (ii) morphology, and (iii) bioenergetics. Therefore, mitochondrial dysfunction mediated by anomalous tau modifications represents a novel mechanism by which these forms contribute to the pathogenesis of AD. In this review, we will discuss the main results reported on pathological tau modifications and their effects on mitochondrial function and their importance for the synaptic communication and neurodegeneration. PMID- 30026682 TI - Total Salvianolic Acid Balances Brain Functional Network Topology in Rat Hippocampi Overexpressing miR-30e. AB - We investigated the therapeutic effects and underlying brain functional network topology mechanisms of total salvianolic acid (TSA) treatment for memory dysfunction by using miR-30e overexpression-induced memory deficit in rat hippocampi. Model rats were developed by lentivirus vectors carrying miR-30e into bilateral hippocampus CA1 region through stereo-surgery. Two weeks after surgery, TSA (20 or 10 mg/mL/kg) or saline were administrated for 14 consecutive days. Memory function was assessed by behavioral tests (Y maze and Morris water maze [MWM]); resting-state functional MRI (RS-fMRI); and molecular alterations of BCL 2, UBC9, and Caspase-3 in the hippocampus CA1 region, as detected by immunohistochemistry. Compared to controls, model rats exhibited significantly impaired working and long-term memory in the Y maze and MWM tests (p < 0.01). The brain functional network topology analyzed based on RS-fMRI data demonstrated that miR-30e disturbed the global integration and segregation balance of the brain (p < 0.01), and reduced edge strength between CA1 and the posterior cingulate, temporal lobe, and thalamus (p < 0.05, false discovery rate corrected). At the molecular level, BCL-2 and UBC9 were downregulated, while Caspase-3 was upregulated (p < 0.01). After TSA (20 mg/mL/kg) treatment, the biomarkers for behavioral performance, global integration and segregation, edge strength, and expression levels of BCL-2, UBC9, and Caspase3 returned to normal levels. The correlation analyses of these results showed that global brain functional network topologic parameters can be intermediate biomarkers correlated with both behavioral changes and molecular alterations. This indicated that the effects of TSA were achieved by inhibiting apoptosis of CA1 neurons to improve global functional network topology. PMID- 30026683 TI - FES-UPP: A Flexible Functional Electrical Stimulation System to Support Upper Limb Functional Activity Practice. AB - There is good evidence supporting highly intensive, repetitive, activity-focused, voluntary-initiated practice as a key to driving recovery of upper limb function following stroke. Functional electrical stimulation (FES) offers a potential mechanism to efficiently deliver this type of therapy, but current commercial devices are too inflexible and/or insufficiently automated, in some cases requiring engineering support. In this paper, we report a new, flexible upper limb FES system, FES-UPP, which addresses the issues above. The FES-UPP system consists of a 5-channel stimulator running a flexible FES finite state machine (FSM) controller, the associated setup software that guides therapists through the setup of FSM controllers via five setup stages, and finally the Session Manager used to guide the patient in repeated attempts at the activities(s) and provide feedback on their performance. The FSM controller represents a functional activity as a sequence of movement phases. The output for each phase implements the stimulations to one or more muscles. Progression between movement phases is governed by user-defined rules. As part of a clinical investigation of the system, nine therapists used the FES-UPP system to set up FES-supported activities with twenty two patient participants with impaired upper-limbs. Therapists with little or no FES experience and without any programming skills could use the system in their usual clinical settings, without engineering support. Different functional activities, tailored to suit the upper limb impairment levels of each participant were used, in up to 8 sessions of FES supported therapy per participant. The efficiency of delivery of the therapy using FES-UPP was promising when compared with published data on traditional face face therapy. The FES-UPP system described in this paper has been shown to allow therapists with little or no FES experience and without any programming skills to set up state-machine FES controllers bespoke to the patient's impairment patterns and activity requirements, without engineering support. The clinical results demonstrated that the system can be used to efficiently deliver high intensity, activity-focused therapy. Nevertheless, further work to reduce setup time is still required. PMID- 30026684 TI - All-Optical Assay to Study Biological Neural Networks. AB - We introduce a novel all-optical assay for functional studies of biological neural networks in vitro. We created a novel optogenetic construct named OptoCaMP which is a combination of a channelrhodopsin variant (CheRiff) and a red genetically encoded calcium indicator (GECI) (jRCaMP1b). It enables simultaneous optical stimulation and recording from large population of neurons with single cell readout. Additionally, we have developed a spatio-temporal all-optical assay to simultaneously stimulate a sub-section of a neural network and record evoked calcium activity, in both stimulated and non-stimulated neurons, thus allowing the investigation of the spread of excitation through an interconnected network. Finally, we demonstrate the sensitivity of this assay to the change of neural network connectivity. PMID- 30026685 TI - Recent Advances in the Therapeutic and Diagnostic Use of Liposomes and Carbon Nanomaterials in Ischemic Stroke. AB - The complexity of the central nervous system (CNS), its limited self-repairing capacity and the ineffective delivery of most CNS drugs to the brain contribute to the irreversible and progressive nature of many neurological diseases and also the severity of the outcome. Therefore, neurological disorders belong to the group of pathologies with the greatest need of new technologies for diagnostics and therapeutics. In this scenario, nanotechnology has emerged with innovative and promising biomaterials and tools. This review focuses on ischemic stroke, being one of the major causes of death and serious long-term disabilities worldwide, and the recent advances in the study of liposomes and carbon nanomaterials for therapeutic and diagnostic purposes. Ischemic stroke occurs when blood flow to the brain is insufficient to meet metabolic demand, leading to a cascade of physiopathological events in the CNS including local blood brain barrier (BBB) disruption. However, to date, the only treatment approved by the FDA for this pathology is based on the potentially toxic tissue plasminogen activator. The techniques currently available for diagnosis of stroke also lack sensitivity. Liposomes and carbon nanomaterials were selected for comparison in this review, because of their very distinct characteristics and ranges of applications. Liposomes represent a biomimetic system, with composition, structural organization and properties very similar to biological membranes. On the other hand, carbon nanomaterials, which are not naturally encountered in the human body, exhibit new modes of interaction with biological molecules and systems, resulting in unique pharmacological properties. In the last years, several neuroprotective agents have been evaluated under the encapsulated form in liposomes, in experimental models of stroke. Effective drug delivery to the brain and neuroprotection were achieved using stealth liposomes bearing targeting ligands onto their surface for brain endothelial cells and ischemic tissues receptors. Carbon nanomaterials including nanotubes, fullerenes and graphene, started to be investigated and potential applications for therapy, biosensing and imaging have been identified based on their antioxidant action, their intrinsic photoluminescence, their ability to cross the BBB, transitorily decrease the BBB paracellular tightness, carry oligonucleotides and cells and induce cell differentiation. The potential future developments in the field are finally discussed. PMID- 30026688 TI - Oxidative Stress in Parkinson's Disease: A Systematic Review and Meta-Analysis. AB - Oxidative stress has been suggested to play a key role in Parkinson's disease, but inconsistent results were found in clinical studies. This study sought to quantitatively summarize the blood and cerebrospinal fluid (CSF) oxidative stress marker data in PD patients. We performed a systematic search of PubMed and Web of Science, and studies were included if they provided data on peripheral blood and CSF oxidative stress marker concentrations in PD patients and healthy control (HC) subjects. Data were extracted by three independent investigators from 80 included studies encompassing 7,212 PD patients and 6,037 HC subjects. Of the 22 oxidative stress markers analyzed, random effects meta-analysis showed that blood concentrations of 8-OhdG, MDA, nitrite, and ferritin were increased in patients with PD compared with HC subjects. In contrast, we showed that blood levels of catalase, uric acid, glutathione, and total-cholesterol were significantly down regulated in patients with PD when compared with controls. There were no significant differences between PD patients and HC subjects for blood, Mn, Cu, Zn, Fe, SOD, albumin, glutathione peroxidase, vitamin E, ceruloplasmin, triglycerides, lactoferrin, transferrin, LDL-cholesterol, and HDL-cholesterol. Due to the limited number of CSF studies with small sample size, this meta analysis only showed non-significant association between CSF 8-OhdG and PD. The findings of our meta-analysis demonstrated higher blood concentrations of 8-OhdG, MDA, nitrite and ferritin, and lower blood concentrations of catalase, uric acid, glutathione and total-cholesterol in PD patients, strengthening the clinical evidence that PD is accompanied by increased oxidative stress. PMID- 30026686 TI - An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration. AB - Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinnings of age-related brain changes are still not well understood, particularly the transition from normal healthy brain aging to neuropathological aging. Aging is an extremely complex, multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization. The buildup of potentially toxic protein aggregates and their spreading through various brain regions has been identified as a major contributor to these pathologies. One of the most striking morphologic changes in neurons during normal aging is the accumulation of lipofuscin (LF) aggregates, as well as, neuromelanin pigments. LF is an autofluorescent lipopigment formed by lipids, metals and misfolded proteins, which is especially abundant in nerve cells, cardiac muscle cells and skin. Within the Central Nervous System (CNS), LF accumulates as aggregates, delineating a specific senescence pattern in both physiological and pathological states, altering neuronal cytoskeleton and cellular trafficking and metabolism, and being associated with neuronal loss, and glial proliferation and activation. Traditionally, the accumulation of LF in the CNS has been considered a secondary consequence of the aging process, being a mere bystander of the pathological buildup associated with different neurodegenerative disorders. Here, we discuss recent evidence suggesting the possibility that LF aggregates may have an active role in neurodegeneration. We argue that LF is a relevant effector of aging that represents a risk factor or driver for neurodegenerative disorders. PMID- 30026687 TI - The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts. AB - Defining functional domains and amino acid residues in G protein coupled receptors (GPCRs) represent an important way to improve rational drug design for this major class of drug targets. The cannabinoid type 1 (CB1) receptor is one of the most abundant GPCRs in the central nervous system and is involved in many physiological and pathophysiological processes. Interestingly, cannabinoid type 1 receptor with a phenylalanine 238 to leucine mutation (CB1F238L) has been already linked to a number of both in vitro and in vivo alterations. While CB1F238L causes significantly reduced presynaptic neurotransmitter release at the cellular level, behaviorally this mutation induces increased risk taking, social play behavior and reward sensitivity in rats. However, the molecular mechanisms underlying these changes are not fully understood. In this study, we tested whether the F238L mutation affects trafficking and axonal/presynaptic polarization of the CB1 receptor in vitro. Steady state or ligand modulated surface expression and lipid raft association was analyzed in human embryonic kidney 293 (HEK293) cells stably expressing either wild-type cannabinoid type 1 receptor (CB1wt) or CB1F238L receptor. Axonal/presynaptic polarization of the CB1F238L receptor was assessed in transfected primary hippocampal neurons. We show that in vitro the CB1F238L receptor displays increased association with lipid rafts, which coincides with increased lipid raft mediated constitutive endocytosis, leading to a reduction in steady state surface expression of the CB1F238L receptor. Furthermore, the CB1F238L receptor showed increased axonal polarization in primary hippocampal neurons. These data demonstrate that endocytosis of the CB1 receptor is an important mediator of axonal/presynaptic polarization and that phenylalanine 238 plays a key role in CB1 receptor trafficking and axonal polarization. PMID- 30026689 TI - Endocannabinoid-LTP Mediated by CB1 and TRPV1 Receptors Encodes for Limited Occurrences of Coincident Activity in Neocortex. AB - Synaptic efficacy changes, long-term potentiation (LTP) and depression (LTD), underlie various forms of learning and memory. Synaptic plasticity is generally assessed under prolonged activation, whereas learning can emerge from few or even a single trial. Here, we investigated the existence of rapid responsiveness of synaptic plasticity in response to a few number of spikes, in neocortex in a synaptic Hebbian learning rule, the spike-timing-dependent plasticity (STDP). We investigated the effect of lowering the number of pairings from 100 to 50, and 10 on STDP expression, using whole-cell recordings from pyramidal cells in rodent somatosensory cortical brain slices. We found that a low number of paired stimulations induces LTP at neocortical layer 4-2/3 synapses. Besides the asymmetric Hebbian STDP reported in the neocortex induced by 100 pairings, we observed a symmetric anti-Hebbian LTD for 50 pairings and unveiled a unidirectional Hebbian spike-timing-dependent LTP (tLTP) induced by 10-15 pairings. This tLTP was not mediated by NMDA receptor activation but requires CB1 receptors and transient receptor potential vanilloid type-1 (TRPV1) activated by endocannabinoids (eCBs). eCBs have been widely described as mediating short- and long-term synaptic depression. Here, the eCB-tLTP reported at neocortical synapses could constitute a substrate operating in the online learning of new associative memories or during the initial stages of learning. In addition, these findings should provide useful insight into the mechanisms underlying eCB plasticity occurring during marijuana intoxication. PMID- 30026690 TI - Alcohol, Self-Regulation and Partner Physical Aggression: Actor-Partner Effects Over a Three-Year Time Frame. AB - The question of how individual differences related to self-regulation interact with alcohol use patterns to predict intimate partner aggression (IPA) is examined. We hypothesized that excessive drinking will be related to partner aggression among those who have low self-regulation. In addition, we explored the extent to which differences in self-regulation in one partner may moderate the relationship between alcohol use and partner aggression. A sample of married or cohabitating community couples (N = 280) ages 18-45 was recruited according to their classification into four drinking groups: heavy drinking in both partners (n = 79), husband only (n = 80), wife only (n = 41), by neither (n = 80), and interviewed annually for 3 years. IPA, drinking, and scores on measures of negative affect, self-control, and Executive Cognitive Functioning (ECF) were assessed for both members of the couple. The Actor Partner Interdependence Model (APIM) was used to analyze longitudinal models predicting the occurrence of IPA from baseline alcohol use, negative affect, self-control and ECF. Actor self control interacted with partner self-control such that IPA was most probable when both were low in self-control. Contrary to prediction, actors high in alcohol use and also high on self-control were more likely to engage in IPA. Partner alcohol use was predictive of actor IPA when the partner was also high in negative affect. Low partner ECF was associated with more actor IPA. These findings suggest that self-regulatory factors within both members of a couple can interact with alcohol use patterns to increase the risk for relationship aggression. PMID- 30026691 TI - Individual Differences in the Neural and Cognitive Mechanisms of Single Word Reading. AB - Written language is a human invention that our brains did not evolve for. Yet, most research has focused on finding a single theory of reading, identifying the common set of cognitive and neural processes shared across individuals, neglecting individual differences. In contrast, we investigated variation in single word reading. Using a novel statistical method for analyzing heterogeneity in multi-subject task-based functional magnetic resonance imaging (fMRI), we clustered readers based on their brain's response to written stimuli. Separate behavioral testing and neuroimaging analysis shows that these clusters differed in the role of the sublexical pathway in processing written language, but not in reading skill. Taken together, these results suggest that individuals vary in the cognitive and neural mechanisms involved in word reading. In general, neurocognitive theories need to account not only for what tends to be true of the population, but also the types of variation that exist, even within a neurotypical population. PMID- 30026692 TI - The Moderating Role of COMT and BDNF Polymorphisms on Transfer Effects Following Multi- and Single-Domain Cognitive Training Among Community-Dwelling Shanghainese Older Adults. AB - Given the increase in research suggesting benefit following cognitive training in older adults, researchers have started to investigate the potential moderating role of genetic polymorphisms on transfer effects. The objective of this study was to evaluate the moderating effect of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) polymorphisms on transfer effects following a single-domain or multi-domain training intervention in healthy community-dwelling older adults. A total of 104 men and women living in Shanghai were randomized to a multi-domain or a single-domain cognitive training (SDCT) group. COMT rs4818 SNP and the BDNF rs6265 SNP were analyzed from blood. At pre intervention, post-intervention and at 6-month follow-up, participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Color-Word Stroop Test (CWST), the Trails Making Test (TMT) and the Visual Reasoning Test (VRT). COMT was found to moderate immediate memory transfer effects following single-domain training only, with G/- carriers displaying greater benefits than C/C carriers. BDNF was found to moderate attention and inhibition independent of the training, with Met/- carriers displaying better performance than Val/Val carriers. Overall, individualizing training methods with full consideration of genetic polymorphisms may promote the maximization of cognitive training benefits. PMID- 30026693 TI - Long-Term DL-3-n-Butylphthalide Treatment Alleviates Cognitive Impairment Correlate With Improving Synaptic Plasticity in SAMP8 Mice. AB - Alzheimer's disease (AD) is the most prevalent form of dementia worldwide. AD is characterized by mild cognitive impairment at onset, irreversibly progressing with age to severe neurodegeneration and cognitive deficits in the late stages. Unfortunately, no effective treatments exist to prevent or delay the cognitive symptoms of AD. Studies have shown that DL-3-n-butylphthalide (DL-NBP) alleviates cognitive impairment induced by amyloid-beta in mice by reducing oxidative stress, inhibiting apoptosis, and decreasing tau phosphorylation. In this study, we examined the effects of DL-NBP administration on cognitive function in the senescence-accelerated mouse prone 8 (SAMP8) model of age-related dementia. DL NBP treatment for 3 months alleviated cognitive impairment in SAMP8 mice as assessed by performance in the Morris water maze test. Moreover, DL-NBP significantly increased the expression of synaptophysin and postsynaptic density protein 95 in the hippocampus of SAMP8 mice, indicative of a protective effect on hippocampal structural synaptic plasticity. In addition, brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling, previously shown to promote synaptic plasticity, was significantly enhanced by the DL-NBP administration. Our findings suggest that DL-NBP is a potential drug candidate for the treatment of cognitive impairment in AD and may serve as the foundation for further research into the development of AD drugs. PMID- 30026694 TI - IGF-1, Inflammation and Retinal Degeneration: A Close Network. AB - Retinal degenerative diseases are a group of heterogeneous diseases that include age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR). The progressive degeneration of the retinal neurons results in a severe deterioration of the visual function. Neuroinflammation is an early hallmark of many neurodegenerative disorders of the retina including AMD, RP and DR. Microglial cells, key components of the retinal immune defense system, are activated in retinal degenerative diseases. In the microglia the interplay between the proinflammatory/classically activated or antiinflammatory/alternatively activated phenotypes is a complex dynamic process that occurs during the course of disease due to the different environmental signals related to pathophysiological conditions. In this regard, an adequate transition from the proinflammatory to the anti-inflammatory response is necessary to counteract retinal neurodegeneration and its subsequent damage that leads to the loss of visual function. Insulin like-growth factor-1 (IGF-1) has been considered as a pleiotropic factor in the retina under health or disease conditions and several effects of IGF-1 in retinal immune modulation have been described. In this review, we provide recent insights of inflammation as a common feature of retinal diseases (AMD, RP and RD) highlighting the role of microglia, exosomes and IGF-1 in this process. PMID- 30026695 TI - Ethnopharmacology of Love. AB - Background: Elixirs conferring eternal youth or inducing amatory and erotic attraction have been searched for without success. Lovesickness is a widespread affliction resulting from unrequited love and/or the impossibility for physical and emotional union. The symptoms are reflections of altered dopamine, serotonin, noradrenaline, testosterone and cortisol levels and range from frenzy and intrusive thinking to despair and depression, sharing traits with the neurochemistry of addiction and compulsive behavior disorder. Although it can seriously impact the quality of life, lovesickness is currently not considered in official disease classification systems. Consequently, no official therapeutic guidelines exist, leaving subjects to seek the cure on their own. Methods: We review literature of the past 2000 years dealing with the concept, diagnosis and the healing of lovesickness and contextualize it with neurochemical, ethnomedical, and ethnographic data. Since neurobiological and pharmacological connections between the love drive and the sex drive exist, we review also the literature about herbal an- and aphrodisiacs, focusing on their excitatory or calmative potential. Results: An overall consensus regarding socio-behavioral regimes exists for dealing with lovesickness from historical through contemporary literature. The herbal drugs used for treating lovesickness or inducing love passion do not possess the alleged properties. The pharmacological effects of aphrodisiacs are heterogeneous, including dopaminergic and adrenergic activities, but there is no evidence for any serotonergic effects. The libido-regulating properties of anaphrodisiacs seem to be associated with sedative and toxic effects or decreasing testosterone levels. CB2 receptors expressed on dopaminergic neurons of the ventral tegmental area, part of the brain's reward circuit, implicated with addiction, orgasm and strong emotions such as love, might constitute a new therapeutic target. Conclusion: The common food additive and CB2 agonist beta-caryophyllene might have the potential to attenuate dopaminergic firing, quenching the reward and thus motivation associated with romantic love. From Greek mythology to modern history, cultural expressions and implications of love, sex and procreation is and was organized along hierarchical lines that put men on top. The neuronal predispositions and activities associated with falling in love will probably forever remain nature's and Eros' secret. PMID- 30026696 TI - Homozygous CREM-IbDeltaC-X Overexpressing Mice Are a Reliable and Effective Disease Model for Atrial Fibrillation. AB - Background: Atrial fibrillation (AF) is a significant cause of morbidity and mortality with foreseeably increasing prevalence. While large animal models of the disease are well established but resource intensive, transgenic AF mouse models are not yet widely used to develop or validate novel therapeutics for AF. Hemizygous mice with a cardiomyocyte-specific overexpression of the human cAMP response element modulator (CREM) isoform IbDeltaC-X spontaneously develop AF on grounds of an arrhythmogenic substrate consisting of alterations in structure, conduction, and calcium handling. Objective: We investigated if homozygous expression of the CREM-IbDeltaC-X transgene in mice alters the time course of AF development, and if homozygous CREM-IbDeltaC-X transgenics could be suitable as a disease model of AF. Methods: Southern Blot, quantitative real-time PCR, and immunoblotting were used to identify and verify homozygous transgenics. Cardiac gravimetry, quantitative real-time RT-PCR, histology, survival analysis, and repeated ECG recordings allowed assessment of phenotypic development and effects of antiarrhythmic drugs. Results: Homozygous animals could be identified by Southern blot and quantitative PCR, showing a strong trend to increased transgenic protein expression. In homozygous animals, atrial hypertrophy appeared earlier and more pronounced than in hemizygous animals, going along with an earlier onset of spontaneous AF, while no increased early mortality was observed. Application of a rate-controlling drug (esmolol) led to the expected result of a decreased heart rate. Application of a rhythm-controlling drug (flecainide) showed effects on heart rate variability, but did not lead to a definitive conversion to sinus rhythm. Conclusion: We suggest homozygous CREM-IbDeltaC-X overexpressing mice as a reliable model of early onset, rapidly progressive AF. PMID- 30026697 TI - c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury. AB - In this article, we review the literature regarding the role of c-Jun N-terminal kinases (JNKs) in cerebral and myocardial ischemia/reperfusion injury. Numerous studies demonstrate that JNK-mediated signaling pathways play an essential role in cerebral and myocardial ischemia/reperfusion injury. JNK-associated mechanisms are involved in preconditioning and post-conditioning of the heart and the brain. The literature and our own studies suggest that JNK inhibitors may exert cardioprotective and neuroprotective properties. The effects of modulating the JNK-depending pathways in the brain and the heart are reviewed. Cardioprotective and neuroprotective mechanisms of JNK inhibitors are discussed in detail including synthetic small molecule inhibitors (AS601245, SP600125, IQ-1S, and SR 3306), ion channel inhibitor GsMTx4, JNK-interacting proteins, inhibitors of mixed-lineage kinase (MLK) and MLK-interacting proteins, inhibitors of glutamate receptors, nitric oxide (NO) donors, and anesthetics. The role of JNKs in ischemia/reperfusion injury of the heart in diabetes mellitus is discussed in the context of comorbidities. According to reviewed literature, JNKs represent promising therapeutic targets for protection of the brain and the heart against ischemic stroke and myocardial infarction, respectively. However, different members of the JNK family exert diverse physiological properties which may not allow for systemic administration of non-specific JNK inhibitors for therapeutic purposes. Currently available candidate JNK inhibitors with high therapeutic potential are identified. The further search for selective JNK3 inhibitors remains an important task. PMID- 30026700 TI - Change in Ubiquitin Proteasome System of Grass Carp Ctenopharyngodon idellus Reared in the Different Stocking Densities. AB - The ubiquitin proteasome system (UPS) is a highly regulated mechanism of intracellular protein degradation and turnover. To evaluate the effect of crowding stress on the UPS in fish, grass carp (Ctenopharyngodon idellus) were randomly reared at low stocking density (LSD, 0.9 kg m-2) or high stocking density (HSD, 5.9 kg m-2) for 70 days. The expression of the genes regulating UPS, stress-related parameters, and profiles of amino acid in white muscle as well as growth rate of fish reared at two stocking densities were investigated. Fish exhibited significantly higher growth rate in the LSD group compared to the HSD group. Serum concentrations of cortisol, total protein, and glucose did not vary significantly in fish between two groups. There was no significant difference in the mRNA levels of nrf2, keap1, and hsp90 in white muscle of fish stocked at two densities at the endpoint of the experiment. In the UPS pathway, the expressions of ub, chip, psmc1 in the LSD group were significantly higher than those in the HSD group (P < 0.05). Ubiquitinated protein level and the content of 3-Methylhistidine elevated significantly in the LSD group (P < 0.05). The mRNA levels of mafbx, murf1, and s6k1 in the LSD group were significantly higher than those in HSD group (P < 0.05). These results illustrate that the fish cultured in lower stocking density would exhibit a greater growth rate and a fast protein turnover in muscle. PMID- 30026702 TI - Remineralization Efficacy of an Amelogenin-Based Synthetic Peptide on Carious Lesions. AB - Objective: The aim of this study was to evaluate the remineralization efficacy of an amelogenin-based peptide on initial enamel carious lesions in vitro. Furthermore, we attempted to provide insights into the possible mechanism of the remineralization, including determining the calcium-binding properties of the peptide and its effects on calcium phosphate mineralization. Methods: The peptide comprising the N-terminus and the C-terminus of porcine amelogenin was synthesized by Synpeptide Co., Ltd. Fifty specimens were randomly assigned to five immersing treatment groups for 12 days: remineralizing medium only; 12.5 MUg/mL peptide + remineralizing medium; 25 MUg/mL peptide + remineralizing medium; 50 MUg/mL peptide + remineralizing medium; fluoride + remineralizing medium. After immersion, mean mineral loss before and after remineralization of each specimen was determined using micro-CT. Mean mineral gain after remineralization was calculated. Calcium binding properties were measured by Isothermal titration calorimetry (ITC). TEM and Fourier transform-infrared were used to determine the effects of the peptide on calcium phosphate mineralization. Results: A significant decrease in mineral loss after remineralization process in all groups was observed (p < 0.05). Treatment in remineralizing medium resulted in the lowest mineral gain while the fluoridated treatment exhibited the highest mineral gain among all groups. Inclusion of synthetic peptide in the remineralizing medium exhibited a higher mineral gain and the gain of 50 MUg/mL group was greater than that of the 25 MUg/mL group. No significant difference in mineral gain was observed between the remineralizing medium only group and the 12.5 MUg/mL peptide group (p > 0.05). ITC values showed that the Ca2+-binding affinity of the peptide is about 9.914 * 104M-1. Furthermore, the peptide was found to inhibit calcium phosphate precipitation and stabilize amorphous calcium phosphate formation for more than 2 h and finally transform into ordered hydroxyapatite crystals. Conclusion: Specific concentrations of the amelogenin based synthetic peptide promoted in vitro remineralization, with higher concentrations exhibiting significantly greater remineralization. This study presented evidence suggesting that the peptide may act as a Ca2+carrier as well as a regulating factor. When the stabilizing calcium and phosphorus ions bind with the peptide they become biologically available for the remineralization of deeper carious lesions, while also regulated by the peptide to transform into ordered hydroxyapatite crystals. PMID- 30026703 TI - Intradialytic Exercise: One Size Doesn't Fit All. AB - Purpose: Hemodialysis patients commonly have impaired physical performance and mental health. We studied the effects of an intradialytic exercise program on these variables. Methods: 27 patients (33% women; 68 +/- 13 years) were enrolled in a 14-week intradialytic endurance-resistance training program ('exercise' group, 40 programmed sessions per patient); 40 hemodialysis patients (28% women; 68 +/- 11 years) performing no exercise during the same time length were used as controls. Endpoints included physical performance (6-min walk test [6MWT], 10 repetition sit to stand [STS-10] and handgrip strength), emotional status (Beck's depression inventory and State-Trait Anxiety Inventory), and mental and physical component scores of the short-from (SF)-12 Health Survey. Results: There were no differences (p> 0.05) between groups at baseline for sex distribution, or mean age, body mass index and time spent on dialysis. Exercise benefits were observed for 6MWT (11 and -3% for the exercise and control groups, respectively; p < 0.001), STS-10 performance time (-22 and 6%; p < 0.001) and handgrip strength (4 and -4%; p < 0.02). No significant benefits (p> 0.05) were observed for emotional status endpoints or SF-12 component scores. Despite significant benefits on physical performance, the proportion of clinically meaningful responders was low (<50%). Responsiveness was dependent on baseline physical performance (p < 0.05) but not on age or sex (p > 0.05). Conclusion: A 14-week intradialytic training program induced significant improvements on physical performance. However, the rate of clinically meaningful responders observed in the present study was low, being the level of responsiveness dependent on baseline physical status. Efforts to individualize exercise prescription are needed in clinical practice. PMID- 30026698 TI - Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. AB - Mental disorders are rising while development of novel psychiatric medications is declining. This stall in innovation has also been linked with intense debates on the current diagnostics and explanations for mental disorders, together constituting a paradigmatic crisis. A radical innovation is psychedelic-assisted psychotherapy (PAP): professionally supervised use of ketamine, MDMA, psilocybin, LSD and ibogaine as part of elaborated psychotherapy programs. Clinical results so far have shown safety and efficacy, even for "treatment resistant" conditions, and thus deserve increasing attention from medical, psychological and psychiatric professionals. But more than novel treatments, the PAP model also has important consequences for the diagnostics and explanation axis of the psychiatric crisis, challenging the discrete nosological entities and advancing novel explanations for mental disorders and their treatment, in a model considerate of social and cultural factors, including adversities, trauma, and the therapeutic potential of some non-ordinary states of consciousness. PMID- 30026701 TI - Elevated Oxidative Stress and Inflammation in Hypothalamic Paraventricular Nucleus Are Associated With Sympathetic Excitation and Hypertension in Rats Exposed to Chronic Intermittent Hypoxia. AB - Obstructive sleep apnea (OSA), characterized by recurrent collapse of the upper airway during sleep leading to chronic intermittent hypoxia (CIH), is an independent risk factor for hypertension. Sympathetic excitation has been shown to play a major role in the pathogenesis of OSA-associated hypertension. Accumulating evidence indicates that oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN), a critical cardiovascular and autonomic center, mediate sympathetic excitation in many cardiovascular diseases. Here we tested the hypothesis that CIH elevates oxidative stress and inflammation in the PVN, which might be associated with sympathetic excitation and increased blood pressure in a rat model of CIH that mimics the oxygen profile in patients with OSA. Sprague-Dawley rats were pretreated with intracerebroventricular (ICV) infusion of vehicle or superoxide scavenger tempol, and then exposed to control or CIH for 7 days. Compared with control+vehicle rats, CIH+vehicle rats exhibited increased blood pressure, and increased sympathetic drive as indicated by the blood pressure response to ganglionic blockade and plasma norepinephrine levels. Pretreatment with ICV tempol prevented CIH-induced increases in blood pressure and sympathetic drive. Molecular studies revealed that expression of NAD(P)H oxidase subunits, production of reactive oxygen species, expression of proinflammatory cytokines and neuronal excitation in the PVN were elevated in CIH+vehicle rats, compared with control+vehicle rats, but were normalized or reduced in CIH rat pretreated with ICV tempol. Notably, CIH+vehicle rats also had increased systemic oxidative stress and inflammation, which were not altered by ICV tempol. The results suggest that CIH induces elevated oxidative stress and inflammation in the PVN, which lead to PVN neuronal excitation and are associated with sympathetic excitation and increased blood pressure. Central oxidative stress and inflammation may be novel targets for the prevention and treatment of hypertension in patients with OSA. PMID- 30026699 TI - Cellular Mechanotransduction: From Tension to Function. AB - Living cells are constantly exposed to mechanical stimuli arising from the surrounding extracellular matrix (ECM) or from neighboring cells. The intracellular molecular processes through which such physical cues are transformed into a biological response are collectively dubbed as mechanotransduction and are of fundamental importance to help the cell timely adapt to the continuous dynamic modifications of the microenvironment. Local changes in ECM composition and mechanics are driven by a feed forward interplay between the cell and the matrix itself, with the first depositing ECM proteins that in turn will impact on the surrounding cells. As such, these changes occur regularly during tissue development and are a hallmark of the pathologies of aging. Only lately, though, the importance of mechanical cues in controlling cell function (e.g., proliferation, differentiation, migration) has been acknowledged. Here we provide a critical review of the recent insights into the molecular basis of cellular mechanotransduction, by analyzing how mechanical stimuli get transformed into a given biological response through the activation of a peculiar genetic program. Specifically, by recapitulating the processes involved in the interpretation of ECM remodeling by Focal Adhesions at cell-matrix interphase, we revise the role of cytoskeleton tension as the second messenger of the mechanotransduction process and the action of mechano-responsive shuttling proteins converging on stage and cell-specific transcription factors. Finally, we give few paradigmatic examples highlighting the emerging role of malfunctions in cell mechanosensing apparatus in the onset and progression of pathologies. PMID- 30026705 TI - Estrogen Modulates the Sensitivity of Lung Vagal C Fibers in Female Rats Exposed to Intermittent Hypoxia. AB - Obstructive sleep apnea is mainly characterized by intermittent hypoxia (IH), which is associated with hyperreactive airway diseases and lung inflammation. Sensitization of lung vagal C fibers (LVCFs) induced by inflammatory mediators may play a central role in the pathogenesis of airway hypersensitivity. In females, estrogen interferes with inflammatory signaling pathways that may modulate airway hyperreactivity. In this study, we investigated the effects of IH on the reflex and afferent responses of LVCFs to chemical stimulants and lung inflammation in adult female rats, as well as the role of estrogen in these responses. Intact and ovariectomized (OVX) female rats were exposed to room air (RA) or IH for 14 consecutive days. On day 15, IH enhanced apneic responses to right atrial injection of chemical stimulants of LVCFs (e.g., capsaicin, phenylbiguanide, and alpha,beta-methylene-ATP) in intact anesthetized females. Rats subjected to OVX prior to IH exposure exhibited an augmented apneic response to the same dose of stimulants compared with rats subjected to other treatments. Apneic responses to the stimulants were completely abrogated by bilateral vagotomy or perivagal capsaicin treatment, which blocked the neural conduction of LVCFs. Electrophysiological experiments revealed that in IH-exposed rats, OVX potentiated the excitability of LVCFs to stimulants. Moreover, LVCF hypersensitivity in rats subjected to OVX prior to IH exposure was accompanied by enhanced lung inflammation, which was reflected by elevated inflammatory cell infiltration in bronchoalveolar lavage fluid, lung lipid peroxidation, and protein expression of inflammatory cytokines. Supplementation with 17beta estradiol (E2) at a low concentration (30 MUg/ml) but not at high concentrations (50 and 150 MUg/ml) prevented the augmenting effects of OVX on LVCF sensitivity and lung inflammation caused by IH. These results suggest that ovarian hormones prevent the enhancement of LVCF sensitivity and lung inflammation by IH in female rats, which are related to the effect of low-dose estrogen. PMID- 30026704 TI - Relation Between Training Load and Recovery-Stress State in High-Performance Swimming. AB - Background: The relation between training load, especially internal load, and the recovery-stress state is of central importance for avoiding negative adaptations in high-performance sports like swimming. The aim of this study was to analyze the individual time-delayed linear effect relationship between training load and recovery-stress state with single case time series methods and to monitor the acute recovery-stress state of high-performance swimmers in an economical and multidimensional manner over a macro cycle. The Acute Recovery and Stress Scale (ARSS) was used for daily monitoring of the recovery-stress state. The methods session-RPE (sRPE) and acute:chronic workload-ratio (ACWR) were used to compare different methods for quantifying the internal training load with regard to their interrelationship with the recovery-stress state. Methods: Internal load and recovery-stress state of five highly trained female swimmers [with a training frequency of 13.6 +/- 0.8 sessions per week and specializing in sprint (50 and 100 m), middle-distance (200 and 400 m), or long distance (800 and 1,500 m) events] were daily documented over 17 weeks. Two different types of sRPE were applied: RPE*duration (sRPEh) and RPE*volume (sRPEkm). Subsequently, we calculated the ratios ACWRh and ACWRkm (sRPE last week: 4-week exponentially weighted moving average). The recovery-stress state was measured by using the ARSS, consisting of eight scales, four of which are related to recovery [Physical Performance Capability (PPC), Mental Performance Capability (MPC), Emotional Balance (EB), Overall Recovery (OR)], and four to stress [Muscular Stress (MS), Lack of Activation (LA), Negative Emotional State (NES), Overall Stress (OS)]. To examine the relation between training load and recovery-stress state a cross correlation (CCC) was conducted with sRPEh, sRPEkm, ACWRh, and ACWRkm as lead and the eight ARSS-scales as lag variables. Results: A large variation of training load can be observed in the individual week-to-week fluctuations whereby the single fluctuations can significantly differ from the overall mean of the group. The range also shows that the CCC individually reaches values above 0.3, especially with sRPEkm as lead variable. Overall, there is a large range with significant differences between the recovery and stress dimensions of the ARSS and between the training load methods, with sRPEkm having the largest span (Range = 1.16). High inter-individual differences between the athletes lie in strength and direction of the correlation | 0.66|<= CCC >=|-0.50|. The time delayed effects (lags 0-7) are highly individual, however, clear patterns can be observed. Conclusion: The ARSS, especially the physical and overall-related scales (PPC, OR, MS, OS), is a suitable tool for monitoring the acute recovery stress state in swimmers. MPC, EB, LA, and NES are less affected by training induced changes. Comparably high CCC and Ranges result from the four internal load methods, whereby sRPE, especially sRPEkm, shows a stronger relation to recovery-stress state than ACWR. Based on these results and the individual differences in terms of time delay in training response, we recommend for swimming to use sRPE to monitor the internal training load and to use the ARSS, with a focus at the physical and overall-scales, to monitor the recovery-stress state. PMID- 30026707 TI - Fluid Osmolarity Acutely and Differentially Modulates Lymphatic Vessels Intrinsic Contractions and Lymph Flow. AB - Lymph formation and propulsion rely on an extrinsic mechanism based on the forces that surrounding tissues exert upon the vessel wall and lumen and an intrinsic mechanism based on spontaneous, rhythmic contractions of the lymphatic muscle layer of collecting vessels. The two spontaneous pacemakers described in literature involve chloride-dependent depolarizations (STDs) and If-like currents, both giving rise to a variable contraction frequency (fc) of lymphatic vessels functional units (lymphangions). Several stimuli have been shown to modulate fc, such as temperature, shear stress, and several tissue chemical modulators (prostaglandins, norepinephrine, acetylcholine, substance P, and others). However, no detailed description is present in literature on the acute modulation of fc by means of osmolarity change of the surrounding interstitial space. Using a well-developed ex-vivo rat diaphragmatic preparation, in which osmolarity was changed by varying the concentration of D-mannitol in the perfusing solution and in later experiments the concentration of NaCl and then of Na+ and Cl- ions separately by ionic substitution, we provide detailed experimental evidences that a stepwise increase in osmolarity from control value (308 mOsm) up to 324 mOsm caused a reduction of fc down to ~-70% within the first 14 min, and that a stepwise decrease in osmolarity up to 290 mOsm induced an early fc increase to ~+34% of control, followed by a decline to an fc of ~-18% of control value. These variations were more dramatic when the same osmolarity changes were obtained by varying NaCl and/or Na+ or Cl- ions concentration, which caused an almost complete arrest of spontaneous contractility within 14 min from the application. Diastolic and systolic diameters and stroke volume were not affected by osmolarity changes, so that modulation of lymph flow closely followed that of fc. Modulation of lymph flow secondary to osmolarity changes is relevant if one considers that interstitial fluid balance is also dependent upon lymph drainage, and thus it is possible that, at least in the acute phase following variations of interstitial fluid osmolarity, its volume control might eventually be impaired due to the reduced or in the worst scenario null lymph drainage. PMID- 30026709 TI - Introjective Individuals Tend Toward Anhedonia: Self-Report and Experimental Evidence. AB - A broad line of research has conceptualized personality based on the interaction of two aspects: interpersonal relatedness and self-definition. This theoretical corpus understands these functions as two poles according to the patterns of interaction and relevance in personality. Additionally, the exacerbation of one of these poles generates a psychopathological model that identifies three types of depressive experience: anaclitic, introjective, or mixed pattern. Understanding the lack of interest as a key symptom of depression, this experiment evaluates a relation for anhedonia and the polarities model configuration using an empirical and experimental protocol. We tested 177 individuals using the Beck Depression Inventory (BDI) subscale for anhedonia and a visual discrimination task with a specific reward system, which was implemented to study reinforcement sensitivity. Participants were classified into four groups by the polarities of experience model. The subscale's results showed that individuals with an introjective character exhibited an enhanced anhedonic symptomatology but no co-occurrence of this evidence on the experimental protocol. These results empirically support the two polarities of the depressive personality model and raise new questions regarding how to experimentally test this relation. PMID- 30026708 TI - Association of MIR137 With Symptom Severity and Cognitive Functioning in Belarusian Schizophrenia Patients. AB - MicroRNA-137 (miRNA-137; miR-137) is one of the important post-transcriptional regulators of the nervous system development, and its MIR137 gene rs1625579 polymorphism was reported to be a potential regulator for schizophrenia susceptibility. However, schizophrenia characteristics controlled by MIR137 rs1625579 polymorphism are still insufficiently understood. There were 3 groups included in the study: (a) subjects with diagnosis of schizophrenia (n = 150; 81 females, 69-males), (b) mentally healthy people (control group; n = 102; 66 females, 36-males) and (c) Belarusian indigenous male group (n = 295). Associations of rs1625579 with schizophrenia, symptom's severity and cognitive performance [by using Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Test (WCST), respectively] were studied, when compared to controls. Allele and genotype frequencies were investigated in Belarusian indigenous males. Rs1625579 displayed no association with schizophrenia in Belarusian population. Significant "symptom severity-genotype" interactions were revealed for schizophrenia patients. Patients with T/G genotype displayed lower severity of positive symptoms and general psychopathology compared to homozygous subjects. T/T genotype was associated with the highest symptom's severity. The negative symptom scores and the total PANSS-score were significantly higher in females carrying genotype T/T vs. T/G+G/G; no significant gene-phenotype associations were found in males. WCST parameters did not show any association with rs1625579 polymorphism. MIR137 rs1625579 polymorphism might be an important sex-dependent factor influencing severity of schizophrenia psychopathological manifestations. These findings also contribute to the knowledge on candidate gene effects on characteristics related to schizophrenia phenotype. As miR 137 is considered to be cancer therapeutic target, miR-137 may also explain the lower incidence of cancer in schizophrenia patients. Further studies with larger sample size are needed to confirm these novel findings. PMID- 30026706 TI - The Yo-Yo Intermittent Tests: A Systematic Review and Structured Compendium of Test Results. AB - Background: Although Yo-Yo intermittent tests are frequently used in a variety of sports and research studies to determine physical fitness, no structured reference exists for comparison and rating of test results. This systematic review of the most common Yo-Yo tests aimed to provide reference values for test results by statistical aggregation of published data. Methods: A systematic literature search for articles published until August 2017 was performed in MEDLINE, Web of Science, SPORTDiscus and Google Scholar. Original reports on healthy females and males >=16 years were eligible for the analysis. Sub-maximal test versions and the Yo-Yo Intermittent Recovery Level 1 Children's test (YYIR1C) were not included. Results: 248 studies with 9,440 participants were included in the structured analysis. The Yo-Yo test types most frequently used were the Yo-Yo Intermittent Recovery Level 1 (YYIR1, 57.7%), the Yo-Yo Intermittent Recovery Level 2 (YYIR2, 28.0%), the Yo-Yo Intermittent Endurance Level 2 (YYIE2, 11.4%), and the Yo-Yo Intermittent Endurance Level 1 (YYIE1, 2.9%) test. For each separate test, reference values (global means and percentiles) for sports at different levels and both genders were calculated. Conclusions: Our analysis provides evidence that Yo-Yo intermittent tests reference values differ with respect to the type and level of sport performed.The presented results may be used by practitioners, trainers and athletes to rate Yo Yo intermittent test performance levels and monitor training effects. PMID- 30026710 TI - Mental Work Requires Physical Energy: Self-Control Is Neither Exception nor Exceptional. AB - The brain's reliance on glucose as a primary fuel source is well established, but psychological models of cognitive processing that take energy supply into account remain uncommon. One exception is research on self-control depletion, where debate continues over a limited-resource model. This model argues that a transient reduction in self-control after the exertion of prior self-control is caused by the depletion of brain glucose, and that self-control processes are special, perhaps unique, in this regard. This model has been argued to be physiologically implausible in several recent reviews. This paper attempts to correct some inaccuracies that have occurred during debate over the physiological plausibility of this model. We contend that not only is such limitation of cognition by constraints on glucose supply plausible, it is well established in the neuroscience literature across several cognitive domains. Conversely, we argue that there is no evidence that self-control is special in regard to its metabolic cost. Mental processes require physical energy, and the body is limited in its ability to supply the brain with sufficient energy to fuel mental processes. This article reviews current findings in brain metabolism and seeks to resolve the current conflict in the field regarding the physiological plausibility of the self-control glucose-depletion hypothesis. PMID- 30026712 TI - Procrastination in Daily Working Life: A Diary Study on Within-Person Processes That Link Work Characteristics to Workplace Procrastination. AB - Procrastination is a form of self-regulation failure characterized by the irrational delay of tasks despite potentially negative consequences. Previous research on procrastination was mainly conducted in academic settings, oftentimes combined with a focus on individual differences. As a consequence, scholarly knowledge about how situational factors affect procrastination in work settings is still scarce. Drawing on job stress literature, we assumed that work characteristics go along with cognitive appraisals of the work situation as a challenge and/or hindrance, that these cognitive appraisals affect employees' self-regulation effort to overcome inner resistances, and that self-regulation effort should in turn be related to workplace procrastination. In our study, we focused on three specific work characteristics that we expected to trigger both challenge and hindrance appraisal simultaneously: time pressure, problem solving, and planning and decision-making. We hypothesized serial indirect effects of these work characteristics on workplace procrastination via cognitive appraisal and self-regulation processes that unfold within individuals over short periods of time. Consequently, we conducted a diary study with three measurement occasions per workday over a period of 12 days. Overall, 762 day-level datasets from 110 employees were included in Bayesian multilevel structural equation modeling (MSEM; controlled for sleep quality and occupational self-efficacy). Our results revealed negative serial indirect effects of all three work characteristics on workplace procrastination via increased challenge appraisal and subsequently reduced self-regulation effort. Further, our results showed a positive serial indirect effect of time pressure (but not of problem solving or planning and decision making) on workplace procrastination via increased hindrance appraisal and subsequently increased self-regulation effort. Overall, our study showed that work characteristics are linked to workplace procrastination via within-person processes of cognitive appraisal and self regulation. Because not all work characteristics triggered hindrance appraisal, we argue that it may make sense to further differentiate challenge stressors in the future. Moreover, cognitive appraisals affected self-regulation effort only on the within-person level. On the between-person level self-regulation effort was strongly negatively related with occupational self-efficacy. Thus, we conclude that depending the perspective on procrastination (e.g., differential psychology perspective vs. situational perspective) different variables will be considered relevant to explain the emergence of procrastination. PMID- 30026713 TI - Does SMS-Support Make a Difference? Effectiveness of a Two-Week Online-Training to Overcome Procrastination. A Randomized Controlled Trial. AB - The primary purpose of this randomized controlled trial (RCT) was to evaluate the efficacy of an unguided, 2-week internet-based training program to overcome procrastination, called ON.TOP. Because adherence is a typical problem among individuals who tend to procrastinate, especially with internet-based interventions, the secondary purpose of the present study was to investigate whether adding SMS support increases subjects' frequency of engagement in training. In a three-armed RCT (N = 161), the effects of the intervention alone and intervention with daily SMS-support were compared to a waiting list control condition in a sample of students. The primary outcome of interest was procrastination. The secondary outcome of interest was the extent of training behavior. Baseline (T0), immediate post-treatment (T1) and 8-week post-treatment (T2) assessments were conducted. Results indicated that procrastination decreased significantly only with intervention group with daily SMS support, relative to control. Moreover, incorporating SMS support also may enhance extent of training behavior. PMID- 30026714 TI - Confirmatory Factor Analysis of the Inventory of Personality Organization-Reality Testing Subscale. AB - The reality testing dimension of the Inventory of Personality Organization, the IPO-RT, has emerged as an important index of proneness to reality testing deficits. However, to date few studies have examined the factorial structure of the IPO-RT in isolation. This is an important and necessary development because studies use the IPO-RT as a discrete measure. Additionally, psychometric evaluation of the IPO suggests alternative factorial solutions. Specifically, recent work supports multidimensionality, whereas initial IPO assessment evinced a unidimensional structure. Accordingly, this study, using a heterogeneous sample (N = 652), tested the fit of several factorial models (one-factor, four-factor oblique, second-order, and bifactor) via maximum likelihood with bootstrapping due to multivariate non-normality. Analysis revealed superior fit for the bifactor solution (correlated errors) (CFI = 0.965, SRMR = 0.036, RMSEA = 0.042). This model comprised a general reality testing dimension alongside four subfactors (auditory and visual hallucinations, delusional thinking, social deficits, and confusion). Inter-factor correlations were in the moderate range. Item loadings and omega reliability supported the notion that the IPO-RT emphasizes a single latent construct. The model demonstrated invariance across gender and partial age invariance. Overall, from a psychometric perspective, the IPO-RT functioned effectively at both global and, to an extent, factorial levels. Findings recommend that the IPO-RT should be scored as a total scale, and rather than treat subscales independently, future studies should consider examining factor variance alongside overall scale scores. PMID- 30026715 TI - The Reciprocal Relationships Between Escalation, Anger, and Confidence in Investment Decisions Over Time. AB - Research on escalation of commitment has predominantly been studied in the context of a single decision without consideration for the psychological consequences of escalating. This study sought to examine (a) the extent to which people escalate their commitment to a failing course of action in a sequential decision-making task, (b) confidence and anger as psychological consequences of escalation of commitment, and (c) the reciprocal relationship between escalation of commitment and confidence and anger. Participants were 110 undergraduate students who completed a series of investment decisions regarding a failing endeavor. Results revealed that although a high proportion of individuals escalate through all decisions, the extent to which they escalated decreased with each decision as they were less willing to invest money in the project. Furthermore, as participants escalated, confidence in one's decision decreased and anger increased. Lastly, the analyses revealed that the relationship between escalation and confidence is reciprocal. Escalation was negatively associated with confidence, and confidence predicted escalation in the subsequent decision. These results highlight the importance of considering both the determinants and psychological consequences of escalation of commitment. PMID- 30026711 TI - Theoretical Modeling of Cognitive Dysfunction in Schizophrenia by Means of Errors and Corresponding Brain Networks. AB - The current evidence of cognitive disturbances and brain alterations in schizophrenia does not provide the plausible explanation of the underlying mechanisms. Neuropsychological studies outlined the cognitive profile of patients with schizophrenia, that embodied the substantial disturbances in perceptual and motor processes, spatial functions, verbal and non-verbal memory, processing speed and executive functioning. Standardized scoring in the majority of the neurocognitive tests renders the index scores or the achievement indicating the severity of the cognitive impairment rather than the actual performance by means of errors. At the same time, the quantitative evaluation may lead to the situation when two patients with the same index score of the particular cognitive test, demonstrate qualitatively different performances. This may support the view why test paradigms that habitually incorporate different cognitive variables associate weakly, reflecting an ambiguity in the interpretation of noted cognitive constructs. With minor exceptions, cognitive functions are not attributed to the localized activity but eventuate from the coordinated activity in the generally dispersed brain networks. Functional neuroimaging has progressively explored the connectivity in the brain networks in the absence of the specific task and during the task processing. The spatio-temporal fluctuations of the activity of the brain areas detected in the resting state and being highly reproducible in numerous studies, resemble the activation and communication patterns during the task performance. Relatedly, the activation in the specific brain regions oftentimes is attributed to a number of cognitive processes. Given the complex organization of the cognitive functions, it becomes crucial to designate the roles of the brain networks in relation to the specific cognitive functions. One possible approach is to identify the commonalities of the deficits across the number of cognitive tests or, common errors in the various tests and identify their common "denominators" in the brain networks. The qualitative characterization of cognitive performance might be beneficial in addressing diffuse cognitive alterations presumably caused by the dysconnectivity of the distributed brain networks. Therefore, in the review, we use this approach in the description of standardized tests in the scope of potential errors in patients with schizophrenia with a subsequent reference to the brain networks. PMID- 30026716 TI - Prevalence of Parasomnias in Patients With Obstructive Sleep Apnea. A Registry Based Cross-Sectional Study. AB - Objective: To assess the prevalence of parasomnias in relation to presence and severity of obstructive sleep apnea (OSA). We hypothesized higher parasomnia prevalence with higher OSA severity. Methods: The sample comprised 4,372 patients referred to a Norwegian university hospital with suspicion of OSA (mean age 49.1 years, 69.8% males). OSA was diagnosed and categorized by standard respiratory polygraphy (type 3 portable monitor). The patients completed a comprehensive questionnaire prior to the sleep study, including questions about different parasomnias during the last 3 months. Pearson chi-square tests explored differences according to the presence and severity of OSA. Furthermore, logistic regression analyses with the parasomnias as dependent variables and OSA severity as predictor were conducted (adjusted for sex, age, marital status, smoking, and alcohol consumption). Results: In all, 34.7% had apnea-hypopnea index (AHI) <5 (no OSA), 32.5% had AHI 5-14.9 (mild OSA), 17.4% had AHI 15-29.9 (moderate OSA), and 15.3% had AHI >=30 (severe OSA). The overall prevalence of parasomnias was 3.3% (sleepwalking), 2.5% (sleep-related violence), 3.1% (sexual acts during sleep), 1.7% (sleep-related eating), and 43.8% (nightmares). The overall parasomnia prevalence was highest in the no OSA group. In the chi-square analyses, including all OSA groups, the prevalence of sleep-related violence and nightmares were inversely associated with OSA severity, whereas none of the other parasomnias were significantly associated with OSA severity. In adjusted logistic regression analyses the odds of sleepwalking was significantly higher in severe compared to mild OSA (OR = 2.0, 95% CI = 1.12-3.55). The other parasomnias, including sleep-related violence and nightmares, were not associated with OSA presence or severity when adjusting for sex and age. Conclusions: We found no increase in parasomnias in patients with OSA compared to those not having OSA. With the exception of sleepwalking, the parasomnias were not associated with OSA severity. PMID- 30026717 TI - Horizontal Spatial Metaphors for Morality: A Cross-Cultural Study of Han Chinese Students and Ethnic Minority Hui Students in China. AB - Metaphor is a bridge for understanding abstract concepts (the target domain) from concrete concepts (the source domain). This study, with two experiments, aimed to investigate the cultural differences of the horizontal spatial metaphors for morality between two groups of students: Han Chinese, the ethnic majority, and Hui Chinese, an ethnic minority in China. Experiment 1 adopted a spatial Stroop task. It showed that neither Hui nor Han students exhibited horizontal spatial metaphors for morality. Experiment 2 adopted a modified implicit association test paradigm to enhance the association between the moral concepts and the horizontal spatial positions. In Experiment 2, we found horizontal spatial metaphors for morality in Hui students, but not in Han students. These results indicated that the differences of horizontal spatial metaphors between Hui and Han participants were influenced by the different cultures they live in. Moreover, this study also found that the association between the source domain and the target domain was an important factor for metaphor formations. PMID- 30026718 TI - Testing Factor Structure and Measurement Invariance Across Gender With Italian Geriatric Anxiety Scale. AB - Late-life anxiety is an increasingly relevant psychiatric condition that often goes unnoticed and/or untreated compared to anxiety in younger populations. Consequently, assessing the presence and severity of clinical anxiety in older adults an important challenge for researchers and clinicians alike. The Geriatric Anxiety Scale is a 30-item geriatric-specific measure of anxiety severity, grouped in three subscales (Somatic, Affective, and Cognitive), with solid evidence for the reliability and validity of its scores in clinical and community samples. Translated into several languages, it has been proven to have strong psychometric properties. In Italy only one recent preliminarily investigative study has appeared on its psychometric properties. However, sample data was largely collected from one specific Italian region (Lombardy) alone. Here, our aim in testing the items of the GAS in a sample of 346 healthy subjects (50% females; 52% from Southern Italy), with mean age of 71.74 years, was 2-fold. First, we aimed to determine factor structure in a wider sample of Italian participants. Confirmatory factor analysis showed that the GAS fits an originally postulated three-factor structure reasonably well. Second, results support gender invariance, entirely supported at the factorial structure, and at the intercept level. Latent means can be meaningfully compared across gender groups. Whereas the means of F1 (Somatic) and F3 (Affective) for males were significantly different from those for females, the means for F2 (Cognitive) were not. More specifically, in light of the negative signs associated with these statistically significant values, the finding showed that F1 and F3 for males appeared to be less positive on average than females. Overall, the GAS displayed acceptable convergent validity with matching subscales highly correlated, and satisfactory internal discriminant validity with lower correlations between non-matching subscales. Implications for clinical practice and research are discussed. PMID- 30026719 TI - Exploring Relationships: A Systematic Review on Intimate Partner Violence and Attachment. AB - Background: Intimate Partner Violence (IPV) is an important public health challenge. In recent years, there has been a greater awareness concerning this phenomenon, its causes and consequences. Due to the relational nature of IPV, attachment theory (Bowlby, 1988) appears a useful framework to read the phenomenon and to better understand its components and its dynamics to provide more precise and tailored interventions in the future. Purpose: To summarize our knowledge of the research concerning IPV and attachment with an aim to better design and implement future research. Methods: Computer database researches were conducted using the following databases: Psychinfo, Psycharticle, Medline, Scopus, Web of Science, and PubMed (all years to the 01/02/2018). Search terms were compiled into two concepts for all database namely Attachment and IPV. Results: After removing the duplicates, a total of 3,598 records was screened, resulting in the identification of 319 full-text articles to be further scrutinized. Upon closer examination, there was consensus that 113 of those studies met the study inclusion criteria. Data was organized considering specifically studies concerning (1) IPV victimization and attachment, (2) IPV perpetration and attachment (both these sections were articulated in Physical, Psychological, and Sexual IPV), and (3) New research (comprising same-sex couples, IPV and attachment in couple contexts and IPV profiles and attachment among perpetrators). Conclusion: A number of studies failed to find significant associations between insecure attachment and IPV victimization or perpetration. Additional research is needed to provide a greater understanding of different IPV forms and to aid in the development of prevention and treatment interventions. PMID- 30026721 TI - Fancies and Fallacies of Spatial Sampling With Transcranial Magnetic Stimulation (TMS). PMID- 30026720 TI - Improved Self-Esteem in Artists After Participating in the "Building Confidence and Self-Esteem Toolbox Workshop". AB - Performing and creative artists have unique occupational and lifestyle stresses and challenges that can negatively affect self-esteem. Low self-esteem not only has serious implications for their psychological and physical health, it can also affect their performance, and creativity. There is a need to establish effective interventions to deal with this issue. To the best of our knowledge, there are no reported studies specific to workshops or interventions on enhancing self-esteem for artists. The Al and Malka Green Artists' Health Centre at the Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada, is a unique multidisciplinary, and integrative clinic serving the special needs of the artist population. We developed a workshop entitled "Building Confidence and Self Esteem Toolbox Workshop" to address this need. We then designed a single-blind, randomized, prospective, pilot study to evaluate the effectiveness of the workshop on enhancing self-esteem in artists, and to evaluate the long-term effectiveness of using the recommended tools in maintaining a healthy self esteem, as well as maintaining physical and emotional health. Both quantitative and qualitative data were collected. A validated "Self-Esteem Checkup" questionnaire was administered pre- and immediately post workshop, as well as at 2, 6, and 12 months post workshop. Open-ended questions were posed to study participants via email at 2 and 12 months following the workshop, and at 6 months in in-person interviews. Thirty-five professional artists consented to participate in the study, with 26 completing all study visits. Mean scores for all time points, and the individual questionnaire statement mean scores for the five timepoints increased significantly post-workshop and remained statistically significantly improved by the 3rd follow-up 12 months later (p < 0.001). The mean self-esteem rating score increased significantly post-workshop and remained statistically significantly improved by the 3rd follow-up 12 months later (p < 0.01). Qualitative data showed positive feedback on the utilization of the tools learned in the workshop that helped maintain this improvement over a 1-year period. This workshop may be an effective means of addressing the issue of self esteem in artists. Further controlled studies of larger sample size and longer duration are needed to confirm these findings. PMID- 30026722 TI - Endovascular Thrombectomy >24-hr From Stroke Symptom Onset. AB - Background: Trials have demonstrated efficacy for endovascular thrombectomy (EVT) for anterior circulation acute ischaemic stroke (AIS) up to 24-h from symptom onset. The magnitude of effect suggests benefit may exist beyond 24-h. Objectives: To perform a retrospective review of all patients undergoing EVT for anterior circulation LVO stroke beyond 24-h from symptom onset and assess safety and efficacy. Methods:A prospectively maintained database of EVT patients treated at two comprehensive stroke centers between January 2016 and December 2017 was retrospectively screened. Patients undergoing EVT for anterior circulation AIS >24-h from symptom onset were selected. Results: A total of 429 AIS patient underwent EVT in the study period. Five patients treated >24-h from symptom onset were identified. The median age was 72 (range 42-84); median ASPECTS 8 (range 6 8); median baseline-NIHSS 9 (range 4-17); and median time from symptom onset to groin puncture 44 h and 55 min (range 25:07-90:10). One patient underwent CT perfusion imaging. The remaining four patients were selected based on non contrast CT brain and CT-angiography. Two patients had tandem cervical carotid lesions and underwent acute stenting. Modified thrombolysis in cerebral ischaemia (mTICI) 3 reperfusion was achieved in four patients. No hemorrhagic transformation occurred. All patients were alive at 90-day follow-up. Four patients achieved functional independence at 90-days (mRS 0-2). Conclusion: Endovascular thrombectomy for AIS patients beyond 24-h from symptom onset appears to be safe and effective in this limited study. There is a need for further evidence-based trials of benefit vs. risk in very prolonged time windows. PMID- 30026723 TI - Multidrug Resistant Brain Abscess Due to Acinetobacter baumannii Ventriculitis Cleared by Intraventricular and Intravenous Tigecycline Therapy: A Case Report and Review of Literature. AB - Objective: Ventricular infection from multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is one of the most severe complications of craniotomy. However, the availability of effective therapeutic options for these infections is limited. Thus, this report aims to describe the efficacy of abscess clearance by intraventricular and intravenous tigecycline therapy in managing patients with multidrug-resistant A. baumannii ventriculitis after neurosurgery. Moreover, the current literature on the use of tigecycline therapy for these life-threatening infections is reviewed and summarized, and a treatment regimen based on the available data is proposed. Methods: A patient with multidrug-resistant A. baumannii ventriculitis was admitted in our hospital and was provided with a detailed therapeutic schedule. Tigecycline treatments for multidrug-resistant A. baumannii ventriculitis that were reported in the literature were also reviewed and summarized. Results: The patient in our hospital underwent abscess clearance on a ventriculoscope and was subsequently subjected to multi-route tigecycline therapy 14 days after the start of the continuous ventricular irrigation (CVI) tigecycline and 3 days after the intraventricular (IVT) tigecycline. The signs of ventriculitis disappeared, and the Acinetobacter cerebrospinal fluid (CSF) load steadily decreased until CSF sterilization. Literature review identified seven cases of ventricular infection from multidrug-resistant A. baumannii treated with tigecycline. In the eight cases, all patients were male adults (>18 years), with a mean age of 46.1 (range: 22-75) years. Meningitis/ventriculitis was secondary to neurosurgery procedures for the management of various central nervous system diseases in all cases. A good clinical outcome was achieved in all eight patients with multidrug-resistant A. baumannii meningitis/ventriculitis treated with CVI and/or IVT tigecycline, and any relevant complications were not observed. Conclusions: CVI and IVT tigecycline and IVT colistin could be considered as the first-line therapy in patients with ventricular infections from MDR/extreme drug resistant A. baumannii. However, more studies should be conducted to confirm our observation. PMID- 30026725 TI - Electrical Vestibular Stimuli Evoke Robust Muscle Activity in Deep and Superficial Neck Muscles in Humans. AB - Neck muscle activity evoked by vestibular stimuli is a clinical measure for evaluating the function of the vestibular apparatus. Cervical vestibular-evoked myogenic potentials (cVEMP) are most commonly measured in the sternocleidomastoid muscle (and more recently the splenius capitis muscle) in response to air conducted sound, bone-conducted vibration or electrical vestibular stimuli. It is currently unknown, however, whether and how other neck muscles respond to vestibular stimuli. Here we measured activity bilaterally in the sternocleidomastoid, splenius capitis, sternohyoid, semispinalis capitis, multifidus, rectus capitis posterior, and obliquus capitis inferior using indwelling electrodes in two subjects exposed to binaural bipolar electrical vestibular stimuli. All recorded neck muscles responded to the electrical vestibular stimuli (0-100 Hz) provided they were active. Furthermore, the evoked responses were inverted on either side of the neck, consistent with a coordinated contribution of all left-right muscle pairs acting as antagonists in response to the electrically-evoked vestibular error of head motion. Overall, our results suggest that, as previously observed in cat neck muscles, broad connections exist between the human vestibular system and neck motoneurons and highlight the need for future investigations to establish their neural connections. PMID- 30026724 TI - Opioidergic Modulation of Striatal Circuits, Implications in Parkinson's Disease and Levodopa Induced Dyskinesia. AB - The functional organization of the dorsal striatum is complex, due to the diversity of neural inputs that converge in this structure and its subdivision into direct and indirect output pathways, striosomes and matrix compartments. Among the neurotransmitters that regulate the activity of striatal projection neurons (SPNs), opioid neuropeptides (enkephalin and dynorphin) play a neuromodulatory role in synaptic transmission and plasticity and affect striatal based behaviors in both normal brain function and pathological states, including Parkinson's disease (PD). We review recent findings on the cell-type-specific effects of opioidergic neurotransmission in the dorsal striatum, focusing on the maladaptive synaptic neuroadaptations that occur in PD and levodopa-induced dyskinesia. Understanding the plethora of molecular and synaptic mechanisms underpinning the opioid-mediated modulation of striatal circuits is critical for the development of pharmacological treatments that can alleviate motor dysfunctions and hyperkinetic responses to dopaminergic stimulant drugs. PMID- 30026726 TI - The Treatment of Autism Spectrum Disorder With Auditory Neurofeedback: A Randomized Placebo Controlled Trial Using the Mente Autism Device. AB - Introduction: Children affected by autism spectrum disorder (ASD) often have impairment of social interaction and demonstrate difficulty with emotional communication, display of posture and facial expression, with recognized relationships between postural control mechanisms and cognitive functions. Beside standard biomedical interventions and psychopharmacological treatments, there is increasing interest in the use of alternative non-invasive treatments such as neurofeedback (NFB) that could potentially modulate brain activity resulting in behavioral modification. Methods: Eighty-three ASD subjects were randomized to an Active group receiving NFB using the Mente device and a Control group using a Sham device. Both groups used the device each morning for 45 minutes over a 12 week home based trial without any other clinical interventions. Pre and Post standard ASD questionnaires, qEEG and posturography were used to measure the effectiveness of the treatment. Results: Thirty-four subjects (17 Active and 17 Control) completed the study. Statistically and substantively significant changes were found in several outcome measures for subjects that received the treatment. Similar changes were not detected in the Control group. Conclusions: Our results show that a short 12 week course of NFB using the Mente Autism device can lead to significant changes in brain activity (qEEG), sensorimotor behavior (posturography), and behavior (standardized questionnaires) in ASD children. PMID- 30026727 TI - MUVEMP: A Portable Interface to Record Vestibular Evoked Myogenic Potentials (VEMPs) With a Smart Phone or Tablet. AB - Background: Cervical VEMPs and ocular VEMPs are tests for evaluating otolith function in clinical practice. We developed a simple, portable and affordable device to record VEMP responses on patients, named MUVEMP. Our aim was to validate and field test the new MUVEMP device. Methods: We recorded cervical VEMPs and ocular VEMPs in response to bone conducted vibration using taps tendon hammer to the forehead (Fz) and to air conducted sounds using clicks. We simultaneously recorded VEMP responses (same subject, same electrode, same stimuli) in three healthy volunteers (2 females, age range: 29-57 years) with the MUVEMP device and with a standard research grade commercial (CED) system used in clinics. We also used the MUVEMP device to record VEMP responses from six patients (6 females, age mean+/-SD: 50.3 +/- 20.8 years) with classical peripheral audio-vestibular diseases (unilateral vestibular neuritis, unilateral neurectomy, bilateral vestibular loss, unilateral superior canal dehiscence, unilateral otosclerosis). Results: The first part of this paper compared the devices using simultaneous recordings. The average of the concordance correlation coefficient was rc = 0.997 +/- 0.003 showing a strong similarity between the measures. VEMP responses recorded with the MUVEMP device on patients with audio vestibular diseases were similar to those typically found in the literature. Conclusions: We developed, validated and field tested a new device to record ocular and cervical VEMPs in response to sound and vibration.This new device is portable (powered by a phone or tablet) with pocket-size dimensions (105 * 66 * 27 mm) and light weight (150 g). Although further studies and normative data are required, our MUVEMP device is simpler (easier to use) and potentially more accessible than standard, commercially available equipment. PMID- 30026728 TI - Using Directional Deep Brain Stimulation to Co-activate the Subthalamic Nucleus and Zona Incerta for Overlapping Essential Tremor/Parkinson's Disease Symptoms. AB - This index case report describes a novel programming approach that utilizes the 8 contact directional Deep Brain Stimulation (DBS) lead to effectively control the akinesia, rigidity and tremor of Parkinson's Disease (PD), as well as a severe kinetic tremor of Essential Tremor (ET), in a patient with overlapping symptoms of both PD and ET. Through utilizing a bipolar directional montage on a single segmented contact, symptom control was attained via likely co-activation of the Subthalamic Nucleus (STN) and the adjacent Zona Incerta (ZI). The patient is a 67 year-old professional guitarist with a long-standing diagnosis of ET manifesting with bilateral kinetic tremor, who then developed right lateralizing symptoms indicative of PD. After optimal medical management did not confer sufficient control, he underwent left-sided unilateral DBS targeting the STN. Both intraoperatively and post-operatively, omnidirectional, and directional electrode review resulted in significant akinesia, rigidity, and as well as resting tremor control but failed to sufficiently improve the kinetic tremor. As electrode 2B was shown to be the most efficacious with the largest therapeutic window, a bipolar directional montage on a single segmented contact was tried with the idea of possibly further extending the axial asymmetry of the directional stimulation toward the adjacent ZI to impact the kinetic tremor. This montage resulted in full kinetic and resting tremor control as well as akinesia and rigidity response [2B cathode (-), 2A anode (+), 2C anode (+) (1.4 mA, rate 160 Hz, pulse width 60 MUs)]. At 6 months post initial programming, no montage changes have been made, and the patient has experienced a reduction in Motor UPDRS scores from 23 to 3 (evaluated off medication), full resolution of kinetic tremor and normalization of handwriting, as well as significant reduction in his medication requirements. This patient's response to a single segment bipolar directional montage, and lack of response from monopolar directional stimulation in the same area, does suggest the possibility of further axial asymmetric tissue activation and thus co activation of both the dorsal STN and adjacent ZI. Further modeling and study are warranted. PMID- 30026729 TI - KL1333, a Novel NAD+ Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts. AB - Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ10, vitamins, and nutrients, but no treatment with proven efficacy is currently available. In this study, we investigated the effects of a novel NAD+ modulator, KL1333, in human fibroblasts derived from a human patient with MELAS. KL1333 is an orally available, small organic molecule that reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate, resulting in increases in intracellular NAD+ levels via NADH oxidation. To elucidate the mechanism of action of KL1333, we used C2C12 myoblasts, L6 myoblasts, and MELAS fibroblasts. Elevated NAD+ levels induced by KL1333 triggered the activation of SIRT1 and AMPK, and subsequently activated PGC 1alpha in these cells. In MELAS fibroblasts, KL1333 increased ATP levels and decreased lactate and ROS levels, which are often dysregulated in this disease. In addition, mitochondrial functional analyses revealed that KL1333 increased mitochondrial mass, membrane potential, and oxidative capacity. These results indicate that KL1333 improves mitochondrial biogenesis and function, and thus represents a promising therapeutic agent for the treatment of MELAS. PMID- 30026730 TI - Thyrotropin Regulates eNOS Expression in the Endothelium by PGRN Through Akt Pathway. AB - To investigate the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) in the aorta of subclinical hypothyroidism (SCH) rat model. The mechanisms underlying thyrotropin (TSH) affecting eNOS and PGRN expression in human umbilical vein endothelial cells (HUVECs) cultured in vitro were investigated. In the current study, SCH rat models were established by the administration of L-T4 injection after thyroidectomy in Wistar rats, as opposed to that in the normal and clinical hypothyroidism (CH) groups. The concentrations of NO (pmol/MUL) in the SCH and CH groups were significantly lower than that in the normal group (40.8 +/- 7.6 and 32.9 +/- 10.8 vs. 51.2 +/- 12.1, P < 0.05). However, the expression level of eNOS is increased significantly (P < 0.05) in both SCH and CH groups; a similar result was observed for the PGRN protein. In cultured HUVECs, TSH can also up-regulate the expression of eNOS; however, it is accompanied by a reduced concentration of NO and increased level of superoxide anion, thereby indicating uncoupled eNOS. As eNOS is increased, we found that Akt in HUVECs were upregulated by TSH, as well as PGRN expression. While inhibiting the expression of PGRN in HUVECs using siRNA, the expression of eNOS, as well as Akt were also inhibited. In conclusion, SCH can induce vascular endothelial dysfunction in rats, and PGRN participated in the process of TSH-induced expression of Akt/eNOS in the endothelium. PMID- 30026731 TI - Comparative Study of Different Diets-Induced NAFLD Models of Zebrafish. AB - Dietary composition has important impact on nonalcoholic fatty liver disease (NAFLD). The purpose of this study was to explore the relationship between NAFLD and major dietary components using zebrafish larvae fed different diets. Zebrafish larvae fed with high cholesterol (HC), high fructose (HF) and extra feeding (EF) diets for 10 days displayed varying degrees steatosis. The incidence and degree of steatosis were the most severe in the EF group. A HC diet severely promoted lipid deposits in the caudal vein. The triglyceride and glucose contents of zebrafish significantly increased in the HF and EF groups compared with the control group. Moreover, the mRNA expression of oxidative stress gene gpx1a, endoplasmic reticulum stress genes ddit3 and grp78, inflammatory genes tnfa, glucose metabolism genes irs2, glut1 and glut2, and lipid metabolism genes cidec, chrebp, ppara and cpt1a were significantly increased in the HF group. The HC diet was associated with upregulation of grp78, and downregulation of irs2, glut1 and glut2. The mRNA expression of lipogenesis and glucose metabolism associated genes were decreased in the EF group. In addition, the autophagy associated genes atg3, atg5, atg7, and atg12, and protein expression of ATG3 and LC3BII were reduced and P62 were elevated in the HC group. We also performed comparative transcriptome analysis of the four groups. A total of 2,492 differentially expressed genes were identified, and 24 statistically significant pathways were enriched in the diet treatment groups. This study extends our understanding of the relationships between diet ingredients and host factors that contribute to the pathogenesis of NAFLD, which may provide new ideas for the treatment of NAFLD. PMID- 30026732 TI - Electrochemically Synthesized Silver Nanoparticles Are Active Against Planktonic and Biofilm Cells of Pseudomonas aeruginosa and Other Cystic Fibrosis-Associated Bacterial Pathogens. AB - A novel, electrochemically synthesized, silver nanoparticles (AgNPs) formulation was evaluated in vitro against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Staphylococcus aureus strains from cystic fibrosis (CF) patients. AgNPs were particularly active against P. aeruginosa and B. cepacia planktonic cells (median MIC: 1.06 and 2.12 MUg/ml, respectively) by a rapid, bactericidal and concentration-dependent effect. AgNPs showed to be particularly effective against P. aeruginosa and S. aureus biofilm causing a viability reduction ranging from 50% (1*MIC) to >99.9% (4*MIC). Electron microscopy showed that AgNPs deconstruct extracellular matrix of P. aeruginosa biofilm, and accumulate at the cell surface causing cell death secondary to membrane damage. Compared to Tobramycin, AgNPs showed comparable, or even better, activity against planktonic and biofilm P. aeruginosa cells. AgNPs at concentrations effective against B. cepacia and P. aeruginosa were not toxic to G. mellonella larvae. Our silver-based formulation might be an alternative to antibiotics in CF patients. Further in vitro and in vivo studies are warranted to confirm this therapeutic potential. PMID- 30026734 TI - Microbial Biogeography Along the Gastrointestinal Tract of a Red Panda. AB - The red panda (Ailurus fulgens) is a herbivorous carnivore that is protected worldwide. The gastrointestinal tract (GIT) microbial community has widely acknowledged its vital role in host health, especially in diet digestion; However, no study to date has revealed the GIT microbiota in the red panda. Here, we characterized the microbial biogeographical characteristics in the GIT of a red panda using high-throughput sequencing technology. Significant differences were observed among GIT segments by beta diversity of microbiota, which were divided into four distinct groups: the stomach, small intestine, large intestine, and feces. The stomach and duodenum showed less bacterial diversity, but contained higher bacterial abundance and the most unclassified tags. The number of species in the stomach and small intestine samples was higher than that of the large intestine and fecal samples. A total of 133 core operational taxonomic units were obtained from the GIT samples with 97% sequence identity. Proteobacteria (52.16%), Firmicutes (10.09%), and Bacteroidetes (7.90%) were the predominant phyla in the GIT of the red panda. Interestingly, Escherichia Shigella were largely abundant in the stomach, small intestine, and feces whereas the abundance of Bacteroides in the large intestine was high. Overall, our study provides a deeper understanding of the gut biogeography of the red panda microbial population. Future research will be important to investigate the microbial culture, metagenomics and metabolism of red panda GIT, especially in Escherichia-Shigella. PMID- 30026733 TI - The Role of Mass Spectrometry in Structural Studies of Flavin-Based Electron Bifurcating Enzymes. AB - For decades, biologists and biochemists have taken advantage of atomic resolution structural models of proteins from X-ray crystallography, nuclear magnetic resonance spectroscopy, and more recently cryo-electron microscopy. However, not all proteins relent to structural analyses using these approaches, and as the depth of knowledge increases, additional data elucidating a mechanistic understanding of protein function is desired. Flavin-based electron bifurcating enzymes, which are responsible for producing high energy compounds through the simultaneous endergonic and exergonic reduction of two intercellular electron carriers (i.e., NAD+ and ferredoxin) are one class of proteins that have challenged structural biologists and in which there is great interest to understand the mechanism behind electron gating. A limited number of X-ray crystallography projects have been successful; however, it is clear that to understand how these enzymes function, techniques that can reveal detailed in solution information about protein structure, dynamics, and interactions involved in the bifurcating reaction are needed. In this review, we cover a general set of mass spectrometry-based techniques that, combined with protein modeling, are capable of providing information on both protein structure and dynamics. Techniques discussed include surface labeling, covalent cross-linking, native mass spectrometry, and hydrogen/deuterium exchange. We cover how biophysical data can be used to validate computationally generated protein models and develop mechanistic explanations for regulation and performance of enzymes and protein complexes. Our focus will be on flavin-based electron bifurcating enzymes, but the broad applicability of the techniques will be showcased. PMID- 30026735 TI - Fluoromycobacteriophages Can Detect Viable Mycobacterium tuberculosis and Determine Phenotypic Rifampicin Resistance in 3-5 Days From Sputum Collection. AB - The World Health Organization (WHO) estimates that 40% of tuberculosis (TB) cases are not diagnosed and treated correctly. Even though there are several diagnostic tests available in the market, rapid, easy, inexpensive detection, and drug susceptibility testing (DST) of Mycobacterium tuberculosis is still of critical importance specially in low and middle-income countries with high incidence of the disease. In this work, we have developed a microscopy-based methodology using the reporter mycobacteriophage mCherrybomb phi for detection of Mycobacterium spp. and phenotypic determination of rifampicin resistance within just days from sputum sample collection. Fluoromycobacteriophage methodology is compatible with regularly used protocols in clinical laboratories for TB diagnosis and paraformaldehyde fixation after infection reduces biohazard risks with sample analysis by fluorescence microscopy. We have also set up conditions for discrimination between M. tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM) strains by addition of p-nitrobenzoic acid (PNB) during the assay. Using clinical isolates of pre-XDR and XDR-TB strains from this study, we tested mCherrybomb Phi for extended DST and we compared the antibiotic resistance profile with those predicted by whole genome sequencing. Our results emphasize the utility of a phenotypic test for M. tuberculosis extended DST. The many attributes of mCherrybomb Phi suggests this could be a useful component of clinical microbiological laboratories for TB diagnosis and since only viable cells are detected this could be a useful tool for monitoring patient response to treatment. PMID- 30026736 TI - Overview on the Bacterial Iron-Riboflavin Metabolic Axis. AB - Redox reactions are ubiquitous in biological processes. Enzymes involved in redox metabolism often use cofactors in order to facilitate electron-transfer reactions. Common redox cofactors include micronutrients such as vitamins and metals. By far, while iron is the main metal cofactor, riboflavin is the most important organic cofactor. Notably, the metabolism of iron and riboflavin seem to be intrinsically related across life kingdoms. In bacteria, iron availability influences expression of riboflavin biosynthetic genes. There is documented evidence for riboflavin involvement in surpassing iron-restrictive conditions in some species. This is probably achieved through increase in iron bioavailability by reduction of extracellular iron, improvement of iron uptake pathways and boosting hemolytic activity. In some cases, riboflavin may also work as replacement of iron as enzyme cofactor. In addition, riboflavin is involved in dissimilatory iron reduction during extracellular respiration by some species. The main direct metabolic relationships between riboflavin and iron in bacterial physiology are reviewed here. PMID- 30026738 TI - High Resolution Assessment of Spatio-Temporal Changes in O2 Concentration in Root Pathogen Interaction. AB - Fusarium wilt, caused by the fungus Fusarium oxysporum f. sp. lycopersici (Fol), is one of the most destructive soil-borne diseases of tomatoes. Infection takes place on the roots and the process starts with contact between the fungus and the roots hairs. To date, no detailed studies are available on metabolic activity in the early stages of the Fol and tomato root interaction. Spatial and temporal patterns of oxygen consumption could provide new insights into the dynamics of early colonization. Here, we combined planar optodes and spatial analysis to assess how tomato roots influence the metabolic activity and growth patterns of Fol. The results shows that the fungal metabolism, measured as oxygen consumption, increases within a few hours after the inoculation. Statistical analysis revealed that the fungus tends to growth toward the root, whereas, when the root is not present, the single elements of the fungus move with a Brownian motion (random). The combination of planar optodes and spatial analysis is a powerful new tool for assessing temporal and spatial dynamics in the early stages of root-pathogen interaction. PMID- 30026737 TI - Stimulatory Effect of Magnetite Nanoparticles on a Highly Enriched Butyrate Oxidizing Consortium. AB - Syntrophic oxidation of butyrate is catabolized by a few bacteria specialists in the presence of methanogens. In the present study, a highly enriched butyrate oxidizing consortium was obtained from a wetland sediment in Tibetan Plateau. During continuous transfers of the enrichment, the addition of magnetite nanoparticles (nanoFe3O4) consistently enhanced butyrate oxidation and CH4 production. Molecular analysis revealed that all bacterial sequences from the consortium belonged to Syntrophomonas with the closest relative of Syntrophomonas wolfei and 96% of the archaeal sequences were related to Methanobacteria with the remaining sequences to Methanocella. Addition of graphite and carbon nanotubes for a replacement of nanoFe3O4 caused the similar stimulatory effect. Silica coating of nanoFe3O4 surface, however, completely eliminated the stimulatory effect. The control experiment with axenic cultivation of a Syntrophomonas strain and two methanogen strains showed no effect by nanoFe3O4. Together, the results in the present study support that syntrophic oxidation of butyrate is likely facilitated by direct interspecies electron transfer in the presence of conductive nanomaterials. PMID- 30026739 TI - Evaluation of the Potential of Lactobacillus paracasei Adjuncts for Flavor Compounds Development and Diversification in Short-Aged Cheddar Cheese. AB - The non-starter microbiota of Cheddar cheese mostly comprises mesophilic lactobacilli, such as Lactobacillus casei, Lactobacillus paracasei, Lactobacillus rhamnosus, and Lactobacillus plantarum. These bacteria are recognized for their potential to improve Cheddar cheese flavor when used as adjunct cultures. In this study, three strains of L. paracasei (DPC2071, DPC4206, and DPC4536) were evaluated for their contribution to the enhancement and diversification of flavor in short-aged Cheddar cheese. The strains were selected based on their previously determined genomic diversity, variability in proteolytic enzyme activities and metabolic capability in cheese model systems. The addition of adjunct cultures did not affect the gross composition or levels of lipolysis of the cheeses. The levels of free amino acids (FAA) in cheeses showed a significant increase after 28 days of ripening. However, the concentrations of individual amino acids in the cheeses did not significantly differ except for some amino acids (aspartic acid, threonine, serine, and tryptophan) at Day 14. Volatile profile analysis revealed that the main compounds that differentiated the cheeses were of lipid origin, such as long chain aldehydes, acids, ketones, and lactones. This study demonstrated that the adjunct L. paracasei strains contributed to the development and diversification of compounds related to flavor in short-aged Cheddar cheeses. PMID- 30026740 TI - Genomic Characterization of Sulphite Reducing Bacteria Isolated From the Dairy Production Chain. AB - Anaerobic sporeformers, specifically spoilage and pathogenic members of the genus Clostridium, are a concern for producers of dairy products, and of powdered dairy products in particular. As an alternative to testing for individual species, the traditional, and still current, approach to detecting these sporeformers, including non-spoilage/non-pathogenic species, in dairy products has involved testing for a sulphite reducing phenotype [Sulphite reducing Clostridia (SRCs)] under anaerobic conditions. This phenotype is conserved throughout the Order Clostridia. Unfortunately, however, this phenotype is exhibited by other sulphite reducing bacteria (SRBs) also, potentially leading to potential for false positives. Here, this risk was borne out through the identification of several SRBs from industry samples that were identified as Proteus mirabilis and various Bacillus/Paenibacillus sp. Genome wide comparison of a number of representative SRCs and SRBs was employed to determine phylogenetic relationships, especially among SRCs, and to characterize the genes responsible for the sulphite reducing phenotype. This screen identified two associated operons, i.e., asrABC in SRCs, and cysJI in Bacillus/Paenibacillus spp. and P. mirabilis. This screen identified spp. belonging to sensu stricto, Lachnospiraceae and Cluster XIV of the Clostridia all producing the SRC phenotype. This study highlights the inaccuracy of the industry standard SRC test but highlights the potential to generate an equivalent molecular test designed to detect the genes responsible for this phenotype in clostridia. PMID- 30026741 TI - Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions. AB - Introduction: Mycobacterium tuberculosis is one of the world's most successful pathogens equipped to establish itself within the human host as a subclinical infection without overt disease. Unable to eradicate the bacteria, the immune system contains the infection in a granuloma structure. Th1 cells that are essential for infection control are recruited to the site of infection directed by chemokines, predominantly CXCL10. It has previously been shown that CXCL10 in the plasma of patients chronically infected with hepatitis C virus is present primarily in an antagonist form. This is due to N-terminal truncation by the enzyme DPP4, which results in the antagonist form that is capable of binding its receptor CXCR3, but does not induce signaling. We aimed to explore whether such CXCL10 antagonism may have an impact on the pathogenesis of tuberculosis (TB). Results: We measured plasma levels of agonist and antagonist CXCL10 by Simoa digital ELISA, as well as DPP4 enzyme activity in the plasma of 20 patients with active TB infection, 10 patients with pneumonia infection, and a group of 10 healthy controls. We found higher levels of total and antagonist CXCL10 and reduced DPP4 enzyme activity in the plasma of TB patients compared to controls. We traced the source of CXCL10 secretion using immunohistochemical and confocal analysis to multinucleated giant cells in the TB lesions, and variable expression by macrophages. Interestingly, these cells were associated with DPP4-positive T cells. Moreover, the analysis of lymphocytes at the site of TB infection (bronchoalveolar lavage) showed a reduced frequency of CXCR3+ T cells. Interpretation: Our data suggests that CXCL10 antagonism may be an important regulatory mechanism occurring at the site of TB pathology. CXCL10 can be inactivated shortly after secretion by membrane bound DPP4 (CD26), therefore, reducing its chemotactic potential. Given the importance of Th1 cell functions and IFN-gamma-mediated effects in TB, our data suggest a possible unappreciated regulatory role of DPP4 in TB. Perspectives: DPP4 is the target for a class of enzyme inhibitors used in the treatment of diabetes, and the results from this study suggest that these drugs could be repurposed as an adjunct immunotherapy of patients with TB and MDR-TB. PMID- 30026742 TI - Combination of Cytokine-Induced Killer Cells and Programmed Cell Death-1 Blockade Works Synergistically to Enhance Therapeutic Efficacy in Metastatic Renal Cell Carcinoma and Non-Small Cell Lung Cancer. AB - Introduction: Programmed cell death-1 (PD-1) inhibition therapy has changed the treatment paradigm of metastatic renal cell carcinoma (MRCC) and non-small cell lung cancer (NSCLC). However, attempts to use the drug as a single agent have achieved only limited clinical success. To further enhance the clinical benefits of monotherapy, combination therapies will likely be necessary. Cytokine-induced killer (CIK) cells are a heterogeneous subset of ex vivo expanded T lymphocytes that have been shown to prolong the survival of cancer patients. We are conducting a study to evaluate the efficacy of PD-1 inhibitor in combination with CIK cells in relapsed/refractory MRCC and NSCLC and to analyze potential biomarkers to predict which patients will benefit most from the combined therapy. Case presentation: The results of two patients treated in an ongoing clinical trial for MRCC and NSCLC are described here. The tumor biopsy from Patient 1 exhibited moderate CD3+ T cell infiltration, but no PD-1 or PD-L1 expression. The tumor cells from Patient 2 strongly expressed PD-L1, and there was extensive tumor infiltration by CD3+ T cells; however, no PD-1 staining was seen. Non synonymous single nucleotide variant (nsSNVs), along with higher indel mutations, in Patient 1 and nsSNVs along with higher tumor mutation burden in Patient 2 correlate with tumor-infiltrating CD3+ lymphocyte density. Patient 1 achieved a complete response, and Patient 2 achieved a near-complete response. Conclusion: A PD-1 inhibitor in combination with CIK cells led to potent antitumor activity in MRCC and NSCLC; CD3+ T cell infiltration in baseline tumor biopsies is a potential predictive biomarker. This approach is being further investigated in an ongoing phase I trial. PMID- 30026743 TI - A Mechanistic Model for Predicting Cell Surface Presentation of Competing Peptides by MHC Class I Molecules. AB - Major histocompatibility complex-I (MHC-I) molecules play a central role in the immune response to viruses and cancers. They present peptides on the surface of affected cells, for recognition by cytotoxic T cells. Determining which peptides are presented, and in what proportion, has profound implications for developing effective, medical treatments. However, our ability to predict peptide presentation levels is currently limited. Existing prediction algorithms focus primarily on the binding affinity of peptides to MHC-I, and do not predict the relative abundance of individual peptides on the surface of antigen-presenting cells in situ which is a critical parameter for determining the strength and specificity of the ensuing immune response. Here, we develop and experimentally verify a mechanistic model for predicting cell-surface presentation of competing peptides. Our approach explicitly models key steps in the processing of intracellular peptides, incorporating both peptide binding affinity and intracellular peptide abundance. We use the resulting model to predict how the peptide repertoire is modified by interferon-gamma, an immune modulator well known to enhance expression of antigen processing and presentation proteins. PMID- 30026744 TI - Epistatic Interactions Between Mutations of Deoxyribonuclease 1-Like 3 and the Inhibitory Fc Gamma Receptor IIB Result in Very Early and Massive Autoantibodies Against Double-Stranded DNA. AB - Autoantibodies against double-stranded DNA (anti-dsDNA) are a hallmark of systemic lupus erythematosus (SLE). It is well documented that anti-dsDNA reactive B lymphocytes are normally controlled by immune self-tolerance mechanisms operating at several levels. The evolution of high levels of IgG anti dsDNA in SLE is dependent on somatic hypermutation and clonal selection, presumably in germinal centers from non-autoreactive B cells. Twin studies as well as genetic studies in mice indicate a very strong genetic contribution for the development of anti-dsDNA as well as SLE. Only few single gene defects with a monogenic Mendelian inheritance have been described so far that are directly responsible for the development of anti-dsDNA and SLE. Recently, among other mutations, rare null-alleles for the deoxyribonuclease 1 like 3 (DNASE1L3) and the Fc gamma receptor IIB (FCGR2B) have been described in SLE patients and genetic mouse models. Here, we demonstrate that double Dnase1l3- and FcgR2b deficient mice in the C57BL/6 background exhibit a very early and massive IgG anti-dsDNA production. Already at 10 weeks of age, autoantibody production in double-deficient mice exceeds autoantibody levels of diseased 9-month-old NZB/W mice, a long established multigenic SLE mouse model. In single gene-deficient mice, autoantibody levels were moderately elevated at early age of the mice. Premature autoantibody production was accompanied by a spontaneous hyperactivation of germinal centers, early expansions of T follicular helper cells, and elevated plasmablasts in the spleen. Anti-dsDNA hybridomas generated from double-deficient mice show significantly elevated numbers of arginines in the CDR3 regions of the heavy-chain as well as clonal expansions and diversification of B cell clones with moderate numbers of somatic mutations. Our findings show a strong epistatic interaction of two SLE-alleles which prevent early and high-level anti-dsDNA autoantibody production. Both genes apparently synergize to keep in check excessive germinal center reactions evolving into IgG anti-dsDNA antibody producing B cells. PMID- 30026745 TI - Influence of Heavy Metals (Ni, Cu, and Zn) on Nitro-Oxidative Stress Responses, Proteome Regulation and Allergen Production in Basil (Ocimum basilicum L.) Plants. AB - One of the most significant biosphere contamination problems worldwide is derived from heavy metals. Heavy metals can be highly reactive and toxic according to their oxidation levels. Their toxic effects are associated with the increased production of reactive oxygen species (ROS) and cellular damage induced in plants. The present study focuses on the effects of nickel (Ni), copper (Cu), and zinc (Zn) applied to the soil on the antioxidant response and allergen production in the aromatic plant basil (Ocimum basilicum L.) following a combined physiological, biochemical and analytical approach. The concentrations used for the three heavy metals were based on the 2002 Regulation of the Polish Ministry of the Environment on Soil Quality Standards [(i) agricultural land (group B): Ni 100 ppm, Ni 210 ppm, Cu 200 ppm, Cu 500 ppm, Zn 720 ppm and (ii) industrial land (group C): Ni 500 ppm, Cu 1000 ppm, Zn 1500 ppm, Zn 3000 ppm]. The highest physiological and cellular damage in basil plants was caused by Cu and Zn. Increasing concentrations of Cu resulted in a further increase in cellular damage and nitro-oxidative stress, correlating with an induction in activity of reactive oxygen and nitrogen species metabolism enzymes (SOD, CAT, APX, NR). Treatment with Cu led to increased concentration of the allergenic protein profilin, while increasing concentrations of Cu and Zn led to a decrease in the concentration of total proteins (likely due to proteolysis) and antioxidant capacity. Interestingly, severe Cu stress resulted in the accumulation of specific proteins related to transpiration and photosynthetic processes. On the basis of these findings, Ni stress in basil plants appears to be less damaging and with lower allergenic potential compared with Cu and Zn stress, while Cu-stressed basil plants experience most detrimental effects and display highest allergen production. PMID- 30026746 TI - Maize Combined Insect Resistance Genomic Regions and Their Co-localization With Cell Wall Constituents Revealed by Tissue-Specific QTL Meta-Analyses. AB - Combinatorial insect attacks on maize leaves, stems, and kernels cause significant yield losses and mycotoxin contaminations. Several small effect quantitative trait loci (QTL) control maize resistance to stem borers and storage pests and are correlated with secondary metabolites. However, efficient use of QTL in molecular breeding requires a synthesis of the available resistance information. In this study, separate meta-analyses of QTL of maize response to stem borers and storage pests feeding on leaves, stems, and kernels along with maize cell wall constituents discovered in these tissues generated 24 leaf (LIR), 42 stem (SIR), and 20 kernel (KIR) insect resistance meta-QTL (MQTL) of a diverse genetic and geographical background. Most of these MQTL involved resistance to several insect species, therefore, generating a significant interest for multiple insect resistance breeding. Some of the LIR MQTL such as LIR4, 17, and 22 involve resistance to European corn borer, sugarcane borer, and southwestern corn borer. Eleven out of the 42 SIR MQTL related to resistance to European corn borer and Mediterranean corn borer. There KIR MQTL, KIR3, 15, and 16 combined resistance to kernel damage by the maize weevil and the Mediterranean corn borer and could be used in breeding to reduce insect-related post-harvest grain yield loss and field to storage mycotoxin contamination. This meta-analysis corroborates the significant role played by cell wall constituents in maize resistance to insect since the majority of the MQTL contain QTL for members of the hydroxycinnamates group such as p-coumaric acid, ferulic acid, and other diferulates and derivates, and fiber components such as acid detergent fiber, neutral detergent fiber, and lignin. Stem insect resistance MQTL display several co-localization between fiber and hydroxycinnamate components corroborating the hypothesis of cross-linking between these components that provide mechanical resistance to insect attacks. Our results highlight the existence of combined-insect resistance genomic regions in maize and set the basis of multiple-pests resistance breeding. PMID- 30026747 TI - Isolation and Characterization of the Flavonol Regulator CcMYB12 From the Globe Artichoke [Cynara cardunculus var. scolymus (L.) Fiori]. AB - Flavonoids are a well-studied group of secondary metabolites, belonging to the phenylpropanoid pathway. Flavonoids are known to exhibit health promoting effects such as antioxidant capacities, anti-cancer and anti-inflammatory activity. Globe artichoke is an important source of bioactive phenolic compounds, including flavonoids. To study the regulation of their biosynthesis, a R2R3-MYB transcription factor, CcMYB12, was isolated from artichoke leaves. Phylogenetic analysis showed that this protein belongs to the MYB subgroup 7 (flavonol specific MYB), which includes Arabidopsis AtMYB12, grapevine VvMYBF1, and tomato SlMYB12. CcMYB12 transcripts were detected specifically in artichoke immature inflorescence and young leaves and overlapped with the profiles of flavonol biosynthetic genes. Electrophoretic mobility shift assays (EMSAs) revealed that recombinant CcMYB12 protein is able to bind to ACII element, a DNA binding site ubiquitously present in the promoters of genes encoding flavonol biosynthetic enzymes. In transgenic Arabidopsis plants, the overexpression of CcMYB12 activated the expression of endogenous flavonol biosynthesis genes, leading to an increase of flavonol accumulation and a decrease of anthocyanins in leaves. Likewise, in transgenic tobacco petals and leaves, the overexpression of CcMYB12 decreased anthocyanin levels and increased flavonols. PMID- 30026748 TI - Overexpression of SSBXoc, a Single-Stranded DNA-Binding Protein From Xanthomonas oryzae pv. oryzicola, Enhances Plant Growth and Disease and Salt Stress Tolerance in Transgenic Nicotiana benthamiana. AB - We previously reported that SSBXoc, a highly conserved single-stranded DNA binding protein from Xanthomonas spp., was secreted through the type III secretion system (T3SS) and functioned as a harpin-like protein to elicit the hypersensitive response (HR) in the non-host plant, tobacco. In this study, we cloned SsbXoc gene from X. oryzae pv. oryzicola (Xoc), the causal agent of bacterial leaf streak in rice, and transferred it into Nicotiana benthamiana via Agrobacterium-mediated transformation. The expression of SsbXoc in transgenic N. benthamiana enhanced growth of both seedling and adult plants. When inoculated with the harpin Hpa1 or the pathogen Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), the accumulation of reactive oxygen species (ROS) was increased more in SsbXoc transgenic lines than that in wild-type (WT) plants. The expression of pathogenesis-related protein genes (PR1a and SGT1), HR marker genes (HIN1 and HSR203J) and the mitogen-activated protein kinase pathway gene, MPK3, was significantly higher in transgenic lines than in WT after inoculation with Pst DC3000. In addition, SsbXoc transgenic lines showed the enhanced resistance to the pathogenic bacteria P. s. tabaci and the improved tolerance to salt stress, accompanied by the elevated transcription levels of the defense- and stress related genes. Taken together, these results indicate that overexpression of the SsbXoc gene in N. benthamiana significantly enhanced plant growth and increased tolerance to disease and salt stress via modulating the expression of the related genes, thus providing an alternative approach for development of plants with improved tolerance against biotic and abiotic stresses. PMID- 30026749 TI - Measuring Activity of Native Plant Sirtuins - The Wheat Mitochondrial Model. AB - Sirtuins are NAD+-dependent deacetylase enzymes that have gained considerable interest in mammals for their recognized importance in gene silencing and expression and in cell metabolism. Conversely, knowledge about plant sirtuins remains limited, although a sirtuin-mediated regulation of mitochondrial energy metabolism has been recently reported in Arabidopsis. However, so far, no information is available about direct measurement of intracellular plant sirtuin activity, i.e., in cell extracts and/or subcellular organelles. In this study, a novel approach was proposed for reliable evaluation of native sirtuin activity in plant samples, based on (i) an adequate combinatory application of enzymatic assays very different for chemical basis and rationale and (ii) a comparative measurement of activity of a recombinant sirtuin isoform. In particular, two sirtuin assays were applied, based on bioluminescence emission and Homogeneous Time-Resolved Fluorescence (HTRF(r)) technology, and the human SIRT1 isoform (hSIRT1) was used for comparison. For the first time in plants, this new approach allowed measuring directly a high and nicotinamide-sensitive sirtuin activity in highly purified mitochondrial fraction obtained from durum wheat (WM). WM-sirtuin activity was 268 +/- 10 mU?mg-1 protein, as measured by HTRF(r) assay, and 166 +/ 12 ng hSIRT1 eq.?mg-1 protein, as evaluated by the bioluminescent assay and calculated on the basis of the hSIRT1 calibration curve. Moreover, effects of resveratrol and quercetin, reported as potent hSIRT1 activators, but whose activation mechanism is still debated, were also studied. No effect of resveratrol was found on both WM-sirtuin and hSIRT1 activities, while only a slight increase, up to about 20%, of hSIRT1 activity by quercetin was observed. In the whole, results of this study indicate that WM may represent a good system for studying native plant sirtuins. In fact, the high yield of purified WM and their high sirtuin activity, together with use of microplate readers, allow performing a large number of measurements from the same preparation, so qualifying the approach for application to large-scale high-throughput screening. Moreover, WM may also represent an excellent tool to investigate physiological role and modulation of plant sirtuins under experimental conditions more physiologically relevant with respect to recombinant purified enzymes. PMID- 30026750 TI - Assessing the Impact of Spatial Resolution on the Estimation of Leaf Nitrogen Concentration Over the Full Season of Paddy Rice Using Near-Surface Imaging Spectroscopy Data. AB - Timely monitoring nitrogen status of rice crops with remote sensing can help us optimize nitrogen fertilizer management and reduce environmental pollution. Recently, the use of near-surface imaging spectroscopy is emerging as a promising technology that can collect hyperspectral images with spatial resolutions ranging from millimeters to decimeters. The spatial resolution is crucial for the efficiency in the image sampling across rice plants and the separation of leaf signals from the background. However, the optimal spatial resolution of such images for monitoring the leaf nitrogen concentration (LNC) in rice crops remains unclear. To assess the impact of spatial resolution on the estimation of rice LNC, we collected ground-based hyperspectral images throughout the entire growing season over 2 consecutive years and generated ten sets of images with spatial resolutions ranging from 1.3 to 450 mm. These images were used to determine the sensitivity of LNC prediction to spatial resolution with three groups of vegetation indices (VIs) and two multivariate methods Gaussian Process regression (GPR) and Partial least squares regression (PLSR). The reflectance spectra of sunlit-, shaded-, and all-leaf leaf pixels separated from background pixels at each spatial resolution were used to predict LNC with VIs, GPR and PLSR, respectively. The results demonstrated all-leaf pixels generally exhibited more stable performance than sunlit- and shaded-leaf pixels regardless of estimation approaches. The predictions of LNC required stage-specific LNC~VI models for each vegetative stage but could be performed with a single model for all the reproductive stages. Specifically, most VIs achieved stable performances from all the resolutions finer than 14 mm for the early tillering stage but from all the resolutions finer than 56 mm for the other stages. In contrast, the global models for the prediction of LNC across the entire growing season were successfully established with the approaches of GPR or PLSR. In particular, GPR generally exhibited the best prediction of LNC with the optimal spatial resolution being found at 28 mm. These findings represent significant advances in the application of ground-based imaging spectroscopy as a promising approach to crop monitoring and understanding the effects of spatial resolution on the estimation of rice LNC. PMID- 30026751 TI - The Complete Chloroplast Genomes of Six Ipomoea Species and Indel Marker Development for the Discrimination of Authentic Pharbitidis Semen (Seeds of I. nil or I. purpurea). AB - Ipomoea L. is the largest genus within the Convolvulaceae and contains 600-700 species. Ipomoea species (morning glories) are economically valuable as horticultural species and scientifically valuable as ecological model plants to investigate mating systems, molecular evolution, and both plant-herbivore and plant-parasite interactions. Furthermore, the dried seeds of I. nil or I. purpurea are used in Korean traditional herbal medicines. In this study, chloroplast (cp) genomes were sequenced from six Ipomoea species, namely, I. nil and I. purpurea and, for the first time, I. triloba, I. lacunosa, I. hederacea, and I. hederacea var. integriuscula. The cp genomes were 161,354-161,750 bp in length and exhibited conserved quadripartite structures. In total, 112 genes were identified, including 78 protein-coding regions, 30 transfer RNA genes, and 4 ribosomal RNA genes. The gene order, content, and orientation of the six Ipomoea cp genomes were highly conserved and were consistent with the general structure of angiosperm cp genomes. Comparison of the six Ipomoea cp genomes revealed locally divergent regions, mainly within intergenic spacer regions (petN-psbM, trnI-CAU-ycf2, ndhH-ndhF, psbC-trnS, and ccsA-ndhD). In addition, the protein coding genes accD, cemA, and ycf2 exhibited high sequence variability and were under positive selection (Ka/Ks > 1), indicating adaptive evolution to the environment within the Ipomoea genus. Phylogenetic analysis of the six Ipomoea species revealed that these species clustered according to the APG IV system. In particular, I. nil and I. hederacea had monophyletic positions, with I. purpurea as a sister. I. triloba and I. lacunosa in the section Batatas and I. hederacea and I. hederacea var. integriuscula in the section Quamoclit were supported in this study with strong bootstrap values and posterior probabilities. We uncovered high-resolution phylogenetic relationships between Ipomoeeae. Finally, indel markers (IPOTY and IPOYCF) were developed for the discrimination of the important herbal medicine species I. nil and I. purpurea. The cp genomes and analyses in this study provide useful information for taxonomic, phylogenetic, and evolutionary analysis of the Ipomoea genome, and the indel markers will be useful for authentication of herbal medicines. PMID- 30026752 TI - QTL Mapping and Validation of Adult Plant Resistance to Stripe Rust in Chinese Wheat Landrace Humai 15. AB - Stripe rust caused by Puccinia striiformis f. sp. tritici (Pst) is a devastating foliar disease that affects common wheat and barley throughout the world. The reasonable deployment of adult plant resistance (APR) wheat varieties is one of the best methods for controlling this disease. Wheat landraces are valuable resources for identifying the genes/QTLs responsible for disease resistance. Humai 15 is a Chinese spring wheat landrace and it has exhibited adequate levels of APR to the prevalent Pst races in field environments for many years. In this study, a population of 177 recombinant inbred lines (RILs) was derived from Humai 15 * Mingxian 169. After screening based on a 90K chip array using 45 RILs and Kompetitive Allelic Specific PCR marker genotyping for the population of RILs, a major effect QTL in Humai 15 was located on the centromere of chromosome 2B, where it accounted for up to 47.2% of the phenotypic variation. Two other minor QTL genes from Humai 15 were located on chromosome arms 3BS and 4BL. The Yr18 gene was identified on chromosome arm 7DS in Mingxian 169. PMID- 30026753 TI - Experimental Verification and Evolutionary Origin of 5'-UTR Polyadenylation Sites in Arabidopsis thaliana. AB - Messenger RNA (mRNA) polyadenylation is an indispensable step during post transcriptional pre-mRNA processing for most genes in eukaryotes. The usage of one poly(A) site over another is known as alternative polyadenylation (APA). APA has been implicated in gene expression regulation through its role of selecting the ends of a transcript. Recent studies of polyadenylation profiles in the Arabidopsis database unexpectedly predicted that a portion of the poly(A) sites are located in the 5'-UTR, which remains to be experimentally verified. We selected 16 genes from a dataset of 744, based on criteria designed to minimize problems in interpretation. Here, we experimentally verify 5'-UTR-APA in Arabidopsis for 10 of the 16 selected genes, and show for the first time existence of independent polyadenylated 5'-UTR transcripts, arising due to alternative polyadenylation. We used 3'-RACE and sequencing to validate poly(A) sites and northern blot to show that the observed short upstream transcripts do not arise from the 3'-end of a previously unrecognized convergent gene. Evidence is reported showing that two of the independent upstream open reading frame (uORF) transcripts studied, one containing a complex dual uORF, very likely arose by exon shuffling following duplication of the 5'-end from the downstream major open reading frame (mORF). Finally, results are presented to show that the uORF in this gene may encode two short functional proteins, based on observation of amino acid sequence conservation encoded by the dual uORFs. PMID- 30026754 TI - Latitude and Altitude Influence Secondary Metabolite Production in Peripheral Alpine Populations of the Mediterranean Species Lavandula angustifolia Mill. AB - Lavandula angustifolia Mill. has a great economic importance in perfumery, cosmetics, food manufacturing, aromatherapy, and pharmaceutical industry. This species finds its phytosociological optimum in the sub-Mediterranean region. Latitudinal and altitudinal gradients are expected to affect species diversification in peripheral alpine populations. In this study, phenotypic traits including morphometric parameters, volatile organic compounds (VOCs) and essential oils (EOs) were analyzed in lavender peripheral populations selected in order to explore different ecological conditions. Plants were cultivated under uniform conditions to observe variations due to the genetic adaptation to native environments and to exclude the short-term response to environmental factors. Results showed qualitatively and quantitatively intra-specific variations in secondary metabolites, mainly along the latitudinal gradient, while minor effect was attributable to the altitude. This latter affected more the morphometric parameters. As the latitude augmented, VOCs showed lower content of monoterpene hydrocarbon (mh) and higher content of oxygenated monoterpenes (om); whereas EOs showed higher content of mh and non-terpene derivatives (nt) and lower content of sesquiterpene hydrocarbons (sh). Lavender aroma and EO composition varied in every population, for a total of 88 and 104 compounds identified, respectively. Eleven and 13 compounds were responsible for 95% of the dissimilarity, with linalool, linalyl acetate and 1,8-cineole as major contributors. As the latitude augmented, linalool decreased and 1,8-cineole increased while linalyl acetate content was unaffected. These results are discussed with regards to the potential adoption of the lavender peripheral alpine populations for the improvement of quality and productivity of lavender cultivations, especially in mountainous areas. PMID- 30026757 TI - Multiview Layer Fusion Model for Action Recognition Using RGBD Images. AB - Vision-based action recognition encounters different challenges in practice, including recognition of the subject from any viewpoint, processing of data in real time, and offering privacy in a real-world setting. Even recognizing profile based human actions, a subset of vision-based action recognition, is a considerable challenge in computer vision which forms the basis for an understanding of complex actions, activities, and behaviors, especially in healthcare applications and video surveillance systems. Accordingly, we introduce a novel method to construct a layer feature model for a profile-based solution that allows the fusion of features for multiview depth images. This model enables recognition from several viewpoints with low complexity at a real-time running speed of 63 fps for four profile-based actions: standing/walking, sitting, stooping, and lying. The experiment using the Northwestern-UCLA 3D dataset resulted in an average precision of 86.40%. With the i3DPost dataset, the experiment achieved an average precision of 93.00%. With the PSU multiview profile-based action dataset, a new dataset for multiple viewpoints which provides profile-based action RGBD images built by our group, we achieved an average precision of 99.31%. PMID- 30026756 TI - Pharmacological and Toxicological Threshold of Bisammonium Tetrakis 4-(N,N Dimethylamino)pyridinium Decavanadate in a Rat Model of Metabolic Syndrome and Insulin Resistance. AB - Vanadium(IV/V) compounds have been studied as possible metallopharmaceutical drugs against diabetes mellitus. However, mechanisms of action and toxicological threshold have been tackled poorly so far. In this paper, our purposes were to evaluate the metabolic activity on dyslipidemia and dysglycemia, insulin signaling in liver and adipose tissue, and toxicology of the title compound. To do so, the previously reported bisammonium tetrakis 4-(N,N dimethylamino)pyridinium decavanadate, the formula of which is [DMAPH]4(NH4)2[V10O28].8H2O (where DMAPH is 4-dimethylaminopyridinium ion), was synthesized, and its dose-response curve on hyperglycemic rats was evaluated. A Long-Evans rat model showing dyslipidemia and dysglycemia with parameters that reproduce metabolic syndrome and severe insulin resistance was generated. Two different dosages, 5 umol and 10 umol twice a week of the title compound (equivalent to 2.43 mg.V/kg/day and 4.86 mg.V/kg/day, resp.), were administered intraperitoneal (i.p.) for two months. Then, an improvement on each of the following parameters was observed at a 5 umol dose: weight reduction, abdominal perimeter, fatty index, body mass index, oral glucose tolerance test, lipid profile, and adipokine and insulin resistance indexes. Nevertheless, when the toxicological profile was evaluated at a 10 umol dose, it did not show complete improvement, tested by the liver and adipose histology, as well as by insulin receptor phosphorylation and GLUT-4 expression. In conclusion, the title compound administration produces regulation on lipids and carbohydrates, regardless of dose, but the pharmacological and toxicological threshold for cell regulation are suggested to be up to 5 umol (2.43 mg.V/kg/day) dose twice per week. PMID- 30026759 TI - A Novel Framework for Ab Initio Coarse Protein Structure Prediction. AB - Hydrophobic-Polar model is a simplified representation of Protein Structure Prediction (PSP) problem. However, even with the HP model, the PSP problem remains NP-complete. This work proposes a systematic and problem specific design for operators of the evolutionary program which hybrids with local search hill climbing, to efficiently explore the search space of PSP and thereby obtain an optimum conformation. The proposed algorithm achieves this by incorporating the following novel features: (i) new initialization method which generates only valid individuals with (rather than random) better fitness values; (ii) use of probability-based selection operators that limit the local convergence; (iii) use of secondary structure based mutation operator that makes the structure more closely to the laboratory determined structure; and (iv) incorporating all the above-mentioned features developed a complete two-tier framework. The developed framework builds the protein conformation on the square and triangular lattice. The test has been performed using benchmark sequences, and a comparative evaluation is done with various state-of-the-art algorithms. Moreover, in addition to hypothetical test sequences, we have tested protein sequences deposited in protein database repository. It has been observed that the proposed framework has shown superior performance regarding accuracy (fitness value) and speed (number of generations needed to attain the final conformation). The concepts used to enhance the performance are generic and can be used with any other population-based search algorithm such as genetic algorithm, ant colony optimization, and immune algorithm. PMID- 30026760 TI - Cryptogenic Organizing Pneumonia with Sarcoidosis Overlap: An Atypical Case Study. AB - Case Summary: We present a case of a young female with subacute symptoms of cough and progressive dyspnoea. On evaluation, the patient was diagnosed as cryptogenic organizing pneumonia based on her histopathological reports. However, her significant elevation of serum angiotensin-converting enzyme (SACE) levels which drop after treatment with oral steroids, relapse, and clinical presentation pointed towards sarcoidosis as clinical diagnosis. Discussion: Here, in this patient, transbronchial biopsy was suggestive of cryptogenic organizing pneumonia along with chest X-ray, and the HRCT finding was also favouring the same. But in this case, we have also seen elevated levels of serum ACE which dropped significantly to the normal level along with a complete clearance of lesions with systemic steroids, and this favours sarcoidosis. Also, the recurrence was in different areas of the lung, and lesions once again responded both clinically and radiologically to steroids with a consistent drop in serum angiotensin-converting enzyme (SACE) levels, which again is a feature common in sarcoidosis. In COP, often complete clearance of the lesions is seldom seen, even though they do respond to steroids but not as dramatically as in our case. Also, recurrence of the lesion with BOOP at different sites is uncommon as it generally progresses in the same site. Conclusion: This case report suggests that sarcoidosis as a possible cause of cryptogenic organizing pneumonia is worth considering with the mixed spectrum of presentation as in our case. And to our knowledge, this type of presentation of cryptogenic organizing pneumonia with sarcoidosis as an overlap disease is very rare, and this possibility needs to be explored by more series of such cases. PMID- 30026755 TI - CRISPR/Cascade 9-Mediated Genome Editing-Challenges and Opportunities. AB - Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and Cascade 9 (also known as Cas9, CRISPR associated protein 9) confer protection against invading viruses or plasmids. The CRISPR/Cascade 9 system constitutes one of the most powerful genome technologies available to researchers today. So far, this technology has enabled efficient genome editing and modification in several model organisms and has successfully been used in biomedicine and biomedical engineering. However, challenges for efficient and safe genetic manipulation in several organisms persist. Here, we review functional approaches and future challenges associated with the use of the CRISPR/Cascade 9 genome editing system and discuss opportunities, ethical issues and future directions within this field. PMID- 30026758 TI - Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease. AB - Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies. PMID- 30026761 TI - IL-1beta-Induced Matrix Metalloprotease-1 Promotes Mesenchymal Stem Cell Migration via PAR1 and G-Protein-Coupled Signaling Pathway. AB - Mesenchymal stem cells (MSCs) are known for homing to sites of injury in response to signals of cellular damage. However, the mechanisms of how cytokines recruit stem cells to target tissue are still unclear. In this study, we found that the proinflammation cytokine interleukin-1beta (IL-1beta) promotes mesenchymal stem cell migration. The cDNA microarray data show that IL-1beta induces matrix metalloproteinase-1 (MMP-1) expression. We then used quantitative real-time PCR and MMP-1 ELISA to verify the results. MMP-1 siRNA transfected MSCs, and MSC pretreatment with IL-1beta inhibitor interleukin-1 receptor antagonist (IL-1RA), MMP tissue inhibitor of metalloproteinase 1 (TIMP1), tissue inhibitor of metalloproteinase 2 (TIMP2), MMP-1 inhibitor GM6001, and protease-activated receptor 1 (PAR1) inhibitor SCH79797 confirms that PAR1 protein signaling pathway leads to IL-1beta-induced cell migration. In conclusion, IL-1beta promotes the secretion of MMP-1, which then activates the PAR1 and G-protein-coupled signal pathways to promote mesenchymal stem cell migration. PMID- 30026762 TI - Bcl-2 Overexpression Improves Survival and Efficacy of Neural Stem Cell-Mediated Enzyme Prodrug Therapy. AB - Tumor-tropic neural stem cells (NSCs) can be engineered to localize gene therapies to invasive brain tumors. However, like other stem cell-based therapies, survival of therapeutic NSCs after transplantation is currently suboptimal. One approach to prolonging cell survival is to transiently overexpress an antiapoptotic protein within the cells prior to transplantation. Here, we investigate the utility and safety of this approach using a clinically tested, v-myc immortalized, human NSC line engineered to contain the suicide gene, cytosine deaminase (CD-NSCs). We demonstrate that both adenoviral- and minicircle-driven expression of the antiapoptotic protein Bcl-2 can partially rescue CD-NSCs from transplant-associated insults. We further demonstrate that the improved CD-NSC survival afforded by transient Bcl-2 overexpression results in decreased tumor burden in an orthotopic xenograft glioma mouse model following administrations of intracerebral CD-NSCs and systemic prodrug. Importantly, no evidence of CD-NSC transformation was observed upon transient overexpression of Bcl-2. This research highlights a critical need to develop clinically relevant strategies to improve survival of therapeutic stem cell posttransplantation. We demonstrate for the first time in this disease setting that improving CD-NSC survival using Bcl-2 overexpression can significantly improve therapeutic outcomes. PMID- 30026763 TI - Challenging diagnosis of congenital hyperinsulinism in two infants of diabetic mothers with rare pathogenic KCNJ11 and HNF4A gene variants. AB - Background: Congenital hyperinsulinism (CHI) is the leading cause of persistent hypoglycemia in infants. The infants of diabetic mothers (IDMs) very frequently present with neonatal hypoglycemia associated to transient hyperinsulinism however the incidence of CHI in IDMs is unknown. Case presentation: Here we report 2 cases of CHI where the diagnoses were challenged and delayed because both patients were infants of diabetic mothers (IDMs) and had concomitant complicated medical conditions. Case 1 was heterozygous for a likely pathogenic variant in KCNJ11(p.Arg206Cys), and Case 2 was heterozygous for a pathogenic HNF4A variant, (p.Arg267Cys). HNF4A-associated CHI is very rare, and this particular case had a clinical phenotype quite different from that of previously described HNF4A-CHI cases. Conclusions: This case series is one of few reports in the medical literature describing two IDMs with persistent recurrent hypoglycemia secondary to CHI, and a different clinical phenotype for HNF4A-associated CHI. IDMs typically present with transient hyperinsulinism lasting no more than 2-3 days. Since being an IDM does not exclude CHI, this diagnosis should always be considered as the mostly likely etiology if neonatal hypoglycemia persists longer than the described time frame and genetic testing for CHI confirmation is highly suggested. PMID- 30026764 TI - Interplay between acute phase response and coagulation/fibrinolysis in chronic spontaneous urticaria. AB - Background: Chronic spontaneous urticaria (CSU) is associated with activation of systemic inflammatory response and coagulation/fibrinolysis. Aim: To study whether there is a relationship between the acute phase response and coagulation/fibrinolysis in chronic spontaneous urticaria (CSU) patients. Methods: Serum concentrations of C-reactive protein (CRP) and interleukin 6 (IL 6), key markers of acute phase response and of D-dimer, a marker of fibrin turnover were investigated in 58 CSU patients assessed with the urticaria activity score (UAS) and the controls. Results: Serum concentrations of IL-6, CRP, and D-dimer were significantly higher in CSU patients as compared with the controls. We found statistically significant correlations between D-dimers concentrations and the inflammatory markers: CRP and IL-6 as well as UAS. Conclusions: Markers of inflammation (IL-6 and CRP) and of fibrinolysis (D-dimer) are related to each other in CSU, suggesting a possible cross-talk between inflammation and coagulation/fibrinolysis. It might be implicated in pathogenesis of the disease and may be associated with higher risks of cardiovascular diseases in CSU patients. PMID- 30026766 TI - Serum Total Antioxidant Capacity of Epileptic Children before and after Monotherapy with Sodium Valproate, Carbamazepine, and Phenobarbital. AB - Objectives: This case-control study was carried out to compare serum total antioxidant capacity (TAC) in the newly diagnosed children with epilepsy and that of a control group of healthy children at the same age and probable effects of antiepileptic drugs (AEDs) prescription on it. Materials & Methods: Overall, 130 participants (65 in each group) aged between 1 and 17 yr old were enrolled. The study was conducted in Children's Medical Center, the Pediatrics Center of Excellence, Tehran, Iran in 2010. Serum TAC test was done for both control and patients group before AED therapy and after 3 months of monotherapy with sodium valproate, carbamazepine and phenobarbital in patients. Serum TAC values were measured based on Erel's method using an automated commercial kit. This method is based on the bleaching of the characteristic color of a more stable 2, 2'azinobis (3ethylbenzothiazoline6sulfonic acid) radical cation by antioxidants. The results were expressed in mmol Trolox equivalent/l. Results: Serum TAC values were significantly lower in the patients group before drug administration [mean (SD): 1.31 (0.19) mmol/L] in comparison with the control group [mean (SD): 1.46 (0.21) mmol/L] (P<0.001). In the patient's group, no differences were found in the serum TAC before and 3 months after AED monotherapy. Conclusion: Reduced serum TAC and an increased vulnerability to oxidative stress should be considered as an etiologic factor in the children with epilepsy. PMID- 30026765 TI - Neurological Manifestations of Primary Immunodeficiencies. AB - Objective: Primary immunodeficiencies (PID) are a heterogeneous group of disorders with a variable clinical spectrum of manifestations. The central nervous system may be involved in PID with symptoms which may present initially or develop at later stages. The purpose of this study was to review the neurological manifestations of different PID syndromes. Materials & Methods: We focused on 104 selected studies on PID with certain neurological abnormalities which may accompany these disorders or may later signify a PID in their course. Results: Diverse neurological deficits accompanying certain PIDs may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of these patients. Conclusion: Early recognition and treatment is important to prevent or reduce future irreversible neurological sequelae. Therefore physicians should be aware of the neurological features accompanying PID. PMID- 30026767 TI - Effect of Multi-sensory Stimulation on Neuromuscular Development of Premature Infants: A Randomized Clinical Trial. AB - Objectives: Preterm birth is considered as a risk factor for developmental disabilities, which can lead to long-term effects on the nervous system of children. The aim of this study was to determine the effect of multi-sensory stimulation on neurodevelopment of premature infants. Materials and Methods: In this two-group double-blind clinical trial in Jahrom Hospital, Jahrom, Iran from Jun to Aug 2016, 80 preterm infants were randomly divided. The intervention group received multisensory stimulation for 12 min per session, 5 sessions per wk along with routine NICU care and the control group received ward's routine care. Neuromuscular maturity for each infant was assessed by New Ballard Score. Data were analyzed using independent t-test. Results: Based on ANOVA with repeated measures, New Ballard score significantly changed in the intervention group before and after intervention (P= 0.001). This change was also significant in the control group (P=0. 04). However, the changes in New Ballard score were significantly different before and after intervention between the two groups (P=0.001). Conclusion: Multi-sensory stimulation can have beneficial effects on the development of neuromuscular in premature infants. PMID- 30026768 TI - Content Validity of the Comprehensive ICF Core Set for Children with Cerebral Palsy Aged 0-6 Years: Iranian Occupational Therapists Perspective. AB - Objectives: Comprehensive ICF Core Set of cerebral palsy (CP) includes a set of functions of children with CP has been created recently. This study determined the content validity of this version based on Iranian Occupational Therapists' perspectives to explore whether the ICF Core Sets for CP include the areas of function of CP in Occupational Therapy practice. Materials & Methods: This qualitative study conducted from Feb 2015 to Apr 2016 in Tehran, Iran. Experts were the academic staffs selected through convenience sampling. Content validity of comprehensive ICF-Core Set of CP with 135 ICF categories was done by them. Delphi survey was used for generating consensus on the final version. Participants were 50 clinical Occupational Therapists invited via email from across Iran. An agreement of 75% was considered as the cut-off for inclusion of each code-category. Results: About 60% of the code-categories of comprehensive version of ICF Core Set of CP were approved by Occupational Therapists. In the final version, 82 code-categories were listed that included 21 code-categories for Body Functions, 40 for Activity/Participation, and 21 for Environmental Factors. Conclusion: The validity of the Iranian ICF Core Set for children with CP aged 0-6 yr was supported by Iranian Occupational Therapists. It could be the basis for evaluation of this population in Occupational Therapy. PMID- 30026769 TI - Causes and Factors Associated with Neonatal Seizure and its Short-term Outcome: A Retrospective Prognostic Cohort Study. AB - Objective: Neonatal seizures are common, difficult to diagnose and treat, and associated with a great mortality rate and long-term risk of neurodevelopmental impairments. We aimed to determine the etiology, clinical presentation, and neurodevelopmental outcome of neonatal seizures. Materials and Methods: In this cross-sectional study, 88 neonates, aged < 28 days, admitted to Mofid Children's Hospital, Tehran, Iran, from September 2011 to 2013 with the initial diagnosis of seizure were enrolled by convenient sampling method. Data, including age, gestational age, birth weight, Apgar of the fifth minute, neonatal intensive care unit (NICU) admission, family history, type, cause, and age of seizure, EEG and paraclinic findings, anticonvulsant used for treatment, neurodevelopmental status, and the final outcome, were collected from medical records and the missed cases were completed by phone calls. The frequency and association of variables were analyzed using SPSS software. Results: Among neonates with seizures, 67% were male, 79.5% were born term, and 72.7% had normal birth weight. The most common type of seizure was multifocal clonic seizures (45.5%). The main diagnosis in neonates with seizures was hypoxic-ischemic encephalopathy (HIE) (23.9%) and hypoglycemia (10.22%). The mortality rate was 11.36% during a mean follow-up period of 21.4+/-6.4 months. Neurodevelopmental assessments showed that 64% were normal, 27% had global delay, and 9% had motor delay. Positive family history of epilepsy (P=0.006), low Apgar score (P=0.002) and epilepsy (P<0.001) were significantly associated with adverse neurodevelopmental outcome. Conclusion: Since HIE and hypoglycemia were the most common cause of neonatal seizures, efforts should be made to improve care during delivery and early breastfeeding. PMID- 30026770 TI - Comparison of Effectiveness of Topiramate and Diazepam in Preventing Risk of Recurrent Febrile Seizure in Children under Age of 2 Years. AB - Objective: Febrile seizures are the most common type of convulsions. Medicinal prophylaxis is sometimes used for children at high risk of recurrent febrile seizure. In certain circumstances, conventional drugs such as diazepam and phenobarbital cannot be used and the need for alternative medicines is felt. This study compared the effectiveness of topiramate and diazepam in preventing the risk of recurrent febrile seizure in children under 2 yr old. Materials and Methods: This randomized controlled trial, in Besat Hospital in Hamedan, Iran from 22 Nov 2013 to 22 Nov 2015 (Registered code: IRCT Number: IRCT2015010120527N1), included 54 patients, at risk of recurrent febrile seizure, inhibited from taking phenobarbital. Samples were randomly divided into two groups. The first group received diazepam treatment during fever episodes and the second group received daily dose of topiramate. A one-year follow-up of recurrent febrile seizure and its complications was also conducted. Results: Thirty-four patients (17 patients in each group) completed the one-year course of the trial. Recurrent febrile seizure was not observed in the course of preventive treatment. The prevalence of minor complications was 29.4% in the diazepam group and 48.5% in the topiramate group. No major complication was observed in among the subjects. Conclusion: Topiramate can be recommended for preventing recurrent febrile seizure when the use of frontline medicines is not possible. PMID- 30026771 TI - Investigating Brain MRI Findings in Children with Headache. AB - Objective: Migraine is a common headache associated with structural changes in brain. The purpose of this study was to evaluate brain MRI findings in children with migraine. Materials & Methods: This cross-sectional study was conducted at Booali Hospital, Mazandaran University of Medical Sciences, Sari, Iran. Participants with headache and age between 5 and 15 yr were evaluated with MRI and their headache type was diagnosed by the standard criteria. The findings of the MRI were interpreted by a radiologist blinded to the diagnoses. Results: Overall, 81 individuals with symptom of headache and the mean age of 9.56+/-3.25 yr were enrolled. Twenty patients with the mean age of 9.65+/-2.75 yr were diagnosed with migraine without aura. Among the 54 male patients, 8 patients (14.8%) were diagnosed with migraine; and among the 27 female patients, 12 patients (44.4%) were diagnosed with migraine (RR: 1.5, 95%CI: 1.07-2.18, P=0.004). Ten migraine patients had abnormal MRI findings (50%), including 8 cases with high signal white matter lesion, and 2 cases with empty sella. The occurrence of the high signal white matter lesions was significantly greater in the migraine patients (RR: 3.91, 95% CI: 2.10-7.25, P=0.001). Conclusion: The possibility of occurrence of the high signal white matter lesions in the brain MRI of children with migraine was significantly higher compared with other headache types. PMID- 30026772 TI - The Association between Failure to Thrive or Anemia and Febrile Seizures in Children between 6 Months to 6 Years Old Age. AB - Objectives: Febrile seizure is the most common seizure disorder in childhood. Anemia or failure to thrive can predispose children to febrile seizure by affecting the nervous system function. The current study investigated the association between febrile seizures and anemia or failure to thrive. Materials and Methods: This case-control study was performed on 307 children 6 months to 6 yr old age hospitalized at the Ali Asghar Children's Hospital, Tehran, Iran from 2011 to 2014 divided into two groups as follows: A case group including 158 children with febrile seizures and a control group including 149 febrile children without seizure. The amount of Hgb, Hct, RBC count, MCV, MCH, and MCHC was recorded and weight-for-age and weight-for-height was calculated based on the WHO Z-Score charts. The data were compared between two groups. Results: There were no differences regarding age and sex between the groups. Statistically significant differences were found regarding the mean RBC count between the case group (4.38*106 +/- 0.72*106) and the control group (4.24*106 +/- 0.84*106) (P=0.013), as well as about the mean MCV that was 78.73 +/- 0.97 and 76.78 +/- 1.00 in the case and control groups, respectively (P=0.005). Anemia was seen in 28.5% of the cases and 42.3% of control group which was statistically significant (P=0.012). There was not statistically significant difference regarding failure to thrive between two groups. Conclusion: In children with febrile seizures, anemia was lower comparing with febrile children without seizure. Moreover, there was not any association between failure to thrive and febrile seizures. PMID- 30026773 TI - Prediction of Response to Treatment in Children with Epilepsy. AB - Objective: This study was conducted to predict the response to treatment in patients treated with anti-epilepsy drugs. Material and Methods: This analytical questionnaire-based study was conducted in 2014 among 128 patients with epilepsy admitted to Mofid Children's Hospital, Tehran, Iran. The inclusion criteria were children 2 months to 12 yr of age with epilepsy and patients who experienced fever and seizure attacks at least once were excluded from the study. Patients were followed up for 6 months and the response to their treatment was recorded. The good response to treatment was defined as the absence of seizure with two drugs during follow up. Results: Seventy-two patients (56.3%) were boys. The age of the first seizure was under 2 yr old in 90 patients (70.3%). History of febrile convulsion, family history of epilepsy and history of asphyxia was found in 16 (12.5%), 41 (32%), and 27 (21.1%) patients, respectively. Seizure etiology was idiopathic in 90 patients (70.3%), and the number of seizures was 1-2 in 36 patients (28.1%). Overall, 57 patients (44.5%) had cerebral lesion according to CT scan or MRI, and EEG was abnormal in 101 patients (78.9%). In 6-month follow up, 40 patients (31.3%) responded well to the treatment and 88 patients (68.8%) responded poorly to the treatment. History of asphyxia (OR = 6.82), neonatal jaundice (OR = 2.81) and abnormal EEG (OR = 0.19) were effective factors in response to treatment. Conclusion: Abnormal EEG is an effective factor in treatment response in the children studied. PMID- 30026774 TI - The Prevalence of Psychological Disorders among Children with Diabetes Aged 5-12 Years Old Referred to the Endocrinology Clinic of Mofid Hospital, Tehran, Iran in 2014-2015. AB - Objective: As there were a few studies on the mental disorders resulting from diabetes in children, this study aimed at investigating the prevalence of psychological disorders among children. Materials & Methods: We enrolled 323 children with diabetes type 1 aged 5-12 yr old referring to Endocrinology Clinic of Mofid Hospital, Tehran, Iran in 2014-2015. In addition, 317 healthy children were considered as control group. The materials used for data analysis were information form and questionnaire CSI-4 filled out by their parents. The filled questionnaires were rated in that day and then analyzed and diagnosed by the Pediatric Psychiatrist in order to determine the type and intensity of psychological disorder. Results were analyzed using SPSS 20. T tests, Scheffe post hoc test and Pearson's correlation test were used for analysis of data. The amounts were significantly different at P<0.05. Results: In terms of Neuro Evolutionary disorders, Attention-deficit (ADD), hyperactivity (HD) and Attention deficit hyperactivity disorders (ADHD) in children with diabetes were significantly higher than those in healthy children (P=0.001). Severe fundamental depressive disorders were higher in diabetic children (P=0.001). In terms of anxiety disorder, a specific phobia and panic was significantly higher in diabetic children (P=0.005). Regarding aggressive behaviors, diabetic children were more disobedient and stubborn than the others. Conclusion: The prevalence of psychological disorders among diabetic children was higher than that of the others. As psychological disorders will effect on the life quality of children, improvement of life quality of diabetic children and adolescents, on-time diagnosis and treatment of psychological disorders in these patients seems essential. PMID- 30026775 TI - A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature. AB - Beta-ketothiolase deficiency is a rare autosomal recessive disorder characterized by an inborn error of isoleucine catabolism and affecting ketone body metabolism. Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients, with an onset during infancy or toddler-hood. A two months old girl presented to pediatric ward of Imam Reza Hospital in Mashhad City, Northwestern Iran in October 2016, with acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma, few days after vaccination. After then similar episodes happened until 7 months age. Bio chemical tests that suggested diagnose of beta ketothiolase deficiency were attacks of ketoacidosis with urinary exertion of 2-methyl-3-hydroxybutyric acid 2 methyl aceto acetic acid tiglylglycine. In genetic assessment, we detected a novel homozygous mutation c.664A> C (p. Ser 222 Arg) in ACAT gene. This is the first report of beta ketothiolase deficiency confirmed by molecular analysis from Iran. We report on a homozygous variant in the ACAT1 gene and that is a novel mutation. We recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members. PMID- 30026776 TI - Chronic Myelogenous Leukemia Presenting with Facial Nerve Palsy in an Infant. AB - When a child presents with cranial nerve palsy and a bulging fontanel, a pediatric neurologist is often consulted to determine the cause of increased intracranial pressure. This report describes an infant with chronic myelogenous leukemia (CML) referred to Ali-bin-Abitaleb Hospital, Zahedan, eastern Iran in 2013 who presented with seventh cranial nerve palsy and bulging fontanel. Chromosomal analysis and peripheral blood smear confirmed the diagnosis of CML. PMID- 30026777 TI - Early Onset Cerebral Infarction in Schimke Immuno-Osseous Dysplasia. AB - Schimke Immuno-osseous Dysplasia (SIOD) is a rare autosomal recessive disease caused by a biallelic mutation in SMARCAL1 gene. Typical findings in SIOD include spondylo-epiphyseal dysplasia, steroid resistance nephrotic syndrome, progressive renal failure, T-cell immunodeficiency, bone marrow failure, and cerebral infarction. In this case report, we describe a 9-yr-old girl who presented with failure to thrive in infancy. Nephrotic syndrome was diagnosed at the age of four years. She had three episodes of admission with cerebral stroke due to moyamoya syndrome. In the last admission at Namazi Hospital, Shiraz, southern Iran, in October 2016, she had new cerebral ischemia, developed seizure, and finally died. PMID- 30026778 TI - Guillain-Barre syndrome in a Child with Ongoing Viral Hepatitis A. AB - Guillain-Barre syndrome (GBS) belongs to the group of peripheral immune-mediated neuropathies often preceded by an inflammatory episode. GBS is rarely associated with hepatitis A virus (HAV) infection, the latter as a rule antecedent of the neurological disorders. This association is quite rare in childhood, and so far, only isolated cases have been described. We report an unusual case of pediatric GBS which development coincided with the development of HAV IgM (+) viral hepatitis A. From the second to the 14th day after admission to the hospital for mild jaundice of the skin and sclera in a 12-yr-old boy, the following neurological disorders have developed: absent Achilles and knee-jerk reflexes, diminished brachioradialis reflex, moderately decreased muscle power in the upper extremities and more pronounced power loss in the lower extremities. Facial palsy developed bilaterally, more expressed to the right. There was albuminocytologic dissociation of the cerebrospinal fluid and electrodiagnostic study showed findings compatible with the GBS subdivision - Acute inflammatory demyelinating polyneuropathy (AIDP). HAV could trigger GBS in the very beginning of liver inflammation in children. This insight may help wide range of medical professionals to early recognize and treat the peripheral neuropathy. PMID- 30026779 TI - Commentary on "Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism. PMID- 30026780 TI - Delta3,2-Hydroxybakuchiol Attenuates Depression in Multiple Rodent Models Possibly by Inhibition of Monoamine Transporters in Brain. AB - Delta3,2-Hydroxybakuchiol is isolated from Psoralea corylifolia (L.), which has therapeutic applications in traditional Chinese medicine. Our previous studies have showed that Delta3,2-hydroxybakuchiol inhibited the decreased activity of reserpinized mice, suggestive of its antidepressive potential. In this study, we explored the antidepressant profile of Delta3,2-hydroxybakuchiol in various rodent models and its possible monoamine-modulating mechanism. Delta3,2 Hydroxybakuchiol significantly reduced immobility time of mice in forced swim test and tail suspension test. Delta3,2-Hydroxybakuchiol also significantly increased sucrose consumption in chronic unpredictable mild stress (CUMS) rat model. Furthermore, isotope uptake study showed that Delta3,2-hydroxybakuchiol inhibited the activity of human dopamine transporter (DAT) and norepinephrine transporter (NET) in transporter-overexpressing pheochromocytoma (PC12) cells with IC50 values similar to the potency of bupropion. Microdialysis showed that Delta3,2-hydroxybakuchiol increased dopamine and norepinephrine concentration in rat striatum. In summary, Delta3,2-hydroxybakuchiol exerts antidepressant effects on various types of depression models through a possible mechanism of monoamine transporter inhibition. PMID- 30026781 TI - Development of Novel Photosensitizer Using the Buddleja officinalis Extract for Head and Neck Cancer. AB - Photodynamic therapy (PDT) is generally safer and less invasive than conventional strategies for head and neck cancer treatment. However, currently available photosensitizers have low selectivity for tumor cells, and the burden and side effects are so great that research is needed to develop safe photosensitizers. In this study, it was confirmed that the Buddleja officinalis (BO) extract, used in the treatment of inflammation and vascular diseases, shows fluorescence when activated by LED light, and, based on this, we aimed to develop a new photosensitive agent suitable for PDT. MTT, Diff-Quick(r) staining, and DCF-DA were performed to measure the effects of treating head and neck cancer cells with BO extract and 625 nm LED light (BO-PDT). Cell cycle, TUNEL, and western blot assays, as well as acridine orange staining, were performed to explore the mechanism of BO-PDT-induced cell death. We found that when the BO extract was irradiated with 625 nm LED light, it showed sufficient fluorescence and stronger intracellular toxicity and ROS effect than the currently commercially available hematoporphyrin. BO-PDT resulted in a decrease of mTOR activity that was correlated with an increase in the levels of ATG5, beclin-1, and LC3-II, which interfere with the formation of autophagosomes. In addition, BO-PDT induced the activation of PARP and led to an increase in the expression of proapoptotic protein Bax and a decrease in the expression of the antiapoptotic protein Bcl-2. Moreover, BO-PDT has been shown to induce the autophagy pathway 4 h after treatment, while apoptosis was induced 16 h after treatment. Finally, we confirmed that BO-PDT caused cell death of head and neck cancer cells via the intrinsic pathway. Therefore, we suggest that BO extract can be used as a new photosensitizer in PDT of head and neck cancer. PMID- 30026782 TI - Antiobesity and Antioxidant Potentials of Selected Palestinian Medicinal Plants. AB - We evaluated the antioxidant and porcine pancreatic lipase inhibition (PPLI) activities of 90 plants extracts. The antioxidant activity was measured using the free-radical scavenging capacity (DPPH) and reducing power (RP) assays. The pancreatic lipase inhibition assay was used to determine the PPLI activity of plant extracts. Among the 90 plant extracts examined, 41.0 % crude extracts showed antilipase activity of more than 50%. The most active plants by means of IC50 value were Camellia sinensis (0.5 mg/ml), Ceratonia siliqua (leaves) (0.8 mg/mL), Curcuma longa (0.8 mg/mL), Sarcopoterium spinosum (1.2 mg/mL), and Mentha spicata (1.2 mg/mL). The antioxidant activity of plant extracts using the DPPH and RP assays reveals comparable results. The most active antioxidant extracts using both assays were the leaves and fruit epicarp of Rhus coriaria, areal parts of Sarcopoterium spinosum, and leaves of Ceratonia siliqua. Our results suggest natural resources that possess strong antioxidant and pancreatic lipase inhibitory activities with potential applications in the treatment and prevention of obesity and overweight. The extracts of Camellia sinensis, Ceratonia siliqua, Curcuma longa, Sarcopoterium spinosum, and Mentha spicata were proved to have a great potential as antioxidants and antiobesity agents. PMID- 30026783 TI - ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications. AB - Background: End-stage renal disease (ESRD) causes premature ageing of the immune system. However, it is not known whether hemodialysis (HD) and peritoneal dialysis (PD) similarly affect the T cell system. Methods: The aim of our study was to analyse whether dialysis modality may mitigate ESRD-induced immune senescence. We explored a large population of patients (675 ESRD patients) and both confirmed and refined the results in a second cohort (84 patients). Results: HD patients exhibited higher inflammatory monocytes counts (44/mm3 (1-520) vs 36/mm3 (1-161); p = 0.005). Patients on HD also had higher frequency of CD8 T cells (24% (7-61) vs 22% (8-42); p = 0.003) and reduced CD4/CD8 ratio. Such results were confirmed in the second cohort. Moreover, both CD4 + CD57 + CD28- (3.25% (0-38.2) vs 1.05% (0-28.5); p = 0.068) and CD8 + CD57 + CD28- (38.5% (3.6 76.8) vs 26.1 (2.1-46.9); p = 0.039) T cells frequencies were increased in HD patients. Telomere length did not differ according to dialysis modality, but was inversely related to ferritin levels (r = - 0.33; p = 0.003). There was a trend towards higher telomerase activity in PD patients (11 +/- 13 vs 6 +/- 11; p = 0.053). Thymic function was not different in PD and HD patients. Patients on PD before transplantation had a higher risk of acute rejection after kidney transplantation (HR, 1.61; 95%CI, 1.02 to 2.56; p = 0.041). Conclusions: More pronounced inflammation with hemodialysis may induce premature aging of the immune system. This observation correlates with a lower risk of acute kidney rejection in patients previously on HD. Clinical consequences in patients maintained on dialysis should be determined. Trial registration: Trial registration: NCT02843867, registered July 8, 2016. PMID- 30026784 TI - Changes in lysophospholipids and liver status after weight loss: the RESMENA study. AB - Background: Obesity and comorbidities such as non-alcoholic fatty liver disease (NAFLD) are major public health burdens. Alterations in lipid metabolism are involved in hepatic diseases. The objective of this study was to assess the influence of weight loss on lysophospholipid (LP) metabolism and liver status in obese subjects as well as to provide new evidence regarding the interaction of LP metabolism as a key factor in the onset and management of obesity-related diseases such as liver damage. Methods: Thirty-three subjects from the RESMENA (Reduction of Metabolic Syndrome in Navarra, NCT01087086) study were selected based on their Fatty Liver Index (FLI). Plasma lipid species (lysophosphatidilcholine: LPC, lysophosphatidilethanolamines: LPE and lysophosphatidylinositols: LPI specifically) were determined by LC-MS, while waist circumference (WC) and other non-invasive liver markers such as, FLI and BAAT scores as well as dietary records, anthropometrical measurements, body composition by DXA and other metabolic determinants were analyzed before and after a six-month hypocaloric nutritional intervention. Results: Computed Z scores of total LP (LPC, LPE, and LPI) were significantly decreased after 6 months of following a hypocaloric diet. Specifically, LPC14:0, LPC15:0, LPC16:1, LPC18:4, LPC20:4, showed clear relationships with weight loss. Changes in FLI score, WC and BAAT score revealed associations with general changes in LPC score. Interestingly the BAAT score was statistically associated with the LPC score after adjustment for weight loss. Conclusion: The lipidomic LPC profile analysis revealed a generalized decrease in circulating lysophospholipids after weight loss. The involvement of particular LP in liver metabolism and obesity merit further attention, as some of these specific non-invasive liver markers were reduced independently of weight loss. Trial registration: NCT01087086. Registered 15 March 2010, retrospectively registry. PMID- 30026785 TI - PPARG2 Pro12Ala polymorphism influences body composition changes in severely obese patients consuming extra virgin olive oil: a randomized clinical trial. AB - Background: Previous intervention studies have reported the association of the PPARG2 Pro12Ala (rs1801282) and IL6 -174G > C (rs1800795) polymorphisms with weight loss; however, their results are inconsistent. We aimed to investigate the effect of the PPARG2 Pro12Ala and IL6 -174G > C polymorphisms on body weight, body composition and metabolic parameters after a 12-week nutritional intervention with a traditional Brazilian diet and extra virgin olive oil supplementation in severely obese patients. Methods: A total of 149 severely obese individuals [body mass index (BMI) >= 35 kg/m2] were randomized into three 12-week nutritional intervention groups - the extra virgin olive oil supplementation (OO) group (n = 50), the traditional Brazilian diet (DieTBra) group (n = 49), and the DieTBra plus extra virgin olive oil supplementation (DieTBra+OO) group (n = 50). Anthropometric measurements, body composition, metabolic parameters, physical activity practise and dietary intake were assessed. The associations were tested using generalized linear models adjusted for confounders. Results: The PPARG2 Pro12Ala polymorphism influenced body composition changes. Ala carriers in the intervention groups with extra virgin olive oil supplementation had greater reductions in the percentage of body fat (%BF) (OO: p = 0.049, DietBra+OO: p = 0.004) and greater increases in both fat free mass (FFM) (OO: p = 0.020, DieTBra: p = 0.007) and lean mass (LM) (OO: p = 0.020, DieTBra+OO: p = 0.007) than did ProPro homozygotes. No association was found for the IL6 -174G > C polymorphism. Conclusions: Extra virgin olive oil intake may modulate favourable body composition changes, promoting a decrease in the %BF and increases in the LM and FFM of severely obese individuals, even without weight loss, in the presence of the Ala allele of the Pro12Ala polymorphism. Trial registration: Registered under ClinicalTrials.gov Identifier No. NCT02463435. PMID- 30026786 TI - Exclusive breastfeeding practice in Ethiopia and its association with antenatal care and institutional delivery: a systematic review and meta-analysis. AB - Background: Despite the World Health Organization recommendation of exclusive breastfeeding (EBF) for the first six months of life, the rate remains low both in developed and developing countries. In Ethiopia, findings regarding the prevalence of EBF have been highly variable. Antenatal care and institutional delivery are the most important factors contributing to the practice of EBF however; their effect has not been investigated in Ethiopia. Methods: In this systematic review and meta-analysis, international databases were systematically searched. All observational studies reporting the prevalence of EBF and its association with antenatal care and institutional delivery in Ethiopia were considered. Two authors independently extracted all necessary data using a standardized data extraction format. A random effects meta-analysis model was computed to estimate the pooled prevalence of exclusive breastfeeding. Moreover, the association of antenatal care and institutional delivery with EBF was determined. Results: After reviewing 619 studies, 32 studies fulfilled the inclusion criteria and were included in the meta-analysis. The pooled prevalence of EBF in Ethiopia was 59.3% (95% Confidence Interval [CI] 53.8, 64.8). The subgroup analysis indicated that the highest prevalence was observed in Afar region (65.6%), followed by SNNP (63.8%), and then by Oromia (61.8%). Additionally, mothers who attended antenatal visits were 2.1 times more likely to practice EBF compared to their counterparts (Odds Ratio [OR] 2.1; 95% CI 1.5, 2.8). Moreover, mothers who gave birth at a health institution were 2.2 times more likely to practice EBF compared to mothers who gave birth at home (OR 2.2; 95% CI 1.3, 3.5). Conclusions: Exclusive breastfeeding in Ethiopia was significantly lower than the global recommendations. There was evidence that mothers who attended antenatal visits and who gave birth at health institutions had better EBF practices. Based on our findings, we strongly recommended that the utilization of antenatal care and institutional delivery should be improved through health extension workers. PMID- 30026787 TI - The effect of mother and newborn early skin-to-skin contact on initiation of breastfeeding, newborn temperature and duration of third stage of labor. AB - Background: Mother and newborn skin-to-skin contact (SSC) after birth brings about numerous protective effects; however, it is an intervention that is underutilized in Iraq where a globally considerable rate of maternal and child death has been reported. The present study was conducted in order to assess the effects of SCC on initiation of breastfeeding, newborn temperature, and duration of the third stage of labor. Methods: A quasi-experimental study was conducted on 108 healthy women and their neonates (56 in the intervention group who received SSC and 52 in the routine care group) at Hawler maternity teaching hospital of Erbil, Iraq from February to May, 2017. Data were collected via structured interviews and the LATCH scale to document breastfeeding sessions. Results: The mean age of the mothers in the SSC and routine care groups were 26.29 +/- 6.13 (M +/- SD) and 26.02 +/- 5.94 (M +/- SD) respectively. Based on the LATCH scores, 48% of mothers who received SSC and 46% with routine care had successful breastfeeding. Newborns who received SSC initiated breastfeeding within 2.41 +/- 1.38 (M +/- SD) minutes after birth; however, newborns who received routine care started breastfeeding in 5.48 +/- 5.7 (M +/- SD) minutes. Duration of the third stage of labor in mothers who practiced SSC after birth was 6 +/- 1.7 min, compared to 8.02 +/- 3.6 min for mothers who were provided with routine care (p < 0.001). Moreover, the prevalence of hypothermia in the newborns who received SSC and routine care was 2 and 42% respectively. Results remained unchanged after using regression modelling to adjust for potential factors and background characteristics. Conclusion: Skin-to-skin contact provides an appropriate and affordable yet high quality alternative to technology. It is easily implemented, even in small hospitals of very low-income countries, and has the potential to save newborns' and mothers' lives. It is necessary to prioritize training of health providers to implement essential newborn care including SSC. Community engagement is also needed to ensure that all women and their families understand the benefits of SSC and early initiation of breastfeeding. Trial registration: ClinicalTrials.gov: NCT03548389. PMID- 30026788 TI - Differentiation between closely-related Impatiens spp. and regional biotypes of Impatiens glandulifera using a highly-simplified and inexpensive method for MALDI TOF MS. AB - Background: Matrix-assisted laser-desorption and ionisation time-of-flight mass spectroscopy (MALDI-TOF MS) is a powerful tool for the characterisation and/or identification of protein-containing samples. Several MALDI-TOF MS sample preparation methods are currently available but few of these are well suited to the analysis of plant material. We have recently developed a simple, rapid, and relatively-cheap method for MALDI-TOF MS that is applicable to plant material (in addition to microbial and insect material), and our aim in this study was to distinguish between closely-related plant species and/or between regional biotypes within an invasive weed species using this method with a view to optimising the selection of biological control agents that can be used for weed management. Results: We have employed a combination of principal-component analysis and closest-relatedness diagrams derived from MALDI-TOF MS spectral comparison data to discriminate between the closely-related Impatiens spp. Impatiens noli-tangere, Impatiens parviflora, Impatiens scabrida, Impatiens balsamina, and two regional biotypes of the invasive weed Impatiens glandulifera. We have also developed a method for sample discrimination based upon comparison between blind-test MALDI-TOF MS spectra and reference-sample spectra. Using this latter method, we have been able to discriminate on the basis of the acid-soluble protein mass spectra generated between four regional biotypes of I. glandulifera that differ in their susceptibility to the biological control agent Himalayan balsam rust (Puccinia komarovii var. glanduliferae) using mature leaf material. Using younger leaves, discrimination was not possible between these four regional biotypes. Conclusions: MALDI-TOF MS analysis is able to discriminate between closely-related plant species within the genus Impatiens and between regional biotypes of I. glandulifera. Because of this, MALDI-TOF MS holds great promise for improving weed biological control, a management technique which uses highly specific co-evolved natural enemies for the control of an invasive non-native plant species, through the optimal matching of biological control agents with susceptible target species/regional biotypes. PMID- 30026789 TI - Factors affecting the efficiency of Rhizobium rhizogenes root transformation of the root parasitic plant Triphysaria versicolor and its host Arabidopsis thaliana. AB - Background: Rhizobium rhizogenes transformation is commonly used to generate transgenic roots traditionally called hairy roots, for both investigative and commercial applications. While fertile plants can be regenerated from transgenic roots, the transgenic roots are more typically used directly, either to investigate root biology or to produce valuable secondary metabolites. Hairy roots have been particularly useful for genetic studies of rhizosphere interactions; including the recognition of host plant roots by the roots of parasitic angiosperms. Results: In this manuscript we analyzed various environmental, nutritional and procedural conditions for their effects on transformation of the model hemi-parasitic plant Triphysaria versicolor and Arabidopsis thaliana, one of its hosts. We first examined the effects of media, gelling agents and co-incubation times on Triphysaria root transformation and determined that while all three affected transformation rates, the media were the most significant. Once those primary conditions were fixed, we examined the roles of seedling age, explant type, acetosyringone, temperature and illumination on Triphysaria hairy root transformation rates. Using the optimized procedure approximately 70% of Triphysaria seedlings developed transgenic roots as judged by expression of YFP. These conditions were then used to transform Arabidopsis and similar transformation rates were obtained. Conclusions: Analyses of root transformation factors provides a method recovering transgenic roots from both parasitic plants and their hosts at high frequency. In addition to providing an effective in vitro approach for genetic investigations of parasitic plant-host plant interactions, these results are applicable to genetic studies of non parasitic plants as well. PMID- 30026790 TI - Microinvasive Glaucoma Surgery: An Evidence-Based Assessment. AB - Introduction: The advent of Microinvasive Glaucoma Surgery (MIGS) offers a novel approach in the treatment of glaucoma with the number of procedures developing at an exciting pace. Areas Covered: MIGS procedures aim to lower intraocular pressure (IOP) via four mechanisms: (1) increasing trabecular outflow, (2) increasing outflow via suprachoroidal shunts, (3) reducing aqueous production, and (4) subconjunctival filtration. A comprehensive search for published studies for each Microinvasive Glaucoma Surgery (MIGS) device or procedure was undertaken using the electronic database PubMed. Search terms included 'minimally invasive glaucoma surgery', 'microincisional glaucoma surgery', and 'microinvasive glaucoma surgery'. A manual search for each device or procedure was also performed. After review, randomized control trials and prospective studies were preferentially included. Expert Opinion: These procedures offer several benefits: an improved safety profile allowing for intervention in earlier stages of glaucoma, combination with cataract surgery, and decreased dependence on patient compliance with topical agents. Established MIGS procedures have proven efficacy and more recent devices and procedures show promising results. Despite this, further study is needed to assess the long term IOP-lowering effectiveness of these procedures. Particularly, rigorous study with more randomized control trials and head-to-head comparisons would allow for better informed clinical and surgical decision-making. MIGS offers new solutions for glaucoma treatment. PMID- 30026791 TI - Split-inducing indels in phylogenomic analysis. AB - Background: Most phylogenetic studies using molecular data treat gaps in multiple sequence alignments as missing data or even completely exclude alignment columns that contain gaps. Results: Here we show that gap patterns in large-scale, genome wide alignments are themselves phylogenetically informative and can be used to infer reliable phylogenies provided the gap data are properly filtered to reduce noise introduced by the alignment method. We introduce here the notion of split inducing indels (splids) that define an approximate bipartition of the taxon set. We show both in simulated data and in case studies on real-life data that splids can be efficiently extracted from phylogenomic data sets. Conclusions: Suitably processed gap patterns extracted from genome-wide alignment provide a surprisingly clear phylogenetic signal and an allow the inference of accurate phylogenetic trees. PMID- 30026792 TI - Prevalence of CagA and antimicrobial sensitivity of H. pylori isolates of patients with gastric cancer in Egypt. AB - Background: Helicobacter pylori (H. pylori) infection has been recognized as a significant threat for gastric cancer. However, studies that investigated the oncogenic factors and antimicrobial resistance of H. pylori in Egyptian isolates with gastric cancer are rare. The current study aimed to examine: (1) The pattern of antimicrobial resistance of H. pylori isolates of Egyptian gastric cancer patients, and (2) the prevalence of Cytotoxin-associated gene A (CagA). Methods: Samples were collected from patients with gastric cancer. Isolation of H. pylori was performed using Columbia blood agar supplemented with 10% horse blood, and selective supplement of H. pylori for 3 to 5 days at 37 degrees C under microaerophilic condition. Isolates were identified by biochemical traits of H. pylori: oxidase, urease and catalase tests. Antimicrobial susceptibility of H. pylori isolates was examined against five antimicrobial agents using disc diffusion method. After that, extraction of DNA and Polymerase Chain Reaction (PCR) were performed to amplify the target genes. Results: Twelve samples were collected from six males and six females Egyptian patients with cancer with an age range from 22 to 65 years. These cases are scarce and samples were collected over a period of almost eleven months. All isolates were confirmed as positive H. pylori through colony morphology and biochemical tests. The most effective antibiotic found was ciprofloxacin whereas all isolates showed resistance to metronidazole and erythromycin. The target CagA oncogene gene with expected product size was reported and seven (out of twelve) isolates (58%) were identified as CagA positive. Conclusion: The current study is unique in two main aspects. First, it reported the pattern of antimicrobial susceptibility and prevalence of CagA gene in H. pylori from Egyptian patients. Second, it exclusively recruited isolates from gastric cancer patients which were confirmed by clinical and laparoscopic examination. The moderately high prevalence of CagA gene in Egyptian cancer patients calls for more vigilance against that oncogene. PMID- 30026793 TI - Tuberculosis contact-tracing among Syrian refugee populations: lessons from Jordan. AB - Background: In response to the influx of displaced Syrians since 2011, the Jordanian National Tuberculosis Program (NTP) implemented a specific Tuberculosis (TB) reduction strategy, including contact-tracing (CT). Contacts of all refugees diagnosed with pulmonary TB (PTB) were registered by the International Organization for Migration and screened for active & latent TB infection (LTBI) in 6 NTP centres.The objectives of this study were to assess prevalence of active TB and LTBI, risk factors for LTBI as well as program performance. Methods: We performed a retrospective study among contacts (N = 481) of all PTB cases diagnosed between March 2011 and May 2014 (N = 76). CT was performed using verbal screening of TB-related symptoms, tuberculin skin test (TST) and chest X-ray. Results: LTBI was diagnosed in 24.1% of contacts tested with TST while active TB was diagnosed in 2.1% of contacts. Main risk factors for positive TST included smear-positive index case (IC) (OR: 6.33) and previous TB infection in the family (OR: 4.94). Among children, the risk of LTBI was higher when their IC was a care giving female (OR: 2.83). Prevalence of active TB was two times higher in children under five (U5 s) (5.3%) compared to adults (2.5%). Conclusion: We found a high prevalence of active TB and LTBI among contacts of PTB cases in the Syrian refugee population, emphasizing the urgent need for host countries to implement CT strategies for refugees. Our results underscore the vulnerability of U5s and contacts of smear-positive IC highlighting the need for specific actions focusing on those groups. PMID- 30026794 TI - Barriers to cardiovascular disease secondary prevention care in the West Bank, Palestine - a health professional perspective. AB - Background: Non-communicable diseases (NCDs) - including cardiovascular disease (CVD), cancer and diabetes - have become a significant global burden on health. Particularly concerning are CVD rates, causing approximately 18 million deaths worldwide every year. The statistics show that the disease is no longer a predominantly high-income country phenomenon, but affects, increasingly, countries in both developing regions and conflict-affected areas. In the occupied Palestinian territory (oPt), the focus of this article, CVD ranks top of ten NCD killers, accounting for approximately 37.6% of deaths. Key risk factors discerned in primary care settings have been related to both structural determinants (i.e. the Israeli occupation) and individual behavioural factors. Unfortunately, no data are available for secondary care settings in the region and, consequently, little is known about patients and their capacity for risk factor behaviour change to manage their CVD.To begin closing this gap in knowledge, our study provides insight into cardiovascular disease secondary prevention care with the overall aim to enhance the understanding of the complexities of managing NCDs like CVD in conflict-affected settings. Specifically, research was carried out among Palestinian health professionals who specialise in coronary artery disease in the West Bank to elicit their views on (a) how socio-political, health system and individual behavioural factors might hinder patients to change their health behaviour and impact on the provision of healthcare and (b) possible solutions for overcoming identified barriers to behaviour change on societal as well as individual-patient levels within secondary care provision in a context of protracted conflict. Methods: This study is based on a qualitative approach in order to provide more in-depth information about health beliefs and behaviours, experiences and views of health professionals with regards to CVD secondary care. In total, 12 semi-structured interviews were conducted among doctors providing treatment to patients with CVD in secondary care settings. Interviews focused on health professionals' perspectives on risk factors and perceived barriers to behaviour change among known CVD patients receiving secondary care. Interviewees were also asked to propose possible actions that could be taken to overcome the identified barriers at both societal and individual patient levels. All interviews were digitally recorded, transcribed and analysed using thematic analysis. Results: Study results confirmed our prior theory of the complex entanglement of socio-political, health system and individual-level factors with regards to CVD experience, health-seeking and treatment. Also confirmed was our assumption that it is crucial to understand experts' definitions and approaches to treatment in order to grasp their visions for appropriate and improved prevention and treatment options. In particular, study participants highlighted how political determinants, notably the detrimental impact of the Israeli occupation, and social determinants, directly and indirectly influence behavioural determinants due to physical and bureaucratic barriers to accessing health facilities, economic hardship and chronic stress. These stressors, in turn, were perceived as having a negative effect on individual behavioural risk factors including smoking, unhealthy diet and an increasingly sedentary lifestyle. Proposed solutions included more focused interventions from the Ministry of Health as well as surveillance, primary prevention and health promotion, and management to positively effect behaviour change in order to address the growing burden of CVD in the region. Conclusions: The study has highlighted medical professionals' perceptions of how structural and individual behavioural determinants influence their own and individual patient's abilities to manage cardiovascular risk factors in a setting affected by chronic conflict. Consequently, we propose that medical and social intervention strategies generally used to address CVD risk, be strategically adapted in order to be useful and effective in contexts of armed conflict. Specifically, we call for a solid understanding of the socio-political context and existing health services as well as health providers' and patients' health beliefs and related behaviours when developing future health options aimed at addressing CVD in the region. Moreover, for health provision to be effective as well as sustainable, attention needs to be given above all towards a solution for political change. PMID- 30026795 TI - Next-generation conservation genetics and biodiversity monitoring. AB - This special issue of Evolutionary Applications consists of 10 publications investigating the use of next-generation tools and techniques in population genetic analyses and biodiversity assessment. The special issue stems from a 2016 Next Generation Genetic Monitoring Workshop, hosted by the National Institute for Mathematical and Biological Synthesis (NIMBioS) in Tennessee, USA. The improved accessibility of next-generation sequencing platforms has allowed molecular ecologists to rapidly produce large amounts of data. However, with the increased availability of new genomic markers and mathematical techniques, care is needed in selecting appropriate study designs, interpreting results in light of conservation concerns, and determining appropriate management actions. This special issue identifies key attributes of successful genetic data analyses in biodiversity evaluation and suggests ways to improve analyses and their application in current population and conservation genetics research. PMID- 30026797 TI - Impact of supplementation on deleterious mutation distribution in an exploited salmonid. AB - Deleterious mutations have important implications for the evolutionary trajectories of populations. While several studies recently investigated the dynamics of deleterious mutations in wild populations, no study has yet explored the fate of deleterious mutations in a context of populations managed by supplementation. Here, based on a dataset of nine wild and 15 supplemented Lake Trout populations genotyped at 4,982 single nucleotide polymorphisms (SNP)s by means of genotype by sequencing (GBS), we explored the effect of supplementation on the frequency of putatively deleterious variants. Three main findings are consequential for the management of fish populations. First, an increase in neutral genetic diversity in stocked populations compared with unstocked ones was observed. Second, putatively deleterious mutations were more likely to be found in unstocked than in stocked populations, suggesting a lower efficiency to purge deleterious mutations in unstocked lakes. Third, a population currently used as a major source for supplementation is characterized by several fixed putatively deleterious alleles. Therefore, other source populations with lower abundance of putatively deleterious mutations should be favored as sources of supplementation. We discuss management implications of our results, especially pertaining to the joint identification of neutral and deleterious mutations that could help refining the choice of source and sink populations for supplementation in order to maximize their evolutionary potential and to limit their mutation load. PMID- 30026796 TI - Guidelines for planning genomic assessment and monitoring of locally adaptive variation to inform species conservation. AB - Identifying and monitoring locally adaptive genetic variation can have direct utility for conserving species at risk, especially when management may include actions such as translocations for restoration, genetic rescue, or assisted gene flow. However, genomic studies of local adaptation require careful planning to be successful, and in some cases may not be a worthwhile use of resources. Here, we offer an adaptive management framework to help conservation biologists and managers decide when genomics is likely to be effective in detecting local adaptation, and how to plan assessment and monitoring of adaptive variation to address conservation objectives. Studies of adaptive variation using genomic tools will inform conservation actions in many cases, including applications such as assisted gene flow and identifying conservation units. In others, assessing genetic diversity, inbreeding, and demographics using selectively neutral genetic markers may be most useful. And in some cases, local adaptation may be assessed more efficiently using alternative approaches such as common garden experiments. Here, we identify key considerations of genomics studies of locally adaptive variation, provide a road map for successful collaborations with genomics experts including key issues for study design and data analysis, and offer guidelines for interpreting and using results from genomic assessments to inform monitoring programs and conservation actions. PMID- 30026799 TI - Theory, practice, and conservation in the age of genomics: The Galapagos giant tortoise as a case study. AB - High-throughput DNA sequencing allows efficient discovery of thousands of single nucleotide polymorphisms (SNPs) in nonmodel species. Population genetic theory predicts that this large number of independent markers should provide detailed insights into population structure, even when only a few individuals are sampled. Still, sampling design can have a strong impact on such inferences. Here, we use simulations and empirical SNP data to investigate the impacts of sampling design on estimating genetic differentiation among populations that represent three species of Galapagos giant tortoises (Chelonoidis spp.). Though microsatellite and mitochondrial DNA analyses have supported the distinctiveness of these species, a recent study called into question how well these markers matched with data from genomic SNPs, thereby questioning decades of studies in nonmodel organisms. Using >20,000 genomewide SNPs from 30 individuals from three Galapagos giant tortoise species, we find distinct structure that matches the relationships described by the traditional genetic markers. Furthermore, we confirm that accurate estimates of genetic differentiation in highly structured natural populations can be obtained using thousands of SNPs and 2-5 individuals, or hundreds of SNPs and 10 individuals, but only if the units of analysis are delineated in a way that is consistent with evolutionary history. We show that the lack of structure in the recent SNP-based study was likely due to unnatural grouping of individuals and erroneous genotype filtering. Our study demonstrates that genomic data enable patterns of genetic differentiation among populations to be elucidated even with few samples per population, and underscores the importance of sampling design. These results have specific implications for studies of population structure in endangered species and subsequent management decisions. PMID- 30026798 TI - Next-generation metrics for monitoring genetic erosion within populations of conservation concern. AB - Genetic erosion is a major threat to biodiversity because it can reduce fitness and ultimately contribute to the extinction of populations. Here, we explore the use of quantitative metrics to detect and monitor genetic erosion. Monitoring systems should not only characterize the mechanisms and drivers of genetic erosion (inbreeding, genetic drift, demographic instability, population fragmentation, introgressive hybridization, selection) but also its consequences (inbreeding and outbreeding depression, emergence of large-effect detrimental alleles, maladaptation and loss of adaptability). Technological advances in genomics now allow the production of data the can be measured by new metrics with improved precision, increased efficiency and the potential to discriminate between neutral diversity (shaped mainly by population size and gene flow) and functional/adaptive diversity (shaped mainly by selection), allowing the assessment of management-relevant genetic markers. The requirements of such studies in terms of sample size and marker density largely depend on the kind of population monitored, the questions to be answered and the metrics employed. We discuss prospects for the integration of this new information and metrics into conservation monitoring programmes. PMID- 30026801 TI - Multifaceted DNA metabarcoding: Validation of a noninvasive, next-generation approach to studying bat populations. AB - As multiple species of bats are currently experiencing dramatic declines in populations due to white-nose syndrome (WNS) and other factors, conservation managers have an urgent need for data on the ecology and overall status of populations of once-common bat species. Standard approaches to obtain data on bat populations often involve capture and handling, requiring extensive expertise and unavoidably resulting in stress to the bats. New methods to rapidly obtain critical data are needed that minimize both the stress on bats and the spread of WNS. Guano provides a noninvasive source of DNA that includes information from the bat, but also dietary items, parasites, and pathogens. DNA metabarcoding is a high-throughput, DNA-based identification technique to assess the biodiversity of environmental or fecal samples. We investigated the use of multifaceted DNA metabarcoding (MDM), a technique combining next-generation DNA sequencing (NGS), DNA barcodes, and bioinformatic analysis, to simultaneously collect data on multiple parameters of interest (bat species composition, individual genotype, sex ratios, diet, parasites, and presence of WNS) from fecal samples using a single NGS run. We tested the accuracy of each MDM assay using samples in which these parameters were previously determined using conventional approaches. We found that assays for bat species identification, insect diet, parasite diversity, and genotype were both sensitive and accurate, the assay to detect WNS was highly sensitive but requires careful sample processing steps to ensure the reliability of results, while assays for nectivorous diet and sex showed lower sensitivity. MDM was able to quantify multiple data classes from fecal samples simultaneously, and results were consistent whether we included assays for a single data class or multiple data classes. Overall, MDM is a useful approach that employs noninvasive sampling and a customizable suite of assays to gain important and largely accurate information on bat ecology and population dynamics. PMID- 30026802 TI - Differentiation measures for conservation genetics. AB - We compare the two main classes of measures of population structure in genetics: (i) fixation measures such as FST,GST, and theta and (ii) allelic differentiation measures such as Jost's D and entropy differentiation. These two groups of measures quantify complementary aspects of population structure, which have no necessary relationship with each other. We focus especially on empirical aspects of population structure relevant to conservation analyses. At the empirical level, the first set of measures quantify nearness to fixation, while the second set of measures quantify relative degree of allelic differentiation. The two sets of measures do not compete with each other. Fixation measures are often misinterpreted as measures of allelic differentiation in conservation applications; we give examples and theoretical explanations showing why this interpretation can mislead. This misinterpretation has led to the mistaken belief that the absolute number of migrants determines allelic differentiation between demes when mutation rate is low; we show that in the finite island model, the absolute number of migrants determines nearness to fixation, not allelic differentiation. We show that a different quantity, the factor that controls Jost's D, is a good predictor of the evolution of the actual genetic divergence between demes at equilibrium in this model. We also show that when conservation decisions require judgments about differences in genetic composition between demes, allelic differentiation measures should be used instead of fixation measures. Allelic differentiation of fast-mutating markers can be used to rank pairs or sets of demes according to their differentiation, but the allelic differentiation at coding loci of interest should be directly measured in order to judge its actual magnitude at these loci. PMID- 30026800 TI - Genetic and genomic monitoring with minimally invasive sampling methods. AB - The decreasing cost and increasing scope and power of emerging genomic technologies are reshaping the field of molecular ecology. However, many modern genomic approaches (e.g., RAD-seq) require large amounts of high-quality template DNA. This poses a problem for an active branch of conservation biology: genetic monitoring using minimally invasive sampling (MIS) methods. Without handling or even observing an animal, MIS methods (e.g., collection of hair, skin, faeces) can provide genetic information on individuals or populations. Such samples typically yield low-quality and/or quantities of DNA, restricting the type of molecular methods that can be used. Despite this limitation, genetic monitoring using MIS is an effective tool for estimating population demographic parameters and monitoring genetic diversity in natural populations. Genetic monitoring is likely to become more important in the future as many natural populations are undergoing anthropogenically driven declines, which are unlikely to abate without intensive adaptive management efforts that often include MIS approaches. Here, we profile the expanding suite of genomic methods and platforms compatible with producing genotypes from MIS, considering factors such as development costs and error rates. We evaluate how powerful new approaches will enhance our ability to investigate questions typically answered using genetic monitoring, such as estimating abundance, genetic structure and relatedness. As the field is in a period of unusually rapid transition, we also highlight the importance of legacy data sets and recommend how to address the challenges of moving between traditional and next-generation genetic monitoring platforms. Finally, we consider how genetic monitoring could move beyond genotypes in the future. For example, assessing microbiomes or epigenetic markers could provide a greater understanding of the relationship between individuals and their environment. PMID- 30026803 TI - Disentangling genetic structure for genetic monitoring of complex populations. AB - Genetic monitoring estimates temporal changes in population parameters from molecular marker information. Most populations are complex in structure and change through time by expanding or contracting their geographic range, becoming fragmented or coalescing, or increasing or decreasing density. Traditional approaches to genetic monitoring rely on quantifying temporal shifts of specific population metrics-heterozygosity, numbers of alleles, effective population size or measures of geographic differentiation such as FST. However, the accuracy and precision of the results can be heavily influenced by the type of genetic marker used and how closely they adhere to analytical assumptions. Care must be taken to ensure that inferences reflect actual population processes rather than changing molecular techniques or incorrect assumptions of an underlying model of population structure. In many species of conservation concern, true population structure is unknown, or structure might shift over time. In these cases, metrics based on inappropriate assumptions of population structure may not provide quality information regarding the monitored population. Thus, we need an inference model that decouples the complex elements that define population structure from estimation of population parameters of interest and reveals, rather than assumes, fine details of population structure. Encompassing a broad range of possible population structures would enable comparable inferences across biological systems, even in the face of range expansion or contraction, fragmentation, or changes in density. Currently, the best candidate is the spatial Lambda-Fleming-Viot (SLFV) model, a spatially explicit individually based coalescent model that allows independent inference of two of the most important elements of population structure: local population density and local dispersal. We support increased use of the SLFV model for genetic monitoring by highlighting its benefits over traditional approaches. We also discuss necessary future directions for model development to support large genomic datasets informing real world management and conservation issues. PMID- 30026804 TI - Relationship between effective and demographic population size in continuously distributed populations. AB - Genetic monitoring of wild populations can offer insights into demographic and genetic information simultaneously. However, widespread application of genetic monitoring is hindered by large uncertainty in the estimation and interpretation of target metrics such as contemporary effective population size, Ne . We used four long-term genetic and demographic studies (>=9 years) to evaluate the temporal stability of the relationship between Ne and demographic population size (Nc ). These case studies focused on mammals that are continuously distributed, yet dispersal-limited within the spatial scale of the study. We estimated local, contemporary Ne with single-sample methods (LDNE, Heterozygosity Excess, and Molecular Ancestry) and demographic abundance with either mark-recapture estimates or catch-per-unit effort indices. Estimates of Ne varied widely within each case study suggesting interpretation of estimates is challenging. We found inconsistent correlations and trends both among estimates of Ne and between Ne and Nc suggesting the value of Ne as an indicator of Nc is limited in some cases. In the two case studies with consistent trends between Ne and Nc , FIS was more stable over time and lower, suggesting FIS may be a good indicator that the population was sampled at a spatial scale at which genetic structure is not biasing estimates of Ne . These results suggest that more empirical work on the estimation of Ne in continuous populations is needed to understand the appropriate context to use LDNe as a useful metric in a monitoring programme to detect temporal trends in either Ne or Nc . PMID- 30026805 TI - Diversity from genes to ecosystems: A unifying framework to study variation across biological metrics and scales. AB - Biological diversity is a key concept in the life sciences and plays a fundamental role in many ecological and evolutionary processes. Although biodiversity is inherently a hierarchical concept covering different levels of organization (genes, population, species, ecological communities and ecosystems), a diversity index that behaves consistently across these different levels has so far been lacking, hindering the development of truly integrative biodiversity studies. To fill this important knowledge gap, we present a unifying framework for the measurement of biodiversity across hierarchical levels of organization. Our weighted, information-based decomposition framework is based on a Hill number of order q = 1, which weights all elements in proportion to their frequency and leads to diversity measures based on Shannon's entropy. We investigated the numerical behaviour of our approach with simulations and showed that it can accurately describe complex spatial hierarchical structures. To demonstrate the intuitive and straightforward interpretation of our diversity measures in terms of effective number of components (alleles, species, etc.), we applied the framework to a real data set on coral reef biodiversity. We expect our framework will have multiple applications covering the fields of conservation biology, community genetics and eco-evolutionary dynamics. PMID- 30026806 TI - A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents. AB - The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug-drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants. PMID- 30026807 TI - Metabolic engineering of Saccharomyces cerevisiae for 7-dehydrocholesterol overproduction. AB - Background: 7-Dehydrocholesterol (7-DHC) has attracted increasing attentions due to its great medical value and the enlarging market demand of its ultraviolet catalyzed product vitamin D3. Microbial production of 7-DHC from simple carbon has been recognized as an attractive complement to the traditional sources. Even though our previous work realized 7-DHC biosynthesis in Saccharomyces cerevisiae, the current productivity of 7-DHC is still too low to satisfy the demand of following industrialization. As increasing the compatibility between heterologous pathway and host cell is crucial to realize microbial overproduction of natural products with complex structure and relative long pathway, in this study, combined efforts in tuning the heterologous Delta24-dehydrocholesterol reductase (DHCR24) and manipulating host cell were applied to promote 7-DHC accumulation. Results: In order to decouple 7-DHC production with cell growth, inducible GAL promoters was employed to control 7-DHC synthesis. Meanwhile, the precursor pool was increased via overexpressing all the mevalonate (MVA) pathway genes (ERG10, ERG13, tHMG1, ERG12, ERG8, ERG19, IDI1, ERG20). Through screening DHCR24s from eleven tested sources, it was found that DHCR24 from Gallus gallus (Gg_DHCR24) achieved the highest 7-DHC production. Then 7-DHC accumulation was increased by 27.5% through stepwise fine-tuning the transcription level of Gg_DHCR24 in terms of altering its induction strategy, integration position, and the used promoter. By blocking the competitive path (DeltaERG6) and supplementing another copy of Gg_DHCR24 in locus ERG6, 7-DHC accumulation was further enhanced by 1.07-fold. Afterward, 7-DHC production was improved by 48.3% (to 250.8 mg/L) by means of deleting NEM1 that was involved in lipids metabolism. Eventually, 7-DHC production reached to 1.07 g/L in 5-L bioreactor, which is the highest reported microbial titer as yet known. Conclusions: Combined engineering of the pathway and the host cell was adopted in this study to boost 7-DHC output in the yeast. 7 DHC titer was stepwise improved by 26.9-fold compared with the starting strain. This work not only opens large opportunities to realize downstream de novo synthesis of other steroids, but also highlights the importance of the combinatorial engineering of heterologous pathway and host to obtain microbial overproduction of many other natural products. PMID- 30026808 TI - Pan-genome analyses of 24 Shewanella strains re-emphasize the diversification of their functions yet evolutionary dynamics of metal-reducing pathway. AB - Background: Shewanella strains are important dissimilatory metal-reducing bacteria which are widely distributed in diverse habitats. Despite efforts to genomically characterize Shewanella, knowledge of the molecular components, functional information and evolutionary patterns remain lacking, especially for their compatibility in the metal-reducing pathway. The increasing number of genome sequences of Shewanella strains offers a basis for pan-genome studies. Results: A comparative pan-genome analysis was conducted to study genomic diversity and evolutionary relationships among 24 Shewanella strains. Results revealed an open pan-genome of 13,406 non-redundant genes and a core-genome of 1878 non-redundant genes. Selective pressure acted on the invariant members of core genome, in which purifying selection drove evolution in the housekeeping mechanisms. Shewanella strains exhibited extensive genome variability, with high levels of gene gain and loss during the evolution, which affected variable gene sets and facilitated the rapid evolution. Additionally, genes related to metal reduction were diversely distributed in Shewanella strains and evolved under purifying selection, which highlighted the basic conserved functionality and specificity of respiratory systems. Conclusions: The diversity of genes present in the accessory and specific genomes of Shewanella strains indicates that each strain uses different strategies to adapt to diverse environments. Horizontal gene transfer is an important evolutionary force in shaping Shewanella genomes. Purifying selection plays an important role in the stability of the core-genome and also drives evolution in mtr-omc cluster of different Shewanella strains. PMID- 30026809 TI - Boosting of enzymatic softwood saccharification by fungal GH5 and GH26 endomannanases. AB - Background: Softwood is a promising feedstock for lignocellulosic biorefineries, but as it contains galactoglucomannan efficient mannan-degrading enzymes are required to unlock its full potential. Results: Boosting of the saccharification of pretreated softwood (Canadian lodgepole pine) was investigated for 10 fungal endo-beta(1->4)-mannanases (endomannanases) from GH5 and GH26, including 6 novel GH26 enzymes. The endomannanases from Trichoderma reesei (TresMan5A) and Podospora anserina (PansMan26) were investigated with and without their carbohydrate-binding module (CBM). The pH optimum and initial rates of enzyme catalysed hydrolysis were determined on pure beta-mannans, including acetylated and deacetylated spruce galactoglucomannan. Melting temperature (Tm) and stability of the endomannanases during prolonged incubations were also assessed. The highest initial rates on the pure mannans were attained by GH26 endomannanases. Acetylation tended to decrease the enzymatic rates to different extents depending on the enzyme. Despite exhibiting low rates on the pure mannan substrates, TresMan5A with CBM1 catalysed highest release among the endomannanases of both mannose and glucose during softwood saccharification. The presence of the CBM1 as well as the catalytic capability of the TresMan5A core module itself seemed to allow fast and more profound degradation of portions of the mannan that led to better cellulose degradation. In contrast, the presence of the CBM35 did not change the performance of PansMan26 in softwood saccharification. Conclusions: This study identified TresMan5A as the best endomannanase for increasing cellulase catalysed glucose release from softwood. Except for the superior performance of TresMan5A, the fungal GH5 and GH26 endomannanases generally performed on par on the lignocellulosic matrix. The work also illustrated the importance of using genuine lignocellulosic substrates rather than simple model substrates when selecting enzymes for industrial biomass applications. PMID- 30026810 TI - Increased drought tolerance in plants engineered for low lignin and low xylan content. AB - Background: We previously developed several strategies to engineer plants to produce cost-efficient biofuels from plant biomass. Engineered Arabidopsis plants with low xylan and lignin content showed normal growth and improved saccharification efficiency under standard growth conditions. However, it remains to be determined whether these engineered plants perform well under drought stress, which is the primary source of abiotic stress in the field. Results: Upon exposing engineered Arabidopsis plants to severe drought, we observed better survival rates in those with a low degree of xylan acetylation, low lignin, and low xylan content compared to those in wild-type plants. Increased pectic galactan content had no effect on drought tolerance. The drought-tolerant plants exhibited low water loss from leaves, and drought-responsive genes (RD29A, RD29B, DREB2A) were generally up-regulated under drought stress, which did not occur in the well-watered state. When compared with the wild type, plants with low lignin due to expression of QsuB, a 3-dehydroshikimate dehydratase, showed a stronger response to abscisic acid (ABA) in assays for seed germination and stomatal closure. The low-lignin plants also accumulated more ABA in response to drought than the wild-type plants. On the contrary, the drought tolerance in the engineered plants with low xylan content and low xylan acetylation was not associated with differences in ABA content or response compared to the wild type. Surprisingly, we found a significant increase in galactose levels and sugar released from the low xylan-engineered plants under drought stress. Conclusions: This study shows that plants engineered to accumulate less lignin or xylan are more tolerant to drought and activate drought responses faster than control plants. This is an important finding because it demonstrates that modification of secondary cell walls does not necessarily render the plants less robust in the environment, and it shows that substantial changes in biomass composition can be achieved without compromising plant resilience. PMID- 30026811 TI - Feature selection for gene prediction in metagenomic fragments. AB - Background: Computational approaches, specifically machine-learning techniques, play an important role in many metagenomic analysis algorithms, such as gene prediction. Due to the large feature space, current de novo gene prediction algorithms use different combinations of classification algorithms to distinguish between coding and non-coding sequences. Results: In this study, we apply a filter method to select relevant features from a large set of known features instead of combining them using linear classifiers or ignoring their individual coding potential. We use minimum redundancy maximum relevance (mRMR) to select the most relevant features. Support vector machines (SVM) are trained using these features, and the classification score is transformed into the posterior probability of the coding class. A greedy algorithm uses the probability of overlapped candidate genes to select the final genes. Instead of using one model for all sequences, we train an ensemble of SVM models on mutually exclusive datasets based on GC content and use the appropriated model to classify candidate genes based on their read's GC content. Conclusion: Our proposed algorithm achieves an improvement over some existing algorithms. mRMR produces promising results in gene prediction. It improves classification performance and feature interpretation. Our research serves as a basis for future studies on feature selection for gene prediction. PMID- 30026812 TI - Soft document clustering using a novel graph covering approach. AB - Background: In text mining, document clustering describes the efforts to assign unstructured documents to clusters, which in turn usually refer to topics. Clustering is widely used in science for data retrieval and organisation. Results: In this paper we present and discuss a novel graph-theoretical approach for document clustering and its application on a real-world data set. We will show that the well-known graph partition to stable sets or cliques can be generalized to pseudostable sets or pseudocliques. This allows to perform a soft clustering as well as a hard clustering. The software is freely available on GitHub. Conclusions: The presented integer linear programming as well as the greedy approach for this PMID- 30026813 TI - Effectiveness of a multicenter training programme to teach point-of-care vascular ultrasound for the detection of peripheral arterial disease in people with diabetes. AB - Background: The primary aim of this study was to evaluate the effectiveness of a training programme to teach a focused bedside ultrasound scan (PAD-scan; Podiatry Ankle Duplex Scan) for the detection of arterial disease in people with diabetes. Methods: Five podiatrists and one diabetologist across two hospitals were enrolled in a structured training programme consisting of a training course (1 day), supervised scanning (5-weeks), independent scanning (3-weeks) and a final evaluation of performance (1-day).Time, technical skills (Duplex Ultrasound Objective Structured Assessment of Technical Skills tool (DUOSATS); minimum score = 6, maximum score = 26) and accuracy (level of agreement with vascular scientist PAD-scan assessment) were assessed for every supervised scan and again for the final evaluation of performance. Results: A total of 90 PAD-scans in 65 patients were performed during the supervised phase. Participants demonstrated significant improvements in median time (19 min(IQR 13.9-25.5) vs 9.3 min (IQR 7.3-10.5);p = 0.028) and DUOSATS scores (17.5 (IQR 16.8-21) vs 25 (IQR 24-25.3); p = 0.027). At the final evaluation, participants completed scans in 5.4 min (IQR 5.3-5.9), achieved full DUOSAT scores and perfect agreement with the vascular scientist. Conclusion: A structured training programme, integrated into diabetic foot clinics, was effective in teaching the PAD-scan. PMID- 30026815 TI - A comparison of different definitions of metabolic syndrome for the risks of atherosclerosis and diabetes. AB - Background: The reported outcomes of the metabolic syndrome (MetS), containing atherosclerotic cardiovascular disease and diabetes, vary according to the definitions used. This study was designed to compare the performance of the Adult Treatment Panel III/American Heart Association/National Heart, Lung, and Blood Institute (ATP III/AHA/NHLBI) and International Diabetes Federation (IDF) criteria for the risks of atherosclerosis and diabetes. Methods: We sifted subjects from a self-paid Health examination program from 1999 to 2015 in this cross-sectional population-based study. On the basis of the ATP III/AHA/NHLBI and IDF criteria, the MetS diagnosis and scores were concluded. A brachial-ankle pulse wave velocity (baPWV) more than or equal to 1400 cm/s indicated more severe arterial stiffness, and a high fasting glucose level more than or equal to 6.99 mmol/L or postprandial glucose level more than or equal to 11.10 mmol/L indicated diabetic-level hyperglycemia. Comparisons of the areas under receiver operating characteristic curves (AUC-ROC) for both MetS scores to correlate with a higher baPWV and diabetic-level hyperglycemia were evaluated. Results: In the 26,735 enrolled subjects with an average age of 55 (+/- 12) years, 6633 and 7388 (24.8% vs. 27.6%, p < 0.001) were classified as having MetS on the basis of the ATP III/AHA/NHLBI and IDF criteria, respectively. The AUC-ROC for the ATP III/AHA/NHLBI-MetS score were higher than those for the IDF-MetS score (0.685 vs. 0.595 to correlate with a higher baPWV, p < 0.001; 0.791 vs. 0.665 to correlate with diabetic-level hyperglycemia, p < 0.001). Conclusions: To the best of our knowledge, this is the first study to demonstrate that through a holistic approach, the performance of the ATP III/AHA/NHLBI-MetS score for the risks of atherosclerosis and diabetes was superior to the IDF-MetS score for Asians. PMID- 30026814 TI - Prevalence, resistance pattern, and molecular characterization of Staphylococcus aureus isolates from healthy animals and sick populations in Henan Province, China. AB - Background: Staphylococcus aureus is one of the most prevalent pathogens and a causative agent of a variety of infections in humans and animals. A total of 640 samples were collected from healthy animals and patients from 2013 to 2014 in Henan Province, China, to investigate the prevalence and perform molecular characterization of S. aureus. Antimicrobial resistance and virulence genes were determined and pulsed-field gel electrophoresis (PFGE) and staphylococcal cassette chromosome mec (SCCmec) typing were performed. Results: Overall, 22.3% (n = 143) of the samples were positive for S. aureus. The prevalence of methicillin-resistant S. aureus (MRSA) was 5.59%. Capsular polysaccharide locus type 5 (Cap5; 56.64%) was the dominant serotype. S. aureus strains showed high resistance to penicillin (96.50%), ciprofloxacin (52.45%), amikacin (67.83%), erythromycin (96.50%), lincomycin (97.20%), and tetracycline (68.53%) and 109 (76.2%) isolates harbored six or more tested resistance genes. The most predominant resistance genes were aphA (52.45%), ermC (53.15%), and tetM (52.45%). Eighty-seven (60.8%) isolates harbored six or more tested virulence genes. The most predominant enterotoxin genes were sed (20.28%), sej (20.98%), sep (14.69%), and set (37.76%). The prevalence of lukED gene was (57.34%), and a small number of isolates carried pvl (5.59%) and TSST-1 (2.80%). A total of 130 (82.52%) isolates could be typed by PFGE with SmaI digestion. PFGE demonstrated that 45 different patterns (P) that were grouped into 17 pulsotypes and 28 separate pulsotypes using a 90% cut-off value. A total of 118 (82.52%) isolates were successfully typed by spa, and 26 spa types were identified, t15075 (14.00%) and t189 (12.59%) were the most common types. SCCmec types were detected from eight MRSA isolates, with the most prevalent type being SCCmec IVa. MRSA-SCCmec Iva-t437 was observed in human isolates. Conclusion: This study revealed a high prevalence of S. aureus in healthy animals and patients from Henan Province, China. Resistant S. aureus exhibited varying degrees of multidrug resistance. The presence of antibiotic resistance and virulence genes may facilitate the spread of S. aureus strains and pose a potential threat to public health, highlighting the need for vigilant monitoring of these isolates at the human-animal interface. PMID- 30026816 TI - Impact of acute diabetes decompensation on outcomes of diabetic patients admitted with ST-elevation myocardial infarction. AB - Background: Acute hyperglycemia is associated with worse outcomes in diabetic patients admitted with ST-elevation myocardial infarction (STEMI). However, the impact of full-scale decompensated diabetes on STEMI outcomes has not been investigated. Methods: We utilized the national inpatient sample (2003-2014) to identify adult diabetic patients admitted with STEMI. We defined decompensated diabetes as the presence of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar state (HHS). We compared in-hospital morbidity and mortality and cost between patients with and without diabetes decompensation before and after propensity-score matching. Results: A total of 73,722 diabetic patients admitted with STEMI were included in the study. Of those, 1131 (1.5%) suffered DKA or HSS during the hospitalization. After propensity-score matching, DKA/HHS remained associated with a significant 32% increase in in-hospital mortality (25.6% vs. 19.4%, p = 0.001). The DKA/HHS group also had higher incidences of acute kidney injury (39.4% vs. 18.9%, p < 0.001), sepsis (7.3% vs. 4.9%, p = 0.022), blood transfusion (11.3% vs. 8.2%) and a non-significant trend towards higher incidence of stroke (3.8% vs. 2.4%, p = 0.087). Also, DKA/HHS diagnosis was associated with lower rates of referral to coronary angiography (51.5% vs. 55.5%, p = 0.023), coronary stenting (26.1% vs. 34.8%, p < 0.001), or bypass grafting (6.2% vs. 8.7%, p = 0.033). Referral for invasive angiography was associated with lower odds of death during the hospitalization (adjusted OR 0.66, 95%CI 0.44-0.98, p = 0.039). Conclusions: Decompensated diabetes complicates ~ 1.5% of STEMI admissions in diabetic patients. It is associated with lower rates of referral for angiography and revascularization, and a negative differential impact on in hospital morbidity and mortality and cost. PMID- 30026817 TI - Deletion of the sex-determining gene SXI1alpha enhances the spread of mitochondrial introns in Cryptococcus neoformans. AB - Background: Homing endonuclease genes (HEGs) are widely distributed genetic elements in the mitochondrial genomes of a diversity of eukaryotes. Due to their ability to self-propagate within and between genomes, these elements can spread rapidly in populations. Whether and how such elements are controlled in genomes remains largely unknown. Results: Here we report that the HEG-containing introns in the mitochondrial COX1 gene in Cryptococcus neoformans are mobile and that their spread in sexual crosses is influenced by mating type (MAT) alpha-specific homeodomain gene SXI1alpha. C. neoformans has two mating types, MATa and MATalpha . In typical crosses between strains of the two mating types, only a small portion (< 7%) of diploid fusants inherited the HEGs from the MATalpha parent. However, disruption of the SXI1alpha gene resulted in the majority (> 95%) of the diploid fusants inheriting the HEG-containing introns from the MATalpha parent, a frequency significantly higher than those of intronless mitochondrial genes. Conclusions: Our results suggest that SXI1alpha not only determines uniparental mitochondrial inheritance but also inhibits the spread of HEG-containing introns in the mitochondrial genome in C. neoformans. PMID- 30026818 TI - The Efficacy and Toxicity of Lobaplatin-contained Chemotherapy in Extensive-stage Small-cell Lung Cancer. AB - To assess the efficacy and toxicity of Lobaplatin (LBP) -contained chemotherapy on extensive stage small-cell lung cancer (ES-SCLC), we conducted a prospective, single-arm, and multicenter Phase IV clinical trial on Lobaplatin (ChiCTR-ONC 13003471), and used the patient clinical data obtained from our cancer center to perform the analysis. Previously untreated patients with ES-SCLC were given LBP intravenously (IV) at 30 mg/m2 on day 1 and etoposide IV at 100 mg/m2 on day 1, 2, and 3. The treatment was cycled every 21 days, lasting for four to six cycles. The patients with second-line treatment or above were also included in the study, and they were treated with LBP-contained regimen: a single dose of LBP at 50 mg/m2 on day 1 through IV; combined application, LBP30 mg/m2 IV on day 1. From May 2015 to August 2016, 36 patients were enrolled in the study at our cancer center. For the 30 first-line patients, the median overall survival (OS) and the median progression-free survival (PFS) was 13.0 months (ranging from 11.2 to 14.7 months) and 4.7 months (ranging from 1.6 to 7.7 months) respectively, with overall response rate of 57 % and disease control rate of 85.7%. For the 6 patients with second-line treatment or above, one patient got a partial response (PR) and four patients got a stable disease (SD). The most frequent drug-related adverse effects were leukopenia and neutropenia, and no grade 3/4 hepatotoxicity or nephrotoxicity was observed. These results indicated that LBP-contained chemotherapy was effective and tolerable for extensive stage SCLC in terms of response and survival. However, due to the small sample size of this study, we need to wait for the OS data of phase III clinical trial and the final data of this multicenter Phase IV study to draw the conclusion. PMID- 30026819 TI - Optimal biopsy strategy for prostate cancer detection by performing a Bayesian network meta-analysis of randomized controlled trials. AB - Objective: With the increasing recognition of the over-diagnosis and over treatment of prostate cancer (PCa), the choice of a better prostate biopsy strategy had confused both the patients and clinical surgeons. Hence, this network meta-analysis was conducted to clarify this question. Methods: In the current network meta-analysis, twenty eligible randomized controlled trials (RCTs) with 4,571 participants were comprehensively identified through Pubmed, Embase and Web of Science databases up to July 2017. The pooled odds ratio (OR) with 95% credible interval (CrI) was calculated by Markov chain Monte Carlo methods. A Bayesian network meta-analysis was conducted by using R-3.4.0 software with the help of package "gemtc" version 0.8.2. Results: Six different PCa biopsy strategies and four clinical outcomes were ultimately analyzed in this study. Although, the efficacy of different PCa biopsy strategies by ORs with corresponding 95% CrIs had not yet reached statistical differences, the cumulative rank probability indicated that overall PCa detection rate from best to worst was FUS-GB plus TRUS-GB, FUS-GB, CEUS, MRI-GB, TRUS-GB and TPUS-GB. In terms of clinically significant PCa detection, CEUS, FUS-GB or FUS-GB plus TRUS GB had a higher, whereas TRUS-GB or TPUS-GB had a relatively lower significant detection rate. Meanwhile, TPUS-GB or TRUS-GB had a higher insignificant PCa detection rate. As for TRUS-guided biopsy, the general trend was that the more biopsy cores, the higher overall PCa detection rate. As for targeted biopsy, it could yield a comparable or even a better effect with fewer cores, compared with traditional random biopsy. Conclusion: Taken together, in a comprehensive consideration of four clinical outcomes, our outcomes shed light on that FUS-GB or FUS-GB plus TRUS-GB showed their superiority, compared with other puncture methods in the detection of PCa. Moreover, TPUS or TRUS-GB was more easily associated with the over-diagnosis and over-treatment of PCa. In addition, targeted biopsy was obviously more effective than traditional random biopsy. The subsequent RCTs with larger sample sizes were required to validate our findings. PMID- 30026822 TI - Aberrant methylation of FAT4 and SOX11 in peripheral blood leukocytes and their association with gastric cancer risk. AB - Background: Aberrant DNA methylation, especially tumor suppressor gene hypermethylation, is a well-recognized biomarker of initial tumorogenesis stages. FAT4 and SOX11 are putative tumor suppressor genes and can be down-regulated by hypermethylation in various cancers tissues. However, in peripheral blood leukocytes, the association between these two genes methylation status, as well as the effects of gene-environment interactions, and gastric cancer (GC) risk remain unclear. Methods: A hospital-based case-control study including 375 cases and 394 controls was conducted. Peripheral blood leukocytes DNA methylation status were detected by methylation-sensitive high-resolution melting (MS-HRM) assay. Logistic regression was adopted to analyze the relationship of FAT4 and SOX11 methylation with GC susceptibility. Results: Positive methylation (Pm) and total positive methylation (Tpm) of FAT4 were significantly increased the risk of GC (OR = 2.204, 95% CI: 1.168-4.159, P = 0.015; OR = 1.583, 95% CI: 1.031-2.430, P = 0.036, respectively). Compared with controls, cases exhibited higher SOX11 Pm frequencies with OR of 2.530 (95% CI: 1.289-4.969, P = 0.007). Nonetheless, no statistically significant association between SOX11 Tpm and GC risk was observed. Additionally, interactions between FAT4 Tpm and increased consumption of freshwater fish (>=1 times/week) displayed an antagonistic effect on GC (OR = 0.328, 95% CI: 0.142-0.762, P = 0.009), and high salt intake interacted with SOX11 Tpm also showed statistically significant (OR = 0.490, 95% CI: 0.242-0.995, P = 0.048). Conclusions:FAT4 aberrant methylation in peripheral blood leukocytes and gene-environment interactions were associated with the risk of GC, while SOX11 was controversial and needed to be more investigated. PMID- 30026820 TI - Gene Expression Detection Assay for Cancer Clinical Use. AB - Cancer is a genetic disease where genetic variations cause abnormally functioning genes that appear to alter expression. Proteins, the final products of gene expression, determine the phenotypes and biological processes. Therefore, detecting gene expression levels can be used for cancer diagnosis, prognosis, and treatment prediction in a clinical setting. In this review, we investigated six gene expression assay systems (qRT-PCR, DNA microarray, nCounter, RNA-Seq, FISH, and tissue microarray) that are currently being used in clinical cancer studies. Some of these methods are also commonly used in a modified way; for example, detection of DNA content or protein expression. Herein, we discuss their principles, sample preparation, design, quantification and sensitivity, data analysis, time for sample preparation and processing, and cost. We also compared these methods according to their sample selection, particularly for the feasibility of using formalin-fixed paraffin-embedded (FFPE) samples, which are routinely archived for clinical cancer studies. We intend to provide a guideline for choosing an assay method with respect to its oncological applications in a clinical setting. PMID- 30026821 TI - Zusanli (ST36) Acupoint Injection with Neostigmine for Paralytic Postoperative Ileus following Radical Gastrectomy for Gastric Cancer: a Randomized Clinical Trial. AB - Background: The Zusanli (ST36) acupoint has been associated with treatment of various gastrointestinal conditions. There have been no studies of acupuncture therapy for paralytic postoperative ileus (PPOI). Materials and methods: Patients with PPOI following gastrectomy for gastric cancer were randomized to receive ST36 acupoint injection with neostigmine, gluteal intramuscular injection with 1.0 mg neostigmine, ST36 acupuncture alone, or standard therapy. The main outcome was the effectiveness rate for recovery of peristalsis. Secondary outcomes were time to bowel sound recovery, time to first flatus, and time to first defecation. Tertiary outcomes were drug-related adverse events, including abdominal pain, diarrhea, nausea, vomiting, tearing, delirium, seizure, and anxiety. Results: ST36 acupoint injection with neostigmine and gluteal intramuscular injection of neostigmine gave a higher rate of peristalsis recovery, and the ST36 acupoint injection group showed significantly higher total effectiveness rate than that of the intramuscular injection group. These interventions gave significantly shorter times to bowel sound recovery, shorter times to first flatus and first defecation compared with ST36 acupuncture and standard post-operative therapy (P < 0.01). ST36 acupoint injection group gave shorter time to bowel sound recovery, shorter time to first flatus and first defecation than those of the intramuscular injection group (P < 0.01). Drug-related adverse events in the intramuscular injection group were more serious than in the ST36 acupoint injection group (P < 0.05). Conclusion: ST36 acupoint injection with neostigmine is safe and effective for treatment of PPOI. PMID- 30026823 TI - Risk Stratification of Upper Urinary Tract Urothelial Carcinoma Patients for Survival Prediction: A Simple Summation Scoring Method. AB - Purpose: To stratify upper urinary tract urothelial carcinoma (UTUC) patients into risk groups in terms of 5-year survival. Methods and materials: All potential UTUC patients recorded in our cancer registry database from 1997 to 2011 were evaluated for authentic presence of UTUC. Age at diagnosis, sex, organ involvement, dialysis, renal transplantation status, clinical stage, survival to the last follow-up, and the cause of death of each patient were recorded. All patients were randomized into a developmental set or a validation set at a 1:1 ratio. Survival prediction models and scores were developed using the developmental set and validated in terms of discrimination and calibration using the validation set. Patients were stratified into risk groups using the summed risk scores and their survival compared by the log rank test. Results: We enrolled 1,120 authentic UTUC patients. In the developmental set, older age, male sex, and higher clinical staging were significant predictors of 5-year death after controlling for other variables. Based on these three clinical variables, patients were stratified into low-, intermediate-, high-, and very high-risk groups using the summed risk scores. The 5-year all-cause and cancer-specific survivals of UTUC patients in the low-, intermediate-, high-, and very high-risk groups were 83.0% and 85.0%, 57.7% and 70.9%, 16.8% and 26.3%, and 2.2% and 7.5%, respectively (p < 0.001). Both discrimination and calibration were good for the validation set (overall concordance index = 0.762). Conclusions: Stratification of UTUC patients using summed risk scores was a simple and useful way to estimate survivals and to select appropriate treatments. PMID- 30026824 TI - The Novel Prognostic Score Combining Red Blood Cell Distribution Width and Body Mass Index (COR-BMI) Has Prognostic Impact for Survival Outcomes in Nasopharyngeal Carcinoma. AB - Background: A novel inflammation-and nutrition-based scoring system based on red blood cell distribution width and body mass index (COR-BMI) has prognostic value in nasopharyngeal carcinoma (NPC). Here, we assessed the prognostic value of COR BMI in NPC. Methods: Retrospective study of 2,318 patients with non-metastatic NPC treated at Sun Yat-sen University Cancer Center was conducted. Patients were stratified into three groups using the COR-BMI score, which is based on two objective and easily measurable parameters: red blood cell distribution width (RDW) and body mass index (BMI). Kaplan-Meier survival analyses were used to compare groups; multivariate Cox proportional models were used to calculate overall survival (OS) and disease-free survival (DFS). Results: Four-year overall survival (OS) rates were 88.7%, 84.5%, and 71.4% for patients with COR-BMI scores of 0, 1, and 2 respectively (P = 0.006). Multivariate Cox proportional hazard analysis revealed COR-BMI was an independent predictor of OS (HR for COR-BMI 1: 1.239, 95% CI: 1.012-1.590; HR for COR-BMI 2: 2.367, 95% CI: 1.311-4.274, P = 0.013), but not DFS (P = 0.482). In subgroup analysis of metastatic NPC, OS rates decreased as COR-BMI increased. In patients with a COR-BMI score of 1, radiotherapy plus chemotherapy led to better OS than radiotherapy alone. Conclusions: COR-BMI may serve as an indicator of poor prognosis in both NPC and metastatic NPC. Radiotherapy plus chemotherapy may benefit patients with a COR BMI score of 1. PMID- 30026826 TI - Stromal Infiltration of Tumor-Associated Macrophages Conferring Poor Prognosis of Patients with Basal-Like Breast Carcinoma. AB - Aims: Tumor associated macrophages (TAMs) play a critical role in the initiation and progression of breast cancer. However, their prognostic significance in the molecular subtype of basal-like breast cancer (BLBC) is poorly understood. The aim of this study was to investigate the extent and patterns of TAMs in BLBC and their associations with clinicopathological features and patient survival. Methods and Results: We evaluated TAMs in 200 cases of BLBC by immunohistochemistry using the M2 macrophage marker CD163 and the pan-macrophage marker CD68 in tumor nest and stroma, and assessed their prognostic significance. The study demonstrated that infiltration of CD163+ and CD68+ macrophages in tumor stroma was of clinical relevance in BLBC, but not those in tumor nest. Increased stromal infiltration of CD68+ or CD163+ macrophages correlated with larger tumor size, higher histological grade, higher 5-year recurrence and 5-year breast cancer mortality. Although both of CD68+ and CD163+ macrophages in tumor stroma were associated with poor recurrence-free survival (RFS) and overall survival (OS), multivariate analysis demonstrated that only CD163+ macrophage was an independent predictor of RFS and OS. Conclusions: Our results highlight the prognostic importance of TAMs' location in BLBC. CD163, a highly specific biomarker for M2 macrophages, is an independent prognostic marker for BLBC patients, and may serve as an indicator or potential target of macrophage-centred therapeutic strategies. PMID- 30026827 TI - MicroRNA-1296 Facilitates Proliferation, Migration And Invasion Of Colorectal Cancer Cells By Targeting SFPQ. AB - MicroRNAs (miRNAs) are involved in cancer genesis and progression via acting as tumor suppressors or oncogenes. Previous studies report that miR-1296 shows upregulation in both colorectal cancer (CRC) tissues and plasma samples. However, the accurate clinical significance of miR-1296 and its role in CRC have not been well investigated. The aim of the present study was to disclose the aberrant expression, clinical significance, and the relevant biological function of miR 1296 in CRC. We found a marked upregulation of miR-1296 expression in CRC tissues compared to tumor-adjacent tissues. MiR-1296 overexpression was detected in five CRC cell lines (HCT116, Caco2, HT29, SW620 and SW480). High miR-1296 level was remarkably correlated with tumor size (>5cm), lymph node metastasis and TNM stage (III+IV). Notably. High miR-1296 expression was identified as a predictive factor for poor prognosis of CRC patients by survival analysis. MiR-1296 knockdown inhibited proliferation, migration, invasion capacities of HCT116 and SW480 cells in vitro. Moreover, miR-1296 silencing restrained the growth of CRC cells in vivo. Splicing factor proline and glutamine rich (SFPQ), a novel RNA binding protein, was identified as a direct target gene of miR-1296 in CRC. Downregulation of SFPQ expression was inversely associated with miR-1296 expression in CRC tissues. The Cancer Genome Atlas (TCGA) data revealed the prognostic value of dysregulated SFPQ in CRC patients. Interestingly, our findings established that the oncogenic role of miR-1296 was at least partially mediated by SFPQ in CRC cells. Collectively, these data indicate that miR-1296 accelerates CRC progression possibly by targeting SFPQ and may serve as a potential predictive factor and therapeutic target for CRC. PMID- 30026825 TI - The Tumor Mutational Burden of Chinese Advanced Cancer Patients Estimated by a 381-cancer-gene Panel. AB - Purpose: Tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is proved to be effective to predict the clinical benefit of immune checkpoint blockades. However, WES is not commonly used in China. We aimed to determine if a 381-caner-gene panel (CGP) could be used to estimate TMB, delineate the landscape of TMB of Chinese patients and identify mutated genes and pathways related to higher TMB. Methods: We first evaluated the correlation between the TMB estimated by a 381-cancer-gene panel MasterView and WES using the data from the melanoma sample cohort. 3023 formalin fixed, paraffin-embedded tumor specimens from 2932 Chinese patients with advanced solid tumor were profiled for 381 gene sequencing, the baits of which covered 4,557 exons of 365 cancer-related genes and 47 introns of 25 genes frequently rearranged in cancer (All performed in a lab who achieved full marks five times in the external quality assessment by College of American Pathologists [CAP]). Using the sequencing data, we estimated the TMB of Chinese advanced solid tumor and identified mutated genes and pathways related to higher TMB level. Results: 381-CGP-mutational burden was strongly associated with those calculated by WES (R2 = 0.978). The median TMB for each tumor type was 5.65 (colorectal cancer), 4.84 (lung cancer), 4.03 (hepatobiliary cancer), 4.03 (gastric carcinoma), 4.03 (breast cancer) mutations/mb respectively. No correlation was observed between TMB level and age (P = 0.577) or gender (P = 0.307). The TMB of patients with mismatch repair (MMR) or DNA repair response (DDR) pathway deficiency was significantly higher than that without MMR or DDR pathway deficiency (P < 0.001). Conclusion: The 381-cancer gene panel is a clinical practicable method to assess tumor mutational burden compared with whole exome sequencing. MMR and DDR deficiency are correlated with higher tumor mutational burden of Chinese patients with advanced solid tumors. PMID- 30026828 TI - A decision tree-based prediction model for fluorescence in situ hybridization HER2 gene status in HER2 immunohistochemistry-2+ breast cancers: a 2538-case multicenter study on consecutive surgical specimens. AB - Objective: To investigate the proportion of HER2 gene amplifications and the association between the HER2-IHC-staining pattern and gene status in IHC-2+ breast cancers according to 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Methods: We retrospectively analyzed and re-evaluated the IHC-staining pattern of 2538 IHC-2+ surgical specimens of breast cancer from November 2014 to October 2015 in 12 institutions. All cases used for building a prediction model of HER2 gene amplification according to the IHC-staining pattern and were randomly divided into a training set (n = 1914) or validation set (n = 624). Results: The overall HER2 fluorescence in situ hybridization (FISH) amplification, non-amplification and equivocation rates in HER2 IHC-2+ cases were 17.8%, 76.2% and 6.0%, respectively. In the training set, cases that had <= 10% of cells with intense, complete and circumferential membrane staining or had > 85% of cells with complete membrane staining of any staining intensity tended to be HER2 gene amplified (77.0% and 60.5%, respectively). And cases with weak and incomplete membrane staining had the lowest amplification rate of 6.1%. The prediction model was constructed based on IHC-staining pattern in the training set and validated using a validation set. The positive and negative prediction values were 51.6% and 79.2%, respectively, in the validation set. Moreover, the HER2 copy number per cell was much higher in cases with amplification-associated staining patterns (7.84 and 8.75) than in cases with non-amplification-associated staining patterns (2.97 to 4.41, P < 0.05). Conclusions: In HER2 IHC-2+ breast cancers, the staining pattern is associated with the HER2 gene status. This finding is compatible with recommendations of 2013 ASCO/CAP guidelines. PMID- 30026829 TI - Enhancer RNAs (eRNAs): New Insights into Gene Transcription and Disease Treatment. AB - Enhancers are cis-acting elements that have the ability to increase the expression of target genes. Recent studies have shown that enhancers can act as transcriptional units for the production of enhancer RNAs (eRNAs), which are hallmarks of activity enhancers and are involved in the regulation of gene transcription. The in-depth study of eRNAs is of great significance for us to better understand enhancer function and transcriptional regulation in various diseases. Therefore, eRNAs may be a potential therapeutic target for diseases. Here, we review the current knowledge of the characteristics of eRNAs, the molecular mechanisms of eRNAs action, as well as diseases related to dysregulation of eRNAs. PMID- 30026830 TI - Prognostic Value of Albumin/Globulin Ratio in Survival and Lymph Node Metastasis in Patients with Cancer: A Systematic Review and Meta-analysis. AB - The impact of albumin to globulin ratio (AGR) on the prognosis of various human cancers has not been well established. Here, a systemic review and meta-analysis has been performed to comprehensively assess the relationships between AGR and lymph node metastasis (LNM) or overall survival (OS). Systematical search through six electronic databases has been carried out to identify reports involving the role of AGR on OS and LNM in human cancers. Hazard ratio (HR), odd ratio (OR) and their 95% confidence intervals (95% CI) were evaluated through meta-analysis according to standard steps. Of 403 studies retrieved, 14 eligible studies with 4136 patients were included in this study. The analysis based on random-effect model demonstrated that low AGR was significantly associated with poor OS in various cancers (HR=1.87, 95% CI 1.50-2.34; P < 0.001). Subsequent results showed a significant increase in the risk of LNM in the low AGR group when compared with high AGR group (HR=2.24; 95% CI=1.49-3.36; P<0.001). To conclusion, this study suggested that AGR was associated with OS and LNM in cancer patients and AGR may be a potential marker to assess prognosis of cancer patients. However, a large scale of samples and prospective studies are needed in the future to validate the role of AGR in practice. PMID- 30026831 TI - Synaptotagmin7 Is Overexpressed In Colorectal Cancer And Regulates Colorectal Cancer Cell Proliferation. AB - Purpose: Synaptotagmin7 (SYT7) belongs to the synaptotagmin gene family and plays an important role in synaptic transmission. However, the function of this gene in most human cancer especially in colorectal cancer (CRC) remains unknown. In this research, we examined SYT7's role in CRC and tried to reveal its underlying mechanism. Methods: We examined SYT7's expression levels in normal colorectal tissue and CRC tissues from 83 patients and analyzed the possible correlation between the expression level of SYT7 and pathological characteristics. The influences of SYT7 knockdown on cell growth were detected by Celigo image cytometer, colony formation assay, cell cycle analysis and apoptosis assay in vitro. The possible molecular mechanism was assessed using a microarray and Ingenuity Pathway Analysis. Results: Our results show that the expression of SYT7 is upregulated in colorectal cancer tissues in comparison with normal tissues and positively correlated with the pathological stage of colorectal cancer. (P=0.015). We examined SYT7's role in human colorectal cancer cell line RKO by using SYT7-shRNA and revealed that SYT7 knockdown inhibit cell proliferation (P=8.6E-5), clonogenic ability (P=4.5E-6) and promoted G2/M Phase arrest and apoptosis (P=4.6E-7). Multiple cancer-associated pathways regulated by SYT7 were unraveled by microarray and Ingenuity Pathway Analysis. Conclusions: Our study suggests that SYT7 plays an important role in the development of CRC and SYT7 may become a new therapeutic target in CRC. PMID- 30026833 TI - NOTCH4 Is a Novel Prognostic Marker that Correlates with Colorectal Cancer Progression and Prognosis. AB - Notch family plays vital role in carcinogenesis and progression of various cancer, however, its clinical significance and prognostic value in colorectal cancer isn't fully investigated. In present study, we first investigated the NOTCH4 expression in The Cancer Genome Atlas (TCGA) (n=361) and GSE39582 (n=474) database and then validated with our own database (n=248). The transcriptional and protein levels of NOTCH4 were evaluated by RT-PCR and immunohistochemistry study, respectively. Univariate and multivariate survival analyses were performed to explore the relationship between various prognostic factors and survival outcomes. In the univariate analysis, NOTCH3 and NOTCH4 were significantly correlated with prognosis in TCGA and GSE39582 database, respectively (P<0.05). For NOTCH3 has been studied in CRC, we chosen NOTCH4 for further study. NOTCH4 mRNA was higher in liver metastases than their primary colorectal cancer or normal mucosa. Increased NOTCH4 levels significantly correlated with advanced N stage (P= 0.002), M stage (P= 0.002), lymphovascular invasion (P= 0.026), and CEA status (P= 0.030). Patients with high NOTCH4 expression had shorter 5-year disease-free survival (DFS) (HR 6.809; 95% CI 3.334-13.904; P< 0.001) and overall survival (OS) (HR 6.476; 95% CI 3.307-12.689; P<0.001) than those with low NOTCH4 expression. Multivariate survival analysis demonstrated that NOTCH4 was an independent prognostic biomarker for both DFS (HR 7.848; 95% CI 3.777-16.308; P<0.001) and OS (HR 5.323; 95% CI 2.668-10.623; P<0.001).Collectively, NOTCH4 may play critical role in colorectal cancer progression and could serve as a novel biomarker to predict survival after colectomy. PMID- 30026834 TI - Modified CLIP score with the albumin-bilirubin grade retains prognostic value in HBV-related hepatocellular carcinoma patients treated with trans-catheter arterial chemoembolization therapy. AB - Background: The Cancer of the Liver Italian Program (CLIP) score is commonly used for prognosis prediction of hepatocellular carcinoma (HCC). The CLIP includes the Child-Pugh grade, which is relatively subjective, for hepatic encephalopathy assessment. A newly developed scoring system called albumin-bilirubin grade (ALBI grade), consists of albumin and bilirubin to assess liver function reserve objectively. Here, we substituted the ALBI grade for the Child-Pugh grade to establish the ALBI-CLIP scoring system and validated its prognostic value in hepatitis B virus (HBV)-related HCC patients treated with trans-catheter arterial chemoembolization (TACE) therapy. Methods: We retrospectively analyzed HBV related HCC patients who received TACE therapy. Baseline characteristics were collected and evaluated to classify patients according to ALBI-CLIP, CLIP and TNM systems. Univariate analyses using the Kaplan-Meier method and the log-rank test, as well as multivariate analysis using the Cox proportional hazards regression model, were conducted to detect independent prognostic factors for overall survival. Receiver operating characteristic (ROC) curves and a likelihood ratio test (LRT) were both utilized to compare the values of ALBI-CLIP, CLIP and TNM staging systems in predicting survival. Results: With a total of 389 patients included in the current study, 301 (77.4%) and 88 (22.6%) were classified as Child-Pugh grade A and B, respectively. However, 152 (39.1%), 227 (58.4%) and 10 (2.5%) patients were correspondingly classified into ALBI grade 1, 2 and 3. The areas under the curves of ALBI-CLIP, CLIP and TNM systems were 0.804, 0.778 and 0.734, respectively, for predicting 3-month survival; 0.796, 0.778 and 0.733, respectively, for 6-month survival; 0.697, 0.687 and 0.644, respectively, for 1 year survival; and 0.618, 0.612 and 0.569, respectively, for 2-year survival. The LRT indicated that the ALBI-CLIP and the CLIP had similar values of chi2 and Akaike information criterion (AIC) while the TNM system had the smallest chi2 value (chi2 = 12.1, 11.9, 10.5; AIC = 2620.2, 2620.5, 2621.1 for ALBI-CLIP, CLIP and TNM, respectively). Conclusions: In conclusion, our present study suggested that the ALBI-CLIP scoring system retained the prognostic value of the CLIP in HBV-related HCC treated with TACE therapy. PMID- 30026832 TI - Distinct Diagnostic and Prognostic Values of Minichromosome Maintenance Gene Expression in Patients with Hepatocellular Carcinoma. AB - Background: The aim of the present study was to identify diagnostic and prognostic values of minichromosome maintenance (MCM) gene expression in patients with hepatocellular carcinoma (HCC). Methods: The biological function of the MCM genes were investigated by bioinformatics analysis. The diagnostic and prognostic values of the MCM genes were investigated by using the data of HCC patients from the GSE14520 and The Cancer Genome Atlas (TCGA) databases. Results: Bioinformatics analysis of the MCM genes substantiated that MCM2-7 genes were significantly enriched in DNA replication and cell cycle, and co-expressed with each other. These genes also co-expressed in HCC tumor tissue in both the GSE14520 and TCGA cohort. We also observed that the expression of the MCM2-7 genes was increased in tumor tissue, and diagnostic receiver operating characteristic analysis of MCM2-7 indicated that these genes could serve as sensitive diagnostic markers in HCC. Survival analysis in the GSE14520 cohort suggested that expression of MCM2, MCM4, MCM5, and MCM6 were significantly associated with hepatitis B virus-related HCC overall survival (OS). However, none of the MCM genes were associated with recurrence-free survival in the GSE14520 cohort. The validation cohort of TCGA suggested that the expression of MCM2, MCM6, and MCM7 were significantly correlated with HCC OS. Conclusion: Our study indicated that MCM2-7 genes may be potential diagnostic biomarkers in patients with HCC. Among them, MCM2 and MCM6 may serve as potential prognostic biomarkers for HCC. PMID- 30026835 TI - PDE4a predicts poor prognosis and promotes metastasis by inducing epithelial mesenchymal transition in hepatocellular carcinoma. AB - Phosphodiesterases (PDEs) was found to be involved in a variety of cancer pathologies by modulating the degradation of levels of cAMP/cGMP. However, the prognostic significance and biological effect of PDE4a in hepatocellular carcinoma (HCC) have not been understood completely. In the present study, PDE4a expression was detected in a cohort of HCC and matched adjacent liver tissues (n = 210) by immunohistochemistry staining and Western immunoblotting assay, And in vitro experiments were conducted to determine the effect of PDE4a on metastatic capacity of HCC cells. The data here displayed that the majority of HCC patients had higher PDE4a expression in tumor tissues compared to matched adjacent liver tissues and enhanced PDE4a expression in tumor tissues was associated positively with HBV infection, liver cirrhosis, higher serum AFP level, advanced TNM stage, vascular embolus, intrahepatic metastases and portal vein tumor thrombus (PVTT). Survival analyses suggested that higher PDE4a was indicated the poor prognosis of HCCs after liver resection. Ectopic expression of PDE4a in Huh7 cells leaded to significant repression of E-cadherin and up-regulated the expression of N cadherin and Vimentin, and facilitated migration and invasion abilities. Silencing PDE4a in MHCC97h cells acquired the opposite results. Taken together, PDE4a triggered EMT in HCC cells and acted as a predictive factor candidate and a potential therapeutic target for HCC. PMID- 30026836 TI - Prognostic Values of CCNE1 Amplification and Overexpression in Cancer Patients: A Systematic Review and Meta-analysis. AB - A number of studies revealed that CCNE1 copy number amplification and overexpression (on mRNA or protein expression level) were associated with prognosis of diverse cancers, however, the results were inconsistent among studies. So we conducted this systematic review and meta-analysis to investigate the prognostic values of CCNE1 amplification and overexpression in cancer patients. PubMed, Cochrane library, Embase, CNKI and WanFang database (last update by February 15, 2018) were searched for literatures. A total of 20 studies were included and 5 survival assessment parameters were measured in this study, which included overall survival (OS), progression free survival (PFS), recurrence free survival (RFS), cancer specific survival (CSS) and distant metastasis free survival (DMFS). Pooled analyses showed that CCNE1 amplification might predict poor OS (HR=1.59, 95% CI: 1.05-2.40, p=0.027) rather than PFS (HR=1.49, 95% CI: 0.83-2.67, p=0.177) and RFS (HR=0.982, 95% CI: 0.2376-4.059, p=0.9801) in various cancers; CCNE1 overexpression significantly correlated with poor OS (HR=1.52, 95% CI: 1.05-2.20, p=0.027), PFS (HR=1.20, 95% CI: 1.07-1.34, p=0.001) and DMFS (HR=1.62, 95% CI: 1.09-2.40, p=0.017) rather than RFS (HR=1.68, 95% CI: 0.81 3.50, p=0.164) and CSS (HR=1.54, 95% CI: 0.74-3.18, p=0.246). On the whole, these results indicated CCNE1 amplification and overexpression were associated with poor survival of patients with cancer, suggesting that CCNE1 might be an effective prognostic signature for cancer patients. PMID- 30026837 TI - Comparison of vascularity observed using contrast-enhanced 3D ultrasonography and pathological changes in patients with hepatocellular carcinoma after sorafenib treatment. AB - Aim: The aim of this study was to compare vascularity observed using contrast enhanced 3D ultrasonography and pathological changes in human hepatocellular carcinoma (HCC) and surrounding non-tumorous areas after sorafenib treatment. Materials and methods: Twelve patients with HCC were enrolled in this clinical study. The maximum tumor diameter as measured using sonography ranged from 15 to 33 mm (mean, 24.0 mm; SD, 5.7 mm). Assessments using contrast-enhanced (0.2 mL of Sonazoid suspension; Daiichi Sankyo, Tokyo, Japan) 3D ultrasonography (LOGIQ 7; GE Healthcare, Milwaukee) were performed in all the patients before and 1 week after sorafenib treatment. The microvessel density (MVD) of the HCC and surrounding non-tumorous area was evaluated based on the immunohistochemical staining of microvessels using an antigen for CD34. Results: Blood flow in the tumor was decreased in all 12 cases after sorafenib treatment. The MVD of the tumorous area at 1 week after sorafenib administration (38.8 +/- 5.2) was significantly lower than that observed before sorafenib administration (72.4 +/- 13.0) (P < 0.01). Blood flow in the non-tumorous area had decreased in 6 cases at 1 week after sorafenib treatment and had not changed in the 6 other cases. In the reduced blood flow group, the MVD of the non-tumorous area at 1 week after sorafenib administration had decreased significantly, compared with the MVD of the non-tumorous area before sorafenib administration. However, in the group with no change in blood flow, the MVD of the non-tumorous area at 1 week after sorafenib treatment had not changed, compared with the MVD of the non-tumorous area before sorafenib treatment. Conclusion: Contrast-enhanced 3D ultrasonography studies showed a correlation between vascularity and pathological changes in human HCC and the surrounding non-tumorous area after sorafenib treatment. PMID- 30026838 TI - ELTD1 Function in Hepatocellular Carcinoma is Carcinoma-Associated Fibroblast Dependent. AB - Introduction: EGF, latrophilin, and seven transmembrane domain containing 1 (ELTD1) constitutes an orphan G-protein-coupled receptor (GPCR) of the adhesion family. High expression of ELTD1 is correlated with favorable prognosis of hepatocellular carcinoma (HCC). After silencing ELTD1 expression, however, tumor invasiveness is drastically reduced. The underlying mechanism of this apparent contradictory phenomenon is unknown. Because adhesion GPCRs couple extracellular adhesion to intracellular signaling, as a member of this family, ELTD1 function may be related to its tumor microenvironment. We therefore investigated the interaction between ELTD1 and the HCC tumor microenvironment. Methods: ELTD1 expression was assessed by immunohistochemical analyses of tissue samples from two independent groups of 333 patients with HCC. Correlations between the ELTD1 expression and the clinicopathological values were examined. We also constructed ELTD1 overexpression and knockdown HCC cell lines and conducted a series of in vivo and in vitro ELTD1 functional assays. We further collected carcinoma associated fibroblast (CAF) culture supernatants to culture HCC cell lines and repeat the respective functional assays in comparison with the control group. Results: Clinicopathologic correlations and in vivo models indicated ELTD1 as a tumor suppressor gene, whereas in vitro experiments suggested that ELTD1 could promote malignancy in HCC cell lines. Immunohistochemical staining of the generated ELTD1 overexpression xenograft tumors demonstrated that the CAF markers vimentin and alpha-SMA were highly expressed compared to the control group. This suggests that ELTD1 expression is correlated to CAF distribution. In addition, culturing with CAF supernatants inhibited HCC cell proliferation and invasion rates, confirming the correlation between CAF and ELTD1. Conclusion: The results of this study indicated that ELTD1 regulation of HCC progression is CAF dependent, suggesting that ELTD1 function is regulated by its tumor microenvironment. Further investigation is required to determine the underlying mechanisms. PMID- 30026839 TI - Additional lymphadenectomy might not improve survival of patients with resectable metastatic colorectal adenocarcinoma of T4 stage, proximal location, poor/undifferentiation, or N3/N4 stages: a large population-based study. AB - This study was performed to evaluate the prognostic effect of lymphadenectomy on outcomes in patients with resectable metastatic colorectal adenocarcinoma (mCRC). We selected patients with mCRC from 2004 to 2013 from Surveillance, Epidemiology, and End Results Program (SEER) database. Kaplan-Meier analysis, univariate Cox regression and multivariate Cox regression analysis were performed to assess the clinical value of lymphadenectomy on overall survival (OS) and cause-specific survival (CSS) of patients with resectable mCRC. A total 24178 eligible patients were included, 23056 (95.36%) of which received lymphadenectomy. Results showed that lymphadenectomy was an independent protective factor for survival of patients with mCRC overall [OS (HR: 0.86, 95%CI: 0.79-0.93, P=0.002) and CSS (HR: 0.85, 95%CI: 0.78-0.93, P<0.001)]. Further analysis showed that lymphadenectomy improved survival of patients with T1 stage [OS (HR: 0.51, 95%CI: 0.39-0.66, P<0.001); CSS (HR: 0.48, 95%CI: 0.36-0.65, P<0.001)], distal [OS (HR: 0.65, 95%CI: 0.56-0.75, P<0.001); CSS (HR: 0.65, 95%CI: 0.65-0.75, P<0.001)], rectal [OS (HR: 0.60, 95%CI: 0.52-0.70, P<0.001); CSS (HR: 0.59, 95%CI: 0.51-0.69, P<0.001)] , well/moderately differentiated [OS (HR: 0.62, 95%CI: 0.56-0.70, P<0.001); CSS (HR: 0.62, 95%CI: 0.55-0.69, P<0.001)], N1 stage [OS (HR: 0.76, 95%CI: 0.67-0.85, P<0.001); CSS (HR: 0.74, 95%CI: 0.65-0.84, P<0.001)] and N2 stage [OS (HR: 0.63, 95%CI: 0.54-0.74, P<0.001; CSS (HR: 0.65, 95%CI: 0.55-0.77, P<0.001)) mCRC. While lymphadenectomy might not improve survival of patients with T4 stage, proximal, poor or undifferentiated, N3 and N4 stage mCRC. In general, Additional lymphadenectomy was suggested for patients with mCRC overall. However, lymphadenectomy might not improve survival of patients with mCRC of higher malignancy tendency, such as T4 stage, proximal location, poor or undifferentiation, N3 and N4 stages. PMID- 30026840 TI - LncRNA MALAT1 negatively regulates MDSCs in patients with lung cancer. AB - Myeloid-derived suppressor cells (MDSCs) have strong immunosuppressive functions and contribute to the formation of the tumor microenvironment. Long non-coding (Lnc) RNAs are highly important factors associated with tumors and may be used as markers for tumor diagnosis, which is valuable for targeted therapy. LncRNA MALAT1 is expressed in various tissues and plays a critical role in cell proliferation, including tumorigenesis and metastasis. However, the role of MALAT1 in MDSCs is unclear. In this study, we observed an increased proportion of MDSCs and elevated levels of the related molecule arginase-1 (ARG-1) in peripheral blood mononuclear cells (PBMCs) obtained from lung cancer patients. The proportion of CD8+ cytotoxic T lymphocyte (CTL) was significantly decreased in PBMCs from lung cancer patients. Moreover, the proportion of CTL cells was negatively correlated with the proportion of MDSCs. Furthermore, MALAT1 levels were decreased in PBMCs from lung cancer patients. The relative expression of MALAT1 was moderate negatively correlated with the proportion of MDSCs. In vitro results indicate that the knockdown of MALAT1 significantly increased the proportion of MDSCs. Our data provide the first evidence that lncRNA MALAT1 negatively regulates MDSCs and is decreased in PBMCs from lung cancer patients. PMID- 30026841 TI - Dosimetric Effects of Head and Neck Immobilization Devices on Multi-field Intensity Modulated Radiation Therapy for Nasopharyngeal Carcinoma. AB - Background: In practice, the dose perturbation effect of head and neck immobilization devices is often overlooked in intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC). Purpose of this study is to verify and analyze the dosimetric effect of head and neck immobilization devices on NPC multi-field IMRT. Methods: Ten patients with nasopharyngeal carcinoma were randomly selected. Two sets of body contours were established for each patient. One set of body contours did not contain the immobilization device, and the other contour set included the immobilization device. For each patient, dose calculations were conducted for the two sets of contours using the same 9-field IMRT plan, which were recorded as Plan- and Plan+. The dose difference caused by the head and neck immobilization devices was assessed by comparing the dose volume histogram (DVH) parameter results and by plan subtraction. The gafchromic EBT3 film and anthropomorphic phantom were used to verify the calculated doses. Results: The target coverage and average dose of Plan+ were lower than those of Plan- : the prescription dose coverage rates for PTVnx, PTVnd, PTV1 and PTV2 decreased by 2.4%, 9.9%, 1.5%, and 3.6%, respectively, and the mean doses were reduced by 0.9%, 1.9%, 1.1%, and 1.5%, respectively. Doses in the organs at risk showed no significant differences or slight reductions (the maximum reduction in mean dose was 1.7%). From the EBT3 measurements, the skin dose on the posterior neck was increased by approximately 53%. Conclusion: The attenuation and bolus effects of the head and neck immobilization device reduce dose coverage rate and average dose of the planning target volumes in nasopharyngeal carcinoma and lead to an increase in the skin dose. During treatment planning and dose calculation, the immobilization device should be included within body contour to account for the dose attenuation and skin dose increment. PMID- 30026842 TI - Effect of FAM196B in human lung adenocarcinoma. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. The present study focused on the function of family with sequence similarity 196 member B (FAM196B) in lung adenocarcinoma (LUAD). We analyzed lung carcinoma patients' data from the Cancer Genome Atlas (TCGA), and verify the change of FAM196B expression in 30 LUAD tissues and matched adjacent non-tumor tissues (> 5 cm) by tissue microarray. To investigate the role of FAM196B in LUAD, we used lentivirus-mediated short hairpin RNA (shRNA) to knockdown FAM196B expression in human LUAD cell line A549 and H1299 and assessed it by RT-qPCR and western blot. Celigo Imaging Cytometry System, MTT assays and colony formation were conducted to evaluate cell proliferation. Cell apoptosis were assayed by Annexin V staining. We found that FAM196B was significantly upregulated (P=5.06E-06) in LUAD compared with adjacent non-tumor tissues. Cell proliferation was inhibited in FAM196B-silenced A549 and H1299 cells using Celigo Imaging Cytometry System, MTT assays and colony formation assays. Apoptosis rate was significantly increased in FAM196B-shRNA group than the control group. In conclusion, Knockdown of FAM196B can inhibit cell proliferation, cell colony formation capacity, and promote cell apoptosis in A549 and H1299 cell lines. FAM196B may be one novel potential targets for treating patients with LUAD. PMID- 30026843 TI - miR-423 rs6505162 C>A polymorphism contributes to decreased Wilms tumor risk. AB - Wilms tumor (WT) is the most prevalent urologic malignancy in childhood. Nonetheless, the genetic factors underlying WT remain largely unknown. The miR 423 rs6505162 C>A polymorphism is associated with the susceptibility to numerous cancers; however, no investigations have been conducted on its association with WT. To evaluate the correlation between the miR-423 rs6505162 C>A polymorphism and WT risk in Chinese children, we genotyped this polymorphism using the Taqman method in 145 cases and 531 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the association. The results showed that the rs6505162 CA genotype was associated with decreased susceptibility to WT (CA versus CC: adjusted OR=0.65, 95% CI=0.42 0.99, P=0.047). In the stratified analysis, we found that CA/AA genotypes conferred a significantly decreased overall risk of WT in children younger than 18 months (adjusted OR=0.30, 95% CI=0.14-0.63, P=0.002) and those with clinical stage I+II WT (adjusted OR=0.42, 95% CI=0.20-0.85, P=0.017) when compared with CC genotype. In summary, the miR-423 rs6505162 C>A polymorphism may negatively modify WT susceptibility in Chinese children. Our findings should be validated in larger studies involving other ethnicities. PMID- 30026844 TI - Impact of Prognostic Nutritional Index on Overall Survival for Patients with Metastatic Urothelial Carcinoma. AB - Background: Prognostic nutritional index (PNI) has been studied in various types of cancer which is significantly correlated with prognosis. The study aims to investigate the predictive role of PNI in patients with metastatic urothelial carcinoma (mUC) treated with systemic chemotherapy. Methods: We retrospectively reviewed 141 patients with mUC who received systemic chemotherapy. PNI was calculated as 10 * serum albumin concentration (g/dL) + 0.005 * lymphocyte count (number/mm2). The optimal cut-off value for PNI was estimated by using receiver operating curve analysis. Independent factors associated with progression-free survival (PFS) and overall survival (OS) were determined by Cox proportional regression models. Results: The recommended cut-off value for PNI was 40. Patients with a low PNI had more visceral metastases (p < 0.0001), leukocytosis (p = 0.006), and anemia (p < 0.0001). On univariate analysis, patients with a low PNI had poor OS than those with a high PNI (p < 0.0001). The multivariate analysis showed PNI was an independent factor to predict OS (p = 0.001). Conclusions: Our study showed PNI is an independent prognostic factor in patients with mUC. Our work is clinically useful for anticipation of outcomes, risks stratification in clinical studies as well as patients counseling. PMID- 30026845 TI - HE4 and eIF3a Expression Correlates with Surgical Outcome and Overall Survival in Ovarian Cancer Patients with Secondary Cytoreduction. AB - For recurrent ovarian cancer (ROC), secondary cytoreductive surgery (SCS) is recommended as one optional treatment. However, little is known about the expression and clinical significance of biomarkers during SCS. Human epididymis protein 4 (HE4) is a clinical biomarker for ovarian cancer. Eukaryotic translation initiation factor 3a (eIF3a) is investigated extensively as a potential biomarker for malignancy. The purpose of this study was to investigate the expressions of HE4 and eIF3a at SCS, as well as their associations with surgical outcome and survival in ROC patients. Immunohistochemistry was performed to determine the expressions of HE4 and eIF3a in ovarian tumors taken from both initial and secondary cytoreductive surgery of 35 ROC patients. eIF3a levels were significantly increased at SCS, compared to those at initial cytoreductive surgery (ICS), while HE4 levels were similar. Both HE4 and eIF3a expressions were associated with surgical outcome, in terms of residual tumor. For ICS, patients with high HE4 expression achieved a higher incidence of optimal cytoreduction than those with low HE4 expression (81.0% vs. 33.3%, P = 0.015). A similar result happened in SCS, indicated by higher incidence of no residual tumor in patients with high HE4 expression (76.4% vs. 44.4%, P = 0.046). And high HE4 expression at SCS was more likely to enhance surgical outcome of SCS (77.8% vs. 29.4%, P = 0.038). Therefore, high HE4 expression at either surgery is a predictor of better overall survival (OS) (P = 0.011 and 0.002). Furthermore, patients with an elevated total score (TS) of HE4 between the two surgeries tended to have prolonged OS, compared to those with a non-elevated TS of HE4 (P = 0.076). For eIF3a, initial eIF3a expression was associated with secondary residual tumor (P = 0.035), and the difference in eIF3a expression between the two surgeries correlated with OS (P = 0.052). The expressions of HE4 and eIF3a in tumor specimens correlated with surgical outcome and predicted OS in ROC patients with SCS, thus meriting further investigation. PMID- 30026846 TI - Cry 1 Regulates the Clock Gene Network and Promotes Proliferation and Migration Via the Akt/P53/P21 Pathway in Human Osteosarcoma Cells. AB - The many circadian clock genes buildup a network structure that controls physiological processes such as sleep cycle, metabolism and hormone secretion. A close relationship exists between circadian rhythm and cancers because cell cycle is affected by clock controlled genes (CCGs), including Cyclin D1, Cyclin A, Cyclin E and P21. The abnormal expression of the core circadian clock gene Cryptochrome 1 (Cry1) was found in many types of cancers. However, it is still unclear the exact mechanism of Cry1 dysregulation influences carcinogenesis and progression of cancers. In this study, we investigated the role of Cry1 in regulating proliferation and migration of Hos and U2os human osteosarcoma cells by silencing Cry1 using short hairpin RNA interference. Our data from in vitro and in vivo experiments confirmed that Cry1 knockdown enhanced proliferation and migration of osteosarcoma cells. Then, Cry2, Per1, Per2, Per3, Bmal1 and Clock were found up regulated, while Dec1, Dec2, CK1epsilon and Npas2 were downregulated at mRNA level. Besides, Akt/P53/P21 signaling was activated after Cry1 silencing and Akt was negatively phosphorylated along with Cry1 expression, while enhanced progression of osteosarcoma cells by Cry1 knockdown was reversed when Akt inhibitor treated. Furthermore, the rescue experiment verified the Akt/P53/P21 was downstream genes of Cry1 to control osteosarcoma progression. Taken together, these findings provide a new insight into how Cry1 regulates clock gene network and promotes proliferation and migration in a Akt dependent manner in human osteosarcoma cells. PMID- 30026847 TI - MCT1 regulates aggressive and metabolic phenotypes in bladder cancer. AB - Background: Monocarboxylate transporter isoform 1 (MCT1) is an important molecule in mediating lactate transportation. Recent studies have shown an oncogenic role of MCT1 in cancer development. Methods: In this study, we aimed to investigate the expression and role of MCT1 in bladder cancer (BCa). MCT1 expression was detected in 124 BCa tissues and their clinicopathological significance was analyzed. We also used The Cancer Genome Atlas database to explore the prognostic association of MCT1 with BCa. Cell proliferation, migration and invasion assays were performed on BCa cells in which MCT1 was downregulated. The effect of MCT1 on BCa cell aerobic glycolysis, as well as its association with HIF-1alpha, was tested. Results: We found that high MCT1 expression correlated with lymph node and distant metastasis. Patients with high-MCT1 expression showed shorter overall survival than those with low-MCT1 expression. Knockdown of MCT1 inhibited BCa cell proliferation, migration and invasion, and affected expression of epithelial mesenchymal transition related proteins. Downregulation of MCT1 decreased lactate levels in cell medium, as well as HK2, GLUT1 and LDHB expression. In addition, MCT1 expression was partly dependent on HIF-1alpha. Conclusions: Taken together, our study has shown a prognostic role of MCT1 in BCa, and provided potential diagnostic and therapeutic options for BCa patients. PMID- 30026848 TI - The significant prognostic value of ZEB1-AS1 up-regulation in patients with cancer. AB - Zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) is a long non-coding RNA, which has found to unregulated in various kinds of cancer. This meta analysis was conducted to demonstrate the association between ZEB1-AS1 expression levels and clinical outcome or prognosis of cancer patients.10 studies with 783 cancer patients were included in this meta-analysis by retrieving 5 databases (PubMed Central, EMBASE, Cochrane Library, Wiley Online Library and Medline).The result showed that overexpression of ZEB1-AS1 is significantly correlated with poor OS (Hazard ratio, HR=2.45, 95% confidence interval, CI: 1.89-3.16). ZEB1-AS1 expression levels were also associated with clinicopathological parameters including lymph node metastasis (Yes vs. No; OR=4.00, 95%CI: 2.23-7.17, P<0.00001), histologic differentiation (Moderate + poor vs. Well; OR=2.72, 95% CI: 1.69-4.37, p<0.0001), tumor metastasis and invasion (Yes vs. No; OR =2.52, 95%CI: 1.12-5.68, P=0.03) and TNM stage (III+IV vs. I+II; OR=2.76, 95 %CI 1.46 5.21, P=0.002). However, ZEB1-AS1 expression was not significantly associated with patients' gender (Male vs. Female; OR=1.20, 95% CI: 0.87-1.66; P=0.27).This meta-analysis indicated the potential value of ZEB1-AS1 as a biomarker for predicting a poor prognosis in patients with cancer. PMID- 30026850 TI - Association of endothelial nitric oxide synthase (eNOS) polymorphisms with EGFR mutated lung adenocarcinoma in Taiwan. AB - EGFR mutation of Non-small cell lung cancers (NSCLC) was predominantly seen in Asian population and it was considered as a predictor of responsiveness. Eendothelial nitric oxide synthase (eNOS) plays a vital role in chronic inflammation and carcinogenesis. In this study, we aimed to explore the association between the genetic polymorphisms of eNOS (-786T/C and 894 G/T) and EGFR mutation in patients with lung adenocarcinoma. A total of 277 patients with diagnosed lung adenocarcinoma were recruited between years 2012 and 2015. All study subjects underwent the analysis of eNOS genetic variants (-786 T/C and 894 G/T) using real-time polymerase chain reaction (PCR) genotyping. Our results showed that, among the 277 patients, variant types (GT + TT) of eNOS 894 G/T polymorphism were significantly positively correlated with EGFR mutation type, specifically exon 19 in-frame deletion. With the subgroup of EGFR L858R mutation, variant genotypes (GT + TT) of eNOS 894 G/T were significantly associated with lymph node invasion. Moreover, in silico analysis indicated that eNOS 894 G/T altered the eNOS expression. In conclusion, our study showed that eNOS 894 G/T variants were significantly associated with EGFR mutation types of lung adenocarcinoma, specifically exon 19 in-frame deletion. This may be utilized as a prediction of tumor invasiveness and therapy responsiveness. PMID- 30026849 TI - Effects of the intestinal microbial metabolite butyrate on the development of colorectal cancer. AB - Colorectal cancer (CRC) is one of the major health threats in developed countries. Changes in dietary components, such as more protein and lipid intake, can increase the risk of CRC. Diet affects CRC in many ways. They regulate the composition and function of gut microbiota, which have an amazing metabolic capacity and can produce short chain fatty acids (SCFAs), such as propionate, acetate, and butyrate. Butyrate is a principal energy source for colonic epithelial cells and plays an important role in maintaining the stability of gut microbiota and the integrity of intestinal epithelium. However, there are few studies reviewing the anti-CRC potentials of butyrate. This review summarizes the recent research progresses in the effect of gut microbiota imbalance and the decrease in intestinal microbial metabolite butyrate caused by unbalanced diet on CRC development, and discusses the mechanisms of butyrate-induced anti-CRC activities, which may guide people to prevent CRC by improving diet structures. PMID- 30026851 TI - Prognostic Value of Programmed Cell Death 1 Ligand-1 (PD-L1) or PD-1 Expression in Patients with Osteosarcoma: A Meta-Analysis. AB - Purpose: Programmed cell death 1 ligand-1 (PD-L1) and PD-1 as prognostic biomarkers have spurred considerable interest in several types of malignant tumors. In the present meta-analysis, we aimed to elucidate the clinicopathological and prognostic values of PD-L1/PD-1 in osteosarcoma. Methods: We systematically searched PubMed, Web of Science, EMBASE, Scopus, CBM and the Cochrane Library databases up to March 3, 2018. Eligible studies assessing the relationship between PD-L1 or PD-1 expression and clinicopathological and prognostic outcomes in osteosarcoma were incorporated. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were used to estimate the outcomes. Results: Eight studies involving 413 patients were incorporated into our meta analysis. Pooled results showed that PD-L1/PD-1 overexpression was significantly associated with metastasis (RR = 1.54, 95% CI: 1.12-2.11, p = 0.008) in osteosarcoma. Furthermore, osteosarcoma patients exhibited a remarkably higher total mortality risk (RR = 1.86, 95% CI: 1.09-3.17, p = 0.021) with PD-L1/PD-1 overexpression. However, no significant reduced overall survival rate (RR = 0.70, 95% CI: 0.46-1.07, p = 0.103) was detected in the study. Conclusion: Our meta analysis indicates that PD-L1/PD-1 may serve as an important biomarker for adverse clinicopathologic features and poor prognosis in patients with osteosarcoma. PMID- 30026852 TI - Association Analysis between Body Mass Index and Genomic DNA Methylation across 15 Major Cancer Types. AB - Cancer incidence and mortality increase with increasing body mass index (BMI), but BMI-associated epigenetic alterations in cancer remain elusive. We hypothesized that BMI would be associated with DNA methylation alterations in cancers. To test this hypothesis, here, we estimated the associations between DNA methylation and BMI through two different methods across 15 cancer types, at approximately 485,000 CpG sites and 2415 samples using data from The Cancer Genome Atlas. After comparing the DNA methylation levels in control BMI and high BMI individuals, we found differentially methylated CpG sites (DMSs) in cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), and uterine corpus endometrial carcinoma (UCEC) (False Discovery Rate < 0.05). The DMSs of COAD or UCEC were enriched in several obesity-induced and cancer-related pathways. Next, when BMI was used as a continuous variable, we identified BMI-associated methylated CpG sites (BMS) (P (Bonferroni) < 0.05) in CHOL (BMS = 1), COAD (BMS = 1), and UCEC (BMS = 4) using multivariable linear regression. In UCEC, three of the BMSs can predict the clinical outcomes and survival of patients with the tumors. Overall, we observed associations between DNA methylation and high BMI in CHOL, COAD, and UCEC. Furthermore, three BMI-associated CpGs were identified as potential biomarkers for UCEC prognosis. PMID- 30026853 TI - Nomograms and risk scores for predicting the risk of oral cancer in different sexes: a large-scale case-control study. AB - Background: Although previous studies have explored the associations of modifiable lifestyle factors with oral cancer risk, few studies integrated these factors and established predictive tools for oral cancer risk in different sexes. Methods: Using a case-control study design, a total of 978 oral cancer cases and 2646 healthy controls were recruited in this study. Nomograms were constructed according to significant factors in multivariable logistic regression. Risk scores were calculated based on the nomograms and quantified the risk of oral cancer using restricted cubic spline. Results: Multivariate analyses demonstrated that smoking, alcohol drinking, tea, intake of fish, seafood, vegetables, fruits, teeth loss, regular dental visits and repetitive dental ulcer were independent factors for male oral cancer. Passive smoking, age at first intercourse, cooking oil fumes exposure, tea, intake of beans, vegetables, fruits, teeth loss, regular dental visits and repetitive dental ulcer were associated with female oral cancer. Then, two nomograms were developed for predicting the probability of oral cancer in men and women with the C-index of 0.768 (95% CI: 0.723-0.813) and 0.700 (95% CI: 0.635-0.765), respectively. Restricted cubic splines graphically revealed the risk of oral cancer in individuals with different risk scores. Moreover, the risk escalated continuously with the increasing number of the risk scores among both sexes. Conclusions: Combining nomograms with risk scores developed in this study could precisely predict oral cancer occurrence and provide an accurate risk assessment. PMID- 30026855 TI - ADAM10 Sheddase Activity is a Potential Lung-Cancer Biomarker. AB - Background: Increases in expression of ADAM10 and ADAM17 genes and proteins are inconsistently found in cancer lesions, and are not validated as clinically useful biomarkers. The enzyme-specific proteolytic activities, which are solely mediated by the active mature enzymes, directly reflect enzyme cellular functions and might be superior biomarkers than the enzyme gene or protein expressions, which comprise the inactive proenzymes and active and inactivated mature enzymes. Methods: Using a recent modification of the proteolytic activity matrix analysis (PrAMA) measuring specific enzyme activities in cell and tissue lysates, we examined the specific sheddase activities of ADAM10 (ADAM10sa) and ADAM17 (ADAM17sa) in human non-small cell lung-carcinoma (NSCLC) cell lines, patient primary tumors and blood exosomes, and the noncancerous counterparts. Results: NSCLC cell lines and patient tumors and exosomes consistently showed significant increases of ADAM10sa relative to their normal, inflammatory and/or benign-tumor controls. Additionally, stage IA-IIB NSCLC primary tumors of patients who died of the disease exhibited greater increases of ADAM10sa than those of patients who survived 5 years following diagnosis and surgery. In contrast, NSCLC cell lines and patient tumors and exosomes did not display increases of ADAM17sa. Conclusions: This study is the first to investigate enzyme-specific proteolytic activities as potential cancer biomarkers. It provides a proof-of-concept that ADAM10sa could be a biomarker for NSCLC early detection and outcome prediction. To ascertain that ADAM10sa is a useful cancer biomarker, further robust clinical validation studies are needed. PMID- 30026856 TI - Prognostic and Clinicopathological Value of Rac1 in Cancer Survival: Evidence from a Meta-Analysis. AB - Purpose: The role of Rac1 in cancer survival has been widely studied. However, the prognostic and clinicopathological value of Rac1 remains inconclusive. We performed a meta-analysis to clarify the role of Rac1 in cancer survival as well as its association with clinicopathological features. Methods: Eligible studies were searched from PubMed, Cochrane Library, Embase, and Web of Science databases. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic and clinicopathological role of Rac1. Results: A total of 14 studies including 1793 patients were enrolled in the present meta-analysis. Pooled HR for overall survival (OS) (HR=2.02, 95% CI: 1.70-2.39) and disease-free survival (DFS) (HR=2.64, 95% CI: 1.71-4.09) indicated a significant poor prognostic effect for Rac1. Positive Rac1 expression was found to be correlated with tumor stage, blood vessel invasion, and lymph metastasis, but not with histological differentiation. Sensitivity test showed no single study altered OS or DFS significantly. No publication bias was detected by Egger's test and Begg's funnel plot test. Conclusion: This meta-analysis indicated that Rac1 could be used as a potential marker to predict cancer prognosis. Additionally, Rac1 expression was associated with the malignancy-related phenotype. PMID- 30026854 TI - The emergence of long non-coding RNAs in hepatocellular carcinoma: an update. AB - Hepatocellular carcinoma (HCC) accounting for roughly 90% of all primary liver neoplasms is the sixth most frequent neoplasm and the second prominent reason of tumor fatality worldwide. As regulators of diverse biological processes, long non coding RNAs (lncRNAs) are involved in onset and development of neoplasms. With the continuous booming of well-featured lncRNAs in HCC from 2016 to now, we reviewed the newly-presented comprehension about the relationship between lncRNAs and HCC in this study. To be specific, we summarized the overview function and study tools of lncRNAs, elaborated the roles of lncRNAs in HCC, and sketched the molecule mechanisms of lncRNAs in HCC. In addition, the application of lncRNAs serving as biomarkers in early diagnosis and outcome prediction of HCC patients was highlighted. PMID- 30026857 TI - Long non-coding RNA CRYBG3 regulates glycolysis of lung cancer cells by interacting with lactate dehydrogenase A. AB - Cancer cells usually utilize glucose as a carbon source for aerobic glycolysis, a phenomenon known as the Warburg effect. And a high rate of glycolysis has been observed in lung cancer cells. The growing evidence indicates that long non coding RNAs (lncRNAs) are important players in lung cancer initiation and progression. However, the correlation between lncRNAs and glycolysis remains unclear. In this study, we recognized a lncRNA, LNC CRYBG3, which can interact with lactate dehydrogenase A (LDHA), a vital enzyme of glycolysis, is highly upregulated in both clinical lung cancer tissues and in vitro cultured lung cancer cell lines. A positive correlation between the expression level of LNC CRYBG3 and LDHA expression levels is observed. In another hand, LNC CRYBG3 is a regulator of glycolysis and its overexpression promoted the uptake of glucose and the production of lactate whereas the knockdown of LNC CRYBG3 led to opposite results and suppressed cell proliferation. These results indicated that LNC CRYBG3 might be a novel target for lung cancer treatment. PMID- 30026858 TI - Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins. AB - Complete tumor removal during surgery has a great impact on patient survival. To that end, the surgeon should detect the tumor, remove it and validate that there are no residual cancer cells left behind. Residual cells at the incision margin of the tissue removed during surgery are associated with tumor recurrence and poor prognosis for the patient. In order to remove the tumor tissue completely with minimal collateral damage to healthy tissue, there is a need for diagnostic tools that will differentiate between the tumor and its normal surroundings. Methods: We designed, synthesized and characterized three novel polymeric Turn-ON probes that will be activated at the tumor site by cysteine cathepsins that are highly expressed in multiple tumor types. Utilizing orthotopic breast cancer and melanoma models, which spontaneously metastasize to the brain, we studied the kinetics of our polymeric Turn-ON nano-probes. Results: To date, numerous low molecular weight cathepsin-sensitive substrates have been reported, however, most of them suffer from rapid clearance and reduced signal shortly after administration. Here, we show an improved tumor-to-background ratio upon activation of our Turn-ON probes by cathepsins. The signal obtained from the tumor was stable and delineated the tumor boundaries during the whole surgical procedure, enabling accurate resection. Conclusions: Our findings show that the control groups of tumor-bearing mice, which underwent either standard surgery under white light only or under the fluorescence guidance of the commercially available imaging agents ProSense(r) 680 or 5-aminolevulinic acid (5-ALA), survived for less time and suffered from tumor recurrence earlier than the group that underwent image-guided surgery (IGS) using our Turn-ON probes. Our "smart" polymeric probes can potentially assist surgeons' decision in real-time during surgery regarding the tumor margins needed to be removed, leading to improved patient outcome. PMID- 30026860 TI - Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo lysosomal route. AB - Protein therapeutics is playing an increasingly critical role in treatment of human diseases. However, current vectors are captured by the digestive endo lysosomal system, which results in an extremely low fraction (<2%) of protein being released in the cytoplasm. This paper reports a drug-delivering-drug platform (HA-PNPplex, 200 nm) for potent intracellular delivery of protein and combined treatment of cancer. Methods: The platform was prepared by loading functional protein on pure drug nanoparticles (PNPs) followed by hyaluronic acid coating and was characterized by dynamic light scattering, transmission electron microscopy, and gel electrophoresis. In vitro, cellular uptake, trafficking, and cytotoxicity were evaluated by flow cytometry and confocal laser microscopy. Protein expression was assayed by western blot. In vivo, blood circulation and biodistribution were studied using a fluorescence imaging system, antitumor efficacy was assessed in a caspase 3-deficient tumor model, and biocompatibility was determined by comparison of hemolytic activity and proinflammatory cytokines and tissue histology. Results: HA-PNPplex delivered the functional protein, caspase 3, to cells via bypassing endo-lysosomes and raised the caspase-3 level 6.5-fold in caspase 3-deficient cells. Promoted tumor accumulation (1.5-fold) and penetration were exhibited, demonstrating a high tumor-targeting ability of HA PNPplex. HA-PNPplex rendered a 7-fold increase in caspase 3 in tumor and allowed for a 100% tumor growth inhibition and >60% apoptosis, implying significant antitumor activities. Conclusions: This platform gains cellular entry without entrapment in the endo-lysosomes and enables efficient intracellular protein delivery and resultant profound cancer treatment. This platform, with extremely high drug-loading, is a valuable platform for combined cancer therapy with small molecule drugs and proteins. More importantly, this work offers a robust and safe approach for protein therapeutics and intracellular delivery of other functional peptides, as well as gene-based therapy. PMID- 30026859 TI - "Three-in-one" Nanohybrids as Synergistic Nanoquenchers to Enhance No-Wash Fluorescence Biosensors for Ratiometric Detection of Cancer Biomarkers. AB - Purpose: Early diagnosis of cancer enables extended survival and reduced symptoms. To this end, a "three-in-one" nanohybrid of MOF@AuNP@GO is designed as synergistic nanoquencher to develop a novel fluorescence biosensor for rapid and sensitive detection of cancer-related biomarkers. Methods: The ssDNA absorption affinities and fluorescence quenching abilities of the MOF@AuNP@GO were evaluated using FAM-labeled single-stranded DNA (ssDNA). Then, two specific dye-labeled ssDNA and aptamer probes were designed for the recognition of p53 gene and prostate specific antigen (PSA), respectively. Fluorescence spectra were recorded and ratiometric signal processing was performed. Results: The designed nanohybrids exhibit enhanced ssDNA binding affinities and fluorescence quenching abilities, which significantly decrease the background signal and increase the signal-to-noise (S/N) ratio, thus lowering the detection limit (LOD). Accordingly, with ratiometric measurement, this developed nanosensor can sensitively measure p53 gene and PSA with LODs of 0.005 nM and 0.01 ng mL-1, respectively. Besides, this method also displays excellent performances with respect to universality, multiplexed detection, specificity, and practicality in human serum. Conclusion: The designed MOF@AuNP@GO-based fluorescence biosensor can serve as a promising platform for washing-free, rapid and sensitive measurement of cancer biomarkers, making this method well-suited for point-of care (POC) diagnosis. PMID- 30026861 TI - Powerful anti-colon cancer effect of modified nanoparticle-mediated IL-15 immunogene therapy through activation of the host immune system. AB - Rationale: Colorectal cancer (CRC) is the third most commonly diagnosed cancer around the world. Over the past several years, immunotherapy has demonstrated considerable clinical benefit in CRC therapy, and the number of immunologic therapies for cancer treatment continues to climb each year. Interleukin-15 (IL15), a potent pro-inflammatory cytokine, has emerged as a candidate immunomodulator for the treatment of CRC. Methods: In this study, we developed a novel gene delivery system with a self-assembly method using DOTAP and MPEG-PLA (DMA) to carry pIL15, denoted as DMA-pIL15 which was used to treat tumor-bearing mice. Results: Supernatant from lymphocytes treated with supernatant derived from CT26 cells transfected with DMA-pIL15 inhibited the growth of CT26 cells and induced cell apoptosis in vitro. Treatment of tumor-bearing mice with DMA-pIL15 complex significantly inhibited tumor growth in both subcutaneous and peritoneal models in vivo by inhibiting angiogenesis, promoting apoptosis, and reducing proliferation through activation of the host immune system. Conclusion: The IL-15 plasmid and DMA complex showed promise for treating CRC clinically as an experimental new drug. PMID- 30026862 TI - Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression. AB - Many plant-specialized metabolites have remedial properties and provide an endless chemical resource for drug discovery. However, most of these metabolites have promiscuous binding targets in mammalian cells and elicit a series of responses that collectively change the physiology of the cells. To explore the potential of these multi-functional and multi-targeted drugs, it is critical to understand the direct relationships between their key chemical features, the corresponding binding targets and the relevant biological effects, which is a prerequisite for future drug modification and optimization. Methods: We introduced and demonstrated a general workflow, called Comparative Profiling of Analog Targets (CPAT), to connect specific biological effects with defined chemical structures of drugs. Using resveratrol (RSV) as an example, we have synthesized and characterized a series of partial functional analogs of RSV. An analog (named RSVN) that specifically lost the inhibitory effect of RSV in cell migration was identified. The binding targets of RSVN and RSV was profiled and compared. Results: Comparative profiling of the RSV and RSVN binding targets showed that, unlike RSV, RSVN failed to target specific components involved in DNA methylation (histone deacetylase 1 [HDAC1] and DNA methyltransferase 3 alpha [DNMT3a]), suggesting that RSV suppresses cell migration through epigenetic regulation. Indeed, RSV treatment recruited HDAC1 and DNMT3a to the promoter region of the focal adhesion kinase (FAK), a key factor involved in cell adhesion, enhanced the promoter methylation, and thus attenuated the protein expression. The inhibitory effect of RSV in cell migration was diminished once FAK expression was restored. Thus, the mechanism of RSV in inhibiting cell migration could be largely accounted to epigenetically control of FAK expression. Conclusion: Our results showed that even though RSV exhibits promiscuous binding, its inhibitory effect on cell migration can be mechanistically understood. First, the presence of 4'-hydroxystilbene within the RSV structure is essential for this activity. Second, it inhibits cell migration through epigenetically based downregulation of FAK expression. Taken together, we propose that CPAT might also be adapted to delineate the specific function of other natural products (NPs) that exhibit binding promiscuity. PMID- 30026863 TI - HUWE1 controls the development of non-small cell lung cancer through down regulation of p53. AB - Lung cancer is the most frequent cancer type and the leading cause of tumor associated deaths worldwide. TP53 is an important tumor suppressor gene and is frequently inactivated in lung cancer. E3 ligases targeting p53, such as MDM2, are involved in the development of lung cancer. The E3 ligase HUWE1, which targets many tumor-associated proteins including p53, has been reported to be highly expressed in lung cancer; however, its role in lung tumorigenesis is unclear. Methods: The expression of HUWE1 and p53 in lung cancer cells was modulated and the phenotypes were assessed by performing soft agar colony forming assays, cell cycle analysis, BrdU incorporation assays, and xenograft tumor growth assays. The effect on tumorigenesis in genetically-engineered mice was also analyzed. The mechanism through which HUWE1 sustained lung cancer cell malignancy was confirmed by western blotting. HUWE1 expression in clinical lung cancer was identified by immunohistochemistry and validated by analyzing lung adenocarcinoma and lung squamous carcinoma samples from the Cancer Genome Atlas (TCGA) database. Finally, we assessed the association between HUWE1 expression and patient outcome using online survival analysis software including survival information from the caBIG, GEO, and TCGA database. Results: Inactivation of HUWE1 in a human lung cancer cell line inhibited proliferation, colony-forming capacity, and tumorigenicity. Mechanistically, this phenotype was driven by increased p53, which was due to attenuated proteasomal degradation by HUWE1. Up regulation of p53 inhibited cancer cell malignancy, mainly through the induction of p21 expression and the down-regulation of HIF1alpha. Huwe1 deletion completely abolished the development of EGFRVIII-induced lung cancer in Huwe1 conditional knockout mice. Furthermore, survival analysis of lung cancer patients showed that increased HUWE1 expression is significantly associated with worse prognosis. Conclusion: Our data suggest that HUWE1 plays a critical role in lung cancer and that the HUWE1-p53 axis might be a potential target for lung cancer therapy. PMID- 30026864 TI - CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice. AB - Rationale: Peripheral blood monocytes are recruited into the ischemic brain and transform into macrophages after stroke. Nevertheless, the exact role of CCR2 dependent monocytes/macrophages in brain injury after stroke remains elusive. Methods: We used CCR2 knockout (KO) mice and the CCR2 pharmacological inhibitor, propagermanium (PG), to address the role of CCR2-dependent monocytes/macrophages in the acute stage and neurological functional recovery after middle cerebral artery (MCA) occlusion and reperfusion. Results: CCR2 KO resulted in smaller infarct size and lower mortality than in wild type (WT) mice, when measured 3 days after stroke. However, from 5 to 28 days after stroke, the KO mice had higher mortality and showed no obvious neurological functional recovery. In addition, WT mice treated with PG had similar stroke outcomes compared with CCR2 KO, as measured by T2 weighted MRI. Flow cytometry and real-time PCR analyses suggest that monocyte-derived macrophages (MoDMs) in the stroke brains mainly polarized to pro-inflammatory macrophages at the early stage, but gradually switched to anti-inflammatory macrophages at 7 days after stroke. In addition, adoptive transfer of anti-inflammatory macrophages into CCR2 KO mice at 4 and 6 days after stroke alleviated mortality and promoted neurological recovery. Conclusion: CCR2-dependent monocytes/macrophages are a double-edged sword; they worsen acute brain injury, but are essential for neurological recovery by promoting anti-inflammatory macrophage polarization. PMID- 30026865 TI - A novel HPV16 E7-affitoxin for targeted therapy of HPV16-induced human cervical cancer. AB - Cervical cancer, the second most common cause of cancer death in women worldwide, is significantly associated with infection of high-risk human papillomaviruses (HPVs), especially the most common genotype, HPV 16. To date, there is no established noninvasive therapy to treat cervical cancer. Methods: Here, we report a novel affitoxin that targets HPV16 E7 protein, one of the primary target proteins in molecular targeted therapy for HPV-induced cervical cancer. The affitoxin, ZHPV16E7 affitoxin384 was generated by fusing the modified Pseudomonas Exotoxin A (PE38KDEL) to the HPV16 E7-specific affibody. The expressed and purified ZHPV16E7 affitoxin384 was characterized using numerous methods. SPR assay, indirect immunofluorescence assay, and near-infrared (NIR) optical imaging were respectively performed to assess the targeting ability of ZHPV16E7 affitoxin384 to HPV16 E7 protein both in vitro and in vivo. Cell viability assays and SiHa tumor-bearing nude mice were used to evaluate the efficacy of ZHPV16 E7 affitoxin384 in vitro and in vivo, respectively. Results: Using in vitro methods the SPR assay and indirect immunofluorescence assay showed that ZHPV16E7 affitoxin384 targeted HPV16 E7 with high binding affinity and specificity. Significant reduction of cell viability in HPV16 positive cells was observed in the presence of ZHPV16 E7 affitoxin384. By NIR optical imaging, ZHPV16 E7 affitoxin384 specifically targeted HPV16 positive tumors in vivo. ZHPV16E7 affitoxin384 showed significant in vivo antitumor efficacy in two kinds of tumor bearing nude mouse models. Conclusions: ZHPV16E7 affitoxin384 is a potent anti cervical cancer therapeutic agent that could be effective against HPV16 positive tumors in humans. PMID- 30026866 TI - Noninvasive imaging of the PD-1:PD-L1 immune checkpoint: Embracing nuclear medicine for the benefit of personalized immunotherapy. AB - Molecular imaging of the immune checkpoint receptor PD-1 and its ligand PD-L1 is increasingly investigated as a strategy to guide and monitor PD-1:PD-L1-targeted immune checkpoint therapy. We provide an overview of the current state-of-the-art on PD-1- and PD-L1-specific imaging agents for quantitative, real-time assessment of PD-1:PD-L1 expression in the tumor environment and discuss their potential for clinical translation. PMID- 30026868 TI - Tumor-targeted hybrid protein oxygen carrier to simultaneously enhance hypoxia dampened chemotherapy and photodynamic therapy at a single dose. AB - Hypoxia is a characteristic feature of solid tumors and an important causation of resistance to chemotherapy and photodynamic therapy (PDT). It is challenging to develop efficient functional nanomaterials for tumor oxygenation and therapeutic applications. Methods: Through disulfide reconfiguration to hybridize hemoglobin and albumin, tumor-targeted hybrid protein oxygen carriers (HPOCs) were fabricated, serving as nanomedicines for precise tumor oxygenation and simultaneous enhancement of hypoxia-dampened chemotherapy and photodynamic therapy. Based on encapsulation of doxorubicin (DOX) and chlorin e6 (Ce6) into HPOCs to form ODC-HPOCs, the mechanism and therapeutic efficacy of oxygen enhanced chemo-PDT was investigated in vitro and in vivo. Results: The precise oxygen preservation and release of the HPOC guaranteed sufficient tumor oxygenation, which is able to break hypoxia-induced chemoresistance by downregulating the expressions of hypoxia-inducible factor-1alpha (HIF-1alpha), multidrug resistance 1 (MDR1) and P-glycoprotein (P-gp), resulting in minimized cellular efflux of chemodrug. Moreover, the oxygen supply is fully exploited for upgrading the generation of reactive oxygen species (ROS) during the photodynamic process. As a result, only a single-dose treatment of the HPOCs-based chemo-PDT exhibited superior tumor suppression. The combination therapy was guided by in vivo fluorescence/photoacoustic imaging with nanoparticle tracking and oxygen monitoring. Conclusion: This well-defined HPOC as a versatile nanosystem is expected to pave a new way for breaking multiple hypoxia-induced therapeutic resistances to achieve highly effective treatment of solid tumors. PMID- 30026867 TI - Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/beta-catenin pathway in hepatocellular carcinoma. AB - It has been reported that the transcription factor activating enhancer-binding protein 4 (TFAP4) is upregulated and associated with an aggressive phenotype in several cancers. However, the precise mechanisms underlying the oncogenic role of TFAP4 remain largely unknown. Methods: TFAP4 expression levels in hepatocellular carcinoma (HCC) cells and tissues were detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of TFAP4 in the tumor-initiating cell (TIC) like phenotype and the tumorigenic capability of HCC cells. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays were performed to determine the underlying mechanism of TFAP4-mediated HCC aggressiveness. Results: TFAP4 was markedly upregulated in human HCC, and was associated with significantly poorer overall and relapse-free survival in patients with HCC. Furthermore, we found that overexpression of TFAP4 significantly enhanced, whereas silencing TFAP4 inhibited, the tumor sphere formation ability and proportion of side-population cells in HCC cells in vitro, and ectopic TFAP4 enhanced the tumorigenicity of HCC cells in vivo. Mechanistically, we demonstrated that TFAP4 played an important role in activating Wnt/beta-catenin signaling by directly binding to the promoters of DVL1 (dishevelled segment polarity protein 1) and LEF1 (lymphoid enhancer binding factor 1). Conclusions: Our results provide new insight into the mechanisms underlying hyperactivation of the Wnt/beta-catenin pathway in HCC, as well the oncogenic ability of TFAP4 to enhance the tumor-forming ability of HCC cells. PMID- 30026869 TI - Cell-penetrating peptide-based nanovehicles potentiate lymph metastasis targeting and deep penetration for anti-metastasis therapy. AB - Lymph metastasis is a vital pathway of cancer cell dissemination, and insidious lymph node metastasis increases the risk of distant cancer metastasis. Current therapies for lymph metastasis are largely restricted by limited targeting and penetration capacity. Herein, we report that an r9 cell-penetrating peptide-based cabazitaxel nanovehicle (r9-CN) displays prominent lymph metastasis targeting and deep penetration ability after intravenous injection for effective anti metastasis therapy. Methods: The r9-CN and CN nanovehicles were prepared by thin film dispersion, using DSPE-PEG2000 as the nano-carrier material and cabazitaxel as the model drug to fabricate r9-modified nano-micelles by self-assembly. The morphology, size, and stability in physiological solutions of r9-CN and CN were characterized. The targeting, biodistribution, deep penetration, and therapeutic efficacy of r9-CN and CN were systematically explored in vitro and in vivo. Results: The r9-CN nanovehicle consists of homogeneous particles with a mean diameter of 13 nm and zeta potential of +0.75 mV. Compared with the nanovehicle lacking the r9 peptide (CN), r9-CN exhibits long retention and deep penetration in the tumor mass, and considerably enhances accumulation and flexible permeation in metastatic lymph nodes, thereby notably suppressing primary tumor growth, lymph node metastasis, and distant lung metastasis. Conclusion: The cumulative findings reveal that r9-CN offers a promising delivery platform, enabling efficient lymph metastasis targeting and deep penetration for effective anti metastasis therapy. PMID- 30026870 TI - Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation. AB - Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response. Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments. Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components. Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80, Cd11b and Tnf and the distant tumors to enhanced Cd11c, Cd3 and Ifng. When ablation was added to immunotherapy, 100% (n=20/20) of directly treated tumors and 90% (n=18/20) of distant tumors were responsive. Comparing the combined ablation-immunotherapy treatment to immunotherapy alone, we find three major mechanistic differences. First, while ablation alone enhanced intratumoral antigen cross-presentation (up to ~8% of CD45+ cells), systemic cross-presentation of tumor antigen remained low. Combining same-site ablation with CpG amplified cross-presentation in the draining lymph node (~16% of CD45+ cells) compared to the ablation-only (~0.1% of CD45+ cells) and immunotherapy-only cohorts (~10% of CD45+ cells). Macrophages and DCs process and present this antigen to CD8+ T-cells, increasing the number of unique T-cell receptor rearrangements in distant tumors. Second, type I interferon (IFN) release from tumor cells increased with the ablation immunotherapy treatment as compared with ablation or immunotherapy alone. Type I IFN release is synergistic with toll-like receptor activation in enhancing cytokine and chemokine expression. Expression of genes associated with T-cell activation and stimulation (Eomes, Prf1 and Icos) was 27, 56 and 89-fold higher with ablation-immunotherapy treatment as compared to the no-treatment controls (and 12, 32 and 60-fold higher for immunotherapy-only treatment as compared to the no-treatment controls). Third, we found that the ablation-immunotherapy treatment polarized macrophages and dendritic cells towards a CD169 subset systemically, where CD169+ macrophages are an IFN-enhanced subpopulation associated with dead-cell antigen presentation. Conclusion: While the local and distant responses are distinct, CpG combined with ablative focal therapy drives a highly effective systemic immune response. PMID- 30026871 TI - Development of a novel peptide aptamer-based immunoassay to detect Zika virus in serum and urine. AB - Zika virus (ZIKV) has been identified as a cause of adverse outcomes of pregnancy, including microcephaly and other congenital diseases. Most people infected with ZIKV do not show any symptoms. Development of a method to discriminate dengue virus (DENV) and ZIKV infections has been challenging, and efficient assays for patient management are limited, attributable to high levels of cross-reactivity among co-circulating Flaviviruses. Thus, there is an urgent need for a specific high-throughput diagnostic assay to discriminate ZIKV infections from other Flavivirus infections. Methods: A novel epitope peptide of the ZIKV envelope protein was predicted using three immune epitope database analysis tools and then further modified. A molecular docking study was conducted using three-dimensional structures of the ZIKV envelope and peptide. Experimentally, interactions between the selected peptides and virus were assessed via a fluorescence-linked sandwich immunosorbent assay (FLISA), and performance of peptide-linked sandwich FLISA was evaluated in virus-spiked human serum and urine. Results: The Z_10.8 peptide (KRAVVSCAEA) was predicted to be a suitable detector, with a higher binding affinity than other candidates based on four criteria (binding affinity, root mean square deviation, position of amine residue of lysine at the N-terminus, and interactive site) in a docking study. Z_10.8 was significantly more efficient at detecting ZIKV than the other two peptides, as shown in the direct FLISA (P < 0.001). Further, the equilibrium dissociation constant (Kd) for the Z_10.8 peptide was 706.0 +/- 177.9 (mean +/- SD, nM), with specificity to discriminate ZIKV from DENV. The limit of detection for the sandwich FLISA was calculated as 1*104 tissue culture infective dose (TCID)50/mL. The presence of serum or urine did not interfere with the performance of the Z_10.8-linked sandwich FLISA. Conclusion: Four criteria are suggested for the development of an in silico modeled peptide aptamer; this computerized peptide aptamer discriminated ZIKV from DENV via immunoassay. PMID- 30026872 TI - Phosphorylation of IRS4 by CK1gamma2 promotes its degradation by CHIP through the ubiquitin/lysosome pathway. AB - IRS4, a member of the insulin receptor substrate protein family, can induce constitutive PI3K/AKT hyperactivation and cell proliferation even in the absence of insulin or growth factors and promote tumorigenesis, but its regulation has only been explored at the transcriptional level. Methods: Scansite was used to predict the potential protein kinases that may regulate the functions of IRS4, and mass spectrometry was used to identify the E3 ligase for IRS4. The protein interaction was carried out by immunoprecipitation, and protein stability was measured by cycloheximide treatment. In vitro kinase assay was used to determine the phosphorylation of IRS4 by casein kinase 1gamma2 (CK1gamma2). Colony formation assay and xenograft-bearing mice were employed to assess the cancer cell growth in vitro and in vivo, respectively. Immunohistochemistry was performed to examine protein levels of both IRS4 and CK1gamma2 in osteosarcoma specimens and their relationship was evaluated by chi2 test. Two-tailed Student's t-test or the Mann-Whitney U test were used to compare the differences between subgroups. Results: IRS4 was phosphorylated at Ser859 by CK1gamma2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). Using osteosarcoma cell lines, the ectopic nonphosphorylated mutant of IRS4 by CK1gamma2 triggered higher level of p-Akt and displayed faster cell proliferation and cancer growth in vitro and in nude mice. In addition, a negative correlation in protein levels between CK1gamma2 and IRS4 was observed in osteosarcoma cell lines and tissue samples. Conclusions: IRS4, as a new substrate of CHIP, is negatively regulated by CK1gamma2 at the posttranslational level, and specific CK1gamma2 agonists may be a potentially effective strategy for treating patients with osteosarcoma. PMID- 30026875 TI - Punching and Electroporation for Enhanced Transdermal Drug Delivery. AB - Transdermal delivery has made an indispensable impact to medical practice, but often been limited by low efficiency due to the barrier of the outer stratum corneum layer of skin. In Issue 9 of Theranostics, Huang et al. [1] proposed a new design of transdermal gene delivery strategy via the combination of a microneedle roller and a flexible interdigitated electroporation array. With the assistance of the microneedle roller, a deep and uniform electric field in the skin can be formed, accompanying an enhanced transport efficiency even at a low voltage. Furthermore, this combination strategy can promote the gene expression and siRNA transfection in mice skin in a safe and convenient process. PMID- 30026874 TI - In vivo tracking and quantification of inhaled aerosol using magnetic particle imaging towards inhaled therapeutic monitoring. AB - Pulmonary delivery of therapeutics is attractive due to rapid absorption and non invasiveness but it is challenging to monitor and quantify the delivered aerosol or powder. Currently, single-photon emission computed tomography (SPECT) is used but requires inhalation of radioactive labels that typically have to be synthesized and attached by hot chemistry techniques just prior to every scan. Methods: In this work, we demonstrate that superparamagnetic iron oxide nanoparticles (SPIONs) can be used to label and track aerosols in vivo with high sensitivity using an emerging medical imaging technique known as magnetic particle imaging (MPI). We perform proof-of-concept experiments with SPIONs for various lung applications such as evaluation of efficiency and uniformity of aerosol delivery, tracking of the initial aerosolized therapeutic deposition in vivo, and finally, sensitive visualization of the entire mucociliary clearance pathway from the lung up to the epiglottis and down the gastrointestinal tract to be excreted. Results: Imaging of SPIONs in the lung has previously been limited by difficulty of lung imaging with magnetic resonance imaging (MRI). In our results, MPI enabled SPION lung imaging with high sensitivity, and a key implication is the potential combination with magnetic actuation or hyperthermia for MPI-guided therapy in the lung with SPIONs. Conclusion: This work shows how magnetic particle imaging can be enabling for new imaging and therapeutic applications of SPIONs in the lung. PMID- 30026873 TI - Angio-LncRs: LncRNAs that regulate angiogenesis and vascular disease. AB - Long noncoding RNAs (lncRNAs) represent a large subgroup of RNAs that are longer than 200 nucleotides and have no apparent protein coding potential. They have diverse functions in different biological processes by regulating chromatin remodeling or protein translation. This review summarizes the recent progress of lncRNAs in angiogenesis and vascular diseases. A general overview of lncRNA functional mechanisms will be introduced. A list of lncRNAs, which are termed "Angio-LncRs", including MALAT1, MANTIS, PUNISHER, MEG3, MIAT, SENCR and GATA6 AS, will be discussed regarding their expression, regulation, function and mechanism of action in angiogenesis. Implications of lncRNAs in vascular diseases, such as atherosclerosis, hypertension, vascular retinopathies and tumor angiogenesis will also be discussed. PMID- 30026876 TI - Take a Deep Breath - Monitoring of Inhaled Nanoparticles with Magnetic Particle Imaging. AB - Magnetic Particle Imaging (MPI) is a new imaging modality based on the visualization of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) using magnetic fields. The potential of MPI was recently evaluated in numerous ex vivo and in vivo studies and the technique can now be considered as an established preclinical imaging modality with a promising perspective of clinical applications. PMID- 30026877 TI - Precise theranostic nanomedicines for inhibiting vulnerable atherosclerotic plaque progression through regulation of vascular smooth muscle cell phenotype switching. AB - Coronary heart disease is a prevalent and fatal killer caused by vulnerable atherosclerotic plaques (VASPs). However, the precise detection and treatment of VASPs remains a difficult challenge. Here, we present the development of noninvasive human serum albumin (HSA)-based theranostic nanomedicines (NMs) for the specific diagnosis and effective therapy of VASPs. Methods: The ICG/SRT@HSA pept NMs were formulated to contain payloads of the near-infrared (NIR) fluorescent dye indocyanine green (ICG) and the sirtuin 1 (Sirt1) activator SRT1720, and modified with a peptide moiety targeting osteopontin (OPN). The in vivo atherosclerotic mouse model was established with the high-fat diet (HFD). The in vitro vascular smooth muscle cells (VSMCs) phenotypic switching was induced using the ox-LDL stimulation. Results: Due to the overexpression of OPN in activated VSMCs and VASPs, the targeted NMs specifically accumulated within the VASPs region after intravenous injection into the atherosclerotic mice, achieving the precise detection of VASPs. In addition, in the presence of SRT1720, the NMs could activate intracellular Sirt1 and activate an antiatherogenesis effect by inhibiting the phenotypic switching of VSMCs, which is an essential contributor to the vulnerability and progression of atherosclerotic plaques. After therapeutic administration of the ICG/SRT@HSA-pept NMs for two weeks, the physiological sizes and plaque compositions of VASPs were markedly improved. Furthermore, ICG/SRT@HSA-pept NMs-treated mice presented a more favorable plaque phenotype than that was observed in free SRT1720-treated mice, suggesting the enhanced delivery of pharmaceutical agents to the atherosclerotic lesions and improved therapeutic efficacy of NMs compared with free SRT1720. Conclusions: The theranostic ICG/SRT@HSA-pept NMs showed great potential for the precise identification and targeted treatment of atherosclerotic diseases. PMID- 30026879 TI - Young, Black, and (Still) in the Red: Parental Wealth, Race, and Student Loan Debt. AB - Taking out student loans to assist with the costs of postsecondary schooling in the US has become the norm in recent decades. The debt burden young adults acquire during the higher education process, however, is increasingly stratified with black young adults holding greater debt burden than whites. Using data from the NLSY 1997 cohort, we examine racial differences in student loan debt acquisition and parental net wealth as a predictor contributing to this growing divide. We have four main results. First, confirming prior research, black young adults have substantially more debt than their white counterparts. Second, we find that this difference is partially explained by differences in wealth, family background, postsecondary educational differences, and family contributions to college. Third, young adults' net worth explain a portion of the black-white disparity in debt, suggesting that both differences in accumulation of debt and ability to repay debt in young adulthood explain racial disparities in debt. Fourth, the black-white disparity in debt is greatest at the highest levels of parents' net worth. Our findings show that while social and economic experiences can help explain racial disparities in debt, the situation is more precarious for black youth, who are not protected by their parents' wealth. This suggests that the increasing costs of higher education and corresponding rise in student loan debt are creating a new form of stratification for recent cohorts of young adults, and that student loan debt may be a new mechanism by which racial economic disparities are inherited across generations. PMID- 30026878 TI - AP-2beta inhibits hepatocellular carcinoma invasion and metastasis through Slug and Snail to suppress epithelial-mesenchymal transition. AB - Transcription factor AP-2beta plays an important role in human cancer, but its clinical significance in hepatocellular carcinogenesis is largely unknown. Methods: AP-2beta expression was detected in human hepatocellular cancer (HCC) tissues and cell lines. The effects of AP-2beta on HCC proliferation, migration, invasion, tumor formation and metastasis were evaluated by MTT, colony formation and transwell assays in vitro and mouse experiments in vivo. The association between AP-2beta and miR-27a/EMT markers in HCC cell lines and tissues was analyzed. Results: AP-2beta expression was decreased in HCC tissues and cell lines. Reduced expression of AP-2beta was significantly associated with more advanced tumor stages and larger tumor sizes. The overexpression of AP-2beta reduced HCC proliferation, migration, invasion, tumor formation and metastasis in vitro and in vivo. Additionally, AP-2beta overexpression increased the sensitivity of HCC cells to cisplatin. Moreover, AP-2beta modulates the levels of EMT markers through Slug and Snail in HCC cell lines and tissues. Furthermore, oncogenic miR-27a inhibits AP-2beta expression by binding to the AP-2beta 3' untranslated region (UTR) and reverses the tumor suppressive role of AP-2beta. Conclusion: These results suggested that AP-2beta is lowly expressed in HCC by inhibiting EMT signaling to regulate HCC cell growth and migration. Therefore, AP 2beta in the novel miR-27a/AP-2beta/Slug/EMT regulatory axis enhances the chemotherapeutic drug sensitivity of HCC and might represent a potential target for evaluating the treatment and prognosis of human HCC. PMID- 30026880 TI - Positive Correlation of Serum N-Acetyl-beta-hexosaminidase with Markers of Atherosclerosis in Diabetes Type 2 Patients with Mild Symptoms of Depression and Anxiety. AB - Background: Analysis of the correlation between diabetes type 2 (DT2) and serum N acetyl-beta-hexosaminidase (HEX) activity with parameters of fat metabolism and symptoms of anxiety and depression. Material and Method: The study was performed using a random sample of 40 DT2 patients (22 women and 18 men) between the ages of 43 and 71 (median 59) and 40 control persons (28 women and 12 men) between the ages of 18 and 64 (median 46). The activity of HEX was determined by a colorimetric method. The activity of the serum exoglycosidase was expressed in pkat/mL. Each participant underwent Hamilton tests, to evaluate level of anxiety and depression. Additionally, the HEX activity and concentration of particular lipidograms were monitored using a blood sample from each participant. Results: In DT2 patients, a significant positive correlation was found between serum HEX activity and the concentration of serum cholesterol LDL fractions, triacylglycerols (TAG), and Castelligro atherogenic indexes. A significantly increased level of anxiety and depression in comparison to the control group was found as well. Conclusion: Serum HEX activity in DT2 patients is a better marker of atherosclerosis than serum total cholesterol level in persons with mild symptoms of depression and anxiety. In DT2 patients, a routine testing of anxiety and depression is recommended. Early detection of these disorders creates the possibility for treatment, an improvement in a patient's quality of life, and the overall longevity of DT2 patients. PMID- 30026882 TI - Biomarkers in Infectious Diseases. PMID- 30026881 TI - A Panel of MicroRNA Signature as a Tool for Predicting Survival of Patients with Urothelial Carcinoma of the Bladder. AB - Introduction and Objectives: MicroRNA (miRNA) expression is altered in urologic malignancies, including urothelial carcinoma of the bladder (UCB). Individual miRNAs have been shown to modulate multiple signaling pathways that contribute to BC. To identify a panel of miRNA signature that can predict aggressive phenotype from normal nonaggressive counterpart using miRNA expression levels and to assess the prognostic value of this specific miRNA markers in patients with UCB. Methods: To determine candidate miRNAs as prognostic biomarkers for dividing aggressive type of UCB, miRNA expression was profiled in patients' samples with an aggressive phenotype or nonaggressive phenotype using 3D-Gene miRNA labeling kit (Toray, Japan). To create a prognostic index model, we used the panel of 9 miRNA signature based on Cancer Genome Atlas (TCGA) data portal (TCGA Data Portal (https://tcgadata.nci.nih.gov/tcga/tcgaHome2.jsp)). miRNA expression data and corresponding clinical data, including outcome and staging information of 84 UCB patients, were obtained. The Kaplan-Meier and log-rank test were performed to quantify the survival functions in two groups. Results: Deregulation of nine miRNAs (hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR 4324, hsa-miR-34b-5p, hsa-miR-29c-3p, hsa-miR-135a-3p, and hsa-miR-33b-3p) was determined in UCB patients with aggressive phenotype compared with nonaggressive subject. To validate the prognostic power of the nine-signature miRNAs using the TCGA dataset of bladder cancer, the survival status and tumor miRNA expression of all 84 TCGA UCB patients were ranked according to the prognostic score values. Of nine miRNAs, six were associated with high risk (hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-4324, hsa-miR-34b-5p, and hsa-miR-135a-3p) and three were shown to be protective (hsa-miR-145-5p, hsa-miR-29c-3p, and hsa-miR-33b-3p). Patients with the high-risk miRNA signature exhibited poorer OS than patients expressing the low-risk miRNA profile (HR = 7.05, p < 0.001). Conclusions: The miRNA array identified nine dysregulated miRNAs from clinical samples. This panel of nine-miRNA signature provides predictive and prognostic value of patients with UCB. PMID- 30026884 TI - Pain of Temporomandibular Disorders: From Etiology to Management. PMID- 30026883 TI - Ozone augments interleukin-8 production induced by ambient particulate matter. AB - Background: Experimental and controlled human exposure studies have demonstrated additive effects of ambient particulate matter and ozone on health. A few epidemiological studies have suggested that ambient particulate matter components are important for the combined effects of ambient particulate matter and ozone on health. However, few studies have examined whether ozone changes the effects of ambient particulate matter on pro-inflammatory cytokine production. In this study, the influence of ozone on pro-inflammatory cytokine production in response to ambient particulate matter was evaluated. Results: Ambient particulate matter smaller than 1 MUm was collected and the suspension of this particulate matter was bubbled through 0.12 ppm and 0.24 ppm ozone. THP1 cells were stimulated by the solution containing the particulate matter with and without bubbling through ozone at 1 MUg/mL. The interleukin-8 concentrations in the supernatants of THP1 cells stimulated by collected particulate matter dissolved in solution were 108.3 +/- 24.7 pg/mL without ozone exposure, 165.0 +/- 26.1 pg/mL for 0.12 ppm ozone bubbling for 1 min, 175.1 +/- 33.1 pg/mL for 0.12 ppm for 5 min, 183.3 +/- 17.8 pg/mL for 0.12 ppm for 15 min, 167.8 +/- 35.9 pg/mL for 0.24 ppm for 1 min, 209.2 +/- 8.4 pg/mL for 0.24 ppm for 5 min, and 209.3 +/- 14.3 pg/mL for 0.24 ppm for 15 min. Ozone significantly increased interleukin-8 concentrations compared to those for particulate matter dissolved in solution without ozone exposure and the solvent only (8.2 +/- 0.9 pg/mL) in an ozone concentration-dependent manner. Collected particulate matter in solutions with or without bubbling through ozone had no effect on interleukin-6 production. The antioxidant N-acetyl-L-cysteine significantly inhibited the increases in interleukin-8 induced by solutions with particulate matter, regardless of ozone exposure. The reactive oxygen species concentration in solutions with collected particulate matter was not associated with ozone bubbling. Conclusion: Ozone may augment the production of interleukin 8 in response to ambient particulate matter by a mechanism unrelated to reactive oxygen species. These results support the epidemiological evidence for combined effects of ambient particulate matter and ozone on human health. PMID- 30026885 TI - Percutaneous cryoablation for stage T1b renal cell carcinoma in a patient with horseshoe kidney. AB - We report the first case of percutaneous cryoablation (PCA) for stage T1b renal cell carcinoma (RCC) in a horseshoe kidney (HK). A 76-year-old man with an HK underwent computed tomography-guided PCA for RCC measuring 42 mm (stage T1b) in diameter. Although transcatheter embolization before the PCA and hydrodissection were required to avoid complication and incomplete ablation, PCA was successfully performed without complication. The complete ablation was confirmed on computed tomography images 1 month after the procedure. There was no recurrence or metastasis during 2 years of follow-up. We believe this is the first report of PCA for stage T1b RCC in a patient with HK. This technique can be performed without regard to tumor size and location and may be considered as a treatment option to avoid complex surgery. PMID- 30026886 TI - An "accidental" discovery: Incidentally found metanephric adenofibroma in a 5 year-old male trauma patient. AB - Metanephric adenofibroma is a rare pediatric renal tumor, which should be considered in cases of solid renal lesions that mimic Wilms tumor on both imaging and histology. We present a case of an incidentally found left renal lesion on a trauma computed tomography scan in a 5-year-old male patient. The patient underwent total nephrectomy, and the diagnosis of metanephric adenofibroma was made on histology. Radiologists should consider this entity in the differential for an incidentally found solitary renal mass in a pediatric patient. Prompting the pathologic diagnosis of this entity can spare patients from unnecessary chemotherapy and allow for nephron-sparing surgery. PMID- 30026887 TI - Highlighting Clinical Metagenomics for Enhanced Diagnostic Decision-making: A Step Towards Wider Implementation. AB - Clinical metagenomics (CMg) is the discipline that refers to the sequencing of all nucleic acid material present within a clinical specimen with the intent to recover clinically relevant microbial information. From a diagnostic perspective, next-generation sequencing (NGS) offers the ability to rapidly identify putative pathogens and predict their antimicrobial resistance profiles to optimize targeted treatment regimens. Since the introduction of metagenomics nearly a decade ago, numerous reports have described successful applications in an increasing variety of biological specimens, such as respiratory secretions, cerebrospinal fluid, stool, blood and tissue. Considerable advancements in sequencing and computational technologies in recent years have made CMg a promising tool in clinical microbiology laboratories. Moreover, costs per sample and turnaround time from specimen receipt to clinical management continue to decrease, making the prospect of CMg more feasible. Many difficulties, however, are associated with CMg and warrant further improvements such as the informatics infrastructure and analytical pipelines. Thus, the current review focuses on comprehensively assessing applications of CMg for diagnostic and subtyping purposes. PMID- 30026888 TI - Prediction of dyslipidemia using gene mutations, family history of diseases and anthropometric indicators in children and adolescents: The CASPIAN-III study. AB - Dyslipidemia, the disorder of lipoprotein metabolism resulting in high lipid profile, is an important modifiable risk factor for coronary heart diseases. It is associated with more than four million worldwide deaths per year. Half of the children with dyslipidemia have hyperlipidemia during adulthood, and its prediction and screening are thus critical. We designed a new dyslipidemia diagnosis system. The sample size of 725 subjects (age 14.66 +/- 2.61 years; 48% male; dyslipidemia prevalence of 42%) was selected by multistage random cluster sampling in Iran. Single nucleotide polymorphisms (rs1801177, rs708272, rs320, rs328, rs2066718, rs2230808, rs5880, rs5128, rs2893157, rs662799, and Apolipoprotein-E2/E3/E4), and anthropometric, life-style attributes, and family history of diseases were analyzed. A framework for classifying mixed-type data in imbalanced datasets was proposed. It included internal feature mapping and selection, re-sampling, optimized group method of data handling using convex and stochastic optimizations, a new cost function for imbalanced data and an internal validation. Its performance was assessed using hold-out and 4-foldcross validation. Four other classifiers namely as supported vector machines, decision tree, and multilayer perceptron neural network and multiple logistic regression were also used. The average sensitivity, specificity, precision and accuracy of the proposed system were 93%, 94%, 94% and 92%, respectively in cross validation. It significantly outperformed the other classifiers and also showed excellent agreement and high correlation with the gold standard. A non-invasive economical version of the algorithm was also implemented suitable for low- and middle-income countries. It is thus a promising new tool for the prediction of dyslipidemia. PMID- 30026889 TI - Current Perspectives of the Chicken Gastrointestinal Tract and Its Microbiome. AB - The microbial communities inhabiting the gastrointestinal tract (GIT) of chickens are essential for the gut homeostasis, the host metabolism and affect the animals' physiology and health. They play an important role in nutrient digestion, pathogen inhibition and interact with the gut-associated immune system. Throughout the last years high-throughput sequencing technologies have been used to analyze the bacterial communities that colonize the different sections of chickens' gut. The most common methodologies are targeted amplicon sequencing followed by metagenome shotgun sequencing as well as metaproteomics aiming at a broad range of topics such as dietary effects, animal diseases, bird performance and host genetics. However, the respective analyses are still at the beginning and currently there is a lack of information in regard to the activity and functional characterization of the gut microbial communities. In the future, the use of multi-omics approaches may enhance research related to chicken production, animal and also public health. Furthermore, combinations with other disciplines such as genomics, immunology and physiology may have the potential to elucidate the definition of a "healthy" gut microbiota. PMID- 30026891 TI - The Rate of Demineralization in the Teeth Prepared by Bur and Er:YAG Laser. AB - Introduction: The present in vitro study evaluated the recurrence rate of caries following cavity preparations with bur (conventional technique) and irradiation by Erbium:Yttrium- Aluminum-Garnet (Er:YAG) laser through micro hardness test. Methods: A total of 72 human extracted molars were randomly divided into 3 groups and class 5 cavities were prepared on them with 3 different methods: G1) conventional bur, G2) Er:YAG laser irradiation alone and G3) laser irradiation + laser treatment. The specimens were immersed in the artificial caries solution with pH of 2.0 and 5.0 (12 days) and then immersed in re-mineralizing solution with pH of 7.0 (25 days). The specimens were longitudinally sectioned and their Vickers micro hardness was determined. Data were statistically analyzed by means of three-way analysis of variance (ANOVA) and Tukey multiple comparisons tests. Results: The micro hardness of the samples was affected by substrate type (enamel and dentin) and low values were achieved in dentin (P<0.001). Moreover, no significant difference was observed between preparation methods by bar and laser irradiation alone (P <=0.499). Although laser irradiation + laser treatment decreased micro hardness of enamel compared to other methods. In dentin samples, different methods of preparation showed no significant effect on micro hardness (P <=0.874). Conclusion: Due to the similar values of micro hardness following G1 and G2, it seems that Er:YAG laser alone is as much effective as the conventional bur to prevent recurrence caries. However, because of the high prices of laser instruments, bur preparations can be done commonly. PMID- 30026890 TI - LANAP, Periodontics and Beyond: A Review. AB - Laser has emerged as an adjunct in several treatment modalities in dentistry in the past few decades. This less invasive bladeless technique is bringing revolutionary outcomes in a plethora of periodontal treatment procedures as well. A unique ameliorative approach termed LANAP, described as laser-assisted new attachment procedure was developed by Gregg and McCarthy. In 1990 they introduced an innovative treatment for diseases of gums incorporating pulsed neodymium yttrium aluminum garnet (Nd: YAG) 1064 nm wavelength laser (PerioLase MVP7). The LANAP concept was endorsed by Yukna et al who conducted a study according to the protocol reinforced at the1996 world workshop in periodontics, which established specific histologic criteria to prove regeneration. Yukna's histological study found that regeneration of the periodontally compromised root could be achieved by Nd: YAG laser. LANAP facilitates refurbishing of new tissues from supporting structures of the periodontium wherein the unhealthy surface of the roots exhibit pristine attachments in human beings. This paper is a review providing a detailed report of LANAP from its inception to recent advances. PMID- 30026892 TI - Effect of Surface Modification on Viability of L929 Cells on Zirconia Nanocomposite Substrat. AB - Introduction: Zirconia bioceramic can be considered for metallic replacement in dental implant applications. A proper method of surface modification may promote better osseointegration. Methods: In study evaluated viability of fibroblast cell following surface treatment. Therefore, viability L929 cells were characterized using MTT assay and scanning electron microscopy. Results: The viability assessment determined significant differences A-Y-TZP20 without surface treatment as compared to laser surface treatment (B), laser surface treatment + hydroxyapatiteyttrium stabilized tetragonal zirconia nanocomposite coat (C) and control. This study demonstrated that L929 cells approximately proliferated and spread on A-Y-TZP20 nanocomposite disk in laser surface treatment(B), Laser surface treatment + hydroxiapatite-yttrium stabilized tetragonal zirconia nanocomposite coat (C) groups similar to control group. Conclusion: Laser surface treatment showed positive effect on the viability of L929 cells. PMID- 30026893 TI - Combined Approach to Treat Medication-Related Osteonecrosis of the Jaws. AB - Introduction: The proper therapeutic plan for medication-related osteonecrosis of the Jaw (MRONJ) is still lacking long-term data up to today. They were several high-technological appliances proposed for the different intervention steps, in addition to tissue repair promoters. The reason for proposing an integrated technique is justified, beyond better compliance of the patients associated to the pain and inflammation reduction and bleeding control, there is also achieving better hard and soft tissues healing. Methods: Patients diagnosed with bisphosphonates-related osteonecrosis of the jaws (BRONJ) at the Odontostomatology and Maxillo-Facial Surgery Unit of the Hospital of Piacenza undergone surgical intervention. The intervention was performed by using different devices: Piezosurgery for removing the necrotic bone tissue and for obtaining the bone specimen essential for histological analysis; Er:YAG laser (2940 nm) to vaporize necrotic hard tissue until reaching the bleeding bone; platelet-rich plasma (PRP) to stimulate hard and soft tissue healing; and finally diode laser (808 nm) to perform a biostimulation of the surgical site. Results: All treated patients demonstrated a good postoperative comfort even without using painkillers, no bleeding, and a fast healing process. Most of the patients (92.85%) reached complete healing with a minimum follow up at 6 months. Histological exams demonstrated a good quality without artifacts. Conclusion: Sequential utilization of different high-technologies devices during all the steps of MRONJ treatment allows to perform a faster and less invasive surgery with a more comfortable postoperative healing process and it may represent a new and original approach for treating this severe adverse event. PMID- 30026894 TI - The Effect of Fractional CO2 Laser Irradiation on Shear Bond Strength of Resin Cement to Feldspathic Porcelain. AB - Introduction: This study investigated the effect of fractional CO2 laser on shear bond strength (SBS) of resin cement to feldspathic porcelain. Methods: Sixty blocks of unglazed feldspathic porcelain were randomly divided into 5 groups of 12 by treatment. Group 1 and 2 underwent etching with 9.6% hydrofluoric acid (HF) and air abrasion with alumina particles, respectively. In groups 3 and 4, a fractional CO2 laser was applied for 10 seconds using 20 W/10 mJ (group 3) or 15 W/20 mJ (group 4). The specimens in group 5 were first treated by fractional CO2 laser (15 W/20 mJ) and then etched by HF acid. After silane application, a resin cement (Clearfil SA) was poured into plastic molds over the porcelain surface and light cured. SBS was assessed by a universal testing machine and the type of bond failure was determined. Results: Analysis of variance (ANOVA) indicated a significant difference in SBS among the study groups (P<0.001). Pairwise comparison demonstrated that the application of fractional CO2 laser followed by HF acid yielded SBS that was significantly greater than that of the other groups (P<0.05). The SBS of both laser groups (groups 3 and 4) were comparable to each other and significantly lower than the other groups (P<0.05). No significant difference was found in the distribution of failure modes among the groups (P=0.522) Conclusion: The application of fractional CO2 laser followed by HF acid treatment can improve SBS of resin cement to feldspathic porcelain and could be recommended when demanding extra retention. PMID- 30026895 TI - Photodynamic Inactivation of Porphyromonas gingivalis utilizing Radachlorin and Toluidine Blue O as Photosensitizers: An In Vitro Study. AB - Introduction:Porphyromonas gingivalis is one of the major pathogens in the development and progression of periodontal disease. Antimicrobial photodynamic therapy (aPDT) is a new approach which is sorted in non-invasive phototherapy for bacterial elimination. This in vitro study was conducted to compare photodynamic inactivation using Radachlorin and Toluidine blue O (TBO) as photosensitizers on P. gingivalis. Methods: Bacterial suspensions (200 uL) of P. gingivalis were exposed to either TBO with concentration of 0.1 mg/mL associated with portable light-emitting diode (LED) device (peak wavelength: 630 nm, output intensity: 2.000 mW/cm2, tip diameter: 6.2 mm) or 0.1% Radachlorin(r) and laser irradiation (InGaAlP, Peak wavelength: 662+/-0.1% nm, output power: 2.5 W, energy density: 6 J/cm2, fiber diameter: 2 mm). Those in control groups were subjected to laser irradiation or LED alone, Radachlorin(r) or TBO alone, and one group received neither photosensitizer nor light irradiation. Then counting of colony forming units (CFU) was performed to determine the bactericidal effects in each subgroup. Results: LED-based aPDT reduced the colony count of P. gingivalis more than that of TBO (P<0.001) or LED group (P=0.957). Also, laser-based aPDT had a great reduction in colony count of P. gingivalis in comparison with Radachlorin(r) (P<0.001) or laser irradiation alone (P=0.28). In addition, the colony count reduction of laser-based aPDT was significantly more than LED-based aPDT (P<0.05). Conclusion: Considering the results of this study, the viability of P. gingivalis was more affected by the combination of laser and Radachlorin(r) 0.1% in comparison with LED and TBO 0.1. PMID- 30026896 TI - Effectiveness of Laser Acupoints on Women With Polycystic Ovarian Syndrome: A Randomized Controlled Trial. AB - Introduction: Polycystic ovarian syndrome (PCOS) is one of the most widely recognized reasons for infertility. The aim of this study was to examine the impact of laser acupuncture on PCOS women. Methods: Twenty-five PCOS women were randomly allocated to either the study group (SG; n=13), treated by laser acupuncture, or the control group (CG; n = 12). Blood hormonal levels and insulin resistance were measured at baseline and after 12 weeks of intervention. Results: The pre-intervention levels showed no statistically significant differences between SG and CG for baseline characteristics (P>0.05). After 12 weeks of intervention, within-group analyses showed that body mass index (BMI), blood hormonal levels, and insulin resistance were significantly decreased (P<0.05), while no significant changes in follicle-stimulating hormone (P>0.05) were recorded in the 2 groups. Between-groups analyses showed that most outcomes measures were significantly decreased (P<0.05) in SG compared with CG, with no significant changes in FSH and BMI (P>0.05). Conclusion: Laser acupuncture can be suggested as an effective management for PCOS women. PMID- 30026897 TI - Therapeutic Effects of Laser on Partial Osteotomy in the Rat Model of Hypothyroidism. AB - Introduction: Several experimental studies have displayed positive result for laser radiation on stimulating bone regeneration in recent years. The purpose of this experimental study was to determine low-level laser (LLL) effects on partial bone defects in hypothyroidism male rat. Methods: Forty male Wistar rats were randomly distributed as below groups: hypothyroidism + laser (Hypo + laser), hypothyroidism (Hypo), and control. Four weeks after surgery, the tibia bone was removed. Biomechanical and histological examinations were performed immediately. Results: Our results showed significant reduction in the absorption of energy, resistance in bending deformation (bending stiffness), maximum force, high stress load, trabecular bone volume, and number of osteocytes, osteoblasts and osteoclasts in the osteotomy site in hypothyroidism rats compared to hypothyroidism + laser group (P<0.05). Conclusion: The results indicated that using laser may improve fracture regeneration and it may accelerate bone healing in hypothyroidism rat. PMID- 30026898 TI - Evaluation of Topical Capislow Extract and Long Pulsed Nd-YAG Laser in the Treatment of Idiopathic Hirsutism. AB - Introduction: Hirsutism is a condition that affects 10% of women worldwide. In many cultures, hirsutism is regarded as loss of femininity and can be psychologically traumatizing to the suffering females. The aim of the present study was to evaluate how topical capislow would affect or enhance the efficacy of laser hair removal. Methods: A randomized, monoblinded, placebo controlled split face study of combined topical capislow and long pulsed Nd-YAG laser on one side of the face versus long pulsed Nd-YAG laser alone on the opposite side of the face. Laser sessions were done at 4 weeks interval for maximum seven sessions. Topical capislow and placebo were applied once daily from the day of the first laser session to the day of the last laser session. Patients were evaluated both subjectively and objectively in each laser session and for six months after the last laser session. Results: Both treatment modalities were well tolerated and accepted with significantly better results in combined capislow and laser group versus laser alone. Conclusion: Topical capislow can represent a safe and effective synergistic method for laser with faster results but this is a temporary effect retained only to the time of its application. PMID- 30026899 TI - Comparative Study Between Low Level Laser and Therapeutic Ultrasound in Second Intention Ulcers Repair in Mice. AB - Introduction: An ulcer is an injury that affects the skin and has many causes. Healing is a way of protecting the body against any infectious agent that tries to infect you through the wound. Low level laser (LLL) in the treatment of ulcers, aims at maintaining the stability of the physiological process of tissue repair and ultrasound (US) acts by increasing the elasticity of tissue and scarring. The aim of this study was to analyze the effects of LLL and US in wound healing of ulcers induced in mice. Methods: In this experimental study, a sample of 36 guinea pigs was divided into 6 groups of 6 mice, 2 groups as control (C7) and (C14), 2 treated with laser (GL7) and (GL14) and the others 2 treated with ultrasound (GU7) and (GU14). The ulcer was induced and after 7 days, 6 mice from each group were sacrificed to obtain the histological sections for analysis, and the remaining 6 mice from each group continued under treatment and in day 14, they were sacrificed to obtain histologic specimens while macroscopic image was also carried out. Results: Three aspects were analyzed, the percentage of wound regression where it was observed that there was a significant difference in the first 7 days. Regarding the inflammatory process, it was observed that in the first 7 days GL7 and GU7 improved significantly and within 14 days of the experimental period GU14 showed a significant difference when compared to C14. The number of fibroblasts present in the GL at 7 days showed a significant difference compared to the others, and at 14 days, the US group had a significant difference compared to the other groups. Conclusion: Thus, it was evident that the US had more effective results with anti-inflammatory action, better organization and increased deposition of collagen and fibroblasts. Therefore, it can be concluded that other studies are consistent with this taking into account the laser must be used during the early days of the initial healing process and the US during the end of this process. PMID- 30026900 TI - Evaluation of the Effects of Low Level Laser Therapy on the Healing Process After Skin Graft Surgery in Burned Patients (A Randomized Clinical Trial). AB - Introduction: Skin graft is the standard therapeutic technique in patients with deep ulcers, but like every surgical procedure, it may present some complications. Although several modern dressings are available to enhance comfort of donor site, the use of techniques that accelerate wound healing may enhance patient's satisfaction. Low level laser therapy (LLLT) has been used in several medical fields, especially for wound healing, but it may take several months for large ulcers treated with laser to heal completely. Methods: Nine patients with bilateral similar grade 3 burn ulcers in both hands or both feet were selected as candidates for split-thickness skin graft (STSG). One side was selected for laser irradiation and the other side as control, randomly. Laser was irradiated every day for 7 days with red 655 nm light, 150 mW, 2 J/cm2 at the bed of the ulcer and with infra-red 808 nm light, 200 mW for the margins. Results: The rate of wound dehiscence after skin graft surgery was significantly lower in laser treated group in comparison to control group which received only classic dressing (P=0.019). Conclusion: The results showed LLLT to be a safe effective method which improves graft survival and wound healing process and decreases the rate of wound dehiscence in patients with deep burn ulcers. PMID- 30026901 TI - Influence of CO2 Laser Irradiation and CPPACP Paste Application on Demineralized Enamel Microhardness. AB - Introduction: It has been suggested that the application of casein phosphopeptide amorphous calcium phosphate paste (CPP-ACP) and CO2 laser irradiation on enamel could increase the resistance of enamel to caries and acid attacks. The aim of the current study was to compare the influence of CPP-ACP paste application and irradiation of CO2 laser on microhardness of demineralized enamel. Methods: Thirty sound maxillary extracted premolars were selected. The crowns were cut at the cervical line and were split into facial and palatal halves. Specimens were mounted in selfcure acrylic blocks in such way that the enamel surface was exposed to 4*4 mm. After a pH cycling of the specimens, they were randomly divided into 4 groups (n=15), as follows: CG: Control group, LAS: CO2 laser, CP: CPP-ACP and LASCP: laser combined CPP-ACP treatment. The Vickers microhardness of the specimens was measured (500 g load, 5 seconds, 3 points). Data were analyzed using one-way ANOVA and post hoc Tukey tests (alpha =0.05). Results: The lowest mean Vickers microhardness value was observed in CG group (192.57+/-50.87 kg/mm2 ) and the highest in LASCP group (361.86+/-22.22 kg/mm2 ). There were significant differences between groups (P<0.001). The pairwise comparison of the groups revealed that there were significant differences between these groups: CG versus LAS, CP, LASCP (P<0.05) and LASCP versus LAS and CP (P<0.05). No significant difference between LAS group versus CP group (P>0.05) was observed. Conclusion: The results of the current study revealed that CO2 laser and CCP-ACP were effective for improvement of enamel hardness value after demineralization. Incorporation of CO2 laser irradiation and CCP-ACP paste application provides additional remineralizing potential for demineralized enamel. PMID- 30026902 TI - Clinical and Radiographic Alterations in Bilateral Avascular Necrosis of the Femoral Head Following Laser Acupuncture: A Case Report. AB - Introduction: Avascular necrosis (AVN) of the femoral head is an increasingly common cause of musculoskeletal disability with unknown etiology. Traumatic and non-traumatic factors can be effective in its occurrence. About 50% of cases are bilateral. The underlying treatment is prosthetic replacement surgical procedure. Case Presentation: We report a case of bilateral AVN of femoral heads who was a candidate for prosthetic replacement surgery but improved significantly, using laser acupuncture. The patient was a 55-year-old woman with a diagnosis of bilateral osteonecrosis of the femoral head for five years. As the patient declined the surgical option, laser acupuncture was started for pain control. Regarding the signs of bilateral femoral head recovery (according to the MRI scan criteria), a total of 3 courses of laser acupuncture (each course was 20 sessions) with 2 months intervals was performed. Ten acupuncture points: Li4, Li11, St36, SP6, LIV3, GB4, GB5, GB6, GB13, GB14, GB20, GB30, GB31, GB34, were irradiated bilaterally using red 650 nm laser, 100 mW, 1505 Hz frequency, duty cycle 50 3 J/point and near infrared 810 nm laser, 100 mW, 1705 Hz frequency, duty cycle 50 3 J/point, for 2 minutes. The patient received 3 laser therapy courses. During the first-course, laser therapy was done every other day to reduce pain. For the second and third courses, according to pain decrease, therapy was done every week. Results: The results of the MRI scans and x-ray studies show progressive regeneration of the right femoral head from VI to B II and of the left from V to C II (based on the standard table of Pennsylvania). Conclusion: It seems that this procedure may be mentioned in future research projects, especially in cases with high risks of surgery. PMID- 30026903 TI - A Method for Tooth Model Reconstruction Based on Integration of Multimodal Images. AB - A complete digital tooth model is needed for computer-aided orthodontic treatment. However, current methods mainly use computed tomography (CT) images to reconstruct the tooth model which may require multiple CT scans during orthodontic progress, and the reconstructed model is also inaccurate in crown area. This study developed a tooth model reconstruction method based on integration of CT images and laser scan images to overcome these disadvantages. In the method, crown models and complete tooth models are first reconstructed, respectively, from laser scan images and CT images. Then, crown models from laser scan images and tooth models from CT images are registered. Finally, the crown from laser scan images and root from CT images were fused to obtain a new tooth model. Experimental results verified that the developed method is effective to generate the complete tooth model by integrating CT images and laser scan images. Using the proposed method, the reconstructed models provide more accurate crown than CT images, and it is feasible to obtain complete tooth models at any stage of orthodontic treatment by using one CT scan at the pretreatment stage and one laser scan at that stage to avoid multiple CT scans. PMID- 30026905 TI - Characterization of Seminiferous Epithelium Stages in the Wild Javan Muntjac (Muntiacus muntjak muntjak) Using the Tubular Morphology Method. AB - Stages of the seminiferous epithelium of the testis of the wild Javan muntjac (Muntiacus muntjak muntjak) in hard antler period were characterized based on the tubular morphology method. The number and the relative frequencies of seminiferous epithelium stages and the morphometry of germinal cell nuclei were identified microscopically. We identified eight stages of seminiferous epithelium in testicular tissue of the Javan muntjac and found that the relative frequencies of stages I to VIII were 14.87, 15.12, 17.75, 6.87, 7.37, 12.37, 13, and 12.62%, respectively. The diameter of the nuclei of germinal cells varied in each stage of seminiferous epithelium. Diplotene-stage primary spermatocytes had prominent and large nuclei ~8.97 +/- 1.0 MUm in stages III and IV. Pachytene primary spermatocytes appeared in most stages, except stage IV, whereas leptotene- and diplotene-stage primary spermatocytes were found in stages I and II, and III and IV, respectively. Round spermatids were observed in stages IV to VIII and in stage I but were absent in stages II and III, while elongated spermatids were observed in all stages except stage I. Our findings show that the stages of seminiferous epithelium in the Javan muntjac are similar to those found in neotropical cervids, small ruminants, and other domestic animals. PMID- 30026906 TI - Carriage Methicillin-Resistant Staphylococcus aureus in Poultry and Cattle in Northern Algeria. AB - Multiresistant and especially Methicillin-Resistant Staphylococcus aureus (MRSA) poses a serious public health problem that requires their immediate identification and antibiotic resistance characteristics. In order to determine antibiotic resistance S. aureus poultry and bovine origin, 8840 samples were collected from slaughterhouses in the northern region of Algeria between years 2009 and 2014. 8375 samples were from an avian origin (1875 from laying hens and 6500 from broiler chickens) and the rest was from bovine origin. Bacteriological isolation and identification were made by classical culture method and antibiotic resistance patterns were determined by disc diffusion test. The prevalence of S. aureus was 42% in laying hens, 12% in broilers, and 55% in bovine samples. The prevalence of MRSA was 57%, 50%, and 31% in laying hens, broiler chickens, and bovine, respectively. While MRSA strains isolated from poultry showed cross resistance to aminoglycosides, fluoroquinolones, macrolides, sulphonamides, and cyclins, those isolated from bovine also revealed similar multiresistance except for sulphonamide. This high percentage of methicillin resistance and multidrug resistance in S. aureus poultry and bovine origin may have importance for human health and curing of human infections. PMID- 30026907 TI - Pseudomyxoma peritonei presenting as irreducible epigastric hernia. AB - Abdominal wall hernia is a common and usually straightforward pathology presenting in surgery clinics. On occasion, the surgeon is faced with unexpected findings requiring difficult intraoperative decision. We present a case of pseudomyxoma peritonei incidentally found during surgery for epigastric hernia. The patient complained of a long lasting epigastric hernia with recent onset pain and growth. Surgery was limited to laparoscopic incisional biopsy of mucinous peritoneal deposit, confirming the diagnosis and suggesting an appendiceal origin. The patient was subsequently referred to a specialized peritoneal cancer unit for definitive treatment which consisted of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy, which can be compromised by previous organ resection. This case highlights the importance of maintaining a high level of suspicion before unusual clinical courses of common pathology. PMID- 30026904 TI - Expression of NK cluster genes in the onychophoran Euperipatoides rowelli: implications for the evolution of NK family genes in nephrozoans. AB - Background: Understanding the evolution and development of morphological traits of the last common bilaterian ancestor is a major goal of the evo-devo discipline. The reconstruction of this "urbilaterian" is mainly based on comparative studies of common molecular patterning mechanisms in recent model organisms. The NK homeobox genes are key players in many of these molecular pathways, including processes regulating mesoderm, heart and neural development. Shared features seen in the expression patterns of NK genes have been used to determine the ancestral bilaterian characters. However, the commonly used model organisms provide only a limited view on the evolution of these molecular pathways. To further investigate the ancestral roles of NK cluster genes, we analyzed their expression patterns in the onychophoran Euperipatoides rowelli. Results: We identified nine transcripts of NK cluster genes in E. rowelli, including single copies of NK1, NK3, NK4, NK5, Msx, Lbx and Tlx, and two copies of NK6. All of these genes except for NK6.1 and NK6.2 are expressed in different mesodermal organs and tissues in embryos of E. rowelli, including the anlagen of somatic musculature and the heart. Furthermore, we found distinct expression patterns of NK3, NK5, NK6, Lbx and Msx in the developing nervous system. The same holds true for the NKL gene NK2.2, which does not belong to the NK cluster but is a related gene playing a role in neural patterning. Surprisingly, NK1, Msx and Lbx are additionally expressed in a segment polarity-like pattern early in development-a feature that has been otherwise reported only from annelids. Conclusion: Our results indicate that the NK cluster genes were involved in mesoderm and neural development in the last common ancestor of bilaterians or at least nephrozoans (i.e., bilaterians to the exclusion of xenacoelomorphs). By comparing our data from an onychophoran to those from other bilaterians, we critically review the hypothesis of a complex "urbilaterian" with a segmented body, a pulsatile organ or heart, and a condensed mediolaterally patterned nerve cord. PMID- 30026910 TI - The dynamic upper limit of human lifespan. AB - We respond to claims by Dong et al. that human lifespan is limited below 125 years. Using the log-linear increase in mortality rates with age to predict the upper limits of human survival we find, in contrast to Dong et al., that the limit to human lifespan is historically flexible and increasing. This discrepancy can be explained by Dong et al.'s use of data with variable sample sizes, age biased rounding errors, and log(0) instead of log(1) values in linear regressions. Addressing these issues eliminates the proposed 125-year upper limit to human lifespan. PMID- 30026909 TI - Chiropractic in Global Health and wellbeing: a white paper describing the public health agenda of the World Federation of Chiropractic. AB - The World Federation of Chiropractic supports the involvement of chiropractors in public health initiatives, particularly as it relates to musculoskeletal health. Three topics within public health have been identified that call for a renewed professional focus. These include healthy ageing; opioid misuse; and women's, children's, and adolescents' health. The World Federation of Chiropractic aims to enable chiropractors to proactively participate in health promotion and prevention activities in these areas, through information dissemination and coordinated partnerships. Importantly, this work will align the chiropractic profession with the priorities of the World Health Organization. Successful engagement will support the role of chiropractors as valued partners within the broader healthcare system and contribute to the health and wellbeing of the communities they serve. PMID- 30026911 TI - Continuous training and certification in neonatal resuscitation in remote areas using a multi-platform information and communication technology intervention, compared to standard training: A randomized cluster trial study protocol. AB - Background: About 10% of all newborns may have difficulty breathing and require support by trained personnel. In Peru, 90% of deliveries occur in health facilities. However, there is not a national neonatal resuscitation and certification program for the public health sector. In addition, the Andes and the Amazon regions concentrate large rural remote areas, which further limit the implementation of training programs and the accomplishment of continuous certification. Neonatal resuscitation training through the use of Information, Communication and Technology (ICT) tools, running on computers, tablets or mobile phones, may overcome such limitations. This strategy allows online and offline access to educational resources, paving the way to more frequent and efficient training, and certification processes. Objective: To evaluate the effects of a neonatal resuscitation training and certification program that uses a Multi Platform ICT (MP-ICT) strategy on neonatal health care in remote areas. Methods: We propose to conduct the study through a cluster-randomized trial, where the study and analysis unit is the health care facility. Eligible facilities will include primary and secondary health care level facilities that are located in provinces with neonatal mortality rates higher than 15 per 1,000 live births. We will compare the proportion of newborns with a heart rate >=100 beats per minute at two minutes after birth in health care facilities that receive MP-ICT training and certification implementation, with those that receive standard training and certification. Discussion: We expect that the intervention will be shown as more effective than the current standard of care. We are prepared to include it within a national neonatal resuscitation training and certification program to be implemented at national scale together with policymakers and other key stakeholders. Trial registration: ClinicalTrials.gov No NCT03210194 Status of the study: This study is ongoing. Study protocol version 1.1 - March 31st, 2017. PMID- 30026912 TI - RSEQREP: RNA-Seq Reports, an open-source cloud-enabled framework for reproducible RNA-Seq data processing, analysis, and result reporting. AB - RNA-Seq is increasingly being used to measure human RNA expression on a genome wide scale. Expression profiles can be interrogated to identify and functionally characterize treatment-responsive genes. Ultimately, such controlled studies promise to reveal insights into molecular mechanisms of treatment effects, identify biomarkers, and realize personalized medicine. RNA-Seq Reports (RSEQREP) is a new open-source cloud-enabled framework that allows users to execute start to-end gene-level RNA-Seq analysis on a preconfigured RSEQREP Amazon Virtual Machine Image (AMI) hosted by AWS or on their own Ubuntu Linux machine. The framework works with unstranded, stranded, and paired-end sequence FASTQ files stored locally, on Amazon Simple Storage Service (S3), or at the Sequence Read Archive (SRA). RSEQREP automatically executes a series of customizable steps including reference alignment, CRAM compression, reference alignment QC, data normalization, multivariate data visualization, identification of differentially expressed genes, heatmaps, co-expressed gene clusters, enriched pathways, and a series of custom visualizations. The framework outputs a file collection that includes a dynamically generated PDF report using R, knitr, and LaTeX, as well as publication-ready table and figure files. A user-friendly configuration file handles sample metadata entry, processing, analysis, and reporting options. The configuration supports time series RNA-Seq experimental designs with at least one pre- and one post-treatment sample for each subject, as well as multiple treatment groups and specimen types. All RSEQREP analyses components are built using open-source R code and R/Bioconductor packages allowing for further customization. As a use case, we provide RSEQREP results for a trivalent influenza vaccine (TIV) RNA-Seq study that collected 1 pre-TIV and 10 post-TIV vaccination samples (days 1-10) for 5 subjects and two specimen types (peripheral blood mononuclear cells and B-cells). PMID- 30026908 TI - Anti-IgE therapy for IgE-mediated allergic diseases: from neutralizing IgE antibodies to eliminating IgE+ B cells. AB - Allergic diseases are inflammatory disorders that involve many types of cells and factors, including allergens, immunoglobulin (Ig)E, mast cells, basophils, cytokines and soluble mediators. Among them, IgE plays a vital role in the development of acute allergic reactions and chronic inflammatory allergic diseases, making its control particularly important in the treatment of IgE mediated allergic diseases. This review provides an overview of the current state of IgE targeted therapy development, focusing on three areas of translational research: IgE neutralization in blood; IgE-effector cell elimination; and IgE+ B cell reduction. IgE-targeted medicines such as FDA approved drug Xolair (Omalizumab) represent a promising avenue for treating IgE-mediated allergic diseases given the pernicious role of IgE in disease progression. Additionally, targeted therapy for IgE-mediated allergic diseases may be advanced through cellular treatments, including the modification of effector cells. PMID- 30026914 TI - Benefits of reversible contraception. AB - Long-acting reversible contraception-intrauterine devices and contraceptive implants-offers the highest protection against unintended pregnancies. In addition, the use of reversible hormonal contraception has added health benefits for women in both the short and the long term. This review will give an overview of the benefits of reversible contraception as well as an evidence-based recommendation on how it should be used to benefit women the most. PMID- 30026913 TI - Recent advances in understanding body weight homeostasis in humans. AB - Presently, control of body weight is assumed to exist, but there is no consensus framework of body weight homeostasis. Three different models have been proposed, with a "set point" suggesting (i) a more or less tight and (ii) symmetric or asymmetric biological control of body weight resulting from feedback loops from peripheral organs and tissues (e.g. leptin secreted from adipose tissue) to a central control system within the hypothalamus. Alternatively, a "settling point" rather than a set point reflects metabolic adaptations to energy imbalance without any need for feedback control. Finally, the "dual intervention point" model combines both paradigms with two set points and a settling point between them. In humans, observational studies on large populations do not provide consistent evidence for a biological control of body weight, which, if it exists, may be overridden by the influences of the obesogenic environment and culture on personal behavior and experiences. To re-address the issue of body weight homeostasis, there is a need for targeted protocols based on sound concepts, e.g. lean rather than overweight subjects should be investigated before, during, and after weight loss and weight regain. In addition, improved methods and a multi level-multi-systemic approach are needed to address the associations (i) between masses of individual body components and (ii) between masses and metabolic functions in the contexts of neurohumoral control and systemic effects. In the future, simplifications and the use of crude and non-biological phenotypes (i.e. body mass index and waist circumference) should be avoided. Since changes in body weight follow the mismatch between tightly controlled energy expenditure at loosely controlled energy intake, control (or even a set point) is more likely to be about energy expenditure rather than about body weight itself. PMID- 30026915 TI - Recent advances in heart transplantation. AB - Despite advances in medical and electrical therapies for heart failure, morbidity and mortality remain high and patients often progress to end-stage heart failure. Over the last five decades, heart transplantation is considered a standard therapy for select patients with end-stage heart failure. However, while heart transplantation has become a treatment of choice for end-stage heart failure, challenges still exist for improvement in the short- and long-term outcomes. While there is an increase in the number of patients with end-stage heart failure, the number of donor organs remains a major limiting factor. Heart transplantation candidates in the current era are also more complex: older, antigen-sensitized, and on mechanical circulatory support at the time of listing and transplant. Such potential heart transplant recipients have an increased chance of problems, including antibody-mediated rejection and primary graft dysfunction. Recent advances could address the current challenges and include: 1) attempts to expand the pool of donor hearts; 2) changes in heart transplantation allocation policy allowing for more equitable organ distribution; and 3) advances in the management of antibody sensitization. Developments in these areas could result in improved survival and quality of life for heart transplantation recipients. PMID- 30026916 TI - Understanding the CD8 T-cell response in natural HIV control. AB - HIV-infected individuals who maintain control of virus without antiretroviral therapy (ART) are called HIV controllers. The immune responses of these individuals suppress HIV viral replication to low levels or, in the case of elite controllers, to undetectable levels. Although some research indicates a role for inferior virulence of the infecting viral strain in natural control, perhaps by way of defective Nef protein function, we find that the majority of research in HIV controllers highlights CD8 T cells as the main suppressor of viral replication. The most convincing evidence for this argument lies in the strong correlation between certain HLA-I alleles, especially B*57, and HIV control status, a finding that has been replicated by many groups. However, natural control can also occur in individuals lacking these specific HLA alleles, and our understanding of what constitutes an effective CD8 T-cell response remains an incomplete picture. Recent research has broadened our understanding of natural HIV control by illustrating the interactions between different immune cells, including innate immune effectors and antigen-presenting cells. For many years, the immune responses of the natural HIV controllers have been studied for clues on how to achieve functional cure in the rest of the HIV-infected population. The goal of a future functional cure to HIV is one where HIV-infected individuals' immune responses are able to suppress virus long-term without requiring ART. This review highlights recent advances in our understanding of how HIV controllers' natural immune responses are able to suppress virus. PMID- 30026917 TI - What can National TB Control Programmes in low- and middle-income countries do to end tuberculosis by 2030? AB - The international community has committed to ending the tuberculosis (TB) epidemic by 2030. This will require multi-sectoral action with a focus on accelerating socio-economic development, developing and implementing new tools, and expanding health insurance coverage. Within this broad framework, National TB Programmes (NTPs) are accountable for delivering diagnostic, treatment, and preventive services. There are large gaps in the delivery of these services, and the aim of this article is to review the crucial activities and interventions that NTPs must implement in order to meet global targets and milestones that will end the TB epidemic. The key deliverables are the following: turn End TB targets and milestones into national measurable indicators to make it easier to track progress; optimize the prompt and accurate diagnosis of all types of TB; provide rapid, complete, and effective treatment to all those diagnosed with TB; implement and monitor effective infection control practices; diagnose and treat drug-resistant TB, associated HIV infection, and diabetes mellitus; design and implement active case finding strategies for high-risk groups and link them to the treatment of latent TB infection; engage with the private-for-profit sector; and empower the Central Unit of the NTP particularly in relation to data-driven supportive supervision, operational research, and sustained financing. The glaring gaps in the delivery of TB services must be remedied, and some of these gaps will require new paradigms and ways of working which include patient centered and higher-quality services. There must also be fast-track ways of incorporating new diagnostic, treatment, and prevention tools into program activities so as to rapidly reduce TB incidence and mortality and meet the goal of ending TB by 2030. PMID- 30026918 TI - Recent advances in the management of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease presenting highly heterogeneous clinical manifestations and multi-systemic involvement. Patients are susceptible to relapse- and remission, thus making management challenging. Moreover, a considerable number of side effects may occur with conventional therapies; therefore, there is clearly a need for new therapeutic strategies. Since the pathogenesis of SLE is highly complex, it is far from being fully understood. However, greater understanding of the pathways and of the cellular and molecular mediators involved in SLE is being achieved. Emerging evidence has allowed the development of new biological therapeutic options targeting crucial molecular mediators involved in the pathogenesis of SLE. This literature review analyzes the availability of biological and target-directed treatments, phase II and III trials, and new therapies that are being developed for the treatment of SLE. PMID- 30026919 TI - Recent advances in understanding and managing acute pancreatitis. AB - This review highlights advances made in recent years in the diagnosis and management of acute pancreatitis (AP). We focus on epidemiological, clinical, and management aspects of AP. Additionally, we discuss the role of using risk stratification tools to guide clinical decision making. The majority of patients suffer from mild AP, and only a subset develop moderately severe AP, defined as a pancreatic local complication, or severe AP, defined as persistent organ failure. In mild AP, management typically involves diagnostic evaluation and supportive care resulting usually in a short hospital length of stay (LOS). In severe AP, a multidisciplinary approach is warranted to minimize morbidity and mortality over the course of a protracted hospital LOS. Based on evidence from guideline recommendations, we discuss five treatment interventions, including intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis. This review also highlights the importance of preventive interventions to reduce hospital readmission or prevent pancreatitis, including alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis. Our review aims to consolidate guideline recommendations and high quality studies published in recent years to guide the management of AP and highlight areas in need of research. PMID- 30026922 TI - A systematic review and critical analysis of cost-effectiveness studies for coronary artery disease treatment. AB - Background: Cardiovascular disease remains the primary cause of death among Australians, despite dramatic improvements in overall cardiovascular health since the 1980s. Treating cardiovascular disease continues to place a significant economic strain on the Australian health care system, with direct healthcare costs exceeding those of any other disease. Coronary artery disease accounts for nearly one third of these costs and spending continues to rise. A range of treatments is available for coronary artery disease yet evidence of cost effectiveness is missing, particularly for the Australian context. Cost effectiveness evidence can signal waste and inefficiency and so is essential for an efficient allocation of healthcare resources. Methods: We used systematic review methods to search the literature across several electronic databases for economic evaluations of treatments for coronary artery disease. We critically appraised the literature found in searches, both against the CHEERS statement for quality reporting of economic evaluations and in terms of its usefulness for policy and decision-makers. Results: We retrieved a total of 308 references, 229 once duplicates were removed. Of these, 26 were excluded as they were not full papers (letters, editorials etc.), 55 were review papers, 50 were not cost effectiveness analyses and 93 related to a highly specific patient sub-group or did not consider all treatment options. This left five papers to be reviewed in full. Conclusions: The current cost-effectiveness evidence does not support the increased use of PCI that has been seen in Australia and internationally. Due to problems with accessibility, clarity and relevance to policy and decision-makers, some otherwise very scientifically rigorous analyses have failed to generate any policy changes. PMID- 30026921 TI - The gut microbiome and irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders encountered in clinical practice. It is a heterogeneous disorder with a multifactorial pathogenesis. Recent studies have demonstrated that an imbalance in gut bacterial communities, or "dysbiosis", may be a contributor to the pathophysiology of IBS. There is evidence to suggest that gut dysbiosis may lead to activation of the gut immune system with downstream effects on a variety of other factors of potential relevance to the pathophysiology of IBS. This review will highlight the data addressing the emerging role of the gut microbiome in the pathogenesis of IBS and review the evidence for current and future microbiome based treatments. PMID- 30026920 TI - Recent advances in understanding and managing diverticulitis. AB - In the past few decades, the increasing socioeconomic burden of acute diverticulitis (AD) has become evident, and with the growth of the population age, this significant economic impact will likely continue to rise. Furthermore, recent evidence showed an increased rate of hospital admissions especially evident among women and younger individuals. The natural history and pathophysiology of this clinical condition is still to be fully defined, and efforts continue to be made in the identification of risk factors and the establishment of relative preventive strategies. The actual therapeutic strategies aimed to modulate gut microbiota, such as rifaximin or probiotics, or to reduce mucosal inflammation, such as mesalazine, present a relatively poor efficacy for both the prevention of the first AD episode (primary prevention) and its recurrence (secondary prevention). In the last few years, the main goal achieved has been in the management of AD in that uncomplicated AD can, to a larger extent, be managed in an outpatient setting with no or little supportive therapy, a strategy that will certainly impact on the health costs of this disease. The problem of AD recurrence remains a topic of debate. The aim of this review is to present updated evidence on AD epidemiology and relative open clinical questions and to analyze in detail predisposing and protective factors with an attempt to integrate their possible modes of action into the several pathogenic mechanisms that have been suggested to contribute to this multifactorial disease. A unifying hypothesis dealing with the colonic luminal and extra-luminal microenvironments separately is provided. Finally, evidence based changes in therapeutic management will be summarized. Because of an ascertained multifactorial pathogenesis of uncomplicated and complicated AD, it is probable that a single 'causa prima' will not be identifiable, and a better stratification of patients could allow one to pursue tailored therapeutic algorithm strategies. PMID- 30026923 TI - Real world evidence (RWE) - a disruptive innovation or the quiet evolution of medical evidence generation? AB - Stakeholders in healthcare are increasingly turning to real world evidence (RWE) to inform their decisions, alongside evidence from randomized controlled trials. RWE is generated by analysing data gathered from routine clinical practice, and can be used across the product lifecycle, providing insights into areas including disease epidemiology, treatment effectiveness and safety, and health economic value and impact. Recently, the US Food and Drug Administration and the European Medicines Agency have stated their ambition for greater use of RWE to support applications for new indications, and are now consulting with their stakeholders to formalize standards and expected methods for generating RWE. Pharmaceutical companies are responding to the increasing demands for RWE by developing standards and processes for each stage of the evidence generation pathway. Some conventions are already in place for assuring quality, whereas other processes are specific to the research question and data sources available. As evidence generation increasingly becomes a core role of medical affairs divisions in large pharmaceutical companies, standards of rigour will continue to evolve and improve. Senior pharmaceutical leaders can drive this change by making RWE a core element of their corporate strategy, providing top-level direction on how their respective companies should approach RWE for maximum quality. Here, we describe the current and future areas of RWE application within the pharmaceutical industry, necessary access to data to generate RWE, and the challenges in communicating RWE. Supporting and building on viewpoints from industry and publicly funded research, our perspective is that at each stage of RWE generation, quality will be critical to the impact that RWE has on healthcare decision-makers; not only where RWE is an established and evolving tool, but also in new areas that have the potential to disrupt and to improve drug development pathways. PMID- 30026924 TI - BED: a Biological Entity Dictionary based on a graph data model. AB - The understanding of molecular processes involved in a specific biological system can be significantly improved by combining and comparing different data set and knowledge resources. However these information sources often use different identification systems and an identifier conversion step is required before any integration effort. Mapping between identifiers is often provided by the reference information resources and several tools have been implemented to simplify their use. However these tools cannot be easily customized and optimized for any specific use. Also the information provided by different resources is not combined to increase the efficiency of the mapping process and deprecated identifiers from former version of databases are not taken into account. Finally finding automatically the most relevant path to map identifiers from one scope to the other is often not trivial. The Biological Entity Dictionary (BED) addresses these challenges by relying on a graph data model describing possible relationships between entities and their identifiers. This model has been implemented using Neo4j and an R package provides functions to query the graph but also to create and feed a custom instance of the database. PMID- 30026925 TI - Revised World Health Organization (WHO)'s causality assessment of adverse events following immunization-a critique. AB - The World Health Organisation (WHO) has recently revised how adverse events after immunization (AEFI) are classified. Only reactions that have previously been acknowledged in epidemiological studies to be caused by the vaccine, are classified as a vaccine-product-related-reaction. Deaths observed during post marketing surveillance are not considered as "consistent with causal association with vaccine", if there was no statistically significant increase in deaths recorded during the small Phase 3 trials that preceded it. Of course, vaccines that caused deaths in the control-trials stage would not be licensed. After licensure, deaths and all new serious adverse reactions are labelled as 'coincidental deaths' or 'unclassifiable', and the association with vaccine is not acknowledged. The resulting paradox is evident. The definition of causal association has also been changed. It is now used only if there is "no other factor intervening in the processes." Therefore, if a child with an underlying congenital heart disease (other factor), develops fever and cardiac decompensation after vaccination, the cardiac failure would not be considered causally related to the vaccine. The Global Advisory Committee on Vaccine Safety has documented many deaths in children with pre-existing heart disease after they were administered the Pentavalent vaccine. The WHO now advises precautions when vaccinating such children and this has reduced the risk of death. Using the new definition of causal association, this relationship would not be acknowledged and lives would be put at risk. In view of the above, it is necessary that the AEFI manual be revaluated and revised urgently. AEFI reporting is said to be for vaccine safety. Child safety (safety of children) rather than vaccine safety (safety for vaccines) needs to be the emphasis. PMID- 30026926 TI - High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis. AB - Background: The only available tuberculosis (TB) vaccine, Bacillus Calmette Guerin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back translated this into a mouse model. Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from Mtb infection by experimental challenge; vaccine-induced interferon gamma (IFNgamma) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates. Results: The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNgamma response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant. Conclusions: These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment. PMID- 30026927 TI - Obstructive sleep apnea as an independent predictor of postoperative delirium and pain: protocol for an observational study of a surgical cohort. AB - Introduction: Postoperative delirium and pain are common complications in adults, and are difficult both to prevent and treat. Obstructive sleep apnea (OSA) is prevalent in surgical patients, and has been suggested to be a risk factor for postoperative delirium and pain. OSA also might impact pain perception, and alter pain medication requirements. This protocol describes an observational study, with the primary aim of testing whether OSA is an independent predictor of postoperative complications, focusing on (i) postoperative incident delirium and (ii) acute postoperative pain severity. We secondarily hypothesize that compliance with prescribed treatment for OSA (typically continuous positive airway pressure or CPAP) might decrease the risk of delirium and the severity of pain. Methods and analysis: We will include data from patients who have been enrolled into three prospective studies: ENGAGES, PODCAST, and SATISFY-SOS. All participants underwent general anesthesia for a non-neurosurgical inpatient operation, and had a postoperative hospital stay of at least one day at Barnes Jewish Hospital in St. Louis, Missouri, from February 2013 to December 2017. Patients included in this study have been assessed for postoperative delirium and pain severity as part of the parent studies. In the current study, determination of delirium diagnosis will be based on the 3-minute Diagnostic Confusion Assessment Method, and the Visual Analogue Pain Scale will be used for pain severity. Data on OSA diagnosis, OSA risk and compliance with treatment will be obtained from the preoperative assessment record. Other variables that are candidate risk factors for delirium and pain will also be extracted from this record. We will use logistic regression to test whether OSA independently predicts postoperative delirium and linear regression to assess OSAs relationship to acute pain severity. We will conduct secondary analyses with subgroups to explore whether these relationships are modified by compliance with OSA treatment. PMID- 30026928 TI - Prevalence of Autism Spectrum Disorder (ASD) among the children aged 18-36 months in a rural community of Bangladesh: A cross sectional study. AB - Background: Autism spectrum disorder (ASD) refers to a group of complex neurodevelopment disorders characterized by repetitive and characteristic patterns of behavior and difficulties with social communication and interaction. In Bangladesh, autism in children is a significant burden of disease. Early identification of ASD could improve quality of life. The study has explored at the prevalence of ASD among rural community children aged between 18-36 months. Methods: A cross sectional study was conducted among the 5286 children aged between 18-36 months in a rural community. Household level data was collected using screening tool MCHAT. Primarily screening positive 66 children were invited for final diagnosis in a health camp. Diagnosis was made by different staging started from primary screening, followed by validation using MCHAT and flash card. Final diagnosis was made by the paediatric neurologists, child clinical psychologists and development therapist using diagnostic tools (DSM-IV & ADOS). Results: 04 children were diagnosed with autism spectrum disorder (ASD). Prevalence of the ASD in rural community was found 0.75/1000 children. Among the four ASD cases three were boys and one was girl and age range was between 20- 30 months. Whereas, the highest prevalence rate found was for the cerebral palsy which was 5.6/1000 children and Developmental delay (2.6/1000) was the next to that. Conclusions: Age specific autism (18-36 months) in children is found higher in rural community of Bangladesh. In order to get more comprehensive information on autism in other age groups of children in rural community, further study is required. Early detection in rural community could help the policy makers to decentralization of health services among the ASD children in rural community. PMID- 30026929 TI - Spectrum of Sellar and Parasellar Region Lesions: A retrospective study from Basrah, Iraq. AB - Background: Sellar and parasellar region lesions spectrum includes a wide variety of diseases. This study aimed at providing a comprehensive overview of such lesions in patients from Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah (Southern Iraq). Methods: Retrospective data analysis from FDEMC for the period January 2012 through June 2017. We included all patients with sellar and parasellar region lesions who received a MRI scan on their pituitary region Results: The total enrolled patients were 232 (84 men and 148 women),with age range 15-75 years.Pituitary disease and adenoma were more common among women. Those with macroadenoma were older than those with microadenoma, with nearly equal gender prevalence of macroadenoma. Pituitary adenoma constituted the bulk of pituitary disease in this setting (67.2%). Growth hormone secreting adenoma were the most common adenoma seen in 41.0%, followed by clinically non-functioning pituitary adenoma (NFPA) in 31.4% and prolactinoma in 26.9%. About 64.8% of pituitary adenoma was macroadenoma. Macroadenoma was seen in 73.4% of growth hormone secreting adenoma (acromegaly), 61.2% in NFPA and 62.0% of prolactinom a(of them six were giant prolactinoma). Conclusion: Pituitary adenoma constituted the bulk of sellar and parasellar region lesions, growth hormone secreting adenoma is the the most common adenoma followed by NFPA and prolactinoma due to referral bias. A change in practice of adenoma treatment is needed. PMID- 30026931 TI - Study protocol for the Anesthesiology Control Tower-Feedback Alerts to Supplement Treatments (ACTFAST-3) trial: a pilot randomized controlled trial in intraoperative telemedicine. AB - Background: Each year, over 300 million people undergo surgical procedures worldwide. Despite efforts to improve outcomes, postoperative morbidity and mortality are common. Many patients experience complications as a result of either medical error or failure to adhere to established clinical practice guidelines. This protocol describes a clinical trial comparing a telemedicine based decision support system, the Anesthesiology Control Tower (ACT), with enhanced standard intraoperative care. Methods: This study is a pragmatic, comparative effectiveness trial that will randomize approximately 12,000 adult surgical patients on an operating room (OR) level to a control or to an intervention group. All OR clinicians will have access to decision support software within the OR as a part of enhanced standard intraoperative care. The ACT will monitor patients in both groups and will provide additional support to the clinicians assigned to intervention ORs. Primary outcomes include blood glucose management and temperature management. Secondary outcomes will include surrogate, clinical, and economic outcomes, such as incidence of intraoperative hypotension, postoperative respiratory compromise, acute kidney injury, delirium, and volatile anesthetic utilization. Ethics and dissemination: The ACTFAST-3 study has been approved by the Human Resource Protection Office (HRPO) at Washington University in St. Louis and is registered at clinicaltrials.gov ( NCT02830126). Recruitment for this protocol began in April 2017 and will end in December 2018. Dissemination of the findings of this study will occur via presentations at academic conferences, journal publications, and educational materials. PMID- 30026933 TI - A cross-sectional study of the use and effectiveness of the Individual Development Plan among doctoral students. AB - Background: The Individual Development Plan (IDP) was introduced as a tool to aid in career planning for doctoral trainees. Despite the National Institutes of Health and academic institutions creating policies that mandate the use of IDPs, little information exists regarding the actual use and effectiveness of the career planning tool. Methods: We conducted a multi-institutional, online survey to measure IDP use and effectiveness. The survey was distributed to potential respondents via social media and direct email. IDP survey questions were formatted using a five-point Likert scale (strongly agree, agree, neutral, disagree and strongly disagree). For data analysis purposes, responses were grouped into two categories (agree versus does not agree/disagree). The data were summarized as one-way frequencies and the Pearson Chi-square test was used to determine statistical significance. Results: Usage of the IDP among doctoral students was low and the tool produces minimal effectiveness with regard to the perception of whether it is helpful to one's career development. Further, our data suggests that the IDP is most effective when doctoral students complete the tool with faculty mentors with whom they have a positive relationship. Respondents who are confident about completing their doctoral training and their post-training career plans, and who take advantage of career development resources at their institution are also more likely to perceive that the IDP is useful for their career development. Conclusion: Given the nuanced use and effectiveness of the IDP, we call for more research to determine why IDP use and effectiveness is low, exactly how IDPs are being used, and whether there are unintended negative consequences created through the use of the tool. Furthermore, we recommend an enhancement of career development infrastructure that would include mentorship training for faculty in order to provide substantially more career planning support to doctoral trainees. PMID- 30026932 TI - Phenotype profiling of white-nose syndrome pathogen Pseudogymnoascus destructans and closely-related Pseudogymnoascus pannorum reveals metabolic differences underlying fungal lifestyles. AB - Background:Pseudogymnoascusdestructans, a psychrophile, causes bat white-nose syndrome (WNS). Pseudogymnoascus pannorum, a closely related fungus, causes human and canine diseases rarely. Both pathogens were reported from the same mines and caves in the United States, but only P. destructans caused WNS. Earlier genome comparisons revealed that P. pannorum contained more deduced proteins with ascribed enzymatic functions than P. destructans. Methods: We performed metabolic profiling with Biolog PM microarray plates to confirm in silico gene predictions. Results:P. pannorum utilized 78 of 190 carbon sources (41%), and 41 of 91 nitrogen sources (43%) tested. P. destructans used 23 carbon compounds (12%) and 23 nitrogen compounds (24%). P. destructans exhibited more robust growth on the phosphorous sources and nutrient supplements (83% and 15%, respectively) compared to P. pannorum (27% and 1%, respectively.). P. pannorum exhibited higher tolerance to osmolytes, pH extremes, and a variety of chemical compounds than P. destructans. Conclusions: An abundance of carbohydrate degradation pathways combined with robust stress tolerance provided clues for the soil distribution of P. pannorum. The limited metabolic profile of P. destructans validated in silico predictions of far fewer proteins and enzymes. P. destructans ability to catabolize diverse phosphorous and nutrient supplements might be critical in the colonization and invasion of bat tissues. The present study of 1,047 different metabolic activities provides a framework for future gene-function investigations of the unique biology of the psychrophilic fungi. PMID- 30026930 TI - The challenges of designing a benchmark strategy for bioinformatics pipelines in the identification of antimicrobial resistance determinants using next generation sequencing technologies. AB - Next-Generation Sequencing (NGS) technologies are expected to play a crucial role in the surveillance of infectious diseases, with their unprecedented capabilities for the characterisation of genetic information underlying the virulence and antimicrobial resistance (AMR) properties of microorganisms. In the implementation of any novel technology for regulatory purposes, important considerations such as harmonisation, validation and quality assurance need to be addressed. NGS technologies pose unique challenges in these regards, in part due to their reliance on bioinformatics for the processing and proper interpretation of the data produced. Well-designed benchmark resources are thus needed to evaluate, validate and ensure continued quality control over the bioinformatics component of the process. This concept was explored as part of a workshop on "Next-generation sequencing technologies and antimicrobial resistance" held October 4-5 2017. Challenges involved in the development of such a benchmark resource, with a specific focus on identifying the molecular determinants of AMR, were identified. For each of the challenges, sets of unsolved questions that will need to be tackled for them to be properly addressed were compiled. These take into consideration the requirement for monitoring of AMR bacteria in humans, animals, food and the environment, which is aligned with the principles of a "One Health" approach. PMID- 30026934 TI - A meta-analysis of narrow-band imaging for the diagnosis of primary nasopharyngeal carcinoma. AB - Background: Narrow band imaging (NBI), an endoscopic technique featuring an augmented definition of microvasculature and mucosal patterns. NBI is increasingly advocated as a tool to characterize neoplasia and intestinal metaplasia in endoscopic standards, such as for colorectal polyps and tumors. Recently NBI has also been studied in the detection of Nasopharyngeal Carcinoma (NPC). Here we aimed to assess the diagnostic utility of NBI for the diagnosis of NPC. Methods: A meta-analysis of studies comparing narrow-band imaging and white light endoscopy in the diagnosis of primary nasopharyngeal carcinoma was performed. The review process involved two independent investigators. The databases used were MEDLINE, PubMed, the Cochrane library, Embase, and the Web of Science. Statistical analysis was performed with OpenMetaAnalyst, MetaDiSc version 1.4, and Medcalc version 17.9.7. Results: Five studies including 2480 patients were included. The sensitivity and specificity for narrow-band imaging were 0.90 (0.73-0.97) and 0.95 (0.81-0.99) respectively. The positive likelihood ratio and negative likelihood ratio were 18.82 (0.31-82.1) and 0.08 (0.02-0.31). For white light endoscopy, the sensitivity and specificity were 0.77 (0.58-0.89) and 0.91 (0.79-0.96). The positive likelihood ratio was 7.61 (3.61-16.04), and the negative likelihood ratio was 0.21 (0.11-0.39). The odds ratio for detection rates between narrow-band imaging and white light endoscopy was 4.29 (0.56-33.03, p = 0.16). Area under the curve for narrow-band imaging was 0.98 (SE: 0.02), and for white light it was 0.93 (SE: 0.03). There was no significant difference in the receiver operating characteristic curves between the two modalities (p = 0.14). Conclusion: Narrow-band imaging showed a higher sensitivity and positive likelihood ratio for the diagnosis of nasopharyngeal carcinoma. However, there was no significant difference in detection rates compared to white light endoscopy. Further investigation with a uniform diagnostic criteria and terminology is needed for narrow-band imaging in the diagnosis of nasopharyngeal carcinoma. PMID- 30026935 TI - Inflatable penile prosthesis in the radical prostatectomy patient: a review. AB - In the population of patients with prostate cancer, survivorship has come to the forefront of continuity-of-care. In addition to urinary control, erectile function is a significant issue after radical pelvic surgery. Penile prosthesis surgery remains an excellent option for restoring erectile function to those for whom more conservative measures have failed. This review article outlines the anatomical, surgical and post-operative consideration involved in the placement of a penile prosthesis in this special patient population. PMID- 30026936 TI - Copycat Layout: Network layout alignment via Cytoscape Automation. AB - The copycatLayout app is a network-based visual differential analysis tool that improves upon the existing layoutSaver app and is delivered pre-installed with Cytoscape, beginning with v3.6.0. LayoutSaver cloned a network layout by mapping node locations from one network to another based on node attribute values, but failed to clone view scale and location, and provided no means of identifying which nodes were successfully mapped between networks. Copycat addresses these issues and provides additional layout options. With the advent of Cytoscape Automation (packaged in Cytoscape v3.6.0), researchers can utilize the Copycat layout and its output in workflows written in their language of choice by using only a few simple REST calls. Copycat enables researchers to visually compare groups of homologous genes, generate network comparison images for publications, and quickly identify differences between similar networks at a glance without leaving their script. With a few extra REST calls, scripts can discover nodes present in one network but not in the other, which can feed into more complex analyses (e.g., modifying mismatched nodes based on new data, then re-running the layout to highlight additional network changes). PMID- 30026937 TI - aMatReader: Importing adjacency matrices via Cytoscape Automation. AB - Adjacency matrices are useful for storing pairwise interaction data, such as correlations between gene pairs in a pathway or similarities between genes and conditions. The aMatReader app enables users to import one or multiple adjacency matrix files into Cytoscape, where each file represents an edge attribute in a network. Our goal was to import the diverse adjacency matrix formats produced by existing scripts and libraries written in R, MATLAB, and Python, and facilitate importing that data into Cytoscape. To accelerate the import process, aMatReader attempts to predict matrix import parameters by analyzing the first two lines of the file. We also exposed CyREST endpoints to allow researchers to import network matrix data directly into Cytoscape from their language of choice. Many analysis tools deal with networks in the form of an adjacency matrix, and exposing the aMatReader API to automation users enables scripts to transfer those networks directly into Cytoscape with little effort. PMID- 30026938 TI - The nociception level index (NOL) response to intubation and incision in patients undergoing video-assisted thoracoscopic surgery (VATS) with and without thoracic epidural analgesia. A pilot study. AB - Background: The PMD100TM (Medasense Biometrics Ltd., Ramat Yishai, Israel) is a novel non-invasive nociception monitor that integrates physiological parameters to compute a real-time nociception level index (NOL) in the anesthetized patients. Thoracic epidural analgesia provides effective analgesia and improves surgical outcomes. Side effects include sympathectomy, hypotension, changes in skin temperature and a decreased cardiac accelerator fiber tone. The purpose of this pilot study was to evaluate changes in NOL values after incision in patients with and without epidural analgesia. Methods: Half of the patients scheduled for Video-Assisted Thoracoscopic Surgery (VATS) received a thoracic epidural catheter, placed and tested 2h before surgery and activated prior to incision. The other half of the patients received i.v. fentanyl (1 mcg/kg) five minutes before incision. Anesthesia and analgesia were maintained in a standardized manner. NOL and heart rate (HR) were compared before and after the nociceptive stimuli intubation and skin incision. Results: NOL significantly increased in all patients after intubation by 10.2 points (CI: 4.5-16.0; p=0.002) as well as HR by 9 beats per minute after intubation in all patients (CI: 3.3-15.6; p=0.01). After incision, in patients without epidural analgesia the NOL increased by 13.9 points (CI: 7.4-20.3; p=0.0001), compared to 5.4 points (CI: -6.3-17.1; p=0.29) in patients with epidural analgesia. HR did not significantly vary after incision in both groups. The area under the curve of delta NOL and delta HR variations after incision were significantly different (p<0.05) between groups and delta NOL variations were significantly different from baseline values but not the delta HR variations. Conclusions: This pilot study suggests that the PMD100TM Monitor may be a useful tool to evaluate the efficacy of an intraoperative thoracic epidural analgesia. Clinical Trial Registry Number: ClinicalTrials.gov record ID: NCT01978379 registered 10/25/2014. PMID- 30026940 TI - Antibiotic use on paediatric inpatients in a teaching hospital in the Gambia, a retrospective study. AB - Background: Antibiotics are useful but increasing resistance is a major problem. Our objectives were to assess antibiotic use and microbiology testing in hospitalized children in the Gambia. Methods: We conducted a retrospective analysis of paediatric inpatient data at The Edward Francis Small Teaching Hospital in Banjul, The Gambia. We extracted relevant data from the admission folders of all patients (aged > 28 days to 15 years) admitted in 2015 (January December), who received at least one antibiotic for 24 h. We also reviewed the microbiology laboratory record book to obtain separate data for the bacterial isolates and resistance test results of all the paediatric inpatients during the study period. Results: Over half of the admitted patients received at least one antibiotic during admission (496/917) with a total consumption of 670.7 Days of Antibiotic Therapy/1000 Patient-Days. The clinical diagnoses included an infectious disease for 398/496, 80.2% of the patients on antibiotics, pneumonia being the most common (184/496, 37.1%). There were 51 clinically relevant bacterial isolates, Klebsiella species being the most common (12/51, 23.5%), mainly from urine (11/12, 91.7%). Antibiotic resistance was mainly to ampicillin (38/51, 74.5%), mainly reported as Coliform species 11/51, 21.6%. Conclusions: More than half of the admitted patients received antibiotics. The reported antibiotic resistance was highest to the most commonly used antibiotics such as ampicillin. Efforts to maximize definitive antibiotic indication such as microbiological testing prior to start of antibiotics should be encouraged where possible for a more rational antibiotic use. PMID- 30026939 TI - Jorg Langowski: his scientific legacy and the future it promises. AB - Background: With the passing of Jorg Langowski 6 May 2017 in a sailplane accident, the scientific community was deprived of a strident and effective voice for DNA and chromatin molecular and computational biophysics, for open access publishing and for the creation of effective scientific research networks. Methods: Here, after reviewing some of Jorg's key research contributions and ideas, we offer through the personal remembrance of his closest collaborators, a deep analysis of the major results of his research and the future directions they have engendered. Conclusions: The legacy of Jorg Langowski has been to propel a way of viewing biological function that considers living systems as dynamic and in three dimensions. This physical view of biology that he pioneered is now, finally, becoming established also because of his great effort. PMID- 30026941 TI - Temporal association between antibiotic use and resistance in Klebsiella pneumoniae at a tertiary care hospital. AB - Background: beta-Lactam/beta-lactamase inhibitors (BLBLIs) were introduced into clinical practice as an alternative to carbapenems for treating multi-drug resistant Klebsiella pneumoniae infections. However, little is known about the relationship between BLBLI treatment and antimicrobial resistance. In this study, we investigated the trends and the temporal association between antibiotic use and antimicrobial resistance in K. pneumoniae isolates obtained between 2012 and 2016. Methods: Data regarding quarterly consumption (total number of prescriptions per quarter) of all BLBLIs, all third-generation cephalosporins, and all fluoroquinolones at a tertiary care hospital were obtained from the Korean Health Insurance Review and Assessment Service. Susceptibility data (isolation rate of antibiotic resistance per quarter) were obtained from the existing database of the same tertiary hospital. Regression analysis was used to analyze annual trends and cross-correlations to assess the temporal association on a quarterly basis between antibiotic consumption and antibiotic resistance in K. pneumoniae. Results: The rate of resistance to piperacillin/tazobactam in K. pneumoniae significantly increased over the study period (p < 0.01). The consumption of all BLBLIs was also found to be significantly correlated with the rate of resistance to piperacillin/tazobactam (beta = 0.66; p < 0.01), ceftazidime (beta = 0.54; p = 0.02), and levofloxacin (beta = - 0.60; p = 0.01) with two-quarter lags. Furthermore, the consumption of all third-generation cephalosporins was significantly correlated with rates of K. pneumoniae resistance to ceftazidime (beta = 0.64; p < 0.01) with a two-quarter lag and levofloxacin (beta = 0.50; p = 0.03) with a quarter lag. The consumption of all fluoroquinolones correlated with resistance rates to ceftazidime (beta = 0.14; p < 0.01) with a two-quarter lag. Conclusions: The rate of resistance to piperacillin/tazobactam in K. pneumoniae increased significantly over the study period and was significantly correlated with BLBLI consumption. While BLBLIs can potentially be utilized as an alternative to carbapenems, our findings reinforce concerns of resistance to these drugs. Further research is needed to understand the implications on resistance of utilizing BLBLIs as a carbapenem-sparing option. PMID- 30026942 TI - Collateral damage of using colistin in hospitalized patients on emergence of colistin-resistant Escherichia coli and Klebsiella pneumoniae colonization and infection. AB - Background: Colistin has been used for therapy of carbapenem-resistant Gram negative infections in Thailand, especially carbapenem-resistant A. baumannii and P. aeruginosa, for more than 10 years. However, the prevalence of colistin resistant A. baumannii or P. aeruginosa is still less than 5%. Colistin-resistant Enterobacteriaceae has been increasingly reported globally over the past few years and the use of colistin in food animals might be associated with an emergence of colistin resistance in Enterobacteriaceae. This study aimed to determine the effect of colistin exposure in hospitalized patients who received colistin on development of colistin-resistant (CoR) Escherichia coli (EC) or Klebsiella pneumoniae (KP) colonization and infection. Methods: A prospective observational study was performed in adult hospitalized patients at Siriraj Hospital who received colistin for treatment of infections during December 2016 and November 2017. The surveillance culture samples were collected from the stool and the site of infection of each patient who received colistin at the study enrollment, days 3 and 7 after the study enrollment, and once a week thereafter for determination of CoR EC and CoR KP. CoR EC and CoR KP were also tested for a presence of mcr-1 gene. Results: One hundred thirty-nine patients were included. Overall prevalence of CoR EC or CoR KP colonization was 47.5% among 139 subjects. Prevalence of CoR EC or CoR KP colonization was 17.3% of subjects at study enrollment, and 30.2% after study enrollment. Use of fluoroquinolones, aminoglycosides, and colistin was found to be significantly associated with CoR EC or CoR KP colonization. The mcr-1 gene was detected in 13.0% of CoR EC or CoR KP isolates, and in 27.3% of subjects with CoR EC or CoR KP colonization. CoR EC or CoR KP colonization persisted in 65.2% of the subjects at the end of the study. Five patients with CoR KP infections received combination antibiotics and they were alive at hospital discharge. Conclusions: Prevalence of CoR EC or CoR KP colonization in hospitalized patients receiving colistin was high and it was associated with the use of colistin. Therefore, patients who receive colistin are at risk of developing CoR EC or CoR KP colonization and infection. PMID- 30026943 TI - Neisseria Gonorrhoae and their antimicrobial susceptibility patterns among symptomatic patients from Gondar town, north West Ethiopia. AB - Background: Neisseria gonorrhoeae, the causative agent of gonorrhoea, is a Gram negative, coffee-bean shaped facultative intracellular diplococcus bacterium, the classical sexually transmitted bacteria. Nowadays, N. gonorrhoeae has developed high-level resistance to all traditional antimicrobials used for the treatment of gonorrhoea and makes the treatment complicated. So, the aim of this study was to determine magnitude and antimicrobial resistance patterns of N. gonorrhoeae. Methods: A cross sectional study was conducted between April and August 2016 among STI clinic clients in Gondar town hospitals and health centers. Urethral swab and cervical swab specimens were inoculated to Thayer Martin media (OXOID, UK) plates. Observation of Gram-negative intracellular diplococcic was a presumptive diagnosis of gonococcal infection. Finally, antimicrobial susceptibility was assessed by using a modified Kirby-Bauer disk diffusion test, with results indicating susceptible, intermediate or resistant. Data were entered and analyzed using SPSS version 20. Results: The overall prevalence of laboratory confirmed N. gonorrhoeae was 25(20.8%). The isolated N. gonorrhoeae was resistant 100% to tetracycline, penicillin and 80% percent was multidrug resistant. Conclusion: Prevalence and drug resistance of N. gonorrhoeae were high in the study area. A large study is needed in order to know the magnitude in the community as well as to increase awareness of both regional health bureaus and the Ministry of Health about the treatment guide-lines. PMID- 30026944 TI - Effect of CD14/TLR4 antagonist on GnRH/LH secretion in ewe during central inflammation induced by intracerebroventricular administration of LPS. AB - Background: Immune stress induced by lipopolysaccharide (LPS) influences the gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion. Presence of LPS interacting Toll-like receptor (TLR) 4 in the hypothalamus may enable the direct action of LPS on the GnRH/LH secretion. So, the aim of the study was to investigate the influence of intracerebroventricular (icv) injection of TLR4 antagonist on GnRH/LH secretion in anestrous ewes during LPS-induced central inflammation. Animals were divided into three groups icv-treated with: Ringer-Locke solution, LPS and TLR4 antagonist followed by LPS. Results: It was demonstrated that TLR4 antagonist reduced LPS-dependent suppression of GnRH gene expression in the preoptic area and in the medial basal hypothalamus, and suppression of receptor for GnRH gene expression in the anterior pituitary gland. It was also shown that TLR4 antagonist reduced suppression of LH release caused by icv injection of LPS. Central administration of LPS stimulated TLR4 gene expression in the medial basal hypothalamus. Conclusions: It was indicated that blockade of TLR4 prevents the inhibitory effect of centrally acting LPS on the GnRH/LH secretion. This suggests that some negative effects of bacterial infection on the hypothalamic-pituitary-gonadal axis activity at the hypothalamic level may be caused by central action of LPS acting through TLR4. PMID- 30026945 TI - Children who are both wasted and stunted are also underweight and have a high risk of death: a descriptive epidemiology of multiple anthropometric deficits using data from 51 countries. AB - Background: Wasting and stunting are common. They are implicated in the deaths of almost two million children each year and account for over 12% of disability adjusted life years lost in young children. Wasting and stunting tend to be addressed as separate issues despite evidence of common causality and the fact that children may suffer simultaneously from both conditions (WaSt). Questions remain regarding the risks associated with WaSt, which children are most affected, and how best to reach them. Methods: A database of cross-sectional survey datasets containing data for almost 1.8 million children was compiled. This was analysed to determine the intersection between sets of wasted, stunted, and underweight children; the association between being wasted and being stunted; the severity of wasting and stunting in WaSt children; the prevalence of WaSt by age and sex, and to identify weight-for-age z-score and mid-upper arm circumference thresholds for detecting cases of WaSt. An additional analysis of the WHO Growth Standards sought the maximum possible weight-for-age z-score for WaSt children. Results: All children who were simultaneously wasted and stunted were also underweight. The maximum possible weight-for-age z-score in these children was below - 2.35. Low WHZ and low HAZ have a joint effect on WAZ which varies with age and sex. WaSt and "multiple anthropometric deficits" (i.e. being simultaneously wasted, stunted, and underweight) are identical conditions. The conditions of being wasted and being stunted are positively associated with each other. WaSt cases have more severe wasting than wasted only cases. WaSt cases have more severe stunting than stunted only cases. WaSt is largely a disease of younger children and of males. Cases of WaSt can be detected with excellent sensitivity and good specificity using weight-for-age. Conclusions: The category "multiple anthropometric deficits" can be abandoned in favour of WaSt. Therapeutic feeding programs should cover WaSt cases given the high mortality risk associated with this condition. Work on treatment effectiveness, duration of treatment, and relapse after cure for WaSt cases should be undertaken. Routine reporting of the prevalence of WaSt should be encouraged. Further work on the aetiology, prevention, case-finding, and treatment of WaSt cases as well as the extent to which current interventions are reaching WaSt cases is required. PMID- 30026946 TI - Factors affecting long acting and permanent contraceptive methods utilization among HIV positive married women attending care at ART clinics in Northwest Ethiopia. AB - Background: Globally, unintended pregnancy has been very high accounting for 27% of maternal deaths. Different studies noted that nearly half of HIV positive women who gave unintended birth were using contraceptive methods prior to their unintended pregnancy. This implies that contraceptive failure contributes to unintended pregnancy. Long-term and permanent contraceptive methods are safe and effective contraceptive options. In women who are using long acting and permanent methods, the unintended pregnancy rate is very low and it is almost the same both in typical and perfect users. However, there is limited information on factors that affect long acting and permanent contraceptive methods utilization among Human Immuno-deficiency Virus (HIV) positive women in Ethiopia. Therefore, the purpose of this study was to assess long acting and permanent contraceptive utilization and its associated factors. Methods: An institution-based cross sectional study was conducted among 505 married women attending care at Anti Retroviral Therapy (ART) clinics in Bahir Dar from March 16, 2014 to April 15, 2014. The data were collected using a structured and interviewer administered questionnaire. Both bivariate and multivariate logistic regressions were used to identify associated factors. Results: A total of 505 married women participated in the study with a response rate of 99.6%. The utilization of long acting and permanent contraceptive methods (LAPMs) was 27.5% [95% CI, 23.8-31.5]. The multivariate analyses showed that women who were getting pre- anti retroviral therapy (Pre-ART) services [Adjusted Odds Ratio = 2.65, 95% confidence interval: 1.44, 4.86], had spousal discussion on family planning sometimes [Adjusted Odds Ratio = 6.03, 95% CI:2.42-15.01] and frequently [Adjusted Odds Ratio = 6.61, 95% confidence interval: 2.49-17.47], had previous experience on long acting contraceptive methods [Adjusted Odds Ratio = 9.06, 95% confidence interval: 5.38 15.26], no exposure to myths about LAPMs [Adjusted Odds Ratio = 2.07, 95% confidence interval: 1.24-3.45], had birth intention after 2 years [Adjusted Odds Ratio = 6.95, 95% confidence interval: 3.35-14.42], and no such intention [Adjusted Odds Ratio = 7.60, 95% confidence interval: 3.77-15.34] were factors significantly associated with utilization of long acting and permanent contraceptive methods. Conclusion: The utilization of long acting and permanent contraceptive methods was relatively high. Discussion with partners on family planning, previous experiences of LAPMs, not hearing myths about LAPMs, women not started ART, and no birth intention were positively associated with LAPMs utilization. It is therefore recommended that health service providers need to make couples counseling on FP, undergo behavioral change communication (BCC) to avoid misconceptions/myths regarding LAPMs. Further research is also recommended to address the gaps mentioned in the limitation section and to explore the reason/s for not using LAPMs (qualitative study). PMID- 30026947 TI - Health Status of Great Frigatebirds (Fregata minor) Determined by Haematology, Biochemistry, Blood Gases, and Physical Examination. AB - The great frigatebird, Fregata minor, is a widely distributed seabird native to the Galapagos archipelago. Haematology and blood chemistry parameters have been published for this species but not from the San Cristobal and North Seymour great frigatebird breeding colonies. Analyses were run on blood samples drawn from 25 great frigatebirds captured by hand at their nests at Punta Pitt on San Cristobal Island and 30 birds on North Seymour Island, Galapagos Islands. A portable blood analyser (iSTAT) was used to obtain near immediate field results for pH, pO2, pCO2, TCO2, HCO3- , haematocrit (Hct), haemoglobin (Hb), sodium (Na), potassium (K), chloride (Cl), ionized calcium (iCa), creatinine, urea nitrogen, anion gap and glucose. Blood lactate was measured using a portable Lactate PlusTM analyser. Average heart rate, respiratory rate, body weight, body temperature, biochemistry and haematology parameters were comparable to healthy individuals of other Fregatidae. The reported results provide baseline data that can be used for comparisons among populations and in detecting changes in health status among Galapagos great frigatebirds. PMID- 30026948 TI - Vinorelbine-induced acute respiratory distress syndrome treated with non-invasive ventilation and immunosuppressive therapy. AB - Severe drug-induced lung disease, resistant to steroids, is a dramatic situation due to the absence of therapeutic alternatives. We describe a case of vinorelbine induced acute respiratory distress syndrome that did not respond to supportive care plus high-dose steroids. Cyclophosphamide pulse therapy was initiated with subsequent clinical and radiological improvement, allowing the patient to be discharged. We suggest that vinorelbine-induced lung toxicity is driven by a primarily immune-mediated mechanism and that it can respond favourably to immunosuppressive therapy. PMID- 30026949 TI - The development of a polypoid intrapulmonary bronchogenic cyst in the bronchial lumen. AB - Intrapulmonary bronchogenic cysts are rare in adults and most are outside the trachea and bronchi. There are reports of clear link with the trachea, but the cyst itself occurs outside the trachea. Thus, bronchoscopy will not reveal the cause, which often leads to a diagnosis by surgical resection. We herein report an extremely rare case of an intrapulmonary bronchogenic cyst that was located entirely within the left main bronchial lumen. Bronchoscopy revealed a shiny and smooth surface mass with abundant blood vessels in the lumen that blocked the left main bronchus. The patient was successfully treated with bronchoscopic resection and remained stable at 16 months of follow-up. To our knowledge, this is the first reported case of an intrapulmonary bronchogenic cyst located entirely within the bronchial lumen. PMID- 30026950 TI - A change from gonadotropin releasing hormone antagonist to gonadotropin releasing hormone agonist therapy does not affect the oncological outcomes in hormone sensitive prostate cancer. AB - Background: The aim of our retrospective study was to evaluate the 5-year survival and time to castration resistant prostate cancer in patients with hormone sensitive prostate cancer treated with the gonadotropin releasing hormone antagonist, degarelix. Another aim was to evaluate the effects of changing the treatment from degarelix to a gonadotropin releasing hormone agonist after achieving stable disease control, on the clinical and oncological outcomes. Results: Our analysis was based on the data of 108 patients with prostate cancer who were treated with degarelix. Of these, the treatment was changed from degarelix to a gonadotropin releasing hormone agonist in 57 patients (changed group), and the treatment with degarelix was continued in the other 51 (continued group). The overall 5-year survival was statistically superior in the changed (96.6%) group than that in the continued (74.1%) group (p = 0.006). The 5-year cancer-specific survival was also superior in the changed (100%) group than that in the continued (84.6%) group (p = 0.027). The average time to castration resistant prostate cancer was comparable in both the changed (43.3 months) and continued (35.2 months) groups (p = 0.117). Lower serum levels of prostate specific antigen and alkaline phosphatase were maintained after changing the therapy from degarelix to a gonadotropin releasing hormone agonist. Conclusions: Degarelix is effective in the treatment of prostate cancer. Degarelix therapy can also be safely changed to a gonadotropin releasing hormone agonist without any adverse clinical or oncological effects. PMID- 30026951 TI - Continuous EEG monitoring in ICU. AB - Background: Continuous electroencephalogram (CEEG) monitoring is increasingly being used for brain monitoring in neurocritical care setting. This is because of the proven effectiveness of CEEG in diagnosing nonconvulsive status epilepticus (NCSE) as a cause of unexplained consciousness disorder. CEEG has been demonstrated to be effective in determining the response to, and outcome of, NCSE treatment. Main body: In this review article, the authors described the indication and methods of CEEG and diagnosis based on EEG pattern. As a condition characterized by unexplained consciousness disorder, NCSE is frequently encountered in the neurocritical care setting and is only accompanied by an altered EEG change without any clinically apparent manifestation, such as convulsion. Thus, it is considered a form of status epilepticus manifesting mainly with consciousness disorder. This is a diagnostic challenge but should not be overlooked as NCSE is a curable condition. However, CEEG is required for the correct diagnosis of NCSE, which is difficult to perform in daily clinical practice. There also are several challenges regarding urgent EEG monitoring in the intensive care unit setting, including system-related problems, such as the preparation of mobile EEG devices and collodion-applied electrodes; human resource-related problems, such as staffing of EEG technicians and physicians who can respond flexibly to unscheduled needs; and EEG-specific difficulties in interpretation/diagnosis. These issues preclude the wide spread of CEEG in daily practice. Conclusion: Recently, importance of CEEG was well accepted; however, no definitive diagnostic criteria exist for identifying EEG patterns suggestive of NCSE, especially the ambiguous significance of periodic discharges (PDs) further complicates the diagnosis of NCSE. Thus, analyzing the change in EEG patterns over time is important for the correct diagnosis of NCSE. Further studies are needed to collect sufficient CEEG data and assess the outcome of patients who have undergone therapeutic interventions. PMID- 30026953 TI - Comment on Hernandez-Vasquez et al., a bibliometric analysis of the global research on biosimilars. AB - A bibliometric analysis provided by Hernandez-Vasquez et al. listed the institutions that have published most extensively in the field of biosimilars. Sandoz and Novartis International were considered as separate entities, but are both are divisions of the same parent company. When considered as a single entity for purposes of tracking publications, Sandoz-Novartis is among the leaders in the number of articles published about biosimilars. PMID- 30026952 TI - How to squat? Effects of various stance widths, foot placement angles and level of experience on knee, hip and trunk motion and loading. AB - Background: Squatting is a core exercise for many purposes. The tissue loading during squatting is crucial for positive adaptation and to avoid injury. This study aimed to evaluate the effect of narrow, hip and wide stance widths, foot position angles (0 degrees , 21 degrees , and 42 degrees ), strength exercise experience, and barbell load (0 and 50% body weight, experts only) during squatting. Methods: Novice (N = 21) and experienced (N = 21) squatters performed 9 different variations of squats (3 stance widths, 3 foot placement angles). A 3D motion capture system (100 Hz) and two force plates (2000 Hz) were used to record mediolateral knee displacement (DeltaD*), range of motion (RoM) at the hip and knee joints, and joint moments at the hip, knee, and lower back. Results: Both stance width and foot placement angles affected the moments at the hip and knee joints in the frontal and sagittal planes. DeltaD* varied with stance width, foot placement angles and between the subjects' level of experience with the squat exercise as follows: increasing foot angle led to an increased foot angle led to an increased DeltaD*, while an increased stance width resulted in a decreased DeltaD*; novice squatters showed a higher DeltaD*, while additional weight triggered a decreased DeltaD*. Conclusions: Suitable stance width and foot placement angles should be chosen according to the targeted joint moments. In order to avoid injury, special care should be taken in extreme positions (narrow stand-42 degrees and wide stance-0 degrees ) where large knee and hips joint moments were observed. PMID- 30026954 TI - A cross-sectional study on the pulmonary function of residents in two urban areas with different PM10 concentrations: data from the fourth Korea national health and nutrition examination survey (KNHANES) 2007-2009. AB - Background: The present study aims to compare the pulmonary function of residents of Seoul special city (Seoul) and Jeju special self-governing province including Jeju city and Seogwipo city (Jeju), characterized by vastly different annual average airborne particulate matter with an aerodynamic diameter less <=10 MUm (PM10) concentrations, with the annual average PM10 concentration in Seoul being significantly higher than that in Jeju. Methods: This cross-sectional study analyzed the pulmonary function test results and sociodemographic data of Korean adults >=19 years of age derived from the 4th KNHANES, 2007-2009. A total of 830 individuals residing in Seoul or Jeju were included in this study. T-tests were used to analyze predicted values of forced expiratory volume in 1 sec (FEV1p), predicted values of forced vital capacity (FVCp) and FEV1/FVC ratio (FEV1/FVC), as dependent variables, to examine the differences in the subjects' pulmonary function according to the city of residence. Stratified analysis was then performed to adjust for variables potentially affecting pulmonary function. The analysis was performed on subjects as a group and also following stratification according to sex and other variables. Results: Seoul residents had a significantly lower FVCp than that of the Jeju residents (difference: 3.48%, p = 0.002). FEV1p, FVCp and FEV1/FVC of male Seoul residents were significantly lower than those of male Jeju residents (difference: 6.99, 5.11% and 0.03, respectively; p < 0.001, p = 0.001, p = 0.001). In male subjects, statistically significant results were obtained even after adjusting the influence of other variables through stratified analysis. Conclusion: The present analysis was based on cross-sectional data collected at one point in time. Therefore, unlike longitudinal studies, it does not establish a clear causal association between the variables. Nevertheless, this study found that pulmonary function among subjects residing in Seoul was significantly decreased compared to that of subjects residing in Jeju. PMID- 30026955 TI - Thyroid cancer among female workers in Korea, 2007-2015. AB - Background: Prevalence of thyroid cancer has been increasing rapidly worldwide, especially among women. There has been a debate as to whether such an increase represents consequences of over-diagnosis or a true increase. To find the occupational risk of Korean female workers in different industry sectors, we analyzed the data of Korean female workers. Methods: National Female Worker Cohort data that contain information on total female workers were used for our analysis of prevalence of thyroid cancer (C73 according to KCD-5, 6 code) derived from National Health Insurance data. By combining industrial codes from National Health Insurance Service and those from Korea Workers' Compensation and Welfare Service, the classification of industrial codes became to consist of the total of thirty three representing both non-office (NO) and office (O) categories. Both an internal comparison among female workers within the cohort and an external comparison to compare female workers with Korean general female population were carried out. Results: Among 149,258 female workers, 2,641 cases of thyroid cancers were identified. Differences in prevalence of thyroid cancer between female workers (40.5%) and general Korean female population (32.6%) were observed; however, the differences in prevalence of thyroid cancer between NO workers and O workers were not apparent. An analysis involving workers in Financial and insurance activities sector revealed that, standardized prevalence rate (SPR) of both NO (2.96, 95% CI = 2.01-4.20) and O workers (3.68, 95% CI = 3.10-4.33) increased significantly and that an AOR (adjusted odds ratio) increased marginally (1.38, 95% CI = 0.97-1.96). Further, when stratified in respect to the duration of employment, an AOR of female workers having been employed for more than 8 years showed a significant increase (1.63, 95% CI = 1.07 2.49). Conclusions: Female workers had a higher risk of thyroid cancer than general female population but the difference between NO workers and O workers was not found to be significant in most industrial sectors. Further studies using data with information regarding specific occupational exposures are needed. PMID- 30026956 TI - Spontaneous partial regression of low-grade mucoepidermoid carcinoma of the maxilla. PMID- 30026957 TI - Endobronchial benign nerve sheath tumour presenting with significant shortness of breath and haemoptysis. AB - Peripheral nerve sheath tumours are rare within the thoracic cavity, with non specific presentation. A 29-year-old patient presented with shortness of breath, cough, haemoptysis and recurrent chest infections. Suspicion of a primary lung carcinoma or a neuroendocrine tumour was raised following a CT and PET-CT. An endobronchial tumour suggested on histology a diagnosis of benign nerve sheath tumour, with positive staining for S100, CD56 and CD34. Following lung resection, the patient complained of fatigue and developed subcutaneous erythematous nodules on the anterior right chest, which raised the suspicion for a differential diagnosis of neurofibromatosis type I. The nodules resolved spontaneously within two weeks and the diagnosis of neurofibromatosis was ruled out on subsequent magnetic resonance imaging head and chest. PMID- 30026958 TI - Assessment of predictors for acute asthma attack in asthmatic patients visiting an Ethiopian hospital: are the potential factors still a threat? AB - Background: Recurrent exacerbations in patients with moderate or severe asthma are the major causes of morbidity, mortality and medical expenditure. Identifying predictors of frequent asthma attack might offer the fertile ground of asthma management. However, systematic data on asthma management is scarce in Ethiopia. Objective: The purpose of the present study was to determine predictors of acute asthma attack in patients with asthma attending emergency department of University of Gondar Comprehensive Specialized Hospital (UOGCSH) in Gondar, northwestern Ethiopia. Methods: An institutional-based cross-sectional self administered survey was conducted on 108 asthmatic patients who came to the emergency department of UOGCSH following acute asthma attack. Data were collected through interviewer administered questionnaire. Logistic regression was done to see the possible association of potential factors that may lead to asthma exacerbation. Result: About half of the respondents (51.9%) were female and one third of patients (38.9%) were within the age range of between 46 and 60 years. The leading potential predictor were frequent exposure to various ongoing allergen (68.5%) followed by revelation to occupational sensitizers (67.6%). Chronic sinusitis (AOR = 3.532, 95% CL = 1.116-11.178), obstructive sleep apnea (AOR = 3.425, 95% CL = 1.255-9.356) and psychological disfunctioning (3.689 (1.327-10.255)) were among the significantly associated factors of acute asthma exacerbation. Conclusions: Now days, the backbone for long-term asthma management is to prevent exacerbations. Chronic sinusitis, obstructed sleep apnea and psychosocial dysfunction were originated to be considerably linked with repeated exacerbations of asthma. Among those significantly associated predictors, obstructed sleep apnea were the most prevalent one. PMID- 30026959 TI - Evaluation of pharmaceutical intervention in direct-acting antiviral agents for hepatitis C virus infected patients in an ambulatory setting: a retrospective analysis. AB - Background: Direct-acting antivirals (DAAs) are known to improve tolerability and have higher efficacy and shorter treatment durations compared with conventional interferon (IFN)-based treatments for hepatitis C virus (HCV) infection. Management of drug interactions and maintenance of patient adherence are important to achieve adequate therapeutic effects, sustained virological response (SVR). In order to maximize the benefits of oral DAA therapy, we established an ambulatory care pharmacy practice, a model of integrated collaboration between physicians and pharmacists, for patients receiving IFN-free DAA therapy. In this study, we evaluated pharmaceutical intervention for patients visiting the ambulatory care pharmacy practice. Methods: HCV-infected outpatients who visited our ambulatory care pharmacy practice between September 2014 and May 2017 were eligible for inclusion in the study. When IFN-free DAAs were first prescribed, the physicians recommended all patients to visit the ambulatory care pharmacy practice after their clinical examination. Subsequently, at the second visit or later, the patients visited the pharmacy service before the physician's examination. The primary endpoint was SVR, defined as HCV RNA below the lower limit of quantification after the completion of treatment. We also evaluated the adherence rate to DAAs, suggestions to the physicians by the pharmacists, and questions from the patients. All data were obtained retrospectively using an electronic medical record system. Results: Among the 401 study subjects, 386 patients completed the IFN-free DAA therapy. A total of 365 patients have reached 12 or 24 weeks after completing the treatment. The overall SVR rate was 98.1% (358/365). The proportion of patients with adherence >=90% was 99.3% (398/401). Two-hundred and sixty-seven (84%) among 318 suggestions of prescription made by the pharmacists mainly to manage the adverse events were accepted by the physicians. The pharmacists received and answered 1072 questions on DAA therapy from the patients. Conclusions: This study indicates that the pharmaceutical intervention may contribute to enhanced adherence to DAAs and higher SVR rates in comparison with previous reports. This study also demonstrates that collaboration between physicians and pharmacists in an ambulatory setting provides favorable outcomes for patients receiving IFN-free DAAs. PMID- 30026960 TI - High-performing farms exploit reproductive potential of high and low prolific sows better than low-performing farms. AB - Background: Our objective was to examine the impact of farm effects and sow potential on various aspects of sow performance. We examined the interaction between sow prolificacy groups categorized at parity 1 and farm productivity groups for reproductive performance across parities, and lifetime performance. Data included 419,290 service records of 85,096 sows, on 98 Spanish farms, from first-service as gilts to removal, that were served between 2008 and 2013. Farms were categorized into three productivity groups based on the upper and lower 25th percentiles of the farm means of annualized lifetime piglets weaned per sow over the 6 years: high-performing (HP), intermediate-performing (IP), and low performing (LP) farms. Also, parity 1 sows were categorized into three groups based on the upper and lower 10th percentiles of piglets born alive (PBA) as follows: 15 piglets or more (H-prolific), 8 to 14 piglets, and 7 piglets or fewer (L-prolific). The farm groups represent farm effects, whereas the sow groups represent sow potential. Linear mixed effects models were performed with factorial arrangements and repeated measures. Results: Mean parity at removal (4.8 +/- 0.01) was not associated with three farm productivity groups (P = 0.43). However, HP farms had 7.7% higher farrowing rates than LP farms (P < 0.05). As a result, H-prolific and L-prolific sows on HP farms had 29.7 and 30.7 fewer non productive days during lifetime than the respective sows on LP farms (P < 0.05). Furthermore, the H-prolific and L-prolific sows on HP farms had 4.9 and 6.2 more annualized piglets weaned than respective H-prolific and L-prolific sows on LP farms (P < 0.05), which was achieved by giving birth to 0.8-1.0 and 1.4-1.7 more PBA per litter, respectively, than on HP farms during parities 2-6 (P < 0.05). During the first parity, HP farms had 18.8% H-prolific sows compared to 6.2% on LP farms. Conclusion: Farm effects substantially affected lifetime performance of sows. Higher lifetime productivity of sows on HP farms was achieved by higher farrowing rate, fewer non-productive days, more PBA and more piglets weaned per sow, regardless of prolific category of the sows. PMID- 30026961 TI - Methods to identify and prioritize patient-centered outcomes for use in comparative effectiveness research. AB - Background: We used various methods for identifying and prioritizing patient centered outcomes (PCOs) for comparative effectiveness research (CER). Methods: We considered potential PCOs ("benefits" and "harms") related to (1) gabapentin for neuropathic pain and (2) quetiapine for bipolar depression. Part 1 (April 2014 to March 2015): we searched for PCO research and core outcome sets (COSs). We conducted electronic searches of bibliographic databases and key websites and examined FDA prescribing information and reports of clinical trials and systematic reviews. We asked patient and clinician co-investigators to identify PCOs. Part 2 (not part of our original study protocol): in 2015, we surveyed members of The TMJ Association, Ltd., a patient group associated with temporomandibular disorders (4130 invitations sent). Participants prioritized (1) the importance of six potential benefits and (2) 21 potential harms selected by the investigators in part 1, using stated preference methods. We calculated descriptive statistics. Results: In part 1, we identified a COS for pain, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations. The COS identified several important benefits, but it lacked specific recommendations about which potential harms to include in CER. We did not identify a COS for bipolar depression. Research reports, prescribing information, and patient co-investigators helped identify but not prioritize outcomes. We abandoned our electronic search for PCO research because we found it would be resource-intensive and yield few relevant reports. In part 2, surveying patients was useful for prioritizing PCOs. Members of The TMJ Association, Ltd., completed the survey (N = 746) and successfully prioritized both benefits and harms. Participants did not identify many benefits other than those we identified in part 1; several participants identified additional harms. Conclusions: These exploratory results could inform future research about identifying and prioritizing PCOs. We found that stakeholder co-investigators and research reports contributed to identifying PCOs; surveying a patient group contributed to prioritizing PCOs. Prioritizing potential harms was particularly challenging because there are many more potential harms than potential benefits. Methods for identifying and prioritizing potential benefits for CER might not be appropriate for harms. Further research is needed to determine the generalizability of these results. PMID- 30026962 TI - Pilot trials in physical activity journals: a review of reporting and editorial policy. AB - Background: Since the early 2000s, a number of publications in the medical literature have highlighted inadequacies in the design, conduct and reporting of pilot trials. This work led to two notable publications in 2016: a conceptual framework for defining feasibility studies and an extension to the CONSORT 2010 statement to include pilot trials. It was hoped that these publications would educate researchers, leading to better use of pilot trials and thus more rigorously planned and informed randomised controlled trials. The aim of the present work is to evaluate the impact of these publications in the field of physical activity by reviewing the literature pre- and post-2016. This first article presents the pre-2016 review of the reporting and the current editorial policy applied to pilot trials published in physical activity journals. Methods: Fourteen physical activity journals were screened for pilot and feasibility studies published between 2012 and 2015. The CONSORT 2010 extension to pilot and feasibility studies was used as a framework to assess the reporting quality of the studies. Editors of the eligible physical activity journals were canvassed regarding their editorial policy for pilot and feasibility studies. Results: Thirty-one articles across five journals met the eligibility criteria. These articles fell into three distinct categories: trials that were carried out in preparation for a future definitive trial (23%), trials that evaluated the feasibility of a novel intervention but did not explicitly address a future definitive trial (23%) and trials that did not have any clear objectives to address feasibility (55%). Editors from all five journals stated that they generally do not accept pilot trials, and none gave reference to the CONSORT 2010 extension as a guideline for submissions. Conclusion: The result that over half of the studies did not have feasibility objectives is in line with previous research findings, demonstrating that these findings are not being disseminated effectively to researchers in the field of physical activity. The low standard of reporting across most reviewed articles and the neglect of the extended CONSORT 2010 statement by the journal editors highlight the need to actively disseminate these guidelines to ensure their impact. PMID- 30026963 TI - Patient advocate involvement in the design and conduct of breast cancer clinical trials requiring the collection of multiple biopsies. AB - Plain English summary: Breast cancer is a diverse and varied disease. Recent research has shown that the collection of multiple biopsies before surgery can help researchers determine how the cancer is responding to treatment and can predict for long-term outcomes. However biopsies can be uncomfortable, and sometimes clinicians and research teams in hospitals may be reluctant to offer clinical trials requiring several biopsies to patients who have been recently diagnosed with breast cancer. The Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU) oversees a large number of breast cancer clinical trials where multiple biopsies are required. ICR-CTSU recognises that patient advocates (patients who have previously had, or cared for someone with, cancer) are key members of the trial design group and should be involved in the clinical trial throughout its lifespan. Patient advocates can provide reassurance regarding the acceptability of trial designs involving multiple biopsies from a patient perspective. This paper summarises patient advocate involvement in ICR CTSU breast cancer trials activity and how this has benefited our research. Abstract: The importance of collecting tissue samples in breast cancer has become increasingly recognised, as the diversity of the disease has become better known. It has been documented in recent research that tumours may change in response to treatment prior to surgery (the neoadjuvant treatment setting). The collection of sequential biopsies over time can identify changes within tumours and potentially predict how the tumour may respond to certain treatments. However, the acceptability of multiple biopsies amongst patients, clinicians and other research staff in hospitals is variable and recruitment into clinical trials requiring multiple biopsies may be challenging.The Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU) is responsible for a portfolio of breast cancer trials where multiple biopsies are key to the trial design. Patient advocate involvement has been essential in helping us to design and deliver complex and innovative cancer trials which require multiple invasive tissue biopsies, often without any direct benefit to the trial participants. The views expressed by patient advocates involved in ICR-CTSU trials supports the published evidence that patients are willing to donate additional tissue for research and that clinicians' concerns about approaching patients for trials involving multiple biopsies are often unfounded.Patient advocate involvement in ICR-CTSU trials activity takes various forms, from membership on protocol development groups and trial management groups, attendance at focus groups and forums, and presentations at trial development and launch meetings. This involvement has provided reassurance to research teams within the NHS and research ethics committees of the importance and acceptability of our trials from a patient perspective. Patient advocate involvement throughout the lifetime of our trials ensures that the patient remains central to our research considerations. PMID- 30026964 TI - Acute retinal vein occlusion and cystic fibrosis. AB - Background: The ocular manifestations of cystic fibrosis typically present with surface irritation or nyctalopia due to Vitamin A deficiency, however, there have been two previous reports of patients with cystic fibrosis that developed retinal vein occlusions. These reports hypothesized that either elevated fibrinogen levels due to chronic infections or elevated homocysteine levels have predisposed patients with cystic fibrosis to develop retinal vein occlusions. Case presentation: We present a case of a 35-year-old male with cystic fibrosis complicated by chronic sinusitis with no history of organ transplantation or chronic pulmonary infections who presented with an acute branch retinal vein occlusion in his left eye with associated macular edema. Evaluation revealed an elevated fibrinogen level, while the rest of his workup was relatively unremarkable including a normal homocysteine level. His vision remained 20/20 throughout his care and he did not require treatment of his macular edema. Conclusions: Patients with cystic fibrosis are at an increased risk of developing retinal vein occlusions likely due to a variety of systemic thrombogenic factors rather than a single risk factor which had been reported previously. Elevated fibrinogen levels in these patients may not be due to chronic infections, but inherent to the cystic fibrosis. PMID- 30026967 TI - The Hong Kong Queen Mary Hospital Second Thoracic Surgery Symposium Focused Issue. PMID- 30026966 TI - An overview of realist evaluation for simulation-based education. AB - This article describes the key features of realist (realistic) evaluation and illustrates their application using, as an example, a simulation-based course for final year medical students. The use of simulation-based education (SBE) is increasing and so too is the evidence supporting its value as a powerful technique which can lead to substantial educational benefits. Accompanying these changes is a call for research into its use to be more theory-driven and to investigate both 'Did it work?' and as importantly 'Why did it work (or not)?' An evaluation methodology that is capable of answering both questions is realist evaluation. Realist evaluation is an emerging methodology that is suited to evaluating complex interventions such as SBE. The realist philosophy positions itself between positivist and constructivist paradigms and seeks to answer the question 'What works for whom, in what circumstances and why?' In seeking to answer this question, realist evaluation sets out to identify three fundamental components of an intervention, namely context, mechanism and outcome. Educational programmes work (successful outcomes) when theory-driven interventions (mechanisms) are applied to groups under appropriate conditions (context). Realist research uses a mixed methods (qualitative and quantitative) approach to gathering data in order to test the proposed context-mechanism-outcome (CMO) configurations of the intervention under investigation. Realist evaluation offers a valuable methodology for researchers investigating interventions utilising simulation-based education. By investigating and understanding the context, mechanisms and outcomes of SBE interventions, realist evaluation can provide the deeper level of understanding being called for. PMID- 30026968 TI - An introduction to the Journal of Thoracic Disease focused issue "Hong Kong Queen Mary Hospital Second Thoracic Surgery Symposium". PMID- 30026965 TI - A complex mosaic of enteroviruses shapes community-acquired hand, foot and mouth disease transmission and evolution within a single hospital. AB - Human enteroviruses (EV) pose a major risk to public health. This is especially so in the Asia-Pacific region where increasing numbers of hand, foot and mouth disease (HFMD) cases and large outbreaks of severe neurological disease associated with EV-A71 have occurred. Despite their importance, key aspects of the emergence, epidemiology and evolution of EVs remain unclear, and most studies of EV evolution have focused on a limited number of genes. Here, we describe the genomic-scale evolution of EV-A viruses sampled from pediatric patients with mild disease attending a single hospital in western Sydney, Australia, over an 18 month period. This analysis revealed the presence of eight viral serotypes Coxsackievirus (CV) A2, A4, A5, A6, A8, A10, A16 and EV-A71-with up to four different serotypes circulating in any 1 month. Despite an absence of large-scale outbreaks, high levels of geographical and temporal mixing of serotypes were identified. Phylogenetic analysis revealed that multiple strains of the same serotype were present in the community, and that this diversity was shaped by multiple introductions into the Sydney population, with only a single lineage of CV-A6 exhibiting in situ transmission over the entire study period. Genomic-scale analyses also revealed the presence of novel and historical EV recombinants. Notably, our analysis revealed no association between viral phylogeny, including serotype, and patient age, sex, nor disease severity (for uncomplicated disease). This study emphasizes the contribution of EV-A viruses other than EV-A71 to mild EV disease including HFMD in Australia and highlights the need for greater surveillance of these viruses to improve strategies for outbreak preparedness and vaccine design. PMID- 30026969 TI - Esophageal resection for cancer in The University of Hong Kong, Queen Mary Hospital, Hong Kong, China (1982-2008). AB - Esophageal resection is a high-risk procedure. In the early 1980s, it carried a mortality of more than 20%. Through a concerted effort which include meticulous surgical technique, vigilant post-operative care, and a low threshold to correct respiratory problem, the mortality rate was reduced to almost 0%. Our single layer continuous anastomotic technique also dramatically reduced the anastomotic leakage rate. PMID- 30026970 TI - Combined esophagectomy and carinal pneumonectomy. PMID- 30026971 TI - Original "double-step" technique for large superior sulcus tumors invading the anterior chest wall without subclavian vessels involvement. AB - Background: In some patients with complex Superior Sulcus tumors, a combination of surgical accesses may be required. For patients with very large tumors which invade the first ribs anteriorly and without subclavian vessels involvement, we developed a "double-step" technique to facilitate resection and reduce surgical trauma. Methods: The technique was performed on five patients with a bulky non small cell lung cancer (NSCLC), four of whom had a Superior Sulcus tumor. All patients received a radical wide thoracectomy en-bloc with an upper lobectomy. Neither significant flail chest nor postoperative respiratory complications were observed. The method is based on the possibility of interrupting the medial extremity of the first rib beneath the clavicle through a limited, preliminary parasternal incision. The remaining ribs involved in the resection are also interrupted at the costo-chondral junction, leaving the sternum and clavicle intact. Once the medial limit of the involved ribs has been sectioned, multiple stitches are placed through the peristernal tissues and temporarily left inside the chest. Through a second posterior incision, the en-bloc chest wall and lung resection is easily completed. The previously placed peristernal stitches are collected and used for the medial fixation of the prosthesis. Results: Using this technique the resection was radical in all cases. No major postoperative complications were registered. Conclusions: The technique has several advantages: trauma related to double access is negligible; radical resection is facilitated, anterior chest wall resection is accomplished without sternal or clavicular injury, en-bloc chest wall and lung resection is made straightforward despite the extended area of resected ribs attached to the tumor, released within the chest cavity; chest wall stabilization is simple and reliable. The only disadvantage is that the patient's surgical position needs to be changed. PMID- 30026972 TI - Chest wall resection and reconstruction for tumors: analysis of oncological and functional outcome. AB - Background: Tumors of the chest wall have a large spectrum of well-assessed indications for resection. However, whether a reconstruction is required or not is not always clear. Complications after chest wall resection and reconstruction (CWRR) are described in literature and potentially severe. There is no evidence of how non-reconstructive management may influence the post-operative complication rate. Methods: A total of 71 patients underwent thoracic demolition for tumors between April 2000 and October 2016. The patients were divided into two groups based on pathological findings: group 1: primary chest wall tumors; group 2: non-small cell lung cancer (NSCLC) invading the thoracic wall. They were then retrospectively analyzed by means of following criteria: TNM staging, histology, infiltration depth, 5-year survival, overall survival (OS), disease free survival (DFS), relapse rate, R-0 resection, number of resected ribs, site of surgical resection and post-operative respiratory complications, flail chest, chronic pain, deformity of the chest wall and cosmetic results. Results: Five year survival, OS, DFS and risk of relapse showed a significant correlation with the presence of free surgical margins in both groups. In group 2, another parameter which correlated to survival, risk of relapse and DFS was lymph-nodal status. Moreover, the risk of post-operative respiratory complications was directly correlated with non-reconstruction after demolition of the chest wall in certain topographical sites. Conclusions: free surgical margins are the main oncological prognostic factor in these patients. In patients who underwent resection of two or more ribs in a critical area, reconstruction of the bony thorax can significantly reduce the post-operative respiratory complication rate. PMID- 30026973 TI - Catheter-based alternative treatment for early-stage lung cancer with a high-risk for morbidity. AB - The mainstream treatment modality for early stage non-small cell lung cancer (NSCLC) is surgery; however, many patients are deemed inoperable and warrant alternative therapeutic options. Several minimally invasive catheter-based therapies are emerging as viable alternatives. In this review, we evaluate the outcomes from radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation (CRA) and photodynamic therapy (PDT) for early-stage lung cancer. Novel technical developments have allowed for endobronchial thermal ablation to be conducted in a hybrid theatre setting, which may optimize treatment outcomes and minimise treatment-related complications. PMID- 30026974 TI - Ex vivo lung perfusion: a potential platform for molecular diagnosis and ex vivo organ repair. AB - Lung transplantation is a proven treatment for selected patients with end-stage lung disease. However, the number of patients on the transplant waiting list far exceeds the number of available donor lungs, resulting in waiting list morbidity and mortality. The problem is further exacerbated by the low utilisation rate of available donor lungs, for fear of selecting a damaged lung and the resultant primary graft dysfunction. In the past decade, ex vivo lung perfusion (EVLP) has become part of standard lung transplant clinical practice in Canada and Europe, and it has been shown to improve the usage of available donor lungs by allowing physiological and radiologic evaluation of explanted donor lungs that are considered "marginal". This allows clinicians a second opportunity to decide whether to proceed to transplantation, instead of declining an organ that appears questionable by standard clinical criteria. However there has been much research activity looking at EVLP as a platform for (I) molecular diagnosis, thereby further improving the diagnostic accuracy regarding quality of the donor lung; (II) organ repair, thereby allowing injured donor lungs to become clinically useable. This manuscript summarises some of the preclinical and clinical research from the Toronto group focusing on these promising aspects of EVLP which may further increase the number of useable donor lungs in lung transplantation. PMID- 30026975 TI - Minimally invasive thoracic surgery: beyond surgical access. AB - Thoracic surgery has evolved throughout the decades. The difficulty of accessing the intrathoracic organs through the bony rib-cage has been a challenge for thoracic surgeons. In the past, large incisions stretching across the chest, such as posterolateral thoracotomies with rib spreading was the standard approach to access the lungs. These methods cause large amounts of trauma to the patient, with high rates of mortality and morbidity. However, with the advances in technology and the improvements in surgical technique, thoracic surgery has progressed to minimise trauma to the patient while still maintaining oncological and surgical principles. State-of-the-art technology, combined with wide variety of old and new surgical techniques give the thoracic surgeon a formidable armamentarium. Although there has been a focus on reducing the number and size of surgical wounds, considerations other than surgical approach can reduce the trauma suffered by the patient. Preservation of pulmonary function via organ preservation and anaesthetic techniques to further minimise the systemic inflammation such as non-intubated anaesthesia have also been shown to improve patient outcomes. This article aims to review the recent advances in minimally invasive thoracic surgery. PMID- 30026977 TI - The history of lung transplantation in Hong Kong. AB - Clinical lung transplant was first performed in Hong Kong in 1995. In the early years, the volume of activity was very low. There has been a clear trend of increasing volume in the past few years. The recipient pathology is very different from the International Society for Heart and Lung Transplantation (ISHLT) database, with complete absence of cystic fibrosis and alpha-1 antitrypsin deficiency, and a predominance of diseases of the pulmonary circulation. Lymphangioleiomyomatosis (LAM) has a much higher representation on the waiting list than the ISHLT. The survival of patients who received a lung transplant in Hong Kong compares favorably with international data. PMID- 30026976 TI - Lobectomy with angioplasty: which is the best technique for pulmonary artery reconstruction? AB - Lobectomies with bronchial and/or vascular reconstruction are conservative procedures aimed at managing locally advanced lung cancer, avoiding a pneumonectomy. Considering morbidity, mortality and the functional consequences of a pneumonectomy, such procedures must be in the technical armamentarium of every thoracic surgeon. Vascular reconstruction of the pulmonary artery (PA) is seldom performed with or without the bronchial sleeve resection. Both functional and oncologic outcomes have been reported to be better than after a pneumonectomy. Different technical options are now available but some aspects and technical details are not standardized. Indications, possible complications, planning and even definitions need to be more solid to allow for definitive improvement in such procedures. This analysis is aimed at assessing the acquired technical data with special emphasis on the PA reconstruction with autologous tissues. PMID- 30026978 TI - Congenital H-type tracheoesophageal fistula in adults. AB - Congenital tracheoesophageal fistulas (TEFs) in the adults are uncommonly reported but they are serious conditions that can cause severe morbidities and mortality. Three cases were identified in the last 16 years. The diagnosis was not easy but they were all successfully surgically repaired with good results. A detailed history and meticulous examination of the radiological studies will help diagnose this condition. Surgical repair should be performed once diagnosed. PMID- 30026979 TI - "Going from strength to strength"-Queen Mary Hospital (QMH) Second Thoracic Surgery Symposium. PMID- 30026980 TI - Prof. Francesco Puma: learning is like rowing upstream-not to advance is to drop back. PMID- 30026982 TI - Dr. Hon Chi Suen: thoracic surgery is full of unknowns-challenging surgeries. PMID- 30026981 TI - Prof. Garrett Lyndon Walsh: minimally invasive surgery continues to improve benefiting more patients. PMID- 30026983 TI - The Prevalence and Associations of Peripheral Retinopathy: Baseline Study of Guangzhou Office Computer Workers. AB - Purpose: To determine the prevalence of peripheral retinopathy and its associated risk factors among a sample of Guangzhou office computer workers. Methods: A cross-sectional study of Guangzhou Chinese computer workstations and operators in different departments and units of the Guangzhou Power Supply Bureau, China, in 2016. Peripheral retinopathy was recorded and analyzed using a scanning laser ophthalmoscope (SLO; Optos, Daytona, United Kingdom) and slit-lamp microscopy combined with a three-mirror contact lens. Results: The 1934 eyes of 967 subjects (513 females and 454 males) were included in this study. In total, 79.1% of the eyes were myopic in workers aged 20-29 years, 72.9% in workers aged 30-39 years, 62.2% in workers aged 40-49 years, and 43.4% in workers aged 50-59 years (p < 0.001). Most eyes had optic nerve crescents (81.3%). Various peripheral degenerations were found: 7 eyes (0.4%) had microcystoid degeneration, 40 (2.1%) had peripheral pigmentary degeneration, 87 (4.5%) had lattice degeneration, and 4 (0.2%) had snail-track degeneration. Nineteen (1.0%) eyes had paving-stone degeneration, 11 (0.6%) eyes had a retinal hole or tear, and 16 (0.8%) eyes had chorioretinal degeneration. Multivariate regression confirmed that greater axial length (OR: 1.18 (1.03, 1.35), p=0.012) and more serious spherical equivalent (OR: 0.82 (0.77, 0.88), p < 0.001) were significant risk factors for peripheral retinal changes. Conclusion: Peripheral retinal degenerative changes were found in a larger proportion of younger computer workers than older ones. Myopia is occurring in younger and younger people, accompanied by peripheral retinal degeneration. PMID- 30026984 TI - The Association between Female Reproductive Factors and Open-Angle Glaucoma in Korean Women: The Korean National Health and Nutrition Examination Survey V. AB - Purpose: We investigated associations between female reproductive factors and open-angle glaucoma (OAG) in Korean females using the Korea National Health and Nutrition Examination Survey (KNHANES). Methods: A nationwide, population-based, cross-sectional study was conducted. We enrolled 23,376 participants from the KNHANES who had undergone ophthalmologic exams from 2010 through 2012. Associations between undiagnosed OAG and female reproductive factors such as age at menarche and menopause, parity, history of lactation, and administration of oral contraceptives (OC) or hormone replacement therapy (HRT) were determined using stepwise logistic regression analyses. Results: Of the enrolled participants, 6,860 participants (397 with OAG and 6,463 without OAG) met our study criteria and were included in the analyses. In the multivariate logistic regression analysis after adjusting for all potential confounding factors, only early menopause (younger than 45 years) was significantly associated with OAG in participants with natural menopause (OR 2.28, 95% CI 1.17-4.46). Age at menarche, parity, history of lactation, and administration of OC or HRT were not significantly associated with OAG. Conclusions: Only early menopause was associated with an increased risk of OAG in our study, in contrast to previous Western studies reporting both early menopause and late menarche as associated factors. PMID- 30026985 TI - Clinical Efficacy of Platelet-Rich Plasma in the Treatment of Neurotrophic Corneal Ulcer. AB - Purpose: Platelet-rich plasma (PRP) is an autologous blood product without preservatives and rich in proteins and growth factors which make it possible for cells to differentiate, proliferate, and migrate, thus stimulating healing and regeneration of tissues. The aim of this study was to evaluate the efficiency of autologous platelet-rich plasma in the treatment of neurotrophic keratopathy. Methods: The study group consists of 25 patients with nonhealing corneal ulcers due to herpes simplex or herpes zoster infection and facial nerve or trigeminal nerve paralysis as a result of a neurosurgical operation caused by a tumour or stroke. The patients were given autologous platelet-rich plasma drops five times a day and additionally preservative-free artificial tears and a vitamin A ointment at night for maximum 3 months. The following were evaluated: best corrected visual acuity (BCVA), healing of corneal surface, subjective symptoms, and changes in corneal thickness with the use of anterior segment optical coherent tomography (AS-OCT). Results: BCVA before the treatment was 0.10 +/- 0.14, and after the treatment it was -0.3 +/- 0.27 (p=0.001). Improved visual acuity and less subjective symptoms were observed in all patients. Complete healing of the ulceration was observed in 20 patients (80%). Four patients (16%) experienced considerable improvement of their clinical condition (reduced size and depth of the ulceration and inflammatory state: smaller conjunctival injection and swelling, improved visual acuity, and less subjective symptoms). In one of the patients, an amniotic membrane was transplanted due to the lack of improvement of his local condition. In all patients, the progression of corneal thinning was stopped. An average corneal thickness in its thinnest point was 322.3 +/- 125.8 um before the treatment, and 404.5 +/- 118.7 um (p < 0.05) after the treatment. None of the patients reported general or local side effects of the treatment. Conclusions: Autologous platelet-rich plasma is a blood-based product which seems efficient in the treatment of neurotrophic keratopathy. PMID- 30026986 TI - Ahmed Glaucoma Valves versus EX-PRESS Devices in Glaucoma Secondary to Silicone Oil Emulsification. AB - Objective: To evaluate and compare the clinical effects of Ahmed glaucoma valves (AGVs) and EX-PRESS implants on glaucoma secondary to silicone oil (SO) emulsification. Methods: A retrospective case-series study was designed. A total of 23 eyes with late intraocular pressure (IOP) elevation secondary to SO emulsification were included in the study. Antiglaucoma surgery with implantation of AGVs or EX-PRESS devices was performed. Pre- and postoperative ocular parameters were recorded at each visit during a 1-year follow-up period. The rates of complete success (IOP < 21 mmHg without medication) and qualified success (IOP < 21 mmHg with <=3 glaucoma medications) were analyzed. Results: A total of 14 eyes underwent AGV implantation, and 9 underwent EX-PRESS implantation. The mean IOP and number of medications used at the last follow-up decreased significantly compared with that before surgery (P < 0.001). The total success rate for all eyes including complete success (7/23) and qualified success (7/23) was 60.9% (14/23) at 1 year. The total success rate in the AGV group was 78.6% (11/14), whereas it was 33.3% (3/9) in the EX-PRESS group; the difference between the 2 groups was significant (P < 0.05). Conclusion: For glaucoma secondary to SO emulsification, glaucoma implants could be effective at lowering IOP, and AGVs might produce better outcomes than EX-PRESS devices. PMID- 30026987 TI - Effects of Iodixanol on Respiratory Functions during Coronary Angiography and the Role of Body Composition. AB - Purpose: The purposes of this study are to assess the acute effects of iodixanol, an iso-osmolar contrast media, on pulmonary functions and to evaluate the body composition in order to find out its role in causing this deterioration. Methods: 35 male and 25 female patients undergoing diagnostic coronary angiography (CA) were enrolled in the study. Before CA, all patients' body compositions were evaluated by measuring their body mass indexes (BMIs) and waist-to-hip ratios (WHRs). Total body waters (TBWs), fat masses (FMs), fat-free masses (FFMs), and basal metabolism rates (BMRs) were measured via bioimpedance analysis. The CA was performed via radial artery route using iodixanol in every patient. The pulmonary function tests of these patients were performed before, during, and 2 hours after the CA. FEV1?, FEF25-75%?, and FVC? parameters were calculated by subtracting the measured baseline value from the measurement after the CA. Results: Angiography caused significant reduction in forced expiratory volume in 1 sec (FEV1, from 94.17 +/- 18.83 to 84.45 +/- 18.31, p < 0.0001), forced vital capacity (FVC, from 96.57 +/- 15.82 to 88.31 +/- 17.96, p < 0.0001), and forced expiratory flow at 25 75% (FEF25-75% from 82.54 +/- 24.26 to 72.11 +/- 25.41, p=0.001) and remained lower after 2 h after CA in male patients, respectively. FEV1 values were 103.40 +/- 17.79 to 94.96 +/- 17.063 (p=0.004); FVC values were 107.20 +/- 19.03 to 99.08 +/- 20.56 (p=0.009); and FEF25-75% values were 83.92 +/- 24.30 to 73.24 +/- 20.45 (p=0.005) before and after CA and remained lower after 2 h after CA in female patients, respectively. FEV1/FVC ratio remained unchanged. FEF25-75%? was statistically correlated with FFM, TBW, and WHR (p < 0.05; r=-0.344, r=-0.347, and r=0.357, resp.), and FVC? was correlated with WHR in male patients (p=0.018, r=397). Conclusions: Our data suggested that diagnostic CA using iodixanol, an iso-osmolar contrast media, leads significant impairment in respiratory functions. Due to the persistence of these reductions even 2 hours after CA, ventilatory functions should be considered especially in patients whose body compositions or hydration levels are not within the desired physiological range. PMID- 30026989 TI - Squamous Cell Carcinoma Arising within Verruca Vulgaris on the Nipple. AB - Cutaneous squamous cell carcinoma (SCC) is a common form of skin cancer and often appears as a hard, scaly lump that occasionally ulcerates. It is usually associated with cumulative exposure to ultraviolet light, although prior scarring, chronic wounds, exposure to radiation, HPV infection, and immunosuppression are also associated risk factors. Primary SCC of the nipple is very rare and only a few cases have been reported. We present a case of a 49-year old female with concerns of a right nipple lesion with erythema and pain. She was initially evaluated for Paget's disease with an underlying malignancy and cellulitis, but, after biopsy and investigation, she was found to have a well differentiated SCC arising from a verruca vulgaris. Current literature does not provide distinct guidelines on management of SCC or its variants on the nipple, and the case was managed based off of SCC at other cutaneous sites as well as other cases of SCC on the nipple. PMID- 30026988 TI - Clinical Application of the Socket-Shield Concept in Multiple Anterior Teeth. AB - A case of rehabilitation of the upper front teeth is presented. To prevent bone resorption following extractions, a socket-shield technique on all the extracted teeth was performed. The combination of a staged extraction approach, the sequence of provisionals together with the minimal bone loss of vestibular volume, allowed solving this high aesthetic demanding case in a satisfactory way for the patient both in duration of the treatment and in its final outcome. PMID- 30026990 TI - The Relationship between Multiple Myeloma with Renal Failure and Metastatic Calcification. AB - While cases of multiple myeloma (MM) with metastatic calcification have been reported, the mechanisms for this calcification have yet to be explained. We observed a case of MM in a patient with end-stage renal failure who developed vascular and pulmonary calcification. A 51-year-old male was diagnosed with Bence Jones type MM and required maintenance hemodialysis. He was treated with bortezomib-dexamethasone, vincristine-doxorubicin-dexamethasone, the M2 protocol, and lenalidomide-dexamethasone (Rd) therapy. During the sixth cycle of Rd therapy, he complained of pain in both lower legs. Well-demarcated ulcers with severe pain had developed on the right lower leg, both exterior thighs, and penis. We found that the patient's serum intact parathyroid hormone level was elevated, while it had previously been permissively controlled. Computed tomography scan showed widespread centrilobular opacities of the bilateral lungs and high-density lesions along small blood vessels in the trunk and all four extremities. Histological calcifications were identified in small blood vessels and the alveolar walls. The risk of metastatic calcification in MM appears to be associated with renal failure, but not with MM itself. PMID- 30026991 TI - An Interesting Case of a 57-Year-Old Male with an Upper Gastrointestinal Bleeding and Obstructive Uropathy with Bilateral Hydronephrosis Diagnosed with Systemic Mucormycosis. AB - Mucormycosis is a rare and invasive fungal disease with high mortality rate caused by members of the order Mucorales. Mucorales species are vasotrophic organisms that may cause angioinvasive disease in immunosuppressed hosts. Risk factors include diabetic ketoacidosis, chronic kidney disease, organ or bone marrow transplantation, neutropenia, burns, malignancies, and steroid therapy. There are six different clinical presentations of mucormycosis, which includes rhino-orbital cerebral, pulmonary, gastrointestinal, cutaneous, disseminated, and miscellaneous infection. Here, we report a case of a 57-year-old male with stage IV sarcoidosis on long-term steroids presenting with upper gastrointestinal bleeding and obstructive uropathy who was diagnosed with systemic mucormycosis. Biopsy obtained by endoscopy revealed necrotic debris with acute leukocytic exudate and numerous variably sized, 90-degree angulated fungal hyphae favoring mucormycosis-causing species. Imaging studies showed hydronephrosis, and cystoscopy findings were consistent with fungal infection of the bladder. Isavuconazonium sulfate was used as systemic salvage therapy along with continuous bladder irrigation with amphotericin-B for localized bladder infection after a trial with first-line systemic treatment with intravenous liposomal amphotericin-B failed. A repeat endoscopy showed inflammatory changes with a pathology report in which mucormycosis was no longer appreciated. The patient was discharged home to complete 6 months of antifungal therapy with monthly follow ups. The patient has been asymptomatic after 12-month completion of therapy. PMID- 30026992 TI - Actinomyces europaeus Isolated from a Breast Abscess in a Penicillin-Allergic Patient. AB - This is a case of Actinomyces europaeus in the breast abscess of a penicillin allergic woman. The mainstay of treatment for actinomycosis is penicillin, and there is a lack of literature describing nonpenicillin treatment options. A 69 year-old woman presented acutely with a breast abscess which was managed with incision and drainage and antibiotic therapy to good response. 21 days after presentation, Actinomyces were grown from the culture of pus, so the patient was recalled and more rigorous treatment and follow-up were initiated. The penicillin allergy led to difficulty in the identification of an appropriate antimicrobial agent that was also logistically feasible to be given on an outpatient IV basis. IV tigecycline followed by oral clarithromycin was found to be effective treatment. PMID- 30026993 TI - A Case of Undetected Neuroborreliosis in a 75-Year-Old Chinese Male. AB - Lyme disease is a multisystem infection caused by the spirochete Borrelia burgdorferi sensu stricto that manifests with characteristic symptoms in patients. Patients are identified based on their clinical symptoms and then diagnosed through enzyme-linked immunosorbent assay (ELISA), Western blot, and blood culture techniques. Here, we present the case of a 75-year-old, Northeast suburban resident complaining of unstable gait, high fevers, malaise, myalgia, and confusion. This patient's symptoms were nonspecific, and his lab titers and blood cultures were repeatedly negative during his stay. It was only late in the course of his treatment that blood titers and cerebrospinal fluid analysis were positive for Lyme IgG and IgM. He was treated with intravenous doxycycline and prescribed oral doxycycline on discharge, resulting in a full recovery. We express the need for physicians to consider Lyme disease in endemic patients presenting with nonspecific systemic signs. PMID- 30026994 TI - Delayed Presentation of Tetralogy of Fallot with Isolated Cyanosis. AB - A pediatric patient with hypoxia or cyanosis can frighten even the most seasoned emergency providers. Patients with these symptoms require immediate evaluation and intervention to stabilize their condition. While the differential can be broad, specific attention must be paid to cardiopulmonary etiologies. Tetralogy of Fallot is the most common cyanotic congenital heart abnormality, and routine screening surprisingly misses a significant amount of these cases. This case serves as an example of a missed diagnosis by screening efforts and reaffirms the resuscitation algorithm of a hypoxic pediatric patient that all emergency providers should be familiar with. PMID- 30026995 TI - Rhinogenic Optic Neuritis Caused by Sphenoid Mucocele with Sinusitis. AB - A 59-year-old male who presented with a nonspecific headache at the vertex, resembling retrobulbar optic neuritis, was treated as such but did not show any improvement. Although optic nerve compression from sphenoid mucocele was finally discovered, the delayed diagnosis and improper treatment led to a permanent visual loss. Optic neuritis could be caused by a common problem, "mucocele/sinusitis," but might be easily overlooked in general practice. Rhinogenic optic neuropathy should, therefore, be considered in every case of optic neuritis whenever atypical presentation occurs or is unresponsive to high dose steroid treatment. PMID- 30026996 TI - A Case of Atorvastatin-Associated Necrotizing Autoimmune Myopathy, Mimicking Idiopathic Polymyositis. AB - Statin-induced necrotizing autoimmune myopathy (SINAM) is a rare side effect of statin use which manifests as progressive muscle weakness. Because statins are a widely prescribed medication for coronary artery disease, hyperlipidemia, and many other diseases, many patients are at risk of developing SINAM or one of the many other statin-induced myopathies. Due to identification of an antibody specific to this disease, we were able to diagnose SINAM in a patient whose symptoms had progressed to the extent that they were debilitating. Our case describes SINAM in a patient undergoing treatment with a statin for an extended period of time, diagnosis of the disease process, treatment, and resolution of symptoms. PMID- 30026997 TI - An Exceptional Case of Ileocolic Intussusception Secondary to Burkitt's Lymphoma: What Variations Are There in the Presentation and Management of Those Patients Who Approach Adolescence? AB - Intussusception is a common cause of abdominal pain among the paediatric population with up to 10% of cases occurring secondary to a pathological lead point. Burkitt's lymphoma (BL) is a highly malignant and rapidly growing B-cell neoplasm which in extremely rare cases can present as intussusception. We report a case in an otherwise healthy 15-year-old male who presented with atypical abdominal pain. Imaging subsequently indicated an ileocolic intussusception, and given that the suspicion of a pathological lead point mandates a laparotomy and bowel resection, he proceeded to surgery. The histopathology confirmed Burkitt's lymphoma as the aetiology responsible for this intussuscepted mass. A detailed discussion including a systematic review of all previous case reports explore the diagnostic dilemma of intussusceptions secondary to BL. This case report aims to highlight the clinical challenges in establishing such a diagnosis and an appreciation for the subtle variations in clinical features, as well as the differences in management between infants and adolescents. PMID- 30026998 TI - Fibrous Pseudotumor of Tunica Albuginea Testis Mimicking Testicular Neoplasm in a Young Man. AB - Intrascrotal lesions are common findings with a majority occurring in paratesticular tissue. Fibrous pseudotumors are rare, benign lesions of the testicular tunics and present with mass lesion(s) in the scrotum. Preoperative clinical and radiological diagnosis is challenging. We report a case of a 34-year old man who presented with a 3-year history of left testicular swelling and was advised left radical orchidectomy by another surgeon. Physical examination revealed a firm, nontender mass attached to the lower pole of the testis. Testicular tumor markers were all negative, and ultrasound scan showed a relatively hypoechoic lesion closely associated with the left testis and suspicious for neoplastic process. The patient underwent a testicular sparing surgery. An intraoperative frozen section biopsy confirmed the lesion to be benign and this was reported on permanent section to be fibrous pseudotumor of the tunica albuginea. We also present the clinical, sonographic, and histopathological findings of this condition along with the literature review. PMID- 30026999 TI - Benign Scrotal Tumor in a Pediatric Patient: Epididymal Cyst. AB - A pediatric patient of 12 years consulted for a left scrotal mass of 2 months of evolution. After suspecting a cystic content due to positive transillumination, on ultrasonography a scrotal cyst separated from the testis, of 5 cm in its maximum length, was confirmed. Due to size, parental anxiety, and the referred short evolution, excision was decided. Given the clinical radiological findings, a scrotal incision was chosen, obtaining complete excision. Biopsy confirmed the diagnosis of simple epididymal cyst (EC). ECs usually present as painless, scrotal swelling in adolescents as a result of dilatation of the efferent epididymal tubules. Many cases (up to 60%) regress spontaneously. In these, average time to involute ranges from 4 to 50 months. Although cases of cyst torsion have been described (with pain derived from ischemia and inflammation), conservative management has been suggested in the majority, both in pediatric and in adult series. Surgery is recommended in some patients, due to testicular pain or increased paratesticular mass, as was our case. PMID- 30027000 TI - Evaluation of seismic potential in a longwall mine with massive sandstone roof under deep overburden. AB - A recent seismic event was recorded by a deep longwall mine in Virginia at 3.7 ML on the local magnitude scale and 3.4 MMS by the United States Geological Survey (USGS) in 2016. Further investigations by the National Institute for Occupational Safety and Health (NIOSH) and Coronado Coal researchers have shown that this event was associated with geological features that have also been associated with other, similar seismic events in Virginia. Detailed mapping and geological exploration in the mining area has made it possible to forecast possible locations for future seismic activity. In order to use the geology as a forecaster of mining-induced seismic events and their energy potential, two primary components are needed. The first component is a long history of recorded seismic events with accurately plotted locations. The second component is a high density of geologic data within the mining area. In this case, 181 events of 1.0 ML or greater were recorded by the mine's seismic network between January, 2009, and October, 2016. Within the mining area, 897 geophysical logs, 224 core holes, and 1031 fiberscope holes were examined by mine geologists. From this information, it was found that overburden thickness, sandstone thickness, and sandstone quality contributed greatly to seismic locations. After the data was analyzed, a pattern became apparent indicating that the majority of seismic events occurred under specific conditions. Three forecast maps were created based on geology of previous seismic locations. The forecast maps have shown an accuracy of within 74%-89% when compared to the recorded 181 events that were 1.0ML or greater when considering three major geological criteria of overburden thickness of 579.12 mor greater, 6.096-12.192 m of sandstone within 15.24 m of the Pocahontas number 3 seam, and a longwall caving height of 4.572 m or less. PMID- 30027001 TI - Issues of accessibility to health services by older Australians: a review. AB - Background: This review provides an in-depth investigation into the difficulties facing older Australians when accessing health care services. Methods: A literature search was conducted in December 2016 using Academic Premier to identify relevant publications. Key search terms were accessibility, health service, older people and Australia. Papers published between 1999 and 2016 were included. Statements of accessibility were extracted and then grouped using the five dimensions of accessibility by Penchansky and Thomas (1981): availability, accessibility, accommodation, affordability and acceptability. Results: Forty-one papers were included. Availability issues identified were inadequate health care services, particularly for culturally and linguistically diverse (CALD) populations and those residing in rural areas. Accessibility issues included difficulties accessing transport to health care services, which in turn restricted choice of appointment time. Issues of accommodation identified were long waiting times for appointments with both general practitioners and medical specialists. Affordability was a common problem, compounded by multi-morbidity requiring high health care use. Issues of acceptability centred on the role of the family, feelings of shame when receiving care from a non-family member, traditional practices and gender sensitivity. Conclusions: The contribution of factors to health service accessibility varies according to an older person's geographical local and their accessibility to transport, as well as their level of multi-morbidity and cultural background. Improving access to health services could be improved by matching services to the population that they serve. PMID- 30027002 TI - Evaluation of Montelukast for the Treatment of Children With Japanese Cedar Pollinosis Using an Artificial Exposure Chamber (OHIO Chamber). AB - Background: This study evaluated the efficacy of montelukast in reducing seasonal allergic rhinitis symptoms in Japanese children with Japanese cedar (JC) pollinosis induced in an artificial exposure chamber (OHIO Chamber). Methods: Pediatric patients aged 10 to 15 years sensitive to JC pollen entered a randomized, double-blind, single-site, crossover study. After confirmation of an allergic response to a JC pollen exposure for 3 hours in the OHIO Chamber during the screening period, subjects received either montelukast 5 mg chewable tablets or placebo for a 7-day treatment period, followed by a 3-hour pollen exposure in the chamber. After a 7-day washout period, subjects crossed over to the other treatment. Subjects were instructed to self-assess their nasal symptoms using 5 point scale for every 30 minutes. The primary end point was the change from baseline (just before entering the exposure chamber for each exposure) in total nasal symptom score (TNSS; the sum of nasal congestion, nasal discharge, and sneezing scores) over 3 hours of pollen exposure. Adverse events (AEs) were evaluated throughout the study. Results: A total of 220 subjects (median age, 12 years) received treatment. For TNSS, the between-group difference in the change (95% confidence interval) was -0.01 (-0.11 to 0.10); the change between placebo and montelukast 5 mg was not significant. TNSS in the screening and treatment periods after receiving placebo for 7 days was 1.58 and 1.31, respectively, suggesting a placebo response. On account of high placebo response, a post hoc analysis was conducted. The analysis in a subgroup of subjects who did not show placebo response demonstrated a difference in the efficacy between montelukast and placebo (nominal P < .037). The most common AE was positive urine protein (4.6% with montelukast vs 7.8% with placebo). Conclusions: Although montelukast was well tolerated, this study did not demonstrate a treatment difference between active drug and placebo in Japanese children exposed to JC pollen in the OHIO Chamber.Trial Registry: ClinicalTrials.gov, NCT01852812. PMID- 30027003 TI - Assessment of Different Cetirizine Dosing Strategies on Seasonal Allergic Rhinitis Symptoms: Findings of Two Randomized Trials. AB - Background: Cetirizine has been shown to be effective for relief of seasonal allergic rhinitis (SAR) symptoms. Allergic rhinitis symptoms have been reported to have circadian variations, with symptoms tending to be most bothersome overnight and in the morning. Objective: To evaluate the effects of different cetirizine dosing schedules in comparison to twice daily (BID) chlorpheniramine and placebo on SAR symptoms at 12 and 24 hours postdose. Methods: Study 1 subjects received cetirizine 10-mg once daily in the morning (QAM), cetirizine 10 mg once daily at bedtime (QHS), cetirizine 5-mg twice daily, or placebo. Study 2 subjects received cetirizine 5-mg QAM, cetirizine 10-mg QHS, chlorpheniramine 8 mg BID, or placebo. The primary end point was total symptom severity complex (TSSC); TSSC was the sum of symptom severity ratings averaged over the 2-week study period. Post hoc analyses of reflective symptom severity assessed in the morning (TSSCAM) and in the evening (TSSCPM) were conducted to evaluate cetirizine's effects at 12 and 24 hours postdose. Results: In study 1, subject- and investigator-assessed TSSC was significantly lower in all cetirizine groups versus placebo (P <= .003). In study 2, subject-assessed TSSC was significantly lower in all cetirizine groups versus placebo (P <= .04) and was numerically lower for investigator-assessed TSSC. Post hoc analyses demonstrated that cetirizine significantly improved TSSCAM at 12 and 24 hours postdose versus placebo in both studies regardless of dosing schedule. TSSCPM significantly improved at 12 and 24 hours postdose in all study 1 cetirizine groups versus placebo. In study 2, versus placebo, TSSCPM significantly improved at 12 hours postdose in cetirizine 5-mg QAM group and numerically improved at 24 hours postdose in cetirizine 10-mg QHS group. Conclusion: Regardless of dosing regimen, cetirizine demonstrates effective 24-hour relief of SAR symptoms, particularly on TSSCAM, which assesses overnight and early morning symptom control. PMID- 30027004 TI - Factors Associated with Functional Decline in Elderly Female Breast Cancer Patients in Appalachia. AB - Background Functional status has been previously shown in the elderly cancer population to predict both mortality as well as treatment tolerance. The goal of this study was to determine if there are certain subsets of the elderly breast cancer population that are at higher risk of experiencing functional decline following treatment. Methods Patient charts from the Edwards Comprehensive Cancer Center in Huntington, West Virginia, from January 2006 - January 2016 were reviewed. Relevant inclusion criteria included patients of 65 years of age and older with a new diagnosis of Stage 0-III breast cancer. Functional decline was defined as an increase of at least one point in Eastern Cooperative Oncology Group (ECOG) scores within one year of diagnosis. ECOG performance status was subjectively determined by the physician. Fisher's exact test and Pearson's Chi squared test were initially utilized to assess potential factors associated with functional decline such as pretreatment ECOG score, age at diagnosis, stage, hormone receptor status, type of surgery received, whether radiation therapy, chemotherapy, or hormonal therapy was received, medical comorbidities, body mass index (BMI), complaints of weakness at diagnosis, and ambulatory status. Factors that were found to be significant were further assessed via multivariate logistic regressions. Results Three-hundred and fourteen patients were identified as meeting inclusion criteria. At one-year follow-up, 45 patients (14.3% of the cohort) had documented functional decline. On initial analysis, factors associated with functional decline included Stage III disease (p=0.002) and complaints of weakness at diagnosis (p=0.004). Following multivariate analysis, Stage III disease (p = 0.02), complaints of weakness at diagnosis (p = 0.04), and bilateral mastectomy (p = 0.03) were significantly associated with functional decline. Conclusion Patients who were diagnosed with Stage III breast cancer, had complaints of weakness at time of diagnosis, or had bilateral mastectomies were more likely to have a decline in functional status at one-year follow-up. Awareness of factors associated with functional decline in the elderly Appalachian population with Stage 0-III breast cancer will be useful during discussions regarding patient expectations, treatment, and goals of care. Elderly breast cancer patients for whom bilateral prophylactic mastectomies are not indicated may be better served by lumpectomy alone (based on patient age, hormone receptor status, and tumor size), lumpectomy followed by radiation therapy, or unilateral mastectomy to maximize the likelihood of functional preservation following treatment. PMID- 30027005 TI - Stercoral Ulcer Not Always Indolent: A Rare Complication of Fecal Impaction. AB - Stercoral sigmoid perforation is a dangerous surgical emergency. It is also a life-threatening situation because the spillage of fecal contents into the abdominal cavity leads to sepsis with many postoperative complications. Chronic, intermittent constipation can lead to fecal impaction, especially in older patients. An 80-year-old male patient presented with intestinal abdominal pain and distention for three days. His chest X-ray showed air under the diaphragm. On laparotomy, a small rent was discovered in the rectosigmoid junction with fecal contamination. The presence of a fecaloma is the speculated reason for the perforation. Primary closure of the defect with a diverting transverse colostomy was performed, and subsequently, the patient recovered well. A colostomy closure was performed six weeks after the primary surgery. It is imperative to understand the incidence of stercoral perforation in a normal bowel. Early treatment and intervention are the important aspects of stercoral pathology. We report a rare case of stercoral sigmoid colonic perforation with fecal peritonitis. PMID- 30027006 TI - Carcinoma of the Maxillary Antrum: A Case Report. AB - Maxillary sinus squamous cell carcinoma is an aggressive tumor, usually diagnosed at an advanced stage and most patients present with very poor prognosis and survival rate. We report a case of the patient who presented with pain and swelling in the left maxillary region. Due to the advanced stage at which it was presented and the involvement of vital structures, the patient was subjected to palliative treatment. The symptoms of maxillary sinus carcinoma can be non specific, resulting in late diagnosis. It is pertinent for the maxillofacial physician to be aware of these sinus pathologies and arrive at an early diagnosis to improve the survival rate. PMID- 30027007 TI - Coracobrachialis Longus Muscle: Humeroepitrochlearis. AB - During a routine anatomical dissection of the right brachium of a 68-year-old male cadaver, an extremely rare variation of the coracobrachialis longus muscle was discovered. It started from the medial surface of the middle part of the humerus with a well-formed muscle portion and then continued into the well presented distal tendinous portion, which was attached to the medial epicondyle of the humerus. We also briefly review the reported variations of the coracobrachialis and their potential clinical significance. PMID- 30027008 TI - Bilateral Earlobe Crease as a Marker of Premature Coronary Artery Disease. AB - Cardiovascular diseases, including heart disease and stroke, are the world's largest killers. More than 800,000 people die from cardiovascular disease each year in the United States (US). Heart disease is estimated to cost 200 billion US Dollars (USD) annually. Early identification of an inexpensive marker which allows for early intervention is the need of the hour. We present a case describing one such marker which can be easily appreciated on physical examination. Several studies have shown, not only the association between the presence of the diagonal earlobe crease (DELC) and coronary artery disease (CAD) but also a correlation with the extent and severity of CAD, independent of cardiovascular risk factors. Our patient who had no known CAD or risk factors presented with an acute coronary syndrome (ACS). On exam, he was noted to have bilateral DELC. Over the course of his workup, he was noted to have severe triple vessel disease and eventually underwent surgical revascularization. We seek to increase awareness of this valuable physical sign which has far-reaching consequences in the prognostication and risk stratification of patients. PMID- 30027009 TI - Influence of Internet and Social Media in the Promotion of Alternative Oncology, Cancer Quackery, and the Predatory Publishing Phenomenon. AB - In the last decade, electronic media has irrupted physician's clinical practice. Patients increasingly use Internet and social media to obtain enormous amounts of unsupervised data about cancer. Blogs, social networking sites, online support groups and forums are useful channels for medical education and experience sharing but also perfect environments for misinformation, quackery, violation of privacy and lack of professionalism. The widespread availability of such electronic resources allows some followers of the alternative oncology to spread useless irrational and controversial remedies for cancer, like false medicaments, miraculous diets, electronic devices, and even psychic therapies, as did charlatans in the past, providing false expectations about cancer treatments. Moreover, so-called predatory journals have introduced confusion and malpractice within the academic biomedical publishing system. This is a rising editorial phenomenon affecting all fields of biomedicine, including oncology that jeopardizes the quality of scientific contribution and damages the image of open access publication. PMID- 30027010 TI - Where is My Spleen? - A Case of Splenosis Diagnosed Years Later after Splenectomy. AB - Hepatic splenosis was first described in 1939 and is a rare condition that results from splenic trauma or splenectomy. A 43-year-old man with a past medical history significant for a prior splenectomy was admitted to the hospital due to right upper quadrant pain for two days. Magnetic resonance imaging (MRI) of the abdomen suggested features of hepatic adenoma, however, a percutaneous biopsy showed the mass within the liver to be a discrete collection of splenic tissue, apparently the result of a traumatic splenic rupture years ago. Hepatic splenosis is a rare entity, and due to the asymptomatic nature of this condition, most cases are found incidentally after different imaging modalities are done. The management of this entity is based on conservative measures. We report this case to emphasize that in the appropriate clinical setting, hepatic splenosis should be considered in the differential diagnosis of a patient with a homogenous well circumscribed liver mass. PMID- 30027011 TI - Restless Genital Syndrome: Case Report of a Rare Disorder from Pakistan. AB - Restless genital syndrome (RGS) is a newly recognized syndrome characterized by difficult to describe genital sensations, including itching, tingling, contractions, and even pain. It can be a source of distress for the patient and may lead to social withdrawal and delayed diagnosis. Many pharmacologic and non pharmacologic treatment options have been documented in the literature. Dopamine agonists have been shown to be the most effective in symptomatic relief. We present a case of an Asian female with symptoms suggestive of RGS for 11 years before she was diagnosed who responded well to ropinirole. We discuss the pathophysiology and reasons for the delayed diagnosis. PMID- 30027012 TI - A Case of a Second Intermetatarsal Space Gouty Tophus with a Presentation Similar to a Morton's Neuroma. AB - Non-infectious soft tissue lesions of the foot and ankle are relatively rare clinically. These include benign and malignant neoplasms, as well as non neoplastic or pseudotumoral lesions such as ganglionic, synovial and epidermoid cysts, intermetatarsal and adventitious bursitis, inflammatory lesions like gouty tophi and rheumatoid nodules, Morton's neuroma, and granuloma annulare. A 48-year old male with a history of medically treated tophaceous gout presented with left foot neuropathic pain and paresthesia, in the setting of a well-circumscribed soft tissue lesion of the second intermetatarsal space, suspected to be a Morton's neuroma. Magnetic resonance imaging (MRI) showed a 4.1 x 2.7 x 2.6 cm heterogeneous soft tissue mass containing multiple cystic areas. Excisional biopsy was performed and histologic examination revealed well-circumscribed nodules of amorphous material containing needle-shaped clefts, rimmed by histiocytes, and multinucleated giant cells consistent with a gouty tophus. This is the first case reported in the literature of an intermetatarsal gouty tophus causing neuropathic pain and paresthesia. While Morton's neuroma is the most common cause of this presentation, this case illustrates that other pseudotumoral lesions, such as a gouty tophus, may present similarly, and should be considered in the differential diagnosis. While most cases of tophaceous gout can be adequately treated with urate-lowering therapy, surgery may be indicated for tophi that do not resolve with medical treatment based upon symptom severity, compression of nearby structures, and functional impairment. PMID- 30027013 TI - Acquired Hemophilia Secondary to Soft-tissue Sarcoma: Case Report from a Latin American Hospital and Literature Review. AB - Acquired hemophilia A is a rare bleeding disorder caused by inhibiting antibodies against factor VIII characterized by the presence of severe bleeding, which in occasions can be lethal. The bleeding manifestations typically have a sudden onset and patients have a negative family and personal histories of bleeding, with a normal prothrombin time (PT) and an extended partial thromboplastin time (PTT). Incidence has been calculated to be between 0.2 and 1.48 cases per million per year. Between 6% and 15% of cases are associated with neoplasms. Here, we present a 52-year-old male with back myxofibrosarcoma who developed acquired hemophilia without response to treatment used and ultimately died. The most common cancers associated with acquired hemophilia are lung and prostate cancer. We found one other case of a patient with Kaposi's sarcoma that was unassociated with HIV infection who presented with severe postoperative bleeding. For bleeding in acquired hemophilia A, the treatments of choice are "bypass" agents, such as recombinant-activated factor VIII (rFVIIa) or activated prothrombin complex concentrate. Any delay in the start of treatment or the usage of insufficient doses is associated with the progression of bleeding symptoms and worsening general condition. In the case of acquired hemophilia secondary to neoplasia, it is recommended that immunosuppressive therapy to eradicate the inhibitors be combined with treatment for the underlying neoplastic disease. In our patient, it was not possible to offer a surgical treatment that enabled the control of the neoplasia, nor he was considered a candidate for chemotherapy or radiotherapy, limiting the treatment to immunosuppressive and "bypass" management. PMID- 30027014 TI - Ice-man Down: Using Simulation to Practice the Safe Extrication of Collapsed Hockey Players in a Confined Space. AB - Sporting event emergencies are common among both spectators and players, with unique sets of challenges associated with patient extrication in unfamiliar and chaotic environments. It is critical for sports physicians and trainers to deliberately train and prepare for emergent situations with limited resources during athletic events. One of the most difficult, yet commonly encountered challenges is determining when and how to safely remove an injured player's helmet and sporting equipment, particularly if a spinal injury is highly suspected. We created a high-fidelity simulation case to practice the safe extrication of a hockey player who collapses on the bench in the player's box, a space-restricted environment. The patient is a 25-year-old male hockey player who becomes unresponsive after a syncopal episode in the player's box, and subsequently transferred to a medical center for further evaluation. Critical actions include extrication of the player at the scene, diagnosis of syncope, placement of the unconscious player on a backboard with cervical-spine precautions, removal of the player's faceguard, removing the player off the ice, checking the electrocardiogram and glucose level, and transferring the player to a controlled environment. The learning objectives were to identify, evaluate, and manage the reversible causes of syncope, and demonstrate appropriate techniques for the optimal removal of sports equipment. Learner assessment was based on participation in the scenario and debriefing learners after the simulation. Post simulation debriefing revealed that participants highly appreciated practicing not-so-commonly encountered hockey-related emergencies. Athletic trainers and emergency providers were able to effectively practice their management of the unresponsive hockey player. The participants were also able to deliberately practice their teamwork and communications skills with their peers. Learning points include proper c-spine immobilization techniques in a tight space and indication for gear-removal in an unconscious patient. As hockey continues to gain popularity, this simulation case will prepare athletic trainers and emergency providers to better address the reversible causes for syncope in hockey players, as well as safely and effectively extricate injured players from space limiting sporting environments. PMID- 30027015 TI - Another Emergent Cause of Headache. AB - We present a case of a subacute headache related to leukostasis secondary to accelerated chronic myeloid leukemia (CML), which required white blood cell (WBC) reduction in the emergency department. A 28-year-old male presented to the emergency department with a chronic headache found to be secondary to leukostasis from accelerated CML with a white blood cell count of 801,000 and 9% blasts. He had bilateral retinal hemorrhage and a headache associated with elevated intracranial pressure. Hydroxyurea and allopurinol were initiated in the emergency department and the patient was eventually transitioned to a tyrosine kinase inhibitor as outpatient therapy. Headaches are a frequent cause of emergency department visits, and this case illustrates another possible etiology of headache requiring emergent intervention. PMID- 30027016 TI - Type-1 Seronegative Autoimmune Pancreatitis: A Rare Case of Autoimmune Pancreatitis with Sclerosing Cholangitis and Hashimoto's Disease. AB - Autoimmune pancreatitis (AIP) is very rarely reported in the literature. It is one of the immunoglobulin-G (IgG) related diseases that commonly presents with abdominal pain, mass, jaundice, and weight changes. The disease also has extrapancreatic manifestations, of which the most common is autoimmune sclerosing cholangitis. We report a case of autoimmune pancreatitis that was further found to be associated with Hashimoto's thyroiditis and sclerosing cholangitis. The clinical manifestations vary and it is important to exclude pancreatic malignancy before diagnosing any patient with AIP. Although further studies need to be done, currently the treatment of choice is steroid therapy. Physicians should also screen patients for other autoimmune diseases to rule out any concern. PMID- 30027017 TI - The Surgical Management of Pilonidal Disease is Uncertain Because of High Recurrence Rates. AB - Background Pilonidal disease is a common condition with no consensus for the best management of chronic disease or current practice in Australia and New Zealand. Methods A survey was distributed among 190 colorectal and 592 general surgeons in Australia and New Zealand. Data was obtained regarding pilonidal surgery volume, procedures performed, non-operative management and recurrence rates. Three clinical scenarios were also presented. Results The response rate was 58% among colorectal surgeons, 18% among general surgeons. Nineteen percent of surgeons were high-volume (>23 operations per year), 47% low-volume (<12 operations per year). The commonest procedure was the Karydakis procedure (77%), with many others performed including rhomboid flaps (36%), Bascom cleft lift (13%), Z plasty (7%), and gluteal rotation flaps (5%). Fifty-five percent of high-volume surgeons offered more than one operation while only 16% of low-volume surgeons did. Nineteen percent operated on all patients with pilonidal disease, 89% believing off-midline closure to be superior to midline. Disease extent was the main driver for non-operative management; patient factors such as cosmesis and time-off work being the least important. Sixty-four percent reported recurrence rates above 5%, and 37% recurrence rates >10%. Six percent reported no recurrences ever. Five percent reported recurrence rates over 20%, but 24% stated that over one-fifth of their practice consists of recurrent disease. Conclusions This study reports higher recurrence rates than in published series, suggesting many surgeons do not see their own recurrences, with current treatment not as successful as previously thought. Combined with the widespread variation in practice, optimal management of this disease remains unclear. PMID- 30027018 TI - Risk Factors and Management of Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy is characterized by transient left ventricular apical ballooning, which results in temporary left ventricular dysfunction. We present a case of a 62-year-old female who presented with chest pain and shortness of breath. Her electrocardiogram was suggestive of myocardial ischemia and her troponin levels were elevated. Cardiac catheterization showed mild coronary artery disease and left ventriculography revealed severe apical hypokinesia. A diagnosis of Takotsubo cardiomyopathy was made. Her hospital stay was complicated by cardiogenic shock. One of the risk factors was cannabis use. Hence, our case highlights the management of Takotsubo cardiomyopathy and its complications, along with focus on cannabis use and its association with Takotsubo cardiomyopathy. PMID- 30027019 TI - Myxedema Ascites: An Unusual Presentation of Uncontrolled Hypothyroidism. AB - We describe a case of myxedema ascites in a 64-year-old male with a history of hypothyroidism noncompliant with medical therapy who presented with syncope, hematemesis, melena, and abdominal distension. The patient received intravenous levothyroxine with a good response and improved upon discharge. This case highlights the importance of considering hypothyroidism as an etiology of unexplained ascites. The analysis of ascites from myxedema may not always have a significantly elevated protein (>2.5g/dL). Appropriate diagnosis should also rely on the clinical presentation along with a rapid and positive response to thyroid hormone replacement therapy. PMID- 30027020 TI - Trends in Demographics, Hospitalization Outcomes, Comorbidities, and Mortality Risk among Systemic Sclerosis Patients. AB - Objective This study determines trends in demographics and hospitalization outcomes among patients admitted for systemic sclerosis (SScl) and evaluates the differences between comorbidities. Methods The study used data from the Nationwide Inpatient Sample (NIS) for the years 2010-2014. We identified SScl as the primary diagnosis and the associated medical and psychiatric comorbidities using validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The differences in comorbidities and in hospital mortality were quantified using multinomial logistic regression (odds ratio (OR)). Results Inpatient admissions for SScl decreased over the period 2010 2014 by 15.9% (p < 0.001). There was an increasing trend in the 61-80 years age group as they had a 29% increase in admissions and a higher risk of in-hospital mortality (OR = 2.113; p = 0.020). The differences between races showed weaker linear trends, with Caucasians (57.5%) showing an increasing trend, and African Americans (24.3%) and Hispanics (11.8%) having a decreasing trend (p < 0.001). However, Hispanics had the highest risk of mortality (OR = 1.295; p = 0.001) during hospitalization. In-hospital mortality had a linear decreasing trend, with a 10.3% decrease in deaths in 2010, and a 9.1% decrease in 2014 (p < 0.001). Hypertension (47.3%), pulmonary circulation disorders (40.1%), pulmonary fibrosis (29.7%), and congestive heart failure (24.4%) constituted the majority of comorbidities. Comorbid diabetes increased the risk of in-hospital mortality in SScl patients by four times (OR = 3.914; p = 0.003). Esophageal reflux disorder was present in only 6.7% of SScl patients, but it increased the risk of in hospital mortality (OR = 2.643: p < 0.001). Among psychiatric comorbidities, depression (OR = 1.526; p = 0.001) and psychosis (OR = 1.743; p = 0.039) both increased the risk of in-hospital mortality. Conclusion We observed the various comorbidities that were associated with substantial and significant differences in the risk of in-hospital mortality. We assert that these findings indicate that comorbid conditions are influential factors that must be considered in models of health-related quality of life (HRQOL) in SScl. More attention needs to be paid to the elderly population at risk of having a higher risk of inpatient death. Further research to guide the development of clinical care models for targeting early diagnosis and treatment of comorbidities in SScl is necessary to reduce both mortality and morbidity, as well as improve the quality of care for these patients. PMID- 30027022 TI - Mid-Term Outcomes of Arthroscopic Treatment in Patients with a Stiff Elbow. AB - Introduction Loss of function and pain are the main complaints at the time of hospital admission for patients with a stiff elbow. In this study, we present mid term radiological and functional results for the use of the arthroscopic release technique in patients admitted to the outpatient clinic with a stiff elbow. Methods A total of 22 patients (six females, 16 males; mean age: 36 years, range: 18 to 56 years) who underwent an arthroscopic intervention for traumatic or non traumatic stiff elbow and arthrosis between January 2005 and November 2015 were included in the study. All patients started elbow movement after the first day following surgery. Pre- and postoperative radiological evaluations of patients were carried out, in addition to functional evaluation to measure the range of motion of the elbow joint and the Disabilities of the Arm, Shoulder and Hand (DASH) scores before and after surgery. Results The mean follow-up was 28.4 (range: 21 to 118) months. The mean preoperative flexion-extension arc of the patients was 89 degrees (range: 0 degrees to 115 degrees ), and the mean flexion-extension arc increased to 103.5 degrees (range: 52 degrees to 128 degrees ) at the final follow-up visit (p < 0.05). The mean preoperative DASH score was 42.17 (range: 33 to 81), decreasing to 30.35 (range: 9.7 to 41.3) postoperatively (p<0.05). In the final visit, none of the patients were found to require additional surgical interventions for the elbow. Conclusions Arthroscopic release can be considered a safe and effective option to obtain range of motion in joints in post-traumatic stiff elbow cases. PMID- 30027023 TI - Hemiplegic Migraine as the Initial Presentation of Biopsy Positive Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. AB - The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in adults can be challenging. Initially, this disease can mimic embolic cerebral infarction, multiple sclerosis, and other neurological diseases on imaging studies. CADASIL is the most common hereditary cerebral angiopathy which is inherited in an autosomal dominant fashion. There is a wide variety of clinical presentations including a migraine headache, mood disturbances, cognitive dysfunction, and recurrent subcortical cerebral infarctions. This case details the hospital course and diagnosis of a 41-year-old male who initially presented with symptoms consistent with his previous diagnosis of a hemiplegic migraine who was later found to have biopsy-positive CADASIL after the symptoms failed to remit. PMID- 30027021 TI - c-index and Subindices of the h-index: New Variants of the h-index to Account for Variations in Author Contribution. AB - Objectives Bibliometrics are used to assess or compare the academic productivity of individuals or groups. Most of these metrics, including the widely used h index, do not recognize the added contribution that is generally provided by authors listed first, second, second-to-last and last (enhanced positions) in a publication citation. We propose the c-index as a novel modification to the h index that will better reflect an individual's academic output, incorporating authorship position. Methods One hundred and sixty-six academic neurosurgeons in eight New York City (NYC) metropolitan region training programs were identified through department websites. Using the Scopus citation database, bibliometric profiles were created for each surgeon. Once an individual's h-index was calculated, the h-core articles (those with h or more citations) were specifically assessed to determine citation author position. Novel bibliometric indices were created to reflect the number of h-core articles that accounted for primary (hp), senior (hs) or internal authorship (hi) position. Weighted "involvement factors" for primary (ip) and senior (is) author contribution were created to reflect the added value of "enhanced position" authorship in an individual's h-core publications. c-indices were created to reflect the author's h-index once augmented by primary (cp), senior (cs), and overall (co) "enhanced position" authorship. Comparisons were made within each institution and across institutions, according to academic rank (assistant professor, associate professor, professor and chairperson). Results Breakdown by academic rank showed an increasing average h-index progressing from assistant professor through professor rank with no significant difference demonstrated between professor and chair status. This pattern was seen across all departments (aggregate) but with fewer instances of significance at the level of individual departments. After h index modification, cp, cs, and co indices showed a similarly significant trend. As faculty rank increased, there was a significant trend toward increasing numbers of articles with authors in enhanced positions and a higher percentage of articles with the author in a senior position. Academic faculty had higher h, cp, and cs indices than clinical faculty. Evaluation of each individual department revealed no significant trend regarding a department's higher average cp or cs. Average c-index for a department paralleled the average h-index of that department, with larger departments tending to have larger cumulative h, cp, cs, and co indices. No consistent correlation was seen between mean h-indices and academic rank at an individual departmental level. Conclusions This study examines the academic productivity of a subset of neurosurgical programs in the NYC metropolitan area as a test bed for novel bibliometric indices. hp, hi, and hs represent the respective number of primary, internal and senior authorship papers that comprise an individual's h-core papers. cp, cs, and co, variations of the h-index metric, are designed to more accurately reflect the contributions by primary, secondary and senior authors. Increasing academic rank was associated with an increased number of articles with the author in enhanced positions and a higher percentage of articles in a senior position. PMID- 30027024 TI - Status of High latitude precipitation estimates from observations and reanalyses. AB - An intercomparison of high-latitude precipitation characteristics from observation-based and reanalysis products is performed. In particular the precipitation products from CloudSat provide an independent assessment to other widely used products, these being the observationally-based GPCP, GPCC and CMAP products and the ERA-Interim, MERRA and NCEP-DOE R2 reanalyses. Seasonal and annual total precipitation in both hemispheres poleward of 55 degrees latitude is considered in all products, and CloudSat is used to assess intensity and frequency of precipitation occurrence by phase, defined as rain, snow or mixed phase. Furthermore, an independent estimate of snow accumulation during the cold season was calculated from the Gravity Recovery and Climate Experiment (GRACE). The intercomparison is performed for the 2007-2010 period when CloudSat was fully operational. It is found that ERA- Interim and MERRA are broadly similar, agreeing more closely with CloudSat over oceans. ERA-Interim also agrees well with CloudSat estimates of snowfall over Antarctica where total snowfall from GPCP and CloudSat is almost identical. A number of disagreements on regional or seasonal scales are identified: CMAP reports much lower ocean precipitation relative to other products, NCEP-DOE R2 reports much higher summer precipitation over northern hemisphere land, GPCP reports much higher snowfall over Eurasia, and CloudSat overestimates precipitation over Greenland, likely due to mischaracterization of rain and mixed-phase precipitation. These outliers are likely unrealistic for these specific regions and time periods. These estimates from observations and reanalyses provide useful insights for diagnostic assessment of precipitation products in high latitudes, quantifying the current uncertainties, improving the products, and establishing a benchmark for assessment of climate models. PMID- 30027025 TI - Closure of a Recurrent Urethrovaginal Fistula in a Girl with Cloacal Anomaly Using Deflux Injection. AB - In a girl born with cloaca, both hemivaginae and rectum were located above the bladder neck, and both ureters were connected to the hemivaginae. After diverting colostomy and cystovaginoscopy on the second day of life, the repair of cloaca was performed at 10 months of age by posterior sagittal anorecto vaginoplasty (PSARVP), including laparotomy and bilateral ureteric reimplantation. Eight months after the surgery, she developed a vesicovaginal fistula, which was repaired and closed by open surgery through the bladder. Three months after this procedure, a tiny urethrovaginal fistula was noticed, which was closed at the age of 2 years using hook diathermy to refresh the edges and was then closed by Deflux injection. The proper closure of the urethrovaginal fistula was confirmed by radiology and cystoscopy 3 months after the surgery. This report shows that injection of Deflux into a tiny urethrovaginal fistula following refreshing the edges may be a valid treatment option in selected cases. PMID- 30027026 TI - HPV Oncogene Manipulation Using Nonvirally Delivered CRISPR/Cas9 or Natronobacterium gregoryi Argonaute. AB - CRISPR/Cas9 technology enables targeted gene editing; yet, the efficiency and specificity remain unsatisfactory, particularly for the nonvirally delivered, plasmid-based CRISPR/Cas9 system. To tackle this, a self-assembled micelle is developed and evaluated for human papillomavirus (HPV) E7 oncogene disruption. The optimized micelle enables effective delivery of Cas9 plasmid with a transient transgene expression profile, benefiting the specificity of Cas9 recognition. Furthermore, the feasibility of using the micelle is explored for another nucleic acid-guided nuclease system, Natronobacterium gregoryi Argonaute (NgAgo). Both systems are tested in vitro and in vivo to evaluate their therapeutic potential. Cas9-mediated E7 knockout leads to significant inhibition of HPV-induced cancerous activity both in vitro and in vivo, while NgAgo does not show significant E7 inhibition on the xenograft mouse model. Collectively, this micelle represents an efficient delivery system for nonviral gene editing, adding to the armamentarium of gene editing tools to advance safe and effective precision medicine-based therapeutics. PMID- 30027027 TI - Liquid Metal-Based Multifunctional Micropipette for 4D Single Cell Manipulation. AB - A novel manufacturing approach to fabricate liquid metal-based, multifunctional microcapillary pipettes able to provide electrodes with high electrical conductivity for high-frequency electrical stimulation and measurement is proposed. 4D single cell manipulation is realized by applying multifrequency, multiamplitude, and multiphase electrical signals to the microelectrodes near the pipette tip to create 3D dielectrophoretic trap and 1D electrorotation, simultaneously. Functions such as single cell trapping, patterning, transfer, and rotation are accomplished. Cell viability and multiday proliferation characterization has confirmed the biocompatibility of this approach. This is a simple, low-cost, and fast fabrication process that requires no cleanroom and photolithography step to manufacture 3D microelectrodes and microchannels for easy access to a wide user base for broad applications. PMID- 30027028 TI - Magnetoresistance Anomaly in Topological Kondo Insulator SmB6 Nanowires with Strong Surface Magnetism. AB - Topological Kondo insulators (TKIs) are a new class of topological materials in which topological surface states dominate the transport properties at low temperatures. They are also an ideal platform for studying the interplay between strong electron correlations and topological order. Here, hysteretic magnetoresistance (MR) is observed in TKI SmB6 thin nanowires at temperatures up to 8 K, revealing the strong magnetism at the surface of SmB6. It is also found that such MR anomaly exhibits an intriguing finite size effect and only appears in nanowires with diameter smaller than 58 nm. These nontrivial phenomena are discussed in terms of the latest Kondo breakdown model, which incorporates the RKKY magnetic interaction mediated by surface states with the strong electron correlation in SmB6. It would provide new insight into the nature of TKI surface states. Additionally, a non-monotonically temperature dependent positive magnetoresistance is observed at intermediate temperatures, suggesting the possible impurity-band conduction in SmB6, other than the surface state transport at low temperatures and the bulk-band transport at high temperatures. PMID- 30027029 TI - 11% Organic Photovoltaic Devices Based on PTB7-Th: PC71BM Photoactive Layers and Irradiation-Assisted ZnO Electron Transport Layers. AB - The enhancement of interfacial charge collection efficiency using buffer layers is a cost-effective way to improve the performance of organic photovoltaic devices (OPVs) because they are often universally applicable regardless of the active materials. However, the availability of high-performance buffer materials, which are solution-processable at low temperature, are limited and they often require burdensome additional surface modifications. Herein, high-performance ZnO based electron transporting layers (ETLs) for OPVs are developed with a novel g ray-assisted solution process. Through careful formulation of the ZnO precursor and g-ray irradiation, the pre-formation of ZnO nanoparticles occurs in the precursor solutions, which enables the preparation of high quality ZnO films. The g-ray assisted ZnO (ZnO-G) films possess a remarkably low defect density compared to the conventionally prepared ZnO films. The low-defect ZnO-G films can improve charge extraction efficiency of ETL without any additional treatment. The power conversion efficiency (PCE) of the device using the ZnO-G ETLs is 11.09% with an open-circuit voltage (VOC), short-circuit current density ( JSC), and fill factor (FF) of 0.80 V, 19.54 mA cm-2, and 0.71, respectively, which is one of the best values among widely studied poly[4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2 b;4,5-b']dithiophene-2,6-diyl-alt-(4-(2-ethylhexyl)-3-fluorothieno[3,4 b]thiophene-)-2-carboxylate-2-6-diyl)]: [6,6]-phenyl-C71-butyric acid methyl ester (PTB7-Th:PC71BM)-based devices. PMID- 30027031 TI - Giant Asymmetric Radiation from an Ultrathin Bianisotropic Metamaterial. AB - Unidirectional radiation is of particular interest in high-power lasing and optics. Commonly, however, it is difficult to achieve a unidirectional profile in such a system without breaking reciprocity. Recently, assisted by metamaterials without structural symmetry, antennas that radiate asymmetrically have been developed, hence providing the possibility of achieving unidirectionality. Nevertheless, it has been challenging to achieve extremely high radiation asymmetry in such antennas. Here, it is demonstrated that this radiation asymmetry is further enhanced when magnetic plasmons are present in the metamaterials. Experimentally, it is shown that a thin metamaterial with a thickness of ~lambda0/8 can exhibit a forward-to-backward emission asymmetry of up to 1:32 without any optimization. The work paves the way for manipulating asymmetric radiation by means of metamaterials and may have a variety of promising applications, such as directional optical and quantum emitters, lasers, and absorbers. PMID- 30027033 TI - Engineering Whole Mammalian Cells for Target-Cell-Specific Invasion/Fusion. AB - Live mammalian cells are equipped with a synthetic cell invasion system that enables their target-specific insertion into other live mammalian cells. By conjugating RhoA activator to a transmembrane protein that is segregated from cell-cell interface when specific cell contact occurs, polarization of RhoA activity is synthetically induced inside the cells in response to specific cell contact. This polarization is a sufficient condition for invader cells to selectively penetrate cells expressing a target antigen. Further, when an acid responsive fusogenic protein is expressed on invader cells, invader/receiver cell fusion occurs after invasion, and the invader's intracellular contents are released into the recipient's cytosol. It is shown that this system can be used for specific cell ablation. This synthetic-biology-inspired cell invasion/fusion system might open the door to using whole mammalian cells for cargo delivery purposes or for ablation of a specific cell type. PMID- 30027032 TI - Simultaneous Imaging of Ribonucleic Acid and Hydrogen Sulfide in Living Systems with Distinct Fluorescence Signals Using a Single Fluorescent Probe. AB - Ribonucleic acid (RNA) and hydrogen sulfide (H2S) are important genes and gaseous signal molecules in physiological environment. However, simultaneous investigation of distribution and interrelation of RNA and H2S in living systems is restricted by lack of functional molecular tools. To address this critical challenge, the development of TP-MIVC is described as the first paradigm of the probes that can concurrently report ribonucleic acid and hydrogen sulfide with distinct fluorescence signals in the cancer cells, zebrafish, and living animals. The advantageous features of the probe include high stability, low background fluorescence, high sensitivity, and two-photon imaging property. Significantly, regardless of normal mice or tumor mice, tumor tissues exhibit stronger fluorescence intensity than other organs. More interestingly, it is found that TP MIVC is capable of distinguishing normal mice and tumor mice by in vivo imaging. This study may open a new pathway for distinguishing malignant and benign tumor by fluorescence imaging of RNA. PMID- 30027030 TI - Recent Advances in Designing High-Capacity Anode Nanomaterials for Li-Ion Batteries and Their Atomic-Scale Storage Mechanism Studies. AB - Lithium-ion batteries (LIBs) have been widely applied in portable electronics (laptops, mobile phones, etc.) as one of the most popular energy storage devices. Currently, much effort has been devoted to exploring alternative high-capacity anode materials and thus potentially constructing high-performance LIBs with higher energy/power density. Here, high-capacity anode nanomaterials based on the diverse types of mechanisms, intercalation/deintercalation mechanism, alloying/dealloying reactions, conversion reaction, and Li metal reaction, are reviewed. Moreover, recent studies in atomic-scale storage mechanism by utilizing advanced microscopic techniques, such as in situ high-resolution transmission electron microscopy and other techniques (e.g., spherical aberration-corrected scanning transmission electron microscopy, cryoelectron microscopy, and 3D imaging techniques), are highlighted. With the in-depth understanding on the atomic-scale ion storage/release mechanisms, more guidance is given to researchers for further design and optimization of anode nanomaterials. Finally, some possible challenges and promising future directions for enhancing LIBs' capacity are provided along with the authors personal viewpoints in this research field. PMID- 30027034 TI - Multicolor T-Ray Imaging Using Multispectral Metamaterials. AB - Recent progress in ultrafast spectroscopy and semiconductor technology is enabling unique applications in screening, detection, and diagnostics in the Terahertz (T-ray) regime. The promise of efficaciously operation in this spectral region is tempered by the lack of devices that can spectrally analyze samples at sufficient temporal and spatial resolution. Real-time, multispectral T-ray (Mul T) imaging is reported by designing and demonstrating hyperspectral metamaterial focal plane array (MM-FPA) interfaces allowing multiband (and individually tunable) responses without compromising on the pixel size. These MM-FPAs are fully compatible with existing microfabrication technologies and have low noise when operating in the ambient environment. When tested with a set of frequency switchable quantum cascade lasers (QCLs) for multicolor illumination, both MM FPAs and QCLs can be tuned to operate at multiple discrete THz frequencies to match analyte "fingerprints." Versatile imaging capabilities are presented, including unambiguous identification of concealed substances with intrinsic and/or human-engineered THz characteristics as well as effective diagnosis of cancerous tissues without notable spectral signatures in the THz range, underscoring the utility of applying multispectral approaches in this compelling wavelength range for sensing/identification and medical imaging. PMID- 30027035 TI - 3D CNTs/Graphene-S-Al3Ni2 Cathodes for High-Sulfur-Loading and Long-Life Lithium Sulfur Batteries. AB - Lithium-sulfur batteries suffer from poor cycling stability at high areal sulfur loadings (ASLs) mainly because of the infamous shuttle problem and the increasing diffusion distance for ions to diffuse along the vertical direction of the cathode plane. Here, a carbon nanotube (CNT)/graphene (Gra)-S-Al3Ni2 cathode with 3D network structure is designed and prepared. The 3D network configuration and the Al in the Al3Ni2 provide an efficient channel for fast electron and ion transfer in the three dimensions, especially along the vertical direction of the cathode. The introduction of Ni in the Al3Ni2 is able to suppress the shuttle effect via accelerating reaction kinetics of lithium polysulfide species conversion reactions. The CNT/Gra-S-Al3Ni2 cathode exhibits ultrahigh cycle ability at 1 C over 800 cycles, with a capacity degradation rate of 0.055% per cycle. Additionally, having high ASLs of 3.3 mg cm-2, the electrode delivers a high reversible areal capacity of 2.05 mA h cm-2 (622 mA h g-1) over 200 cycles at a higher current density of 2.76 mA cm-2 with high capacity retention of 85.9%. The outstanding discharge performance indicates that the design offers a promising avenue to develop long-life cycle and high-sulfur-loading Li-S batteries. PMID- 30027036 TI - From Checkerboard-Like Sand Barriers to 3D Cu@CNF Composite Current Collectors for High-Performance Batteries. AB - While the architecture, surface morphology, and electrical conductivity of current collectors may significantly affect the performance of electrochemical cells, many challenges still remain in design and cost-effective fabrication of highly efficient current collectors for a new generation of energy storage and conversion devices. Here the findings in design and fabrication of a 3D checkerboard-like Cu@CNF composite current collector for lithium-ion batteries are reported. The surface of the current collector is modified with patterned grooves and amorphous carbon nanofibers, imitating the checkerboard-like sand barriers in desert regions. Due to a combined effect of the grooves and the carbon nanofibers, a battery based on this current collector retains a reversible capacity of 410.1 mAh g-1 (beyond the theoretical capacity of carbonaceous materials of 372 mAh g-1) with good capacity retention (greater than 84.9% of the initial capacity after 50 cycles), resulting in 66.2% and 42.6% improvement in reversible capacity and capacity retention, respectively, compared to the batteries using traditional Cu current collectors. Based on the excellent electrochemical performance, this composite current collector is believed to be an attractive alternative to the traditional commercially used current collectors for the anode of high-power energy storage systems. PMID- 30027037 TI - Novel Intrapolymerization Doped Manganese-Eumelanin Coordination Nanocomposites with Ultrahigh Relaxivity and Their Application in Tumor Theranostics. AB - While magnetic resonance imaging contrast agents have potential in noninvasive image-guided tumor treatment, further developments are needed to increase contrast, biodegradability, and safety. Here, novel engineered manganese eumelanin coordination nanocomposites (MnEMNPs) are developed via a facile one pot intrapolymerization doping (IPD) approach in aqueous solution, through simple chemical oxidation-polymerization of the 3,4-dihydroxy-DL-phenylalanine precursor with potassium permanganate serving as the Mn source and an oxidant. The resulting MnEMNPs possess ultrahigh longitudinal relaxivity (r1 value up to 60.8 mM-1 s-1 at 1.5 T) attributed to the high manganese doping efficiency (>10%) and geometrically confined conformation. Due to their high manganese chelation stability, excellent biocompatibility, and strong near-infrared absorption, high performance longitudinal-transverse (T1-T2) dual-modal magnetic resonance/photoacoustic imaging and photothermal tumor ablation are achieved. Furthermore, the hydrogen peroxide-triggered decomposition behavior of MnEMNPs circumvents the poor biodegradation issue of many nanomaterials. This facile, convenient, economical, and efficient IPD strategy will open up new avenues for the development of high-performance multifunctional theranostic nanoplatforms in bionanomedicine. PMID- 30027038 TI - B, N Codoped and Defect-Rich Nanocarbon Material as a Metal-Free Bifunctional Electrocatalyst for Oxygen Reduction and Evolution Reactions. AB - The development of highly active, inexpensive, and stable bifunctional oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalysts to replace noble metal Pt and RuO2 catalysts remains a considerable challenge for highly demanded reversible fuel cells and metal-air batteries. Here, a simple approach for the facile construction of a defective nanocarbon material is reported with B and N dopants (B,N-carbon) as a superior bifunctional metal-free catalyst for both ORR and OER. The catalyst is prepared by pyrolyzing the composites of ethyl cellulose and high-boiling point 4-(1-naphthyl)benzeneboronic acid in NH3 atmosphere with an inexpensive Zn-based template. The obtained porous B,N-carbon with rich carbon defects exhibits excellent ORR and OER performances, including high activity and stability. In alkaline medium, B,N-carbon material shows high ORR activity with an onset potential (Eonset) reaching 0.98 V versus reversible hydrogen electrode (RHE), very close to that of Pt/C, a high electron transfer number and excellent stability. This catalyst also presents the admirable ORR activity in acidic medium with a high Eonset of 0.81 V versus RHE and a four electron process. The OER activity of B,N-carbon is superior to that of the precious metal RuO2 and Pt/C catalysts. A Zn-air battery using B,N-carbon as the air cathode exhibits a low voltage gap between charge and discharge and long-term stability. The excellent electrocatalytic performance of this porous nanocarbon material is attributed to the combined positive effects of the abundant carbon defects and the heteroatom codopants. PMID- 30027039 TI - Atomic-Scale Mott-Schottky Heterojunctions of Boron Nitride Monolayer and Graphene as Metal-Free Photocatalysts for Artificial Photosynthesis. AB - Heterojunction photocatalysts at present are still suffering from the low charge separation/transfer efficiency due to the poor charge mobility of semiconductor based photocatalysts. Atomic-scale heterojunction-type photocatalysts are regarded as a promising and effective strategy to overcome the drawbacks of traditional photocatalysts for higher photoenergy conversion efficiencies. Herein, an atomic-scale heterojunction composed of a boron nitride monolayer and graphene (h-BN-C/G) is constructed to significantly shorten the charge transfer path to promote the activation of molecular oxygen for artificial photosynthesis (exemplified with oxidative coupling of amines to imines). As the thinnest heterojunction, h-BN-C/G gives the highest conversion, which is eightfold higher than that of the mechanical mixture of graphene and boron nitride monolayers. h BN-C/G exhibits a high turnover frequency value (4.0 mmol benzylamine g-1 h-1), which is 2.5-fold higher than that of the benchmark metal-free photocatalyst in the literature under even critical conditions. PMID- 30027040 TI - FeIn2S4 Nanocrystals: A Ternary Metal Chalcogenide Material for Ambipolar Field Effect Transistors. AB - An ambipolar channel layer material is required to realize the potential benefits of ambipolar complementary metal-oxide-semiconductor field-effect transistors, namely their compact and efficient nature, reduced reverse power dissipation, and possible applicability to highly integrated circuits. Here, a ternary metal chalcogenide nanocrystal material, FeIn2S4, is introduced as a solution processable ambipolar channel material for field-effect transistors (FETs). The highest occupied molecular orbital and the lowest unoccupied molecular orbital of the FeIn2S4 nanocrystals are determined to be -5.2 and -3.75 eV, respectively, based upon cyclic voltammetry, X-ray photoelectron spectroscopy, and diffraction reflectance spectroscopy analyses. An ambipolar FeIn2S4 FET is successfully fabricated with Au electrodes (EF = -5.1 eV), showing both electron mobility (14.96 cm2 V-1 s-1) and hole mobility (9.15 cm2 V-1 s-1) in a single channel layer, with an on/off current ratio of 105. This suggests that FeIn2S4 nanocrystals may be a promising alternative semiconducting material for next generation integrated circuit development. PMID- 30027041 TI - LncRNA MT1DP Aggravates Cadmium-Induced Oxidative Stress by Repressing the Function of Nrf2 and is Dependent on Interaction with miR-365. AB - Although cadmium (Cd)-induced hepatoxicity is well established, pronounced knowledge gaps remain existed regarding the inherent cellular signaling that dictates Cd toxicity. Specifically, the molecular basis for determining the equilibrium between prosurvival and proapoptotic signaling remains poorly understood. Thus, it is recently revealed that long non-coding RNA (lncRNA) MT1DP, a pseudogene in the metallothionein (MT) family, promoted Cd-induced cell death through activating the RhoC-CCN1/2-AKT pathway and modulating MT1H induction. Here, first the dependency of MT1DP induction on MTF1, an important transcriptional factor in driving the mRNA expression of MT1 members is defined. Additionally, a bridge molecule between MT1DP and nuclear factor erythroid 2 related factor 2 (Nrf2) is established: miR-365. Mechanistically, MT1DP induction under Cd stress decreases the nuclear factor erythroid 2-related factor 2 (Nrf2) level to evoke oxidative stress through the elevation of miR-365, which acted to repress the Nrf2 level via direct binding to its 3'UTR. In contrast to the competing endogenous RNA (ceRNA) mechanism, a new mechanism is proposed: MT1DP elevated the miR-365 level though stabilizing its RNA via direct binding. Collectively, the combined data demonstrate a crucial role of MT1DP in reducing the Nrf2-mediated protection of cells, and this is dependent on the interplay with miR-365. Hence, the study further expands the knowledge of inducible endogenous lncRNA in modulating oxidative stress. PMID- 30027042 TI - Intragranular Dispersion of Carbon Nanotubes Comprehensively Improves Aluminum Alloys. AB - The room-temperature tensile strength, toughness, and high-temperature creep strength of 2000, 6000, and 7000 series aluminum alloys can be improved significantly by dispersing up to 1 wt% carbon nanotubes (CNTs) into the alloys without sacrificing tensile ductility, electrical conductivity, or thermal conductivity. CNTs act like forest dislocations, except mobile dislocations cannot annihilate with them. Dislocations cannot climb over 1D CNTs unlike 0D dispersoids/precipitates. Also, unlike 2D grain boundaries, even if some debonding happens along 1D CNT/alloy interface, it will be less damaging because fracture intrinsically favors 2D percolating flaws. Good intragranular dispersion of these 1D strengtheners is critical for comprehensive enhancement of composite properties, which entails change of wetting properties and encapsulation of CNTs inside Al grains via surface diffusion-driven cold welding. In situ transmission electron microscopy demonstrates liquid-like envelopment of CNTs into Al nanoparticles by cold welding. PMID- 30027043 TI - Sub-50 nm Iron-Nitrogen-Doped Hollow Carbon Sphere-Encapsulated Iron Carbide Nanoparticles as Efficient Oxygen Reduction Catalysts. AB - Sub-50 nm iron-nitrogen-doped hollow carbon sphere-encapsulated iron carbide nanoparticles (Fe3C-Fe,N/C) are synthesized by using a triblock copolymer of poly(styrene-b-2-vinylpyridine-b-ethylene oxide) as a soft template. Their typical features, including a large surface area (879.5 m2 g-1), small hollow size (~16 nm), and nitrogen-doped mesoporous carbon shell, and encapsulated Fe3C nanoparticles generate a highly active oxygen reduction reaction (ORR) performance. Fe3C-Fe,N/C hollow spheres exhibit an ORR performance comparable to that of commercially available 20 wt% Pt/C in alkaline electrolyte, with a similar half-wave potential, an electron transfer number close to 4, and lower H2O2 yield of less than 5%. It also shows noticeable ORR catalytic activity under acidic conditions, with a high half-wave potential of 0.714 V, which is only 59 mV lower than that of 20 wt% Pt/C. Moreover, Fe3C-Fe,N/C has remarkable long-term durability and tolerance to methanol poisoning, exceeding Pt/C regardless of the electrolyte. PMID- 30027045 TI - An Ultrahigh Capacity Graphite/Li2S Battery with Holey-Li2S Nanoarchitectures. AB - The pairing of high-capacity Li2S cathode (1166 mAh g-1) and lithium-free anode (LFA) provides an unparalleled potential in developing safe and energy-dense next generation secondary batteries. However, the low utilization of the Li2S cathode and the lack of electrolytes compatible to both electrodes are impeding the development. Here, a novel graphite/Li2S battery system, which features a self assembled, holey-Li2S nanoarchitecture and a stable solid electrolyte interface (SEI) on the graphite electrode, is reported. The holey structure on Li2S is beneficial in decomposing Li2S at the first charging process due to the enhanced Li ion extraction and transfer from the Li2S to the electrolyte. In addition, the concentrated dioxolane (DOL)-rich electrolyte designed lowers the irreversible capacity loss for SEI formation. By using the combined strategies, the graphite/holey-Li2S battery delivers an ultrahigh discharge capacity of 810 mAh g 1 at 0.1 C (based on the mass of Li2S) and of 714 mAh g-1 at 0.2 C. Moreover, it exhibits a reversible capacity of 300 mAh g-1 after a record lifecycle of 600 cycles at 1 C. These results suggest the great potential of the designed LFA/holey-Li2S batteries for practical use. PMID- 30027044 TI - Light-Ultrasound Driven Collective "Firework" Behavior of Nanomotors. AB - It is of great interest and big challenge to control the collective behaviors of nanomotors to mimic the aggregation/separation behavior of biological systems. Here, a light-acoustic combined method is proposed to control the aggregation/separation of artificial nanomotors. It is shown that nanomotors aggregate at the pressure node in acoustic field and afterward present a collective "firework" separation behavior induced by light irradiation. The collective behavior is found to be applicable for metallic materials and polymers even different light wavelengths are used. Physical insights on the collective firework behavior resulting from the change of acoustic streaming caused by optical force are provided. It is found that diffusion velocity and diffusion region of cluster can be controlled by adjusting light intensity and acoustic excitation voltage, and irradiation direction, respectively. This harmless, controllable, and widely applicable method provides new possibilities for groups of nanomachines, drug release, and cargo transport in nanomedicine and nanosensors. PMID- 30027047 TI - NIR-Activated Polydopamine-Coated Carrier-Free "Nanobomb" for In Situ On-Demand Drug Release. AB - Carrier-free nanoparticles with high drug loading have attracted increasing attention; however, in situ on-demand drug release remains a challenge. Here, a novel near-infrared (NIR) laser-induced blasting carrier-free nanodrug delivery system is designed and fabricated by coating doxorubicin (DOX) nanoparticles (DNPs) with a polydopamine film (PDA) that would prolong the blood circulation time of DNPs and avoid the preleakage of the DOX during blood circulation. Meanwhile, the NH4HCO3 is introduced to trigger in situ "bomb-like" release of DOX for the production of carbon dioxide (CO2) and ammonia (NH3) gases driven by NIR irradiated photothermal effect of PDA. Both in vitro and in vivo studies demonstrate that the carrier-free nanovectors with high drug loading efficiency (85.8%) prolong tumor accumulation, enhance chemotherapy, achieve the synergistic treatment of chemotherapy and photothermal treatment, and do not induce any foreign-body reaction over a three-week implantation. Hence, the delicate design opens a self-assembly path to develop PDA-based NIR-responsive multifunctional carrier-free nanoparticles for tumor therapy. PMID- 30027046 TI - Networked Cages for Enhanced CO2 Capture and Sensing. AB - It remains a great challenge to design and synthesize a porous material for CO2 capture and sensing simultaneously. Herein, strategy of "cage to frameworks" is demonstrated to synthesize fluorescent porous organic polymer (pTOC) by using tetraphenylethylene-based oxacalixarene cage (TOC) as the monomer. The networked cages (pTOC) have improved porous properties, including Brunauer-Emmett-Teller surface area and CO2 capture compared with its monomer TOC, because the polymerization overcomes the window-to-arene packing modes of cages and turns on their pores. Moreover, pTOC displays prominent reversible fluorescence enhancement in the presence of CO2 in different dispersion systems and fluorescence recovery for CO2 release in the presence of NH3.H2O, and is thus very effective to detect and quantify the fractions of CO2 in a gaseous mixtures. PMID- 30027049 TI - Bifunctional Nitrogen and Cobalt Codoped Hollow Carbon for Electrochemical Syngas Production. AB - Electrochemical conversion of CO2 and H2O into syngas is an attractive route to utilize green electricity. A competitive system economy demands development of cost-effective electrocatalyst with dual active sites for CO2 reduction reaction (CO2RR) and hydrogen evolution reaction (HER). Here, a single atom electrocatalyst derived from a metal-organic framework is proposed, in which Co single atoms and N functional groups function as atomic CO2RR and HER active sites, respectively. The synthesis method is based on pyrolysis of ZnO@ZIF (zeolitic imidazolate framework). The excess in situ Zn evaporation effectively prevents Co single atoms (~3.4 wt%) from aggregation and maintains appropriate Co/N ratio. The as-prepared electrocatalyst is featured with high graphitic degree of carbon support for rapid electron transport and sponge-like thin carbon shells with hierarchical pore system for facilitating active site exposure and mass transport. Therefore, the electrocatalyst exhibits a nearly 100% Faradic efficiency and a high formation rate of ~425 mmol g-1 h-1 at 1.0 V with the gaseous product ratio (CO/H2) approximating ideal 1/2. With the assistance of an extensive material characterization and density functional theory (DFT) calculations, it is identified that Co single atoms are uniformly coordinated in the form of Co-C2N2 moieties, and act as the major catalytic sites for CO2 reduction. PMID- 30027048 TI - Recent Advance in Solution-Processed Organic Interlayers for High-Performance Planar Perovskite Solar Cells. AB - Planar heterojunction perovskite solar cells (PSCs) provide great potential for fabricating high-efficiency, low-cost, large-area, and flexible photovoltaic devices. In planar PSCs, a perovskite absorber is sandwiched between hole and electron transport materials. The charge-transporting interlayers play an important role in enhancing charge extraction, transport, and collection. Organic interlayers including small molecules and polymers offer great advantages for their tunable chemical/electronic structures and low-temperature solution processibility. Here, recent progress of organic interlayers in planar heterojunction PSCs is discussed, and the effect of chemical structures on device performance is also illuminated. Finally, the main challenges in developing planar heterojunction PSCs based on organic interlayers are identified, and strategies for enhancing the device performance are also proposed. PMID- 30027050 TI - Dirac Signature in Germanene on Semiconducting Substrate. AB - 2D Dirac materials supported by nonmetallic substrates are of particular interest due to their significance for the realization of the quantum spin Hall effect and their application in field-effect transistors. Here, monolayer germanene is successfully fabricated on semiconducting germanium film with the support of a Ag(111) substrate. Its linear-like energy-momentum dispersion and large Fermi velocity are derived from the pronounced quasiparticle interference patterns in a ?3 * ?3 superstructure. In addition to Dirac fermion characteristics, the theoretical simulations reveal that the energy gap opens at the Brillouin zone center of the ?3 * ?3 restructured germanene, which is evoked by the symmetry breaking perturbation potential. These results demonstrate that the germanium nanosheets with ?3 * ?3 germanene can be an ideal platform for fundamental research and for the realization of high-speed and low-energy-consumption field effect transistors. PMID- 30027051 TI - The Cucurbit[7]Uril-Based Supramolecular Chemistry for Reversible B/Z-DNA Transition. AB - As a left-handed helical structure, Z-DNA is biologically active and it may be correlated with transcription and genome stability. Until recently, it remained a significant challenge to control the B/Z-DNA transition under physiological conditions. The current study represents the first to reversibly control B/Z-DNA transition using cucurbit[7]uril-based supramolecular approach. It is demonstrated that cucurbit[7]uril can encapsulate the central butanediamine moiety [HN(CH2)4NH] and reverses Z-DNA caused by spermine back to B-DNA. The subsequent treatment with 1-adamantanamine disassembles the cucurbit[7]uril/spermine complex and readily induces reconversion of B- into Z DNA. The DNA conformational change is unequivocally demonstrated using different independent methods. Direct evidence for supramolecular interactions involved in DNA conformational changes is further provided. These findings can therefore open a new route to control DNA helical structure in a reversible way. PMID- 30027053 TI - Self-Sensing Paper Actuators Based on Graphite-Carbon Nanotube Hybrid Films. AB - Soft actuators have demonstrated potential in a range of applications, including soft robotics, artificial muscles, and biomimetic devices. However, the majority of current soft actuators suffer from the lack of real-time sensory feedback, prohibiting their effective sensing and multitask function. Here, a promising strategy is reported to design bilayer electrothermal actuators capable of simultaneous actuation and sensation (i.e., self-sensing actuators), merely through two input electric terminals. Decoupled electrothermal stimulation and strain sensation is achieved by the optimal combination of graphite microparticles and carbon nanotubes (CNTs) in the form of hybrid films. By finely tuning the charge transport properties of hybrid films, the signal-to-noise ratio (SNR) of self-sensing actuators is remarkably enhanced to over 66. As a result, self-sensing actuators can actively track their displacement and distinguish the touch of soft and hard objects. PMID- 30027052 TI - A Highly Efficient Synthesis of Polyubiquitin Chains. AB - A robust, microwave-assisted, highly efficient, solid-phase peptide synthesis method for preparing isopeptide-linked 62-mer and 76-mer isoubiquitins and polyubiquitin is developed. The strategy avoids the use of costly resins and pseudoprolines, and the isopeptide-linked building blocks can be assembled with high initial purity within 1 day. All seven diubiquitins are successfully synthesized on a multi-milligram scale; a four-segment, three-ligation method is used to obtain a K33-/K11-linked mixed triubiquitin in excellent yield. Circular dichroism and crystallographic analyses are used to verify the structures of the well-folded, synthetic polyubiquitin chains. The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of isopeptide-linked isoUbs and to pave the way for the study of longer polyubiquitin chains. PMID- 30027054 TI - Advanced Hierarchical Vesicular Carbon Co-Doped with S, P, N for High-Rate Sodium Storage. AB - Hierarchical nanoscale carbons have received wide interest as electrode materials for energy storage and conversion due to their fast mass transfer processes, outstanding electronic conductivity, and high stability. Here, heteroatom (S, P, and N) doped hierarchical vesicular carbon (HHVC) materials with a high surface area up to 867.5 m2 g-1 are successfully prepared using a surface polymerization of hexachloro-cyclotriphosphazene (HCCP) and 4,4'-sulfonyldiphenol (BPS) on the ZIF-8 polyhedrons. Significantly, it is the first time to achieve a controllability of the wall thickness for this unique carbon, ranging from 18 to 52 nm. When utilized as anodes for sodium ion batteries, these novel carbon materials exhibit a high specific capacity of 327.2 mAh g-1 at 100 mA g-1 after 100 cycles, which can be attributed to the expanded interlayer distance and enhanced conductivity derived from the doping of heteroatoms. Importantly, a high capacity of 142.6 mAh g-1 can be obtained even at a high current density of 5 A g 1, assigning to fast ion/electronic transmission processes stemming from the unique hierarchical vesicular structure. This work offers a new route for the fabrication/preparation of multi-heteroatom doped hierarchical vesicular materials. PMID- 30027055 TI - Atomically Thin 2D Multinary Nanosheets for Energy-Related Photo, Electrocatalysis. AB - The severe energy crisis and environmental issues have led to an increase in research on the development of sustainable energy. Atomically thin 2D multinary nanosheets with tunable components show advantages for producing sustainable energy via photo, electrocatalysis processes. Here, recent progress of atomically thin 2D multinary nanosheets from the design, synthesis, tuning, and sustainable energy production via photo, electrocatalysis processes is summarized. The regulating strategies such as alloying, doping, vacancy engineering, pores construction, surface modification, and heterojunction are summarized, focusing on how to optimize the catalytic performance of atomically thin 2D multinary nanosheets. In addition, advancements in versatile energy-related photo, electrocatalytic applications in the areas of oxygen evolution, oxygen reduction, hydrogen evolution, CO2 reduction, and nitrogen fixation are discussed. Finally, existing challenges and future research directions in this promising field are presented. PMID- 30027056 TI - DIY 3D Microparticle Generation from Next Generation Optofluidic Fabrication. AB - Complex-shaped microparticles can enhance applications in drug delivery, tissue engineering, and structural materials, although techniques to fabricate these particles remain limited. A microfluidics-based process called optofluidic fabrication that utilizes inertial flows and ultraviolet polymerization has shown great potential for creating highly 3D-shaped particles in a high-throughput manner, but the particle dimensions are mainly at the millimeter scale. Here, a next generation optofluidic fabrication process is presented that utilizes on-the fly fabricated multiscale fluidic channels producing customized sub-100 um 3D shaped microparticles. This flexible design scheme offers a user-friendly platform for rapid prototyping of new 3D particle shapes, providing greater potential for creating impactful engineered microparticles. PMID- 30027057 TI - Room Temperature Uniaxial Magnetic Anisotropy Induced By Fe-Islands in the InSe Semiconductor Van Der Waals Crystal. AB - The controlled manipulation of the spin and charge of electrons in a semiconductor has the potential to create new routes to digital electronics beyond Moore's law, spintronics, and quantum detection and imaging for sensing applications. These technologies require a shift from traditional semiconducting and magnetic nanostructured materials. Here, a new material system is reported, which comprises the InSe semiconductor van der Waals crystal that embeds ferromagnetic Fe-islands. In contrast to many traditional semiconductors, the electronic properties of InSe are largely preserved after the incorporation of Fe. Also, this system exhibits ferromagnetic resonances and a large uniaxial magnetic anisotropy at room temperature, offering opportunities for the development of functional devices that integrate magnetic and semiconducting properties within the same material system. PMID- 30027058 TI - Ultrahigh Power Factor in Thermoelectric System Nb0.95M0.05FeSb (M = Hf, Zr, and Ti). AB - Conversion efficiency and output power are crucial parameters for thermoelectric power generation that highly rely on figure of merit ZT and power factor (PF), respectively. Therefore, the synergistic optimization of electrical and thermal properties is imperative instead of optimizing just ZT by thermal conductivity reduction or just PF by electron transport enhancement. Here, it is demonstrated that Nb0.95Hf0.05FeSb has not only ultrahigh PF over ~100 uW cm-1 K-2 at room temperature but also the highest ZT in a material system Nb0.95M0.05FeSb (M = Hf, Zr, Ti). It is found that Hf dopant is capable to simultaneously supply carriers for mobility optimization and introduce atomic disorder for reducing lattice thermal conductivity. As a result, Nb0.95Hf0.05FeSb distinguishes itself from other outstanding NbFeSb-based materials in both the PF and ZT. Additionally, a large output power density of ~21.6 W cm-2 is achieved based on a single-leg device under a temperature difference of ~560 K, showing the realistic prospect of the ultrahigh PF for power generation. PMID- 30027060 TI - Screening Small Metabolites from Cells as Multifunctional Coatings Simultaneously Improves Nanomaterial Biocompatibility and Functionality. AB - Currently, nanomaterials face a dilemma due to their advantageous properties and potential risks to human health. Here, a strategy to improve both nanomaterial biocompatibility and functionality is established by screening small metabolites from cells as nanomaterial coatings. A metabolomics analysis of cells exposed to nanosilver (nAg) integrates volcano plots (t-tests and fold change analysis), partial least squares-discriminant analysis (PLS-DA), and significance analysis of microarrays (SAM) and identifies six metabolites (l-aspartic acid, l-malic acid, myoinositol, d-sorbitol, citric acid, and l-cysteine). The further analysis of cell viability, oxidative stress, and cell apoptosis reveals that d-sorbitol markedly reduces nAg cytotoxicity. Subsequently, small molecule loading, surface oxidation, and ionic release experiments support d-sorbitol as the optimal coating for nAg. Importantly, d-sorbitol loading improves the duration of the antibacterial activity of nAg against Escherichia coli and Staphylococcus aureus. The biocidal persistence of nAg-sorbitol is extended beyond 9 h, and the biocidal effects at 12 h are significantly higher than those of naked nAg. This work proposes a new strategy to improve the biocompatibility and functionality of nAg simultaneously by screening small metabolites from cells as nanomaterial functional coatings, a method that can be applied to mitigate the side effects of other nanomaterials. PMID- 30027059 TI - A Metal Chelator as a Plasmonic Signal-Generation Superregulator for Ultrasensitive Colorimetric Bioassays of Disease Biomarkers. AB - Enzyme-based assays have been widely applied in clinical diagnosis for decades. However, the intrinsic limitations of enzymes, such as low operation stability, mediocre sensitivity, and high cost in production and purification, heavily constrain their detection application. Here, an enzyme-free assay is reported that relies on the strong chelating capability of ethylenediamine tetraacetic acid disodium salt (EDTA*2Na, the chelator) for Au3+ ions, in which the cheap EDTA*2Na labeled by targeting moieties can selectively regulate the growth of plasmonic gold nanoparticles (AuNPs) at the target site subjecting to the concentration of analyte in samples. Independent of ambient temperature and unstable H2O2, EDTA*2Na perform superregulation in AuNPs plasmonic signal generation with distinct tonality and outstanding reliability. Upon integrating with silica nanoparticles as the signal amplifying platform, EDTA*2Na-regulated bioassay can lead to detection-sensitivity enhancements exceeding three orders of magnitude in protein detection, compared with the gold-standard assay. The limit of detection of the HBsAg and alpha fetoprotein (AFP) pushes down to 2.6 * 10-15 and 2.5 * 10-19 g mL-1, respectively. EDTA*2Na-regulated bioassay is also challenged in the clinical serum sample detection and a good consistency is found with the chemiluminescence immunoassay method in clinics. PMID- 30027061 TI - Self-Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase-Cleavable Linker. AB - Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target-positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin alphavbeta3 and releases cytotoxins upon entering cells or by caspase-3. This allows the prodrug to kill integrin alphavbeta3 positive cells and upregulate caspase-3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase-3, which activate more prodrugs leading to another round of adjacent cell death and caspase-3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy. PMID- 30027062 TI - Nanoscale Artificial Plasmonic Lattice in Self-Assembled Vertically Aligned Nitride-Metal Hybrid Metamaterials. AB - Nanoscale metamaterials exhibit extraordinary optical properties and are proposed for various technological applications. Here, a new class of novel nanoscale two phase hybrid metamaterials is achieved by combining two major classes of traditional plasmonic materials, metals (e.g., Au) and transition metal nitrides (e.g., TaN, TiN, and ZrN) in an epitaxial thin film form via the vertically aligned nanocomposite platform. By properly controlling the nucleation of the two phases, the nanoscale artificial plasmonic lattices (APLs) consisting of highly ordered hexagonal close packed Au nanopillars in a TaN matrix are demonstrated. More specifically, uniform Au nanopillars with an average diameter of 3 nm are embedded in epitaxial TaN platform and thus form highly 3D ordered APL nanoscale metamaterials. Novel optical properties include highly anisotropic reflectance, obvious nonlinear optical properties indicating inversion symmetry breaking of the hybrid material, large permittivity tuning and negative permittivity response over a broad wavelength regime, and superior mechanical strength and ductility. The study demonstrates the novelty of the new hybrid plasmonic scheme with great potentials in versatile material selection, and, tunable APL spacing and pillar dimension, all important steps toward future designable hybrid plasmonic materials. PMID- 30027063 TI - CsPbCl3-Driven Low-Trap-Density Perovskite Grain Growth for >20% Solar Cell Efficiency. AB - Charge recombination in grain boundaries is a significant loss mechanism for perovskite (PVK) solar cells. Here, a new strategy is demonstrated to effectively passivate trap states at the grain boundaries. By introducing a thin layer of CsPbCl3 coating before the PVK deposition, a passivating layer of PbI2 is formed at the grain boundaries. It is found that at elevated temperature, Cl- ions in the CsPbCl3 may migrate into the PVK via grain boundaries, reacting with MA+ to form volatile MACl and leaving a surface layer of PbI2 at the grain boundary. Further study confirms that there is indeed a small amount of PbI2 distributed throughout the grain boundaries, resulting in increased photoluminescence intensity, increased carrier lifetime, and decreased trap state density. It is also found that the process passivates only grain surfaces, with no observable effect on the morphology of the PVK thin film. Upon optimization, the obtained PVK-film-based solar cell delivers a high efficiency of 20.09% with reduced hysteresis and excellent stability. PMID- 30027064 TI - Erratum: Diarylboron-Based Asymmetric Red-Emitting Ir(III) Complex for Solution Processed Phosphorescent Organic Light-Emitting Diode with External Quantum Efficiency above 28. AB - [This corrects the article DOI: 10.1002/advs.201701067.]. PMID- 30027066 TI - Effect of Dexmedetomidine Versus Nalbuphine as an Adjuvant on Paravertebral Block to Manage Postoperative Pain After Mastectomies. AB - Background and Objective: Breast cancer is the commonest cancer in women worldwide. Many patients are frequently admitted to the operating theaters for mastectomies. Thoracic paravertebral block (PVB) is increasingly used as an effective means for post-operative pain relief. The present study aimed at evaluating the effectiveness and safety of dexmedetomidine and nalbuphine as an adjuvant to bupivacaine local anesthetic in thoracic paravertebral block in breast cancer surgeries. Methods: A total of 60 female patients aged 18 to 78 were included in the study, and ASA I, II, III were scheduled for mastectomy. These patients were unsystematically assigned into three 20-member groups: group PB received bupivacaine (0.3 mL/ kg) + 1 mL (0.9% sodium chloride) normal saline; group PBD received bupivacaine (0.3 mL/kg) + dexmedetomidine 1 MUg/kg; and Group PBN received bupivacaine (0.3 mL/kg) and 10 mg (1 mL) nalbuphine. Demographic data, intraoperative SPO2, ETCO2, HR, SBP and DBP, pain scores (at rest and movement), and sedation scores were recorded every 30 minutes during the initial 2 hours and 4, 8, 24, and 48 hours from T0. Also, postoperative tramadol consumption, the time to the first analgesic request, and any complications were also recorded. Results: There were no statistically significant differences among the three groups regarding demographic data, SPO2, ETCO2, HR, SBP and DBP intraoperatively. Moreover, no significant difference was found in HR, SBP and DBP postoperatively. Postoperative pain scores were significantly higher in group BP, whether at rest or movement. The sedation was significantly higher in PBD group in the first 12 hours postoperatively. There was a significantly lower postoperative tramadol consumption in PBN group and a significantly longer time to the first analgesic request than other groups. No complications were reported in any group. Conclusions: Addition of nalbuphine 10 mg as an adjuvant to bupivacaine local anesthetic in PVB improved the quality of the block and decreased postoperative analgesic requirements than the bupivacaine only group and dexmedetomidine and bupivacaine group. However, adding dexmedetomidine to bupivacaine increased the time to the first analgesic request and more sedation than bupivacaine and bupivacaine and nalbuphine. PMID- 30027067 TI - Occlusion of the Ascenda Catheter in a Patient with Pump Twiddler's Sydrome: A Case Report. AB - Introduction: Intrathecal baclofen (ITB) therapy is an effective way to manage spasticity in numerous conditions, including multiple sclerosis, stroke, and cerebral palsy. While pump failure is a common complication of ITB, improvements in device design have led to reduction of complications. In particular, the Ascenda catheter from Medtronic, Inc. was designed to resist kinking and associated complications; indeed, no incidences of catheter twisting or occlusion have been reported in literature prior to this case. Case Report: We report a case of a 32-year old gentleman who presented to the clinic with symptoms of baclofen withdrawal 19 months after he had a programmable pump implanted for spasticity. During the diagnostic evaluation it was discovered that the patients pump had flipped in his abdominal pocket. He was taken to surgery to reorient the pump, during which time it was noted the catheter was tightly coiled on itself occluding flow. The twisted catheter was excised and replaced with a new segment.His symptoms subsequently resolved. Conclusions: Although catheter occlusions have subsided since the approval of the Ascenda catheter, pump twiddler's syndrome remains a risk factor for this complication. This is the first report describing this syndrome in a patient with the Ascenda catheter. PMID- 30027065 TI - Heparan Sulfate Proteoglycans in Human Colorectal Cancer. AB - Colorectal cancer is the third most common cancer worldwide, accounting for more than 610,000 mortalities every year. Prognosis of patients is highly dependent on the disease stage at diagnosis. Therefore, it is crucial to investigate molecules involved in colorectal cancer tumorigenesis, with possible use as tumor markers. Heparan sulfate proteoglycans are complex molecules present in the cell membrane and extracellular matrix, which play vital roles in cell adhesion, migration, proliferation, and signaling pathways. In colorectal cancer, the cell surface proteoglycan syndecan-2 is upregulated and increases cell migration. Moreover, expression of syndecan-1 and syndecan-4, generally antitumor molecules, is reduced. Levels of glypicans and perlecan are also altered in colorectal cancer; however, their role in tumor progression is not fully understood. In addition, studies have reported increased heparan sulfate remodeling enzymes, as the endosulfatases. Therefore, heparan sulfate proteoglycans are candidate molecules to clarify colorectal cancer tumorigenesis, as well as important targets to therapy and diagnosis. PMID- 30027069 TI - Radiological evaluation of the femoral tunnel positioning in anterior cruciate ligament reconstruction. AB - Objective: To evaluate the inclination and the length of the femoral tunnel in patients submitted to anterior cruciate ligament reconstruction (ACL) surgery by transtibial and anatomical techniques. Methods: This is an analytical observational study in patients with ACL injury that underwent arthroscopic reconstruction through transtibial and anatomical surgical techniques. In the immediate postoperative period, computed tomography (CT) and anteroposterior (AP) view digital radiographs (X-rays) were performed to evaluate the inclination and length of the femoral tunnel. Results: Forty-two patients were analyzed: 27 underwent anatomical reconstruction and 15, transtibial reconstruction. The inclination angle and tunnel length by the transtibial technique are always greater than by the anatomical technique. The mean inclination angles were 59.75 degrees (53.9-66.1 degrees ) in the X-rays and 54.17 degrees (43.5-62.3 degrees ) in CT for the transtibial technique, and 42.91 degrees (29.3-57.4 degrees ) in the X-rays and 39.10 degrees (23.8-50.6 degrees ) in CT for the anatomical technique. Regarding the length of the femoral tunnel, the transtibial technique promotes longer tunnels: mean 55.7 mm (40.0-70.2 mm) in the transtibial and 35.5 mm (24.5-47 mm) in the anatomical technique. No statistically significant correlation was observed between the length and the inclination of the tunnel, regardless of the technique used. Thus, these variables can be considered as independent. Conclusion: The anatomical reconstruction technique presented shorter femoral tunnels and lower angle of inclination than the transtibial technique. The CT showed smaller inclination angle than the X-rays, regardless of the surgical technique. PMID- 30027068 TI - The Stringent Response-Regulated sRNA Transcriptome of Borrelia burgdorferi. AB - The Lyme disease spirochete Borrelia (Borreliella) burgdorferi must tolerate nutrient stress to persist in the tick phase of its enzootic life cycle. We previously found that the stringent response mediated by RelBbu globally regulates gene expression to facilitate persistence in the tick vector. Here, we show that RelBbu regulates the expression of a swath of small RNAs (sRNA), affecting 36% of previously identified sRNAs in B. burgdorferi. This is the first sRNA regulatory mechanism identified in any spirochete. Threefold more sRNAs were RelBbu-upregulated than downregulated during nutrient stress and included antisense, intergenic and 5' untranslated region sRNAs. RelBbu-regulated sRNAs associated with genes known to be important for host infection (bosR and dhhp) as well as persistence in the tick (glpF and hk1) were identified, suggesting potential mechanisms for post-transcriptional regulation of gene expression. PMID- 30027070 TI - Ultrasonography for evaluation of hamstring tendon diameter: is it possible to predict the size of the graft? AB - Objective: Perform the preoperative measurement of the hamstring tendons using ultrasound imaging, validating and correlating the measured value with that found during surgical reconstruction of the ligament. Methods: A cross-sectional study was carried out with 24 patients who underwent ultrasonographic measurement of the semitendinosus and gracilis muscle tendons and were subsequently submitted to surgical reconstruction of the ACL, with ipsilateral semitendinosus and gracilis tendon grafting. Results: The patients' ages ranged from 16 to 43 years, with a mean of 24.8 years (SD = 8.4 years), 79.2% were men, and the distribution by side was 41.7% right knees and 58.3% left knees. A non-significant correlation coefficient was found between the area calculated by ultrasound (2 * semitendinosus area + 2 * gracilis area) and the intraoperative measurement (r = 0.16; p = 0.443). No evidence of a difference between intraoperative measurements <8 mm and >=8 mm was found for the area calculated by the ultrasound (p = 0.746). The difference observed between the groups was -0.01 (95% CI: -0.09 to 0.07). Conclusion: Preoperative ultrasound imaging of the semitendinosus and gracilis tendons does not present a statistically significant correlation with the intraoperative measurement of the quadruple hamstring graft for ligament reconstruction. PMID- 30027071 TI - Patellar position in patients with patellofemoral syndrome as characterized by anatomo-radiographic study. AB - Objectives: To determine the prevalence of high patella in adult patients with knee pain, and to correlate patellar height with symptoms of patellar instability, episode of patellofemoral dislocation and anterior pain in the knee; and also verify the concordance correlation between the Insall-Salvati and Caton Deschamps indices. Method: Cross-sectional study analyzing the medical records of patients with knee pain, using lateral view knee radiographs with 30 degrees degrees of flexion and computed tomography. The values of the Insall-Salvati index and the Caton-Deschamps index were used to determine the patellar height. Results: A total of 756 records were analyzed, resulting in 140 knees studied, 39% men and 61% women. Both indices produced statistically significant associations for the occurrence of high patella and signs of instability and episodes of dislocation, but there was no significant association for anterior knee pain. The Kappa index obtained when analyzing the concordance correlation between the Insall-Salvati index and Caton-Deschamps index points to a regular association between them. Conclusion: Patients with high patella present a higher prevalence of instability. Having a high patella has no significant relationship with the presence of anterior knee pain. The Insall-Salvati and Caton-Deschamps indices demonstrate a regular agreement on the presentation of patellar heights results. PMID- 30027072 TI - Histological study of the posterior cruciate ligament femoral insertion. AB - Objectives: To describe the microscopic anatomy of the posterior cruciate ligament femoral insertion in order to identify and establish differences between the direct and indirect insertions of this ligament. Methods: Ten cadaveric knees were used for this study. The posterior cruciate ligament femoral insertion was observed microscopically. Hematoxylin and eosin staining was performed to observe the morphology of the posterior cruciate ligament insertion. Alcian blue staining was performed to determine the location of the cartilage matrix and better assist in the observation and differentiation between direct and indirect insertions. Results: The direct insertion was observed to be a more complex structure than the indirect insertion because it showed four different histological layers (ligament, uncalcified fibrocartilage, calcified fibrocartilage, and bone). Chondrocytes were observed in the uncalcified and calcified fibrocartilage layers. It was observed that the indirect insertion was composed of two layers in which the ligament was anchored directly to the bone by collagen fibers. Indirect insertion was located in the marginal region of the posterior cruciate ligament between the direct insertion and the anterior articular cartilage. Conclusion: Through histological analysis, it was demonstrated that the indirect insertion was adjacent to the anterior articular cartilage and presents a histological pattern where the collagen fibers insert directly into the bone (two-layer insertion). The direct insertion is posterior to the indirect insertion and has four histologically distinct layers. PMID- 30027073 TI - Descriptive anatomy of the anterior cruciate ligament femoral insertion. AB - Objective: To evaluate the morphology of the anterior cruciate ligament (ACL) femoral insertion in order to describe its anatomical features and insertion site location, with the aim of verifying if the ACL femoral insertion has individual characteristics and to provide information for appropriate femoral tunnel placement on anatomic ACL reconstruction. Methods: Sixteen knees obtained from amputations were studied. The ACL femoral bundles and insertion shape were observed macroscopically, and the ligaments insertion length and thickness were measured with a digital caliper. The distances between the limits of the ligament to the articular cartilage, and the measurement of the area of insertion were checked using ImageJ software. Results: The ACL femoral insertion site was eccentric, closer to the deep condyle cartilage. In ten knees (62.5%), the ACL femoral insertion was oval; the mean length of the insertion was 16.4 mm, varying from 11.3 to 19.3 mm, the mean thickness varied from 7.85 to 11.23 mm, and the mean area of the insertion was 99.7 mm2, varying from 80.9 a 117.2 mm2. The mean distances between the limits of the ligament to the superficial, deep, and inferior articular cartilage were 9.77 +/- 1.21, 2.60 +/- 1.20, and 1.86 +/- 1.15 mm, respectively. Conclusion: There was a 30% to 40% difference between the minimum and maximum results of measurements of ACL femoral insertion length, thickness, and area demonstrating an important individual variation. The insertion site was eccentric, closer to the deep cartilage of the lateral femoral condyle. PMID- 30027074 TI - The femoral tunnel view test during ACL reconstruction can ensure tunnel integrity. AB - Objective: Violation of the posterior femoral cortex commonly referred to as posterior wall blowout, can be a devastating intraoperative complication in anterior cruciate ligament reconstruction (ACLR) and can lead to loss of graft fixation or early graft failure. This study describes and analyzes whether the femoral tunnel view test can ensure the integrity of the femoral tunnel during ACLR. Methods: Intraoperative femoral tunnel integrity using the 360 degrees arthroscopic view test was performed in 584 ACLR patients between 2014 and 2016. Posterior wall blowouts were described by their location along the femoral tunnel (i.e., near the aperture or more proximal) and by the depth of the tunnel blowout (<3 mm, 3-5 mm, >5 mm), corresponding to the length of the posterior cortical wall of the violated femoral tunnel. The time spent for the test was measured during ACLR. Complications related to the femoral tunnel view test were also evaluated. Results: The femoral tunnel view test was performed in all 584 patients. In 12 patients (1%), the femoral tunnel presented a posterior cortical blowout that did not extend beyond 3 mm. Only four patients (0.6%) presented posterior wall blowout that extended beyond 5 mm. The time for the test was 40 s (+/-20 s). No complications related to the test were reported. Conclusion: The femoral tunnel view test is effective for ensuring the integrity of the femoral tunnel during ACL reconstruction, without increasing the surgical time and without an increase in the complications rate. Clinical relevance: The femoral tunnel view test is a quick and straightforward test able to provide an adequate view of the patient's anatomy to ensure tunnel integrity during ACLR. PMID- 30027075 TI - Total knee and hip arthroplasty: the reality of assistance in Brazilian public health care. AB - Objective: To analyze the number of hospital permits for total knee arthroplasty (TKA) and total hip arthroplasty (THA) in Brazil between 2008 and 2015, and correlate them with regional, national, and international demographic and epidemiological aspects. Methods: Data on demographics, economic level, and TKA and THA were obtained from the website of the Ministry of Health/DATASUS, Brazilian Institute of Geography and Statistics, and the National Health Agency to assess the assistance provided by the Public Health Care System in arthroplasties for elderly Brazilian population without private health care. Results: The South and Southeast had the best care, with 8.07 and 6.07 TKAs/100,000 inhabitants, one TKA per 1811 and 2624 seniors, 17.3 and 10.99 THAs/100,000 inhabitants, and one THA per 923 and 1427 seniors, respectively. The worst rates were found in the North and Northeast, with 0.88 and 0.98 TKAs/100,000, one TKA per 6930 and 10,411 seniors, 0.96 and 3.25 THAs/100,000, and one THA per 6849 and 2634 seniors, respectively. The national average was 4.00 TKAs/100,000, one TKA per 3249 seniors, 8.01 THAs/100,000, and one THA per 1586 seniors. The international average was 142.8 TKAs/100,000 and 191.8 THAs/100,000. Conclusion: The results expressed unsatisfactory results for TKA and THA in Brazil, with greater relevance in the North and Northeast. PMID- 30027076 TI - Correlation between the UCLA and Constant-Murley scores in rotator cuff repairs and proximal humeral fractures osteosynthesis. AB - Objective: To evaluate the correlation between the UCLA and Constant-Murley scores in the surgical treatment of rotator cuff tears and proximal humeral fractures (PHF). Methods: Retrospective study evaluating patients submitted to arthroscopic rotator cuff repair and surgical treatment of PHF with 2-year follow up. Patients were evaluated by the UCLA and Constant-Murley scores in the preoperative period for the rotator cuff repairs, and 3, 6, 12 and 24 months after surgery for both diagnoses. Pearson's correlation coefficient (r) was calculated to measure the degree of correlation between the two clinical scales. Results: We evaluated 109 patients: 54 with rotator cuff tear and 55 with PHF. Twenty-four months after surgical treatment, the scores according to the UCLA and Constant-Murley scores were 32.6 +/- 4.0 and 85.0 +/- 12.0 for the rotator cuff tears and 30.3 +/- 5.3 and 73.8 +/- 13.9 for the PHF, demonstrating significant improvements in both, in relation to the initial evaluation (p < 0.001). The scales demonstrated high correlation (r = 0.88, p < 0.001). The scores obtained in the two scales showed high or very high correlation in all the postoperative clinical evaluations (r = 0.79-0.91, p < 0.001). The correlation was high in the preoperative evaluation (r = 0.73, p < 0.001). Conclusion: The UCLA and Constant Murley scores presented high or very high correlation in the evaluation of surgical treatment of rotator cuff tears and PHF. The correlation in the preoperative evaluation was high. PMID- 30027077 TI - Arthroscopic rotator cuff repair: single-row vs. double-row - clinical results after one to four years. AB - Objective: Evaluate and compare the results of single-row (SR) vs. double-row (DR) arthroscopic rotator cuff repair. Methods: From December 2009 to May 2013, 115 arthroscopic rotator cuff repairs were performed using suture anchors. After applying the exclusion criteria, there were 75 patients (79 shoulders) to be evaluated, retrospectively, of whom 53 (56 shoulders) attended re-evaluation. The patients were divided into two groups: SR with 29 shoulders, and DR) with 27 shoulders. The scoring systems for clinical evaluation were those of the University of California at Los Angeles (UCLA) and the American Shoulder and Elbow Surgeons (ASES). Results: The mean follow-up period in the SR group was 37.8 months vs. 41.0 months in the DR group. The average UCLA score was 30.8 in the SR group vs. 32.6 in the DR group. This difference was not statistically significant (p > 0.05). The averages measured by the ASES score also showed no significant difference - 82.3 and 88.8 in the SR and DR groups, respectively. Conclusion: No statistically significant difference was found between SR and DR arthroscopic rotator cuff repair performed by a single surgeon in the comparative analysis of UCLA and ASES scores. PMID- 30027078 TI - Bankart lesion repair: biomechanical and anatomical analysis of Mason-Allen and simple sutures in a swine model. AB - Objective: To evaluate the labral height and pullout resistance after the repair of Bankart lesions in the glenohumeral joint of swine models, using double-loaded anchors with two suture configurations: simple and Mason-Allen. Methods: Ten swine shoulders were used, in which Bankart lesions were created. For each specimen, the lesion was sutured randomly with Mason-Allen sutures or simple sutures. The labral height was measured before the lesion was created and after the labral repair. The specimens were submitted to a tensile test for biomechanical evaluation. Results: In specimens submitted to simple suture (n = 5), the mean labral height observed before the lesion was 3.86 mm, and after suturing, 3.33 mm. In specimens submitted to Mason-Allen suture (n = 5), it was observed that the mean labral height before the lesion was 3.92 mm, and after suturing, 3.48 mm. When comparing the labral height after simple suture and Mason Allen suture, no significant difference was observed. The pullout force at the end of the tensile test on specimens with single suture was 130 N, and in specimens with Mason-Allen suture, 128.6 N. No statistically significant differences were observed between the shoulders treated with single suture and Mason-Allen suture; p = 0.885. Conclusions: Repair of Bankart lesions with Mason Allen suture provides increased labrum height; however, it does not increase the pullout strength. PMID- 30027080 TI - Bone metastasis as the first symptom of tumors: role of an immunohistochemistry study in establishing primary tumor. AB - Objectives: To determine the role of immunohistochemistry in identifying the primary site of tumors, and in establishing which bones are most frequently involved, their relationship with the primary tumor site, and the rate of pathologic bone fracture as the first symptom of a malignant tumor. Methods: A retrospective analysis of all medical records on bone metastases the cases treated between January 2006 and December 2011 at the Department of Orthopedics and Traumatology was performed. Results: Immunohistochemistry correctly determined the primary tumor site in 61.2% of cases analyzed. Regarding the metastatic site, the most affected bone was the femur, accounting for 49.6% of the sample. Bone metastasis was the first symptom of the tumor in only 20.2% of patients, and of these, 95% were admitted for pathologic bone fracture. Conclusion: The study showed that the primary sites and their incidence rate are consistent with the literature reviewed. It was noted that in this sample, most patients did not present with pathologic bone fracture as the first clinical symptom of neoplastic disease. However, analysis of those patients that had a metastasis as the first clinical symptom revealed that it manifested itself as a pathologic fracture in almost all cases. The immunohistochemical study was consistent with the primary tumor site in most cases, indicating the value of the method in the detection of the primary site. PMID- 30027079 TI - Terrible triad of the elbow: evaluation of surgical treatment. AB - Objective: This study aims at analyzing retrospectively the clinical-functional and radiographic results of surgical treatment of the terrible elbow triad, with at least 12 months of postoperative follow-up evaluating elbow function. Methods: A group of patients for retrospective analysis from 2004 to 2015 was defined, in which 12 patients were studied. They underwent surgery due to fracture of the radial head, coronoid fracture, and elbow dislocation; they were evaluated by the Disabilities of the Arm, Shoulder and Hand (DASH) score, the degree of patient satisfaction, the degree of trauma energy, radiographic images, range of motion, and complications. Results: There was a higher incidence of Regan and Morrey type II coronoid process fractures; in relation to the injuries, nine patients had deinsertion of the brachialis. Half of the patients suffered a fall from their own height as the mechanism of trauma. The extent of elbow flexion and extension averaged 126.6 and 24.1 degrees, respectively; the averages for pronation and supination were 64.1 and 62.0 degrees, respectively. All patients presented muscle strength of grade IV or V. The mean DASH score was 14.3, the mean pain score was 2.5, and a majority of the patients were satisfied with the treatment. Conclusion: Despite the total loss of range of motion of the elbow, especially in extension, the treatment was satisfactory for most patients. PMID- 30027081 TI - Epidemiological study on calcaneus fractures in a tertiary hospital. AB - Objective: To analyze the epidemiology and characteristics of patients with calcaneus fractures. Methods: This is a retrospective revision of patients with calcaneus fractures hospitalized in the Institute of Orthopedics and Traumatology of this institution between 2006 and 2010. Data such as age, gender, laterality, trauma mechanism, type of fracture, associated injuries, compound fractures, and time from injury to surgery were analyzed. Results: The analysis of 52 patients showed that men were more commonly affected than women, at a ratio of 5.5:1. Bilateral fractures were observed in ten cases, resulting in a total of 62 calcaneus fractures. A fall from a height was the most frequent trauma mechanism (75%), followed by motorcycle accidents (11.5%) and automobile accidents (9.6%). The most frequent fractures were intra-articular, with 47 cases. Compound fractures were observed in 15 patients (28.9%). Non-surgical management was adopted for 11 patients while 41 patients underwent surgery. The mean time between trauma and the definitive treatment was 7.8 days (range: 0-21 days), and 58.5% of cases were treated within seven days. Conclusion: Patients with calcaneus fractures, most commonly young men, were admitted to a high complexity care hospital, victims of a fall from a height with associated injuries. The great severity of these fractures is characterized by the high prevalence of bilateral (19.2%) and compound fractures (28.9%) in this population group. PMID- 30027082 TI - Treatment of stable intertrochanteric fractures of the femur with proximal femoral nail versus dynamic hip screw: a comparative study. AB - Objective: To evaluate and compare the clinical and radiological outcomes of patients with stable intertrochanteric fractures treated with proximal femoral nail vs. dynamic hip screw. Methods: Sixty patients with stable intertrochanteric fractures, aged over 18 years, were randomly divided into the proximal femoral nail and dynamic hip screw groups. Dynamic hip screw with a three-hole side-plate and an anti-rotation screw were used, as well as a modified ultra-short proximal femoral nail for the smaller Asian population. The intra-operative, early and late complications were recorded, and the functional outcome of each group was assessed using the Harris Hip Score. Results: In the dynamic hip screw group, the one-month mean Harris Hip Score was slightly lower than that of the proximal femoral nail group. However, at the three- and six-month monthly follow-ups, the dynamic hip screw group presented higher mean scores than the proximal femoral nail group; at the one-year follow-up, both the groups attained similar scores. Conclusion: Proximal femoral nail provides a significantly shorter surgery with a smaller incision that leads to less wound-related complications. However, the incidence of technical errors was significantly higher in proximal femoral nail when compared with dynamic hip screw as it is a technically more demanding surgery that leads to more implant failures and the consequent re-operations. PMID- 30027083 TI - Outcome of surgical treatment for displaced acetabular fractures: a prospective study. AB - Objective: The aim of this study was to evaluate the functional outcome of surgically treated acetabular fractures. Methods: A prospective longitudinal study was undertaken in this hospital during the period from December 2010 to December 2014. A total number of 46 patients with the diagnosis of acetabular fracture were included in the study. The main cause of the acetabular injury was a road traffic accident. All the patients were treated surgically with plates and screws. Outcome was assessed radiologically and functionally, employing the Harris Hip Score. The mean follow-up period of the patients in the postoperative period was 30 months (24-36 months). Results: The results were excellent in 60.86%, good in 21.73%, fair in 8.69%, and poor in 8.69%. Post-operative complications of acetabular fracture such as heterotopic ossification were found in 2.17%, osteoarthritis in 6.52%, skin infections in 4.34%, nerve lesions in 2.17%, and vascular necrosis in 4.34% of patients. More than 80% of patients were satisfied with the results of acetabular surgeries. Conclusion: These results show that internal fixation of acetabular fractures leads to a good outcome in the majority of patients. PMID- 30027084 TI - A rare case of bilateral central subluxation of the hip joint with associated bilateral quadrilateral plate fracture in an elderly male due to seizure activity. AB - Musculoskeletal injuries such as dislocation of the shoulder and hip joints and fractures of the femoral neck are known complications of seizures. Bilateral central subluxation of the hip joint with associated bilateral quadrilateral plate fracture is a rare entity and is prone to delayed diagnosis, even more so in patients who experience post-seizure disorientation. The authors report the case of a 74-year-old male patient with bilateral central subluxation of the hip joint with associated bilateral quadrilateral plate fracture due to seizure activity. Bilateral open reconstruction and fixation of the quadrilateral plate with a 3.5-mm pre-bent reconstruction plate reinforced with 3.5-mm pelvic brim reconstruction plate was performed. In conclusion, this case is an example of rare bilateral quadrilateral plate fracture caused due to seizure activity, a fracture for which a high level of suspicion should be kept in mind while evaluating the patient post-seizure episode. PMID- 30027085 TI - Case report: treatment of Fournier's gangrene of the shoulder girdle. AB - Fournier's gangrene is a rare, high-mortality infection that affects the subcutaneous tissue with rapidly progressive necrosis. The objective is to report a case of Fournier's gangrene involving the region of the shoulder girdle after closed fracture of the clavicle, and to discuss this unusual evolution. The patient underwent a series of surgical procedures and was followed up on an outpatient basis for 12 months, at which point she was discharged. Fournier's gangrene is an aggressive lesion and requires early diagnosis (clinical laboratory correlation) with the appropriate adequate surgical approach and clinical stabilization. PMID- 30027086 TI - Osteochondritis dissecans of the trochlea: case report. AB - The authors report a rare case of osteochondritis dissecans of the trochlea. The treatment of these lesions, in which the osteochondral fragment is not viable, is difficult and often limited in Brazil. A clinical case is presented with functional and radiological outcomes after treatment with microfracture technique, bone graft, and collagen membrane coverage. PMID- 30027087 TI - Total knee arthroplasty in patients with permanent patella dislocation. Report of two cases and literature review. AB - The occurrence of permanent patellar dislocation associated with severe osteoarthritis is considered rare and difficult to treat. Literature: The literature is quite controversial on the subject. The objective of the study is to report two rare cases of severe osteoarthritis with permanent dislocation of the patella that underwent total knee arthroplasty, in addition to a review of the literature on the subject and related surgical technique. Total knee arthroplasty with using the medial parapatellar approach associated with lateral release was a good surgical option in patients with permanent patellar dislocation associated with advanced osteoarthritis. PMID- 30027088 TI - Tibial tubercle fracture associated with distal rupture of the patellar tendon: case report. AB - Avulsion of the tibial tubercle is an uncommon injury that occurs in the young athlete, resulting from an eccentric contraction of the extensor mechanism with the leg fixed to the ground. Concomitant injuries to the patellar tendon are very rare, with few cases reported in the literature. The authors present a case of a 15-year-old basketball player who suffered an avulsion of the tibial tubercle associated with complete distal rupture of the patellar tendon while training. It was treated with open reduction of the tibial fragment and reconstruction of the patellar tendon with mini-anchors and cannulated screws, as well as hamstring autograft tendon reinforcement. The patient showed excellent results and returned to sports after 12 months of follow-up. PMID- 30027089 TI - Immunotherapy in Advanced Gastric Cancer: An Overview of the Emerging Strategies. AB - Gastric cancer (GC) remains a public health problem, being the fifth most common cancer worldwide. In the western countries, the majority of patients present with advanced disease. Additionally, 65 to 75% of patients treated with curative intent will relapse and develop systemic disease. In metastatic disease, systemic treatment still represents the state of the art, with less than a year of median overall survival. The new molecular classification of GC was published in 2014, identifying four distinct major subtypes of gastric cancer, and has encouraged the investigation of new and more personalized treatment strategies. This paper will review the current evidence of immunotherapy in advanced gastric cancer. PMID- 30027090 TI - Size and Charge Evaluation of Standard Humic and Fulvic Acids as Crucial Factors to Determine Their Environmental Behavior and Impact. AB - In this work, the size and charge of humic and fulvic standards purchased from the International Humic Substances Society are presented and discussed. The secondary structure of humic substances in water environment as well as the size and shape of the dissolved humic species and their changes are ill-defined, very dynamic and can be strongly affected by environmental conditions as the concentration, pH, and ionic strength. They have a strong propensity to aggregate which control their interactions with other components, mobility, and functioning in the environment. Particle size distributions were determined by means of dynamic light scattering, zeta potential by Doppler electrophoresis. The intensity, volume, and number particle size distribution were obtained. Two or three different size fractions were detected in the studied systems. Large macroparticles (>1 MUm) were observed in the majority of them, mainly in the case of more concentrated solutions. Medium fractions of fulvic submicroparticles had higher average diameters (500-1,200 nm) than those in humic acids (300-600 nm). Small nanoparticles (<100 nm) were detected mainly in alkaline solutions. Fulvic acids with more functional groups (active sites) can form more easily bigger particles mainly in medium concentration region. Alkaline conditions supported the expansion of humic and fulvic coils and liberation of small particles from them. The colloidal stability, indicated by more negative zeta potentials, was higher for humic acids. In the case of fulvic acids, the colloidal stability increased with increasing pH as a result of the dissociation of their functional groups. The increase of particle size corresponded usually with higher stability. PMID- 30027092 TI - High Quality de Novo Transcriptome Assembly of Croton tiglium. PMID- 30027091 TI - Combining Cellulose and Cyclodextrins: Fascinating Designs for Materials and Pharmaceutics. AB - Cellulose and cyclodextrins possess unique properties that can be tailored, combined, and used in a considerable number of applications, including textiles, coatings, sensors, and drug delivery systems. Successfully structuring and applying cellulose and cyclodextrins conjugates requires a deep understanding of the relation between structural, and soft matter behavior, materials, energy, and function. This review focuses on the key advances in developing materials based on these conjugates. Relevant aspects regarding structural variations, methods of synthesis, processing and functionalization, and corresponding supramolecular properties are presented. The use of cellulose/cyclodextrin conjugates as intelligent platforms for applications in materials science and pharmaceutical technology is also outlined, focusing on drug delivery, textiles, and sensors. PMID- 30027093 TI - Presumed Caudal Cerebellar Artery Infarction in Three Cats: Neurological Signs, MRI Findings, and Outcome. AB - Ischemic cerebrovascular disease (CVD) is a relatively common condition in dogs but infrequent in cats, with acute or peracute onset of non-progressive neurological signs. Cerebellar artery infarction appears to be very uncommon in cats, with only two cases reported affecting the rostral cerebellar artery (RCA). This study aims to report for the first time the neurological signs, magnetic resonance imaging (MRI) findings and outcome in three cats diagnosed with presumed caudal cerebellar artery (CCA) infarction. Unique presentation of vestibular signs associated with CCA in three cats and similarities between dogs and humans are discussed. PMID- 30027094 TI - Expression Analysis of Nitrogen Metabolism-Related Genes Reveals Differences in Adaptation to Low-Nitrogen Stress between Two Different Barley Cultivars at Seedling Stage. AB - The excess use of nitrogen fertilizers causes many problems, including higher costs of crop production, lower nitrogen use efficiency, and environmental damage. Crop breeding for low-nitrogen tolerance, especially molecular breeding, has become the major route to solving these issues. Therefore, in crops such as barley (Hordeum vulgare L.), it is crucial to understand the mechanisms of low nitrogen tolerance at the molecule level. In the present study, two barley cultivars, BI-04 (tolerant to low nitrogen) and BI-45 (sensitive to low nitrogen), were used for gene expression analysis under low-nitrogen stress, including 10 genes related to primary nitrogen metabolism. The results showed that the expressions of HvNIA2 (nitrite reductase), HvGS2 (chloroplastic glutamine synthetase), and HvGLU2 (ferredoxin-dependent glutamate synthase) were only induced in shoots of BI-04 under low-nitrogen stress, HvGLU2 was also only induced in roots of BI-04, and HvGS2 showed a rapid response to low-nitrogen stress in the roots of BI-04. The expression of HvASN1 (asparagine synthetase) was reduced in both cultivars, but it showed a lower reduction in the shoots of BI-04. In addition, gene expression and regulation differences in the shoots and roots were also compared between the barley cultivars. Taken together, the results indicated that the four above-mentioned genes might play important roles in low-nitrogen tolerance in barley. PMID- 30027095 TI - Predicting the Future Need of Walking Device or Assistance by Moderate to Vigorous Physical Activity: A 2-Year Prospective Study of Women Aged 75 Years and Above. AB - Objective: To examine the association between daily moderate to vigorous physical activity (MVPA) and the change in mobility function among community-dwelling Japanese women aged 75 years and above. Methods: This prospective study included 330 older women aged 75 years and above who could walk without a walking device or assistance. MVPA and light-intensity physical activity (LPA) were assessed using an accelerometer for seven consecutive days. MVPA was defined as an activity with an intensity of >3 metabolic equivalents. The study outcome was a change in mobility function, defined as the need of walking device or assistance, during the two-year period. Results: The results of the logistic regression analysis showed that MVPA was inversely associated with a decline in mobility function after controlling for LPA and potential confounders (adjusted odds ratio (OR) = 0.93 per 1 min/d, 95% confidence interval (CI) = 0.88-0.99; P = 0.017), whereas LPA was not when adjusted for MVPA and confounders (adjusted OR = 0.99 per 1 min/d, 95% CI = 0.96-1.01; P = 0.245). The receiver operating characteristics analysis identified a 7.9 min/d of MVPA as the cut-off value. Conclusions: The results of this study suggest the importance of promoting daily MVPA for preventing mobility limitation in older women aged 75 years and above. PMID- 30027096 TI - Development of Novel Single-Chain Antibodies against the Hydrophobic HPV-16 E5 Protein. AB - The human papilloma virus type 16 infects genital mucosa with high prevalence in the oncogenesis of cervical and oropharyngeal cancers. The E5 protein of this virus is a small hydrophobic protein, whose expression generally decreases as the infection progresses to malignancy. These characteristics point to a role of E5 in the establishment of HPV infection and the initiation into cell transformation. The study of the HPV-16 E5 functions has been hindered because of the lack of antibodies. Detection is very difficult because of its hydrophobic nature, membrane location, and very low levels of expression. Thus, the objective of this study was to select single-chain antibodies against the full size E5 protein, which was coexpressed with maltose-binding protein. We report that the E5 protein was recognized by the antibody and was validated in W12 cells by fluorescent microscopy, including a colocalization with one of its host substrates. The use of this antibody could increase our knowledge about the functions of the oncogenic HPV-16 E5 protein during the earliest stages of keratinocyte infection in human. PMID- 30027097 TI - Identification of the Key MicroRNAs and the miRNA-mRNA Regulatory Pathways in Prostate Cancer by Bioinformatics Methods. AB - Objective: To identify key microRNAs (miRNAs) and their regulatory networks in prostate cancer. Methods: Four miRNA and three gene expression microarray datasets were downloaded for analysis from Gene Expression Omnibus database. The differentially expressed miRNA and genes were accessed by a GEO2R. Functional and pathway enrichment analyses were performed using the DAVID program. Protein protein interaction (PPI) and miRNA-mRNA regulatory networks were constructed using the STRING and Cytoscape tool. Moreover, the results and clinical significance were validated in TCGA data. Results: We identified 26 significant DEMs, 633 upregulated DEGs, and 261 downregulated DEGs. Functional enrichment analysis indicated that significant DEGs were related to TGF-beta signaling pathway and TNF signaling pathway in PCa. Key DEGs such as HSPA8, PPP2R1A, CTNNB1, ADCY5, ANXA1, and COL9A2 were found as hub genes in PPI networks. TCGA data supported our results and the miRNAs were correlated with clinical stages and overall survival. Conclusions: We identified 26 miRNAs that may take part in key pathways like TGF-beta and TNF pathways in prostate cancer regulatory networks. MicroRNAs like miR-23b, miR-95, miR-143, and miR-183 can be utilized in assisting the diagnosis and prognosis of prostate cancer as biomarkers. Further experimental studies are required to validate our results. PMID- 30027098 TI - Genetic Polymorphism in the RYR1 C6487T Is Associated with Severity of Hypospadias in Chinese Han Children. AB - Objective: Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown etiology, which is probably a mix of monogenic and multifactorial forms, implicating both genetic and environmental factors. Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital diseases associated with both dominant and recessive inheritance in humans. Herein, we evaluated the correlations of RYR1 C6487T polymorphism with the risk and severity of hypospadias. Methods: 263 congenital hypospadias children and 312 healthy children were recruited. The polymorphism of RYR1 C6487T in the peripheral blood was detected by polymerase chain reaction-restriction fragment length polymorphism, and different genotypes and allelic genes were analyzed to explore their associations with the risk of congenital hypospadias. Results: The distribution frequencies of CC/CT/TT genotypes and two alleles (C and T) at RYR1 C6487T showed significant differences between the case and control groups (P < 0.05). The frequency of C allele in the case and control groups was 46.95% and 54.94%, respectively, and of T allele was 53.05% and 45.06% (P < 0.05). In addition, the distribution frequency of CC/CT/TT genotypes exhibited significant difference between patients with mild hypospadias and those with moderate or severe hypospadias (all P > 0.05), suggesting that RYR1 C6487T polymorphism is correlated with the severity of congenital hypospadias (X2 = 13.722, P = 0.001). Conclusion: Our study demonstrated that RYR1 C6487T polymorphism might be associated with an increased risk of congenital hypospadias in Chinese Han children. Our findings highlight the heterogeneous nature of hypospadias genetic susceptibility. PMID- 30027099 TI - A Novel UDP-Glycosyltransferase of Rhodiola crenulata Converts Tyrosol to Specifically Produce Icariside D2. AB - Rhodiola crenulata is a Tibetan native herbal plant belonging to the family of Crassulaceae, which produces the pharmaceutical icariside D2 with the activities of inhibiting angiotensin-converting enzyme and killing leukemia cancer cells. In this study, we functionally characterized a novel UDP-glycosyltransferase (RcUGT1) that converted tyrosol to specifically produce icariside D2 from R. crenulata at molecular and biochemical levels. RcUGT1 was highly expressed in flowers and roots, while the icariside D2 content was much higher in stems than that in other organs, suggesting the potential translocation of icariside D2 from flowers and roots to stems. The high production of icariside D2 in stems provided a reasonable suggestion to farmers to harvest stems instead of roots for icariside D2 production. Enzymatic assays of recombinant RcUGT1 indicated that it converted tyrosol to specifically form icariside D2, with the values of Km 0.97+/ 0.10 mM, Vmax 286+/-8.26 pKat/mg, Kcat 0.01552 s-1, and Kcat/Km 159.55 s-1 M-1. Functional identification of RcUGT1 facilitated the icariside D2 production through metabolic engineering in plants or synthetic biology in microbes. PMID- 30027101 TI - Organ-Specific Phytochemical Profiling and Antioxidant Analysis of Parthenium hysterophorus L. AB - Parthenium hysterophorus is a weed of global concern with high threshold of tolerance against most of biotic and abiotic stresses. Phytochemical profile and in vitro antioxidant analysis may help in understanding its tolerance to stresses. Root, stem, leaf, phyllary, and receptacle (including disc and ray florets) were chemotyped employing GC tof-MS and assessed for antioxidant activity by DPPH, FRAP, HRSA, and TAC assays. Phytochemicals identified were terpenes, fatty acids, hydrocarbons, phytosterols, and compounds of miscellaneous chemical nature. Organ-specific maximum concentration of metabolite was beta vatirenene (root), hexadecanoic acid methylester (stem), aristolene epoxide (leaf), hexadecanoic acid methylester (phyllary), and hexadecanoic acid methylester (receptacle). Identified metabolites could be associated with stress tolerance mechanisms, basic metabolism, and allelopathy, etc. Root extracts showed highest antioxidant potential followed by receptacle. It can be concluded that diverse and unique phytochemical profile and great antioxidant potential make P. hysterophorus stress-tolerant, hence a weed of global habitat. PMID- 30027100 TI - Maternal Overnutrition Programs Central Inflammation and Addiction-Like Behavior in Offspring. AB - Obesity or maternal overnutrition during pregnancy and lactation might have long term consequences in offspring health. Fetal programming is characterized by adaptive responses to specific environmental conditions during early life stages. Programming alters gene expression through epigenetic modifications leading to a transgenerational effect of behavioral phenotypes in the offspring. Maternal intake of hypercaloric diets during fetal development programs aberrant behaviors resembling addiction in offspring. Programming by hypercaloric surplus sets a gene expression pattern modulating axonal pruning, synaptic signaling, and synaptic plasticity in selective regions of the reward system. Likewise, fetal programming can promote an inflammatory phenotype in peripheral and central sites through different cell types such as microglia and T and B cells, which contribute to disrupted energy sensing and behavioral pathways. The molecular mechanism that regulates the central and peripheral immune cross-talk during fetal programming and its relevance on offspring's addictive behavior susceptibility is still unclear. Here, we review the most relevant scientific reports about the impact of hypercaloric nutritional fetal programming on central and peripheral inflammation and its effects on addictive behavior of the offspring. PMID- 30027102 TI - A Novel Inflammation-Based Prognostic Score: The Fibrinogen/Albumin Ratio Predicts Prognoses of Patients after Curative Resection for Hepatocellular Carcinoma. AB - Background: Inflammation is an important hallmark of cancer. Fibrinogen and albumin are both vital factors in systemic inflammation. This study investigated the prognostic value of the fibrinogen/albumin ratio in HCC patients who underwent curative resection. Methods: HCC patients (n = 151) who underwent curative resection were evaluated retrospectively. The optimal cutoff value for the fibrinogen/albumin ratio was selected by receiver operating characteristic (ROC) curve analysis. Correlations between preoperative fibrinogen/albumin ratios and clinicopathologic characteristics were analyzed by chi2 test. The area under the receiver operating characteristic curve (AUC) was calculated to compare the prognostic value of the fibrinogen/albumin ratio with other prognostic scores (neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and albumin-bilirubin (ALBI) score). The overall survival (OS) and time to recurrence (TTR) were assessed by the log-rank test and the Cox proportional hazard regression model. Results: An optimal cutoff value of the preoperative fibrinogen/albumin ratio (0.062) was determined for 151 patients who underwent curative resection for HCC via a ROC curve analysis. Fibrinogen/albumin ratio > 0.062 was significantly associated with microvascular invasion, an advanced BCLC stage, and ALBI grade. Multivariate analyses revealed that fibrinogen/albumin ratio was an independent predictor for OS (P = 0.003) and TTR (P = 0.035). The prognostic ability of fibrinogen/albumin ratio was comparable to other prognostic scores (NLR, PLR, and ALBI score) by AUC analysis. Patients with a fibrinogen/albumin ratio > 0.062 had lower 1-, 3-, and 5-year OS rates (66.0%, 41.8%, and 28.2% versus 81.9%, 69.3%, and 56.1%, resp., P < 0.001) and higher 1-, 3-, and 5-year recurrence rates (60.9%, 79.2%, and 90.5% versus 49.5%, 69.1%, and 77.1%, resp., P = 0.008) compared with patients with fibrinogen/albumin ratio <= 0.062. Conclusion: The preoperative fibrinogen/albumin ratio is an effective prognostic factor for HCC patients who underwent curative resection. An elevated fibrinogen/albumin ratio significantly correlates with poorer survival and a higher risk of recurrence in HCC patients. PMID- 30027104 TI - Cladribine tablets added to IFN-beta in active relapsing MS: The ONWARD study. AB - Objective: To evaluate the safety and efficacy of cladribine tablets in patients still experiencing active relapsing MS despite interferon (IFN)-beta treatment. Methods: A 96-week phase II study, randomizing patients treated with IFN-beta to cladribine tablets 3.5 mg/kg/IFN-beta or placebo/IFN-beta. Patients were to receive cladribine tablets 3.5 mg/kg/IFN-beta or placebo/IFN-beta in a 2:1 ratio (n = 172) with safety and exploratory efficacy outcomes being assessed. Results: Adverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia. Fifty of 124 (40.3%) cladribine/IFN-beta recipients vs 0% of placebo/IFN-beta recipients reported lymphopenia as an AE, with grade 3/4 lymphopenia (laboratory lymphocyte count < 500 cells/mm3) experienced by 79/124 (63.7%) vs 1 (2.1%), respectively. Patients treated with cladribine tablets 3.5 mg/kg/IFN-beta were 63% less likely to have a qualifying relapse than placebo/IFN beta recipients, and cladribine tablets 3.5 mg/kg/IFN-beta reduced most MRI measures of disease activity. Conclusions: In patients with active relapsing MS despite IFN-beta treatment, cladribine tablets 3.5 mg/kg/IFN-beta reduced relapses and MRI lesion activity over 96 weeks compared with placebo/IFN-beta but led to an increased incidence of lymphopenia. Classification of evidence: This study provides Class I evidence that for patients with active relapsing MS despite IFN-beta treatment, cladribine tablets added to IFN-beta reduced relapses and MRI lesion activity over 96 weeks and increased the incidence of lymphopenia. Clinical trial registration: NCT00436826. PMID- 30027105 TI - Drug reaction with eosinophilia and systemic symptoms after daclizumab therapy in MS. PMID- 30027103 TI - Impact of Direct-Acting Antivirals on the Burden of HCV Infection Among Persons Who Inject Drugs and Men Who Have Sex With Men in the Swiss HIV Cohort Study. AB - In the Swiss HIV Cohort Study, the number of people who inject drugs with replicating hepatitis C virus (HCV) infection decreased substantially after the introduction of direct-acting antivirals (DAAs). Among men who have sex with men, the increase in DAA uptake and efficacy was counterbalanced by frequent incident HCV infections. PMID- 30027106 TI - GFAPalpha IgG-associated encephalitis upon daclizumab treatment of MS. AB - Objective: To describe a case of glial fibrillary acidic protein (GFAP)alpha immunoglobulin G (IgG)-associated encephalitis in a patient referred to us with MS on daclizumab treatment and to summarize characteristics of 5 additional recent German MS cases of serious encephalitis along with a previously published American case of CNS vasculitis associated with daclizumab. Methods: Evaluation of cause, clinical symptoms, and treatment response. Results: The 6 patients included 4 women and 2 men. The median age at onset was 38 years (range 32-51 years). Clinical presentation was marked by progressing neuropsychologic and/or neurologic deficits. Additional drug rash with eosinophilia was seen in 3 patients, whereas 2 patients showed a highly active demyelinating process. Examination of CSF samples detected pleocytosis, elevated total protein levels, and GFAPalpha IgG antibodies, which were not found in serum. In our case, we discovered autoimmune GFAP astrocytopathy associated with encephalitis as secondary autoimmunity, which was steroid responsive. Clinical outcome of other cases was marked by partial recovery in 4 patients and persistent foster care in 1 patient. Conclusions: Our case of GFAPalpha IgG-associated encephalitis along with 12 other cases of serious inflammatory brain disorders following daclizumab treatment so far indicates that interfering with NK cells and Tregs by anti-CD25 antibody therapy can result in severe secondary CNS autoimmunity in man. PMID- 30027107 TI - Intracerebral lymphoproliferative disorder in an MS patient treated with fingolimod. PMID- 30027108 TI - A Large Endoplasmic Reticulum-Resident Pool of TRPM1 in Retinal ON-Bipolar Cells. AB - The chemical signal of light onset, a decrease in glutamate release from rod and cone photoreceptors, is processed by a postsynaptic G protein signaling cascade in ON-bipolar cells (BPCs). The metabotropic glutamate receptor mGluR6, along with other cascade elements, is localized synaptically at the BPC dendritic tips. The effector ion channel protein transient receptor potential melastatin-1 (TRPM1), in contrast, is located not only at the dendritic tips but also in BPC bodies and axons. Little is known about the intracellular localization of TRPM1, or its trafficking route to the dendritic tip plasma membrane. Recombinant TRPM1 expressed in mammalian cells colocalized with endoplasmic reticulum (ER) markers, with little or none detected at the plasma membrane. In mouse retina, somatic TRPM1 was similarly intracellular, and not at the plasma membrane. Labeling of ER membranes by expression of a fluorescent marker showed that in BPCs the ER extends into axons and dendrites, but not dendritic tips. In cell bodies, TRPM1 colocalized with the ER, and not with the Golgi apparatus. Fluorescence protease protection (FPP) assays with TRPM1-GFP fusions in heterologous cells revealed that the N and C termini are both accessible to the cytoplasm, consistent with the transmembrane domain topology of related TRP channels. These results indicate that the majority of TRPM1 is present in the ER, from which it can potentially be transported to the dendritic tips as needed for ON light responses. The excess of ER-resident TRPM1 relative to the amount needed at the dendritic tips suggests a potential new function for TRPM1 in the ER. PMID- 30027109 TI - Pharmacological Dopamine Manipulation Does Not Alter Reward-Based Improvements in Memory Retention during a Visuomotor Adaptation Task. AB - Motor adaptation tasks investigate our ability to adjust motor behaviors to an ever-changing and unpredictable world. Previous work has shown that punishment based feedback delivered during a visuomotor adaptation task enhances error reduction, whereas reward increases memory retention. While the neural underpinnings of the influence of punishment on the adaptation phase remain unclear, reward has been hypothesized to increase retention through dopaminergic mechanisms. We directly tested this hypothesis through pharmacological manipulation of the dopaminergic system. A total of 96 young healthy human participants were tested in a placebo-controlled double-blind between-subjects design in which they adapted to a 40 degrees visuomotor rotation under reward or punishment conditions. We confirmed previous evidence that reward enhances retention, but the dopamine (DA) precursor levodopa (LD) or the DA antagonist haloperidol failed to influence performance. We reason that such a negative result could be due to experimental limitations or it may suggest that the effect of reward on motor memory retention is not driven by dopaminergic processes. This provides further insight regarding the role of motivational feedback in optimizing motor learning, and the basis for further decomposing the effect of reward on the subprocesses known to underlie motor adaptation paradigms. PMID- 30027111 TI - Extending the Time Domain of Neuronal Silencing with Cryptophyte Anion Channelrhodopsins. AB - Optogenetic inhibition of specific neuronal types in the brain enables analysis of neural circuitry and is promising for the treatment of a number of neurological disorders. Anion channelrhodopsins (ACRs) from the cryptophyte alga Guillardia theta generate larger photocurrents than other available inhibitory optogenetic tools, but more rapid channels are needed for temporally precise inhibition, such as single-spike suppression, of high-frequency firing neurons. Faster ACRs have been reported, but their potential advantages for time-resolved inhibitory optogenetics have not so far been verified in neurons. We report RapACR, nicknamed so for "rapid," an ACR from Rhodomonas salina, that exhibits channel half-closing times below 10 ms and achieves equivalent inhibition at 50 fold lower light intensity in lentivirally transduced cultured mouse hippocampal neurons as the second-generation engineered Cl--conducting channelrhodopsin iC++. The upper limit of the time resolution of neuronal silencing with RapACR determined by measuring the dependence of spiking recovery after photoinhibition on the light intensity was calculated to be 100 Hz, whereas that with the faster of the two G. theta ACRs was 13 Hz. Further acceleration of RapACR channel kinetics was achieved by site-directed mutagenesis of a single residue in transmembrane helix 3 (Thr111 to Cys). We also show that mutation of another ACR (Cys to Ala at the same position) with a greatly extended lifetime of the channel open state acts as a bistable photochromic tool in mammalian neurons. These molecules extend the time domain of optogenetic neuronal silencing while retaining the high light sensitivity of Guillardia ACRs. PMID- 30027110 TI - White-Matter Pathways for Statistical Learning of Temporal Structures. AB - Extracting the statistics of event streams in natural environments is critical for interpreting current events and predicting future ones. The brain is known to rapidly find structure and meaning in unfamiliar streams of sensory experience, often by mere exposure to the environment (i.e., without explicit feedback). Yet, we know little about the brain pathways that support this type of statistical learning. Here, we test whether changes in white-matter (WM) connectivity due to training relate to our ability to extract temporal regularities. By combining behavioral training and diffusion tensor imaging (DTI), we demonstrate that humans adapt to the environment's statistics as they change over time from simple repetition to probabilistic combinations. In particular, we show that learning relates to the decision strategy that individuals adopt when extracting temporal statistics. We next test for learning-dependent changes in WM connectivity and ask whether they relate to individual variability in decision strategy. Our DTI results provide evidence for dissociable WM pathways that relate to individual strategy: extracting the exact sequence statistics (i.e., matching) relates to connectivity changes between caudate and hippocampus, while selecting the most probable outcomes in a given context (i.e., maximizing) relates to connectivity changes between prefrontal, cingulate and basal ganglia (caudate, putamen) regions. Thus, our findings provide evidence for distinct cortico-striatal circuits that show learning-dependent changes of WM connectivity and support individual ability to learn behaviorally-relevant statistics. PMID- 30027112 TI - Neurons Specifically Activated by Fear Learning in Lateral Amygdala Display Increased Synaptic Strength. AB - The lateral amygdala (LA) plays a critical role in the formation of fear conditioned associative memories. Previous studies have used c-fos regulated expression to identify a spatially restricted population of neurons within the LA that is specifically activated by fear learning. These neurons are likely to be a part of a memory engram, but, to date, functional evidence for this has been lacking. We show that neurons within a spatially restricted region of the LA had an increase in both the frequency and amplitude of spontaneous postsynaptic currents (sPSC) when compared to neurons recorded from home cage control mice. We then more specifically addressed if this increased synaptic activity was limited to learning-activated neurons. Using a fos-tau-LacZ (FTL) transgenic mouse line, we developed a fluorescence-based method of identifying and recording from neurons activated by fear learning (FTL+ ) in acute brain slices. An increase in frequency and amplitude of sPSCs was observed in FTL+ neurons when compared to nonactivated FTL- neurons in fear-conditioned mice. No learning-induced changes were observed in the action potential (AP) input-output relationships. These findings support the idea that a discrete LA neuron population forms part of a memory engram through changes in synaptic connectivity. PMID- 30027113 TI - Surface-modulated palladium-nickel icosahedra as high-performance non-platinum oxygen reduction electrocatalysts. AB - The search for high-performance non-platinum (Pt) electrocatalysts is the most challenging issue for fuel cell technology. Creating bimetallic non-Pt nanocrystals (NCs) with core/shell structures or alloy features has widely been explored as the most effective way for enhancing their electrochemical properties but still suffered from undesirable performance due to the limited interactions between the different components. By addressing the above issue, we report on a new class of active and stable bimetallic non-Pt electrocatalysts with palladium (Pd) icosahedra as the core and nickel (Ni) decorating the surface toward cathodic oxygen reduction reaction (ORR) under alkaline conditions. The optimized Pd6Ni icosahedra with unique interaction between an icosahedral Pd core and surface Ni yield the highest ORR activity with a mass activity of 0.22 A mgPd-1, which is better than those of the conventional Pd6Ni icosahedra with alloy surfaces or Pd-rich surfaces, and even two times higher than that of the commercial Pt/C (0.11 A mgPt-1), representing one of the best non-Pt electrocatalysts. Simulations reveal that the Pd icosahedra decorated with Ni atoms emerged in the subsurface can weaken the interaction between the adsorbed oxygen and Pd (111) facet and enhance the ORR activities due to an obvious shift of d-band center. More significantly, under electrochemical accelerated durability test, the Pd6Ni icosahedra can endure at least 10,000 cycles with negligible activity decay and structural change. The present work demonstrates an important advance in surface tuning of bimetallic NCs as high-performance non-Pt catalysts for catalysis, energy conversion, and beyond. PMID- 30027114 TI - Addressable electron spin resonance using donors and donor molecules in silicon. AB - Phosphorus donor impurities in silicon are a promising candidate for solid-state quantum computing due to their exceptionally long coherence times and high fidelities. However, individual addressability of exchange coupled donors with separations ~15 nm is challenging. We show that by using atomic precision lithography, we can place a single P donor next to a 2P molecule 16 +/- 1 nm apart and use their distinctive hyperfine coupling strengths to address qubits at vastly different resonance frequencies. In particular, the single donor yields two hyperfine peaks separated by 97 +/- 2.5 MHz, in contrast to the donor molecule that exhibits three peaks separated by 262 +/- 10 MHz. Atomistic tight binding simulations confirm the large hyperfine interaction strength in the 2P molecule with an interdonor separation of ~0.7 nm, consistent with lithographic scanning tunneling microscopy images of the 2P site during device fabrication. We discuss the viability of using donor molecules for built-in addressability of electron spin qubits in silicon. PMID- 30027115 TI - Dissecting spin-phonon equilibration in ferrimagnetic insulators by ultrafast lattice excitation. AB - To gain control over magnetic order on ultrafast time scales, a fundamental understanding of the way electron spins interact with the surrounding crystal lattice is required. However, measurement and analysis even of basic collective processes such as spin-phonon equilibration have remained challenging. Here, we directly probe the flow of energy and angular momentum in the model insulating ferrimagnet yttrium iron garnet. After ultrafast resonant lattice excitation, we observe that magnetic order reduces on distinct time scales of 1 ps and 100 ns. Temperature-dependent measurements, a spin-coupling analysis, and simulations show that the two dynamics directly reflect two stages of spin-lattice equilibration. On the 1-ps scale, spins and phonons reach quasi-equilibrium in terms of energy through phonon-induced modulation of the exchange interaction. This mechanism leads to identical demagnetization of the ferrimagnet's two spin sublattices and to a ferrimagnetic state of increased temperature yet unchanged total magnetization. Finally, on the much slower, 100-ns scale, the excess of spin angular momentum is released to the crystal lattice, resulting in full equilibrium. Our findings are relevant for all insulating ferrimagnets and indicate that spin manipulation by phonons, including the spin Seebeck effect, can be extended to antiferromagnets and into the terahertz frequency range. PMID- 30027116 TI - Room temperature in-plane ferroelectricity in van der Waals In2Se3. AB - Van der Waals (vdW) assembly of layered materials is a promising paradigm for creating electronic and optoelectronic devices with novel properties. Ferroelectricity in vdW layered materials could enable nonvolatile memory and low power electronic and optoelectronic switches, but to date, few vdW ferroelectrics have been reported, and few in-plane vdW ferroelectrics are known. We report the discovery of in-plane ferroelectricity in a widely investigated vdW layered material, beta'-In2Se3. The in-plane ferroelectricity is strongly tied to the formation of one-dimensional superstructures aligning along one of the threefold rotational symmetric directions of the hexagonal lattice in the c plane. Surprisingly, the superstructures and ferroelectricity are stable to 200 degrees C in both bulk and thin exfoliated layers of In2Se3. Because of the in-plane nature of ferroelectricity, the domains exhibit a strong linear dichroism, enabling novel polarization-dependent optical properties. PMID- 30027117 TI - Domain Meissner state and spontaneous vortex-antivortex generation in the ferromagnetic superconductor EuFe2(As0.79P0.21)2. AB - The interplay between superconductivity and magnetism is one of the oldest enigmas in physics. Usually, the strong exchange field of ferromagnet suppresses singlet superconductivity via the paramagnetic effect. In EuFe2(As0.79P0.21)2, a material that becomes not only superconducting at 24.2 K but also ferromagnetic below 19 K, the coexistence of the two antagonistic phenomena becomes possible because of the unusually weak exchange field produced by the Eu subsystem. We demonstrate experimentally and theoretically that when the ferromagnetism adds to superconductivity, the Meissner state becomes spontaneously inhomogeneous, characterized by a nanometer-scale striped domain structure. At yet lower temperature and without any externally applied magnetic field, the system locally generates quantum vortex-antivortex pairs and undergoes a phase transition into a domain vortex-antivortex state characterized by much larger domains and peculiar Turing-like patterns. We develop a quantitative theory of this phenomenon and put forth a new way to realize superconducting superlattices and control the vortex motion in ferromagnetic superconductors by tuning magnetic domains-unprecedented opportunity to consider for advanced superconducting hybrids. PMID- 30027118 TI - Adsorbate-driven reactive interfacial Pt-NiO1-x nanostructure formation on the Pt3Ni(111) alloy surface. AB - The origin of the synergistic catalytic effect between metal catalysts and reducible oxides has been debated for decades. Clarification of this effect, namely, the strong metal-support interaction (SMSI), requires an understanding of the geometric and electronic structures of metal-metal oxide interfaces under operando conditions. We show that the inherent lattice mismatch of bimetallic materials selectively creates surface segregation of subsurface metal atoms. Interfacial metal-metal oxide nanostructures are then formed under chemical reaction environments at ambient pressure, which thus increases the catalytic activity for the CO oxidation reaction. Our in situ surface characterizations using ambient-pressure scanning tunneling microscopy and ambient-pressure x-ray photoelectron spectroscopy exhibit (i) a Pt-skin layer on the Pt-Ni alloyed surface under ultrahigh vacuum, (ii) selective Ni segregation followed by the formation of NiO1-x clusters under oxygen gas, and (iii) the coexistence of NiO1 x clusters on the Pt-skin during the CO oxidation reaction. The formation of interfacial Pt-NiO1-x nanostructures is responsible for a highly efficient step in the CO oxidation reaction. Density functional theory calculations of the Pt3Ni(111) surface demonstrate that a CO molecule adsorbed on an exposed Pt atom with an interfacial oxygen from a segregated NiO1-x cluster has a low surface energy barrier of 0.37 eV, compared with 0.86 eV for the Pt(111) surface. PMID- 30027120 TI - Correction for the Research Article: "Revealing pathways from payments for ecosystem services to socioeconomic outcomes" by H. Yang, W. Yang, J. Zhang, T. Connor and J. Liu. AB - [This corrects the article DOI: 10.1126/sciadv.aao6652.]. PMID- 30027119 TI - A new strategy to efficiently cleave and form C-H bonds using proton-coupled electron transfer. AB - Oxidative activation and reductive formation of C-H bonds are crucial in many chemical, industrial, and biological processes. Reported here is a new strategy for these transformations, using a form of proton-coupled electron transfer (PCET): intermolecular electron transfer coupled to intramolecular proton transfer with an appropriately placed cofactor. In a fluorenyl-benzoate, the positioned carboxylate facilitates rapid cleavage of a benzylic C-H bond upon reaction with even weak 1e- oxidants, for example, decamethylferrocenium. Mechanistic studies establish that the proton and electron transfer to disparate sites in a single concerted kinetic step, via multi-site concerted proton electron transfer. This work represents a new elementary reaction step available to C-H bonds. This strategy is extended to reductive formation of C-H bonds in two systems. Molecular design considerations and possible utility in synthetic and enzymatic systems are discussed. PMID- 30027121 TI - Factors influencing adherence to an app-based exercise program in adolescents with painful hyperkyphosis. AB - Background: Software applications (apps) could potentially promote exercise adherence. However, it is unclear whether adolescents with painful hyperkyphosis will use an app designed for a home exercise program. The purpose of this study is to assess factors regarding adherence to an app-based home exercise program in adolescents with hyperkyphosis and back pain who were provided a one-time exercise treatment. Methods: Twenty-one participants were instructed in a one time exercise treatment and asked to complete a home exercise program 3 times a week for 6 months using an app called PT PAL. At a 6-month follow-up, 14 participants completed a survey assessing factors related to their experiences using the app and their treatment engagement. Results: Although most participants did not use the app, they reported performing their exercises a few times per week. The adolescent participants considered the app to be more of a barrier than a supportive measure for promoting exercise adherence. Most participants still reported bothersome back pain. Conclusions: Although adherence to the 6-month app based home exercise program was not successful, adolescents still viewed technology support such as text reminders as a potential solution. Trial registration: ClinicalTrials.gov Identifier: NCT03212664. Registered 11 July 2017. Retrospectively registered. PMID- 30027122 TI - Healthcare choices in Mumbai slums: A cross-sectional study. AB - Background: Informal urban settlements, known as slums, are the home for a large proportion of the world population. Healthcare in these environments is extremely complex, driven by poverty, environmental challenges, and poor access to formal health infrastructures. This study investigated healthcare challenges faced and choices made by slum dwellers in Mumbai, India. Methods: Structured interviews with 549 slum dwellers from 13 slum areas in Mumbai, India, were conducted in order to obtain a population profile of health-related socio-economic and lifestyle factors, disease history and healthcare access. Statistical tools such as multinomial logistic regression were used to examine the association between such factors and health choices. Results: Private providers (or a mixture of public and private) were seen to be preferred by the study population for most health conditions (62% - 90% health consultations), apart from pregnancy (43% health consultations). Community-based services were also preferred to more remote options. Stark differences in healthcare access were observed between well known conditions, such as minor injuries, pulmonary conditions, and pregnancy and emerging challenges, such as hypertension and diabetes. A number of socio economic and lifestyle factors were found to be associated with health-related decisions, including choice of provider and expenditure. Conclusions: Better planning and coordination of health services, across public and private providers, is required to address mortality and morbidity in slum communities in India. This study provides insights into the complex landscape of diseases and health providers that slum dwellers navigate when accessing healthcare. Findings suggest that integrated services and public-private partnerships could help address demand for affordable community-based care and progress towards the target of universal health coverage. PMID- 30027123 TI - Life course programming of stress responses in adolescents and young adults in India: Protocol of the Stress Responses in Adolescence and Vulnerability to Adult Non-communicable disease (SRAVANA) Study. AB - Background: Early life nutrition may affect individuals' susceptibility to adult non-communicable diseases (NCD). Psychological stress is a well-recognised NCD risk factor. Recent evidence suggests that impaired foetal nutrition alters neuro endocrine pathways, and hypothalamic-pituitary-adrenal axis feedback systems, resulting in abnormal stress responses, and NCD risk. This study aims to examine adolescent cortisol and cardiovascular stress responses in relation to maternal nutrition and contemporaneous NCD risk markers. Methods: The study sample will be drawn from three well-established birth cohorts in India; the Parthenon cohort, Mysore (N=550, age~20y), the SARAS KIDS prenatal intervention cohort, Mumbai (N=300, age~10-12y) and the Pune Rural Intervention in Young Adults/ PRIYA cohort, Pune (N=100, age~22y). We will perform the 'Trier Social Stress Test (TSST)', a well-accepted stress-test module which involves participants performing 5-minutes each of public speaking and mental arithmetic tasks in front of unfamiliar 'judges' (stressor). Repeated measures of salivary cortisol and autonomic cardiovascular outcomes relative to the stressor will be assessed. Measures of psychological stress, cognitive function, blood pressure, glucose insulin metabolism and depression will be carried out. Mechanistic studies including DNA methylation in gluco-corticoid receptor ( NR3C1) and 11beta-HSD2 gene loci and neuroimaging will be carried out in a subsample. Qualitative interviews and focus group discussions in a subsample of the Parthenon cohort will explore the perception of stress and stressors among the youth. We will convert repeated measures into time-weighted averages before analysis. We will carry out multivariable regression analysis to test the associations. We will further refine the analyses using the mixed-model regression and conditional analyses for the association with repeated measures. Ethics and dissemination: This study has been approved by the research ethics committee of CSI Holdsworth Memorial Hospital, Mysore. The findings will be disseminated locally and at international meetings, and reports will be submitted to open access peer reviewed journals. PMID- 30027126 TI - Radiologic and endoscopic findings of intramural esophageal dissection combined with gastric mucosal dissection. PMID- 30027124 TI - Trends and birth outcomes in adolescent refugees and migrants on the Thailand Myanmar border, 1986-2016: an observational study. AB - Background: Currently there are more adolescents (10-19 years old) and young adults (20-24 years old) than ever. Reproductive health among this age group is often overlooked, although it can have a profound impact on the future. This is especially the case in conflict zones and refugee settings, where there is a heightened need for reproductive health care, and where both the resources and possibility for data collation are usually limited. Methods: Here we report on pregnancies, birth outcomes and risk factors for repeat pregnancies among adolescent and young adult refugees and migrants from antenatal clinics on the Thailand-Myanmar border across a 30 year time span. Results: Pregnancy and fertility rates were persistently high. Compared with 20-24-year-olds, 15-19-year olds who reported being unable to read had 2.35 (CI: 1.97 - 2.81) times the odds for repeat pregnancy (gravidity >2). In primigravidae, the proportion of small for gestational age (SGA) and preterm births (PTB), and neonatal deaths (NND) decreased with increasing maternal age (all p <0.001). After adjustment, this association retained significance for PTB (cut-off point, <=18 years) but not for SGA and NND. Conclusions: There is considerable room for improvement in adolescent pregnancy rates in these border populations, and educational opportunities may play a key role in effective interventions. PMID- 30027125 TI - Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda. AB - Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27) amongst those with a known outcome. Adjusting for definite TBM diagnosis and antiretroviral therapy use, and using imputed data, assuming 50% of those with an unknown outcome died, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three. Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: As TBM diagnostics have improved, microbiologically-confirmed TBM diagnoses have increased and in-hospital mortality has declined. Yet, mortality due to TB meningitis remains unacceptably high and further measures are needed to improve outcomes from TBM in Uganda. PMID- 30027127 TI - Different endoscopic management of 2 cases of acute buried bumper syndrome. PMID- 30027128 TI - EUS-guided drainage of hepatic abscess in the right side of the liver of a patient with Chilaiditi syndrome. PMID- 30027129 TI - EUS-guided biliary drainage for internalization of percutaneous transhepatic biliary drainage. PMID- 30027130 TI - Hemostatic powder: a new ally in the management of postsphincterotomy bleeding. PMID- 30027131 TI - The use of a lumen-apposing metal stent for a short malignant duodenal stricture in a patient with a coexisting metal biliary stent. PMID- 30027132 TI - Esophageal stent placement without optical or fluoroscopic visualization. PMID- 30027133 TI - Endoscopic diagnosis of paraesophageal hernia with gastric volvulus. PMID- 30027134 TI - Successful EUS-guided nondilated pancreatic duct stent placement in patient with refractory pancreatic fistula after pancreaticoduodenectomy. PMID- 30027135 TI - Successful obliteration of bleeding duodenal varices by EUS-guided injection of N butyl-2-cyanoacrylate. PMID- 30027136 TI - Self-expandable metal stent through the tumor to treat an intestinal obstruction due to pancreatic squamous cell carcinoma. PMID- 30027137 TI - Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes. AB - Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of insulin resistance, which is the hallmark of type 2 diabetes (T2D). NAFLD is a known risk factor for developing T2D and has a very high prevalence in those with existing T2D. The diabetes spectrum includes several conditions from prediabetes to T2D to insulin-dependent diabetes leading to macrovascular and microvascular complications. Similarly, NAFLD has a histologic spectrum that ranges from the relatively benign nonalcoholic fatty liver to the aggressive form of nonalcoholic steatohepatitis with or without liver fibrosis to nonalcoholic steatohepatitis cirrhosis leading to end-stage liver disease. The management of T2D has witnessed significant changes over the past few decades with multiple new drug classes entering the treatment algorithm. Unfortunately, there are no U.S. Food and Drug Administration-approved medications to treat NAFLD, and guidelines for the management of NAFLD are less established. However, the field of drug development in NAFLD has witnessed a revolution over the past 5 years with the establishment of a regulatory pathway for Food and Drug Administration approval; this has generated substantial interest from pharmaceutical companies. Several diabetes medications have been studied as potential treatments for NAFLD with promising results; moreover, drugs that target specific pathways that play a role in NAFLD development and progression are being developed at a rapid pace. Given the similarities between NAFLD and T2D in terms of pathogenesis, underlying risk factors, and disease spectrum, lessons learned from optimizing treatment for T2D can be extrapolated to the management of NAFLD. The aim of this review is to use the founding principles of the comprehensive type 2 diabetes management algorithm to optimize the management of NAFLD. (Hepatology Communications 2018;2:778-785). PMID- 30027138 TI - Patatin-like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events. AB - Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin-like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss-of-function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well-established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low-density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile. (Hepatology Communications 2018;2:798-806). PMID- 30027139 TI - Metabolomic-based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 +/- 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 +/- 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 +/- 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy. (Hepatology Communications 2018;2:807-820). PMID- 30027140 TI - Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP-305, a novel farnesoid X receptor agonist. AB - We examined a novel farnesoid X receptor agonist, EDP-305, for its antifibrotic effect in bile duct ligation (BDL) and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) models of hepatic injury. We used molecular magnetic resonance imaging with the type 1 collagen-binding probe EP-3533 and the oxidized collagen-specific probe gadolinium hydrazide to noninvasively measure treatment response. BDL rats (n = 8 for each group) were treated with either low or high doses of EDP-305 starting on day 4 after BDL and were imaged on day 18. CDAHFD mice (n = 8 for each group) were treated starting at 6 weeks after the diet and were imaged at 12 weeks. Liver tissue was subjected to pathologic and morphometric scoring of fibrosis, hydroxyproline quantitation, and determination of fibrogenic messenger RNA expression. High-dose EDP-305 (30 mg/kg) reduced liver fibrosis in both the BDL and CDAHFD models as measured by collagen proportional area, hydroxyproline analysis, and fibrogenic gene expression (all P < 0.05). Magnetic resonance signal intensity with both EP-3533 in the BDL model and gadolinium hydrazide in the CDAHFD model was reduced with EDP-305 30 mg/kg treatment (P < 0.01). Histologically, EDP-305 30 mg/kg halted fibrosis progression in the CDAHFD model. Conclusion: EDP-305 reduced fibrosis progression in rat BDL and mouse CDAHFD models. Molecular imaging of collagen and oxidized collagen is sensitive to changes in fibrosis and could be used to noninvasively measure treatment response in clinical trials. (Hepatology Communications 2018;2:821-835). PMID- 30027141 TI - Dominant strictures in primary sclerosing cholangitis: A multicenter survey of clinical definitions and practices. AB - Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC associated DSs. We conducted an anonymous, 23-question, survey-based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow-up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Conclusion: Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence-based consensus, and increase adherence to societal guidelines. (Hepatology Communications 2018;2:836 844). PMID- 30027142 TI - Endothelial Wnts regulate beta-catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt-Wnt situation. AB - beta-Catenin in hepatocytes, under the control of Wnts, regulates pericentral gene expression. It also contributes to liver regeneration (LR) after partial hepatectomy (PH) by regulating cyclin-D1 gene expression as shown in the beta catenin and Wnt coreceptors low-density lipoprotein receptor-related protein 5/6 conditional knockouts (KO). However, conditional deletion of Wntless (Wls), required for Wnt secretion, in hepatocytes, cholangiocytes, or macrophages lacked any impact on zonation, while Wls deletion in macrophages only marginally affected LR. Here, we address the contribution of hepatic endothelial cells (ECs) in zonation and LR by characterizing EC-Wls-KO generated by interbreeding Wls floxed and lymphatic vessel endothelial hyaluronan receptor (Lyve1)-cre mice. These mice were also used to study LR after PH. While Lyve1 expression in adult liver is limited to sinusoidal ECs only, Lyve1-cre mice bred to ROSA26 Stopflox/flox-enhanced yellow fluorescent protein (EYFP) mice showed EYFP labeling in sinusoidal and central vein ECs. EC-Wls-KO mice showed decreased liver weights; lacked glutamine synthetase, cytochrome P450 2e1, and cytochrome P450 1a2; and were resistant to acetaminophen-induced liver injury. After PH, EC Wls-KO showed quantitative and qualitative differences in cyclin-D1 expression at 24-72 hours, which led to a lower hepatocyte proliferation at 40 hours but a rebound increase by 72 hours. ECs and macrophages isolated from regenerating livers at 12 hours showed significant up-regulation of Wnt2 and Wnt9b messenger RNA; these are the same two Wnts involved in baseline beta-catenin activity in pericentral hepatocytes. Conclusion: At baseline, ECs secrete Wnt proteins essential for beta-catenin activation in pericentral hepatocytes. During LR, sinusoidal and central vein ECs and secondarily macrophages secrete Wnt2, while predominantly central vein ECs and secondarily macrophages are the likely source of Wnt9b. This process spatiotemporally regulates beta-catenin activation in hepatocytes to induce cell proliferation. (Hepatology Communications 2018;2:845 860). PMID- 30027143 TI - MicroRNA-26-5p functions as a new inhibitor of hepatoblastoma by repressing lin 28 homolog B and aurora kinase a expression. AB - Hepatoblastoma (HB) is the most common liver tumor in children. Despite recent improvements in treatment strategies, the survival of children with hepatoblastoma remains poor. In this study, we identified a novel role of microRNA-26a-5p (miR-26a-5p), lin-28 homolog B (LIN28B), Ras-related nuclear protein (RAN), and aurora kinase A (AURKA) in HB. The expression of LIN28B, RAN, and AURKA was significantly up-regulated in human HB livers and cell lines. Knockdown of LIN28B and RAN by small interfering RNAs inhibited HB tumor cell proliferation and foci formation. We also elucidated miR-26a-5p-mediated translational inhibition of LIN28B and AURKA in HB. Overexpression of miR-26a-5p markedly decreased LIN28B and AURKA 3'-untranslated region activities and protein expression and repressed HB cell proliferation and colony formation. In contrast, re-expression of LIN28B and AURKA rescued miR-26a-5p-mediated suppression of HB cell growth and clonality. Importantly, a decreased miR-26a-5p expression correlated with the poor outcome of patients with HB. Conclusion: miR-26a-5p is a newly identified repressor of HB growth through its inhibition of the oncogenic LIN28B-RAN-AURKA pathway. (Hepatology Communications 2018;2:481-491). PMID- 30027145 TI - Granulocyte-colony stimulating factor may improve pregnancy outcome in patients with history of unexplained recurrent implantation failure: An RCT. AB - Background: Family of colony-stimulating factors (CSF) have an essential role on early cross talk between embryo and uterine endometrium. Objective: The aim of this study was to evaluate the effects of the single dose of Granulocyte-CSF (G CSF) injection on clinical outcome of assisted reproductive technology cycle in patients with repeated implantation failures. Materials and Methods: This randomized control trial study was performed on 52 infertile women who referred to the clinic with the history of more than three previous In vitro fertilization/Intracytoplasmic sperm injection-embryo transfer failures. All patients were stimulated with standard long protocol. All embryos were transferred on day five in blastocyst stage in both groups. The treated group received 300 ug (0.5 ml) recombinant human G-CSF subcutaneously which was injected 30 min before blastocyst embryo transfer. Results: There was not statistically significant differences in abortion rate in G-CSF and control group (p=0.09). G-CSF treated group showed higher clinical pregnancy rate in comparison with control group (56.2% vs. 40.0%) but it was not statistically significant (p=0.09). Although live birth rate in G-CSF group was higher than control group (53.1% vs. 35.0%) but there wasn't statistically significant difference in the overall live birth rate between the two groups (p=0.10). G-CSF group had a twin pregnancies while in control group there was no twin pregnancy. Conclusion: Our result demonstrates the possibility that pregnancy outcome is better in women with repeated unexplained In vitro fertilization failure who are treated with G CSF. PMID- 30027144 TI - Detection of Somatic Structural Variants Enables Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors. AB - Objective: Liquid biopsies are being rapidly used in adult cancers as new biomarkers of disease. Circulating tumor DNA (ctDNA) levels have been reported to be proportional to disease burden, correlate with treatment response, and predict relapse. However, little is known about how frequently ctDNA is detectable in pediatric patients with solid tumors. Therefore, we developed a next-generation sequencing approach to detect and quantify ctDNA in the blood of patients with the most common pediatric solid tumors. Methods: Detection of ctDNA requires assays sensitive to somatic events typically observed in the cancer type being studied. In pediatric solid tumors, structural variants are more common than recurrent point mutations. We adapted an ultralow passage whole-genome sequencing approach to capture copy number variants and a hybrid capture sequencing assay to detect translocations in liquid biopsy samples from pediatric patients. Results: Copy number changes seen by ultralow passage whole-genome sequencing enabled detection of ctDNA in patients with osteosarcoma, neuroblastoma, alveolar rhabdomyosarcoma, and Wilms tumor. In Ewing sarcoma, detection of the EWSR1 translocation was a more sensitive approach. For patients with samples collected at multiple time points, changes in ctDNA levels corresponded to treatment response. We also found that disease-specific genomic biomarkers of prognosis were detectable in ctDNA. Conclusion: This study demonstrates that liquid biopsy approaches that detect somatic structural variants are well suited to pediatric solid tumors. We show that children with the most common solid tumor malignancies have detectable levels of ctDNA, which may be used to track disease response and identify genomic subclassifiers of disease. Efforts to profile larger collections of clinically annotated specimens are under way to validate the clinical use of these assays. PMID- 30027146 TI - Effect of the estrus cycle stage on the establishment of murine endometriosis lesions. AB - Background: Establishment of a standardized animal endometriosis model is necessary for evaluation of new drug effects and for explaining different ethological aspects of this disease. For this purpose, we need a model which has more similarity to human endometriosis. Objective: Our objective was to establish an autologous endometriosis mouse model based on endogenous estrogen level and analyze the influence of estrus cycle on the maintenance of endometriotic lesions. Materials and Methods: In this experimental study, endometriotic lesions were induced in 52 female NMRI mice by suturing uterine tissue samples to the abdominal wall. The transplantation was either performed at proestrus/estrus or at metestrus/diestrus cycles. Urine-soaked beddings from males and also male vasectomized mice were transferred to the cages to synchronize and maintenance of estrus cycle in female mice. The mice were sacrificed after different transplantation periods (2, 4, 6 or 8 wk). The lesions size, macroscopic growth, model success rate, histological and immune-histochemical analyses were assessed at the end. Results: From a total of 200 tissue samples sutured into the peritoneal cavity, 83 endometriotic lesions were confirmed by histopathology (41.5%). Model success rate for proestrus/estrus mice was 60.7% vs. 79.2% for metestrus/diestrus mice. The endometriotic lesions had similar growth in both groups. Number of caspase-3, Ki67-positive cells and CD31-positive micro vessels were also similar in endometriotic lesions of two groups. Conclusion: If we maintain the endogenous estrogen levels in mice, we can induce endometriosis mouse model in both proestrus/estrus and metestrus/diestrus cycle without any significant difference. PMID- 30027148 TI - Atorvastatin attenuates the ovarian damage induced by cyclophosphamide in rat: An experimental study. AB - Background: Cyclophosphamide (CP), as an anticancer agent, causes ovarian toxicity and subsequent infertility in women. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. Objective: The aim of this study was to investigate the protective effect of ATV against CP-induced ovarian injury in rat. Materials and Methods: In this experimental study, thirty-two female Wistar rats were randomly divided into four groups as I) control, II) ATV (10 mg/kg), III) CP (150 mg/kg), and IV) CP +ATV. The ATV treated groups were received ATV for 10 days via oral gavage. In the CP+ATV group, ATV was administrated on 5 days before and 5 days after CP injection. Histological structure, apoptosis (caspase-3), oxidative stress parameters as malondialdehyde, reactive oxygen species, protein carbonyl levels and cell viability were evaluated in ovary tissue by histological scores, immunohistochemistry, histochemical and biochemical assays. The levels of estrogen and progesterone hormones were measured on the 12th day of study. Results: ATV pretreatment significantly decreased the levels of oxidative stress biomarkers as malondialdehyde, reactive oxygen species and protein carbonyl levels and increased cell death in CP-treated rats as compared with the CP alone group. ATV significantly increased estrogen and progesterone levels in CP-treated rats. In addition, the histological examination showed ATV mitigated acute inflammation, degenerative cells in stroma and follicles, stromal edema, vacuolization, atresia of the follicles and congestion of blood vessels in the CP-treated animals. Furthermore, ATV significantly reduced immunoreactivity level of caspase-3 in CP treated rats. Conclusion: Our results showed that the ATV with antioxidant and anti-apoptosis (caspase-3) activities protected ovarian against CP-induced toxicity. PMID- 30027147 TI - Troxerutin protect sperm, seminiferous epithelium and pituitary-gonadal axis from torsion-detorsion injury: An experimental study. AB - Background: Troxerutin is a flavonoid antioxidant that protect different organ against damage caused by ischemia-reperfusion. Objective: The aim of this study was to evaluate the effect of troxerutin in reducing the damages caused by ischemia-reperfusion in rat's testis. Materials and Methods: 40 Male Wistar rats (2 month old) were divide to four groups (n=10). Group1 (sham), Group 2 (control, ischemia-reperfusion (I/R) without treatment), Group 3 (I/R+150 mg/kg of troxerutin), and group 4 (I/R+20 mg/kg of vitamin C). Treatment of group 3 and group 4 during torsion (twists 720 counter clock at 90 min) followed by 50 days detorsion. After 50 days, blood samples were collected and rats in all study groups were killed and their testes were removed, and fixed with Bouin's solution. Testis was stained with hematoxylin and eosin dye and the level of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured with ELISEA methods. TUNEL was employed to detect apoptosis. Epididymis caudal part was removed and total sperm count was determined. Johnson techniques were used for assessment of seminiferous tubules quality. Results: Troxerutin treated group has higher Johnson score's (p<=0.001), antiapoptotic properties (p<=0.001), sperm count (p=0.065), and higher LH (p<=0.001), FSH (p<=0.001) and testosterone (p=0.002) levels than control group. Vitamin C treated group showed increase level of testosterone but didn't show significant differences on the number of apoptotic cells, Johnson scores, LH, FSH and sperm count than control group. Conclusion: Troxerutin has protective effects on testicular torsion induced injury and can ameliorate spermatogenesis in the torsion-detorsion models. PMID- 30027149 TI - In vitro antiapoptotic effects of the calligonum extract on spermatogonial stem cells. AB - Background: Spermatogonial stem cells are the foundation of spermatogenesis and male fertility. So, their maintenance and culture are very important. Objective: In this study, we assessed protective effects of the Calligonum on in vitro viability and apoptotic and antiapoptotic genes expression of spermatogonial stem cells. Materials and Methods: After 24 hr of culture, the spermatogonial stem cells were treated with 30 MUM dose of H2O2 and then 10 MUg/ml the Calligonum extract was added for 3 wks. Viability was assessed by Trypan blue, apoptosis using PI-Annexin and finally Bax, Bcl-2 and P53 genes expression by Real-Time Polymerase chain reaction. Results: After 3 wk of treatment, viability in the Calligonum extract+H2O2 group was significantly higher than H2O2 group alone (p=0.001). In the Calligonum extract+H2O2 group, apoptosis, as well as expression of apoptotic genes (Bax and P53), was significantly lower than the group treated with H2O2 alone. Conclusion: The results of this study showed that 30 MUM H2O2 increased apoptosis but decreased viability in spermatogonial stem cells. Calligonum has antioxidant properties that can reduce apoptosis, Bax and P53 expression and increase the viability and Bcl-2 expression. PMID- 30027150 TI - Cervical bacterial colonization in women with preterm premature rupture of membrane and pregnancy outcomes: A cohort study. AB - Background: One of the most important etiologies in pretermpremature rupture of membranes (PPROM) is cervical bacterial colonization. Objective: This study evaluated cervical bacterial colonization in women with PPROM and the pregnancy outcomes. Materials and Methods: In this cohort study, 200 pregnant women with PPROM at 27-37 wk of gestation who were admitted in an academic hospital of Mashhad University of Medical Sciences from March 2015 to July 2016 were studied. samples were obtained from endocervical canal for detection of routine bacteria and Gram staining. Also, we obtained one blood culture from neonates. Maternal endocervical culture, chorioamnionitis, neonatal intensive care unit admission, neonatal positive blood culture, neonatal sepsis, and mortality were documented. Results: Most common isolated microorganism of endocervical culture were Escherichia coli (24.2%), Coagulase negative Staphylococci (27.2%), Enterococcus and candida each one (11.7%). The prevalence of GBS was only 2.2%. Simultaneous positive blood cultures were seen in 3% of neonates. Among them, Gram-negative bacilli accounted for (66.6%), while Gram-positive cocci and candida made up only (16.7%). Endocervical colonization was associated with a higher admission rate (p=0.004), but there was no significant correlation between endocervical colonization and chorioamnionitis, positive blood culture and neonatal mortality rate. Conclusion: With regard to low GBS colonization rate, appropriate antibiotic regimens should be considered in PPROM cases according to the most prevalent micro organisms of endocervical bacterial colonization. Maybe cervical bacterial colonization had some effects on neonatal outcomes. There was no significant association between endocervical bacterial colonization and chorioamnionitis, positive neonatal blood culture and neonatal mortality. PMID- 30027152 TI - The role of conception type in the definition of primary and secondary infertility. PMID- 30027151 TI - Elements associated with Iranian women's sexual behaviours: A cross-sectional study. AB - Background: Women constitute about half of the Iranian population. Sexual behaviour is one of the most important elements in their lives. Identifying the elements associated with sexual behaviours seems necessary in order to draw a thorough picture of Iranian women's sexuality. Objective: To elicit information from Iranian women at their reproductive ages on sexual behaviours related to their elements including sexual capacity, sexual motivation, performance and sexual scripts. Materials and Methods: Study participants involved 295 women at reproductive age from five different cities. Women completed a national self reporting questionnaire on elements related to sexual behaviours. The elements included sexual capacity, sexual motivation, sexual performance, and sexual script. Pearson's correlation variance analysis and multi-linear regression were used to analyze data. Results: Significant positive correlation was found between the sexual capacity, motivation, performance, and sexual script (p<0.001). Linear regression showed that the effective variable on the sexual performance were women's ages (p=0.02), and tertiary education (p=0.05). A significant association was found between age and sexual motivation score, too. A significant relation was observed between the history of pregnancy and level of education with a positive response to sexual script questions. Conclusion: Identifying the elements of sexual behaviours would help women understand their sexual behaviours and related influencing factors. Therefore, enrichment of women's sexuality is needed; also a well-planned educational program is a need for women to understand their sexuality-related potentials. PMID- 30027153 TI - A rare case of bilateral spontaneous indirect caroticocavernous fistula treated previously as a case of conjunctivitis. AB - Carotid cavernous fistula is an abnormal communication between the carotid arterial system and the cavernous sinus. We present an interesting, rare case of bilateral spontaneous 'Barrow type- C' fistula treated presumptively as conjunctivitis. A 66 year old patient presented in the eye casualty at North Devon District Hospital in January 2016, referred from her General practitioner complaining of bilateral red eyes. She was found to have large, prominently diffused and engorged scleral blood vessels on both sides along with raised intraocular pressures of 26mm of Hg bilaterally. The patient was diagnosed with an indirect carotic cavernous fistulas bilaterally in view of the clinical and radiology findings. Barrow type - C dural fistulas were reported to be seen bilaterally on radiology findings. Patient was referred for interventional treatment to the closest neurosurgical center where she had four failed attempts of coil embolization after which she was referred to a second neurosurgery center at Bristol where she underwent successful coil catheterization as the treatment for her carotid cavernous fistula. Indirect carotid cavernous fistula most commonly occur spontaneously. Bilateral spontaneous indirect carotid cavernous fistula is a very rare diagnosis and and there are very few cases reported in the literature without an underlying etiology or a known cause like Ehlers -Danlos syndrome or diabetes mellitus. Bilateral spontaneous carotid cavernous fistulas are difficult to diagnose due to mild symptoms and no history of trauma. We conclude that carotid cavernous fistulas are a threat to the vision if left untreated due to delayed diagnosis. We recommend considering bilateral carotid cavernous fistula as a differential diagnosis in patients with an ongoing history of red eyes or those unresponsive to conventional topical treatment for conjunctivitis like symptoms. PMID- 30027154 TI - Diacylglycerol kinase zeta (DGKzeta) and Casitas b-lineage proto-oncogene b deficient mice have similar functional outcomes in T cells but DGKzeta-deficient mice have increased T cell activation and tumor clearance. AB - Targeting negative regulators downstream of the T cell receptor (TCR) represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase zeta (DGKzeta), a regulator of Ras and PKC-theta signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKzeta, Cbl-b, or both (double knockout, DKO) in T cells, and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model. We found that whereas deletion of Cbl-b primarily served to enhance NF-kappaB signaling, deletion of DGKzeta enhanced TCR mediated signal transduction downstream of Ras/Erk and NF-kappaB. Deletion of DGKzeta or Cbl-b comparably enhanced CD8+ T cell functional responses, such as proliferation, production of IFNgamma, and generation of granzyme B when compared with WT T cells. DKO T cells demonstrated enhanced function above that observed with single knockout T cells after weak, but not strong, stimulation. Deletion of DGKzeta, but not Cbl-b, however, resulted in significant increases in numbers of activated (CD44hi) CD8+ T cells in both non-treated and tumor-bearing mice. DGKzeta-deficient mice also had enhanced control of pancreatic tumor cell growth compared to Cbl-b-deficient mice. This represents the first direct comparison between mice of these genotypes and suggests that T cell immunotherapies may be better improved by targeting TCR signaling molecules that are regulated by DGKzeta as opposed to molecules regulated by Cbl-b. PMID- 30027156 TI - Speed-Dial: A Surrogate Mouse for Non-Visual Web Browsing. AB - Sighted people can browse the Web almost exclusively using a mouse. This is because web browsing mostly entails pointing and clicking on some element in the web page, and these two operations can be done almost instantaneously with a computer mouse. Unfortunately, people with vision impairments cannot use a mouse as it only provides visual feedback through a cursor. Instead, they are forced to go through a slow and tedious process of building a mental map of the web page, relying primarily on a screen reader's keyboard shortcuts and its serial audio readout of the textual content of the page, including metadata. This can often cause content and cognitive overload. This paper describes our Speed-Dial system which uses an off-the-shelf physical Dial as a surrogate for the mouse for non visual web browsing. Speed-Dial interfaces the physical Dial with the semantic model of a web page, and provides an intuitive and rapid access to the entities and their content in the model, thereby bringing blind people's browsing experience closer to how sighted people perceive and interact with the Web. A user study with blind participants suggests that with Speed-Dial they can quickly move around the web page to select content of interest, akin to pointing and clicking with a mouse. PMID- 30027155 TI - Live-Cell Imaging of Chromatin Condensation Dynamics by CRISPR. AB - The spatiotemporal organization of chromatin plays central roles in cellular function. The ribosomal DNA (rDNA) chromatin undergoes dynamic structural changes during mitosis and stress. Here, we developed a CRISPR-based imaging system and tracked the condensation dynamics of rDNA chromatin in live yeast cells under glucose starvation. We found that acute glucose starvation triggers rapid condensation of rDNA. Time-lapse microscopy revealed two stages for rDNA condensation: a "primary stage," when relaxed rDNA chromatin forms higher order loops or rings, and a "secondary stage," wehen the rDNA rings further condense into compact clusters. Twisting of rDNA rings accompanies the secondary stage. The condensin complex, but not the cohesin complex, is required for efficient rDNA condensation in response to glucose starvation. Furthermore, we found that the DNA helicase Sgs1 is essential for the survival of cells expressing rDNA bound dCas9, suggesting a role for helicases in facilitating DNA replication at dCas9-binding sites. PMID- 30027157 TI - The New Classes of Synthetic Illicit Drugs Can Significantly Harm the Brain: A Neuro Imaging Perspective with Full Review of MRI Findings. AB - Synthetic drugs contain substances that are pharmacologically similar to those found in traditional illicit drugs. Some of the most commonly abused synthetic drugs include synthetic marijuana, bath salts, ecstasy, N-bomb, methamphetamine and anabolic steroids. Many of them share the same chemical properties and physiologic responses with the drugs they mimic and may exaggerate the pathologic response in the brain leading to addiction. These drugs have detrimental (and often irreversible) effects on the brain and primarily affect the central nervous system by two mechanisms: 1) Neural hyper stimulation via increasing activation of certain neurotransmitters (norepinephrine, dopamine, and serotonin), 2) Cause significant reduction in CNS neural connectivity affecting various brain regions such as the basal ganglia, hippocampus, cerebellum, parietal lobe, and globus pallidus. Furthermore these drugs sometimes have severe, life-threatening adverse effects on the human body. A few structural MRI studies have been conducted in synthetic drug abusers to reveal the effects of these drugs on the brain parenchyma. This review article will describe the potential brain imaging findings in synthetic drug abusers as demonstrated by several case reports and the primary literature. PMID- 30027158 TI - "It's hard to argue with a computer:" Investigating Psychotherapists' Attitudes towards Automated Evaluation. AB - We present CORE-MI, an automated evaluation and assessment system that provides feedback to mental health counselors on the quality of their care. CORE-MI is the first system of its kind for psychotherapy, and an early example of applied machine-learning in a human service context. In this paper, we describe the CORE MI system and report on a qualitative evaluation with 21 counselors and trainees. We discuss the applicability of CORE-MI to clinical practice and explore user perceptions of surveillance, workplace misuse, and notions of objectivity, and system reliability that may apply to automated evaluation systems generally. PMID- 30027159 TI - Write-it-Yourself with the Aid of Smartwatches: A Wizard-of-Oz Experiment with Blind People. AB - Working with non-digital, standard printed materials has always been a challenge for blind people, especially writing. Blind people very often depend on others to fill out printed forms, write checks, sign receipts and documents. Extant assistive technologies for working with printed material have exclusively focused on reading, with little to no support for writing. Also, these technologies employ special-purpose hardware that are usually worn on fingers, making them unsuitable for writing. In this paper, we explore the idea of using off-the-shelf smartwatches (paired with smartphones) to assist blind people in both reading and writing paper forms including checks and receipts. Towards this, we performed a Wizard-of-Oz evaluation of different smartwatch-based interfaces that provide user-customized audio-haptic feedback in real-time, to guide blind users to different form fields, narrate the field labels, and help them write straight while filling out these fields. Finally, we report the findings of this study including the technical challenges and user expectations that can potentially inform the design of Write-it-Yourself aids based on smartwatches. PMID- 30027160 TI - Short-term and Long-lasting Effects of Hypo-Cariogenic Dietary Advice and Oral Care on Oral Flora: a Randomised Clinical Trial. AB - PURPOSE: To investigate the short- and long-term effects of different combinations of dietary instructions on cariogenic food intake and salivary cariogenic bacteria (Streptococcus mutans [SM] and Lactobacillus [LB]). MATERIALS AND METHODS: In this randomised 2-arm parallel study, 75 6-year-old subjects were assigned to repeated (group A; 19M/19F) or isolated (group B; 17M/20F) verbal and/or written dietary advice (VWDA), with foods classified by cariogenic potential. Both groups underwent a baseline salivary test for SM/LB, kept a monthly food diary, and attended 4 weekly visits (T1-T4). At T1-T2; group A only received VDA. At T3, both groups received VWDA. At T4, participants handed in their food diaries and underwent another salivary test. After 1 year (T5), subjects were recalled for weekly food diary monitoring and salivary testing. Relative risk (RR) of high-to-low SM/LB density was calculated at T4 and T5. RESULTS: Comparing groups A and B, VDA determined an increase in the intake of weakly cariogenic food (p < 0.05) and a decrease in that of intermediately cariogenic food (p < 0.05). After VWDA, a statistically significant increase in intake of weakly cariogenic food and a statistically significant decrease in the RR of high-density SM/LB colonies occurred in both groups. At T5, group A showed less intake of highly cariogenic food than did group B (p = 0.05) and persistent, although non-significant, reduction in the RR of high-density SM/LB colonies. CONCLUSIONS: Reinforcement measures on behavioural changes towards a noncariogenic diet not only help maintain long-lasting, healthier eating habits, but also decrease the cariogenic bacterial load in the short term, which tends to persist over time. PMID- 30027161 TI - Editorial: Branding Periodontal Health - Supporting a Healthy Lifestyle. PMID- 30027162 TI - Association Between the Severity of Malocclusion, Assessed by Occlusal Indices, and Oral Health Related Quality of Life: A Systematic Review and Meta-Analysis. AB - PURPOSE: To assess whether different levels of malocclusion have different effects on the oral health-related quality of life (OHRQoL) and which domains of OHRQoL could be affected. MATERIALS AND METHODS: Nine electronic databases were searched. To make studies comparable, studies using the Child Perceptions Questionnaire (CPQ) to measure OHRQoL, and the Dental Aesthetic Index, Index of Orthodontic Treatment Need, and Index of Complexity, Outcome and Need to measure malocclusion were selected for systematic review. Meta-analysis was performed to calculate the weighted mean scores of CPQ. The two independent samples t-test was used to detect whether different severity groups of malocclusion have different CPQ scores. RESULTS: A total of 22 studies were included in this review and 6 were included in the meta-analysis. Most studies used a cross-sectional design and convenience sampling. Meta-analysis showed that the weighted mean scores of CPQ increased with malocclusion severity. The t-test showed nearly all levels of malocclusion affected the domains of functional limitation and social well-being; only very severe malocclusion affected the domains of oral symptoms, emotional well-being and the overall OHRQoL (p < 0.05). CONCLUSION: When OHRQoL was assessed by CPQ11-14 and malocclusion was assessed by orthodontic indices, children with malocclusion could have oral functional limitations and worse social lives; children with very severe malocclusion could further develop oral symptoms and had worse emotional experiences. Future longitudinal population based studies would be helpful to confirm these results. PMID- 30027164 TI - Clinical Outcomes of Lithium Disilicate Single Crowns after a Mean Duration of 3 Years - A Retrospective Study. AB - PURPOSE: To investigate the clinical performance and clinical survival rate of lithium disilicate-based core ceramic (IPS e.max Press) utilised in single crowns and to the accompanying periodontal health status. MATERIALS AND METHODS: A total of 47 patients with 88 IPS e.max Press single crowns were examined at the Faculty of Dentistry, University of Malaya, using modified United States Public Health Service evaluation criteria (USPHS). These 88 crowned teeth included 19 vital and 69 nonvital teeth that were restored with different post and core materials. The periodontal status was compared using the plaque index (PI), gingival recession (GR), modified papillary bleeding index (MPBI) and probing pocket depth (PPD) between the crowned teeth and contralateral control (sound) teeth. RESULTS: About 96.6% of the crowns exhibited satisfactory clinical performance. The mean survival rate at three years was 97.7%, and 100% at two years with a low incidence of fractures. There were no staitistically significant differences in the mean gingival recession (p = 0.182) and mean plaque scores (p = 0.102) between crowned and control teeth. The crowned teeth had higher mean MPBI (p = 0.000) and PPD (p = 0.051) compared to the contralateral sound teeth. Periodontal response in relation to subgingival crown margins, was statistically significantly lower regarding pocket depths (p = 0.01) and bleeding on probing (p = 0.00). CONCLUSION: IPS e.max Press crowns exhibited satisfactory clinical performance with high survival rate. No dentinal sensitivity was recorded. Plaque retention and gingival recession were similar to contralateral control teeth. Poor periodontal health was related to the subgingival crown margins. PMID- 30027163 TI - Oral Health-Related Quality of Life Among a Portuguese Sample of Institutionalised Alcoholic Patients under Rehabilitation Therapy. AB - PURPOSE: To assess the self-reported Oral Health Related Quality of Life (OHRQoL) among institutionalised patients in an alcoholic detoxification programme in northern Portugal. MATERIALS AND METHODS: This analytical cross-sectional study using the Oral Health Impact Profile-49 (OHIP-49) was carried out in 300 individuals institutionalised for alcohol detoxification in withdrawal units. The seven OHIP-49 domain scores and three summary indicators were examined: 'Prevalence' (percentage of people reporting one or more of 49 items at least 'fairly often'), 'Extent' (number of impacts [items] reported at least 'fairly often') and 'Severity' (mean sum of the participants' OHIP score). RESULTS: The sample comprised 83.3% males with a mean age of 44 +/- 8.6 years and an abusive alcoholic consumption history of 21.2 +/- 11.5 years. The results show a 'prevalence' of 62.4% (95% CI: 56.7%-67.7%), the mean 'extent' was 3.8 (95% CI: 3.2-4.5) impacts and the mean 'severity' level was 54.8 (95% CI: 49.9-59.7). 'Prevalence' was significantly and positively associated with patients with gastroesophageal reflux disease (GERD), those with a higher estimated daily alcohol intake, who previously used hashish and who brushed their teeth after drinking alcohol. 'Extent' was higher among females, those with higher levels of education, patients with GERD, smokers, and those with a higher estimated daily alcohol consumption; it was negatively associated with not brushing teeth. 'Severity' was significantly and positively associated with female gender and smoking, and negatively associated with not brushing teeth. CONCLUSION: This population of alcohol-dependent patients undergoing an addiction rehabilitation programme presented a high prevalence of negative oral health impacts, but not a high extent or severity. PMID- 30027165 TI - Impact of Health Locus of Control on Oral Health Status among a Cohort of IT Professionals. AB - PURPOSE: To assess the relationship between health locus of control and oral health status among Information Technology (IT) professionals in Hyderabad, India. MATERIALS AND METHODS: A cross-sectional questionnaire study was carried out among IT employees in Hyderabad city. The behaviour, attitude and perceptions of individuals towards health were assessed using the multidimensional health locus of control scale. Oral health status was evaluated clinically utilising the simplified oral hygiene index, community periodontal index, and loss of attachment index. Data were statistically analysed using SPSS software (v 21.0). RESULTS: A convenience sample of 989 employees (response rate of 82.4%, mean age 26.3 +/- 5.0 years) completed the questionnaire. The overall highest mean domain score was recorded for 'chance locus of control' (CLOC; 9.0 +/- 2.1) and lowest overall mean domain score for 'internal locus of control' (ILOC; 6.7 +/- 0.9). The overall mean scores of DI-S, CI-S and OHI-S were 0.7 +/- 0.4, 0.7 +/- 0.5 and 1.4 +/- 0.8, respectively; there was an inverse relation with age groups. The mean CPI and LOA scores observed among males, ranging from 0.4 +/- 0.6 to 1.6 +/- 1.1, were statistically significantly higher than those of females, ranging from 0.2 +/- 0.5 to 1.3 +/- 1.2 (p = 0.00). Powerful locus of control had a statistically significant negative correlation with oral hygiene indices. In contrast, a positive correlation was observed between ILOC and DI-S and OHI-S (r = 0.0672 and r = 0.0639, respectively). CONCLUSION: This study highlighted that people with a positive attitude regulate their health behaviour and maintain good oral hygiene. PMID- 30027166 TI - Relationship Between Mothers' Knowledge and Attitude Towards the Importance of Oral Health and Dental Status of their Young Children. AB - PURPOSE: To examine the relationship between mothers' knowledge, attitude and dental caries status and their young children's dental caries status. MATERIALS AND METHODS: In this cross-sectional study, 153 2- to 6-year old children old and their mothers were dentally examined. Mothers' decayed, missing or filled teeth (DMFT) and children's decayed, missing or filled teeth (dmft) were recorded. A validated questionnaire was used to examine maternal knowledge and attitudes regarding the importance for the oral health of their children. RESULTS: The average age of children and mothers were 5.1 and 31 years, respectively. The mothers' and children's mean DMFT and dmft were 12 and 6, respectively. The mean level of mothers' knowledge was 31.5 out of 40, while the mean attitude was 24.5 out of 30 points. There was a statistically significant inverse correlation between mothers' knowledge and their DMFT (r = -0.7), and between mothers' knowledge and children's dmft (r = -0.6). Also, there was an inverse correlation between mothers' attitude and DMFT (r = -0.8), and between mothers' attitude and dmft (r = -0.7). A direct correlation between mothers' DMFT and children's dmft (r = +0.6) was observed. CONCLUSION: Attempts at improving the knowledge and attitude in parents have a substantial impact on improving the oral health of next generation. PMID- 30027167 TI - C-Reactive Protein Levels and Periodontal Diseases During Pregnancy in Malaysian Women. AB - PURPOSE: To investigate the association between plasma CRP levels and periodontal disease during pregnancy. MATERIALS AND METHODS: Fifty-six pregnant women attending the Antenatal Clinic, UMMC for their first antenatal check-up consented and were recruited for this study: 28 subjects with diseased periodontium (test group) and 28 subjects with healthy periodontium (control). The test group underwent nonsurgical periodontal therapy and the control group was given oral hygiene education. Periodontal parameters and CRP levels were evaluated at baseline and 6 weeks. Pregnancy outcome data were recorded from the Antenatal Clinic, UMMC. RESULTS: Plasma CRP levels in the test group were statistically significantly elevated compared to the control group (8.55 +/- 5.28 mg/l vs 5.66 +/- 2.91 mg/l). After nonsurgical periodontal therapy, a statistically significant reduction in the CRP level in the test group (2.06 mg/l) along with statistically significant improvement in periodontal status in both groups was observed. The mean birth weight for infants of both groups showed no statistically significant difference. CONCLUSIONS: Plasma CRP levels in pregnant women with diseased periodontium were statistically significantly reduced after nonsurgical periodontal therapy. However, no association between CRP levels and adverse pregnancy outcome was observed. PMID- 30027168 TI - Determination and Comparison of Dermatoglyphic Patterns and Salivary Streptococcus mutans Counts and Its Correlation with Dental Caries among 3- to 6 year-old Children. AB - PURPOSE: To determine and compare the dermatoglyphic patterns and salivary Streptococcus mutans counts, as well as its correlation with dental caries among 3- to 6-year-old children. MATERIALS AND METHODS: Children 3 to 6 years old who had decayed/extracted/filled teeth (def) >= 5 were selected as the study group (n = 50) and those who had def = 0 were selected as controls (n = 50). Dermatoglyphics was recorded using the ink stamp-pad method. Salivary S. mutans levels were estimated by microbial culture of the collected salivary samples; for further confirmation, optochin and bacitracin antibiotic sensitivity tests were done. The chi-squared test, Mann-Whitney U-test, independent Student's t-test, one-way ANOVA were used for comparison among the variables. Correlation was analysed using Pearson's correlation coefficient (r). RESULTS: The study group showed a significantly higher mean number for whorls and S. mutans count, and the control group showed significantly higher ulnar loops and total ridge count. A positive and significant correlation was observed between mean def and S. mutans. Whorls showed a significant and positive correlation with caries and S. mutans, whereas ulnar loops and total ridge count showed a negative correlation. CONCLUSION: There was a strong correlation between dermatoglyphic patterns (especially ulnar loops, whorls and total ridge count), dental caries and S. mutans level. PMID- 30027169 TI - Comparison of the antibacterial efficacy of sonic- and two ultrasonic-activated irrigation techniques in reducing intracanal Enterococcus faecalis populations. AB - OBJECTIVE: This in-vitro study evaluated the antibacterial efficacy of sonic and ultrasonic irrigation with either intermittent or continuous flush in root canals infected with Enterococcus faecalis. METHOD AND MATERIALS: Seventy single-rooted, extracted teeth with straight root canals were prepared with FlexMaster NiTi instruments, sterilized, inoculated with E faecalis and incubated for 72 hours. Sixty roots were randomly divided into four experimental groups as well as into infection and sterile controls (n = 10 each). The remaining teeth were used for SEM analysis of smear layer removal (n = 5) and infection with E faecalis (n = 5). Irrigation in the experimental groups was performed with 1% NaOCl and syringe irrigation, sonic activation of the irrigant with EndoActivator, ultrasonic activation with intermittent flush, or ultrasonic activation with continuous flush. Microbial sampling was performed by collecting dentin shavings from the root canal walls. Colony-forming units were counted and statistical analysis was performed using nonparametric rank-based ANOVA-type tests for longitudinal data (P < .05). RESULTS: A significant reduction of E faecalis of 3 log10 steps compared to the infection control was achieved by all irrigation techniques (P < .0001). There were no significant differences in antibacterial efficacy between syringe irrigation, sonically, or ultrasonically activated irrigation (P > .45). CONCLUSION: Activation of 1% NaOCl with either sonic or ultrasonic devices did not increase the antimicrobial efficacy against E faecalis compared to conventional syringe irrigation in straight root canals. PMID- 30027170 TI - Impact of glide path preparation on the incidence of dentinal defects after preparation of severely curved root canals. AB - OBJECTIVE: The purpose of this study was to evaluate the impact of glide path preparation on the incidence of dentinal defects after preparation of severely curved canals using ProTaper Next, F6 SkyTaper, and One Shape instruments. METHOD AND MATERIALS: One hundred and forty human mandibular molars with mesiobuccal canals with angles of curvatures ranging between 25 and 35 degrees and radii ranging between 4 and 9 mm were assigned to seven homogenous groups (n = 20 teeth per group). In half of the teeth of each of the seven groups a manual glide path (size 15) was created prior to instrumentation. The root canals were instrumented using the three different types of instruments to an apical size 25. One group served as control as no canal preparation was performed. Roots were sectioned horizontally at 3, 6, and 9 mm from the apex and evaluated under a microscope using 25-fold magnification. The presence of dentinal defects (complete/incomplete cracks) was noted and analyzed using Fisher's exact test. RESULTS: No defects were observed in the controls. All canal preparations created dentinal defects. More incomplete and complete cracks were found in the apical (n = 4) and the middle (n = 3) canal third than in the coronal (n = 1), without any significant differences between the three instruments (P > .05). Prior glide path preparation had no significant impact on the incidence of dentinal defects (P > .05). CONCLUSION: A glide path preparation seems not to be mandatory to reduce the risk of dentinal defects formation when using the tested instruments in severely curved canals. PMID- 30027171 TI - A classification for assessing surgical difficulty in the extraction of mandibular impacted third molars: Description and clinical validation. AB - OBJECTIVE: Surgical time prediction is an important factor to plan both clinical and organizational aspects of mandibular impacted third molar extraction. Many classifications have been proposed over the years, but their accuracy in surgical time prediction remained questionable. The present study introduced a modification of Juodzbalys and Daugela (JD) classification, and had the aim to validate its effectiveness in predicting the duration of the surgery. METHOD AND MATERIALS: Three centers treated patients needing impacted mandibular third molar extraction, following inclusion and exclusion criteria. Extractions were performed following a standardized approach, and surgical time was recorded. A blinded assessor assigned scores to each extracted tooth, according to original and modified JD classifications. Differences among the operators were evaluated though Kruskal-Wallis test, and backward multiple linear regressions were performed to evaluate the variables associated with surgical time, considered as the main outcome of the study. RESULTS: 124 patients were treated with mandibular third molar extraction. Mean surgical time was 24.1 +/- 22.2 minutes, with significant differences among the centers (P = .001). Surgical times among groups derived from both former and modified JD classifications were significantly different (P = .002 and P = .001, respectively). In the multivariate analysis, the statistical model including modified JD score was more efficient than the model with former JD score in predicting surgical time (R2 = .204 and R2 = .126, respectively). CONCLUSION: Modified JD classification resulted in a reliable tool for predicting surgical time of impacted mandibular third molar extraction; this could represent an adjunctive tool for clinician and patient in the decision making process. PMID- 30027172 TI - Computerized three-dimensional design for accurate orienting and dimensioning artificial dental socket for tooth autotransplantation. AB - OBJECTIVE: To present an improved, accurate, and efficient method for planning and preparing an artificial socket for autotransplantation, by using a three dimensional (3D) surgical guide and a replica of the transplanted donor tooth. The guide and the tooth replica were fabricated using a computerized 3D simulation. A case treated with this approach is presented. METHOD AND MATERIALS: Cone beam computed tomography (CBCT) and computerized 3D simulations (Simplant plus registration as stereolithography) were used for planning the optimal artificial socket position and dimensions, within the limitations of the alveolar bone borders and the adjacent teeth roots, and for producing a metal replica of the transplanted tooth. The replica was used to assure the correct socket preparation and orientation before extraction and replantation of the donor premolar. RESULTS: The entire procedure time for autotransplantation of a permanent second premolar to the incisor site without the buccal plate was about 45 minutes. At 15 months' follow up, clinical examination of the transplanted tooth demonstrated both normal mobility and no sensitivity to cold stimulation. A radiographic examination revealed continuous root development and pulp obliteration. The adjacent teeth maintained their vitality with no pathologic signs. CONCLUSION: We present an improved technique for autotransplantation based on computerized 3D simulations and guidance for accurate dimensioning and optimal locating of the artificial socket relative to the alveolar bone borders and the adjacent teeth roots. This technique may significantly simplify the autotransplantation procedure and will probably also increase its success rate and use in young patients, even in cases with absence of a buccal plate. PMID- 30027173 TI - Efficacy of flapless intentional replantation with enamel matrix derivative in the treatment of hopeless teeth associated with endodontic-periodontal lesions: A 2-year prospective case series. AB - OBJECTIVE: In this prospective case series, the effects of flapless intentional replantation (IR) with root surface conditioning with enamel matrix derivative (EMD) was evaluated for the treatment of periodontally-endodontally involved hopeless teeth. METHOD AND MATERIALS: A total of 17 teeth (17 patients, aged 40 to 73) with >= 10 mm attachment loss and radiographic bone loss to the apex were included in the study. The affected teeth were atraumatically extracted using a flapless approach, then granulation tissues, calculus, and necrotic cementum on the root surfaces were removed. EMD was applied for 5 minutes to the root surfaces. The teeth were reinserted to the socket without any bone grafts and splinted. RESULTS: After 2 years, clinical healing was uneventful in 16 cases and the radiographs revealed no root resorption or ankylosis. IR with EMD treatment provided statistically significant reduction in probing depth (6.4 +/- 2.6 mm), gain in clinical attachment level (5.9 +/- 2.5 mm), and gain in radiographic bone level (48.2 +/- 26.1%) compared to baseline values (P < .01). CONCLUSION: Within the limitations of the study, flapless IR with EMD treatment appeared to act as an alternative strategy to extraction of severely compromised teeth with endodontic-periodontal lesions beyond the root apex. PMID- 30027174 TI - Randomized clinical trial on the comparison of bleaching outcomes using either ozone or hydrogen peroxide. AB - OBJECTIVE: To evaluate the efficacy of in-office tooth bleaching following application of either ozone (O3) or hydrogen peroxide (H2O2). METHOD AND MATERIALS: 32 participants were randomly distributed into two groups (n = 16 each). Participants' maxillary anterior teeth were treated with ozone (produced via a healOzone X4 device; Curozone) for 60 seconds in Group 1, or with 38% H2O2 for 20 minutes in Group 2. Tooth shades were evaluated by means of a colorimeter (CR-400, Minolta) measuring Vita classic shades in addition to L*a*b* shade values before and following bleaching in each group. A visual analog scale was used to evaluate tooth sensitivity before and after bleaching. Statistically significant differences were identified at P < .05. RESULTS: Teeth obtained lighter shades (increased L* and reduced a* and b* values) following bleaching in both groups (P < .001). Both groups revealed comparable bleaching outcomes (P > .05). However, bleaching with ozone did not result in tooth sensitivity, whilst using H2O2 was accompanied with significantly increased bleaching sensitivity (P < .001). CONCLUSION: Similar bleaching outcomes and lighter tooth shades (both for Vita shades and L*a*b* values) were obtained following in-office bleaching with either 60 seconds of ozone or 20 minutes of 38% H2O2. Notwithstanding, tooth sensitivity was significantly increased following bleaching with H2O2 in comparison to ozone. Ozone obviously does reduce the regularly clinically observed inconveniences of bleaching by means of H2O2; thus, ozone would seem worth considering for patients asking for in-office tooth bleaching. PMID- 30027175 TI - Accelerating CALYPSO structure prediction by data-driven learning of a potential energy surface. AB - Ab initio structure prediction methods have been nowadays widely used as powerful tools for structure searches and materials discovery. However, they are generally restricted to small systems owing to the heavy computational cost of the underlying density functional theory (DFT) calculations in structure optimizations. In this work, by combining a state-of-art machine learning (ML) potential with our in-house developed CALYPSO structure prediction method, we developed two acceleration schemes for the structure prediction of large systems, in which a ML potential is pre-constructed to fully replace DFT calculations or trained in an on-the-fly manner from scratch during the structure searches. The developed schemes have been applied to medium- and large-sized boron clusters, both of which are challenging cases for either the construction of ML potentials or extensive structure searches. Experimental structures of B36 and B40 clusters can be readily reproduced, and the putative global minimum structure for the B84 cluster is proposed, where the computational cost is substantially reduced by ~1 2 orders of magnitude if compared with full DFT-based structure searches. Our results demonstrate a viable route for structure prediction in large systems via the combination of state-of-art structure prediction methods and ML techniques. PMID- 30027176 TI - Syntheses and characterization of hepta-coordinated Group 4 amidinate complexes. AB - Tri-amidinate chloride complexes M[MeC(NiPr)2]3Cl [M = Zr (1), Hf (2)] have been prepared from MCl4 and lithium amidinate Li[MeC(NiPr)2]. The uncommon hepta coordinated complexes Zr-Cl (1) and Hf-Cl (2) undergo metathesis reactions with 1 equiv. of MeLi and EtMgCl to give alkyl derivatives M[MeC(NiPr)2]3R [R = Me, M = Zr (3), Hf (4); R = Et, M = Zr (5), Hf (6)]. The dynamic behaviors of Zr-Cl (1) and Hf-Cl (2) in solution have been studied using variable-temperature 1H NMR (VT 1H NMR), giving activation parameters DeltaH?, DeltaS?, and DeltaG? for several exchange processes in Zr-Cl (1) and Hf-Cl (2). 1H-15N gHMBC NMR spectroscopy gives the chemical shifts of the N atoms in 1-6. The 1H-15N gHMBC NMR spectra of 1-4 at elevated temperatures are needed to obtain signals. Crystal structures of Zr-Cl (1), Hf-Cl (2), Zr-Et (5), and Hf-Et (6) have been determined via X-ray diffraction. DART-MS studies of Zr-Cl (1) and Hf-Cl (2) in air give MS of 1-2, cations M[MeC(NiPr)2]3+ [M = Zr (7), Hf (8)], and hydroxyl complexes M[MeC(NiPr)2]3OH [M = Zr (9), Hf (10)]. In comparison, DART-MS spectra of 3-6 in air show only 7-8 and 9-10, indicating lability of the alkyl ligands and/or their fast hydrolysis by moisture. PMID- 30027177 TI - Effects of the dipolar double layer on elemental electrode processes at micro- and macro-interfaces. AB - Determination of heterogeneous rate constants of redox reactions or charge transfer resistances always involves ambiguities due to their participation in double layer (DL) capacitances and solution resistances. The rate constants determined by steady-state voltammograms at ultra-microelectrodes are inconsistent with time-dependent voltammograms, implying participation of the DL impedance. We examine controlling factors of DLs through the frequency-dependence of the capacitance on the basis of the definition of the current and the capacitance. The capacitance obeys the power law of the frequency. It is controlled by the orientation of a limited amount of solvent dipoles, independent of salts. Redox species, dipoles of which are oriented oppositely to the solvent dipoles, decrease the DL capacitance and make the value negative at high concentrations of the species. The decrease in the capacitance increases the real impedance, as predicted from the phase angle, yielding an extra resistance. This may be a ghost charge transfer resistance. However, there are actually a number of well-defined charge transfer resistances, which are observed as transferring rates through films on electrodes. PMID- 30027178 TI - Neuroglobin is capable of self-oxidation of methionine64 introduced at the heme axial position. AB - Neuroglobin (Ngb), with its physiological role not fully understood, was found to be capable of self-oxidation of methionine64 introduced at the heme axial position (H64M Ngb), adopting a high-spin heme state and producing both methionine sulfoxide (SO-Met) and sulfone (SO2-Met), which represents the structure and function of cytochrome c in a non-native state. PMID- 30027179 TI - Materials discovery by chemical analogy: role of oxidation states in structure prediction. AB - The likelihood of an element to adopt a specific oxidation state in a solid, given a certain set of neighbours, might often be obvious to a trained chemist. However, encoding this information for use in high-throughput searches presents a significant challenge. We carry out a statistical analysis of the occurrence of oxidation states in 16 735 ordered, inorganic compounds and show that a large number of cations are only likely to exhibit certain oxidation states in combination with particular anions. We use this data to build a model that ascribes probabilities to the formation of hypothetical compounds, given the proposed oxidation states of their constituent species. The model is then used as part of a high-throughput materials design process, which significantly narrows down the vast compositional search space for new ternary metal halide compounds. Finally, we employ a machine learning analysis of existing compounds to suggest likely structures for a small subset of the candidate compositions. We predict two new compounds, MnZnBr4 and YSnF7, that are thermodynamically stable according to density functional theory, as well as four compounds, MnCdBr4, MnRu2Br8, ScZnF5 and ZnCoBr4, which lie within the window of metastability. PMID- 30027180 TI - Hydrogen-bond mediated columnar liquid crystalline assemblies of C3-symmetric heptazine derivatives at ambient temperature. AB - A new class of hydrogen (H) bonded fluorescent liquid crystals (FLCs) based on a newly discovered s-heptazine fluorophore discotic component have been synthesized. The tendency of the s-heptazine core to form H-bonded LCs has been explored for the first time. Interestingly, the pure heptazine derivatives (non mesomorphic) on complexation with tri-alkoxy benzoic acids exhibit enantiotropic columnar mesomorphism over a wide range of temperatures including room temperature. This indicates the strength of the resulting H-bonded complexes. The H-bonded supramolecular complexes were studied through FT-IR, temperature dependent FT-IR and NMR studies and H-D exchange studies, and their thermal behaviour was deduced through polarized optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. Because of the inherently fluorescent pure heptazine derivative, the resulting complexes exhibit fluorescent behaviour in the solution state as well as in the solid state. PMID- 30027181 TI - Strategy for marker-based differentiation of pro- and anti-inflammatory macrophages using matrix-assisted laser desorption/ionization mass spectrometry imaging. AB - Macrophages are large phagocytes playing a crucial role in the development and progression of atherosclerosis. The phenotypic polarization and activation of macrophages in atherosclerotic plaques depends on their complex micro-environment and at the same time has a major impact on the vulnerability or stability of advanced atherosclerotic lesions. Many in vitro and in vivo studies have been designed to define markers for macrophage subtypes to better understand the mechanism of plaque progression but they have rather added to the confusion. Nonetheless, some of the in vitro defined macrophage subtypes, like the pro inflammatory M1 or the anti-inflammatory M2a/b/c macrophage, have been shown to be present in atherosclerotic plaques. Herein, we developed a comprehensive workflow to distinguish between human in vitro differentiated pro-inflammatory M1 and anti-inflammatory M2a and M2c macrophages. The cells were analyzed using qPCR and FACS analyses for defining suitable markers on the transcript (mRNA) and protein level as well as MALDI MSI for the assignment of metabolic markers, which can be used for the identification of the corresponding macrophage subtypes in atherosclerotic plaques. Data obtained using both qPCR and FACS analyses were in agreement with the literature. For the analysis of the macrophages with MALDI MSI, a comprehensive workflow was developed and the obtained data were subjected to different statistical analysis methods like principal component analysis (PCA) to define markers for each macrophage type. Our MALDI MSI results revealed that the method produces reliable and reproducible results but that the heterogeneity of the monocytes derived from different donors is too high to define universal markers on the metabolic level. Moreover, the results show that a sample set of three biological replicates is not sufficient to obtain representative data and therefore we recommend performing ring experiments in which the samples are measured by different laboratories. PMID- 30027182 TI - Bis(oxazoline)-derived N-heterocyclic carbene ligated rare-earth metal complexes: synthesis, structure, and polymerization performance. AB - Bis(oxazoline)-derived N-heterocyclic carbene (IBiox) supported rare-earth (Sc, Y, Lu) trialkyl complexes have been synthesized and structurally characterized, and their catalytic activity in the (co)polymerization of alpha-olefins has been studied. The treatment of Ln(CH2SiMe3)3(THF)2 with one equivalent of freshly prepared IBiox afforded the rare-earth metal complexes (IBiox)Ln(CH2SiMe3)3THFn (Ln = Sc (1), n = 0; Y (2), n = 1; and Lu (3), n = 1) in good yields. Single crystal X-ray diffraction study showed that 1 is pseudo tetrahedral, while 2 and 3 are distorted trigonal bipyramidal with coordinated THF. The Ln-C(carbene) bond distances in 1, 2, and 3 are 2.352, 2.550, and 2.479 A, respectively. DFT calculations were performed to study the bonding scheme and the structural stability. Complex 1 showed a high activity for 1-hexene polymerization by activation with 2 equivalents of [Ph3C][B(C6F5)4], and the resultant polymers are predominantly vinylene end groups (ca. 95%). Moreover, the catalyst system based on 1 proved to be effective for the copolymerization of 1-hexene with 1,7 octadiene, affording the copolymers with about 20% pendant vinyl groups. The hydrophilicity of the copolymers was improved by modifying the vinyl groups with carboxyls via a thiol-ene reaction. PMID- 30027183 TI - Regulating glutathione-responsiveness of naphthalimide-based fluorescent probes by an oxidation strategy. AB - Two naphthalimide-based fluorescent probes containing a thiomorpholine (Np-NS) or a sulfoxide-morpholine (Np-NSO) component are reported. The morpholine unit of non-fluorescent Np-NS and Np-NSO can transform into sulphone-morpholine and be accompanied by blue fluorescence upon oxidative stress, ascribed to the formation of sulphone-morpholine on probes. This sensing behavior displays that they can selectively respond to glutathione to generate a green emission by a sulfonamide based detection moiety both in vitro and in living cells. Interestingly, the different oxidation states of a sulphur atom on a thiomorpholine ring can be utilized to regulate responsiveness of these probes towards glutathione. Such an oxidation strategy would provide a possibility for enhancing the response rate. PMID- 30027184 TI - Reducing possible combinations of Wyckoff positions for zeolite structure prediction. AB - Zeolites are an important class of tetrahedrally coordinated inorganic materials that have been widely used in many chemical industries as catalysts, adsorbents, and ion-exchangers. To date, over 200 types of zeolite framework have been discovered. Predicting not-yet-discovered zeolite frameworks is of great importance not only for zeolite structure determination but also for the identification of promising synthetic candidates with desirable functions. However, owing to the complexity and diversity of zeolite framework topologies, zeolite structure prediction has been a challenging task for several decades. Many efforts have been devoted towards this end, among which the computer-aided assembly of zeolite framework constituent atoms (T atoms) in predefined Wyckoff positions (WPs) is a promising approach because of its high efficiency in configuration space searching. However, this approach suffers from high computational overheads caused by the large number of possible WP combinations. On the basis of the analysis of known zeolite structures, we find that the site symmetries of many WPs are incompatible with the tetrahedral coordination of T atoms. Moreover, to avoid the formation of chemically unfeasible distorted tetrahedral coordination, T atoms cannot be too "crowded" in some WPs. We define, for the first time, the T atom distribution (TAD) densities for special site symmetries as the numbers of T atoms per special point, per unit length of rotation axes, or per unit area of mirror planes, respectively. By restricting the number of T atoms in every WP so as not to exceed the highest allowed TAD density, WP combinations for zeolite structure prediction can be reduced by 1-4 orders of magnitude. Taking advantage of this discovery, the efficiency of zeolite structure prediction based on the enumeration of WP combinations can be significantly improved. PMID- 30027185 TI - Enantioselective total synthesis and biological evaluation of (-)-solanacol. AB - An enantioselective synthesis of the phenyl ring-containing strioglactone, (-) solanocol, is described. Application of a Dynamic Kinetic Resolution (DKR) in the stereo-defining step enabled a step-economical synthesis to be achieved, and allowed access to natural and non-natural enantiomers with equal facility. Results of seed germination assays and Differential Scanning Fluorimetry (DSF) measurements with the known strigolactone receptor protein, Decreased Apical Dominance 2 (DAD2), are reported. PMID- 30027186 TI - An anionic iridium(iii) complex as a visible-light absorbing photosensitizer. AB - In this work, a new anionic Ir(iii) complex (Ir2) was synthesized using coumarin 6 and orotate ligands, and its use as a photosensitizer in photochemical hydrogen (H2) generation was demonstrated. For comparison purposes, we also prepared a known anionic Ir(iii) complex (Ir1) bearing 2-phenylpyridine and orotate ligands, which was previously reported as an emitting material by another research group. The photophysical properties of complexes Ir1 and Ir2 were examined in several solvents including aqueous acetonitrile (CH3CN-H2O), which is frequently used in photocatalytic H2-generating experiments. Ir1 was found to be weakly emissive in CH3CN-H2O, which is probably due to the effect of hydrogen bonding between the orotate ligands and H2O molecules. In sharp contrast, Ir2 exhibited remarkable properties that include strong visible-light absorption (epsilon = 78 800 M-1 cm 1 at 462 nm), a high phosphorescence quantum yield (50%), and a long-lived excited state (15 MUs), even in the same solvent. Actually, Ir2 functioned as a photosensitizer during visible-light-driven H2 generation using sodium ascorbate and a cobalt(iii) diglyoxime complex as the electron donor and water-reduction catalyst, respectively. To the best of our knowledge, this is the first example of the use of an anionic Ir(iii) sensitizer in a photoinduced electron-transfer reaction. The results of this study suggest that Ir2 can be applied to future photochemical H2-generating systems that are based on ion-paired photocatalysts. PMID- 30027187 TI - Vanadocene dichloride inhibits cell proliferation by targeting Aurora B. AB - Vanadocene dichloride (VDC) was shown to exhibit antitumor properties against a wide spectrum of tumor cell lines. Many studies have been carried out to reveal the bioactivities of VDC and the interaction mechanism of VDC with biological molecules in test tubes. One of the bioactivities of VDC is to arrest the cell cycle at the G2/M phase. However, its underlying mechanisms of action and cytotoxicity profile are still not fully understood. HeLa cells were used in this study, and the IC50 value of VDC was 8.61 MUM after a 24-hour treatment. We used an immunofluorescence staining method to analyze the morphology of cells in the mitosis stage to elucidate what defects caused cell arrest in mitosis. Chromosomal misalignment was found to be the major phenotype. One of the proteins responsible for chromosome alignment at the metaphase is Aurora B kinase. Results of immunoblotting assay showed that Aurora B kinase activity was inhibited by VDC treatment. More than 50% of the Aurora B activity was inhibited when cells were treated with VDC at a concentration of 6.25 MUM. That VDC was able to induce defects in chromosomal alignment at the metaphase by inhibiting the activity of Aurora B kinase is an important mechanism of VDC to be developed as an antitumor agent. PMID- 30027188 TI - A molecular-regulation strategy towards low-voltage driven, multi degree of freedom IPMC catheters. AB - A multi degree of freedom ionic polymer-metal composite (IPMC) active catheter with controllable bending ability (from micrometer to millimeter level) under a low voltage (~1.0 V) was developed. And its actuation properties were enhanced effectively through a molecular-regulation strategy. PMID- 30027189 TI - Phase transitions in polymorphic materials probed using space-resolved diffusing wave spectroscopy. AB - We use space-resolved dynamic light scattering in the highly multiple scattering regime (Photon Correlation Imaging Diffusing Wave Spectroscopy, PCI-DWS) to investigate temperature-induced phase transitions in polymorphic materials. We study paraffin wax as a simple model system and chocolate, a prototypical example of fat-based products exhibiting complex, history-dependent phase transitions. We find that microscopic dynamics measured using PCI-DWS show remarkable, non monotonic behavior upon heating: they transiently accelerate when crossing phase transition and slow down above the transition temperature. Sub-micron resolution measurements of the local drift of the sample surface reveal that the speed-up of the dynamics is due to the strain field induced by the change in density at transition temperature. The transition temperatures obtained from PCI-DWS are found to be in excellent agreement with those inferred from complementary differential scanning calorimetry and X-ray scattering experiments, thereby validating PCI-DWS as a new, powerful tool for the characterization of phase transitions in complex soft matter. Finally, we demonstrate the unique possibilities afforded by space-resolved DWS by investigating the spatially heterogeneous response of poorly manufactured or composite chocolate samples. PMID- 30027190 TI - Correction: Heparin-induced tau filaments are structurally heterogeneous and differ from Alzheimer's disease filaments. AB - Correction for 'Heparin-induced tau filaments are structurally heterogeneous and differ from Alzheimer's disease filaments' by Yann Fichou et al., Chem. Commun., 2018, 54, 4573-4576. PMID- 30027191 TI - Anti-fatigue effects of small-molecule oligopeptides isolated from Panax quinquefolium L. in mice. AB - American ginseng (Panax quinquefolium L.) was reported to have extensive biological activities and pharmaceutical properties. In most of the studies, the anti-fatigue effects of American ginseng are attributed to ginsenoside, and in only a few studies, they have been attributed to oligopeptides. Therefore, the aim of this study was to observe the anti-fatigue effects of small-molecule oligopeptides isolated from Panax quinquefolium L. (QOPs) in mice. At first, mice chosen for the study were randomly divided into four experimental groups; each group of mice was further divided into five subgroups: vehicle control group, whey protein group (450 mg per kg BW), and three groups of QOPs at different doses (225 mg per kg BW, 450 mg per kg BW, and 900 mg per kg BW). Test substances were given by gavage once a day for 30 days. QOPs can significantly prolong the forced swimming time, decrease the serum urea nitrogen (SUN) and blood lactate (BLA) levels, and increase the lactate dehydrogenase (LDH) activity and hepatic glycogen content. QOPs also markedly enhanced the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity and attenuated the malondialdehyde (MDA) levels. Notably, QOPs enhanced the activity of succinate dehydrogenase (SDH), Na+ K+-ATPase, and Ca2+-Mg2+-ATPase and increased the mRNA expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) and the mitochondrial DNA (mtDNA) content in skeletal muscles. These results indicate that treatment with QOPs induces anti-fatigue effects, which may be due to the inhibition of oxidative stress and the improvement of mitochondrial function in skeletal muscles. QOPs can be used as a novel natural agent for relieving physical fatigue. PMID- 30027197 TI - Uracil grafted imine-based covalent organic framework for nucleobase recognition. AB - An imine-based covalent organic framework (COF) decorated in its cavities with uracil groups has shown selective recognition towards adenine in water. These results show how the confinement of the base-pair inside the COF's pores allows a remarkable selective recognition in aqueous media. PMID- 30027198 TI - Carbodiimides as energy materials: which directions for a reasonable future? AB - A little less than a decade after their quantum-chemical prediction and eventual synthesis, solid-state transition-metal carbodiimides and closely related compounds have somewhat unexpectedly emerged as energy materials. In these carbodiimides, the O2- oxide dianion has been replaced by the complex NCN2- dianion, and the outstanding properties of such materials are likely related to their metastability and their higher amount of covalency compared to related oxides. When used as anode materials in rechargeable Li- and Na-ion batteries, one finds a conversion reaction, and further improving their performance will likely involve studying the redox behavior of NCN2-, the synthesis of novel ternary carbodiimides, in particular those with redox-active transition metals, and controlling their morphology. At present, such materials serve as catalysts in photochemical water oxidation, where they outperform their oxide cousins. PMID- 30027199 TI - Milk fat protects Bifidobacterium animalis subsp. lactis Bb-12 from in vitro gastrointestinal stress in potentially synbiotic table spreads. AB - The viability and the in vitro gastrointestinal survival of Bifidobacterium animalis subsp. lactis Bb-12 (Bifidobacterium Bb-12) in table spreads with different proportions of milk fat (MF) and palm olein (PO) (MF : PO 40 : 60 and MF : PO 20 : 80) were investigated for up to 28 days of storage at 5 degrees C. Moreover, qPCR alone and combined with propidium monoazide (PMA) were compared with the traditional plate count method for determining the in vitro gastrointestinal survival of Bifidobacterium Bb-12 in table spreads after 35 days of storage. Formulations showed probiotic viabilities ranging from 8 to 9 log CFU g-1 across the whole storage period, and the milk fat and palm olein in different concentrations did not affect this viability. Bifidobacterium Bb-12 showed good survival after six hours under in vitro simulated gastrointestinal conditions during the studied storage period, with average reductions of 1.70 (MF : PO 40 : 60) and 2.16 log CFU g-1 (MF : PO 20 : 80). The results of the qPCR with PMA treatment and the plate count method were similar and the qPCR without PMA treatment was shown to overestimate the Bifidobacterium Bb-12 populations. However, the MF : PO 40 : 60 spread showed a Bb-12 population between 0.76 and 1.43 log CFU g-1 higher than that of MF : PO 20 : 80. Thus, the results showed that table spreads, especially food matrices with a higher proportion of milk fat, are suitable for the incorporation of Bifidobacterium Bb-12. PMID- 30027200 TI - Correlating cobalt redox couples to photovoltage in the dye-sensitized solar cell. AB - We report a series of structurally analogous cobalt mediators related to [Co bpy]Z (bpy = 2,2'-bipyrimidine, Z = 2+ or 3+) to demonstrate a linear relationship between the redox potential of the Co(iii/ii)-based redox couple (Emed) and open-circuit voltage (VOC) of the DSSC. The Emed values vary from 0.42 to 1.07 V vs. NHE depending on the number of nitrogen atoms and the presence of tert-butyl substituents on the ligand. A 64-mV gain in photovoltage was calculated for every +100 mV shift in Emed. Differences in the mediator sizes, diffusion coefficients, light absorption profiles, and spin state configurations for the complexes were not significant and therefore not expected to contribute to changes in the VOC. A decrease in the photocurrent, downward shift in quasi Fermi level (EF,n) and shorter electron lifetime (Tn) with increasingly positive Emed were instead attributed to enhanced electron recombination from the TiO2 film to oxidized mediator species in the electrolyte. PMID- 30027201 TI - Multichromophore arrays of dibenzotetraaza[14]annulene: a promising platform for bioorganic chemistry. AB - The first series of discrete multichromophore arrays of dibenzotetraaza[14]annulene (DBTAA), containing flexible bridges, have been synthesized in 40-46% isolated yields. The key asymmetrical intermediates, carrying two distinctly addressable functionalities (ROH vs. ROCH2-C[triple bond, length as m-dash]C-H and R(CH2)nBr vs. ROCH2-C[triple bond, length as m-dash]C-H) at the macrocycle periphery, were synthesized in moderate to high (30-78%) isolated yields. Facile synthetic protocols developed for the synthesis of discrete DBTAA arrays offer several advantages such as operational simplicity and easy post-synthetic workup that overcome the need for laborious chromatographic purification. All new compounds were characterized by microanalysis, mass spectrometry, UV-Vis, FTIR-ATR, and 1H and 13C NMR spectroscopy. Structural features were briefly discussed with emphasis on several potential applications. PMID- 30027202 TI - Preparation and reactivity of rhodium and iridium complexes containing a methylborohydride based unit supported by two 7-azaindolyl heterocycles. AB - The synthesis and characterisation of a new anionic flexible scorpionate ligand, methyl(bis-7-azaindolyl)borohydride [MeBai]- is reported herein. The ligand was coordinated to a series of group nine transition metal centres forming the complexes, [Ir(MeBai)(COD)] (1), [Rh(MeBai)(COD)] (2), [Rh(MeBai)(CODMe)] (2-Me) and [Rh(MeBai)(NBD)] (3), where COD = 1,5-cyclooctadiene, CODMe = 3-methyl-1,5 cyclooctadiene and NBD = 2,5-norbornadiene. In all cases, the boron based ligand was found to bind to the metal centres via a kappa3-N,N,H coordination mode. The ligand and complexes were fully characterised by spectroscopic and analytical methods. The structures of the ligand and three of the complexes were confirmed by X-ray crystallography. The potential for migration of the "hydride" or "methyl" units from boron to the metal centre was also explored. During these studies an unusual transformation, involving the oxidation of the rhodium centre, was observed in complex 2. In this case, the eta4-COD unit transformed into a eta1,eta3-C8H12 unit where the ring was bound via one sigma bond and one allyl unit. This is the first time such a transformation has been observed at a rhodium centre. PMID- 30027203 TI - Bilateral Painless Cervical Lymphadenopathy in a Child. PMID- 30027204 TI - Complementary Medicine, Refusal of Conventional Cancer Therapy, and Survival Among Patients With Curable Cancers. AB - Importance: There is limited information on the association among complementary medicine (CM), adherence to conventional cancer treatment (CCT), and overall survival of patients with cancer who receive CM compared with those who do not receive CM. Objectives: To compare overall survival between patients with cancer receiving CCT with or without CM and to compare adherence to treatment and characteristics of patients receiving CCT with or without CM. Design, Setting, and Participants: This retrospective observational study used data from the National Cancer Database on 1 901 815 patients from 1500 Commission on Cancer accredited centers across the United States who were diagnosed with nonmetastatic breast, prostate, lung, or colorectal cancer between January 1, 2004, and December 31, 2013. Patients were matched on age, clinical group stage, Charlson Deyo comorbidity score, insurance type, race/ethnicity, year of diagnosis, and cancer type. Statistical analysis was conducted from November 8, 2017, to April 9, 2018. Exposures: Use of CM was defined as "Other-Unproven: Cancer treatments administered by nonmedical personnel" in addition to at least 1 CCT modality, defined as surgery, radiotherapy, chemotherapy, and/or hormone therapy. Main Outcomes and Measures: Overall survival, adherence to treatment, and patient characteristics. Results: The entire cohort comprised 1 901 815 patients with cancer (258 patients in the CM group and 1 901 557 patients in the control group). In the main analyses following matching, 258 patients (199 women and 59 men; mean age, 56 years [interquartile range, 48-64 years]) were in the CM group, and 1032 patients (798 women and 234 men; mean age, 56 years [interquartile range, 48-64 years]) were in the control group. Patients who chose CM did not have a longer delay to initiation of CCT but had higher refusal rates of surgery (7.0% [18 of 258] vs 0.1% [1 of 1031]; P < .001), chemotherapy (34.1% [88 of 258] vs 3.2% [33 of 1032]; P < .001), radiotherapy (53.0% [106 of 200] vs 2.3% [16 of 711]; P < .001), and hormone therapy (33.7% [87 of 258] vs 2.8% [29 of 1032]; P < .001). Use of CM was associated with poorer 5-year overall survival compared with no CM (82.2% [95% CI, 76.0%-87.0%] vs 86.6% [95% CI, 84.0%-88.9%]; P = .001) and was independently associated with greater risk of death (hazard ratio, 2.08; 95% CI, 1.50-2.90) in a multivariate model that did not include treatment delay or refusal. However, there was no significant association between CM and survival once treatment delay or refusal was included in the model (hazard ratio, 1.39; 95% CI, 0.83-2.33). Conclusions and Relevance: In this study, patients who received CM were more likely to refuse additional CCT, and had a higher risk of death. The results suggest that mortality risk associated with CM was mediated by the refusal of CCT. PMID- 30027205 TI - Analytical Validity and Clinical Utility of Tumor Biomarkers. PMID- 30027206 TI - Associations of Observed Performance Monitoring During Preschool With Obsessive Compulsive Disorder and Anterior Cingulate Cortex Volume Over 12 Years. AB - Importance: Monitoring one's performance is necessary for learning and adaptive behavior; however, heightened performance monitoring is a purported endophenotype of obsessive-compulsive disorder (OCD). The anterior cingulate cortex (ACC), a brain region implicated in the pathogenesis of OCD, is associated with performance monitoring. Whether performance monitoring early in development is an identifiable risk factor for OCD and whether early childhood performance monitoring is associated with later alterations in ACC volume are unknown. Objective: To determine whether an observed indicator of heightened performance monitoring during the preschool age is associated with later onset of OCD and altered dorsal ACC (dACC) volume through adolescence. Design, Setting, and Participants: This longitudinal observational cohort study was performed at an academic medical center as part of the Preschool Depression Study. A sample of 292 children oversampled for depression from September 22, 2003, through May 12, 2005, completed a performance-based observational task during which they received persistent negative evaluation. Blind raters behaviorally coded child performance monitoring. During the next 12 years, children completed annual diagnostic assessments; 133 completed the final behavioral follow-up and 152 contributed 1 to 3 magnetic resonance imaging scans. Follow-up was completed on August 14, 2017. Main Outcomes and Measures: Onset of DSM-5 diagnosis of OCD from baseline to the final behavioral assessment and whole-brain-adjusted dACC volume at the 3 waves of scanning. Results: Among the 292 preschool children who completed the baseline evaluation (51.4% boys; mean [SD] age, 4.5 [0.8] years), when controlling for demographic and clinical indicators, those who exhibited observed heightened performance monitoring were 2 times more likely to develop OCD (n = 35) during the next 12 years (odds ratio, 2.00; 95% CI, 1.06-3.78; P = .03). Multilevel modeling of dACC volume across the 3 scan waves (n = 152) demonstrated that heightened performance monitoring was associated with smaller right dACC volume (intercept estimate, -0.14; SE, 0.07; t = -2.17; P = .03). Conclusions and Relevance: An ecologically valid indicator of performance monitoring in early childhood was associated with onset of OCD and smaller dACC volumes in later childhood and adolescence. Early childhood observed performance monitoring is a readily observed risk factor of OCD that can be identified in preschool-aged children. PMID- 30027207 TI - Probiotics to Prevent Clostridium difficile Infection in Patients Receiving Antibiotics. AB - Clinical Question: In adults and children prescribed antibiotics, is co administration of a probiotic associated with a lower risk of symptomatic Clostridium difficile infection without an increase in adverse events? Bottom Line: Moderate-quality evidence suggests that probiotics are associated with a lower risk of C difficile infection and very low-quality evidence suggests that probiotics are associated with fewer adverse events vs placebo or no treatment. PMID- 30027208 TI - Frequency of Visual Deficits in Children With Developmental Dyslexia. AB - Importance: Developmental dyslexia (DD) is a specific learning disability of neurobiological origin whose core cognitive deficit is widely believed to involve language (phonological) processing. Although reading is also a visual task, the potential role of vision in DD has been controversial, and little is known about the integrity of visual function in individuals with DD. Objective: To assess the frequency of visual deficits (specifically vergence, accommodation, and ocular motor tracking) in children with DD compared with a control group of typically developing readers. Design, Setting, and Participants: A prospective, uncontrolled observational study was conducted from May 28 to October 17, 2016, in an outpatient ophthalmology ambulatory clinic among 29 children with DD and 33 typically developing (TD) children. Main Outcomes and Measures: Primary outcomes were frequencies of deficits in vergence (amplitude, fusional ranges, and facility), accommodation (amplitude, facility, and accuracy), and ocular motor tracking (Developmental Eye Movement test and Visagraph eye tracker). Results: Among the children with DD (10 girls and 19 boys; mean [SD] age, 10.3 [1.2] years) and the TD group (21 girls and 12 boys; mean [SD] age, 9.4 [1.4] years), accommodation deficits were more frequent in the DD group than the TD group (16 [55%] vs 3 [9%]; difference = 46%; 95% CI, 25%-67%; P < .001). For ocular motor tracking, 18 children in the DD group (62%) had scores in the impaired range (in the Developmental Eye Movement test, Visagraph, or both) vs 5 children in the TD group (15%) (difference, 47%; 95% CI, 25%-69%; P < .001). Vergence deficits occurred in 10 children in the DD group (34%) and 5 children in the TD group (15%) (difference, 19%; 95% CI, -2.2% to 41%; P = .08). In all, 23 children in the DD group (79%) and 11 children in the TD group (33%) had deficits in 1 or more domain of visual function (difference, 46%; 95% CI, 23%-69%; P < .001). Conclusions and Relevance: These findings suggest that deficits in visual function are far more prevalent in school-aged children with DD than in TD readers, but the possible cause and clinical relevance of these deficits are uncertain. Further study is needed to determine the extent to which treating these deficits can improve visual symptoms and/or reading parameters. PMID- 30027209 TI - Live-Born Major Congenital Heart Disease in Denmark: Incidence, Detection Rate, and Termination of Pregnancy Rate From 1996 to 2013. AB - Importance: The occurrence of major congenital heart disease (CHD) is affected by several variables. Determining the development of the true incidence is critical to the establishment of proper treatment of these patients. Objective: To evaluate time trends in incidence, detection rate, and termination of pregnancy (TOP) rate of major CHD in fetuses in Denmark and assess the influence of the introduction of general prenatal screening in 2004. Design, Setting, and Participants: Nationwide, population-based, retrospective observational study in Denmark from 1996 to 2013 that included a consecutive sample of 14 688 live-born children and terminated fetuses diagnosed as having CHD. Patient records on TOP and children with major CHD were reviewed to validate the diagnoses. Major CHD included univentricular heart, transposition of the great arteries, congenitally corrected transposition of the great arteries, truncus arteriosus, interrupted aortic arch, atrioventricular septal defects, double outlet right ventricle, coarctatio of the aorta, Ebstein anomaly, pulmonary atresia with ventricular septal defect, pulmonary atresia with intact ventricular septum, and tetralogy of Fallot. Data were analyzed between January 2017 and March 2018. Main Outcomes and Measures: Temporal changes in incidence, detection rate, and TOP of major CHD. Results: Of 14 688 children and fetuses diagnosed with CHD, 2695 (18.4%; 95% CI, 17.8-19.1) had major CHD. A total of 7131 boys (1304 with major CHD) and 6926 girls (920 with major CHD) were included, with a median age of 11 years (interquartile range, 6-15 years). During the study period, the live-birth incidence of CHD was constant at 1.22% (95% CI, 1.18-1.26), whereas it decreased for major CHD. When including TOP, the incidence of major CHD did not change over time. The detection rate of major CHD increased from 4.5% (95% CI, 1.2-7.8) to 71.0% (95% CI, 63.3-78.7) (P < .001). At the end of the study, all cases of double outlet right ventricle, Ebstein anomaly, congenitally corrected transposition of the great arteries, and pulmonary atresia with ventricular septal defect were detected prenatally, whereas coarctation of the aorta had the lowest detection rate (21.7%; 95% CI, 3.5-40.0). The TOP rate increased from 0.6% (95% CI, -0.6 to 1.9) to 39.1% (95% CI, 30.9-47.4) (P < .001) among all major CHD. For prenatally diagnosed major CHD, 57.8% of cases were terminated and the proportion did not change significantly throughout the study. Diagnoses leading to TOP included all major CHD diagnoses. Conclusions and Relevance: Detection rates of major CHD improved during the study. This has led to increased TOP rates, with a subsequent 39% decrease in the live-birth incidence of major CHD. PMID- 30027212 TI - Computer-Assisted Bilateral Orbitozygomatic Reconstruction in a Patient With Treacher Collins Syndrome Using Bicortical Calvarial Graft. PMID- 30027213 TI - Association of Brain Reward Learning Response With Harm Avoidance, Weight Gain, and Hypothalamic Effective Connectivity in Adolescent Anorexia Nervosa. AB - Importance: Anorexia nervosa (AN) is associated with adolescent onset, severe low body weight, and high mortality as well as high harm avoidance. The brain reward system could have an important role in the perplexing drive for thinness and food avoidance in AN. Objective: To test whether brain reward learning response to taste in adolescent AN is altered and associated with treatment response, striatal-hypothalamic connectivity, and elevated harm avoidance. Design, Setting, and Participants: In this cross-sectional multimodal brain imaging study, adolescents and young adults with AN were matched with healthy controls at a university brain imaging facility and eating disorder treatment program. During a sucrose taste classical conditioning paradigm, violations of learned associations between conditioned visual and unconditioned taste stimuli evoked the dopamine related prediction error (PE). Dynamic effective connectivity during sweet taste receipt was studied to investigate hierarchical brain activation across the brain network that regulates eating. The study was conducted from July 2012 to May 2017, and data were analyzed from June 2017 to December 2017. Main Outcomes and Measures: Prediction error brain reward response across the insula, caudate, and orbitofrontal cortex; dynamic effective connectivity between hypothalamus and ventral striatum; and treatment weight gain, harm avoidance scores, and salivary cortisol levels and their correlations with PE brain response. Results: Of 56 female participants with AN included in the study, the mean (SD) age was 16.6 (2.5) years, and the mean (SD) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 15.9 (0.9); of 52 matched female controls, the mean (SD) age was 16.0 (2.8) years, and the mean (SD) BMI was 20.9 (2.1). Prediction error response was elevated in participants with AN in the caudate head, nucleus accumbens, and insula (multivariate analysis of covariance: Wilks lambda, 0.707; P = .02; partial eta2 = 0.296), which correlated negatively with sucrose taste pleasantness. Bilateral AN orbitofrontal gyrus rectus PE response was positively correlated with harm avoidance (right rho, 0.317; 95% CI, 0.091 to 0.539; P < .02; left rho, 0.336; 95% CI, 0.112 to 0.550; P < .01) but negatively correlated with treatment BMI change (right rho, -0.282; 95% CI, -0.534 to -0.014; P < .04; left rho, -0.268; 95% CI, -0.509 to -0.018; P < .045). Participants with AN showed effective connectivity from ventral striatum to hypothalamus, and connectivity strength was positively correlated with insula and orbitofrontal PE response. Right frontal cortex PE response was associated with cortisol, which correlated with body dissatisfaction. Conclusions and Relevance: These results further support elevated PE signal in AN and suggest a link between PE and elevated harm avoidance, brain connectivity, and weight gain in AN. Prediction error may have a central role in adolescent AN in driving anxiety and ventral striatal-hypothalamus circuit-controlled food avoidance. PMID- 30027215 TI - Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays-Reply. PMID- 30027214 TI - Association of Apathy With Risk of Incident Dementia: A Systematic Review and Meta-analysis. AB - Importance: Fear of dementia is pervasive in older people with cognitive concerns. Much research is devoted to finding prognostic markers for dementia risk. Studies suggest apathy in older people may be prodromal to dementia and could be a relevant, easily measurable predictor of increased dementia risk. However, evidence is fragmented and methods vary greatly between studies. Objective: To systematically review and quantitatively synthesize the evidence for an association between apathy in dementia-free older individuals and incident dementia. Data Sources: Two reviewers conducted a systematic search of Medline, Embase, and PsychINFO databases. Study Selection: Inclusion criteria were (1) prospective cohort studies, (2) in general populations or memory clinic patients without dementia, (3) with clear definitions of apathy and dementia, and (4) reporting on the association between apathy and incident dementia. Data Extraction and Synthesis: PRISMA and MOOSE guidelines were followed. Data were extracted by 1 reviewer and checked by a second. Main Outcomes and Measures: Main outcomes were pooled crude risk ratios, maximally adjusted reported hazard ratios (HR), and odds ratios (OR) using DerSimonian-Laird random effects models. Results: The mean age of the study populations ranged from 69.2 to 81.9 years (median, 71.6 years) and the percentage of women ranged from 35% to 70% (median, 53%). After screening 2031 titles and abstracts, 16 studies comprising 7365 participants were included. Apathy status was available for 7299 participants. Studies included populations with subjective cognitive concerns (n = 2), mild cognitive impairment (n = 11), cognitive impairment no dementia (n = 1), or mixed cognitive and no cognitive impairment (n = 2). Apathy was present in 1470 of 7299 participants (20.1%). Follow-up ranged from 1.2 to 5.4 years. In studies using validated apathy definitions (n = 12), the combined risk ratio of dementia for patients with apathy was 1.81 (95% CI, 1.32-2.50; I2 = 76%; n = 12), the hazard ratio was 2.39 (95% CI, 1.27-4.51; I2 = 90%; n = 7), and the odds ratio was 17.14 (95% CI, 1.91-154.0; I2 = 60%; n = 2). Subgroup analyses, meta-regression, and individual study results suggested the association between apathy and dementia weakened with increasing follow-up time, age, and cognitive impairment. Meta regression adjusting for apathy definition and follow-up time explained 95% of heterogeneity in mild cognitive impairment. Conclusions and Relevance: Apathy was associated with an approximately 2-fold increased risk of dementia in memory clinic patients. Moderate publication bias may have inflated some of these estimates. Apathy deserves more attention as a relevant, cheap, noninvasive, and easily measureable marker of increased risk of incident dementia with high clinical relevance, particularly because these vulnerable patients may forgo health care. PMID- 30027216 TI - Potential Child Health Consequences of the Federal Policy Separating Immigrant Children From Their Parents. PMID- 30027218 TI - How to Combat the Opioid Epidemic, 1 Nudge at a Time. PMID- 30027217 TI - Observational Outcomes of Initial Trabeculectomy With Mitomycin C in Patients of African Descent vs Patients of European Descent: Five-Year Results. AB - Importance: There is evidence that patients of African descent (AD) experience higher surgical failure rate after trabeculectomy without antimetabolites. Objective: To compare outcomes of initial trabeculectomy with mitomycin C in AD patients with those of patients of European descent (ED) and to identify prognostic factors for failure. Design, Setting, and Participants: In this retrospective matched cohort study, 135 eyes of 105 AD patients were matched with 135 eyes of 117 ED patients by age (within 5 years), surgeon, lens status, and follow-up time (within 1 year) from a single tertiary academic center. Interventions: Initial trabeculectomy with mitomycin C. Main Outcomes and Measures: Criteria A, B, and C defined qualified success rates as final intraocular pressure of 18 mm Hg or less, 15 mm Hg or less, and 12 mm Hg or less, respectively, in addition to 20% or more, 25% or more, and 30% or more reduction of intraocular pressure or reduction of 2 or more medications. Kaplan-Meier survival curves were compared with log-rank test in AD and ED patients, and Cox proportional hazard models were used to estimate the influence of race/ethnicity on surgical success accounting for confounding variables. Results: Of the 105 AD patients, 56 (53.3%) were female, and the mean (SD) age was 67.5 (10.4) years; of the 117 ED patients, 64 (54.7%) were female, and the mean (SD) age was 68.2 (10.0) years. For AD patients compared with ED patients, the qualified success rates at 5 years for criteria A were 61% and 67%, respectively (difference, 7.3%; 95% CI, 4.4-10.4); for criteria B, 43% and 60% (difference, 17.6%; 95% CI, 15.2 20.0); and for criteria C, 25% and 40% (difference, 15.8%; 95% CI, 11.1-20.5). On multivariable Cox regression analyses, AD was associated with higher failure rate with criteria B and C for qualified success and with all criteria for complete success (ie, no need for medications). Incidence of bleb leaks was higher in the AD group (29 vs 11 eyes; P = .002). Additionally, AD patients required additional glaucoma surgeries more often than ED patients (47 vs 26 eyes; P = .004). Conclusions and Relevance: African descent was associated with higher failure rates and higher incidence of bleb leaks after initial trabeculectomy with mitomycin C compared with European descent. If this is subsequently shown to be a cause and effect, the findings need to be considered when surgical treatment of glaucoma is contemplated in AD patients. PMID- 30027219 TI - Scabies-An Ancient Disease With Unanswered Questions in Modern Times. PMID- 30027220 TI - Laparoscopic vs Open Surgery for Colorectal Liver Metastases. AB - Importance: Surgery represents the mainstay treatment of colorectal liver metastases. Indications for the laparoscopic approach in this setting have been widened and there is a need to confirm the benefits of minimally invasive liver surgery (MILS) in patients with complex disease states. Objective: To compare outcomes of laparoscopic surgery with those of open surgery for liver metastases from colorectal cancer, focusing on the characteristics of modern MILS and therefore overcoming possible selection bias related to different policies for patients' eligibility for MILS over time. Design, Setting, and Participants: A cohort study of 885 resections performed for liver metastases from colorectal cancer between January 1, 2004, and June 30, 2017, at the Hepatobiliary Surgery Unit of San Raffaele Hospital, Milano, Italy, comprising 187 laparoscopic and 698 open resections. Procedures performed using the MILS approach with a ratio of MILS to total resections per year of more than 30% were considered and were matched by propensity scores (ratio of 1:4) to procedures performed using the open approach with a ratio of MILS to total resections per year of less than 30%. Main Outcomes and Measures: The primary end point was short-term outcomes, including morbidity, mortality, functional recovery, and interval between surgery and adjuvant treatments; the secondary end point was long-term outcomes. Results: Among this cohort (104 patients in the MILS group; 46 women and 58 men; median age, 62 years [range, 35-81 years]; and 412 patients in the open group; 181 women and 231 men; median age, 60 years [range, 37-80 years]), primary end-point data showed a significantly higher incidence of postoperative morbidity in patients who underwent open resections compared with those who underwent MILS (94 [22.8%] vs 21 [20.2%]; P = .04). Patients in the MILS group had fewer major complications (Dindo-Clavien grades III-V) compared with patients in the open group (Dindo Clavien grades III-V; 7 [6.7%] vs 35 [8.5%]; P = .03) as well as shorter lengths of stay (median [range] duration, 3 [2-35] vs 5 [4-37] days; P = .02). Oncologic results were not compromised by the laparoscopic approach. Conclusions and Relevance: In this study, the results of the propensity score matching analysis between modern laparoscopic surgery and previous open surgery appear to confer more comparable cohorts for complexity, further supporting the advantages of laparoscopy in the surgical treatment of liver metastases from colorectal cancer. The increase in use that laparoscopy has experienced appears to be based on increased feasibility, widening of eligibility criteria for patients, enhanced clinical effectiveness, and oncologic outcomes. All these elements together suggest that up to 70% of patients appear to be candidates for this minimally invasive surgical approach in high-volume centers. PMID- 30027221 TI - Development of Multimodal Analgesia Pathways in Outpatient Thyroid and Parathyroid Surgery and Association With Postoperative Opioid Prescription Patterns. AB - Importance: Prescription opioid use contributes to drug-related adverse effects and risk for dependence and abuse. Multimodal analgesia (MMA) has been shown to be useful in reducing opioid use following orthopedic, gynecologic, and colorectal surgery, but adoption in head and neck surgery has lagged. Recently, we published findings related to the feasibility of MMA protocols in same-day thyroid, parathyroid, and parotid surgery. However, whether such strategies lead to effective and durable reduction in frequency of opioid prescriptions, and affect physician prescribing practices, remains unclear. Objective: To observe trends in adoption and adherence to institutional MMA protocols following thyroid and parathyroid surgery, and to assess the association of institutional multimodal (nonopioid) analgesia protocols with opioid use and physician prescribing patterns following outpatient thyroid and parathyroid surgery. Design, Setting, and Participants: Cohort study at a head and neck surgery service at a tertiary care hospital of prescription patterns and retrospective review of patient medical records following implementation of an optional institutional MMA protocol in 2015, based on preoperative administration of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and gabapentin, and postoperative use of acetaminophen and ibuprofen for analgesia after thyroid and parathyroid surgery. There were 528 adult patients who underwent thyroid and parathyroid surgery between January 1, 2015, and June 30, 2017. Main Outcomes and Measures: We report on adherence to the MMA protocol over the study period as measure of physician buy-in and adoption of the technique. The frequency of opioid use and physician prescription patterns following thyroid and parathyroid surgery is reported over the study period to study the association of the available MMA pathway with these variables. Results: A total of 528 patients (mean [SD] age, 53.1 [15.7] years; 80.3% female) underwent outpatient thyroid and parathyroid surgery. The frequency of postoperative opioid prescriptions decreased during the study period (16 of 122 [13.1%] in 2015, 22 of 244 [9.0%] in 2016, 3 of 162 [1.9%] in 2017). Adherence to the MMA protocol increased (0 of 122 cases in 2015, 106 of 244 [43.4%] cases in 2016, 142 of 162 [87.7%] cases in 2017), with reduced likelihood of opioid prescription on discharge (2017 vs 2015 odds ratio, 0.13; 95% CI, 0.04-0.44). Only 1 postoperative hematoma was recorded in the study cohort, and 352 (66.7%) patients achieved same-day discharge, whereas 176 (33.3%) maintained outpatient status but received overnight observation prior to discharge. Conclusions and Relevance: Adoption and adherence to the MMA protocol increased substantially over the study period for patients undergoing thyroid and parathyroid surgery and was associated with a simultaneous significant decline in prescription of postoperative opioid analgesics. Use of nonopioid multimodal agents, incorporating NSAIDs, was safe and did not lead to increased incidence of bleeding. Availability of effective nonopioid MMA pathways may favorably influence physician prescribing practices and avoid unnecessary opioid prescriptions. PMID- 30027222 TI - Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays. PMID- 30027223 TI - Ethical Implications of Direct-to-Consumer Hereditary Cancer Tests. PMID- 30027226 TI - Association of Tumor Size With Histologic and Clinical Outcomes Among Patients With Cytologically Indeterminate Thyroid Nodules. AB - Importance: Tens of thousands of unnecessary operations are performed each year for diagnostic purposes among patients with cytologically indeterminate thyroid nodules. Whereas a diagnostic lobectomy is recommended for most patients with solitary indeterminate thyroid nodules, a total thyroidectomy is preferred for nodules larger than 4 cm. Objective: To determine whether histologic or clinical outcomes of indeterminate thyroid nodules 4 cm or larger are worse than those for nodules smaller than 4 cm, thus justifying a more aggressive initial surgical approach. Design, Setting, and Participants: In this retrospective cohort study, 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules >=4 cm) with surgical follow-up were consecutively evaluated at an academic cancer center from October 1, 2008, through April 30, 2016. Exposure: Tumor size. Main Outcomes and Measures: Differences in cancer rates, rates of invasive features, cancer aggressiveness, and response to therapy between indeterminate thyroid nodules smaller than 4 cm and 4 cm or larger. Results: A total of 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules >=4 cm) from 589 patients (mean [SD] age, 53.1 [13.8] years; 453 [76.9%] female) were studied. No differences were found in the baseline characteristics of patients or nodules between the 2 size groups. Tumor size was not associated with the cancer rate as a categorical (140 of 546 [25.6%] for nodules <4 cm and 33 of 106 [31.1%] for nodules >=4 cm; effect size, 0.05; 95% CI, 0.002-0.12) or continuous (odds ratio [OR], 1.03; 95% CI, 0.92-1.15) variable. No association was found between nodule size and prevalence of extrathyroidal extension, positive margins, lymphovascular invasion, lymph node metastasis, or distant metastasis. Most malignant tumors were low risk in both size groups (70% in the nodules <4 cm and 72% in the nodules >=4 cm), and tumor size was not associated with tumor aggressiveness as a categorical (effect size, 0.10; 95% CI, 0.03-0.31) or continuous variable (OR for intermediate-risk cancer, 0.91; 95% CI, 0.72-1.14; OR for high-risk cancer, 1.43; 95% CI, 0.96-2.15). At the last follow-up visit, 88 of 105 patients (83.8%) with malignant tumors in the smaller than 4 cm group and 21 of 25 (84.0%) in the 4 cm or greater group had no evidence of disease, and tumor size was not associated with response to therapy (effect size, 0.13; 95% CI, 0.07-0.33). Conclusions and Relevance: Most indeterminate thyroid nodules are benign or low-risk malignant tumors regardless of tumor size. In the absence of other indications for total thyroidectomy, this study suggests that a thyroid lobectomy is sufficient initial treatment for most solitary cytologically indeterminate thyroid nodules independent of the tumor size. PMID- 30027227 TI - Incidence of Atrial Fibrillation and Mineralocorticoid Receptor Activity in Patients With Medically and Surgically Treated Primary Aldosteronism. AB - Importance: Primary aldosteronism (PA) is an ideal condition to evaluate the role of the mineralocorticoid receptor (MR) in the pathogenesis of atrial fibrillation (AF). Objective: To investigate whether MR antagonist therapy or surgical adrenalectomy in PA influence the risk for incident AF. Design: This cohort study included patients aged 18 years and older. Patients with PA and age-matched patients with essential hypertension were identified via electronic health records. Patients with a history of AF, myocardial infarction, congestive heart failure, or stroke were excluded. Data were collected between 1991 and the end of 2016 in an academic medical center, with a mean follow-up duration of approximately 8 years. Exposures: Patients with PA treated with MR antagonists or surgical adrenalectomy were compared with patients with essential hypertension. Patients with PA who were treated with MR antagonists were categorized by whether their plasma renin activity remained suppressed (< 1 ng/mL/h) or substantially increased (>= 1 ng/mL/h), as proxies for insufficient or sufficient MR blockade. Main Outcomes and Measure: Incident AF. Results: A total of 195 patients with PA who were treated with MR antagonists and 201 patients with PA treated with surgical adrenalectomy were included, as well as 40 092 age-matched patients with essential hypertension. Despite similar blood pressure at study entry and throughout follow-up, patients with PA who were treated with MR antagonists whose renin remained suppressed had a higher risk for incident AF than patients with essential hypertension (adjusted HR, 2.55 [95% CI, 1.75-3.71]). They also had an adjusted 10-year cumulative AF incidence difference of 14.1 (95% CI, 6.7-21.5) excess cases per 100 persons compared with patients with essential hypertension. In contrast, patients with PA who were treated with MR antagonists and whose renin increased and patients with PA who were treated with surgical adrenalectomy had no statistically significant difference in risk for incident AF compared with patients with essential hypertension. Conclusions and Relevance: When compared with patients with essential hypertension, patients with PA treated with MR antagonists such that renin remained suppressed (as a proxy for insufficient MR blockade) had a significantly higher risk for incident AF; however, treatment of PA with MR antagonists to substantially increase renin (suggesting sufficient MR blockade), or with surgical adrenalectomy (to remove the source of aldosteronism), was associated with no significant difference in risk for developing AF. These findings add to the growing body of evidence suggesting that MR blockade may be a potential therapy to decrease the incidence of AF. PMID- 30027228 TI - Data Errors in Figure 3 and Labels Transposed in Figure 4. PMID- 30027229 TI - Removal of Drug Name From the Table. PMID- 30027230 TI - Carcinoembryonic Antigen for Diagnosis of Colorectal Cancer Recurrence. PMID- 30027231 TI - Digital Media and Symptoms of Attention-Deficit/Hyperactivity Disorder in Adolescents. PMID- 30027233 TI - FDA Prods "Clean Meat" Discussion. PMID- 30027232 TI - The Status of End-of-Life Care in the United States: The Glass Is Half Full. PMID- 30027234 TI - Caffeine Supplement Warning. PMID- 30027235 TI - Generic for Opioid Use Disorder. PMID- 30027237 TI - The Risks and Benefits of Expedited Drug Reviews. PMID- 30027238 TI - Relation of Education to Preventive Medicine. PMID- 30027239 TI - Clinical Trial Evidence Supporting FDA Approval of Drugs Granted Breakthrough Therapy Designation. PMID- 30027240 TI - Diagnosis and Treatment of Acute Respiratory Distress Syndrome. PMID- 30027241 TI - Diagnosis and Treatment of Acute Respiratory Distress Syndrome. PMID- 30027242 TI - Prophylactic Haloperidol for Critically Ill Adults. PMID- 30027243 TI - Prophylactic Haloperidol for Critically Ill Adults. PMID- 30027244 TI - Off-label Use of Medications. PMID- 30027245 TI - Diagnosis and Treatment in Acute Respiratory Distress Syndrome-Reply. PMID- 30027246 TI - Prophylactic Haloperidol for Critically Ill Adults-Reply. PMID- 30027247 TI - Off-label Use of Medications-Reply. PMID- 30027248 TI - Association of Digital Media Use With Subsequent Symptoms of Attention Deficit/Hyperactivity Disorder Among Adolescents. AB - Importance: Modern digital platforms are easily accessible and intensely stimulating; it is unknown whether frequent use of digital media may be associated with symptoms of attention-deficit/hyperactivity disorder (ADHD). Objective: To determine whether the frequency of using digital media among 15- and 16-year-olds without significant ADHD symptoms is associated with subsequent occurrence of ADHD symptoms during a 24-month follow-up. Design, Setting, and Participants: Longitudinal cohort of students in 10 Los Angeles County, California, high schools recruited through convenience sampling. Baseline and 6-, 12-, 18-, and 24-month follow-up surveys were administered from September 2014 (10th grade) to December 2016 (12th grade). Of 4100 eligible students, 3051 10th graders (74%) were surveyed at the baseline assessment. Exposures: Self-reported use of 14 different modern digital media activities at a high-frequency rate over the preceding week was defined as many times a day (yes/no) and was summed in a cumulative index (range, 0-14). Main Outcomes and Measures: Self-rated frequency of 18 ADHD symptoms (never/rare, sometimes, often, very often) in the 6 months preceding the survey. The total numbers of 9 inattentive symptoms (range, 0-9) and 9 hyperactive-impulsive symptoms (range, 0-9) that students rated as experiencing often or very often were calculated. Students who had reported experiencing often or very often 6 or more symptoms in either category were classified as being ADHD symptom-positive. Results: Among the 2587 adolescents (63% eligible students; 54.4% girls; mean [SD] age 15.5 years [0.5 years]) who did not have significant symptoms of ADHD at baseline, the median follow-up was 22.6 months (interquartile range [IQR], 21.8-23.0, months). The mean (SD) number of baseline digital media activities used at a high-frequency rate was 3.62 (3.30); 1398 students (54.1%) indicated high frequency of checking social media (95% CI, 52.1%-56.0%), which was the most common media activity. High-frequency engagement in each additional digital media activity at baseline was associated with a significantly higher odds of having symptoms of ADHD across follow-ups (OR, 1.11; 95% CI, 1.06-1.16). This association persisted after covariate adjustment (OR, 1.10; 95% CI, 1.05-1.15). The 495 students who reported no high frequency media use at baseline had a 4.6% mean rate of having ADHD symptoms across follow-ups vs 9.5% among the 114 who reported 7 high-frequency activities (difference; 4.9%; 95% CI, 2.5%-7.3%) and vs 10.5% among the 51 students who reported 14 high-frequency activities (difference, 5.9%; 95% CI, 2.6%-9.2%). Conclusions and Relevance: Among adolescents followed up over 2 years, there was a statistically significant but modest association between higher frequency of digital media use and subsequent symptoms of ADHD. Further research is needed to determine whether this association is causal. PMID- 30027249 TI - Risk Assessment for Cardiovascular Disease With Nontraditional Risk Factors. PMID- 30027253 TI - Efforts to Address Snakebite. PMID- 30027251 TI - And Still We Believed. PMID- 30027254 TI - Global Temperature Affects Dengue. PMID- 30027255 TI - Older People With Disabilities Overlooked in Humanitarian Response. PMID- 30027256 TI - A New Dark Skin Lesion in a 3-Year-Old Undergoing Induction Therapy for Acute Lymphoblastic Leukemia. PMID- 30027257 TI - Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays. PMID- 30027258 TI - Considerations in Pediatric Proptosis. PMID- 30027261 TI - Ethical Implications of Prenatal Screening for Congenital Heart Disease. PMID- 30027262 TI - Is Oculomotor Testing Important in Developmental Dyslexia? PMID- 30027263 TI - Computed Tomographic Coronary Angiography Identification of Plaque Inflammation: An Imaging Target Within Reach? PMID- 30027264 TI - Vermilion-Mucosal Advancement Flap: A Scarless Technique of Adynamic Wedge Resection of the Lower Lip in Patients With Facial Palsy. PMID- 30027265 TI - At "Crisis Pregnancy Centers," Critics Say, Ideology Trumps Evidence. PMID- 30027266 TI - Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays. PMID- 30027267 TI - Spiky Skin in a Renal Transplant Recipient. PMID- 30027268 TI - Adverse Effects of Computers During Bedside Rounds in a Critical Care Unit. PMID- 30027269 TI - Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial. AB - Importance: Previous randomized clinical trials have reported inconsistent results on the effect of vitamin D supplementation on cancer incidence. Objective: To examine whether high-dose vitamin D supplementation received monthly, without calcium, is associated with a reduction in cancer incidence and cancer mortality in the general population. Design, Setting, and Participants: This is a post hoc analysis of data from the Vitamin D Assessment (ViDA) study, a randomized, double-blind, placebo-controlled trial that recruited participants from family practices and community groups in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up completed December 31, 2015. Participants were adult community residents aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants withdrew consent, and all others (n = 5108) were included in the primary analysis. Data analysis was by intention to treat. Interventions: Oral vitamin D3, in an initial bolus dose of 200 000 IU and followed by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main Outcomes and Measures: Post hoc primary outcome was the number of all primary invasive and in situ malignant neoplasms (excluding nonmelanoma skin cancers) diagnosed from randomization until the study medication was discontinued on July 31, 2015. Results: Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 58.1% were male, and 4253 (83.3%) were of European or another race/ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25-hydroxyvitamin D concentration was 26.5 (9.0) ng/mL. In a random sample of 438 participants, the mean follow-up 25 hydroxyvitamin D concentration consistently was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of cancer comprised 328 total cases of cancer (259 invasive and 69 in situ malignant neoplasms) and occurred in 165 of 2558 participants (6.5%) in the vitamin D group and 163 of 2550 (6.4%) in the placebo group, yielding an adjusted hazard ratio of 1.01 (95% CI, 0.81-1.25; P = .95). Conclusions and Relevance: High-dose vitamin D supplementation prescribed monthly for up to 4 years without calcium may not prevent cancer. This study suggests that daily or weekly dosing for a longer period may require further study. Trial Registration: anzctr.org.au Identifier: ACTRN12611000402943. PMID- 30027270 TI - A Comparison of Tanning Habits Among Gym Tanners and Other Tanners. PMID- 30027271 TI - Trends in Insurance Coverage for Gender-Affirming Surgeries. PMID- 30027273 TI - Determining If Race Should Be Considered Within the Choice of Glaucoma Surgery. PMID- 30027272 TI - Potential Diagnosis of Vitreoretinal Lymphoma by Detection of MYD88 Mutation in Aqueous Humor With Ultrasensitive Droplet Digital Polymerase Chain Reaction. AB - Importance: The diagnostic workup of patients suspected of having vitreoretinal lymphoma (VRL) is primarily based on vitreous fluid analysis, including the recently emerging myeloid differentiation primary response gene 88 (MYD88) mutation analysis. Aqueous humor paracentesis is a relatively less invasive and safer procedure than taking vitreous fluid specimens, and aqueous humor-based MYD88 mutation analysis would provide an additional liquid biopsy tool to diagnose and monitor patients with VRL. Objective: To investigate whether the detection of MYD88 L265P by highly sensitive droplet digital polymerase chain reaction (ddPCR) is feasible in the vitreous fluid and aqueous humor of patients with VRL. Design, Setting, and Participants: This cohort study includes aqueous humor and vitreous fluid samples from patients with VRL who were treated at the University Medical Center Utrecht, in Utrecht, the Netherlands, from August 2005 to August 2017. Ocular fluids were randomized and masked before MYD88 L265P analysis, which was performed using an in-house validated ddPCR platform. Patients with uveitis were included as a comparison group. Main Outcomes and Measures: The presence of MYD88 L265P mutation detected by ddPCR in AH and VF. Results: The study included 96 samples from 63 individuals, including 23 patients with VRL (of whom 10 were female and 13 male, with a mean [SD] age of 72 [7.3] years) and 40 individuals with uveitis (of whom 23 were female and 17 male, with a mean [SD] age of 58 [20.9] years). In 17 of 23 patients with VRL (74%), MYD88 L265P was detected; it was not detected in any of the patients with uveitis. It was detectable in both vitreous fluid and aqueous humor samples. In the paired samples, the mutation was detected in 8 of 9 aqueous humor samples (89%) of the MYD88 L265P-positive vitreous fluid samples. In vitreous fluid, the MYD88 ddPCR test showed a sensitivity of 75% (95% CI, 50%-92%) and a positive predictive value of 100%; in aqueous humor, sensitivity was 67% (95% CI, 42%-92%), and positive predictive value was 100%. Specificity was 100% in both fluids. After treatment, the mutation was no longer detectable in any ocular fluids. Conclusions and Relevance: The high concordance between aqueous humor and vitreous fluid samples suggests that use of the easily accessible aqueous humor is nearly as informative as vitreous fluid in the identification of key somatic mutations in patients with VRL. This approach may provide an additional minimally invasive tool for accurate diagnosis, detection of recurrence, and monitoring of treatment. PMID- 30027275 TI - Left Ventricular Ejection Fraction Cut Point of 50% for Heart Failure With Preserved Ejection Fraction. PMID- 30027274 TI - Is Venous Thromboembolism in Asian Patients Undergoing Gastrectomy Different From Venous Thromboembolism in Their Western Counterparts? PMID- 30027276 TI - Detection of MYD88 Mutations in Vitreoretinal Lymphoma and Its Implications. PMID- 30027277 TI - Left Ventricular Ejection Fraction Cut Point of 50% for Heart Failure With Preserved Ejection Fraction-Reply. PMID- 30027278 TI - Timing of Onset of Adverse Cutaneous Reactions Associated With Programmed Cell Death Protein 1 Inhibitor Therapy. AB - Importance: An increasing number of cutaneous adverse reactions resulting from use of programmed cell death protein 1 (PD-1) inhibitors have been described, but with relatively little focus to date on the timing of these reactions. Objective: To determine the timing of cutaneous drug reactions after initiation of PD-1 inhibitor therapy. Design, Setting, and Participants: This retrospective observational study included patients referred to an academic dermatology clinic by an oncologist from January 1, 2014, through February 28, 2018, with at least 1 skin biopsy specimen of a skin reaction associated with PD-1 inhibitor use. Participants were included if they had a biopsy-proven cutaneous reaction in response to a PD-1 inhibitor used alone or in combination with ipilimumab. Exposures: All patients included in this study received pembrolizumab, nivolumab, or nivolumab with ipilimumab as immunotherapy for cancer. Main Outcomes and Measures: The main outcome measure was time to onset of biopsy-proven cutaneous reactions that occurred during or after use of pembrolizumab or nivolumab. Results: A total of 17 patients (12 men, 5 women; mean [SD] age, 68.6 [11.1] years) were identified who presented with cutaneous adverse reactions associated with PD-1 inhibitor therapy; these reactions included lichenoid dermatitis, bullous pemphigoid, erythema multiforme, eczema, lupus, and sarcoidosis. Twelve patients presented with reactions at least 3 months after beginning pembrolizumab or nivolumab therapy. The skin reactions presented a median (range) of 4.2 months (0.5-38.0 months) after drug initiation. In 5 cases, the cutaneous adverse reactions attributed to the PD-1 inhibitor therapy developed after the drug therapy was terminated. Conclusions and Relevance: Diverse cutaneous adverse reactions secondary to PD-1 inhibitor use may present with delayed onsets and even after discontinuation of therapy. Dermatologists should be aware of the potential for delayed presentations of cutaneous adverse reactions. PMID- 30027279 TI - Completion Node Dissection After Sentinel Node Biopsy in Melanoma. PMID- 30027280 TI - Sunscreen Use and Melanoma Risk Among Young Australian Adults. AB - Importance: There are limited data among young adults on sunscreen use during childhood and adulthood and on the association of sunscreen use with melanoma risk. Objective: To assess correlates of early-life sunscreen use and the association between sunscreen use and risk of cutaneous melanoma before age 40 years. Design, Setting, and Participants: This population-based, case-control family study analyzed Australian Melanoma Family Study data for persons with questionnaire data on sunscreen use collected by interview from 2001 to 2005 across 3 states in Australia, representing two-thirds of the country's population. Case participants (aged 18-39 years) had confirmed first primary melanoma. Siblings of case participants were included, and case participants without a sibling control were excluded. Unrelated controls (aged 18-44 years) were recruited from the electoral roll or were a spouse, partner, or friend nominated by case participants. Data analyses were conducted from October 2017 to February 2018. Exposures: Self- and parent-reported sunscreen use, sun exposure, and other candidate risk factors during childhood and adulthood. Main Outcomes and Measures: Logistic regression analyses adjusted for potential confounders were used to estimate odds ratios (ORs) for melanoma and for correlates of sunscreen use. Results: Participation was 629 of 830 contactable cases (76%) (629 of 1197 overall [53%]), 240 of 570 contactable controls (42%) from the electoral roll (240 of 1068 overall [23%]), and 295 of 371 nominated spouse or friend controls (80%); analysis incuded 603 cases and 1088 controls. The median (interquartile range) age was 32 (28-36) years for 603 cases, 35 (30-38) years for 478 unrelated controls, and 34 (29-38) years for 610 sibling controls. There were more women than men (range, 57%-62%) in all groups, approximately 40% (range, 39%-43%) of participants had a university education, and most participants (range, 58%-73%) had British/northern European ethnicity. Risk of melanoma was less with higher use of sunscreen in childhood (OR for highest vs lowest tertiles, 0.60; 95% CI, 0.42-0.87; P = .02 for trend) and across the lifetime (OR, 0.65; 95% CI, 0.45-0.93; P = .07 for trend). Subgroup analyses suggested that the protective association of sunscreen with melanoma was stronger for people reporting blistering sunburn, receiving a diagnosis of melanoma at a younger age, or having some or many nevi. Total lifetime sun exposure was unrelated to melanoma risk (OR for highest vs lowest tertile, 0.97; 95% CI, 0.66 1.43; P = .94 for trend). By contrast, total sun exposure inversely weighted by sunscreen use (as a measure of sun exposure unprotected by sunscreen) was significantly associated with melanoma risk (OR, 1.80; 95% CI, 1.22-2.65; P = .007 for trend) and appeared stronger for people having lighter pigmentation or some or many nevi or using sunscreen to stay longer in the sun. Regular users of sunscreen were more likely to be female, younger, and of British or northern European ancestry and to have higher educational levels, lighter skin pigmentation, and a stronger history of blistering sunburn. Conclusions and Relevance: Our findings provided evidence that regular sunscreen use is significantly associated with reduced risk of cutaneous melanoma among young adults and identified several characteristics associated with less sunscreen use. PMID- 30027282 TI - Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays. PMID- 30027281 TI - Venous Thromboembolism Incidence and Prophylaxis Use After Gastrectomy Among Korean Patients With Gastric Adenocarcinoma: The PROTECTOR Randomized Clinical Trial. AB - Importance: The guidelines by the National Comprehensive Cancer Network and the American Society for Clinical Oncology recommend the routine use of thromboprophylaxis for patients with gastric adenocarcinoma. However, many physicians in Asian countries use venous thromboembolism (VTE) prophylaxis much less often because of the perceived lower VTE incidence in this population. Objectives: To evaluate the incidence of postgastrectomy VTE in Korean patients with gastric adenocarcinoma, and to identify the complications and evaluate the efficacy and safety of VTE prevention methods. Design, Setting, and Participants: The Optimal Prophylactic Method for Venous Thromboembolism After Gastrectomy in Korean Patients (PROTECTOR) randomized clinical trial was conducted between August 1, 2011, and March 31, 2015. Patients with histologically confirmed gastric adenocarcinoma presenting to a single center (Seoul St Mary's Hospital in Seoul, South Korea) were enrolled. Patients were randomized to either an intermittent pneumatic compression (IPC)-only group or an IPC+low-molecular weight (LMW) heparin sodium group. The data were analyzed on intention-to-treat and per protocol bases. Data analysis was performed from April 1, 2016, to October 30, 2017. Main Outcomes and Measures: Venous thromboembolism incidence was the primary outcome. Postoperative complications, particularly those associated with VTE prophylaxis methods, were the secondary end point. Results: Of the 682 patients enrolled and randomized, 447 (65.5%) were male and 245 (34.5%) were female, with a mean (SD) age of 57.67 (12.94) years. Among the 666 patients included in the analysis, the overall incidence of VTE was 2.1%. The incidence of VTE was statistically significantly higher in the IPC-only group compared with the IPC+LMW heparin group (3.6%; 95% CI, 2.05%-6.14% vs 0.6%; 95% CI, 0.17%-2.18%; P = .008). Among the 14 patients (2.1%) with VTE, 13 were asymptomatic and received a deep vein thrombosis diagnosis, whereas 1 patient received a symptomatic pulmonary thromboembolism diagnosis. The overall incidence of bleeding complications was 5.1%. The incidence of bleeding complications was significantly higher in the IPC+LMW heparin group compared with the IPC-only group (9.1% vs 1.2%; P < .001). No cases of VTE-associated mortality were noted. Conclusions and Relevance: Use of IPC alone is inferior to the use of IPC+LMW heparin in preventing postoperative VTE. Because LMW heparin is associated with a high bleeding risk, further study is needed to stratify the patients at high risk for perioperative development of VTE. Trial Registration: ClinicalTrials.gov Identifier: NCT01448746. PMID- 30027283 TI - Effect of Stress Ball Use or Hand-holding on Anxiety During Skin Cancer Excision: A Randomized Clinical Trial. AB - Importance: Patients undergoing skin surgery under local anesthesia can experience anxiety. Adjuvant intraoperative anxiety reduction methods may help. Objectives: To assess whether hand-holding or holding a stress ball reduces patient anxiety during excisional surgery of head or neck skin cancer with the patient under local anesthesia and to measure pain and patient satisfaction. Design, Setting, and Participants: In this nonblinded, single-center randomized clinical trial, performed from January 24 through April 26, 2017, at a dermatology outpatient service in an urban, academic medical center, a consecutive sample of 135 adults who required excisional removal of nonmelanoma skin cancer of the head or neck was randomized and studied. Interventions: Participants were randomized 1:1:1 to 3 groups: hand-holding, stress ball, or control (treatment as usual). Participants in the hand-holding group had a female researcher hold one of their hands during administration of anesthesia and extirpation, and those in the stress ball group held a round compressible ball and squeezed it as desired during the same period. Main Outcomes and Measures: The primary outcome was anxiety, measured by a visual analog scale (VAS), 6-item State Trait Anxiety Inventory (STAI), and physiologic measures (blood pressure and heart rate). Secondary outcomes were pain during the procedure and overall participant satisfaction. In addition, participants were asked how many hours they spent researching the procedure before surgery. Results: A total of 135 participants, 45 per study arm, were enrolled (mean [SD] age, 65.5 [13.9] years; 84 [62.2%] male; 134 [99.3%] white). There were no withdrawals or dropouts. Anxiety decreased over time in all groups, but no significant differences were found in the 3 anxiety measures across the 3 groups (VAS anxiety score before: control group, 3.11; hand-holding group, 3.04; stress ball group, 3.09 [P > .99]; VAS anxiety score during: control group, 1.89; hand-holding group, 2.31; stress ball group, 2.47 [P = .55]; STAI score: control group, 8.91; hand-holding group, 8.93; stress ball group, 8.76 [P = .96]). The 3 groups also did not significantly differ in postprocedure pain scores (control group, 0.78; hand-holding group, 0.64; stress ball group, 0.67; P = .85). Almost all participants (134 [99.2%]) were very satisfied. Participants who had done research had higher preoperative VAS anxiety scores (researched, 3.84; did not research, 2.62; P = .04). Conclusions and Relevance: Hand-holding and squeezing a stress ball do not appear to provide incremental anxiety reduction in patients during excisional skin cancer surgery. It is possible that some subgroups may respond better or that patients may respond better when able to select and tailor their preferred anxiety reduction method. Trial Registration: ClinicalTrials.gov identifier: NCT02816996. PMID- 30027284 TI - Incidence and Risk of Second Primary Malignant Neoplasm After a First Head and Neck Squamous Cell Carcinoma. AB - Importance: Second primary malignant neoplasms (SPMNs) are the leading cause of death in survivors of head and neck squamous cell carcinoma (HNSCC). Recently, human papillomavirus (HPV) has emerged as a risk factor for oropharyngeal squamous cell carcinoma and has different prognosis from classic tobacco/alcohol associated HNSCC. This suggests that there also may be different risks and burden of SPMNs among patients who's HNSCC were from HPV or tobacco and/or alcohol. Objective: To assess SPMN risks and burden in a large US cohort of patients with a first potentially HPV-associated HNSCC vs non-HPV-associated HNSCC. Design, Setting, and Participants: In this population-based retrospective cohort study, 109 512 adult patients diagnosed with HNSCC between 2000 and 2014 were identified from the Surveillance, Epidemiology, and End Results registry. Exposures: HPV relatedness based on whether patients' first HNSCC was potentially associated with HPV. Patients were grouped into 2 cohorts: potentially HPV-associated HNSCC, and non-HPV-associated HNSCC. Main Outcomes and Measures: The primary outcome was incidence of SPMN (defined as the first subsequent primary cancer occurring at least 2 months after first cancer diagnosis). Excess SPMN risk was calculated using relative (standardized incidence ratios [SIRs]) and absolute (excess absolute risk [EAR] per 10 000 person-years at risk [PYR]). Results: A total of 109 512 patients with HNSCC (mean [SD] age, 61.9 [12.1] years; 83 305 [76.1%] men) were identified. The overall SIR was 2.18 (95% CI, 2.14-2.22) corresponding to 160 excess cases per 10 000 PYR. The risk among patients with first potentially HPV-associated HNSCC (SIR, 1.98; EAR, 114 excess cases per 10 000 PYR) was lower than those with first non-HPV-associated HNSCC (SIR, 2.28; EAR, 188 excess cases per 10 000 PYR). Overall, the largest SIRs and EARs were observed for cancers of the head and neck, lung, and esophagus. However, the risks of SPMN were lower among potentially HPV-associated HNSCC patients. Conclusions and Relevance: Patients diagnosed with HNSCC experience excess risk of SPMN, which was higher among those with non-HPV-associated HNSCC than from potentially HPV-associated HNSCC. Clinicians should implement strategies that prevent or detect SPMN early in patients with HNSCC. PMID- 30027285 TI - Pericoronary Adipose Tissue Computed Tomography Attenuation and High-Risk Plaque Characteristics in Acute Coronary Syndrome Compared With Stable Coronary Artery Disease. AB - Importance: Pericoronary adipose tissue (PCAT) computed tomography (CT) attenuation measured from coronary CT angiography (CTA) may be a promising metric in identifying high-risk plaques. Objective: To determine whether high-risk plaque characteristics from coronary CTA are associated with PCAT CT attenuation in patients with a first acute coronary syndrome (ACS) and matched controls with stable coronary artery disease (CAD). Design, Setting, and Participants: This retrospective, single-center case-control study (data were acquired at the University of Erlangen from 2009-2010) analyzed the CTA data sets of 19 patients who presented with ACS and 16 controls with stable CAD who were matched based on sex, age, and risk factors. Study observers were blinded to patients' clinical data. Semiautomated software was used to quantify and characterize plaques. The CT attenuation (Hounsfield unit [HU]) of PCAT was automatically measured around all lesions. Main Outcomes and Measures: To investigate the association between high-risk plaque characteristics from CTA and PCAT CT attenuation as a novel surrogate measure of coronary inflammation. Results: A total of 35 patients (mean [SD] age, 59.5 [11.3] years; 30 men [86%] and 5 women [14%]) were included in the analysis. Low- and intermediate-attenuation noncalcified plaque (NCP) burden were increased in culprit lesions (n = 19) compared with both nonculprit lesions (n = 55) in patients with ACS (12.6% vs 3.6%; P < .001; 38.4% vs 19.4%; P < .001) and the control group's highest-grade stenosis lesions (n = 16) (12.6% vs 5.6%; P = .002; 38.4% vs 22.1%; P < .001). Pericoronary adipose tissue attenuation was increased around culprit lesions (n = 19) compared with nonculprit lesions (n = 55) in patients with ACS (-69.1 HU vs -74.8 HU; P = .01) and highest-grade stenosis lesions in control patients (n = 16) (-69.1 HU vs -76.4 HU; P = .01). Pericoronary adipose tissue CT attenuation of all lesions in patients with ACS (n = 74) correlated more strongly with intermediate-attenuation (r = 0.393; P = .001) over low-attenuation (r = 0.221; P = .06) and high-attenuation NCP burden (r = -0.103; P = .38). In a multivariable analysis, low- and intermediate attenuation NCP burden and PCAT CT attenuation were independently associated with the presence of culprit lesions (P < .05). Conclusions and Relevance: Pericoronary CT attenuation was increased around culprit lesions compared with nonculprit lesions of patients with ACS and the lesions of matched controls. Combined quantitative high-risk plaque features and PCAT CT attenuation may allow for a more reliable identification of vulnerable plaques. PMID- 30027286 TI - Key Points Section Missing. PMID- 30027289 TI - Association of Lowering Default Pill Counts in Electronic Medical Record Systems With Postoperative Opioid Prescribing. AB - Importance: Reliance on prescription opioids for postprocedural analgesia has contributed to the opioid epidemic. With the implementation of electronic medical record (EMR) systems, there has been increasing use of computerized order entry systems for medication prescriptions, which is now more common than handwritten prescriptions. The EMR can autopopulate a default number of pills prescribed, and 1 potential method to alter prescriber behavior is to change the default number presented via the EMR system. Objective: To investigate the association of lowering the default number of pills presented when prescribing opioids in an EMR system with the amount of opioid prescribed after procedures. Design, Setting, and Participants: A prepost intervention study was conducted to compare postprocedural prescribing patterns during the 3 months before the default change (February 18 to May 17, 2017) with the 3 months after the default change (May 18 to August 18, 2017). The setting was a multihospital health care system that uses Epic EMR (Hyperspace 2015 IU2; Epic Systems Corporation). Participants were all patients in the study period undergoing 1 of the 10 most common operations and discharged by postoperative day 1. Intervention: The default number of opioid pills autopopulated in the EMR when prescribing discharge analgesia was lowered from 30 to 12. Main Outcomes and Measures: Linear regression estimating the change in the median number of opioid pills and the total dose of opioid prescribed was performed. Opioid doses were converted into morphine milligram equivalents (MME) for comparison. The frequency of patients requiring analgesic prescription refills was also evaluated. Results: There were 1447 procedures (mean [SD] age, 54.4 [17.3] years; 66.9% female) before the default change and 1463 procedures (mean [SD] age, 54.5 [16.4] years; 67.0% female) after the default change. After the default change, the median number of opioid pills prescribed decreased from 30 (interquartile range, 15-30) to 20 (interquartile range, 12-30) per prescription (P < .001). The percentage of prescriptions written for 30 pills decreased from 39.7% (554 of 1397) before the default change to 12.9% (183 of 1420) after the default change (P < .001), and the percentage of prescriptions written for 12 pills increased from 2.1% (29 of 1397) before the default change to 24.6% (349 of 1420) after the default change (P < .001). Regression analysis demonstrated a decrease of 5.22 (95% CI, -6.12 to -4.32) opioid pills per prescription after the default change, for a total decrease of 34.41 (95% CI, -41.36 to -27.47) MME per prescription. There was no statistical difference in opioid refill rates (3.0% [4 of 135] before the default change vs 1.5% [2 of 135] after the default change, P = .41). Conclusions and Relevance: Lowering the default number of opioid pills prescribed in an EMR system is a simple, effective, cheap, and potentially scalable intervention to change prescriber behavior and decrease the amount of opioid medication prescribed after procedures. PMID- 30027290 TI - Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays. PMID- 30027291 TI - Revisiting the 2015 American Thyroid Association Guidelines With Respect to Indeterminate Thyroid Nodules in the Era of Noninvasive Follicular Thyroid Neoplasm With Papillary-like Nuclear Features. PMID- 30027292 TI - Association of Transforming Growth Factor beta Polymorphism C-509T With Radiation Induced Fibrosis Among Patients With Early-Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Whether genetic factors can identify patients at risk for radiation induced fibrosis remains unconfirmed. Objective: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. Design, Setting, and Participants: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. Exposures: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. Main Outcomes and Measures: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Results: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P = .02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P = .02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P < .001) were significantly associated with breast fibrosis risk. Conclusions and Relevance: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer. Trial Registration: ClinicalTrials.gov identifier: NCT01266642. PMID- 30027293 TI - Psychometric Properties of the Standardized Cosmesis and Health Nasal Outcomes Survey: Item Response Theory Analysis. PMID- 30027294 TI - Reward System Abnormalities in Anorexia Nervosa: Navigating a Path Forward. PMID- 30027296 TI - Schizencephaly revisited. AB - PURPOSE: In this paper, I will report the range of appearances of schizencephaly in children and fetuses by reviewing a 10-year experience from a single centre and detail classification systems for the different forms of schizencephaly. This will lead to re-assessment of possible aetiological and mechanistic causes of schizencephaly. METHODS: All cases of pediatric and fetal schizencephaly were located on the local database between 2007 and 2016 inclusive. The studies were reviewed for the presence, location and type of schizencephaly, as well as the state of the (cavum) septum pellucidum, the location of the fornices and the presence of other brain abnormalities. RESULTS: The review included 21 children and 11 fetuses with schizencephaly. Schizencephaly (type 1) was found in 9% of children but no fetuses, schizencephaly (type 2) was present in 67% of the pediatric cases and in 45% of fetuses, whilst schizencephaly (type 3) was present in approximately 24% of children and 55% of fetuses. Other brain abnormalities were found in 67% of children and 55% of fetuses. CONCLUSION: I have proposed a new system for classifying schizencephaly that takes into account all definitions of the abnormality in the literature. Using that approach, I have described the appearances and associations of pediatric and fetal cases of schizencephaly from a single centre. Review of the current literature appears to favour an acquired destructive aetiology for most cases of schizencephaly, and I have proposed a mechanism to explain the cortical formation abnormalities found consistently in and around areas of schizencephaly. PMID- 30027295 TI - Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis. AB - Fibrosis is a pathological form of aberrant tissue repair, the complications of which account for nearly half of all deaths in the industrialized world. All tissues are susceptible to fibrosis under particular pathological sets of conditions. Though each type of fibrosis has characteristics and hallmarks specific to that particular condition, there appear to be common factors underlying fibrotic diseases. One of these ubiquitous factors is the paradigm of the activated myofibroblast in the promotion of fibrotic phenotypes. Recent research has implicated metabolic byproducts of the amino acid tryptophan, namely serotonin and kynurenines, in the pathology or potential pharmacologic therapy of fibrosis, in part through their effects on development of myofibroblast phenotypes. Here, we review literature underlying what is known mechanistically about the effects of these compounds and their respective pathways on fibrosis. Pharmacologic administration of kynurenine improves scarring outcomes in vivo likely not only through its well-characterized immunosuppressive properties but also via its demonstrated antagonism of fibroblast activation and of collagen deposition. In contrast, serotonin directly promotes activation of fibroblasts via activation of canonical TGF-beta signaling, and overstimulation with serotonin leads to fibrotic outcomes in vivo. Recently discovered feedback inhibition between serotonin and kynurenine pathways also reveals more information about the cellular physiology of tryptophan metabolism and may also underlie possible paradigms for anti-fibrotic therapy. Together, understanding of the effects of tryptophan metabolism on modulation of fibrosis may lead to the development of new therapeutic avenues for treatment through exploitation of these effects. PMID- 30027297 TI - Effect of a community-based childhood obesity intervention program on changes in anthropometric variables, incidence of obesity, and lifestyle choices in Spanish children aged 8 to 10 years. AB - : Results of community-based childhood obesity intervention programs do not provide strong evidence for their effectiveness. In this study, we evaluated the effect of the Thao-Child Health Program (TCHP), a community-based, multisetting, multistrategy intervention program for healthy weight development and lifestyle choices. In four Catalan cities, a total of 2250 children aged 8 to 10 years were recruited. Two cities were randomly selected for the TCHP intervention, and two cities followed usual health care policy. Children were selected from 41 elementary schools. Weight, height, and waist circumference were measured at baseline and after a mean follow-up of 15 months. Physical activity and adherence to the Mediterranean diet were measured with validated questionnaires. Generalized estimating equations (GEE) models were fitted to determine the intervention's effect on body mass index (BMI) z-score, waist-to-height ratio, Mediterranean diet adherence, and physical activity. Fully adjusted models revealed that the intervention had no significant effect on the BMI z-score, incidence of general and abdominal obesity, Mediterranean diet adherence, and physical activity. Waist-to-height ratio was significantly lower in controls than in the intervention group at follow-up (p < 0.004). CONCLUSIONS: The TCHP did not improve weight development, diet quality, and physical activity in the short term. What is Known: * There is inconsistent evidence for the efficacy of school based childhood obesity prevention programs. * There is little evidence on the efficacy of childhood obesity intervention programs in other settings. What is New: * This paper contributes information about the efficacy of a multisetting and multistrategy Community Based Intervention (CBI) program that uses the municipality as its unit of randomization. * This CBI had no effect on the prevention and treatment of childhood obesity in the short term. PMID- 30027298 TI - Prevalence of vitamin D deficiency in cord blood of newborns and the association with maternal vitamin D status. AB - : Vitamin D deficiency is common in Southeast Asia but there are limited data in pregnant women and neonates. This study aimed to determine the prevalence of vitamin D deficiency in cord blood of newborns and the association with maternal vitamin D status. A total of 94 pregnant women and their neonates were included. Clinical data and venous maternal blood for calcium, phosphate, albumin, alkaline phosphatase, magnesium, intact parathyroid hormone (iPTH), and vitamin D (25OHD) were obtained on the day of labor. Cord blood was collected following delivery to evaluate vitamin D status of newborns. Mean serum maternal and cord blood 25OHD levels were 25.42 +/- 8.07 and 14.85 +/- 5.13 ng/mL. The prevalence of vitamin D deficiency (25OHD < 12 ng/mL) and insufficiency (25OHD 12-20 ng/mL) in cord blood of newborns were 20.2 and 69.1%, respectively. There was a significant correlation between maternal and cord blood vitamin D levels (r = 0.86; P < 0.001). The factors associated with cord blood vitamin D deficiency were low maternal 25OHD level and no vitamin D supplement during pregnancy. CONCLUSION: There is a high prevalence of vitamin D deficiency among Thai neonates. Adequate prenatal vitamin D supplementation should be implemented as routine antenatal care. What is Known: * Vitamin D deficiency is prevalent in Southeast Asia. * There are widespread vitamin D deficiency among Thai populations including pregnant women. What is New: * There is a high prevalence of vitamin D deficiency among Thai neonates. * The factors associated with cord blood vitamin D deficiency are low maternal vitamin D level and no vitamin D supplement during pregnancy. PMID- 30027299 TI - IPD-MHC: nomenclature requirements for the non-human major histocompatibility complex in the next-generation sequencing era. AB - The IPD-MHC Database is the official repository for non-human MHC sequences, overseen and supported by the Comparative MHC Nomenclature Committee, providing access to curated MHC data and associated analysis tools. To address the increasing amount and complexity of data being submitted, an entirely upgraded version of the IPD-MHC Database was recently released to maintain IPD-MHC as the central platform for the comparison of curated MHC data. As a consequence, a new level of nomenclature standardisation is required between the different species to enable data submission and to allow the unambiguous inter- and intra-species comparison of alleles. However, any changes must retain the flexibility demanded by the unique biology of different taxonomic groups. Here, we describe the rationale for a standardised nomenclature system and summarise the changes that have been driven by the requirements of implementing the IPD-MHC database. This modified nomenclature system is essential to maintain the current functionality of IPD-MHC and provide a scalable future-proof database organisation to fully exploit the bioinformatic tools used for analysis. PMID- 30027300 TI - Sexual health in long-term breast cancer survivors. AB - PURPOSE: Sexual dysfunction is reported in women with breast cancer (BC). It is unclear whether symptoms persist over time as data comparing long-term survivors to controls are lacking. We compared sexual functioning in long-term breast cancer survivors (BCS) to controls and determined the impact of adjuvant therapy on sexual health. METHODS: A cohort of women with localized BC (1989-1996) was prospectively followed. BCS and controls (2005-2007) completed self-reported questionnaires. Sexual health was measured with the Sexual Activity Questionnaire (SAQ). Vasomotor, gynecological, and bladder symptoms were scored using the Menopausal Symptom Scale. Regression analysis was used to compare groups, with adjustment for age and secondly menopausal status. RESULTS: BCS (n = 248, 87%) and controls (n = 159, 95%) completed the SAQ at a median time from diagnosis of 12.5 years. BCS were older (62 vs 59 years, p = 0.0004) and more likely to be menopausal (94 vs 86%, p = 0.0025). Sexual activity did not differ significantly between BCS and controls, but when adjusted for menopausal status, pre/peri menopausal BCS were less likely to be sexually active than pre/peri-controls (odds ratio OR 0.12, p = 0.012). In those sexually active, no significant differences were noted on the SAQ Pleasure, Discomfort, and Habit scales. BCS reported worse gynecological symptoms and pre/peri-menopausal patients had more bladder complaints (standardized effect size 0.36 p = 0.002 and 1.11, p = 0.011). Adjuvant treatments were not significantly associated with sexual function, but BCS treated with chemotherapy reported worse gynecological symptoms. CONCLUSION: Sexual health and uro-genital symptom counseling should be provided to BCS, particularly pre/peri-menopausal patients, even at long-term follow-up. PMID- 30027301 TI - The evolution of three siderophore biosynthetic clusters in environmental and host-associating strains of Pantoea. AB - For many pathogenic members of the Enterobacterales, siderophores play an important role in virulence, yet the siderophores of the host-associating members of the genus Pantoea remain unexplored. We conducted a genome-wide survey of environmental and host-associating strains of Pantoea to identify known and candidate siderophore biosynthetic clusters. Our analysis identified three clusters homologous to those of enterobactin, desferrioxamine, and aerobactin that were prevalent among Pantoea species. Using both phylogenetic and comparative genomic approaches, we demonstrate that the enterobactin-like cluster was present in the common ancestor of all Pantoea, with evidence for three independent losses of the cluster in P. eucalypti, P. eucrina, and the P. ananatis-P. stewartii lineage. The desferrioxamine biosynthetic cluster, previously described and characterized in Pantoea, was horizontally acquired from its close relative Erwinia, with phylogenetic evidence that these transfer events were ancient and occurred between ancestral lineages. The aerobactin cluster was identified in three host-associating species groups, P. septica, P. ananatis, and P. stewartii, with strong evidence for horizontal acquisition from human pathogenic members of the Enterobacterales. Our work identifies and describes the key siderophore clusters in Pantoea, shows three distinct evolutionary processes driving their diversification, and provides a foundation for exploring the roles that these siderophores may play in human opportunistic infections. PMID- 30027302 TI - Fully automatic cross-modality localization and labeling of vertebral bodies and intervertebral discs in 3D spinal images. AB - PURPOSE: We present a cross-modality and fully automatic pipeline for labeling of intervertebral discs and vertebrae in volumetric data of the lumbar and thoracolumbar spine. The main goal is to provide an algorithm that is applicable to a wide range of different sequences and acquisition protocols, like T1- and T2 weighted MR scans, MR Dixon data, and CT scans. This requires that the learned models generalize without retraining to modalities and scans with unseen image contrasts. METHODS: We address this challenge by automatically localizing the sacral region combining local entropy-optimized texture models with convolutional neural networks. For subsequent labeling, local three-disc entropy models are matched iteratively to the spinal column. Every model-matched position is further refined by an intensity-based template-matching approach, based solely on the reduced intensity scale provided by the entropy models. RESULTS: We evaluated our method on 161 publicly available scans, acquired on various scanners. We showed that our method can deal with a wide range of different MR protocols as well as with CT data. We achieved a sacrum detection rate of 93.6%. Mean center accuracies ranged from 2.5 +/- 1.5 to 5.7 +/- 3.8 mm for the different sets of scans. CONCLUSION: We present a novel spine labeling framework that is applicable to a highly heterogeneous set of scans without retraining of the method. Our approach achieves high sacrum localization accuracy and shows promising labeling results. To the best of our knowledge, an algorithm able to deal with such a diverse set of MR and CT scans has not yet been presented in the literature. PMID- 30027303 TI - Autonomous neuro-registration for robot-based neurosurgery. AB - PURPOSE: Neuro-registration is of primary importance as it has a bearing on the accuracy of neurosurgery. Although the accuracy of surgical robots is within the acceptable medical standards, the overall surgical accuracy is dictated by the errors in the neuro-registration process. The purpose of this work is to automate the neuro-registration process to improve the overall accuracy of the robot-based neurosurgery. METHOD: A highly accurate 6-degree-of-freedom Parallel Kinematic Mechanism (6D-PKM) robot is used for both neuro-registration and neurosurgery. In neuro-registration, after measurement of points in the medical image space, the end-platform of the 6D-PKM surgical robot carrying the camera will autonomously navigate towards the fiducial markers to measure its coordinates in the real patient space. An accurate relationship between the medical image space and the real patient space is established, and the same robot will navigate the surgical tool to the target. RESULTS: In order to validate the proposed method for autonomous neuro-registration, experiments are performed using four phantoms. The four phantoms are as follows: PVC skull model, two acrylic blocks and a glass jar with coaxial shells. These phantoms are specifically designed to simulate the neurosurgical process. All the phantoms are registered successfully using the above-stated method. After autonomous neuro-registration, the coordinates of the target point are determined. Neurosurgery validation is carried out by attaching a 1-mm-diameter needle to the robot platform, which is autonomously traversed to reach the target point passing through the two 2-mm-diameter coaxial holes. The experiments are repeated, and the results reveal very good repeatability. CONCLUSION: A method for autonomous neuro-registration has been developed. The robot has been successfully registered using the above method. After successful neuro-registration the overall accuracy of the robot-based neurosurgery is considerably improved. The other benefits of the above method are as follows: elimination of line-of-sight problem, no need of extra unit for neuro registration, less time for registration, intraoperative registration, human error reduction and low cost. PMID- 30027304 TI - Reduced Clearance of Phenobarbital in Advanced Cancer Patients near the End of Life. AB - BACKGROUND AND OBJECTIVES: Little is known about the pharmacokinetics of phenobarbital in terminally ill cancer patients. We investigated whether phenobarbital clearance alters depending on the length of survival. METHODS: We retrospectively reviewed the clinical, laboratory, and therapeutic drug monitoring (TDM) records of patients who received parenteral or oral phenobarbital for 21 consecutive days or longer between 2000 and 2016. Patients were divided into non-cancer and cancer groups. Cancer patients were further stratified according to the survival interval after TDM: those who survived > 3 months were classified as long-surviving and the remainders short-surviving cancer patients. Phenobarbital clearance (CLPB) was calculated at steady state. Multiple comparisons of median CLPB were conducted among the three groups. RESULTS: Data were collected from 44 non-cancer patients and 34 cancer patients comprising 24 long-surviving and 10 short-surviving cancer patients. Among 10 short-surviving cancer patients, 4 had hepatic metastasis. Median CLPB (range) in short-surviving cancer patients [0.076 (0.057-0.114) L/kg/day] was significantly (p < 0.05) lower than that in non-cancer patients [0.105 (0.060-0.226) L/kg/day] and in long-surviving cancer patients [0.100 (0.082-0.149) L/kg/day]. CONCLUSION: Terminally ill patients with advanced cancer may have reduced CLPB, thereby TDM is recommended for these patients particularly near the end of life. PMID- 30027305 TI - Bioaccumulation and Cycling of Polycyclic Aromatic Hydrocarbons (PAHs) in Typical Mangrove Wetlands of Hainan Island, South China. AB - Mangrove wetlands are important coastal ecosystems in tropical and subtropical regions, and mangrove sediments and tissues often are the pollutant sinks due to their high organic matter contents. Polycyclic aromatic hydrocarbons (PAHs) in the mangrove sediments and tissues of nine species from three typical mangrove wetlands of Hainan Island were studied. The average concentration of PAHs in all mangrove tissues was 403 ng g-1 dw, with PAHs concentrations in leaf, branch, root, and fruit of 566, 335, 314, and 353 ng g-1 dw, respectively. PAHs levels were much higher in leaf than in other mangrove tissues, which may be caused partly by atmospheric deposition of PAHs. The dominant individual PAH compounds in mangrove tissues were phenanthrene (41.3%), fluoranthene (14.7%), and pyrene (11.4%), while in sediments were naphthalene (73.4%), phenanthrene (3.9%), and pyrene (3.6%), respectively. The biota-sediment accumulation factors of PAH congeners in the mangrove wetlands showed different patterns, with the most predominant of phenanthrene. The cycling of PAHs in the mangrove wetlands of Hainan Island also were estimated, and the results showed that the standing accumulation, the annual absorption, the annual net retention, the annual return, and the turnover period in all mangrove tissues of the community were 2228 ug m 2, 869 ug m-2 a-1, 206 ug m-2 a-1, 663 ug m-2 a-1, and 3.4 a, respectively. These results indicated that mangroves are playing an important role in retaining PAHs. PMID- 30027306 TI - Mercury Bioaccumulation in Two Species of Insectivorous Bats from Urban China: Influence of Species, Age, and Land Use Type. AB - Mercury (Hg) is a widespread, toxic pollutant, and China is the world's largest emitter. We investigated Hg concentrations of fur in Japanese pipistrelles (Pipistrellus abramus) and Chinese noctules (Nyctalus plancyi) from Chengdu, Sichuan Province, in relation to degree of urbanization. Bats were mist-netted in June and July 2013, and the fur was analyzed via atomic absorption. Statistical comparisons were made between ages, species, and site types with unpaired t tests and between Hg concentration and body condition with Spearman's rank correlations. Across sites, adult pipistrelles (n = 10) had significantly greater concentrations than adult noctules (n = 16). Adult N. plancyi (n = 16) had significantly greater concentrations than juvenile N. plancyi (n = 14). Contrary to our predictions, there was no significant difference in Hg values between urban (n = 3) and peri-urban (n = 6) locations for P. abramus. While small sample sizes precluded additional comparisons, the highest value (33 mg/kg) came from an adult female P. abramus in the agricultural area. The relationship between body condition and Hg concentration was insignificant. However, most pipistrelles (7/13) and no noctules (0/31) had concentrations > 10 mg/kg, a threshold associated with disruption of homeostatic control and mobility. All bats had concentrations > 0.2 mg/kg, which is associated with compromised immunity. These are the first published records of contaminant concentrations from bats in China. For future studies, we recommend P. abramus as a regional bioindicator, longer term assessments of pre- and post-exposure effects, and simultaneous assessment of blood and fur Hg concentrations. PMID- 30027307 TI - Endometrial cancer subtypes are associated with different patterns of recurrence. AB - PURPOSE: To evaluate the pattern of endometrial cancer recurrence according to its biological subtype in a large cohort of patients. PATIENTS AND METHODS: Patients were stage eligible if they had a description of registry risk of recurrence status and were not primary metastatic. Data were prospectively collected. The primary endpoints were the subtype-dependent pattern and time of recurrence. RESULTS: The median follow-up time was 84 months. The highest 10-year recurrence-free and overall survival were seen in the group of patients at low risk of recurrence, 83.1 and 94.1%, respectively. The 10-year recurrence-free survival for intermediate and high risk group was 65.7 and 56.2%, respectively, whereas the estimated 10-year overall survival for both groups was 84.5 and 79.3%, respectively. Patients at high risk demonstrated the highest levels of disease recurrence in the first 3-4 years after diagnosis and the most common site of metastasis was the lung. In contrast, the rate of recurrence for patients at intermediate and low risk of recurrence in the first 5 years was relatively low but remained continuous up to 10 years of follow-up. Overall, the most common site of relapse was local recurrence. CONCLUSION: Endometrial cancer subtypes are associated with different times and patterns of recurrence and this should be considered when determining the treatment strategy. PMID- 30027308 TI - Public awareness of sepsis is still poor: we need to do more. PMID- 30027311 TI - EUROSPINE Meetings 2018: Abstracts, 19-21 September. PMID- 30027309 TI - Rationale and Design of the Evaluation of Oral Anticoagulation for Reduction of Thrombo-embolism in Chinese Patients with Device-Detected Subclinical Atrial Fibrillation (ART-CAF) Trial: an Open-Label Registry-Based Clinical Trial. AB - PURPOSE: Subclinical atrial fibrillation (AF) was found in a large number of pacemaker patients. It is not certain whether there is a similar risk/benefit ratio for oral anticoagulation in patients with subclinical AF compared to patients with similar risk profiles and clinically diagnosed AF. Given the weakness of clinical evidence for oral anticoagulation in patients with device detected subclinical AF, specific recommendations in most guidelines for this population are scarce and rarely similar. METHODS: ART-CAF trial was primarily designed to evaluate the efficacy and safety of oral anticoagulant agent use in patients with device-detected subclinical AF at the approved dosage to prevent stroke and systemic arterial embolism. It is an open-label, registry-based, prospective, multicenter, cohort study, recruiting patients with subclinical AF first detected by a pacemaker, implantable cardioverter-defibrillator, or insertable cardiac monitor after device implantation for more than 3 months. The primary outcome is a composite of ischemic stroke and systemic arterial embolism. The primary safety outcome is the occurrence of clinically overt major bleeding. Approximately 750 patients will be needed to be enrolled to the two treatment groups in a 1:1 ratio until 66 primary efficacy outcomes are observed. The anticipated follow-up period is approximately 70 months from the enrollment of the first patient. CONCLUSIONS: ART-CAF evaluates the feasibility of selecting high-risk patients suitable for anticoagulation by AF burden combined with CHA2DS2-VASc score after pacemaker implantation and aims to select patients who could benefit from anticoagulation. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx ChiCTR1800016221. PMID- 30027312 TI - The fabrication of biomineralized fiber-aligned PLGA scaffolds and their effect on enhancing osteogenic differentiation of UCMSC cells. AB - The key factor of scaffold design for bone tissue engineering is to mimic the microenvironment of natural bone extracellular matrix (ECM) and guide cell osteogenic differentiation. The biomineralized fiber-aligned PLGA scaffolds (a PLGA/CaPs) was developed in this study by mimicking the structure and composition of native bone ECM. The aligned PLGA fibers was prepared by wet spinning and then biomineralized via an alternate immersion method. Introduction of a bioceramic component CaP onto the PLGA fibers led to changes in surface roughness and hydrophilicity, which showed to modulate cell adhesion and cell morphology of umbilical cord mesenchymal stem cells (UCMSCs). It was found that organized actin filaments of UCMSCs cultured on both a-PLGA and a-PLGA/CaP scaffolds appeared to follow contact guidance along the aligned fibers, and those cells grown on a PLGA/CaP scaffolds exhibited a more polarized cellular morphology. The a-PLGA/CaP scaffold with multicycles of mineralization facilitated the cell attachment on the fiber surfaces and then supported better cell adhesion and contact guidance, leading to enhancement in following proliferation and osteogenic differentiation of UCMSCs. Our results give some insights into the regulation of cell behaviors through design of ECM-mimicking structure and composition and provide an alternative wet-spun fiber-aligned scaffold with HA-mineralized layer for bone tissue engineering application. PMID- 30027313 TI - Acute and residual effects of aerobic exercise on fructose-induced postprandial lipemia on lean male subjects. AB - PURPOSE: The addition of fructose to one or more meals daily may lead to increased postprandial lipemia (PPL). Aerobic exercise has been successful in preventing those increases; however, the duration of exercise effects is still unknown. The aim of this study was to evaluate the acute and residual effects of aerobic exercise and fructose ingestion on PPL. METHODS: Twelve young and sedentary men completed a crossover blinded randomized trial. On day 0, they performed 45 min of aerobic exercise at 60% of VO2peak, or 45 min of resting. On day 1, they received a high-fat meal together with one of the following conditions: (a) a fructose-rich beverage (FRUCT), or (b) exercise performed 13 h before the fructose-rich beverage ingestion (FRUCTEX), or (c) a dextrose-based beverage (DEX). On day 2, all subjects received a high-fat meal plus dextrose. Five blood samples were taken on days 1 and 2, to measure triglycerides (TG), HDL cholesterol, VLDL, total cholesterol (TC), glucose and insulin. RESULTS: On day 1, the delta of the TG peak was higher for FRUCT compared to DEX condition (+ 73.7%; p = 0.019). Total area under the curve (AUC) of TG was lower on the condition FRUCTEX compared to FRUCT (+ 30%; p = 0.001). There was no effect of the beverages or the exercise on VLDL, TC, HDL and non-HDL cholesterol (p > 0.05). There were no differences found in any of the parameters assessed on day 2 (p > 0.05). CONCLUSIONS: Fructose consumption (0.5 g/kg) severely increased postprandial TG on day 1, but not on day 2. Previous exercise performance could lead to ~ 30% reduction on the AUC of postprandial TG in 13 h, but not after 37 h followed by fructose consumption. The regularity of physical exercise practice seems to be essential to promote a constant hypolipemic effect. PMID- 30027314 TI - The association between the inflammatory potential of diet and risk of developing, and survival following, a diagnosis of ovarian cancer. AB - PURPOSE: Inflammation has been implicated in ovarian carcinogenesis. This study evaluated two dietary indices: the Dietary Inflammatory Index (DII(r)) and the Empirical Dietary Inflammatory Pattern (EDIP), in relation to risk of developing, and survival following, a diagnosis of ovarian cancer. METHODS: Data came from the Australian Ovarian Cancer Study (1375 cases, 1415 population controls). DII and EDIP scores were computed from dietary information obtained using a semiquantitative food-frequency questionnaire. Logistic regression was used to assess the association between DII and EDIP scores and risk of ovarian cancer and proportional hazards models were used for survival analysis. RESULTS: A high DII score, reflecting a more pro-inflammatory diet, was associated with a modest increased risk of ovarian cancer [odds ratio (OR) DII scoreQ4 vs.Q1 = 1.31, 95% CI 1.06-1.63, ptrend = 0.014]. Likewise a high EDIP score was associated with an increase in risk of ovarian cancer [OR EDIP scoreQ4 vs.Q1 = 1.39, 95% confidence interval (CI) 1.12-1.73, ptrend = 0.002]. We found no association between DII or EDIP score and overall or ovarian cancer-specific survival. CONCLUSION: In conclusion, our results suggest that a pro-inflammatory diet modestly increases the risk of developing ovarian cancer. PMID- 30027315 TI - Ultra turrax(r) tube drive for the extraction of pesticides from egg and milk samples. AB - The Ultra turrax(r) tube drive, already successfully applied for the extraction of plant materials, has also proved to be suitable for the analysis of pesticides in eggs and milk. In comparison to the matrix solid-phase dispersion (MSPD), the extraction is less time-consuming at excellent extraction efficiency. Further advantages are the flexibility of the extraction conditions with respect to the pH value and water activity. So, even strongly acidic pesticides such as phenoxy carboxylic acids can be extracted. Eighty-nine GC-amenable and 75 LC-amenable pesticides, which had been detected successfully in whole chicken eggs following MSPD extraction and further processing according to Hildmann et al., could also be analyzed with the modified method. In addition, the analysis spectrum could be expanded by 4 GC- and 37 LC-amenable substances. Of the 208 pesticides tested, 205 substances could be detected in whole chicken eggs. Similar excellent results were achieved for the milk matrix. Furthermore, the modified extraction method allows a determination of the fat content from the same analysis approach. PMID- 30027316 TI - An optimized band-target entropy minimization for mass spectral reconstruction of severely co-eluting and trace-level components. AB - Gas chromatography-mass spectrometry (GC-MS) is a versatile analytical method but its data is usually complicated by the presence of severely co-eluting and trace level components. In this work, we introduce an optimized band-target entropy minimization approach for the analysis of complex mass spectral data. This new approach enables an automated mass spectral analysis which does not require any user-dependent inputs. Moreover, the approach provides improved sensitivity and accuracy for mass spectral reconstruction of severely co-eluting and trace-level components. The accuracy of our approach is compared to the automatic mass spectral deconvolution and identification system (AMDIS) with two controlled mixtures and a sample of Eucalyptus essential oil. Our approach was able to putatively identify 130 compounds in Eucalyptus essential oil, which was 46% in excess of that identified by AMDIS. This new approach is expected to benefit GC MS analysis of complex mixtures such as biological samples and essential oils, in which the data are often complicated by co-eluting and trace-level components. Graphical abstract ?. PMID- 30027317 TI - Methodical studies of the simultaneous determination of anions and cations by IC*CE-MS using arsenic species as model analytes. AB - The separation of the constituents of complex sample mixtures is a challenging task in analytical chemistry. Multidimensional separation systems are widely used to enhance the peak capacity. The comprehensive hyphenation of ion chromatography (IC) and capillary electrophoresis (CE) is promising because the two most important instrumental techniques in ion analysis are combined. In this report a new configuration for capillary anion chromatography is presented enabling the simultaneous IC*CE analysis of anions and cations using a switching valve. Electrospray ionization mass spectrometry (MS) was used for detection. A mixture of organic and inorganic arsenic species served as a model system. The coupling of anion chromatography to CE-MS was done via a modulator enabling periodical injections of the IC effluent into the CE. The injection parameters of the modulator were studied taking into account the complex transport situation. Graphical abstract ?. PMID- 30027318 TI - ZnO flower-rod/g-C3N4-gold nanoparticle-based photoelectrochemical aptasensor for detection of carcinoembryonic antigen. AB - A highly sensitive and selective photoelectrochemical (PEC) aptasensor was constructed for carcinoembryonic antigen (CEA) detection based on ZnO flower-rods (ZnO FRs) modified with g-C3N4-Au nanoparticle (AuNP) nanohybrids. The nanohybrids of g-C3N4-AuNPs can improve the visible light absorbance of ZnO FRs and enhance the PEC property. We designed a sandwichlike structure formed with DNA hybridization of NH2-probe1, CEA aptamer, and CuS-NH2-probe2 to detect CEA. The p-type semiconductor CuS nanocrystals (NCs) at the terminational part of sandwichlike structure work as electron traps to capture photogenerated electrons and consequently lead to a magnified photocurrent change. The results indicate that the photocurrent is increased when CEA antigen (Ag) is introduced. Since the sandwichlike structure is destroyed, CuS NCs are restricted to capture photogenerated electron. The PEC aptasensor for CEA determination is ranged from 0.01 ng.mL-1 to 2.5 ng.mL-1 with a detection of 1.9 pg.mL-1. The proposed aptasensor exhibits satisfactory PEC performances with rapid detection, great sensitivity and specificity. Specially, this PEC aptasensor shows a reliable result for the determination of CEA in invalid human serum compared with the ELISA method. The designed aptasensor may provide a new idea for a versatile PEC platform to determine various molecules. Graphical abstract ?. PMID- 30027319 TI - Quantification of Hv1-induced proton translocation by a lipid-coupled Oregon Green 488-based assay. AB - Passive proton translocation across membranes through proton channels is generally measured with assays that allow a qualitative detection of the H+ transfer. However, if a quantitative and time-resolved analysis is required, new methods have to be developed. Here, we report on the quantification of pH changes induced by the voltage-dependent proton channel Hv1 using the commercially available pH-sensitive fluorophore Oregon Green 488-DHPE (OG488-DHPE). We successfully expressed and isolated Hv1 from Escherichia coli and reconstituted the protein in large unilamellar vesicles. Reconstitution was verified by surface enhanced infrared absorption (SEIRA) spectroscopy and proton activity was measured by a standard 9-amino-6-chloro-2-methoxyacridine assay. The quantitative OG488-DHPE assay demonstrated that the proton translocation rate of reconstituted Hv1 is much smaller than those reported in cellular systems. The OG488-DHPE assay further enabled us to quantify the KD-value of the Hv1-inhibitor 2 guanidinobenzimidazole, which matches well with that found in cellular experiments. Our results clearly demonstrate the applicability of the developed in vitro assay to measure proton translocation in a quantitative fashion; the assay allows to screen for new inhibitors and to determine their characteristic parameters. Graphical abstract ?. PMID- 30027320 TI - Synthesis and application of ratio fluorescence probe for chloride. AB - As chloride ions (Cl-) play a vital role in maintaining normal physiological activity, detection of chloride ions is quite urgent. Hence, we developed chloride fluorescence probes to highly selectively and sensitively monitor chloride ions. The probe M2 with single emission has a high fluorescence quantum yield (Phi = 45%), and it is capable of quantitative detection of Cl- under physiological conditions (pH = 7.4) and pH = 5.0 with a linear range of 0.1-4.0 mM; nevertheless, it is of the switch-off type. We further synthesized a ratiometric fluorescent probe MY with M2 as raw material, which featured excellent selectivity and anti-interference, and large two-photon cross section (555 GM). The probe is conveniently used to detect Cl- in water samples and biological samples including human sweat, serum, and urine samples, indicating it holds great promise for chloride detection and biological application. Graphical abstract ?. PMID- 30027321 TI - Patient delay in TIA: a systematic review. AB - BACKGROUND: Patients who suffer a transient ischemic attack (TIA) have a high short-term risk of developing ischemic stroke, notably within the first 48 h. Timely diagnosis and urgent preventive treatment substantially reduce this risk. We conducted a systemic review to quantify patient delay in patients with (suspected) TIA, and assess determinants related to such delay. METHODS: A systematic review using MEDLINE and EMBASE databases up to March 2017 to identify studies reporting the time from onset of TIA symptoms to seeking medical help. RESULTS: We identified nine studies providing data on patient delay, published between 2006 and 2016, with 7/9 studies originating from the United Kingdom (UK). In total 1103 time-defined TIA patients (no remaining symptoms > 24 h), and 896 patients with a minor stroke (i.e., mild remaining symptoms > 24 h) were included (49.1% men, mean age 72.2 years). Patient's delay of more than 24 h was reported in 33.1-44.4% of TIA patients, with comparable proportions for minor stroke patients. Delays were on average shorter in patients interviewed at the emergency department than among patients seen at TIA outpatient clinics. Univariably associated with a shorter delay were (1) a longer duration of symptoms, (2) motor symptoms, (3) a higher ABCD2 score, and (4) correct patient's recognition as possible ischemic cerebrovascular event. CONCLUSIONS: More than a third of patients experiencing a TIA delays medical attention for more than a day, thus critically extending the initiation of stroke preventive treatment. There still seems to be insufficient awareness among lay people that symptoms suggestive of TIA should be considered as an emergency. Additional data and multivariable analyses are needed to define main determinants of patient delay. PMID- 30027322 TI - Bringing order to higher order motor disorders. AB - Majority of movements in everyday situations are complex and involve volition, planning of the movement and selection of the motor programme, all occurring before movement execution. Higher order motor disorders may be defined as abnormal motor behaviours resulting from disruption of any of the cortical processes that precede execution of the motor act. They are common in patients with neurodegenerative disorders, psychiatric diseases and structural brain lesions. These abnormal behaviours may be overlooked in the clinic, unless specifically evoked by the examiner. We discuss clinical and pathophysiological aspects of higher order motor disorders including: (1) disorders of disinhibition, such as grasp reflex and grasping behaviour, utilisation and imitation behaviour, motor preservations and paratonia; (2) disorders of motor intention such as motor neglect and motor impersistence; (3) alien limb syndrome; and (4) motor overflow phenomena, such as mirror movements and synkinesias. A video illustration of each phenomenon is provided. We place the findings from recent neurophysiological studies within the framework of theories of motor control to provide better insight into pathophysiology of different disorders. PMID- 30027325 TI - Editorial: Hand surgery and anatomy. PMID- 30027324 TI - Dermacentor reticulatus ticks (Acari: Ixodidae) distribution in north-eastern Poland: an endemic area of tick-borne diseases. AB - Dermacentor reticulatus is the second most important tick species in Poland. Although the north-eastern region of Poland is considered typical for D. reticulatus and is treated as a contiguous area of Eastern populations of the meadow ticks, the occurrence of this tick species in this region to date has been recorded as separate foci. The present report supplements data on the geographical distribution of D. reticulatus in urban and natural biotopes of north-eastern Poland (Warmia and Mazury province). In 2015-2017 (during the springtime activity of ticks) adult questing D. reticulatus were found in 13 of 25 monitored localities. Six sites are located in urbanized areas, within the administrative borders of the city of Olsztyn and seven sites are in natural biotopes in the central part of Warmia and Mazury. A total of 398 adult D. reticulatus ticks, including 257 females and 141 males, were collected. A comparison of data grouped according to urban and natural type of area revealed no statistical differences between them. Taking into account the habitat type, the mean tick density was the highest in open landscapes. The identification of new foci D. reticulatus in the endemic areas of Lyme borreliosis, tick-borne encephalitis and canine babesiosis is crucial for determining the risk of diseases transmitted by ticks and taking proper preventive measures. PMID- 30027323 TI - In vitro acaricidal activity of Piper nigrum and Piper longum fruit extracts and their active components against Rhipicephalus (Boophilus) microplus ticks. AB - In vitro acaricidal activity of Piper nigrum and P. longum fruit extracts and their active components (piperine for P. nigrum and piperine and piperlonguminine for P. longum) was evaluated against adults engorged females of Rhipicephalus (Boophilus) microplus using adult immersion test. Three concentrations of each extract with four replications were used in the bioassay. Extracts significantly affected mortality rates of ticks in dose-dependent manner ranged 12.5-95.8% for P. nigrum and 29.2-87.5% for P. longum, with an additional effect on the reproductive physiology of ticks by inhibiting oviposition (28.1-96.9% by P. nigrum and 36.1-89.3% by P. longum). However, the acaricidal and oviposition limiting properties were decreased significantly when the active component(s) of each extract was tested separately. However, the combination of piperine and piperlonguminine (obtained from P. longum extract) caused 79.2% mortality of ticks which is equivalent to the corresponding concentration (~ 5%) of the extract. It can be concluded that the fruit extracts of P. nigrum and P. longum had both acaricidal and oviposition limiting actions against the adults of R. (B.) microplus which could make it a valuable component of developing sustainable strategy for integrated tick management. PMID- 30027326 TI - The SAVE Technique : Large-Scale Experience for Treatment of Intracranial Large Vessel Occlusions. AB - BACKGROUND: The stent retriever assisted vacuum-locked extraction (SAVE) technique was introduced as an effective thrombectomy method in stroke patients suffering from intracranial large vessel occlusion (LVO). This article presents our multicenter, large-scale experience with SAVE. METHODS: The study involved a retrospective core team analysis of 200 patients undergoing mechanical thrombectomy using the SAVE technique due to intracranial LVO at 4 German centers. Primary endpoints were first-pass and overall complete/near complete reperfusion, defined as a modified thrombolysis in cerebral infarction (mTICI) score of 2c and 3. Secondary endpoints were the number of passes, time from groin puncture to reperfusion, embolization to new territories (ENT), postinterventional symptomatic intracranial hemorrhage (sICH), and favorable outcome at discharge, defined as a modified Rankin Scale (mRS) score <= 2. RESULTS: The median age was 78 years (interquartile range IQR 68-85). Median National Institutes of Health stroke scale (NIHSS) at admission was 16 (IQR 12 20). Occlusions sites were: internal carotid artery (ICA-T) in 39/200 (19.5%), M1 in 126/200 (63%), M2 in 30/200 (15%), and others in 5/200 (2.5%) cases. The primary endpoints were documented in 114/200 (57% first pass mTICI 2c or 3) and 154/200 (77% overall mTICI 2c or 3) patients, respectively. The overall median time from groin puncture to reperfusion was 34 min (IQR 25-52) with a median of 1 (IQR 1-2) attempts. An ENT was observed in 3 patients (1.5%) and the rate of sICH was 2.6%. The rate of successful reperfusion (mTICI >= 2b) on final angiograms was 95%. At discharge, 73/200 (36.5%) patients revealed a favorable outcome. CONCLUSION: Mechanical thrombectomy using the SAVE technique seems to be effective, fast and safe. First-line use of SAVE leads to high rates of complete and near complete reperfusion. PMID- 30027327 TI - MRI Phenotype of RELA-fused Pediatric Supratentorial Ependymoma. AB - PURPOSE: Epigenetic profiling has recently identified clinically and molecularly distinct subgroups of ependymoma. The 2016 World Health Organization (WHO) classification recognized supratentorial ependymomas (ST-EPN) with REL-associated protein/p65 (RELA) fusion as a clinicopathological entity. These tumors represent 70% of pediatric ST-EPN characterized by recurrent C11orf95-RELA fusion transcripts, which lead to pathological activation of the nuclear factor 'kappa light-chain-enhancer' of activated B-cells (NF-kappaB) signaling pathway. Cyclin dependent kinase inhibitor 2A (CDKN2A) inactivation has also been reported to correlate with poor prognosis. Here, we systematically describe magnetic resonance imaging (MRI) characteristics of RELA-fused ST-EPN, with respect to CDKN2A deletion status. METHODS: Our cohort of patients with ST-EPN (n = 57) was obtained from the database of the German Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy (DGNN), and tumors were diagnosed according to the 2016 WHO classification. Molecular characterization identified 47 RELA-fused tumors. We analyzed the preoperative MRI according to standardized criteria, and comparison was performed between CDKN2A altered (n = 21) and CDKN2A wild type (n = 26) tumors. RESULTS: The RELA-fused ST-EPN showed a spectrum of predominantly hemispheric tumors with cysts and necrosis. Statistical analysis on CDKN2A status revealed significant differences in terms of younger manifestation age (p =0.002) and more intratumoral hemorrhage in T2-weighted imaging (T2WI) (p =0.010) in wild type tumors; however, the location was not a parameter for differentiation. CONCLUSION: This study first provides comprehensive MRI data for RELA-fused ST-EPN as a distinct entity, with further interest on CDKN2A genomic status. Patient stratification by morphological MRI alone seems difficult at present. The results may support ongoing research in ST EPN within the framework of the radiogenomics concept. PMID- 30027328 TI - The experiences of older caregivers of cancer patients following hospital discharge. AB - PURPOSE: This study addressed the experiences of older caregivers of cancer patients in the 2 weeks following a hospital discharge. It sought to understand the challenges they face in providing supportive care to patients at home. METHODS: Qualitative descriptive interviews with a narrative approach were conducted with each caregiver at 1 and 2 weeks following the patient's discharge from the hospital. A thematic analysis approach was used to identify the themes that emerged from the caregiver interviews. RESULTS: Caregivers were primarily Caucasian (77%), were mostly 68 years of age or older (62%), and were primarily caring for a spouse (69%). Three key themes emerged from the qualitative analysis: caregiver and patient wellness are connected, caregivers' struggle with control issues, and challenges in communication with health professionals. CONCLUSIONS: These findings highlight psychosocial changes that caregivers experience over the 2-week time period following hospital discharge. Implications include the need to identify interventions to better prepare caregivers for the post-discharge period. PMID- 30027329 TI - Clinical and epidemiological factors associated with suicide in colorectal cancer. AB - PURPOSE: While increased suicidal tendencies among cancer patients have been well documented, this study aims to examine suicide rates and factors associated with suicide specifically in patients with colorectal cancer (CRC). METHODS: Patients diagnosed with CRC between the years of 1988-2010 were selected from the Surveillance, Epidemiology, and End Result (SEER) database. Comparisons with the general population were done using the National Center for Disease Control registry. RESULTS: One thousand three hundred eighty-one suicides among 884,529 patients were identified, with a standardized mortality ratio (SMR) of 1.53 (95% CI, 1.13-1.33) compared to the general population. No statistically significant difference in suicide rate was found with respect to age, marital status, socio economic status, surgical intervention, histologic subtype, or stage at diagnosis. Within the CRC population, Whites were significantly more likely to commit suicide than non-Whites (OR, 2.28; 95% CI, 1.89-2.75; P < 0.001), and males were significantly more likely than females (OR, 5.635; 95% CI, 4.85-6.54; P < 0.001). Most suicides occurred in patients with distal lesions in the sigmoid/rectosigmoid junction (P < 0.001). SMRs for CRC patients were 4.24 for females (95% CI, 3.69-4.86), 1.35 for males (95% CI, 1.28-1.43), 0.38 for African Americans (95% CI, 0.28-0.52), 1.77 for Whites (95% CI, 1.68-1.87), and 0.90 for other races (95% CI, 0.72-1.12). CONCLUSION: Identification of risk factors associated with suicide among patients with CRC is an important step in developing screening strategies and management of psychosocial stressors. These results could be helpful in formulating a comprehensive suicide risk scoring system for screening all cancer patients. PMID- 30027330 TI - Ex-Gaussian, Frequency and Reward Analyses Reveal Specificity of Reaction Time Fluctuations to ADHD and Not Autism Traits. AB - Both attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have been linked to increased reaction time variability (RTV), a marker of attentional fluctuation. Here we test whether specificity to either trait emerges when we examine (1) detailed ex-Gaussian and frequency RTV subcomponents, (2) effects while controlling for the other trait and (3) improvement in the RTV measures following rewards or a faster event rate. 1110 children aged 7-10 years from a population-based sample completed a Go/No-Go task under three conditions (slow, fast and incentives). We measured RTV with standard deviation of RT (SDRT), ex-Gaussian distribution measures (Sigma and Tau), RT fluctuations in cycles of ~14-90 s in all conditions (Slow-4 and Slow-5), and RT fluctuations in cycles of 2-14 s in the fast condition (Slow-2 and Slow-3). Parent-rated ADHD and ASD traits were obtained. All refined RTV components were linked to ADHD traits only and not to ASD traits, while Sigma did not relate to either trait. Although both ADHD and ASD social-communication traits were associated with SDRT, the association with social-communication impairments disappeared when controlling for ADHD traits. A reward-induced improvement in RTV measures, indicating malleability, emerged in relation to ADHD traits but not ASD traits. Under closer inspection, specificity emerges of high RTV to ADHD traits. For the clinician, our findings indicate that attentional fluctuation in children with high ASD traits may be due to co-occurring ADHD traits and emphasise how the effectiveness of rewards does not generalise from ADHD to ASD traits. PMID- 30027331 TI - Influence of Time Interval from Bariatric Surgery to Conception on Pregnancy and Perinatal Outcomes. AB - INTRODUCTION: Pregnancy in women submitted to bariatric surgery is increasing. Recommendations for surveillance of these pregnancies have been suggested, but an adequate time interval from surgery to conception, to avoid perinatal negative outcomes, is still controversial. MATERIAL AND METHODS: Medical records of pregnancies in women with previous bariatric surgery were retrieved and outcomes were assessed according to three different time thresholds (12, 18 and 24 months). The association between time from surgery to conception and the presence of adverse outcomes was analysed. RESULTS: Eighty-six pregnancies were assessed. Weight gain was higher (p = 0.014) and more adequate (p = 0.041) when pregnancy occurred more than 12 months after surgery. Foetal growth percentile was lower when pregnancy was achieved before 24 months following surgery (p = 0.021). No differences among groups were found in other assessed outcomes (BMI, gestational age at delivery, type of delivery, gestational diabetes, pregnancy hypertensive disease, anaemia, preterm delivery, foetal weight, foetal growth restriction, Apgar score, admission to neonatal intensive unit) in all considered thresholds. No association between time from surgery to conception and the presence of adverse outcomes was found. CONCLUSION: Despite differences found in maternal weight gain and foetal growth percentile, our study does not support the recommendation to delay pregnancy based on a fixed deadline. Other factors, including a more individualised approach, need to be considered. PMID- 30027332 TI - Perioperative Outcomes of Primary Bariatric Surgery in North-Western Europe: a Pooled Multinational Registry Analysis. AB - INTRODUCTION: The global prevalence of obesity has increased in recent decades, and bariatric surgery has become a part of the treatment algorithm of obesity. National high-quality registries enable large-scale evaluations of the use and outcome of bariatric surgery and may allow for improved knowledge. The main objective was to evaluate the rate and type of complications after primary bariatric surgery in three North-Western European countries using nationwide registries. MATERIALS AND METHODS: Data from three registries for bariatric surgery were used (January 2015-December 2016). All registries have nationwide coverage with data on patient characteristics, obesity-related diseases, surgical technique, complications, grading of complications, reinterventions, readmissions, and mortality. Eligibility criteria for bariatric surgery were similar and included body mass index of >= 40.0 or >= 35.0 kg/m2, with one or more obesity-associated diseases. RESULTS: A total of 35,858 procedures (32,177 primary) were registered. The most common procedure was gastric bypass in the Netherlands (78.9%) and Sweden (67.0%), and sleeve gastrectomy in Norway (58.2%). A total of 904 (2.8%) patients developed major complications after primary surgery and 12 patients (0.04%) died within 30 days. Total number of complications between the registries were comparable (p = 0.939). However, significant differences were seen for Clavien-Dindo Classification grades IIIb and IV (p < 0.001). Pooled readmission rates were 4.3% (n = 1386). DISCUSSION: Bariatric surgery is safely performed in the three evaluated countries. Standardization of registries and consensus of variables are essential for international comparison and may contribute to improved quality of treatment across nations. PMID- 30027333 TI - [Histopathological research laboratories in translational research : Conception and integration into the infrastructure of pathological institutes]. AB - A systematic review of histopathology from experimental animal systems is an essential part of up-to-date biomedical research. Pathologists at university hospitals are especially and increasingly challenged by these specialized and time-consuming duties. This article presents and analyzes a new laboratory structure of comparative experimental pathology-jointly lead by veterinary and human pathologists-which might solve this problem. The focus is on the establishment and full integration of this laboratory structure into a local, regional, and nationwide biomedical research cluster. A detailed comparison with an established structure of routine histopathology laboratories discusses merits and benefits as well as disadvantages. PMID- 30027334 TI - Relationship between vection and motion perception in depth. AB - This study examined the effects of cues to motion in depth - namely, stereoscopic (i.e., changing-disparity cues and interocular velocity differences) and changing size cues on forward and backward vection. We conducted four experiments in which participants viewed expanding or contracting optical flows with the addition of either or both cues. In Experiment 1, participants reported vection by pressing a button whenever they felt it. After each trial, they also rated the magnitude of the vection (from 0 to 100). In Experiments 2 and 3, the participants rated the perceived velocity and motion-in-depth impression of the flows relative to standard stimuli, respectively. In Experiment 4, the participants rated the perceived depth and distance of the display. We observed enhancements in vection, motion-in-depth impression, and perceived depth and distance when either or both types of cues indicated motion-in-depth, as compared to those when the cues did not (Experiments 1, 3, and 4). The perceived velocity changed with cue conditions only for the high velocity condition (Experiment 2). Correlational analyses showed that the vection can be best explained by the motion-in-depth impression. This was partially supported by the multiple regression analyses. These results indicate that the enhancement of vection caused by cues is related to the impression of motion-in-depth rather than the perceived velocity and perceived three-dimensionality. PMID- 30027336 TI - Implementing Optimal Designs for Dose-Response Studies Through Adaptive Randomization for a Small Population Group. AB - In dose-response studies with censored time-to-event outcomes, D-optimal designs depend on the true model and the amount of censored data. In practice, such designs can be implemented adaptively, by performing dose assignments according to updated knowledge of the dose-response curve at interim analysis. It is also essential that treatment allocation involves randomization-to mitigate various experimental biases and enable valid statistical inference at the end of the trial. In this work, we perform a comparison of several adaptive randomization procedures that can be used for implementing D-optimal designs for dose-response studies with time-to-event outcomes with small to moderate sample sizes. We consider single-stage, two-stage, and multi-stage adaptive designs. We also explore robustness of the designs to experimental (chronological and selection) biases. Simulation studies provide evidence that both the choice of an allocation design and a randomization procedure to implement the target allocation impact the quality of dose-response estimation, especially for small samples. For best performance, a multi-stage adaptive design with small cohort sizes should be implemented using a randomization procedure that closely attains the targeted D optimal design at each stage. The results of the current work should help clinical investigators select an appropriate randomization procedure for their dose-response study. PMID- 30027337 TI - Cyclic shift scheduling with on-call duties for emergency medical services. AB - In workforce scheduling for emergency medical services, it is important to ensure sufficient coverage at all time. Thus, planning has to consider unpredictable employee absences. To hedge against this type of uncertainty, on-call duties can be assigned to employees. In practice, these are often assigned ex-post based on the regular schedule. Little literature on workforce scheduling for ambulances or the planning of on-call duties exists. We present new set covering based integer programming formulations for cyclic stint-based staff scheduling with on-call duties. It is desirable for employees to work on consecutive days, called a stint, with a subsequent recovery period. On-call duties can be individually scheduled in-between two stints. Our model formulations integrate different cycle times for regular and on-call duties. A simple schedule that repeats quickly is devised for regular duties, while the on-call duty schedule rotates after each cycle to ensure fairness. The proposed models are applied to a local German emergency medical services provider. Using our stint-based model formulations, the planning complexity has been greatly reduced and reasonably large problem instances can be solved to optimality. Employee preferences, such as fairness, less work on weekends and longer recovery times, were taken into account to a high degree. PMID- 30027338 TI - Resveratrol as a Therapy to Restore Neurogliogenesis of Neural Progenitor Cells Infected by Toxoplasma gondii. AB - The intracellular protozoan Toxoplasma gondii may cause congenital toxoplasmosis and serious brain damage in fetus. However, the underlying mechanism of neuropathogenesis in brain toxoplasmosis remains unclear. For this study, neural progenitor cells (NPCs) were obtained from embryo telencephalons (embryonic day 13) and induced to proliferation in the presence of growth factors (GFs). For gathering insights into the biological effects of resveratrol (RSV) on neurogenesis, this study aimed to investigate effects of RSV concentrations (0.1 to 100 MUM) on proliferation, migration and differentiation of NPCs infected by T. gondii. T. gondii infection increased the presence of cells in Sub G1 phase, reducing the global frequency of undifferentiated cells in S and G2/M phases of cell cycle and reduced cell viability/mithochondrial activity of infected NPCs. Moreover T. gondii stimulated neural migration and gliogenesis during neutral differentation. However, the treatment with RSV stimulated cell proliferation, restored cellular viability of infected NPCs and exerted an inhibitory effect on gliogenesis of infected NPCs favorecing neuronal maturation during toxoplasmosis infection. Thus, we have successfully to demonstrated that RSV is promising as therapeutic for congenital toxoplasmosis. PMID- 30027339 TI - Correction to: Growth Factors and Neuroglobin in Astrocyte Protection Against Neurodegeneration and Oxidative Stress. AB - The original version of this article unfortunately contained a typo error. The name of author "Ghulam Md Ashrad" should be written as "Ghulam Md Ashraf". PMID- 30027340 TI - IVIG Delays Onset in a Mouse Model of Gerstmann-Straussler-Scheinker Disease. AB - Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti Abeta autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Straussler-Scheinker (GSS) Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases. PMID- 30027341 TI - Hepcidin Mediates Transcriptional Changes in Ferroportin mRNA in Differentiated Neuronal-Like PC12 Cells Subjected to Iron Challenge. AB - Ferroportin is the only known iron exporter, and its regulation seems to be controlled at both transcriptional, post-transcriptional, and post-translational levels. The objective of the current work was to investigate how cellular iron status affects the expression of the ferroportin gene Fpn under the influence of hepcidin, known to post-translational lower the available ferroportin protein. Nerve growth factor-beta (NGF-beta)-differentiated PC12 cells, used as a model of neuronal cells, were evaluated in terms of their viability and expression of ferroportin after inducing cellular iron overload with ferric ammonium citrate (FAC) or hepcidin, iron deficiency with deferoxamine (DFO), or hepcidin in combination with FAC or DFO. Ferritin mRNA was significantly upregulated following treatment with 20 mM FAC. The viability of the differentiated PC12 cells was significantly reduced after treatment with 30 mM FAC or 1.0 MUM hepcidin, but when combining FAC and hepcidin treatment, the cells remained unaffected. The expression of Fpn was concurrently upregulated after treatment with FAC in combination with hepcidin. Fifty millimolar DFO also increased Fpn. Together, these data point towards a transcriptional induction of Fpn in response to changes in cellular iron levels. Epigenetic regulation of Fpn may also occur as changes in genes associated with epigenetic regulation of Fpn were demonstrated. PMID- 30027342 TI - Inhibition of GSK-3beta on Behavioral Changes and Oxidative Stress in an Animal Model of Mania. AB - The present study evaluated the effects of AR-A014418 on behavioral and oxidative stress parameters of rats submitted to the animal model of mania induced by ouabain (OUA). Wistar rats were submitted to stereotaxic surgery and received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF), OUA, or AR-A014418. After 7 days, the animals were submitted to open field test. After behavioral analysis, the brains were dissected in frontal cortex and hippocampus to the evaluation of oxidative stress. The OUA induced manic-like behavior in rats, which was reversed by AR-A014418 treatment. The ICV administration of OUA increases the levels of superoxide in submitochondrial particles, lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane, protein carbonyl, 3-nitrotyrosine, and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in both structures evaluated. In general, the treatment with AR-A014418 reversed these effects of OUA on the submitochondrial particles, LPH, 4-HNE, 8-isoprostane, protein carbonyl, 3-nitrotyrosine levels, and SOD activity. Furthermore, the injection of OUA decreased the catalase activity, and AR-A014418 promoted an increase in activity of this enzyme in the brain structures. These results suggest that GSK 3beta inhibition can modulate manic-like behaviors. Also, it can be suggested that inhibition of GSK-3beta can be effective against oxidative stress. However, more studies are needed to better elucidate these mechanisms. Graphical Abstract The effects of AR-A014418 on the behavioral and oxidative stress parameters in the animal model of mania induced by ouabain. Superoxide = superoxide production in submitochondrial particles; LPH = lipid hydroperoxide; 4-HNE = 4 hydroxynonenal; SOD = superoxide dismutase; GPx = glutathione peroxidase; GR = glutathione reductase. PMID- 30027343 TI - [Detection of drug risks after approval : Methods development for the use of routine statutory health insurance data]. AB - Adverse drug reactions are among the leading causes of death. Pharmacovigilance aims to monitor drugs after they have been released to the market in order to detect potential risks. Data sources commonly used to this end are spontaneous reports sent in by doctors or pharmaceutical companies. Reports alone are rather limited when it comes to detecting potential health risks. Routine statutory health insurance data, however, are a richer source since they not only provide a detailed picture of the patients' wellbeing over time, but also contain information on concomitant medication and comorbidities.To take advantage of their potential and to increase drug safety, we will further develop statistical methods that have shown their merit in other fields as a source of inspiration. A plethora of methods have been proposed over the years for spontaneous reporting data: a comprehensive comparison of these methods and their potential use for longitudinal data should be explored. In addition, we show how methods from machine learning could aid in identifying rare risks. We discuss these so-called enrichment analyses and how utilizing pharmaceutical similarities between drugs and similarities between comorbidities could help to construct risk profiles of the patients prone to experience an adverse drug event.Summarizing these methods will further push drug safety research based on healthcare claim data from German health insurances which form, due to their size, longitudinal coverage, and timeliness, an excellent basis for investigating adverse effects of drugs. PMID- 30027344 TI - [Breastfeeding in Germany-what do we know?] PMID- 30027345 TI - Highly sensitive fluorometric determination of thrombin by on-chip signal amplification initiated by terminal deoxynucleotidyl transferase. AB - The article describes an on-chip amplification scheme initiated by a terminal deoxynucleotidyl transferase (TdT) for highly sensitive fluorometric determination of protein. Two thrombin-binding aptamers were designed to capture thrombin as they can form a sandwich structure for improved specificity. An amino modified aptamer (TBA29) was first immobilized on a silicon chip. After capture of thrombin, a second aptamer (TBA15) was conjugated to the second binding site of thrombin. The 3'-terminal of aptamer TBA15 is exposed on the chip surface, and then fluorescein-labeled 12-dATP associates to the 3'-terminal with the help of TdT. This results in signal amplification, and eventually leads to highly sensitive detection. Under optimal conditions, fluorescence intensity is linearly related to the logarithm of thrombin concentration in the range of 100 fM - 0.1 MUM, and the detection limit is as low as 2.0 fM. The assay is sensitive and selective even over potentially interfering proteins and in the presence of human serum. Graphical abstract Schematic strategy for thrombin detection. Two thrombin binding aptamers were designed to capture thrombin to form a sandwich structure for improved specificity. The protein detection is based on TdT initiated on-chip fluorescent amplification. PMID- 30027347 TI - Neuroimaging Findings in Sepsis-Induced Brain Dysfunction: Association with Clinical and Laboratory Findings. AB - BACKGROUND: Incidence and patterns of brain lesions of sepsis-induced brain dysfunction (SIBD) have been well defined. Our objective was to investigate the associations between neuroimaging features of SIBD patients and well-known neuroinflammation and neurodegeneration factors. METHODS: In this prospective observational study, 93 SIBD patients (45 men, 48 women; 50.6 +/- 12.7 years old) were enrolled. Patients underwent a neurological examination and brain magnetic resonance imaging (MRI). Severity-of-disease scoring systems (APACHE II, SOFA, and SAPS II) and neurological outcome scoring system (GOSE) were used. Also, serum levels of a panel of mediators [IL-1beta, IL-6, IL-8, IL-10, IL-12, IL-17, IFN-gamma, TNF-alpha, complement factor Bb, C4d, C5a, iC3b, amyloid-beta peptides, total tau, phosphorylated tau (p-tau), S100b, neuron-specific enolase] were measured by ELISA. Voxel-based morphometry (VBM) was employed to available patients for assessment of neuronal loss pattern in SIBD. RESULTS: MRI of SIBD patients were normal (n = 27, 29%) or showed brain lesions (n = 51, 54.9%) or brain atrophy (n = 15, 16.1%). VBM analysis showed neuronal loss in the insula, cingulate cortex, frontal lobe, precuneus, and thalamus. Patients with abnormal MRI findings had worse APACHE II, SOFA, GOSE scores, increased prevalence of delirium and mortality. Presence of MRI lesions was associated with reduced C5a and iC3b levels and brain atrophy was associated with increased p-tau levels. Regression analysis identified an association between C5a levels and presence of lesion on MRI and p-tau levels and the presence of atrophy on MRI. CONCLUSIONS: Neuronal loss predominantly occurs in limbic and visceral pain perception regions of SIBD patients. Complement breakdown products and p-tau stand out as adverse neuroimaging outcome markers for SIBD. PMID- 30027348 TI - The Interictal Continuum: Look Before You Leap. PMID- 30027346 TI - The renal vasodilatory effect of prostaglandins is ameliorated in isolated perfused kidneys of endotoxemic mice. AB - Endotoxemia-related acute kidney injury (AKI) is associated with increased formation of prostaglandins, which may serve as a compensatory mechanism to maintain renal function. We hypothesized that an increase of renal EP2 or EP4 receptors and/or a downregulation of renal EP1 and EP3 receptors enhances PGE2 induced renal vasodilatation. Injection of lipopolysaccharide (LPS; 3 mg/kg i.p.) increased microsomal prostaglandin E synthase (mPGES)-1 and prostacyclin synthase expression, whereas mPGES-2 expression was unaltered. Further, LPS increased the mRNA abundance for the prostaglandin EP4 receptor, whereas the expressions of the EP1 and EP3 receptors were decreased. In isolated-perfused kidneys from control mice, PGE2 exerted a dual effect on renal vascular tone, inducing vasodilatation at lower concentrations and vasoconstriction at higher concentrations. In kidneys from endotoxemic mice, the vasodilatory component was more pronounced, whereas the vasoconstriction at higher PGE2 concentrations was absent. Similarly, prostacyclin (PGI2)-induced vasodilatation was more pronounced in endotoxemic kidneys. The enhanced vasodilatory effect was paralleled by an increase in renal vascular EP4 and prostacyclin IP receptor mRNA expression. Further, stimulation of renin secretion rate by PGE2 and PGI2 was enhanced in endotoxemic kidneys. Pretreatment with the cyclooxygenase (COX)-2 inhibitor SC-236 (10 mg/kg) did not alter the basal GFR, but augmented the LPS-induced decline in GFR, and attenuated the LPS-induced increase in plasma renin concentration in vivo. Our data suggest that an activation of the COX-2/mPGES-1 synthetic pathway is responsible for the increased renal formation of PGE2 in response to LPS and that the vasodilatory effect of PGE2 and PGI2 is enhanced during endotoxemia. PMID- 30027349 TI - Dupilumab: A Review in Moderate-to-Severe Atopic Dermatitis. AB - Dupilumab (Dupixent(r)), a subcutaneously administered, fully human IgG4 monoclonal antibody directed against the IL (interleukin)-4 receptor alpha subunit, blocks the signalling of IL-4 and IL-13, two T helper cell type 2 cytokines implicated in the immunopathology of atopic dermatitis (AD). It is the first biologic therapy to have been approved for the treatment of adult patients with moderate-to-severe AD in the EU and USA. In phase III trials in adults with moderate-to-severe AD who were inadequately controlled with topical medications and/or systemic treatments, such as ciclosporin, or for whom these therapies were not advisable, 16 weeks' treatment with dupilumab as monotherapy or in combination with topical corticosteroids (TCS) improved multiple measures of disease severity, pruritus, sleep disturbance, anxiety and depression, and quality of life compared with placebo. Moreover, the benefits of combination therapy at week 16 were maintained during long-term treatment for up to 1 year. Dupilumab, alone or added to TCS, was generally well tolerated, with low rates of serious adverse events and treatment discontinuations due to adverse events. Common adverse reactions included conjunctivitis, injection-site reactions and oral herpes. Thus, dupilumab represents a valuable new treatment option for adults with moderate-to-severe AD deemed appropriate for systemic therapy, a patient population for whom historically there has been a lack of safe and effective long-term treatments. PMID- 30027350 TI - Knowledge of features of inflammatory back pain in primary care in the West Midlands: a cross-sectional survey in the United Kingdom. AB - KEY MESSAGES: There is a relative lack of confidence among GPs in the assessment and management of IBP vs. mechanical back pain. A simple screening tool for SpA, applicable in primary care urgently needs to be developed. It is reasonable for patients with symptoms suggestive of inflammatory back pain to be referred to secondary care without further investigations. The objective of this study was to assess current practice of our local general practitioners (GPs) in using clinical features, as well as radiological and laboratory investigations to assess patients with IBP. An online, observational questionnaire-based survey was done in 10 West Midlands CCGs including disparate geographical and socioeconomic areas. The survey consisted of 23 questions based on Calin, Berlin and ESSG Criteria for spondyloarthropathies. GPs were asked to rate the importance of a range of symptoms as indications of IBP IBP (10 point scale, range 1-10), and what their views were on which were the most important treatments for patients with suspected inflammatory back pain(4 point scale, range 1-4). The 4 most important symptoms for predicting inflammatory back pain according to our local cohort of GPs were 'morning stiffness' 'sleep disturbances caused by back pain' 'insidious onset' and 'age of onset' < 45. Among the treatment options, NSAIDs were ranked as the most important treatment option for IBP. DMARDS were rated as the next most important treatment option, ahead of physiotherapy and anti-TNF therapy. This study has highlighted relative lack of confidence among GPs in the assessment of IBP. Whether this reflects a need for education or poor performance of these questions in primary care populations requires further study. PMID- 30027351 TI - A health professions education editors' open letter to our community. PMID- 30027352 TI - Intraprosthetic dislocation of dual mobility total hip arthroplasty: still occurring? AB - PURPOSE: The objective was to identify predictive factors for intraprosthetic dislocation (IPD) and to understand how improvements in dual mobility cups (DMC) have helped to reduce dramatically the occurrence of this complication. METHODS: DM mobile inserts retrieved from 93 hips were divided into three groups: first generation DMC with IPD ("firstDMC-IPD"), first-generation DMC with over 15 years of implantation without IPD ("firstDMC-noIPD"), and latest-generation DMC ("newDMC"). The predictive factors for IPD based on clinical, prosthetic, radiological and intraoperative characteristics were analysed by multivariate analysis. The surface of each retrieved mobile insert was analysed using three dimensional CT scan in order to compare their rim wear. RESULTS: Three predictive factors for IPD were found: a high BMI, a wide rough stem neck and a large cup size. Wear of the firstDMC-noIPD inserts was significantly less than those of firstDMC-IPD inserts and significantly more than those of newDMC inserts. For the firstDMC-IPD inserts, the rim's outer surface wear was significantly greater than the rim's inner surface wear. CONCLUSIONS: IPD is a specific complication related to wear of the DM mobile insert due to failure of the liner's retaining rim, especially from the rim's outer surface. This long-term issue is different to the early traumatic complication, which can happen after an attempt at closed reduction of a DM THA dislocation. Recent modifications in the design and the coating of contemporary DMC and femoral stems, as well as improvements in the mobile insert itself, seem to corroborate our assumptions about the IPD mechanism and contribute to the quasi-disappearance of this complication. PMID- 30027353 TI - Percutaneous endoscopic decompression via transforaminal approach for lumbar lateral recess stenosis in geriatric patients. AB - PURPOSE: We aimed to investigate the surgical strategy, safety, and efficacy of percutaneous endoscopic decompression via transforaminal approach for lumbar lateral recess stenosis in geriatric patients. METHODS: From January 2012 to June 2014, 25 elderly patients (18 males and 7 females) with symptomatic lumbar lateral recess stenosis were performed percutaneous endoscopic transforaminal decompression. The ages of patients ranged from 70 to 93 years (mean 79.6 years). Clinical outcomes were assessed mainly by leg pain visual analogue scale (VAS), Oswestry disability index (ODI) score, MacNab criteria, and post-operative computerized tomographic (CT) scanning. RESULTS: The surgery was successfully completed in all patients with an average operation time of 75 minutes (range, 50 110 min). The lumbar CT images at two days after the operation demonstrated distinct enlargement of the foramen intervertebrale as well as satisfactory decompression of the lumbar lateral recess. And 24 patients of the group were followed up for a mean duration of 29 +/- six months (range, 12-44 months). The leg pain VAS score decreased from 8.52 +/- 1.11 pre-operatively to 1.80 +/- 0.63, 1.33 +/- 0.89, 1.05 +/- 0.69, and 0.71 +/- 0.50 at one, three, six and 12 months after the operation, respectively. Besides, the ODI score also dropped from 59.43 +/- 10.04 pre-operatively to 29.42 +/- 10.33, 20.13 +/- 8.18, 13.98 +/- 6.16, and 9.86 +/- 5.03 at one, three, six and 12 months during the post-operative follow up period. Statistically significant differences existed in both VAS score and ODI score at each follow-up time point when compared with the pre-operative scores (P < 0.05). The mean reciprocal angulation change of the operated segment in dynamic lumbar lateral view was 3.2 degrees +/- 1.6 degrees at the last follow-up. And there were 18 excellent cases, three good cases, and three fair cases according to the MacNab criteria, and the excellent and good rate was 87.5% at 12 months after the operation. There was no aggravation of the coexisting medical conditions after operation in this group. Only 1 case was found complicated with lower extremity numbness, which was recovered by conservative treatment for two weeks. No persistent neurological deficit or soft tissue infection occurred in all patients post-operatively. CONCLUSIONS: We considered that percutaneous endoscopic transforaminal decompression achieved satisfactory results and provided a safe, effective, and less invasive alternative for treating lumbar lateral recess stenosis in geriatric patients. PMID- 30027354 TI - One-stage surgery for adult chronic osteomyelitis: concomitant use of antibiotic loaded calcium sulphate and bone marrow aspirate. AB - PURPOSE: To report our experience with one-stage treatment of chronic osteomyelitis using a prospective protocol involving the concomitant use of the antibiotic-loaded calcium sulphate pellets with addition of bone marrow aspirate after bony debridement. PATIENTS AND METHODS: A total of 30 patients with the mean age of 26.2 years were treated according to a protocol that included (1) surgical debridement of bone and infected tissues, (2) local antibiotic therapy including vancomycin and garamycin loaded on calcium sulphate space filling biodegradable pellets, (3) bone marrow aspirate added to the biocomposite, (4) primary closure with external fixation (when needed) and (5) intravenous antibiotics according to culture and sensitivity results. RESULTS: After a minimum of one year follow-up, infection was eradicated in 23 (76.7%) patients, the average rate of filling of the bony defect was 70.47%, complete filling of defect in 15 patients (50%) and pathological fracture in one patient. CONCLUSION: The technique proved safety and efficacy in eradicating the infection and bony healing of the defects after debridement. Simple bone marrow aspiration is cheap, reproducible, safe and not exhausting the scanty autograft resources. PMID- 30027355 TI - Correction to: Effectiveness of adjunctive hyaluronic acid application in coronally advanced flap in Miller class I single gingival recession sites: a randomized controlled clinical trial. AB - The figure 2 of the original version of this article was incorrect. Correct figure is presented below. PMID- 30027356 TI - A numerical study on hemodynamics in the left coronary bifurcation with normal and hypertension conditions. AB - In this study, a three-dimensional analysis of the non-Newtonian blood flow was carried out in the left coronary bifurcation. The Casson model and hyperelastic and rigid models were used as the constitutive equation for blood flow and vessel wall model, respectively. Physiological conditions were considered first normal and then compliant with hypertension disease with the aim of evaluating hemodynamic parameters and a better understanding of the onset and progression of atherosclerosis plaques in the coronary artery bifurcation. Two-way fluid structure interaction method applying a fully implicit second-order backward Euler differencing scheme has been used which is performed in the commercial code ANSYS and ANSYS CFX (version 15.0). When artery deformations and blood pressure are associated, arbitrary Lagrangian-Eulerian formulation is employed to calculate the artery domain response using the temporal blood response. As a result of bifurcation, noticeable velocity reduction and backflow formation decrease shear stress and made it oscillatory at the starting point of the LCx branch which caused the shear stress to be less than 1 and 2 Pa in the LCx and the LAD branches, respectively. Oscillatory shear index (OSI) as a hemodynamic parameter represents the increase in residence time and oscillatory wall shear stress. Because of using the ideal 3D geometry and realistic physiological conditions, the values obtained for shear stress are more accurate than the previous studies. Comparing the results of this study with previous clinical investigations shows that the regions with low wall shear stress less than 1.20 Pa and with high OSI value more than 0.3 are in more potential risk to the atherosclerosis plaque development, especially in the posterior after the bifurcation. PMID- 30027357 TI - An infant with hypercalcemia and hyperammonia: inborn error of metabolism or not? Questions. PMID- 30027358 TI - An infant with hypercalcemia and hyperammonia: inborn error of metabolism or not? Answers. PMID- 30027360 TI - Expression of iron-regulators in the bone tissue of rats with and without iron overload. AB - Recently, more and more studies indicate that iron overload would cause osteopenia or osteoporosis. However, the molecular mechanism of it remains unclear. Moreover, very little is known about the iron metabolism in bone tissue at present. Therefore, the mRNA expression of iron-regulators, transferrin receptor1 (Tfr1), divalent metal transporter1 (Dmt1 + IRE and Dmt1 - IRE), ferritin (FtH and FtL), and ferroportin1 (Ireg1), and the localization of ferroportin1 protein were examined in the bone tissue of rats. In addition, the mRNA expression of each gene was compared between groups of rats with and without iron overload. The results showed that ferroportin1 protein was localized in the cytoplasm of osteoblast, osteocyte, chondrocyte and osteoclast of rats' femur. The six iron-regulatory genes, Tfr1, ferritin (FtH and FtL), (Dmt1 + IRE and Dmt1 - IRE) and ferroportin1 (Ireg1), were found in femurs of rats. In addition, significantly up-regulated expression of FtH and FtL mRNA, and markedly down regulated expression of Tfr1, Dmt1 + IRE and Ireg1 mRNA, were observed in the iron overload group compared with the control group. The result indicates that ferroportin1 protein is localized in the cytoplasm of bone cells of rats. Tfr1, Dmt1, ferritin and ferroportin1 exist in bone tissue of rats, and they may be involved in the pathological process of iron overload-induced bone lesion. PMID- 30027359 TI - Self assembly and controlled drug release of a nano-laminated graphite carbon nitride/methotrexate complex. AB - In this study, g-C3N4/methotrexate (g-C3N4/MTX) nanohybrids were obtained via a self assembly method. XRD and TEM demonstrated that bulk g-C3N4 had been stripped into thin nanosheets with size range of 150-250 nm. FTIR investigation indicated that the self assembly of the hybrid was attributed to the hydrogen bond between g-C3N4 nanosheets and MTX molecules. It is confirmed by the UV-vis spectra that the hybrids can achieve a sustained drug release within long period for 70 h. Furthermore, the drug release mechanism was investigated by kinetic models and a first-order relationship was concluded, which indicated that the drug release is a simple diffusion process cohydroxyapatite/methotrexate complexntrolled by gradient drug concentration. Cell viability tests confirmed that g-C3N4 presented excellent biocompatibility and g-C3N4/MTX hybrids had obvious suppression efficiency on MG63 cells which showed a positive correlation to the drug concentration and incubation time. PMID- 30027361 TI - Lanthanum-containing bioparticles are associated with the influence of lanthanum on high phosphate mediated bone marrow stromal cells viability. AB - Lanthanum (La)-based binder appears effective in reducing serum inorganic phosphate (Pi) levels among chronic dialysis patients, yet concern remains about La accumulation in bone during long-term oral administration. In this study, the effect of lanthanum chloride (LaCl3) on bone marrow stromal cells (BMSCs) viability was investigated under high Pi situation. We found low concentration (10-9 M) of LaCl3 increased BMSCs viability, while high concentration (10-5 M) of LaCl3 not only inhibited BMSCs viability but also stimulated high Pi induced cell apoptosis. In addition, La-containing calcium phosphate (CaP) particles can be detected on cell surfaces and inside cells. We also found that inhibition of CaP formation by adding sodium pyrophosphate, a recognized inhibitor of hydroxyapatite formation, abrogated LaCl3 induced the BMSCs viability. For isolated La-containing CaP particles, the particle size increased and crystal phase switched with elevated concentration of LaCl3. These results demonstrated that La-containing CaP particles were associated with the process of LaCl3 mediated BMSCs viability and the physicochemical properties of these particles played an important role in modulating BMSCs function. PMID- 30027362 TI - Simultaneous determination of five azadirachtins in the seed and leaf extracts of Azadirachta indica by automated online solid-phase extraction coupled with LC-Q TOF-MS. AB - Neem (Azadirachta indica) extract is well-known as a natural pesticide for the control of agricultural pests. Azadirachtin A and its structural analogues are considered as active compounds. However, the amounts of azadirachtins varies in neem extracts, providing a variety of insecticidal activities. In this study, a novel method of automated online solid-phase extraction coupled with liquid chromatography/quadrupole-time-of-flight mass spectrometry (SPE-LC-Q-TOF-MS) was developed and validated for simultaneous quantification of five azadirachtins (azadirachtins A, B, D, H and I) in seed and leaf extracts of A. indica. Different experimental parameters (such as SPE cartridge, injection volume and washing step) were optimized. The optimized SPE-LC-Q-TOF-MS method showed good recovery (82.0-102.8%), linearity (r2 >= 0.9991) and precision (0.83-4.83%). The limit of detections (LODs) for the five analytes ranged from 0.34 to 0.76 ng mL 1. The validated method was successfully applied for determination of the analytes in the neem leaves and seeds from different locations and a neem formulation. The online SPE-LC-Q-TOF-MS method was found to be a simple, precise and accurate and can be used as a powerful tool for quality control of neem extracts or its formulations. PMID- 30027363 TI - Source apportionment of soil PAHs and human health exposure risks quantification from sources: the Yulin National Energy and Chemical Industry Base, China as case study. AB - The Yulin National Energy and Chemical Industry Base is widely known for its rich mineral resources and multi-type fossil chemical industry, yet little is known regarding the level of contaminants. Therefore, this study investigates the spatial distributions and potential exposure risk of ubiquitous polycyclic aromatic hydrocarbons (PAHs) contamination in this region and apportions PAHs source and source-oriented risk using two mathematical models, principal component analysis-multiple linear regression (PCA-MLR) model and positive matrix factorization (PMF) model coupling human health exposure risk. Results showed that ?16PAHs concentrations ranged from 110 to 4934 MUg/kg dw in 38 soil sampling sites. Compared with PCA-MLR model, PMF model is preferred method for source apportionment. Source apportionment results derived from PMF model indicated that the dominant contribution to ?16PAHs was from coal-derived sources (34% for coke oven emissions and 33% coal combustion source), followed by wood combustion (22%) and vehicular emission (11%). The human health exposure risk of each source category was quantitatively calculated for three exposure routes by combining the total carcinogenic risk (Total-CR) and total hazard index (Total-HI) values with identified source contributions. The results showed that increased Total-CR was highly apportioned from coke oven emissions source and coal combustion was identified as the major cause of increased Total-HI, even though it was less contributed to ?16PAHs. Moreover, the distributions of Total-CR and Total-HI apportionment for each source were significantly influenced by land utilization types. PMID- 30027365 TI - A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1alpha-SIRT3-UCP2 Axis. AB - A ketogenic diet (KD; high-fat, low-carbohydrate) can benefit refractory epilepsy, but underlying mechanisms are unknown. We used mice inducibly expressing a mutated form of the mitochondrial DNA repair enzyme UNG1 (mutUNG1) to cause progressive mitochondrial dysfunction selectively in forebrain neurons. We examined the levels of mRNAs and proteins crucial for mitochondrial biogenesis and dynamics. We show that hippocampal pyramidal neurons in mutUNG1 mice, as well as cultured rat hippocampal neurons and human fibroblasts with H2O2 induced oxidative stress, improve markers of mitochondrial biogenesis, dynamics and function when fed on a KD, and when exposed to the ketone body beta hydroxybutyrate, respectively, by upregulating PGC1alpha, SIRT3 and UCP2, and (in cultured cells) increasing the oxygen consumption rate (OCR) and the NAD+/NADH ratio. The mitochondrial level of UCP2 was significantly higher in the perikarya and axon terminals of hippocampus CA1 pyramidal neurons in KD treated mutUNG1 mice compared with mutUNG1 mice fed a standard diet. The beta-hydroxybutyrate receptor GPR109a (HCAR2), but not the structurally closely related lactate receptor GPR81 (HCAR1), was upregulated in mutUNG1 mice on a KD, suggesting a selective influence of KD on ketone body receptor mechanisms. We conclude that progressive mitochondrial dysfunction in mutUNG1 expressing mice causes oxidative stress, and that exposure of animals to KD, or of cells to ketone body in vitro, elicits compensatory mechanisms acting to augment mitochondrial mass and bioenergetics via the PGC1alpha-SIRT3-UCP2 axis (The compensatory processes are overwhelmed in the mutUNG1 mice by all the newly formed mitochondria being dysfunctional). PMID- 30027366 TI - Dietary Iron Modulates Glucose and Lipid Homeostasis in Diabetic Mice. AB - Imbalance of iron homeostasis has been involved in clinical courses of metabolic diseases such as type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver, through mechanisms not yet fully elucidated. Herein, we evaluated the effect of dietary iron on the development of diabetic syndromes in genetically obese db/db mice. Mice (aged 7 weeks) were fed with high-iron (HI) diets (1000 mg/kg chow) or low-iron (LI) diets (12 mg/kg) for 9 weeks. HI diets increased hepatic iron threefold and led to fourfold higher mRNA levels of hepcidin. HI also induced a 60% increase in fasting glucose due to insulin resistance, as confirmed by decreased hepatic glycogen deposition eightfold and a 21% decrease of serum adiponectin level. HI-fed mice had lower visceral adipose tissue mass estimated by epididymal and inguinal fat pad, associated with iron accumulation and smaller size of adipocytes. Gene expression analysis of liver showed that HI diet upregulated gluconeogenesis and downregulated lipogenesis. These results suggested that excess dietary iron leads to reduced mass, increased fasting glucose, decreased adiponectin level, and enhancement of insulin resistance, which indicated a multifactorial role of excess iron in the development of diabetes in the setting of obesity. PMID- 30027364 TI - Berberine Protects Secondary Injury in Mice with Traumatic Brain Injury Through Anti-oxidative and Anti-inflammatory Modulation. AB - Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide. Novel and effective therapy is needed to prevent the secondary spread of damage beyond the initial injury. The aim of this study was to investigate whether berberine has a neuroprotective effect on secondary injury post-TBI, and to explore its potential mechanism in this protection. The mice were randomly divided into Sham-saline, TBI-saline and TBI-Berberine (50 mg/kg). TBI was induced by Feeney's weight-drop technique. Saline or berberine was administered via oral gavage starting 1 h post-TBI and continuously for 21 days. Motor coordination, spatial learning and memory were assessed using beam-walking test and Morris water maze test, respectively. Brain sections were processed for lesion volume assessment, and expression of neuronal nuclei (NeuN), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), 8-hydroxy-2 deoxyguanosine (8-OHdG), ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) were detected via immunohistochemistry and immunofluorescence. There were statistically significant improvement in motor coordination, spatial learning and memory in the TBI-Berberine group, compared to the TBI-saline group. Treatment with berberine significantly reduced cortical lesion volume, neuronal loss, COX-2, iNOS and 8-OHdG expression in both the cortical lesion border zone (LBZ) and ipsilateral hippocampal CA1 region (CA1), compared to TBI-saline. Berberine treatment also significantly decreased Iba1- and GFAP-positive cell number in both the cortical LBZ and ipsilateral CA1, relative to saline controls. These results indicated that berberine exerted neuroprotective effects on secondary injury in mice with TBI probably through anti-oxidative and anti-inflammatory properties. PMID- 30027367 TI - Zinc Chelator Inhibits Zinc-Induced Islet Amyloid Polypeptide Deposition and Apoptosis in INS-1 Cells. AB - Amyloid deposition and beta cell apoptosis are characteristic pathological features of type 2 diabetes mellitus (DM). Islet amyloid polypeptide (IAPP) is the most abundant component of amyloid deposition. Monomeric IAPP does not form amyloid deposition, but the fibrous IAPP may aggregate and form amyloid deposits. Previous studies have shown that zinc is closely related to IAPP deposition through crosslink with monomeric IAPP into fibrous aggregates. In this study, we aimed to investigate whether chelating zinc could inhibit zinc-induced amyloid deposits and apoptosis of islet beta cell. N, N, N', N'-Tetrakis (2 pyridylmethyl) ethylenediamine (TPEN) is a specific chelator of zinc, with membrane permeability. It could effectively reduce the concentration of intracellular zinc. So, we used TPEN to treat hIAPP-transfected INS-1 cells. By MTT assay, the concentration (1 MUM) and incubation time (12 h) of TPEN without affecting cell viability were determined. The results showed that TPEN reduced zinc-induced IAPP deposition in the culture system. Furthermore, we analyzed the effect of zinc and TPEN on the apoptosis and insulin level. The results showed that TPEN could reverse zinc-induced INS-1 cell apoptosis and insulin secretion. And the anti-apoptosis effects of TPEN is related to extracellular regulated protein kinases (ERK)/c-jun N-terminal kinase (JNK) signaling pathway. The present data indicated that chelating zinc could inhibit zinc-induced amyloid deposition and beta cell apoptosis. Thus, maintaining zinc homeostasis in islet beta cell might become a useful strategy for DM therapy. PMID- 30027369 TI - A pediatric radiologist in Rwanda. PMID- 30027368 TI - The evidence for fungus in Crohn's disease pathogenesis. AB - Current evidence suggests the etiology of inflammatory bowel diseases (IBD) involves the confluence of host genetic, environmental, and microbial factors that lead to chronic, and often refractory, disease in susceptible individuals. The involvement of microbial triggers in IBD, including Crohn's disease (CD), is increasingly evident with supporting data provided with advancements in metagenomic sequencing that have identified perturbations in microbial structure and function-broadly termed dysbiosis-in CD patients compared with healthy subjects. This concept is supported by the finding germ-free animals with CD genetic susceptibility fail to develop disease; demonstrating microorganisms are necessary but not sufficient for CD. The vast majority of CD microbiome research has focused on the complex bacterial communities and microbiome dysbiosis in the gut with 16S metagenomic sequencing. However, emerging data capturing eukaryotes suggest fungal opportunistic pathogens are also associated with IBD pathogenesis and chronicity. This hypothesis is further supported by historical observations that CD patient populations display elevated antibodies against fungal targets, even evident before disease diagnosis. This review discusses the current findings in the field, followed by historical and metagenomic evidence for fungal pathogens in the development and recurrence of CD in adult and pediatric populations. PMID- 30027370 TI - A retrospective segmentation analysis of placental volume by magnetic resonance imaging from first trimester to term gestation. AB - BACKGROUND: Abnormalities of the placenta affect 5-7% of pregnancies. Because disturbances in fetal growth are often preceded by dysfunction of the placenta or attenuation of its normal expansion, placental health warrants careful surveillance. There are limited normative data available for placental volume by MRI. OBJECTIVE: To determine normative ranges of placental volume by MRI throughout gestation. MATERIALS AND METHODS: In this cross-sectional retrospective analysis, we reviewed MRI examinations of pregnant females obtained between 2002 and 2017 at a single institution. We performed semi-automated segmentation of the placenta in images obtained in patients with no radiologic evidence of maternal or fetal pathology, using the Philips Intellispace Tumor Tracking Tool. RESULTS: Placental segmentation was performed in 112 women and had a high degree of interrater reliability (single-measure intraclass correlation coefficient =0.978 with 95% confidence interval [CI] 0.956, 0.989; P<0.001). Normative data on placental volume by MRI increased nonlinearly from 6 weeks to 39 weeks of gestation, with wider variability of placental volume at higher gestational age (GA). We fit placental volumetric data to a polynomial curve of third order described as placental volume = -0.02*GA3 + 1.6*GA2 - 13.3*GA + 8.3. Placental volume showed positive correlation with estimated fetal weight (P=0.03) and birth weight (P=0.05). CONCLUSION: This study provides normative placental volume by MRI from early first trimester to term gestation. Deviations in placental volume from normal might prove to be an imaging biomarker of adverse fetal health and neonatal outcome, and further studies are needed to more fully understand this metric. Assessment of placental volume should be considered in all routine fetal MRI examinations. PMID- 30027371 TI - Liposomal borrelidin for treatment of metastatic breast cancer. AB - Borrelidin is an inhibitor of threonyl-tRNA synthetase with both anticancer and antiangiogenic activities. Although borrelidin could be a potent drug that can treat metastatic cancer through synergistic therapeutic effects, its severe liver toxicity has limited the use for cancer therapeutics. In this study, we developed a liposomal formulation of borrelidin to treat metastatic breast cancer effectively through its combined anticancer and antiangiogenic effects while reducing the potential liver toxicity. The liposomal formulation was optimized to maximize loading stability and efficiency of lipophilic borrelidin in the liposomal membrane and its delivery efficiency to primary tumor in a mouse model of metastatic breast cancer. Liposomal borrelidin showed significant in vitro therapeutic effects on proliferation and migration of tumor cells and angiogenesis of endothelial cells. Furthermore, liposomal borrelidin exhibited superior inhibitory effects on primary tumor growth and lung metastasis in vivo compared to free borrelidin. More importantly, liposomal borrelidin did not induce any significant systemic toxicity in the mouse model after multiple injections. PMID- 30027372 TI - Bone-targeted delivery of simvastatin-loaded PEG-PLGA micelles conjugated with tetracycline for osteoporosis treatment. AB - This study aimed to investigate the improved therapeutic efficacy and pharmacokinetic profiles of simvastatin (SIM) with imparted bone targeting potential using tetracycline-mediated PEG-PLGA (TC-PEG-PLGA) micelles in osteoporotic rats. The SIM-loaded TC-PEG-PLGA (TC-PEG-PLGA/SIM) micelles were evaluated for particle size, morphology, stability, loading efficiency, cell viability, bone mineral binding ability in vitro, mineralization, pharmacokinetics, and pharmacodynamics. TC-PEG-PLGA conjugates were successfully and could self-assembly form micelles in aqueous medium with a 19.4 MUg/mL critical micelle concentration. Then, TC-PEG-PLGA/SIM micelles were prepared with solvent diffusion method, and the obtained micelles (56.21 +/- 7.39 nm average size; 81.8 +/- 3.1% encapsulation efficiency; and 7.56 +/- 0.27% drug loading) led to the prolonged release of SIM from micelles. Cellular uptake test indicated that TC had no effects on micellar internalization and micellar internalization was mainly involved with clathrin-mediated endocytic pathway. In vivo pharmacokinetic results indicated that TC-PEG-PLGA/SIM micelles exhibited a significantly prolonged time in systemic circulation and were preferentially accumulated in bone tissue. TC-PEG-PLGA/SIM micelles showed better therapeutic effects, as reflected by the improved bone mineral density, bone mineral content, and bone mechanical strength. Overall, these results suggested that TC-PEG PLGA/SIM micelles provide several advantages, including prolonged systemic circulation, enhanced bone tissue distribution, and improved therapeutic outcomes in osteoporotic rats. PMID- 30027373 TI - Site-specific investigation and spatial modeling of canopy drip effect on element concentrations in moss. AB - In this study, the canopy drip effect on the exposure of forests to atmospheric deposition of potentially toxic metals and nitrogen (N) and element accumulation was investigated. Thereby, the respective element concentrations of metals and N in moss specimens were investigated by example of North-Western Germany. To this end, on the one hand, the concentrations of Al, As, Cd, Cr, Cu, Fe, Hg, Pb, Ni, Sb, V, Zn, and N in mosses sampled under, outside, and at the edge of forest canopies were examined for statistical significant differences. On the other hand, vegetation structures parameterizing the canopy drip effect were quantified by use of information collected, in addition to the element data, at each moss sampling site. The statistical relations between ratios of vegetation parameters and ratios of element concentrations were modeled by regression analysis, and the respective element concentration in moss was geostatistically estimated and mapped for unsampled locations throughout Germany. This article tackles regression models with R2 > 0.5 (Cu, Hg, Pb, Sb, and N) to adapt the element concentrations measured at the 400 sites of the European Moss Survey (EMS) to three different features of hypothetical vegetation structures. To this end, the continuum of vegetation structures were represented as follows: open land (meadows) described by a leaf area index (LAI) value of 2.96 and under canopy sites in coniferous forests represented by a LAI value of 11. The arithmetic mean of LAI values at 400 EMS sites throughout Germany amounts to 5.1. The element concentrations for these target LAIs representing three site categories were calculated and mapped. Then, these LAI-dependent element concentration maps were compared with the maps depicting the spatial patterns of "pure" element concentrations. Spatial differences were evaluated and supposed to be of great value for the validation of atmospheric deposition modeling. PMID- 30027374 TI - Treatment of synthetic dye baths by Fenton processes: evaluation of their environmental footprint through life cycle assessment. AB - Inorganic and organic constituents present in textile effluents have a noticeable effect on the performance of Fenton processes. However, studies have been focused on simple wastewater matrices that do not offer enough information to stakeholders to evaluate their real potential in large-scale facilities. Chemical auxiliaries, commonly present in textile wastewaters (NaCl = 30 g/L, Na2CO3 = 5 g/L, and CH3COONa = 1 g/L), affect both the economic and environmental performance of the process because they increase the treatment time (from 0.5 to 24 h) and the consumption of H2SO4 (657%) and NaOH (148%) during conditioning steps. The life cycle assessment (LCA) performed with the IPCC-2013 method revealed that dyeing auxiliaries increase from 1.06 to 3.73 (252%) the emissions of carbon dioxide equivalent (CO2-Eqv/m3). Electricity consumption can be considered an environmental hotspot because it represents 60% of the carbon footprint of the Fenton process. Also, the presence of auxiliaries is critical for the process because it results in the increase of the relative impact (between 50 and 80%) in all environmental categories considered by the ReCiPe 2008 method. Chemical auxiliaries increased the costs of the treatment process in 178% (US$2.22/m3) due to the higher energy consumption and the additional reagent requirements. It is worthwhile mentioning that the technical simplicity of the Fenton process and its low economic and environmental costs turn this process into an attractive alternative for the treatment of textile effluents in emerging economies. PMID- 30027375 TI - Potential of four aquatic plant species to remove 60Co from contaminated water under changing experimental conditions. AB - This study aimed to compare the potential of Lemna minor, Spirodela sp., Eichhornia crassipes and Pistia stratiotes to remove 60Co from a realistic aquatic environment. Although all four plant species performed similarly well after 3 days of exposure to 50 kBq L-1 60Co, Lemna minor and Spirodela sp. came forward as having higher 60Co removal potential. This conclusion is, in first instance, based on the high 60Co removal percentage obtained after a short contact time (e.g. more than 95% could be removed after 6 h by Spirodela sp.). Additionally, Lemna minor and Spirodela sp. accumulated a high amount of 60Co per gram of biomass. For example, Lemna minor accumulated over three times more 60Co per gram of biomass compared to Pistia stratiotes and Eichhornia crassipes. Both plants also performed well in the pH range 5-9. We used Lemna minor to test the influence of the initial 60Co concentration (10, 50, 100 and 200 kBq L-1 60Co) on its phytoremediation capacity but no differences could be observed in removal percentage. In addition, it was shown that by optimising the initial amount of biomass, radioactive waste production can be minimised whilst maintaining high 60Co removal rates. Our study shows that these aquatic plants can be used for phytoremediation of 60Co from contaminated water and can be considered as a "green" addition or alternative for conventional remediation techniques. PMID- 30027377 TI - Robustness of eco-industrial symbiosis network: a case study of China. AB - As a complex network, eco-industrial symbiosis network is featured with complexity, openness, and non-linearity. A methodology is proposed to analyze and optimize the eco-industrial symbiosis network from the perspective of complex network theory. Structural robustness index and performance robustness index are established as the analysis model. Consequently, a robust method is developed to optimize the eco-industrial symbiosis network system based on the percolation theory. A conceptual framework is put forward to improve the robustness of eco industrial symbiosis network system by introducing the "spare core" enterprise which is validated by quantitative analysis. The empirical results show that the robustness of eco-industrial symbiosis network varies under both random failure and intentional disturbance scenarios. However, eco-industrial symbiosis network system has strong self-regulation capability as long as the core enterprise is still in operation. It is recommended that supplementary chain could be added to those enterprises with lower network node connectivity to form "spare core" enterprise. This can not only effectively reduce the dependence of other enterprises on core enterprises, but also further improve the robustness of eco industrial symbiosis network. This methodology is practically validated by a case analysis of eco-industrial park in China. The findings provide useful inputs to the design and operation of eco-industrial parks. PMID- 30027376 TI - Arsenic removal from water by metal-organic framework MIL-88A microrods. AB - Fe-based metal-organic framework MIL-88A microrods were synthesized by hydrothermal method, which were used to adsorb As(V) in water for the first time. The experimental results indicated that MIL-88A has a very fast adsorption rate towards arsenic in water. The kinetic and isothermal data for arsenic removal were better fitted to the pseudo-second-order kinetic model and Langmuir model, respectively, implying a chemical and monolayer adsorption for As(V) on MIL-88A microrods. Two rate-controlling processes during adsorption were revealed by the intraparticle diffusion model. The maximum adsorption capacity of MIL-88A reached 145 mg g-1, higher than those of Fe-based MIL adsorbents reported previously, which probably originates from its unique microstructure with abundant OH- groups and an unusual large swelling towards water. These show that Fe-based MIL-88A is a good candidate for arsenic removal. PMID- 30027378 TI - Linguistic abilities in major vascular cognitive impairment: a comparative study with Alzheimer's disease. AB - We assessed the linguistic abilities of multi-infarct (cortical) dementia and subcortical ischemic vascular dementia (VaD) patients and compared the linguistic performance of VaD and Alzheimer's Disease (AD) patients. A total of 23 VaD patients, 20 mild AD patients, and 31 controls participated in the study. All were evaluated using the Arizona Battery for Communication Disorders of Dementia (ABCD). Neuropsychological testing was performed to ascertain that VaD and AD patients had comparable cognitive performance. Both dementia groups performed more poorly than controls in the ABCD measures, except for the comparative question subtest. Comparison between VaD and AD patients showed statistically significant differences only in the confrontation naming subtest (p < 0.05), where paraphasias and visual errors were the most prevalent. AD patients showed a trend towards more circumlocution errors than VaD patients (p = 0.0483). When compared to controls, linguistic abilities of VaD patients were impaired in all measures of linguistic expression and linguistic comprehension, except for the comparative question subtest. Linguistic differences between VaD and AD patients were observed only in the confrontation naming subtest. PMID- 30027379 TI - Adjunctive interferon-gamma immunotherapy in a pediatric case of Aspergillus terreus infection. AB - Aspergillus terreus causes invasive aspergillosis (IA) in immunocompromised patients. Treatment is complicated by intrinsic resistance to amphotericin B and thereby contributing to a high mortality. Therefore, we conducted in vitro studies to investigate the effectivity of adjunctive recombinant interferon-gamma immunotherapy. We describe a pediatric patient with A. terreus IA who received adjunctive recombinant interferon-gamma (rIFNgamma) immunotherapy. In vitro studies were conducted to investigate the capacity of rIFNgamma to improve antifungal host defense in terms of fungal killing ability and the release of pro inflammatory cytokines in cells of the patient as well as healthy controls. An 8 year-old female pediatric patient with leukemia developed A. terreus IA. She clinically deteriorated and had high serum galactomannan levels despite broad antifungal therapy. Therefore, adjunctive immune stimulatory therapy with rIFNgamma was initiated. After 3 weeks of treatment, galactomannan levels decreased and the patient clinically showed improvement. Addition of rIFNgamma boosted the capacity of monocytes of healthy volunteers to mount TNFalpha and IL 1beta cytokine responses to Escherichia coli LPS, and increased TNFalpha response to both A. terreus and Aspergillus fumigatus. Monocytes isolated from the patient's blood demonstrated a similar augmented cytokine induction in response to rIFNgamma. In addition, rIFNgamma increased the capacity of monocytes from healthy volunteers as well as monocytes from the patient to kill A. terreus spores. Adjuvant immunotherapy with rIFNgamma might be a promising additional treatment strategy that could be used to improve outcome in patients with refractory invasive A. terreus infections or other resistant invasive Aspergillus infections. PMID- 30027380 TI - The pregnancy outcomes in patients with stage 3-4 chronic kidney disease and the effects of pregnancy in the long-term kidney function. AB - OBJECTIVE: To investigate the pregnancy outcomes for patients with stage 3-4 chronic kidney disease (CKD) and the effects of pregnancy on kidney function. METHODS: Clinical data of pregnant women with CKD in the Peking University First Hospital between January 1st 2005 and October 1st 2016 were retrospectively analysed. The pregnancy outcomes of patients with different stages of CKD were compared. Patients with stage 3-4 CKD were followed up by telephone interview, and non-pregnant patients with stage 3-4 CKD were selected using the propensity score method to analyse the effects of pregnancy on kidney function. RESULTS: A total of 293 women with 300 pregnancies met the study criteria. There were 30 cases of stage 3-4 CKD. The incidence of adverse pregnancy outcomes of patients with stage 3-4 CKD was significantly higher than that with stage 1 CKD. The mean postpartum follow-up time of pregnant patients with CKD was 49.0 +/- 33.1 months. A total of 26 cases of stage 3-4 CKD were followed up. During the follow-up period, 8 patients progressed to ESRD. A total of 28 non-pregnant patients with stage 3-4 CKD were selected as the control group. The results of multivariate analysis revealed that pregnancy did not increase the risk of deterioration of kidney function. CONCLUSION: Patients with stage 3-4 CKD in early pregnancy had a significantly increased risk of adverse pregnancy outcomes. Pregnancy itself did not seem to accelerate kidney disease progression in patients with stage 3-4 CKD. PMID- 30027381 TI - Comparison of the outcome of laparoscopic procedures for GERD. AB - A total laparoscopic fundoplication has become the procedure of choice for the surgical treatment of gastroesophageal reflux disease in patients with normal esophageal motility, with reduced postoperative pain, faster recovery and similar long-term outcomes compared to conventional open total fundoplication. Most controversial surgical aspects are the division of the short gastric vessels and the insertion of a bougie to calibrate the wrap. The anterior 180 degrees and the posterior partial fundoplications lead to similar control of heartburn when compared to total fundoplication with lower risk of dysphagia. However, when performed, 24-h pH monitoring shows pathologic reflux more frequently after partial than total fundoplication. Disappointing results are achieved by anterior 90 degrees partial fundoplication. More recently, a magnetic sphincter augmentation with the LINX Reflux Management System (Torax Medical) and the lower esophageal sphincter Electrical Stimulation (EndoStim) have been developed, seeking for a durable and effective minimally invasive alternative to laparoscopic fundoplication for the treatment of reflux. Both devices seem to be promising, with very low postoperative complications and good short-term functional outcomes. Large randomized controlled trials comparing them with laparoscopic fundoplication over a long period of follow-up are needed to verify their indications and outcomes. PMID- 30027382 TI - Absence of dihydropteroate synthase gene mutations in Pneumocystis jirovecii strains isolated from Aegean region of Turkey. AB - Sulfonamide group drugs and their antimetabolite combinations are the most preferred drugs in the treatment and prophylaxis of Pneumocystis jirovecii pneumonia (PCP). Especially with the long-term use of trimethoprim sulfamethoxazole (TMP-SMX) and dapsone, certain point mutations in the Pneumocystis jirovecii (P. jirovecii) dihydropteroate synthase (DHPS) gene are known to play an important role in the development of resistance. In the present study, we investigated the 165th and 171st nucleotide mutations in the DHPS gene in the P. jirovecii isolates from immunosuppressed and immunocompetent cases. P. jirovecii isolates from the bronchoalveolar lavage fluid (BALF) samples of 31 hospitalized cases and lung tissue samples of 37 autopsy cases were included in the study. For the analysis of wild-type and mutant genotypes, after the touchdown-PCR amplification method, the restriction fragment length polymorphism (RFLP) method was used. In this study, P. jirovecii DHPS gene was amplified in 28 of 68 (41%) of the samples. The RFLP method revealed that all the isolates in which the DHPS gene was amplified were considered as wild-type genotypes. To our knowledge, this present study is the first study in Turkey investigating P. jirovecii DHPS gene mutations associated with the sulfonamide resistance. All the isolates showed a wild-type pattern indicating that the occurrence of P. jirovecii DHPS mutations in Turkey is very low or absent. PMID- 30027384 TI - More Things in Heaven and Earth: Spirit Possession, Mental Disorder, and Intentionality. AB - Spirit possession is a common phenomenon around the world in which a non corporeal agent is involved with a human host. This manifests in a range of maladies or in displacement of the host's agency and identity. Prompted by engagement with the phenomenon in Egypt, this paper draws connections between spirit possession and the concepts of personhood and intentionality. It employs these concepts to articulate spirit possession, while also developing the intentional stance as formulated by Daniel Dennett. It argues for an understanding of spirit possession as the spirit stance: an intentional strategy that aims at predicting and explaining behaviour by ascribing to an agent (the spirit) beliefs and desires but is only deployed once the mental states and activity of the subject (the person) fail specific normative distinctions. Applied to behaviours that are generally taken to signal mental disorder, the spirit stance preserves a peculiar form of intentionality where behaviour would otherwise be explained as a consequence of a malfunctioning physical mechanism. Centuries before the modern disciplines of psychoanalysis and phenomenological psychopathology endeavoured to restore meaning to 'madness,' the social institution of spirit possession had been preserving the intentionality of socially deviant behaviour. PMID- 30027385 TI - Who Originally Described Pindborg Tumor? PMID- 30027383 TI - Molecular characterization of triosephosphate isomerase from Echinococcus granulosus. AB - Cystic echinococcosis (CE) is a zoonosis that can be caused by the larvae of Echinococcus granulosus; this disease occurs worldwide and is highly endemic in China. E. granulosus can produce energy by glycolysis as well as both aerobic and anaerobic respirations. Triosephosphate isomerase is a glycolytic enzyme present in a wide range of organisms and plays an important role in glycolysis. However, there has been little research on triosephosphate isomerase from E. granulosus (Eg-TIM). Here, we present a bioinformatic characterization and the experimentally determined tissue distribution characteristics of Eg-TIM. We also explored its potential value for diagnosing CE in sheep using indirect enzyme linked immunosorbent assay (ELISA). Native Eg-TIM was located in the neck and hooks of protoscoleces (PSCs), as well as the tegument and parenchyma tissue of adult worms. The entire germinal layer was also Eg-TIM positive. Western blots showed that recombinant Eg-TIM (rEg-TIM) reacts with positive serum from sheep and had good immunogenicity. Indirect ELISA exhibited low specificity (53.6%) and low sensitivity (87.5%) and cross-reacted with both Taenia multiceps and Taenia hydatigena. Our results suggest that TIM may take part in the growth and development of E. granulosus. Furthermore, we determined that rEg-TIM is not a suitable serodiagnostic antigen for CE in sheep. PMID- 30027386 TI - Consistent LEF-1 and MYB Immunohistochemical Expression in Human Papillomavirus Related Multiphenotypic Sinonasal Carcinoma: A Potential Diagnostic Pitfall. AB - Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a distinct, newly-described sinonasal tract neoplasm characterized by a salivary gland tumor-like appearance with myoepithelial and ductal cells, frequent surface squamous dysplasia, and relatively indolent behavior. When considering a diagnosis of HMSC, aggressive high-grade salivary gland carcinomas, particularly those with a basaloid morphology such as basal cell adenocarcinoma and adenoid cystic carcinoma, enter the differential diagnosis. The full morphologic and immunophenotypic profile of HMSC continues to be unraveled. In this series of ten cases, we demonstrate that this tumor has consistent, strong immunohistochemical expression of LEF-1 yet lacks nuclear expression of beta-catenin, and also has consistent yet variable expression of MYB protein. While LEF-1 expression may be a useful diagnostic adjunct, it can also be a pitfall, as other salivary tumors such as basal cell adenocarcinoma have been previously shown to express LEF-1. Additionally, MYB protein expression is not a discriminatory marker when trying to separate HMSC from adenoid cystic carcinoma. PMID- 30027387 TI - Expedient multicomponent synthesis of a small library of some novel highly substituted pyrido[2,3-d]pyrimidine derivatives mediated and promoted by deep eutectic solvent and in vitro and quantum mechanical study of their antibacterial and antifungal activities. AB - A facile and efficient catalyst- and oxidant-free multicomponent synthesis of a small library of highly substituted pyrido[2,3-d]pyrimidine derivatives is reported. The products were obtained within relatively short reaction times in good to excellent yields in the presence of deep eutectic solvents as media and promoters. Simple purification and reusability of the deep eutectic solvent were the other beneficial factors of the reported protocol. All of the synthesized derivatives were thoroughly screened for possible in vitro antibacterial and antifungal effects against twenty-two bacterial and three fungal pathogens. Some of the prepared pyrido[2,3-d]pyrimidine derivatives showed remarkable antibacterial and antifungal activities in comparison with some typical known antibacterial and antifungal agents. Finally, the derivatives possessing bioactivity effects were subjected to quantum chemical computational studies in order to reveal the probable structural and electronic effects governing the spotted bioactivities. It was found that the observed bioactivities could be best devoted to the HOMO-LUMO energy gap and para delocalization index of the corresponding derivatives. PMID- 30027388 TI - Predictors of engagement in post-discharge quitline counseling among hospitalized smokers. AB - Quitlines provide evidence-based tobacco treatment and multiple calls yield higher quit rates. This study aimed to identify subgroups of smokers with greater quitline engagement following referral during hospitalization. Data were from a randomized clinical trial assessing the effectiveness of fax referral (referral faxed to proactive quitline) versus warm handoff (patient connected to quitline at bedside) (n = 1054). Classification and regression trees analyses evaluated individual and treatment/health system-related variables and their interactions. Among all participants, warm handoff, higher ratings of the tobacco treatment care transition, and being older predicted completing more quitline calls. Among patients enrolled in the quitline, higher transition of care ratings, being older, and use of cessation medication post-discharge predicted completing more calls. Three of the four factors influencing engagement were characteristics of treatment within the hospital (quality of tobacco treatment care transition and referral method) and therapy (use of cessation medications), suggesting potential targets to increase quitline engagement post-discharge. PMID- 30027389 TI - Co-occurring reasons for medication nonadherence within subgroups of patients with hyperlipidemia. AB - Medication nonadherence is a significant clinical problem among individuals taking statins. Poor adherence is often attributable to several reasons, yet most adherence interventions target a single reason. Baseline data were examined from a randomized clinical trial of 236 patients with hyperlipidemia. A latent class analysis was then performed on patients reporting any nonadherence (n = 109). A 4 class solution provided the most optimal fit and differentiation of classes. Class 1 (N = 59, 54%) included patients who reported occasionally forgetting. Class 2 (N = 16, 14%) represented patients who were concerned about side effects. Class 3 (N = 17, 16%) represented patients who reported out-of-routine life events as contributing to nonadherence. Class 4 (N = 17, 16%) represented patients who endorsed a large number reasons indiscriminately. Class membership was almost uniformly unrelated to any patient demographic factors or treatment arm. Each cluster of reasons defining these patients may be best addressed through different intervention strategies. PMID- 30027391 TI - Could sentinel lymph node biopsy be exempted for ductal carcinoma in situ after mastectomy? PMID- 30027393 TI - [No superiority of mattress versus conventional interrupted sutures for pancreaticojejunostomy]. PMID- 30027390 TI - Inflammatory Profiles of the Interleukin Family and Network in Cerebral Hemorrhage. AB - Cerebral hemorrhage is a series of devastating cerebrovascular diseases with high mortality, morbidity and recurrence rate. Localized and systemic immuno-reactions are involved. Aggregation of immunocytes, which were both recruited from the peripheral circulation and resident in the central nervous system, is induced and activated by hematoma-related blood components. Subsequently, various cytokines, chemokines, free radicals and toxic chemicals are secreted to participant host defense responses. Among these, neuro-inflammation plays critical roles in both the pathologic processes of secondary injuries and recovery of neural damages. Numerous treatment strategies have been proposed, aiming at controlling the balance between anti- and proinflammation. Here, we summarized our current understanding and potential clinical applications for cytokines of the interleukin family in the pathogenesis of hemorrhagic stroke. In addition, we conducted protein-protein network, gene ontology and KEGG analysis on the interleukins using online bioinformatic tools to further elaborate the comprehensive mechanisms of interleukins in cerebral hemorrhage. PMID- 30027394 TI - Correction to: Relevance of neuroimaging for neurocognitive and behavioral outcome after pediatric traumatic brain injury. AB - JC Goslings is the correct name of the sixth author of this article. PMID- 30027396 TI - Treatment dropout in a family-based partial hospitalization program for eating disorders. AB - Treatment dropout is a significant challenge in the treatment of eating disorders. In day hospital/partial hospitalization program settings, little is known about factors associated with treatment dropout. The purpose of the present study was to assess factors associated with treatment dropout in a partial hospitalization program for adolescents and young adults with anorexia nervosa. Patients and parents completed self-report and interview-based measures at baseline and at end of treatment in the partial hospitalization program. Few factors were found that differentiated the two groups. Those who dropped out had lower body weight at end of treatment, were less likely to have purged in the previous month, and had fathers who scored higher on the criticism subscale of expressed emotion. Patients who are purging may be seen as having more severe symptoms, thus possibly reducing the chances of parents prematurely discontinuing treatment. Parental criticism is a potentially modifiable factor in treatment. Further research is needed to identify effective ways to reduce parental criticism, and to identify additional modifiable factors associated with treatment dropout to reduce dropout rates in this population.Level IV: Evidence obtained from multiple time series with or without the intervention, such as case studies. PMID- 30027395 TI - Austrian recommendations for the management of polycythemia vera. AB - Polycythemia vera (PV) is a clonal disease arising from hematopoietic stem cells. Erythrocytosis is the hallmark of the disease but leukocytosis, thrombocytosis and splenomegaly may also be present. Thromboembolic complications occur in about 20% of patients. Circulatory disturbances as well as pruritus represent frequent symptoms of the disease. Mutations in the JAK2 gene are present in 95% of patients in exon 14 (V617F) and in 3% in exon 12. The main goal of the treatment for patients with PV is the prevention of thromboembolic events, transformation to myelofibrosis and acute myeloid leukemia. Interferon alpha and hydroxyurea are used as first-line treatment for high risk patients. For patients unresponsive to first-line therapy ruxolitinib is available. PMID- 30027398 TI - Regenerative Therapies for Parkinson's Disease: An Update. AB - Parkinson's disease is the second most common neurodegenerative disorder. It is characterised by a typical movement disorder that occurs in part because of the selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. Current treatment for the motor disorder of Parkinson's disease consists of dopaminergic medications, but these come with significant adverse effects, themselves an important part of the clinical course of Parkinson's disease, particularly in advanced stages. Therefore, treatment is needed that can restore dopaminergic tone in the striatum in a physiological and targeted manner to avert these side effects. A number of potential regenerative treatments have been developed with a view to achieving this. Following decades of optimisation and development of stem-cell-based treatments and viral gene delivery, clinical trials are on the horizon. For these treatments to be widely useful, they must be clinically effective, cost efficient and safe, and a number of practical aspects regarding storage and delivery of treatment must be optimised. Many barriers have been overcome, and the field of regenerative medicine for Parkinson's disease is now increasingly focussed on how these treatments will be delivered, demonstrating the significant progress that has been made and the optimism surrounding these approaches. PMID- 30027397 TI - Short- and long-term outcome of males treated for anorexia nervosa: a review of the literature. AB - PURPOSE: To give an overview of existing studies on the short- and long-term outcome for males treated for anorexia nervosa and to compare the outcome between adolescents and adults as well as between males and females. METHODS: A systematic literature search was conducted in PubMed, PsycINFO and PSYNDEX and complemented by a manual search of the references from all relevant studies. RESULTS: Out of 1064 search results, 18 studies met our inclusion criteria. A combined total of 1129 males of varying age groups were followed 0.5-27 years post-treatment. For 1009 individuals, only vital status was ascertained. Length of follow-up and outcome definitions varied considerably. Limited data-especially in adults-prevented adequate age comparisons. In both adolescents and adults outcome and mortality differed widely across studies with no firm evidence for gender differences. Outcome in mixed samples of adolescents and adults was inconsistent. Studies rarely compared the genders statistically, and when they did, the results were nonsignificant. CONCLUSIONS: Knowledge on the outcome of males treated for anorexia nervosa is scarce. Only few studies comprising insufficient numbers of males exist. Results based on these findings are inconclusive and in part contradicting. Further research is needed, including large sample sizes of reliably diagnosed males, adequate follow-up intervals, follow-up assessments with carefully defined outcome criteria, and comparisons to matched female patient samples. LEVEL OF EVIDENCE: Level I, Systematic review. PMID- 30027399 TI - Does Late Levodopa Administration Delay the Development of Dyskinesia in Patients with De Novo Parkinson's Disease? AB - BACKGROUND: It remains controversial whether late levodopa administration is a reasonable approach to reducing the risk of levodopa-induced dyskinesia in Parkinson's disease. OBJECTIVE: This study aimed to investigate the effects of levodopa sparing on the development of levodopa-induced dyskinesia. METHODS: We retrospectively reviewed medical records for patients with de novo Parkinson's disease who visited the Yonsei Parkinson Center between April 2009 and June 2015 and received at least 2 years of treatment. Among 657 patients with drug-naive Parkinson's disease who met the study criteria, 90 were initially treated with dopamine agonists (levodopa-sparing group; levodopa supplementation after 2.15 years). Another 90 patients who were initially treated with levodopa (levodopa group) were matched to the 90 patients for age, sex, follow-up duration, Parkinson's disease duration, Unified Parkinson's Disease Rating Scale Part III scores, and baseline dopamine transporter availability in the posterior putamen. The effects of levodopa sparing on dyskinesia development were assessed with Kaplan-Meier estimates and a stratified Cox regression model adjusted for age of onset, sex, dopamine transporter availability, and daily levodopa dose per weight. RESULTS: The levodopa-sparing group had a comparable age of onset (54.80 +/- 7.36 years) to the levodopa group (56.53 +/- 6.16 years). The Kaplan-Meier analysis revealed that the risk of levodopa-induced dyskinesia after treatment initiation was similar between the groups. Once the levodopa-sparing group started levodopa supplementation, they had a higher risk of developing levodopa induced dyskinesia. However, a stratified Cox regression model indicated that hazard ratios for levodopa sparing to levodopa-induced dyskinesia development were 0.138 (95% confidence interval 0.024-0.785) after treatment initiation and 0.438 (95% confidence interval 0.105-1.832) after levodopa initiation. CONCLUSION: Late levodopa administration was associated with a low risk of dyskinesia after adjusting for confounding effects and may be a reasonable strategy for prolonging the levodopa-induced dyskinesia-free period in Parkinson's disease. PMID- 30027400 TI - Nusinersen: A Review in 5q Spinal Muscular Atrophy. AB - Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder most commonly caused by a deletion or mutation in the survival motor neuron 1 (SMN1) gene, which leads to insufficient levels of survival motor neuron (SMN) protein. In such patients, SMN protein production relies on the SMN2 gene. Nusinersen (Spinraza(r)) is a modified antisense oligonucleotide (ASO) approved in several countries worldwide, including the USA, Japan and those of the EU, for the treatment of 5q SMA. It binds to a specific site in the intron downstream of exon 7 on the SMN2 pre-messenger ribonucleic acid (pre-mRNA), modulating the splicing of SMN2 mRNA and thus increasing the production of SMN protein. In multinational phase III studies, nusinersen (administered intrathecally) provided significant improvements in motor function in patients with infantile- and later onset 5q SMA compared with a sham procedure. It was also associated with significant improvements in event-free survival and overall survival in patients with infantile-onset 5q SMA, with preliminary data from an ongoing multinational phase II study suggesting a potential clinical benefit with early intervention (i.e. before symptom onset) with nusinersen. Preliminary subgroup data from a phase III extension study suggested continued improvements in motor function with longer-term therapy. Nusinersen demonstrated a favourable safety profile in clinical studies in symptomatic and presymptomatic patients, with no safety concerns due to nusinersen exposure. In conclusion, although studies in presymptomatic patients and over the long term in symptomatic patients are ongoing, current evidence indicates that nusinersen modifies 5q SMA and has a favourable safety profile and, thus, is a valuable treatment for this patient population. PMID- 30027402 TI - Correction to: Treatment Strategies for Dravet Syndrome. AB - Page 335, Abstract: The sentence that read. PMID- 30027401 TI - Assessment and Management of Neuropsychiatric Symptoms in Parkinson's Disease. AB - Neuropsychiatric symptoms are highly prevalent in Parkinson's disease and associated with decreased quality of life and adverse health outcomes. In this review, the assessment and management of common neuropsychiatric symptoms are discussed: depression, anxiety, psychosis, cognitive impairment, dementia and apathy. Validated assessment scales are now available for the majority of symptoms. Balancing dopaminergic therapy plays an important role in their management as increasing doses of dopaminergic agents might address depression and anxiety related to 'off' phases, non-motor fluctuations and apathy, while dose reduction might alleviate psychotic symptoms. More targeted treatment is possible through medications utilising different pathways. Although efficacy profiles of individual agents require further exploration, antidepressants as a drug class have shown utility in depression and anxiety in Parkinson's disease. Psychological therapies, especially cognitive behavioural approaches, are effective. Pimavanserin allows the treatment of psychosis in Parkinson's disease without directly affecting the dopaminergic and cholinergic system. The cholinergic system is currently the only target in Parkinson's disease dementia, and antagonists of this system, as are many psychotropic drugs, need to be used with caution. Management of apathy largely relies on non-pharmacological strategies adapted from dementia care, with antidepressants being ineffective and the role of stimulant therapy needing further evaluation. PMID- 30027406 TI - The effect of hexanic extract of Serenoa repens on prostatic inflammation: results from a randomized biopsy study. AB - PURPOSE: To evaluate the effect of hexanic extract of Serenoa repens (HESr) on prostatic inflammation in patients with diagnosed prostatic inflammation. METHODS: Patients with prostatic inflammation histologically confirmed by TRUS prostatic biopsy were randomized either to receive HESr (320 mg/day) or no treatment. A second biopsy was performed 6 months later according to standard clinical practice. Inflammation was assessed by the Irani's score and immunohistochemical staining using the CD3, CD4 and CD8 (for T-leucocytes), CD20 (for B-leucocytes) and CD163 (for macrophages) antibodies. RESULTS: Overall 97 patients were eligible for analysis. In the HESr group the mean inflammation grading and aggressiveness grading score significantly decreased from 1.55 and 1.55 at baseline to 0.79 (p = 0.001) and 0.87 (p = 0.001) at the second biopsy, respectively. In the control group the mean inflammation grading score was 1.44 at first biopsy and 1.23 at the second biopsy. The mean aggressiveness gradings core was 1.09 and 0.89, respectively. No statistical significance was found (p = 0.09 and p = 0.74).The mean decrease in all inflammation scores was statistically higher in the HESr patients compared to controls. The immunohistochemical staining showed a significant change in the expression of the analyzed antibodies for the HESr patients compared to the first biopsy. In the nontreatment group, no significant difference was found at the second biopsy. The change in expression of each antibody in the HESr group was statistical significant compared to control. CONCLUSIONS: HESr seems to reduce prostatic inflammation in terms of histological and immunohistochemical parameters in this specific patients population. PMID- 30027405 TI - Associations between tooth agenesis and displaced maxillary canines: a cross sectional radiographic study. AB - BACKGROUND: The aim of present study was to test the association between hypodontia and displaced maxillary canine when compared with a control group. METHODS: The study group was composed of 336 subjects with a mean age of 10.7 +/- 1.2 years, presenting with at least one missing tooth. Exclusion criteria included syndromes, craniofacial malformations, extractions and trauma history and previous orthodontic treatment. The control group consisted of 336 subjects with a mean age of 10.7 +/- 1.2 years, without agenesis. Stepwise multiple logistic regression using the backwards elimination and the Wald test method was performed to identify the best combination of hypodontia and displaced maxillary canine (P < 0.05). RESULTS: The most represented category in study group consisted in mild agenesis (86.9%); moderate and severe agenesis groups respectively represented the 11.7 and 1.4% of study group. Agenesis was diagnosed in both arches in 46 subjects. Maxillary hypodontia and mandibular hypodontia was respectively detected in 156 and 134 subjects. The most frequent missing teeth were mandibular second premolars (45.8%), lateral incisors (41.7%) and maxillary second premolars (17.8%). A significant correlation between agenesis and displaced maxillary canine was observed in the study group (P < 0.05). Only the agenesis of maxillary lateral incisors remained in the final model during backward stepwise deletion. Significant association between the severity of dental agenesis and prevalence of displaced maxillary canine was not assessed. CONCLUSIONS: The outcomes revealed no difference related to the severity of dental agenesis and prevalence of displaced maxillary canine. Only the agenesis of maxillary lateral incisors should be considered directly connected with displaced maxillary canine. PMID- 30027407 TI - Artificial intelligence in radiology: how will we be affected? PMID- 30027408 TI - Pre-operative ADC predicts early recurrence of HCC after curative resection. AB - OBJECTIVES: To assess a correlation between the preoperative diffusion-weighted imaging (DWI) and early recurrence (<2 years) and to determine the best DWI parameters as the risk factor of early recurrence after surgery in single hepatocellular carcinoma (HCC). METHODS: The study included 114 patients with surgically resected single HCC (<=5 cm) who underwent preoperative magnetic resonance imaging (MRI) with DWI. Radiologists evaluated the diffusion restriction of the tumours using qualitative assessment and the mean and minimum apparent diffusion coefficient values (ADCmean and ADCmin) of the tumours using quantitative measurement. Clinical and laboratory findings and DWI parameters as a risk factor for early recurrence were identified by using Cox proportional hazards model. RESULTS: No significant difference was observed in early recurrence rates of HCCs between those with and those without diffusion restriction (p = 0.484). Early recurrence rates of HCCs with ADCmean and ADCmin values lower than the optimal cut-offs (1.023 and 0.773 * 10-3 mm2/s, respectively) were significantly higher compared with those with values higher than the optimal cut-offs (p = 0.001 and p < 0.001, respectively). In the multivariable analysis, tumour size [hazard ratio (HR) per centimetre, 2.011; 95% CI, 1.304-3.102; p = 0.002] and ADCmin <=0.773 * 10-3 mm2/s (HR, 13.339; 95% CI, 4.422-40.240; p < 0.001) were independent risk factors for early HCC recurrence. CONCLUSIONS: DWI is a promising imaging tool for early recurrence of HCC. Among qualitative and quantitative assessments of DWI, ADCmin is a significant risk factor for early recurrence after surgery in single HCC. KEY POINTS: * The performance of minimum apparent diffusion coefficient (ADCmin) is significantly better than that of mean apparent diffusion coefficient (ADCmean) for identifying early recurrence. * ADCmin is a significantly independent risk factor of early HCC recurrence after surgery. * ADCmin correlates with early recurrence after curative resection of single HCC, reflecting histopathological features of the tumours including histological grade and microvascular invasion. PMID- 30027403 TI - Mutual concessions and compromises between stromal cells and cancer cells: driving tumor development and drug resistance. AB - BACKGROUND: Various cancers have been found to be associated with heterogeneous and adaptive tumor microenvironments (TMEs) and to be driven by the local TMEs in which they thrive. Cancer heterogeneity plays an important role in tumor cell survival, progression and drug resistance. The diverse cellular components of the TME may include cancer-associated fibroblasts, adipocytes, pericytes, mesenchymal stem cells, endothelial cells, lymphocytes and other immune cells. These components may support tumor development through the secretion of growth factors, evasion from immune checkpoints, metabolic adaptations, modulations of the extracellular matrix, activation of oncogenes and the acquisition of drug resistance. Here, we will address recent advances in our understanding of the molecular mechanisms underlying stromal-tumor cell interactions, with special emphasis on basic and pre-clinical information that may facilitate the design of novel personalized cancer therapies. CONCLUSIONS: This review presents a holistic view on the translational potential of the interplay between stromal cells and cancer cells. This interplay is currently being employed for the development of promising preclinical and clinical biomarkers, and the design of small molecule inhibitors, antibodies and small RNAs for (combinatorial) cancer treatment options. In addition, nano-carriers, tissue scaffolds and 3-D based matrices are being developed to precisely and safely deliver these compounds. PMID- 30027409 TI - Detection of in-stent protrusion (ISP) by intravascular ultrasound during carotid stenting: Usefulness of stent-in-stent placement for ISP. AB - OBJECTIVES: As in-stent protrusion (ISP) during carotid artery stenting (CAS) may cause postoperative embolism, ISP detection is important. Intravascular ultrasound examination (IVUS) is useful for ISP detection because the blood vessel cross-section can be drawn as a tomogram from the lumen. Our objective was to clarify the occurrence of ISP during CAS using IVUS and relevant factors, and to report the usefulness of stent-in-stent placement when treating ISP. METHODS: In 142 consecutive patients (128 men, average age 71.7 years; 69 symptomatic) who underwent CAS using dual protection and the blood aspiration method, and subsequent IVUS after stent placement were included. The outcome of CAS, and the occurrence rate of ISP and related factors (plaque characteristics, stent design, intraoperative debris capture rate and postoperative diffusion-weighted imaging (DWI) positive rate) were examined. RESULTS: All CAS procedures were successful and no major adverse events (MAEs) were observed at 30 days. ISP was found in 12% (17/142), and stent-in-stent placement was performed in all cases. Vulnerable plaques were observed in 12 of 17 ISP cases (71%). A closed stent was used in 13 of 17 ISP cases (71%). The intraoperative debris capture rate was 100%, and no neurological symptoms were observed in any patients. A significant increase in ISP susceptibility was related to vulnerable plaques and the intraoperative debris capture rate. CONCLUSIONS: Vulnerable plaques and debris capture were significantly correlated with ISP occurrence. In all ISP cases, stent-in-stent placement was performed and good results were obtained. KEY POINTS: * ISP detection during CAS using IVUS is important. * ISP-positive patients were correlated with NASCET >= 80%, vulnerable plaques and stent length. * Adequate additional treatment of stent in stenting under reliable protection against ISP positive patients achieved low perioperative complications. PMID- 30027404 TI - Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events. AB - AIMS/HYPOTHESIS: Diabetes has been shown to be a risk factor for some cancers. Whether diabetes confers the same excess risk of cancer, overall and by site, in women and men is unknown. METHODS: A systematic search was performed in PubMed for cohort studies published up to December 2016. Selected studies reported sex specific relative risk (RR) estimates for the association between diabetes and cancer adjusted at least for age in both sexes. Random-effects meta-analyses with inverse-variance weighting were used to obtain pooled sex-specific RRs and women to-men ratios of RRs (RRRs) for all-site and site-specific cancers. RESULTS: Data on all-site cancer events (incident or fatal only) were available from 121 cohorts (19,239,302 individuals; 1,082,592 events). The pooled adjusted RR for all-site cancer associated with diabetes was 1.27 (95% CI 1.21, 1.32) in women and 1.19 (1.13, 1.25) in men. Women with diabetes had ~6% greater risk compared with men with diabetes (the pooled RRR was 1.06, 95% CI 1.03, 1.09). Corresponding pooled RRRs were 1.10 (1.07, 1.13) for all-site cancer incidence and 1.03 (0.99, 1.06) for all-site cancer mortality. Diabetes also conferred a significantly greater RR in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower RR for liver cancer. CONCLUSIONS/INTERPRETATION: Diabetes is a risk factor for all-site cancer for both women and men, but the excess risk of cancer associated with diabetes is slightly greater for women than men. The direction and magnitude of sex differences varies by location of the cancer. PMID- 30027410 TI - Does gadoxetate disodium affect MRE measurements in the delayed hepatobiliary phase? AB - OBJECTIVES: To assess if the administration of gadoxetate disodium (Gd-EOB-DTPA) significantly affects hepatic magnetic resonance elastography (MRE) measurements in the delayed hepatobiliary phase (DHBP). METHODS: A total of 47 patients (15 females, 32 males; age range 23-78 years, mean 54.28 years) were assigned to standard hepatic magnetic resonance imaging (MRI) with application of Gd-EOB-DTPA and hepatic MRE. MRE was performed before injection of Gd-EOB-DTPA and after 40 50 min in the DHBP. Liver stiffness values were obtained before and after contrast media application and differences between pre- and post-Gd-EOB-DTPA values were evaluated using a Bland-Altman plot and the Mann-Whitney-Wilcoxon test. In addition, the data were compared with regard to the resulting fibrosis classification. RESULTS: Mean hepatic stiffness for pre-Gd-EOB-DTPA measurements was 4.01 kPa and post-Gd-EOB-DTPA measurements yielded 3.95 kPa. We found a highly significant individual correlation between pre- and post-Gd-EOB-DTPA stiffness values (Pearson correlation coefficient of r = 0.95 (p < 0.001) with no significant difference between the two measurements (p =0.49)). Bland-Altman plot did not show a systematic effect for the difference between pre- and post stiffness measurements (mean difference: 0.06 kPa, SD 0.81). Regarding the classification of fibrosis stages, the overall agreement was 87.23% and the intraclass correlation coefficient was 96.4%, indicating excellent agreement. CONCLUSIONS: Administration of Gd-EOB-DTPA does not significantly influence MRE stiffness measurements of the liver in the DHBP. Therefore, MRE can be performed in the DHBP. KEY POINTS: * MRE of the liver can reliably be performed in the delayed hepatobiliary phase. * Gd-EOB-DTPA does not significantly influence MRE stiffness measurements of the liver. * MRE performed in the delayed hepatobiliary phase is reasonable in patients with reduced liver function. PMID- 30027411 TI - Intravoxel incoherent motion diffusion-weighted imaging for assessment of histologic grade of hepatocellular carcinoma: comparison of three methods for positioning region of interest. AB - OBJECTIVES: To prospectively compare the diagnostic performances of three methods of region of interest (ROI) placement for the measurements of intravoxel incoherent motion (IVIM) diffusion-weighted MR imaging in differentiating the histologic grade of hepatocellular carcinoma (HCC). METHODS: Eighty-seven patients with 91 newly diagnosed HCCs were studied using IVIM imaging. Two attending radiologists separately identified the selection of tumour tissue for ROI positioning. Three different ROI positioning methods, namely the whole tumour volume (WTV) method, three-ROI method and one-section method, were used for the measurement. Kruskal-Wallis rank test or one-way ANOVA was used to compare the difference in IVIM parameters and ADC across the three different ROI positioning methods. Spearman correlation analysis was used to determine the correlation between each parameter and Edmondson-Steiner (E-S) grade. Receiver operating characteristics (ROC) curve analyses were performed to evaluate the diagnostic performance. RESULTS: For the ADC and ADCslow, the mean value measured by using the WTV method was significant higher than the one-section and three-ROI methods (all p < 0.01). For the ADCslow, the highest area under curve (AUC) with a value of 0.969 was obtained by using the WTV method, followed by the one-section method (AUC = 0.938) and three-ROI method (AUC = 0.873). Additionally, for the ADC, AUC values were 0.861 for WTV method, 0.840 for one-section method and 0.806 for three-ROI method. CONCLUSIONS: Different ROI positioning methods used significantly affect the IVIM parameters and ADC measurements. Measurements of ADCslow value derived from WTV method entailed the highest diagnostic performance in grading HCC. KEY POINTS: * Diffusion MRI is useful for non-invasively differentiating the histologic grade of hepatocellular carcinoma. * Different ROI positioning methods used significantly affect the IVIM parameters and ADC measurements. * IVIM model is advantageous over mono-exponential model for assessing the histologic grade of hepatocellular carcinoma. PMID- 30027412 TI - Bioleaching of copper- and zinc-bearing ore using consortia of indigenous iron oxidizing bacteria. AB - Indigenous iron-oxidizing bacteria were isolated on modified selective 9KFe2+ medium from Baiyin copper mine stope, China. Three distinct acidophilic bacteria were isolated and identified by analyzing the sequences of 16S rRNA gene. Based on published sequences of 16S rRNA gene in the GenBank, a phylogenetic tree was constructed. The sequence of isolate WG101 showed 99% homology with Acidithiobacillus ferrooxidans strain AS2. Isolate WG102 exhibited 98% similarity with Leptospirillum ferriphilum strain YSK. Similarly, isolate WG103 showed 98% similarity with Leptospirillum ferrooxidans strain L15. Furthermore, the biotechnological potential of these isolates in consortia form was evaluated to recover copper and zinc from their ore. Under optimized conditions, 77.68 +/- 3.55% of copper and 70.58 +/- 3.77% of zinc were dissolved. During the bioleaching process, analytical study of pH and oxidation-reduction potential fluctuations were monitored that reflected efficient activity of the bacterial consortia. The FTIR analysis confirmed the variation in bands after treatment with consortia. The impact of consortia on iron speciation within bioleached ore was analyzed using Mossbauer spectroscopy and clear changes in iron speciation was reported. The use of indigenous bacterial consortia is more efficient compared to pure inoculum. This study provided the basic essential conditions for further upscaling bioleaching application for metal extraction. PMID- 30027413 TI - Demographic, clinical and lifestyle factors associated with high-intensity statin therapy in Australia: the AusDiab study. AB - PURPOSE: Clinical guidelines specify who should receive high-intensity statins; however, it is unclear how high-intensity statins are used in Australia. Our objective was to determine the demographic, clinical, and lifestyle factors associated with high-intensity statin therapy in Australia. METHODS: Data from the Australian Diabetes, Obesity and Lifestyle study collected in 2011-2012 were analyzed. High-, moderate-, and low-intensity statins were defined as use of statins at doses demonstrated to reduce low-density lipoprotein cholesterol levels by > 50, 30-50, and < 30%, respectively. Logistic regression was used to estimate adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for factors associated with high- versus low-to-moderate-intensity statin therapy. RESULTS: Overall, 1108 (24%) study participants used a statin. Data on statin intensity were available for 1072 participants. The proportions of high-, moderate-, and low-intensity statin therapy were 32 (n = 341), 65 (n = 696), and 3% (n = 35), respectively. Overall, 51% of people with prior cardiovascular disease (CVD) used a high-intensity statin. In addition to prior CVD (OR = 3.34, 95% CI = 1.95 5.73), no (OR = 1.84, 95%CI 1.02-3.31) or insufficient physical activity (OR = 1.51, 95% CI = 1.01-2.25), obesity (OR = 1.87, 95% CI = 1.13-3.10), and consuming > 2 alcoholic drinks daily (OR = 1.66, 95% CI = 1.08-2.55) were associated with high versus low-to-moderate-intensity statin therapy. Conversely, age 65-74 vs. < 65 years was inversely associated with high-intensity statin therapy (OR = 0.62, 95% CI = 0.41-0.94). CONCLUSIONS: Prior CVD was the strongest factor associated with high-intensity statin therapy. Although the prevalence of CVD increases with age, older people were less likely to be treated with high-intensity statins. PMID- 30027415 TI - Correction to: Relationship Between Care Burden and Religious Beliefs Among Family Caregivers of Mentally Ill Patients. AB - The original version of this article unfortunately contained a mistake in the author name. The co-author name should be Reza Masoudi instead of Reza Masoodi. PMID- 30027414 TI - The ATAF1 transcription factor is a key regulator of aldehyde dehydrogenase 7B4 (ALDH7B4) gene expression in Arabidopsis thaliana. AB - MAIN CONCLUSIONS: ALDH7B4 expression contributes to abiotic stress tolerance. The NAC transcription factor ATAF1 is a main regulator of expression of the ALDH7B4 gene in Arabidopsis thaliana as shown by ATAF1 mutants. The aldehyde dehydrogenase 7B4 (ALDH7B4) protein has important roles in detoxification of excessive aldehydes, elimination of reactive oxygen species (ROS) and inhibition of lipid peroxidation when plants are exposed to abiotic stress. However, the regulation of the expression of the ALDH7B4 gene under stress is largely unknown. Promoter studies revealed crucial cis-elements in the ALDH7B4 promoter in response to heat and stress combinations. Using a yeast one-hybrid assay, several NAC transcription factors, including ATAF1 were isolated. These transcription factors play an important role in plant adaptation to abiotic stress. ATAF1 activates the expression of the ALDH7B4 gene by directly binding to the promoter. Overexpression of ATAF1 in Arabidopsis plants results in elevated expression of ALDH7B4 in seeds, seedlings, and mature plants, whereas ATAF1 knock-out mutant plants abolished the expression of ALDH7B4. This study implies that ATAF1 may confer stress tolerance by up-regulating the target gene ALDH7B4. PMID- 30027416 TI - Adolescent personality traits, low self-esteem and self-harm hospitalisation: a 15-year follow-up of the Norwegian Young-HUNT1 cohort. AB - Affective disorders are closely related to self-harm and suicidal behaviours. Less is known about how adolescent personality traits and self-esteem influence the development of later self-harm. We examined associations between personality traits such as neuroticism, psychoticism and extroversion, and self-esteem, in adolescence, and the risk of future self-harm hospitalisation. Baseline information from 13 to 19-year-old participants in the Norwegian Young-HUNT1 study in 1995-97 (n = 8965) was linked to endpoint data recorded from participants' hospital records, describing self-harm hospitalisation episodes within the catchment area. Crude and adjusted hazard ratios (HR) were estimated by Cox regression analyses. A one-unit increase on the 0-6 scale for neuroticism was associated with a HR of 1.29, 95% confidence interval (CI) 1.14-1.47. Corresponding HR for psychoticism was 1.30, 95% CI 1.03-1.63 per unit increase, and for extroversion risk was reduced (HR 0.89, 95% CI 0.77-1.04). Positive perception of self-esteem was more strongly associated with reduced risk of self harm hospitalisation (HR per unit increase on the 0-12 scale was 0.74, 95% CI 0.68-0.82). Additional adjustment for alcohol use and symptoms of combined anxiety and depression symptoms attenuated effect estimates, in particular for neuroticism (HR 1.13, 95% CI 0.96-1.32) and psychoticism (HR 1.07, 95% CI 0.82 1.40). In contrast, self-esteem associations remained largely the same after adjustment. Our results indicate that brief assessments of personality and self esteem might add additional relevant information, and could be included as a supplement to standard suicidal risk assessment in adolescents. PMID- 30027417 TI - Head circumference and child ADHD symptoms and cognitive functioning: results from a large population-based cohort study. AB - The aim of this study is to understand the association between prenatal, newborn and postnatal head circumference (HC) and preschool neurodevelopment in a large population-based birth cohort. The INMA project followed 1795 children from 12 weeks of pregnancy to preschool years. HC measurements were carried out prospectively, and following a standardized protocol during pregnancy (12, 20 and 34 weeks), birth, and child ages of 1-1.5 and 4 years old; and z-scores were further estimated. Prenatal head growth was assessed using conditional z-scores between weeks 12-20 and 20-34. Several neuropsychological tests [MSCA (cognition), CPT (attention)] and behavioral rating scales [DSM-IV-ADHD, CAST (autism), CPSCS (social competence)] were carried out during the last follow-up (5 years old). Multivariable models adjusted for family and child characteristics were applied to analyze associations between HC and neurodevelopment. In fully adjusted models, prenatal HC and head growth showed little or no associations with the neurodevelopment outcomes. Independent associations were observed between HC z-scores at birth, 1-1.5 years and 4 years and MSCA global cognitive scores and DSM-IV inattention symptoms. Specifically, z-score at birth was positively associated with general cognitive scores [beta 1.22, 95% confidence interval (CI) 0.59, 1.85], and we observed a protective association with ADHD-DSM IV total symptoms, mean ratio (MR) 0.85 (0.75, 0.96). Prenatal HC and head growth measurements gave little information about child cognitive abilities and behavior at preschool years. However, HC at birth and early childhood was positively associated with a range of neuropsychological outcomes, including protective associations with ADHD symptoms. PMID- 30027418 TI - Glibenclamide Mini-tablets with an Enhanced Pharmacokinetic and Pharmacodynamic Performance. AB - In an attempt to decrease the dose, anticipated side effects, and the cost of production of glibenclamide, GLC, a potent oral hypoglycemic drug, the enhancement of the dissolution and hence the oral bioavailability were investigated. Adsorption and co-adsorption techniques using carriers having a very large surface area and surface active agents were utilized to enhance the drug dissolution. Moreover, the Langmuir adsorption isotherms were constructed to identify the type and mechanism of adsorption. The optimized formulation showing the highest in vitro release was compressed into mini-tablet to facilitate drug administration to elderly patients and those having swallowing difficulties. The produced mini-tablets were tested for their mechanical strength and in vitro release pattern. In addition, the pharmacodynamic and pharmacokinetic studies in New Zealand rabbits were performed using the optimized mini-tablet formulation. Mini-tablets containing GLC co-adsorbate with Pluronic F-68 and Laponite RD showed 100 +/- 1.88% of GLC released after 20 min. Pharmacodynamic studies in rabbits revealed significantly higher (p <= 0.05) hypoglycemic effect with the optimized mini-tablets at a lower GLC dose compared to mini-tablets containing the commercial GLC dose. Moreover, pharmacokinetic analysis showed significantly higher (p <= 0.05) AUC, Cmax, and shorter Tmax. The optimized mini-tablet formulation showed 1.5-fold enhancement of the oral bioavailability compared to mini-tablets containing untreated GLC. It could be concluded that the co adsorption technique successfully enhanced the oral bioavailability of GLC. Furthermore, the produced mini-tablets have a higher oral bioavailability with a lower GLC dose, which could offer economic benefit for industry as well as acceptability for patients. PMID- 30027419 TI - Diagnostic performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrent prostate cancer. AB - PURPOSE: The introduction of ligands targeting prostate-specific membrane antigen (PSMA), especially 68Ga-PSMA-11, has changed the management of patients with prostate cancer (PCa). 18F-Labelled ligands can be produced in larger amounts and therefore can improve availability for a larger group of patients. The aim of this study was to evaluate the diagnostic performance of the recently introduced 18F-PSMA-1007 in patients with recurrent PCa. METHODS: This retrospective analysis included 100 consecutive patients with biochemical relapse (mean age 68.75 +/- 7.6 years) referred for PSMA PET/CT. Whole-body PET/CT imaging (from the lower limbs to the skull) was performed in all patients 120 min after injection of 338 +/- 44.31 MBq 18F-PSMA-1007. Prostatectomy, radiation beam therapy of the prostate bed and androgen-deprivation therapy had been performed in 92%, 45% and 27% of the patients, respectively. Radiation beam therapy of the prostate bed had been performed in addition to surgery in 38 patients (38%) and 10 patients (10%) had received all three therapy modalities. The probability of a 18F-PSMA-1007 PET/CT scan suggestive of pathology was compared with the Gleason score (GS) and PSA level. RESULTS: Of the 100 patients, 95 (95%) showed at least one pathological finding on 18F-PSMA-1007 PET/CT. The overall median PSA level was 1.34 ng/ml (range 0,04-41.3 ng/ml). The rates of pathological scans were 86%, 89%, 100% and 100% among patients with PSA levels <=0.5, 0.51-1.0, 1.1-2.0 and > 2.0 ng/ml, respectively. The median GS was 7 (range 5-10). The majority of patients (70) with a GS available had a score in the range 7-9. The rate of pathological scans in these patients was 93% (65/70). The median SUVmax values of the pathological findings were 10.25, 14.32, 13.16 and 28.87 in patients with PSA levels <=0.5, 0.51-1.0, 1.1-2.0 and >2.0 ng/ml, respectively. The median SUVmax in patients with a PSA level of >2.0 ng/ml was significantly higher than in all other PSA groups. CONCLUSION: 18F-PSMA-1007 PET/CT can detect recurrent PCa in a high percentage of patients with biochemical relapse. The probability of a pathological 18F-PSMA-1007 PET/CT scan seems to be high even in patients with a low PSA level <=0.5 ng/ml, and this may have a significant impact on the management of this relevant group of patients. PMID- 30027420 TI - Correction to: Medication Errors: A Characterisation of Spontaneously Reported Cases in EudraVigilance. AB - In the original publication of the article, the trend line for non-EEA cases in figure 4 is incorrect. In this correction, the original Fig. 4 (Fig. 1) and the correct Fig. 4 (Fig. 2) are published. PMID- 30027421 TI - Posterior perineal translevator hernia: application of MRI, 3D ultrasound, and computerized modeling. PMID- 30027422 TI - Use of bacterial biosurfactants as natural collectors in the dissolved air flotation process for the treatment of oily industrial effluent. AB - The aim of the present study was to investigate the separation of oil from water using a bench-scale DAF prototype with the addition of biosurfactants isolated from Pseudomonas cepacia CCT6659 and Bacillus cereus UCP1615. The best operating conditions for the DAF prototype were determined using a central composite rotatable design. The results demonstrated that the biosurfactants from P. cepacia and B. cereus increased the oil separation efficiency from 53.74% (using only microbubbles) to 94.11 and 80.01%, respectively. The prediction models for both DAF-biosurfactant systems were validated, showing an increase in the efficiency of the DAF process from 53.74% to 98.55 and 70.87% using the formulated biosurfactants from P. cepacia and B. cereus, respectively. The biosurfactant from P. cepacia was selected as the more promising product and used for the treatment of oily effluent from a thermoelectric plant, achieving removal rates ranging between 75.74 (isolated biosurfactant) and 95.70% (formulated biosurfactant), respectively. PMID- 30027423 TI - Dental acid etchant as a sensitizing agent in photodynamic therapy to reduce S. mutans in dentinal carious lesions. AB - The study aims to assess the utility of dental acid etchant containing 37% phosphoric acid and methylene blue dye (DAE) as a sensitizing agent for photodynamic therapy (PDT) to reduce Streptococci mutans in dentinal caries. Forty-five permanent third molars were sectioned and the coronal dentin exposed. A cariogenic challenge was performed using brain-heart infusion (BHI) supplemented with 0.5% yeast extract, 1% glucose, 1% sucrose, and S. mutans ATCC 25175 standardized to 0.5 McFarland turbidity. Specimens were incubated in anaerobic jars at 37 degrees C for 15 days. During this period, BHI broth was renewed every 24 h. After 15 days, specimens were randomly divided into three groups (n = 15): DAE, application of dental acid etchant containing 37% phosphoric acid and methylene blue dye for 15 s; LLL, application of low-level laser (wavelength 660 nm, energy 4 J/cm2, power 5 W) for 15 s; and PDT, application of DAE for 15 s followed by LLL irradiation (660 nm, 4 J/cm2, 5 W). Carious tissue from each specimen was collected before and after the applications. Five decimal dilutions were performed and the resulting solution was seeded in mitis-salivarius-bacitracin agar. Plates were incubated in anaerobic jars at 37 degrees C for 48 h. Analysis of variance (ANOVA) with post hoc Tukey's test was used to compare total S. mutans counts. Significant reductions in S. mutans were observed after DAE application (40.70%, p < 0.0001), LLL (12.35%, p = 0.0036), and PDT (55.22%, p < 0.0001). Dental acid etchant containing 37% phosphoric acid and methylene blue dye can be used as a photosensitizing agent for PDT to reduce S. mutans burden in dentinal caries. PMID- 30027424 TI - Treatment of intravitreal bevacizumab combined with focal laser photocoagulation in the case of macular telangiectasia type 2 with retinal arterial macroaneurysm. AB - Macular telangiectasia type 2 (Mac Tel 2) is a bilateral disease of unknown cause with characteristic changes of the retinal vasculature. To the best of our knowledge, we could not find any reported cases of Mac Tel 2 with retinal arterial macroaneurysm (RAM). Our aim is to report a case of Mac Tel 2 with RAM. PMID- 30027425 TI - Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop. AB - Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy. PMID- 30027426 TI - What Employer Actions Are Considered Most Important for the Return to Work of Employees with Cancer? A Delphi Study Among Employees and Employers. AB - Purpose Employers are important stakeholders in the return to work (RTW) of employees with cancer. However, it is unclear what employer actions are most important to that process. The objective, therefore, was to reach consensus on what employer actions are considered most important for the RTW of employees with cancer, by employers and employees separately. Methods A two-round online Delphi study was conducted with two expert panels: one with 23 employers and one with 29 employees with cancer. The results from each panel were analysed separately. Out of 24 suggested employer actions, participants selected the 10 they considered most important for RTW in each of the following RTW phases: (1) disclosure, (2) treatment, (3) RTW plan, and (4) actual RTW. The consensus threshold was set at >= 80% during the second round. Results The employer and employee expert panels both reached consensus on the importance of 'emotional support', 'practical support', 'allow sufficient sick leave', 'plan return to work', 'adjust expectations', 'assess work ability', and 'show appreciation'. Employers also reached consensus on 'communicate' and 'treat normally', and employees on 'handle unpredictability'. All these employer actions were considered to be specific for one to three RTW phases. Conclusions Employers reached consensus on the importance of nine employer actions, employees on eight. Both stakeholder perspectives showed great similarities, but did vary regarding important employer actions during the employee's treatment. We recommend developing interventions targeting the employer, meeting both employer and employee needs in each RTW phase, to enhance RTW support for employees with cancer. PMID- 30027427 TI - The Burden of Untreated HCV Infection in Hospitalized Inmates: a Hospital Utilization and Cost Analysis. AB - Hepatitis C virus (HCV) is highly prevalent in incarcerated populations. The high cost of HCV therapy places a major burden on correctional system healthcare budgets, but the burden of untreated HCV is not known. We investigated the economic impact of HCV through comparison of length of stay (LOS), frequency of 30-day readmission, and costs of hospitalizations in inmates with and without HCV using a 2004-2014 administrative claims database. Inmates with HCV had longer LOS, higher frequency of 30-day readmission, and increased cost of hospitalizations. Costs were higher in inmates with HCV even without advanced liver disease and in inmates with HIV/HCV compared to HCV alone. We conclude that although HCV treatment may not avert all of the observed increases in hospitalization, modest reductions in hospital utilization with HCV cure could help offset treatment costs. Policy discussions on HCV treatment in corrections should be informed by the costs of untreated HCV infection. PMID- 30027428 TI - Personal Versus Group Experiences of Racism and Risk of Delivering a Small-for Gestational Age Infant in African American Women: a Life Course Perspective. AB - The majority of studies investigating the relationship between racism/racial discrimination and birth outcomes have focused on perceived experiences of racism/racial discrimination directed at oneself (personal racism). However, evidence suggests individuals report with greater frequency racism/racial discrimination directed at friends, family members, or other members of their racial/ethnic group (group racism). We examined how much African American (AA) women report lifetime experiences of perceived racism or racial discrimination, both personal and group, varied by maternal age. We also investigated whether reports of personal and group racism/racial discrimination were associated with the risk of delivering a small-for-gestational age (SGA) infant and how much maternal age in relation to developmental life stages (adolescence [<= 18 years], emerging adulthood [19-24 years], and adulthood [>= 25 years]) moderated the relationship. Data stem from the Baltimore Preterm Birth Study, a hybrid prospective/retrospective cohort study that enrolled 872 women between March 2000 and July 2004 (analyzed in 2016-2017). Spline regression analyses demonstrated a statistically significant (p value for overall association < 0.001) and non linear (p value = 0.044) relationship between maternal age and the overall racism index. Stratified analysis showed experiences of racism overall was associated with a higher odds ratio of delivering an SGA infant among AA women aged >= 25 years (OR = 1.45, 95% CI 1.02-2.08). The overall racism index was not associated with the SGA infant odds ratio for emerging adults (OR = 0.86, 95% CI 0.69-1.06) or adolescents (OR = 0.92, 95% CI 0.66-1.28). Multiple aspects of racism and the intersection between racism and other contextual factors need to be considered. PMID- 30027430 TI - A Dendritic Cell-Targeted Adenoviral Vector Facilitates Adaptive Immune Response Against Human Glioma Antigen (CMV-IE) and Prolongs Survival in a Human Glioma Tumor Model. AB - Antitumor immunotherapeutic strategies represent an especially promising set of approaches with rapid translational potential considering the dismal clinical context of high-grade gliomas. Dendritic cells (DCs) are the body's most professional antigen-presenting cells, able to recruit and activate T cells to stimulate an adaptive immune response. In this regard, specific loading of tumor specific antigen onto dendritic cells potentially represents one of the most advanced strategies to achieve effective antitumor immunization. In this study, we developed a DC-specific adenoviral (Ad) vector, named Ad5scFvDEC205FF, targeting the DC surface receptor, DEC205. In vitro analysis shows that 60% of DCs was infected by this vector while the infectivity of other control adenoviral vectors was less than 10%, demonstrating superior infectivity on DCs. Moreover, an average of 14% of DCs were infected by Ad5scFvDEC205FF-GFP, while less than 3% of non-DCs were infected following in vivo administration, demonstrating highly selective in vivo DC infection. Importantly, vaccination with this vehicle expressing human glioma-specific antigen, Ad5scFvDEC205FF-CMV-IE, shows a prolonged survival benefit in GL261CMV-IE-implanted murine glioma models (p < 0.0007). Furthermore, when rechallenged, cancerous cells were completely rejected. In conclusion, our novel, viral-mediated, DC-based immunization approach has the significant therapeutic potential for patients with high-grade gliomas. PMID- 30027429 TI - Efficacy and safety of obinutuzumab in patients with previously untreated follicular lymphoma: a subgroup analysis of patients enrolled in Japan in the randomized phase III GALLIUM trial. AB - GALLIUM is a global phase III study that demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with obinutuzumab plus chemotherapy (G-chemo) versus rituximab plus chemotherapy (R chemo) in previously untreated patients with follicular lymphoma (FL). In this single-country subgroup analysis, we explored patterns of efficacy and safety in patients enrolled in the GALLIUM study in Japan (Japanese subgroup). Patients were randomized to open-label induction treatment with G-chemo or R-chemo. Responders received maintenance monotherapy with their randomized antibody for up to 2 years. The primary endpoint was investigator-assessed PFS. Overall, 123 patients with FL were randomized in the Japanese subgroup (G-chemo, n = 65; R chemo, n = 58). The majority of patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (82.9 vs 33.1% in the global GALLIUM FL population). PFS at 3 years was 89.9% (G-chemo) vs. 74.7% (R-chemo); hazard ratio 0.42; 95% confidence interval 0.15, 1.15; P = 0.08. Higher rates of grade 3-5 adverse events (96.9 vs. 89.7%) and serious adverse events (35.4 vs. 22.4%) were observed with G-chemo vs R-chemo, respectively. Neutropenia was frequent in the Japanese subgroup (92.3% G-chemo; 79.3% R-chemo). Overall, the results in the Japanese subgroup were consistent with those in the global GALLIUM population. PMID- 30027431 TI - Clinical and genetic findings of a Japanese patient with RP1-related autosomal recessive retinitis pigmentosa. AB - PURPOSE: This study reports the ophthalmic and genetic findings of a Japanese patient with autosomal recessive retinitis pigmentosa (arRP) caused by retinitis pigmentosa 1 (RP1) mutations. PATIENT AND METHODS: The 34-year-old female patient and her unaffected parents underwent comprehensive ophthalmic examinations, including visual acuity measurements, perimetry, electroretinography (ERG), and optical coherence tomography. Fundus autofluorescence was also evaluated in the patient. To identify potential pathogenic variants, 111 inherited eye disease genes were examined by targeted next-generation sequencing. RESULTS: The patient had night blindness from the first decade of her life. Fundus examination revealed typical RP findings with additional macular degeneration. Her visual field and acuity were severely affected, and ERG scans showed undetectable responses. Bioinformatics analysis revealed two heterozygous potentially pathogenic variants in RP1 in the patient, one of which is novel. Co-segregation analysis in the unaffected parents confirmed that the two variants were in trans. The parents were both carriers of one RP1 variant but did not show any visual symptoms. Therefore, the identified compound heterozygous variants were proposed as the probable arRP-causing mutations in the family. CONCLUSION: This is the first description of a Japanese patient with arRP caused by RP1 mutations. Additional data are necessary to more accurately determine the clinical course and mutation spectrum in patients with RP1-related arRP. PMID- 30027432 TI - Assessing the clinical and molecular diagnosis of inherited forms of impaired sensitivity to thyroid hormone from a single tertiary center. AB - AIM: Resistance to thyroid hormone (RTH), characterized by persistent hyperthyroxinemia with non-suppressed thyrotropin (TSH), is mostly caused by mutations in thyroid hormone receptor beta gene (THRB). Two differential diagnoses should be considered due to similar clinical and laboratory findings: TSH-producing pituitary adenoma (TPA) and Familial Dysalbuminemic Hyperthyroxinemia (FDH). The aim of this study is to describe our single tertiary center experience in the molecular diagnosis of RTH in Brazilian patients, analyzing their clinical and laboratory characteristics and the most common differential diagnosis. SUBJECTS AND METHODS: We enrolled 30 subjects with clinical and laboratory features of RTH. Patient's evaluations included clinical examination, thyroid hormone profile and imaging tests. Sequencing analysis for THRB hot spot region was conducted on all patients, and those without mutations in beta isoform of the thyroid hormone receptor (TRbeta) (non-TR-RTH) were investigated for albumin gene (ALB) mutation. RESULTS: Seventeen patients presented mutations in TRbeta (RTHbeta); six were non-TR-RTH, three had a diagnosis of FDH with a mutation in ALB, and four were diagnosed with TPA. Two characteristics were different to what is commonly described in the literature: higher serum TSH levels in RTHbeta patients when compared to the non-TR-RTH group, but this difference did not extend to free T4 (FT4) level; also the percentage of non-TR-RTH was higher than what was reported in other series. CONCLUSION: In the present series, most cases were RTHbeta with higher levels of TSH. We described three novel mutations in THRB (p.M313V, p.R320G and p.R438P) and the first patients with FDH molecular diagnosis (p.R242H) documented in Brazil. PMID- 30027433 TI - Water intake keeps type 2 diabetes away? Focus on copeptin. AB - INTRODUCTION: In both diabetic subjects and animal models high levels of vasopressin (AVP) have beendetected. The relationship between AVP and glucose metabolism is mediated through several direct andindirect effects and most of them are still unknown. METHODS: We have reviewed 100 manuscripts retrieved from Cochrane Library, Embase and Pubmeddatabases in order to highlight a possible relationship between copeptin and type 2 diabetes and to provideinsights on the molecular mechanism that could explain this association. RESULTS AND CONCLUSIONS: AVP potentiates CRH action at pituitary level resulting in an increased ACTH secretion and in turn in an increased cortisol secretion that escapes the negative feedback loop. Further, AVP regulates insulin and glucagon secretion through V1b receptor and promotes hepatic glycogenolysis and gluconeogenesis through V1a receptor. In addition to worsen glucose metabolism, AVP has been reported to have a role in the pathogenesis of diabetic complications such as cardiovascular diseases, kidney and ocular complications. Due to the very low concentration of AVP in the blood, the small size and poor stability, the assay of AVP is very difficult to perform. Thus, copeptin, the stable C-terminal portion of the prepro-vasopressin peptide has been identified as an easier assay to be measured and that mirrors AVP activity. Although there are promising evidence that copeptin could be involved in the pathogenesis of type 2 diabetes, further studies need to demonstrate the importance of copeptin as clinical marker to predict glucose metabolism derangements. PMID- 30027434 TI - Androgenic modulation of AR-Vs. AB - PURPOSE: The importance of androgen receptor variants (AR-Vs) is recognized in prostate cancer. AR-Vs have been the focus of many studies. Expression of AR-Vs has been proposed as a biomarker for resistance to androgen deprivation therapy for metastatic disease. Herein, we show dynamic changes in AR-Vs expression in response to androgen modulation. METHODS: The C4-2B cell line was exposed to low (10-13 M) and high (10-8 M) androgen (dihydrotestosterone, DHT) levels, with or without flutamide. mRNA and protein expression levels were assessed by qPCR and immunohistochemistry, respectively. RESULTS: We demonstrated that high levels of DHT downregulate AR-FL and AR-Vs. Even though AR-Vs did not present ligand binding domain, thus were not capable of binding to DHT, they present dynamic changes under androgen treatment. Treatment with flutamide alone or in association with low levels of DHT stimulates growth of prostatic cells. CONCLUSIONS: Importantly, we provide evidence that AR-Vs respond differently to androgenic modulation. These findings have implications for a better understanding of the role of AR-Vs in prostate carcinogenesis. PMID- 30027436 TI - Long-term follow-up of a single institution pilot study of sirolimus, tacrolimus, and short course methotrexate for graft versus host disease prophylaxis in mismatched unrelated donor allogeneic stem cell transplantation. PMID- 30027435 TI - The role of bortezomib in newly diagnosed diffuse large B cell lymphoma: a meta analysis. AB - Although the survival rate of diffuse large B cell lymphoma (DLBCL) has increased with years, there are still patients who do not achieve complete remission or who relapse, especially patients with activated B cell-like (ABC) DLBCL. Bortezomib, a proteasome inhibitor, has shown activity in diffuse large B cell lymphoma, especially in the subtype of ABC DLBCL. We conducted a meta-analysis to compare the efficacy and adverse events in bortezomib-containing regimens with standard R CHOP regimen in treating DLBCL. Our results show that comparing to standard R CHOP regimen, bortezomib-containing regimen could not prolong the survival in patients with ABC DLBCL. And patients who received bortezomib had a trend of higher risk with peripheral neuropathy, although there is no significant statistical difference. PMID- 30027437 TI - Necrotizing tracheobronchitis caused by influenza and Staphylococcus aureus co infection. PMID- 30027439 TI - Impact of anatomic origin of primary squamous cell carcinomas of the nasal cavity and ethmoidal sinus on clinical outcome. AB - PURPOSE: Since squamous cell carcinomas (SCCs) of the nasoethmoidal complex are rare and aggressive malignancies, the purpose of this study was to evaluate whether anatomic subsites of SCCs of the nasal cavity and ethmoid sinuses affect clinical outcome. METHODS: We retrospectively analyzed data from 47 patients with primary SCCs of the nasal cavity and ethmoid sinuses who were treated at the Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, between 1993 and 2018. The impact of anatomic subsites of nasoethmoidal SCCs was evaluated with respect to tumor and nodal classification, disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: Of the 47 cases, 17 SCCs (36.2%) originated from lateral nasal wall followed by 13 (27.7%) tumors of the edge of naris to mucocutaneous junction, 11 (23.4%) SCCs of the nasal septum, 3 tumors of the nasal floor (6.4%) and 3 SCCs of the ethmoid sinuses (6.4%), respectively. SCCs of the nasal septum were associated with significantly higher rates of neck node metastasis (p = 0.007), which represented a significantly worse prognostic factor for DSS (HR 7.87; p < 0.001). Moreover, advanced tumor stage (HR 5.38; p = 0.014) and tumor origin of nasal septum (HR 4.05; p = 0.025) were also significantly worse prognostic factors for DSS. Fourteen patients (29.8%) developed recurrent disease, including eight local (17.0%), five regional (10.6%) and one distant (2.1%) recurrence. Elective neck dissection (ND) was associated with lower (0 vs. 20.0%) but not significantly different regional and distant DFS (p = 0.075). CONCLUSION: Anatomic origin of nasal SCC has significant impact on clinical outcome. SCCs of the nasal septum were associated with higher rates of positive neck nodes and worse outcome. PMID- 30027438 TI - The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial. AB - : Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS). METHODS: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up. RESULTS: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, - 0.041 [- 0.055, - 0.027]; placebo group - 0.046 [- 0.058, - 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively). CONCLUSIONS: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00657943). PMID- 30027440 TI - Evaluation of surgical margin status in patients with early glottic cancer (Tis T2) treated with transoral CO2 laser microsurgery, on local control. AB - PURPOSE: To assess the impact of surgical margins status on local control in patients with primary early glottic (Tis-T2) squamous cell carcinoma after treatment with transoral CO2 laser microsurgery (TLM) and to assess the significance of additional wound bed biopsies. METHODS: Patients with Tis-T2 tumours treated with TLM type I-III resections according to the European Laryngological Society classification between 2009 and 2013 were included in retrospective analysis. Recurrence rate was determined in patients with free versus non-free specimen margins and wound biopsies. Five-year survival rates were determined using the Kaplan-Meier method. Prognostic impact of pT-category, resection margin status, tumour differentiation, wound bed biopsy status, and number of biopsies on local control (LC) were tested with the log-rank test. RESULTS: Eighty-four patients were included in the analysis. Positive margins were seen in 68 patients (81.0%). Margin status after TLM did not significantly influence LC (p = 0.489), however, additional wound bed biopsies were significantly associated with lower LC (p = 0.009). Five-year LC, disease specific survival, overall survival and laryngeal preservation were 78.6, 78.0, 98.6 and 100%, respectively. CONCLUSIONS: Additional wound bed biopsies can help predict local recurrence in patients treated with TLM for early glottic carcinoma. We propose that there is enough evidence to support a wait-and-see policy in patients with positive specimen margins and negative wound bed biopsies. For patients with positive wound bed biopsies, further treatment is warranted. PMID- 30027441 TI - Temporary olfactory improvement in chronic rhinosinusitis with nasal polyps after treatment. AB - PURPOSE: Olfactory dysfunction in chronic rhinosinusitis with nasal polyps (CRSwNP) is a severe type of inflammatory olfactory disorders which greatly impair quality of life. The aim of this review is to summarize the current literature and to provide a comprehensive guide to the key metrics of the olfactory dysfunction, evaluations, treatment responses, and pathophysiological mechanisms in CRSwNP patients with olfactory dysfunction. METHODS: A review of the literature for olfaction in CRSwNP was conducted. The key terms ("chronic rhinosinusitis", "nasal polyps", and "olfaction") were used to search relevant articles in Pubmed. RESULTS: Inflammation within the olfactory cleft is a well recognized cause of the olfactory loss in patients with CRSwNP. Although the current treatment could significantly improve the olfactory function, olfaction in patients with CRSwNP tends to deteriorate after temporary improvement. Recent research has focused on the change of olfactory cleft and its association with the olfactory function which shed light on the mechanisms of both conductive and sensorineural olfactory dysfunctions in patients with CRSwNP. The state of the olfaction in patients with CRSwNP is directly associated with the degree of inflammation control and disturbed normal turnover of the olfactory sensory neurons induced by chronic inflammation, especially the eosinophilic inflammation contributes to the olfactory dysfunction. Refractory factors contributing to the olfactory deterioration are the promising therapeutic target to maintain the olfactory function in patients with CRSwNP. CONCLUSIONS: The current evidence supports temporary olfactory improvement in CRSwNP patients which accords with the refractory nature of CRSwNP. Future treatment should aim to the continuous elimination of inflammation and promote the normal turnover of the olfactory epithelium. PMID- 30027443 TI - Hypotension after induction of general anesthesia: occurrence, risk factors, and therapy. A prospective multicentre observational study. AB - BACKGROUND: Hypotension after induction of general anesthesia (GAIH) is common in anesthesiology practice and can impact outcomes. METHODS: In this prospective multicenter, cross-sectional, observational study, the hypotension was defined as a decrease in mean arterial pressure of > 30% compared to the first measurement in the operation theatre before general anesthesia (GA) induction. Blood pressure was measured immediately at the time of endotracheal intubation (TETI), at five (T5) and 10 (T10) minutes after. All subjects aged > 18 years undergoing elective non-cardiac surgery under GA were included. The goals were description of GAIH occurrence, the association of GAIH with selected comorbidities, chronic medications, and anesthetics with GAIH, and the type and efficacy of interventions used to correct hypotension. RESULTS: Data from 661 subjects, whose GA was induced with propofol and sufentanil, were analyzed. In 36.5% of subjects, GAIH was observed at >= 1 of the assessed time points. GAIH was present in 2.9% subjects at all time points. The probability of GAIH is raising with age, degree of hypertension at time of arrival to theatre and presence of diabetes. The type of volatile anesthetic was not associated with the occurrence of GAIH. The overall efficiency of interventions to correct hypotension was 94.4%. Bolus fluids were the most often used intervention and was 96.4% effective. CONCLUSION: GAIH rate depends on age, degree of blood pressure decompensation prior the surgery, and presence of diabetes mellitus type II. PMID- 30027444 TI - The electrostatic embedding contribution to DFT calculations of ligand-amino acid residues interaction. AB - In this work, we demonstrate that the inclusion of long-range interactions has a significant impact on the estimation of ligand-protein binding energies. Within the scope of the electrostatically embedded adaptation of the molecular fragmentation with conjugated caps (EE-AMFCC) scheme, we unveil the role played by long-range contributions in distinct levels of quantum mechanical calculations. As a prototypical system, we consider ibuprofen coupled to the human serum albumin. In particular, we show that some relevant ligand-residue interaction energies can only be accurately captured in density functional theory (DFT) approaches when the electrostatic background is properly represented by an explicit point charge distribution. Graphical Abstract (left) The binding site FA3/FA4 of HSA containing the attached IBU. (right) Absolute value of difference between the biding energies calculated including the electrostatic embedding and the energies calculated without the electrostatic embedding using the HF, B3LYP, CAM-B3LYP, and MP2 methodologies. PMID- 30027442 TI - Early corrected serum calcium value can predict definitive calcium serum level after total thyroidectomy in asymptomatic patients. AB - INTRODUCTION: Hypocalcemia is the most common complication of thyroidectomy, requiring supplementation as well as prolonged hospitalization. Our study's objective was to determine a corrected calcium (CCa) level on day 1 after thyroidectomy predictive of no calcium and vitamin supplementation. MATERIALS AND METHODS: A single-center prospective study conducted between January 2012 and July 2015 in 396 patients, consisting of 331 cases of total thyroidectomy, with seven completion surgeries. The data collected were age, sex, type of thyroid surgery, etiology, anatomical pathological analysis, and the need for calcium and vitamin supplementation therapy as well as its duration. CCa levels were analyzed 20 and 30 h after surgery then on days 2 and 3. To determine a cut-off value for CCa, a ROC curve analysis was performed. The population was described in terms of numbers and associated percentages for categorical variables, and mean. RESULTS: Mean CCa on 20 h after surgery was 2.09 mmol/L (p < 0.001) and 30 h was 2.06 mmol/L p = 0.02. CCa of less than 2.13 mmol/L was predictive of calcium and vitamin supplementation with 56% sensitivity and 97% specificity. On the evening of day 1, the cut-off value for CCa was 2.06 mmol/L with 67% sensitivity and 65% specificity. CONCLUSION: This prospective study confirms that CCa on the first morning after surgery is reliable when it is more than 2.13 mmol/L. In total, analyzing CCa on day 1 after total thyroidectomy allows the discharge of 70% of patients on the first day after surgery, with no risk of hypocalcemia. PMID- 30027445 TI - Mesh-augmented versus direct abdominal closure in patients undergoing open abdomen treatment. AB - BACKGROUND: Open abdomen (OA) may be required in patients with abdominal trauma, sepsis or compartment syndrome. Vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) is a widely used approach for temporary abdominal closure to close the abdominal wall. However, this method is associated with a high incidence of re-operations in short term and late sequelae such as incisional hernia. The current study aims to compare the results of surgical strategies of OA with versus without permanent mesh augmentation. METHODS: Patients with OA treatment undergoing vacuum-assisted wound closure and an intraperitoneal onlay mesh (VAC-IPOM) implantation were compared to VAWCM with direct fascial closure which represents the current standard of care. Outcomes of patients from two tertiary referral centers that performed the different strategies for abdominal closure after OA treatment were compared in univariate and multivariate regression analysis. RESULTS: A total of 139 patients were included in the study. Of these, 50 (36.0%) patients underwent VAC-IPOM and 89 (64.0%) patients VAWCM. VAC-IPOM was associated with reduced re-operations (adjusted incidence risk ratio 0.48 per 10-person days; CI 95% = 0.39-0.58, p < 0.001), reduced duration of stay on intensive care unit (ICU) [adjusted hazard ratio (aHR) 0.53; CI 95% = 0.36-0.79, p = 0.002] and reduced hospital stay (aHR 0.61; CI 95% = 0.040-0.94; p = 0.024). In-hospital mortality [22.5 vs 18.0%, risk difference - 4.5; confidence interval (CI) 95% = - 18.2 to 9.3; p = 0.665] and the incidence of intestinal fistula (18.0 vs 22.0%, risk difference 4.0; CI 95% = -10.0 to 18.0; p = 0.656) did not differ between the two groups. In Kaplan-Meier analysis, hernia-free survival was significantly increased after VAC-IPOM (p = 0.041). CONCLUSIONS: In patients undergoing OA treatment, intraperitoneal mesh augmentation is associated with a significantly decreased number of re operations, duration of hospital and ICU stay and incidence of incisional hernias when compared to VAWCM. PMID- 30027446 TI - Soil Enzymatic Activities as Influenced by Lead and Nickel Concentrations in a Vertisol of Central India. AB - A pot-culture was conducted in Completely Randomized Design with three replicates to study the effect of Pb and Ni on enzymatic activities in a Vertisols. Results indicated that increasing in the levels of Pb from 0, 100, 150 and 300 mg kg-1 soil significantly reduced the dehydrogenase activity (DHA) 38.9, 32.1, 30.9, 18.1 ug triphenylformazan g-1 soil 24 h-1; acid phosphatase activities 73, 61, 58, 55 ug PNP g-1 soil h-1 and alkaline phosphatase activities 80.7, 69.4, 66.2 and 64.0 ug PNP g-1 soil h-1, respectively. Application of Ni up to 100 mg kg-1 had significantly improved the soil enzymatic activities and thereafter there was no such change up to the highest level (300 mg Ni kg-1). Among soil enzymatic activities, DHA was more sensitive to Pb application. The findings generated through this study can be useful for managing waste water for safe disposal as well as sustainable crop production. PMID- 30027448 TI - Clinicopathological features of considerable reduction in androgen receptor expression in sebaceous gland carcinoma of the eyelid. AB - PURPOSE: This study aimed to evaluate the relationships between androgen receptor (AR) expression and clinicopathologic features of sebaceous gland carcinoma (SGC) of the eyelid. METHODS: AR expression was evaluated via immunohistochemistry analysis of surgically derived samples from 11 patients with SGC of the eyelid. RESULTS: The expression of AR was evident in 9 of 11 patients (82%). We divided patients into high AR (7 patients) and low AR (4 patients: 2 patients with low expression and 2 patients with no expression) groups. The low AR group showed significantly greater progression than the high AR group with regard to T category and exhibited a lower grade of differentiation. CONCLUSION: In patients with SGC of the eyelid, a marked decrease in AR expression may be associated with a poor prognosis. AR may be a prognostic factor and a potential therapeutic target in cases of SGC of the eyelid. PMID- 30027449 TI - Contribution of traumatic deployment experiences to the burden of mental health problems in Canadian Armed Forces personnel: exploration of population attributable fractions. AB - PURPOSE: Mental health problems are prevalent after combat; they are also common in its absence. Estimates of deployment-attributability vary. This paper quantifies the contribution of different subtypes of occupational trauma to post deployment mental health problems. METHODS: Participants were a cohort of 16,193 Canadian personnel undergoing post-deployment mental health screening after return from the mission in Afghanistan. The screening questionnaire assessed post traumatic stress disorder, depression, panic disorder, generalized anxiety disorder, and exposure to 30 potentially traumatic deployment experiences. Logistic regression estimated adjusted population attributable fractions (PAFs) for deployment-related trauma, which was treated as count variables divided into several subtypes of experiences based on earlier factor analytic work. RESULTS: The overall PAF for overall deployment-related trauma exposure was 57.5% (95% confidence interval 44.1, 67.7) for the aggregate outcome of any of the four assessed problems. Substantial PAFs were seen even at lower levels of exposure. Among subtypes of trauma, exposure to a dangerous environment (e.g., receiving small arms fire) and to the dead and injured (e.g., handling or uncovering human remains) had the largest PAFs. Active combat (e.g., calling in fire on the enemy) did not have a significant PAF. CONCLUSIONS: Military deployments involving exposure to a dangerous environment or to the dead or injured will have substantial impacts on mental health in military personnel and others exposed to similar occupational trauma. Potential explanations for divergent findings in the literature on the extent to which deployment-related trauma contributes to the burden of mental disorders are discussed. PMID- 30027447 TI - Ecological Risk Assessment of HCH and DDT Residues in a Sediment Core from the Kucukcekmece Lagoon, Turkey. AB - The residues of organochlorine pesticides (HCHs and DDTs) in a dated (137Cs and 210Pb) sediment core from the Kucukcekmece Lagoon, an urban lake at the southern entrance of the future Canal Istanbul Project, an artificial watercourse, were analyzed with the gas chromatograph equipped with electron capture detector (GC 63Ni-ECD). Concentrations of ?HCH and ?DDT along the core varied between 0.4 and 469.4 (average 51.4) ng g-1 dw, and between 0.5 and 72.0 (average 7.4) ng g-1 dw, respectively. alpha-HCH was the predominant isomer (98%) and followed by gamma isomer (2%). The highest concentrations of technical HCH were found in the sediments dated 1963-1972, whilst the DDT concentrations had their maximum around 1945. The highest concentrations of gamma-HCH and p,p'-DDT exceeded probable effect level values which can lead to frequently cause adverse effects on aquatic biota. PMID- 30027451 TI - HEIRECA! The HEIdelberg REvolution of CAncer classification and what it means for neurooncology and neuropathology. PMID- 30027452 TI - The Potential Role of TNF-alpha (rs361525 and rs1800629) in Hepatocellular Carcinoma: Multivariate Analysis (Meta-Analysis). AB - PURPOSE: Tumor necrosis factor-alpha has been suggested to play a crucial role in the development andprogression of hepatocellular carcinoma (HCC). Previous reports have indicated that rs361525 and rs1800629 might be risk factors for various cancers. Increasing studies have been conducted on the association of these two SNPs with HCC risk but the results remain inconclusive. METHODS: In order to detect association between TNF- alpha and HCC, a meta-analysis was performed. Five studies with 541 cases and 795 controls were used for rs361525, while six studies including 925 cases and 1307 controls were collected for investigating rs1800629. The grouping of countries from data were obtained was done by Principal Coordinate Analysis plot (PCA). Moreover, association between geographical area and grouping of genotypes was determined by Canonical Correspondence Analysis (CCA). RESULTS: Our meta-analysis showed that rs361525 and rs1800629 were not significantly associated with the risk of HCC. CCA analysis illustrated that there was not any correlation between genotype distribution and geographical distance for rs1800629 but there was significant correlation between genotype distribution and geographical features for rs361525. PCA analysis for both SNPs showed India and Korea were placed near each other and also China and Brazil were in same part of PCA plot. CONCLUSION: To sum up, this meta-analysis suggests that the rs361525 and rs1800629 are not associated with HCC development while geographical distance effect on rs361525 genetic inheritance but not effect on rs1800629. However, it is necessary to conduct further studies with larger sample. Moreover, gene-gene and gene-environment interactions should also be considered. PMID- 30027450 TI - Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. AB - Neurotropic herpesviruses can establish lifelong infection in humans and contribute to severe diseases including encephalitis and neurodegeneration. However, the mechanisms through which the brain's immune system recognizes and controls viral infections propagating across synaptically linked neuronal circuits have remained unclear. Using a well-established model of alphaherpesvirus infection that reaches the brain exclusively via retrograde transsynaptic spread from the periphery, and in vivo two-photon imaging combined with high resolution microscopy, we show that microglia are recruited to and isolate infected neurons within hours. Selective elimination of microglia results in a marked increase in the spread of infection and egress of viral particles into the brain parenchyma, which are associated with diverse neurological symptoms. Microglia recruitment and clearance of infected cells require cell autonomous P2Y12 signalling in microglia, triggered by nucleotides released from affected neurons. In turn, we identify microglia as key contributors to monocyte recruitment into the inflamed brain, which process is largely independent of P2Y12. P2Y12-positive microglia are also recruited to infected neurons in the human brain during viral encephalitis and both microglial responses and leukocyte numbers correlate with the severity of infection. Thus, our data identify a key role for microglial P2Y12 in defence against neurotropic viruses, whilst P2Y12 independent actions of microglia may contribute to neuroinflammation by facilitating monocyte recruitment to the sites of infection. PMID- 30027453 TI - Variations in circulating hemocytes are affected by age and caste in the stingless bee Melipona quadrifasciata. AB - The insect immune system faces various challenges; particularly in social bees, caste system and age polyethism expose individuals to numerous environmental and working conditions. However, little is known about how cellular defenses in social bees may be organized to respond to a variety of immune challenges. Here, we describe the morphological features and the total and differential counts of hemocytes in different female classes (newly emerged workers, nurses, foragers, and virgin queens) of the eusocial stingless bee Melipona quadrifasciata. Granulocytes and prohemocytes were, respectively, the most and the least abundant cells among all classes of females. Furthermore, there were more prohemocytes in virgin queens than in foragers. The total number of hemocytes was smaller in foragers, whereas the largest number was observed in nurse workers. This reduced amount of hemocytes in foragers might allow energy savings to perform colony activities such as foraging and defense. Foragers also had the biggest hemocytes (either prohemocytes, granulocytes, or plasmatocytes) in comparison to the other classes of females, which might have arisen as a compensation for the reduction in number of these cells during aging. These results suggest that profiles of hemocytes of M. quadrifasciata vary according to the caste and age of this eusocial bee. PMID- 30027454 TI - Mental models and omissive causation. AB - Some causal relations refer to causation by commission (e.g., "A gunshot causes death"), and others refer to causation by omission (e.g., "Not breathing causes death"). We describe a theory of the representation of omissive causation based on the assumption that people mentally simulate sets of possibilities-mental models-that represent causes, enabling conditions, and preventions (Goldvarg & Johnson-Laird, 2001). The theory holds that omissive causes, enabling conditions, and preventions each refer to distinct sets of possibilities. For any such causal relation, reasoners typically simulate one initial possibility, but they are able to consider alternative possibilities through deliberation. These alternative possibilities allow them to deliberate over finer-grained distinctions when reasoning about causes and effects. Hence, reasoners should be able to distinguish between omissive causes and omissive enabling conditions. Four experiments corroborated the predictions of the theory. We describe them and contrast the results with the predictions of alternative accounts of causal representation and inference. PMID- 30027455 TI - Correction to: Open resection of hypothalamic hamartomas for intractable epilepsy revisited, using intraoperative MRI. AB - The authors apologize to have sent a final manuscript draft omitting "Athanasius Chawira" from the list of authors. The correct list of authors is given in this article.The original article has been corrected. PMID- 30027456 TI - Special Annual Issue on CNS Infections. PMID- 30027457 TI - Antipsychotic-Related Movement Disorders: Drug-Induced Parkinsonism vs. Tardive Dyskinesia-Key Differences in Pathophysiology and Clinical Management. AB - INTRODUCTION: Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are stigmatizing movement disorders associated with exposure to dopamine receptor blocking agents such as antipsychotics, but they differ in their pathophysiology and clinical management. Treatment for one may worsen the other, and there are important diagnostic clues that assist in making an accurate assessment and instituting a rational treatment plan. METHODS: A literature review was executed to identify articles relating to the presentation, pathophysiology, epidemiology, and management of DIP and TD. RESULTS: DIP and TD prevalence estimates range from approximately 20 to 35% among antipsychotic users, but may be higher in select populations. DIP often presents as bradykinesia and rigidity, as well as rhythmic tremor, and the majority of cases appear within hours to weeks of initiation of therapy with an antipsychotic, or if dosage of the antipsychotic is increased. TD onset is delayed, typically appearing after at least 3 months or longer of treatment, and patients will commonly present with involuntary, abnormal facial movements such as lip smacking, puckering, chewing, or tongue protrusion. DIP often resolves with discontinuation of the causative agent, but TD may be permanent. Broadly, proposed mechanisms underlying these adverse events include decreased dopamine concentrations in the nigrostriatal pathway of the striatum and dopamine hypersensitivity, for DIP and TD, respectively. Pharmacologic treatment approaches for DIP have commonly included anticholinergic agents such as benztropine; however, anticholinergic medications can make TD worse. Switching the antipsychotic medication to one with lower propensity for DIP is an option for some patients. Amantadine, a non-anticholinergic agent used for the treatment of DIP, may be preferred in patients with comorbid DIP and TD. In TD, treatment options include the new reversible vesicular monoamine 2 transporter inhibitors, valbenazine and deutetrabenazine. CONCLUSIONS: It is important for clinicians to be able to recognize DIP and TD in patients using antipsychotics so that they can minimize the impact of these adverse events on their patients' quality of life. Accurate diagnosis will drive the selection of the correct treatment. Plain language summary available for this article. PMID- 30027458 TI - Correction to: Lymph Node Status in Breast Cancer Does Not Predict Tumor Biology. AB - In the "Results" section third paragraph, second sentence, there is an error. The corrected sentence is as follows. PMID- 30027459 TI - Pharmacologic Properties of the Carrier Solutions for Hyperthermic Intraperitoneal Chemotherapy: Comparative Analyses Between Water and Lipid Carrier Solutions in the Rat Model. AB - BACKGROUND: Carrier solutions play an important role in the distribution, plasma absorption, chemical stability, and solubility of anticancer agents during hyperthermic intraperitoneal chemotherapy (HIPEC). In the current study, lipophilic properties of carrier solutions were evaluated to determine whether they improved anticancer drug absorption rates using mitomycin-C (MMC) or oxaliplatin HIPEC as compared to hydrophilic carrier solutions. METHODS: Sprague Dawley rats were divided into two groups: MMC and oxaliplatin treatment groups. Each group was then further subdivided by carrier solution: Dianeal(r) PD-2 peritoneal dialysis solution, 5% dextrose solution and 20% lipid solution (Lipision(r)). HIPEC was performed over 60 min at 41-42 degrees C using the anticancer drugs MMC (35 mg/m2) or oxaliplatin (460 mg/m2). The plasma area under the curve (AUC; AUCplasma), peritoneal AUC (AUCperitoneum), and peritoneal/plasma AUC ratios were compared among HIPEC carrier solutions. RESULTS: Plasma drug concentrations were significantly different among carrier solutions, varying by time. In contrast, peritoneal drug concentrations did not change with carrier solution. In the MMC group, the peritoneal/plasma AUC ratio of a lipid solution was three times higher than Dianeal(r) (p < 0.001). In the oxaliplatin group, the peritoneal/plasma AUC ratio was significantly different between carrier solutions (p = 0.046). Although the oxaliplatin AUCperitoneum did not vary (p = 0.941), the AUCplasma of a lipid solution was lower than that of 5% dextrose solution (p = 0.039). CONCLUSIONS: The lipid carrier solution increases the peritoneal/plasma AUC ratio and decreases plasma absorption rates. However, further study is required before clinical uses, considering its pharmacologic properties and possible risks after HIPEC. PMID- 30027460 TI - Lessons from Cre-Mice and Indicator Mice. AB - The adult human adipose tissue is predominantly composed of white adipocytes. However, within certain depots, adipose tissue contains thermogenically active brown-like adipocytes, which have been evolutionarily conserved in mammals. This chapter will give a brief overview on the methods used to genetically target and trace both white and brown adipocytes using techniques such as bacterial artificial chromosome (BAC) cloning to create transgenic mouse models and the tools with which genetic recombination is mediated in vivo (e.g., Cre-loxP, CreERT, and Tet-On). The chapter furthermore critically discusses the strength and limitation of the various systems used to target mature white and brown adipocytes (ap2-Cre, Adipoq-Cre, and Ucp1-Cre). Based on these systems, it is evident that our knowledge of mature adipocyte categorization into brown, white, brite, or beige adipocytes is strongly influenced by the use of the various genetic mouse models described in this chapter. Our evaluation of different studies using the aforementioned systems focuses on key genes, which have been reported to maintain adipocyte's function (insulin receptor, Raptor, or Atgl). PMID- 30027461 TI - Effect of Extrusion Conditions and the Optimization of Phenolic Compound Content and Antioxidant Activity of Wheat Bran Using Response Surface Methodology. AB - The extrusion process (EP) consists of heat and mechanical treatments under different conditions of moisture, shear, and pressure and rapidly causes structural alterations and changes in the functional properties of the extruded material. The aim of this study was to evaluate the effect of extrusion conditions and optimize the wheat bran extrusion conditions to achieve the greatest content of phenolic compounds and antioxidant activity using response surface methodology. The EP factors evaluated were feed moisture (FM) (25-33.54%) and final extrusion temperature (T) (140-180 degrees C). The properties evaluated in the extruded material were bound total phenol content (BTPC), total phenolic compounds and antioxidant activity (AOX). Analysis of variance (ANOVA) and response surface methodology were used in the evaluation. The determination coefficients, (FM)2 and (T)2, very significantly affected the BTPC and bound 2,2 diphenyl-1-picrylhydrazyl content (BDPPHC). The optimization was performed by overlaying two contour plots to predict the best combination regions. The optimized extrusion conditions were the following: FM = 30% and T = 140 degrees C, which provided BTPC = 3547.01 MUgGAE/g (predicted: 3589.3 MUgGAE/g) and BDPPHC = 9.5 MUmolTE/g (predicted: 10.4 MUmolTE/g); and FM = 30% and T = 180 degrees C, which provided BTPC = 3342.3 MUgGAE/g (predicted: 3727.7 MUgGAE/g) and BDPPHC = 9.5 MUmolTE/g (predicted: 9.3 MUmolTE/g). The EP increased the phenolic compounds and AOX, and enhancement of these properties in wheat bran products could make them functional foods. PMID- 30027464 TI - A phase II study of carboplatin, pemetrexed, and bevacizumab followed by erlotinib and bevacizumab maintenance for non-squamous non-small cell lung cancer with wild-type EGFR (HOT1101). AB - BACKGROUND: This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR. METHODS: Enrolled patients had treatment-naive, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4-6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL). RESULTS: Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1-6) and 4 (range 1-20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0-72.6%]. The ORR was 48.0% (95% CI 34.8-61.5%), and disease control rate was 86.0% (95% CI 73.8-93.0%). The median PFS and OS were 6.5 months (95% CI 5.8-7.2 months) and 21.4 months (95% CI 15.9-26.9 months), respectively. Although grades >= 3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment. CONCLUSIONS: Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR. TRIAL REGISTRATION: UMIN000005872. PMID- 30027463 TI - Cofilin and profilin: partners in cancer aggressiveness. AB - This review covers aspects of cofilin and profilin regulations and their influence on actin polymerisation responsible for cell motility and metastasis. The regulation of their activity by phosphorylation and nitration, miRs, PI(4,5)P2 binding, pH, oxidative stress and post-translational modification is described. In this review, we have highlighted selected similarities, complementarities and differences between the two proteins and how their interplay affects actin filament dynamics. PMID- 30027467 TI - Correction to: A Semi-passive Planar Manipulandum for Upper-Extremity Rehabilitation. AB - Authors would like to correct their acknowledgments. Correct acknowledgments appear here. PMID- 30027466 TI - Combination of plasma white blood cell count, platelet count and C-reactive protein level for identifying surgical necrotizing enterocolitis in preterm infants without pneumoperitoneum. AB - PURPOSE: To evaluate whether plasma white blood cell count (WBC), platelet count (PLT), and C-reactive protein level (CRP) can be used to differentiate surgical necrotizing enterocolitis (NEC) from medical NEC. METHODS: Preterm infants admitted between January 1, 2011 and July 31, 2015 were stratified by the need of surgery as surgical NEC (n = 41) and medical NEC (n = 43). The values of WBC, PLT and CRP were collected at time before NEC occurred (T0), at onset of NEC (T1) and when surgical assessment was required (T2). Patients admitted between August 1, 2015 and March 1, 2018 (n = 53) were collected for further verification. RESULTS: Variables identified in logistic regression analysis predicting surgical NEC were WBC and PLT at T2 (WBC2 and PLT2). The predictive probability of surgery (P) could be calculated by the equation [Formula: see text]. The area under curve of P was 0.84 and the ideal cutoff value was 0.55, with sensitivity and specificity of 85 and 81%, respectively. This cutoff value got an sensitivity of 80% and specificity of 79% in the verification group. CONCLUSION: Combination of WBC and PLT can effectively differentiate surgical NEC from medical NEC infants when surgical assessment was required. PMID- 30027465 TI - Association Between Maternal 2nd Trimester Plasma Folate Levels and Infant Bronchiolitis. AB - Objectives Viral bronchiolitis is the most common cause of infant hospitalization. Folic acid supplementation is important during the periconceptional period to prevent neural tube defects. An area of investigation is whether higher prenatal folate is a risk factor for childhood respiratory illnesses. We investigated the association between maternal 2nd trimester plasma folate levels and infant bronchiolitis. Methods We conducted a retrospective cohort analysis in a subset of mother-infant dyads (n = 676) enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study and Tennessee Medicaid. Maternal folate status was determined using 2nd trimester (16-28 weeks) plasma samples. Bronchiolitis diagnosis in the first year of life was ascertained using International Classification of Diagnosis-9 codes from Medicaid administrative data. We used multivariable logistic regression to assess the adjusted association of prenatal folate levels and infant bronchiolitis outcome. Results Half of the women in this lower-income and predominately African-American (84%) study population had high levels of folate (median 2nd trimester level 19.2 ng/mL) and 21% of infants had at least one bronchiolitis healthcare visit. A relationship initially positive then reversing between maternal plasma folate and infant bronchiolitis was observed that did not reach statistical significance (poverall = .112, pnonlinear effect = .088). Additional adjustment for dietary methyl donor intake did not significantly alter the association. Conclusions for Practice Results did not confirm a statistically significant association between maternal 2nd trimester plasma folate levels and infant bronchiolitis. Further work is needed to investigate the role of folate, particularly higher levels, in association with early childhood respiratory illnesses. PMID- 30027462 TI - Intermediate filaments in cardiomyopathy. AB - Intermediate filament (IF) proteins are critical regulators in health and disease. The discovery of hundreds of mutations in IF genes and posttranslational modifications has been linked to a plethora of human diseases, including, among others, cardiomyopathies, muscular dystrophies, progeria, blistering diseases of the epidermis, and neurodegenerative diseases. The major IF proteins that have been linked to cardiomyopathies and heart failure are the muscle-specific cytoskeletal IF protein desmin and the nuclear IF protein lamin, as a subgroup of the known desminopathies and laminopathies, respectively. The studies so far, both with healthy and diseased heart, have demonstrated the importance of these IF protein networks in intracellular and intercellular integration of structure and function, mechanotransduction and gene activation, cardiomyocyte differentiation and survival, mitochondrial homeostasis, and regulation of metabolism. The high coordination of all these processes is obviously of great importance for the maintenance of proper, life-lasting, and continuous contraction of this highly organized cardiac striated muscle and consequently a healthy heart. In this review, we will cover most known information on the role of IFs in the above processes and how their deficiency or disruption leads to cardiomyopathy and heart failure. PMID- 30027468 TI - Human metabolism and kinetics of tri-(2-ethylhexyl) trimellitate (TEHTM) after oral administration. AB - Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for PVC material and is used for medical devices as an alternative to di-(2-ethylhexyl) phthalate. As plasticizers are known to migrate easily into contact liquids, exposure of patients to TEHTM is highly probable. In the present study, human metabolism pathways of TEHTM and its elimination kinetics were investigated. For that purpose, four healthy volunteers were orally exposed to a single dose of TEHTM. TEHTM and its postulated primary metabolites were investigated in blood samples (up to 48 h after exposure), and in urine samples (collected until 72 h after exposure) using liquid chromatography tandem mass spectrometry (LC-MS/MS). TEHTM was found to be regioselectively hydrolyzed to its diesters di-2-(ethylhexyl) trimellitates (1,2-DEHTM, 2,4-DEHTM) with maximum blood concentrations at 3-h post-exposure, and to its monoester isomers mono-2-(ethylhexyl) trimellitates (1 MEHTM, 2-MEHTM) with peak blood concentrations 5-h post-exposure. For the elimination of investigated urinary metabolites, biphasic elimination kinetics was observed. The most dominant urinary biomarker was found to be 2-MEHTM (2-mono (2-ethylhexyl) trimellitate), followed by several specific secondary metabolites. All in all, approximately 5.8% of the orally administered dose was recovered in urine over a period of 72 h, indicating a comparatively low resorption rate of TEHTM in humans in combination with an apparently rather slow metabolism and excretion rate. In fact, TEHTM and selected metabolites were still detectable in blood and urine 48-h and 72-h post-exposure, respectively. This study is the first to elucidate TEHTM metabolism pathways in humans and to identify metabolites of TEHTM in blood and urine by usage of especially designed human biomonitoring methods. Powerful tools for exposure monitoring and risk assessment of TEHTM are therewith available for future research. PMID- 30027469 TI - Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models. AB - Tributyltin (TBT), a peroxisome proliferator-activated receptor gamma (PPARgamma)/retinoid X receptor (RXR) ligand and founding member of the environmental obesogen chemical class, induces adipocyte differentiation and suppresses bone formation. A growing number of environmental PPARgamma ligands are being identified. However, the potential for environmental PPARgamma ligands to induce adverse metabolic effects has been questioned because PPARgamma is a therapeutic target in treatment of type II diabetes. We evaluated the molecular consequences of TBT exposure during bone marrow multipotent mesenchymal stromal cell (BM-MSC) differentiation in comparison to rosiglitazone, a therapeutic PPARgamma ligand, and LG100268, a synthetic RXR ligand. Mouse primary BM-MSCs (female, C57BL/6J) undergoing bone differentiation were exposed to maximally efficacious and human relevant concentrations of rosiglitazone (100 nM), LG100268 (100 nM) or TBT (80 nM) for 4 days. Gene expression was assessed using microarrays, and in silico functional annotation was performed using pathway enrichment analysis approaches. Pathways related to osteogenesis were downregulated by all three ligands, while pathways related to adipogenesis were upregulated by rosiglitazone and TBT. However, pathways related to mitochondrial biogenesis and brown-in-white (brite) adipocyte differentiation were more significantly upregulated in rosiglitazone-treated than TBT-treated cells. The lack of induction of genes involved in adipocyte energy dissipation by TBT was confirmed by an independent gene expression analysis in BM-MSCs undergoing adipocyte differentiation and by analysis of a publically available 3T3 L1 data set. Furthermore, rosiglitazone, but not TBT, induced mitochondrial biogenesis and respiration. This study is the first to show that an environmental PPARgamma ligand has a limited capacity to induce health-promoting activities of PPARgamma. PMID- 30027470 TI - Association of Genetic Variants in NF-kB with Susceptibility to Breast Cancer: a Case Control Study. AB - Insofar as altered NF-kappaB signaling stemming from the presence of specific genetic variants in NF-kappaB gene contribute to cancer pathogenesis, this study evaluated the association between NF-kappaB rs147574894/I552V, rs148626207/M860T rs3774937 and rs1598859 variants and breast cancer and associated features and complications. This was a retrospective case-control study, which involved 207 women with breast cancer, and 214 cancer-free women who served as controls. NF kappaB genotyping was done by real-time PCR. Significantly higher rs3774937 minor allele frequencies (MAF), and lower rs147574894 MAF were seen among breast cancer patients, thereby imparting disease susceptibility and protective nature to these variants, respectively. Significant association of rs3774937 and rs147574894 genotypes with breast cancer was seen under the dominant model. Histological type and grade, molecular type, Her2 positivity and ER+/Her2- correlated positively, while distant metastasis negatively correlated with rs3774937. On the other hand, rs147574894 negatively correlated with histological type and grade, tumor size, Her2 positivity, molecular type, and ER+/Her2-, while rs148626207 correlated positively with histological grade, but negatively with distant metastasis and triple-negative status. Breast cancer-susceptible and -protective 4-locus haplotypes were also identified. This is the first report that addresses the contribution of NF-kappaB variants to the pathogenesis of breast cancer in Middle Eastern-North African population, and the first to document positive association of rs3774937 with breast cancer. PMID- 30027472 TI - Screening of the Enterocin-Encoding Genes and Their Genetic Determinism in the Bacteriocinogenic Enterococcus faecium GHB21. AB - Enterococci are well-known for their ability to produce a variety of antimicrobial peptides called enterocins. Most of these enterocins withstand extreme conditions and are very effective against a broad spectrum of undesirable bacteria including some Gram-negative bacteria. The same enterococci strain can produce multiple enterocins simultaneously. The genetic determinants of these bacteriocins can either be located on plasmids or on bacterial chromosome. Digestion of Enterococcus faecium GHB21 plasmids with various restriction endonucleases suggests the presence of two plasmids named pGHB-21.1 and pGHB-21.2 whose respective sizes are ~ 10.0 kb and ~ 3.3 kb. The screening of enterocin encoding genes among E. faecium GHB21 genome by PCR followed by amplicon sequencing indicated the presence of three different enterocin structural genes similar to entA, entB, and entP genes previously detected in other E. faecium strains. These enterocin genes were, subsequently, localized on the bacterial chromosome based on PCR-targeted screening using total DNA and plasmids of E. faecium GHB21 as separate templates. PMID- 30027471 TI - Recurrent Pulmonary Embolism and Hypersensitivity Pneumonitis Secondary to Aspergillus, in a Compost Plant Worker: Case Report and Review of Literature. AB - Activation of blood coagulation pathways as a component of an allergic response has been studied in animal models. In patients with allergic diseases, clot qualities have been noted to be different in terms of denser fibrin clot with reduced plasmin-mediated clot lysis. Correlation between occupational hypersensitivity pneumonitis (HP) with thromboembolic events is scarce in the general patient population. We present a case of a 52-year-old man with recurrent venous thromboembolism with HP secondary to bioaerosol exposure in a compost plant. Biochemical evaluation found no evidence of underlying hypercoagulable state, with only remarkable findings of elevated levels of total serum immunoglobulin E and raised Aspergillus sp. IgG antibodies. The patient decided to change his working environment to one without exposure to compost or other fungal elements. His symptoms and pulmonary function tests gradually improved without any subsequent intervention. The patient chose against the advice of his care providers to discontinue warfarin anti-coagulation that had been recommended for lifelong duration after recurrent pulmonary thromboembolism. At a 4-year follow-up he has remained free of any further episodes of venous thromboembolic events without any anti-coagulation. Repeated imaging studies after cessation of exposure demonstrated clearance of multiple lung nodules and improvement in DLco. PMID- 30027473 TI - Evaluation of Fresh Cheese Quality Prepared with Newly Isolated Nisin Z-Producing Lactococcus lactis Bacteria. AB - The main task of the present study was to evaluate an impact of three nisin Z producing Lactococcus lactis bacteria newly isolated from raw goat milk for some fresh cow cheese characteristics during the storage. Microbiological evaluation for Listeria monocytogenes, Staphylococcus aureus, and viable lactic acid bacteria counts and determination of pH, titratable acidity, and lactic acid concentration of produced cheese were performed after 0, 24, 48, 72, and 96 h. Sensory analysis for the evaluation of acidity, flavor intensity, color intensity, bitterness, and crumbliness of prepared cheese was performed. The changes of volatile compounds in fresh cheese were evaluated using headspace solid phase microextraction (SPME) coupled with gas chromatography-mass spectrometry. Chemometric methods were applied for the data analysis. Study showed that tested bacteria are suitable for the manufacturing of fresh cheese and possible application for fresh cheese biopreservation, as pathogenic bacteria did not grow during 4 days (96 h); chemometric analysis revealed that L. lactis strain LL56 was the most similar to commercially available L. lactis ATCC11454. PMID- 30027474 TI - Correction to: Assessment of tumor necrosis factor alpha polymorphism TNF-alpha 238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients. AB - The title of the original article has been corrected to: Assessment of tumor necrosis factor alpha polymorphism TNF-alpha-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients. The original article has been corrected to reflect the correct title. PMID- 30027475 TI - Efficiency of RAPD, ISSR and ITS markers in detecting genetic variability among Salacia species sampled from the Western Ghats of Karnataka. AB - Diversity and phylogenetic relationship between four closely related Salacia species, i.e., Salacia chinensis, Salacia macrosperma, Salacia fruticosa and Salacia oblonga, collected from the Western Ghats of Karnataka, India, was assessed. Ten each of RAPD and ISSR primers generated a total of 76 and 68 loci, generating polymorphisms of 92.21 and 89.71%, respectively. Maximum likelihood analysis of the ITS sequences revealed three clades. Dendrogram analyses of RAPD and ISSR revealed two and four clusters, respectively. Overall polymorphism revealed by RAPD was 41.45 +/- 10%, ISSR was 33.58 +/- 6.52%, and ITS was 25.50 +/- 17.25%. Molecular variance revealed significant variance within and among the Salacia species. Tajima's D neutrality test and Fu's Fs were negative for all four species, implying presences of rare alleles and population expansion. Comparative study of RAPD, ISSR and ITS for Salacia species has given an insight into the efficiency of each technique in detecting diversity within and among the population sampled in the Western Ghats of Karnataka. PMID- 30027477 TI - [Airway separation and one-lung ventilation : A special challenge for anesthetists]. PMID- 30027476 TI - Transcription factor 7-like 2 single nucleotide polymorphisms are associated with lipid profile in the Balinese. AB - Transcription factor 7-like 2 (TCF7L2) protein plays an important role in glucose and lipid metabolisms. Single nucleotide polymorphisms (SNPs) in the TCF7L2 gene contribute to increased fasting plasma glucose (FPG) and body mass index (BMI), and altered lipid concentrations in various population. We investigated whether the TCF7L2 SNPs were associated with obesity, high FPG and altered lipid profile in the Balinese. A total of 608 Balinese from rural and urban Bali, Indonesia, were recruited. Triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and FPG were measured, and BMI was calculated. Ratios of TG/HDL-C, LDL-C/HDL-C, and TC/HDL-C were determined. Genotyping of SNPs rs7903146, rs10885406, and rs12255372 were done in all samples. Genetic association analyses under a dominant model showed that the rs7903146 (OR 5.50, 95% CI 2.34-12.91, p = 8.5 * 10-5), rs12255372 (OR 4.15, 95% CI 1.66-10.33, p = 0.003) and rs10885406 (OR 2.43, 95% CI 1.39-4.25, p = 0.003) were significantly associated with high TC/HDL-C ratio. The rs10885406 also presented a significant association with high TG (OR 2.21, 95% CI 1.29-3.81, p = 0.004) and low HDL-C (OR 3.02, 95% CI 1.58-5.80, p = 0.001) concentrations, as well as high TG/HDL-C ratio (OR 1.95, 95% CI 1.16-3.27, p = 0.013). None of the SNPs exhibited significant association with obesity or high FPG. SNPs in the TCF7L2 gene are associated with altered lipid profile in the Balinese. PMID- 30027478 TI - Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label, Multicenter Study. AB - INTRODUCTION: Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients. METHODS: In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9-14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg. RESULTS: Mean maximum plasma concentration (Cmax) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (Tmax) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration-time curve (AUC) from 0 24 h post-dose (AUC0-24) and 0 h to infinity (AUC0-inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment emergent adverse events considered to be related to azilsartan occurred during the study. CONCLUSION: Our data suggest that pediatric patients weighing less than 50 kg may have approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02451150. FUNDING: Takeda Pharmaceutical Co. Ltd. PMID- 30027479 TI - A Single-Dose, Crossover-Design Bioequivalence Study Comparing Two Nicotine Gum Formulations in Healthy Subjects. AB - INTRODUCTION: Nicotine replacement therapy (NRT) benefits smokers who wish to quit; nicotine gum represents one NRT. New formulations of nicotine gum have been developed to consider consumer preferences and needs. A new mint-flavored nicotine gum with a different texture was developed that may provide a more appealing taste and chewing experience. This study evaluated this new nicotine gum (2 and 4 mg strengths) for bioequivalence versus the original flavor sugar free nicotine gum at corresponding dosages. METHODS: All subjects randomized in this crossover study received a single dose of all treatments, i.e., 2 and 4 mg doses of test and reference gums, separated by 2-7 days of washout between treatments. Subjects' maximal plasma nicotine concentration (Cmax) and extent of nicotine absorption (AUC0-t) following the administration of each treatment were calculated from plasma nicotine concentrations. Ratios of test/reference for Cmax and AUC0-t were calculated to evaluate bioequivalence between the two products. RESULTS: Both 2 and 4 mg doses of the new mint-flavored nicotine gum were bioequivalent to the dose-matched reference product as determined by the ratio of the geometric means and their 90% confidence intervals for Cmax and AUC0-t as well as secondary pharmacokinetic parameters. The safety profiles of the test and reference gums were similar; all treatments were well tolerated. CONCLUSIONS: A new mint-flavored nicotine gum with modified taste and texture is bioequivalent to the original flavor sugar-free nicotine gum at both the 2 and 4 mg dosage strengths and has a similar safety profile. FUNDING: GlaxoSmithKline. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01847443. PMID- 30027480 TI - Fruit and Vegetable Intake of US Hispanics by Food Store Type: Findings from NHANES. AB - This study examined fruit and vegetable intake by food store type shopped among US Hispanics. Using National Health and Nutrition Examination Survey 2011-2012 data, T test and chi-square tests examined differences between Hispanic consumers by food store type. Negative binomial regression analyses estimated associations between fruit and vegetable intake and food store type. Hispanics who only purchased fruits and vegetables from convenience stores were younger and more likely US born. They reported lower intakes of fruit and vegetables than individuals who purchased these foods from supermarket/grocery stores. Those who primarily purchased fruits and vegetables from supermarkets/grocery stores consumed 0.92 (p < .001) greater fruit cup equivalents and 0.26 (p = .001) greater vegetable cup equivalents than those who only purchased from convenience stores. Research on the influence of shopping in multiple food store types is needed to develop targeted in-store intervention strategies to encourage healthier food purchases. Results provide support for policy-level research such as minimum stocking requirements for healthy foods in convenience stores. PMID- 30027481 TI - Correction to: Parameters influencing complaints and joint function in patients with osteochondral lesions of the ankle-an investigation based on data from the German Cartilage Registry (KnorpelRegister DGOU). AB - The original version of this article contained an error. PMID- 30027482 TI - Poor static balance is a risk factor for non-contact anterior cruciate ligament injury. AB - BACKGROUND: This prospective study aimed to investigate the relationship between static balance and the incidence of non-contact anterior cruciate ligament (ACL) injury in female high school athletes. METHODS: This study included 276 female high school handball or basketball players. At the time of admission, each subject's static balance was measured with a gravicorder, and the incidence of non-contact ACL injury was investigated in the 3 years until the student graduated. The measured parameters of postural sway were locus length per time (the distance that a center of gravity of the foot pressure moves per second) and environmental area (AR: the area surrounded by the integumentary covering of the trace of the center of gravity). Twenty-seven players (9.8%) experienced an ACL injury during the 3-year observation period. Twenty-four injured players sustained a non-contact injury and three injured players sustained a contact injury. In this study, the three contact injury players were excluded. We compared the differences in the static balance between injured and uninjured players. RESULTS: The locus length per time was significantly longer in injured than in uninjured players (p = 0.046). Though there was no statistically significant difference between the two groups in AR (p = 0.190), AR tended to be larger in the ACL injured group. CONCLUSIONS: This result shows that poor static balance is a risk factor for non-contact ACL injury. PMID- 30027484 TI - Fixed-bearing unicompartmental knee arthroplasty tolerates higher variance in tibial implant rotation than mobile-bearing designs. AB - BACKGROUND: UKA necessitates a learning period. From this point of view, it would be logical to prefer the design that tolerates suboptimal tibial rotations better, especially for inexperienced surgeons. The aim of this study was to evaluate and compare the clinical and radiological results of mobile-bearing and fix-bearing UKA designs in case of suboptimal tibial rotations. METHODS: A retrospective case-control evaluation was made of all the patients with medial compartment osteoarthritis, treated between January 2011 and January 2015. 324 patients ideal femoral rotation were enrolled in the study. 153 patients (Group 1) were treated with fix-bearing design with a mean 28.8 +/- 11.3 month follow-up and 171 patients (Group 2) were treated with mobile-bearing design with a 31 +/- 14.3 month follow-up. Each patient in groups was subdivided into (A): optimal tibial rotation, (B): external rotation of tibial component > 5 degrees , (C): internal rotation of tibial component > 5 degrees subgroups. WOMAC and KSS scores of each patient at preoperative and postoperative final control were compared between groups and subgroups. RESULTS: No significant differences were determined between the groups in terms of mean follow-up time (p = 0.0612), preoperative WOMAC, and KSS scores (p = 0.754 and p = 0.832, respectively). No significant differences were determined between subgroups 1A and 2A in terms of WOMAC and KSS scores at the final evaluation (p = 0.314 and p = 0.546, respectively). A significant difference was determined between subgroups 1B and 2B in terms of WOMAC and KSS scores (p = 0.021 and p = 0.012, respectively). In addition, the difference between subgroups 1C and 2C was significant (p = 0.047 and p = 0.034, respectively) at the final evaluation. CONCLUSION: Both mobile- and fix-bearing designs are beneficial in the treatment of medial compartment osteoarthritis of the knee. However, in case of both tibial internal or external suboptimal tibial rotations, fix-bearing design have better results compared to mobile-bearing design. STUDY DESIGN: Level III retrospective comparative clinical study. PMID- 30027483 TI - Fast-track total knee arthroplasty improved clinical and functional outcome in the first 7 days after surgery: a randomized controlled pilot study with 5-year follow-up. AB - INTRODUCTION: Fast-track protocols (FP) are used more and more to optimize results after total knee arthroplasty (TKA). Many studies evaluating FP in TKA concentrate on clinical outcome and medium to long-term results. Since discharge from hospital after TKA is achieved increasingly quicker worldwide using FP in an increasingly younger and active patient population, the effects of FP on functional outcome in the first days after TKA become more important. The purpose of the current study was to compare FP with a regular joint care protocol (RP), with an emphasis on the first 7 days after surgery. MATERIALS AND METHODS: A non blinded randomized controlled clinical pilot study was performed with 25 patients assigned to a FP group and 25 patients assigned to a RP group. Primary outcome was functional outcome, clinical outcome, pain, and complications for each day in the first week after surgery. Patients were followed up to 5 years after surgery. RESULTS: Significantly lower VAS scores for knee pain, faster Timed-Up and Go test times and more mobility on functional tests were seen on several days in the first week in the FP group compared to the RP group. Few other significant differences were found at 2, 6 weeks, and no significant differences were found at 12 weeks and 1, 2 and 5 years after surgery. CONCLUSIONS: Fast-track protocol for primary TKA showed significantly lower knee pain scores and improved functional outcome in the first 7 days after TKA compared to a regular protocol. PMID- 30027485 TI - Genomes shed light on the secret life of Candida glabrata: not so asexual, not so commensal. AB - Candida glabrata is an opportunistic yeast pathogen, whose incidence has increased over the last decades. Despite its genus name, this species is actually more closely related to the budding yeast Saccharomyces cerevisiae than to other Candida pathogens, such as Candida albicans. Hence, C. glabrata and C. albicans must have acquired the ability to infect humans independently, which is reflected in the use of different mechanism for virulence, and survival in the host. Yet, research on C. glabrata suffers from assumptions carried over from the more studied C. albicans. Regarding the adaptation of C. glabrata to the human host, the prejudice was that, just as C. albicans, C. glabrata is a natural human commensal that turns deadly when immune defenses weaken. It was also considered asexual, as no one has observed mating, diploids, or spores, despite great efforts. However, the recent analysis of whole genomes from globally distributed C. glabrata isolates have shaken these assumptions. C. glabrata seems to be only secondarily associated to humans, as indicated by a lack of co-evolution with its host, and genomic footprints of recombination shows compelling evidence that this yeast is able to have sex. Here, we discuss the implications of this and other recent findings and highlight the new questions opened by this change in paradigm. PMID- 30027486 TI - Information equilibria, subsystem entanglement, and dynamics of the overall entropic descriptors of molecular electronic structure. AB - Overall descriptors of the information (determinicity) and entropy (uncertainty) content of complex molecular states are reexamined. These resultant concepts combine the classical (probability) contributions of Fisher and Shannon, and the relevant nonclassical supplements due to the state phase/current. The information theoretic principles determining equilibria in molecules and their fragments are explored and the nonadditive part of the global entropy is advocated as a descriptor of the classical index of the quantum entanglement of molecular subsystems. Affinities associated with the probability and phase fluxes are identified and the criterion of vanishing overall information-source is shown to identify the system stationary electronic states. The production of resultant density of the gradient-information is expressed in terms of the conjugate affinities (forces, perturbations) and fluxes (currents, responses). The Schrodinger dynamics of probability and phase components of molecular electronic states is used to determine the temporal evolution of the overall gradient information and complex entropy. The global sources of the resultant information/entropy descriptors are shown to be of purely nonclassical origin, thus identically vanishing in real electronic states, e.g., the nondegenerate ground state of a molecule. PMID- 30027487 TI - Overexpression of a virus-like particle influenza vaccine in Eri silkworm pupae, using Autographa californica nuclear polyhedrosis virus and host-range expansion. AB - Ecological investigations of silkworms have revealed that Eri silkworms (Samia cynthia ricini) possess useful morphological and ecological characteristics for virus-like particle (VLP) production, namely non-seasonal breeding, longer lengths, and heavier weights than Bombyx mori silkworms. Furthermore, when vector DNA from Bombyx mori nuclear polyhedrosis virus (BmNPV), which is unable to replicate in Sf9 cells from Eri silkworms, was replaced with the Autographa californica nuclear polyhedrosis virus (AcNPV) vector, three improved AcNPV influenza virus recombinants capable of replication in Sf9 cells were obtained. Although VLP antigens produced previously in silkworms were not evaluated individually, the present recombinant Fukushima (FkH5) and Anhui (AnH7) VLP antigens were detected in tissue fluids and fat bodies of Eri silkworms. Here, we aimed to determine the function of the AcNPV vector and P143 gene by expressing recombinants in Sf9 cells and eri silkworm pupae. The FkH5 recombinant produced high yields of haemagglutinin (HA)-positive VLPs, showing a mean HA titre of 1.2 million. Similarly, high production of H7 HA VLPs was observed in the fat bodies of eri silkworm pupae. Antigenic analysis and electron microscopy examination of Eri-silkworm-produced H5 HA VLPs showed characteristic antigenicity and morphology similar to those of the influenza virus. Although FkH5 recombinants possessing the AcNPV vector did not replicate in Bm-N cells, the introduction of the helicase p143 gene from BmNPV resulted in their production in Bm-N and Sf9 cells. PMID- 30027489 TI - Transmission of porcine cysticercosis in the Portuguesa state of Venezuela. AB - The aim of this study was to assess transmission of Taenia solium cysticercosis in Palmarito Arriba, a small village in the rural area of the Portuguesa state of Venezuela, through (1) an evaluation of T. solium transmission risk factors present in the community and (2) serological detection of the secreted metacestode HP10 antigen (HP10 Ag) and of anti-metacestode antibodies in sera from rural pigs. Risk factors associated with transmission of cysticercosis were the following: 100% (23/23) of the households lacked piped water, 87.0% (20/23) of households lacked latrines, 88.0% (100/114) of inhabitants routinely defecated in the open/air, 19.05% (12/63) of the interviewed population had observed proglottids in their stools. More significantly, 9/13 householders breeding pigs reported seeing proglottids in their stools. Of the 25 pigs available for bleeding and serological testing, 64% (16/25) were free roaming and 36% (9/25) were "backyard" animals; 28% (7/25) were seropositive for both the HP10 Ag and antibody, 20.0% (5/25) were seropositive for HP10 Ag alone, and 36.0% (9/25) were seropositive for antibody alone. Given this clear evidence of endemic porcine cysticercosis, further studies are needed to assess and control the level of porcine and human taeniasis and cysticercosis in this and neighboring communities. PMID- 30027488 TI - Down from the treetops: red langur (Presbytis rubicunda) terrestrial behavior. AB - Using direct observations and camera traps at eight sites across Indonesian Borneo we show how red langurs (Presbytis rubicunda) are more terrestrial than previously believed, regularly coming to the ground. This unusual behavior has been found at six of the eight sites surveyed. We find that red langurs come to the ground more frequently in disturbed forests, specifically ones which have been impacted by logging, fire, and hunting, though more data are needed to confirm this as a direct correlation. We also found a trend towards decreased ground use with increased elevation of the habitat. When on the ground, red langurs are predominantly engaged in feeding (50% direct observations, 61% camera traps) and traveling (29% direct observations, 13% camera traps). Red langurs are found on the ground throughout the day, at similar times to activity periods of the apex predator, the Sunda clouded leopard (Neofelis diardi). We suggest that ground use by red langurs could be an adaptation to disturbed forest to exploit additional food sources and to facilitate travel. PMID- 30027490 TI - Expression of Gre2p improves tolerance of engineered xylose-fermenting Saccharomyces cerevisiae to glycolaldehyde under xylose metabolism. AB - Engineered S. cerevisiae employing the xylose reductase pathway enables efficient xylose valorization to fuels and chemicals. However, toxicity of thermochemically pretreated biomass hydrolysate on S. cerevisiae is one of the key technical challenges to upgrade biomass-derived sugars including xylose and glucose into high-value products. We investigated the effect of glycolaldehyde, one of the biomass-derived highly toxic aldehyde compounds, and its combinatorial inhibitory effect with other major fermentation inhibitors commonly found in plant hydrolysate such as methylglyoxal, 5-HMF, furfural, vanillin, and acetic acid on engineered xylose-fermenting S. cerevisiae in xylose and/or glucose media. We elucidated that glycolaldehyde and methylglyoxal are the key inhibitory short aliphatic aldehydes on engineered xylose-fermenting S. cerevisiae in xylose containing medium. Indeed, the degree of toxicity of these tested fermentation inhibitors varies with the sole carbon source of the medium. We demonstrate that genome integration of an extra copy of autologous GRE2 with its native promotor substantially improved the toxic tolerance of engineered xylose-fermenting S. cerevisiae to major inhibitory compounds including glycolaldehyde in the xylose containing medium, and xylose-rich, lignocellulosic hydrolysate derived from Miscanthus giganteus, and concurrently improved the ethanol fermentation profile. Outcomes of this study will aid the development of next-generation robust S. cerevisiae strains for efficient fermentation of hexose and pentose sugars found in biomass hydrolysate. PMID- 30027491 TI - Mushroom cultivation in the circular economy. AB - Commercial mushrooms are produced on lignocellulose such as straw, saw dust, and wood chips. As such, mushroom-forming fungi convert low-quality waste streams into high-quality food. Spent mushroom substrate (SMS) is usually considered a waste product. This review discusses the applications of SMS to promote the transition to a circular economy. SMS can be used as compost, as a substrate for other mushroom-forming fungi, as animal feed, to promote health of animals, and to produce packaging and construction materials, biofuels, and enzymes. This range of applications can make agricultural production more sustainable and efficient, especially if the CO2 emission and heat from mushroom cultivation can be used to promote plant growth in greenhouses. PMID- 30027492 TI - Purine and pyrimidine salvage pathway in thermophiles: a valuable source of biocatalysts for the industrial production of nucleic acid derivatives. AB - Due to their similarity to natural counterparts, nucleic acid derivatives (nucleobases, nucleosides, and nucleotides, among others) are interesting molecules for pharmaceutical, biomedical, or food industries. For this reason, there is increasing worldwide demand for the development of efficient synthetic processes for these compounds. Chemical synthetic methodologies require numerous protection-deprotection steps and often lead to the presence of undesirable by products or enantiomeric mixtures. These methods also require harsh operating conditions, such as the use of organic solvents and hazard reagents. Conversely, enzymatic production by whole cells or enzymes improves regio-, stereo-, and enantioselectivity and provides an eco-friendly alternative. Because of their essential role in purine and pyrimidine scavenging, enzymes from purine and pyrimidine salvage pathways are valuable candidates for the synthesis of many different nucleic acid components. In recent years, many different enzymes from these routes, such as nucleoside phosphorylases, nucleoside kinases, 2' deoxyribosyltransferases, phosphoribosyl transferases, or deaminases, have been successfully employed as biocatalysts in the production of nucleobase, nucleoside, or nucleotide analogs. Due to their great activity and stability at extremely high temperatures, the use of enzymes from thermophiles in industrial biocatalysis is gaining momentum. Thermophilic enzymes not only display unique characteristics such as temperature, chemical, and pH stability but also provide many different advantages from an industrial perspective. This mini-review aims to cover the most representative enzymatic approaches for the synthesis of nucleic acid derivatives. In this regard, we provide detailed comments about enzymes involved in crucial steps of purine and pyrimidine salvage pathways in thermophiles, as well as their biological role, biochemical characterization, active site mechanism, and substrate specificity. In addition, the most interesting synthetic examples reported in the literature are also included. PMID- 30027493 TI - Laparoscopic delayed coloanal anastomosis without diverting ileostomy for low rectal cancer surgery: 85 consecutive patients from a single institution. AB - BACKGROUND: Surgical treatment for low rectal cancer septic complications often requires an ileostomy for fecal diversion. Delayed coloanal anastomosis (CAA) has been performed for several years to reduce septic complications and to avoid ileostomy. The aim of this study was to report the technical, functional and oncological results of delayed CAA in patients operated on for low rectal cancer focusing on pelvic septic complications. METHODS: All consecutive patients operated on for low rectal cancer suitable for total mesorectal excision and two step delayed CAA at a single institution between May 2000 and September 2013 were included in the study. Patients' characteristics, operative and postoperative outcomes, long-term technical, functional and oncological results from a prospectively maintained database, were retrospectively analyzed. RESULTS: A total of 85 consecutive patients (69 men), of median age 63 years (range 42-83 years) were included. Median delay between the first and the second step of the operation was 6 days (range 2-13 days). Twenty-one patients (25%) developed pelvic sepsis, nine of them (10.6%) developed an anastomotic leak. Twenty-three patients had a definitive stoma at the end of follow-up. Seventeen patients (29%) experienced a poor functional result. Thirty-three patients (38%) presented with recurrence at a median follow-up of 59 months (range 12-135 months). Seven (8.2%) developed a local recurrence, 18 a distant metastasis (21.1%) and 8 (9.4%) both a local and distant recurrence. CONCLUSIONS: In our series, laparoscopic total mesorectal excision with delayed coloanal anastomosis was associated with septic complications and oncologic results similar to those reported after total mesorectal excision with conventional anastomosis and ileostomy, nearly one-third of patients experience a poor functional result. A randomized trial comparing these two options for low rectal cancer is under way. PMID- 30027494 TI - Conscientious objection and person-centered care. AB - Person-centered care offers a promising way to manage clinicians' conscientious objection to providing services they consider morally wrong. Health care centered on persons, rather than patients, recognizes clinicians and patients on the same stratum. The moral interests of clinicians, as persons, thus warrant as much consideration as those of other persons, including patients. Interconnected moral interests of clinicians, patients, and society construct the clinician as a socially embedded and integrated self, transcending the simplistic duality of private conscience versus public role expectations. In this milieu of blurred boundaries, person-centered care offers a constructive way to accommodate conscientious objection by clinicians. The constitutionally social nature of clinicians commits and enables them, through care mechanisms such as self-care, to optimize the quality of health care and protect the welfare of patients. To advance these conditions, it is recommended that the medical profession develop a person-centered culture of care, along with clinician virtues and skills for person-centered communication. PMID- 30027495 TI - Computed tomographic features of abdominal tuberculosis: unmask the impersonator! AB - PURPOSE: Abdominal tuberculosis (ATB) mimics various infectious, inflammatory, and neoplastic conditions and hence requires a high index of suspicion for accurate diagnosis, especially in low prevalence areas. It is difficult to consistently establish a histopathological diagnosis of ATB which underlines the importance of supportive evidences for institution of prompt empirical therapy to prevent associated morbidity and mortality. METHODS: We retrospectively evaluated clinical and imaging features of 105 ATB cases and classified their CT findings based on peritoneal, lymph node, bowel, and solid organ involvement. Concomitant pulmonary and extra-pulmonary involvement was assessed. RESULTS: Abdominal pain (78.1%) followed by fever (42.9%) were the commonest presenting symptoms. Peritoneal TB (77.14%) most commonly presented with a mix of ascites (49.38%), peritoneal (28.40%), and omental involvement (27.16%). Lymphadenopathy (57.1%) most commonly presented as necrotic nodes (81.67%) at mesenteric, peripancreatic, periportal, and upper paraaortic regions. Commonest site of bowel involvement (cumulative of 62.85%) was ileocecal region, with the commonest pattern of involvement being circumferential bowel wall thickening without bowel stratification with mild luminal narrowing. Hepatic (13.33%) and splenic (16.2%) involvement predominantly presented as multiple microabscesses. Adrenal and pancreatic involvement was noted in 4.7% and 1.9% of patients, respectively. 38.1% patients showed concomitant pulmonary and extra-pulmonary TB. CONCLUSION: ATB has varied radiological features; however, peritoneal involvement in the form of mild ascites, smooth peritoneal thickening, smudgy omentum, multi-focal bowel involvement, necrotic nodes, and multiple visceral microabscesses point towards a diagnosis of ATB in appropriate clinical setting. PMID- 30027496 TI - Dopamine, time perception, and future time perspective. AB - RATIONALE: Impairment in time perception, a critical component of decision making, represents a risk factor for psychiatric conditions including substance abuse. A therapeutic that ameliorates this impairment could be advantageous in the treatment of impulsivity and decision-making disorders. OBJECTIVES: Here we hypothesize that the catechol-O-methyltransferase (COMT) inhibitor tolcapone, which increases dopamine tone in frontal cortex (Ceravolo et al Synapse 43:201 207, 2002), improves time perception, with predictive behavioral, genetic, and neurobiological components. METHODS: Subjects (n = 66) completed a duration estimation task and other behavioral testing in each of two sessions after receiving a single oral dose of tolcapone (200 mg) or placebo in randomized, double-blind, counterbalanced, crossover fashion. Resting state fMRI data were obtained in a subset of subjects (n = 40). Subjects were also genotyped for the COMT (rs4680) polymorphism. RESULTS: Time perception was significantly improved across four proximal time points ranging from 5 to 60 s (T(524) = 2.04, p = 0.042). The degree of this improvement positively correlated with subjective measures of stress, depression, and alcohol consumption and was most robust in carriers of the COMT Val158 allele. Using seed regions defined by a previous meta analysis (Wiener et al Neuroimage 49:1728-1740, 2010), we found not only that a connection from right inferior frontal gyrus (RIFG) to right putamen decreases in strength on tolcapone versus placebo (p < 0.05, corrected), but also that the strength of this decrease correlates inversely with the increase in duration estimation on tolcapone versus placebo (r = - 0.37, p = 0.02). CONCLUSIONS: Compressed time perception can be ameliorated by administration of tolcapone. Additional studies should be conducted to determine whether COMT inhibitors may be effective in treating decision-making disorders and addictive behaviors. PMID- 30027497 TI - The effect of NAD-299 and TCB-2 on learning and memory, hippocampal BDNF levels and amyloid plaques in Streptozotocin-induced memory deficits in male rats. AB - RATIONALE: Alzheimer's disease (AD) is the most common form of dementia characterized by a progressive decline in cognitive function. The serotonergic system via the 5-HT1A receptor and 5-HT2A receptor is proposed to affect the cognitive process. OBJECTIVE: In the present study, the effects of NAD-299 (5 HT1AR antagonist) and TCB-2 (5-HT2AR agonist) on learning and memory processes, hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal necrosis, and Abeta plaque production have been investigated on the intracerebroventricular (icv) injection of streptozotocin (STZ)-induced memory deficits in rats. METHODS: Fifty-four adult male Wistar rats (250-300 g) were divided into six groups (n = 9 in each group): control, sham-operated, AD (icv-STZ (3 mg/kg, 10 MUl)), AD+NAD 299 (5 MUg/1 MUl icv for 30 days), AD+TCB-2 (5 MUg/1 MUl icv for 30 days), and AD+NAD-299 + TCB-2 (NAD-299 (5 MUg/0.5 MUl icv) and TCB-2 (5 MUg/0.5 MUl icv) for 30 days). Following the treatment period, rats were subjected to behavioral tests of learning and memory. Then, hippocampal BDNF, amyloid-beta (Abeta) plaque, and neuronal loss were determined by ELISA Kit, Congo red staining, and Nissl staining, respectively. RESULTS: The results of behavioral tests showed that icv STZ injection decreased the discrimination index in the novel object recognition (NOR) test. In the passive avoidance learning (PAL) task, icv-STZ injection significantly decreased step-through latency (STLr) and increased time spent in dark compartment (TDC). Treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 attenuated the STZ-induced memory impairment in both NOR and PAL tasks. icv-STZ induced a decrease in hippocampal BDNF levels and increased Abeta plaques production in the brain, whereas treatment with NAD-299, TCB-2, and NAD-299 + TCB 2 reduced Abeta plaques in the brain and increased the hippocampal BDNF level. Results of Nissl staining showed that icv-STZ injection increased neuronal loss in the hippocampus, while treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced hippocampal neurodegeneration. CONCLUSION: These findings suggest that 5 HT1AR blockade by NAD-299 and 5-HT2AR activation by TCB-2 improve cognitive dysfunction in icv-STZ-treated rats, and these drugs may potentially prevent the progression of AD. PMID- 30027499 TI - Study Design of the Graft Patency After FFR-Guided Versus Angiography-Guided CABG Trial (GRAFFITI). AB - : Clinical benefit of invasive functionally guided revascularization has been mostly investigated and proven for percutaneous coronary intervention. It has never been prospectively evaluated whether a systematic fractional flow reserve (FFR) assessment is also beneficial in guiding coronary artery bypass graft surgery (CABG). The objective of the GRAft patency after FFR-guided versus angiography-guIded CABG (GRAFFITI) trial was to compare an FFR-guided revascularization strategy to the traditional angiography-guided revascularization strategy for patients undergoing CABG. Patients were enrolled with significantly diseased left anterior descending or left main stem and at least one major coronary artery with angiographically intermediate stenosis (30 90% diameter stenosis) that was assessed by FFR. Thereafter, while the FFR values were kept concealed, cardiac surgeons decided their intended procedural strategy based on the coronary angiography alone. At this point, patients underwent 1:1 randomization to either an FFR-guided or an angiography-guided CABG strategy. In case the patient was randomized to angiography-guided arm, cardiac surgeons kept their intended procedural strategy, i.e., CABG was guided solely on the basis of the coronary angiography. In case the patient was randomized to the FFR-guided arm, FFR values were disclosed to the surgeons who revised the surgical protocol according to the functional significance of each coronary stenosis. The primary endpoint of the trial was the rate of graft occlusion at 12 months, assessed by coronary computed tomography or coronary angiography. The secondary endpoints were (1) length of postoperative hospital stay; (2) changes in surgical strategy depending upon FFR results (in FFR-guided group only); and (3) rate of major adverse cardiac and cerebrovascular events, i.e., composite of death, myocardial infarction, stroke, and any revascularization during the follow-up period. This study is the first prospective randomized trial investigating potential clinical benefits, associated with FFR-guided surgical revascularization. TRIAL REGISTRATION: NCT01810224. PMID- 30027498 TI - Oprm1 A112G, a single nucleotide polymorphism, alters expression of stress responsive genes in multiple brain regions in male and female mice. AB - BACKGROUND: OPRM1 A118G, a functional human mu-opioid receptor (MOR) polymorphism, is associated with drug dependence and altered stress responsivity in humans as well as altered MOR signaling. MOR signaling can regulate many cellular processes, including gene expression, and many of the long-term, stable effects of drugs and stress may stem from changes in gene expression in diverse brain regions. A mouse model bearing an equivalent polymorphism (Oprm1 A112G) was previously generated and studied. Mice homozygous for the G112 allele show differences in opioid- and stress-related phenotypes. APPROACH: The current study examines the expression of 24 genes related to drug and stress responsivity in the caudoputamen, nucleus accumbens, hypothalamus, hippocampus, and amygdala of drug-naive, stress-minimized, male and female mice homozygous for either the G112 variant allele or the wild-type A112 allele. RESULTS: We detected nominal genotype-dependent changes in gene expression of multiple genes. We also detected nominal sex-dependent as well as sex-by-genotype interaction effects on gene expression. Of these, four genotype-dependent differences survived correction for multiple testing: Avp and Gal in the hypothalamus and Oprl1 and Cnr1 in the hippocampus. CONCLUSIONS: Changes in the regulation of these genes by mu-opioid receptors encoded by the G112 allele may be involved in some of the behavioral and molecular consequences of this polymorphism observed in mice. PMID- 30027500 TI - [Heart or lung? : Diagnostics and management of unclear exertional dyspnea]. AB - Exertional dyspnea is a nonspecific symptom with a variety of underlying causes. It can be challenging to differentiate a beginning cardiac disease from a pulmonary disease or from deconditioning alone. In the presence of obesity, the overall assessment is even more difficult. Rare diseases, such as pulmonary hypertension with dyspnea on exertion as the cardinal symptom are usually diagnosed late in the course of disease. The starting point of a successful evaluation is a thorough patient history. The combination of symptoms, clinical signs and findings leads to a preferred differential diagnosis. Readily available basic findings, such as physical examination, electrocardiogram (ECG), spirometry and laboratory tests help with the diagnosis. For unexplained causes, extended diagnostics such as echocardiography, blood gas analysis and finally special examinations are available. Cardiopulmonary exercise testing (CPET) and exercise echocardiography as well as right heart catheterization at rest and during exercise in the hands of experienced physicians allow an exact differentiation. PMID- 30027503 TI - In appreciation of our 2017 reviewers. PMID- 30027501 TI - Blue light reduces photosynthetic efficiency of cyanobacteria through an imbalance between photosystems I and II. AB - Several studies have described that cyanobacteria use blue light less efficiently for photosynthesis than most eukaryotic phototrophs, but comprehensive studies of this phenomenon are lacking. Here, we study the effect of blue (450 nm), orange (625 nm), and red (660 nm) light on growth of the model cyanobacterium Synechocystis sp. PCC 6803, the green alga Chlorella sorokiniana and other cyanobacteria containing phycocyanin or phycoerythrin. Our results demonstrate that specific growth rates of the cyanobacteria were similar in orange and red light, but much lower in blue light. Conversely, specific growth rates of the green alga C. sorokiniana were similar in blue and red light, but lower in orange light. Oxygen production rates of Synechocystis sp. PCC 6803 were five-fold lower in blue than in orange and red light at low light intensities but approached the same saturation level in all three colors at high light intensities. Measurements of 77 K fluorescence emission demonstrated a lower ratio of photosystem I to photosystem II (PSI:PSII ratio) and relatively more phycobilisomes associated with PSII (state 1) in blue light than in orange and red light. These results support the hypothesis that blue light, which is not absorbed by phycobilisomes, creates an imbalance between the two photosystems of cyanobacteria with an energy excess at PSI and a deficiency at the PSII-side of the photosynthetic electron transfer chain. Our results help to explain why phycobilisome-containing cyanobacteria use blue light less efficiently than species with chlorophyll-based light-harvesting antennae such as Prochlorococcus, green algae and terrestrial plants. PMID- 30027502 TI - Nano-Diamino-Tetrac (NDAT) Enhances Resveratrol-Induced Antiproliferation by Action on the RRM2 Pathway in Colorectal Cancers. AB - Cancer resistance to chemotherapeutic agents is a major issue in the management of cancer patients. Overexpression of the ribonucleotide reductase regulatory subunit M2 (RRM2) has been associated with aggressive cancer behavior and chemoresistance. Nano-diamino-tetrac (NDAT) is a nanoparticulate derivative of tetraiodothyroacetic acid (tetrac), which exerts anticancer properties via several mechanisms and downregulates RRM2 gene expression in cancer cells. Resveratrol is a stilbenoid phytoalexin which binds to a specific site on the cell surface integrin alphavbeta3 to trigger cancer cell death via nuclear translocation of COX-2. Here we report that resveratrol paradoxically activates RRM2 gene expression and protein translation in colon cancer cells. This unanticipated effect inhibits resveratrol-induced COX-2 nuclear accumulation. RRM2 downregulation, whether achieved by RNA interference or treatment with NDAT, enhanced resveratrol-induced COX-2 gene expression and nuclear uptake which is essential to integrin alphavbeta3-mediated-resveratrol-induced antiproliferation in cancer cells. Elsewhere, NDAT downregulated resveratrol-induced RRM2 expression in vivo but potentiated the anticancer effect of the stilbene. These findings suggest that RRM2 appears as a cancer cell defense mechanism which can hinder the anticancer effect of the stilbene via the integrin alphavbeta3 axis. Furthermore, the antagonistic effect of RRM2 against resveratrol is counteracted by the administration of NDAT. PMID- 30027504 TI - Long-term prognostic value of low-dose normal stress-only myocardial perfusion imaging by wide beam reconstruction: A competing risk analysis. AB - BACKGROUND: A normal stress myocardial perfusion single-photon emission computed tomography (MPS) is associated with a good clinical outcome. New iterative algorithms, such as wide beam reconstruction (WBR), which improve image interpretation with half-dose or half-time acquisition, have been proposed for cardiac MPS. The aim of this study was to assess the long-term predictive value of a low-dose normal stress-only MPS with WBR using conventional Anger camera in patients with known or suspected coronary artery disease (CAD). METHODS AND RESULTS: A total of 2106 patients with known or suspected CAD and normal perfusion at half-dose stress-only MPS protocol were followed for a mean of 6.6 +/- 2.7 years. MPS data were reconstructed with WBR iterative algorithm. End point events were cardiac death or nonfatal myocardial infarction. Noncardiac death was considered the competing event. During follow-up, 149 cardiac events occurred with an annualized event rate of 1.2%. Independent predictors of cardiac events at Cox analysis were age, male gender, diabetes mellitus, previous myocardial infarction and the need for pharmacologic stress testing. At Fine-Gray analysis the cumulative incidence of cardiac events progressively increases with age and in the presence of diabetes for any combination of gender and stress type. Survival tree analysis confirmed that long-term prognosis considerably varies according of risk factors profile. CONCLUSIONS: Low-dose normal stress only WBR MPS has a reliable long-term prognostic value in patients with suspected or known CAD. This finding supports the introduction of such a method into clinical practice with a consistent dose optimization in the interest of patients and exposed staff. PMID- 30027505 TI - Participation of Turkish Migrants in an Epidemiological Study: Does the Recruitment Strategy Affect the Sample Characteristics? AB - Migrants are often poorly represented in epidemiological studies which limits the generalizability of the results of population-based studies. This study aimed to assess whether a community-based sampling (CBS) of persons of Turkish origin leads to differences in the participants' characteristics compared to a register based sampling (RBS). The two sampling strategies were used to recruit participants in three cities in Germany (CBS: n = 641; RBS: n = 578). We compared sociodemographic, migration- and health-related characteristics. Census data were used as an external reference. Lower German language skills and a lower acculturation status were more prevalent in the CBS than in the RBS. While age and sex adjusted obesity prevalence differed [CBS: 37.8 (33.6-42.4); RBS 30.0 (26.3-34.0); census data 19.1 (18.2-20.1)], most other health indicators were similar across the samples. In conclusion, the CBS approach led to a greater representation of persons of Turkish origin with lower language skills and lower acculturation status. Nevertheless, both recruitment strategies provided similar estimates of health status indicators. PMID- 30027507 TI - Mitochondrial Redox Sensor for Drosophila Female Germline Stem Cells. AB - Mitochondrial reactive oxygen species (mROS), a major source of ROS within cells, functions as an important signaling molecule and has the ability to damage cellular macromolecules including DNA and proteins. Monitoring mROS levels is therefore essential to understand cell-cell communication and programmed cell death in all types of cell including stem cells. Here, we describe generation and characterization of a redox sensor for mROS that is specifically expressed in the germline stem cells (GSCs) in Drosophila. This redox sensor can be used to monitor the production of mROS and mitophagy in the GSCs during oogenesis. PMID- 30027506 TI - Factors Associated with the Presence of Strong Social Supports in Bhutanese Refugee Women During Pregnancy. AB - Social support may mitigate stress related to the refugee experience, including during resettlement. For refugee women, social support can play an important role during pregnancy. In-depth interviews were conducted within a sample of 45 Bhutanese refugee women. Perceived social support was measured using the Norbeck Social Support Questionnaire. Averaged social support scores are reported to account for personal network size. Participants were identified as "low support" and "high support" based on their reported score. The mean social support score reported was 18.9. Participants experiencing a secondary resettlement within the U.S. were 4.52 (95% CI 1.19-17.15) times as likely to report a "high support" network compared to participants who resettled directly from Nepal. Personal social networks are an important source of support for resettled refugee women during pregnancy in the U.S.. Refugee women who experience secondary resettlement may perceive stronger support from their personal connections. PMID- 30027508 TI - Isolation and Characterization of Cutaneous Epithelial Stem Cells. AB - The outer layer of mammalian skin is a multilayered epithelium that perpetually renews multiple differentiated lineages. During homeostasis, the maintenance of skin epithelial turnover is ensured by regionalized populations of stem cells that largely remain dedicated to distinct epithelial lineages including squamous, follicular, sebaceous, Merkel, and sweat glands. Cutting edge developments in this field have focused on: (1) stem cell activation cues derived from a number of extrinsic sources including neurons, dermal fibroblasts and adipocyte, and immune cells; and (2) characterization of epithelial stem cell homeostasis via hierarchical versus stochastic paradigms. The techniques outlined in this chapter are designed to facilitate such studies and describe basic procedures for cutaneous stem cell isolation and purification, which are based on leveraging their unique expression of surface proteins for simultaneous targeting and purifying of multiple subpopulations in adult skin. In addition, protocols for assessment of in vitro and ex vivo progenitor capacity as well as techniques to visualize progenitor populations in whole skin are discussed. PMID- 30027509 TI - Acute Flaccid Paralysis: Intravenous Immunoglobulin is Not the Drug of Choice Always! PMID- 30027510 TI - Short-term and long-term results of a randomized study comparing high tie and low tie inferior mesenteric artery ligation in laparoscopic rectal anterior resection: subanalysis of the HTLT (High tie vs. low tie) study. AB - BACKGROUND: In rectal anterior resection, a clear consensus regarding the optimal level of inferior mesenteric artery (IMA) ligation does not exist because of a lack of randomized trials. We conducted a randomized trial to determine if the IMA should be tied at the origin (high tie, HT) or distal to the left colic artery (low tie, LT) (HTLT study). This study is a subanalysis of HTLT study for laparoscopic surgery. METHODS: All candidates were randomly divided into the HT or LT groups. The lymph node dissection around the origin of the IMA was performed in the LT group. The stratified factor was the approach (open or laparoscopy). Evaluation parameters were operative factors, short-term and long term results. In the present study, laparoscopic surgeries were examined as subgroup analysis. RESULTS: From June 2006 to September 2012, 331 patients were registered. Two hundred and fifteen patients (107 for HT: 108 for LT) underwent laparoscopic surgeries. There was no difference between the groups in background. The incidence of anastomotic leakage (HT: LT %) showed no significant differences for grade 2 or higher (11.2:9.3), and grade 3 or higher (2.8:4.6). There were no differences in operative time (200:205 min), blood loss (15:15 ml), number of dissected lymph nodes (22:20), and postoperative hospital stay (10:10 days). The incidence of bowel obstruction in HT was significant (3.7 vs. 0%, p = 0.043). There were no significant differences in overall survival (5-year: 91.3 vs. 90.2%, p = 0.850) and disease-free survival (5-year: 83.2 vs. 78.0%, p = 0.525). There were no differences in the first recurrent site and death reason between both groups. The risk factors for leakage were being male and an anastomotic level in a multivariate analysis by logistic regression. CONCLUSION: The IMA ligation level was unrelated to anastomotic leakage. No significant difference was detected in long-term results between HT and LT. PMID- 30027511 TI - Laparoscopic surgery for perforated peptic ulcer: an English national population based cohort study. AB - BACKGROUND: Randomized controlled trials have shown that laparoscopic approach to surgery for perforated peptic ulcer (PPU) is associated with improved short-term outcomes; however, there is limited evidence concerning national practice. The aim of this investigation was to evaluate the effect of laparoscopic approach to PPU surgery upon mortality and morbidity in England. METHODS: Patients with a primary diagnosis of PPU, admitted as an emergency to a hospital in England, and receiving surgical intervention, between 2005 and 2012 were identified from the Hospital Episode Statistics database. Outcomes analyzed included 30-day and 90 day mortality, 30-day complications, and length of hospital stay. Univariate and multivariate analyses were used to identify patient, hospital, and treatment related factors associated with use of laparoscopy and mortality. RESULTS: The study included 13,022 patients who underwent emergency surgery for PPU in England over an 8-year period. From 2005 to 2012, the utilization of laparoscopic surgery for PPU increased from 0 to 13% and was more commonly used in high volume emergency centers. Laparoscopic surgery was associated with significant reductions in 30-day (7% vs. 15.7%; P < 0.001) and 90-day mortality (8.9% vs. 19.6%; P < 0.001), pneumonia (6% vs. 10.1%; P < 0.001), ischemic cardiac events (1% vs. 2.4%; P = 0.007), as well as length of hospital stay (median 5 vs. 7 days; P < 0.001). Factors associated with a reduced utilization of laparoscopic surgery included age >= 70 years (Odds ratio (OR) = 0.58 (95% CI) 0.49-0.68) and Charlson Comorbidity Index score >= 2 (OR = 0.73; 95% CI 0.57-0.94). CONCLUSION: The rate of laparoscopic repair of PPU is increasing at a national level and more common in high volume emergency centers. It is associated with reduced rates of mortality; pneumonia and shorter length of hospital stay, highlighting the need for strategies to improve dissemination of laparoscopic techniques necessary for PPU repair. PMID- 30027512 TI - Authors' Reply to Standing et al.: "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials". PMID- 30027513 TI - Comment on "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials". PMID- 30027515 TI - Role of Diagnostic Preoperative Upper Gastrointestinal Endoscopy in Radiologically Confirmed Gastric Volvulus. AB - BACKGROUND AND AIMS: Gastric volvulus (GV) is a life-threatening condition that warrants prompt diagnosis and treatment. GV is a radiologic diagnosis. The role of preoperative upper gastrointestinal endoscopy (UGIE) for individuals with radiologically confirmed GV is poorly defined. Our objective was to assess the diagnostic yield of UGIE in the preoperative evaluation of patients presenting with radiologically confirmed GV. METHODS: Retrospective review of all adult patients undergoing surgery for GV between July 1996 and August 2016 has been carried out. We performed analyses evaluating diagnostic yield of preoperative UGIE and compared outcomes in patients who did and did not undergo preoperative UGIE. Outcomes were diagnostic yield of preoperative UGIE, length of hospital stay, postoperative complications, and mortality at 30 days and 1 year. RESULTS: In the preoperative UGIE group, the diagnostic yield was 34.6% (27/78). The most common endoscopic findings were erosive esophagitis (13/27) and clean based gastric or duodenal ulcers (5/27). There were no cases of esophago-gastric malignancy. Three patients had ulcers with stigmata of recent bleeding, and three patients had features suggestive of gastric ischemia. Endoscopic findings did not influence surgical management. There was no statistically significant difference in mortality between patients who did and did not undergo preoperative UGIE, both at 30 days (0 vs. 2.5%) and 1 year (3.8 vs. 7.5%). CONCLUSION: Among patients with radiologically confirmed GV, preoperative UGIE rarely demonstrates clinically significant findings and can potentially delay definitive surgical intervention. PMID- 30027516 TI - Extraperitoneal vs. transperitoneal robot-assisted laparoscopic radical prostatectomy-analysis of perioperative outcomes, a single surgeon's experience. AB - Robot-assisted laparoscopic radical prostatectomy (RRP) has traditionally been done using transperitoneal (TP) approach. This requires patients to be in the steep Trendelenburg position with antecedent risks of high intraoperative ventilatory pressure, post-operative confusion status, corneal and cerebral edema, deep vein thrombosis (DVT), predisposes risk of intestinal injury and slight delay in bowel recovery. Extraperitoneal (EP-RRP) approach circumvents the above given issues. Between July 2013 and October 2016, 57 patients underwent RRP for adenocarcinoma done by a single surgeon (NR). Salvage prostatectomies were excluded. RRP was performed using techniques TP (n = 23) and EP (n = 34). Patients were selected in a non-randomized fashion. Clinico-pathologic parameters and perioperative outcomes were compared in both groups using nonparametric tests. Patient demographics, clinico-pathological features, length of stay and total operative time were similar in both groups. Dock (Trendelenburgh) time was shorter in EP-RRP compared to TP-RRP [median (1st-3rd quartiles) (p value)] [180 (150-220) min vs. 220 (180-230) min (p = 0.039)]. Other significant differences includes EP-RRP vs. TPRRP, ventilatory pressures (cm of H2O) [34 (32-34) vs. 40 (38-40) (p = 0.000)], ETCO2 (mm of Hg) [38 (36-40) vs. 32 (30-34) (p = 0.000)], ambulation (day) [0.00 (0-1) vs. 0.00 (0-2) (p = 0.022)], return of bowel activity (day) [1.0 (1.0-2.0) vs. 2.0 (2.0-2.0) (p = 0.000)] and opening of bowel (day) [2.0 (1.0-2.0) vs. 3.0 (3.0-3.0) (p = 0.000)]. EP-RRP offers similar clinical outcomes to TPRRP but with the advantages of shorter Trendelenburgh time, early recovery of bowel functions with avoidance of bowel injury and intraperitoneal urine leak. Overall, early recovery of patients who had undergone EP-RRP potentiates it to be performed as day care procedure. PMID- 30027514 TI - Sleep Disturbances Can Be Prospectively Observed in Patients with an Inactive Inflammatory Bowel Disease. AB - BACKGROUND: Poor sleep quality is associated with adverse health consequences. Sleep disturbances can impact the immune function and inflammatory processes. Little is known about sleep disturbances in patients with inflammatory bowel disease (IBD), while not in flare, i.e., inactive. AIMS: To prospectively explore the sleep quality of patients with an inactive IBD. METHODS: This pilot study included 36 consecutive patients with IBD and 27 healthy volunteers. All IBD patients had an inactive disease. Participants underwent an overnight ambulatory polysomnography. Data on disease duration, medications, complications, and treatment were collected from the medical records. RESULTS: The mean age of the IBD and the control groups was 39 +/- 15 and 34.6 +/- 9.6 years. A significantly less rapid eye movement (REM) sleep was noted in the IBD group vs. control (23.7 vs. 27.8%, p = 0.047); light sleep percentage and REM latency were also longer in the IBD group. Moreover, oxygen desaturation below 90% was more common in the IBD group. All other sleep parameters including respiratory disturbance index, apnea hypopnea index, number of wakes, sleep latency, and snoring strength were similar in both groups. CONCLUSIONS: Inactive IBD is associated with sleep disturbances. A larger prospective study should be conducted to confirm these findings. PMID- 30027517 TI - Correction to: Postural responses to target jumps and background motion in a fast pointing task. AB - The original publication of this paper contained an error. The background motion speeds were actually 20 and 60 cm/s instead of the 2 and 6 cm/s mentioned in the paper (also in figures). It does not affect any of the results, interpretation or conclusion. PMID- 30027518 TI - Reply to Dereke, J., Hillman, M. "The significance of biomarkers such as FABP4 in gestational diabetes mellitus and the importance of rigorous peer review" Acta Diabetol (2017) 54:885. https://doi.org/10.1007/s00592-017-1026-6. PMID- 30027519 TI - Edaphorhabdus rosea gen. nov., sp. nov., a new member of the family Cytophagaceae isolated from soil in South Korea. AB - A Gram-stain negative, aerobic, oxidase and catalase positive, non-flagellated, pink coloured bacterium with gliding motility, designated as strain UDD1T was isolated from soil. The bacterium lacked flexirubin-type pigments. Phylogenetic analysis based on its 16S rRNA gene sequence revealed that strain UDD1T formed a lineage within the family Cytophagaceae of the phylum Bacteroidetes, and forms a distinct clade with type strains of the closely related genus Pontibacter with similarities of 91.36-93.62%. Strain UDD1T contained MK-7 as the predominant menaquinone and summed feature 4 (iso-C17:1 I and/or anteiso-C17:1 B) and iso C15:0 as the major fatty acids. The major polar lipids were phosphatidylethanolamine and an unidentified glycolipid. The DNA G+C content of strain UDD1T was 49 mol%. On the basis of phenotypic, genotypic and phylogenetic analyses, the strain UDD1T represents a novel species of a new genus in the family Cytophagaceae, for which the name Edaphorhabdus rosea gen. nov., sp. nov., is proposed. The type strain of Edaphorhabdus rosea is UDD1T (= KCTC 62117T = JCM 32366T). The Digital Protologue Database Taxon number for strain UDD1T is GA00058. PMID- 30027520 TI - Step time asymmetry increases metabolic energy expenditure during running. AB - : To improve locomotor performance, coaches and clinicians encourage individuals with unilateral physical impairments to minimize biomechanical asymmetries. Yet, it is unknown if biomechanical asymmetries per se, affect metabolic energy expenditure in individuals with or without unilateral impairments during running. Thus, inter-leg biomechanical asymmetries may or may not influence distance running performance. PURPOSE: We sought to determine whether running with asymmetric step times affects metabolic rate in unimpaired individuals. METHODS: Ten unimpaired individuals were instructed to run on a force-measuring treadmill at 2.8 m/s and contact the ground simultaneously to the beat of an audible metronome. The metronome either played at time intervals equal to the respective participant's preferred step times (0% asymmetry), or at time intervals that elicited asymmetric step times between legs (7, 14, and 21% step time asymmetry); stride time remained constant across all trials. We measured ground reaction forces and metabolic rates during each trial. RESULTS: Every 10% increase in step time and stance average vertical ground reaction force asymmetry increased net metabolic power by 3.5%. Every 10% increase in ground contact time asymmetry increased net metabolic power by 7.8%. More asymmetric peak braking and peak propulsive ground reaction forces, leg stiffness, as well as positive and negative external mechanical work, but not peak vertical ground reaction force, increased net metabolic power during running. Step time asymmetry increases the net metabolic power of unimpaired individuals during running. Therefore, unimpaired individuals likely optimize distance-running performance by using symmetric step times and overall symmetric biomechanics. PMID- 30027522 TI - Correction to: Prevalence of hypertension and diabetes after exposure to extracorporeal shock-wave lithotripsy in patients with renal calculi: a retrospective non-randomized data analysis. AB - The ninth author name was incorrectly published in the original publication. The correct name should read as 'Cedric Poyet'. PMID- 30027523 TI - Correction to: The incidence, prevalence, and survival of systemic sclerosis in the UK Clinical Practice Research Datalink. AB - The above article originally published with an error present in the 2nd sentence in the 4th paragraph of the discussion section and is now presented correctly in this article. The remainder of the article remains unchanged. PMID- 30027521 TI - Spatial and temporal migration of sweat: from skin to clothing. AB - PURPOSE: Moisture accumulation in clothing affects human performance and productivity through its impact on thermal balance and various aspects of discomfort. Building on our laboratory's work on mapping sweat production across the body, this study aimed to obtain detailed spatial and temporal maps showing how this sweat migrates into a single clothing layer (T-shirt) during physical exercise. METHOD: Eight male participants performed running exercise in a warm environment. Garment sweat absorption was mapped over a total running time of 50 min, in 10 separated running trials of different durations (5 min increments). After running, the garment was dissected into 22 different parts and local sweat absorption (ABSlocal) was quantified by weighing each garment part before and after drying. From ABSlocal, garment total sweat absorption (ABStotal) was estimated. RESULTS: After 50 min, Tcore rose from 37 +/- 0.2 to 38.6 +/- 0.3 degrees C, HR increased from 69 +/- 15 to 163 +/- 12 bpm (p < 0.001), GSL was 586 +/- 86 g m-2. Clear patterns of sweat absorption reduction from superior-to inferior and from medial-to-lateral T-shirt zones were observed, with the mid back medial and the low front hem showing the highest, respectively. CONCLUSIONS: Quantitative data on garment total and regional sweat absorption were obtained and considerable variation between different garment zones was identified. These data can support the development of sport and personal protective clothing with the end goal to prevent workers' heat-related injuries as well as maximise human performance and productivity. PMID- 30027524 TI - Experiences of patients seeking to participate in variant of uncertain significance reclassification research. AB - Patients' understanding of a genetic variant of unknown clinical significance (VUS) is likely to influence beliefs about risk implications, consequent medical decisions, and other actions such as involvement in research. We interviewed 26 self-selected participants with a clinically identified VUS before they enrolled into a VUS reclassification study. Semi-structured interviews addressed topics including motivation to get genetic test, experience with the VUS result, affective responses to receiving VUS, and perceived effect of VUS and reclassification on medical care. We found that family and personal history of disease were the most prevalent motivators for getting a genetic test. Participants demonstrated mixed understanding of VUS. Most expressed negative effect on learning of their VUS result and uncertainty about its impact on clinical management. Most expected reclassification efforts to benefit their family members but not themselves. Some expressed distrust of their providers following a VUS result. Participation in the VUS reclassification study appeared to be motivated by four factors for patients with VUS-negative effect about VUS, uncertainty about its impact on clinical management, concern for family members' well-being, and to advance science. Perhaps the direct acknowledgement and appraisal of uncertainty as a means of coping was missing in some pre-test counseling experienced by our participants and thus they were not psychologically prepared for atypical VUS results. The finding of VUS-induced provider distrust suggests a need for careful consideration of appropriate pre- and post-test counseling about VUS. PMID- 30027526 TI - Dental Sleep Medicine redefined. PMID- 30027525 TI - GD2 ganglioside-binding antibody 14G2a and specific aurora A kinase inhibitor MK 5108 induce autophagy in IMR-32 neuroblastoma cells. AB - The process of autophagy and its role in survival of human neuroblastoma cell cultures was studied upon addition of an anti-GD2 ganglioside (GD2) 14G2a mouse monoclonal antibody (14G2a mAb) and an aurora A kinase specific inhibitor, MK 5108. It was recently shown that combination of these agents significantly potentiates cytotoxicity against IMR-32 and CHP-134 neuroblastoma cells in vitro, as compared to the inhibitor used alone. In this study we gained mechanistic insights on autophagy in the observed cytotoxic effects exerted by both agents using cytotoxicity assays, RT-qPCR, immunoblotting, and autophagy detection methods. Enhancement of the autophagy process in the 14G2a mAb- and MK-5108 treated IMR-32 cells was documented by assessing autophagic flux. Application of a lysosomotropic agent-chloroquine (CQ) affected the 14G2a mAb- and MK-5108 stimulated autophagic flux. It is our conclusion that the 14G2a mAb (40 MUg/ml) and MK-5108 inhibitor (0.1 MUM) induce autophagy in IMR-32 cells. Moreover, the combinatorial treatment of IMR-32 cells with the 14G2a mAb and CQ significantly potentiates cytotoxic effect, as compared to CQ used alone. Most importantly, we showed that interfering with autophagy at its early and late step augments the 14G2a mAb-induced apoptosis, therefore we can conclude that inhibition of autophagy is the primary mechanism of the CQ-mediated sensitization to the 14G2a mAb-induced apoptosis. Although, there was no virtual stimulation of autophagy in the 14G2a mAb-treated CHP-134 neuroblastoma cells, we were able to show that PHLDA1 protein positively regulates autophagy and this process exists in a mutually exclusive manner with apoptosis in PHLDA1-silenced CHP-134 cells. PMID- 30027527 TI - Diagnosis and Management of Exocrine Pancreatic Insufficiency. AB - PURPOSE OF REVIEW: Recent studies have documented that many patients with pancreatic exocrine insufficiency (EPI) are not identified and are not treated with appropriate dosages of pancreatic enzyme replacement therapy. This review will summarize the approach to diagnosis, treatment, and monitoring for treatment effect and complications in patients with exocrine insufficiency. RECENT FINDINGS: While chronic pancreatitis is the most commonly identified cause of EPI, pancreatic cancer and pancreatic surgery are increasingly important. The diagnosis of EPI remains challenging, but fecal elastase is the most clinically useful test. Treatment requires an understanding of the appropriate dosage and timing of enzyme replacement, but recent studies show that clinicians often do not have this understanding. Monitoring and prevention of complications of EPI is increasingly important, particularly osteopenia and osteoporosis. In those that fail to respond, coexistent small intestinal bacterial overgrowth should be considered. Many clinicians do not consider EPI in the differential diagnosis, and patients with EPI are routinely undertreated in the USA. Appropriate identification of those at risk and use of appropriate enzyme therapy, along with monitoring for metabolic complications of EPI, are essential to provide effective care for these patients. PMID- 30027528 TI - Diabetic Gastroparesis. AB - This editorial addresses the importance of diabetic gastroparesis as a marker of poor glycemic control, other vascular complications, and suboptimal therapeutic outcomes. Highlighting the need to prevent and manage gastroparesis, it tries to understand why the condition has not received its due share of attention. Complexities in screening, diagnosis, and management all contribute to the lack of focus on this autonomic neuropathy. The editorial reinforces the need to enhance awareness about diabetic gastroparesis and utilize good clinical sense and rational prescription writing in order to limit the impact of this complication. PMID- 30027529 TI - Harvest, After 50 Years of Sowing. PMID- 30027531 TI - Correction to: Contraction behaviour reduces embryo competence in high-quality euploid blastocysts. AB - The original version of this article unfortunately contained a mistake in the author group section. PMID- 30027530 TI - Selection of stable expressed reference genes in native and vitrified/thawed human ovarian tissue for analysis by qRT-PCR and Western blot. AB - PURPOSE: To select reference genes with stable messenger RNA (mRNA) expression for quantitative real-time reverse transcription-polymerase chain reaction (qRT PCR) analysis of vitrified/thawed human ovarian tissue and to evaluate in human ovarian tissue the levels of key proteins which are commonly used as reference proteins. METHODS: Pieces of ovarian tissue were obtained during laparoscopy from patients (n = 10, 24-36 years old) who suffered from types of cancer that does not affect reproductive system. Tissue strips from the intact group were immediately placed into liquid nitrogen. Tissue strips from the second group were successively placed into solutions with cryoprotective agents. Then, these strips were rapidly placed into liquid nitrogen. After thawing, ovarian tissue strips were cultured during 2 h in complete growth medium. Gene expression levels were measured using quantitative RT-PCR. Also, protein levels of three key reference genes were measured using Western blot. Statistical analysis of obtained data was performed by BestKeeper, NormFinder, and geNorm software utilities; correlation coefficients were also calculated. RESULTS: The most suitable reference genes for qRT-PCR analysis of human cortical ovarian tissue after cryopreservation by vitrification are genes of ribosomal proteins RPL4, RPLP0, RPS18, and heat shock protein HSP90AB1. The protein levels of three commonly used reference genes (ACTB, GAPDH, and HSP90) were measured in two groups of samples of human ovarian tissue: intact and vitrified/thawed. The levels of ACTB, GAPDH, and HSP90 proteins were similar in native and vitrified/thawed samples. CONCLUSION: Selection of suitable reference genes is the first aim of any research dedicated to the investigation of gene expression, because the interpretation of obtained results largely depends on selection of appropriate reference genes. Nowadays, there are many mathematical approaches allowing to select not only single reference gene but also a group of the most stably expressed reference genes. The use of mathematical models which take into account multiple reference genes will allow to obtain more accurate data on the expression of target genes. PMID- 30027533 TI - The Economic Burden of Abuse of Prescription Opioids: A Systematic Literature Review from 2012 to 2017. AB - BACKGROUND: Abuse of prescription opioids [opioid use disorder (OUD), poisoning, and fatal and non-fatal overdose] is a public health and economic challenge that is associated with considerable morbidity and mortality in the USA and globally. OBJECTIVE: To systematically review and summarize the health economics literature published over the last 5 years that describes the economic burden of abuse of prescription opioids. METHODS: Findings from searches of databases including MEDLINE, Embase, and Cochrane CENTRAL as well as hand searches of multiple conference abstracts were screened against predefined inclusion criteria to identify studies reporting cost and healthcare resource utilization (HRU) data associated with abuse of prescription opioids. RESULTS: A total of 49 unique studies were identified. Most of the studies examined direct costs and HRU, which were substantially higher for abusers of prescription opioids than non-abuser controls in several matched cohort analyses (US$20,343-US$28,718 vs US$9716 US$14,079 for mean direct combined annual healthcare costs reported in 6 studies). Although only a small number of studies reported indirect costs, these findings suggest a high societal burden related to productivity losses, absenteeism, morbidity, and mortality among those who abuse opioids. Studies of medication-assisted treatment demonstrated that factors such as adherence, dose, formulation (film or tablet), and relapse during treatment, were associated with direct costs and HRU among treated patients. CONCLUSIONS: This systematic literature review shows that abuse of prescription opioids is characterized by substantial direct healthcare costs, medical utilization, and related societal costs. Future research should further investigate the indirect costs of opioid abuse. PMID- 30027537 TI - Adaptation of Radiology Software to Improve Cardiology Results Reporting. AB - OBJECTIVE: Twenty-four hour ambulatory electrocardiograms ("Holter" monitors) are a key diagnostic test in cardiology. Commercial electronic medical record (EMR) tools have not been designed for pediatric Holter monitor reporting and paper based methods are inefficient. METHODS: Our tertiary pediatric hospital adapted a radiology EMR tool to a cardiology workflow in order to report Holter monitor results. A retrospective review was performed at 4 time points: prior to intervention, immediately post-intervention, at 6 months and at 12 months post intervention. The primary outcome variable was time to reporting of Holter findings. RESULTS: Holter reports were reviewed on 527 studies (patient ages: 1 day to 42 years). The time between the date the patient returned the Holter monitor until the date the referring physician received a final report improved from 19.8 days to 1.5 days (p<0.001). This result was durable over the next 12 months of follow-up. Physician interpretation time improved from 2.1 days to 0.6 days (p=0.01). Transcriptionist time and result scanning time were eliminated (removing 1.9 days and 14 days from the workflow, respectively). CONCLUSION: EMR systems are not typically designed for pediatric cardiology, but existing systems can be adapted, yielding important gains for patient care. In specialties like pediatric cardiology, there is insufficient volume nationally to drive development of commercial systems. This study demonstrates the general principle that creative adaptation of EMR systems can improve result reporting in pediatric cardiology and likely in other cardiology practices.Citation: Webster G, Ward K, Deal BJ, Anderson JB, Tsao S. Adaptation of Radiology Software to Improve Cardiology Results Reporting. Appl Clin Inform 2017; 8: 936-944 https://doi.org/10.4338/ACI-2017-03-RA-0051. PMID- 30027539 TI - The International Classification of Functioning, Disability and Health (ICF) in Electronic Health Records. AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) is the World Health Organization's standard for describing health and health-related states. Examples of how the ICF has been used in Electronic Health Records (EHRs) have not been systematically summarized and described yet. OBJECTIVES: To provide a systematic review of peer-reviewed literature about the ICF's use in EHRs, including related challenges and benefits. METHODS: Peer reviewed literature, published between January 2001 and July 2015 was retrieved from Medline(r), CINAHL(r), Scopus(r), and ProQuest(r) Social Sciences using search terms related to ICF and EHR concepts. Publications were categorized according to three groups: Requirement specification, development and implementation. Information extraction was conducted according to a qualitative content analysis method, deductively informed by the evaluation framework for Health Information Systems: Human, Organization and Technology-fit (HOT-fit). RESULTS: Of 325 retrieved articles, 17 publications were included; 4 were categorized as requirement specification, 7 as development, and 6 as implementation publications. Information regarding the HOT-fit evaluation framework was summarized. Main benefits of using the ICF in EHRs were its unique comprehensive perspective on health and its interdisciplinary focus. Main challenges included the fact that the ICF is not structured as a formal terminology as well as the need for a reduced number of ICF codes for more feasible and practical use. CONCLUSION: Different approaches and technical solutions exist for integrating the ICF in EHRs, such as combining the ICF with other existing standards for EHR or selecting ICF codes with natural language processing. Though the use of the ICF in EHRs is beneficial as this review revealed, the ICF could profit from further improvements such as formalizing the knowledge representation in the ICF to support and enhance interoperability.Citation: Maritz R, Aronsky D, Prodinger B. The International Classification of Functioning, Disability and Health (ICF) in Electronic Health Records. Appl Clin Inform 2017; 8: 964-980 https://doi.org/10.4338/ACI 2017050078. PMID- 30027542 TI - Response to Lapkoff and Sittig. PMID- 30027532 TI - Linking the gut and liver: crosstalk between regulatory T cells and mucosa associated invariant T cells. AB - The gut-liver axis is increasingly considered to play a vital part in the progression of chronic inflammatory gut and liver diseases. Hence, a detailed understanding of the local and systemic regulatory mechanisms is crucial to develop novel therapeutic approaches. In this review, we discuss in-depth the roles of regulatory T cells (Tregs) and mucosal-associated invariant T cells (MAITs) within the context of inflammatory bowel disease, primary sclerosing cholangitis, and non-alcoholic steatohepatitis. Tregs are crucial in maintaining peripheral tolerance and preventing autoimmunity. MAIT cells have a unique ability to rapidly recognize microbial metabolites and mount a local immune response and act as a 'biliary firewall' at the gut and biliary epithelial barrier. We also outline how current knowledge can be exploited to develop novel therapies to control the propagation of chronic gut- and liver-related inflammatory and autoimmune conditions. We specifically focus on the nature of the Tregs' cell therapy product and outline an adjunctive role for low-dose IL-2. All in all, it is clear that translational immunology is at crucial crossroads. The success of ongoing clinical trials in cellular therapies for inflammatory gut and liver conditions could revolutionize the treatment of these conditions and the lives of our patients in the coming years. PMID- 30027541 TI - Designing An Individualized EHR Learning Plan For Providers. AB - : Electronic Health Records (EHRs) have been quickly implemented for meaningful use incentives; however these implementations have been associated with provider dissatisfaction and burnout. There are no previously reported instances of a comprehensive EHR educational program designed to engage providers and assist in improving efficiency and understanding of the EHR. Utilizing adult learning theory as a framework, Stanford Children's Health designed a tailored provider efficiency program with various inputs from: (1) provider specific EHR data; (2) provider survey data; and (3) structured observation sessions. This case report outlines the design of this individualized training program including team structure, resource requirements, and early provider response. CITATION: Stevens LA, DiAngi YT, Schremp JD, Martorana MJ, Miller RE, Lee TC, Pageler NM. Designing An Individualized EHR Learning Plan. Appl Clin Inform 2017; 8:924-935 https://doi.org/10.4338/040054. PMID- 30027543 TI - Lynch syndrome - cancer pathways, heterogeneity and immune escape. AB - Recent work has provided evidence for genetic and molecular heterogeneity in colorectal cancers (CRCs) arising in patients with Lynch syndrome (LS), dividing these into two groups: G1 and G2. In terms of mutation and gene expression profile, G1 CRCs bear resemblance to sporadic CRCs with microsatellite instability (MSI), whereas G2 CRCs are more similar to microsatellite-stable CRCs. Here we review the current state of knowledge on pathways of precursor progression to CRC in LS and how these might tie in with the new findings. Immunotherapies are an active field of research for MSI cancers and their potential use for cancer therapy for both sporadic and LS MSI cancers is discussed. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30027544 TI - A two-drug combination simulation study for metastatic castrate resistant prostate cancer. AB - BACKGROUND: Prostate cancer often evolves resistance to androgen deprivation therapy leading to a lethal metastatic castrate-resistant form. Besides androgen independence, subpopulations of the tumor are genetically heterogeneous. With the advent of tumor genome sequencing we asked which has the greater influence on reducing tumor size: genetic background, heterogeneity, or drug potency? METHODS: A previously developed theoretical evolutionary dynamics model of stochastic branching processes is applied to compute the probability of tumor eradication with two targeted drugs. Publicly available data sets were surveyed to parameterize the model. RESULTS: Our calculations reveal that the greatest influence on successful treatment is the genetic background including the number of mutations overcoming resistance. Another important criteria is the tumor size at which it is still possible to achieve tumor eradication, for example, 2-4 cm large tumors have at best a 10% probability to be eradicated when 50 mutations can confer resistance to each drug. CONCLUSION: Overall, this study finds that genetic background and tumor heterogeneity are more important than drug potency in treating mCRPC. It also points toward identifying metastatic sites early using biochemical assays and/or dPET. PMID- 30027545 TI - AT-rich interactive domain 5B regulates androgen receptor transcription in human prostate cancer cells. AB - BACKGROUND: The androgen receptor (AR) is one of the most important and dynamically regulated factors in prostate cancer (PCa) progression. Despite the importance of AR expression regulation, the precise mechanisms are not fully understood. ARID5B, an AT-rich interaction domain DNA-binding motif-containing transcription factor, is expressed higher in primary PCa than normal prostate, and correlated with AR expression. We therefore hypothesized that ARID5B could regulate AR expression. METHODS: Correlation between AR and ARID5B expression was analyzed using publicly and commercially available microarray data. To examine the role of ARID5B in AR expression, ARID5B was knocked down in VCaP and LNCaP cells, then mRNA and protein levels of AR were measured and an in vitro cell proliferation assay was performed. Chromatin immunoprecipitation was performed to further examine molecular mechanisms. RESULTS: Knockdown of ARID5B suppressed the AR mRNA and protein expression in VCaP and LNCaP cells and decreased in vitro cell proliferation. Suppression of ARID5B decreased the occupancy of active RNA polymerase II in the AR promoter, indicating that ARID5B regulates AR transcription. The active histone mark, H3K4me3, occupancy was decreased with ARID5B knockdown. CONCLUSION: Our study revealed that AR transcription is positively regulated by ARID5B through H3K4me3 recruitment in the AR promoter. Our findings reveal novel mechanisms of AR transcription, which is dynamically regulated in prostate tumor progression. PMID- 30027546 TI - Protein-Metal-Ion Networks: A Unique Approach toward Metal Sulfide Nanoparticles Embedded In Situ in Nanocomposites. AB - Nanoscale metal sulfides are of tremendous potential in biomedicine. Generally, the properties and performances of metal sulfide nanoparticles (NPs) are highly related to their structures, sizes and morphologies. Recently, a strategy of using sulfur-containing protein-metal-ion networks for preparing metal sulfide embedded nanocomposites was proposed. Within the networks, proteins can play multiple roles to drive the transformation of these networks into protein encapsulated metal sulfide NPs with ultrasmall size and defined structure (as both a template and a sulfur provider) or metal sulfide NP-protein hydrogels with injecting and self-healing properties (as a template, a sulfur provider, and a gelator) in a controlled manner. In this Concept, the synthesis strategy, the formation mechanism, and the biomedical applications of the gained nanocomposites are presented. Moreover, the challenges and opportunities of using protein-metal ion networks to construct functional materials for biomedical applications are analyzed. PMID- 30027547 TI - Methods for calculation of per capita alcohol consumption in a Muslim majority country with a very low drinking level: Findings from the 2011 Iranian mental health survey. AB - INTRODUCTION AND AIMS: There is a paucity of data on volume of alcohol use from Muslim majority countries. We aimed to present estimation methods for alcohol consumption with the use of survey data for these societies and provide an estimation for age 15+ per capita consumption of pure alcohol for Iran. DESIGN AND METHODS: The Iranian Mental Health Survey was a nationally representative household survey on individuals aged 15-64 years, with a multistage, cluster sampling design. We used the 'Last Week' method and 'Quantity-Frequency' methods for gathering data on alcohol consumption and combined these to provide more complete estimates. RESULTS: The response rate was 85.7%. From the total of 7840 respondents, 5.7% and 1% reported past 12 months and past week alcohol use, respectively. The highest estimation for age 15+ per capita consumption of pure alcohol was yielded by the 'combination method' (0.108 L ethanol/person/year) followed by the Quantity-Frequency method (0.079 L). The 'Last Week' method provided the lowest estimate (0.059 L). DISCUSSION AND CONCLUSIONS: Unlike in surveys of non-Muslim countries, frequency of drinking from recent recall (last week) was much lower than from recall of usual drinking in the last year. We conclude that 0.108 L (SE = 0.03) is the best survey-based estimate of age 15+ per capita consumption, which translates to about 5 750 000 L of national consumption per year in Iran. However, this method is still likely to under estimate per capita consumption due to evidence of under-reporting in the survey. PMID- 30027548 TI - Evaluating the Long-, Short-, and Oblique-Axis Approaches for Ultrasound-Guided Vascular Access Cannulation. AB - BACKGROUND: Our goal was to conduct a network meta-analysis of randomized controlled trials to compare the effects of the long-axis (LAX), short-axis (SAX), and oblique-axis (OAX) ultrasound guidance approaches for vascular access cannulation. METHODS: We searched 5 databases, including the Cochrane Central Register of Controlled Trials in the Cochrane Library, Embase, MEDLINE, CINAHL, and Web of Science. Seven randomized clinical trials assessing ultrasound guidance for vascular access cannulation via the LAX, SAX, or OAX approach were included. The primary end point was the first-pass success rate. Secondary end points included the mean time to success and average number of attempts until success. We used random-effects models to calculate weighted mean differences with 95% confidence intervals for continuous outcomes and relative risks with 95% confidence intervals for dichotomous outcomes. RESULTS: There were no significant differences between the LAX, SAX, and OAX techniques with respect to the first pass success rate, mean time to success, average number of attempts until success, or the incidence of hematoma. CONCLUSION: There was insufficient evidence to definitively recommend the LAX, SAX, or OAX approach for patients undergoing ultrasound-guided vascular access cannulation. PMID- 30027549 TI - Tracking pressure injuries as adverse events: National use of the Global Trigger Tool over a 4-year period. AB - AIM: To examine the frequency, preventability, and consequences of hospital acquired pressure injuries in acute care hospitals over a 4-year period. METHOD: A retrospective record review was performed using the Swedish version of the Global Trigger Tool (GTT). A total of 64 917 hospital admissions were reviewed. Data were collected between 2013 and 2016 from all 63 Swedish acute care hospitals. RESULTS: The prevalence of pressure injuries (category 2-4) was 1%. Older patients, "satellite patients", and patients with acute admissions had more pressure injuries. Most pressure injuries (91%) were determined to be preventable. The mean extended length of hospital stay was 15.8 days for patients who developed pressure injuries during hospitalization. CONCLUSION: The GTT provides a useful and complementary national perspective on hospital acquired pressure injuries across hospitals, informing health care providers on safety priorities to reduce patient harm. Clinical leaders can use information on the preventability and the consequences of pressure injuries, as well as evidence based arguments for improving the health care organization. PMID- 30027550 TI - Influence of Ultrasound System and Gain on Grayscale Median Values. AB - OBJECTIVES: The purpose of this study was to determine the reliability of grayscale median (GSM) measurements across different ultrasound (US) systems and effects of gain on GSM values. METHODS: Two vessels in a grayscale vascular phantom were imaged with 7 US systems at 3 gain settings. Two human participants were imaged at 3 gain settings. Each image was normalized, standardized, and segmented by expert and novice readers using grayscale analysis software. The concordance correlation coefficient (CCC) assessed agreement of GSM values for each system across gain settings and vessels and between readers. The intraclass correlation coefficient (ICC) assessed system-level reader concordance across gain settings and vessels. A general linear mixed model for repeated measures was used to assess within- and between-system mean GSM values. RESULTS: Grayscale median measurements performed on images from the same US system yielded excellent (CCC) (95% confidence intervals): 0.85 (0.75, 0.92) to 0.96 (0.92, 0.98). ICC per system were 0.94 to 0.98 for the expert reader and 0.85 to 0.95 for the novice reader. Gain adjustments above and below an optimal setting contributed to significantly different intrasystem GSM values on 4 of 7 systems in the near zone and 5 of 7 systems in the far zone (P < .05). Intersystem GSM values differed on 5 of 7 systems (P < .05). Images from the human participants showed differences in GSM values at optimum gain values +/- 10 dB/%. CONCLUSIONS: Grayscale median measurements are highly reproducible when obtained from the same US system with similar gain settings. Grayscale median values differ significantly across gain values and between systems. Researchers should consider the impact of US system and gain settings on GSM values when working to minimize system- and operator dependent factors. PMID- 30027552 TI - Which client characteristics predict home-care needs? Results of a survey study among Dutch home-care nurses. AB - Fee-for-service, funding care on an hourly rate basis, creates an incentive for home-care providers to deliver high amounts of care. Under casemix funding, in contrast, clients are allocated-based on their characteristics-to homogenous, hierarchical groups, which are subsequently funded to promote more effective and efficient care. The first step in developing a casemix model is to understand which client characteristics are potential predictors of home-care needs. Nurses working in home care (i.e. home-care nurses) have a good insight into clients' home-care needs. This study was conducted in co-operation with the Dutch Nurses' Association and the Dutch Healthcare Authority. Based on international literature, 35 client characteristics were identified as potential predictors of home-care needs. In an online survey (May, 2017), Dutch home-care nurses were asked to score these characteristics on relevance, using a 9-point Likert scale. They were subsequently asked to identify the top five client characteristics. Data were analysed using descriptive statistics. The survey was completed by 1,007 home-care nurses. Consensus on relevance was achieved for 15 client characteristics, with "terminal phase" being scored most relevant, and "sex" being scored as the least relevant. Relevance of the remaining 20 characteristics was uncertain. Additionally, based on the ranking, "ADL functioning" was ranked as most relevant. According to home-care nurses, both biomedical and psychosocial client characteristics need to be taken into account when predicting home-care needs. Collaboration between clinical practice, policy development, and science is necessary to realise a funding model, to work towards the Triple Aim (improved health, better care experience, and lower costs). PMID- 30027551 TI - Synthesis, Characterization, and Cytotoxicity of the Cobalt (III) Complex with N,N-Diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline. AB - A cobalt(III) complex, [Co(L)2 ](ClO4 )3 (1), in which the ligand L was N,N diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline (L), was synthesized and fully characterized. This new cobalt(III) complex 1 exhibited selective cytotoxicity against HeLa, T-24, A549, MGC80-3, HepG2, and SK-OV-3 cells with IC50 values in the micromolar range (0.52 - 4.33 MUm), and it exhibited low cytotoxicity against normal HL-7702 cells. The complex 1 was the most potent against the T-24 cells. It was found that 1 could cause the cell cycle arrest in G1 phase, and it exerted its antitumor activity mainly via disruption of mitochondrial function. PMID- 30027553 TI - One step ahead: timing and sexual networks in population mobility and HIV prevention and care. PMID- 30027554 TI - Plasmid-mediated quinolone resistance in human non-typhoidal Salmonella infections: An emerging public health problem in the United States. AB - Invasive Salmonella infections in adults are commonly treated with fluoroquinolones, a critically important antimicrobial class. Historically, quinolone resistance was the result of chromosomal mutations, but plasmid mediated quinolone resistance (PMQR) has emerged and is increasingly being reported in Enterobacteriaceae worldwide. PMQR may facilitate the spread of quinolone resistance, lead to higher-level quinolone resistance, and make infections harder to treat. To better understand the epidemiology of PMQR in non typhoidal Salmonella causing human infections in the United States, we looked at trends in quinolone resistance among isolates submitted to the Centers for Disease Control and Prevention. We reviewed demographic, exposure and outcome information for patients with isolates having a PMQR-associated phenotype during 2008-2014 and tested isolates for quinolone resistance mechanisms. We found that PMQR is emerging among non-typhoidal Salmonella causing human infections in the United States and that international travel, reptile and amphibian exposure, and food are likely sources of human infection. PMID- 30027555 TI - Community pharmacists at transition to independent practice: Isolated, unsupported, and stressed. AB - While there is evidence from nursing and medicine that transition to independent practitioner is challenging and has implications for patient care, there is little research exploring novice community pharmacists' (NCPs) transition. This study aimed to identify the challenges faced by NCPs at transition to independent practitioner and perceptions of the relative importance of these challenges. Nominal group discussions were held between November 2015 and April 2016, in North West England, with purposively sampled NCPs, early career pharmacists, work based preregistration tutors, and pharmacy support staff. In response to the question "What are the challenges faced by NCPs at transition?" participants individually wrote down and subsequently called out, in round-robin fashion, then discussed, and broadly categorised challenges before ranking them in order of importance. Discussions were audio-recorded with consent, transcribed, and analysed thematically. Twenty-five participants from independent, supermarket, and small and large multiple pharmacies took part in five nominal group discussions. Challenges experienced through interacting with the workplace environment were identified as: (in order of importance) relationship management; confidence; decision-making; being in charge and accountable; and adapting to the workplace. With the exception of disagreement between pharmacists and pharmacy support staff regarding whether adapting to the team was challenging for NCPs, all participants reported challenges experienced through interacting with the workplace environment. Challenges were described as inducing psychosocial stress, particularly because NCPs acquired immediate professional accountability, worked in isolation from experienced peers, and faced job-related pressures. Interpretation of the findings suggests that the Karasek job-demand-control support (JDCS) model of occupational stress provides valuable insight about transition for NCPs. NCPs' jobs are classified as high strain, where high workplace demands coupled with NCPs' lack of control in being able to meet demands, together with isolation and lack of support, result in transition being characterised as causing isostrain, where the workplace becomes a "noxious" environment. PMID- 30027556 TI - Possible link between photosynthesis and leaf modulus of elasticity among vascular plants: a new player in leaf traits relationships? AB - A compromise between carbon assimilation and structure investment at the leaf level is broadly accepted, yet the relationship between net assimilation per area (An ) and leaf mass per area has been elusive. We propose bulk modulus of elasticity (epsilon) as a suitable parameter to reflect both leaf structure and function, and an inverse relationship between epsilon and An and mesophyll conductance (gm ) is postulated. Using data for An , gm and epsilon from previous studies and new measurements on a set of 20 species covering all major growth forms, a negative relationship between An or gm and epsilon was observed. High epsilon was also related to low leaf capacitance and higher diffusive limitations to photosynthesis. In conclusion, epsilon emerges as a key trait linked with photosynthetic capacity across vascular plants, and its relationship with gm suggests the existence of a common mechanistic basis, probably involving a key role of cell walls. PMID- 30027557 TI - Distal mesonephric duct anomalies in association with penile ectopia and complex hypospadias. PMID- 30027558 TI - Surface molecularly imprinted polymers prepared by two-step precipitation polymerization for the selective extraction of oleanolic acid from grape pomace extract. AB - Surface molecularly imprinted polymers were successfully prepared by a novel two step precipitation polymerization method. The first-step allowed the formation of 4-vinylpyridine divinylbenzene and trimethylolpropane trimethacrylate copolymeric microspheres. In the second-step precipitation polymerization, microspheres were modified with a molecularly imprinting layer of oleanolic acid as template, methacrylic acid as functional monomer, and divinylbenzene/ethylene glycol dimethacrylate as cross-linker. The obtained polymers had an average diameter of 4.43 MUm and a polydispersity index of 1.011; adsorption equilibrium was achieved within 40 min, with adsorption capacity reaching 27.4 mg/g. Subsequently, the polymers were successfully applied as the adsorbents of molecularly imprinted solid-phase extraction to separate and purify the oleanolic acid from grape pomace. The content of oleanolic acid in the grape pomace extract was enhanced from 13.4 to 93.2% after using the molecularly imprinted solid-phase extraction process. This work provides an efficient way for effective oleanolic acid separation and enrichment from complex matrices, which is especially valuable in industrial production. PMID- 30027559 TI - Transplantation of Ears Provides Insights into Inner Ear Afferent Pathfinding Properties. AB - Numerous tissue transplantations have demonstrated that otocysts can develop into normal ears in any location in all vertebrates tested thus far, though the pattern of innervation of these transplanted ears has largely been understudied. Here, expanding on previous findings that transplanted ears demonstrate capability of local brainstem innervation and can also be innervated themselves by efferents, we show that inner ear afferents grow toward the spinal cord mostly along existing afferent and efferent fibers and preferentially enter the dorsal spinal cord. Once in the dorsal funiculus of the spinal cord, they can grow toward the hindbrain and can diverge into vestibular nuclei. Inner ear afferents can also project along lateral line afferents. Likewise, lateral line afferents can navigate along inner ear afferents to reach hair cells in the ear. In addition, transplanted ears near the heart show growth of inner ear afferents along epibranchial placode-derived vagus afferents. Our data indicate that inner ear afferents can navigate in foreign locations, likely devoid of any local ear specific guidance cues, along existing nerves, possibly using the nerve associated Schwann cells as substrate to grow along. However, within the spinal cord and hindbrain, inner ear afferents can navigate to vestibular targets, likely using gradients of diffusible factors that define the dorso-ventral axis to guide them. Finally, afferents of transplanted ears functionally connect to native hindbrain vestibular circuitry, indicated by eliciting a startle behavior response, and providing excitatory input to specific sets of extraocular motoneurons. PMID- 30027560 TI - In Situ Growth of Pd Nanosheets on g-C3 N4 Nanosheets with Well-Contacted Interface and Enhanced Catalytic Performance for 4-Nitrophenol Reduction. AB - Loading novel metal nanosheets onto nanosheet support can improve their catalytic performance, but the morphological incompatibility makes it difficult to construct a well-contacted interface, which is of particular interest in supported catalysts. Herein, Pd nanosheets (Pd NSs) are supported onto graphitic carbon nitride nanosheets (CNNSs) with intimate face-to-face contact through an in situ growth method. This method overcomes the limitations of the morphological incompatibility and ensures the intimate interfacial contact between Pd NSs and CNNSs. The nitrogen-rich nature of CNNSs endows Pd NSs with abundant anchoring sites, which optimizes the electronic structure and improves the chemical and morphological stability of Pd NSs. The supported Pd NSs demonstrate high dispersion and exhibit largely enhanced activity toward the reduction of 4 nitrophenol. The concentration-normalized rate constant is up to 3052 min-1 g-1 L, which is 5.4 times higher than that obtained by unsupported Pd NSs. No obvious deactivation is observed after six runs of the recycling experiments. It is believed that the supported novel metal nanosheets with the intimately contacted interface may show promising applications in catalysis. PMID- 30027561 TI - VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. AB - Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans complex formation is an independent predictor of PDAC patient survival. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 30027563 TI - Response to a comment on "Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing". PMID- 30027564 TI - Does Patient Posture Affect the Ultrasound Evaluation of Pelvic Organ Prolapse? AB - OBJECTIVES: Translabial ultrasound (US) imaging is an emerging method for the evaluation of pelvic organ prolapse (POP). Normative data to date are limited to imaging in the supine position. The purpose of this study was to evaluate the effect of posture changes on US pelvic organ mobility. METHODS: This work was a retrospective study of 175 women seen in a tertiary urogynecologic center for symptoms of lower urinary tract and pelvic floor dysfunction. All underwent a standardized interview, POP quantification prolapse assessment, and 4-dimensional translabial US examination in supine and standing positions. Offline measurement of organ descent on the Valsalva maneuver was undertaken at a later date and was blinded against all other data. RESULTS: The mean age was 58 (SD, 13.5; range, 17 to 89) years, with a mean body mass index of 29 (SD, 6.1; range, 18 to 53) kg/m2 . In total, 58.9% (n = 103) presented with symptoms of prolapse. Clinically, 82.8% (n = 145) had substantial prolapse on the POP quantification assessment. On imaging, bladder, uterine, and rectal ampulla positions were significantly lower, and the hiatal area on the Valsalva maneuver was larger in the standing position (P < .03). On receiver operating characteristic statistics assessing correlations between POP symptoms and US pelvic organ descent, the area under the curve was higher in the standing position, but the difference was not statistically significant. CONCLUSIONS: Measurements of organ descent and hiatal dimensions are generally higher in the standing position. However, they are not reflected in a stronger association between symptoms and organ descent. Hence, imaging in the standing position can be limited to those patients in whom a false-negative assessment result is suspected. PMID- 30027565 TI - Modelling the distribution of the vector Aedes aegypti in a central Argentine city. AB - Aedes aegypti (Diptera: Culicidae) is an urban mosquito involved in the transmission of numerous viruses, including dengue, chikungunya and Zika. In Argentina, Ae. aegypti is the main vector of dengue virus and has been involved in several outbreaks in regions ranging from northern to central Argentina since 2009. In order to evaluate areas of potential vector-borne disease transmission in the city of Cordoba, Argentina, the present study aimed to identify the environmental, socioeconomic and demographic factors driving the distribution of Ae. aegypti larvae through spatial analysis in the form of species distribution models (SDMs). These models elucidate relationships between known occurrences of a species and environmental data in order to identify areas with suitable habitats for that species and the consequent risk for disease transmission. The maximum entropy species distribution model was able to fit the training data well, with an average area under the receiver operating characteristic curve (AUC) of > 0.8, and produced models with fair extrapolation capacity (average test AUC: > 0.75). Human population density, distance to vegetation and water channels were the main variables predictive of the vector suitability of an area. The results of this work will be used to target surveillance and prevention measures, as well as in mosquito management. PMID- 30027562 TI - Genomic mosaicism in the developing and adult brain. AB - Since the discovery of DNA, the normal developing and functioning brain has been assumed to be composed of cells with identical genomes, which remains the dominant view even today. However, this pervasive assumption is incorrect, as proven by increasing numbers of reports within the last 20 years that have identified multiple forms of somatically produced genomic mosaicism (GM), wherein brain cells-especially neurons-from a single individual show diverse alterations in DNA, distinct from the germline. Critically, these changes alter the actual DNA nucleotide sequences-in contrast to epigenetic mechanisms-and almost certainly contribute to the remarkably diverse phenotypes of single brain cells, including single-cell transcriptomic profiles. Here, we review the history of GM within the normal brain, including its major forms, initiating mechanisms, and possible functions. GM forms include aneuploidies and aneusomies, smaller copy number variations (CNVs), long interspersed nuclear element type 1 (LINE1) repeat elements, and single nucleotide variations (SNVs), as well as DNA content variation (DCV) that reflects all forms of GM with greatest coverage of large, brain cell populations. In addition, technical considerations are examined, along with relationships among GM forms and multiple brain diseases. GM affecting genes and loci within the brain contrast with current neural discovery approaches that rely on sequencing nonbrain DNA (e.g., genome-wide association studies (GWAS)). Increasing knowledge of neural GM has implications for mechanisms of development, diversity, and function, as well as understanding diseases, particularly considering the overwhelming prevalence of sporadic brain diseases that are unlinked to germline mutations. (c) 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol, 2018. PMID- 30027566 TI - Pinosylvin enhances leukemia cell death via down-regulation of AMPKalpha expression. AB - Resveratrol at high concentrations (50-100 MUmol/L) is known to induce cell death in leukemia cells. Here, we investigated whether pinosylvin, a resveratrol analogue, induced cell death in leukemia cells. Cell death was found to be markedly elevated by 50- to 100-MUmol/L pinosylvin in THP-1 and U937 cells. It was also shown that pinosylvin induced caspase-3 activation, flip-flop of phosphatidylserine, LC3-II accumulation, LC3 puncta, and p62 degradation in both THP-1 and U937 cells. These data indicate that pinosylvin-induced cell death may occur through apoptosis and autophagy. In addition, we showed that pinosylvin down-regulates AMP-activated protein kinase alpha1 (AMPKalpha1) in leukemia cells. Therefore, we correlated AMPKalpha1 down-regulation and leukemia cell death. AMPKalpha1 inhibition appeared to decrease pinosylvin-induced apoptosis and autophagy in leukemia cells, implying that AMPK is a key regulator of leukemia cell death. Moreover, we found that both pinosylvin-induced autophagy and apoptotic progress were reduced in AMPKalpha1-overexpressed leukemia cells, when compared with vector-transfected cells. Cell death was elevated by AMPKalpha1 overexpression, whereas pinosylvin-induced cell death was markedly decreased by caspase-3 inhibitors or autophagy inhibitors. These results suggest that pinosylvin-induced depletion of AMPKalpha1 enhances cell death via apoptosis and autophagy in leukemia cells. PMID- 30027568 TI - Rehabilitation service utilisation among adults with intellectual disabilities: Trends and socioeconomic disparities in China. AB - BACKGROUND: Intellectual disabilities (IDs) have become a public health concern worldwide, but few studies on rehabilitation service utilisation in this population were conducted in developing countries. We aimed to examine trends and socioeconomic disparities in the utilisation of rehabilitation services among adults with IDs in China. METHODS: We obtained data from a population-based survey by using a multistage, randomised, cluster sampling process to ascertain adults with IDs in 2006 and a selected subsample for follow-up surveys during 2007-2013. Psychiatrists ascertained individuals with IDs ascertained by intelligence quotient score under 70, deficits in two or more adaptive behaviours and age of onset under 18 years. RESULTS: Overall, the utilisation rate of rehabilitation services significantly increased from 10.1% in 2007 to 33.7% in 2013, with an annual average percentage growth of 34.3% when adjusting for multiple confounders. The mounting trends remained significant in all socioeconomic groups. The growth rates among lower socioeconomic participants were much higher than those among higher socioeconomic participants, and the strength in the association between socioeconomic position (education and region) and rehabilitation service utilisation declined in 2007-2013. CONCLUSIONS: This study found an upward trend in rehabilitation service utilisation in Chinese adults with IDs during 2007-2013, and socioeconomic disparities in rehabilitation service use in this population showed a downward trend over time. PMID- 30027567 TI - A bittersweet symphony: Evidence for taste-sound correspondences without effects on taste quality-specific perception. AB - Music has been associated with taste and shown to influence the dining experience. We asked whether sound that is associated with taste affects taste perception of food. In two studies (study 1: N = 20, 13 women; study 2: N = 20, 17 women), participants evaluated the taste of cinder toffee while listening to either of two soundscapes associated with sweet and bitter taste, respectively, or no sound. In study 1, participants rated the taste on a visual-analog scale (VAS) anchored with "bitter" and "sweet", aiming to replicate a previous study (Crisinel et al., ). In contrast, four separate scales were used in study 2 to report the extent of bitter, sweet, sour, and salty taste to test whether taste qualities were influenced by sound differentially. Additionally, taste intensity and pleasantness were rated in both studies. Taste intensity was increased in the presence of a sound, while pleasantness was not affected. In study 1, sound shifted bitter-sweet ratings in the direction of the congruent sound, i.e. samples tasted sweeter with "sweet" sound and more bitter with "bitter" sound, replicating Crisinel et al.'s () results. However, this effect was abolished when a "no-sound" control was included in the statistical model. Taste ratings in study 2 showed no effect of sound on any specific taste quality, suggesting that the influence of sound on taste in study 1 reflects an artifact of the scale rather than an actual shift in perception. Together, the data provide evidence for taste-sound correspondences without effects on taste-quality specific perception. PMID- 30027569 TI - The guidelines challenge-Philosophy, practice, policy. PMID- 30027570 TI - Ferrocene-Containing Inverse Opals by Melt-Shear Organization of Core/Shell Particles. AB - In this work, the preparation of redox-responsive elastomeric inverse opal films featuring switchable structural colors is reported. The pristine core/shell particle architecture consists of a silica core having a metallopolymer shell, that is, poly(2-(methacryloyloxy)ethyl ferrocene carboxylate) (PFcMA) copolymerized with n-butyl methacrylate (PFcMA-co-PnBuMA) synthesized via seeded and stepwise emulsion polymerization protocols. This tailor-made, inorganic core/hybrid organic shell architecture leads to monodisperse particles, which were then subjected to the so-called melt-shear organization technique. After a cross-linking reaction and the core particle removal, vivid structural colors are obtained due to the well-ordered voids within the metallopolymer-containing matrix. In addition, redox responsiveness is shown by the addition of chemical oxidation and reducing agents as well as by cyclic voltammetry studies, thus revealing both a change of surface wettability and a change of the structural reflection colors. Herein, the described one-pot strategies for the preparation of metallopolymer-containing core/shell hybrid particles and application of the melt-shear ordering technique paves the way to novel redox-responsive porous opal films, which are expected to be promising materials in the field of remote switchable sensors or electrochemical adsorbents. PMID- 30027571 TI - Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host. AB - There has been growing interest in performing organocatalysis within a supramolecular system as a means of controlling reaction reactivity and stereoselectivity. Here, a protein is used as a host for iminium catalysis. A pyrrolidine moiety is covalently linked to biotin and introduced to the protein host streptavidin for organocatalytic activity. Whereas in traditional systems stereoselectivity is largely controlled by the substituents added to the organocatalyst, enantiomeric enrichment by the reported supramolecular system is completely controlled by the host. Also, the yield of the model reaction increases over 10-fold when streptavidin is included. A 1.1 A crystal structure of the protein-catalyst complex and molecular simulations of a key intermediate reveal the chiral scaffold surrounding the organocatalytic reaction site. This work illustrates that proteins can be an excellent supramolecular host for driving stereoselective secondary amine organocatalysis. PMID- 30027572 TI - HIV-1 Entry Inhibitors: A Review of Experimental and Computational Studies. AB - The HIV-1 life cycle consists of different events, such as cell entry and fusion, virus replication, assembly and release of the newly formed virions. The more logical way to inhibit HIV transmission among individuals is to inhibit its entry into the immune host cells rather than targeting the intracellular viral enzymes. Both viral and host cell surface receptors and co-receptors are regarded as potential targets in anti-HIV-1 drug design process. Because of the importance of this topic it was decided to summarize recent reports on small-molecule HIV-1 entry inhibitors that have not been considered in the latest released reviews. All the computational studies reported in the literature regarding HIV-1 entry inhibitors since 2014 was also considered in this review. PMID- 30027573 TI - Fungal bioprospecting and antifungal treatment on a deteriorated Brazilian contemporary painting. AB - This study aims at identifying the populations of filamentous fungi present on a Brazilian contemporary painting, whose conservation status was compromised and showed evident signs of deterioration by microbial action. In addition, to correlate the biodeterioration potential of the isolated fungal strains, cellulolytic activity testing was performed and, finally, the biocide treatment against microbial growth was carried out. A total of nine isolates of filamentous fungi were detected and three distinct taxa were identified: Aspergillus flavus, Aspergillus niger and Penicillium citrinum. The detection of the enzymatic activity of the isolates by cellulolytic plate assay revealed the potential of filamentous fungal species in causing the deterioration of paintings. Our results showed that the presence of each strain of filamentous fungi correlated with the distribution of the paint colour, suggesting a tropism of certain species for specific dyes used. In addition, strains of A. niger showed a lower enzymatic activity index, despite the aesthetic damage that this fungal specie caused on the artwork. In conclusion, this study demonstrated that the identification of the microbiota obtained from the painting may help contrasting its biodeterioration and it described a successful antifungal treatment on a contemporary art piece. Contemporary art in Brazil arose from postmodernism, through the artistic manifestations included in the Neoconcrete Manifest of 1959, as well as with the use of innovative techniques. It was a consequence of the interaction between concept and language, displayed by the artists on a set of unconventional materials and objects. Despite being a 20th century painting, the concern of the artist to keep the art object in a good conservation state has driven the realization of this work and these microbial prospecting studies, associated with artwork deterioration, may contribute to the preservation of the Brazilian contemporary heritage. PMID- 30027575 TI - Time trends regarding the etiology of renal artery stenosis: 18 years' experience from the China Center for Cardiovascular Disease. AB - The time trends regarding the etiology of renal artery stenosis (RAS) are changing, but few investigations have focused on these issues. This study aimed to analyze the time trends regarding the etiology of RAS in a large patient sample from the China Center for Cardiovascular Disease. Consecutive inpatients with RAS from January 1999 to December 2016 were enrolled in this study. The etiologic diagnosis of RAS was based on established criteria. We retrospectively analyzed the time trends regarding the etiology of RAS during an 18-year period. A total of 2905 patients with RAS were enrolled. There were 2393 (82.4%) patients with atherosclerosis (AS), 345 (11.9%) with Takayasu arteritis (TA), 126 (4.3%) with fibromuscular dysplasia (FMD), and 41 (1.4%) with other causes. Among all patients (n = 2905), patients aged <= 40 years (n = 450), patients aged >40 years (n = 2455), female patients (n = 1097), male patients (n = 1808), female patients aged >40 years (n = 808), and male patients aged >40 years (n = 1647), there were a gradual increase in the proportion of atherosclerotic RAS (P < 0.05), a gradual decrease in the proportion of RAS caused by TA (P < 0.05), and almost no change in the proportion of RAS caused by FMD during the 18-year period (P > 0.05). The data show that the primary causes of RAS are AS, TA, and FMD. The proportion of RAS caused by AS and TA gradually increased and decreased, respectively, over time, and the proportion of RAS caused by FMD showed no significant change. PMID- 30027574 TI - Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12. AB - The sensitivity of breast cancer cells to epirubicin (EPI) is closely related to the efficacy of the drug and the prognosis of patients. A growing body of research has suggested that autophagy is involved in the treatment of a variety of cancers, including breast cancer, and modifies the sensitivity of anticancer drugs. However, the mechanism by which autophagy participates in cancer therapy and modulates drug sensitivity has not been fully elucidated. In this study, we showed that the expression of Autophagy/Beclin 1 regulator 1 (Ambra1), a key protein of autophagy, was negatively correlated with EPI sensitivity in breast cancer cells. In addition, it altered the sensitivity of breast cancer cells to EPI by regulating EPI-induced autophagy. As a potential mechanism, we demonstrated that autophagy-related protein 12 (ATG12) was a downstream protein that Ambra1-regulated EPI-induced autophagy. Therefore, Ambra1 plays an important role in regulating the sensitivity of breast cancer cells to EPI. And the regulatory effect of Ambra1 on EPI sensitivity is achieved through the regulation of autophagy by targeting ATG12. Overall, we propose a novel mechanism by which autophagy modulates the sensitivity of breast cancer cells to EPI. ATG12 is a novel targeting protein of Ambra1 in regulating EPI-induced autophagy. In addition, the important role of Ambra1 in modulating the sensitivity of breast cancer cells to EPI is confirmed in vivo. This finding indicates that Ambra1 might be a target for developing breast cancer treatments. PMID- 30027576 TI - The microemulsion electrokinetic capillary chromatography combined with reversed electrode polarity stacking mode for enriching and quantifying lignanoids and ginsenosides in TCMs preparation Shengmai injection. AB - An on-line large volume sample stacking with polarity switching (LVSS) method was proposed for simultaneously determining lignanoids and ginsenosides in MEEKC. The parameters including the pH value and concentration of buffer solution, SDS, organic modifier, oil phase, running voltage, and temperature as well as injection time, sample matrix, stacking voltage, and time influencing separation and stacking were systematically optimized. The method was verified by performing precision, accuracy, stability, and recovery. Its reliability was proved by separating and quantifying two lignanoids and three ginsenosides in Shengmai injectionSMI. The sensitivity of these compounds was improved by MEEKC-LVSS method for 6-11 times than conventional MEEKC. Thus, this developed on-line MEEKC LVSS method was sensitive, practical, and reliable. PMID- 30027578 TI - Hierarchical CdS Nanorod@SnO2 Nanobowl Arrays for Efficient and Stable Photoelectrochemical Hydrogen Generation. AB - An efficient photoanode based on CdS nanorod@SnO2 nanobowl (CdS NR@SnO2 NB) arrays is designed and fabricated by the preparation of SnO2 nanobowl arrays via nanosphere lithography followed by hydrothermal growth of CdS nanorods on the inner surface of the SnO2 nanobowls. A photoelectrochemical (PEC) device constructed by using this hierarchical CdS NR@SnO2 NB photoanode presents significantly enhanced performance with a photocurrent density of 3.8 mA cm-2 at 1.23 V versus a reversible hydrogen electrode (RHE) under AM1.5G solar light irradiation, which is about 2.5 times higher than that of CdS nanorod arrays. After coating with a thin layer of SiO2 , the photostability of the CdS NR@SnO2 NB arrays is greatly enhanced, resulting in a stable photoanode with a photocurrent density of 3.0 mA cm-2 retained at 1.23 V versus the RHE. The much improved performance of the CdS NR@SnO2 NB arrays toward PEC hydrogen generation can be ascribed to enlarged surface area arising from the hierarchical nanostructures, improved light harvesting owing to the NR@NB architecture containing multiple scattering centers, and enhanced charge separation/collection efficiency due to the favorable CdS-SnO2 heterojunction. PMID- 30027577 TI - Comparison of sparse domain approaches for 4D SPECT dynamic image reconstruction. AB - PURPOSE: Dynamic imaging (DI) provides additional diagnostic information in emission tomography in comparison to conventional static imaging at the cost of being computationally more challenging. Dynamic single photon emission computed tomography (SPECT) reconstruction is particularly difficult because of the limitations in the sampling geometry present in most existing scanners. We have developed an algorithm Spline Initialized Factor Analysis of Dynamic Structures (SIFADS) that is a matrix factorization method for reconstructing the dynamics of tracers in tissues and blood directly from the projections in dynamic cardiac SPECT, without first resorting to any 3D reconstruction. METHODS: SIFADS is different from "pure" factor analysis in dynamic structures (FADS) in that it employs a dedicated spline-based pre-initialization. In this paper, we analyze the convergence properties of SIFADS and FADS using multiple metrics. The performances of the two approaches are evaluated for numerically simulated data and for real dynamic SPECT data from canine and human subjects. RESULTS: For SIFADS, metrics analyzed for reconstruction algorithm convergence show better features of the metric curves vs iterations. In addition, SIAFDS provides better tissue segmentations than that from pure FADS. Measured computational times are also typically better for SIFADS implementations than those with pure FADS. CONCLUSION: The analysis supports the utility of the pre-initialization of a factorization algorithm for better dynamic SPECT image reconstruction. PMID- 30027579 TI - Efficacy of pemetrexed and carboplatin with or without bevacizumab in lung adenocarcinoma patients with EGFR non-T790M mutations after progression on first line EGFR-tyrosine kinase inhibitors. AB - BACKGROUND: The purpose of this study was to compare the effects of pemetrexed and carboplatin plus bevacizumab (PC + B) versus pemetrexed and carboplatin (PC) in lung adenocarcinoma patients with EGFR non-T790M mutations after progression on first-line EGFR-tyrosine kinase inhibitors (TKIs). METHODS: Patients with EGFR positive lung adenocarcinoma who had received second-line PC with or without bevacizumab harboring EGFR non-T790M mutations after progression on first-line EGFR-TKIs between April 2015 and 2017 at Tianjin Medical University Cancer Institute and Hospital were enrolled in the study. The primary endpoint was progression-free survival and secondary endpoints were overall survival, objective response rate, disease control rate, and safety. RESULTS: A total of 85 patients were eligible for the study: 55 and 30 cases were enrolled in the PC and PC + B groups, respectively. The median progression-free survival was prolonged with PC + B compared to PC (median 8.2 vs. 5.1 months; P = 0.037). The objective response rate was improved with PC + B compared to PC (46.7% vs. 25.5%; P = 0.047) and overall survival prolonged with PC + B compared to PC (median 26.3 vs. 19.2 months; P = 0.012). Safety was similar to previous studies of bevacizumab in non-small cell lung cancer: one patient experienced grade 3 hypertension and proteinuria but did not require the discontinuation of therapy. CONCLUSION: The addition of bevacizumab to PC was superior to PC alone as second-line therapy in patients with advanced non-T90M EGFR-positive lung adenocarcinoma. However, this result needs to be confirmed by prospective clinical trials. PMID- 30027581 TI - Autism-related behaviors in the cyclooxygenase-2-deficient mouse model. AB - Prostaglandin E2 (PGE2) is an endogenous lipid molecule involved in normal brain development. Cyclooxygenase-2 (COX2) is the main regulator of PGE2 synthesis. Emerging clinical and molecular research provides compelling evidence that abnormal COX2/PGE2 signaling is associated with autism spectrum disorder (ASD). We previously found that COX2 knockout mice had dysregulated expression of many ASD genes belonging to important biological pathways for neurodevelopment. The present study is the first to show the connection between irregular COX2/PGE2 signaling and autism-related behaviors in male and female COX2-deficient knockin, (COX)-2- , mice at young (4-6 weeks) or adult (8-11 weeks) ages. Autism-related behaviors were prominent in male (COX)-2- mice for most behavioral tests. In the open field test, (COX)-2- mice traveled more than controls and adult male (COX)-2 mice spent less time in the center indicating elevated hyperactive and anxiety linked behaviors. (COX)-2- mice also buried more marbles, with males burying more than females, suggesting increased anxiety and repetitive behaviors. Young male (COX)-2- mice fell more frequently in the inverted screen test revealing motor deficits. The three-chamber sociability test found that adult female (COX)-2- mice spent less time in the novel mouse chamber indicative of social abnormalities. In addition, male (COX)-2- mice showed altered expression of several autism-linked genes: Wnt2, Glo1, Grm5 and Mmp9. Overall, our findings offer new insight into the involvement of disrupted COX2/PGE2 signaling in ASD pathology with age-related differences and greater impact on males. We propose that (COX)-2- mice might serve as a novel model system to study specific types of autism. PMID- 30027580 TI - Combined treatment with GSNO and CAPE accelerates functional recovery via additive antioxidant activities in a mouse model of TBI. AB - Traumatic brain injury (TBI) is the major cause of physical disability and emotional vulnerability. Treatment of TBI is lacking due to its multimechanistic etiology, including derailed mitochondrial and cellular energy metabolism. Previous studies from our laboratory show that an endogenous nitric oxide (NO) metabolite S-nitrosoglutathione (GSNO) provides neuroprotection and improves neurobehavioral function via anti-inflammatory and anti-neurodegenerative mechanisms. To accelerate the rate and enhance the degree of recovery, we investigated combining GSNO with caffeic acid phenethyl ester (CAPE), a potent antioxidant compound, using a male mouse model of TBI, controlled cortical impact in mice. The combination therapy accelerated improvement of cognitive and depressive-like behavior compared with GSNO or CAPE monotherapy. Separately, both GSNO and CAPE improved mitochondrial integrity/function and decreased oxidative damage; however, the combination therapy had greater effects on Drp1 and MnSOD. Additionally, while CAPE alone activated AMPK, this activation was heightened in combination with GSNO. CAPE treatment of normal animals also significantly increased the expression levels of pAMPK, pACC (activation of AMPK substrate ACC), and pLKB1 (activation of upstream to AMPK kinase LKB1), indicating that CAPE activates AMPK via LKB1. These results show that while GSNO and CAPE provide neuroprotection and improve functional recovery separately, the combination treatment invokes greater recovery by significantly improving mitochondrial functions and activating the AMPK enzyme. Both GSNO and CAPE are in human consumption without any known adverse effects; therefore, a combination therapy based multimechanistic approach is worthy of investigation in human TBI. PMID- 30027582 TI - Distribution and prevalence of T. bryosalmonae in Austria: A first survey of trout from rivers with a shrinking population. AB - The first evidence of proliferative kidney disease (PKD) in an Austrian river (the River Kamp) was documented in 2016, and no information on the PKD infection status of trout in other rivers was available. Since then, brown trout (Salmo trutta fario) and rainbow trout (Oncorhynchus mykiss) have been collected from rivers in Upper and Lower Austria for different diagnostic purposes. In this study, we summarize the recent findings of a first survey concerning the distribution of Tetracapsuloides bryosalmonae, the causative agent of proliferative kidney disease (PKD), from these samples. Between September 2015 and October 2017, a total of 280 brown trout and 39 rainbow trout were collected from 21 rivers in the provinces of Upper and Lower Austria. T. bryosalmonae was detected by PCR of kidney tissue in 17 of 21 sampled rivers and in 138 of 280 brown trout as well as in 11 of 39 rainbow trout. Pathological signs of PKD (e.g., hypertrophy of the kidney) were observed in 33 analysed brown trout and six rainbow trout samples. No correlations between fish infected by T. bryosalmonae and the parameters size and age class, condition factor, geological origin of the streams and distribution within the river course were found, while positively tested fish are significantly increased at sampling sites exceeding water temperatures of 15 degrees C for median periods of 115 days. The prevalence within the affected streams or stream sections is highly variable, and in single rivers, infection rates of up to 90% are confirmed. PMID- 30027583 TI - Linkage to care, mobility and retention of HIV-positive postpartum women in antiretroviral therapy services in South Africa. AB - INTRODUCTION: Linkage to care and mobility postpartum present challenges to long term retention after initiating antiretroviral therapy (ART) in pregnancy, but there are few insights from sub-Saharan Africa. We aimed to describe postpartum linkage to care, mobility, retention and viral suppression after ART initiation in pregnancy. METHODS: Using routine electronic data we assessed HIV-specific health contacts and clinic movements among women initiating ART in an integrated antenatal care (ANC) and ART clinic in Cape Town, South Africa. The local care model includes mandatory transfer to general ART clinics postpartum. We investigated linkage to care after leaving the integrated clinic and mobility to new clinics until 30 months on ART. We used Poisson regression to explore predictors of linkage, retention (accessing care at least once at both 12 [6 to <18] and 24 [18 to <30] months on ART), and viral suppression (HIV viral load [VL] <=50 and <=1000 copies/mL after 12 months on ART). RESULTS: Among 617 women, 23% never linked to care; 71% and 65% were retained at 12 and 24 months on ART respectively, with 59% retained in care at both times. Those who linked (n = 485) accessed HIV care at 98 different clinics and 21% attended >=2 clinics. Women >25 years, married/cohabiting or presenting early for ANC were more likely to link. Younger and unemployed women were more likely to attend >=2 clinics (adjusted risk ratio [aRR] 1.10 95% confidence interval [CI] 1.02 to 1.18 and aRR 1.06 95% CI 0.99 to 1.12 respectively). Age >25 years (aRR 1.17 95% CI 1.02 to 1.33) and planned pregnancy (aRR 1.20 95% CI 1.09 to 1.33) were associated with being retained. Among 338 retained women with VL available, attending >=2 clinics reduced the likelihood of viral suppression when defined as <=50 copies/mL (aRR 0.81 95% CI 0.69 to 0.95). Distance moved was not associated with VL. CONCLUSIONS: These data show that a substantial proportion of women do not link to postpartum ART care in this setting and, among those that do, long-term retention remains a challenge. Women move to a variety of clinics and young women appear particularly vulnerable to attrition. Interventions promoting linkage and continued retention for women initiating ART during pregnancy warrant urgent consideration. PMID- 30027584 TI - Clonal distribution and intratumour heterogeneity of the B-cell repertoire in oesophageal squamous cell carcinoma. AB - Recent successes in tumour immunotherapies have highlighted the importance of tumour immunity. However, most previous studies to date have focused on T-cell immune response, although B cells are key players in the core immune network and are associated with T-cell immune response. Based on our previous study delineating T-cell receptor (TCR) repertoire in seven patients with oesophageal squamous cell carcinoma (ESCC), this study profiled the B-cell receptor (BCR) repertoire of multiple tumour regions, adjacent normal tissue, and blood from the same seven patients to reveal the characteristics of B-cell immunity and the relationship to TCR repertoire in ESCC patients. We found that intratumour BCR repertoire was significantly more oligoclonal than matched adjacent normal tissue or peripheral blood and, moreover, clonal amplification of B cells in multiple tumour regions was significantly heterogeneous, although clonal amplification of the TCR repertoire across different tissue compartments and regions of the same tumour was similar. However, both BCR and TCR repertoires in the tumour microenvironment were distinct from those in adjacent normal tissues and blood, and thus represented a group of B and T cells that were spatially confined to the tumour microenvironment and could react to tumour antigens. Additionally, B- and T-cell clones varying between different tumour regions showed intratumour heterogeneity of B- and T-cell immune response. Thus, multiple tumour biopsies could be essential to comprehensively delineate the adaptive immune response to an individual ESCC. These findings expand our understanding of adaptive anti tumour immunity and shed more light on ESCC immunotherapy. This study provides insights into the intratumour heterogeneity of the BCR repertoire as well as the difference and relationship between the BCR and TCR repertoire in ESCC, expanding our understanding of adaptive anti-tumour immunity and ESCC immunotherapy. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30027585 TI - Ultrasonography of Complications in Surgical Repair of the Distal Biceps Brachii Tendon. PMID- 30027586 TI - Shear Wave Elastography in the Evaluation of the Kidneys in Pediatric Patients with Unilateral Vesicoureteral Reflux. AB - OBJECTIVES: To evaluate the ability of shear wave elastography (SWE) to detect renal parenchymal scar formation in patients with vesicoureteral reflux. METHODS: We prospectively evaluated 49 patients with unilateral grade 2 or higher-degree VUR. All patients underwent dimercaptosuccinic acid (DMSA) scintigraphy for evaluation of the renal parenchymal scar. After the DMSA scan, 2 radiologists, who were blinded to clinical data and each other's measurements, evaluated the kidneys of the patients using SWE. The kidneys were divided into 3 parts: upper pole, middle region, and lower pole, and 3 regions of interest were placed to each part. Shear wave velocity (SWV) values were calculated using meters per second as a unit and recorded for each region. Afterward, SWV values were compared to DMSA results. RESULTS: There was no significant difference between the observers' mean SWV values of kidneys with VUR without scar formation (mean +/- SD, 2.11 +/- 0.06 and 2.09 +/- 0.05 m/s) and the contralateral normal kidney SVW values (2.11 +/- 0.06 and 2.10 +/- 0.05 m/s; P = .936 and .724, respectively). We observed a significant difference between the mean SWV values of the kidneys with VUR accompanied by scar formation (2.28 +/- 0.10 and 2.27 +/- 0.11 m/s) and the mean SWV values of the contralateral normal kidneys (2.09 +/- 0.05 and 2.10 +/- 0.04 m/s; P < .001 for both observers). CONCLUSIONS: Shear wave elastography could detect scar tissue in kidneys; however, the variability of the stiffness due to the kidney's complex structure, and variations in blood perfusion and the glomerular filtration rate of the kidney might limit the use of SWE in current clinical diagnostic algorithms for VUR. PMID- 30027587 TI - Cerebrospinal fluid flow increases from newborn to adult stages. AB - Solute transport through the brain is of major importance for the clearance of toxic molecules and metabolites, and it plays key roles in the pathophysiology of the central nervous system. This solute transport notably depends on the cerebrospinal fluid (CSF) flow, which circulates in the subarachnoid spaces, the ventricles and the perivascular spaces. We hypothesized that the CSF flow may be different in the perinatal period compared to the adult period. Using in vivo magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF), we assessed the dynamic of the CSF flow in rodents at different ages. By injecting a contrast agent into the CSF, we first used MRI to demonstrate that CSF flow gradually increases with age, with the adult pattern observed at P90. This observation was confirmed by NIRF, which revealed an increased CSF flow in P90 rats when compared with P4 rats not only at the surface of the brain but also deep in the brain structures. Lastly, we evaluated the exit routes of the CSF from the brain. We demonstrated that indocyanine green injected directly into the striatum spread throughout the parenchyma in adult rats, whereas it stayed at the injection point in P4 rats. Moreover, the ability of CSF to exit through the nasal mucosa was increased in the adult rodents. Our results provide evidence that the perinatal brain has nonoptimal CSF flow and exit and, thus, may have impaired clean-up capacity. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018. PMID- 30027588 TI - Bringing population mobility into focus to achieve HIV prevention goals. PMID- 30027589 TI - In ovo feeding of beta-hydroxy beta-methylbutyrate and dextrin optimized growth performance of broiler for pre-placement holding time using the Box-Behnken response surface design. AB - To investigate the effect of in ovo feeding (IOF) of beta-hydroxy beta methylbutyrate (HMB), dextrin and post-hatching water and feed deprivation time on growth performance of broilers, 1,500 eggs were assigned into 15 experimental runs of Box-Behnken design, including three levels IOF of HMB (0%, 0.5% and 1%), dextrin (0%, 20% and 40%) and three levels of the first water and feed deprivation (6, 27 and 48 hr). After hatching, day-old chicks (seven males and seven females) from each replicate were then selected and randomly assigned to 60 floor pens for a 42-day feeding trial. The experimental data were fitted to the quadratic response surface models, and the goodness of fit of the models was expressed by the R2 value. The interaction between IOF of dextrin and timing of first feed deprivation had the largest effect on body weight of chicks at day 7 (BW7) and corrected European production efficiency factor (EPEF). In ovo feeding of dextrin reduced negative effects of delayed access to feed and water after hatch up to 48 hr on BW7, body weight of chicks at day 42, EPEF and corrected EPEF. The results of the current study suggested that the EPEF corrected by hatchability could provide the better understanding of IOF experimental findings. The ridge optimization analysis revealed that the optimal levels of HMB and dextrin inclusion in eggs and timing of first feed deprivation for maximum corrected EPEF were 0.37, 15.94% and 7.22 hr, respectively. These results demonstrate that the Box-Behnken statistical design and response surface models are effective to describe the relationship between IOF of nutrients and pre placement holding time and predict the performance of broilers to achieve the optimal target. PMID- 30027590 TI - The effect of baked milk on accelerating unheated cow's milk tolerance: A control randomized clinical trial. AB - BACKGROUND: Assessing the effect of adding baked milk products to the diet of patients with cow's milk allergy on accelerating the formation of tolerance. METHOD: A randomized clinical trial was carried out with 84 patients (6 months-3 years old) diagnosed with allergy to cow's milk who tolerated baked milk in form of muffin in oral food challenge (OFC). The subjects were divided randomly into case and control groups matched for age and sex. Patients in the case group were asked to consume baked milk in the form of muffin for 6 months and then to consume baked cheese in the form of pizza for another 6 months. The control group were instructed to strictly avoid any milk products for 1 year. Skin prick test (SPT) and serum-specific immunoglobulin E (sIgE) levels (ImmunoCAP) of milk, casein, and beta-lactoglobulin were measured before and after the study. In addition, those in the case group who had satisfactorily tolerated baked products during the study as well as all the subjects in the control group underwent an OFC to evaluate unheated milk tolerance at the end of the study. RESULTS: It was shown that by the end of the 1-year study period, 88.1% (37/42) of the patients in the case group and 66.7% (28/42) of those in control group had developed tolerance to unheated milk (P-value: 0.018). The results of milk-specific SPT and sIgE levels showed a significant decrease in the case group. Initial sIgE levels could not predict unheated milk tolerance in case and control groups. CONCLUSION: Introducing baked milk products into the diet of patients with milk allergy can accelerate the tolerance of unheated milk in these patients. sIgE levels of milk, casein, and beta-lactoglobulin did not predict the tolerance of unheated milk. PMID- 30027591 TI - Relationship between PSA kinetics and Tc-99m HYNIC PSMA SPECT/CT detection rates of biochemical recurrence in patients with prostate cancer after radical prostatectomy. AB - BACKGROUND: Prostate-specific antigen (PSA) levels should reflect or be proportional to the size and the metabolic activity of prostatic metastases. Moreover, a rapid change in PSA kinetics, either before or after treatment, is an indicator of poor prognosis after radical prostatectomy. Therefore, the purpose of this study was to investigate the effect of total PSA at the time of Tc-99m HYNIC PSMA SPECT/CT (trigger PSA), PSA velocity (PSAvel), and PSA doubling time (PSAdt) on the Tc-99m HYNIC PSMA SPECT/CT detection rate in prostate cancer patients who showed biochemical recurrence after radical prostatectomy during follow-up. METHODS: In total, 208 patients who showed an increase in PSA were evaluable for this retrospective analysis covering November 2015 to March 2017. Data were available for calculation of PSAvel in 112 patients and for PSAdt in 157 patients. Logistic regression analysis was used to determine whether there was a relationship between the PSA levels and PSA kinetics and the rate of detection of relapse using Tc-99m HYNIC PSMA SPECT/CT. RESULTS: Tc-99m HYNIC PSMA SPECT/CT detected disease relapse in 151 of 208 patients (72.6%). The PSA level (P < 0.0001) and PSAdt (P = 0.0036) were significantly different between SPECT positive patients (higher PSA level, shorter PSAdt) and SPECT-negative patients (lower PSA, longer PSAdt). ROC analysis showed that a PSA level of 1.30 ng/mL and a PSAdt of 2.9 months were optimal cut-off values. Patients with purely local recurrence had lower PSAvel and longer PSAdt values (P < 0.001). According to the multivariate analysis, a pathological positive SPECT/CT scan was associated with the PSA level (P < 0.001), PSAdt <6 months (P < 0.05), and Gleason scores (GSC) >7 (P < 0.05). CONCLUSION: The Tc-99m HYNIC PSMA SPECT/CT detection rate is influenced by trigger PSA, PSAdt, and PSAvel. Like PSA, PSAdt is an independent predictor of Tc-99m HYNIC PSMA SPECT/CT. PSAdt should be taken into account by physicians especially when PSA <1 ng/mL. PMID- 30027593 TI - Conventional and unconventional therapies in typical and atypical chronic inflammatory demyelinating polyneuropathy with different clinical course of progression. AB - Intravenous immunoglobulin (IVIG), corticosteroids and therapeutic plasma exchange (TPE) are evidence-based conventional treatments for chronic inflammatory demyelinating polyneuropathy (CIDP). In many centres, unconventional treatments are frequently used as alternatives. We evaluated the outcome of conventional and unconventional therapies in 31 CIDP patients. Overall response rate with conventional first-line immunotherapies was 77% (20/26), comparable between IVIG and corticosteroids (80% vs 70%). Use of TPE was limited. Treatment response among typical and atypical CIDP were comparable (76 vs 80%). Non responders were patients with progressive form of typical CIDP and DADS. Majority (21/26, 81%) of patients with persistent neurological deficits received maintenance therapy. Two subgroups of patients frequently treated with maintenance immunosuppressants were those with improving or stable disease following first-line treatment (12, 57%) and those with progressive form of CIDP (2, 10%). Primary indications for immunosuppressant use were corticosteroids sparing and additional immunosuppression effects. Nine (64%) patients with improving or stable disease given azathioprine were taken off corticosteroids after a median duration of 14 months (range 12-108). Two (14%) eventually achieved cure or clinical remission without treatment. Maintenance IVIg was given to 6 (29%) relapsing CIDP patients; none of achieved cure or remission after similar median duration of treatment. Less potent immunosuppressant drugs (azathioprine, mycophenolate mofetil, and methotrexate) were frequently used, with moderate adverse effect profiles. In resource limited setting, unconventional treatments were commonly used among CIDP patients with different clinical course of progression. In most cases, careful risk-benefit re-assessment is required to justify its further use. PMID- 30027592 TI - Dialysate potassium concentration: Should mass balance trump electrophysiology? AB - Nephrologists are faced with a difficult dilemma in choosing the ideal dialysis prescription to maintain neutral potassium mass balance. Should potassium mass balance goals prioritize the normalization of serum potassium levels using low potassium dialysate at the expense of provoking intradialytic arrhythmias, or should mass balance goals favor permissive hyperkalemia using higher dialysate potassium to avoid rapid intradialytic fluxes at the risk of more interdialytic arrhythmias? This review examines the factors that determine potassium mass balance among HD patients, the relationships between serum and dialysate potassium levels and outcomes, and concludes by examining currently available approaches to reducing risk of arrhythmias while managing potassium mass balance. PMID- 30027594 TI - Influence of Magnetic Nanoparticles on PISA Preparation of Poly(Methacrylic Acid) b-Poly(Methylmethacrylate) Nano-Objects. AB - This article presents the synthesis of poly(methacrylic acid)-b-poly(methyl methacrylate) diblock copolymer via polymerization-induced self-assembly in the presence of iron-oxide nanoparticles. Detailed phase diagrams with and without inorganic nanoparticles were constructed. Scanning transmission electron microscopy and energy dispersive X-ray photometry studies confirme the decoration of the polymeric nanoparticles with the iron-oxide nanoparticles. These hybrid nanoparticles were used to prepare porous thin film membranes by spin coating. Finally, the magneto-responsive properties of the membranes were assessed using water filtration tests in the presence and absence of a magnetic field. PMID- 30027595 TI - Resilience of patients with chronic diseases: A systematic review. AB - The purpose of this research was to contribute to the development of a resilience promoting programme for patients with chronic diseases. A systematic review of literature concerning resilience interventions for patients with chronic diseases was conducted by searching PubMed (including Medline), Science Direct, Web of Science, PsycARTICLES, CINAHL Plus, Embase, and the Cochrane Database for articles featuring the terms "resilience," "resiliency," "resilient," "cancer," "stroke," "heart disease," "diabetes" and "COPD" and published between 8 January 2017 and 15 January 2017. We included all English studies relevant to the topic; however, we excluded: (1) nonrandomised controlled trials and (2) those that mentioned the term "resilience" but did not apply it in their analysis. Seventeen studies-10 on cancer, four on cardiovascular diseases and three on diabetes-were deemed suitable for analysis. We found that, in these studies, (1) diverse definitions of resilience were applied, (2) various intervention durations were used and (3) complex programmes were applied within the resilience-improving programmes. Our research encourages efforts to operationalise the construct of resilience, so it can be applied in clinical settings, and for the development of more systematic intervention programmes. PMID- 30027596 TI - A Bayesian K-PD model for synergy: A case study. AB - Coadministration of 2 or more compounds can alter both the pharmacokinetics and pharmacodynamics of individual compounds. While experiments on pharmacodynamic drug-drug interactions are usually performed in an in vitro setting, this experiment focuses on an in vivo setting. The change over time of a safety biomarker is modeled using an indirect response model, in which the virtual pharmacokinetic profile of one compound drives the effect of the other. Several experiments at different dose level combinations were performed sequentially. While a traditional frequentist analysis consists of estimating the model parameters based on all the data simultaneously, in this work, we consider a Bayesian inference framework allowing to incorporate the results from a historical dose-response experiment. PMID- 30027597 TI - The Value of Needle-Guidance Technology in Ultrasound-Guided Percutaneous Procedures Performed by Radiology Residents: A Comparison of Freehand, In-Plane, Fixed-Angle, and Electromagnetic Needle Tracking Techniques. AB - OBJECTIVES: Radiology residents typically learn ultrasound-guided procedures by performing supervised procedures on patients who may experience longer procedure times and higher complication rates. The purpose of this study was to determine if existing technologies, such as in-plane, fixed-angle guidance (IPFA) and electromagnetic needle tracking (ENT), can improve resident procedure time and accuracy. METHODS: Radiology residents (18 total) were randomized to 1 of 3 ultrasound-guidance technique groups-freehand, IPFA, or ENT-and instructed to place a needle into 4 liver lesions in a humanoid phantom, each increasing in difficulty. For each lesion, residents were timed from skin puncture to needle placement, and the number of times the needle was pulled back and redirected (pullbacks) was recorded. Primary outcomes were total time and total number of pullbacks for all 4 lesions. Secondary outcomes were individual time and number of pullbacks for each lesion. RESULTS: Compared to the freehand group, the IPFA and ENT groups demonstrated lower procedural time and number of pullbacks both in total and for each individual lesion. Differences in total time and total number of pullbacks were significant (P < .001), as were differences for lesion 3 (P = .002-.02) and lesion 4 (P < .001). Differences for lesions 1 and 2 were not statistically significant. CONCLUSIONS: Radiology resident procedure time and procedure accuracy (as judged by number of pullbacks) are significantly improved by the use IPFA and ENT guidance technologies. PMID- 30027598 TI - Retinal imaging to identify target organ damage in older Africans: A pilot study. AB - By 2030, sub-Saharan Africa is forecast to see the steepest rise in the number of people with hypertension of any world region. Hypertensive retinopathy is known to be a common complication of hypertension in developed countries and some studies suggest it is associated with the presence of other hypertension-related end-organ damage (EOD) such as stroke and cardiovascular disease. In Tanzania hypertension is relatively more common than in other parts of sub-Saharan Africa, especially in the older population; however, the prevalence of hypertensive retinopathy and its association with EOD remain unknown. The authors conducted a cross-sectional study of elderly, community-dwelling, rural Tanzanians to determine the prevalence of hypertensive retinopathy and its association with hypertension and other forms of EOD. Hypertensive retinopathy was diagnosed based on retinal imaging. In a cohort of 61 patients with gradable images, the authors found the overall prevalence of hypertensive retinopathy to be 64% (n = 39), which was strongly associated with hypertension (X2 [1] = 4.207, P = .004), with a significant trend towards more severe retinopathy with more severe hypertension (r = .377, P = .003). The authors did not find hypertensive retinopathy to be associated with other forms of EOD. Hypertensive retinopathy is highly prevalent in this population and is associated in most but not all cases with hypertension. These findings do not suggest that it could be used as a screening tool for EOD, but it is important to identify and educate patients with retinopathy about possible complications of the condition. PMID- 30027599 TI - Novel insights into the spatial and temporal complexity of hypothalamic organization through precision methods allowing nanoscale resolution. AB - The mammalian hypothalamus contains an astounding heterogeneity of neurons to achieve its role in coordinating central responses to virtually any environmental stressor over the life-span of an individual. Therefore, while core features of intrahypothalamic neuronal modalities and wiring patterns are stable during vertebrate evolution, integration of the hypothalamus into hierarchical brain wide networks evolved to coordinate its output with emotionality, cognition and conscious decision-making. The advent of single-cell technologies represents a recent milestone in the study of hypothalamic organization by allowing the dissection of cellular heterogeneity and establishing causality between opto- and chemogenetic activity modulation of molecularly-resolved neuronal contingents and specific behaviours. Thus, organizational rules to accumulate an unprecedented variety of hierarchical neuroendocrine command networks into a minimal brain volume are being unravelled. Here, we review recent understanding at nanoscale resolution on how neuronal heterogeneity in the mammalian hypothalamus underpins the diversification of hormonal and synaptic output and keeps those sufficiently labile for continuous adaptation to meet environmental demands. Particular emphasis is directed towards the dissection of neuronal circuitry for aggression and food intake. Mechanistic data encompass cell identities, synaptic connectivity within and outside the hypothalamus to link vegetative and conscious levels of innate behaviours, and context- and circadian rhythm-dependent rules of synaptic neurophysiology to distinguish hypothalamic foci that either tune the body's metabolic set-point or specify behaviours. Consequently, novel insights emerge to explain the evolutionary advantages of non-laminar organization for neuroendocrine circuits coincidently using fast neurotransmitters and neuropeptides. These are then accrued into novel therapeutic principles that meet therapeutic criteria for human metabolic diseases. PMID- 30027600 TI - The impact of population dynamics on the population HIV care cascade: results from the ANRS 12249 Treatment as Prevention trial in rural KwaZulu-Natal (South Africa). AB - INTRODUCTION: The universal test and treat strategy (UTT) was developed to maximize the proportion of all HIV-positive individuals on antiretroviral treatment (ART) and virally suppressed, assuming that it will lead to a reduction in HIV incidence at the population level. The evolution over time of the cross sectional HIV care cascade is determined by individual longitudinal trajectories through the HIV care continuum and underlying population dynamics. The purpose of this paper is to quantify the contribution of each component of population change (in- and out-migration, HIV seroconversion, ageing into the cohort and definitive exit such as death) on the HIV care cascade in the context of the ANRS 12249 Treatment as Prevention (TasP) cluster-randomized trial, investigating UTT in rural KwaZulu-Natal, South Africa, between 2012 and 2016. METHODS: HIV test results and information on clinic visits, ART prescriptions, viral load and CD4 count, migration and deaths were used to calculate residency status, HIV status and HIV care status for each individual on a daily basis. Position within the HIV care continuum was considered as a score ranging from 0 (undiagnosed) to 4 (virally suppressed). We compared the cascade score of each individual joining or leaving the population of resident adults living with HIV with the average score of their cluster at the time of entry or exit. Then, we computed the contribution of each entry or exit on the average cascade score and their annualized total contribution, by component of change. RESULTS: While the average cascade score increased over time in all clusters, that increase was constrained by population dynamics. Permanent exits and ageing into the people living with HIV cohort had a marginal effect. Both in-migrants and out-migrants were less likely to be retained at each step of the HIV care continuum. However, their overall impact on the cross-sectional cascade was limited as the effect of in- and out-migration balanced each other. The contribution of HIV seroconversions was negative in all clusters. CONCLUSIONS: In a context of high HIV incidence, the continuous flow of newly infected individuals slows down the efforts to increase ART coverage and population viral suppression, ultimately attenuating any population-level impact on HIV incidence. CLINICAL TRIAL NUMBER: NCT01509508 (clinicalTrials.gov)/DOH-27 0512-3974 (South African National Clinical Trials Register). PMID- 30027601 TI - Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management. AB - OBJECTIVES: There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities. METHODS: Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children. RESULTS: Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients. CONCLUSION: The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases. PMID- 30027602 TI - Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. AB - The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes. PMID- 30027603 TI - One step for Legionella pneumophila detection in environmental samples by DNA gold nanoparticle probe. AB - AIMS: To develop and evaluate a DNA-gold nanoparticle (DNA-AuNP) probe assay to detect Legionella pneumophila, which causes Legionnaires' disease, compared with the gold standard culture method. METHODS AND RESULTS: Gold nanoparticles (AuNPs) were conjugated with DNA probes to detect the mip gene of L. pneumophila. The DNA AuNP probe assay was evaluated for its specificity, sensitivity and stability. The results showed that only L. pneumophila mixed with this probe resulted in a red solution that was easily detected by the naked eye, and the colour was stable when 10 mmol l-1 MgSO4 was added. The 100 Legionella isolates and 10 other bacteria led to 100% specificity. Compared with the culture method, our method showed a 100% negative predictive value, 100% sensitivity (kappa = 0.87), and a detection limit of 4.5 ng DNA MUl-1 with a 6-min response time for the 124 colonies suspected of being Legionella. The DNA-AuNP probe reagents were stable for more than 6 months. CONCLUSIONS: The developed DNA-AuNP probe assay has good negative predictive value, sensitivity, rapidity and ease of use, which is helpful for ruling out negative samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The DNA-AuNP probe assay can detect the mip gene of L. pneumophila. Therefore, it may be an alternative method for screening colonies suspected of being L. pneumophila. PMID- 30027604 TI - An evaluation of mental health service provision in Northern Ireland. AB - Although Northern Ireland has high levels of mental health problems, there has been a relative lack of systematic research on mental health services that can provide an evidence base for legal, policy, and service developments. This article aims to provide a review of the central issues relating to mental health service provision in Northern Ireland, and to gather the perceptions of different stakeholders of these services. The study utilised in-depth qualitative interviews, focus groups, and an online survey to collect data from respondents throughout the region. This method involved the completion of semistructured interviews with significant mental health commissioners and senior managers, and with service-users and their key workers. Focus groups sessions were also completed with mental health professionals, service-users, and carers. Data collection occurred between December 2014 and June 2015. Thematic analysis was used to identify key issues. The findings identified that considerable progress had been made not only in the development of mental health services in the last decade, but also highlighted the significant limitations in current services. Most notably, strengths in provision included the transition from long-stay hospital care to community-based services and person-centred approaches. The researchers identified the need to improve funding, address problems with fragmentation, and gaps in service provision. Based on these findings, the authors consider the implications for practice and policy relating to the human and organisational aspects of service development. In particular, services should be developed focusing on a recovery ethos and on person-centred and relationship based approaches. The needs of carers should additionally be considered and programmes developed to tackle stigma. PMID- 30027605 TI - The pharmacokinetics of ketamine following intramuscular injection to F344 rats. AB - Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well-characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography-mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non-compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co administration with the SOC following nerve agent exposure in animal models. PMID- 30027606 TI - Phytochemical Profiles of Alpine Plant Horminum pyrenaicum L. during Phenological Growth Stages. AB - Horminum pyrenaicum L. is a medicinal, aromatic and ornamental plant native to the Pyrenees and Alps. The phytochemical composition is affected by various ecological factors, climatic conditions and cultivating factors, and especially phenological growth stages. Flavonoids, phenolic acids and triterpenic acids were identified and quantified in the above-ground parts of H. pyrenaicum during the phenological stages. The massive flowering was distinguished with the greatest total amounts of phenolic compounds (22232.8 MUg/g), and rosmarinic acid was the predominant compound. The amounts of triterpenic compounds were at the lowest during the intense growth stage and significantly increased up to the massive flowering. The prevailing compounds were ursolic acid and betulinic acid, 12092.4 MUg/g and 2618.9 MUg/g, respectively. The major essential oil compounds were beta phellandrene (56.6%), caryophyllene oxide (5.9%), (Z)-caryophyllene (4.4%), myrcene (4.1%) and thymol (3.6%). Selecting the optimal harvesting time could ensure the herbal raw material rich with preferred bioactive compounds. PMID- 30027608 TI - Emergency Department Resource Use in Pediatric Pneumonia: Point-of-Care Lung Ultrasonography versus Chest Radiography. AB - OBJECTIVES: Point-of-care lung ultrasonography (US) is an alternative to chest radiography for imaging of suspected community-acquired pneumonia (CAP) in children. We compared pediatric emergency department (ED) time metrics between children who received point-of-care lung US versus chest radiography. Secondary objectives were comparisons of health system costs and other resources in these imaging groups. METHODS: This work was a retrospective matched cohort study of children aged 0 to 18 years in an academic urban pediatric ED who were imaged for suspected CAP with either point-of-care lung US or chest radiography. RESULTS: A total of 202 patients (101 in each group) were included in the study. The point of-care lung US group spent a mean of 75.9 (SE, 14.3) minutes less from physician assessment to discharge (P < .0001) and 60.9 (SE, 18.1) minutes less in the overall ED length of stay (P = .0008). Physician billings and facility fees were both significantly lower (P < .0001) in the point-of-care lung US group, for a mean health systems savings of CAN$187.1 (SE, CAN$21.9). CONCLUSIONS: In children undergoing imaging for suspected CAP in our pediatric ED, point-of-care lung US by pediatric emergency medicine physicians was associated with decreased time and cost compared with chest radiography. PMID- 30027609 TI - Long-term clinical outcomes of patients with hematologically unexplained cytopenia after routine assessment: A single center study. AB - OBJECTIVE: We investigated mortality and long-term development of malignant hematological disease, cancer, liver-, renal-, and rheumatic disease in patients with unexplained cytopenia (UC). METHODS: We screened all patients referred to the outpatient clinic at the Department of Hematology, Rigshospitalet, Copenhagen, with a suspected myeloid neoplasm from June 2009 to the end of 2012. Through registry linkage, we obtained information on hospital-based ICD-10 diagnoses and survival. We estimated cumulative incidences of disease and hazard ratios of all-cause mortality using the Aalen-Johansen estimator and Cox regression. We compared incidences and mortality with a control cohort. RESULTS: Among 1820 referrals, 221 had UC. The UC group had a 5-year cumulative incidence of malignant hematological disease of 8.91% (CI 95%: 4.98-12.84) compared to 0.93(CI 95%: 0.32-1.55) in the matched controls. In addition, UC patients had higher incidences of cancer, liver, and rheumatic disease. Mortality was higher in UC patients compared to the matched controls with a HR of 1.43 [P = 0.038, CI 95%: 1.02-2.00] adjusted for comorbidity, sex, and age. Most of the mortality and morbidity were ascribed to patients 50 years or older. CONCLUSIONS: Unexplained cytopenia patients had a higher incidence of malignant hematological-, cancer-, liver-, and rheumatic disease and increased mortality compared to the general population. PMID- 30027607 TI - Home-based exergaming among children with overweight and obesity: a randomized clinical trial. AB - BACKGROUND: Given children's low levels of physical activity and high prevalence of obesity, there is an urgent need to identify innovative physical activity options. OBJECTIVE: This study aims to test the effectiveness of exergaming (video gaming that involves physical activity) to reduce children's adiposity and improve cardiometabolic health. METHODS: This randomized controlled trial assigned 46 children with overweight/obesity to a 24-week exergaming or control condition. Intervention participants were provided a gaming console with exergames, a gameplay curriculum (1 h per session, three times a week) and video chat sessions with a fitness coach (telehealth coaching). Control participants were provided the exergames following final clinic visit. The primary outcome was body mass index (BMI) z-score. Secondary outcomes were fat mass by dual energy X ray absorptiometry and cardiometabolic health metrics. RESULTS: Half of the participants were girls, and 57% were African-American. Intervention adherence was 94.4%, and children's ratings of acceptability and enjoyment were high. The intervention group significantly reduced BMI z-score excluding one control outlier (intervention [standard error] vs. control [standard error]: -0.06 [0.03] vs. 0.03 [0.03], p = 0.016) with a marginal difference in intent-to-treat analysis (-0.06 [0.03] vs. 0.02 [0.03], p = 0.065). Compared with control, the intervention group improved systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein-cholesterol and moderate-to-vigorous physical activity (all p values <0.05). CONCLUSIONS: Exergaming at home elicited high adherence and improved children's BMI z-score, cardiometabolic health and physical activity levels. Exergaming with social support may be promoted as an exercise option for children. PMID- 30027610 TI - MRI Contrast Agents Based on Conjugated Polyelectrolytes and Dendritic Polymers. AB - Three complexes of gadolinium-based on dentritic molecules are reported as magnetic resonance imaging (MRI) contrast agents. Their ligands feature four carboxylate groups, which contribute to good water solubility and a strong combination with metal ions. As a new attempt, coupling polymerization is carried out to make a combination of conjugated polyelectrolytes and dendrimers for MRI contrast agents. For comparison, mononuclear and binuclear complexes are also reported. The investigation suggests that the contrast agent with the newly designed macromolecular skeleton provides higher longitudinal relaxivity value (36.2 mm -1 s-1 ) and more visible enhancement in in vivo and in vitro MR images than the small molecular ones. In addition, extremely low cytotoxicity and main clearance via hepatobiliary are confirmed, which reduces the deterioration of chronic kidney disease. All the results indicate that these three complexes are generally applicable as promising clinical contrast agents. PMID- 30027611 TI - Uterus transplantation as radical reproduction: Taking the adoption alternative more seriously. AB - This paper urges reconsideration of analyses of the alternatives to reproductive uterus transplantation (UTx). I focus here specifically on the adoption alternative. Importantly, my purpose is not to oppose UTx provision. Rather, it is to propose ways in which ethical analysis and provision of UTx can potentially accommodate the concerns discussed here. I argue that the adoption alternative to UTx is too readily dismissed, and that this is a dismissal with significant moral costs. I suggest that the radical nature of UTx as a form of assisted reproduction calls for an equivalently radical socio-moral agenda for reform and transformation of adoption law, policy and practice, as well as of the norms that prevail within our presently strongly bio-normative reproductive context. In doing so I widen the ethical frame of responsible provision of assisted reproduction to encompass not just obligations towards donors and recipient, but also our broader social responsibilities to ensure that we are doing our best to meet the significant needs of some of the most vulnerable members of our society. PMID- 30027612 TI - Antiaging efficacy of a retinaldehyde-based cream compared with glycolic acid peel sessions: A randomized controlled study. AB - BACKGROUND: Glycolic acid (GA) chemical peels are a popular treatment for photoaged skin rejuvenation, but retinaldehyde (RAL)-based cosmetic creams have also demonstrated efficacy in improving photoaging, and are potentially better tolerated than chemical peels. AIMS: To compare the efficacy and safety of an antiaging cream containing 0.1% RAL associated with Glycylglycine Oleamide (GGO, Relastide(r) ) and Pre-tocopheryl(r) , to GA peels sessions in the treatment of photoaging. PATIENTS AND METHODS: Fifty-five women with photoaging were randomized in 2 treatment groups: (1) Daily application of the antiaging cream for 8 weeks or (2) Three sequential GA peels (20%, 50%, and 70%), 2-3 weeks apart. Skin surface texture, length of wrinkles, complexion radiance, and evenness of pigmentation and texture were assessed by profilometry using skin replicas, computer image analysis, and self-assessment. RESULTS: Efficacy of both treatments was similar in reducing crow's feet wrinkles depth (STm -7.61%, P = .0007 vs -4.34%, P = .0348; P = .3049 intergroup) and volume, crow's feet and periorbital wrinkle length, and number of fine lines and wrinkles at end of treatments. The efficacy of the cream in refining skin texture was superior to the peels (contrast: -5.61%, P = .0025 vs +3.54, P = .08; P intergroup = .0252). The 8-week treatment with the antiaging cream was well tolerated; adverse events were fewer and of milder intensity than with the peels, (12-fold lower incidence of physical signs). CONCLUSION: A dermocosmetic cream containing 0.1% RAL, GGO (Relastide(r) ) and Pre-tocopheryl(r) is as effective as 3 sequential GA peels, better tolerated, and is an alternative in the management of photoaged skin. PMID- 30027613 TI - Synergistic action of GCN5 and CLAVATA1 in the regulation of gynoecium development in Arabidopsis thaliana. AB - In Arabidopsis thaliana the CLAVATA1 (CLV1) receptor and GENERAL CONTROL NON DEREPRESSIBLE 5 (GCN5) histone acetyltransferase both regulate inflorescence meristem size and affect the expression of the meristem-promoting transcription factor WUSCHEL (WUS). Single and multiple mutants of GCN5 and CLAVATA members, were analysed for their gynoecium development, using morphological, physiological, genetic and molecular approaches. The clv1-1gcn5-1 double mutants exhibited novel phenotypes including elongated gynoecia with reduced valves and enlarged stigma and style, indicating a synergistic action of CLAVATA signaling and GCN5 action in the development of the gynoecium. Reporter line and gene expression analysis showed that clv1-1gcn5-1 plants have altered auxin and cytokinin response, distribution and ectopic overexpression of WUS. WUS expression was found in the style of wild-type gynoecia stage 10-13, suggesting a possible novel role for WUS in the development of the style. CLV1 and GCN5 are regulators of apical-basal and mediolateral polarity of the Arabidopsis gynoecium. They affect gynoecium morphogenesis through the negative regulation of auxin biosynthesis and promotion of polar auxin transport. They also promote cytokinin signaling in the carpel margin meristem and negatively regulate it at the stigma. Finally, they synergistically suppress WUS at the centre of the gynoecium. PMID- 30027614 TI - Late-onset fever and engraftment syndrome following autologous stem cell transplant: Impact on resource utilization. PMID- 30027615 TI - Antibiotic prophylaxis in clean head and neck surgery: A prospective randomised controlled trial. AB - OBJECTIVE: Antibiotic prophylaxis is not indicated for clean head and neck surgery. However, its role in revision cases is not known. The objective was to prospectively test whether antibiotics are useful in this patient group. DESIGN: This was a prospective, double-blind, randomised, placebo-controlled study. SETTING: A single-centre study in a tertiary care centre. PARTICIPANTS: The patients were selected from a referred sample of adult patients (>18 years old) who were planned to undergo revision clean head and neck surgery and who had no preoperative indication for prophylactic antibiotics (eg previous radiation therapy, tracheostomy, active infection, immunosuppression). A total of 59 patients were approached for the study. After exclusion, 53 were available for final analysis. INTERVENTION: The intervention group received a single-dose cefazolin, while the control group received placebo. MAIN OUTCOMES: The primary end-point was the combined rate of surgical wound infection, bacteremia and sepsis. The secondary end-points were length of hospital stay and drug-induced adverse reactions. RESULTS: A total of 53 patients were randomised to 2 groups: 31 to antibiotics group and 22 to control group. There was no difference between the groups in baseline characteristics. The primary end-point occurred in both groups at the same rate. There was no difference in secondary end-point rate, as well. CONCLUSION: Prophylactic antibiotics appear to have no benefit in revision, clean head and neck surgery. Further studies in larger populations and other settings are needed. (ClinicalTrials.gov number NCT01980082, clinicaltrials.gov/ct2/show/NCT01980082). PMID- 30027616 TI - Six-Transmembrane Epithelial Antigen of the Prostate-1 (STEAP-1)-Targeted Ultrasound Imaging Microbubble Improves Detection of Prostate Cancer In Vivo. AB - PURPOSE: To investigate the feasibility of the 6-transmembrane epithelial antigen of the prostate-1 (STEAP-1)-targeted microbubbles for enhancing ultrasound imaging of prostate tumors in the nude mouse xenograft models. METHODS: Contrast agents were established by conjugating biotinylated STEAP-1 monoclonal antibodies with streptavidin coated SonoVue microbubbles. Then, ordinary SonoVue (Bracco, Milan, Italy) microbubble and STEAP-1-targeted SonoVue microbubble were used, respectively, for contrast-enhanced sonography to detect prostate tumors in the nude mouse xenograft models. The characteristics, including peak intensity, time to peak, area under the curve, and mean transit time, were measured. RESULTS: The biological characteristics of STEAP-1-targeted SonoVue microbubbles were stable. STEAP-1-targeted SonoVue microbubbles can successfully conjugate to prostate cancer cell lines in vitro. Enhancement of ultrasound signal intensity was determined after injection of STEAP-1-targeted SonoVue microbubble, compared with ordinary SonoVue microbubble. Higher intensities of ultrasound signals in xenograft tumor of prostate cancer were associated with increased levels of STEAP 1 expression. CONCLUSION: Our results suggest that SonoVue microbubble carrying STEAP-1 monoclonal antibody could improve the ultrasound visualization of prostate cancer and identify the tumor more effectively in vivo. A prospective study is required to validate our finding in patients with prostate cancer. PMID- 30027618 TI - The role of social enterprise in food insecurity among asylum seekers. AB - People seeking asylum in high-income countries are vulnerable to food insecurity due to limited opportunities for social and economic participation. Given this vulnerability, nongovernment organisations are attempting to improve food security outcomes through targeted programmes. This study explored the role of a subsidised mobile fresh fruit and vegetable market (the Food Justice Truck-FJT) on the experience of food insecurity for people seeking asylum living in Melbourne, Australia. This research uses a mixed methods approach, employing surveys and semistructured interviews to explore the lived experiences of asylum seekers using the FJT, including their experiences of food insecurity. Half of the asylum seekers interviewed in this study were found to be experiencing food insecurity. Participants in this study sourced food from multiple locations, with the FJT providing a supplemental, but highly valued source of fresh produce. The FJT was identified as positive social setting for some participants included in this research. This research has identified the ability of programmes such as the FJT to act as positive social settings. PMID- 30027619 TI - Equations for the Right-to-Left Ventricular Ratio and Right and Left Ventricular Widths Do Not Match the Corresponding Tables. PMID- 30027617 TI - Genetic and clinical characterization of B7-H3 (CD276) expression and epigenetic regulation in diffuse brain glioma. AB - Gliomas are the most common malignant tumors of the brain. Immune checkpoints have been increasingly emphasized as targets for treating malignant tumors. B7-H3 has been identified as an immune checkpoint that shows potential value for targeting therapies. We set out to characterize the expression pattern and biological function of B7-H3 in brain gliomas using high-throughput data obtained from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) projects. B7-H3 was upregulated more in higher-grade gliomas than that in lower grade gliomas in both CGGA and TCGA datasets. Isocitrate dehydrogenase (IDH) mutation seemed to exert significant influence on B7-H3 expression in gliomas but led to quite different results between grade II gliomas and higher-grade gliomas. In addition to IDH, methylation of B7-H3 promoter and microRNA-29 family also showed a potential regulatory effect on B7-H3 expression. Gene ontology analysis revealed that B7-H3 was associated with mitotic cell cycle, cell proliferation and immune response. Further investigation suggested that B7-H3 was mostly involved in the Toll-like receptor signaling pathway. Survival analysis indicated that B7-H3 was an independent unfavorable prognosticator for glioma patients in both CGGA and TCGA datasets. B7-H3 expression is regulated by multiple mechanisms and is potentially involved in the T-cell receptor signaling pathway. Higher B7 H3 expression indicates a worse prognosis for glioma patients, which warrants further research into the development of inhibitors for targeting this immune checkpoint, but we still need to be cautious about immune checkpoint inhibition for central nervous system tumors. PMID- 30027620 TI - Vital signs: Valid indicators to assess pain in intensive care unit patients? An observational, descriptive study. AB - Pain is a stressor for intensive care unit (ICU) patients, and inadequate pain assessment has been linked to increased morbidity and mortality. One hundred and twenty patients were evaluated during three periods: (T1) 1 min before, (T2) during, and (T3) 20 min after the nociceptive procedure. For each patient, data were obtained through at least two nociceptive procedures. Conscious patients' self-reports of pain were assessed using the Numerical Rating Scale and Visual Analog Scale. For unconscious patients, the Behavioral Pain Scale was used instead. Descriptive statistical methods, Friedman's test, and Spearman's rank correlation coefficient were used for the data analysis. Significant changes were observed in heart rate (HR), respiratory rate (RR), and peripheral oxygen saturation (SpO2 ) during nociceptive procedures. The HR, RR, and pain scores increased, while the SpO2 decreased. Positive correlation coefficients were observed between the pain intensity and HR and RR levels. According to our study findings, vital signs are not strong indicators for pain assessment in neurosurgery ICU patients. However, HR and RR can be used as cues when behavioral indicators are not valid in these unconscious patients. PMID- 30027621 TI - Moving forward: why responding to migration, mobility and HIV in South(ern) Africa is a public health priority. AB - INTRODUCTION: Global migration policy discussions are increasingly driven by moral panics - public anxiety about issues thought to threaten the moral standards of society. This includes the development of two Global Compacts - agreed principles to guide an international response - for (1) "Refugees" and (2) "Safe, Regular and Orderly Migration." While the need to address migration and health is increasingly recognized at the global level, concerns are raised about if this will be reflected in the final Compacts. The Compacts focus on securitization, an approach that aims to restrict the movement of people, presenting potentially negative health consequences for people who move. Globally, concern is raised that migration-aware public health programming initiatives could be co-opted through a global health security agenda to further restrict movement across borders. This is particularly worrying in the Southern African Development Community (SADC) - a regional economic community associated with high levels of migration and the largest population of people living with HIV globally; this case is used to explore concerns about the health implications of the Global Compacts. DISCUSSION: Current HIV responses in SADC do not adequately engage with the movement of healthcare users within and between countries. This negatively affects existing HIV interventions and has implications for the development of universal HIV testing and treatment (UTT) programmes. Drawing on literature and policy review, and ongoing participant observation in policy processes, I outline how Global Compact processes may undermine HIV prevention efforts in SADC. CONCLUSIONS: The global health imperative of developing migration-aware and mobility-competent health responses must not be undermined by moral panics; the resultant international policy processes run the risk of jeopardizing effective action at the local level. Globally, migration is increasingly recognized as a central public health concern, providing strategic opportunities to strengthen public health responses for all. Without mainstreaming migration, however, health responses will struggle. This is particularly concerning in SADC where HIV programmes - including UTT initiatives - will struggle, and key health targets will not be met. Globally, contextually appropriate migration-aware responses to health are needed, including and a specific focus on HIV programming in SADC. PMID- 30027622 TI - Substrate Patterning Using Regular Macroporous Block Copolymer Monoliths as Sacrificial Templates and as Capillary Microstamps. AB - Polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) monoliths containing regular arrays of macropores (diameter ~1.1 um, depth ~0.7 um) at their surfaces are used to pattern substrates by patterning modes going beyond the functionality of classical solid elastomer stamps. In a first exemplary application, the macroporous PS-b-P2VP monoliths are employed as sacrificial templates for the deposition of NaCl nanocrystals and topographically patterned iridium films. One NaCl nanocrystal per macropore is formed by evaporation of NaCl solutions filling the macropores followed by iridium coating. Thermal PS-b-P2VP decomposition yields topographically patterned iridium films consisting of ordered arrays of hexagonal cells, each of which contains one NaCl nanocrystal. For the second exemplary application, spongy-continuous mesopore systems are generated in the macroporous PS-b-P2VP monoliths by selective-swelling induced pore generation. Infiltrating the spongy-continuous mesopore systems with ink allows capillary microstamping of continuous ink films with holes at the positions of the macropores onto glass slides compatible with advanced light microscopy. Capillary microstamping can be performed multiple times under ambient conditions without reinking and without quality deterioration of the stamped patterns. The macroporous PS-b-P2VP monoliths are prepared by double replication of primary macroporous silicon molds via secondary polydimethylsiloxane molds. PMID- 30027623 TI - In Situ Polymerization Approach to Graphene-Oxide-Reinforced Silicone Composites for Superior Anticorrosive Coating. AB - Novel graphene-oxide-reinforced silicone composites (GO?SC) are prepared by in situ polymerization of silanes and low concentrations (<0.15 wt%) of silylated GO (S?GO). After modification, the distances of the S?GO nanosheets are successfully increased from 0.72 to 0.87 nm. Compared with GO, the S?GO shows better dispersibility in organic solvents as well as remarkably enhanced decomposition temperature (T d improved by 100 degrees C). After covalently grafting onto silicone resins via in situ polymerization, the obtained GO?SC exhibits greatly enhanced thermal stability (T d up to 400 degrees C and T g improved by 3-5 degrees C), increased storage modulus, loss modulus, and complex viscosity. The morphology, microstructure, interfacial adhesion of the developed GO?SC coatings were carefully investigated. The GO?SC coatings on metal exhibit good transparency (up to 90%), hydrophobicity, and excellent anticorrosion capability. This work provides a new strategy for developing high performance graphene-based silicone composite materials. PMID- 30027624 TI - Chromatolysis: Do injured axons regenerate poorly when ribonucleases attack rough endoplasmic reticulum, ribosomes and RNA? AB - After axonal injury, chromatolysis (fragmentation of Nissl substance) can occur in the soma. Electron microscopy shows that chromatolysis involves fission of the rough endoplasmic reticulum. In CNS neurons (which do not regenerate axons back to their original targets) or in motor neurons or dorsal root ganglion neurons denied axon regeneration (e.g., by transection and ligation), chromatolysis is often accompanied by degranulation (loss of ribosomes from rough endoplasmic reticulum), disaggregation of polyribosomes and degradation of monoribosomes into dust-like particles. Ribosomes and rough endoplasmic reticulum may also be degraded in autophagic vacuoles by ribophagy and reticulophagy, respectively. In other words, chromatolysis is disruption of parts of the protein synthesis infrastructure. Whereas some neurons may show transient or no chromatolysis, severely injured neurons can remain chromatolytic and never again synthesize normal levels of protein; some may atrophy or die. Ribonuclease(s) might cause the following features of chromatolysis: fragmentation and degranulation of rough endoplasmic reticulum, disaggregation of polyribosomes and degradation of monoribosomes. For example, ribonucleases in the EndoU/PP11 family can modify rough endoplasmic reticulum; many ribonucleases can degrade mRNA causing polyribosomes to unchain and disperse, and they can disassemble monoribosomes; Ribonuclease 5 can control rRNA synthesis and degrade tRNA; Ribonuclease T2 can degrade ribosomes, endoplasmic reticulum and RNA within autophagic vacuoles; and Ribonuclease IRE1alpha acts as a stress sensor within the endoplasmic reticulum. Regeneration might be improved after axonal injury by protecting the protein synthesis machinery from catabolism; targeting ribonucleases using inhibitors can enhance neurite outgrowth and could be a profitable strategy in vivo. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018. PMID- 30027625 TI - Secondary amplification of siRNA machinery limits the application of spray induced gene silencing. AB - Spray-induced gene silencing (SIGS) is an innovative strategy for crop protection. However, the mechanism of SIGS is not known. Here, we first demonstrate that secondary small interfering RNA (siRNA) amplification limits the application of SIGS. A myosin5 gene (Myo5) was chosen as the target of SIGS in an agronomically important pathogen-Fusarium asiaticum. Five segments corresponding to the different regions of the Myo5 gene were found to efficiently silence Myo5, resulting in cell wall defects, life cycle disruption and virulence reduction. Myo5-8 (one of the Myo5 segments) induced sequence-specific RNA interference (RNAi) activity in F. asiaticum, F. graminearum, F. tricinctum and F. oxysporum, but not in other fungi, in vitro. Remarkably, the silencing of Myo5 lasted for only 9 h unless the double-stranded RNA (dsRNA) was continuously supplied, because F. asiaticum is unable to maintain siRNA amplification. After spraying on plants, dsRNAs were more efficiently taken up via the wounded surface. The antifungal activity of dsRNAs taken up by plant cells was higher and longer lasting than that dried onto the plant surface. In contrast with dsRNAs in fungi, dsRNAs in plant cells could efficiently turn into substantial siRNAs via secondary amplification machinery. Our findings provide new implications to develop SIGS as a mainstream disease control strategy against Fusarium and other fungi. PMID- 30027626 TI - Evaluation of Intratesticular Lesions With Strain Elastography Using Strain Ratio and Color Map Visual Grading: Differentiation of Neoplastic and Nonneoplastic Lesions. AB - OBJECTIVE: To investigate the role of strain elastography using calculated strain ratio and visual elastography score in differentiating nonneoplastic, benign, and malignant neoplastic intratesticular lesions. MATERIALS AND METHODS: The study was approved by the hospital review board as a retrospective review of 86 patients examined with gray scale, color Doppler ultrasonography and strain elastography (visual elastography score and strain ratio). Sensitivity, specificity, and positive and negative likelihood ratio of color Doppler and stain elastography were documented. Receiver operator characteristic curves assessed the diagnostic accuracy of strain elastography to discriminate nonneoplastic, benign, and malignant neoplasms. Histology or follow-up ultrasonography determined lesion character. RESULTS: Thirty-one of 86 (36.0%) intratesticular malignant neoplasms, 17 of 86 (19.8%) benign neoplasms, and 38 of 86 (44.2%) nonneoplastic lesions were confirmed with histology (n = 52) or follow up sonography (n = 34); 89.5% of intratesticular lesions were heterogeneous or hypoechoic on gray scale, with no difference between benign and malignant. Sensitivity, specificity, positive and negative likelihood ratio for nonneoplasm versus neoplasm were documented: color Doppler: 68.8%, 97.4%, 26.5, 0.32; visual elastography score: 81.3%, 57.9%, 1.93, 0.32; strain ratio: 68.8%, 81.6%, 3.73, 0.38. Neoplastic lesions showed a higher strain ratio than nonneoplastic lesions (P < .001), with strong correlation between median strain ratio and visual elastography score (Spearman's coefficient, 0.693; P < .001). Strain ratio is a significantly better assessment than visual elastography score for malignant lesions (P = .025). Logistic regression analysis revealed significant associations between size (P = .001), hypervascularity (P < .001), and malignancy. CONCLUSION: Higher strain ratio and visual elastography score are associated with neoplastic lesions and offer an alternative to assess tissue characteristics but do not improve the diagnostic accuracy when compared with the color Doppler pattern. PMID- 30027627 TI - Topography of Vertebral Artery Origin Plaques: Characteristics and Determinants. AB - BACKGROUND: Atherosclerotic plaques located at the vertebral artery ostium (VAo) are a mechanism for posterior circulation stroke, but little is known about VAo plaque topography and formation. In this study, we describe the topography of atherosclerotic plaques involving the origin of the vertebral artery (VA). METHODS: Cross-sectional analyses of extracranial duplex studies were performed, and VAo plaques were classified based on their topography in 3 groups: (1) exclusively at the VA ostium; (2) predominantly subclavian, with extension into the vertebral ostium; and (3) predominantly ostial, with extension into the subclavian artery). Chi-square and analysis of variance tests were performed to investigate the association between VAo plaque topography and continuous and categorical variables, respectively. RESULTS: A total of 99 of 481 (21%) ultrasound duplex studies showed VAo plaques. The majority of the plaques (60%) were found to extend from the subclavian to the ostium. Plaques occurred more frequently at the medial wall of the VAo. No vascular risk factors were associated with plaque formation; however, women were more likely to have plaques involving predominantly or exclusively the VAo (P = .004). CONCLUSIONS: We describe 3 different patterns of VAo involvement in patients with ostial atherosclerotic VA disease. VAo plaques occurred almost exclusively at the medial wall of the vessel. Women had more plaques involving predominantly the origin. Prospective studies are needed to investigate the clinical significance of these findings. PMID- 30027628 TI - Efficacy of fibre-optic laryngeal potassium titanyl phosphate laser surgery under local anaesthesia for the treatment of vocal polyps: A prospective study of 65 patients. PMID- 30027630 TI - Automated quantitative analysis of multiple cardiomyocytes at the single-cell level with three-dimensional holographic imaging informatics. AB - Cardiomyocytes derived from human pluripotent stem cells are a promising tool for disease modeling, drug compound testing, and cardiac toxicity screening. Bio image segmentation is a prerequisite step in cardiomyocyte image analysis by digital holography (DH) in microscopic configuration and has provided satisfactory results. In this study, we quantified multiple cardiac cells from segmented 3-dimensional DH images at the single-cell level and measured multiple parameters describing the beating profile of each individual cell. The beating profile is extracted by monitoring dry-mass distribution during the mechanical contraction-relaxation activity caused by cardiac action potential. We present a robust two-step segmentation method for cardiomyocyte low-contrast image segmentation based on region and edge information. The segmented single-cell contains mostly the nucleus of the cell since it is the best part of the cardiac cell, which can be perfectly segmented. Clustering accuracy was assessed by a silhouette index evaluation for k-means clustering and the Dice similarity coefficient (DSC) of the final segmented image. 3D representation of single of cardiomyocytes. The cell contains mostly the nucleus section and a small area of cytoplasm. PMID- 30027631 TI - Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. AB - BACKGROUND: This is the first update of the review published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. OBJECTIVES: To determine if 'lower' blood pressure targets (<= 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (<= 140 to 160/90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2018: Cochrane Hypertension Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982), along with the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. We applied no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that included more than 50 participants per group and provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (<= 135/85 mmHg) compared with standard targets for blood pressure (<= 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and extracted data using standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six RCTs that involved a total of 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data.We found no change in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; moderate-quality evidence). Similarly, we found no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; low-quality evidence). Studies reported more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low quality evidence). Blood pressures were lower in the lower target group by 8.9/4.5 mmHg. More drugs were needed in the lower target group, but blood pressure targets were achieved more frequently in the standard target group. AUTHORS' CONCLUSIONS: We found no evidence of a difference in total mortality, serious adverse events, or total cardiovascular events between people with hypertension and cardiovascular disease treated to a lower or to a standard blood pressure target. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on adverse events, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (<= 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to examine this topic. PMID- 30027633 TI - An updated weight of evidence approach for deriving a health-based guidance value for 4-nonylphenol. AB - 4-Nonylphenol (NP) is a persistent estrogen-active compound. Human exposure to NP is primarily through water and food. Although risk assessments of NP have been conducted by the European Union and a few other countries, only the Danish Veterinary and Food Administration, in 2000, proposed a tolerable daily intake of 0.005 mg kg-1 body weight (bw) day-1 . New data have been accumulated since then, prompting an update on the risk assessment of NP. A weight of evidence approach is recommended for use in scientific assessments by several agencies, e.g., European Food Safety Authority, etc. Based on the results of a weight of evidence approach, two methods were used to derive the health-based guidance value (HBGV) for NP in this study, namely a no observed adverse effects level/lowest observable adverse effect level method, and a benchmark dose method. Considering the considerable uncertainty of benchmark dose model fitting of the available data, a tolerable daily intake value of 0.025 mg kg-1 bw day-1 was derived as a provisional HBGV for NP based on the lowest observable adverse effect level value of 15 mg kg-1 bw day-1 of the renal toxicity in rats, together with the uncertainty factor of 600. However, the HBGV of NP still needs further investigation. PMID- 30027632 TI - "The people make it fun, the activities we do just make sure we turn up on time." Factors influencing older adults' participation in community-based group programmes in Perth, Western Australia. AB - Rapid ageing in western societies is placing increasing strain on health and social care services. In response, governments and health agencies have sought to promote healthy ageing through a range of interventions, many of which aim to enhance social engagement and participation among older people. Such interventions are based on evidence that being socially engaged through participation in various activities leads to better physical, mental and psychosocial health outcomes. The research reported here employed focus groups and individual interviews to address research aims: (a) identify enablers and barriers to participation in community-based group activities among a sample of older people (n = 35, median age 71 years) living in a local government area in the northern suburbs of Perth, Western Australia, and (b) examine how these factors differ between those who regularly participate and those who do not. Our research highlighted four themes: Friendship and Function; Availability and Accessibility; Competing Responsibilities and Priorities; and Changing of the Guard. In particular, this research highlighted the importance of group activities in offering social support as a platform to develop friendships. The findings also indicated that opportunities for social interaction should be embedded in the structure of the group, beyond that which may occur incidentally during activities. This is important, given that while interest may motivate older people to join a group, a sense of belonging and connectedness generated through the group is more likely to maintain their attendance. Barriers included limited availability of local programmes, limited accessibility related to programme scheduling, and lack of programmes relevant to those who do not find traditional seniors' centres appealing. Recommendations include incorporating social engagement as an outcome measure when evaluating the efficacy of programmes targeting older people, and encouraging local governments to work with seniors' centres in developing activities attractive to a broader cohort of older people. PMID- 30027634 TI - Changing practice using recovery-focused care in acute mental health settings to reduce aggression: A qualitative study. AB - Consumer aggression is common in acute mental health settings and can result in direct or vicarious psychological or physical impacts for both consumers and health professionals. Using recovery-focused care, nurses can implement a range of strategies to reduce aggression and empower consumers to self-regulate their behaviour, when faced with challenging situations, such as admission to the acute care setting. Currently, there is limited literature to direct nurses in the use of recovery-focused care and how it can be used to reduce consumer aggression. Twenty-seven mental health nurses participated in this study. The constructivist grounded theory method guided data collection and analysis to identify categories that accurately described participants' experiences. Five categories emerged that described how nurses can implement recovery-focused care clinically to reduce the risk of consumer aggression: (i) identify the reason for the behaviour before responding; (ii) being sensitive to the consumer's trigger for aggression; (iii) focus on the consumer's strengths and support, not risks; (iv) being attentive to the consumer's needs; and (v) reconceptualize aggression as a learning opportunity. As the importance of promoting consumer recovery is now embedded in mental health policies internationally, nurses need to prioritize the application of recovery-focused care clinically. Further research to provide evidence-based outcomes supporting the use of recovery-focused care is needed. PMID- 30027629 TI - Toward sustainable environmental quality: Priority research questions for Europe. AB - The United Nations' Sustainable Development Goals have been established to end poverty, protect the planet, and ensure prosperity for all. Delivery of the Sustainable Development Goals will require a healthy and productive environment. An understanding of the impacts of chemicals which can negatively impact environmental health is therefore essential to the delivery of the Sustainable Development Goals. However, current research on and regulation of chemicals in the environment tend to take a simplistic view and do not account for the complexity of the real world, which inhibits the way we manage chemicals. There is therefore an urgent need for a step change in the way we study and communicate the impacts and control of chemicals in the natural environment. To do this requires the major research questions to be identified so that resources are focused on questions that really matter. We present the findings of a horizon scanning exercise to identify research priorities of the European environmental science community around chemicals in the environment. Using the key questions approach, we identified 22 questions of priority. These questions covered overarching questions about which chemicals we should be most concerned about and where, impacts of global megatrends, protection goals, and sustainability of chemicals; the development and parameterization of assessment and management frameworks; and mechanisms to maximize the impact of the research. The research questions identified provide a first-step in the path forward for the research, regulatory, and business communities to better assess and manage chemicals in the natural environment. Environ Toxicol Chem 2018;37:2281-2295. (c) 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 30027635 TI - Red Phosphorus Nanoparticle@3D Interconnected Carbon Nanosheet Framework Composite for Potassium-Ion Battery Anodes. AB - Red phosphorus (P) has been recognized as a promising storage material for Li and Na. However, it has not been reported for K storage and the reaction mechanism remains unknown. Herein, a novel nanocomposite anode material is designed and synthesized by anchoring red P nanoparticles on a 3D carbon nanosheet framework for K-ion batteries (KIBs). The red P@CN composite demonstrates a superior electrochemical performance with a high reversible capacity of 655 mA h g-1 at 100 mA g-1 and a good rate capability remaining 323.7 mA h g-1 at 2000 mA g-1 , which outperform reported anode materials for KIBs. The transmission electron microscopy and theoretical calculation results suggest a one-electron reaction mechanism ofP + K+ + e- -> KP, corresponding to a theoretical capacity of 843 mA h g-1 ,which is the highest value for anode materials investigated for KIBs. The study not only sheds light on the rational design of high performance red P anodes for KIBs but also offers a fundamental understanding of the potassium storage mechanism of red P. PMID- 30027636 TI - Postnatal Development of the Posterior Hypothalamic Theta Rhythm and Local Cell Discharges in Rat Brain Slices. AB - Theta rhythms have been recorded from rat brain slices of the posterior hypothalamic area (PHa), including the supramammillary and posterior hypothalamic nuclei. Additionally, in numerous studies theta-related neurons were identified in the PHa according to the classification of Bland and Colom (Progress in Neurobiology, 41, 157-208, 1993). It is currently widely accepted that the PHa contributes to the process of HPC theta frequency programming at least in certain behavioral states. The postnatal development of the HPC and its ability to generate theta has also been a subject of studies. Specifically, it was found that theta oscillations are present in the HPC of 8-10 days old rat pups and turn into a well-synchronized and high-amplitude activity in the following few days. In our current study, we therefore focused on the postnatal development of cholinergically-induced theta rhythm and theta-related neuronal activity in PHa slices obtained from 8 to 24 days old rat pups. Theta activity was observed in the PHa preparations at the age of 8-10 days and then progressively increased its probability of occurrence, amplitude and synchrony up to the age of 22-24 days when it reached a plateau phase. A steady increase in the number of recorded neurons correlated with local theta oscillations was also observed. PMID- 30027637 TI - High field magnetic resonance imaging contributes to diagnosis of equine distal tarsus and proximal metatarsus lesions: 103 horses. AB - Injury of the distal tarsus and proximal metatarsus commonly causes lameness. Magnetic resonance imaging (MRI) allows concurrent assessment of both the distal tarsal joints and suspensory ligament origin, and aids identification of lesions that may otherwise go undetected by other modalities. In this retrospective observational study, the medical records of a veterinary imaging center were searched for MRI exams of the distal tarsus and proximal metatarsus for the years 2012 through 2014. Studies for 125 limbs of 103 horses were identified and retrospectively evaluated by two board-certified veterinary radiologists. Soft tissue and osseous changes were characterized and graded by degree of severity. The patients' signalment, lameness severity, and results of diagnostic analgesia were recorded. Osteoarthritic changes of the distal intertarsal and tarsometatarsal joints were the most common findings. Other findings included bone marrow lesions, degenerative changes of the small cuboidal bones, subchondral cystic lesions, and intertarsal desmopathy. Suspensory ligament desmopathy was found in 53% of limbs. Fourty-seven percent of limbs that responded to analgesia of the proximal suspensory ligament had more severe lesions in the distal tarsus. Bone marrow lesions of the third tarsal bone were the only MRI finding that correlated with grade of lameness in patients for which lameness grade was reported. The grade of lameness has a poor correlation with the severity of lesions found on MRI. The findings support the use of MRI for simultaneous evaluation of the proximal metatarsus and distal tarsus, particularly given the difficulty of lesion localization with diagnostic analgesia. PMID- 30027638 TI - A comment on "Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing". PMID- 30027639 TI - Diagnostic Value of Transthoracic Echocardiography Combined With Contrast Enhanced Ultrasonography in Mediastinal Masses. AB - OBJECTIVES: Multiple types of mediastinal masses, especially masses in the anterior mediastinum, may be encountered in routine echocardiographic examinations for symptomatic or asymptomatic patients. The aim of this study was to evaluate the diagnostic value of transthoracic echocardiography combined with contrast-enhanced ultrasonography in determining the location, composition, and vascularization of mediastinal masses. METHODS: A retrospective analysis was conducted on 48 consecutive patients who first had a diagnosis of mediastinal masses by echocardiography. The location of the mass, tissue components, and relationships with the heart and great vessels were analyzed on the basis of multiple transthoracic echocardiographic views. Further contrast-enhanced ultrasonography was performed to determine the vascularization of masses in 25 patients. The clinical, computed tomographic, and histopathologic findings were all recorded and analyzed. RESULTS: The localization, ultrasonographic characteristics of the mass, degree of vascularization, and relationships with the heart and great vessels assessed on echocardiography allowed a correct diagnosis in most of the cases. CONCLUSIONS: Transthoracic echocardiography is a useful method for diagnosing mediastinal. Further contrast-enhanced ultrasonography could provide more details on the degree of vascularization, which could facilitate accurate diagnosis and differentiation diagnosis. PMID- 30027640 TI - Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review. AB - Organophosphorus compounds (OPCs), inhibitors of acetylcholinesterase (AChE), are useful agents as pesticides, but also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. Better therapeutic results are obtained, when reversible AChE inhibitors are administered before OPC exposure. This review summarizes the history of such a pretreatment approach and sums up a set of experiments undertaken in search of compounds that are efficacious when given before a broad range of OPCs. The prophylactic efficacy of 10 known AChE inhibitors, either already used clinically for different indications (physostigmine, pyridostigmine, ranitidine, tiapride, tacrine, amiloride, metoclopramide, methylene blue) or developed for possible therapeutic use in the future (7-methoxytacrine, K-27) was compared, when administered before exposure to six chemically diverse OPCs in the same experimental setting: ethyl-paraoxon, methyl-paraoxon, diisopropylfluorophosphate, terbufos sulfone, azinphos-methyl and dicrotophos. The experimental oxime K-27 was the most efficacious compound, affording best protection, when administered before terbufos sulfone, azinphos methyl and dicrotophos, second best before ethyl- and methyl-paraoxon exposure and third best before diisopropylfluorophosphate administration. This ranking was similar to that of physostigmine, which was superior to the Food and Drug Administration-approved pretreatment for soman with pyridostigmine. Tiapride, amiloride, metoclopramide, methylene blue and 7-methoxytacrine did not achieve protection. No correlation was observed between the IC50 of the reversible AChE inhibitors and their protective efficacy. These studies indicate that K-27 can be considered a very promising broad-spectrum prophylactic agent in case of imminent organophosphate exposure, which may be related to its AChE reactivating activity rather than its AChE inhibition. PMID- 30027641 TI - Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice. AB - OBJECTIVE: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE(r) OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice. METHOD: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. RESULTS: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (>=partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months' median follow up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. CONCLUSION: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population. PMID- 30027642 TI - Distribution of alpha-neoendorphin, ACTH (18-39) and beta-endorphin (1-27) in the alpaca brainstem. AB - Using an immunocytochemical technique, we have studied in the alpaca brainstem the distribution of immunoreactive structures containing prodynorphin (alpha neoendorphin)- and pro-opiomelanocortin (adrenocorticotrophin hormone (18-39) (ACTH), beta-endorphin (1-27))-derived peptides. No peptidergic-immunoreactive cell body was observed. Immunoreactive fibres were widely distributed, although in most of the brainstem nuclei the density of the peptidergic fibres was low or very low. In general, the distribution of the immunoreactive fibres containing the peptides studied was very similar. A close anatomical relationship occurred among the fibres containing alpha-neoendorphin, ACTH or beta-endorphin (1-27), suggesting a functional interaction among the three peptides in many of the brainstem nuclei. The number of fibres belonging to the prodynorphin system was higher than that of the pro-opiomelanocortin system. A moderate/low density of immunoreactive fibres was observed in 65.11% (for alpha-neoendorphin (1-27)), 18.18% (for ACTH) and 13.95% (for beta-endorphin) of the brainstem nuclei/tracts. In the alpaca brainstem, a high density of immunoreactive fibres was not observed. The neuroanatomical distribution of the immunoreactive fibres suggests that the peptides studied are involved in auditory, motor, gastric, feeding, vigilance, stress, respiratory and cardiovascular mechanisms, taste response, sleep-waking cycle and the control of pain transmission. PMID- 30027644 TI - Controlling the Hierarchical Assembly of pi-Conjugated Oligoelectrolytes. AB - Here, a means of controlling the assembly pathways of p-conjugated oligoelectrolytes into supramolecular fibers and microtubes is presented, and it is shown how the addition of small end-caps to well-defined and pH-responsive conjugated oligomers can alter the balance between repulsive and attractive supramolecular forces and enables control of the morphology of the hierarchical assembly process. The assembly stages from nuclei to protofibers are evidenced and a hypothesis on the mechanism of microtubes formation using a combination of analytical methods is provided, revealing different degrees of order at different scales along the structural hierarchy. PMID- 30027643 TI - Spinning plates: livelihood mobility, household responsibility and anti retroviral treatment in an urban Zambian community during the HPTN 071 (PopART) study. AB - INTRODUCTION: Qualitative data are lacking on the impact of mobility among people living with HIV (PLHIV) and their decision-making around anti-retroviral treatment (ART). We describe challenges of juggling household responsibility, livelihood mobility and HIV management for six PLHIV in urban Zambia. METHODS: Six PLHIV (three men and three women, aged 21 to 44) were recruited from different geographic zones in one urban community drawn from a qualitative cohort in a social science component of a cluster-randomized trial (HPTN071 PopART). Participants were on ART (n = 2), not on ART (n = 2) and had started and stopped ART (n = 2). At least two in-depth interviews and participant observations, and three drop-in household visits with each were carried out between February and August 2017. Themed and comparative analysis was conducted. RESULTS: The six participants relied on the informal economy to meet basic household needs. Routine livelihood mobility, either within the community and to a nearby town centre, or further afield for longer periods of time, was essential to get by. Although aware of ART benefits, only one of the six participants managed to successfully access and sustain treatment. The other five struggled to find time to access ART alongside other priorities, routine mobility and when daily routines were more chaotic. Difficulty in accessing ART was exacerbated by local health facility factors (congestion, a culture of reprimanding PLHIV who miss appointments, sporadic rationed drug supply), stigma and more limited social capital. CONCLUSIONS: Using a time-space framework illustrated how household responsibility, livelihood mobility and HIV management every day were like spinning plates, each liable to topple and demanding constant attention. If universal lifelong ART is to be delivered, the current service model needs to adjust the limited time that some PLHIV have to access ART because of household responsibilities and the need to earn a living moving around, often away from home. Practical strategies that could facilitate ART access in the context of livelihood mobility include challenging the practice of reprimand, improving drug supply, having ART services more widely distributed, mapped and available at night and weekends, and an effective centralized client health information system. PMID- 30027645 TI - Oriented Overgrowths of Poly(l-Lactide) on Oriented Isotactic Polypropylene: A Sequence of Soft and Hard Epitaxies. AB - The crystallization behavior of an amorphous poly(l-lactide) (PLLA) layer deposited on uniaxially oriented isotactic polypropylene (iPP) substrate is been studied by atomic force microscopy (AFM) and electron microscopy combined with electron diffraction. A patterned PLLA structure with two fixed lamella and chain orientations is observed. Electron diffraction demonstrates that the major lamellar set is oriented with molecular chains perpendicular to the chain direction of the iPP. The minor lamellar set is inclined at ~64 degrees to both the iPP chain axis direction and the lamellae of the major set as judged from both the bright field electron micrograph and the AFM image. The orientation of the main set is explained in terms of "soft" epitaxy or graphoepitaxy, in which PLLA chains oriented parallel to the ditches of the iPP substrate caused by alternatively arranged crystalline and amorphous regions. The minor set is due to a homoepitaxy of PLLA with parallelism of the helical paths. The orientation of this minor set of lamellae therefore depends on and can help determine the chirality-l or d-of the PLA investigated. PMID- 30027646 TI - Lipoma removal using a high-frequency ultrasound-guided injection of a Class III CE-marked device-Empirical findings. AB - BACKGROUND: Lipomas are very common benign neoplasms, which constitute 99% of all adipose-derived tumors. Main treatment option includes surgical excision, which is unacceptable for a number of patients seeking ways to improve esthetic appearance of their skin. Therefore, alternative treatment options are being sought. OBJECTIVE: The aim of the present study was to assess the efficacy of lipoma removal using a Class III CE-marked device (AqualyxTM) administered as a high-frequency ultrasound-guided injection (intralipotherapy). METHODS: A total of 17 lipomas were treated. The procedure involved a high-frequency ultrasound guided injection. A maximum of 3 injections per a lipoma were performed. High frequency ultrasound was used for assessing the size of lipomas and monitoring treatment-induced changes to the lipomas and adjacent tissue. RESULTS: Response to treatment was achieved in all cases. A complete removal was achieved in 70.59% of lipomas. The remaining 29.41% of lipomas were not completely removed, yet significantly reduced in size. CONCLUSION: An injection of AqualyxTM, a CE-marked drug, is a good noninvasive treatment of lipomas. Ultrasound guided procedure is recommended, as it ensures appropriate technique and enables monitoring treatment induced changes. Considering a low number of published reports of such treatment, it is crucial to continue this research. PMID- 30027647 TI - Molecular Features and mRNA Expression of the Receptor for Activated C Kinase 1 from Symbiodinium microadriaticum ssp. microadriaticum During Growth and the Light/Dark cycle. AB - Two genes of the RACK1 homolog from the photosynthetic dinoflagellate Symbiodinium microadriaticum ssp. microadriaticum (SmicRACK1), termed SmicRACK1A and SmicRACK1B, were found tandemly arrayed and displayed a single synonymous substitution (T/C) encoding threonine. They included two exons of 942 bp each, encoding 313 amino acids with seven WD-40 repeats and two PKC-binding motifs. The protein theoretical mass and pI were 34,200 Da and 5.9, respectively. SmicRACK1 showed maximum identities with RACK1 homologs at the amino acid and nucleotide level, respectively, of 92 and 84% with S. minutum, and phylogenetic analysis revealed clustered related RACK1 sequences from the marine dinoflagellates S. minutum, Heterocapsa triquetra, Karenia brevis, and Alexandrium tamarense. Interestingly, light-dependent regulatory elements were found both within the 282 bp SmicRACK1A promotor sequence, and within an intergenic sequence of 359 nucleotides that separated both genes, which strongly suggest light-related functions. This was further supported by mRNA accumulation analysis, which fluctuated along the light and dark phases of the growth cycle showing maximum specific peaks under either condition. Finally, qRT-PCR analysis revealed differential SmicRACK1 mRNA accumulation with maxima at 6 and 20 d of culture. Our SmicRACK1 characterization suggests roles in active growth and proliferation, as well as light/dark cycle regulation in S. microadriaticum. PMID- 30027648 TI - Video head impulse test results suggest that different pathomechanisms underlie sudden sensorineural hearing loss with vertigo and vestibular neuritis: Our experience in fifty-two patients. PMID- 30027649 TI - Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. PMID- 30027650 TI - Physical Activity, Well-Being, and the Basic Psychological Needs: Adopting the SDT Model of Eudaimonia in a Post-Cardiac Rehabilitation Sample. AB - BACKGROUND: The theoretical conceptualisation of hedonic (HWB; pleasure) and eudaimonic (EWB; meaning) well-being has rarely been examined among cardiac rehabilitation (CR) graduates, including its relationship with moderate-to vigorous physical activity (MVPA). First, this study examined the potential bidirectional relationship between MVPA and HWB/EWB. Second, this study tested the self-determination theory (SDT) model of eudaimonia where MVPA was set to predict the model's pathway between eudaimonic motives (seeking meaning), the basic psychological needs (autonomy, competence, and relatedness), and both types of well-being. METHODS: Individuals who completed a CR program within the last five years (N = 57) answered well-being and basic psychological needs questionnaires and wore an accelerometer to measure MVPA at baseline and three months later. RESULTS: MVPA predicted changes in both HWB (beta = .13) and EWB (beta = .13) three months later. Only the EWB-MVPA relationship (beta = .16) approached significance, hinting at a bidirectional relationship. The SDT model of eudaimonia was supported and MVPA had a moderate to small relationship with eudaimonic motives. CONCLUSION: This study showed a potential bidirectional relationship between MVPA and EWB and tested the SDT model of eudaimonia with MVPA in post-cardiac rehabilitation. Future interventions could look to simultaneously promote eudaimonia and MVPA among this population. PMID- 30027651 TI - Understanding reasons for discontinued antiretroviral treatment among clients in test and treat: a qualitative study in Swaziland. AB - INTRODUCTION: Retention on antiretroviral therapy (ART) is critical for the successful adoption of the test and treat policy by sub-Saharan African countries, and for realizing the United Nations programme on HIV and AIDS target of 90-90-90. This qualitative study explores HIV positive clients' reasons for discontinuing ART under the MaxART test and treat implementation study in Swaziland. METHODS: Clients identified as lost to follow-up (LTFU) in the programme database, who had initiated ART under the intervention arm of the MaxART study, were purposively selected from two facilities. LTFU was defined as stopping ART refill for three months or longer from the date of last appointment, and not being classified as transferred out or deceased. Semi-structured face-to face interviews were conducted with nine clients and one treatment supporter between July and August 2017. All interviews were conducted in the local language, audio-recorded, summarized or transcribed and translated to English for thematic analysis. RESULTS: Respondents described mobility as the first step in a chain of events that affected retention in care. It was entwined with precarious employment, care delivery, interactions with health workers, lack of social support, anticipated stigma and ART-related side-effects, including the exacerbation of hunger. The chains of events involved several intersecting reasons that occurred one after the other as a series of contiguous and linked events that led to clients' eventual discontinuation of ART. The individual accounts of step-by-step decision-making revealed the influence of multi-layered contexts and the importance of critical life-events. CONCLUSIONS: Clients' reasons for abandoning ART are a complex, inextricably interwoven chain of events rather than a single occurrence. Mobility is often the first step in the process and commonly results from precarious economic and social circumstances. Currently the health system poorly caters to the reality of people's mobile lives. Interventions should seek to increase healthcare workers' understanding of the chain of events leading up to discontinuation on ART and the social dilemmas that clients face. PMID- 30027652 TI - Prosthetic mesh placement for the prevention of parastomal herniation. AB - BACKGROUND: Parastomal herniation is a common problem following formation of a stoma after both elective and emergency abdominal surgery. Symptomatic hernias give rise to a significant amount of patient morbidity, and in some cases mortality, and therefore may necessitate surgical treatment to repair the hernial defect and/or re-site the stoma. In an effort to reduce this complication, recent research has focused on the application of a synthetic or biological mesh, inserted during stoma formation to help strengthen the abdominal wall. OBJECTIVES: The primary objective was to evaluate whether mesh reinforcement during stoma formation reduces the incidence of parastomal herniation. Secondary objectives included the safety or potential harms or both of mesh placement in terms of stoma-related infections, mesh-related infections, patient-reported symptoms/postoperative quality of life, and re-hospitalisation/ambulatory visits. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2018, Issue 1), Ovid MEDLINE (1970 to 11 January 2018), Ovid Embase (1974 to 11 January 2018), and Science Citation Index Expanded (1970 to 11 January 2018). To identify ongoing studies, we also searched the metaRegister of Controlled Trials (mRCT) on 11 January 2018. SELECTION CRITERIA: We considered for inclusion all randomised controlled trials (RCTs) of prosthetic mesh (including biological/composite mesh) placement versus a control group (no mesh) for the prevention of parastomal hernia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies identified by the literature search for potential eligibility. We obtained the full articles for all studies that potentially met the inclusion criteria and included all those that met the criteria. Any differences in opinion between review authors were resolved by consensus. We pooled study data into a meta-analysis. We assessed heterogeneity by calculation of I2 and expressed results for each variable as a risk ratio (RR) with corresponding 95% confidence intervals (CI). We expressed continous outcomes as mean difference (MD) with corresponding 95% CIs. MAIN RESULTS: We included 10 RCTs involving a total of 844 participants. The primary outcome was overall incidence of parastomal herniation. Secondary outcomes were rate of reoperation at 12 months, operative time, postoperative length of hospital stay, stoma related infections, mesh-related infections, quality of life, and rehospitalisation rate. We judged the risk of bias across all domains to be low in six trials. We judged four trials to have an overall high risk of bias.The overall incidence of parastomal hernia was less in participants receiving a prophylactic mesh compared to those who had a standard ostomy formation (RR 0.53, 95% CI 0.43 to 0.66; 10 studies, 771 participants; I2 = 69%; low-quality evidence). In absolute numbers, the incidence of parastomal hernia was 22 per 100 participants (18 to 27) receiving prophylactic mesh compared to 41 per 100 participants having a standard ostomy formation.There were no differences in the need for reoperation (RR 0.90, 95% CI 0.50 to 1.64; 9 studies, 757 participants; I2 = 0%; low-quality evidence); operative time (MD -6.50 (min), 95% CI -18.24 to 5.24; 6 studies, 671 participants; low-quality evidence); postoperative length of hospital stay (MD -0.95 (days), 95% CI -2.03 to 0.70; 4 studies, 500 participants; moderate-quality evidence); or stoma-related infections (RR 0.89, 95% CI 0.32 to 2.50; 6 studies, 472 participants; I2 = 0%; low-quality evidence) between the two groups.We were unable to analyse mesh-related infections, quality of life, and rehospitalisation rate due to sparse data or because the outcome was not reported in the included studies. AUTHORS' CONCLUSIONS: This Cochrane Review included 10 RCTs with a total of 844 participants. The review demonstrated a reduction in the incidence of parastomal hernia in people who had a prophylactic synthetic mesh placed at the time of the index operation compared to a standard ostomy formation. However, our confidence in this estimate is low due to the presence of a large degree of clinical heterogeneity, as well as high variability in follow-up duration and technique of parastomal herniation detection. We found the rate of stoma-related infection to be similar in both the intervention and control groups. PMID- 30027653 TI - Protective potential of glutathione peroxidase-1 gene against cocaine-induced acute hepatotoxic consequences in mice. AB - Since the cocaine-induced oxidative stress has been established to lead to hepatotoxicity, we examined the role of the glutathione peroxidase (GPx)-1 gene in cocaine-induced hepatotoxicity. Cocaine treatment significantly increased superoxide dismutase activity in as little as 1 hour, with a maximum level at 6 hours in wild-type mice, while significantly decreasing GPx activity and subsequently inducing oxidative damage (i.e., reactive oxygen species, lipid peroxidation and protein carbonylation). These changes were more prominent in the mitochondrial fraction than in the cytosolic fraction. In contrast, genetic overexpression of GPx-1 significantly attenuated cocaine-induced oxidative damage in mice. Cocaine treatment significantly increased alanine aminotransferase and aspartate aminotransferase levels in the serum. Consistently, cocaine significantly enhanced cleaved caspase-3 expression and intramitochondrial Ca2+ , while significantly reducing mitochondrial transmembrane potential. Cocaine treatment potentiated cleavage of protein kinase C delta (PKCdelta), mitochondrial translocation of PKCdelta, cytosolic release of cytochrome c and activation of caspase-3, followed by hepatopathologic changes. These results were more prominent in GPx-1 knockout than in wild-type mice, and they were less pronounced in overexpressing transgenic than in non-transgenic mice. Combined, our results suggest that the GPx-1 gene possesses protective potential against mitochondrial oxidative burden, mitochondrial dysfunction and hepatic degeneration induced by cocaine and that the protective mechanisms are associated with anti-apoptotic activity via inactivation of PKCdelta. PMID- 30027654 TI - Veno-Arterial ECMO Weaning Failure in the Operating Room: Have You Considered Preweaning Bronchoscopy? AB - Current guidelines on postcardiotomy veno-arterial extracorporeal oxygenation ECMO (vaECMO) do not mention the assessment of pulmonary function, especially prior to the weaning procedure in the operation room (OR). Mucociliary dysfunction, a nearly ubiquitous finding among mechanically ventilated patients, might put these patients at risk for potential airway problems and associated weaning failure at the time of vaECMO weaning in the OR. In conformity to veno venous ECMO management, we suggest routine bronchoscopy with bronchial hygiene in the ICU prior to vaECMO weaning in the OR. Likewise, an assessment of patient pleura for effusions should be routinely performed. Although cardiac and respiratory failure often co-exist and there are multiple causes of respiratory failure in patients who require vaECMO, we anticipate that vaECMO patients would significantly benefit from an expanded focus on the pulmonary function and possible respiratory mucous congestion. A routine preweaning bronchoscopy would reduce the frequency of weaning failures in this particular setting, especially in those patients with successfully restored cardiac function. PMID- 30027655 TI - Is sex an influential factor in type-1 diabetes neurofunctional development? A preliminary study. AB - The aim of the study was to evaluate the neurofunctional effect of gender in Type 1 Diabetes Mellitus (T1DM) patients during a Visual Spatial Working Memory (VSWM) task. The study included 28 participants with ages ranging from 17-28 years. Fourteen well-controlled T1DM patients (7 female) and 14 controls matched by age, sex, and education level were scanned performing a block-design VSWM paradigm. Behavioral descriptive analyses and mean comparisons were done, and between-group and condition functional activation patterns were also compared. Whole-brain cumulative BOLD signal (CumBS), voxel-wise BOLD level frequency, Euclidean distance, and divergence indices were also calculated. There were no significant differences between or within-group sex differences for correct responses and reaction times. Functional activation analyses showed that females had activation in more brain regions, and with larger clusters of cortical activations than males. Furthermore, BOLD activation was higher in males. Despite the preliminary nature of the present study given the relatively small sample size, current results acknowledge for the first time that sex might contribute to differences in functional activation in T1DM patients. Findings suggest that sex differences should be considered when studying T1DM-disease development. PMID- 30027656 TI - Reply. PMID- 30027657 TI - First detection of tilapia lake virus (TiLV) in wild river carp (Barbonymus schwanenfeldii) at Timah Tasoh Lake, Malaysia. PMID- 30027658 TI - Ex vivo stone surgery in donor kidneys at renal transplantation. AB - OBJECTIVE: To report our experience on the outcomes of ex vivo ureteroscopy and ex vivo pyelolithotomy carried out on the donor kidney before living donor renal transplantation. METHODS: Between 2009 and 2016, 13 stone-bearing donor kidneys underwent ex vivo bench surgery after donor nephrectomy. Of these, six patients underwent ex vivo ureteroscopy and seven patients underwent ex vivo pyelolithotomy. Data were analyzed for technical feasibility, intraoperative and postoperative complications, stone clearance, and stone recurrence. RESULTS: The mean stone burden was 9.1 mm (range 5-15 mm). Renal collecting system access and stone extraction were successfully achieved, and a stone-free status was accomplished with both techniques. The mean duration of ex vivo ureteroscopy was 12.5 min (range 9-20 min), and the mean duration of ex vivo pyelolithotomy was 3.1 min (range 1-8 min). One patient in the pyelolithotomy group developed urinary leakage and underwent surgical repair on the third postoperative day. The mean long-term follow-up duration was 49.6 months (range 14-101 months). None of the 13 patients included in the study suffered from stone recurrence. CONCLUSIONS: Our experience suggests that both ex vivo ureteroscopy and ex vivo pyelolithotomy procedures can safely and effectively be carried out in stone bearing living donor kidneys, without compromising renal allograft function. PMID- 30027659 TI - Reversible impairment of coronary flow reserve in acute myocarditis. AB - OBJECTIVE: Acute myocarditis is accompanied by an impaired coronary microcirculation. These microcirculatory disturbances are not well defined, and data are derived from complex invasive measurements. Therefore, this study aimed to evaluate the inflammation-induced microcirculatory dysfunction including its reversibility and association with markers of inflammation severity (extent of LGE on CMR imaging and laboratory markers of myocardial necrosis) using the noninvasive technique of echocardiographic CFR measurement. METHODS: Patients (n = 14) with clinically suspected acute myocarditis in the absence of coronary artery disease were prospectively enrolled, and echocardiographic CFR was determined by measuring peak diastolic coronary blood flow velocity at rest (PDV1) and under adenosine-induced hyperemia (PDV2) at baseline and 3-month follow-up. RESULTS: Eight of 14 (57.1%) patients showed an impaired baseline CFR (PDV2/PDV1 < 2). These patients were characterized by higher levels of cardiac troponin T (0.55 +/- 0.39 vs 0.18 +/- 0.08; P = 0.008) and larger areas of LGE on CMR. At 3-month follow-up, CFR was normal in all patients. CONCLUSION: A reversibly impaired coronary microcirculation is a frequent finding in acute myocarditis and is associated with markers of inflammation severity. Echocardiographic CFR measurement represents a feasible and safe method for its assessment. PMID- 30027660 TI - Ultrasound Features of Palmar Fibromatosis or Dupuytren Contracture. AB - OBJECTIVES: To retrospectively characterize the ultrasound appearance of palmar fibromatosis in patients with a surgical or clinical diagnosis of palmar fibromatosis. METHODS: A search of ultrasound reports from 2005 to 2015 and a subsequent search of medical records were performed to identify patients with a surgical or clinical diagnosis of palmar fibromatosis. The ultrasound images were retrospectively reviewed to record the lesion location, size, echogenicity, compressibility, hyperemia, and calcification. RESULTS: A total of 36 patients were identified (average age, 60 years; 61% male), yielding a total of 55 palmar fibromatosis lesions, of which 2%, 7%, 29%, 36%, 20%, and 5% were located at the first, second, third, fourth, and fifth digits and between the fourth and fifth digits, respectively. The lesions were located directly superficial to the flexor tendons in 93% with their epicenters at the distal metacarpal in 89%. Average lesion dimensions were 13.1 mm in length, 6.8 mm in width, and 2.5 mm in depth. On ultrasound images, the lesions were characteristically hypoechoic (98%) and noncompressible (95%). Atypical features included calcification (2%), compressibility (5%), hyperemia on color Doppler images (6%), epicenters at the metacarpophalangeal joint (7%) or proximal phalanx (4%), and location superficial but lateral to the flexor tendons (7%). CONCLUSIONS: Palmar fibromatosis most commonly appears hypoechoic and is located directly superficial to the flexor tendons with an epicenter at the distal metacarpal, most commonly the fourth digit. However, the epicenter location may be at the distal metacarpal and proximal phalanx of other digits, adjacent to the flexor tendons, with possible hyperemia and calcification. PMID- 30027661 TI - Herbicides and herbivory interact to drive plant community and crop-tree establishment. AB - Land management practices often directly alter vegetation structure and composition, but the degree to which ecological processes such as herbivory interact with management to influence biodiversity is less well understood. We hypothesized that large herbivores compound the effects of intensive forest management on early seral plant communities and plantation establishment (i.e., tree survival and growth), and the degree of such effects is dependent on the intensity of management practices. We established 225-m2 wild-ungulate (deer and elk) exclosures, nested within a manipulated gradient of management intensity (no herbicide control, light herbicide, moderate herbicide, and intensive herbicide treatments), replicated at the scale of whole harvest units (10-19 ha). Vegetation structure, composition, and crop-tree responses to herbivory varied across the gradient of herbicide application during the first two years of stand establishment, with herbivory effects most evident at light and moderate herbicide treatments. In the moderate herbicide treatment, which approximates management applied to >2.5 million hectares in the Pacific Northwest, United States, foraging by deer and elk resulted in simplified, low-cover plant communities more closely resembling the intensive herbicide treatment. Herbivory further suppressed the growth of competing vegetation in the light herbicide treatment, improving crop-tree survival, and providing early evidence of an ecosystem service. By changing community composition and vegetation structure, intensive forest management alters foraging selectivity and subsequent plant herbivore interactions; initial shifts in early seral communities are likely to influence understory plant communities and tree growth in later stages of forest development. PMID- 30027662 TI - Summertime. PMID- 30027663 TI - Photo-Controlled Polymerization-Induced Self-Assembly (Photo-PISA): A Novel Strategy Using In Situ Bromine-Iodine Transformation Living Radical Polymerization. AB - A series of hydrophilic poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA) macroinitiators and stabilizers are synthesized in methanol through in situ photo-controlled bromine-iodine transformation living radical polymerization, where ethyl alpha-bromophenylacetate (EBPA) is the initial initiator and is converted to an iodo-type initiator in the presence of NaI. The subsequent photo-controlled polymerization-induced self-assembly (photo-PISA) process is achieved by adding a second monomer, hydrophobic benzyl methacrylate (BnMA), under irradiation with blue light emitting diode (LED) light at room temperature. The effect of the target degree of polymerization (DP) of PPEGMA, PBnMA, as well as the solids content on the self-assembly behavior of block copolymer PPEGMA-b-PBnMA is evaluated by gel permeation chromatography (GPC), nuclear magnetic resonance (NMR) spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS) characterization. Resulting uniform spherical micelles and vesicle aggregates are observed. PMID- 30027664 TI - Renal artery stenosis in China: The state of changes. PMID- 30027665 TI - "I will leave the baby with my mother": Long-distance travel and follow-up care among HIV-positive pregnant and postpartum women in South Africa. AB - INTRODUCTION: It is common in urban African settings for postpartum women to temporarily return to family in distant settings. We sought to explore mobility among peripartum HIV-positive women to understand the timing and motivation of travel, particularly vis-a-vis delivery, and how it may affect healthcare access. METHODS: Using the same mobility measurements within three different studies, we examined long-distance travel of mother and infant before and after delivery in three diverse clinics within greater Johannesburg, South Africa (n = 150). Participants were interviewed prior to delivery at two sites (n = 125) and after delivery at one (n = 25). Quantitative and qualitative results are reported. RESULTS: Among 150 women, median age was 29 years (IQR: 26 to 34) and 36.3% were employed. Overall, 76.7% of the participants were born in South Africa: 32.7% in Gauteng Province (Johannesburg area) and 44.0% in other South African provinces, but birthplace varied greatly by site. Almost half (44.0%) planned to travel around delivery; nearly all after delivery. Median duration of stay was 30 days (IQR: 24 to 90) overall, but varied from 60 days at two sites to just 7 days at another. Participants discussed travel to eight of South Africa's nine provinces and four countries. Travel most frequently was to visit family, typically to receive help with the new baby. Nearly all the employed participants planned to return to work in Johannesburg after delivery, sometimes leaving the infant in the care of family outside of Johannesburg. All expressed their intent to continue HIV care for themselves and their infant, but few planned to seek care at the destination site, and care for the infant was emphasized over care for the mother. CONCLUSIONS: We identified frequent travel in the peripartum period with substantial differences in travel patterns by site. Participants more frequently discussed seeking care for the infant than for themselves. HIV-exposed children often were left in the care of family members in distant areas. Our results show the frequent mobility of women and infants in the peripartum period. This underscores the challenge of ensuring a continuity of HIV care in a fragmented healthcare system that is not adapted for a mobile population. PMID- 30027666 TI - Dual doped biocompatible multicolor luminescent carbon dots for bio labeling, UV active marker and fluorescent polymer composite. AB - We report on metal-non-metal doped carbon dots with very high photoluminescent properties in solution. Magnesium doping to tamarind extract associated with nitrogen-doping is for the first time reported here which also produce very high quantum yield. Our aim is to develop such dual doped carbon dots which can also serve living cell imaging with easy permeation towards cells and show non cytotoxic attributes. More importantly, the chemical signatures of the carbon dots unveiled in this work can support their easy solubilization into water; even in sub-ambient temperature. The cytotoxicity assay proves the almost negligible cytotoxic effect against human cell lines. Moreover, the use of carbon dots in UV active marker and polymer composites are also performed which gave clear distinguishable features of fluorescent nanoparticles. Hitherto, the carbon dots can be commercially prepared without adopting any rigorous methods and also can be used as non-photo-bleachable biomarkers of living cells. PMID- 30027667 TI - Perceptions of falls and falls prevention interventions among Personal Alert Victoria clients. AB - This paper explores the perceptions and experiences of falls among Personal Alert Victoria (PAV) clients and identifies barriers and enablers to engagement in falls prevention interventions. Data were collected via semistructured telephone interviews (n = 12) and a client survey with open-ended and closed-ended questions (n = 46). Descriptive statistics and thematic analysis was guided by the COM-B model (capability, opportunity, and motivation) for behaviour change. The interview and survey explored experiences of falls, falls risk factors, access and participation in falls prevention interventions, access to health and support services, and experiences using the PAV service. Capability barriers identified included poor health, lack of time, low health literacy, and perceived high intensity of exercise classes. Opportunity barriers were lack of transport, high cost, and long waiting times for falls prevention interventions. Motivation barriers were the belief that falls are inevitable and a perceived lack of relevance of falls prevention interventions. Enablers identified were a focus on broader health and well-being benefits (capability), hospitalisations or rehabilitation that incorporates falls prevention in recovery (opportunity), and raising awareness of falls risk (motivation). Findings suggest that further research is required to inform the tailoring of positive health messages to improve the uptake of falls prevention interventions by PAV clients. PMID- 30027668 TI - Population mobility associated with higher risk sexual behaviour in eastern African communities participating in a Universal Testing and Treatment trial. AB - INTRODUCTION: There are significant knowledge gaps concerning complex forms of mobility emergent in sub-Saharan Africa, their relationship to sexual behaviours, HIV transmission, and how sex modifies these associations. This study, within an ongoing test-and-treat trial (SEARCH, NCT01864603), sought to measure effects of diverse metrics of mobility on behaviours, with attention to gender. METHODS: Cross-sectional data were collected in 2016 from 1919 adults in 12 communities in Kenya and Uganda, to examine mobility (labour/non-labour-related travel), migration (changes of residence over geopolitical boundaries) and their associations with sexual behaviours (concurrent/higher risk partnerships), by region and sex. Multilevel mixed-effects logistic regression models, stratified by sex and adjusted for clustering by community, were fitted to examine associations of mobility with higher-risk behaviours, in past 2 years/past 6 months, controlling for key covariates. RESULTS: The population was 45.8% male and 52.4% female, with mean age 38.7 (median 37, IQR: 17); 11.2% had migrated in the past 2 years. Migration varied by region (14.4% in Kenya, 11.5% in southwestern and 1.7% in eastern and Uganda) and sex (13.6% of men and 9.2% of women). Ten per cent reported labour-related travel and 45.9% non-labour-related travel in past 6 months-and varied by region and sex: labour-related mobility was more common in men (18.5%) than women (2.9%); non-labour-related mobility was more common in women (57.1%) than men (32.6%). In 2015 to 2016, 24.6% of men and 6.6% of women had concurrent sexual partnerships; in past 6 months, 21.6% of men and 5.4% of women had concurrent partnerships. Concurrency in 2015 to 2016 was more strongly associated with migration in women [aRR = 2.0, 95% CI(1.1 to 3.7)] than men [aRR = 1.5, 95% CI(1.0 to 2.2)]. Concurrency in past 6 months was more strongly associated with labour-related mobility in women [aRR = 2.9, 95% CI(1.0 to 8.0)] than men [aRR = 1.8, 95% CI(1.2 to 2.5)], but with non-labour-related mobility in men [aRR = 2.2, 95% CI(1.5 to 3.4)]. CONCLUSIONS: In rural eastern Africa, both longer-distance/permanent, and localized/shorter-term forms of mobility are associated with higher-risk behaviours, and are highly gendered: the HIV risks associated with mobility are more pronounced for women. Gender-specific interventions among mobile populations are needed to combat HIV in the region. PMID- 30027670 TI - How closely do blood gas electrolytes and haemoglobin agree with serum values in adult emergency department patients: An observational study. AB - OBJECTIVE: The aims of this study were to establish the bias (mean difference) and 95% limits of agreement (LoA) between electrolyte values (sodium and potassium) and haemoglobin between whole blood analysed by the ED resuscitation room blood gas analyser and specimens analysed using standard techniques in the central hospital laboratory and to determine the proportion of analyses falling outside defined clinically acceptable LoA and pathology expert defined standards. METHODS: Prospective cohort study. Paired blood gas analyser and laboratory samples taken no more than 10 min apart were included. The primary outcome of interest was bias and 95% LoA by Bland-Altman analysis. Subgroup analyses for values outside the normal range were also conducted. RESULTS: Three hundred and fifty-two sample pairs were included in the analysis. For sodium concentration the bias was 0.6 mmol/L (95% LoA -3.3 to 4.6 mmol/L). For potassium concentration the bias was 0.21 mmol/L (95% LoA -0.36 to 0.79 mmol/L). For haemoglobin concentration the bias was -1.6 g/dL (95% LoA -10.2 to 6.9 g/dL). For sodium and haemoglobin concentrations, >95% of results fell within the defined clinically acceptable limits. For potassium concentration, >90% of results fell within the defined clinically acceptable limits. In general, serum sodium and potassium concentrations were slightly higher than blood gas levels and for haemoglobin serum levels were slightly lower. CONCLUSION: Agreement between blood gas analysis and laboratory analysis for sodium, potassium and haemoglobin concentrations shows acceptable agreement for use in time critical clinical decision-making in ED. PMID- 30027669 TI - Clinical and genetic ancestry profile of a large multi-centre sickle cell disease cohort in Brazil. AB - Approximately 3500 children with sickle cell disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children <18 years (55.9%) and females (53.0%). Haemoglobin (Hb) SS was the most common SCD genotype (70.7%), followed by HbSC (23%), Sbeta0 (3.0%) and Sbeta+ (2.9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed. PMID- 30027671 TI - Modulating effects of on-line low frequency electromagnetic fields on hippocampal long-term potentiation in young male Sprague-Dawley rat. AB - The low frequency electromagnetic fields (LF-EMFs) are attracting more attention and studied deeply because of their effects on human health and biology. Recent reports indicate that exposure of rats to LF-EMFs induces persistent changes in neuronal activity. The studies used the following standard methods: the rats or rat brain slices were first stimulated in an external electromagnetic exposure system, and then moved to a patch clamp perfusion chamber to record electrophysiological characteristics (off-line magnetic exposure). However, this approach is susceptible to many disturbances, such as the effects of brain slice movements. In this paper, we describe a novel patch-clamp setup which is modified to allow accurate on-line LF-EMFs stimulation. We performed the computational simulations of the stimulation coils to describe the uniformity of the distribution of the on-line magnetic field. The 0.5, 1, 2 mT magnetic field of 15 Hz, 50 Hz, and 100 Hz was produced and applied to slices to study the effect of LF-EMFs on synaptic plasticity. We demonstrated that the slope of field excitatory postsynaptic potentials (fEPSPs) decreased significantly under the priming on-line uninterrupted or pulsed sinusoidal LF-EMFs stimulation. In the present study, we investigated whether LF-EMFs can induce long-term potentiation (LTP) in male Sprague-Dawley rat hippocampal slices in vitro. Interestingly, these results highlight the role of 100 Hz pulsed sinusoidal LF-EMFs only as a modulator, rather than an LTP inducer. PMID- 30027672 TI - Right Ventricular Dissipative Energy Loss Detected by Vector Flow Mapping in Children: Characteristics of Normal Values. AB - OBJECTIVES: The feasible application of vector flow mapping (VFM)-derived right ventricular (RV) energy loss (EL) is lacking. This study was designed to determine reference values of VFM-derived EL within the right ventricle and evaluate potential correlated variables. METHODS: A total of 90 healthy children were enrolled. Velocity vector fields of the intra-RV outflow tract and pulmonary trunk (OP) and RV blood flow were obtained from the parasternal short-axis view and RV focused apical 4-chamber view, respectively. RV-EL and OP-EL values during diastole and systole were calculated using VFM analysis. The potential relationships between demographic and echocardiographic parameters and the dissipative EL were also identified. RESULTS: Mean subject age was 8.99 +/- 5.35 years. The median (interquartile range) values were 8.82 (5.47-14.30) W/m for RV diastolic EL, 3.17 (2.11-5.54) W/m for RV systolic EL, 18.82 (13.93-24.92) W/m for OP diastolic EL, and 29.88 (20.62-40.78) W/m for OP systolic EL, respectively. The dissipative EL values were negatively correlated with age and RV global strain, and positively correlated with heart rate and RV Tei index. Multivariate analysis showed that age was the primary independent predictor of these 4 types of EL, while heart rate and strain were contributors of the RV diastolic EL and OP systolic EL. CONCLUSIONS: The present study initially validated the application of vector flow mapping-derived EL analysis in right ventricle and established reference values for the future assessment of children with cardiopulmonary disease. Age, heart rate, and strain were independent variables correlated with the dissipative EL. PMID- 30027673 TI - Examining the double-deficit hypothesis in vowelized-transparent Arabic in a national representative sample of Grades 3 and 4. AB - We examined the double-deficit hypothesis in Arabic by investigating the reading and cognitive profiles of readers with selective deficits in naming speed, phonological awareness, or both. In a nationally representative sample of 486 children in the third and fourth grades, we identified 171 children with reading difficulties: 20 (12%) were classified as having a phonological deficit, 31 (18%) as having a naming speed deficit, and 41 (24%) as having a double deficit. Differences between the subgroups extended to reading, cognitive, and linguistic processes beyond phonological and naming abilities. Children with a double deficit performed worse than those with a naming speed deficit but similar to those with a phonological deficit. Numerous unconfirmed theories led to an in depth analysis of the nature of rapid automatized naming and its relation to orthographic processing. Surprisingly, our findings revealed that orthographic processing may be considered a novel and separate core deficit, suggesting a triple deficit in Arabic rather than a double deficit. The findings are discussed in light of the uniqueness and complexity of Arabic orthography and orthographic transparency in the Arabic language. PMID- 30027674 TI - Fleas of the genus Neotyphloceras associated with rodents from Bolivia: new host and distributional records, description of a new species and remarks on the morphology of Neotyphloceras rosenbergi. AB - The flea genus Neotyphloceras Rothschild (Siphonaptera: Ctenophthalmidae) includes five species and two subspecies distributed from Venezuela to southern Chile and Argentina. Only Neotyphloceras crassispina hemisus Jordan has been registered in Bolivia. The present study examines species of Neotyphloceras collected in Bolivian localities in the Departments of La Paz, Cochabamba and Tarija, and describes the morphology of the modified abdominal segments in males and females of Neotyphloceras rosenbergi Rothschild on the basis of type material and specimens collected from Tarija. A new species, Neotyphloceras boliviensis n. sp., is described and new host associations are reported for N. rosenbergi, Neotyphloceras crassispina crassispina and N. crassispina hemisus. Neotyphloceras c. crassispina and N. rosenbergi are reported for the first time in Bolivia. The distribution of N. rosenbergi is extended 1600 km to the south. Given the potential medical and veterinary significance of fleas as disease vectors, and considering that in the Departments of La Paz and Tarija several human cases of plague have been reported, and species of flea have been identified as main vectors of these diseases, the new records of fleas in Bolivia reported herein may be useful for epidemiological studies on flea-borne diseases. PMID- 30027675 TI - Evaluation of Left Ventricular Systolic Function and Mass in Primary Hypertensive Patients by Echocardiography. AB - Hypertension is an independent risk factor for cardiovascular diseases. The accurate evaluation of cardiovascular risk is of paramount importance in the management of hypertensive patients. Conventional echocardiographic methods have provided the assessment of left ventricular systolic function and mass for many years. Tissue Doppler imaging, 3-dimensional echocardiography, and speckle tracking echocardiography are newer echocardiographic modalities for the left ventricular systolic function and mass quantification. The major emphasis of this review is to evaluate the left ventricular systolic function and mass by conventional and newly developed echocardiographic in hypertensive patients. PMID- 30027676 TI - Robust Bayesian nonlinear mixed-effects modeling of time to positivity in tuberculosis trials. AB - Early phase 2 tuberculosis (TB) trials are conducted to characterize the early bactericidal activity (EBA) of anti-TB drugs. The EBA of anti-TB drugs has conventionally been calculated as the rate of decline in colony forming unit (CFU) count during the first 14 days of treatment. The measurement of CFU count, however, is expensive and prone to contamination. Alternatively to CFU count, time to positivity (TTP), which is a potential biomarker for long-term efficacy of anti-TB drugs, can be used to characterize EBA. The current Bayesian nonlinear mixed-effects (NLME) regression model for TTP data, however, lacks robustness to gross outliers that often are present in the data. The conventional way of handling such outliers involves their identification by visual inspection and subsequent exclusion from the analysis. However, this process can be questioned because of its subjective nature. For this reason, we fitted robust versions of the Bayesian nonlinear mixed-effects regression model to a wide range of TTP datasets. The performance of the explored models was assessed through model comparison statistics and a simulation study. We conclude that fitting a robust model to TTP data obviates the need for explicit identification and subsequent "deletion" of outliers but ensures that gross outliers exert no undue influence on model fits. We recommend that the current practice of fitting conventional normal theory models be abandoned in favor of fitting robust models to TTP data. PMID- 30027677 TI - White matter changes associated with cognitive visual dysfunctions in children with cerebral palsy: A diffusion tensor imaging study. AB - Children with cerebral palsy often present with cognitive-visual dysfunctions characterized by visuo-perceptual and/or visuo-spatial deficits associated with a malfunctioning of visual-associative areas. The neurofunctional model of this condition remains poorly understood due to the lack of a clear correlation between cognitive-visual deficit and morphological brain anomalies. The aim of our study was to quantify the pattern of white matter abnormalities within the whole brain in children with cerebral palsy, and to identify white matter tracts sub-serving cognitive-visual functions, in order to better understand the basis of cognitive-visual processing. Nine subjects (three males, mean age 8 years 9 months) with cerebral palsy underwent a visual and cognitive-visual evaluation. Conventional brain MRI and diffusion tensor imaging were performed. The fractional anisotropy maps were calculated for every child and compared with data from 13 (four males, mean age 10 years 7 months) healthy children. Children with cerebral palsy showed decreased fractional anisotropy (a marker of white matter integrity) in corticospinal tract bilaterally, left superior longitudinal fasciculus and bilateral hippocampus. Focusing on the superior longitudinal fasciculus, the mean fractional anisotropy values were significantly lower in children affected by cerebral palsy with cognitive-visual deficits than in those without cognitive-visual deficits. Our findings reveal an association between cognitive-visual profile and the superior longitudinal fasciculus integrity in children with cerebral palsy, supporting the hypothesis that visuo-associative deficits are related to changes in fibers connecting the occipital cortex with the parietal-frontal cortices. Decreased fractional anisotropy within the superior longitudinal fasciculus could be considered a biomarker for cognitive visual dysfunctions. PMID- 30027679 TI - Evaluation of age-dependent changes of myocardial velocity using pulsed wave and colour tissue Doppler imaging in adult warmblood horses. AB - Our aim was to evaluate the influence of the ageing process on the myocardium using pulsed wave tissue Doppler (PW-TDI) and colour tissue Doppler imaging (cTDI) to measure myocardial velocities at three different myocardial regions (right ventricular free wall: RVFW, interventricular septum: IVS, left ventricular free wall: LVFW). A total of 60 healthy warmblood horses, aged from 3 to 30 years, were examined. The horses were divided into five age groups (group 1: 3-8 years, n = 14; group 2: 9-13 years, n = 9; group 3: 14-18 years, n = 10; group 4: 19-23 years, n = 14; group 5: 24-30 years, n = 10). The results showed that age has a significant influence on the radial myocardial velocity of horses in different myocardial regions. This influence was detectable by both echocardiographic techniques, although PW-TDI measurements showed a higher reproducibility due to lower intraindividual variation coefficients. Systolic contraction velocity (p <= 0.01) and early diastolic relaxation velocity (p <= 0.001) in the LVFW decreased significantly with ageing, while late diastolic contraction velocity increased (0.001 < p <= 0.01). Early and late diastolic contraction velocities at the IVS increased significantly with ageing (p <= 0.001). Systolic and late-diastolic contraction velocities at the RVFW increased significantly with ageing (p <= 0.001). The results indicated a decrease in left ventricular contraction ability and reduced myocardial relaxation and altered diastolic function in the right ventricle with increasing age. These functional changes may be signs of age-related structural myocardial changes or cardiac remodelling, such as increased myocardial stiffness. Thus, an assessment of the radial myocardial velocities of a horse's heart with TDI should always consider physiological age-related changes in contractility. Comparing the two examination techniques (PW-TDI and cTDI) we used in our study, we found that both methods showed comparable age-related alterations. Nevertheless, differences in absolute values were found with a tendency of higher values using PW-TDI in comparison to cTDI. PMID- 30027678 TI - Digital count summing vs analog charge summing for photon counting detectors: A performance simulation study. AB - PURPOSE: Charge sharing is a significant problem for CdTe-based photon counting detectors (PCDs) and can cause high-energy photons to be misclassified as one or more low-energy events. Charge sharing is especially problematic in PCDs for CT because the high flux necessitates small pixels, which increase the magnitude of charge sharing. Analog charge summing (ACS) is a powerful solution to reduce spectral distortion arising from charge sharing but may be difficult to implement. We investigate correction of the signal after digitization by the comparator ("digital count summing"), which is only able to correct a subset of charge sharing events but may have implementation advantages. We compare and quantify the relative performance of digital and ACS in simulations. METHODS: Transport of photons in CdTe was modeled using Monte Carlo simulations. Energy deposited in the CdTe substrate was converted to electrical charges of a predetermined shape, and all charges within the detector pixel are assumed to be perfectly collected. In ACS, the maximum charge received over any 2 * 2 block of pixels was grouped together prior to digitization. In digital count summing (DCS), the charge was digitized in each pixel, and subsequently, adjacent pixels that detected events grouped their charge to record a single, higher energy event. All simulations were performed at the limit of low flux (no pileup). The default tube voltage was 120 kVp, object thickness was 20 cm of water, pixel pitch was 250 MUm, and charge cloud modeled as a Gaussian with sigma = 40 MUm. Variation of these parameters was examined in a sensitivity analysis. RESULTS: Detectors that used no correction, DCS, and ACS misclassified 51%, 39%, and 15% of incident photons, respectively. For iodine basis material imaging, DCS exhibited 100% greater dose efficiency compared to uncorrected, and ACS exhibited an additional 111% greater dose efficiency compared to digital charge summing. For a nonspectral task, the dose efficiency improvement as estimated by improvement of zero-frequency detective quantum efficiency, DQE(0) was 10% for DCS compared to uncorrected and 10% for ACS compared to DCS. A sensitivity analysis showed that DCS generally achieved half the benefit of ACS over a range of conditions, although the benefit was markedly less if the charge cloud was instead modeled as a small sphere. CONCLUSIONS: Summing of counts after digitization may be a simpler alternative to summing of charge prior to digitization due to the relative complexity of analog circuit design. Over most conditions studied, it provides roughly half the benefit of ACS and may offer certain implementation advantages. PMID- 30027680 TI - Assessment of Parotid and Submandibular Glands With Shear Wave Elastography Following Radioactive Iodine Therapy for Papillary Thyroid Carcinoma. AB - OBJECTIVES: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Radioactive iodine (RAI) therapy is used for remnant ablation following thyroidectomy. Side effects such as dysphagia, xerostomia, and sialoadenitis may occur. We aimed to determine the differences in the parotid and submandibulary glands between healthy patients and patients with PTC who had undergone RAI therapy and have dry mouth symptoms using both shear wave elastography and ultrasonography. METHODS: We enrolled 30 patients with PTC who had undergone RAI therapy following surgery and 30 healthy controls. Ultrasonography and shear wave elastography of submandibular and parotid glands were performed. The volume of the submandibular glands and the thickness of parotid glands were determined. Ten independent measurements were obtained from each gland, with the region of interest placed at different points on the glands. The mean shear wave velocities (SWVs) were calculated and compared between the patients and controls. RESULTS: In the PTC group, there was a significant reduction in the volume of the submandibular glands (P < .05) and in the thickness of the parotid glands (P < .05) compared with the control group. The mean SWVs of the parotid glands and submandibular glands were significantly higher in the PTC group compared with the control group (P < .0001). The SWVs of the parotid glands were higher than the SWVs of the submandibular glands (P < .0001). CONCLUSIONS: Shear wave elastography could be a noninvasive and easy assessment method of parotid and submandibular glands in patients who had undergone RAI therapy and experience dry mouth. PMID- 30027681 TI - Transmission of classically entangled beams through mouse brain tissue. AB - Light transmission of Laguerre-Gaussian vector vortex beams in different local regions in mouse brain tissue is investigated. Transmittance is measured in the ballistic and diffusive regions with various polarizations states and orbital angular momentums (OAM). The transmission change observed with structured light other than linear polarization is attributed to chiroptical phenomena from the chiral brain media and the handedness of the light. For instance, classically entangled beams showed higher transmittance and constant value dependency on OAM modes than linear modes did. Also, circular polarization beam transmittance showed strong increase with topical charge OAM ( l), which could be attributed to chiroptical effect. PMID- 30027682 TI - A Helicate-Based Three-State Molecular Switch. AB - The control of structural transformations triggered by external signals is important for the development of novel functional devices. In the present study, it is demonstrated that helicates can be designed to structurally respond to the presence of different counterions and to adopt either a compressed or an expanded structure. Reversible switching is not only possible between those two states, furthermore, the twist of the aggregate also can be controlled. Thus, three out of four possible states of a helicate (expanded/left-handed, expanded/right handed, compressed/left-handed) based on an enantiomerically pure ester bridged dicatecholate ligand are specifically addressed by introduction, exchange, or removal of countercations. This approach is used to reversibly switch between the different states or to successively address them. PMID- 30027683 TI - MTA1 drives malignant progression and bone metastasis in prostate cancer. AB - Prostate cancer often metastasizes to the bone, leading to morbidity and mortality. While metastasis-associated protein 1 (MTA1) is highly overexpressed in metastatic tumors and bone metastatic lesions, its exact role in the development of metastasis is unknown. Here, we report the role of MTA1 in prostate cancer progression and bone metastasis in vitro and in vivo. We found that MTA1 silencing diminished formation of bone metastases and impaired tumor growth in intracardiac and subcutaneous prostate cancer xenografts, respectively. This was attributed to reduced colony formation, invasion, and migration capabilities of MTA1 knockdown cells. Mechanistic studies revealed that MTA1 silencing led to a significant decrease in the expression of cathepsin B (CTSB), a cysteine protease critical for bone metastasis, with an expected increase in the levels of E-cadherin in both cells and xenograft tumors. Moreover, meta analysis of clinical samples indicated a positive correlation between MTA1 and CTSB. Together, these results demonstrate the critical role of MTA1 as an upstream regulator of CTSB-mediated events associated with cell invasiveness and raise the possibility that targeting MTA1/CTSB signaling in the tumor may prevent the development of bone metastasis in prostate cancer. PMID- 30027684 TI - A home but how to connect with others? A qualitative meta-synthesis of experiences of people with mental illness living in supported housing. AB - Supported housing principles emphasise the importance of decent, stable and affordable housing, and the provision of individualised support to enable people experiencing mental illness to live in their preferred communities, and to recover. This study sought to synthesise qualitative research addressing the question: how does living in supported housing facilitate social connections and participation from the viewpoints of people living with mental illness? Three databases (CINAHL, PsycINFO, Medline) were systematically searched to identify 19 peer-reviewed reports on 17 studies published during 2001-2016, in which the views and experiences of supported housing residents with mental illness were reported. Most studies were informed by grounded theory and used interview methods. Appraisal indicated the reports were of varying quality, but all met the inclusion criterion of reporting qualitative data relevant to the research question. Constant comparative methods were used to synthesise the reported data, and to identify themes across the studies. There were four overarching themes regarding the lived experience of supported housing for people with mental illness: (a) living in supported housing gave individuals privacy, a sense of control, stability and security; (b) stable housing supported residents' confidence to rebuild an identity and meaning in life, (c) there is a delicate balance between appreciating privacy and dealing with loneliness, and (d) opportunities and support to reconnect with families, friends and community are valued. The meta-synthesis findings highlight that supported housing residents face challenges of protecting their privacy and being lonely when on their own. Individualised support approaches need to attend to personal preferences for social participation and their varied meanings and significance. Further research is required to better understand how individualised forms of support can enable supported housing residents to connect with family, friends and community in their preferred ways. PMID- 30027685 TI - Peptide Nanophotonics: From Optical Waveguiding to Precise Medicine and Multifunctional Biochips. AB - Optical waveguiding phenomena found in bioinspired chemically synthesized peptide nanostructures are a new paradigm which can revolutionize emerging fields of precise medicine and health monitoring. A unique combination of their intrinsic biocompatibility with remarkable multifunctional optical properties and developed nanotechnology of large peptide wafers makes them highly promising for new biomedical light therapy tools and implantable optical biochips. This Review highlights a new field of peptide nanophotonics. It covers peptide nanotechnology and the fabrication process of peptide integrated optical circuits, basic studies of linear and nonlinear optical phenomena in biological and bioinspired nanostructures, and their passive and active optical waveguiding. It is shown that the optical properties of this generation of bio-optical materials are governed by fundamental biological processes. Refolding the peptide secondary structure is followed by wideband optical absorption and visible tunable fluorescence. In peptide optical waveguides, such a bio-optical effect leads to switching from passive waveguiding mode in native alpha-helical phase to an active one in the beta-sheet phase. The found active waveguiding effect in beta sheet fiber structures below optical diffraction limit opens an avenue for the future development of new bionanophotonics in ultrathin peptide/protein fibrillar structures toward advanced biomedical nanotechnology. PMID- 30027688 TI - Multiple data sources and freely available code is critical when investigating species distributions and diversity: a response to Knouft (2018). AB - A recent comment from Knouft () has suggested that our original article (Dallas et al. ) was an 'inappropriate application of biodiversity data'. Here, we affirm our results, and address the more general point about biodiversity data use. PMID- 30027687 TI - Households, fluidity, and HIV service delivery in Zambia and South Africa - an exploratory analysis of longitudinal qualitative data from the HPTN 071 (PopART) trial. AB - INTRODUCTION: Population distributions, family and household compositions, and people's sense of belonging and social stability in southern Africa have been shaped by tumultuous, continuing large-scale historical disruptions. As a result, many people experience high levels of geographic and social fluidity, which intersect with individual and population-level migration patterns. We describe the complexities of household fluidity and HIV service access in South Africa and Zambia to explore implications for health systems and service delivery in contexts of high household fluidity. METHODS: HPTN 071 (PopART) is a three-arm cluster randomized controlled trial implemented in 21 peri-urban study communities in Zambia and South Africa between 2013 and 2018. A qualitative cohort nested in the trial included 148 purposively sampled households. Data collection was informed by ethnographic and participatory research principles. The analysis process was reflexive and findings are descriptive narrative summaries of emergent ideas. RESULTS: Households in southern Africa are extremely fluid, with people having a tenuous sense of security in their social networks. This fluidity intersects with high individual and population mobility. To characterize fluidity, we describe thematic patterns of household membership and residence. We also identify reasons people give for moving around and shifting social ties, including economic survival, fostering interpersonal relationships, participating in cultural, traditional, religious, or familial gatherings, being institutionalized, and maintaining patterns of substance use. High fluidity disrupted HIV service access for some participants. Despite these challenges, many participants were able to regularly access HIV testing services and participants living with HIV were especially resourceful in maintaining continuity of antiretroviral therapy (ART). We identify three key features of health service interactions that facilitated care continuity: disclosure to family members, understanding attitudes among health services staff including flexibility to accommodate clients' transient pressures, and participants' agency in ART-related decisions. CONCLUSIONS: Choices made to manage one's experiential sense of household fluidity are intentional responses to livelihood and social support constraints. To enhance retention in care for people living with HIV, policy makers and service providers should focus on creating responsive, flexible health service delivery systems designed to accommodate many shifts in client circumstances. PMID- 30027689 TI - Tuning the Amount of Oxygen Vacancies in Sputter-Deposited SnOx films for Enhancing the Performance of Perovskite Solar Cells. AB - This work demonstrates the effect of oxygen vacancies in SnOx thin films on the performance of perovskite solar cells. Various SnOx films with different amounts of oxygen vacancies were deposited by sputtering at different substrate temperatures (25-300 degrees C). The transmittance of the films decreased from 82 to 66 % with increasing deposition temperature from 25 to 300 degrees C. Both X-ray photoelectron spectroscopy and electron-spin resonance spectroscopy confirmed that a higher density of oxygen vacancies was created within the SnOx film at a high substrate temperature, which caused narrowing of the SnOx bandgap from 4.1 (25 degrees C) to 3.74 eV (250 degrees C). Combined ultraviolet photoelectron spectroscopy and UV/Vis spectroscopy showed an excellent conduction band position alignment between the methylammonium lead iodide perovskite layer (3.90 eV) and the SnOx electron transport layer deposited at 250 degrees C (3.92 eV). As a result, a significant enhancement of the open-circuit voltage from 0.82 to 1.0 V was achieved, resulting in an increase of the power conversion efficiency of the perovskite solar cells from 11 to 14 %. This research demonstrated a facile approach for controlling the amount of oxygen vacancies in SnOx thin films to achieve a desirable energy alignment with the perovskite absorber layer for enhanced device performance. PMID- 30027690 TI - The Role of Axon Transport in Neuroprotection and Regeneration. AB - Retinal ganglion cells and other central nervous system neurons fail to regenerate after injury. Understanding the obstacles to survival and regeneration, and overcoming them, is key to preserving and restoring function. While comparisons in the cellular changes seen in these non-regenerative cells with those that do have intrinsic regenerative ability has yielded many candidate genes for regenerative therapies, complete visual recovery has not yet been achieved. Insights gained from neurodegenerative diseases, like glaucoma, underscore the importance of axonal transport of organelles, mRNA, and effector proteins in injury and disease. Targeting molecular motor networks, and their cargoes, may be necessary for realizing complete axonal regeneration and vision restoration. PMID- 30027686 TI - HIV testing history and access to treatment among migrants living with HIV in Europe. AB - INTRODUCTION: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe. METHODS: A cross sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV-positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign-born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men. RESULTS: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three-quarters of people on antiretrovirals had an HIV viral load <50 copies/mL. CONCLUSIONS: Migrants access healthcare in Europe and while many migrants had previously tested for HIV, that they went on to test positive at a later date suggests that opportunities for HIV prevention are being missed. Expansion of testing beyond sexual health and antenatal settings is still required and testing opportunities should be linked with combination prevention measures such as access to PrEP and treatment as prevention. PMID- 30027691 TI - Poor Prognostic Implication of ASXL1 Mutations in Korean Patients With Chronic Myelomonocytic Leukemia. AB - BACKGROUND: Molecular genetic abnormalities are observed in over 90% of chronic myelomonocytic leukemia (CMML) cases. Recently, several studies have demonstrated the negative prognostic impact of ASXL1 mutations in CMML patients. We evaluated the prognostic impact of ASXL1 mutations and compared five CMML prognostic models in Korean patients with CMML. METHODS: We analyzed data from 36 of 57 patients diagnosed as having CMML from January 2000 to March 2016. ASXL1 mutation analysis was performed by direct sequencing, and the clinical and laboratory features of patients were compared according to ASXL1 mutation status. RESULTS: ASXL1 mutations were detected in 18 patients (50%). There were no significant differences between the clinical and laboratory characteristics of ASXL1-mutated (ASXL1+) CMML and ASXL1-nonmutated (ASXL1-) CMML patients (all P>0.05). During the median follow-up of 14 months (range, 0-111 months), the overall survival (OS) of ASXL1+ CMML patients was significantly inferior to that of ASXL1- CMML patients with a median survival of 11 months and 19 months, respectively (log rank P=0.049). An evaluation of OS according to the prognostic models demonstrated inferior survival in patients with a higher risk category according to the Mayo molecular model (log-rank P=0.001); the other scoring systems did not demonstrate a significant association with survival. CONCLUSIONS: We demonstrated that ASXL1 mutations, occurring in half of the Korean CMML patients examined, were associated with inferior survival. ASXL1 mutation status needs to be determined for risk stratification in CMML. PMID- 30027692 TI - Complete Blood Count Reference Intervals and Patterns of Changes Across Pediatric, Adult, and Geriatric Ages in Korea. AB - BACKGROUND: Sampling a healthy reference population to generate reference intervals (RIs) for complete blood count (CBC) parameters is not common for pediatric and geriatric ages. We established age- and sex-specific RIs for CBC parameters across pediatric, adult, and geriatric ages using secondary data, evaluating patterns of changes in CBC parameters. METHODS: The reference population comprised 804,623 health examinees (66,611 aged 3-17 years; 564,280 aged 18-59 years; 173,732 aged 60-99 years), and, we excluded 22,766 examinees after outlier testing. The CBC parameters (red blood cell [RBC], white blood cell [WBC], and platelet parameters) from 781,857 examinees were studied. We determined statistically significant partitions of age and sex, and calculated RIs according to the CLSI C28-A3 guidelines. RESULTS: RBC parameters increased with age until adulthood and decreased with age in males, but increased before puberty and then decreased with age in females. WBC and platelet counts were the highest in early childhood and decreased with age. Sex differences in each age group were noted: WBC count was higher in males than in females during adulthood, but platelet count was higher in females than in males from puberty onwards (P<0.001). Neutrophil count was the lowest in early childhood and increased with age. Lymphocyte count decreased with age after peaking in early childhood. Eosinophil count was the highest in childhood and higher in males than in females. Monocyte count was higher in males than in females (P<0.001). CONCLUSIONS: We provide comprehensive age- and sex-specific RIs for CBC parameters, which show dynamic changes with both age and sex. PMID- 30027693 TI - An Automated Draft Report Generator for Peripheral Blood Smear Examinations Based on Complete Blood Count Parameters. AB - BACKGROUND: Complete blood count (CBC) results play an important role in peripheral blood smear (PBS) examinations. Many descriptions in PBS reports may simply be translated from CBC parameters. We developed a computer program that automatically generates a PBS draft report based on CBC parameters and age- and sex-matched reference ranges. METHODS: The Java programming language was used to develop a computer program that supports a graphical user interface. Four hematology analyzers from three different laboratories were tested: Sysmex XE 5000 (Sysmex, Kobe, Japan), Sysmex XN-9000 (Sysmex), DxH800 (Beckman Coulter, Brea, CA, USA), and ADVIA 2120i (Siemens Healthcare Diagnostics, Eschborn, Germany). Input data files containing 862 CBC results were generated from hematology analyzers, middlewares, or laboratory information systems. The draft reports were compared with the content of input data files. RESULTS: We developed a computer program that reads CBC results from a data file and automatically writes a draft PBS report. Age- and sex-matched reference ranges can be automatically applied. After examining PBS, users can modify the draft report based on microscopic findings. Recommendations such as suggestions for further evaluations are also provided based on morphological findings, and they can be modified by users. The program was compatible with all four hematology analyzers tested. CONCLUSIONS: Our program is expected to reduce the time required to manually incorporate CBC results into PBS reports. Systematic inclusion of CBC results could help improve the reliability and sensitivity of PBS examinations. PMID- 30027694 TI - Removing Lipemia in Serum/Plasma Samples: A Multicenter Study. AB - BACKGROUND: Lipemia, a significant source of analytical errors in clinical laboratory settings, should be removed prior to measuring biochemical parameters. We investigated whether lipemia in serum/plasma samples can be removed using a method that is easier and more practicable than ultracentrifugation, the current reference method. METHODS: Seven hospital laboratories in Spain participated in this study. We first compared the effectiveness of ultracentrifugation (108,200*g) and high-speed centrifugation (10,000*g for 15 minutes) in removing lipemia. Second, we compared high-speed centrifugation with two liquid-liquid extraction methods-LipoClear (StatSpin, Norwood, USA), and 1,1,2 trichlorotrifluoroethane (Merck, Darmstadt, Germany). We assessed 14 biochemical parameters: serum/plasma concentrations of sodium ion, potassium ion, chloride ion, glucose, total protein, albumin, creatinine, urea, alkaline phosphatase, gamma-glutamyl transferase, alanine aminotransferase, aspartate-aminotransferase, calcium, and bilirubin. We analyzed whether the differences between lipemia removal methods exceeded the limit for clinically significant interference (LCSI). RESULTS: When ultracentrifugation and high-speed centrifugation were compared, no parameter had a difference that exceeded the LCSI. When high-speed centrifugation was compared with the two liquid-liquid extraction methods, we found differences exceeding the LCSI in protein, calcium, and aspartate aminotransferase in the comparison with 1,1,2-trichlorotrifluoroethane, and in protein, albumin, and calcium in the comparison with LipoClear. Differences in other parameters did not exceed the LCSI. CONCLUSIONS: High-speed centrifugation (10,000*g for 15 minutes) can be used instead of ultracentrifugation to remove lipemia in serum/plasma samples. LipoClear and 1,1,2-trichlorotrifluoroethane are unsuitable as they interfere with the measurement of certain parameters. PMID- 30027696 TI - Clinical Utility and Cross-Reactivity of Insulin and C-Peptide Assays by the Lumipulse G1200 System. AB - BACKGROUND: Measurement of insulin and C-peptide concentrations is important for deciding whether insulin treatment is required in diabetic patients. We aimed to investigate the analytical performance of insulin and C-peptide assays using the Lumipulse G1200 system (Fujirebio Inc., Tokyo, Japan). METHODS: We examined the precision, linearity, and cross-reactivity of insulin and C-peptide using five insulin analogues and purified proinsulin. A method comparison was conducted between the Lumipulse G1200 and Roche E170 (Roche Diagnostics, Mannheim, Germany) systems in 200 diabetic patients on insulin treatment. Reference intervals for insulin and C-peptide concentrations were determined in 279 healthy individuals. RESULTS: For insulin and C-peptide assays, within-laboratory precision (% CV) was 3.78-4.14 and 2.89-3.35%, respectively. The linearity of the insulin assay in the range of 0-2,778 pmol/L was R2=0.9997, and that of the C-peptide assay in the range of 0-10 nmol/L was R2=0.9996. The correlation coefficient (r) between the Roche E170 and Lumipulse G1200 results was 0.943 (P<0.001) for insulin and 0.996 (P<0.001) for C-peptide. The mean differences in insulin and C-peptide between Lumipulse G1200 and the Roche E170 were 19.4 pmol/L and 0.2 nmol/L, respectively. None of the insulin analogues or proinsulin showed significant cross-reactivity with the Lumipulse G1200. Reference intervals of insulin and C-peptide were 7.64 70.14 pmol/L and 0.17-0.85 nmol/L, respectively. CONCLUSIONS: Insulin and C peptide tests on the Lumipulse G1200 show adequate analytical performance and are expected to be acceptable for use in clinical areas. PMID- 30027695 TI - Plasma Neutrophil Gelatinase-Associated Lipocalin as a Marker of Tubular Damage in Diabetic Nephropathy. AB - BACKGROUND: An increase in neutrophil gelatinase-associated lipocalin (NGAL) indicates tubular injury. Diabetic nephropathy causes typical changes in the kidney, characterized by glomerulosclerosis and eventual tubular damage. We validated the usefulness of plasma NGAL (pNGAL) as a biomarker of tubular damage in patients with diabetic nephropathy. METHODS: We included 376 patients with diabetes mellitus (260 patients with chronic renal insufficiency who had not received hemodialysis and 116 hemodialyzed due to diabetic nephropathy) and 24 healthy controls. Patients with chronic renal insufficiency were divided into three groups according to urinary albumin excretion (UAE) levels. pNGAL levels were measured using the Triage NGAL test (Alere, San Diego, CA, USA) and were compared between groups. We also examined whether pNGAL level was related to the degree of albuminuria and cystatin C-based glomerular filtration rate (GFR). RESULTS: Mean pNGAL levels of the healthy controls, chronic renal insufficiency patients with diabetes mellitus, and hemodialyzed patients were 61.9+/-5.3 ng/mL, 93.4+/-71.8 ng/mL, and 1,536.9+/-554.9 ng/mL, respectively. pNGAL level increased significantly in patients with severe albuminuria (P<0.001) and had a moderate correlation with the degree of albuminuria (r=0.467; P<0.001) and GFR (r=0.519; P<0.001). Multivariate regression analysis showed that the pNGAL level was associated with tubular damage independent of patient age, sex, and GFR. CONCLUSIONS: pNGAL level independently reflects the degree of tubular damage in patients with diabetic nephropathy. Measurement of pNGAL, combined with UAE, would enable simultaneous, highly reliable assessments of tubular damage for such patients. PMID- 30027697 TI - Serum Copeptin Levels Predict Clinical Outcomes After Successful Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction. AB - BACKGROUND: Serum copeptin has been demonstrated to be useful in early risk stratification and prognostication of patients with acute myocardial infarction (AMI). However, the prognostic value of copeptin after percutaneous coronary intervention (PCI) for clinical outcomes remains uncertain. We investigated the prognostic role of serum copeptin levels immediately after successful PCI as a prognostic marker for major adverse cardiac events (MACE; comprising death, repeat PCI, recurrent MI, or coronary artery bypass grafting) in patients with AMI. METHODS: A retrospective study was performed in 149 patients with AMI who successfully received PCI. Serum copeptin levels were analyzed in blood samples collected immediately after PCI. The association between copeptin levels and MACE during the follow-up period was evaluated. RESULTS: MACE occurred in 34 (22.8%) patients during a median follow-up of 30.1 months. MACE patients had higher copeptin levels than non-MACE patients did. Multiple logistic regression analysis showed that the increase in serum copeptin levels was associated with increased MACE incidence (odds ratio=1.6, P=0.005). CONCLUSIONS: A high level of serum copeptin measured immediately after PCI was associated with MACE in patients with AMI during long-term follow-up. Serum copeptin levels can serve as a prognostic marker in patients with AMI after successful PCI. PMID- 30027698 TI - Differences in Colistin-resistant Acinetobacter baumannii Clinical Isolates Between Patients With and Without Prior Colistin Treatment. AB - BACKGROUND: The increasing morbidity and mortality rates associated with Acinetobacter baumannii are due to the emergence of drug resistance and the limited treatment options. We compared characteristics of colistin-resistant Acinetobacter baumannii (CR-AB) clinical isolates recovered from patients with and without prior colistin treatment. We assessed whether prior colistin treatment affects the resistance mechanism of CR-AB isolates, mortality rates, and clinical characteristics. Additionally, a proper method for identifying CR-AB was determined. METHODS: We collected 36 non-duplicate CR-AB clinical isolates resistant to colistin. Antimicrobial susceptibility testing, Sanger sequencing analysis, molecular typing, lipid A structure analysis, and in vitro synergy testing were performed. Eleven colistin-susceptible AB isolates were used as controls. RESULTS: Despite no differences in clinical characteristics between patients with and without prior colistin treatment, resistance-causing genetic mutations were more frequent in isolates from colistin-treated patients. Distinct mutations were overlooked via the Sanger sequencing method, perhaps because of a masking effect by the colistin-susceptible AB subpopulation of CR-AB isolates lacking genetic mutations. However, modified lipid A analysis revealed colistin resistance peaks, despite the population heterogeneity, and peak levels were significantly different between the groups. CONCLUSIONS: Although prior colistin use did not induce clinical or susceptibility differences, we demonstrated that identification of CR-AB by sequencing is insufficient. We propose that population heterogeneity has a masking effect, especially in colistin non-treated patients; therefore, accurate testing methods reflecting physiological alterations of the bacteria, such as phosphoethanolamine-modified lipid A identification by matrix assisted laser desorption ionization-time of flight, should be employed. PMID- 30027699 TI - Detection of mcr-1 Plasmids in Enterobacteriaceae Isolates From Human Specimens: Comparison With Those in Escherichia coli Isolates From Livestock in Korea. AB - BACKGROUND: The emerging mobile colistin resistance gene, mcr-1, is an ongoing worldwide concern and an evaluation of clinical isolates harboring this gene is required in Korea. We investigated mcr-1-possessing Enterobacteriaceae among Enterobacteriaceae strains isolated in Korea, and compared the genetic details of the plasmids with those in Escherichia coli isolates from livestock. METHODS: Among 9,396 Enterobacteriaceae clinical isolates collected between 2010 and 2015, 1,347 (14.3%) strains were resistant to colistin and those were screened for mcr 1 by PCR. Colistin minimum inhibitory concentrations (MICs) were determined by microdilution, and conjugal transfer of the mcr-1-harboring plasmids was assessed by direct mating. Whole genomes of three mcr-1-positive Enterobacteriaceae clinical isolates and 11 livestock-origin mcr-1-positive E. coli isolates were sequenced. RESULTS: Two E. coli and one Enterobacter aerogenes clinical isolates carried carried IncI2 plasmids harboring mcr-1, which conferred colistin resistance (E. coli MIC, 4 mg/L; E. aerogenes MIC, 32 mg/L). The strains possessed the complete conjugal machinery except for E. aerogenes harboring a truncated prepilin peptidase. The E. coli plasmid transferred more efficiently to E. coli than to Klebsiella pneumoniae or Enterobacter cloacae recipients. Among the three bacterial hosts, the colistin MIC was the highest for E. coli owing to the higher mcr-1-plasmid copy number and mcr-1 expression levels. Ten mcr-1 positive chicken-origin E. coli strains also possessed mcr-1-harboring IncI2 plasmids closely related to that in the clinical E. aerogenes isolate, and the remaining one porcine-origin E. coli possessed an mcr-1-harboring IncX4 plasmid. CONCLUSIONS: mcr-1-harboring IncI2 plasmids were identified in clinical Enterobacteriaceae isolates. These plasmids were closely associated with those in chicken-origin E. coli strains in Korea, supporting the concept of mcr-1 dissemination between humans and livestock. PMID- 30027700 TI - Delamanid, Bedaquiline, and Linezolid Minimum Inhibitory Concentration Distributions and Resistance-related Gene Mutations in Multidrug-resistant and Extensively Drug-resistant Tuberculosis in Korea. AB - BACKGROUND: Delamanid, bedaquiline, and linezolid have recently been approved for the treatment of multidrug- and extensively drug-resistant (MDR and XDR, respectively) tuberculosis (TB). To use these drugs effectively, drug susceptibility tests, including rapid molecular techniques, are required for accurate diagnosis and treatment. Furthermore, mutation analyses are needed to assess the potential for resistance. We evaluated the minimum inhibitory concentrations (MICs) of these three anti-TB drugs for Korean MDR and XDR clinical strains and mutations in genes related to resistance to these drugs. METHODS: MICs were determined for delamanid, bedaquiline, and linezolid using a microdilution method. The PCR products of drug resistance-related genes from 420 clinical Mycobacterium tuberculosis strains were sequenced and aligned to those of M. tuberculosis H37Rv. RESULTS: The overall MICs for delamanid, bedaquiline, and linezolid ranged from <=0.025 to >1.6 mg/L, <=0.0312 to >4 mg/L, and <=0.125 to 1 mg/L, respectively. Numerous mutations were found in drug-susceptible and resistant strains. We did not detect specific mutations associated with resistance to bedaquiline and linezolid. However, the Gly81Ser and Gly81Asp mutations were associated with resistance to delamanid. CONCLUSIONS: We determined the MICs of three anti-TB drugs for Korean MDR and XDR strains and identified various mutations in resistance-related genes. Further studies are needed to determine the genetic mechanisms underlying resistance to these drugs. PMID- 30027701 TI - Detection of Rifampicin- and Isoniazid-Resistant Mycobacterium tuberculosis Using the Quantamatrix Multiplexed Assay Platform System. AB - BACKGROUND: The increasing prevalence of drug-resistant tuberculosis (TB) infection represents a global public health emergency. We evaluated the usefulness of a newly developed multiplexed, bead-based bioassay (Quantamatrix Multiplexed Assay Platform [QMAP], QuantaMatrix, Seoul, Korea) to rapidly identify the Mycobacterium tuberculosis complex (MTBC) and detect rifampicin (RIF) and isoniazid (INH) resistance-associated mutations. METHODS: A total of 200 clinical isolates from respiratory samples were used. Phenotypic anti-TB drug susceptibility testing (DST) results were compared with those of the QMAP system, reverse blot hybridization (REBA) MTB-MDR assay, and gene sequencing analysis. RESULTS: Compared with the phenotypic DST results, the sensitivity and specificity of the QMAP system were 96.4% (106/110; 95% confidence interval [CI] 0.9072-0.9888) and 80.0% (72/90; 95% CI 0.7052-0.8705), respectively, for RIF resistance and 75.0% (108/144; 95% CI 0.6731-0.8139) and 96.4% (54/56; 95% CI 0.8718-0.9972), respectively, for INH resistance. The agreement rates between the QMAP system and REBA MTB-MDR assay for RIF and INH resistance detection were 97.6% (121/124; 95% CI 0.9282-0.9949) and 99.1% (109/110; 95% CI 0.9453-1.0000), respectively. Comparison between the QMAP system and gene sequencing analysis showed an overall agreement of 100% for RIF resistance (110/110; 95% CI 0.9711 1.0000) and INH resistance (124/124; 95% CI 0.9743-1.0000). CONCLUSIONS: The QMAP system may serve as a useful screening method for identifying and accurately discriminating MTBC from non-tuberculous mycobacteria, as well as determining RIF and INH-resistant MTB strains. PMID- 30027702 TI - Development of a Rapid Automated Fluorescent Lateral Flow Immunoassay to Detect Hepatitis B Surface Antigen (HBsAg), Antibody to HBsAg, and Antibody to Hepatitis C. AB - BACKGROUND: Accurate, rapid, and cost-effective screening tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may be useful in laboratories that cannot afford automated chemiluminescent immunoassays (CLIAs). We evaluated the diagnostic performance of a novel rapid automated fluorescent lateral flow immunoassay (LFIA). METHODS: A fluorescent LFIA using a small bench-top fluorescence reader, Automated Fluorescent Immunoassay System (AFIAS; Boditech Med Inc., Chuncheon, Korea), was developed for qualitative detection of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HCV (anti-HCV) within 20 minutes. We compared the diagnostic performance of AFIAS with that of automated CLIAs-Elecsys (Roche Diagnostics GmbH, Penzberg, Germany) and ARCHITECT (Abbott Laboratories, Abbott Park, IL, USA)-using 20 seroconversion panels and 3,500 clinical serum samples. RESULTS: Evaluation with the seroconversion panels demonstrated that AFIAS had adequate sensitivity for HBsAg and anti-HCV detection. From the clinical samples, AFIAS sensitivity and specificity were 99.8% and 99.3% for the HBsAg test, 100.0% and 100.0% for the anti-HBs test, and 98.8% and 99.1% for the anti-HCV test, respectively. Its agreement rates with the Elecsys HBsAg, anti-HBs, and anti-HCV detection assays were 99.4%, 100.0%, and 99.0%, respectively. AFIAS detected all samples with HBsAg genotypes A-F and H and anti-HCV genotypes 1, 1a, 1b, 2a, 2b, 4, and 6. Cross-reactivity with other infections was not observed. CONCLUSIONS: The AFIAS HBsAg, anti-HBs, and anti-HCV tests demonstrated diagnostic performance equivalent to current automated CLIAs. AFIAS could be used for a large-scale HBV or HCV screening in low-resource laboratories or low-to middle-income areas. PMID- 30027703 TI - Weak D Testing is not Required for D- Patients With C-E- Phenotype. AB - BACKGROUND: Although testing to detect weak D antigens using the antihuman globulin reagent is not required for D- patients in many countries, it is routinely performed in Korea. However, weak D testing can be omitted in D- patients with a C-E- phenotype as this indicates complete deletion of the RHD gene, except in rare cases. We designed a new algorithm for weak D testing, which consisted of RhCE phenotyping followed by weak D testing in C+ or E+ samples, and compared it with the current algorithm with respect to time and cost effectiveness. METHODS: In this retrospective study, 74,889 test results from January to July 2017 in a tertiary hospital in Korea were analyzed. Agreement between the current and proposed algorithms was evaluated, and total number of tests, time required for testing, and test costs were compared. With both algorithms, RHD genotyping was conducted for samples that were C+ or E+ and negative for weak D testing. RESULTS: The algorithms showed perfect agreement (agreement=100%; kappa=1.00). By applying the proposed algorithm, 29.56% (115/389 tests/yr) of tests could be omitted, time required for testing could be reduced by 36% (8,672/24,084 min/yr), and the test cost could be reduced by 16.53% (536.11/3,241.08 USD/yr). CONCLUSIONS: Our algorithm omitting weak D testing in D patients with C-E- phenotype may be a cost-effective testing strategy in Korea. PMID- 30027704 TI - Association of FOXP3 Single Nucleotide Polymorphisms With Clinical Outcomes After Allogenic Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: Forkhead box P3 (FOXP3) is an important marker of regulatory T cells. FOXP3 polymorphisms are associated with autoimmune diseases, cancers, and allograft outcomes. We examined whether single nucleotide polymorphisms (SNPs) at the FOXP3 locus are associated with clinical outcomes after allogenic hematopoietic stem cell transplantation (HSCT). METHODS: Five FOXP3 SNPs (rs5902434, rs3761549, rs3761548, rs2232365, and rs2280883) were analyzed by PCR sequencing of 172 DNA samples from allogenic HSCT patients. We examined the relationship between each SNP and the occurrence of graft-versus-host disease (GVHD), post-HSCT infection, relapse, and patient survival. RESULTS: Patients with acute GVHD (grades II-IV) showed higher frequencies of the rs3761549 T/T genotype, rs5902434 ATT/ATT genotype, and rs2232365 G/G genotype than did patients without acute GVHD (P=0.017, odds ratio [OR]=5.3; P=0.031, OR=2.4; and P=0.023, OR=2.6, respectively). Multivariate analysis showed that the TT genotype of rs3761549 was an independent risk factor for occurrence of acute GVHD (P=0.032, hazard ratio=5.6). In contrast, the genotype frequencies of rs3761549 T/T, rs5902434 ATT/ATT, and rs2232365 G/G were lower in patients with post-HSCT infection than in patients without infection (P=0.026, P=0.046, and P=0.031, respectively). CONCLUSIONS: rs3761549, rs5902434, and rs2232365 are associated with an increased risk of acute GVHD and decreased risk of post-HSCT infection. PMID- 30027705 TI - Frequency of Red Blood Cell Antigens According to Parent Ethnicity in Korea Using Molecular Typing. AB - Frequencies of red blood cell (RBC) blood group antigens differ by ethnicity. Since the number of immigrants is increasing in Korea, RBC antigens should be assessed in children/youths with parents of different ethnicities to ensure safe transfusions. We investigated the frequency of RBC antigens, except for ABO and RhD, in 382 children and youths with parents having Korean and non-Korean ethnicities. Subjects were divided into those with ethnically Korean parents (Korean group; N=252) and those with at least one parent of non-Korean ethnicity (non-Korean group; N=130). The 37 RBC antigens were genotyped using the ID CORE XT system (Progenika Biopharma-Grifols, Bizkaia, Spain). The frequencies of the Rh (E, C, e, hr(S), and hr(B)), Duffy (Fy(a)), MNS (Mi(a)), and Cartwright (Yt(b)) antigens differed significantly between the two groups. Eight and 11 subjects in the Korean and non-Korean groups, respectively, exhibited negative expression of high-frequency antigens, whereas 14 subjects in the non-Korean group showed positive expression of low-frequency antigens. The frequency of RBC antigens has altered alongside demographic changes in Korea and might lead to changes in distribution of RBC antibodies that cause acute or delayed hemolytic transfusion reaction. PMID- 30027706 TI - First Case of Necrotizing Fasciitis Caused by Skermanella aerolata Infection Mimicking Vibrio Sepsis. PMID- 30027707 TI - The First Case of Chronic Otitis Media due to Kerstersia gyiorum in Korea. PMID- 30027708 TI - Utility of 16S rRNA PCR in the Synovial Fluid for the Diagnosis of Prosthetic Joint Infection. PMID- 30027709 TI - A Case of Cruoricaptor ignavus Isolated From the Blood of a Patient With Ewing Sarcoma. PMID- 30027710 TI - Clinical Features of Multiple Acyl-CoA Dehydrogenase Deficiency With ETFDH Variants in the First Korean Cases. PMID- 30027712 TI - Image reconstruction with the Heaviside equation in photoacoustic tomography accounting for dispersive acoustic media. AB - A challenging issue in photoacoustic biomedical imaging is to take into account the presence of dispersive acoustic media, since these are prone to induce amplitude attenuation and scattering of the photoacoustic frequency components. These perturbations are largely the cause for which the photoacoustic tomographic image reconstruction from projections lacks a plane-wave transport formalism. Attending this problem, we further develop an analytic formalism of the transport and its numerical implementation accounting for dispersive acoustic media. We differentiate three variations of an acoustically perturbing media. Our object of interest is a numerical description of the light absorption map of a coronal human breast image. Then, we analyze conditions for which the propagation of photoacoustic perturbations can obey the generalized Heaviside telegraph equation. In addition, we provide a study of the causality consistency of the wave propagation models. We observe transport implications due to the presence of dispersive acoustic media and derive model adjustments that include attenuation and diffusion approximations within the two-dimensional forward problem. Next, we restore the inverse problem description with the deduced perturbation components. Finally, we solve the nonlinear inverse problem with a numerical strategy for a filtered backprojection reconstruction. At a stage prior to the image reconstruction, we compensate for the effect of acoustic attenuation and diffusion to calculate the inversions of the wave perturbations located within the projections. In this way, we manage to significantly reduce reconstruction artifacts. In consequence, we prevent the use of some additional image processing of noise reduction. We demonstrate a feasible strategy on how to solve the stated nonlinear inverse problem of photoacoustic tomography accounting for dispersive acoustic media. In particular, we emphasize efforts to achieve an analytical description, and thus an algorithm is placed, for imaged sound perturbations to be cleaned from acoustic scattering in a simplified manner. PMID- 30027711 TI - Characterizing Atypical BCL6 Signal Patterns Detected by Digital Fluorescence In Situ Hybridization (FISH) Analysis. PMID- 30027713 TI - Current Status of Prostaglandins for Cervical Ripening. AB - OBJECTIVE: To review the safety and efficacy of administering various prostaglandin formulations to achieve cervical ripening and spontaneous vaginal delivery in women near or at term.STUDY DESIGN: Peer-reviewed clinical research articles in English and searchable on PubMed.com. A thorough literature search was conducted on PubMed.com using the following terms: [misoprostol], [dinoprostone], [prostaglandin E1], [prostaglandin E2], [PGE1], [PGE2], [cervical ripening], [induction of labor].RESULTS: The review shows conflicting opinions concerning the safety and efficacy of current standard-of-care formulations for cervical ripening. A gold standard option for optimal treatment has not been confirmed.CONCLUSION: While the clinical evidence suggests that prostaglandin E1 (PGE1) and E2 (PGE2) both could be used for cervical ripening when no contraindications are present, PGE2 formulations remain the only commercially available prostaglandin products for cervical ripening approved by the U.S. Food and Drug Administration. We conclude that more research is warranted on the risks of treatment-emergent adverse events and serious complications during induction of labor. PMID- 30027714 TI - Use of Concomitant FSH with hCG at the Time of Trigger May Improve Success Rates of Couples with Poor Ovarian Response Undergoing Gonadotropin Therapy with IUI. AB - OBJECTIVE: To investigate if administration of an additional dose of gonadotropins concomitantly to human chorionic gonadotropin (hCG) trigger increases pregnancy rates in patients undergoing intrauterine insemination (IUI) with controlled ovarian hyperstimulation (COH).STUDY DESIGN: This is a retrospective cohort study of all gonadotropin-IUI cycles performed by a single physician in a private practice between January 2012 and September 2013. Control cycles were those in which follicle-stimulating hormone (FSH) was discontinued prior to the day of hCG trigger shot, and study cycles received continuous FSH including the day of hCG trigger shot. A total of 423 cycles from 239 patients were included; 275 (65.5%) were control cycles (137 patients), and 146 (34.7%) were study cycles (102 patients).RESULTS: Pregnancy rates were comparable in both control and study groups (15.27% vs. 15.07%, respectively, p=0.956). There was a 42% increase in multiple gestations in the study group; however, the difference was not statistically significant (p=0.155). Upon multivariate logistic regression, male factor infertility was the only variable that was associated with pregnancy outcomes.CONCLUSION: Continuous administration of FSH including the day of hCG trigger in patients undergoing COH with IUI does not seem to increase pregnancy rates. Our suggested protocol might be beneficial in patients with poor ovarian response. PMID- 30027715 TI - HER-2 Expression and Response to Radiotherapy in Patients with Advanced Cervical Cancer. AB - Glauco Baiocchi, M.D., Ph.D., Maria Dirlei Begnami, M.D., Ph.D., Michael Jenwei Chen, M.D., Elza Mieko Fukazawa, M.D., Ph.D., Levon Badiglian-Filho, M.D., Ph.D., Antonio Cassio Assis Pellizzon, M.D., Ph.D., Fernando Augusto Soares, M.D., Ph.D., and Ademar Lopes, M.D., Ph.D. OBJECTIVE: To evaluate HER-2 expression as a predictor of the response to radiotherapy and its value as a prognostic marker.STUDY DESIGN: A retrospective analysis was performed in a series of 34 individuals with advanced stage cervical cancer who underwent radiotherapy followed by radical hysterectomy. HER-2 expression was measured by immunohistochemistry in biopsies from all patients prior to radiotherapy and in 14 patients with residual tumors after radiotherapy. The presence of gene amplification was also examined.RESULTS: Eighteen (53%) patients had residual disease after radical hysterectomy. HER-2 was expressed in 26.5% of cases. Gene amplification by FISH was detected in 2.9% of cases. HER-2 expression was associated with a higher risk of residual disease after radiotherapy (p= 0.019). HER-2 expression did not correlate with the risk of recurrence or death.CONCLUSION: The prevalence of HER-2 expression is low in cervical cancer, and although HER-2 can predict the response to radiotherapy, it does not correlate with poor outcomes. PMID- 30027716 TI - Human Embryo Morphokinetics Correlation with Obstetric Outcomes and Antepartum Biomarkers. AB - OBJECTIVE: To evaluate the correlation between em-bryo morphology and antepartum biomarker levels and obstetric outcomes following single embryo transfers (SETs).STUDY DESIGN: In vitro fertilization patients who delivered at the study site's partnering hospital were included. Embryo morphology was compared to antepartum biomarkers and pregnancy outcomes.RESULTS: At a single academic reproductive endocrinology/infertility center, 2,882 SETs (day 3, 5, or 6) were performed from July 1, 2001, to June 30, 2013. Embryologic, serologic, and obstetric outcomes were available for 78 patients (cleavage [n=23]; blastocyst [n=55]). Embryos with a lower quality inner cell mass (ICM) demonstrated higher second trimester maternal serum alpha-fetoprotein (AFP) (p=0.0241) and AFP multiple of median (MoM) (p= 0.0036). After adjusting for age, body mass index, parity, and smoking status, this statistical significance remained (p=0.0319 for AFP; p=0.0026 for AFP MoM).CONCLUSION: Embryo morphokinetics did not correlate with perinatal outcome or a majority of placental biomarkers. A low ICM score was associated with higher second trimester maternal serum AFP values. This warrants further investigation, especially due to the risks of potential adverse obstetric outcomes associated with high AFP levels. Despite these findings, no difference in obstetric outcomes between low and high ICM scores was observed after controlling for maternal confounding variables. Patients should be reassured that embryo implantation, regardless of morphological score, results in similar obstetric outcomes. PMID- 30027717 TI - Role of Capecitabine in the Management of Gestational Trophoblastic Neoplasia: A Drug for Two Settings. AB - OBJECTIVE: To evaluate the role of capecitabine in the management of gestational trophoblastic neoplasia (GTN).STUDY DESIGN: The medical records of 155 patients with GTN were reviewed. All patients were treated and followed at our center.RESULTS: All patients were scored and stratified with the FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease. In the low-risk group (118 patients), 4 selected patients received capecitabine as second line of treatment, with a 75% response rate and long-term disease-free survival, and 1 of those patients needed EMA/CO to achieve cure. The cure rate was 100%. In the high-risk group 37 patients were reviewed. Capecitabine was indicated after EMA/CO or EMA/PE failure in the second, third, or sixth line. Six patients received capecitabine, with a 50% response rate, and remain as long-term survivors. Two patients who progressed with capecitabine were cured with TP/TE and EMA/PE regimens. One patient was refractory to all lines of chemotherapy.CONCLUSION: The use of capecitabine avoids multi-ple drug schemes and further toxicity for patients with curative disease, where long-term effects of therapy should be considered a second target. Its convenient oral route of administration and efficacy make capecitabine a drug to be taken into account in future studies of patients with GTN showing progression to standard regimens. Its use as new regimen in these patients must be evaluated. A greater number of cases and ideally a randomized study is needed to confirm our observation. PMID- 30027718 TI - Comparison of Loop Electrosurgical Excision Procedure Using a Ring-Shaped Loop Versus a Right-Angled Triangular Loop. AB - OBJECTIVE: To compare the resection margin (RM) status and postoperative severe hemorrhage using different loop electrosurgical excision procedure (LEEP) techniques for cervical intraepithelial neoplasia (CIN) 2/3 treatment.STUDY DESIGN: We retrospectively reviewed 278 patients who underwent LEEPs for CIN 2/3 treatment at our institute between 2005-2014. In type A surgery (N=148), a ring shaped loop was used. If the first pass failed to remove the entire lesion, separate loop excisions for the intracervical portion were performed. In type B surgery (N=130), a right-angled triangular loop in a single pass was used. Surgical outcomes and postoperative severe hemorrhage were compared between the two groups. Logistic regression analysis was performed to identify the independent predictors of RM status.RESULTS: The mean LEEP depth was larger after type A surgery (2.2 vs. 2.0 cm, respectively; p=0.04). Type B surgery showed lower rate of 30-day postoperative hemorrhage (13.8% vs. 26.4%, p<0.05) and higher rate of negative RM (68.9% vs. 82.3%, p<0.05). Multivariate analysis identified the surgery type (p=0.01, OR=0.45 [0.24-0.83]) and a postoperative pathological diagnosis of CIN3 (p=0.01, OR=2.53 [1.22-5.26]) as independent risk factors for positive RM.CONCLUSION: LEEPs using a right-angled triangular loop could reduce positive RMs. PMID- 30027719 TI - Gene Expression Analysis Identifies Common and Distinct Signatures Underlying Ductal and Lobular Breast Cancers. AB - OBJECTIVE: To uncover potential genes and biological processes that contribute to breast cancer development.STUDY DESIGN: We studied gene expression profiles, which are publicly available from the Gene Expression Omnibus database, for the 2 most prevailing subtypes of breast cancer: lobular and ductal invasive breast carcinomas.RESULTS: We identified a total of 98 genes that shared regulation pattern in both subtypes of breast carcinoma. Further functional annotations indicated that 124 biological processes and 8 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were over-represented, such as cell surface receptor signaling pathway. We also identified unique gene expression profiles in each subtype of breast cancer. A total of 460 genes were solely differentially expressed between ductal cancer cells and normal cells, and 75 biological processes and 10 KEGG pathways were enriched by these 460 differential genes, including cell proliferation and regulation of cell death. Meanwhile, 308 genes were found to be differentially expressed between lobular cancer cells and normal cells. Intriguingly, only 11 biological processes and 8 KEGG pathways showed overrepresentation among these 308 genes, such as collagen metabolic process.CONCLUSION: Cumulatively, our results indicate that the invasive lobular and ductal carcinomas share a similar profile of gene expression and pathway alteration but also harbor subtype-specific mechanisms of tumorigenesis. PMID- 30027721 TI - Analysis of Related Causes for No Embryos Transferred and Corresponding Coping Measures in Assisted Reproductive Technology. AB - OBJECTIVE: To analyze the related causes for no embryos transferred in assisted reproductive technology (ART) in order to provide corresponding coping measures for infertile couples.STUDY DESIGN: The data of 607 couples who underwent ART and had no embryos transferred in our reproductive center between January 2010 and January 2014 were retrospectively analyzed.RESULTS: The cycles of no embryos transferred accounted for 3.99% (607/15,224) of total cycles. Of those, complete fertilization failure, oocyte retrieval failure, and complete abnormal fertilization accounted for 28.3% (172/607), 25.7% (156/607) and 22.24% (135/607), respectively. The incidence of complete abnormal fertilization was higher in IVF than in ICSI (p<0.05). In both IVF and ICSI cycles, the incidences of no embryos transferred were higher in the patients retrieving <=3 oocytes than in the patients retrieving >3 oocytes (p<0.05). In IVF cycles the incidences of no embryos transferred were higher in the patients with primary infertility than in those with secondary infertility (p<0.05).CONCLUSION: The main causes of no embryos transferred are complete fertilization failure, oocyte retrieval failure, and complete abnormal fertilization. Retrieving adequate number of mature oocytes is the key to success of ART. Patients who experienced complete abnormal fertilization in IVF or the patients with primary infertility who experienced complete fertilization failure or normal fertilization without cleavage should receive ICSI in the next treatment. PMID- 30027722 TI - Cesarean Section Rates and Clinical Indications at a Large North African Hospital. AB - OBJECTIVE: To investigate the trend of cesarean section (CS) delivery rate and CS indications between January 2009 and December 2013 at Hassan II Hospital, Settat, Morocco.STUDY DESIGN: The demographic characteristics of women who gave birth at the hospital during the study period were collected. A total of 36,965 puerperal patients (aged 14-52 years at 33-42 weeks' gestation) were enrolled. Delivery outcomes and the indication for CS delivery were studied.RESULTS: The CS rate increased from 11.48% in 2009 to 14.76% in 2013 (p<0.05), and the perinatal mortality rate decreased from 3.34% in 2009 to 2.24% in 2013 (p<0.05). The 3 most common indications for CS delivery were previous lower segment CS, cephalopelvic disproportion, and intrauterine growth restriction.CONCLUSION: There is a trend of increasing CS rate at Hassan II Hospital. Previous lower segment CS, cephalopelvic disproportion, and intrauterine growth restriction are the 3 most common CS indications. PMID- 30027723 TI - Contribution of Magnetic Resonance Imaging to Ultrasound for the Evaluation of Fetal Central Nervous System Anomalies. AB - OBJECTIVE: To evaluate whether magnetic resonance imaging (MRI) contributes to ultrasound for the evaluation of fetal central nervous system (CNS) anomalies. The secondary objective was to investigate whether MRI adds more information regarding the evaluation of specific pathologies or conditions.STUDY DESIGN: We retrospectively compared fetal MRI findings with ultrasound findings in CNS anomalies with respect to certain pathologic groups. Additionally, we evaluated diagnostic accuracy by comparing fetal MRI and ultrasound findings with postnatal findings.RESULTS: A total of 34 patients had 40 provisional diagnoses by fetal ultrasound, and of those patients 14 had a provisional diagnosis of ventriculomegaly and 14 had a provisional diagnosis of cerebellar or posterior fossa anomalies. MRI added to or changed the diagnosis in 52.5% of the patients with CNS abnormalities. The contribution rate in ventriculomegaly was 71.4%, and MRI changed the diagnosis in all indefinite diagnoses by ultrasound. Additionally, of the 15 patients with postnatal findings, there were no cases in which only the ultrasound findings were correct, but the MRI findings were incorrect.CONCLUSION: MRI contributes to ultrasound in the diagnosis of CNS anomalies. Cases of indefinite diagnosis and ventriculomegaly by ultrasound had greater benefit from MRI. PMID- 30027724 TI - Effect of Obesity on Clinical Parameters and Pregnancy Rates in Women with Polycystic Ovary Syndrome Undergoing Ovulation Induction Cycles. AB - OBJECTIVE: To evaluate the effect of obesity on clinical parameters and pregnancy rates in infertile women with polycystic ovary syndrome (PCOS), who have undergone ovulation induction.STUDY DESIGN: This retrospective study included 177 women with PCOS who presented to our gynecological endocrinology outpatient clinic for diagnosed infertility. All of the patients initially received clomiphene citrate (CC), and if CC resistance was noted, gonadotropins were used. The patients were classified into 2 groups according to BMI (<30 kg/m2=control group and >=30 kg/m2=study group). Pregnancy was assessed by beta-hCG levels and a visible gestational sac in the endometrium.RESULTS: The demographic and hormonal parameters were similar between the groups. The mean duration of infertility was longer in the study group (p<0.05). In the study group, cycle cancellation due to CC resistance (p=0.039) and mean baseline LH levels (p=0.026) was statistically more likely than in the control group. On follow-up, 4 (9.3%) patients in the study group had conceived and 26 (19.4%) patients in the control group had conceived (p=0.041).CONCLUSION: Obesity adversely affects pregnancy rates in women with PCOS who undergo ovulation induction cycles. Clinicians should recommend weight loss in these patients before ovulation induction. PMID- 30027720 TI - [Epidemiology of Q fever in Spain (2018)]. AB - Q fever is an anthropozoonosis whose causative agent is Coxiella burnetii, which has an important impact from the human and animal health point of view. In this review, a brief historical reference of the infection by C. burnetii and Q fever has been made initially. In a second section the basic epidemiological aspects of this infection are described (reservoirs/ sources of infection, form of transmission and epidemiological forms). Subsequently, the data of the infection by C. burnetii in Spain will be are indicated, particularly the clinical series, the seroepidemiological studies in humans, the affectation of different types of mammals and the participation of the ticks in the biological cycle. In addition, basic data on C. burnetii infection/ disease in other regions of the world will be are also included. Finally, and taking into account the previous data will indicate the main epidemiological characteristics of Q fever at present. PMID- 30027725 TI - Low Expression of LEFTY1 in Placental Villi Is Associated with Early Unexplained Miscarriage. AB - OBJECTIVE: To investigate the function and underlying mechanism of transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signaling pathway in early unexplained miscarriage.STUDY DESIGN: Expression profiles of genes involved in TGF-beta/BMP signaling pathway were compared between placental villous tissue samples from 2 women with missed abortion and those from 2 women with induced abortion by microarray assay. The protein expression level of the most downregulated gene-LEFTY1-was further measured using western blotting in another 8 women with missed abortion and 7 women with induced abortion.RESULTS: A total of 24 genes showed differential expression level between the 2 groups. Their functions were further investigated, of which 6 of 13 upregulated genes were TGF-beta responsive genes. The most reduced gene is LEFTY1, an antagonist of TGF-beta ligand. The protein expression level of LEFTY1 was confirmed to show the same trend as microarray using western blotting.CONCLUSION: A reduced expression of LEFTY1 in women with missed abortion was identified as com-pared with women with induced abortion, which may result in a dysregulation of TGF-beta signaling and may be the underlying mechanism of missed abortion. PMID- 30027726 TI - From Research Conclusions to Real Change: Understanding the First Amendment's (Non)Response to the Negative Effects of Media on Children by Looking to the Example of Violent Video Game Regulations. AB - Through the careful examination of a case taken up by the U.S. Supreme Court during the 2010 Term, Schwarzenegger v. Entertainment Merchants Ass'n, this article assesses a new perspective on the issue of regulating children's access to mass media. The dominant influence of mass media on children is recognized by experts across many disciplines, including child development, communication theory, psychology, sociology, and medicine. Numerous studies demonstrate potential harm to children from exposure to mass media and marketing sources. Nevertheless, courts have been reluctant to recognize such consequences, primarily on the basis of First Amendment and free speech concerns. Indeed, in a significant line of cases the courts have invalidated every legislative effort to regulate children's access to violent video games. This legal reluctance presents a major barrier to the real world application of and benefit from research conclusions regarding the impact of media violence and consumer culture on children. While research of this nature has supported attempts at industry self regulation or voluntary compliance with ethical guidelines, such efforts have achieved little success. The disconnect between law and social science has led scholars like Professor Barbara Bennett Woodhouse to propose a reframing of the issues. She calls for a paradigm shift from family law's traditional approach of the parent-child-state triangle to recognize the influence of what she terms "mass-media marketing." She proposes a new "child-centered approach to environmental ethics," or in her words "ecogenerism," and suggests that those who advocate for protection of children from the harms of mass media and marketing have much to learn from the environmental law and ethics movement. Woodhouse's proposal offers an appealing perspective for those who support regulation of children's access to harmful media. The real issue, however, is whether ecogenerism will evolve from academic theory to actual practice. This article tests her theory by revisiting the line of violent video game cases to evaluate whether her ecogenerist perspective can achieve any real change in the courts' decisions. Particular attention is devoted to challenges presented by First Amendment free speech protections with a primary focus on the Ninth Circuit's decision in Schwarzenegger to invalidate a California statute prohibiting the sale or rental of violent video games to minors, a case that the Supreme Court is poised to soon decide. While some speculate that the Supreme Court is unlikely to reverse the Ninth Circuit's decision given the uniform position of other courts on this issue, this article reveals that an ecogenerist perspective demands a reversal by the Court precisely for that reason. Should the Court affirm the Ninth Circuit's invalidation of the statute, the article concludes by proposing recommendations for future research and regulatory efforts from an ecogenerist perspective. PMID- 30027727 TI - Effect of Varicocele Repair in Patients with Nonobstructive Azoospermia. AB - OBJECTIVE: To evaluate the efficacy of varicocele repair in patients with nonobstructive azoospermia.STUDY DESIGN: Ten patients with nonobstructive azoospermia and clinical varicoceles who underwent varicocele repair were retrospectively investigated. According to the postoperative appearance of motile spermatozoa in the ejaculate, the patients were divided into 2 groups: Responder and Nonresponder. The outcomes of each group were investigated.RESULTS: There were 4 (40%) patients in the Responder group. Serum follicle-stimulating hormone levels were significantly higher in the Nonresponder group than in the Responder group (19.9+/-6.4 IU/mL vs. 10.8+/- 4.0 IU/mL, p<0.05). Mean sperm concentration was 5.4 million spermatozoa/mL in the Responder group. One patient achieved a spontaneous pregnancy, and another achieved an assisted pregnancy. In the Nonresponder group 5 patients underwent microdissection testicular sperm extraction (micro-TESE) postoperatively. In 1 patient, motile spermatozoa were successfully retrieved. Histopathological findings in the other 4 patients were Sertoli-cell-only.CONCLUSION: The present study suggested that varicocele repair could be considered in men with nonobstructive azoospermia who have clinical varicoceles. Moreover, varicocele repair seemed to improve sperm retrieval rate during micro-TESE for those in the Nonresponder group. PMID- 30027729 TI - Patenting the Human Body: The Constitutionality of Gene Patents and Suggested Remedies for Reform. PMID- 30027728 TI - Histomorphometric Alterations Induced in the Testicular Tissues by Variable Sizes of Silver Nanoparticles. AB - OBJECTIVE: To investigate the histomorphometric alterations induced in testicular tissues by variable sizes of silver nanoparticles (SNPs).STUDY DESIGN: Male mice (BALB/C) were treated with SNPs (1 mg/kg) using 5 different sizes (10, 20, 40, 60, and 100 nm) for 35 days. Testicular biopsies from all mice under study were examined histomorphologically.RESULTS: SNPs sized 10 and 20 nm had provoked morphometric changes in the testes of the subjected mice together with the following histological alterations: seminiferous tubules, degeneration, spermatocyte cytoplasmic vacuolation, spermatocyte sloughing, and spermatid giant cell formation. Larger SNPs (40, 60, and 100 nm) induced little or no testicular histomorphometric alterations.CONCLUSION: The findings of the present work may indicate that subchronic exposure to SNPs could have a deleterious impact on the testicular tissues and spermatogenic process that could affect fertility and reproduction, with smaller SNPs being more toxic than larger ones. PMID- 30027730 TI - Room-Temperature Pressure Synthesis of Layered Black Phosphorus-Graphene Composite for Sodium-Ion Battery Anodes. AB - Sodium-ion batteries offer an attractive option for grid-level energy storage due to the high natural abundance of sodium and low material cost of sodium compounds. Phosphorus (P) is a promising anode material for sodium-ion batteries, with a theoretical capacity of 2596 mAh/g. The red phosphorus (RP) form has worse electronic conductivity and lower initial Coulombic efficiency than black phosphorus (BP), but high material cost and limited production capacity have slowed the development of BP anodes. To address these challenges, we have developed a simple and scalable method to synthesize layered BP/graphene composite (BP/rGO) by pressurization at room temperature. A carbon-black-free and binder-free BP/rGO anode prepared with this method achieved specific charge capacities of 1460.1, 1401.2, 1377.6, 1339.7, 1277.8, 1123.78, and 720.8 mAh/g in a rate capability test at charge and discharge current densities of 0.1, 0.5, 1, 5, 10, 20, and 40 A/g, respectively. In a cycling performance test, after 500 deep cycles, the capacity of BP/rGO anodes stabilized at 1250 and 640 mAh/g at 1 and 40 A/g, respectively, which marks a significant performance improvement for sodium-ion battery anodes. PMID- 30027731 TI - Self-Assembled Close-Packed MnO2 Nanoparticles Anchored on a Polyethylene Separator for Lithium-Sulfur Batteries. AB - Separator modification has been proved to be an effective approach for overcoming lithium polysulfide (LiPS) shuttling in lithium-sulfur (Li-S) cells. However, the weight and stability of the modified layer also affect the cycling properties and the energy density of Li-S cells. Here, we initially construct an ultrathin and lightweight MnO2 layer (380 nm, 0.014 mg cm-2) on a commercial polyethylene (PE) separator (MnO2@PE) through a chemical self-assembly method. This MnO2 layer is tightly anchored onto the PE substrate because of the presence of oxygen containing groups that form a relatively strong chemical force between the MnO2 nanoparticles and the PE substrate. In addition, the mechanical strength of the separator is not affected by this modification procedure. Moreover, because of the catalytic effect and compactness of the MnO2 layer, the MnO2@PE separator can greatly suppress LiPS shuttling. As a result, the application of this MnO2@PE separator in Li-S batteries leads to high reversible capacity and superior cycling stability. This strategy provides a novel approach to separator surface modification. PMID- 30027732 TI - How To Optimize Materials and Devices via Design of Experiments and Machine Learning: Demonstration Using Organic Photovoltaics. AB - Most discoveries in materials science have been made empirically, typically through one-variable-at-a-time (Edisonian) experimentation. The characteristics of materials-based systems are, however, neither simple nor uncorrelated. In a device such as an organic photovoltaic, for example, the level of complexity is high due to the sheer number of components and processing conditions, and thus, changing one variable can have multiple unforeseen effects due to their interconnectivity. Design of Experiments (DoE) is ideally suited for such multivariable analyses: by planning one's experiments as per the principles of DoE, one can test and optimize several variables simultaneously, thus accelerating the process of discovery and optimization while saving time and precious laboratory resources. When combined with machine learning, the consideration of one's data in this manner provides a different perspective for optimization and discovery, akin to climbing out of a narrow valley of serial (one-variable-at-a-time) experimentation, to a mountain ridge with a 360 degrees view in all directions. PMID- 30027733 TI - Aromatic Thiolate-Protected Series of Gold Nanomolecules and a Contrary Structural Trend in Size Evolution. AB - Thiolate-protected gold nanoparticles (AuNPs) are a special class of nanomaterials that form atomically precise NPs with distinct numbers of Au atoms ( n) and thiolate (-SR, R = hydrocarbon tail) ligands ( m) with molecular formula [Au n(SR) m]. These are generally termed Au nanomolecules (AuNMs), nanoclusters, and nanocrystals. AuNMs offer atomic precision in size, which is desired to underpin the rules governing the nanoscale regime and factors affecting the unique properties conferred by quantum confinement. Research since the 1990s has established the molecular nature of these compounds and investigated their unique size-dependent optical and electrochemical properties. Pioneering work in X-ray crystallography of Au102(SC6H4COOH)44 and Au25(SC2H4Ph)18- revolutionized the field by providing significant insight into the structural assembly of AuNMs and surface protection modes. Recent discoveries involving bulky and rigid ligands to favor crystal growth as a solution to the nanostructure problem have led to crystal structure determinations of several AuNMs ( n = 18 to 279). However, there are several open questions, such as the following: How does the structure evolve with size? Does the atomic structure determine the properties? What determines the atomic structure? What factors govern the stability: geometry or electronic properties or ligands? Where does the molecule-to-metal transition occur? Answering these questions requires the elucidation of governing rules in the nanoscale regime. In this Account, we discuss patterns and trends observed in structures, growth, and surface protection modes of 4- tert-butylbenzenethiolate (TBBT)-protected AuNMs and others to answer some of the important open questions. The TBBT series of AuNMs comprises Au28(SR)20, Au36(SR)24, Au44(SR)28, Au52(SR)32, Au92(SR)44, Au133(SR)52, and Au279(SR)84, where Au28 to Au133 are molecule-like with discrete electronic structures and Au279 exhibits metal-like properties with a surface plasmon resonance (SPR) at 510 nm. The TBBT series of AuNMs have dihedral symmetry, except for Au133(SR)52, which has no symmetry. We synthesize the scaling law and the rules of surface assembly, one-, two-, and three-dimensional growth patterns, the structural evolution trend, and an overarching trend for diverse types of thiolate-protected AuNMs. This Account sheds light on a new perspective in structural evolution for the TBBT series based on observations, namely, face-centered cubic (FCC) to decahedral to icosahedral to FCC, which contrasts with the contemporary understanding of the structural evolution of naked metal clusters (NMCs) from icosahedral to decahedral to FCC. We also hope that this Account will be of pedagogical value and spur further experimental and computational studies on this wide range of structures to delineate the underlying stability factors in the magic series. PMID- 30027734 TI - Remarkable Synergistic Catalysis of Ni-Doped Ultrafine TiO2 on Hydrogen Sorption Kinetics of MgH2. AB - Catalysts play an extraordinarily important role in accelerating the hydrogen sorption rates in metal-hydrogen systems. Herein, we report a surprisingly synergetic enhancement of metal-metal oxide cocatalyst on the hydrogen sorption properties of MgH2: only 5 wt % doping of Ni into ultrafine TiO2 enables a significant increase in hydrogen desorption kinetics; it absorbs 4.50 wt % hydrogen even at a low temperature of 50 degrees C. The striking improvement is partially ascribed to the formation of a particular Ni@TiO2 core-shell structure, thereby forming versatile interfaces. This study provides insights into the way of designing high-efficiency catalysts in hydrogen storage and other energy related fields. PMID- 30027735 TI - Discovery of Immunologically Inspired Small Molecules That Target the Viral Envelope Protein. AB - Dengue virus is a major human pathogen that infects over 390 million people annually leading to approximately 500 000 hospitalizations due to severe dengue. Since the only marketed vaccine, Dengvaxia, has recently been shown to increase disease severity in those lacking natural immunity, antivirals to prevent or treat dengue infection represent a large, unmet medical need. Small molecules that target the dengue virus envelope protein, E, on the surface of the virion could act analogously to antibodies by engaging E extracellularly to block infection; however, a shortage of target-based assays suitable for screening and medicinal chemistry studies has limited efforts in this area. Here we demonstrate that the dengue E protein offers a tractable drug target for preventing dengue infection by developing a target-based assay using a recombinantly expressed dengue serotype 2 E protein. We performed a high-throughput screen of ~20 000 compounds followed by secondary assays to confirm target-binding and antiviral activity and counter-screens to exclude compounds with nonspecific activities. These efforts yielded eight distinct chemical leads that inhibit dengue infection by binding to E and preventing E-mediated membrane fusion with potencies equal to or greater than previously described small molecule inhibitors of E. We show that a subset of these compounds inhibit viruses representative of the other three dengue serotypes and Zika virus. This work provides tools for discovery and optimization of direct-acting antivirals against dengue E and shows that this approach may be useful in developing antivirals with broad-spectrum activity against other flavivirus pathogens. PMID- 30027736 TI - Photoinduced Orientation Change of the Dimer Structure of the Pr-I State of Cph1Delta2. AB - Phytochromes are red and far-red light sensor proteins found in many organisms. Photoisomerization of a chromophore triggers subsequent reactions leading to conformational changes that are essential for signaling. Conformational changes of the N-terminal sensor domain of cyanobacterium phytochrome 1 from Synechocystis sp. PCC6803 (Cph1Delta2) were studied in this report primarily by the transient grating (TG) method in the time domain. Although the reaction kinetics monitored by ultraviolet-visible absorption changes were insensitive to variations in pH, it was found for the first time that the diffusion coefficient and molecular volume monitored by the TG method are significantly dependent on pH. This pH sensitivity indicates that the conformational changes of Cph1Delta2 during the reaction are modulated by pH and was explained consistently by two contributions from two isomers (Pr-I and Pr-II) possessing different protonation states of His260. Thus, His260 is responsible for the conformational heterogeneity of Pr, as discussed previously, and this protonation difference leads to different conformational changes of the sensor domain of Cph1 during the reaction. The photoreaction dynamics of the Pr-I state was studied in detail, and a significant diffusion change was observed, which was attributed to a change in the orientation (quaternary structure) of the dimer with a time constant of 400 MUs. Furthermore, it was revealed that this reorientation of the dimer was induced by a conformational change in the tongue region. New site-directed mutations to change the dimer-monomer equilibrium were reported. PMID- 30027737 TI - Catalytic Ozonation in Arrayed Zinc Oxide Nanotubes as Highly Efficient Mini Column Catalyst Reactors (MCRs): Augmentation of Hydroxyl Radical Exposure. AB - Reactor design is significant to catalytic ozonation for an efficient mass transfer and exposure of the powerful but short-lived hydroxyl radicals (HO*). Herein, five groups of zinc oxide nanotube arrays with pore sizes from 168 to 10 nm were produced as mini-column catalyst reactors (MCRs) for internal catalytic ozonation, whose performance was comparatively studied on the kinetics of ozone transfer, consumption, and radical probe interaction. Using an RCT value describing HO* exposure, all the MCRs with sufficient ozone transfer featured an RCT level of at least 3.2 * 10-6, which is substantially higher than most values in referenced works (10-9~10-6) and that for microscale reactors in our work (~10 8). Furthermore, the HO* exposure dramatically increased with diminishing pore size, causing an elevated RCT up to 8.0 * 10-5 for the smallest MCR with 10 nm pore. The interphase formed in this flow-through system might have enriched HO* radicals produced via surface, and for a smaller MCR, the effect would be greater with a more confined microfluidic region. Investigations on electron paramagnetic resonance and the treatment of ozone-recalcitrant organics corroborated the nanoscale effect of MCR on augmentation of HO* exposure. This study offers a new way to design nanotube reactors for internal HO*-based heterogeneous catalysis. PMID- 30027738 TI - Excited-State Electronic Asymmetry Prevents Photoswitching in Terthiophene Compounds. AB - The diarylethene moiety is one of the most extensively used switches in the field of molecular electronics. Here we report on spectroscopic and quantum chemical studies of two diarylethene-based compounds with a non- C3-symmetric triethynyl terthiophene core symmetrically substituted with RuCp*(dppe) or trimethylsilyl termini. The ethynyl linkers are strong IR markers that we use in time-resolved vibrational spectroscopic studies to get insight into the character and dynamics of the electronically excited states of these compounds on the picosecond to nanosecond time scale. In combination with electronic transient absorption studies and DFT calculations, our studies show that the conjugation of the non- C3-symmetric triethynyl terthiophene system in the excited state strongly affects one of the thiophene rings involved in the ring closure. As a result, cyclization of the otherwise photochromic 3,3"-dimethyl-2,2':3',2"-terthiophene core is inhibited. Instead, the photoexcited compounds undergo intersystem crossing to a long-lived triplet excited state from which they convert back to the ground state. PMID- 30027739 TI - Catalytic Removal of Aqueous Contaminants on N-Doped Graphitic Biochars: Inherent Roles of Adsorption and Nonradical Mechanisms. AB - Environmentally friendly and low-cost catalysts are important for the rapid mineralization of organic contaminants in powerful advanced oxidation processes (AOPs). In this study, we reported N-doped graphitic biochars (N-BCs) as low-cost and efficient catalysts for peroxydisulfate (PDS) activation and the degradation of diverse organic pollutants in water treatment, including Orange G, phenol, sulfamethoxazole, and bisphenol A. The biochars at high annealing temperatures (>700 degrees C) presented highly graphitic nanosheets, large specific surface areas (SSAs), and rich doped nitrogen. In particular, N-BC derived at 900 degrees C (N-BC900) exhibited the highest degradation rate, which was 39-fold and 6.5-fold of that on N-BC400 and pristine biochar, respectively, and the N-BC900 surpassed most popular metal or nanocarbon catalysts. Different from the radical based oxidation in N-BC400/PDS via the persistent free radicals (PFRs), singlet oxygen and nonradical pathways (surface-confined activated persulfate-carbon complexes) were discovered to dominate the oxidation processes in N-BC900/PDS. Moreover, the adsorption of organics was determined to be the key step determining reaction rate, revealing that the pre-adsorption of reactants significantly accelerated the nonradical oxidation pathway. This study not only provides robust and cheap carbonaceous materials for environmental remediation but also enables the first insight into the graphitic biochar-based nonradical catalysis. PMID- 30027740 TI - Printed Colorimetric Arrays for the Identification and Quantification of Acids and Bases. AB - Solid supported colorimetric sensing arrays have the advantage of portability and ease of use when deployed in the field, such as crime scenes, disaster zones, or in war zones, but many sensor arrays require complex fabrication methods. Here, we report a practical method for the fabrication of 4 * 4 colorimetric sensor arrays, which are printed on nylon membranes, using a commercially available inkjet printer. In order to test the efficacy of the printed arrays, they were exposed to 43 analytes at concentrations ranging from 0.001 to 3.0 M for a total of 559 samples of inorganic and organic acids or bases including hydrochloric, acetic, phthalic, malonic, picric, and trifluoroacetic acid, ammonium hydroxide, sodium hydroxide, lysine, and water as the control. Colorimetric data from the imaged arrays was analyzed with linear discriminant analysis and k-nearest neighbors to determine the analyte and concentration with ~88-90% accuracy. Overall, the arrays have impressive analytical power to identify a variety of analytes at different concentrations while being simple to fabricate. PMID- 30027741 TI - Isolation of gamma-Glutamyl-Transferase Rich-Bacteria from Mouse Gut by a Near Infrared Fluorescent Probe with Large Stokes Shift. AB - Bacterial gamma-glutamyltranspeptidases (gamma-GT) is a well-known metabolic enzyme, which could cleave the gamma-glutamyl amide bond of gamma-glutamyl analogues. As a key metabolic enzyme of bacteria and a virulence factor for the host, bacterial gamma-GT was determined to be a novel pharmaceutical target for new antibiotics development. However, there is no efficient method for the sensing of gamma-GT activity in bacteria and the recognition of gamma glutamyltransferase rich-bacteria. In the present work, a dicyanoisophorone derivative (ADMG) has been designed and developed to be a sensitive and selective near-infrared fluorescent probe for the sensing of bacterial gamma-GT. ADMG not only sensed bacterial gamma-GT in vitro, but also imaged intestinal bacteria in vivo. More interesting, the intestinal bacteria existed in the duodenum section of mouse displayed significant fluorescence emission. Under the guidance of the sensing of gamma-GT using ADMG, three intestinal bacteria strains K. pneumoniae CAV1042, K. pneumoniae XJRML-1, and E. faecalis were isolated successfully, which expressed the bacterial gamma-GT. Therefore, the fluorescent probe ADMG not only sensed the endogenous bacterial gamma-GT and imaged the intestinal bacteria but also guided the isolation of intestinal bacteria possessing gamma-GT efficiently, which suggested a novel biological tool for the rapid isolation of special bacteria from a mixed sample. PMID- 30027742 TI - Competition between Polar and Antiferrodistortive Modes and Correlated Dynamics of the Methylammonium Molecules in MAPbI3 from Anelastic and Dielectric Measurements. AB - The mechanisms behind the exceptional photovoltaic properties of the metallorganic perovskites are still debated and include a ferroelectric (FE) state from the ordering of the electric dipoles of the organic molecules. We present the first anelastic (complex Young's modulus) and new dielectric measurements on CH3NH3PbI3, which provide new insight into the reorientation dynamics of the organic molecules and the reason why they do not form a FE state. The permittivity is fitted within the tetragonal phase with an expression that includes the coupling between FE and octahedral tilt modes, indicating that the coupling is competitive and prevents FE ordering. The onset of the orthorhombic phase is accompanied by sharp stiffening, analogous to the drop of permittivity, due to the hindered molecular dynamics. On further cooling, an intense anelastic relaxation process without a dielectric counterpart suggests the reorientation of clusters of molecules with strong antiferroelectric correlations. PMID- 30027743 TI - Lead Levels at the Tap and Consumer Exposure from Legacy and Recent Lead Service Line Replacements in Six Utilities. AB - Profile, regulatory, and investigative sampling were completed in six utilities to study the impact of partial and full lead service line replacements (LSLRs) on water lead levels (WLLs) and consumer's exposure. As compared to households with no replacement, lead release after partial LSLR (PLSLR) was generally greater in the short term (3-50 days), and comparable or lower in the medium (<2 years) and long-term (>2 years). This was mainly explained by insufficient time elapsed to stabilize scales after disturbances to the service line. One utility showed sustained lead release over 18 months after PLSLR. Moreover, the reduction in WLLs was small when analyzing results for the same households. As a comparison, full LSLR decreased WLLs drastically and immediately. The occurrence of low (0-5 MUg/L) to high (>=50 MUg/L) WLLs in the profiles varied between households and reflected the variability of exposure among households in the same system. Using this probability of occurrence, the distribution of WLLs of exposure was estimated for households with or without a PLSLR, and used to model young children blood lead levels (BLLs) for both groups of households. The range of modeled BLLs decreased slightly for households with PLSLR, but still overlapped the range estimated for households with no replacement. This analysis suggests that, in a system, PLSLRs do not reduce young children blood lead levels except in a fraction of households. PMID- 30027744 TI - Legumain-Specific Near-Infrared Fluorescence "Turn On" for Tumor-Targeted Imaging. AB - Legumain is one of the cysteine proteases which can serve as an essential indicator for cancer diagnosis. Near-infrared (NIR) nanoprobes with fluorescence "Turn On" property are advantageous in cancer diagnosis. However, to the best of our knowledge, using a completely organic NIR nanoprobe to image legumain activity either in vitro or in vivo has not been reported. Herein, employing a CBT-Cys click condensation reaction, we used a rationally designed NIR probe Cys(StBu)-Ala-Ala-Asn-Lys(Cy5.5)-CBT (1) to synthesize its nanoprobes 1-NPs with self-quenched fluorescence. Cell and animal experiments indicated that our nanoprobes were able to specifically image legumain activity in living cells and tumors with a NIR fluorescence "Turn On" manner. We envision that the nanoprobes could be applied for the diagnosis of legumain-related diseases in the near future. PMID- 30027746 TI - Interdependent Roles of Electrostatics and Surface Functionalization on the Adhesion Strengths of Nanodiamonds to Gold in Aqueous Environments Revealed by Molecular Dynamics Simulations. AB - Molecular dynamics simulations demonstrate that adhesion strengths as a function of charge for aqueous nanodiamonds (NDs) interacting with a gold substrate result from an interdependence of electrostatics and surface functionalization. The simulations reveal a water layer containing Na+ counterions between a negative ND with surface -COO- functional groups that is not present for a positively charged ND with -NH3+ functional groups. The closer proximity of the positive ND to the gold surface and the lack of cancelation of electrostatic interactions due to counterions and the water layer lead to an electrostatic adhesion force for the positive ND that is nearly three times larger than that of the negative ND. Prior interpretations of experimental tribological studies of ND-gold systems suggested that electrostatics or surface functionalization could be responsible for observed adhesion strength differences. The present work demonstrates how these two effects work together in determining adhesion for this system. PMID- 30027745 TI - Effect of ILV6 Deletion and Expression of aldB from Lactobacillus plantarum in Saccharomyces uvarum on Diacetyl Production and Wine Flavor. AB - Diacetyl generates an aromatic off-flavor in wine at a high level. The present study expressed alpha-acetolactate decarboxylase (ALDB) from Lactobacillus plantarum and/or inactivated acetohydroxyacid synthase (Ilv6) in Saccharomyces uvarum, and the effects on diacetyl production and wine flavor in mutants were investigated through sequential fermentation and cofermentation in mixed cultures of S. uvarum and L. plantarum. The diacetyl content of WYDDelta6 (disrupted one ILV6 allele), WYSDelta6 ( ILV6 complete deletion), WYADDelta6 (disrupted one ILV6 allele with aldB expression), and WYASDelta6 ( ILV6 complete deletion with aldB expression) decreased by 25.71%, 41.30%, 47.77%, and 50.00%, respectively, after sequential fermentation and decreased by 15.15%, 26.72%, 35.26%, and 43.80%, respectively, after cofermentation, compared with that of the parental strain. In addition, Ilv6 inactivation not only decreased the acetic acid content but also balanced the flavor profile in wine effectively. This work provided a valuable insight into the metabolic pathway of diacetyl and wine flavor in S. uvarum. PMID- 30027747 TI - Factor Structure and Incremental Utility of the Distress Tolerance Scale: A Bifactor Analysis. AB - The Distress Tolerance Scale (DTS) is a self-report measure of perceived capacity to withstand aversive emotions. Initial factor analysis of this measure suggested a structure comprising one higher-order factor and four lower-order domain specific factors. However, there is limited evidence in support of the DTS's purported multidimensionality, and despite use of the DTS subscales, research has yet to assess their incremental utility. The current investigation sought to rectify the paucity of evidence in support of the DTS's factor structure and independent use of DTS subscales via bifactor analysis. In the present study ( N = 826 community adults), a bifactor model of the DTS provided the best fit to the data. However, an examination of statistical indices associated with bifactor modeling, as well as results from an examination of incremental utility, suggest that the domain-specific factors are largely redundant with the general factor and do not provide incremental utility in predicting relevant clinical constructs beyond the general factor. Measurement invariance between sexes was confirmed. Taken together, results support use of a DTS total score, but not subscale scores. PMID- 30027748 TI - Laparoscopic Radical Prostatectomy in Patients with High-Risk Prostate Cancer: Feasibility and Safety. Results of a Multicentric Study. AB - INTRODUCTION: In Western countries about 25% of prostate cancer (PCa) are high risk tumors at presentation and its treatment is still a matter of debate among urologists. When a surgical approach is preferred the use of a mininvasive tecnique is still difficult due to the lack of data supporting it in literature. The aim of this study is to evaluate feasibility and safety of laparoscopic radical prostatectomy (LRP) for high-risk PCa. MATERIALS AND METHODS: The study included 1114 patients with high-risk PCa submitted to LRP between 1998 and 2014. High-risk patients were defined according to D'Amico classification. We collected functional and oncological long-term outcomes and evaluated with univariate and multivariate analyses the role of predictive factors for survival and biochemical recurrence (BR). RESULTS: Mean age at treatment was 62 +/- 8 years; mean follow up was 74 +/- 50 months. We obtained an overall survival (OS) of 96.6% at a mean follow-up of 74 months (1076 patients) and a disease-free survival of 66.2% (737 patients). Age (p = 0.0006), pT (p < 0.0001), pN (p = 0.0018), and surgical margins (p = 0.0076) resulted as independent predictors for BR in multivariate analysis. pN (p = 0.0025) and Gs (p = 0.0003) are independent predictors for OS and cancer-specific survival in a univariate analysis; just the Gs results significant in the multivariate model. CONCLUSIONS: According to our encouraging data about oncological and functional outcomes we believe that radical prostatectomy represents an effective treatment for patients with high-risk PCa and that laparoscopy is a safe approach offering a mini-invasive alternative to open surgery. PMID- 30027749 TI - Perceived Usefulness of Continuous Glucose Monitoring Devices at the Workplace: Secondary Analysis of Data From a Qualitative Study. AB - BACKGROUND: Previous research suggests that psychosocial working conditions may detrimentally affect diabetes self-management behavior at work, including self monitoring of glucose levels. We aimed to better understand the potential usefulness of continuous glucose monitoring devices at the workplace according to employees with diabetes. METHODS: We carried out secondary analyses of data from a qualitative study, which sought to explore potential barriers to and solutions for effective diabetes self-management at work. Interviews were carried out in face-to-face contact or by telephone and were transcribed and content-analyzed using MaxQDA. The used topic guide did not specifically inquire after continuous glucose monitoring devices, but views on the suitability of those devices at the workplace repeatedly emerged from the interviews. Data from 25 employed adults with diabetes mellitus type 1 or type 2 on insulin therapy were included. RESULTS: The major perceived improvements associated with the use of continuous glucose monitoring devices pertained to their time-saving application that allowed for an increased frequency of glucose level assessments and for socially covert glucose measurement. The socially less noticeable way of monitoring glucose level was specifically perceived as beneficial, as employees with diabetes believed their illness would thereby attract less attention. Fewer or shorter interruptions as well as the reliability of integrated alarm systems were perceived to increase concentration at work and workability. CONCLUSIONS: Continuous glucose monitoring devices were perceived to facilitate glucose management at the workplace, which may exert positive effects on compliance as well as functioning at work. Further research would be of interest to statistically confirm our findings in occupational samples. PMID- 30027750 TI - Drivers of women's sanitation practices in informal settlements in sub-Saharan Africa: a qualitative study in Mathare Valley, Kenya. AB - Despite evidence suggesting women are disproportionately affected by the lack of adequate and safe sanitation facilities around the world, there is limited information about the factors that influence women's ability to access and utilize sanitation, especially in sub-Saharan Africa. The purpose of this study was to explore factors influencing women's sanitation practices in informal settlements in Nairobi, Kenya. Information from 55 in-depth interviews conducted in 2016 with 55 women in Mathare Valley Informal Settlement in Nairobi was used to carry out cross-case, thematic analysis of women's common sanitation routines. Women identified neighborhood disorganization, fear of victimization, lack of privacy, and cleanliness/dirtiness of facilities as important factors in the choices they make about their sanitation practices. This suggests that future sanitation-related interventions and policies may need to consider strategies that focus not only on toilet provision or adoption but also on issues of space and community dynamics. PMID- 30027751 TI - The effect of the application direction of the kinesiology tape on the strength of fatigued quadriceps muscles in athletes. AB - This study aimed to determine the effects of application direction of the kinesiology tape on the strength of fatigued quadriceps muscles, and included 15 athletes (mean: age, 19.53 +/- 2.42 years; height, 176.93 +/- 6.9 cm; weight, 72.87 +/- 13.02 kg). The kinesiology tape was randomly applied to the quadriceps from origin to insertion (n = 7) or from insertion to origin (n = 8) after inducing quadriceps muscle fatigue. After 1 week, the kinesiology tape was applied in the opposite direction (insertion to origin [n = 7] or origin to insertion [n = 8]) after inducing quadriceps muscle fatigue. The peak torque of the fatigued quadriceps muscles was measured before and after tape application. Increased peak torque values were observed irrespective of the direction of taping. No significant differences were noted in the peak torque of the fatigued quadriceps muscles with respect to application direction. Kinesiology tape application may improve the strength of fatigued quadriceps muscles regardless of application direction. PMID- 30027752 TI - Healthcare delay in breast cancer patients: a case study in a low-density population region from Mexico. AB - AIM: To describe delay intervals, their impact on clinical stage and initiation of first oncologic treatment, and evaluate associated factors in breast cancer patients in Yucatan, Mexico, a low-density population region. PATIENTS & METHODS: A retrospective analysis was done of 92 medical records, and bivariate and multivariate models applied to identify associations between healthcare delay and several factors. RESULTS: System delay accounted for most of the delay (median: 86 days; 61% of delay). Socioeconomic status and delivery to tertiary-care hospital predicted delay. Clinical stage determined initiation of first oncologic treatment. CONCLUSION: Delay in treatment was largely due to system delay. Only a few variables explained this delay. Clinical stage had the strongest effect on initiation of first oncologic treatment. PMID- 30027753 TI - Kinship analysis and allelic dropout: a forensic approach on an archaeological case. AB - BACKGROUND: This study relies on the discovery of two pit burials (LTA and LTB) of the Bronze Age Cogotas I archaeological culture (circa 3600-2950 BP) in Spain. LTA was a single burial and LTB contained three skeletal remains of two adults and a newborn or foetus at term. AIM: The central question posed by this find was whether the LTB tomb constituted a traditional nuclear family (father, mother and son or daughter). METHODS: Ancient and forensic DNA protocols were employed to obtain reliable results. Autosomal, X-STR markers and mitochondrial DNA were amplified. Subsequently, different kinship probabilities were estimated by means of LR values calculated using the Familias 3 software. Furthermore, an allelic dropout sensitivity test was developed in order to evaluate the influence of allelic dropout phenomena on the results. RESULTS: It was possible to determine the molecular sex of all individuals and to establish a maternal relationship between the perinatal individual and one of the adults. CONCLUSION: The remains in the LTB tomb were not a traditional nuclear family (father, mother and son/daughter) and it was probably a tomb where two women, one of them pregnant, were buried. PMID- 30027754 TI - HIV-1 Transmission Clustering and Phylodynamics Highlight the Important Role of Young Men Who Have Sex with Men. AB - More persons living with HIV reside in the Southern United States than in any other region, yet little is known about HIV molecular epidemiology in the South. We used cluster and phylodynamic analyses to evaluate HIV transmission patterns in middle Tennessee. We performed cross-sectional analyses of HIV-1 pol sequences and clinical data collected from 2001 to 2015 among persons attending the Vanderbilt Comprehensive Care Clinic. Transmission clusters were identified using maximum likelihood phylogenetics and patristic distance differences. Demographic, risk behavior, and clinical factors were assessed evaluating "active" clusters (clusters including sequences sampled 2011-2015) and associations estimated with logistic regression. Transmission risk ratios for men who have sex with men (MSM) were estimated with phylodynamic models. Among 2915 persons (96% subtype-B sequences), 963 (33%) were members of 292 clusters (distance <=1.5%, size range 2 39). Most clusters (62%, n = 690 persons) were active, either being newly identified (n = 80) or showing expansion on existing clusters (n = 101). Correlates of active clustering among persons with sequences collected during 2011-2015 included MSM risk and <=30 years of age. Active clusters were significantly more concentrated in MSM and younger persons than historical clusters. Young MSM (YMSM) (<=26.4 years) had high estimated transmission risk [risk ratio = 4.04 (2.85-5.65) relative to older MSM] and were much more likely to transmit to YMSM. In this Tennessee cohort, transmission clusters over time were more concentrated by MSM and younger age, with high transmission risk among and between YMSM, highlighting the importance of interventions among this group. Detecting active clusters could help direct interventions to disrupt ongoing transmission chains. PMID- 30027755 TI - Bladder Cancer in Lebanon: Incidence and Comparison to Regional and Western Countries. AB - Lebanon has one of the highest estimated age-standardized incidence rate (ASR(w)) of bladder cancer (BC) worldwide. The aim of this study is to analyze the incidence rates for BC in Lebanon over a period of 7 years and to compare them to the rates in other countries. Data were obtained from the Lebanese National Cancer Registry for the currently available years 2005 to 2011. The calculated ASR(w) and age-specific rates were expressed as per 100 000 population. From 2005 to 2011, BC has been ranked as the third most common cancer in Lebanon. It accounted for 9.0% of all newly diagnosed cancer cases excluding nonmelanoma skin cancer. It ranked second in males and ninth in females. The average ASR(w) over this period was 31.2 in men and 7.3 in women. These incidence rates are among the highest worldwide across all age groups in both sexes. This study shows that the incidence of BC in Lebanon is high and it is among the highest worldwide. It is important to reduce the risk of BC through tobacco control and by decreasing exposure to avoidable environmental and occupational risk factors. PMID- 30027757 TI - Ultrasonography Findings in Severe Carpal Tunnel Syndrome. AB - BACKGROUND: Increasing severity of carpal tunnel syndrome (CTS), as graded by nerve conduction studies (NCS), has been demonstrated to predict the speed and completeness of recovery after carpal tunnel release (CTR). The purpose of this study is to compare the cross-sectional area (CSA) of the median nerve in patients with severe and nonsevere CTS as defined by NCS. METHODS: Ultrasound CSA measurements were taken at the carpal tunnel inlet at the level of the pisiform bone by a hand fellowship-trained orthopedic surgeon. Severe CTS on NCS was defined as no response for the distal motor latency (DML) and/or distal sensory latency (DSL). RESULTS: A total of 274 wrists were enrolled in the study. The median age was 51 years (range: 18-90 years), and 72.6% of wrists were from female patients. CSA of median nerve and age were comparatively the best predictors of severity using a linear regression model and receiver operator curves. Using cutoff of 12 mm2 for severe CTS, the sensitivity and specificity are 37.5% and 81.9%, respectively. CONCLUSIONS: Ultrasound can be used to grade severity in younger patients (<65 years) with a CTS-6 score of >12. PMID- 30027756 TI - Acupuncture for Bortezomib-Induced Peripheral Neuropathy: Not Just for Pain. AB - BACKGROUND: Bortezomib-induced peripheral neuropathy (BIPN) is a common and debilitating side effect. Our pilot study demonstrated that acupuncture is safe and can decrease total neuropathic symptoms. However, there is lack of knowledge in which individual BIPN symptoms benefited from acupuncture. PURPOSE: To characterize individual symptoms reduced by acupuncture in patients with BIPN. METHODS: Patients with multiple myeloma treated with bortezomib who developed BIPN grade 2 or above, based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), were enrolled and received 10 acupuncture treatments over 10 weeks. Self-reported BIPN-associated symptoms assessments were collected weekly at baseline, during, and after acupuncture treatment using the Neuropathy Pain Scale (NPS) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaires. Changes in individual symptoms were analyzed based on FACT/GOG Ntx and NPS scores. RESULTS: There were statistically significant reductions in individual symptoms in both NPS and FACT/GOG-Ntx. The FACT/GOG-Ntx reductions were most pronounced in hand/feet numbness/tingling, discomfort, and trouble walking. The sensory symptoms, such as tingling and numbness, especially in the feet, reduced the most ( P < .0001), and motor dysfunction also reduced significantly ( P = .0001). Both hearing and dysfunction scores were also statistically significantly increased, indicating improved symptoms. The NPS scores showed significant symptom relief in all 10 items from the NPS assessment, particularly in cold sensitivity and an unpleasant feeling. CONCLUSIONS: Acupuncture can improve multiple symptoms associated with BIPN, particularly numbness and tingling in hands and feet, cold sensitivity, and an unpleasant feeling. Further randomized control trials are warranted to confirm our findings. PMID- 30027758 TI - Using DNA Immunization to Elicit Monoclonal Antibodies in Mice, Rabbits, and Humans. AB - In recent vaccine studies, DNA immunization was found to effectively stimulate both innate and adaptive immunities to elicit high levels of antigen-specific antibody responses. The DNA molecule itself can activate multiple pathways of innate immunity. The in vivo production of antigens allows for presentation by major histocompatibility complexes, so that T-cell responses are generated to help in the development of antigen-specific B cells, leading to high-affinity antibody response. By using the same process, DNA immunization should also be effective at producing functionally potent monoclonal antibodies (mAbs). Furthermore, the in vivo expressed proteins can maximally maintain the native structures and go through appropriate post-transcriptional modifications. By combining such advantages, DNA immunization can be expected to play more important roles in the future to elicit mAbs against difficult targets from a wide range of host systems. The current report shares our group's experience in using DNA immunization to elicit mAbs in the mouse, rabbit, and human models. PMID- 30027759 TI - AggLr, a novel aggregation factor in Lactococcus raffinolactis BGTRK10-1: its role in surface adhesion. AB - The ability of lactic acid bacteria to form multi-cellular aggregates via self aggregation is regarded as an important mechanism for stress tolerance, adhesion, colonization and genetic material exchange. The novel aggLr gene encoding for the auto-aggregation promoting protein (AggLr) of Lactococcus raffinolactis BGTRK10-1 was cloned. Heterologous expression of AggLr enabled auto-aggregation, higher hydrophobicity and collagen and fibronectin binding of the carrier strains. Domain analysis and the type of aggregates formed by cells expressing AggLr confirmed that this aggregation factor belongs to the family of high molecular weight proteins that the authors propose to be called Snow-flake Forming Collagen Binding Aggregation Factors (SFCBAF). An additional feature of SFCBAF is that they are rich in threonine and lysine and are free of cysteine in all of the aggregation factors described so far. In contrast to previously discovered SFCBAF, the gene encoding for AggLr is located on the chromosome in the strain BGTRK10-1. PMID- 30027760 TI - The Impact of Serious Educational Gameplay on Adolescent Binge Drinking Intentions: A Theoretically Grounded Empirical Examination. AB - INTRODUCTION: Game On: Know Alcohol, a school-based alcohol education program, aimed to educate adolescents on the harmful effects of (excessive) alcohol consumption. The program included two user-centered serious educational games, Perfect Pour and Dumb Driver. PURPOSE: To evaluate the objective effect of playing Perfect Pour and Dumb Driver on the key psychosocial determinants of adolescent binge drinking intentions in the context of the theory of reasoned action (TRA). METHODS: Data were drawn from four Game On: Know Alcohol program schools ( N = 303 adolescents aged 14-16 years), and two TRA models incorporating four game metrics were analyzed using structural equation modeling. RESULTS: The theoretically guided TRA models linked to gameplay data explained 66% of variance in adolescents' binge drinking intentions. Average game duration and average score of Perfect Pour were significantly associated with adolescents' attitudes toward binge drinking, whereas no objective effect on the key psychosocial determinants was observed for Dumb Driver. CONCLUSIONS: Inconclusive findings suggest that further research is needed to fully understand how serious educational games may be designed to effectively influence adolescents' binge drinking intentions. Opportunities to extend theory application beyond evaluation are noted in addition to other opportunities for future research. PMID- 30027761 TI - Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort. AB - Recombinant adeno-associated virus (rAAV) vectors are a promising platform for in vivo gene therapy. The presence of neutralizing antibodies (Nab) against AAV capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. Novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials; however, the prevalence of antibodies against such capsids remains largely unknown. We therefore assessed the seroprevalence of antibodies against a novel synthetic liver-tropic capsid AAV-LK03. We measured seroprevalence of immunoglobulin (Ig)G (i.e., neutralizing and nonneutralizing) antibodies and Nab to AAV-LK03 in a cohort of 323 UK patients (including 260 pediatric) and 52 juvenile rhesus macaques. We also performed comparative analysis of seroprevalence of Nab against wild-type AAV8 and AAV3B capsids. Overall IgG seroprevalence for AAV-LK03 was 39% in human samples. The titer increased with age. Prevalence of Nab was 23%, 35%, and 18% for AAV-LK03, AAV3B, and AAV8, respectively, with the lowest seroprevalence between 3 and 17 years of age for all serotypes. Presence of Nab against AAV-LK03 decreased from 36% in the youngest cohort (birth to 6 months) to 7% in older primary school-age children (9 11 years) and then progressively increased to 54% in late adulthood. Cross reactivity between serotypes was >60%. Nab seroprevalence in macaques was 62%, 85%, and 40% for AAV-LK03, AAV3B, and AAV8, respectively. When planning for AAV gene therapy clinical trials, knowing the seropositivity of the target population is critical. In the population studied, AAV seroprevalence for AAV serotypes tested was low. However, high cross-reactivity between AAV serotypes remains a barrier for re-injection. Shifts in Nab seroprevalence during the first decade need to be confirmed by longitudinal studies. This possibility suggests that pediatric patients could respond differently to AAV therapy according to age. If late childhood is an ideal age window, intervention at an early age when maternal Nab levels are high may be challenging. Nab-positive children excluded from trials could be rescreened for eligibility at regular intervals because this status may change. PMID- 30027762 TI - Prevalence and Clinical Manifestations of the Anconeus Epitrochlearis and Cubital Tunnel Syndrome. AB - BACKGROUND: The true prevalence of the anconeus epitrochlearis (AE) and the natural history of cubital tunnel syndrome associated with this anomalous muscle are unknown. The purpose of this study was to evaluate the prevalence of AE and to characterize the preoperative and postoperative features of cubital tunnel syndrome caused by compression from an AE. METHODS: All elbow magnetic resonance imaging (MRI) scans and all patients undergoing cubital tunnel surgery during a 20-year period were identified and retrospectively reviewed for the presence of an AE. All patients with an AE identified intra-operatively were matched to patients with no AE identified at surgery based on age, sex, concomitant procedures, and year of surgery. Preoperative and postoperative physical exam findings, electrodiagnostic study results, time to improvement, and reoperations were compared between the groups. RESULTS: A total of 199 patients had an elbow MRI, and 27 (13.6%) patients were noted to have an AE present. Average time to improvement after surgical release was 23.0 days for patients with an AE and 33.2 days for patients with no AE. Twenty-seven patients with an AE noted improvement at the first postoperative visit (68%) compared to 15 patients without an AE (33%). No patients with an AE underwent reoperation for recurrent symptoms (0%) compared with four patients (10%) without an AE. CONCLUSIONS: The prevalence of AE in our study is 13.6%. These patients experience quicker and more reliable symptom improvement after surgical release than those without the anomalous muscle. PMID- 30027764 TI - Parental obligations, care and HIV treatment: How care for others motivates self care in Zimbabwe. AB - This article examines how parental obligations of care intersect with HIV treatment-seeking behaviours and retention. It draws on qualitative data from eastern Zimbabwe, produced from 65 interviews. Drawing on theories of practice and care ethics, our analysis revealed that norms of parental obligation and care acted as key motivators for ongoing engagement with HIV services and treatment. Parents' attentiveness to the future needs of their children ( caring about), and sense of obligation ( taking care of) and improved ability to care ( caregiving) following treatment initiation, emerged as central to understanding their drive for self-care and engagement with HIV services. PMID- 30027763 TI - Concussion clinic presentation and symptom duration for pediatric sports-related concussions following Ohio concussion law. AB - In 2013, Ohio enacted a law to mitigate consequences of pediatric sports-related concussions. This study aimed to describe changes in clinic visits and symptom duration for pediatric sports-related concussions before and after this law. 3,133 new visits by 2,861 unique patients (10-18 years) presenting between April 2012 and April 2015 for sports-related concussions within 30 days of injury were included. There were 937 (29.9%), 1,132 (36.1%) and 1,064 (34.0%) concussion visits for pre-law, immediate-post law, and post-law periods, respectively. A greater proportion of concussion visits was observed among females from pre-law to post-law (P < 0.0001). No differences were observed across the three periods in symptom scores at injury (P = 0.5028) or at first clinic visit (P = 0.5686). However, patients presented to concussion clinics significantly earlier (17.6 vs. 22.8 days, P < 0.0001) and had quicker recovery (26.5 vs. 40.6 days, P < 0.0001) post-law than pre-law. PMID- 30027766 TI - Chronic Scapholunate Interosseous Ligament Disruption: A Systematic Review and Meta-Analysis of Surgical Treatments. AB - BACKGROUND: Although many techniques have been described, there is no clear optimal surgical treatment for chronic scapholunate interosseous ligament (SLIL) disruption. METHODS: We identified 255 articles reporting outcomes of SLIL reconstruction. Of these, 40 studies (978 wrists) met eligibility requirements and reported sufficient data on radiographic outcomes to be included in the study. The mean and standard deviation of preoperative and follow-up assessments including scapholunate gap (SLG) and scapholunate angle (SLA) were used to calculate pooled standardized mean differences (SMD) with 95% confidence intervals (CIs). For other radiographic or clinical outcomes, there were not enough reported data to calculate a pooled effect size, and pooled nonstandardized comparisons were made. RESULTS: The SMD between preoperative and postoperative SLA in tenodesis reconstruction was 0.7 (CI, 0.29 to 1.11, P = .001) and 0.04 (CI, -0.27 to 0.38, P = .8) for capsulodesis reconstruction. For SLG, tenodesis demonstrated an SMD of 1.1 (CI, 0.6 to 1.55, P < .001) compared with 0.1 (CI, -0.36 to 0.59, P = .6) for capsulodesis reconstruction. Tenodesis had a significant improvement compared with capsulodesis in SLA ( P = .01) and SLG ( P = .005). Tenodesis also showed improvement in grip strength and Disabilities of the Arm, Shoulder and Hand scores. CONCLUSIONS: Comparing preoperative and postoperative radiographic measurements, tenodesis reconstruction demonstrated significantly improved SLG and SLA relative to capsulodesis. Interpreted in the context of the limitations, existing data demonstrates some benefit of tenodesis reconstruction. PMID- 30027767 TI - CRISPR-Cas9 therapies in experimental mouse models of cancer. AB - The CRISPR-Cas9, a part of the defence mechanism from bacteria, has rapidly become the simplest, fastest and the most precise genome-editing tool available. The therapeutic applications of CRISPR are boundless: correction of mutations in several disorders, inactivation of oncogenes and viral oncoproteins, and activation of tumor suppressor genes. In this review, we expose recent advances concerning animal models of cancer that use CRISPR-Cas9, addressing also the current efforts to develop CRISPR-Cas9-based therapies, focusing on proof-of concept studies. Finally, the review exposes some of the main challenges that this genome-editing tool faces. The key issue remains: does CRISPR-Cas9 have real potential for therapeutic application or will it just remain a wonderful research tool? PMID- 30027769 TI - A metabolic energy expenditure model with a continuous first derivative and its application to predictive simulations of gait. AB - Whether humans minimize metabolic energy in gait is unknown. Gradient-based optimization could be used to predict gait without using walking data but requires a twice differentiable metabolic energy model. Therefore, the metabolic energy model of Umberger et al. ( 2003 ) was adapted to be twice differentiable. Predictive simulations of a reaching task and gait were solved using this continuous model and by minimizing effort. The reaching task simulation showed that energy minimization predicts unrealistic movements when compared to effort minimization. The predictive gait simulations showed that objectives other than metabolic energy are also important in gait. PMID- 30027768 TI - Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine. AB - Intradermal (i.d.) and intramuscular (i.m.) injections when administered with or without electroporation (EP) have the potential to tailor the immune response to DNA vaccination. This Phase I randomized controlled clinical trial in human immunodeficiency virus type 1-negative volunteers investigated whether the site and mode of DNA vaccination influences the quality of induced cellular and humoral immune responses following the DNA priming phase and subsequent protein boost with recombinant clade C CN54 gp140. A strategy of concurrent i.d. and i.m. DNA immunizations administered with or without EP was adopted. Subtle differences were observed in the shaping of vaccine-induced virus-specific CD4+ and CD8+ T cell-mediated immune responses between groups receiving: i.d.EP + i.m., i.d. + i.m.EP, and i.d.EP + i.m.EP regimens. The DNA priming phase induced 100% seroconversion in all of the groups. A single, non-adjuvanted protein boost induced a rapid and profound increase in binding antibodies in all groups, with a trend for higher responses in i.d.EP + i.m.EP. The magnitude of antigen-specific binding immunoglobulin G correlated with neutralization of closely matched clade C 93MW965 virus and Fc-dimer receptor binding (FcgammaRIIa and FcgammaRIIIa). These results offer new perspectives on the use of combined skin and muscle DNA immunization in priming humoral and cellular responses to recombinant protein. PMID- 30027770 TI - Characteristics of multi-component formulation granules formed using distributive mixing elements in twin screw granulation. AB - This work examines the influence of pharmaceutical powder formulation characteristics on granule properties formed using distributive mixing elements (DMEs) in twin screw granulation. High and low drug dose formulations with three different active pharmaceutical ingredients (APIs) were considered. The type and concentration of the API in the formulation significantly affected the dry blend particle size distribution and the wet blend dynamic yield strength. However, despite the differences in blend properties, the granule size distributions were not significantly affected by the type of API used. The granule size distributions were solely the functions of the liquid-to-solid ratio and screw element geometry. However, the granule porosities were observed to be dependent on both the liquid-to-solid ratio and the dynamic yield strength of the blends. This work is the first to study the influence of drug loading and API type on the granule attributes produced using distributive mixing elements. PMID- 30027771 TI - Patient and family engagement in incident investigations: exploring hospital manager and incident investigators' experiences and challenges. AB - Objective There is growing recognition among health care providers and policy makers that when things go wrong, the patient or their families should be heard and participate in the incident investigation process. This paper explores how Dutch hospitals organize patient or family engagement in incident investigations, maps out incident investigators' experiences of involving patients or their families in incident investigations and identifies the challenges encountered. Methods Semi-structured interviews were conducted with managers and incident investigators in 13 Dutch hospitals. Study participants (n = 18) were asked about the incident investigation routines and their experiences of involving affected patients or family members. Interview transcripts were coded and analysed using thematic content analysis. Results Our findings reveal that patient or family involvement in incident investigations is typically organized as a one-time interview event. Interviews with patients or their families were considered to be valuable and important in their own right and seen as a way to do justice to the individual needs of the patient or their family. Yet, the usefulness and validity of the patient or family perspective for incident investigations was often seen to be limited, with the professional perspective afforded more weight. This was particularly the case when the patient or their family were unable to provide verifiable details of the incident under investigation. Study participants described challenges when involving patients or family members, including in relation to the available timeframe for incident investigations, legal issues, managing trust and working with intense emotions. Conclusions We propose that by placing patient and family criteria of significance at the centre of incident investigations (i.e. an 'emic' research approach), hospitals may be able to expand their learning potential and improve patient-centeredness following an incident. PMID- 30027772 TI - Include, invest, innovate: health systems for prosperity and solidarity. PMID- 30027773 TI - Synchronized release of bufadienolides in a stable Lutrol F127 based solid dispersion prepared with spray congealing. AB - OBJECTIVE: The objective of this study was to design and prepare a novel solid dispersion using spray congealing to achieve fast and synchronous dissolution of bufalin, cinobufagin, and resibufogenin, three therapeutically complementary drugs. METHODS: The solid dispersion was characterized with dissolution, X-ray diffractometry, and fourier transform infrared spectroscopy after preparation and storage for four weeks at different temperatures and relative humidity. RESULTS: It was found that all drugs were molecularly dispersed within matrix and had a significant enhancement (~4-fold higher) of dissolution rate. Furthermore, synchronized release of different drugs from a single carrier was achieved due to the highly molecular dispersibility and the excellent solubilization properties of F127. In addition, the solid dispersion was physically stable for at least four weeks at controlled conditions. But for samples under stress conditions, the results showed that drug-rich phase was formed and storage temperature was the dominant factor in determining stability of the solid dispersion (SD). CONCLUSIONS: These findings highlight the fitness of spray congealing to co deliver multiple drugs, which open new perspectives for the development of more advanced combination of multiple therapeutic agents, presumably improving the bioavailability and therapeutic efficacy. PMID- 30027774 TI - Oral disintegrating patient-tailored tablets of warfarin sodium produced by 3D printing. AB - Individualized medicine is a new direction in the field of modern pharmacy. In this study, we assessed the feasibility and accuracy of 3D printing techniques for the preparation of individualized doses of mouth-disintegrating tablets of warfarin. Warfarin sodium, D-sucrose, pregelatinized starch, povidone K30, microcrystalline cellulose, and silicon dioxide (at a ratio of 1:42.45:46.15:5.1:4.9:0.4) were mixed and used as the printing powder in the 3D printer; preset parameters were used. The dosage of the tablet was controlled by the number of printing layers. The content, dose uniformity, dose accuracy, hardness, friability, disintegration time, dissolution, and the microstructural and overall appearance were determined to evaluate the printed tablets. For the doses of 3, 2, and 1 mg that were produced in the experiment, the disintegration times were 50.0 +/- 5.2, 35.7 +/- 4.3, and 11.0 +/- 2.2 s, respectively, and the relative errors of the dose were -2.33, -1.50, and 0%, respectively. The other indicators were consistent with the preparation requirements of pharmaceutical tablets. It is possible to prepare tablets with excellent properties and controlled drug doses by using 3D printing techniques. This technology will be an important means to achieve individualized medicine. PMID- 30027775 TI - Closed-loop insulin delivery: current status of diabetes technologies and future prospects. AB - INTRODUCTION: Type 1 diabetes is characterised by destruction of pancreatic beta cells, leading to insulin deficiency and hyperglycaemia. The mainstay of treatment remains lifelong insulin therapy as a sustainable cure has as yet proven elusive. The burden of daily management of type 1 diabetes has contributed to suboptimal outcomes for people living with the condition. Innovative technological approaches have been shown to improve glycaemic and patient-related outcomes. Areas covered: We discuss recent advances in technologies in type 1 diabetes including closed-loop systems, also known as the 'artificial pancreas. Its various components, technical aspects and limitations are reviewed. We also discuss its advent into clinical practice, and other systems in development. Evidence from clinical studies are summarised. Expert commentary: The recent approval of a hybrid closed-loop system for clinical use highlights the significant progress made in this field. Results from clinical studies have shown safety and glycaemic benefit, however challenges remain around improving performance and acceptability. More data is required to establish long-term clinical efficacy and cost-effectiveness, to fulfil the expectations of people with type 1 diabetes. PMID- 30027776 TI - The concentration of total sialic acid in chronic hepatitis B and C. AB - Background The synthesis and glycosylation of glycoproteins and glycolipids take place in the liver. Thus, liver diseases may affect serum concentrations of some carbohydrate derivatives, especially the concentration of sialic acid which is attached to the end of oligosaccharide chains. The aim of this study was to measure and compare the serum concentration of total sialic acid in chronic hepatitis B and C. The hypothesis is that both viruses responsible for the development of inflammation work differently at the cellular level. Methods Serum samples were obtained from 90 patients suffering from liver diseases: 50 from chronic hepatitis B and 40 from chronic hepatitis C at the time of diagnosis. The total sialic acid concentration in the serum was measured according to the enzymatic method using a colorimetric procedure. Results The mean total sialic acid concentration in patients with chronic hepatitis B was significantly lower than the mean concentration in the healthy group, while in patients with chronic hepatitis C, it was significantly higher than that in healthy people and in patients suffering from chronic hepatitis B. There were no significant differences in total sialic acid concentrations in patients with chronic hepatitis B and C according to the grade of portal/periportal activity, the grade of lobular activity and the stage of fibrosis. Conclusions We conclude that chronic viral hepatitis affects the total serum concentration of sialic acid. Moreover, the concentration of total sialic acid may be a useful marker to differentiate between chronic hepatitis B and C but is not useful for evaluation of the progression of these diseases. PMID- 30027777 TI - Falsely decreased ferritin concentrations in two patients with haemophagocytic lymphohistiocytosis: A case report. AB - The high-dose hook effect, or prozone effect, can lead to negative or falsely lowered plasma ferritin results. Here, cases of a 16-year-old boy and a 70-year old woman with haemophagocytic lymphohystiocytosis with extremely high concentrations of plasma ferritin (387,000 MUg/L and 138,000 MUg/L, respectively) are presented. In both cases, falsely lowered ferritin results were reported without any analyser flag. This article emphasizes the importance of recognition of the high-dose hook effect, since a watertight solution is lacking. PMID- 30027778 TI - A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables, wet media milling process parameters and excipient variability on drug product quality attributes. AB - Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus(r), Kollidon(r) VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension. PMID- 30027779 TI - Percutaneous cholecystostomy for biliary decompression in patients with cholangitis and pancreatitis. AB - Objective This study was performed to assess the effectiveness and safety of percutaneous cholecystostomy (PC) for biliary decompression. Methods We retrospectively analyzed our institution's PC database from March 2015 to August 2017 and selected patients with biliary obstruction. The primary outcomes were the technical and clinical success rates. As secondary outcomes, adverse events and pain after PC were compared with those of patients who underwent PC for acute cholecystitis during the same period. Results Twenty patients underwent PC for biliary obstruction (cholangitis, 19; pancreatitis, 1). The technical and clinical success rates were 100%. The median serum total bilirubin level decreased considerably from 4.5 to 1.4 mg/dL after PC. An adverse event (catheter migration) occurred in 1 patient, and 17 patients developed pain after PC. During the same period, 104 patients underwent PC for cholecystitis. Adverse events occurred in 7 patients, and 62 developed pain. There was no significant difference in the adverse event rate between the cholangitis/pancreatitis and cholecystitis groups (5.0% vs. 6.7%, respectively), but pain occurred considerably more frequently in the cholangitis/pancreatitis group (94.4% vs. 63.9%, respectively). Conclusions PC is an effective and safe method for biliary decompression in selected patients. However, attention should be paid to postoperative pain. PMID- 30027780 TI - Splenic artery embolization with detachable balloons for hypersplenism. AB - Objective This study was performed to investigate the efficacy of proximal splenic artery embolization using detachable balloons for patients with hypersplenism and portal hypertension. Methods Twelve patients diagnosed with hypersplenism with thrombocytopenia or leukocytopenia caused by portal hypertension were treated by proximal splenic artery embolization with detachable balloons and metallic fibered coils. All patients were followed for up to 6 months. Blood parameters, coagulation factors, and liver function indicators were measured. Enhanced computed tomography and abdominal ultrasonography examinations were also performed in advance to confirm the infarction area and evaluate the changes in spleen size. Results Postoperative angiography demonstrated complete embolization of the proximal splenic artery in all 12 patients. Thrombocyte and leukocyte counts rose significantly in all patients in 2 weeks and stayed significantly higher than those before embolization throughout the 6-month follow up. The total bilirubin concentration and prothrombin activity recovered significantly and returned to normal levels 6 months later. Computed tomography revealed partial infarction and liquefaction of the splenic parenchyma in nine patients. Conclusions Proximal splenic artery embolization using detachable balloons could be considered a safe and effective therapeutic modality in alleviating hypersplenism secondary to portal hypertension. PMID- 30027781 TI - Protective effects of pentoxifylline in small intestine after ischemia reperfusion. AB - Objective This study was performed to determine the healing effects of pentoxifylline on molecular responses and protection against severe ischemic damage in the small intestine. Methods Thirty-six Wistar albino rats were divided into six groups. The superior mesenteric artery was clamped for 120 minutes, and reperfusion was performed for 60 minutes. Saline (0.4 mL), pentoxifylline (1 mg/kg), and pentoxifylline (10 mg/kg) were intraperitoneally administered to the rats in the C1, P1, and P3 groups, respectively, 60 minutes before ischemia and to the rats in the C2, P2, and P4 groups, respectively, during reperfusion onset. Malondialdehyde, myeloperoxidase, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 in serum and tissue were measured by enzyme-linked immunosorbent assay. Intestinal ischemic injury was histopathologically evaluated by the Chiu score and immunohistochemical staining. Results All serum and tissue molecular responses were significantly blunted in the pentoxifylline-treated groups compared with the controls. Significant improvement in ischemic damage was demonstrated in the pentoxifylline-treated groups by histological grading and immunohistochemical scoring. Conclusions The protective effects of pentoxifylline were confirmed by molecular responses and histopathological examination. PMID- 30027782 TI - Effects of long periods of pneumoperitoneum combined with the head-up position on heart rate-corrected QT interval during robotic gastrectomy: an observational study. AB - OBJECTIVE: Pneumoperitoneum and the head-up position reportedly stimulate the sympathetic nervous system, potentially increasing the risk of cardiac arrhythmia. We evaluated the effects of a long duration of pneumoperitoneum in the head-up position on the heart rate-corrected QT (QTc) interval during robotic gastrectomy. METHODS: This prospective observational study involved 28 patients undergoing robotic gastrectomy. The QTc interval was recorded at the following time points: before anaesthetic induction (baseline); 10 minutes after tracheal intubation; 1, 5, 30, 60, and 90 minutes after pneumoperitoneum induction in the head-up position; after pneumoperitoneum desufflation in the supine position; and at the end of surgery. The primary outcome was the QTc interval, which was measured 90 minutes after pneumoperitoneum combined with the head-up position. RESULTS: Compared with baseline, the QTc interval was significantly prolonged at 1 and 60 minutes after pneumoperitoneum, peaked at 90 minutes, and was sustained and notably prolonged until the end of surgery. However, no considerable haemodynamic changes developed. CONCLUSION: A long period of carbon dioxide pneumoperitoneum application in a head-up position significantly prolonged the QTc interval during robotic gastrectomy. Therefore, diligent care and close monitoring are required for patients who are susceptible to developing ventricular arrhythmia. Trial Registration: Registered at ClinicalTrials.gov; https://clinicaltrials.gov/ct2/show/NCT02604979 ; Registration number NCT02604979. PMID- 30027783 TI - Surgical treatment for terrible triad injury of the elbow with anteromedial coronoid fracture through a combined surgical approach. AB - Objective To report the results of the surgical treatment of terrible triad injury with anteromedial coronoid fracture through a combined surgical approach. Methods This retrospective study evaluated data from patients who underwent surgery to repair terrible triad injuries and anteromedial coronoid fractures. Surgical treatment involved radial head repair or replacement, medial and lateral collateral ligament repair, and coronoid fracture fixation through combined approaches. Evaluations were performed using the Mayo Elbow Performance Score (MEPS) and anteroposterior and lateral radiographs of the elbow. Results Twenty two patients (15 males, seven females; mean +/- SD age, 47.5 +/- 11.4 years) were enrolled in this study. Fracture union and concentric reduction of both the ulnotrochlear and radiocapitellar articulations were achieved in all patients. The mean +/- SD follow-up was 31.6 +/- 11.9 months. The mean +/- SD arc of flexion-extension was 110.3 degrees +/- 26.3 degrees and arc of forearm rotation was 139.5 degrees +/- 17.1 degrees . The mean +/- SD MEPS was 88.1 +/- 12.2 points, with results classified as excellent in eight elbows, good in ten, and fair in four. Six patients had radiographic signs of post-traumatic arthritis. Three patients required secondary surgeries. Conclusion Combined surgical approaches can be considered for the treatment of terrible triad injuries in association with anteromedial coronoid fractures. PMID- 30027784 TI - Palestinian Adolescents' Prolonged Exposure to Political Violence, Self- Esteem, and Post-Traumatic Stress Symptoms. AB - The goal of this study was to understand the relation between adolescents' long term exposure to political violence (EPV) and post-traumatic stress symptoms (PTSS). We examined the relations among EPV, PTSS, and self-esteem to determine whether self-esteem could buffer the effects of EPV on PTSS. A systematic cluster random sample of 2,934 Palestinian adolescent boys and girls in the West Bank area of the Palestinian Authority and in East Jerusalem participated in a study using a self-administered questionnaire. Multiple regression analysis showed that the more Palestinian youth were exposed to political violence during the last year and during previous years, the more they exhibited PTSS and its three manifestations, that is, avoidance, intrusion, and arousal. In addition, EPV showed effects on PTSS after controlling for sociodemographic variables and self esteem. Girls and residents of the West Bank reported more PTSS than boys and residents of East Jerusalem, respectively. Higher levels of EPV correlated with lower levels of self-esteem, and children with relatively low self-esteem were likely to report more PTSS than children with high self-esteem. Hence, the correlations between participants' EPV and some of the PTSS were found to be partially dependent on the levels of their self-esteem, indicating moderating and mediating effects for self-esteem on the relation between degree of EPV and PTSS. The limitations of the study and implications for future research are discussed. PMID- 30027785 TI - Acute high-intensity exercise test in soccer athletes affects salivary biochemical markers. AB - Saliva has been reported as a potential biological fluid for biochemical monitoring. This study investigated salivary markers of exercise intensity, oral mucosal immunity, and redox homeostasis in soccer athletes subjected to an acute high-intensity interval exercise (HIIE) protocol characterised by a repeated sprint ability test. Thirty-two professional soccer athletes were recruited and saliva aliquots were collected at rest and immediately after HIIE protocol. When compared with pre-test values we observed that HIIE protocol induced moderate changes for total protein (p = .015; effect size (ES) = 0.51; smallest worthwhile change (SWC)factor = 5.7) and for cortisol levels (p < .0001; ES = 0.49; SWCfactor = 3.9). Lactate levels showed very large changes (p < .000; ES = 1.35; SWCfactor = 10.8), while Ig-A alterations were considered unclear. Besides, transferrin changes were trivial and maintained its levels at rest and after HIIE below the proposed threshold of 0.5 mg/dL. Regarding redox homeostasis we observed unclear effects for TBARs, MDA, GSH, GSSG, CAT, and SOD while uric acid showed large decreases (p = .005; ES = 0.80; SWCfactor = -5.4). HIIE protocol as a physical test conducted in soccer athletes increased salivary concentration of exercise intensity markers, such as lactate, total protein, and cortisol, but did not affect Ig-A levels. Redox homeostasis in saliva seems to be more related with uric acid levels as a possible key factor TBARs homeostasis. PMID- 30027786 TI - Respiratory syncytial virus prevents the subsequent development of ovalbumin induced allergic responses by inhibiting ILC2 via the IL-33/ST2 pathway. AB - AIM: How respiratory syncytial virus (RSV) influences the development of ovalbumin (OVA)-induced asthma remains elusive. As potent T helper (Th)2 cytokine producers, group 2 innate lymphoid cells (ILC2s) are known to serve important functions in the pathogenesis of allergic inflammation. However, how RSV infection affects innate immunity, especially with regard to the function of ILC2s in OVA-induced allergic airway inflammation, is largely unknown. MATERIALS & METHODS: RSV was used to infect adult BALB/c mice intranasally prior to sensitization and subsequent challenge with OVA. ILC2 frequencies and Th2 cytokine production by ILC2s were assessed by flow cytometry. Cytokine levels were detected both by real-time PCR and ELISA. RESULTS: Previous infection with RSV attenuated airway inflammation and decreased Th2 cytokine production in mice sensitized and challenged with OVA. Furthermore, previous infection with RSV inhibited the influx of ILC2s into the lung, and constrained their Th2 cytokine production. Adoptive transfer of ILC2s increased asthma-associated airway inflammation in mice previously infected with RSV. These results indicate that previous infection with RSV prevents OVA-induced asthma development via inhibition of ILC2s. Previous infection with RSV attenuated IL-33 production in lung tissue and reduced relative ST2L expression in lung ILC2s, meaning that previous infection with RSV may alter ILC2 function via the IL-33/ST2 signaling pathway. CONCLUSION: These results demonstrate that previous infection with RSV attenuates OVA-induced airway inflammation by inhibiting the recruitment and Th2 cytokine production of ILC2s via the IL-33/ST2 pathway. PMID- 30027787 TI - The Determinants of Informal, Formal, and Mixed In-Home Care in the Canadian Context. AB - OBJECTIVE: This study employed the behavioral model of service utilization to assess the impact of social support and other predisposing, enabling, and health need factors on the receipt of informal, formal, and/or combination of both types of in-home care. METHOD: The study utilized data from the 2008-2009 Canadian Community Health Survey and focused on individuals aged 45 and older with one or more functional limitations ( N = 5,898). RESULTS: A broad array of predisposing and enabling factors influenced the receipt of care both directly and indirectly through health-related needs for care. Different types of support were influential including affectionate support, positive social interaction, and tangible assistance. DISCUSSION: Findings support the utility of the behavioral model of service utilization to examine the determinants of in-home care arrangements. Findings also point to the need to broaden our focus on the importance of support networks beyond their direct involvement in the provision of care itself. PMID- 30027788 TI - Failure to Meet Nurse Staffing Standards: A Litigation Case Study of a Large US Nursing Home Chain. AB - Large for-profit nursing home chains in the United States have generally reported low nurse staffing levels. This historical case study examined a class action litigation case regarding staffing levels, resident rights, and quality outcomes in 12 Arkansas nursing homes owned by a large for-profit chain. The questions were as follows: (1) How did the residents' care needs compare with actual nurse staffing levels? (2) How did the staffing levels compare with federal and state nurse staffing requirements and professional staffing standards? (3) Did the facilities comply with state and federal residents' rights and quality of care requirements? The findings showed staffing levels marginally above state minimum standards, staffing shortages that violated state standards, staffing levels not adjusted for resident acuity, and shortages that resulted in omitted care. Staffing levels were lower than needed according to nursing directors, lower than average facilities in the state, and lower than professional standards. The findings showed many resident grievances regarding basic care and residents' rights, clinical measures of poor quality, and state deficiencies. A large settlement was agreed on to compensate the residents. The case shows that chain's management, as well as the regulatory system, failed to ensure adequate staffing levels that took into account regulatory requirements and professional standards and resulted in violations of residents' rights, health, safety, and well-being. PMID- 30027789 TI - Midregional pro-atrial natriuretic peptide, an important member of the natriuretic peptide family: potential role in diagnosis and prognosis of cardiovascular disease. AB - Midregional pro-atrial natriuretic peptide (MR-proANP), first isolated in 1981, is a novel peptide with multiple biological functions, especially within the cardiovascular system. This peptide plays an important role in many processes, including natriuresis, diuresis, and other physiological and pathophysiological pathways in the human body. Several electronic databases (PubMed, EBSCO, Scopus, and ScienceDirect) were analyzed in the present literature review. The aim of this study was to elucidate the wide roles of MR-proANP, which can be analyzed because of the development of a new sandwich immunoassay, and to determine the possible diagnostic and prognostic implications of MR-proANP on cardiovascular disease and other disorders. The studies discussed in this literature review provide valuable data on the role of ANP in the pathogenesis, diagnostic process, prognosis, and potential therapeutic strategies for disease. Although ANP is mainly associated with cardiovascular disease, it may be used as a biomarker in diabetology, neurology, and metabolic disorders. PMID- 30027790 TI - Histopathologic differentiation as a prognostic factor in patients with carcinoma of the hepatopancreatic ampulla of Vater. AB - OBJECTIVE: Periampullary carcinomas are a group of neoplasms with variable histopathology that originate from the anatomical junction of different epithelial types including the bile duct, pancreatic duct, and duodenal mucosa. This study was performed to determine whether the histopathologic type of these tumors should be considered an independent prognostic factor. METHODS: We analyzed the specimen histopathology of 37 patients who underwent radical cephalic pancreatoduodenectomy for carcinoma of the ampulla of Vater during a 5 year period. We excluded patients with other tumors with an indication for Whipple's procedure and those in whom R0 resection was not achieved. RESULTS: The carcinomas of the hepatopancreatic ampulla were intestinal in 23 (62%) patients, pancreatobiliary in 13 (35%), and mixed type in 1 (3%). The analysis demonstrated significantly more advanced local tumor spread, a more aggressive lymph node metastasizing pattern, and more frequent lymphatic and perineural invasion in patients with pancreatobiliary than intestinal and mixed type tumors. CONCLUSION: Pancreatobiliary type of ampullary carcinoma is associated with a poorer prognosis than intestinal and mixed types because of its more aggressive behavior. Histopathology should be regarded as an independent predictor of survival and may have therapeutic and prognostic implications for patients. PMID- 30027791 TI - Treatment of secondary hyperparathyroidism in patients on hemodialysis using a novel synthetic peptide calcimimetic, etelcalcetide: a short-term clinical study. AB - OBJECTIVE: Secondary hyperparathyroidism (SHPT) is a major complication in patients with chronic kidney disease (CKD). SHPT is related to chronic kidney disease-mineral bone disorder, leading to increased morbidity and mortality. Etelcalcetide is intravenously administered at the end of hemodialysis (HD). Etelcalcetide differs from the oral calcimimetic cinacalcet because it reduces gastrointestinal adverse events, thereby improving therapeutic effects. Etelcalcetide has only been approved by the U.S. Food and Drug Administration for several months. Therefore, there have only been a few reports regarding treatment of SHPT using etelcalcetide. This study aimed to evaluate the efficacy of etelcalcetide in patients on HD with SHPT. METHODS: Nine patients on HD (four men and five women, aged 58 +/- 10 years) were enrolled in this study. All of the patients received etelcalcetide (5-10 mg, three times a week after HD). The observation period was 4.4 +/- 1.0 months. RESULTS: All of the patients showed a significant reduction in serum parathyroid hormone levels during the observation period (-59% +/- 20%). No significant adverse effects were observed. CONCLUSIONS: Although this study had an uncontrolled small group and a short observation period, our results suggest that etelcalcetide could be a promising agent for SHPT treatment. PMID- 30027792 TI - Forcible Rape and Adolescent Friendship Networks. AB - Studies have found that sexual victimization can adversely affect an adolescent's psychological well-being, physical health, and behavior. Little is known, however, about how friendships are influenced by such victimization. Drawing on research on sexual violence and the salience of peers among adolescents, the current study extends prior work by examining the effects of forcible rape on adolescent social networks. Using a subsample of females from the National Longitudinal Study of Adolescent to Adult Health ( N = 4,386), the study employs multivariate regression analyses to estimate the effects of youth forcible rape on the popularity, centrality, and density of adolescent friendship networks and to determine whether depression and attachment to others (e.g., to friends and to school) mediate these effects. The analyses indicated that forcible rape was associated with a decrease in the popularity and centrality of females within their friendship networks; however, no effect on the density of these networks was identified. In addition, forcible rape effects on popularity and centrality were partially mediated by depression and social attachments. The results suggest that forcible rape may adversely affect adolescent females' levels of popularity and centrality within their friendship networks. Combined with prior research, the results indicate that the harmful effects of rape have the potential to extend across diverse domains, including social relationships. This possibility suggests that services and assistance to female adolescents may be useful in navigating these relationships after victimization. It suggests, too, that potential benefits that may arise from interventions that educate adolescents victims and nonvictims alike-about the challenges that victims of sexual violence experience. PMID- 30027793 TI - Uric acid levels are independent of anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease: A reappraisal of the role of S. cerevisiae in this setting. PMID- 30027794 TI - KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats. AB - Background Diabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study. Methods The mRNA levels of KCNQ2/3/5 channels were analyzed by real time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively. Results The mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats. Conclusion The findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms. PMID- 30027797 TI - A New Approach to Treat Childhood Leukemia: Novartis' CAR-T Therapy. PMID- 30027795 TI - Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models. AB - Cancer-induced bone pain is one of the most severe types of pathological pain, which often occurs in patients with advanced prostate, breast, and lung cancer. It is of great significance to improve the therapies of cancer-induced bone pain due to the opioids' side effects including addiction, sedation, pruritus, and vomiting. Sinomenine, a traditional Chinese medicine, showed obvious analgesic effects on a rat model of chronic inflammatory pain, but has never been proven to treat cancer-induced bone pain. In the present study, we investigated the analgesic effect of sinomenine after tumor cell implantation and specific cellular mechanisms in cancer-induced bone pain. Our results indicated that single administration of sinomenine significantly and dose-dependently alleviated mechanical allodynia in rats with cancer-induced bone pain and the effect lasted for 4 h. After tumor cell implantation, the protein levels of phosphorylated Janus family tyrosine kinase 2 (p-JAK2), phosphorylated-signal transducers and activators of transcription 3 (p-STAT3), phosphorylated-Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), and phosphorylated-cyclic adenosine monophosphate response element-binding protein (p-CREB) were persistently up-regulated in the spinal cord horn. Chronic intraperitoneal treatment with sinomenine markedly suppressed the activation of microglia and effectively inhibited the expression of JAK2/STAT3 and CAMKII/CREB signaling pathways. We are the first to reveal that up-regulation of microglial JAK2/STAT3 pathway are involved in the development and maintenance of cancer-induced bone pain. Moreover, our investigation provides the first evidence that sinomenine alleviates cancer-induced bone pain by inhibiting microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades. PMID- 30027798 TI - Biochemical studies evaluating the chemopreventive potential of brucine in chemically induced mammary carcinogenesis of rats. AB - The present study was aimed to investigate the dose dependent chemopreventive activity of brucine against 7, 12-dimethylbenz (a) anthracene induced mammary gland tumorigenesis in rats. The mammary tumor was induced by a single dose of DMBA (25 mg/rat) injected subcutaneously near the mammary gland. We observed reduced body weight and increased in tumor incidence the total number of tumors and tumor volume in DMBA alone injected rats and also observed decreased antioxidant status (SOD, CAT, GPX, and GSH) and increased lipid peroxidation (TBARS and LOOH) in plasma and mammary tissues. Increased levels of CYP450, Cyt b5 and decreased levels of phase II (GST and GR) biotransformation enzymes noticed in the liver and mammary tissues. Further increased levels of lipid profile (TC, TG, PL, and FFA) and lipoprotein (LDL and VLDL) were noticed. Whereas, decreased the level of HDL in plasma and decreased levels of PL and FFA in mammary tissues. Oral administration of brucine in different doses (2, 4 and 8 mg/kg bw) inhibited the tumor incidence and restored the levels of biochemical markers near to normal in dose responsive manner. Biochemical findings are supported by histopathological studies. The results suggest that brucine at a dose of 8 mg/kg bw shows more significant chemopreventive activity in DMBA induced mammary carcinogenesis. PMID- 30027796 TI - Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus. AB - The ubiquitous fungus Aspergillus flavus is notorious for contaminating many important crops and food-stuffs with the carcinogenic mycotoxin, aflatoxin. This fungus is also the second most frequent Aspergillus pathogen after A. fumigatus infecting immunosuppressed patients. In many human fungal pathogens including A. fumigatus, the ability to defend from toxic levels of copper (Cu) is essential in pathogenesis. In A. fumigatus, the Cu-fist DNA binding protein, AceA, and the Cu ATPase transporter, CrpA, play critical roles in Cu defense. Here, we show that A. flavus tolerates higher concentrations of Cu than A. fumigatus and other Aspergillus spp. associated with the presence of two homologs of A. fumigatus CrpA termed CrpA and CrpB. Both crpA and crpB are transcriptionally induced by increasing Cu concentrations via AceA activity. Deletion of crpA or crpB alone did not alter high Cu tolerance, suggesting they are redundant. Deletion of both genes resulted in extreme Cu sensitivity that was greater than that following deletion of the regulatory transcription factor aceA. The DeltacrpADeltacrpB and DeltaaceA strains were also sensitive to ROI stress. Compared to wild type, these mutants were impaired in the ability to colonize maize seed treated with Cu fungicide but showed no difference in virulence on non-treated seed. A mouse model of invasive aspergillosis showed DeltacrpADeltacrpB and to a lesser degree DeltaaceA to be significantly reduced in virulence, following the greater sensitivity of DeltacrpADeltacrpB to Cu than DeltaaceA. PMID- 30027799 TI - Association Between 5-Star Nursing Home Report Card Ratings and Potentially Preventable Hospitalizations. AB - Nursing homes' publicly reported star ratings increased substantially since Centers for Medicare & Medicaid Services's Nursing Home Compare adopted a 5-star rating system. Our objective was to test whether the improvements in nursing home 5-star ratings were correlated with reductions in rates of hospitalization. We hypothesized that increased attention to 5-star star ratings motivated nursing homes to make changes that improved their star ratings but did not affect their hospitalization rate, resulting in a weakened association between ratings and hospitalizations. We used 2007-2010 Medicare hospital claims and nursing home clinical assessment data to compare the correlation between nursing home 5-star ratings and hospitalization rates before versus after 5-star ratings were publicly released. The correlation between the rate of hospitalization and a nursing home's 5-star rating weakened slightly after the ratings became publicly available. This decrease in correlation was concentrated among patients receiving post-acute care, who experienced relatively more hospitalizations from best-rated nursing homes. The improvements in nursing home star ratings after the release of Medicare's 5-star rating system were not accompanied by improvements in a broader measure of outcomes for post-acute care patients. Although this dissociation may be due to better matching of sicker patients to higher-quality nursing homes or superficial improvements by nursing homes to increase their ratings without substantial investments in quality improvement, the 5-star ratings nonetheless became less meaningful as an indicator of nursing home quality for post-acute care patients. PMID- 30027800 TI - Clinicopathological features of pediatric renal biopsies in the plateau regions of China. AB - OBJECTIVE: This study aimed to analyze the clinicopathological features of pediatric renal biopsies from plateau regions of China. METHODS: Clinicopathological features of pediatric renal biopsies were compared between plateau and non-plateau regions in patients who were admitted to West China Second University Hospital, Sichuan University between April 2001 and March 2017. Patients were children younger than 18 years. RESULTS: The proportion of primary glomerular disease in the plateau group was lower than that in the non-plateau group (45.56% vs 62.09%, respectively). In the plateau group, IgA nephropathy (IgAN) was the major primary glomerulonephritis (GN) pathology. IgAN accounted for 36.54% and 21.63% of GN cases with nephrotic syndrome and hematuria, respectively. Henoch-Schonlein purpura nephritis was the most common secondary GN in both groups. The proportion of hepatitis B virus-associated GN was higher and that of lupus nephritis was lower in the plateau group than in the non-plateau group. CONCLUSIONS: There are differences in renal pathological types between children in plateau regions and those in non-plateau regions. Among children in plateau regions, IgAN and Henoch-Schonlein purpura nephritis were the most common kidney diseases. PMID- 30027801 TI - Prunasin production using engineered Escherichia coli expressing UGT85A47 from Japanese apricot and UDP-glucose biosynthetic enzyme genes. AB - Japanese apricot, Prunus mume Sieb. et Zucc., biosynthesizes the l-phenylalanine derived cyanogenic glucosides prunasin and amygdalin. Prunasin has biological properties such as anti-inflammation, but plant extraction and chemical synthesis are impractical. In this study, we identified and characterized UGT85A47 from Japanese apricot. Further, UGT85A47 was utilized for prunasin microbial production. Full-length cDNA encoding UGT85A47 was isolated from Japanese apricot after 5'- and 3'-RACE. Recombinant UGT85A47 stoichiometrically catalyzed UDP glucose consumption and synthesis of prunasin and UDP from mandelonitrile. Escherichia coli C41(DE3) cells expressing UGT85A47 produced prunasin (0.64 g/L) from racemic mandelonitrile and glucose. In addition, co-expression of genes encoding UDP-glucose biosynthetic enzymes (phosphoglucomutase and UTP-glucose 1 phosphate uridiltransferase) and polyphosphate kinase clearly improved prunasin production up to 2.3 g/L. These results showed that our whole-cell biocatalytic system is significantly more efficient than the existing prunasin production systems, such as chemical synthesis. PMID- 30027802 TI - Comparative proteomics of two Mycoplasma hyopneumoniae strains and Mycoplasma flocculare identified potential porcine enzootic pneumonia determinants. AB - Mycoplasma hyopneumoniae and Mycoplasma flocculare are genetically similar bacteria, which coinhabit the porcine respiratory tract. These mycoplasmas share most of the known virulence factors, but, while M. hyopneumoniae causes porcine enzootic pneumonia (PEP), M. flocculare is a commensal species. To identify potential PEP determinants and provide novel insights on mycoplasma-host interactions, the whole cell proteomes of two M. hyopneumoniae strains, one pathogenic (7448) and other non-pathogenic (J), and M. flocculare were compared. A cell fractioning approach combined with mass spectrometry (LC-MS/MS) proteomics was used to analyze cytoplasmic and surface-enriched protein fractions. Average detection of ~ 50% of the predicted proteomes of M. hyopneumoniae 7448 and J, and M. flocculare was achieved. Many of the identified proteins were differentially represented in M. hyopneumoniae 7448 in comparison to M. hyopneumoniae J and M. flocculare, including potential PEP determinants, such as adhesins, proteases, and redox-balancing proteins, among others. The LC-MS/MS data also provided experimental validation for several genes previously regarded as hypothetical for all analyzed mycoplasmas, including some coding for proteins bearing virulence related functional domains. The comprehensive proteome profiling of two M. hyopneumoniae strains and M. flocculare provided tens of novel candidates to PEP determinants or virulence factors, beyond those classically described. PMID- 30027804 TI - Binaural Pitch Fusion: Effects of Amplitude Modulation. AB - Hearing-impaired adults, including both cochlear implant and bilateral hearing aid (HA) users, often exhibit broad binaural pitch fusion, meaning that they fuse dichotically presented tones with large pitch differences between ears. The current study was designed to investigate how binaural pitch fusion can be influenced by amplitude modulation (AM) of the stimuli and whether effects differ with hearing loss. Fusion ranges, the frequency ranges over which binaural pitch fusion occurs, were measured in both normal-hearing (NH) listeners and HA users with various coherent AM rates (2, 4, and 8 Hz); AM depths (20%, 40%, 60%, 80%, and 100%); and interaural AM phase and AM rate differences. The averaged results show that coherent AM increased binaural pitch fusion ranges to about 2 to 4 times wider than those in the unmodulated condition in both NH and bilateral HA subjects. Even shallow temporal envelope fluctuations (20% AM depth) significantly increased fusion ranges in all three coherent AM rate conditions. Incoherent AM introduced through interaural differences in AM phase or AM rate led to smaller increases in binaural pitch fusion range compared with those observed with coherent AM. Significant differences between groups were observed only in the coherent AM conditions. The influence of AM cues on binaural pitch fusion shows that binaural fusion is mediated in part by central processes involved in auditory grouping. PMID- 30027803 TI - Senescent Changes in Sensitivity to Binaural Temporal Fine Structure. AB - Differences in the temporal fine structure (TFS) of sounds at the two ears are used for sound localization and for the perceptual analysis of complex auditory scenes. The ability to process this binaural TFS information is poorer for older than for younger participants, and this may contribute to age-related declines in the ability to understand speech in noisy situations. However, it is unclear how sensitivity to binaural TFS changes across the older age range. This article presents data for a test of binaural sensitivity to TFS, the "TFS-adaptive frequency" (AF) test, for 118 listeners aged 60 to 96 years with normal or near normal low-frequency hearing, but a variety of patterns of hearing loss at higher frequencies. TFS-AF scores were significantly lower (i.e., poorer) than those for young adults. On average, scores decreased by about 162 Hz for each 10-year increase in age over the range 60 to 85 years. Individual variability increased with increasing age. Scores also declined as low-frequency audiometric thresholds worsened. The results illustrate the range of scores that can be obtained as a function of age and may be useful for the diagnosis and management of age-related hearing difficulties. PMID- 30027805 TI - Pathogenic bacterial profile and drug resistance analysis of community-acquired pneumonia in older outpatients with fever. AB - OBJECTIVES: To study the pathogenic bacterial profile and drug resistance in older patients with community-acquired pneumonia (CAP) in outpatients with fever, and provide evidence to diagnose and treat CAP timely and accurately. METHODS: We studied older (>60 years) patients with CAP in Beijing Shijitan Hospital from 2016 to 2017. Pathogenic bacteria from sputum of patients were isolated and identified and their resistance to antibiotics was tested. Risk factors for multidrug-resistant CAP (MDR-CAP) and clinical outcomes were analyzed. RESULTS: A total of 5563 outpatients with fever were recruited and 391 had CAP. A total of 117 isolates of pathogenic bacteria were obtained from 176 CAP cases. The main pathogenic bacteria were Klebsiella pneumoniae (27.4%), Escherichia coli (17.9%), Staphylococcus aureus (12.0%), Pseudomonas aeruginosa (10.3%), and Streptococcus pneumoniae (9.4%). A drug sensitivity test (DST) showed that K. pneumoniae, E. coli, and P. aeruginosa had good sensitivity to imipenem, cefoperazone/sulbactam, piperacillin/tazobactam, and amikacin. Staphylococcus aureus and Streptococcus pneumoniae had strong sensitivity to vancomycin, linezolid, and levofloxacin. Previous multiple antibiotic treatment was an independent risk factor for MDR CAP. CONCLUSIONS: Gram-negative bacteria are the main pathogenic bacteria in older patients with CAP. Identification and DSTs of pathogens could enable accurate diagnosis and treatment of CAP. PMID- 30027806 TI - The Effect of Transient Location on the Resolution of Bistable Visual and Audiovisual Motion Sequences. AB - We examined the attention and inference accounts of audiovisual perception using the stream/bounce display, a visual stimulus wherein two identical objects move toward each other, completely superimpose, then move apart. This display has two candidate percepts: stream past each other or bounce off each other. Presented without additional visual or auditory transients, the motion sequence tends to yield the streaming percept, but when coupled with a tone or flash at the point of coincidence, the response bias flips toward bouncing. We explored two competing accounts of this effect: the attentional hypothesis and the inference hypothesis. Participants watched a series of motion sequences where a transient, when present, occurred at the moment of coincidence either colocalised with the motion sequence (congruent presentation) or on the opposite side of the display (incongruent presentation). Assuming the spotlight or zoom lens metaphor, an attentional account predicts that incongruent presentations should be associated with a higher percentage of bouncing responses than congruent presentations, while the inferential account predicts the opposite effect. No effect was found for tone-only trials. However, in trials containing a visual transient, results showed higher proportions of bounce responses within congruent over incongruent presentations, favouring the inference hypothesis over a spotlight or zoom lens attentional account. PMID- 30027807 TI - Examining the Impact of Group Size on the Treatment Intensity of a Tier 2 Mathematics Intervention Within a Systematic Framework of Replication. AB - Group size and treatment intensity are understudied topics in mathematics intervention research. This study examined whether the treatment intensity and overall intervention effects of an empirically validated Tier 2 mathematics intervention varied between intervention groups with 2:1 and 5:1 student-teacher ratios. Student practice opportunities and the quality of explicit instruction served as treatment intensity metrics. A total of 465 kindergarten students with mathematics difficulties from 136 intervention groups participated. Results suggested comparable performances between the 2:1 and 5:1 intervention groups on six outcome measures. Observation data indicated that student practice differed by group size. Students in the 5:1 groups received more opportunities to practice with their peers, while students in the 2:1 groups participated in more frequent and higher quality individualized practice opportunities. Implications in terms of delivering Tier 2 interventions in small-group formats and engaging at-risk learners in meaningful practice opportunities are discussed. PMID- 30027808 TI - Single channel kinetic analysis of the cAMP effect on IKs mutants, S209F and S27D/S92D. AB - The IKs current is important in the heart's response to sympathetic stimulation. beta-adrenergic stimulation increases the amount of IKs and creates a repolarization reserve that shortens the cardiac action potential duration. We have recently shown that 8-CPT-cAMP, a membrane-permeable cAMP analog, changes the channel kinetics and causes it to open more quickly and more often, as well as to higher subconductance levels, which produces an increase in the IKs current. The mechanism proposed to underlie these kinetic changes is increased activation of the voltage sensors. The present study extends our previous work and shows detailed subconductance analysis of the effects of 8-CPT-cAMP on an enhanced gating mutant (S209F) and on a double pseudo-phosphorylated IKs channel (S27D/S92D). 8-CPT-cAMP still produced kinetic changes in S209F + KCNE1, further enhancing gating, while S27D/S92D + KCNE1 showed no significant response to 8-CPT cAMP, suggesting that these last two mutations fully recapitulate the effect of channel phosphorylation by cAMP. PMID- 30027809 TI - When Forgiveness Signals Power: Effects of Forgiveness Expression and Forgiver Gender. AB - Forgiveness has been regarded as a sign of power, yet empirical evidence is mixed. This research seeks to resolve this inconsistency by looking into how and from whom forgiveness is expressed. Integrating theories on forgiveness, communication, and gender role, we hypothesized and found, in two experiments, that a third party's perception of forgiver power is jointly influenced by forgiveness expression (explicit vs. implicit) and forgiver gender. Female forgivers were perceived as less powerful than their male counterparts when forgivers expressed implicit forgiveness, whereas this gender difference was not found when forgivers expressed explicit forgiveness. Perceived forgiver power, in turn, positively influenced third parties' cooperation with the forgiver in subsequent interaction. This research represents an initial step to understanding forgiveness from a communication perspective. It demonstrates the social implications of forgiveness on uninvolved third parties. Our findings also resonate with several others in showing that forgiveness does not always yield interpersonal benefits. PMID- 30027810 TI - From Patient to Provider: The Lived Experience of Pediatric Oncology Survivors Who Work as Pediatric Oncology Nurses. AB - There is little known about the experiences of former pediatric oncology patients that are currently working as pediatric oncology nurses. Literature reviews yielded no direct research studies involving this group of nurses. The purpose of this phenomenological study was to describe the experiences of these former oncology patients that are now oncology nurses. Eleven pediatric oncology nurses were interviewed for this study, and the following themes emerged: Awe and Awkwardness, Guilt and Gratitude, Sharing My Story, Wanting to Remember/Wanting to Forget, and Past Treatment/Current Challenges. The results of this study demonstrate the unique challenges these survivors face as they transition into their professional roles. Information about these nurses' experiences is important when considering their education and support throughout their careers. PMID- 30027811 TI - Living in Fear and Prioritizing Safety: Exploring Women's Lives After Traumatic Brain Injury From Intimate Partner Violence. AB - There is increasing evidence that women are receiving a traumatic brain injury (TBI) during episodes of intimate partner violence (IPV), but little qualitative research exists around how surviving this experience impacts the lives of women. Primary and secondary data ( N = 19) were used with a constructivist grounded theory approach to explore the lives of women aged 18 to 44 years, who were living with a TBI from IPV. Women described multiple aspects of living in fear that shaped their daily lives and ability to seek help and access resources. The central process of prioritizing safety emerged, with salient dimensions of maintaining a present orientation, exhibiting hyperprotection of children, invoking isolation as protection, and calculating risk of death. These findings add to the growing body of knowledge that women living with IPV are at high risk for receiving a TBI and are therefore a subgroup in need of more prevention and treatment resources. PMID- 30027812 TI - Enabling Technology in Cell-Based Therapies: Scale-Up, Scale-Out, or Program In Place. PMID- 30027813 TI - Rapid Microbiology Screening in Pharmaceutical Workflows. AB - Recently advances in miniaturization and automation have been utilized to rapidly decrease the time to result for microbiology testing in the clinic. These advances have been made due to the limitations of conventional culture-based microbiology methods, including agar plate and microbroth dilution, which have long turnaround times and require physicians to treat patients empirically with antibiotics before test results are available. Currently, there exist similar limitations in pharmaceutical sterility and bioburden testing, where the long turnaround times associated with standard microbiology testing drive costly inefficiencies in workflows. These include the time lag associated with sterility screening within drug production lines and the warehousing cost and time delays within supply chains during product testing. Herein, we demonstrate a proof-of concept combination of a rapid microfluidic assay and an efficient cell filtration process that enables a path toward integrating rapid tests directly into pharmaceutical microbiological screening workflows. We demonstrate separation and detection of Escherichia coli directly captured and analyzed from a mammalian (i.e., CHO) cell culture with a 3.0 h incubation. The demonstration is performed using a membrane filtration module that is compatible with sampling from bioreactors, enabling in-line sampling and process monitoring. PMID- 30027814 TI - Life Sciences Discovery and Technology Highlights. PMID- 30027815 TI - Detention under section 136: Why is it increasing? AB - There has been a significant increase in the use of section 136 of the Mental Health Act 1983 in England and Wales, particularly over the past 10 years, but the reasons for this increase remain unclear. This paper presents a history of English mental-health legislation and the current evidence relating to the use of section 136. It suggests that changing police attitudes, socio-economic factors and diminished resources amongst both the police and mental-health services may have contributed towards its increase. The strain placed on health services may have also resulted in a greater reliance on the police force as an access point to NHS care and could result in the inappropriate use of section 136. With the principle of the 'least restrictive option' at the heart of the Mental Health Act, this advocates the need for reform. PMID- 30027816 TI - High-Throughput Flow Cytometry in Drug Discovery. PMID- 30027817 TI - Short 2-H in Situ Trauma Team Simulation Training Effectively Improves Non Technical Skills of Hospital Trauma Teams. AB - BACKGROUND AND AIMS: As conducting the regular trauma team simulation training is expensive and time-consuming, its effects must be explored. The objective was to evaluate the efficacy of a structured 2-h in situ multiprofessional trauma team simulation training course on non-technical skills. MATERIALS AND METHODS: This prospective study comprised 90 trauma teams with 430 participants. The structured, 2-h course consisted of an introductory lecture and two different simulations with debriefings. Data were collected using a pre-post self assessment questionnaire. In addition, the expert raters used the T-NOTECHS scale. RESULTS: The following non-technical skills improved significantly among both medical doctors and nurses: knowledge of the trauma resuscitation guidelines, problem identification, decision making, situation awareness/coping with stress, communication and interaction, time management, being under authority, and confidence in one's role in a team. The teams improved significantly in leadership, cooperation and resource management, communication and interaction, assessment and decision making, and situation awareness/coping with stress. CONCLUSION: A short, structured 2-h in situ trauma team simulation training course is effective in improving non-technical skills. PMID- 30027818 TI - Towards a theory of delusions. PMID- 30027819 TI - The Gift of Psychological Closeness: How Feasible Versus Desirable Gifts Reduce Psychological Distance to the Giver. AB - Gift-giving is a common form of social exchange but little research has examined how different gift types affect the psychological distance between giver and recipient. We examined how two types of gifts influence recipients' perceived psychological distance to the giver. Specifically, we compared desirable gifts focused on the quality of the gift with feasible gifts focused on the gift's practicality or ease of use. We found that feasible (vs. desirable) gifts led recipients to feel psychologically closer to givers (Studies 1-4). Further clarifying the process by which receiving a desirable versus feasible gift affects perceived distance, when recipients were told that the giver focused on the gift's practicality or ease of use (vs. the gift's overall quality), while holding the specific features of the gifts constant, they felt closer to the gift giver (Study 5). These results shed light on how different gifts can influence interpersonal relationships. PMID- 30027820 TI - Bifunctional properties and characterization of a novel sialidase with esterase activity from Bifidobacterium bifidum. AB - Sialidases catalyze the removal of terminal sialic acid from various complex carbohydrates. In the gastrointestinal tract, sialic acid is commonly found in the sugar chain of mucin, and many enteric commensals use mucin as a nutrient source. We previously identified two different sialidase genes in Bifidobacterium bifidum, and one was cloned and expressed as an extracellular protein designated as exo-alpha-sialidase SiaBb2. The other exo-alpha-sialidase gene (siabb1) from the same bifidobacterium encodes an extracellular protein (SiaBb1) consisting of 1795 amino acids with a molecular mass of 189 kDa. SiaBb1 possesses a catalytic domain that classifies this enzyme as a glycoside hydrolase family 33 member. SiaBb1 preferentially hydrolyzes alpha2,3-linked sialic acid over alpha2,6-linked sialic acid from sialoglycan, which is the same as SiaBb2. However, SiaBb1 has an SGNH hydrolase domain with sialate-O-acetylesterase activity and an N-terminal signal sequence and C-terminal transmembrane region. SiaBb1 is the first bifunctional sialidase identified with esterase activity. Abbreviations: GalNAc: N-acetyl-D-galactosamine; Fuc: L-fucose; Gal: D-galactose. PMID- 30027821 TI - The gut microbiota of wild rodents: Challenges and opportunities. AB - The gut microbiota can have important, wide-ranging effects on its host. To date, laboratory animals, particularly mice, have been the major study system for microbiota research. It is now becoming increasingly clear that laboratory animals often poorly model aspects of the biology of wild animals, and this concern extends to the study of the gut microbiota. Here, the relatively few studies of the microbiota of wild rodents are reviewed, including a critical assessment of how the gut microbiota differs between laboratory and wild rodents. Finally, the many potential advantages and opportunities of wild-animal systems for research into the gut microbiota are considered. PMID- 30027822 TI - Canine mammary tumor risk is associated with polymorphisms in RAD51 and STK11 genes. AB - Cancer is a complex disease involving genetic and phenotypic changes. Several single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer development in women; however, little is known regarding their influence on canine mammary tumor risk. We assessed the influence of SNPs in genes related to human breast cancer susceptibility, with respect to the risk of development of mammary tumors in dogs. Sixty-seven canine SNPs in proto oncogenes, tumor suppressor genes, genes involved in DNA repair, and in hormonal metabolism were evaluated in 212 bitches with mammary tumors and in 161 bitches free of mammary neoplasia. A significant association with mammary neoplasia risk was identified for 2 SNPs in RAD51 ( rs23623251 and rs23642734) and one SNP in the STK11 gene ( rs22928814). None of the other SNPs were related to the risk of mammary tumor development. The identification of genetic profiles associated with risk of mammary neoplasia is of great importance, supporting the implementation of specific clinical management strategies in high-risk animals. PMID- 30027823 TI - Loss of loved ones or home due to a disaster: Effects over time on distress in immigrant ethnic minorities. AB - Exposure to mass trauma may bring about increased sensitivity to new or ongoing stressors. It is unclear whether sensitivity to stress associated with ethnic minority/immigrant status may be affected by severe exposure to mass trauma. We examined whether the loss of loved ones or home due to a disaster is associated with more persistent disaster-related distress in ethnic minorities compared with Dutch natives in the Netherlands. In residents affected by a fireworks disaster ( N = 1029), we assessed disaster-related distress after 3 weeks, 18 months, and 4 years. The effects of loss of loved ones or home and ethnic minority/immigrant status on distress were analyzed using latent growth modeling. After controlling for age, gender, education, employment, and post-disaster stressful life events, the loss of loved ones was associated with more persistent disaster-related distress in ethnic minorities compared with natives at 18 months, and the loss of home was associated with more persistent disaster-related distress in ethnic minorities compared with natives between 18 months and 4 years. Our results suggest that the loss of loved ones may increase sensitivity to stress associated with ethnic minority/immigrant status during the early phase of adaptation to a disaster. Loss of home may lead to further resource loss and thereby increase sensitivity to stress associated with ethnic minority/immigrant status in the long term. Efforts to prevent stress-related psychopathology following mass trauma should specifically target ethnic minority groups, notably refugees and asylum seekers, who often experienced multiple losses of loved ones as well as their homes. PMID- 30027824 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry identification of Moraxella bovoculi and Moraxella bovis isolates from cattle. AB - Infectious bovine keratoconjunctivitis (IBK) is an economically significant disease caused by Moraxella bovis. Moraxella bovoculi, although not reported to cause IBK, has been isolated from the eyes of cattle diagnosed with IBK. Identification of M. bovis and M. bovoculi can be performed using biochemical or DNA-based approaches, both of which may be time consuming and inconsistent between laboratories. We conducted a comparative evaluation of M. bovoculi and M. bovis identification using matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) with a database provided by Bruker Daltonics (termed the BDAL database), the BDAL database supplemented with spectra generated in our study (termed the UNLVDC database), and with PCR-restriction fragment length polymorphism (PCR-RFLP) typing. M. bovoculi ( n = 250) and M. bovis ( n = 18) isolates from cattle with or without IBK were used. MALDI-TOF MS using the UNLVDC database correctly identified 250 of 250 (100%) of M. bovoculi and 17 of 18 (94%) of M. bovis isolates. With the BDAL database, MALDI-TOF MS correctly identified 249 of 250 (99%) of M. bovoculi and 7 of 18 (39%) of M. bovis isolates. In comparison, the PCR-RFLP test correctly identified 210 of 250 (84%) of M. bovoculi and 12 of 18 (66%) of M. bovis isolates. Thus, MALDI-TOF MS with the UNLVDC database was the most effective identification methodology for M. bovis and M. bovoculi isolates from cattle. PMID- 30027825 TI - Wealthy, urban, educated. Who is represented in population surveys of women's menstrual hygiene management? AB - Inadequate menstrual hygiene presents a barrier to women's dignity and health. Recent attention to this marginalised challenge has resulted in the first national assessments of menstrual practices. Intuitively, surveys require women to have had a recent menses to be eligible. This study seeks to determine if there are demographic differences between women who are eligible and ineligible to answer questions about their menstrual hygiene during these assessments. Secondary analyses were undertaken on nationally or state representative data collected by the Performance Monitoring and Accountability 2020 survey programme across eight countries (Burkina Faso, Ethiopia, Ghana, India, Kenya, Niger, Nigeria, and Uganda). Female respondents were included in the study and compared on whether they had a menstrual period within the past three months and thus were eligible to answer questions regarding menstrual practices. On average, 29% of surveyed women across samples were ineligible to be asked menstrual hygiene questions. Higher levels of education, wealth, and urban residence were associated with higher odds of eligibility. Young and unmarried women were also more likely to be eligible. Demographic differences between eligible and ineligible women were consistent across all countries. Wealthy, urban, and educated women are more likely to be eligible to answer survey questions about menstrual hygiene. While population surveys may be representative of menstruating women, proportions of menstrual hygiene practices reported underrepresent the experiences of more vulnerable groups. These groups are likely to have greater struggles with menstrual hygiene when they are menstruating. PMID- 30027826 TI - Inhibited symptoms of Reactive Attachment Disorder: links with working models of significant others and the self. AB - To better understand Reactive Attachment Disorder (RAD), the current study tested whether emotionally and behaviorally disordered children with versus without RAD differ with regard to the quality of their interpersonal behavior during interactions with teachers and with regard to their representations of self and others. Therefore, 77 children were screened for RAD symptoms and 22 likely cases of inhibited RAD were identified. To measure quality of the interactions with teachers, we observed children's trust and positive affect in dyadic interactions with teachers. For the representations of others, we measured self-reported trust in parents and teachers. For the representations of the self, two self-esteem assessments were individually administered. Results showed that, compared to children with other emotional and behavior disorders, RAD children's behavior reflected less trust in their teachers. At the level of representations, children reported less trust in teacher care. Instead, no links were found with self report measures focusing on representations of parents and of self. These findings will be discussed in light of the ongoing discussion about whether or not attachment disorder and insecure attachment are associated concepts. PMID- 30027827 TI - Necrotizing interstitial pneumonia and suppurative myocarditis associated with Bartonella henselae infection in three Florida pumas. AB - Three Florida pumas ( Puma concolor coryi) that had spent time in captivity prior to being released in the wild were found exhibiting respiratory signs and reluctance to move. All 3 pumas died shortly after immobilization, despite supportive veterinary care. Significant autopsy findings included necrotizing interstitial pneumonia, with pulmonary edema and hyaline membranes, and suppurative myocarditis. Organisms morphologically consistent with Bartonella henselae were identified in intravascular histiocytes in the lung of one of the pumas on histopathology and confirmed via transmission electron microscopy. B. henselae was detected in fresh lung tissue and confirmed by PCR and sequence analysis (16S-23S spacer region, pap31, and rpoB genes) from one of the affected pumas. In all affected pumas, B. henselae was detected by PCR in formalin-fixed, paraffin-embedded lung tissue, and positively staining organisms were identified in sections of lung by immunohistochemistry for B. henselae. In situ hybridization detected B. henselae DNA in lung tissue from 2 of 3 affected pumas. Our case series suggests that B. henselae can be associated with a fatal disease syndrome in Florida pumas. The cause of susceptibility to fatal disease associated with B. henselae infection in these pumas remains unknown. PMID- 30027828 TI - Typicality-based semantic treatment for anomia results in multiple levels of generalisation. AB - This study investigated the effects of typicality-based semantic feature analysis (SFA) treatment on generalisation across three levels: untrained related items, semantic/phonological processing tasks, and measures of global language function. Using a single-subject design with group-level analyses, 27 persons with aphasia (PWA) received typicality-based SFA to improve their naming of atypical and/or typical exemplars. Progress on trained, untrained, and monitored items was measured weekly. Pre- and post-treatment assessments were administered to evaluate semantic/phonological processing and overall language ability. Ten PWA served as controls. For the treatment participants, the likelihood of naming trained items accurately was significantly higher than for monitored items over time. When features of atypical items were trained, the likelihood of naming untrained typical items accurately was significantly higher than for untrained atypical items over time. Significant gains were observed on semantic/phonological processing tasks and standardised assessments after therapy. Different patterns of near and far transfer were seen across treatment response groups. Performance was also compared between responders and controls. Responders demonstrated significantly more improvement on a semantic processing task than controls, but no other significant change score differences were found between groups. In addition to positive treatment effects, typicality-based SFA naming therapy resulted in generalisation across multiple levels. PMID- 30027829 TI - Hematology reference intervals for adult cows in France using the Sysmex XT 2000iV analyzer. AB - In order to develop bovine hematology reference intervals (RIs) in accordance with new international recommendations, we analyzed 156 blood specimens of healthy adult dairy and beef cows from 32 farms with a Sysmex XT-2000iV analyzer, and by manual scoring of platelet clumps and white blood cell (WBC) differential. We established RIs by the nonparametric method, and examined effects of age, production type (beef vs. dairy), and stage of lactation. RIs could not be determined for platelet count and indices because clumps were observed in 80% of specimens. Optical and impedance red blood cell (RBC) counts were similar, although statistically different. RIs for analyzer and manual WBC differentials were not different except for lymphocyte concentration, the subpopulations of which were counted manually. Hematocrit was higher in beef than dairy cattle, and hemoglobin was lower in early lactation. Increases in RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and RBC distribution width were noted with increasing age, along with decreases in WBC count, neutrophils, and lymphocytes. Most RIs in our study, with the exception of neutrophils, were similar to those previously reported using a flow cytometry analyzer. PMID- 30027830 TI - Comparison of immunohistochemistry and immunofluorescence techniques using anti lambda light chain antibodies for identification of immune complex deposits in canine renal biopsies. AB - Comprehensive renal biopsy evaluation of canine glomerular disease uses immunofluorescence (IF) labeling of fresh frozen tissue to detect immune complexes that are confirmed with transmission electron microscopy. This methodology requires the veterinarian to harvest additional tissue samples, whereas sections for immunohistochemistry (IHC) could be performed on paraffin sections. If adequate IHC labeling of formalin-fixed, paraffin-embedded tissue was possible, the additional tissue samples would be unnecessary. We compared the specificity and sensitivity of IHC to IF for diagnosis of immune complex-mediated glomerulonephritis (ICGN). Commercial anti-canine IHC and IF antibodies targeting the lambda light chain component of immunoglobulins were evaluated, using previously diagnosed cases of ICGN and cases without immune complexes (non-ICGN). Because the pattern of IF labeling is crucial for accurate interpretation, sections were evaluated by a trained nephropathologist and a novice to assess the impact of experience in the diagnosis of ICGN. Unfortunately, our attempts to develop an IHC protocol that could improve the workflow for clinicians and laboratory personnel were unsuccessful; the IHC protocol did not demonstrate staining patterns that could be detected reliably by either evaluator. Moreover, the IHC antibody demonstrated abundant nonspecific staining in non-ICGN cases, and 60% of true ICGN cases were misdiagnosed as non-ICGN. We did not achieve a reliable IHC protocol for the anti-lambda light chain antibody and, therefore, IF for lambda light chain remains the method of choice for ICGN detection. PMID- 30027831 TI - An Overview of the Tissue Engineering Market in the United States from 2011 to 2018. AB - This report seeks to provide an update of the tissue engineering industry from 2011 to 2018. Public tissue engineering companies with a presence in the United States were the focus of this report due to the publicly accessible financial data that they provide on an annual basis. Over the course of this analysis, 49 tissue engineering companies were identified, 21 of which were in the commercial phase of development and had tissue engineering products on the market. These 21 companies made an estimated $9 billion in sales of tissue engineering-related products in 2017. Based on previous reports and market trends, the field of tissue engineering is forecasted to continue to build revenue for the years to come. PMID- 30027832 TI - Transcutaneous Recording During Intraoperative Neuromonitoring in Thyroid Surgery. AB - BACKGROUND: Recurrent laryngeal nerve (RLN) palsy remains a major source of morbidity after thyroid surgeries. Intraoperative neural monitoring (IONM) has gained increasing acceptance as an adjunct to standard practice of visual RLN identification. Endotracheal tube (ETT) surface recording electrodes systems are now widely used for IONM; however, a malpositioned ETT can cause false IONM results and requires time-consuming intraoperative verification of the ETT position and readjustment by the anesthesiologist. The aim of this experimental study was to evaluate the feasibility of the transcutaneous approach for recording evoked laryngeal electromyography (EMG) signals during IONM. METHODS: A porcine model with well-established applicability in IONM research was used. Twelve piglets (24 nerve sides) were enrolled. Electrically evoked EMGs were recorded from surface electrodes on the ETT and from the adhesive pre-gelled surface electrodes on the anterior neck skin. The evoked EMG waveforms were measured and analyzed. The real-time signal stability of the electrodes during tracheal displacement and their accuracy in reflecting adverse EMG changes during RLN stress were evaluated during continuous IONM performed with automatic periodic vagus nerve (VN) stimulation. RESULTS: In all nerves, both the ETT and neck adhesive skin electrodes successfully recorded typical evoked laryngeal EMG waveforms from the RLNs and VNs under stimulation with 1 mA. The transcutaneous electrodes recorded mean EMG amplitudes of 264 MUV (+/-79) under RLN stimulation and 202 MUV (+/-55) under VN stimulation. The electrodes recorded mean EMG latencies of 2.98 ms (+/-0.20) under RLN stimulation, 4.51 ms (+/-0.50) under right VN stimulation, and 8.13 ms (+/-0.94) under left VN stimulation, respectively. When tracheal displacement was experimentally induced, the EMG signals obtained by ETT electrodes varied significantly, but those obtained by transcutaneous electrodes did not. When RLN traction stress was experimentally induced, both ETT and transcutaneous electrodes recorded the same pattern of progressively degrading EMG amplitude with gradual recovery after release of traction. CONCLUSIONS: This study confirms the feasibility of transcutaneous recording of evoked laryngeal EMG during IONM. Although this study confirms the stability and accuracy of the transcutaneous approach, it also revealed the need for new electrode designs to improve EMG amplitudes before practical clinical application of this approach. PMID- 30027833 TI - The origins and early years of the Magnetic and Meteorological department at Greenwich Observatory, 1834-1848. AB - As one of his first acts upon becoming Astronomer Royal in 1835, George Airy made moves to set up a new observatory at Greenwich to study the Earth's magnetic field. This paper uses Airy's correspondence to argue that, while members of the reform movement in British science were putting pressure on the Royal Observatory to branch out into geomagnetism and meteorology, Airy established the magnetic observatory on his own initiative, ahead of Alexander von Humboldt's request for British participation in the worldwide magnetic charting project that later became known as the 'Magnetic Crusade'. That the Greenwich magnetic observatory did not become operational until 1839 was due to a series of incidental factors that provide a case study in the technical and political obstacles to be overcome in building a new government observatory. Airy attached less importance to meteorology than he did to geomagnetism. In 1840, he set up a full programme of meteorological observations at Greenwich - and thus turned his magnetic observatory into the 'Magnetic and Meteorological department' - only as the price of foiling an attempt by Edward Sabine and others in the London scientific elite to found a rival magnetic and meteorological observatory. Studying the origins of Airy's Magnetic and Meteorological department highlights how important the context of other institutions and trends in science is to understanding the development of Britain's national observatory. PMID- 30027835 TI - Effect of chemical clarification of oral fluids on the detection of porcine reproductive and respiratory syndrome virus IgG. AB - Routine collection and testing of oral fluid (OF) samples facilitates porcine reproductive and respiratory syndrome virus (PRRSV) surveillance in commercial swine herds in a cost-effective, welfare-friendly fashion. However, OFs often contain environmental contaminants that may affect liquid handling and test performance. Traditional processing methods (e.g., filtration or centrifugation) are not compatible with high-throughput testing because of the burden of additional processing costs and time. OF "clarification" using chemical flocculants is an alternative approach not widely explored. Therefore, we evaluated the effect of chitosan-based clarification treatment on a commercial PRRSV OF ELISA. Serum and individual OFs were collected from vaccinated pigs ( n = 17) at -7 to 42 d post-vaccination and subdivided into 4 aliquots. Each aliquot was clarified (treatment A, B, C), with the 4th aliquot serving as untreated control. All samples were tested by PRRSV OF ELISA immediately after treatment and then were held at 4 degrees C to be re-tested at 2, 4, 6, and 14 d post treatment. Quantitative and qualitative treatment effects were evaluated. A Kruskal-Wallis test found no significant difference in ELISA S/P responses among treatments by days post-treatment. No difference was detected in the proportion of positive PRRSV antibody samples among treatments (Cochran Q, p > 0.05). Treatment of swine OFs using chitosan-based formulations did not affect the performance of a commercial PRRSV OF ELISA. Chitosan (or other flocculants) could improve OF characteristics and could be adapted for use in the field or in high throughput laboratories. PMID- 30027837 TI - New Emerging Trends in Protein and Peptide Based Therapeutic Approaches - Part I. PMID- 30027836 TI - Learning rapidly about the relevance of visual cues requires conscious awareness. AB - Humans have been shown to be capable of performing many cognitive tasks using information of which they are not consciously aware. This raises questions about what role consciousness actually plays in cognition. Here, we explored whether participants can learn cue-target contingencies in an attentional learning task when the cues were presented below the level of conscious awareness and how this differs from learning about conscious cues. Participants' manual (Experiment 1) and saccadic (Experiment 2) response speeds were influenced by both conscious and unconscious cues. However, participants were only able to adapt to reversals of the cue-target contingencies (Experiment 1) or changes in the reliability of the cues (Experiment 2) when consciously aware of the cues. Therefore, although visual cues can be processed unconsciously, learning about cues over a few trials requires conscious awareness of them. Finally, we discuss implications for cognitive theories of consciousness. PMID- 30027834 TI - Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia. AB - The voltage-gated L-type calcium channel (LTCC) is essential for multiple cellular processes. In the heart, calcium influx through LTCC plays an important role in cardiac electrical excitation. Mutations in LTCC genes, including CACNA1C, CACNA1D, CACNB2 and CACNA2D, will induce the dysfunctions of calcium channels, which result in the abnormal excitations of cardiomyocytes, and finally lead to cardiac arrhythmias. Nevertheless, the newly found mutations in LTCC and their functions are continuously being elucidated. This review summarizes recent findings on the mutations of LTCC, which are associated with long QT syndromes, Timothy syndromes, Brugada syndromes, short QT syndromes, and some other cardiac arrhythmias. Indeed, we describe the gain/loss-of-functions of these mutations in LTCC, which can give an explanation for the phenotypes of cardiac arrhythmias. Moreover, we present several challenges in the field at present, and propose some diagnostic or therapeutic approaches to these mutation-associated cardiac diseases in the future. PMID- 30027838 TI - Hybrid Compounds & Oxidative Stress Induced Apoptosis In Cancer Therapy. AB - Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs. PMID- 30027839 TI - Recent Advances in Drug Repurposing for Parkinson's Disease. AB - As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson's disease is a growing health threat to our ever aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progress. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost effective and time-efficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson's disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson's disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson's disease will be discussed. PMID- 30027840 TI - Signal Transducer and Activator of Transcription Protein 3 (STAT3): an Update on its Direct Inhibitors as Promising Anticancer Agents. AB - BACKGROUND: Since Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor which plays an important role in multiple aspects of cancer, including progression and migration, and it is constitutively activated in various human tumors, STAT3 inhibition has emerged as a validated strategy for the treatment of several malignancies. The aim of this review is to provide an update on the identification of new promising direct inhibitors targeting STAT3 domains, as potential anticancer agents. METHODS: A thorough literature search focused on recently reported STAT3 direct inhibitors was undertaken. We considered the relevant developments regarding the STAT3 domains, which have been identified as potential drug targets. RESULTS: In detail, 135 peer-reviewed papers and 7 patents were cited; the inhibitors we took into account targeted the DNA binding domain (compounds were grouped into natural derivatives, small molecules, peptides, aptamers and oligonucleotides), the SH2 binding domain (natural, semi-synthetic and synthetic compounds) and specific residues, like cysteines (natural, semi-synthetic, synthetic compounds and dual inhibitors) and tyrosine 705. CONCLUSION: The huge number of direct STAT3 inhibitors recently identified demonstrates a strong interest in the investigation of this target, although it represents a challenging task considering that no drug targeting this enzyme is currently available for anticancer therapy. Notably, many studies on the available inhibitors evidenced that some of them possess a dual mechanism of action. PMID- 30027841 TI - Genetic Polymorphisms within Interferon-lambda Region and Interferon-lambda3 in the Human Pathophysiology: Their Contribution to Outcome, Treatment, and Prevention of Infections with Hepatotropic Viruses. AB - Genetic polymorphisms within the interferon lambda (IFN-lambda) chromosomal region, mainly rs12979860 of IFN-lambda4 gene (IFNL4), are known as associated with spontaneous hepatitis C virus (HCV) resolution and sustained viral response to therapy with pegylated interferon-alpha and ribavirin. Strong linkage disequilibrium of IFNL4 rs12979860 with IFNL4 rs368234815, which is casually associated with HCV spontaneous and therapeutical eradication, at least partially explains favorable HCV outcomes attributed to major homozygosity in rs12979860. Effects of IFN-based antiviral treatment are associated with pretreatment expression of the IFN-lambda1 receptor, expression of hepatic IFN-stimulated genes, production of IFN-lambda4, and preactivation of the JAK-STAT signaling. Nowadays direct-acting antivirals (DAAs) became a potent tool in the treatment of hepatitis C, but IFN-lambdas are still under investigation as potential antivirals and might be an option in HCV infection (DAA resistance, recurrent viremia, adverse effects). Patients with altered immunocompetence are especially prone to infections. In uremic subjects, polymorphisms within the IFN-lambda chromosomal region associate with spontaneous HCV clearance, similarly like in the non-uremic population. Circulating IFN-lambda3 shows positive correlation with plasma titers of antibodies to surface antigen of hepatitis B virus (anti HBs), which are crucial for protection against hepatitis B virus. More efficient anti-HBs production in the presence of higher IFN-lambda3 levels might occur due to IFN-lambda3-induced up-regulation of indoleamine 2,3-dioxygenase (IDO) expression. IFN-stimulated response element is a part of IDO gene promoter. It is worth further investigation whether IDO gene, circulating IDO, genetic polymorphisms within the IFN-lambda region, and circulating IFN-lambda3 act in concordance in immunological response to hepatotropic viruses. PMID- 30027842 TI - Migraine: Genetic Variants and Clinical Phenotypes. AB - Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes. PMID- 30027843 TI - Carbohydrates: potential sweet tools against cancer. AB - Cancer, one of the most devastating degenerative diseases nowadays, is one of the main targets in Medicinal Chemistry and Pharmaceutical industry. Due to the significant increase in the incidence of cancer within world population, together with the complexity of such disease, featured with a multifactorial nature, access to new drugs targeting different biological targets connected to cancer is highly necessary. Among the vast arsenal of compounds exhibiting antitumor activities, this review will cover the use of carbohydrate derivatives as privileged scaffolds. Their hydrophilic nature, together with their capacity of establishing selective interactions with biological receptors located on cell surface, involved in cell-to-cell communication processes, have allowed the development of an ample number of new templates useful in cancer treatment. Their intrinsic water solubility has allowed their use as of pro-drug carriers for accessing more efficiently the pharmaceutical target. The preparation of glycoconjugates in which the carbohydrate is tethered to a pharmacophore has also allowed a better permeation of the drug through cellular membranes, in which selective interactions with the carbohydrate motifs are involved. In this context, the design of multivalent structures (e.g. gold nanoparticles) has been demonstrated to enhance crucial interactions with biological receptors, like lectins, glycoproteins that can be involved in cancer progression. Moreover, the modification of the carbohydrate structural motif, by incorporation of metal complexes, or by replacing their endocyclic oxygen, or carbon atoms with heteroatoms has led to new antitumor agents. Such diversity of sugar-based templates with relevant antitumor activity will be cover in this review. PMID- 30027844 TI - A Walk in Nature. Sesquiterpene Lactones as Multi-Target Agents Involved in Inflammatory Pathways. AB - Inflammatory states are among the most common and most treated medical conditions. Inflammation comes along with swelling, pain and uneasiness in using the affected area. Inflammation is not always a simple symptom; more often is part of a defensive response of the body to an external threat or is a sign that the damaged tissue has not healed yet and needs to rest. The management of the pain associated with an inflammatory state could be a tricky task. In fact, most remedies simply quench the pain, leaving the inflammatory state unaltered. This review focuses on sesquiterpene lactones, a class of natural compounds, that represents a future promise in the treatment of inflammation. Sesquiterpene lactones are efficient inhibitors of multiple targets of the inflammatory process. Their natural sources are often ancient remedies with relevant traditional uses in folk medicines. This work also aims to elucidate how these compounds may represent the starting material for the development of new anti inflammatory drugs. PMID- 30027845 TI - Silver nanomaterials in contemporary molecular physiology research. AB - Silver nanoparticles have numerous potential applications in engineering, industry, biology and medicine. Because of their unique chemical properties, they have become the focus of many research teams all over the world. Silver nanoparticles may exhibit significant antimicrobial and anticancer effects, and they may be a valuable part of various bioassays and biosensors. However, the research on biological and medical uses of AgNPs is related with numerous potential problems and challenges that need to be overcome in the years ahead. Possible toxic effects of silver nanoparticles on living organisms represent a great concern, both in clinical medicine and public health. Nevertheless, in the future, it may be expected that all metallic nanomaterials, including the ones made from silver will greatly benefit almost all natural scientific fields. In this short review, we focus on the recent research on silver nanoparticles in experimental physiology, as well as other areas of fundamental and clinical medicine. PMID- 30027846 TI - Cancer biomarker discovery for precision medicine: new progresses. AB - BACKGROUND: Precision medicine puts forward customized healthcare for cancer patients. An important way to accomplish this task is to stratify patients into those who may respond to a treatment and those who may not. For this purpose, diagnostic and prognostic biomarkers have been pursued. OBJECTIVE: This review focuses on novel approaches and concepts of exploring biomarker discovery under the circumstances that technologies are developed, and data are accumulated for precision medicine. RESULTS: The traditional mechanism-driven functional biomarkers have the advantage of actionable insights, while data-driven computational biomarkers can fulfill more needs, especially with tremendous data on the molecules of different layers (e.g. genetic mutation, mRNA, protein etc.) which are accumulated based on a plenty of technologies. Besides, the technology driven liquid biopsy biomarker is very promising to improve patients' survival. The developments of biomarker discovery on these aspects are promoting the understanding of cancer, helping the stratification of patients and improving patients' survival. CONCLUSION: Current developments on mechanisms-, data- and technology-driven biomarker discovery are achieving the aim of precision medicine and promoting the clinical application of biomarkers. Meanwhile, the complexity of cancer requires more effective biomarkers, which could be accomplished by a comprehensive integration of multiple types of biomarkers together with a deep understanding of cancer. PMID- 30027847 TI - Role of Topological, Electronic, Geometrical, Constitutional and Quantum Chemical Based Descriptors in QSAR: mPGES-1 as a Case Study. AB - Quantitative Structure Activity Relationship (QSAR) is one of the widely used ligand based drug design strategies. Although a number of QSAR studies have been reported, debates over the limitations and accuracy of QSAR models are at large. In this review the applicability of various classes of molecular descriptors in QSAR has been explained. Protocol for QSAR model development and validation is presented. Here we discuss a case study on 7-Phenyl-imidazoquinolin-4(5H)-one derivatives as potent mPGES-1 inhibitors to identify crucial physicochemical properties responsible for mPGES-1 inhibition. The case study explains the methodology for QSAR analysis, validation of the developed models and role of diverse classes of molecular descriptors in defining the inhibitory activity of considered inhibitors. Various molecular descriptors derived from 2D/3D structure and quantum mechanics were considered in the study. Initially, QSAR models for the training set compounds were developed individually for each class of molecular descriptors. Further, a combined QSAR model was developed using the best descriptor from all the classes. The models obtained were further validated using an external test set. Combined QSAR model exhibited the best correlation (r = 0.80) between the predicted and experimental biological activities of test set compounds. The results of the QSAR analysis were further backed by docking studies. From the results of the case study it is evident that rather than a single class of molecular descriptors, a combination of molecular descriptors belonging to different classes significantly improves the QSAR predictions. The techniques and protocol discussed in the present work might be of significant importance while developing QSAR models of various drug targets. PMID- 30027848 TI - Computer Aided Design of Non-toxic Antibacterial Peptides. AB - Antimicrobial resistance is increasing at an alarming rate and the number of new antibiotics developed and approved has decreased in the last decades, basically for economic and regulatory obstacles. Pathogenic bacteria that are resistant to multiple or all available antibiotics are isolated frequently. Hence, new antibacterial agents are urgently needed and antimicrobial peptides are being considered as a potential solution to this important threat. These molecules are small host defense proteins that are part of the immune systems of most living organisms such as plants, bacteria, invertebrates, vertebrates, and mammals. These peptides are found in those parts of organisms that are exposed to pathogens and they are active against multiple organisms such as virus, bacteria, and parasites, among others. This review shows different strategies in the computational design of new antibacterial peptides, the physicochemical properties that are considered as the most relevant for the antibacterial activity and toxicity, and it suggests guidelines in order to help in the finding of new non-toxic antibacterial peptides through the development of computational models. PMID- 30027849 TI - Role of Noncoding RNA in Pulmonary Arterial Hypertension and Potential Drug Therapeutic Target. AB - Pulmonary arterial hypertension (PAH) is a devastating disease without effective drugs available for its treatment. An in-depth exploration of the pathogenesis of PAH, as well as inquiry into potential therapeutic targets, remains an urgent issue. Non-coding RNAs (ncRNAs) have arisen as key players in malignant tumors, cardiovascular diseases and more recently in PAH progression and development. Network pharmacology is a new discipline based on system biology, which can predict potential therapeutic targets in diseases regulated by multiple genes. In this review, we discuss the current knowledge of ncRNAs and network pharmacology regulated genes involved in PAH, as well as the search for potential drug targets for PAH. PMID- 30027850 TI - Drug Target Interplay: A Network-based Analysis of Human Diseases and the Drug Targets. AB - Screening and identifying a disease-specific novel drug target is the first step towards a rational drug designing approach. Due to the advent of high throughput data generation techniques, the protein search space has now exceeded 24,500 human protein coding genes, which encodes approximately 1804proteins. This work aims at mining out the relationship between target proteins, drugs, and diseases genes through a network-based systems biology approach. A network of all FDA approved drugs, along with their targets were utilized to construct the proposed Drug Target (DT) network. Further, the experimental drugs were mapped into the DT network to infer the functional relationship by utilizing the respective network attributes. Similar to the DT network, a network of disease genes was created through OMIM Gene Map and Morbid Map, to link the binary associations of disorder disease genes. In the proposed model of Human Interactome Network, shortest path length between the target protein and disease gene was used to infer the correlation between 'Drug Targets' and 'Disease-Gene'. This network-based study will help researchers to analyze, infer and identify disease-specific novel drug targets through harnessing the graph theory based network attributes. PMID- 30027851 TI - Recent Advances on the Network Models in Target-based Drug Discovery. AB - With the advancement of "proteomics" data and systems biology, new techniques are needed to meet the new era of drug discovery. Network theory is increasingly applied to describe complex biological systems, thus implying its essential roles in system-based drug design. In this review, we first summarized general network parameters used in describing biological systems, and then gave some recent applications of these network parameters as topological indices in drug design in terms of Protein Structure Networks (PSNs), Protein-Protein Interaction Networks (PPINs) including related structural PPINs, and Elastic Network Models (ENMs). These network models have enabled the development of new drugs relying on allosteric effects, describing anti-cancer targets, targeting hot spots and key proteins at the protein-protein interfaces and PPINs, and helped drug design by modulating conformational flexibility. Accordingly, we highlighted the integration of network models bringing new paradigms into the next-generation target-based drug discovery. PMID- 30027852 TI - A Case of Severe Transaminase Elevation Following a Single Ustekinumab Dose with Remission After Drug Withdrawal. AB - BACKGROUND: Ustekinumab is a fully human monoclonal antibody which binds Interleukin (IL)-12/23. It is indicated for the treatment of moderate-severe psoriasis and active psoriatic arthritis. Few data are available about the possibility of an interaction between ustekinumab and the liver. CASE DESCRIPTION: We reported a case of a 61-year old woman admitted to our Unit for severe transaminase elevation (aspartate transaminase 756 IU/l, alanine transaminase 1212 IU/l) occurred after a single Ustekinumab infusion for psoriasis. All other possible causes of liver damage, including drugs, hepatitis viruses, auto-antibodies and metabolic disorders were excluded. Liver biopsy showed lymphocytic infiltration, biliary duct damage and piecemeal necrosis. On the bases of the nonspecific histological picture and Rucam score, we accomplished the diagnosis of "liver injury of iatrogenic origin". After drug withdrawal, a spontaneous normalization of liver enzymes occurred within six months. PMID- 30027853 TI - The Use of Stem Cells in Neural Regeneration: A Review of Current Opinion. AB - Nerve injury is a large problem that produces much pain in patients. Injury to the nervous system causes serious consequences and affects a person's quality of life. The development of tissue engineering has created a brighter future for nerve regeneration, and research has not stopped since the discovery of stem cells. Stem cells are a type of pluripotent cell that exhibits the capacity of selfdifferentiation and proliferation. Many studies have demonstrated the ability of stem cells to differentiate into other types of cells, including neurons, after induction with trophic factors in vivo and in vitro. Scientists have isolated a variety of stem cells from different organs and tissues in the human body and demonstrated that these cells were efficacious in regenerative medicine. The use of these cells provides a non-surgical method for the treatment of neurological diseases, such as nerve defects. However, many problems must be resolved before using these cells in the clinical field. The microenvironment and delivery methods of cells also affect the regeneration process. The present article comprehensively summarizes the progress of stem cells in the field of nerve regeneration in the recent decades. PMID- 30027854 TI - Transplantation of adipose tissue-derived stem cells into brain through cerebrospinal fluid in rat models: Protocol development and initial outcome data. AB - Cell therapy is an important strategy for the treatment of incurable diseases including those that occur in the central nervous system (CNS). Among different strategies, the method of delivering or transplantation of cells into the brain has shown significant effects on regeneration. In this study, a new protocol has been developed for the transplantation of adipose tissue-derived stem cells into the brain through cerebrospinal fluid (CSF) in rat models. For this purpose, a wide range of ages (7-30 days old) of male neonates of Wistar rats was used. Moreover, human adipose tissue was obtained from a superficial layer of abdomen through liposuction surgery. The size of the inserted part of needle to access middle cranial fossa and subarachnoid space in animals with an average weight of 10-80 g was determined. In addition, to confirm the entrance of needle into the subarachnoid space, CSF was aspirated slowly and then injection was done within two minutes. The findings showed the presence of transplanted human adipose derived stem cells (hADSC) in the cerebellum and basal ganglia following three days and also after two months that confirmed the entrance of transplanted cells into the cerebrospinal fluid and migration of them into the brain tissue. All the animals survived after the transplantation process, with the lowest side effects compared to the available conventional methods. It can be concluded that the cells could be efficiently transplanted into CSF through subarachnoid space by injection via superior orbital fissure with a minimally invasive technique. PMID- 30027855 TI - Amplified Crosstalk Between Estrogen Binding and GFR Signaling Mediated Pathways of ER Activation Drives Responses in Tumors Treated with Endocrine Disruptors. AB - BACKGROUND: The pharmaceutical development of endocrine disruptors could not achieve appropriate advances in the field of anticancer fight. OBJECTIVE: Considerations on the principles of currently used endocrine therapies. METHODS: Comparison of the results of genetic studies being performed on breast cancer cells treated with estrogens, synthetic estrogens and antiestrogens. RESULTS: In breast cancer cells, increased estrogen concentrations amplify ER-signaling via a synergistic upregulation of both liganded and unliganded ER-activations and increased aromatase expression. The higher the upregulation of ER-signaling, the stronger is the tumor response. Low doses of synthetic estrogens exert an inhibition on the ligand-independent AF1-domain in breast cancer cells, while provoke compensatory activation on the superior, ligand-dependent AF2-domain of ERs and estrogen synthesis. Conversely, high doses of synthetic estrogens induce uncompensated genome-wide disruption in ER-regulated genes leading to toxic symptoms and unpredictable tumor responses. Treatment with antiestrogens, either ER-blockers or aromatase inhibitors, obstructs the crucial AF2-domain of ERs strongly deteriorating the activation of genomic machinery. Tumor responses to antiestrogen treatment depend on the compensatory activation of ER-signaling and the restoration of genomic stability. Recent patents provide methods for the conversion of ER-negative cancers to ER-positive ones improving the possibility of successful treatment. CONCLUSION: In tumor cells, the stabilization of genomic machinery and self-directed death may be achieved via a balanced activation of the AF1 and AF2 domains of ERs by natural estrogen treatment. In contrast, the blockade of either AF1 or AF2 domain by endocrine disruptors leads to toxic symptoms and unforeseeable tumor responses. PMID- 30027856 TI - Effects of Highly Active Antiretroviral Therapy on Renal Function and Renal Phosphate Handling in African Adults with Advanced HIV and CKD AB - BACKGROUND: Highly Active Antiretroviral Therapy (HAART) has been implicated in renal dysfunction with hypophosphataemia. OBJECTIVE: we prospectively evaluated renal phosphate excretion during HAART use. METHOD: Newly diagnosed human immunodeficiency virus (HIV)-infected individuals were treated with Tenofovir/Emtricitabine/Efavirenz (TDF/FTC/EFV), n=33; Zidovudine/Lamivudine /Nevirapine (ZDV/3TC/NVP), n=53; and Zidovudine/Lamivudine/Efavirenz (ZDV/3TC/EFV), n=16. Creatinine and phosphate were assayed in blood and urine simultaneously at baseline, 1, 3, 6 and 9 months. Glomerular filtration rate (eGFR), fractional phosphate excretion and reabsorption (FEPi % and TRP), and the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR (TmP/GFR) were estimated. RESULTS: At baseline, eGFR showed moderate chronic kidney disease (mean: 35.50 +/- 2.02, 33.14 +/- 1.63, and 39.97+/-1.84 ml/min/1.73m2 in the 3 groups respectively); 54 (52.9%) patients had hyperphosphataemia (>1.4mmo/L); 43 (42.2%) had normophosphataemia (0.6-1.4mmol/L); 5 (4.9%) had hypophosphataemia (<0.6mmol/L). eGFR improved significantly from 1 month (>=60, 58.65 +/- 1.11, and 51.76 +/-1.59 ml/min/1.73m2; p=0.04, <0.001, 0.67 respectively), with a relapse at 9 months in TDF-treated subjects (50.10 +/- 1.89 ml/min/1.73m2). Of the 54 with hyperphosphataemia, 12(22.2%) remained unresolved; of the 5 with hypophosphataemia, 3 remained unresolved. FEP% progressively increased with HAART duration, more in TDF-treated group; TRP was elevated (>0.86), implying non maximal phosphate reabsorption. TmP/GFR values were elevated, (>1.35mmol/l), suggesting a decrease in phosphate flow into the extracellular space. CONCLUSION: HIV causes kidney dysfunction with reduced phosphate excretion resulting in hyperphosphataemia but HAART improves renal function and phosphate clearance. Prolonged use of TDF can cause renal toxicity with hypophosphataemia as fractional excretion progressively increased with duration of therapy. PMID- 30027857 TI - Development of a novel prevention bundle for pediatric healthcare-associated viral infections. AB - OBJECTIVE: To reduce the healthcare-associated viral infection (HAVI) rate to 0.70 infections or fewer per 1,000 patient days by developing and sustaining a comprehensive prevention bundle. SETTING: A 546-bed quaternary-care children's hospital situated in a large urban area.PatientsInpatients with a confirmed HAVI were included. These HAVIs were identified through routine surveillance by infection preventionists and were confirmed using National Healthcare Safety Network definitions for upper respiratory infections (URIs), pneumonia, and gastroenteritis. METHODS: Quality improvement (QI) methods and statistical process control (SPC) analyses were used in a retrospective observational analysis of HAVI data from July 2012 through June 2016. RESULTS: In total, 436 HAVIs were identified during the QI initiative: 63% were URIs, 34% were gastrointestinal infections, and 2.5% were viral pneumonias. The most frequent pathogens were rhinovirus (n=171) and norovirus (n=83). Our SPC analysis of HAVI rate revealed a statistically significant reduction in March 2014 from a monthly average of 0.81 to 0.60 infections per 1,000 patient days. Among HAVIs with event reviews completed, 15% observed contact with a sick primary caregiver and 15% reported contact with a sick visitor. Patient outcomes identified included care escalation (37%), transfer to ICU (11%), and delayed discharge (19%). CONCLUSIONS: The iterative development, implementation, and refinement of targeted prevention practices was associated with a significant reduction in pediatric HAVI. These practices were ultimately formalized into a comprehensive prevention bundle and provide an important framework for both patient and systems level interventions that can be applied year-round and across inpatient areas. PMID- 30027858 TI - First molecular identification of Strongyloides fuelleborni in long-tailed macaques in Thailand and Lao People's Democratic Republic reveals considerable genetic diversity. AB - Strongyloides fuelleborni is a soil-transmitted nematode parasite of non-human primates. The worm is prevalent also in human populations in Africa and South East Asia. In this study, we amplified and sequenced a portion of the 18S ribosomal RNA gene (rRNA) and of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene of Strongyloides adult males recovered from faecal samples from long tailed macaques (Macaca fascicularis) in Thailand and Lao PDR. The prevalence in Thailand was 31.1% (55/177) and in Lao PDR it was 62.1% (41/66), with an overall prevalence of 39.5% (96/243). All 18S rRNA sequences that we obtained (n = 96) showed 100% identity with published S. fuelleborni sequences. The 96 cox1 sequences that we obtained represented 32 new haplotypes. When included with the 17 previously known haplotypes from S. fuelleborni, the cox1 sequences fell into four clusters, which had clear geographical structure. This is the first molecular confirmation of S. fuelleborni in long-tailed macaques in Thailand and Lao PDR. Clearly, awareness needs to be raised of the zoonotic potential of S. fuelleborni. A monitoring programme should be organized, taking into account the role of reservoir hosts (i.e. monkeys) in the natural background of human strongyloidiasis caused by S. fuelleborni. PMID- 30027860 TI - Twins Reared Apart and Twins in Families: The Findings Behind the Fascination. AB - Dr. Irving I. Gottesman was very creative in applying twin research designs to test hypotheses and predictions about human behavior. Two designs stand out among others: twins reared apart from birth and the twin-family study. I (NS) was inspired to incorporate both of these approaches into my own research programs at California State University, Fullerton. Gottesman's involvement and contributions to reared-apart twin research are described, followed by selected findings from the Minnesota Study of Twins Reared Apart (MISTRA), the Fullerton Study of Chinese Twins Reared Apart (CTA), a case report on separated monozygotic (MZ) female twins from South Korea, and doubly exchanged MZ male twin pairs from Colombia, South America. Recent findings from an ongoing twin-family study of social closeness, and future directions, are also presented. PMID- 30027859 TI - F-fluorodeoxyglucose-positive emission tomography/CT imaging for left ventricular assist device-associated infections in children. AB - Left ventricular assist device implantation is an important therapeutic option for children with end-stage heart failure. However, device-related complications such as infection may occur while the patient is supported. Device-associated infection can be life-threatening, and early detection is critical. F fluorodeoxyglucose positron emission tomography and CT is a highly sensitive imaging modality for the detection of an inflammatory response and is useful to evaluate the response to antibiotic therapy. We present two case reports of a left ventricular assist device-associated infection detected by F fluorodeoxyglucose positron emission tomography and CT in children. PMID- 30027861 TI - Symposium in Honor of Irving I. Gottesman (December 29, 1930-June 29, 2016). AB - The June 2016 death of our esteemed colleague, Dr Irving I. Gottesman, was felt as an extreme loss at so many levels by colleagues, students, friends, and family across the globe. Irv's stellar contributions to the field of twin research will continue to be remembered and cited for many years to come. In commemoration of his life and work, I organized a symposium at the 16th meeting of the International Society for Twin Studies, held in Madrid, Spain, November 16-18, 2017. The panelists included mostly former students, as well as colleagues, who presented their scientific research and personal remarks reflecting Irv's profound influence in shaping their lives and careers. A chronology of Irv's academic positions and honors is included in the introduction to this special issue of Twin Research and Human Genetics, followed by brief sketches of the panel participants; their scholarly papers and personal reflections follow. PMID- 30027862 TI - Gene-Environment Correlations Affecting Children's Early Rule-Breaking and Aggressive Play Behaviors. AB - Play among peers is an important developmental context for child socialization. We have earlier shown that children at genetic risk for aggression were more likely to be treated aggressively by unfamiliar peers during peer play, reflecting genotype-evoked behaviors manifested during play. In this study, 118 5 year-old twin pairs were paired randomly with an unfamiliar, same-age, same-sex child, thus controlling for parent- and child-chosen environments (passive and active rGE). Twins played separately from each other with unmatched children. Play behaviors were coded for aggressive and assertive behaviors. Children were also independently rated by parents for rule-breaking problem behaviors at age 5, and 97 children were rated again on these behaviors 2-10 years later. Analyses showed that children at genetic risk for early rule-breaking were more likely to have partners who behaved more aggressively, suggesting that this was evoked behavior during play. Some evidence of an 'early bloomer' phenomenon emerged via early difficult temperament and parent-rated delinquency significantly predicting later delinquency. Children's play, which is one of the most important influences on early development, requires further study from an rGE perspective. PMID- 30027863 TI - Rereading 'Biogenetics of Race and Class' 50 Years Later. AB - In 1968, long before the publication of Stephen J. Gould's The Mismeasure of Man, Herrnstein and Murray's The Bell Curve, or Arthur Jensen's Bias in Mental Testing, Irving Gottesman published a book chapter that addressed head-on the issues that would define the relationship between the genetics of social behavior and large-scale social theory for the next 50 years. That he could do so with his characteristic scholarly thoroughness and scientific tough-mindedness without once lapsing into regressive hereditarianism is a testimony to the scope of his scientific knowledge and the generosity of his intellectual spirit. PMID- 30027864 TI - Irving I. Gottesman's Collaboration in Psychiatric Genetics Research in Denmark. AB - Irving I. Gottesman played an important role for psychiatric genetic research in Denmark through more than 40 years of collaboration with Danish scientists, resulting in important twin and family studies based upon the unique national registers available in Denmark. PMID- 30027865 TI - Mapping Risk from Genes to Behavior: The Enduring and Evolving Influence of Irving Gottesman's Endophenotype Concept. AB - One of Irving I. Gottesman's many contributions to behavior genetics, and part of his enduring legacy, was his introduction of the term 'endophenotype' to the field of psychiatry. Gottesman argued that focusing on endophenotypes, rather than complex heterogeneous clinical diagnoses, could help elucidate disease etiology. Although a different strategy for gene identification ultimately proved successful (that of amassing extremely large sample sizes in order to overcome the 'noise' of heterogeneity and have sufficient power to find genes of very small effect), the endophenotype concept continues to make a meaningful contribution to the field. The endophenotype concept forced the field to move beyond a simple disease model of finding genes 'for' psychiatric outcomes, and reminded us that genes are quite distal from complex behavioral outcomes and disorders. Endophenotypes called our attention to the steps along that pathway. In that process, the concept of endophenotypes evolved and expanded to include discussion of the role that other intermediary traits and psychological processes play in the development and genetic etiology of psychiatric and substance use disorders. As large-scale consortia continues to identify genes and generate genome-wide polygenic scores that are associated with behavioral outcomes, the next important step will be to characterize the pathways and mechanisms by which genetic risk unfolds. This essential step of mapping risk from genes to behavior is an evolution that follows naturally from the endophenotype concept, and could ultimately translate into improved prevention and intervention for individuals who are pre-disposed to mental health challenges. PMID- 30027866 TI - Understanding Mechanisms of Genetic Risk for Adolescent Internalizing and Externalizing Problems: The Mediating Role of Parenting and Personality. AB - Genetic predispositions play an important role in the development of internalizing and externalizing behaviors. Understanding the mechanisms through which genetic risk unfolds to influence these developmental outcomes is critical for developing prevention and intervention efforts, capturing key elements of Irv's research agenda and scientific legacy. In this study, we examined the role of parenting and personality in mediating the effect of genetic risk on adolescents' major depressive disorder and conduct disorder symptoms. Longitudinal data were drawn from a sample of 709 European American adolescents and their mothers from the Collaborative Studies on Genetics of Alcoholism. Results from multivariate path analysis indicated that adolescents' depressive symptoms genome-wide polygenic scores (DS_GPS) predicted lower parental knowledge, which in turn was associated with more subsequent major depressive disorder and conduct disorder symptoms. Adolescents' DS_GPS also had indirect effects on these outcomes via personality, with a mediating effect via agreeableness but not via other dimensions of personality. Findings revealed that the pattern of associations was similar across adolescent gender. Our findings emphasize the important role of evocative gene-environment correlation processes and intermediate phenotypes in the pathways of risk from genetic predispositions to complex adolescent outcomes. PMID- 30027867 TI - Human Dizygotic Twinning: Evolutionary-Based Explanations/Twin Research Reviews: Conjoined Twins in a Triplet Pregnancy; Double Embryo Transfer; Health Anxiety; Delayed Delivery of the Second Twin/In the Media: Digital Marketing Twins; Bereaved Twin at March for Our Lives; Exchange of Places; Football Players Reunite as Patriots. AB - Human twinning poses a conundrum for researchers, given that the female uterus is optimally designed to carry a single fetus. Evolutionary explanations of dizygotic (DZ or fraternal) twinning provide insight and understanding of this reproductive event. This review is followed by summaries of recent twin research and reports concerning twins in a triplet pregnancy, double embryo transfer; a twin study of health anxiety, and delayed delivery of the second twin. Twin events reported in the media include a pair of digital marketing twins, a speech by a bereaved twin at the March for Our Lives in Washington, D.C., twins who exchanged places, and a same-team reunion of twin football players. PMID- 30027868 TI - THG volume 21 issue 4 Cover and Front matter. PMID- 30027870 TI - Closing Remarks-A Twin Research Legacy. AB - Like families, professors transmit bits of wisdom to their students, not just by what they say but what they do. Colleagues share methods and data, but more importantly, ideas and visions. Irving I. Gottesman was unique in this respect, both brilliant in his field and wise when it came to teaching, guiding, and supporting. His academic pedigree extends across many generations and will for generations to come. PMID- 30027871 TI - From Genes to Behavior Through Sex Hormones and Socialization: The Example of Gender Development. AB - Irving Gottesman is known primarily for his work in psychopathology, but he also had a long-standing interest in understanding psychological development generally (typical and atypical). Through his mentorship, he also influenced work in gender development. Characteristics related to sex and gender are ideally suited to study the interplay of genes and environment across development. We discuss how gender development is influenced by gonadal hormones present during early life, but not in a simple way. We describe some of the challenges and opportunities to extend our understanding of the complexity of gender development. Throughout, we consider the kinds of questions Gottesman would likely have asked and emphasize his influence on our work. PMID- 30027872 TI - THG volume 21 issue 4 Cover and Back matter. PMID- 30027874 TI - Predictors of disengagement from Early Intervention in Psychosis services. AB - BACKGROUND: The effectiveness of Early Intervention in Psychosis (EIP) services for individuals with a first episode of psychosis (FEP) could be thwarted by high rates of early disengagement.AimsTo investigate which factors predict disengagement with EIP services. METHOD: Using data from a naturalistic cohort of 786 EIP clients in East Anglia (UK), we investigated the association between sociodemographic and clinical predictors and disengagement using univariable and multivariable Cox proportional hazards models. RESULTS: Over half (54.3%) of our sample were discharged before receiving 3 years of EIP care, with 92 (11.7%) participants discharged due to disengagement. Milder negative symptoms, more severe hallucinations, not receiving an FEP diagnosis, polysubstance use and being employed were associated with greater disengagement. CONCLUSIONS: Our findings highlight heterogeneous reasons for disengagement with EIP services. For some patients, early disengagement may hinder efforts to sustain positive long term EIP outcomes. Efforts to identify true FEP cases and target patients with substance use problems and more severe positive symptoms may increase engagement.Declaration of interestNone. PMID- 30027875 TI - A realist approach to the evaluation of complex mental health interventions. AB - SummaryConventional approaches to evidence that prioritise randomised controlled trials appear increasingly inadequate for the evaluation of complex mental health interventions. By focusing on causal mechanisms and understanding the complex interactions between interventions, patients and contexts, realist approaches offer a productive alternative. Although the approaches might be combined, substantial barriers remain.Declaration of interestAll authors had financial support from the National Institute for Health Research Health Services and Delivery Research Programme while completing this work. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the National Health Service, the National Institute for Health Research, the Medical Research Council, Central Commissioning Facility, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre, the Health Services and Delivery Research Programme or the Department of Health. S.P.S. is part funded by Collaboration for Leadership in Applied Health Research and Care West Midlands. K.B. is editor of the British Journal of Psychiatry. PMID- 30027876 TI - The benefits of antidepressants: news or fake news? AB - SummaryAlthough antidepressant drugs are commonly effective, several meta analyses of antidepressant drug trials undertaken decades after their introduction suggested that they were effectively acting as placebos. A recent meta-analysis concluded that they were effective. Both conclusions have been widely taken up by the media. This paper seeks to explain the disconnect.Declaration of interestNone. PMID- 30027878 TI - Personality disorder and suicide. PMID- 30027877 TI - Schizophrenia and anxiety: yes, they are relatives not just neighbours. PMID- 30027879 TI - A letter to Jim Crabb et al. PMID- 30027881 TI - The art of science for mental health research. PMID- 30027880 TI - Rethinking rebranding. PMID- 30027882 TI - Cognitive-behavioural therapy for chronic fatigue syndrome: neither efficacious nor safe. PMID- 30027883 TI - A structured review of baculovirus infection process: integration of mathematical models and biomolecular information on cell-virus interaction. AB - The baculovirus expression vector system (BEVS) is an emerging tool for the production of recombinant proteins, vaccines and bio-pesticides. However, a system-level understanding of the complex infection process is important in realizing large-scale production at a lower cost. The entire baculovirus infection process is summarized as a combination of various modules and the existing mathematical models are discussed in light of these modules. This covers a systematic review of the present understanding of virus internalization, viral DNA replication, protein expression, budded virus (BV) and occlusion-derived virus (ODV) formation, few polyhedral (FP) and defective interfering particle (DIP) mutant formation, cell cycle modification and apoptosis during the viral infection process. The corresponding theoretical models are also included. Current knowledge regarding the molecular biology of the baculovirus/insect cell system is integrated with population balance and mass action kinetics models. Furthermore, the key steps for simulating cell and virus densities and their underlying features are discussed. This review may facilitate the further development and refinement of mathematical models, thereby providing the basis for enhanced control and optimization of bioreactor operation. PMID- 30027885 TI - Antimicrobial Resistance in Leptospira, Brucella, and Other Rarely Investigated Veterinary and Zoonotic Pathogens. AB - Leptospira, Brucella, and Borrelia are major agents of zoonotic disease, causing high morbidity and, in some cases, significant mortality in humans. For all three genera, prompt diagnosis and appropriate antimicrobial therapy are required to prevent the development of chronic, debilitating illness. Leptospira spp. are intrinsically resistant to several antimicrobial classes; however, there is little evidence in the literature for development of acquired resistance to antimicrobial agents used for clinical treatment of acute leptospirosis. For Brucella infections, there are numerous reports of relapses following therapy, but it is unclear whether this is due to sequestration within infected sites (e.g., bone) or the development of acquired resistance. Brucella have maintained their susceptibility to doxycycline and rifampicin, which in combination remain the most common treatments of brucellosis in humans. In vitro induced point mutations are described as imparting resistance to rifampicin (rpoB) and fluoroquinolones (gyrA). The clinical significance of these mutations is unclear. For Borrelia burgdorferi, although acquired resistance to some antimicrobial agents has been described, resistance due to bacterial persister cells surviving in the presence of antimicrobial, with no apparent increase in the MIC of the organism, have been recently described. Of the remaining veterinary fastidious pathogens, Lawsonia intracellularis is the most interesting from an antimicrobial resistance perspective because it can only be grown in cell culture, making in vitro susceptibility testing challenging. MIC testing has been undertaken on a small number of isolates, and some differences in susceptibility to macrolides have been demonstrated between isolates obtained from different regions. PMID- 30027884 TI - Antimicrobial Resistance in Listeria Species. AB - For nearly a century the use of antibiotics to treat infectious diseases has benefited human and animal health. In recent years there has been an increase in the emergence of antibiotic-resistant bacteria, in part attributed to the overuse of compounds in clinical and farming settings. The genus Listeria currently comprises 17 recognized species found throughout the environment. Listeria monocytogenes is the etiological agent of listeriosis in humans and many vertebrate species, including birds, whereas Listeria ivanovii causes infections mainly in ruminants. L. monocytogenes is the third-most-common cause of death from food poisoning in humans, and infection occurs in at-risk groups, including pregnant women, newborns, the elderly, and immunocompromised individuals. PMID- 30027886 TI - Antimicrobial Resistance in Bordetella bronchiseptica. AB - Bordetella bronchiseptica is involved in respiratory tract infections mainly in dogs and pigs but may also cause infections in humans. Valid and representative data on antimicrobial susceptibility of B. bronchiseptica is rare. Approved antimicrobial susceptibility testing methods have been published, but very few clinical breakpoints are available. The MIC values are low for most agents but high for beta-lactam antibiotics and macrolides. Information on the genetic basis of resistance is scarce. For a small number of isolates that are resistant or show elevated MICs, the molecular basis of resistance was identified. Three tetracycline resistance genes, tet(A), tet(C), and tet(31), coding for major facilitator superfamily efflux pumps, were identified. Two other major facilitator superfamily exporter genes confer resistance to chloramphenicol (cmlB1) or to chloramphenicol and florfenicol (floR). Two class B chloramphenicol acetyltransferase genes (catB1 and catB3), which confer resistance to nonfluorinated phenicols by enzymatic inactivation, have been identified in B. bronchiseptica. Like the trimethoprim resistance genes dfrA1 and dfrB1, which code for trimethoprim-insensitive dihydrofolate reductases, the genes catB1 and catB3 were located on gene cassettes and found in class 1 integrons also harboring the sulfonamide resistance gene sul1. In addition, the gene sul2 has also been detected. Both sul1 and sul2 code for sulfonamide-insensitive dihydropteroate synthases. A gene cassette harboring the beta-lactamase gene blaOXA-2 was also identified, whereas beta-lactam resistance in B. bronchiseptica seems to be more likely due to reduced influx in combination with the species specific beta-lactamase encoded by blaBOR-1. The resistance genes were mostly located on conjugative plasmids. PMID- 30027887 TI - Antimicrobial Resistance in Nontyphoidal Salmonella. AB - Non-typhoidal Salmonella is the most common foodborne bacterial pathogen in most countries. It is widely present in food animal species, and therefore blocking its transmission through the food supply is a prominent focus of food safety activities worldwide. Antibiotic resistance in non-typhoidal Salmonella arises in large part because of antibiotic use in animal husbandry. Tracking resistance in Salmonella is required to design targeted interventions to contain or diminish resistance and refine use practices in production. Many countries have established systems to monitor antibiotic resistance in Salmonella and other bacteria, the earliest ones appearing the Europe and the US. In this chapter, we compare recent Salmonella antibiotic susceptibility data from Europe and the US. In addition, we summarize the state of known resistance genes that have been identified in the genus. The advent of routine whole genome sequencing has made it possible to conduct genomic surveillance of resistance based on DNA sequences alone. This points to a new model of surveillance in the future that will provide more definitive information on the sources of resistant Salmonella, the specific types of resistance genes involved, and information on how resistance spreads. PMID- 30027888 TI - Small RNAs Involved in Regulation of Nitrogen Metabolism. AB - Global (metabolic) regulatory networks allow microorganisms to survive periods of nitrogen starvation or general nutrient stress. Uptake and utilization of various nitrogen sources are thus commonly tightly regulated in Prokarya (Bacteria and Archaea) in response to available nitrogen sources. Those well-studied regulations occur mainly at the transcriptional and posttranslational level. Surprisingly, and in contrast to their involvement in most other stress responses, small RNAs (sRNAs) involved in the response to environmental nitrogen fluctuations are only rarely reported. In addition to sRNAs indirectly affecting nitrogen metabolism, only recently it was demonstrated that three sRNAs were directly involved in regulation of nitrogen metabolism in response to changes in available nitrogen sources. All three trans-acting sRNAs are under direct transcriptional control of global nitrogen regulators and affect expression of components of nitrogen metabolism (glutamine synthetase, nitrogenase, and PII like proteins) by either masking the ribosome binding site and thus inhibiting translation initiation or stabilizing the respective target mRNAs. Most likely, there are many more sRNAs and other types of noncoding RNAs, e.g., riboswitches, involved in the regulation of nitrogen metabolism in Prokarya that remain to be uncovered. The present review summarizes the current knowledge on sRNAs involved in nitrogen metabolism and their biological functions and targets. PMID- 30027889 TI - Multichannel ZnO nanowire field effect transistors by lift-off process. AB - This paper describes a new, low-cost, top-down fabrication process, which makes it possible to define nanowire field effect transistor arrays with different numbers of nanowires simultaneously and systematically comparing their electrical performance. The main feature of this process is a developed bilayer photoresist pattern with a retrograde profile, which enables the modification of the nanowire in width, length, height and the number of transistor channels. The approach is compatible with low-cost manufacture without electron beam lithography, and benefits from process temperatures below 190 degrees C. Process reliability has been investigated by scanning electron microscopy, transmission electron microscopy and atomic force microscopy. Electrical measurements demonstrate enhancement mode transistors, which show a scalable correlation between the number of nanowires and the electrical characteristics. Devices with 100 nanowires exhibit the best performance with a high field effect mobility of 11.0 cm2 Vs-1, on/off current ratio of 3.97 * 107 and subthreshold swing of 0.66 V dec 1. PMID- 30027890 TI - Two-tag correlations and nonequilibrium fluctuation-response relation in ageing single-file diffusion. AB - Spatiotemporally correlated motions of interacting Brownian particles, confined in a narrow channel of infinite length, are studied in terms of statistical quantities involving two particles. A theoretical framework that allows analytical calculation of two-tag correlations is presented on the basis of the Dean-Kawasaki equation describing density fluctuations in colloidal systems. In the equilibrium case, the time-dependent Einstein relation holds between the two tag displacement correlation and the response function corresponding to it, which is a manifestation of the fluctuation-dissipation theorem for the correlation of density fluctuations. While the standard procedure of closure approximation for nonlinear density fluctuations is known to be obstructed by inconsistency with the fluctuation-dissipation theorem, this difficulty is naturally avoided by switching from the standard Fourier representation of the density field to the label-based Fourier representation of the vacancy field. In the case of ageing dynamics started from equidistant lattice configuration, the time-dependent Einstein relation is violated, as the two-tag correlation depends on the waiting time for equilibration while the response function is not sensitive to it. Within linear approximation, however, there is a simple relation between the density (or vacancy) fluctuations and the corresponding response function, which is valid even if the system is out of equilibrium. This non-equilibrium fluctuation response relation can be extended to the case of nonlinear fluctuations by means of closure approximation for the vacancy field. PMID- 30027891 TI - Ab initio study of the moisture stability of lead iodine perovskites. AB - The stability of hybrid lead iodine perovskite in a humid environment has been a major obstacle to developing long-term photovoltaic devices. However, understanding the detailed degradation mechanism of lead iodine perovskite in moisture is still challenging. Herein, using first-principles calculations, we show that embedded water molecules will facilitate the decomposition of lead iodine perovskite. Alloying FAPbI3 and CsPbI3 to form mixed-cation lead iodine perovskites not only can optimize the tolerance factor to obtain better phase stability, but also can improve the moisture stability of them. With the accumulation of water molecules in the perovskite lattice, the optical absorption spectra show a blue-shift and decreased intensity, and the moisture stabilities of lead iodine perovskites are further lowered. The iodine vacancy in lead iodine perovskites can facilitate the water molecule migration and thus is a disadvantage in improving the moisture stability of them, which should be minimized during perovskite growth. These findings provide new insight in understanding the poor moisture stability of lead iodine perovskites, which should be helpful for the future design and optimization of stable perovskite solar cells. PMID- 30027892 TI - Phase interfaces within different vesicle shapes. AB - Liquid droplets on flat surfaces generally exhibit a contact angle in a range from 0 to [Formula: see text], but the two-phase interface within a vesicle membrane is very fascinating due to the involved force balance along three bending interfaces. Giant lipid vesicles encapsulated with the poly(ethylene glycol)/dextran aqueous two-phase system are established recently, and the phase interfaces within vesicle membrane are very interesting as experimentally observed. The developed theoretical framework by a combination of the Helfrich curvature elastic theory for vesicle membranes and self-consistent field theory for polymers has been extended to explore aqueous two phases within vesicles. The intrinsic contact angle [Formula: see text] that represents the material parameter, is introduced to describe this phase interfaces within vesicles, especially the transitions from complete wetting to partial wetting, from partial wetting to complete dewetting. The dependence of intrinsic contact angles on the parameters, such as the interaction strengths between the polymers [Formula: see text] and between the membrane and polymer [Formula: see text], the volume fraction [Formula: see text], impermeability of the membrane to the enclosed polymers [Formula: see text] and membrane spontaneous curvature c 0, are thoroughly investigated, as well as these wetting/dewetting transitions are extensively discussed in the present study. PMID- 30027893 TI - Converting CO2 into fuels by graphitic carbon nitride-based photocatalysts. AB - A metal-free photocatalyst, graphitic carbon nitride (GCN) with a moderate band gap catering for visible-light excitation, shows amazing potential in various photocatalytic applications. Carbon dioxide reduction using diversified photocatalysts has been attracting increasing public attention and the extensively studied GCN is one of the most promising photocatalysts. However, because of the low concentration and high recombination rate of photogenerated carriers, and some other disadvantages of the pristine GCN photocatalyst, the solar-to-fuel conversion efficiency is too low for practical use. Modifications or optimizations of GCN are therefore important to enhance its CO2 photocatalytic conversion performance. This review summarizes the research progress made during the past five years on GCN-based photocatalysts in two main areas, which includes pristine GCN and its molecular modifications, and heterostructure composite photocatalysts based on GCN, for CO2 reduction. It is expected that this review may benefit the development of GCN-based photocatalysts for CO2-to-fuel conversion. PMID- 30027894 TI - Enhanced spin polarization and valley polarization in monolayer MoS2 junctions. AB - Special resonant modes in unique quantum structure can enhance spin and valley filtering effect. Hence we investigated resonant tunneling effect with large incident angles through single electric barrier in monolayer MoS2 junctions consisting of normal/ferromagnetic/normal parts. We found that for large incident angles the spin- and valley-dependent line-type resonances appear in the transmission and conductance spectra, which results in the transmission probabilities of spin-up and spin-down electrons at K and [Formula: see text] valleys being all improved to 100[Formula: see text] but for different special gate voltage. Therefore, both the spin and valley polarizations are increased, the perfect 100[Formula: see text] spin and valley polarizations are observed. Furthermore, the numbers of the line-type resonant peaks are multiplied with the increasing of the barrier's width. And the spin- and valley-polarized direction can be switched by changing the gate voltage. These intriguing features indicate that a valley or spin filter with high accuracy and efficiency can be designed, which is controllable by the electric field. PMID- 30027895 TI - Chain-length dependence of lipophilic force: comparison with the two-body van der Waals' force. AB - Hydrophobic dodecanethiol capped Au nanoparticles (AuNPs) form two-dimensional patterns in monolayers of amphiphilic fatty acids ([Formula: see text]) at the air water interface. An interplay between the various lipophilic interactions, in turn, decides the NP cluster size, where stronger NP-monolayer and monolayer monolayer attraction in fatty acid monolayers with longer tail length oppose nanoparticle aggregation resulting in a decrease in cluster size in both in-plane and out-of-plane directions. The decrease in the in-plane cluster size is steepest for 14 < n < 18, n being the total number of C atoms in the fatty acid, and levels off for higher fatty acids and cannot be explained on the basis of the two body van der Waals pair potential atleast at initial phases of pattern formation. The potential can be used only at later times, closer to stability. PMID- 30027896 TI - Spin caloritronics in armchair silicene nanoribbons with sp 3 and sp 2-type alternating hybridizations. AB - Finite-layer nanoribbon materials have long been considered as potential candidates for nanodevices with novel quantum effects. Here we constructed a series of ferromagnetic armchair silicene nanoribbons (ASiNRs) with sp 3 and sp 2 type alternating hybridizations, and found that the ASiNRs with different widths are localized in different spin-resolved electronic states. As the width parameter N is increased from 5 to 22, the ASiNR transits from indirect-gap half metallicity (HM), to indirect-gap spin semiconductor (SC), then to direct-gap SC and finally to direct-gap HM. When a temperature gradient is produced along the nanoribbons, the spin-dependent currents with the opposite flow directions are driven and a nearly perfect spin-dependent Seebeck effect (SDSE) occurs. Moreover, attributing to symmetrical spin-resolved transport channels, nearly pure thermal spin current without any accompanying charge current can be generated. In addition, for some ASiNRs with proper widths, both the thermal spin up current and spin-down one are contributed by the electrons in energy valleys, resulting in a well-defined valley-dependent SDSE. These theoretical findings suggest that the ASiNRs with the sp 3 and sp 2-type alternating hybridizations can be outstanding candidates for future spin caloritronic devices. PMID- 30027897 TI - Cardiotocography and beyond: a review of one-dimensional Doppler ultrasound application in fetal monitoring. AB - One-dimensional Doppler ultrasound (1D-DUS) provides a low-cost and simple method for acquiring a rich signal for use in cardiovascular screening. However, despite the use of 1D-DUS in cardiotocography (CTG) for decades, there are still challenges that limit the effectiveness of its users in reducing fetal and neonatal morbidities and mortalities. This is partly due to the noisy, transient, complex and nonstationary nature of the 1D-DUS signals. Current challenges also include lack of efficient signal quality metrics, insufficient signal processing techniques for extraction of fetal heart rate and other vital parameters with adequate temporal resolution, and lack of appropriate clinical decision support for CTG and Doppler interpretation. Moreover, the almost complete lack of open research in both hardware and software in this field, as well as commercial pressures to market the much more expensive and difficult to use Doppler imaging devices, has hampered innovation. This paper reviews the basics of fetal cardiac function, 1D-DUS signal generation and processing, its application in fetal monitoring and assessment of fetal development and wellbeing. It also provides recommendations for future development of signal processing and modeling approaches, to improve the application of 1D-DUS in fetal monitoring, as well as the need for annotated open databases. PMID- 30027898 TI - Paradigm for disease deconvolution in rare neurodegenerative disorders in Indian population: insights from studies in cerebellar ataxias. AB - Cerebellar ataxias are a group of rare progressive neurodegenerative disorders with an average prevalence ranges from 4.8 to 13.8 in 100,000 individuals. The inherited disorders affect multiple members of the families, or a community that is endogamous or consanguineous. Presence of more than 3000 mutations in different genes with overlapping clinical symptoms, genetic anticipation and pleiotropy, as well as incomplete penetrance and variable expressivity due to modifiers pose challenges in genotype-phenotype correlation. Development of a diagnostic algorithm could reduce the time as well as cost in clinicogenetic diagnostics and also help in reducing the economic and social burden of the disease. In a unique research collaboration spanning over 20 years, we have been able to develop a paradigm for studying cerebellar ataxias in the Indian population which would also be relevant in other rare diseases. This has involved clinical and genetic analysis of thousands of families from diverse Indian populations. The extensive resource on ataxia has led to the development of a clinicogenetic algorithm for cost-effective screening of ataxia and a unique ataxia clinic in the tertiary referral centre in All India Institute of Medical Sciences. Utilizing a population polymorphism scanning approach, we have been able to dissect the mechanisms of repeat instability and expansion in many ataxias, and also identify founders, and trace the mutational histories in the Indian population. This provides information for genetic testing of at-risk as well as protected individuals and populations. To dissect uncharacterized cases which comprises more than 50% of the cases, we have explored the potential of next-generation sequencing technologies coupled with the extensive resource of baseline data generated in-house and other public domains. We have also developed a repository of patient-derived peripheral blood mononuclear cells, lymphoblastoid cell lines and neuronal lineages (derived from iPSCs) for ascribing functionality to novel genes/mutations. Through integrating these technologies, novel genes have been identified that has broadened the diagnostic panel, increased the diagnostic yield to over 75%, helped in ascribing pathogenicity to novel mutations and enabled understanding of disease mechanisms. It has also provided a platform for testing novel molecules for amelioration of pathophysiological phenotypes. This review through a perspective on CAs suggests a generic paradigm fromdiagnostics to therapeutic interventions for rare disorders in the context of heterogeneous Indian populations. PMID- 30027899 TI - Lafora disease: from genotype to phenotype. AB - The progressive myoclonic epilepsy of Lafora or Lafora disease (LD) is a neurodegenerative disorder characterized by recurrent seizures and cognitive deficits. With typical onset in the late childhood or early adolescence, the patients show progressive worsening of the disease symptoms, leading to death in about 10 years. It is an autosomal recessive disorder caused by the loss-of function mutations in the EPM2A gene, coding for a protein phosphatase (laforin) or the NHLRC1 gene coding for an E3 ubiquitin ligase (malin). LD is characterized by the presence of abnormally branched water insoluble glycogen inclusions known as Lafora bodies in the neurons and other tissues, suggesting a role for laforin and malin in glycogen metabolic pathways. Mouse models of LD, developed by targeted disruption of the Epm2a or Nhlrc1 gene, recapitulated most of the symptoms and pathological features as seen in humans, and have offered insight into the pathomechanisms. Besides the formation of Lafora bodies in the neurons in the presymptomatic stage, the animal models have also demonstrated perturbations in the proteolytic pathways, such as ubiquitin proteasome system and autophagy, and inflammatory response. This review attempts to provide a comprehensive coverage on the genetic defects leading to the LD in humans, on the functional properties of the laforin and malin proteins, and on how defects in any one of these two proteins result in a clinically similar phenotype. We also discuss the disease pathologies as revealed by the studies on the animal models and, finally, on the progress with therapeutic attempts albeit in the animal models. PMID- 30027902 TI - Models and mechanisms of repeat expansion disorders: a worm's eye view. AB - The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system Caenorhabditis elegans has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models. PMID- 30027900 TI - Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches, success, challenges and prospects. AB - Neurodegenerative diseases constitute a large proportion of disorders in elderly, majority being sporadic in occurrence with ~5-10% familial. A strong genetic component underlies the Mendelian forms but nongenetic factors together with genetic vulnerability contributes to the complex sporadic forms. Several gene discoveries in the familial forms have provided novel insights into the pathogenesis of neurodegeneration with implications for treatment. Conversely, findings from genetic dissection of the sporadic forms, despite large genomewide association studies and more recently whole exome and whole genome sequencing, have been limited. This review provides a concise account of the genetics that we know, the pathways that they implicate, the challenges that are faced and the prospects that are envisaged for the sporadic, complex forms of neurodegenerative diseases, taking four most common conditions, namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington disease as examples. Poor replication across studies, inability to establish genotype phenotype correlations and the overall failure to predict risk and/or prevent disease in this group poses a continuing challenge. Among others, clinical heterogeneity emerges as the most important impediment warranting newer approaches. Advanced computational and system biology tools to analyse the big data are being generated and the alternate strategy such as subgrouping of case control cohorts based on deep phenotyping using the principles of Ayurveda to overcome current limitation of phenotype heterogeneity seem to hold promise. However, at this point, with advances in discovery genomics and functional analysis of putative determinants with translation potential for the complex forms being minimal, stem cell therapies are being attempted as potential interventions. In this context, the possibility to generate patient derived induced pluripotent stem cells, mutant/gene/genome correction through CRISPR/Cas9 technology and repopulating the specific brain regions with corrected neurons, which may fulfil the dream of personalized medicine have been mentioned briefly. Understanding disease pathways/biology using this technology, with implications for development of novel therapeutics are optimistic expectations in the near future. PMID- 30027901 TI - Huntington's disease: the coming of age. AB - Huntington's disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells.The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions. PMID- 30027904 TI - Mitochondrial dysfunction in protein conformational disorders. AB - Protein aggregation is a hallmark of many neurodegenerative diseases. In Parkinson's disease protein misfolding of alpha-synuclein involves conformational changes in the protein structure that often results in self-association and aggregation leading to accumulation of alpha-synuclein in neuronal cells. The underlying mechanisms by which aggregations can lead to impaired cellular functions are often not understood. Meanwhile, there is growing evidence that links mitochondrial dysfunction to Parkinson's disease. As both mitochondria and protein aggregation of alpha-synuclein have been shown to play a major role in Parkinson's disease, it seems likely that a converging mechanism exists that links the two pathways. PMID- 30027903 TI - Neurodegenerative diseases: model organisms, pathology and autophagy. AB - A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a leading causative reason for damage seen at the cellular and organ levels. While investigative therapies that aim at dissolving aggregates have failed, and the promises of silencing expression of ND associated pathogenic proteins or the deployment of engineered induced pluripotent stem cells (iPSCs) are still in the horizon, emerging literature suggests degrading aggregates through autophagy related mechanisms hold the current potential for a possible cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway where superfluous or unwanted cellular cargoes (such as peroxisomes, mitochondria, ribosomes, intracellular bacteria and misfolded protein aggregates) are wrapped in double membrane vesicles called autophagosomes that eventually fuses with lysosomes for their degradation. The selective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy. Here, we cover the workings of aggrephagy detailing its selectivity towards aggregates. The diverse cellular adaptors that bridge the aggregates with the core autophagy machinery in terms of autophagosome formation are discussed. In ND, essential protein quality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis. This phenomenonwhen combined with the fact that neurons can neither dilute out the aggregates by cell division nor the dead neurons can be replaced due to low neurogenesis, makes a compelling case for aggrephagy pathway as a potential therapeutic option. PMID- 30027905 TI - Regulation of membrane dynamics by Parkinson's disease-associated genes. AB - Parkinson's disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, develops sporadically, and its cause is unknown. However, 5 10% of PD cases are inherited as monogenic diseases, which provides a chance to understand the molecular mechanisms underlying neurodegeneration. Over 20 causative genes have already been identified and are being characterized. These PD-associated genes are broadly classified into two groups: genes involved in mitochondrial functions and genes related to membrane dynamics such as intracellular vesicle transport and the lysosomal pathway. In this review, we summarize the latest findings on the mechanism by which members of the latter group of PD-associated genes regulate membrane dynamics, and we discuss how mutations of these genes lead to dopaminergic neurodegeneration. PMID- 30027906 TI - Parkinson's disease: what the model systems have taught us so far. AB - Parkinson's disease (PD) is a debilitating neurodegenerative disorder, for which people above the age of 60 show an increased risk. Although there has been great advancement in understanding the disease-related abnormalities in brain circuitry and development of symptomatic treatments, a cure for PD remains elusive. The discovery of PD associated gene mutations and environmental toxins have yielded animal models of the disease. These models could recapitulate several key aspects of PD, and provide more insights into the disease pathogenesis. They have also revealed novel aspects of the disease mechanism including noncell autonomous events and spreading of pathogenic protein species across the brain. Nevertheless, none of these models so far can comprehensively represent all aspects of the human disease. While the field is still searching for the perfect model system, recent developments in stem cell biology have provided a new dimension to modelling PD, especially doing it in a patient-specific manner. In the current review, we attempt to summarize the key findings in the areas discussed above, and highlight how the core PD pathology distinguishes itself from other neurodegenerative disorders while also resembling them in many aspects. PMID- 30027908 TI - Pathways to neurodegeneration: lessons learnt from unbiased genetic screens in Drosophila. AB - Neurodegenerative diseases are a complex set of disorders that are known to be caused by environmental as well as genetic factors. In the recent past, mutations in a large number of genes have been identified that are linked to several neurodegenerative diseases. The pathogenic mechanisms in most of these disorders are unknown. Recently, studies of genes that are linked to neurodegeneration in Drosophila, the fruit flies, have contributed significantly to our understanding of mechanisms of neuroprotection and degeneration. In this review, we focus on forward genetic screens in Drosophila that helped in identification of novel genes and pathogenic mechanisms linked to neurodegeneration. We also discuss identification of four novel pathways that contribute to neurodegeneration upon mitochondrial dysfunction. PMID- 30027909 TI - Neurofibrillary tangles mediated human neuronal tauopathies: insights from fly models. AB - Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal and glial fibrillar lesions known as neurofibrillary tangles (NFTs). Tau is a neuron specific microtubule binding protein which is required for the integrity and functioning of neuronal cells, and hyperphosphorylation of tau and its subsequent aggregation and paired helical filaments (PHFs) and NFTs has emerged as one of the major pathogenic mechanisms of tauopathies in human and mammalian model systems. Modeling of human tauopathies in Drosophila results in manifestation of associated phenotypes, and a recent study has demonstrated that similar to human and mammalian models, accumulation of insoluble tau aggregates in the form of typical neurotoxic NFTs triggers the pathogenesis of tauopathies in fly models. In view of the availability of remarkable genetic tools, Drosophila tau models could be extremely useful for in-depth analysis of the role of NFTs in neurodegeneration and tau aetiology, and also for the screening of novel gene(s) and molecule(s) which suppress the toxicity of tau aggregates. PMID- 30027911 TI - The efficacy of temporary placement of nasobiliary drainage following endoscopic metal stenting to prevent post-ERCP cholangitis in patients with cholangiocarcinoma. AB - Background/Aims: Although endoscopic metal biliary endoprosthesis (EMBE) is widely accepted as the most suitable drainage method for patients with unresectable malignant obstruction, uncontrolled post-procedural cholangitis is still a problem. We aimed to validate a new treatment modality to prevent post ERCP cholangitis in patients with unresectable cholangiocarcinoma. Patients and Methods: A total of 378 patients who were diagnosed with unresectable malignant biliary obstruction and underwent EMBE or temporary endoscopic nasobiliary drainage (ENBD) following EMBE placement, from January 2010 to July 2016, were enrolled in this retrospective study. Incidence of cholangitis, related infectious indicators, success rate of biliary drainage, and occurrence of complications were evaluated. Results: The risk of overall cholangitis and related infectious indicators was significantly lower in EMBE plus ENBD group than that in EMBE group. The occurrence of cholangitis was 2.4% versus 11.9% (P = 0.004). On further analysis of subgroups, although no difference was detected in nonhilar cholangiocarcinoma subgroup, the incidence of cholangitis and related infectious indicators in hilar cholangiocarcinoma subgroup with EMBE modality were distinctly higher than that with EMBE plus ENBD modality (type I + II was 18.5% vs 0%, P < 0.05; type III + IV was 19.8% vs 3.8%, P < 0.05). No significant difference was found in successful biliary drainage rate and procedure-related complications when all subgroups were compared. Conclusions: The temporary placement of ENBD following EMBE is a simple and effective treatment modality to prevent post-ERCP cholangitis, especially in patients with hilar cholangiocarcinoma. PMID- 30027910 TI - Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks. AB - Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are pressing health concerns in modern societies for which effective therapies are still lacking. Recent high-throughput genomic technologies have enabled genome-scale, multidimensional investigations to facilitate a better understanding of the underlying mechanisms and the identification of novel targets. Here we review the molecular insights gained through such studies, and compare the similarities and differences between neurodegenerative diseases revealed by systems genomics and gene network modelling approaches. We focus specifically on the shared mechanisms at multiple molecular scales ranging from genetic factors to gene expression to network-level features of gene regulation, and whenever possible also point out mechanisms that distinguish one disease from another. Our review sets the stage for similar genomewide inspection in the future on shared/distinct features of neurodegenerative diseases at the levels of cellular, proteomic or epigenomic signatures, and how these features may interact to determine the progression and treatment response of different diseases afflicting the same individual. PMID- 30027912 TI - The effectiveness of adding low-level light therapy to minoxidil 5% solution in the treatment of patients with androgenetic alopecia. AB - Background: Androgenetic alopecia is the commonest type of alopecia affecting over half of men and women. Low-level light therapy is a new technique for stimulating hair growth in both genders. Aims: To overcome the shortcomings of previous epidemiological studies and a lack of controlled clinical trials on the subject, this study compared the effectiveness of adding low-level light therapy to minoxidil topical solution in the treatment of androgenetic alopecia in patients presenting to two skin clinics in Isfahan, Iran during 2014-2015. Materials and Methods: This clinical trial included 50 patients aged 17-45 presenting to Khorshid and Alzahra educational centers and skin diseases research center for androgenetic alopecia during 2014-2015. The patients were randomly divided into a control and a case group. The case group received topical minoxidil 5% solution plus low-level light therapy twice per day. The control group was given the same topical solution and a laser comb system that was turned off to act as a placebo. Changes in patients' hair density and diameter and its overall regrowth as well as their satisfaction with the treatment were assessed at months 0 (baseline), 3, 6, 9 and 12. Results: The percentage of recovery from androgenetic alopecia and the patients' satisfaction with their treatment were significantly higher in the case group compared to the control group. The patients' mean hair density and diameter were found to be higher in the case group after the intervention compared to the control group. Limitations: The study limitations included patient compliance, small sample size, patient insight due to novelty of the method and clinical judgement. Conclusion: As a new method of treatment, low-level light therapy can help improve the percentage of recovery from androgenetic alopecia and increase patients' satisfaction with their treatment. PMID- 30027907 TI - Tied up: Does altering phosphoinositide-mediated membrane trafficking influence neurodegenerative disease phenotypes? AB - Phosphoinositides are a class of membrane lipids that are found on several intracellular compartments and play diverse roles inside cells, such as vesicle formation, protein trafficking, endocytosis etc. Intracellular distribution and levels of phosphoinositides are regulated by enzymes that generate and breakdown these lipids as well as other proteins that associate with phosphoinositides. These events lead to differing levels of specific phosphoinositides on different intracellular compartments. At these intracellular locations, phosphoinositides and their associated proteins, such as Rab GTPases, dynamin and BAR domain containing proteins, regulate a variety of membrane trafficking pathways. Neurodegenerative phenotypes in disorders such as Parkinson's disease (PD) can arise as a consequence of altered or hampered intracellular trafficking. Altered trafficking can cause proteins such as alpha-synuclein to aggregate intracellularly. Several trafficking pathways are regulated bymaster regulators such as LRRK2,which is known to regulate the activity of phosphoinositide effector proteins. Perturbing either the levels of phosphoinositides or their interactions with different proteins disrupts intracellular trafficking pathways, contributing to phenotypes often observed in disorders such as Alzheimer's or PDs. Thus, studying phosphoinositide regulation and its role in trafficking can give us a deeper understanding of the contribution of disrupted trafficking to neurodegenerative phenotypes. PMID- 30027913 TI - Hair manifestations of endocrine diseases: A brief review. AB - Hair disorders are common in clinical practice and depending upon social and ethnic norms, it can cause significant psychosocial distress. Hair growth, cycling and density are regulated by many endogenous factors, mainly circulating hormones. Thus, diseases affecting the endocrine system can cause varied changes in physiological hair growth and cycling. Diagnosis and treatment of these disorders require a multidisciplinary approach involving a dermatologist, gynecologist and an endocrinologist. In this review, we briefly discuss the influence of hormones on the hair cycle and hair changes in various endocrine disorders. PMID- 30027914 TI - Optimizing q-switched lasers for melasma and acquired dermal melanoses. AB - The Q-switched Nd:YAG laser is an established modality of treatment for epidermal and dermal pigmented lesions. The dual wavelengths of 1064nm and 532nm are suited for the darker skin tones encountered in India. Though this laser has become the one of choice for conditions such as nevus of Ota, Hori's nevus and tattoos, its role in the management of melasma and other acquired dermal melanoses is not clear. Despite several studies having been done on the Q-switched Nd:YAG laser in melasma, there is no consensus on the protocol or number of sessions required. Acquired dermal melanoses are heterogenous entities with the common features of pigment incontinence and dermal melanophages resulting in greyish macular hyperpigmentation. This article reviews the current literature on laser toning in melasma and the role of the Q-switched Nd:YAG laser in stubborn pigmentary disorders such as lichen planus pigmentosus. As the pathology is primarily dermal or mixed epidermal-dermal in these conditions, the longer wavelength of 1064nm is preferred due to its deeper penetration. Generally multiple sessions are needed for successful outcomes. Low fluence Q-switched Nd:YAG laser at 1064nm utilizing the multi-pass technique with a large spot size has been suggested as a modality to treat melasma. Varying degrees of success have been reported but recurrences are common on discontinuing laser therapy. Adverse effects such as mottled hypopigmentation have been reported following laser toning; these can be minimized by using larger spot sizes of 8 to 10mm with longer intervals (2 weeks) between sessions. PMID- 30027915 TI - Methods to overcome poor responses and challenges of laser hair removal in dark skin. AB - Conventional and advance technologies are available for laser hair removal. Complete and permanent hair reduction is not yet possible by treatment with lasers. Ideal patient for any conventional laser hair removal treatment is one who has thick, dark terminal hair, light skin and normal hormonal status. Factors that contribute to variable outcomes in laser hair removal can be broadly divided into patient related ones and the technology related ones. Skin type, hair color, thickness and density, degree of tan, hormonal dysfunction etc., constitute the patient related factors. The wavelength, fluence, spot size and pulse duration of the laser system are the technology related factors. There are some patients who respond variably, unpredictably or poorly to laser hair removal despite ensuring that indication for treatment is appropriate with adequate parameters of the laser system. This article reviews various patient related and technology related factors which lead to variable-to-poor outcomes in laser hair removal; and various challenges and limitations of laser hair removal technology in patients with dark skin types. PMID- 30027916 TI - Pathogenesis, diagnostic challenges and treatment of zika virus disease in resource-limited settings. AB - The association of Zika virus (ZIKV) infection with congenital malformation and neurological sequelae has brought significant global concern. Consequently, the World Health Organization (WHO) declared it "a public health emergency of International concern" on 1 February, 2016. A critical review of its pathogenesis would lead to a better understanding of the clinical features and the neurological complications. This review is based on literature search in PubMed/Medline, Google Scholar and the WHO, http://www.who.int. This include all relevant articles written in English published through June 2018, with subject heading and keywords such as Zika, ZIKV, Zika pathogenesis, diagnosis of Zika, Zika Nigeria, Zika Africa and Zika resource-limited settings. Following ZIKV infection, viraemia ensues targeting primarily the monocytes for both the Asian and African strains. ZIKV infection by an African strain appears to be more pathogenic, in early pregnancy tends to result in spontaneous abortion. Whereas an Asian strain tends to be less pathogenic and more chronic, this allows the pregnancy to continue, ultimately resulting in congenital malformations. There is no routine laboratory diagnosis of ZIKV infection in resource-constrained countries. Serologic tests should be interpreted with caution since there can be cross-reactivity with other flaviviruses, especially in Africa where the burden of infection with flaviviruses is comparatively high. There is a paucity of well equipped laboratories for comprehensive ZIKV diagnosis. It is imperative to strengthen the health systems, improve health workforce and diagnostic capacity of such settings. PMID- 30027917 TI - Assessment of factors affecting self-rated health among elderly people in Southwest Nigeria. AB - Context: Self-rated health (SRH) is a subjective measure of health considered valid to predict mortality among the elderly. With the rapid increase of older people living in Nigeria and the lack of adequate social security, it is important to identify factors affecting their SRH. Social support has also taken on added importance among the elderly in view of scarce resources. Objective: To determine the level of satisfaction with the forms of social support received by the elderly and the factors associated with their SRH. Settings and Design: The study was a descriptive cross-sectional study design among the elderly in Southwest Nigeria. Subjects and Methods: A multistage sampling technique was employed to select 360 elderly respondents for the study. A standardised questionnaire, Short Form Health Survey-36 was interviewer administered. The data were analysed using Statistical Package for the Social Sciences version 20. Significant associations between categorical variables were evaluated using Chi square (chi2) test. Multiple regression test and adjusted odds ratios (ORs) were employed to assess the relationship of the various predictors of SRH. The level of significance was set at P < 0.05. Results: The mean age of the 360 elderly respondents was 73 +/- 9.3 years, 60.3% were female and 43.9% were widowed. Almost all (91.9%) the respondents received emotional while domestic support was the least in 50.3%. About 30.0% of the elderly self-rated their health as poor. The predictors of good SRH after multiple logistic regression included being married (OR = 1.84, 95% confidence interval [CI]: 1.01-3.33, P = 0.04); engagement in work (OR = 2.27, 95% CI: 1.11-4.63, P = 0.02); the absence of morbid conditions (OR = 12.6, 95% CI: 2.86-55.4, P = 0.001) and higher levels of education (OR = 0.41, 95% CI: 0.19-0.91, P = 0.03). Conclusions: About one-third of the elderly had poor SRH. Targeted interventions such as creating employment fit for the elderly and improving healthcare access is recommended. PMID- 30027918 TI - Sonographic evaluation of axillary lymph nodes in women with newly diagnosed breast cancer at the university college hospital Ibadan, Nigeria. AB - Background: Axillary lymph node (LN) status of patients with breast cancer is important in the surgical management. Sonographic evaluation of axillary LNs in newly diagnosed breast cancer is required to predict prognosis. Objective: The purpose of this study was to describe the morphologic features by sonographic evaluation of the cortices and sinuses as well as patterns of blood flow of axillary LNs and correlate same with the clinical staging in women with newly diagnosed breast cancer in a tertiary referral centre. Patients and Methods: This was a prospective and descriptive study of 106 newly diagnosed female breast cancer patients recruited from the surgical outpatient clinic of the University College Hospital, Ibadan, during a period of 9 months in 2015. All 106 patients had clinical evaluation, sociodemographic documentation and ultrasound scans of the breast and axillae performed. Results: The mean age of patients was 48.1 (+/ 11.1) years with age range 20-82 years. Most patients have a negative family history of breast cancer as seen in 97 (91.4%) of them. Abnormal cortex-hilum area ratio was more frequent in the right (66.7%) than the left (41.2%) axillary LNs. Longitudinal-transverse ratio was abnormal in 93.5% and 86.3% of LNs in the right and left axillae, respectively. Slit-like hilum, eccentric cortical thickening, replaced node and rat-bite appearance, respectively, were found in 40.7%, 10.4%, 48.4% and 44.4% of LNs in the right axilla. The peripheral flow type was demonstrated in 46.8% and 48.1% of LNs in the right and left axillae, respectively. Conclusion: Ultrasonography is a good diagnostic tool that can be employed with reasonable accuracy in the initial assessment of axillary involvement in breast cancer. Although the assessment of tumour size and clinical staging leaves little doubt as to the stage of breast cancer disease, sonographic evaluation of the breast and the axilla painted a more ominous picture. PMID- 30027919 TI - Tracking stillbirths by referral pattern and causes in a rural tertiary hospital in Southern Nigeria. AB - Background: The burden of stillbirth is disproportionately more in rural areas of developing countries where unskilled birth attendants contribute a large quota in the management of pregnant women. Tracking stillbirth should include the pattern of referral from the primary institutions that take care of these women. Aims and Objectives: This study evaluated the causes and determinants of stillbirth by the referral pattern in a rural area in southern Nigeria. Subjects and Methods: This was a retrospective case-controlled study of stillbirth at the Madonna University Teaching Hospital, Elele, from 2010 to 2014. The lying-in, delivery and theatre registers were used to extract the relevant information. For each stillbirth, two controls were selected which were live births. Data analysis was performed using SPSS version 20. The confidence interval was 95% set at value of P = 0.05. Result: During the study, a total of 1243 neonates were delivered at the hospital, the number of live births and stillbirths were 1025 and 218, respectively. This gives a stillbirth rate of 175/1000 deliveries. Only 179 neonates whose case files were retrieved were used in the analysis. There were 87 fresh and 92 macerated stillbirths. Intrapartum complications contributed 91 (51.40%) of the stillbirths with traditional birth attendants and maternity homes contributing 72%. Determinants include booking status, educational level, abruptio placentae, preeclampsia, ruptured uterus, prolonged labor and low birthweight. Conclusion: The study showed an unacceptably high rate of stillbirth in rural Nigeria. Early recognition of complications and prompt referral may reduce stillbirth rate. PMID- 30027920 TI - Assessment of seminal biomarker of lipid peroxidation among male partners of infertile couples at the university of ilorin teaching hospital, Nigeria. AB - Background: Seminal fluid analysis (SFA) is the most important investigation of infertile males. It is however limited in revealing the aetiologies of the various spermatozoa abnormalities observed on microscopy. Increasing prevalence of male infertility and the challenges of diagnosis require biochemical investigations, such as assay of seminal malondialdehyde (MDA), a marker of sperm peroxidation and to support SFA in investigation of infertile males. Aims: The aim of this study was to determine the seminal level of biomarker of lipid peroxidation by measuring seminal MDA levels among infertile males in Ilorin. Settings and Design: This was a descriptive cross-sectional study. Subjects and Methods: One hundred and thirty infertile males served as patients and 50 fertile males as controls. Seminal MDA was assayed using ELISA method. Statistical Analysis Used: Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA) was used. Normally distributed data were expressed as mean +/- standard deviation. Results: The mean age of the patients who were mainly civil servants was 38.6 +/- 6.6 years compared to 37.0 +/- 5.8 years among controls. Seminal MDA was significantly higher among infertile males in this study (P < 0.05) indicating higher degree of lipid peroxidation in their semen. Seminal MDA concentrations were found to be significantly higher among infertile males with a history of alcohol consumption (P < 0.05), cigarette smoking (P < 0.001) and sexually transmitted infections (P < 0.001) when compared to control with similar history. Conclusions: There is significant lipid peroxidation of spermatozoa among infertile males with lifestyle playing a significant role. Evaluation of infertile males should include assessment of seminal MDA. Prophylactic administration of antioxidants to this group of patients may be beneficial. PMID- 30027921 TI - Comparison of the incidence of flare-up and time efficiency in single visit root canal treatment employing either rotary or manual step-back canal preparatory technique. AB - Aim: This study aims to compare the incidence of flare-up and operating time in root canal treatments where rotary or manual step-back canal preparatory technique was employed. Materials and Methods: A randomised study was conducted in a Nigerian Teaching Hospital. One hundred and twenty teeth belonging to 95 patients were randomised into two (Rotary and Manual) groups. Root canal treatment was performed using either rotary or manual step-back canal preparatory technique. Canal preparation time and total operating time were measured. Patients were monitored for severe pain and/or swelling over 1-week. Data were analysed using SPSS version 20.0, at alpha-level of P <= 0.05. Chi-square and independent Student's t-test were employed for comparison where categorical and numeric variables were involved, respectively. Results: There was neither associated pain/swelling before treatment in 28 (46.7%) of the teeth in rotary group nor in 27 (45.0%) of the teeth in manual group. Pain incidence was 11.7% and 16.7% in rotary and manual groups, respectively, at 1-week review. Severe pain was experienced by 3.3% patients in both groups at 1-week review. Only 1.7% and 6.7% in rotary and manual groups, respectively, presented with swelling over 1-week. Flare-up incidence at 1-week review was 3.3% in rotary and 8.3% in manual groups, the difference was not significant (P = 0.243). Canal preparation and total operating times were significantly shorter (P < 0.05) in the rotary group in all tooth categories. Conclusion: No significant difference was noted in flare up incidence between rotary and manual groups. Canal preparation time and total operating time were significantly shorter for rotary technique. Time efficiency is clinically invaluable, especially for multi-rooted teeth. PMID- 30027922 TI - Pattern of childhood visual impairment and blindness among students in schools for the visually impaired in Lagos State: An update. AB - Aim: The aim of this study was to determine the pattern of childhood visual impairment and blindness (VI and BL) among students attending schools for the visually impaired in Lagos State, with a view to providing information on avoidable causes as well as emerging trends that would be useful to policy-makers for the planning and implementation of strategies for the control of avoidable childhood BL in Lagos State. Subjects and Methods: The study was conducted among students enrolled in two schools for the visually impaired in Lagos State who developed VI/BL before the age of 16 years. Participants and their parents/guardians were interviewed to obtain medical history. Ocular and systemic examinations were also performed. Information was recorded using a modified World Health Organization/Prevention of BL Eye Examination Record for Children with BL and Low Vision and analysed using the Statistical Package for the Social Sciences version 23.0. Z-test determined differences in the proportions of the causes of VI/BL between this study and an earlier study. Results: A total of 116 students were enrolled in this study of which 65 (56.0%) were males. Avoidable causes accounted for 58.5% of VI/BL. Preventable causes predominated with measles (15; 12.9%) accounting for the largest proportion. Surgical complications (16; 13.8%) were the largest cause of VI/BL. A statistically significant decrease (P = 0.004; 95% confidence interval = 0.09-0.50) in the proportion of avoidable BL between a previous study carried out in Lagos State and this study was found. Hereditary cataract and cortical VI were the findings of this study not recorded in the previous study. Conclusion: Avoidable causes of childhood VI/BL still predominate among students in the schools for the visually impaired in Lagos State; however, there is a statistically significant decrease. PMID- 30027923 TI - Effect of age and sex on ocular dimensions in emmetropic children in South West Nigeria. AB - Background: Ocular dimensions are important in the refractive status of the eye. Aim: The aim of this study is to determine the effect of age and gender on ocular axial dimensions of emmetropic Nigerian Children. Materials and Methods: A cross sectional study of 468 children from selected pre-nursery, nursery and primary schools with normal visual acuity were recruited into the study. Lens thickness (LT), anterior chamber depth (ACD) and vitreous chamber depth (VCD) were measured using a B-mode CLEA Vue 550 PHILLIP ultrasound Machine 2013 model, with a 4-12 MHz linear transducer. Results were entered into the personal computer and analysed using the SPSS statistical package version 21. Results: There were 235 boys (50.2%) and 233 girls (49.8%) with a ratio of 1.01: 1. Mean age for the study participants as a whole, 8.81 +/- 3.81 years. The mean ACD, LT, and VCD were 3.6 mm, 3.7 mm and 17.5 mm in the RE and 3.7 mm, 3.8 mm and 24.8 mm in the LE. Only LT showed a significant difference between the sexes in both eyes. All ocular dimensions increased with age with the exception of ACD in the left eye. Conclusion: Of all the ocular dimensions, only LT showed the effect of gender, but no effect of age and age groups, particularly on the left eye. PMID- 30027924 TI - Managing the sequelae of urology medical tourism: A single center experience. AB - Background: Medical tourism is a fast-growing business worldwide with almost every country involved as either a provider and/or consumer. The degree of participation may vary depending on the status of health-care system in that country. This study aims to present our experience in the management of patients who sought urologic care abroad or returned from medical tourism with urologic complications. Methods: The method of study was based on the documentation of interaction with patients, patients' relations and their agents in a questionnaire between January 2010 and December 2015. The data obtained included, their demographics, indications/motivations for seeking treatment abroad, procedures performed and complications. We also documented the secondary procedures that were performed and complications managed in our center. The data were entered into Microsoft Excel and analysed using descriptive statistics, tables and figures. Results: A total of 113 have either indicated intention of going to seek for urological care abroad or had already had urologic procedures abroad but were attending our clinic for follow up or for management of complications. Only about 12% of these patients were found to have genuine indications for seeking care abroad. Most of the indications were not justifiably based on the current capabilities of our health facility but more due to a lack of trust in the system or at worst pretentious. Conclusion: Patients seek for treatment abroad for variable reasons but and most could not be justified based on available local options. India and some Middle-East countries were the favoured destinations, and the quality of care and relative lower cost are the major attractions. The rising trend in medical tourism is fuelled by the poor state of our health-care system, perceived dearth of expertise and a general apathy and lack of trust. PMID- 30027925 TI - Prevalence and impact of abnormal routine pre-operative test results among elective surgical patients with or without co-morbidity: An observational comparative study. AB - Background: At present, selective and clinical assessment-based pre-operative investigations are advocated, but it is yet far from routine practice. Aim: This study aims to assess the prevalence and impact of abnormal routine pre-operative test results among co-morbid and non-co-morbid elective surgical patients. Methods: Data for this prospective study were collected by reviewing the medical charts of the patients attending pre-anaesthetic clinic from December 2016 to April 2017. The cohort was divided into non-co-morbid and co-morbid. Routine pre operative tests were done, their results and impacts of abnormal test results were noted; number needed to investigate (NNI) was calculated. Data were compared using Fisher's exact test, unpaired t-test, etc., P < 0.05 was considered statistically significant. Results: Data from 887 patients; 322 (36.30%) co morbid were analysed. Co-morbid patients were older (53.79 +/- 14.99 vs. 40.33 +/ 15.68 year). No difference was found in the number of tests done in co-morbid patients except significantly higher number of electrocardiogram and echocardiography (P < 0.0001). Abnormal test results were significantly higher among co-morbid (relative risk - 1.63, P < 0.0001). Impacts were similar in co morbid as compared to non-co-morbid for most of the tests, but thyroid function and blood sugar tests showed NNI for significant impact below 10 in co-morbid group. Conclusion: Co-morbid patients have more abnormal results than non-co morbid patients, but impacts of such tests are nearly indifferent. Routine testing is not favourable even in co-morbid patients. Selective or co-morbid disease-specific tests are having more significant impacts and should replace the 'routine testing' even in co-morbid patients. PMID- 30027926 TI - Non-ossifying fibroma of the right clavicle. AB - Non-ossifying fibromas (NOFs) or fibroxanthomas are benign intracortical, multilocular and well-circumscribed lesions, which most commonly affect children and adolescents with an estimated prevalence of 30%-40% of all normal children. They are most commonly located in the distal femoral and distal tibial metaphysis although they can also be found in the fibula and upper extremity. Clinically, NOFs are asymptomatic and are detected only incidentally on radiographs where they appear as solitary, eccentric and lytic lesion in the metaphysis of a long bone and often polycyclic in shape. In most cases, no treatment is needed for an NOF other than simple observation due to a high rate of spontaneous regression at skeletal maturity. However, surgical treatment is considered in certain cases when the NOF is large or symptoms are present. We present an unusual case of a large NOF in the right clavicle of a 27-year-old woman who came to us with a 3 year history of a painless swelling on the right side of her upper chest. Radiographic evaluation of her tumour revealed a Ritschl Stage C lesion which was subsequently treated successfully by a near-total cleidectomy without recurrence over a 4-year of the follow-up period. We concluded that open-mindedness remains an important attribute a doctor must possess in order not to miss some rather unlikely diagnosis. PMID- 30027927 TI - The Institute of Urology, Peking University prostatectomy score: a simple preoperative classification of prostate cancer for predicting surgical difficulty and risk. AB - Traditional laparoscopic radical prostatectomy is a treatment choice in many developing countries and regions for most patients with localized prostate cancer; however, no system for predicting surgical difficulty and risk has been established. This study aimed to propose a simple and standard preoperative classification system of prostate cancer using preoperative data to predict surgical difficulty and risk and to evaluate the relationship between the data and postoperative complications. We collected data from 236 patients and divided them into three groups to evaluate and validate the relationships among preoperative, operative, and postoperative data. This new scoring system is based on the body mass index, ultrasonic prostate volume, preoperative prostate specific antigen level, middle lobe protrusion, and clinical stage. In the scoring group, we classified 89 patients into two groups: the low-risk group (score of <4) and high-risk group (score of >=4), and then compared the postoperative data between the two groups. The positive surgical margin rate was higher in the high-risk group than low-risk group. The results in validation Groups A and B were similar to those in the scoring group. The focus of our scoring system is to allow for preliminary assessment of surgical difficulty by collecting the patients' basic information. Urologists can easily use the scoring system to evaluate the surgical difficulty and predict the risks of a positive surgical margin and urinary incontinence in patients undergoing laparoscopic radical prostatectomy. PMID- 30027928 TI - National Comprehensive Cancer Network (NCCN) risk classification in predicting biochemical recurrence after radical prostatectomy: a retrospective cohort study in Chinese prostate cancer patients. AB - This study aimed to assess the role of the National Comprehensive Cancer Network (NCCN) risk classification in predicting biochemical recurrence (BCR) after radical prostatectomy (RP) in Chinese prostate cancer patients. We included a consecutive cohort of 385 patients with prostate cancer who underwent RP at Fudan University Shanghai Cancer Center (Shanghai, China) from March 2011 to December 2014. Gleason grade groups were applied at analysis according to the 2014 International Society of Urological Pathology Consensus. Risk groups were stratified according to the NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer version 1, 2017. All 385 patients were divided into BCR and non BCR groups. The clinicopathological characteristics were compared using an independent sample t-test, Chi-squared test, and Fisher's exact test. BCR-free survival was compared using the log-rank test and multivariable Cox proportional hazard analysis. During median follow-up of 48 months (range: 1-78 months), 31 (8.05%) patients experienced BCR. The BCR group had higher prostate-specific antigen level at diagnosis (46.54 +/- 39.58 ng ml-1 vs 21.02 +/- 21.06 ng ml-1, P= 0.001), more advanced pT stage (P = 0.002), and higher pN1 rate (P < 0.001). NCCN risk classification was a significant predictor of BCR (P = 0.0006) and BCR free survival (P = 0.003) after RP. As NCCN risk level increased, there was a significant decreasing trend in BCR-free survival rate (Ptrend = 0.0002). This study confirmed and validated that NCCN risk classification was a significant predictor of BCR and BCR-free survival after RP. PMID- 30027929 TI - Muscarinic acetylcholine receptor M1 mediates prostate cancer cell migration and invasion through hedgehog signaling. AB - The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 (CHRM1) expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 (GLI1), patched 1 (PTCH1), and sonic hedgehog (SHH) expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hedgehog signaling pathway. PMID- 30027930 TI - Pretreatment serum albumin/globulin ratio as a prognostic biomarker in metastatic prostate cancer patients treated with maximal androgen blockade. AB - The pretreatment serum albumin/globulin ratio (AGR) has been used as a prognostic biomarker for various cancer types. However, the prognostic value of the AGR for prostate cancer, especially for metastatic prostate cancer (mPCa) after maximal androgen blockade (MAB), remains unclear. The aim of this study was to evaluate the prognostic value of the pretreatment serum AGR for mPCa treated with MAB. This retrospective study included 214 mPCa patients receiving MAB from October 2007 to March 2017. The correlation of the AGR with survival was estimated using Kaplan-Meier analysis and Cox proportional hazards models. The cutoff value of the AGR was 1.45 according to the receiver operating characteristic curve. Kaplan Meier analysis demonstrated that patients with a low AGR (<1.45) had poor outcomes in terms of progression-free survival (PFS) and cancer-specific survival (CSS). Multivariate Cox analyses showed that the AGR was an independent predictor of PFS (hazard ratio [HR] = 0.642; 95% confidence interval [CI]: 0.430-0.957; P = 0.030) and CSS (HR = 0.412; 95% CI: 0.259-0.654; P < 0.001). Furthermore, in a subset of 79 patients with normal serum albumin levels (>=40.0 g l-1), the serum AGR remained an independent predictor of CSS (P = 0.009). The pretreatment AGR was an independent prognostic biomarker for PFS and CSS in patients with mPCa receiving MAB. In addition, the AGR remained effective for the prediction of CSS in patients with normal albumin levels (>=40 g l-1). However, further prospective studies are needed to confirm our conclusions. PMID- 30027931 TI - Genes associated with testicular germ cell tumors and testicular dysgenesis in patients with testicular microlithiasis. AB - Testicular microlithiasis (TM) is one of the symptoms of testicular dysgenesis syndrome (TDS). TM is particularly interesting as an informative marker of testicular germ cell tumors (TGCTs). KIT ligand gene (KITLG), BCL2 antagonist/killer 1 (BAK1), and sprouty RTK signaling antagonist 4 (SPRY4) genes are associated with a high risk of TGCTs, whereas bone morphogenetic protein 7 gene (BMP7), transforming growth factor beta receptor 3 gene (TGFBR3), and homeobox D cluster genes (HOXD) are related to TDS. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, we investigated allele and genotype frequencies for KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) in 142 TGCT patients, 137 TM patients, and 153 fertile men (control group). We found significant differences in the KITLG GG_rs995030 genotype in TM (P = 0.01) and TGCT patients (P = 0.0005) compared with the control. We also revealed strong associations between KITLG_rs1508595 and TM (G allele, P = 0.003; GG genotype, P = 0.01) and between KITLG_rs1508595 and TGCTs (G allele, P = 0.0001; GG genotype, P = 0.0007). Moreover, there was a significant difference in BMP7_rs388286 between the TGCT group and the control (T allele, P = 0.00004; TT genotype, P = 0.00006) and between the TM group and the control (T allele, P = 0.04). HOXD also demonstrated a strong association with TGCTs (rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001). Furthermore, significant differences were found between the TGCT group and the control in the BAK1_rs210138 G allele (P = 0.03) and the GG genotype (P = 0.01). KITLG and BMP7 genes, associated with the development of TGCTs, may also be related to TM. In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development. PMID- 30027932 TI - Male external genitalia growth curves and charts for children and adolescents aged 0 to 17 years in Chongqing, China. AB - Genital size is a crucial index for the assessment of male sexual development, as abnormal penile or testicular size may be the earliest visible clinical manifestation of some diseases. However, there is a lack of data regarding penile and testicular size measurements for Chinese boys at all stages of childhood and puberty. This cross-sectional study aimed to develop appropriate growth curves and charts for male external genitalia among children and adolescents aged 0-17 years in Chongqing, China. A total of 2974 boys were enrolled in the present study. Penile length was measured using a rigid ruler, penile diameter was measured using a pachymeter, and testicular volume was determined using a Prader orchidometer. Age-specific percentile curves for penile length, penile diameter, and testicular volume were drawn using the generalized additive models for location, scale, and shape. Very similar growth curves were found for both penile length and penile diameter. Both of them gradually rose to 10 years of age and then sharply increased from 11 to 15 years of age. However, testicular volume changed little before the age of 10 years. This study contributes to the literature covering age-specific growth curve and charts about male external genitalia in Chinese children and adolescents. These age-related values are valuable in evaluating the growth and development status of male external genitalia and could be helpful in diagnosing genital disorders. PMID- 30027934 TI - [Genomics of neuroendocrine tumors of the lung and gastrointestinal tract: similarities and differences]. AB - The incidence of neuroendocrine tumors sharply increased in the past years. It is also important that beside the relatively benign, slow growing tumors, prevalence of aggressive neuroendocrine carcinomas is also increasing. It is now evident that the carcinoids are genetically heterogeneous entities, localized to lung, pancreas or to the small intestines. A significant proportion of these neuroendocrine tumors are associated with hereditary syndromes but the etiology of the sporadic versions is still unknown, although in case of the lung, neuroendocrine carcinomas have a similar etiology than the non-endocrine carcinomas. This review summarizes the results of recent complex genomic analyses. Based on these data it is evident that the neuroendocrine tumors of the lung are different as compared to gastrointestinal ones. These genetic differences may fundamentally affect their biology, prognosis and therapy which must be considered. PMID- 30027933 TI - miRNA-125b-5p Suppresses Hypothyroidism Development by Targeting Signal Transducer and Activator of Transcription 3. AB - BACKGROUND A deficiency of maternal thyroid hormones (THs) during pregnancy has severe impacts on fetal brain development. Neural stem cells (NSCs) are major targets of THs and provided a powerful model to explore the underlying mechanism of THs during brain development. Although miRNA-125 might be associated with the NSCs differentiation, the relationship between miR-125 and hypothyroidism (HypoT) development remains unclear. MATERIAL AND METHODS In our study, we screened a differentially expressed gene miR-125b-5p from brain between euthyroid (EuT) and HypoT rats. In vitro, we employed anion exchange resin to remove THs to stimulate HypoT. QRT-PCR and Western blot were used to examine the expression of signal transducer and activator of transcription 3 (Stat3). The relationship between miR 125b-5p and Stat3 was detected via a dual-luciferase assay. RESULTS QRT-PCR results showed that the level of miR-125b-5p in HypoT rat brains was significantly suppressed, suggesting some relationship between miR-125b-5p and HypoT. In C17.2, miR-125b-5p promoted cell differentiation into neurons by regulating the expression of tubulin beta chain 3 (TUBB3) and glial fibrillary acid protein (GFAP). QRT-PCR and Western blot results revealed that miR-125b-5p mimic modulated the contents of total Stat3 and p-Stat3. A dual-luciferase assay showed that miR-125b-5p negatively regulated the expression of Stat3 by binding with the first site in 3' UTR of Stat3. CONCLUSIONS These results revealed Stat3 is a new target of miR-125b-5p and revealed the mechanism of miR-125b-5p suppressing HypoT development. These findings provide a new target for HypoT therapy. PMID- 30027935 TI - [Pathology of lung neuroendocrine tumors]. AB - The heterogeneous group of lung neuroendocrine tumors are divided into four main types: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Classification is based on the analysis of surgical resection specimens, which, in addition to basic morphological features, takes into account the mitotic count in 2 mm2, the presence or absence of necrosis. According to prognosis, TC is low grade, AC is intermediate grade, while SCLC and LCNEC are high grade carcinomas with very poor prognosis. The morphological diagnosis can be refined by the use of neuroendocrine immunohistochemical markers. Based on the histological diagnosis, clinical prognosis is not always clear. Application of Ki-67 labeling can get closer to real biological behavior. Recently, more than 2/3 of the cases are small samples (core biopsy, bronchoscopic biopsy, cytological smears). Diagnostic algorithms developed for resection specimens has limited usage for these samples. In a single case, a wide range of histological techniques should be used in the processing of the sample, and still only an unsatisfactory result is obtained. Knowing the potential information content of the samples can help the clinician to set up a diagnostic and therapeutic plan. PMID- 30027936 TI - [Clinicopathological characterization of gastro-entero- pancreatic neuroendocrine tumors]. AB - Tumors arising from the diffuse neuroendocrine (NE) system are mostly located in gastro-entero-pancreatic (GEP) tract and in the lung, and show increasing incidence and wide spectrum appearance. Different therapeutic possibilities need accurate diagnosis, classification and prognosis prediction, which determination for pathological diagnostics is a great challenge. All of these are based on the WHO classification, TNM classification of tumors of different location, and clinicopathological characterization. This review provides a comprehensive overview of the general characteristics of NE tumors, in particular the clinical pathological properties of gastro-entero-pancreatic tumors and the requirements of correct pathological diagnosis for treatment. PMID- 30027937 TI - [The treatment of gastroenteropancreatic neuroendocrine tumors]. AB - Gastroenteropancreatic neuroendocrine tumors have been increasing in frequency over the past decades. The goal of this paper is to provide a concise overview of various treatment options based mainly on consensus guidelines. The only curative therapy for these tumors is timely surgical intervention including endoscopic removal of early stage neuroendocrine tumors. Since at initial diagnosis about half of these patients present with advanced disease, systemic drug and non-drug treatments are discussed in details. Therapeutic approaches of advanced stages include surgical, medical, interventional radiological and nuclear medicine strategies. The aims of treatment are to provide an appropriate antisecretory and antiproliferative effect. Optimization of diverse treatment strategies is best achieved by multidisciplinary approaches. PMID- 30027938 TI - [Laboratory diagnostics of lung neuroendocrine tumors]. AB - Perhaps innovations in protein and peptide analysis utilizing immunochemistry methodology have been the most demarcating in the field of routine laboratory diagnostics in the past few decades. Presently, the state of art immunochemistry (e.g., immunofluorimetry, electrochemiluminescence) and separation techniques (e.g., high pressure liquid chromatography) facilitate achievement of detection limits well below the nmol/L range. These techniques have allowed reproducible and high throughput analysis with a short turnaround time of tumor markers, among others, in the routine diagnostic laboratory setting. Tumor marker determination is an integral part of the diagnostic work-up of tumors, and is indispensable in therapeutic monitoring and clinical decision-making. This article presents the utility of tumor markers in the diagnostics of lung neuroendocrine tumors (NET). Furthermore, since the majority of the tests used in lung NET diagnostics are infrequently requested, quite a few practical issues are also discussed. The generally applicable rule pertaining to tumor markers is also valid for NET diagnostics, i.e., improved sensitivity and specificity is widely achieved with a combination of tumor markers, as such, promoting diagnosis, efficient therapeutic monitoring and defining the prognosis. PMID- 30027939 TI - [Diagnosis and treatment of the neuroendocrine tumors of the lung]. AB - Lung neuroendocrine tumors comprise 20% of all pulmonary tumors. Their appearance and behavior are very heterogeneous. Histologically they are divided into four groups, well-differentiated and low-malignant typical carcinoid, poorly differentiated and worse prognosis atypical carcinoid, and highly malignant small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. Of these, the most common is small cell lung cancer with an incidence of 15%, while those of large cell neuroendocrine tumors and lung carcinoids are 3% and 2%, respectively. The treatment and prognosis of carcinoids are very different from those of highly malignant small cell and large cell neuroendocrine carcinomas. The paper summarizes the characteristics of lung neuroendocrine tumors. PMID- 30027940 TI - [Genome engineering using the CRISPR-Cas9 system and applications in cancer research]. AB - Today, we have to investigate the effects of selected mutations and molecular alterations - this is made possible by the new genome editing technologies. In these, either a section of the DNA is deleted or moved, or a targeted mutation is introduced into the cell. Here, we describe in detail the CRISPR-Cas9 genome editing method. The technology is based on a feature used by bacteria to combat recurrent viral infections. At present, commencing a set of modifications, the method is functional and can be applied in eukaryotic cells as well. The method has three major steps: first, the system has to be carefully designed and constructed, then the construct has to be introduced into the target cells by transfection, and finally, the achieved effect has to be functionally validated. The reliability of the method enables multiple applications in oncology, including the detailed and efficient investigation of oncogenes, tumor suppressor genes, chromosomal translocations and other molecular changes. At the moment, available CRISPR-Cas9 protocols enable both in vitro and in vivo application. All these already made CRISPR-Cas9 one of the basic methods required for future-proof oncology research. PMID- 30027942 TI - Effect of unsaturated substituents in the reaction of Criegee intermediates with water vapor. AB - Criegee intermediates (CIs), formed in the reactions of unsaturated hydrocarbons with ozone, are very reactive carbonyl oxides and have recently been suggested as important oxidants in the atmosphere. In this work, we studied the substituent effect on the water monomer and dimer reaction with CIs which include up to three carbon atoms at the QCISD(T)/CBS//B3LYP/6-311+G(2d,2p) level. Our calculation showed that for saturated CIs with a hydrogen atom on the same side as the terminal oxygen atom, the reaction with water vapor would likely dominate the removal processes of these CIs in the atmosphere. On the other hand, for unsaturated CIs, the reactivity toward water vapor decreases compared to the saturated species allowing them to survive in humid atmospheric environments. We also evaluated the kinetic isotope effect in the reaction between CI and water vapor by performing calculations with deuterated water. We found that tunneling is not important and the kinetic isotope effect mainly comes from the difference in the zero point energy between water and deuterated water. PMID- 30027941 TI - [The effect of early psychotrauma on the behavior of patients undergoing active oncologic therapy]. AB - Physical and sexual trauma during childhood is a matter of public health problem. The consequences of cumulative childhood trauma follows on one's journey through life and are decisive for nerve development, social, emotional and cognitive functioning, and leads to the development of other health risk behaviors as well as to early death. 22-44% of patients in health care suffered from childhood trauma. This ratio is even higher in case of cancer patients. Traumatised oncological patients are particularly characterised by delaying tests or rejecting treatment even in the case of noticeable complaints. According to the recommendations of international literature, questions regarding childhood sexual abuse should be added to the routine exploration, however, screening is difficult because of the sensitivity of the subject. The aim of my study is to explore the frequent problems of traumatised cancer patients through presenting specific cases, in order to bring the specifically vulnerable group of patients closer to help, and mainly to deeper understanding. PMID- 30027943 TI - Synthesis, electronic structure and redox properties of the diruthenium sandwich complexes [Cp*Ru(MU-C10H8)RuCp*]x (x = 0, 1+; Cp* = C5Me5; C10H8 = naphthalene). AB - The dinuclear ruthenium complex [Cp*Ru(MU-C10H8)RuCp*] (1; Cp* = eta5-C5Me5) was prepared by reduction of the cationic precursor [Cp*Ru(eta6-C10H8)]PF6 with KC8. Diamagnetic 1 has a symmetric molecular structure with an anti-facial configuration of the Cp*Ru moieties coordinating to naphthalene. Density Functional Theory (DFT) studies showed an electronic structure similar to that of the analogous diiron complex [Cp*Fe(MU-C10H8)FeCp*]. Cyclic voltammetry and UV vis spectroelectrochemistry showed that 1 can be reversibly oxidized to 1+ and 12+. Chemical oxidation with [Cp2Fe]BArF4 afforded the paramagnetic compound [1]BArF4, which was investigated by EPR, single-crystal X-ray diffractometry and DFT calculations. Reaction of 1 with Brookhart's acid gave the hydride complex [3]BArF4, which was characterized spectroscopically and crystallographically. Cyclic voltammetry showed that [3]+ is converted back to 1 upon reduction and oxidation. PMID- 30027944 TI - A biosensor based on a 3D-DNA walking machine network and distance-controlled electrochemiluminescence energy transfer for ultrasensitive detection of tenascin C and lead ions. AB - An electrochemiluminescence biosensor was proposed based on distance-controlled energy transfer and a 3D-DNA walking machine network to significantly improve mass transport and offer an ultrasensitive and controllable strategy for the detection of different types of target. PMID- 30027945 TI - Photophysical properties of free-base and manganese(iii) N-confused porphyrins. AB - The photophysical properties of N-confused 5,10,15,20-tetraphenyl porphyrin derivatives have been studied using steady-state and time-resolved spectroscopic techniques. The peripherally substituted N-confused 5,10,15,20-tetraphenyl free base porphyrins (NCTPPs) show stronger B-band absorptions in DCM than in DMAc, while much stronger emissions have been observed in DMAc, which may be due to the shorter times (tauIC) of internal conversion from the B-band to the Q-band. The Q band spectral structures of NCTPPs in DCM are significantly different from those in DMAc. The introduction of ortho-OCH3 results in the strongest emission in both DCM and DMAc and significant fluorescence after N-methylation even though the emissions of other N-methyl complexes are quenched. The N-methylation of NCTPPs leads to a larger tauIC and shorter emission lifetime. The excited-state dynamics of manganese(iii) N-confused porphyrins (Mn(Cl)NCH3NCTPPs) are influenced by both peripheral substituents and manganese(iii) metal ion, and exhibit ultrafast intersystem crossing processes. PMID- 30027946 TI - Enhanced temperature stability in the R-T phase boundary with dominating intrinsic contribution. AB - In this study, 0.96KNNSx-0.01SZ-0.03BNZ ceramics (x = 0-0.08) were used as examples to illustrate the effects of phase boundaries on strain property and temperature stability. The addition of Sb5+ resulted in a rhombohedral-tetragonal (R-T) phase boundary at x = 0.05-0.07, as confirmed by temperature-dependent Raman spectra. In the R-T region, an improved piezoelectric constant (d33 = 390 440 pC N-1) and high unipolar strain (Suni = 0.14-0.15%) were observed due to the dominating intrinsic contribution. More importantly, a favorable temperature stability of Suni was observed in the ceramics with x = 0.05; for example, there was a slight variation of +5% to -13% when the temperature was increased from 20 degrees C to 180 degrees C. Through systematic investigations of composition and temperature-dependent strain, methods to improve Suni and consolidate its temperature stability in KNN-based ceramics were subsequently suggested. We believe that this study can promote the understanding and design of KNN-based ceramics with high strain and favorable temperature stability. PMID- 30027947 TI - Influence of the lattice constant on defects in cerium oxide. AB - The lattice constant has a crucial effect on the defect chemistry and defect kinetics in solid state materials. However, within density functional theory, some functionals perform badly in reproducing the experimental lattice constant. In this study, energies of defect formation, interaction and migration in the model system ceria were calculated for different lattice constants to investigate the impact on the energies. The GGA+U functional in the PBE and PBEsol parametrization as well as the hybrid functional HSE06 were applied and results are compared among these three commonly applied functionals. The results suggest a strong influence of the lattice constant on the energies especially regarding oxygen ion migration. This influence has an impact on the accurate prediction of defect properties from first principles but can also be utilized for specific tailoring of material properties by chemo-mechanical design. In addition, the issue of the correct lattice constant, which should be used in the defect calculations, is discussed in this paper. PMID- 30027948 TI - Structural, vibrational and thermal expansion properties of Sc2W4O15. AB - A novel oxide material with the formula of Sc2W4O15 and orthorhombic symmetry is synthesized by solid state reactions and its structure, composition, vibrational properties and thermal expansion are investigated and identified by temperature dependent X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), X-ray photoelectron spectrometry (XPS) and dilatometry. It is shown that the oxide material with an orthorhombic symmetry shows a similar structure to that of Sc2W3O12, but with W partially occupying the position of Sc, leading to not only the corner-sharing ScO6-WO4 connections but also the corner-sharing WO6-WO4 connections. Raman spectroscopic studies show that compared to Sc2W3O12, the FWHMs of most Raman modes in Sc2W4O15 increase due to the occupation of W6+ in the Sc3+ position. Besides, the W-O bonds in Sc2W4O15 are slightly harder than those in Sc2W3O12. An intrinsic thermal contraction in a wide range of temperatures (93-572 K) is demonstrated, which is attributed to the librational and translational vibrations of the corner-sharing polyhedra as well as the transverse vibrations of the bridging O atoms in the Sc-O-W and W-O-W linkages. PMID- 30027949 TI - Photophysics of indole upon X-ray absorption. AB - A photofragmentation study of gas-phase indole (C8H7N) upon single-photon ionization at a photon energy of 420 eV is presented. Indole was primarily inner shell ionized at its nitrogen and carbon 1s orbitals. Electrons and ions were measured in coincidence by means of velocity map imaging. The angular relationship between ionic fragments is discussed along with the possibility to use the angle-resolved coincidence detection to perform experiments on molecules that are strongly oriented in their recoil-frame. The coincident measurement of electrons and ions revealed fragmentation-pathway-dependent electron spectra, linking the structural fragmentation dynamics to different electronic excitations. Evidence for photoelectron-impact self-ionization was observed. PMID- 30027950 TI - Molecular dynamics simulations of mono-tethered particles at solid surfaces. AB - We use molecular dynamics simulations to study the behavior of mono-tethered nanoparticles on solid surfaces. In our model particle-particle and particle chain interactions are repulsive, while chain-chain interactions are attractive. Two surfaces are considered: the first one attracts particles and the other attracts chains. Excess adsorption isotherms are presented for both the surfaces and different lengths of tethers. The mechanism of adsorption is discussed. We find that depending on the assumed parameters the mono-tethered particles can be adsorbed as single particles or as different aggregates. Our main goal is to explore the structure of surface films. We show that the morphology of the adsorbed layer depends mainly on the type of the surface but the influence of the particle diameter, the chain length and the density is also important. We prove that the shape of aggregates changes near the substrate. For certain parameters the aggregates can break under the influence of the surface. PMID- 30027951 TI - Unexpected reactivity of cyclic perfluorinated iodanes with electrophiles. AB - We have found that cyclic perfluorinated iodanes react with electrophiles (E+ = Br, Cl, F, I) to afford perfluorinated E-RF compounds. This reactivity is unexpected since cyclic perfluorinated iodanes are considered as electrophilic reagents that normally react with nucleophiles (e.g. Nu- = SR, OR) to afford Nu RF products. The utility of this new transformation is demonstrated for a [18F]CF3CF2-containing compound which was prepared from [18F]XeF2 obtained from cyclotron produced [18F]fluoride. PMID- 30027953 TI - Rational design of atomically dispersed nickel active sites in beta-Mo2C for the hydrogen evolution reaction at all pH values. AB - Atomically dispersed Ni species on beta-Mo2C (Ni/beta-Mo2C) is designed and synthesized through a simple thermal treatment process. Benefitting from the synergistic effect between Ni species and beta-Mo2C, Ni/beta-Mo2C exhibits high activities for the HER at all pH values. PMID- 30027954 TI - Complexation of asymmetric diborenes with magnesium bromide. AB - The synthesis of neutral Mg complexes of asymmetric diborenes is reported. X-ray diffraction analysis reveals that the Mg center is unsymmetrically coordinated to the B2 units of diborenes. Theoretical calculations manifest the donation of electrons from the pi-type orbitals of diborenes to an empty orbital of Mg. PMID- 30027952 TI - Insights into beta-ketoacyl-chain recognition for beta-ketoacyl-ACP utilizing AHL synthases. AB - Beta-ketoacyl-ACP utilizing enzymes in fatty acid, polyketide and acyl-homoserine lactone biosynthetic pathways are important targets for developing antimicrobial, anticancer and antiparasitic compounds. Published reports on successful isolation of beta-ketoacyl-ACPs in a laboratory remain scarce to date and thus most beta ketoacyl-ACP utilizing enzymes are routinely characterized using small molecule substrates in lieu of the bonafide 3-oxoacyl-ACPs. We report the systematic investigation into the electronic, geometric and spatial aspects of beta-ketoacyl chain recognition to develop 3-oxoacyl-ACP substrate mimics for two beta-ketoacyl ACP utilizing quorum signal synthases. PMID- 30027955 TI - On the importance of non-covalent interactions for porous membranes: unraveling the role of pore size. AB - Membrane-based gas separation technology is of crucial importance in the current economy and nanoporous graphene, given its single-atomic layer, is an essential building-block material to achieve efficiency towards permeability and selectivity for such processes. Classically, pore size is the main feature that governs the diffusion energy barrier. Its nature, nevertheless, is also affected by other non-negligible physical mechanisms not yet discussed. Here we propose a theoretical study on the role of non-covalent interactions towards H2 diffusion through two graphene-based membranes. Symmetry-Adapted Perturbation Theory (SAPT) was used to investigate the total interaction energy and its physically meaningful components (electrostatics, exchange, induction and dispersion). The study reveals the importance of quantum effects such as polarization and electron delocalization in order to counterbalance the abiding idea of pore size being the dominant factor accounting for the energy barrier. These results have important implications for the rational design of efficient nanoporous devices for separation applications. PMID- 30027956 TI - Understanding the function of water during the gelation of globular proteins by temperature-dependent near infrared spectroscopy. AB - Water plays an indispensable role in the gelation of proteins, but its function still remains unclear. In this work, the variation of water species with the structural changes of globular proteins was investigated using temperature dependent near infrared (NIR) spectroscopy. Ovalbumin (OVA) was used as a model protein, which forms a gel-like structure as the temperature increases through three phases, i.e., phase I (native), phase II (molten globule state), and phase III (gel state). The structural change and the content variation of different water species in the three phases of gelation were analyzed by two-dimensional correlation NIR spectroscopy and Gaussian fitting. A decrease in the water species with two hydrogen bonds (S2) was found and the change follows the same phases as OVA. In the first two phases, the change occurs after those of other water species but in the third phase, the change is faster than that of free water species. The result indicates that in the native and molten globule states, S2 is located in the hydration shell of OVA to maintain the stability of the protein structure, and then in the gel state, high temperature weakens the hydrogen bonding of S2 and leads to the destruction of the hydration shell, making OVA clusters form a gel structure. PMID- 30027957 TI - Scanning tunneling microscopy investigations of unoccupied surface states in two dimensional semiconducting beta-?3 * ?3-Bi/Si(111) surface. AB - Two-dimensional surface structures often host a surface state in the bulk gap, which plays a crucial role in the surface electron transport. The diversity of in gap surface states extends the category of two-dimensional systems and gives us more choices in material applications. In this article, we investigated the surface states of beta-?3 * ?3-Bi/Si(111) surface by scanning tunneling microscopy. Two nearly free electron states in the bulk gap of silicon were found in the unoccupied states. Combined with first-principles calculations, these two states were verified to be the Bi-contributed surface states and electron accumulation-induced quantum well states. Due to the spin-orbit coupling of Bi atoms, Bi-contributed surface states exhibit free-electron Rashba splitting. The in-gap surface states with spin splitting can possibly be used for spin polarized electronics applications. PMID- 30027959 TI - Work function: a determining factor of the photodegradation rate of methyl orange via hollow octadecahedron Cu2O crystals. AB - Currently, photocatalytic degradation of methyl orange by Cu2O nanocrystals with different morphologies is mainly attributed to their narrow bandgap (Eg) and highly active lattice facets. Herein, three different sizes of hollow octadecahedron Cu2O crystals, with different degrees of exposed {110} facets, were developed and exhibited excellent, stable photocatalytic degradation performances. This study has shown that the intermediates in the photocatalytic degradation process are mainly peroxy radicals from the reaction of excited electrons in the Cu2O conduction band with oxygen molecules adsorbed on the surface. In the photodegradation process of the hollow octadecahedron (HO) Cu2O crystals, the excited-state electrons must break away from the work function restriction before participating in the reaction. HO-2 has achieved the best photocatalytic properties due to its smallest work function as a determining factor affecting the photocatalytic activity. PMID- 30027958 TI - A novel design of a polynuclear co-delivery system for safe and efficient cancer therapy. AB - We report a novel and easy-to-fabricate polynuclear nanoparticle based on the collaborative re-assembly of nanoparticles as a robust chemogene co-delivery platform. Specifically, the polynuclear nanoparticle carrying DOX and siBcl-2 exerts remarkable co-delivery efficiency, increases tumour cell apoptosis and inhibits tumour cell proliferation in vitro and in vivo. PMID- 30027960 TI - Corrosion inhibition performance of newly synthesized 5-alkoxymethyl-8 hydroxyquinoline derivatives for carbon steel in 1 M HCl solution: experimental, DFT and Monte Carlo simulation studies. AB - Three new organic compounds primarily based on 8-hydroxyquinoline have been successfully synthesized and characterized via different spectroscopic methods (FTIR, 1H, and 13C NMR). The synthesized compounds, namely 5-propoxymethyl-8 hydroxyquinoline (PMHQ), 5-methoxymethyl-8-hydroxyquinoline (MMHQ) and 5 hydroxymethyl-8-hydroxyquinoline (HMHQ), were evaluated as corrosion inhibitors for carbon steel in 1 M HCl solution using electrochemical impedance spectroscopy, potentiodynamic polarization and weight loss measurements at 298 K. Electrochemical measurements confirmed that the newly synthesized 5-alkoxymethyl 8-hydroxyquinoline derivatives are mixed type corrosion inhibitors and confirmed maximum protection efficiencies of 94, 89 and 81% for PMHQ, MMHQ, and HMHQ, respectively, at the optimum concentration of 10-3 M. The EIS spectra confirmed a slightly depressed semi-circle profile with a single time constant in Bode diagrams for the three organic compounds over the whole concentration and temperature ranges studied. The adsorption of PMHQ, MMHQ, and HMHQ on the carbon steel surface followed the Langmuir adsorption isotherm. In addition, the kinetic and thermodynamic parameters for carbon steel corrosion and inhibitor adsorption, respectively, were determined and discussed. Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) analyses supported the formation of a protective film on carbon steel in the presence of PMHQ, MMHQ, and HMHQ. Density functional theory calculations (DFT) showed that the effectiveness of the inhibitive actions of the studied compounds correlates well with their electron donating ability, whilst Monte Carlo simulations revealed that the extent and favourability of adsorption of inhibitor molecules on the carbon steel surface establish their corrosion inhibition performances. PMID- 30027961 TI - Real-time mass-spectrometric screening of droplet-scale electrochemical reactions. AB - A droplet-scale, real-time electrochemical reaction screening platform based on droplet spray ionization mass spectrometry (DSI-MS) has been developed. The N,N dimethylaniline (DMA) radical cation with a half-life of microseconds was readily detected by MS during the electrooxidation of DMA, and the subsequent reactions were followed in real time for minutes. PMID- 30027962 TI - Open nanofluidic films with rapid transport and no analyte exchange for ultra-low sample volumes. AB - Moving to ultra-low (<100 nL) sample volumes presents numerous challenges, many of which can be resolved by implementation of open nanofluidic films. These nanofluidic films are fabricated using a hexagonal network of gold-coated open microchannels which capture all of the following innovative advantages: (1) sample volumes of <100 nL cm-2; (2) zero analyte exchange and loss with the film materials; (3) rapid and omni-directional wicking transport of >500 nL min-1 per square of film; (4) ultra-simple roll-to-roll fabrication; (5) stable and bio compatible super-hydrophilicity for weeks in air by peptide surface modification. Validation includes both detailed in vitro characterization and in vivo validation with sweat transport from the human skin. Sampling times (skin-to sensor) of <3 min were achieved, setting new benchmarks for the field of wearable sweat sensing. This work addresses significant challenges for sweat biosensing, or for any other nano-liter regime (<100 nL) fluid sampling and sensing application. PMID- 30027963 TI - Two-dimensional self-assembled nanostructures of nucleobases and their related derivatives on Au(111). AB - The construction of two-dimensional (2D) self-assembled nanostructures has been one of the considerably interesting areas of on-surface chemistry in the past few decades, and has benefited from the rapid development and improvement of scanning probe microscopy techniques. In this research field, many attempts have been made in the controllable fabrication of well-ordered and multifunctional surface nanostructures, which attracted interest because of the prospect for artificial design of functional molecular nanodevices. DNA and RNA are considered to be programmable self-assembly systems and it is possible to use their base sequences to encode instructions for assembly in a predetermined fashion at the nanometer scale. As important constituents of nucleic acids, nucleobases, with intrinsic functional groups for hydrogen bonding, coordination bonding, and electrostatic interactions, can be employed as a potential system for the versatile construction of various biomolecular nanostructures, which may be used to structure the self-assembly of DNA-based artificial molecular constructions and play an important role in novel biosensors based on surface functionalization. In this article, we will review the recent progress of on-surface self-assembly of nucleobases and their derivatives together with different reactants (e.g., metals, halogens, salts and water), and as a result, various 2D surface nanostructures are summarized. PMID- 30027964 TI - Activation of Kagome lattice-structured Cu3V2O7(OH)2.2H2O volborthite via hydrothermal crystallization for boosting visible light-driven water oxidation. AB - We report a feasible strategy via hydrothermal crystallization to activate Kagome lattice-structured Cu3V2O7(OH)2.2H2O volborthite mineral as a stable visible light-driven photocatalyst. It was demonstrated to play a crucial role in stimulating absorption ability and photodegradation performance for the removal of methylene blue present in high concentration. In contrast, direct calcination was almost ineffective, whereas post-calcination was significantly detrimental. Moreover, the photocatalytic water oxidation activity of hydrothermally crystallizated volborthite was comparable to that of BiVO4, and it was clearly higher than those of WO3 and g-C3N4 from aqueous NaIO3 solution. By further in situ decoration with an optimum amount of CoOx cocatalysts (i.e., 2 wt%), the oxygen evolution rate of volborthite was greatly enhanced, and it was 1.6-fold, 1.8-fold and 2.9-fold higher than those of BiVO4, WO3 and g-C3N4, respectively. The importance of hydrothermal crystallization can be elucidated in terms of water-Kagome lattice structure interactions involving built-in intrinsic electric field and formation of single hydrogen bonds. PMID- 30027965 TI - 1,2-Diarylation of alkenes with aryldiazonium salts and arenes enabled by visible light photoredox catalysis. AB - A mild and general visible light photoredox catalysis-induced intermolecular three-component alkene 1,2-diarylation involving aryl C(sp2)-H functionalization is described. The key to controlling the chemoselectivity toward alkene 1,2 diarylation is the employment of a 2,2'-bipyridine base, thus allowing the formation of two new C(sp3)-C(sp2) bonds via aryl radical formation from aryldiazonium salts, addition across the C[double bond, length as m-dash]C bonds, and aryl C(sp2)-H functionalization cascades. PMID- 30027966 TI - Feedstock-dependent nitrogen configurations of nitrogen-doped single-walled carbon nanotubes in a CVD process. AB - The modification of nitrogen configurations is a viable way to control the electronic properties of nitrogen-doped single-walled carbon nanotubes (N-doped SWCNTs). N-doped SWCNTs were synthesized by a conventional chemical vapor deposition process with a mixed carbon/nitrogen (C/N) feedstock. While higher feedstock flow rates promote the formation of encapsulated N2 molecules, lower flow rates show a predominance of pyridinic and graphitic nitrogen structures as revealed by X-ray photoemission spectroscopy. Therefore, the nitrogen doping in the sp2 carbon network can be controlled by the flow rate of the C/N feedstock. PMID- 30027967 TI - High-precision nanofabrication technology for metal nanoparticle ensembles using nanotemplate-guided thermal dewetting. AB - We present a hybrid nanofabrication technology for realizing single-crystalline metal nanoparticle ensembles, such as trimers, heptamers and periodic arrays; well-suited for nanoplasmonics applications. Top-down engineered nanotemplates result in the deterministic formation of isolated polycrystalline gold islands with precise volume and position, which are transformed into single-crystalline nanoparticles using bottom-up self-assembly based on nanotemplate-guided thermal dewetting. PMID- 30027968 TI - Crystallisation of freeze-dried sucrose in model mixtures that represent the amorphous sugar matrices present in confectionery. AB - Recrystallisation occurs frequently in confectionery. More information on sucrose re-crystallisation will aid our understanding of popular foods like chocolate. However, progress has been limited due the lack of a robust method for the production of amorphous sucrose, with known purity. Poor control has led to the glass transition temperatures (Tg's) for amorphous sucrose varying between 48-78 degrees C in the literature. Our objective was to investigate the recrystallization of sucrose in the presence of lactose, NaCl and water. The purity of sucrose was confirmed by ion chromatography, polarimetry and differential scanning calorimetry. Amorphous sucrose was prepared by freeze drying 10% w/v aqueous solutions. Fisher (99.7%) and Silver Spoon (98.4%) sucrose samples melted at 186 +/- 0.6 degrees C & 189 +/- 0.3 degrees C respectively. For the Fisher sample the absence of invert sugars and low mineral content allowed the observation of a small endotherm (~ 150 degrees C). The Tg of amorphous sucrose was 58.3 +/- 1.1 degrees C with a recrystallization enthalpy (DeltaHcrys) of 72.8 +/- 6.0 J g-1. NaCl reduced both the Tg (54.8 +/- 1.8 degrees C) and the DeltaHcrys (35.7 +/- 3.8 J g-1) without affecting the onset temperature of sucrose's re-crystallization (Tcrys, 129.5 +/- 6.9 degrees C), suggesting that a proportion of the sample remained amorphous. The presence of water (1.6 +/- 0.07%) inside the hermetically sealed pans caused an earlier onset of Tg (52.3 +/- 1.3 degrees C) and Tcrys (85.1 +/- 4.0 degrees C), as well as lowering DeltaHcrys (45.2 +/- 2.4 J g-1) compared to samples contained in pin holed pans (where evaporation was possible). The presence of lactose inhibited the crystallization of sucrose completely. On the basis of this study, it is apparent that sucrose crystallization is highly dependent on the presence of other common food ingredients within the matrix. PMID- 30027969 TI - Enhanced magnetic microcytometer with 3D flow focusing for cell enumeration. AB - We report the design and characterization of a lateral and vertical hydrodynamic focusing feature for whole cell detection on a miniaturized flow cytometer. The developed system, based on magnetic sensing, incorporates spin valve sensors on the bottom of the microfluidic channels that detect cells labeled with magnetic beads. An adaptable 3D hydrodynamic focusing system was developed that pushes labeled cells towards the bottom of the microchannel, closer to the sensors, allowing increased signal amplitude for cells labeled with magnetic beads and enhanced discrimination of labeled cells. Fluorescence microscopy indicates that the lateral and vertical hydrodynamic focusing effect was adequately implemented, consistent with simulation predictions. The sensitivity of the system to detect labeled cells was improved by at least two-fold. By estimating the coverage of magnetic beads on cells, the signal from labeled cells could be predicted using a mathematical model, which also demonstrated the sensitivity of the signal to the height of the cells relative to the sensor. The system is versatile allowing interchangeable flow rates for cells with different diameters. PMID- 30027971 TI - Distributions of manganese in diverse human cancers provide insights into tumour radioresistance. AB - Many cancers are variably resistant to radiation treatment: some patients die within months, while others with the same tumour type and equivalent radiation protocol, survive for years. To determine why some tumours are radiosensitive, while others return after radiotherapy, requires new non-traditional approaches to oncology. Herein we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to test the hypothesis that Mn functions as a metabolic radioprotector and is an apex predictor of tumour radioresponsiveness. The genesis of this hypothesis lies in microbial and in vitro chemical systems. We measured the levels and spatial distributions of Mn in tissue sections of 7 specifically chosen tumour types with distinct clinically documented radioresponsiveness and patient outcomes, namely testis, lung, brain, skin, mesothelium, prostate and breast. Mn levels varied nearly 60-fold between individual tumours, from 0.02 MUg g-1 to 1.15 MUg g-1. The most radiosensitive cancer type, (testis), had the lowest Mn levels and the highest patient survival. Tumours at the radioresistant extreme (glioblastomas and melanomas) had the highest Mn levels and lowest patient survival. A direct association was found between total Mn contents and their variation, and clinically-inferred radioresponsiveness in each of these 7 tumour types, while no such association existed with Cu, Zn or Fe. The LA-ICP-MS data provided unique patient-specific 2D maps of the spatial metallomic heterogeneity of cancer cells and their stroma. These maps have fundamental and far reaching clinical implications. For the first time, Mn-based tumour data may allow for more precise radiodosages and improved treatment for the individual patient. PMID- 30027972 TI - Identifying pragmatic quasi-harmonic electronic structure approaches for modeling molecular crystal thermal expansion. AB - Quasi-harmonic approaches provide an economical route to modeling the temperature dependence of molecular crystal structures and properties. Several studies have demonstrated good performance of these models, at least for rigid molecules, when using fragment-based approaches with correlated wavefunction techniques. Many others have found success employing dispersion-corrected density functional theory (DFT). Here, a hierarchy of models in which the energies, geometries, and phonons are computed either with correlated methods or DFT are examined to identify which combinations produce useful predictions for properties such as the molar volume, enthalpy, and entropy as a function of temperature. The results demonstrate that refining DFT geometries and phonons with single-point energies based on dispersion-corrected second-order Moller-Plesset perturbation theory can provide clear improvements in the molar volumes and enthalpies compared to those obtained from DFT alone. Predicted entropies, which are governed by vibrational contributions, benefit less clearly from the hybrid schemes. Using these hybrid techniques, the room-temperature thermochemistry of acetaminophen (paracetamol) is predicted to address the discrepancy between two experimental sublimation enthalpy measurements. PMID- 30027970 TI - The tactile receptive fields of freely moving Caenorhabditis elegans nematodes. AB - Sensory neurons embedded in skin are responsible for the sense of touch. In humans and other mammals, touch sensation depends on thousands of diverse somatosensory neurons. By contrast, Caenorhabditis elegans nematodes have six gentle touch receptor neurons linked to simple behaviors. The classical touch assay uses an eyebrow hair to stimulate freely moving C. elegans, evoking evasive behavioral responses. This assay has led to the discovery of genes required for touch sensation, but does not provide control over stimulus strength or position. Here, we present an integrated system for performing automated, quantitative touch assays that circumvents these limitations and incorporates automated measurements of behavioral responses. The Highly Automated Worm Kicker (HAWK) unites a microfabricated silicon force sensor holding a glass bead forming the contact surface and video analysis with real-time force and position control. Using this system, we stimulated animals along the anterior-posterior axis and compared responses in wild-type and spc-1(dn) transgenic animals, which have a touch defect due to expression of a dominant-negative alpha-spectrin protein fragment. As expected from prior studies, delivering large stimuli anterior and posterior to the mid-point of the body evoked a reversal and a speed-up, respectively. The probability of evoking a response of either kind depended on stimulus strength and location; once initiated, the magnitude and quality of both reversal and speed-up behavioral responses were uncorrelated with stimulus location, strength, or the absence or presence of the spc-1(dn) transgene. Wild type animals failed to respond when the stimulus was applied near the mid-point. These results show that stimulus strength and location govern the activation of a characteristic motor program and that the C. elegans body surface consists of two receptive fields separated by a gap. PMID- 30027973 TI - Alignment of twisted nanoribbons formed by C17H35CO-Val-Ala sodium salts. AB - C17H35CO-l-Val-l-Ala and C17H35CO-d-Val-d-Ala sodium salts can form physical gels in water, and self-assemble into right- and left-handed twisted nanoribbons, respectively. FT-IR and 1H NMR spectra indicate that the H-bonding between the neighboring valine residues and electrostatic interactions of carboxylate groups play important roles in the formation of helical nanoribbons. Circular dichroism characterization and theoretical chemical calculations indicate that the dipeptide segments pack in a helical manner. X-ray diffraction patterns and theoretical chemical simulations indicate an interdigitated bilayer structure. The hydrogels exhibit a thixotropic behavior. The twisted nanoribbons are able to align under directional force. PMID- 30027974 TI - The radical acylarylation of N-arylacrylamides with aliphatic aldehydes using the photolysis of hypervalent iodine(iii) reagents. AB - This article describes a variety of 3,3-disubstituted 2-oxindoles that bear carbonyl groups, which are efficiently obtained from a radical reaction between N arylacrylamides and aliphatic aldehydes. The reaction is initiated by the photolysis of hypervalent iodine(iii) reagents and proceeds smoothly under mild, metal-free conditions. PMID- 30027975 TI - Structure and properties of polydisperse polyelectrolyte brushes studied by self consistent field theory. AB - Two complementary self-consistent field theoretical approaches are used to analyze the equilibrium structure of binary and ternary brushes of polyions with different degrees of polymerization. Stratification in binary brushes is predicted: the shorter chains are entirely embedded in the proximal sublayer depleted of end-points of longer chains while the peripheral sublayer contains exclusively terminal segments of longer chains. The boundary between sublayers is enriched with counterions that neutralize the residual charge of the proximal sublayer. These analytical predictions for binary brushes are confirmed and extended to ternary brushes using the numerical Scheutjens-Fleer approach. PMID- 30027976 TI - Diisopropylethylamine-triggered, highly efficient, self-catalyzed regioselective acylation of carbohydrates and diols. AB - A diisopropylethylamine (DIPEA)-triggered, self-catalyzed, regioselective acylation of carbohydrates and diols is presented. The hydroxyl groups can be acylated by the corresponding anhydride in MeCN in the presence of a catalytic amount of DIPEA. This method is comparatively green and mild as it uses less organic base compared with other selective acylation methods. Mechanistic studies indicate that DIPEA reacts with the anhydride to form a carboxylate ion, and then the carboxylate ion could catalyze the selective acylation through a dual H bonding interaction. PMID- 30027977 TI - Highly efficient synthesis of benzodioxins with a 2-site quaternary carbon structure by secondary amine-catalyzed dual Michael cascade reactions. AB - Salicylic acids and substituted ynones were employed as substrates to afford a class of valuable 4H-benzo[d][1,3]dioxin-4-ones with a 2-site quaternary carbon structure in up to 92% yield by secondary amine-catalyzed dual Michael cascade reactions under mild reaction conditions. The alpha,beta-unsaturated ketone as the key intermediate in the cascade process was successfully separated and characterized. As a result, a new reaction route for ynone species is demonstrated, which is totally different from the existing allenamine activation model. PMID- 30027978 TI - Predicting the structures and associated phase transition mechanisms in disordered crystals via a combination of experimental and theoretical methods. AB - Disordered materials make up a large proportion of condensed phase systems, but the difficulties in describing their structures and molecular dynamics limit their potential applications. Disordered crystalline systems, also known as plastic crystals, offer a unique perspective into these factors because the systems retain a degree of crystallinity, reducing the degrees of freedom that must be explored when interpreting the results. However, while disordered crystals do diffract X-rays, it is difficult to fully resolve meaningful crystalline structures, with the best scenario resulting in lattice parameters. In this study, we use a combination of experimental terahertz time-domain spectroscopy, and theoretical solid-state ab initio density functional theory and molecular dynamics simulations to fully elucidate the structures and associated dynamics of organic molecular solids. The results highlight that this combination provides a complete description of the energetic and mechanistic pathways involved in the formation of disordered crystals, and highlights the importance of low-frequency dynamics in their properties. Finally, with structures fully determined and validated by the experimental results, recent progress into anharmonic calculations, namely the quasi-harmonic approximation method, enables full temperature and pressure-dependent properties to be understood within the framework of the potential energy hyper-surface structure. PMID- 30027979 TI - Pd(ii)-Catalyzed aerobic 1,2-difunctionalization of conjugated dienes: efficient synthesis of morpholines and 2-morpholones. AB - A novel and efficient methodology concerning the Pd(ii)-catalyzed intermolecular difunctionalization of conjugated dienes is reported to synthesize a series of functionalized morpholines and 2-morpholones. Widely distributed and easily obtained beta-amino alcohols and alpha-amino acids, as starting nitrogen and oxygen sources, are successfully applied in the difunctionalization of conjugated dienes respectively. The majority of the desired products were obtained in moderate to excellent yields. Oxygen was successfully employed as a terminal oxidant. Further transformation of the generated products allowed for the expansion of structural diversity. PMID- 30027980 TI - Large magnetoelectric effects mediated by electric-field-driven nanoscale phase transformations in sputtered (nanoparticulate) and electrochemically dealloyed (nanoporous) Fe-Cu films. AB - Large magnetoelectric effects are observed in as-sputtered (nanoparticulate-like) and electrochemically dealloyed (nanoporous) 200 nm thick Fe-Cu films. Application of positive voltages decreases both the saturation magnetization (MS) and coercivity (HC) of the films, while negative voltages cause the reverse effect (increase of MS and HC). The relative variations are as high as 20% for MS and beyond 100% for HC, both for the as-sputtered and dealloyed states. These changes in magnetic properties are caused by controlled and reversible electric field-driven nanoscale phase transformations between face-centered cubic (fcc) and body-centered cubic (bcc) structures. These phase transitions are in turn due to selective redox reactions induced by the applied voltage, which can be regarded as a "magnetoionic effect." The controlled tuning of HC and MS with the moderate values of applied voltage, together with the sustainable composition of the investigated alloys (not containing noble metals, as opposed to many previous works on magnetoelectric effects in thin films), pave the way towards the implementation of magnetic and spintronic devices with enhanced energy efficiency and functionalities. PMID- 30027981 TI - Application of a bodipy-C70 dyad in triplet-triplet annihilation upconversion of perylene as a metal-free photosensitizer. AB - A bodipy-C70 dyad was synthesized and applied in triplet-triplet annihilation (TTA) upconversion of perylene as a novel metal-free organic photosensitizer. The photophysical processes were investigated by the methods of steady-state UV-Vis absorption and fluorescence spectroscopy, nanosecond time-resolved transient absorption spectroscopy, cyclic voltammetry, and density functional theory calculations. The bodipy-C70 dyad showed an increased molar extinction coefficient up to 82 300 mol-1 cm-1 at 518 nm compared with the C70 monomer. With photo-excitation of the bodipy moiety at 532 nm, the intramolecular singlet singlet energy transfer between bodipy and C70 units was efficient with a quantum yield of nearly 100%, and the lowest triplet state of the dyad was subsequently populated via ISC of the C70 moiety, with a lifetime of ca. 80 MUs in toluene. Electrochemical investigation suggested that the intramolecular electron transfer of the excited dyad was thermodynamically prohibited in toluene due to the positive DeltaGCS for charge-separation. With the presence of perylene in solution as the triplet energy acceptor and emitter, the TTA upconverted fluorescence was observed with a maximum quantum yield of 10.3%. The overall upconversion capability of 4417 M-1 cm-1 exceeded that of C70 approximately two fold. Moreover, the bodipy-C70 dyad also exhibited an enhanced optical stability under intense irradiation. All data indicated that the dyad was another ideal photosensitizer for TTA upconversion of perylene in the fullerene derivative family. PMID- 30027982 TI - Bulk synthesis of silver-head colloidal rodlike micromotors. AB - Colloidal particles with asymmetric catalytic activities are emerging micro/nanomotors that harvest chemical energy for propulsion in fluids. It is of general interest to produce such particles with high performance, in large quantity and at low cost. In this paper, we present a facile bulk method to synthesize silver-head colloidal silica rods. These particles self-propel towards their active sites by reacting with hydrogen peroxide, and the velocity is tuned via the fuel concentration. We show that these motors are highly efficient; compared to the currently available chemical-phoretic micro/nanomotors they show similar performance of self-propulsion at fuel concentrations that are two orders of magnitude smaller. PMID- 30027983 TI - Multiscale porous molybdenum phosphide of honeycomb structure for highly efficient hydrogen evolution. AB - The hydrogen evolution reaction (HER) based on electrochemical water splitting is considered a promising strategy to produce clean and sustainable hydrogen energy. Searching for non-noble metal based electrocatalysts with high efficiency and durability toward the HER is vitally necessary. In this work, we report a novel method for synthesizing molybdenum phosphide (MoP) supported on multiscale porous honeycomb carbon (MoP@HCC) and the application of this catalyst material in acidic media for water electrolysis. Due to the unique structure of the catalyst material, the as-prepared MoP@HCC shows remarkable electrocatalytic activity and stability in 0.5 M H2SO4 aqueous solution. The hybrid catalyst could deliver a current density of 10 mA cm-2 at a low overpotential of 129 mV, with an onset overpotential of 69 mV and a Tafel slope of 48 mV dec-1, outperforming most of the current noble-metal-free electrocatalysts. This study demonstrates an effective way for multiscale control of the MoP structure via overall consideration of the mass transport, and the accessibility, quantity and capability of active sites toward the HER. PMID- 30027984 TI - Plasmonic circular dichroism of vesicle-like nanostructures by the template-less self-assembly of achiral Janus nanoparticles. AB - Chiral nanostructures have been attracting extensive interest in recent years primarily because of the unique materials properties that can be exploited for diverse applications. In this study, gold Janus nanoparticles, with hexanethiolates and 3-mercapto-1,2-propanediol segregated on the two hemispheres of the metal cores (dia. 2.7 +/- 0.4 nm), self-assembled into vesicle-like, hollow nanostructures in both water and organic media, and exhibited apparent plasmonic circular dichroism (PCD) absorption in the visible range. This was in contrast to individual Janus nanoparticles, bulk-exchange nanoparticles where the two ligands were homogeneously mixed on the nanoparticle surface, or nanoparticles capped with only one kind of ligand. The PCD signals were found to become intensified with increasing coverage of the 3-mercapto-1,2-propanediol ligands on the nanoparticle surface. This was accounted for by the dipolar property of the structurally asymmetrical Janus nanoparticles, and theoretical simulations based on first principles calculations showed that when the nanoparticle dipoles self-assembled onto the surface of a hollow sphere, a vertex was formed which gave rise to the unique chiral characteristics. The resulting chiral nanoparticle vesicles could be exploited for the separation of optical enantiomers, as manifested in the selective identification and separation of d alanine from the l-isomer. PMID- 30027985 TI - Ambient N2 fixation to NH3 electrocatalyzed by a spinel Fe3O4 nanorod. AB - Industrially, NH3 is mainly produced via the Haber-Bosch process which is not only energy-consuming but emits a large amount of CO2. Electrochemical reduction is regarded as an environmentally-benign alternative for sustainable NH3 synthesis, and its efficiency heavily depends on the identification of Earth abundant catalysts with high activity for the N2 reduction reaction (NRR). In this work, we report that a spinel Fe3O4 nanorod on a Ti mesh (Fe3O4/Ti) acts as an efficient and durable NRR electrocatalyst under ambient conditions. When tested in 0.1 M Na2SO4, such Fe3O4/Ti achieves a high faradaic efficiency of 2.6% and a NH3 yield 5.6 * 10-11 mol s-1 cm-2 and at -0.4 V vs. a reversible hydrogen electrode. PMID- 30027986 TI - Thermoresponsive luminescence properties of polyfluorinated bistolane-type light emitting liquid crystals. AB - We developed and characterized four polyfluorinated bistolane derivatives. These compounds, which possess either two alkoxy substituents or an alkoxy group and a bromine atom in their two molecular terminals, were synthesized from readily available 4-alkoxy-1-ethynylbenzene with a facile three-step procedure. Their thermodynamic and photophysical properties were evaluated in detail, and they were found to display both liquid-crystalline (LC) and photoluminescence properties. Remarkably, the photoluminescence behaviors dramatically changed during the thermal phase transition between the crystal and LC phases. Thus, these polyfluorinated bistolanes may be promising candidates for thermoresponsive luminous molecules. PMID- 30027987 TI - Investigations into the biosynthesis of the antifungal strobilurins. AB - The strobilurins are important antifungal metabolites isolated from a number of basidiomycetes and have been valuable leads for the development of commercially important fungicides. Isotopic labelling studies with early and advanced intermediates confirm for the first time that they are produced via a linear tetraketide, primed with the rare benzoate starter unit, itself derived from phenylalanine via cinnamate. Isolation of a novel biphenyl metabolite, pseudostrobilurin B, provides evidence for the involvement of an epoxide in the key rearrangement to form the beta-methoxyacrylate moiety essential for biological activity. Formation of two bolineol related metabolites, strobilurins Y and Z, also probably involves epoxide intermediates. Time course studies indicate a likely biosynthetic pathway from strobilurin A, with the simplest non subsubstituted benzoate ring, to strobilurin G with a complex dioxepin terpenoid derived substituent. Precursor-directed biosynthetic studies allow production of a number of novel ring-halogenated analogues as well as a new pyridyl strobilurin. These studies also provide evidence for a non-linear biosynthetic relationship between strobilurin A and strobilurin B. PMID- 30027988 TI - Impact of Epilepsy on Adolescents in a Rural Nigerian Community: A Case-Control Study. AB - BACKGROUND: Epilepsy is associated with impaired physical, psychological and social functioning. Assessing its impact on these parameters is important to improving the wellbeing of those with the disorder. OBJECTIVE: To assess the impact of epilepsy on the physical, psychological and social status of adolescents in a rural community. METHODS: Adolescents with epilepsy (Subjects) were identified in a community house to house survey. Controls (adolescents without epilepsy) matched for age and sex were randomly selected from the community. Information obtained from the subjects, controls and their care givers using a structured questionnaire included: Age, Sex, Social Class, Knowledge of epilepsy, Characteristics of epilepsy, Treatment options utilized, Health-Related Quality of Life (HRQOL), Body Mass Index (BMI), Academic performance and Epilepsy related problems. RESULTS: Eighteen subjects, 10.5/1000 of the adolescent (10-19 years) population, had epilepsy. The mean age was 16.7+/- 2.6 years and 16.3+/- 2.6 years for the subjects and controls respectively. Most of the subjects were males (83.3%). All the subjects had generalized epilepsy, were on traditional medication and none was on orthodox medical therapy. Occurrence of seizures, cost of accessing orthodox medical treatment and stigma were the major problems identified. Ingestion of traditional medication was the commonest modality for overcoming the major problems identified. Seven (38.8%) were underweight but it was not significant (p>0.05). Epilepsy was significantly associated with impaired HRQOL, academic performance and social relationships (p>0.05). CONCLUSION: Epilepsy had a negative impact on the psychosocial and academic status of adolescents. It highlights the need to provide comprehensive adolescent health and social services in epilepsy management. PMID- 30027989 TI - Paediatric Septic Arthritis in a Nigerian Tertiary Hospital: A 5-Year Clinical Review. AB - BACKGROUND: Septic arthritis is a relatively common condition in the paediatric population. It is both a medical and a surgical emergency with potential high morbidity. This disabling disease requires early diagnosis and prompt management for optimal outcome. OBJECTIVE: This study determined the epidemiological pattern of septic arthritis and analysed factors affecting morbidity and mortality in the paediatric population. MATERIALS AND METHODS: Retrospective data was obtained over a 5-year period in NKST rehabilitation hospital, Mkar, Nigeria. Forty patients aged 0-17 years met the criteria for inclusion. Joint aspirates were taken for microbiologic investigation. Data was analysed using SPSS version 21. RESULTS: A total of 40 patients with 48 septic joints were studied. Twenty-two (55.0%) were males and eighteen (45.0%) were female with a male to female ratio of 1.2:1. The hip was the commonest 24(50.0%) joint involved; followed by the knee joint 18(37.5%), shoulder joint 4 (8.4%) and ankle joint 2(4.2%). Result of aspirate cultures yielded Staphylococcus aureus in 34 (70.8%) cases, Escherichia coli in 8 (16.7%), Haemophillus influenzae in 2(4.2%) and no growth was obtained in 4(8.3%) cases. Complications encountered after follow up include stiffness in 8(16.6%) joints, pain and stiffness in 2(4.1%) joint and bony ankylosis in 4(8.4%) joints and limb shortening in 2(4.1%) joints. CONCLUSION: The keys to proper management are a high index of suspicion in any child with painful joint dysfunction and strict adherence to the principles of treatment. With prompt treatment, all complications might be avoided, and normal joint function and future growth may be preserved. PMID- 30027990 TI - Characteristics of Critically Ill Elderly Patients Admitted to a Tertiary Intensive Care Unit in Nigeria and Outcome of Management. AB - BACKGROUND: The management and outcome of elderly patients aged 65 years and above admitted to the intensive care unit (ICU) are often complicated by the presence of co-morbidities and reduced physiological reserve. METHODOLOGY: This was a retrospective, case-control study. Patients aged 65 years and above admitted to the unit from January 2012 to June 2013 were included in the study. Admission and discharge register in the ICU was examined. A patient before and after each elderly patient were recruited to serve as controls in the study. RESULTS: Seventy-nine (79) elderly patients were admitted to the ICU and it constituted 12.6% of total ICU admission with a mortality rate of 49.6%. Male:Female ratio was 2:1. Postoperative care constituted the highest indication for ICU admission (41.8%) followed by cerebrovascular accident (stroke), 12.6%. Younger patients were about twice more likely to be mechanically ventilated than elderly patients. (p=0.05, OR=1.855) Conclusion: The mortality rate of elderly patients admitted to the ICU was high. Appropriate admission criteria and protocol for the management of elderly patients in the ICU should, therefore, be developed to improve outcome. PMID- 30027991 TI - Public Awareness of Hepatitis B Virus Infection in Cross River State, Nigeria: A Population-Based Survey. AB - BACKGROUND: Hepatitis B Virus (HBV) infection is a public health problem that is endemic in Nigeria. Cross River State, a tourist state, located in the coastal area of Nigeria has a relatively high prevalence rate. Insufficient knowledge and negative attitudes are barriers to effective control of infectious diseases. OBJECTIVES: To determine the Knowledge, Attitude and Practice (KAP) of HBV amongst residents of Cross River State, Nigeria. METHODS: This was a cross sectional descriptive study. A total of 1,620 healthy adults from the three senatorial districts in Cross River State participated in the study from March to September, 2015. KAP towards HBV was assessed using a structured pre-tested questionnaire. Categorical variables were described as frequencies and continuous variables as median and interquartile range. In the inferential analysis, Kruskal Wallis test was used to determine the relationship between socio-demographic variables and median KAP scores. A p value < 0.05 was considered significant. All analyses were performed using Stata 12 statistical package. RESULTS: A total of 1,465 respondents completed the questionnaire correctly giving a response rate of 91%. The M: F ratio was 1:1.8. The median age was 38 years. Majority (61%) was married and 32% had formal education up to the tertiary level. Only 45% knew that HBV causes hepatitis. Knowledge of routes of transmission was >50% for blood transfusion, sexual contact and sharps but < 48% for vertical transmission. Median and interquartile range of knowledge scores for the south, central and northern senatorial districts were 8 (2-14), 13 (5-17) and 14 (6-18) which varied significantly with age (p =0.027). The overall attitude and practice towards persons living with HBV was poor. There was good correlation between KAP scores (p<0.05). CONCLUSION: Knowledge of hepatitis B is low among adults in Cross River State. This correlates with poor attitude and practice towards HBV. There is need to utilize health education strategies to improve awareness among the populace, if Nigeria is to meet the global target of elimination of viral hepatitis by 2030. PMID- 30027992 TI - Pattern of Accidental Childhood Poisoning at the Children Emergency Room of the University of Benin Teaching Hospital, Benin City, Nigeria. AB - BACKGROUND: Accidental childhood poisoning contributes significantly to childhood morbidity and mortality worldwide. A review of the agents which cause poisoning in our locality from time to time is important in planning prevention strategies and treatment modalities. OBJECTIVE: To document the pattern of accidental childhood poisoning at the Children Emergency Room (CHER) of the University of Benin Teaching Hospital (UBTH), Benin City, Nigeria. METHODS: A retrospective study in which records of admissions as well as case notes of patients admitted because of ingestion of poisons from October 2011 to June 2014 were obtained. Demographic characteristics, type of poison, where poison was kept, route of poisoning and outcome were extracted from medical records of the patients. RESULTS: Fifty-five (1.44%) patients were admitted for accidental poisoning of a total of 3,822 admissions. Thirty-nine (70.9%) were males while 16 (29.1%) were females. The median and modal age at presentation was two years (range of 0.5-7 years). Route of poisoning was by ingestion in 54 (98.2%) patients. The commonest agent of poisoning was kerosene (32.7%); followed by medicines (18.2%), insecticides (16.4%) and caustic soda (12.7%). Forty-nine (89.1%) patients were discharged home with fatality in one (1.8%). CONCLUSION: Kerosene is still the major agent of poisoning in Benin City, although the prevalence has decreased. Alcohol poisoning has also decreased while ingestion of medicines has increased. The use of beverage and disposable water containers to store poisonous substances and keeping them in easily accessible areas in the home is still rampant. Measures to prevent access of children to these substances will greatly reduce the burden of accidental poisoning. PMID- 30027993 TI - Long-term effects of Maternal HIV Infection and Anti-Retroviral Medications on the Hearing of HIV-Exposed Infants. AB - BACKGROUND: The long-term effect of maternal HIV and antiretroviral medication on the hearing of HIV-exposed infants has not been well studied. We determined and compared the hearing thresholds of HIV-exposed infants with that of HIV-unexposed infants within the first month of life and at three, six and nine months of life. MATERIALS AND METHODS: This was a Case control study of 126 HIV-exposed newborns and 121 HIV-unexposed newborns. Data collected included Socio-demographic, clinical characteristics and risk factors for hearing loss. Hearing was evaluated at newborn, 3, 6, and 9 months of life. Within and between groups analyses were done with appropriate statistics. Level of significance was P<0.05. RESULTS: In both ears, the mean hearing thresholds of HIV-exposed infants were greater than those of the HIV-unexposed infants at baseline, 3, 6 and 9 months (P>0.05). In both groups, there was a decline in the mean hearing thresholds from baseline (new born) till 6 months of age. The highest mean threshold was recorded at 9 months. The mean hearing thresholds of infants at 3, 6, and 9 months were lower for HIV-exposed infants and higher for HIV-unexposed infants than the corresponding mean hearing thresholds measured at baseline. There was a significant strong correlation among hearing thresholds at 3, 6 and 9 months but weakly correlated with hearing thresholds at baseline. CONCLUSION: There was a tendency towards higher hearing thresholds in HIV-exposed infants than the HIV unexposed infants throughout the infancy period. This appears to have association with in-utero exposure to HIV. PMID- 30027994 TI - Rhabdomyosarcoma in All Age Groups at the Jos University Teaching Hospital. AB - BACKGROUND: The designation Rabdomyosarcoma (RMS) is used to describe the malignant mesenchymal neoplasm that exhibits varying degree of skeletal muscle differentiation. RMS is the commonest malignancy of soft tissues afflicting children and adolescent up until age 20. It constitutes 5-10% of pediatric malignancies, and 7-9.5% of pediatric soft tissue sarcomas. The site of origin of RMS can be one of three possibilities: myogenous; extramyogenous; and ectopic (heterotopia). This was a retrospective study of consecutive cases of RMS seen at the Histopathology Department of the Jos University Teaching Hospital, Jos, between January 2007 and December 2016. The study was aimed at analyzing RMS in relation to age, sex, site, and histological type. METHODOLOGY: Patients' information including: age; sex; anatomical site of lesion; and histopathological diagnosis were extracted from patients' records in the Medical Records Department and the Histopathology Department. Archival tissue blocks were retrieved, sectioned into 5mm slides, stained with haematoxylin and eosin, and reviewed microscopically to confirm the diagnosis of RMS and sub-classify the disease. All histologically confirmed cases were included in the study, while those with inadequate bio-data and record of topography were excluded. RESULTS: Seventy (70) cases of RMS were seen during the study period. The age range was 3 months to 80 years. The mean age at diagnosis was 23.4+/-21.1 years. There were 40 (57.4%) males and 30 (42.9%) females with male female ratio of 1.3:1. The head and neck region was the commonest site of occurrence of RMS accounting for 27.1%. CONCLUSION: The commonest histologic variants of rhabdomyosarcoma were the embryonal, alveolar, and pleomorphic types. More than half of this malignancy occurred in children, and the adolescent. The head and neck, extremities, and trunk in decreasing order were the commonest sites of occurrence of this tumor, with a male predominance. PMID- 30027995 TI - Translation and Validation of the Nigerian Pidgin English Version of the Early Childhood Oral Health Impact Scale (NAIJA ECOHIS). AB - OBJECTIVES: The Early Childhood Oral Health Impact Scale (ECOHIS) has been used in different countries and in different versions to assess the impact of oral health conditions on preschoolers. This study aimed to develop the Nigeria Pidgin English version of ECOHIS and investigate its psychometric properties. METHODS: The Nigerian Pidgin English version (NAIJA ECOHIS) was developed from the English version using the forward-backward translation technique. One hundred and four children aged 2-5 years attending a clinic were recruited for the study and the new version was administered to their parents/caregivers. Validity of the instrument was assessed based on the relationship between the NAIJA-ECOHIS scores and the global health rating scores using Spearman's rank correlation. The internal consistency reliability was tested using Cronbach's alpha coefficient while the test-retest reliability was assessed using intraclass correlation coefficient by using scores of fifty participants who reported no change in their symptoms after one week. RESULTS: The NAIJA-ECOHIS version was created with some modifications to the original version. The association between the NAIJA ECOHIS scores and the two global questions as well as the correlation between the child and family sections were statistically significant (p <0.001). Cronbach's alpha coefficient for the child section, family section and Total NAIJA ECOHIS scores were 0.83, 0.79 and 0.86 respectively demonstrating good internal consistency. CONCLUSION: The NAIJA ECOHIS version was valid and reliable for assessing oral health related quality of life of preschool children whose parents/caregivers speak the Nigerian Pidgin English. PMID- 30027996 TI - Prevalence and Pattern of Chronic Kidney Disease and its Associated Risk Factors in a Rural Community in South Western Nigeria. AB - BACKGROUND: Chronic kidney disease (CKD) has now become a disease of public health importance. The increased prevalence in the population of patients with end stage renal disease (ESRD) is partly related to the failure of early detection of the pre-clinical stages of the disease and its associated risk factors. This study aimed to determine the prevalence of chronic kidney disease and its associated risk factors in Aiyepe community in Ogun state, south western Nigeria as well as determining the awareness level of the population about CKD. MATERIALS AND METHODS: It was a cross-sectional community-based study involving 456 participants recruited through cluster and simple random sampling techniques.Participants were screened for urinary albumin by dipstick and/or albumin creatinine ratio. Serum creatinine, fasting blood sugar and serum lipid profile were determined while glomerular filtration rate was estimated using Cockroft and Gault formula from serum creatinine. RESULTS: The mean age +/- standard deviation (SD) of the study population was 48.09(+/-15.7) years, and the age range was 18-80 years. Hypertension was seen in 28.9% of studied participants while only 4.2% were diabetic. The mean waist-hip ratio (WHR) of the participants was 0.94(+/-0.55). The mean BMI of the participants was 26.62(+/-6.0) kg/m2 with a range of 15.04 to 48.68 kg/m2. The prevalence of overweight and obesity was found to be 24.4% and 30% respectively. The prevalence of proteinuria was 16.3% while 3.7% of the participants had history of haematuria. The prevalence of CKD was 27.6%. Age (OR-1.080, CI-95%, 1.059-1.102), female gender (OR-0.550, CI-95%, 0.320-0.945), BMI (OR-0.832, CI-95%, 0.785-0.882) and dyslipidaemia (OR-1.007, CI 95%, 0.978-1.037) were found to be predictive of CKD in this study. CONCLUSION: The prevalence of CKD and its associated risk factors is high in Aiyepe community in Ogun state, south western Nigeria. If this is true for other rural communities generally, it will pose huge challenges on the available healthcare resources. PMID- 30027997 TI - Association of Squamous Cell Carcinoma of the Tongue with Cigarette and Alcohol Exposure: A Retrospective Clinicopathological Study. AB - BACKGROUND: Squamous cell carcinoma of the oral tongue (SCCOT) has been linked to modifiable risk factors; such as tobacco use and excessive alcohol consumption. OBJECTIVE: To describe the clinical presentation of SCCOT as well as its association with history of tobacco and alcohol use. METHODS: A retrospective review of SCCOT at Oral Pathology Department from 1990 to 2012. Information retrieved from patients' medical records includes: age, gender, occupation, history of alcohol and tobacco use. Also, the first symptoms observed by patients at the onset of disease, and what was done for patients at the place of first consultation were documented. RESULTS: SCCOT accounted for 26% of all oral squamous cell carcinoma (SCC); mean age at presentation was 58.3 +/-12.6 years. Two patients diagnosed of SCCOT before 40 years as well as female SCCOT patients denied exposure to either alcohol or tobacco; while about 80% and 70% of males with complete history were exposed to tobacco and alcohol respectively. At the onset of disease, 70.2% of patients noticed a lingual ulcer, 13% experienced pain, but at presentation, only one patient was not experiencing pain. About 85.3% of patients presented with stage III and IV disease. All patients but two were treated with antibiotics and analgesics at first presentation in a hospital. CONCLUSION: The most common symptoms at the onset of disease were ulceration and pain. Men above age forty years had exposure to alcohol and tobacco. PMID- 30027998 TI - Fractures in Children Aged 0-12 Years and their Management as seen in North Central Nigeria. AB - BACKGROUND: Childhood injuries are often associated with fractures, and it is said to account for about 25% of all paediatrics trauma. There is a male preponderance and the peak incidence occurs among primary and secondary school age groups. The occurrence and management of these fractures are influenced by season, geographical location, educational and socio-economic status of the populace as well as time of presentation and availability of suitable facilities for treatment. OBJECTIVES: To analyse the demographic characteristics of the subjects, aetiological factors, fracture distribution, educational and occupational status of their parents, mode of treatment and their outcomes. SUBJECTS AND METHODS: We carried out a prospective study on children 0-12 years of age at the University Teaching Hospital, Zaria, Nigeria, with fractures who consented to the study from January 2013 to December, 2016. Eight-six children were recruited through the Accident and Emergency Department. Diagnosis was made by both clinical and radiological assessment. They were managed by either non operative or operative modality. Their complications were also managed. Their follow-up was for 12 months. RESULTS: A total of 86 children with 86 fractures were enrolled with mean age of 7 years and male/female ratio of 2:1. The main aetiological factors were road traffic accidents (52.4% from cars, motorcycle and tricycle), followed by falls from heights (40.0%). Forearm bone fractures were the commonest (30.2%). Non-operative modality dominated the management (72.1%). Complication rate was 20.4%. CONCLUSION: Fractures in children have a male prepon derance with the radius being most commonly involved. Non-operative management was the main modality of treatment. PMID- 30027999 TI - Peno-Scrotal Elephantiasis Nostras Verrucosa: Rare Disorder in a Young Nigerian. AB - Elephantiasis Nostras Verrucosa (ENV) is a rare cutaneous complication of chronic lymphatic obstruction. It represents the late stage of chronic non-filarial lymphoedema, resulting in the recurrent and progressive swelling of the affected part, and is marked by both physical and psychological impairment in health related quality of life. Morphologically it appears as clusters of verrucous (wart-like) papules and nodules arranged in a cobblestone-like pattern, often presenting a mossy appearance. I hereby describe the case of a young man with progressively worsening peno-scrotal ENV; highlighting the delay in diagnosis occasioned by the low level awareness of this harrowing affliction among medical practitioners, and mentioning the negative impact on the patient's health-related quality of life (HRQoL). Filarial lymphoedema is predominantly seen in the tropics; however, despite the dearth of reports, this case confirms the existence of ENV in this region. Following an extensive literature search and to the best of my knowledge, I am yet to come across other reported cases of elephantiasis nostras verrucosa emanating from Africa. PMID- 30028000 TI - Use of PD-1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre. PMID- 30028001 TI - Incidence of intracranial bleeding in anticoagulated patients with minor head injury: a systematic review and meta-analysis of prospective studies. AB - Guidelines advise performing a computed tomography head scan for all anticoagulated head injured patients, but the risk of intracranial haemorrhage (ICH) after a minor head injury is unclear. We conducted a systematic review and meta-analysis to determine the incidence of ICH in anticoagulated patients presenting with a minor head injury and a Glasgow Coma Score (GCS) of 15. We followed Meta-Analyses and Systematic Reviews of Observational Studies guidelines. We included all prospective studies recruiting consecutive anticoagulated emergency patients presenting with a head injury. Anticoagulation included vitamin-K antagonists (warfarin, fluindione), direct oral anticoagulants (apixaban, rivaroxaban, dabigatran and edoxaban) and low molecular weight heparin. A total of five studies (including 4080 anticoagulated patients with a GCS of 15) were included in the analysis. The majority of patients took vitamin K antagonists (98.3%). There was significant heterogeneity between studies with regards to mechanism of injury and methods. The random effects pooled incidence of ICH was 8.9% (95% confidence interval 5.0-13.8%). In conclusion, around 9% of patients on vitamin K antagonists with a minor head injury develop ICH. There is little data on the risk of traumatic intracranial bleeding in patients who have a GSC 15 post-head injury and are prescribed a direct oral anticoagulant. PMID- 30028002 TI - Novel SBF2 mutations and clinical spectrum of Charcot-Marie-Tooth neuropathy type 4B2. AB - Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling. PMID- 30028003 TI - Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. AB - Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan aspartate repeat domain 72 (WDR72) (c.1777A>G [p.R593G] and c.2522T>A [p.L841Q]) in three affected siblings of a family with dRTA. Both variants segregated with dRTA in the family and were not observed in normal control subjects. Homologous modeling and in silico mutagenesis indicated that R593G and L841Q alter the H bond formations in the nearby residues, affecting the WDR72 protein structure. All these evidences indicate that the identified WDR72 variations were probably to have caused hereditary dRTA in the reported family. In addition, homozygous nonsense mutation (c.2686C>T [p.R896X]) was identified in another family, strongly supporting the causal role of WDR72 in dRTA. Based on our literature review, WDR72 mutations associated with dRTA have not been previously described. This is the first identification of pathogenic variations in WDR72 as a cause of hereditary dRTA. PMID- 30028004 TI - An effective and promising treatment with adalimumab for impetigo herpetiformis with postpartum flare-up. PMID- 30028005 TI - Arsenic trioxide and all-trans retinoic acid treatment for childhood acute promyelocytic leukaemia. PMID- 30028006 TI - Strategies to Reduce Solute Carrier-Mediated Toxicity. AB - Toxicity is among the greatest concerns during clinical use of drugs, and it has been well documented that transporter proteins facilitate such events by regulating drug accumulation. However, an important question is whether strategies could be adopted to diminish such toxicities. Although the field is currently in its infancy, some examples exist demonstrating how mechanistic understanding of the role of transporters in drug disposition can aid in alleviating transporter-mediated toxic effects. PMID- 30028007 TI - The roles of delay and probability discounting in texting while driving: Toward the development of a translational scientific program. AB - A sample of 109 college students completed a survey to assess how frequently they send or read text messages while driving. In a novel discounting task with a hypothetical scenario in which participants receive a text message while driving, they rated the likelihood of replying to a text message immediately versus waiting to reply until arriving at a destination. The scenario presented several delays to a destination and probabilities of a motor vehicle crash. The likelihood of waiting to reply decreased as a function of both the delay until the destination and the probability of a motor vehicle crash. Self-reported higher frequencies of texting while driving were associated with greater rates of both delay and probability discounting. The degree of delay discounting was altered as a function of the probability of a motor vehicle crash and vice versa. These results suggest that both delay and probability discounting are important underlying mechanisms of drivers' decision to text while driving. PMID- 30028008 TI - Clinical management of Anti-TNF-alpha-induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review. AB - Tumor necrosis factor alpha inhibitors (anti-TNF-alpha) completely revolutionized the treatment of inflammatory bowel disease (IBD). However, anti-TNF-alpha induced cutaneous side effects have been increasingly reported in the literature. Particularly, psoriasis and the recently recognized psoriasiform lesions are of particular concern, as anti-TNF-alpha agents are also used in the treatment of psoriasis, seemingly reflecting an immunological paradox. The clinical management of these cutaneous lesions is particularly challenging, owing to the potential need of anti-TNF-alpha discontinuation and scarcity of other therapeutic options. Therefore, optimization of current topical and systemic therapies and incorporation of new therapeutic agents is of great interest. Our aim is to review data in the literature regarding the clinical management of these cutaneous lesions and provide a therapeutic algorithm, supported by our experience as a tertiary referral center for IBD. Although in older reports no distinction was made, anti-TNF-alpha-induced psoriasiform lesions are not only more prevalent but also bear notable differences from classical psoriasis, possibly reflecting a different nosological entity. Onset of lesions has been related to periods of IBD remission, as supported by low levels of fecal calprotectin. Psoriasiform lesions can be adequately managed either by topical (glucocorticoids, calcineurin inhibitors, and antibiotics) or systemic (phototherapy, acitretin, glucocorticoids, and antibiotics) therapies and/or switch to other anti-TNF-alpha agents. Data referring to patients who were able to continue on the same IBD therapy ranged from 30.7 to 100%, reinforcing the importance of an adequate control of these lesions. The recently approved ustekinumab offers another step in the management of anti-TNF-alpha-intolerant patients. PMID- 30028010 TI - PD-1 is highly expressed by neoplastic B-cells in Richter transformation. PMID- 30028009 TI - A laboratory model for evaluating relapse of undesirable caregiver behavior. AB - The success of behavioral treatments like functional communication training depends on their continued implementation outside of the clinical context, where failures in caregiver treatment adherence can lead to the relapse of destructive behavior. In the present study, we developed a laboratory model for evaluating the relapse of undesirable caregiver behavior that simulates two common sources of disruption (i.e., changes in context and in treatment efficacy) believed to affect caregiver treatment adherence using simulated confederate destructive behavior. In Phase 1, the caregiver's delivery of reinforcers for destructive behavior terminated confederate destructive behavior in a home-like context. In Phase 2, the caregiver implemented functional communication training in a clinical context in which providing reinforcers for destructive or alternative behavior terminated confederate destructive behavior. In Phase 3, the caregiver returned to the home-like context, and caregiver behavior produced no effect on confederate destructive or alternative behavior, simulating an inconsolable child. Undesirable caregiver behavior relapsed in three of four treatment adherence challenges. PMID- 30028011 TI - Non-oxidative hair dye products on the European market: What do they contain? AB - BACKGROUND: Hair dyeing is very common and may cause allergic contact dermatitis. Oxidative (often termed permanent or semi-permanent) hair dye products have constituted the focus of market surveys and toxicological risk assessments, while non-oxidative (semi-permanent, temporary or direct) products have not been assessed. OBJECTIVES: To identify the hair dye substances presently used in non oxidative hair dye products in Europe. METHODS: Ingredient label data on eligible products in 5 European countries were collected, and 289 different non-oxidative hair dye products were included in this study. RESULTS: Up to 9 hair dye substances were present in each product. Sixty-eight individual hair dye substances were identified on the 289 product labels, and their occurrence ranged from 0.3% to 34%. There were differences concerning substances used and their number per product between products of different consistency and colour. CONCLUSIONS: The hair dye substances in non-oxidative hair dye products are different from those in oxidative hair dye products, and are currently not covered by patch test series. The toxicological and skin-sensitizing profile of the substances in non-oxidative hair dye products, as well as their concentrations, should be further investigated. PMID- 30028012 TI - Betanodavirus infection in bath-challenged Solea senegalensis juveniles: A comparative analysis of RGNNV, SJNNV and reassortant strains. AB - Senegalese sole has been shown to be highly susceptible to betanodavirus infection, although virulence differences were observed between strains. To study the mechanisms involved in these differences, we have analysed the replication in brain tissue of three strains with different genotypes during 15 days after bath infection. In addition, possible portals of entry for betanodavirus into sole were investigated. The reassortant RGNNV/SJNNV and the SJNNV strain reached the brain after 1 and 2 days postinfection, respectively. Although no RGNNV replication was detected until day 3-4 postinfection, at the end of the experiment this strain yielded the highest viral load; this is in accordance with previous studies in which sole infected with the reassortant showed more acute signs and earlier mortality than the RGNNV and SJNNV strains. Differences between strains were also observed in the possible portals of entry. Thus, whereas the reassortant strain could infect sole mainly through the skin or the oral route, and, to a minor extent, through the gills, the SJNNV strain seems to enter fish only through the gills and the RGNNV strain could use all tissues indistinctly. Taken together, all these results support the hypothesis that reassortment has improved betanodavirus infectivity for sole. PMID- 30028013 TI - Water stress limits transpiration and growth of European larch up to the lower subalpine belt in an inner-alpine dry valley. AB - Climate change will further constrain water availability in dry inner-alpine environments and affect water relations and growth conditions in mountain forests, including the widespread larch forests. To estimate the effects of climate conditions on water balance and growth, variation in sap flow and stem radius of European larch was measured for 3 yr along an elevation transect from 1070 to 2250 m above sea level (asl) in an inner-alpine dry valley in South Tyrol/Italy. Additionally, long-term climate-growth relations were derived from tree cores. Sap flow and radial growth were reduced in dry periods up to an elevation of 1715 m, leading to maximum annual growth at 2000 m. In a wet year no growth difference between elevations was observed. Long-term tree ring data showed a positive growth response to precipitation up to 1715 m and to temperature only above 2000 m. Our results demonstrate that reduced water availability and higher atmospheric water demand limit larch at low elevation within dry Alpine regions. This indicates a general upward shift of this species' elevational amplitude upon climate change, and respective negative effects on future silvicultural use and ecosystem services at lower elevations in the European Alps. PMID- 30028014 TI - High-density lipoprotein mimetic peptide 4F mitigates amyloid-beta-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia. AB - The apolipoprotein E (apoE) epsilon4 allele is the primary genetic risk factor for late-onset Alzheimer's disease (AD). ApoE in the brain is produced primarily by astrocytes; once secreted from these cells, apoE binds lipids and forms high density lipoprotein (HDL)-like particles. Accumulation of amyloid-beta protein (Abeta) in the brain is a key hallmark of AD, and is thought to initiate a pathogenic cascade leading to neurodegeneration and dementia. The level and lipidation state of apoE affect Abeta aggregation and clearance pathways. Elevated levels of plasma HDL are associated with lower risk and severity of AD; the underlying mechanisms, however, have not been fully elucidated. This study was designed to investigate the impact of an HDL mimetic peptide, 4F, on the secretion and lipidation of apoE. We found that 4F significantly increases apoE secretion and lipidation in primary human astrocytes as well as in primary mouse astrocytes and microglia. Aggregated Abeta inhibits glial apoE secretion and lipidation, causing accumulation of intracellular apoE, an effect that is counteracted by co-treatment with 4F. Pharmacological and gene editing approaches show that 4F mediates its effects partially through the secretory pathway from the endoplasmic reticulum to the Golgi apparatus and requires the lipid transporter ATP-binding cassette transporter A1. We conclude that the HDL mimetic peptide 4F promotes glial apoE secretion and lipidation and mitigates the detrimental effects of Abeta on proper cellular trafficking and functionality of apoE. These findings suggest that treatment with such an HDL mimetic peptide may provide therapeutic benefit in AD. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14554. PMID- 30028015 TI - Kallikrein-related peptidases are activators of the CC chemokine CCL14. AB - Chemokine CCL14 is inactive in its proform. Here, we show that inflammation- and cancer-associated kallikrein-related peptidases KLK5 and KLK8 remove the N terminal eight amino acids from the proform thereby converting CCL14 to its active state. Activity of the chemokine is demonstrated by migration of myeloid cells expressing relevant receptors. PMID- 30028016 TI - Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial. AB - Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Munster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10.3 years (range 0.5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12.4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3.73, P = 0.009; >15 years vs. <10 years: HR 5.46, P = 0.001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2.696, P = 0.015) as significant independent risk factors for the development of sON. PMID- 30028017 TI - A study on gender differences in newly detected leprosy cases in Sichuan, China, 2000-2015. AB - BACKGROUND: Many researches on gender differences in leprosy found that female patients were detected with the disease later and had more serious disabilities than male patients. We analyzed the gender differences related to epidemiological characteristics of new leprosy cases detected from 2000 to 2015 in Sichuan Province, China. METHODS: A retrospective study was undertaken to analyze the gender differences with respect to age, delay in disease detection, the main modes of detection, and disability grade. The chi-squared test and t test were applied for the comparison using Epi Info 7.2 with a significance level of a = 0.05. The data were collected from the Leprosy Management Information System in China. RESULTS: A total of 2900 new leprosy cases were detected from 2000 to 2015, of whom 2075 (71.6%) were male and 825 (28.4%) were female with a gender ratio of 2.5. The gender ratio of patients aged 15-30 was significantly lower than that of patients aged 31-45 and 46-60. Male cases were older than female cases when they were detected. The proportion of Grade 2 Disability (G2D) among men (20.6%) was significantly higher than that among women (17.3%). The average period of delay in detection among male cases was similar with that among females cases. CONCLUSIONS: Gender-related differences existed among the leprosy cases detected from 2000 to 2015. Female patients were younger than male patients. The detection of leprosy in women was not later than in the case of men. The disability situation in men was more serious than in women. PMID- 30028019 TI - Working conditions, job satisfaction and challenging encounters in dentistry: a cross-sectional study. AB - OBJECTIVES: The aim was to evaluate job satisfaction, challenging encounters and work-related outcomes in dentistry and their association with the work-related outcomes scales 'burnout inventory', 'general life satisfaction' and 'cognitive stress symptoms'. METHODS: This cross-sectional study was based on the results of a questionnaire administered to a sample of 1,811 dentists in the German federal state of Schleswig-Holstein. Besides sociodemographic data and practice characteristics, topics such as challenging patient traits and job satisfaction, and three work-related outcome scales, were evaluated. Descriptive statistics and linear regression analyses were computed to explore potential associations with the three work-related outcome scales. RESULTS: A response rate of 35.2% (638/1,811 participants) was observed for this study. Dentists described that 25% of their patients were challenging. The highest rate was found for 'aggressive patients' and the lowest rate for 'anxious patients'. The proportion of challenging patient traits was significantly correlated with the three work related outcomes whereby the highest significant correlation was observed for 'burnout inventory'. CONCLUSIONS: As shown by our results, the higher perception of the proportion of anxious patients, the higher the risk of burnout. Therefore, special management of the treatment of anxious patients is necessary, which could have a positive implication on the perceived work-related stress. A crucial aspect for well-being at work as a dentist (besides job satisfaction and work related aspects) is the evaluation of what kind of patients result in a challenging encounter. PMID- 30028018 TI - The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease. AB - Huntington's Disease (HD) is an autosomal-dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5-positive allosteric modulators (PAMs) can ameliorate pathology and the phenotypic signs of a mouse model of HD. In this study, we investigated the molecular mechanisms involved in mGluR5 PAMs effect on memory. Our results demonstrate that subchronic treatment with the mGluR5 PAM VU0409551 was effective in reversing the memory deficits exhibited by BACHD mice, a mouse model for HD. Moreover, VU0409551 treatment stabilized mGluR5 at the cellular plasma membrane of BACHD mice, increasing the expression of several genes important for synaptic plasticity, including c-Fos, brain-derived neurotrophic factor, Arc/Arg3.1, syntaxin 1A, and post-synaptic density-95. In addition, VU0409551 treatment also increased dendritic spine density and maturation and augmented the number of pre-synaptic sites. In conclusion, our results demonstrate that VU0409551 triggered the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open science-badges/. PMID- 30028020 TI - Determinants of oral hygiene behaviour among patients with moderate and severe chronic periodontitis based on the theory of planned behaviour. AB - OBJECTIVES: Health interventions based on cognitive theories effectively bring about behaviour change. Therefore, the present study aimed to assess the determinants of oral hygiene behaviour (OHB) based on the theory of planned behaviour (TPB) among patients with moderate and severe periodontitis. METHODS: A cross-sectional study was conducted using a 47-item self-report questionnaire to evaluate oral health knowledge (OHK), expected social outcomes (ESO) and OHB based on the variables of TPB [attitude (ATT), social norms (SN) and perceived behavioural control (PBC)] of patients with moderate and severe periodontitis. Analysis of variance was used for comparison between the parameters. Regression analyses identified the significant determinants of OHB. RESULTS: A total of 543 patients meeting the inclusion criteria were included. ESO (B = 0.04) and OHK (B = 0.14) significantly predicted intention to perform OHB. None of the TPB variables significantly predicted OHB. Apart from ESO and OHK, which were significant predictors for both genders, ATT (beta = 0.22) additionally predicted OHB among men. Also, for university graduates, ESO (beta = 0.13) and OHK (beta = 0.17) significantly predicted OHB. Lastly, OHB showed a significant and positive correlation with all the parameters (P < 0.05). CONCLUSION: The study concludes that the TPB model facilitates the evaluation of psychosocial determinants of OHB among patients with periodontitis. Also, a significant relationship between gender, OHB and variables of TPB further highlights the importance of patient focused preventive oral health care education. PMID- 30028021 TI - Assessment of oral health-related quality of life as a function of non-invasive treatment with high-fluoride toothpastes for root caries lesions in community dwelling elderly. AB - PURPOSE: Non-invasive treatment of root caries lesions (RCLs) may impact oral health-related quality of life (OHRQoL), but no evidence is available. The purpose of the study was to assess changes in OHRQoL among patients exposed to non-invasive treatment of RCLs with conventional or high-fluoride dentifrices. METHODS: To be eligible, subjects had to be >=60 years of age, independently living, with at least five teeth and one RCL. The 14-item Oral Health Impact Profile for adults in Spanish (OHIP-14Sp), oral examination and sociodemographic data were documented at the beginning of the study (T0). The presence and activity of RCLs were detected and diagnosed. Subjects were randomly assigned to either the control (1,450 ppm fluoride) or the experimental (5,000 ppm fluoride) treatment group. A new set of measurements was obtained at 12 months (T1). Mean comparisons were carried out using the Student's t-test for total OHIP-14Sp scores. To determine whether T1 OHRQoL scores were different regarding sex, age, educational level and socio-economic status, mean OHIP-14Sp scores were obtained and compared with those variables at 12 months. RESULTS: An overall improvement in OHRQoL after the non-invasive treatment of RCLs was verified when T1 was compared with T0 (P < 0.0001). Regarding treatment type, no significant differences were detected between groups (P = 0.114). Subjects with higher income and more years of formal education had better OHRQoL than those with a lower salary (P < 0.0001) and with fewer years of education (P = 0.0006). CONCLUSIONS: Non-invasive treatment for RCLs in community-dwelling elders appears to cause a positive impact on OHRQoL. Better OHRQoL was associated with higher socio economic status and educational level. No significant differences were detected regarding the fluoride concentration in the dentifrices. PMID- 30028022 TI - Homeologue-specific expression divergence in the recently formed tetraploid Capsella bursa-pastoris (Brassicaceae). AB - Following allopolyploid formation, extensive genome evolution occurs, with the eventual loss of many homeologous gene copies. Although this process of diploidization has occurred many times independently, the evolutionary forces determining the probability and rate of gene loss remain poorly understood. Here, we conduct genome and transcriptome sequencing in a broad sample of Chinese accessions of Capsella bursa-pastoris, a recently formed allotetraploid. Our whole genome data reveal three groups of these accessions: an Eastern group from low-altitude regions, a Western group from high-altitude regions, and a much more differentiated Northwestern group. Population differentiation in total expression was limited among closely related populations; by contrast, the relative expression of the two homeologous copies closely mirrors the genome-wide SNP divergence. Consistent with this, we observe a negative correlation between expression changes in the two homeologues. However, genes showing population genomic evidence for adaptive evolution do not show an enrichment for expression divergence between homeologues, providing no clear evidence for adaptive shifts in relative gene expression. Overall, these patterns suggest that neutral drift may contribute to the population differentiation in the expression of the homeologues, and drive eventual gene loss over longer periods of time. PMID- 30028023 TI - Expression of CD56 defines a distinct subgroup in childhood T-ALL with inferior outcome. Results of the ALL-BFM 2000 trial. AB - This study reports the prognostic impact of the expression of the natural killer cell marker CD56 in a large series of risk-adapted paediatric patients with T cell acute lymphoblastic leukaemia (T-ALL; n = 493) treated within the ALL-Berlin Frankfurt-Munster (BFM) 2000 protocol. The immunophenotype was analysed centrally at diagnosis using flow cytometry and correlated with clinical parameters and outcome. CD56 expression was detected in 7.1% and early T-cell precursor (ETP) phenotype in 6.7% of all T-ALL patients. The percentage of ETP in the CD56+ T-ALL cohort was 4-fold higher than in the whole cohort. CD56+ T-ALL frequently expressed the progenitor marker CD34 and myeloid antigens CD13 and CD33. The 5 year event-free survival (EFS) rates for the European Group for the Immunological classification of Leukaemias/World Health Organization subgroups and the ETP phenotype were not statistically different. By contrast, patients with CD56 expression had a significantly reduced EFS (60 +/- 8%) and overall survival (60 +/- 8%) at 5 years, with a hazard ratio of 2.46 (P = 0.002) and 2.99 (P < 0.001), respectively. Moreover, CD56 expression in combination with the minimal residual disease (MRD)-based high risk assignment defined a population with a 'very-high' risk probability of relapse in the ALL-BFM 2000 trial. The CD56 marker has the potential to augment MRD-based risk stratification and may serve as a molecular target for antibody-based treatment strategies in childhood T-ALL. PMID- 30028024 TI - Pharmacokinetics of intravenous, subcutaneous, and topical administration of lidocaine hydrochloride and metabolites 3-hydroxylidocaine, monoethylglycinexylidide, and 4-hydroxylidocaine in horse. AB - Intravenous (iv), subcutaneous (sq), and topical (tp) lidocaine was administered to six horses in a cross-over, randomized design study. Samples were collected for up to 72 hr. Compartmental models were used to investigate the pharmacokinetics of (LD) and its metabolites 3-hydroxylidocaine (3-OH), 4 hydroxylidocaine (4-OH), and monoethylglycinexylidide (MEGX). Metabolites 3-OH and 4-OH were present in conjugated forms, whereas LD and metabolite MEXG were present primarily in the un-conjugated form. Plasma concentrations of LD after iv administration (100 mg) were described by three-compartment model with an additional three compartments to describe the elimination of metabolites. Median (range) elimination micro-constants (Ke ) for LD, 3-OH, 4-OH, and MEXG were 4.12 (2.62-6.23), 1.25 (1.10-2.15), 1.79 (1.22-2.39), and 1.69 (1.03-1.99)/hr, respectively. Median (range) values of alpha (t1/2alpha ), beta (t1/2beta ), and gamma (t1/2gamma ) half-lives were 0.08 (0.07-0.13), 0.57 (0.15-1.25), and 4.11 (0.52-7.36) hr. Plasma concentrations of LD after sq (200 mg) administration were described by absorption and two-compartment elimination model. The median (range) of the LD absorption half-life (t1/2ab ) was 0.47 (0.29-0.61) hr. The Ke for LD, 3-OH, 4-OH, and MEXG was 3.91 (1.48-9.25), 1.00 (0.78-1.08), 1.76 (0.96-2.11), and 1.13 (0.69-1.33)/hr. The median (range) of t1/2alpha and t1/2beta was 0.15 (0.06-0.27) and 3.04 (2.53-6.39) hr. Plasma concentrations of LD after tp (400 mg) application were described by one-compartment model with a t1/2ab of 8.49 (5.16-11.80) hr. The Ke for LD, 3-OH, and MEXG was 0.24 (0.10-0.81), 0.41 (0.08 0.93), and 0.38 (0.26-1.14)/hr. PMID- 30028025 TI - Paranoia and interpersonal functioning across the continuum from healthy to pathological - Network analysis. AB - OBJECTIVE: Previous research has suggested that paranoia is associated with impaired social functioning in patients with schizophrenia and healthy individuals with high levels of paranoid ideation. This study analysed the relationship between paranoia and interpersonal functioning across the paranoia continuum using network analysis. METHOD: Levels of paranoid ideation and interpersonal functioning were measured in a non-clinical sample (N = 853) and in patients with schizophrenia spectrum disorders (N = 226). Network analyses were used to examine the nature of paranoia's relation to interpersonal functioning in both populations. RESULTS: Although the most central characteristic of paranoia in both samples was the feeling of being talked about behind one's back, across samples, individual characteristics were differentially related to various aspects of interpersonal functioning. Among clinical individuals, difficulties in interpersonal functioning were related to perceived previous experiences of being treated poorly by others, whereas among the non-clinical sample, interpersonal functioning was related to negative beliefs about others. CONCLUSIONS: The current results support previous findings linking paranoid ideation to interpersonal functioning in both clinical and non-clinical samples. Patterns of these relationships differed slightly across groups. Results in general support a continuum model of paranoia. PRACTITIONER POINTS: Network analyses were used to identify central aspects of persecutory ideation in both clinical and non clinical samples. Qualitative assessment of clinical and non-clinical networks revealed similar central symptoms and supported a continuum model of paranoia. Central aspects of paranoia, that is, feeling that others have talked about oneself behind one's back, being disappointed by others, and having distressing feelings of being watched by others, were associated with deficits in interpersonal functioning in both samples. Central aspects of paranoia may be beneficial targets for psychosocial interventions aimed at reducing paranoid ideation and improving interpersonal functioning. Demographic characteristics for this study differed between samples which may limit generalization of findings. Future research is needed to explore temporal associations and moment-to-moment dynamics between paranoid ideation and problems in interpersonal functioning. PMID- 30028026 TI - Rectal administration of metronidazole with and without rectal evacuation prior to use in horses. AB - In a randomized crossover design study, 10 adult horses were administered crushed metronidazole tablets rectally at 20 mg/kg. Horses' rectums were either evacuated (E) or not evacuated (NE) of manure prior to the administration of the drug. Serum samples were taken over 24 hr and plasma concentrations were determined via high pressure liquid chromatography. At 15 min post-administration, group E had a significantly higher plasma concentration (p = 0.027), but there were no concentration differences at any other time points. There was large variability in relative bioavailability in the NE group, with a median of 86.7%. Based on our results, there is no advantage to manually evacuating a horse's rectum prior to rectal administration of metronidazole. Further study at higher dosages as well as examination of clinical efficacy is warranted. PMID- 30028027 TI - Developmental defects of enamel increase caries susceptibility in Chinese preschool children. AB - OBJECTIVES: The present epidemiological study aimed to compare the prevalence and severity of developmental defects of enamel (DDE) and dental caries between urban and suburban Chinese preschool children. METHODS: A total of 1351 3- to 6-year old children were invited to participate in this study and received dental examinations. A modified DDE index was used to assess the prevalence and severity of DDE. The dental caries diagnosis was based on the World Health Organization (WHO) health survey methods for field studies and was recorded using the decayed, missing and filled tooth (dmft) index. The caries status was further classified as caries or severe caries according to a modification of the American Academy of Pediatric Dentistry definition. RESULTS: Overall, the DDE prevalence was 48.3% among the 1351 preschool children. The DDE prevalence was higher in innercity children (54.1%) than in suburban children (42.0%; P < 0.001). In contrast, the suburban children had a higher prevalence of dental caries (65.2% vs 57.5%; P = 0.004) and a higher mean dmft score (3.5 +/- 4.2 vs 2.9 +/- 3.8; P = 0.005) than the innercity children. Only 23.9% of the children were free of both DDE and caries. The caries risk increased significantly and independently as DDE severity increased (linear trend, 95% confidence interval = [1.32, 1.69], age [1.60, 1.88], urban residence [1.18, 2.15] and breastfeeding experience [1.04, 1.60]) after controlling for other demographic risk factors. CONCLUSIONS: The study provides new evidence that DDE is a significant contributing factor for the highly prevalent and progressive dental caries observed in Chinese preschool children. These results highlight the importance of including DDE in caries risk assessments. PMID- 30028028 TI - Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and liver fibrosis: A review. AB - : Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are key producer of reactive oxygen species in liver cells. Hepatic stellate cells (HSCs) and Kupffer cells (KCs) are the two key cells for expression of NOX in liver. KCs produce only NOX2, while HSCs produce NOX1, 2, and 4, all of which play essential roles in the process of fibrogenesis within liver. These NOX subtypes are contributed to induction of liver fibrosis by acting through multiple pathways including induction of HSC activation, proliferation, survival and migration, stimulation of hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both KCs and HSCs. SIGNIFICANCE: KCs and HSCs are two key cells for production of NOX in liver in relation to the pathology of liver fibrosis. NOX subtypes 1, 2, and 4 are inducers of fibrogenesis in liver. NOX activation favors hepatocyte apoptosis, HSC activation, and KC-mediated inflammatory cascade in liver, all of which are responsible for generation of liver fibrosis. PMID- 30028029 TI - Effect of pulmonary vein isolation on left atrial appendage flow in paroxysmal atrial fibrillation. AB - BACKGROUND: Left atrial appendage (LAA) functional modification in the context of pulmonary vein isolation has been a focus point of research and LAA emptying flow velocity (LAAEFV) is considered to reflect LAA contractility, stunning, and fibrosis. OBJECTIVE: In the present study, we sought to prospectively evaluate short-term LAAEFV changes after radiofrequency (RF) or cryoballoon ablation in paroxysmal AF. METHODS: This was a prospective substudy of the Effect of Cryoballoon and RF Ablation on Left Atrial Function (CryoLAEF) study (ClinicalTrials.gov Identifier: NCT02611869). Thirty patients, randomly assigned to RF or cryoablation, were prospectively followed. Transesophageal echocardiograms were performed at baseline and at 3 months postablation to measure LAAEFV. RESULTS: All measurements were performed in sinus rhythm. Overall, LAAEFV was 44.2 [38.5-62.8] cm/s at baseline and was increased to 70.8 [64.8-77.6] cm/s at 3 months' postablation (P < 0.001). Baseline LAAEFV was 52.5 [37.7-68.0] cm/s in the RF group and 42.8 [38.7-52.9] cm/s in the CryoBalloon group (P = 0.653). At 3 months, the corresponding values were 68.5 [61.9-76.6] cm/s and 73.9 [69.2-79.9] cm/s, respectively (P = 0.081 for the difference between the two groups at 3 months). The median change in LAAEFV was 11.0 [4.7 26.2] cm/s in the RF group versus 29.6 [15.8-37.0] cm/s in the CryoBalloon group (P = 0.033). CONCLUSION: LAA function is improved after catheter ablation with RF or balloon cryoablation in patients with paroxysmal AF, evaluated while in sinus rhythm both at baseline and on follow-up. PMID- 30028030 TI - Extracellular mycosynthesis of gold nanoparticles using Trichoderma hamatum: optimization, characterization and antimicrobial activity. AB - : Synthesis of gold nanoparticles (AuNPs) has become a needed domain of applied science. Biological method for synthesis of AuNPs by Trichoderma hamatum SU136 aqueous mycelial extract was achieved. The culture filtrate of the fungus was exposed to three different concentrations of gold chloride. The culture filtrate of the fungus was exposed to three different concentrations of gold chloride (0.25, 0.5 and 1.0 mmol l-1 ). In all cases, the gold ions (Au3+ ) were reduced to Au0 , leading to the formation of stable AuNPs. The AuNPs were identified by UV-visible spectrometry, TEM and FT-IR. The presence of a surface plasmon band around 530 nm indicates AuNPs synthesis. Trichoderma hamatum SU136 synthesized 5 30 nm sized; spherical, pentagonal and hexagonal morphologies of AuNPs by TEM. The existence and binding of proteins with nanoparticles was approved by FT-IR study. Parameters optimization showed the smallest size of AuNPs was obtained with (0.5 mmol l-1 gold chloride, pH 7 at 38 degrees C). Interestingly, AuNPs exhibited antimicrobial activity against four pathogenic bacterial strains in the presence of the standard antibiotic, streptomycin. SIGNIFICANCE AND IMPACT OF THE STUDY: Mycosynthesis of AuNPs by Trichoderma hamatum would provide some useful data for oriented biosynthesis of AuNPs. In addition, the applications of mycosynthesized AuNPs were studied against some pathogenic bacteria. Therefore, the gained results detect that these antimicrobial nanoparticles could be explored as hopeful candidates for a variety of biomedical and pharmaceutical applications. This study should provide a further prudence for the fungal mediated synthesis of AuNPs. PMID- 30028031 TI - Insulin-like growth factor binding protein 4 inhibits proliferation of bone marrow mesenchymal stem cells and enhances growth of neurospheres derived from the stem cells. AB - Insulin-like growth factor binding protein 4 (IGFBP-4) was reported to trigger cellular senescence and reduce cell growth of bone marrow mesenchymal stem cells (BMSCs), but its contribution to neurogenic differentiation of BMSCs remains unknown. In the present study, BMSCs were isolated from the femur and tibia of young rats to investigate effects of IGFBP-4 on BMSC proliferation and growth of neurospheres derived from BMSCs. Bone marrow mesenchymal stem cell proliferation was assessed using CCK-8 after treatment with IGFBP-4 or blockers of IGF-IR and beta-catenin. Phosphorylation levels of Akt, Erk, and p38 in BMSCs were analysed by Western blotting. Bone marrow mesenchymal stem cells were induced into neural lineages in NeuroCult medium; the number and the size of BMSC-derived neurospheres were counted after treatment with IGFBP-4 or the blockers. It was shown that addition of IGFBP-4 inhibited BMSC proliferation and immunodepletion of IGFBP-4 increased the proliferation. The blockade of IGF-IR with AG1024 increased BMSC proliferation and reversed IGFBP-4-induced proliferation inhibition; however, blocking of beta-catenin with FH535 did not. p-Erk was significantly decreased in IGFBP-4-treated BMSCs. IGFBP-4 promoted the growth of neurospheres derived from BMSCs, as manifested by the increases in the number and the size of the derived neurospheres. Both AG1024 and FH535 inhibited the formation of NeuroCult-induced neurospheres, but FH535 significantly inhibited the growth of neurospheres in NeuroCult medium with EGF, bFGF, and IGFBP-4. The data suggested that IGFBP-4 inhibits BMSC proliferation through IGF-IR pathway and promotes growth of BMSC-derived neurospheres via stabilizing beta-catenin. PMID- 30028032 TI - The place of private care governance in the South African health care system. AB - BACKGROUND: South Africa essentially has two health care systems-the public and private ones. While much is known about how the public system operates, little work has been conducted on the private sector, perhaps not surprisingly in a profit-oriented, proprietary system. But it is a massive system with its own agenda, interests, and organizations. In this paper, we address the place of private care governance issues, one seen by government as maldistributed, costly, and controlled by few groups and the medical search for profit. METHODS: Using qualitative in-depth interviews, 10 top executive managers of the hospital were asked about its functionality in terms of patient care, profitability, and the practice of governance. Data were analyzed based on themes using NVivo 10 software. RESULTS: The study demonstrates that private hospital functionality finds meaning in board structure, composition and functions, purposeful governance practices as evidenced in well-designed management structures and roles, systematizing governance through the planning of activities, and devising appropriate strategies to deal with both internal and external pressures in the health care environment. CONCLUSION: The study findings establish that shareholders and managers goals converge resulting in the institutionalization and consolidating of relational governance practices in the hospital. Yet other stakeholders appeared to be sidelined. PMID- 30028033 TI - The Indirect Effect of Posttraumatic Stress Disorder Symptoms on Current Alcohol Use Through Negative Cognitions in Sexual Minority Men. AB - Self-medication theory posits that some trauma survivors use alcohol to cope with posttraumatic stress disorder (PTSD) symptoms, but the role of negative posttraumatic cognitions in this relationship is not well defined. We examined associations among PTSD symptoms, posttraumatic cognitions, and alcohol intoxication frequency in 290 men who have sex with men (MSM), who reported a history of childhood sexual abuse (CSA). Using a bootstrap approach, we examined the indirect effects of PTSD symptoms on alcohol intoxication frequency through posttraumatic cognitions regarding the self, world, and self-blame. In separate regression models, higher levels of PTSD symptoms and posttraumatic cognitions were each associated with more frequent intoxication, accounting for 2.6% and 5.2% of the variance above demographics, respectively. When examined simultaneously, posttraumatic cognitions remained significantly correlated with intoxication frequency whereas PTSD symptoms did not. Men reporting elevated posttraumatic cognitions faced increased odds for current alcohol dependence, odds ratio (OR) = 2.19, 95% CI [1.13, 4.22], compared with men reporting low posttraumatic cognitions, independent of current PTSD diagnosis. A higher level of PTSD symptom severity was indirectly associated with more frequent alcohol intoxication through cognitions about the self and world; the indirect to total effect ratios were 0.74 and 0.35, respectively. Negative posttraumatic cognitions pertaining to individuals' self-perceptions and appraisals of the world as dangerous may play a role in self-medication with alcohol among MSM with a history of CSA. Interventions targeting these cognitions may offer potential for reducing alcohol misuse in this population, with possible broader implications for HIV-infection risk. PMID- 30028035 TI - Addressing publication bias in the anatomical literature by reporting zero prevalence of bicuspid aortic valve. PMID- 30028034 TI - Involvement of PorK, a component of the type IX secretion system, in Prevotella melaninogenica pathogenicity. AB - Prevotella melaninogenica is a gram-negative anaerobic commensal bacterium that resides in the human oral cavity and is isolated as a pathogen of suppurative diseases both inside and outside the mouth. However, little is known about the pathogenic factors of P. melaninogenica. The periodontal pathogens Porphyromonas gingivalis and Tanerella forsythia secrete virulence factors such as protease and bacterial cell surface proteins via a type IX secretion system (T9SS) that are involved in pathogenicity. P. melaninogenica also possesses all known orthologs of T9SS. In this study, a P. melaninogenica GAI 07411 mutant deficient in the orthologue of the T9SS-encoding gene, porK, was constructed. Hemagglutination and biofilm formation were decreased in the porK mutant. Furthermore, following growth on skim milk-containing medium, the diameters of the halos surrounding the porK mutant were smaller than those of the wild-type strain, suggesting a decrease in secretion of proteases outside the bacterium. To investigate this in detail, culture supernatants of wild-type and porK mutant strains were purified and compared by two-dimensional electrophoresis. In the mutant strain, fewer spots were detected, indicating fewer secreted proteins. In infection experiments, the mortality rate of mice inoculated with the porK mutant strain was significantly lower than in the wild-type strain. These results suggest that P. melaninogenica secretes potent virulence factors via the T9SS that contribute to its pathogenic ability. PMID- 30028036 TI - Decreased cognitive function is associated with dysphagia risk in nursing home older residents. AB - OBJECTIVE: To examine the association between cognitive function and dysphagia risk among Japanese nursing home residents. BACKGROUND: Reduction in cognitive function can influence the intake of food during swallowing, and may be an aggravating factor in dysphagia. METHODS: This cross-sectional study included 236 residents aged >=60 years from eight nursing homes. Screening of dysphagia, especially aspiration risk, was conducted using the Modified Water Swallow Test, whose scores from one to three were classified as at risk of dysphagia. Cognitive function was evaluated using Mini-Mental State Examination (MMSE). Number of teeth and occlusal support were evaluated by clinical examination. The participants were stratified into dentulous and edentulous groups, because the number of teeth could influence swallowing function. The odds ratio (OR) and 95% confidence interval (CI) for dysphagia risk based on the scores of MMSE were calculated using logistic regression. Demographic characteristics, activity of daily living, comorbidities, health behaviour and occlusal support were used as covariates. RESULTS: Among the 236 participants (111 dentulous participants and 125 edentulous participants) included in our analysis, 16.9% belonged to risk of dysphagia. Dentulous participants with higher scores of MMSE tended to have significantly lower odds of dysphagia risk after adjusting for covariates (OR = 0.87, 95% CI = 0.80-0.96). Despite the lack of significant differences, edentulous participants with higher score of MMSE tended to have lower odds of dysphagia risk (OR = 0.92, 95% CI = 0.83-1.00). CONCLUSION: Decreased cognitive function may be an independent predictor of dysphagia among dentulous and edentulous adults. PMID- 30028037 TI - Sorafenib Combined with 5-azacytidine in Older Patients with Untreated FLT3-ITD Mutated Acute Myeloid Leukemia. AB - Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on 2 separate protocols of AZA plus sorafenib were analyzed. The clinical trials were registered at clinicaltrials.gov (NCT02196857 and NCT01254890). Overall, 27 patients with untreated FLT3 mutated AML (median age of 74 years, range, 61-86) were enrolled. The overall response rate was 78% (7 [26%] CR, 12 [44%] CRi/CRp, and 2 [7%] PR). Patients received a median of 3 treatment cycles (1-35). The median duration of CR/CRp/CRi is 14.5 months (1.1-28.7 months). Three (11%) responding patients (1 CR, 2 CRi) proceeded to allogeneic stem cell transplant. The median follow-up for surviving patients was 4.1 months (3.0-17.3 months). The median overall survival for the entire group was 8.3 months, and 9.2 months in the 19 responders. The regimen was well tolerated in elderly patients with untreated FLT3 mutated AML with no early deaths. PMID- 30028039 TI - Transepidermal water loss, stratum corneum hydration, and skin surface pH of female African and Caucasian nursing students. AB - BACKGROUND: Conflicting evidence exists on how skin barrier function compares between Africans and Caucasians. This study measured skin barrier function of South African first year nursing students before their practical training started to compare skin barrier function between the racial groups. METHODS: Transepidermal water loss (TEWL), stratum corneum (SC) hydration, and skin surface (SS) pH was measured on female first year nursing students (19 African and 31 Caucasian; age range 18-40 years). Geometric means and ranges were calculated and the influence of anatomical areas and racial differences were evaluated respectively. RESULTS: No significant difference in TEWL was established between the racial groups. SC hydration was significantly lower (P <= 0.05) and SS-pH was significantly higher (P <= 0.0001) in African nursing students when compared to Caucasians. African nursing students had significantly lower (P <= 0.05) SC hydration on their palms when compared to the other anatomical areas. CONCLUSION: Stratum corneum hydration and SS-pH differed significantly between African and Caucasian skin, while no difference was found for TEWL, the primary parameter used to evaluate skin barrier function. Low SC hydration and high SS-pH of African nursing students prior to their practical training, may suggest a higher risk for developing occupational skin diseases. PMID- 30028038 TI - Financial implications of laparoscopic hot gallbladder service in a nontertiary District General Hospital. AB - INTRODUCTION: The service of providing index admission laparoscopic cholecystectomy (IALC), as recommended by NIC guidelines, often falls short in nontertiary centres because of a combination of limited resources and financial constraints. METHODS: This retrospective study in a single-centre District General Hospital included 50 patients, eligible to undergo IALC, and calculated potential savings from performing IALC on the day of admission by considering admission tariffs, bed, and operating costs. RESULTS: The IALC was provided in 19 patients (38%), with a mean delay from admission to operation of (median) 3 days. Mean surplus tariff was L1421 and L1571 in IALC and non-IALC groups, respectively. Performing immediate IALC (on the day of admission) for acute cholecystitis (AC) is predicted to increase mean surplus tariff to L2132 per patient, raising total predicted annual surplus by L53 000. Immediate IALC is also predicted to reduce waiting time for day-case LC by freeing up 53 day-case slots, attracting additional L95 600 annually, along with freeing up many inpatient bed days. CONCLUSIONS: This study demonstrates that reduction of preoperative stay in AC by expediting operations in every eligible patient promises significant surplus revenue. Additional advantages include reducing inpatient bed days and freeing up operating lists that are otherwise taken up by patients for interval cholecystectomy. PMID- 30028040 TI - The cell re-association-based whole-tooth regeneration strategies in large animal, Sus scrofa. AB - OBJECTIVES: Whole-tooth regeneration for tooth loss has long been a goal of dentistry. There is also an increasing demand to carry out pre-clinical in vitro and in vivo research methods in large animal model similar to human. The miniature pig has proven to be an alternative as a large mammal model owing to its many similarities to human. However, whole-tooth regeneration in large animal remains a challenge. Here, we investigated the feasibility of cell re-association based whole-tooth regeneration in miniature pigs. MATERIALS AND METHODS: Single cells from the forth deciduous molar germs (p4) of pig were reconstituted to bioengineered tooth bud using different treatment for in vitro culture and in vivo transplantation in mouse subrenal capsules and jawbones. RESULTS: The bioengineered tooth bud from re-aggregated epithelial to mesenchymal single cells with and without compartmentalization restored the morphogenesis, interactions or self-sorting between 2 cells in vitro culture. The pig bioengineered tooth bud transplanted in mouse subrenal capsules and jawbones restored odontogenesis and developed into large size tooth. CONCLUSIONS: We characterized the morphogenesis and interaction of single-tooth germ cells in vitro, and first addressed efficient long-term survival and growth through transplantation of pig bioengineered tooth bud under mouse subrenal capsules or in mouse jawbones, where it can develop into large size tooth. Our study extends the feasibility of whole tooth regeneration in large animal. PMID- 30028041 TI - Phosphenium-Cation-Mediated Formal Cycloaddition Approach to Benzophospholes. AB - A phosphenium-cation-mediated formal [3+2]-cycloaddition reaction of internal alkynes is reported. The reaction proceeds under metal-free conditions to give the corresponding C-P rearranged benzophospholes regioselectively, even when ortho- and para-substituted arylphosphine oxides are starting substrates. Mechanistic studies by 31 P{1 H} NMR analysis suggest an involvement of three membered phosphirenium cation species and C-P rearrangement prior to a ring closure for benzophosphole skeleton formation. PMID- 30028042 TI - Expression of aquaporin 4 in the chicken oviduct following tamoxifen treatment. AB - This study was designed to examine whether aquaporin 4 (AQP4) is present in the chicken oviduct, and if so, whether its expression changes during pause in laying induced by tamoxifen (TMX; oestrogen receptor modulator) treatment. The control chickens were injected with a vehicle (ethanol) and the experimental ones with TMX at a dose of 6 mg/kg of body weight. Birds were treated daily until complete cessation of egg laying. The oviductal parts, that is the infundibulum, magnum, isthmus, shell gland and vagina were isolated from hens on day 8 of the experiment, and subsequently, the gene and protein expressions of AQP4 in tissues were examined by real-time PCR and Western blot, respectively. Immunohistochemical localization of AQP4 in the wall of the chicken oviduct was also investigated. Both mRNA and protein of AQP4 were found in all segments of the chicken oviduct. The relative expression [RQ] of AQP4 was the highest in the infundibulum and the vagina and the lowest, less detectable, in the magnum and isthmus. The pattern of AQP4 protein expression was similar to that of mRNA. Treatment of hens with TMX decreased the mRNA and protein levels of AQP4 in the oviduct. Immunohistochemistry demonstrated tissue and cell-dependent localization of AQP4 protein in the oviductal wall. The intensity of the immunopositive reaction was as follows: the infundibulum > vagina > shell gland >= isthmus >? magnum. In the control chickens, the immunoreactivity for AQP4 in all oviductal segments was stronger compared with the TMX-treated hens. The results obtained indicate that AQP4 takes part in the regulation of water transport required for the formation of egg in the chicken oviduct. Moreover, a relationship between oestrogen action and AQP4 gene and protein expression is suggested. PMID- 30028043 TI - Multimodal Microscopy Distinguishes Extracellular Aggregation and Cellular Uptake of Single-Walled Carbon Nanohorns. AB - The low toxicity, high surface area, and ease of functionalisation of carbon nanohorns (CNH) makes them attractive systems for cellular imaging, diagnostics and therapeutics. However, challenges remain for the biomedical translation of these and other nanomaterials. A significant task is tuning the surface chemistry to achieve optimal cellular interactions. Herein, we combine real-time fluorescent imaging of nanoparticle cellular uptake and real-time differential interference contrast (DIC) imaging of extracellular media to monitor a) nanoparticle/nanoparticle and b) nanoparticle/cell interactions for CNHs covalently modified with an OFF/ON near-IR dye, the fluorescence of which is switched OFF in extracellular environments and triggered upon cellular internalisation. CHN samples modified with different loadings of the hydrophobic dye are taken as a simple model of drug-loaded nanoparticle systems. The punctate fluorescence suggests the CNHs are delivered to lysosomes and other vesicles of the endocytic pathway. DIC imaging highlights the competition that exists for many particle types, between extracellular aggregation and cellular internalization, the efficiency of which would be dependent upon the amount of fluorophore loading. The results of this study illustrate how complementary real time imaging methods together with physicochemical characterisation can be used to address the challenges involved in optimising nanoparticle/cell interactions for biomedical applications. PMID- 30028044 TI - Aerobic Aliphatic Hydroxylation Reactions by Copper Complexes: A Simple Clip-and Cleave Concept. AB - A simple imine clip-and-cleave concept has been developed for the selective hydroxylation of non-activated CH bonds in aliphatic aldehydes with dioxygen through a copper complex. The synthetic protocol involves reaction of a substrate aldehyde with N,N-diethyl-ethylendiamine to give the corresponding imine, which is used as a bidentate donor ligand forming a copper(I) complex with [Cu(CH3 CN)4 ][CF3 SO3 ]. After exposure of the reaction mixture to dioxygen acidic cleavage and aqueous workup liberates the corresponding beta-hydroxylated aldehyde. The concept for the hydroxylation of trimethylacetaldehyde as well as adamantane and diamantane 1-carbaldehydes was investigated and the corresponding beta-hydroxy aldehydes were obtained with high selectivities. The results of low temperature stopped-flow measurements indicate the formation of a bis(MU-oxido)dicopper complex as reactive intermediate. According to density functional theory (DFT, RI BLYP-D3/def2-TZVP(SDD)/ COSMO(CH2 Cl2 )//RI-PBE-D3/def2-TZVP(SDD)) computations CH bonds suitably predisposed to the [Cu2 O2 ]2+ core undergo hydroxylation in a concerted step with particularly low activation barriers, which explains the experimentally observed regioselectivities. PMID- 30028045 TI - Phase-Engineered Growth of Ultrathin InSe Flakes by Chemical Vapor Deposition for High-Efficiency Second Harmonic Generation. AB - As a novel layered indium selenide (InSe) semiconductor has been attracting considerable interest in the field of modern (opto)-electronics. Despite current progress, the synthesis of ultrathin InSe nanoflakes still poses quite a challenge, due to its universal co-existing varied stoichiometric compounds. In this work, a novel phase-engineered route is proposed for synthesizing ultrathin single-crystalline InSe nanoflakes with the assistance of a stable mass-transfer process in a space-confined chemical vapor deposition (CVD) system. By finely tuning the growth parameters, InSe can be obtained through engineering a phase transition thereby eliminating the undesirable In2 Se3 phase, revealed by the synergistic effect of high-content H2 and deficient Se. Furthermore, owing to the non-centrosymmetric structure, the CVD-grown InSe nanoflakes exhibit a high performance second harmonic generation (SHG), making it very promising for future SHG applications in 2D configurations. This approach paves the way for the synthesis of other similar ultrathin materials with multiphase homologous compounds. PMID- 30028046 TI - SC1 sustains the self-renewal capacity and pluripotency of chicken blastodermal cells by inhibiting the phosphorylation of ERK1 and promoting the phosphorylation of Akt. AB - Small molecules discovered during the recent years can be used to regulate the growth of embryonic stem cells (ES cells). Chicken blastodermal cells (cBCs) play an important role in both basic and transgenic researches as an important ES cell. However, the regulatory mechanism of small molecules involved in the self renewal and pluripotency of cBCs remains unknown. This study revealed that the small molecule, SC1, can maintain cBCs in an undifferentiated, pluripotent state in serum- and feeder-free E8 media without leukaemia inhibitory factor. Furthermore, SC1 inhibits downregulation of pluripotency-related genes caused by retinoic acid and promotes the proliferation of cBCs. Furthermore, the results of this study indicated that SC1 functions by inhibiting ERK1 phosphorylation and promoting Akt phosphorylation, thus promoting the expression of pluripotency related genes and maintaining the pluripotency of cBCs. The results also demonstrated that SC1 sustains the self-renewal capacity and pluripotency of cBCs cells by inhibiting ERK1 phosphorylation and promoting Akt phosphorylation. This kind of regulatory mechanism might be conserved in avian ES cells. Other molecules, similar to SC1, might provide insights into the molecular mechanisms that control the fate of stem cells and ultimately help in-vivo stem cell biology and therapy. PMID- 30028048 TI - Nonmedical benzodiazepine use in adults with alcohol use disorder: The role of anxiety sensitivity and polysubstance use. AB - BACKGROUND AND OBJECTIVES: The nonmedical use of benzodiazepines-defined as use without a prescription or at a dose or frequency higher than prescribed-is increasing among adults in substance use disorder treatment and is associated with risk for overdose. The aim of the current study was to characterize the prevalence of nonmedical benzodiazepine use among adults seeking treatment for alcohol use disorder and to examine whether nonmedical benzodiazepine use was associated with: (1) polysubstance use and (2) greater anxiety sensitivity. METHODS: A sample of 461 treatment-seeking adults with alcohol use disorder who were recruited for a cross-sectional study were included in this analysis. RESULTS: A total of 89 participants (19%) reported nonmedical benzodiazepine use in the previous 30 days. Results of a logistic regression indicated that polysubstance use (number of substances used in the past month) was associated with nonmedical benzodiazepine use. The association between anxiety sensitivity and nonmedical benzodiazepine misuse was moderated by gender; anxiety sensitivity was associated with benzodiazepine use among women, but not men. DISCUSSION AND CONCLUSIONS: These results replicate findings from research on opioid use disorder suggesting that anxiety sensitivity is associated with nonmedical benzodiazepine use in women and not men. SCIENTIFIC SIGNIFICANCE: Targeted intervention to those with polysubstance use-including education on overdose risk when benzodiazepines are combined with other substances-is indicated in men and women with alcohol use disorder. Anxiety sensitivity may be a potential therapeutic target to reduce nonmedical benzodiazepine use among women with alcohol use disorder. (Am J Addict 2018;27:485-490). PMID- 30028047 TI - Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation. AB - BACKGROUND: Asthma is a chronic inflammatory disease with structural changes present. Burgess and colleagues recently found tumstatin markedly reduced in adult asthmatic lung tissue compared with nonasthmatics. ECM fragments such as tumstatin are named matrikines and act independently of the parent molecule. The role of Col IV matrikines in neutrophil inflammation (eg. exacerbation in asthma) has not been investigated to date. Severe adult asthma phenotypes are dominated by neutrophilic inflammation and show a high frequency of severe exacerbations. OBJECTIVE: This study sought to investigate the role of a novel active region within tumstatin (CP17) and its implication in neutrophil inflammatory responses related to asthma exacerbation. METHODS: For reactive oxygen production, isolated neutrophils were preincubated with peptides or vehicle for 1 hour and stimulated (PMA). Luminescence signal was recorded (integration over 10 seconds) for 1.5 hours. Neutrophil migration was performed according to the SiMA protocol. Mice were sensitized to OVA/Alumn by intraperitoneal (i.p.) injections. Mice were then treated with CP17, vehicle (PBS) or scrambled peptide (SP17) after OVA exposure (days 27 and 28, polyI:C stimulation). All animals were killed on day 29 with lung function measurement, histology and lavage. RESULTS: CP17 decreased total ROS production rate to 52.44% (0.5 MUmol/L, P < 0.05 vs SP17), reduced the in vitro directionality (vs SP17, P = 1 * 10-6 ) and migration speed (5 MUmol/L, P = 1 * 10-3 ). In vivo application of CP17 decreased neutrophil inflammation ~1.8 fold (P < 0.001 vs SP17) and reduced numbers of mucus-producing cells (-29%, P < 0.05). CONCLUSION: CP17 reduced the ROS production rate, migrational speed and selectively inhibited neutrophil accumulation in the lung interstitium and lumen. CLINICAL RELEVANCE: CP17 may serve as a potential precursor for drug development to combat overwhelming neutrophil inflammation. PMID- 30028049 TI - Anti-ApoA-I IgG antibodies are not associated with carotid artery disease progression and first-time cardiovascular events in middle-aged individuals. AB - OBJECTIVE: IgG antibodies against apolipoprotein A-I (ApoA-I) have been found to be elevated in subjects from the general population with clinically manifest cardiovascular disease and in myocardial infarction patients with an adverse prognosis. Here, we investigated whether these antibodies are prospectively associated with carotid artery disease progression and with the risk for first time cardiovascular events in individuals with no previous history of cardiovascular disease. APPROACH AND RESULTS: We selected 383 subjects from the cardiovascular cohort of Malmo Diet and Cancer study who suffered a coronary event during a median follow-up period of 15.4 (10.3-16.4) years and 395 age- and sex-matched controls. None of the study participants had a previous history of coronary artery disease or stroke. Anti-ApoA-I IgG were measured by ELISA in serum samples collected at baseline. Intima-media thickness (IMT) was measured in the common carotid artery and in the carotid bifurcation at baseline and after 15.9 (+/-1.5) years. We found no associations between anti-ApoA-I IgG and carotid artery IMT at baseline or with IMT progression during follow-up. In Cox proportional hazards analyses adjusted for traditional cardiovascular risk factors, the hazard ratio (HR 95%CI) for the primary outcome, incident coronary events, was 0.97 (0.75-1.25), P = 0.782, in subjects with anti-ApoA-I IgG within the highest tertile compared with the lowest tertile. Similarly, we did not find any associations with the secondary outcome, incident first-time stroke. CONCLUSIONS: Serum autoantibodies against ApoA-I do not correlate with disease progression and adverse events in cardiovascular disease-free individuals from the general population. PMID- 30028050 TI - Price elasticities of pharmaceuticals in a value based-formulary setting. AB - Empirical estimates of price elasticities of demand (PED) for pharmaceuticals suggest that they are relatively price inelastic. However, in many settings, a medication and its substitutes and complements face simultaneous differential changes in prices that affect the observed "composite" PED. We exploit an implementation of a value-based formulary (VBF) that utilized drug-specific incremental cost-effectiveness ratios (ICERs) to inform drug copayments, resulting in increases in copayments for some medications and decreases in copayments for others. We first show theoretically that by changing the price of a medication and its substitute in opposite directions, VBF designs can leverage cross-price effects to increase the range of composite PEDs. We then empirically estimate PED and welfare effects using a consumer surplus approach. Overall PED was -0.16, similar to the RAND Health Insurance Experiment estimate. However, there was substantial dispersion of PED across the VBF copayment tiers ranging from -0.09 to -0.87 with a statistically significant trend aligned with the levels of value as reflected by the ICER estimates (p < 0.001). The net welfare increase was $147,000 for the cohort or $28 per member over the postpolicy year. Further experimentations of VBF designs with alternative cost-effectiveness thresholds, copayment levels and value definitions could be quite promising for improving welfare. PMID- 30028051 TI - The Impact of Nicotine and Cigarette Smoke Condensate on Metabolic Activity and Biofilm Formation of Candida albicans on Acrylic Denture Material. AB - PURPOSE: Smokers have increased denture stomatitis caused primarily by Candida albicans. The primary aim of this study was to demonstrate the impact of a wide range of nicotine and cigarette smoke condensate (CSC) concentrations on biofilm formation and metabolic activity of C. albicans on acrylic denture material. MATERIALS AND METHODS: C. albicans (ATCC strain 10231) was used. Standardized denture acrylic (PMMA) specimens (total of 135 specimens) were incubated with C. albicans and exposed to nicotine and CSC at different concentrations (0, 0.25, 0.5, 1, 2, 4, 8, 16, and 32 mg/ml) and (0, 0.25, 0.5, 1, 2, and 4 mg/ml), respectively. For each experiment, 3 samples per nicotine and CSC concentration and a total of 45 specimens (27 specimens for the nicotine and 18 specimens for the CSC-treated samples) were used and were selected randomly for each group. The control group consisted of 0 mg/ml of nicotine or CSC. The viability of C. albicans was measured using spiral plating on blood agar plates. The effect of nicotine and CSC concentrations on planktonic cells was were measured using a microplate reader. Metabolic activity of 24-hour-old established C. albicans biofilm exposed to nicotine and CSC for 24 hours in microtiter plates was determined using a 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium carboxanilide (XTT) reduction assay. RESULTS: The viability of C. albicans increased concomitant with increasing concentrations of CSC and nicotine, particularly at 0.5 and 2 mg/ml, respectively. Concentrations of CSC and nicotine above this resulted in an inhibitory effect on C. albicans viability. CSC and nicotine at 4 and 16 mg/ml, respectively, increased C. albicans biofilm metabolic activity. CONCLUSION: Nicotine and CSC up to certain concentrations caused increases in biofilm formation, metabolic activity, viability, and planktonic cell absorbance of C. albicans. This in vitro study demonstrates the effectiveness of tobacco on promoting the growth of C. albicans and suggests their potential contributing factor in C. albicans biofilm related infections in smokers. PMID- 30028052 TI - Effect of Aging Time and Thickness on Low-Temperature Degradation of Dental Zirconia. AB - PURPOSE: To evaluate the influence of specimen thickness and low-temperature degradation (LTD) on yttrium-stabilized tetragonal zirconia polycrystals (Y-TZP). MATERIALS AND METHODS: Thin discs of Y-TZP from four manufacturers were sintered according to each manufacturer's recommendations, cut into 23 mm (length) * 4 mm (width) * 0.8 mm/1.5 mm (thickness) specimens, artificially aged under standard autoclave sterilization conditions (34 degrees C at 0.2 MPa for 10 and 20 hours), and finally ground and polished. Tetragonal to monoclinic transformation was confirmed by X-ray diffraction (XRD) analysis. Flexural strength was measured by 3-point bending tests and Vickers hardness measurements. Fracture surfaces were examined by scanning electron microscopy (SEM). RESULTS: SEM investigation revealed that with increasing aging time, the surface defects and grain size increased, particularly in the 20-hour group. Compared with the 1.5 mm group, the 0.8 mm group showed more significant defects, irrespective of aging time. The flexural strengths of Y-TZP materials decreased with a decrease in the thickness. Moreover, LTD of Y-TZP can cause significant tetragonal to monoclinic transformation, which also results in a statistically significant decrease in the flexural strength. CONCLUSION: A thinner Y-TZP specimen was likely to present surface defects and microcracks after aging. In addition, the flexural strengths decreased with a decrease in the thickness, a notable fact for further studies. PMID- 30028053 TI - The quality of randomized controlled trials of psychotherapy for eating disorders. AB - OBJECTIVE: We investigated the quality of randomized controlled trials (RCTs) that included direct comparisons of psychotherapy for adults with an eating disorder (ED). METHOD: Thirty-five direct comparison RCTs of psychotherapy for adults diagnosed with an ED were rated using the Randomized Controlled Trials Psychotherapy Quality Rating Scale (RCT-PQRS). RESULTS: The mean total RCT-PQRS score (mean = 28.26; SD = 7.04) was in line with those that were reported for RCTs of psychotherapy for depression and anxiety disorders. Several standards of quality were unfulfilled by over half of the RCTs of treatment for EDs, including therapist supervision while treatment was being provided (62.9% unfulfilled); outcome assessment performed by raters blind to treatment group/condition (54% unfulfilled); and adequate sample size (66% unfulfilled). More recent RCTs were of higher quality, and higher quality was moderately associated with lower effect sizes. CONCLUSIONS: To improve the quality of RCTs of psychotherapy of EDs, we recommend that researchers address the quality criteria listed in the RCT-PQRS. Psychotherapy trials should be registered, have a published protocol, and be reported following the Consolidated Standards of Reporting Trials guidelines. Authors should take into account the quality of the research when using that research to inform ED treatment guidelines. PMID- 30028054 TI - A narrative synthesis of the quality of cancer care and development of an integrated conceptual framework. AB - The general paradigms that exist to guide measures in quality of care do not sufficiently deal with the changing needs of cancer management. The aim of this study was to review the literature regarding the quality of cancer care and develop a conceptual framework relevant to current practice. A textual narrative review of the literature was conducted by searching electronic databases from the last 10 years. Articles were then screened and included if they were both relevant to the management of cancer and standards in quality of care. Thematic analysis of the included articles was performed. Eighty-three articles were included and 12 domains identified and integrated with current models to develop a conceptual framework. These included: healthcare delivery system; timeliness; access; appropriateness of care; multidisciplinary and coordinated care; patient experience; technical aspects; safety; patient-centred outcomes; disease-specific outcomes; innovation and improvement and value. We propose a conceptual framework for the quality of cancer care based on relevant and current oncology practice. This presents a more practical and comprehensive approach than general models, and can be used by healthcare providers, managers and policy makers to guide and identify the need for metrics for quality improvements. PMID- 30028055 TI - Implant Placement under Existing Removable Dental Prostheses and the Effect on Follow-Up and Prosthetic Maintenance. AB - PURPOSE: The aim of this prospective clinical study was to compare the maintenance interventions required for solely implant-retained overdentures (I OD) with that of overdentures retained by a combination of telescopic crowns and implants (T/I-OD). MATERIALS AND METHODS: The participants in this study were 22 patients who initially presented either with a removable complete denture (n = 11) or with an overdenture retained by 1 to 2 telescopic crowns on natural teeth (n = 11). Subsequently, the total number of abutments was increased to 5 to 6 (maxilla) or 4 to 5 (mandible) by placing implants in strategically advantageous regions, generating two distinct groups: I-OD and T/I-OD. Ball attachments were connected to the implants and integrated into the existing denture. The maintenance aspects were analyzed according to the type of treatment (preventive, biological, and technical) and to the severity of treatment (minimal, moderate, and extensive). RESULTS: During a mean observation time of 6.5 years, the tooth survival rate was 89% (T/I-OD) and the implant survival rate 100% (both groups). The survival rates of the overdentures ranged from 90.9% (I-OD) to 100% (T/I-OD). A mean number of 0.6 (I-ODs) and 2.0 (T/I-OD) treatments were performed for biological reasons; and 8.2 (I-ODs) and 9.6 (T/I-OD) for technical reasons, per patient, during the observation time. From biological aspects, significantly more extensive maintenance was found to be necessary in the T/I-OD group than in the I OD group. CONCLUSIONS: The therapeutic concept of implant placement under existing prostheses was promising when performed in indicated cases. PMID- 30028056 TI - Barriers to care for breast cancer: A qualitative study in Ireland. AB - Disparities in survival after breast cancer persist. Cancer registry data that are often used to assess associated factors only explain some of the differences. The purpose of this study was to obtain information from disadvantaged Irish women concerning possible barriers to care for breast cancer above and beyond risk factors collected by cancer registries. We used a qualitative interview study with disadvantaged women in treatment for breast cancer, following the methods of thematic analysis. Important themes potentially related to disparity occurred in each treatment phase. Before diagnosis themes included delays in diagnosis. During treatment themes concerned surgical complications, communication difficulties and use of alternative therapies. During the post treatment phase a strong theme was lack of compliance with hormone therapy. Overarching themes were stress related to disadvantage, including financial difficulties, obesity, alcohol use, fears of eviction from home, worry about dependent relatives. Future studies of the breast cancer survival gap arising from socio-economic disadvantage may benefit from a mixed-methods approach that combines cancer registry data with personal interviews to understand the persistence of survival disparities. As breast cancer rates continue to rise disparities in survival due to socio-economic disadvantage will continue, but can be addressed and mitigated. PMID- 30028057 TI - MiR-616-3p modulates cell proliferation and migration through targeting tissue factor pathway inhibitor 2 in preeclampsia. AB - OBJECTIVES: Despite improvements in diagnosis and treatment, preeclampsia (PE) continues to pose a significant risk of maternal and foetal morbidity and mortality if not addressed promptly. An increasing number of studies have suggested that tissue factor pathway inhibitor 2 (TFPI2) acts as a suppressor gene, possibly inhibiting multiple serine proteases affecting cell proliferation and migration. It plays an essential role in the occurrence and development of PE, but the pathogenesis remains unclear. MATERIALS AND METHODS: In our research, we performed western blotting, immunohistochemistry and qPCR assays to investigate TFPI2 and miR-616-3p expression in preeclamptic placental tissues. Cell assays were performed in HTR-8/SVneo and JEG3 cell lines. Cell proliferation and migration events were investigated by MTT, EdU and transwell assays. In conjunction with bioinformatics analysis, luciferase reporter assays were performed to elucidate the mechanism by which miR-616-3p binds to TFPI2 mRNA. RESULTS: We established that TFPI2 protein levels were significantly upregulated in PE placental tissues. In addition, we found that miR-616-3p binds specifically to the 3'-UTR region of TFPI2 mRNA. Furthermore, miR-616-3p knockdown or TFPI2 overexpression substantially impaired cell growth and migration, whereas miR-616 3p upregulation or TFPI2 knockdown stimulated cell proliferation and migration. This miR-616-3p/TFPI2 axis was also found to affect the epithelial-mesenchymal transition process in PE. CONCLUSIONS: Our results demonstrated that TFPI2 plays a vital role in the progression of PE and might provide a prospective therapeutic strategy to mitigate the severity of the disorder. PMID- 30028058 TI - Withdrawal severity and early response to treatment in the outpatient transition from opioid use to extended release naltrexone. AB - BACKGROUND AND OBJECTIVES: Long acting naltrexone has improved the therapy of opioid use disorder (OUD), and safe and effective withdrawal management during naltrexone induction may help advance treatment. Despite the uncertain role of opioid withdrawal in predicting successful outcomes, early symptom control may favor detoxification completion. METHODS: We explored withdrawal severity and early response to treatment, safety, and clinical measures in 35 adult patients with DSM-5 OUD during a 7-day office-based buprenorphine-naltrexone and ancillary medications transition to extended-release naltrexone (XR-NTX). RESULTS: Subjective and objective measures of withdrawal intensity improved consistently throughout treatment in the whole sample. Participants who went on to receive XR NTX (n = 27, 77%) reported a greater attenuation of symptoms by treatment day 2 (r = .595, p = .001), and were less likely to be injection drug users (r = -.501, p = .004). Adverse events (AEs) were recorded in 20% of participants: the majority (n = 6, 85.7%) consisted of single episodes of increased withdrawal which were well controlled using ancillary medications. One serious AE was unrelated to treatment. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Early opioid withdrawal changes may be a useful indicator of treatment response, helping adjust the transition protocol to the individual patients' need and gather valuable information for a better understanding of the relationship between initiating and remaining in treatment. (Am J Addict 2018;27:471-476). PMID- 30028059 TI - The neural development of pragmatic inference-making in natural discourse. AB - Older interlocutors are more likely than younger ones to make pragmatic inferences, that is, inferences that go beyond the linguistically encoded meaning of a sentence. Here we ask whether pragmatic development is associated with increased activity in brain structures associated with inference-making or in those associated with Theory of Mind. We employed a reading task that presents vignettes in one of two versions, one of which is expected to prompt more pragmatic processing. Both versions present a major premise containing three possibilities (e.g., Xavier is considering Thursday, Friday or Saturday for inviting his girlfriend out). In the Fully-Deductive (control) condition, the major premise is followed by two disjunction-elimination premises through two separate lines (one indicating that Saturday is not convenient and another saying that Thursday is not convenient); this is followed by a valid conclusion (e.g., "I'll reserve Friday"). In the Implicated-Premise condition, the first disjunction-elimination premise is followed by a second similar one that eliminates the same disjunction (e.g., both lines explain why Saturday is not convenient). In this condition, readers may pragmatically enrich the conclusion (i.e., "I'll reserve Friday" pragmatically implicates that Xavier is also eliminating Thursday from consideration). Reading times in Experiment 1 showed that processing the speaker's conclusion in the Implicated-Premise condition becomes increasingly more effort-demanding as readers reach adolescence. Experiment 2 showed that this developmental pattern is related to age-related increases in fMRI activity in fronto-parietal regions typically involved in inference-making processes. We found no evidence indicating age effects related to Theory of Mind areas. PMID- 30028060 TI - Are there differences between men and women in outcome of intensive inpatient treatment for anorexia nervosa? An analysis of routine data. AB - OBJECTIVE: Anorexia nervosa (AN) in men is rare and understudied. We compared admission characteristics and response to specialized inpatient treatment between men and women with AN. METHOD: One hundred sixteen consecutive male patients with AN were matched to 116 female patients. Patients completed the self-rating Structured Inventory for Anorexic and Bulimic Syndromes (SIAB-S) at admission and discharge. Differences at admission and in treatment response were examined with independent samples t-tests and ANOVA for repeated measures, respectively. RESULTS: Men had lower body mass index (BMI)-percentiles (Cohen's d = -0.55), higher levels of weight suppression (d = 0.65), and higher scores in the SIAB-S general psychopathology and social integration scale (d = 0.47) at admission. There were no differences in response to treatment except for changes in BMI percentile (F = 4.49, p = 0.035). CONCLUSIONS: There were more similarities than differences between genders in AN. Because this similarity might be confounded with traditionally "feminine" conceptualizations of AN, further studies of male AN are needed. PMID- 30028061 TI - The Influence of Age, Gender, Mandibular Bone Height, Previous Experience with Prostheses, and Fabrication Methods on Masticatory Performance of Complete Denture Wearers. AB - PURPOSE: To evaluate the influence of age, gender, mandibular bone height, previous experience with prostheses, and methods for denture fabrication on masticatory performance of complete denture (CD) wearers. MATERIALS AND METHODS: For this study, 29 individuals treated with CDs fabricated by simplified or conventional methods had their masticatory performance assessed 4 weeks after the prostheses' adjustment and control, using the sieve method and almonds as a natural food test. Experimental variables related to age, gender, and previous use of complete dentures were collected from dental records. Panoramic digital radiographs were used to determine mandibular bone height according to the criteria described by the American College of Prosthodontists. Data on masticatory performance were assessed using t-test for independent samples to make comparison between simplified and conventional methods, and a multiple linear regression analysis was performed to evaluate the influence of age, gender, previous experience with CDs, and mandibular bone height on masticatory performance using SPSS software with a significance level of 5%. RESULTS: There was no significant influence regarding the method for CD fabrication (p = 0.92), age (p = 0.36), mandibular bone height (p = 0.37), and previous experience with prostheses (p = 0.15) on masticatory performance of CD wearers. Female patients presented lower masticatory performance than male (p = 0.04) patients did. CONCLUSIONS: Considering the limitations of this study, it was concluded that gender might be considered a risk factor for masticatory performance of CD wearers. Female patients demonstrated reduced masticatory performance in comparison to male patients. PMID- 30028062 TI - Suitability of a Mobile Phone Colorimeter Application for Use as an Objective Aid when Matching Skin Color during the Fabrication of a Maxillofacial Prosthesis. AB - PURPOSE: Color matching a facial prosthesis to human skin is very challenging. Colorimeters aid this process by adding objectivity to what is an otherwise subjective procedure. Mobile phone colorimeter applications offer a less expensive and widely available alternative to dedicated colorimeter devices for color measurement. There is a lack of evidence in the literature regarding the suitability of mobile phone colorimeter applications for the development of silicone shades for facial prosthetics. The purpose of this study is to determine the suitability of a mobile phone colorimeter application for matching natural skin colors during the fabrication of maxillofacial prostheses. MATERIALS AND METHODS: Ten pigmented maxillofacial silicone elastomer swatches were fabricated to mimic a range of human skin tones. Color measurements of these swatches were recorded using a test instrument-the mobile phone colorimeter application (RGB Colorimeter) and a reference instrument-the commercially available skin color measurement device e-skin spectrocolorimeter. Comparisons in trueness and precision of the color measurements were made using previously described methods. Data analysis was performed on the recorded results for each of the parameters at three distances (25, 30, and 35 mm) of the test instrument from the target against both a black and a white background. RESULTS: The trueness of the mobile phone colorimeter application relative to the colorimeter device varied depending on the distance from the target and the background color. The relative trueness of the color difference measurements fell just within the documented upper threshold of acceptable limits of color difference (?E 3.0 - 4.4). The calculated precision of the CIE L*a*b* and ?E measurements of the mobile phone colorimeter application was good, with the latter being well within the documented acceptable limits. CONCLUSIONS: A mobile phone colorimeter application would be a suitable aid in objectifying the process of color matching a silicone maxillofacial prosthesis. Further investigation into image calibration to improve trueness and the control of variables such as background noise, uniformity of illumination, and measuring distance is required. PMID- 30028063 TI - Effect of Resin Cement Brand on the Color of Zirconia-Based Restorations. AB - PURPOSE: The purpose of this in vitro study was to evaluate the effect of resin cement brand on the color of zirconia-based restorations. MATERIALS AND METHODS: Ninety A2 shade veneered zirconia disc specimens (0.5 mm zirconia thickness, 1 mm veneer thickness, 10 mm diameter) and 90 A3.5 shade composite resin background specimens (10 mm height, 10 mm diameter) with a superficial cement space (0.1 mm depth, 8 mm diameter) were fabricated. The zirconia specimens were cemented to the background specimens using universal resin cements: RelyX Unicem 2 (RU), PANAVIA SA Cement Plus (PS), and NX3 Nexus (NN). CIELab values were measured with a spectrophotometer before and after cementation. ?E values were calculated to determine the color differences between before and after cementation of specimens (?E1 ), and between the A2 VITA classical shade tab and specimens before cementation (?E2 ) and after cementation (?E3 ). The DeltaE values were compared with an acceptability threshold (DeltaE = 3.7) to evaluate color changes/matches. Welch, 1-way ANOVA, Games-Howell, Tukey HSD, and 1-sample t test were used to analyze data (p < 0.05). RESULTS: Mean DeltaE1 values were 0.6 +/- 0.3 for RU, 0.8 +/- 0.4 for PS, and 0.6 +/- 0.2 for NN. Resin cement brand significantly affected the DeltaE1 (p = 0.029) and the DeltaE3 (p < 0.001). Mean DeltaE3 values were 3.6 +/- 0.3 for RU, 3.5 +/- 0.3 for PS, and 3.9 +/- 0.3 for NN. RU (p = 0.960) and PS (p = 0.999) showed a color match, but NN did not (p < 0.001). CONCLUSIONS: The resin cement brand affected the color match of zirconia-based restorations. Although the tested cements created minor color changes, RU and PS were better than NN for color match. The use of resin cements with the corresponding shade to the target shade is indicated. PMID- 30028064 TI - Reference centiles for the gross motor function measure and identification of therapeutic effects in children with cerebral palsy. AB - RATIONALE, AIMS, AND OBJECTIVES: Children with cerebral palsy (CP) can show an increase in gross motor function until the age of 9 to 10 years under the standard of care. Additionally, the motor development can have large individual fluctuations. Therefore, in clinical setting, it is not trivial to estimate the effect of an additional therapeutic intervention at this age interval. The study aim was to develop a method which allows quantification of the gross motor function changes over 6 months of the individual child with CP. METHOD: The present study was a single center retrospective analysis. Data were collected in children with CP who participated in a rehabilitation program between 2006 and 2016. The gross motor function of the children was measured with the Gross Motor Function Measurement (GMFM-66). Reference centiles for the GMFM-66 were created with data before starting the rehabilitation program. The variability of the evolution of the GMFM-66 was assessed with data at the start and the end of a 6 month observational phase of standard of care. RESULTS: In total, the GMFM-66 data of 919 children before starting the rehabilitation program were available (age 6.49 +/- 2.49 years, GMFCS-level I-V). For 515 study participants (6.76 +/- 2.30 years, GMFCS-level I-V), data were also available at the start and the end of a 6-month observational phase. CONCLUSIONS: The presented method helps to guide the clinician to track the individual patient's gross motor development and assess the additional effect of an additionally applied intervention while taking into account the expected progression of gross motor function under standard of care. PMID- 30028065 TI - Viewing dressing evaluation through a pragmatic lens: The application of Dewey's experimentalism in the development of evidence for dressing selection. AB - RATIONALE, AIMS, AND OBJECTIVES: The aim of this paper is to (1) summarize the challenges with developing evidence for dressing selection in wound care, (2) discuss the limiting influence that the Evidence-Based Practice movement has had in this field, and (3) discuss the opportunities offered by Dewey's theory of experimentalism as a pragmatic solution to develop a structured body of evidence. FINDINGS: Whilst the number of dressings available on the market continue to proliferate, limited progress has taken place to develop a methodology for dressing evaluation that is relevant to clinical practice. It is proposed that experimentalism can be operationalized with a mixed-methods approach that may include the following: (1) medical histories and patient's stories; (2) participant observation and informal interviews; (3) a comparative study between a new dressing and standard care; (4) a patient's satisfaction survey; (5) a staff survey; (6) a cost examination; (7) an evaluation of the packaging and procurement route; and finally (8) a clinical meeting to triangulate the data and reach a consensus. CONCLUSION: Experimentalism offers a framework for the construction of evidence used for dressing selection. Central to this concept is the integration of experience to the data collected. The context of the evaluation has equal weight to the data thus collected. PMID- 30028066 TI - The role of phenotypic plasticity and pollination environment in the cleistogamous, mixed mating breeding system of Triodanis perfoliata. AB - The role of variable pollination environments in maintaining mixed mating systems is an active area of research. Dimorphic cleistogamy, in which a plant reproduces by both open, facultative outcrossing chasmogamous (CH) flowers and closed, cleistogamous (CL) flowers presents an excellent opportunity to study mixed mating. For example, plastic responses in allocation to an optimal floral type could serve as an adaptive strategy that maintains mixed mating under variable pollination environments. We tested for pollen limitation and plastic responses in allocation to different floral types under manipulated pollination conditions in the dimorphic cleistogamous, mixed mating annual, Triodanis perfoliata. Using a field population, we quantified pollen limitation, auto-fertility and plastic responses in the breeding system by measuring allocation to flower number and seed set of floral types. We found no evidence for pollen limitation for CH flowers, and CH flowers had low efficacy of autonomous selfing. Importantly, we found that T. perfoliata alters floral number following changes in pollination conditions, with pollen-supplemented plants having lower relative CH flower number than non-supplemented plants. Breeding system plasticity may allow for benefits from outcrossing through CH flowers, but also increased overall fitness through relatively cheap CL reproduction. After CH flowers receive pollen, subsequent production of CH flowers was reduced, which may be due to resource limitation. Our findings did not support a theoretical model predicting increased CH flowers with high pollination levels. These results increase our understanding of the role of pollination services and resource allocation in the maintenance of mixed mating systems, which also warrants further investigation. PMID- 30028067 TI - Glycemic variability in the development of cardiovascular complications in diabetes. AB - Diabetes mellitus represents a major risk factor for the development of coronary artery disease and other vascular complications. Glycated haemoglobin, fructosamine, and fasting blood glucose levels are partial parameters to exhaustively describe patient dysglycemic status. Thus, recently the new concept of glycemic variability has emerged, including information about two major aspects: the magnitude of blood glucose excursions (from nadir to peak, thus lower and higher spikes) and the time intervals in which these fluctuations occur. Despite the lack of consensus regarding the most appropriate definition and tools for its assessment, glycemic variability seems to have more deleterious effects than sustained hyperglycemia in the pathogenesis of diabetic cardiovascular complications. This manuscript aimed to review the most recent evidence on glycemic variability and its potential use in everyday clinical practice to identify diabetic patients at higher risk of cardiovascular complications and thus needing stricter monitoring and treatment. PMID- 30028068 TI - UV Photoionization of Sodium-Doped Formic Acid Clusters. AB - The processes involved in the photoionization of sodium-doped clusters are complex, not fully understood for many systems and still strongly debated, especially because of the discrepancy between experimental results and predicted cluster structures. We have performed a study on sodium doped formic acid clusters based on UV photoionization spectroscopy and DFT/TDDFT calculations. Apart from the monomer, all the predicted structures show vertical ionization potential values higher than those obtained by the photoionization measurements. We have calculated the absorption spectra and found many Rydberg-like states near the adiabatic ionization potentials and, crucially, in the UV range where the clusters appearance energies fall. This finding supports the hypothesis of adiabatic contributions in the measured ionization potentials for these clusters. PMID- 30028069 TI - Achieving Cure From Hepatitis C Virus Is Good for More Than Just the Liver Graft. PMID- 30028070 TI - Transcriptomic approach and membrane fatty acid analysis to study the response mechanisms of Escherichia coli to thyme essential oil, carvacrol, 2-(E)-hexanal and citral exposure. AB - AIMS: The application of essential oils (EOs) and their components as food preservatives is promising but requires a deeper understanding of their mechanisms of action. This study aims to evaluate the effects of thyme EO, carvacrol, citral and 2-(E)-hexenal, on whole-genome gene expression (the transcriptome), as well as the fatty acid (FA) composition of the cell membranes of Escherichia coli K12. METHODS AND RESULTS: Therefore, we studied the response against 1 h of exposure to sublethal concentrations of natural antimicrobials, of exponentially growing E. coli K12, using DNA microarray technology and a gas chromatographic method. The results show that treatment with a sublethal concentration of the antimicrobials strongly affects global gene expression in E. coli for all antimicrobials used. Major changes in the expression of genes involved in metabolic pathways as well as in FA biosynthesis and protection against oxidative stress were evidenced. Moreover, the sublethal treatments resulted in increased levels of unsaturated and cyclic FAs as well as an increase in the chain length compared to the controls. CONCLUSIONS: The down-regulation of genes involved in aerobic metabolism indicates a shift from respiration to fermentative growth. Moreover, the results obtained suggest that the cytoplasmic membrane of E. coli is the major cellular target of EOs and their components. In addition, the key role of membrane unsaturated FAs in the response mechanisms of E. coli to natural antimicrobials has been confirmed in this study. SIGNIFICANCE AND IMPACT OF THE STUDY: The transcriptomic data obtained signify a further step to understand the mechanisms of action of natural antimicrobials also when sublethal concentrations and short-term exposure. In addition, this research goes in deep correlating the transcriptomic modification with the changes in E. coli FA composition of cell membrane identified as the main target of the natural antimicrobials. PMID- 30028072 TI - Perceptions, knowledge, and perceived barriers of Yemeni pharmacists and pharmacy technicians towards evidence-based practice. AB - RATIONAL, AIMS, AND OBJECTIVE: The aim of this study was to assess the knowledge and perception towards evidence-based practice (EBP) and identify the perceived barriers to practicing EBP among Yemeni pharmacists and pharmacy technicians. METHODS: A cross-sectional survey study was carried out among 153 Yemeni pharmacists and pharmacy technicians who are working in hospitals or community pharmacies. This study took place between the 15th of August and the 8th of November 2017 using a self-administered validated questionnaire. The study was approved by the ethics committee/scientific research center of Yemen University, Yemen (Reference number: ERC/2017/103). RESULTS: Completed questionnaires were received from 153 (46.6% response rate). Most of the respondents showed a positive attitude towards EBP; however, their understanding of the basic terms used in EBP was poor (34.6%). The types of source that the respondent used in high percentage to make their decisions were own judgement and consulting the colleagues that can no longer be accurate and evidence based. The barriers to practicing EBP identified by most respondents were the limited access to EBP sources and lack of personal time. CONCLUSION: These results reveal strong support for EBP among pharmacists and pharmacy technicians in Yemen but only a minority indicated that they understood the technical terms of EBP. Training and continuing education programs on EBP and guidelines for pharmacists are strongly needed. These findings may help in planning the use and the application of EBP process in pharmacy practice. PMID- 30028073 TI - Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases. AB - The average lifespan of circulating erythrocytes usually exceeds hundred days. Prior to that, however, erythrocytes may be exposed to oxidative stress in the circulation which could cause injury and trigger their suicidal death or eryptosis. Oxidative stress activates Ca2+ -permeable nonselective cation channels in the cell membrane, thus, stimulating Ca2+ entry and subsequent cell membrane scrambling resulting in phosphatidylserine exposure and activation of Ca2+ -sensitive K+ channels leading to K+ exit, hyperpolarization, Cl- exit, and ultimately cell shrinkage due to loss of KCl and osmotically driven water. While the mechanistic link between oxidative stress and anemia remains ill-defined, several diseases such as diabetes, hepatic failure, malignancy, chronic kidney disease and inflammation have been identified to display both increased oxidative stress as well as eryptosis. Recent compelling evidence suggests that oxidative stress is an important perpetrator in accelerating erythrocyte loss in different systemic conditions and an underlying mechanism for anemia associated with these pathological states. In the present review, we discuss the role of oxidative stress in reducing erythrocyte survival and provide novel insights into the possible use of antioxidants as putative antieryptotic and antianemic agents in a variety of systemic diseases. PMID- 30028074 TI - Mini-review: Phytoplankton-derived polysaccharides in the marine environment and their interactions with heterotrophic bacteria. AB - Within the wealth of molecules constituting marine dissolved organic matter, carbohydrates make up the largest coherent and quantifiable fraction. Their main sources are from primary producers, which release large amounts of photosynthetic products - mainly polysaccharides - directly into the surrounding water via passive and active exudation. The organic carbon and other nutrients derived from these photosynthates enrich the 'phycosphere' and attract heterotrophic bacteria. The rapid uptake and remineralization of dissolved free monosaccharides by heterotrophic bacteria account for the barely detectable levels of these compounds. By contrast, dissolved combined polysaccharides can reach high concentrations, especially during phytoplankton blooms. Polysaccharides are too large to be taken up directly by heterotrophic bacteria, instead requiring hydrolytic cleavage to smaller oligo- or monomers by bacteria with a suitable set of exoenzymes. The release of diverse polysaccharides by various phytoplankton taxa is generally interpreted as the deposition of excess organic material. However, these molecules likely also fulfil distinct, yet not fully understood functions, as inferred from their active modulation in terms of quality and quantity when phytoplankton becomes nutrient limited or is exposed to heterotrophic bacteria. This minireview summarizes current knowledge regarding the exudation and composition of phytoplankton-derived exopolysaccharides and acquisition of these compounds by heterotrophic bacteria. PMID- 30028071 TI - Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells. AB - Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2-mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCdeltadependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria-targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2-mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial specific interventions as a key aspect of antioxidant and antiaging therapies. PMID- 30028075 TI - Quantification of eight active ingredients in crude and processed radix polygoni multiflori applying miniaturized matrix solid-phase dispersion microextraction followed by UHPLC. AB - A rapid, efficient, and green sample preparation method has been developed to extract eight active ingredients (gallic acid, catechins, epicatechin, polydatin, 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside, resveratrol, emodin, and physcion) in radix polygoni multiflori by miniaturized matrix solid-phase dispersion microextraction. Simple and sensitive ultra high performance liquid chromatography combined with ultraviolet detection has been applied to analyze the multiple compounds. The best results were obtained by adding 25 mg sample into 25 mg adsorbent and grinding for 2 min with disorganized silica as adsorbent and 1 mL 150 mM 1-dodecyl-3-methylimidazolium bromide as a green eluting solvent. Good linearity (r2 > 0.998) for each analyte was obtained by this method. The intra-day and inter-day precision (RSD) were both below 5.31%, and the recoveries of the analytes ranged from 93.3 to 100.0%. This simple miniaturized matrix solid phase dispersion microextraction method for analyzing the compounds in radix polygoni multiflori needs a short time and requires little sample and reagent. Thus, this method is far more eco-friendly and efficient than traditional extraction methods (reflux and ultrasound-assisted extraction). The present investigation provided a promising method for the fast preparation and discrimination of chemical differences in crude and processed radix polygoni multiflori. PMID- 30028076 TI - Donor-Specific Antibodies' Meaningful Impact on Liver Transplantation. PMID- 30028077 TI - Effect of orthodontic treatment on the subgingival microbiota: A systematic review and meta-analysis. AB - The aim of this systematic review was to assess qualitative changes induced by fixed appliance orthodontic treatment on the subgingival microbiota. Seven databases were searched up to August 2017 for randomized and nonrandomized clinical studies assessing the effect of orthodontic appliances on the subgingival bacteria in human patients. After elimination of duplicate studies, data extraction and risk of bias assessment according to the Cochrane guidelines, random-effects meta-analyses of relative risks (RR) and their 95% confidence intervals (CIs) were performed. According to controlled studies, the presence of Aggregatibacter actinomycetemcomitans in the subgingival crevicular fluid of orthodontic patients was increased 3-6 months after fixed appliance insertion compared to untreated patients (2 studies; RR = 15.54; 95% CI = 3.19-75.85). There was still increased subgingival prevalence of Aggregatibacter actinomycetemcomitans (3 studies; RR = 3.98; 95% CI = 1.23-12.89) and Tannerella forsythia in orthodontic patients up to 6 months after appliance removal compared to untreated patients. However, caution is warranted due to high risk of bias and imprecision. Insertion of orthodontic fixed appliances seems to be associated with a qualitative change of subgingival microbiota, which reverts to some extent back to normal in the first months after appliance removal. However, there is limited evidence on the timing and extent of these changes. PMID- 30028078 TI - The Probiotic Lactobacillus fermentum Prevents Dysbiosis and Vascular Oxidative Stress in Rats with Hypertension Induced by Chronic Nitric Oxide Blockade. AB - SCOPE: Whether the probiotic Lactobacillus fermentum CECT5716 (LC40) ameliorates hypertension in rats with chronic nitric oxide (NO) synthase inhibition is tested. METHODS AND RESULTS: Rats are randomly divided into four different groups and treated for 4 weeks: a) vehicle (control), b) vehicle plus NG -nitro-l arginine methyl ester (l-NAME; 50 mg 100 mL-1 in drinking water), c) LC40 (109 colony-forming units d-1 by gavage), and d) LC40 plus l-NAME. l-NAME induces gut dysbiosis, characterized mainly by an increased Fimicutes/Bacteroidetes (F/B) ratio and reduced Bifidobacterium content, increased Th17 cells and reduced Treg in mesenteric lymph nodes (MLN), increased aortic Th17 infiltration and reactive oxygen species, reduced aortic endothelium-dependent relaxant response to acetylcholine, and hypertension. LC40 prevents gut dysbiosis, alters the Th17/Treg balance in MLN, vascular oxidative stress, and inflammation, slightly improves endothelial dysfuncion but do not inhibit the development of l-NAME induced hypertension. CONCLUSION: Chronic LC40 treatment, in this model of chronic inhibition of NO synthesis, reduces early events involved in atherosclerosis development, such as vascular oxidative stress and pro inflammatory status, as a result of prevention of gut dysbiosis and immune changes in MLN, but not hypertension, confirming the critical role of NO in the antihypertensive effects of LC40 in genetic hypertension. PMID- 30028080 TI - TAF7 is a heat-inducible unstable protein and is required for sustained expression of heat shock protein genes. AB - TATA-binding protein-associated factor 7 (TAF7), a dissociable component of the general transcription factor IID (TFIID), plays a role as a check-point regulator at the step of RNA polymerase II (Pol II) transcription initiation. Here, we focused on the role of TAF7 in heat-shocked cells, where its expression is induced by heat shock factor HSF1. TAF7 is a phosphoprotein, and the phosphorylation status is related to its interaction with TFIID and to its stability controlled by the ubiquitin-proteasome pathway. TAF7 is necessary for the prolonged expression of heat shock protein genes and for efficient recovery of heat-shocked cells. During sustained transcription, TAF7, presumably its TFIID independent form, binds the promoter and enhances the levels of Pol II at the gene body but not the promoter. These results showed the novel function of TAF7 that is necessary for the transition from initiation to elongation in multiple round transcription. PMID- 30028079 TI - NAT6 acetylates the N-terminus of different forms of actin. AB - All forms of mammalian actin comprise at their N-terminus a negatively charged region consisting of an N-acetylated aspartate or glutamate followed by two or three acidic residues. This structural feature is unique to actins and important for their interaction with other proteins. The enzyme catalyzing the acetylation of the N-terminal acidic residue is thought to be NAA10, an enzyme that acetylates multiple intracellular proteins. We report here that this acetylation is essentially carried out by NAT6 (Fus2), a protein of unknown function. Tests of the activity of human recombinant NAT6 on a series of purified proteins showed that the best substrate had several acidic residues near its N-terminus. Accordingly NAT6 was particularly active on highly acidic peptides with sequences corresponding to the N-terminus of different forms of mammalian actins. Knocking out of NAT6 in two human cell lines led to absence of acetylation of the first residue of mature beta-actin (Asp2) and gamma-actin-1 (Glu2). Complete acetylation of these two actins was restored by re-expression of NAT6, or by incubation of extracts of NAT6-deficient cells with low concentrations of recombinant NAT6, while NAA10 showed much less or no activity in such assays. Alpha-actin-1 expressed in NAT6-knockout cells was not acetylated at its N terminus, indicating that the requirement of NAT6 for acetylation of actin N termini also applies to the skeletal muscle actin isoform. Taken together, our findings reveal that NAT6 plays a critical role in the maturation of actins by carrying out the acetylation of their N-terminal acidic residue. PMID- 30028081 TI - Validation of self-reported influenza vaccination in the current and prior season. AB - Self-reported influenza vaccination is generally accurate for the current season, but the accuracy of self-report for vaccination in prior seasons is largely unknown. This study evaluated the accuracy of self-report for current and prior season influenza vaccination among patients with medically attended acute respiratory illness enrolled in a study of influenza vaccine effectiveness during the 2014-15 influenza season. It demonstrates there is a greater potential for exposure misclassification when prior season vaccinations are ascertained by self report. Percent agreement between self-report and final status was high for both current and prior season vaccination: 97.7% and 93.2%, respectively. PMID- 30028082 TI - Microbial diversity and biogeography in Arctic soils. AB - Microorganisms dominate terrestrial environments in the polar regions and Arctic soils are known to harbour significant microbial diversity, far more diverse and numerous in the region than was once thought. Furthermore, the geographic distribution and structure of Arctic microbial communities remains elusive, despite their important roles in both biogeochemical cycling and in the generation and decomposition of climate active gases. Critically, Arctic soils are estimated to store over 1500 Pg of carbon and, thus, have the potential to generate positive feedback within the climate system. As the Arctic region is currently undergoing rapid change, the likelihood of faster release of greenhouse gases such as CO2 , CH4 and N2 O is increasing. Understanding the microbial communities in the region, in terms of their diversity, abundance and functional activity, is key to producing accurate models of greenhouse gas release. This review brings together existing data to determine what we know about microbial diversity and biogeography in Arctic soils. PMID- 30028083 TI - Influenza forecast optimization when using different surveillance data types and geographic scale. AB - BACKGROUND: Advance warning of influenza incidence levels from skillful forecasts could help public health officials and healthcare providers implement more timely preparedness and intervention measures to combat outbreaks. Compared to influenza predictions generated at regional and national levels, those generated at finer scales could offer greater value in determining locally appropriate measures; however, to date, the various influenza surveillance data that are collected by state and county departments of health have not been well utilized in influenza prediction. OBJECTIVES: To assess whether an influenza forecast model system can be optimized to generate accurate forecasts using novel surveillance data streams. METHODS: Here, we generate retrospective influenza forecasts with a dynamic, compartmental model-inference system using surveillance data for influenza-like illness (ILI), laboratory-confirmed cases, and pneumonia and influenza mortality at state and county levels. We evaluate how specification of 3 system inputs-scaling, observational error variance (OEV), and filter divergence (lambda)-affects forecast accuracy. RESULTS: In retrospective forecasts, and across data types, there were no clear optimal combinations for the 3 system inputs; however, scaling was most critical to forecast accuracy, whereas OEV and lambda were not. CONCLUSIONS: Forecasts using new data streams should be tested to determine an appropriate scaling value using historical data and analyzed for forecast accuracy. PMID- 30028084 TI - Elevated blood levels of Dickkopf-1 are associated with acute infections. AB - INTRODUCTION: Dickkopf-1 (DKK1) is a soluble protein and antagonist of the Wnt/beta-catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer-prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections. METHODS: Plasma samples were collected from 58 children admitted to the Centre Mere-Enfant Soleil du Centre Hospitalier de Quebec-Universite Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the Hema Quebec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA. RESULTS: Patients with acute infections showed dramatically high levels of DKK1 (6072 +/- 518 pg/ml) in their blood compared to healthy blood donors (1726 +/- 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 +/- 147.5 pg/ml) than healthy blood donors (1726 +/- 95 pg/ml) but significantly lower than patients with acute infections. CONCLUSION: These findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses. PMID- 30028085 TI - Evidence of cardiac electrical remodeling in patients with Huntington disease. AB - OBJECTIVE: Although Huntington's disease (HD) is a disease of the central nervous system, HD mortality surveys indicate heart disease as a major cause of death. Cardiac dysfunction in HD might be a primary consequence of peripherally expressed mutant huntingtin or secondary to either a general decline in health or the onset of neurological dysfunction. The aim of the study was to clarify the heart muscle involvement. MATERIALS AND METHODS: We measured conventional and advanced resting ECG indices. Thirty-one subjects with a confirmed huntingtin gene mutation and 31 age- and gender-matched controls were included. The HD subjects were divided into four groups based on their Unified Huntington Disease Rating Scale (UHDRS) motor score. RESULTS: We detected changes in advanced ECG variables connected with electrical ventricular remodeling (t test, p < 0.01). The increase in the unexplained part of both QT variability and the standard deviation of normal-to-normal QT intervals, presumably reflecting beat-to-beat changes in repolarization, was most pronounced. Further, both variables correlated with the product of the cytosine-adenine-guanine (CAG) triplets' repeat length and the subjects' age (CAP), the former R = 0.423 (p = 0.018) and the latter R = 0.499 (p = 0.004). There was no correlation between the CAP score and any of variables representing autonomic nervous system activity. CONCLUSIONS: Both autonomic nervous system dysfunction and cardiac electrical remodeling are present in patients with HD. The changes in advanced ECG variables observed in the study evolve with HD progression. The increased values of QT unexplained variability may be a marker of temporal inhomogeneity in ventricular repolarization associated with malignant ventricular arrhythmias. PMID- 30028086 TI - Thiol disulfide exchange reactions in human serum albumin: the apparent paradox of the redox transitions of Cys34. AB - Human serum albumin (HSA) is characterized by 17 disulfides and by only one unpaired cysteine (Cys34 ), which can be free in the reduced albumin or linked as a mixed disulfide with cysteine, or in minor amount with other natural thiols, in the oxidized albumin. In healthy subjects, the level of the oxidized form is about 35%, but it rises up to 70% after oxidative insults or in patients with kidney diseases. Oxidized albumin is therefore considered a short-term biomarker of oxidative stress as its level may increase or decrease under appropriate redox inputs in discrete temporal spans. This paper defines, for the first time, the kinetic properties of reduced and oxidized Cys34 of HSA in their reactions with natural disulfides and thiols. Kinetic constants support the evidence that the Cys34 redox oscillations observed in vivo are mainly due to the interaction with cysteine and cystine without the involvement of any enzymatic support. This study gives also a plausible explanation for the absence of involvement of the 17 disulfides naturally present in HSA in these redox transitions. This inert behavior toward cysteine is marginally due to solvent accessibility or flexibility factors of these bonds but mainly to their strong thermodynamic stability, which is caused essentially by a proximity effect. A similar mechanism is likely at play in the many proteins that maintain disulfide bridges in a reducing medium like the cytosol. PMID- 30028087 TI - Sex bias in rhinology research. AB - BACKGROUND: Analysis of general surgery literature has revealed noteworthy sex bias and underreporting. Our objective was to determine the prevalence of sex bias and underreporting in rhinology. METHODS: All articles in 2016 issues of Rhinology, the American Journal of Rhinology and Allergy (AJRA), and the International Forum of Allergy and Rhinology (IFAR) were reviewed. Of 369 articles, 248 met inclusion criteria. Excluded studies were cadaveric, meta analysis/review, and editorial. Data collected included study type, demographics, and sex-based statistical analysis. RESULTS: There were 202 clinical and 46 basic science/translational studies. From 188 of 202 clinical studies with known sex, 1 included participants of a single sex. Sex matching >50% (SM50 ) was found in 81.9%, and 55.9% performed sex-based statistical analysis. Domestic clinical studies performed sex-based analysis more frequently than international (54.9% vs 44.4%) and exhibited a higher rate of SM50 (84.5% vs 80.3%), though these differences were not statistically significant. For basic/translational studies, 54.5% (24/44) provided sex breakdown. Among these, 29.2% included 1 sex, and 8.3% performed sex-based analysis. Of 10 using animals, 70.0% utilized 1 sex. The remaining 30.0% did not report sex. None of 4 cell line studies reported cell sex. Less than half (46.2%) of domestic and 56.3% of international studies reported sex breakdown; 7.7% of domestic and 3.0% of international studies performed sex-based analysis. CONCLUSION: Although sex may impact outcomes, research without sex reporting and analysis is prevalent, particularly among basic science/translational studies. Future research must account for sex in demographics and analysis to best inform evidence-based clinical guidelines. PMID- 30028088 TI - Determinants of dopaminergic neuron loss in Parkinson's disease. AB - The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological, and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD-linked pathology creates translational opportunities for slowing or stopping disease progression. PMID- 30028090 TI - Additional options in chronic rhinosinusitis management. PMID- 30028089 TI - Gallium Hydrides and O/N-Donors as Tunable Systems in C-F Bond Activation. AB - The gallium hydrides (iBu)2 GaH (1 a), LiGaH4 (1 b) and Me3 N?GaH3 (1 c) hydrodefluorinate vinylic and aromatic C-F bonds when O and N donor molecules are present. 1 b exhibits the highest reactivity. Quantitative conversion to the hydrodefluorination (HDF) products could be observed for hexafluoropropene and 1,1,3,3,3-pentafluoropropene, 94 % conversion of pentafluoropyridine and 49 % of octafluorotoluene. Whereas for the HDF with 1 b high conversions are observed when catalytic amounts of O donor molecules are added, for 1 a, the addition of N donor molecules lead to higher conversions. The E/Z selectivity of the HDF of 1,1,3,3,3-pentafluoropropene is donor-dependent. DFT studies show that HDF proceeds in this case via the gallium hydride dimer-donor species and a hydrometallation/elimination sequence. Selectivities are sensitive to the choice of donor, as the right donor can lead to an on/off switching during catalysis, that is, the hydrometallation step is accelerated by the presence of a donor, but the donor dissociates prior to elimination, allowing the inherently more selective donorless gallium systems to determine the selectivity. PMID- 30028092 TI - Electromyostimulation to fight atrophy and to build muscle: facts and numbers. AB - In recent years, electrical myostimulation (EMS) is becoming more and more popular to increase muscle function and muscle weight. Especially it is applied in healthy individual after injury to rebuild muscle mass and in severely atrophic patients who are not able or willing to perform conventional exercise training programs. Studies in experimental models as well as in human subjects confirmed that EMS can increase muscle mass by around 1% and improve muscle function by around 10-15% after 5-6 weeks of treatment. Despite a severe increase in circulating creatine kinase during the first session, EMS can be regarded as a safe therapeutic intervention. At the molecular level, EMS improves the anabolic/catabolic balance and stimulates the regenerative capacity of satellite cells. EMS intensity should be as high as individually tolerated, and a minimum of three sessions per week [large pulses (between 300-450 MUs), high frequency (50-100 Hz in young and around 30 Hz in older individuals)] for at least 5-6 weeks should be performed. EMS improved functional performances more effectively than voluntary training and counteracted fast type muscle fibre atrophy, typically associated with sarcopenia. The effect of superimposing EMS on conventional exercise training to achieve more muscle mass and better function is still discussed controversially. Nevertheless, EMS should not be regarded as a replacement of exercise training per se, since the beneficial effect of exercise training is not just relying on building muscle mass but it also exerts positive effects on endothelial, myocardial, and cognitive function. PMID- 30028093 TI - Safe and effective use of supplemental oxygen therapy. AB - Nurses have an important role in early identification of factors that can compromise oxygen delivery to the lungs and tissues in the body, and in ensuring that patients who may require supplemental oxygen therapy are assessed and managed safely and competently. This article provides an overview of the anatomy and physiology in relation to oxygen delivery to the lungs and tissues in the body, and outlines the common indications and contraindications for supplemental oxygen therapy. It also discusses the approaches that nurses can adopt to assess a patient's clinical need for supplemental oxygen therapy, as well as the safety considerations required. PMID- 30028094 TI - The Health Care Reform Act of 2010 and Medical Malpractice Liability: Worlds in Collision or Ships Passing in the Night. AB - The Patient Protection and Affordable Care Act of 2010 tackles many health care related issues, but medical malpractice liability reform is not one of them. Despite being a perennial target of health care reform-with accompanying assertions that a medical malpractice liability crisis is corrupting the delivery of health care in the United States-only three short sections that made little substantive change to existing law were devoted to it in a bill that eventually totaled over 900 pages in length. This Article describes what the bill did, what it failed to do, and its likely and perhaps unanticipated consequences for the ongoing medical malpractice liability reform debate. PMID- 30028091 TI - Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain. AB - Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR-/- mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR-deficient neural stem cells are impaired in their self-renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRDeltabrain ) show low penetrance of cortical degeneration compared to EGFR-/- mice despite genetic recombination of the conditional allele. Adult EGFRDelta mice establish a proper blood-brain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acid-induced epileptic seizures. EGFR-deficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and region-specific neurodegeneration observed in EGFR-deficient brains. PMID- 30028095 TI - The Americans with Disabilities Act - The Fifth Circuit's Narrow Interpretation of Services Creates a Split and Burdens the Disabled in Frame v. City of Arlington. PMID- 30028096 TI - Analysis of Gene Expression in Mice Testes Exposed to 1.765 GHz Microwave in Utero. AB - OBJECTIVE: To evaluate the effects of 1.765 GHz microwave on fetal testicular gene expression in mice.STUDY DESIGN: We used a 1.765 GHz microwave generator with 26.7 dBm output power on average and with the estimated specific absorption rate of 0.38-1.71 W/kg. Twelve mice in the experimental group had been exposed to 1.765 GHz micro-waves for 8 hours every day. The testicular gene expression extracted from the neonates separated from all the offspring were compared with microarray and reverse transcription polymerase chain reaction (RT-PCR).RESULTS: There was no significant difference between the mice in the 2 groups in regards to birthweight of offspring, number of offspring, the pregnancy period, or maternal body temperature during the experimental period. The differences of the numbers of testicular gene expression between the 2 groups were observed using measurements obtained by the microarray. We found 3 (Tssk2, Ovol1, and Mea1) downregulated genes confirmed by real-time RT-PCR.CONCLUSION: The expression of Tssk2, Ovol1, and Mea1 in the experimental group was downregulated lower than those in the control group by real-time RT-PCR. PMID- 30028097 TI - Balancing Privacy, Autonomy, and Scientific Needs In Electronic Health Records Research. AB - The ongoing transition from paper medical files to electronic health records will provide unprecedented amounts of data for biomedical research, with the potential to catalyze significant advances in medical knowledge. But this potential can be fully realized only if the data available to researchers is representative of the patient population as a whole. Thus, allowing individual patients to exclude their health information, in keeping with traditional notions of informed consent, may compromise the research enterprise and the medical benefits it produces. This Article analyzes the tension between realizing societal benefits from medical research and granting individual preferences for privacy. It argues for a shift in the conceptual and regulatory frameworks that govern biomedical research. When studies involve electronic record review rather than human experimentation, the traditional, autonomy-dominated model should give way to one that emphasizes the common good. In record-based studies, the limited benefits of individual informed consent come at too high a cost-difficult administrative burdens, significant expenses, and a tendency to create selection biases that distort study outcomes. Other mechanisms can better protect data subjects' privacy and dignitary interests without compromising research opportunities. In this Article, we formulate a novel, multi-faceted approach to achieve these ends. This approach recognizes that technical means for achieving identity concealment and information security are necessary but not sufficient to protect patients' medical privacy and to foster public trust while facilitating research. Hence, we call for supplementing such means with (1) an oversight process that is tailored to record-based research and applies even to de-identified patient records, which are currently exempt from scrutiny, and (2) public notice and education about the nature and potential benefits of such research. PMID- 30028098 TI - Randomized Controlled Trial of Autologous Endometrial Coculture Versus Traditional in Vitro Fertilization. AB - OBJECTIVE: To determine if autologous endometrial cell coculture improves embryo development and clinical outcomes.STUDY DESIGN: Patients who met the inclusion criteria were randomized to either traditional in vitro fertilization (IVF) (control, n=73) or autologous endometrial cell coculture (AECC) (n=61). All patients underwent endometrial biopsy on cycle day 5-10 post luteinizing hormone surge. A total of 129 patients underwent embryo transfer (69 control, 60 AECC). Clinical outcomes as well as embryonic quality measures were then compared between the 2 groups.RESULTS: The mean age, day 3 follicle-stimulating hormone, number of oocytes collected, and clinical outcomes were similar between the 2 groups. Embryo development was overall similar, with the exception that embryonic grade was significantly better with AECC than with control: 1.5 (0.04) vs. 2.6 (0.03), p<0.0001. There was no difference in implantation, live birth or multiple gestation rates.CONCLUSION: This is one of the largest prospective randomized controlled trials of AECC versus traditional IVF. There was significant improvement in embryo morphology in the coculture group, although clinical outcomes were similar between the groups. Further studies are necessary to achieve enough power to fully delineate the effects of coculture on IVF outcome. PMID- 30028099 TI - Long Bone Fractures Associated with Abdominal Breech Deliveries: A Report of Two Cases. AB - BACKGROUND: Birth-related injuries are a well-known complication of vaginal breech deliveries but are not anticipated during cesarean breech deliveries. However, long bone fractures in the neonate can result from delivery of the breech presentation by cesarean section. CASES: We report 2 cases of long bone fractures that occurred during cesarean section for breech presentation. No underlying bone pathology or systemic illness could be identified in either case. There were no other predisposing risk factors for fractures except breech presentation. Both infants were managed with cast application and outpatient physical therapy and recovered without any residual deformity.CONCLUSION: Obstetricians should be aware of the possibility of long bone fractures with abdominal breech deliveries. Their prompt recognition and conservative management, including physical therapy, can prevent bone deformities. PMID- 30028100 TI - Birth of a Mosaic Non-Down Syndrome Offspring to a 45,XY,t(21;21)(q10;q10) Homologous Robertsonian Translocation Carrier: A Case Report. AB - BACKGROUND: Homologous Robertsonian translocation carriers have been considered to have no chance, theoretically, of having a normal embryo. For these carriers, traditional genetic counseling would suggest using donated sperm or oocyte rather than using their own gametes.CASE: This study reports the case of a 45,XY,t(21;21)(q10;q10) homologous Robertsonian translocation carrier who had an approximately normal offspring with a mosaic karyotype: 46,XX,[86]/46, XX,t(21;21)[14].CONCLUSION: Carriers of homologous Robertsonian translocations might have a chance of having normal offspring. For these carriers, besides traditional assisted reproductive technology such as using gametes from a donor, preimplantation genetic diagnosis might have clinical value. PMID- 30028101 TI - Initial hCG Levels in Ectopic Pregnancies After Embryo Transfer: Use of the Bayes Classifier for Risk Assessment. AB - OBJECTIVE: To determine whether the Bayes classifier can be used to distinguish between an ectopic and intrauterine pregnancy following embryo transfer based on early human chorionic gonadotropin (hCG) levels.STUDY DESIGN: Retrospective chart review of patients undergoing in vitro fertilization and diagnosed with a singleton intrauterine or with an ectopic pregnancy. Blood was drawn for hCG levels between days 12 and 20 after transvaginal oocyte aspiration. Statistical analysis was performed using a mixed effects model and the Bayes classifier.RESULTS: Singleton intrauterine (n=91) and ectopic gestations (n=14) were analyzed. hCG levels increased by 51% daily in both groups, but levels in ectopic pregnancies were only 14% of those from the control group on the same day (p<1*10-15). Using the Bayes classifier, an hCG value <18 IU/L indicated a large probability (>75%) that the pregnancy was ectopic. There was no statistically significant difference in regards to endometrial thickness (p=0.77), fresh or frozen embryo transfer (p=0.53), number of embryos transferred (p=0.13), donor or autologous oocytes (p=0.76), or the day of hCG draw (p=0.13 and 0.43 for first and second measurement).CONCLUSION: The Bayes classifier can be used as a tool to alert the healthcare provider of a possible ectopic gestation. PMID- 30028102 TI - Sexting: 21st-Century Statutory Rape. AB - The "cyberworld" in which we live has fundamentally and irrevocably changed the nature of human interaction. For many, electronic mail, texting, and social networking sites have significantly limited traditional face-to-face interaction. While the benefits of technological progress are self-evident, the ease with which people can share personal information virtually has also produced troubling byproducts. The transmission of sexually provocative images between teenagers, known colloquially as "sexting," is one such example. As suicides and other sexting-related tragedies multiply, jurisdictions coast-to-coast are searching frantically for ways to curb the practice. Due to the harshness of existing criminal statutes, legislators have favored the creation of a separate sexting offense to address misconduct. Because these new laws vary greatly in both content and severity of prescribed penalties, some have argued that they are unprincipled. In light of contemporary societal disinterest in prosecuting consensual sexual activity between adolescents, critics also consider them misguided and anachronistic. These allegations suffer from their failure to place anti-sexting initiatives in proper historical context. These laws represent a present-day manifestation of the protectionist and paternalistic impulses that motivated statutory rape laws in the 18th, 19th, and 20th centuries. Both anti sexting and statutory rape laws share the same fundamental goal: avoiding reputational ruin and its untoward consequences. Whereas sexual intercourse was once the necessary catalyst, electronic devices used to disseminate sexually explicit material now create the risk. In today's virtual world, sexting represents a sort of statutory rape by proxy where cell phones, laptops, and iPads provide the violative act that can ruin lives. In sum, the campaign to outlaw sexting is neither misguided nor anachronistic. It reflects a widespread belief in the need to protect adolescents from sexting-related harm, coupled with a paternalistic desire to restore some of the moral innocence that is rapidly disappearing in the teenage cyberworld. PMID- 30028103 TI - Conference takes OR business leaders to the next level. PMID- 30028104 TI - 12-week program prepares new nurses for the OR. PMID- 30028105 TI - CMS immediate jeopardy trail may lead to the OR. PMID- 30028107 TI - Arm your staff with strategies to prevent HAIs. PMID- 30028106 TI - DNV accreditation: A positive spin on survey preparation. PMID- 30028108 TI - Adding new business to the ASC, one procedure at a time-Part 2. PMID- 30028109 TI - When Is a Change Going to Come: Separate and Unequal Treatment in Health Care Fifty Years after the Title VI of the Civil Rights Act of 1964. PMID- 30028110 TI - The Spending Power after NFIB: New Direction, or Medicaid Exception? PMID- 30028111 TI - Drug-induced anaphylaxis: seven-year single-center survey. AB - Summary: Background and Objective. Drug-induced anaphylaxis (DIA) is the most common cause of fatal anaphylaxis. We aimed to characterize patients with DIA and their allergological workup. Methods. Systematic review of patients with history of DIA referred to our center over 7 years. Results. Included 125 patients (10% pediatric age), being 36 years the median age of first episode (from 1 to 74 years). The main culprits were nonsteroidal anti-inflammatory drugs (NSAIDs) (43%), antibiotics (42%) and anesthetic agents (6%). In 24% the reactions occurred in hospital setting and 14% perioperative. The etiology was confirmed in 75% through allergological workup. Conclusions. NSAIDs and antibiotics were responsible for most of DIA. The heterogeneity of mechanisms, the severity of the reactions and the lack of standardized in vivo and/or in vitro tests for some drugs do not allow to confirm the diagnosis in all cases. Patients with DIA should be evaluated in specialized centers to perform accurate diagnosis, to prevent recurrence and to find safe alternatives. PMID- 30028112 TI - Promoting Health with Sports: When Should Nonprofits Qualify for Tax Benefits? AB - Medical researchers are sounding the alarm that our society's shift to sedentary jobs is triggering an epidemic of chronic diseases, such as type 2 diabetes. This Article brings that modern medical research to a tax debate and hopes to help revolutionize the sports world. This Article's proposal seeks to shift our current excessive emphasis on youth, college, and elite sports to an emphasis on participation by all. Currently, the tax exemption rules vigorously promote youth and college sports but generally deny most-favored tax status to nonprofits promoting nonelite adult sports. These rules are based on doctrines linking sports with education, which developed in a bygone era when sports were for students and the idle rich, and most adults got plenty of physical activity at work. As recently as 1960, approximately fifty percent of all jobs required at least moderate physical activity. By 2006, that figure had plummeted to twenty percent, and the average U.S. male age forty to fifty was thirty-two pounds heavier than his counterpart in 1960. Over this same time span, there has been a dramatic increase in chronic diseases associated with inactivity. Scientists say that greater physical activity and improved diet are the ways to fight this epidemic. This Article makes the case for granting most-favored tax status to organizations that promote nonelite adult athletics and do not charge high fees that would exclude a significant portion of the community. PMID- 30028113 TI - Personalized Medicine in the Information Age: Myriad's De Facto Monopoly on Breast Cancer Research. PMID- 30028114 TI - Quarantine and the Federal Role in Epidemics. AB - Every recent presidential administration has faced an infectious disease threat, and this trend is certain to continue. The states have primary responsibility for protecting the public's health under their police powers, but modern travel makes diseases almost impossible to contain intrastate. How should the federal government respond in the future? The Ebola scare in the U.S. repeated a typical response--demands for quarantine. In January 2017, the Department of Health and Human Services and the Centers for Disease Control and Prevention issued final regulations on its authority to issue Federal Quarantine Orders. These regulations rely heavily on confining persons who may or may not be ill, raising serious questions about federal commitment to due process protections as well as the scope of statutory authority to impose quarantine. As the Supreme Court has stated in United States v. Salerno, "liberty is the norm, and detention prior to trial or without trial is the carefully limited exception." Unconstrained use of quarantines undermines both the rule of law and public confidence in government decisions in times of crisis. This article analyzes the regulations and argues for a rights-based approach to infectious disease control that also protects public health. By respecting constitutional rights, the federal government can encourage public trust and cooperation and minimize harm, both essential requirements for controlling an epidemic. PMID- 30028115 TI - Prussian Blue Nanozyme with Multienzyme Activity Reduces Colitis in Mice. AB - The overproduction of reactive oxygen species (ROS) is central to the progression of inflammatory bowel disease (IBD), which may be the potential therapeutic target. Prussian blue (PB) nanoparticles with good biosafety can act as an artificial nanozyme, effectively scavenging ROS. To date, PB-based nanomaterials have not been developed and utilized for treatment of IBD. In this study, poly(vinylpyrrolidone)-modified Prussian blue (PPB) nanoparticles are constructed with good physiological stability and biosafety by a simple and efficient method. The prepared PPBs with capabilities of scavenging ROS and inhibiting proinflammatory cytokine significantly reduce colitis in mice without distinct side effects via intravenous administration. This report provides a demonstration of the protective effect of PB-based nanomedicine against IBD in living animals, offering hope and a potential alternative treatment option for patients suffering from IBD. PMID- 30028116 TI - Ultrathin Silver Film Electrodes with Ultralow Optical and Electrical Losses for Flexible Organic Photovoltaics. AB - Improving the wetting ability of Ag on chemically heterogeneous oxides is technically important to fabricate ultrathin, continuous films that would facilitate the minimization of optical and electrical losses to develop qualified transparent Ag film electrodes in the state-of-the-art optoelectronic devices. This goal has yet to be attained, however, because conventional techniques to improve wetting of Ag based on heterogeneous metallic wetting layers are restricted by serious optical losses from wetting layers. Herein, we report on a simple and effective technique based on the partial oxidation of Ag nanoclusters in the early stages of Ag growth. This promotes the rapid evolution of the subsequently deposited pure Ag into a completely continuous layer on the ZnO substrate, as verified by experimental and numerical evidence. The improvement in the Ag wetting ability allows the development of a highly transparent, ultrathin (6 nm) Ag continuous film, exhibiting an average optical transmittance of 94% in the spectral range 400-800 nm and a sheet resistance of 12.5 Omega sq-1, which would be well-suited for application to an efficient front window electrode for flexible solar cell devices fabricated on polymer substrates. PMID- 30028117 TI - Vortex Fluidic Mediated Synthesis of Macroporous Bovine Serum Albumin-Based Microspheres. AB - Macroporous bovine serum albumin (BSA) nanoparticles with controllable diameter were readily fabricated in a rapidly rotating angled glass tube in a vortex fluidic device (VFD). Systematically varying the rotational speed and the ratio of BSA, ethanol, and glutaraldehyde led to conditions for generating ca. 600 nm diameter macroporous particles that have intrinsic fluorescence emission at 520 nm when excited at 490 nm. The presence of the macropores increased the absorption efficiency of rhodamine B with potential applications for drug delivery purpose, compared with BSA nanoparticles having surfaces devoid of pores. Further control over the size of BSA nanoparticles occurred in the presence of C-phycocyanin protein during the VFD processing, along with control of their shape, from spheres to pockets, as established in exploring the parameter space of the microfluidic device. PMID- 30028118 TI - Alignment Control of Nematic Liquid Crystal using Gold Nanoparticles Grafted by the Liquid Crystalline Polymer with Azobenzene Mesogens as the Side Chains. AB - The gold nanoparticles highly grafted by a liquid crystalline polymer (LCP) with azobenzene mesogens as the side chain (denoted as Au@TE-PAzo NPs) are successfully designed and synthesized by the two-phase Brust-Schiffrin method. The chemical structures of the monomer and polymer ligands have been confirmed by nuclear magnetic resonance, and the molecular weight of the polymer is determined by gel permeation chromatography. The combined analysis of transmission electron microscopy and thermogravimetric analysis shows that the size of the nanoparticles is 2.5(+/-0.4) nm and the content of the gold in the Au@TE-PAzo NPs is ca. 17.58%. The resultant Au@TE-PAzo NPs can well disperse in the nematic LC of 5CB. The well-dispersed mixture with appropriate doping concentrations can automatically form a perfect homeotropic alignment in the LC cell. The homeotropic alignment is attributed to the brush formed by Au@TE-PAzo NPs on the substrate, wherein the Au@TE-PAzo NPs gradually diffuse onto the substrate from the mixture. On the contrary, the pure side chain LCPs cannot yield vertical alignment of 5CB, which indicates that the alignment of 5CB is ascribed to the synergistic interaction of the nanoparticles and the grafted LCPs. Moreover, Au@TE-PAzo NPs show excellent film-forming property on account of their periphery of high densely grafted LCPs, which can form uniform thin film by spin-coating. The resultant thin film also can prompt the automatical vertical alignment of the nematic 5CB. Further, upon alternative irradiation of UV and visible light, the alignment of 5CB reversibly switches between vertical and random orientation because of the trans-cis photoisomerization of the azobenzene group on the periphery of Au@TE-PAzo NPs. These experimental results suggest that this kind of nanoparticles can be potentially applied in constructing the remote-controllable optical devices. PMID- 30028119 TI - Scalable Synthesis of Uniform Nanosized Microporous Carbon Particles from Rigid Polymers for Rapid Ion and Molecule Adsorption. AB - Porous carbon materials are of great importance for many applications such as energy storage, catalysis, and adsorption. Rational design and low-cost synthesis of carbon structures that can simultaneously offer high surface area and rapid ion/molecule transport properties remain desired for target functions. Here, we report a cost-effective and scalable synthesis of high surface area, size-uniform microporous carbon nanoparticles. A combination of using rigid polymer nanoparticles as the precursor, precarbonization, and activation process leads to carbon nanoparticles with a high surface area (up to 2789 m2 g-1), a large pore volume (up to 1.85 cm3 g-1), and a high packing density (0.5 g cm-3), which is due to the existence of a large amount of highly accessible micropores. Such a unique carbon structure exhibits not only large capacity but also rapid adsorption for both ions and small molecules, demonstrated in high-performance supercapacitors and as an efficient sorbent for removal of pollutants from water. This study provides a new strategy that can be used to further design and tune nanostructured carbon and composite particles to explore many other applications. PMID- 30028120 TI - Overcoming Chemoresistance in Cancer via Combined MicroRNA Therapeutics with Anticancer Drugs Using Multifunctional Magnetic Core-Shell Nanoparticles. AB - In this study, we report the use of a multifunctional magnetic core-shell nanoparticle (MCNP), composed of a highly magnetic zinc-doped iron oxide (ZnFe2O4) core nanoparticle and a biocompatible mesoporous silica (mSi) shell, for the simultaneous delivery of let-7a microRNA (miRNA) and anticancer drugs (e.g., doxorubicin) to overcome chemoresistance in breast cancer. Owing to the ability of let-7a to repress DNA repair mechanisms (e.g., BRCA1 and BRCA2) and downregulate drug efflux pumps (e.g., ABCG2), delivery of let-7a could sensitize chemoresistant breast cancer cells (MDA-MB-231) to subsequent doxorubicin chemotherapy both in vitro and in vivo. Moreover, the multifunctionality of our MCNPs allows for the monitoring of in vivo delivery via magnetic resonance imaging. In short, we have developed a multifunctional MCNP-based therapeutic approach to provide an attractive method with which to enhance our ability not only to deliver combined miRNA therapeutics with small-molecule drugs in both selective and effective manner but also to sensitize cancer cells for the enhanced treatment via the combination of miRNA replacement therapy using a single nanoplatform. PMID- 30028121 TI - Inkjet-Printed Photoluminescent Patterns of Aggregation-Induced-Emission Chromophores on Surface-Anchored Metal-Organic Frameworks. AB - Organic chromophores that exhibit aggregation-induced emission (AIE) are of interest for applications in displays, lighting, and sensing, because they can maintain efficient emission at high molecular concentrations in the solid state. Such advantages over conventional chromophores could allow thinner conversion layers of AIE chromophores to be realized, with benefits in terms of the efficiency of the optical outcoupling, thermal management, and response times. However, it is difficult to create large-area optical quality thin films of efficiently performing AIE chromophores. Here, we demonstrate that this can be achieved by using a surface-anchored metal-organic framework (SURMOF) thin film coating as a host substrate, into which the tetraphenylethylene (TPE)-based AIE chromophore can be printed. We demonstrate that the SURMOF constrains the AIE chromophore molecular conformation, affording efficient performance even at low loading densities in the SURMOF. As the loading density of the AIE chromophore in the SURMOF is increased, its absorption and emission spectra are tuned due to increased interaction between AIE molecules, but the high photoluminescent quantum yield (PLQY = 50% for this AIE chromophore) is maintained. Lastly, we demonstrate that patterns of the AIE chromophore with 70 MUm feature sizes can be easily created by inkjet printing onto the SURMOF substrate. These results foreshadow novel possibilities for the creation of patterned phosphor thin films utilizing AIE chromophores for display or lighting applications. PMID- 30028122 TI - Exploring Ethylene/Polar Vinyl Monomer Copolymerizations Using Ni and Pd alpha Diimine Catalysts. AB - The most ubiquitous polymer, polyethylene (PE), is produced either through a radical-initiated process or, more commonly, through a coordination/insertion process employing early transition metal catalysts, particularly titanium- and chromium-based systems. These oxophilic early metal catalysts are not functional group-tolerant and thus cannot be used to synthesize copolymers of ethylene and polar vinyl monomers such as alkyl acrylates and vinyl acetate. Such PE copolymers have enhanced properties relative to PE and are made through radical polymerization processes, requiring exceptionally high pressures and temperatures. Copolymerizations of polar vinyl monomers with ethylene using more functional group-tolerant late metal catalysts potentially offer an attractive alternative for generating such value-added copolymers since ligand variations may provide more control of polymer microstructures and milder reaction conditions would apply. This Account describes our efforts, particularly through detailed mechanistic studies, to probe and develop this potential using Pd(II) and Ni(II) alpha-diimine catalysts. To inform discussions of the copolymerizations, we briefly review key aspects of ethylene homopolymerizations using these diimine catalysts. These include ligand designs that incorporate axial blocking groups that retard chain transfer and promote production of a high polymer rather than an oligomer. These ligand designs also lead to unique branched polyethylenes via migration of the metal along the chain ("chain walking") prior to insertion. Mechanistic investigations of copolymerizations of ethylene with polar vinyl monomers using the diimine complexes have revealed several impediments to developing practical catalysts: (1) The polar group of the comonomer can coordinate strongly to the metal center, blocking coordination of ethylene. (2) Weak binding affinity of the polar monomer relative to ethylene can result in very low levels of comonomer incorporation. (3) A metal alkyl chain bearing a heteroatom, X, on the beta-carbon atom can undergo beta-X elimination leading to deactivation of the catalyst. (4) Stable chelate formation following insertion of a polar comonomer can greatly retard the rate of chain growth. (5) A metal alkyl chain bearing an electron-withdrawing heteroatom at the ?-carbon atom can result in a high insertion barrier. A patent disclosure by the DuPont Versipol group and our extensive mechanistic studies reveal that, remarkably, vinyl trialkoxysilanes are ideal comonomers and circumvent all of the impediments noted above. The Pd-catalyzed copolymerization of vinyl trialkoxysilanes with ethylene produces highly branched, low molecular weight copolymers with activities comparable to those of analgous ethylene homopolymerizations. A 1,2- insertion of the vinyl silane results in the formation of a five-membered Pd O(R)Si chelate which is readily opened by ethylene and thus does not reduce the rate of chain growth. beta-Silyl elimination results in chain transfer and accounts for the lower molecular weight polymer. The nickel alpha-diimine catalyzed copolymerizations produce high molecular weight copolymers with structures that vary from nearly linear to moderately branched. Both four- and five-membered chelates are catalyst resting states but are rapidly opened by ethylene, and thus turnover frequencies are only slightly reduced relative to ethylene homopolymerizations. Finally, a convenient and practical nickel-based system has been developed for the efficient synthesis of this copolymer which can be cross-linked to form PEX- b, a commercial PE plastic used for hot water plumbing pipes and power cable coatings. PMID- 30028123 TI - Investigation on the Electrochemical Properties and Stabilized Surface/Interface of Nano-AlPO4-Coated Li1.15Ni0.17Co0.11Mn0.57O2 as the Cathode for Lithium-Ion Batteries. AB - Being considered as one of the most potential cathode materials, Li1.15Ni0.17Co0.11Mn0.57O2 draws plenty of attention towards its optimization on cycling and rate performance. The surface coating process provides a longer cycling life and better rate performance for the cathodes. A systematic investigation has been carried out on the nano-AlPO4 coating layer for the Li1.15Ni0.17Co0.11Mn0.57O2 cathode material through a facile in situ dispersion process. The 1% coated cathode material can hold about 90% capacity retention after 100 cycles. Besides, the surface coating enhances the rate ability of Li1.15Ni0.17Co0.11Mn0.57O2, which holds a reversible capacity of 202.3 mAh g-1 at the rate of 1C. Surface information is collected during cycling, which reveals that less side reactions occur on the electrode-electrolyte interface after the coating process for improved cycling and rate performance. PMID- 30028124 TI - Dual Activity of Rose Bengal Functionalized to Albumin-Coated Lanthanide-Doped Upconverting Nanoparticles: Targeting and Photodynamic Therapy. AB - A modified version of a desolvation method was used to render lanthanide-doped upconverting nanoparticles NaGdF4:Yb3+/Er3+ (Ln-UCNPs) water-dispersible and biocompatible for photodynamic therapy. Bovine serum albumin (BSA) was used as surface coating with a direct conjugation to NaGdF4:Yb3+/Er3+ nanoparticles forming a ~2 nm thick shell. It was estimated that approximately 112 molecules of BSA were present and cross-linked per NaGdF4:Yb3+/Er3+ nanoparticle. Analysis of the BSA structural behavior on the Ln-UCNP surfaces displayed up to 80% loss of alpha-helical content. Modification of the Ln-UCNPs with a BSA shell prevents luminescence quenching from solvent molecules (H2O) with high energy vibrations that can interact with the excited states of the optically active ions Er3+ and Yb3+ via dipole-dipole interactions. Additionally, the photosensitizer rose bengal (RB) was conjugated to albumin on the surface of the Ln-UCNPs. Emission spectroscopy under 980 nm excitation was carried out, and an energy transfer efficiency of 63% was obtained. In vitro cell studies performed using human lung cancer cells (A549 cell line) showed that Ln-UCNPs coated with BSA were not taken by the cells. However, when RB was conjugated to BSA on the surface of the nanoparticles, cellular uptake was observed, and cytotoxicity was induced by the production of singlet oxygen under 980 nm irradiation. PMID- 30028125 TI - Reversing Redox Responsiveness of Hydrogels due to Supramolecular Interactions by Utilizing Double-Network Structures. AB - Stimuli-responsive hydrogels have been actively researched, and some of them have been put into practical use. When we create and use stimuli-responsive hydrogel materials, controlling stimuli responsiveness of hydrogels is a very important issue. In this research, we prepared hydrogels having single-network (SN) or double-network (DN) gel structures with the host-guest interaction groups cyclodextrin and methyl viologen and evaluated their stimuli responsiveness. The results of the tensile and compression tests showed that the hydrogels with SN and DN structures exhibited opposite stimuli responsiveness in response to the redox reaction of methyl viologen through the association and dissociation of the host molecule, beta-cyclodextrin, and the guest molecule, methyl viologen. Spectroscopic measurements and rheological studies all indicated that this difference in stimuli responsiveness originated from the polymer-network structures. In addition, a chemically cross-linked DN gel was prepared and its redox responsiveness was evaluated. PMID- 30028126 TI - Sodium Doping to Enhance Electrochemical Performance of Overlithiated Oxide Cathode Materials for Li-Ion Batteries via Li/Na Ion-Exchange Method. AB - Overlithiated oxide cathode materials show high capacity but poor cycle stability and voltage attenuation. In this work, a concentration difference driven molten salt ion exchange strategy is used to replace a small quantity of lithium ions by sodium ions. With the entry of sodium ions, the interplanar spacing is increased and the structure is stabilized. The electrochemical properties of materials have been improved obviously. The powder X-ray diffraction, inductively coupled plasma atomic emission spectroscopy, scanning electron microscopy, and transmission electron microscopy are used to detect the entry of sodium ions and structural changes. The modified materials display high discharge specific capacity, excellent cycling performance, and reduced voltage attenuation. PMID- 30028127 TI - Scalable Fabrication of Nanostructured Tin Oxide Anodes for High-Energy Lithium Ion Batteries. AB - Although tin and tin oxides have been considered very promising anode materials for future high-energy lithium-ion batteries due to high theoretical capacity and low cost, the development of commercial anodes falls short of expectations. This is due to several challenging issues related to a massive volume expansion during operation. Nanostructured electrodes can accommodate the volume expansion but typically suffer from cumbersome synthesis routes and associated problems regarding scalability and cost efficiency, preventing their commercialization. Herein, a facile, easily scalable, and highly cost-efficient fabrication route is proposed based on electroplating and subsequent electrolytic oxidation of tin, resulting in additive-free tin oxide anodes for lithium-ion batteries. The electrodes prepared accordingly exhibit excellent performance in terms of gravimetric and volumetric capacity as well as promising cycle life and rate capability, making them suitable for future high-energy lithium-ion batteries. PMID- 30028128 TI - Facile Preparation of Haggite by Reducing V2O5 in Guaiacol/Methanol Solution. AB - Haggite-structured V4O6(OH)4 is prepared via a one-step reduction of V2O5 in a mixture of guaiacol and methanol. Guaiacol delays the overreduction of Haggite to V2O3. The time window for the stable existence of the Haggite phase is enlarged at low temperature. PMID- 30028129 TI - Cell-Based Biosensors Based on Intein-Mediated Protein Engineering for Detection of Biologically Active Signaling Molecules. AB - Live-cell-based biosensors have emerged as a useful tool for biotechnology and chemical biology. Genetically encoded sensor cells often use bimolecular fluorescence complementation or fluorescence resonance energy transfer to build a reporter unit that suffers from nonspecific signal activation at high concentrations. Here, we designed genetically encoded sensor cells that can report the presence of biologically active molecules via fluorescence translocation based on split intein-mediated conditional protein trans-splicing (PTS) and conditional protein trans-cleavage (PTC) reactions. In this work, the target molecules or the external stimuli activated intein-mediated reactions, which resulted in activation of the fluorophore-conjugated signal peptide. This approach fully valued the bond-making and bond-breaking features of intein mediated reactions in sensor construction and thus eliminated the interference of false-positive signals resulting from the mere binding of fragmented reporters. We could also avoid the necessity of designing split reporters to refold into active structures upon reconstitution. These live-cell-based sensors were able to detect biologically active signaling molecules, such as Ca2+ and cortisol, as well as relevant biological stimuli, such as histamine-induced Ca2+ stimuli and the glucocorticoid receptor agonist, dexamethasone. These live-cell-based sensing systems hold large potential for applications such as drug screening and toxicology studies, which require functional information about targets. PMID- 30028130 TI - Rational Design and Facile Synthesis of a Highly Tunable Quinoline-Based Fluorescent Small-Molecule Scaffold for Live Cell Imaging. AB - Small-molecule fluorescent probes are powerful tools for chemical biology; however, despite the large number of probes available, there is still a need for a simple fluorogenic scaffold, which allows for the rational design of molecules with predictable photophysical properties and is amenable to concise synthesis for high-throughput screening. Here, we introduce a highly modular quinoline based probe containing three strategic domains that can be easily engineered and optimized for various applications. Such domains are allotted for (1) compound polarization, (2) tuning of photophysical properties, and (3) structural diversity. We successfully synthesized our probes in two steps from commercially available starting materials in overall yields of up to 95%. Facile probe synthesis was permitted by regioselective palladium-catalyzed cross-coupling, which enables combinatorial development of structurally diverse quinoline-based fluorophores. We have further applied our probes to live-cell imaging, utilizing their unique two-stage fluorescence response to intracellular pH. These studies provide a full demonstration of our strategy in rational design and stream-lined probe discovery to reveal the diverse potential of quinoline-based fluorescent compounds. PMID- 30028131 TI - Conformationally Regulated Peptide Bond Cleavage in Bradykinin. AB - Ion mobility and mass spectrometry techniques are used to investigate the stabilities of different conformations of bradykinin (BK, Arg1-Pro2-Pro3-Gly4 Phe5-Ser6-Pro7-Phe8-Arg9). At elevated solution temperatures, we observe a slow protonation reaction, i.e., [BK+2H]2++H+ -> [BK+3H]3+, that is regulated by trans -> cis isomerization of Arg1-Pro2, resulting in the Arg1- cis-Pro2- cis-Pro3-Gly4 Phe5-Ser6- cis-Pro7-Phe8-Arg9 (all- cis) configuration. Once formed, the all- cis [BK+3H]3+ spontaneously cleaves the bond between Pro2-Pro3 with perfect specificity, a bond that is biologically resistant to cleavage by any human enzyme. Temperature-dependent kinetics studies reveal details about the intrinsic peptide processing mechanism. We propose that nonenzymatic cleavage at Pro2-Pro3 occurs through multiple intermediates and is regulated by trans -> cis isomerization of Arg1-Pro2. From this mechanism, we can extract transition state thermochemistry: Delta G? = 94.8 +/- 0.2 kJ.mol-1, Delta H? = 79.8 +/- 0.2 kJ.mol 1, and Delta S? = -50.4 +/- 1.7 J.mol-1.K-1 for the trans -> cis protonation event; and, Delta G? = 94.1 +/- 9.2 kJ.mol-1, Delta H? = 107.3 +/- 9.2 kJ.mol-1, and Delta S? = 44.4 +/- 5.1 J.mol-1.K-1 for bond cleavage. Biological resistance to the most favored intrinsic processing pathway prevents formation of Pro3-Gly4 Phe5-Ser6- cis-Pro7-Phe8-Arg9 that is approximately an order of magnitude more antigenic than BK. PMID- 30028132 TI - Discovery of beta-Arrestin Biased Ligands of 5-HT7R. AB - Though many studies have been published about therapeutic potentials of selective 5-HT7R ligands, there have been few biased ligands of 5-HT7R. The development of potent and selective biased ligands of 5-HT7R would be of great help in understanding the relationship between pharmacological effects and G protein/beta arrestin signaling pathways of 5-HT7R. In order to identify 5-HT7R ligands with biased agonism, we designed and synthesized a series of tetrahydroazepine derivatives 1 and 2 with arylpyrazolo moiety or arylisoxazolo moiety. Through several biological evaluations such as binding affinity, selectivity profile, and functions in G protein and beta-arrestin signaling pathways, 3-(4-chlorophenyl) 1,4,5,6,7,8-hexahydropyrazolo[3,4- d]azepine 1g was discovered as the beta arrestin biased ligand of 5-HT7R. In an electroencephalogram (EEG) test, 1g increased total non-rapid eye movement (NREM) sleep time and decreased total rapid eye movement (REM) sleep time. PMID- 30028133 TI - From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus. AB - The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N terminal interactions. PMID- 30028134 TI - SAR-Guided Scoring Function and Mutational Validation Reveal the Binding Mode of CGS-8216 at the alpha1+/gamma2- Benzodiazepine Site. AB - The structural resolution of a bound ligand-receptor complex is a key asset to efficiently drive lead optimization in drug design. However, structural resolution of many drug targets still remains a challenging endeavor. In the absence of structural knowledge, scientists resort to structure-activity relationships (SARs) to promote compound development. In this study, we incorporated ligand-based knowledge to formulate a docking scoring function that evaluates binding poses for their agreement with a known SAR. We showcased this protocol by identifying the binding mode of the pyrazoloquinolinone (PQ) CGS-8216 at the benzodiazepine binding site of the GABAA receptor. Further evaluation of the final pose by molecular dynamics and free energy simulations revealed a close proximity between the pendent phenyl ring of the PQ and gamma2D56, congruent with the low potency of carboxyphenyl analogues. Ultimately, we introduced the gamma2D56A mutation and in fact observed a 10-fold potency increase in the carboxyphenyl analogue, providing experimental evidence in favor of our binding hypothesis. PMID- 30028135 TI - Bronsted Acid-Promoted Friedel-Crafts Alkylation/Cyclization of (7 Hydroxynaphthalenyl)pyrrole or (2-Hydroxyphenyl)pyrroles with Isatins for the Construction of Pyrrolospirooxindole Derivatives. AB - An efficient trifluoroacetic acid-catalyzed cascade Friedel-Crafts alkylation/cyclization of 1-(7-hydroxynaphthalenyl)pyrrole or 1-(2 hydroxyphenyl)pyrroles with isatins has been developed, providing practical access to a variety of biologically important pyrrole-containing spirooxindoles. PMID- 30028136 TI - Enantioselective Formal [4 + 2] Annulation of ortho-Quinone Methides with ortho Hydroxyphenyl alpha,beta-Unsaturated Compounds. AB - The highly efficient enantioselective [4 + 2] cycloaddition of o-QMs with ortho hydroxyphenyl-substituted alpha,beta-unsaturated compounds was realized by using a chiral N, N'-dioxide-Sc(III) complex as catalyst. A variety of chiral chromane derivatives with three continuous stereocenters were obtained in excellent results (up to 99% yield, >19:1 dr, and 99% ee) under as low as 0.005-1 mol % catalyst loading. Besides, a catalytic cycle with a possible transition state model was proposed to elucidate the origin of the chirality. PMID- 30028137 TI - Antifreeze Glycoproteins Bind Irreversibly to Ice. AB - Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) inhibit ice growth via an adsorption-inhibition mechanism that assumes irreversible binding of AF(G)Ps to embryonic ice crystals and the inhibition of further growth. The irreversible binding of antifreeze glycoproteins (AFGPs) to ice has been questioned and remains poorly understood. Here, we used microfluidics and fluorescence microscopy to investigate the nature of the binding of small and large AFGP isoforms. We found that both AFGP isoforms bind irreversibly to ice, as evidenced by microfluidic solution exchange experiments. We measured the adsorption rate of the large AFGP isoform and found it to be 50% faster than that of AFP type III. We also found that the AFGP adsorption rate decreased by 65% in the presence of borate, a well-known inhibitor of AFGP activity. Our results demonstrate that the adsorption rate of AFGPs to ice is crucial for their ice growth inhibition capability. PMID- 30028138 TI - Visible-Light-Activated Catalytic Enantioselective beta-Alkylation of alpha,beta Unsaturated 2-Acyl Imidazoles Using Hantzsch Esters as Radical Reservoirs. AB - An efficient and practical method for the enantioselective beta-functionalization of alpha,beta-unsaturated 2-acyl imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Lambda-RhS, 4 mol %) along with Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit upon substrate binding and as the asymmetric catalyst. The method provides up to quantitative yields with excellent enantioselectivities up to 98% ee and can be classified as a redox neutral, electron-transfer-catalyzed reaction. PMID- 30028139 TI - Radical Carbonylation Mediated by Continuous-Flow Visible-Light Photocatalysis: Access to 2,3-Dihydrobenzofurans. AB - The annulative carbonylation of alkenyl-tethered arenediazonium salts using visible-light photocatalysis in continuous flow is described. The method furnishes a diverse series of novel acetate-functionalized 2,3-dihydrobenzofurans at room temperature and moderate CO pressure (25 atm), delivering these products in a short time with straightforward scale-up. This continuous flow and free radical approach overcomes the limitation of traditional Pd-catalyzed annulative carbonylation, giving valuable 2,3-dihydrobenzofurans in a predictable and regioselective manner. PMID- 30028140 TI - Anomalous Fraunhofer Patterns in Gated Josephson Junctions Based on the Bulk Insulating Topological Insulator BiSbTeSe2. AB - One-dimensional Majorana modes are predicated to form in Josephson junctions based on three-dimensional topological insulators (TIs). While observations of supercurrents in Josephson junctions made on bulk-insulating TI samples have been reported recently, the Fraunhofer patters observed in such TI-based Josephson junctions, which sometimes present anomalous features, are still not well understood. Here, we report our study of highly gate-tunable TI-based Josephson junctions made of one of the most bulk-insulating TI materials, BiSbTeSe2, and Al. The Fermi level can be tuned by gating across the Dirac point, and the high transparency of the Al-BiSbTeSe2 interface is evinced by a high characteristic voltage and multiple Andreev reflections, with peak indices reaching 12. Anomalous Fraunhofer patterns with missing lobes were observed in the entire range of gate voltage. We found that, by employing an advanced fitting procedure to use the maximum entropy method in a Monte Carlo algorithm, the anomalous Fraunhofer patterns are explained as a result of inhomogeneous supercurrent distributions on the TI surface in the junction. Besides establishing a highly promising fabrication technology, this work clarifies one of the important open issues regarding TI-based Josephson junctions. PMID- 30028141 TI - Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1. AB - Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC50 values down to 3 MUM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization. PMID- 30028142 TI - Liquid Chromatography-Tandem Mass Spectrometry Method Revealed that Lung Cancer Cells Exhibited Distinct Metabolite Profiles upon the Treatment with Different Pyruvate Dehydrogenase Kinase Inhibitors. AB - Pyruvate dehydrogenase kinases (PDKs) dominate the critical switch between mitochondria-based respiration and cytoplasm-based glycolysis by controlling pyruvate dehydrogenase (PDH) activity. Up-regulated PDKs play a great role in the Warburg effect in cancer cells and accordingly present a therapeutic target. Dichloroacetate (DCA) and AZD7545 are the two most-well-known PDK inhibitors exhibiting distinct pharmacological profiles. DCA showed anticancer effects in various preclinical models and clinical studies, while the primary preclinical indication of AZD7545 was on the improvement of glucose control in type II diabetes. Little, if any, study has been undertaken the elucidation of the effects of PDK inhibition on the metabolites in the tricarboxylic acid (TCA) cycle. Herein, the metabolite alterations of lung cancer cells (A549) upon the treatment with PDK inhibitors were studied using a reliable liquid-chromatography based tandem mass spectrometry method. The developed method was validated for quantification of all common glycolysis and TCA cycle catabolites with good sensitivity and reproducibility, including glucose, pyruvate, lactate, acetyl coenzyme A, citrate, alpha-ketoglutarate, fumarate, succinate, malate, and oxaloacetate. Our results suggested that A549 cells exhibited distinct metabolite profiles following the treatment with DCA or AZD7545, which may reflect the different pharmacological indications of these two drugs. PMID- 30028144 TI - Impact of Electric Fields on the Nanoscale Behavior of Lipid Monolayers at the Surface of Graphite in Solution. AB - The nanoscale organization and dynamics of lipid molecules in self-assembled membranes is central to the biological function of cells and in the technological development of synthetic lipid structures as well as in devices such as biosensors. Here, we explore the nanoscale molecular arrangement and dynamics of lipids assembled in monolayers at the surface of highly ordered pyrolytic graphite (HOPG), in different ionic solutions, and under electrical potentials. Using a combination of atomic force microscopy and fluorescence recovery after photobleaching, we show that HOPG is able to support fully formed and fluid lipid membranes, but mesoscale order and corrugations can be observed depending on the type of the lipid considered (1,2-dioleoyl- sn-glycero-3-phosphocholine, 1,2 dioleoyl- sn-glycero-3-phospho-l-serine (DOPS), and 1,2-dioleoyl-3 trimethylammoniumpropane) and the ion present (Na+, Ca2+, Cl-). Interfacial solvation forces and ion-specific effects dominate over the electrostatic changes induced by moderate electric fields (+/-1.0 V vs Ag/AgCl reference electrode) with particularly marked effects in the presence of calcium, and for DOPS. Our results provide insights into the interplay between the molecular, ionic, and electrostatic interactions and the formation of dynamical ordered structures in fluid lipid membranes. PMID- 30028143 TI - Saponin Adsorption at the Air-Water Interface-Neutron Reflectivity and Surface Tension Study. AB - Saponins are a large group of glycosides present in many plant species. They exhibit high surface activity, which arises from a hydrophobic scaffold of triterpenoid or steroid groups and attached hydrophilic saccharide chains. The diversity of molecular structures, present in various plants, gives rise to a rich variety of physicochemical properties and biological activity and results in a wide range of applications in foods, cosmetics, medicine, and several other industrial sectors. Saponin surface activity is a key property in such applications and here the adsorption of three triterpenoid saponins, escin, tea saponins, and Quillaja saponin, is studied at the air-water interface by neutron reflectivity and surface tension. All these saponins form adsorption layers with very high surface visco-elasticity. The structure of the adsorbed layers has been determined from the neutron reflectivity data and is related to the molecular structure of the saponins. The results indicate that the structure of the saturated adsorption layers is governed by densely packed hydrophilic saccharide groups. The tight molecular packing and the strong hydrogen bonds between the neighboring saccharide groups are the main reasons for the unusual rheological properties of the saponin adsorption layers. PMID- 30028145 TI - Antibacterial Mimics of Natural Products by Side-Chain Functionalization of Bicyclic Tetramic Acids. AB - Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such complex molecules. An efficient route to functionalize the C(6)-acyl group of a bicyclic tetramate was developed and utilized to prepare a small chemical library with a range of saturated and unsaturated side-chains. The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for Gram positive bacteria, and the best compound was 37-fold more potent than the cephalosporin C control and with an appropriate therapeutic window. PMID- 30028146 TI - B Meson Anomalies in a Pati-Salam Model within the Randall-Sundrum Background. AB - Lepton number as a fourth color is the intriguing theoretical idea of the famous Pati-Salam (PS) model. While in conventional PS models, the symmetry breaking scale and the mass of the resulting vector leptoquark are stringently constrained by K_{L}->MUe and K->piMUe, the scale can be lowered to a few TeV by adding vectorlike fermions. Furthermore, in this case, the intriguing hints for lepton flavor universality violation in b->sMU^{+}MU^{-} and b->ctaunu processes can be addressed. Such a setup is naturally achieved by implementing the PS gauge group in the five-dimensional Randall-Sundrum background. The PS symmetry is broken by boundary conditions on the fifth dimension, and the resulting massive vector leptoquark automatically has the same mass scale as the vectorlike fermions and all other resonances. We consider the phenomenology of this model in the context of the hints for lepton flavor universality violation in semileptonic B decays. Assuming flavor alignment in the down sector, we find that in b->sl^{+}l^{-} transitions, the observed deviations from the standard model predictions [including R(K) and R(K^{*})] can be explained with natural values for the free parameters of the model. Even though we find sizable effects in R(D), R(D^{*}), and R(J/Psi), one cannot account for the current central values in the constrained setup of our minimal model due to the stringent constraints from D D[over -] mixing and tau->3MU. PMID- 30028147 TI - Enhancing Cancer Cell Collective Motion and Speeding up Confluent Endothelial Dynamics through Cancer Cell Invasion and Aggregation. AB - We report the experimental observation of speeded-up collective motion of the monolayer endothelia-cancer mixture on a collagen-coated substrate, after the invasion of a small fraction of motile cancer cells into the confluent endothelial monolayer, through disrupting cell-cell junctions. It is found that, with an increasing waiting time, the cancer-free confluent endothelial monolayer exhibits a dynamical slowing-down of liquidlike micromotion with a gradually decreasing degree of superdiffusion. After invasion, cancer cells aggregate and exhibit turbulentlike cooperative motion, which is enhanced with the increasing size of gradually aggregated cancer clusters, confined by the fluctuating boundaries of surrounding endothelial cells. It, in turn, enhances the surrounding endothelial cell motion and speeds up the originally slowed-down motion. PMID- 30028149 TI - Detecting Equilibrium and Dynamical Quantum Phase Transitions in Ising Chains via Out-of-Time-Ordered Correlators. AB - Out-of-time-ordered (OTO) correlators have developed into a central concept quantifying quantum information transport, information scrambling, and quantum chaos. In this Letter, we show that such an OTO correlator can also be used to dynamically detect equilibrium as well as nonequilibrium phase transitions in Ising chains. We study OTO correlators of an order parameter both in equilibrium and after a quantum quench for different variants of transverse-field Ising models in one dimension, including the integrable one as well as nonintegrable and long-range extensions. We find for all the studied models that the OTO correlator in ground states detects the quantum phase transition. After a quantum quench from a fully polarized state, we observe numerically for the short-range models that the asymptotic long-time value of the OTO correlator signals still the equilibrium critical points and ordered phases. For the long-range extension, the OTO correlator instead determines a dynamical quantum phase transition in the model. We discuss how our findings can be observed in current experiments of trapped ions or Rydberg atoms. PMID- 30028148 TI - Intrinsic Spin-Orbit Torque Arising from the Berry Curvature in a Metallic Magnet/Cu-Oxide Interface. AB - We report the observation of the intrinsic dampinglike spin-orbit torque (SOT) arising from the Berry curvature in metallic-magnet/CuO_{x} heterostructures. We show that a robust dampinglike SOT, an order of magnitude larger than a fieldlike SOT, is generated in the heterostructure despite the absence of the bulk spin orbit effect in the CuO_{x} layer. Furthermore, by tuning the interfacial oxidation level, we demonstrate that the fieldlike SOT changes drastically and even switches its sign, which originates from oxygen-modulated spin-dependent disorder. These results provide important information for a fundamental understanding of the physics of the SOTs. PMID- 30028150 TI - Active Suspensions have Nonmonotonic Flow Curves and Multiple Mechanical Equilibria. AB - We point out unconventional mechanical properties of confined active fluids, such as bacterial suspensions, under shear. Using a minimal model of an active liquid crystal with no free parameters, we predict the existence of a window of bacteria concentration for which a suspension of E. Coli effectively behaves, at steady state, as a negative viscosity fluid and reach a quantitative agreement with experimental measurements. Our theoretical analysis further shows that a negative apparent viscosity is due to a nonmonotonic local velocity profile, and it is associated with a nonmonotonic stress versus strain rate flow curve. This implies that fixed stress and fixed strain rate ensembles are not equivalent for active fluids. PMID- 30028151 TI - Collective Spin Modes of a Trapped Quantum Ferrofluid. AB - We report on the observation of a collective spin mode in a spinor Bose-Einstein condensate. Initially, all spins point perpendicular to the external magnetic field. The lowest energy mode consists of a sinusoidal oscillation of the local spin around its original axis, with an oscillation amplitude that linearly depends on the spatial coordinates. The frequency of the oscillation is set by the zero-point kinetic energy of the BEC. The observations are in excellent agreement with hydrodynamic equations. The observed spin mode has a universal character, independent of the atomic spin and spin-dependent contact interactions. PMID- 30028152 TI - Quantum Algorithm for Spectral Measurement with a Lower Gate Count. AB - We present two techniques that can greatly reduce the number of gates required to realize an energy measurement, with application to ground state preparation in quantum simulations. The first technique realizes that to prepare the ground state of some Hamiltonian, it is not necessary to implement the time-evolution operator: any unitary operator which is a function of the Hamiltonian will do. We propose one such unitary operator which can be implemented exactly, circumventing any Taylor or Trotter approximation errors. The second technique is tailored to lattice models, and is targeted at reducing the use of generic single-qubit rotations, which are very expensive to produce by standard fault tolerant techniques. In particular, the number of generic single-qubit rotations used by our method scales with the number of parameters in the Hamiltonian, which contrasts with a growth proportional to the lattice size required by other techniques. PMID- 30028153 TI - Cooperative Gas Adsorption without a Phase Transition in Metal-Organic Frameworks. AB - Cooperative adsorption of gases by porous frameworks, which permits more efficient uptake and removal than the more usual noncooperative (Langmuir-type) adsorption, usually results from a phase transition of the framework. Here we show how cooperativity emerges in the class of metal-organic frameworks mmen M_{2}(dobpdc) in the absence of a phase transition. Our study provides a microscopic understanding of the emergent features of cooperative binding, including the position, slope, and height of the isotherm step, and indicates how to optimize gas storage and separation in these materials. PMID- 30028154 TI - Probing Quantum Turbulence in ^{4}He by Quantum Evaporation Measurements. AB - Theory of superfluid ^{4}He shows that, due to strong correlations and backflow effects, the density profile of a vortex line has the character of a density modulation and it is not a simple rarefaction region as found in clouds of cold bosonic atoms. We find that the basic features of this density modulation are represented by a wave packet of cylindrical symmetry in which rotons with a positive group velocity have a dominant role: The vortex density modulation can be viewed as a cloud of virtual excitations, mainly rotons, sustained by the phase of the vortex wave function. This suggests that in a vortex reconnection some of these rotons become real so that a vortex tangle is predicted to be a source of nonthermal rotons. The presence of such vorticity induced rotons can be verified by measurements at low temperature of quantum evaporation of ^{4}He atoms. We estimate the rate of evaporation and this turns out to be detectable by current instrumentation. Additional information on the microscopic processes in the decay of quantum turbulence will be obtained if quantum evaporation by high energy phonons should be detected. PMID- 30028155 TI - Quantum Limitation to the Coherent Emission of Accelerated Charges. AB - Accelerated charges emit electromagnetic radiation. According to classical electrodynamics, if the charges move along sufficiently close trajectories they emit coherently; i.e., their emitted energy scales quadratically with their number rather than linearly. By investigating the emission by a two-electron wave packet in the presence of an electromagnetic plane wave within strong-field QED, we show that quantum effects deteriorate the coherence predicted by classical electrodynamics even if the typical quantum nonlinearity parameter of the system is much smaller than unity. We explain this result by observing that coherence effects are also controlled by a new quantum parameter which relates the recoil undergone by the electron to the width of its wave packet in momentum space. PMID- 30028156 TI - Dissociation Energy of the Hydrogen Molecule at 10^{-9} Accuracy. AB - The ionization energy of ortho-H_{2} has been determined to be E_{I}^{o}(H_{2})/(hc)=124 357.238 062(25) cm^{-1} from measurements of the GK(1,1)-X(0,1) interval by Doppler-free, two-photon spectroscopy using a narrow band 179-nm laser source and the ionization energy of the GK(1,1) state by continuous-wave, near-infrared laser spectroscopy. E_{I}^{o}(H_{2}) was used to derive the dissociation energy of H_{2}, D_{0}^{N=1}(H_{2}), at 35 999.582 894(25) cm^{-1} with a precision that is more than one order of magnitude better than all previous results. The new result challenges calculations of this quantity and represents a benchmark value for future relativistic and QED calculations of molecular energies. PMID- 30028157 TI - Bounds on Dark-Matter Annihilations from 21-cm Data. AB - The observation of an absorption feature in the 21-cm spectrum at redshift z~17 implies bounds on dark-matter (DM) annihilations for a broad range of masses, given that significant heating of the intergalactic medium would have erased such a feature. The resulting bounds on the DM annihilation cross sections are comparable to the strongest ones from all other observables. PMID- 30028158 TI - Strain-Induced Asymmetric Line Segregation at Faceted Si Grain Boundaries. AB - The unique combination of atomic-scale composition measurements, employing atom probe tomography, atomic structure determination with picometer resolution by aberration-corrected scanning transmission electron microscopy, and atomistic simulations reveals site-specific linear segregation features at grain boundary facet junctions. More specific, an asymmetric line segregation along one particular type of facet junction core, instead of a homogeneous decoration of the facet planes, is observed. Molecular-statics calculations show that this segregation pattern is a consequence of the interplay between the asymmetric core structure and its corresponding local strain state. Our results contrast with the classical view of a homogeneous decoration of the facet planes and evidence a complex segregation patterning. PMID- 30028159 TI - Topological Order Generated by a Random Field in a 2D Exchange Model. AB - We study a 2D exchange model with a weak static random field on lattices containing over 10^{8} spins. Ferromagnetic correlations persist on the Imry-Ma scale inversely proportional to the random-field strength and decay exponentially at greater distances. We find that the average energy of the correlated area is close to the ground-state energy of a Skyrmion, while the topological charge of the area is close to +/-1. The correlation function of the topological charge density changes sign at a distance determined by the ferromagnetic correlation length, while its Fourier transform exhibits a maximum. These findings suggest that static randomness transforms a 2D ferromagnetic state into a Skyrmion-anti Skyrmion glass. PMID- 30028160 TI - Phonon Influence on Bulk Photovoltaic Effect in the Ferroelectric Semiconductor GeTe. AB - The shift current (SHC) has been accepted as the primary mechanism of the bulk photovoltaic effect (BPVE) in ferroelectrics, which is much different from the typical p-n junction-based photovoltaic mechanism in heterogeneous materials. In the present work, we use first-principles calculations to investigate the SHC response in the ferroelectric semiconductor GeTe, which is found possess a large SHC response due to its intrinsic narrow band gap and high covalency. We explore the changes of SHC response induced by phonon vibrations, and analytically fit current versus vibrational amplitude to reveal the quantitative relationships between vibrations and the SHC response. Furthermore, we demonstrate the temperature dependence of the SHC response by averaging the phonon vibration influence in the Brillouin zone. Our investigation provides an explicit experimental prediction about the temperature dependence of BPVE and can be extended to other classes of noncentrosymmetric materials. PMID- 30028161 TI - Magnetic Trapping of an Ultracold Gas of Polar Molecules. AB - We demonstrate the efficient transfer of molecules from a magneto-optical trap into a conservative magnetic quadrupole trap. Our scheme begins with a blue detuned optical molasses to cool SrF molecules to ~50 MUK. Next, we optically pump the molecules into a strongly trapped sublevel. This two-step process reliably transfers ~40% of the molecules initially trapped in the magneto-optical trap into a single quantum state in the magnetic trap. Once loaded, the molecule cloud is compressed by increasing the magnetic field gradient. We observe a magnetic trap lifetime of over 1 s. This opens a promising new path to study ultracold molecular collisions, and potentially to produce quantum-degenerate molecular gases via sympathetic cooling with co-trapped atoms. PMID- 30028162 TI - Critical Percolation without Fine-Tuning on the Surface of a Topological Superconductor. AB - We present numerical evidence that most two-dimensional surface states of a bulk topological superconductor (TSC) sit at an integer quantum Hall plateau transition. We study TSC surface states in class CI with quenched disorder. Low energy (finite-energy) surface states were expected to be critically delocalized (Anderson localized). We confirm the low-energy picture, but find instead that finite-energy states are also delocalized, with universal statistics that are independent of the TSC winding number, and consistent with the spin quantum Hall plateau transition (percolation). PMID- 30028164 TI - Double-Copy Structure of One-Loop Open-String Amplitudes. AB - In this Letter, we provide evidence for a new double-copy structure in one-loop amplitudes of the open superstring. Their integrands with respect to the moduli space of genus-one surfaces are cast into a form where gauge-invariant kinematic factors and certain functions of the punctures-so-called generalized elliptic integrands-enter on completely symmetric footing. In particular, replacing the generalized elliptic integrands by a second copy of kinematic factors maps one loop open-string correlators to gravitational matrix elements of the higher curvature operator R^{4}. PMID- 30028163 TI - Lifetime Measurements and Triple Coexisting Band Structure in ^{43}S. AB - Lifetime measurements of excited states in the neutron-rich nucleus ^{43}S were performed by applying the recoil-distance method on fast rare-isotope beams in conjunction with the Gamma-Ray Energy Tracking In-beam Nuclear Array. The new data based on gammagamma coincidences and lifetime measurements resolve a doublet of (3/2^{-}) and (5/2^{-}) states at low excitation energies. Results were compared to the pi(sd)-nu(pf) shell model and antisymmetrized molecular dynamics calculations. The consistency with the theoretical calculations identifies a possible appearance of three coexisting bands near the ground state of ^{43}S: the K^{pi}=1/2^{-} band built on a prolate-deformed ground state, a band built on an isomer with a 1f_{7/2}^{-1} character, and a suggested excited band built on a newly discovered doublet state. The latter further confirms the collapse of the N=28 shell closure in the neutron-rich region. PMID- 30028165 TI - How a dc Electric Field Drives Mott Insulators Out of Equilibrium. AB - Out of equilibrium phenomena are a major issue of modern physics. In particular, correlated materials such as Mott insulators experience fascinating long-lived exotic states under a strong electric field. Yet, the origin of their destabilization by the electric field is not elucidated. Here we present a comprehensive study of the electrical response of canonical Mott insulators GaM_{4}Q_{8} (M=V, Nb, Ta, Mo; Q=S, Se) in the context of a microscopic theory of electrical breakdown where in-gap states allow for a description in terms of a two-temperature model. Our results show how the nonlinearities and the resistive transition originate from a massive creation of hot electrons under an electric field. These results give new insights for the control of the long-lived states reached under an electric field in these systems which has recently open the way to new functionalities used in neuromorphic applications. PMID- 30028167 TI - One-Shot Coherence Distillation. AB - We characterize the distillation of quantum coherence in the one-shot setting, that is, the conversion of general quantum states into maximally coherent states under different classes of quantum operations. We show that the maximally incoherent operations (MIO) and the dephasing-covariant incoherent operations (DIO) have the same power in the task of one-shot coherence distillation. We establish that the one-shot distillable coherence under MIO and DIO is efficiently computable with a semidefinite program, which we show to correspond to a quantum hypothesis testing problem. Further, we introduce a family of coherence monotones generalizing the robustness of coherence as well as the modified trace distance of coherence, and show that they admit an operational interpretation in characterizing the fidelity of distillation under different classes of operations. By providing an explicit formula for these quantities for pure states, we show that the one-shot distillable coherence under MIO, DIO, strictly incoherent operations, and incoherent operations is equal for all pure states. PMID- 30028168 TI - Parametric Instability Driven by Weakly Trapped Particles in Nonlinear Plasma Waves. AB - This Letter describes a new parametric instability mechanism caused by a distribution f_{T} of particles trapped in the potential wells of a wave train. The mechanism explains a nonlinear instability in Trivelpiece-Gould (TG) waves, and it could also be a destabilizing factor in a range of nearly collisionless nonlinear plasma waves. The theory is compared to particle in cell simulations of TG waves. PMID- 30028166 TI - Helium-Iron Compounds at Terapascal Pressures. AB - We investigate the binary phase diagram of helium and iron using first-principles calculations. We find that helium, which is a noble gas and inert at ambient conditions, forms stable crystalline compounds with iron at terapascal pressures. A FeHe compound becomes stable above 4 TPa, and a FeHe_{2} compound above 12 TPa. Melting is investigated using molecular dynamics simulations, and a superionic phase with sublattice melting of the helium atoms is predicted. We discuss the implications of our predicted helium-iron phase diagram for interiors of giant (exo)planets and white dwarf stars. PMID- 30028169 TI - Bipolarons in a Bose-Einstein Condensate. AB - Mobile impurities in a Bose-Einstein condensate form quasiparticles called polarons. Here, we show that two such polarons can bind to form a bound bipolaron state. Its emergence is caused by an induced nonlocal interaction mediated by density oscillations in the condensate, and we derive using field theory an effective Schrodinger equation describing this for an arbitrarily strong impurity boson interaction. We furthermore compare with quantum Monte Carlo simulations finding remarkable agreement, which underlines the predictive power of the developed theory. It is found that bipolaron formation typically requires strong impurity interactions beyond the validity of more commonly used weak-coupling approaches that lead to local Yukawa-type interactions. We predict that the bipolarons are observable in present experiments, and we describe a procedure to probe their properties. PMID- 30028170 TI - Erratum: Topological Magnon Bands and Unconventional Superconductivity in Pyrochlore Iridate Thin Films [Phys. Rev. Lett. 118, 177201 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.177201. PMID- 30028172 TI - Constraining Baryon-Dark-Matter Scattering with the Cosmic Dawn 21-cm Signal. AB - The recent detection of an anomalously strong 21-cm signal of neutral hydrogen from cosmic dawn by the EDGES low-band radio experiment can be explained if cold dark matter particles scattered off the baryons draining excess energy from the gas. In this Letter we explore the expanded range of the 21-cm signal that is opened up by this interaction, varying the astrophysical parameters as well as the properties of dark matter particles in the widest possible range. We identify models consistent with current data by comparing to both the detection in the low band region and the upper limits from the EDGES high-band antenna. We find that consistent models predict a 21-cm fluctuation during cosmic dawn that is between 3 and 30 times larger than the largest previously expected without dark matter scattering. The expected power spectrum exhibits strong baryon acoustic oscillations imprinted by the velocity-dependent cross section. The latter signature is a conclusive evidence of the velocity-dependent scattering and could be used by interferometers to verify the dark matter explanation of the EDGES detection. PMID- 30028171 TI - Emergent Universal Dynamics for an Atomic Cloud Coupled to an Optical Waveguide. AB - We study the dynamics of a single collective excitation in a cold ensemble of atoms coupled to a one-dimensional waveguide. The coupling between the atoms and the photonic modes provides a coherent and a dissipative dynamics for this collective excitation. While the dissipative part accounts for the collectively enhanced and directed emission of photons, we find a remarkable universal dynamics for increasing atom numbers exhibiting several revivals under the coherent part. While this phenomenon provides a limit on the intrinsic dephasing for such a collective excitation, a setup is presented where the universal dynamics can be explored. PMID- 30028173 TI - Measuring the Local Velocity along Transition Paths during the Folding of Single Biological Molecules. AB - Transition paths are the most interesting part of folding reactions but remain little studied. We measured the local velocity along transition paths in DNA hairpin folding using optical tweezers. The velocity distribution agreed well with diffusive theories, yielding the diffusion coefficient. We used the average velocity to calculate the transmission factor in transition-state theory (TST), finding observed rates that were ~10^{5}-fold slower than predicted by TST. This work quantifies the importance of barrier recrossing events and highlights the effectiveness of the diffusive model of folding. PMID- 30028174 TI - Unfolding Hidden Barriers by Active Enhanced Sampling. AB - Collective variable (CV) or order parameter based enhanced sampling algorithms have achieved great success due to their ability to efficiently explore the rough potential energy landscapes of complex systems. However, the degeneracy of microscopic configurations, originating from the orthogonal space perpendicular to the CVs, is likely to shadow "hidden barriers" and greatly reduce the efficiency of CV-based sampling. Here we demonstrate that systematic machine learning CV, through enhanced sampling, can iteratively lift such degeneracies on the fly. We introduce an active learning scheme that consists of a parametric CV learner based on deep neural network and a CV-based enhanced sampler. Our active enhanced sampling algorithm is capable of identifying the least informative regions based on a historical sample, forming a positive feedback loop between the CV learner and sampler. This approach is able to globally preserve kinetic characteristics by incrementally enhancing both sample completeness and CV quality. PMID- 30028175 TI - Severely Constraining Dark-Matter Interpretations of the 21-cm Anomaly. AB - The EDGES Collaboration has recently reported the detection of a stronger-than expected absorption feature in the global 21-cm spectrum, centered at a frequency corresponding to a redshift of z?17. This observation has been interpreted as evidence that the gas was cooled during this era as a result of scattering with dark matter. In this Letter, we explore this possibility, applying constraints from the cosmic microwave background, light element abundances, Supernova 1987A, and a variety of laboratory experiments. After taking these constraints into account, we find that the vast majority of the parameter space capable of generating the observed 21-cm signal is ruled out. The only viable models are those in which a small fraction, ~0.3%-2%, of the dark matter consists of particles with a mass of ~10-80 MeV and which couple to the photon through a small electric charge, roughly 10^{-6}-10^{-4} as large as the electron charge. Furthermore, in order to avoid being overproduced in the early Universe, such models must be supplemented with an additional depletion mechanism, such as annihilations through a L_{MU}-L_{tau} gauge boson or annihilations to a pair of rapidly decaying hidden sector scalars. PMID- 30028176 TI - Translational and Rotational Dynamical Heterogeneities in Granular Systems. AB - We use x-ray tomography to investigate the translational and rotational dynamical heterogeneities of a three dimensional hard ellipsoid granular packing driven by oscillatory shear. We find that particles which translate quickly form clusters with a size distribution given by a power law with an exponent that is independent of the strain amplitude. Identical behavior is found for particles that are translating slowly, rotating quickly, or rotating slowly. The geometrical properties of these four different types of clusters are the same as those of random clusters. Different cluster types are considerably correlated or anticorrelated, indicating a significant coupling between translational and rotational degrees of freedom. Surprisingly, these clusters are formed already at time scales that are much shorter than the alpha-relaxation time, in stark contrast to the behavior found in glass-forming systems. PMID- 30028177 TI - Enhanced Absorption by Linewidth Narrowing in Optically Excited Type-II Semiconductor Heterostructures. AB - We experimentally report a surprising linewidth narrowing of the direct exitonic 1 s heavy-hole transition in a type-II quantum well system. This narrowing, which builds up on a pico- to nanosecond timescale, causes a transient enhanced absorption at the spectral peak position of the excitonic resonance. We discuss how this effect depends on experimental parameters such as excitation density, temperature, and barrier width. We cannot attribute this effect to known physical mechanisms. PMID- 30028178 TI - Chiral Orbital Magnetism of p-Orbital Bosons in Optical Lattices. AB - Chiral magnetism is a fascinating quantum phenomena that has been found in low dimensional magnetic materials. It is not only interesting for understanding the concept of chirality, but also important for potential applications in spintronics. Past studies show that chiral magnets require both a lack of inversion symmetry and spin-orbit coupling to induce the Dzyaloshinskii-Moriya interaction. Here we report that the combination of inversion symmetry breaking and quantum degeneracy of orbital degrees of freedom will provide a new paradigm to achieve chiral orbital magnetism. By means of density matrix renormalization group calculation, we demonstrate that chiral orbital magnetism can be found when considering bosonic atoms loaded in the p band of an optical lattice in the Mott regime. The high tunability of our scheme is also illustrated through simply manipulating the inversion symmetry of the system for cold atom experimental conditions. PMID- 30028179 TI - Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer. AB - CONTEXT: - Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD-L1) protein expression as a companion diagnostic to identify likely responders to therapy. OBJECTIVE: - To develop an immunohistochemical scoring algorithm that includes PD-L1 expression for tumor and immune cells, that is, the combined positive score. DESIGN: - Four previously treated tumor types in the KEYNOTE-012 and KEYNOTE-028 studies were analyzed descriptively with a version of the PD-L1 immunohistochemical 22C3 pharmDx assay labeled for investigational use only to determine the relative importance of PD-L1 expression in tumor versus immune cells as a biomarker for pembrolizumab response. A combined positive score was developed as a novel scoring method and was compared with the tumor proportion score in cohort 1 from the KEYNOTE-059 study (G/GEJ cancer). External reproducibility was assessed. RESULTS: - Per combined positive score cutoff of 1 or more, the prevalence of PD L1 expression in patients with G/GEJ cancer was 57.6% (148 of 257 patients), with reasonable enrichment of responses (odds ratio, 2.8). Per tumor proportion score cutoff of 1% or more, prevalence was 12.5% (32 of 257 patients), with minimal enrichment (odds ratio, 1.4). External reproducibility assessments demonstrated interpathologist overall agreement of 96.6% (591 of 612; 95% CI, 94.0%-98.7%) and intrapathologist overall agreement of 97.2% (595 of 612; 95% CI, 95.3%-98.9%). CONCLUSIONS: - Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with G/GEJ cancer. This novel scoring method supported US Food and Drug Administration approval of pembrolizumab as third-line therapy for G/GEJ cancer and has facilitated investigation in other indications. PMID- 30028180 TI - Dosimetric analysis of patients with gastro entero pancreatic neuroendocrine tumors (NETs) treated with PRCRT (peptide receptor chemo radionuclide therapy) using Lu-177 DOTATATE and capecitabine/temozolomide (CAP/TEM). AB - OBJECTIVE:: Two radiosensitizing chemotherapeutic drugs, capecitabine (CAP) and temozolomide (TEM), are administered concurrently to enhance the therapeutic efficacy of peptide receptor radionuclide therapy (PRRT). This study aims to assess the biodistribution and normal-organ and tumor radiation dosimetry for Lu 177 DOTATATE administered concurrently with CAP/TEM. METHODS:: 20 patients with non-resectable histologically confirmed gastroenteropancreatic neuroendocrine tumors with normal kidney function, a normal haematological profile and somatostatin receptor expression of the tumor lesions, as scintigraphically assessed by a Ga-68 DOTANOC scan, were included in two groups-case group (n = 10) and control group (n = 10). Patients included in case group were those who were advised concomitant CAPTEM therapy by the treating medical oncologist. Patients were administered CAP orally at a dose of 600mg m-2 bovine serum albumin twice a day for 14 days starting 9 days prior to PRRT and oral TEM as a single dose at a dose of 75 mg m-2 was given concurrently for the last 5 days commencing on the day of PRRT (days 9-14). In the control group, patients were treated with Lu-177 DOTATATE only. For PRRT, 6.4 GBq-7.6 GBq (173-207 mCi) of Lu-177 DOTATATE was administered as infusion into each patient over 10-15 min in a solution with positively charged amino acids for renal protection. Dosimetric calculations were done using the HERMES software. RESULTS:: Physiological uptake of Lu-177 DOTATATE was seen in all patients in liver, spleen kidneys, and bone marrow. Radiation absorbed doses (mean +/- standard deviation) were obtained as 0.29 +/- 0.12 mGy/MBq for kidneys, 0.30 +/- 0.18 mGy/MBq for liver, 0.63 +/- 0.37 mGy/MBq for spleen, 0.019 +/- 0.001 mGy/MBq for bone marrow and 3.85 +/- 1.74 mGy/MBq for tumours in the case group and they were 0.31+/- 0.26, 0.24 +/- 0.14, 0.64 +/- 0.42, 0.017 +/- 0.016, 5.6 +/- 11.27 mGy/MBq in kidneys, liver, spleen, bone marrow and neuroendocrine tumour, respectively, in the control group. Mann Whitney U test between the variables of two groups showed an insignificant difference (p > 0.05). CONCLUSIONS:: The authors demonstrated no significant difference between the tumor and organ doses with Lu-177 DOTATATE in the patients treated with and without concomitant chemotherapy. ADVANCES IN KNOWLEDGE:: To our knowledge, this is the first dedicated study exhibiting dosimetric analysis in patients undergoing PRRT in combination with chemotherapy. PMID- 30028183 TI - Ambient dose during intraoral radiography with current techniques: Part 1 conversion factor for scattered radiation using a rectangular collimator. AB - OBJECTIVES:: The aim of this study was to establish a conversion factor for assessing the scattered radiation produced during intraoral radiography with a rectangular collimator in areas where the remnant beam is not present. The dose level in the remnant beam will be addressed in another study. METHODS:: A radiological phantom (Rando) in the upright position was exposed to radiation delivered by a Planmeca Intra X-ray unit over 9 exposure geometries (right side of a full mouth series). For each geometry, the scattered radiation dose was measured at 5 locations in the horizontal plane and 4 locations in the vertical plane in front of the patient. The measurements were corrected for background and leakage radiation. An inventory of the distributions of the different geometries with respect to their share of the total workload was created in order to assign the correct weightings of the total ambient scattered radiation for the different geometries. The weightings were used to construct a scattered radiation pattern for a representative mix of exposures. The maximum value found in this pattern was used to arrive at a safe conversion factor. RESULTS:: The scattered ambient radiation dose was evenly distributed over the horizontal plane. The scattered ambient radiation dose ranged from 20 to 65% lower in the vertical plane. CONCLUSIONS:: The conversion factor established for scattered ambient radiation was 0.05 uSv per mAs at 1 meter. This factor is 3-fold lower than the conversion factors reported previously. PMID- 30028181 TI - Contrast-enhanced ultrasonography vs MRI for evaluation of local invasion by cervical cancer. AB - OBJECTIVE:: The purpose of this study is to compare contrast-enhanced ultrasound (CEUS) to MRI for evaluating local invasion of cervical cancer. METHODS:: A total of 108 patients with cervical cancer were included in this study. All the enrolled patients were Stage IIA2-IVB according to the International Federation of Obstetrics and Gynecology and treated with volumetric modulated arc therapy. Tumour size in different dimensions was compared between MRI and CEUS. The correlation coefficients (r) between MRI and CEUS for diagnosing local invasion, parametrial extension, and invasion to vagina, uterine corpus and adjacent organs were assessed. RESULTS:: Measurements by MRI and CEUS were strongly correlated in the three dimensions: left-right r = 0.84, craniocaudal r = 0.86 and anteroposterior r = 0.88. Vaginal and parametrial invasion were detected by both MRI and CEUS with moderate concordance, and invasion of uterine corpus, bladder and rectum with good concordance. CONCLUSION:: CEUS is comparable to MRI for measuring tumour size, with good concordance for evaluating invasion of cervical cancer. ADVANCES IN KNOWLEDGE:: CEUS is a less expensive non-invasive modality for assessment of tumour size and invasion of cervical cancer. PMID- 30028184 TI - Pictorial review: non-anatomical cardiovascular gas: causes, appearances and consequences. AB - Gas does not occur naturally in the cardiovascular system, although it is not unusual to identify it on imaging. The true incidence is difficult to know as asymptomatic cases are rarely recorded. In iatrogenic instance, this occurs when atmospheric air enters the cardiovascular system from a high to low pressure, or when gas is forcibly injected into a vessel. The source of air must be promptly identified and treatment must be expedited to reduce morbidity and mortality. This pictorial review aims to give an overview of the causes (with particular emphasis on the conditions that may be encountered by a Radiologist), appearances of cardiovascular gas, and any subsequent treatment. PMID- 30028182 TI - Patient doses in endovascular and hybrid revascularization of the lower extremities. AB - OBJECTIVE:: Hybrid surgical methods such as remote endarterectomy and endovascular revascularization are fluoroscopy-guided procedures successfully replacing conventional open surgery for treatment of peripheral artery disease (PAD). The aim of this study was to: (1) evaluate the dose parameters describing exposure of patients undergoing endovascular or hybrid revascularization of the lower limb (below the inguinal ligament); (2) compare the data available in the literature with the evaluations of patients' dose values and related factors for patients undergoing such procedures; (3) examine the correlation of doses with certain parameters; (4) estimate the peak skin dose and assess the potential for radiation-induced skin injuries during the procedures. METHODS:: Data for 259 patients were extracted retrospectively and analyzed. The procedures were grouped by type of intervention, vascular approach, and level of complexity. The analyses included the correlation of dose values with the operating team. RESULTS:: The air kerma-area product (KAP) and fluoroscopy time (FT) values greatly varied depending on the procedure type but also among patients undergoing the same procedure. The type of vascular access has the largest impact on patients' doses. The KAP and FT values for brachial artery were: 347 Gy.cm2 and FT: NA; for contralateral common femoral artery (CFA) approach: 207 Gy.cm2 and 153 s; e.g. significantly higher than for ipsilateral CFA: 96 Gy.cm2 and 78 s; for hybrid surgery: 77 Gy.cm2 and 41 s; and for ipsilateral retrograde popliteal approach: 61 Gy.cm2 and 53 s. The same tendency is observed for the peak skin dose (PSD) values: the highest are for brachial artery (2053 mGy) and contralateral CFA (1325 mGy) approach, followed by the ipsilateral CFA (748 mGy), hybrid surgery (649 mGy), and ipsilateral retrograde popliteal approach (566 mGy). CONCLUSION:: Registered dose values and FT for the different procedures do not exceed the International Atomic Energy Agency (IAEA) proposed trigger values for patients' follow-up for radiation-induced skin injuries. The type of vascular access has the highest negative impact on radiation dose levels and resultant KAP, PSD, and FT values. There is a significant increase of the dose values with increase of the number of inserted stents and the level of complexity. This should be considered in planning, especially for patients who undergo multiple diagnostic and therapeutic procedures. ADVANCES IN KNOWLEDGE:: This study gives a systematic understanding for patient radiation exposure in endovascular and hybrid revascularization of the lower extremities, thus far absent in the literature. PMID- 30028185 TI - An systematic review of e-learning outcomes in undergraduate dental radiology curricula-levels of learning and implications for researchers and curriculum planners. AB - OBJECTIVES: To examine the outcomes of e-learning or blended learning interventions in undergraduate dental radiology curricula and analyze the nature of the knowledge levels addressed in learning interventions. METHODS: A systematic literature review was performed using a search strategy based on MeSH key words specific to the focus question and indexed in the MEDLINE database. The search again was supplemented by hand-searching of selected journals. Data were extracted relating to outcomes of knowledge and student perceptions. Analysis of the e-learning intervention was performed using a new framework to examine the level of knowledge undertaken: (1) remember/understand (2) analysis or evaluation or diagnosis and (3) performance ("knows how" or "shows how"). RESULTS: From the selected 17 papers, 11 were positive about student reported outcomes of the interventions, and 8 reported evidence that e-learning interventions enhanced learning. Out of the included studies, 8 used e-learning at the level of remember/understand, 4 at the level of analysis/evaluate/diagnosis, and 5 at the level of performance ("knows how," "shows how"). CONCLUSIONS: The learning objectives, e-learning intervention, outcome measures and reporting methods were diverse and not well reported. This makes comparison between studies and an understanding of how interventions contributed to learning impractical. Future studies need to define "knowledge" levels and performance tasks undertaken in the planning and execution of e-learning interventions and their assessment methods. Such a framework and approach will focus our understanding in what ways e learning is effective and how it contributes to better evidence-based e-learning experiences. PMID- 30028186 TI - Computed tomography cavernosography combined with volume rendering to observe venous leakage in young patients with erectile dysfunction. AB - OBJECTIVE:: To observe the venous leakage of penile veins through cavernosometry and cavernosography, using CT combined with three-dimensional volume rendering. METHODS:: 186 consecutive erectile dysfunction patients (20-40 years old) with suspected venous leakage diagnosed by clinicians were enrolled. All patients underwent intracavernous injection of vasoactive agents combined with Doppler ultrasound to identify venous leakage. RESULTS:: Taking intracavernous injection combined with Doppler ultrasound as the "gold-standard", 47/186 (25.3%) patients had negative venous leakage, and 139/186 (74.7%) patients had positive venous leakage. CT cavernosography showed that 22/139 (15.8%) cases were isolated deep dorsal vein or crural vein leakage, and 117/139 (84.2%) cases were complex venous leakage. Three types of deep dorsal vein were seen: single-branch 42/139 (30.2.%), double-branch 45/139 (32.4%), and complex 31/139 (22.3%). Three types of prostatic venous plexus were seen: single-branch 26/139 (18.7%), multiple branch 36/139 (25.9%), and plexus 39/139 (28.1%). A total of 166 crural veins were revealed in 129 patients. Crural veins had three origins: medial dorsal side (112/166, 67.5%), lateral ventral side (30/166, 18.1%) and the curs tip (24/166, 14.4%). CONCLUSION:: To achieve the expected success rate of ligation surgery or endovascular embolization, candidates for the procedures should be carefully selected through CT cavernosography, which can provide elaborate images and information about the venous leakage. ADVANCES IN KNOWLEDGE:: A modified evaluation method was used in this study to monitor the intracavernous pressure during examination. New classifications of the deep dorsal vein, prostatic venous plexus and crural vein are described in this study. PMID- 30028188 TI - Multi-slice real-time MRI of temporomandibular joint dynamics. AB - OBJECTIVES: The purpose of this work was to improve the clinical versatility of high-speed real-time MRI studies of temporomandibular joint (TMJ) dynamics by simultaneous recordings of multiple MRI movies in different sections. METHODS: Real-time MRI at 3 T was realized using highly undersampled radial FLASH acquisitions and image reconstruction by regularized nonlinear inversion (NLINV). Multi-slice real-time MRI of two, three or four slices at 0.75 mm resolution and 6 to 8 mm thickness was accomplished at 50.0 ms, 33.3 ms or 25.5 ms temporal resolution, respectively, yielding simultaneous movies at 2 * 10, 3 * 10 or 4 * 10 frames per second in a frame-interleaved acquisition mode. Real-time MRI movies were evaluated by three blinded raters for visibility of the anterior and posterior border of disc, shape of the disk body and condyle head as well as movement of the disc and condyle (1 = excellent, 5 = no visibility). RESULTS: Effective delineation of the disk atop the mandibular condyle was achieved by T1 weighted images with opposed-phase water-fat contrast. Compared to 8 mm sections, multi-slice recordings with 6 mm thickness provided sharper delineation of relevant structures as confirmed by inter-rater evaluation. Respective dual-slice and triple-slice recordings of a single TMJ as well as dual-slice recordings of both joints (one slice per TMJ) received the highest visibility ratings of <= 2 corresponding to high confidence in diagnostic content. CONCLUSIONS: The improved access to TMJ dynamics by multi-slice real-time MRI will contribute to more effective treatment of temporomandibular disorders. PMID- 30028187 TI - Predicting the dose absorbed by organs at risk during intensity modulated radiation therapy for nasopharyngeal carcinoma. AB - OBJECTIVE:: To develop a model for predicting the dose absorbed by organ at risk (OAR) during intensity modulated radiation therapy for nasopharyngeal carcinoma (NPC). METHODS:: 55 patients underwent intensity modulated radiation therapy for NPC. The OARs were divided into several suborgans, and SPSS software was used to evaluate multiple linear method for fitting the normalized volume for each suborgan, normalized mean dose (Dmean) Dnm (Dnm = Dmean/Dprescription), and normalized D10%-D100% values Dn10%-n100%(Dn10%-n100% = D10%-D100%/Dprescription) for each OAR. Based on the Matlab software, the predicted Dn10%-n100% value was fitted to obtain the predicted DVH curve. RESULTS:: The multiple linear fitting formulas revealed significant results for the oral cavity Dn100% (p = 0.017), the parotid gland Dn100% (p = 0.001), and the remaining OAR (all p < 0.0001). The correlation coefficients and p values indicated that the fitting formula was a good fit. The p values for the White test show that the prediction model is robust. This method was successfully used for verification cases. CONCLUSION:: The present study provided a simple and effective model for predicting the dose absorbed by OAR for NPC. ADVANCES IN KNOWLEDGE:: This method is a relatively simple mathematical model, just use prescription dose and V0-Vn to predict the Dmean and D10%-100%, which predict does not require buying new modules of treatment planning software or extracting the distance of each sampling point of the OAR with the dose information. PMID- 30028189 TI - Digital breast volume estimation (DBVE)-A new technique. AB - OBJECTIVE:: There are several limitations with current methods of breast volume measurement; principally relating to assumption of fixed shape forms. This study, utilizing computer aided volume estimates, developed a new method using the digital mapping of breast area and compares results to existing techniques of breast volume measurement and actual breast volume. METHODS:: 50 consecutive breast cancer patients had breast volume calculated from mammograms [craniocaudal (CC) and mediolateral oblique views]; using breast height, width, radius, area and compression thickness. Area was recorded using cursor measurement tool for AGFA(r) ImpaxTM6 software. The new volumetric estimation is based on the basic formula for the volume of a solid. The technique was compared with three known breast volume estimation techniques. Subsequently, 15 patients undergoing mastectomy had pre-op breast volume calculated using this new method and 3 existing techniques; values were compared to fresh mastectomy weights/volumes. RESULTS:: 50 patients, mean age 63.2 +/- 14.4 (range 38-88) had breast volume estimation. The CC view appears to provide the best correlation with existing techniques. Scatterplots show a significant correlation of all the methods with the digital breast volume estimation method. Mastectomy volume compared with four breast volume techniques in n = 15, confined to the CC, shows good correlation between the digital technique and real volume. Scatterplots show significant correlation between digital breast volume estimation and mastectomy weight. CONCLUSION:: This study provided a novel simple tool to estimate breast volume in patients. ADVANCES IN KNOWLEDGE:: This may aid in planning cosmetic outcome and oncoplastic approaches in breast cancer and breast reduction surgery. PMID- 30028190 TI - Worth syndrome "mandibular osteosclerosis" as an incidental finding: a report of 2 cases. AB - This report presents two cases of Worth syndrome involving the mandible which were identified as an incidental finding on radiologic evaluation. Both patients were females who presented with enlarged mandibles. Radiologic evaluation revealed multiple bilateral mandibular enostoses, widened and thickened inferior cortical border of the mandible, with no other major clinical finding on examination. One of the patients received orthognathic surgery and healed uneventfully with no post-surgical complications. In this report, we reviewed possible differential diagnoses to this syndrome to facilitate identification among general dentists and oral and maxillofacial radiologists. PMID- 30028191 TI - Correlation between biomarkers of creatine metabolism and serum indicators of peripheral muscle fatigue during exhaustive exercise in active men. AB - Exhaustive exercise induces various disturbances of homeostasis, with impaired bioenergetics often associated with strenuous muscular work. However, no study so far validated serum biomarkers of creatine metabolism vs. traditional markers of exhaustive exercise and fatigue. Here, we investigated how well changes in serum guanidinoacetic acid (GAA), creatine and creatinine correlate with responses in blood lactate, creatine kinase, interleukin-6 and cortisol in 11 young active men (age 23.2 +/- 3.7 years; VO2max 49.5 +/- 5.4 ml/kg/min) exposed to exhaustive exercise. All participants were subjected to running at individual running speed at anaerobic threshold until exhaustion, with venous blood drawn at baseline and during an exercise session at 5-min intervals. Running-to-exhaustion markedly affected serum GAA and creatine levels, with circulating GAA increased for 5.3 +/ 8.5%(95% CI, -0.4 to 11.0), and serum creatine elevated by 33.9 +/- 21.8% (95% CI, 19.3 to 48.6) compared to baseline levels (P <= 0.05). In addition, moderate to-strong positive linear correlations were found between exhaustive exercise induced changes in serum cortisol and GAA levels (r = 0.79; P = 0.03), and cortisol and creatine concentrations (r = 0.81; P = 0.03). This suggests a link between cortisol and heavy exercise-induced impaired bioenergetics, with future studies needed to evaluate a cause-and-effect interconnection between cortisol and GAA-creatine axis. PMID- 30028192 TI - "Witchdoctors" in White Coats: Politics and Healing Knowledge in Tanzania. AB - At the center of conflict between the state and traditional healers (waganga wa kienyeji) over the meanings of traditional healing in contemporary Tanzania are debates about what constitutes knowledge, the production of knowledge, and the legitimacy of "traditional" ways of knowing. Drawing on media analysis and ethnographic fieldwork carried out between 2004 and 2016, I describe how healers locate their knowledge in experience, ancestors, and spirits, while the state imagines a future where traditional healers are formally educated and practice in white uniforms. While embedded in a larger colonial and postcolonial history, this conflict arose in response to the attribution of violence against persons with albinism to traditional healers. PMID- 30028194 TI - Cyborg Preparedness: Incorporating Knowing and Caring Bodies into Emergency Infrastructures. AB - Biopreparedness exercises are commonly depicted as indispensable means to enable people to respond to outbreaks of highly pathogenic infectious diseases. In this article, based on a 4-year multisited ethnography conducted in Frankfurt and London, we argue that exercises mobilize past and present events in a continuous rehearsal for the implementation and stabilization of emergency infrastructures. While relying on the embodied knowledge and the body techniques of its participants, these infrastructures necessitate continuous attention, investment, and training. Through these techniques, preventive assemblages create what we term "cyborg preparedness," whereby human bodies, clinical architectures, and technical artifacts are subject to emerging forms of urban governance. PMID- 30028193 TI - Comparison of CT and magnetic resonance mDIXON-Quant sequence in the diagnosis of mild hepatic steatosis. AB - OBJECTIVE:: To determine the diagnostic performance of CT in the assessment of mild hepatic steatosis by comparison with MR mDIXON-Quant as a reference standard, and to explore their clinical applications. METHODS:: In this prospective study 169 volunteers were included. Each subject underwent CT and MR mDIXON-Quant examinations. Hepatic steatosis evaluations were performed via liver attenuation alone (CT L), liver to spleen attenuation ratio (CT L/S), difference between liver and spleen attenuation (CT L-S), and MR mDIXON-Quant imaging. The effectiveness of CT L, CT L/S, and CT L-S in diagnosing hepatic steatosis severity of >=5%, >=10%, and >=15% was compared, using mDIXON-Quant results as standard. RESULTS:: 65 subjects exhibited mild hepatic steatosis. Hepatic steatosis measurement with mDIXON-Quant was strongly correlated with the three CT methods. Using cutoff value, the sensitivity and specificity of diagnosing hepatic steatosis >=5, >=10, and >=15% were 64.6, 91.3, 100%, and 90.4, 89.7, 93.0% for CT L; 50.8, 87.0, 100%, and 96.2, 98.6, 97.5% for CT L/S; and 67.7, 87.0, 100%, and 81.7, 98.6, 97.5% for CT L-S, respectively. ROC analysis indicated that 58.9, 56.5, and 52.8 HU for CT L; 1.06, 0.98, and 0.90 HU for CT L/S; and 6.21,-1.04, and -4.93 HU for CT L-S were cutoff values for diagnosing hepatic steatosis >=5%,>=10%, and >=15%, respectively. CONCLUSIONS:: The three CT methods exhibit better agreements with mDIXON-Quant imaging for diagnosing hepatic steatosis >=10%. Hence, CT and mDIXON-Quant could serve as suitable tools for the accurate quantification of mild hepatic steatosis. SIGNIFICANT FINDS OF THE STUDY:: The close agreement between the three different CT methods (based on our cutoff values) and mDIXON-Quant imaging suggests that CT could accurately diagnose hepatic steatosis >=10%. Thus, CT and mDIXON-Quant imaging can accurately measure mild hepatic steatosis. WHAT THIS STUDY ADDS:: Only few studies have compared hepatic steatosis quantification between CT and mDIXON Quant. We are the first to determine the diagnostic performance of unenhanced CT for quantitatively assessing mild hepatic steatosis, in reference to magnetic resonance mDIXON-Quant imaging. PMID- 30028195 TI - Use of tungsten sheet as an alternative for reducing the radiation dose behind the digital imaging plate during intra-oral radiography. AB - OBJECTIVES: To verify the use of tungsten sheet as an alternative to lead foil for reducing the radiation dose behind storage phosphor plates (SPPs). METHODS: At six sites (incisor, canine, and molar sites in both the maxilla and mandible) in a head phantom, radiation doses were initially measured behind conventional film packets containing two films and a lead foil. At the same sites, radiation doses were also measured behind packets containing only SPPs. Thereafter, the same dose measurements were performed with shielding materials (lead foil or tungsten sheet) within the packets. These doses were defined as behind doses. RESULTS: There were no differences in the mean behind doses between the conventional film packets and the SPP packets without shielding materials for any of the six sites examined. The behind doses were reduced by both lead foil and tungsten sheet, with significant differences in all sites when compared with no shielding. Lead foil reduced the behind dose of the SPP packet to 37.6% on average, while tungsten sheet reduced the behind dose to less than 20% in all of the sites examined, with an average of 14.7%. CONCLUSIONS: Tungsten sheet appeared to be effective as an alternative shielding material, sufficiently reducing the doses behind the SPP packets to less than 20% when compared with sheetless packets in all of the six sites examined. PMID- 30028196 TI - FGF23 impairs peripheral microvascular function in renal failure. AB - BACKGROUND: Cardiovascular diseases account for approximately 50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. METHODS: Mice were subjected to partial nephrectomy (5/6Nx) or sham-surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections, and CKD mice received FGF23 blocking antibodies following 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. RESULTS: 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside (SNP) or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine (ADMA) concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. CONCLUSIONS: In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. PMID- 30028199 TI - New insights into arterial stiffening: does sex matter? AB - This review discusses sexual dimorphism in arterial stiffening, disease pathology interactions, and the influence of sex on mechanisms and pathways. Arterial stiffness predicts cardiovascular mortality independent of blood pressure. Patients with increased arterial stiffness have a 48% higher risk for developing cardiovascular disease. Like other cardiovascular pathologies, arterial stiffness is sexually dimorphic. Young women have lower stiffness than aged-matched men, but this sex difference reverses during normal aging. Estrogen therapy does not attenuate progressive stiffening in postmenopausal women, indicating that currently prescribed drugs do not confer protection. Although remodeling of large arteries is a protective adaptation to higher wall stress, arterial stiffening increases afterload to the left ventricle and transmits higher pulsatile pressure to smaller arteries and target organs. Moreover, an increase in aortic stiffness may precede or exacerbate hypertension, particularly during aging. Additional studies are needed to elucidate the mechanisms by which females are protected from arterial stiffness to provide insight into its mechanisms and, ultimately, therapeutic targets for treating this pathology. PMID- 30028198 TI - Astrocyte-produced carbon monoxide and the carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by prolonged neonatal asphyxia. AB - Neonatal asphyxia leads to cerebrovascular disease and neurological complications via a mechanism that may involve oxidative stress. Carbon monoxide (CO) is an antioxidant messenger produced via a heme oxygenase (HO)-catalyzed reaction. Cortical astrocytes are the major cells in the brain that express constitutive HO 2 isoform. We tested the hypothesis that CO, produced by astrocytes, has cerebroprotective properties during neonatal asphyxia. We developed a survival model of prolonged asphyxia in newborn pigs that combines insults of severe hypoxia, hypercapnia, and acidosis while avoiding extreme hypotension and cerebral blood flow reduction. During the 60-min asphyxia, CO production by brain and astrocytes was continuously elevated. Excessive formation of reactive oxygen species during asphyxia/reventilation was potentiated by the HO inhibitor tin protoporphyrin, suggesting that endogenous CO has antioxidant effects. Cerebral vascular outcomes tested 24 and 48 h after asphyxia demonstrated the sustained impairment of cerebral vascular responses to astrocyte- and endothelium-specific vasodilators. Postasphyxia cerebral vascular dysfunction was aggravated in newborn pigs pretreated with tin protoporphyrin to inhibit brain HO/CO. The CO donor CO-releasing molecule-A1 (CORM-A1) reduced brain oxidative stress during asphyxia/reventilation and prevented postasphyxia cerebrovascular dysfunction. The antioxidant and antiapoptotic effects of HO/CO and CORM-A1 were confirmed in primary cultures of astrocytes from the neonatal pig brain exposed to glutamate excitotoxicity. Overall, prolonged neonatal asphyxia leads to neurovascular injury via an oxidative stress-mediated mechanism that is counteracted by an astrocyte-based constitutive antioxidant HO/CO system. We propose that gaseous CO or CO donors can be used as novel approaches for prevention of neonatal brain injury caused by prolonged asphyxia. NEW & NOTEWORTHY Asphyxia in newborn infants may lead to lifelong neurological disabilities. Using the model of prolonged asphyxia in newborn piglets, we propose novel antioxidant therapy based on systemic administration of low doses of a carbon monoxide donor that prevent loss of cerebral blood flow regulation and may improve the neurological outcome of asphyxia. PMID- 30028197 TI - Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs. AB - Sudden cardiac death from ventricular arrhythmias is more common in adult patients with with heart failure compared with pediatric patients with heart failure. We identified age-specific differences in arrhythmogenesis using a guinea pig model of acute beta-adrenergic stimulation. Young and adult guinea pigs were exposed to the beta-adrenergic agonist isoproterenol (ISO; 0.7 mg/kg) for 30 min in the absence or presence of flecainide (20 mg/kg), an antiarrhythmic that blocks Na+ and ryanodine channels. Implanted cardiac monitors (Reveal LINQ, Medtronic) were used to monitor heart rhythm. Alterations in phosphorylation and oxidation of ryanodine receptor 2 (RyR2) were measured in left ventricular tissue. There were age-specific differences in arrhythmogenesis and sudden death associated with acute beta-adrenergic stimulation in guinea pigs. Young and adult guinea pigs developed arrhythmias in response to ISO; however, adult animals developed significantly more premature ventricular contractions and experienced higher arrhythmia-related mortality than young guinea pigs treated with ISO. Although there were no significant differences in the phosphorylation of left ventricular RyR2 between young and adult guinea pigs, adult guinea pigs exposed to acute ISO had significantly more oxidation of RyR2. Flecainide treatment significantly improved survival and decreased the number of premature ventricular contractions in young and adult animals in association with lower RyR2 oxidation. Adult guinea pigs had a greater propensity to develop arrhythmias and suffer sudden death than young guinea pigs when acutely exposed to ISO. This was associated with higher oxidation of RyR2. The incidence of sudden death can be rescued with flecainide treatment, which decreases RyR2 oxidation. NEW & NOTEWORTHY Clinically, adult patients with heart failure are more likely to develop arrhythmias and sudden death than pediatric patients with heart failure. In the present study, older guinea pigs also showed a greater propensity to arrhythmias and sudden death than young guinea pigs when acutely exposed to isoproterenol. Although there are well-described age-related cardiac structural changes that predispose patients to arrhythmogenesis, the present data suggest contributions from dynamic changes in cellular signaling also play an important role in arrhythmogenesis. PMID- 30028201 TI - Surgical reinforcement alters collagen alignment and turnover in healing myocardial infarcts. AB - Previous studies have suggested that the composition and global mechanical properties of the scar tissue that forms after a myocardial infarction (MI) are key determinants of long-term survival, and emerging therapies such as biomaterial injection are designed in part to alter those mechanical properties. However, recent evidence suggests that local mechanics regulate scar formation post-MI, so that perturbing infarct mechanics could have unexpected consequences. We therefore tested the effect of changes in local mechanical environment on scar collagen turnover, accumulation, and alignment in 77 Sprague-Dawley rats at 1, 2, 3 and 6 wk post-MI by sewing a Dacron patch to the epicardium to eliminate circumferential strain while permitting continued longitudinal stretching with each heart beat. We found that collagen in healing infarcts aligned parallel to regional strain and perpendicular to the preinfarction muscle and collagen fiber direction, strongly supporting our hypothesis that mechanical environment is the primary determinant of scar collagen alignment. Mechanical reinforcement reduced levels of carboxy-terminal propeptide of type I procollagen (PICP; a biomarker for collagen synthesis) in samples collected by microdialysis significantly, particularly in the first 2 wk. Reinforcement also reduced carboxy-terminal telopeptide of type I collagen (ICTP; a biomarker for collagen degradation), particularly at later time points. These alterations in collagen turnover produced no change in collagen area fraction as measured by histology but significantly reduced wall thickness in the reinforced scars compared with untreated controls. Our findings confirm the importance of regional mechanics in regulating scar formation after infarction and highlight the potential for therapies that reduce stretch to also reduce wall thickness in healing infarcts. NEW & NOTEWORTHY This study shows that therapies such as surgical reinforcement, which reduce stretch in healing infarcts, can also reduce collagen synthesis and wall thickness and modify collagen alignment in postinfarction scars. PMID- 30028202 TI - Normal patterns of thoracic aortic wall shear stress measured using four dimensional flow MRI in a large population. AB - Wall shear stress (WSS) plays a governing role in vascular remodeling and a pathogenic role in vessel wall diseases. However, little is known of the normal WSS patterns in the aorta as there is currently no practical means to routinely measure WSS and no normal ranges derived from population data exist. WSS measurements were made on the aorta of 224 subjects with normal anatomy using four-dimensional flow MRI with multiple encoding velocities and an optimized postprocessing routine. The spatial and temporal variation in WSS and oscillatory shear index was analyzed using a flat map representation of the unfolded aorta. The influence of aortic shape and velocity on WSS was evaluated using regression analysis. WSS in the thoracic aorta is dominated by axial flow. Average peak systolic WSS was 1.79 +/- 0.71 Pa in the aortic arch and was significantly higher at 2.23 +/- 1.04 Pa in the descending aorta, with a strong negative correlation with advancing age. The spatial distribution of WSS is highly heterogeneous, with a localized region of elevated WSS along the length of the anterior wall seen across all individuals. Our data demonstrate that accurate four-dimensional flow derived WSS measurement is feasible, and we further provide a standardized parametric approach for presentation and analysis. We present a normal range for WSS across the lifespan, demonstrating a decrease in WSS with advancing age as well as illustrating the high degree of spatial and temporal variation. NEW & NOTEWORTHY With the use of four-dimensional flow MRI and postprocessing, accurate direct measurement of wall shear stress (WSS) was performed in a population of normal thoracic aortas ( n = 224). WSS was higher in the descending aorta compared with the aortic arch and decreased with age. A heterogeneous pattern of elevated WSS along the length of the aorta anterior wall was consistent across the population. This work provides normal data across the adult age range, permitting comparison with pathology. PMID- 30028203 TI - Caveolin-3 KO disrupts t-tubule structure and decreases t-tubular ICa density in mouse ventricular myocytes. AB - Caveolin-3 (Cav-3) is a protein that has been implicated in t-tubule formation and function in cardiac ventricular myocytes. In cardiac hypertrophy and failure, Cav-3 expression decreases, t-tubule structure is disrupted, and excitation contraction coupling is impaired. However, the extent to which the decrease in Cav-3 expression underlies these changes is unclear. We therefore investigated the structure and function of myocytes isolated from the hearts of Cav-3 knockout (KO) mice. These mice showed cardiac dilatation and decreased ejection fraction in vivo compared with wild-type control mice. Isolated KO myocytes showed cellular hypertrophy, altered t-tubule structure, and decreased L-type Ca2+ channel current ( ICa) density. This decrease in density occurred predominantly in the t-tubules, with no change in total ICa, and was therefore a consequence of the increase in membrane area. Cav-3 KO had no effect on L-type Ca2+ channel expression, and C3SD peptide, which mimics the scaffolding domain of Cav-3, had no effect on ICa in KO myocytes. However, inhibition of PKA using H-89 decreased ICa at the surface and t-tubule membranes in both KO and wild-type myocytes. Cav 3 KO had no significant effect on Na+/Ca2+ exchanger current or Ca2+ release. These data suggest that Cav-3 KO causes cellular hypertrophy, thereby decreasing t-tubular ICa density. NEW & NOTEWORTHY Caveolin-3 (Cav-3) is a protein that inhibits hypertrophic pathways, has been implicated in the formation and function of cardiac t-tubules, and shows decreased expression in heart failure. This study demonstrates that Cav-3 knockout mice show cardiac dysfunction in vivo, while isolated ventricular myocytes show cellular hypertrophy, changes in t-tubule structure, and decreased t-tubular L-type Ca2+ current density, suggesting that decreased Cav-3 expression contributes to these changes in cardiac hypertrophy and failure. PMID- 30028205 TI - Use of Simplified Molecular Input Line Entry System and molecular graph based descriptors in prediction and design of pancreatic lipase inhibitors. AB - AIM: The inhibition of pancreatic lipase (PL) enzyme is the most explored strategy for the treatment of obesity. The present study describes the development of quantitative structure-activity relationship (QSAR) models for a diverse set of 293 PL inhibitors by means of the Monte Carlo optimization technique. Methodology & results: The hybrid optimal descriptors were used to build QSAR models with three subsets of three splits. The developed QSAR models were further validated with corresponding external sets. The best QSAR model has the following statistical particulars: R2 = 0.752, Q LOO 2 = 0 . 736 for the test set and R2 = 0.768, Q F 1 2 = 0 . 628 , Q F 2 2 = 0 . 621 for the validation set. CONCLUSION: The developed QSAR models were robust, stable and predictive and led to the design of novel PL inhibitors. PMID- 30028200 TI - Statistical considerations in reporting cardiovascular research. AB - The problem of inadequate statistical reporting is long standing and widespread in the biomedical literature, including in cardiovascular physiology. Although guidelines for reporting statistics have been available in clinical medicine for some time, there are currently no guidelines specific to cardiovascular physiology. To assess the need for guidelines, we determined the type and frequency of statistical tests and procedures currently used in the American Journal of Physiology-Heart and Circulatory Physiology. A PubMed search for articles published in the American Journal of Physiology-Heart and Circulatory Physiology between January 1, 2017, and October 6, 2017, provided a final sample of 146 articles evaluated for methods used and 38 articles for indepth analysis. The t-test and ANOVA accounted for 71% (212 of 300 articles) of the statistical tests performed. Of six categories of post hoc tests, Bonferroni and Tukey tests were used in 63% (62 of 98 articles). There was an overall lack in details provided by authors publishing in the American Journal of Physiology-Heart and Circulatory Physiology, and we compiled a list of recommended minimum reporting guidelines to aid authors in preparing manuscripts. Following these guidelines could substantially improve the quality of statistical reports and enhance data rigor and reproducibility. PMID- 30028206 TI - Foreword: computational special focus issue. PMID- 30028208 TI - Psychometric Properties of ADHD Symptoms in Toddlers. AB - The purpose of this study is to examine the psychometric properties of the 18 Diagnostic and Statistical Manual of Mental Disorders (DSM) symptoms of attention deficit/hyperactivity disorder (ADHD) in 2-year-old children. ADHD is typically diagnosed in elementary school, but research suggests that many children with ADHD first show symptoms during the toddler years. An important first step in identifying toddlers who are at high risk for developing ADHD is to better understand the properties of DSM symptoms of ADHD in young children. Parents of 2 year-old children (N = 434; 240 boys, 194 girls; M = 29.07 months, SD = 3.42) across the United States were recruited online through Amazon's Mechanical Turk to complete surveys about their children's ADHD symptoms and temperament. Confirmatory factor analysis showed that 2- and 3-factor models fit well. All but one verbal hyperactive/impulsive symptom loaded highly on their respective factors. Relations between ADHD symptoms and temperament traits provided some support for convergent and divergent validity of the symptoms. Finally, item response theory analyses showed that items showed moderate to high levels of discrimination between toddlers with high and low levels of ADHD symptoms. Psychometric properties in 2-year-old children were generally comparable to those in older children, with similar factor structure, good reliability and validity, and good though somewhat lower discrimination, particularly for verbal symptoms. The study provides support for conducting prospective studies to determine whether these symptoms have utility for identifying at-risk toddlers. PMID- 30028204 TI - Oxidation of ryanodine receptor after ischemia-reperfusion increases propensity of Ca2+ waves during beta-adrenergic receptor stimulation. AB - beta-Adrenergic receptor (beta-AR) activation produces the main positive inotropic response of the heart. During ischemia-reperfusion (I/R), however, beta AR activation can trigger life-threatening arrhythmias. Because I/R is frequently associated with oxidative stress, we investigated whether ryanodine receptor (RyR) oxidation contributes to proarrythmogenic Ca2+ waves during beta-AR activation. Measurements of contractile and electrical activity from Langendorff perfused rabbit hearts revealed that I/R produces tachyarrhythmias. Ventricular myocytes isolated from I/R hearts had an increased level of oxidized glutathione (i.e., oxidative stress) and a decreased level of free thiols in RyRs (i.e., RyR oxidation). Furthermore, myocytes from I/R hearts were characterized by increased sarcoplasmic reticulum (SR) Ca2+ leak and enhanced fractional SR Ca2+ release. In myocytes from nonischemic hearts, beta-AR activation with isoproterenol (10 nM) produced only a positive inotropic effect, whereas in myocytes from ischemic hearts, isoproterenol at the same concentration triggered spontaneous Ca2+ waves. beta-AR activation produced a similar effect on RyR phosphorylation in control and I/R myocytes. Treatment of myocytes from I/R hearts with the reducing agent mercaptopropionylglycine (100 MUM) attenuated RyR oxidization and decreased Ca2+ wave frequency during beta-AR activation. On the other hand, treatment of myocytes from nonischemic hearts with H2O2 (50 MUM) increased SR Ca2+ leak and triggered Ca2+ waves during beta-AR activation. Collectively, these results suggest that RyR oxidation after I/R plays a critical role in the transition from positive inotropic to arrhythmogenic effects during beta-AR stimulation. Prevention of RyR oxidation can be a promising strategy to inhibit arrhythmias and preserve positive inotropic effect of beta-AR activation during myocardial infarction. NEW & NOTEWORTHY Oxidative stress induced by ischemia plays a critical role in triggering arrhythmias during adrenergic stimulation. The combined increase in sarcoplasmic reticulum Ca2+ leak (because of ryanodine receptor oxidation) and sarcoplasmic reticulum Ca2+ load (because of adrenergic stimulation) can trigger proarrythmogenic Ca2+ waves. Restoring normal ryanodine receptor redox status can be a promising strategy to prevent arrhythmias and preserve positive inotropic effect of adrenergic stimulation during myocardial infarction. PMID- 30028210 TI - Who's Distressed by Sexual Difficulties? Exploring Associations Between Personal, Perceived Partner, and Relational Distress and Sexual Difficulties in Heterosexual Men and Women. AB - While not all sexual difficulties cause distress, research and clinical experience suggest that, apart from personal distress, partner and relational sexual distress are also often an important reason to seek professional help. The current study explored the associations between personal, perceived partner, and relational distress that men and women experience as a result of sexual difficulties. Data from heterosexual Flemish individuals ages 16 to 74 who were in a relationship (13,800 men and 13,242 women, mean age of 43.69, SD = 14.94) were collected via an online survey. Presence and severity of sexual difficulties and associated personal, perceived partner, and relational sexual distress were assessed. Among men and women with desire difficulties, either the three types of sexual distress were almost equally common or partner distress was most common. Arousal, orgasm, and sexual pain difficulties were most often associated with personal distress, particularly in men. Both men and women, however, most commonly reported that they experienced all three types of distress. These results are discussed in relation to Western gender-specific sexual scripts. Clinical implications and the importance of couples therapy and suggestions for clinically useful diagnostic criteria are presented. PMID- 30028209 TI - Targeting caregivers with context specific behavior change training increased uptake of recommended hygiene practices during food preparation and complementary feeding in Dedza district of Central Malawi. AB - The effect of a targeted training intervention on uptake of recommended hygiene practices by caregivers of children 6-23 months was assessed. A sub-sample of 40 mothers from 303 households was used for a detailed study of hygiene practices during preparation of complementary foods after training. Mothers and caregivers were observed for 6 months and evaluated using a questionnaire. Data were analyzed using SPSS and Chi-square test was used to determine the differences in proportions of mothers and caregivers who adopted recommended practices. Results showed significant increase in the proportions of mothers and caregivers who followed recommended hygiene practices after training. There was significant decrease in prevalence of diarrhea among the children (45% to 8.6%). It can be concluded that targeted training on practical hands-on activities such as hand washing, cleaning of cooking and serving utensils, covering of food and water increase adoption of recommended hygiene and sanitation practices. PMID- 30028211 TI - Exploring the Impact of Personal and Partner Traits on Sexuality: Sexual Excitation, Sexual Inhibition, and Big Five Predict Sexual Function in Couples. AB - Sexual difficulties are common among women and men and are associated with various mental and physical health problems. Although psychological traits are known to impact sexual attitudes and behavior, sexuality- and personality-related traits have not been jointly investigated to assess their relevance for sexual functioning in couples. The aim of this study was to investigate how psychological traits of two partners influence women's and men's sexual function. Data from 964 couples, representative of the adult population in Germany, were analyzed. Sexual function was assessed with the Female Sexual Function Index (FSFI) and the International Index of Erectile Function (IIEF). Sexuality-related traits were measured with the Sexual Excitation/Sexual Inhibition Inventory for Women and Men (SESII-W/M). Personality was measured with self-report and partner rating versions of the Big Five Inventory (BFI). Sexual excitation was a positive and sexual inhibition was a negative predictor of sexual function in both genders. Women whose partners were sexually inhibited reported lower sexual function. Conscientious individuals reported better sexual function. Women whose partners were more conscientious also had better sexual function. Assessing partner-related factors may be helpful to identify predisposing and maintaining factors of sexual dysfunctions, especially in women. PMID- 30028212 TI - Associations of Alcohol and Marijuana Use With Condom Use Among Young Adults: The Moderating Role of Partner Type. AB - This study used multiple levels of analysis to examine associations of alcohol and marijuana (AM) use with condom use, including the moderating role of partner type, in a general sample of 754 sexually active young adults (mean age = 18.6, SD = 0.63; 77% non-White). Multivariable models examined associations over the past 30 days (global) and at the most recent sexual event (event specific). Over the past 30 days, participants who had a recent casual partner and used both substances reported a higher proportion of condom-protected sexual events during this period compared to AM nonusers, whereas those who had a recent steady partner and used alcohol, marijuana, or both substances reported a lower proportion of condom-protected sexual events compared to AM nonusers. At the most recent sexual event, participants who used both substances were four times more likely than AM nonusers to have condom-protected sex if the event involved a casual partner; however, there were no significant associations if the event involved a steady partner. Marijuana use, particularly combined with alcohol use, deserves greater attention in the context of condom use. Future research should consider different levels of analysis and partner types to fully understand these complex associations. PMID- 30028213 TI - Studying the Motivations Behind Sexual Agreements: A First Look at the Motivations Behind Agreement (MBA) Scale for Male Couples. AB - Sexual agreements are ubiquitous among male couples, yet little is known about motivations behind agreements and their association with sexual risk for human immunodeficiency virus (HIV). Qualitative interviews with 39 couples informed the development of the items in the Motivations Behind Agreement (MBA) scale. The scale was validated via exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) using quantitative data from two (790 and 882 men) independent samples of couples. The EFA yielded two factors: relationship quality enhancement motive (RQEM) and sex life enhancement motive (SLEM). The CFA indicated satisfactory global model data fit. Finally, in predicting sexual risk, RQEM and SLEM showed significant interactions with agreement type. For men with monogamous agreements, higher RQEM was associated with less condomless anal sex (CAS) with an outside partner of discordant or unknown serostatus (aOR = 0.15; 95% CI = 0.05, 0.46). For men with nonmonogamous agreements, higher RQEM was associated with less CAS (aOR = 0.76; 95% CI = 0.60, 0.97) while higher SLEM was associated with greater odds of CAS (aOR = 1.57; 95% CI = 1.18, 2.08). Men whose agreements were highly motivated by relationship enhancement were less likely to engage in sexual risk with outside partners regardless of agreement type. HIV-prevention interventions targeting male couples will benefit from incorporating an understanding of couples' agreement motivations. PMID- 30028214 TI - Short-Term Administration of Astaxanthin Attenuates Retinal Changes in Diet Induced Diabetic Psammomys obesus. AB - OBJECTIVES: Psammomys obesus is a high-fat diet (HFD)-fed animal model of obesity and type 2 diabetes recently explored as a model of non-proliferative diabetic retinopathy. This study tested the protective effect of the pigment astaxanthin (AST) in the P. obesus diabetic retina. METHODS: Young adult P. obesus were randomly assigned to two groups. The control group received a normal diet consisting of a plant-based regimen, and the HFD group received an enriched laboratory chow. After 3 months, control and diabetic rodents were administered vehicle or AST, daily for 7 days. Body weight, blood glucose, and plasma pentosidine were assessed. Frozen sections of retinas were immunolabeled for markers of oxidative stress, glial reactivity and retinal ganglion cell bodies, and imaged by confocal microscopy. RESULTS: Retinal tissue from AST-treated control and HFD-diabetic P. obesus showed a greater expression of the antioxidant enzyme heme oxygenase-1 (HO-1). In retinas of HFD-diabetic AST-treated P. obesus, cellular retinaldehyde binding protein and glutamine synthetase in Muller cells were more intense compared to the untreated HFD-diabetic group. HFD-induced diabetes downregulated the expression of glial fibrillary acidic protein in astrocytes, the POU domain protein 3A in retinal ganglion cells, and synaptophysin throughout the plexiform layers. DISCUSSION: Our results show that type 2-like diabetes induced by HFD affected glial and neuronal retinal cell homeostasis. AST treatment induced the antioxidant enzyme HO-1 and reduced glial reactivity. These findings suggest that diabetic P. obesus is a useful model of HFD-induced obesity and diabetes to evaluate early neuroglial retinal alterations and antioxidant neuroprotection mechanisms in DR. PMID- 30028215 TI - Improvement of bone microarchitecture in methylprednisolone induced rat model of osteoporosis by using thiolated chitosan-based risedronate mucoadhesive film. AB - OBJECTIVE: In this study, we investigated the potential of thiolated chitosan based mucoadhesive film, loaded with risedronate sodium in the treatment of osteoporosis. SIGNIFICANCE: Risedronate sodium is a bisphosphonate derivative having very low bioavailability when administered through the oral route. Moreover, the adverse effects associated with the drug when administered through GIT necessitate an alternative and feasible route which can improve its bioavailability and therapeutic efficacy. METHODS: Thiolation of chitosan was interpreted by different analytical techniques. The mucoadhesive films were prepared by the solvent evaporation method and evaluated for drug content analysis, swelling degree, mucoadhesive parameters, and permeation characterization. For the screening of preclinical efficacy and pharmacodynamic parameters, a methylprednisolone induced osteoporotic rat model was used. The trabecular microarchitecture and biochemical markers were evaluated for determination of bone resorption. RESULTS: The different analytical characterization of synthesized thiolated chitosan revealed that chitosan was successfully incorporated with thiol groups. The formulation containing 2:1 ratio of thiolated chitosan and HPMC-4KM was found to have the maximum swelling degree, mucoadhesive strength with a good force of adhesion and better in vitro permeability compared to the marketed formulation. With respect to trabecular microarchitecture, the drug-loaded film formulation showed superior and promising results. Furthermore, the film formulation also improved the serum level of biomarkers better than the marketed formulation. CONCLUSIONS: The results significantly suggest that risedronate loaded novel mucoadhesive film formulation could be a logical approach in the therapeutic intervention of osteoporosis. PMID- 30028216 TI - The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease. AB - INTRODUCTION: Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR anion channel. In the absence of functional CFTR, the epithelial Na+ channel is also dysregulated. Airway surface liquid (ASL) hydration is maintained by a balance between epithelial sodium channel (ENaC)-led Na+ absorption and CFTR-dependent anion secretion. This finely tuned homeostatic mechanism is required to maintain sufficient airway hydration to permit the efficient mucus clearance necessary for a sterile lung environment. In CF airways, the lack of CFTR and increased ENaC activity lead to ASL/mucus dehydration that causes mucus obstruction, neutrophilic infiltration, and chronic bacterial infection. Rehydration of ASL/mucus in CF airways can be achieved by inhibiting Na+ absorption with pharmacological inhibitors of ENaC. Areas covered: In this review, we discuss ENaC structure and function and its role in CF lung disease and focus on ENaC inhibition as a potential therapeutic target to rehydrate CF mucus. We also discuss the failure of the first generation of pharmacological inhibitors of ENaC and recent alternate strategies to attenuate ENaC activity in the CF lung. Expert opinion: ENaC is an attractive therapeutic target to rehydrate CF ASL that may serve as a monotherapy or function in parallel with other treatments. Given the increased number of strategies being employed to inhibit ENaC, this is an exciting and optimistic time to be in this field. PMID- 30028217 TI - Physiological responses during clinical spasticity evaluation in elbow flexors in children with cerebral palsy. AB - BACKGROUND: The Tardieu test is often used to identify and evaluate the severity of spasticity for clinical decision-making and treatment evaluation in cerebral palsy (CP). OBJECTIVE: The study's objective was to gain further insight into the construct validity of clinical spasticity evaluation in children with CP. METHODS: The kinematics and neuromuscular response of the biceps brachii (BB) during passive elbow extension were studied when performing the Tardieu test with its corresponding clinical interpretation. Fifteen children with unilateral spastic CP and 15 typically developing (TD) peers 15 (median/interquartile range age; 13/4 and 12/5 years, respectively) participated. RESULTS: A clinical catch was detected in 9 of the 15 children with CP. During fast passive elbow extension, the CP group had higher BB activation (p = 0.041), lower fast maximal angular velocity (p = 0.001), and decelerated earlier in the extension movement (p = 0.001). DISCUSSION: On average, the CP group without a clinical detected catch were closer to TD for all those variables, but this only reached statistical 20 significance in the latter variable (p = 0.018). This inconsistency also shows in possibly one false positive and three false negative catch observations. CONCLUSION: The Tardieu test should be carried out with caution on individual level and more studies including kinematic and neuromuscular measures are necessary. PMID- 30028218 TI - Intra-Ethnic Racial Differences in Waterpipe Tobacco Smoking among Latinos? AB - BACKGROUND AND OBJECTIVES: This study examined differences in waterpipe smoking (both lifetime and current) by race and ethnicity. More specifically, we evaluated intra-ethnic racial differences among Latinos using a nationally representative sample. METHODS: Pooled data from the National Adult Tobacco Survey (NATS) [2012-2014] was used, in which Log-Poisson multivariable regression models were deployed to determine the prevalence of waterpipe smoking behavior. Models were stratified by gender and we further investigated acculturation, controlling for relevant sociodemographic characteristics. RESULTS: In fully adjusted models assessing lifetime WTS, Black Latinos and White Latinos exhibited an increase prevalence of lifetime WTS compared to their non-Hispanic white counterparts. Once stratifying by gender, Black Latino men (PR = 1.49; 95% CI = 1.16, 1.90) exhibited increased prevalence of lifetime WTS compared to their non Hispanic white men counterparts; although white Latino men (PR = 0.88; 95% CI = 0.80, 0.98) exhibited decreased prevalence compared to their non-Hispanic white male counterparts. Similar trends were found for current WTS among men. In fully adjusted models assessing lifetime WTS, among women, only white Latina's (PR = 1.23; 95% CI = 1.04, 1.46) exhibited increased prevalence compared to their non Hispanic white women counterparts. When evaluating current WTS, Black Latina's (PR = 2.19; 95% CI = 1.32, 3.65) and white Latinas (PR = 1.28; 95% CI = 1.00, 1.63) exhibited increased prevalence of WTS compared to their non-Hispanic white women counterparts. Conclusions/Importance: Among the U.S. general adult population, intra-ethnic racial differences in WTS behaviors exist among Latinos; and is shaped by gender. Future efforts to eliminate racial disparities in WTS should be attentive intra-ethnic racial differences among Latinos. PMID- 30028219 TI - Mental disorders in commentaries by the late medieval theologians Richard of Middleton, John Duns Scotus, William Ockham and Gabriel Biel on Peter Lombard's Sentences. AB - In their commentaries on the Sentences, Richard of Middleton, John Duns Scotus, William Ockham and Gabriel Biel reflect whether mentally-disturbed people can receive the sacraments (Baptism, Eucharist, confession, marriage) and fulfil juridical actions (make a will or take an oath). They consider that the main problem in 'madmen' in relation to the sacraments and legal actions is their lack of the use of reason. Scotus and Ockham especially are interested in the causes of mental disorders and the phenomena which happen in madmen's minds and bodies. In considering mental disorders mostly as naturally caused psycho-physical phenomena, Scotus and Ockham join the rationalistic mental disorder tradition, which was to become dominant in the early modern era and later. PMID- 30028220 TI - The current understanding of the interactions between nanoparticles and cytochrome P450 enzymes - a literature-based review. AB - Nanoparticles (NPs) have wide spectrum applications in the areas of industry and biomedicine. However, concerns about their toxic and negative impacts on the environments as well as human health have been raised. Cytochrome P450s (CYPs) are involved in endogenous and exogenous metabolism. Modulations of CYP can adversely damage drug metabolism, detoxification of xenobiotics and animal physiology functions. This article focused on NPs-CYP interactions for humans and animals available in the literature. It was found that different NPs process specific inhibitory potencies against CYPs involved in drug metabolism. Moreover, NPs were able to modify the expression of CYPs genes or protein in humans and other animals, which highlighted their detoxification functions. Nonetheless, changes of CYPs responsible for hormone synthesis and metabolism resulted in endocrine disturbances. Hence, there is a need to screen newly developed NPs to evaluate their interactions with CYPs. The future studies should further strategize the in vitro approaches to reveal the molecular mechanisms behind interactions by taking full considerations of the interference of co-factors, buffers, substrates and metabolites with NPs. Moreover, in vivo studies should compare the influences of NPs via different administration routes and different duration of treatments to reveal the physiological significance. PMID- 30028221 TI - An overview of angiodysplasia: management and patient prospects. AB - INTRODUCTION: Gastrointestinal angiodysplasias (GIADs) have a wide variety of presentations, which can be significant and debilitating in a subset of patients. Endoscopic ablation is currently the most effective treatment for GIADs, however re-bleeding rates are high. Several medical have been used for GIADs and reported in the literature, however these medications have significant side effect profiles and randomized controlled trials are lacking. A relatively poor understanding of the pathophysiology of GIAD formation has limited the development of more effective treatments and improved diagnostic and prognostic markers for GIAD. However, recent advances in research in the area of angiogenesis have identified a potential role for certain angiogenic factors including Angiopoeitin 1 and 2, in the pathophysiology of GIAD. Areas covered: We performed an extensive pubmed search of all articles mentioning GIAD and summarized our findings focussing on patient management and prospects. We summarize the available literature regarding the medical, endoscopic, and radiological management of GIAD and the value of clinical prognostic factors. Expert commentary: Although the area of angiogenesis is a novel area of research in GIAD, it represents an exciting avenue for development with the potential to improve diagnostic and prognostic tools to improve patient outcome. PMID- 30028223 TI - Facilitation of movement: New perspectives provide expanded insights to guide clinical practice. AB - Hands-on therapeutic interactions are essential to neurological physiotherapy. Facilitation of movement is a particular aspect of such interactions that potentiates self-initiation of movement. This process involves interactions between the physiotherapist and the patient through three integrated phases: (1) "make movement possible;" (2) "make movement necessary;" and (3) "let movement happen," in which communicative aspects are considered important. The purpose of this paper is to explore a theoretical foundation for this approach by utilizing an extended framework. Dynamic systems theory clarifies the physiotherapist's handling as the adjusted manipulation of the patient's constraints upon movement complemented by tailoring of the specific attributes of the task and environment; however, this theory provides inadequate coverage of the involved communicative aspects. Phenomenology, which perceives the body as the center of experience and expression, offers a path to understanding such hands-on interactions as a form of communication. Enactive theory clarifies these physical interactions of the physiotherapist and the patient as essential in co-construction of meaning that evolves as an interactive and dynamic process within a specific context. This extended framework, in which neuro- and movement sciences are integrated, provides an appropriate theoretical anchoring of facilitation of movement that is beneficial for guiding clinical practice and training. PMID- 30028222 TI - Effect of metformin/irinotecan-loaded poly-lactic-co-glycolic acid nanoparticles on glioblastoma: in vitro and in vivo studies. AB - AIM: The present study was designed to evaluate the effects of irinotecan hydrochloride (IRI)- or metformin hydrochloride (MET)-loaded poly-lactic-co glycolic acid (PLGA) nanoparticles (NPs) for the treatment of glioblastoma multiforme using in vitro neuron and U-87 MG glioblastoma cell cultures and in vivo animal model. METHODS: The cytotoxic and neurotoxic effects of pure drugs, blank NPs and MET- and IRI-loaded PLGA NPs were investigated in vitro (using methylthiazolyldiphenyl-tetrazolium bromide assay) and in vivo (using Cavalieri's principle for estimation of cancer volume). RESULTS: 1 and 2 mM doses of MET and MET-loaded PLGA NPs, respectively, significantly reduced the volume of extracted cancer. CONCLUSION: Consequently, MET- and IRI-loaded PLGA NPs may be a promising approach for the treatment of glioblastoma multiforme. PMID- 30028224 TI - Theranostic micelles combined with multiple strategies to effectively overcome multidrug resistance. AB - AIM: To develop precise targeting and versatile Fe3O4@SiO2-P123/PTX-ZnPc nanoparticles (FSP-PTX-ZnPc NPs) to reverse paclitaxel (PTX)-induced multidrug resistance in breast cancer. MATERIALS & METHODS: PTX and zinc (II) phthalocyanine (ZnPc) co-loaded FSP-PTX-ZnPc NPs were designed. The resulting multifunctional NPs were evaluated systematically in vitro and in vivo, and the mechanism of drug-resistance reversal was investigated. RESULTS: The NPs enhanced drug uptake in MCF-7/PDR cells by increasing drug solubility and impairing P glycoprotein efflux. Additionally, magnetic targeting and enhanced permeation and retention (EPR) effect enhanced drug accumulation in tumor, facilitating the chemotherapeutic and photodynamic therapy effects. Moreover, FSP-PTX-ZnPc NPs could penetrate the blood-brain barrier, a desirable trait for brain disease therapy. CONCLUSION: The multifunctional FSP-PTX-ZnPc NPs are an effective tool for overcoming drug resistance in breast cancer. PMID- 30028225 TI - Health Care Utilization and Expenditures Following Diagnosis of Nontuberculous Mycobacterial Lung Disease in the United States. AB - BACKGROUND: Nontuberculous mycobacterial lung disease (NTMLD) is an important public health concern that has been increasing in prevalence. OBJECTIVES: To (a) describe hospitalizations and health care expenditures among patients with newly diagnosed NTMLD and (b) estimate attributable hospitalizations and expenditures to NTMLD in the United States. METHODS: In this matched cohort study, patients and controls were identified from a large U.S. national managed care insurance database containing aggregated health claims of up to 18 million fully covered members annually. NTMLD was defined based on diagnostic claims for NTMLD on >= 2 separate occasions >= 30 days apart between 2007 and 2016. Thirty-six months of continuous enrollment (12 months before and 24 months after the first diagnostic claim) was required. Health care utilization and standardized health care expenditures were summarized over 12 months before NTMLD diagnosis and for 2 subsequent years. The percentage of patients that were hospitalized in years 1 and 2 was evaluated using a generalized mixed effects model with adjustment for baseline hospitalizations, Charlson Comorbidity Index, and baseline diseases. A general estimating equation model was used to evaluate health care expenditures. RESULTS: There were 1,039 patients in the NTMLD cohort and 2,078 in the control cohort. NTMLD patients had a 55.0% risk of hospitalization in year 1 (95% CI = 45.4-64.3) and a 38.8% risk in year 2 (95% CI = 30.0-48.4). The adjusted risk of hospitalization was significantly higher in the NTMLD group compared with the control group in year 1 (OR = 4.64; 95% CI = 3.74-5.76; P < 0.001) and year 2 (OR = 2.26; 95% CI = 1.78-2.87; P < 0.001). Year 1 adjusted mean health care expenditures for the total NTMLD patient population were $72,475 (95% CI = $58,510-$86,440) and for the matched control population were $28,405 (95% CI = $8,859-$47,950), with a difference of $44,070 (95% CI = $27,132-$61,008; P < 0.001). Year 2 adjusted mean expenditures for the overall NTMLD patient group were $48,114 (95% CI = $31,722-$64,507) and for the matched control group were $28,990 (95% CI = $9,429-$48,552), with a difference of $19,124 (95% CI = $7,865 $30,383; P < 0.001). CONCLUSIONS: Patients with NTMLD have a significantly greater risk of hospitalization and higher total health care expenditures than matched control patients without NTMLD. DISCLOSURES: This study was financially sponsored by Insmed. Marras reports fees from Insmed, Astra Zeneca, RedHill, and Horizon, all outside the current work. Mirsaeidi has nothing to disclose. Eagle, Q. Zhang, Chou, and Leuchars are employees of Insmed. R. Zhang is a contracted consultant at Insmed. The views expressed here are those of the authors and are not to be attributed to their respective affiliations. PMID- 30028226 TI - Trait-Based Profiles of ADHD in Adolescents and Young Adults. AB - Empirical work has examined the utility of using person-centered statistical approaches emphasizing traits to parsing attention deficit/hyperactivity disorder (ADHD) heterogeneity in preschool and school-age children. However, trait-based profiles have not yet been examined in other age ranges, specifically adolescence and young adulthood. Therefore, the goal of the present study is to examine trait based profiles in adolescents and young adults with ADHD to evaluate their similarity with trait-based profiles in preschoolers and children with ADHD and through comparison with external correlates (e.g., comorbidity). One hundred eighty-two adolescents and 287 young adults completed measures of ADHD symptoms, personality and temperament traits, and comorbid internalizing and externalizing problems. Latent profile analysis suggested at least 3 consistent trait-based profiles related to ADHD within adolescents and young adults: low extraversion, high extraversion, and high neuroticism. These profiles were largely similar to those found in preschool and middle childhood and demonstrated similar comorbidity patterns, namely, the low-extraversion profile exhibited higher internalizing problems, the high-extraversion profile exhibited higher externalizing problems, and the small high-neuroticism profile exhibited descriptively higher levels of all comorbid problems. Such profiles may have utility for personalization of intervention based on trait profiles and comorbidity patterns, as well as-more speculatively-possible prognostic utility. PMID- 30028227 TI - Initial report of the genitourinary and gastrointestinal toxicity of post prostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy. AB - PURPOSE: To report acute and late genitourinary (GU) and gastrointestinal (GI) toxicities associated with post-prostatectomy proton therapy (PT). METHODS: The first 100 consecutive patients from 2010 to 2016 were retrospectively assessed. Baseline characteristics, prospectively graded CTCAE v4.0 toxicities, and patient reported outcomes were reported. Late outcomes were reported for 79 patients with 3 months minimum follow up. Toxicity-free survival Kaplan-Meier curves were estimated. Logistic regression assessed associations between toxicities and clinical and treatment characteristics (p < .05 significance). RESULTS: Median age, months after surgery, and months of follow-up were respectively 64 years (range 42-77), 25 (5-216), and 25 (0-47). PT received was 70.2 Gy (RBE) (89%), salvage (93%), prostate bed only (80%), pencil beam scanning (86%), with IMRT (31%), and with androgen deprivation (34%). Acute and late maximum toxicities, respectively were: GU grade 0 (14%; 18%), 1 (71%; 62%), 2 (15%; 20%), >=3 (0), and GI: grade 0 (66%; 73%), 1 (34%; 27%), >=2 (0). Toxicity-free survival at 24 months was GU grade 2 (83%) and GI grade 1 (74%). Mean (+/-std dev) baseline International Prostate Symptom Score (IPSS), International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 6.6 +/- 6.1, 10.5 +/- 7.3, 90.9 +/- 10.8, 93.3 +/- 11.2, respectively, and largely unchanged at 2 years: 6.3 +/- 3.6, 11.1 +/- 6.3, 92.8 +/- 5.8, and 90.9 +/- 10.3. On multivariate analysis, baseline IPSS (p = .009) associated with GU grade 2 acute toxicity. Bladderless-CTV median dose, V30, and V40 associated with GU grade 2 acute toxicity and maximum dose with late (Ps <0.05). For GI, on multivariate analysis, baseline bowel function (p = .033) associated with acute grade 1 toxicity. Rectal minimum and median dose, V10, and V20, and anterior rectal wall median dose and V10 through V65 associated with acute grade 1 GI toxicity (Ps < .05). CONCLUSIONS: Post-prostatectomy PT for prostate cancer is feasible with a favorable GU and GI toxicity profile acutely and through early follow up. PMID- 30028228 TI - Nutritional Intake in Australian Football Players: Sports Nutrition Knowledge and Macronutrient and Micronutrient Intake. AB - This study compared the energy, macronutrient, and micronutrient intake in elite and sub-elite Australian football players and compared nutritional intake to current recommendations. Sports nutrition knowledge was also quantified and compared between elite and sub-elite players. Nutritional intake was quantified in elite (n = 35) and sub-elite (n = 31) players using the Automated Self Administered 24-Hour Dietary Assessment Tool. The 88-item Sports Nutrition Knowledge Questionnaire was used to quantify knowledge related to general nutrition concepts, fluid, recovery, weight control, and supplements. Elite players had a higher nutritional intake (mean +/- SD) for energy (14,140 +/- 5,887 kJ [elite players] vs 10,412 +/- 3,316 kJ [sub-elite players]; P = .002) and fat (40% +/- 6% [elite players] vs 34% +/- 6% [sub-elite players]; P < .001). Protein intake exceeded the recommended intake in 77% of elite players and 68% of sub-elite players, and carbohydrate intake was below the recommended intake for 91% of elite players and 97% of sub-elite players. Sodium intake recommendations were exceeded by 100% of elite and sub-elite players. Both elite and sub-elite players answered 51% of the Sports Nutrition Knowledge Questionnaire questions correctly. The percentage of correctly answered questions specific to supplements was 27% for elite players and 18% for sub-elite players. The results of the current investigation suggest that Australian football players' nutritional intake is inconsistent with current recommendations for macronutrients and some micronutrients. Furthermore, players may benefit from additional knowledge of the risks and benefits of supplement use. PMID- 30028230 TI - Corrigendum. PMID- 30028229 TI - Pharmacogenetics and cognitive symptoms in schizophrenia patients treated with antipsychotics. PMID- 30028231 TI - Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions. AB - It is well established that the CYP2C19 nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines. PMID- 30028233 TI - In Silico Analyses of Rice Thionin genes and the Antimicrobial Activity of OsTHION15 against Phytopathogens. AB - Thionins are a family of antimicrobial peptides. We performed in silico expression analyses of the 44 rice (Oryza sativa L.) thionins (OsTHIONs). Modulated expression levels of OsTHIONs under different treatments suggest their involvement in many processes, including biotic, abiotic and nutritional stress responses, and in hormone signaling. OsTHION15 (LOC_Os06g32600) was selected for further characterization based on several in silico analyses. OsTHION15 in O. sativa L. ssp. indica 'KDML 105' was expressed in all of the tissues/organs examined, including germinating seeds, leaves and roots of seedlings and mature plants, and inflorescences. To investigate the antimicrobial activity of OsTHION15, we produced a recombinant peptide in Escherichia coli Rosetta-gami (DE3). The recombinant OsTHION15 exhibited inhibitory activities toward rice pathogenic bacteria, such as Xanthomonas oryzae pv. oryzae and Pectobacterium carotovorum pv. atroseptica, with minimum inhibitory concentrations of 112.6 and 14.1 ug ml-1, respectively. A significant hyphal growth inhibition was also observed towards Fusarium oxysporum ssp. cubense and Helminthosporium oryzae. In addition, we demonstrated the in planta antibacterial activity of this peptide in Nicotiana benthamiana against Xanthomonas campestris pv. glycines. These activities suggest the possible application of OsTHION15 in plant disease control. PMID- 30028232 TI - Microsatellite analysis and urediniospore dispersal simulations support the movement of Puccinia graminis f. sp. tritici from southern Africa to Australia. AB - The Australian wheat stem rust (Puccinia graminis f. sp. tritici) population was shaped by the introduction of four exotic incursions into the country. It was previously hypothesized that at least two of these (races 326-1,2,3,5,6 and 194 1,2,3,5,6 first detected in 1969) had an African origin and moved across the Indian Ocean to Australia on high-altitude winds. We provide strong supportive evidence for this hypothesis by combining genetic analyses and complex atmospheric dispersion modelling. Genetic analysis of 29 Australian and South African P. graminis f. sp. tritici races using microsatellite markers confirmed the close genetic relationship between the South African and Australian populations, thereby confirming previously described phenotypic similarities. Lagrangian Particle Dispersion Model simulations using finely resolved meteorological data showed that long distance dispersal events between southern Africa and Australia are indeed possible, albeit rare. Simulated urediniospore transmission events were most frequent from central South Africa (viable spore transmission on ~7% of all simulated release days) compared with other potential source regions in southern Africa. The study acts as a warning of possible future P. graminis f. sp. tritici dispersal events from southern Africa to Australia, which could include members of the Ug99 race group, emphasizing the need for continued surveillance on both continents. PMID- 30028234 TI - The clinical use of parvovirus B19 assays: recent advances. AB - INTRODUCTION: Parvovirus B19 (B19V), a single-stranded DNA virus in the family Parvoviridae, is a human pathogenic virus, characterized by a selective but not exclusive tropism for erythroid progenitor cells. Widely diffuse, it is responsible for an ample range of clinical manifestations, whose characteristics and outcomes depend on the interplay between the viral properties and the physiological and immune status of the infected individuals. The complexity of virus-host relationship and the diversity of the clinical course of infection pose a diagnostic challenge that may require non-trivial solutions. Areas covered: The review includes an updated description of the course of B19V infection in its complexity and diversity of pathogenetic mechanisms, discusses the consequent requirements for different and appropriated diagnostic approaches, presents the main diagnostic techniques, more recent technical advancements, and their application to the diverse clinical situations. Expert commentary: The complex scenario of the infectious process and the diversity in possible pathogenetic mechanisms make necessary a multi-parametric approach for an accurate and informative laboratory diagnosis of B19V infection, combining as much as possible the molecular detection of viral components, mainly viral DNA, to commonly followed immunological detection of virus-specific antibodies and a critical assessment of laboratory findings. PMID- 30028235 TI - Finite element analysis of the impact of screw insertion distal to the trochanter minor on the risk of iatrogenic subtrochanteric fracture. AB - Iatrogenic subtrochanteric fractures are rarely encountered after cannulated screw fixation of femoral neck fractures; however, when they do occur, there can be several complications. Many orthopedic surgeons have concerns about the potential for iatrogenic subtrochanteric fractures after screw fixation distal to the trochanter minor; therefore, some surgeons are typically reluctant to perform this procedure. This study focused on the risk of an iatrogenic subtrochanteric fracture after treating femoral neck fractures with cannulated screws. The main purpose of the study was to understand iatrogenic subtrochanteric fractures and evaluate the effects on these fractures of an inverted triangular-shaped configuration for placement of the cannulated screws. A femur bone with an femoral neck fracture at a 40 degrees incline to the horizontal plane was generated along with a representation of a three-dimensional finite element model, and three inverted triangular-shaped configurations for placement of the cannulated screws were investigated using finite element analyses. Statistical results indicated that the occurrence risk of ISF increases when the screw is located distal to the trochanter minor. Moreover, the risk of occurrence of intertrochanteric fracture increases when the screw is located medial to the trochanter minor because of local concentrated stress on the surface of the screw canals. To avoid the vulnerability of the subtrochanteric region, it was found that proximal placement of the screws using the inverted triangular-shaped configuration could yield better results. In addition, the results of this study provide suggestions on improved screw configurations. PMID- 30028236 TI - Regeneration of insulin-producing islets from dental pulp stem cells using a 3D culture system. AB - AIM: In this study, we aimed to establish the differentiation protocol of dental pulp stem cells (DPSCs) into pancreatic islets using a 3D structure. MATERIALS & METHODS: DPSCs were differentiated in a 3D culture system using a stepwise protocol. Expression of beta-cell markers, glucose-stimulated insulin secretion, and PI3K/AKT and WNT pathways were compared between monolayer-cultured pancreatic cells and islets. RESULTS: Islet formation increased insulin and C-peptide production, and enhanced the expression of pancreatic markers. Glucose-dependent secretion of insulin was increased by islets. Pancreatic endocrine markers, transcriptional factors, and the PI3K/AKT and WNT pathways were also upregulated. CONCLUSION: Pancreatic islets were generated from DPSCs in a 3D culture system. This system could provide novel strategies for controlling diabetes through regenerative medicine. PMID- 30028237 TI - Use of mirtazapine in patients with chronic breathlessness: A case series. AB - BACKGROUND: Breathlessness remains a common and distressing symptom in people with advanced disease with few effective treatment options. Repurposing of existing medicines has been effective in other areas of palliative care, for example, antidepressants to treat pain, and offers an opportunity to deliver improved symptom control in a timely manner. Previous case series have shown reduced breathlessness following the use of sertraline (a selective serotonin reuptake inhibitor) in people with chronic obstructive pulmonary disease. CASES: Six cases where mirtazapine, a noradrenergic and specific serotonergic antidepressant, was used to treat chronic breathlessness in advanced lung disease. Case management: All cases received mirtazapine at a starting dose of 15 mg, prescribed under the care of their primary care physician. Cases had been receiving mirtazapine for a variable time period (2 weeks to 5 months) at the time of the interviews. Case outcome: All cases reported less breathlessness and being able to do more. They described feeling more in control of their breathing, and being able to recover more quickly from episodes of breathlessness. Some cases also reported beneficial effects on anxiety, panic, appetite and sleep. No adverse effects were reported. DISCUSSION: Patients with chronic breathlessness in this case series reported benefits during mirtazapine treatment. To determine the effectiveness of mirtazapine in alleviating breathlessness and improving quality of life in chronic lung disease, blinded randomised trials are warranted. PMID- 30028239 TI - Nonfatal Suicidal Behaviors in the Administrative Records of Activated U.S. Army National Guard and Army Reserve Soldiers, 2004-2009. AB - OBJECTIVE: The U.S. Army suicide rate increased sharply during the wars in Iraq and Afghanistan. There is limited information about medically documented, nonfatal suicidal behaviors among soldiers in the Army's Reserve Component (RC), which is composed of the Army National Guard and Army Reserve. Here we examine trends and sociodemographic correlates of suicide attempts, suspicious injuries, and suicide ideation among activated RC soldiers. METHODS: Data come from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) Historical Administrative Data Study (HADS), which integrates administrative records for all soldiers on active duty for the years 2004 through 2009 (n = 1.66 million). RESULTS: We identified 2,937 unique RC soldiers on active duty with a nonfatal suicidal event documented at some point during the HADS study period. There were increases in the annual incidence rates of suicide attempts (71 to 204/100,000 person-years) and suicide ideation (326 to 425/100,000 person-years). Incidence rates for suspicious injuries also generally increased but were more variable. Using hierarchical classification rules, we identified the first instance of each soldier's most severe behavior (suicide attempt versus suspicious injury versus suicide ideation). For each of those suicide- or injury related outcomes, we found increased risk among those who were female, younger, non-Hispanic White, less educated, never married, and lower-ranking enlisted. These sociodemographic associations significantly differed across outcomes, although the patterns were similar. CONCLUSION: Results provide a broad overview of nonfatal suicidal trends in the RC during the period 2004 through 2009. They also demonstrate that integration of multiple administrative data systems enriches analysis of the predictors of such events. PMID- 30028238 TI - Recantation of Sexual Abuse Disclosure Among Child Victims: Accommodation Syndrome. AB - BACKGROUND: Disclosing the sexual abuse may be related on many individual and/or environmental factors in all age groups. The sociocultural context is the most influential factor of the disclosing process especially for those living in patriarchal cultural values. This study compares the impacts of sexual abuse and other sociodemographic variables between recanting and non-recanting victimized groups in Adana city from Turkey. METHODS: The samples attending our department were divided into two groups: group 1 comprised victims who recanted their first abuse disclosure, and group 2 comprised victims who insisted on the veracity of their first report at further evaluations. The characteristics of the child, family, and abuser were compared between recanting victims and non-recanting victims by retrospective data. RESULTS: Each group included 27 children, for a total of 54 subjects. All adverse social reactions after the sexual abuse, including keeping secrets and a repressive family attitude, were higher among group 1 victims than group 2 victims (p < 0.0001). CONCLUSIONS: Although they are victimized by protecting family integrity, victims may show a tendency to keep secrets and to not immediately disclose an abuse event. PMID- 30028240 TI - Applicability of lignin polymers for automobile brake pads as binder and filler materials and their performance characteristics. AB - We present environmentally friendly brake pads produced with three different types of lignin, soda lignin (SL), sulphuric acid lignin (SAL) and heat-treated SAL (HL), as frictional materials to replace phenol formaldehyde resin (PFR, binder) and cashew nut shell liquid (CNSL, filler) in commercial automobile brake pad. Then the performance characteristics of the lignin-added brake pads were tested and compared using several fundamental tests. The results showed that lignin-added brake pads adhered to the SAE standard (0.25) for friction coefficient, which is the primary contributor to the performance of a braking system. In particular, the replacement of PFR with SL demonstrated a better friction coefficient than did replacement with SAL or HL, reaching up to 0.6. On the other hand, when lignin was substituted for CNSL as filler, HL-added brake pads showed a significant improvement in wear resistance of 0.12 g (dust generation) compared to SL and SAL, which had a resistance of approximately 0.25 g. PMID- 30028241 TI - Self-Selected and Prescribed Intensity Exercise to Improve Physical Activity Among Inactive Retirees. AB - A randomized controlled study explored the effects of two intensity-oriented exercise interventions on affect to exercise and physical activity behavior. Inactive retirees finished the 12-week group-based exercise intervention and 3 month telephone follow-up with 27 in self-selected intensity group and 26 in prescribed intensity group. Repeated measures of daily step counts (measured by Yamax pedometers), positive and negative affect to exercise, weight, height, waist circumference, and blood pressure were done at baseline, postintervention, and 3-month follow-up. Increased daily step counts and positive affect, and reduced body mass index, waist circumference, blood pressure of both groups, and negative affect of self-selected intensity group were found at different measuring times. Although self-selected intensity group had no significantly different daily step counts from prescribed intensity group, the former had a more positive and less negative affect to exercise. Findings suggest that future exercise programs use self-selected intensity exercise programs to improve pleasure affect to exercise. PMID- 30028242 TI - Palliative care in the emergency department: A systematic literature qualitative review and thematic synthesis. AB - BACKGROUND: Despite a fast-paced environment, the emergency clinician has a duty to meet the palliative patient's needs. Despite suggested models and interventions, this remains challenging in practice. AIM: To raise awareness of these challenges by exploring the experience of palliative care patients and their families and informal carers attending the emergency department, and of the clinicians caring for them. DESIGN: Qualitative systematic literature review and thematic synthesis. Search terms related to the population (palliative care patients, family carers, clinicians), exposure (the emergency department) and outcome (experience). The search was international but restricted to English and used a qualitative filter. Title, abstracts and, where retrieved, full texts were reviewed independently by two reviewers against predefined inclusion criteria arbitrated by a third reviewer. Studies were appraised for quality but not excluded on that basis. DATA SOURCES: MEDLINE [1946-], Embase[1947-], CINAHL [1981-] and PsycINFO [1987-] with a bibliography search. RESULTS: 19 papers of 16 studies were included from Australia ( n = 5), the United Kingdom ( n = 5), and United States ( n = 9) representing 482 clinical staff involved in the emergency department (doctors, nurses, paramedics, social workers, technicians), 61 patients and 36 carers. Nine descriptive themes formed three analytic themes: 'Environment and Purpose', 'Systems of Care and Interdisciplinary Working' and 'Education and Training'. CONCLUSION: In the included studies, provision of emergency palliative care is a necessary purpose of the emergency department. Failure to recognise this, gain the necessary skills or change to systems better suited to its delivery perpetuates poor implementation of palliative care in this environment. PMID- 30028243 TI - How Much Stereoscopic Effect Does Laparoscopy Need? Controlled, Prospective Randomized Trial on Surgical Task Efficiency in Standardized Phantom Tasks. AB - BACKGROUND: To regain 2-eyed vision in laparoscopy, dual-channeled optics have been introduced. With this optics design, the distance between the 2 front lenses defines how much stereoscopic effect is seen. This study quantifies the impact of an enhanced and a reduced stereo effect on surgical task efficiency. METHODS: A prospective single-blinded study was performed with 20 laparoscopic novices in an inanimate experimental setting. A standard bichannelled stereo system was used to perform a suturing and knotting task. The working distance and the task size were scaled to vary the stereo effect and, thereby, simulate hypothetic stereo optics with enhanced and reduced optical bases. The task performances were timed, and the number of trials for stitching out was counted. The participants finally filled out a questionnaire to collect subjective impressions. RESULTS: The increase of the stereo effect by 50% caused no objective improvement in laparoscopic knotting compared with typical 3D (control group with stereo basis of 4.5 mm). But ergonomic disadvantages (headache) were subjectively reported in 1 of 20 cases in the questionnaire. The reduction of the stereo effect by one third led to a significantly longer average execution time. There was no significant dependence found between stereo effect and number of stich-out trials, stitching precision, or knotting quality. CONCLUSIONS: Considering laparoscopy, it does not seem advisable to enhance the stereo effect because of ergonomic problems. Otherwise, a miniaturization of the 3D scope (5 mm version) is problematic because its benefit mostly shrinks with the reduced stereo effect. PMID- 30028244 TI - Multidimensional factors of determining trajectories in self-rated health and depressive symptoms among Korean children and adolescents. AB - Understanding health disparities in the early stage of life is complicated by the complex interplay of psychosocial and environment factors. Despite these complexities, few studies have investigated multidimensional aspects of determining health trajectories of Korean children and adolescents. Thus, this study aims to investigate the impact of intrapersonal, interpersonal, and environmental factors on trajectories in self-rated health and depressive symptoms. Totally, 2378 Korean student samples were selected from the Korean Children and Young Panel Survey for data analysis. The findings indicated that higher levels of self-esteem, attachment to parents, and relationship with friends predicted better self-rated health and less depressive symptoms at baseline. Perception on community only predicted better self-rated health but not depressive symptoms at baseline. Among multidimensional factors, only self-esteem predicted the rate of changes in self-rated health and depressive symptoms. This study suggested that enhancing self-esteem and supportive environment should be provided throughout childhood and adolescence. PMID- 30028245 TI - Effect of Soy Milk on Metabolic Status of Patients with Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial. AB - OBJECTIVE: Studies in experimental models of nonalcoholic fatty liver disease (NAFLD) have reported positive effects of soy components in improving metabolic parameters. Whether such effects could be achieved through consumption of whole soy foods in patients with NAFLD is still unclear. Therefore, this trial was conducted to assess the effects of soy milk on metabolic parameters of patients with NAFLD. METHODS: This parallel randomized clinical trial was conducted on 70 patients with NAFLD. Patients in the soy milk group consumed 240 ml of soy milk daily as a part of low-calorie diet (i.e., 500-deficit calorie diet) for 8 weeks. Patients in the control group just followed the low-calorie diet. Grade of fatty liver, liver enzymes, lipid profile, serum high-sensitivity C-reactive protein (hs-CRP), and anthropometric indices were measured at baseline and the end of the trial. RESULTS: At the end of the trial, the soy milk group had significantly higher reduction in serum alanine aminotransferase (ALT) (-12.06 +/- 17.61 IU/L in the soy milk group versus -5 +/- 8.58 IU/L in the control group, p = 0.04) and hs-CRP (-1.32 +/- 1.60 mg/L in the soy milk group versus -0.36 +/- 1.54 mg/L in the control group, p = 0.01) compared to the control group. However, changes in fatty liver grade and other liver enzymes, including aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase, as well as lipid profile and anthropometric indices were not significantly different between the treatment groups. CONCLUSION: Consumption of soy milk in the context of a restricted calorie diet for 8 weeks had favorable effects on serum ALT and hs-CRP in patients with NAFLD. PMID- 30028246 TI - Cross-Validating a Structural Model of Factors Influencing Diabetes Self Management in Chinese Americans with Type 2 Diabetes. AB - INTRODUCTION: The purpose of this study was to cross-validate a structural model depicting the effects of individual and environmental factors on diabetes self management in Chinese Americans with type 2 diabetes. METHODOLOGY: A cross sectional survey was administered to a convenience sample of 209 Chinese Americans with type 2 diabetes in the Midwest of the United States. Structural equation modeling was used to cross-validate the model fit. RESULTS: Provider patient communication indirectly influenced self-management via belief in treatment. Knowledge indirectly influenced self-management via belief in treatment and self-efficacy. Social support indirectly influenced self-management via belief in treatment and knowledge. DISCUSSION: This study demonstrated that the structural model, previously tested with Chinese diabetes patients in China, also fits Chinese Americans in the United States with few modifications. The cross-validated model provides a theoretical basis for developing culturally relevant diabetes self-management interventions for Chinese Americans, which may lead to health improvements in this ethnic population. PMID- 30028247 TI - Novel electrospun fibers with incorporated commensal bacteria for potential preventive treatment of the diabetic foot. AB - AIM: A novel electrospun biocompatible nanofibrous material loaded with commensal bacteria for potential preventive treatment of the diabetic foot was developed. MATERIALS & METHODS: Two biocompatible polymers (carboxymethylcellulose and polyethylene oxide) were combined with a bacterium isolate from the skin located between the toes of a healthy adult (identified using a matrix-assisted laser desorption/ionization mass spectrometry-based method as a strain of Staphylococcus epidermidis). Higher bacteria loads in the material were assured through their encapsulation in polyethylenimine. The nanofibrous material was characterized using scanning electron microscopy, zeta-potential measurements and through evaluation of cell growth and viability. RESULTS & DISCUSSION: nanometer formation was confirmed using scanning electron microscopy, while the zeta potential measurements revealed successful bacteria encapsulation. Viable and sufficiently growing cells were confirmed prior and after their incorporation. CONCLUSION: The prepared materials were proven suitable to deliver viable commensal bacteria in a comparable share to the Staphylococcaceae in the foot microbiome making this approach promising for preventive diabetic foot treatment. PMID- 30028248 TI - Thymoquinone loaded in nanostructured lipid carrier showed enhanced anticancer activity in 4T1 tumor-bearing mice. AB - AIM: To investigate the enhancement of anticancer activity of thymoquinone (TQ) by the use of nanostructured lipid carrier (NLC) in 4T1 tumor-bearing female BALB/c mice. MATERIAL & METHODS: TQ was incorporated into NLC (TQNLC) by using high pressure homogenization. TQNLC and TQ were orally administered to the mice. RESULTS & CONCLUSION: TQNLC and TQ are potential chemotherapeutic drugs as they exhibited anticancer activity. The use of NLC as a carrier has enhanced the therapeutic property of TQ by increasing the survival rate of mice. The antimetastasis effect of TQNLC and TQ to the lungs was evidence by downregulation of MMP-2. TQNLC and TQ induced apoptosis via modulation of Bcl-2 and caspase-8 in the intrinsic apoptotic pathway. PMID- 30028249 TI - Potentials of combining nanomaterials and stem cell therapy in myocardial repair. AB - Cardiac diseases have become the leading cause of death worldwide. Developing efficient strategies to treat such diseases is of great urgency. Stem cell-based regeneration medicine offers a novel approach for heart repair. However, low retention and poor survival rate of engrafted cells limit its applications. Nanomaterials have shown great potentials in addressing above issues due to nanoparticles-bio interactions. Therefore, combining nanomaterials and stem cell therapy is of great interest and significance for heart repair. Herein, we provide a comprehensive understanding of the applications of four types of nanomaterials (nanogels, polymeric nanomaterials, inorganic nanomaterials and exosomes) in stem cell therapy for myocardial repair. In addition, we launch an initial discussion on current problems and more importantly, possible solutions for myocardial repair. PMID- 30028250 TI - p38 siRNA-encapsulated PLGA nanoparticles alleviate neuropathic pain behavior in rats by inhibiting microglia activation. AB - AIM: To investigate whether p38 small-interfering RNA-loaded nanoparticles (p38 siRNA NPs) attenuate spinal nerve ligation (SNL)-induced neuropathic pain in rats by suppressing spinal microglia activation via p38 targeting. MATERIALS & METHODS: After synthesizing p38 siRNA NPs with sonication, physical characteristics were measured for size and zeta potential. p38 siRNA NPs were then administrated intrathecally into SNL rats if they could reduce pain behavior excellently. RESULTS: p38 siRNA NPs significantly reduced mechanical allodynia as well as microgliosis in the spinal dorsal horns of SNL rats, consistent with a downregulation of p38-related proinflammatory mediators. CONCLUSION: As p38 in the spinal microglia plays a critical role in neuropathic pain, we expect that p38 siRNA NPs could be a promising tool for the treatment of neuropathic pain. PMID- 30028251 TI - Uptake mechanism of metabolic-targeted gold nanoparticles. AB - AIM: To elucidate the interactions, uptake mechanisms and cytotoxicity profile of glucose-functionalized gold nanoparticles (2GF-GNPs), for expanding and advancing the recently proposed technology of metabolic-based cancer detection to a variety of cancer diseases. METHODS: Several cell types with different metabolic features were used to assess the involvement of GLUT-1 and different endocytosis pathways in 2GF-GNP uptake, and the cytotoxicity profile of 2GF-GNPs. RESULTS: Cellular uptake of 2GF-GNP strongly correlated with GLUT-1 surface expression, and occurred mainly through clathrin-mediated endocytosis. 2GF-GNPs showed no toxic effect on cell cycle and proliferation. CONCLUSION: These findings promote development of metabolic-based cancer detection technologies, and suggest that 2GF-GNPs may enable specific cancer detection in a wide range of tumors characterized by high GLUT-1 expression. PMID- 30028252 TI - In vivo assessment of spinal cord elasticity using shear wave ultrasound in dogs. AB - OBJECTIVE: Evaluation of living tissue elasticity has wide applications in disease characterization and prognosis prediction. Few previous ex vivo attempts have been made to characterize spinal cord elasticity (SCE). Recently, tissue elasticity assessment has been clinically feasible using ultrasound shear wave elastography (SWE). The current study aims to characterize SCE in healthy dogs, in vivo, utilizing SWE, and to address SCE changes during compression. METHODS: Ten Greyhound dogs (mean age 14 months; mean weight 14.3 kg) were anesthetized and tracheally intubated, with hemodynamic and neurological monitoring. A 3 level, midcervical laminectomy was performed. SCE was assessed at baseline. Next, 8- and 13-mm balloon compressions were sequentially applied ventral to the spinal cord. RESULTS: The mean SCE was 18.5 +/- 7 kPa. Elasticity of the central canal, pia mater, and dura mater were 21.7 +/- 9.6 kPa, 26.1 +/- 14.8 kPa, and 63.2 +/- 11.5 kPa, respectively. As expected, the spinal cord demonstrated less elasticity than the dura mater (p < 0.0001) and pia mater (trend toward significance p = 0.08). Notably, the 13-mm balloon compression resulted in a stiffer spinal cord than at baseline (233 +/- 73 kPa versus 18.5 +/- 7 kPa, p < 0.0001) and 8-mm balloon compression (233 +/- 73 kPa versus 185 +/- 68 kPa, p < 0.048). CONCLUSIONS: In vivo SCE evaluation using SWE is feasible and comparable to earlier reports, as demonstrated by physical sectioning of the spinal cord. The compressed spinal cord is stiffer than a free spinal cord, with a linear increase in SCE with increasing mechanical compression. Knowledge of the biomechanical properties of the spinal cord including SCE has potential implications for disease management and prognosis. PMID- 30028253 TI - A longitudinal survey of adult spine and peripheral nerve case entries during neurosurgery residency training. AB - OBJECTIVE: Currently, there is a lack of research assessing residents' operative experience and caseload variability. The current study utilizes data from the Accreditation Council for Graduate Medical Education (ACGME) case log system to analyze national trends in neurosurgical residents' exposure to adult spinal procedures. METHODS: Prospectively populated ACGME resident case logs from 2013 to 2017 were retrospectively reviewed. The reported number of spinal procedures was compared to the ACGME minimum requirements for each surgical category pertaining to adult spine surgery. A linear regression analysis was conducted to identify changes in operative caseload by residents graduating during the study period, as well as a one-sample t-test using IBM SPSS software to compare the mean number of procedures in each surgical category to the ACGME required minimums. RESULTS: A mean of 427.42 total spinal procedures were performed throughout residency training for each of the 877 residents graduating between 2013 and 2017. The mean number of procedures completed by graduating residents increased by 19.96 (r2 = 0.95) cases per year. The number of cases in every procedural subspecialty, besides peripheral nerve operations, significantly increased during this time. The two procedural categories with the largest changes were anterior and posterior cervical approaches for decompression/stabilization, which increased by 8.78% per year (r2 = 0.95) and 9.04% per year (r2 = 0.95), respectively. There was also a trend of increasing cases logged for lead resident surgeons and a decline in cases logged for senior resident surgeons. Residents' mean caseloads during residency were found to be vastly greater than the ACGME required minimums: residents performed at least twice as many procedures as the required minimums in every surgical category. CONCLUSIONS: Graduating neurosurgical residents reported increasing case volumes for adult spinal cases during this 5-year interval. An increase in logged cases for lead resident surgeons as opposed to senior resident surgeons indicates that residents were logging more cases in which they had a more critical role in the procedure. Moreover, the average resident was noted to perform more than twice the number of procedures required by the ACGME in every surgical category, indicating that neurosurgical residents are getting greater exposure to spine surgery than expected. Given the known correlation between case volume and improved surgical outcomes, this data demonstrates each graduating neurosurgical residency class experiences an augmented training in spine surgery. PMID- 30028254 TI - The influence of spinopelvic parameters on adjacent-segment degeneration after short spinal fusion for degenerative spondylolisthesis. AB - OBJECTIVE: Spinopelvic parameters, such as the pelvic incidence (PI) angle, sacral slope angle, and pelvic tilt angle, are important anatomical indices for determining the sagittal curvature of the spine and the individual variability of the lumbar lordosis (LL) curve. The aim of this study was to investigate the influence of spinopelvic parameters and LL on adjacent-segment degeneration (ASD) after short lumbar and lumbosacral fusion for single-level degenerative spondylolisthesis. METHODS: The authors retrospectively reviewed the records of all short lumbar and lumbosacral fusion surgeries performed between August 2003 and July 2010 for single-level degenerative spondylolisthesis in their orthopedic department. RESULTS: A total of 30 patients (21 women and 9 men, mean age 64 years) with ASD after lower lumbar or lumbosacral fusion surgery comprised the study group. Thirty matched patients (21 women and 9 men, mean age 63 years) without ASD comprised the control group, according to the following matching criteria: same diagnosis on admission, similar pathologic level (<= 1 level difference), similar sex, and age. The average follow-up was 6.8 years (range 5-8 years). The spinopelvic parameters had no significant influence on ASD after short spinal fusion. CONCLUSIONS: Neither the spinopelvic parameters nor a mismatch of PI and LL were significant factors responsible for ASD after short spinal fusion due to single-level degenerative spondylolisthesis. PMID- 30028255 TI - Development of lupus nephritis in a patient with previous scleroderma renal crisis. AB - We present a case of scleroderma overlap syndrome with systemic lupus erythematosus (SLE) including complications of both scleroderma renal crisis and lupus nephritis. Our patient was initially diagnosed with undifferentiated connective tissue disease in 1996. A diagnosis of scleroderma was made in 2010 after she developed scleroderma renal crisis. She remained stable until 2016, when she presented with Salmonella bacteremia, renal failure, nephrotic range proteinuria and microscopic hematuria. Laboratory findings were consistent lupus with positive ds-DNA, hypocomplementemia and repeat renal biopsy showed lupus nephritis. PMID- 30028256 TI - Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus in a patient with progressive systemic sclerosis. AB - A 60-year-old female was diagnosed with progressive systemic sclerosis and interstitial lung disease of two months' duration. The patient was treated for Raynaud phenomenon with aspirin, nifedipine, colchicine, and naproxen. Two weeks after treatment, she developed widespread erythematous patches with blistering eruptions on the face, torso, and extremities, and also had erosion on the oral mucosa. Skin biopsy for histopathology and direct immunofluorescent studies were suggestive of lupus erythematosus. To the best of our knowledge, this is the first case of toxic epidermal necrolysis-like acute cutaneous lupus erythematosus in a patient with progressive systemic sclerosis. PMID- 30028258 TI - Factors associated with development and mortality of pulmonary hypertension in systemic lupus erythematosus patients. AB - Objectives This study aims to identify the factors associated with the development and mortality of pulmonary hypertension (PH) in systemic lupus erythematosus (SLE) patients. Methods We conducted a prospective study of SLE patients in a single tertiary center. PH was defined as a systolic pulmonary arterial pressure >=30 mmHg on transthoracic echocardiography. We assessed potential associated factors contributing to the development and mortality of PH in SLE patients. Results Of 1110 patients with SLE, 48 patients were identified to have PH. Multivariable analysis indicated that pleuritis or pericarditis (odds ratio (OR) = 4.62), anti-RNP antibody (OR = 2.42), interstitial lung disease (ILD) (OR = 8.34) and cerebro-cardiovascular disease (OR = 13.37) were independently associated with the development of PH in SLE. Subgroup analysis among patients with PH demonstrated that there were no statistically significant factors associated with PH mortality in SLE. Conclusions The prevalence of PH was 4.3% in our cohort. There were significant associations with pleuritis or pericarditis, anti-RNP antibody, ILD, and cerebro-cardiovascular disease in SLE, which may contribute to the development of PH. However, there were no statistically significant factors associated with PH mortality in SLE. PMID- 30028257 TI - Antiphospholipid antibodies in women with severe preeclampsia and placental insufficiency: a case-control study. AB - Objective Preterm delivery for preeclampsia or placental insufficiency (PREPI) is a clinical criterion for antiphospholipid syndrome (APS), but no prior prospective studies have used the international classification criteria for APS. Our objective is to determine the proportion of women with PREPI who test positive for aPL using international criteria for antiphospholipid antibody (aPL) assays. Methods We conducted a prospective, case-control study of 148 women delivered < 36 weeks because of PREPI compared to 148 controls. PREPI cases delivered < 36 weeks were compared to matched controls. Cases and controls were tested for aPL. Demographic variables were compared with chi-squared and Wilcoxon rank-sum statistics. Rates of + aPL were compared using adjusted odds ratios (aORs) for maternal body mass index (BMI) and Caucasian race. Positive aPL (+aPL) was defined as lupus anticoagulant (LA), anticardiolipin (aCL) immunoglobulin G (IgG) (GPL) or immunoglobulin M (IgM) (MPL) >= 40, or anti-beta2-glycoprotein I (abeta2GPI) IgG (SGU) or IgM (SMU) >= 40. Results Controls were more likely to be Caucasian (87% vs 70%, p = 0.006) and had lower BMIs (BMI 26 vs 33, p < 0.001). Positive aPL were found more commonly in cases than controls (11.5% vs 1.4%, aOR 8.9 (95% CI 1.9-41.4)). In + aPL cases, 76% had + LA, 41% had + aCL, and 24% had + abeta2GPI. Conclusion Women requiring early delivery for PREPI are more likely to have aPL (and thus APS) than controls. This is the first prospective study using both obstetric definitions and laboratory criteria in accordance with APS international criteria. PMID- 30028259 TI - Clinical characteristics of lupus enteritis in Japanese patients: the large intestine-dominant type has features of intestinal pseudo-obstruction. AB - This study was performed to investigate the clinical characteristics of lupus enteritis in Japanese patients with systemic lupus erythematosus (SLE). A total of 481 patients with SLE admitted to our hospital between 2001 and 2015 were retrospectively reviewed. Diagnosis of lupus enteritis was based on the following three criteria: (1) abdominal symptoms, (2) diffuse long-segment bowel thickening and (3) a requirement for glucocorticoid therapy. Lupus enteritis was identified in 17 patients (3.5%) and there were two distinct types: small intestine-dominant and large intestine-dominant. Significant differences between the two types were noted with respect to the age, frequency of biopsy-proven lupus nephritis, frequency of rectal involvement, maximum bowel wall thickness, and requirement for steroid pulse therapy. Among patients with large intestine-dominant lupus enteritis, 60% had extra-intestinal symptoms (hydroureter, bladder wall thickening, and bile duct dilatation) that are known complications of intestinal pseudo-obstruction. Two patients with large intestine-dominant lupus enteritis developed intestinal pseudo-obstruction either before or after diagnosis of lupus enteritis. Five patients (29%) developed recurrence during a median observation period of 7.2 years (1.4-14.4 years). In conclusion, large intestine-dominant lupus enteritis resembles intestinal pseudo-obstruction and these two diseases may have a common pathogenesis. PMID- 30028260 TI - The correlation between accumulation of amyloid beta with enhanced neuroinflammation and cognitive impairment after intraventricular hemorrhage. AB - OBJECTIVE Intraventricular hemorrhage (IVH) is found in approximately 40% of intracerebral hemorrhages and is associated with increased mortality and poor functional outcome. Cognitive impairment is one of the complications and occurs due to various pathological changes. Amyloid beta (Abeta) accumulation and neuroinflammation, and the Alzheimer disease-like pathology, may contribute to cognitive impairment. Iron, the degradation product of hemoglobin, correlates with Abeta. In this study, the authors investigated the correlation between Abeta accumulation with enhanced neuroinflammation and cognitive impairment in a rat model of IVH. METHODS Nine male Sprague-Dawley rats underwent an intraventricular injection of autologous blood. Another 9 rats served as controls. Cognitive function was assessed by the Morris water maze and T-maze rewarded alternation tests. Biomarkers of Abeta accumulation, neuroinflammation, and c-Jun N-terminal kinase (JNK) activation were examined. RESULTS Cognitive function was impaired in the autologous blood injection group compared with the control group. In the blood injection group, Abeta accumulation was observed, with a co-located correlation between iron storage protein ferritin and Abeta. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity was elevated. Microgliosis and astrogliosis were observed in hippocampal CA1, CA2, CA3, and dentate gyrus areas, with elevated proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. Protein levels of phosphorylated JNK were increased after blood injection. CONCLUSIONS Abeta accumulation and enhanced neuroinflammation have a role in cognitive impairment after IVH. A potential therapeutic method requires further investigation. PMID- 30028261 TI - Gamma Knife stereotactic radiosurgery for cavernous sinus meningioma: long-term follow-up in 200 patients. AB - OBJECTIVE The authors of this study evaluate the long-term outcomes of stereotactic radiosurgery (SRS) for cavernous sinus meningioma (CSM). METHODS The authors retrospectively assessed treatment outcomes 5-18 years after SRS in 200 patients with CSM. The median patient age was 57 years (range 22-83 years). In total, 120 (60%) patients underwent Gamma Knife SRS as primary management, 46 (23%) for residual tumors, and 34 (17%) for recurrent tumors after one or more surgical procedures. The median tumor target volume was 7.5 cm3 (range 0.1-37.3 cm3), and the median margin dose was 13.0 Gy (range 10-20 Gy). RESULTS Tumor volume regressed in 121 (61%) patients, was unchanged in 49 (25%), and increased over time in 30 (15%) during a median imaging follow-up of 101 months. Actuarial tumor control rates at the 5-, 10-, and 15-year follow-ups were 92%, 84%, and 75%, respectively. Of the 120 patients who had undergone SRS as a primary treatment (primary SRS), tumor progression was observed in 14 (11.7%) patients at a median of 48.9 months (range 4.8-120.0 months) after SRS, and actuarial tumor control rates were 98%, 93%, 85%, and 85% at the 1-, 5-, 10-, and 15-year follow ups post-SRS. A history of tumor progression after microsurgery was an independent predictor of an unfavorable response to radiosurgery (p = 0.009, HR = 4.161, 95% CI 1.438-12.045). Forty-four (26%) of 170 patients who had presented with at least one cranial nerve (CN) deficit improved after SRS. Development of new CN deficits after initial microsurgical resection was an unfavorable factor for improvement after SRS (p = 0.014, HR = 0.169, 95% CI 0.041-0.702). Fifteen (7.5%) patients experienced permanent CN deficits without evidence of tumor progression at a median onset of 9 months (range 2.3-85 months) after SRS. Patients with larger tumor volumes (>= 10 cm3) were more likely to develop permanent CN complications (p = 0.046, HR = 3.629, 95% CI 1.026-12.838). Three patients (1.5%) developed delayed pituitary dysfunction after SRS. CONCLUSIONS This long-term study showed that Gamma Knife radiosurgery provided long-term tumor control for most patients with CSM. Patients who underwent SRS for progressive tumors after prior microsurgery had a greater chance of tumor growth than the patients without prior surgery or those with residual tumor treated after microsurgery. PMID- 30028262 TI - Macrophage CD163 expression in cerebrospinal fluid: association with subarachnoid hemorrhage outcome. AB - OBJECTIVE Even though heme-induced cerebral inflammation contributes to many of the adverse sequelae seen in patients with subarachnoid hemorrhage (SAH), little is known about the mechanism; mouse models have shown a critical role for macrophages/microglia. Macrophage CD163 is a hemoglobin scavenger receptor involved in blood clearance after SAH. The authors hypothesized that the modified Fisher score is independently associated with cerebrospinal fluid (CSF) macrophage CD163 expression on postictal day 1, and that CSF macrophage CD163 expression is associated with 1-month neurological outcome. METHODS CSF macrophages from 21 SAH and 28 unruptured aneurysm patients (control) were analyzed for CD163 expression using flow cytometry and confocal microscopy on postictal day 1. Significant associations with modified Fisher scale grades or modified Rankin Scale scores were determined using linear regression and a matched case control analysis. RESULTS CSF macrophage CD163 expression was significantly increased in SAH patients compared with controls (p < 0.001). The modified Fisher scale (mF) grades (beta = 0.407, p = 0.005) and CSF bilirubin concentrations (beta = 0.311, p = 0.015) were positively and independently associated with CSF macrophage CD163 expression when the analysis was controlled for age and sex. CSF macrophages from an SAH patient with a high mF grade had increased co-localization of CD163 and glycophorin A (CD235a, an erythrocyte marker) compared with those from an SAH patient with a low mF grade. The controls had no co-localization. CSF macrophage CD163 expression (p = 0.003) was inversely associated with 1-month neurological outcome, when SAH patients were matched based on mF grade. CONCLUSIONS This early study suggests that CSF macrophage CD163 expression, as measured by flow cytometry, may have some neuroprotective function given its inverse association with outcome and provides unique insights into the neuroinflammatory process after SAH. PMID- 30028263 TI - Therapeutic strategy for pineal parenchymal tumor of intermediate differentiation (PPTID): case report of PPTID with malignant transformation to pineocytoma with leptomeningeal dissemination 6 years after surgery. AB - Pineal parenchymal tumor of intermediate differentiation (PPTID) is rare. The WHO first classified PPTID in 2000 as a pineal parenchymal tumor (PPT) with an intermediate prognosis between pineocytoma (PC) and pineoblastoma (PB). It is considered an intermediate-grade tumor and divided into WHO grade II or III. The number of available reports about PPTID is presently limited, and the appropriate management for this tumor has not yet been determined. The authors report a rare case of PC in a 63-year-old woman who presented with lower-extremity weakness and gait disturbance. A pineal mass lesion was detected on MRI. A diagnosis of PC was established after microsurgical gross-total tumor resection, and the patient received no adjuvant therapy after surgery. Two years after surgery, a partial recurrence was recognized and Gamma Knife radiosurgery was performed. Fours years later, the patient developed diffuse leptomeningeal dissemination. She was successfully treated with craniospinal irradiation. Leptomeningeal dissemination may develop 6 years after the initial diagnosis of PC. A histopathological study of the recurrent tumor revealed a malignant change from PC to PPTID. The present case shows the importance of long-term follow-up of patients with PPTs following resection and the efficacy of craniospinal irradiation in the treatment of leptomeningeal dissemination. PMID- 30028264 TI - Hemi-laryngopharyngeal spasm as a novel cause of inducible laryngeal obstruction with a surgical cure: report of 3 cases. AB - Inducible laryngeal obstruction has been described under at least 40 different monikers, including vocal cord dysfunction, paroxysmal vocal fold motion, and irritable larynx. The etiology of this condition is believed to be laryngeal hyperactivity in response to psychological issues or acid reflux. Most patients are treated with some combination of proton pump inhibitors, speech therapy, and psychotherapy. However, a small cohort of patients remains refractory to all medical interventions. The authors describe a novel condition, hemi laryngopharyngeal spasm (HELPS), which can cause severe episodic stridor leading to unconsciousness in association with cough. The first recognized and surgically cured patient with HELPS was reported in an earlier issue of this journal. Three additional patients have been followed up for at least a year postoperatively, and their cases are reported here. Each patient presented with a similar pattern of episodic coughing and choking that increased in frequency, severity, and duration over years. The episodes eventually occurred while sleeping and could cause severe stridor with loss of consciousness. All three patients were initially misdiagnosed with a psychiatric illness and subjected to multiple intubations and one tracheostomy. Unilateral botulinum toxin injections in the vocal fold eased the severity of the throat contractions but not the cough. Magnetic resonance imaging showed a looping posterior inferior cerebellar artery juxtaposed to a vagus nerve in each case. Microvascular decompression (MVD) of that vessel relieved all symptoms. The introduction of this new medical condition may help a small cohort of patients with inducible laryngeal obstructions that have not responded to the current standard treatments. Patients are asymptomatic between episodes of progressively severe coughing and choking with stridor that may lead to intubation. Severe anxiety about the unpredictable symptoms is expected and may contribute to a psychiatric misdiagnosis. Microvascular decompression for HELPS is more difficult than that for trigeminal neuralgia because the involved nerve is more susceptible to manipulation. Ultimately, the final proof that HELPS is a real and distinct syndrome will require its recognition and successful treatment by colleagues around the world. PMID- 30028265 TI - Editorial. Considering a neurovascular compression etiology. PMID- 30028266 TI - How to improve obliteration rates during volume-staged stereotactic radiosurgery for large arteriovenous malformations. AB - OBJECTIVE The management of large-volume arteriovenous malformations (AVMs) with stereotactic radiosurgery (SRS) remains challenging. The authors retrospectively tested the hypothesis that AVM obliteration rates can be improved by increasing the percentage volume of an AVM that receives a minimal threshold dose of radiation. METHODS In 1992, the authors prospectively began to stage anatomical components in order to deliver higher single doses to AVMs > 15 cm3 in volume. Since that time 60 patients with large AVMs have undergone volume-staged SRS (VS SRS). The median interval between the first stage and the second stage was 4.5 months (2.8-13.8 months). The median target volume was 11.6 cm3 (range 4.3-26 cm3) in the first-stage SRS and 10.6 cm3 (range 2.8-33.7 cm3) in the second-stage SRS. The median margin dose was 16 Gy (range 13-18 Gy) for both SRS stages. RESULTS AVM obliteration after the initial two staged volumetric SRS treatments was confirmed by MRI alone in 4 patients and by angiography in 11 patients at a median follow-up of 82 months (range 0.4-206 months) after VS-SRS. The post-VS SRS obliteration rates on angiography were 4% at 3 years, 13% at 4 years, 23% at 5 years, and 27% at 10 years. In multivariate analysis, only >= 20-Gy volume coverage was significantly associated with higher total obliteration rates confirmed by angiography. When the margin dose is >= 17 Gy and the 20-Gy SRS volume included >= 63% of the total target volume, the angiographically confirmed obliteration rates increased to 61% at 5 years and 70% at 10 years. CONCLUSIONS The outcomes of prospective VS-SRS for large AVMs can be improved by prescribing an AVM margin dose of >= 17 Gy and adding additional isocenters so that >= 63% of the internal AVM dose receives more than 20 Gy. PMID- 30028267 TI - Multipotent mesenchymal stromal cell-derived exosomes improve functional recovery after experimental intracerebral hemorrhage in the rat. AB - OBJECTIVE Previous studies have demonstrated that transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after experimental intracerebral hemorrhage (ICH). In this study the authors tested the hypothesis that administration of multipotent MSC-derived exosomes promotes functional recovery, neurovascular remodeling, and neurogenesis in a rat model of ICH. METHODS Sixteen adult male Wistar rats were subjected to ICH via blood injection into the striatum, followed 24 hours later by tail vein injection of 100 MUg protein of MSC-derived exosomes (treatment group, 8 rats) or an equal volume of vehicle (control group, 8 rats); an additional 8 rats that had identical surgery without blood infusion were used as a sham group. The modified Morris water maze (mMWM), modified Neurological Severity Score (mNSS), and social odor-based novelty recognition tests were performed to evaluate cognitive and sensorimotor functional recovery after ICH. All 24 animals were killed 28 days after ICH or sham procedure. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume and neurovascular and white matter remodeling. RESULTS Compared with the saline-treated controls, exosome treated ICH rats showed significant improvement in the neurological function of spatial learning and motor recovery measured at 26-28 days by mMWM and starting at day 14 by mNSS (p < 0.05). Senorimotor functional improvement was measured by a social odor-based novelty recognition test (p < 0.05). Exosome treatment significantly increased newly generated endothelial cells in the hemorrhagic boundary zone, neuroblasts and mature neurons in the subventricular zone, and myelin in the striatum without altering the lesion volume. CONCLUSIONS MSC derived exosomes effectively improve functional recovery after ICH, possibly by promoting endogenous angiogenesis and neurogenesis in rats after ICH. Thus, cell free, MSC-derived exosomes may be a novel therapy for ICH. PMID- 30028268 TI - Patient Perceptions of Hidradenitis Suppurativa Stressors. PMID- 30028269 TI - Identification of initial settlement of municipal solid waste layers in Indonesian landfill. AB - This study presents the measurement of municipal solid waste (MSW) compressibility and subsequent development of a landfill settlement estimation model incorporating a correction factor accounting for initial settlement prior to the addition of pressure/municipal solid waste layers. Three layers of municipal solid waste obtained from a temporary waste station in Bandung, Indonesia, were placed in each of three different lysimeters/treatments (MSWorganic, layer height 35 cm; MSWmixed-1, layer height 70 cm; and MSWmixed-2, layer height 35 cm), with a time lag of sample layer input of 2 days. Tests were then undertaken based on the ASTM D2435 test standard - Standard Test Method for One-Dimensional Consolidation Properties of Soils - revealing large immediate and secondary compression ratio values reflecting the high moisture and organic matter content of the analysed municipal solid waste. From the test results, it was also detected that the initial settlement of the analysed municipal solid waste was considerable even before the addition of pressure/further layers, ranging from 10% to 17%. Thus, a modification was made to the classical Sowers settlement estimation model in the form of a correction factor representing the initial settlement occurring prior to the addition of the municipal solid waste layers. This modification resulted in a decrease in the difference between estimated and actual settlement values, from 17% to 24% based on the Sowers equation model to below 5% using the proposed modified settlement model. PMID- 30028270 TI - Safety and efficacy of stereoelectroencephalography in pediatric focal epilepsy: a single-center experience. AB - OBJECTIVE: Patients with medically refractory localization-related epilepsy (LRE) may be candidates for surgical intervention if the seizure onset zone (SOZ) can be well localized. Stereoelectroencephalography (SEEG) offers an attractive alternative to subdural grid and strip electrode implantation for seizure lateralization and localization; yet there are few series reporting the safety and efficacy of SEEG in pediatric patients. METHODS: The authors review their initial 3-year consecutive experience with SEEG in pediatric patients with LRE. SEEG coverage, SOZ localization, complications, and preliminary seizure outcomes following subsequent surgical treatments are assessed. RESULTS: Twenty-five pediatric patients underwent 30 SEEG implantations, with a total of 342 electrodes placed. Ten had prior resections or ablations. Seven had no MRI abnormalities, and 8 had multiple lesions on MRI. Based on preimplantation hypotheses, 7 investigations were extratemporal (ET), 1 was only temporal-limbic (TL), and 22 were combined ET/TL investigations. Fourteen patients underwent bilateral investigations. On average, patients were monitored for 8 days postimplant (range 3-19 days). Nearly all patients were discharged home on the day following electrode explantation. There were no major complications. Minor complications included 1 electrode deflection into the subdural space, resulting in a minor asymptomatic extraaxial hemorrhage; and 1 in-house and 1 delayed electrode superficial scalp infection, both treated with local wound care and oral antibiotics. SEEG localized the hypothetical SOZ in 23 of 25 patients (92%). To date, 18 patients have undergone definitive surgical intervention. In 2 patients, SEEG localized the SOZ near eloquent cortex and subdural grids were used to further delineate the seizure focus relative to mapped motor function just prior to resection. At last follow-up (average 21 months), 8 of 15 patients with at least 6 months of follow-up (53%) were Engel class I, and an additional 6 patients (40%) were Engel class II or III. Only 1 patient was Engel class IV. CONCLUSIONS: SEEG is a safe and effective technique for invasive SOZ localization in medically refractory LRE in the pediatric population. SEEG permits bilateral and multilobar investigations while avoiding large craniotomies. It is conducive to deep, 3D, and perilesional investigations, particularly in cases of prior resections. Patients who are not found to have focally localizable seizures are spared craniotomies. PMID- 30028271 TI - Management of hydrocephalus and subdural hygromas in pediatric patients after decompression of Chiari malformation type I: case series and review of the literature. AB - OBJECTIVE: Hydrocephalus associated with subdural hygromas is a rare complication after decompression of Chiari malformation type I (CM-I). There is no consensus for management of this complication. The authors present a series of 5 pediatric patients who underwent CM-I decompression with placement of a dural graft complicated by posterior fossa hygromas and hydrocephalus that were successfully managed nonoperatively. METHODS: A retrospective review over the last 5 years of patients who presented with hydrocephalus and subdural hygromas following foramen magnum decompression with placement of a dural graft for CM-I was conducted at 2 pediatric institutions. Their preoperative presentation, perioperative hospital course, and postoperative re-presentation are discussed with attention to their treatment regimen and ultimate outcome. In addition to reporting these cases, the authors discuss all similar cases found in their literature review. RESULTS: Over the last 5 years, the authors have encountered 194 pediatric cases of CM-I decompression with duraplasty equally distributed at the 2 institutions. Of those cases, 5 pediatric patients with a delayed postoperative complication involving hydrocephalus and subdural hygromas were identified. The 5 patients were managed nonoperatively with acetazolamide and high-dose dexamethasone; dosages of both drugs were adjusted to the age and weight of each patient. All patients were symptom free at follow-up and exhibited resolution of their pathology on imaging. Thirteen similar pediatric cases and 17 adult cases were identified in the literature review. Most reported cases were treated with CSF diversion or reoperation. There were a total of 4 cases previously reported with successful nonoperative management. Of these cases, only 1 case was reported in the pediatric population. CONCLUSIONS: De novo hydrocephalus, in association with subdural hygromas following CM-I decompression, is rare. This presentation suggests that these complications after posterior fossa decompression with duraplasty can be treated with nonoperative medical management, therefore obviating the need for CSF diversion or reoperation. PMID- 30028272 TI - Letter to the Editor. Altered intracranial venous physiology. PMID- 30028273 TI - Performance of minimally invasive sagittal synostectomy with supine patient positioning: technical note. AB - The authors report their initial experience with supine patient positioning for minimally invasive treatment of sagittal craniosynostosis. Supine positioning offers potential advantages that include reduced anesthetic risk and may be considered as an option by craniofacial surgeons performing minimally invasive synostectomy for sagittal craniosynostosis. PMID- 30028274 TI - Frameless robot-assisted pallidal deep brain stimulation surgery in pediatric patients with movement disorders: precision and short-term clinical results. AB - OBJECTIVE: The purpose of this study was to verify the safety and accuracy of the Neuromate stereotactic robot for use in deep brain stimulation (DBS) electrode implantation for the treatment of hyperkinetic movement disorders in childhood and describe the authors' initial clinical results. METHODS: A prospective evaluation of pediatric patients with dystonia and other hyperkinetic movement disorders was carried out during the 1st year after the start-up of a pediatric DBS unit in Barcelona. Electrodes were implanted bilaterally in the globus pallidus internus (GPi) using the Neuromate robot without the stereotactic frame. The authors calculated the distances between the electrodes and their respective planned trajectories, merging the postoperative CT with the preoperative plan using VoXim software. Clinical outcome was monitored using validated scales for dystonia and myoclonus preoperatively and at 1 month and 6 months postoperatively and by means of a quality-of-life questionnaire for children, administered before surgery and at 6 months' follow-up. We also recorded complications derived from the implantation technique, "hardware," and stimulation. RESULTS: Six patients aged 7 to 16 years and diagnosed with isolated dystonia ( DYT1 negative) (3 patients), choreo-dystonia related to PDE2A mutation (1 patient), or myoclonus dystonia syndrome SGCE mutations (2 patients) were evaluated during a period of 6 to 19 months. The average accuracy in the placement of the electrodes was 1.24 mm at the target point. At the 6-month follow-up, patients showed an improvement in the motor (65%) and functional (48%) components of the Burke-Fahn-Marsden Dystonia Rating Scale. Patients with myoclonus and SGCE mutations also showed an improvement in action myoclonus (95%-100%) and in functional tests (50%-75%) according to the Unified Motor-Rating Scale. The Neuro-QOL score revealed inconsistent results, with improvement in motor function and social relationships but worsening in anxiety, cognitive function, and pain. The only surgical complication was medial displacement of the first electrode, which limited intensity of stimulation in the lower contacts, in one case. CONCLUSIONS: The Neuromate stereotactic robot is an accurate and safe tool for the placement of GPi electrodes in children with hyperkinetic movement disorders. PMID- 30028275 TI - Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis. AB - OBJECTIVE: Pediatric spinal astrocytomas are rare spinal lesions that pose unique management challenges. Therapeutic options include gross-total resection (GTR), subtotal resection (STR), and adjuvant chemotherapy or radiation therapy. With no randomized controlled trials, the optimal management approach for children with spinal astrocytomas remains unclear. The aim of this study was to conduct a systematic review and meta-analysis on pediatric spinal astrocytomas. METHODS: The authors performed a systematic review of the PubMed/MEDLINE electronic database to investigate the impact of histological grade and extent of resection on overall survival among patients with spinal cord astrocytomas. They retained publications in which the majority of reported cases included astrocytoma histology. RESULTS: Twenty-nine previously published studies met the eligibility criteria, totaling 578 patients with spinal cord astrocytomas. The spinal level of intramedullary spinal cord tumors was predominantly cervical (53.8%), followed by thoracic (40.8%). Overall, resection was more common than biopsy, and GTR was slightly more commonly achieved than STR (39.7% vs 37.0%). The reported rates of GTR and STR rose markedly from 1984 to 2015. Patients with high-grade astrocytomas had markedly worse 5-year overall survival than patients with low grade tumors. Patients receiving GTR may have better 5-year overall survival than those receiving STR. CONCLUSIONS: The authors describe trends in the management of pediatric spinal cord astrocytomas and suggest a benefit of GTR over STR for 5 year overall survival. PMID- 30028276 TI - Principal component analysis identifies differential gender-specific dietary patterns that may be linked to mental distress in human adults. AB - : Independent reports describe the structural differences between the human male and female brains and the differential gender-susceptibility to mood disorders. Nutrition is one of the modifiable risk factors that has been reported to impact brain chemistry and affect mental health. OBJECTIVES: To study dietary patterns in adult men and women in relation to mental distress. Another aim was to develop evidence-based prototypes using System Dynamic Modeling methodology to better describe our findings. METHODS: An anonymous internet-based survey was sent through social media platforms to different social and professional networks. Multivariate analyses were used for data mining. Data were stratified by gender and further by tertiles to capture the latent variables within the patterns of interest. RESULTS: Mental distress in men associated with a consumption of a Western-like diet. In women, mental wellbeing associated with a Mediterranean like diet and lifestyle. No other patterns in both genders were linked to mental distress. Based on the generated prototypes, men are more likely to experience mental wellbeing until nutritional deficiencies arise. However, women are less likely to experience mental wellbeing until a balanced diet and a healthy lifestyle are followed. In men, dietary deficiencies may have a profound effect on the limbic system; whereas dietary sufficiency in women may potentiate the mesocortical regulation of the limbic system. DISCUSSION AND CONCLUSION: Our results may explain the several reports in the literature that women are at a greater risk for mental distress when compared to men and emphasize the role of a nutrient-dense diet in mental wellbeing. PMID- 30028277 TI - Kinetic modelling of total petroleum hydrocarbon in spent lubricating petroleum oil impacted soil under different treatments. AB - The integration of first and second order kinetic model in parameter estimation for the degradation pattern of total petroleum hydrocarbon (TPH) in spent lubricating petroleum oil (SLPO) over a four-month period was the subject of the present investigation. Study design considered four treatment microcosms notably; sewage sludge (SB), monitored natural recovery (MNR), surfactant (SA) and control (SO). The rate of TPH degradation using sewage sludge as amendment material depicted effective TPH removal within ten weeks. A maximum allowable concentration of residual TPH (4300 mg kg-1) was obtained through an amendment with sewage sludge. Degradation constant (k) produced by both first and second order rates significantly demonstrated the performance of sewage sludge biomass over the other three treatments applied, however, experimental data adequately fitted into the first order kinetics (k = 0.27 d-1, t1/2 = 3.0 d). TPH removal efficiency of sewage sludge and detergent were 96.0% and 81.0% respectively. The use of sewage sludge biomass significantly (p < .05) improved soil biological characteristics and produced optimum dehydrogenase activity (DHA >= 8.8 TPFg-1 d), germination index (%IG >= 88%), and chlorophyll content (chl >= 100 ug cm-2), thus, recommended for field scale application in soil hydrocarbon pollution remediation. PMID- 30028278 TI - How to identify suitable ways for the hydrothermal treatment of wet bio-waste? A critical review and methods proposal. AB - A considerable amount of wet biogenic residues and waste has no resource efficient use in several European countries yet. Hydrothermal processes (HTP) seem to be promising for treating such biomass as they best work with substrates with 70% to 90% water content. However, thus far the suitability of HTP for this purpose has not been sufficiently evaluated, for which this work aims to identify suitable multi-criteria analysis (MCA) methods that can be used to identify promising ways for the hydrothermal treatment of wet bio-waste. A review on 31 recent MCA studies in bio-waste management was conducted with the aim of comparing them to methodological requirements for evaluating HTP. Furthermore, an MCA approach for HTP based on the review findings is proposed. Results show that no observed MCA method is directly transferable for assessing HTP, for which a customized approach combining the analytical hierarchy process and the technique for order preference by similarity to ideal solutions is proposed and preliminarily validated with literature data. These preliminary calculations indicate that hydrothermal gasification seems most promising under consideration of multiple criteria using the available average and exemplary data. However, needless to say there is still a long way to go to obtain the sufficient adequate data to validate and use the model appropriately, for which further studies are necessary to acquire more reliable data and to assess also future technology developments of HTP. PMID- 30028279 TI - Review of Desulfotomaculum species and proposal of the genera Desulfallas gen. nov., Desulfofundulus gen. nov., Desulfofarcimen gen. nov. and Desulfohalotomaculum gen. nov. AB - The genus Desulfotomaculumis a heterogeneous group of spore-forming sulfate reducing bacteria. The type species of the genus is Desulfotomaculum nigrificans (Approved Lists 1980) emend. Visser et al. 2014. The results of phylogenetic analysis demonstrated that the genus Desulfotomaculum already has lost the clustering monophyly and was segregated into some distinct groups with low sequence similarity. Major features of the type strains in these groups were compared, and four novel genera, Desulfallas gen. nov., Desulfofundulus gen. nov., Desulfofarcimen gen. nov. and Desulfohalotomaculum gen. nov. were proposed to accommodate species transferred from the genus Desulfotomaculum. PMID- 30028280 TI - Pueribacillus theae gen. nov., sp. nov., isolated from Pu'er tea. AB - A novel bacterial strain, designated T8T, isolated from ripened Pu'er tea, was investigated by using a polyphasic taxonomic approach. Cells stained Gram positive and were aerobic, sporogenous and rod-shaped with flagella. Phylogenetic analysis of 16S rRNA gene sequences revealed the strain belonged to the family Bacillaceae in the class Bacilli and represented an independent taxon separated from other genera. Strain T8T shared low levels of 16S rRNA gene sequence similarity (<94 %) to members of other genera in the family Bacillaceae and was most closely related to Bacillus composti SgZ-9T (93.3 % sequence similarity). The DNA G+C content of strain T8T was 40 mol%. The major fatty acids (>10 %) of strain T8T were iso-C15 : 0 and iso-C16 : 0. The strain had a cell-wall type A1gamma peptidoglycan with meso-diaminopimelic acid as the diagnostic diamino acid. MK-7 (62 %), MK-6 (31 %) and MK-8 (7 %) were detected as the isoprenoid quinones. The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylmethylethanolamine and six unidentified phospholipids. On the basis of the polyphasic evidence presented, strain T8T is considered to represent a novel genus and species in the family Bacillaceae, for which we propose the name Pueribacillus theae gen. nov., sp. nov. The type strain is T8T (=CGMCC 1.15924T=KCTC 333888T). PMID- 30028281 TI - Zhengella mangrovi gen. nov., sp. nov., a novel member of family Phyllobacteriaceae isolated from mangrove sediment. AB - A Gram-negative strain, designed X9-2-2T, was isolated from mangrove sediment in Yunxiao Mangrove National Nature Reserve, China. Strain X9-2-2T showed less than 96.2 % 16S rRNA gene sequence similarity to type strains of species with validly published names. Phylogenetic analysis based on 16S rRNA gene sequences and rpoB protein sequences revealed that strain X9-2-2T formed a distinct monophyletic clade within the family Phyllobacteriaceae and clustered distantly with the genera Aliihoeflea, Phyllobacterium and Hoeflea. Cells of X9-2-2T were rod shaped, motile with subpolar or lateral flagella and facultative anaerobic. Optimal growth occurred at 30-37 degrees C, at pH 7 and in the presence of 2 % NaCl. The DNA G+C content of strain X9-2-2T was 64.9 mol%. The major fatty acids were summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c 56.0 %), iso -C17 : 0 (9.1 %) and C12 : 0 (6.6 %). The predominant respiratory quinone was ubiquinone-10 and the major polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylmonomethylethanolamine, an unidentified aminolipid and two unidentified polar lipids. According to its morphology, physiology, fatty acid composition and 16S rRNA gene signature nucleotide patterns, strain X9-2-2T represents a novel species of a novel genus in the family Phyllobacteriaceae, for which the name Zhengella mangrovi gen. nov., sp. nov. is proposed. The type strain is X9-2-2T (=MCCC 1K03307T=JCM 32107T). PMID- 30028282 TI - Thalassorhabdus alkalitolerans gen. nov., sp. nov., a novel Bacillaceae member isolated from marine sediment. AB - A novel Gram-stain-variable, rod-shaped, non-motile and non-endospore-forming bacterium (strain G27T) was isolated from near Dhuvaran, Gujarat, India. Based on 16S rRNA gene sequence analysis, strain G27T was identified as a member of the class Firmibacteria and was most closely related to Bacillus populi FJAT-45347T (94.9 % sequence similarity), Salipaludibacillus aurantiacus S9T (94.9 %), Salipaludibacillus neizhouensis KCTC 13187T (94.7 %), Alteribacillus iranensis DSM 23995T (94.6 %) and other Firmibacteria (<94.6 %). The DNA G+C content of strain G27T was 43.4+/-0.6 mol%. The cell-wall peptidoglycan contained meso diaminopimelic acid. Polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid and five unidentified lipids. The predominant isoprenoid quinone was menaquinone MK 7. Major fatty acids (>5 %) included anteiso-C15:0, iso-C15 : 0, anteiso-C17:0, C16 : 0 and iso-C16 : 0. The results of phylogenetic, chemotaxonomic and biochemical tests allowed the clear differentiation of strain G27T from all other members of the family Bacillaceae.It is therefore considered to represent a novel species of a new genus, for which the name Thalassorhabdus alkalitolerans gen. nov., sp. nov., is proposed. The type strain of Thalassorhabdus alkalitolerans is G27T (=MCC 3411T=CGMCC 1.15772T=KCTC 33941T). PMID- 30028283 TI - Clostridium beihaiense sp. nov., an anaerobic bacterium isolated from activated sludge. AB - A Gram-positive, strictly anaerobic, rod-shaped bacterium, designated YB-7T, was isolated from activated sludge of an anaerobic baffled reactor pond in Weizhou terminal wastewater treatment plant, Beihai, Guangxi, China. Strain YB-7T grew at pH 5.0-12.0 (optimum, pH 7.0), 20-45 degrees C (37 degrees C) and NaCl concentration of 0-5 % w/v (optimum, 5 %). 16S rRNA gene sequence analysis results showed that strain YB-7T belonged to the genus Clostridium and it was most closely related to Clostridium tetanomorphum DSM 4474T (96.9 % similarity). The DNA-DNA relatedness of strain YB-7T to Clostridium tetanomorphum DSM 4474T was 47.4 %. The DNA G+C content of strain YB-7T was determined to be 32.3 mol%, and the predominant cellar fatty acid (>10 %) was C16 : 0. Polar lipids of strain YB-7T included diphosphatidylglycerol, phosphatidylethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, two unidentified aminophospholipids, two unidentified phospholipids and unidentified lipids. The results of this study supported the conclusion that strain YB-7T should be assigned to a new member of the genus Clostridium, for which the name Clostridium beihaiense sp. nov. is proposed. The type strain is YB-7T (=CICC 24109T=KCTC 15555T). PMID- 30028284 TI - Chromobacterium pseudoviolaceum Kampfer et al. 2009 is a later heterotypic synonym of Chromobacterium violaceum Bergonzini 1880. AB - Published data on the genome sequences of Chromobacterium pseudoviolaceum LMG 3953T and Chromobacterium violaceum ATCC 12472T suggest that both isolates belong to the same species. Previous 16S rRNA gene sequence comparisons had demonstrated that these species share 99.9 % sequence similarity. Initial investigations of fatty acid patterns and substrate utilization had shown only a few differences between the type strains of both species. Despite the 47.5 % homology by DNA-DNA hybridization studies between these strains, in silico whole genome sequence comparisons have clearly demonstrated that OrthoANIu and Mash/MinHash values were >99.18 %. Molecular phylogeny based on the estimated phylogenetic positions of the published genome sequences of the two type strains, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analyses indicate that these strains are members of the same species. Due to priority of publication and validation of names, Chromobacterium pseudoviolaceum is reclassified as Chromobacterium violaceum. PMID- 30028285 TI - Shewanella saliphila sp. nov., Shewanella ulleungensis sp. nov. and Shewanella litoralis sp. nov., isolated from coastal seawater. AB - Three Gram-negative, non-spore-forming, rod-shaped and motile bacterial strains, designated MMS16-UL250T, MMS16-UL253T and MMS16-UL482T, were isolated from coastal seawater and subjected to taxonomic characterization. All isolates grew at 4-30 degrees C (optimum, 25 degrees C), at pH 6-10 (pH 7) and in the presence of up to 8 % NaCl (2.5-4.5 %). The 16S rRNA gene sequence similarities between the three isolates and Shewanella algicola St-6T, the closest species, were 98.1-99.2 %, and those among the isolates were 98.5-99.0 %. In the phylogenetic tree, MMS16-UL250T formed a cluster with S. algicola St-6T, but the DNA-DNA relatedness between the two strains was 28.8+/-1.5 %, thus confirming their separation at species level. The other two strains formed separate phylogenetic lines respectively. The main quinones for all strains were Q-7, Q-8, MK-7 and MMK-7, which is typical for Shewanella. The major polar lipids of all strains were phosphatidylglycerol and phosphatidylethanolamine, and the common major fatty acid was a summed feature consisting of C16 : 1omega7c and/or C16 : 1omega6c while the proportions varied among the three strains. The DNA G+C contents of the strains also varied between 42.1 and 43.7 mol%. Phenotypic properties distinguished each strain from S. algicola as well as from one another. Based on the polyphasic analysis, each strain is considered to represent a novel species of Shewanella, for which the names Shewanellasaliphila sp. nov. (type strain, MMS16-UL250T=KCTC 62131T=JCM 32304T), Shewanella ulleungensis sp. nov. (type strain, MMS16-UL253T=KCTC 62130T=JCM 32305T) and Shewanella litoralis sp. nov. (type strain, MMS16-UL482T=KCTC 62129T=JCM 32306T) are proposed. PMID- 30028286 TI - Nocardioides currus sp. nov., isolated from a mobile car air-conditioning system. AB - A strictly aerobic Gram-stain-positive bacterial strain, designated IB-3T, was isolated from a car air-conditioning system in the Republic of Korea. Cells were non-motile rods showing catalase- and oxidase-positive reactions. Growth of IB-3T was observed at 20-40 degrees C (optimum, 25 degrees C), at pH 6.5-9.0 (optimum, pH 7.5) and in the presence of 0-1 % (w/v) NaCl (optimum, 0 %). Menaquinone-8 (H4) was detected as the predominant respiratory quinone and iso C16 : 0, 10-methyl-C17 : 0, iso-C17 : 0, C18 : 1omega9c, C17 : 1omega8c, C18 : 0, 10-methyl-C18 : 0 (TBSA) and C17 : 0 were identified as the major cellular fatty acids. Phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine and phosphatidylinositol were detected as the major polar lipids. The major cell wall peptidoglycan type was ll-2,6-diaminopimelic acid. The G+C content of the genomic DNA was 71.5 mol%. IB-3T was most closely related to Nocardioides terrigenaDS-17T with a 98.0 % 16S rRNA gene sequence similarity. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that IB-3T formed a distinct phylogenetic lineage within the genus Nocardioidesof the family Nocardioidaceae. On the basis of the phenotypic, chemotaxonomic and molecular features, IB-3T represents a novel species of the genus Nocardioides, for which the name Nocardioidescurrus sp. nov. is proposed. The type strain is IB-3T (=KACC 19522T=JCM 32672T). PMID- 30028287 TI - Hymenobacter rufus sp. nov., a bacterium isolated from soil. AB - A bacterial strain, S1-2-2-6T, was isolated from a soil sample collected in Jeollabuk-do province, Republic of Korea. Cells of this strain were observed to be Gram-stain-negative, short and rod-shaped, and colonies were red to pink in colour. Analysis of 16S rRNA gene sequences identified this strain as representing a member of the genus Hymenobacter in the family Cytophagaceae, with the highest levels of sequence similarity being observed in relation to Hymenobacter terrae DG7AT (98.2 %), Hymenobacter rubidus DG7BT (97.9 %), Hymenobacter soli PB17T (97.7 %), and Hymenobacter daeguensis 16F3Y-2T (97.3 %). Growth of S1-2-2-6T was observed at 4-30 degrees C, pH 6-8 and in the presence of 0-0.5 % NaCl. The predominant respiratory quinone of this strain was menaquinone-7, the major fatty acids were C15 : 0 iso, C15 : 0 anteiso, and Summed feature 3 (C16 : 1omega7c/C16 : 1omega6c), and the major polar lipid was phosphatidylethanolamine. The genomic DNA G+C content of S1-2-2-6T was 60.7 mol%. DNA-DNA hybridization experiments with H. terrae, H. rubidus, H. soli and H. daeguensisresulted in relatedness values of 35.9 and 38.4 %, 34.2 and 30.4 %, 28.3 and 33.1 %, and 23.5 and 27.9 %, respectively. These DNA-DNA hybridization results, in addition to some differentiating phenotypic properties, clearly indicate that S1-2-2-6T is a representative of a novel species of the genus Hymenobacter, for which the name Hymenobacter rufus sp. nov. is proposed. The type strain is S1-2-2-6T (=KCTC 52736T=JCM 32196T). PMID- 30028288 TI - Rhizobium wuzhouense sp. nov., isolated from roots of Oryza officinalis. AB - Three bacterial isolates, designated W44T, W15 and W11, were isolated from the root of Oryza officinalis grown in Wuzhou, China. These isolates were Gram negative, aerobic, motile and rod-shaped; demonstrated cellulase and urea activities; and formed cream-coloured colonies. The 16S rRNA gene sequence analysis indicated that the similarities between strain W44T and strains W15 and W11 were 100 %; all of them belonged to the genus Rhizobium and had the highest sequence similarity to Rhizobium rosettiformans W3T (98.7 %), followed by Rhizobium ipomoeae shin9-1T (98.2 %). Sequencing of housekeeping genes (recA, atpD, rpoB and glnA) of the novel isolates revealed similarities to members of established Rhizobium species to be less than 94.3 %. The values of DNA-DNA hybridization between strain W44T and the reference strains (R. rosettiformans W3T and R. ipomoeae shin9-1T) were 41.3 and 29.2 %, respectively. The major cellular fatty acid of strain W44T was summed feature 8 (C18 : 1omega9t and/or C18 : 1omega9c and/or C18 : 1omega7c). The polar lipid profile of strain W44T consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified lipids and two unidentified aminophospholipids. The G+C content of strain W44T was 62.4 mol%. In nodulation tests, none of the three strains could induce nodule formation in Glycine max, Phaseolus vulgaris or Medicago sativa. The nodulation gene (nodA), nitrogenase reductase gene (nifH) and virulence gene (virC) were not detected by PCR in these strains. Based on the above results and phenotypic features, a novel species, Rhizobium wuzhouense sp. nov., is proposed, with strain W44T (=CCTCC AB 2017179T=GDMCC 1.1257T=KCTC 62194T) as the type strain. PMID- 30028289 TI - Morphologic and molecular characterization of Brachonella pulchra (Kahl, 1927) comb. nov. (Armophorea, Ciliophora) with comments on cyst structure and formation. AB - In this article we provide morphologic and morphometric data based on in vivo observation, protargol impregnation, scanning electron microscopy and an 18S rRNA gene sequence for another member of the genus Brachonella, Brachonella pulchra comb. nov. (basionym: Metopus pulcher Kahl, 1927). We also provide preliminary data on resting cyst structure and formation in Brachonella pulchra and discuss the possible taxonomic usefulness of these structures. PMID- 30028290 TI - Thalassospira marina sp. nov., isolated from surface seawater. AB - Two novel marine bacteria, designated strains CSC3H3T and CSC1P2, were isolated from surface seawater of the South China Sea. Both strains were Gram-negative, oxidase-positive, catalase-positive, curved rods and motile. They grew at 10-40 degrees C, pH 5-10 and in the presence of 0-15 % (w/v) NaCl. Their 16S rRNA gene sequences were identical to each other. Phylogenetic analysis based on 16S rRNA gene sequences indicated that they belong to the genus Thalassospira, and shared 97.5-98.3 % sequence similarity to all other validly type strains of the genus Thalassospira, and the highest similarity was to the type strain Thalassospira povalilyticaZumi 95T (98.3 %), followed by Thalassospira australica NP3b2T (98.2 %). The digital DNA-DNA hybridization value between the two strains was 80.4 %, while the values with T. povalilyticaZumi 95T and T. australica NP3b2T were only 20.5-20.7 % and 20.4-20.5 %, respectively. The two strains possess similar major cellular fatty acids including C18 : 1omega7c, C16 : 0, C19 : 0omega8c cyclo, C18 : 1 2-OH and C17 : 0 cyclo. The G+C contents of the chromosomal DNA of strains CSC3H3T and CSC1P2 were 54.6 and 54.5 mol%, respectively. The major respiratory quinone was ubiquinone 10. Phosphatidylethanolamine, phosphatidylglycerol and several unidentified phospholipids, aminolipid and lipids were present in both strains. Based on phenotypic and genotypic characteristics, the two strains represent a novel species within the genus Thalassospira, for which the name Thalassospira marina sp. nov. is proposed. The type strain is CSC3H3T (=MCCC 1A11786T=KCTC 62333T). PMID- 30028291 TI - Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures. AB - Cyclic nucleotide-modulated channels have important roles in visual signal transduction and pacemaking. Binding of cyclic nucleotides (cAMP/cGMP) elicits diverse functional responses in different channels within the family despite their high sequence and structure homology. The molecular mechanisms responsible for ligand discrimination and gating are unknown due to lack of correspondence between structural information and functional states. Using single particle cryo electron microscopy and single-channel recording, we assigned functional states to high-resolution structures of SthK, a prokaryotic cyclic nucleotide-gated channel. The structures for apo, cAMP-bound, and cGMP-bound SthK in lipid nanodiscs, correspond to no, moderate, and low single-channel activity, respectively, consistent with the observation that all structures are in resting, closed states. The similarity between apo and ligand-bound structures indicates that ligand-binding domains are strongly coupled to pore and SthK gates in an allosteric, concerted fashion. The different orientations of cAMP and cGMP in the 'resting' and 'activated' structures suggest a mechanism for ligand discrimination. PMID- 30028293 TI - Parvovirus minute virus of mice interacts with sites of cellular DNA damage to establish and amplify its lytic infection. AB - We have developed a generally adaptable, novel high-throughput Viral Chromosome Conformation Capture assay (V3C-seq) for use in trans that allows genome-wide identification of the direct interactions of a lytic virus genome with distinct regions of the cellular chromosome. Upon infection, we found that the parvovirus Minute Virus of Mice (MVM) genome initially associated with sites of cellular DNA damage that in mock-infected cells also exhibited DNA damage as cells progressed through S-phase. As infection proceeded, new DNA damage sites were induced, and virus subsequently also associated with these. Sites of association identified biochemically were confirmed microscopically and MVM could be targeted specifically to artificially induced sites of DNA damage. Thus, MVM established replication at cellular DNA damage sites, which provide replication and expression machinery, and as cellular DNA damage accrued, virus spread additionally to newly damaged sites to amplify infection. MVM-associated sites overlap significantly with previously identified topologically-associated domains (TADs). PMID- 30028292 TI - Cell-intrinsic and -extrinsic mechanisms promote cell-type-specific cytokinetic diversity. AB - Cytokinesis, the physical division of one cell into two, is powered by constriction of an actomyosin contractile ring. It has long been assumed that all animal cells divide by a similar molecular mechanism, but growing evidence suggests that cytokinetic regulation in individual cell types has more variation than previously realized. In the four-cell Caenorhabditis elegans embryo, each blastomere has a distinct cell fate, specified by conserved pathways. Using fast acting temperature-sensitive mutants and acute drug treatment, we identified cell type-specific variation in the cytokinetic requirement for a robust forminCYK-1 dependent filamentous-actin (F-actin) cytoskeleton. In one cell (P2), this cytokinetic variation is cell-intrinsically regulated, whereas in another cell (EMS) this variation is cell-extrinsically regulated, dependent on both SrcSRC-1 signaling and direct contact with its neighbor cell, P2. Thus, both cell intrinsic and -extrinsic mechanisms control cytokinetic variation in individual cell types and can protect against division failure when the contractile ring is weakened. PMID- 30028297 TI - To unsubscribe, please click here. PMID- 30028298 TI - Late clinical outcome of suboptimal stent implantation defined by intracoronary optical coherence tomography. PMID- 30028294 TI - Novel functions for integrin-associated proteins revealed by analysis of myofibril attachment in Drosophila. AB - We use the myotendinous junction of Drosophila flight muscles to explore why many integrin associated proteins (IAPs) are needed and how their function is coordinated. These muscles revealed new functions for IAPs not required for viability: Focal Adhesion Kinase (FAK), RSU1, tensin and vinculin. Genetic interactions demonstrated a balance between positive and negative activities, with vinculin and tensin positively regulating adhesion, while FAK inhibits elevation of integrin activity by tensin, and RSU1 keeps PINCH activity in check. The molecular composition of myofibril termini resolves into 4 distinct layers, one of which is built by a mechanotransduction cascade: vinculin facilitates mechanical opening of filamin, which works with the Arp2/3 activator WASH to build an actin-rich layer positioned between integrins and the first sarcomere. Thus, integration of IAP activity is needed to build the complex architecture of the myotendinous junction, linking the membrane anchor to the sarcomere. PMID- 30028296 TI - Residential Surrounding Greenness and Cognitive Decline: A 10-Year Follow-up of the Whitehall II Cohort. AB - BACKGROUND: Evidence on beneficial associations of green space with cognitive function in older adults is very scarce and mainly limited to cross-sectional studies. OBJECTIVES: We aimed to investigate the association between long-term residential surrounding greenness and cognitive decline. METHODS: This longitudinal study was based on three waves of data from the Whitehall II cohort, providing a 10-y follow-up (1997-1999 to 2007-2009) of 6,506 participants (45-68 y old) from the United Kingdom. Residential surrounding greenness was obtained across buffers of 500 and around the participants' residential addresses at each follow-up using satellite images on greenness (Normalized Difference Vegetation Index; NDVI) from a summer month in every follow-up period. Cognitive tests assessed reasoning, short-term memory, and verbal fluency. The cognitive scores were standardized and summarized in a global cognition z-score. To quantify the impact of greenness on repeated measurements of cognition, linear mixed effect models were developed that included an interaction between age and the indicator of greenness, and controlled for covariates including individual and neighborhood indicators of socioeconomic status (SES). RESULTS: In a fully adjusted model, an interquartile range (IQR) increase in NDVI was associated with a difference in the global cognition z-score of 0.020 [95% confidence interval (CI): 0.003, 0.037; p=0.02] in the 500-m buffer and of 0.021 (95% CI: 0.003, 0.039; p=0.02) in the 1,000-m buffer over 10 y. The associations with cognitive decline over the study period were stronger among women than among men. CONCLUSIONS: Higher residential surrounding greenness was associated with slower cognitive decline over a 10-y follow-up period in the Whitehall II cohort of civil servants. https://doi.org/10.1289/EHP2875. PMID- 30028299 TI - The promise of vascular reparative therapy in standby mode. How long before a final decision? Complete vessel wall regeneration and vascular scaffold resorption after left anterior descending reconstructions. PMID- 30028295 TI - A Rho signaling network links microtubules to PKD controlled carrier transport to focal adhesions. AB - Protein kinase D (PKD) is a family of serine/threonine kinases that is required for the structural integrity and function of the Golgi complex. Despite its importance in the regulation of Golgi function, the molecular mechanisms regulating PKD activity are still incompletely understood. Using the genetically encoded PKD activity reporter G-PKDrep we now uncover a Rho signaling network comprising GEF-H1, the RhoGAP DLC3, and the Rho effector PLCepsilon that regulate the activation of PKD at trans-Golgi membranes. We further show that this molecular network coordinates the formation of TGN-derived Rab6-positive transport carriers delivering cargo for localized exocytosis at focal adhesions. PMID- 30028300 TI - Valve-in-valve TAVR using the SAPIEN 3 transcatheter heart valve: still plagued by patient-prosthesis mismatch. PMID- 30028301 TI - TAVI durability beyond five years: no alarms, but stay alert. PMID- 30028303 TI - What is new in the armamentarium of coronary surgeons to compete with PCI? PMID- 30028302 TI - Navigating the complexity of percutaneous coronary intervention in patients at high risk for bleeding. PMID- 30028304 TI - Extended benefits of TAVR in young patients with low-intermediate risk score: proceed with care. PMID- 30028305 TI - Reply to the letter to the editor by Doshi regarding the article "In-hospital outcomes after transcatheter or surgical aortic valve replacement in younger patients less than 75 years old: a propensity-matched comparison". PMID- 30028307 TI - Bias in Contraceptive Provision to Young Women Among Private Health Care Providers in South West Nigeria. AB - CONTEXT: Health care providers' biases regarding the provision of contraceptives to adolescent and young adult women may restrict women's access to contraceptive methods. METHODS: Two mystery client visits were made to each of 52 private sector health care facilities and individual providers in South West Nigeria in June 2016. In one visit, the mystery client portrayed an unmarried, nulliparous adolescent, and in the other, the client portrayed a married adult woman with two children. During subsequent in-depth interviews, providers were read vignettes describing hypothetical clients with these same profiles, and were asked how they would interact with each. Descriptive analyses of mystery client interactions were combined with thematic analyses of the interview data. RESULTS: In greater proportions of married-profile visits than of unmarried-profile visits, mystery clients reported that providers had asked about past contraceptive use and method preference; the opposite was true in regard to providers' using side effects to dissuade clients from practicing contraception. In in-depth interviews, providers expressed concerns about fertility loss among unmarried women who used hormonal contraceptives. Providers more commonly recommended condoms, emergency contraception and the pill for unmarried clients, and longer-acting methods for married clients. The restriction of methods was typically explained by providers of various backgrounds in terms of protecting younger, unmarried clients from damaging their fertility. CONCLUSIONS: Provider bias in the provision of contraceptives to adolescent and young adult women in South West Nigeria may affect quality of care and method choice. Interventions to reduce provider bias should go beyond technical training to address the underlying sociocultural beliefs that lead providers to impose restrictions that are not based on evidence. PMID- 30028306 TI - Benefits and Challenges of Safer-Conception Counseling for HIV Serodiscordant Couples in Uganda. AB - CONTEXT: Safer-conception counseling may help people living with HIV to reduce the risk of transmission to partners and children. However, such counseling is rarely offered or evaluated in low-income countries. METHODS: In 2014-2015, in depth qualitative interviews were conducted at a Ugandan HIV clinic with 42 HIV positive clients and 16 uninfected partners who had participated in a safer conception counseling intervention for serodiscordant couples seeking to have a child. Participants attended up to six monthly counseling sessions in which they received instruction and ongoing support in using the safer-conception method they selected. Content analysis of interview transcripts was used to identify themes related to the benefits and challenges of safer-conception counseling. RESULTS: Almost two-thirds of participants felt that safer-conception counseling was an empowering experience that enabled them to make informed choices regarding childbearing, learn how to conceive safely and understand how to stay healthy while trying to conceive. Timed unprotected intercourse was the most frequently used safer-conception method. Seven couples had successful pregnancies, and no uninfected partners seroconverted. Participants' primary concerns and challenges regarding counseling and method use were issues with manual self-insemination, difficulty with engaging partners and fear of HIV infection. CONCLUSIONS: Counseling can help HIV-infected individuals make informed choices about childbearing and safer-conception methods; however, a controlled clinical trial is needed to determine whether clients use such methods correctly and to assess rates of pregnancy and transmission. Policymakers need to consider including safer-conception counseling as part of routine HIV care. PMID- 30028308 TI - Antiviral effects of Cacicol(r), a heparan sulfate biomimetic for corneal regeneration therapy, for herpes simplex virus type-1 and varicella zoster virus infection. AB - BACKGROUND: Cacicol(r), a topical eye biopolymer containing a poly carboxymethylglucose sulfate solution that is a regenerating matrix therapy agent, intended for wound healing of persistent corneal epithelial defects. Based on the chemical composition, we hypothesized that Cacicol(r) may compete with natural heparan sulfate (HS) which initiates cell surface attachment of herpes simplex virus type-1 (HSV-1), varicella zoster virus (VZV) and human adenovirus (HAdV), three viruses associated with corneal infections. METHODS: Cacicol(r) was compared to vehicle in the following viral strains: HSV-1 SC16 strain and HSV-1 PSLR, a clinical isolate highly resistant to acyclovir and foscarnet; VZV ATH and VZV FLO, two VZV clinical isolates; and HAdV-D37 strain. Viruses in Cacicol(r) or vehicle were added to cells for 1 h during adsorption then viral replication was assessed by plaque reduction assays on Vero cells for HSV-1 and MeWo cells for VZV and by immunostaining assay on Hep-2 cells for HAdV-D37. RESULTS: The vehicle had no effect, dose-dependent effects were demonstrated when HSV-1 SC16, HSV-1 PSLR, VZV ATH and VZV FLO were inoculated in the presence of Cacicol(r), inhibiting viral replication by 98.4%, 98.9%, 90.1% and 89.0%, respectively. Cacicol(r) had no antiviral effect against HAdV-D37. CONCLUSIONS: Cacicol(r) has a significant antiviral activity on HSV-1 and VZV, but not on HAdV-D37. The lack of effect on HAdV is probably because it is less dependent on HS interactions for cell entry. Clinical studies are necessary to determine Cacicol(r) for an adjunct or alternative therapy of corneal HSV-1 or VZV infection, particularly for the management of antiviral resistant HSV-1. PMID- 30028309 TI - Natural melanin-loaded nanovesicles for near-infrared mediated tumor ablation by photothermal conversion. AB - Photothermal therapy requires a biocompatible material to absorb near-infrared (NIR) light and generate sufficient heat. Herein, we suggest natural melanin loaded nanovesicles (melasicles) as photothermal therapeutic agents (PTA) for NIR mediated cancer therapy in vivo. The mean size of these melasicles was 140 +/- 15 nm. They showed excellent colloidal stability. After irradiation from 808 nm NIR laser at 1.5 W cm-2, the melasicles showed good photothermal conversion efficiencies both in vitro and in vivo. In drug release study, laser irradiation increased fluidity of vesicle membrane due to photothermal generation from melanin. Initial drug release in the laser irradiation group was higher than that in the no laser irradiation group. After injecting the melasicles into tail veins of CT-26 bearing mice, tumors were suppressed or eliminated after irradiation at 1.5 W cm-2 for 5 min once or twice. These results suggest that melasicles could be used as attractive PTA for cancer therapy and localized drug release. PMID- 30028310 TI - Optimized poly(methyl methacrylate)-mediated graphene-transfer process for fabrication of high-quality graphene layer. AB - Graphene grown on a copper (Cu) substrate by chemical vapor deposition (CVD) is typically required to be transferred to another substrate for the fabrication of various electrical devices. PMMA-mediated wet process is the most widely used method for CVD-graphene-transfer. However, PMMA residue and wrinkles that inevitably remain on the graphene surface during the transfer process are critical issues degrading the electrical properties of graphene. In this paper, we report on a PMMA-mediated graphene-transfer method that can effectively reduce the density and size of the PMMA residue and the height of wrinkles on the transferred graphene layer. We found out that acetic acid is the most effective PMMA stripper among the typically used solutions to remove the PMMA residue. In addition, we observed that an optimized annealing process can reduce the height of the wrinkles on the transferred graphene layer without degrading the graphene quality. The effects of the suggested wet transfer process were also investigated by evaluating the electrical properties of field-effect transistors fabricated on the transferred graphene layer. The results of this work will contribute to the development of fabrication processes for high-quality graphene devices, given that the transfer of graphene from the Cu substrate is essential process to the application of CVD-graphene. PMID- 30028311 TI - The impact of hypoxic-ischemic brain injury on stem cell mobilization, migration, adhesion, and proliferation. AB - Neonatal hypoxic-ischemic encephalopathy continues to be a significant cause of death or neurodevelopmental delays despite standard use of therapeutic hypothermia. The use of stem cell transplantation has recently emerged as a promising supplemental therapy to further improve the outcomes of infants with hypoxic-ischemic encephalopathy. After the injury, the brain releases several chemical mediators, many of which communicate directly with stem cells to encourage mobilization, migration, cell adhesion and differentiation. This manuscript reviews the biomarkers that are released from the injured brain and their interactions with stem cells, providing insight regarding how their upregulation could improve stem cell therapy by maximizing cell delivery to the injured tissue. PMID- 30028312 TI - Subcellular localization of alpha-synuclein aggregates and their interaction with membranes. AB - For more than a decade numerous evidence has been reported on the mechanisms of toxicity of alpha-synuclein (alphaS) oligomers and aggregates in alpha synucleinopathies. These species were thought to form freely in the cytoplasm but recent reports of alphaS multimer conformations when bound to synaptic vesicles in physiological conditions, have raised the question about where alphaS aggregation initiates. In this review we focus on recent literature regarding the impact on membrane binding and subcellular localization of alphaS toxic species to understand how regular cellular function of alphaS contributes to pathology. Notably alphaS has been reported to mainly associate with specific membranes in neurons such as those of synaptic vesicles, ER/Golgi and the mitochondria, while toxic species of alphaS have been shown to inhibit, among others, neurotransmission, protein trafficking and mitochondrial function. Strategies interfering with alphaS membrane binding have shown to improve alphaS-driven toxicity in worms and in mice. Thus, a selective membrane binding that would result in a specific subcellular localization could be the key to understand how aggregation and pathology evolves, pointing out to alphaS functions that are primarily affected before onset of irreversible damage. PMID- 30028313 TI - Glaucomatous optic neuropathy treatment options: the promise of novel therapeutics, techniques and tools to help preserve vision. AB - Peripheral vision loss followed by "tunnel vision" and eventual irreversible blindness is the fate of patients afflicted by various forms of glaucoma including primary open-angle glaucoma (POAG) and normotensive glaucoma (NTG). These complex and heterogeneous diseases are characterized by extensive death of retinal ganglion cells (RGCs) accompanied by retraction and severance of their axonal connections to the brain and thus damage to and thinning of the optic nerve. Since patients suffering from this glaucomatous optic neuropathy (GON) first notice visual impairment when they have lost > 40% of their RGCs, early diagnosis is the key to retard the progression of glaucoma. Elevated intraocular pressure (IOP), low cerebrospinal and/or low intracranial fluid pressure, advancing age, and ethnicity are major risk factors associated with POAG. However, retinal vascular abnormalities and a high sensitivity of RGCs and optic nerve head components to neurotoxic, inflammatory, oxidative and mechanical insults also contribute to vision loss in POAG/GON. Current treatment modalities for POAG and NTG involve lowering IOP using topical ocular drugs, combination drug products, and surgical interventions. Two recently approved multi pharmacophoric drugs (e.g., rho kinase inhibitor, Netarsudil; a drug conjugate, Latanoprostene Bunod) and novel aqueous humor drainage devices (iStent and CyPass) are also gaining acceptance for treating POAG/ NTG. Neuroprotective and regenerative agents, coupled with electroceutical, mechanical support systems, stem cell transplantation and gene therapy are emerging therapeutics on the horizon to help combat GON. The latter techniques and approaches hope to rejuvenate RGCs and repair the optic nerve structures, thereby providing a gain of function of the visual system for the glaucoma patients. PMID- 30028314 TI - Factors that modulate olfactory dysfunction. AB - The olfactory system is one of a few areas in the nervous system which is capable of regeneration throughout the life. Olfactory sensory neurons reside in the nasal cavity are continuously replenished with new neurons arising from stem cells. Some factors such as aging, neurodegenerative diseases, head trauma, brain tumor extraction and infection cause olfactory dysfunction which significantly influences physical wellbeing, quality of life, mental health, nutritional status, memory processes, identifying danger and is associated with increased mortality. Therefore, finding a treatment to improve olfactory dysfunction is needed. Recent research efforts in the field have shown some very promising new approaches to treat olfactory dysfunction. This review explores the current studies that have addressed therapeutic approaches to improve olfactory neuron regeneration based on cell transplantation therapy, modulation of physiological olfactory dysfunction and drug treatments. PMID- 30028315 TI - What can computational modeling offer for studying the Ca2+ dysregulation in Alzheimer's disease: current research and future directions. AB - Ca2+ dysregulation is an early event observed in Alzheimer's disease (AD) patients preceding the presence of its clinical symptoms. Dysregulation of neuronal Ca2+ will cause synaptic loss and neuronal death, eventually leading to memory impairments and cognitive decline. Treatments targeting Ca2+ signaling pathways are potential therapeutic strategies against AD. The complicated interactions make it challenging and expensive to study the underlying mechanisms as to how Ca2+ signaling contributes to the pathogenesis of AD. Computational modeling offers new opportunities to study the signaling pathway and test proposed mechanisms. In this mini-review, we present some computational approaches that have been used to study Ca2+ dysregulation of AD by simulating Ca2+ signaling at various levels. We also pointed out the future directions that computational modeling can be done in studying the Ca2+ dysregulation in AD. PMID- 30028317 TI - Amyloid beta and free heme: bloody new insights into the pathogenesis of Alzheimer's disease. AB - The cerebral formation of Amyloid beta (Abeta) is a critical pathological feature of Alzheimer's disease (AD). An accumulation of this peptide as senile plaques (SP) was already reported by Alois Alzheimer, the discoverer of the disease. Yet the exact contribution of Abeta to AD development remains elusive. Moreover, while extensive cerebral Abeta formation leads to fibril formation in many species, AD-like symptoms apparently depend on the highly conserved N-terminal residues R5, Y10 and H13. The amino acids were also shown to lead to the formation of Abeta-heme complexes, which exhibit peroxidase activity in the presence of H2O2. Taking together these observations we propose that the formation and enzymatic activity of the named complexes may represent an essential aspect of AD pathology. Furthermore, Abeta is also known to lead to cerebral micro-vessel destruction (CAA) as well as to hemolytic events. Thus we suggest that the Abeta-derived cerebral accumulation of blood-derived free heme represents a likely precondition for the subsequent formation of Abeta-heme complexes. PMID- 30028318 TI - Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage. AB - Aneurysmal subarachnoid hemorrhage remains devastating, and the most important determinant of poor outcome is early brain injury (EBI). In clinical settings, as a surrogate marker of EBI, loss of consciousness at ictus, poor initial clinical grades, and some radiographic findings are used, but these markers are somewhat subjective. Thus, it is imperative to find biomarkers of EBI that have beneficial prognostic and therapeutic implications. In our opinion, an ideal biomarker is a molecule that is implicated in the pathogenesis of both EBI and subsequently developing delayed cerebral ischemia (DCI), being a therapeutic target, and can be measured easily in the peripheral blood in an acute stage. A good candidate of such a biomarker is a matricellular protein, which is a secreted, inducible and multifunctional extracellular matrix protein. There are many kinds of matricellular proteins reported, but only tenascin-C, osteopontin, galectin-3 and periostin are reported relevant to EBI and DCI. Reliable biomarkers of EBI may stratify aneurysmal subarachnoid hemorrhage patients into categories of risk to develop DCI, and allow objective monitoring of the response to treatment for EBI and earlier diagnosis of DCI. This review emphasizes that further investigation of matricellular proteins as an avenue for biomarker discovery is warranted. PMID- 30028319 TI - Optimization of nanofiber scaffold properties towards nerve guidance channel design. PMID- 30028316 TI - Molecular mechanism of noradrenaline during the stress-induced major depressive disorder. AB - Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate. Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression. Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder (MDD) and several antidepressants functions by increasing the monoamine level at the synapses in the brain. However, it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant. Contrary to noradrenergic receptor stimulation, it has been suggested that the desensitization of beta adrenoceptor is involved in the therapeutic effect of antidepressant. In addition, enhanced noradrenaline (NA) release is central response to stress and thought to be a risk factor for the development of MDD. Moreover, fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus (LC). However, it is unclear how they alter the firing activity of LC neurons. These inconsistent reports about antidepressant effect of NA-reuptake inhibitors (NRIs) and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD. In this review, we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD. We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons, hypothalamic-pituitary-adrenal axis (HPA-axis) and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD. PMID- 30028320 TI - Vascular endothelial growth factor: an essential neurotrophic factor for motoneurons? PMID- 30028321 TI - Bone morphogenetic protein signaling: a promising target for white matter protection in perinatal brain injury. PMID- 30028322 TI - Neurodegenerative diseases are a function of matrix breakdown: how to rebuild extracellular matrix and intracellular matrix. PMID- 30028323 TI - Brain repair for Parkinson's disease: is the answer in the matrix? PMID- 30028324 TI - Developing biomarkers for neurodegenerative diseases using genetically-modified common marmoset models. PMID- 30028325 TI - Histone methylation in Huntington's disease: are bivalent promoters the critical targets? PMID- 30028326 TI - Lateral olfactory tract usher substance (LOTUS) protein, an endogenous Nogo receptor antagonist, converts a non-permissive to permissive brain environment for axonal regrowth. PMID- 30028327 TI - Houshiheisan and its components promote axon regeneration after ischemic brain injury. AB - Houshiheisan, a classic prescription in traditional Chinese medicine, contains Flos Chrysanthemi, Radix Saposhnikoviae, Ramulus Cinnamomi, Rhizoma Chuanxiong, Radix et Rhizoma Asari, Radix Platycodonis, Rhizoma Atractylodis macrocephalae, Poria, Rhizoma Zingiberis, Radix Angelicae sinensis, Radix et Rhizoma Ginseng, Radix Scutellariae and Concha Ostreae. According to traditional Chinese medicine theory, Flos Chrysanthemi, Radix Saposhnikoviae, Ramulus Cinnamomi, Rhizoma Chuanxiong, Radix et Rhizoma Asari and Radix Platycodonis are wind-dispelling drugs; Rhizoma Atractylodis macrocephalae, Poria, Rhizoma Zingiberis, Radix Angelicae sinensis and Radix et Rhizoma Ginseng are deficiency-nourishing drugs. A large number of randomized controlled trials have shown that Houshiheisan is effective in treating stroke, but its mechanism of action is unknown. Axonal remodeling is an important mechanism in neural protection and regeneration. Therefore, this study explored the effect and mechanism of action of Houshiheisan on the repair of axons after cerebral ischemia. Rat models of focal cerebral ischemia were established by ligating the right middle cerebral artery. At 6 hours after model establishment, rats were intragastrically administered 10.5 g/kg Houshiheisan or 7.7 g/kg wind-dispelling drug or 2.59 g/kg deficiency nourishing drug. These medicines were intragastrically administered as above every 24 hours for 7 consecutive days. Houshiheisan, and its wind-dispelling and deficiency-nourishing components reduced the neurological deficit score and ameliorated axon and neuron lesions after cerebral ischemia. Furthermore, Houshiheisan, and its wind-dispelling and deficiency-nourishing components decreased the expression of proteins that inhibit axonal remodeling: amyloid precursor protein, neurite outgrowth inhibitor protein A (Nogo-A), Rho family small GTPase A (RhoA) and Rho-associated kinase 2 (Rock2), and increased the expression of growth associated protein-43, microtubule-associated protein-2, netrin-1, Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42). The effect of Houshiheisan was stronger than wind-dispelling drugs or deficiency-nourishing drugs alone. In conclusion, Houshiheisan, and wind dispelling and deficiency-nourishing drugs promote the repair of axons and nerve regeneration after cerebral ischemia through Nogo-A/RhoA/Rock2 and Netrin 1/Rac1/Cdc42 signaling pathways. These effects are strongest with Houshiheisan. PMID- 30028328 TI - Ginkgolide B promotes the proliferation and differentiation of neural stem cells following cerebral ischemia/reperfusion injury, both in vivo and in vitro. AB - Neural stem cells have great potential for the development of novel therapies for nervous system diseases. However, the proliferation of endogenous neural stem cells following brain ischemia is insufficient for central nervous system self repair. Ginkgolide B has a robust neuroprotective effect. In this study, we investigated the cell and molecular mechanisms underlying the neuroprotective effect of ginkgolide B on focal cerebral ischemia/reperfusion injury in vitro and in vivo. Neural stem cells were treated with 20, 40 and 60 mg/L ginkgolide B in vitro. Immunofluorescence staining was used to assess cellular expression of neuron-specific enolase, glial fibrillary acid protein and suppressor of cytokine signaling 2. After treatment with 40 and 60 mg/L ginkgolide B, cells were large, with long processes. Moreover, the proportions of neuron-specific enolase-, glial fibrillary acid protein- and suppressor of cytokine signaling 2-positive cells increased. A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion. Six hours after ischemia, ginkgolide B (20 mg/kg) was intraperitoneally injected, once a day. Zea Longa's method was used to assess neurological function. Immunohistochemistry was performed to evaluate the proportion of nestin-, neuron-specific enolase- and glial fibrillary acid protein positive cells. Real-time quantitative polymerase chain reaction was used to measure mRNA expression of brain-derived neurotrophic factor and epidermal growth factor. Western blot assay was used to analyze the expression levels of brain derived neurotrophic factor and suppressor of cytokine signaling 2. Ginkgolide B decreased the neurological deficit score, increased the proportion of nestin-, neuron-specific enolase- and glial fibrillary acid protein-positive cells, increased the mRNA expression of brain-derived neurotrophic factor and epidermal growth factor, and increased the expression levels of brain-derived neurotrophic factor and suppressor of cytokine signaling 2 in the ischemic penumbra. Together, the in vivo and in vitro findings suggest that ginkgolide B improves neurological function by promoting the proliferation and differentiation of neural stem cells in rats with cerebral ischemia/reperfusion injury. PMID- 30028329 TI - Is transesophageal echocardiography needed for evaluating tissue-based transient ischemic attack? AB - Transient ischemic attack (TIA) is a warning signal for stroke. A comprehensive evaluation of TIA may reduce the risk for subsequent stroke. Data on the findings of cardiac evaluation with transesophageal echocardiography (TEE) in patients with TIA are sparse. Our aims were to determine the frequency of TEE performance and to investigate the findings of TEE in patients with TIA based on the new definition of TIA (i.e., transient neurological symptoms without evidence of infarction). During a 4-year period (2011-2014), 1071 patients (mean age, 70 +/- 13 years; female, 49.7%) with TIA were included in a prospective study and evaluated. Of 1071 consecutive patients suffering from TIA, 288 patients (27%) underwent TEE. The median time between admission and TEE was 6 days. Patients with TIA who were evaluated by TEE were younger (67 vs. 71 years, P < 0.001) than those who were not evaluated by TEE. They had a higher rate of sensibility disturbance as a TIA symptom (39% vs. 31%, P = 0.012) but a lower rate of previous stroke (15% vs. 25%, P = 0.001) and atrial fibrillation (2% vs. 21%, P < 0.001) than those who did not. Foramen ovale was detected in 71 patients (25.7%), atrial septal aneurysm in 13 patients (4.6%), and severe atherosclerotic plaques (grade 4 and 5) in the aortic arch in 25 patients (8.7%). One patient (0.3%) had a fibroma detected by TEE. In 17 of the 288 patients (6%) who underwent TEE, the indication for anticoagulation therapy was based on the TEE results, and 1 patient with fibroma underwent heart surgery. During hospitalization, 7 patients experienced a subsequent stroke, and 27 patients had a recurrent TIA. At 3 months following discharge, the rates of readmission, stroke, recurrent TIA, and death were 19%, 2.7%, 4.2%, and 1.6%, respectively. The rates of mortality (0.9% vs. 1.8%, P = 0.7), stroke risk (1.9% vs. 3.0%, P = 0.8), and recurrent TIA (5.0% vs. 3.9%, P = 0.8) were similar in patients who underwent TEE and in those who did not. Performing TEE in patients with tissue-based TIA is helpful in detecting cardiac sources for embolism and may indicate for anticoagulation. PMID- 30028330 TI - MicroRNA-219 alleviates glutamate-induced neurotoxicity in cultured hippocampal neurons by targeting calmodulin-dependent protein kinase II gamma. AB - Septic encephalopathy is a frequent complication of sepsis, but there are few studies examining the role of microRNAs (miRs) in its pathogenesis. In this study, a miR-219 mimic was transfected into rat hippocampal neurons to model miR 219 overexpression. A protective effect of miR-219 was observed for glutamate induced neurotoxicity of rat hippocampal neurons, and an underlying mechanism involving calmodulin-dependent protein kinase II gamma (CaMKIIgamma) was demonstrated. miR-219 and CaMKIIgamma mRNA expression induced by glutamate in hippocampal neurons was determined by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). After neurons were transfected with miR-219 mimic, effects on cell viability and apoptosis were measured by 3 (4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. In addition, a luciferase reporter gene system was used to confirm CaMKIIgamma as a target gene of miR-219. Western blot assay and rescue experiments were also utilized to detect CaMKIIgamma expression and further verify that miR-219 in hippocampal neurons exerted its effect through regulation of CaMKIIgamma. MTT assay and qRT-PCR results revealed obvious decreases in cell viability and miR-219 expression after glutamate stimulation, while CaMKIIgamma mRNA expression was increased. MTT, flow cytometry, and caspase-3 activity assays showed that miR-219 overexpression could elevate glutamate-induced cell viability, and reduce cell apoptosis and caspase-3 activity. Moreover, luciferase CaMKIIgamma-reporter activity was remarkably decreased by co-transfection with miR-219 mimic, and the results of a rescue experiment showed that CaMKIIgamma overexpression could reverse the biological effects of miR-219. Collectively, these findings verify that miR-219 expression was decreased in glutamate-induced neurons, CaMKIIgamma was a target gene of miR-219, and miR-219 alleviated glutamate-induced neuronal excitotoxicity by negatively controlling CaMKIIgamma expression. PMID- 30028331 TI - Chronic stress causes protein kinase C epsilon-aldehyde dehydrogenase 2 signaling pathway perturbation in the rat hippocampus and prefrontal cortex, but not in the myocardium. AB - Chronic stress is strongly associated with the occurrence and development of depression and cardiovascular disease. Stress can induce altered mitochondrial function and activation of apoptosis in the cardio-cerebral system. However, it is unknown whether the protein kinase C epsilon (PKCepsilon)-aldehyde dehydrogenase 2 (ALDH2) pathway is altered under chronic stress, and this study sought to address this question. A rat model of depression was established using a chronic unpredictable mild stress (CUMS) protocol. After experiencing CUMS for 4 weeks, the sucrose preference test and the forced swim test verified depressive like behaviors. Enzyme linked immunosorbent assays showed that ALDH2 activity was decreased in the rat hippocampus and prefrontal cortex, but was not altered in the myocardium. Western blot assays demonstrated reduced levels of ALDH2 and PKCepsilon, but increased levels of 4-hydroxy-2-nonenal (4HNE) adducts. Caspase-3 expression did not obviously alter, but active forms of caspase-3 were increased in the hippocampus and prefrontal cortex. In the myocardium, expression of ALDH2, PKCepsilon and 4HNE adducts did not remarkably alter; while caspase-3 expression was reduced and the active forms of caspase-3 were upregulated. Pearson's correlation test demonstrated that expression of 4HNE adducts was positively correlated with levels of the active forms of caspase-3 in the hippocampus and prefrontal cortex, but not in the myocardium. In conclusion, chronic stress can damage the PKCepsilon-ALDH2 signaling pathway in the hippocampus and prefrontal cortex, but not in the myocardium. Moreover, 4HNE is associated with active forms of caspase-3 in the hippocampus and prefrontal cortex. PMID- 30028332 TI - A partition-type tubular scaffold loaded with PDGF-releasing microspheres for spinal cord repair facilitates the directional migration and growth of cells. AB - The best tissue-engineered spinal cord grafts not only match the structural characteristics of the spinal cord but also allow the seed cells to grow and function in situ. Platelet-derived growth factor (PDGF) has been shown to promote the migration of bone marrow stromal cells; however, cytokines need to be released at a steady rate to maintain a stable concentration in vivo. Therefore, new methods are needed to maintain an optimal concentration of cytokines over an extended period of time to effectively promote seed cell localization, proliferation and differentiation. In the present study, a partition-type tubular scaffold matching the anatomical features of the thoracic 8-10 spinal cord of the rat was fabricated using chitosan and then subsequently loaded with chitosan encapsulated PDGF-BB microspheres (PDGF-MSs). The PDGF-MS-containing scaffold was then examined in vitro for sustained-release capacity, biocompatibility, and its effect on neural progenitor cells differentiated in vitro from multilineage differentiating stress-enduring cells (MUSE-NPCs). We found that pre-freezing for 2 hours at -20 degrees C significantly increased the yield of partition-type tubular scaffolds, and 30 MUL of 25% glutaraldehyde ensured optimal crosslinking of PDGF-MSs. The resulting PDGF-MSs cumulatively released 52% of the PDGF-BB at 4 weeks in vitro without burst release. The PDGF-MS-containing tubular scaffold showed suitable biocompatibility towards MUSE-NPCs and could promote the directional migration and growth of these cells. These findings indicate that the combination of a partition-type tubular scaffold, PDGF-MSs and MUSE-NPCs may be a promising model for the fabrication of tissue-engineered spinal cord grafts. PMID- 30028333 TI - Effects of decompression joint Governor Vessel electro-acupuncture on rats with acute upper cervical spinal cord injury. AB - Decompression is the major therapeutic strategy for acute spinal cord injury, but there is some debate about the time window for decompression following spinal cord injury. An important goal and challenge in the treatment of spinal cord injury is inhibiting or reversing secondary injury. Governor Vessel electroacupuncture can improve symptoms of spinal cord injury by inhibiting cell apoptosis and improving the microenvironment of the injured spinal cord. In this study, Governor Vessel electroacupuncture combined with decompression at different time points was used to treat acute spinal cord injury. The rat models were established by inserting a balloon catheter into the atlanto-occipital space. The upper cervical spinal cord was compressed for 12 or 48 hours prior to decompression. Electroacupuncture was conducted at the acupoints Dazhui (GV14) and Baihui (GV 20) (2 Hz, 15 minutes) once a day for 14 consecutive days. Compared with decompression alone, hind limb motor function recovery was superior after decompression for 12 and 48 hours combined with electroacupuncture. However, the recovery of motor function was not significantly different at 14 days after treatment in rats receiving decompression for 12 hours. Platelet activating factor levels and caspase-9 protein expression were significantly reduced in rats receiving electroacupuncture compared with decompression alone. These findings indicate that compared with decompression alone, Governor Vessel electroacupuncture combined with delayed decompression (48 hours) is more effective in the treatment of upper cervical spinal cord injury. Governor Vessel electroacupuncture combined with early decompression (12 hours) can accelerate the recovery of nerve movement in rats with upper cervical spinal cord injury. Nevertheless, further studies are necessary to confirm whether it is possible to obtain additional benefit compared with early decompression alone. PMID- 30028334 TI - Controlled release of FK506 from micropatterned PLGA films: potential for application in peripheral nerve repair. AB - After decades of research, peripheral nerve injury and repair still frequently results in paralysis, chronic pain and neuropathies leading to severe disability in patients. Current clinically available nerve conduits only provide crude guidance of regenerating axons across nerve gap without additional functionality. FK506 (Tacrolimus), an FDA approved immunosuppressant, has been shown to enhance peripheral nerve regeneration but carries harsh side-effects when delivered systemically. The objective of this study was to develop and evaluate a bioresorbable drug delivery system capable of local extended delivery of FK506 that also provides topological guidance cues to guide axon growth via microgrooves. Photolithography was used to create micropatterned poly(lactide-co glycolic acid) (PLGA) films embedded with FK506. Non-patterned, 10/10 MUm (ridge/groove width), and 30/30 MUm patterned films loaded with 0, 1, and 3 MUg/cm2 FK506 were manufactured and characterized. In vitro FK506 rate of release testing indicated that the films are capable of an extended (at least 56 days), controlled, and scalable release of FK506. Neurite extension bioactivity assay indicated that FK506 released from the films (concentration of samples tested ranged between 8.46-19.7 ng/mL) maintained its neural bioactivity and promoted neurite extension similar to control FK506 dosages (10 ng/mL FK506). The multi functional FK506 embedded, micropatterned poly(lactide-co-glycolic acid) films developed in this study have potential to be used in the construction of peripheral nerve repair devices. PMID- 30028335 TI - Spatiotemporal microRNA profile in peripheral nerve regeneration: miR-138 targets vimentin and inhibits Schwann cell migration and proliferation. AB - While the peripheral nervous system has regenerative ability, restoration of sufficient function remains a challenge. Vimentin has been shown to be localized in axonal growth fronts and associated with nerve regeneration, including myelination, neuroplasticity, kinase signaling in nerve axoplasm, and cell migration; however, the mechanisms regulating its expression within Schwann cell (SC) remain unexplored. The aim of this study was to profile the spatial and temporal expression profile of microRNA (miRNA) in a regenerating rat sciatic nerve after transection, and explore the potential role of miR-138-5p targeting vimentin in SC proliferation and migration. A rat sciatic nerve transection model, utilizing a polyethylene nerve guide, was used to investigate miRNA expression at 7, 14, 30, 60, and 90 days during nerve regeneration. Relative levels of miRNA expression were determined using microarray analysis and subsequently validated with quantitative real-time polymerase chain reaction. In vitro assays were conducted with cultured Schwann cells transfected with miRNA mimics and assessed for migratory and proliferative potential. The top seven dysregulated miRNAs reported in this study have been implicated in cell migration elsewhere, and GO and KEGG analyses predicted activities essential to wound healing. Transfection of one of these, miRNA-138-5p, into SCs reduced cell migration and proliferation. miR-138-5p has been shown to directly target vimentin in cancer cells, and the luciferase assay performed here in rat Schwann cells confirmed it. These results detail a role of miR-138-5p in rat peripheral nerve regeneration and expand on reports of it as an important regulator in the peripheral nervous system. PMID- 30028337 TI - Zishenpingchan granules for the treatment of Parkinson's disease: a randomized, double-blind, placebo-controlled clinical trial. AB - Levodopa preparations remain the preferred drug for Parkinson's disease. However, long-term use of levodopa may lead to a series of motor complications. Previous studies have shown that the combination of levodopa and Zishenpingchan granules (consisting of Radix Rehmanniae preparata, Lycium barbarum, Herba Taxilli, Rhizoma Gastrodiae, Stiff Silkorm, Curcuma phaeocaulis, Radix Paeoniae Alba, Rhizoma Arisaematis, Scorpio and Centipede) can markedly improve dyskinesia and delay the progression of Parkinson's disease, with especially dramatic improvements of non-motor symptoms. However, the efficacy of this combination has not been confirmed by randomized controlled trials. The current study was approved by the Hospital Ethics Committee and was registered in the Chinese Clinical Trial Register (registration number: ChiCTR-INR-1701194). From December 2014 to December 2016, 128 patients (72 males and 56 females, mean age of 65.78 +/- 6.34 years) with Parkinson's disease were recruited from the Department of Neurology of Longhua Hospital and Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine in China. Patients were equally allocated into treatment and control groups. In addition to treatment with dopamine, patients in treatment and control groups were given Zishenpingchan granules or placebo, respectively, for 24 weeks. Therapeutic efficacy was assessed using the Unified Parkinson's Disease Rating Scale, on-off phenomenon, Hoehn-Yahr grade, Scales for Outcomes in Parkinson's disease-Autonomic, Parkinson's disease sleep scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Mini-Mental State Examination, and the Parkinson's Disease Quality of Life Questionnaire. Artificial neural networks were used to determine weights at which to scale these parameters. Our results demonstrated that Zishenpingchan granules significantly reduced the occurrence of motor complications, and were useful for mitigating dyskinesia and non-motor symptoms of Parkinson's disease. This combination of Chinese and Western medicine has the potential to reduce levodopa dosages, and no obvious side effects were found. These findings indicate that Zishenpingchan granules can mitigate symptoms of Parkinson's disease, reduce toxic side effects of dopaminergic agents, and exert synergistic and detoxifying effects. PMID- 30028336 TI - Puerarin ameliorates allodynia and hyperalgesia in rats with peripheral nerve injury. AB - Puerarin is a major active ingredient of the traditional Chinese plant medicine, Radix Puerariae, and commonly used in the treatment of myocardial and cerebral ischemia. However, the effects of puerarin on neuropathic pain are still unclear. In this study, a neuropathic pain animal model was created by partial sciatic nerve ligation. Puerarin (30 or 60 mg/kg) was intraperitoneally injected once a day for 7 days. Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment. Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats, especially at 7 days after model establishment. At 7 days after model establishment, quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed mRNA expression of transient receptor potential vanilloid 1 (Trpv1) and transient receptor potential ankyrin 1 (Trpa1) in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury. These results suggest that puerarin dose dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up regulation in dorsal root ganglion of neuropathic pain rats. PMID- 30028340 TI - Injury of the superior longitudinal fasciculus by ventriculoperitoneal shunt: a diffusion tensor tractography study. PMID- 30028339 TI - Degree of dopaminergic degeneration measured by 99mTc-TRODAT-1 SPECT/CT imaging. AB - To prevent and treat Parkinson's disease in its early stages, it is essential to be able to detect the degree of early dopaminergic neuron degeneration. Dopamine transporters (DAT) in the striatum regulate synaptic dopamine levels, and striatal 99mTc-TRODAT-1 single-photon emission computed tomography (-SPECT) imaging is a marker for presynaptic neuronal degeneration. However, the association between the degree of dopaminergic degeneration and in vivo 99mTc TRODAT-1 SPECT imaging is unknown. Therefore, this study investigated the association between the degree of 6-hydroxydopamine (6-OHDA)-induced dopaminergic degeneration and DAT imaging using 99mTc-TRODAT-1 SPECT in rats. Different degrees of nigrostriatal dopamine depletion were generated by injecting different doses of 6-OHDA (2, 4, and 8 MUg) into the right medial forebrain bundle. The degree of nigrostriatal dopaminergic neuron degeneration was assessed by rotational behavior and immunohistochemical staining. The results showed that striatal 99mTc-TRODAT-1 binding was significantly diminished both in the ipsilateral and the contralateral sides in the 4 and 8 MUg 6-OHDA groups, and that DAT 99mTc-TRODAT-1 binding in the ipsilateral striatum showed a high correlation to apomorphine-induced rotations at 8 weeks post-lesion (r = -0.887, P < 0.01). There were significant correlations between DAT 99mTc-TRODAT-1 binding in the ipsilateral striatum and the amount of tyrosine hydroxylase immunoreactive neurons in the ipsilateral substantia nigra in the 2, 4, and 8 MUg 6-OHDA groups at 8 weeks post-lesion (r = 0.899, P < 0.01). These findings indicate that striatal DAT imaging using 99mTc-TRODAT-1 is a useful technique for evaluating the severity of dopaminergic degeneration. PMID- 30028338 TI - Differences in brain pathological changes between rotenone and 6-hydroxydopamine Parkinson's disease models. AB - Rotenone and 6-hydroxydopamine are two drugs commonly used to generate Parkinson's disease animal models. They not only achieve degenerative changes of dopaminergic neurons in the substantia nigra, but also satisfy the requirements for iron deposition. However, few studies have compared the characteristics of these two models by magnetic resonance imaging. In this study, rat models of Parkinson's disease were generated by injection of 3 MUg rotenone or 10 MUg 6 hydroxydopamine into the right substantia nigra. At 1, 2, 4, and 6 weeks after injection, coronal whole-brain T2-weighted imaging, transverse whole-brain T2 weighted imaging, and coronal diffusion tensor weighted imaging were conducted to measure fractional anisotropy and T2* values at the injury site. The fractional anisotropy value on the right side of the substantia nigra was remarkably lower at 6 weeks than at other time points in the rotenone group. In the 6 hydroxydopamine group, the fractional anisotropy value was decreased, but T2* values were increased on the right side of the substantia nigra at 1 week. Our findings confirm that the 6-hydroxydopamine-induced model is suitable for studying dopaminergic neurons over short periods, while the rotenone-induced model may be appropriate for studying the pathological and physiological processes of Parkinson's disease over long periods. PMID- 30028341 TI - Modulation of microglial functions by methyl jasmonate. AB - Neuroinflammation contributes to the neurodegenerative processes in Alzheimer's disease (AD); therefore, characterization of novel drug candidates aimed at combatting inflammation in the central nervous system is one of the potential avenues for the development of effective AD treatment and prevention strategies. Non-neuronal microglial cells orchestrate neuroinflammatory reactions, and their adverse activation has been linked to AD pathogenesis. Methyl jasmonate (MJ) has anti-cancer properties and has also been shown to reduce peripheral inflammation in pre-clinical models. Recently, anti-neuroinflammatory activity of MJ was demonstrated in mice, but the exact cellular and molecular mechanisms responsible for this beneficial effect are unknown. We hypothesized that MJ can regulate select microglial functions, and used two different in vitro models of microglia to test this hypothesis. MJ inhibited the production of damaging reactive oxygen species by differentiated human HL-60 promyelocytic leukemia cells without reducing their viability. MJ also selectively upregulated phagocytic activity of murine BV-2 microglia, but had no effect on nitric oxide secretion by these cells. Since microglial phagocytosis can be beneficial for clearance of amyloid beta aggregates in AD, the observed upregulation of phagocytic activity by MJ, combined with its inhibitory effect on reactive oxygen species production, supports continued studies of MJ as a candidate drug for managing adverse neuroinflammation in AD. PMID- 30028344 TI - Assumptions Underlying the Trend-in-Trend Research Design. PMID- 30028343 TI - Use of Dipeptidyl Peptidase-4 Inhibitors and New-onset Rheumatoid Arthritis in Patients with Type 2 Diabetes. AB - BACKGROUND: Case reports have suggested a link between dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic drugs used as second- to third-line treatments, and incidence of rheumatoid arthritis. Because the DPP-4 enzyme is involved in several immunologic processes and possibly in the pathophysiology of rheumatoid arthritis, further research is warranted. This population-based study aimed to determine whether use of DPP-4 inhibitors is associated with incidence of rheumatoid arthritis. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we conducted a cohort study among 144,603 patients with type 2 diabetes initiating antidiabetic drugs between 2007 and 2016. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for incident rheumatoid arthritis using time-dependent Cox proportional hazards models, comparing use of DPP-4 inhibitors with use of other antidiabetic drugs. We imposed a 6-month exposure lag period for latency and diagnostic delays. Secondary analyses included assessment of the duration-response relation and comparison with other second-line antidiabetic drugs, among others. RESULTS: During 567,169 person years of follow-up, 464 patients were newly diagnosed with rheumatoid arthritis (crude incidence rate: 82 per 100,000/year). Compared with use of other antidiabetic drugs, use of DPP-4 inhibitors was not associated with an increased risk of rheumatoid arthritis (82 vs. 79 per 100,000/year; HR = 1.0; 95% CI = 0.8, 1.3), with no evidence of duration-response relation. The results did not change after using second-line antidiabetic drugs as the comparator group. CONCLUSIONS: In this large population-based study, use of DPP-4 inhibitors was not associated with an increased risk of incident rheumatoid arthritis. PMID- 30028345 TI - A Call for Caution in Using Information Criteria to Select the Working Correlation Structure in Generalized Estimating Equations. PMID- 30028346 TI - Forty-year Seasonality Trends in Occurrence of Myocardial Infarction, Ischemic Stroke, and Hemorrhagic Stroke. AB - BACKGROUND: The occurrence of myocardial infarction (MI), ischemic stroke, and hemorrhagic stroke has decreased in recent years, but trends in seasonal occurrence remain unclear. METHODS: Using Danish healthcare databases, we identified all patients with a first-time MI, ischemic stroke, or hemorrhagic stroke during the study period (1977-2016). We summarized monthly cases for each disease separately and computed the peak-to-trough ratio as a measure of seasonal occurrence of one cycle. To examine trends over time in seasonal occurrence, we computed the peak-to-trough ratio for each of the 40 years. We also quantified the amount of bias arising from random error in peak-to-trough ratios. RESULTS: Before consideration of bias, the peak-to-trough ratio of summarized monthly cases was 1.11 (95% confidence interval [CI] = 1.10, 1.12) for MI, 1.08 (95% CI = 1.07, 1.09) for ischemic stroke, and 1.12 (95% CI = 1.10, 1.14) for hemorrhagic stroke. The peak-to-trough ratio of MI occurrence increased from 1.09 (95% CI = 1.04, 1.15) in 1977 to 1.16 (95% CI = 1.09, 1.23) in 1999. The trend then remained stable. The peak-to-trough ratio of ischemic stroke occurrence declined continuously during the study period, dropping from 1.12 (95% CI = 1.02, 1.24) in 1977 to 1.06 (95% CI = 1.00, 1.12) in 2016. The peak-to-trough ratio of hemorrhagic stroke occurrence remained stable over time. However, after adjusting for potential bias, time trends in peak-to-trough ratios were almost flat. CONCLUSIONS: We found no substantial seasonality for MI, ischemic stroke, or hemorrhagic stroke occurrence during 1977-2016. Modest peak-to-trough ratios should be interpreted after considering bias induced by random variation. PMID- 30028347 TI - Do Epidural Catheter Size and Flow Rate Affect Bolus Injection Pressure in Different Programmed Intermittent Epidural Bolus Regimens? An In Vitro Study. AB - BACKGROUND: The optimal programmed intermittent epidural bolus regimen for labor analgesia remains unknown. Some studies indicate that better drug spread in the epidural space results from greater injection pressure; however, there is a lack of data regarding the maximum pressure generated by epidural bolus injection using different catheters and flow rates. METHODS: We evaluated the flow and pressure characteristics of 11 commonly used epidural catheters combined with 3 different infusion pumps that deliver epidural infusions according to the programmed intermittent epidural bolus regimen. Pressure changes were measured over time at flow rates of 100, 250, and 400 mL.hour and with a bolus volume of 10 mL. To account for repeated measures, linear mixed models were used. Features were selected with a backward stepwise procedure continued until only statistically significant variables were left in the model. RESULTS: We performed 660 measurements. The mean maximal pressure generated during bolus injection ranged from 86 to 863 mm Hg for different flow rates and catheter designs. The interaction between flow rate and catheter gauge resulted in 1.31, 1.65, and 2.00 mm Hg of pressure increase for 18G, 19G, and 20G catheters, respectively, per 1 mL.hour of increased flow rate (P< .001). Analyses including wire-reinforced catheters revealed a 1.16, 1.76, and 2.36 mm Hg pressure increase for 18G, 19G, and 20G catheters, respectively, per 1 mL.hour of increased flow rate (P< .001). In some cases, it triggered the occlusion pump alarm. CONCLUSIONS: Significant differences were observed in the in vitro maximum pressure value among the various catheter and flow rate combinations with a higher pressure value for wire reinforced catheters used in the study. The optimal flow rate and epidural catheter combination may allow for delivery of the bolus with high flow rate without triggering the occlusion alarm. PMID- 30028342 TI - Stem cells: a promising candidate to treat neurological disorders. AB - Neurologic impairments are usually irreversible as a result of limited regeneration in the central nervous system. Therefore, based on the regenerative capacity of stem cells, transplantation therapies of various stem cells have been tested in basic research and preclinical trials, and some have shown great prospects. This manuscript overviews the cellular and molecular characteristics of embryonic stem cells, induced pluripotent stem cells, neural stem cells, retinal stem/progenitor cells, mesenchymal stem/stromal cells, and their derivatives in vivo and in vitro as sources for regenerative therapy. These cells have all been considered as candidates to treat several major neurological disorders and diseases, owing to their self-renewal capacity, multi-directional differentiation, neurotrophic properties, and immune modulation effects. We also review representative basic research and recent clinical trials using stem cells for neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and age-related macular degeneration, as well as traumatic brain injury and glioblastoma. In spite of a few unsuccessful cases, risks of tumorigenicity, and ethical concerns, most results of animal experiments and clinical trials demonstrate efficacious therapeutic effects of stem cells in the treatment of nervous system disease. In summary, these emerging findings in regenerative medicine are likely to contribute to breakthroughs in the treatment of neurological disorders. Thus, stem cells are a promising candidate for the treatment of nervous system diseases. PMID- 30028348 TI - In Response. PMID- 30028349 TI - Preventing Adverse Events in Cataract Surgery: Sub-Tenon's Block. PMID- 30028350 TI - The 10 fundamental principles of lay resuscitation: Recommendations by the German Resuscitation Council. PMID- 30028351 TI - Sex and body weight are major determinants of venlafaxine pharmacokinetics. AB - We assessed the effect of body weight and BMI on plasma concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), active moiety (AM=VEN+ODVEN), and dose-corrected plasma concentrations (C/D). A database containing concentrations of VEN and ODVEN including 737 of 1594 eligible patients was analyzed. Analyses included sex, body weight, and BMI as well as concentrations of VEN, ODVEN, AM, and C/D. A positive correlation was detected between body weight and daily dosage (rs=0.168, P<0.001). A negative correlation was found between body weight and AM (rs=-0.124, P=0.001) and ODVEN (rs=-0.137, P<0.001). Negative correlations were also found between body weight and C/D ratios (C/D VEN: rs=-0.134, P<0.001, C/D ODVEN: rs=-0.239, P<0.001, C/D AM: rs=-0.256, P<0.001). No correlations were detected between BMI and concentrations for VEN, ODVEN, and AM. Comparing low-BMI (<20 kg/m2), medium-BMI (20-29.9 kg/m2), and high-BMI (>=30 kg/m2) groups, higher values of some pharmacokinetic variables in the lower BMI group did not remain significant after controlling for sex. Women had higher VEN, ODVEN, AM, and C/D values for AM, VEN, and ODVEN than men (P<0.001 for all comparisons). Our results highlight the role of different pharmacokinetically relevant parameters and foremost of sex as mediators for the effect of BMI on VEN metabolism. PMID- 30028352 TI - Older Adults' Sedentary Behavior and Physical Activity After Hip Fracture: Results From an Outpatient Rehabilitation Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Prolonged sedentary time and limited physical activity can result in deleterious effects on health and mobility, especially for older adults with fall-related hip fracture. Therefore, the purpose of this study was to examine the effect of a multidisciplinary clinic on sedentary behavior and physical activity (prespecified secondary outcomes) and provide descriptions of activity patterns over 1 year for men and women. METHODS: We conducted a parallel group, single-blinded randomized controlled trial comparing a multidisciplinary clinic and usual care (intervention) with usual care (control). We recruited 53 community-dwelling older adults aged 65+ years who were 3 to 12 months postfracture and collected data at baseline, 6, and 12 months; study staff were blinded to group allocation. The clinic included a geriatric assessment by the geriatrician, physiotherapist, and occupational therapist. Referrals were made to other professionals, when indicated. We collected the accelerometer-measured sedentary behavior and physical activity at 3 time points. We used linear mixed effects models to compare groups at 6 and 12 months and mixed models to compare outcomes between men and women. RESULTS: Participants were sedentary for more than 10 hours of a 13-hour day, and there were no significant differences between the study groups at 6 months (2.4 [95% confidence interval: -22.4 to 27.2] minutes) or 12 months (-3.7 [95% confidence interval: -33.6 to 26.1] minutes). Compared with women, men spent 47.2 min/d more in sedentary time (P = .052) and 43.8 min/d less in light physical activity (P = .047). DISCUSSION: Older adults after hip fracture spend prolonged periods of waking hours sedentary with very little activity. PMID- 30028353 TI - Expression of Laminin Receptor 1 in Normal, Hyperplastic, and Malignant Endometrium. AB - Laminin receptor 1 may have a role in the progression from endometrial hyperplasia with or without atypia to endometrial cancer. Therefore, we aimed to investigate the pattern, percentage, and intensity of laminin receptor 1 expression in normal, hyperplastic, and neoplastic endometrium. Paraffin blocks of 131 specimens with the diagnoses of normal endometrium (n=25), endometrial hyperplasia with atypia (n=21) or without atypia (n=55), and endometrial cancer (n=30) were immunostained with laminin receptor 1 antibody, and its expression percentage, pattern, and intensity in the epithelial cytoplasm, basement membrane, and endometrial stroma of these tissues were assessed. When compared with hyperplasia with or without atypia and endometrial cancer, the percentage of nonstaining with laminin receptor 1 in the epithelial basement membrane was higher (96%), and the percentage of <50% staining with laminin receptor 1 was lower (4%) in the normal endometrium (P=0.001). While a progressive increment in staining percentage and density of epithelial cytoplasm and basement membrane was noted through an orderly progression from normal endometrium to endometrial hyperplasia without atypia, endometrial hyperplasia with atypia, and cancer of endometrium (P<0.001), such a relationship was not found for the staining percentage and density of endometrial stroma (P>0.05). Disease progression related gradual increment in laminin receptor 1 expression in the epithelial basement membranes of hyperplastic endometrium with or without atypia and cancer of endometrium reveals that it may play a substantial role in the transition from premalignant to the malignant state endometrial lesions. PMID- 30028354 TI - Next-generation Sequencing of an Ovarian Spindle Cell Tumor Identified an Ovarian Low-grade Endometrial Stromal Sarcoma: A Rare Entity. AB - Ovarian spindle cell tumors comprise a heterogeneous group of ovarian neoplasms from benign to malignant. Since this morphologic finding describes a broad category of ovarian neoplasms, it is not easy to determine an accurate diagnosis. Low-grade endometrial stromal sarcoma (LG-ESS) is a rare gynecological malignancy that presents with spindle cell lesions. To identify ovarian LG-ESS, we performed whole-exome sequencing and transcriptome sequencing of a spindle cell tumor. The tumor harbored JAZF1-SUZ12, a well-known gene fusion commonly found in uterine LG ESS. Moreover, 28 non-silent somatic mutations (13 frameshift, 12 missense, 2 nonsense and 1 splicing mutations) with five cancer-related genes (ACSL3, ATM, DST, HGF and PKHD1) were detected. Our results indicate that next-generation sequencing combined with conventional immunohistochemical analysis may be a better strategy than conventional analysis alone to identify ovarian LG-ESS with spindle cell lesions. Moreover, our data suggest that ovarian LG-ESS can harbor genetic characteristics similar to those of uterine LG-ESS. PMID- 30028355 TI - A Cell Line-based Immunohistochemical p53 Expression Pattern Control Panel. AB - TP53 gene mutations are known to manifest in distinct p53 immunohistochemical staining patterns; overexpression, wild-type, and null. These stratified staining patterns are routinely utilized in subtyping ovarian cancer subtypes. Three ovarian cancer cell lines were used in the construction of an immunohistochemical p53 expression pattern control panel that highlight respective TP53 mutation status. The cell line control panel sections demonstrated consistent clean and easily interpretable p53 immunohistochemical staining. Procured resection, biopsy, and cytologic specimens were submitted along with either standard control tissue or a p53 cell line control panel to pathologists of varying experience for interrater reliability analysis. Individual interrater reliability was near perfect and was improved with the p53 cell line control panel when compared with the tissue control. The cell line control panel demonstrated decreased misinterpretation of null expression pattern as wild-type. Next-generation sequencing analysis was performed on the cell lines and select cases, in which there was discordance in p53 expression pattern interpretation. Next-generation sequencing analysis demonstrated low-frequency variant mutations in some cases in which there was reviewer discordance. This study suggests the addition of a p53 cell line expression pattern control panel could potentially increase p53 interpretation accuracy for ovarian cancer subtypes. We developed a cell line based p53 control panel that has the potential to increase individual interrater reliability for p53 immunohistochemical expression pattern determination, support immunohistochemical optimization, and direct submission of difficult to interpret p53 staining cases to next-generation sequencing. PMID- 30028356 TI - Acute Pancreatitis Caused by Isolated Pancreatic Metastasis From Uterine Choriocarcinoma. AB - Choriocarcinoma is an aggressive gestational trophoblastic neoplasia known for its widely metastatic potential. However, isolated pancreatic metastasis is an extremely rare occurrence and has not been documented in the English literature to the best of our knowledge. The metastatic deposits in the index case led to widespread hemorrhage and necrosis of the pancreatic parenchyma, causing severe acute pancreatitis. The patient succumbed to her illness before chemotherapy was administered. Thus, we present an autopsy case of a uterine choriocarcinoma with isolated pancreatic metastasis presenting as severe acute pancreatitis in a 27-yr old woman following a molar pregnancy. PMID- 30028357 TI - A Retrospective Review of Physician Assistant Education Association End of Rotation Examinations. AB - The PAEA End of RotationTM exams were developed to assess medical knowledge of the 7 core supervised clinical practice experiences, including Emergency Medicine, Family Medicine, Internal Medicine, General Surgery, Pediatrics, Women's Health, and Psychiatry and Behavioral Health. The examinations were created by experienced PA educators and national exam experts with continual review and content updates. This paper summarizes changes since the inception of the exam program, including test construction and development, reliability, validity, and scale scoring. They are built using content blueprints and topic lists that were developed by experienced PA educators and national examination experts. All examination items are peer reviewed by PA educators and statistically validated for accuracy and consistency by psychometricians who specialize in examination development. This article will review the changes since the inception of the exam program including test construction and development, reliability, validity and scale scoring. Also addressed is an update on the PAEA End of CurriculumTM examination. PMID- 30028358 TI - Using a Hands-On Approach to Teaching Concepts of Evidence-Based Medicine to Physician Assistant Students in Their Didactic Coursework. PMID- 30028359 TI - Is Internet Addiction a Clinical Symptom or a Psychiatric Disorder? A Comparison With Bipolar Disorder. AB - The general purpose of this review is to present an updated literature overview of neurobiological/clinical aspects of Internet addiction (IA), particularly of overlaps and differences with bipolar affective disorder (BPAD). Articles with clinical/neurobiological aspects of IA or similarities/differences with BPAD as main topics, from 1990 to present and written in English language, were included. Comorbidity between IA and other psychiatric disorders, including BPAD, is common. Dysfunctions in dopaminergic pathways have been found both in IA and in mood disorders. Most of investigations in IA support a chronic hypodopaminergic dysfunctional state in brain reward circuit and an excessive reward experience during mood elevation. Neuroimaging studies show prefrontal cortex abnormalities shared between addictive and bipolar patients. BPAD and IA present numerous overlaps, such as polymorphisms in nicotinic receptors genes, anterior cingulate/prefrontal cortex abnormalities, serotonin/dopamine dysfunctions, and good response to mood stabilizers. The future is to clarify diagnostic criteria to better define the IA/BPAD relationship. PMID- 30028360 TI - Emotion Regulation Difficulties in Relation to Anxiety, Depression, and Functional Impairment Among Treatment-Seeking Smokers. AB - Psychological distress is elevated among smokers and plays a key role in the maintenance of smoking behavior. Although research has implicated emotion regulation (ER) difficulties as a transdiagnostic construct for psychological distress, empirical work has not yet investigated ER difficulties among treatment seeking smokers. The purpose of the current study was to increase understanding of ER difficulties in relation to depression, anxious arousal, and functional impairment among treatment-seeking smokers. Participants included adult daily treatment-seeking smokers (N = 568; Mage = 37, SD = 13.46; 51.9% male). Results indicated that global ER difficulties were significantly related to depression, anxious arousal, and functional impairment. Analyses focused on the lower-order facets of ER and indicated that limited access to ER strategies, difficulty engaging in goal-directed behavior, and lack of emotional clarity were significantly related to depression; limited access to ER strategies, nonacceptance of emotions, and impulsivity were significantly associated with anxious arousal; and limited access to ER strategies and difficulty engaging in goal-directed behavior were significantly related to functional impairment. The significant ER effects were evident above and beyond the variance accounted for by neuroticism and tobacco dependence. These findings highlight the importance of considering ER difficulties to better understand psychological distress among smokers. PMID- 30028361 TI - Visual and Positional Modulation of Pendular Seesaw Nystagmus: Implications for the Mechanism. AB - BACKGROUND: The mechanisms of pendular seesaw nystagmus (SSN) remain unknown. METHODS: We evaluated modulation of pendular SSN by removal of visual fixation, convergence, and positional changes in 2 patients, one with bitemporal hemianopia due to a traumatic damage of the optic chiasm and the other with platybasia compressing the medulla and lower cerebellum. RESULTS: In both patients, the pendular SSN markedly decreased or disappeared with convergence, without visual fixation in darkness, during static head tilt toward each shoulder while sitting and while supine. CONCLUSIONS: The similar patterns of nystagmus modulation observed in our patients with a different etiology indicate a common role of both visual and otolithic inputs in generating pendular SSN. PMID- 30028362 TI - Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock. AB - OBJECTIVES: Mounting evidence has shown that critically ill patients are commonly thiamine deficient. We sought to test the hypothesis that critically ill patients with septic shock exposed to thiamine would demonstrate improved lactate clearance and more favorable clinical outcomes compared with those not receiving thiamine. DESIGN: Retrospective, single-center, matched cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adult patients admitted with an International Classification of Diseases, 9th Edition, or International Classification of Diseases, 10th Edition, diagnosis code of septic shock to either the medicine or surgery ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients who received IV thiamine supplementation within 24 hours of hospital admission were identified and compared with a matched cohort of patients not receiving thiamine. The primary objective was to determine if thiamine administration was associated with a reduced time to lactate clearance in septic shock. Secondary outcomes included 28-day mortality, acute kidney injury, and need for renal replacement therapy, and vasopressor and mechanical ventilation free days. Two-thousand two-hundred seventy-two patients were screened, of whom 1,049 were eligible. The study consisted of 123 thiamine-treated patients matched with 246 patients who did not receive thiamine. Based on the Fine-Gray survival model, treatment with thiamine was associated with an improved likelihood of lactate clearance (subdistribution hazard ratio, 1.307; 95% CI, 1.002-1.704). Thiamine administration was also associated with a reduction in 28-day mortality (hazard ratio, 0.666; 95% CI, 0.490-0.905). There were no differences in any secondary outcomes. CONCLUSIONS: Thiamine administration within 24 hours of admission in patients presenting with septic shock was associated with improved lactate clearance and a reduction in 28-day mortality compared with matched controls. PMID- 30028363 TI - The Association Between Inhaled Nitric Oxide Treatment and ICU Mortality and 28 Day Ventilator-Free Days in Pediatric Acute Respiratory Distress Syndrome. AB - OBJECTIVES: To investigate the association between inhaled nitric oxide treatment and ICU mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome. DESIGN: Retrospective cohort study. A propensity score for inhaled nitric oxide treatment was developed and used in the analysis. SETTING: Two quaternary care PICUs. PATIENTS: Children with pediatric acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 499 children enrolled in this study with 143 (28.7%) receiving inhaled nitric oxide treatment. Children treated with inhaled nitric oxide were more likely to have a primary diagnosis of pneumonia (72% vs 54.8%; p < 0.001), had a higher initial oxygenation index (median 16.9 [interquartile range, 10.1-27.3] vs 8.5 [interquartile range, 5.8-12.2]; p < 0.001), and had a higher 72-hour maximal Vasoactive-Inotrope Score (median 15 [interquartile range, 6-25] vs 8 [interquartile range, 0-17.8]; p < 0.001) than those not receiving inhaled nitric oxide. Mortality was higher in the inhaled nitric oxide treatment group (25.2% vs 16.3%; p = 0.02), and children in this group had fewer 28-day ventilator-free days (10 d [interquartile range, 0-18 d] vs 17 d (interquartile range 5.5-22 d]; p < 0.0001). We matched 176 children based on propensity score for inhaled nitric oxide treatment. In the matched cohort, inhaled nitric oxide treatment was not associated with mortality (odds ratio, 1.3 [95% CI, 0.56-3.0]) or 28-day ventilator-free days (incidence rate ratio, 0.91 [95% CI, 0.80-1.04]). These results remained consistent in the entire study cohort when the propensity score for inhaled nitric oxide treatment was used for either inverse probability weighting or stratification in regression modeling with the exception that subjects treated with inhaled nitric oxide were more likely to have 0 ventilator free days (p <= 0.02). In secondary analysis stratified by oxygenation response, inhaled nitric oxide treatment was not associated with mortality or 28-day ventilator-free days in children with a positive oxygenation response (all p > 0.2) CONCLUSIONS:: Treatment with inhaled nitric oxide in pediatric acute respiratory distress syndrome is not associated with improvement in either mortality or ventilator-free days and may be associated with harm. Further prospective trials are required to define the role of inhaled nitric oxide treatment in pediatric acute respiratory distress syndrome. PMID- 30028364 TI - Moderate and Severe Acute Respiratory Distress Syndrome: Hemodynamic and Cardiac Effects of an Open Lung Strategy With Recruitment Maneuver Analyzed Using Echocardiography. AB - OBJECTIVES: Open lung ventilation with a recruitment maneuver could be beneficial for acute respiratory distress syndrome patients. However, the increased airway pressures resulting from the recruitment maneuver may induce cardiac dysfunction, limiting the benefit of this maneuver. We analyzed the effect of a recruitment maneuver and decremental positive end-expiratory pressure titration on cardiac function. SETTINGS: Medical ICU Amiens, France. PATIENTS: Twenty patients with moderate to severe acute respiratory distress syndrome INTERVENTIONS:: Patients underwent a stepwise recruitment maneuver with respiratory evaluation and echocardiography assessment of cardiac function including longitudinal strain at baseline, peak positive end-expiratory pressure of recruitment maneuver (positive end-expiratory pressure 40 cm H2O), and at "optimal" positive end-expiratory pressure. The patients were divided into two groups based on change on the PaO2/FIO2 ratio (nonresponders < 50%; responders >= 50%). MEASUREMENTS AND MAIN RESULTS: At peak positive end-expiratory pressure during the recruitment maneuver, the arterial pressure, cardiac output, left ventricular size decreased and right ventricular size increased. The left ventricular ejection fraction decreased from 60% +/- 13% to 48% +/- 18% (p = 0.05). Both left and right ventricular global longitudinal strain were impaired (-15.8% +/- 4.5% to -11% +/- 4.7% and -19% +/- 5% to -14% +/- 6% [p = 0.05] respectively). Fifty percent of patients were nonresponders and demonstrated a lower hemodynamic tolerance to the recruitment maneuver than responders. Optimal positive end-expiratory pressure was 14 +/- 5 cm H2O (vs 11 +/- 4 cm H2O at baseline), and PaO2/FIO2 ratio increased from 111 +/- 25 to 197 +/- 89 mm Hg (p < 0.0001). All hemodynamic variables returned to their baseline value after the recruitment maneuver despite a higher positive end-expiratory pressure. CONCLUSIONS: An open lung strategy with a stepwise recruitment maneuver permitted a higher positive end-expiratory pressure and improved oxygenation without any cardiac impairment. The recruitment maneuver was associated with mild and transient, cardiac dysfunction, with nonresponders demonstrating poorer tolerance. PMID- 30028365 TI - Systemic High-Mobility Group Box-1: A Novel Predictive Biomarker for Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVES: To investigate the release of proinflammatory damage-associated molecular pattern molecule "high-mobility group box-1" in the serum of patients after aneurysmal subarachnoid hemorrhage and its association with cerebral vasospasm. DESIGN: Retrospective observational study. SETTING: University hospital. PATIENTS: Aneurysmal subarachnoid hemorrhage patients admitted within 24 hours of ictus. INTERVENTIONS: Standard subarachnoid hemorrhage treatment after clipping or coiling of aneurysm. MEASUREMENTS AND MAIN RESULTS: We enrolled 53 aneurysmal subarachnoid hemorrhage patients from which peripheral venous blood was withdrawn on days 1, 3, 5, 7, 9, 11, and 13 and once from the controls to obtain the serum. Serum high-mobility group box-1 concentration was quantified by enzyme-linked immunosorbent assay. Serum interleukin-6 and peripheral blood leukocytes were also determined over the first 2 weeks after subarachnoid hemorrhage. Patients' data were recorded prospectively. Serum high-mobility group box-1 was significantly elevated in subarachnoid hemorrhage patients from day 1 to day 13 when compared with nonsubarachnoid hemorrhage patients (p < 0.05). Patients with cerebral vasospasm showed significantly higher high-mobility group box-1 starting from day 1 to day 13 when compared with patients without cerebral vasospasm. Cumulative levels of high-mobility group box-1 showed significant correlation with peripheral blood leukocytes and interleukin-6 levels (p < 0.05). Receiver operating characteristic curve analysis showed that serum high-mobility group box-1 level at admission may be a predictive biomarker for cerebral vasospasm with a sensitivity of 59% and a specificity of 82% at a cutoff value of 5.6 ng/mL. CONCLUSIONS: Serum high-mobility group box-1 is differentially elevated after subarachnoid hemorrhage. Serum high-mobility group box-1 levels were elevated early after subarachnoid hemorrhage (day 1) and remained significantly high until day 13 in patients who developed cerebral vasospasm. Our data suggest that serum high-mobility group box-1 may be a predictive biomarker for the detection of CVS. PMID- 30028366 TI - Effects of the OPRM1 A118G Polymorphism (rs1799971) on Opioid Analgesia in Cancer Pain: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Although previous studies have demonstrated that the OPRM1 A118G polymorphism may influence the analgesia response to cancer pain, the results are inconsistent. In this article we aimed to fully examine the association between OPRM1 A118G (rs1799971) polymorphism and opioid analgesia by analyzing published information. This will provide information for better cancer pain management. MATERIALS AND METHODS: A systematic search of the literature dating to August 31, 2017 was conducted using PubMed, EMBase, Sinomed, and the Cochrane Library databases. The standardized mean difference (SMD) of required amounts of opioids between AA homozygotes and the G-allele was calculated. Subgroup analyses for race and opioid use was performed. In addition, drug sensitivity analysis, heterogeneity description, and publication bias assessment were performed. RESULTS: Of the 467 screened studies, 12 including 2118 participants were eligible to be included in our analysis. The meta-analysis results indicated that G-allele carriers (AG+GG) of the OPRM1 A118G polymorphism required higher opioid doses for pain management than those with the AA homozygotes (SMD=-0.3; 95% confidence interval [CI], -0.45 to -0.15; P<0.001). In subgroup analysis, we did not find statistically significant correlation between OPRM1 A118G polymorphism and opioid pain relief among Caucasian patients (SMD=-0.15; 95% CI, -0.29 to 0.00; P=0.04), as well as among morphine users (SMD =-0.20; 95% CI, -0.40 to 0.00, P=0.05), except for Asian patients (SMD=-0.42; 95% CI, -0.62 to -0.23; P<0.001). DISCUSSION: Our meta-analysis indicates that G allele (AG+GG) carriers of OPRM1 A118G polymorphism required more opioid analgesia in cancer pain management. The OPRM1 A118G polymorphism may help predict individuals' response to analgesia and achieve satisfactory cancer pain control. PMID- 30028368 TI - Do Physicians Underestimate Pain in Terminal Cancer Patients? A Prospective Study in a Hospice Setting. AB - OBJECTIVES: Unrelieved pain is present in a majority of terminal cancer patients. However, the treatment of pain in palliative and hospice care is affected by the lack of validated pain assessment. The goal of this study was to evaluate differences in pain evaluation between terminal cancer patients and physicians and evaluate the pain levels as a survival biomarker. MATERIALS AND METHODS: Patients were evaluated every 7 days for a total of 4 assessments. Physicians evaluated patients' pain on an numeric rating scale (NRS) scale after clinical examination, after which the patients completed NRS, Quality of Life Questionnaire Core 15 Pal (QLQ-C15-PAL), and Edmonton Symptom Assessment System (ESAS) questionnaires. RESULTS: On average, physicians minimally underestimated the pain level in patients (3.47 vs. 3.94 on an NRS scale). Pain was overestimated in 28% and underestimated in 46% of the patients. However, half of all underestimation was clinically meaningful, compared with 28% of the overestimation. For patients with an NRS score of >=7, pain underestimation was both clinically and statistically significant (5.56 vs. 8.17). Pain ratings exhibited a very small correlation to survival (up to r=-0.22), limiting their use as a survival biomarker. DISCUSSION: Although physicians can accurately assess mild pain in terminal cancer patients in the hospice setting, the underestimation of pain is still clinically significant in almost a quarter of patients, and especially pronounced in patients with higher levels of pain and in female patients. Hence, validated pain assessment is a necessity in hospice care, with the choice of pain evaluation tool dependent on patient and physician preference. PMID- 30028369 TI - A New Interprofessional Beginning and Reflection: Past, Present, and Future. PMID- 30028367 TI - Risk and Resilience in Pediatric Pain: The Roles of Parent and Adolescent Catastrophizing and Acceptance. AB - OBJECTIVES: Both pediatric and parent pain catastrophizing and pain acceptance are key factors associated with pediatric pain outcomes; however, the interactive effects of these factors within the parent-child dyad have yet to be tested. The aims of this study were to examine: (1) the mediating role of child catastrophizing between parent catastrophizing and child outcomes (pain interference and mobility), (2) the mediating role of child acceptance between parent acceptance and child outcomes, and (3) whether child acceptance buffers the relation between parent catastrophizing and child catastrophizing, which in turn impacts child outcomes. MATERIALS AND METHODS: Cross-sectional data from 324 youth with chronic pain ages 10 to 17 years (mean age=14.72, [SD=2.12]; 73.1% female; 59% Caucasian) and their parents were collected. Participants completed measures assessing pediatric Patient-Reported Outcome Measurement Information System (PROMIS) domains (mobility and pain interference), pain catastrophizing, pain acceptance, and child pain intensity. Mediation was conducted via 1000-draw bootstrap-adjusted analyses in Mplus. RESULTS: Parent pain catastrophizing was indirectly associated with child pain interference via child catastrophizing but was not associated with mobility difficulties in the mediation model. Parent pain acceptance was indirectly associated with both child pain interference and mobility via child acceptance. We did not find evidence of child acceptance buffering parent and child pain catastrophizing. DISCUSSION: The findings of this study highlight the need for caregiver involvement in multidisciplinary treatments to mitigate risk and enhance resilience in youth with chronic pain. PMID- 30028370 TI - Leveraging Technology to Enhance Access to Wound Care. PMID- 30028371 TI - Compliance Tips to Prevent Claim Denials: Part 2. PMID- 30028372 TI - The Effect of Vacuum-Assisted Closure Therapy on Methicillin-Resistant Staphylococcus aureus Wound Biofilms. AB - Biofilm-associated wound infections are a major global health issue, and methicillin-resistant Staphylococcus aureus (MRSA) is among the greatest therapeutic challenges. Vacuum-assisted closure (VAC) therapy is now being revisited as an alternative treatment for both acute and chronic wounds. However, data supporting the concept of its antibiofilm effect remain limited. Using quantitative biofilm-forming assay and a range of genotypic methods (spa, SCCmec, and agr typing), study authors showed that VAC therapy can significantly prevent biofilm formation (P < .01) of a range of MRSA wound isolates differing widely in their biofilm-forming abilities and genetic background. The best effect was presented on CC5-MRSA-SCCmecI-agrII, a dominant MRSA clone among wound isolates worldwide. An assessment of effects of different protocols on dressing changes (1 or 2 times per week) demonstrated significantly greater antibiofilm activity (P < .05) of 3-day dressing changes. These findings support the use of VAC therapy as a topical antibiofilm treatment for the effective management of wound healing. PMID- 30028373 TI - Activity-Based Restorative Therapy and Skin Tears in Patients with Spinal Cord Injury. AB - OBJECTIVES: To determine the risk factors associated with skin tear development while participating in activity-based restorative therapy (ABRT), describe the possible consequences of skin tears incurred during therapy, and provide risk reduction strategies. METHODS: This was a retrospective review of electronic medical records from 2012 to 2015 in a spinal cord outpatient rehabilitation center; 21 of 54 patients who reported a wound at initial evaluation were diagnosed with skin tears. Nine of the 21 patients acquired skin tears during their course of ABRT. Of those 9, 7 were diagnosed with tetraplegia and 2 with paraplegia. All patients were treated by a wound care specialist 2 to 3 times per week while participating in therapy, with plan-of-care modifications to improve wound healing and maximize benefits of ABRT. MAIN OUTCOME MEASURES: Primary outcome measures were level of injury, International Standards for Neurological Classification of Spinal Cord Injury, age at initial evaluation, Spinal Cord Independence Measure, and International Skin Tear Advisory Panel skin tear classification. MAIN RESULTS: Six of 9 patients completed their full scheduled course of therapy with wounds closing within 30 days. Two patients' treatments were discontinued, and 1 patient was discharged because of exacerbation of a preexisting pressure injury. CONCLUSIONS: Skin tears can affect therapy by altering patient outcomes. Patient and clinician education, policy modifications, and risk management plans improved skin protection and prevented skin tears in this patient population. Only 2 subsequent cases of therapy-related skin tears were recorded in 2016. PMID- 30028374 TI - Clinical Evaluation of Portable Wound Volumetric Measurement Devices. AB - OBJECTIVE: Wound dimensional assessments are important in determining the progress of a wound and the effect of interventions on wound healing. The FastSCAN (FS; Polhemus Inc, Colchester, Vermont) and Silhouette Mobile (SM; ARANZ Medical, Christchurch, New Zealand) are portable devices that quantify surface area, depth, and volume of wounds. This study evaluated their reliability in producing accurate wound measurements. DESIGN AND SETTING: This study was conducted at the Waikato Hospital, Hamilton, New Zealand. PATIENTS AND INTERVENTION: Eleven vascular patients with a combined total of 16 wounds underwent simultaneous wound measurements using three-dimensional computed tomography (CT) reconstruction, FS, and SM. MAIN OUTCOME MEASURE: The validity of FS and SM was tested against CT. Additionally, the interoperator reliability and intraoperator reliability of FS and SM were determined. MAIN RESULTS: The intraoperator reliability and interoperator reliability for volume recordings of the SM were 0.97 and 0.97, respectively, and for the FS were 0.96 and 0.97, respectively. The FS and SM measurements were not significantly different from CT. The SM consistently produced smaller wound volume and depth measurements compared with CT. In contrast, overestimation was observed for FS when compared with CT. However, the volume measurements in one wound were anomalous, being 10 times larger than CT measurements. Excluding this wound, there were strong correlations in wound volumes for SM and CT (r = 0.81; P <= .0001), for FS and CT (r = 0.99; P <= .001), and for SM and FS (r = 0.99; P <= .0001). CONCLUSIONS: Measurements from FS and SM were comparable to CT. Therefore, SM and FS devices both offer the benefit of being noncontact portable devices that produce reproducible and reliable readings. PMID- 30028375 TI - The Free Exchange of Health Information: Preventing Information Blocking. PMID- 30028376 TI - Exploring Patient and Caregiver Perceptions of Primary Healthcare Sector Home Care for Simple Acute Wounds. PMID- 30028377 TI - Inosine alleviates depression-like behavior and increases the activity of the ERK CREB signaling in adolescent male rats. AB - Inosine, a major breakdown product of adenosine by the enzyme adenosine deaminase, binds to adenosine receptors and initiates intracellular signaling events. Adenosine and inosine have already been described as capable of modulating depression-like behavior in adult rodent model. In this study, we investigated the antidepressant-like effect of inosine, acutely administered (10 or 50 mg/kg, intraperitoneal), in postnatal day 28 male Sprague-Dawley rats. The effects of inosine were assessed using the forced swimming test and locomotor activity test. Changes in the extracellular signal-regulated kinases (ERK)-cyclic AMP response element binding protein (CREB) signaling pathway in the hippocampus and prefrontal cortex were examined by western blot analysis. The results showed that inosine had an antidepressant-like effect in the forced swimming test in adolescent rats without affecting locomotor activity. Furthermore, we found that inosine increased the activity of ERK and CREB in the hippocampus and prefrontal cortex. Inosine administered intraperitoneally may alleviate depression-like behaviors in adolescent rats, and the ERK-CREB signal system may be the target of the antidepressant action of inosine. PMID- 30028379 TI - Beyond Emergence: Understanding postoperative Cognitive Dysfunction (POCD). PMID- 30028378 TI - Narirutin produces antidepressant-like effects in a chronic unpredictable mild stress mouse model. AB - Depression is a highly debilitating and life-threatening mental disorder, which is accompanied by dysregulation of the peripheral and central immune system. Narirutin (NR), which has antioxidant and anti-inflammatory activities, is one of the active constituents isolated from Citrus unshiu. However, its potential antidepressant-like and anxiolytic-like effects are poorly understood. The present study was aimed to investigate whether NR confers an antidepressant-like effect in mice exposed to a chronic mild stress (CMS) model of depression. The results showed that NR treatment for 1 week significantly alleviated the depressive-like behaviours of CMS-exposed mice, as indicated by restored decreased sucrose preference and shortened floating time in the forced swimming test. Moreover, NR treatment significantly blocked the CMS-induced anxiety-like behaviors, including increased time spent in the central zone in the open field test, and shortened the latency to feeding in the novelty suppressed feeding test. Taken together, our findings suggested that NR exerted potential antidepressant-like and anxiolytic-like effects in CMS mice model of depression, which support further exploration into developing NR as a novel agent to treat depression and even other stress-related disorders. PMID- 30028380 TI - Bubble Trouble: Venous Air Embolism in Endoscopic Retrograde Cholangiopancreatography. PMID- 30028381 TI - Rashomon Effect and the Contradiction of Data, Practice, and Regulations. PMID- 30028382 TI - Agreement Between Transesophageal Echocardiography and Thermodilution-Based Cardiac Output. PMID- 30028383 TI - The Costs and Costing of Regulatory Compliance. PMID- 30028384 TI - Vascular Air Embolism and Endoscopy: Every Bubble Matters. PMID- 30028385 TI - Treating Chronic Pain: Is Buprenorphine the (or Even an) Answer? PMID- 30028386 TI - The Mythology of Plasma Transfusion. PMID- 30028388 TI - Surveying the Literature: Synopsis of Recent Key Publications. PMID- 30028387 TI - Troubleshooting Technical Difficulties With Videolaryngoscope Use in Children: Initial Steps Toward Improving Tracheal Tube Passage. PMID- 30028389 TI - The Stress Hormone Cortisol Enhances Interferon-upsilon-Mediated Proinflammatory Responses of Human Immune Cells. AB - BACKGROUND: Cortisol is a prototypical human stress hormone essential for life, yet the precise role of cortisol in the human stress response to injury or infection is still uncertain. Glucocorticoids (GCs) such as cortisol are widely understood to suppress inflammation and immunity. However, recent research shows that GCs also induce delayed immune effects manifesting as immune stimulation. In this study, we show that cortisol enhances the immune-stimulating effects of a prototypical proinflammatory cytokine, interferon-upsilon (IFN-upsilon). We tested the hypothesis that cortisol enhances IFN-upsilon-mediated proinflammatory responses of human mononuclear phagocytes (monocyte/macrophages [MOs]) stimulated by bacterial endotoxin (lipopolysaccharide [LPS]). METHODS: Human MOs were cultured for 18 hours with or without IFN-upsilon and/or cortisol before LPS stimulation. MO differentiation factors granulocyte-macrophage colony stimulating factor (GM-CSF) or M-CSF were added to separate cultures. We also compared the inflammatory response with an acute, 4-hour MO incubation with IFN-upsilon plus cortisol and LPS to a delayed 18-hour incubation with cortisol before LPS exposure. MO activation was assessed by interleukin-6 (IL-6) release and by multiplex analysis of pro- and anti-inflammatory soluble mediators. RESULTS: After the 18-hour incubation, we observed that cortisol significantly increased LPS-stimulated IL-6 release from IFN-upsilon-treated undifferentiated MOs. In GM CSF-pretreated MOs, cortisol increased IFN-upsilon-mediated IL-6 release by >4 fold and release of the immune stimulant IFN-alpha2 (IFN-alpha2) by >3-fold, while suppressing release of the anti-inflammatory mediator, IL-1 receptor antagonist to 15% of control. These results were reversed by either the GC receptor antagonist RU486 or by an IFN-upsilon receptor type 1 antibody antagonist. Cortisol alone increased expression of the IFN-upsilon receptor type 1 on undifferentiated and GM-CSF-treated MOs. In contrast, an acute 4-hour incubation of MOs with IFN-upsilon and cortisol showed classic suppression of the IL-6 response to LPS. CONCLUSIONS: These results reveal a surprisingly robust proinflammatory interaction between the human stress response hormone cortisol and the immune activating cytokine IFN-upsilon. The results support an emerging physiological model with an adaptive role for cortisol, wherein acute release of cortisol suppresses early proinflammatory responses but also primes immune cells for an augmented response to a subsequent immune challenge. These findings have broad clinical implications and provide an experimental framework to examine individual differences, mechanisms, and translational implications of cortisol enhanced immune responses in humans. PMID- 30028390 TI - Rehabilitation of Postextractive Socket in the Premaxilla: A 12-Year Study on 27 Titanium Plasma Spray Resorbable Calcium Phosphate Coated Single Implants. AB - OBJECTIVES: The purpose of this study was to evaluate the peri-implant bone tissue level on postextractive resorbable calcium phosphate coated single implants placed in premaxillary sites grafted with autologous bone, anorganic bovine bone (ABB), platelet-rich plasma (PRP), and keratinized epithelial connective graft over 12 years. MATERIALS AND METHODS: A total of 27 patients received a postextractive single implant in premaxillary sites grafted with ABB and PRP. Two months later, a keratinized epithelial connective graft was applied and the implants loaded. Clinical and radiographical evaluations were performed at baseline, 6 and 18 months, 4 and 6 years after the implant insertion, and then every 2 years up to the 12th year. RESULTS: After 12 years, a total of 22 implants (81.48%), were available for the final data analysis; the implants achieved a 100% cumulative survival rate, and only a mild degree of periodontal tissue inflammation was recorded. The radiographic evaluation revealed a physiological marginal bone remodeling over the follow-up. CONCLUSION: Although a good preservation of the residual bone tissue in postextraction implant sites treated with keratinized epithelial connective tissue grafts was observed, the low number of treated cases does not allow us to propose this experimental protocol to all cases of bone defects but it certainly represents a new option. Further studies on a greater number of patients and using implants with different surface characteristics should be conducted for a better understanding of the indications of the proposed treatment. PMID- 30028391 TI - Use of Combination of Allografts and Xenografts for Alveolar Ridge Preservation Procedures: A Clinical and Histological Case Series. AB - AIM: To perform a clinical and histomorphometric evaluation of a combination of allograft and xenograft for alveolar ridge preservation (ARP) procedures. METHODS: Seven consecutive cases in need of nonmolar tooth extraction and posterior implant placement were treated by ARP, using a combination of a cortico trabecular allograft and a mineralized xenograft. All sites received a minimally traumatic tooth extraction, bone graft, collagen membrane placement, and flap closure as possible. Healing time was 4 months for the majority of cases. After tooth removal and just before implant installation, clinical measurements were taken; after the healing time, bone biopsies were taken. RESULTS: All sites healed uneventfully. Bone dimensional changes were small; a mid-buccal vertical bone gain of 1.0 mm (SD, 3.2 mm) and a horizontal bone reduction of 1.6 mm (1.6) were recorded. Histomorphometric analysis showed large variability in percentages of new bone (mean 22.3% [17.3], range: 1.8%-35.2%) and a considerable amount of residual bone graft material (mean 33.2% [13.2], range: 5.5%-45.8%). CONCLUSION: Favorable clinical results were observed after the use of the combined bone graft, although a large variability in tissue proportions was present at 4-month healing time, especially for new mature bone. PMID- 30028392 TI - Evaluation of Anatomical and Volumetric Characteristics of the Nasopalatine Canal in Anterior Dentate and Edentulous Individuals: A CBCT Study. AB - OBJECTIVE: To examine the nasopalatine canal (NPC) anatomical and volumetric measurements in anterior edentulous (AE) and anterior dentate (AD) individuals and to compare these findings according to sex, age, shape, and severity of resorption in the premaxilla. METHODS: Two hundred cone beam computed tomography images were divided into 2 groups: AE and AD. The diameter, the length of the NPC and the width, the length of the buccal bone anterior to the NPC were measured and recorded. Linear and volumetric measurement results were evaluated in terms of age, sex, dental status, shape, and severity of resorption. RESULTS: No significant differences were observed between the AE and AD groups in terms of the NPC volume (P = 0.289). In the AE group, the spindle shape had the highest volume, and in the same group, with aging, the volume significantly increased (P = 0.00). The mean NPC volume was found to be statistically significantly larger in males than females (P = 0.02). A statistically significant relation was observed between NPC volume and resorption status. CONCLUSION: Severe bone resorption due to sustained edentation complicated implant surgery because of the increase in incisive and nasal foramen diameters and decrease in buccal residual bone dimensions. The NPC volume was found fewer in edentulous patients, and by the resorption, the volume was decreased. PMID- 30028393 TI - Reconstruction of Contracted Eye Socket With Autogenic Dermal Sphere Connected to Epidermis. AB - BACKGROUND: Because of the deficiency of blood circulation and soft tissue, reconstruction of the eye socket for severe conjunctival sac stenosis in anophthalmic patients is very difficult. In this article, the authors report an innovative technique for conducting a 1-stage operation to reconstruct the contracted eye socket with an autogenic dermal sphere connected to the epidermis (ADSE). METHODS: Five patients, each having a single severely contracted eye socket and conjunctival sac, were included in this study. An ADSE was transplanted into the contracted eye socket and conjunctival sac. After the operation, several observation indexes were evaluated, such as the survival and stability of implanted autologous tissue, the improvement of the contracted eye socket, and the degree of patients' satisfaction with their appearance. RESULTS: All of the implanted epidermal and dermal tissues survived well after 6 months' observation. Although somewhat absorbed, the transplanted dermal ball was plump in the eye socket, and the epithelial tissues merged well with the residual conjunctival epithelium. Moreover, the transplanted epidermis assumed a mucosal appearance in 4 of 5 patients. After reconstruction of the eye socket, the size of the conjunctival sac and depth of the eye socket were corrected sufficiently for patients to wear an ocular prosthesis. CONCLUSIONS: The implantation of an ADSE can reconstruct a severely contracted eye socket in anophthalmic patients. Because of the high survival rate and limited absorption ratio, this 1-stage operation satisfied both patients and their ophthalmologists. PMID- 30028394 TI - Sinusitis Due to the Presence of a Dental Implant Inside the Maxillary Sinus. AB - The migration of a dental implant into the maxillary sinus is an uncommon event of occurrence. Disrespect for concepts of implantology, low alveolar bone density at the site, high incidence of masticatory force in posterior region, and clinical intercurrences predispose to failure in rehabilitation. PMID- 30028395 TI - Strategies to Evaluate Bilateral Cleft Lip Treatment. AB - OBJECTIVE: Evaluate treatment of patients with bilateral cleft lip operated during the last 10 years, using the methodology of Mortier and Anastassov. METHODS: A total of 84 patients were evaluated using a preoperative score assessing fissure severity and a postsurgical score assessing of uncorrected or secondary deformities. A pre- and postcorrelation analysis was performed to evaluate the gain and identify the main postoperative alterations, using Spearman's statistical test (P < 0.001). RESULTS: About 89.3% underwent surgery between 4 and 7 months. Surgical techniques used Millard 65.5% and Mulliken 34.5%. Presurgical evaluation classified fissures as mild (0%), moderate (2.4%), severe (19.1%), or very severe (78.6%). Postoperative evaluation classified results as poor (24%), satisfactory (12%), good (15, 6%), very good (34.6%), or excellent (14.3%). The postoperative changes on the lip were the notch in the vermilion and the defect in the edge of the vermilion, and in the bow of the wide cupid; in the nose, the most frequent were deficiency in the upper nasal nostril, insufficient rotation of the alar base, broad tip, and short columella; in the scar and alveolar portion, the most frequent were alveolar cleft, premaxilla protrusion, and poor scar. Spearman correlation of preoperative and postoperative was positive of 0.43. CONCLUSION: The proposed measurement method is technically simple and can be performed without equipment allowing pre- and postoperative evaluation to identify the main alterations to be corrected. PMID- 30028396 TI - Prevention of Vascular Anastomotic Stenosis With 2-Octylcyanoacrylate. AB - Although conventional microvascular anastomoses are well-studied, postoperative anastomotic stenoses remain a common surgical complication. The use of 2 octylcyanoacrylate to stabilize vascular anastomoses using a rabbit anastomosis model was investigated. A carotid artery anastomosis model was established in 20 New Zealand rabbits (2.5-3.0 kg): 10 underwent conventional anastomosis surgery with sutures only, while 10 underwent suture ligation, followed by the application of 2-octylcyanoacrylate. Vascular patency and pulse strength were observed after adhesive solidification. The artery diameter was measured preoperatively and at 5 minutes, 2 weeks, and 4 weeks postoperatively. An angiography was performed at 4 weeks postoperatively. Hyperplasia and the induced nitric oxide synthase (iNOS) content of the intima and media layers from the anastomotic stoma were assessed using immunohistochemistry. The artery inner diameter of experimental group decreased at each time point postoperatively (1.686 +/- 0.066 cm; 1.656 +/- 0.069 cm; 1.646 +/- 0.074 cm) (P <= 0.01). At 4 weeks postoperatively, the intima and the media around the anastomosis was both significantly thinner in the experimental group (13.21 +/- 0.84 MUm; 234.86 +/- 13.84 MUm) than in the control group (17.06 +/- 0.96 MUm; 279.88 +/- 34.22 MUm) (P < 0.05). At 4 weeks postsurgery, intravascular iNOS expression was increased in both groups but was higher in the experimental group (82.5% versus 47.5%). The above results indicated that 2-octylcyanoacrylate adhesive can inhibit stenosis of vascular anastomoses. PMID- 30028397 TI - Reduction of Supraorbital Fractures via a Short Sub-Brow Incision. AB - The authors report a short-incision supraorbital approach through an upper eyebrow skin incision that was used to treat supraorbital rim fractures in 2 patients.With the patient in the supine position, short incision lines were designed. Their length was usually less than 1 cm (1 or 2 mm medial to the frontal nerve and lateral to the supraorbital nerve), and they were designed at the inferior margin of the eyebrow to avoid injuring the frontal, supraorbital, or supratrochlear nerve. The skin was incised and blunt dissection was performed to reach the supraorbital rim. The periosteum was incised and a cleft palate periosteal elevator was introduced below the fracture segments. Gentle forward and upward traction was applied through the elevator and a click could be heard when the segment was reduced into its anatomical position. An intraoperative skull lateral X-ray was taken and the reduction was confirmed. The skin was repaired layer by layer.In supraorbital rim fractures, this short-incision supraorbital approach through an upper eyebrow skin incision could be applied without injuring the supraorbital nerve, instead of the bicoronal approach. PMID- 30028398 TI - The Application of Three-Dimensional Simulation Program and Three-Dimensional Printing in Secondary Rhinoplasty. AB - BACKGROUND: In recent years, efficacy of 3-dimensional (3D) simulation, in preoperative planning of aesthetic and reconstructive surgeries and prediction of the postoperative result, has been reported in many clinical studies. Especially in rhinoplasty, it can be used not only for prediction the outcome but also for fabricating implants that will strictly match with the anatomical needs of patient. CLINICAL REPORT: A 30-year-old male after traffic accident visited emergency room complaining on painful swelling and contour deformity of nose. Under the diagnosis of nasal bone fracture and deviated nose, he had been admitted to our hospital. Considering his medical history of rhinoplasty, which was performed in the local aesthetic clinic 6 years ago, the authors decided to perform the operation with 3D simulation program and 3D printed implant. There were no specific complications, such as hematoma, infection, or necrosis. Patient was discharged on fourth postoperation day. DISCUSSION: There is no doubt that creating an ideal dorsal aesthetic line is critically important in rhinoplasty. Therefore creating individual implants for certain patient's anatomical nasal structure is highly significant in the rhinoplasty. Although usefulness of primary rhinoplasty using patient-specific 3D implant is introduced in previous study, the authors successfully applied the patient-specific 3D implant to patient who has fracture of nasal bone and primary rhinoplasty history. It means that the patient-specific implants are stable and can be used not only in primary rhinoplasty patients but also for the patients who had primary rhinoplasty previously. PMID- 30028399 TI - Surgical Management of Strabismus in Patients With Orbital Fracture. AB - PURPOSE: Till date, the surgical policy of strabismus in patients with orbital fracture is scarcely described in literature. The purpose of this study was to describe the clinical features and surgical experience in patients with strabismus and persistent diplopia after orbital fracture repair, or in patients who need not receive surgery for orbital fracture. PATIENTS AND METHODS: Retrospective review was performed on patients with orbital fracture who received strabismus surgery between 2004 and 2016 in Eye Hospital, Zhongshan Ophthalimc Center, Sun Yat-sen University, China. The following clinical data were recorded from the patients' charts: the nature of fracture, age at surgery, preoperative motor alignment, stereoacuity, surgical methods, surgical outcomes, and complications. Deviations of 10 prism diopter (PD) or less of horizontal angle and deviation of 5 PD or less of vertical angle in the primary position were considered to be a successful outcome. RESULTS: A total of 29 patients (23 males and 6 females) with an average age of 32.4 +/- 16.6 years (2-61 years) were recruited in this study. The strabismus was paralytic in 16 patients, restrictive in 2 patients, and both paralytic and restrictive in 11 patients. The surgical methods were quite various in each patient; however, all patients underwent either rectus recession or rectus recession plus resection. With at least 6 months of follow-up, preoperative horizontal deviation of 32.79 +/- 22.84 PD was reduced to 6.69 +/- 13.01 PD (P < 0.01). The vertical deviation was reduced from 22.76 +/- 17.66 PD to 6.59 +/- 7.98 PD (P < 0.01). Sixteen patients (55.2%) were considered as success, whereas a surgical undercorrection was observed in 44.8%. There were no surgical complications. CONCLUSIONS: The clinical manifestations of strabismus in patients with orbital fracture or after fracture repair are quite complex, often involving both paralytic and restrictive factors. The surgical treatment of each patient needs to be individualized. The rectus muscle recession and resection seems to be predictable, effective, and stable. PMID- 30028400 TI - Horizontal Maxillary Osteotomy Stability Using Mandibular Outer Cortex Bone Grafts in Patients With Cleft Lip and Palate. AB - OBJECTIVE: To investigate horizontal maxillary osteotomy stability after using bone grafts for the treatment of patients with unilateral cleft lip and palate (UCLP). DESIGN: Retrospective cohort study. SETTING: Plastic surgery hospital. PATIENTS: Fifty-eight patients with UCLP and maxillary hypoplasia requiring a maxillary Le Fort I advancement of 6 to 9 mm. INTERVENTIONS: The test group (TG) was comprised of 28 patients who underwent mandibular outer cortex bone grafting in the gaps created by a modified Le Fort I osteotomy. The control group (CG) was comprised of 30 patients who underwent a Le Fort I osteotomy without bone grafts. MAIN OUTCOME MEASURES: Maxillary horizontal advancement (recorded during the operation using a Vernier caliper) and horizontal relapse at 12 months after surgery (based on a manual cephalometric analysis of pre- and postoperative lateral teleradiographs). RESULTS: In the TG, the mean maxillary horizontal advancement was 7.13 +/- 0.7 mm (range: 6.01-8.23 mm), and the mean postoperative horizontal relapse was 25.07 +/- 6.64%. In the CG, the mean maxillary horizontal advancement was 6.90 +/- 0.55 mm (range: 6.05-7.39 mm), and the mean postoperative horizontal relapse was 24.89 +/- 4.25%. There were no significant between-group differences in the mean horizontal relapses. CONCLUSION: The use of mandibular outer cortex bone grafts as physical barriers in patients with UCLP does not increase postoperative stability when the maxillary advancement is 6 to 9 mm. PMID- 30028401 TI - An Algorithmic Approach to the Management of Ballistic Facial Trauma in the Civilian Population. AB - Annual incidence of non-fatal ballistic civilian has been increasing for the last decade. The aim of the present study was to clarify the optimal reconstructive management of civilian ballistic facial injuries. A systematic review of PubMed was performed. Articles were evaluated for defect type and site, reconstructive modality, complications, and outcomes. A total of 30 articles were included. Most common region of injury was mandibular with a 46.6% incidence rate. All-cause complication rate after reconstruction was 31.0%. About 13.3% of patients developed a postoperative infection. Gunshot wounds had overall lower complication rates as compared with shotgun wounds at 9.0% and 17.0%. By region, complications for gunshot wounds were 35% and 34% for mandible and maxilla, respectively. Immediate surgical intervention with conservative serial debridement is recommended. However, for patients with pre-existing psychiatric disorders, secondary revisions should be delayed until proper psychiatric stabilization. When there is extensive loss of soft tissue in the midface, aesthetic outcomes are achieved with a latissimus dorsi or anterolateral thigh free flap. Radial forearm flap is favored for thin lining defects. Open reduction is suggested for bony-tissue stabilization. The fibula flap is recommended for bony defects >5 cm in both midface and mandible. For bony defects, <5 cm bone grafting was preferred. Delaying bone grafting does not worsen patient outcomes. Surgical treatment of ballistic facial trauma requires thorough preparation and precise planning. An algorithm that summarizes the approach to the main decision points of surgical management and reconstruction after ballistic facial trauma has been presented in this study. PMID- 30028402 TI - Evaluation of Heart Functions With Detailed Echocardiogram in Patients With Septum Deviation. AB - BACKGROUND: One of the most important reasons for nasal congestion is septum deviation. Nasal septal deviation increases airway resistance and can cause systemic problems. In this study, echocardiographic findings were compared with the normal population to see how cardiac function was affected in patients with obstructive nasal septum deviation. METHODS: This study included a young patient group with 44 obstructive septum deviation patients and 30 healthy individuals with no nasal-related problems. Echocardiography was performed by the same cardiologist and results were compared with normal patients. The authors got permission from the ethics committee of faculty for the study (E. 116795). RESULTS: In the patient group with septum deviation, pulmonary artery pressure was high. In addition, the size of the right heart chambers was also increased. TAPSE, pulmonary acceleration time, ejection fraction, and right ventricular outflow tract-fractional shortening were found to be lower than the normal group. CONCLUSION: Patients with obstructive septum deviations should be evaluated early for cardiologic functions. PMID- 30028403 TI - Split-Skin-Graft Wrapped Conformer to Treat Severe Contracted Sockets. AB - This case series present the surgical management of cases with severe contracted sockets using a split-skin-graft wrapped conformer. Eight patients with severely contracted anophthalmic sockets underwent surgery. The surgical technique is described and a chart review was performed to collect patient data pre- and postoperatively. Preoperatively, all patients had grade 3 or 4 contracted sockets with shallow or obliterated fornices and patients were unable to retain an external prosthesis in place. Donor material was harvested from the supraclavicular area. The split-skin-graft was successfully performed in all cases without fornix-deepening sutures. All patients underwent a significant improvement of socket contracture enabling retention of the prosthesis and were satisfied with the outcomes. The split-skin-graft wrapped conformer is a rapid and less surgically challenging option to correct severe contracted anophthalmic sockets. PMID- 30028404 TI - Cleft Alveolus Reconstruction Using a Three-Dimensional Printed Bioresorbable Scaffold With Human Bone Marrow Cells. AB - Bone tissue engineering technology based on scaffold has been applied for cleft lip and palate treatment. However, clinical applications of patient-specific three-dimensional (3D) scaffolds have rarely been performed. In this study, a clinical case using patient-specific 3D-printed bioresorbable scaffold with bone marrow stromal cells collected from iliac crest in the operating room has been introduced. At 6-month after transplantation, the bone volume of the newly regenerated bone was approximately 45% of the total defect volume. Bone mineral density of the newly regenerated bone was about 75% compared to the surrounding bone. The Hounsfield unit value was higher than that of cancellous maxillary alveolar bone and lower than that of the cortical maxillary alveolar bone. Bone marrow-derived mesenchymal stem cells-seeded 3D-printed patient-specific polycaprolactone scaffolds offer a promising alternative for alveolar cleft reconstruction and other bony defects. PMID- 30028405 TI - Stylohyoid Muscle Transfer in Marginal Mandibular Nerve Palsy. AB - Isolated paralysis of the marginal mandibular nerve results in an asymmetrical lip appearance with aesthetic and functional losses. Until today treatment options include mainly muscle transfers, and botulinium toxin injections for temporary issues. Since it was first reported by Edgerton, the technique of anterior belly of digastric transfer has been one of the most preferred. Alternatives for this technique still remain limited. In this clinical report, a new alternative technique was defined, stylohyoid muscle transfer, for the situations that digastric muscle is absent. The technique was compared with other conventional treatment methods and the outcomes were discussed. PMID- 30028406 TI - Anthropometric Analysis of the Dental Arches of Five-Year-Old Children With Cleft Lip and Palate. AB - This study aimed to analyze the dimensional alterations of the dental arches of 5 year-old children with cleft lip and palate and to compare these dimensions with children without oral clefts. One hundred twenty children were divided into the following groups: unilateral cleft lip (UCL), unilateral cleft lip and palate (UCLP), cleft palate (CP), and control (C). A specific software was used to digitize the dental casts and perform the anthropometric analyses through the measurement of transversal linear intercanine and intermolar distances on the maxilla and mandible. The intergroup comparisons of the maxillary dimensions exhibited that the intercanine distances of groups C and UCL were statistically greater than that of groups UCLP and CP. The intermolar distance was significantly smaller in group UCLP than in the other groups. No statistically significant difference occurred in the mandibular intercanine and intermolar distance among groups. The analysis of the superposition of the maxillary over the mandibular transversal distances showed statistically significant differences among groups. This study showed that at 5-year old, the children with cleft involving the palate had more maxillary dimensional alterations than those without cleft palate. PMID- 30028407 TI - Audiological Alterations in Patients With Cleft Palate. AB - INTRODUCTION: Chronic otitis media with effusion (OME) is a recurrent complication, usually found in cleft palate patients.Conductive hearing loss is the result of the Eustachian tube dysfunction caused by the absence of fusion and the altered insertion of the muscles of the secondary palate. It is also the consequence of an ineffective muscular reconstruction after primary cleft palate repair. METHODS: This is a cohort study to compare 4 groups of patients born with isolated cleft lip (ICL), unilateral cleft lip/palate (UCLP), bilateral cleft lip/palate (BCLP), and isolated cleft palate (ICP), received in our hospital between June 2015 to September 2017, operated by the same surgeon, using the same surgical technique and protocol.Complete cleft palate repair was performed, in average, at 10 months, and placement of ventilation tubes, if necessary, was made in the same operatory act.After palate repair, primary or secondary hearing loss was checked, joint to the connection with the type of used ventilation tubes, recurrences and complications also were considered. RESULTS: The study sample was integrated by 69 patients, 2 of 11 patients with ICL (18.18%), 30 of 34 patients with UCLP (88.23%), 17 of 19 patients with BCLP (89.47%), and 4 of 5 patients with ICP (80.00%) were diagnosed with OME requiring ventilation tubes at the time of surgery. It can be established that the average hearing loss in patients with diabolos in the postoperative period is 19.4 db and in those patients with T tubes it is 14.2 db, the difference being statistically significant (P < 0.05). CONCLUSION: Hearing improvement prior to language acquisition is essential for a proper speech development. Early trans tympanic tubes implantation during cleft palate repair contributes to a correct short-term ventilation of the middle ear, being the T tubes the best option. PMID- 30028408 TI - NOVEL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY BIOMARKER IN BRANCH RETINAL VEIN OCCLUSION MACULAR EDEMA. AB - PURPOSE: To evaluate the association between deep-superficial flow ratio (DSFR) and the treatment response of macular edema in branch retinal vein occlusion. METHODS: Thirty eyes from 30 patients with branch retinal vein occlusion who had received optical coherence tomography angiography examination were included. Seventeen normal fellow eyes acted as the control group. Patients were classified into the "good response group" and the "refractory group" by absence or presence of macular edema after 6 months of treatment. The DSFRs were calculated by dividing deep capillary plexus vessel density by superficial capillary plexus vessel density on optical coherence tomography angiography. RESULTS: The DSFR was 1.00 (SD +/- 0.05) over parafoveal area in the control group. Among branch retinal vein occlusion eyes, parafoveal DSFR remained stable in the good response group (P = 0.822) and significantly decreased in the refractory group (P = 0.002). The DSFRs in the most severe nonperfusion area were significantly lower in the refractory group than in the good response group (0.85 +/- 0.13 vs. 1.01 +/- 0.15, P = 0.004). The DSFR in the most severe nonperfusion area was associates with treatment response in multivariate logistic regression (P = 0.015). CONCLUSION: Deep-superficial flow ratio can represent the relative damage of deep capillary plexus to superficial capillary plexus. Decreased DSFR was found in branch retinal vein occlusion eyes with refractory macular edema. PMID- 30028410 TI - PATTERNS OF CHORIOCAPILLARIS FLOW SIGNAL VOIDS IN CENTRAL SEROUS CHORIORETINOPATHY: An Optical Coherence Tomography Angiography Study. AB - PURPOSE: To investigate choriocapillaris flow signal void distribution on optical coherence tomography (OCT) angiography in central serous chorioretinopathy (CSCR) and its correlation to choroidal vessel morphology. METHODS: Fifty-three CSCR eyes (48 patients) and 34 healthy control eyes were included, retrospectively. Exclusion criteria were refractive error >2D, previous laser or photodynamic therapy, low-quality OCT angiography, or excessive shadowing artifacts. Choriocapillaris OCT angiography scans were processed by local-threshold binarization to identify signal voids, and extract their cumulative area. The locations of the two largest voids in each eye were reported on the corresponding enhanced depth imaging OCT raster scan. Choriocapillaris thickness and diameter of underlying outer choroidal vessels were measured at the level of flow voids and of adjacent outer choroidal vessels, not colocalizing with voids. RESULTS: There were 22 acute, 16 recurrent, and 15 chronic CSCR eyes. Total flow void area was larger in CSCR than control eyes. In univariate analysis, the total flow void area on OCT angiography increased with age (P = 0.0002), duration since CSCR diagnosis (P = 0.004), extension of autofluorescence alterations (P = 0.016), and CSCR severity (P < 0.0001). In multivariate analysis, age (P = 0.014) and CSCR type (P = 0.046) influenced independently the total flow void area. On enhanced depth imaging OCT, outer choroidal vessel diameter was higher (P < 0.0001), and choriocapillaris was thinner (P < 0.0001) at flow voids compared with adjacent sites, independently from eccentricity from the fovea. CONCLUSION: Choriocapillaris flow voids colocalize with choriocapillaris thinning and deep choroidal vessel dilation in CSCR eyes. Age and CSCR severity influence choriocapillaris flow, a key contributor to CSCR pathophysiology and clinical expression. PMID- 30028409 TI - BILATERAL SIMULTANEOUS RHEGMATOGENOUS RETINAL DETACHMENT: Clinical Characteristics and Surgical Outcome. AB - PURPOSE: To elucidate the clinical characteristics and surgical outcome of consecutive patients with bilateral simultaneous retinal detachment who reported to a tertiary eye care institution over a period of 10 years. METHODS: Retrospective interventional consecutive study of 168 eyes of 84 patients with bilateral simultaneous retinal detachment, observed by indirect ophthalmoscopy at the initial examination was performed. Demographic and clinical characteristics were collected before and after surgery. Patients with attached retina at final follow-up were considered to have anatomical success and those with two or more lines improvement in visual acuity were considered to have functional success. RESULTS: Most cases (90% in the better eye and 82.1% in the worse eye) were managed by scleral buckling procedure. With scleral buckle, anatomical success was seen in 99% and functional success was seen in 87% of the cases. Pars plana vitrectomy was performed in remaining cases with anatomical success in 83% and functional success in 78% of cases. Eyes with partial retinal detachment, without macular involvement, and eyes in which additional surgeries were not performed had significantly better anatomical and functional results. CONCLUSION: Early sequential surgery gives good anatomical and functional outcomes. Surgical outcomes were better with scleral buckling than pars plana vitrectomy. PMID- 30028411 TI - AGE-RELATED MACULAR DEGENERATION-ASSOCIATED PERIPAPILLARY CHOROIDAL NEOVASCULARIZATION IN THE ERA OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY. AB - PURPOSE: To characterize the natural history and response of age-related macular degeneration-associated peripapillary choroidal neovascularization to anti vascular endothelial growth factor therapy. METHODS: This was a retrospective case series of patients with peripapillary choroidal neovascularization secondary to neovascular age-related macular degeneration. All patients underwent complete ophthalmologic examination and retinal imaging including fluorescein angiography and spectral domain optical coherence tomography at each visit. Eyes with subretinal or intraretinal macular fluid were treated with anti-vascular endothelial growth factor monotherapy using a modified as-needed treatment algorithm. RESULTS: Thirty-three eyes of 27 patients were included. The median age was 82 years (range, 62-94), and the median duration of follow-up was 65 months (range, 6-165). Fourteen eyes (58%) without fovea-involving fluid at baseline subsequently developed exudation after a median observation period of 16 months (range, 4-107). Ten of 24 eyes (42%) without initial macular fluid remained dry during the entire follow-up. The median number of injections required until complete fluid reabsorption was 3 (range, 1-21) during the first treatment cycle. The median time to fluid recurrence was 6 months (range, 3-74). CONCLUSION: Peripapillary choroidal neovascularization secondary to wet age related macular degeneration has a slow progression, may not require treatment for a prolonged period, and responds rapidly to anti-vascular endothelial growth factor treatment with good visual outcomes. PMID- 30028412 TI - Handover of Patients From Prehospital Emergency Services to Emergency Departments: A Qualitative Analysis Based on Experiences of Nurses. AB - BACKGROUND: During the transfer of patients, both ambulance and hospital emergency service professionals need to exchange necessary, precise, and complete information for an effective handover. Some factors threaten a quality handover such as excessive caseload, patients with multiple comorbidities, limited past medical history, and frequent interruptions. PURPOSE: To explore the viewpoint of nurses on their experience of patient handovers, describing the essential aspects of the process and areas for improvement, and establishing standardized elements for an effective handover. METHODS: A qualitative research method was used. RESULTS: Nurses identified the need to standardize the patient transfer process by a written record to support the verbal handover and to transmit patient information adequately, in a timely manner, and in a space free of interruptions, in order to increase patient safety. CONCLUSIONS: An organized method does not exist. The quality of handovers could be enhanced by improvements in communication and standardizing the process.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30028413 TI - Redesigning Hospital Diabetes Education: A Qualitative Evaluation With Nursing Teams. AB - BACKGROUND: Methods to deliver diabetes education are needed to support patient safety and glycemic control in the transition from hospital to home. PURPOSE: This study examined barriers and facilitators of integrating web-based, iPad delivered diabetes survival skills education (DSSE) into the nursing inpatient unit workflow. METHODS: Nurses, nurse managers, and patient care technicians (PCTs) from 3 medical-surgical and 2 behavioral health units participated in semistructured interviews and focus groups. RESULTS: Four themes emerged: educational program and content; platform usability; tablet feasibility (eg, theft prevention, infection control, and charging); and workflow considerations. Behavioral health unit-specific concerns were also identified. Findings indicated that nurses and PCTs were eager to find approaches to deliver DSSE. CONCLUSIONS: Implementation of a web-based DSSE program for inpatients needs adaptation to overcome challenges at the patient, care team, and process levels. PMID- 30028414 TI - Rethinking Regenerative Medicine From a Transplant Perspective (and Vice Versa). AB - No field in health sciences has more interest than organ transplantation in fostering progress in regenerative medicine (RM) because the future of no other field more than the future of organ transplantation will be forged by progress occurring in RM. In fact, the most urgent needs of modern transplant medicine - namely, more organs to satisfy the skyrocketing demand and immunosuppression-free transplantation -, cannot be met in full with current technologies and are at risk of remaining elusive goals. Instead, in the past few decades, groundbreaking progress in RM is suggesting a different approach to the problem. New, RM inspired technologies among which decellularization, 3D printing and interspecies blastocyst complementation, promise organoids manufactured from patients' own cells and bear potential to render the use of currently used allografts obsolete. Transplantation, a field that has traditionally been immunology-based, is therefore destined to become a RM-based discipline.However, the contours of RM remain unclear, mainly due to the lack of a universally accepted definition, the lack of clarity of its potential modalities of application and the unjustified and misleading hype that often follows the reports of clinical application of RM technologies. All this generates excessive and unmet expectations and an erroneous perception of what RM really is and can offer.In this manuscript, we will (i) discuss these aspects of RM and transplant medicine, (ii) propose a definition of RM, and (iii) illustrate the state of the art of the most promising RM-based technologies of transplant interest. PMID- 30028415 TI - Regenerative Medicine 3.TX: What Can We Learn About Organ Regeneration From Organ Replacement. PMID- 30028416 TI - A Clinical Decision Support System Can Help Facilitate Living Kidney Donor Assessments. PMID- 30028417 TI - Deep Profiling of the CD8+ T cell Compartment identifies Activated cell subsets and Multifunctional Responses Associated with Control of Cytomegalovirus Viremia. AB - BACKGROUND: Human cytomegalovirus (HCMV) is a common opportunistic pathogen in transplant recipients. Patterns of viremia and reactivation are influenced by the host immune response, including CD8 T cells. However, the cellular deficits or phenotypic differences that account for differential outcomes during HCMV viremia are incompletely understood. METHODS: PBMCs were collected from 20 transplant recipients (10 viremia controllers and 10 noncontrollers) at onset of HCMV viremia and 4-weeks post. We utilized mass cytometry to perform in-depth characterization of cell-surface and intracellular CD8 T cell markers and to compare frequencies of these cells between groups. RESULTS: Deep profiling identified 2 TCM subsets at onset and 5 TEMRA subsets at 4 weeks that were associated with control of HCMV viremia, in addition to 6 TEMRA subsets at onset and 4 weeks associated with relapsing or remitting HCMV viremia. In general, CD8 T cell clusters associated with poorly controlled HCMV viremia lacked markers of activation or terminal differentiation including CD38, CD69, CD25, CD57 and HLA DR. We also measured the production of 8 HCMV-specific effector molecules (TNFalpha, IFNgamma, IL2, granzyme B, perforin, MIP1beta, IL10 and CD107a) in CD8 T cells. Viremia controllers had greater diversity of HCMV-specific multi functional responses at both time points, including significantly higher frequencies of HCMV-specific TNFalphaIFNgamma CD8 T cells at onset. These multifunctional cells had a phenotype consistent with activated TEM/TEMRA cells. CONCLUSIONS: Uncontrolled CMV viremia is associated with specific clusters of memory T cell subsets and lower frequencies of HCMV-specific multifunctional CD8 T cells. PMID- 30028418 TI - Development of a Clinical Decision Support System for Living Kidney Donor Assessment Based on National Guidelines. AB - BACKGROUND: Live donor nephrectomy is an operation that places the donor at risk of complications without the possibility of medical benefit. Rigorous donor selection and assessment is therefore essential to ensure minimization of risk and for this reason robust national guidelines exist. Previous studies have demonstrated poor adherence to donor guidelines. METHODS: We developed a clinical decision support system (CDSS), based on national living donor guidelines, to facilitate the identification of contraindications, additional investigations, special considerations, and the decision as to nephrectomy side in potential living donors. The CDSS was then tested with patient data from 45 potential kidney donors. RESULTS: The CDSS comprises 17 core tasks completed by either patient or nurse, and 17 optional tasks that are triggered by certain patient demographics or conditions. Decision rules were able to identify contraindications, additional investigations, special considerations, and predicted operation side in our patient cohort. Seventeen of 45 patients went on to donate a kidney, of whom 7 had major contraindications defined in the national guidelines, many of which were not identified by the clinical team. Only 43% of additional investigations recommended by national guidelines were completed, with the most frequently missed investigations being oral glucose tolerance testing and routine cancer screening. CONCLUSIONS: We have demonstrated the feasibility of turning a complex set of national guidelines into an easy-to-use machine readable CDSS. Comparison with real-world decisions suggests that use of this CDSS may improve compliance with guidelines and informed consent tailored to individual patient risks. PMID- 30028420 TI - Impact of Internet Websites, Forums, and Blogs on the Orthopaedic Patient. PMID- 30028419 TI - Burnout: When It's More Than "Just a Bad Day". PMID- 30028421 TI - Comment on Adolescents' Experiences of Scoliosis Surgery and the Trajectory of Self-Reported Pain: A Mixed-Methods Study. PMID- 30028422 TI - Sickle Cell Disease: Bone, Joint, Muscle, and Motor Complications. AB - Sickle cell disease (SCD) is a group of inherited disorders caused by a mutation of the hemoglobin gene, resulting in the formation of abnormal, sickle-shaped red blood cells. It is a lifelong condition characterized by anemia, vaso-occlusion, and decreased blood flow to vital tissues. Sickle cell disease affects every major organ and significantly reduces life expectancy of the affected individuals. Patients with SCD are at an increased risk for developing musculoskeletal complications that decrease quality of life and contribute to the significant burden of the disease. Understanding these complications, as well as the genetics, pathophysiology, and epidemiology of SCD, will assist orthopaedic nurses in providing evidence-informed care. PMID- 30028423 TI - Sickle Cell Disease: Bone, Joint, Muscle, and Motor Complications. PMID- 30028425 TI - Low-Fidelity Code Blue Simulation on the Orthopaedic Unit. PMID- 30028424 TI - Low-Fidelity Code Blue Simulation on the Orthopaedic Unit. AB - Orthopaedic nurses care for a range of patients with comorbid conditions, but because of the implementation of Rapid Response Teams, rarely do orthopaedic patients experience cardiac or respiratory arrest. Rapid Response Teams decrease emergent arrest situations on nursing units by intervening to treat clinical deterioration or move patients to a higher level of care prior to cardiac or respiratory arrest. Orthopaedic nurses still need to be prepared to act emergently with basic life support skills, which are only renewed every 2 years. Review of actual code blue events and the implementation of low-fidelity code blue simulation may improve comfort levels and performance of basic life support skills. The purpose of this article is to describe how educators designed a low fidelity mandatory annual code blue simulation exercise for nurses to help increase confidence when faced with the rare cardiac or respiratory arrest emergency. The low-fidelity code blue simulation has been repeated annually and has been an effective exercise for orthopaedic nurses. PMID- 30028427 TI - Integrative Review for Patients With Bilateral Total Knee Replacement: A Call for Nursing Practice Guidelines. PMID- 30028426 TI - Integrative Review for Patients With Bilateral Total Knee Replacement: A Call for Nursing Practice Guidelines. AB - BACKGROUND: The aim of this joint project between the National Association of Orthopaedic Nurses and the Association of Rehabilitation Nurses was to develop nursing practice guidelines for patients who experience bilateral knee arthroplasty (BTKA) across the continuum of care. No guidelines existed and an integrative review was completed to address this gap. METHODS: An integrative review of refereed quantitative and qualitative research in published and gray literature was completed to answer the clinical questions: (1) What is the scope of evidence-based nursing interventions for patients undergoing BTKA? (2) What are patients' experiences with BTKA across the care continuum? The scope of the literature search was patients with bilateral and unilateral total knee arthroplasty. An evidence-based system was used to rate the strength of studies that met the criteria for inclusion in this review. RESULTS: The search method identified 588 potential titles but the analysis of the abstracts supported only 128 studies for possible inclusion in this project. The authors independently reviewed these studies and concluded that 126 studies did not meet the inclusion criteria and 2 quantitative studies were eligible for inclusion. CONCLUSIONS: Understanding which interventions are most effective for pain management, functional gains, quality of life, and other nurse-sensitive outcomes is best derived from empirical studies. Most likely, BTKA nursing care is being guided by clinical experts and not by empirical nursing evidence. In the absence of empirical evidence, it is feasible that nurses can extrapolate findings from other studies to guide and support the care of BTKA patients. Research recommendations include the exploration of early mobilization interventions, development of nursing care bundles, and evaluation of patient-centered outcomes at the points of transitional care. PMID- 30028428 TI - The Effect of Functional Disability and Quality of Life on Decision to Have Surgery in Patients With Lumbar Disc Herniation. AB - BACKGROUND/PURPOSE: This study aimed to determine the effect of functional disability and quality of life (QoL) on the decision to have surgery in patients with lumbar disc herniation (LDH). METHOD/DESIGN: This is descriptive and cross sectional survey. A total of 239 patients were included in the study. Data were collected using a personal information form, Surgical Belief and Attitudes Questionnaire (SBAQ), Visual Analog Scale (VAS), Oswestry Disability Index (ODI), Roland-Morris Disability Questionnaire (RMDQ) and Short Form-36 (SF-36). The data analysis was undertaken using Mann-Whitney U test, chi test, and logistic regression model. RESULTS: Patients were found to have low mean scores in the SF 36 subscales and SBAQ and high mean scores in ODI, RMDQ, and VAS. Six weeks after the first interview, 48.1% of patients decided to undergo surgery. A statistically significant difference was found between a decision to have surgery and the ODI, RMDQ, VAS, SBAQ scores and 6 of the 8 SF-36 subscales (except for role physical and general health; p < .05). Patients who had higher functional disability, pain intensity, and SBAQ score and those with lower QoL were more likely to decide to undergo surgery. CONCLUSIONS: The results of the study showed that patients with LDH who have been referred for surgery experience high functional disability and pain and a poor QoL, and that these factors have an impact on their decision to have surgery process. PMID- 30028429 TI - Anaesthesia for Hip Fracture Surgery in Adults. PMID- 30028432 TI - Meniscus Tear. PMID- 30028431 TI - Meniscus Tear. PMID- 30028433 TI - Change Management and a Culture of Ownership. PMID- 30028435 TI - Crutch Fitting. PMID- 30028434 TI - Crutch Fitting. PMID- 30028436 TI - New Certificants January 1-March 31, 2018. PMID- 30028437 TI - Reply. PMID- 30028438 TI - Reply. PMID- 30028439 TI - Correspondence. PMID- 30028440 TI - Reply. PMID- 30028441 TI - Correspondence. PMID- 30028442 TI - Reply. PMID- 30028443 TI - Pancreatic Fat Content Detected by Computed Tomography and Its Significant Relationship With Intraductal Papillary Mucinous Neoplasm. AB - OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic ductal adenocarcinomas (PDACs). Fat accumulation in the pancreas is increasingly recognized as a cause of PDAC. We aimed to identify factors that are relevant between IPMN and metabolic-related factors, including pancreatic fat. METHODS: The database for 781 subjects who underwent a health checkup and upper abdominal magnetic resonance imaging was searched and computed tomography attenuation indexes (pancreatic and spleen attenuation, pancreas-to spleen attenuation ratio) were decided by measuring the regions of interest in the pancreas and spleen on nonenhanced images, using Hounsfield units. Eighty five subjects from each of the IPMN and noncyst groups were matched for age, sex, and glycemic status and statistically compared in clinical characteristics. RESULTS: There was no difference in metabolic-related factors except for apolipoprotein A1 and high-density lipoprotein cholesterol between the 2 groups in univariate analysis. Multivariate logistic regression analysis showed that both indexes were significantly associated with IPMN (odds ratio, 0.905 [95% confidence intervals, 0.851-0.963; P = 0.002]; odds ratio, 0.006 [95% confidence intervals, 0.000-0.152; P = 0.002]). CONCLUSIONS: Pancreatic fat content measured by computed tomography was significantly associated with IPMN. These results suggest that IPMN may develop secondary to pancreatic steatosis that could be an overlapping risk factor for PDAC and IPMN. PMID- 30028445 TI - Comparison of the Survival Outcomes of Pancreatic Cancer and Intraductal Papillary Mucinous Neoplasms. AB - OBJECTIVES: The aims of the study were to compare survival outcomes between patients with pancreatic ductal adenocarcinoma (PDAC) and invasive intraductal papillary mucinous neoplasms (IPMN) and to determine candidates for adjuvant chemotherapy. METHODS: A total of 579 consecutive patients, including 375 PDAC and 204 IPMN patients, were reviewed. Stage-matched comparisons of survival data were conducted using the Cox proportional hazards model and propensity analysis. To evaluate prognostic factors, univariate and multivariate Cox regression analyses were performed. RESULTS: The overall survival for invasive IPMN was significantly longer than that for PDAC (hazard ratio, 2.34; P = 0.0001). When the analysis was limited to stage I patients, the 5-year overall survival rate of invasive IPMN patients was significantly better than that of PDAC patients (100% vs 74.1%, P = 0.0092); however, no difference was observed between stage II patients with invasive IPMN and PDAC (hazard ratio, 1.49; P = 0.09). The Cox proportional hazards model and propensity analysis demonstrated no difference in stage-matched survival. Multivariate analysis revealed that only T (>=3) was an independent prognostic factor for invasive IPMN. CONCLUSIONS: Stage-matched analysis did not show a significant survival difference between invasive IPMN and PDAC patients, and T3 or higher was an independent prognostic factor for invasive IPMN. PMID- 30028444 TI - Cholecystectomy During Index Admission for Acute Biliary Pancreatitis Lowers 30 Day Readmission Rates. AB - OBJECTIVES: Few studies have evaluated national readmission rates after acute pancreatitis (AP) in the United States. We sought to evaluate modifiable factors impacting 30-day readmissions after AP hospitalizations. METHODS: We used the Nationwide Readmission Database (2013) involving all adults with a primary discharge diagnosis of AP. Multivariable logistic regression models assessed independent predictors for specific outcomes. RESULTS: Among 180,480 patients with AP index admissions, 41,094 (23%) had biliary AP, of which 10.5% were readmitted within 30 days. The 30-day readmission rate for patients who underwent same-admission cholecystectomy (CCY) was 6.5%, compared with 15.1% in those who did not (P < 0.001). Failure of index admission CCY increased the risk of readmissions (odds ratio [OR], 2.27; 95% confidence interval [CI], 2.04-2.56). Same-admission CCY occurred in 55% (n = 19,274) of patients without severe AP. Severe AP (OR, 0.73; 95% CI, 0.65-0.81), sepsis (OR, 0.63; 95% CI, 0.52-0.75), 3 or more comorbidities (OR, 0.74; 95% CI, 0.68-0.79), and admissions to small (OR, 0.76; 95% CI, 0.64-0.91) or rural (OR, 0.78; 95% CI, 0.65-0.95) hospitals were less likely to undergo same-admission CCY. CONCLUSIONS: Same-admission CCY should be considered in patients with biliary AP when feasible. This national appraisal recognizes modifiable risk factors to reduce readmission in biliary AP and reinforces adherence to major society guidelines. PMID- 30028446 TI - Safety and Feasibility of Integrating Yttrium-90 Radioembolization With Capecitabine-Temozolomide for Grade 2 Liver-Dominant Metastatic Neuroendocrine Tumors. AB - OBJECTIVES: An integrated protocol combining capecitibine-temozolomide with yttrium-90 radioembolization (CapTemY90) for liver-dominant grade 2 neuroendocrine tumors (NETs) was designed in the hope of achieving synergistic improvement in liver disease control with no more than additive toxicities. This report describes the feasibility and safety of this regimen. METHODS: Twenty-one patients with unresectable grade 2 NET liver-dominant metastases without contraindications to radioembolization or to CapTem initiated therapy with capecitabine 600 mg/m twice daily for 14 days and temozolomide 150 to 200 mg/m in 2 divided doses on days 10 to 14, with 14 days between cycles. During the first cycle, simulation angiography was performed. The dominant lobe was radioembolized on day 7 of the second cycle. In patients with bilobar disease, the other lobe was treated on day 7 of the third or fourth cycle. RESULTS: Nineteen of 21 patients completed the protocol. Adverse events were as expected. Objective response rate was 74% in the liver and 55% for extrahepatic tumor. Median progression-free survival was not reached. Progression-free survival at 3 years was 67%, with 74% progression-free in the liver. CONCLUSIONS: CapTemY90 is feasible and safe for grade 2 NETs. Toxicities were additive. Oncologic outcomes suggest synergy. PMID- 30028447 TI - Pancreatic Pseudocysts and Parenchymal Necrosis in Patients With Autoimmune Pancreatitis: A Systematic Review. AB - OBJECTIVE: To investigate the prevalence and natural history of pancreatic pseudocysts (PCs) and parenchymal necrosis in autoimmune pancreatitis (AIP). METHOD: A search using PubMed, Embase, Scopus, and Cochrane was performed. Search terms were AIP, PC, acute fluid collection, and pancreatic necrosis. RESULTS: Fifteen studies with 17 patients were included. In 8 of 17 patients, PC was noted concurrently with the AIP diagnosis, whereas in the other half, PC appeared months or years after. In 10 of 17 cases, PC appeared as solitary. The location was variable. Pseudocysts were small (<3 cm) in 4 cases and large (>3 cm) in 13 cases. A normal pancreatic duct was observed in 6 of 17 cases, whereas 9 of 17 had pancreatic duct stenosis. Steroids were given to 4 of 4 small and 10 of 13 large PC. All small PC resolved with steroids, whereas only 4 of 10 large PC treated had some response. Most (9/13) of large PC underwent endoscopic or surgical procedures. None of the 17 cases developed necrosis. CONCLUSIONS: Pseudocysts in AIP are rare. Pancreatic pseudocyst can present in variable number, size, and location. Small PC resolved with steroids. Large PC had poor response to steroids requiring invasive interventions. Necrosis in AIP has not been reported. PMID- 30028448 TI - Utility of Endoscopic Ultrasound-Guided Biopsy for Next-Generation Sequencing of Pancreatic Exocrine Malignancies. AB - OBJECTIVES: Endoscopic ultrasound-guided fine-needle biopsy and aspiration (EUS FNB/A) are the standard diagnostic tests for pancreatic malignancies. Oncologists increasingly use tumor genomic analysis for management. Adequacy of FNB/A tissue for next-generation sequencing (NGS) has not been evaluated. This study examined FNB/A and other biopsy types for features that might predict adequacy for NGS. METHODS: Seventy-six pancreatic exocrine malignancy biopsies submitted for NGS were assessed for adequacy, which was compared with other tumor/biopsy features. RESULTS: Twenty-two (29%) of 76 samples were inadequate, including 16 (30%) of 54 FNBs and 4 (57%) of 7 FNAs. Larger-gauge needles were associated with adequacy in all samples (P = 0.0047) and in FNBs (P = 0.05). Metastatic samples were more likely to be adequate for NGS compared with pancreatic samples (P = 0.0357). Percutaneous biopsies were more likely to be adequate than EUS-guided FNB/As, although this trend was not significant (P = 0.0558). Other tumor/biopsy characteristics were not associated with adequacy. CONCLUSIONS: Endoscopic US FNA and FNB provided similar NGS adequacy rates. Metastatic lesions accessible by percutaneous biopsy may be preferable to EUS FNB/A of primary lesions for obtaining tissue for NGS. All biopsies, including EUS FNB, were more likely to be successful using larger-gauge needles. PMID- 30028449 TI - [Self-evaulation of personal physical health, accidents while performing duty and preventive treatment of stress in Prison Service]. AB - BACKGROUND: The purpose of the work was to assess the level of health, estimate the number of accidents during service and to identify the use and perceived effectiveness of the prevention of occupational stress in Prison Service (PS). MATERIAL AND METHODS: The questionnaire survey was carried out in 2015 at the Central Prison Service Training Center in Kalisz and in selected prisons and detention centers for the group of 250 officers. The questionnaire, which had been constructed for the purpose of the cooperation with the Occupational Safety Body of the Central Board of the Prison Service, was used. There were questions about the frequency of headaches, hypertension, sleep disorders, taking painkillers, accidents during service and prevention of occupational stress. RESULTS: For frequent headaches, sleep disorders and hypertension complain 9-14% of officers. Every 8th officer in the period of 5 years preceding the survey had an accident during his service. Participation rate in the stress prevention and interpersonal training workshops accounted for 70%, and most officers consider them to be effective. The lack of the possibility to make holidays in accordance with the schedule represents the percentage share of 10% of the sample tested, and every 20th of the PS must stop it due to the situation in the service. It was revealed that preferences in the area of applied coping strategies turned out to be slightly differentiating between officers undertaking and not undertaking activity in the field of occupational stress prevention. CONCLUSIONS: Officers serving in the multi-shift system and with a longer service period should be covered by greater prevention from the PS work medicine. Conducting training in the prevention of occupational stress should take place at the beginning of the service. Med Pr 2018;69(4):425-438. PMID- 30028450 TI - Nanoscale surface dynamics of Bi2Te3(111): observation of a prominent surface acoustic wave and the role of van der Waals interactions. AB - We present a combined experimental and theoretical study of the surface vibrational modes of the topological insulator Bi2Te3. Using high-resolution helium-3 spin-echo spectroscopy we are able to resolve the acoustic phonon modes of Bi2Te3(111). The low energy region of the lattice vibrations is mainly dominated by the Rayleigh mode which has been claimed to be absent in previous experimental studies. The appearance of the Rayleigh mode is consistent with previous bulk lattice dynamics studies as well as theoretical predictions of the surface phonon modes. Density functional perturbation theory calculations including van der Waals corrections are in excellent agreement with the experimental data. Comparison of the experimental results with theoretically obtained values for films with a thickness of several layers further demonstrate, that for an accurate theoretical description of three-dimensional topological insulators with their layered structure the inclusion of van der Waals corrections is essential. The presence of a prominent surface acoustic wave and the contribution of van der Waals bonding to the lattice dynamics may hold important implications for the thermoelectric properties of thin-film and nanoscale devices. PMID- 30028451 TI - Surface dependent enhancement in water vapor permeation through nanochannels. AB - Selective permeation of water vapor over liquid phase water through hydrophobic conduits finds broad use in separation processes, including desalination and membrane distillation. The tangential momentum accommodation coefficient (TMAC), a fundamental parameter that dictates momentum changes to a molecule colliding with a wall remains unknown for water vapor at room temperature and pressure conditions. Here, a nanofluidic platform with tunable hydrophobic regions that selectively barricaded flow of liquid water was patterned within glass nanochannels. The surface functionalization with an alkyltrichlorosilane led to either a fluoride or a methyl terminal group generating partially hydrophobic regions along the length of the nanochannels. Differential osmotic pressure solutions on either side of the hydrophobic region cause an isothermal evaporation-condensation process, which drives net water vapor transport from higher to lower vapor pressure solution, similar to osmotic distillation. Water vapor transport under such conditions for the 80 nm deep nanochannels was in the transitional regime with the Knudsen number ~O(1). The TMAC was estimated experimentally to be of the order of 10-4-10-3 for both the hydrophobic coatings leading to a near-elastic collision of H2O molecules with the nanochannel walls. Use of the low TMAC surfaces was evaluated in two proof-of-concept technology demonstrations: (1) osmotic distillation using hyper-saline (brine) 3 M Utica shale flowback water as both the feed and draw and (2) separation of trace amounts of toluene and chloroform from water at high flux and selectivity. The results reported here likely provide new insights in designing hydrophilic hydrophobic junctions for nanoscale liquid/vapor fluid transport with enhanced flux and selectivity. PMID- 30028452 TI - Organophosphoric acid-derived CoP quantum dots@S,N-codoped graphite carbon as a trifunctional electrocatalyst for overall water splitting and Zn-air batteries. AB - Developing highly efficient, low-cost, and multifunctional electro-catalysts to replace noble metals is of significant importance for energy storage and conversion systems. Herein, we demonstrate a facile strategy for the preparation of CoP quantum dots (QDs) embedded in S,N-codoped graphite carbon (CoP@SNC) by using organophosphoric acid as both phosphorus and carbon sources. Benefiting from the strong coupling and synergistic effect between CoP QDs and highly conductive S,N-codoped carbon, well-structured porosity and high specific surface area, the resulting CoP@SNC exhibits excellent activities for oxygen evolution reaction (OER), hydrogen evolution reaction (HER), and oxygen reduction reaction (ORR), making it a trifunctional electro-catalyst for overall water splitting and rechargeable Zn-air batteries. When CoP@SNC is used for overall water splitting, a cell voltage as low as 1.64 V is required to reach the current density of 10 mA cm-2; the obtained rechargeable Zn-air battery with CoP@SNC as the air cathode exhibits a high open-circuit voltage of 1.45 V, a very low discharge-charge voltage gap (0.83 V at 10 mA cm-2), and a long cycle life (up to 180 cycles). This work not only offers a new strategy for the synthesis of CoP@SNC but also presents its huge potential as a trifunctional electro-catalyst for clean energy systems. PMID- 30028453 TI - A theoretical insight into an isentropic strategy for enhancing magnetoelectric coupling of organic multiferroics. AB - The cross-coupling between magnetic and ferroelectric orders in spin-driven organic multiferroics provides great potential for realizing multi-state logic memory. Creating strong magnetoelectric coupling around room-temperature is the key to eliminate the main roadblock for practical application. Herein, quantum correlation controlled means are employed to tune the transition temperature TC = 300 K, as the optimal operating temperature. After that, based on the magnetocaloric or electrocaloric effect, a temperature mediated mechanism is proposed to enhance magnetoelectric coupling within an isentropic rather than an isothermal process. Furthermore, a moderate magnetic field combined with a relatively weak electric field can jointly control and dramatically enhance the isentropic magnetoelectric coupling around room-temperature. PMID- 30028454 TI - Detection of a transient FeV(O)(OH) species involved in olefin oxidation by a bio inspired non-haem iron catalyst. AB - The Fe(TPA) (TPA = tris(pyridyl-2-methyl)amine) class of non-haem Fe catalysts is proposed to carry out selective hydrocarbon oxidations through the generation of high-valent iron species. Using ambient mass spectrometry, we obtain direct evidence for the formation of an FeV(O)(OH) species under catalytic conditions. In addition, 18O-labelling suggests that this FeV(O)(OH) species serves as the active oxidant in hydrocarbon oxidation catalysis. PMID- 30028455 TI - Correction: An efficient and recyclable ionic diphosphine-based Ir-catalyst for hydroaminomethylation of olefins with H2O as the hydrogen source. AB - Correction for 'An efficient and recyclable ionic diphosphine-based Ir-catalyst for hydroaminomethylation of olefins with H2O as the hydrogen source' by Huan Liu et al., Chem. Commun., 2018, 54, 7979-7982. PMID- 30028456 TI - Controlling the phase and morphology of amorphous Se nanoparticles: their prolonged stabilization and anticancer efficacy. AB - Applications of amorphous Se nanoparticles (NPs) are limited due to their meticulous synthetic procedures and rapid phase transformation leading to low stability. A highly facile one-pot green method is being reported, wherein apart from tuning the morphology and the phase of the Se NPs, their stabilization could be prolonged to months as compared to a few minutes-to-days, known hitherto. PMID- 30028457 TI - TopoFF: MOF structure prediction using specifically optimized blueprints. AB - For the structure prediction of MOFs and related crystalline framework materials we have proposed the Reversed Topological Approach (RTA), where the default embedding of a topology is used as a blueprint. The optimal rotational insertion of the building blocks (BBs) at the fixed vertex positions of the blueprint is performed by minimizing the target function of the average angle deviation (AAD). Here we extend this idea by pre-optimizing the maximum symmetry embedding of a topology in order to minimize the overall mean AAD for the given set of BBs. By this fast and essentially parameter-free topoFF method, the vertex positions and cell parameters of the blueprint are further optimized in order to fit the structural needs of the BBs, which speeds up the overall search for the most energetically favorable structure. In addition, different topologies can be ranked in a quantitative and intuitive way. The definition and implementation of topoFF is explained and its application for the RTA-based structure prediction of MOFs is demonstrated with a number of instructive examples. PMID- 30028458 TI - Diastereoselective self-assembly of bisheptahelicene on Cu(111). AB - Stereochemical effects during two-dimensional crystallization of bisheptahelicene diastereomers on a Cu(111) surface have been studied with scanning tunnelling microscopy. The (M,M)- and (P,P)-enantiomers crystallize into a monolayer racemate lattice, whereas the (M,P)-diastereomers aggregate into their own monolayer phase. PMID- 30028459 TI - Self-assembly of conformationally flexible molecules under 2D confinement: structural analysis from computer simulations. AB - Monte Carlo simulations were used to decipher the individual role of tripod molecular conformers in the surface-confined metal-organic self-assembly. Our calculations revealed the extent of structural heterogeneity introduced by the different conformers. PMID- 30028460 TI - Segregation of polymers under cylindrical confinement: effects of polymer topology and crowding. AB - Monte Carlo computer simulations are used to study the segregation behaviour of two polymers under cylindrical confinement. Using a multiple-histogram method, the conformational free energy, F, of the polymers was measured as a function of the centre-of-mass separation distance, lambda. We examined the scaling of the free energy functions with the polymer length, the length and diameter of the confining cylinder, the polymer topology (i.e. linear vs. ring polymers), and the packing fraction and size of mobile crowding agents. In the absence of crowders, the observed scaling of F(lambda) is similar to that predicted using a simple model employing the de Gennes blob model and the approximation that the free energy of overlapping chains in a tube is equal to that of two isolated chains each in a tube of half the cross-sectional area. Simulations were used to test the latter approximation and reveal that it yields poor quantitative predictions. This, along with generic finite-size effects, likely gives rise to the discrepancies between the predicted and measured values of scaling exponents for F(lambda). For segregation in the presence of crowding agents, the free energy barrier generally decreases with increasing crowder packing fraction, thus reducing the entropic forces driving segregation. However, for fixed packing fraction, the barrier increases as the crowder/monomer size ratio decreases. PMID- 30028461 TI - Influence of amino acid sequence in a peptidic Cu+-responsive luminescent probe inspired by the copper chaperone CusF. AB - Copper(i) is a soft metal ion that plays an essential role in living organisms and Cu+-responsive probes are required to detect Cu+ ions in physiological conditions and understand its homeostasis as well as the diseases associated with its misregulation. In this article, we describe a series of cyclic peptides, which are structurally related to the copper chaperone CusF, and that behave as Cu+-repsonsive probes. These peptide probes comprise the 16-amino acid loop of CusF cyclized by a beta-turn inducer dipeptide and functionalized by a Tb3+ complex for its luminescence properties. The mechanism of luminescence enhancement relies on the modulation of the antenna effect between a tryptophan residue and the Tb3+ ion within the probe when Cu+ forms a cation-pi interaction with the tryptophan. Here, we investigate the influence of the amino acid sequence of these cyclic peptides on the copper-induced modulation of Tb3+ emission and show that the rigid beta-turn inducer Aib-d-Pro and insertion of the Tb3+ complex close to its tryptophan antenna are required to obtain turn-on Cu+ responsive probes. We also show that the amino acid sequence, especially the number and position of proline residues has a significant impact on metal-induced luminescence enhancement and metal-binding constant of the probes. PMID- 30028462 TI - Inexpensive NaX (X = I, Br, Cl) as a halogen donor in the practical Ag/Cu mediated decarboxylative halogenation of aryl carboxylic acids under aerobic conditions. AB - Versatile and practical Ag/Cu-mediated decarboxylative halogenation between readily available aryl carboxylic acids and abundant NaX (X = I, Br, Cl) has been achieved under aerobic conditions in moderate to good yields. The halodecarboxylation is shown to be an effective strategy for S-containing heteroaromatic carboxylic acid and benzoic acids with nitro, chloro and methoxyl substituents at the ortho position. A gram-scale reaction and a three-step procedure to synthesize iniparib have been performed to evaluate the practicality of this protocol. A preliminary mechanistic investigation indicates that Cu plays a vital role and a radical pathway is involved in the transformation. PMID- 30028463 TI - Correction: A facile and high-yield formation of dipyrrin-boronic acid dyads and triads: a light-harvesting system in the visible region based on the efficient energy transfer. AB - Correction for 'A facile and high-yield formation of dipyrrin-boronic acid dyads and triads: a light-harvesting system in the visible region based on the efficient energy transfer' by Masaki Yamamura et al., Org. Biomol. Chem., 2015, 13, 2574-2581. PMID- 30028464 TI - Isomeric cationic ionenes as n-dopant agents of poly(3,4-ethylenedioxythiophene) for in situ gelation. AB - Three isomeric ionene polymers containing 1,4-diazabicyclo[2.2.2]octane (DABCO) and N,N'-(x-phenylene)dibenzamide (x = ortho-/meta-/para-) linkages have been used as dopant agents to produce n-doped poly(3,4-ethylenedioxythiophene) (PEDOT) electrodes by reducing already dedoped conducting polymer (CP) films. This work focuses on the influence of the ionene topology on both the properties of n-doped PEDOT:ionene electrodes and the success of the in situ thermal gelation of the ionene inside the CP matrix. The highest doping level is reached for the para isomeric ionene-containing electrode, even though the content of ortho- and meta topomers in the corresponding n-doped PEDOT:ionene electrodes is greater. Thus, many of the incorporated ionene units are not directly interacting with CP chains and, therefore, they do not play an active role as n-dopant agents but they are crucial for the in situ formation of the ionene hydrogels. The effect of the ionene topology is practically non-existent on properties such as the specific capacitance and wettability of PEDOT:ionene films, and it is small but non negligible on the electrochemical and thermal stability. In contrast, the surface morphology, topography, and distribution of dopant molecules significantly depend on the ionene topology. In situ thermal gelation was successful in PEDOT films n doped with the ortho- and para-topomers, even though this assembly process was much faster for the former than for the latter. The gelation considerably improved the mechanical response of the electropolymerized PEDOT film, which was practically non-existent before it. Molecular dynamics simulations prove that the strength and abundance of PEDOTionene specific interactions (i.e. pi-pi stacking, N-HS hydrogen bonds and both N+O and N+S interactions) are higher for the meta isomeric ionene, for which the in situ gelation was not achieved, than for the ortho- and para-ones. PMID- 30028465 TI - The anti-soiling performance of highly reflective superhydrophobic nanoparticle textured mirrors. AB - The anti-soiling (AS) performance of solar mirrors coated with a highly transparent, superhydrophobic nanoparticle-textured coating has been characterized. The AS coatings were created on the mirror surface by depositing nano-textured silica nanoparticle layers of ~250 nm thickness using a draw-down coating process, followed by fluorination of the nanoparticles in a molecular vapor deposition process. Highly uniform surface features of the AS-coated mirrors (20 * 30 cm2, no measurable loss in specular reflectance, and water contact angle >165 degrees ) provided an outstanding AS performance. A 4* reduction in the rate of dust accumulation as determined by gravimetric measurement of the accumulated dust on coated versus uncoated mirrors was observed. Additional evidence of a significant reduction in soiling rate was determined during measurements of specular reflectance in an outdoor environment test. The adhesion force between a model sand particle and nano-textured coatings in the hydrophobic to superhydrophobic range was also studied. A dramatic decrease in adhesive force acting on the particle was observed with increasing surface hydrophobicity. The results align well with the observed dust accumulation on the AS-coated mirrors. The AS-coated mirror maintains a high reflectivity by shedding dust and resisting dust accumulation, providing a potential benefit when applied to mirrors in the solar field of a concentrated solar power generation plant. PMID- 30028466 TI - How accurate are static polarizability predictions from density functional theory? An assessment over 132 species at equilibrium geometry. AB - Static polarizabilities are the first response of the electron density to electric fields, and are therefore important for predicting intermolecular and molecule-field interactions. They also offer a global measure of the accuracy of the treatment of excited states by density functionals in a formally exact manner. We have developed a database of benchmark static polarizabilities for 132 small species at equilibrium geometry, using coupled cluster theory through triple excitations (extrapolated to the complete basis set limit), for the purpose of developing and assessing density functionals. The performance of 60 popular and recent functionals are also assessed, which indicates that double hybrid functionals perform the best, having RMS relative errors in the range of 2.5-3.8%. Many hybrid functionals also give quite reasonable estimates with 4-5% RMS relative error. A few meta-GGAs like mBEEF and MVS yield performance comparable to hybrids, indicating potential for improved excited state predictions relative to typical local functionals. Some recent functionals however are found to be prone to catastrophic failure (possibly as a consequence of overparameterization), indicating a need for caution in applying these. PMID- 30028467 TI - Correction: Lithographically fabricated gold nanowire waveguides for plasmonic routers and logic gates. AB - Correction for 'Lithographically fabricated gold nanowire waveguides for plasmonic routers and logic gates' by Long Gao et al., Nanoscale, 2018, 10, 11923 11929. PMID- 30028468 TI - Transition-metal-free synthesis of polysubstituted pyrrole derivatives via cyclization of methyl isocyanoacetate with aurone analogues. AB - Presented herein is an unprecedented transition-metal-free cyclization of methyl isocyanoacetate with aurone analogues catalyzed by NaOH. Various 2,3,4 trisubstituted pyrroles were obtained in excellent yields (up to 99%). The high efficiency of this synthetic procedure, coupled with the operational simplicity and atom economy, makes it an attractive method for the synthesis of polysubstituted pyrroles. PMID- 30028470 TI - Split resonances for simultaneous detection and control measurements in a single bulk acoustic wave (BAW) sensor. AB - A self-referenced resonator consisting of two distinct areas of the top electrode made from Mo and a thin (5-30 nm) functional Au layer is shown. The fundamental frequencies for both the shear (~1 GHz) and longitudinal (~2 GHz) modes are split in two, such that mass attachment on the functional layer region causes frequency shifts in only one of the resonances, allowing a new approach of using the difference between the two frequencies to be used to measure mass attachment; this reduces the importance of device-to-device variability in absolute resonant frequency as a result of device fabrication. PMID- 30028469 TI - Stability and degradation of indocyanine green in plasma, aqueous solution and whole blood. AB - Fluorescence-based imaging has evolved into an important technology during recent years. Specifically indocyanine green (ICG) has invaded most fields of diagnostic and interventional medicine. Considering the numerous advantages of the substance like the rapid degradation and rare adverse reactions, ICG is currently the most commonly used fluorescing agent. High-performance liquid chromatography (HPLC) was used for measuring absorbance and fluorescence of ICG and its potential degradation compounds. Stability and degradation were evaluated under light exposure or in darkness at various temperatures. Under these conditions, degradation of ICG was evaluated over a period of 11 days. Additional, stability measurements of ICG were performed in EDTA whole blood samples at 37 degrees C incubation temperature while monitoring. Furthermore, we used mass spectrometric (MS) and nuclear magnetic resonance (NMR) analyses for the identification of supposed ICG degradation compound. Potential quenching effect of ICG was examined in aqueous and plasma solutions at concentrations ranging from 0.01-100 MUg ml-1. When diluted in water and stored at 4 degrees C in the dark, ICG is stable for three days with only 20% of fluorescence intensity lost in this time-span. ICG incubated at 37 degrees C in whole blood under light exposure is stable for 5 h. In our study we observed the degradation of ICG into two degradation compounds with a mass of m/z 785.32 and m/z 1501.57, respectively. Based on our observations we suggest that ICG should be used within one or two days after preparation, if the ICG solution is stored at 4 degrees C. PMID- 30028471 TI - Reduction of graphene oxide alters its cyto-compatibility towards primary and immortalized macrophages. AB - Graphene oxide (GO) and its derivatives (e.g., reduced graphene oxide, RGO) have shown great promise in biomedicine. Although many studies have been conducted to understand the relative cyto-compatibility between GO and RGO materials, the results are inconclusive and controversial. In this study, we compared the biocompatibility aspects (e.g. cytotoxicity, pro-inflammatory effects and impairment of cellular morphology) between parental and reduced GOs towards macrophages using primary bone marrow-derived macrophages (BMDMs) and J774A.1 cell line. Two RGOs (RGO1 and RGO2) with differential reduction levels relative to the parental GO were prepared. Intriguingly, besides loss of oxygen-containing functional groups, significant morphological alteration of GO occurred, from the sheet-like structure to a polygonal curled shape for RGO, without significant aggregation in biological medium. Cytotoxicity assessment unveiled that the RGOs were more toxic than pristine GO to both types of cells. It was surprising to find for the first time (to our knowledge) that GO and RGOs elicited different effects on the morphological changes of BMDMs, as reflected by elongated protrusions from GO treatment and shortened protrusions from the RGOs. Furthermore, RGOs induced greater pro-inflammatory responses than GO, especially in BMDMs. Compromised cyto-compatibility of RGOs was attributable (at least partially) to their greater oxidative stress in macrophages. Mechanistically, these differences in bio-reactivities between GO and RGO should be boiled down to (at least in part) the synergistic effects from the variation of oxygen containing functional groups and the distinct morphology in between. This study unearthed the crucial contribution of reduction-mediated detrimental cellular effects between GO and RGO towards macrophages. PMID- 30028472 TI - Application of a micro-meso-structured reactor (NETmix) to promote photochemical UVC/H2O2 processes - oxidation of As(iii) to As(v). AB - A micro-meso-structured reactor (NETmix) was used for the first time to promote photochemical UVC/H2O2 processes. The NETmix photoreactor consists of a network of chambers and channels, where the liquid flows, sealed with a quartz slab with high UVC transparency. Due to the small size of channels and chambers, the NETmix presents a uniform irradiance through the entire reactor depth, short molecular diffusion distances and large specific interfacial areas, maximizing the pollutant/oxidant contact. In this study, the NETmix photoreactor was evaluated for As(iii) oxidation to As(v) using a photochemical UVC/H2O2 system. The effect of the UVC lamp power (4, 6 or 11 W), the number of UVC lamps (2 or 3 lamps) and the UVC lamp layout (parallel or perpendicular to the flow direction) was evaluated, in order to ensure uniform irradiation of the entire reaction mixture. The optimum H2O2 concentration for each light distribution system was also evaluated. At the best configuration, 3 lamps of 11 W positioned parallel to the flow direction, total As(iii) oxidation ([As(iii)]0 = 1.33 * 10-2 mM) was achieved in 15 min with an absorbed photon flux density of 1.9 * 10-1 einstein per m3 per s. Significant differences were highlighted between the photon flux actually received in the photoreactor and the radiant power emitted by the lamp. A kinetic model able to represent the As(iii) oxidation employing UVC radiation and H2O2 in a micro-meso-structured reactor was presented. The photochemical space time yield (PSTY) values obtained for the micro-meso-structured reactor are higher than for conventional batch reactors, showing that the NETmix technology can be a good solution for application in photochemical processes. PMID- 30028473 TI - Comparison of the T-cell response to human cytomegalovirus (HCMV) as detected by cytokine flow cytometry and QuantiFERON-CMV assay in HCMV-seropositive kidney transplant recipients. AB - Human cytomegalovirus (HCMV)-specific T-cell response in kidney transplant recipients (KTR) helps to identify patients at risk for severe infection. To assess the T-cell response, this study compared our in-house developed reference test, based on T-cell (both CD4+ and CD8+) stimulation by autologous HCMV infected dendritic cells (iDC) and subsequent detection by cytokine flow cytometry (CFC-iDC), with the Quanti-FERON-CMV (QF-CMV) assay. Fifty-three HCMV seropositive KTR were enrolled. At the DNAemia peak, 33 (62%) had low viral load (LVL, <3x105 DNA copies/mL) self-resolving infection, 19 (36%) high viral load (HVL, >3x105 DNA copies/mL) infection treated with antivirals, and one LVL patient (2%) tissue-invasive disease alone. Both assays showed a delayed recovery of HCMV-specific T-cell immunity in HVL vs LVL patients. Immune reconstitution kinetics did not significantly differ between the two assays in HVL patients. QF CMV and CFC-iDC showed comparable sensitivities, but QF-CMV had a lower (although not significantly) specificity. Indeed, 7/19 HVL patients (37%) were erroneously considered protected from severe infection by QF-CMV, whereas CFC-iDC misidentified only 3/19 (16%) patients as protected. Although our reference test takes longer to complete, it appears slightly better at predicting patients at risk for severe HCMV infection. Moreover, QF-CMV may provide false negative results with some HLA types. PMID- 30028474 TI - A first molecular characterization of Listeria monocytogenes isolates circulating in humans from 2009 to 2014 in the Italian Veneto region. AB - Listeriosis is a disease usually associated with the consumption of low-processed ready-to-eat food products contaminated by Listeria monocytogenes. In Italy, listeriosis has an incidence of 0.19-0.27 cases per 100000 persons. Since detailed information concerning the molecular characterization of listeriosis in the Italian Veneto region is currently lacking, we analyzed 36 L. monocytogenes clinical isolates collected between 2009 and 2014. Results show that the serotype 1/2a was the most represented among the tested samples. No antimicrobial resistance was detected in selected isolates representing the main pulsotypes. PMID- 30028476 TI - [Patient satisfaction with nursing practices about postoperative pain management: A systematic review]. AB - OBJECTIVES: The aim of this study was to investigate patient satisfaction with nursing practices regarding postoperative pain management. METHODS: A systematic review of the literature published between 2005 and 2015 was conducted, comprising a search of 7 databases: ScienceDirect, Turkish Medline, PsycINFO, Ovid, Prequest, Google Scholar, and the ULAKBIM Turkish Medical Database. Five articles were identified as eligible for review. The methodological quality of the studies was assessed using the Turkish version of the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI -MAStARI) Critical Appraisal Checklist. The data were extracted using a standard data extraction form developed for this study, and subsequently evaluated. RESULTS: In the articles eligible for this review, the study samples comprised patients with blunt or penetrating trauma sent to the emergency room (n=418) and those who underwent total knee replacement (n=120); heart, lung, or gastrointestinal system surgery (n=559); or open heart surgery (n=52). The maximum pain score was 7.20+/ 1.95 (min-max: 0-10) and the maximum satisfaction score was 100%. The findings revealed that pharmacological methods were most frequently used for postoperative pain management and non-pharmacological methods were not used sufficiently by nurses. Nevertheless, the patients were satisfied with the postoperative pain relief nursing care. CONCLUSION: In this systematic review, scientific evidence indicated that patient satisfaction with nursing practices related to postoperative pain management was high; however, non-pharmacological methods were used insufficiently in the last decade. PMID- 30028475 TI - Detection of ST1702 Escherichia coli blaNDM-5 and blaCMY-42 genes positive isolates from a Northern Italian hospital. AB - We describe two multi drug-resistant (MDR) carbapenemase-producing Escherichia coli clinical isolates from an acute hospital in Milan. Both strains, isolated from a surgical wound sample and a surveillance rectal swab respectively, were positive for a blaNDM-type gene by Xpert Carba-R test. The whole-genome sequence characterization disclosed several resistance determinants: blaNDM-5, blaCMY-42, blaTEM-198, rmtB, mphA. The two isolates belonged to phylogenetic group A, sequence type (ST) 1702 and serotype O89:H9. PCR-based replicon typing and conjugation assay demonstrated an IncI1 plasmid localization for both blaNDM-5 and blaCMY-42 genes. This is the first report of a ST1702 NDM-5 and CMY-42- producing E. coli clone in Italy. PMID- 30028477 TI - Effect of applying reflexology massage on nitroglycerin-induced migraine-type headache: A placebo-controlled clinical trial. AB - OBJECTIVES: Nitroglycerin (NTG)-induced migraine-type headache is the most prominent side effect of nitrate therapy. Therefore, the aim of this study was to clarify the effectiveness of reflexology massage on intravenous NTG-induced headache in coronary care unit (CCU) inpatients. METHODS: This was a randomized clinical trial. The study sample included 75 patients that were randomly divided into three groups: control, intervention, and placebo groups. The intensity of baseline headache in patients who received NTG was measured by the numeric rating scale for pain (NRS Pain). Patients in the intervention group received reflexology massage two times for 20 min (at 3-h interval), wherein the upper part of patient's both foot thumbs, which is the reflection point of the head, was massaged. In the placebo group, an unspecified point on the foot (heel), which was not related to the head, was massaged. Patients in the control group did not receive any massage. RESULTS: No baseline differences existed among the three groups for the mean pain scale score (p=0.66) before the study; but the difference between the groups after the application was statistically significant (p=0.000). CONCLUSION: Reflexology massage can reduce the intensity of NTG induced headache. PMID- 30028478 TI - Evaluation of the effects of subcostal transversus abdominis plane block on acute and subacute pain development following inguinal herniography: Randomized clinical study. AB - OBJECTIVES: The effect of subcostal transversus abdominis plane (TAP) block on postoperative pain is contradictive. The aim of this study was to evaluate the effect of subcostal TAP block on subacute pain in patients who have undergone inguinal herniography. METHODS: Patients aged between 18 and 75 years with American Society of Anesthesiologists 1-3 and who were to undergo elective unilateral inguinal herniography with mesh under general anesthesia were included. Fifty patients were under an intravenous analgesic regimen (group I) and 50 patients underwent subcostal TAP block postoperatively in addition to the intravenous analgesic regimen (group II). The primary outcome measure was pain scores 1 month postoperatively by comparing Numerical Rating Scale values with the Mann-Whitney U test between groups I and II. Secondary outcome measures were life qualification scores 1 month postoperatively and pain scores 24 h and 15 days postoperatively. RESULTS: Postoperative 15th-min; 1st-, 6th-, 12th-, and 24th-h; 15th-day (p=0.00); and 1st-month Numerical Rating Scale values were significantly lower in group II than in group I (p=0.02). No significant difference was observed between the groups in terms of LQS 15 days postoperatively (p=0.013). On group comparison, LQS was higher in the 1st month than at the 15th day postoperatively in group I (p=0.201). CONCLUSION: Subcostal TAP block provides an effective postoperative pain treatment in the acute period and in the 1st postoperative month in patients undergoing inguinal herniography. PMID- 30028479 TI - Effect of proprioceptive training on balance in patients with chronic neck pain. AB - OBJECTIVES: The aim of this randomized controlled study was to investigate the effect of proprioceptive training on balance in patients with chronic neck pain (CNP). METHODS: Forty patients participating in the study were randomly divided into study and control groups. Both of the groups underwent conventional physical therapy; additionally, the study group was rehabilitated with gaze direction recognition exercise (GDRE) for proprioceptive training. Exercises were performed during 3 weeks with five sessions per week. Pain intensity [visual analog scale (VAS)], neck disability [Neck Disability Index (NDI)], and balance [four step square test (FSST), single leg balance test (SLBT) with eyes opened and closed] assessments were conducted in the patients before and after the treatment and 3 weeks after the last session. RESULTS: No differences were observed between the groups in terms of pre-treatment measurements. There was a statistically significant decrease in VAS scores in both groups compared with pre-treatment conditions (p<0.05). In addition, whereas a statistically significant improvement in the study group's NDI, FSST, and SLBT with eyes opened and closed scores was observed after the treatment, pre- and post-treatment results were similar in the control group (p>0.05). CONCLUSION: Proprioceptive training should be included in physiotherapy programs to improve balance; it decreases the disability level in patients with CNP. PMID- 30028480 TI - Laparoscopic gastrostomy under awake thoracic epidural anesthesia: A successful experience. AB - General anesthesia is the first choice as an anesthesia method particularly for abdominal operations. However, because neuromuscular blockade induced during general anesthesia will increase atelectasis in a patient with pulmonary disease, it will also increase postoperative ventilator dependence, which will be even more apparent in cases of chronic obstructive pulmonary disease (COPD) that pose a risk, particularly for postoperative complications. Herein, thoracic epidural anesthesia (TEA) was found to be a better option for our patient with severe COPD and stage IV lung cancer, as it provided sufficient anesthesia and better postoperative care for laparoscopic gastrostomy. PMID- 30028481 TI - Idiopathic intracranial hypertension without headache: A case report and literature review. AB - This study reports the case of a 23-year-old man with idiopathic intracranial hypertension (IIH) who presented with blurred vision and diplopia, without accompanying headache. Although headache is the most common symptom associated with IIH, occasionally, it may not be observed clinically. This situation is more frequently observed in males, young adults, children, and in patients with low body mass index. This case highlights a crucial aspect; patients who present with serious visual symptoms without headache must be treated aggressively because vision loss will develop rapidly. PMID- 30028482 TI - Unruptured aneurysm producing thunderclap headache treated with endovascular coil embolization. AB - The abrupt onset of acute, high-intensity headache, unlike any experienced before, can be an urgent medical condition, which requires attention. A 32-year old female patient developed thunderclap headache attacks had applied with increasing intensity and frequency since 1 week. She had visited the emergency department several times, and cranial computed tomography findings were normal. On the last presentation, neurological examination showed complete oculomotor nerve palsy on the left. Brain magnetic resonance imaging together with intracranial brain angiography revealed left posterior communicating aneurysm compressing the ipsilateral oculomotor nerve, with no evidence of subarachnoid hemorrhage. The patient was treated with endovascular balloon-assisted coil embolization of the aneurysm under digital subtraction angiography. As a result, the headache resolved soon after the intervention. Furthermore, complete ptosis recovered by the third month. Although thunderclap headache has rarely been attributed to an enlarging unruptured cerebral aneurysm, early recognition and treatment are rather important as it may indicate a high risk of rupture. PMID- 30028483 TI - Ultrasound-guided distal adductor canal catheter placement for continuous postoperative analgesia in lower leg surgery. PMID- 30028484 TI - Effect of beta-glucan on serum levels of IL-12, hs-CRP, and clinical outcomes in multiple-trauma patients: a prospective randomized study. AB - BACKGROUND: Trauma is associated with a profound immunological dysfunction. This predisposes patients to infections and adverse outcomes. beta-glucan has been implicated in the initiation of anti-microbial immune response. The present study aimed to evaluate the effects of an enteral diet containing beta-glucan on serum levels of IL-12 and highly-sensitive C-reactive protein (hs-CRP), occurrence of infection, and clinical outcomes in critically ill multiple-trauma patients. METHODS: Forty multiple trauma patients requiring enteral nutrition for at least 10 days were randomly assigned to the intervention group (n=20) or the placebo group (n=20). The intervention group received a high-protein enteral diet providing 3 g beta-glucan, and the control group received a similar diet, except for 3 g of maltodextrin as a placebo. Serum levels of IL-12 and hs-CRP were measured on days 0, 10, and 21. RESULTS: The beta-glucan group showed significantly higher serum levels of IL-12 on day 21 compared to the control group. Infection frequency and duration of mechanical ventilation were significantly lower in the beta-glucan group. A significant difference was found in the Sequential Organ Failure Assessment (SOFA) score in favor of the beta glucan group. No difference was found in the serum levels of hs-CRP, length of ICU stay, occurrence of infection, and mortality rates between the two groups. CONCLUSION: beta-glucan may increase serum levels of IL-12, shorten the duration of mechanical ventilation, and reduce organ failure in critically ill multiple trauma patients. PMID- 30028485 TI - Top 100 cited articles in traumatology: A bibliometric analysis. AB - BACKGROUND: In this bibliometric study, we aimed to conduct multi-dimensional citation analysis of the top 100 cited articles in traumatology. METHODS: We analyzed the top 100 cited articles among 56.980 trauma articles published between 1975 and 2017, which we obtained from databases in Web of Science and PubMed based on their citation rates and publication years, countries of origin, institutions or organizations, the most common subjects, funding status, article types, and levels of evidence. RESULTS: In the top 100 cited articles, the number of total authors was 649 and average authorship was 6.49+/-5.46 (1-32); group author or study group number was eight, and the number of total collaborators was 1241. USA was the top country in terms of country of origin and institutions or organizations and also the number of proceedings papers in scientific activities. We found that 70 of the top 100 cited articles were supported by funding agencies in developed countries. In the present study, the three most common subjects were central nervous system trauma (21 articles), major trauma-hemorrhage-bleeding control-transfusion-early coagulopathy (18 articles), and trauma care and systems (eight articles), respectively. The average level of evidence of the top 100 cited articles was 2.45+/-1.05 (range: 1-4). We also found that 66 of the 100 most frequently cited articles in traumatology were published in scientific journals that had an impact factor of >=2.6 (range: 2.648-72.406). We found that the most commonly preferred article type by authors is clinical research (92 articles) and sub-type is prospective comparative studies (27 articles). Evidence groups of classical papers in traumatology were B (54 articles), A (26 articles), and C (20 articles), respectively. CONCLUSION: Despite some flaws in determining the scientific values of articles, citation analysis of classical papers in traumatology can provide important scientific contributions. PMID- 30028486 TI - The epidemiology of acute occupational hand injuries treated in emergency departments in Foshan City, South China. AB - BACKGROUND: Despite the magnitude of occupational hand injuries, there are no authoritative guidelines for hand injury prevention, and little research has been done to investigate the epidemiology of acute occupational hand injuries in South China or other developing areas. In this study, the epidemiology of acute occupational hand injuries treated in emergency departments (EDs) in Foshan City, South China, was examined and data were supplied to assist with preventive strategies in similar developing regions. METHODS: A multicenter study was prospectively designed and conducted in 5 large hospital EDs in Foshan City from July 2010 to June 2011. An anonymous questionnaire was designed specifically to collect the data for this study. RESULTS: A total of 2142 patients with acute occupational hand injury completed the questionnaire within the 1-year study period. Results indicated that most occupational hand injuries were caused by machinery. Hand injury type and site of the injury did not correspond to age, but were related to gender and job category. July and August 2010 were the peak periods of admission to EDs, while January and February 2010 were the trough periods. CONCLUSION: Epidemiological data enhance our knowledge of acute occupational hand injuries and could play a role in the prevention and treatment of future occupational hand injuries. PMID- 30028487 TI - Emergency computed tomography for the diagnosis of acute appendicitis: How effectively we use it? AB - BACKGROUND: Technological developments support using ultrasonography (US) in all patients, if available, and advanced diagnostic methods such as abdominal computed tomography (CT) in case of clinical suspicion during diagnostic process of acute appendicitis. We aimed to investigate whether CT was appropriately and efficiently used in the diagnosis of acute appendicitis. METHODS: Between May 2013 and February 2016, 811 patients who underwent appendectomy were retrospectively reviewed from an IRB-approved database, and those who underwent a preoperative CT were enrolled into the study. Results of Alvarado scores and US were recorded in addition to which clinic requested the CT (general surgery or emergency department). RESULTS: The frequency of CT use in the diagnostic process was 25% (n=208/811). Ultrasound was negative for appendicitis in 53% of these patients. The mean Alvarado score was 5+/-1.5 (range: 3-8). General surgeons requested 57% of CTs. Alvarado scores were significantly higher in patients whose CT was requested by general surgery than in those whose CT was requested by the emergency clinic (5.6 vs. 4.7, p=0.013). Regarding histopathological results, age and Alvarado scores were significantly lower (p=0.015 and 0.037, respectively), whereas the frequency of negative CT was significantly higher (p=0.042) in those with negative appendectomy (n=29, 14%). CONCLUSION: Most patients who underwent CT in the diagnostic process had an Alvarado score between 5 and 8 and negative ultrasound for appendicitis preoperatively. These findings may provide efficient use of CT in the diagnosis of appendicitis with an acceptable rate of 25% compared with the findings in current literature. However, further research is needed to ensure more efficient use of CT because negative appendectomy has been a concern in our series despite promising results of this study. PMID- 30028488 TI - Multislice computed tomographic measurements of optic nerve sheath diameter in brain injury patients. AB - BACKGROUND: Currently, the measurement of optic nerve sheath diameter (ONSD) has been offered as a possible indicator of intracranial pressure (ICP). Increased ICP is observed during intracranial injury. The objective of this study was to evaluate the relationship between increased ONSD and positive intracranial findings from multislice computed tomography (CT) of the brain. METHODS: In total, CT scans of 161 patients were retrospectively reviewed. The image that showed the largest ONSD was magnified five times. RESULTS: The CT scan revealed intracranial lesions in 54 patients and no intracranial lesions in 107 patients. A significant relationship was observed between positive CT findings and increased ONSD: 5.60+/-0.75 mm vs. 5.35+/-0.75 mm (p=0.038). The area under the receiver operating characteristic curve was 0.600 (95% confidence interval, 0.508 0.692; p<0.039). A cut-off value of >=5.0 mm had a sensitivity and specificity of 80% and 36%, respectively. CONCLUSION: This study demonstrated a significant yet poor relationship between intracranial injury and increased ONSD from the multislice CT scan. Severe structural changes in the brain and trauma that causes bleeding have only limited effects on the extension of the optic nerve. PMID- 30028489 TI - Effects of temporary abdominal closure methods on mortality and morbidity in patients with open abdomen. AB - BACKGROUND: Open abdomen (OA) in which the abdomen is closed with temporary abdominal closure methods is the most effective in patients who develop severe abdominal sepsis or abdominal compartment syndrome. Major techniques used are Vacuum-Assisted Closure Method (VACM) and non-vacuum assisted closure method (NVACM). In the present study, the effects of different abdominal closure methods on morbidity and mortality were evaluated. METHODS: In the study, the temporary abdominal closure methods of the patients with OA during 2013-2016 were studied retrospectively. OA etiopathologies, mortality prediction scores, final abdominal closure periods and methods, hospitalization periods, complications (enteroatmospheric fistula, mesh infection, and incisional hernia), and mortality rates of patients who underwent VACM and NVACM were determined and compared. RESULTS: The present study included 123 patients who underwent VACM (n=65) and NVACM (n=58). There was no difference between the groups in terms of age, gender, and etiopathogenesis (p>0.05). The mean APACHE 4 and Multiple Organ Dysfunction Score (MODS) scores in the VACM/NVACM groups in treatment period were 47/63 and 11/14, respectively (p<0.05). The mean intensive care and hospitalization periods in the VACM/NVACM groups were 11/16 (days) and 22/28 (days), respectively (p<0.05). The collection and abscess development rates in the VACM and NVACM groups were 46.2% and 77.6%, respectively (p<0.05). The rate of enteroatmospheric fistula (EAF) development in the VACM and NVACM groups were 15.4% and 56.9%, respectively (p<0.05). The mean abdominal closure times in the VACM and NVACM groups were 13 and 17 days, respectively (p<0.05). Mortality rate in the VACM and NVACM groups were 18% (n=18) and 55% (n=32), respectively (p<0.05). CONCLUSION: In patients with OA, the temporary abdominal closure technique VACM has lower complication and mortality rates and shorter hospitalization period than other methods. Therefore, it is an effective and safe method for the treatment of OA. PMID- 30028490 TI - Utility of HAPS for predicting prognosis in acute pancreatitis. AB - BACKGROUND: Acute pancreatitis (AP) is a common abdominal disorder, which requires early diagnosis and treatment. Several prognostic scoring systems introduced to clinical practice are not suitable in emergency department (ED) because these require much time and complex parameters. Recently, the harmless acute pancreatitis score (HAPS) has been introduced to identify AP with a nonsevere course. The aim of this study was to determine the utility of HAPS in predicting the severity of AP. METHODS: All patients aged >16 years who were diagnosed as AP in ED were enrolled in this retrospective study. The study included 144 patients with a mean age of 58.7+/-15.4 years, and 69 (47.9%) of them were males and 75 (52.1%) were females. Patient data were collected from hospital database. The utility of HAPS was analyzed and compared using the Ranson's score. RESULTS: HAPS was statistically significant for predicting mild disease (p=0.008) and has demonstrated a specificity of 81%, a positive predictive value (PPV) of 96%, and an odds ratio of 5.57 (1.51-20.50). The predictability of Ranson's scores was not significant. The measure of agreement (kappa) between the two scores was 0.15, indicating a low agreement. CONCLUSION: HAPS is a simple and useful scoring algorithm to predict the non-severe course of AP in ED. HAPS-0 patients did not require early aggressive treatments and advanced radiological screening tools during the early stages of the disease. PMID- 30028491 TI - Efficacy of laboratory tests and ultrasonography in the diagnosis of acute appendicitis in gravid patients according to the stages of pregnancy. AB - BACKGROUND: Normal physiologic changes during pregnancy result in similar laboratory and symptomatology changes as those during acute appendicitis (AA), making the diagnosis extremely difficult. The aim of the present study was to analyze the efficacy of conventional laboratory and radiologic tests in the diagnosis of AA according to different stages of pregnancy. METHODS: Twenty-five pregnant patients with pathologically confirmed AA operated at our department between 2012 and 2017 were retrospectively analyzed in terms of changes in conventional laboratory parameters as well as neutrophil-to lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios to aid the diagnosis of AA according to different stages of pregnancy. RESULTS: There were no significant changes in C reactive protein levels, leukocyte and neutrophil counts, and accuracy of ultrasonography between patients in the first (group 1) and second + third trimesters (group 2) (p>0.05). Lymphocyte count was significantly lower (p>0.05), whereas NLR and PLR were significantly higher in group 2 (p<0.05). CONCLUSION: Laboratory values change significantly during pregnancy, and NLR and PLR seems to be valuable tools for evaluating AA in a stage-specific manner in pregnant patients. PMID- 30028492 TI - Adherence to vaccination recommendations after traumatic splenic injury. AB - BACKGROUND: The occurrence of a serious infection called overwhelming post splenectomy infection (OPSI) increases more than 50 times in patients who have hyposplenia. The aim of this study was to investigate the adherence to vaccination recommendations after traumatic splenic injury. METHODS: We identified patients who underwent total splenectomy due to abdominal trauma between May 2012 and March 2016. We recorded the clinical, laboratory, and pathological features of the patients. We calculated the vaccination proportions before discharge, after discharge, and final. RESULTS: Twenty-seven patients underwent total splenectomy. For the vaccination status before discharge, after discharge, and final, the number of patients who received all the three vaccinations were 0 (0%), 0 (0%), and 8 (18.5%) and those who received none were 13 (48.2%), 11 (40.8%), and 9 (33.4%), respectively. The data of 17 patients were available for developing OPSI. The median follow-up time was 17.8 (4.4-41.2) months, and no OPSI cases were observed. CONCLUSION: Adherence to vaccination recommendations remains still low. Establishing a vaccination tracking system and following vaccination recommendations will be helpful to prevent serious infections, such as OPSI, after traumatic splenectomy. PMID- 30028493 TI - Antivenom use in bite and sting cases presenting to a public hospital. AB - BACKGROUND: To evaluate the distribution of bite and sting cases presenting to a district public hospital and the use of antivenom in scorpion sting and snake bite cases. METHODS: The demographic characteristics of patients with bites/stings reporting to a public hospital in 2014, the agent involved, the season of reporting, severity of clinical findings during presentation, and use of antivenom in scorpion sting and snake bite cases were evaluated retrospectively. chi2 test was used for statistical analysis. RESULTS: Bite and sting cases comprised 0.5% of all the patients reporting to the hospital's emergency department, with scorpion sting cases comprising almost half (54.2%) of these hospital presentations, followed by Hymenoptera (bee and wasp) sting (30.8%) and snake bite (5.5%) cases. Unnecessary antihistamine administration was found to be significantly high in asymptomatic patients (p=0.00006). Furthermore, antivenom use was found to be significantly high in patients with scorpion sting and snake bite despite the absence of systemic or local indications (p<0.0001, chi2=80.595). CONCLUSION: The study results showed that antivenom was used in scorpion sting and snake bite cases even when it was not indicated. Therefore, primary practitioners should be provided training for management of envenomation cases and should be made aware of the updated guidelines and references to raise their knowledge levels. PMID- 30028494 TI - Initial inferior vena cava and aorta diameter parameters measured by ultrasonography or computed tomography does not correlate with vital signs, hemorrhage or shock markers in trauma patients. AB - BACKGROUND: Ultrasonography (US) is noninvasive, readily available, and cheap. The diameter of inferior vena cava (dIVC) and its respiratory variation were proposed as a good surrogate of the hemodynamic state. However, recent studies have shown conflicting results, and the value of IVC-derived parameters in the estimation of fluid status and hemorrhage remains unclear. METHODS: This was an observational study of trauma patients who presented to emergency department. dIVC and aorta diameter (dAorta) were measured at the initial US and CT in all patients. The correlation of these measurements and all parameters derived from those measurements along with the initial vital signs and laboratory values of hemorrhage (hemoglobin, hematocrit) and shock (lactate, base excess) were assessed. US and CT values were also compared for accuracy using Bland-Altman analysis. RESULTS: The final study population was 140, with a mean age of 38 years and 79.3% were male. dIVC and dAorta did not have any clinically significant correlation with any of the vital signs or laboratory values of hemorrhage or shock when measured by US or CT. A good and significant correlation was observed between dIVC and dAorta measured by US and CT. CONCLUSION: The value of an initial and single measurement of IVC and aorta parameters in the evaluation of trauma patients should be questioned. However, the change in the measured parameters may be of value and should be investigated in further studies. PMID- 30028495 TI - Comparison of the functional results of radial head resection and prosthesis for irreparable mason type-III fracture. AB - BACKGROUND: The radial head is essential for the rotational stability of the forearm and resistance to valgus stress. Radial head fractures are the most common elbow fracture in adults. Various treatment options are available, depending on the fracture severity. However, the treatment of Type-III fractures is controversial. The aim of this study was to evaluate functional results in patients with irreparable Mason Type-III radial head fractures treated with radial head resection or prosthesis. METHODS: Fourteen irreparable Mason Type-III radial head fracture patients treated with radial head resection (n=7) or radial head prosthesis (n=7) were evaluated in this multicenter, retrospective study. Disabilities of the Arm, Shoulder and Hand (DASH) and Mayo Elbow and Wrist scores were used to determine clinical outcomes. A hydraulic hand dynamometer was used to measure grip strength on the operated and unoperated sides to avoid potential bias. Measurements were made three times for each extremity, and the mean value was recorded. Grip strength was calculated as a percentage of the strength of the unoperated side. RESULTS: Functional outcomes for resection and prosthesis patients were the following: mean DASH scores, 25.8 and 17.2; mean Mayo Elbow scores, 74 and 84.1; mean Mayo Wrist scores, 84 and 92.5; and maximum grip strengths, 48.8% and 77.8%, respectively. The range of motion of the respective resection and prosthesis groups were as follows: flexion, 112.14 degrees and 104.29 degrees ; extension, -10.00 degrees and -25.00 degrees ; pronation, 70.00 degrees and 47.86 degrees ; and supination, 70.00 degrees and 52.14 degrees . CONCLUSION: Although range of motion was restricted in the radial head resection group, functional results and grip strength were superior in patients treated with a radial head prosthesis. These results support the radial head prosthesis as a superior treatment modality for patients with irreparable Mason Type-III radial head fractures with respect to patient satisfaction and functional outcomes. PMID- 30028496 TI - Reconstruction of extensive scalp defects with anterolateral thigh flap. AB - BACKGROUND: Extensive scalp defects caused by various etiologies often require free-tissue transfer. We aimed to review our experience in the reconstruction of extensive scalp defects with free anterolateral flaps. METHODS: A retrospective analysis was performed on all patients with extensive scalp defects that were reconstructed with free anterolateral thigh flaps from November 2007 to April 2015. Eleven patients with a mean age of 44 years were included in this study. RESULTS: Eleven free-tissue transfers were used to reconstruct the extensive scalp defects. The flaps were 7-14 cm in width and 10-34 cm in length. CONCLUSION: Microvascular free-tissue transfer is the mainstay for the treatment of extensive scalp defects. We recommend anterolateral thigh free flap use for challenging and complex cases, given the method's numerous advantages, including reliability and safety. PMID- 30028497 TI - Three-dimensional printing-assisted surgical technique with limited operative exposure for both-column acetabular fractures. AB - BACKGROUND: It is often difficult to achieve satisfactory reduction and fixation of both-column acetabular fractures owing to the complexity of the regional anatomy of the pelvis and the fracture configuration, which is commonly associated with a high degree of comminution. Herein, we describe the use of a three-dimensional (3D) patient-specific printed model of the pelvis to facilitate preoperative planning, simulate the fracture reduction procedure, and pre-contour the fixation plates for treating both-column acetabular fractures. METHODS: The 3D-printed model was constructed using a fused deposition modeling method with computed tomography images as inputs. Operative and clinical outcomes were evaluated for 5 patients with both-column acetabular fractures (mean age: 41.4 years). The status of fracture reduction was classified using the Matta criteria, and the functional outcome was assessed using the modified Merle d'Aubigne score. RESULTS: Reduction was classified as excellent in 4 patients and good in 1 patient, and good functional outcomes were achieved in all patients at the final follow-up. The average incision length was 6.9 cm with an average operative time of 124 min. CONCLUSION: We successfully applied 3D printing for the surgical management of both-column acetabular fractures, thereby improving surgical outcomes while achieving good-to-excellent reduction and good medium-term functional outcomes. PMID- 30028498 TI - Strangulated Morgagni hernia in an adult: Synchronous prolapse of the liver and transverse colon. AB - Morgagni hernia (MH) is a very rare congenital defect found in the anterior aspect of the diaphragm between the costal and sternal portions of the muscle. The most common defect is congenital diaphragmatic hernia, 90% of which are Bochdalek type. MHs account for approximately 3% of all diaphragmatic hernias. Most MHs are found and repaired in children, but 5% are found in adults. Here, we present the case of an incarcerated and strangulated MH with synchronous prolapse of the liver and transverse colon in a 77-year-old man who was admitted to our hospital for abdominal pain and symptoms of intestinal obstruction. PMID- 30028499 TI - Effects of peritoneal lavage and dry cleaning on bacterial translocation in a model of peritonitis developed using cecal ligation and puncture. AB - BACKGROUND: Currently, all progress in diagnostic techniques, surgical techniques, antibiotherapy, and intensive care units is accompanied by a decrease in the mortality due to severe secondary peritonitis; however, the rate is still unacceptably high. To remove the source of peritonitis, a surgeon has several options, such as closure, exclusion, and resection, depending on the preference of the surgeon and the condition of the patient. The aim of this study is to determine the rates of bacterial translocation by comparing the dry cleaning method (gauze squeezed with saline) and peritoneal lavage method (cleaning with saline), which are among the peritoneal cleaning methods. METHODS: A total of 64 rats were studied as sham, control, dry cleaning, and saline cleaning groups. Only laparotomy was performed in the sham group, and cecal ligation puncture was performed in the control group. After ligation puncture operations in the other two groups, one of them was subjected to dry cleaning and the other to isotonic cleaning. The samples obtained from the liver, spleen, and mesothelium were sacrificed and cultured under aerobic and anaerobic environments. RESULTS: There was no significant difference in the anaerobic bacterial counts, although there was a significant difference in the results of the aerobic bacterial counts in liver, spleen, and mesothelium samples on comparing the dry cleaning and saline cleaning groups. CONCLUSION: According to our study, the cleaning of intraabdominal infections with dry gauze is more effective than the cleaning with physiological saline for the elimination of aerobic bacteria. There is no difference observed with respect to the anaerobic bacterial counts. PMID- 30028500 TI - The need for specific paediatric tools for stroke recognition. PMID- 30028501 TI - Early effector maturation of naive human CD8+ T cells requires mitochondrial biogenesis. AB - The role of mitochondrial biogenesis during naive to effector differentiation of CD8+ T cells remains ill explored. In this study, we describe a critical role for early mitochondrial biogenesis in supporting cytokine production of nascent activated human naive CD8+ T cells. Specifically, we found that prior to the first round of cell division activated naive CD8+ T cells rapidly increase mitochondrial mass, mitochondrial respiration, and mitochondrial reactive oxygen species (mROS) generation, which were all inter-linked and important for CD8+ T cell effector maturation. Inhibition of early mitochondrial biogenesis diminished mROS dependent IL-2 production - as well as subsequent IL-2 dependent TNF, IFN gamma, perforin, and granzyme B production. Together, these findings point to the importance of mitochondrial biogenesis during early effector maturation of CD8+ T cells. PMID- 30028502 TI - Austerity and families with disabled children: a European survey. AB - AIM: To describe the impact austerity measures have had on families with disabled children across Europe and on professionals providing services for them. METHOD: Cross-sectional surveys were disseminated via professional and family networks in 32 European countries for 3 months from December 2016. RESULTS: Families (n=731), of whom 45% met UNICEF criteria for severe poverty, and professionals (n=959) responded from 23 and 32 countries respectively. Respondents were grouped into those from countries with and without austerity. The direct and indirect impact of austerity cuts and worse working conditions were reported more often by professionals from countries with austerity, compared to those without. Most families reported services to be worse in quality than 3 years ago. Families with completely dependent disabled children said the needs of their disabled children are significantly less well met now, compared to 10 years ago. INTERPRETATION: A decline in quality of services for disabled children was reported by most family and many professional respondents across Europe, regardless of austerity. Where implemented, austerity measures were reported to have impacted significantly on families with disabled children. What this paper adds Stigma about disability remains a challenge in many countries across Europe. Most families and many health care professionals reported worsening quality of services than 3 years ago, regardless of austerity. Austerity cuts are reported to have impacted especially negatively on families with dependent disabled children. PMID- 30028503 TI - Alzheimer's disease: Only prevention makes sense. AB - Alzheimer's disease therapeutics is one of the most important endeavours in today's clinical investigation. Over more than 30 years of research, no disease modifying treatment has been approved by either the FDA or the EMA to treat Alzheimer's disease. Recently, the evidence of pathological alterations in the brain tissue has been gathered showing that the signs of brain damage appear more than 20 years before the onset of Alzheimer's dementia. The major aim of this review is to underpin the idea that in Alzheimer's therapeutics, only prevention makes sense. It is difficult to visualise that would-be patients may be treated with endovenous administration of antibodies for several years to delay the onset of dementia. Rather, changes in lifestyle that should be specific, stratified and personalised are a likely alternative to delay the transition from asymptomatic Alzheimer's to minimal cognitive impairment and from there to dementia. These efforts are of the utmost importance. If we could delay the onset of full-blown dementia by 5 years, the number of demented patients would be almost halved. Thus, emphasis on preventive measures that can be implemented for decades must be supported. This approach, where even mild changes in cognition are of the greatest importance, cannot be underestimated in terms of both the individual and society's viewpoints. PMID- 30028504 TI - Sleep deprivation and melatonin for inducing sleep in paediatric electroencephalography: a prospective multicentre service evaluation. AB - AIM: To compare the efficacy of the main methodologies in attaining sleep and electroencephalography (EEG) abnormalities in children with a view to producing recommendations on best practice. METHOD: Fifty-one UK centres participated. Methods for sleep induction (sleep deprivation, melatonin, and combined sleep deprivation/melatonin) were compared. Data pertaining to demographics, achievement of stage II sleep, and recording characteristics (duration of study, presence of epileptiform activity in awake/sleep states) were prospectively collected for consecutive patients in November and December 2013. RESULTS: Five hundred and sixty-five patients were included. Age range was 1 years to 17 years (mean 7y 10mo), 27.7 per cent had an underlying neurobehavioural condition. Stage II sleep was achieved in 69 per cent of sleep deprived studies, 77 per cent of melatonin studies, and 90 per cent of combined intervention studies (p<0.001, chi2 ). In children who slept, there was no difference between the three interventions in eliciting epileptiform discharges. In children who did not sleep, epileptiform abnormalities were seen more often than after sleep deprivation alone (p=0.02, chi2 ). Seizures were rare. INTERPRETATION: Combined sleep deprivation/melatonin is more effective than either method alone in achieving sleep. The occurrence of epileptiform activity during sleep is broadly similar across the three groups. We recommend the combined intervention to induce sleep for paediatric EEG. What this paper adds Combined sleep deprivation/melatonin is more effective in achieving sleep than either sleep deprivation or melatonin alone. Sleep latency is shorter with combined sleep deprivation/melatonin. When children do sleep, there is no difference in the occurrence of epileptiform abnormalities between different induction methods. Seizures are rare in sleep electroencephalography recordings. PMID- 30028505 TI - Structural brain abnormalities in adolescents and young adults with congenital heart defect: a systematic review. AB - AIM: The primary objective of this systematic review is to define and quantify brain structural abnormalities present in adolescents and young adults with complex congenital heart defect (CHD). We also aim to evaluate the extent to which these structural abnormalities are associated with functional outcomes. METHOD: A search of studies examining brain structure by magnetic resonance imaging in adolescents and young adults with complex CHD was performed in Embase, MEDLINE, and Web of Science. A meta-analysis was conducted to determine the odds of brain abnormalities in young people with CHD. Results not included in the meta analysis were collated using descriptive statistics. RESULTS: Two hundred and fifty-four studies were identified through the literature search. Among these, 14 original studies were included in the review. The odds of brain abnormalities in young people with CHD were 7.9 times higher (p<0.001) than in typically developing comparison individuals. Focal and multifocal lesions were the most common types of abnormality (odds ratio 22.5 [p<0.001]). Preliminary evidence from volumetric, cortical, and microstructural integrity measurements suggests that brain abnormalities are associated with poorer neurocognitive outcomes. INTERPRETATION: This review provides strong evidence that adolescents and young adults with CHD are at increased risk of presenting with structural brain abnormalities and highlights the contribution of advanced quantitative magnetic resonance imaging techniques to identify the subtle but frequent brain alterations in this population. However, more studies are needed to clarify how these abnormalities relate to function. WHAT THIS PAPER ADDS: There is a high prevalence of brain abnormalities in young people with congenital heart defect (CHD). Brain volumes, cortical measurements, and white matter microstructure are altered in young people with CHD. Brain abnormalities are associated with poorer function in young people with CHD. PMID- 30028506 TI - Musculocutaneous neuropathy. AB - INTRODUCTION: Isolated musculocutaneous neuropathy is uncommon. In this study we aimed to determine its causes and clinical presentation and interpret the electrodiagnostic findings associated with this condition. METHODS: Our investigation was a retrospective review of patients diagnosed with musculocutaneous neuropathy at the Mayo Clinic (Rochester, Minnesota) electromyography (EMG) laboratory between 1997 and 2015. RESULTS: Thirty-two patients with musculocutaneous neuropathy and 5 patients with lateral antebrachial cutaneous neuropathy were identified. The most common cause was acute trauma or surgery (65%). Fourteen percent of the cases were idiopathic and 14% were inflammatory. Pain and sensory disturbance were more common presentations than weakness. Weakness from nerve injury was not noted in 2 patients, suggesting that other muscles may provide adequate elbow flexion/supination. The bilateral absence of lateral antebrachial cutaneous nerve sensory responses suggests an inflammatory cause. DISCUSSION: Musculocutaneous neuropathy usually results from trauma or iatrogenic injury. Nerve conduction studies alone are insufficient to confirm neuropathy, and needle EMG examination should be a routine part of the diagnostic evaluation. Muscle Nerve 58: 726-729, 2018. PMID- 30028507 TI - Extraforaminal Lumbar Disk Herniations Lead To Neuroplastic Changes: a Study Using Quantitative Sensory Testing. AB - INTRODUCTION: Extraforaminal lumbar disk herniations are characterized by distinct clinical features in comparison to paramedian lumbar disk herniations. METHODS: We applied the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain in 63 patients with a single lumbar disk herniation. They were categorized in 2 groups: (I) an intraspinal (group I; n = 47, 75%) and an extraforaminal (group E; n = 16, 25%). RESULTS: The wind-up ratio for assessing endogenous pain-modulating pathways was higher in group E (2.9 +/- 2) than in group I (1.4 +/- 1; P = 0.021). After a subsequent series of pinprick stimuli, an increase in pain assessed by the numeric rating scale could be shown in group E (2.1 +/- 2 vs 1.1 +/- 1; P = 0.032). DISCUSSION: Extraforaminal compression is associated with chronic as well as neuropathic pain, presumably caused by direct compression of the dorsal root ganglion, which may preferentially promote specific chronic pain mechanisms. Muscle Nerve 58: 676 680, 2018. PMID- 30028508 TI - The Different Physical and Chemical Composition of Grape Juice and Marc Influence Saccharomyces cerevisiae Strains Distribution During Fermentation. AB - : During white-grape winemaking, grape marc is separated from juice immediately after crushing. Both mark and juice are obtained from the same grapes, but they differ strongly for their physical and chemical properties. Marc is mainly composed of solid residues. Its pH is usually higher than that of the juice and Saccharomyces cerevisiae strains are largely present. Therefore, it can be considered as a potential alternative environment for the selection of industrial yeasts. In order to evaluate the effect of different pH and physical state of the two matrices on grapes yeast population composition, the isolation of S. cerevisiae, from both grape juice and marc during simultaneous fermentations, was performed. After yeast identification and genotyping, strains present at high frequencies were tested in fermentation at different pH values. Biofilm production was also tested to evaluate strain ability to develop on a solid matrix. Genotype analysis showed that high-frequency strains were always more abundant in one of the two environments, suggesting the existence of a selective effect. Generally, fermentations at different pH revealed that the best fermentation performance of each strain, in terms of CO2 production, was in the pH range of its original environment. Only one strain, mostly present in grape marc, produced a high biofilm level. Therefore, biofilm production does not seem to favor strain adaptation to grape marc condition. PRACTICAL APPLICATION: These results demonstrate that grape juice and marc represent two different environments able to influence yeast strains distribution. The pH level can be included among the selection factors acting on yeast strains distribution. Grape marc can be considered a yeasts reservoir and its fermentation can be used for the development and isolation of new strains, genetically and physiologically different from those present in the grape juice. PMID- 30028509 TI - Modeling of Effective Moisture Diffusivity in Corn Tortilla Baking. AB - : The objective of this work was to model the mass transfer in corn tortilla baking using different approaches for effective diffusivity based on the Fick's law of diffusion and to evaluate the impact of the process on quality parameters. The 1st one assumes constant effective diffusivity (method of slopes by subperiods and method of successive approximations) and the 2nd one considers variable effective diffusivity (quadratic function of time and Weibull distribution). In addition, the Weibull distribution was applied to fracturability. The effective moisture diffusivity inside the tortilla during baking is not constant and the estimations generated when considering variable diffusivity with quadratic time and Weibull distribution showed better fits (both, R2 = 0.999) to the average moisture content. Quality parameter fracturability was affected by the baking process and the Weibull model adequately described (R2 = 0.996) the fracturability behavior. This work will allow an adequate estimation of the concentration profiles and histories for mass transfer operations in products that can be represented as an infinite plate. The obtained analytical solutions with variable diffusivity will help to estimate the optimal conditions of the baking process to achieve the required final moisture content for baked corn tortilla shells. PRACTICAL APPLICATION: The analytical solutions of the Fick's law of diffusion for the moisture content in products that can be represented as an infinite plate, considering variable diffusivity, can be useful in studies when accurate estimations of effective diffusivity and concentration are needed. PMID- 30028510 TI - Adult neurogenesis and its role in brain injury and psychiatric diseases. AB - In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self-renewal ability and capacity to differentiate into neurons and glia as demonstrated by in vitro studies. However, their contribution to tissue repair in disease and injury is limited, lending credence to the claim by prominent neuropathologist Ramon y Cajal that 'once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably'. However, recent progress toward understanding the fundamental biology of adult NSCs and their role in pathological conditions has provided new insight into the potential therapeutic utility of endogenous NSCs. In this short review, we highlight two topics: the altered behavior of NSCs after brain damage and the dysfunction of NSCs and oligodendrocyte precursor cells, another type of undifferentiated cell in the adult brain, in mood affective disorders. PMID- 30028511 TI - Sonographic similarities of inclusion body myositis and myotonic dystrophy. PMID- 30028512 TI - EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. AB - Drug hypersensitivity reactions (DHRs) are common, and the skin is by far the most frequently involved organ with a broad spectrum of reaction types. The diagnosis of cutaneous DHRs (CDHR) may be difficult because of multiple differential diagnoses. A correct classification is important for the correct diagnosis and management. With these guidelines, we aim to give precise definitions and provide the background needed for doctors to correctly classify CDHR. PMID- 30028513 TI - Structure of monomeric full-length ARC sheds light on molecular flexibility, protein interactions, and functional modalities. AB - The activity-regulated cytoskeleton-associated protein (ARC) is critical for long term synaptic plasticity and memory formation. Acting as a protein interaction hub, ARC regulates diverse signalling events in postsynaptic neurons. A protein interaction site is present in the ARC C-terminal domain (CTD), a bilobar structure homologous to the retroviral Gag capsid domain. We hypothesized that detailed knowledge of the three-dimensional molecular structure of monomeric full length ARC is crucial to understand its function; therefore, we set out to determine the structure of ARC to understand its various functional modalities. We purified recombinant ARC and analyzed its structure using small-angle X-ray scattering and synchrotron radiation circular dichroism spectroscopy. Monomeric full-length ARC has a compact, closed structure, in which the oppositely charged N-terminal domain (NTD) and CTD are juxtaposed, and the flexible linker between them is not extended. The modeled structure of ARC is supported by intramolecular live-cell Forster resonance energy transfer imaging in rat hippocampal slices. Peptides from several postsynaptic proteins, including stargazin, bind to the N lobe, but not to the C-lobe, of the bilobar CTD. This interaction does not induce large-scale conformational changes in the CTD or flanking unfolded regions. The ARC NTD contains long helices, predicted to form an anti-parallel coiled coil; binding of ARC to phospholipid membranes requires the NTD. Our data support a role for the ARC NTD in oligomerization as well as lipid membrane binding. The findings have important implications for the structural organization of ARC with respect to distinct functions, such as postsynaptic signal transduction and virus like capsid formation. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our services/open-science-badges/. PMID- 30028514 TI - Is triceps hypertrophy associated with ulnar nerve luxation? AB - INTRODUCTION: The mechanism of ulnar nerve luxation is unclear, but the triceps brachii muscle may be a contributing factor. Therefore, we explored whether hypertrophy of the triceps brachii muscle is more frequently accompanied by nerve luxation. METHODS: In this investigation we used a cross-sectional design to study a group of amateur bodybuilders (n = 31) in a comparison with a group of age-matched healthy controls (n = 31). Triceps hypertrophy was determined clinically and sonographically. The position of the ulnar nerve in relation to the medial epicondyle was classified according to a graded (0-4) scale. RESULTS: In full flexion of 62 hypertrophic arms, 22 (35.5%) revealed subluxation and 27 (43.5%) complete luxation. In the controls, 21 (33.9%) demonstrated subluxation and 10 (16.1%) complete luxation. DISCUSSION: The higher frequency of ulnar nerve luxation in arms with hypertrophic triceps indicates that triceps muscle mass may be a factor contributing to ulnar nerve luxation. Muscle Nerve 58: 523-527, 2018. PMID- 30028515 TI - Control of Allergic Rhinitis and Asthma Test with 1-week recall: Validation of paper and electronic version. PMID- 30028516 TI - Nutritional Challenges in Patients After Intestinal Autotransplantation and Ex Vivo Surgery. AB - BACKGROUND: Intestinal autotransplantation (IATx) and ex vivo resection is a novel surgical strategy to treat patients with unresectable abdominal neoplasms involving the mesenteric root. Nutritional challenges after IATx and ex vivo surgery have not been well described. METHODS: Eleven patients, aged 7-68 years (median, 49 years) underwent IATx and ex vivo resection at our center from 2009 to 2016. A retrospective chart review was performed to evaluate nutrition status, tolerance of an oral diet, and need for parenteral nutrition (PN) and enteral (EN) nutrition. These factors were assessed preoperatively and at 3 months postoperatively. RESULTS: Prior to surgery, 10 of 11 patients were tolerating oral diets without need for additional PN or EN. Postoperatively, PN was initiated in all patients from 1-15 days after surgery (median, 5 days) and continued from 12-122 days (median, 32.5 days), except for of 1 patient who underwent a total enterectomy and required subsequent allotransplantation with ongoing PN. EN was initiated in 9 patients from 4-117 days after surgery (median, 17 days) and has been ongoing in 5 patients. Oral diets were initiated in all patients from 5-115 days (median, 14 days) postoperatively; at 3 months, 11 of 12 patients were tolerating oral diets. CONCLUSION: IATx and ex vivo resection presents a unique challenge with respect to nutrition management. Patients undergoing these complex surgeries may have difficulty maintaining adequate nutrition with an oral diet alone in the immediate postoperative period and beyond and may require prolonged nutrition support. PMID- 30028517 TI - Regeneration of nerve crush injury using adipose-derived stem cells: A multimodal comparison. AB - INTRODUCTION: To restore full function following nerve crush injuries is critical but challenging. In an attempt to develop a viable therapy, we evaluated the effect of rat adipose-derived stem cells (rASC) in 2 different settings of a sciatic crush injury model. METHODS: In the first group, after 14 days of nerve crush injury, rASCs were injected distal to the lesion under ultrasound guidance. In the other group, alleviation of compression through clip removal (CR) was combined with epineural injection of rASCs. Gait analyses, MRI, gastrocnemius muscle weight ratio (MWR), and histomorphometry were performed for outcome analysis. RESULTS: CR combined with rASC injection resulted in less muscle atrophy, as evidenced by MWR. These findings are further supported by better functional and anatomical outcomes. DISCUSSION: Animals treated with CR and epineural stem cell injection showed enhanced anatomical and functional recovery. Muscle Nerve 58: 566-572, 2018. PMID- 30028518 TI - Multi-omics analysis points to altered platelet functions in severe food associated respiratory allergy. AB - BACKGROUND: Prevalence and severity of allergic diseases have increased worldwide. To date, respiratory allergy phenotypes are not fully characterized and, along with inflammation progression, treatment is increasingly complex and expensive. Profilin sensitization constitutes a good model to study the progression of allergic inflammation. Our aim was to identify the underlying mechanisms and the associated biomarkers of this progression, focusing on severe phenotypes, using transcriptomics and metabolomics. METHODS: Twenty-five subjects were included in the study. Plasma samples were analyzed using gas and liquid chromatography coupled to mass spectrometry (GC-MS and LC-MS, respectively). Individuals were classified in four groups-"nonallergic," "mild," "moderate," and "severe"-based on their clinical history, their response to an oral challenge test with profilin, and after a refinement using a mathematical metabolomic model. PBMCs were used for microarray analysis. RESULTS: We found a set of transcripts and metabolites that were specific for the "severe" phenotype. By metabolomics, a decrease in carbohydrates and pyruvate and an increase in lactate were detected, suggesting aerobic glycolysis. Other metabolites were incremented in "severe" group: lysophospholipids, sphingosine-1-phosphate, sphinganine-1 phosphate, and lauric, myristic, palmitic, and oleic fatty acids. On the other hand, carnitines were decreased along severity. Significant transcripts in the "severe" group were found to be downregulated and were associated with platelet functions, protein synthesis, histone modification, and fatty acid metabolism. CONCLUSION: We have found evidence that points to the association of severe allergic inflammation with platelet functions alteration, together with reduced protein synthesis, and switch of immune cells to aerobic glycolysis. PMID- 30028519 TI - Deflazacort versus prednisone/prednisolone for maintaining motor function and delaying loss of ambulation: A post HOC analysis from the ACT DMD trial. AB - INTRODUCTION: ACT DMD was a 48-week trial of ataluren for nonsense mutation Duchenne muscular dystrophy (nmDMD). Patients received corticosteroids for >=6 months at entry and stable regimens throughout study. This post hoc analysis compares efficacy and safety for deflazacort and prednisone/prednisolone in the placebo arm. METHODS: Patients received deflazacort (n = 53) or prednisone/prednisolone (n = 61). Endpoints included change from baseline in 6 minute walk distance (6MWD), timed function tests, estimated age at loss of ambulation (extrapolated from 6MWD). RESULTS: Mean changes in 6MWD were -39.0 m (deflazacort; 95% confidence limit [CL], -68.85, -9.17) and -70.6 m (prednisone/prednisolone; 95% CL, -97.16, -44.02). Mean changes in 4-stair climb were 3.79 s (deflazacort; 95% CL, 1.54, 6.03) and 6.67 s (prednisone/prednisolone; 95% CL, 4.69, 8.64). CONCLUSIONS: This analysis, limited by its post hoc nature, suggests greater preservation of 6MWD and 4-stair climb with deflazacort vs. prednisone/prednisolone. A head-to-head comparison will better define these differences. Muscle Nerve 58: 639-645, 2018. PMID- 30028520 TI - Prolonged attacks of weakness with hypokalemia in SCN4A-related paramyotonia congenita. PMID- 30028521 TI - A prospective study of benign fasciculation syndrome and anxiety. AB - INTRODUCTION: Benign fasciculations are common. Despite the favorable prognosis of benign fasciculation syndrome (BFS), patients are often anxious about their symptoms. In this study, we prospectively followed 35 patients with BFS over a 24 month period. METHODS: We conducted serial questionnaires to assess anxiety, associated symptoms, and duration. RESULTS: 71.4% of patients were men, and 34.4% were employed in the medical field. Most reported anxiety, but only 14% were anxious as measured by the Zung self-rating anxiety scale. Fasciculations were most common in the calves and persisted in 93% of patients. Anxiety levels did not change over time. Associated symptoms (subjective weakness, sensory symptoms, and cramps) were common and resolved to varying degrees. No patients developed motor neuron disease. DISCUSSION: BFS is a benign disorder that usually persists over time. Commonly associated symptoms include subjective weakness, sensory symptoms, and cramps. BFS is usually not associated with pathologic anxiety. Muscle Nerve, 2018. PMID- 30028522 TI - Grading the loss of sensation in diabetic patients: A psychometric evaluation of the rotterdam diabetic foot study test battery. AB - INTRODUCTION: Static- and moving 2-point discrimination (S2PD, M2PD), 10-g monofilaments- and tuning fork are validated outcome measures of clinical manifestations of diabetes-related neuropathy. No modern statistical techniques have been used to investigate how well these instruments combine to measure sensory loss. METHODS: To grade sensory loss at the feet, we fitted parametric forms of Item Response Theory models to the data of these instruments. RESULTS: The fit statistics indicate that the loss of sensation is gradable, with readily available instruments. S2PD and M2PD are lost first, followed by vibration sense, the 10-g monofilament and the ability to feel a cold stimulus. CONCLUSIONS: This test battery appears to provide sound measurement properties in a group of diabetic patients with diverse amounts of sensory loss. This approach may be used in clinical practice to grade sensory loss reliably and quickly, with instruments that are easy to use. Muscle Nerve 58: 559-565, 2018. PMID- 30028523 TI - Multiparametric quantitative MRI assessment of thigh muscles in limb-girdle muscular dystrophy 2A and 2B. AB - INTRODUCTION: The aim of this study was to apply quantitative MRI (qMRI) to assess structural modifications in thigh muscles of subjects with limb girdle muscular dystrophy (LGMD) 2A and 2B with long disease duration. METHODS: Eleven LGMD2A, 9 LGMD2B patients and 11 healthy controls underwent a multi-parametric 3T MRI examination of the thigh. The protocol included structural T1-weighted images, DIXON sequences for fat fraction calculation, T2 values quantification and diffusion MRI. Region of interest analysis was performed on 4 different compartments (anterior compartment, posterior compartment, gracilis, sartorius). RESULTS: Patients showed high levels of fat infiltration as measured by DIXON sequences. Sartorius and anterior compartment were more infiltrated in LGMD2B than LGMD2A patients. T2 values were mildly reduced in both disorders. Correlations between clinical scores and qMRI were found. CONCLUSIONS: qMRI measures may help to quantify muscular degeneration, but careful interpretation is needed when fat infiltration is massive. Muscle Nerve 58: 550-558, 2018. PMID- 30028524 TI - Immunoexpression of calcitonin and glucocorticoid receptors in central giant cell lesions of the jaws. AB - BACKGROUND: This study analyzed the immunoexpression of calcitonin receptor (CTR) and glucocorticoid receptor (GR) in central giant cell lesions (CGCLs) and verified potential associations with patient's response to clinical treatment with intralesional injection of triamcinolone. MATERIALS AND METHODS: Fifty-four cases of CGCLs, including 22 non-aggressive, and 32 aggressive, were investigated by immunohistochemistry. RESULTS: Surgery was the therapeutic choice for 53.1% of the aggressive CGCLs, and 46.9% were submitted to the conservative treatment with intralesional triamcinolone injections. Among patients submitted to conservative treatment, 60% (n = 9) showed favorable response. CTR expression was observed in 68.51%, and GR in 94.44% of the total sample. There were no differences in the expression of CTR, neither GR in mononucleated stromal cells (MSCs) or multinucleated giant cells (MGCs), in relation to aggressiveness, treatment performed for and the response to conservative treatment. Both markers showed a positive correlation between their expression in MSCs and MGCs in the total sample (P < 0.0001). CTR expression on MSCs showed a positive correlation with MGCs in the aggressive and non-aggressive groups (P < 0.0001). CONCLUSIONS: Calcitonin receptor and GR expression were diffuse and similar in non-aggressive and aggressive cases, and it did not influence the response to clinical treatment with triamcinolone in the sample studied. PMID- 30028525 TI - Preventive justice: A paradigm in need of testing. AB - This article is a revision of an address made at the 2016 annual conference of the American Psychology-Law Society, in honor of receiving that organization's Distinguished Contribution Award. It sets forth a vision of the criminal justice system, and in particular the sentencing process, that is oriented toward preventive, rather than retributive, justice. After explaining preventive justice - a concept that in one form or another has been discussed for decades - and why it is worth revisiting at this time, the article proposes a number of hypotheses about the assumptions underlying preventive and retributive justice regimes. In the course of doing so, it references how the articles in this Special Issue of Behavioral Sciences and the Law address these hypotheses, and calls for further research from psychologists and other social scientists designed to test the fundamental assumptions of criminal law. PMID- 30028526 TI - Predicting physically violent misconduct in prison: A comparison of four risk assessment instruments. AB - Violence in correctional facilities is an important issue for both prisoners and prison staff. Risk assessment instruments have demonstrated their accuracy in predicting the risk of (re) offending and institutional violence in psychiatric settings, but less is known about their ability to predict violent misconduct in prison. The present study applied four risk assessment instruments (Structured Assessment of Protective Factors for violence risk, Historical Clinical Risk Management-20, Psychopathy checklist - Revised, and Violent Risk Appraisal Guide) to 52 violent offenders in a Swiss prison in order to evaluate the instruments' predictive validities. Outcomes were instances of physically violent, other and any misconduct as recorded in prison files during the 12 months following the prisoners' assessments. Approximately 15% of offenders committed physically violent misconduct and approximately 42% committed any misconduct. The results show that mainly dynamic assessment tools are as good predictors of physically violent misconduct as mainly static assessment tools. Targeting dynamic factors could increase the effectiveness of interventions to reduce the risk of physical violence in prison. PMID- 30028527 TI - Effects of mesenchymal stromal cells on type 1 diabetes mellitus rat muscles. AB - INTRODUCTION: Type 1 diabetes mellitus (DM) causes marked skeletal muscle atrophy. Mesenchymal stromal cells (MSC) are an attractive therapy to avoid diabetic complications because of their ability to modify the microenvironment at sites of tissue injury. The objective of this study was to evaluate the effects of MSC transplantation on muscle adaptation caused by diabetes. METHODS: DM was induced by streptozotocin (STZ), and the diabetic animals received systemic MSC transplantation. The von Frey test and footprint analysis were used to assess sensation and sensory motor performance, respectively. Tibialis anterior muscles were investigated by morphology; molecular markers atrogin-1/muscle RING-finger protein-1, nuclear factor kappaB/p38 mitogen-activated protein kinase, tumor necrosis-like weak inducer of apoptosis/fibroblast growth factor-inducible 14, myostatin, myogenic differentiation 1, and insulin-like growth factor 1 were also assessed. RESULTS: MSC transplantation improved sensation and walking performance and also decreased muscle fibrosis in DM rats by modulating atrogenes but did not prevent muscle atrophy. DISCUSSION: MSCs can reduce muscle and functional complications that result from type 1 DM in rats. Muscle Nerve 58: 583-591, 2018. PMID- 30028528 TI - Alterations in mitochondrial fission, fusion, and mitophagic protein expression in the gastrocnemius of mice after a sciatic nerve transection. AB - INTRODUCTION: Paralysis and unloading of skeletal muscle leads to a rapid loss in muscle size, function and oxidative capacity. The reduction in metabolic capability after disuse leads to dysregulation and increased breakdown of mitochondria by mitophagy. METHODS: Eight-week-old C57BL/6 male mice were given a sham surgery or sciatic nerve transection. Animals were euthanized at 7, 14, 21, or 35 days postsurgery. Whole gastrocnemius muscles were isolated from the animal, weighed and used for Western blotting. RESULTS: Markers of mitochondrial fusion were reduced while fission proteins were elevated following a sciatic nerve transection. There were elevations in phosphorylated unc-51-like kinase 1 (ULK1S555 ) and total expression of Beclin1, and of the mitophagy markers PINK1, p62, and microtubule-associated proteins 1A/1B light chain 3b (LC3-II). CONCLUSIONS: Paralysis of the gastrocnemius leads to a progressive elevation in expression of mitochondrial fission and mitophagic proteins. Rehabilitative or pharmaceutical interventions to limit excess mitophagy may be effective therapies to protect paralyzed muscle mass and function. Muscle Nerve 58: 592-599, 2018. PMID- 30028530 TI - Optimal location for eliciting the tibial H-reflex and motor response. AB - INTRODUCTION: Although there are numerous protocols to adjust the amplitude of the Hoffmann reflex (H-reflex) relative to the size of the direct motor response (M-response), the optimal stimulating location has not been described. We sought to determine the optimal positioning of the stimulating cathode when evoking the tibial nerve H-reflex and M-response. METHODS: A small cathode was placed on defined points in the popliteal fossa while an anode was fixed on the patella. The tibial nerve was stimulated electrically, and the response of the soleus muscle was recorded using intramuscular and surface electromyography. RESULTS: We found that more-lateral points along a line drawn across the popliteal fossa were the best locations to obtain only the M-response, whereas stimulating the midpoint was optimal for obtaining only the H-reflex. DISCUSSION: By using specified locations for electrical stimulation to evoke H-reflex and M-response, the functionality of the tibial nerve can be assessed. Muscle Nerve, 2018. PMID- 30028529 TI - Muscle endurance deficits in myositis patients despite normal manual muscle testing scores. AB - INTRODUCTION: It is unclear whether quantifying muscle endurance adds nonredundant information useful for the care of patients with muscular disease. METHODS: Records were retrospectively reviewed for all Johns Hopkins Myositis Center patients with a muscle endurance assessment (n=128, 226 patient-visits). Muscle endurance and strength were quantified with the Myositis Functional Index 2 (FI2) and manual muscle testing (MMT), respectively. RESULTS: Composite FI2 muscle endurance scores were comparable in inclusion body myositis (n=58), dermatomyositis (n=31), and polymyositis (n=39). Overall, muscle endurance correlated with and evolved similarly to strength, inversely to serum creatine kinase. However, in patients with normal or near-normal strength (mean MMT >9.75/10), muscle endurance was typically abnormal and highly variable (mean FI2, 5.6/10; interquartile range, 3.3-7.8/10). DISCUSSION: Muscle endurance testing may identify muscle impairment inadequately described by MMT, particularly in patients with high MMT scores. This article is protected by copyright. All rights reserved. PMID- 30028531 TI - Social participation of adult patients with spinal muscular atrophy: Frequency, restrictions, satisfaction, and correlates. AB - INTRODUCTION: In this study we assessed social participation in 62 adults with spinal muscular atrophy (SMA) types 1c-4. METHODS: The outcome measure used was the Utrecht Scale of Evaluation Rehabilitation-Participation (USER-P) with Frequency, Restrictions, and Satisfaction scores, and a hierarchical regression analysis. RESULTS: Early-onset (types 1, 2, and 3a) and late-onset (types 3b and 4) SMA patients reported similar frequency and satisfaction scores. "Age," "motor skills," "pain," and "feelings of depression" correlated with frequency; "motor skills" and "feelings of depression" correlated with restrictions; and "level of education," "fatigue," and "feelings of depression" correlated with satisfaction. "Motor skills" and "feelings of depression" explained 33% of variance in frequency of participation. "Motor skills" explained 26% of variance of restrictions in participation. "Fatigue" and "feelings of depression" explained 50% of variance in satisfaction with participation. DISCUSSION: Motor skills, feelings of depression and fatigue are correlates of participation in daily life. This knowledge can be used to optimize care for SMA patients. Muscle Nerve, 2018. PMID- 30028532 TI - Unique presentation of rapidly fluctuating symptoms in a child with congenital myasthenic syndrome due to RAPSN mutation. PMID- 30028533 TI - Toll-like receptor 1, 2 and 6 polymorphisms: no association with 11 serum cytokine concentrations. PMID- 30028534 TI - Diagnosis of erectile dysfunction can be used to improve screening for Type 2 diabetes mellitus. AB - AIMS: To assess the diagnostic accuracy of four undiagnosed Type 2 diabetes mellitus risk scores accounting for erectile dysfunction status. METHODS: This was a population-based cross-sectional study. Type 2 diabetes was defined according to a oral glucose tolerance test and self-reported physician diagnosis. Erectile dysfunction was defined according to the answer to the question, 'Have you had difficulties obtaining an erection in the last 6 months?' (yes/no). The risk scores used were the FINDRISC, LA-FINDRISC, American Diabetes Association score and the Peruvian Risk Score. A Poisson regression model was fitted to assess the association between Type 2 diabetes and erectile dysfunction. The area under the receiver-operating characteristic curve was estimated overall and by erectile dysfunction status. RESULTS: A total of 799 men with a mean (sd) age of 48.6 (10.7) years were included in the study. The overall prevalence of Type 2 diabetes was 9.3%. Compared with healthy men, men with Type 2 diabetes had 2.71 (95% CI 1.57-4.66) higher chances of having erectile dysfunction. Having excluded men aware of Type 2 diabetes status (N=38), the area under the receiver-operating characteristic curve of three of the risk scores (not the American Diabetes Association score) improved among those who had erectile dysfunction in comparison with those who did not; for example, the area under the receiver operating characteristic curve of the LA-FINDRISC score was 89.6 (95% CI 78.7 99.9) in men with erectile dysfunction and 76.5 (95% CI 68.5-84.4) overall. CONCLUSIONS: In a population-based study, erectile dysfunction was more common in men with Type 2 diabetes than in the otherwise healthy men. Screening for erectile dysfunction before screening for Type 2 diabetes seems to improve the accuracy of well-known risk scores for undiagnosed Type 2 diabetes. PMID- 30028535 TI - First urinary tract infections in children: the role of the risk factors proposed by the Italian recommendations. AB - AIM: In 2009, the Italian society for paediatric nephrology suggested the need for cystography, following a first febrile urinary tract infection (UTI), only in children at high risk for dilating vesicoureteral reflux or in the event of a second infection. The aim of this study was to evaluate the adequacy of the risk factors proposed by the Italian guidelines. METHODS: Children aged 2-36 months, managed by 10 Italian hospitals between 2009 and 2013, with a first febrile UTI were retrospectively evaluated. RESULTS: Four hundred and fourteen children were included: 51% female, mean age eight months. Escherichia coli was responsible of 84% UTIs. 269 children (65%) presented at least one risk factor, thus were further investigated: 44% had a reflux. The presence of a pathogen other than E. coli significantly predicted high-grade reflux, both in the univariate (Odd Ratio 2.52, 95% Confidence Interval 1.32-4.81, p < 0.005) and multivariate analysis (OR 2.74, 95% CI: 1.39-5.41, p: 0.003). 26/145 children (18%) with no risk factors experienced a second UTI, which prompted the execution of cystography, showing a dilating reflux in 11. CONCLUSION: Among the risk factors proposed by the Italian guidelines, only the presence of a pathogen other than E. coli significantly predicted reflux. Cystography can be postponed in children with no risk factors. PMID- 30028536 TI - The least-cost biodiversity impact mitigation hierarchy with a focus on marine fisheries and bycatch issues. AB - Least-cost implementation of the mitigation hierarchy of impacts on biodiversity minimizes the cost of a given level of biodiversity conservation, at project or ecosystem levels, and requires minimizing costs across and within hierarchy steps. Incentive-based policy instruments that price biodiversity to alter producer and consumer behavior and decision making are generally the most effective way to achieve least-cost implementation across and within the different hierarchy steps and across all producers and conservation channels. Nonetheless, there are circumstances that favor direct regulation or intrinsic motivation. Conservatory offsets, introduced within the conservatory first three steps of the mitigation hierarchy, rather than the fourth step to compensate the residual, provide an additional incentive-based policy instrument. The least-cost mitigation hierarchy framework, induced through incentive-based policy instruments, including conservatory offsets, mitigates fisheries bycatch consistent with given targets, the Law of the Sea, and the Convention on Biological Diversity. PMID- 30028537 TI - Amyotrophic lateral sclerosis-specific quality of life-short form (ALSSQOL-SF): A brief, reliable, and valid version of the ALSSQOL-R. AB - INTRODUCTION: The Amyotrophic Lateral Sclerosis (ALS)-Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL-R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL-SF) suitable for limited clinic time and patient stamina. METHODS: The ALSSQOL-SF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A cross validation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOL-SF compared with psychosocial and physical functioning measures. RESULTS: The ALSSQOL-SF consisted of 20 items. Compared with the ALSSQOL-R, optimal precision was retained, and completion time was reduced from 15-25 minutes to 2-4 minutes. Psychometric properties for the ALSSQOL-SF and its subscales were strong. DISCUSSION: The ALSSQOL-SF is a disease-specific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646-654, 2018. PMID- 30028538 TI - Population-based longitudinal study showed that children born small for gestational age faced a higher risk of hospitalisation during early childhood. AB - AIM: We examined the effects of being born small for gestational age (SGA) on the risk of being hospitalised for common diseases during childhood. METHODS: This Japanese nationwide, population-based longitudinal survey followed babies born before 42 weeks of gestation from 10 to 17 January and from 10 to 17 July 2001, using data from the Government's Longitudinal Survey of Babies in the 21st Century. Our study followed 41 268 children until 5.5 years of age: 39 107 full term (8.7% SGA) and 2161 preterm (15.5% SGA). We evaluated the relationship between SGA status and hospitalisation using their history of hospitalisation for common diseases and comparing full-term or preterm births. Logistic regression analysis, adjusted for potential confounders, estimated the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The full-term and preterm children who were born SGA were more likely to be hospitalised during infancy and early childhood than those born non SGA. The ORs for hospitalisation from six months to 18 months of age were 1.23 (95% CI: 1.10-1.37) for full-term and 1.67 (95% CI: 1.23-2.25) for preterm subjects. Higher risks of hospitalisation due to bronchitis, pneumonia, bronchial asthma and diarrhoea were also observed. CONCLUSION: Being born SGA was associated with all-cause and cause-specific hospitalisation in early childhood, particularly for term infants. PMID- 30028539 TI - Sequence data of six unusual alleles at SE33 and D1S1656 STR Loci. AB - When profiling a reference dataset of 500 DNA samples for the population of Saudi Arabia, using the GlobalFiler(r) PCR amplification kit, six unusual alleles were detected. At the SE33 locus, four novel alleles were found: 2, 14.3, 20.3, and 38; two alleles at the D1S1656 locus: 7 and 8 had been previously reported, but no published sequence data was available. The D1S1656 alleles were sequenced using ForenSeqTM DNA Signature Prep with the MiSeq FGx System (Illumina, USA). As the SE33 is not reported by available Massively Parallel Sequencing (MPS) systems, samples that exhibited the unreported alleles were sequenced using BigDyeTM Terminator v3.1 Cycle Sequencing Kit. Here we present the sequence and structure of the previously uncharacterized alleles. PMID- 30028540 TI - Clinical value of Naa10p and CEA levels in saliva and serum for diagnosis of oral squamous cell carcinoma. AB - BACKGROUND: N-alpha-acetyltransferase 10 protein (Naa10p) is a potential prognostic biomarker that modulates the phenotypes of several cancer types. Carcinoembryonic antigen (CEA) is currently the most well-known biomarker for the detection of epithelial malignancies. Our objective was to evaluate the clinical value of Naa10p, CEA, and their combined detection for diagnosis of oral squamous cell carcinoma (OSCC). METHODS: This study included 202 individuals: 112 patients with OSCC, 30 patients with oral premalignant lesions (OPMLs), and 60 cancer-free and without OPML patients as control. Naa10p and CEA were determined in serum and saliva samples utilizing enzyme-linked immunosorbent assays. RESULTS: Salivary and serum levels of Naa10p and CEA in OSCC patients were significantly higher than those detected in OPML and the control groups, although patients with OPMLs also showed increased salivary and serum Naa10p and CEA levels as compared to the control group. Salivary Naa10p level in OSCC patients is correlated with the degree of differentiation and lymph node metastasis, and serum Naa10p level is specifically correlated with patient age. Additionally, salivary CEA level is correlated with the clinical stage and lymph node metastasis, whereas serum CEA level is correlated with lymph node metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value of combined detection were greater than any single detection. CONCLUSIONS: Combined use of salivary Naa10p and CEA as tumor markers for OSCC was more sensitive than serum Naa10p and CEA. These results indicated that combined detection of salivary Naa10p and CEA improved diagnostic performance and early detection rate for OSCC. PMID- 30028541 TI - A CCDC50 splice variant is modulated by SRSF3 and promotes hepatocellular carcinoma via the Ras signaling pathway. AB - Deregulation of alternative splicing contributes to the malignant progression of cancer. Little is known about the significant alternative splicing events in hepatocellular carcinoma (HCC). High through-put sequencing revealed that CCDC50 pre-mRNA is aberrantly spliced in 50% of our HCC cases. A BaseScope assay was performed to examine the expression of CCDC50S (a truncated oncogenic splice variant) in HCC tissues. Compared with liver benign tumors and several types of solid tumors, CCDC50S mRNA was up-regulated in HCC, with a diagnostic potential (sensitivity: 0.711, specificity: 0.793). High expression of CCDC50S mRNA in HCC was significantly correlated with poor tumor differentiation, advanced TNM stage and unfavorable prognosis. Overexpression of CCDC50S exerted tumorigenic activities that promoted HCC growth and metastasis via activation of Ras/Foxo4 signaling. Either suppression of MEK/ERK phosphorylation or overexpression of Foxo4 markedly attenuated CCDC50S-mediated phenotypes. Furthermore, serine and arginine rich splicing factor 3 (SRSF3) directly bound to CCDC50S mRNA to maintain its stability in the cytoplasm. The cytosolic retention of SRSF3 was mediated by the interaction of HBx and 14-3-3beta. Ectopic HBx expression induced the expression of cytosolic SRSF3 and CCDC50S. Our study provided compelling evidence that up-regulation of CCDC50S was modulated by HBx/SRSF3/14-3-3beta complex, and enhanced the oncogenic progression of HCC via the Ras/Foxo4 signaling pathway. These data suggest that CCDC50S may serve as a novel diagnostic and prognostic biomarker, and probably a promising therapeutic target in HCC. This article is protected by copyright. All rights reserved. PMID- 30028542 TI - John Langdon Down (1828-1896) - a pioneer in caring for mentally disabled patients. PMID- 30028543 TI - Redox Isomeric Surface Structures Are Preferred over Odd-Electron Pt1. AB - The formation of metal-ligand coordination networks on surfaces that contain redox isomers is a topic of considerable interest and is important for bifunctional metallochemistry, including heterogeneous catalysis. Towards this end, a tetrazine with two electron withdrawing pyrimidinyl substituents was co deposited with platinum metal on the Au(100) surface. In a 2:1 metal:ligand ratio, only half of the platinum is oxidized to the +2 oxidation state, with the remainder coordinating to the ligand without charge transfer, as Pt0 . The resultant Pt0 /PtII mixed valence structure is thought to form due to the aversion of the ligand towards a four-electron reduction and the strong preference of Pt towards 0 and +2 oxidation states. These results were confirmed through a series of experiments varying the on-surface metal:ligand stoichiometry in the redox assembly formed: added oxidant does not oxidize the already complexed Pt0 . Scanning tunneling microscopy reveals irregular chain structures that are attributed to the mixture of Pt valence states, each with distinct local coordination geometries. Density functional theory calculations give further detail about these local geometries. These results demonstrate the formation of a mixture of valence states in on-surface redox assembly of metal-organic networks that extends the library of single-site metal structures for surface chemistry and catalysis. Redox-isomeric Pt0 versus Pt2+ surface structures can coexist in this ligand environment. PMID- 30028544 TI - Nitro-functionalized Bis(pyrazolate) Metal-Organic Frameworks as Carbon Dioxide Capture Materials under Ambient Conditions. AB - The metal-organic frameworks (MOFs) M(BPZNO2 ) (M=Co, Cu, Zn; H2 BPZNO2 =3-nitro 4,4'-bipyrazole) were prepared through solvothermal routes and were fully investigated in the solid state. They showed good thermal stability both under a N2 atmosphere and in air, with decomposition temperatures peaking up to 663 K for Zn(BPZNO2 ). Their crystal structure is characterized by 3D networks with square (M=Co, Zn) or rhombic (M=Cu) channels decorated by polar NO2 groups. As revealed by N2 adsorption at 77 K, they are micro-mesoporous materials with BET specific surface areas ranging from 400 to 900 m2 g-1 . Remarkably, under the mild conditions of 298 K and 1.2 bar, Zn(BPZNO2 ) adsorbs 21.8 wt % CO2 (4.95 mmol g-1 ). It shows a Henry CO2 /N2 selectivity of 15 and an ideal adsorbed solution theory (IAST) selectivity of 12 at p=1 bar. As a CO2 adsorbent, this compound is the best-performing MOF to date among those bearing a nitro group as a unique chemical tag. High-resolution powder X-ray diffraction at 298 K and different CO2 loadings revealed, for the first time in a NO2 -functionalized MOF, the insurgence of primary host-guest interactions involving the C(3)-NO2 moiety of the framework and the oxygen atoms of carbon dioxide, as confirmed by Grand Canonical Monte Carlo simulations. This interaction mode is markedly different from that observed in NH2 -functionalized MOFs, for which the carbon atom of CO2 is involved. PMID- 30028545 TI - Electricity Generation through Light-Responsive Diving-Surfacing Locomotion of a Functionally Cooperating Smart Device. AB - Mini-generators converting other forms of energy into electric energy are ideal power supplies for widely used microelectronic devices because they need only a low power supply in the range of uW to mW. Among various creative strategies to fabricate mini-generators, recently developed functionally integrated systems combining self-propulsion of small objects and the application of Faraday's law show advantages such as facile, noncontact, low resistance, and durability. However, wide application of such functionally integrated systems is currently restricted by artificial energy inputs, such as chemical fuels or mechanical work, and harvesting energy available in the environment or nature is urgently required. Herein, a light-responsive functionally cooperating smart device is developed as a mini-generator that can directly harvest naturally available light energy for diving-surfacing motions, thus converting mechanical energy into electricity through Faraday's law. The mini-generator generates a maximum voltage of 1.72 V with an energy conversion efficiency of 2.44 * 10-3 % to power LEDs and shows a lifetime of at least 30 000 s. By using environmental energy, the study may promote the concept of a functionally cooperating system as an economic and facile power supply for microelectronics, reducing their dependence on batteries. PMID- 30028546 TI - Microfluidic Analyte Transport to Nanorods for Photonic and Electrochemical Sensing Applications. AB - There has recently been a growing use of surface bound nanorods within electrochemical and optical sensing applications. Predictions of the microfluidic rate of analyte transport to such nanorods (either individual or to an array) remain important for sensor design and data analysis; however, such predictions are difficult, as nanorod aspect ratios can vary by several orders of magnitude. In this study, through the use of numerical simulation, we propose an explicit analytical approach to predict the steady-state diffusion-limited rate of mass transport to (individual) surface bound nanorods of variable aspect ratio. We show that, when compared to simulation, this approach provides accurate estimations across a wide range of Peclet numbers. PMID- 30028547 TI - Janus Membranes: Creating Asymmetry for Energy Efficiency. AB - Membranes are recognized as a key component in many environment and energy related applications, but conventional membranes are challenged to satisfy the growing demand for ever more energy-efficient processes. Janus membranes, a novel class with asymmetric properties on each side, have recently emerged and represent enticing opportunities to address this challenge. With an inner driving force arising from their asymmetric configuration, Janus membranes are appealing for enhancing energy efficiency in a variety of membrane processes by promoting the desired transport. Here, the fundamental principles to prepare Janus membranes with asymmetric surface wettability and charges are summarized, and how they work in conventional and unconventional membrane processes is demonstrated. PMID- 30028548 TI - Surfactant-Guided Synthesis of Porous Pt Shells with Ordered Tangential Channels, Coated on Pd Nanostructures, and Their Enhanced Catalytic Activities. AB - High-quality (Pd cube)@(Pt helix) core@shell nanoparticles, with a novel spiral structured shell and highly-ordered tangential channels are successfully fabricated through a facile wet chemistry method with the help of N,N dimethyloctadecyl ammonium bromide acetate sodium (OTAB-Na). A bottom-up synthesis strategy provides accurate control of layers by simply changing the molar ratio of Pt/Pd with a uniform layer thickness of 2 nm maintained in all (1 3)-rounds samples. The irregular Pt superstructures of the shells, and sophisticated core@shell hybrid materials endow the as-produced samples with highly enhanced catalytic properties, when evaluated for hydrogenation of nitrobenzene as a probe reaction. PMID- 30028549 TI - Improvement in clinical outcomes and replacement factor VIII use in patients with haemophilia A after factor VIII pharmacokinetic-guided prophylaxis based on Bayesian models with myPKFiT(r). AB - OBJECTIVES: Patients with severe haemophilia A (HA) receive factor VIII (FVIII) replacement therapy as prophylaxis. myPKFiT(r) is an online medical application that allows authorized users to simulate dosing regimens with patient pharmacokinetic (PK) profiles based on only 2 blood samples. Our aim was to assess the impact of using this medical device in routine practice in terms of FVIII consumption and clinical outcomes. METHODS: Thirty-six patients with severe HA on prophylaxis with Advate(r) were recruited in 3 centres in Spain. Annual bleeding rate (ABR), annual joint bleeding rate (AJBR) and annual FVIII consumption before and after adjustment were obtained using the patient's clinical history (12 months before) and prospectively recorded data (12 months after), respectively. Adjustment was based on PK parameters provided by myPKFiT(r) , joint status and relative risk associated with physical activity and bleeding phenotype. RESULTS: ABR and AJBR were significantly reduced after adjustment in the overall sample (-2.2 +/- 1.3, P = .018 and -1.9 +/- 1.2, P = .012, respectively) and in patients aged >15 years (-2.6 +/- 1.4, P = .011 and 2.0 +/- 1.2, P = .005, respectively). Adjustment had an effect on the individual FVIII consumption of most patients: annual amount was reduced in 18 cases and increased in 14. There was no significant effect on the mean amount (198 784 +/- 110 387) compared to that used the year prior to myPKFiT(r) -adjusted prophylaxis (199 466 +/- 103 670; P = .737). DISCUSSION: Our results suggest that PK-guided prophylaxis using myPKFiT(r) improved clinical outcomes and optimized FVIII consumption in the study population. This personalized approach may reduce bleeding rates without significantly increasing the overall cost of FVIII therapy. PMID- 30028551 TI - Neuronal susceptibility to beta-amyloid toxicity and ischemic injury involves histone deacetylase-2 regulation of endophilin-B1. AB - Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Abeta induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD. PMID- 30028552 TI - Circadian rhythms and influencing factors of xerostomia among Parkinson's disease patients. AB - OBJECTIVES: Parkinson's disease (PD) patients suffer from xerostomia, but limited information exists regarding associations with dysphagia, drooling, daily habits, PD characteristics, or possible circadian rhythms. SUBJECTS AND METHODS: A questionnaire was administered, including (a) clinical characteristics (comorbidities, prescribed medications, levodopa equivalent daily dose [LEDD], disease duration); (b) self-assessment of dysphagia, xerostomia, drooling (10-cm visual analogue scale [VAS]); (c) 24-hr diary of motor impairment, dyskinesia, xerostomia, dysphagia, drooling, daily habits. RESULTS: Of 75 PD patients who completed the study, 67% reported dysphagia (mean +/- standard deviation VAS 4 +/ 2), 76% drooling (5 +/- 2), 77% xerostomia (5 +/- 2). Xerostomia was associated with comorbidities (p = 0.021) and smoking (p = 0.010) and affected by tremor (p = 0.003), dyskinesia (p = 0.010), dysphagia (p < 0.001), food intake (p = 0.005), sleep (p = 0.011), age (p = 0.018), medication intake (p = 0.063), LEDD (p = 0.052), daytime (p = 0.075), disease duration (p = 0.004). Xerostomia peaked at 9 a.m. and 9 p.m. CONCLUSIONS: PD patients suffer from xerostomia, dysphagia, and drooling. Subjective dysphagia is associated with drooling and xerostomia, but drooling prevalence or intensity does not influence xerostomia symptoms. Tremor, dyskinesia, and disease duration, which characterise PD, affect xerostomia. Additionally, food intake, sleep, age, LEDD, and daytime (peaks at 9 a.m. and 9 p.m.) increase xerostomia occurrence. This knowledge may improve dentists' advice to patients and aid development of patient-centred, symptom-relieving products. PMID- 30028550 TI - The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behaviour. AB - Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) (also known as Rev-erb alpha) has been linked to circadian rhythm regulation, mood-related behaviour and disorders associated with social deficits. Recent work from our laboratory found striking decreases in Nr1d1 in the nucleus accumbens (NAc) in the maternal condition and indirect evidence that Nr1d1 was interacting with numerous addiction and reward-related genes to modulate social reward. In this study, we applied our insights from the maternal state to nonparental adult mice to determine whether decreases in Nr1d1 expression in the NAc via adeno-associated viral (AAV) vectors and short hairpin RNA (shRNA)-mediated gene knockdown were sufficient to modulate social behaviours and mood-related behaviours. Knockdown of Nr1d1 in the NAc enhanced sociability and reduced anxiety, but did not affect depressive-like traits in female mice. In male mice, Nr1d1 knockdown had no significant behavioural effects. Microarray analysis of Nr1d1 knockdown in females identified changes in circadian rhythm and histone deacetylase genes and suggested possible drugs, including histone deacetylase inhibitors, that could mimic actions of Nr1d1 knockdown. Quantitative real-time PCR (qPCR) analysis confirmed expression upregulation of gene period circadian clock 1 (Per1) and period circadian clock 2 (Per2) with Nr1d1 knockdown. The evidence for roles for opioid-related genes opioid receptor, delta 1 (Oprd1) and preproenkephalin (Penk) was also found. Together, these results suggest that Nr1d1 in the NAc modulates sociability and anxiety-related behaviour in a sex-specific manner, and circadian, histone deacetylase and opioid-related genes may be involved in the expression of these behavioural phenotypes. PMID- 30028553 TI - Comparison of clinical and radiographic peri-implant parameters among obese and non-obese patients: A 5-year study. AB - BACKGROUND: It is postulated that peri-implant parameters are worse in obese individuals as compared to nonobese. OBJECTIVE: The aim of the present 5-year longitudinal study was to analyze and compare the changes in clinical and radiographic peri-implant parameters among obese and non-obese patients. MATERIALS AND METHODS: Twenty patients with body mass index >= 27.5 kg/m2 and 18 non-obese controls were included. All patients were indicated for single tooth maxillary or mandibular molar replacement with the adjacent teeth intact. Peri implant clinical (plaque index [PI], bleeding on probing [BOP], probing depth [PD]) and radiographic (marginal bone loss [MBL]) parameters were measured at 12, 24, and 60 months of follow-up. RESULTS: All peri-implant parameters showed statistically significant difference between obese and non-obese individuals. Obese group recorded significant higher BOP, PD, and MBL at different observation times. Probing depth and MBL increased significantly with advance of time in both groups. After 60 months of follow-up period, greater PI and BOP was observed in obese patients (P < 0.01). At 60 months follow-up period, obese patients showed significant increased PD (3.69 mm) as compared to non-obese individuals (2.46 mm). Marginal bone loss in non-obese individuals varied from 0.30 mm after 12 months, reaching 0.55 mm after 60 months of follow-up period, while in obese patients MBL values went from 0.36 mm after 12 months to 0.91 mm at 60 months follow-up (P < 0.01). CONCLUSIONS: Patients with obesity are at risk of increased localized peri-implant soft and hard tissue inflammation. It is recommended that clinicians should educate obese patients about risk of increased peri-implant tissue inflammation and susceptibility to bone loss and stipulate stringent oral hygiene care for ideal peri-implant health. PMID- 30028554 TI - Fronto-Insular Connectivity during Pain Distraction Is Impaired in Patients with Somatoform Pain. AB - BACKGROUND AND PURPOSE: Somatoform pain disorder is characterized by chronic pain and various psychological symptoms including increased attention to mental and physical processes. Given that the medial prefrontal cortex (mPFC) of the default mode network (DMN) and the anterior insula of the salience network are critically involved in intrinsic and attentional processes, we investigated the involvement of these networks during the distraction from physical pain in somatoform pain patients. METHODS: During painful and nonpainful heat stimulation, attentional distraction from physical processes was modulated with a Stroop task. Thirteen patients were investigated with functional magnetic resonance imaging (fMRI) and compared to 13 controls. Main outcomes were spatial maps of coherent fMRI activity based on independent component analysis and functional connectivity (FC) resulting from psychophysiological interaction analysis. RESULTS: Behavioral pain intensity ratings were reduced during the distraction task in both groups. At brain level, we found deviant network activities in the DMN (particularly in the mPFC) and in the salience network (bilaterally in the anterior insula) in patients. During pain stimulation, Stroop-induced distraction decreased the FC between the mPFC and anterior insula in controls but not in patients. CONCLUSIONS: Modulating the FC between the mPFC and the insula may be highly relevant for shifting the attention away from external stimuli, including nociceptive input. The observed alterations in somatoform pain patients may foster new strategies in cognitive behavioral training tools for these patients. PMID- 30028556 TI - Contactin-associated protein-like 2, a protein of the neurexin family involved in several human diseases. AB - Contactin-associated protein-like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2-related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting-up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage-gated potassium channel (VGKC) complex that is composed of TAG-1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up-to-date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation. PMID- 30028557 TI - Focal multimodality radiation therapy: A promising treatment for recalcitrant Darier disease. PMID- 30028555 TI - Vasoactive intestinal peptide induces proliferation of human hepatocytes. AB - OBJECTIVES: Proliferation of hepatocytes in vitro can be stimulated by growth factors such as epidermal growth factor (EGF), but the role of vasoactive intestinal peptide (VIP) remains unclear. We have investigated the effect of VIP on maintenance and proliferation of human hepatocytes. MATERIALS AND METHODS: Human hepatocytes were isolated from liver specimens obtained from patients undergoing liver surgery. Treatment with VIP or EGF was started 24 h after plating and continued for 3 or 5 d. DNA replication was investigated by Bromodeoxyuridine (BrdU) incorporation and cell viability detected by MTT assay. Cell lysate was analysed by western blotting and RT-PCR. Urea and albumin secretion into the culture supernatants were measured. RESULTS: VIP increased DNA replication in hepatocytes in a dose-dependant manner, with a peak response at day 3 of treatment. VIP treatment was associated with an increase in mRNA expression of antigen identified by monoclonal antibody Ki-67 (MKI-67) and Histone Cluster 3 (H3) genes. Western blotting analysis showed that VIP can induce a PKA/B-Raf dependant phosphorylation of extracellular signal-regulated kinases (ERK). Although EGF can maintain hepatocyte functions up to day 5, no marked efffect was found with VIP. CONCLUSIONS: VIP induces proliferation of human hepatocytes with little or no effect on hepatocyte differentiation. Further investigation of the role of VIP is required to determine if it may ultimately support therapeutic approaches of liver disease. PMID- 30028558 TI - A cost-effective treatment model in dystrophic epidermolysis bullosa with congenital absence of skin. PMID- 30028559 TI - Brimonidine tartrate gel plus topical steroid for the prevention of laser therapy related postinflammatory hyperpigmentation. AB - Brimonidine gel, originally approved for the treatment of facial rosacea, causes direct vasoconstriction and possesses extensive utilization in dermatologic fields. A Q-switched (QS) neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is generally used to treat solar lentigo (SL), often leaving unwanted postinflammatory hyperpigmentation (PIH), especially in dark-skinned individuals. A 58-year-old man with Fitzpatrick skin type IV presented to remove solar lentigines from his face. Prior to and after laser treatment, topical brimonidine gel and steroid cream were applied. In this study, we investigated whether topical application of the alpha-adrenergic receptor agonist brimonidine could reduce PIH after QS laser treatment of lentigine in a dark-skinned patient. PMID- 30028560 TI - One-year mortality among newly admitted older patients in a long-term care hospital in South Korea. AB - OBJECTIVES: Older Korean people's admission to long-term care (LTC) hospitals is increasing. This study aimed to investigate one-year mortality and related factors among older patients admitted to a LTC hospital. METHODS: Medical records of 330 patients admitted to a LTC hospital in 2014 were reviewed. Factors related to death were identified using the Cox proportional hazards model. RESULTS: About 35% of the patients died within a year, and their average length of survival was 42.3 (SD = 68.4) days. Predictors of mortality within one year were as follows: cancer (hazard ratio (HR) = 3.04); aged 85 and older (HR = 2.61); dependency: K ADL >= 21 (HR = 2.14); male sex (HR = 1.95); respiratory disease (HR = 1.68); cognitive function (HR = 1.65); and abnormal serum sodium level (HR = 1.65). CONCLUSION: At admission, proper assessment and planning for older patients at risk are beneficial to minimise negative consequences. The roles of LTC hospitals need further discussion. PMID- 30028561 TI - Evaluation of volumetric wear of abutments on the retention loss of ball attachment systems in implant-retained overdentures: An in vitro study. AB - BACKGROUND: There is a lack of studies evaluating the wear of the male components of the ball attachment systems of implant-retained overdentures. PURPOSE: The purpose of this study was to compare the volumetric wear patterns four commercially used ball abutments. MATERIALS AND METHODS: Forty-eight identical polyethylene and acrylic blocks were fabricated and four groups consisting of 12 polyethylene blocks with two implants and 12 acrylic blocks, which were used as overdentures, were generated (two groups with plastic females, one group with gold and one group with titanium females). Every specimen underwent 5000 insertion and removal cycles (~4.5 years) and retention forces were measured. For the evaluation of volumetric wear, all the ball abutments were scanned before and after the 5000 cycles using a three-dimensional scanner and the data were analyzed using the software supplied by the manufacturer. RESULTS: Statistically significant retention force differences were observed between the groups at each cycle (P < .05). Among the four groups, retention force was lowest in the group with titanium females (5.59 +/- 2.27) and highest in the group with gold females (43.0 +/- 6.3) at the end of 5000 cycles. Statistically significant dimensional changes in the male components were observed between the groups (P < .05). Volumetric losses were 11%-13% in Group I and II, 1% in Group III, and 25% in Group IV. Group III showed significantly lower volumetric wear whereas Group IV showed significantly higher volumetric wear than all the other groups (P < .001). No significance was detected between Group I and II (P > .05). CONCLUSION: Within the limitations, it can be concluded that although clinical studies are needed to ensure the findings of the present study, due to severe retention loss and volumetric abutment wear, ball attachments with titanium female components should be used with caution. PMID- 30028562 TI - A competency framework for clinical pharmacists and heart failure. AB - OBJECTIVES: Heart failure is an escalating 'pandemic' with malignant outcomes. Clinical pharmacist heart failure services have been developing for the past two decades. However, little clarity is available on the additional advanced knowledge, skills and experience needed for pharmacists to practice safely and competently. We aimed to provide an expert consensus on the minimum competencies necessary for clinical pharmacists to deliver appropriate care to patients with heart failure. METHODS: There were four methodological parts; (1) establishing a project group from experts in the field; (2) review of the literature, including existing pharmacy competency frameworks in other specialities and previous heart failure curricula from other professions; (3) consensus building, including developing, reviewing and adapting the contents of the framework; and (4) write up and dissemination to widen the impact of the project. KEY FINDINGS: The final framework defines minimum competencies relevant to heart failure for four different potential levels of specialism: all pharmacists regardless of role (Stage 1); all patient-facing clinical pharmacists (Stage 2); clinical pharmacists with specific planned roles in the care of heart failure patients (Stage 3); and regionally/nationally/internationally recognised expert pharmacists with a direct specialism in heart failure (Stage 4). CONCLUSIONS: The framework delivers the vital first step needed to help standardise care, give pharmacists a blueprint for career progression and continuing professional development and bring clarity to the role of the pharmacist. Future collaboration between professional bodies and training providers is needed to develop structured programmes to align with the framework and facilitate training and resultant accreditation. PMID- 30028563 TI - Alcohol use disorders and insomnia mediate the association between PTSD symptoms and suicidal ideation in Korean firefighters. AB - BACKGROUND: There has been a strong association between posttraumatic stress disorder (PTSD) and suicidal ideation, which are both major mental health concerns in firefighters. Alcohol use disorders (AUDs) and insomnia are linked with both PTSD and suicidal ideation, but no studies have examined whether the relationship between PTSD and suicidal ideation can be explained by AUDs and insomnia. The purpose of this study was to investigate the mediating role of AUDs and insomnia in the relationship between PTSD symptoms and suicidal ideation. METHODS: A total of 7190 Korean firefighters filled out self-reported questionnaires to assess the number of exposure to incident stressors and the severity of PTSD symptoms, suicidal ideation, AUDs, and insomnia. Hierarchical multivariable linear regression analyses were performed to identify the relationship of AUDs and insomnia with suicidal ideation. Path analyses were applied to investigate the mediation effects of AUDs and insomnia on the relationship between PTSD symptoms and suicidal ideation. RESULTS: AUDs and insomnia showed significant associations with suicidal ideation, even after adjusting for demographic factors, number of traumatic events, and PTSD symptoms. The relationship between PTSD symptoms and suicidal ideation was partially mediated by AUDs and insomnia. AUDs also had both direct and indirect effects on suicidal ideation, with the indirect effect mediated by insomnia. CONCLUSIONS: We presented a model in which AUDs and insomnia mediate the relationship between PTSD symptoms and suicidal ideation in firefighters. Efforts to treat AUDs and alleviate insomnia could be beneficial in minimizing suicidal ideation in firefighters. PMID- 30028564 TI - CBT and positive psychology interventions for clinical depression promote healthy attentional biases: An eye-tracking study. AB - BACKGROUND: Although there is a growing interest in the role of attentional biases in depression, there are no studies assessing changes in these biases after psychotherapeutic interventions. METHODS: We used a validated eye-tracking procedure to assess pre-post therapy changes in attentional biases toward emotional information (i.e., happy, sad, and angry faces) when presented with neutral information (i.e., neutral faces). The sample consisted of 75 participants with major depression or dysthymia. Participants were blindly assigned to one of two 10 weekly sessions of group therapy: a cognitive behavior therapy intervention (N = 41) and a positive psychology intervention (N = 34). RESULTS: Both treatments were equally efficacious in improving depressive symptoms (p = .0001, eta2 = .68). A significant change in attentional performance after therapy was observed irrespective of the intervention modality. Comparison of pre-post attentional measures revealed a significant reduction in the total time of fixations (TTF) looking at negative information (i.e., sad and angry faces) and a significant increase in the TTF looking at positive information (i.e., happy faces)-all p < .02. CONCLUSIONS: Findings reveal for the first time that psychotherapeutic interventions are associated with a significant change in attentional biases as assessed by a direct measure of attention. Furthermore, these changes seem to operate in the same direction typically found in healthy populations (i.e., a bias away from negative information and a parallel bias toward positive information). These findings illustrate the importance of considering attentional biases as clinical markers of depression and suggest the viability of modifying these biases as a potential tool for clinical change. PMID- 30028565 TI - What Can Environmental Sequences Tell Us About the Distribution of Low-Rank Taxa? The Case of Euplotes (Ciliophora, Spirotrichea), Including a Description of Euplotes enigma sp. nov. AB - Environmental sequences have become a major source of information. High throughput sequencing (HTS) surveys have been used to infer biogeographic patterns and distribution of broad taxa of protists. This approach is, however, more questionable for addressing low-rank (less inclusive) taxa such as species and genera, because of the increased chance of errors in identification due to blurry taxonomic boundaries, low sequence divergence, or sequencing errors. The specious ciliate genus Euplotes partially escapes these limitations. It is a ubiquitous, monophyletic taxon, clearly differentiated from related genera, and with a relatively well-developed internal systematics. It has also been the focus of several ecological studies. We present an update on Euplotes biogeography, taking into consideration for the first time environmental sequences, both traditional (Sanger) and HTS. We inferred a comprehensive small subunit rRNA gene phylogeny of the genus including a newly described marine species, Euplotes enigma, characterized by a unique question mark-shaped macronucleus. We then added available environmental sequences to the tree, mapping associated metadata. The resulting scenario conflicts on many accounts with previously held views, suggesting, for example, that a large diversity of anaerobic Euplotes species exist, and that marine representatives of mainly freshwater lineages (and vice versa) might be more common than previously thought. PMID- 30028566 TI - A Comparison of Different Ciliate Metabarcode Genes as Bioindicators for Environmental Impact Assessments of Salmon Aquaculture. AB - Ciliates are powerful indicators for monitoring the impact of aquaculture and other industrial activities in the marine environment. Here, we tested the efficiency of four different genetic markers (V4 and V9 regions of the SSU rRNA gene, D1 and D2 regions of the LSU rRNA gene, obtained from environmental (e)DNA and environmental (e)RNA) of benthic ciliate communities for environmental monitoring. We obtained these genetic metabarcodes from sediment samples collected along a transect extending from below salmon cages toward the open sea. These data were compared to benchmark data from traditional macrofauna surveys of the same samples. In beta diversity analyses of ciliate community structures, the V4 and V9 markers had a higher resolution power for sampling sites with different degrees of organic enrichment compared to the D1 and D2 markers. The eDNA and eRNA V4 markers had a higher discriminatory power than the V9 markers. However, results obtained with the eDNA V9 marker corroborated better with the traditional macrofauna monitoring. This allows for a more direct comparison of ciliate metabarcoding with the traditional monitoring. We conclude that the ciliate eDNA V9 marker is the best choice for implementation in routine monitoring programs in marine aquaculture. PMID- 30028567 TI - An enlightening tripartite event in Hanoi: Third Indochina Academy of Dermatology Conference, World Health Academy Dermatology Summit, and the Vietnamese Society of Dermatology Annual Meeting. PMID- 30028568 TI - Mohs micrographic surgery combined local flaps in treatment of EMPD: A retrospective case. PMID- 30028569 TI - Greatly Improved Conductivity of Double-Chain Polymer Network Binder for High Sulfur Loading Lithium-Sulfur Batteries with a Low Electrolyte/Sulfur Ratio. AB - Binders have been considered to play a key role in realizing high-energy-density lithium-sulfur batteries. However, the accompanying problems of limited conductivity and inferior affinity of soluble polysulfide intermediates bring down their comprehensive performance for practical applications. Herein, the synthesis of a novel double-chain polymer network (DCP) binder by polymerizing 4,4'-biphenyldisulfonic acid connected pyrrole monomer onto viscous sodium carboxymethyl cellulose matrix, yielding a primary crystal structure is reported. Consequently, the resulted binder enables superior rate performance from 0.2 C (1326.9 mAh g-1 ) to 4 C (701.4 mAh g-1 ). Moreover, a high sulfur loading of 9.8 mg cm-2 and a low electrolyte/sulfur ratio (5:1, uL mg-1 ) are achieved, exhibiting a high area capacity of 9.2 mAh cm-2 . In situ X-ray diffraction analysis is conducted to monitor the structural modifications of the cathode, confirming the occurrence of sulfur reduction/recrystallization during charge discharge process. In addition, in situ UV-vis measurements demonstrate that DCP binder impedes the polysulfide migration, thereby giving rise to high capacity retention for 400 cycles. PMID- 30028570 TI - Facile Synthesis of Vanadium Metal-Organic Frameworks for High-Performance Supercapacitors. AB - Compared to traditional metal oxides, metal-organic frameworks exhibit excellent properties, such as a high surface area, significant thermal stability, low density, and excellent electrochemical performance. Here, a simple process is proposed for the fabrication of rod-like vanadium metal-organic frameworks (VIV (O)(bdc), bdc = 1,4-benzenedicarboxylate, or MIL-47), and the effect of the structure on the electrochemical performance is investigated via a series of electrochemical measurements. The VIV (O)(bdc) electrode exhibits a maximum specific capacitance of 572.1 F g-1 at current densities of 0.5 A g-1 . More significantly, aqueous and solid-state asymmetric supercapacitors are successfully assembled. The solid-state device shows an excellent energy density of 6.72 mWh cm-3 at a power density of 70.35 mW cm-3 . This superior performance confirms that VIV (O)(bdc) electrodes are promising materials for applications in supercapacitors. PMID- 30028571 TI - Key Role of Lanthanum Oxychloride: Promotional Effects of Lanthanum in NiLaOy /NaCl for Hydrogen Production from Ethyl Acetate and Water. AB - The hydrogen economy is accelerating technological evolutions toward highly efficient hydrogen production. In this work, the catalytic performance of NiO/NaCl for hydrogen production via autothermal reforming of ethyl acetate and water is further improved through lanthanum modification, and the resulted 3% NiLaOy /NaCl catalyst achieves as high as 93% H2 selectivity and long-term stability at 600 degrees C. The promoting effect is caused by the strong interactions between lanthanum and NiO/NaCl, by which LaNiO3 and a novel LaOCl phase are formed. The key role of LaOCl in promoting low-temperature hydrogen production is highlighted, while effects of LaNiO3 are well known. The LaOCl (010) facet possesses high adsorption capacity toward co-chemisorbing ethyl acetate and water. LaOCl strongly interacts with ethyl acetate and H2 O in the form of hydrogen bonding and coordination effect. The interactions induce tensions inside ethyl acetate and H2 O, activate the molecules, and hence decrease the energy barrier for reaction. In situ Fourier transform infrared spectroscopy (FTIR) reveals that LaOCl along with NaCl enhances the adsorption ability of NiO/NaCl. Moreover, LaOCl improves the dispersion of Ni species in NiO LaNiO3 -LaOCl nanosheets, which possess abundant active sites. The effects together promote hydrogen evolution. Furthermore, the NiLaOy /NaCl catalyst can be easily reborn after deactivation due to the water solubility of NaCl. PMID- 30028572 TI - Nanotopography-Promoted Formation of Axon Collateral Branches of Hippocampal Neurons. AB - Axon collateral branches, as a key structural motif of neurons, allow neurons to integrate information from highly interconnected, divergent networks by establishing terminal boutons. Although physical cues are generally known to have a comprehensive range of effects on neuronal development, their involvement in axonal branching remains elusive. Herein, it is demonstrated that the nanopillar arrays significantly increase the number of axon collateral branches and also promote their growth. Immunostaining and biochemical analyses indicate that the physical interactions between the nanopillars and the neurons give rise to lateral filopodia at the axon shaft via cytoskeletal changes, leading to the formation of axonal branches. This report, demonstrates that nanotopography regulates axonal branching, and provides a guideline for the design of sophisticated neuron-based devices and scaffolds for neuro-engineering. PMID- 30028573 TI - First-Pass Metabolism of Chlorophylls in Mice. AB - SCOPE: The dietary intake of chlorophylls is estimated to be ~50 mg d-1 . However, their first pass metabolism and systemic assimilation is not well characterized. METHODS AND RESULTS: A group of 30 mice are fed a diet rich in chlorophylls, while 10 mice received a standard diet without chlorophylls (control group). Liver extracts are analyzed every 15 days by HPLC-ESI(+)/APCI(+) hrTOF- MS/MS to measure the accretion of specific chlorophyll metabolites. The chlorophyll profile found in the livers of mice fed a chlorophyll-rich diet shows that the formation and/or absorption of pheophorbides, pyro-derivatives, and phytyl-chlorin e6 require the occurrence of a precise first-pass metabolism. In addition, the apical absorption of pheorphorbide a-rich micelles is significantly inhibited in Caucasian colon adenocarcinoma-2 cells pre-incubated with BLT1. CONCLUSION: Pheophorbide a absorption is, at least partly, protein-mediated through SR-BI. This active absorption process could explain the specific accumulation of pheophorbide a in the livers of animals fed a chlorophyll-rich diet. A complementary mechanism could be the de-esterification of pheophytin a in the liver, yielding pheophorbide a and phytol, which can explain the origin of phytol in the liver. Hence, the results suggest two molecular mechanisms responsible for the accumulation of the health-promoting compounds pheophorbide and phytol. PMID- 30028575 TI - Near-Infrared Switchable Fullerene-Based Synergy Therapy for Alzheimer's Disease. AB - C60 has a special dual function; it can act as both a powerful reactive oxygen species (ROS) producer under UV or visible light and an ROS scavenger in the dark. However, ROS has double-edged effects in living systems. It is still a great challenge for biomedical application to switch and adjust the two opposite properties of C60 in one system. Herein, UCNP@C60 -pep (UCNP: upconversion nanoparticle, pep: Abeta-target peptide KLVFF) is designed as a near-infrared switchable nanoplatform for synergy therapy of Alzheimer's disease (AD). Under near-infrared (NIR) light, the Abeta-targeting hybrid nanoparticles produce ROS and result in Abeta photooxygenation, which can hinder Abeta aggregation and mitigate the attendant cytotoxicity. In the dark, UCNP@C60 -pep shows protective effects against the increased oxidative stress. The ROS-generating and ROS quenching abilities of UCNP@C60 -pep are both beneficial for decreasing Abeta induced neurotoxicity and extending the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Moreover, UCNP@C60-pep can also be used for upconversion luminescence (UCL) and magnetic resonance imaging (MRI), which has benefits for "image-guided therapy." This study may offer a new perspective for the biological applications of C60 . PMID- 30028574 TI - Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis. AB - Based on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionarily related protease adenain, a target-hopping screening approach on a focused set of adenain inhibitors was investigated. The cyanopyrimidine-based inhibitors identified represent the first active-site-directed small-molecule inhibitors of Cdu1. High resolution crystal structures of Cdu1 in complex with two covalently bound cyanopyrimidines, as well as with its substrate ubiquitin, were obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into the substrate recognition of Cdu1, active-site pocket flexibility and potential hotspots for ligand interaction. Combined, these data provide a strong basis for future structure-guided medicinal chemistry optimization of this cyanopyrimidine scaffold into more potent and selective Cdu1 inhibitors. PMID- 30028576 TI - Controllable Colloidal Synthesis of Tin(II) Chalcogenide Nanocrystals and Their Solution-Processed Flexible Thermoelectric Thin Films. AB - A systematic colloidal synthesis approach to prepare tin(II, IV) chalcogenide nanocrystals with controllable valence and morphology is reported, and the preparation of solution-processed nanostructured thermoelectric thin films from them is then demonstrated. Triangular SnS nanoplates with a recently-reported pi cubic structure, SnSe with various shapes (nanostars and both rectangular and hexagonal nanoplates), SnTe nanorods, and previously reported Sn(IV) chalcogenides, are obtained using different combinations of solvents and ligands with an Sn4+ precursor. These unique nanostructures and the lattice defects associated with their Sn-rich composition allow the production of flexible thin films with competitive thermoelectric performance, exhibiting room temperature Seebeck coefficients of 115, 81, and 153 MUV K-1 for SnS, SnSe, and SnTe films, respectively. Interestingly, a p-type to n-type transition is observed in SnS and SnSe due to partial anion loss during post-synthesis annealing at 500 degrees C. A maximum figure of merit (ZT) value of 0.183 is achieved for an SnTe thin film at 500 K, exceeding ZT values from previous reports on SnTe at this temperature. Thus, a general strategy to prepare tin(II) chalcogenide nanocrystals is provided, and their potential for use in high-performance flexible thin film thermoelectric generators is demonstrated. PMID- 30028577 TI - Solid-State Rechargeable Zinc-Air Battery with Long Shelf Life Based on Nanoengineered Polymer Electrolyte. AB - Zinc-air batteries (ZABs) are vulnerable to the ambient environment (e.g., humidity and CO2 ), and have serious selfdischarge issues, resulting in a short shelf life. To overcome these challenges, a near-neutral quaternary ammonium (QA) functionalized polyvinyl alcohol electrolyte membrane (different from conventional alkali-type membranes) has been developed. QA functionalization leads to the formation of interconnected nanochannels by creating hydrophilic/ phobic separations at the nanoscale. These nanochannels selectively transport OH- ions with a reduced migration barrier, while inhibiting [Zn(NH3 )6 ]2+ crossover. Owing to the superior water retention ability and enhanced chemical stability of the membrane, the solid-state zinc-air battery (SZAB) displays outstanding flexibility, a promising cycle lifetime, and a large volumetric energy density. More importantly, the self-discharge rate of SZAB is depressed to less than 7 % per month, and the fully dehydrated SZAB could recover its rechargeability upon replenishment of the solution of NH4 Cl. PMID- 30028578 TI - High-Coulombic-Efficiency Carbon/Li Clusters Composite Anode without Precycling or Prelithiation. AB - Lithium metal has attracted much research interest as a possible anode material for high-energy-density lithium-ion batteries in recent years. However, its practical use is severely limited by uncontrollable deposition, volume expansion, and dendrite formation. Here, a metastable state of Li, Li cluster, that forms between LiC6 and Li dendrites when over-lithiating carbon cloth (CC) is discovered. The Li clusters with sizes in the micrometer and submicrometer scale own outstanding electrochemical reversibility between Li+ and Li, allowing the CC/Li clusters composite anode to demonstrate a high first-cycle coulombic efficiency (CE) of 94.5% +/- 1.0% and a stable CE of 99.9% for 160 cycles, which is exceptional for a carbon/lithium composite anode. The CC/Li clusters composite anode shows a high capacity of 3 mAh cm-2 contributed by both Li+ intercalation and Li-cluster formation, and excellent cycling stability with a signature sloping voltage profile. Furthermore, the CC/Li clusters composite anode can be assembled into full cells without precycling or prelithiation. The full cells containing bare CC as the anode and excessive LiCoO2 as the cathode exhibit high specific capacity and good cyclic stability in 200 cycles, stressing the advantage of controlled formation of Li clusters. PMID- 30028579 TI - Clinical outcomes of exclusive transcanal endoscopic tympanoplasty with tragal perichondrium in 129 patients. PMID- 30028580 TI - 21st Chinese Society of Dermatology Annual Meeting, Hefei, Anhui, China. PMID- 30028581 TI - Preparation of Musk-Smelling Macrocyclic Lactones from Biomass: Looking for the Optimal Substrate Combination. AB - Macrocyclic musk belongs to a well-known and valued class of the fragrance family. Originally, natural musks were obtained from rectal musk glands which often led to the death of the animals. Recently, a lot of effort was invested to obtain such macrocycles in a synthetic way. This research presents a study on the preparation of macrocyclic lactones with the musk scent by ring-closing metathesis (RCM) using biomass-derived starting materials: oleic and 9-decenoic acid. An experimental rule correlating the C-C double bond substitution pattern in the starting diene and the yield for the RCM macrocyclization was proposed. PMID- 30028582 TI - Do Carbon Nanotubes Improve the Thermomechanical Properties of Benzoxazine Thermosets? AB - Fillers are widely used to improve the thermomechanical response of polymer matrices, yet often in an unpredictable manner because the relationships between the mechanical properties of the composite material and the primary (chemical) structure of its molecular components have remained elusive so far. Here, we report on a combined theoretical and experimental study of the structural and thermomechanical properties of carbon nanotube (CNT)-reinforced polybenzoxazine resins, as prepared from two monomers that only differ by the presence of two ethyl side groups. Remarkably, while addition of CNT is found to have no impact on the glass-transition temperature ( Tg) of the ethyl-decorated resin, the corresponding ethyl-free composite features a surge by ~47 degrees C (50 degrees C) in Tg, from molecular dynamics simulations (dynamic mechanical analysis measurements), as compared to the neat resin. Through a detailed theoretical analysis, we propose a microscopic picture for the differences in the thermomechanical properties of the resins, which sheds light on the relative importance of network topology, cross-link and hydrogen-bond density, chain mobility, and free volume. PMID- 30028583 TI - Spirally Configured ( cis-Stilbene) Trimers: Steady-State and Time-Resolved Photophysical Studies and Organic Light-Emitting Diode Applications. AB - This article reports for the time-resolved photophysical studies of spirally configured ( cis-stilbene) trimers and their spin-coated organic light-emitting diode (OLED) device performances. Transient absorption profiles of spirally configured, ter-( cis-stilbene) were studied by pulse radiolysis. The emission profiles after charge recombination of their incipient radical ions in benzene provides insights into the emission mechanism and efficiency in OLED devices. Blue-, sky blue-, and green-emitting OLED devices for a maximum external quantum efficiency are 4.32%, 4.70%, and 2.77%, respectively, by solution process. PMID- 30028584 TI - Biodegradable Nanoglobular Magnetic Resonance Imaging Contrast Agent Constructed with Host-Guest Self-Assembly for Tumor-Targeted Imaging. AB - Gadolinium-based macromolecular magnetic resonance imaging (MRI) contrast agents (CAs) have attracted increasing interest in tumor diagnosis. However, their practical application is potentially limited because the long-term retention of gadolinium ion in vivo will induce toxicity. Here, a nanoglobular MRI contrast agent (CA) PAMAM-PG- g-s-s-DOTA(Gd) + FA was designed and synthesized on the basis of the facile host-guest interaction between beta-cyclodextrin and adamantane, which initiated the self-assembly of poly(glycerol) (PG) separately conjugated with gadolinium chelates by disulfide bonds and folic acid (FA) molecule onto the surface of poly(amidoamine) (PAMAM) dendrimer, finally realizing the biodegradability and targeting specificity. The nanoglobular CA has a higher longitudinal relaxivity ( r1) than commercial gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), showing a value of 8.39 mM-1 s-1 at 0.5 T, and presents favorable biocompatibility on the observations of cytotoxicity and tissue toxicity. Furthermore, MRI on cells and tumor-bearing mice both demonstrate the obvious targeting specificity, on the basis of which the effective contrast enhancement at tumor location was obtained. In addition, this CA exhibits the ability of cleavage to form free small-molecule gadolinium chelates and can realize minimal gadolinium retention in main organs and tissues after tumor detection. These results suggest that the biodegradable nanoglobular PAMAM-PG- g-s-s-DOTA(Gd) + FA can be a safe and efficient MRI CA for tumor diagnosis. PMID- 30028585 TI - Insight into the Nature of Iron Sulfide Surfaces During the Electrochemical Hydrogen Evolution and CO2 Reduction Reactions. AB - Greigite and other iron sulfides are potential, cheap, earth-abundant electrocatalysts for the hydrogen evolution reaction (HER), yet little is known about the underlying surface chemistry. Structural and chemical changes to a greigite (Fe3S4)-modified electrode were determined at -0.6 V versus standard hydrogen electrode (SHE) at pH 7, under conditions of the HER. In situ X-ray absorption spectroscopy was employed at the Fe K-edge to show that iron-sulfur linkages were replaced by iron-oxygen units under these conditions. The resulting material was determined as 60% greigite and 40% iron hydroxide (goethite) with a proposed core-shell structure. A large increase in pH at the electrode surface (to pH 12) is caused by the generation of OH- as a product of the HER. Under these conditions, iron sulfide materials are thermodynamically unstable with respect to the hydroxide. In situ infrared spectroscopy of the solution near the electrode interface confirmed changes in the phosphate ion speciation consistent with a change in pH from 7 to 12 when -0.6 V versus SHE is applied. Saturation of the solution with CO2 resulted in the inhibition of the hydroxide formation, potentially due to surface adsorption of HCO3-. This study shows that the true nature of the greigite electrode under conditions of the HER is a core-shell greigite-hydroxide material and emphasizes the importance of in situ investigation of the catalyst under operation to develop true and accurate mechanistic models. PMID- 30028586 TI - Retraction of "Substrate Stiffness Regulates the Development of Left-Right Asymmetry in Cell Orientation". PMID- 30028587 TI - Simple in Vivo Gene Editing via Direct Self-Assembly of Cas9 Ribonucleoprotein Complexes for Cancer Treatment. AB - Cas9 ribonucleoprotein (RNP)-mediated delivery has emerged as an ideal approach for in vivo applications. However, the delivery of Cas9 RNPs requires electroporation or lipid- or cationic-reagent-mediated transfection. Here, we developed a carrier-free Cas9 RNP delivery system for robust gene editing in vivo. For simultaneous delivery of Cas9 and a guide RNA into target cells without the aid of any transfection reagents, we established a multifunctional Cas9 fusion protein (Cas9-LMWP) that forms a ternary complex with synthetic crRNA:tracrRNA hybrids in a simple procedure. Cas9-LMWP carrying both a nuclear localization sequence and a low-molecular-weight protamine (LMWP) enables the direct self-assembly of a Cas9:crRNA:tracrRNA ternary complex (a ternary Cas9 RNP) and allows for the delivery of the ternary Cas9 RNPs into the recipient cells, owing to its intrinsic cellular and nuclear translocation ability with low immunogenicity. To demonstrate the potential of this system, we showed extensive synergistic anti-KRAS therapy (CI value: 0.34) via in vitro and in vivo editing of the KRAS gene by the direct delivery of multifunctional Cas9 RNPs in lung cancer. Thus, our carrier-free Cas9 RNP delivery system could be an innovative platform that might serve as an alternative to conventional transfection reagents for simple gene editing and high-throughput genetic screening. PMID- 30028588 TI - Statistical Analysis of Scanning Fluorescence Correlation Spectroscopy Data Differentiates Free from Hindered Diffusion. AB - Cells rely on versatile diffusion dynamics in their plasma membrane. Quantification of this often heterogeneous diffusion is essential to the understanding of cell regulation and function. Yet such measurements remain a major challenge in cell biology, usually due to low sampling throughput, a necessity for dedicated equipment, sophisticated fluorescent label strategies, and limited sensitivity. Here, we introduce a robust, broadly applicable statistical analysis pipeline for large scanning fluorescence correlation spectroscopy data sets, which uncovers the nanoscale heterogeneity of the plasma membrane in living cells by differentiating free from hindered diffusion modes of fluorescent lipid and protein analogues. PMID- 30028589 TI - Effects of Catalyst Processing on the Activity and Stability of Pt-Ni Nanoframe Electrocatalysts. AB - Pt-based alloys have shown great promise as cathodic catalysts for cost-effective proton-exchange membrane fuel cells. Post-synthesis treatment has been recognized as a critical step to improve the catalytic performance of Pt-based alloys. Here, we present the effects of catalyst processing on the catalytic behavior of Pt-Ni nanoframe electrocatalysts in oxygen reduction reaction. The Pt-Ni nanoframes were made by corroding the Ni-rich phase from solid rhombic dodecahedral particles. A total of three different corrosion procedures were compared. Among them, electrochemical corrosion led to the highest initial specific activity (1.35 mA cm-2 at 0.95 V versus reversible hydrogen electrode) by retaining more Ni in the nanoframes. However, the high activity gradually went down in a subsequent stability test due to continuous Ni loss and concomitant surface reconstruction. On the other hand, the best stability was achieved by a more aggressive corrosion using oxidative nitric acid. Although the initial activity was compromised, this procedure imparted a less-defective surface, and thus, the specific activity dropped by only 7% over 30 000 potential cycles. These results indicate a delicate trade-off between the activity and stability of Pt-Ni nanoframe electrocatalysts. The obtained understanding of how to balance the activity-stability trade-off via catalyst processing can be generalized to other Pt-based alloys. PMID- 30028590 TI - Crystalline Cyclophane-Protein Cage Frameworks. AB - Cyclophanes are macrocyclic supramolecular hosts famous for their ability to bind atomic or molecular guests via noncovalent interactions within their well-defined cavities. In a similar way, porous crystalline networks, such as metal-organic frameworks, can create microenvironments that enable controlled guest binding in the solid state. Both types of materials often consist of synthetic components, and they have been developed within separate research fields. Moreover, the use of biomolecules as their structural units has remained elusive. Here, we have synthesized a library of organic cyclophanes and studied their electrostatic self assembly with biological metal-binding protein cages (ferritins) into ordered structures. We show that cationic pillar[5]arenes and ferritin cages form biohybrid cocrystals with an open protein network structure. Our cyclophane protein cage frameworks bridge the gap between molecular frameworks and colloidal nanoparticle crystals and combine the versatility of synthetic supramolecular hosts with the highly selective recognition properties of biomolecules. Such host guest materials are interesting for porous material applications, including water remediation and heterogeneous catalysis. PMID- 30028592 TI - Design and Clinical Verification of Surface-Enhanced Raman Spectroscopy Diagnostic Technology for Individual Cancer Risk Prediction. AB - The use of emerging nanotechnologies, such as plasmonic nanoparticles in diagnostic applications, potentially offers opportunities to revolutionize disease management and patient healthcare. Despite worldwide research efforts in this area, there is still a dearth of nanodiagnostics which have been successfully translated for real-world patient usage due to the predominant sole focus on assay analytical performance and lack of detailed investigations into clinical performance in human samples. In a bid to address this pressing need, we herein describe a comprehensive clinical verification of a prospective label-free surface-enhanced Raman scattering (SERS) nanodiagnostic assay for prostate cancer (PCa) risk stratification. This contribution depicts a roadmap of (1) designing a SERS assay for robust and accurate detection of clinically validated PCa RNA targets; (2) employing a relevant and proven PCa clinical biomarker model to test our nanodiagnostic assay; and (3) investigating the clinical performance on independent training ( n = 80) and validation ( n = 40) cohorts of PCa human patient samples. By relating the detection outcomes to gold-standard patient biopsy findings, we established a PCa risk scoring system which exhibited a clinical sensitivity and specificity of 0.87 and 0.90, respectively [area-under curve of 0.84 (95% confidence interval: 0.81-0.87) for differentiating high- and low-risk PCa] in the validation cohort. We envision that our SERS nanodiagnostic design and clinical verification approach may aid in the individualized prediction of PCa presence and risk stratification and may overall serve as an archetypical strategy to encourage comprehensive clinical evaluation of nanodiagnostic innovations. PMID- 30028591 TI - Engineering a Rugged Nanoscaffold To Enhance Plug-and-Display Vaccination. AB - Nanoscale organization is crucial to stimulating an immune response. Using self assembling proteins as multimerization platforms provides a safe and immunogenic system to vaccinate against otherwise weakly immunogenic antigens. Such multimerization platforms are generally based on icosahedral viruses and have led to vaccines given to millions of people. It is unclear whether synthetic protein nanoassemblies would show similar potency. Here we take the computationally designed porous dodecahedral i301 60-mer and rationally engineer this particle, giving a mutated i301 (mi3) with improved particle uniformity and stability. To simplify the conjugation of this nanoparticle, we employ a SpyCatcher fusion of mi3, such that an antigen of interest linked to the SpyTag peptide can spontaneously couple through isopeptide bond formation (Plug-and-Display). SpyCatcher-mi3 expressed solubly to high yields in Escherichia coli, giving more than 10-fold greater yield than a comparable phage-derived icosahedral nanoparticle, SpyCatcher-AP205. SpyCatcher-mi3 nanoparticles showed high stability to temperature, freeze-thaw, lyophilization, and storage over time. We demonstrate approximately 95% efficiency coupling to different transmission blocking and blood-stage malaria antigens. Plasmodium falciparum CyRPA was conjugated to SpyCatcher-mi3 nanoparticles and elicited a high avidity antibody response, comparable to phage-derived virus-like particles despite their higher valency and RNA cargo. The simple production, precise derivatization, and exceptional ruggedness of this nanoscaffold should facilitate broad application for nanobiotechnology and vaccine development. PMID- 30028594 TI - Correction to "Detection of a Peptide Biomarker by Engineered Yeast Receptors". PMID- 30028593 TI - Combined Organic Fouling and Inorganic Scaling in Reverse Osmosis: Role of Protein-Silica Interactions. AB - We investigated the relationship between silica scaling and protein fouling in reverse osmosis (RO). Flux decline caused by combined scaling and fouling was compared with those by individual scaling or fouling. Bovine serum albumin (BSA) and lysozyme (LYZ), two proteins with opposite charges at typical feedwater pH, were used as model protein foulants. Our results demonstrate that water flux decline was synergistically enhanced when silica and protein were both present in the feedwater. For example, flux decline after 500 min was far greater in combined silica scaling and BSA fouling experiments (55 +/- 6% decline) than those caused by silica (11 +/- 2% decline) or BSA (9 +/- 1% decline) alone. Similar behavior was observed with silica and LYZ, suggesting that this synergistic effect was independent of protein charge. Membrane characterization by scanning electron microscopy and Fourier transform infrared spectroscopy revealed distinct foulant layers formed by BSA and LYZ in the presence of silica. A combination of dynamic light scattering, transmission electron microscopy , and energy dispersive X-ray spectroscopy analyses further suggested that BSA and LYZ facilitated the formation of aggregates with varied chemical compositions. As a result, BSA and LYZ were likely to play different roles in enhancing flux decline in combined scaling and fouling. Our study suggests that the coexistence of organic foulants, such as proteins, largely alters scaling behavior of silica, and that accurate prediction of RO performance requires careful consideration of foulant-scalant interactions. PMID- 30028595 TI - Disruptive Environmental Research. PMID- 30028596 TI - Asymmetric Cationic Phosphines: Synthesis, Coordination Chemistry, and Reactivity. AB - A single enantiomer of a cationic phosphine, [alpha-CgPAmHMe]BF4, containing two asymmetric subunits, an amidinium group (AmH) and a phosphacycle (CgP), has been synthesized and isolated. The ligand, which is of an extremely rare class, has been coordinated to Rh(I), Au(I), Ag(I), Cu(I), and Pt(0) to enable an empirical assessment of its donor properties. Analysis of the IR stretching frequency of the carbonyl ligand in trans-[Rh(alpha-CgPAmHMe)2(CO)Cl](BF4)2 coupled with metric data obtained from crystal-state molecular structures of pertinent complexes confirms the strong pi-accepting properties of the ligand. The integrity of the N-P bond is compromised upon addition of base to both [Cu(alpha CgPAmHMe)Cl]BF4 and [Ag(alpha-CgPAmHMe)(OTf)]BF4 where, instead of isolating anticipated chelating and/or bridging forms of the neutral, deprotonated alpha CgPAmMe derivative, decomposition products were obtained containing a phosphacycle fragment and/or amidine ligands. The fragility of the N-P bond is also evident in uncoordinated [alpha-CgPAmHMe]BF4 as treatment with aqueous base releases a neutral amidine fragment and generates the P-P dimer [alpha,alpha CgPP(O)Cg]. These fortuitous observations show [alpha-CgPAmHMe]BF4 to be a very useful synthon for the potential production of novel asymmetric phosphines. PMID- 30028597 TI - ZnGaNO Photocatalyst Particles Prepared from Methane-Based Nitridation Using Zn/Ga/CO3 LDH as Precursor. AB - Methane-based nitridation was employed to produce wurtzite zinc-gallium oxynitride (ZnGaNO) photocatalyst particles using Zn/Ga/CO3 layered double hydroxides (LDHs) as precursor. Introduction of methane to nitridation would promote the formation of Zn-O bonding and suppress shallow acceptor complexes such as V(Zn)-Ga(Zn) and Ga-Oi in ZnGaNO particles. On the other hand, high flow rate of methane would induce breaking of Ga-N bonding and enhance surface deposition of metallic Ga atoms. After loading with Rh and RuO2, ZnGaNO particles had free electron density in an order of S50 > S20 > S90 > S0, which correlated well with their photocatalytic performance upon visible-light irradiation. The best performance of the loaded S50 was ascribed to the relatively flat surface band bending of the particle. Methane-based nitridation of Zn/Ga/CO3 LDHs would provide a new route to tune the surface chemistry of ZnGaNO and enhance the photocatalytic performance to its full potential. PMID- 30028600 TI - Complementary Steric Engineering at the Protein-Ligand Interface for Analogue Sensitive TET Oxygenases. AB - Ten-eleven translocation (TET) enzymes employ O2, earth-abundant iron, and 2 ketoglutarate (2KG) to perform iterative C-H oxidation of 5-methylcytosine in DNA to control expression of the mammalian genome. Given that more than 60 such C-H oxygenases are present in humans, determining context-dependent functions of each of these enzymes is a pivotal challenge. In an effort to tackle the problem, we developed analogue-sensitive TET enzymes to perturb the activity of a specific member. We rationally engineered the TET2-2KG interface to develop TET2 variants with an expanded active site that can be specifically inhibited by the N oxalylglycine (NOG) derivatives carrying a complementary steric "bump". Herein, we describe the identification and engineering of a bulky gatekeeper residue for TET proteins, characterize the orthogonal mutant-inhibitor pairs, and show generality of the approach. Employing cell-permeable NOG analogues, we show that the TET2 mutant can be specifically inhibited to conditionally modulate cytosine methylation in chromosomal DNA in intact human cells. Finally, we demonstrate application of the orthogonal mutant-inhibitor pair to probe transcriptional activity of a specific TET member in cells. Our work provides a general platform for developing analogue-sensitive 2KG-dependent oxygenases to unravel their functions in diverse signaling processes. PMID- 30028598 TI - Parameterized Yields of Semivolatile Products from Isoprene Oxidation under Different NO x Levels: Impacts of Chemical Aging and Wall-Loss of Reactive Gases. AB - We developed a parametrizable box model to empirically derive the yields of semivolatile products from VOC oxidation using chamber measurements, while explicitly accounting for the multigenerational chemical aging processes (such as the gas-phase fragmentation and functionalization and aerosol-phase oligomerization and photolysis) under different NO x levels and the loss of particles and gases to chamber walls. Using the oxidation of isoprene as an example, we showed that the assumptions regarding the NO x-sensitive, multigenerational aging processes of VOC oxidation products have large impacts on the parametrized product yields and SOA formation. We derived sets of semivolatile product yields from isoprene oxidation under different NO x levels. However, we stress that these product yields must be used in conjunction with the corresponding multigenerational aging schemes in chemical transport models. As more mechanistic insights regarding SOA formation from VOC oxidation emerge, our box model can be expanded to include more explicit chemical aging processes and help ultimately bridge the gap between the process-based understanding of SOA formation from VOC oxidation and the bulk-yield parametrizations used in chemical transport models. PMID- 30028602 TI - Temperature Dependence of Dissolved Organic Matter Fluorescence. AB - The temperature dependence of organic matter fluorescence apparent quantum yields (Phif) was measured for a diverse set of organic matter isolates (i.e., marine aquatic, microbial aquatic, terrestrial aquatic, and soil) in aqueous solution and for whole water samples to determine apparent activation energies ( Ea) for radiationless decay processes of the excited singlet state. Ea was calculated from temperature dependent Phif data obtained by steady-state methods using a simplified photophysical model and the Arrhenius equation. All aquatic-derived isolates, all whole water samples, and one soil-derived fulvic acid isolate exhibited temperature dependent Phif values, with Ea ranging from 5.4 to 8.4 kJ mol-1 at an excitation wavelength of 350 nm. Conversely, soil humic acid isolates exhibited little or no temperature dependence in Phif. Ea varied with excitation wavelength in most cases, typically exhibiting a decrease between 350 and 500 nm. The narrow range of Ea values observed for these samples when compared to literature Ea values for model fluorophores (~5-30 kJ mol-1) points to a similar photophysical mechanism for singlet excited states nonradiative inactivation across organic matter isolates of diverse source and character. In addition, this approach to temperature dependent fluorescence analysis provides a fundamental, physical basis, in contrast to existing empirical relationships, for correcting online fluorescence sensors for temperature effects. PMID- 30028601 TI - Multiplexed Instrument-Free Bar-Chart SpinChip Integrated with Nanoparticle Mediated Magnetic Aptasensors for Visual Quantitative Detection of Multiple Pathogens. AB - A portable multiplexed bar-chart SpinChip (MB-SpinChip) integrated with nanoparticle-mediated magnetic aptasensors was developed for visual quantitative instrument-free detection of multiple pathogens. This versatile multiplexed SpinChip combines aptamer-specific recognition and nanoparticle-catalyzed pressure amplification to achieve a sample-to-answer output for sensitive point of-care testing (POCT). This is the first report of pathogen detection using a volumetric bar-chart chip, and it is also the first bar-chart chip using a "spinning" mechanism to achieve multiplexed bar-chart detection. Additionally, the introduction of the spin unit not only enabled convenient sample introduction from one inlet to multiple separate channels in the multiplexed detection, but also elegantly solved the pressure cross-interference problem in the multiplexed volumetric bar-chart chip. This user-friendly MB-SpinChip allows visual quantitative detection of multiple pathogens simultaneously with high sensitivity but without utilizing any specialized instruments. Using this MB-SpinChip, three major foodborne pathogens including Salmonella enterica, Escherichia coli, and Listeria monocytogenes were specifically quantified in apple juice with limits of detection of about 10 CFU/mL. This MB-SpinChip with a bar-chart-based visual quantitative readout has great potential for the rapid simultaneous detection of various pathogens at the point of care and wide applications in food safety, environmental surveillance, and infectious disease diagnosis. PMID- 30028604 TI - Resolution of Electronic and Structural Factors Underlying Oxygen-Evolving Performance in Amorphous Cobalt Oxide Catalysts. AB - Non-noble-metal, thin-film oxides are widely investigated as promising catalysts for oxygen evolution reactions (OER). Amorphous cobalt oxide films electrochemically formed in the presence of borate (CoBi) and phosphate (CoPi) share a common cobaltate domain building block, but differ significantly in OER performance that derives from different electron-proton charge transport properties. Here, we use a combination of L edge synchrotron X-ray absorption (XAS), resonant X-ray emission (RXES), resonant inelastic X-ray scattering (RIXS), resonant Raman (RR) scattering, and high-energy X-ray pair distribution function (PDF) analyses that identify electronic and structural factors correlated to the charge transport differences for CoPi and CoBi. The analyses show that CoBi is composed primarily of cobalt in octahedral coordination, whereas CoPi contains approximately 17% tetrahedral Co(II), with the remainder in octahedral coordination. Oxygen-mediated 4 p-3 d hybridization through Co-O-Co bonding was detected by RXES and the intersite dd excitation was observed by RIXS in CoBi, but not in CoPi. RR shows that CoBi resembles a disordered layered LiCoO2-like structure, whereas CoPi is amorphous. Distinct domain models in the nanometer range for CoBi and CoPi have been proposed on the basis of the PDF analysis coupled to XAS data. The observed differences provide information on electronic and structural factors that enhance oxygen evolving catalysis performance. PMID- 30028603 TI - Total Synthesis of (-)-Nodulisporic Acids D, C, and B: Evolution of a Unified Synthetic Strategy. AB - A unified synthetic strategy leading to the total synthesis of (-)-nodulisporic acids D, C, and B is described. Key synthetic transformations include a nickel chromium-mediated cyclization, an aromatic ring functionalization employing a novel copper-promoted alkylation, a palladium-catalyzed cross-coupling cascade/indole ring construction, and a palladium-mediated regio- and diastereoselective allylic substitution/cyclization reaction, the latter to construct ring D. PMID- 30028605 TI - Characterization of Fluorescently Labeled Protein with Electrospray Ionization-MS and Fluorescence Spectroscopy: How Random is Random Labeling? AB - Solvent exposed lysine residues are abundantly present in many proteins. Their highly reactive epsilon-amino groups serve as universal targets for coupling with active esters of various extrinsic labels including a vast arsenal of fluorescent probes. Here, we describe fluorescent properties and preferential localization of two frequently used fluorescent labels, AlexaFluor488 (AF488) and Cy3, on the surface of a small highly soluble serum protein neutrophil gelatinase-associated lipocalin (NGAL), which serves as a diagnostic marker for acute kidney failure. Using a standard protocol for labeling with either AF488-SDP or AF488-NHS, we achieved >95% labeling efficiency of the protein as determined by UV-vis absorption and electrospray ionization (ESI)-MS. However, fluorescence intensity of the labeled protein was less than 10% of the expected value. To understand the unusually high quenching of the probe, we identified the sites of AF488 attachments by means of LC-MS/MS combined with trypsin digestion. Surprisingly, we found that the AF488 label is not randomly distributed among accessible lysines but predominantly bound to the residues K125, K126, or K135, which are located in the NGAL calyx and are likely quenched by neighboring tryptophans and tyrosines. In contrast, when NGAL was labeled with Cy3, the probe's fluorescence was almost fully retained. The LC-MS/MS data indicated that Cy3 was predominately bound to another lysine, K31, on the protein surface on the opposite side of the calyx. Our findings suggest that a combination of the inherent properties of the label and the specifics of the protein microenvironment may selectively lead probes to specific lysine residues and thus challenge the common view that protein labeling is a random process. PMID- 30028606 TI - An Alkaloid from Scorpion Venom: Chemical Structure and Synthesis. AB - While most scorpion venom components identified in the past are peptidic or proteinic in nature, we report here a new alkaloid isolated from the venom of the Mexican scorpion Megacormus gertschi. Nuclear magnetic resonance and mass spectrometric investigations elucidate the structure of the alkaloid as ( Z)- N (2-(1 H-imidazol-4-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)-2-methoxyacrylamide (1). A chemical method of synthesizing this alkaloid is also described. Although abundant in venom, the above alkaloid was not found to have insecticidal activity. Structural analysis suggests that this venom alkaloid might be of potential interest for evaluating its medicinal effect. PMID- 30028607 TI - Dual Utilization of Medicinal and Aromatic Crops as Bioenergy Feedstocks. AB - Dual production of biofuels and chemicals can increase the economic value of lignocellulosic bioenergy feedstocks. We compared the bioenergy potential of several essential oil (EO) crops with switchgrass ( Panicum virgatum L.), a crop chosen to benchmark biomass and lignocellulosic biofuel production. The EO crops of interest were peppermint ( Mentha * piperita L.), "Scotch" spearmint ( Mentha * gracilis Sole), Japanese cornmint ( Mentha canadensis L.), and sweet sagewort ( Artemisia annua L.). We also assessed each crop for EO production in a marginal production environment in Wyoming, USA, with irrigation and nitrogen (N) rates using a split-plot experimental design. Oil content ranged from 0.31 to 0.4% for Japanese cornmint, 0.23 to 0.26% for peppermint, 0.38 to 0.5% for spearmint, and the overall mean of sweet sagewort was 0.34%. Oil yields ranged from (in kg ha-1) 34 to 165 in Japanese cornmint, 25 to 108 in peppermint, 29.3 to 126 in spearmint, and 39.7 in sweet sagewort. EO production, but not composition, was sensitive to N fertilization. The alternative bioenergy crops and switchgrass produced similar amounts of ethanol from bench-scale simultaneous saccharification and fermentation assays. Value-added incomes from the EO proceeds were estimated to be between $1055 and $5132 ha-1 from peppermint, $1309 and $5580 ha-1 from spearmint, $510 and $2460 ha-1 from Japanese cornmint, and $3613 ha-1 from sweet sagewort under Wyoming growth conditions. The advantage of the proposed crops over traditional lignocellulosic species is the production of high-value natural products in addition to lignocellulosic biofuel production. PMID- 30028608 TI - Copper-Catalyzed Oxidative Trifunctionalization of Olefins: An Access to Functionalized beta-Keto Thiosulfones. AB - Aerobic oxidative trifunctionalization of olefins for the synthesis of functionalized beta-keto thiosulfones has been described. The transformation proceeds through molecular oxygen activation under copper catalysis and forms the two new C-S bonds in a single operation using mild conditions. A novel Cu catalyzed sulfonyl radical addition/oxidation/funtionalization relay mechanism was proposed for the discovered reaction. PMID- 30028609 TI - Origin of Many-Body Vibrational Frequency Shifts in Water Clusters. AB - We have demonstrated the application of many-body expansions to calculations of the anharmonic, local-mode, OH-stretching vibrational frequencies of water clusters. We focused on five low-lying isomers of the water hexamer and the DD*(20,1) isomer of (H2O)21. Our approach provides accurate OH-stretching vibrational frequencies when treating one- and two-body interactions with the CCSD(T)-F12 level of theory and the three- and four-body interactions with the DF MP2-F12 level. Additionally, we have investigated the physical origin of the large contribution that two- and three-body interactions make to the shifts of vibrational frequencies using symmetry-adapted perturbation theory (SAPT). We conclude that while two-body vibrational frequency shifts can be correlated linearly with electrostatic energies, all strongly shifted three-body interactions can be correlated to the induction energy with a single regression coefficient of approximately 70 cm-1 (kcal.mol-1)-1. PMID- 30028610 TI - Radical Arene Addition vs Radical Reduction: Why Organometal Hydride Chain Reactions Stop and How To Make Them Go. AB - Nonideal kinetic chain analysis was used to examine the kinetic limitations of free-radical synthesis. Homolytic aromatic substitution (HAS: ArH + R* -> ArR + H*) occurs in a chain-terminating side reaction to the tributyltin hydride ( SnH) reduction chain (RX + SnH + ( i*)cat. -> RH + SnX). Kinetic modeling of premixed and slow reagent addition reactions have clarified the mechanisms of SM HAS, with the azo initiator ( iNN i) acting not only as radical source but also (as an H* acceptor) as the redox catalyst for aromatization, and/or as a postaddition oxidant. Refractory halides and other hitherto baffling anomalies may arise from the build up of ipso (rather than ortho)-cycloadduct radicals in the steady-state radical population. The implications of these findings for "tin-free" radical chains (and emerging photoredox methods) are considered via historical and recent examples of the effects of chain-degrading radical transfer (to substrate, product, solvent, initiator, and/or reagent ligands) on the reagent's chain. PMID- 30028611 TI - Simulation of Mixed Self-Assembled Monolayers on Gold: Effect of Terminal Alkyl Anchor Chain and Monolayer Composition. AB - Self-assembling monolayers provide a reproducible synthetic microenvironment for tethering lipid bilayers to incorporate proteins and lay the ground for numerous applications in nanotechnology and biomedical engineering. Although the structure of single-component monolayers is well investigated, there is far less insight into the molecular behavior at the interface of mixed monolayers at different mole fractions. Here, we present and apply a novel procedure to simulate and analyze multicomponent self-assemblies of alkanethiols over a wide range of mole concentrations of anchoring compounds. In particular, the structural features of monolayers consisting of a matrix compound and either a short (C8) or a long (C16) anchor compound on Au(111)-like surfaces were investigated first using coarse-grained and subsequently full-atomistic molecular dynamics simulations. Different scenarios of spatial distributions (random vs clustering) of anchoring molecules on flat surfaces were probed. The results of the simulations are in excellent agreement with the experimental data from ellipsometry and infrared reflection absorption spectroscopy. For short anchoring molecules, a random spatial distribution in the matrix is obtained. At low, experimentally relevant anchor compound mole fractions < 0.1, only for long-chain (C16)-terminal alkyls, phase segregation and self-association of the anchoring molecules can be observed, which are also seen in experiment. PMID- 30028612 TI - Antiangiogenic Activity and Chemical Derivatization of the Neurotoxic Acetogenin Annonacin Isolated from Asimina triloba. AB - Annonacin (1) was isolated from the North American pawpaw ( Asimina triloba), as reported earlier from these laboratories. Natural 1 was submitted to the rat aortic ring bioassay for evaluation of antiangiogenic activity and was found to inhibit microvessel growth (IC50 value of 3 MUM). 4,10,15,20-Tetraazido derivatives of 1 were prepared by permesylation followed by azide displacement or by iodination followed by azide displacement. The tetraazide derived from mesylation/azidation was antiangiogenic, while that derived from iodination/azidation exhibited no appreciable activity. The membrane permeability of natural 1 was evaluated using the parallel artificial membrane permeability assay and was found to be marginally permeable as compared to several clinically relevant compounds. PMID- 30028613 TI - A One-Pot Approach to 2,3-Diarylbenzo[ b]furans through N-Heterocyclic Carbene Catalyzed 1,6-Conjugate Addition Followed by Acid Mediated Dehydrative Annulation. AB - A one-pot protocol for the synthesis of 2,3-diarylbenzo[ b]furan derivatives through an N-heterocyclic carbene catalyzed 1,6-conjugate addition of aromatic aldehydes to 2-hydroxyphenyl-substituted para-quinone methides followed by acid mediated dehydrative annulation has been developed. This protocol allowed us to access a wide range of 2,3-diarylbenzo[ b]furan derivatives in moderate to good yields. PMID- 30028614 TI - On the Relation between Equation-of-Motion Coupled-Cluster Theory and the GW Approximation. AB - We discuss the analytic and diagrammatic structure of ionization potential (IP) and electron affinity (EA) equation-of-motion coupled-cluster (EOM-CC) theory, in order to put it on equal footing with the prevalent GW approximation. The comparison is most straightforward for the time-ordered one-particle Green's function, and we show that the Green's function calculated by EOM-CC with single and double excitations (EOM-CCSD) includes fewer ring diagrams at higher order than does the GW approximation, due to the former's unbalanced treatment of time ordering. However, the EOM-CCSD Green's function contains a large number of vertex corrections, including ladder diagrams, mixed ring-ladder diagrams, and exchange diagrams. By including triple excitations, the EOM-CCSDT Green's function includes all diagrams contained in the GW approximation, along with many high-order vertex corrections. In the same language, we discuss a number of common approximations to the EOM-CCSD equations, many of which can be classified as elimination of diagrams. Finally, we present numerical results by calculating the principal charged excitations energies of the molecules contained in the so called GW100 test set [ J. Chem. Theory Comput. 2015 , 11 , 5665 - 5687 ]. We argue that (in molecules) exchange is as important as screening, advocating for a Hartree-Fock reference and second-order exchange in the self-energy. PMID- 30028615 TI - Tailoring of a Potential Nanoformulated Form of Gibberellic Acid: Synthesis, Characterization, and Field Applications on Vegetation and Flowering. AB - Nanoformulation of agrochemicals has become a potential choice to improve the physicochemical properties, enhance the utilization efficiency, and reduce the side effects and ecotoxicity of many hazardous chemicals. Here, we tailored a new formulation platform for gibberellic acid (GA) using the layered double hydroxides (LDH) as a potential carrier. Typically, we synthesized, characterized, and potentially applied the newly nanoformulated form of GA on the quantity and quality properties of Dendranthema grandiflorum cultivar. We also evaluated the synergetic effect of the carrier LDH on the release behavior of GA, showing a remarkable impact on the utilization efficiency of GA. The nanohybrid structure of GA also showed an enhanced thermal stability and safe preservation for the incorporated moieties. Taking into account the hazardous effect of free GA on the environment and human health, the hybrid technique of GA is one of the best choices among all of the studied protocols. PMID- 30028616 TI - 5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes. AB - This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1 yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future. PMID- 30028617 TI - Intermolecular Potential-Based Equations of State from Molecular Simulation and Second Virial Coefficient Properties. AB - The importance of both the Boyle temperature ( TB) and temperature maximum ( Tmax) for the ability of intermolecular potential-based equations of state to accurately predict second virial coefficient ( B) behavior was examined. The TB, Tmax, and B vs T behavior of several Lennard-Jones equations of state, developed from molecular simulation data, were compared with exact theoretical values. The analysis spanned low ( T <= TB), mid ( TB < T <= Tmax), and high ( T ? Tmax) temperatures. The value of TB was accurately predicted by most equations of state studied, whereas most failed to adequately predict Tmax. The ability to accurately predict both TB and Tmax appears to be correlated with the accurate prediction of B values for the entire range of temperatures. This provides a useful criterion to improve future potential-based equations of state. The Mecke et al. and Thol et al. Lennard-Jones equations of state yielded the most accurate results. In some cases, a many-fold improvement in accuracy was observed compared with alternative equations of state. The exact B data were also used to obtain accurate polynomial relationships covering different ranges of temperatures. PMID- 30028618 TI - Measurements and Simulations of the Acidity Dependence of the Kinetics of the Iron-Catalyzed Belousov-Zhabotinsky Reaction: Proton-Catalysis in the Electron Transfer Reaction Involving the [Fe(phen)3]3+ Species. AB - The acidity dependence of the iron-catalyzed bromate-malonic acid Belousov Zhabotinsky reaction was studied in the range 0.36 M < [H2SO4]0 < 1.20 M, and the temporal evolutions of the oscillation patterns were analyzed. The experimental results show that the period times PT i decrease exponentially with increasing acidity and that the period times parallel the decrease of the reduction times RT with increasing acidity. Simulations using the reactions of the commonly accepted core reaction mechanism failed to match the measurements even in a qualitative fashion. However, we found that compelling agreement between the experiments and the simulations can be achieved over the entire range with the inclusion of second-order proton-catalysis of the oxidation of bromomalonic acid (BrMA) by the [Fe(phen)3]3+ species in the reaction identified in this paper as reaction 9 (R9), and this [H+] dependence is informative about the species involved in the outer sphere electron transfer reaction. The trication [Fe(phen)3]3+ species is stabilized by ion pairing and solvation, and one may anticipate the presence of [Fe(phen)3(HSO4) n(H2O) m](3- n)+ species ( n = 0-3). Our results suggest that the removal of aggregating HSO4- ions by protonation creates a better oxidant and facilitates the approach of the reductant BrMA, and the second-order [H+] dependence further suggests that BrMA is primarily oxidized by a doubly charged [Fe(phen)3(HSO4)1(L) k]2+ species. Considering the complexity of the BZ system and the uncertainties in the many reaction rate constants, we were somewhat surprised to find this high level of agreement by (just) the replacement of R9 by R9'. In fact, the near-quantitative agreement presents a powerful corroboration of the core reaction mechanism of the BrMA-rich BZ reaction, and the replacement of R9 by R9' extends the validity of this core reaction mechanism to acidities above and below the typical acidity of BZ reactions ([H+] ~ 1 M). PMID- 30028619 TI - Synthesis of Multisubstituted Furans via a Catalyst- and Additive-Free Tandem Reaction of Enynones with Sulfinic Acids in Water. AB - A facile and efficient tandem reaction of enynones with arylsulfinic acids was developed. A variety of multisubstituted furans were obtained in satisfactory yields via an O2-oxidative single-electron-transfer process without any catalyst and additive in water. PMID- 30028620 TI - Friction of Poroelastic Contacts with Thin Hydrogel Films. AB - We report on the frictional behavior of thin poly(dimethylacrylamide) hydrogel films grafted on glass substrates in sliding contact with a glass spherical probe. Friction experiments are carried out at various velocities and normal loads applied with the contact fully immersed in water. In addition to friction force measurements, a novel optical setup is designed to image the shape of the contact under steady-state sliding. The velocity dependence of both friction force Ft and contact shape is found to be controlled by a Peclet number, Pe, defined as the ratio of the time tau needed to drain the water out of the contact region to a contact time a/ v, where v is the sliding velocity and a is the contact radius. When Pe < 1, the equilibrium circular contact achieved under static normal indentation remains unchanged during sliding. Conversely, for Pe > 1, a decrease in the contact area is observed together with the development of a contact asymmetry when the sliding velocity is increased. A maximum in Ft is also observed at Pe ~1. These experimental observations are discussed in the light of a poroelastic contact model based on a thin-film approximation. This model indicates that the observed changes in contact geometry are due to the development of a pore pressure imbalance when Pe > 1. An order-of-magnitude estimate of the friction force and its dependence on normal load and velocity are also provided under the assumption that most of the frictional energy is dissipated by poroelastic flow at the leading and trailing edges of the sliding contact. PMID- 30028621 TI - Uniform-Sized Silica Nanocapsules Produced by Addition of Salts to a Water-In-Oil Emulsion Template. AB - Size control of silica hollow particles was achieved using a water-in-oil (W/O) emulsion system, where interfacial condensation of organosilanes (octyltrichlorosilane and methyltrichlorosilane) took place around the aqueous droplets. Good emulsion stability was obtained using soybean oil as the oil phase because of its high viscosity. This high stability led to bimodal distributions in the sizes of the aqueous droplets and final hollow particles, with particle sizes observed of a few tens of nanometers and a few micrometers. The presence of NaCl was found to be required in the water phase to afford uniform-sized silica hollow spheres. Hydrolysis of the organosilanes caused a supersaturation of the aqueous NaCl solution dispersing in the oil continuous phase, followed by crystallization from droplets. Nanosized aqueous droplets acted as a template to form uniform-sized nanospherical hollow silica particles as a result of the diminishing number of larger aqueous droplets. PMID- 30028622 TI - Simultaneous Delivery of Electrostatically Complexed Multiple Gene-Targeting siRNAs and an Anticancer Drug for Synergistically Enhanced Treatment of Prostate Cancer. AB - Simultaneous silencing of multiple apoptosis-related genes is an attractive approach to treat cancer. In this article, we present a multiple gene-targeting siRNA/drug delivery system for prostate cancer treatment with a high efficiency. Bcl-2, survivin, and androgen receptor genes involved in the cell apoptosis pathways were chosen as silencing targets with three different siRNAs. The colloidal nanocomplex delivery system (<10 nm in size) was formulated electrostatically between anionic siRNAs and a cationic drug (BZT), followed by encapsulation with the Pluronic F-68 polymer. The formulated nanocomplex system exhibited sufficient stability against nuclease-induced degradation, leading to successful intracellular delivery for the desired therapeutic performance. Silencing of targeted genes and apoptosis induction were evaluated in vitro on human prostate LNCaP-LN3 cancer cells by using various biological analysis tools (e.g., real-time PCR, MTT cell viability test, and flow cytometry). It was demonstrated that when the total loaded siRNA amounts were kept the same in the nanocomplexes, the simultaneous silencing of triple genes with co-loaded siRNAs (i.e., Bcl-2, survivin, and AR-targeting siRNAs) enhanced BZT-induced apoptosis of cancer cells more efficiently than the silencing of each single gene alone, offering a novel way of improving the efficacy of gene therapeutics including anticancer drug. PMID- 30028623 TI - Bioengineered Macrophages Can Responsively Transform into Nanovesicles To Target Lung Metastasis. AB - Specific drug delivery to metastatic tumors remains a great challenge for antimetastasis therapy. We herein report a bioengineered macrophage-based delivery system (LD-MDS) that can be preferentially delivered to lung metastases and intelligently transformed into nanovesicles and secondary nanovesicles for antimetastasis therapy. LD-MDS was prepared by anchoring a legumain-specific propeptide of melittin (legM) and cytotoxic soravtansine (DM4) prodrug onto the membrane of living macrophages. LD-MDS is responsively activated by legumain protease and converted into DM4-loaded exosome-like nanovesicles (DENs), facilitating efficient internalization by metastatic 4T1 cancer cells and considerable cell death. Afterward, the damaged 4T1 cells can release secondary nanovesicles and free drug molecules to destroy neighboring cancer cells. In vivo, LD-MDS displays superior targeting efficiency for lung metastatic lesions with diameters less than 100 MUm and remarkably inhibits lung metastasis. This study provides a new opportunity to explore endogenous macrophages as living drug delivery vehicles with controlled drug release to target metastatic lung tumors. PMID- 30028624 TI - Synthesis and Biological Activity of Tetrameric Ribitol Phosphate Fragments of Staphylococcus aureus Wall Teichoic Acid. AB - A systematically designed and synthesized ribitol phosphate (RboP) oligomer using a series of building blocks, which make up the wall teichoic acid (WTA) of S. aureus, is presented. Based on the use of a solution-phase phosphodiester synthesis, a library of ribitol phosphate tetramers, decorated with d-alanine and N-acetylglucosamine (GlcNAc), were generated. The synthesized RboP tetramers showed increased cytokine levels in mice in a subcutaneous air pouch model. PMID- 30028625 TI - Catalytic Asymmetric Total Syntheses of Naturally Occurring Amarylidaceae Alkaloids, (-)-Crinine, (-)- epi-Crinine, (-)-Oxocrinine, (+)- epi-Elwesine, (+) Vittatine, and (+)- epi-Vittatine. AB - An expeditious approach to catalytic enantioselective total syntheses of crinine type Amaryllidaceae alkaloids has been accomplished via a Pd-catalyzed enantioselective decarboxylative allylation of allylenol carbonates as a key step (up to 96% ee). Using this strategy, collective total syntheses of Amaryllidaceae alkaloids such as (-)- epi-elwesine (1b), (-)-crinine (1c), (-)- epi-crinine (1e), (-)-oxocrinine (1f), and (-)-buphanisine (1d) have been accomplished. Gratifyingly, naturally occurring Amaryllidaceae alkaloids such as (+)-vittatine (1g), (+)- epi-vittatine (1h), and (+)- epi-elwesine (1i) [enantiomers of (-)-1c, (-)-1e, and (-)-1b, respectively] have also been achieved by switching the antipode of ligand used in the catalytic enantioselective step. PMID- 30028626 TI - Self-Assembly of Two Unit Cells into a Nanodomain Structure Containing Five-Fold Symmetry. AB - Five-fold symmetry was forbidden for the periodic crystals until the discovery of the Al-Mn icosahedral quasicrystal. We report a kind of precipitated rod-shaped nanophase containing five-fold symmetry but not belonging to any crystals or quasicrystals discovered so far. These metastable nanodomain phases, which precipitated in Mg-6Zn alloy during isothermal aging at 200 degrees C, contain two separate unit cells in the 2D plane perpendicular to the five-fold axis but with periodic atom arrangement along the five-fold axis, that is, 72 degrees rhombus structure and 72 degrees equilateral hexagon structure. The self assembly of two unit cells under some geometrical constraints into a nanodomain contains the 2D five-fold, C14, and C15 structures. This finding confirms the existence of solid matters in a special structure between the crystals and quasicrystals, and it is expected to provide a way to understand the atomic arrangement and stacking behavior in condensed matters. PMID- 30028627 TI - Micropore Size Distribution and Surface Characteristics Co-influence on 4 Chlorophenol Adsorption Mechanism from Organic Solvents. AB - The effects of co-influence of pore size distribution and surface chemistry of activated carbon (AC) on the p-chlorophenol (PCP) adsorption from water, heptane, and cyclohexane have been studied. To modify the surface basicity, commercial activated carbon and ash-free commercial activated carbon were subjected to heat treatment in a hydrogen atmosphere. The ACs were also oxidized with hydrogen peroxide to increase the acidity. All applied modifications caused negligible changes in the porous texture and a significant modification on the surface characteristics. The adsorption of PCP was carried out in static conditions at an ambient temperature. The time needed to obtain the adsorption equilibrium from organic solvent was shorter than from water. The boundary layer effect was found to increase in the direction of water < cyclohexane < heptane and was heteroatom dependent. The equilibrium adsorption isotherms showed all spectrum of isotherm types according to the Giles classification. The strong relationship between the volume of the PCP adsorbed and the volume of ACs micropore with size smaller than 1.6 nm was presented. This work shows that the surface heterogeneity influences the adsorption mechanism in the low adsorbate concentration range, more specifically, the final adsorption capacity is pore-size-dependent regardless of the kind of solvent used. PMID- 30028628 TI - Direct Assembly of 4-Substituted Quinolines with Vinyl Azides as a Dual Synthon via C?C and C-N Bond Cleavage. AB - An unprecedented Zn-promoted selective cleavage of vinyl azides for the synthesis of 4-substituted quinolines is developed. In this conversion, vinyl azides function as a dual synthon via C?C and C-N bond cleavage with two C?C bonds and one C?N bond formation in a one-step manner. The reaction is appreciated for its readily accessible substrates, high step economy, mild conditions, and use of air as the sole oxidant. PMID- 30028630 TI - Electric Field Assembly of Colloidal Superstructures. AB - The assembly of materials from building blocks has been in the core of a wide range of applications from catalysis to photonics and electronics. External electric fields enable the interactions between building blocks to be controlled via induced dipoles. Dipolar interactions were used so far to obtain one dimensional chains or three-dimensional non-close-packed lattices. However, complex colloidal assemblies and clusters of simple spherical particles are rare. Here we demonstrate a novel self-assembly approach enabling the formation of regular axially symmetric clusters, an array of colloidal assemblies as per design of posts, and hierarchical complex assemblies by using posts and dipolar interactions or combining them. Regulating the polarization of the particles from positive to negative allows us to control the interparticle interactions from attractive to repulsive at the poles or equator of the particles. Therefore, such particle-particle interactions enable switching between Saturn ring-like and candle-flame-like axially symmetric assemblies, which could potentially be exploited for display applications. PMID- 30028629 TI - Monitoring Translation Activity of mRNA-Loaded Nanoparticles in Mice. AB - Targeting mRNA to eukaryotic cells is an emerging technology for basic research and provides broad applications in cancer immunotherapy, vaccine development, protein replacement, and in vivo genome editing. Although a plethora of nanoparticles for efficient mRNA delivery exists, in vivo mRNA targeting to specific organs, tissue compartments, and cells remains a major challenge. For this reason, methods for reporting the in vivo targeting specificity of different mRNA nanoparticle formats will be crucial. Here, we describe a straightforward method for monitoring the in vivo targeting efficiency of mRNA-loaded nanoparticles in mice. To achieve accurate mRNA delivery readouts, we loaded lipoplex nanoparticles with Cre-recombinase-encoding mRNA and injected these into commonly used Cre reporter mouse strains. Our results show that this approach provides readouts that accurately report the targeting efficacy of mRNA into organs, tissue structures, and single cells as a function of the used mRNA delivery system. The method described here establishes a versatile basis for determining in vivo mRNA targeting profiles and can be systematically applied for testing and improving mRNA packaging formats. PMID- 30028631 TI - Oxygen Reduction Reaction: Rapid Prediction of Mass Activity of Nanostructured Platinum Electrocatalysts. AB - Tailored Pt nanoparticle catalysts are promising candidates to accelerate the oxygen reduction reaction (ORR) in fuel cells. However, the search for active nanoparticle catalysts is hindered by the laborious effort of experimental synthesis and measurements. On the other hand, density functional theory-based approaches are still time-consuming and often not efficient. In this study, we introduce a computational model which enables rapid catalytic activity calculation of unstrained pure Pt nanoparticle electrocatalysts. Regarding particle size effects on Pt nanoparticles, experimental catalytic mass activities from previous studies are accurately reproduced by our computational model. Moreover, beyond available experiments, our computational model identifies potential enhancement in mass activity up to 190% over the experimentally detected maximum. Importantly, the rapid activity calculation enabled by our computational model may pave the way for extensive nanoparticle screening to expedite the search for improved electrocatalysts. PMID- 30028632 TI - Does Dose Matter? PMID- 30028633 TI - The Psychometric Properties of the Hypersexual Behavior Inventory Using a Large Scale Nonclinical Sample. AB - The conceptualization of hypersexuality has begun to converge as a result of proposed diagnostic criteria. However, its measurement is still diverse. The Hypersexual Behavior Inventory (HBI) is one of the most appropriate scales used to assess hypersexuality, but further examination is needed to test its psychometric properties among different clinical and nonclinical groups, including samples outside of the United States. The aim of the present study was to investigate the reliability and the generalizability of HBI and to determine a cutoff score on a large, diverse, online, nonclinical sample (N = 18,034 participants; females = 6132; 34.0%; Mage = 33.6 years, SDage = 11.1). Confirmatory factor analysis (CFA) and reliability indices provided support for the structure of the HBI and demonstrated excellent reliability. Employing latent profile analysis (LPA), seven classes emerged, but they could not be reliably distinguished by objective sexuality-related characteristics. Moreover, it was not possible to determine an adequate cutoff score, most likely due to the low prevalence rate of hypersexuality in the population. HBI can be reliably used to measure the extent of hypersexual urges, fantasies, and behavior; however, objective indicators and a clinical interview are essential to claim that a given individual may exhibit features of problematic sexual behavior. PMID- 30028634 TI - Face Masks Reduce the Release of Pseudomonas aeruginosa Cough Aerosols When Worn for Clinically Relevant Periods. PMID- 30028635 TI - Economic impact of outreach athletic trainers on a health system: implications for program growth and sustainability. AB - OBJECTIVES: There are numerous benefits of organized athletics, but there is an inherent risk with competitive participation. The need for proper care for high school and community athletes can be met with comprehensive community sports medicine programs, and the employment of certified athletic trainers (AT-Cs). The benefit of clinic-based AT-C has been clearly demonstrated, but there has been little published on the economics of outreach AT-C serving directly in the community. Our hypothesis was that outreach AT-Cs are economically sustainable to an academic health system. METHODS: Evaluation of clinical business generated from the outreach Sports Medicine AT-C program at our institution was performed from fiscal years 2012 to 2015 to determine new referrals, billable patient encounters (bpe), and corresponding revenue generated. Data were retrieved from an existing aggregate business analysis, including both professional billing and hospital billing; data were restricted to the fiscal year of the initial referral. Both new patients and patients with established care were identified. Total revenue was determined, as well as the distribution across clinical departments within our health system. RESULTS: 8570 bpe resulted from 843 patients referred into the system, yielding $2286,733 in total revenue. Of these, 187 were new patients, yielding 1602 bpe. Each patient generated an average of 10.17 bpe, by combining revenue across services; this yielded an average of $2712 per patient generated through the AT-C program. CONCLUSION: Affiliation between a health system and community sports teams through an outreach AT-C program is an economically sustainable, symbiotic relationship. Additionally, there is not only a positive economic impact for sports medicine and orthopaedic providers but also a distinct benefit to the entire health system. This is the first study to demonstrate that an outreach AT-C program is financially sustainable and directly benefits the entire health system across many subspecialties. PMID- 30028636 TI - Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. AB - Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches. Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F.-F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., Finck, B. N. Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice. PMID- 30028637 TI - Automated scoring of dicentric chromosomes differentiates increased radiation sensitivity of young children after low dose CT exposure in vitro. AB - PURPOSE: Automated detection of dicentric chromosomes from a large number of cells was applied to study age-dependent radiosensitivity after in vitro CT exposure of blood from healthy donors. MATERIALS AND METHODS: Blood samples from newborns, children (2-5 years) and adults (20-50 years) were exposed in vitro to 0 mGy, 41 mGy and 978 mGy using a CT equipment. In this study, automated scoring based on 13,000-31,000 cells/dose point/age group was performed. Results for control and low dose points were validated by manually counting about 26,000 cells/dose point/age group. RESULTS: For all age groups, the high number of analyzed cells enabled the detection of a significant increase in the frequency of radiation induced dicentric chromosomes in cells exposed to 41 mGy as compared to control cells. Moreover, differences between the age groups could be resolved for the low dose: young donors showed significantly increased risk for induced dicentrics at 41 mGy compared to adults. CONCLUSIONS: The results very clearly demonstrate that the automated dicentric scoring method is capable of discerning radiation induced biomarkers in the low dose range (<100 mGy) and thus may open possibilities for large-scale molecular epidemiology studies in radiation protection. PMID- 30028638 TI - Fumonisins and their analogues in contaminated corn and its processed foods - a review. AB - One of the food security problems faced worldwide is the occurrence of mycotoxins in grains and their foods. Fumonisins (FBs) are mycotoxins which are prevalent in corn (Zea mays L.) and its based foods. Their intake and exposure have been epidemiologically and inconclusively associated with oesophageal cancer and neural tube defects in humans, and other harmful health effects in animals. The toxic effects of FBs can be acute or chronic and these metabolites bioaccumulate mainly in liver and kidney tissues. Among FBs, fumonisin B1 (FB1) is the most relevant moiety although the 'hidden' forms produced after food thermal processes are becoming relevant. Corn is the grain most susceptible to Fusarium and FBs contamination and the mould growth is affected both by abiotic and biotic factors during grain maturation and storage. Mould counts are mainly affected by the grain water activity, the environmental temperature during grain maturation and insect damage. The abiotic factors affected by climatic change patterns have increased their incidence in other regions of the world. Among FBs, the hidden forms are the most difficult to detect and quantify. Single or combined physical, chemical and biological methods are emerging to significantly reduce FBs in processed foods and therefore diminish their toxicological effects. PMID- 30028639 TI - Drug treatment options for premature ejaculation. AB - INTRODUCTION: Various drugs are available for lifelong and acquired premature ejaculation (PE), but only dapoxetine and FortacinTM have been officially registered. On the other hand, all sorts of pharmacologically not-investigated over-the-counter-products (OTCs) are used by men with complaints of PE with normal ejaculation time durations (subjective PE). There is a need to critically review the current state of registered and nonregistered drugs for PE. Areas covered: In this review, the authors use the guideline of the International Society for Sexual Medicine (ISSM) for the treatment of PE and provide evidence based recommendations for the pharmacotherapy of lifelong and acquired PE. This should always be accompanied by psychoeducation, counseling, and information about common and rare side effects of the various available drugs. Expert opinion: As long as subjective PE is not officially recognized as the third PE subtype, registration authorities will continue to demand drugs for subjective PE to be studied in men with lifelong PE. This is unfortunate as the method and design of studies of drugs for subjective PE differ from those of lifelong PE but also because drugs for subjective PE need to be investigated in men with subjective PE and not in men with lifelong PE. PMID- 30028641 TI - Stellate Cells in Tissue Repair, Inflammation, and Cancer. AB - Stellate cells are resident lipid-storing cells of the pancreas and liver that transdifferentiate to a myofibroblastic state in the context of tissue injury. Beyond having roles in tissue homeostasis, stellate cells are increasingly implicated in pathological fibrogenic and inflammatory programs that contribute to tissue fibrosis and that constitute a growth-permissive tumor microenvironment. Although the capacity of stellate cells for extracellular matrix production and remodeling has long been appreciated, recent research efforts have demonstrated diverse roles for stellate cells in regulation of epithelial cell fate, immune modulation, and tissue health. Our present understanding of stellate cell biology in health and disease is discussed here, as are emerging means to target these multifaceted cells for therapeutic benefit. PMID- 30028640 TI - Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference replicated, crossover study. AB - BACKGROUND: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations. RESEARCH DESIGN AND METHODS: The single center, open-label, randomized, three-period, three-sequence, reference replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC0-72h, AUC0-?, Cmax, Tmax, T1/2 and Kel. RESULTS: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for Cmax, the 90% CI for this parameter for itraconazole was 93.49-133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15-138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events. CONCLUSIONS: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria. PMID- 30028642 TI - Regulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing. AB - Posttranscriptional mechanisms provide powerful means to expand the coding power of genomes. In nervous systems, alternative splicing has emerged as a fundamental mechanism not only for the diversification of protein isoforms but also for the spatiotemporal control of transcripts. Thus, alternative splicing programs play instructive roles in the development of neuronal cell type-specific properties, neuronal growth, self-recognition, synapse specification, and neuronal network function. Here we discuss the most recent genome-wide efforts on mapping RNA codes and RNA-binding proteins for neuronal alternative splicing regulation. We illustrate how alternative splicing shapes key steps of neuronal development, neuronal maturation, and synaptic properties. Finally, we highlight efforts to dissect the spatiotemporal dynamics of alternative splicing and their potential contribution to neuronal plasticity and the mature nervous system. PMID- 30028643 TI - Assembly and Positioning of the Oocyte Meiotic Spindle. AB - Fertilizable eggs develop from diploid precursor cells termed oocytes. Once every menstrual cycle, an oocyte matures into a fertilizable egg in the ovary. To this end, the oocyte eliminates half of its chromosomes into a small cell termed a polar body. The egg is then released into the Fallopian tube, where it can be fertilized. Upon fertilization, the egg completes the second meiotic division, and the mitotic division of the embryo starts. This review highlights recent work that has shed light on the cytoskeletal structures that drive the meiotic divisions of the oocyte in mammals. In particular, we focus on how mammalian oocytes assemble a microtubule spindle in the absence of centrosomes, how they position the spindle in preparation for polar body extrusion, and how the spindle segregates the chromosomes. We primarily focus on mouse oocytes as a model system but also highlight recent insights from human oocytes. PMID- 30028644 TI - Characteristic properties of muscular-derived extracellular matrix and its application in rat abdominal wall defects. AB - AIM: To investigate the behavior of porcine-derived decellularized muscular matrix (DMM) in vitro and compare the performance of this biological mesh with that of acellular dermal matrix from pig in a full abdominal wall defect model. MATERIALS & METHODS: To describe the in vitro properties of the DMM scaffold with extracellular matrix histological analysis, growth factor quantification and scanning electron microscopy analysis. To compare structural and functional remodeling between acellular dermal matrix and DMM implants in a rodent full abdominal wall defect model. RESULTS & CONCLUSION: The results demonstrated that cellular components were effectively removed in the DMM scaffold, which also maintained a 3D architecture, biochemical components and strong mechanical properties. In vivo experiments confirm that the DMM mesh could promote remodeling and reconstruction of functional skeletal muscle tissue. PMID- 30028645 TI - Genetic Contribution to Variation in Risk Taking: A Functional MRI Twin Study of the Balloon Analogue Risk Task. AB - Excessive risk-taking behaviors have been implicated as a potential endophenotype for substance use disorders and psychopathological gambling. However, the genetic and environmental influences on risk taking and the risk-related brain activations remain unclear. This study investigated the heritability of risk taking and the genetic influence on individual variation in risk-related brain activation. The Balloon Analogue Risk Task was used to assess individuals' risk taking behavior. In a sample of 244 pairs of young adult twins, we found that there was a moderate heritability (41%) of risk taking. Using voxel-level analysis, we found a moderate genetic influence on risk-related brain activation. We also found a moderate genetic correlation between risk-taking behavior and risk-related brain activation in the left insula, right striatum, and right superior parietal lobule in the active-choice condition. The present study provides important evidence for the genetic correlation between risk-taking behavior and risk-related brain activation. PMID- 30028646 TI - Removal of heavy metals from landfill leachate using zero valent iron and granular activated carbon. AB - The possibility of a landfill leachate pre-treatment, aiming at heavy metals removal, by means of either zero valent iron (ZVI), or granular activated carbon (GAC) or by a mixture of the two materials, was investigated in this paper through batch and column tests. For this purpose, a synthetic landfill leachate containing heavy metals (i.e. Cu, Ni, Zn), chloride, sulphates, ammonium and organic matter was prepared. Batch tests results demonstrated the efficiency of ZVI, GAC and ZVI/GAC mixture in heavy metals removal (efficiency > 90%) and their negligible effect on the other contaminants. Column tests showed as pure ZVI is by far more efficient than pure GAC in the long term. The influence of humic acids (HA) on the reactive and hydraulic behaviour of ZVI was also studied through column tests. The presence of HA in the leachate caused a reduction of ZVI removal efficiency and a considerable decrease in its hydraulic conductivity. Results of a column test carried out using the ZVI/GAC granular mixture showed as the removal efficiency over time ranges from 100% to 89% for Cu, from 93% to 80% for Ni and from 98% to 95% for Zn. The use of a filter filled with the ZVI/GAC mixture could find application for leachate pre-treatment having the objective of removing heavy metals prior the final co-treatment with municipal wastewater minimizing adverse side effect on the process (e.g. transfer of heavy metals in the excess sludge to be used in agriculture). PMID- 30028647 TI - Reply to Palmer et al.: Does Dose Matter? PMID- 30028648 TI - Novel multiplex PCR-RFLP assay discriminates bovine, porcine and fish gelatin substitution in Asian pharmaceuticals capsule shells. AB - Gelatin is widely used in pharmaceuticals as a protective coating, such as soft and hard capsule shells. However, the animal source of gelatin is a sensitive issue because certain gelatins such as porcine and bovine gelatins are not welcome in Halal, Kosher and Hindus' consumer goods. Recently, we have documented DNA barcoding and multiplex PCR platforms for discriminating porcine, bovine and fish gelatins in various fish and confectionary products; but those assays were not self-authenticating and also not tested in highly refined pharmaceutical products. To address this knowledge gap, here we report a self-authenticating multiplex PCR-restriction fragment length polymorphism (RFLP) assay to identify animal sources of various gelatin in pharmaceutical capsules. Three different restriction enzymes, BsaAI, Hpy188I and BcoDI were used to yield distinctive RFLP patterns for gelatin-based bovine (26, 94 bp), fish (97, 198 bp) and porcine (17, 70 bp) DNA in control experiments. The specificity was cross-tested against 16 non-target species and the optimised assay was used to screen gelatin sources in 30 halal-branded pharmaceuticals capsule shells. Bovine and porcine DNA was found in 27 and 3 of the 30 different capsules products. The assay was suitable for detecting 0.1 to 0.01 ng total DNA extracted from pure and mixed gelatins. The study might be useful to authenticate and monitor halal, kosher, vegetarian and Hindu compliant pharmaceuticals, foods and cosmetics. PMID- 30028649 TI - Evaluation of the influence of in vivo exposure to extremely low-frequency magnetic fields on the plasma levels of pro-inflammatory cytokines in rats. AB - PURPOSE: Epidemiological data suggest that there is a link between exposure to extremely low-frequency magnetic fields (ELF-MFs), immune response, and the occurrence of neurodegenerative diseases. The exact nature of this phenomenon remains speculative and requires detailed laboratory investigation. In the present study, we evaluate changes in plasma concentration of pro-inflammatory and regulatory cytokines as well as alternations of the hematological parameters in rats exposed to an ELF-MF. MATERIALS AND METHODS: Male Wistar rats were repeatedly exposed for either 1 h/day for 7 days, or continuously for 24 h, to a sinusoidal ELF-MF (50 Hz, 7 mT). Control groups were sham exposed for either 1 h/day for 7 days, or continuously for 24 h, respectively. The levels of cytokines: interleukin (IL)-1beta, IL-2, IL-6, and IL-10 in plasma obtained from blood samples were determined using enzyme-linked immunosorbent assay (ELISA). The changes in blood parameters were determined using an automatic hematology analyzer in whole blood samples immediately after collection. RESULTS: We found that a single continuous (lasting 24 h) exposure provoked a significant increase of the plasma IL-1beta, IL-6, and IL-2 levels, and caused an elevation in blood parameters, such as white blood cells, lymphocytes, hemoglobin, and hematocrit levels. In contrast, however, repetitive exposure of rats to an ELF-MF for 1 h/day for 7 days did not lead to any changes in plasma levels of cytokines and hematological counts. CONCLUSIONS: Based on these data we conclude that exposure duration (dose-response) plays a significant role in the immune response, specifically at the cellular level. While single 24 h-lasting exposure provoked changes that indicate an immune alarm stimulation, under the conditions which are typical for therapeutic use of ELF-MFs (repeated short daily exposure) the immune potentially harmful response has not been observed. PMID- 30028650 TI - Navigating the future of gerontology education: curriculum mapping to the AGHE competencies. AB - The recent adoption of gerontology competencies for undergraduate and graduate education emphasize a need for competency-based education. The purpose of this manuscript is to describe the approach one program took to mapping and aligning courses to the newly adopted Association for Gerontology in Higher Education's (AGHE) competencies in an effort to clarify curriculum needs for a diverse student population, increase the measurability of objectives, and apply for Program of Merit status through AGHE. Assessment of current courses led to mapping objectives to competencies, identifying missing content, and revising courses to reduce knowledge gaps. Barriers and facilitators to this process are examined in an effort to share the implications of one program's competency alignment process. PMID- 30028651 TI - Development of adjuvanted recombinant zoster vaccine and its implications for shingles prevention. AB - INTRODUCTION: GSK has developed a two-dose adjuvanted recombinant zoster vaccine (Shingrix, RZV) to protect people aged >=50 years (50+) against herpes zoster (HZ) and its complications. RZV showed >90% efficacy against HZ, sustained over 4 years of follow-up, in all studied age groups. Areas covered: This article reviews the scientific rationale underlying the design of RZV; the clinical evidence demonstrating immunogenicity, safety, and efficacy in persons 50+; and the public health implications and cost-effectiveness. Expert commentary: A decline in varicella zoster virus (VZV) immunity is associated with increased risk of HZ in adults 50+ and immunocompromised individuals. RZV was designed to restore levels of anti-VZV cellular and humoral immunity to prevent VZV reactivation. RZV includes the recombinant gE glycoprotein antigen, and Adjuvant System AS01B which promotes cellular and antibody responses. In two Phase III studies in subjects aged 50+ and 70+ years, RZV efficacy against HZ compared to placebo was >90% and >=89% against post-herpetic neuralgia (PHN). RZV is expected to dramatically impact HZ morbidity including its complications, and associated health-care costs. In the US population aged 50+ years, vaccination with RZV can be cost-effective compared to no vaccination and cost-saving compared to the currently available live-attenuated HZ vaccine (Zostavax, Merck). PMID- 30028652 TI - What is adverse effect of wireless local area network, using 2.45 GHz, on the reproductive system? AB - AIM: To investigate the inflammatory effect and testicular damage on rats exposed to low level of electromagnetic fields (EMF) at 2.45 GHz microwave radiation. METHODS: Twenty two Wistar rats were divided into two groups. Group 1 was the control group and not exposed to EMF. Group 2 was exposed to low level EMF (average E-field 3.68 +/- 0.36 V/m, whole body average SAR, 0.0233 W/kg, in 10 g tissue) at 2.45 GHz for 1 hour/day for 30 consecutive days. At the end of the study, interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-32 (IL-32), C reactive protein (CRP) were measured in rat serum and IL-6, IL-10, IL-32 were measured in rat testis tissue. Furthermore, testicular tissues were evaluated histopathologically in terms of spermatogenesis and coagulation necrosis. RESULTS: Serum IL-6 and CRP levels were found to be significantly different in the study group compared to the control group (p < .05), but no significant difference was found in serum IL-10, IL-32 levels and testis tissue IL-6, IL-10, IL-32 levels compared to the control group (p > .05). On the other hand, histopathological evaluation of testicular tissue revealed a significant difference in necrosis and spermatogenesis when compared with the control group (p < .05). CONCLUSIONS: It may be concluded that low level EMF at 2.45 GHz increases inflammation and testicular damage and negative impact on male reproductive system function. PMID- 30028653 TI - Effect of acute exposure to radiofrequency electromagnetic fields emitted by a mobile phone (GSM 900 MHz) on electrodermal responsiveness in healthy human. AB - PURPOSE: The present study aimed to determine the effect of acute exposure to electromagnetic fields (EMF) emitted by a mobile phone on electrodermal activity (EDA) in response to an auditory stimulus. MATERIALS AND METHODS: The EDA of 28 young volunteers was recorded following 26 min of exposure to a GSM mobile phone (900 MHz). Palmar sensors enabled repeat recording of 2 min 45 s in the pre exposure, exposure and post-exposure phases in response to sound stimuli. RESULTS: The latency, amplitude of skin conductance responses (SCRs), integral of skin conductance response and number of SCRs in response to the auditory stimuli were not modified by exposure. Skin conductance and tonic activity decomposition of the recorded signal were significantly different between the two sessions (p < .0001), but the changes could not be attributed to EMF exposure. There was also a tendency toward a fast reduction in the amplitude and number of electrodermal responses after placement of the mobile phone. In response to successive stimuli, there was a significant difference between the first response and subsequent responses for all variables except latency. CONCLUSIONS: Our results showed a decrease in the number of responses and their amplitude as a result of placement of the mobile device and whether it was turned 'on' or 'off', but there were no changes associated with exposure to GSM radiofrequency waves in this group of volunteers. PMID- 30028654 TI - Caring for stroke survivors: experiences of family caregivers in Sri Lanka - a qualitative study. AB - BACKGROUND: Stroke is a life-changing event for both stroke survivors and their family caregivers. After receiving acute care at the hospital, family members are expected to take care of stroke survivors at home and to continue treatment and rehabilitation. The new role of "informal caregiver" is a challenge that creates many difficulties for family caregivers that are not explicit in the Sri Lankan context. OBJECTIVES: This study aimed at exploring family caregivers' experiences of providing informal care for dependent stroke survivors. METHODS: The sample was chosen by purposive sampling with a maximum variation by age, ethnicity, religion, educational level, relationship, and monthly income. Ten informal family caregivers to stroke survivors with hemiplegia who had been treated at the National Hospital of Sri Lanka participated in in-depth interviews analyzed using conventional content analysis. RESULTS: Qualitative content analysis of data resulted in an overriding theme, "Caring with love, against all odds," along with four categories, "Life alterations," "Lack of resources," "Compassionate care," and "Coping strategies." Although the increased workload, restricted social life, physical problems, and knowledge and financial deficits were challenging for the family caregivers, self-strength and supportive social networks helped them to compassionately care for their stroke survivor. CONCLUSIONS: The phenomenon of family caregivers providing informal care for stroke survivors was explicated as compassionate care, notwithstanding numerous difficulties. The findings motivate further research and strategies to minimize family caregivers' burden and facilitate the positive aspects of caregiving to promote the health and well being of both stroke survivors and their families. PMID- 30028655 TI - Systemic Therapy for Elderly Patients With Advanced Non-Small-Cell Lung Cancers. PMID- 30028656 TI - Cisplatin-Based First-Line Treatment of Elderly Patients With Advanced Non-Small Cell Lung Cancer: Joint Analysis of MILES-3 and MILES-4 Phase III Trials. AB - Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed alpha of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES 4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC. PMID- 30028657 TI - Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment. AB - Purpose Enzalutamide resistance could result from raised androgens and be overcome by combination with abiraterone acetate. PLATO ( ClinicalTrials.gov identifier: NCT01995513) interrogated this hypothesis using a randomized, double blind, placebo-controlled design. Patients and Methods In period one, men with chemotherapy-naive metastatic castration-resistant prostate cancer received open label enzalutamide 160 mg daily. Men with no prostate-specific antigen (PSA) increase at weeks 13 and 21 were treated until PSA progression (>= 25% increase and >= 2 ng/mL above nadir), then randomly assigned at a one-to-one ratio in period two to abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily with either enzalutamide or placebo (combination or control group, respectively) until disease progression as defined by the primary end point: progression-free survival (radiographic or unequivocal clinical progression or death during study). Secondary end points included time to PSA progression and PSA response in period two. Results Of 509 patients enrolled in period one, 251 were randomly assigned in period two. Median progression-free survival was 5.7 months in the combination group and 5.6 months in the control group (hazard ratio, 0.83; 95% CI, 0.61 to 1.12; P = .22). There was no difference in the secondary end points. Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) were more frequent in the combination than the control group. Conclusion Combining enzalutamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzalutamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy. PMID- 30028659 TI - Reliability of remote evaluation for the Fugl-Meyer assessment and the action research arm test in hemiparetic patients after stroke. AB - Background Blinding for outcome assessors is considered less possible in rehabilitation treatment trials than in pharmacologic trials. This problem can be solved in part by the standardized remote evaluation system, in which researchers video-record patients for centralized assessment using prospectively standardized shooting procedures, and then outside assessors evaluate the videos using prospectively standardized methods. Objective To assess the inter-rater reliability of remote evaluation for the Fugl-Meyer assessment (FMA) and the action research arm test (ARAT) in hemiparetic patients after stroke. Methods A prospective, cross-sectional, single-center study involving 30 patients with mild to-severe hemiparesis was conducted (Clinical Trial Registration-URL: http://www.umin.ac.jp/ . Unique identifier: UMIN000022192). Two assessments (direct observation and video observation) were performed for each participant by trained assessors. The direct observation assessment was video-recorded for the video observation assessment. In the current study, a standardized guidebook for test administration and scoring was used, along with prospectively standardized shooting procedures. Results Regarding the sum scores of the total/subtests of the FMA and ARAT, the intraclass correlation coefficient ranged from 0.992 to 0.998 (95% confidence interval [CI], 0.960-0.999; p < 0.0001) and Spearman's rho ranged from 0.949 to 1.000 (95% CI, 0.985-1.000; p < 0.0001). Regarding the individual item scores of the outcome measures, weighted kappa (median of the sum scores of total/subtests) ranged from 0.921 to 1.000. Conclusions Remote evaluation of the FMA and ARAT reliably assesses the affected upper extremities in patients with mild-to-severe hemiparesis after stroke. PMID- 30028658 TI - Risk factors for the development of chest infections in acute stroke: a systematic review. AB - BACKGROUND: Chest infections occur in approximately one-third of patients following acute stroke, and are associated with poor outcomes. Limitations in previous reviews restricted the accuracy of results. OBJECTIVES: To perform a systematic review to reliably identify modifiable risk factors for chest infections following acute stroke. METHODS: Ovid Medline, CINAHL, Cochrane, EMBASE and AMED were searched from 1946 to April 2017 for observational studies where risk factors for chest infections in patients hospitalized with acute stroke were reported. Key words used to identify included chest infection or pneumonia. Included studies were evaluated based on methodological criteria and scientific quality. Results were collated and separate meta-analyses were performed for risk factors examined in three or more studies where quality and homogeneity criteria were met. RESULTS: 3172 studies were identified, 15 were eligible for inclusion. Data collection methods included primary data collection, medical record audit and registry data. Chest infections were diagnosed 2-30 days following acute stroke in ten studies. Of the 39 risk factors identified, four were included in the meta-analysis. These were mechanical ventilation: 4 studies, OR: 3.83, 95%CI: 3.21, 4.57; diabetes: 4 studies, OR: 1.06, 95%CI: 1.04, 1.08; pre-existing respiratory conditions: 3 studies, OR: 1.48, 95%CI 1.21, 1.81 and atrial fibrillation: 3 studies, OR: 1.21, 95%CI: 1.17, 1.24. Common risk factors not eligible for meta-analysis were dysphagia and cardiac comorbidities. CONCLUSION: Evidence has been comprehensively synthesized to provide reliable estimates of the association between important risk factors and chest infection. Monitoring patients meeting these criteria may promote early identification and treatment to improve long-term outcomes. PMID- 30028660 TI - Clinimetric properties of the Fugl-Meyer assessment with adapted guidelines for the assessment of arm function in hemiparetic patients after stroke. AB - Background Against the background of linguistic and cultural differences, there is a need for translation and adaptation from the English version of the Fugl Meyer Assessment (FMA) to Japanese. In addition, there is no study of inter-rater reliability of FMA all domains for affected upper extremities with appropriate sample size based on the intraclass correlation coefficient (ICC) focusing on non simultaneous assessment. Objective This study aimed (1) to translate the English version of the FMA and its administration/scoring manual; and (2) to investigate the psychometric properties of the Japanese version of the FMA in patients with stroke. Methods A prospective single-center study involving 30 patients was conducted. The FMA and the Action Research Arm Test, the Box-and-Block Test, and the Motor Activity Log were employed. The inter-rater/intra-rater reliability, the internal consistency, the validity, and the floor/ceiling effects were assessed. Results Regarding the non-simultaneous and simultaneous inter-rater reliability, ICC ranged from 0.809-0.983 (P<0.001) and 0.991-0.999 (P<0.001), respectively. Regarding the simultaneous intra-rater reliability, ICC ranged from 0.994-0.999 (P<0.001). The Cronbach's alpha was 0.973 in the non-simultaneous evaluation and 0.981 in the simultaneous evaluation. Regarding the validity, Spearman's rhos were higher than 0.92 for the FMA all domains and motor domain. The patients who showed the highest score and the lowest score of the FMA (all domains and motor domain) were 10% and 0%, respectively. Conclusions The Japanese version of the FMA motor domain and all domains can reliably assess the affected upper extremities in patients with mild-to-severe hemiparesis after stroke for both non-simultaneous and simultaneous assessment. PMID- 30028661 TI - Inter-rater and test/retest reliabilities of the isokinetic measurements: assessing strength and endurance of the trunk muscles in two different protocols for able-bodied and post-stroke hemiparesis. AB - Background Stroke represents the largest cause of chronic disability resulting in muscle weakness and instability in the trunk muscles. Despite the reliable measures from isokinetic devices for upper/lower limb muscles, there is a lack of measures for trunk muscles in post-stroke hemiparesis. Objectives To investigate the reliability of the strength and endurance measures from an isokinetic dynamometer for able-bodied and post-stroke hemiparesis people. Methods The measures were taken from both groups (control/hemiparesis) performing antagonistic movements (flexion/extension) during different protocols (seated compressed and semi-standing) to assess strength (60o/s) and endurance (120o/s). The intra-class correlation coefficient (ICC) and limits of agreement (LOA) defined the quality and magnitude of reliability on the measurements plotted with 95% confidence interval (95% CI) by Bland-Altman method. Results ICC ranged from 0.58 to 0.99, with few ICC values classified as moderate when repeated by raters during test and a single value during retest. The total work was the only variable to present LOA higher than the limits. Conclusion Results indicate acceptable reliability, in two different protocols, confirming the repeatability of the isokinetic measures for trunk muscles in able-bodied and post-stroke hemiparesis. PMID- 30028662 TI - Evaluation of the FilmArray Blood Culture Identification Panel compared to direct MALDI-TOF MS identification for rapid identification of pathogens. AB - To improve time to identification of pathogens and detection of resistance genes, we evaluated the BioFire FilmArray Blood Culture Identification Panel (BCID) as compared to: (1) direct MALDI-TOF MS (DM) and (2) standardized culture-based identification (ID) with antibiotic susceptibility testing (AST). BCID gave an accurate identification in 102/112 (91 %) of cases (102/103 for on-panel organisms). DM gave an accurate identification in 91/112 (81 %) of cases, with 13/91 (14 %) requiring repeat testing from the residual pellet. The mean time to an identification result was 2.4 and 2.9 h for BCID and DM, respectively. Standardized ID and AST results were available at a mean time of 26.5 and 33 h, respectively. There were 44 BCID/DM results that had an antimicrobial treatment change made based on rapid identification and resistant gene detection of pathogens. Both BCID and DM are accurate and rapid methods for the identification of new positive blood culture pathogens. PMID- 30028664 TI - Characterisation of a monooxygenase in Shiraia bambusicola. AB - A monooxygenase-encoding gene (Mono) is located in the hypocrellin gene cluster of Shiraia sp. SUPER-H168 and was targeted by a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. The DeltaMono mutant abolished hypocrellin production, whereas the DeltaMono complement mutant restored hypocrellin production. Relative expression levels of the Mono and its adjacent genes were abolished in the DeltaMono mutant compared with the wild-type strain. These results indicate the essential role of Mono in hypocrellin biosynthesis. The Mono gene of Shiraia bambusicola was further expressed in Pichia pastoris and salicylate monooxygenase activity was detected, which suggested that this monooxygenase has the ability to catalyse decarboxylative hydroxylation. The relative growth ratio of the DeltaMono mutant was significantly improved compared with the wild-type strain. In contrast to the wild-type strain, the DeltaMono mutant also represented excellent oxidative stress tolerance after exposure to high concentrations of H2O2 (16 mM) based on the increasing activities of superoxide dismutase, catalase, and glutathione peroxidase. These results suggest that DeltaMono mutants could be used as microbial cell factories to produce metabolites that will cause oxidative stress. This study also enhances our understanding of hypocrellin biosynthesis and opens an avenue for decoding the hypocrellin pathway. PMID- 30028663 TI - Naturally occurring polymorphisms in the virulence regulator Rsp modulate Staphylococcus aureus survival in blood and antibiotic susceptibility. AB - Nasal colonization by the pathogen Staphylococcus aureus is a risk factor for subsequent infection. Loss of function mutations in the gene encoding the virulence regulator Rsp are associated with the transition of S. aureus from a colonizing isolate to one that causes bacteraemia. Here, we report the identification of several novel activity-altering mutations in rsp detected in clinical isolates, including for the first time, mutations that enhance agr operon activity. We assessed how these mutations affected infection-relevant phenotypes and found loss and enhancement of function mutations to have contrasting effects on S. aureus survival in blood and antibiotic susceptibility. These findings add to the growing body of evidence that suggests S. aureus 'trades off' virulence for the acquisition of traits that benefit survival in the host, and indicates that infection severity and treatment options can be significantly affected by mutations in the virulence regulator rsp. PMID- 30028665 TI - Pyrosequencing: a rapid and effective sequencing method to diagnose drug resistant tuberculosis. AB - PURPOSE: This study was undertaken to evaluate the efficiency of the pyrosequencing (PSQ) assay for the rapid detection of resistance to rifampicin (RIF), fluoroquinolones (FQs) and second-line injectables (SLIs) such as capreomycin (CAP) and kanamycin (KAN) in Mycobacterium tuberculosis (Mtb) clinical isolates. METHODOLOGY: Pyrosequencing is a simple and accurate short read DNA sequencing method for genome analysis. DNA extraction from Mtb clinical isolates was performed using Tris-HCl buffer and chloroform. The rpoB (RIF), gyrA (FQs) and rrs (aminoglycosides) genes were amplified, followed by sequencing using the PyroMark Q24 ID system. The PSQ results were compared with the results from the conventional drug susceptibility testing performed in the laboratory. RESULTS: The sensitivity of the PSQ assay for the detection of resistance to RIF, FQ, CAP and KAN was 100 %, 100 %, 40 % and 50 %, respectively. The specificity of the PSQ assay was 100 %. CONCLUSION: The PSQ assay is a rapid and effective method for detecting drug resistance mutations from Mtb clinical isolates in a short period of time. PMID- 30028666 TI - Aortic Endograft Infection with Mycobacterium chimaera and Granulicatella adiacens, Switzerland, 2014. AB - We describe an aortic endograft infection caused by Mycobacterium chimaera and Granulicatella adiacens, successfully treated with prolonged antimicrobial drug therapy after complete explantation of the infected endoprosthesis and extra anatomical reconstruction. Whole-genome sequencing analysis did not indicate a close relationship to bacterial strains known to cause infections after cardiac surgery. PMID- 30028671 TI - Efficacy of Bilateral Transcutaneous Posterior Tibial Nerve Stimulation for Fecal Incontinence. AB - CONTEXT: Posterior tibial nerve stimulation is a new second-line treatment for refractory fecal incontinence. OBJECTIVE: To assess the efficacy of bilateral transcutaneous posterior tibial nerve stimulation (BTPTNS) for treatment of fecal incontinence in Japanese patients and its impact on quality of life. DESIGN: A prospective observational-interventional study was conducted from May 2015 to June 2017 in patients with fecal incontinence in whom conservative treatment had failed. All patients received a 30-minute session of stimulation twice weekly for 6 consecutive weeks. Evaluation at baseline and at 6 weeks involved the Wexner score, Fecal Incontinence Quality of Life (FIQL) questionnaire, and anal manometry. Patients recorded episodes of incontinence in a weekly diary. MAIN OUTCOME MEASURES: Reduction of 50% or greater in incontinence episodes, decreased Wexner score, and improved FIQL scores. RESULTS: Twenty-two patients with a median age of 64.1 years (range, 26-81 years) and men:women ratio of 9:13 completed BTPTNS. Mean episodes of fecal incontinence were significantly reduced from 4.7 to 1.5 (p < 0.05). An improvement of 50% or better in episodes of fecal incontinence was achieved in 77.2% of patients. The median Wexner score significantly decreased from 10.2 to 6.9 (p < 0.05). The median FIQL score improved from 2.7 to 3.1 (p = 0.06), and significant improvement was seen in the embarrassment domain (2.2 vs 2.8, p < 0.05). Resting and squeezing anal pressures revealed no significant changes. CONCLUSION: Our findings suggest that BTPTNS is safe and well tolerated and may improve symptoms of fecal incontinence. This technique offers an additional noninvasive, less expensive form of treatment. PMID- 30028667 TI - Listening Beyond Auscultating: A Quality Initiative to Improve Communication Scores in the Hospital Consumer Assessment of Health Care Practitioners and Systems Survey. AB - INTRODUCTION: Physician communication is critical to patient care. However, integration of sound communication practice with clinical workflows has proven difficult. In this quality improvement initiative, medical students used the rapid improvement model to test interventions that could enhance patients' perception of listening by physicians as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems survey. METHODS: Literature review and process analysis yielded 42 potential interventions, of which 24 were feasible for implementation. Small-scale testing established the 4 most promising interventions; pilot testing was subsequently undertaken on the entire Medicine service. Patient and physician feedback guided further refinement. The final intervention used a structured reminder embedded in the electronic health record to direct physicians to begin interviews by eliciting patient concerns. RESULTS: Patient concerns elicited after implementation included pain symptoms (28%), disease or treatment course (16%), and discharge planning (10%). In the Hospital Consumer Assessment of Healthcare Providers and Systems survey, physician listening scores rose from a 2014 average of 73.6% to 77% in 2015. DISCUSSION: Among 24 tested interventions, an open-ended question was most feasible and had the greatest perceived impact by hospitalists and patients. A structured reminder embedded in required electronic medical record documentation facilitated the behavioral change without being overly burdensome to physicians and established a mechanism to enact change in practice. CONCLUSION: Medical students used established improvement methods to promote patient-centered care and align patient and physician agendas, providing a strategy to improve hospitalized patients' perceptions of physician listening. PMID- 30028672 TI - Lifestyle Medicine in Inflammatory Bowel Disease. PMID- 30028673 TI - Comparative Effectiveness of Surgical Options for Patients with Ductal Carcinoma In Situ: An Instrumental Variable Approach. AB - CONTEXT: Many patients with ductal carcinoma in situ (DCIS) receive treatment that is too extensive. OBJECTIVE: To take a holistic approach in comparing the effectiveness in cancer prevention between mastectomy and breast-conserving surgery (BCS) for patients with DCIS. DESIGN: Female Kaiser Permanente Southern California members who underwent surgery for treatment of single primary DCIS from 2004 to 2014 were identified by the Kaiser Permanente Southern California cancer registry and HealthConnect database. METHOD: Two-stage residual inclusion with the surgeon's preference of surgical procedure type as the instrumental variable was used to examine the effect of surgical choice on DCIS recurrence, breast cancer progression, and other cancer progression. Traditional Cox proportional hazards models were used for comparison. RESULTS: Of qualified subjects, 72.2% underwent BCS and 27.8% underwent mastectomy. Patients were likelier to receive BCS if their surgeon preferred to perform BCS in the past 5 years (odds ratio = 1.02, 95% confidence interval = 1.02-1.03). Although traditional Cox proportional hazards models suggested an association between BCS and higher risk of DCIS recurrence, no significant effect was observed when we adjusted for endogeneity. Neither model showed significant differences between mastectomy and BCS in progression of any cancer. CONCLUSION: No significant benefit was observed with a more aggressive surgical procedure in preventing DCIS recurrence or cancer progression in a diverse population. Many patients with DCIS could benefit from BCS with preservation of their body image. Breast conservation followed-up with cancer surveillance is a rational approach to ensure affordable, effective care for patients with DCIS. PMID- 30028674 TI - Molecular characterization and new genotypes of Enterocytozoon bieneusi in minks (Neovison vison) in China. AB - Microsporidiosis is an emerging and opportunistic disease, and Enterocytozoon bieneusi is the main cause of this disease in humans. Little information is available on prevalence and genotyping of E. bieneusi in minks. We collected 559 feces samples of minks from Heilongjiang and Jilin provinces in 2017, and studied E. bieneusi prevalence by nested PCR. A total of 23 out of 559 minks (4.1%) were detected as E. bieneusi-positive, and were raised in five of the seven investigated farms. Age was the only risk factor associated with E. bieneusi prevalence in investigated minks through logistic regression analysis. Sequence analysis of the ITS gene revealed that five E. bieneusi ITS genotypes, including Peru11, EbpC, and three novel genotypes (HLJM-1, HLJM-2 and JLM-1) were present, suggesting minks may be a potential source of human microsporidiosis. PMID- 30028676 TI - National Trends in Inferior Vena Cava Filter Placement and Retrieval Procedures in the Medicare Population Over Two Decades. AB - PURPOSE: To assess trends in inferior vena cava (IVC) filter placement and retrieval procedures in Medicare beneficiaries over the last two decades. METHODS: Using Physician/Supplier Procedure Summary Master Files from 1994 through 2015, we calculated utilization rates for IVC filter placement and retrieval procedures in Medicare fee-for-service beneficiaries. Services were stratified by provider specialty group and site of service. RESULTS: IVC filter placement rates increased from 1994 to 2008 (from 65.0 to 202.1 per 100,000 beneficiaries, compound annual growth rate [CAGR] +8.4%) and then decreased to 128.9 by 2015 (CAGR -6.2%). This decrease was observed across all specialty groups and sites of service. From 1994 to 2015, placement procedure market share increased for radiologists (from 45.1% to 62.7%) and cardiologists (from 2.5% to 6.7%) but decreased for surgeons (from 46.6% to 27.9%). Overall, procedures shifted slightly from the inpatient (from 94.5% to 86.5% of all procedures) to outpatient hospital (from 4.9% to 14.9%) settings. Between 2012 and 2015, retrieval rates increased from 12.0 to 17.7 (CAGR +13.9%). Retrievals as a percentage of placement procedures were similar across specialties in 2015 (range 13.0%-13.8%). CONCLUSION: Despite prior dramatic growth, the utilization of IVC filters in Medicare beneficiaries markedly declined over the last decade, likely relating to evolving views regarding efficacy and long-term safety. This decline was accompanied by several filter-related market shifts, including increasing placement by radiologists and cardiologists, increasing outpatient placement procedures, and increasing retrieval rates. PMID- 30028677 TI - Self Driving and Self Diagnosing: With Emerging Technology, Your Car May Soon Serve Not Only as Personal Chauffeur and Entertainment Center but as a Health Advisor Too. AB - Advances in automobile technology have made headlines over the last few years, and not always for good reasons. In March 2018, an Uber self-driving car ran over a pedestrian in Arizona-the latest in a handful of casualties tied to automated car systems. Despite such tragedies, however, cutting-edge technologies in cars may prove beneficial for people?s health overall. In 2016, a driver who suffered a pulmonary embolism while on the road credited the autopilot features of his Tesla Model X with saving his life: the car managed to navigate the 20 miles to the nearest hospital during the incident. PMID- 30028675 TI - Impaired spatial memory codes in a mouse model of Rett syndrome. AB - The Mecp2+/- mouse model recapitulates many phenotypes of patients with Rett syndrome (RTT), including learning and memory deficits. It is unknown, however, how the disease state alters memory circuit functions in vivo in RTT mice. Here we recorded from hippocampal place cells, which are thought to encode spatial memories, in freely moving RTT mice and littermate controls. We found that place cells in RTT mice are impaired in their experience-dependent increase of spatial information. This impairment is accompanied by an enhanced baseline firing synchrony of place cells within ripple oscillations during rest, which consequently occludes the increase in synchrony after a novel experience. Behaviorally, contextual memory is normal at short but not long time scale in RTT mice. Our results suggest that hypersynchrony interferes with memory consolidation and leads to impaired spatial memory codes in RTT mice, providing a possible circuit mechanism for memory deficits in Rett Syndrome. PMID- 30028678 TI - Engineering Opportunities in Cancer Immunotherapy: After Decades of Missteps and Delays, a Growing Immune-Oncology Market and Improved Cancer Treatment Outcomes Open New Prospects for Biomedical Engineers and Data Scientists. AB - More than a century ago, the American surgeon William Coley noticed a correlation between cancer remissions and postoperative infections: some patients who had battled an infection also experienced a regression of their cancer. Because of these observations, Coley hypothesized that a patient's immune response to a bacterial infection could be leveraged to treat cancer. To test his hypothesis, Coley injected live bacteria into an inoperable tumor of one of his patients. The patient's tumor regressed, and Coley went on to experiment with direct injections of live, and later heat-killed, bacteria into more than a thousand patients over the next 40-plus years. Coley's toxins never achieved widespread clinical success due to concerns over reproducibility, although a strain of mycobacterium, bacillus Calmette-Guerin, is still routinely administered to treat early-stage bladder cancers. PMID- 30028679 TI - The Many Textures of Robotics: Flexible Materials That Conform to and Interact with the Human Body May Mean Better Outcomes for Patients. AB - Innovative researchers are employing flexible, rather than rigid materials in combination with new design approaches as part of the emerging field of biomedical soft robotics. The idea is to generate tools that conform to and interact with the human body in a much more natural and lightweight way, providing better treatment options for clinicians and translating into better outcomes for patients. PMID- 30028680 TI - Can AI Truly Transform Health Care?: A Recent IEEE Pulse on Stage Forum Offers Some Perspective. AB - As scholars have predicted and researchers have now shown, we are entering an age of global artificial intelligence (AI) convergence. Health care is just one area in which AI is gaining a foothold, as evidenced by two parallel conferences held in March 2018 in Las Vegas, Nevada. The first of these was the annual meeting of the Hospital Information and Management Systems Society, attended by nearly 45,000 participants; the second was a more focused, engineering-oriented conference on biomedical health informatics and biosensor networks, attended by about 450. Straddling those two meetings, IEEE Pulse held its second IEEE Pulse on Stage event, focusing (not surprisingly) on the use of AI in health care (Figure 1). PMID- 30028681 TI - Toward Better Treatment for Women's Reproductive Health: New Devices, Nanoparticles, and Even Robotic Sperm May Hold the Key to Preventing a Range of Health Conditions. AB - Although women and men share many similar health challenges throughout their lifetimes, women are not necessarily healthier. Some conditions that only women experience-such as pregnancy, ovarian cancer, or the abnormal growth of the uterus called endometriosis- can become great health risks. HIV, AIDS, and sexually transmitted infections (STIs) are also serious medical and social issues for women worldwide. And because a woman's reproductive system is complex and delicate-which makes it particularly vulnerable to dysfunction or disease-finding ways to treat conditions that take root in the reproductive tract often prove challenging. PMID- 30028682 TI - Controlling Seizures with Technology: Researchers Are Working to Predict and Prevent Epileptic Seizures Before They Happen. AB - Mike McKenna was tired of epilepsy controlling his life. For years, he tried different medications and therapies to no avail; his seizures, which occurred every three to six days, dictated what he could do and where he could live. Then, about ten years ago, he joined a clinical trial for a new, implantable medical device from a company called NeuroPace. The RNS System monitors brain activity, detects patterns that indicate an imminent seizure, and responds by sending brief electrical pulses to disrupt the abnormal brain activity, stopping seizures in their tracks. PMID- 30028683 TI - Will the Real Designer Please Stand Up? [Senior Design]. AB - In the 1950s and 1960s, there was a popular television show called To Tell the Truth, on which three contestants claimed to be a person with an unusual occupation or distinction. Two of them were impostors, and the other was telling the truth. Four panelists asked the contestants questions to determine who was being truthful. After each panelist chose the contestant he or she thought was telling the truth, the host would ask "Will the real _____ please stand up?" To create drama, each contestant would rise at different times and then sit, leaving the contestant with the unusual occupation or distinction standing. PMID- 30028684 TI - Bayesian Multi-Objective Optimisation with Mixed Analytical and Black-Box Functions: Application to Tissue Engineering. AB - Tissue engineering and regenerative medicine looks at improving or restoring biological tissue function in humans and animals. We consider optimising neotissue growth in a three-dimensional scaffold during dynamic perfusion bioreactor culture, in the context of bone tissue engineering. The goal is to choose design variables that optimise two conflicting objectives: (i) maximising neotissue growth and (ii) minimising operating cost. We make novel extensions to Bayesian multi-objective optimisation in the case of one analytical objective function and one black-box, i.e. simulation-based, objective function. The analytical objective represents operating cost while the black-box neotissue growth objective comes from simulating a system of partial differential equations. The resulting multi-objective optimisation method determines the trade off in the variables between neotissue growth and operating cost. Our method outperforms the most common approach in literature, genetic algorithms, in terms of data efficiency, on both the tissue engineering example and standard test functions. The resulting method is highly applicable to real-world problems combining black-box models with easy-to-quantify objectives like cost. PMID- 30028685 TI - An Independent Component Analysis Approach to Motion Noise Cancellation of Cardio Mechanical Signals. AB - This work proposes a new framework for measuring sternal cardio-mechanical signals from moving subjects using multiple sensors. An array of inertial measurement units (IMUs) are attached to the chest wall of subjects to measure the seismo-cardiogram (SCG) from accelerometers and the gyro-cardiogram (GCG) from gyroscopes. A digital signal processing method based on constrained independent component analysis is applied to extract the desired cardio mechanical signals from the mixture of vibration observations. Electrocardiogram (ECG) and photoplethysmography (PPG) modalities are evaluated as reference sources for the constrained independent component analysis algorithm. Experimental studies with fourteen young, healthy adult subjects demonstrate the feasibility of extracting seismo- and gyro-cardiogram signals from walking and jogging subjects, with speeds of 3.0 miles per hour and 4.6 miles per hour, respectively. Beat-to-beat and ensemble-averaged features are extracted from the outputs of the algorithm. The beat-to-beat cardiac interval results demonstrate average detection rates of 91.44% during walking and 86.06% during jogging from SCG, and 87.32% during walking and 76.30% during jogging from GCG. The ensemble averaged pre-ejection period (PEP) calculation results attained overall squared correlation coefficients of 0.9048 from SCG and 0.8350 from GCG with reference PEP from impedance cardiogram (ICG). Our results indicate that the proposed framework can improve the motion tolerance of cardio-mechanical signals in moving subjects. The effective number of recordings during day time could be potentially increased by the proposed framework, which will push forward the implementation of cardio-mechanical monitoring devices in mobile healthcare. PMID- 30028686 TI - Functional Informed Fiber Tracking Using Combination of Diffusion and Functional MRI. AB - Fiber tractography using diffusion weighted MRI (DWI) is a primary tool for mapping structural connectivity in the human brain in vivo. However, this method suffers from a number of inherent limitations that have a significant impact on its capability in faithfully constructing fiber bundles for specific function. In this paper, a novel tractography algorithm combining DWI and functional MRI (fMRI) was proposed. Specifically, a spatio-temporal correlation tensor that characterizes the anisotropy of fMRI signals in white matter was introduced to complement the estimation of fiber orientation density function from DWI. The proposed method has been demonstrated to identify functional pathways implicated in fMRI task. It can effectively follow tracts in the genu of the corpus callosum that connects to the frontal lobe cortex, obtain connections between the thalamus and the anterior insula under sensory simulation, and reconstruct optic radiations in the visual circuit under visual stimulation. Taken together, the method we proposed in this work may benefit our understanding of structure function relations in the human brain. PMID- 30028687 TI - A Novel Synchronous Micro Motor for Intravascular Ultrasound Imaging. AB - OBJECTIVE: Intravascular ultrasound (IVUS) is an important method for evaluating lumen dimensions and guiding intervention. However, the current IVUS catheter using a proximal motor and flexible drive shaft is easily rotated at an unstable speed when it passes through along bending vessel. One approach to solve this problem is to develop a catheter driven by a distal motor. METHODS: This work presents a rotation device incorporating a high-frequency transducer as an attempt to facilitate this approach. A novel micro distal synchronous micro motor with 3.7 mm length and 1.2 mm outer diameter was proposed as an actuator for the IVUS catheter. A 0.5 mm * 0.5 mm (PMN-PT) single crystal 1-3 composite single element transducer was designed and manufactured. The probe is fixed to the front end of the catheter. The 45 degrees reflector which is opposite to the probe was used to steer ultrasound to the tissue. RESULTS: The results showed that the maximum torque and rotation speed of the motor were 2.79 MUNm and 275 revolutions per second (RPS), respectively, at a driving current of 0.34 A. The maximum angular error was 7 degrees at 0.13 A and 30 Hz. The center frequency and -6 dB fractional bandwidth of single element were 34 MHz and 72%, respectively. At the center frequency, the two-way insertion loss was 14 dB. CONCLUSION: The integrated distal motor IVUS catheter, with small dimensions, a good torque, speed stability, and good ultrasound imaging performance, has tremendous potential in blood vessel imaging. SIGNIFICANCE: The novel structure of the catheter could facilitate endoluminal sonography, reducing risks of the clinical diagnosis. PMID- 30028688 TI - Wearable Sensors for Frequency-Multiplexed EIT and Multilead ECG Data Acquisition. AB - This paper presents a wearable sensor architecture for frequency-multiplexed electrical impedance tomography (EIT) and synchronous multilead electrocardiogram (ECG) data acquisition. The system is based on a novel electronic sensing architecture, called cooperative sensors, that significantly reduces the cabling complexity and enables flexible EIT stimulation and measurement patterns. The cooperative-sensor architecture was initially designed for ECG and has been extended for multichannel bioimpedance measurement. This approach allows for an adjustable EIT stimulation pattern via frequency-division multiplexing. This work also shows a calibration procedure as well as EIT system noise performance assessment. Preliminary measurements on a healthy volunteer showed the ability of the wearable system to measure EIT data synchronously with multilead ECG. Ventilation-related and heartbeat-related EIT images were reconstructed, demonstrating the feasibility of the proposed architecture for noninvasive cardiovascular monitoring. PMID- 30028689 TI - Non-Invasive Quantification of Cell Density in 3D Gels by MRI. AB - OBJECTIVE: For tissue engineering, there is a need for quantitative methods to map cell density inside 3D bioreactors to assess tissue growth over time. The current cell mapping methods in 2D cultures are based on optical microscopy. However, optical methods fail in 3D due to increased opacity of the tissue. We present an approach for measuring the density of cells embedded in a hydrogel to generate quantitative maps of cell density in a living, 3D tissue culture sample. METHODS: Quantification of cell density was obtained by calibrating the 1H T2, magnetization transfer (MT) and diffusion-weighted nuclear magnetic resonance (NMR) signals to samples of known cell density. Maps of cell density were generated by weighting NMR images by these parameters post-calibration. RESULTS: The highest sensitivity weighting arose from MT experiments, which yielded a limit of detection (LOD) of in a 400 MHZ (9.4 T) magnet. CONCLUSION: This mapping technique provides a non-invasive means of visualizing cell growth within optically opaque bioreactors. SIGNIFICANCE: We anticipate that such readouts of tissue culture growth will provide valuable feedback for controlled cell growth in bioreactors. PMID- 30028690 TI - Scattering Networks for Hybrid Representation Learning. AB - Scattering networks are a class of designed Convolutional Neural Networks (CNNs) with fixed weights. We argue they can serve as generic representations for modelling images. In particular, by working in scattering space, we achieve competitive results both for supervised and unsupervised learning tasks, while making progress towards constructing more interpretable CNNs. For supervised learning, we demonstrate that the early layers of CNNs do not necessarily need to be learned, and can be replaced with a scattering network instead. Indeed, using hybrid architectures, we achieve the best results with predefined representations to-date, while being competitive with end-to-end learned CNNs. Specifically, even applying a shallow cascade of small-windowed scattering coefficients followed by convolutions results in AlexNet accuracy on the ILSVRC2012 classification task. Moreover, by combining scattering networks with deep residual networks, we achieve a single-crop top-5 error of 11.4% on ILSVRC2012. Also, we show they can yield excellent performance in the small sample regime on CIFAR-10 and STL-10 datasets, exceeding their end-to-end counterparts, through their ability to incorporate geometrical priors. For unsupervised learning, scattering coefficients can be a competitive representation that permits image recovery. We use this fact to train hybrid GANs to generate images. Finally, we empirically analyze several properties related to stability and reconstruction of images from scattering coefficients. PMID- 30028691 TI - Zero-Shot Learning - A Comprehensive Evaluation of the Good, the Bad and the Ugly. AB - Due to the importance of zero-shot learning, i.e. classifying images where there is a lack of labeled training data, the number of proposed approaches has recently increased steadily. We argue that it is time to take a step back and to analyze the status quo of the area. The purpose of this paper is three-fold. First, given the fact that there is no agreed upon zero-shot learning benchmark, we first define a new benchmark by unifying both the evaluation protocols and data splits of publicly available datasets used for this task. This is an important contribution as published results are often not comparable and sometimes even flawed due to, e.g. pre-training on zero-shot test classes. Moreover, we propose a new zero-shot learning dataset, the Animals with Attributes 2 (AWA2) dataset which we make publicly available both in terms of image features and the images themselves. Second, we compare and analyze a significant number of the state-of-the-art methods in depth, both in the classic zero-shot setting but also in the more realistic generalized zero-shot setting. Finally, we discuss in detail the limitations of the current status of the area which can be taken as a basis for advancing it. PMID- 30028693 TI - Packing Convolutional Neural Networks in the Frequency Domain. AB - Deep convolutional neural networks (CNNs) are successfully used in a number of applications. However, their storage and computational requirements have largely prevented their widespread use on mobile devices. Here we present a series of approaches for compressing and speeding up CNNs in the frequency domain, which focuses not only on smaller weights but on all the weights and their underlying connections. By treating convolutional filters as images, we decompose their representations in the frequency domain as common parts (i.e., cluster centers) shared by other similar filters and their individual private parts (i.e., individual residuals). A large number of low-energy frequency coefficients in both parts can be discarded to produce high compression without significantly compromising accuracy. Furthermore, we explore a data-driven method for removing redundancies in both spatial and frequency domains, which allows us to discard more useless weights by keeping similar accuracies. After obtaining the optimal sparse CNN in the frequency domain, we relax the computational burden of convolution operations in CNNs by linearly combining the convolution responses of discrete cosine transform (DCT) bases. The compression and speed-up ratios of the proposed algorithm are thoroughly analyzed and evaluated on benchmark image datasets to demonstrate its superiority over state-of-the-art methods. PMID- 30028692 TI - Solving Square Jigsaw Puzzle by Hierarchical Loop Constraints. AB - We present a novel computational puzzle solver for square-piece image jigsaw puzzles with no prior information such as piece orientation or anchor pieces. By "piece" we mean a square d x d block of pixels, where we investigate pieces as small as 7 x 7 pixels. To reconstruct such challenging puzzles, we propose to find maximum geometric consensus between pieces, specifically hierarchical piece loops. The proposed algorithm seeks out loops of four pieces and aggregates the smaller loops into higher order loops of loops in a bottom-up fashion. In contrast to previous puzzle solvers which aim to maximize compatibility measures between all pairs of pieces and thus depend heavily on the pairwise compatibility measures used, our approach reduces the dependency on the pairwise compatibility measures which become increasingly uninformative for small scales and instead exploits geometric agreement among pieces. Our contribution also includes an improved pairwise compatibility measure which exploits directional derivative information along adjoining boundaries of the pieces. We verify the proposed algorithm as well as its individual components with mathematical analysis and reconstruction experiments. PMID- 30028694 TI - Optimization of the trade-off between speckle reduction and axial resolution in frequency compounding. AB - We measured the reduction of speckle by frequency compounding using Gaussian pulses, which have the least timebandwidth product. The experimental results obtained from a tissue mimicking phantom agree quantitatively with numerical simulations of randomly distributed point scatterers. For a fixed axial resolution, the amount of speckle reduction is found to approach a maximum as the number of bands increases while the total spectral range that they cover is kept constant. An analytical solution of the maximal speckle reduction is derived and shows that the maximal speckle reduction improves approximately as the square root of the inverse of the Gaussian pulse bandwidth. Since the axial resolution is proportional to the inverse of the pulse bandwidth, an optimized trade-off between speckle reduction and axial resolution is obtained. Considerations for the applications of the optimized trade-off are discussed. PMID- 30028695 TI - Spatially Adaptive Varying Correlation Analysis for Multimodal Neuroimaging Data. AB - In this article, we study a central problem in multimodal neuroimaging analysis, i.e., identification of significantly correlated brain regions between multiple imaging modalities.We propose a spatially varying correlation model and the associated inference procedure, which improves substantially over the common alternative solutions of voxel-wise and region-wise analysis. Compared to voxel wise analysis, our method aggregates voxels with similar correlations into regions, takes into account spatial continuity of correlations at nearby voxels, and enjoys a much higher detection power. Compared to region-wise analysis, our method does not rely on any pre-specified brain region map, but instead finds homogenous correlation regions adaptively given the data. We applied our method to a multimodal positron emission tomography study, and found brain regions with significant correlation between tau and glucose metabolism that voxel-wise or region-wise analysis failed to identify. Our findings conform and lend additional support to prior hypotheses about how the two pathological proteins of Alzheimer's disease, tau and amyloid, interact with glucose metabolism in the aging human brain. PMID- 30028696 TI - Visualization of the intensity field of a focused ultrasound (FUS) source in situ. AB - In an increasing number of applications of focused ultrasound (FUS) therapy, such as opening of the blood brain barrier or collapsing microbubbles in a tumor, elevation of tissue temperature is not involved. In these cases, real-time visualization of the field distribution of the FUS source would allow localization of the FUS beam within the targeted tissue and allow repositioning of the FUS beam during tissue motion. In this work, in order to visualize the FUS beam in situ, a 6- MHz single-element transducer (f/2) was used as the FUS source and aligned perpendicular to a linear array which passively received scattered ultrasound from the sample. An image of the reconstructed intensity field pattern of the FUS source using bistatic beamforming was then superimposed on a registered Bmode image of the sample acquired using the same linear array. The superimposed image is used to provide anatomical context of the FUS beam in the sample being treated. The intensity field pattern reconstructed from a homogeneous scattering phantom was compared to the field characteristics of the FUS source characterized by the wire technique. The beamwidth estimates at the FUS focus using the in situ reconstruction technique and the wire technique were 1.5 mm and 1.2 mm, respectively. The depth of field estimates for the in situ reconstruction technique and the wire technique were 11.8 mm and 16.8 mm, respectively. The FUS beams were also visualized in a two layer phantom and a chicken breast. The novel reconstruction technique was able to accurately visualize the field of an FUS source in the context of the interrogated medium. PMID- 30028697 TI - Rapid Wave Velocity Measurement by Brillouin Scattering Using Coherent Phonons Induced by ScAlN Piezoelectric Thin-Film Transducer. AB - It is difficult to perform 2-D imaging of elastic properties using the Brillouin scattering technique because the weak thermal phonon signal in the sample leads to low measurement accuracy and long measurement times. To improve the phonon signal, we artificially induced acoustic phonons using a ScAlN thin-film piezoelectric transducer, which has a giant piezoelectricity. The film was grown using RF magnetron sputtering of a ScAl alloy target on a silica glass bar sample. Using a microwave probe, the electric power applied to the film was 1 mW at 875 MHz. We obtained the enhancement of the Brillouin scattering signal in the silica glass bar sample due to the induced phonons. Compared with and without the induced phonons from the ScAlN film transducer, the peak intensity improved by nearly 3 orders of magnitude. This technique can significantly shorten the time required for the Brillouin scattering measurements. PMID- 30028698 TI - High-Frame-Rate Contrast Echocardiography using diverging waves: initial in-vitro and in-vivo evaluation. AB - Contrast Echocardiography (CE) ultrasound with microbubble contrast agents (UCA) has significantly advanced our capability for assessment of cardiac function, including myocardium perfusion quantification. However in standard CE techniques obtained with line by line scanning, the frame rate and image quality are limited. Recent research has shown significant frame rate improvement in non contrast cardiac imaging. In this work we present and initially evaluate, both in vitro and in-vivo, a high frame rate (HFR) CE imaging system using diverging waves and pulse inversion sequence. An imaging frame rate of 5500 frames per second before and 250 frames per second after compounding is achieved. A destruction-replenishment sequence has also been developed. The developed HFR CE is compared with standard CE in-vitro on a phantom and then in-vivo on a sheep heart. The image signal to noise ratio, contrast between the myocardium and the chamber are evaluated. Results show up to 13.4 dB improvement in contrast for HFR CE over standard CE when compared at the same display frame-rate even when the average spatial acoustic pressure in HFR CE is 36% lower than the standard CE. It is also found that when coherent compounding is used the HFR CE image intensity can be significantly modulated by the flow motion in the chamber. PMID- 30028699 TI - Contrast in Haze Removal: Configurable Contrast Enhancement Model Based on Dark Channel Prior. AB - Conventional haze-removal methods are designed to adjust the contrast and saturation, and in so doing enhance the quality of the reconstructed image. Unfortunately, the removal of haze in this manner can shift the luminance away from its ideal value. In other words, haze removal involves a tradeoff between luminance and contrast. We reformulated the problem of haze removal as a luminance reconstruction scheme, in which an energy term is used to achieve a favorable tradeoff between luminance and contrast. The proposed method bases the luminance values for the reconstructed image on statistical analysis of haze-free images, thereby achieving contrast values superior to those obtained using other methods for a given brightness level. We also developed a novel module for the estimation of atmospheric light using the color constancy method. This module was shown to outperform existing methods, particularly when noise is taken into account. The proposed framework requires only 0.55 seconds to process a 1 megapixel image. Experimental results demonstrate that the proposed haze-removal framework conforms to our theory of contrast. PMID- 30028700 TI - Robust and Fast Decoding of High-Capacity Color QR Codes for Mobile Applications. AB - The use of color in QR codes brings extra data capacity, but also inflicts tremendous challenges on the decoding process due to chromatic distortion-cross channel color interference and illumination variation. Particularly, we further discover a new type of chromatic distortion in high-density color QR codes-cross module color interference-caused by the high density which also makes the geometric distortion correction more challenging. To address these problems, we propose two approaches, LSVM-CMI and QDA-CMI, which jointly model these different types of chromatic distortion. Extended from SVM and QDA, respectively, both LSVM CMI and QDA-CMI optimize over a particular objective function and learn a color classifier. Furthermore, a robust geometric transformation method and several pipeline refinements are proposed to boost the decoding performance for mobile applications. We put forth and implement a framework for high-capacity color QR codes equipped with our methods, called HiQ. To evaluate the performance of HiQ, we collect a challenging large-scale color QR code dataset, CUHK-CQRC, which consists of 5390 high-density color QR code samples. The comparison with the baseline method [2] on CUHK-CQRC shows that HiQ at least outperforms [2] by 188% in decoding success rate and 60% in bit error rate. Our implementation of HiQ in iOS and Android also demonstrates the effectiveness of our framework in real world applications. PMID- 30028701 TI - Contour-Seed Pairs Learning-Based Framework for Simultaneously Detecting and Segmenting Various Overlapping Cells/Nuclei in Microscopy Images. AB - In this paper, we propose a novel contour-seed pairs learning-based framework for robust and automated cell/nucleus segmentation. Automated granular object segmentation in microscopy images has significant clinical importance for pathology grading of the cell carcinoma and gene expression. The focus of the past literature is dominated by either segmenting a certain type of cells/nuclei or simply splitting the clustered objects without contours inference of them. Our method addresses these issues by formulating the detection and segmentation tasks in terms of a unified regression problem, where a cascade sparse regression chain model is trained and then applied to return object locations and entire boundaries of clustered objects. In particular, we first learn a set of online convolutional features in each layer. Then, in the proposed cascade sparse regression chain, with the input from the learned features, we iteratively update the locations and clustered object boundaries until convergence. In this way, the boundary evidences of each individual object can be easily delineated and be further fed to a complete contour inference procedure optimized by the minimum description length principle. For any probe image, our method enables to analyze free-lying and overlapping cells with complex shapes. Experimental results show that the proposed method is very generic and performs well on contour inferences of various cell/nucleus types. Compared with the current segmentation techniques, our approach achieves state-of-the-art performances on four challenging datasets, i.e., the kidney renal cell carcinoma histopathology dataset, Drosophila Kc167 cellular dataset, differential interference contrast red blood cell dataset, and cervical cytology dataset. PMID- 30028702 TI - Relative CNN-RNN: Learning Relative Atmospheric Visibility From Images. AB - We propose a deep learning approach for directly estimating relative atmospheric visibility from outdoor photos without relying on weather images or data that require expensive sensing or custom capture. Our data-driven approach capitalizes on a large collection of Internet images to learn rich scene and visibility varieties. The relative CNN-RNN coarse-to-fine model, where CNN stands for convolutional neural network and RNN stands for recurrent neural network, exploits the joint power of relative support vector machine, which has a good ranking representation, and the data-driven deep learning features derived from our novel CNN-RNN model. The CNN-RNN model makes use of shortcut connections to bridge a CNN module and an RNN coarse-to-fine module. The CNN captures the global view while the RNN simulates human's attention shift, namely, from the whole image (global) to the farthest discerned region (local). The learned relative model can be adapted to predict absolute visibility in limited scenarios. Extensive experiments and comparisons are performed to verify our method. We have built an annotated dataset consisting of about 40000 images with 0.2 million human annotations. The large-scale, annotated visibility data set will be made available to accompany this paper. PMID- 30028703 TI - Machine Learning-Based Fast Angular Prediction Mode Decision Technique in Video Coding. AB - In this paper we propose a machine learning-based fast intra-prediction mode decision algorithm, using random forest that is an ensemble model of randomized decision trees. The random forest is used to estimate an intra-prediction mode from a prediction unit and to reduce encoding time significantly by avoiding the intensive Rate-Distortion optimization of a number of intra-prediction modes. To this aim, we develop a randomized tree model including parameterized split functions at nodes to learn directional block-based features. The feature uses only four pixels reflecting a directional property of a block, and, thus the evaluation is fast and efficient. To integrate the proposed technique into the conventional video coding standard frameworks, the intra-prediction mode derived from the proposed technique, called an inferred mode (IM), is used to shrink the pool of the candidate modes before carrying out the Rate-Distortion (R-D) optimization. The proposed technique is implemented into the High Efficiency Video Coding Test Model (HM) reference software of the state-of-the-art video coding standard and Joint Exploration Model (JEM) reference software, by integrating the random forest trained off-line into the codecs. Experimental results demonstrate that the proposed technique achieves significant encoding time reduction with only slight coding loss as compared the reference software models. PMID- 30028704 TI - Vision-based Parking-slot Detection: A DCNN-based Approach and A Large-scale Benchmark Dataset. AB - In the automobile industry, recent years have witnessed a growing interest in developing self-parking systems. For such systems, how to accurately and efficiently detect and localize the parking-slots defined by regular line segments near the vehicle is a key and still unresolved issue. In fact, kinds of unfavorable factors, such as the diversity of ground materials, changes in illumination conditions, and unpredictable shadows caused by nearby trees, make the vision-based parking-slot detection much harder than it looks. In this paper, we attempt to solve this issue to some extent and our contributions are twofold. First, we propose a novel DCNN (Deep Convolutional Neural Networks) based parking slot detection approach, namely DeepPS, which takes the surround-view image as the input. There are two key steps in DeepPS, identifying all the marking-points on the input image and classifying local image patterns formed by pairs of markingpoints. We formulate both of them as learning problems, which can be solved naturally by modern DCNN models. Second, to facilitate the study of vision based parking-slot detection, a largescale labeled dataset is established. This dataset is the largest in this field, comprising 12,165 surround-view images collected from typical indoor and outdoor parking sites. For each image, the marking-points and parking-slots are carefully labeled. The efficacy and efficiency of DeepPS have been corroborated on our collected dataset. To make our results fully reproducible, all the relevant source codes and the dataset have been made publicly available at https://cslinzhang.github.io/deepps/. PMID- 30028705 TI - Opinion-Unaware Blind Quality Assessment of Multiply and Singly Distorted Images via Distortion Parameter Estimation. AB - Over the past couple of decades, numerous image quality assessment (IQA) algorithms have been developed to estimate the quality of images that contain a single type of distortion. Although in practice, images can be contaminated by multiple distortions, previous research on quality assessment of multiply distorted images is very limited. In this paper, we propose an efficient algorithm to blindly assess the quality of both multiply and singly distorted images based on predicting the distortion parameters using a bag of natural scene statistics (NSS) features. Our method, called MUltiply- and Singlydistorted Image QUality Estimator (MUSIQUE), operates via three main stages. In the first stage, a two-layer classification model is employed to identify the distortion types (i.e., Gaussian blur, JPEG compression, and white noise) that may exist in an image. In the second stage, specific regression models are employed to predict the three distortion parameters (i.e., sigmaG for Gaussian blur, Q for JPEG compression, and sigmaN for white noise) by learning the different NSS features for different distortion types and combinations. In the final stage, the three estimated distortion parameter values are mapped and combined into an overall quality estimate based on quality-mapping curves and the most-apparent-distortion strategy. Experimental results tested on three multiply-distorted and seven singly-distorted image quality databases demonstrate that the proposed MUSIQUE algorithm can achieve better/competitive performance as compared to other state of-the-art FR/NR IQA algorithms. PMID- 30028706 TI - Binary Codification Design for Compressive Imaging by Uniform Sensing. AB - Recently, an important set of high dimensional signals (HDS) applications has successfully implemented compressive sensing (CS) sensors in which their efficiency depends on physical elements that perform a binary codification over the HDS. The structure of the binary codification is crucial as it determines the HDS sensing matrices. For a correct reconstruction, this class of matrices drastically differs from the dense or i.i.d. assumptions usually made in CS. Therefore, current CS matrix design algorithms are impractical. This paper proposes a novel strategy to design structured, sparse, and binary HDS measurement matrices based on promoting linear independence between rows by minimizing the number of its zero singular values. The design constraints lead to keep uniform both, the number of non-zero elements per row and also the number of non-zero elements per column. An algorithm based on an optimal selection of non zero entries positions is developed to implement this strategy. Simulations show that the proposed optimization improves the quality of the reconstructed HDS in up to 8 dB of PSNR compared with non-optimized matrices. PMID- 30028707 TI - A Robust Edge Detection Approach in the Presence of High Impulse Noise Intensity through Switching Adaptive Median and Fixed Weighted Mean Filtering. AB - This study introduces a robust edge detection method that relies on an integrated process for denoising images in the presence of high impulse noise. This process is shown to be resilient to impulse (or salt and pepper) noise even under high intensity levels. The proposed switching adaptive median and fixed weighted mean filter (SAMFWMF) is shown to yield optimal edge detection and edge detail preservation, an outcome we validate through high correlation, structural similarity index and peak signal to noise ratio measures. For comparative purposes, a comprehensive analysis of other denoising filters is provided based on these various validation metrics. The nonmaximum suppression method and new edge following maximum-sequence are two techniques used to track the edges and overcome edge discontinuities and noisy pixels, especially in the presence of high-intensity noise levels. After applying predefined thresholds to the grayscale image and thus obtaining a binary image, several morphological operations are used to remove the unwanted edges and noisy pixels, perform edge thinning to ultimately provide the desired edge connectivity which results in an optimal edge detection method. The obtained results are compared to other existing state-of-the-art denoising filters and other edge detection methods in support of our assertion that the proposed method is resilient to impulse noise even under high-intensity levels. PMID- 30028708 TI - Measuring and Modeling the Feature Detection Threshold Functions of Colormaps. AB - Pseudocoloring is one of the most common techniques used in scientific visualization. To apply pseudocoloring to a scalar field, the field value at each point is represented using one of a sequence of colors (called a colormap). One of the principles applied in generating colormaps is uniformity and previously the main method for determining uniformity has been the application of uniform color spaces. Here we present a new method for evaluating the feature discrimination threshold function across a colormap. The method is used in crowdsourced studies for the direct evaluation of nine colormaps for three feature sizes. The results are used to test the hypothesis that a uniform color space (CIELAB) gives too much weight to chromatic differences compared to luminance differences because of the way it was constructed. The hypothesis that feature discrimination can be predicted solely on the basis of luminance is also tested. The results reject both hypotheses and we demonstrate how reduced weights on the green-red and blue-yellow terms of the CIELAB color space creates a more accurate model when the task is the detection of smaller features in colormapped data. Both the method itself and modified CIELAB can be used in colormap design and evaluation. PMID- 30028709 TI - FeatureLego: Volume Exploration Using Exhaustive Clustering of Super-Voxels. AB - We present a volume exploration framework, FeatureLego, that uses a novel voxel clustering approach for efficient selection of semantic features. We partition the input volume into a set of compact super-voxels that represent the finest selection granularity. We then perform an exhaustive clustering of these super voxels using a graph-based clustering method. Unlike the prevalent brute-force parameter sampling approaches, we propose an efficient algorithm to perform this exhaustive clustering. By computing an exhaustive set of clusters, we aim to capture as many boundaries as possible and ensure that the user has sufficient options for efficiently selecting semantically relevant features. Furthermore, we merge all the computed clusters into a single tree of meta-clusters that can be used for hierarchical exploration. We implement an intuitive user-interface to interactively explore volumes using our clustering approach. Finally, we show the effectiveness of our framework on multiple real-world datasets of different modalities. PMID- 30028710 TI - A New Constrained Spatiotemporal ICA Method Based on Multi-Objective Optimization for fMRI Data Analysis. AB - Compared with independent component analysis (ICA), constrained ICA (CICA) has unique advantages in functional magnetic resonance image (fMRI) data analysis by introducing some priori information into the estimation process. However, there are still some controversies in the current CICA methods, such as how to choose the threshold parameter to restrain the similarity, and how to reduce the accuracy requirements for a priori information. In this paper, we propose a new constrained spatiotemporal ICA (CSTICA) method based on the framework of multi objective optimization, where the inequality constraint of the traditional CICA method is transformed into the objective optimization function of the CSTICA, and both temporal and spatial a priori information are included simultaneously. The simulated, hybrid, and real fMRI data experiments are designed to evaluate the performance of the proposed CSTICA method in comparison with the classical ICA and CICA methods. Compared with the traditional CICA methods, the CSTICA has circumvented the problem of threshold parameter selection. Furthermore, the experimental results demonstrate that the source recovery ability of the CSTICA has been improved to a certain extent especially in the cases of a priori information with low accuracies. Meanwhile, the results also indicate that the CSTICA reduces dependency on the accuracy of a priori information. PMID- 30028711 TI - Highly Stable 177Lu-Organic Framework as a Potential Agent for Treatment of Metastatic Bone. AB - In this paper, the metal organic framework (MOF) concept is contributed to rearrange the bone-seeking agent composed of carrier-free lutetium-177 (Lu-177), 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaminomethylenephosphonate (DOTMP) and cupper (II) (Cu (II)) for preparation of a potential agent for treatment of bone metastases. The product was characterized (infra-red spectroscopy, IR, and X-ray diffraction analysis) and quality-controlled (radio thin layer chromatography, (RTLC)). The stability and in vitro hydroxyapatite binding was checked up to 1.5 month at 37 degrees C in human serum. Radio-MOF crystals and radio-MOF particles that were obtained by varying the synthesizing conditions (including pH and temperature) showed similar IR patterns and similar elemental analysis results. The final product was synthesized at pH = 8, stirring at room temperature (yield >99%, RTLC, particle size: 90 +/- 20 nm). Biodistribution study experiments showed interesting bone-seeking (%ID/g: 8.5%) affinity of the prepared formula with no significant liver or lung uptake. Also high accumulation of radio-complex in bone tissue was estimated by the modeling of the radiation dose delivery using radiation dose assessment resource software. This novel radio-MOF with promising therapeutic results is the first study of the usage of the MOF concept to provide a high payload of Lu-177 for treatment of bone metastases. As it was expected, the most important outcome of the paper was higher bone-uptake rates rather than conventional 177Lu-DOTMP. PMID- 30028712 TI - Changes in Cytomorphology, Expression of Retinoblastoma Related Gene, and Superoxide Dismutase Enzyme Activity in Maize Cell Culture Exposed to Silver Nanoparticles. AB - The ever-increasing use of silver nanoparticles (nAg) in various products necessitates investigation of the behavior of biological systems encountering these particles. In this paper, considering maize as a biological model, the effects of colloidal nAg (<80nm) on its cell culture were investigated. For comparison purposes, silver nitrate was used as a representative of silver ion (Ag+). After stabilization of cell suspensions, they were treated with nAg and Ag+ (1 mg/l), then cell suspension growth was measured and the microscopic analysis and a cell viability test were performed. In addition, the activity of superoxide dismutase (SOD) enzyme was explored. Owing to the key role of retinoblastoma-related protein (RBR) in cell cycle as well as in development and differentiation processes, the relative expression of ZmRBR1 was studied in nAg and Ag+ exposure. Microscopic analyses revealed that cells in suspensions treated by nAg and Ag+ were morphologically classified into five types: embryogenic; larvae-like; long; swollen; and polarized. The results showed an increase in percentages of large and live cells in the treated suspensions. Remarkably, we observed some cells which were differentiated into trichomes along with some stages of trichome development in the treated cell suspensions. Moreover, exposure to nAg and Ag+ did not elevate the activity of SOD enzyme in the treated cells. Also, the relative expression of ZmRBR1 was slightly reduced in the treated cells. The findings of these experimentations indicated that nAg affected maize suspension-cultured cells in the same manner as Ag+. PMID- 30028713 TI - Paper-Based Membraneless Co-Laminar Microfluidic Glucose Biofuel Cell With MWCNT Fed Bucky Paper Bioelectrodes. AB - This paper establishes a membraneless, co-laminar flow-based approach to develop a cost-effective microfluidic paper-based analytical device for enzymatic biofuel cell ( PAD-EBFC). The developed PAD-EBFC supporting the self-capillary fluid transport action consists of Y-shaped paper microchannel with the fuel (glucose) and oxidant (O2) streaming in parallel over carbon nanotube-based bucky paper electrodes modified with biocompatible electrocatalytic enzymes, such as glucose oxidase and laccase without any additional redox cofactor. The electrochemical performance for the modified bioelectrodes, i.e., electrocatalytic oxidation and reduction reaction, was carried out using linear sweep voltammetry, cyclic voltammetry, and open circuit potential. The overall performance of PAD-EBFC was evaluated using the polarization studies. Subsequently, the catalytic activity of enzymes on the electrode surface was validated by the scanning electron microscope. This simple and portable PAD-EBFC can generate the maximum power density to the order of /cm2 ( /cm2) at 0.505 V over prolonged durations of around 50 h. Hence, the presented PAD-EBFC shows good power density and stability, leading to its strong potential to power miniaturized microelectronics devices and sensors. PMID- 30028714 TI - Optimizing Autoencoders for Learning Deep Representations from Health Data. AB - Analysing patients' health data using machine learning techniques can improve both patient outcomes and hospital operations. However, heterogeneous patient data (e.g., vital signs) and inefficient feature learning methods affect the implementation of machine learning-based patient data analysis. In this paper, we present a novel unsupervised Deep learning-based Feature Learning (DFL) framework to automatically learn compact representations from patient health data for efficient clinical decision making. Real-world pneumonia patient data from the National University Hospital (NUH) in Singapore are collected and analysed to evaluate the performance of DFL. Furthermore, publicly available electroencephalogram (EEG) data are extracted from the UCI Machine Learning Repository to test and support our findings. Using both data sets, we compare the performance of DFL to that of several popular feature learning methods and demonstrate its advantages. PMID- 30028715 TI - Changes in Daily Measures of Blood Pressure and Heart Rate Improve Weight-based Detection of Heart Failure Deterioration in Patients on Telemonitoring. AB - Blood pressure (BP) and heart rate (HR) are often captured in conjunction with weight in telemonitoring systems, but the additional prognostic potential of daily measurements of BP and HR in providing information on upcoming hospitalizations for worsening heart failure (HFH) have not been explored thoroughly. We retrospectively analyzed 267 daily home-telemonitored heart failure (HF) subjects. We extracted those episodes of HFHs that had sufficient data entries in the days leading up to hospitalization and tested the prognostic potential of 48 trend features based on weight, systolic BP, diastolic BP, pulse pressure (PP) and HR with a Naive Bayesian model. The single best-performing trend feature-with a cross-validated estimate of 0.64 for the area under the curve (AUC) with a standard deviation (SD) of 0.01-is based on a 2-day weight trend. The best multivariate feature set (cross-validated AUC=0.70, SD=0.01) comprises of 2-day trend features based on weight, systolic BP, and HR. There were large variations in the weight trends preceding hospitalizations and weight change alone had a modest predictive ability. Readily interpretable features capturing trends in BP and HR provided additional prognostic information and can be used for improving classification. PMID- 30028716 TI - Multi-level Feature Representation of FDG-PET Brain Images for Diagnosing Alzheimer's Disease. AB - Using a single imaging modality to diagnose Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) is a challenging task. FluoroDeoxyGlucose Positron Emission Tomography (FDG-PET) is an important and effective modality usedforthatpurpose.Inthispaper,wedevelopanovelmethodby using single modality (FDG PET) but multi-level feature, which considers both region properties and connectivities between regions to classify AD or MCI from Normal Control (NC). First, three levels of features are extracted: statistical, connectivity and graph-based features. Then the connectivity features are decomposed into 3 different sets of features according to a proposed similarity-driven ranking method, which can not only reduce the feature dimension but also increase the classifier's diversity. Last, after feeding the 3 levels of features to different classifiers, a new classifier selection strategy, maximum Mean squared Error (mMsE), is developed to select a pair of classifiers with high diversity. In order to do the majority voting, a decision-making scheme, a nested cross validation technique is applied to choose another classifier according to the accuracy. Experiments on Alzheimer's Disease Neuroimaging Initiative (ADNI) database show that the proposed method outperforms most FDG-PET-based classification algorithms, especially for classifying progressive MCI (pMCI) from stable MCI (sMCI). PMID- 30028717 TI - Switching Stabilization for Type-2 Fuzzy Systems With Network-Induced Packet Losses. AB - This paper is concerned with the stabilization problem of type-2 fuzzy systems with network-induced packet losses. By regarding the packet lost process as an unstable mode of a switched system, the stability of the system is then guaranteed with the aid of the mode-dependent average dwell time approach in the sense of the slow and fast switching. The discrete-time multiple discontinuous Lyapunov function is also utilized for the analysis. Two sufficient conditions regarding the stability and the stabilization of the system are proposed. The state-feedback matrices can be then calculated from the conditions to ensure the criterion that the packet-loss rate is no larger than a specific constant. Two practical examples are given to illustrate the feasibility and effectiveness of the proposed method. PMID- 30028718 TI - Event-Based Rendezvous Control for a Group of Robots With Asynchronous Periodic Detection and Communication Time Delays. AB - In this paper, we propose an event-triggered rendezvous control method for multiple two-wheeled mobile robots (2WMRs) subject to time-varying communication delays. By checking the integral-type event-triggering conditions asynchronously and periodically, each 2WMR determines whether or not to sample and broadcast its states. When the information used in an agent's controller is updated, the 2WMR calculates its x (or y) control input, and then a Rotate and Compensate and Run Rendezvous Scheme is provided for 2WMRs to update their states. We present a sufficient condition for 2WMRs to asymptotically reach rendezvous, and the convergence analysis is conducted using the Lyapunov functional approach. Experiments are further presented to validate the effectiveness of the proposed control method. PMID- 30028719 TI - User Centered Neuro-Fuzzy Energy Management Through Semantic-Based Optimization. AB - This paper presents a cloud-based building energy management system, underpinned by semantic middleware, that integrates an enhanced sensor network with advanced analytics, accessible through an intuitive Web-based user interface. The proposed solution is described in terms of its three key layers: 1) user interface; 2) intelligence; and 3) interoperability. The system's intelligence is derived from simulation-based optimized rules, historical sensor data mining, and a fuzzy reasoner. The solution enables interoperability through a semantic knowledge base, which also contributes intelligence through reasoning and inference abilities, and which are enhanced through intelligent rules. Finally, building energy performance monitoring is delivered alongside optimized rule suggestions and a negotiation process in a 3-D Web-based interface using WebGL. The solution has been validated in a real pilot building to illustrate the strength of the approach, where it has shown over 25% energy savings. The relevance of this paper in the field is discussed, and it is argued that the proposed solution is mature enough for testing across further buildings. PMID- 30028720 TI - An Evolutionary Multiobjective Carpool Algorithm Using Set-Based Operator Based on Simulated Binary Crossover. AB - Sharing vehicle journeys with other passengers can provide many benefits, such as reducing traffic congestion and making urban transportation more environmentally friendly. For the procedure of sharing empty seats, we need to consider increased ridership and driving distances incurred by carpool detours resulting from matching passengers to drivers, as well as maximizing the number of simultaneous matches. In accordance with these goals, this paper proposes and defines the multiobjective optimization carpool service problem (MOCSP). Previous studies have used evolutionary algorithms by combining multiple objectives into a single objective through a weighted linear or/and nonlinear combination of different objectives, thus turning to a single-objective optimization problem. These single objective problems are optimized, but there is no guarantee of the performance of the respective objectives. By improving the individual representation and genetic operation, we developed a set-based simulated binary and multiobjective carpool matching algorithm that can more effectively solve MOCSP. Furthermore, the proposed algorithm can provide better driver-passenger matching results than can the binary-coded and set-based nondominated sorting genetic algorithms. PMID- 30028721 TI - A Statistical Study on Parameter Selection of Operators in Continuous State Transition Algorithm. AB - The state transition algorithm (STA) has been emerging as a novel metaheuristic method for global optimization over the past few years. In our previous study, the parameter of transformation operator in continuous STA is kept constant or decreasing itself in a periodical way. In this paper, the optimal parameter selection of operators in continuous STA is taken into consideration. First, a statistical study with four benchmark 2-D functions is conducted to show how these parameters affect the search ability of the STA. Based on the experience gained from the statistical study, then, a new continuous STA with optimal parameter strategy is proposed to accelerate its search process. The proposed STA is successfully applied to 12 benchmarks with 20-D, 30-D, and 50-D space. A comparison with other metaheuristics has also demonstrated the effectiveness of the proposed method. PMID- 30028722 TI - Distributed Hinfinity Filtering for Switched Stochastic Delayed Systems Over Sensor Networks With Fading Measurements. AB - This paper is concerned with the problem of distributed Hinfinity filtering for switched stochastic time-delay systems with fading measurements over sensor networks. The underlying target plants are subject to fading measurements where the fading rates are described by continuous-time random variables with known statistical properties dependent on the system modes. The adjacency matrices characterizing the topology of the sensor networks are also allowed to be mode dependent. Based on the multiple Lyapunov functional approach and average dwell time concept, the distributed Hinfinity filter is designed by means of the convex optimization scheme. A dedicated technique is developed via a simple algebraic equality in order to avoid solving a transcendental equation used in the existing results. With the designed filter, the error dynamics of the state estimation is guaranteed to have the mean-square exponential stability with a prescribed Hinfinity disturbance attenuation level. Finally, a numerical example is used to demonstrate the effectiveness of the method. PMID- 30028723 TI - Parallel Intelligent Systems for Integrated High-Speed Railway Operation Control and Dynamic Scheduling. AB - The information exchange gap between current operation control and dynamic scheduling in high-speed railway systems (HRSs) still exists, and this gap has hindered the further integrative improvement of HRSs. This paper aims to explore a feasible solution to bridging the information exchange gap for further improving the efficiency of HRSs, with the parallel intelligent systems for integrated HRS operation control and dynamic scheduling first analyzed and constructed using the ACP approach, that is, "artificial systems" (A), "computational experiments," (C) and "parallel execution" (P). Then, on the basis of the constructed parallel intelligent systems, experiments on several typical scenarios in HRSs are conducted to achieve a set of control and management strategies for actual HRSs. Experimental results show that a number of powerful tools provided by the proposed parallel intelligent systems can be utilized not only to study the current HRSs, but also to further undertake research on integrated operation control and dynamic scheduling for HRSs. PMID- 30028724 TI - Hyperspectral imaging in perfusion and wound diagnostics - methods and algorithms for the determination of tissue parameters. AB - Blood perfusion is the supply of tissue with blood, and oxygen is a key factor in the field of minor and major wound healing. Reduced perfusion of a wound bed or transplant often causes various complications. Reliable methods for an objective evaluation of perfusion status are still lacking, and insufficient perfusion may remain undiscovered, resulting in chronic processes and failing transplants. Hyperspectral imaging (HSI) represents a novel method with increasing importance for clinical practice. Therefore, methods, software and algorithms for a new HSI system are presented which can be used to observe tissue oxygenation and other parameters that are of importance in supervising healing processes. This could offer an improved insight into wound perfusion allowing timely intervention. PMID- 30028725 TI - Van Wyk-Grumbach syndrome with hemangioma in an infant. AB - Background Van Wyk-Grumbach syndrome (VWGS) is characterized by juvenile primary hypothyroidism, delayed bone age and isosexual incomplete precocious puberty with reversal to the prepubertal state following thyroid hormone replacement. Case presentation In this case, an 18-month-old girl presented with premature menarche since 9 months of age, delayed bone age and enlarged bilateral multicystic ovaries along with a superficial infantile hemangioma over the upper anterior chest. VWGS was diagnosed based on the clinical features. High serum thyroid stimulating hormone and low free thyroxine with the absence of any carpal bones in the wrist X-ray were suggestive of congenital hypothyroidism. Interestingly, the coexisting hemangioma could also play a role in the etiology of the hypothyroidism through "consumptive hypothyroidism". Thyroid hormone replacement resulted in the complete resolution of signs and symptoms. Conclusions Untreated congenital hypothyroidism of short duration, onset of symptoms in infancy and association of an infantile hemangioma in VWGS were the unique features in our case. PMID- 30028726 TI - Propofol-based Total Intravenous Anesthesia Is Associated with Better Survival Than Desflurane Anesthesia in Colon Cancer Surgery. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Previous research has shown different effects of anesthetics on cancer cell growth. Here, the authors investigated the association between type of anesthetic and patient survival after elective colon cancer surgery. METHODS: A retrospective cohort study included patients who received elective colon cancer surgery between January 2005 and December 2014. Patients were grouped according to anesthesia received: propofol or desflurane. After exclusion of those who received combined propofol anesthesia with inhalation anesthesia or epidural anesthesia, survival curves were constructed from the date of surgery to death. After propensity matching, univariable and multivariable Cox regression models were used to compare hazard ratios for death. Subgroup analyses were performed for tumor-node-metastasis staging and postoperative metastasis. RESULTS: A total of 706 patients (307 deaths, 43.5%) with desflurane anesthesia and 657 (88 deaths, 13.4%) with propofol anesthesia were eligible for analysis. After propensity matching, 579 patients remained in each group (189 deaths, 32.6%, in the desflurane group vs. 87, 15.0%, in the propofol group). In the matched analyses, the propofol-treated group had a better survival, irrespective of lower tumor-node-metastasis stage (hazard ratio, 0.22; 95% CI, 0.11 to 0.42; P < 0.001) or higher tumor-node-metastasis stage (hazard ratio, 0.42; 95% CI, 0.32 to 0.55; P < 0.001) and presence of metastases (hazard ratio, 0.67; 95% CI, 0.51 to 0.86; P = 0.002) or absence of metastases (hazard ratio, 0.08; 95% CI, 0.01 to 0.62; P = 0.016). Simple propensity score adjustment produced similar findings. CONCLUSIONS: Propofol anesthesia for colon cancer surgery is associated with better survival irrespective of tumor-node-metastasis stage. PMID- 30028727 TI - Resting-state Dynamics as a Cortical Signature of Anesthesia in Monkeys. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The mechanism by which anesthetics induce a loss of consciousness remains a puzzling problem. We hypothesized that a cortical signature of anesthesia could be found in an increase in similarity between the matrix of resting-state functional correlations and the anatomical connectivity matrix of the brain, resulting in an increased function-structure similarity. METHODS: We acquired resting-state functional magnetic resonance images in macaque monkeys during wakefulness (n = 3) or anesthesia with propofol (n = 3), ketamine (n = 3), or sevoflurane (n = 3). We used the k-means algorithm to cluster dynamic resting state data into independent functional brain states. For each condition, we performed a regression analysis to quantify function-structure similarity and the repertoire of functional brain states. RESULTS: Seven functional brain states were clustered and ranked according to their similarity to structural connectivity, with higher ranks corresponding to higher function-structure similarity and lower ranks corresponding to lower correlation between brain function and brain anatomy. Anesthesia shifted the brain state composition from a low rank (rounded rank [mean +/- SD]) in the awake condition (awake rank = 4 [3.58 +/- 1.03]) to high ranks in the different anesthetic conditions (ketamine rank = 6 [6.10 +/- 0.32]; moderate propofol rank = 6 [6.15 +/- 0.76]; deep propofol rank = 6 [6.16 +/- 0.46]; moderate sevoflurane rank = 5 [5.10 +/- 0.81]; deep sevoflurane rank = 6 [5.81 +/- 1.11]; P < 0.0001). CONCLUSIONS: Whatever the molecular mechanism, anesthesia led to a massive reconfiguration of the repertoire of functional brain states that became predominantly shaped by brain anatomy (high function-structure similarity), giving rise to a well-defined cortical signature of anesthesia-induced loss of consciousness. PMID- 30028728 TI - Pitfalls in anaphylaxis. AB - PURPOSE OF REVIEW: Anaphylaxis is an acute medical emergency characterized by sudden presentation of life-threatening respiratory and cardiovascular symptoms. Rapid diagnosis of anaphylaxis is crucial to implement an appropriate treatment and management plan. However, mistakes in the diagnosis of anaphylaxis may occur because of the limited time during which the diagnosis must be made, the stressful environment of the emergency room, the often aspecific or incomplete clinical features of early anaphylaxis and the lack of useful laboratory markers. RECENT FINDINGS: Several disorders may mimick anaphylaxis and cause wrong or delayed diagnosis increasing chances of fatal outcomes. In addition, certain clinical situations, like general anesthesia, may complicate detection of early signs of anaphylaxis. Drugs like beta-blockers, angiotensin converting enzyme inhibitors, antihistamines or steroids may hide or blunt initial clinical manifestations of anaphylaxis. SUMMARY: A careful evaluation of clinical signs in all organs is mandatory to quickly establish and confirm a diagnosis of anaphylaxis. Alternative diagnosis should be considered, particularly in the case of unresponsive patients. Avoiding pitfalls in anaphylaxis diagnosis will help to establish rapidly effective treatments and would further reduce the rate of fatal events. PMID- 30028729 TI - Applications of left ventricular strain measurements to patients undergoing chemotherapy. AB - PURPOSE OF REVIEW: We aim to summarize the utility of strain in monitoring the effects of cancer therapy-related cardiotoxicity (CTRC) on the development of left ventricular (LV) dysfunction. RECENT FINDINGS: Serial assessment of cardiac function at baseline and during treatment is recommended in patients undergoing cancer treatment. Historically, the use of left ventricular ejection fraction (LVEF) has been used to monitor for cardiac toxicity from cancer therapies but myocardial mechanic parameters, in particular global longitudinal strain (GLS), have emerged as powerful adjunctive tools. On the basis of longitudinal cohort studies in patients treated with anthracyclines and trastuzumab and retrospective studies of childhood survivors of cancers, strain has been used to detect subclinical LV dysfunction prior to changes in LVEF. Strain parameters decrease during both anthracycline and trastuzumab and these changes can persist after completion of therapy. Baseline GLS and changes in GLS during therapy can be independently prognostic for developing CTRC. Further, GLS has appeared to have an additive predictive value in addition to the traditional clinical parameters and baseline LVEF in the development of cardiotoxicity. The inclusion of strain parameters in clinical decision making and therapeutic planning is an area of intense research. SUMMARY: This review seeks to highlight the importance of echocardiographic strain measurements in early detection, treatment and prevention of LV dysfunction from CTRC. PMID- 30028730 TI - Cardiovascular disease prevention: challenges remain; opportunities grow. PMID- 30028731 TI - Fatal Transorbital Intracranial Penetrating Injury Due to a Bicycle Brake Handle. AB - Transorbital intracranial injuries are uncommon and mostly accidental in nature. These injuries are usually associated with high mortality. The key to preventing this mortality involves an early diagnosis of intracranial injuries and immediate and appropriate management. Any delay can pose a serious risk to the patient's life. A case of a 55-year-old man who had experienced an accidental self-fall while riding a bicycle is presented. Initially, he was treated at a primary health center. He was referred to the tertiary care institute due to unavailability of ancillary investigation at the primary health center. He was declared dead on arrival at the casualty in the tertiary institute. On autopsy, it was observed that the injury above the right side of the upper eyelid was penetrating the right side roof of the orbit and the right cerebral cortex and brainstem. The highlighting feature of the case is that, despite the fatal penetrating brain injury, the eyeball did not sustain any major injury. PMID- 30028732 TI - Differences in Sampling Site on Postmortem Cerebrospinal Fluid Biochemistry: A Preliminary Study. AB - Cerebrospinal fluid (CSF) is often analyzed at postmortem. The presented preliminary study compared postmortem CSF samples for biochemical analysis from the subarachnoid space around the spinal cord and ventricular space of the brain. This study compared 15 paired CSF samples in which the CSF from the subarachnoid space via lumbar puncture had higher sodium and chloride levels and lower magnesium and potassium levels than CSF from the ventricles. The differences correlated significantly with the deceased's age and had a similar trend with postmortem interval. This study suggests that CSF from different collection sites has different electrolyte concentrations, which are age and possibly postmortem interval dependent. When collecting CSF, the pathologist should document the collection site, age, and postmortem interval, and the mixing of CSF samples from different sites should be avoided. Further studies are warranted to clarify other possible reasons to explain the observed differences. PMID- 30028733 TI - Mechanisms of acute and chronic pain after surgery: update from findings in experimental animal models. AB - PURPOSE OF REVIEW: Management of postoperative pain is still a major issue and relevant mechanisms need to be investigated. In preclinical research, substantial progress has been made, for example, by establishing specific rodent models of postoperative pain. By reviewing most recent preclinical studies in animals related to postoperative, incisional pain, we outline the currently available surgical-related pain models, discuss assessment methods for pain-relevant behavior and their shortcomings to reflect the clinical situation, delineate some novel clinical-relevant mechanisms for postoperative pain, and point toward future needs. RECENT FINDINGS: Since the development of the first rodent model of postoperative, incisional pain almost 20 years ago, numerous variations and some procedure-specific models have been emerged including some conceivably relevant for investigating prolonged, chronic pain after surgery. Many mechanisms have been investigated by using these models; most recent studies focussed on endogenous descending inhibition and opioid-induced hyperalgesia. However, surgical models beyond the classical incision model have so far been used only in exceptional cases, and clinical relevant behavioral pain assays are still rarely utilized. SUMMARY: Pathophysiological mechanisms of pain after surgery are increasingly discovered, but utilization of pain behavior assays are only sparsely able to reflect clinical-relevant aspects of acute and chronic postoperative pain in patients. PMID- 30028734 TI - Know the Flow: Milk Flow Rates From Bottle Nipples Used in the Hospital and After Discharge. AB - BACKGROUND: Milk flow rate may play an important role in an infant's ability to safely and efficiently coordinate sucking, swallowing, and breathing during feeding. PURPOSE: To test milk flow rates from bottle nipples used in the hospital and after discharge. METHODS: Bottle nipples used in hospitals (10 unique types) and available nationwide at major retailers (15 unique types) were identified. For each of the 25 nipple types, 15 nipples of that type were tested by measuring the amount of infant formula extracted in 1 minute by a breast pump. Mean milk flow rate (mL/min) and coefficient of variation (CV) were calculated for each nipple type. Comparisons between nipple types were made within brand and within category (eg, Slow, Standard). A cluster analysis was conducted to identify nipples of comparable flow. RESULTS: A total of 375 individual nipples were tested. Milk flow rates varied widely, from 0.86 to 37.61 mL/min. There was also a wide range of CVs, from 0.03 to 0.35. Packing information did not accurately reflect the flow rates of bottle nipples. The cluster analysis revealed 5 clusters of nipples, with flow rates from Extra Slow to Very Fast. IMPLICATIONS FOR PRACTICE: These data can be used to guide decisions regarding nipples to use for feeding infants with medical complexity in the hospital and after discharge. IMPLICATIONS FOR RESEARCH: Research on infant feeding should consider the flow rate and variability of nipples used, as these factors may impact findings. PMID- 30028735 TI - Oral Feeding Success: A Concept Analysis. AB - BACKGROUND: The term "oral feeding success" (OFS) is frequently used in clinical practice and research. However, OFS is inconsistently defined, which impacts the ability to adequately evaluate OFS, identify risk factors, and implement interventions in clinical practice and research. PURPOSE: To develop the defining attributes, antecedents, and consequences for the concept of OFS in preterm infants during their initial hospitalization. METHODS: PubMed, CINAHL, and PsycINFO databases were searched for English articles containing the key words "oral feeding success" and "preterm infants." The Walker and Avant method for concept analysis was employed. RESULTS: Sixteen articles revealed the defining attributes, antecedents, and consequences. Defining attributes included (1) physiologic stability; (2) full oral feeding; and (3) combined criteria of feeding proficiency (>=30% of the prescribed volume during the first 5 minutes), feeding efficiency (>=1.5 mL/min over the entire feeding), and intake quantity (>=80% of the prescribed volume). IMPLICATIONS FOR PRACTICE: The 3 defining attributes may be used in clinical practice to consistently evaluate OFS. The antecedents of OFS provide clinicians with a frame of reference to assess oral feeding readiness, identify risk factors, and implement effective interventions. The consequences of OFS allow clinicians to anticipate challenges when OFS is not achieved and create a care plan to support the infants. IMPLICATIONS FOR RESEARCH: The empirical referents of OFS provide consistent and clear operational definitions of OFS for use in research. The antecedents and consequences may guide researchers to select specific measures or covariates to evaluate valid measures of OFS. PMID- 30028736 TI - How useful is muscle ultrasound in the diagnostic workup of neuromuscular diseases? AB - PURPOSE OF REVIEW: This review focuses on developments in muscle ultrasound as a noninvasive and accurate tool for the diagnosis and follow-up of neuromuscular disease. It discusses current muscle ultrasound applications with already proven clinical value, and highlights recent technical developments that may further advance muscle ultrasounds' diagnostic qualities. RECENT FINDINGS: The sensitivity and specificity of muscle ultrasound for detecting a neuromuscular disorder are high (90-95%), and quantitative ultrasound is well suited to monitor disease progression in several disorders. Adding ultrasound to electromyography significantly improves diagnostic certainty in patients with suspected motor neuron disease, and ultrasound increases the detection of fasciculations with 30 50%. New developments include speckle tracking of tissue motion to quantify diaphragm excursions and diminished muscle contractility in dystrophy, and strain elastography to detect changes in muscle stiffness and anisotropy during contraction and in disease states. Deep learning algorithms are being developed to predict the presence of a muscle disease and differentiate between disorders. SUMMARY: Muscle ultrasound is excellent for screening, diagnosing, and follow-up of neuromuscular disease. New developments are underway to automate and objectify the diagnostic process, and to quantify tissue motion that can provide new insights in pathophysiology and serve as a biomarker. PMID- 30028737 TI - Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. AB - PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS. RECENT FINDINGS: The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental work to identify the genetic underpinnings of familial ALS and develop relevant disease models. Preclinical studies have also identified promising targets for sporadic ALS (sALS). Moreover, encouraging results in adeno associated virus (AAV)-based therapies for spinal muscular atrophy (SMA) provide a roadmap for continued improvement in delivery and design of molecular therapies for ALS. SUMMARY: Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated. PMID- 30028738 TI - Pilsicainide Poisoning: An Autopsy Case and Review of Literature. AB - We describe an autopsy case of fatal poisoning due to accidental overdose of pilsicainide, which is a Vaughan Williams class IC antiarrhythmic drug (a pure sodium channel blocker). A man in his 50s was found dead in his home at approximately noon. He had ischemic heart disease and insomnia, and had previously demonstrated improper prescription drug adherence. The autopsy revealed old coronary artery bypass grafting and mild fibrosis of myocardium, but no acute myocardial infarction was found in microscopic examination. Toxicological analysis also identified a high blood concentration of pilsicainide (femoral vein blood, 14.9 MUg/mL), more than 15 times higher than reported therapeutic levels. The blood concentrations of other drugs were at therapeutic levels, and no alcohol was detected. We concluded that the cause of death was pilsicainide poisoning, based on the results of the autopsy and the toxicological examination. This is the first autopsy report of fatal poisoning due to pilsicainide as a single agent. PMID- 30028739 TI - Antibiotic treatment of hospital-acquired pneumonia: is it different from ventilator-associated pneumonia? AB - PURPOSE OF REVIEW: Hospital-acquired pneumonia (HAP) is a form of nosocomial pneumonia, distinct from ventilator-associated pneumonia (VAP). This review compares HAP and VAP, highlighting differences in natural history, risk factors, and bacteriology that necessitate a different approach to the therapy of HAP, compared with VAP. RECENT FINDINGS: HAP can arise out of the ICU, or in the ICU, and can lead to severe illness, including the need for intubation and mechanical ventilation. New American and European nosocomial pneumonia guidelines make therapy recommendations for HAP. The American guidelines recommend broader spectrum therapy than the European guidelines, but recent studies support the idea that not all HAP patients need antipseudomonal therapy. When the American guideline approach to HAP has been studied, it led to both overtreatment and inappropriate therapy for the identified pathogens. An algorithm, modified from the European guideline, proposes an approach to therapy that necessitates dual antipseudomonal therapy in less than 25% of all HAP patients. SUMMARY: Although more prospective therapy trials of HAP are needed, based on currently available data, it is possible to use an approach that provides appropriate therapy without the overuse of broad-spectrum therapy. PMID- 30028740 TI - Diagnosis of nonventilated hospital-acquired pneumonia: how much do we know? AB - PURPOSE OF REVIEW: To describe the current knowledge about clinical and microbiological diagnosis of nonventilated hospital-acquired pneumonia (NV-HAP). RECENT FINDINGS: NV-HAP is emerging as a new challenge for clinicians, particularly because VAP incidence has been decreasing. The clinical diagnosis of NV-HAP uses the classical clinical symptoms and signs. However standard evaluation of their accuracy and the evaluation of new criterion (e.g. lung ultrasound) must be conducted particularly in NV-HAP patients. The use of sputum must be encouraged in patients with NV-HAP, assuring its lower respiratory tract representativeness and quality. It is not clear that invasive approaches (e.g. BAL) are associated with improvements in patient-centred outcomes, and further research is needed to assure their correct indication, guaranteeing safety. Rapid diagnosis methods are promising in NV-HAP, particularly for the quick results and information about antibiotic resistance. SUMMARY: NV-HAP poses several barriers for diagnosis compared with VAP, and the available knowledge is limited. A call for further research in diagnosis of nonventilated HAP is urgent. PMID- 30028741 TI - Subverting bradykinin-evoked inflammation by co-opting the contact system: lessons from survival strategies of Trypanosoma cruzi. AB - PURPOSE OF REVIEW: During Chagas disease, Trypanosoma cruzi alternates between intracellular and extracellular developmental forms. After presenting an overview about the roles of the contact system in immunity, I will review experimental studies showing that activation of the kallikrein-kinin system (KKS) translates into mutual benefits to the host/parasite relationship. RECENT FINDINGS: T. cruzi trypomastigotes initiate inflammation by activating tissue-resident innate sentinel cells via the TLR2/CXCR2 pathway. Following neutrophil-evoked microvascular leakage, the parasite's major cysteine protease (cruzipain) cleaves plasma-borne kininogens and complement C5. Tightly regulated by angiotensin converting enzyme (ACE), kinins and C5a in turn further propagate inflammation via iterative cycles of mast cell degranulation, contact system activation, bradykinin release and activation of endothelial bradykinin B2 receptors (B2R). Recently, studies in the intracardiac model of infection revealed a dichotomic role for bradykinin and endothelin-1: generated upon contact activation (mast cell/KKS pathway), these pro-oedematogenic peptides reciprocally stimulate trypomastigote invasion of heart cells that naturally overexpress B2R and endothelin receptors (ETaR/ETbR). SUMMARY: Studies focusing on the immunopathogenesis of Chagas disease revealed that the contact system plays a dual role in host/parasite balance: T. cruzi co-opts bradykinin-induced plasma leakage as a strategy to increment heart parasitism and increase immune resistance by upregulating type-1 effector T-cell production in secondary lymphoid tissues. PMID- 30028742 TI - The plasma contact system as a modulator of innate immunity. AB - PURPOSE OF REVIEW: The contact system is a plasma protease cascade, which activates the proinflammatory kallikrein-kinin system and the procoagulant intrinsic coagulation pathway. Recent advances demonstrating the novel functions of this system as a key player of innate immune system will be introduced in the present review. RECENT FINDINGS: The role of the contact system is to initiate and participate in pathophysiological responses to injury, mainly the processes of coagulation and inflammation. The past few years have seen substantial progress, showing a new role of this system in regulation of innate immunity. The relationship between high-molecular-weight kininogen and lipopolysaccharide (LPS) has been investigated and a new function of high-molecular-weight kininogen has been identified as the critical LPS carrier supporting endotoxemia. In contrast, the role of high-molecular-weight kininogen in Klebsiella pneumoniae sepsis is limited. Coagulation factor XII (FXII) plays a detrimental role in murine wound healing and host defense against K. pneumoniae sepsis. In the pathogenesis of arthritis and colitis, the activation of plasma kallikrein and downstream cleavage of high-molecular-weight kininogen and release of bradykinin constitutes a critical pathway in the innate immune mechanism, whereas FXII is not important. SUMMARY: Current findings indicate that the plasma contact system functions as an important constituent of innate immune system, contributing to the pathogenesis of the immunological and infectious diseases. PMID- 30028743 TI - New insights in the pathogenesis of T-cell lymphomas. AB - PURPOSE OF REVIEW: Peripheral T-cell lymphomas (PTCLs) represent diverse and aggressive malignancies, with few recent therapeutic improvements. Recent high throughput genomic studies have revealed the complex mutational landscape of these rare diseases. These novel findings provide the grounds to a more comprehensive classification of these diseases, reflected in the 2017 WHO classification. RECENT FINDINGS: Our review is focused on selected PTCL entities. Angioimmunoblastic T-cell lymphoma and other lymphomas derived from T follicular helper cells feature a rather homogeneous mutational landscape. These neoplasms recapitulate a multistep oncogenic process associating epigenetic deregulation, and second hit mutations affecting the T-cell receptor signaling pathway. This model inferred from comprehensive analyses of patients samples, was confirmed in mouse models. Among ALK-negative anaplastic large-cell lymphomas, translocation associated subsets are found in both systemic and cutaneous types, and the newly described breast implant-associated type is usually indolent. Extranodal lymphomas of the innate immune system also harbor a combination of mutations affecting different classes of epigenetic modifiers, and mutation-induced activation of the Janus Kinase/signal transduction and activator of transcription pathway. SUMMARY: Understanding of PTCL pathogenesis has substantially improved, and oncogenic events have been identified. The current challenge is to mount efficient therapeutic strategies targeting these aberrations to improve patients' outcome. PMID- 30028744 TI - Effective, recommended, underutilized: a review of the literature on barriers to adolescent usage of long-acting reversible contraceptive methods. AB - PURPOSE OF REVIEW: Teenage pregnancy rates in the United States remain at epidemic proportions. To help stem the tide of adolescent pregnancy, both the American Academy of Pediatrics and American College of Obstetricians and Gynecologists have released policy statements that long-acting reversible contraceptives (LARC) be considered the first-line option for contraception in adolescents. Despite the recommendations and efficacy, LARCs are utilized by less than 5% of American teens. The purpose of this review is to elucidate the barriers to adolescent access to LARC, which are broken down into provider, patient, and cultural barriers. RECENT FINDINGS: Recent literature suggests that shortcomings in physician training in LARC method counseling and placement begin as early as medical school and are further augmented by the clinical cost and logistical difficulty of device placement. Patients experience barriers due to cost, confidential access, and perceptions or misconceptions about contraceptive options. Cultural barriers are derived from the absence of expectation for adolescents to pursue safe and effective contraceptive options, as well as the historical complications from intrauterine devices (IUDs) and implants. SUMMARY: These barriers have led to poor utilization of the most effective methods in preventing adolescent pregnancy. It is essential that pediatricians be up-to-date on the most current recommendations surrounding LARC to help negate barriers and provide the best care to adolescent patients. PMID- 30028745 TI - Overview of benign and malignant lacrimal gland tumors. AB - PURPOSE OF REVIEW: The goal of this article is to review the key clinical and radiological features, treatment strategies, and prognosis of lacrimal gland tumors. RECENT FINDINGS: Debulking of the orbital lobe of the lacrimal gland may offer improved control rates in dacryoadenitis without compromise of tear film function. Contrary to previous belief, careful biopsy of the lacrimal gland prior to excision does not appear to increase the risk of recurrence in cases with suspected pleomorphic adenoma. Low-dose radiation (4 Gy) in two 2-Gy fractions appears to be effective and well tolerated in indolent non-Hodgkin lymphoma of the ocular adnexa with high local control rate. Eye-sparing surgery for adenoid cystic carcinoma (ACC) leaving minimal or no tumor residual in the orbit followed by adjuvant radiation therapy or chemoradiotherapy may provide good local control and long-term survival outcomes. Intra-arterial chemotherapy has been found to decrease recurrence and improve survival in ACC and can also be used as part of an eye-sparing treatment strategy. The development of targeted drugs may offer palliation for patients with unresectable or metastatic disease in lacrimal gland carcinoma. SUMMARY: This article offers an update on diagnosis, management, and prognosis of the major lacrimal gland lesions. PMID- 30028746 TI - Assessment of vestibular function in elderly patients. AB - PURPOSE OF REVIEW: Individuals over the age of 60 are at an increased risk of falls, even if they do not have an isolated dysfunction of the vestibular system. The aim of this article is to review the various vestibular testing currently available and its usefulness in determining the presence of vestibular dysfunction in the elderly population. The primary vestibular tests to be reviewed include: balance function testing, vestibular evoked myogenic potentials (VEMPs), and video head impulse testing (vHIT). RECENT FINDINGS: Balance function testing is important as it evaluates the integration of vestibular information along with sensory and visual information, which may also be impaired. VEMP testing provides a small diagnostic yield as most elderly patients have absent or reduced responses. vHIT gain is reduced in this population, but will still be within the normal range for individuals with normal balance function. SUMMARY: The combination of various vestibular tests provides complimentary information instead of redundant information on the patient's balance function. Each test evaluates various aspects of the vestibular system which are all needed to determine stable balance in the elderly population. PMID- 30028747 TI - Advances in computer-aided design for bony free-flap reconstruction. AB - PURPOSE OF REVIEW: The current article reviews the most recent publications of computer-assisted reconstruction using bony free flaps, emphasizing on comparative reports using these novel techniques. RECENT FINDINGS: Computer-aided reconstruction has shown some benefits in comparison with traditional techniques and some of the perceived limitations are currently being addressed in the latest reports. Still, there is a lack of appropriate comparative studies and unblinded measurements to establish solid conclusions. SUMMARY: Despite the application of new technologies showed encouraging results, it is premature to state that the traditional technique should be replaced by the modern approaches. PMID- 30028748 TI - Comparison of Visual Acuity Outcomes Between Nanothin Descemet Stripping Automated Endothelial Keratoplasty and Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To compare the visual outcomes and complications between nanothin Descemet stripping automated endothelial keratoplasty (NT-DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). METHODS: A prospective comparative case series of 28 consecutive cases of NT-DSAEK (less than or equal to 50 MUm) and DMEK was undertaken. Inclusion criteria were a diagnosis of Fuchs dystrophy, presence of pseudophakia, or planned combined cataract surgery/endothelial keratoplasty, with a minimum of 6-month follow-up. Exclusion criteria were any concurrent ocular comorbidities. Primary outcomes measures were best spectacle corrected visual acuity (BSCVA) and complications. RESULTS: Mean thickness of NT DSAEK grafts was 41.0 +/- 7.5 MUm (range 26-50 MUm). At 1 month postoperatively, the DMEK group had significantly better mean BSCVA of 0.18 +/- 0.20 logarithm of the minimum angle of resolution (logMAR) (20/33) compared with 0.28 +/- 0.16 logMAR (20/40) for NT-NSAEK (P = 0.049). At 3, 6, and 12 months postoperatively, mean BSCVA was comparable between both groups [3 months: NT-DSAEK 0.17 +/- 0.12 logMAR (20/30) versus DMEK 0.13 +/- 0.17 (20/27), P = 0.31; 6 months: NT-DSAEK 0.11 +/- 0.10 logMAR (20/26) versus DMEK 0.09 +/- 0.10 (20/25), P = 0.63; 12 months: NT-DSAEK 0.07 +/- 0.09 logMAR (20/24) versus DMEK 0.07 +/- 0.11 logMAR (20/24), P = 0.95]. Other than 1 NT-DSAEK graft that was successfully rebubbled, no other complications were encountered in either group. CONCLUSIONS: Compared with DMEK, NT-DSAEK provides comparable visual outcomes and complications rates. PMID- 30028749 TI - Anterior Segment Changes After Femtosecond Laser-Assisted Implantation of a 355 Degree Intrastromal Corneal Ring Segment in Advanced Keratoconus. AB - PURPOSE: To study anterior segment changes after implantation of a Keraring with a 355-degree arc length in central advanced keratoconus. METHODS: Thirty eyes of 22 patients with advanced central keratoconus (grade 3) and absent corneal scarring underwent femtosecond laser-assisted (VisuMax) implantation of a Keraring 355-degree arc length intrastromal corneal ring segment (ICRS) with a segment thickness of 300 MUm. Comprehensive ocular evaluations were performed preoperatively and postoperatively to assess uncorrected distance visual acuity, corrected distance visual acuity, K1, K2, Kmax, corneal volume, anterior chamber depth, corneal elevations, and actual segment position 6 months after the procedure. RESULTS: Corrected distance visual acuity in decimal notation improved significantly from 0.22 +/- 0.17 to 0.49 +/- 0.22 (P < 0.01). Statistically significant changes were found in the measured parameters with marked reconstruction of the cornea and anterior chamber. However, the actual depth percent of the ring segment was 61.7% +/- 5.9%, which was shallower than the intended depth of 80% of corneal thickness. CONCLUSIONS: These findings may help explain the marked improvement in visual parameters obtained from the Keraring 355 degrees in advanced central keratoconus. In addition, these types of rings may be a safe, effective, and minimally invasive way to avoid corneal grafting in advanced keratoconus with a clear cornea. PMID- 30028750 TI - Human Corneal Changes After Rose Bengal Photodynamic Antimicrobial Therapy for Treatment of Fungal Keratitis. PMID- 30028751 TI - Median Nerve Symptoms, Signs, and Electrodiagnostic Abnormalities Among Working Adults. AB - INTRODUCTION: Diagnostic screening tests for carpal tunnel syndrome (CTS) have not been rigorously assessed in large populations. METHODS: This study is a cross sectional analysis from a prospective cohort study. Participants' (n = 1,194) symptoms and disease prevalence were measured. Sensitivity, specificity, and positive and negative predictive values (NPVs) were calculated. RESULTS: When defining CTS as tingling/numbness in at least two median nerve-served digits and an abnormal median nerve conduction study, the prevalence was 8.9%. The sensitivity of paresthesias with nocturnal awakening was 77.4%. The sensitivity of the Phalen sign was 52.8% and that of the Hoffman-Tinel sign was only 37.7%. DISCUSSION: The highest sensitivity (77.4%) for a case definition of CTS in this population of workers was for nocturnal tingling/numbness in a median nerve distribution, and the highest specificity (97.5%) was for continuous tingling/numbness. The Phalen sign has a sensitivity of 52.8% and NPV of 95%, suggesting that the NPV is of particular diagnostic value. Hoffman-Tinel signs seem primarily helpful for the NPV (93.7%). LEVEL OF EVIDENCE: Level II diagnostic study. PMID- 30028752 TI - Financial Implications of Atypical Mycobacterial Infections After Cosmetic Tourism: Is It Worth the Risk? AB - BACKGROUND: Cosmetic tourism has become increasingly popular despite many associated risks. The economic impact of atypical mycobacterial infections in cosmetic tourism is poorly defined in the literature. We sought to investigate the costs and clinical course of patients with these infections. METHODS: A retrospective review of all patients managed by the Plastic Surgery Division at Columbia University Medical Center from 2013 to 2014 with atypical mycobacterial surgical site infections after cosmetic surgery outside the United States was performed. Data including patient demographics, procedure costs, clinical course, impact on daily life, and costs associated with complications were collected using hospital billing information, patient questionnaires, telephone interviews, and clinical charts. Cost analysis was done to identify the personal and societal costs of these complications. RESULTS: Data from 10 patients were collected and analyzed. Management of mycobacterial infections cost an average of $98,835.09 in medical charges. The indirect cost of these infections was $24,401 with a mean return to work time of 6.7 months. Total patient savings from cosmetic tourism was $3419. The total cost of a mycobacterial infection was greater than $123,236.47. Although the incidence of mycobacterial infection abroad is unknown, the potential cost of an infection alone outweighs the financial benefits of cosmetic tourism if the risk exceeds 2.77%. CONCLUSIONS: Atypical mycobacterial infections as a result of cosmetic tourism come at considerable cost to patients and the health care system. When our results are taken into consideration with other risks of cosmetic tourism, the financial risks likely far outweigh the benefits. PMID- 30028753 TI - Response to the Letter to the Editor. PMID- 30028754 TI - Curcumin and Biodegradable Membrane Promote Nerve Regeneration and Functional Recovery After Sciatic Nerve Transection in Adult Rats. AB - BACKGROUND: Curcumin has immunomodulatory anti-inflammatory, antioxidant, and neuroprotective properties. The goal of this study was to determine the effects of curcumin and biodegradable membrane on nerve healing in rat sciatic nerve transected injuries. METHODS: Rats were divided into groups: (1) control group (Ctrl), (2) curcumin group (Cur), (3) membrane group (Mem), and (4) membrane and curcumin group (Mem + Cur). Functional recovery was evaluated at 2, 4, 6, and 8 weeks after surgery. At the end of the eighth week after surgery, histological assessments were done. RESULTS: At the end of 8th week after surgery, functional assessments (sciatic nerve index, withdrawal reflex latency, and electromyography) in the Mem + Cur group improved compared with other groups (P < 0.05). Histological results (number of nerve fibers, diameter of nerve fibers, and myelin thickness) improved in the Mem + Cur group compared with the control, Cur, and Mem groups (P < 0.05). CONCLUSION: The present study showed the positive effects of Mem + Cur on nerve regeneration of transected sciatic nerve in rat model. PMID- 30028755 TI - Understanding the Anatomy of the Transverse Nasalis Aponeurotic Fibers and Its Importance in Asian Rhinoplasty. AB - BACKGROUND: A complete release of the transverse nasalis aponeurotic fibers (TNAFs) during Asian rhinoplasty is critical for accurate positioning of the nasal implant and lengthening of the short nose. The objectives of this article are to clarify the anatomy of the TNAFs using cadaveric dissections and to present the clinical results after complete TNAF release in Asian rhinoplasty. METHODS: An anatomical dissection was performed in 8 cadavers to study the TNAFs, specifically the origin, insertion, and boundary of the TNAFs and the effect of the TNAF release on nasal length. Between January 2012 and December 2014, 2314 open implant augmentation rhinoplasties (1777 primary and 537 secondary) were performed by the senior author (J.J.). The records of these patients were retrospectively reviewed for results of TNAF release. A separately designed prospective clinical study was performed to document the nasal envelope extension after TNAF release in 52 consecutive patients. RESULTS: In the cadaver study, the anatomy and the boundaries of the TNAFs were clearly visualized and documented. With accurate release of the TNAFs, the ideal pocket for nasal implant can be defined, and the effect of the release of the TNAFs recorded. Release of the TNAFs also allows extension of the nasal envelope. However, measurements of the nasal envelope were not studied in the cadaver because the skin was degloved.From the clinical study with a follow-up ranging from 6 months to 1.5 years, the overall complication of open rhinoplasty using silicone implants incorporating TNAF release was 6%. In this group, 3.4% of patients required revision rhinoplasty. Releasing the TNAFs ensures an accurate implant pocket reducing the risk of implant deviation and implant visibility and increases the nasal length by 2.1 mm. CONCLUSIONS: Complete release of the TNAFs is especially important in Asian rhinoplasty to facilitate accurate pocket dissection, allowing the extension of the nasal envelope in order to correct short nose or secondary contracted nose. PMID- 30028756 TI - Breast Reconstruction May Improve Work Ability and Productivity After Breast Cancer Surgery. AB - OBJECTIVE: The aim of this study was to evaluate work ability and productivity in women who had undergone different types of surgical treatment for breast cancer, as well as breast reconstruction after mastectomy. METHODS: This cross-sectional study assessed 152 women between 30 and 60 years of age, who worked outside the home in formal or informal jobs, or as self-employed. Thirty-eight of them had no history of breast cancer (control group), and 114 had undergone surgical treatment for breast cancer at least 1 year before their enrollment in the study, and were allocated as follows: mastectomy group (n = 38), breast-conserving surgery group (n = 38), or breast reconstruction breast reconstruction group (n = 38). The validated Brazilian versions of the Work Productivity and Activity Impairment-General Health questionnaire and Work Limitations Questionnaire were self-administered. RESULTS: The groups were homogeneous regarding age, education level, and other sociodemographic characteristics. Patients in the mastectomy and breast-conserving surgery groups showed reduced work performance and productivity compared with women in the breast reconstruction and control groups (P = 0.0004 and P = 0.0006, respectively). In addition, women in the mastectomy group had more difficulty in performing activities of daily living compared with those in other groups (P = 0.0121). CONCLUSIONS: Women who had undergone mastectomy or breast-conserving surgery had decreased work ability and productivity compared with women without a history of breast cancer and to those who had undergone breast reconstruction. PMID- 30028757 TI - Current Practices for Multimodal Pain Management Using Liposomal Bupivacaine in Extracapsular and Intracapsular Hip Fracture Surgery: Expert Panel Opinion. AB - BACKGROUND: Liposomal bupivacaine (LB) has demonstrated efficacy across a range of surgical settings, including shoulder, knee, and hip surgery. However, data are limited on the use of LB as part of a multimodal pain management approach in hip fracture surgery. METHODS: On April 1, 2017, 4 orthopaedic surgeons and 3 anesthesiologists convened to discuss current practices and develop a consensus statement related to local infiltration analgesia with LB for hip fracture surgical procedures within the context of a multimodal opioid-sparing pain management approach. Separate workshops addressed intracapsular and extracapsular hip fracture surgery. RESULTS: Multimodal strategies before, during, and after hip fracture surgery are paramount to optimizing pain control and minimizing opioid requirements. LB infiltration should occur intraoperatively near the time of closing the incision. For both intracapsular and extracapsular procedures, oral or intravenous acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID) of choice, and tramadol should be given preoperatively. Presurgical fascia iliaca block with bupivacaine HCl may help bridge the period before LB takes effect. After both procedures, patients should receive 1 dose of intravenous acetaminophen, an NSAID, and opioid rescue medication as needed, starting with tramadol. Postoperative NSAIDs may help minimize opioid use. Patient and provider education are integral to managing patient expectations and alleviating concerns about pain and opioid use. Standardized, validated, and appropriately timed pain assessments are also necessary to optimize postsurgical pain management. CONCLUSIONS: These consensus recommendations regarding multimodal pain management protocols incorporating local infiltration analgesia with LB for extracapsular and intracapsular hip fracture procedures serve as a basis for additional research. LEVEL OF EVIDENCE: Level V. PMID- 30028758 TI - Infiltration Techniques for Local Infiltration Analgesia With Liposomal Bupivacaine in Extracapsular and Intracapsular Hip Fracture Surgery: Expert Panel Opinion. AB - BACKGROUND: Liposomal bupivacaine (LB) has demonstrated efficacy in improving pain scores and reducing opioid consumption across a variety of surgical settings, including orthopaedic surgery. However, meticulous infiltration techniques combined with a multimodal approach are important to optimizing outcomes. METHODS: A panel of 4 orthopaedic surgeons and 3 anesthesiologists convened on April 1, 2017, to discuss current practices and develop a consensus statement regarding local infiltration analgesia with LB for extracapsular and intracapsular hip fracture surgery, including LB infiltration techniques. RESULTS: Optimizing surgical outcomes with LB in hip fracture surgery requires an understanding of the neuroanatomy of the surgical site and the pharmacology of the drug. Meticulous infiltration technique is critical to achieve optimal results with LB given its viscosity and reduced diffusion compared with bupivacaine HCl. For extracapsular procedures, a total injection volume of 120 mL is recommended, whereas intracapsular procedures typically require a lower volume (~80 mL). In both cases, infiltration is best achieved using a 22-gauge needle and applying a tracking and/or fanning technique. To ensure optimal placement, LB should be infiltrated using multiple, small-volume (1- to 5-mL) injections spaced at 1.0-cm intervals. CONCLUSIONS: These consensus recommendations regarding LB infiltration techniques can serve as a resource for designing clinical studies to evaluate outcomes using periarticular infiltration of LB in extracapsular and intracapsular hip fracture surgery as part of a multimodal pain management approach. LEVEL OF EVIDENCE: Level V. PMID- 30028759 TI - Multimodal Pain Strategies Including Liposomal Bupivacaine for Isolated Acetabular Fracture Surgery. AB - BACKGROUND: The incidence of isolated acetabular fractures has been increasing, particularly in older adult patients. These fractures can be debilitating and may require prolonged immobilization and/or complex surgical reconstruction. Liposomal bupivacaine (LB) is a prolonged-release form of bupivacaine demonstrated to be effective in orthopaedic surgery. Defining a multimodal pain management plan, which incorporates optimized techniques for use of LB in acetabular surgery, may improve outcomes for patients. METHODS: Two orthopaedic surgeons specializing in orthopaedic traumatology discussed best practices for infiltration of LB and recommendations for perioperative use of LB plus other anesthetics/analgesics for isolated acetabular fracture surgery. RESULTS: Consensus techniques for isolated posterior and anterior acetabular fractures were developed. LB (266 mg/20 mL) should be expanded with 50 mL of bupivacaine HCl 0.25% and saline to a total volume of 120 or 300 mL for the posterior or anterior techniques, respectively. A 3.5-inch spinal needle is inserted tangentially, infiltrating 1 mL/cm into the fracture site, periosteum, muscle fascia, subcutaneous tissue, and skin. Patients receive acetaminophen, celecoxib, gabapentin, and opioids before surgery, adjusting appropriately for patient comorbidities and potential drug-drug interactions. At the end of the surgery, before closure, LB is infiltrated and patients receive a dose of intravenous acetaminophen. Presurgical medications are continued after surgery for approximately 10-14 days, after which opioids are only considered to treat breakthrough pain. CONCLUSIONS: These recommendations can be used to optimize and streamline care for patients with isolated acetabular fractures and act as a foundation for additional clinical research. LEVEL OF EVIDENCE: Therapeutic Level V. PMID- 30028760 TI - Fibrous Papule: A Histopathologic Review. AB - Fibrous papule (FP) is a common benign lesion located primarily in the nose. Although its histogenesis has been marred with controversies in the past, the dermal dendrocyte is now largely accepted to be the putative cell of origin. Histopathologic diagnosis of an FP is straightforward in most cases, which shows characteristics of an angiofibroma. Several histologic variants have been described, recognition of which is important to avoid a misdiagnosis and inappropriate treatment. This review presents a historical perspective into the histogenesis, discusses the histopathologic features and potential diagnostic pitfalls of classic FP, and lists the various histologic variants and their differential diagnoses. PMID- 30028761 TI - A Painful Firm Plaque on the Midback of a 53-Year-Old Woman: Answer. PMID- 30028762 TI - Multiple Tumors on the Extremities: Answer. PMID- 30028763 TI - A Painful Firm Plaque on the Midback of a 53-Year-Old Woman: Challenge. PMID- 30028764 TI - Establishing Frameworks for Quality and Safety Education for Nurses Competency Integration. PMID- 30028765 TI - Transforming Health Care Through Meaningful Doctor of Nursing Practice Community Partnerships. AB - BACKGROUND: A critical component of doctor of nursing practice (DNP) education is practice immersion. DNP programs require 1000 hours of clinical practice experience to obtain the DNP degree. PROBLEM: Faculty struggle with providing meaningful clinical experiences congruent with the role of the DNP. APPROACH: This article describes a unique practice immersion course joining DNP students with community health care partners to provide meaningful experiences with the potential to transform health care. DNP students are assigned system-level projects designed to create organizational change. OUTCOMES: Over the course of 4 years, the practice immersion opportunities more than doubled from 30 to 66 live projects. Integrating collaborative practice immersion into the curriculum builds students' leadership skills and strengthens long-standing bonds among academia, practice, and the community. CONCLUSIONS: The creation of structured, meaningful collaborations between DNP students and community partners is an approach that has the potential to facilitate transformative, sustainable change in health care. PMID- 30028766 TI - Nursing Students' Perceptions of Skills Learning: A Phenomenological Study. AB - BACKGROUND: Deliberate practice (DP) and cognitive load theory have renewed educators' interest in effective psychomotor skills teaching. PURPOSE: The purpose of this research was to explore how prelicensure nursing students learned psychomotor skills. METHODS: Nine senior nursing students participated in this phenomenological study to capture how they experienced learning nursing skills. Colaizzi's method was used to analyze in-depth interviews of open-ended questions. RESULTS: Six themes emerged: (a) the umbrella of emotion, (b) practice, (c) learning through technology, (d) fidelity affects learning, (e) teaching matters, and (f) importance of peers. Students found creative ways to learn nursing skills. Research findings contributed to a greater understanding of student experiences in gaining competency in nursing skills. CONCLUSIONS: Participants used aspects of DP, cognitive load theory, and technology to learn skills. These findings provide current information to nurse educators about skills learning and recommendations for effective skills teaching. PMID- 30028767 TI - Improving Venous Thromboembolism Prophylaxis Administration Within an Acute Surgical Unit. AB - OBJECTIVES: Venous thromboembolism (VTE) prophylaxis regimes frequently have a wide variation in application. Nepean acute surgical unit was established in 2006 as a novel model for emergency surgical care. As part of the model's rollout, there were several areas of clinical management targeted for improvement, one being VTE prophylaxis compliance. It was decided all patients older than 18 years treated for a variety of acute surgical conditions within the acute surgical unit should be administered routine VTE prophylaxis with heparin and compression stockings. A novel multifaceted intervention was implemented at the time to achieve this goal. The primary aim of this study was to determine VTE prophylaxis administration rates before and after this intervention. METHODS: A before-after study conducted as a retrospective review of medical records of all patients 18 years or older, having an appendicectomy in 3 periods: Before acute surgical unit (ASU) (November 2004 to October 2006), Early ASU (November 2006 to October 2008), and Established ASU (January 2012 to December 2013). Outcomes were mechanical and pharmacological VTE prophylaxis administration rates for each group. RESULTS: There were 1149 patients included in the study: Before ASU, 167; Early ASU, 375; and Established ASU, 607. There was a significant stepwise increase in parmacological VTE prophylaxis administration: Before ASU, 54.5%; Early ASU, 74.7%; and Established ASU, 96.9% (Before versus Early: odds ratio [OR], 2.46; 95% confidence interval [CI], 1.68-3.61; P < 0.001; Early versus Established: OR, 10.500; 95% CI, 6.29-17.53; P < 0.001). Mechanical VTE prophylaxis was significantly increased in the established group (Before versus Established: OR, 47.18; 95% CI, 25.61-86.91; P < 0.001). CONCLUSIONS: There was a significant increase in VTE prophylaxis administration after the implementation of our multifaceted intervention. Allocating a responsible provider dedicated to VTE prophylaxis prescription and compliance checking was a key component to this intervention. PMID- 30028768 TI - Recognizing and treating Lyme disease. AB - Lyme disease is the most commonly reported vector-borne disease in the United States. After initial antibiotic treatment for patients with Lyme disease, ongoing symptoms that may persist have considerable long-term impact on healthcare costs. Posttreatment Lyme disease syndrome is characterized by a host of chronic symptoms that can leave patients physically and mentally disabled. PMID- 30028770 TI - Managing sexually transmitted infections: Beyond the 2015 guidelines. PMID- 30028769 TI - The emotional burden of diabetes: A look at diabetes distress. AB - Patients with diabetes are sometimes overwhelmed with the burden of self-care associated with the disease. Although it may seem appropriate to diagnose patients experiencing such emotional burdens with depression, the literature over the past 20 years has matured the concept of diabetes distress, which may more accurately describe the phenomenon. PMID- 30028771 TI - Mind & body practices in the treatment of adolescent anxiety. AB - Although anxiety is the most common mental health condition among adolescents in the United States, the current standards of practice for treatment are expensive, may be difficult to obtain, and potentially harmful. Although mind and body practices show great promise in the treatment of adolescent anxiety, financial constraints, lack of education, and structural barriers can hinder the integration of these practices into primary care. PMID- 30028772 TI - Mind & body practices in the treatment of adolescent anxiety. PMID- 30028773 TI - Low health literacy: Implications for managing cardiac patients in practice. AB - There are limited data on racial and ethnic disparities related to quality of life (QoL) and health literacy in adults with multiple cardiac conditions. This article evaluates the relationship between health literacy and QoL among patients with cardiac conditions in a multiethnic community in New York City. PMID- 30028775 TI - Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis. AB - The association between the long-term use of proton pump inhibitors (PPIs) and the risks of various diseases remains controversial. Therefore, the primary objective of this study was to quantify the associations as presented in the literature and to also provide this information to healthcare professionals and patients about their potentially adverse effects. In July 2016, we searched through Medline (PubMed), Embase, and the Cochrane Library from inception using common keywords. We included observational studies that provided risk estimates on the long-term use of PPIs and their adverse effects. Overall, 43 studies were included in the systematic review, of which 28 studies were also included in the random effect meta-analysis. Odds of community-acquired pneumonia, hip fracture, and colorectal cancer were 67% [odds ratio (OR)=1.67; 95% confidence interval (CI): 1.04-2.67], 42% (OR=1.42; 95% CI: 1.33-1.53), and 55% (OR=1.55; 95% CI: 0.88-2.73) higher in patients with long-term PPIs use compared with patients who did not use PPIs. Although the use of PPIs provides short-term health benefits, their prolonged use is associated with minor and also potentially major adverse health outcomes. Hence, we strongly recommend that the prescription of PPIs should be done with caution to improve the medication's efficacy and patients' safety. PMID- 30028776 TI - High proportions of liver fibrosis and cirrhosis in an ageing population of people who use drugs in Amsterdam, The Netherlands. AB - BACKGROUND: The incidence and prevalence of hepatitis C virus (HCV) infection among people who use drugs (PWUD) peaked in the 1980s in Amsterdam. As liver cirrhosis develops several decades after HCV infection and PWUD have other risk factors for liver fibrosis, we hypothesized that significant liver fibrosis or cirrhosis is now common among PWUD in Amsterdam. METHODS: PWUD were recruited from the Amsterdam Cohort Studies, methadone programmes and addiction clinics during 2009-2016. Transient elastography was performed to assess liver stiffness. We estimated METAVIR fibrosis levels on the basis of the following liver stiffness measurements (LSMs) cut-offs: F0-F2 (no/mild) less than 7.65 kPa; F2-F3 (moderate/severe) at least 7.65 to less than 13 kPa; and F4 (cirrhosis) at least 13 kPa. Using linear regression models, we assessed the association between LSM and sociodemographic, clinical and behavioural determinants in (a) all PWUD and (b) chronic hepatitis C virus (cHCV)-infected PWUD. RESULTS: For 140 PWUD, the median LSM was 7.6 kPa (interquartile range=4.9-12.0); 26.4% had moderate/severe fibrosis and 22.9% had cirrhosis. Of 104 chronically infected PWUD, 57.7% had evidence of significant fibrosis (>=F2). In multivariable analysis including all PWUD, increased LSM was associated significantly with cHCV monoinfection and HIV/HCV coinfection. In cHCV-infected PWUD, older age was associated significantly with increased LSM. In all groups, longer duration of heavy alcohol drinking was associated with increased LSM. CONCLUSION: A high proportion of PWUD had significant fibrosis or cirrhosis that were associated with cHCV infection, HIV/HCV coinfection and duration of heavy alcohol drinking. Increased uptake of HCV treatment and interventions to reduce alcohol use are needed to decrease the liver disease burden in this population. PMID- 30028777 TI - Klippel-Feil Syndrome with Auxiliary Anterior Cervical Meningomyelocele and Thoracic Syringomyelia: A Case Report. AB - STUDY DESIGN: Case report. OBJECTIVES: Since this is the first ever case of a male patient with Klippel-Feil syndrome with anterior cervical meningomyelocele and syringomyelia. All four previously reported cases were female patients. This makes this case unique. SUMMARY OF BACKGROUND DATA: Klippel-Feil syndrome with auxiliary anterior cervical meningomyelocele is a rare entity. To best of our knowledge so far only four cases are reported. METHODS: A 22-year-old male patient was presented to neurology outpatient department with two years history of left- hand paresthesia and progressive weakness. The diagnostic evaluation showed Klippel-Feil syndrome with auxiliary anterior cervical meningomyelocele and thoracic syringomyelia. RESULTS: Patient was sent to neurosurgery department for intervention. After discussing the possible risks & complications of intervention he opted for conservative therapy and declined the surgery. CONCLUSIONS: The paucity of data is the key reason for any recommended protocol for management of such patients but the available literature recommends neurosurgical intervention in symptomatic patients. LEVEL OF EVIDENCE: 5. PMID- 30028778 TI - Increased Proportion of Fusion Surgery for Degenerative Lumbar Spondylolisthesis and Changes in Reoperation Rate: A Nationwide Cohort Study with a Minimum 5-Year Follow-Up. AB - STUDY DESIGN: A retrospective cohort study OBJECTIVE.: The objectives of the present study were to examine the changes in the number of surgeries, surgical methods selected and reoperation rates between the years 2003 and 2008. SUMMARY OF BACKGROUND DATA: The selection of the appropriate surgical method between decompression only (D) and decompression plus fusion (DF) represents a challenging clinical dilemma in patients with degenerative lumbar spinal spondylolisthesis (DLS). DF is selected in greater than 90% of patients, mostly due to the associated low reoperation rate. However, the outcomes of D have been improved with minimally invasive decompression surgery techniques. METHODS: The Health Insurance Review & Assessment Service database was used to create cohorts of all Korean patients who underwent surgery for DLS in 2003 (2003-cohort, n = 5,624) and 2008 (2008-cohort, n = 11,706). All patients were followed up for at least 5 years. Reoperation was defined as the occurrence of any type of second lumbar surgery during the follow-up period. The probabilities of reoperation were calculated using the Kaplan-Meier method. RESULTS: The number of surgeries increased 2.08-fold in 2008. Patients greater than 60 years old comprised 38.6% of the 2003 cohort and 52.4% of the 2008-cohort. The proportion of DF surgery was 31.13% in the 2003-cohort but 91.54% in the 2008-cohort. However, the high proportion of fusion surgery failed to reduce the reoperation probability in the 2008-cohort (8.1%) compared with that in the 2003-cohort (6.2%). The cost of DF was US$5,264 and that of D was $2,719 in 2008. DF decreased the reoperation probability by 1% at the cost of $421/patient in the 2008-cohort. CONCLUSIONS: The increased proportion of fusion surgery without improvement in reoperation probability in an aging society may be cautiously addressed in deciding future health policies. LEVEL OF EVIDENCE: 4. PMID- 30028780 TI - Effect of Sideritis leptoclada against HT-144 human malignant melanoma. AB - Sideritis leptoclada O. Schwarz et P.H. Davis extracts were evaluated for its singlet oxygen production capacity using spectrophotometric method. The extracts producing singlet oxygen were then evaluated for cytotoxicity against malignant melanoma cancer (HT-144) and fibroblast (3T3) cell lines using the 3-[4,5 dimethylthiazole-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. The photocytotoxicity against the HT-144 human melanoma cell line in the presence of illumination (~>=400 nm) was also evaluated. In the standard MTT assay, the ethanol extract of S. leptoclada (100 ug/ml) showed 83.49+/-3.33% inhibition of HT-144 cancer cells, whereas in the illuminated MTT assay, it showed 77.46+/ 1.97% inhibition of HT-144 cancer cells. The effects of ethanol extract on reactive oxygen species production, apoptosis, and tumor necrosis factor-alpha secretion were also evaluated on HT-144 cell lines. The extract triggered an increase in intracellular reactive oxygen species production and tumor necrosis factor-alpha secretion compared with the respective controls. Thus, the ethanol extract may cause apoptosis. The LC-MS/MS analyses of S. leptoclada ethanolic extract showed that it has quinic acid (137213+/-11.25 ug/g extract), malic acid (1468+/-0.16 ug/g extract), chlorogenic acid (881.7+/-0.06 ug/g extract), and apigetrin (223.2+/-0.13 ug/g extract) as major constituents. The ethanolic extract of S. leptoclada should be further investigated as a potential treatment for malignant melanoma cancer. PMID- 30028779 TI - Female genitourinary tract melanoma: mutation analysis with clinicopathologic correlation: a single-institution experience. AB - Female genitourinary tract melanoma (FGTM) is a rare and often-fatal form of mucosal melanoma. We describe our institutional experience with 55 cases of FGTM, 16 of which were evaluated with next-generation sequencing targeting 151 cancer associated genes. Tumors tended to be thicker than conventional melanoma at presentation (median: 3.2 mm), were frequently ulcerated (50%), and characterized by incomplete initial resections. Regional lymph nodes showed tumor involvement at presentation in 28% of cases. With a median follow-up of 23.6 months, the median recurrence free survival was 14.5 months and the median overall survival was 29.6 months. Genomic analysis revealed mutually exclusive mutations in TP53 and KIT in 25%, while 19% of cases showed BRAF mutation. NRAS mutation was found in 13% of cases. Mutation in ATRX, previously undescribed in mucosal melanoma, was seen in three (10%) of 16 patients. Only invasive melanoma cases were included in statistical analyses. Patients with three or more mutations had marginally worse overall survival rates than those with two or less (P=0.07). Further studies are required for potential adjuvant treatment modalities to improve survival outcomes of FGTM. PMID- 30028781 TI - Discharge Plasma Activated Saline Protects Against Abdominal Sepsis by Promoting Bacterial Clearance. AB - AIM: The aim of the present study was to investigate the effect of cold atmospheric discharge plasma activated saline (DPAS) on abdominal sepsis. METHODS: For in vitro research, Methicillin-resistant Staphylococcus aureus (MRSA) was treated with DPAS, and the survival was detected. For in vivo research, male C57BL/6 mice were induced to sepsis by cecal ligation and puncture (CLP) and were randomly allocated into Saline and DPAS control groups, CLP group, low or high doses of DPAS (CLP + DPAS 5 and CLP + DPAS 10) groups. In experiment 1, mice were monitored for 120 h to conduct a Kaplan-Meier survival curve analysis. In experiment 2, blood, peritoneal fluid, and lung and intestinal tissues in experimental groups were collected at 4, 8 and 24 h after the CLP/sham operation to determine the severity of sepsis. RESULTS: In vitro results showed that DPAS significantly inhibited MRSA proliferation. In vivo results showed that both low and high doses of DPAS could significantly improve septic survival in the mice. DPAS treatment also significantly attenuated the lung and intestine histopathological injuries; lung wet/dry ratio; inflammatory reaction; bacterial load in the peritoneal cavity, blood and lungs; HMGB1 and NF-kappaB p65 expression levels, cell apoptosis in the lung and intestine. However, there was no difference between CLP + DPAS 5 and CLP + DPAS 10 groups. CONCLUSION: In conclusion, DPAS had markedly protective effects on abdominal sepsis in mice, and the potential mechanism was associated with the ability of reactive species in DPAS to promote bacterial clearance, inhibit the inflammatory response and cell apoptosis. PMID- 30028782 TI - Etoposide and Corticosteroid Combination Therapy Improves Acute Respiratory Distress Syndrome in Mice. AB - Excessive inflammation reactions with a cytokine storm in the lungs have historically been thought as the primary cause of fatal acute respiratory distress syndrome (ARDS). However, interruption of inflammatory cytokine activation failed to attenuate ARDS, suggesting that other therapies are required to treat this illness and improve survival. Etoposide (ET), a cytotoxic agent, and prednisolone (PSL), a corticosteroid with strong anti-inflammatory activity, have been used to treat other disease involving similar cytokine-activated macrophages and hemophagocytic activity. However, they have not been previously tested as ARDS therapeutics alone or in combination. In the present study, we used a fatal ARDS mouse model induced via administration of alpha Galactosylceramide and lipopolysaccharide, which resulted in the development of severe lung injury with hypercytokinemia and hemophagocytosis, all of which were observed in ARDS patients infected with highly pathogenic respiratory viruses. The ET and PSL combination therapy, but not ET or PSL alone, reduced the recruitment and activation of inflammatory cells including macrophages, NKT cells and neutrophils, and significantly improved the survival rate in this model. Furthermore, while ET alone improved lung edema, it did not increase the survival rate, indicating the necessity of PSL in the treatment of ARDS. Surprisingly, combination therapy did not reduce the production of cytokines and chemokines in the lungs, demonstrating that inflammatory cells, rather than hypercytokinemia, is the direct target of these compounds and is the primary cause of ARDS-related death. Thus, combination therapy with ET and PSL that targets inflammatory cells has the potential to attenuate fatal ARDS. PMID- 30028783 TI - Thirty-Day Acute Health Care Resource Utilization Following Outpatient Anterior Cruciate Ligament Surgery. AB - BACKGROUND AND OBJECTIVES: The need for hospital-based acute care following outpatient surgical procedures is expensive and measured as marker for quality. However, little information is available about events leading to emergency department visit or inpatient admission after ambulatory anterior cruciate ligament (ACL) surgery. METHODS: We studied adult patients who underwent outpatient ACL surgery in New York State between 2009 and 2013 using the Healthcare Cost and Utilization Project database. Emergency department visits and inpatient admissions within 30 days of surgery were identified by cross-matching 2 additional independent Healthcare Cost and Utilization Project databases. RESULTS: The final cohort included 26,873 subjects. We identified 1208 (3.90%; 95% confidence interval [CI], 3.6%-4.1%) secondary health care encounters of interest. The majority of these encounters were emergency department visits (951). The most common reasons were musculoskeletal pain (349 [28.9%]), any infection (122 [10.1%]), drug abuse (98 [8.1%]), wound infection (87 [7.2%]), deep venous thrombosis (77 [6.4%]), and psychotic events (54 [4.5%]). Patients operated on in high-volume surgical centers were less likely to require acute care (odds ratio, 0.47; P < 0.001; 95% CI, 0.34-0.63), whereas Medicare/Medicaid patients carried higher odds (odds ratio, 2.52; 99% CI, 2.07-3.07). CONCLUSIONS: The rate of hospital-based acute care following outpatient ACL surgery was 3.90%. Many of the events were expected complications related to surgery, such as infection and deep venous thrombosis. However, musculoskeletal pain, drug abuse, and psychotic events featured more prominently than expected. Our findings may direct efforts to address these reasons for seeking acute care after ACL surgery, reduce cost, and improve quality of care. PMID- 30028784 TI - Cardiac Surgery-Associated Kidney Injury in Children and Renal Oximetry. AB - OBJECTIVES: Cardiac surgery-associated acute kidney injury is common in children and associates with negative outcomes. Novel interventions to reduce cardiac surgery-associated acute kidney injury require knowledge of its pathophysiology. States of altered perfusion, oxygen delivery, and energy consumption occur during cardiopulmonary bypass and could protect against or contribute to renal cellular injury and recovery. Near-infrared spectroscopy is noninvasive technology for monitoring regional blood flow and tissue oxygenation. This study evaluated the relationship between renal regional oxygen saturation and cardiac surgery associated acute kidney injury, using near-infrared spectroscopy monitoring before, during, and after cardiopulmonary bypass in children. DESIGN: Prospective cohort study. SETTING: Single-center, tertiary care pediatric hospital (Stollery Children's Hospital, Edmonton, AB, Canada). PATIENTS: Children less than or equal to 10 kg undergoing congenital heart disease repair with cardiopulmonary bypass. Heart transplant, preoperative dialysis, sepsis, extracorporeal life support, congenital renal disease, and preoperative nephrotoxins were exclusions. INTERVENTIONS: Renal regional near-infrared spectroscopy monitoring before, during, and after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Outcome measure was cardiac surgery-associated acute kidney injury (defined according to Kidney Disease: Improving Global Outcomes criteria). Regional oxygen saturation was measured continuously using near-infrared spectroscopy (INVOS 5100C Cerebral/Somatic Oximeter; Medronic, Troy, MI) from time of anesthesia to time of transfer to intensive care. Cardiac surgery-associated acute kidney injury occurred in 65%. Lower baseline (precardiopulmonary bypass) regional oxygen saturation was associated with decreased risk of cardiac surgery-associated acute kidney injury (p = 0.01); children with baseline regional oxygen saturation in the highest tertile were 7.14 times more likely to get cardiac surgery- associated acute kidney injury (vs lowest tertile). Area under the curve for ability of baseline regional oxygen saturation to predict cardiac surgery associated acute kidney injury was 0.73 (95% CI, 0.60-0.85). Children with lower baseline glomerular filtration rate had lower mean renal regional oxygen saturation. CONCLUSIONS: Findings demonstrate that preoperative oxygen supply/demand balance is an important predictor of cardiac surgery-associated acute kidney injury, suggesting lower preoperative (and intraoperative) renal blood flow may be protective. There is not yet a definite link between remote ischemic preconditioning and prevention of cardiac surgery-associated acute kidney injury; however, renal protective effects of sublethal ischemia should continue to be explored. PMID- 30028785 TI - Transplant-free Survival in Chronic Liver Disease Presenting as Acute Liver Failure in Childhood. AB - BACKGROUND: in adults, the absence of a preexisting chronic liver disease (CLD) is required to diagnose acute liver failure (ALF). The paediatric classification does not considered this aspect, thus previous studies pooled together children with ALF and children with unknown CLD presenting with acute hepatic decompensation (ALF-CLD). We aimed to compare prevalence, features and outcome of children with ALF-CLD to those with a proper ALF. METHODS: Patients admitted between 1996-2017 because of ALF defined by PALF criteria (raised transaminases, INR >=2.0, no history of liver disease) were classified as ALF-CLD if diagnosed with autoimmune hepatitis (AIH), Wilson disease (WD), Budd-Chiari syndrome, HBV reactivation, inborn errors of metabolism (IEM). The others were classified as ALF. RESULTS: 74 children [median age 4 years, 1.0-8.8, M/F =36/38] with ALF were found ; 18 of <1 year of age were excluded. Fifty-six [median age 6.6 years (2.7 11.7), M/F = 23/33], 22 with ALF-CLD (AIH n=14, WD n=6, IEM n=2) and 34 with ALF (paracetamol overdose n=6, viral infections n=3, mushroom poisoning n=5, indeterminate n=20) were compared. In ALF-CLD the median age at onset was higher, ALT, albumin and INR levels were lower, splenomegaly, ascites and cirrhosis were more common (all p<0.01). On multivariate analysis the diagnosis of ALF-CLD was an independent predictor of transplant free survival (p = 0.006). CONCLUSIONS: In children ALF-CLD is common, has peculiar features and is associated with a favourable outcome. This study suggests the need to distinguish this entity from other forms of ALF in children. PMID- 30028786 TI - A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology. AB - The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward. PMID- 30028787 TI - CLINICAL PRESENTATIONS, DIAGNOSTIC DILEMMA, AND MANAGEMENT OUTCOMES OF CHRONIC POSTOPERATIVE ENDOPHTHALMITIS CAUSED BY STEPHANOASCUS CIFERRII. AB - PURPOSE: To report the diagnosis and management of a series of chronic postoperative endophthalmitis caused by Stephanoascus ciferrii. METHODS: This is a retrospective consecutive case series at a tertiary eye care institute. Case records of consecutive cases of chronic postoperative endophthalmitis caused by a novel fungus S. ciferrii were analyzed. The clinical presentations, microbiologic workup including microscopy, culture, antifungal susceptibility and polymerase chain reaction for fungal DNA of clinical samples, and the clinical management were noted. The cases underwent anterior chamber tap, vitreous biopsy, core vitrectomy, and intraocular lens explantation, and the management consisted of a combination of topical and systemic therapy and intravitreal injections of antimicrobial agents. RESULTS: The report includes four eyes of four patients. All patients were diagnosed as chronic postcataract surgery endophthalmitis, and they showed variable levels of persistent low-grade intraocular inflammation till the intraocular lens was explanted. S. ciferrii (identified by the Vitek 2 compact system) was grown in culture from one or more of the clinical samples such as vitreous, anterior chamber fluid, capular bag, and intraocular lens. Fungal DNA was detected from vitreous in one case. One isolate tested for antifungal susceptibility was resistant to amphotericin B; however, the patient responded to treatment with the drug. Good clinical outcome was achieved in all patients. CONCLUSION: We describe successful treatment of endophthalmitis caused by S. ciferrii. A good response is obtained after pars plana vitrectomy and intraocular lens explantation. PMID- 30028788 TI - TOPICAL DORZOLAMIDE FOR CYSTOID MACULAR EDEMA IN BIETTI CRYSTALLINE RETINAL DYSTROPHY. AB - PURPOSE: To report a case of Bietti crystalline retinal dystrophy with cystoid macular edema (CME) that was successfully treated with topical carbonic anhydrase inhibitor. METHODS: A 35-year-old otherwise healthy woman, with a known case of Bietti crystalline retinal dystrophy, presented with progressive visual impairment in her right eye for 3 months. The best-corrected visual acuity was 20/50 in the right eye and 20/25 in the left eye. On the basis of the multimodal imaging findings, the patient was diagnosed with Bietti crystalline retinal dystrophy with unilateral CME. Carbonic anhydrase inhibitor therapy twice a day was initiated. RESULTS: Three months later, visual acuity improved to 20/25 in the right eye, and CME had resolved based on spectral domain ocular coherence tomography findings, although the CME reoccurred after discontinuation of the drug. Three months after resuming the therapy, the best-corrected visual acuity improved back to 20/25. CONCLUSION: Cystoid macular edema is one of the main causes of central visual worsening in patients with Bietti crystalline retinal dystrophy. This complication may be resolved with topical carbonic anhydrase inhibitor, resulting in improved anatomical and visual outcomes. PMID- 30028789 TI - DISAPPEARING CHOROIDAL MELANOMA ON OPTOS: THE NOSE ARTIFACT. AB - PURPOSE: To illustrate a potentially concerning artifact on Optos wide-angle imaging. METHODS: Case report. RESULTS: A healthy 11-year-old girl, with no medical history, was found to have a lightly pigmented superotemporal choroidal tumor, suspicious for melanoma, which was detected on Optos wide-angle imaging by her optometrist. On referral to the retinal specialist, the mass was not visible on funduscopy. B-scan ultrasonography depicted flat retina and no visible mass. Review of the Optos image revealed that the pseudomelanoma represented the patient's nose. CONCLUSION: Optos wide-angle imaging provides broad retinal imaging; however, artifacts from patient positioning can lead to the nose artifact. PMID- 30028790 TI - Prevalence of chronic pain with or without neuropathic characteristics in France using the capture-recapture method: a population-based study. AB - Capture-recapture methods are increasingly used to determine the prevalence of numerous chronic conditions but have never been used in the context of chronic pain (CP). This study sought to provide up-to-date estimates of the prevalence of people experiencing CP +/- neuropathic characteristics in France using the capture-recapture method. In 2013 to 2015, 3 data sources were used: the French prescription drug database (D-list), the national hospital discharge database (H list), and the French pain center database (P-list). Patients aged 18 years and older treated with analgesic drugs for >=6 months (D-list) or with a diagnosis of CP +/- neuropathic characteristics (H- and P-lists) were included. Two successive capture-recapture analyses were conducted, with log-linear regression for each analysis performed. A total of 63,557 and 9852 distinct cases of CP and chronic neuropathic pain were captured, respectively. The estimated prevalence of CP and chronic neuropathic pain in the adults ranged from 27.2% (95% confidence interval: 26.1-28.4) to 32.7% (26.0-43.3) and from 5.55% (2.89-19.0) to 7.30% (6.40-8.41), respectively. Most patients were female, median ages were 67 (55-80) and 63 (51-76) years for chronic and neuropathic pain, respectively. The analgesic drugs most frequently used in CP patients were paracetamol (62.1%), weak opioids (39.7%), and nonsteroidal anti-inflammatory drugs (32.7%), whereas in neuropathic pain patients, anticonvulsants (45.3%), tricyclic antidepressants (18.1%), and serotonin-norepinephrine reuptake inhibitors (13.3%) were more frequently used. This first electronic health record-based study on CP using the capture-recapture method revealed a high prevalence of CP, with a significant proportion of neuropathic pain patients. PMID- 30028792 TI - EXUDATIVE RETINAL DETACHMENT DOCUMENTED BY HANDHELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY AFTER RETINAL LASER PHOTOCOAGULATION FOR RETINOPATHY OF PREMATURITY. AB - BACKGROUND: Few cases of exudative retinal detachments have been reported in the literature after laser treatment for retinopathy of prematurity, and none of the cases include optical coherence tomography images. METHODS: Case report. RESULTS: A 469-g birth weight, 25-week gestational age baby girl at 35-week postmenstrual age received a retinal laser (1,724 spots in the right eye and 1,287 spots in the left eye) for bilateral Stage 3 Zone II plus disease retinopathy of prematurity. The patient developed a large macular exudative retinal detachment seen in the right eye at the first follow-up, 5 days after the laser. Serial handheld optical coherence tomography demonstrated resolution of retinal detachment and intraretinal fluid over the course of 4 weeks with only topical tobramycin/dexamethasone ophthalmic ointment 3 to 4 times daily for 2 weeks. The patient was left with a residual subretinal scar and outer retinal loss on optical coherence tomography, with a later appearance of a dragged macula on funduscopic examination noted at 52-week postmenstrual age. It is unclear whether systemic steroid therapy, intravitreal bevacizumab, or surgery would hasten resolution of exudative retinal detachment after the retinopathy of prematurity laser and avoid photoreceptor damage seen on optical coherence tomography in this case. CONCLUSION: This case suggests that post-retinopathy of prematurity laser exudative retinal detachments can resolve without aggressive intervention, but may cause permanent retinal sequelae. PMID- 30028791 TI - Long-term changes in biopsychosocial characteristics related to temporomandibular disorder: findings from the OPPERA study. AB - Painful temporomandibular disorders (TMDs) are both consequence and cause of change in multiple clinical, psychosocial, and biological factors. Although longitudinal studies have identified antecedent biopsychosocial factors that increase risk of the TMD onset and persistence, little is known about long-term change in those factors after TMD develops or remits. During a 7.6-year median follow-up period, we measured change in psychosocial characteristics, pain sensitivity, cardiovascular indicators of autonomic function, and clinical jaw function among 189 participants whose baseline chronic TMD status either persisted or remitted and 505 initially TMD-free participants, 83 of whom developed TMD. Among initially TMD-free participants who developed TMD, symptoms and pain sensitivity increased, whereas psychological function worsened. By contrast, participants with chronic TMD at baseline tended to show improved TMD symptoms, improved jaw function, reduced somatic symptoms, and increased positive affect. In general, clinical and psychosocial variables more frequently changed in parallel with TMD status compared with pain sensitivity and autonomic measures. These findings demonstrate a complex pattern of considerable changes in biopsychosocial function associated with changes in TMD status. In particular, several biopsychosocial parameters improved among participants with chronic TMD despite pain persisting for years, suggesting considerable potential for ongoing coping and adaptation in response to persistent pain. PMID- 30028793 TI - Opportunistic CT Screening for Osteoporosis in Patients With Pelvic and Acetabular Trauma: Technique and Potential Clinical Impact. AB - OBJECTIVES: To present a technique for the use of computed tomography (CT) scans in opportunistic screening for osteoporosis in patients with pelvic and acetabular fractures and to quantify the potential clinical impact in a geriatric trauma population. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS: A total of 335 patients older than 60 years of age who presented to a Level 1 trauma center with a diagnosis of pelvic or acetabular fracture and were evaluated with a CT scan between the years 2010 and 2016. A subset of 255 patients were evaluated with a dual-energy x-ray absorptiometry scan within 6 months of the CT scan. INTERVENTION: Measurement of Hounsfield units (HU) was performed at the midpoint of the femoral neck using a standardized, ovoid section, followed by Livewire measurement. Application of this technique retrospectively to a population of geriatric patients with pelvic or acetabular fractures. MAIN OUTCOME MEASUREMENTS: (1) HUs were measured in a cross section at the midpoint of the femoral neck and, discriminant function analysis was used to establish thresholds for normal bone mineral density, osteopenia, and osteoporosis. (2) Change in the number of diagnoses of osteoporosis after application of the protocol the geriatric trauma cohort. RESULTS: Patients with osteopenia were identified correctly 67.5% of the time (14.3% were incorrectly grouped as normal, and 18.3% were grouped as having osteopenia). Patients with osteoporosis were identified correctly 88.9% of the time (the remaining 11.1% were assigned to osteopenic). The results of discriminant function analysis were used to establish CT thresholds for osteopenia (345 HUs) and osteoporosis (262 HUs). CONCLUSION: CT imaging obtained for pelvic and acetabular fractures can identify patients with osteoporosis without additional radiation exposure or cost. The fitted ovoid region of interest is a standard feature in most CT scan platforms and is quite simple to perform. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 30028794 TI - Intraoperative Evaluation of the Anatomic Lateral Distal Femoral Angle and Its Variation due to Positioning. AB - BACKGROUND/PURPOSE: Preoperative evaluation of the contralateral anatomic lateral distal femoral angle (aLDFA) at our institution is used to judge coronal plane alignment. In our study, we investigated 4 different techniques for obtaining an anteroposterior intraoperative fluoroscopic image of the distal femur to determine which technique provides (1) the greatest interobserver reliability; (2) the lowest variability from the previously published population mean; and (3) the lowest side-to-side variability. METHODS: Inclusion criteria included lower extremity injuries needing fixation that required intraoperative fluoroscopy with an intact femur and an intact extensor mechanism (N = 100). Fluoroscopic images were obtained of the distal femur in 4 positions differentiated by the position of the limb and the orientation of the C-arm beam to the femoral shaft. RESULTS: All measurement techniques resulted in mean measurements within one degree of 81 degrees. Variance between measurements was small among patients with all views, but images that involved a true anteroposterior with the beam perpendicular to the femur had the lowest rate of measurements that were <78 or >84 degrees. CONCLUSION: Side-to-side differences in patients were <2 degrees on average with every image used. With the best-performing images, 20% of patients had an aLDFA > 3 degrees different from the population mean of 81 degrees and 3% of patients were >5 degrees different. Although restoring aLDFA to 81 degrees will be within 3 degrees of the contralateral side the vast majority of the time, matching the aLDFA to the injured side will be the most accurate reconstruction. PMID- 30028795 TI - The Relationship of Multiplanar Distal and Uniplanar Proximal Interlocking Screws to Neurovascular Structures with the Depuy Synthes Humeral Nail-EX: An Anatomic Study. AB - OBJECTIVE: To determine the proximity of neurovascular structures to multiplanar distal interlocking screws and proximal interlocking devices for an antegrade inserted humeral nail. METHODS: Humeral nails (Depuy Synthes Humeral Nail-EX, Paoli, PA) were inserted into 10 matched cadavers with 3 distal interlocking trajectories: anterior to posterior (A-P), anterolateral to posteromedial, and anteromedial to posterolateral (AM-PL). The distance of the screw path and screw head to the radial, lateral antebrachial cutaneous nerve (LACN), and median nerves and the brachial artery was measured. Proximally, the distance of spiral blades and/or interlocking screws to the axillary nerve was measured. RESULTS: The median distance of the screw path/screw head inserted (A-P) to the LACN was 0 mm/0 mm in the left arm and 3.5 mm/1.6 mm in the right arm. The median distance of the screw path/screw head inserted AM-PL to the median nerve was 7.08 mm/0 mm in the left arm and 0 mm/0.12 mm in the right arm. The median distance of the screw path/screw head inserted AM-PL to the brachial artery was 4.05 mm/3.83 mm in the left arm and 2.19 mm/2.84 mm in the right arm. The humeral head was radiographically divided into 3 zones. The average distances of the axillary nerve to interlocking devices placed into zone 2 and zone 3 of the humeral head are 14.65 mm and 1.07 mm, respectively. CONCLUSIONS: When using the DePuy Synthes Humeral Nail-EX, AM-PL screws may risk the median nerve and brachial artery; thus, this trajectory is not recommended. The LACN may be at risk with A-P and to a lesser degree, anterolateral to posteromedial screws. Proximally, interlocking devices in zone 3 of the humeral head may risk the axillary nerve. PMID- 30028796 TI - Manipulation Under Anesthesia as a Treatment of Posttraumatic Elbow Stiffness. AB - OBJECTIVES: Evaluate the safety and efficacy of manipulation under anesthesia (MUA) for posttraumatic elbow stiffness. DESIGN: Retrospective, case series. SETTING: Single institution; level 1 trauma center. PATIENTS/PARTICIPANTS: Chart review of 45 patients over a 10-year period treated with MUA for posttraumatic elbow stiffness after elbow injuries treated both operatively and nonoperatively. INTERVENTION: None. MAIN OUTCOME MEASURES: Change in total flexion arc pre- to postmanipulation; time to manipulation; complications. RESULTS: Average time from most recent surgical procedure or date of injury to MUA was 115 days. Average premanipulation flexion arc was 57.9 degrees; average flexion arc at the final follow-up was 83.7 degrees. The improvement in elbow flexion arc of motion was statistically significant (P < 0.001). Post hoc analysis of the data revealed 2 distinct groups: 28 patients who underwent MUA within 3 months of their most recent surgical procedure (early manipulation), and 17 patients who underwent MUA after 3 months (late manipulation). Average improvement in elbow flexion arc in the early MUA group was 38.3 degrees (P < 0.001); improvement in the late MUA group was 3.1 degree. Comparison of improvement between the early and late MUA groups found a significant difference (P < 0.001) in mean flexion arc improvement from premanipulation to postmanipulation, favoring the early group. One patient had a complication directly attributable to MUA. Nineteen patients required additional procedures on the injured extremity after MUA. CONCLUSIONS: MUA is a safe and effective adjunct to improving motion in posttraumatic elbow stiffness when used within 3 months from the original injury or time of surgical fixation. After 3 months, MUA does not reliably increase elbow motion. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30028797 TI - Comparative Analysis of Bibliometric, Authorship, and Collaboration Trends Over the Past 30-Year Publication History of the Journal of Orthopaedic Trauma and Injury. AB - OBJECTIVES: In the scientific and medical field, authorship has become increasingly important for tenure and career advancement in addition to improvement in medical care. It was the purpose of this study to investigate changes in bibliometric variables, authorship, and collaboration trends in the Journal of Orthopaedic Trauma (JOT) and Injury over a 30-year period. METHODS: A bibliometric analysis was completed for all manuscripts meeting the inclusion criteria and published throughout 1 representative year of each decade over the past 30 years. A total of 444 and 1105 manuscripts for JOT and Injury, respectively, met the inclusion criteria. Standard statistical analyses were performed with nonparametric methods for continuous variables and Pearson chi and Cochran linear trend tests for categorical variables. A P < 0.05 was considered statistically significant. RESULTS: There were significant increases over time in all bibliometric variables for both journals, except in the number of countries and pages in JOT. For JOT, the overall percentage of female first authors increased 2.3 times from 1987 to 2015 (P = 0.021). The overall percentage of female corresponding authors was 7.3%. For Injury, the overall percentage of female first authors increased 1.5 times (P = 0.007). The overall percentage of female corresponding authors was 13.1%. CONCLUSIONS: Understanding changes in publishing characteristics over time and by region is critical with the rising demands of publishing in academic medicine. JOT and Injury have showed an increase in most variables analyzed. However, female authorship in JOT is climbing at a higher rate than Injury. PMID- 30028798 TI - Validation of the Korean Version of the MacNew Heart Disease Health-Related Quality of Life Questionnaire. AB - BACKGROUND: Health-related quality of life (HRQoL) is an importantconcept in patients with cardiac diseases, including myocardial infarction (MI). Disease specific tools offer valuable insights into the impact of a disease on various aspects of a patient's life. PURPOSE: The aim of this study was to assess the psychometric properties of the Korean version of the MacNew Heart Disease HRQoL Questionnaire (Korean MacNew). METHODS: One hundred thirty-six patients who had experienced MI about 3 months earlier were recruited from two tertiary hospitalsin South Korea. The internal consistency and various types of validity of the Korean MacNew were assessed. Exploratory factor analysis with varimax rotation was performed to identify a better structure for this instrument. RESULTS: The internal consistency of the Korean MacNew was established with Cronbach's alpha coefficients ranging from .88 to .93. Face validity and construct validity (both discriminant and concurrent) of the Korean MacNew were established. Strong positive correlations were found between the total Korean MacNew and the single-item global QoL scale (r = .73, p < .001). As expected, the total Korean MacNew also had strong negative correlations with the Depression Anxiety and Stress Scale 21 (r = -.81, p < .001) and the single-item fatigue scale (r = -.51, p < .001). The outcomes of exploratory factor analysis showed a better result with the five-factor structure in the Korean MacNew. CONCLUSIONS: The Korean MacNew showed consistently acceptable psychometric properties of reliability and validity in patients with MI. Therefore, this instrument may be recommended for assessing the HRQoL of patients with MI in Korea. However, caution should be taken in using the subscale scores. PMID- 30028799 TI - Care Needs of Patients at the End of Life With a Noncancer Diagnosis Who Live at Home. AB - BACKGROUND: As the population ages, the prevalence of various chronic diseases increases. Palliative care for patients at the end of life with a noncancer diagnosis is currently limited because of the difficulties of demarcating the boundaries of the end-of-life care period and of determining the various care needs of patients at the end of life. PURPOSE: This study aimed to investigate the levels of importance and difficulty of the multidimensional care needs for patients with a noncancer diagnosis during various end-of-life stages. METHODS: This study is a retrospective survey. Home health care nurse specialists (HHNS) reviewed medical and nursing records and responded to a structured questionnaire. The caring experiences of HHNS with 115 patients, who were 40 years or older, had received home care nursing throughout the stable (between the onset of the end-of life stage and 1 week before death) and near-death (1 week before death) stages at Seoul St. Mary's Hospital in Korea, and had died between September 1, 2014, and December 31, 2015, were analyzed. RESULTS: The care needs of "coordination among family or relatives" and "support for fundamental needs" were more important in the stable stage than in the near-death stage. The care need of "loss, grief care" was more important in the near-death stage than in the stable stage. The care need of "physical symptoms management" was the most difficult to meet in both stages. Lower Palliative Performance Scale score was associated with a higher level of care need, particularly in the "management of physical symptoms" and "psychological support" realms in the stable stage and in the "coordination among family or relatives" realm in both stages. CONCLUSIONS: End of-life stage and initial score on the Palliative Performance Scale were found to have a significant influence on the multidimensional care needs of patients with a noncancer diagnosis. Thus, healthcare professionals should assess patient care needs according to disease trajectory to provide continuous and holistic care. PMID- 30028800 TI - Osteonecrosis and Multifocal Bone Infarction in Systemic Lupus Erythematosus. PMID- 30028801 TI - Low Back Pain With Radiographic Change in Sacroiliac Joints Mimicking Spondyloarthritis. PMID- 30028802 TI - Response to Anakinra in 3 Patients With Erosive Osteoarthritis. PMID- 30028803 TI - Tofacitinib and Risk of Peripheral Neuropathy? Experience of 2 Cases in Patients With Rheumatoid Arthritis. PMID- 30028805 TI - Transient Osteoporosis of the Hip Mimicking Flare of Psoriatic Arthritis. PMID- 30028804 TI - Lung Ultrasound as a Screening Method for Interstitial Lung Disease in Patients With Systemic Sclerosis. AB - BACKGROUND: Patients with systemic sclerosis (SSc) undergo chest radiographs and high-resolution computed tomography (HRCT) of the thorax both for interstitial lung disease (ILD) detection and for disease progression monitoring. OBJECTIVE: The aim of this study was to assess whether lung ultrasound (LUS) is a useful screening tool for ILD in patients with SSc in comparison with HRCT. METHODS: This was a prospective cohort study carried out from December 2015 to April 2016. An LUS was performed to examine B-lines in 67 consecutive patients who met the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc and had a previous HRCT. B-lines were quantified and classified according to the score modified from Picano. Severity and extent of lung involvement on the HRCT were determined by means of the Warrick score. RESULTS: Twenty-nine patients had both abnormal HRCT (Warrick score >7) and abnormal LUS, 2 had a mild score (6-15 B-lines), and 27 had either moderate or severe scores (>=16 B-lines). Of the 38 patients with negative HRCT, 25 presented some degree of lung involvement on the LUS. Thus, LUS has a sensitivity of 100% and a specificity of 34%. Receiver operating characteristic curve analysis showed the analytic relation between the number of B-lines and the presence of ILD on the HRCT (area under the curve, 0.80; 95% confidence interval, 0.69-0.90). CONCLUSIONS: Lung ultrasound may be a method to detect abnormal lung findings in a noninvasive manner in patients with SSc. Because of its high sensitivity, a low score almost rules out the need for an HRCT. PMID- 30028806 TI - The Montreal Cognitive Assessment Test: A Useful Tool in Screening of Cognitive Impairment in Patients With Systemic Lupus Erythematosus. AB - BACKGROUND/OBJECTIVE: Systemic lupus erythematosus (SLE) is an inflammatory, chronic, and multisystemic disease, which may be associated with a wide range of neuropsychiatric manifestations, including cognitive impairment. Cognitive evaluations based on screening tests might identify early SLE-related cognitive alterations. The aim of this study was to evaluate and to compare the efficacy of three screening tests (Montreal Cognitive Assessment [MoCA], Mini Mental State Examination [MMSE], Cognitive Symptom Inventory [CSI]) against the gold standard (neuropsychological battery), in order to identify the most efficient screening test for cognitive impairment in patients with SLE. METHODS: This observational cross-sectional study recruited 44 patients, from August to December 2017, who were diagnosed with SLE according to the Systemic Lupus International Collaborating Clinics (SLICC) Criteria 2012, and had no medical or psychiatric comorbidities. The patients were evaluated using the MoCA, MMSE, CSI, and the gold standard. Spearman's correlation and area under the curve analysis were performed; P < 0.05 was considered significant. RESULTS: The MoCA test showed the highest correspondence with the gold standard (AUC = 99.4%, P < 0.001), sensitivity (84%), and specificity (100%). This was followed by the MMSE (AUC = 92.6%, P < 0.001; sensitivity, 54.8%; specificity, 100%) and the CSI (AUC = 30.6%, P < 0.05; sensitivity, 54.8%; specificity, 30.76%). CONCLUSION: The MoCA is a brief, easily applied screening test that is highly effective for detecting cognitive impairment in SLE patients. It could be useful in clinical follow-up as a tool for early detection of cognitive alterations.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial -No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30028807 TI - Clinical Associations of Uveitis in Axial Spondyloarthritis Group and Ankylosing Spondylitis Group: Do They Represent the Same Disease? AB - OBJECTIVE: The aim of this study was to determine the prevalence and associated factors for uveitis in ethnic Chinese patients with axial spondyloarthritis (SpA) and ankylosing spondylitis (AS). METHODS: This was a cross-sectional study. Patients fulfilling the Assessment of SpondyloArthritis international Society axial SpA criteria were recruited consecutively from 3 rheumatology centers in Hong Kong from March 2014 to July 2017. Clinical and biochemical parameters were collected. History of uveitis was inquired from both history and medical records. All patients received lumbosacral spine x-rays and whole-spine and sacroiliac joint magnetic resonance imaging. Patients were defined as axial SpA if they fulfilled the Assessment of SpondyloArthritis international Society criteria and AS if they fulfilled the modified New York criteria. Clinical and radiological findings were compared between patients with and without uveitis in the 2 groups. Factors associated with uveitis were identified with univariate analyses and multivariate logistic regression analyses. RESULTS: Among 252 patients, 67 patients (26.6%) had a history of uveitis. The male-to-female ratio was 55.4 to 44.6. Disease duration was 12.3 +/- 11.7 years. In the axial SpA group, multivariate regression showed that older age (odds ratio [OR], 1.05; P = 0.01), human leukocyte antigen B27 positivity (OR, 11.79; P = 0.01), and history of inflammatory bowel disease (OR, 9.74; P = 0.04) were positively associated with uveitis. In the AS group, multivariate regression showed that back pain duration (OR, 1.05; P = 0.01) and male sex (OR, 3.46; P = 0.03) were associated with uveitis. CONCLUSIONS: Axial SpA represents a spectrum of diseases. Its clinical associations with uveitis should be distinguished from those of traditional AS. PMID- 30028808 TI - Lack of Uptake of Prophylactic Human Papilloma Virus Vaccine Among Women With Systemic Lupus Erythematosus Seen at a Regional Medical Center. AB - BACKGROUND/OBJECTIVE: Women with systemic lupus erythematosus (SLE) are at increased risk for cervical neoplasia likely due to infection with high-risk human papillomavirus (HR-HPV) and should be considered for HPV vaccination. We sought to determine frequency of HR-HPV infection and uptake of HPV vaccination in our regional female lupus population. METHODS: For this retrospective cohort study, data were analyzed from our electronic health records EPIC for women with International Classification of Diseases -10 or International Classification of Diseases -9 billing codes for SLE seen June 6, 2007, to May 1, 2017. This study was approved by the Central Michigan University/Covenant Medical Center institutional review board. Statistical analyses consisted of Student t test, chi, and Z test for proportions using SPSS v. 24 software. RESULTS: A total of 1349 women with SLE were identified, mean age of 53 years, 70.8% white, 20.8% African American, with 49% exposed to cigarette smoke. High-risk HPV testing performed in 195 (14.5%; mean age, 50 years) showed 16.9% (33/195) were positive, with those testing positive for HR-HPV being slightly younger (P < 0.05).Comparing our proportion testing positive for HR-HPV (0.169) versus National Health and Nutrition Examination Survey (0.088), we calculated a Z = 3.99 (P < 0.001) indicating HPV infection is significantly higher (2*) in our female SLE cohort. Only 16.0% (38/238) of the 238 women eligible to receive an HPV vaccine were tested for HR-HPV with 9 being positive and only 4.6% (11/238) vaccinated. CONCLUSIONS: Human papillomavirus infection is a serious health issue in women with SLE, but HPV testing and vaccination rates remain low. Efforts should be directed to promote awareness of the importance of HPV vaccination in this high-risk population. PMID- 30028809 TI - Pan-American League of Associations for Rheumatology-Central American, Caribbean and Andean Rheumatology Association Consensus-Conference Endorsements and Recommendations on the Diagnosis and Treatment of Chikungunya-Related Inflammatory Arthropathies in Latin America. AB - BACKGROUND/OBJECTIVE: Although mortality rates related with chikungunya (CHIK) outbreaks in Latin America's (LA's) dengue-endemic rural and new urban regions are low, dealing with symptoms and sequelae can both produce a significant burden of disease and diminish quality of life-from many months to years-after the acute phase of the infection, with a significant impact on public and individual health.The aim of this work was to establish Pan-American League of Associations for Rheumatology-Central American, Caribbean and Andean Rheumatology Association (ACCAR) consensus-conference endorsements and recommendations on the diagnosis and treatment of CHIK-related inflammatory arthropathies transmitted by Aedes aegypti and Aedes albopictus in LA. METHODS: Based on the Consensus Development Conference format, a panel of ACCAR rheumatologist voting members (n = 10) took part in this Pan-American League of Associations for Rheumatology initiative. Experts voted from a previous content analysis of the medical literature on CHIK, 4 subsequent topic conferences, and a workshop. Consensus represents the majority agreement (>=80%) achieved for each recommendation. RESULTS: The experts' panel reached 4 overarching principles: (1) CHIK virus (CHIKV) is a re-emergent virus transmitted by 2 species of mosquitoes: A. aegypti and A. albopictus; (2) CHIKV caused massive outbreaks in LA; (3) chronic CHIKV infection produces an inflammatory joint disease that, in some cases, can last for several months to years, and (4) currently, there are no vaccines or antivirals licensed for CHIKV infections. RECOMMENDATIONS: Pan-American League of Associations for Rheumatology ACCAR achieved 13 endorsements and recommendations on CHIK categorized in 3 groups: (1) epidemiology and clinical manifestations, (2) diagnosis, and (3) treatment, representing the consensus agreement from the panel's members. PMID- 30028810 TI - Leveraging Continuing Professional Development to Meet Your Organization's Strategic Goals. AB - In this month's Magnet Perspectives column, the director of Primary and Joint Accreditation for the American Nurses Credentialing Center reflects on the importance of continuing professional development for the chief nursing officer (CNO), the nurses, and the healthcare team the CNO leads, as well as the impact on patients. PMID- 30028811 TI - Transitioning Emerging Leaders Into Nurse Leader Roles. AB - Millennials will soon comprise 50% of the nursing workforce. Leaders in organizations look to this generation to assume leadership roles. This is proving to be challenging in many settings. Learning how to more effectively recruit, transition, and retain these emerging nurse leaders will be critical to organizations and the future of nursing. This article presents academic and organizational practices in emerging leader transition tailored to the needs of the millennial generation. PMID- 30028812 TI - AONE Foundation Embarks on New Initiatives. AB - The AONE Foundation for Nursing Leadership Research and Education has created new grant opportunities and last year funded research projects that will directly assist nurse leaders. This article outlines the foundation's direction and priorities going forward. PMID- 30028813 TI - The Development and Validation of an Acuity Tool in a Pediatric Outpatient Burn Clinic. AB - In outpatient settings, the role of nursing has shifted from episodic, reactive care to management of patients with higher acuity. In a pediatric outpatient clinic specializing in burn injuries, it became apparent that the lack of an acuity tool to measure patient complexity challenged efficient nurse staffing and patient satisfaction. In this quality improvement project, we developed a patient acuity tool to help determine nurse staffing, improve workload efficiencies, and improve the delivery of care. PMID- 30028814 TI - Relationships Among Nurse Manager Leadership Skills, Conflict Management, and Unit Teamwork. AB - OBJECTIVE: The aim of this study is to examine the relationships among staff nurse perceptions of their nurse manager (NM) leadership ability, conflict management, and team backup on medical-surgical units. BACKGROUND: Team backup, an important component of teamwork, is crucial to patient safety and outcomes. A threat to successful teamwork is ineffective conflict management. There is scant knowledge, however, about NM conflict management skills and unit teamwork through the concept of team backup. METHODS: Secondary analyses were conducted utilizing data previously collected from a sample of 257 staff nurses. A series of multiple regressions, including a mediation model, were estimated to determine relationships among variables. RESULTS: Positive relationships were substantiated among the variables of NM leadership ability, conflict management, and team backup. Staff nurse perceptions of NM leadership ability were a significant predictor of conflict management and team backup. CONCLUSION: Findings support the importance of the NM demonstrating skilled leadership and the ability to manage conflicts and to develop team backup. This study further highlights the importance of conflict management as a leadership competency. PMID- 30028815 TI - C-Suite Roles and Competencies to Support a Culture of Shared Governance and Empowerment. AB - OBJECTIVE: The aim of this study was to examine C-suite executives' perspectives on empowerment early in shared governance implementation. BACKGROUND: Leadership influences a workplace culture for empowerment. However, the literature lacks clarity regarding the specific roles of C-suite executives in fostering empowerment. METHODS: A system's top 47 executives were invited to participate in a Delphi study. Two Delphi rounds identified leadership empowerment philosophies, plus techniques for (a) understanding staff needs, (b) embedding empowerment, and (c) ensuing leadership accountability. In round 3, leaders rated the 3 types of techniques for ease and impact. RESULTS: Results revealed a passive C-suite culture regarding empowerment. However, C-suite executives recognized the need for active promotion of an empowering culture. Optimal techniques for understanding staff empowerment needs were identified. CONCLUSIONS: Modeling empowerment by the C-suite executives enables alignment between councils and levels of nursing leadership, allowing organizations to achieve the goals for professional nursing practice and shared governance. PMID- 30028816 TI - Exploring the Relationship Between Nursing Specialty Certification and Surgical Site Infections. AB - OBJECTIVE: The aim of this study is to explore the relationship between nursing specialty certification and surgical site infections (SSIs) for colon (COLO) and abdominal hysterectomy (HYST) surgical procedures. BACKGROUND: SSI following COLO and HYST procedures is a preventable complication now included in the Centers for Medicare & Medicaid Services' Hospital Inpatient Quality Reporting Program. METHODS: Data from 69 hospitals, 346 units, and 6585 RNs participating in the National Database of Nursing Quality Indicators and SSI data on 22 188 patient COLO and HYST procedures from the National Healthcare Safety Network were examined in multivariate logistic regression analysis. RESULTS: Magnet(r) status was associated with lower SSI occurrence after adjusting for other variables. Higher American Society of Anesthesiologists scores, longer surgical procedure time, and wound class were associated with higher SSI occurrence. CONCLUSIONS: Future theory-based research should examine the association of nursing specialty certification with patient outcomes and investigate the effect of Magnet status on SSI. PMID- 30028817 TI - Intentional Clinical Process Design to Improve Outcomes for Patients Who Require Emergency Surgery. AB - Ruptured abdominal aortic aneurysms (AAAs) are associated with a 90% overall mortality and $150 000 cost of care per patient. Despite improvements in intensive care and surgical technology, morbidity and mortality remain unchanged over the past 20 years. The most significant predictor of survival is time from the door of the hospital to the operating room. To streamline operational efficiency, a team utilized Lean Six Sigma methodologies, team training, and intentional clinical process design to institute changes in our clinical processes, enhance care coordination, and improve communication. Changes led to a $1.8 million profit on operations, 10-day reduction in length of stay, and 89% survival rate among patients with ruptured AAA. PMID- 30028818 TI - CNO Rounding Using an Electronic Tracking Tool: Closing the Loop. AB - Nurse executives must develop creative solutions to improve staff perceptions of the work environment and decrease turnover, as well as stay connected with their staff. This article summarizes an innovative closed feedback loop using an electronic record incorporated into chief nursing officer rounding and the impact on NDNQI survey results. PMID- 30028819 TI - Cryptic ETV6-ABL1 Fusion and MLL2 Truncation Revealed by Integrative Clinical Sequencing in Multiply Relapsed Acute Lymphoblastic Leukemia. AB - The ETV6-ABL1 fusion is a rare genetic aberration classified as Philadelphia chromosome-like high-risk B-cell precursor acute lymphoblastic leukemia. We present the case of a child with multiply relapsed B-cell precursor acute lymphoblastic leukemia in which next-generation sequencing identified this cryptic fusion, undetected by standard testing, resulting in sustained clinical response to targetted therapy with imatinib. Upon subsequent relapse, repeat next generation sequencing identified an additional aberration, MLL2-ADCY9, as a possible molecular driver conferring resistance to therapy. This report demonstrates the exciting potential of integrative clinical sequencing in identifying previously undetected actionable findings leading to improved outcomes in pediatric oncology patients. PMID- 30028820 TI - Congenital Neutropenia Patient With Hypomorphic Biallelic CSF3R Mutation Responding to GCSF. AB - Congenital neutropenia (CN) is a rare disorder, and the most common gene responsible for CN is ELANE. Furthermore, the mutations of HAX1, G6PC3, and JAGN1 genes may cause CN. These patients generally find great benefit from subcutaneous administration of Granulocyte Colony Stimulating Factor (GCSF). In recent years, Biallelic Colony Stimulating Factor 3 Receptor (CSF3R) mutations have been described as an underlying defect of CN in several children. In contrast to the previous group, the patients who have a CSF3R mutation do not respond to GCSF treatment. Here, we present a CN patient with hypomorphic biallelic CSF3R mutation responding to GCSF. PMID- 30028821 TI - A Rare Cause of Pancytopenia in an Exclusively Breastfed Infant. AB - Vitamin B12 (B12) deficiency in infancy can present with nonspecific symptoms. We report a 5-month old exclusively breastfed full-term infant with emesis, lethargy, progressive pancytopenia, hemolysis, hypofibrinogenemia, elevated lactate dehydrogenase and a hypercellular bone marrow with dyserythropoiesis. The B12 level in the serum was undetectable. The infant's lethargy resolved within 48 hours of intramuscular B12 injection, followed by rapid improvement of pancytopenia. The asymptomatic mother had a normal hemoglobin and mean corpuscular volume, but undetectable B12 level and positive antibodies to intrinsic factor, consistent with pernicious anemia masked by folate supplementation in the mother but causing symptoms in her infant. PMID- 30028822 TI - A New Variant of PKLR Gene Associated With Mild Hemolysis may be Responsible for the Misdiagnosis in Pyruvate Kinase Deficiency. AB - Pyruvate kinase deficiency (PKD) is the most common glycolytic defect leading to hemolytic anemia. PKD is caused by the mutations in the PKLR gene; however, the detection of a decreased PK activity should be first measured for rapid diagnosis. We report here the case of a 1-year-old girl with mild hemolysis and PKD. At the time of the study, the patient showed a hemoglobin level of 9.5 g/dL, mean corpuscular volume of 93 fL, reticulocyte of 6.7%, and lactate dehydrogenase of 218 IU/L. Peripheral blood smear showed polychromasia, anisocytosis, tear drop cells, fragmented eyrtrocytes, and target cells. When a biochemical analysis was performed in our patient and her parents who had consanguinity, a decreased PK activity was detected in the patient and her father. After the molecular study of PKLR gene, a new homozygote variant, c.1708G>T (pVal570Leu), was found in our patient and her father. Her father had a misdiagnosis of Gilbert syndrome because he had unconjugated hyperbilirubinemia and not anemia. Her mother was also a carrier of the mutation in heterozygous state. Patients presenting with hemolytic anemia, either severe or mild hemolytic anemia, should be screened for PKD in the first year of life. Patients with mild hemolytic findings can be followed-up with misdiagnoses. PMID- 30028823 TI - Syncytial Variant Nodular Sclerosis Classical Hodgkin Lymphoma in an Adolescent and Review of the Literature: A Unique Entity. AB - Syncytial variant of nodular sclerosis (SV-NS) classical Hodgkin lymphoma (cHL) with its histologic features and clinical presentation is uncommon in adults and extremely rare in children. Here, we report a female teenager presenting with long-standing B symptoms, prominent soft tissue and bone involvement mimicking sarcoma and significant nodal disease who is diagnosed with advanced SV-NS cHL. Rare Reed-Sternberg-like cells displaying neutrophil and erythrocyte emperipolesis were seen on bone marrow aspiration slides. Despite initial complete response to chemotherapy and radiotherapy, the patient experienced early relapse suggestive of high-risk biology. This variant may constitute a unique entity. PMID- 30028824 TI - A Quality Improvement Bundle to Improve Informed Choice for Children With Typical, Newly Diagnosed Immune Thrombocytopenia. AB - IVIG has been the predominant therapy for the initial management of children with newly diagnosed immune thrombocytopenia at our hospital. With current guidelines supporting more conservative management, we undertook a quality improvement initiative to lead practice change. Over a 2-year time period (2013 to 2015), we strove to decrease use of hospital resources (use of IVIG, length of stay) while optimizing family satisfaction. An interdisciplinary working group was struck and a quality improvement bundle was implemented. The bundle comprised a patient information sheet; an evidence-informed, consensus-based protocol; and promotion of shared decision-making via stakeholder engagement and education. Data were collected prospectively; baseline data from a 2007 to 2009 audit were used for comparison. In total, 27 patients were included. Mean initial platelet count was 4*10/L. Bleeding was classified as none or mild in 56% of patients. IVIG use decreased from 88% to 55% of patients, corticosteroid prescription increased from 6% to 15%, and observation increased from 6% to 30% of patients. Hospital length of stay decreased from 47 to 36 hours. Family satisfaction was stable across treatment groups. Through introduction of a quality improvement initiative, we were able to improve family-centered care and decrease use of hospital resources. PMID- 30028825 TI - Special Therapy and Psychosocial Needs Identified in a Multidisciplinary Cancer Predisposition Syndrome Clinic. AB - Identification of patients with cancer predisposition syndromes (CPSs) can provide vital information to guide care of an existing cancer, survey for future malignancy, and counsel families. The same underlying mutation responsible for a CPS may also result in other phenotypic abnormalities amenable to therapeutic intervention. The purpose of this study was to examine patients followed in our multidisciplinary CPS clinic to determine the prevalence and scope of medical and psychosocial needs. Data from a baseline evaluation of a single-center patient registry was reviewed. Eligible patients included those with a known or suspected CPS. Over 3 years, 73 patients consented and had successful follow-up. Utilization rate of special therapies, defined as speech therapy, occupational therapy, and/or physical therapy, in the CPS population was 50.7%, significantly higher than a representative sample of children with special needs. Prevalence of 504/IEP (Individualized Education Program) utilization was 20.5%. Patients with CPSs have a high prevalence of medical and psychosocial needs beyond their risk for cancer, for which early screening for necessary interventions should be offered to maximize the patient's developmental potential. Future research is needed to further define the developmental and cognitive phenotypes of these syndromes, and to evaluate the effectiveness of subsequent interventions. PMID- 30028826 TI - Brown Recluse Spider Bites in Patients With Neutropenia: A Single-institution Experience. AB - Brown recluse spider bites can cause local and systemic signs, including rash, dermonecrosis, edema, hemolysis, and acute kidney failure. These are mostly attributed to sphingomyelinase D, the main toxin. To evaluate the severity of the disease in pediatric patients with and without neutropenia, we retrospectively reviewed records of patients treated at St. Jude Children's Research Hospital between 1970 and 2015 and identified 19 patients who met the inclusion criteria. Variables of interest included the type of underlying illness, presence of neutropenia, number of days of hospitalization, disease signs and outcome of the bite, and treatments administered. We used descriptive statistics to summarize the manifestations and severity of spider bites in patients with and without neutropenia. Six patients experienced pain from the bite, 11 had erythema, 7 developed edema, and 5 had fever. The response to spider bites in neutropenic patients was no milder than that in non-neutropenic individuals. Six patients developed systemic complications. Compared with non-neutropenic patients, neutropenic patients had antibiotics prescribed more often and experienced longer hospital stays. Spider bites do not seem to have a different clinical course in neutropenic patients. Therefore, a conservative approach may be best for these patients, with close monitoring and local wound care. PMID- 30028827 TI - Liver Biopsy Can Be Safely Performed in Pediatric Acute Liver Failure to Aid in Diagnosis and Management. AB - OBJECTIVES: Liver biopsy can be a valuable tool to help determine the etiology of pediatric acute liver failure (PALF), but is often not performed due to safety concerns. The primary aim was to describe the incidence of major complications after liver biopsy performed in the setting of PALF. METHODS: Medical records from 2006 to 2016 were reviewed. Patients age 0 to 17 years, who met criteria for PALF, and had a liver biopsy performed while their international normalized ratio (INR) was >=1.5 were included. RESULTS: A total of 26 cases of liver biopsy in the setting of PALF were identified. The majority (n = 22, 85%) of patients had primary liver disease. Most biopsies (n = 17, 65%) were performed by the transjugular route, with 5 (19%) performed percutaneously under ultrasound guidance and 4 (15%) during a surgical procedure. Median INR before biopsy was 2.1 (IQR = 1.73-2.9). Blood products were given before or during the procedure in 23 (88%) cases. One patient (3.8%) had a major complication of biopsy-associated bleeding requiring a blood transfusion. An additional 3 patients had a hemoglobin decrease of 2.1 to 2.9 g/dL post-biopsy that was attributed to the procedure but no interventions were necessary. Biopsy results contributed to establishing a diagnosis in 62% (n = 16) of cases, and influenced treatment decisions in 9 of those cases. CONCLUSIONS: Liver biopsy is safe in the majority of patients with PALF and associated with infrequent major complications. Clinicians should consider performing liver biopsy in this setting, especially when the transjugular approach is feasible, since findings may guide diagnosis and therapy. PMID- 30028828 TI - Growth, Body Composition, and Micronutrient Abnormalities During and After Weaning Off Home Parenteral Nutrition. AB - OBJECTIVES: The aim of the study is to assess growth, body composition, and micronutrient abnormalities in children with intestinal failure (IF) over time, both during and after weaning off parenteral nutrition (PN). METHODS: Retrospective study in children on home PN between 2001 and 2015. Weight-for-age (WFA) and height-for-age (HFA) SD scores (SDS) were calculated, as well as fat mass (FM) and fat-free mass (FFM) SDS obtained by dual energy x-ray absorptiometry. The course of growth parameters and body composition was analyzed with linear-mixed models. All micronutrient measurements during the study period were obtained. RESULTS: Fifty-two patients were included with a median follow-up of 3.4 years. Seventy-one percent weaned off after a median PN duration of 0.9 years. One year after the start of PN, 28 patients were still PN-dependent with median WFA-SDS of -0.66 and median HFA-SDS of -0.96, both significantly lower than zero. Catch-up growth was achieved during PN, but HFA-SDS decreased after weaning (P = 0.0001). At a median age of 6.2 years, median %FM SDS was 0.30 and FFM SDS was -1.21, the latter significantly lower than zero. Frequent micronutrient abnormalities during PN were vitamin A (90%), zinc (87%), and iron (76%) and after weaning vitamin A (94%), E (61%), and 25-OH vitamin D (59%). CONCLUSIONS: Children with IF demonstrate abnormal growth and body composition and frequent micronutrient abnormalities. Longitudinal evaluation showed that catch-up growth occurs during PN, but height SDS decreases after weaning. This underlines the need for close monitoring, also after reaching enteral autonomy. PMID- 30028829 TI - Is the WHO Creating Unnecessary Confusion Over Breast Milk Substitutes? AB - A recent statement by WHO that "breast milk substitutes should be understood to include any milks ...that are specifically marketed for feeding infants and young children up to the age of 3 years" differs significantly from the definition in the International Code which states "a breast milk substitute is any food being marketed or otherwise presented as a partial or total replacement for breast milk, whether or not suitable for that purpose." The new interpretation, which lacks consultation and endorsement, is also ambiguous, with the boundaries between breast milk substitutes and complementary foods being blurred during the first 3 years of life. The logical definitions of breast milk substitutes and complementary foods contained within the Code should be maintained and inappropriate promotion of foods and fluids for infants and young children should be addressed through effective regulation of composition and labelling standards. PMID- 30028830 TI - Interictal Epileptiform Discharge Detection in EEG in Different Practice Settings. AB - OBJECTIVE: The goal of the study was to measure the performance of academic and private practice (PP) neurologists in detecting interictal epileptiform discharges in routine scalp EEG recordings. METHODS: Thirty-five EEG scorers (EEGers) participated (19 academic and 16 PP) and marked the location of ETs in 200 30-second EEG segments using a web-based EEG annotation system. All participants provided board certification status, years of Epilepsy Fellowship Training (EFT), and years in practice. The Persyst P13 automated IED detection algorithm was also run on the EEG segments for comparison. RESULTS: Academic EEGers had an average of 1.66 years of EFT versus 0.50 years of EFT for PP EEGers (P < 0.0001) and had higher rates of board certification. Inter-rater agreement for the 35 EEGers was fair. There was higher performance for EEGers in academics, with at least 1.5 years of EFT, and with American Board of Clinical Neurophysiology and American Board of Psychiatry and Neurology-E specialty board certification. The Persyst P13 algorithm at its default setting (perception value = 0.4) did not perform as well at the EEGers, but at substantially higher perception value settings, the algorithm performed almost as well human experts. CONCLUSIONS: Inter-rater agreement among EEGers in both academic and PP settings varies considerably. Practice location, years of EFT, and board certification are associated with significantly higher performance for IED detection in routine scalp EEG. Continued medical education of PP neurologists and neurologists without EFT is needed to improve routine scalp EEG interpretation skills. The performance of automated detection algorithms is approaching that of human experts. PMID- 30028831 TI - Halo Formation Around Cherry Angiomas: A Rare But Substantial Finding. AB - BACKGROUND I meticulously inspected trunks of 488 patients aged 40 years or older who had at least 1 truncal cherry angioma. MATERIAL AND METHODS The median number of truncal cherry angiomas was 4. Their median size was 3 millimeters. A pale halo around cherry angiomas was seen in 5.1% of the patients or in 2.0% of the lesions. It was more prevalent in patients aged 60 years or older and in patients having more than 4 lesions. A pale halo was found more frequently around lesions larger than 3 millimeters. RESULTS The median number of truncal cherry angiomas was four. Their median size was three millimeters. A pale halo around cherry angiomas was seen in 5.1% of the patients or in 2.0% of the lesions. Its occurrence was more frequent in patients aged 60 years or older and in patients having more than four lesions. Again, a pale halo was found more frequently around lesions larger than three millimeters. CONCLUSIONS These findings show that halo formation around cherry angiomas is a rare but substantial change, especially in the late phase of their natural course. However, these findings should be confirmed in more comprehensive studies, including patients in all age groups and examining the whole skin surface. PMID- 30028833 TI - Exploration and stabilization of Ras1 mating zone: A mechanism with positive and negative feedbacks. AB - In mating fission yeast cells, sensing and response to extracellular pheromone concentrations occurs through an exploratory Cdc42 patch that stochastically samples the cell cortex before stabilizing towards a mating partner. Active Ras1 (Ras1-GTP), an upstream regulator of Cdc42, and Gap1, the GTPase-activating protein for Ras1, localize at the patch. We developed a reaction-diffusion model of Ras1 patch appearance and disappearance with a positive feedback by a Guanine nucleotide Exchange Factor (GEF) and Gap1 inhibition. The model is based on new estimates of Ras1-GDP, Ras1-GTP and Gap1 diffusion coefficients and rates of cytoplasmic exchange studied by FRAP. The model reproduces exploratory patch behavior and lack of Ras1 patch in cells lacking Gap1. Transition to a stable patch can occur by change of Gap1 rates constants or local increase of the positive feedback rate constants. The model predicts that the patch size and number of patches depend on the strength of positive and negative feedbacks. Measurements of Ras1 patch size and number in cells overexpressing the Ras1 GEF or Gap1 are consistent with the model. PMID- 30028834 TI - Prognostic value of pneumococcal urinary antigen test in community-acquired pneumonia. AB - BACKGROUND: The pneumococcal urinary antigen test (UAT) has been known to improve sensitivity and specificity for the diagnosis of pneumococcal pneumonia. Associations of UAT results with prognosis in community acquired pneumonia (CAP) are not known. We hypothesized that positive UAT is associated with a good prognosis, and incorporation of UAT into CRB65 would improve its prognostic performance. METHODS: In this registry-based retrospective study, we analyzed CAP patients over a 10-year period beginning in April 2008. Patients who had UAT results were included in multivariable extended Cox-regression analyses to determine the association between UAT positivity and 30-day mortality. UAT results were incorporated for patients with a CRB65 score of 1 by subtracting 1 from the scoring system if the test was positive. The performance of the modified scoring systems was assessed with area under the receiver operating characteristic (AUROC) curves. RESULTS: Among 5145 CAP patients, total 2280 patients had UAT results and were included in analyses. A positive UAT result was associated with a good prognosis after a week of hospitalization (aHR, 0.14; p = 0.007). After modification of CRB65 using UAT results, positive and negative predictive values for 30-day mortality were increased from 7.7 to 8.3 (p<0.001) and 98.9 to 99.1 (p = 0.010). The AUROC increased from 0.73 to 0.75 (p<0.001). CONCLUSIONS: Positive results on UAT could be considered as a good prognostic factor in CAP. UAT could be used as a useful tool in deciding whether to refer patients to the hospital, especially in moderate CAP with a CRB score of 1. PMID- 30028832 TI - Genome-wide maps of ribosomal occupancy provide insights into adaptive evolution and regulatory roles of uORFs during Drosophila development. AB - Upstream open reading frames (uORFs) play important roles in regulating the main coding DNA sequences (CDSs) via translational repression. Despite their prevalence in the genomes, uORFs are overall discriminated against by natural selection. However, it remains unclear why in the genomes there are so many uORFs more conserved than expected under the assumption of neutral evolution. Here, we generated genome-wide maps of translational efficiency (TE) at the codon level throughout the life cycle of Drosophila melanogaster. We identified 35,735 uORFs that were expressed, and 32,224 (90.2%) of them showed evidence of ribosome occupancy during Drosophila development. The ribosome occupancy of uORFs is determined by genomic features, such as optimized sequence contexts around their start codons, a shorter distance to CDSs, and higher coding potentials. Our population genomic analysis suggests the segregating mutations that create or disrupt uORFs are overall deleterious in D. melanogaster. However, we found for the first time that many (68.3% of) newly fixed uORFs that are associated with ribosomes in D. melanogaster are driven by positive Darwinian selection. Our findings also suggest that uORFs play a vital role in controlling the translational program in Drosophila. Moreover, we found that many uORFs are transcribed or translated in a developmental stage-, sex-, or tissue-specific manner, suggesting that selective transcription or translation of uORFs could potentially modulate the TE of the downstream CDSs during Drosophila development. PMID- 30028835 TI - Toxicological assessment of multi-walled carbon nanotubes combined with nonylphenol in male mice. AB - Carbon nanotubes have attracted increasing attention attributable to their widespread application. To evaluate the joint toxicity of multi-walled carbon nanotubes (MWCNTs) and nonylphenol (NP), we investigated the toxicological effects of NP, pristine MWCNTs, and MWCNTs combined with NP in male mice. After exposing male mice by gavage for 5 days, intracellular superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, as well as malondialdehyde (MDA) and glutathione (GSH) levels in tissues were determined to evaluate in vivo oxidative stress. In addition, genotoxicity was assessed by examining DNA damage in mouse liver and sperm via the comet assay, and transmission electron microscopy (TEM) was used for direct visual observations of mitochondrial damage in the liver. Results from the oxidative damage and DNA damage experiments indicate that after adsorbing NP, MWCNTs at a high dose induce oxidative lesions in the liver and cause DNA damage in mouse sperm; these data offer new insights regarding the toxicological assessment of MWCNTs. PMID- 30028836 TI - Punishment and inspection for governing the commons in a feedback-evolving game. AB - Utilizing common resources is always a dilemma for community members. While cooperator players restrain themselves and consider the proper state of resources, defectors demand more than their supposed share for a higher payoff. To avoid the tragedy of the common state, punishing the latter group seems to be an adequate reaction. This conclusion, however, is less straightforward when we acknowledge the fact that resources are finite and even a renewable resource has limited growing capacity. To clarify the possible consequences, we consider a coevolutionary model where beside the payoff-driven competition of cooperator and defector players the level of a renewable resource depends sensitively on the fraction of cooperators and the total consumption of all players. The applied feedback-evolving game reveals that beside a delicately adjusted punishment it is also fundamental that cooperators should pay special attention to the growing capacity of renewable resources. Otherwise, even the usage of tough punishment cannot save the community from an undesired end. PMID- 30028839 TI - The same video game in 2D, 3D or virtual reality - How does technology impact game evaluation and brand placements? AB - Video game technology is changing from 2D to 3D and virtual reality (VR) graphics. In this research, we analyze how an identical video game that is either played in a 2D, stereoscopic 3D or Head-Mounted-Display (HMD) VR version is experienced by the players, and how brands that are placed in the video game are affected. The game related variables, which are analyzed, are presence, attitude towards the video game and arousal while playing the video game. Brand placement related variables are attitude towards the placed brands and memory (recall and recognition) for the placed brands. 237 players took part in the main study and played a jump'n'run game consisting of three levels. Results indicate that presence was higher in the HMD VR than in the stereoscopic 3D than in the 2D video game, but neither arousal nor attitude towards the video game differed. Memory for the placed brands was lower in the HMD VR than in the stereoscopic 3D than in the 2D video game, whereas attitudes towards the brands were not affected. A post hoc study (n = 53) shows that cognitive load was highest in the VR game, and lowest in the 3D game. Subjects reported higher levels of dizziness and motion-sickness in the VR game than in the 3D and in the 2D game. Limitations are addressed and implications for researchers, marketers and video game developers are outlined. PMID- 30028838 TI - The evolutionary dynamics of metabolic protocells. AB - Protocell multilevel selection models have been proposed to study the evolutionary dynamics of vesicles encapsulating a set of replicating, competing and mutating sequences. The frequency of the different sequence types determines protocell survival through a fitness function. One of the defining features of these models is the genetic load generated when the protocell divides and its sequences are assorted between the offspring vesicles. However, these stochastic assortment effects disappear when the redundancy of each sequence type is sufficiently high. The fitness dependence of the vesicle with its sequence content is usually defined without considering a realistic account on how the lower level dynamics would specify the protocell fitness. Here, we present a protocell model with a fitness function determined by the output flux of a simple metabolic network with the aim of understanding how the evolution of both kinetic and topological features of metabolism would have been constrained by the particularities of the protocell evolutionary dynamics. In our model, the sequences inside the vesicle are both the carriers of information and Michaelis Menten catalysts exhibiting saturation. We found that the saturation of the catalysts controlling the metabolic fluxes, achievable by modifying the kinetic or stoichiometric parameters, provides a mechanism to ameliorate the assortment load by increasing the redundancy of the catalytic sequences required to achieve the maximum flux. Regarding the network architecture, we conclude that combinations of parallel network motifs and bimolecular catalysts are a robust way to increase the complexity of the metabolism enclosed by the protocell. PMID- 30028837 TI - Mechanotransduction in talin through the interaction of the R8 domain with DLC1. AB - The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes. PMID- 30028840 TI - Close relatives of Mediterranean endemo-relict hoverflies (Diptera, Syrphidae) in South Africa: Morphological and molecular evidence in the Merodon melanocerus subgroup. AB - An ongoing study of the genus Merodon Meigen, 1803 in the Republic of South Africa (RSA) has revealed the existence of new species related to M. melanocerus Bezzi, 1915. The M. melanocerus subgroup belongs to the Afrotropical lineage of the M. desuturinus group. Revision of all available material from museums and detailed analyses of newly -collected specimens from our own expeditions to RSA resulted in delimitation of five species: M. capensis Hurkmans sp. n., M. commutabilis Radenkovic et Vujic sp. n., M. drakonis Vujic et Radenkovic sp. n., M. flavocerus Hurkmans sp. n. and M. melanocerus. In addition to classical morphological characters, sequences of the mitochondrial COI gene are provided for four related taxa. Results of molecular phylogenetic analyses supports monophyly of the M. desuturinus group and confirmed delimitation between species. Links between Palaearctic and Afrotropical faunas of this group, as well as possible evolutionary paths, are discussed. Based on phylogenetic analyses, four lineages (putative subgenera) have been recognized within the genus Merodon; besides the three previously established ones, albifrons+desuturinus, aureus (sensu lato) and avidus-nigritarsis, one new lineage named natans is distinguished. PMID- 30028841 TI - Medical waste management in three areas of rural China. AB - OBJECTIVE: The purpose of this paper is to describe current practices of medical waste management, including its generation, investments, collection, storage, segregation, and disposal, and to explore the level of support from upper tiers of the government and health care system for medical waste management in rural China. METHODS: The authors draw on a dataset comprised of 209 randomly selected rural township health centers (THCs) in 21 counties in three provinces of China: Anhui, Shaanxi and Sichuan. Surveys were administered to health center administrators in sample THCs in June 2015. RESULTS: The results show that the generation rate of medical waste was about 0.18 kg/bed, 0.15 kg/patient, or 0.13 kg/person per day on average. Such per capita levels are significant given China's large rural population. Although investments of medical waste facilities and personnel in THCs have improved, results show that compliance with national regulations is low. For example, less than half of hazardous medical waste was packed in sealed containers or containers labeled with bio-hazard markings. None of the THCs segregated correctly according to the categories required by formal Chinese regulations. Many THCs reported improper disposal methods of medical waste. Our results also indicate low levels of staff training and low rates of centralized disposal in rural THCs. CONCLUSIONS: Medical waste is a serious environmental issue that is rising on the agenda of policymakers. While a large share of THCs has invested in medical waste facilities and personnel, it appears that actual compliance remains low. Using evidence of low rates of training and centralized disposal, we surmise that a lack of support from upper tiers of management is one contributing factor. Given these findings, we recommend that China's policymakers should enhance support from upper tiers and improve monitoring as well as incentives in order to improve medical waste management. PMID- 30028842 TI - Hepatic changes by benznidazole in a specific treatment for Chagas disease. AB - Chagas disease (Cd) is the third most common parasitic disease that causes damage to human health. Even a century after its description by Carlos Chagas and advances in its control, it remains a neglected disease. To eradicate the parasite or reduce the parasitic load, specific treatment for Trypanosoma cruzi (T. cruzi) is advisable; benznidazole (BNZ) is the drug that is currently prescribed. The purpose of this study is to report the adverse events (AE) due to the use of BNZ as a specific treatment for Cd, with a particular focus on hepatic changes. This was an observational, cross-sectional cohort study that included patients who were treated with BNZ. The medical records of patients who joined the Grupo de Estudo em doenca de Chagas [Chagas Disease Study Group]/UNICAMP/Brazil and were treated with BNZ were reviewed for epidemiological, clinical, laboratory and AE parameters for the drug. The 204 patients who were assessed had an average age of 40.6 years +/- 13.5 years, and 104 of them were women (50.98%). Fourteen (6.86%) individuals were in the acute phase of Cd, and 190 (93.13%) were in its chronic phase. AEs occurred in 85 patients (41.66%), 35 (41.17%) of whom had AEs related to the liver, characterized by an elevation of AST liver enzymes, ALT, alkaline phosphatase and gamma-glutamyltransferase (gammaGT). Other AEs that were observed included the following: 48 cases of cutaneous changes (56.47%), 8 cases of epigastric pain (9.41%), 7 cases of blood alteration (8.23%), and 3 cases of peripheral neuropathy (3.52%). Treatment was interrupted in 32 patients (37.64%) due to AD. Adverse events related to the liver secondary to the use of BNZ for Cd-specific treatment were frequent in this study and were characterized by an elevation of liver enzymes. Therefore, it is suggested that these enzymes be monitored during treatment with benznidazole. PMID- 30028843 TI - The interdependence of cigarette, alcohol, and marijuana use in the context of school-based social networks. AB - The concurrent or sequential usage of multiple substances during adolescence is a serious public health problem. Given the importance of understanding interdependence in substance use during adolescence, the purpose of this study is to examine the co-evolution of cigarette smoking, alcohol, and marijuana use within the ever-changing landscape of adolescent friendship networks, which are a primary socialization context for adolescent substance use. Utilizing Stochastic Actor-Based models, we examine how multiple simultaneous social processes co evolve with adolescent smoking, drinking, and marijuana use within adolescent friendship networks using two school samples from early waves of the National Longitudinal Study of Adolescent to Adult Health (Add Health). We also estimate two separate models examining the effects from using one substance to the initiation and cessation of other substances for each sample. Based on the initial model results, we simulate the model forward in time by turning off one key effect in the estimated model at a time, and observe how the distribution of use of each substance changes. We find evidence of a unilateral causal relationship from marijuana use to subsequent smoking and drinking behaviors, resulting in the initiation of drinking behavior. Marijuana use is also associated with smoking initiation in a school with a low substance use level, and smoking cessation in a school with a high substance use level. In addition, in a simulation model excluding the effect from marijuana use to smoking and drinking behavior, the number of smokers and drinkers decreases precipitously. Overall, our findings indicate some evidence of sequential drug use, as marijuana use increased subsequent smoking and drinking behavior and indicate that an adolescent's level of marijuana use affects the initiation and continuation of smoking and drinking. PMID- 30028844 TI - Spatio-temporal ecology of sympatric felids on Borneo. Evidence for resource partitioning? AB - Niche differentiation, the partitioning of resources along one or more axes of a species' niche hyper-volume, is widely recognised as an important mechanism for sympatric species to reduce interspecific competition and predation risk, and thus facilitate co-existence. Resource partitioning may be facilitated by behavioural differentiation along three main niche dimensions: habitat, food and time. In this study, we investigate the extent to which these mechanisms can explain the coexistence of an assemblage of five sympatric felids in Borneo. Using multi-scale logistic regression, we show that Bornean felids exhibit differences in both their broad and fine-scale habitat use. We calculate temporal activity patterns and overlap between these species, and present evidence for temporal separation within this felid guild. Lastly, we conducted an all-subsets logistic regression to predict the occurrence of each felid species as a function of the co-occurrence of a large number of other species and showed that Bornean felids co-occurred with a range of other species, some of which could be candidate prey. Our study reveals apparent resource partitioning within the Bornean felid assemblage, operating along all three niche dimension axes. These results provide new insights into the ecology of these species and the broader community in which they live and also provide important information for conservation planning for this guild of predators. PMID- 30028845 TI - Androgen receptor isoforms expression in benign prostatic hyperplasia and primary prostate cancer. AB - The role of molecular changes in the androgen receptor (AR) as AR variants (AR Vs) is not clear in the pathophysiology of benign prostatic hyperplasia (BPH) and hormone-naive PCa. The aim of the current work was to identify the presence of AR isoforms in benign tissue and primary PCa, and to evaluate the possible association with tumor aggressiveness and biochemical recurrence in primary PCa. The mRNA levels of full length AR (AR-FL) and AR-Vs (AR-V1, AR-V4 and AR-V7) were measured using RT-qPCR. The protein expression of AR-FL (AR-CTD and AR-NTD) and AR-V7 were evaluated by the H-Score in immunohistochemistry (IHC). All investigated mRNA targets were expressed both in BPH and PCa. AR-FL mRNA levels were similar in both groups. AR-V4 mRNA expression showed higher levels in BPH, and AR-V1 and AR-V7 mRNA expression were higher in PCa. The AR-V7 protein showed a similar H-Score in both groups, while AR-CTD and AR-NTD were higher in nuclei of epithelial cells from BPH. These results support the assumption that these constitutively active isoforms of AR are involved in the pathophysiology of primary PCa and BPH. The role of AR-Vs and their possible modulation by steroid tissue levels in distinct types of prostate tumors needs to be elucidated to help guide the best clinical management of these diseases. PMID- 30028846 TI - How font size affects judgments of learning: Simultaneous mediating effect of item-specific beliefs about fluency and moderating effect of beliefs about font size and memory. AB - Numerous studies have provided experience-based or theory-based frameworks for the basis of judgment of learning (JOL). However, few studies have directly measured processing experience and beliefs related to the same cue in one experiment and examined their joint contribution to JOLs. The present study focused on font-size effects and aimed to examine the simultaneous contribution of processing fluency and beliefs to the effect of font size on JOLs. We directly measured processing fluency via self-paced study time. We also directly measured participants' beliefs via two approaches: pre-study global differentiated predictions (GPREDs) as an indicator of preexisting beliefs about font size and memory and ease of learning judgments (EORs) as online generated item-specific beliefs about fluency. In Experiment 1, EORs partially mediated the font-size effect, whereas self-paced study time did not. In Experiments 2a and 2b, EORs mediated the font-size effect; at the same time, beliefs about font size and memory moderated the font-size effect. In summary, the present study demonstrates a major role of beliefs underlying the font-size effect. PMID- 30028847 TI - nNOS splice variants differentially regulate myofilament function but are dispensable for intracellular calcium and force transients in cardiac papillary muscles. AB - Cardiac muscle expresses three neuronal nitric oxide synthase (nNOS) splice variants: nNOSalpha, nNOSMU and nNOSbeta. The functions of these nNOS splice variants in cardiac muscle, particularly myofilament-associated nNOSbeta are unclear. To decipher cardiac nNOS splice variant function we investigated myofilament function and intracellular calcium and force transients in demembranated and intact papillary muscles from two lines of nNOS knockout mice. The first line (KN1) lacks nNOSalpha and nNOSMU. The second line (KN2) lacks active nNOSalpha, nNOSMU and nNOSbeta. Demembranated KN1 papillary muscles exhibited reduced myofilament ATPase activity (-35%) and specific force (-10%) relative to controls. Demembranated KN2 muscles exhibited a smaller decrease in myofilament ATPase activity (-21%), but a greater reduction in specific force ( 26%) relative to controls. Myofilament calcium sensitivity in demembranated KN1 and KN2 papillary muscles was similar to controls. Thus, papillary muscle expressed nNOS splice variants are necessary for control levels of myofilament ATPase activity and force generation, but dispensable for myofilament calcium sensitivity. The greater reduction in myofilament ATPase relative to specific force in KN1, but not KN2 muscle, reduced the energy cost of muscle contraction, suggesting that nNOSbeta increased the energetic efficiency of contraction in the absence of nNOSMU and nNOSalpha. Analyses of intact KN1 and KN2 papillary muscles showed that both intracellular calcium transients and their evoked force transients were similar to controls at stimulation frequencies between 1 and 3 Hz. Therefore, nNOS was dispensable for baseline excitation-contraction coupling. In summary, these data suggest that nNOS splice variants differentially regulate myofilament function, but not baseline calcium handling in papillary muscles. More importantly, they suggest that nNOSbeta is a novel modulator of myofilament function, and ultimately the energetic efficiency of cardiac papillary muscle contraction. PMID- 30028848 TI - A low-noise silicon nitride nanopore device on a polymer substrate. AB - We report a novel low-noise nanopore device employing a polymer substrate. The Si substrate of a fabricated Si-substrate-based silicon nitride (Si3N4) membrane was replaced with a polymer substrate. As such, laser machining was used to make a micro-size hole through the polyimide (PI) substrate, and a thin Si3N4 membrane was then transferred onto the PI substrate. Finally, a nanopore was formed in the membrane using a transmission electron microscope for detection of biomolecules. Compared to the Si-substrate-based device, the dielectric noise was greatly reduced and the root-mean-square noise level was decreased from 146.7 to 5.4 pA. Using this device, the translocation of double-strand deoxyribonucleic acid (DNA) was detected with a high signal/noise (S/N) ratio. This type of device is anticipated to be available for future versatile sequencing technologies. PMID- 30028849 TI - The Baltic Sea Atlantis: An integrated end-to-end modelling framework evaluating ecosystem-wide effects of human-induced pressures. AB - Achieving good environmental status in the Baltic Sea region requires decision support tools which are based on scientific knowledge across multiple disciplines. Such tools should integrate the complexity of the ecosystem and enable exploration of different natural and anthropogenic pressures such as climate change, eutrophication and fishing pressures in order to compare alternative management strategies. We present a new framework, with a Baltic implementation of the spatially-explicit end-to-end Atlantis ecosystem model linked to two external models, to explore the different pressures on the marine ecosystem. The HBM-ERGOM initializes the Atlantis model with high-resolution physical-chemical-biological and hydrodynamic information while the FISHRENT model analyses the fisheries economics of the output of commercial fish biomass for the Atlantis terminal projection year. The Baltic Atlantis model composes 29 sub-areas, 9 vertical layers and 30 biological functional groups. The balanced calibration provides realistic levels of biomass for, among others, known stock sizes of top predators and of key fish species. Furthermore, it gives realistic levels of phytoplankton biomass and shows reasonable diet compositions and geographical distribution patterns for the functional groups. By simulating several scenarios of nutrient load reductions on the ecosystem and testing sensitivity to different fishing pressures, we show that the model is sensitive to those changes and capable of evaluating the impacts on different trophic levels, fish stocks, and fisheries associated with changed benthic oxygen conditions. We conclude that the Baltic Atlantis forms an initial basis for strategic management evaluation suited for conducting medium to long term ecosystem assessments which are of importance for a number of pan-Baltic stakeholders in relation to anthropogenic pressures such as eutrophication, climate change and fishing pressure, as well as changed biological interactions between functional groups. PMID- 30028850 TI - Functional analysis of the HD-Zip transcription factor genes Oshox12 and Oshox14 in rice. AB - The homeodomain-leucine zipper (HD-Zip) transcription factor family plays vital roles in plant development and morphogenesis as well as responses to biotic and abiotic stresses. In barley, a recessive mutation in Vrs1 (HvHox1) changes two rowed barley to six-rowed barley, which improves yield considerably. The Vrs1 gene encodes an HD-Zip subfamily I transcription factor. Phylogenetic analysis has shown that the rice HD-Zip I genes Oshox12 and Oshox14 are the closest homologues of Vrs1. Here, we show that Oshox12 and Oshox14 are ubiquitously expressed with higher levels in developing panicles. Trans-activation assays in yeast and rice protoplasts demonstrated that Oshox12 and Oshox14 can bind to a specific DNA sequence, AH1 (CAAT(A/T)ATTG), and activate reporter gene expression. Overexpression of Oshox12 and Oshox14 in rice resulted in reduced panicle length and a dwarf phenotype. In addition, Oshox14 overexpression lines showed a deficiency in panicle exsertion. Our findings suggest that Oshox12 and Oshox14 may be involved in the regulation of panicle development. This study provides a significant advancement in understanding the functions of HD-Zip transcription factors in rice. PMID- 30028851 TI - The effect of epidural analgesia on cancer progression in patients with stage IV colorectal cancer after primary tumor resection: A retrospective cohort study. AB - Retrospective clinical studies showed perioperative epidural analgesia (EA) was associated with better postoperative oncologic outcomes in patients with specific types of non-metastatic cancers. This study aimed to investigate the effects of EA on cancer prognosis after surgical intervention for stage IV colorectal cancer. In this retrospective study, patients with stage IV colorectal cancer undergoing primary tumor resection and metastasectomy between January 2005 and December 2014 were classified into two groups based on their use of perioperative EA or not and evaluated through August 2016. Primary and secondary endpoints were postoperative progression-free survival (PFS) and overall survival (OS), respectively. A total of 999 patients were included and 165 (16.5%) of them received EA. The median follow-up interval was 17.5 months and no significant difference in PFS or OS was noted between the EA and non-EA groups in the univariate analysis. Multivariable Cox proportional hazards model identified four independent risk factors both for disease progression and mortality, including American Society of Anesthesiologists (ASA) physical status >= 3, higher pretreatment carcinoembryonic antigen (CEA), multiple distant metastases, and pathologic lymphovascular invasion. After adjustment for the selected risk factors, the effects of EA on PFS and OS remained non-significant (hazard ratio: 1.06, 95% CI: 0.87 to 1.29, for PFS and 0.90, 95% CI: 0.68 to 1.20 for OS). Similar findings were demonstrated by propensity score analysis. Our results did not support the association between perioperative epidural analgesia and better progression-free or overall survival in patients following stage IV colorectal cancer surgery. PMID- 30028852 TI - Integrated point-of-care testing (POCT) of HIV, syphilis, malaria and anaemia in antenatal clinics in western Kenya: A longitudinal implementation study. AB - BACKGROUND: In sub-Saharan Africa, HIV, syphilis, malaria and anaemia are leading preventable causes of adverse pregnancy outcomes. In Kenya, policy states women should be tested for all four conditions (malaria only if febrile) at first antenatal care (ANC) visit. In practice, while HIV screening is conducted, coverage of screening for the others is suboptimal and early pregnancy management of illnesses is compromised. This is particularly evident at rural dispensaries that lack laboratories and have parallel programmes for HIV, reproductive health and malaria, resulting in fractured and inadequate care for women. METHODS: A longitudinal eight-month implementation study integrating point-of-care diagnostic tests for the four conditions into routine ANC was conducted in seven purposively selected dispensaries in western Kenya. Testing proficiency of healthcare workers was observed at initial training and at three monthly intervals thereafter. Adoption of testing was compared using ANC register data 8.5 months before and eight months during the intervention. Fidelity to clinical management guidelines was determined by client exit interviews with success defined as >=90% adherence. FINDINGS: For first ANC visits at baseline (n = 529), testing rates were unavailable for malaria, low for syphilis (4.3%) and anaemia (27.8%), and near universal for HIV (99%). During intervention, over 95% of first attendees (n = 586) completed four tests and of those tested positive, 70.6% received penicillin or erythromycin for syphilis, 65.5% and 48.3% received cotrimoxazole and antiretrovirals respectively for HIV, and 76.4% received artemether/lumefantrine, quinine or dihydroartemisinin-piperaquine correctly for malaria. Iron and folic supplements were given to nearly 90% of women but often at incorrect doses. CONCLUSIONS: Integrating point-of-care testing into ANC at dispensaries with established HIV testing programmes resulted in a significant increase in testing rates, without disturbing HIV testing rates. While more cases were detected and treated, treatment fidelity still requires strengthening and an integrated monitoring and evaluation system needs to be established. PMID- 30028853 TI - Expansion of the TLO gene family enhances the virulence of Candida species. AB - The TLO genes are a family of subtelomeric ORFs in the fungal pathogens Candida albicans and C. dubliniensis encoding a subunit of the Mediator complex homologous to Med2. The more virulent pathogen C. albicans has 15 copies of the gene whereas the less pathogenic species C. dubliniensis has only two. To investigate if expansion of the TLO repertoire in C. dubliniensis has an effect on phenotype and virulence we expressed three representative C. albicans TLO genes (TLObeta2, TLOgamma11 and TLOalpha12) in a wild type C. dubliniensis background, under the control of either their native or the ACT1 promoter. Expression of TLObeta2 resulted in a hyperfilamentous phenotype, while overexpression of TLOgamma11 and TLOalpha12 resulted in enhanced resistance to oxidative stress. Expression of all three TLO genes from the ACT1 promoter resulted in increased virulence in the Galleria infection model. In order to further investigate if individual TLO genes exhibit differences in function we expressed six representative C. albicans TLO genes in a C. dubliniensis Deltatlo1/Deltatlo2 double mutant. Differences were observed in the ability of the expressed CaTLOs to complement the various phenotypes of the mutant. All TLO genes with the exception of TLOgamma7 could restore filamentation, however only TLOalpha9, gamma11 and alpha12 could restore chlamydospore formation. Differences in the ability of CaTLO genes to restore growth in the presence of H2O2, calcofluor white, Congo red and at 42 degrees C were observed. Only TLOalpha3 restored wild-type levels of virulence in the Galleria infection model. These data show that expansion of the TLO gene family in C. dubliniensis results in gain of function and that there is functional diversity amongst members of the gene family. We propose that this expansion of the TLO family contributes to the success of C. albicans as a commensal and opportunistic pathogen. PMID- 30028855 TI - Seasonal variation in preference dictates space use in an invasive generalist. AB - BACKGROUND: The spatiotemporal distribution of resources is a critical component of realized animal distributions. In agricultural landscapes, space use by generalist consumers is influenced by ephemeral resource availability that may produce behavioral differences across agricultural seasons, resulting in economic and production consequences and increased human-wildlife conflict. Our objective was to assess changes in habitat selection across seasons in an invasive generalist omnivore (feral pigs, Sus scrofa). Hypothesizing that pig space use is primarily driven by forage availability, we predicted strong selection for the most nutritionally beneficial crops and resource types as agricultural seasons progressed. We deployed GPS collars on 13 adult feral pigs in the Mississippi Alluvial Valley to study resource selection in a fragmented agricultural landscape. We estimated resource selection using mixed-effect logistic regression to assess variation in selection across planting, growing, harvest, and fallow seasons. RESULTS: We found that feral pigs varied resource selection across seasons, particularly for corn (Zea mais). We also detected seasonal dependencies in proportional coverage on the net probability of selection of a land unit (e.g., selection was generally strongest for locations composed of both agricultural and natural habitat), resulting in marked variation in predicted space use among agricultural seasons. CONCLUSIONS: These findings indicate behavioral changes in selection across agricultural seasons are driven by complex interactions between the availabilities of temporally dynamic resources and temporally static natural cover. Temporal variations in resource selection trends indicate seasonal responses to crop phenology which suggests a season-specific habitat functional response. PMID- 30028854 TI - Estimating the discretization dependent accuracy of perfusion in coupled capillary flow measurements. AB - One-compartment models are widely used to quantify hemodynamic parameters such as perfusion, blood volume and mean transit time. These parameters are routinely used for clinical diagnosis and monitoring of disease development and are thus of high relevance. However, it is known that common estimation techniques are discretization dependent and values can be erroneous. In this paper we present a new model that enables systematic quantification of discretization errors. Specifically, we introduce a continuous flow model for tracer propagation within the capillary tissue, used to evaluate state-of-the-art one-compartment models. We demonstrate that one-compartment models are capable of recovering perfusion accurately when applied to only one compartment, i.e. the whole region of interest. However, substantial overestimation of perfusion occurs when applied to fractions of a compartment. We further provide values of the estimated overestimation for various discretization levels, and also show that overestimation can be observed in real-life applications. Common practice of using compartment models for fractions of tissue violates model assumptions and careful interpretation is needed when using the computed values for diagnosis and treatment planning. PMID- 30028856 TI - Evaluation of pathogenicity of Salmonella Gallinarum strains harbouring deletions in genes whose orthologues are conserved pseudogenes in S. Pullorum. AB - The diseases caused by Salmonella Gallinarum and S. Pullorum in chickens known as fowl typhoid and pullorum disease, respectively, pose a great threat to the poultry industry mainly in developing countries, since they have already been controlled in the developed ones. These bacteria are very similar at the genomic level but develop distinct host-pathogen relationships with chickens. Therefore, a deep understanding of the molecular mechanisms whereby S. Gallinarum and S. Pullorum interact with the host could lead to the development of new approaches to control and, perhaps, eradicate both diseases from the chicken flocks worldwide. Based on our previous study, it was hypothesised that metabolism related pseudogenes, fixed in S. Pullorum genomes, could play a role in the distinct host-pathogen interaction with susceptible chickens. To test this idea, three genes (idnT, idnO and ccmH) of S. Gallinarum str. 287/91, which are pseudogenes on the S. Pullorum chromosomes, were inactivated by mutations. These genetically engineered strains grew well on the solid media without any colony morphology difference. In addition, similar growth curves were obtained by cultivation in M9 minimal medium containing D-gluconate as the sole carbon source. Infection of chickens with idnTO mutants led to increased numbers of bacteria in the livers and spleens at 5 days post-infection, but with slightly decreased heterophil infiltration in the spleens when compared to the wild-type strain. On the other hand, no significant phenotypic change was caused by mutation to ccmH genes. Apart from the above-mentioned alterations, all S. Gallinarum strains provoked similar infections, since mortality, clinical signs, macroscopic alterations and immune response were similar to the infected chickens. Therefore, according to the model applied to this study, mutation to the idnTO and ccmH genes showed minor impact on the fowl typhoid pathogenesis and so they may be relics from the ancestor genome. Our data hints at a more complex mechanism driving the distinct host-pathogen interaction of S. Gallinarum/Pullorum with chickens than differential inactivation of a few genes. PMID- 30028857 TI - Twin Peaks: A spatial and temporal study of twinning rates in Brazil. AB - Twin births are an important public health issue due to health complications for both mother and children. While it is known that contemporary factors have drastically changed the epidemiology of twins in certain developed countries, in Brazil, relevant data are still scarce. Thus, we carried out a population-based study of live births in spatial and temporal dimensions using data from Brazil's Live Birth Information System, which covers the entire country. Over 41 million births registered between 2001 and 2014 were classified as singleton, twin or multiple. Twinning rates (TR) averaged 9.41 per 1,000 for the study period and a first-order autoregressive model of time-series analysis revealed a global upward trend over time; however, there were important regional differences. In fact, a Cluster and Outlier Analysis (Anselin Local Moran's I) was performed and identified clusters of high TR in an area stretching from the south of Brazil's Northeast Region to the South Region (Global Moran Index = 0.062, P < 0.001). Spearman's correlation coefficient and a Wilcoxon matched pairs test revealed a positive association between Human Development Index (HDI) and TRs in different scenarios, suggesting that the HDI might be an important indicator of childbearing age and assisted reproduction techniques in Brazil. Furthermore, there was a sharp increase of 26.42% in TR in women aged 45 and over during study period. The upward temporal trend in TRs is in line with recent observations from other countries, while the spatial analysis has revealed two very different realities within the same country. Our approach to TR using HDI as a proxy for underlying socioeconomic changes can be applied to other developing countries with regional inequalities resembling those found in Brazil. PMID- 30028860 TI - Impact of intense disturbance on the structure and composition of wet-eucalypt forests: A case study from the Tasmanian 2016 wildfires. AB - Fire is a key process in eucalypt communities, exerting a strong influence on the composition, structure and functioning of forests. Much of the research on the fire response of temperate, wet-sclerophyll trees in Australia comes from Victoria, where the dominant eucalypt is Eucalyptus regnans. In contrast, central and northern Tasmanian forests, dominated by Eucalyptus delegatensis, are relatively understudied. There is a need to determine whether Tasmanian wet sclerophyll forests, though the same forest type in name, are functionally different in floristics and response to fire. Here we document the forest community response to a natural wildfire event in Tasmania-using opportunistic before/after control/impact (BACI) data from pre-existing monitoring plots. Uniting pre- and post-fire floristic data, we quantified mortality and regeneration of eucalypt, acacia and other dominant tree species, and tree ferns, Dicksonia antarctica, in response to wildfire. We also evaluated the density of eucalypt and acacia seedling establishment between burnt and unburnt forests, and quantified faunal responses to fire. Despite moderate-to-high intensity burning in patches across the plot, mortality of eucalypts, acacias and tree ferns due to fire were low. By contrast, fire-sensitive rainforest species showed low survival, though were able to persist in unburnt refugia. Eucalypt and acacia seedling regeneration was high in the burnt plot, suggesting that E. delegatensis forests regenerate without stand-replacing fire events. This contrasts to Victorian E. regnans forests, whose persistence is dependent on high-severity stand-replacing events. We also found some group-specific avifaunal and invertebrate responses to the fire event, which are broadly reflective of responses documented in other Victorian-based studies. Our results have implications for Tasmanian wet-forest silvicultural practices, which are based on the principle of stand-replacement after fire. The broader relevance of this work to forest ecology is in demonstrating the serendipitous opportunities that can arise with baseline monitoring plots. PMID- 30028859 TI - Genome-wide association studies of inflammatory bowel disease in German shepherd dogs. AB - Canine Inflammatory Bowel Disease (IBD) is considered a multifactorial disease caused by complex interactions between the intestinal immune system, intestinal microbiota and environmental factors in genetically susceptible individuals. Although IBD can affect any breed, German shepherd dogs (GSD) in the UK are at increased risk of developing the disease. Based on previous evidence, the aim of the present study was to identify single nucleotide polymorphisms (SNPs), which may confer genetic susceptibility or resistance to IBD using a genome-wide association study (GWAS). Genomic DNA was extracted from EDTA blood or saliva samples of 96 cases and 98 controls. Genotyping of cases and controls was performed on the Canine Illumina HD SNP array and data generated was analyzed using PLINK. Several SNPs and regions on chromosomes 7,9,11 and 13 were detected to be associated with IBD using different SNP-by-SNP association methods and FST windows approach. Searching one Mb up-and down-stream of the most significant SNPs, as identified by single SNP analysis as well as 200Kb before and after the start and the end position of the associated regions identified by FST windows approach, we identified 63 genes. Using a combination of pathways analysis and a list of genes that have been reported to be involved in human IBD, we identified 16 candidate genes potentially associated with IBD in GSD. PMID- 30028861 TI - The role of energy in health facilities: A conceptual framework and complementary data assessment in Malawi. AB - BACKGROUND: Modern energy enables health service delivery. Access to electricity is, however, unreliable in many health facilities in developing countries. Little research has explored the relationships between energy and service delivery. METHODS: Based on extensive literature searches and iterative discussions within the research team, we first develop a conceptual framework of the role of energy in health facilities. We then use this framework to explore how characteristics of electricity supply affect distinct energy uses in health facilities (e.g. lighting), and how functional or non-functional lighting affects the provision of night-time care services in Malawi. To do so we apply descriptive statistics and conduct logistic and multinomial regressions using data from the Service Provision Assessment (SPA) of the Demographic and Health Surveys (DHS) for all health facilities in Malawi in 2013/2014. RESULTS: The conceptual framework depicts the pathways from different energy types and their characteristics, through to distinct energy uses in health facilities (e.g. medical devices) and health-relevant service outputs (e.g. safe medical equipment). These outputs can improve outcomes for patients (e.g. infection control), facilities (e.g. efficiency) and staff (e.g. working conditions) at facilities level and, ultimately, contribute to better population health outcomes. Our exploratory analysis suggests that energy uses were less likely to be functional in facilities with lower-quality electricity supply. Descriptive statistics revealed a critical lack of functional lighting in facilities offering child delivery and night-time care; surprisingly, the provision of night-time care was not associated with whether facilities had functional lighting. Overall, the DHS SPA dataset is not well-suited for assessing the relationships depicted within the framework. CONCLUSION: The framework conceptualizes the role of energy in health facilities in a comprehensive manner. Over time, it should be empirically validated through a combination of different research approaches, including tracking of indicators, detailed energy audits, qualitative and intervention studies. PMID- 30028858 TI - Updated evidence of the association between toxocariasis and epilepsy: Systematic review and meta-analysis. AB - OBJECTIVE: To gain further insight on the association between human toxocariasis and epilepsy in light of the new evidence in the last years. METHODS: A systematic review was conducted without date and language restriction in the following electronic databases: MEDLINE (PubMed), Ingenta Connect, Science Direct (Elsevier), RefDoc, Scopus, HighWire, Scielo and the database of the Institute of Neuroepidemiology and Tropical Neurology of the Limoges University (IENT). Two investigators independently conducted the search up to November 2017. A pooled odds ratio (OR) was estimated using a random effects model. Meta-regression was conducted to investigate potential sources of heterogeneity. RESULTS: Database search produced 204 publications. Eleven case-control studies were included that were carried out in 13 countries worldwide. A total number of 4740 subjects were considered (2159 people with epilepsy and 2581 people without epilepsy). The overall pooled OR was 1.69 (95% CI 1.42-2.01) for the association between epilepsy and Toxocara spp. seropositivity. A positive association was constantly reported in the restricted analysis (WB as confirmatory or diagnostic test, younger population, and population-based studies). Meta-regression showed no statistically significant association between covariates and outcome. CONCLUSION: The updated meta-analysis provides epidemiological evidence of a positive association between Toxocara seropositivity and epilepsy. New surveys supported the association, mainly population-based studies. On this basis, health strategies to reduce the impact of Toxocara spp are strongly advised. Further research should be performed to understand the physiopathological mechanisms of toxocara-associated epileptogenesis. PMID- 30028862 TI - Prehypertension increases the risk of atherosclerosis in drug-naive Japanese patients with type 2 diabetes mellitus. AB - PURPOSE: Hypertension is a risk factor of atherosclerotic diseases. However, the importance of prehypertension in Japanese patients with type 2 diabetes mellitus (T2DM) is controversial. The aim of this study was to examine association between prehypertension, hypertension and atherosclerosis in T2DM. METHODS: We recruited 179 Japanese patients with T2DM, who never took any medication for diabetes, hypertension, dyslipidemia, or atherosclerosis. Intima-media thickness (IMT) of common carotid artery was evaluated by high-resolution B-mode ultrasonography. RESULTS: Multiple regression analysis adjusted for age, duration of diabetes, body mass index, HbA1c, fasting C-peptide, triglyceride, HDL-cholesterol, LDL cholesterol, and estimated glomerular filtration rate showed that systolic blood pressure (SBP), but not diastolic BP, was significantly and positively associated with maximum IMT (IMT-max), mean IMT, and plaque score (beta = 0.28, p<0.001; beta = 0.26, p = 0.047; and beta = 0.25, p = 0.006, respectively). ROC analysis showed that the cut-off value of SBP to detect atherosclerosis (IMT-max 1.8mm, the mean of IMT-max of this subjects) was 133.5 (p = 0.008), while DBP was not useful to detect it (p = 0.433). Then, participants were categorized as normotension (SBP <119 mmHg), prehypertension (SBP 120-139 mmHg), and hypertension (>140 mmHg). Multiple logistic regression analysis adjusted for the variables described above plus gender and smoking showed that prehypertension and hypertension were significantly associated with the increased risk of atherosclerosis [prehypertension; odds ratio (OR) 3.45, 95% confidence interval (CI) 1.11-10.76, p = 0.033, and hypertension; OR 7.29, 95%CI 1.99-26.78, p = 0.003]. CONCLUSION: These findings suggest that prehypertension categorized by SBP is an important risk factor of atherosclerosis independently of conventional risk factors in patients with T2DM. PMID- 30028863 TI - Patient empowerment in young persons with chronic conditions: Psychometric properties of the Gothenburg Young Persons Empowerment Scale (GYPES). AB - PURPOSE: Empowerment in patients can lead to a higher participation in care and self-management skills. However, there are a limited number of high-quality instruments to assess empowerment and its various dimensions in young persons. The aim was to develop and assess the psychometric properties of the Gothenburg Young Persons Empowerment Scale (GYPES). METHODS: The GYPES is a 15-item questionnaire designed to measure patient empowerment in young persons with chronic conditions. Three studies were conducted to evaluate the psychometric properties of the scale. Studies I and II assessed face, content and factorial validity, as well as responsiveness and reliability in young persons with congenital heart disease and diabetes. After these studies problematic items were identified and reworded and the final version of the GYPES was tested in young persons with diabetes in study III. RESULTS: The content and face validity of the scale was confirmed in study I. Confirmatory factor analyses (CFA) in study II supported the five-factor structure of the GYPES. However, one item had a low factor loading. The scale was revised and evaluated in study III. CFA of this version supported adequate model fit with factor loadings ranging from 0.385 0.941. A second-order model had an adequate fit to the data. Cronbach's alpha for the overall scale was 0.858 and for each subscale, alphas range from 0.609-0.858. CONCLUSIONS: GYPES was developed to measure patient empowerment in young persons with chronic conditions. Preliminary evidence supports that the GYPES may be a valid and reliable tool for assessing young persons' empowerment. PMID- 30028864 TI - Testing a novel isokinetic dynamometer constructed using a 1080 Quantum. AB - This study sought to assess the reliability and comparability of two custom-built isokinetic dynamometers (Model A and Model B) with the gold-standard (Humac Norm). The two custom-built dynamometers consisted of commercially available leg extension machines attached to a robotically controlled resistance device (1080 Quantum), able to measure power, force and velocity outputs. Twenty subjects (14m/6f, 26+/-4.8yr, 176+/-7cm, 74.4+/-12.4kg) performed concentric leg extensions on the custom-built dynamometers and the Humac Norm. Fifteen maximal leg extensions were performed with each leg at 180 degrees s-1, or the linear equivalent (~0.5m s-1). Peak power (W), mean power (W), and fatigue indexes (%) achieved on all three devices were compared. Both custom-built dynamometers revealed high reliability for peak and mean power on repeated tests (ICC>0.88). Coefficient of variation (CV) and standard error of measurement (SEM) were small when comparing power outputs obtained using Model A and the Humac Norm ([Formula: see text] CV = 9.0%, [Formula: see text] SEM = 49W; peak CV = 8.4%, peak SEM = 49W). Whereas, Model B had greater variance ([Formula: see text] CV = 13.3% [Formula: see text] SEM = 120W; peak CV = 14.7%, peak SEM = 146W). The custom built dynamometers are capable of highly reliable measures, but absolute power outputs varied depending on the leg extension model. Consistent use of a single model offers reliable results for tracking muscular performance over time or testing an intervention. PMID- 30028865 TI - Social knowledge and social reasoning abilities in a neurotypical population and in children with Down syndrome. AB - Social knowledge refers to the ability to analyze and reason about social situations in relation to social rules which are essential to the development of social skills and social behavior. The present research aimed to assess these abilities with the "Social resolution task" in a neurotypical population of 351 children (4 to 12 years) and 39 young adults, and in 20 participants (10 to 18 years) with Down syndrome. Results showed that young children aged 4 to 6 were well able to distinguish between appropriate and inappropriate social behavior but they had significantly more difficulties in judging and identifying social cues for the transgression of conventional rules than for moral ones. Between age 4 and 8, their social reasoning was mainly based on factual answers, while older children showed significantly more social awareness, making more reference to emotional and social consequences for the "victims". The representation of a more universal applicability of social rules seemed to develop later in childhood, as of age 8. In contrast, participants with Down syndrome exhibited significantly more difficulties in judging, identifying and reasoning about transgression of social rules without social awareness. In conclusion, the results have shown that social reasoning abilities develop throughout childhood. Social awareness seems to have a long developmental course, which includes a sensibility about welfare and intersubjectivity, critical for the development of prosocial behavior. The clinical population with difficulties in social interaction and socio-emotional behavior could benefit from an early assessment and from learning social reasoning abilities to improve social skills. PMID- 30028866 TI - Comparing species richness, functional diversity and functional composition of waterbird communities along environmental gradients in the neotropics. AB - Waterbirds have a major functional role in wetlands, and understanding how functional traits of waterbirds depend on environmental characteristics can facilitate management of ecosystems and their services. We investigate how the waterbird community in a Neotropical river-floodplain system responds to environmental gradients, identifying how they affect waterbird species richness, functional diversity (measured as functional dispersion) and functional composition (specific functional traits). We sampled 22 lakes in the Upper Parana floodplain system in southern Brazil, and modelled avian functional diversity and species richness as a function of environmental variables. Then we used a unified RLQ and fourth-corner analysis to evaluate environment-trait relationships. Waterbird species richness and functional diversity varied according to different environmental variables. Lake area and diversity of aquatic vegetation were associated with avian species richness, while relative abundance of grass and emergent macrophytes and mean and variation of depth were related to functional diversity. Furthermore, changes in functional diversity seemed to be mainly driven by presence of species that depend on perches for foraging (e.g. kingfishers, cormorants, and kites), whose presence was mainly associated with deep water and emergent macrophytes. Nevertheless, changes in functional diversity and functional composition did not depend on exactly the same set of environmental variables, suggesting that trait combinations (e.g. below surface feeders who feed on fish), not only specific traits, are important drivers of the variation in functional diversity between lakes. Given the observed differences in responses of species richness and functional diversity, both these diversity metrics should be used as complementary tools in ecosystem management. Furthermore, our results show that functional diversity and composition are partially coupled, suggesting that although functional diversity is influenced by the environmental filtering of particular traits, it also reflects other ecological mechanisms (e.g. competitive interactions among species). PMID- 30028867 TI - Comparative validation of a microcapsule-based immunoassay for the detection of proteins and nucleic acids. AB - To detect and study diseases, research and clinical laboratories must quantify specific biomarkers in the plasma and urine of patients with precision, sensitivity, and cost-effectiveness. Newly developed techniques, such as particle based immunoassays, must be validated in these terms against standard methods such as enzyme-linked immunosorbent assays (ELISAs). Here, we compare the performance of assays that use hollow polyelectrolyte microcapsules with assays based on solid plastic beads, and with standard microplate immunoassays. The polyelectrolyte microcapsules detect the disease biomarker beta-2 microglobulin with a fifty-fold increase in sensitivity than polystyrene (PS) beads. For sequence-specific nucleic acid detection, the oligonucleotide-coated microcapsules exhibit a two-fold lower increase in sensitivity over PS beads. The microcapsules also detect the presence of a monoclonal antibody in hybridoma supernatant at a fifty-six-fold increase in sensitivity compared to a microplate assay. Overall, polyelectrolyte microcapsule-based assays are more sensitive for the detection of protein and nucleic acid analytes than PS beads and microplate assays, and they are viable alternatives as a platform for the rapid quantitative detection of analytes at very low concentrations. PMID- 30028868 TI - BST-2 controls T cell proliferation and exhaustion by shaping the early distribution of a persistent viral infection. AB - The interferon inducible protein, BST-2 (or, tetherin), plays an important role in the innate antiviral defense system by inhibiting the release of many enveloped viruses. Consequently, viruses have evolved strategies to counteract the anti-viral activity of this protein. While the mechanisms by which BST-2 prevents viral dissemination have been defined, less is known about how this protein shapes the early viral distribution and immunological defense against pathogens during the establishment of persistence. Using the lymphocytic choriomeningitis virus (LCMV) model of infection, we sought insights into how the in vitro antiviral activity of this protein compared to the immunological defense mounted in vivo. We observed that BST-2 modestly reduced production of virion particles from cultured cells, which was associated with the ability of BST-2 to interfere with the virus budding process mediated by the LCMV Z protein. Moreover, LCMV does not encode a BST-2 antagonist, and viral propagation was not significantly restricted in cells that constitutively expressed BST-2. In contrast to this very modest effect in cultured cells, BST-2 played a crucial role in controlling LCMV in vivo. In BST-2 deficient mice, a persistent strain of LCMV was no longer confined to the splenic marginal zone at early times post infection, which resulted in an altered distribution of LCMV-specific T cells, reduced T cell proliferation / function, delayed viral control in the serum, and persistence in the brain. These data demonstrate that BST-2 is important in shaping the anatomical distribution and adaptive immune response against a persistent viral infection in vivo. PMID- 30028869 TI - 3D similarities between the binding sites of monoaminergic target proteins. AB - The study of binding site similarities can be relevant to understand the interaction of different drugs at several molecular targets. The increasing availability of protein crystal structures and the development of novel algorithms designed to evaluate three-dimensional similarities, represent a great opportunity to explore the existence of electronic and shape features shared by clinically relevant proteins, which could assist drug design and discovery. Proteins involved in the recognition of monoaminergic neurotransmitters, such as monoamine transporters or monoamine oxidases (MAO) have been related to several psychiatric and neurological disorders such as depression or Parkinson's disease. In this work, we evaluated the possible existence of similarities among the binding sites of the serotonin transporter (SERT), the dopamine transporter (DAT), MAO-A and MAO-B. This study was carried out using molecular simulation methodologies linked to the statistical algorithm PocketMatch, which was modified in order to obtain similarities profiles. Our results show that DAT and SERT exhibit a high degree of 3-D similarities all along the pathway that is presumably involved in the substrate transport process. Distinct differences, on the other hand, were found both at the extracellular and the intracellular ends of the transporters, which might be involved in the selective initial recognition of the corresponding substrate. Similarities were also found between the active (catalytic) site of MAO-A and the extracellular vestibule of SERT (the S2 binding site). These results suggest some degree of structural convergence for these proteins, which have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand (serotonin). Beyond the functional implications, these findings are valuable for the design of both selective and non-selective ligands. PMID- 30028870 TI - Expression and purification of a functional heteromeric GABAA receptor for structural studies. AB - The GABA-gated chloride channels of the Cys-loop receptor family, known as GABAA receptors, function as the primary gatekeepers of fast inhibitory neurotransmission in the central nervous system. Formed by the pentameric arrangement of five identical or homologous subunits, GABAA receptor subtypes are defined by the subunit composition that shape ion channel properties. An understanding of the structural basis of distinct receptor properties has been hindered by the absence of high resolution structural information for heteromeric assemblies. Robust heterologous expression and purification protocols of high expressing receptor constructs are vital for structural studies. Here, we describe a unique approach to screen for well-behaving and functional GABAA receptor subunit assemblies by using the Xenopus oocyte as an expression host in combination with fluorescence detection size exclusion chromatography (FSEC). To detect receptor expression, GFP fusions were introduced into the alpha1 subunit isoform. In contrast to expression of alpha1 alone, co-expression with the beta subunit promoted formation of monodisperse assemblies. Mutagenesis experiments suggest that the alpha and beta subunits can tolerate large truncations in the non-conserved M3/M4 cytoplasmic loop without compromising oligomeric assembly or GABA-gated channel activity, although removal of N-linked glycosylation sites is negatively correlated with expression level. Additionally, we report methods to improve GABAA receptor expression in mammalian cell culture that employ recombinant baculovirus transduction. From these methods we have identified a well-behaving minimal functional construct for the alpha1/beta1 GABAA receptor subtype that can be purified in milligram quantities while retaining high affinity agonist binding activity. PMID- 30028872 TI - Tissue-resident NK cells differ in their expression profile of the nutrient transporters Glut1, CD98 and CD71. AB - Metabolism is a critical basis for immune cell functionality. It was recently shown that NK cell subsets from peripheral blood modulate their expression of nutrient receptors following cytokine stimulation, demonstrating that NK cells can adjust to changes in metabolic requirements. As nutrient availability in blood and tissues can significantly differ, we examined NK cells isolated from paired blood-liver and blood-spleen samples and compared expression of the nutrient transporters Glut1, CD98 and CD71. CD56bright tissue-resident (CXCR6+) NK cells derived from livers and spleens expressed lower levels of Glut1 but higher levels of the amino acid transporter CD98 following stimulation than CD56bright NK cells from peripheral blood. In line with that, CD56dim NK cells, which constitute the main NK cell population in the peripheral blood, expressed higher levels of Glut1 and lower levels of CD98 and CD71 compared to liver CD56bright NK cells. Our results show that NK cells from peripheral blood differ from liver- and spleen-resident NK cells in the expression profile of nutrient transporters, consistent with a cell-adaptation to the different nutritional environment in these compartments. PMID- 30028871 TI - An annotated CNS transcriptome of the medicinal leech, Hirudo verbana: De novo sequencing to characterize genes associated with nervous system activity. AB - The medicinal leech is one of the most venerated model systems for the study of fundamental nervous system principles, ranging from single-cell excitability to complex sensorimotor integration. Yet, molecular analyses have yet to be extensively applied to complement the rich history of electrophysiological study that this animal has received. Here, we generated the first de novo transcriptome assembly from the entire central nervous system of Hirudo verbana, with the goal of providing a molecular resource, as well as to lay the foundation for a comprehensive discovery of genes fundamentally important for neural function. Our assembly generated 107,704 contigs from over 900 million raw reads. Of these 107,704 contigs, 39,047 (36%) were annotated using NCBI's validated RefSeq sequence database. From this annotated central nervous system transcriptome, we began the process of curating genes related to nervous system function by identifying and characterizing 126 unique ion channel, receptor, transporter, and enzyme contigs. Additionally, we generated sequence counts to estimate the relative abundance of each identified ion channel and receptor contig in the transcriptome through Kallisto mapping. This transcriptome will serve as a valuable community resource for studies investigating the molecular underpinnings of neural function in leech and provide a reference for comparative analyses. PMID- 30028873 TI - Retrograde axonal transport of rabies virus is unaffected by interferon treatment but blocked by emetine locally in axons. AB - Neuroinvasive viruses, such as alpha herpesviruses (alphaHV) and rabies virus (RABV), initially infect peripheral tissues, followed by invasion of the innervating axon termini. Virus particles must undergo long distance retrograde axonal transport to reach the neuron cell bodies in the peripheral or central nervous system (PNS/CNS). How virus particles hijack the axonal transport machinery and how PNS axons respond to and regulate infection are questions of significant interest. To track individual virus particles, we constructed a recombinant RABV expressing a P-mCherry fusion protein, derived from the virulent CVS-N2c strain. We studied retrograde RABV transport in the presence or absence of interferons (IFN) or protein synthesis inhibitors, both of which were reported previously to restrict axonal transport of alphaHV particles. Using neurons from rodent superior cervical ganglia grown in tri-chambers, we showed that axonal exposure to type I or type II IFN did not alter retrograde axonal transport of RABV. However, exposure of axons to emetine, a translation elongation inhibitor, blocked axonal RABV transport by a mechanism that was not dependent on protein synthesis inhibition. The minority of RABV particles that still moved retrograde in axons in the presence of emetine, moved with slower velocities and traveled shorter distances. Emetine's effect was specific to RABV, as transport of cellular vesicles was unchanged. These findings extend our understanding of how neuroinvasion is regulated in axons and point toward a role for emetine as an inhibitory modulator of RABV axonal transport. PMID- 30028874 TI - A bimodal switch in global protein translation coupled to eIF4H relocalisation during advancing cell-cell transmission of herpes simplex virus. AB - We used the bioorthogonal protein precursor, homopropargylglycine (HPG) and chemical ligation to fluorescent capture agents, to define spatiotemporal regulation of global translation during herpes simplex virus (HSV) cell-to-cell spread at single cell resolution. Translational activity was spatially stratified during advancing infection, with distal uninfected cells showing normal levels of translation, surrounding zones at the earliest stages of infection with profound global shutoff. These cells further surround previously infected cells with restored translation close to levels in uninfected cells, reflecting a very early biphasic switch in translational control. While this process was dependent on the virion host shutoff (vhs) function, in certain cell types we also observed temporally altered efficiency of shutoff whereby during early transmission, naive cells initially exhibited resistance to shutoff but as infection advanced, naive target cells succumbed to more extensive translational suppression. This may reflect spatiotemporal variation in the balance of oscillating suppression recovery phases. Our results also strongly indicate that a single particle of HSV 2, can promote pronounced global shutoff. We also demonstrate that the vhs interacting factor, eIF4H, an RNA helicase accessory factor, switches from cytoplasmic to nuclear localisation precisely correlating with the initial shutdown of translation. However translational recovery occurs despite sustained eIF4H nuclear accumulation, indicating a qualitative change in the translational apparatus before and after suppression. Modelling simulations of high multiplicity infection reveal limitations in assessing translational activity due to sampling frequency in population studies and how analysis at the single cell level overcomes such limitations. The work reveals new insight and a revised model of translational manipulation during advancing infection which has important implications both mechanistically and with regards to the physiological role of translational control during virus propagation. The work also demonstrates the potential of bioorthogonal chemistry for single cell analysis of cellular metabolic processes during advancing infections in other virus systems. PMID- 30028875 TI - Potent and selective effect of the mir-10b inhibitor MN-anti-mir10b in human cancer cells of diverse primary disease origin. AB - Since microRNAs (miRNAs, miRs) have been implicated in oncogenesis, many of them have been identified as therapeutic targets. Previously we have demonstrated that miRNA-10b acts as a master regulator of the viability of metastatic tumor cells and represents a target for therapeutic intervention. We designed and synthesized an inhibitor of miR-10b, termed MN-anti-miR10b. We showed that treatment with MN anti-miR10b led to durable regression/elimination of established metastases in murine models of metastatic breast cancer. Since miRNA-10b has been associated with various metastatic and non-metastatic cancers, in the present study, we investigated the effect of MN-anti-miR10b in a panel of over 600 cell lines derived from a variety of human malignancies. We observed an effect on the viability of multiple cell lines within each cancer type and a mostly dichotomous response with cell lines either strongly responsive to MN-anti-miR10b or not at all even at maximum dose tested, suggesting a very high specificity of the effect. Genomic modeling of the drug response showed enrichment of genes associated with the proto-oncogene, c-Jun. PMID- 30028876 TI - Light induces oxidative damage and protein stability in the fungal photoreceptor Vivid. AB - Flavin-binding photoreceptor proteins sense blue-light (BL) in diverse organisms and have become core elements in recent optogenetic applications. The light oxygen-voltage (LOV) protein Vivid (VVD) from the filamentous fungus Neurospora crassa is a classic BL photoreceptor, characterized by effecting a photocycle based on light-driven formation and subsequent spontaneous decay of a flavin cysteinyl adduct. Here we report that VVD presents alternative outcomes to light exposure that result in protein self-oxidation and, unexpectedly, rise of stability through kinetic control. Using optical absorbance and mass spectrometry we show that purified VVD develops amorphous aggregates with the presence of oxidized residues located at the cofactor binding pocket. Light exposure increases oxidative levels in VVD and specific probe analysis identifies singlet oxygen production by the flavin. These results indicate that VVD acts alternatively as a photosensitizer, inducing self-oxidative damage and subsequent aggregation. Surprisingly, BL illumination has an additional, opposite effect in VVD. We show that light-induced adduct formation establishes a stable state, delaying protein aggregation until photoadduct decay occurs. In accordance, repeated BL illumination suppresses VVD aggregation altogether. Furthermore, photoadduct formation confers VVD stability against chemical denaturation. Analysis of the aggregation kinetics and testing of stabilizers against aggregation reveal that aggregation in VVD proceeds through light-dependent kinetic control and dimer formation. These results uncover the aggregation pathway of a photosensor, where light induces a remarkable interplay between protein damage and stability. PMID- 30028877 TI - Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus. AB - Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. How RABV interacts with host neuron membrane receptors to become internalized and cause rabid symptoms is not yet fully understood. Here, we identified a novel receptor of RABV, which RABV uses to infect neurons. We found that metabotropic glutamate receptor subtype 2 (mGluR2), a member of the G protein-coupled receptor family that is abundant in the central nervous system, directly interacts with RABV glycoprotein to mediate virus entry. RABV infection was drastically decreased after mGluR2 siRNA knock-down in cells. Antibodies to mGluR2 blocked RABV infection in cells in vitro. Moreover, mGluR2 ectodomain soluble protein neutralized the infectivity of RABV cell-adapted strains and a street strain in cells (in vitro) and in mice (in vivo). We further found that RABV and mGluR2 are internalized into cells and transported to early and late endosomes together. These results suggest that mGluR2 is a functional cellular entry receptor for RABV. Our findings may open a door to explore and understand the neuropathogenesis of rabies. PMID- 30028878 TI - Human immune cell engraftment does not alter development of severe acute Rift Valley fever in mice. AB - Rift Valley fever (RVF) in humans is usually mild, but, in a subset of cases, can progress to severe hepatic and neurological disease. Rodent models of RVF generally develop acute severe clinical disease. Here, we inoculated humanized NSG-SGM3 mice with Rift Valley fever virus (RVFV) to investigate whether the presence of human immune cells in mice would alter the progression of RVFV infection to more closely model human disease. Despite increased human cytokine expression, including responses mirroring those seen in human disease, and decreased hepatic viral RNA levels at terminal euthanasia, both high- and low dose RVFV inoculation resulted in lethal disease in all mice with comparable time to-death as unengrafted mice. PMID- 30028879 TI - Body mass index >=23 is a risk factor for insulin resistance and diabetes in Japanese people: A brief report. AB - BACKGROUND: Screening for undiagnosed type 2 diabetes mellitus is recommended for Asian Americans with a body mass index >=23. However, the optimal body mass index cut-off score for predicting the risk of diabetes mellitus in Japanese people is not well known. The aim of this study was to determine the best body mass index cut-off score for predicting insulin resistance and diabetes mellitus in the Japanese population. METHODS: This study had two parts, a clinical investigation and a retrospective observational investigation. In the clinical part of the study, 58 participants (26 with type 2 diabetes mellitus and 32 non-diabetics) underwent a hyperinsulinemic-euglycemic clamp from which their glucose disposal rate was measured. For the retrospective part of the study, medical check-up data from 88,305 people in the Tottori Prefecture were analyzed for clinical evidence of diabetes mellitus. The optimal BMI cut-off scores for prediction of insulin resistance and diabetes mellitus were determined. RESULTS: In the clamp study, the optimal body mass index cut-off score to predict insulin resistance in non diabetic patients was 22.7. All participants with type 2 diabetes mellitus were insulin resistant, and the optimal body mass index cut-off score for prediction of severe insulin resistance was 26.2. When the data from the type 2 diabetic and the non-diabetic participants were combined, the optimal body mass index cut-off score for prediction of insulin resistance was 23.5. Analysis of 88,305 medical check-up records yielded an optimal body mass index cut-off score for prediction of diabetes mellitus of 23.6. CONCLUSIONS: These results suggest that having a body mass index >=23 is a risk factor for insulin resistance and diabetes mellitus in the Japanese population. PMID- 30028880 TI - Nrf2 protects stellate cells from Smad-dependent cell activation. AB - Hepatic stellate cells (HSC) orchestrate the deposition of extracellular matrix (ECM) and are the primary effector of liver fibrosis. Several factors, including TGF-beta1, PDGF and oxidative stress, have been shown to trigger HSC activation. However, the involvement of cellular defence mechanisms, such as the activation of antioxidant response by Nrf2/Keap1 in the modulation of HSC activation is not known. The aim of this work was to elucidate the role of Nrf2 pathway in HSC trans-differentiation involved in the development of fibrosis. To this end, we repressed Nrf2 and Keap1 expression in HSC with specific siRNAs. We then assessed activation markers, as well as proliferation and migration, in both primary and immortalised human HSCs exposed to Smad inhibitors (SB-431542 hydrate and SB 525334), TGF-beta1 and/or PDGF. Our results indicate that knocking down Nrf2 induces HSC activation, as shown by an increase in alphaSMA-positive cells and by gene expression induction of ECM components (collagens and fibronectin). HSC with reduced Nrf2-levels also showed an increase in migration and a decrease in proliferation. We could also demonstrate that the activation of Nrf2-deficient HSC involves the TGF-beta1/Smad pathway, as the activation was successfully inhibited with the two tested Smad inhibitors. Moreover, TGF-beta1 elicited a stronger induction of HSC activation markers in Nrf2 deficient cells than in wild type cells. Thus, our data suggest that Nrf2 limits HSCs activation, through the inhibition of the TGF-beta1/Smad pathway in HSCs. PMID- 30028881 TI - It's not the 'what', but the 'how': Exploring the role of debt in natural resource (un)sustainability. AB - A debt-based economy cannot survive without economic growth. However, if private debt consistently grows faster than GDP, the consequences are financial crises and the current unprecedented level of global debt. This policy dilemma is aggravated by the lack of analyses factoring the impact of debt-growth cycles on the environment. What is really the relationship between debt and natural resource sustainability, and what is the role of debt in decoupling economic growth from natural resource availability? Here we present a conceptual Agent Based Model (ABM) that integrates an environmental system into an ABM representation of Steve Keen's debt-based economic models. Our model explores the extent to which debt-driven processes, within debt-based economies, enhance the decoupling between economic growth and the availability of natural resources. Interestingly, environmental and economic collapse in our model are not caused by debt growth, or the debt-based nature of the economic system itself (i.e. the 'what'), but rather, these are due to the inappropriate use of debt by private actors (i.e. the 'how'). Firms inappropriately use bank credits for speculative goals-rather than production-oriented ones-and for exponentially increasing rates of technological development. This context creates temporal mismatches between natural resource growth and firms' resource extraction rates, as well as between economic growth and the capacity of the government to effectively implement natural resource conservation policies. This paper discusses the extent to which economic growth and the availability of natural resources can be re-coupled through a more sustainable use of debt, for instance by shifting mainstream banking forces to partially support environmental conservation as well as economic growth. PMID- 30028882 TI - Autumn distribution of Bristol Bay red king crab using fishery logbooks. AB - Spatial distributions of fished species must be well characterized to avoid local depletions, identify critical habitat, and predict and mitigate interactions with other fisheries. The Bristol Bay red king crab (Paralithodes camtschaticus) fishery is one of the largest crab fisheries in Alaska. Summer crab distributions have been well documented by decades of bottom trawl surveys. However, crab movement and distribution are poorly understood outside the summer survey period, which creates several management challenges. One important component of fishery management is the existence of no-trawl zones, which are intended to protect crab from bottom trawl fisheries. However, it is difficult to evaluate the placement of no-trawl zones, because most crab bycatch occurs in trawl fisheries during winter when crab distributions are unknown. Daily fishing logs, kept by skippers in the red king crab fleet since 2005, contain detailed information on the spatial distribution of catch and effort of legal sized male crab during the autumn crab fishery. However, data contained in these hand-written logbooks have not been readily accessible. We digitized daily fishing logs from 2005 to 2016 and used spatial information on catch and effort to infer geographic distributions of legal sized male king crab during the crab fishing season. Changes in distribution were tracked across this 12-yr period and comparisons were made between warm and cold temperature regimes. In warm years (2005, 2014 2016), crab aggregated in the center of Bristol Bay, Alaska, while in cold years (2007-2013) they were closer to the Alaska Peninsula. The majority of crab were caught in no-trawl areas (63.4% on average), but variations occurred among years and with temperature regime (40.0-86.8% in no-trawl zones). As temperatures continue to shift in the Bering Sea, it will be important to continue monitoring crab distributions outside the summer survey period. PMID- 30028883 TI - Optimization of the sterilizing doses and overflooding ratios for the South American fruit fly. AB - The Sterile Insect Technique (SIT) is an autocidal control method that relies on inundative releases of sterilized mass-reared insects. This technology has been used in several area-wide programmes for the suppression/eradication of fruit fly populations. Choosing the optimum sterilizing dose and the sterile release density is an essential step of the SIT. Considering unsolved issues related to the application of this technique against Anastrepha fraterculus (Wiedemann), this study aimed to define accurately the central target dose for both sexes of this species and to verify the induction of sterility in fertile flies at different sterile:fertile ratios. The results from the regression analyses proved that the sterilization process for the A. fraterculus Brazilian-1 morphotype (the most common in southern Brazil and Argentina) could consist of irradiating pupae 72 h before adult emergence at 40 Gy, with no detrimental effects to standard quality control parameters. The ovarian development in irradiated females was characterized, demonstrating that doses equal to or higher than 25 Gy cause complete and irreversible ovarian atrophy. The laboratory and field cage tests showed that the sterility induction increased with the proportion of sterile flies, and a sterile:fertile ratio of 50:1 should be appropriate in SIT field trials. The sterile females apparently did not distract the sterile males, despite of the slightly higher reductions in pupal yield for all ratios in their absence. The data generated in this study have a great practical value and will help decision-makers in planning field trials to evaluate the efficacy of the SIT against A. fraterculus populations. PMID- 30028884 TI - The emergence of inequality in social groups: Network structure and institutions affect the distribution of earnings in cooperation games. AB - From small communities to entire nations and society at large, inequality in wealth, social status, and power is one of the most pervasive and tenacious features of the social world. What causes inequality to emerge and persist? In this study, we investigate how the structure and rules of our interactions can increase inequality in social groups. Specifically, we look into the effects of four structural conditions-network structure, network fluidity, reputation tracking, and punishment institutions-on the distribution of earnings in network cooperation games. We analyze 33 experiments comprising 96 experimental conditions altogether. We find that there is more inequality in clustered networks compared to random networks, in fixed networks compared to randomly rewired and strategically updated networks, and in groups with punishment institutions compared to groups without. Secondary analyses suggest that the reasons inequality emerges under these conditions may have to do with the fact that fixed networks allow exploitation of the poor by the wealthy and clustered networks foster segregation between the poor and the wealthy, while the burden of costly punishment falls onto the poor, leaving them poorer. Surprisingly, we do not find evidence that inequality is affected by reputation in a systematic way but this could be because reputation needs to play out in a particular network environment in order to have an effect. Overall, our findings suggest possible strategies and interventions to decrease inequality and mitigate its negative impact, particularly in the context of mid- and large-sized organizations and online communities. PMID- 30028885 TI - Non-cardioembolic risk factors in atrial fibrillation-associated ischemic stroke. AB - INTRODUCTION: Cardioembolic (CE) risks is usually considered as the main mechanism of ischemic stroke in non-valvular atrial fibrillation (NVAF) patients. However, a substantial number of ischemic strokes in NVAF patients are related to non-CE mechanisms. The aim of this study was to investigate the non-CE risk factors in ischemic stroke patients had NVAF. METHODS: We included 401 patients (65.6% male, 68.6 +/- 9.6 years old) who had been hospitalized due to ischemic stroke and had a known or newly diagnosed NVAF. The CE (intracardiac thrombus, dense spontaneous echo contrast, or low left atrial appendage flow velocity) and non-CE (complex aortic plaque, significant carotid stenosis, or intracranial arterial stenosis) risk factors were investigated at the time of the index stroke. RESULTS: The number of CE and non-CE risk factors increased with increasing CHA2DS2-VASc scores (p for trends < 0.001). The presence of CE risk factors was independently associated with persistent atrial fibrillation (p < 0.001), body mass index (p = 0.003), heart failure (p = 0.003), and left atrial volume index (p < 0.001). In contrast, the presence of non-CE risk factors was independently associated with age (p < 0.001), hypertension (p = 0.049), diabetes (p = 0.030), and coronary artery calcium score (CACS; p < 0.001). CACS had the added value in predicting non-CE risk factors of ischemic stroke regardless of the CHA2DS2-VASc risk category (p < 0.001). CONCLUSION: Non-CE risk factors in ischemic stroke patients with NVAF are associated with high CHA2DS2-VASc score and CACS. Atherosclerotic non-CE risk factors should be considered as potential mechanisms of stroke even in patients with AF-associated ischemic stroke. PMID- 30028886 TI - Impact of residual covariance structures on genomic prediction ability in multi environment trials. AB - In plant breeding, one of the main purpose of multi-environment trial (MET) is to assess the intensity of genotype-by-environment (G*E) interactions in order to select high-performing lines of each environment. Most models to analyze such MET data consider only the additive genetic effects and the part of the non-additive genetic effects are confounded with the residual terms and this may lead to the non-negligible residual covariances between the same trait measured at multiple environments. In breeding programs it is also common to have the phenotype information from some environments available and values are missing in some other environments. In this study we focused on two problems: (1) to study the impact of different residual covariance structures on genomic prediction ability using different models to analyze MET data; (2) to compare the ability of different MET analysis models to predict the missing values in a single environment. Our results suggests that, it is important to consider the heterogeneous residual covariance structure for the MET analysis and multivariate mixed model seems to be especially suitable to predict the missing values in a single environment. We also present the prediction abilities based on Bayesian and frequentist approaches with different models using field data sets (maize and rice) having different levels of G*E interactions. PMID- 30028889 TI - The inexplicable rise of medication prices. AB - Prescription medications are now the fastest-growing medical costs. Prices of brand name medications are exorbitant. An example is long-acting injectable aripiprazole, which costs more than $2,400 for a single injection in the United States, while in Canada this cost is less than $500 and in Turkey it is approximately $150. That brings the annual cost to use this medication in the United States to approximately $30,000. PMID- 30028887 TI - Lateral inhibition: Two modes of non-autonomous negative autoregulation by neuralized. AB - Developmental patterning involves the progressive subdivision of tissue into different cell types by invoking different genetic programs. In particular, cell cell signaling is a universally deployed means of specifying distinct cell fates in adjacent cells. For this mechanism to be effective, it is essential that an asymmetry be established in the signaling and responding capacities of the participating cells. Here we focus on the regulatory mechanisms underlying the role of the neuralized gene and its protein product in establishing and maintaining asymmetry of signaling through the Notch pathway. The context is the classical process of "lateral inhibition" within Drosophila proneural clusters, which is responsible for distinguishing the sensory organ precursor (SOP) and non SOP fates among adjacent cells. We find that neur is directly regulated in proneural clusters by both proneural transcriptional activators and Enhancer of split basic helix-loop-helix repressors (bHLH-Rs), via two separate cis regulatory modules within the neur locus. We show that this bHLH-R regulation is required to prevent the early, pre-SOP expression of neur from being maintained in a subset of non-SOPs following SOP specification. Lastly, we demonstrate that Neur activity in the SOP is required to inhibit, in a cell non-autonomous manner, both neur expression and Neur function in non-SOPs, thus helping to secure the robust establishment of distinct cell identities within the developing proneural cluster. PMID- 30028888 TI - Predicting hospital admission at emergency department triage using machine learning. AB - OBJECTIVE: To predict hospital admission at the time of ED triage using patient history in addition to information collected at triage. METHODS: This retrospective study included all adult ED visits between March 2014 and July 2017 from one academic and two community emergency rooms that resulted in either admission or discharge. A total of 972 variables were extracted per patient visit. Samples were randomly partitioned into training (80%), validation (10%), and test (10%) sets. We trained a series of nine binary classifiers using logistic regression (LR), gradient boosting (XGBoost), and deep neural networks (DNN) on three dataset types: one using only triage information, one using only patient history, and one using the full set of variables. Next, we tested the potential benefit of additional training samples by training models on increasing fractions of our data. Lastly, variables of importance were identified using information gain as a metric to create a low-dimensional model. RESULTS: A total of 560,486 patient visits were included in the study, with an overall admission risk of 29.7%. Models trained on triage information yielded a test AUC of 0.87 for LR (95% CI 0.86-0.87), 0.87 for XGBoost (95% CI 0.87-0.88) and 0.87 for DNN (95% CI 0.87-0.88). Models trained on patient history yielded an AUC of 0.86 for LR (95% CI 0.86-0.87), 0.87 for XGBoost (95% CI 0.87-0.87) and 0.87 for DNN (95% CI 0.87-0.88). Models trained on the full set of variables yielded an AUC of 0.91 for LR (95% CI 0.91-0.91), 0.92 for XGBoost (95% CI 0.92-0.93) and 0.92 for DNN (95% CI 0.92-0.92). All algorithms reached maximum performance at 50% of the training set or less. A low-dimensional XGBoost model built on ESI level, outpatient medication counts, demographics, and hospital usage statistics yielded an AUC of 0.91 (95% CI 0.91-0.91). CONCLUSION: Machine learning can robustly predict hospital admission using triage information and patient history. The addition of historical information improves predictive performance significantly compared to using triage information alone, highlighting the need to incorporate these variables into prediction models. PMID- 30028890 TI - Experiences of gender incongruence and the relationship between social exclusion, psychological distress, and dysfunction among South African transgender adults: A field-study for ICD-11. AB - BACKGROUND: The classification of sexuality-related conditions and conditions relating to transgender identity has generated controversy. Growing evidence suggests that the distress and dysfunction reported by transgender individuals is more likely associated with social exclusion, stigmatization, and violence than as a result of gender incongruence per se. Our study aimed to explore the experiences of South African transgender individuals through: 1) their self reported accounts of gender incongruence, and 2) associations between their experiences of social exclusion and violence, and their reports of psychological distress and dysfunction during adolescence. METHODS: Our sample of 57 South African transgender adults completed a structured interview, in English, including questions related to experiences of gender incongruence duration, distress, dysfunction, social exclusion, and violence. RESULTS: Many transgender individuals reported having experienced an intense desire to be a different gender, with all noting discomfort with several aspects of their bodies. Importantly, psychological distress and dysfunction were significantly associated with social exclusion (most commonly perpetuated by family and friends) and not with gender incongruence per se. CONCLUSIONS: This study adds to the growing evidence that experiences of social exclusion play a significant role in the psychological distress and dysfunction reported by transgender persons. PMID- 30028891 TI - What is the overlap between subjective and objective cognitive impairments in MDD? AB - BACKGROUND: Cognitive impairments, such as memory deficits and executive impairment, are common among patients with major depressive disorder (MDD) and can be captured with objective or subjective assessments. The aim of this post hoc analysis of the CONNECT study was to assess the degree of overlap between subjective and objective cognitive impairment among MDD patients, and to evaluate associated clinical characteristics. METHODS: The study was conducted from April 2012 to February 2014 and enrolled a total of 602 patients with MDD who reported subjective cognitive impairment. Efficacy was assessed using a battery of objective tests of cognitive function representing multiple domains: Digit Symbol Substitution Test performance, Trail Making Test A, Trail Making Test B, Congruent and Incongruent Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task, and One-Back Task. The Cognitive and Physical Functioning Questionnaire (CPFQ) was used to capture patient-reported assessments of cognitive function. RESULTS: Although 48% of patients with MDD met our conservative criteria for subjectively defined marked cognitive impairment, 64% of patients with MDD met our conservative criteria for objectively defined cognitive impairment. Therefore, the proportion of patients defined as having impaired cognition was somewhat similar regardless of methodology. Overall, 80% of patients with MDD in this study reported either subjective or objective cognitive impairment per subjective and objective scales. However, the proportion of patients meeting criteria for both subjectively and objectively defined cognitive impairment was only 31%. This could be explained by the fact that the CPFQ total score was only modestly-although significantly-correlated with all but one of the objective tests. CONCLUSIONS: This post-hoc study shows that approximately 80% of patients with MDD participating in an antidepressant trial reported either subjective or objective cognitive impairment. PMID- 30028892 TI - Academic skills in pediatric obsessive-compulsive disorder: A preliminary study. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a prevalent and debilitating illness that often begins in childhood and has a significant impact on the functioning of youth and their families. Given that schooling represents a considerable portion of youth's lives and is a key contributor to their development, identifying impacts of OCD on school performance is important. METHODS: The present study evaluated academic skill differences in OCD-affected youth age 7 to 18 (n = 25) compared with matched healthy controls (HCs; n = 25), as captured via standardized testing. Analysis of variance was used to examine group effects on the outcome variables. RESULTS: In comparison with HCs, OCD affected youth presented with significantly poorer performance in math calculation (P = .029), although mean scores fell in the normative range. Thirty six percent of the OCD group were in the Below Average range, compared with 12% of the HCs (P = .047). There were no significant between-group differences in word reading or spelling. Academic skills were not associated with symptom severity. CONCLUSIONS: Findings suggest that underperformance in math may be present in a higher-than-expected proportion of OCD-affected youth. Further studies of academic skills are warranted to replicate the current findings and to examine roles of academic enhancers in this vulnerable population. PMID- 30028893 TI - Body temperature rises following improvement of depression with ECT. AB - BACKGROUND: Recent studies have reported hyperthermia is an efficacious treatment for depression. Thus, we hypothesized that a proven depression therapy such as electroconvulsive therapy (ECT) would be associated with an increase in body temperature. METHODS: A retrospective chart analysis was conducted on 33 participants who recovered from depression after a course of ECT. All were hospitalized for recurrent, severe symptoms and had no previous ECT treatment. Oral temperature recordings before and after the first and last ECT treatments were collected for each participant. Statistical analysis was performed using paired t test. RESULTS: No significant change in mean oral temperature occurred after the first ECT, but a significant increase from baseline was observed after the final ECT treatment when depression symptoms had clinically remitted (P < .009). CONCLUSIONS: Improvement in clinical depression with ECT is correlated with an increase in body temperature. Body temperature may have potential as a biomarker for ECT efficacy, and possibly for antidepressant pharmacotherapies. PMID- 30028894 TI - Is ondansetron beneficial for psychosis associated with dementia?. AB - BACKGROUND: This systematic review identified published studies that evaluated the use of ondansetron in individuals with psychosis associated with dementia. METHODS: A literature search was conducted of PubMed, MEDLINE, EMBASE, PsycINFO, and Cochrane Collaboration databases for randomized controlled trials (RCTs), cohort studies, and case reports that evaluated the use of ondansetron for individuals with psychosis associated with dementia. Bibliographic databases of published articles were also searched for additional studies. RESULTS: A total of 4 studies were identified, all of which were open-label trials of ondansetron for psychosis associated with Parkinson's disease. All trials showed improvements in visual hallucinations and paranoid ideations in most patients, as well as a modest improvement in functioning, but no evidence of cognitive improvement. CONCLUSIONS: Ondansetron appears to have benefit in improving positive symptoms of psychosis in individuals with Parkinson's disease, but RCTs are needed before routine use is recommended. There is a paucity of evidence for the use of ondansetron for psychosis associated with other forms of dementia. PMID- 30028895 TI - Depression and substance use disorders in the offspring of depressed parents as a function of the parent's borderline personality disorder symptomatology. AB - BACKGROUND: Parental major depressive disorder (MDD) and borderline personality disorder (BPD) are associated with increased risk of offspring psychopathology. It is unclear whether BPD in depressed parents infers greater risk than depression alone. We hypothesized that BPD features in depressed parents would be associated with higher morbid risk of offspring MDD and substance use disorders (SUDs). METHODS: Participants included 912 psychiatric outpatients with a principal diagnosis of MDD. Semi-structured interviews determined diagnoses of parents and their 2,011 reported offspring. We compared the offspring's morbid risk of MDD and SUDs based on whether their parents had BPD, >=1 BPD criteria, and by each criterion. RESULTS: Offspring of parents with >=1 BPD criteria had higher morbid risk of MDD and SUDs. Differences were insignificant when comparing by BPD diagnosis. Anger and impulsivity were associated with increased risk of MDD, and emptiness was associated with increased risk of SUDs. CONCLUSIONS: Results suggest that BPD features confer additional risk to offspring beyond that of parental depression alone. Parental anger and impulsivity may be particularly important in determining risk of MDD, and parental feelings of emptiness may be particularly important for risk of SUDs. Limitations, future directions, and treatment implications are discussed. PMID- 30028896 TI - Does diagnosing a patient with borderline personality disorder negatively impact patient satisfaction with the initial diagnostic evaluation? AB - BACKGROUND: Research has found that clinicians have less sympathetic attitudes and behave less empathically toward patients with borderline personality disorder (BPD). Anecdotal conversations with clinicians and trainees reveal that some have a reluctance to tell their patients that they have BPD due to a concern that these patients will react badly. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we examined whether diagnosing BPD resulted in lower satisfaction with the initial evaluation. METHODS: One thousand ninety-three patients presenting to the Rhode Island Hospital partial hospital program completed the Clinically Useful Patient Satisfaction Scale (CUPSS), a reliable and valid measure of satisfaction with the initial evaluation. The usual clinical practice in our program is to discuss with the patients their diagnoses. RESULTS: Approximately one-sixth of the patients were diagnosed with BPD (15.6%, n = 171). There were no significant differences in satisfaction ratings on the 16 items of the CUPSS between patients with and without BPD. CONCLUSIONS: There was no evidence that diagnosing BPD was associated with reduced satisfaction with the initial diagnostic evaluation. Approaches toward making the diagnosis of BPD also are discussed. PMID- 30028897 TI - Empathy changes in neurocognitive disorders: A review. AB - BACKGROUND: Empathy can be broadly defined as the ability to understand what others feel (cognitive empathy) and feel what others feel (affective empathy). The capacity to empathize may be impaired in certain major neurocognitive disorders (MNCDs), affecting not only the patient, but also the caregivers. METHODS: PubMed and Google Scholar databases were searched for studies investigating empathy changes, using an objective scale, in patients with MNCDs. RESULTS: The Interpersonal Reactivity Index was most commonly used to evaluate empathy in this population. Impairments in cognitive but not affective empathy were found in patients with Alzheimer's disease (AD), and may be attributable to overall cognitive decline. Patients with frontotemporal dementia (FTD) have demonstrated severe deficits in empathy, correlating with greater caregiver burden. Empathy changes in patients with dementia with Lewy bodies, vascular dementia, and Parkinson's disease dementia have not yet been studied. Intranasal oxytocin has emerged as a promising therapeutic approach for empathy loss, but it has not been explored yet in patients with MNCDs. CONCLUSIONS: Caregivers need to be educated about empathy loss, which is an important part of the disease process in AD and FTD. Future research should further assess empathy changes in other MNCDs, as well as explore novel treatment options in this field. PMID- 30028898 TI - The use of memantine in neuropsychiatric disorders: An overview. AB - BACKGROUND: Memantine is a non-competitive N-methyl-d-aspartate receptor antagonist currently used for the treatment of Alzheimer's disease as an approved indication. However, as knowledge of signaling pathways is increasing, the therapeutic potential of memantine is being applied for the treatment of various psychiatric illnesses. METHODS: The PubMed online database was searched for the use of memantine in various psychiatric disorders. Case studies, open-label trials, and controlled trials from the search were included. RESULTS: Memantine monotherapy was found to exert efficacy in several neuropsychiatric conditions, including autism spectrum disorder, binge eating disorder, and attention deficit/hyperactivity disorder. For posttraumatic stress disorder and generalized anxiety disorder, memantine was found efficacious in augmentation with other medications. In obsessive-compulsive disorder (OCD), memantine was used as both an augmentation to selective serotonin reuptake inhibitors and standalone therapy, and most published studies found it to improve OCD symptoms. For schizophrenia, memantine has been reported to be consistently effective for negative symptoms only. The manic phase of bipolar disorder also appears to benefit from memantine. The depressive phase of bipolar disorder and major depressive disorder did not respond significantly to memantine. Catatonia as a symptom of various disorders improved in several case studies when memantine was used in combination with other medications. CONCLUSIONS: Memantine may have several therapeutic applications in psychiatry, reflecting the involvement of glutamate pathways in multiple psychiatric disorders. PMID- 30028899 TI - Remission of chronic inflammatory demyelinating polyneuropathy after hepatitis C virus eradication with sofosbuvir and ledipasvir therapy. PMID- 30028900 TI - A Study on the Asymmetry of the Human Left and Right Pubic Symphyseal Surfaces Using High-Definition Data Capture and Computational Shape Methods. AB - The pubic symphysis is among the most commonly used bilateral age indicators. Because of potential differences between right and left sides, it is necessary to investigate within-individual asymmetry, which can inflate age estimation error. This study uses 3D laser scans of paired pubic symphyses for 88 documented White males. Scan data are analyzed by numerical shape algorithms, proposed as an alternative to traditional visual assessment techniques. Results are used to quantify the within-individual asymmetry, evaluating if one side produces a better age-estimate. Relationships between the asymmetry and advanced age, weight, and stature are examined. This analysis indicates that the computational, shape-based techniques are robust to asymmetry (>80% of paired differences are within 10 years and >90% are within 15 years). For notably more asymmetric cases, differences in estimates are not associated with life history factors. Based on this study, either side can be used for age-at-death estimation by the computational methods. PMID- 30028901 TI - A dipeptidyl peptidase-4 inhibitor promotes wound healing in normoglycemic mice by modulating keratinocyte activity. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a well-known and novel class of oral antihyperglycaemic drugs. DPP-4 inhibition facilitates ulcer healing in patients with diabetes. However, the actual mechanisms, which are independent of lower blood glucose levels, are still unknown. Therefore, the aim of this study was to analyse the effect of the DPP-4 inhibitor sitagliptin on wound healing through a glucose-independent pathway. In this study, DPP-4 inhibitors facilitate keratinocyte differentiation and the proliferation, increase blood flow in the cutaneous of wounds in healthy C57BL/6 mice. Additionally, the administration of the DPP-4 inhibitor ameliorates wound healing and enhances adiponectin expression in healthy C57BL/6 mice. Taken together, our results reveal a protective role for the DPP-4 inhibitor sitagliptin in wound healing by regulating adiponectin and phospho-eNOS levels in keratinocytes. Based on these results, the DPP-4 inhibitor may have therapeutic potential for healing wounds through a diabetes-independent mechanism. PMID- 30028902 TI - Altered bone-regulating myokine expression in skeletal muscle Of Duchenne muscular dystrophy mouse models. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) has been well characterized as a disease that affects both skeletal muscle and bone. The pathophysiology responsible for the deficits in bone tissue is still unclear. METHODS: Quantitative reverse-transcription polymerase chain reaction and Western blot analyses of known myokines from skeletal muscle were performed on dystrophic mouse models and wild-type (WT) controls to identify differentially expressed bone-regulating myokines. RESULTS: Twenty-four of 43 myokine genes demonstrated significantly different mRNA expression in the skeletal muscles of dystrophic mice when compared with muscles of WT mice. Several differently expressed bone regulating myokine genes were identified, and their protein levels were also verified by Western blot. CONCLUSIONS: Dystrophic skeletal muscle demonstrated a significantly altered myokine gene expression profile. mRNA and protein levels of several bone-regulating myokines were significantly altered in dystrophic skeletal muscle, which suggests pathological role of bone-regulating myokines on bone homeostasis in DMD. Muscle Nerve 58: 573-582, 2018. PMID- 30028903 TI - Inhibition of the voltage-dependent K+ current by the class Ic antiarrhythmic drug flecainide in rabbit coronary arterial smooth muscle cells. AB - This study examined the inhibitory effect of flecainide, a class 1c antiarrhythmic agent (Na+ channel blocker), on voltage-dependent K+ (Kv) channels in smooth muscle cells isolated from coronary arteries. Flecainide decreased the vascular Kv channel current in a dose-dependent manner with an IC50 value of 5.90 +/- 0.87 MUmol/L and a Hill coefficient of 0.77 +/- 0.06. Although the steady state activation curve was not affected by flecainide, it shifted the steady state inactivation curves toward a more negative potential. Application of train pulses such as 1 or 2 Hz did not change the flecainide-induced inhibition of Kv channels, indicating that the inhibitory effect of flecainide was not use dependent. Using perforated-patch clamp experiments, we found that inhibition of Kv channels by flecainide caused membrane depolarization. Together, these results suggest that flecainide inhibits Kv channels in a concentration-dependent, but not use-dependent manner by changing the inactivation gating properties. Furthermore, Kv channel inhibition by flecainide occurs regardless of Na+ channel inhibition. PMID- 30028905 TI - The health and economic outcomes of early egg introduction strategies. AB - BACKGROUND: Studies suggest early egg introduction (EEI) in the first year of life is associated with reduced risk of developing egg allergy. No US recommendations exist regarding optimally implementing EEI. METHODS: Using simulation and Markov modelling over a 20-year horizon, we explored optimal EEI strategies applied to US, European and Canadian populations, comparing screening of high-risk infants (skin prick testing [SPT] or serum-specific IgE[sIgE]) before introducing cooked egg at 6 months of life vs egg introduction at home, without screening, for all infants. RESULTS: A no-screen approach dominated egg SPT screening of high-risk infants with early-onset eczema. Base model per patient incremental costs of SPT were $6865 US dollars (USD), 6801 euros and $10 610 Canadian dollars (CAD). For egg sIgE screening in primary care settings, base model incremental costs were $16 722 USD, 18 072 euros and $28 193 CAD. As the simulation concluded 2.5% were egg allergic without screening vs 9.5%, 12% and 21.4% of children undergoing SPT, delayed introduction or sIgE screening. Incremental societal costs from screening reached $2 009 351 175 USD for SPT and $4 894 445 790 USD for sIgE testing. In sensitivity analyses, if the risk of reaction with initial egg ingestion was >=22.5%, SPT before EEI became a preferred strategy. A no-screen approach dominated both EEI of raw pasteurized egg and delayed cooked egg introduction approaches. CONCLUSIONS: Assuming initial reaction rates < 22.5%, a no-screening EEI cooked egg approach has superior health and economic benefits in terms of number of egg allergy cases prevented and total healthcare costs vs screening testing. PMID- 30028906 TI - Dissecting the role of a large chromosomal inversion in life history divergence throughout the Mimulus guttatus species complex. AB - Chromosomal inversions can play an important role in adaptation, but the mechanism of their action in many natural populations remains unclear. An inversion could suppress recombination between locally beneficial alleles, thereby preventing maladaptive reshuffling with less-fit, migrant alleles. The recombination suppression hypothesis has gained much theoretical support but empirical tests are lacking. Here, we evaluated the evolutionary history and phenotypic effects of a chromosomal inversion which differentiates annual and perennial forms of Mimulus guttatus. We found that perennials likely possess the derived orientation of the inversion. In addition, this perennial orientation occurs in a second perennial species, M. decorus, where it is strongly associated with life history differences between co-occurring M. decorus and annual M. guttatus. One prediction of the recombination suppression hypothesis is that loci contributing to local adaptation will predate the inversion. To test whether the loci influencing perenniality pre-date this inversion, we mapped QTLs for life history traits that differ between annual M. guttatus and a more distantly related, collinear perennial species, M. tilingii. Consistent with the recombination suppression hypothesis, we found that this region is associated with life history in the absence of the inversion, and this association can be broken into at least two QTLs. However, the absolute phenotypic effect of the LG8 inversion region on life history is weaker in M. tilingii than in perennials which possess the inversion. Thus, while we find support for the recombination suppression hypothesis, the contribution of this inversion to life history divergence in this group is likely complex. PMID- 30028907 TI - Nonparametric extraction of oscillations in short time series. AB - Oscillations are important for functional homeostasis. However, the oscillatory processes are sometimes masked by noise. A nonparametric method to extract oscillatory components does not assume stability in period or amplitude, it is resistant to linear components and phase insensitive, and it allows statistical inference. PMID- 30028904 TI - Cancer phenotype in myotonic dystrophy patients: Results from a meta-analysis. AB - INTRODUCTION: Recent studies have provided evidence that patients with myotonic dystrophy (DM) are at excess risk of cancer. However, inconsistencies regarding affected anatomic sites persist. METHODS: We performed a meta-analysis of cancer risk in DM, searching among studies published between January 1, 1990 and December 31, 2016. Eligible studies were full reports of DM cohorts with site specific risks. RESULTS: The analysis included 5 studies, comprising 2,779 patients. Risk estimates for cancers of the endometrium and cutaneous melanoma were reported in all studies. The pooled standardized incidence ratio (pSIRs) for endometrial cancer was 7.48 (95% confidence interval [CI] 4.72-11.8) and for cutaneous melanoma was 2.45 (95% CI 1.31-4.58). Among cancers reported in 4 of 5 studies, elevated risks were observed for thyroid (pSIR = 8.52, 95% CI 3.62 20.1), ovarian (pSIR = 5.56, 95% CI 2.99-10.3), testicular (pSIR = 5.95, 95% CI 2.34-15.1), and colorectal (pSIR = 2.2, 95% CI 1.39-3.49) cancers. DISCUSSION: Our data refine the DM cancer phenotype, which may guide patient clinical management and inform plans for molecular investigations to understand DM-related carcinogenesis. Muscle Nerve 58: 517-522, 2018. PMID- 30028908 TI - Pyroptosis Induction and Detection. AB - Pyroptosis is a form of programmed pro-inflammatory cell death that plays a protective role in the host response to infection, but can also promote pathogenic inflammation. Pyroptosis is mediated by the cysteine protease, caspase 1. Caspase-1 cleaves gasdermin D, releasing the N-terminal pore-forming domain, which inserts into the plasma membrane and drives osmotic lysis. Caspase-1 also proteolytically activates the inflammatory cytokines interleukin 1beta (IL-1beta) and IL-18. This unit describes methods for stimulating pyroptosis and assessing subsequent loss of plasma membrane integrity. We also describe an ELISA to quantify released IL-1beta. These methods can be applied to many different types of experiments. (c) 2018 by John Wiley & Sons, Inc. PMID- 30028909 TI - Effects of Rodent Diet Choice and Fiber Type on Data Interpretation of Gut Microbiome and Metabolic Disease Research. AB - Poor diet reporting and improperly controlling laboratory animal diet continues to reduce our ability to interpret data effectively in animal studies. In order to make the best use of our resources and improve research transparency, proper reporting methods that include a diet design are essential to improving our understanding of the links between gut health and metabolic disease onset. This unit will focus on the importance of diet choice in laboratory animal studies, specifically as it relates to gut health, microbiome, and metabolic disease development. The two most commonly used diet types, grain-based (GB) diets, and purified ingredient diets, will each be described, with particular emphasis on their differences in dietary fiber. A further description of how these diet types and fiber can affect gut morphology and microbiota will be provided as well as how purified ingredient diets may be improved upon. (c) 2018 by John Wiley & Sons, Inc. PMID- 30028910 TI - Single-Cell, Time-Lapse Reactive Oxygen Species Detection in E. coli. AB - Detection of reactive oxygen species (ROS) in bacteria has been limited to bulk biochemical assays. Although they are powerful and quantitative tools to understand the overall production of ROS in E. coli, such assays provide limited spatial and temporal information when correlating cellular phenotype with perturbations such as antibiotics or other treatments. We have developed single cell, time-lapse assays to detect ROS in live E. coli. The assays utilize flow systems on a fluorescence microscope to correlate symptoms aroused from biological or chemical perturbations with the in situ detection of ROS. ROS is detected by fluorogenic dyes that accumulate inside the cell, allowing detection of ROS in single cells in both homogeneous and heterogeneous samples using CellROX Green and Amplex(r) Red/APEX2. (c) 2018 by John Wiley & Sons, Inc. PMID- 30028911 TI - Flow Cytometry Analysis of Fungal Ploidy. AB - Ploidy, the number of sets of homologous chromosomes in a cell, can alter cellular physiology, gene regulation, and the spectrum of acquired mutations. Advances in single-cell flow cytometry have greatly improved the understanding of how genome size contributes to diverse biological processes including speciation, adaptation, pathogenesis, and tumorigenesis. For example, fungal pathogens can undergo whole genome duplications during infection of the human host and during acquisition of antifungal drug resistance. Quantification of ploidy is dramatically affected by the nucleic acid staining technique and the flow cytometry analysis of single cells. Ploidy in fungi is also impacted by samples that are heterogeneous for both ploidy and morphology, and control strains with known ploidy must be included in every flow cytometry experiment. To detect ploidy changes within fungal strains, the following protocol was developed to accurately and dependably interrogate single-cell ploidy. (c) 2018 by John Wiley & Sons, Inc. PMID- 30028912 TI - Incidence of otic barotrauma in Canadian Armed Forces shallow-water diver candidate students 2011-2015. AB - Introduction: While otic barotrauma (OBT) is a common condition experienced by divers, data related to military divers is limited. This study aimed to determine the incidence of OBT in Canadian armed forces (CAF) shallow-water diver (SWD) students trained through the Fleet Dive Unit (Atlantic) (FDU[A]) between 2011 2015. Methods: A retrospective cohort evaluation was performed. The study group consisted of all SWD candidates who embarked on an SWD course through FDU(A) between 2011-2015. A total of 241 subjects comprised the final data analysis. Results: A total of 56 individuals (23.2%) suffered 60 instances of OBT, yielding an incidence density rate of 8.68 per 1,000 person-days on course. A total of 73 diving days (10.44 per 1,000 planned person-course days, or 4.87 diving days per course) were lost due to OBT. Of the reported OBT cases, 18% resulted in cessation of training, 72% in temporary removal from diving. There was no statistically significant association between sex, history of environmental allergies, previous dive qualification, age or rank and the development of OBT. Conclusions: This study reveals that OBT is prevalent among CAF SWD candidates, with operational impact due to missed diving days. This study is limited, and further prospective study is recommended. PMID- 30028913 TI - Effects of sleep and fatigue on teams in a submarine environment. AB - Successful submarine operations rely on the performance of tactical teams who must work under conditions of physiological and cognitive fatigue. Sleep loss and circadian disruption contribute to fatigue in this setting and, although the effects of this fatigue have been studied extensively in individuals, little is understood about how fatigue impacts team performance Respecially in a submarine environment. The present review provides an overview of the fatigue on submarine teams and is divided into four main sections: 1) A discussion of factors that should be considered in team fatigue research. 2) An outline of how sleep and circadian rhythms of submariners are impacted by submarine-specific factors. 3) A discussion of the known effects of fatigue from sleep loss and circadian disruption on individual performance. 4) A consideration of how this fatigue impacts team performance. As the submarine force has recognized the need to protect submariner sleep and improve team dynamics, it is vital that future research accounts for the interplay between these two factors. PMID- 30028914 TI - Consensus guideline: Pre-hospital management of decompression illness: expert review of key principles and controversies. AB - (Mitchell SJ, Bennett MH, Bryson P, Butler FK, Doolette DJ, Holm JR, Kot J, Lafere P. Pre-hospital management of decompression illness: expert review of key principles and controversies. Diving and Hyperbaric Medicine. 2018 March;48(1):45e.doi.10.28920/dhm48.1.45-55.) Guidelines for the pre-hospital management of decompression illness (DCI) had not been formally revised since the 2004 Divers Alert Network/Undersea and Hyperbaric Medical Society workshop held in Sydney, entitled "Management of mild or marginal decompression illness in remote locations." A contemporary review was initiated by the Divers Alert Network and undertaken by a multinational committee with members from Australasia, the USA and Europe. The process began with literature reviews by designated committee members on: the diagnosis of DCI; first aid strategies for DCI; remote triage of possible DCI victims by diving medicine experts; evacuation of DCI victims; effect of delay to recompression in DCI; pitfalls in management when DCI victims present at hospitals without diving medicine expertise and in water recompression. This was followed by presentation of those reviews at a dedicated workshop at the 2017 UHMS Annual Scientific Meeting, discussion by registrants at that workshop and, finally, several committee meetings to formulate statements addressing points considered of prime importance to the management of DCI in the field. The committee placed particular emphasis on resolving controversies around the definition of "mild DCI" arising over 12 years of practical application of the 2004 workshop's findings, and on the controversial issue of in-water recompression. The guideline statements are promulgated in this paper. The full workshop proceedings are in preparation for publication. PMID- 30028916 TI - The Gradient Perfusion Model Part 2: Substantiation of the GPM with clinical cases. AB - Introduction: In Part 1 of this three-part series, we provided an explanation as to why and at what sites decompression sickness (DCS) occurs, using the Gradient Perfusion Model (GPM). In this part, we provide information to substantiate the concept and present clinical cases that were initially labeled as "unexplained DCS," but later disordering events were identified to explain the clinical presentations. Materials and Methods: Among 500 cases of DCS we have managed for over 50 years, a cohort of these patients was initially diagnosed as unexplained DCS. However, some have shown that disordering events are the likely cause of their DCS. Results: By pairing the tissue involved with the patient's dive history, a gradient-perfusion imbalance connection was identified. In all serious (Type 2) presentations of DCS, alterations in perfusion of the fast tissues were able to account for the clinical findings. The consequences demonstrated that the gradients overwhelmed the ability of altered perfusion to offgas/offload the inert gas. Pain-only and peripheral neuropathy presentations involved both intermediate and slowly perfused tissues. Rather than perfusion, gradient limitations were the reasons for the clinical presentations of these patients. Conclusions: The GPM accounts for signs and symptom presentations in DCS. This provides the basis for appropriate treatments and logical recommendations for return to diving. We recommend that the label "unexplained DCS" be discontinued and that the GPM be used to determine the cause. Once the cause is established, "DCS due to disordered decompression" becomes the appropriate term. PMID- 30028915 TI - The Gradient Perfusion Model Part 1: Why and at what sites decompression sickness can occur. AB - Introduction: Decompression sickness (DCS) is manifested by the quantity and location of bubbles in body tissues after reduction in ambient pressures. Models have been formulated to explain why bubbles form, but none provide satisfactory explanations as to why the findings of DCS occur as they do. This first of a three-part series explains why and at what sites DCS occurs. Materials and Methods: Over a 50-year span and 500 cases of DCS we have managed, it has become apparent that almost all "unexplained" DCS (i.e., cases with no obvious explanation as to how/why they occurred) have physiological explanations. The vagaries of the physiology of tissue perfusion and the physics of gradients as a cause of autochthonous bubble formation were analyzed. Findings: Perfusion is highly variable, with so-called "fast" tissues (i.e., tissues with a rapid rate of saturation) requiring a constant blood supply, "intermediate" tissues requiring a blood supply proportional to needs, and "slow" tissues having minimal perfusion requirements. The 5-liter blood volume in a vascular system with greater than a 20-liter capacity requires careful regulation. Disruptions in the regulation and/or overwhelming gradients explain why DCS occurs. Conclusions: Our Gradient-Perfusion Model provides an explanation as to why disordering events account for almost all cases of unexplained DCS. We propose that this latter term be discarded and "disordering events" be sought for DCS cases that have no obvious explanations. PMID- 30028917 TI - The Gradient Perfusion Model Part 3: An extraordinary case of decompression sickness. AB - Introduction: Decompression sickness (DCS) has been associated with unusual circumstances such as breath-hold diving, shallow depths, and short bottom times. We report a case of DCS with an extraordinary cause and course. Materials and Methods: A 72-year-old healthy Hispanic female was referred to our 24/7 Hyperbaric Medicine Unit for emergency hyperbaric oxygen recompression treatment (HBO2 RCT) after developing lower-extremity paralysis following a hyperbaric air exposure in a homemade hyperbaric chamber. Results: After an uneventful exposure to hyperbaric air at a maximum 72-foot depth (3.2 ATA, 32.3 psig), the patient had the delayed onset of abdominal pain and paraplegia after eating a meal. After HBO2 RCT in accordance with our management algorithm, the patient had a full recovery. Conclusions: This patient's presentation and course corresponded to what we label as "disordered decompression" and conformed to our Gradient Perfusion Model. With a finite blood volume and the need to perfuse two "intermediate" tissues simultaneously, we postulate that a "steal" syndrome arose to cause the abdominal and paralysis symptoms. PMID- 30028918 TI - Risk perception in small-scale fishers and hyperbaric personnel: A risk assessment of hookah diving. AB - Hookah diving is a fishing method used in many small-scale fisheries in the Gulf of Mexico and the Caribbean Sea, as well as in many coastal fisheries around the world. Many high-value species like sea cucumber and spiny lobster, among others, are harvested via hookah diving. However, the fishing method presents a risk for both decompression illness and carbon monoxide poisoning, both causes of disabilities and death among small-scale fishers, and with significant negative impacts on the social and economic status of households and coastal communities. Currently, there is a misunderstanding among fishers concerning diving risks. Using a mixed-method analysis, this study reports the risk perceptions of small scale fishers and hyperbaric personnel about hookah diving, and the actual diving accidents which occur in the spiny lobster and sea cucumber fisheries in the Yucatan northeastern ports. The study highlights the need for appropriate fishing technologies and increased awareness among fishers about the consequences of hookah diving. Fishery managers and health services can make priority decisions based on the information generated. PMID- 30028919 TI - Protective effects of hyperbaric oxygen preconditioning against LPS-induced acute lung injury in rats. AB - Introduction: Acute lung injury (ALI) is generally caused by oxidative damages and pulmonary overinflammations. Hyperbaric oxygen preconditioning (HBO2-PC) has been proven protective against oxidative-stress-related injuries. In this study, we investigated the effect of HBO2-PC on lipopolysaccharide (LPS)-induced ALI in rats. Methods: Thirty-two Sprague-Dawley rats randomly assigned into Sham, HBO2 PC, ALI and HBO2-PC/ALI groups (eight in each group) were sacrificed at 12 hours after the injection of LPS. The severity of ALI in rats was assessed in terms of histopathological changes in addition to wet/dry weight ratios. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta in serum and lung homogenates were measured by enzyme-linked immunosorbent and qRT-PCR assays. Activities by hydrogen peroxide (H2O2), malondialdehyde (MDA), myeloperoxidase (MPO) as well as superoxide dismutase (SOD) in rat lungs were tested for neutrophil infiltration. Meanwhile the oxidative stress molecular markers nuclear factor-kappa B(NF-kappaB) p65 and nuclear factor erythroid 2 related factor 2 (Nrf2), together with its downstream heme-oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) were also quantified. Results: HBO2-PC significantly alleviated LPS-induced ALI, lowered the lung injury scores, reduced lung water content, and reduced H2O2, MDA levels as well as MPO activity, while simultaneously improving the arterial partial oxygen pressure (PaO2) and SOD activity. Furthermore, HBO2-PC inhibited the nuclear translocation of NF-kappaB p65 while enhancing the nuclear translocation of Nrf2, thus upregulating HO-1 and NQO1. Conclusions: Our results suggest that HBO2-PC was potentially protective for LPS-induced ALI lungs in rats, with a presumed mechanism that suppressed NF kappaB while activating Nrf2. We propose that HBO2-PC should be considered a potential therapeutic strategy against ALI in rats. PMID- 30028920 TI - Neuronal nitric oxide inhibition attenuates the protective effect of HBO2 during cyanide poisoning. AB - Purpose: Experiments have shown that hyperbaric oxygen (HBO2) therapy reduces cyanide-induced cerebral distress. The exact mechanism behind HBO2's neuroprotective effect is unknown, but has been proposed to be mediated by an increased neuronal nitric oxide (NO) bioavailability, which may compete with cyanide for the active site of cytochrome oxidase in the mitochondrial respiratory chain. We hypothesized that the ameliorating effect of HBO2 is caused by an increased bioavailability of NO, which can be attenuated by injection of the selective neuronal NO synthase inhibitor, 7-nitroindazole, preceding the HBO2 procedure. Methods: A total of 41 anesthetized female Sprague-Dawley rats were allocated to four groups: 1) vehicle [1.2 ml isotonic NaCl via intra-arterial administration]; 2) cyanide [5.4 mg/kg potassium CN (KCN) intra-arterial] plus 7 nitroindazole [25 mg/kg 7-nitroindazole via intraperitoneal injection]; 3) cyanide plus 7-nitroindazole plus HBO2 [284 kPa for 90 minutes]; 4) cyanide plus 7-nitroindazole plus normobaric oxygen [101.3 kPa for 90 minutes]. Cerebral interstitial lactate, glucose, glycerol and pyruvate were evaluated by means of microdialysis. Results: HBO2 during inhibition of nNOS worsened cerebral metabolism compared to both solely CN-intoxicated animals and normobaric oxygen treated animals. This was indicated by elevated lactate (in mM; 0.85 vs. 0.63 and 0.42, P=0.006 and P ? 0.001, respectively), glycerol (in mM; 46 vs. 17 and 14, both P ? 0.001), glucose (in mM; 0.58 vs. 0.31 and 0.32, both P ? 0.001). Conclusions: The results indicate that a specific nNOS inhibition offsets the ameliorating effect of HBO2 during cerebral CN intoxication. However, other factors might contribute to this neuroprotective effect as well. PMID- 30028921 TI - PDTC ameliorates decompression induced-lung injury caused by unsafe fast buoyancy ascent escape via inhibition of NF-kappaB pathway. AB - Nuclear factor kappa B (NF-kappaB) is the critical transcriptional factor in the pathogenesis of acute lung injury (ALI). NF-kappaB regulates the expression changes of inflammatory factors such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin 6 (IL-6). In a previous study we showed that decompression sickness (DCS) caused by simulated unsafe fast buoyancy ascent escape (FBAE) could result in ALI, which was characterized by expression changes of inflammatory factors in rat lung tissue. The purpose of the present work was to study the roles of NF-kappaB and TNF-alpha in the process of DCS induced rat lung injury caused by simulated unsafe FBAE. The research methods aimed to detect the rat lung tissue messenger ribonucleic acid (mRNA) and protein level variations of NF-kappaB, inhibitory *B (I*B), TNF-alpha, IL-1beta, IL-6, IL 10 and IL-13 by using pretreatment of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and TNF-alpha antibody (Ab). Our experimental results demonstrated that PDTC could improve the survival rate of the rats with DCS caused by unsafe FBAE more effectively than TNF-alpha Ab. However, the inhibition of TNF-alpha Ab on the nuclear translocated protein expression of NF-kappaB was more effective than PDTC. Both PDTC and TNF-alpha Ab can abrogate the increment of the rat lung tissue mRNA levels of TNF-alpha, IL-1beta, IL-6 and protein levels of NF-kappaB, TNF-alpha, IL-1beta effectively and increase the rat lung tissue content of I*B significantly. In conclusion, TNF-alpha-mediated NF-kappaB signaling may be one of the critical signaling pathways in the pathogenesis of DCS-induced rat lung injury caused by simulated unsafe FBAE. PDTC may ameliorate this type of injury partly through inhibiting the NF-kappaB pathway. PMID- 30028922 TI - Efficacy of hyperbaric oxygen therapy as a supplementary therapy of sudden sensorineural hearing loss in the Slovak Republic. AB - We evaluated the efficacy of hyperbaric oxygen (HBO2) therapy used as a supplement to the first-line medical treatment of sudden sensorineural hearing loss (SSNHL). We tested 68 patients suffering from SSNHL within seven days of hearing loss: 21 patients received the standard treatment protocol of our department (control group) and 47 individuals were treated with an additional application of HBO2 therapy. Treatment success was assessed using pre- and post treatment audiograms. Outcomes of our study showed a statistically significant improvement in auditory threshold in all frequency groups for the HBO2 group (P ? 0.001), whereas in the control group the statistically significant mean auditory gain was observed only for the frequency zone 1,000 to 2,000 Hertz (P = 0.01). Furthermore, the rate of hearing gain in the HBO2 group was more than doubled (61.7%) compared to the control group (28.6%). Complete recovery of the hearing gain in the control group was observed only in the first two frequency groups (14.29%; 4.76%; 0.00%), whereas in the HBO2 group complete recovery was seen in all the frequency groups (19.15%; 21.13%; 6.38%) as well as in the whole frequency range (6.38%). The efficiency of both treatment protocols was statistically significant (P ? 0.001) in both groups of patients, but supplementation of the therapy with HBO2 demonstrated a statistically significantly increase in the effect of pharmacotherapy (P ? 0.001) by 11.5 decibels (dB) up to the final hearing gain of 20 dB. HBO2 is therefore a promising modality of SSNHL treatment, but specific mechanisms of HBO2 in patients with SSNHL are still unknown. Further investigations are warranted to explore the mechanisms of action. PMID- 30028923 TI - Stability of residual hearing and cochlear implant function following multiple scuba dives: case report. AB - Objectives: There are limited data regarding the safety of cochlear implants during exposure to pressure changes associated with scuba and hyperbaric oxygen therapy. There are no data regarding the effects of barometric pressure changes on preserved low-frequency hearing after cochlear implantation. This case report evaluates the effect of barometric pressure changes on preserved low-frequency hearing after cochlear implantation. Patient: This is a case report of a patient who underwent successful cochlear implantation with postoperative preservation of residual low-frequency hearing. Interventions: 20 scuba dives up to depths of 92 feet (3.8 atmospheres absolute). Results: Audiometric testing both before and after scuba shows no change in hearing thresholds. The internal receiver stimulator of the cochlear implant was unaffected by prolonged and repeated pressures up to approximately 3.8 atmospheres absolute. The patient had no adverse middle ear effects during or after the dives, and no evidence of inner ear barotrauma or decompression sickness as a result of the elevated pressures. Conclusions: This is the first report of preserved hearing after cochlear implantation being maintained following scuba diving, and corroborates previous literature showing that exposure to increased pressures with a cochlear implant in situ is safe without adverse effects on the implant hardware or software. Scuba diving appears safe not only with cochlear implants but also in patients with residual hearing. PMID- 30028924 TI - Call for a multicenter study on the intra-subject variability of venous gas emboli. PMID- 30028926 TI - UHMS Position Statement: Topical Oxygen for Chronic Wounds. PMID- 30028925 TI - Excessive mechanism research about HBO2 on peripheral neuropathic pain. PMID- 30028927 TI - Connected toothbrushes: Bridging the gap to personalized oral health. AB - PURPOSE: To describe the health-related metrics available from a connected toothbrush and potential insights into individualized toothbrushing behavior and performance. METHODS: A total of 1,926 patients used a new connected electronic toothbrush within a 4-month period. Data were collected from the brush using a smartphone application including frequency of use, duration and surface coverage of each brushing session across 16 zones covering occlusal, buccal and lingual surfaces. RESULTS: The population was comprised of 73% males, and 11% were left handed. Overall, there was no statistical difference between gender or handedness and mean duration (124 seconds) or mean proportional zonal duration (70%) of a brushing session. Both duration and zonal duration improved with usage of brush up to 60 days. CLINICAL SIGNIFICANCE: The use of connected toothbrushes in patients' home care routines can improve overall brushing duration and zonal duration and offers the opportunity to understand authentic brushing habits on both an individual and population level. As such these data are of interest to practicing clinicians, clinical trialists and public health dentists. Such brushes are in their infancy and further developments will enhance these insights into whole mouth care and the link to oral and general health. PMID- 30028928 TI - Effect of oral antimicrobial mouthrinses containing alcohol on viability of Streptococcus mutans and microcosm biofilm and on the prevention of enamel caries lesions. AB - PURPOSE: To evaluate the effect of PerioGard, Listerine, Noplak, Malvatricin and Cepacol commercial mouthrinses containing alcohol on the viability of Streptococcus mutans strain and of a microcosm biofilm and on the prevention of enamel demineralization. METHODS: The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined against S. mutans (ATCC 25175). Microcosm biofilm formed from human saliva mixed with McBain saliva was created on bovine enamel for 5 days. From the 2nd to the 5th day, the enamel samples were exposed to McBain with 0.2% sucrose and to the mouthrinses (1 x 60 seconds). The biofilm viability was determined by fluorescence and the enamel demineralization by TMR. RESULTS: The lowest MIC and MBC values were observed for Cepacol, while the highest values were found for Listerine. The mouthrinses significantly increased the number of dead bacteria in biofilm, varying from 38.0+/- 11.2% (Noplak) to 58.5+/- 13.9% (Listerine), compared to control (12.7+/- 10.6%), except Periogard (30.1+/- 12.4%). All mouthrinses reduced mineral loss (P< 0.0001), but only Noplak and Cepacol were able to significantly reduce lesion depth. Cepacol and Noplak presented the best anti-caries effect under this experimental model. CLINICAL SIGNIFICANCE: This study shows that the anti-caries potential may vary between the commercial mouthrinses, which should be taken into account for their prescription. PMID- 30028929 TI - Efficacy of a new light-cured anesthetic gel for clamp placement before rubber dam isolation in children: A triple-blinded randomized controlled clinical trial. AB - PURPOSE: To evaluate the efficacy of a new light-cured anesthetic gel for pain control associated with the clamp placement for rubber dam isolation in children. METHODS: 82 children in need of sealant placement on the first permanent mandibular molars were selected to take part in this randomized, split-mouth, triple-blinded study. Before rubber dam placement, the light-cured anesthetic gel (test) or a placebo gel (control) was applied on the gingival margins of the molars. The hemi-arches were isolated with cotton rolls and the gels were applied; the anesthetic gel was light-cured. After 30 seconds, clamp #26 was positioned on tooth 36 or 46. If there was pain, the clamp was removed and rescue anesthesia was applied. The absolute risk and intensity of pain were registered using three scales: facial expression (Wong-Baker), observational (FLACC) and numerical (NRS). Data were analyzed by McNemar's test and Wilcoxon Signed Rank (alpha= 5%). RESULTS: Differences were detected for the risk of pain between groups (P= 0.0002) and for the different intensity of pain scales used (P< 0.001) with positive results for the anesthetic gel. CLINICAL SIGNIFICANCE: The new developed light-cured topical anesthetic is an alternative to infiltrative anesthesia for pain control during clamp adaptation for rubber dam isolation. Its use helps to overcome the fear of needles, which can trigger pain, anxiety and discomfort for the majority of the patients, hampering the behavior management in children. PMID- 30028930 TI - Gingival displacement using diode laser or retraction cords: A comparative clinical study. AB - PURPOSE: To compare two systems used for conditioning the gingival sulcus and exposing the finish line before the final impression for a fixed denture: retraction cords and diode laser. METHODS: All subjects participating in the study had healthy gingival and periodontal status before intervention for fixed prosthesis. 74 abutments for complete crown restoration were randomly divided into two groups for displacing the gingival sulcus before the final impression: gingival retraction cords (RC) and diode laser (DL). The height of the clinical crowns was measured by a blinded examiner in three points of the buccal surface (mesial, midline and distal) at four different times: after tooth preparation (T0), 15 days after tooth preparation, before exposing the finish line with RC or with DL (T1), 10 minutes after exposing the finish line (T2), and 15 days after the final impression was taken (T3). The amount of gingival retraction produced (DeltaT2-T1) and restoration to baseline (DeltaT3-T1) were calculated. Ease of technique and patient comfort were evaluated through the Visual Analog Scale. The time required to carry out the technique and bleeding during and after the conditioning procedure were also evaluated. RESULTS: There was no difference between the two techniques with regard to the height differences: DeltaT2-T1 was 0.65+/-0.33 for RC and 0.66#177;0.43 for the DL (P= 0.966), while DeltaT3-T1 was 0.03#177;0.27 for RC and 0.02#177;0.46 for DL (P= 0.286). DL required less time, was easier for the operator and more comfortable than RC for the patient (all P<0.001). CLINICAL SIGNIFICANCE: The amount of gingival retraction and restoration to baseline resulting from use of gingival retraction cords or diode laser technique is similar, but diode laser required less time, was simpler for the operator and was more comfortable to the patient than retraction cords. PMID- 30028931 TI - Use of a toothpaste containing 8% arginine and calcium carbonate for immediate and lasting relief of dentin hypersensitivity: A simple and effective in-office procedure. AB - PURPOSE: To evaluate the effectiveness in reducing dentin hypersensitivity (DH) of a commercial toothpaste containing 8% arginine, calcium carbonate and fluoride when applied by a dental professional immediately prior to a professional dental prophylaxis and again after subjects brushed twice daily with the toothpaste at home for 2 weeks, and additionally to assess whether the % reductions in DH observed in the study are comparable to those found in previously published pivotal studies. METHODS: This clinical study was a single-center, user-blind, monadic study conducted in Mississauga, Canada. Adult subjects who presented with a tactile hypersensitivity score (Yeaple Probe) between 10 and 50 grams of force and an air blast hypersensitivity score of 2 or 3 (Schiff Cold Air Sensitivity Scale) and met all inclusion and exclusion criteria were entered into the study. Immediately following baseline assessment, qualifying subjects received a single topical application of the test toothpaste to two selected hypersensitive teeth by a dental professional using a fingertip and massage for 1 minute per tooth, after which they received a professional dental prophylaxis. Subjects then brushed at-home twice daily for 1 minute with their assigned toothpaste for a period of 2 weeks. Tactile and air blast sensitivity examinations were conducted after the dental cleaning procedure and again after 2 weeks of routine twice daily tooth brushing. RESULTS: 39 subjects complied with the protocol and completed the clinical study. Immediately post-prophylaxis, subjects exhibited statistically significant reductions from baseline of 228.9% (P< 0.001) in tactile hypersensitivity and 48.9% (P< 0.001) in air blast hypersensitivity. Furthermore, after brushing twice daily (morning and evening) for a period of 2 weeks, subjects exhibited statistically significant reductions from baseline of 317.8% (P< 0.001) in tactile hypersensitivity and 90.1% (P< 0.001) in air blast hypersensitivity. These results are consistent with the results of previously published clinical studies, which demonstrated similar % reductions in DH to a single in-office professional application of the desensitizing prophylaxis paste and to a single direct topical self-application of the desensitizing toothpaste. CLINICAL SIGNIFICANCE: The results of this clinical study, together with the results of published pivotal studies, demonstrate that a desensitizing toothpaste containing 8% arginine and calcium carbonate, with or without fluoride, provides statistically significant reductions in dentin hypersensitivity when applied by a dental professional prior to a professional dental prophylaxis. The results also demonstrate that this desensitizing toothpaste provides statistically significant reductions in dentin hypersensitivity when used subsequently as an adjunct to routine twice daily tooth brushing. PMID- 30028932 TI - Sealing effectiveness against Staphylococcus aureus of five different implant abutment connections. AB - PURPOSE: To compare the sealing effectiveness of four different implant-abutment connections against Staphylococcus aureus (S. aureus). The null hypotheses stated that there was no difference on sealing ability among the implant-abutment connections tested. METHODS: Five diverse commercially available dental implants were used to investigate the degree of microleakage at the implant-abutment junction (IAJ): Group 1: Torque Type conical implant with double conic connection - TTc (Winsix); Group 2: Torque Type conical implant with Cone Morse connection - TTcm (Winsix); Group 3: Free Lock connection - K type implant (Winsix); Group 4: Internal double hexagon - OsseoSpeed; Group 5: Internal hexagon - Aadva Implant. Nine implants were tested in each group and one group was used as the negative control (Group 4). The abutments were connected to implants according to manufacturers' recommendations. All procedures involving connection and disconnection of implants were performed in sterile conditions in a laminar flow biological safety cabinet. S. aureus ATCC 6538, a methicillin susceptible reference strain, was chosen for the experiments to test the degree of microleakage. Statistical analysis was performed in order to find significant differences among the five groups regarding sealing capability of the implant abutment connections tested. The recorded data were statistically analyzed. RESULTS: One implant from Group 4 was excluded from the study because of the growth of a contaminant after 48 hours of incubation in all three wells (i.e. Paenibacillus pabuli, environmental Gram-positive bacteria). Wells A and B (i.e. wells where the samples were passed before being located in the final well C) of all other samples (n = 46) remained sterile over the 72 hours of incubation, indicating the lack of external contamination during implant-abutment connection. Similarly, no bacterial growth was observed in the five negative controls (i.e. one implant for each type), which had been inoculated with sterile saline and processed as the others. Bacterial microleakage was demonstrated with three samples, including one sample of Group 1, one of Group 3 and one of Group 5, in which growth of S. aureus in wells C after 48 hours of incubation was demonstrated (Table 1). No statistically significant difference between groups was noticed (P> 0.05). CLINICAL SIGNIFICANCE: Within the limitations of the present in vitro model, the results obtained suggest a tendency toward a better sealing capability for conical connections and internal hexagon. PMID- 30028933 TI - Effects of artificial staining on bulk-filled resin composites. AB - PURPOSE: To evaluate the color stability of bulk-fill resin composites (RC) in comparison to conventional RC submitted to artificial staining. METHODS: 15 specimens of each RC were prepared. Five bulk-fill RC [X-tra Base (XB), Filtek Bulk-Fill Flowable (FBF), Admira Fusion X-tra (AD), Tetric N-Ceram Bulk-Fill (TB), and Filtek Bulk-Fill (FB) ], and two conventional RC [GrandioSO (GO) and Filtek Z350XT (FXT) ] were used. After preparation of the samples, the specimens were immersed in a staining broth for 5 weeks and repolished. The color change was assessed using a spectrophotometer. Data were analyzed using one-way ANOVA, Tukey's tests, and paired t-test. RESULTS: The bulk-fill flowable (XB and FBF) presented color change clinically acceptable (DeltaE< 2.7) after staining. Among the bulk-fill regular resins, only AD presented clinically acceptable values (DeltaE= 1.99). Regarding the conventional resins, GO presented a significantly lower color change than the other resins, but was not significantly different from AD. For all the resins, except AD, the repolishing procedures resulted in a significant decrease of color change. Tested resins did not present the same behavior under staining, despite their similarities. All the resins stained above the perceptibility threshold (DeltaE> 1.2). After repolishing, the color change was reduced overall. CLINICAL SIGNIFICANCE: Color stability of resin composites was related to the properties of the resin material. The staining degree was related to the replacement of the restorations and repolishing contributes to the maintenance and longevity of these composites. PMID- 30028934 TI - A novel antimicrobial and remineralizing toothpaste containing CaCl2/chitosan microspheres. AB - PURPOSE: To investigate the feasibility of exploiting amorphous calcium phosphate (ACP) formed in situ from chitosan calcium microspheres and phosphate ions in water during brushing for caries control. METHODS: A prototype toothpaste, namely Chi-ACP paste, was specially formulated containing CaCl2/chitosan microspheres. The efficiency of Chi-ACP paste for remineralization on human tooth enamel was evaluated via an in vitro pH cycling approach. After 15 demineralization/remineralization cycles, the treated teeth were analyzed using scanning electron microscope (SEM) /energy dispersive X-ray spectroscopy (EDX), and polarized light microscope (PLM). RESULTS: EDX analysis showed the treated enamel in the Chi-ACP paste group had statistically significantly higher calcium content and Ca/P weight ratios than those in the negative control group, while the MI plus group had a slightly higher Ca content and a slightly higher Ca/P weight ratio. PLM analysis revealed that the Chi-ACP paste group had a larger remineralization band in treated enamel than the negative control group, although there was no statistically significant difference on the demineralization depths in the enamel among the three groups. CLINICAL SIGNIFICANCE: Antibacterial chitosan could be used to encapsulate CaCl2 and then formulated into toothpaste for caries control through in-situ formed amorphous calcium phosphate (ACP) during brushing. PMID- 30028935 TI - Mild acids facilitate functional dentin remineralization under thermo-mechanical stimuli. AB - PURPOSE: To evaluate if mechanical and thermal cycling promote remineralization at the resin-dentin interface after bonding with three different adhesive approaches. METHODS: Dentin surfaces were subjected to three different treatments: demineralization (1) by 37% phosphoric acid followed by application of an etch-and-rinse dentin adhesive Single Bond (Adper Single Bond) (SB); (2) by 0.5 M ethylenediaminetetraacetic acid (EDTA) followed by SB; (3) application of a self-etch dentin adhesive: Clearfil-SEB (Clearfil SE Bond). Bonded interfaces were stored during 24 hours and then submitted for 3 months to: (1) storage at 37oC, (2) load cycling, (3) thermocycling, and (4) thermo+load cycling. One section was extracted from each tooth, monthly. Resin-dentin interfaces were analyzed by AFM nano-indentation, Raman spectroscopy/cluster analysis and Masson's trichrome staining at 24 hours, 1, 2 and 3 months, to determine remineralization at the interface. RESULTS: Thermo+load cycling promoted the highest biomimetic remineralization at the hybrid layer formed with EDTA+SB and Clearfil-SEB, at the 1 month time point. A narrow mineral-depleted zone was observed after thermo+load cycling with EDTA+ SB, and at those specimens bonded with Clearfil-SEB. Thermo+load cycling remineralized the dentin interface treated with EDTA+SB and Clearfil-SEB, after 1 month of study period, providing bioactivity and maturity of formed minerals. CLINICAL SIGNIFICANCE: In vitro challenging (thermo+load cycling) favors dentin remineralization at the resin dentin bonded interfaces promoted with mild conditioning acids. PMID- 30028936 TI - Dentin and enamel demineralization inhibition at restoration margins of Vitremer, Z 100 and Cention N. AB - PURPOSE: To examine the in vitro caries inhibition of a resin-modified glass ionomer cement, and a fluoride and calcium releasing resin-based composite. METHODS: Standardized Class V preparations were placed in 30 molars, the gingival margin placed below the cemento-enamel junction. Randomly, 10 Vitremer, 10 Z 100 and 10 Cention N restorations were placed according to manufacturer's instructions, in 30 teeth. The Z 100 non fluoride-releasing resin-based composite group acted as the control. All teeth had an acid-resistant varnish placed to within 1 mm of restoration margins and they were placed into artificial saliva for 2 weeks, the saliva being replenished every 48 hours. All teeth were subjected to thermocycling each day and to an artificial caries challenge (pH 4.4) for one hour twice a day. Sections of 100 um were obtained, photographed under polarized light microscopy and then demineralized areas adjacent to restorations were quantitated. RESULTS: The mean (+/- S.D.) area (um 2) demineralization 100 um from the enamel and dentin margins were: Vitremer 1,554 +/- 1,153, 4,125 +/- 301; Cention N 3580 +/- 1,518, 6,246 +/- 630; Z 100 13,257 +/- 3,794, 8,842 +/- 1,799. A Mann-Whitney Rank Sum Test indicated that Vitremer had significantly less enamel demineralization then Cention N (P< 0.003) and Z 100 (P< 0.001) and Cention N had significantly less enamel demineralization than Z 100 (P< 0.001) and Z 100 (P< 0.001). Vitremer also had significantly less dentin demineralization than Cention N (P< 0.001) and Cention N had significantly less dentin demineralization than Z 100 (P< 0.001). CLINICAL SIGNIFICANCE: Recurrent caries remains a concern and this in vitro research indicates that Cention N, as well as Vitremer may clinically inhibit caries at restoration margins. PMID- 30028940 TI - Polydopamine Nanoparticles as Efficient Scavengers for Reactive Oxygen Species in Periodontal Disease. AB - Antioxidative therapy has been considered an efficient strategy for the treatment of a series of excessive reactive oxygen species (ROS)-triggered diseases, including oxidative-stress-induced periodontal disease. However, current natural enzymes and nanozymes often show their high specificity toward given ROS and have insufficient antioxidative effects against multiple ROS generated in the diseases process. Meanwhile, multienzyme-based antioxidant defense systems are usually confined by the complicated synthesis as well as potential unwanted residue and toxicity. Various supports are highly needed to immobilize natural enzymes and antioxidants during the biorelated usages due to their low operational stability and difficulty of reuse. To overcome these limitations, we develop a high performance platform by using biodegradable polydopamine nanoparticles (PDA NPs) as smart ROS scavengers in oxidative stress-induced periodontal disease. Although PDA-based materials are well-known to eliminate ROS both in vitro and in vivo, their antioxidative performance in periodontal disease and relative mechanisms have yet to be well-explored. In this study, PDA NPs can act as ROS scavengers in dental specialties with ideal outcomes. Spectroscopic and in vitro experiments provide strong evidence for the roles of PDA NPs in scavenging multiple ROS and suppressing ROS-induced inflammation reactions. In addition to the above investigations, the results from a murine periodontitis model clearly demonstrate the feasibility of PDA NPs as robust antioxidants with which to remove ROS and decrease periodontal inflammation without any side effects. Taken together, the results from our present study will provide valuable insight into the development of safe and efficient antioxidant defense platforms for further biomedical uses. PMID- 30028941 TI - Achieving Long-Term Biocompatible Silicone via Covalently Immobilized S-Nitroso- N-acetylpenicillamine (SNAP) That Exhibits 4 Months of Sustained Nitric Oxide Release. AB - Ever since the role of endogenous nitric oxide (NO) in controlling a wide variety of biological functions was discovered approximately three decades back, multiple NO-releasing polymeric materials have been developed. However, most of these materials are typically short lived due to the inefficient incorporation of the NO donor molecules within the polymer matrix. In the present study, S-nitroso- N acetyl penicillamine (SNAP) is covalently attached to poly(dimethylsiloxane) (PDMS) to create a highly stable nitric oxide (NO) releasing material for biomedical applications. By tethering SNAP to the cross-linker of PDMS, the NO donor is unable to leach into the surrounding environment. This is the first time that a sustainable NO release and bacterial inhibition for over 125 days has been achieved by any NO-releasing polymer with supporting evidence of potential long term hemocompatibility and biocompatibility. The material proves to have very high antibacterial efficacy against Staphylococcus aureus by demonstrating a 99.99% reduction in the first 3 days in a continuous flow CDC bioreactor, whereas a similar inhibitory potential of 99.50% was maintained by the end of 1 month. Hemocompatibility of SNAP-PDMS was tested using a rabbit extracorporeal circuit (ECC) model over a 4 h period. Thrombus formation was greatly reduced within the SNAP-PDMS-coated ECCs compared to the control circuits, observing a 78% reduction in overall thrombus mass accumulation. These results demonstrate the potential of utilizing this material for blood and tissue contacting biomedical devices in long-term clinical applications where infection and unwanted clotting are major issues. PMID- 30028942 TI - Vacuum Ultraviolet Laser Desorption/Ionization Mass Spectrometry Imaging of Single Cells with Submicron Craters. AB - Mass spectrometry imaging (MSI) is a crucial label-free method to distinguish the localization patterns in single cells. MALDI-TOF MS and ToF-SIMS are now bearing the responsibility. However, MALDI-TOF MS is limited to micron spatial resolution and ToF-SIMS suffers from severe molecular fragmentation. Here, we proposed a new MSI methodology of vacuum ultraviolet laser desorption/ionization (VUVDI) with high spatial resolution, achieving higher ion yields and less fragmentation compared with ToF-SIMS at submicron level. The fluorescence image and mass spectrum of VUVDI were obtained simultaneously. In addition, the adjustable laser fluence acquired selective detection for different molecular and fragmental ions, thus realizing molecular identification. Furthermore, MSIs of single cells with submicron craters were presented. These results suggest VUVDI is a potential mass spectrometry method that provides a soft ionization source and submicron spatial resolution for molecular analysis in life science. PMID- 30028943 TI - des-Formylflustrabromine (dFBr): A Structure-Activity Study on Its Ability To Potentiate the Action of Acetylcholine at alpha4beta2 Nicotinic Acetylcholine Receptors. AB - The naturally occurring indole alkaloid des-formylflustrabromine (dFBr; 1) is one of the first agents shown to act as a selective positive allosteric modulator (PAM) at alpha4beta2 nicotinic acetylcholine receptors (nAChRs). We previously deconstructed this agent to determine which of its structural features contribute to its actions and have identified an agent that might serve as the basis for a " working pharmacophore". Here, we elaborate the dFBr (1; EC50 = 0.2 MUM) structure to identify how various structural modifications impact its actions. Electrophysiological studies with Xenopus laevis oocytes identified several compounds with dFBr-like potency and one, the 5-bromo analogue of 1 (i.e., 5 bromo dFBr; 25; EC50 = 0.4 MUM), with more than twice the efficacy of 1 as a PAM at alpha4beta2 nAChRs. PMID- 30028944 TI - Enhancing the Water Accounting and Vulnerability Evaluation Model: WAVE. AB - Due to the increasing relevance of analyzing water consumption along product life cycles, the water accounting and vulnerability evaluation model (WAVE) has been updated and methodologically enhanced. Recent data from the atmospheric moisture tracking model WAM2-layers is used to update the basin internal evaporation recycling (BIER) ratio, which denotes atmospheric moisture recycling within drainage basins. Potential local impacts resulting from water consumption are quantified by means of the water deprivation index (WDI). Based on the hydrological model WaterGAP3, WDI is updated and methodologically refined to express a basin's vulnerability to freshwater deprivation resulting from the relative scarcity and absolute shortage of water. Compared to the predecessor version, BIER and WDI are provided on an increased spatial and temporal (monthly) resolution. Differences compared to annual averages are relevant in semiarid and arid basins characterized by a high seasonal variation of water consumption and availability. In order to support applicability in water footprinting and life cycle assessment, BIER and WDI are combined to an integrated WAVE+ factor, which is provided on different temporal and spatial resolutions. The applicability of the WAVE+ method is proven in a case study on sugar cane, and results are compared to those obtained by other impact assessment methods. PMID- 30028945 TI - Halloysite Nanotubes Loaded with Calcium Hydroxide: Alkaline Fillers for the Deacidification of Waterlogged Archeological Woods. AB - A novel green protocol for the deacidifying consolidation of waterlogged archaeological woods through aqueous dispersions of polyethylene glycol (PEG) 1500 and halloysite nanotubes containing calcium hydroxide has been designed. First, we prepared functionalized halloysite nanotubes filled with Ca(OH)2 in their lumen. The controlled and sustained release of Ca(OH)2 from the halloysite lumen extended its neutralization action over time, allowing the development of a long-term deacidification of the wood samples. A preliminary thermomechanical characterization of clay/polymer nanocomposites allows us to determine the experimental conditions to maximize the consolidation efficiency of the wood samples. The penetration of the halloysite-Ca(OH)2/PEG composite within the wooden pores conferred the robustness of the archaeological woods based on the clay/polymer composition of the consolidant mixture. Compared to the archeological woods treated with pure PEG 1500, the addition of modified nanotubes in the consolidant induced a remarkable improvement in the mechanical performance in terms of flexural strength and rigidity. The pH measurements of the treated woods showed that the halloysite-Ca(OH)2 are effective alkaline fillers. Accordingly, the modified nanotubes provided a long-term protection for lignin present in the woods that are exposed to artificial aging under acidic atmosphere. The attained knowledge shows that an easy and green protocol for the long-term preservation of wooden artworks can be achieved by the combination of PEG polymers and alkaline tubular nanostructures obtained through the confinement of Ca(OH)2 within the halloysite cavity. PMID- 30028946 TI - Assessing Current Local Capacity for Agrifood Production To Meet Household Demand: Analyzing Select Food Commodities across 377 U.S. Metropolitan Areas. AB - Increasing food production in local urban and peri-urban areas is articulated as a potential way for local governments to achieve multiple sustainability outcomes (environmental, social, and human health). However, scientific judgements on localization are difficult to make because the degree of current food localization has not been systematically measured or defined across large numbers of cities. We develop new methods to quantify current local capacity for food production to meet total household agrifood demand, harmonizing bottom-up and top down approaches to assess direct-plus-embodied agrifood demand of both fresh and processed foods. We find unique patterns of localization for different agrifoods, with 21% of U.S. metropolitan statistical areas (MSAs) currently capable of local self-sufficiency for eggs and milk equivalents embodied in diet, versus 12% and 16% of MSAs self-sufficient in fruits and vegetables, respectively. Focusing only on the direct fresh food demand, increased current local capacity (e.g., 45% MSAs self-sufficient in direct fluid milk), which also increases with production distances around cities. Overall, significant agricultural production is found to already occur in and around U.S. MSAs for these items. Multivariable analysis finds that state policies that promote urban agriculture may influence greater localization, which, interestingly, is independent of population density. Such spatial demand-production analysis is the first step in informing sustainable city or regional food policies and envisioning spatial food supply chains to urban areas. PMID- 30028948 TI - Isolated Zr Surface Sites on Silica Promote Hydrogenation of CO2 to CH3OH in Supported Cu Catalysts. AB - Copper nanoparticles supported on zirconia (Cu/ZrO2) or related supported oxides (Cu/ZrO2/SiO2) show promising activity and selectivity for the hydrogenation of CO2 to CH3OH. However, the role of the support remains controversial because most spectroscopic techniques provide information dominated by the bulk, making interpretation and formulation of structure-activity relationships challenging. In order to understand the role of the support and in particular of the Zr surface species at a molecular level, a surface organometallic chemistry approach has been used to tailor a silica support containing isolated Zr(IV) surface sites, on which copper nanoparticles (~3 nm) are generated. These supported Cu nanoparticles exhibit increased CH3OH activity and selectivity compared to those supported on SiO2, reaching catalytic performances comparable to those of the corresponding Cu/ZrO2. Ex situ and in situ X-ray absorption spectroscopy reveals that the Zr sites on silica remain isolated and in their +4 oxidation state, while ex situ solid-state nuclear magnetic resonance spectroscopy and catalytic performances show that similar mechanisms are involved with the single-site support and ZrO2. These observations imply that Zr(IV) surface sites at the periphery of Cu particles are responsible for promoting CH3OH formation on Cu-Zr based catalysts and provide a guideline to develop selective CH3OH synthesis catalysts. PMID- 30028947 TI - Improved Physical Stability and Aerosolization of Inhalable Amorphous Ciprofloxacin Powder Formulations by Incorporating Synergistic Colistin. AB - This study aimed to develop dry powder inhaler (DPI) combination formulations of ciprofloxacin and colistin for use in respiratory infections. Effects of colistin on physical stability and aerosolization of spray-dried ciprofloxacin were examined. The combination DPI formulations were produced by co-spray drying colistin and ciprofloxacin in mass ratios of 1:1, 1:3, and 1:9. Colistin and ciprofloxacin were also co-sprayed with l-leucine in the mass ratio of 1:1:1. The physical and aerosolization stability of the selected co-sprayed formulations stored at 20, 55, and 75% relative humidity (RH) were examined. Formulation characterizations were carried out using powder X-ray diffraction (PXRD) for crystallinity, scanning electron microscopy for morphology and particle size distribution, and dynamic vapor sorption for moisture sorption. Particle surface analysis was performed using X-ray photoelectron spectroscopy, energy dispersive X-ray spectrometry, and nano-time-of-flight secondary ion mass spectrometry. Potential intermolecular interactions were studied using Fourier-transform infrared spectroscopy (FTIR). Aerosol performance was evaluated using a multistage liquid impinger with a RS01 monodose inhaler device. PXRD diffractograms showed that the co-spray-dried colistin-ciprofloxacin formulation in the mass ratio (1:1) was amorphous at 55% RH for up to 60 days; whereas the co spray-dried colistin-ciprofloxacin (1:3) and colistin-ciprofloxacin (1:9) crystallized after storage for 3 days at 55% RH. However, the extent of crystallization for the combination formulations was less as compared to the spray-dried ciprofloxacin alone formulation. Surface morphology of the co-spray dried formulations at different concentrations did not change even after storage at 55% RH for 60 days, unlike the spray-dried ciprofloxacin alone powder which became rougher after 3 days of storage at 55% RH. Surface analysis data indicated surface enrichment of colistin in the co-spray-dried formulations. Increasing colistin concentration on the composite particles surfaces improved aerosol performance of ciprofloxacin. FTIR data demonstrated intermolecular interactions between colistin and ciprofloxacin, thereby delaying and/or preventing crystallization of ciprofloxacin when co-spray-dried. Co-spray drying ciprofloxacin with colistin in the mass ratio (1:1) completely prevented crystallization of ciprofloxacin at 55% RH for up to 60 days. However, the colistin-ciprofloxacin formulation (1:1) began to fuse when stored at 75% RH due to moisture absorption resulting in a compromised aerosol performance. In contrast, the colistin-ciprofloxacin-leucine (1:1:1) formulation demonstrated no particle fusion, enabling a stable aerosol performance at 75% RH for 7 days. This study demonstrated that incorporation of colistin in the spray-dried formulations can improve physical stability and aerosolization of amorphous ciprofloxacin at 55% RH. At 75% RH, further addition of l-leucine in the formulation prevented particle fusion and deterioration in aerosol performance, attributed to the enrichment of nonhygroscopic l-leucine on the particle surface. PMID- 30028949 TI - Influence of Biochar Addition on Nitrogen Transformation during Copyrolysis of Algae and Lignocellulosic Biomass. AB - Algae are extremely promising sustainable feedstock for fuels and chemicals, while they contain high nitrogen content, which may cause some serious nitrogen emission during algae pyrolysis utilization. In this study, we proposed a feasible method to control the nitrogen emission during algae pyrolysis by introducing lignocellulosic biomass and biochar addition. Nitrogen transformation mechanism was investigated through quantitative analysis of N-species in the pyrolysis products. Results showed that copyrolysis of algae and lignocellulosic biomass greatly increased nitrogen in solid char with large amount of NH3 and HCN releasing (~20 wt %), while nitrogen in bio-oil decreased largely. With biochar addition, NH3, HCN, and N-containing intermediates (amines/amides and nitriles) reacted with higher active O-species (O-C?O, -OH, and -COOH) in biochar addition, and formed large amounts of amine/amide-N, pyridinic-N, pyrrolic-N, and quaternary-N on the surface of biochar addition, which led to most nitrogen being enriched in char product and biochar addition (over 75 wt %) at the expense of amines/amides, nitriles, and N-containing gas (only 3 wt % NH3 and HCN emission; decrease of 85%). These results demonstrated that biochar addition showed a positive influence on fixation of N-species during thermochemical conversion of algae and could convert nitrogen to valuable N-doped biochar materials. PMID- 30028950 TI - Impact of Environmental Radiation on the Health and Reproductive Status of Fish from Chernobyl. AB - Aquatic organisms at Chernobyl have now been chronically exposed to environmental radiation for three decades. The biological effects of acute exposure to radiation are relatively well documented, but much less is known about the long term effects of chronic exposure of organisms in their natural environment. Highly exposed fish in freshwater systems at Chernobyl showed morphological changes in their reproductive system in the years after the accident. However, the relatively limited scope of past studies did not allow robust conclusions to be drawn. Moreover, the level of the radiation dose at which significant effects on wildlife occur is still under debate. In the most comprehensive evaluation of the effects of chronic radiation on wild fish populations to date, the present study measures specific activities of 137Cs, 90Sr, and transuranium elements (238Pu, 239,240Pu, and 241Am), index conditions, distribution and size of oocytes, as well as environmental and biological confounding factors in two fish species perch ( Perca fluviatilis) and roach ( Rutilus rutilus) from seven lakes. In addition, relative species abundance was examined. The results showed that both fish species are, perhaps surprisingly, in good general physiological and reproductive health. Perch, however, appeared to be more sensitive to radiation than roach: in the most contaminated lakes, a delay of the maturation of the gonads and the presence of several undeveloped phenotypes were evident only for perch and not for roach. PMID- 30028951 TI - Measured and Modeled Residue Dynamics of Famoxadone and Oxathiapiprolin in Tomato Fields. AB - A reliable analytical method for the simultaneous determination of famoxadone and oxathiapiprolin dissipation kinetics as well as the metabolites of oxathiapiprolin (IN-E8S72 and IN-WR791) in tomato and soil was developed. We studied the dissipation of famoxadone and oxathiapiprolin in tomatoes grown using different kinetic curves in the area of Beijing in 2015 and 2016. Our results show that the most suitable model for two fungicides in 2015 and 2016 was first order kinetic and second-order kinetic with the half-lives of 3.4 to 5.2 and 2.4 to 3.0 days, respectively. In addition, we applied the dynamic plant uptake model dynamiCROP and combined it with results from the field experiments to investigate the uptake and translocation of famoxadone and oxathiapiprolin in the soil-tomato environment. Modeled and measured results of two years fitted well with R2 values ranging from 0.8072 to 0.9221. The fractions of famoxadone and oxathiapiprolin applied during tomato cultivation that are eventually ingested by humans via residues in crop harvest were finally evaluated and found to be in the range of one part per thousand, that is one gram intake per kilogram applied. PMID- 30028952 TI - Tailoring Single-Cycle Near Field in a Tunnel Junction with Carrier-Envelope Phase-Controlled Terahertz Electric Fields. AB - Light-field-driven processes occurring under conditions far beyond the diffraction limit of the light can be manipulated by harnessing spatiotemporally tunable near fields. A tailor-made carrier envelope phase in a tunnel junction formed between nanogap electrodes allows precisely controlled manipulation of these processes. In particular, the characterization and active control of near fields in a tunnel junction are essential for advancing elaborate manipulation of light-field-driven processes at the atomic-scale. Here, we demonstrate that desirable phase-controlled near fields can be produced in a tunnel junction via terahertz scanning tunneling microscopy (THz-STM) with a phase shifter. Measurements of the phase-resolved subcycle electron tunneling dynamics revealed an unexpected large carrier-envelope phase shift between far-field and near-field single-cycle THz waveforms. The phase shift stems from the wavelength-scale feature of the tip-sample configuration. By using a dual-phase double-pulse scheme, the electron tunneling was coherently manipulated over the femtosecond time scale. Our new prescription-in situ tailoring of single-cycle THz near fields in a tunnel junction-will offer unprecedented control of electrons for ultrafast atomic-scale electronics and metrology. PMID- 30028953 TI - Role of red blood cells "annexin V" and platelets "P-selectin" in patients with thalassemia. AB - OBJECTIVE/BACKGROUND: Certain hemostatic anomalies found in patients with thalassemia suggest the existence of a chronic hypercoagulable state. Several etiologic factors may play a role in the pathogenesis of the hypercoagulable state in those patients. One of these factors is abnormal thalassemic red blood cells (RBCs), which may provide a procoagulant. To substantiate these findings, we measured the ability of RBCs from thalassemia patients to bind annexin V with increased fraction of platelets carrying the activation marker CD62P (P selectin). To study the expression of RBC annexin V and platelets P-selectin in study patients (those with thalassemia major, thalassemia intermedia, thalassemia minor) and control group, four-color flow cytometry was performed and the correlation between these two markers was evaluated. METHODS: A case-control study was conducted on 50 beta-thalassemia patients (10 patients with thalassemia minor, 30 patients with thalassemia major, and 10 patients with thalassemia intermedia, with 10 normal adult volunteers as a control) from June 2016 to March 2017. Flow cytometry was used to study the expression of anionic phospholipids (Annexin V) on the RBCs and CD62P (P-selectin) on the activated platelet. RESULTS: The mean expression of annexin V in patients with thalassemia major and intermedia was significantly higher than that in the control group and patients with thalassemia minor. Although the mean expression was higher in patients with thalassemia intermedia than in those with thalassemia major, it was not statistically significant. CONCLUSION: The mean expression of platelets P selectin in patients with thalassemia major and thalassemia intermedia was significantly higher than that in controls and patients with thalassemia minor. However, its expression was significantly higher in patients with thalassemia intermedia than in those with thalassemia major. Annexin V also showed a positive correlation with P-selectin, and both markers positively correlated with regularity of blood transfusion. PMID- 30028954 TI - Recommendations for a Standard Magnetic Resonance Imaging Protocol of Temporomandibular Joints in Juvenile Idiopathic Arthritis. PMID- 30028955 TI - Molecular imaging in dementia: Past, present, and future. AB - Molecular imaging techniques using 18F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases. PMID- 30028956 TI - Purification and reconstitution of polyspecific H+/organic cation antiporter human MATE1. AB - Human MATE1 (multidrug and toxin extrusion 1, hMATE1) is a H+/organic cation (OC) exchanger responsible for the final step of toxic organic cation excretion in the kidney and liver. To investigate the mechanism of transport, we have established an in vitro assay procedure that includes its expression in insect cells, solubilization with octyl glucoside, purification, and reconstitution into liposomes. The resultant proteoliposomes containing hMATE1 as the sole protein component took up radiolabeled tetraethylammonium (TEA) in a ?pH-dependent and electroneutral fashion. Furthermore, lipid-detergent micelle containing hMATE1 showed ?pH-dependent TEA binding similar to transport. Mutated hMATE1 with replacement E273Q completely lacked these TEA binding and transport. In the case of divalent substrates, transport was electrogenic. These observations indicate that the stoichiometry of OC/H+ exchange is independent of substrate charge. Purification and reconstitution of hMATE1 is considered to be suitable for understanding the detailed molecular mechanisms of hMATE1. The results suggest that Glu273 of hMATE1 plays essential roles in substrate binding and transport. PMID- 30028957 TI - How to minimize dye-induced perturbations while studying biomembrane structure and dynamics: PEG linkers as a rational alternative. AB - Organic dye-tagged lipid analogs are essential for many fluorescence-based investigations of complex membrane structures, especially when using advanced microscopy approaches. However, lipid analogs may interfere with membrane structure and dynamics, and it is not obvious that the properties of lipid analogs would match those of non-labeled host lipids. In this work, we bridged atomistic simulations with super-resolution imaging experiments and biomimetic membranes to assess the performance of commonly used sphingomyelin-based lipid analogs. The objective was to compare, on equal footing, the relative strengths and weaknesses of acyl chain labeling, headgroup labeling, and labeling based on poly-ethyl-glycol (PEG) linkers in determining biomembrane properties. We observed that the most appropriate strategy to minimize dye-induced membrane perturbations and to allow consideration of Brownian-like diffusion in liquid ordered membrane environments is to decouple the dye from a membrane by a PEG linker attached to a lipid headgroup. Yet, while the use of PEG linkers may sound a rational and even an obvious approach to explore membrane dynamics, the results also suggest that the dyes exploiting PEG linkers interfere with molecular interactions and their dynamics. Overall, the results highlight the great care needed when using fluorescent lipid analogs, in particular accurate controls. PMID- 30028959 TI - Mycophenolate mofetil sensor based on molecularly imprinted polymer/multi-walled carbon nanotubes modified carbon paste electrode. AB - Using square wave voltammetry, a carbon paste electrode modified by molecularly imprinted polymer (MIP) as a recognition element of mycophenolate mofetil (MMF) and multi-walled carbon nanotubes was used for MMF monitoring To investigate the electrode during modification, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were utilized. After optimization of the effective parameters, the anodic peak current of MMF was utilized for dynamic range study which was linear in 9.9 nM-87 MUM range. The detection limit of the sensor was 7.0 nM. The capture ability of MIP to target was compared with that of non imprinted polymer (NIP). The practical application of the sensor in biological fluid samples analysis demonstrates its selectivity, sensitivity, and stability. PMID- 30028958 TI - Mechanistic Insights into Colorectal Cancer Phenomics from Fundamental and Organotypic Model Studies. AB - Colorectal cancer (CRC) diagnosis and prognostic stratification are based on histopathologic assessment of cell or nuclear pleomorphism, aberrant mitotic figures, altered glandular architecture, and other phenomic abnormalities. This complexity is driven by oncogenic perturbation of tightly coordinated spatiotemporal signaling to disrupt multiple scales of tissue organization. This review clarifies molecular and cellular mechanisms underlying common CRC histologic features and helps understand how the CRC genome controls core aspects of tumor aggressiveness. It further explores a spatiotemporal framework for CRC phenomics based on regulation of living cells in fundamental and organotypic model systems. The review also discusses tissue homeostasis, considers distinct classes of oncogenic perturbations, and evolution of cellular or multicellular cancer phenotypes. It further explores the molecular controls of cribriform, micropapillary, and high-grade CRC morphology in organotypic culture models and assesses relevant translational studies. In addition, the review delves into complexities of morphologic plasticity whereby a single molecular signature generates heterogeneous cancer phenotypes, and, conversely, morphologically homogeneous tumors show substantive molecular diversity. Principles outlined may aid mechanistic interpretation of omics data in a setting of cancer pathology, provide insight into CRC consensus molecular subtypes, and better define principles for CRC prognostic stratification. PMID- 30028960 TI - Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. AB - We have previously shown that SIRT1 mRNA expression was significantly lower in relapsing MS patients compared to those in remission. Our goal was to longitudinally investigate the role of active, phosphorylated SIRT1 (p-SIRT1) as a potential biomarker of relapse and predictor for response to glatiramer acetate (GA) treatment in patients with relapsing remitting multiple sclerosis (MS). We also want to investigate the downstream effects of SIRT1 activation by measuring the trimethylation of histone 3 at lysine 9 (H3K9me3). A cohort of 15 GA-treated patients was clinically monitored using the Expanded Disability Status Scale (EDSS) and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months after initiation of the therapy. P-SIRT1 and H3K9me3 levels were assayed by Western blotting using specific antibodies. Statistically significant lower levels of p-SIRT1 protein (p < 0.0001) and H3K9me3 (p = 0.001) were found during relapses when compared to stable MS patients. Non-responders to GA treatment were defined as patients who exhibited at least two relapses following initiation of GA treatment. Statistically significant lower levels of p-SIRT1 protein (p = 0.02) and H3K9me3 (p = 0.004) were found in GA non-responders compared to responders. Using receiver operating characteristic analysis, area under the curve (AUC) for p-SIRT1 was 77% (p = 0.007) and for H3K9me3 was 81% (p = 0.002) for prediction of relapse. For predicting responsiveness to GA treatment, AUC was 75% (P = 0.01) for H3K9me3. Our data suggest that p-SIRT1 and H3K9me3 could serve as potential biomarkers for MS relapse. In addition, H3K9me3 could serve as possible biomarker to predict response to GA treatment. PMID- 30028961 TI - Circulating tumor cells and their advances to promote cancer metastasis and relapse, with focus on glioblastoma multiforme. AB - In the late stages of their development, cancers can form metastases. Formation of metastases was found to be associated with the capacity of cancer cells to quit the tumor mass and journey through the circulation to distant organs. This cell population is called circulating tumor cells (CTCs). They exhibit several advanced properties such as epithelial-to-mesenchymal transition (EMT) and dormancy that are essential for supporting their survival in the bloodstream, radio- and chemoresistance, their escape from the anti-cancer immune response, and metastasis initiation. CTCs, and especially dormant tumor cells, are responsible for post-surgery tumor recurrence. CTCs were detected in the blood of patients affected with glioblastoma multiforme (GBM)-the most frequent, invasive, and deadly neoplasm among primary brain tumors. The identification of glioblastoma CTCs might have a promising clinical potential for early tumor diagnosis and prognosis. A variety of CTC enrichment and detection techniques have been developed to date. For several epithelial cancers, especially for breast carcinoma, a prognostic value of CTCs was reported. Similar efforts should be performed for GBM to evaluate clinical the significance of CTCs. PMID- 30028962 TI - Lymphocyte-to-monocyte ratio in esophageal squamous cell carcinoma prognosis. AB - INTRODUCTION: Recently, the prognostic value of the lymphocyte-to-monocyte ratio (LMR) has been widely evaluated in multiple malignancies. However, its prognostic value in patients with esophageal squamous cell carcinoma (ESCC) remains controversial. Herein, we perform a meta-analysis to assess the prognostic value of the preoperative LMR in ESCC. METHODS: Relevant studies were systematically retrieved from the online Cochrane, MEDLINE, and EMBASE databases published until March 2018. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) were weighted by generic inverse-variance and pooled in either fixed-effects models or random effects meta-analysis. Seven eligible studies involving 1701 patients were analyzed in this meta-analysis. RESULTS: The synthesized analysis showed that patients with low LMR had a significantly shorter overall survival (OS) (HR: 0.67, 95% CI: 0.58-0.78, p < 0.001) and disease-free survival (DFS)/progression-free survival (PFS) (HR: 0.67, 95% CI: 0.50-0.92, p = 0.01). Additionally, low LMR was correlated with TNM stage (III-IV vs. I-II; HR = 1.94, 95% CI: 1.16-3.22, P = 0.01) and tumor recurrence (yes vs. no; HR = 1.71, 95% CI: 1.06-2.77, P = 0.03). CONCLUSION: Low LMR was associated with advanced clinicopathological features and poor prognosis as a predicative biomarker in patients with ESCC. PMID- 30028963 TI - Evaluation of lipid peroxidation and the level of some elements in rat erythrocytes during separate and combined vanadium and magnesium administration. AB - The impact of vanadium (V) and magnesium (Mg) as sodium metavanadate (SMV, 0.125 mg V/ml) and magnesium sulfate (MS, 0.06 mg Mg/ml) on lipid peroxidation (LPO) and selected elements in the rat erythrocytes (RBCs) was investigated. Relationships between some indices determined in RBC were also studied. SMV alone (Group II) elevated the malondialdehyde level (MDARBC) (by 95% and 60%), compared with the control (Group I) and MS-supplemented rats (Group III), respectively, reduced the concentration of CuRBC (by 23.5%), in comparison with Group I, but did not change the levels of NaRBC, KRBC, and CaRBC, whereas MS alone (Group III) only reduced the CuRBC concentration (by 22%), compared with Group I. The SMV + MS combination (Group IV) reduced and elevated the CuRBC (by 24%) and CaRBC (by 111%) concentrations, respectively, in comparison with Groups I and III, and these changes were induced by the V-Mg antagonistic and synergistic interaction, respectively. The combined SMV + MS effect also enhanced the MDARBC level, compared with Groups I (by 79%) and III (by 47%) and slightly limited its concentration, compared with Group II, which, in turn, resulted from the distinct trend toward the V-Mg antagonistic interaction. We can conclude that V (as SMV) is able to stimulate LPO in rat RBCs and that V-Mg interactive effects are involved in changes in CuRBC, CaRBC, and MDARBC. Further studies are needed to elucidate the exact mechanisms of the V-Mg antagonistic/synergistic interactions and to provide insight into the biochemical mechanisms of changes in rats suffering from anemia [1], characterized by a disrupted antioxidant barrier in RBCs [2] and an intensified free radical process in these cells. PMID- 30028964 TI - Tumor-promoting and pro-angiogenic effects of roxarsone via VEGFR2/PLCgamma/PKC signaling. AB - Roxarsone is an organoarsenic feed additive used in livestock and poultry production that is released into the environment, where it poses a risk to human health. It is known to have a tumor-promoting effect that is brought about by pro angiogenic factors such as vascular endothelial growth factor (VEGF) and it receptors (VEGFR). However, little information is available about the other signaling molecules that could be involved. This study aims to investigate the role of PLCgamma/PKC signaling in roxarsone-induced angiogenesis in a mouse B16 F10 melanoma xenograft model and rat vascular endothelial cells (ECs). Results showed treatment with 5 mg/kg and 25 mg/kg roxarsone resulted in an obvious increase in the weight and volume of B16-F10 xenografts and PLCgamma/PKC phosphorylation in a dose-dependent manner in C57BL/6 mice. SU5416, a VEGFR2 inhibitor, significantly attenuated the tumor growth induced by roxarsone. Further, 1.0 MUmol/L roxarsone treatment in rat ECs was observed to significantly increase the optical density rate in the MTT assay, the number of BrdU-positive cells in the proliferation assay, the migration distance in the scratch test, and the number of meshes formed in the tube formation assay. In addition, treatment with 1.0 MUmol/L roxarsone was associated with significantly higher phosphorylation of PLCgamma/PKC than the control treatment. U73122, a PLCgamma inhibitor, was found significantly to combat the effects of 1.0 MUmol/L roxarsone on the ECs. Roxarsone is capable of promoting the growth of mouse B16-F10 xenografts and tube formation in vascular ECs. Moreover, VEGFR2/PLCgamma/PKC signaling may play a regulatory role in in vivo and in vitro roxarsone-induced angiogenesis. PMID- 30028965 TI - Click chemistry in sphingolipid research. AB - The term "click chemistry" was firstly coined by K. B. Sharpless in 2001 to refer to reactions that are high yielding, wide in scope, produce only easily removable byproducts and are stereospecific and simple to perform. Since then, this concept has been further developed and a large number of chemical reactions that fulfil totally or partially these criteria have been identified, contributing to widen the structural diversity in drug discovery campaigns, and providing chemical biologists with invaluable tools for the development of bioorthogonal reactions. In this context, several examples of the application of this concept in glycobiology and in the study of protein-protein, protein-nucleic acid and even protein-lipid interactions can be found. However, far fewer protocols have been described for the interrogation of cellular processes related to sphingolipid functions and metabolism. This review seeks to provide a concise overview of the most recent additions of click chemistry strategies to the current chemical biology toolbox, including the use of sphingolipid probes suitably functionalized for in situ click reactions, and the preparation of novel sphingolipid analogues whose design has been driven by the versatility of the archetypal [3 + 2] azide alkyne cycloaddition. PMID- 30028966 TI - Biological study of Trypanosoma caninum under co-culture with different feeder layer cells. AB - Trypanosoma caninum is a parasite isolated from domestic dogs, of which several biological aspects remain unknown, including evolutive forms found in vertebrate hosts. The objective of this study was to evaluate co-cultures of T. caninum with different cell lines as feeder layers to monitor the differentiation process and investigate infective potential. The study was performed using DH-82, MDCK, and Lulo cell lines. T. caninum from axenic culture was added to the cultured adherent cells. At intervals over 30 days, aliquots of the supernatant were collected for quantification and assessment of differentiation. Infectivity assays were performed on the aforementioned cell lines seeded on glass coverslips and evaluated after 6, 24, and 72 h. In the supernatant of the feeder layer, T. caninum presented similar growth profiles, with epimastigote and trypomastigote forms in binary and multiple divisions. During co-culture with DH-82 and MDCK cells, a higher level of differentiation to trypomastigotes was observed. This study shows that the differentiation process of this parasite can vary according to culture conditions and that DH-82 and MDCK lineages could be applied to the study of trypomastigote forms. All forms of T. caninum described until now (aflagellar epimastigotes, typical epimastigotes, or trypomastigotes) were unable to infect the cell line Finally, this study provides additional data about morphobiological aspects. Although the biological cycle of T. caninum has not been established, the present data suggest the importance of feeder layers in promoting the growth and differentiation of this new parasite. PMID- 30028967 TI - Pharmacological Therapy of COPD: Reasons for Optimism. AB - The number of pharmacological medications available to treat patients with COPD has increased over the past few decades. Most of the improvement has come from the modification of older compounds that are now more potent, of longer duration, and delivered in improved devices. They are now available as single, double, and even triple combinations that, although attempting to simplify administration, have also resulted in a large number of preparations. These medications are clearly effective and should be used as a central component of the multidimensional approach to the patient affected with COPD. The preferred route remains the inhaled direct delivery to the airways, but the favorable results obtained with systemic agents such as macrolides and roflumilast and the preliminary results of some biologicals are opening the door for the development of new drugs or reformulation of medications that have been used for other indications. Perhaps the most pressing need is to study the effect of these agents at early points in the course of the disease, because until now most, if not all, studies have been conducted in patients usually older than age 60 years, when most of the natural course of the disease has already been run. This monograph reviews the available pharmacological therapy based on current evidence and provides practical recommendations to health providers caring for patients with COPD. PMID- 30028968 TI - Predictors of Asthma/COPD Overlap in FDNY Firefighters With World Trade Center Dust Exposure: A Longitudinal Study. AB - BACKGROUND: Previously healthy firefighters with World Trade Center (WTC) dust exposure developed airway disease. Risk factors for irritant-associated asthma/COPD overlap are poorly defined. METHODS: This study included 2,137 WTC exposed firefighters who underwent a clinically indicated bronchodilator pulmonary function test (BD-PFT) between 9/11/2001 and 9/10/2017. A post-BD FEV1 increase of > 12% and 200 mL from baseline defined asthma, and a post-BD FEV1/FVC ratio < 0.7 identified COPD cases. Participants who met both criteria had asthma/COPD overlap. Eosinophil levels were measured on screening blood tests performed shortly after 9/11/2001 and prior to BD-PFT; a subgroup of participants also had serum IgE and 21 cytokines measured (n = 215). Marginal Cox regression models for multiple events assessed the associations of eosinophil levels or serum biomarkers with subsequent diagnosis, with age, race, smoking, WTC exposure, first post-9/11 FEV1/FVC ratio, and BMI included as covariates. RESULTS: BD-PFT diagnosed asthma/COPD overlap in 99 subjects (4.6%), isolated asthma in 202 (9.5%), and isolated-COPD in 215 (10.1%). Eosinophil concentration >= 300 cells/MUL was associated with increased risk of asthma/COPD overlap (hazard ratio [HR], 1.85; 95% CI, 1.16-2.95) but not with isolated-asthma or isolated-COPD. Serum IL-4 also predicted asthma/COPD overlap (HR, 1.51 per doubling of cytokine concentration; 95% CI, 1.17-1.95). Greater IL-21 concentration was associated with both isolated-asthma and isolated-COPD (HRs of 1.73 [95% CI, 1.27-2.35] and 2.06 [95% CI, 1.31-3.23], respectively). CONCLUSIONS: In WTC-exposed firefighters, elevated blood eosinophil and IL-4 levels are associated with subsequent asthma/COPD overlap. Disease-specific T helper cell type 2 biomarkers present years before diagnosis suggest patient intrinsic predisposition to irritant-associated asthma/COPD overlap. PMID- 30028969 TI - Schwann cells protect against CaMKII- and PKA-dependent Acrylamide-induced Synapsin I phosphorylation. AB - OBJECTIVES: To explore the effects of Acrylamide (ACR), as well as the influence of Schwann cells (SCs), on the signal transduction pathway and phosphorylation of Synapsin I in a Human neuroblastoma cell line (NB-1). METHODS: NB-1s, NB-1s co cultured with SCs, and a negative control group (NB-1 cells without ACR) were exposed to gradient concentrations of ACR for 48 h. Cell proliferation and viability were determined by MTT. Protein and mRNA expression levels of typical kinases (i.e., cAMP-dependent protein kinase [PKA], calcium/calmodulin-dependent protein kinase II [CaMKII], and mitogen-activated protein kinase-extracellular signal-regulated kinases [MAPK-Erk]), their phosphorylation status, as well as Synapsin I and its phosphorylation status, were tested by western blotting and polymerase chain reaction, respectively. Further, the effect of SCs on ACR induced NB-1 cell toxicity was evaluated. RESULTS: (1) The MTT assay showed a sustained, dose- and time-dependent inhibition of NB-1s exposed to ACR. (2) ACR exposure increased the phosphorylation of CaMKII and PKA, which subsequently increased the phosphorylation of Synapsin I (at Serine603 [a substrate site of CaMKII] and Serine9 [a substrate site of PKA]). Pretreatment with CaMKII and PKA inhibitors blocked the ACR-mediated increase in phosphorylation. The above described results were all significantly different when compared to the control group (p < 0.05). (3) When co-cultured with SCs, ACR-induced NB-1 inhibition was obviously decreased, and the trend of change of phosphorylated CaMKII, PKA, and Synapsin I were changed (first slightly increased and then decreased), which was inconsistent with what we observed in NB-1s cultured alone. CONCLUSIONS: The toxic effects of ACR on neurons may be mediated by CaMKII and PKA-dependent signaling pathways in which Synapsin I may act as a downstream effector. Furthermore, glial cells (SCs) may be able to prevent a certain degree of ACR induced neuronal damage. PMID- 30028970 TI - Oxysterol-binding protein-related protein (ORP) 6 localizes to the ER and ER plasma membrane contact sites and is involved in the turnover of PI4P in cerebellar granule neurons. AB - Oxysterol-binding protein (OSBP)-related proteins (ORPs) are conserved lipid binding proteins found in organisms ranging from yeast to mammals. Recent findings have indicated that these proteins mainly localize to contact sites of 2 different membranous organelles. ORP6, a member of the ORP subfamily III, is one of the least studied ORPs. Using approaches in molecular cell biology, we attempted to study the characteristics of ORP6 and found that ORP6 is abundantly expressed in mouse cultured neurons. Deconvolution microscopy of cultured cerebellar granular cells revealed that ORP6 is localized to the endoplasmic reticulum (ER) and ER-plasma membrane (PM) contact sites, where it co-localized with extended synaptotagmin2 (E-Syt2), a well-known ER-PM contact site marker. E Syt2 also co-localized with ORP3, another subfamily III member, and ORP5, a subfamily IV member. However, ORP5 does not distribute to the same ER-PM contact sites as subfamily III members. Also, the co-expression of ORP3 but not ORP5 altered the distribution of ORP6 into the processes of cerebellar neurons. Immunoprecipitation demonstrated binding between the intermediate region of ORP6 and ORP3 or ORP6 itself. Additionally, the localization of ORP6 in the PM decreased when co-expressed with the intermediate region of ORP6, in which the pleckstrin homology (PH) domain and OSBP-related ligand binding domain (ORD) are deleted. Over-expression of this intermediate region shifted the location of a phophtidylinositol-4-phosphate (PI4P) marker from the Golgi to the PM. Knockdown of ORP6 resulted in the same shift of the PI4P marker. Collectively, our data suggests that the recruitment of ORP6 to ER-PM contact sites is involved in the turnover of PI4P in cerebellar granular neurons. PMID- 30028971 TI - Diagnostic and prognostic properties of procalcitonin in patients with acute dyspnea: Data from the ACE 2 Study. AB - BACKGROUND: Procalcitonin (PCT) concentrations increase during bacterial infections and could improve diagnosis of pneumonia and risk stratification in patients with acute dyspnea. METHODS: PCT concentrations were measured <24 h of admission in 310 patients with acute dyspnea and compared to C-reactive protein (CRP) and white blood cells (WBC) in the total cohort and the subset of patients with concomitant acute heart failure (HF). RESULTS: We diagnosed pneumonia in 16 out of 140 patients with acute HF (11%) and in 45 out of 170 patients with non-HF related dyspnea (27%). PCT concentrations were higher in patients with pneumonia vs. patients without pneumonia, both among acute HF patients (median 2.79 [Q1-3 0.18-5.80] vs. 0.10 [0.07-0.14] ng/mL, p < .001) and non-HF patients (0.22 [Q1-3 0.13-0.77] vs. 0.07 [0.05-0.10] ng/mL, p < .001). CRP and WBC were also higher in patients with pneumonia in both groups, but among acute HF patients, only PCT concentrations were associated with pneumonia in multivariate analysis. In patients with acute HF, receiver-operating statistics area under the curve (ROC AUC) to diagnose pneumonia was 0.90 (95% CI 0.81-0.98) for PCT, 0.84 (0.73-0.94) for CRP, and 0.72 (0.57-0.87) for WBC. The corresponding ROC-AUCs among patients with non-HF-related dyspnea were 0.88 (0.82-0.93), 0.94 (0.90-0.98), and 0.79 (0.72-0.87), respectively. During a median follow-up of 823 days (Q1-3 471-998) 114 patients died, and PCT and CRP, but not WBC concentrations were associated with all-cause mortality. CONCLUSION: In acute HF patients, PCT concentrations were superior to CRP and WBC to diagnose concurrent pneumonia. PMID- 30028972 TI - NETs detection and quantification in paraffin embedded samples using confocal microscopy. AB - Detection and quantification of Neutrophil Extracellular Traps (NETs) in tissue samples has become a topic of great interest to understand their pathological role in various diseases. We describe a semi-automatic method of visualization and quantification of NETs in paraffin-embedded intracoronary thrombus aspirate samples. This study is based on colocalization of myeloperoxidase (MPO) and citrullinated histone 3 (H3Cit) as hallmark of the presence of NETs. For the analysis we used the confocal immunofluorescence microscopy technology to quantify the number of fields and the total area (in MUm2) containing NETs in each thrombus sample. This observer-independent quantification method could be a useful tool to standardize the study of NETs in paraffin-embedded tissues, enabling comparison of results among different laboratories. PMID- 30028973 TI - Lipid Modulation of Membrane Protein Function. AB - In the last decade, native mass spectrometry has emerged as a powerful tool for studying the interactions of lipids and other small molecules with integral membrane proteins and their complexes. In this issue of Cell Chemical Biology, Pyle et al. (2018) establishes the role of phosphatidyl-inositol in dimerization and activity of a eukaryotic purine transporter (UapA). PMID- 30028974 TI - A "Smart Lock" for Preventing Hepatitis B Entry into Cells. AB - In this issue of Cell Chemical Biology, Passioura et al. (2018) report another interesting application of the powerful random non-standard peptide integrated discovery (RaPID) screening method. They identify several high-affinity macrocyclic peptides for the sodium taurocholate co-transporting polypeptide (NTCP), the protein through which hepatitis B virus (HBV) enters the cell. PMID- 30028975 TI - Dual Modifications of alpha-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity. PMID- 30028976 TI - Reply. PMID- 30028977 TI - Uniportal Subxiphoid Video-Assisted Thoracoscopic Anatomical Segmentectomy: Technique and Results. AB - BACKGROUND: Performing sublobar resection for early stage non-small cell lung carcinoma is becoming increasingly popular, with studies suggesting equivalent outcomes to lobectomy when sufficient lymph node sampling is performed. Furthermore, there has been a move to minimally invasive thoracic surgery facilitating enhanced recovery and reduced postoperative morbidity. The subxiphoid video-assisted thoracic surgery (SVATS) approach is a novel technique that is becoming increasingly popular, with evidence of reduced postoperative pain. Here, we report experience and the technique of performing segmentectomy by the uniportal SVATS approach. METHODS: The uniportal SVATS approach was used to perform all possible segmentectomies. Specific instruments were designed to facilitate performing surgery through this approach, and the operative technique is described and demonstrated with videos. RESULTS: Between September 2014 and April 2017, 242 segmentectomies were performed by uniportal SVATS. Twenty-nine of the patients underwent bilateral procedures. The mean duration of surgery was 2.14 +/- 0.78 hours. Lymph node stations were accessible, and a mean of 4.00 +/- 1.00 lymph node stations and 10.64 +/- 3.38 lymph nodes were sampled. The mean postoperative hospital length of stay was 4.67 +/- 9.54 days. Only 4 cases required conversion to thoracotomy, and 3 required conversion to full lobectomy. There were no perioperative deaths, with 30-day survival of 100%. CONCLUSIONS: This report demonstrates that the uniportal SVATS approach can be safely and effectively utilized to perform pulmonary segmentectomies. Our series demonstrates that it is possible to access and resect all segments by this novel approach to VATS. PMID- 30028978 TI - Electric Shock-Induced Coronary Artery Thrombosis and Dissection. AB - Electric shock-induced myocardial infarction is rare. Shock-induced coronary artery thrombosis and dissection in multiple distributions have not been reported. After shock, coronary thrombosis may cause anginal symptoms, and any coronary artery may be damaged. A 32-year-old man presented with angina and ischemia-related symptoms post 6,000-V electric shock. He reported occasional exertional angina; stress echocardiography was positive for ischemia. Catheterization showed severe multivessel disease, occluded left anterior descending coronary artery, and occluded circumflex with collateralization to distal left anterior descending coronary artery. Surgical intervention detected global coronary dissection and thrombosis. Bypass grafting achieved complete revascularization. Patient was successfully discharged home. PMID- 30028979 TI - Reply. PMID- 30028980 TI - Surgical Treatment of Acute Thoracic Stent-Graft Occlusion. AB - An adolescent male presented with acute onset paraplegia related to complete occlusion of a thoracic stent-graft placed 2 years earlier for repair of traumatic type B aortic dissection. Following emergency surgery comprising reestablishment of aortic flow by stent removal and aortic reconstruction, the paraplegia started to resolve partly, despite an estimated 5 hours interval of preoperative myelum ischemia. Anatomical characteristics of the stent-graft placement appear to have played a role in causing this rare complication. Six months later, the patient could walk again with a stick. This case shows that early intervention in case of full paraplegia may be considered. PMID- 30028981 TI - Reply. PMID- 30028982 TI - Is Spread Through Air Spaces a Prognostic Factor in Sublobar Resection of Non Small Cell Lung Cancer? PMID- 30028984 TI - Thoracic Endovascular Aortic Repair for Aneurysm: How I Teach It. PMID- 30028983 TI - Molecular Genetics of Lidocaine-Containing Cardioplegia in the Human Heart During Cardiac Surgery. AB - BACKGROUND: During cardiac surgery with cardiopulmonary bypass, delivery of cardioplegia solution to achieve electromechanical cardiac quiescence is obligatory. The addition of lidocaine to cardioplegia has advantages, although its consequences at a molecular level remain unclear. We performed whole-genome RNA sequencing of the human left ventricular (LV) myocardium to elucidate the differences between whole-blood (WB) cardioplegia with and without addition of lidocaine (LC) on gene expression. METHODS: We prospectively enrolled 130 patients undergoing aortic valve replacement surgery. Patients received high potassium blood cardioplegia either with (n = 37) or without (n = 93) lidocaine. The LV apex was biopsied at baseline, and after an average of 74 minutes of cold cardioplegic arrest. We performed differential gene expression analysis for 18,258 genes between these 2 groups. Clinical and demographic variables were adjusted in the model. Gene ontology (GO) and network enrichment analysis of the retained genes were performed using g:Profiler and Cytoscape. RESULTS: A total of 1,298 genes were differentially expressed between cardioplegic treatments. Compared with the WB group, genes upregulated in the LC group were identified by network enrichment to play a protective role in ischemic injury by inhibiting apoptosis, increasing transferrin endocytosis, and increasing cell viability. Downregulated genes in the LC group were identified to play a role in inflammatory diseases, oxygen transport, and neutrophil aggregation. CONCLUSIONS: The addition of lidocaine to cardioplegia had pronounced effects on a molecular level with genes responsible for decreased inflammation, reduced intracellular calcium binding, enhanced antiapoptotic protection, augmented oxygen accessibility through transferrins, and increased cell viability showing measurable differences. PMID- 30028985 TI - A Clinical Trial of TumorGlow to Identify Residual Disease During Pleurectomy and Decortication. AB - BACKGROUND: Macroscopic complete resection can improve survival in a select group of patients with malignant pleural mesothelioma. During resection, differentiating residual tumor from inflammation or scar can be challenging. This trial evaluated near-infrared (NIR) intraoperative imaging using TumorGlow (a novel NIR imaging approach utilizing high-dose indocyanine green and delayed imaging) technology to improve detection of macroscopic residual disease. METHODS: Twenty subjects were enrolled in an open-label clinical trial of NIR intraoperative imaging with TumorGlow (Indocyanine Green for Solid Tumors [NCT02280954]). Twenty-four hours before pleural biopsy or pleurectomy and decortication (P/D), patients received intravenous indocyanine green. All specimens identified during standard-of-care surgical resection and with NIR imaging underwent histopathologic profiling and correlative microscopic fluorescent tomographic evaluation. For subjects undergoing P/D (n = 13), the hemithorax was evaluated with NIR imaging during P/D to assess for residual disease. When possible, additional fluorescent lesions were resected. RESULTS: Of 203 resected specimens submitted for evaluation, indocyanine green accumulated within 113 of 113 of resected mesothelioma specimens, with a mean signal-to background fluorescence ratio of 3.1 (SD, 2.2 to 4.8). The mean signal-to background fluorescence ratio of benign tissues was 2.2 (SD, 1.4 to 2.4), which was significantly lower than in malignant specimens (p = 0.001). NIR imaging identified occult macroscopic residual disease in 10 of 13 subjects. A median of 5.6 resectable residual deposits per patient (range, 0 to 11 deposits per patient), with a mean size of 0.3 cm (range, 0.1 to 1.5 cm), were identified. CONCLUSIONS: TumorGlow for malignant pleural mesothelioma is safe and feasible. Excellent sensitivity allows for to reliable detection of macroscopic residual disease during cytoreductive surgical procedures. PMID- 30028986 TI - Effect of antiprotozoal molecules on hypnospores of Perkinsus spp. parasite. AB - Perkinsus protozoan parasites have been associated with high mortality of bivalves worldwide, including Brazil. The use of antiproliferative drugs to treat the Perkinsosis is an unusual prophylactic strategy. However, because of their environment impact it could be used to control parasite proliferation in closed system, such as hatchery. This study evaluated the anti-Perkinsus activity potential of synthesized and commercial compounds. Viability of hypnospores of Perkinsus spp. was assessed in vitro. Cells were incubated with three 2-amino thiophene (6AMD, 6CN, 5CN) and one acylhydrazone derivatives (AMZ-DCL), at the concentrations of 31.25; 62.5; 125; 250 and 500 MUM and one commercial chlorinated phenoxy phenol derivative, triclosan (2, 5, 10 and 20 MUM), for 24-48 h. Two synthetic molecules (6CN and AMZ-DCL) caused a significant decline (38 and 39%, respectively) in hypnospores viability, at the highest concentration (500 MUM), after 48 h. Triclosan was the most cytotoxic compound, causing 100% of mortality at 20 MUM after 24 h and at 10 MUM after 48 h. Cytotoxic effects of the compounds 6CN, AMZ-DCL, and triclosan were investigated by measuring parasite's zoosporulation, morphological changes and metabolic activities (esterase activity, production of reactive oxygen species and lipid content). Results showed that zoosporulation occurred in few cell. Triclosan caused changes in the morphology of hypnospores. The 6CN and AMZ-DCL did not alter the metabolic activities studied whilst Triclosan significantly increased the production of reactive oxygen species and changed the amount and distribution of lipids in the hypnospores. These results suggest that three compounds had potential to be used as antiprotozoal drugs, although further investigation of their mechanism of action must be enlightened. PMID- 30028987 TI - Sex differences in testosterone reactivity during marital conflict. AB - When attempting to resolve relationship problems, individuals in close relationships sometimes challenge their partners with statements that oppose their partners' point of view. Such oppositional behaviors may undermine those partners' relational value and threaten their status within the relationship. We examined whether perceptions of opposition from a partner during a series of problem-solving interactions were associated with reactivity in testosterone levels and whether those associations were different for men and women. Fifty newlywed couples discussed four marital problems. Each member of the couple reported how much oppositional behavior they perceived from their partner during the discussions. Pre- and post-discussion saliva samples were assayed for testosterone. For men, but not for women, perceptions of oppositional behavior were associated with heightened testosterone reactivity, and this result replicated across three different measures of testosterone reactivity. Findings were specific to men's perceptions of oppositional behavior, and held controlling for objective measures of oppositional behavior coded from videos of the conversations. Results highlight the benefits of considering pair-bonded relationships as a novel context for investigating associations involving hormones and behavior. Findings also raise the possibility that sex differentiated hormonal reactions to opposition partly explain why conflict among heterosexual partners can be so divisive. PMID- 30028988 TI - In vitro approach to elucidate the relevance of carboxylesterase 2 and N acetyltransferase 2 to flupirtine-induced liver injury. AB - The use of flupirtine, an analgesic, has been restricted in European countries because it causes liver injury in rare cases. Flupirtine is primarily metabolized to D-13223, an acetylamino form. In the process of D-13223 formation, it has been hypothesized that a reactive metabolite is formed which may be involved in flupirtine hepatotoxicity. The purpose of this study was to identify the potential reactive metabolite and the responsible enzymes in the human liver to get a clue to the mechanism of hepatotoxicity. Using recombinant enzymes, we found that D-13223 was formed from flupirtine via hydrolysis by carboxylesterase 2 (CES2) and subsequent acetylation by N-acetyltransferase (NAT) 2. A conjugate of N-acetyl-l-cysteine (NAC), a nucleophile, was detected by incubation of flupirtine with CES2, and the conjugate formation in human liver microsomes was inhibited by CES2 inhibitors, indicating that a reactive metabolite, which may be a quinone diimine, was produced in the process of CES2-mediated hydrolysis of flupirtine. The formation of the NAC conjugate in liver S9 samples from NAT2 slow acetylators was significantly higher than that from NAT2 rapid/intermediate acetylators, indicating that NAT2 could function as a detoxification enzyme for flupirtine. CES2-overexpressing HepG2 cells showed remarkable lactate dehydrogenase leakage under flupirtine treatment, while no cytotoxicity was observed in control cells, suggesting that the reactive metabolite formed by CES2 mediated hydrolysis of flupirtine would be a trigger of hepatotoxicity. NAT2 slow acetylators with high CES2 activity could be highly susceptible to flupirtine induced liver injury. PMID- 30028989 TI - Novel dual incretin agonist peptide with antidiabetic and neuroprotective potential. AB - Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP 1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(d-Ala2)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(d-Ala2)GIP/GLP-1-exe significantly (P < 0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P < 0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P < 0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P < 0.05) 8 h post-injection. Twice-daily injection of N-ac(d-Ala2)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P < 0.05-P < 0.001) reduced body weight, HbA1c, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P < 0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P < 0.05-P < 0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(d-Ala2)GIP/GLP-1-exe treated mice exhibited improved (P < 0.01) recognition memory which was accompanied by enhanced (P < 0.05-P < 0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(d-Ala2)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes. PMID- 30028991 TI - Effects of n-3 PUFA enriched and n-3 PUFA deficient diets in naive and Abeta treated female rats. AB - Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble Abeta1-42 peptide has been receiving great importance in the development of depression, also since depression is highly comorbid with Alzheimer's disease and other neurodegenerative illnesses. Accordingly, we have previously shown that central Abeta injection is able to elicit depressive-like phenotype in male rats. In the present study, we reproduced for the first time the Abeta-induced depressive-like model in female rats, evaluating behavioural and neurochemical outcomes. Moreover, we studied the effect of lifelong exposure to either n-3 PUFA enriched or n-3 PUFA deficient diet, in female rats, both intact and after central Abeta administration. Our results confirmed the Abeta-induced depressive like profile also in female rats. Moreover, chronic exposure to n-3 PUFA deficient diet led to highly negative alterations in behavioural and neurochemical parameters, while lifelong exposure to n-3 PUFA enriched diet was able to restore the Abeta-induced depressive-like profile in female rats. In conclusion, the Abeta-induced depressive-like profile was reversed by n-3 PUFA supplementation, indicating a possible therapeutic role of n-3 PUFA in the treatment of the burden of depressive disorders. PMID- 30028990 TI - A novel fluorinated triazole derivative suppresses macrophage activation and alleviates experimental colitis via a Twist1-dependent pathway. AB - Hyperactivated macrophages play a key role in the initiation and perpetuation of mucosal inflammation in Crohn's disease (CD). Increasing evidence suggests that the basic helix-loop-helix (bHLH) repressor Twist1 can suppress activation of nuclear factor-kappaB (NF-kappaB) and the subsequent production of TNF-alpha, which are both essential elements of macrophage activation. Thus, developing novel therapeutic strategies to enhance Twist1 expression and to inhibit macrophage activation may be beneficial for CD treatment. In the present study, a series of trifluoroethyl thiazolo[3,2-b][1,2,4]triazole derivatives were used to investigate their potential anti-inflammatory activities and the underlying mechanism. In a biological activity screen, compound 7# (Thiazolo[3,2 b][1,2,4]triazole-5-methanamine, 6-phenyl-alpha-(trifluoromethyl)-, (alphaR)-, TT TFM) suppressed the activation of macrophages. Consistent with the in vitro data, TT-TFM protected against 2,4,6-trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS)-induced acute colitis and IL-10 knockout (KO) chronic colitis, as judged by body weight changes and colonic pathological damage. A mechanistic study based on microarray analysis and gene interference experiments indicated that TT-TFM exerted anti-inflammatory effects by enhancing Twist1 expression and subsequently blocking the NF-kappaB/TNF-alpha pathway. In addition, pretreatment with lentiviruses encoding shRNA targeting Twist1 could abolish the therapeutic effect of TT-TFM in TNBS colitis. Ultimately, TT-TFM showed anti-colitis activity by reducing NF-kappaB activation and the TNF-alpha level by promoting Twist1 expression; thus, TT-TFM may offer a therapeutic strategy for CD patients. PMID- 30028993 TI - Small molecules bind human mTOR protein and inhibit mTORC1 specifically. AB - Inhibition of mTOR activity (mechanistic target of rapamycin) is an anti-cancer therapeutic strategy. mTOR participates in two functional complexes, mTORC1 and mTORC2. Since mTORC1 is specifically activated in multiple tumors, novel molecules that inhibit mTORC1 could be therapeutically important. To identify potentially novel modulators of mTOR pathways, we screened 1600 small molecule human drugs for mTOR protein binding, using novel biolayer interferometry technology. We identified several small molecules that bound to mTOR protein in a dose-dependent manner, on multiple chemical scaffolds. As mTOR participates in two major complexes, mTORC1 and mTORC2, the functional specificities of the binders were measured by S6Kinase and Akt phosphorylation assays. Three novel 'mTOR general' binders were identified, carvedilol, testosterone propionate, and hydroxyprogesterone, which inhibited both mTORC1 and mTORC2. By contrast, the piperazine drug cinnarizine dose-dependently inhibited mTORC1 but not mTORC2, suggesting it as a novel mTORC1-specific inhibitor. Some of cinnarizine's chemical analogs also inhibited mTORC1 specifically, whereas others did not. Thus we report the existence of a novel target for some related piperazines including cinnarizine and hydroxyzine, i.e. specific inhibition of mTORC1 activity. Since mTOR inhibition is a general anti-cancer strategy, and mTORC1 is specifically activated in some tumors, we suggest the piperazine scaffold, including cinnarizine and hydroxyzine, could be proposed for rational therapy in tumors in which mTORC1 is specifically activated. Related piperazines have shown toxicity to cancer cells in vitro as single agents and in combination chemotherapy. Thus piperazine-based mTOR inhibitors could become a novel chemotherapeutic strategy. PMID- 30028992 TI - Strategies and limitations associated with in vitro characterization of vitamin D receptor activators. AB - In vitro cell-based assays are common screening tools used for the identification of new VDR ligands. For 25-hydroxyvitamin D3 [25(OH)D3] and 1alpha-hydroxyvitamin D3 [1alpha(OH)D3], protein expressions of CYP2R1 and CYP27B1, respectively, that form the active 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] ligand were detected in human embryonic kidney (HEK293) cells expressing the GAL4-hVDR, the human brain microvessel endothelial (hCMEC/D3) and adenocarcinoma colonic (Caco-2) cells. The impact of bioactivation enzymes was shown upon the addition of ketoconazole (10 MUM KTZ), a pan-CYP inhibitor, which reduced the apparent potency of 25(OH)D3 and increased the EC50 from 272 to 608 nM in HEK293 cells. EIA assays verified that 1,25(OH)2D3 was formed and contributed to VDR activity independently of its precursors. In hCMEC/D3 cells where enzyme protein levels were lowest, changes in MDR1/P-gp expression with KTZ were minimal. In Caco-2 cells, the induction of TRPV6 (calcium channel), CYP24A1, CYP3A4, OATP1A2 and MDR1 mRNA expression was 1,25(OH)2D3 > 1alpha(OH)D3 > 25(OH)D3, with the magnitude of change being blunted by KTZ. Upon inclusion of KTZ in the cell-based assays, high transcriptional activities were observed for synthetic VDR activators from Teijin Pharma. Cyclopentanone derivatives: TPD-003, TPD-005, TPD 006, TPD-008 and TPD-009 (EC50s 0.06 to 67 nM, unchanged with KTZ) were found more potent over straight chain and lactone derivatives (antagonists). Most TPD compounds activated OATP1A2, CYP24A1, CYP3A4, and MDR1 (28-67%) and TRPV6 transcriptionally in Caco-2 cells. The results identified that cell-based assays with added KTZ could accurately identify new VDR activators, although these may be hypercalcemic with strong TRPV6 inducing properties. PMID- 30028994 TI - Effects of human sulfotransferases on the cytotoxicity of 12-hydroxynevirapine. AB - Nevirapine, a non-nucleoside reverse transcriptase inhibitor used for the treatment of AIDS, can cause serious skin rashes and hepatotoxicity. Previous studies have indicated that the benzylic sulfate 12-sulfoxynevirapine, the formation of which is catalyzed by human sulfotransferases (SULTs), may play a causative role in these toxicities. To characterize better the role of 12 sulfoxynevirapine in nevirapine-induced cytotoxicity, the ability of 12 expressed human SULT isoforms to conjugate 12-hydroxynevirapine was assessed. Of the 12 human SULTs, no detectable 12-sulfoxynevirapine was observed with SULT1A3, SULT1C2, SULT1C3, SULT2B1, SULT4A1, or SULT6B1. As determined by the Vmax/Km ratio, SULT2A1 had the highest overall 12-hydoxynevirapine sulfonation activity; lower activities were observed with SULT1A1, SULT1A2, SULT1B1, SULT1C4, and SULT1E1. Incubation of 12-sulfoxynevirapine with glutathione and cysteine led to adduct formation; lower yields were obtained with deoxynucleosides. 12 Hydroxynevirapine was more cytotoxic than nevirapine to TK6, TK6/SULT vector, and TK6/SULT2A1 cells. With nevirapine, there was no difference in cytotoxicity among the three cell lines, whereas with 12-hydroxynevirapine, TK6/SULT2A1 cells were more resistant than TK6 and TK6/SULT vector cells. Co-incubation of 12 hydroxynevirapine with the competitive SULT2A1 substrate dehydroepiandrosterone decreased the level of 12-sulfoxynevirapine and increased the cytotoxicity in TK6/SULT2A1 cells. These data demonstrate that although 12-sulfoxynevirapine reacts with nucleophiles to form adducts, sulfonation of 12-hydroxynevirapine decreases the cytotoxicity of 12-hydroxynevirapine in TK6 cells. PMID- 30028995 TI - Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines. AB - Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic. PMID- 30028996 TI - Impact of allosteric modulation: Exploring the binding kinetics of glutamate and other orthosteric ligands of the metabotropic glutamate receptor 2. AB - While many orthosteric ligands have been developed for the mGlu2 receptor, little is known about their target binding kinetics and how these relate to those of the endogenous agonist glutamate. Here, the kinetic rate constants, i.e. kon and koff, of glutamate were determined for the first time followed by those of the synthetic agonist LY354740 and antagonist LY341495. To increase the understanding of the binding mechanism and impact of allosteric modulation thereon, kinetic experiments were repeated in the presence of allosteric modulators. Functional assays were performed to further study the interplay between the orthosteric and allosteric binding sites, including an impedance-based morphology assay. We found that dissociation rate constants of orthosteric mGlu2 ligands were all within a small 6-fold range, whereas association rate constants were ranging over more than three orders of magnitude and correlated to both affinity and potency. The latter showed that target engagement of orthosteric mGlu2 ligands is kon-driven in vitro. Moreover, only the off-rates of the two agonists were decreased by a positive allosteric modulator (PAM), thereby increasing their affinity. Interestingly, a PAM increased the duration of a glutamate-induced cellular response. A negative allosteric modulator (NAM) increased both on- and off-rate of glutamate without changing its affinity, while it did not affect these parameters for LY354740, indicating probe-dependency. In conclusion, we found that affinity- or potency-based orthosteric ligand optimization primarily results in ligands with high kon values. Moreover, positive allosteric modulators alter the binding kinetics of orthosteric agonists mainly by decreasing koff, which we were able to correlate to a lengthened cellular response. Together, this study shows the importance of studying binding kinetics in early drug discovery, as this may provide important insights towards improved efficacy in vivo. PMID- 30028997 TI - Inhibiting Jumoji domain containing protein 3 (JMJD3) prevent neuronal apoptosis from stroke. AB - Control of p53 by histone methylation is closely related in the neuronal apoptosis following ischemic stroke. In mammalian cells, demethylation of methylated lysine residue of histones is catalyzed by Jumonji domain-containing proteins (JMJD) family. Among them, JMJD3 is reported to be a hypoxic target gene and expressed in all cell types of brain including neurons. However, the role of JMJD3 on process of neuronal apoptosis after ischemic stroke is still largely unknown. PCR, immunostaining and Western blotting results indicated that JMJD3 expression was upregulated in cultured neurons upon oxygen-glucose deprivation (OGD) injury. Jmjd3-/- neurons exhibited inhibited cell apoptosis and tolerance to the OGD injury. Chromatin immunoprecipitation and promoter reporter assays showed that the underlying mechanism was through transcriptional activation of p53, thus altering the downstream Bax and Caspase-3 genes. Silencing Jmjd3 improved neurological deficit and reduced infarct volume following ischemic injury in vivo. The present study suggested that JMJD3 was a critical promoter of neuronal apoptosis by regulating the expression of Bax and Caspase-3, and inhibition of JMJD3 might provide a new therapeutic intervention for treating cerebral ischemia. PMID- 30028998 TI - Pioneers Invade the Nucleosomal Landscape. AB - Two papers in Molecular Cell (Kubik et al., 2018; Yan et al., 2018) explore the mechanisms by which transcription factors bind their sites in chromatin, providing fresh insights into the much-debated question of how transcription factors can be "pioneers." PMID- 30028999 TI - A Translation Tuning HuDdle for Neurons. AB - In this issue of Molecular Cell, Tebaldi et al. (2018) identify the neuron specific RNA-binding protein HuD as a regulator of global protein synthesis and translation enhancer of specific mTORC1-responsive transcripts. Importantly, the authors identify that the Y3 small non-coding RNA binds HuD to modulate translation and neurogenesis. PMID- 30029000 TI - Spoon-Feeding Ribosomes to Autophagy. AB - The ribosome, a ribonucleoprotein machine for protein synthesis, can also serve as an abundant nutrient source under starvation conditions. In a recent issue of Science, Wyant et al. (2018) discovered a specialized "spoon" to "scoop up" more ribosomes for degradation by autophagy. PMID- 30029001 TI - Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis. AB - Macrophages are a dominant leukocyte population in the tumor microenvironment and actively promote cancer progression. However, the molecular mechanism underlying the role of macrophages remains poorly understood. Here we show that polarized M2 macrophages enhance 3-phosphoinositide-dependent protein kinase 1 (PDPK1) mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting interleukin-6 (IL-6). This phosphorylation facilitates a PGK1-catalyzed reaction toward glycolysis by altering substrate affinity. Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophage-derived IL-6 abrogates macrophage-promoted glycolysis, proliferation, and tumorigenesis. In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL-6 expression, and macrophage infiltration in human glioblastoma multiforme (GBM). Moreover, PGK1 T243 phosphorylation also correlates with malignance and prognosis of human GBM. Our findings demonstrate a novel mechanism of macrophage-promoted tumor growth by regulating tumor cell metabolism, implicating the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation. PMID- 30029002 TI - SRCP1 Conveys Resistance to Polyglutamine Aggregation. AB - The polyglutamine (polyQ) diseases are a group of nine neurodegenerative diseases caused by the expansion of a polyQ tract that results in protein aggregation. Unlike other model organisms, Dictyostelium discoideum is a proteostatic outlier, naturally encoding long polyQ tracts yet resistant to polyQ aggregation. Here we identify serine-rich chaperone protein 1 (SRCP1) as a molecular chaperone that is necessary and sufficient to suppress polyQ aggregation. SRCP1 inhibits aggregation of polyQ-expanded proteins, allowing for their degradation via the proteasome, where SRCP1 is also degraded. SRCP1's C-terminal domain is essential for its activity in cells, and peptides that mimic this domain suppress polyQ aggregation in vitro. Together our results identify a novel type of molecular chaperone and reveal how nature has dealt with the problem of polyQ aggregation. PMID- 30029003 TI - Translational Control through Differential Ribosome Pausing during Amino Acid Limitation in Mammalian Cells. AB - Limitation for amino acids is thought to regulate translation in mammalian cells primarily by signaling through the kinases mTORC1 and GCN2. We find that a selective loss of arginine tRNA charging during limitation for arginine regulates translation through ribosome pausing at two of six arginine codons. Surprisingly, limitation for leucine, an essential and abundant amino acid in protein, results in little or no ribosome pausing. Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation leads to loss of tRNA charging and ribosome pausing. Ribosome pausing decreases protein production and triggers premature ribosome termination without reducing mRNA levels. Together, our results suggest that amino acids that are not optimally sensed by the mTORC1 and GCN2 pathways still regulate translation through an evolutionarily conserved mechanism based on codon-specific ribosome pausing. PMID- 30029004 TI - HuD Is a Neural Translation Enhancer Acting on mTORC1-Responsive Genes and Counteracted by the Y3 Small Non-coding RNA. AB - The RNA-binding protein HuD promotes neurogenesis and favors recovery from peripheral axon injury. HuD interacts with many mRNAs, altering both stability and translation efficiency. We generated a nucleotide resolution map of the HuD RNA interactome in motor neuron-like cells, identifying HuD target sites in 1,304 mRNAs, almost exclusively in the 3' UTR. HuD binds many mRNAs encoding mTORC1 responsive ribosomal proteins and translation factors. Altered HuD expression correlates with the translation efficiency of these mRNAs and overall protein synthesis, in a mTORC1-independent fashion. The predominant HuD target is the abundant, small non-coding RNA Y3, amounting to 70% of the HuD interaction signal. Y3 functions as a molecular sponge for HuD, dynamically limiting its recruitment to polysomes and its activity as a translation and neuron differentiation enhancer. These findings uncover an alternative route to the mTORC1 pathway for translational control in motor neurons that is tunable by a small non-coding RNA. PMID- 30029006 TI - Functions of FACT in Breaking the Nucleosome and Maintaining Its Integrity at the Single-Nucleosome Level. AB - The human FACT (facilitates chromatin transcription) complex, composed of two subunits SPT16 (Suppressor of Ty 16) and SSRP1 (Structure-specific recognition protein-1), plays essential roles in nucleosome remodeling. However, the molecular mechanism of FACT reorganizing the nucleosome still remains elusive. In this study, we demonstrate that FACT displays dual functions in destabilizing the nucleosome and maintaining the original histones and nucleosome integrity at the single-nucleosome level. We found that the subunit SSRP1 is responsible for maintenance of nucleosome integrity by holding the H3/H4 tetramer on DNA and promoting the deposition of the H2A/H2B dimer onto the nucleosome. In contrast, the large subunit SPT16 destabilizes the nucleosome structure by displacing the H2A/H2B dimers. Our findings provide mechanistic insights by which the two subunits of FACT coordinate with each other to fulfill its functions and suggest that FACT may play essential roles in preserving the original histones with epigenetic identity during transcription or DNA replication. PMID- 30029005 TI - LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs. AB - LIN28 is a bipartite RNA-binding protein that post-transcriptionally inhibits the biogenesis of let-7 microRNAs to regulate development and influence disease states. However, the mechanisms of let-7 suppression remain poorly understood because LIN28 recognition depends on coordinated targeting by both the zinc knuckle domain (ZKD), which binds a GGAG-like element in the precursor, and the cold shock domain (CSD), whose binding sites have not been systematically characterized. By leveraging single-nucleotide-resolution mapping of LIN28 binding sites in vivo, we determined that the CSD recognizes a (U)GAU motif. This motif partitions the let-7 microRNAs into two subclasses, precursors with both CSD and ZKD binding sites (CSD+) and precursors with ZKD but no CSD binding sites (CSD-). LIN28 in vivo recognition-and subsequent 3' uridylation and degradation of CSD+ precursors is more efficient, leading to their stronger suppression in LIN28-activated cells and cancers. Thus, CSD binding sites amplify the regulatory effects of LIN28. PMID- 30029007 TI - Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module. AB - Class II phosphoinositide 3-kinases (PI3K-C2) are large multidomain enzymes that control cellular functions ranging from membrane dynamics to cell signaling via synthesis of 3'-phosphorylated phosphoinositides. Activity of the alpha isoform (PI3K-C2alpha) is associated with endocytosis, angiogenesis, and glucose metabolism. How PI3K-C2alpha activity is controlled at sites of endocytosis remains largely enigmatic. Here we show that the lipid-binding PX-C2 module unique to class II PI3Ks autoinhibits kinase activity in solution but is essential for full enzymatic activity at PtdIns(4,5)P2-rich membranes. Using HDX MS, we show that the PX-C2 module folds back onto the kinase domain, inhibiting its basal activity. Destabilization of this intramolecular contact increases PI3K C2alpha activity in vitro and in cells, leading to accumulation of its lipid product, increased recruitment of the endocytic effector SNX9, and facilitated endocytosis. Our studies uncover a regulatory mechanism in which coincident binding of phosphoinositide substrate and cofactor selectively activate PI3K C2alpha at sites of endocytosis. PMID- 30029008 TI - The evolutionary history and human settlement of Australia and the Pacific. AB - Understanding the timing and processes involved in the human settlement of Australia and the Pacific has significance for addressing some key debates relating to human origins and population expansions worldwide. Despite this, for many years, Pacific populations were seriously under-represented in genetic studies of human origins. The last 15 years, however, have seen some major genetic studies involving Australian and Pacific populations which have shed light on their origins and interactions, and the last five years have seen some major developments that are challenging long-held concepts of Pacific settlement. PMID- 30029009 TI - Fine-tuning of Approximate Bayesian Computation for human population genomics. AB - Approximate Bayesian Computation (ABC) is a flexible statistical tool widely applied to addressing a variety of questions regarding the origin and evolution of humans. The significant growth of genomic scale data from diverse geographic populations has facilitated the use of ABC in modelling the complex processes that underlie human demography and local adaptation. However, a fundamental issue still remains in how to efficiently capture patterns of genetic variation with a set of summary statistics in order to achieve better approximation of Bayesian inference. Here, we review recent advances in ABC methodology and its applications for human population genomics, with a particular focus on optimal tuning of ABC approaches for different types of genetic data and different sets of evolutionary parameters. PMID- 30029010 TI - vFLIP upregulates IKKepsilon, leading to spindle morphology formation through RelA activation. AB - Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) vFLIP, a latent gene of KSHV, was first identified as a FLICE-inhibitory protein (FLIP) protecting cells from apoptosis. The vFLIP protein has been shown to activate the NF-kappaB signaling involved in spindle morphology formation both in HUVECs infected with KSHV and Kaposi's sarcoma (KS) itself. In this study, we independently established stably vFLIP-expressing cells and showed that they exhibited upregulated NF-kappaB family protein expression independent of the ability of IKKs to bind vFLIP. Further, vFLIP induced upregulation of IKKepsilon, phosphorylation of RelA at Ser468 (p-RelA S468) and nuclear localization of Re1A concomitant with spindle morphology formation, and these effects were reversed by knockdown of IKKepsilon and treatment with Bay-11. Overexpression of IKKepsilon alone also showed spindle morphology formation with p-RelA S468. In conclusion, the spindle cell morphology in KS should be induced by RelA activation (p-RelA S468) by IKKepsilon upregulation in vFLIP-expressing EA hy926 cells. PMID- 30029011 TI - Molecular footprints of selective pressure in the neuraminidase gene of currently circulating human influenza subtypes and lineages. AB - Influenza neuraminidase (NA) is under selective pressure (SP) of both host immune system and drug use. Here, we assembled large datasets of NA sequences of worldwide circulating viruses to estimate the global and site-specific SP acting on all current subtypes/lineages of human influenza NA. An overall negative SP of similar magnitude and a prevalence of negatively selected sites were observed for all subtypes/lineages. Positively selected sites varied according to the subtype/lineage, including N1-NA sites 247 and 275, N2-NA sites 148 and 151, and B/Victoria-NA site 395 associated with drug-resistance or reduced susceptibility. These results evidenced a potential role of positive selection in the low-level spread of A(H1N1)pdm09-H275Y drug-resistant viruses, and alerted for a potential higher risk of spread of a synergistic A(H1N1)pdm09 drug-resistant variant (H275Y/S247N). The positive selection detected at N2-NA sites 148 and 151 was probably an artefact from cell-culture. Overall mapping revealed six potential new druggable regions. PMID- 30029012 TI - Detailed mapping of the linear B Cell epitopes of the hemagglutinin (HA) protein of swine influenza virus. AB - Using the Hemagglutinin (HA) protein peptide array of H1N1 pdm09 and a panel of swine antisera against various swine influenza H1 and H3 clusters, we identified three immunoreactive epitopes with one (peptide 15) located in HA1 (amino acids 57-71) and two (peptides 121 and 139) in HA2 (amino acids 481-495 and 553-566). Further analysis showed that all swine antisera of H1 clusters efficiently recognized two HA2 epitopes; peptides 121 and 139, with only a subset of antisera reactive to HA1-derived peptide 15. Interestingly, none of these peptides were reactive to SIV H3 antisera. Finally, intranasal inoculation of peptides 15 and 121 into pigs revealed that peptide 121, not peptide 15, was able to generate antibody responses in some animals. The results of our experiments provide an important foundation for further analyzing the immune response against these peptides during natural viral infection and also provide peptide substrates for diagnostic assays. PMID- 30029013 TI - Molecular characterization of emerging avian reovirus variants isolated from viral arthritis cases in Western Canada 2012-2017 based on partial sigma (sigma)C gene. AB - Viral Arthritis (VA), a disease caused by Avian Reovirus (ARV), has emerged as a significant cause of economic losses in broiler chicken flocks in Western Canada. These outbreaks were characterized by 4-13% morbidity, followed by a spike in mortality/culling that in extreme cases required total flock depopulation. From 2012-2017, 38 ARV isolates were recovered. Molecular characterization of a partial segment of the sigma (sigma)C gene shows all six previously known ARV clusters in Western Canadian broiler chickens. The most numerous clusters were Cluster#4 and Cluster #5 while the most variable clusters were Cluster#1 (76.7 100% identity), Cluster#2 (66-99.3%), and Cluster#4 (62-100%). This variation suggests that an autogenous vaccine may not protect against a same-cluster challenge virus. This is the first publication showing the wide genetic diversity of ARV Cluster#4, the circulation of all six worldwide reported ARV clusters in Canada, and important differences in ARV Cluster classification among researchers. PMID- 30029014 TI - Pathogenicity and cross-reactive immune responses of a historical and a contemporary Senecavirus A strains in pigs. AB - The goals of this study were to compare the pathogenicity and infection dynamics of a historical and a contemporary SVA strains (SVV 001 and SD15-26) and to assess cross-neutralizing and cross-reactive T cell responses following experimental infection in pigs. Both SVA strains successfully infected all inoculated animals, resulting in viremia and robust antibody and cellular immune responses. SVA SD15-26 infection resulted in characteristic clinical signs and vesicular lesions, however, SVA SVV 001 did not cause overt clinical disease with inoculated animals remaining clinically normal during the experiment. Notably, neutralization- and -recall IFN-gamma expression-assays revealed marked cross neutralizing antibody and cross-reactive T cell responses between the two viral strains. Together these results demonstrate that the historical SVA SVV 001 strain presents low virulence in pigs when compared to the contemporary SVA SD15 26 strain. Additionally, immunological assays indicate that SVA SVV 001 and SD15 26 are antigenically related and share conserved antigenic determinants. PMID- 30029015 TI - Murine cytomegalovirus M72 promotes acute virus replication in vivo and is a substrate of the TRiC/CCT complex. AB - Betaherpesvirus dUTPase homologs are core herpesvirus proteins, but little is known about their role during infection. Human cytomegalovirus (HCMV) UL72 and murine cytomegalovirus (MCMV) M72 have been designated dUTPase homologs, and previous studies indicate UL72 is dispensable for replication and enzymatically inactive. Here, we report the initial characterization of MCMV M72. M72 does not possess dUTPase activity, and is expressed as a leaky-late gene product with multiple protein isoforms. Importantly, M72 augments MCMV replication in vitro and during the early stage of acute infection in vivo. We identify and confirm interaction of M72 with the eukaryotic chaperonin tailless complex protein -1 (TCP-1) ring complex (TRiC) or chaperonin containing tailless complex polypeptide 1 (CCT). Accumulating biochemical evidence indicates M72 forms homo-oligomers and is a substrate of TRiC/CCT. Taken together, we provide the first evidence of M72's contribution to viral pathogenesis, and identify a novel interaction with the TRiC/CCT complex. PMID- 30029016 TI - Revisiting the utility of retrospective pre-post designs: The need for mixed method pilot data. AB - The retrospective pre-post design affords many benefits to program staff and, accordingly, has piqued renewed interest among applied program evaluators. In particular, the field has witnessed increasing application of a post-program-only data collection strategy in which only posttest and retrospective pretest data are collected. A post-program-only assessment strategy takes considerably less time than is required for collecting pre-program data and presumably has the added benefit of eliminating the impact of response-shift bias. Response-shift bias occurs when the knowledge, skills, or experiences participants gain through program participation leads them to interpret questionnaire items in a qualitatively different manner at pretest versus posttest. In this article, we discuss the strengths and weaknesses associated with administering retrospective pretest assessments and underscore the importance of thoroughly evaluating any application of a retrospective measurement strategy prior to its broader implementation. We provide a practical illustration of this evaluation process using a mixed-method study that assesses one measure of parenting education program effectiveness-the Parenting Skills Ladder. PMID- 30029017 TI - New insights on the transmission mechanism of tenuiviruses by their vector insects. AB - Tenuiviruses, which cause serious diseases in rice, wheat, maize and other gramineae crops, recently have been assigned to the family Phenuiviridae in the order Bunyavirales. Transmission of tenuiviruses to host plants depends on the specific vector planthoppers. The interaction between the virus and insect offers critical points for developing an efficient management strategy. This review focuses on recent advancements in our understanding of the interactions between the virus and insect components. Vector components such as various proteins play major roles in virus replication, stability and transovarial transmission. The virus can either directly interact with these proteins or regulate expression of genes that encode them to alter the metabolism or defense mechanisms of the insect vectors. However, the vector components that are involved in virus infection and movement in midgut and salivary glands are not as well explored and are targets for further study. PMID- 30029018 TI - An MRI evaluation of grey matter damage in African Americans with MS. AB - OBJECTIVE: Multiple sclerosis (MS) is less prevalent in African Americans (AAs) than Caucasians (CAs) but in the former the disease course tends to be more severe. In order to clarify the MRI correlates of disease severity in AAs, we performed a multimodal brain MRI study to comprehensively assess the extent of grey matter (GM) damage and the degree of functional adaptation to structural damage in AAs with MS. METHODS: In this cross-sectional study, we characterized GM damage in terms of focal lesions and volume loss and functional adaptation during the execution of a simple motor task on a sample of 20 AAs and 20 CAs with MS and 20 healthy controls (CTRLs). RESULTS: In AAs, we observed a wider range of EDSS scores than CAs, with multisystem involvement being more likely in AAs (p < 0.01). While no significant differences were detected in lesion loads and global brain volumes, AAs showed regional atrophy in the posterior lobules of cerebellum, temporo-occipital and frontal regions in comparison with CAs (p < 0.01), with cerebellar atrophy being the best metric in differentiating AAs from CAs (p = 0.007, AUC = 0.96 and p = 0.005, AUC = 0.96, respectively for right and left cerebellar clusters). In AAs, the functional analysis of cortical activations showed an increase in task-related activation of areas involved in high level processing and a decreased activation in the medial prefrontal cortex compared to CAs. INTERPRETATION: In our study, the direct comparison of AAs and CAs points to cerebellar atrophy as the main difference between subgroups. PMID- 30029020 TI - Deposition regularity in a rainwater pipeline based on variable transport flux. AB - Experiments of the deposition of suspended particles in a rainwater pipeline were combined with mathematical model fitting to explore deposition regularity under variable transport flux. The simulation results showed that four primary factors affected deposition regularity in a rainwater pipeline. In particular, the deposition and flushing processes alternately dominated when the flow and initial suspended solids (SS) concentration changed simultaneously. The migration of the easy deposition position (EDP, the position with the largest deposition velocity) displayed an obvious regularity, shifting from front to back along the pipe regularly at increasing flow, and from back to front when flow decreased. PMID- 30029019 TI - Nicotine affects ethanol-conditioned taste, but not place, aversion in a simultaneous conditioning procedure. AB - The conditioned taste aversion (CTA) induced by ethanol is a key factor limiting ethanol intake. Nicotine, a drug co-consumed with ethanol, may decrease this aversion by modulating the unconditioned effects of ethanol or by disrupting the association between ethanol and its associated cues. This study analyzed ethanol induced CTA and conditioned place aversion (CPA) in Long-Evans rats with subchronic exposure to nicotine. The rats were treated with nicotine (0.0 or 0.4 mg/kg) three times before conditioning (on lickometer training sessions 3, 4, and 5) and across conditioning days. During the conditioning the rats were given ethanol (1.3 g/kg) preceded and followed by presentation of a taste (NaCl) and tactile (rod or hole floors) conditioned stimulus (CS+), respectively. On CS- conditioning days, the rats were given vehicle and exposed to alternative stimuli. Three CTA and CPA testing sessions were then conducted. It was found that nicotine reduced ethanol-induced CTA and enhanced locomotor activity, but did not significantly modify the magnitude of ethanol-induced CPA. The effects of nicotine on CTA were observed during both conditioning and testing sessions, and were specific to the NaCl CS+, having no effect on reactivity to water. The dissociation between the effect of nicotine on ethanol-induced CTA and CPA suggests that nicotine does not alter ethanol's motivational properties by generally increasing its positive rewarding effects, nor does it blunt all aversive-like responses to this drug. Instead, nicotine may impede ethanol induced CTA induced by ethanol by disrupting the neural underpinnings of this specific form of associative learning. PMID- 30029021 TI - Effect of nasal or nasopharyngeal apneic oxygenation on desaturation during induction of anesthesia and endotracheal intubation in the operating room: A narrative review of randomized controlled trials. AB - OBJECTIVES: To determine whether apneic oxygenation through nasal or nasopharyngeal catheters can counteract hypoxemia and desaturation during induction of anesthesia and endotracheal intubation. DESIGN: Narrative review of randomized controlled trials. SETTING: Operating room. PATIENTS: 295 ASA I-II patients in elective surgery. INTERVENTION: PubMed and Embase databases were searched for studies with apneic oxygenation. The review included randomized controlled trials with apneic oxygenation through nasal or nasopharyngeal catheters as the intervention in the setting of endotracheal intubation in adults. MEASUREMENTS: Outcome measures were time until desaturation or degree of hypoxemia. MAIN RESULTS: Eight randomized controlled trials were included, with a total of 295 patients. Apneic oxygenation was administered by nasopharyngeal catheter in four studies and by nasal catheter in four studies. The eight included articles studied apneic oxygenation at flow rates of 3-10 l/min in ASA I II patients undergoing elective anesthesia in the operating room. Apneic oxygenation significantly prolonged time until desaturation opposed to the control groups in seven of the eight studies of patients undergoing anesthesia for elective surgery. CONCLUSION: Apneic oxygenation through nasal or nasopharyngeal catheters can prolong time to desaturation and decrease degree of desaturation during induction of anesthesia and endotracheal intubation in adult ASA I-II patients undergoing anesthesia for elective surgery. PMID- 30029022 TI - Communal space and depression: A structural-equation analysis of relational and psycho-spatial pathways. AB - The new urban landscape in countries experiencing unprecedented urban transformation has a profound impact on the global burden of depression. Based on survey data from 39 neighborhoods in Guangzhou, China, this study assesses the relationship between communal space and depression. To unravel the relational and psycho-spatial embeddedness of communal space, a structural equation analysis suggests that neither the use of nor the sense of communal space has a direct association with depressive symptoms. Instead, the indirect effect of the use of communal space on depression is mediated by neighborhood-based social networks and neighborhood attachment, while the indirect effect of the sense of communal space on depression is only mediated by neighborhood attachment. Given the presence of indirect relational and psycho-spatial pathways linking communal space and depression, this study argues that the place-making and relational approaches should be integrated to provide a holistic view of the socio-spatial nature of urban landscape. PMID- 30029023 TI - The current state of stem cell therapy for ocular disease. AB - Herein, we review the safety, efficacy, regulatory standards and ethical implications of the use of stem cells in ocular disease. A literature review was conducted, registered clinical trials reviewed, and expert opinions sought. Guidelines and codes of conduct from international societies and professional bodies were also reviewed. Collated data is presented on current progress in the field of ocular regenerative medicine, future challenges, the clinical trial process and ethical considerations in stem cell therapy. A greater understanding of the function and location of ocular stem cells has led to rapid advances in possible therapeutic applications. However, in the context of significant technical challenges and potential long-term complications, it is imperative that stem cell practices operate within formal clinical trial frameworks. While there remains broad scope for innovation, ongoing evidence-based review of potential interventions and the development of standardized protocols are necessary to ensure patient safety and best practice in ophthalmic care. PMID- 30029024 TI - Clerodane diterpenoids from the Chinese liverwort Jamesoniella autumnalis and their anti-inflammatory activity. AB - Nine previously undescribed clerodane-type diterpenoids, jamesoniellides M-T and one ent-labdane-type diterpenoid, as well as one known analogue, were isolated from the Chinese liverwort Jamesoniella autumnalis (DC.) Stephani. Their structures were determined using MS, NMR spectroscopy, and electronic circular dichroism (ECD) calculations. Inhibition on LPS-induced NO production in RAW 264.7 murine macrophages was investigated, and the results showed that jamesoniellides Q-S exhibited moderate anti-inflammatory activity, with 50-80% maximum inhibition rate of NO production under the nontoxic tested concentration. PMID- 30029025 TI - Donald Duck's garden: The effects of observing iconic reinforcing and contradictory gestures on narrative comprehension. AB - Both speech and gesture play a vital role in human communication. Gesture itself provides an external support to a spoken message. As a consequence, when presented together with speech, gesture has the ability to benefit learning across a variety of tasks, including narrative comprehension. However, the exact mechanisms underlying how the observation of gestures benefits learning are yet to be well understood and cannot be understood without further investigation into the types of gesture that benefit learning. Specifically, gestures themselves are not a homogeneous set, with different kinds of gestures having varying effects on learning. In the current study, we examined the effects of observing iconic gestures that either reinforce (i.e., reinforcing gestures) or contradict (i.e., contradictory gestures) the content of accompanying speech on narrative comprehension in preschool-aged children. Children were presented with a short video narrative that contained either reinforcing gestures, contradictory gestures, or no gestures accompanying the verbal narrative. Results indicated that observing reinforcing gestures significantly benefited narrative comprehension beyond when no gestures were observed. However, observing contradictory gestures was neither significantly beneficial nor significantly detrimental to narrative comprehension beyond observing reinforcing or no gestures. The results from the current study provide valuable insight into the benefits of observing different kinds of iconic gestures on narrative comprehension in preschool-aged children. PMID- 30029026 TI - The effect of ageing on the neural substrates of incidental encoding leading to recollection or familiarity. AB - It is well-known that the ageing process disrupts episodic memory. The aim of this study was to use an fMRI visual recognition task to characterize age-related changes in cerebral regions activated, during encoding, for images that would subsequently lead to a recollection-based or to a familiarity-based recognition. Results show that, for subsequent recollection, young adults activated regions related to semantic processing more extensively than older ones. On the other hand, despite putatively producing less semantic elaboration, older adults activated contralateral regions supplementary to those found in young adults (which might represent attempted compensation), as well as regions of the default mode network. These results suggest older adults could achieve subsequent recollection through different processes, for instance an appraisal of the self relevance of the stimuli. For subsequent familiarity, the comparisons only revealed greater activations in young adults, in the dorsal frontoparietal attention system as well as in the hippocampus, again suggesting that, even if older adults are able to produce recollection- and familiarity-based recognition, the semantic processing might still be weaker in old adults, who might nonetheless use qualitatively different strategies in order to produce such responses. Further studies are necessary in order to characterize those strategies. PMID- 30029027 TI - Computational method for discovery of biomarker signatures from large, complex data sets. AB - We present an efficient method for identifying of reliable biomarker panels from large multivariate data sets that typically result from experiments that monitor changes in RNA, small molecule, or protein abundance. Our computational methodology is developed and validated on the toxicogenomics database Drug Matrix that in its largest category contains 1656 recognition targets, characterized by the toxicant, dose and time (or duration) of the exposure. We were able to recognize both individual experimental conditions (compound, dose and time combinations) and the cases where the values for dose and time variables fall within the intervals in the training data, but do not match the training data exactly. Inclusion of gene expression information for multiple organs improved accuracy of recognition. Inclusion of time response information into consideration allowed us to develop particularly accurate marker panels for a large number of targets: we were able to recognize 176 compounds (out of 316) at greater than 90% accuracy. The presented methodology has an immediate application for discovery of diagnostic biomarker panels for exposure to various toxicity hazards, and may also be useful for development of biological markers for medical applications. PMID- 30029029 TI - Environmentally friendly synthesis and formation mechanism of copper nanowires with controlled aspect ratios from aqueous solution with ascorbic acid. AB - Copper (Cu) nanowires (NWs) were synthesized by the reduction of Cu-chloride complexes using ascorbic acid (AA) as a mild reducing agent, polyvinylpyrrolidone (PVP) as a capping agent, and NaCl as an additive under atmospheric conditions at 80 degrees C. Surface analyses revealed that both Cl ions and PVP were required for the synthesis of Cu NWs. Together, the Cl ions and PVP capped the Cu (1 0 0) side faces, leading to anisotropic growth of Cu NWs along the [1 1 0] direction. To obtain Cu NWs with high aspect ratios, we evaluated the synthetic mechanism under different reaction conditions. The results indicated that the presence of dissolved oxygen (DO) was the dominant factor affecting aspect ratio of Cu NWs. DO and hydrogen peroxide resulting from the reaction between DO and AA oxidized the surfaces of the growing Cu NWs, preventing further growth. Decreasing the amount of oxides on the Cu NW surfaces and removing DO increased the aspect ratios of the Cu NWs. The results indicated that DO should be removed from the reaction solution to obtain high-aspect-ratio Cu NWs in aqueous solutions containing AA. PMID- 30029028 TI - BIGO: A web application to analyse gene enrichment analysis results. AB - BACKGROUND AND OBJECTIVE: Gene enrichment tools enable the analysis of the relationships between genes with biological annotations stored in biological databases. The results obtained by these tools are usually difficult to analyse. Therefore, researchers require new tools with friendly user interfaces available on all types of devices and new methods to make the analysis of the results easier. METHODS: In this work, we present the BIGO Web tool. BIGO is a friendly Web tool to perform enrichment analyses of a collection of gene sets. On the basis of the obtained enrichment analysis results, BIGO combines the biological terms to organize them and graphically represents the relationships between gene sets to make the interpretations of the results easier. RESULTS: BIGO offers useful services that provide the opportunity to focus on a concrete subset of results by discarding too general biological terms or to obtain useful knowledge by means of the visual analysis of the functional connections between the sets of genes being analysed. CONCLUSIONS: BIGO is a web tool with a novel and modern design that provides the possibility to improve the analysis tasks applied to gene enrichment results. PMID- 30029030 TI - Uniform Pt quantum dots-decorated porous g-C3N4 nanosheets for efficient separation of electron-hole and enhanced solar-driven photocatalytic performance. AB - Uniform Pt quantum dots-decorated porous g-C3N4 nanosheets (Pt/CN) are fabricated by a facile impregnation-ultrasonic-calcination method, using melamine as precursor. The as-prepared samples are evidently investigated by X-ray diffraction, UV-vis diffuse reflection spectra, N2 adsorption, transmission electron microscope, surface photovoltage spectroscopy and photoluminescence. The deposited Pt quantum dots with particle size of ~5 nm are decorated on the surface of porous g-C3N4 nanosheets uniformly. The Pt/CN nanosheets show conspicuous solar-driven photocatalytic activity for splitting water to produce H2. The solar-driven photocatalytic hydrogen production rate of Pt/CN is up to ~107 MUmol h-1 g-1, which is about 5 times higher than that of pristine g-C3N4. The enhancement can be attributed to the porous structure offering adequate surface active sites and the efficient decoration of uniform Pt quantum dots on g C3N4 nanosheets facilitating the separation of photogenerated electron-hole pairs, which is confirmed by surface photovoltage spectroscopy and photoluminescence. The strategy for fabricating Pt quantum dots-decorated g-C3N4 nanosheets offers new insights for constructing other high-performance quantum dot-semiconductor photocatalytic materials. PMID- 30029032 TI - Structure of surfactant and phospholipid monolayers at the air/water interface modeled from neutron reflectivity data. AB - Specular neutron reflectometry is a powerful technique to resolve interfacial compositions and structures in soft matter. Surprisingly however, even after several decades, a universal modeling approach for the treatment of data of surfactant and phospholipid monolayers at the air/water interface has not yet been established. To address this shortcoming, first a systematic evaluation of the suitability of different models is presented. The result is a comprehensive validation of an optimum model, which is evidently much needed in the field, and which we recommend as a starting point for future data treatment. While its limitations are openly discussed, consequences of failing to take into account various key aspects are critically examined and the systematic errors quantified. On the basis of this physical framework, we go on to show for the first time that neutron reflectometry can be used to quantify directly in situ at the air/water interface the extent of acyl chain compaction of phospholipid monolayers with respect to their phase. The achieved precision of this novel quantification is ~10%. These advances together enhance significantly the potential for exploitation in future studies data from a broad range of systems including those involving synthetic polymers, proteins, DNA, nanoparticles and drugs. PMID- 30029031 TI - Polymeric electrospun scaffolds for bone morphogenetic protein 2 delivery in bone tissue engineering. AB - HYPOTHESIS: The development of novel scaffolds based on biocompatible polymers is of great interest in the field of bone repair for fabrication of biodegradable scaffolds that mimic the extracellular matrix and have osteoconductive and osteoinductive properties for enhanced bone regeneration. EXPERIMENTS: Polycaprolactone (PCL) and polycaprolactone/polyvinyl acetate (PCL/PVAc) core shell fibers were synthesised and decorated with poly(lactic-co-glycolic acid) [PLGA] particles loaded with bone morphogenetic protein 2 (BMP2) by simultaneous electrospinning and electrospraying. Hydroxyapatite nanorods (HAn) were loaded into the core of fibers. The obtained scaffolds were characterised by scanning and transmission electron microscopy, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. The in vitro potential of these materials for bone regeneration was assessed in biodegradation assays, osteoblast viability assays, and analyses of expression of specific bone markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). FINDINGS: PLGA particles were homogeneously distributed in the entire fibre mat. The growth factor load was 1.2-1.7 MUg/g of the scaffold whereas the HAn load was in the 8.8 12.6 wt% range. These scaffolds were able to support and enhance cell growth and proliferation facilitating the expression of osteogenic and osteoconductive markers (OCN and OPN). These observations underline the great importance of the presence of BMP2 in scaffolds for bone remodelling as well as the good potential of the newly developed scaffolds for clinical use in tissue engineering. PMID- 30029033 TI - Protein crosslinking improves the thermal resistance of plastocyanin immobilized on a modified gold electrode. AB - Increasing the thermal stability of immobilized proteins is a motivating goal for improving the performance of electrochemical biodevices. In this work, we propose the immobilization of crosslinked plastocyanin from the thermophilic cyanobacterium Phormidium laminosum by simultaneous incubation of a mixture of plastocyanin and the coupling reagents. The thermal stability of the so built covalently immobilized protein films has been assessed by cyclic voltammetry in the 0-90 degrees C temperature range and has been compared to that of physisorbed films. It is shown that the protein loss along a thermal cycle is significantly reduced in the case of the crosslinked films, whose redox properties remain unaltered along a cyclic heating-cooling thermal scan, and can withstand the contact with 70 degrees C solutions for four hours. Comparison of thermal unfolding curves obtained by circular dichroism spectroscopy of both free and crosslinked protein confirms the improved thermic resistance of the crosslinked plastocyanin. Notably, the electron transfer thermodynamics of physisorbed and crosslinked plastocyanin films are quite similar, suggesting that the formation of intra- and inter-protein amide bonds do not affect the integrity and functionality of the copper redox centers. UV-Vis absorption and circular dichroism measurements corroborate that protein crosslinking does not alter the coordination geometry of the metal center. PMID- 30029034 TI - The effect of quercetin on the electrical properties of model lipid membranes and human glioblastoma cells. AB - Quercetin is a naturally-occurring flavonoid claimed to exert many beneficial health effects. In this report, the influence of quercetin on the surface charge of phosphatidylcholine liposomes and human glioblastoma LN-229 and LN-18 cells was studied using microelectrophoretic mobility measurements. The effect of quercetin on the electrical resistance and capacitance of bilayer lipid membranes was analyzed via electrochemical impedance spectroscopy. The results showed that after flavonoid treatment, the cell lines demonstrated changes in surface charge only in alkaline pH solutions, whereas there were no significant alterations in quercetin-treated vs. control cells in acidic pH solutions. The same tendency was found for liposomal membranes proving that quercetin insertion into membranes is strongly pH-dependent. Capacitance and resistance measurements conducted in acidic electrolyte solutions demonstrated an increase in both electrical parameters, indicating an increased amount of quercetin inserted into the bilayers. Moreover, the cytotoxic effect of quercetin confirms that the flavonoid enters the cells and perturbs the proliferation of LN-229 and LN-18 glioblastoma cell lines. As such, our results indicate that the specific localization of quercetin, membrane-bound or cell-entering, might be crucial for its pharmacological activity. However, further studies are necessary prior to applying these physicochemical measurements as standard methods of evaluating drug activity. PMID- 30029035 TI - Designing strategies for operating Microbial Electrochemical Systems to clean up polluted soils under non-flooded conditions. AB - Microbial Electrochemical Systems can be setup in soil either for the harvesting of energy from microbial metabolism (sediment microbial fuel cell, SMFC) or for the bioremediation of polluted environments (Microbial Electroremediating Cell, MERC). However, the precieved need for this technology to be located in flooded environments, to assure the ionic contact between anode and cathode, has limited its implementation in standard soils. This work describes a new configuration that overcomes this limitation by integrating an out-of-soil cathodic chamber with a ceramic barrier so a closed circuit system can be achieved without flooding the soil. On top of harvesting energy under this new configuration we have outperformed natural bioremediation by restoring an atrazine polluted soil as proof of concept. Our results showed that >98% of the initially available atrazine was efficiency removed after 2 weeks with this new MERC configuration, in contrast with a mere 58% removal obtained under natural attenuation. Moreover, a set of toxicological tests using green algae, Salmonella typhimurium and Sorghum saccharatum strongly confirmed a marked lack of toxicity in the soil after the bioelectrochemical treatment in contrast with the natural attenuation that was unable to fulfill the non-toxic level. PMID- 30029038 TI - Alignment of cytoskeletal structures across cell boundaries generates tissue cohesion during organ formation. AB - One of the most fascinating aspects of development is the complexity and diversity of tissues and organs that are formed from simple primordia, involving complex coordination between large groups of cells. Lack of coordination leads to developmental defects and failure in organ formation. The simple primordia are often polarised epithelial sheets, with cells connected to neighbours apically via Cadherin-based cell-cell junctions that intracellularly link to the cytoskeleton. Coordination of cells in epithelia during morphogenesis occurs in part at these junctions. Furthermore, in many tissues a striking supracellular order and alignment of cytoskeletal structures can be observed, likely playing an important part in the coordination of cells. Here, we will introduce examples of morphogenetic events where this supracellular order of the cytoskeleton is very apparent and will discuss recent advances in understanding the generation and function of this order. PMID- 30029036 TI - Side effects of intra-gastric photodynamic therapy: an in vitro study. AB - Since many years it has been acknowledged that some bacterial species, among which H. pylori, P. aeruginosa, P. acnes accumulate endogenous photosensitizers (PS) in the form of porphyrins. This makes antibacterial photodynamic therapy (PDT) easier to perform due to the possible avoidance of external PS. In this study, we focus on gastric infections associated with the presence of Helicobacter pylori (H. pylori), known to accumulate and release both protoporphyrin IX (PPIX) and coproporphyrins. PDT versus H. pylori can be carried out by modified endoscopes or by new ingestible luminous devices under development. In both cases of in vitro and in vivo applications, either for therapy (PDT) or diagnosis, scientific literature lacks studies on the possible side-effects of light treatments on the surrounding tissues. To this aim we evaluated in vitro side-effects due to a possible intrinsic photosensitivity of gastric mucosa or to a photosensitization by the PS released from the bacterium itself. Photo-toxicity studies were conducted on the AGS cell line (ATCC(r) CRL 1739TM), commonly used as a model for the stomach mucosa tissue, considering PPIX as the photosensitizing agent. After first evaluations of PPIX dark toxicity, its uptake and accumulation sites, photo-toxicity tests were conducted using a LED light source peaked at 400 nm, by varying both PPIX concentration (50 nM - 2 MUM) and light dose in the range 0.6-13 J/cm2, representing different treatment procedures found in literature. The oxidative stress consequent to irradiation was investigated both in terms of ROS production and assessment of the activity of enzymes involved in ROS-related biological mechanisms. A significant phototoxic effect was found only for PPIX concentration > 100 nM for all tested light doses. This indicates that the evaluated photo-treatments do not cause side effects even with the sensitization due to PPIX released by the bacteria. PMID- 30029039 TI - Cardiovascular diseases in middle aged and older adults in China: the joint effects and mediation of different types of physical exercise and neighborhood greenness and walkability. AB - BACKGROUND: Both physical exercise and the built environment are associated with cardiovascular diseases (CVDs). Yet, the influence of the multiple dimensions of the built environment and different types of physical exercise on CVDs is not well understood. Further, little is known about the joint effects of physical exercise and the built environment, nor whether one mediates the effect of the other on the risk of CVDs. We aim to investigate the risk of CVDs on middle aged and older Chinese adult populations by analyzing the independent effects, as well as potential interactions and mediation effects of different types of physical exercise and two dimensions of the built environment; namely, greenness and walkability. METHODS: Data were collected from a community-based cross-sectional study (n = 1944). The study participants, aged 40 years or older, came from 32 communities across urban, suburban, and rural areas in Longzihu district of Bengbu, a typical second-tier city in eastern China. Physical exercise data were obtained from the International Physical Activity Questionnaire (IPAQ) question survey. We used a satellite-based Normalized Difference Vegetation Index (NDVI) score to assess greenness exposure. We used both the Walk Score index and the Neighborhood Environment Walkability Scale (NEWS) to assess walkability. Multilevel logistic regression, also known as mixed-effects logistic regression, was used to estimate the associations between physical exercise and the built environment (greenness and walkability) on CVD outcomes while accounting for within-community and within-subdistrict correlations. We followed Baron and Kenny's framework and used bootstrapping to quantify the mediation of physical exercise between built environment and CVD outcomes. Stratified analysis was conducted by age (middle aged and older adults) and gender. RESULTS: Compared to the reference group with little to low physical activities, we found a significantly reduced risk of hypertension (about 20-45% reduction) and coronary heart disease (about 35-55% reduction) among those with moderate to high activities in walking/square dancing or morning exercising/Tai Chi, and a significantly reduced risk of stroke (about 25% reduction) among those with moderate to high activities in walking/square dancing. Compared to the reference group with low NDVI-based greenness exposure, we found a significant reduction in risk of hypertension (about 55-85% reduction), coronary heart disease (about 75% reduction) and stroke (about 45% reduction) among those with moderate to high levels of exposure. Compared to the reference groups with low walkability, we observed about 30-60% lower risk of hypertension and coronary heart disease associated with moderate to high levels of Walk score, and about 20-30% lower risk of hypertension and stroke associated with moderate to high levels of NEWS based walkability. We found no interactions between physical exercise and the built environment. The associations of greenness and walkability with CVDs were partially explained by physical exercise (up to 55% of the total effect). CONCLUSIONS: Both physical exercise and built environment factors were associated with the risk of CVDs. Our observed association between CVDs and neighborhood greenness exposure and walkability was explained, in part, by physical exercises. Such a role, if confirmed in future studies, could have important implications for policies and programs aimed at increasing green spaces and improving walkability in both urban and rural settings as strategies to promote physical exercise in middle aged and older population. PMID- 30029040 TI - Improving the efficacy of sewage treatment decreases norovirus contamination in oysters. AB - As human population increases worldwide, water quality will become increasingly problematic, and food consumed raw may be of higher risk. This is already evident for oysters grown in coastal areas - despite regulations based on bacterial indicators, oysters are still implicated in food-borne outbreaks worldwide. The pathogens most frequently detected are human noroviruses, which are shed at high concentrations in human excreta and are very resistant to environmental conditions. Sewage treatment plants usually apply a variety of steps such as activated sludge treatment, chlorine or UV disinfection to eliminate contaminants, these processes have variable efficacy. This study demonstrates the impact of replacing an old lagoon-based sewage treatment plant with a new membrane bioreactor sewage treatment plant on human norovirus levels in treated sewage and oysters. While comparable norovirus concentrations were detected in the influent samples, a clear difference was observed in effluent quality, as norovirus was only detected in one sample after treatment in the new membrane bioreactor system, confirming the efficiency of such technology. As a direct impact, oysters located close to the membrane bioreactor sewage outfall were less frequently contaminated by norovirus, and showed lower concentrations compared to the first period of the study when they were exposed to sewage effluent from the lagoon outfall. Shellfish located upstream showed comparable contamination levels suggesting that there are also other sources of norovirus contamination in the estuary. Considering the health benefits of shellfish consumption, improving wastewater quality will make an important contribution to enhancing the safety of shellfish and international food security. PMID- 30029042 TI - Exploring mentors' interpretation of terminology and levels of competence when assessing nursing students: An integrative review. AB - OBJECTIVES: The purpose of this integrative review is to evaluate the empirical and theoretical literature on the challenges mentors face in interpreting and assessing levels of competence of student nurses in clinical practice. DESIGN: An integrative review of the literature. DATA SOURCES: An extensive and systematic literature search was conducted covering the period 1986-September 2016 across twelve databases covering health and education related publications. Grey literature was searched from wide relevant sources. REVIEW METHODS: Sources were eligible for review when they referred to mentor's interpretation or assessment of student nurses' level of competence in practice settings. Methodological rigor of the included studies was evaluated with the Mixed Methods Appraisal Tool. RESULTS: After screening 1951 records by titles, abstracts and full text, 8 were selected for review. The methodological quality of the studies was moderate. The studies reported: Accurate and fair assessment of students is impeded by a lack of transparent and explicit criteria. CONCLUSIONS: There is a need to establish a transparent and common language to distinguish between and facilitate interpretation of different levels of competence. Well-designed rubrics might offer the solution to the challenges faced in practice-based assessment and necessitates further research into their use. PMID- 30029041 TI - Undergraduate nursing students' strategies for coping with their first clinical placement: Descriptive survey study. AB - BACKGROUND: Clinical placement is an essential component in academic nursing programs to provide nursing students with an opportunity to apply theoretical knowledge to practice. The first clinical placement can be an extremely stressful experience for some nursing students, which may affect their decision to be a nurse. OBJECTIVE: The aim of this study was to identify factors and strategies that enable a positive experience of the first clinical placement for first year nursing students. DESIGN: Mixed methods descriptive survey design. SETTINGS: The study was conducted in a nursing school at one university in South Australia. RESPONDENTS: Respondents were all first year undergraduate nursing students at a higher education facility in South Australia. METHODS: Data collection tool was an online questionnaire including quantitative and qualitative questions. Coping strategies framework informed qualitative analysis. RESULTS: Respondents identified a range of strategies that had enabled them to positively cope with their first clinical placement experience. Strategies included use of debriefing sessions with their clinical lecturers and seeking-out their friends and family to talk about their first clinical placement experiences. Other strategies included being adequately prepared before the clinical placement, identifying and seeking advice from supportive nursing staff and effective communication between nursing schools and clinical institutions about placement arrangements and expectations. CONCLUSIONS: It must not be forgotten how stressful first clinical placements are. This experience will leave a lasting impression on students' introduction to the nursing profession. Sharing coping strategies used by nursing students will assist to provide a positive introduction to nursing practice. PMID- 30029043 TI - Attachment theory grows up: a developmental approach to pair bonds. AB - The application of Bowlby's Attachment Theory (AT) to sexual pair bonds has sparked wide ranging investigations which largely support, and further elaborate, key tenets of AT. Most notably, adults, like children, derive security from, and function optimally, when they feel they have the commitment of a loving other. Recent neuroscience findings further support the premise that parent-child and sexual pair bonds share some of the same neural architecture and physiology. The application of AT to adult pair bonds has also provoked controversy and raised empirical questions that warrant greater attention. Some of these questions include whether platonic friendships or kin can serve at least some of the functions of sexual partnerships in adulthood, and when, in the course of their development, do sexual relationships become pair bonds. Attention to key differences between infant and adult attachment, and the application of a developmental approach to pair bonds, would lead to productive directions for future research. PMID- 30029044 TI - Physical separation in adult attachment relationships. AB - Attachment theory suggests that at all stages of life, regular contact with attachment figures fosters a fundamental sense of safety and security. Yet an increasing number of romantic couples undergo prolonged physical separations from one another, rangingfrom several weeks to several years, and involving widely varying opportunities for communication and contact. This article reviews contemporary research on the implications of such separations for attachment related dynamics, including relationship satisfaction and psychobiological attunement between partners. Recent technological innovations in computer mediated contact (such as video calls and electronic messaging) and their capacity to 'stand in' for direct physical contact are also discussed, along with directions for future research in the diverse psychobiological mechanisms underlying attachment formation and functioning at different stages of life and in different contexts. PMID- 30029045 TI - Molecular design of 1,3,5,7-TetraCN derivatives with reduced bioconcentration using 3D-QSAR modeling, full factorial design, and molecular docking. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were established for polychlorinated naphthalenes (PCNs) using the logarithms of experimental bioconcentration factors of 10 PCNs in fish as the dependent variable and their molecular structures as the independent variable. The models were used to design PCN derivatives with lower bioconcentration than the parent compounds. The contour maps from the 3D-QSAR models were used to evaluate sites and different substituents for monosubstitution. A full factorial experiment based on the target molecule (1,3,5,7-tetraCN, CN-42) was used to evaluate sites for disubstitution. The established 3D-QSAR models had good predictive abilities for the remaining 65 PCN congeners. Comparative molecular field analysis and comparative molecular similarity indices analysis models showed that PCN bioconcentration was dominated by the electrostatic field. Taking CN-42 as a template, 15 new monosubstituted compounds and 19 new disubstituted compounds with lower bioconcentration than CN-42 were designed using the 3D-QSAR model and full factorial design, respectively. Furthermore, the persistent organic pollutant properties and the practicability of these compounds were evaluated using Gaussian 09. The new compounds were less toxic than CN-42 but showed similar migration, stability, insulation, and flame retardancy. Molecular docking was used to screen for CN-42 derivatives that showed lower bioconcentration than CN-42 in specific tissues. PMID- 30029046 TI - Normative values for sleep parameters in pre-schoolers using actigraphy. AB - OBJECTIVE: There are currently no reference values for actigraphy-measured sleep length and fragmentation in preschool children. We created standardized parameters using a community sample. METHODS: Ninety-seven 2-to-6-year-old children (56 boys) wore an actigraph on their non-dominant wrist for seven days. The data was extracted and scored, calculating total sleep time, sleep latency, sleep efficiency, fragmentation index, circadian rhythm length, cosine peak and light/dark ratio. Subjects were divided into groups of 2-3-year-olds, 4-5-year olds and 6-year-olds. Means and standard deviations were calculated, and reference values were created using the 2.5th and the 97.5th percentiles. RESULTS: Reference intervals were 7 h 23 min-9 h 47 min for 24-hour total sleep time, 0.2-48.4 min for sleep latency, 69-87% for sleep efficiency, 23-53% for fragmentation index, 23 h 39 min-24 h 24 min for circadian rhythm length, 12:37 15:53 for the timing of the cosine peak, and 1.14-5.63 for the light-dark ratio. With increasing age, daily sleep time, sleep latency, sleep fragmentation, and napping decreased. CONCLUSIONS: We were able to create previously non-established reference values, including trends with increasing age, on actigraphy-assessed sleep in preschool children. SIGNIFICANCE: Sleep disorders in young children are easier to evaluate against normative data. PMID- 30029047 TI - Decreased occipital alpha oscillation in children who stutter during a visual Go/Nogo task. AB - OBJECTIVE: Our goal was to discover attention- and inhibitory control-related differences in the main oscillations of the brain of children who stutter (CWS) compared to typically developed children (TDC). METHODS: We performed a time frequency analysis using wavelets, fast Fourier transformation (FFT) and the Alpha/Theta power ratio of EEG data collected during a visual Go/Nogo task in 7-9 year old CWS and TDC, including also the time window between consecutive tasks. RESULTS: CWS showed significantly reduced occipital alpha power and Alpha/Theta ratio in the "resting" or preparatory period between visual stimuli especially in the Nogo condition. CONCLUSIONS: The CWS demonstrate reduced inhibition of the visual cortex and information processing in the absence of visual stimuli, which may be related to problems in attentional gating. SIGNIFICANCE: Occipital alpha oscillation is elementary in the control and inhibition of visual attention and the lack of occipital alpha modulation indicate fundamental differences in the regulation of visual information processing in CWS. Our findings support the view of stuttering as part of a wide-ranging brain dysfunction most likely involving also attentional and inhibitory networks. PMID- 30029048 TI - Cellular fibroepithelial lesions of the breast: A long term follow up study. AB - Some fibroepithelial lesions (FEL) of the breast are difficult to classify as cellular fibroadenoma (CFA) or benign phyllodes tumor (BPT) due to overlapping histologic features. This indeterminate group is histologically characterized by prominent stromal cellularity, mild atypia, and mitotic activity. The local recurrence potential of cellular FEL (CFEL) has been insufficiently studied. The objective of this study was to evaluate the histologic features, characterize the long-term follow-up and recurrence rate of CFEL, and compare this data with the recurrence rate of definitive BPT. Ninety CFEL that were <4 cm were recovered from the benign breast disease cohort. The control group comprised of 10 randomly selected patients with BPT. Cases were classified based on a combination of mitotic activity, intracanalicular growth, stromal atypia, stromal prominence, and fat infiltration. None of the CFEL was widely excised. Of the 90 CFEL cases, there were 22 BPT-like, 35 CFA, and 33 indeterminate. The mean age of the patients was 40.1 years. The mean tumor size was 2.4 cm. All patients had at least two years of follow-up (median 27). None of the patients with BPT-like CFEL showed ipsilateral recurrence. Five of the 35 patients with CFA had recurrent ipsilateral CFA. This occurred within 1 to 11 years after the initial diagnosis. One of 33 patients with indeterminate type had a recurrent ipsilateral lesion five years after the initial diagnosis with histologic features of CFA. None of the patients in control group had any recurrence. In conclusion, as a group, CFEL have a low proclivity for recurrence, even when enucleated with close or positive margins. The presence of histologic features of BPT did not correlate with an increased potential for recurrence. PMID- 30029049 TI - The zinc transporter SLC39A7 (ZIP7) harbours a highly-conserved histidine-rich N terminal region that potentially contributes to zinc homeostasis in the endoplasmic reticulum. AB - The zinc transporter SLC39A7 (ZIP7)1 is a resident endoplasmic reticulum (ER) protein that is involved in controlling the release of zinc from this organelle into the cytosol. Subsequently, zinc plays a major role in processes that preserve cellular homeostasis. The ER contains a high concentration of zinc, and under normal physiological responses, maintains ER function. Disturbances in the concentration and distribution of zinc in the ER leads to abnormal processes that typify many disease states. ZIP7 is protective against ER stress and is a critical 'gate-keeper' of zinc release from the ER during processes that require cellular maintenance. However, it is not known how ZIP7 achieves this protective activity while maintaining cellular function. Bioinformatics analysis was utilised to determine the relationship between ZIP7 and other zinc transporters across humans and the animal and plant kingdom to determine the structure of this transporter in binding zinc in the ER. Analysis of the amino acid sequence of ZIP7 revealed several potential histidine binding sites for zinc in the N terminal region that were significantly different in comparison to the other members of this family. Moreover, this histidine-rich region in the N-terminal of ZIP7 was highly conserved across the animal and plant kingdom. Accordingly, the highly conserved histidine-rich region in the N-termini of ZIP7 across the animal and plant kingdom suggests that this domain has critical function(s). We hypothesise that ER-localized ZIP7 can potentially sequester zinc to these histidine-rich regions and therefore provides a mechanism that is protective of this cellular structure. PMID- 30029050 TI - Latent comorbid depression and anxiety symptoms across sex and race/ethnic subgroupings in a national epidemiologic study. AB - The heterogeneity of mood and anxiety disorders has been widely documented and epidemiologic studies have found different prevalence rates for psychiatric disorders across subgroups (i.e. sex and race/ethnic). The current study compares the latent class structure across sex and race/ethnic groups to determine group differences in these latent class configurations. This study utilized data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample from the United States (N = 43,093). First, latent class analyses (LCAs) were used to assess subtypes of symptoms of depression and anxiety that characterize a latent class structure for the population represented by NESARC. Second, group LCAs were conducted across sex and race/ethnicity to compare the latent class structure across these groups. The results suggest a 7-class model is the best fit for the population as well as for the male, non-Hispanic White, and Black subgroups. Females fit best an 11-class model, Hispanics a 5-class model and Asian and American Indian subgroups a 4 class model. These results indicate that subgroups of sex and race/ethnicity do not share the same latent construct for symptoms of anxiety and depression. Understanding the variability in the presentation of comorbid mood and anxiety across subgroups has the potential to inform person-centered approaches to care as well as targeted and multicultural interventions to improve population health. PMID- 30029051 TI - Which levels of cognitive impairments and negative symptoms are related to functional deficits in schizophrenia? AB - BACKGROUND: Negative symptoms and cognitive impairments predict difficulties in aspects of everyday functioning in schizophrenia, with little research to date attempting to determine if there are threshold levels of impairment required to predict the severity of functional deficits. METHODS: People diagnosed with chronic schizophrenia (n = 821) were assessed with the MCCB and PANSS, and rated by high contact informants with SLOF. Negative symptoms of reduced emotional experience were specifically targeted for analysis because of their previously identified relationships with social outcomes. We identified patients with moderate negative symptoms (at least one PANSS item >=4) versus less severe symptoms (PANSS items <=3) and divided patients on the basis of a single latent trait global cognition score (neuropsychologically normal vs neuropsychologically impaired; performance at or below 1.0 SD from the normative population mean, T = 40), then examined correlations between cognition, negative symptoms and everyday functioning in the groups with lower and higher negative symptoms and those with/without cognitive impairment. RESULTS: Even low levels of negative symptoms were correlated with ratings of social functioning. Cognitive performance in the neuropsychologically normal range, in contrast, was not correlated with any aspects of everyday functioning while more impaired performance predicted greater functional impairments. CONCLUSIONS: Even minimal symptoms may be a target for clinical attention in the domains of negative symptoms, consistent with previous findings regarding social deficits in populations with modest negative symptoms (e.g., schizotypal personality disorder). Cognitive rehabilitation treatments might not improve social functioning if even low levels of negative symptoms (social amotivation) are present. PMID- 30029052 TI - Altered gut microbiota profile in patients with generalized anxiety disorder. AB - Close relationships have recently been established between gut microbiota and some mental disorders. Here, we performed a systematic comparative analysis of the gut microbiome in patients with generalized anxiety disorder (GAD) and healthy controls (HCs). We first conducted a cross-sectional study of 40 patients with GAD in the active state and 36 HCs. Second, subgroup analysis consisting of 12 antidepressant-naive patients and 22 controls was performed to validate the results. Finally, a prospective study was performed in a subgroup of nine patients with GAD who underwent analysis in the active state of anxiety and in remission. Compared with the HCs, we found markedly decreased microbial richness and diversity, distinct metagenomic composition with reduced short-chain fatty acid (SCFA)-producing bacteria (associated with a healthy status) and overgrowth of bacteria, such as Escherichia-Shigella, Fusobacterium and Ruminococcus gnavus. Unexpectedly, these changes in the genera were not reversed in remissive GAD. This study identified microbiota dysbiosis of gut microbiota in GAD patients, suggesting that targeting the microbiome may be a useful therapeutic and preventive target for GAD. PMID- 30029053 TI - Competing mortality risks among women aged 50-79 years when diagnosed with invasive breast cancer, Queensland, 1997-2012. AB - BACKGROUND: Understanding the burden of competing (non-breast cancer) mortality is important for the growing number of breast cancer survivors. We quantity these patterns, and the impact of two leading non-cancer causes of death, within ten years of breast cancer diagnosis. METHODS: Population based cancer registry study of 23,809 women aged 50-79 diagnosed with first primary breast cancer in Queensland, Australia, 1997 to 2012 with additional data linkage to identify individual non-cancer mortality causes. Flexible parametric competing-risks models were used to estimate the crude and adjusted probabilities of death. RESULTS: While overall mortality increased with age at diagnosis, this effect was strongest for non-cancer (such as cardiovascular and cerebrovascular disease) mortality. Women diagnosed with advanced breast cancer had a higher crude probability of breast cancer death (23.1% versus 4.5% for localised) but similar probability of competing mortality (11.6% versus 11.3%). Within each category of spread of disease, the probability of breast-cancer deaths remained relatively constant with age, while the probability of competing deaths increased. The 10 year probability of dying from breast cancer was 3.7%, 4.2% and 5.6% among women with localised disease aged 50 to 59, 60-69 and 70-79 respectively, but 3.1%, 7.8% and 22.9% for competing mortality. Increasing age, advanced disease and being unpartnered were independently associated with increased risk of breast cancer and competing deaths. CONCLUSIONS: Promotion of improved health behaviors after a cancer diagnosis and development of individualized strategies for clinical management should be prioritized as part of optimal care for breast cancer survivors. PMID- 30029054 TI - Survivorship issues as determinants of quality of life after breast cancer treatment: Report from a limited resource setting. AB - OBJECTIVES: Quality of life (QOL) in breast cancer survivors is affected by various long term sequelae of breast cancer treatment. The present study was conducted with the objectives to estimate prevalence of various survivorship issues, and to identify those which are most predictive of limitations in QOL after completion of primary therapy. MATERIAL &METHODS: This study was conducted in 230 breast cancer survivors (BCs) and 112 controls at an academic centre in Northern India. Assessment of QOL was done by SF-36 and FACT-B questionnaires. Survivorship issues were noted from a checklist of 14 commonly reported symptoms. Main outcome measures were (1) frequencies of survivorship issues and QOL scores among three groups of survivors divided on the basis of time elapsed since treatment (<2, 2-5, and >5 year follow up) (2) Issues most predictive of limitations in QOL, identified by stepwise logistic regression analysis. RESULTS: Longer term BCs showed higher QOL scores as compared to those in early follow up. However their QOL scores remained poorer compared to healthy women. The most prevalent survivorship issues were fatigue (60%), restriction of shoulder movement (59.6%), body and joint pain (63.5%), chemotherapy induced cessation of menstruation (73.3%) and loss of sexual desire (60%). Issues which had maximum impact on QOL scores were emotional distress (r = -11.375), fatigue (r = -9.27) and premature menopause (r = -2.085) and its related symptoms. CONCLUSION: Management of these issues should be priority areas for supportive care, especially in settings with limited resource. PMID- 30029055 TI - Differentiation of human iPSCs into VSMCs and generation of VSMC-derived calcifying vascular cells. AB - Vascular calcification displays a major cause of death worldwide, which involve mainly vascular smooth muscle cells (VSMCs). Since 2007, there are increasing numbers of protocols to obtain different cell types from human induced pluripotent stem cells (iPSCs), however a protocol for calcification is missing. Few protocols exist today for the differentiation of iPSCs towards VSMCs and none are known for their calcification. Here we present a protocol for the calcification of iPSC-derived VSMCs. We successfully differentiated iPSCs into VSMCs based on a modified protocol. Calcification in VSMCs is induced by a commercial StemXVivoTM osteogenic medium. Calcification was verified using Calcein and Alizarin Red S staining or Calcium assays, and molecular analyses showed enhanced expression of calcification-associated genes. The presented method could help to study genetic risk variants, using the CRISPR/Cas technology through the introduction of Knockouts or Knockins of risk variants. Finally, this method can be applied for drug screening. PMID- 30029056 TI - The meaning of "capacity building" for the nurse workforce in sub-Saharan Africa: An integrative review. AB - BACKGROUND: "Capacity building" is an international development strategy which receives billions of dollars of investment annually and is utilized by major development agencies globally. However, there is a lack of consensus around what "capacity building", or even "capacity" itself, means. Nurses are the frequent target of capacity building programming in sub-Saharan Africa as they provide the majority of healthcare in that region. OBJECTIVES: This study explored how "capacity" was conceptualized and operationalized by capacity building practitioners working in sub-Saharan Africa to develop its nursing workforce, and to assess Grindle and Hilderbrand's (1995) "Dimensions of Capacity" model was for fit with "capacity's" definition in the field. DESIGN: An integrative review of the literature using systematic search criteria. DATA SOURCES SEARCHED INCLUDED: PubMed, the Cumulative Index for Nursing and Allied Health Literature Plus, the Excerpt Medica Database, and Web of Science. REVIEW METHODS: This review utilized conventional content analysis to assess how capacity building practitioners working in sub-Saharan Africa utilize the term "capacity" in the nursing context. Content analysis was conducted separately for how capacity building practitioners described "capacity" versus how their programs operationalized it. Identified themes were then assessed for fit with Grindle and Hilderbrand's (1995) "Dimensions of Capacity" model. RESULTS: Analysis showed primary themes for conceptualization of capacity building of nurses by practitioners included: human resources for health, particularly pre- and post- nursing licensure training, and human (nursing) resource retention. Other themes included: management, health expenditure, and physical resources. There are several commonly used metrics for human resources for health, and a few for health expenditures, but none for management or physical resources. Overlapping themes of operationalization include: number of healthcare workers, post-licensure training, and physical resources. The Grindle and Hilderbrand (1995) model was a strong fit with how capacity is defined by practitioners working on nursing workforce issues in sub Saharan Africa. CONCLUSIONS: This review indicates there is significant informal consensus on the definition of "capacity" and that the Grindle and Hilderbrand (1995) framework is a good representation of that consensus. This framework could be utilized by capacity building practitioners and researchers as those groups plan, execute, and evaluate nursing capacity building programming. PMID- 30029057 TI - Significant correlation between regulatory T cells and vitamin D status in term and preterm labor. AB - BACKGROUND AND AIM: Vitamin D insufficiency and deficiency have been associated with an increased risk of adverse pregnancy outcomes. Also, vitamin D is known to play a role in promoting the function of regulatory T-cells (Tregs). Tregs play an important role in suppressing the immune response during pregnancy. Our study aimed to investigate Tregs phenotypes in preterm and tem laboring women and its association with vitamin D level. METHODS: This cross-sectional study included 82 pregnant women, divided into 46 term and 36 preterm laboring women in addition to 30 healthy non-pregnant women. The percentage of CD4+CD25+Foxp3+Treg cells and their composition of four different Treg subsets were evaluated using flow cytometric analysis. Also, serum vitamin D levels were measured by ELISA. RESULTS: The percentage of the CD4+ CD25+ FoxP3+ Tregs were significantly decreased in term and preterm laboring women compared to the non-pregnant controls. The percentage of CD45RA+ Tregs, was significantly increased in term laboring women than preterm laboring women and non-pregnant women. Also, term labor women had increased proportion of HLA-DRhighTregs. Preterm labor women had significant increased proportion of HLA-DRnegative Tregs compared to term labor women. The overall prevalence of vitamin D deficiency and vitamin D insufficiency was higher in preterm than term laboring women and non-pregnant women. Significant positive correlations were found between serum level of 25 (OH)D and percentage of CD4+ CD25+ Foxp3+Tregs and percentage HLA-DRhighTregs among term and preterm laboring women with vitamin D deficiency. CONCLUSION: There is a strong association between the percentage of Treg phenotypes and vitamin D level in term and preterm labor women with vitamin D deficiency. Also, the onset of term and preterm labor is associated with changes in the composition of the total Treg pool with different Treg subsets which in turn may be responsible for immunologic mechanisms that associated with labor induction. PMID- 30029058 TI - Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2. AB - Endothelial dysfunction and vascular complications induced by hyperglycemia play an important role in the pathological development of atherosclerosis in diabetes. Humanin, a 24-amino acid mitochondria-derived polypeptide, has displayed its cytoprotective effects in diverse cell types and tissues. In the current study, we aimed to characterize the effects of humanin on high glucose-induced endothelial dysfunction. Firstly, we found that humanin treatment induced the expression of Kruppel-like factor 2 (KLF2), an essential transcriptional regulator of endothelial function, at the transcriptional level in human umbilical vein endothelial cells (HUVECs). Additionally, our results indicate that humanin treatment regulated the expression of KLF2 target genes such as endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1). Evidence demonstrated that the effects of humanin on KLF2 expression was mediated by the phosphorylation of extracellular signal regulated kinase 5 (ERK5). Furthermore, humanin restored high glucose-induced reduction of KLF2 expression. We also showed that humanin significantly reduced the expression of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Notably, humanin treatment markedly prevented high glucose-induced attachment of the monocyte THP-1 cells to HUVECs. However, knockdown of KLF2 abolished these effects. Lastly, we report that humanin treatment inhibited high glucose-induced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). These findings suggest that humanin may have therapeutic potential for the treatment of hyperglycemia associated endothelial dysfunction. PMID- 30029059 TI - Myeloid-derived suppressor cells exacerbate Sjogren's syndrome by inhibiting Th2 immune responses. AB - Myeloid-derived suppressor cells (MDSCs) can regulate various aspects of immune responses based on their potent immune-suppressive activity. Studies reported that MDSCs participated in many autoimmune diseases. However, the role of MDSCs in Sjogren's syndrome (SS) is unknown. In this study, we determined the frequencies and function of MDSCs in non-obese diabetic (NOD) mice and SS patients. The NOD mice were adoptively transferred with MDSCs or treated with anti-Gr1 antibody. Results showed that peripheral MDSCs increased significantly with the development of SS-like syndrome in NOD mice and the percentage of MDSCs was higher in SS patients than healthy controls. The SS-like syndrome aggravated after transfer of MDSCs in NOD mice. The deletion of MDSCs in NOD mice alleviated SS-like syndrome. Mechanistically, MDSCs down-regulated the percentages of Th2 cells in NOD mice and SS patients. In summary, our findings suggested that MDSCs exacerbated Sjogren's syndrome by inhibiting Th2 cells. PMID- 30029060 TI - A novel Abeta epitope vaccine based on bacterium-like particle against Alzheimer's disease. AB - Amyloid-beta (Abeta) plaque accumulation in the brain is one of the hallmarks of Alzheimer's disease (AD). Immunotherapy against Abeta was considered a potential strategy for reducing the Abeta load in the brain. However, none of the Abeta immunotherapies have produced clinically meaningful results to date, due to poor safety or lack of efficacy. Thus, we aimed to design a safe and effective vaccine against AD. In this study, we used bacterium-like particles (BLPs) as carriers and different copy numbers of the Abeta 1-6 peptide as epitopes to design four Abeta active immunization vaccines. The epitopes containing different copy numbers of the Abeta 1-6 peptide were specifically loaded on the surface of BLPs via fusion with a peptidoglycan anchoring domain. These four BLP-based Abeta vaccines successfully induced high levels of Abeta42-specific antibodies in mice. However, none of the vaccines induced a T-cell-mediated immune response. Importantly, the antibodies induced by these four vaccines were effective in blocking Abeta42 oligomer toxicity at the cellular level. Among the four vaccines, 6copy-Abeta 1-6 -PA-BLP was the most effective in inducing Abeta specific antibodies, indicating that a suitable epitope copy number is critical for high immunogenicity of the BLP-based vaccine. Furthermore, high levels of serum Abeta-specific antibodies could still be detected 3 months after the final administration of 6copy-Abeta 1-6 -PA-BLP. Thus, 6copy-Abeta 1-6 -PA-BLP may be a potential therapeutic treatment for AD. PMID- 30029061 TI - Molecular identification and gene expression profiles of the T cell receptors and co-receptors in developing red-tailed phascogale (Phascogale calura) pouch young. AB - Expressed coding sequences were identified for the T cell receptors TCRalpha, TCRbeta, TCRgamma, TCRdelta, TCRMU, and co-receptors CD3epsilon, CD4, and CD8alpha in the red-tailed phascogale (Phascogale calura). Expression of these genes was examined in the developing thymus and spleen of pouch young and juvenile individuals to detect any changes in expressionrelative to developmental stages. Transcripts of CD3epsilon, CD4, TCRdelta and TCRMU were first detected in the thorax at 1 day postpartum (dpp), and transcripts of all target genes were detected in the thymus from 3 dpp, and the spleen from 17 dpp. The relative expression of all target genes changed significantly over the course of pouch life and was associated with histological milestones of both the thymus and the spleen. Peak gene expression was observed early in pouch life in the thymus, with a decrease in expression associated with timing of thymic involution, while expression peaked later in the spleen and was associated with the initial differentiation of the red and white pulp and a population of T cells forming the periarterial lymphatic sheath (PALS). Active expression of these target genes within the thymus and spleen indicates that the young marsupials are actively developing immunocompetence during pouch life. PMID- 30029062 TI - Locus of control in US combat veterans: Unique associations with posttraumatic stress disorder 5-factor model symptom clusters. AB - Given elevated rates of posttraumatic stress disorder (PTSD) among US military veterans, identifying correlates of PTSD and specific PTSD symptom clusters that best represent PTSD in veterans (i.e., the five-factor Dysphoric Arousal model) is critical to prevention and intervention efforts. One potential correlate is locus of control (i.e., the extent to which individuals believe they have control over events in their lives). The aim of this study was to examine the relations between locus of control and five-factor model PTSD symptom clusters (i.e., re experiencing, avoidance, numbing, dysphoric arousal, anxious arousal) among combat veterans. Eighty-nine combat exposed veterans completed self-report measures of demographics, locus of control, PTSD symptoms, and combat exposure. Bivariate correlations indicated relations between locus of control and overall PTSD symptoms, avoidance symptoms, and numbing symptoms. When controlling for sex and combat exposure in regression analyses, only avoidance remained a significant correlate of locus of control. Among veterans with the most extreme scores (n = 26), external locus of control predicted overall PTSD symptoms and avoidance symptoms. External locus of control is uniquely associated with avoidance symptoms, and represents a potentially modifiable factor to address in trauma focused treatments. PMID- 30029064 TI - The impact of clinical comorbidities and residual depressive symptoms in sleep quality in euthymic/interepisodic bipolar subjects. AB - Sleep disturbances are feasibly linked with poorer outcome in BD. This study aims to cross-sectionally investigate clinical factors associated with sleep disruption in euthymic BD patients. We assessed sleep quality in a sample of 209 euthymic BD patients with the Pittsburgh Sleep Quality Index. After multiple logistic regression analysis controlling for several confounding factors, the variables number of clinical diseases and Hamilton global score remained significant and independently associated with poor sleep quality. Our results suggest that euthymic BD patients presenting poor sleep quality are more likely to have clinical comorbidities and manifest subsyndromal depressive symptomatology. PMID- 30029063 TI - Deficits in physiological and self-conscious emotional response to errors in hoarding disorder. AB - Hoarding disorder (HD) has been hypothesized to arise from deficits in error monitoring and abnormalities in emotional processing, but the relationship between error monitoring and emotional processing has not been examined. We examined measures of self-report, as well as behavioral, physiological, and facial responses to errors during a Stop-Change Task. 25 participants with HD and 32 healthy controls (HC) were recruited. Participants reported on number of errors committed and pre/post emotional response to errors. Skin conductance response (SCR) during correct and error commission trials was examined. Facial expression during task performance was coded for self-conscious and negative emotions. HD and HC participants had significantly different error rates but comparable error correction and post-error slowing. SCR was significantly lower for HD during error commission than for HC. During error trials, HD participants showed a significant deficit in displays of self-conscious emotions compared to HC. Self-reported emotions were increased in HD, with more negative and self conscious emotion reported than was reported for HC participants. These findings suggest that hypoactive emotional responding at a physiological level may play a role in how errors are processed in individuals with HD. PMID- 30029065 TI - Childhood trauma and somatic symptoms among psychiatric outpatients: Investigating the role of shame and guilt. AB - Previous research suggests a link between experiences of childhood maltreatment and adult somatic symptom distress. Contributing mechanisms, however, are not yet well understood. It is possible that shame and guilt may function as mediators in the relationship between childhood trauma and adult somatic distress. The present study was developed to investigate the relationship between childhood maltreatment and adult somatic distress, including the potential mediating role of shame and guilt, among psychiatric outpatients. Using data from a sample of 99 Canadian psychiatric outpatients, mediation models with shame and guilt as parallel mediators were evaluated for relationships between childhood emotional abuse, sexual abuse, emotional neglect, and somatic symptoms. Controlling for current depressive symptoms, a significant indirect effect was found for the relationship between emotional abuse and shame, but not guilt, in contributing to somatic symptoms. A similar result was obtained regarding the mediating role of shame in the relationship between emotional neglect and somatic symptoms. Mediation was non-significant regarding childhood sexual abuse, which was directly related to somatic distress after controlling for depressive symptoms. The findings provide further evidence of the link between childhood trauma and somatic symptom distress, with shame as a mechanism for the effects of emotional abuse and neglect. PMID- 30029066 TI - Survey and experimental study on metric learning methods. AB - Distance metric learning has been a hot research spot recently due to its high effectiveness and efficiency in improving the performance of distance related methods, such as k nearest neighbors (kNN). Metric learning aims to learn a data dependent metric to make intra-class distance smaller and inter-class larger. A large number of methods have been proposed for various applications and a survey to evaluate and compare these methods is imperative. The existing surveys just analyze the algorithms theoretically or compare them experimentally with a narrow time scope. Therefore, the paper reviews classical and influential methods that were proposed between 2003 and 2017 and presents a taxonomy based on the most distinct character of each method. All the methods are categorized into five classes, including pairwise cost, probabilistic framework, boost-like approaches, advantageous variants and specific applications. A comprehensive experimental study is made to compare all the selected methods, exploring the ability in improving accuracy, the relation between distance change and accuracy, the relation between accuracy and kNN neighbor size. PMID- 30029067 TI - Typical visual-field locations facilitate access to awareness for everyday objects. AB - In real-world vision, humans are constantly confronted with complex environments that contain a multitude of objects. These environments are spatially structured, so that objects have different likelihoods of appearing in specific parts of the visual space. Our massive experience with such positional regularities prompts the hypothesis that the processing of individual objects varies in efficiency across the visual field: when objects are encountered in their typical locations (e.g., we are used to seeing lamps in the upper visual field and carpets in the lower visual field), they should be more efficiently perceived than when they are encountered in atypical locations (e.g., a lamp in the lower visual field and a carpet in the upper visual field). Here, we provide evidence for this hypothesis by showing that typical positioning facilitates an object's access to awareness. In two continuous flash suppression experiments, objects more efficiently overcame inter-ocular suppression when they were presented in visual-field locations that matched their typical locations in the environment, as compared to non-typical locations. This finding suggests that through extensive experience the visual system has adapted to the statistics of the environment. This adaptation may be particularly useful for rapid object individuation in natural scenes. PMID- 30029069 TI - Sense of autonomy and daily and scholastic functioning among children with cerebral palsy. AB - BACKGROUND: There is growing evidence that children's sense of autonomy is an important psychological need closely linked with the development of self-esteem and motivation. Among children with physical disabilities, motor or cognitive limitations may negatively affect child's sense of autonomy (CSA) and competency. PURPOSE: To examine how sense of autonomy among children with cerebral palsy (CP) directly and indirectly relates to their activity of daily living (ADL) and scholastic performance. METHODS: Seventy-three children with CP and their mothers participated in this study. Child's ADL skills and scholastic performance were assessed using the Pediatric Evaluation Disability Inventory (PEDI) and the Scholastic Skills Rating Scale (SSRS), respectively. Level of impairment was assessed using the Gross Motor Function Measure-66 (GMFM-66). CSA was established via videotaped mother-child interactions. Regression analyses were conducted to examine factors predicting child's functional level (ADL and scholastic). The overall model was tested for goodness-of-fit and test of mediation. RESULTS: GMFM and CSA significantly predicted child's ADL and scholastic functioning. GMFM explained 15% of the variance for CSA, 84% for PEDI, and 24% for scholastic functioning. CSA positively mediated the association between GMFM and child's ADL skills. GMFM was positively associated with CSA. CONCLUSION: Motor impairment has a substantial impact on child's level of functioning. However, child's functioning is a complex construct that is also affected by her or his sense of autonomy. Therefore, sense of autonomy can serve as a potential point of intervention to improve functioning among children with CP. PMID- 30029068 TI - Obesity and renal cell carcinoma risk by histologic subtype: A nested case control study and meta-analysis. AB - BACKGROUND: Although obesity is an established risk factor for renal cell carcinoma (RCC), it is unclear whether this relationship varies across histologic subtypes. METHODS: We conducted a nested case-control study within the Kaiser Permanente Northern California (KPNC) health care network, and meta-analysis combining our results with those of previously published studies. Our KPNC study included 685 RCC cases [421 clear cell; 65 papillary; 24 chromophobe; 35 other; 141 not otherwise specified (NOS)] and 4266 controls. Subtype-specific odds ratios (ORs) and 95% confidence intervals (CIs) for categories of body mass index (BMI) and were computed from the case-control data using polytomous logistic regression. Findings from this and other relevant studies were combined by meta analysis using a random effects model. RESULTS: In the KPNC study, obesity (BMI >= 30 kg/m2) was associated with clear cell RCC (OR 1.5, 95% CI 1.1-2.1) and chromophobe RCC (OR 2.5, 95%CI 0.8-8.1), but not with papillary RCC (OR 1.0, 95% CI 0.5-1.9). In meta-analysis including three additional studies, a similar pattern of summary relative risks (SRR) for obesity was observed across subtypes (clear cell: SRR 1.8, 95% CI 1.5-2.2; chromophobe: SRR 2.2, 95% CI 1.3-3.7; papillary, SRR 1.2, 95% CI 0.8-1.6). CONCLUSIONS: These findings support the hypothesis that histologic subtypes of RCC possess distinct etiologic pathways, with obesity important for the development of clear cell and, possibly, chromophobe RCC, but not papillary RCC. PMID- 30029070 TI - Next-generation DNA sequencing to identify novel genetic risk factors for cerebral vein thrombosis. AB - BACKGROUND: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. AIM: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). METHODS: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. RESULTS: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52-2.73; P = 2.07 * 10-6; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF <= 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. CONCLUSION: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT. PMID- 30029071 TI - Accelerations from wearable accelerometers reflect knee loading during running after anterior cruciate ligament reconstruction. AB - BACKGROUND: Following anterior cruciate ligament reconstruction, individuals exhibit sagittal plane knee loading deficits as they underload their injured limb during running. These between-limb biomechanical differences are difficult to clinically detect. Wearable accelerometers may aid in the development of early rehabilitation programs to improve symmetrical loading. This study aimed to identify whether segment accelerations from wearable accelerometers can predict knee loading asymmetry in an anterior cruciate ligament reconstructed population. METHODS: 14 individuals 5-months post-anterior cruciate ligament reconstruction performed self-selected speed running. Data were collected concurrently using a marker-based motion system and accelerometers positioned on participants' shanks and thighs. Stepwise linear regression was used to determine predictive value of accelerometer data on biomechanical variables. FINDING: Shank acceleration was not predictive of any biomechanical variable. Between-limb differences in thigh axial acceleration explained 30% of the variance in between-limb differences in knee power absorption (p = 0.045), suggesting that accelerometers placed on proximal joint segments may provide information regarding knee loading asymmetry. Between-limb differences in thigh axial acceleration also explained 38% of the variance in between-limb differences in ground reaction force (p = 0.002). INTERPRETATION: These relationships indicate that accelerations from wearable accelerometers may provide some useful information regarding knee loading during running in individuals following anterior cruciate ligament reconstruction. PMID- 30029072 TI - Autologous reference types can confound the detection of somatic mutation in solid cancers. AB - Vast number of somatic mutations has been proved to be affected by the factors of sequencing methods, analysis pipelines and validation methods. We here showed the effect of autologous reference types on the detection of cancer-associated somatic mutations with the somatic single nucleotide variations (SNVs) and clinical data of solid tumors from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). The distribution of somatic SNVs was significantly different among groups of autologous references in 6 cancers detected by whole genome sequencing (WGS) and 5 cancers detected by the random sequencing of exonic regions selected from the genome (WXS), especially in protein coding region of 5 cancers with age, gender and TNM adjusted. In addition, only 60.24% (95% CI: 49.65%-70.83%) of the somatic SNVs called from normal blood by WXS were found in those called from normal solid tissue tested by WXS / WGS, while 31.78% (95%CI: 4.14%-59.42%) of the somatic SNVs called from normal tissue adjacent to primary by WXS were found in those from normal blood tested by WXS / WGS. These findings suggested that more representative types of normal tissues should be included in detection of cancer-associated somatic mutations. PMID- 30029073 TI - Cannabis decriminalization: A study of recent policy change in five U.S. states. AB - BACKGROUND: A number of public health professional organizations support the decriminalization of cannabis due to adverse effects of cannabis-related arrests and legal consequences, particularly on youth. We sought to examine the associations between cannabis decriminalization and both arrests and youth cannabis use in five states that passed decriminalization measures between the years 2008 and 2014: Massachusetts (decriminalized in 2008), Connecticut (2011), Rhode Island (2013), Vermont (2013), and Maryland (2014). METHODS: Data on cannabis possession arrests were obtained from federal crime statistics; data on cannabis use were obtained from state Youth Risk Behavior Survey (YRBS) surveys, years 2007-2015. Using a "difference in difference" regression framework, we contrasted trends in decriminalization states with those from states that did not adopt major policy changes during the observation period. RESULTS: Decriminalization was associated with a 75% reduction in the rate of drug-related arrests for youth (95% CI: 44%, 89%) with similar effects observed for adult arrests. Decriminalization was not associated with any increase in the past-30 day prevalence of cannabis use overall (relative change=-0.2%; 95% CI: -4.5%, 4.3%) or in any of the individual decriminalization states. CONCLUSIONS: Decriminalization of cannabis in Massachusetts, Connecticut, Rhode Island, Vermont, and Maryland resulted in large decreases in cannabis possession arrests for both youth and adults, suggesting that the policy change had its intended consequence. Our analysis did not find any increase in the prevalence of youth cannabis use during the observation period. PMID- 30029074 TI - Medical breast ultrasound image segmentation by machine learning. AB - Breast cancer is the most commonly diagnosed cancer, which alone accounts for 30% all new cancer diagnoses for women, posing a threat to women's health. Segmentation of breast ultrasound images into functional tissues can aid tumor localization, breast density measurement, and assessment of treatment response, which is important to the clinical diagnosis of breast cancer. However, manually segmenting the ultrasound images, which is skill and experience dependent, would lead to a subjective diagnosis; in addition, it is time-consuming for radiologists to review hundreds of clinical images. Therefore, automatic segmentation of breast ultrasound images into functional tissues has received attention in recent years, amidst the more numerous studies of detection and segmentation of masses. In this paper, we propose to use convolutional neural networks (CNNs) for segmenting breast ultrasound images into four major tissues: skin, fibroglandular tissue, mass, and fatty tissue, on three-dimensional (3D) breast ultrasound images. Quantitative metrics for evaluation of segmentation results including Accuracy, Precision, Recall, and F1measure, all reached over 80%, which indicates that the method proposed has the capacity to distinguish functional tissues in breast ultrasound images. Another metric called the Jaccard similarity index (JSI) yields an 85.1% value, outperforming our previous study using the watershed algorithm with 74.54% JSI value. Thus, our proposed method might have the potential to provide the segmentations necessary to assist the clinical diagnosis of breast cancer and improve imaging in other modes in medical ultrasound. PMID- 30029075 TI - Kriging model to study the dynamics of a bubble subjected to tandem shock waves as used in biomedical applications. AB - The purpose of this work was to develop a metamodel (Kriging model) to identify the most important input parameters of shock wave pressure profiles as used in biomedical applications without solving a large number of differential equations. Shock wave-induced cavitation is involved in several biological effects. During bubble collapse, secondary shock waves and microjets are formed. For some applications, it is desirable to enhance this phenomenon by applying a second shock wave before bubble collapse; however, the delay between the leading shock wave and the second pressure pulse has yet to be optimized. This optimization can be done using numerical analysis. A metamodel that predicts the most convenient ranges for the input variables and provides information on the joint effects between the input variables was tested. Because the metamodel is an analytical expression, running it fifty thousand times and analyzing variables, such as the pressure amplitude, delay between pulses, and pressure rise time, was fast and easy. Furthermore, this method can be a helpful tool to study the joint effect between the input variables and reduce the computation time. The metamodel can also be adapted to analyze simulations based on equations different from the Gilmore-Akulichev formulation, which was used in this study. PMID- 30029077 TI - Impact of brine and antiscalants on reef-building corals in the Gulf of Aqaba - Potential effects from desalination plants. AB - Seawater reverse osmosis (SWRO) is becoming an increasingly important source of potable water in arid and semi-arid regions worldwide. Discharge of brine effluent from desalination facilities has been shown to significantly impact coastal marine ecosystems ranging from seagrass meadows to microbial communities. In this study, we examined the impacts of increased salinity (10% above ambient) and presence of antiscalants (0.2 mg L-1, polyphosphonate-based) on three reef building coral species; Stylophora pistillata, Acropora tenuis and Pocillopora verrucosa, from the Gulf of Aqaba (northern Red-Sea). Our results indicate that the corals, as well as associated bacteria and algae, were significantly impaired by the elevated salinity and antiscalants, leading to partial bleaching. Specifically, the abundance of bacteria and symbiotic algae as well as calcification rates were typically lower (20-85%, 50-90% and 40-50%, respectively) following incubations with both amendments. However, the impact of desalination brine was often species-specific. Thus, we propose that the ecotoxicological criteria used for hard corals should be determined based on the sensitivity of key species in the community dominating the area affected by desalination discharge. PMID- 30029076 TI - The interplay between total mercury, methylmercury and dissolved organic matter in fluvial systems: A latitudinal study across Europe. AB - Large-scale studies are needed to identify the drivers of total mercury (THg) and monomethyl-mercury (MeHg) concentrations in aquatic ecosystems. Studies attempting to link dissolved organic matter (DOM) to levels of THg or MeHg are few and geographically constrained. Additionally, stream and river systems have been understudied as compared to lakes. Hence, the aim of this study was to examine the influence of DOM concentration and composition, morphological descriptors, land uses and water chemistry on THg and MeHg concentrations and the percentage of THg as MeHg (%MeHg) in 29 streams across Europe spanning from 41 degrees N to 64 degrees N. THg concentrations (0.06-2.78 ng L-1) were highest in streams characterized by DOM with a high terrestrial soil signature and low nutrient content. MeHg concentrations (7.8-159 pg L-1) varied non-systematically across systems. Relationships between DOM bulk characteristics and THg and MeHg suggest that while soil derived DOM inputs control THg concentrations, autochthonous DOM (aquatically produced) and the availability of electron acceptors for Hg methylating microorganisms (e.g. sulfate) drive %MeHg and potentially MeHg concentration. Overall, these results highlight the large spatial variability in THg and MeHg concentrations at the European scale, and underscore the importance of DOM composition on mercury cycling in fluvial systems. PMID- 30029078 TI - Labial repositioning using polymethylmethracylate (PMMA)-based cement for esthetic smile rehabilitation-A case report. AB - INTRODUCTION: One of the most common esthetic complaints among dental patients is a gingival smile, which may be of multifactorial etiology, e.g. gingival hyperplasia, skeletal deformities featuring overgrowth of the anterior maxilla, altered passive eruption, maxillary alveolar tooth extrusion, fine lip and hypermobility of lip elevator muscles, which must be diagnosed prior to treatment so that the appropriate management approach can be selected. Maxillary overgrowth may give rise to subnasal skeletal depression where the upper lip retracts to during smiling, causing gingival exposure. The objective of this case report was to describe a lip repositioning technique using polymethylmethacrylate (PMMA) based bone cement for esthetic smile rehabilitation. CASE REPORT: A 23-year-old female attended the Esthetic Dentistry Clinic of our institute, reporting dissatisfaction with her smile, due to the size of her teeth and the amount of gingiva exposed when smiling. A rehabilitation planning was designed, which was performed with periodontal surgical intervention to fill the subnasal depression with PMMA-based bone cement. After crown lengthening, the PMMA-based bone cement was prepared with gentamicin in a sterile surgical bowl. When the mixture stopped sticking to the surgical gloves, it was then positioned into the subnasal pit, under constant and copious saline irrigation. With the cement in place, the prosthesis was shaped in a maximum thickness of 7-mm. After complete polymerization and under abundant cooling, refinement and finishing of the PMMA prosthesis was performed. The prosthesis was fixed onto the bone with two titanium-based bone graft fixation screws. The smile aesthetic rehabilitation was complemented using 10 lithium disilicate-based ceramic veneers. DISCUSSION AND CONCLUSION: PMMA-based bone cement proved effective when combined to clinical crown lengthening for esthetic smile rehabilitation, acting as a filling material for subnasal depression, providing new lip support. PMID- 30029079 TI - A case report of bleeding from a duodenal varix: Rare cause of upper gastrointestinal bleeding. AB - INTRODUCTION: Ectopic variceal bleeding is uncommon, accounts for 2-5% of variceal bleeding, of which 17% is in duodenum. PRESENTATION OF CASE: 62-year-old lady with newly diagnosed liver cirrhosis on admission, presented with severe upper gastrointestinal bleeding (UGIB), was ultimately diagnosed with bleeding duodenal varices with single-balloon enteroscopy, after multiple oesophagogastroduodenoscopies (OGDs) and CT scans which failed to identify the varices. She was treated successfully with duodenectomy. DISCUSSION: Endoscopy and CT angiography remain the diagnostic modalities of choice. However, diagnosis can be difficult as evidenced by three OGDs and two CTMAs yielding negative findings in this case. Endoscopic diagnosis is challenging and often delayed due to its rarity and unusual location. CONCLUSION: Ectopic variceal bleeding is a rare but important cause of UGIB. Diagnosis is challenging and management of this condition should take a multidisciplinary approach, involving experienced gastroenterologists, interventional radiologists and surgeons. Endoscopic ligation or sclerotherapy is the first-line of treatment. PMID- 30029080 TI - Toxicity and metabolomics study of isocarbophos in adult zebrafish (Danio rerio). AB - Although isocarbophos is a widely used insecticide, its toxicity to aquatic organisms has not been well characterized. In this study, zebrafish were exposed to isocarbophos at concentrations of 50 ug L-1 and 200 ug L-1 to assess its bioaccumulation, metabolic disruption, and oxidative stress. Metabolomics analysis based on 1H NMR spectroscopy showed that 50 ug L-1 and 200 ug L-1 isocarbophos exposure induced increases in leucine, isoleucine, valine, and alanine compared to levels in the control. Lactate, creatine, and taurine were reduced in the 50 ug L-1 isocarbophos exposure group, and only lactate decreased in response to 200 ug L-1 isocarbophos. After zebrafish were exposed to 50 and 200 ug L-1 isocarbophos for 28 days, the activities of antioxidant enzymes (SOD, CAT, and GPx) and GSH contents decreased significantly in the liver. This result indicates that there was significant oxidative stress in the liver. Furthermore, changes in metabolite profiles significantly covaried with changes in several oxidative stress endpoints based on partial least squares regression. These results will contribute to the environmental risk assessment of isocarbophos and clarify the mechanism underlying its toxicity in zebrafish. PMID- 30029081 TI - New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8. AB - In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not form favorable interactions in cruzain, which is in common with our experimental results. Further, inhibitor 18 bearing a free carboxylic acid attached to the aziridine moiety showed a time-dependent inhibition of LmCPB2.8 (Ki = 0.41 MUM; k2nd = 190,569 M-1 min-1). Docking results suggested a strong ionic interaction with the positively charged His163 of the active site. Biological and theoretical data confirm that the novel selective aziridine-based inhibitors are promising candidates for further optimization as LmCPB2.8 inhibitors. PMID- 30029082 TI - Quantitative analysis of mammalian chromosome by scanning transmission soft X-ray microscopy. AB - Soft X-ray spectromicroscopy was applied to study the quantitative distribution of DNA and protein in a mammalian chromosome at the spatial resolution of 100 nm. The quantities of DNA and protein were evaluated using 1s-pi* transition in the NEXAFS spectra at the nitrogen K absorption edge. DNA was not uniformly distributed in the chromosome and DNA/protein ratio was less than 0.497. The present analysis revealed the clues to identify other molecules that contribute to the absorption spectrum of the sample. The results suggested that accumulation of the absorption spectra of relevant molecules would support the refinement of the analysis. PMID- 30029084 TI - Barriers and facilitators of accessing perinatal mental health services: The perspectives of women receiving continuity of care midwifery. AB - OBJECTIVE: To explore what factors midwifery care recipients perceive to prevent or facilitate access to mental health care in the perinatal period. DESIGN: A qualitative descriptive study based on semi-structured individual interviews and focus groups. SETTING: Ottawa, Ontario, Canada. PARTICIPANTS: Sixteen mothers who had received or were currently receiving midwifery care. Eligibility criteria were being 18 or older and self-identifying as having experienced or experiencing perinatal mental health concerns. FINDINGS: Five salient themes emerged from the data: cultural values, knowledge, relationships, flexibility, and system gaps. Barriers and facilitators to accessing perinatal mental health services are grouped under each theme. Stigma and fear, broken referral pathways, distant service location, lack of number/capacity of specialised services, baby centredness, discharge from midwifery care at six weeks postpartum, and cost were barriers to accessing care. Information and midwives' knowledge/experience were context-specific factors that could hinder or facilitate access. Continuity, community, and advocacy were facilitators to accessing care. Many of these facilitators are an inherent part of the Ontario midwifery model of care. Conversely, some aspects of midwives' scope of practice in Ontario impeded access to perinatal mental health care, including inability to make direct referrals to psychiatrists and discharge from care at six weeks postpartum. KEY CONCLUSION: Midwifery care based on the principles of continuity of care, woman-centred care, informed choice, and advocacy may help to enhance the uptake of perinatal mental health care, but access to such care also remains dependent on the characteristics of mental health services themselves. IMPLICATIONS FOR PRACTICE: Midwives can enhance access to perinatal mental health services by developing relationships that create safe conditions for disclosure; providing information about symptoms of perinatal mental health concerns, treatment, and services to clients and their social support network; being knowledgeable about existing resources and referral pathways; and identifying when women need additional support to seek care and facilitating connections to available services. PMID- 30029083 TI - Postpartum depression in Mongolia: A qualitative exploration of health care providers' perspectives. AB - OBJECTIVE: Postpartum depression (PPD) is defined as depression with symptom onset during pregnancy or within 6 weeks after childbirth. It is now estimated that 16% percent of pregnant women and 20% of postpartum women in low- and middle income countries experience depression, which can negatively influence everyday functioning, social relationships, and child development. This qualitative study aims to elucidate the perspectives and experiences of Mongolian health care providers regarding PPD. SETTING: This study was conducted in Mongolia's capital city, Ulaanbaatar, at the National Center for Maternal and Child Health (NCMCH), which serves patients from both urban and rural areas. Research on PPD in Mongolia is extremely limited. DESIGN: We conducted three interviews and three focus group discussions (FGDs) with health care providers (N = 15) to explore risk factors, causes, signs and symptoms, lay perceptions, recognition, and treatment in relation to PPD. The interviews and FGDs were audio recorded, transcribed and translated into English. PARTICIPANTS: The providers included five nurse-midwives, one family clinic nurse, four obstetrician-gynaecologists (OB-GYNs), two family physicians, one psychologist, one monk, and one traditional healer. FINDINGS: The majority of providers reported some basic knowledge of PPD, though limited experience in working with PPD patients. Most described signs and symptoms based on their own observations and perceptions rather than what women themselves reported. Providers generally characterised PPD as a multifactorial condition, recognising the role of obstetric, psychologic, socioeconomic and cultural factors in its development. A traditional concept of PPD ("sav khuurukh") was prominently mentioned. Though they had diverse ideas regarding where women seek help for PPD, almost all providers agreed that a critical strategy for identifying PPD is patient-provider discussion. However, such discussions are rare because of providers' lack of confidence in recognising and treating women with PPD, lack of training, time constraints, and/or other related barriers. KEY CONCLUSIONS: The results demonstrate that while providers have some understanding of key aspects of PPD, many lack a clear conception of what defines the condition and how to effectively identify and treat it. IMPLICATIONS FOR PRACTICE: Based on our findings, we make seven recommendations for how to enhance PPD detection and treatment considering local Mongolian culture, practices and context. PMID- 30029085 TI - The effect of educational intervention on nurses' knowledge, attitude, intention, practice and incidence rate of physical restraint use. AB - The use of physical restraint exposes patients and staff to negative effects, including death. Therefore, teaching nursing staff to develop the improve knowledge, skills, and attitudes regarding physical restraint has become necessary. A quasi-experimental pre-post design was used to evaluate the effect of educational intervention on nurses' knowledge, attitude, intention, practice and incidence rate of physical restraint in 12 wards of a hospital using a self reported questionnaire and a restraint order form in Malaysia. The educational intervention, which included a one-day session on minimising physical restraint use in hospital, was presented to 245 nurses. The results showed a significant increase in the mean knowledge, attitude sand practice score and a significant decrease in the mean intention score of nurses to use physical restraint after intervention. There was a statistically significant decrease in the incidence rate of physical restraint use in the wards of the hospital except geriatric rehabilitation wards after intervention. PMID- 30029087 TI - Selective metal cation concentration during the solidification of stainless steel EAF dust and slag mixtures from high temperatures for increased Cr recovery. AB - The selective concentration of valuable metal cations in FetO-Cr2O3-NiO-MnO containing stainless steel dust has been studied. The hazardous metal cations Fe, Cr, Ni and Mn could be locally concentrated during the solidification of a molten stainless steel slag and dust mixture from high temperatures by controlling the primary crystalline spinel phase. The nucleation and growth of the primary spinel phase could be controlled by varying the slag to dust mixing ratio and the cooling temperature. Significant redistribution between the primary spinel and amorphous phases could be observed, where the contents of Cr and Mn in the crystalline phase could be increased up to 40% and 10%, respectively, from their initial contents of 5% and 4% in the melt. Using the specified controlled cooling conditions, a primary spinel phase concentrated with Fe-Cr-Ni-Mn could be formed, which could be clearly distinguished and eventually separated from the amorphous matrix. The mixed stainless steel slag and dust samples were quenched at various cooling temperatures and with varying amounts of dust to identify and optimize the crystalline phases formed using SEM-EDS (scanning electron microscopy-energy dispersive spectroscopy) and XRD (X-ray diffraction) analyses. PMID- 30029086 TI - Age-related changes in Na, K-ATPase expression, subunit isoform selection and assembly in the stria vascularis lateral wall of mouse cochlea. AB - Due to the critical role of cochlear ion channels for hearing, the focus of the present study was to examine age-related changes of Na, K-ATPase (NKA) subunits in the lateral wall of mouse cochlea. We combined qRT-PCR, western blot and immunocytochemistry methodologies in order to determine gene and protein expression levels in the lateral wall of young and aged CBA/CaJ mice. Of the seven NKA subunits, only the mRNA expressions of alpha1, beta1 and beta2 subunit isoforms were detected in the lateral wall of CBA/CaJ mice. Aging was accompanied by dys-regulation of gene and protein expression of all three subunits detected. Hematoxylin and eosin (H&E) staining revealed atrophy of the cochlear stria vascularis (SV). The SV atrophy rate (20%) was much less than the ~80% decline in expression of all three NKA isoforms, indicating lateral wall atrophy and NKA dys regulation are independent factors and that there is a combination of changes involving the morphology of SV and NKA expression in the aging cochlea which may concomitantly affect cochlear function. Immunoprecipitation assays showed that the alpha1-beta1 heterodimer is the selective preferential heterodimer over the alpha1-beta2 heterodimer in cochlea lateral wall. Interestingly, in vitro pathway experiments utilizing cultured mouse cochlear marginal cells from the SV (SV-K1 cells) indicated that decreased mRNA and protein expressions of alpha1, beta1 and beta2 subunit isoforms are not associated with reduction of NKA activity following in vitro application of ouabain, but ouabain did disrupt the alpha1 beta1 heterodimer interaction. Lastly, the association between the alpha1 and beta1 subunit isoforms was present in the cochlear lateral wall of young adult mice, but this interaction could not be detected in old mice. Taken together, these data suggest that in the young adult mouse there is a specific, functional selection and assembly of NKA subunit isoforms in the SV lateral wall, which is disrupted and dys-regulated with age. Interventions for this age-linked ion channel disruption may have the potential to help diagnose, prevent, or treat age related hearing loss. PMID- 30029088 TI - Evaluation of brain damage resulting from penetrating and non-penetrating stunning in Nelore Cattle using pneumatically powered captive bolt guns. AB - Brain damage resulting from penetrating and non-penetrating stunning of Nelore cattle using pneumatically powered captive bolt guns was evaluated. Heads were shot using penetrating captive bolt gun with 160 psi (P1; n = 10), 175 psi (P2; n = 10), 190 psi (P3; n = 12), and non-penetrating operating with 220 psi (NP; n = 10). Skin and bone thickness, bolt penetration angle, bolt penetration depth, haemorrhage over the cerebral hemispheres and laceration were assessed. Only P1 had shots that failed to perforate the skull (n = 2; 20%). Bolt penetration depth and haemorrhage over the right cerebral hemisphere was significantly (P <= 0.05) greater for P3. Subarachnoid haemorrhage over the frontal, parietal and occipital lobes was higher for NP. Lacerations were observed only for penetrating gun in the cortical region of frontal and parietal lobes. Subarachnoid haemorrhage surrounding the brainstem and laceration in the midbrain and pons was only found for P3. Thus, penetrating captive bolt gun operating with 190 psi is more effective to achieve unconsciousness. PMID- 30029090 TI - An interpretative phenomenological analysis of young people's self-harm in the context of interpersonal stressors and supports: Parents, peers, and clinical services. AB - RATIONALE: Self-harm in young people is of significant clinical concern. Multiple psychological, social and clinical factors contribute to self-harm, but it remains a poorly understood phenomenon with limited effective treatment options. OBJECTIVE: To explore young women's experience of self-harm in the context of interpersonal stressors and supports. METHOD: Fourteen adolescent females (13-18 years) who had self-harmed in the last six months completed semi-structured interviews about self-harm and supports. Interpretative phenomenological analysis was undertaken. RESULTS: Themes identified were: 1) Arguments and worries about family breakdown; 2) Unhelpful parental response when self-harm discovered and impact on seeking support; 3) Ongoing parental support; 4) Long-term peer victimization/bullying as a backdrop to self-harm; 5) Mutual support and reactive support from friends (and instances of a lack of support); 6) Emotions shaped by others (shame, regret and feeling 'stupid to self-harm'); and 7) 'Empty promises' - feeling personally let down by clinical services. These themes were organised under two broad meta-themes (psychosocial stressors, psychosocial supports). Two additional interconnected meta-themes were identified: Difficulties talking about self-harm and distress; and Impact on help-seeking. CONCLUSION: Parents and peers play a key role in both precipitating self-harm and in supporting young people who self-harm. The identified themes, and the apparent inter-relationships between them, illustrate the complexity of self-harm experienced in the context of interpersonal difficulties, supports, and emotions. These results have implications for improving support from both informal and clinical sources. PMID- 30029089 TI - Childhood Absence Epilepsy evolving to Eyelid Myoclonia with Absence Epilepsy. AB - PURPOSE: Children with Childhood Absence Epilepsy (CAE) may develop generalized tonic-clonic seizure or juvenile myoclonic epilepsy. A possible evolution to Eyelid Myoclonia with Absence Epilepsy (EMA) hasn't been documented yet. We report the electroclinical features of a case series of children with CAE that evolved to EMA after therapy withdrawal. METHOD: Of 108 patients with CAE referred at our Epilepsy Center in the last ten years, 5 satisfied the inclusion criteria: CAE diagnosis, a minimum of 3 years follow-up, a progression to EMA after therapy withdrawal. RESULTS: All the six subjects were females. CAE was characterized by typical absences induced by hyperventilation; intermittent photic stimulation (IPS) was negative. All subjects were treated successfully with valproate. After drug withdrawal, all the six girls presented EMA. EMA was characterized by eyelid myoclonia with or without brief absences related to generalized spike/polyspike-waves discharges induced by IPS and less frequently by eye-closure. CONCLUSIONS: Our study documented another possible evolution of CAE into EMA. These results support the hypothesis that these two epileptic conditions are dynamic processes evolving into one another. CAE and EMA could be considered "system epilepsy" characterized by a high susceptibility to changes in the brain networks during specific life periods such as childhood and puberty. PMID- 30029091 TI - Experience of stigma and discrimination in families of persons with schizophrenia in the Czech Republic. AB - RATIONALE: Mental health-related stigma and discrimination not only affect persons living with schizophrenia but also their whole families. Stigma and discrimination reduction is key to respond to the unmet needs of persons with mental illness. The local context is of particular importance in this endeavor, as stigma and its manifestations depend on the specific conditions of the target population and across cultures and settings. Evidence on effective approaches to reduce stigma is sparse and lacking from Central and Eastern Europe, including from the Czech Republic. OBJECTIVE: Our aim was to inform an anti-stigma campaign undertaken in the framework of the national mental health reform in the Czech Republic. METHODS: We conducted a qualitative study based on semi-structured in depth interviews with relatives of patients diagnosed with schizophrenia in the Czech Republic. Initial respondents were identified through local mental health services and users' organizations with a consecutive chain-referral sampling. Transcribed narratives were thematically analyzed within a pre-developed four level thematic framework to comprehensively identify experiences of stigma and discrimination in all areas of the respondents' lives. RESULTS: Stigma experiences of 25 diverse family members of persons living with schizophrenia spanned four levels of respondents' lives (macro-, meso-, micro-, and intro level). The overarching issues were: (1) general lack of understanding and misconceptions about mental illness; (2) structural discrimination and paucity of governmental and public support system; (3) burden of "pervasive and unlimited" care and inability of independent living. CONCLUSIONS: We identified several features of mental health related stigma and the ensuing discrimination in Czech Republic experienced by persons with severe mental illness and their relatives. We developed a set of recommendations for policy-makers aimed at reducing ignorance and prejudice amongst the public and professionals, improving health and social services-including employment, housing and community integration-and the provision of family support. PMID- 30029092 TI - How does psychiatric diagnosis affect young people's self-concept and social identity? A systematic review and synthesis of the qualitative literature. AB - Receiving a psychiatric diagnosis in childhood or adolescence can have numerous social, emotional and practical repercussions. Among the most important of these are the implications for a young person's self-concept and social identity. To ensure diagnoses are communicated and managed in a way that optimally benefits mental health trajectories, understanding young people's first-hand experience of living with a diagnosis is paramount. This systematic review collates, evaluates and synthesises the qualitative research that has explored how psychiatric diagnosis interacts with young people's self-concept and social identity. A search of 10 electronic databases identified 3892 citations, 38 of which met inclusion criteria. The 38 studies were generally evaluated as moderate-to-high quality research. Thematic synthesis of their findings highlighted the multifaceted ways diagnosis affects young people's self-concept and social identity. Diagnosis can sometimes threaten and devalue young people's self concept, but can also facilitate self-understanding, self-legitimation and self enhancement. A diagnosis can lead to social alienation, invalidation and stigmatisation, yet can also promote social identification and acceptance. Further research is needed to clarify which self and identity outcomes can be expected in a given set of circumstances, and to establish how self and identity effects interact with diagnoses' other clinical, practical, social and emotional consequences. PMID- 30029093 TI - Physical frailty and cognitive status over-60 age populations: A systematic review with meta-analysis. AB - The aim of this meta-analysis was to analyse the magnitude of the effect-size of the cognitive status of populations over 60 years of age, when comparing nonfrail versus pre-frail and nonfrail versus frail subgroups. A systematic review of prospective studies published from 2000 to 2017 was completed in Medline, B-on, Ebsco, Ebsco Health, Scielo, ERIC, LILACS and Sport discus databases and observational, cohort and cross-sectional studies were selected. The Mini-Mental State Examination to screening cognitive status and the Fried phenotype for assess physical frailty state was used as clinical outcomes. After applying additional search criteria, 14 manuscripts (26,798 old participants) were selected from an initial universe of 1681 identified. When comparing the scores of cognitive status of the participants who were non-frail (n = 12,729, 47.4%) versus pre-frail (n = 11,559, 43.2%) and non-frail versus frail (n = 2452, 9.4%) subgroups, significant statistical differences were found for both comparisons (M +/- SD = 0.60, 95%CI: 0.50-0.62, p < 0.001 and M +/- SD = 3.43, 95%CI: 2.26-4.60, p < 0.001, respectively). It is clear that poor cognitive function is strongly closed associated with pre-frailty and frailty subgroups in older populations around the world. PMID- 30029094 TI - Linearity check of an ionisation chamber through 99 mTc half-life measurements. AB - The half-life of 99 mTc was measured at the JRC using the ionisation chamber 'IC1' (type Centronic IG12). The result, T1/2(99 mTc) = 6.00660 (18) h, is in good agreement with literature data. One experiment was performed in IC1's default set-up with the ionisation current being integrated over an air capacitor and read out as a voltage increase over time. This ensured excellent linearity and precision throughout the dynamic range, but the maximum current was limited to 2 nA. In a second test, the current was directly read out with a Keithley 6517 A electrometer. Applying correction factors for the automatic range switching of the electrometer, an acceptable linearity was demonstrated over a range of 12 half-life periods starting at 20 nA. Range switching and autocorrelation of the current readout increase the systematic and random error propagation factors. Piecewise fitting of the decay curve over periods of 6 h yields the same 99 mTc half-life value within 0.04% (0.0025 h) standard deviation over an activity range spanning at least 10 half-life periods (3 orders of magnitude). PMID- 30029095 TI - Electron shuttles enhance the degradation of sulfamethoxazole coupled with Fe(III) reduction by Shewanella oneidensis MR-1. AB - The ability of anthraquinone-2,6-disulfonate (AQDS) and riboflavin to enhance the sulfamethoxazole (SMX) degradation coupled with the Fe(III) reduction by Shewanella oneidensis MR-1 was investigated. The results indicated that the SMX degradation rate was 38.5% with an initial SMX concentration at 0.04 mM. For the overall performance of AQDS and riboflavin mediated SMX degradation and iron reduction, the SMX degradation rate was gradually increased with the enhancement of iron reduction. Riboflavin had a stronger enhancement on SMX degradation and iron reduction than AQDS, but the enhancement was not positively correlated with electron shuttles concentration. A quantitative characterization of the electron transfer capacity (ETC) of the electron shuttles showed that the ETC was higher for riboflavin than AQDS. The S. oneidensis MR-1 16S rRNA gene copies results indicated that electron shuttles had a positive effect on the microbial activity of S. oneidensis MR-1. The LCMS result indicated that the products of the SMX biodegradation were 3-amino-5-methylisoxazole and 4-aminobenzenesulfonic acid, which suggested that the SMX biodegradation was caused by SN bond cleavage. This study indicates that the biochemical mechanisms play a vital role in SMX transformation and Fe(II) generation in this system. PMID- 30029097 TI - Women and girls in resource poor countries experience much greater exposure to household air pollutants than men: Results from Uganda and Ethiopia. AB - Household Air Pollution (HAP) from burning biomass fuels is a major cause of mortality and morbidity in low-income settings worldwide. Little is known about the differences in objective personal HAP exposure by age and gender. We measured personal exposure to HAP across six groups defined by age and gender (young children, young males, young females, adult males, adult females, and elderly) in rural households in two sub-Saharan African countries. Data on 24-hour personal exposure to HAP were collected from 215 participants from 85 households in Uganda and Ethiopia. HAP exposure was assessed by measuring carbon monoxide (CO) and/or fine particulate matter (PM2.5) concentrations using five types of devices. 24 h PM2.5 personal exposure was highest among adult females with Geometric Mean (GM) and Geometric Standard Deviation (GSD) concentrations of 205 MUg/m3 (1.67) in Ethiopia; 177 MUg/m3 (1.61 GSD) in Uganda. The lowest PM2.5 exposures were recorded among young males GM (GSD) 30.2 MUg/m3 (1.89) in Ethiopia; 26.3 MUg/m3 (1.48) in Uganda. Young females had exposures about two-thirds of the adult female group. Adult males, young children and the elderly experienced lower exposures reflecting their limited involvement in cooking. There was a similar pattern of exposure by age and gender in both countries and when assessed by CO measurement. There are substantial differences in exposure to HAP depending on age and gender in sub-Saharan Africa rural households reflecting differences in household cooking activity and time spent indoors. Future work should consider these differences when implementing exposure reduction interventions. There was a strong agreement between optical and gravimetric devices measurements although optical devices tended to overestimate exposure. There is need to calibrate optical devices against a gravimetric standard prior to quantifying exposure. PMID- 30029096 TI - Maternal intake of pesticide residues from fruits and vegetables in relation to fetal growth. AB - OBJECTIVES: To examine the associations of maternal intake of fruits and vegetables (FVs), considering pesticide residue levels, with fetal growth. METHODS: We studied 1777 mothers (1275 white, 502 non-white) and their infants from Project Viva, a prospective pre-birth cohort (1999-2002). We categorized FVs as containing high or low pesticide residues using data from the US Department of Agriculture. We then used a food frequency questionnaire to estimate each participant's intake of high and low pesticide residue FVs in the first and second trimester. The primary outcomes were small-for-gestational-age (SGA; <10th percentile in birth-weight-for-gestational-age), large-for-gestational-age (LGA; >=10th percentile in birth-weight-for-gestational-age) and preterm birth (gestational age <37 weeks). We also evaluated whether the associations between high pesticide residue FV intake and birth outcomes were modified by race/ethnicity. RESULTS: 5.5% of newborns were SGA, 13.7% were LGA, and 7.3% were preterm. Intakes of high or low pesticide residue FVs, regardless of pregnancy trimester, were not associated with risks of SGA, LGA, or preterm birth. In addition, the associations of high pesticide FV intake with SGA and LGA were not modified by race/ethnicity. However, we observed heterogeneity in the relationship between first trimester high pesticide FV intake and risk of preterm birth by race/ethnicity (P value for interaction = 0.01), although this relationship did not persist after correction for multiple comparisons (Bonferroni corrected level of significance: P < 2.8 * 10-3). CONCLUSIONS: There were no clear associations between high or low pesticide FV intake during pregnancy with SGA, LGA or preterm birth. PMID- 30029098 TI - Fluorescent activatable gadofullerene nanoprobes as NIR-MR dual-modal in vivo imaging contrast agent. AB - Dual mode imaging technology is widely developed to achieve the early-stage precision cancer diagnosis. Here we designed a dual-modal magnetic resonance/near infrared fluorescence optical imaging contrast agent (GdF-SS-NIR783) with the fluorescence activatable and safer gadofullerene. The nanoprobes were fabricated by conjugating the gadofullerene derivatives with a NIR fluorescence imaging agent (NIR783) via the disulfide bond. The obtained nanoprobes showed no fluorescence (OFF), but the fluorescence turned on when incubated within reduction environment such as GSH solution. The clear fluorescence signal in tumor site was observed obviously after their intratumor injection. The nanoprobes also revealed efficient MRI contrast enhancement both in vitro and in vivo. And they showed good biocompatibility and did not demonstrate any tissue toxicity in vivo. This work gave the new possibility in designing more efficient and safer nanoprobes for future medical diagnoses. PMID- 30029099 TI - Plasma high density lipoproteins: Therapeutic targeting and links to atherogenic inflammation. AB - Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis. Human genetic deficiency of CETP caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial. However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD. PMID- 30029100 TI - The effect of biotic and abiotic environmental factors on Pd(II) adsorption and reduction by Bacillus wiedmannii MSM. AB - In this paper, we found a bacteria (Bacillus wiedmannii MSM) that could not only culture quickly under aerobic condition, but also can biological reduction of Pd (II) under both aerobic and anaerobic conditions. For reducing Pd (II) by Bacillus wiedmannii MSM, the best electron donor was sodium formate and the best growth time was 24 h (mid-log growth phase cells). TEM indicated that a lot of palladium nanoparticles (Pd-NPs) were mainly located in the periplasmic space of the live cells. However, the autoclaved cells could not synthesize Pd-NPs, which proved the role of enzyme in the reduction of Pd (II). A few of Pd-NPs were only formed on the surface of Cu2+-treated cells, which proved the main but not the only role of periplasmic hydrogenase in the reduction of Pd (II). XRD and XPS also proved that Pd-NPs could be synthesized by live cells over broad ranges of temperature (20-40 degrees C) and pH (pH 3.0-7.0). This may be especially useful for in situ reduction and remediation of Pd (II) for both anaerobic and aerobic wastewater. PMID- 30029101 TI - Bioaccumulation of heavy metals in fish, crustaceans, molluscs and echinoderms from the Tuscany coast. AB - The concentration of As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were analyzed in the edible part of several species of fish, crustaceans, molluscs and echinoderms collected in sensitive areas of the Tuscany coast (northern Italy). The concentration of As (0.39-78.1 MUg g-1) and Hg (0.01-1.56 MUg g-1) resulted in most cases higher than reference thresholds. Target hazard quotient (THQ) and lifetime cancer risk (TR) indexes were calculated to assess cancer and non-cancer risk due to oral exposure; the highest THQ values referred to As and Hg, with values >= 1 in 39% and 48% of cases, respectively. Total target hazard quotients (TTHQ) values suggested that the local population could experience adverse health effects due to consumption of local seafood, mainly of demersal and benthic species. Cancer risk was mainly associated with As exposure, and with Cd intake, especially through molluscs consumption. The NMDS model highlighted species specific bioaccumulation processes and specific sensitivity of species to different bioavailable heavy metals. Specifically, Mullus spp. and Scorpaena porcus preferentially accumulate Hg and Cr, Octopus vulgaris specimens were discriminated by the presence of Pb and Zn, while an evident preference for Cd and Cu was recorded in Squilla mantis. In addition, the distribution of heavy metals in organisms revealed sound differences between Follonica and Livorno sampling sites, demonstrating a highly heterogeneous anthropogenic impact in terms of heavy metals input from the industrial activity resting on land. PMID- 30029102 TI - Effect of inoculation with arbuscular mycorrhizal fungi and blanching on the bioaccessibility of heavy metals in water spinach (Ipomoea aquatica Forsk.). AB - A plant's tolerance to heavy metals (HMs) and its detoxification mechanisms are associated with the subcellular distribution of HMs and their chemical forms. In this study, water spinach (Ipomoea aquatica Forsk.) was grown in two soils contaminated with a single HM (cadmium, Cd) or combined HMs (Cd and nickel, Ni). Inoculation of arbuscular mycorrizal fungi (AMF) was conducted to increase the accumulation of phosphorus (P) in plants. One major exception was to decrease the migration and accumulation of HMs in edible parts by the formation of P-HM complexes. The effects of blanching and simulated digestion on bioaccessibility were also assessed. The experimental results showed that the water spinach species used in this study had a high capacity to accumulate HMs. AMF treatment improved water spinach growth and decreased the accumulation of Ni but not that of Cd. Soluble and inorganic Cd and Ni were the major subcellular fractions and chemical forms in water spinach; these two HMs also exhibited higher migration capacities in comparison to chromium (Cr). Relative to raw tissues, 45-84% of Cd, Cr, and Ni were leached after blanching. Approximately 32-55%, 16-50%, and 27-40% of Cd, Cr, and Ni, respectively, were bioaccessible and could be metabolized by in vitro digestive fluids. PMID- 30029103 TI - Low-temperature construction of MoS2 quantum dots/ZnO spheres and their photocatalytic activity under natural sunlight. AB - Zinc oxide (ZnO) nanophotocatalyst is a promising candidate for degrading organic pollutants but has an extremely low photocatalytic activity under nature sunlight. In this work, flower-like MoS2 quantum dots/ZnO (MQ/ZnO) nanospheres with the size of approximately 1.26 MUm are prepared at low temperature. The resultant flower-like MQ/ZnO nanospheres displayed higher photocatalytic activity than pure ZnO nanospheres under natural sunlight and without stirring, with the decomposition rate of the MQ/ZnO composites approximately 3.3 times higher than that of the pure ZnO nanospheres. Furthermore, the introduction of MoS2 QDs endowed ZnO nanospheres with optical memory ability. The enhanced sunlight-driven photocatalytic activity is dependent on the unique electrical properties of MoS2 QDs and the synergistic effect between ZnO and MoS2 QDs. PMID- 30029104 TI - Life Cycle Assessment of a shale gas exploration and exploitation project in the province of Burgos, Spain. AB - Natural gas (NG) from shale formations (or shale gas) is an unconventional energy resource whose potential environmental impacts are still not adequately assessed. Hence, this study performs a Life Cycle Assessment (LCA) of shale gas considering a gas well under appraisal in Burgos, Spain. An attributional model was developed, considering the NG pre-production and production phases in the system boundaries, considering 1 MJ of processed NG as a functional unit. Results were obtained through the CML-IA baseline method (developed by the Center of Environmental Science of Leiden University) and showed that well design, drilling and casing, hydraulic fracturing, NG production, gathering, and processing are critical processes. To better address the environmental impacts, a comparison with similar studies was carried out, as well as a sensitivity and an uncertainty analysis using Monte Carlo simulation (MCS). The model was found to be particularly sensitive to water usage in hydraulic fracturing and to the number of workovers with hydraulic fracturing. Limited data availability for shale gas exploration still poses a challenge for an accurate LCA. Even though shale gas remains controversial, it still can be considered as a strategic energy resource, requiring a precautionary approach when considering its exploitation and exploration. PMID- 30029105 TI - Accumulation and exposure assessment of persistent chlorinated and fluorinated contaminants in Korean birds. AB - To date, information is scarce on the accumulation and potential risks of persistent chlorinated and fluorinated contaminants in birds. In this study, organohalogen contaminants (OHCs), such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and perfluoroalkyl substances (PFASs), were measured in the liver tissues of 10 bird species (n = 69) from Korea. Among the OHCs, PFASs showed the highest concentration, ranging from 5.40 to 11,300 (median: 294) ng/g wet weight. The median concentrations of OCPs and PCBs in all the bird samples were 147 and 81.9 ng/g lipid weight, respectively. The maximum concentration of perfluorooctane sulfonate (PFOS) observed in our bird samples was highest reported so far. Concentrations of OHCs in predatory birds were significantly greater than those measured in non-predatory birds, indicating the importance of diet and trophic position for bioaccumulation of these contaminants. In addition, different accumulation patterns of OHCs were found between predatory and non-predatory birds. Significant correlations were found between organochlorine concentrations and stable nitrogen isotope ratio (delta15N) measurements, whereas no correlation was found between PFASs and delta15N. Although the concentrations of PCBs and DDTs in birds were lower than the threshold levels, 25% and 49% of birds exceeded the toxicity reference value and predicted no effect concentration for PFOS, respectively, implying potential health risks to Korean birds. PMID- 30029107 TI - Assessment of heavy metal contamination, distribution and source identification in the sediments from the Zijiang River, China. AB - In this study, the contents of 10 heavy metals (Sb, Cd, Cr, Mn, Co, Ni, Cu, Zn, As, and Pb) in 49 sediment samples from the Zijiang River were determined by using inductively coupled plasma-optical emission spectrometry. Contamination indexes including geoaccumulation index, modified degree of contamination, sediment quality guidelines, potential ecological risk index, together with potential ecological risk factor were used to assess heavy metal contamination in the sediments of the Zijiang River. Pearson's correlation analysis and principal component analysis were used to identify the sources of heavy metals. The results indicated that the mean values of heavy metals in the Zijiang River's sediments were found to be significantly higher than the corresponding background values. But when comparing with that in other rivers in the world, they were at medium levels except for Sb. Furthermore, a comparison of the heavy metal concentrations and the consensus-based sediment quality guidelines showed that the heavy metal pollutions (Cd, Cr, Ni, Cu, Zn, As, and Pb) tended to occasionally pose harmful impacts on the ecosystem. The values of contamination indexes revealed that serious heavy metal contamination and relatively high potential ecological risks were mainly existed in the downstream of antimony mining and smelting factories (S23-S49). In addition, high potential ecological risks of Sb were observed in sampling sites that were close to those factories (S23, S24, S25, and S27), and high potential ecological risks of Cd were observed in the downstream (S37-S49). Basing on the Pearson's correlation analysis and principal component analysis, three main sources were identified. Co, Zn, Cd, and Cu contaminants were mainly derived from agricultural activities; As, Sb, Mn, and Pb mainly came from mining and smelting activities; Cr and Ni were mainly from natural sources. PMID- 30029106 TI - Simulation of a hydraulic fracturing wastewater surface spill on agricultural soil. AB - Hydraulic fracturing wastewaters (HFWWs) contain synthetic organic components and metal ions derived from the formation waters. The risk of spills of HFWW that could impact soil quality and water resources is of great concern. The ability of synthetic components, such as surfactants, in HFWW to be transported through soil and to mobilize metals in soil was examined using column experiments. A spill of HFWW was simulated in bench scale soil column experiments that used an agricultural soil and simulated seven 10-year rain events representing a total of one year's worth of precipitation for Weld County, Colorado. Although no surfactants or their transformation products were found in leachate samples, copper, lead, and iron were mobilized at environmentally relevant concentrations. In general, after the initial spill event, metal concentrations increased until the fourth rain event before decreasing. Results from this study suggest that transport of metals was caused by the high concentrations of salts present in HFWW. This is the first study utilizing authentic HFWWs to investigate the transport of surfactants and their effect on metal mobilization. Importantly, a significant decrease in the water infiltration rate of the soil was observed, leading to the point where water was unable to percolate through due to increasing salinity, potentially having a severe impact on crop production. PMID- 30029108 TI - Optimization of flocculation conditions for soluble cadmium removal using the composite flocculant of green anion polyacrylamide and PAC by response surface methodology. AB - In this work, we describe a flocculation performance evaluation of a novel anionic polyacrylamide (APAM) synthesized using low dose gamma-ray initiation. The APAM structure and morphology were characterized using Fourier transform infrared spectroscopy (FTIR), High performance liquid chromatography (HPLC), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) techniques. In comparison to commercially purchased APAM (Mw = 1.0 * 107), gamma ray initiation was demonstrated to be a more effective method to increase molecular weight, decrease the residual acrylamide monomer, and improve thermal stability. Flocculant performance was evaluated by assessing their ability to remove Cd(II) from water. We utilized the Plackett-Burman (PB), steepest ascent, and response surface methodology (RSM) experimental design to identify the optimal flocculating conditions for the removal of soluble Cd(II). Under optimal conditions [26.84 mg L-1 CaO, 71.28 mg L-1 polyaluminium chloride (PAC) and 2.87 mg L-1 APAM], the maximum percent removal of Cd(II) was observed to reach 93.65%. A potential flocculation mechanism for the Cd(II) removal from water was further studied by evaluating the colloid Zeta potential. Results from these studies demonstrated that PAC had a greater capability to change the Zeta potential of collide under alkaline conditions, while APAM played a critical role in the bridging, enmeshment, and sweeping effect. The composite of two types of predominance makes considerable sense in regards to enhancing flocculating efficiency, decreasing secondary pollution, and reducing flocculant cost. PMID- 30029109 TI - Monitoring of classical, oxidized, and heteroatomic naphthenic acids species in oil sands process water and groundwater from the active oil sands operation area. AB - The classical, oxidized, and heteroatomic naphthenic acids (NAs) species were monitored in the oil sands process water (OSPW) and groundwater from the active oil sands operation area, using solid phase extraction sample preparation and high resolution mass spectrometry analysis. Groundwater samples include Pleistocene channel aquifer groundwater (PLCA) and oil sands basal aquifer groundwater (OSBA) from different depth of underground. The concentrations of Ox NAs decreased from OSPW to PLCA, and then increased from PLCA to OSBA, which is deeper than PLCA. The NAs in PLCA mainly comprised of Ox-NAs and N-NAs and the percentage of S-NAs was negligible. Results revealed relative abundances of individual NA species in total NAs varies among different water layers and the potential environmental impacts are expected to be variable. Principal component analysis results of O2-NAs or O4-NAs could be used for differentiation of water types. O2-NAs with n = 12-16 and |Z| = 4-6, and O4-NAs with n = 14-20 and |Z| = 6 8, were identified as marker compounds that could serve as surrogates of the larger complex NA mixture for source differentiation. This work utilized a combination of sample preparation, instrumental analysis, and statistical analysis methods to obtain knowledge of the occurrence, composition, and transfer of NAs in the groundwater of the Alberta oil sands operation area. PMID- 30029110 TI - Unravelling long-term source removal effects and chlorinated methanes natural attenuation processes by C and Cl stable isotopic patterns at a complex field site. AB - The effects of contaminant sources removal in 2005 (i.e. barrels, tank, pit and wastewater pipe sources) on carbon tetrachloride (CT) and chloroform (CF) concentration in groundwater were assessed at several areas of a fractured multi contaminant aquifer (Odena, Spain) over a long-term period (2010-2014). Changes in redox conditions, in these chlorinated methanes (CMs) concentration and in their carbon isotopic compositions (delta13C) were monitored in multilevel wells. delta13C values from these wells were compared to those obtained from sources (barrels, tank and pit before their removal, 2002-2005) and to commercial solvents values in literature. Additionally, CMs natural attenuation processes were identified by C-Cl isotope slopes (Lambda). Analyses revealed the downstream migration of the pollutant focus and an efficient removal of DNAPLs in the pit source's influence area. However, the removal of the contaminated soil from former tank and wastewater pipe was incomplete as leaching from unsaturated zone was proved, evidencing these areas are still active sources. Nevertheless, significant CMs degradation was detected close to all sources and Lambda values pointed to different reactions. For CT in the tank area, Lambda value fitted with hydrogenolysis pathway although other possible reduction processes were also uncovered. Near the wastewater pipe area, CT thiolytic reduction combined with hydrogenolysis was derived. The highest CT degradation extent accounted for these areas was 72 +/- 11% and 84 +/- 6%, respectively. For CF, the Lambda value in the pit source's area was consistent with oxidation and/or with transport of CF affected by alkaline hydrolysis from upstream interception trenches. In contrast, isotope data evidenced CF reduction in the tank and wastewater pipe influence areas, although the observed Lambda slightly deviates from the reference values, likely due to the continuous leaching of CF degraded in the non-saturated zone by a mechanism different from reduction. PMID- 30029111 TI - Silica - A trace geogenic element with emerging nephrotoxic potential. AB - Silica is a trace-geogenic compound with limited-bioavailability. It inflicts health-perils like pulmonary-silicosis and chronic kidney disease (CKD), when available via anthropogenic-disturbances. Amidst silica-imposed pathologies, pulmonary toxicological-mechanisms are well-described, ignoring the renal pathophysiological mechanisms. Hence, the present-study aimed to elucidate cellular-cum-molecular toxicological-mechanisms underlying silica-induced renal pathology in-vitro. Various toxicity-assessments were used to study effects of silica on the physiological-functions of HK-cells (human-kidney proximal-tubular cells - the toxin's prime target) on chronic (1-7 days) sub-toxic (80 mg/L) and toxic (100-120 mg/L) dosing. Results depicted that silica triggered dose-cum-time dependent cytotoxicity/cell-death (MTT-assay) that significantly increased on long-term dosing with >=100 mg/L silica; establishing the nephrotoxic-potential of this dose. Contrarily, insignificant cell-death on sub-toxic (80 mg/L) dosing was attributed to rapid intracellular toxin-clearance at lower-doses preventing toxic-effects. The proximal-tubular (HK-cells) cytotoxicity was found to be primarily mediated by silica-triggered incessant oxidative-stress (elevated ROS)..This enhanced ROS inflicted severe inflammation and subsequent fibrosis, evident from increased pro-inflammatory-cum-fibrogenic cytokines generation (IL 1beta, IL-2, IL-6, TNF-alpha and TGF-beta). Simultaneously, ROS induced persistent DNA-damage (Comet-assay) that stimulated G2/M arrest for p53-mediated damage-repair, aided by checkpoint-promoter (Chk1) activation and mitotic inducers (i.e. Cdc-25, Cdk1, cyclinB1) inhibition. However, DNA-injuries surpassed the cellular-repair, which provoked the p53-gene to induce mitochondrial-mediated apoptotic cell-death via activation of Bax, cytochrome-c and caspase-cascade (9/3). This persistent apoptotic cell-death and simultaneous incessant inflammation culminated in the development of tubular-atrophy and fibrosis, the major pathological-manifestations of CKD. These findings provided novel-insights into the pathological-mechanisms (cellular and molecular) of silica-induced CKD, inflicted on chronic toxic-dosing (>=100 mg/L).Thereby, encouraging the development of therapeutic-strategies (e.g. anti-oxidant treatment) for specific molecular-targets (e.g. ROS) to retard silica-induced CKD progression, for reduction in the global-CKD burden. PMID- 30029112 TI - Metals and elements in sardine and anchovy: Species specific differences and correlations with proximate composition and size. AB - Species - specific differences in the levels of 26 metals and elements in sardine and anchovy are investigated and the factors of proximate composition (proteins, lipids, ash) and body size (length, weight) that may affect the metal and elemental concentrations in fish are explored. Statistical analysis revealed that levels of metals and elements in fish seem to strongly depend on species. Significantly higher levels of most of the metals and elements studied have been observed in anchovy compared to sardine at each of six different sites. The observed species-specific differences in metal content could be attributed to different proximate composition and size among other factors. The significant (positive or negative) correlations found between lipids, proteins, ash, weight, length and metals or elements, suggest that higher levels of most of the metals and elements studied can be associated with lower lipid content, greater protein and ash content and smaller size. PMID- 30029113 TI - Climate-driven synchrony in growth-increment chronologies of fish from the world's largest high-elevation river. AB - Understanding how sensitive aquatic ecosystems respond to climate change is essential for effective biodiversity conservation and management. The Tibetan Plateau (TP) is one of the most globally sensitive areas to climate change with potentially serious implications for resident fish populations and aquatic food webs. However, how the growth of TP fish responds to climate change, and how this response varies with the trophic level of different species remain unknown. We established growth-increment chronologies of two important Schizothoracinae fishes that are endemic to the TP (e.g., the omnivorous Schizopygopsis younghusbandi and the carnivorous Oxygymnocypris stewartii) from the Yarlung Tsangpo River, using otolith increment width measurements and dendrochronological methods. These growth chronologies were correlated with key indicators of environmental variation (temperature, precipitation, and river discharge) to examine the potential effects of climate change. The two chronologies displayed synchronous responses to recent climate change. In this glacial-fed river, the growth of both fish species was significantly and negatively correlated with the mean annual air temperature, while it was positively but not significantly correlated with precipitation and discharge. The higher trophic level species O. stewartii was more sensitive to climate than was the lower trophic level species S. younghusbandi, with temperature variables explaining a higher proportion of growth variability in O. stewartii (64.6%) than in S. younghusbandi (46.4%). The results collectively indicate that both species are highly sensitive to climate change, which may affect fish growth by altering water environment, fish physiological fitness and food availability. This study provides further empirical evidence of the utility of growth-increment chronologies for investigating the effects of climate change on aquatic ecosystems across different basins and water body types of the TP. These findings can inform conservation and management actions related to addressing climate change on the TP and other high-elevation temperate systems found worldwide. PMID- 30029114 TI - Activated charcoal as a capture material for silver nanoparticles in environmental water samples. AB - Silver nanoparticles (AgNPs), due to their antibacterial activity, have been incorporated into numerous consumer products. Their environmental impact however, is currently unclear. Uncertainties surround the concentration, fate, and effects of AgNPs in aquatic environments. This study examined the suitability of activated charcoal as a capture material for AgNPs from water. Samples of 100 ppb AgNPs were initially generated and exposed to activated charcoal for 24 h to examine the ability of charcoal to capture AgNPs. The decrease in Ag concentration was measured using ICP-MS. Following initial investigations, the surface area of the charcoal was increased firstly with a pestle and mortar and secondly by milling the charcoal using a ball mill. The increased surface area of the milled charcoal increased the capture of the AgNPs from 11.9% to 63.6% for the 100 ppb samples. Further investigations were carried out examining the effect on the capture of AgNP concentration (with concentration ranging from 10 to 100 ppb), particle coating and the effect of exposure time to the activated charcoal. The capture of AgNP increased with decreasing concentration. A hydrochloric acid (HCl) leaching procedure was also developed which successfully removed the captured silver allowing the fraction captured by the charcoal to be quantified with an average of 94.8% recovery. The results show that milled activated charcoal, can successfully capture AgNPs from water samples, and that therefore, activated charcoal may prove to be a cost effective material for the remediation of waters impacted by AgNP or other nano-wastes. PMID- 30029115 TI - Perigestational exposure to low doses of PBDE-47 induces excessive ER stress, defective autophagy and the resultant apoptosis contributing to maternal thyroid toxicity. AB - Brominated flame retardant 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is known to induce developmental neurotoxicity by disturbing thyroid hormones (THs). Evidence shows that maternal THs are crucial for brain development and growth of fetuses and infants. However, little is known about the effects of PBDE-47 on maternal thyroid status and its mode of action. Here, using female Sprague-Dawley rats orally exposed to low doses of PBDE-47 (0.1, 1.0, 10 mg/kg/day) from pre pregnancy until weaning of offspring to mimic human exposure, we show that perigestational exposure to PBDE-47 elevated serum triiodothyronine and thyroxine levels in mother rats. This is accompanied by disrupted thyroid follicle structure including expanded follicles, hyperplastic epithelial cells and shed cell remnants filled in the exhausted follicular lumen. Mechanistically, PBDE-47 enhanced apoptosis in thyroid tissue, as demonstrated by Caspase-3 activation, PARP cleavage and DNA fragmentation. Further study identified that PBDE-47 upregulated the levels of GRP78, ATF4, active Caspase-12 and CHOP, suggesting endoplasmic reticulum (ER) stress and unfolded protein response activation. Moreover, PBDE-47 reduced the levels of LC3-II, an autophagy marker protein essential for the autophagosomes formation, while increased the autophagy substrate p62 accumulation, indicating autophagy defect. Importantly, the colocalization of apoptotic cells with CHOP, a key mediator of ER stress-induced apoptosis, or p62, uncovered the contribution of excessive ER stress and defective autophagy to apoptosis. Collectively, our results suggest that excessive ER stress, defective autophagy and the resultant apoptosis are implicated in maternal thyroid injury following perigestational PBDE-47 exposure, which offers insight into a better understanding of PBDE-47-induced maternal thyroid toxicity. PMID- 30029116 TI - Towards a better understanding of the aggregation mechanisms of iron (hydr)oxide nanoparticles interacting with extracellular polymeric substances: Role of pH and electrolyte solution. AB - Extracellular polymeric substances (EPS) are ubiquitous in the soil and water environment and interact strongly with mineral surfaces. However, these interactions and their impacts on the behavior and fate of minerals remain poorly understood. Here, for a better understanding of the colloidal stability of minerals in the environment, we investigated the aggregation of goethite (alpha FeOOH) nanoparticles (NPs) in the presence of EPS from Bacillus subtilis under different environmental conditions (pH, ionic strength and ionic valence). Results showed that the aggregation processes of goethite NPs are determined by the solution chemistry, and the colloidal stability of goethite NPs is strongly influenced by the addition of EPS. In the absence of ionic strength, the addition of EPS promotes the aggregation of goethite NPs only when the pH (pH = 6) is less than the point of zero charge for the goethite nanoparticles (pHpzc ~ 8). In the presence of ionic strength, the aggregation rate of goethite NPs increases with increasing concentration of NaCl, NaNO3 and Na2SO4 solutions, and after the addition of EPS solution, the critical coagulation concentrations (CCC) of goethite NPs are increased from 43.0, 56.7 and 0.39 mM to 168.0, 304.9 and 126.2 mM in the three electrolyte solutions, indicating that the addition of EPS inhibits the aggregation of goethite NPs. While in Na3PO4 solution, when the concentration of Na3PO4 solution ranged from 0 to 1 mM, the aggregation rate of goethite NPs increases first, followed by a decrease, and with the concentration of Na3PO4 solution exceeding 1 mM, the aggregation rate of goethite NPs increases again, due to the charge screening by sodium counter ions. This study provides a fundamental understanding of the behavior of goethite NPs in natural soil and water environments. PMID- 30029118 TI - Occurrence of antibiotic residues and antibiotic-resistant bacteria in effluents of pharmaceutical manufacturers and other sources around Hanoi, Vietnam. AB - Pharmaceutical manufacturers in Vietnam are producing a wide variety of antibiotics for human and veterinary use. Consequently, the water discharged from those facilities can contain residues of antibiotics, which could have adverse impact on the environment. However, studies on the occurrence of antibiotics in the wastewater from pharmaceutical manufacturers in Vietnam are almost non existent. In this study, water samples were collected at around the outlets of four pharmaceutical manufacturing plants as well as from a hospital and an aquaculture farm around Hanoi in 2016 and 2017. Fifteen antibiotics from four major classes (beta-lactam, quinolones, macrolides, sulfonamides) were monitored, using a validated LC-MS/MS method, based on their number of registrations at the Ministry of Health. Ten antibiotics, ampicillin, cefuroxime, cefotaxime, clarithromycin, azithromycin, sulfamethoxazole, trimethoprim, ofloxacin, norfloxacin, and ciprofloxacin were detected in the samples at different concentrations. Notably, sulfonamides and quinolones were occasionally detected at very high concentration, such as sulfamethoxazole (252 MUg/L), trimethoprim (107 MUg/L), ofloxacin (85 MUg/L), and ciprofloxacin (41 MUg/L). In this study, concentrations of antibiotic residues in effluent of pharmaceutical plants were higher than those from other sources. The antibiotic-resistance tests indicated the widespread resistance to common antibiotics like quinolone and sulfonamides in the collected samples. This finding suggests that wastewater from pharmaceutical manufacturers could be an important source of antibiotics and antibiotic-resistant bacteria in the aquatic environment of Vietnam. PMID- 30029117 TI - Influence of new agromining cropping systems on soil bacterial diversity and the physico-chemical characteristics of an ultramafic soil. AB - Most of the research dedicated to agromining has focused on cultivating a single hyperaccumulator plant, although plant diversity has been shown to positively modify soil characteristics. Hence, we compared the effect of cropping a nickel hyperaccumulator Alyssum murale with a legume (Vicia sativa) to A. murale's mono culture, on the bacterial diversity and physico-chemical characteristics of an ultramafic soil. A pot experiment with 5 replicates was conducted in controlled conditions for 11 months. The treatments studied were: co-cropping and rotation vs. mineral fertilization controls and bare soil. The introduction of legumes induced a clearly positive effect on the soil's microbial biomass carbon and nitrogen. Arylsulfatase and urease activities tended to be enhanced in the co cropping and rotation treatments and to be lessened in the mineral fertilization treatments. However, beta-glucosidase and phosphatase activities were seen to decrease when legumes were used. Our results showed that the rotation treatment induced a higher organic matter content than the fertilized control did. Actinobacteria was the most-represented bacterial phyla and had lower relative abundance in treatments associating legumes. Conversely, the relative abundance of Acidobacteria and Gemmatimonadetes phyla increased but not significantly in treatments with legumes. The relative abundance of Chloroflexi phylum was shown to be significantly higher for the fertilized rotation control. The relative abundance of beta-Proteobacteria subphylum increased but not significantly in treatments with legumes. NMDS analysis showed a clear separation between planted treatments and bare soil and between co-cropping and rotation and fertilized controls. Shannon index showed reduction in microbial diversity that was mainly due to chemical inputs in the soil. This study showed that these new cropping systems influenced both the bacterial diversity and the physico-chemical characteristics of an ultramafic soil. In addition, this study provides evidence that mineral fertilization can negatively impact bacterial communities and some of their functions linked to biogeochemical cycles. PMID- 30029119 TI - Airborne bacteria and persistent organic pollutants associated with an intense Saharan dust event in the Central Mediterranean. AB - In this paper, we present a comprehensive taxonomic survey of the bacterial community and accurate quantification of polycyclic aromatic hydrocarbons (PAHs) associated with an intense Saharan dust advection, which impacted Central Mediterranean area in the whole 2014-2015 period. This work is part of an intensive field campaign at the EMEP regional background site of Monte Martano (Central Italy), considered well representative of long-range transport in the Central Mediterranean area. 22 samples have been characterized in their provenance region and have been considered for the chemical and biological characterization. The event described in the present paper was exceptionally intense at the sampling site allowing a detailed evaluation of the dust load on a regional scale, an estimation of the impact of PAH based on the Toxic Equivalency Factor methodology and a thorough characterization of the airborne bacterial fraction performed by High Throughput Sequencing approach. Afterward, we cultured viable bacteria and evaluated several enzymatic activities and conducted UV survival tests. Principal findings include: (i) the striking evidence that, during the Saharan dust event, a highly diverse and abundant bacterial community was associated with PAH concentrations higher than the yearly mean; (ii) the tangible presence of cultivable microbes; (iii) the proof that the isolates recovered from Saharan dust had the potential to be metabolically active and that almost all of them were able to persist following UV radiation exposure. Comparisons of results for the present case study with mean values for the 2014 2015 experimental campaign are presented. The bacterial community and chemical speciation associated with the Saharan dust advection were specific and very different from those associated with other air masses. The particular case of North-Western Atlantic, which represents one of the most typical advection route reaching the sampling site is discussed in detail. PMID- 30029120 TI - Natural resources and climate change: A study of the potential impact on Manila clam in the Venice lagoon. AB - A crucial aspect in climate change is to understand how an ecosystem will adapt under different environmental conditions and how it will influence the ecological resources and the connected human activities. In this study, a numerical model reproduces the growth dynamics, dispersion and settlement of clam's larvae in the Venice lagoon. On the basis of the last IPCC scenarios for the years 2050 and 2100, the model simulates the changes in larval settlement, showing how the geographical distribution and, consequently, the nursery area changes over time. Our results indicate that climate change will modify, not only the timing of the settlements (from spring-summer to winter autumn) and the spatial distribution of nursery areas (from central to southern lagoon), but also the absolute quantity of settled larvae in the lagoon. This can strongly affect aquaculture in terms of availability of seed and farming practice. Given that these changes are due to the variations in temperature and circulation, similar processes are likely to happen in other transitional environments all over the world affecting the global aquaculture resources. In this regard, the tool we developed could support local policymakers in the knowledge-based planning and sustainable management of clam aquaculture in vulnerable environments. PMID- 30029121 TI - Response of vegetation to water balance conditions at different time scales across the karst area of southwestern China-A remote sensing approach. AB - This work identifies the vegetation communities, landform types and seasons in which vegetation is most sensitive to water imbalance in the karst area of southwestern China. The normalized difference vegetation index (NDVI) and standardized precipitation and evapotranspiration index (SPEI) were used to evaluate the effects of water balance conditions on vegetation in different seasons and at different time scales. During the growing seasons from 1982 to 2013, the vegetation growth in 79% of the study area was statistically significantly sensitive to the water balance condition (p < 0.05). The vegetation in the spring and autumn responded more visibly to water imbalances. The SPEI over the last 6 months was statistically significantly correlated with the monthly maximum NDVI during the growing season over the larger areas compared with the SPEI over other time periods. Therefore, the vegetation was most likely sensitive to six months of water imbalance in this area. Among the selected vegetation types, the shrubland and sparse woodland were the most sensitive to water imbalances, whereas grasslands and forests were less sensitive. The maximum correlation coefficient between the NDVI and SPEI for each karst landform type was statistically significantly different (p < 0.01). The vegetation in the peak cluster depressions was the most sensitive to water imbalances, whereas the vegetation in the middle and high karst mountains was the least sensitive to water imbalances. Overall, although the climate of the karst region of southwestern China is humid and subtropical, the vegetation is still vulnerable to water imbalances in particular regions and soils. PMID- 30029122 TI - Arsenic removal mediated by acidic pH neutralization and iron precipitation in microbial fuel cells. PMID- 30029123 TI - Diffusive gradients in thin films based on MOF-derived porous carbon binding gel for in-situ measurement of antibiotics in waters. AB - Diffusive gradients in thin films (DGT) can achieve the time-weighted-average (TWA) concentrations of analytes in the period of deployment. Here we developed an approach based on DGT with a novel binding gel using porous carbon material (PCM) derived from metal-organic framework (MOF) for in-situ measurement of antibiotics in water samples. The diffusion coefficients of 20 antibiotics (nine sulfonamides, ten fluoroquinolones, and trimethoprim) in agarose diffusive gel were 1.41 * 10-6 cm2/s to 4.75 * 10-6 cm2/s at 25 degrees C. The capacity of PCM binding gel toward the antibiotics was ~100 MUg per gel disc. The masses of the antibiotics accumulated by PCM-based DGT increased linearly with time, and they were almost independent of pH (4.2-8.4) and ionic strength (1-500 mM). The performance of the novel DGT was evaluated using freshwater and synthetic seawater spiked with the antibiotics in laboratory. The results showed good agreement with the theoretical predications except sulfacetamide. The detection limits achieved by the DGT with three devices together for deploying up to seven days were 1.0-18.0 ng/L. Field deployment in municipal wastewater treatment plant effluent and seawater showed that the TWA concentrations of antibiotics were 3.8 1342.5 ng/L and 5.6-43.3 ng/L, respectively, which were comparable to those measured by grab sampling. The proposed DGT was an efficient tool for the measurement of antibiotics in environmental waters. PMID- 30029124 TI - Temporal variations in ambient particulate matter reduction associated short-term mortality risks in Guangzhou, China: A time-series analysis (2006-2016). AB - Numerous studies have reported associations between ambient particulate matter (PM) and daily mortality; however, little is known about temporal variations in ambient air pollution associated mortality risks, particularly in developing countries with limited long time-series air monitoring data. In present study, we assessed the associations and temporal relationships between ambient PM and daily mortality in Guangzhou, China, during 2006-2016. With this unique 11-year dataset, we related daily concentrations of PM with aerodynamic diameter < 2.5 MUm (PM2.5), between 2.5 and 10 MUm (PM10-2.5) and <10 MUm (PM10) to daily mortality in Guangzhou. We applied overdispersed Poisson regression with adjustment for time trend and potential confounding factors. Multiple level sensitivity analyses were conducted to examine the robustness of main results. Between 2006 and 2016, annual concentrations of PM2.5 decreased by 50.8% to 27.0 MUg/m3, of PM10-2.5 by 27.6% to 16.2 MUg/m3, and of PM10 by 44.1% to 43.3 MUg/m3 in Guangzhou. In this study, per 10 MUg/m3 increases in mean concentrations at current day and 6 prior days of death (lag06), we observed increases in total mortality risks of 0.55% (95% Confidence Interval (CI): 0.24%, 0.86%) for PM2.5, 0.99% (95%CI: 0.48%, 1.50%) for PM10-2.5, and 0.44% (95%CI: 0.22%, 0.65%) for PM10. Stronger associations were observed for ambient PM on cardio-respiratory mortality and people at age >= 65 years. Despite drastic reductions in annual PM levels, PM2.5 associated cardiovascular and respiratory mortality risks remained significant at 1.26% (95%CI: 0.19%, 2.35%) and 1.91% (95%CI: 0.25%, 3.60%) during 2014-2016. Further, PM2.5 and PM10 associated respiratory mortality risks showed increasing trend over time (p-value = 0.03 for PM2.5). In summary, though ambient PM levels decreased substantially in Guangzhou in recent years, PM2.5 and PM10 associated cardio-respiratory mortality risks remained significant and respiratory mortality risks even increased. Our findings provide strong rationale for continuation of ambient air pollution control effort for public health protection in the future. PMID- 30029125 TI - Fine particle attachment to quartz sand in the presence of multiple interacting dissolved components. AB - In natural aquatic systems water chemistry is complicated and fine particles encounter multiple water components simultaneously, yet the combined effects of some multiple components on the fate and transport of these particles have not been elucidated. In this study nTiO2 and illite colloid attachment to quartz sand was investigated in 1 mM NaCl and 0.5 mM CaCl2 background solutions using a range of phosphate concentrations (0 to 10 mg/L) at pH 5 and 9. The results obtained from the batch experiments indicated that without using phosphate, nTiO2 aggregation and attachment was strongly influenced by pH and Ca2+, both of which modified nTiO2 surface charges. nTiO2 attachment was high in CaCl2 solution at pH 9 due to attractive forces between nTiO2 and sand, as well as ripening. Furthermore, phosphate adsorption to nTiO2 was higher in CaCl2 solution at pH 9 than that at pH 5 due to attractive forces between nTiO2 and phosphate anions, and also potential surface precipitation of Ca-P minerals at pH 9. Phosphate adsorption to illite was low owing to strong repulsive forces between illite and phosphate. The effect of phosphate on nTiO2 and illite attachment to sand was influenced by pH and cation valency. A decreasing trend in nTiO2 attachment with phosphate addition was observed in NaCl solution at pH 5 and 9, and in CaCl2 solution at pH 5; however, in CaCl2 solution at pH 9, the surface charge of nTiO2 reversed from negative to positive and a substantial amount of nTiO2 attached to sand. Moreover, illite attachment to sand was much lower than that of nTiO2 under all the conditions tested in this study. These findings are important for understanding of the fate and transport of nTiO2 and illite colloids in natural aquatic systems where various anions and cations co-exist. PMID- 30029126 TI - Knowledge, attitude and practices of farmers about pesticide use, risks, and wastes; a cross-sectional study (Kermanshah, Iran). AB - This study was aimed to investigate the knowledge, attitude, and behavior of farmers about the pesticide use and wastes, and to determine the factors affecting the use of pesticides and their health effects, in agricultural lands located in Kermanshah province, western Iran. Three hundred eleven (311) farmers were included in this study, and filled a structured questionnaire containing questions about their basic information, their knowledge and attitude regarding pesticides, and their practices for pesticide disposal. In addition, the type and amount of pesticide consumption, and the health symptoms during the last year were recorded. Prevalence ratios and linear regression were used to evaluate the association between the different factors, and health symptoms and the amount of pesticide use, respectively. The majority of respondents had not been trained formally for the use of pesticides before. Approximately 10%, 45%, and 17% of pesticides contained highly hazardous, moderately hazardous, and slightly hazardous compounds, respectively. The farmers mainly had incorrect knowledge about pesticides and their risks, and used incorrect and high-risk methods for handling and application of pesticides and relevant wastes. Health symptoms were more associated with age >= 65, having no education, having income < 482 USD, not trained for pesticide use, and applying highly hazardous pesticides. In addition, the factors contributing to the amount of pesticide use included age, education level, and pesticide training. In order to reduce the amount of pesticide released to the environment, comprehensive training programs and implementing a waste management system could be effective. PMID- 30029127 TI - Syngas production from air-steam gasification of biomass with natural catalysts. AB - Biomass has a great potential for production of syngas and chemicals; however, it has stood in the shadow of natural gas (NG) and coal due to technical problems and issues such as tar formation. In this paper, syngas production from catalytic air-steam gasification of biomass in a fluidized bed was investigated. To enhance the yield of produced syngas and reduce its tar content by cracking, limestone, calcined dolomite, and olivine were used as catalyst. The maximum mole fraction of H2 was found to be 49.1 vol% at 1000 degrees C and a steam/biomass ratio (S/B) of 1.0 with dolomite present. Compared to olivine and dolomite, calcined dolomite was proved to be more effective for gas production and tar destruction. The results also showed that the particle size has a weak influence on gasifier performance, with only a slight decrease in tar content with decreasing biomass particle size. PMID- 30029128 TI - Nitrogen removal in pilot-scale partially saturated vertical wetlands with and without an internal source of carbon. AB - The aim was to evaluate and compare total nitrogen (TN) removal in pilot-scale partially saturated vertical wetlands (PSVWs) with and without an internal solid source of organic carbon (corncob) in order to distinguish the role of nitrification-denitrification and ANAMMOX in the removal process. The height of the free-drainage zone (FDZ) was 40 cm and the saturated zone (SZ) was 30 cm in system I (SI) and system II (SII) and 40 cm in system III (SIII) and system IV (SIV). In SII and SIV, approximately 30 kg of dry, 5 cm-length corncob was added. The systems were evaluated during two periods, that is, P1 and P2. Measurements of water quality parameters including BOD5, COD, organic nitrogen (Org-N), ammonium, nitrate and nitrite were taken in the influent and effluents on a weekly basis; nitrate measurements were also taken at the interface. Measurements of pH, dissolved oxygen (DO) and oxidation-reduction potential (ORP) were taken in the SZ. The height of both SZ (40 cm vs. 30 cm in P1) and FDZ (40 vs. 25 and 30 cm in SI/SIII in P2) did not affect the efficiencies (p > 0.05) but the presence or absence of corn cob did (p < 0.05). Thus, SII and SIV were superior when compared to SI and SIII (p < 0.05) with TN average removal efficiencies of 72.9% and 73.2% in P1, and 59.8% and 64.2% in P2, respectively; showing a tendency to lower values when the biodegradable organics supplied by the corncob diminished. In SI and SIII, TN removals were 47.6% and 40.3% in P1, and 46.1% and 44.1% in P2, respectively. In SII and SIV, denitrification took place in both the lower semi-saturated part of the FDZ (probably also ANAMMOX) and SZ; whereas in SI and SIII, ANAMMOX took place in the lower semi-saturated part of the FDZ. PMID- 30029129 TI - Valorisation of olive agro-industrial by-products as a source of bioactive compounds. AB - A large amount of olive-derived biomass is generated yearly in Spain, which could be used as a potential source of bioactive compounds. The present work evaluates the recovery of natural antioxidants from olive tree pruning (OTP) and olive mill leaves (OML). For this purpose, the effect of different solvents on the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity was evaluated. The solvent was found to have a significant effect (p < 0.05) on the TPC, TFC, and the DPPH, ABTS, and FRAP activity, affording similar results for the extracts from the two by-products. The extracts obtained using 50% ethanol showed high TPC (23.85 and 27.54 mg GAE/gdw for OTP and OML, respectively) and TFC (52.82 and 52.39 mg RE/gdw for OTP and OML, respectively). Also, the OTP and OML extracts exhibited notable antioxidant activity as measured by the ABTS method (45.96 and 42.71 mg TE/gdw, respectively). Using pyrolysis-gas chromatography/mass spectrometry, 30 bioactive compounds were detected in both extracts. Additionally, UPLC-DAD-ESI-MS allowed the identification of 15 compounds in the samples. Furthermore, the antioxidant extracts were found to inhibit the growth of several food pathogenic bacteria. This research demonstrates that these by-products from olive grove farming are a good source of antioxidant compounds with antibacterial properties, which have potential applications in the food and pharmaceutical industries. PMID- 30029130 TI - Effects of sublethal herbicides on offspring germination and seedling growth: Redroot pigweed (Amaranthus retroflexus) vs. velvetleaf (Abutilon theophrasti). AB - The effects of sublethal doses of herbicides on plants cannot be ignored, yet little is known about the effects of sublethal doses of herbicides on the F1 generation of plants. Seed germination and seedling growth of native and invasive plants following the sublethal exposure of parent plants to herbicides were comparatively analyzed in this study. Sublethal atrazine and tribenuron-methyl had carry-over effects on the germination and seedling growth of the F1 generation of invasive redroot pigweed (Amaranthus retroflexus L.) and native velvetleaf (Abutilon theophrasti Medicus), both of which had different responses to the carry-over effects of sublethal herbicide. The germination percentage of the F1 redroot pigweed (decreased) was greater than that of the F1 velvetleaf (increased or not significantly changed) following parental exposure to atrazine or tribenuron-methyl. Atrazine reduced the radical growth of 7-day-old velvetleaf seedlings and decreased the difference in seedling length between velvetleaf and redroot pigweed, while tribenuron-methyl had no significant effects on the growth of 7-day-old velvetleaf seedlings. The herbicide inhibition effect on the germination and growth of F1 velvetleaf and redroot pigweed did not increase as the sublethal dose increased. This study suggests that carry-over effects of sublethal herbicides weaken the growth advantage of the F1 velvetleaf at the seedling stage and may have a more negative influence on progeny population development of native velvetleaf compared with invasive redroot pigweed. PMID- 30029131 TI - Synergistically enhancing Fenton-like degradation of organics by in situ transformation from Fe3O4 microspheres to mesoporous Fe, N-dual doped carbon. AB - Nanocarbon materials are emerging as alternative activators of peroxymonosulfate (PMS) for organics decomposition. However, the relatively low activity and complex syntheses hindered their practical application and innovation with respect to rational design of carbocatalysts is highly desired. Herein, an in situ replication and transformation strategy was employed to facilely convert porous Fe3O4 microspheres into novel Fe/N codoped large-pore mesoporous carbon spheres (M-Fe/NC) as Fenton-like catalysts for PMS activation. Benefiting from the abundance of active sites induced by dual heteroatom doping, the enhanced active site exposure due to the unique mesoporous structure, and the high stability of carbon component, the derived M-Fe/NC was superior to the pristine Fe3O4 for PMS activation to degrade various organics and was efficient over a wide pH range (2-9). Compared with the proposed mechanisms of previous reports, both radical (surface-bound SO4- and OH) and nonradical (1O2 and direct oxidation) pathways are involved in the M-Fe/NC/PMS system. Furthermore, experimental observations in combination with DFT calculations reveal that graphitic N and FeN4 sites serve as dual reaction centers in the catalysis. This research opened an avenue for development of novel multi-doped carbocatalysts used to activate PMS for sustainable remediation. PMID- 30029132 TI - Treatment of oil sands produced water using combined electrocoagulation and chemical coagulation techniques. AB - Hybrid electrocoagulation-chemical coagulation (EC-CC) process has attracted a growing attention for the removal of various types of wastewaters contaminants. In this paper, the feasibility of EC-CC technique as an alternative to conventional chemical processes for the treatment of steam assisted gravity drainage (SAGD) produced water has been systematically studied. Eight parameters, namely electrode material, cell configuration, pH and temperature of the solution, chemical coagulant dosage, intensity of the electrical current, mixing rate, and treatment time were studied. To explore the synergistic effect of the design parameters, the experimental trials were arranged using Taguchi method. Analysis of variance (ANOVA) was performed to evaluate the effect of each design parameter on the organic matter removal from the SAGD produced water. It was found that all parameters except the electrode arrangement had a significant effect on the removal efficiency of the EC-CC process. Among these parameters, the chemical coagulant and the treatment time had the most significant contribution to the efficiency by 40% and 26%, respectively. The optimum condition for the highest TOC removal efficiency (39.8%) was obtained by applying 0.34 A to Al electrode in a bipolar (BP) configuration when the pH, temperature, coagulant concentration, mixing rate, and reaction time were set to 8, 60 degrees C, 200 mg/L, 700 rpm, and 90 min, respectively. Moreover, a second-order polynomial regression model was proposed to predict the removal efficiency in terms of design parameters. An excellent agreement between the model predictions and experimental data was obtained with the adjusted R2 of about 99%. PMID- 30029133 TI - Temporalis, a generic method and tool for dynamic Life Cycle Assessment. AB - The limitations of the static nature of Life Cycle Assessment (LCA) are well known. To overcome the loss of temporal information due to the aggregation of flows in the Life Cycle Inventory (LCI), several dynamic LCA methodologies have been proposed. In this paper we present a new generic and operational methodology for dynamic LCA that allows for the introduction of temporal information in both in the inventory and the Life Cycle Impact Assessment (LCIA) phases. The method makes use of graph traversal and convolution to calculate the temporally differentiated inventory, and makes it possible to use several types of dynamic impact assessment. We describe our method and apply it to a cradle-to-grave dynamic LCA of a glued laminated timber (glulam) product. We also test the sensitivity of the global warming results to temporal explicit LCI data. There is a considerable difference in outcome between the static and dynamic approaches. We have implemented our framework in the free and open source software Temporalis that is fully operational and can be used with existing LCA databases. PMID- 30029134 TI - Occurrence and distribution of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in natural forest soils: A nationwide study in China. AB - Forests serve as the primary reservoir for organic carbon above ground. Previous studies have revealed that forest soils play key roles in the retention of persistent organic pollutants (POPs). In this study, the occurrence and distribution of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were investigated in 54 surface soil samples from 28 natural forested mountain sites across China between 2012 and 2013. The detection frequency of PFOA (70%) was significantly higher than that of PFOS (4%). PFOA levels ranged from <0.9 to 9.0 pg.g-1 dry weight (dw). Levels of PFOA and PFOS in forest soils were significantly lower than those in agricultural, urban and rural areas in China. Relatively high levels of PFOA were detected in Hubei Province (Jiugong Mountain, average: 3.4 pg.g-1 dw) and Jiangxi Province (Wugong Mountain, average: 4.4 pg.g-1 dw), where many domestic fluoropolymer manufacturers are located. PFOS was only detected in these two provinces (2.2 pg.g-1 dw and 2.7 pg.g-1 dw, respectively). From most of the surveyed mountains, the concentrations of PFOA increased with elevation. The lower temperature and greater precipitation probably made PFOA and its precursors available to transport and degrade more readily at higher altitude sites. A relatively higher level (1.9 +/- 1.3 pg.g-1 dw) of PFOA was found in the broadleaf evergreen forest area, mainly due to the high industrial emissions, plant retention, and precipitation rate in this area. Source were the dominant factor controlling the spatial distribution of PFOA in natural forest soils in China. PMID- 30029135 TI - Late Quaternary environmental dynamics in Lenin Peak area (Pamir Mountains, Kyrgyzstan). AB - The Pamir Mountains include peaks exceeding 7000 m, such as Lenin Peak (7134 m) in the northern Zaalai Range. Here, we examine the distribution of soils and geomorphological processes and landforms in its northern slope, from the highest glaciated environments until Alai valley floor. We present the first geomorphological map of the study area as well as an accurate description the main geomorphological units in order to reconstruct landscape dynamics in the area from Quaternary cold stages until present-day. Five main units are distributed: (1) valley floor (2900-3040 m), an area that must have been ice-free during Quaternary glaciations and is currently being reshaped by glaciofluvial processes, with a large alluvial fan reworked by aeolian activity; (2) hummocky terrain (3040-3500 m) including two moraine systems left by a piedmont glacier during the Last Glaciation as well as hilly deposits originated by a catastrophic rockfall event; (3) U-shaped glacial valley (3500-3800 m), including some moraine ridges as well as a sedimentary cover composed of glacial till that is being eroded by fluvial and mass-wasting processes; (4) high mountain valleys (up to 4600-4800 m) adjacent to the main valley floor with small cirque and alpine glaciers and widespread periglacial processes in ice-free environments; (5) glaciers flowing from the Lenin Peak summit until the foot of the mountain, where they form a debris-covered (surge-type) glacier. The existence of abundant glacial, periglacial and rockfall deposits (moraines, till, erratic boulders) allows inferring five different environmental stages since the Last Glaciation. The latest glacial advances took place during the 20th century and the Little Ice Age and deposited two moraine systems near the glacial front. The occurrence of active rock glaciers and protalus lobes indicates that the limit of permafrost conditions is now located at 3400-3500 m, with seasonal frozen ground in lower areas. PMID- 30029136 TI - Microhabitat change alters abundances of competing species and decreases species richness under ocean acidification. AB - Niche segregation allows competing species to capture resources in contrasting ways so they can co-exist and maintain diversity, yet global change is simplifying ecosystems and associated niche diversity. Whether climate perturbations alter niche occupancy among co-occurring species and affect species diversity is a key, but unanswered question. Using CO2 vents as natural analogues of ocean acidification, we show that competing fish species with overlapping diets are partially segregated across microhabitat niches and differently orientated substrata under ambient CO2 conditions. Under elevated CO2, benthic microhabitats experienced a significant increase in non-calcifying turf and fleshy algae but a sharp reduction in calcareous algae. The increased availability of turf and fleshy algae supported increased densities of a competitively dominant species, whilst the reduction in calcifying algal microhabitats decreased densities of several subordinate species. The change in microhabitat availability also drove an increased overlap in microhabitat use among competing fishes at the vents, associated with a reduced fish species richness on horizontal substrates. We conclude that loss of preferred microhabitat niches, exacerbated by population proliferation of competitively dominant species, can drive population losses of less common and subordinate species, and reduce local species richness. The indirect effects of ocean acidification on microhabitat availability can therefore impair maintenance of species populations, and drive changes in local community and biodiversity patterns. PMID- 30029137 TI - Tree species diversity promotes soil carbon stability by depressing the temperature sensitivity of soil respiration in temperate forests. AB - The diversity-stability interrelationship suggests that high diversity can buffer fluctuations in environmental conditions such as temperature; we thus hypothesize that tree species diversity will lower the temperature sensitivity of soil respiration (Rs), known as Q10 value. Our hypothesis was tested in a deciduous broad-leaf and a coniferous-broad-leaf mixedwood stand in the warm temperate region in China. We measured soil respiration and indices of tree species diversity including species richness (S), the Berger-Parker index (d), the Simpson index (lambda), the Shannon index (He'), and the Pielou evenness index (Je). Our results generally confirm our hypothesis that Q10 was positively correlated to lambda, but negatively related to He', d, and Je, and independent of S, in both stands. However, Rs was independent of the diversity indices. These findings imply that tree species diversity promotes soil carbon stability by depressing the Q10. Furthermore, different biotic and abiotic variables explained the variations of species diversity and Q10 in the broad-leaf and mixedwood forests, suggesting that the mechanisms underlining the effects of tree species diversity on Q10 are different between the two forest types. We conclude that sustainable forest management that improves tree species diversity will increase soil carbon stability and benefit our efforts to mitigate climate change. PMID- 30029138 TI - Rainfall isotope variations over the Australian continent - Implications for hydrology and isoscape applications. AB - This paper presents a continental scale interpretation of delta2H and delta18O in Australian precipitation, incorporating historical GNIP data at seven sites (1962 2002) and 8-12 years of new monthly data from 15 sites from 2003 to 2014. The more than doubling of stations and the significant time series duration allow for an improved analysis of Australian precipitation isotopes. Local meteoric water lines were developed for each site, and for the Australian continent. When the annual precipitation weighted values were used, the Australian meteoric water line was delta2H = 8.3 delta18O + 14.10/00. Precipitation amount was found to be a stronger driver of precipitation isotopes than temperature at most sites, particularly those affected by tropical cyclones and the monsoon. Latitude, elevation and distance from the coast were found to be stronger drivers of spatial variability than temperature or rainfall amount. Annual isoscapes of delta2H, delta18O and deuterium excess were developed, providing an improved tool to estimate precipitation isotope inputs to hydrological systems. Because of the complex climate, weather and oceanic moisture sources affecting Australia, regional groupings were used instead of the climate zone approach and additional data was included to improve the coverage in data poor regions. Regression equations for the isoscape were derived using latitude, altitude and distance from the coast as predictor variables. We demonstrate how this isoscape can be used as a tool for interpreting groundwater recharge processes using examples from across Queensland and New South Wales, including the Murray Darling Basin. Groundwater isotopes at sites where direct local recharge occurs are similar to rainfall, but for inland sites, which are often arid or semi-arid, a disconnect between shallow groundwater and local rainfall is observed; the departure in deuterium excess for these sites increases with aridity and distance from the headwaters where flooding originates. PMID- 30029139 TI - Delving the environmental impact of roundwood production from poplar plantations. AB - The environmental impact of timber production from poplar plantation was evaluated by means of Life Cycle Assessment (LCA) using an attributional approach. A comparison was performed between a baseline scenario and an alternative one in which different harvesting operations were identified. An economic allocation was adopted to solve the multi-functionality of the studied process, by taking into account the price of the main product and of co-products. Sensitivity analysis was performed on alternative mass allocation and yield variations that derive from using high sustainability plants or from climate stress. A different characterization method was also analyzed. Among the different field operations, crop management involves a higher impact respect to field preparation-planting and harvesting-soil restoring. Emissions related to fertilizers' applications are the main responsible for acidification, eutrophications and particular matter formation. The results show that the modelling of the environmental impact of timber production is robust. The alternative scenario resulted better than baseline for all impact categories (impact reduction ranging from 0.1% to 12.4%), except for HT-noc (+12.2%) and POF (+20.6%), due to fuel and oil consumption in the chainsaw used for harvesting. In the next years, introducing high-sustainability clones (characterized by higher yield and higher resistance to pests and drought) could be an effective way for reducing the environmental impact of poplar roundwood production. PMID- 30029140 TI - Artificial neural networks: Modeling tree survival and mortality in the Atlantic Forest biome in Brazil. AB - Models to predict tree survival and mortality can help to understand vegetation dynamics and to predict effects of climate change on native forests. The objective of the present study was to use Artificial Neural Networks, based on the competition index and climatic and categorical variables, to predict tree survival and mortality in Semideciduous Seasonal Forests in the Atlantic Forest biome. Numerical and categorical trees variables, in permanent plots, were used. The Agricultural Reference Index for Drought (ARID) and the distance-dependent competition index were the variables used. The overall efficiency of classification by ANNs was higher than 92% and 93% in the training and test, respectively. The accuracy for classification and number of surviving trees was above 99% in the test and in training for all ANNs. The classification accuracy of the number of dead trees was low. The mortality accuracy rate (10.96% for training and 13.76% for the test) was higher with the ANN 4, which considers the climatic variable and the competition index. The individual tree-level model integrates dendrometric and meteorological variables, representing a new step for modeling tree survival in the Atlantic Forest biome. PMID- 30029141 TI - Insights into mixed contaminants interactions and its implication for heavy metals and metalloids mobility, bioavailability and risk assessment. AB - Mobility of heavy metals at contaminated sites is mainly influenced by the soil physicochemical properties and environmental conditions, therefore assessing heavy metals (HMs) and metalloids fractionation can provide insights into their potential risk and the mechanisms that regulate bioavailability. A 12-months mesocosms experiment was setup to investigate the effect of physicochemical factors (pH, moisture, and temperature) and weathering (time) on HMs and metalloids fractionation in three different multi-contaminated soil matrices (low, medium, and high contamination) collected from a soil treatment facility located in the United Kingdom, and two rural contaminated soil samples. The study demonstrates that even though Pb and Zn were found associated with the exchangeable fraction in the soil with the highest contamination (total average Pb 3400 mg/kg, and total average Zn 2100 mg/kg in Soil C), neither the condition applied nor the weathering caused an increase in their mobility. Although it was expected that lower pH (4.5) would favours the dissociation of HMs and metalloids, no significant differences were observed, potentially due to the initial alkaline pH of the genuine-contaminated soil samples. The results show that even though total concentration of Pb, Cu, and Zn exceed the soil standards and guideline values, HMs were predominantly associated with the non-exchangeable fraction, while only 5% were dissolved in the pore water fraction (potentially bioavailable). In addition, the mobility and bioavailability of HMs remained constant over the 12 months monitoring, suggesting that these soils pose negligible risk to the environment. PMID- 30029142 TI - Accelerated crystallization of magnetic 4A-zeolite synthesized from red mud for application in removal of mixed heavy metal ions. AB - To cope with the increasing environmental issues of red mud, an integrated technological route for its comprehensive utilization was developed through the extraction of valuable components and the synthesis of magnetic 4A-zeolite. To accelerate the crystallization process of the synthesized 4A-zeolite, sodium chloride (NaCl) was innovatively employed under hydrothermal treatment. The effects of various parameters, including mass ratio of red mud/NaOH, alkali fusion temperature, alkali fusion time and molar ratio of NaCl/Al2O3, were systematically investigated. The results showed that approximately 81.0% Al, 76.1% Si and 95.8% Fe were utilized from red mud using alkali fusion and acid leaching methods. The optimal conditions of the alkali fusion process were determined as: mass ratio of red mud/NaOH = 1/2, alkali fusion temperature of 800 degrees C, and time of 90 min. Furthermore, when the molar ratio of NaCl/Al2O3 was kept at 1.5, the crystallization time reduced from 240 min to 150 min, and particle size distributions narrowed from 20-100 MUm to 1-10 MUm. The practical applications in removal of mixed heavy metal ions (Zn2+, Cu2+, Cd2+, Ni2+, and Pb2+) from wastewater indicated that the as-synthesized magnetic 4A-zeolite is a promising candidate for heavy metals adsorption. PMID- 30029143 TI - Building a heading signal from anatomically defined neuron types in the Drosophila central complex. AB - A network of a few hundred neurons in the Drosophila central complex carries an estimate of the fly's heading in the world, akin to the mammalian head-direction system. Here we describe how anatomically defined neuronal classes in this network are poised to implement specific sub-processes for building and updating this population-level heading signal. The computations we describe in the fly central complex strongly resemble those posited to exist in the mammalian brain, in computational models for building head-direction signals. By linking circuit anatomy to navigational physiology, the Drosophila central complex should provide a detailed example of how a heading signal is built. PMID- 30029144 TI - Comparison of performance between boron-doped diamond and copper electrodes for selective nitrogen gas formation by the electrochemical reduction of nitrate. AB - The electrochemical nitrate reduction by using boron-doped diamond (BDD) and copper (Cu) electrodes was investigated at various potentials. Product selectivity of nitrate reduction was strongly dependent on the applied potential for both electrodes. The highest selectivity of nitrogen gas production was obtained at -2.0 V (vs. Ag/AgCl) by using a BDD electrode with a faradaic efficiency as high as 45.2%. Compared with Cu electrode, nitrate reduction on BDD electrode occurred at more positive potential, and the production of nitrogen gas was larger. The transformation of surface-adsorbed nitrate into molecular nitrogen would be accelerated on BDD electrode with hindering nitrite production. In addition, low concentration of surface-adsorbed hydrogen on the BDD would also retard the ammonia generation, leading to increase in the selectivity of nitrogen gas formation. Meanwhile, BDD electrode could hinder the hydrogen evolution reaction, which enhanced the efficiency for nitrate reduction and decreased energy consumption. BDD electrode has excellent stability to remain better performance for reducing nitrate during electrolysis without any variation of surface morphology or chemical components. PMID- 30029145 TI - Lethal and sublethal toxicity of abamectin and difenoconazole (individually and in mixture) to early life stages of zebrafish. AB - In recent years, the need for the development of alternative test methods for the conventional acute fish toxicity test (AFT) with adult fish has often been discussed. In addition, concerns have been raised on the potential risks related with environmentally realistic pesticide mixtures since risk evaluations have traditionally been based on individual pesticides. The insecticide/acaricide abamectin and the fungicide difenoconazole are the main pesticides that are intensively used in Brazilian strawberry crop and are hence likely to occur simultaneously in edge-of-field waterbodies. The aim of the present study was therefore to evaluate the lethal and sublethal toxicity of single and mixture exposures of these pesticides to zebrafish early life stages (embryos and juveniles). By comparing the derived toxicity data of the individual compounds with that previously determined for zebrafish adults, the order of life stage sensitivity was juvenile > adult > embryo. The pesticide mixture revealed a dose level dependent deviation of the independent action model, with antagonism at low dose levels and synergism at high dose levels. Sublethal parameters (especially those related with locomotion) were considerably more sensitive than lethality. Subsequently, the inclusion of sublethal parameters may greatly improve the sensitivity of FET tests and hence its suitability as a substitution of adult fish testing in risk assessment evaluations. PMID- 30029146 TI - A pilot-scale investigation of disinfection by-product precursors and trace organic removal mechanisms in ozone-biologically activated carbon treatment for potable reuse. AB - Although granular activated carbon (GAC) has been broadly applied in ozone biologically activated carbon filtration (O3/BAC) systems for potable reuse of municipal wastewater, the mechanisms of various pollutant removal remain largely unknown as the regenerated GAC develops microbial populations resulting in biofiltration but loses significant adsorption capacity as it becomes spent GAC. Therefore, pilot-scale parallel performance comparisons of spent and regenerated GAC, along with a range of pre-oxidant ozone doses, were used to shed light on the mechanisms responsible for the removal of various types of treatment byproduct precursors and trace organic compounds. It was confirmed from this pilot-study that ozone alone can effectively degrade chlorinated trihalomethane (THM) and haloacetic acid (HAA) precursors, chloramine-reactive N nitrosodimethylamine (NDMA) precursors, and 29 PPCPs. In contrast, biodegradation by microbial population on spent or regenerated GAC can remove NDMA and 22 PPCPs, while the adsorption by regenerated GAC can remove chlorinated THM and HAA precursors, PFAS, flame retardants, and 27 PPCPs. The results of this pilot study are intended to provide those interested in potable reuse with an example of the simultaneous removal capabilities and mechanisms that can be anticipated for treating a complex mixture of organics present in real municipal wastewater effluent. PMID- 30029147 TI - Effectiveness of a neutral electrolysed oxidising water (NEOW) device in reducing Legionella pneumophila in a water distribution system: A comparison between culture, qPCR and PMA-qPCR detection methods. AB - Disinfection of hot water systems is critical for reducing Legionnaires' disease in high-risk buildings. The use of neutral electrolysed oxidising water (NEOW) is a promising method for the control of microorganisms in hot water systems. However, full-scale evaluations of the efficacy of NEOW devices to control Legionella pneumophila are currently lacking. The aim of this study was to assess the effectiveness of a NEOW device in reducing L. pneumophila in a hotel water network. Water samples (n = 67) were collected from different sites of a hotel distribution system before and after the installation of the NEOW device at the 1st, 4th, 8th and 12th week. Detection of L. pneumophila was performed comparing culture, qPCR and PMA-qPCR methods. Total bacterial counts (22 degrees C and 37 degrees C), Pseudomonas spp. and physico-chemical parameters were also monitored. The NEOW treatment resulted in a reduction of the amount of L. pneumophila positive samples (-32%) and of the number of heavily contaminated points (>104 CFU/L and >103 CFU/L) (-100% and -96%, respectively). Treatment maintained L. pneumophila at low levels (<102 CFU/L), which do not require specific intervention measures. The effectiveness of the disinfection system was also confirmed by PMA-qPCR (p < 0.001). The use of PMA resulted in a signal decrease in almost all samples upon the disinfection treatment. The NEOW disinfection device appears to be a promising approach to reduce the colonisation of hot water systems by L. pneumophila; however, further investigations are needed to ascertain its efficiency over longer time periods. PMID- 30029148 TI - Screening of biological sulfate reduction conditions for sulfidogenesis promotion using a methanogenic granular sludge. AB - Effluents containing great amounts of oxidized sulfur compounds, such as sulfate or sulfite, can be valorized as elemental sulfur from a sequential reduction oxidation biological process. However, the most important, challenging step to be optimized is the reduction of sulfate. The present study aimed at seeking out the optimal conditions to promote sulfidogenesis instead of methanogenesis using waste carbon sources and a methanogenic granular sludge. Crude glycerol showed better results in terms of the consumed COD/S-Sulfate ratio compared with acetate, cheese whey, pig slurry, and vinasse. Then, the screening of several conditions (T, pH, and COD/S-Sulfate ratio) and the effects of air presence and dissolved sulfide inhibition on sulfate reduction was carried out. Sulfidogenesis was promoted at 35 degrees C, pH = 8.5, COD/S-Sulfate ratio above 7.0 g O2 g-1 S, microaerophilic conditions, and dissolved sulfide concentrations below 250 mg S2- L-1. These conditions were tested for nearly 3 months in the startup and operation of a 2 L UASB reactor. An inlet sulfate concentration of 220 mg S L-1 and an HRT of 2 h were set. Removal efficiencies of approximately 90% were obtained with less than 20% of organic matter destined for biogas production. PMID- 30029150 TI - Modulations of TCDD-mediated induction of zebrafish cyp1a1 and the AHR pathway by administering Cd2+in vivo. AB - Trace metal ions such as cadmium (Cd2+) and trace organics typified by 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) are common co-contaminants in the environment and cause toxic effects in aquatic organisms that pose serious health risks. We studied the effects of Cd2+ on the regulation of cytochrome P450 1A1 (cyp1a1) gene-induction by TCDD using zebrafish embryos and larvae and adult zebrafish tissues. Our results showed that TCDD induced the cyp1a1 gene in all developmental stages and tissues of zebrafish, and the induction was higher in females than males. However, for the upstream genes (ahr2 and arnt2b) that mediate cyp1a1 gene induction in the zebrafish liver cell line was not induced by TCDD similar to the pattern of cyp1a1 in all investigated groups. After co treatment with Cd2+, induction of the aryl hydrocarbon receptor pathway by TCDD was inhibited in the zebrafish larvae and the livers, intestines, kidneys and gills of adult zebrafish, but not in the embryos or brains of adult zebrafish, indicating that the toxicological effects of Cd2+ on TCDD are dependent on the developmental stages and tissue types. The present study confirms that Cd2+ blocks the TCDD-induced cyp1a1 gene in vivo but emphasizes that the effects are specific to the developmental stage, type of tissue and sex. The combined effects of Cd2+ and TCDD must be taken into consideration together with these parameters to accurately predict and assess cadmium and TCDD-induced toxicity in fish and carcinogenesis in animals in general. PMID- 30029149 TI - Efficient prevention of nanomaterials transport in the porous media by treatment with polyelectrolytes. AB - Contamination of soil by engineered nanomaterials (ENM) is an emergent environmental problem that urges the development of robust treatment protocols to prevent ENM transport through soil. We developed a method for efficient entrapment and retention of ENM in solid porous media of quartz sand with grain size of 300-500 MUm used as a simple model of soil and studied the transport properties of multi-walled carbon nanotubes, fullerenes, silica and gold nanoparticles through the sand-packed column by UV-vis and fluorescent spectroscopy. The treatment of ENM-contaminated porous media with a mixture of oppositely charged polyelectrolytes, cationic poly(diallyldimethylammonium chloride) and anionic poly(acrylic acid) sodium salt, dissolved in NaCl solution followed by dilution in the column results in strong electrostatic interaction between the polyelectrolytes and a formation of inter-polyelectrolyte complexes (IPEC) that induce flocculation of ENM and adsorption to the surface of sand. The method demonstrates excellent ENM entrapment efficiency (>90%) and high capacity of several grams of ENM per 1 g of polyelectrolytes. The IPEC network formed after the treatment also serves as an efficient protection barrier for newly added ENM contaminants. The method is universal for various types of ENM (carbon ENM, metal and oxide nanoparticles) and equally efficient for distilled water, tap water, or lake water eluents. PMID- 30029152 TI - Cohort study of the relationship between individual psychotherapy and pregnancy outcomes. AB - INTRODUCTION: Antenatal depression is associated with poor obstetric outcomes, but it has not been determined if treatment improves these outcomes. We hypothesized that psychotherapy for antenatal depression would decrease rates of low Apgar score, preterm birth, low birthweight, and high maternal weight gain. METHODS: Using longitudinal clinical data from the electronic health record (EHR) of a large academic medical center, we examined the association between exposure to psychotherapy during pregnancy among women with a history of major depressive disorder and obstetric outcomes. We compared outcomes between women with and without psychotherapy treatment during pregnancy, and included a dose response analysis. RESULTS: Of 50,856 women with pregnancies between 1998 and 2013, 5413 had a lifetime diagnosis of depression (948 had a diagnosis of depression during pregnancy), and 536 received psychotherapy at least once during pregnancy. Women who received one or more psychotherapy sessions during pregnancy had increased odds of preterm delivery and decreased odds of high maternal weight gain (more than 40 pounds). Individuals who received four or more psychotherapy sessions during pregnancy had increased odds of preterm birth and low infant birth weight and decreased odds of high maternal weight gain. LIMITATIONS: Patients may have pursued treatment outside of this hospital's EHR data, and we cannot control for the quality of treatment or type of psychotherapy. DISCUSSION: Psychotherapy was associated with negative obstetric outcomes. While treatment of depression in pregnant women has been shown to benefit the mother, the absence of benefit in terms of pregnancy outcomes merits further investigation. PMID- 30029151 TI - CHRNA7 copy number gains are enriched in adolescents with major depressive and anxiety disorders. AB - OBJECTIVE: Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the alpha7 nAChR encoded by the gene CHRNA7, have been implicated in behavior regulation in animal models. In humans, copy number variants (CNVs) of CHRNA7 are found in a range of neuropsychiatric disorders, including mood and anxiety disorders. Here, we aimed to determine the prevalence of CHRNA7 CNVs among adolescents and young adults with major depressive disorder (MDD) and anxiety disorders. METHODS: Twelve to 21 year-old participants with MDD and/or anxiety disorders (34% males, mean +/- std age: 18.9 +/- 1.8 years) were assessed for CHRNA7 copy number state using droplet digital PCR (ddPCR) and genomic quantitative PCR (qPCR). Demographic, anthropometric, and clinical data, including the Beck Anxiety Index (BAI), Beck Depression Inventory (BDI), and the Inventory of Depressive Symptoms (IDS) were collected and compared across individuals with and without a CHRNA7 CNV. RESULTS: Of 205 individuals, five (2.4%) were found to carry a CHRNA7 gain, significantly higher than the general population. No CHRNA7 deletions were identified. Clinically, the individuals carrying CHRNA7 duplications did not differ significantly from copy neutral individuals with MDD and/or anxiety disorders. CONCLUSIONS: CHRNA7 gains are relatively prevalent among young individuals with MDD and anxiety disorders (odds ratio = 4.032) without apparent distinguishing clinical features. Future studies should examine the therapeutic potential of alpha7 nAChR targeting drugs to ameliorate depressive and anxiety disorders. PMID- 30029153 TI - Experimentally investigating the joint effects of physical activity and sedentary behavior on depression and anxiety: A randomized controlled trial. AB - OBJECTIVE: To experimentally examine whether increasing sedentary behavior, among a young adult active population, for one week is still associated with increased depression and anxiety symptomology even when allowing for a moderate engagement in physical activity (PA). METHODS: Participants were confirmed as active via self-report and accelerometry during baseline and randomly assigned to one of three experimental groups. The No Exercise Group (n = 19) was instructed to reduce steps to less than 5000/day and were not allowed to exercise for one-week; the Reduced MVPA (moderate-to-vigorous PA) Group (n = 18) was instructed to reduce steps to less than 5000/day but exercised for 50% of their previously reported vigorous PA for one-week; and the Control Group (n = 20) maintained normal activity for one-week. PA, depression, and anxiety levels were assessed at baseline, post-intervention, and after one week of resumed normal activity for the intervention groups. RESULTS: The experiment was successful in altering physical activity levels among the intervention groups and maintaining activity habits in the control group (FInteraction = 16.053, P < 0.001, eta2p = 0.391). Anxiety and depression symptomology remained constant across the two time periods in the control group. For both intervention groups (No Exercise Group and Reduced MVPA Group), depression statistically significantly increased during the inactive week and then resumed back to baseline levels after a week of resumed activity. However, there were no differential trends in anxiety (FInteraction = 0.073, P = 0.897, eta2p = 0.002) or depression (FInteraction = 0.276, P = 0.760, eta2p = 0.008) among these two intervention groups. CONCLUSION: We provide experimental evidence that reducing habitual physical activity causes an increase in depression symptomology among young active adults. We did not, however, observe a joint effect of sedentary behavior and exercise on changes in anxiety and depression. At this point, it is still uncertain as to whether reduced MVPA or increased sedentary behavior were driving the observed changes in psychological function. Future research may help determine if these negative effects are from increased sedentary behavior or a reduction in MVPA. PMID- 30029154 TI - Substance use among older adults with bipolar disorder varies according to age at first treatment contact. AB - BACKGROUND: The use of alcohol and drugs is common among people with bipolar disorder, but it is unclear if age of onset modifies this association. AIMS: To determine the cross-sectional and longitudinal association between age of onset of bipolar disorder (BD) and disorders associated with the use of alcohol or other substances in later life, as well as their impact on mortality. METHODS: Cohort study of a community-representative sample of 38,173 men aged 65-85 years at the start of the follow up period of 18 years. We used the Western Australian Data Linkage System to ascertain the presence of BD and substance use disorders according to the International Classification of Diseases (ICD). We also collected information on concurrent morbidities: diabetes, hypertension, ischaemic heart disease and stroke. RESULTS: 175 men had BD onset < age 60 years and 75 >= 60 years. Compared with older men without BD, the adjusted odds of alcohol use disorders were 3.87 (95%CI = 2.52, 5.93) for men with BD onset < 60 years and 2.38 (95%CI = 1.08, 5.25) for those with onset >= 60 years. The adjusted hazard ratio of incident disorders associated with the use of alcohol and other substances was 3.23 (95%CI = 1.87, 5.58) and 2.38 (95%CI = 1.38, 4.11) respectively for men with BD onset < 60 years. BD with onset >= 60 years was not associated with substance use disorders. The mortality hazard was not affected by the interaction between BD and the use of substances. CONCLUSIONS: Substance use disorders (alcohol or others) are more prevalent among older adults with than without BD, but new cases are only more frequent among men with BD onset < 60 years of age. Grouping BD into early and late onset is clinically informative and may affect approach to assessment and management. PMID- 30029155 TI - Correlations between changes in the hypothalamic-pituitary-adrenal axis and neurochemistry of the anterior cingulate gyrus in postpartum depression. AB - BACKGROUND: This study aimed to investigate associations between indicators of hypothalamic-pituitary-adrenal axis (HPA) functioning and metabolite levels in the anterior cingulate gyrus (ACG) of women with postpartum depression (PPD). METHODS: The sample (mean age = 28.5 +/- 4.6 years) consisted of 20 women with PPD and 19 postpartum euthymic (PPE) women. Brain metabolites were quantified by proton magnetic resonance spectroscopy (1H-MRS). Salivary cortisol samples were collected upon awakening and 30 min and 12 h later, at 20.6 +/- 6.6 (PPD) and 23.0 +/- 7.4 (PPE) weeks after childbirth. RESULTS: There were no significant differences between groups in respect to metabolite levels in the ACG. Compared with PPE, PPD women had less diurnal variation (DVr%). In the PPD group, positive correlations were found between DVr% and myo-inositol (mI/Cr) levels, and between cortisol awakening response (CARi%) and glutamate + glutamine (Glx/Cr) levels. The correlation between CARi% and Glx/Cr remained significant even after controlling for the interval, in weeks, from birth and MR spectroscopy and to hormonal data collection, and the use of contraceptives. LIMITATIONS: The limitations of the study include the small sample size and the use of oral contraceptives by around half of the sample. CONCLUSIONS: In the remote postpartum period (mean 21.8 +/- 6.9 weeks) and in the presence of depressive episodes, the decreased responsiveness of the HPA axis after awakening and a smaller decrease in cortisol levels over the day were associated with lower levels of metabolites in the ACG. These results may contribute to the development of biological models to explain the etiology of PPD. PMID- 30029156 TI - Erythropoietin levels and erythroid differentiation parameters in patients with lower-risk myelodysplastic syndromes. PMID- 30029157 TI - Alcohol consumption is positively associated with fasting serum ghrelin in non dependent adults: Results from the population-based LIFE-Adult-Study. AB - BACKGROUND: Animal experiments and studies in alcohol dependent patients indicate that ghrelin signaling in the brain is causally involved in the regulation of alcohol reward and intake. Increasing ghrelin levels enhances alcohol craving and intake, blocking ghrelin receptors abolishes these effects. If ghrelin is also involved in non-dependent alcohol consumption in humans, though, remains unknown. The aim was therefore to investigate the relationship between ghrelin serum levels and alcohol consumption in a large population-based sample. METHODS: Total ghrelin was determined after an overnight fast in 1666 subjects participating in a population-based cross-sectional study ('LIFE') including 10,000 adults. 1521 subjects were included in this analysis. Alcohol consumption was assessed using a food frequency questionnaire (FFQ). Multiple linear regression analyses and extreme group comparisons testing for statistical differences of alcohol consumption between the highest and lowest quartile according to ghrelin levels were performed. RESULTS: Alcohol consumption was positively associated with serum ghrelin; total sample: beta = 0.003, p = 0.002; men: beta = 0.005, p = 0.023; women: beta = 0.002, p = 0.007, adjusted for age, BMI and smoking status. Mean alcohol consumption in men/women belonging to the highest quartile of serum ghrelin levels (men: 21.5 (21.1) g/day; women: 7.5 (11.4) g/day) was considerably higher than in those belonging to the lowest quartile (men: 16.5 (19.3) g/day p < 0.002; women: 4.59 (10.7) g/day p = 0.0001). CONCLUSION: This is the first study showing that alcohol consumption is positively associated with serum ghrelin in a population-based sample. The study provides an initial indication that ghrelin is also involved in the regulation of alcohol consumption in non-dependent subjects. PMID- 30029158 TI - Social-evaluative threat, cognitive load, and the cortisol and cardiovascular stress response. AB - BACKGROUND: Current evidence suggests that exposure to social-evaluative threat (SET) can elicit a physiological stress response, especially cortisol, which is an important regulatory hormone. However, an alternative explanation of these findings is that social-evaluative laboratory tasks are more difficult, or confer greater cognitive load, than non-evaluative tasks. Thus, the current experiment tested whether social-evaluative threat, rather than cognitive load, is truly an "active ingredient" in eliciting a cortisol response to stressors. METHODS: Healthy undergraduate students (N = 142, 65% female) were randomly assigned to one of four speech-stressor conditions in a fully-crossed two (social-evaluative threat [SET] manipulation: non-SET versus SET) by two (cognitive load manipulation: low versus high) stressor manipulation. Social-evaluative threat was manipulated by the presence (SET) or absence (non-SET) of two evaluators, while cognitive load was manipulated by the presence (LOAD) or absence (non-LOAD) of a tone-counting task during the speech stressor. Salivary cortisol and cardiovascular measures were taken before, during, and after the speech stressor. RESULTS: Compared to the non-SET condition, SET condition led to greater cortisol and cardiovascular responses to the speech stressor. There were no main or additive effects of cognitive load on cortisol and cardiovascular responses to the speech stressor. CONCLUSIONS: These findings suggest that social-evaluative threat is a central aspect of stressors that elicits a cortisol response; however we found no evidence that increased difficulty, or cognitive load, contributed to greater cardiovascular or cortisol responses to stressors. PMID- 30029159 TI - Factors associated with the receipt of documented evidence-based psychotherapy for PTSD in VA. AB - OBJECTIVES: The VA has mandated that evidence-based psychotherapies (EBPs) be offered to patients with PTSD, but only a small minority of the psychotherapy delivered to VA patients with PTSD is a documented EBP. It is unknown what factors are associated with receiving a documented EBP. METHOD: Patients who received an EBP in FY2015 that was documented using a templated progress note (N = 21,808) were compared with patients who received psychotherapy for PTSD that was not documented using a template (N = 251,886). RESULTS: Among psychotherapy recipients, VA patients with markers of clinical complexity such as service connection for PTSD, comorbid bipolar or psychotic disorder, longer duration of PTSD diagnosis, and a benzodiazepine prescription for PTSD had lower odds of receiving a documented EBP. CONCLUSIONS: Recipients of documented EBPs differed from those who did not receive documented EBPs on several sociodemographic characteristics and indicators of treatment need. A limitation of our study is that some individuals in the group without EBP documentation may still have received an EBP, but did not receive EBP documentation in the electronic health record. Nevertheless, our results suggest that high-need or complex VA patients with PTSD may be less likely to receive documented EBPs. PMID- 30029160 TI - Initial outcomes of a real-world multi-site primary care psychotherapy program. AB - OBJECTIVE: Although anxiety, mood, and adjustment disorders are commonly treated in primary care, little evidence exists regarding psychotherapy outcomes within this setting. The primary objective of this study was to describe outcomes of a large-scale primary care psychotherapy program. METHODS: Patients (N = 2772) participated in cognitive behavioral therapy (CBT) as part of a multi-site primary care program. A tracking system was utilized to collect data on demographics, diagnoses, course of care, anxiety and depressive symptoms, and frequencies of psychotherapy principles used over the course of primary care CBT. RESULTS: Anxiety disorders were most frequent, often comorbid with depression. Over two-thirds of the sample participated in at least one CBT session. Case formulation, cognitive interventions, exposure, and behavioral activation were frequently utilized approaches. Significant improvements on the GAD-7 and PHQ-9 occurred for all groups, yielding medium effect sizes (d = 0.50-0.68). Rates of reliable change (48-80%), response (35-53%), and remission (21-36%) were noted for those scoring in the moderate range of severity. CONCLUSION: Patients suffering from anxiety, depression, and adjustment disorders can be effectively treated in primary care with CBT. Future efforts are needed to match patient characteristics with the types and timing of therapy interventions to improve clinical and functional outcomes. PMID- 30029161 TI - Immigrant paradox? Generational status, alcohol use, and negative consequences across college. AB - The current study examined linkages between generational status, alcohol use, wanting to get drunk, and negative alcohol-related consequences during college. We tested whether immigrant students' longitudinal alcohol use trajectories converged to dominant unhealthy patterns or whether immigrant students maintained healthier patterns across college. We also examined if the weekend exerted equal risk for students of different generations. Furthermore, we explored whether patterns were consistent among Latinx and Asian American students. Stratified random sampling identified first-year students attending a US college. A longitudinal daily diary design was used; students completed web-based surveys for up to 14 days within each of 7 semesters. Each day, participants (N = 689; n1st generation = 114; n2nd generation = 244; 51% female) reported their alcohol use and consequences (N = 55,829 days). Multi-level models demonstrated that compared to 3rd generation students, 1st generation students were more likely to abstain from alcohol and less likely to binge drink and want to get drunk. First generation students also experienced fewer negative alcohol-related consequences. The protective effect of being 1st generation was maintained across college semesters, with subgroup analyses focusing on Latinx and Asian American students largely supporting the main findings. However, for abstaining and negative consequences, the weekend effect was less pronounced for immigrants than later generation students. For example, the difference in negative consequences between 1st (vs. 3rd) generation students was largest on the weekend. Additional work is needed to understand how 1st generation students leverage protective factors to abstain from alcohol use even when exposed repeatedly to "wet" drinking environments. PMID- 30029162 TI - Perceived peer norms and alcohol use among college students in China. AB - INTRODUCTION: Currently, there has been little research on peer drinking norms with non-English speaking college populations. Using a Chinese college student sample, the present study investigated perceived peer norms and their associations with individual alcohol-related behaviors. METHODS: Past six-month drinkers (n = 436, 50% men, mean age = 20.49) recruited from one college in China took an anonymous paper-and-pencil survey. To examine the differences in alcohol related behaviors among groups, one-way repeated measures analysis of variance and chi-square tests were conducted. To investigate the associations between perceived peer norms and individual alcohol-related behaviors, sequential linear and logistic regression analyses were conducted. RESULTS: There were overall mean differences in alcohol use among participants, perceived best friends, and perceived average student for both men (F (1.98, 421.06) = 13.12, p < .001) and women (F (1.89, 399.70) = 5.79, p < .01). The proportion of best friends perceived as having had heavy episodic drinking was higher than that of participants who had had heavy episodic drinking (chi2 (1, N = 415) = 61.85, p < .001). So was the proportion of the average student perceived as having had heavy episodic drinking (chi2 (1, N = 414) = 68.17, p < .001). After controlling for demographic variables, perceived peer alcohol use explained 17% of the variance in individual alcohol use; perceived peer heavy episodic drinking contributed to 2.6 to 3.6 times higher odds of participants' reporting heavy episodic drinking. CONCLUSIONS: Replication research is needed to inform social norms interventions for Chinese college students. PMID- 30029163 TI - Specific PTSD symptom clusters mediate the association of military sexual trauma severity and sexual function and satisfaction in female service members/veterans. AB - BACKGROUND: Sexual satisfaction and function are vastly understudied in female service members/veterans (SM/Vs). Military sexual trauma (MST) is associated with poorer sexual satisfaction and function, but the mechanism through which MST relates to sexual satisfaction and function is unknown. Posttraumatic stress disorder (PTSD) is one of the most frequent diagnoses following MST, and those with poorer sexual satisfaction and function experience higher PTSD symptoms, particularly numbing and anhedonia symptom clusters. In this study, we examined which symptom clusters (re-experiencing, avoidance, negative alterations in cognition and mood [NACM], anhedonia, dysphoric and anxious arousal) mediated the relationship between MST and sexual satisfaction and function. METHOD: Female SM/Vs (N = 1,189) completed self-report measures of MST severity (none, harassment only, assault), PTSD, sexual satisfaction, and sexual function, as well as a demographic inventory. RESULTS: Anhedonia and dysphoric arousal fully mediated the association between assault MST and sexual satisfaction and function. NACM fully mediated the association between harassment and assault MST and sexual satisfaction. Finally, dysphoric arousal significantly mediated the association of harassment MST with sexual satisfaction and function. LIMITATIONS: Data was cross-sectional and based on self-report. CONCLUSIONS: The relationship between MST and sexual satisfaction and function may be mediated through specific PTSD symptom clusters. As there are no evidenced-based treatments to improve sexual satisfaction and function in female SM/Vs, additional research is needed to develop and pilot interventions. Among those with a history of MST, targeting NACM, anhedonia, and dysphoric arousal may be most effective in addressing sexual concerns. PMID- 30029167 TI - Measurement of deformation heterogeneities in additive manufactured lattice materials by Digital Image Correlation: Strain maps analysis and reliability assessment. AB - The mechanical behaviour of porous lattice materials for potential orthopaedic applications was investigated at a fine scale by means of digital image correlation (DIC). Specimens with cubic, body cubic-centered reinforced (BCCZ), and diamond mesostructures were tested in quasi-static compression up to failure. Images were continuously recorded by an imaging setup and processed by a custom DIC program, OpenDIC. The resulting strain maps were analyzed in both spatial and temporal scales, displaying the onset and evolution of strain heterogeneities. The three geometries show different failure modes, i.e. collective buckling of an entire row for cubic, diagonal shearing band for BCCZ, and generalized crushing for diamond. The strain maps correlate well with these patterns. Most importantly, they show early strain localization below the macroscopic elastic limit. After failure, a phenomenon of strain release was witnessed and evaluated in the parts of the specimen that do not fracture. In the cubic geometry, the vertical struts sustain most of the deformation. Further analysis shows that the rows of vertical struts have similar, yet scattered, evolutions until failure. Interestingly, the row that leads to specimen failure is not necessarily the first one to deform. In addition to these experimental results, the uncertainties of the method were thoroughly assessed by means of calibration procedures. PMID- 30029166 TI - Made from concentrate? A national web survey assessing dab use in the United States. AB - BACKGROUND: Cannabis concentrates, including dabs, contain extremely high levels of Delta9-tetrahydrocannabinol (THC). Although these products appear to be gaining popularity among recreational cannabis consumers, little data exists regarding concentrate use in the US. We conducted a national web-based survey to examine patterns of concentrate use, specifically dabbing. METHODS: 4077 respondents completed a survey designed to assess the use of conventional flower cannabis relative to dabs. Individuals provided information about frequency and magnitude of use, and also completed the Marijuana Motives Measure and Severity of Dependence Scale to examine whether dab users have different motives for use and/or demonstrate more severe consequences of use compared to those who only use conventional flower products. RESULTS: 58% of respondents reported they had tried dabs at least once and 36.5% endorsed regular use (once a month or more). Those who use regularly use dabs were significantly more likely to report using for experimentation (feeling "curious") relative to reasons for using conventional flower products. Interestingly, motives reflecting positive effects (i.e., coping, sleep problems, relieving social anxiety) were endorsed more highly for flower use. In addition, regular dab users reported being more worried about their use of cannabis products relative to those who had tried dabs but did not use regularly. CONCLUSIONS: Results indicate that cannabis consumers do not necessarily choose dabs over flower products for positive effects, but rather appear to choose these highly potent products for experimentation. As concentrate use may lead to increased cannabis-related problems, studies directly assessing concentrate users are needed. PMID- 30029165 TI - Matrix metalloproteinase-2-induced epidermal growth factor receptor transactivation impairs redox balance in vascular smooth muscle cells and facilitates vascular contraction. AB - Increased reactive oxygen species (ROS) formation may enhance matrix metalloproteinase (MMP)-2 activity and promote cardiovascular dysfunction. We show for the first time that MMP-2 is upstream of increased ROS formation and activates signaling mechanisms impairing redox balance. Incubation of vascular smooth muscle cells (VSMC) with recombinant MMP-2 increased ROS formation assessed with dihydroethidium (DHE) by flow cytometry. This effect was blocked by the antioxidant apocynin or by polyethylene glycol-catalase (PEG-catalase), and by MMP inhibitors (doxycycline or GM6001). Next, we showed in HEK293 cells that MMP-2 transactivates heparin-binding epidermal growth factor (HB-EGF) leading to EGF receptor (EGFR) activation and increased ROS concentrations. This effect was prevented by the EGFR kinase inhibitor Ag1478, and by phospholipase C (PLC) or protein kinase C (PKC) inhibitors (A778 or chelerythrine, respectively), confirming the involvement of EGFR pathway in MMP-2-induce responses. Next, we showed that intraluminal exposure of aortas to MMP-2 increased vascular MMP-2 levels detected by immunofluorescence and gelatinolytic activity (by in situ zimography) in association with increased ROS formation. This effect was inhibited by MMP inhibitors (phenanthroline or doxycycline) and by apocynin or PEG-catalase. MMP-2 also increased aortic contractility to phenylephrine and this effect was prevented by MMP inhibitor GM6001 and by apocynin or PEG-catalase, showing again that increased ROS formation mediates functional effects of MMP-2. These results show that MMP-2 activates the EGFR and triggers downstream signaling pathways increasing ROS formation and promoting vasoconstriction. These findings may have various implications for cardiovascular diseases. PMID- 30029168 TI - Concentrations, spatial distributions, and congener profiles of polychlorinated dibenzo-p-dioxins and dibenzofurans around original plastic solid waste recovery sites in China. AB - The concentrations, profiles, and spatial distributions of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in soil and sediment samples from several typical plastic solid waste (PSW) recovery sites (particularly from areas in which PSW is burned openly) in China were investigated. The results showed that burning PSW directly influenced PCDD/F concentrations immediately around the burning area. All of the samples in which soil contained black burning residue, collected from immediately around burning areas, had PCDD/F concentrations (mean 21708 ng kg-1) and toxic equivalent (TEQ) concentrations (mean 2140 ng I-TEQ kg-1 or 1877 ng WHO2006-TEQ kg-1) more than 100 times higher than the concentrations in samples collected away from burning areas (mean 222 ng kg-1, 8.75 ng I-TEQ kg 1, 7.96 ng WHO2006-TEQ kg-1). Principal component analysis and hierarchical cluster analysis indicated that the PCDD/F concentrations in seven soil samples from near PSW burning areas were influenced by PSW burning but that the PCDD/Fs in these soil samples may have had other or multiple sources. PCDD/F distributions at PSW recovery sites have been investigated in few previous studies. The results presented here indicate that appropriate measures should be taken to decrease the ecological risks posed by PSW recovery and to prevent, control, and remediate PCDD/F and other chemical contamination caused by PSW recovery. PMID- 30029164 TI - Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. AB - Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD. PMID- 30029169 TI - Evaluation of PM10, CO2, airborne bacteria, TVOCs, and formaldehyde in facilities for susceptible populations in South Korea. AB - Poor indoor air quality can have adverse effects on human health, especially in susceptible populations; however, few studies have measured multiple pollutants in facilities for susceptible populations at a national scale in South Korea. Therefore, we measured the concentrations of indoor pollutants (fine particulate matter (PM10), CO2, airborne bacteria (AB), total volatile organic compounds (TVOCs), and formaldehyde) to determine their possible relation to other indoor environmental factors and characteristics of facilities with susceptible populations, such as hospitals, geriatric hospitals, elderly care facilities, and postnatal care centers throughout South Korea. Indoor pollutants were sampled at 82 indoor facilities, including 62 facilities for susceptible populations. Spearman's correlation, Kruskal-Wallis, and Mann-Whitney analyses were used to examine the relationship among and differences between pollutants at indoor facilities and indoor/outdoor differences in PM10 concentration. There were significant correlations between indoor temperature and AB concentration (r = 0.37, p < 0.01), TVOCs, and formaldehyde (r = 0.264, p < 0.01). Indoor PM10 concentrations were higher than outdoor concentrations at all facilities for susceptible populations (p < 0.01). CO2 might be a good indicator for predicting indoor pollutants when categorized into two levels (<=750 ppm and >750 ppm). The hazard quotient of formaldehyde was higher than the acceptable level of 1 for children under the age of eight in postnatal care centers, indicative of unsafe levels. Therefore, more depth study for exposure characteristics of formaldehyde and indoor air quality (IAQ) in postnatal care facilities as a national scale is needed for finding the children exposure levels. PMID- 30029170 TI - Lambda-cyhalothrin delays pubertal Leydig cell development in rats. AB - Lambda-cyhalothrin (LCT) is a widely used broad-spectrum pyrethroid insecticide and is expected to cause deleterious effects on the male reproductive system. However, the effects of LCT on Leydig cell development during puberty are unclear. The current study addressed these effects. Twenty-eight-day-old male Sprague Dawley rats orally received LCT (0, 0.25, 0.5 or 1 mg/kg body weight/day) for 30 days. The levels of serum testosterone, luteinizing hormone, and follicle stimulating hormone, Leydig cell number, and its specific gene and protein expression were determined. LCT exposure lowered serum testosterone levels at doses of 0.5 and 1 mg/kg and luteinizing hormone levels at a dose of 1 mg/kg, but increased follicle-stimulating hormone levels at doses of 0.5 and 1 mg/kg. LCT lowered Star and Hsd3b1 mRNA or their protein levels at a dose of 1 mg/kg. Immature Leydig cells were purified from pubertal rats and treated with different concentrations of LCT for 24 h and medium androgen levels, Leydig cell mRNA and protein levels, the mitochondrial membrane potential (?Psim), and the apoptotic rate of immature Leydig cells were investigated. LCT inhibited androgen production at 5 MUM and downregulated Scarb1 at 0.05 MUM, Hsd3b1 and Hsd11b1 at 0.5 MUM, and Cyp11a1 at 5 MUM. LCT also decreased ?Psim at 0.5 and 50 MUM. In conclusion, LCT can influence the function of Leydig cells. PMID- 30029172 TI - Enhancement effect of earthworm (Eisenia fetida) on acetochlor biodegradation in soil and possible mechanisms. AB - Acetochlor is a widely used chloroacetanilide herbicide and has posed environmental risks in soil and water due to its toxicity and high leaching capacity. Earthworm represents the dominant invertebrate in soil and can promote the decomposition of organic pollutants. The effect of earthworm on acetochlor degradation in soil was studied by soil column experiment with or without acetochlor and earthworm in sterile and natural soils. The degradation capacities of drilosphere components to acetochlor were investigated by microcosm experiments. Bacterial and fungal acetochlor degraders stimulated by earthworm were identified by high-throughput sequencing. The degradation kinetics of acetochlor suggested that both indigenous microorganisms and earthworm played important roles in acetochlor degradation. Acetochlor degradation was quicker in soil with earthworms than without earthworms, with the degradation rates increased by 62.3 +/- 15.2% and 9.7 +/- 1.7% in sterile and natural treatments respectively. The result was related to the neutralized pH, higher enzyme activities and enhanced soil microbial community diversity and richness in the presence of earthworms. Earthworm cast was the degradation hotpot in drilosphere and exhibited better anaerobic degradation capacity in microcosm experiments. The acetochlor degradation rate of cast in anaerobic environment was 12.0 +/- 0.1% quicker than that in aerobic environment. Residual acetochlor in soil conferred a long-term impairment on fungal community, and this inhibition could be repaired by earthworm. Earthworm stimulated indigenous degraders like Sphingomonas and Microascales and carried suspected intestinal degraders like Mortierella and Escherichia_coli to degradation process. Cometabolism between nutrition cycle species and degraders in casts also contributed to its faster degradation rates. The study also presented some possible anaerobic degradation species like Rhodococcus, Pseudomonas_fulva and Methylobacillus. PMID- 30029173 TI - Market characteristics associated with community health assessments by local health departments. AB - OBJECTIVES: Community health assessments (CHAs) have been promoted as a strategy for population health. This study uses the resource dependence theory (RDT) to examine how external market characteristics are associated with CHAs conducted by local health departments (LHDs) and subsequent partnering with hospitals for CHAs in the United States. STUDY DESIGN: The RDT was used to guide the conceptualization of the market in the context of local public health. RDT emphasizes that organizations are not in control of all the resources they need and, to some extent, must rely on the external environment to provide those necessary resources. Binary measures were used to examine whether LHDs conducted CHAs and whether they did so in partnership with a local hospital. Independent variables were identified to measure the RDT constructs of munificence (resource availability in the environment), complexity (level of heterogeneity), and dynamism (level of environmental turbulence). METHODS: Bivariate (Chi-squared and t-tests) and multivariate (logistic regression) cross-sectional analyses were conducted using secondary data from the National Association of County and City Health Officials 2013 Profile Survey, the 2013 County Health Rankings data set, and the Health Resources and Services Administration's Area Health Resource File. RESULTS: Two of three variables measuring munificence were positively associated with having conducted a CHA; one variable was also related to doing so in conjunction with a local hospital. One measure of market complexity was negatively associated with having conducted a CHA. No measure of dynamism was related to the dependent variables. CONCLUSIONS: Study results provide partial support for the use of RDT in understanding the relationship between market factors and LHDs' activities around CHAs. Local hospitals as partners and other market factors should be considered by LHDs when conducting CHAs. Findings from this work will be of interest to public health practitioners, policy-makers, and researchers interested in public health and population health improvement. PMID- 30029171 TI - Re-emission of legacy mercury from soil adjacent to closed point sources of Hg emission. AB - Mercury (Hg) emissions from point sources to air may disperse over long distance depending on Hg speciation in the plume. A significant fraction of Hg, particularly in its divalent forms, deposits locally and causes pollution to surrounding biomes. The objective of this study was to investigate (1) the historic Hg deposition to the immediate vicinity of an industrial complex that had intentional use of Hg (i.e., chlor-alkali and polyvinyl chloride production) for 5 decades until 2011, and (2) the Hg0 re-emission from soil to air soon after the closure of the facility. The spatial distribution of near-ground Hg0 vapor in air, soil Hg concentration and stable isotope ratio, air-soil Hg0 flux and Hg0 concentration in soil pore-gas were measured. It was found that the surrounding soils are severely contaminated with Hg due to the Hg release of the industrial complex, displaying soil Hg content up to 4.8 MUg g-1. A spatial trend of Hg mass dependent isotope fractionation signature (delta202Hg = -2.110/00 to 0.720/00) with respect to the distance from the closed facility was identified, representing a mixing between regional background and industrial Hg sources. Hg release from the industrial operation enhanced surface soil Hg content within a 6.5-km radius from the facility. Inside the facility, residual Hg wastes (i.e., electrolysis sludge and consumed HgCl2 catalyst) represent a strong localized emission source of atmospheric Hg0. Near-ground atmospheric Hg0 concentration and soil Hg0 efflux progressively elevated toward the facility with an increase by 2 3 orders of magnitude compared to the values observed in the off-site background. These results suggest that the natural soil surfaces surrounding the closed industrial facility act as a large nonpoint source emitting legacy deposited Hg as much as the release from naturally enriched mines. PMID- 30029174 TI - New insight into the effect of fungal mycelia present in the bio-pretreated paddy straw on their enzymatic saccharification and optimization of process parameters. AB - Assessment of Pleurotus florida efficiency on paddy straw pretreatment and optimization of saccharification parameters were studied. P. florida growth was monitored by the estimation of fungal cell wall component (glucosamine). The control bio-pretreatment sample showed high glucosamine content by 397 mg/g in 28 days of incubation. But, the Inhibitor Mediated Biological (IMB) Pretreatment showed 29% lower result due to the inhibition of cellulase enzyme limits mycelial penetration rate inside the paddy straw. Fungal components present inside the pretreated straw renders nonspecific interactions with the hydrolytic enzymes during saccharification process and reducing the hydrolysis efficiency. IMB pretreated paddy straw showed maximum saccharification efficiency up to 75.3% with optimized condition (Biomass loading- 10% (w/v), Enzyme loading- 20 FPU/g and saccharification time - 72 h) than control pretreatment sample. Thus, the study brings out new insight into the effect of fungal residues inside the bio pretreated paddy straw during enzymatic saccharification to improve the efficiency. PMID- 30029175 TI - Response of antibiotic and heavy metal resistance genes to two different temperature sequences in anaerobic digestion of waste activated sludge. AB - Response of antibiotic resistance genes (ARGs) and heavy metal resistance genes (HMRGs) to two different temperature sequences (i.e., mesophilic-thermophilic and thermophilic-mesophilic) were investigated. Higher removal of total ARGs (twenty one targeted subtypes) and HMRGs (three targeted subtypes) was achieved by the mesophilic-thermophilic sequence than by the thermophilic-mesophilic sequence. The sequence of mesophilic-thermophilic showed the highest removal of total ARGs, but the sequence of thermophilic-mesophilic proved more suitable for removal of class 1 integrons (intI1). Correlation analysis indicated that intI1 correlated significantly with tetG, tetQ, tetX, sul2, aac(6')-lb-cr, blaTEM, ermB and floR. High-throughput sequencing revealed that the mesophilic-thermophilic sequence TPAD removed more human bacterial pathogens (HBPs) than did the thermophilic mesophilic sequence. Also, significantly positive correlation was observed between ARGs and HBPs. For instance, Mycoplasma pneumonia showed significantly positive correlation with several ARGs including tetE, tetQ, tetX, tetZ, sul1, sul2, aac(6')-lb-cr and floR. PMID- 30029177 TI - Dual function of ammonium acetate in acetone-butanol-ethanol fermentation by Clostridium acetobutylicum. AB - In this study, a compound nitrogen source, integrating the advantages of ammonium acetate and soybean meal, was proposed to further improve acetone-butanol-ethanol fermentation. Unfortunately, this compound nitrogen source was found to effectively inhibit cellular performance, as the introduction of NH4+ significantly decreased the yield of butanol and total solvents by 34.78% and 35.14%, to only 6.62 g/L and 10.76 g/L, respectively. Meanwhile, the regulatory mechanism was further elucidated at different levels. As a result, the NH4+ could down-regulate the transcriptional levels of key genes involved in butanol synthesis, and the activity of acetoacetyl-CoA/acyl-CoA transferase, and then decrease the accumulation of key intermediates. Therefore, ammonium acetate has a dual function in ABE fermentation, as it effectively improves ABE fermentation when it is the sole nitrogen source but significantly decreases fermentation performance in the presence of soybean meal, broadening the understanding of nitrogen regulation mechanism of C. acetobutylicum. PMID- 30029176 TI - Bioprocess development for biolubricant production using microbial oil derived via fermentation from confectionery industry wastes. AB - Microbial oil produced from confectionery and wheat milling side streams has been evaluated as novel feedstock for biolubricant production. Nutrient-rich fermentation media were produced by a two-step bioprocess involving crude enzyme production by solid state fermentation followed by enzymatic hydrolysis of confectionery industry waste. Among 5 yeast strains and 2 fungal strains cultivated on the crude hydrolysate, Rhodosporidium toruloides and Cryptococcus curvatus were selected for further evaluation for biolubricant production based on fermentation efficiency and fatty acid composition. The extracted microbial oils were enzymatically hydrolysed and the free fatty acids were esterified by Lipomod 34-MDP in a solvent-free system with trimethylolpropane (TMP) and neopentyl glycol (NPG). The highest conversion yields were 88% and 82.7% for NPG esters of R. toruloides and C. curvatus, respectively. This study also demonstrates that NPG esters produced from microbial oil have promising physicochemical properties for bio-based lubricant formulations that could substitute for conventional lubricants. PMID- 30029178 TI - Synergistic effect of modified activated carbon and ionic liquid in the conversion of microcrystalline cellulose to 5-Hydroxymethyl Furfural. AB - This study highlights cellulose conversion for the production of 5-Hydroxymethyl Furfural using synergistic effect of modified activated carbon and ionic liquid under moderate reaction conditions. Modified Activated carbon after acid treatment (ACS, ACP, ACH) were used to examine their catalytic activity on hydrolysis of cellulose in [Bmim]Cl medium. Changes in physical-chemical properties were characterized using XRD, FE-SEM, EDX, FT-IR and BET surface area analyser techniques. Modified activated carbon is found competent in enhancing cellulose conversion to Total Reducing Sugars and 5-Hydroxymethyl Furfural. Further, the effect of six metal ions i.e Cr+3, Fe+3, Cu+2, Zn+2, K+ and Al+3 impregnated on sulfuric acid treated activated carbon (ACS) was explored. The catalytic performance improves with the impregnation of metals in the decreasing order: Cr+3> Fe+3> Cu+2> Zn+2> Al+3> K+. These modified catalysts with ionic liquid as solvent are found promising to generate eco-friendly system and cost effective cellulose conversion to value added products. PMID- 30029179 TI - Microwave-assisted in-situ elimination of primary tars over biochar: Low temperature behaviours and mechanistic insights. AB - An efficient method for microwave-assisted low temperature catalytic elimination of primary tars using cheap biochar as catalyst has been developed along with H2 rich syngas production. Tar removal efficiency reached 94.03% after 8 min reaction at 600 degrees C, while the concentration of H2 and syngas was up to 50.5 vol% and 94.5 vol% respectively, which were significantly comparable to conventional technologies at 700-900 degrees C. The FT-IR, ICP and EDX results indicated that the biochar surface contained O-containing functional groups and 12.6 wt% uniformly dispersed alkali and alkaline earth metals (AAEMs) in the carbon skeleton. The low temperature behaviours were attributed to the hot spots, which were induced by the increased dielectric properties of biochar and decentralized AAEMs under microwave heating. Possible reaction mechanism for the elimination of primary tars over biochar catalysts were discussed based on this experimental study. PMID- 30029180 TI - Buoy-bead flotation harvesting of the microalgae Chlorella vulgaris using surface layered polymeric microspheres: A novel approach. AB - To improve microalgae harvesting efficiency and to reduce the addition of chemicals in the buoy-bead flotation process, a novel buoy-bead flotation approach has been developed for harvesting Chlorella vulgaris, using surface layered polymeric microspheres (SLPMs). Next, the detachment of microalgae cell SLPM aggregates and the reusability of SLPMs were investigated. The experimental results showed that a maximum harvesting efficiency of 98.43% was achieved at a SLPM dosage of 0.7 g/L and a pH of 9, and harvesting efficiency quickly decreased with increasing ionic strength. A detachment efficiency of 78.46% and a concentration factor of 19.56 were achieved at an ionic strength of 700 mM and a mixing speed of 3000 rpm without changing the pH. Reused SLPMs can still reach an efficiency of 72.13% after five cycles. The presented results show that this method can potentially be applied for large-scale microalgae harvesting. PMID- 30029181 TI - Insights into the economic viability of cellulases recycling on bioethanol production from recycled paper sludge. AB - The economics of Recycled Paper Sludge conversion into ethanol was here assessed with emphasis on integrating a cellulase recycling system. Without cellulases recycling this process presented positive economic outputs (payback period of 7.85 years; 10.90 Million US$ of accumulated NPV) despite the modest ethanol titers. Recycling both free and solid-bound enzymes allowed considerable savings of enzyme but also an increase on annual costs (0.88%), resulting on a superior economic output: payback period decreased to 7.25 years; accumulated NPV increased to 14.44 Million US$. Recycling exclusively the liquid fraction enabled a clear costs reduction, however, also total ethanol decreased, attenuating the abovementioned benefits. Targeting higher ethanol concentrations, superior solids consistencies were also evaluated. Despite a costs reduction, total ethanol decreased due to a higher ethanol retention on the solid. A sensitivity analysis further revealed that the cost of enzymes and ultrafiltration membrane may be critical on enzyme recycling economic feasibility. PMID- 30029182 TI - Food waste compost as an organic nutrient source for the cultivation of Chlorella vulgaris. AB - The present study investigates the prospective of substituting inorganic medium with organic food waste compost medium as a nutrient supplement for the cultivation of Chlorella vulgaris FSP-E. Various percentages of compost mixtures were replaced in the inorganic medium to compare the algal growth and biochemical composition. The use of 25% compost mixture combination was found to yield higher biomass concentration (11.1%) and better lipid (10.1%) and protein (2.0%) content compared with microalgae cultivation in fully inorganic medium. These results exhibited the potential of combining the inorganic medium with organic food waste compost medium as an effective way to reduce the cultivation cost of microalgae and to increase the biochemical content in the cultivated microalgae. PMID- 30029183 TI - Geometry of Gene Expression Space of Wilms' Tumors From Human Patients. AB - Wilms' tumor is a pediatric malignancy that is thought to originate from faulty kidney development during the embryonic stage. However, there is a large variation between tumors from different patients in both histology and gene expression that is not well characterized. Here we use a meta-analysis of published microarray datasets to show that Favorable Histology Wilms' Tumors (FHWT's) fill a triangle-shaped continuum in gene expression space of which the vertices represent three idealized "archetypes". We show that these archetypes have predominantly renal blastemal, stromal, and epithelial characteristics and that they correlate well with the three major lineages of the developing embryonic kidney. Moreover, we show that advanced stage tumors shift towards the renal blastemal archetype. These results illustrate the potential of this methodology for characterizing the cellular composition of Wilms' tumors and for assessing disease progression. PMID- 30029185 TI - Rapid determination by near infrared spectroscopy of theaflavins-to-thearubigins ratio during Congou black tea fermentation process. AB - The theaflavin-to-thearubigin ratio (TF/TR) is an important parameter for evaluating the degree of fermentation and quality characteristics of Congou black tea. Near infrared (NIR) spectroscopy, one of the most promising techniques for evaluating large-scale tea processing quality, in association with chemometrics, can be used as a selection tool when a fast determination of the requested parameters is required. The aim of this work is to develop a unique model for the determination of TF/TR. First, 11 key wavelength variables were screened by synergy interval partial least-squares regression (SI-PLS) and competitive adaptive reweighted sampling (CARS). Based on these characteristic variables, a new extreme learning machine (ELM) combined with an adaptive boosting (ADABOOST) algorithm (ELM-ADABOOST) was applied to construct the nonlinear prediction model for TF/TR, and an independent external set was used for the validation. A determinate coefficient (Rp2) of 0.893, root mean square error of prediction (RMSEP) of 0.0044, RSD below 10%, and RPD above 3 were acquired in the prediction model. These results demonstrate that NIR can be used to rapidly determine the TF/TR value during fermentation, and it effectively simplify the model and improve the prediction accuracy when combined with the SI-CARS variable. PMID- 30029184 TI - Proteomic and transcriptomic approaches to identify resistance and susceptibility related proteins in contrasting rice genotypes infected with fungal pathogen Rhizoctonia solani. AB - The devastating sheath blight disease caused by Rhizoctonia solani Kuhn (teleomorph: Thanatephorus cucumeris) causes major yield loss in most rice growing regions of the world. In this study, two moderately tolerant and four susceptible genotypes of rice were selected for R. solani induced proteome analysis using two-dimensional polyacrylamide gel electrophoresis. Forty five differentially expressed proteins (DEPs) were identified and analyzed by Mass Spectrometry. Based on their functions, these proteins were classified into different groups, viz., photosynthesis, resistance and pathogenesis, stress, cell wall metabolism and cytoskeleton development associated proteins, and hypothetical or uncharacterized proteins. Expression of 14 genes encoding DEPs was analyzed by quantitative PCR which showed consistency in transcripts and genes expression pattern. Furthermore, the expression of 16 other genes involved in diverse biological functions was analyzed. Up-regulation of these genes in the tolerant genotype Pankaj during sheath blight disease suggested efficient genetic regulation of this cultivar under stress. Also, expression analysis of conserved microRNAs (miRNAs) and their target genes revealed important role of miRNAs in post-transcriptional gene regulation during development of rice sheath blight disease. Genome-wide discovery of miRNAs and further characterization of DEPs and genes will help in better understanding of the molecular events during sheath blight disease development in rice. PMID- 30029186 TI - Negative infrared bands-A new phenomenon in the vibrational spectroscopy of water oligomers. AB - Infrared spectra of small amounts of water on the "hydrophobic" polymers, polyethylene (PE), polypropylene (PP) and polytetrafluoroethylene (PTFE), include many negative infrared bands that become positive with increasing temperature. The new species that the bands represent must arise through absorption of the incident radiation to form short-lived femtosecond states that disappear by (a) induced (Einstein) emission, thus leading to negative IR bands, or (b) fragmentation with loss of vibrational energy or (c) are replaced by an infrared excited state. In addition, we must note that polyethylene, polypropylene and polytetrafluoroethylene carry water! and many water oligomers (chair, boat, and prism hexamer) are easily observed. PMID- 30029187 TI - The effect of Sn on the physical and optical properties of (Se0.6As0.1Ge0.3)100 xSnx glasses. AB - Chalcogenide glasses are significant materials for semiconducting and infrared imaging because of their infrared (IR) transparency. In the present study, Se-Ge As based chalcogenide glasses with chemical composition of (Se0.6As0.1Ge0.3)100-x Snx doped with different amounts of Sn were prepared by conventional melting quenching method. Physical properties of glasses were investigated by studying density and molar volume. Based on differential scanning calorimetry (DSC) results and density measurements, the binary role of Sn was proved. Fourier transform infrared spectroscopy (FT-IR) study of the samples approved presence of impurities. Using the UV-Vis spectra, optical properties including Fermi energy level, direct and indirect optical band gap and Urbach energy were determined. The results showed a decrease in density of glasses with the increase of Sn from 2 to 6 mol%. Increasing Sn in the glassy microstructure of samples provides a semiconducting character to Se based chalcogenide glass by reducing the direct and indirect optical band gaps of glass samples from 1.29 to 1.15 (eV) and 1.16 to 1.01 (eV), respectively. PMID- 30029188 TI - Novel chemical sensor for detection Ca(II) ions based on ferutinin. AB - A new optical chemical sensor based on medicinal compound, jaeschkeanadiol p hydroxyben-zoate (Ferutinin), has been designed and utilized for Ca(II) ions detections. This natural optical sensor exhibits immense selectivity including fluorescence and absorption ratiometric for Ca(II) ions within precious physiological pH range. Further, the chelation process of the Ca(II) ions with the medicinal optical sensor ferutinin yields a 1:1 (metal: ligand) complex which is accompanied by fluorescence enhancement of the main emission band centered at 355 nm of the medicinal probe. The fluorescence "turn-on" effect is a clear evidence for the chelation process between ferutinin medicinal probe and Ca(II) ions and this could be simply detected. The new sensor was proposed depending on significant fluorescence mechanism, (MLCT, metal-ligand charge transfer). However, the interaction of the medicinal optical sensor with Ca(II) in presence of other cations was examined without any significant interference. Also, the new developed optical sensor consecutively exhibits low limit of detection (LOD) 1.5 nM for Ca(II) which is detected in very significant physiological pH range (pH = 7.4). Also, the probe provides high binding affinity towards Ca(II) with large binding constant Kb 5.97 * 104 M-1. As a result, this optical sensor may apply for detection Ca(II) in cell or biological samples. PMID- 30029189 TI - FTIR and dispersive gas phase fundamental infrared intensities of the fluorochloromethanes: Comparison with QCISD/cc-pVTZ results. AB - New experimental values of the fundamental infrared gas phase intensities of the fluorochloromethanes have been determined by integrating the areas of vibrational bands contained in the PNNL spectral library using homemade software. The root mean square differences of these values and averages of experimental values determined at lower resolution during the latter part of the 20th century is 26.6 km mol-1. All but one of the low resolution intensities are smaller than the PNNL values. The exception is the nu1,nu4 overlapped band intensity of CF3Cl that has a standard deviation of the low resolution values of +/-112.5 km mol-1, larger than the observed difference of 102.5 km mol-1. The use of an augmented triple zeta basis set at the QCISD level results in an rms difference of only 8.4 km mol 1 for the fluoro- and chloromethane PNNL intensities, whereas a comparison of these with results at the QCISD/cc-pVTZ level produces an error twice as large, 16.2 km mol-1. As such these results suggest that future comparisons of theoretical intensities with experimental values should take into account integrated intensities that can be obtained from hundreds of spectra in the PNNL library. Furthermore, the intensity values obtained from the PNNL spectra confirm electronegativity model results previously reported based on the low resolution intensities. PMID- 30029190 TI - A naphthalene-quinoline based chemosensor for fluorescent "turn-on" and absorbance-ratiometric detection of Al3+ and its application in cells imaging. AB - A new naphthalene-quinoline based chemosensor L was prepared and structurally characterized. L exhibited excellent selectivity and sensitivity to Al3+ through distinct fluorescence enhancement (335-fold) and ratiometric detection in DMF/H2O (v/v, 1/9) based on the combined mechanisms of ESIPT and CHEF. The recognizing behavior of L toward Al3+ had been investigated in detail through Job's Plot, FT IR, HNMR, and HRMS analysis. The limit of detection (LOD) for Al3+ was as low as and 3.67 * 10-8 M. L was successfully applied in real sample detection and construction of molecular logic gate. Moreover, L was verified to be of low cytotoxicity and good imaging characteristics for the detection of Al3+ in cells HSC. PMID- 30029191 TI - Rational design of an "on-off-on" fluorescent switch for Cu2+ and histidine based on chiral macrocyclic dioxopolyamine. AB - A novel chemosensor 1 having a chiral macrocyclic dioxopolyamine of C2 symmetry as a receptor and anthracene as a signal unit has been designed and synthesized for cations and alpha-amino acids recognition in DMSO-HEPES buffer (1:9, v/v, pH 7.2). The ligand exhibited selective response to Cu2+ even in the presence of other metal ions with a fluorescence "switch-off" behavior. Additionally, the in situ generated 1-Cu2+ ensemble displayed specific recognition to histidine by a "switch-on" fluorescence response. For this dual functional switch, its sensing behavior via a displacement mode was confirmed by 1H NMR titration and ESI mass spectroscopy. Sequential "on-off-on" fluorescence responses of 1 to Cu2+ and histidine are successfully applied in HeLa cells. PMID- 30029192 TI - An experimental ninhydrin design approach for the sensitive spectrofluorimetric assay of milnacipran in human urine and plasma. AB - Women are the most ones who susceptible to a common syndrome called fibromyalgia syndrome, up to 90% of all people with fibromyalgia are women. It affects mainly muscles and soft tissue and cause for them muscle pain, sleep problems and painful tender points. Milnacipran is acting as a serotonin-norepinephrine reuptake inhibitor (SNRI) therefore, it is recommended for the treatment of this syndrome. The widespread use of this compound in our market requires the development and validation of a simple, sensitive, cheap, fast and reproducible spectrofluorimetric method for the assay of milnacipran hydrochloride in its pure state, pharmaceutical tablets and spiked human urine and plasma. In the current work ninhydrin and phenylacetaldehyde in Teorell and Stenhagen buffer (pH 7) reacts with the amino moiety of milnacipran through a sensitive condensation reaction resulting in formation of a fluorescent product, which exhibits its fluorescence emission intensity at 465 nm after excitation at 390 nm. It is observed that, in the concentration range 0.5 to 3.0 MUgmL-1, the constructed calibration curve was linear with a good correlation coefficient (0.9998). The condensation reaction was successfully applied for the assay of the studied drug in Avermilan(r) tablets, spiked human urine and plasma without interference from the components of the sample matrix with average percentage recoveries of 101.73 +/- 0.56 and 100.55 +/- 0.64 for urine and plasma, respectively. PMID- 30029193 TI - Photoconversion of an anthraquinone derivative in the presence of human serum albumin. AB - Photconversion of an anthraquinone photochrome (AQP) from Trans to Ana forms were studied by different methods and techniques. Solution of AQP was irradiated under UV light in buffer condition, pH = 7.5, 10 mM phosphate buffer in the absence and presence of human serum albumin at 27 and 37 degrees C. The results showed that a new peak at higher wavelength was observed that indicative of producing the Ana form. Rate of Trans to Ana conversion increases in the presence of human serum albumin (HSA). Electron transport calculations were carried out from the first principles with a method based on non-equilibrium Green's functions (NEGF) combined with DFT. The results showed that electron transport is easier in Ana form due to increasing the resonance length and electron delocalization. Binding study by docking and spectroscopy showed that Trans form has more tendency to interact with HSA due to higher number of HSA-Trans hydrogen bond. Structural studies by circular dichroism and molecular dynamics results show that at lower concentration of AQP, percentage of helix was increased and then decreases at higher concentration. In addition structural parameters such as RMSD, accessible surface area, hydrogen bond, in associated with experimental results showed that protein folded at low concentration. PMID- 30029194 TI - Experimental and theoretical investigations of tartaric acid isomers by terahertz spectroscopy and density functional theory. AB - The terahertz (THz) absorption spectra of l-, d-, and dl-tartaric acid have been measured in the frequency range from 0.2 to 2.0 THz by terahertz time-domain spectroscopy (THz-TDS). The characteristic absorption peaks of these three tartaric acid isomers were obtained, which showed remarkable difference between enantiomers (l- and d-tartaric acid) and the racemic compound (dl-tartaric acid) in their peak frequencies. In parallel with the experimental study, theoretical calculations on isolated-molecule and unit cell of tartaric acids using density functional theory (DFT) were also performed for simulating the experimental THz spectrum features, which were in good agreement with the experimental data. Results demonstrate that THz-TDS can distinguish the tiny diversity between tartaric acid chiral isomers and its racemic compound, and provided an effective method for molecular identification in biological and biomedical engineering. PMID- 30029195 TI - Analysis of raw EEM fluorescence spectra - ICA and PARAFAC capabilities. AB - Excitation-Emission fluorescence spectroscopy is a versatile technique and has been used to detect, characterize and quantify residual Dissolved Organic Matter (DOM) in aquatic domains. PARAllel FACtor Analysis (PARAFAC) has been extensively used in the analysis of excitation-emission matrices (EEM), allowing for a better identification and quantification of contributions resulting from spectral decomposition. In this work we have adapted Independent Component Analysis (ICA) in order to make it suitable to the analysis of three-way EEM datasets, and tested ICA and PARAFAC performances for the study of three available datasets (Claus, Dorrit and drEEM). Semi-empirical simulation allowed us to assess the impact of (a) sample size, (b) signal sources and (c) composition dependencies, and the presence of (d) unspecific signal contributions (e.g. light scattering) upon both algorithms. PARAFAC and ICA have similar performances in processing ideal three-way EEM datasets but, in the presence of non-trilinear responses, ICA leads to a more realistic approach, yielding a better decomposition of contributing sources and their identification and quantification. This makes this algorithm more suitable for the analysis of real, raw EEM data, without the need of preprocessing to remove any unspecific contributions. PMID- 30029196 TI - Peptide modified paper based impedimetric immunoassay with nanocomposite electrodes as a point-of-care testing of Alpha-fetoprotein in human serum. AB - Treatment for cancer depends on the type of cancer, and the stage or its development, and thus the need for point-of-care technology that can allow rapid and precise detection of biomarkers is increasing. Here, we present a simple on chip electrical detection of Alpha-fetoprotein (AFP). We rely on using a novel peptide modified plastic-paper microfluidic chips to perform efficient and specific impedimetric detection of AFP in human serum. The chips are prepared from a lower sheet of plastic and upper layer of cellulose chromatography paper modified with silver-20 wt% graphene printed electrodes. Diphenylalanine (FF) was proposed to involve in detection zone of the fabricated microchips in order to improve the sensing performance and the stability of immobilized antibodies according to amine-aldehyde reaction. The target protein is captured on the surface of microchips using specific monoclonal antibodies and the electrical response of the chip is monitored in the presence and absence of different concentrations of AFP. The influence of several parameters including the material types for screen printing of electrodes, FF concentrations, solvent and pH of FF solution on electrical response and cellulose fibers morphology was explored. The impedance measurements of AFP on the fabricated microchip in the optimized parameters exhibited a detection limit of 1 and 10 ng ml-1 in PBS and plasma, respectively. This platform developed here can be adopted to develop systems for rapid detection of biomarkers using portable electric devices. PMID- 30029197 TI - Ultra-rapid fabrication of highly surface-roughened nanoporous gold film from AuSn alloy with improved performance for nonenzymatic glucose sensing. AB - Using one-step anodization strategy, a nanoporous gold film (HNPG) with large surface area was rapidly fabricated on Au80Sn20 (wt%) alloy in just 80 s. The formation of highly surface-roughened nanoporous structures results from a complex process of electrochemical dealloying of Sn component from AuSn alloy, anodic electrodissolution, disproportion and deposition of Au component, and spontaneous redox reaction between electrodissolved Sn2+ and AuCl4-species at the applied anodic potential. As-prepared HNPG/AuSn shows enhanced electrochemical performance for glucose oxidation in alkaline electrolyte. At a low potential of 0.1 V (vs. SCE), it offers a short response time of 4 s, a wide linear detection range of 2 MUM to 8.11 mM, an ultralow detection limit of 0.36 MUM (S/N = 3), an ultrahigh sensitivity of 4374.6 MUA cm-2 mM-1, and satisfactory selectivity and reproducibility. Specifically, after 6 weeks, no obvious loss of glucose amperometric signal was observed on HNPG/AuSn. The facile preparation and excellent sensing performance of HNPG/AuSn electrode make sure that it is a promising candidate for advanced enzyme-free glucose sensors. PMID- 30029198 TI - Electrochemical immunosensor for IL-13 Receptor alpha2 determination and discrimination of metastatic colon cancer cells. AB - This work describes the first electrochemical immunosensor reported for the determination of IL-13 receptor Ralpha2 (IL-13Ralpha2), an emerging relevant biomarker in metastatic colon cancer. The approach involves the formation of sandwich immunocomplexes using specific capture (CAb) and biotinylated detector antibodies (BDAb) further labeled with an streptavidin-horseradish peroxidase (Strep-HRP) polymer, onto carboxylic acid-modified magnetic microbeads (HOOC MBs). Amperometric detection at disposable carbon screen-printed electrodes (SPCEs) using the (H2O2)/hydroquinone (HQ) system was employed to monitor the affinity reactions. The developed immunosensor exhibits a linear calibration plot over the 3.9-100 ng mL-1 concentration range, a LOD of 1.2 ng mL-1 and excellent selectivity against other non-target proteins. The amperometric immunosensor was applied successfully to quantify for the first time the IL-13Ralpha2 expression in raw lysates of colon cancer cells and to discriminate the metastatic potential of intact cells through recognition of this target extracellular receptor. In comparison with the commercial Enzyme-Linked ImmunoSorbent Assay (ELISA) kit involving the same immunoreagents, the immunosensor provides a similar LOD in a half-time for the assay. PMID- 30029199 TI - Label-free photoelectrochemical immunosensor for NT-proBNP detection based on La CdS/3D ZnIn2S4/Au@ZnO sensitization structure. AB - A new, photoelectrochemical immunosensor was proposed on the basis of the La CdS/3D ZnIn2S4/Au@ZnO sensitization structure for detection of aminoterminal pro brain natriuretic peptides (NT-proBNP). The Au@ZnO-modified electrode was first assembled with 3D ZnIn2S4, and then further deposited with lanthanum doped cadmium sulfide (La-CdS) via successive ionic layer adsorption and reaction strategy. The Au@ZnO has excellent photoelectric activity and electrical conductivity. The ZnIn2S4 with 3D architectures not only exhibit high photocurrent intensity under visible-light irradiation but also have large surface for the La-CdS deposition. Meanwhile, the La-CdS doped structure could depress the charge recombination, which effectively promotes separation of the generated electron-hole (e-/h+) pairs and consequently enhances the photocurrent conversion efficiency. The polydopamine (PDA) was used not only as a cross-linker reagent for the immobilization of the anti-NT-proBNP but also as an electron donor for promoting the photo-generated e-/h+ separation of the semiconductors. Under optimal conditions, the well-designed photoelectrochemical immunoassay exhibited a low detection limit of 0.32 pg mL-1 and a wide linear range from 0.8 pg mL-1 to 45 ng mL-1 for target NT-proBNP detection. Meanwhile, it also presented good reproducibility, specificity, and stability and might open a new promising strategy for the detection of other important tumor markers. PMID- 30029200 TI - Emerging nano-biosensing with suspended MNP microbial extraction and EANP labeling. AB - Emerging nano-biosensing with suspended MNP microbial extraction and EANP labeling may ensure a secure microbe-free food supply, as rapid response detection of microbial contamination is of utmost importance. Many biosensor designs have been proposed over the past two decades, covering a broad range of binding ligands, signal amplification, and detection mechanisms. These designs may consist of self-contained test strips developed from the base up with complicated nanoparticle chemistry and intricate ligand immobilization. Other methods use multiple step-wise additions, many based upon ELISA 96-well plate technology with fluorescent detection. In addition, many biosensors use expensive antibody receptors or DNA ligands. But many of these proposed designs are impracticable for most applications or users, since they don't FIRST address the broad goals of any biosensor: Field operability, Inexpensive, with Real-time detection that is both Sensitive and Specific to target, while being as Trouble free as possible. Described in this review are applications that utilize versatile magnetic nanoparticles (MNP) extraction, electrically active nanoparticles (EANP) labeling, and carbohydrate-based ligand chemistry. MNP provide rapid pathogen extraction from liquid samples. EANP labeling improves signal amplification and expands signaling options to include optical and electrical detection. Carbohydrate ligands are inexpensive, robust structures that are increasingly synthesized for higher selectivity. Used in conjunction with optical or electrical detection of gold nanoparticles (AuNP), carbohydrate functionalized MNP-cell-AuNP nano-biosensing advances the goal of being the FIRST biosensor of choice in detecting microbial pathogens throughout our food supply chain. PMID- 30029201 TI - Comparing phospholipid profiles of mitochondria and whole tissue: Higher PUFA content in mitochondria is driven by increased phosphatidylcholine unsaturation. AB - Phospholipids content in cellular and mitochondrial membranes is essential for maintaining normal function. Previous studies have found a lower polyunsaturated fatty acid (PUFA) content in mitochondria than whole tissue, theorizing decreased PUFA protects against oxidative injury. However, phospholipids (PPLs) are uniquely difficult to quantify without class separation and, as prior approaches have predominately used reverse-phase HPLC or shotgun analysis, quantitation of PPL classes may have been complicated due to the existence of numerous isobaric and isomeric species. We apply normal-phase HPLC with class separation to compare whole tissue and mitochondrial PPL profiles in rat brain, heart, kidney, and liver. In addition, we establish a novel method to ascertain PPL origin, using cardiolipin as a comparator to establish relative cardiolipin /PPL ratios. We report a higher PUFA content in tissue mitochondria driven by increased phosphatidylcholine unsaturation, suggesting mitochondria purposefully incorporate higher PUFA PPLs. PMID- 30029202 TI - Development and validation of an UHPLC-MS/MS method for simultaneous quantification of ibrutinib and its dihydrodiol-metabolite in human cerebrospinal fluid. AB - Ibrutinib is an orally administered first-in-class irreversible Bruton's tyrosine kinase (BTK) covalent inhibitor for the treatment of patients with B-cell malignancies. Several isolated clinical observations reported its efficacy in central nervous system dissemination. Herein, we described the development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedure for the quantification of ibrutinib and its active metabolite PCI-45227 in cerebrospinal fluid (CSF). This is the first complete validated method for quantification of ibrutinib and PCI-45227 in CSF. The compounds were eluted on a Waters BEH C18 column (50.0 * 2.1 mm; 1.7 MUm) using a gradient elution with a mobile phase composed of ammonium formate buffer 5 mM pH 3.2 and acetonitrile +0.1% formic acid with a flow rate of 400 MUL.min-1. Two deuterated internal standards were used to obtain the most accurate quantification. The CSF samples were prepared by a simple and rapid dilution. The method was validated by testing the selectivity, response function, intra-day and inter-day precisions, trueness, limits of detection (LOD) and lower limits of quantification (LLOQ). The validation results proved that the methods were suitable to quantify ibrutinib and PCI-45227 in real biological CSF samples from 0.50 (ibrutinib) or 1.00 (PCI-45227) to 30.00 ng.mL-1. Furthermore, the developed method was adapted to allow the quantification of both compounds in plasma and the results were compared to those reported in literature. The plasmatic samples were treated by protein precipitation and the method was validated to quantify ibrutinib and PCI-45227 in real biological plasmatic samples from 5.00 to 491 ng.mL-1. Lastly, for both matrices, accuracy profiles were plotted from the trueness and precision results using a 20% alpha-risk (beta = 80%) and the tolerance intervals were comprised within the acceptance limits fixed at +/-25% for the LLOQ and +/-15% for the other concentrations. Finally, these methods were successfully applied to quantify ibrutinib and PCI-45227 in real human CSF and plasma samples. PMID- 30029203 TI - Cancer stem cell in breast cancer therapeutic resistance. AB - Development of therapeutic resistance and metastasis is a major challenge with current breast cancer (BC) therapy. Mounting evidence suggests that a subpopulation of cancer stem cells (CSCs) contribute to the cancer therapeutic resistance and metastasis, leading to the recurrence and death in patients. Breast cancer stem cells (BCSCs) are not only a consequence of mutations that overactivate the self-renewal ability of normal stem cells or committed progenitors but also a result of the de-differentiation of cancer cells induced by somatic mutations or microenvironmental components under treatment. Eradication of BCSCs may bring hope and relief to patients whose lives are threatened by recurrent BCs. Therefore, a better understanding of the generation, regulatory mechanisms, and identification of CSCs in BC therapeutic resistance and metastasis will be imperative for developing BCSC-targeted strategies. Here we summarize the latest studies about cell surface markers and signalling pathways that sustain the stemness of BCSC and discuss the associations of mechanisms behind these traits with phenotype and behavior changes in BCSCs. More importantly, their implications for future study are also evaluated and potential BCSC-targeted strategies are proposed to break through the limitation of current therapies. PMID- 30029204 TI - Training effects of Interactive Metronome(r) on golf performance and brain activity in professional woman golf players. AB - During putting in golf, the direction and velocity of the club head should be consistent across swings. In order to maintain consistency in swing timing, the cerebellum provides temporal information, motor timing, control of rhythm, and timing of movements. We utilized Interactive Metronome (IM), a brain training software program that combines the concepts of neurotechnology with the abilities of a computer, to improve an individual's rhythm and timing. We propose that IM would activate neural networks involved in decreasing variation in putt swing. Twenty professional female golfers (KLPGA) were randomly assigned to either an IM training group (n = 10, 35-40 min per session, twice a week for 6 weeks) or a control group (n = 10). The golf putting movements and brain activity were analyzed using Kinovea Software and resting state functional MRI, respectively. Consistency was measured as the standard deviation of mean swing speed (SSD) during three sections of the swing: backswing (AD-BS), backswing-impact (BS-IMP), and impact-finish (IMP-FIS). Our results show that the consistency of the IM group improved in the time between the back swing and impact in the 2 m putt and 5 m putt compared to the control group. Using functional MRI, after the training period, the IM group showed increased functional connectivity from the superior cerebellar vermis to the right medial frontal gyrus, left superior temporal gyrus, right middle occipital gyrus, right middle temporal gyrus, right cingulate gyrus, and right supramarginal gyrus (uncorrected p < 0.001, voxels > 40). These findings suggest that IM training in professional female golf players may improve consistency in putt timing. In addition, IM training may increase brain connectivity from the cerebellum to the frontal cortex, which plays an important role in motor control and timing. PMID- 30029205 TI - Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score-based analysis of a before-after cohort study. AB - PURPOSE: To evaluate the efficacy of combined vitamin C, hydrocortisone, and thiamine in patients with severe pneumonia. MATERIALS AND METHODS: All consecutive patients with severe pneumonia who were treated with the vitamin C protocol (6 g of vitamin C per day) in June 2017-January 2018 (n = 53) were compared to all consecutive patients with severe pneumonia who were treated in June 2016-January 2017 (n = 46). Propensity score analysis was used to adjust for potential baseline differences between the groups. RESULTS: In the propensity matched cohort (n = 36/group), the treated patients had significantly less hospital mortality than the control group (17% vs. 39%; P = 0.04). The vitamin C protocol associated independently with decreased mortality in propensity score adjusted analysis (adjusted odds ratio = 0.15, 95% confidence interval = 0.04 0.56, P = 0.005). Relative to the control group, the treatment group had a significantly higher median improvement in the radiologic score at day 7 compared with baseline (4 vs. 2; P = 0.045). The vitamin C protocol did not increase the rates of acute kidney injury or superinfection. CONCLUSIONS: Combined vitamin C, hydrocortisone, and thiamine therapy may benefit patients with severe pneumonia. PMID- 30029206 TI - A review of measurement methodologies and their applications to environmental 90Sr. AB - The high fission yield product 90Sr has been released into the environment in large amounts due to nuclear weapon tests, nuclear power plant accidents, and nuclear fuel reprocessing industries. It is a long half-life radionuclide (28.9 y), with serious consequences to human health; hence, it is desirable to perform routine monitoring of 90Sr in environmental samples. Many 90Sr radiometric methods have been developed in the past decades, which generally require complicated separation and purification steps with a relatively long analytical time. Moreover, some nominally rapid methods usually have high method detection limits, making them unsuitable for the environmental samples with ultra-low 90Sr levels. In this review, some rapid and practical methods for 90Sr routine monitoring are summarized. Different sample pretreatments and major purification procedures for 90Sr developed in recent years, such as variable digestion methods and extraction chromatography using Sr resin or DGA resin, are especially described. Additionally, four conventional and widely used beta spectrometric and mass spectrometric methods are demonstrated. Finally, 90Sr evaluations focusing on contaminated soil and seawater samples collected after the Fukushima Daiichi Nuclear Power Plant accident, and 90Sr application as tracers for environmental behavior are also reviewed. PMID- 30029207 TI - Comparative Fluid-Structure Interaction Analysis of Polymeric Transcatheter and Surgical Aortic Valves' Hemodynamics and Structural Mechanics. AB - Transcatheter aortic valve replacement (TAVR) has emerged as an effective alternative to conventional surgical aortic valve replacement (SAVR) in high-risk elderly patients with calcified aortic valve disease. All currently FDA-approved TAVR devices use tissue valves that were adapted to but not specifically designed for TAVR use. Emerging clinical evidence indicates that these valves may get damaged during crimping and deployment- leading to valvular calcification, thrombotic complications, and limited durability. This impedes the expected expansion of TAVR to lower-risk and younger patients. Viable polymeric valves have the potential to overcome such limitations. We have developed a polymeric SAVR valve, which was optimized to reduce leaflet stresses and offer a thromboresistance profile similar to that of a tissue valve. This study compares the polymeric SAVR valve's hemodynamic performance and mechanical stresses to a new version of the valve- specifically designed for TAVR. Fluid-structure interaction (FSI) models were utilized and the valves' hemodynamics, flexural stresses, strains, orifice area, and wall shear stresses were compared. The TAVR valve had 42% larger opening area and 27% higher flow rate versus the SAVR valve, while wall shear stress distribution and mechanical stress magnitudes were of the same order, demonstrating the enhanced performance of the TAVR valve prototype. The TAVR valve FSI simulation and Vivitro pulse duplicator experiments were compared in terms of the leaflets' kinematics and the effective orifice area. The numerical methodology presented can be further used as a predictive tool for valve design optimization for enhanced hemodynamics and durability. PMID- 30029208 TI - A comprehensive fluid-structure interaction model of the left coronary artery. AB - A fluid structure interaction model of a left anterior descending (LAD) coronary artery was developed, incorporating transient blood flow, cyclic bending motion of the artery, and myocardial contraction. The 3D geometry was constructed based on a patient's computed tomography angiography data. To simulate disease conditions, a plaque was placed within the LAD to create a 70% stenosis. The bending motion of the blood vessel was prescribed based on the LAD spatial information. The pressure induced by myocardial contraction was applied to the outside of the blood vessel wall. The fluid domain was solved using the Navier Stokes equations. The arterial wall was defined as a nonlinear elastic, anisotropic, and incompressible material, and the mechanical behavior was described using the modified hyper-elastic Mooney-Rivlin model. The fluid (blood) and solid (vascular wall) domains were fully coupled. The simulation results demonstrated that besides vessel bending/stretching motion, myocardial contraction had a significant effect on local hemodynamics and vascular all stress/strain distribution. It not only transiently increased blood flow velocity and fluid wall shear stress, but also changed shear stress patterns. The presence of the plaque significantly reduced vascular wall tensile strain. Compared to the coronary artery models developed previously, the current model had improved physiological relevance. PMID- 30029209 TI - An analytical poroelastic model of a non-homogeneous medium under creep compression for ultrasound poroelastography applications - Part II. AB - An analytical theory for the unconfined creep behavior of a cylindrical inclusion (simulating a soft tissue tumor) embedded in a cylindrical background sample (simulating normal tissue) is presented and analyzed in this paper. Both the inclusion and the background are considered as fluid-filled, porous materials, each of them being characterized by a set of mechanical parameters. Specifically, in this derivation, the inclusion is assumed to have significantly higher interstitial permeability than the background. The formulations of the effective Poisson's ratio (EPR) and fluid pressure in the inclusion and in the background are derived for the case of a sample subjected to a creep compression. The developed analytical expressions are validated using finite element models (FEM). Statistical comparison between the results obtained from the developed model and the results from FEM demonstrates accuracy of the proposed theoretical model higher than 99.4%. The model presented in this paper complements the one reported in the companion paper (Part I), which refers to the case of an inclusion having less interstitial permeability than the background. PMID- 30029210 TI - Prediction of ACL Force Produced by Tibiofemoral Compression During Controlled Knee Flexion: A New Robotic Testing Methodology. AB - Tibiofemoral compression force (TCF) is an important component of anterior cruciate ligament (ACL) injuries. A new robotic testing methodology was utilized to predict ACL forces generated by TCF without loading the ligament. We hypothesized that ACL force, directly recorded by a miniature load cell during an unconstrained test, could be predicted by measurements of anterior tibial restraining force (ARF) recorded during a constrained test. The knee was first flexed under load control with 25N TCF (tibia unconstrained) to record a baseline kinematic pathway. Tests were repeated with increasing levels of TCF, while recording ACL force and knee kinematics. Then tests with increasing TCF were performed under displacement control to reproduce the baseline kinematic pathway (tibia constrained), while recording ARF. This allowed testing to 1500N TCF since the ACL was not loaded. TCF generated ACL force for all knees (n=10) at 50 degrees flexion, and for 8 knees at 30 degrees flexion. ACL force and ARF had strong linear correlations with TCF at both flexion angles (R2 from 0.85 to 0.99), and ACL force was strongly correlated with ARF at both flexion angles (R2 from 0.76 to 0.99). Under 500N TCF the mean error between ACL force prediction from ARF regression and measured ACL force was 4.8 +/- 7.3 N at 30 degrees and 8.8 +/- 27.5 N at 50 degrees flexion. Our hypothesis was confirmed for TCF levels up to 500N, and ARF had a strong linear correlation with TCF up to 1500N TCF. PMID- 30029211 TI - Design of semi-rigid wearable devices based on skin strain analysis. AB - Nowadays, both usability and comfort play a key role in the development of medical and wearable products. When designing any device that is in contact with the human body, the mechanical behaviour of the embraced soft tissue must be known. The unavoidable displacement of the soft tissue during motion may lead to discomfort adn, thus, the withdrawal of the wearable product. This work presents a new methodology to design and test a wearable device based on the measurement of the dynamic skin strain field. Furthermore, from this field, the anatomical lines with minimum strain (Lines of non extension, LoNEs) are calculated to design the structural parts of the wearable device. Whith this new criteria, the resulting product is not only optimized to reduce the friction in skin-device interface, but fully personalized to the patient's morphology and motion. The methodology is applied to the design of an ankle-foot wearable orthosis for subjects with ankle dorsiflexors muscles weakness due to nervous system disorders. The results confirm that the use of LoNEs may benefit the design of products with a high interaction with the skin. PMID- 30029212 TI - Effects of visual distractors on vergence eye movements. AB - Visual attention is an important aspect of everyday life, which can be incorporated in the assessment of many diagnoses. Another important characteristic of visual attention is that it can be improved via therapeutic interventions. Fifteen subjects with normal binocular vision were presented with visual distractor stimuli at various spatial locations while initiating disparity vergence eye movements (inward or outward rotation of eyes) within a haploscope system. First, a stationary distractor stimulus was presented in either the far, middle, or near visual spaces while the subjects were instructed to follow a target stimulus that was either stationary, converging (moving toward subject), or diverging (moving away from subject). For the second experiment, a dynamic distractor stimulus within the far, middle, or near visual space that was converging or diverging was presented while the target stimulus was also converging or diverging. The subjects were instructed to visually follow the target stimulus and ignore the distractor stimulus. The vergence responses had a final vergence angle between the target and distractor stimuli which has been termed a center of gravity (CoG) effect. Statistically significant differences were observed between the convergence peak velocities (p < 0.001) and response amplitudes (p < 0.001) comparing responses without distractors to responses with the presence of a vergence distractor. The results support that vergence eye movements are influenced by visual distractors, which is similar to how distractors influence saccadic eye movements. The influence of visual distractors within vergence eye movements may be useful to assess binocular dysfunction and visual distraction which are common post brain injury. PMID- 30029213 TI - Simultaneous density contrast and binocular integration. AB - Most research on texture density has utilized textures rendered as two dimensional (2D) planar surfaces, consistent with the conventional definition of density as the number of texture elements per unit area. How the brain represents texture density information in the three-dimensional (3D) world is not yet clear. Here we tested whether binocular information affects density processing using simultaneous density contrast (SDC), in which the perceived density of a texture region is changed by a surround of different density. We considered the effect on SDC of two types of binocular information: the stereoscopic depth relationships and the interocular relationships between the center and surround textures. Observers compared the perceived density of two random dot patterns, one with a surround (test stimulus) and one without (match), using a 2AFC staircase procedure. In Experiment 1 we manipulated the stereo-depth of the surround plane systematically from near to far, relative to the center plane. SDC was reduced when the difference in stereo-depth between test center and surround increased. In Experiment 2 we spread the surround dots randomly across a stereo-depth volume from small to large volume sizes, and found that SDC was slightly reduced with volume size. The decrease of SDC in both experiments was observed with dense surrounds only, but not with sparse surrounds. In the last experiment we presented center and surround in the same depth plane but dichopticly, monopticly, and binocularly. A strong interocular transfer of SDC was found in the dichoptic condition. Together these results show that texture density processing is sensitive to binocularity. PMID- 30029214 TI - Depth variation and stereo processing tasks in natural scenes. AB - Local depth variation is a distinctive property of natural scenes, but its effects on perception have only recently begun to be investigated. Depth variation in natural scenes is due to depth edges between objects and surface nonuniformities within objects. Here, we demonstrate how natural depth variation impacts performance in two fundamental tasks related to stereopsis: half occlusion detection and disparity detection. We report the results of a computational study that uses a large database of natural stereo-images and coregistered laser-based distance measurements. First, we develop a procedure for precisely sampling stereo-image patches from the stereo-images and then quantify the local depth variation in each patch by its disparity contrast. Next, we show that increased disparity contrast degrades half-occlusion detection and disparity detection performance and changes the size and shape of the spatial integration areas ("receptive fields") that optimize performance. Then, we show that a simple image-computable binocular statistic predicts disparity contrast in natural scenes. Finally, we report the most likely spatial patterns of disparity variation and disparity discontinuities (half-occlusions) in natural scenes. Our findings motivate computational and psychophysical investigations of the mechanisms that underlie stereo processing tasks in local regions of natural scenes. PMID- 30029215 TI - Contour interaction under photopic and scotopic conditions. AB - In the present study, we asked whether contour interaction undergoes significant changes for different luminance levels in the central and peripheral visual field. This study included nine normal observers at two laboratories (five at Palacky University Olomouc, Czech Republic and four at the University of Houston, USA). Observers viewed a randomly selected Sloan letter surrounded by four equally spaced bars for several separations measured edge-to-edge in min arc. Stimuli were viewed foveally under photopic and mesopic luminances and between 5 degrees and 12 degrees peripherally for four different background luminances of the display monitors, corresponding to photopic, mesopic, scotopic, and dim scotopic levels. The extent of the contour interaction in the fovea is approximately 20 times smaller than in the periphery. Whereas the magnitude of foveal contour interaction markedly decreases with decreasing luminance, no consistent luminance-induced change occurs in peripheral contour interaction. The extent of contour interaction does not scale with the size of the target letter, either in the fovea or peripherally. The results support a neural origin of contour interaction consistent with the properties of center-surround antagonism. PMID- 30029217 TI - Assessing the generalizability of eye dominance across binocular rivalry, onset rivalry, and continuous flash suppression. AB - It is commonly assumed that one eye is dominant over the other eye. Eye dominance is most frequently determined by using the hole-in-the-card test. However, it is currently unclear whether eye dominance as determined by the hole-in-the-card test (so-called sighting eye dominance) generalizes to tasks involving interocular conflict (engaging sensory eye dominance). We therefore investigated whether sighting eye dominance is linked to sensory eye dominance in several frequently used paradigms that involve interocular conflict. Eye dominance was measured by the hole-in-the-card test, binocular rivalry, and breaking continuous flash suppression (b-CFS). Relationships between differences in eye dominance were assessed using Bayesian statistics. Strikingly, none of the three interocular conflict tasks yielded a difference in perceptual report between eyes when comparing the dominant eye with the nondominant eye as determined by the hole-in-the-card test. From this, we conclude that sighting eye dominance is different from sensory eye dominance. Interestingly, eye dominance of onset rivalry correlated with that of ongoing rivalry but not with that of b-CFS. Hence, we conclude that b-CFS reflects a different form of eye dominance than onset and ongoing rivalry. In sum, eye dominance seems to be a multifaceted phenomenon, which is differently expressed across interocular conflict paradigms. Finally, we highly discourage using tests measuring sighting eye dominance to determine the dominant eye in a subsequent experiment involving interocular conflict. Rather, we recommend that whenever experimental manipulations require a priori knowledge of eye dominance, eye dominance should be determined using pretrials of the same task that will be used in the main experiment. PMID- 30029216 TI - Meaning guides attention in real-world scene images: Evidence from eye movements and meaning maps. AB - We compared the influence of meaning and of salience on attentional guidance in scene images. Meaning was captured by "meaning maps" representing the spatial distribution of semantic information in scenes. Meaning maps were coded in a format that could be directly compared to maps of image salience generated from image features. We investigated the degree to which meaning versus image salience predicted human viewers' spatiotemporal distribution of attention over scenes. Extending previous work, here the distribution of attention was operationalized as duration-weighted fixation density. The results showed that both meaning and image salience predicted the duration-weighted distribution of attention, but that when the correlation between meaning and salience was statistically controlled, meaning accounted for unique variance in attention whereas salience did not. This pattern was observed in early as well as late fixations, fixations including and excluding the centers of the scenes, and fixations following short as well as long saccades. The results strongly suggest that meaning guides attention in real-world scenes. We discuss the results from the perspective of a cognitive-relevance theory of attentional guidance. PMID- 30029218 TI - Assessing the relationship between pupil diameter and visuocortical activity. AB - Visuocortical activity and pupil diameter both increase in tasks involving memory, attention, and physiological arousal. Thus, the question arises whether pupil dilation prompts a subsequent increase in visuocortical activity. In this study, we investigated the extent to which changes in visuocortical activity relate to changes in pupil diameter. The amplitude of the sustained visuocortical response to a flickering stimulus (i.e., steady-state visually evoked potential [ssVEP] power) was examined in 39 participants while pupil diameter was measured. To generalize across stimulus conditions, Gabor stimuli varied in brightness and ssVEP driving frequency. As expected, brighter stimuli prompted pupil constriction and larger ssVEP power. To determine whether momentary fluctuations in pupil size contribute to the ssVEP amplitude under conditions of constant luminance and frequency, the single-trial means from each measure were correlated and the shape of the pupil-diameter waveform related to the ssVEP amplitude time course, both within and between participants. Under constant conditions, changes in pupil diameter were not related to changes in ssVEP amplitude, at any luminance level or driving frequency. Findings suggest that pupil dilation does not systematically prompt subsequent changes in visuocortical activity, and thus is not a sufficient cause of visuocortical modulation in cognitive or affective tasks. PMID- 30029220 TI - Perceptual insensitivity to higher-order statistical moments of coherent random dot motion. AB - When the visual system analyzes distributed patterns of sensory inputs, what features of those distributions does it use? It has been previously demonstrated that higher-order statistical moments of luminance distributions influence perception of static surfaces and textures. Here, we tested whether the brain also represents higher-order moments of dynamic stimuli. We constructed random dot kinematograms, where dots moved according to probability distributions that selectively differed in terms of their mean, variance, skewness, or kurtosis. When viewing these stimuli, human observers were sensitive to the mean direction of coherent motion and to the variance of dot displacement angles, but they were insensitive to skewness and kurtosis. Observer behavior accorded with a model of directional motion energy, suggesting that information about higher-order moments is discarded early in the visual processing hierarchy. These results demonstrate that use of higher-order moments is not a general property of visual perception. PMID- 30029221 TI - Timing in the absence of a clock reset. AB - Prominent models of time perception assume a reset of the timing mechanism with an explicit onset of the interval to be timed. Here we investigated the accuracy and precision of temporal estimations when the duration does not have such an explicit onset. Participants were tracking a disc moving on a circular path with varying speeds, and estimated the duration of one full revolution before the stimulus stopped. The onset of that revolution was either cued (explicit), or undetermined until the stimulus stopped (implicit). Reproduced duration was overestimated for short and underestimated for long durations, and variability of the estimates scaled with the duration in both temporal conditions. However, the bias was more pronounced in the implicit condition. In addition, if the stimulus path was partially occluded, duration of the occluded motion was correctly estimated. In a second experiment, we compared the precision in the explicit and implicit conditions by asking participants to discriminate the duration of one revolution before the stimulus stopped to that of a static stimulus presentation in a forced-choice task. Sensitivity of discrimination was worse in the implicit onset condition, but surprisingly, still comparable to the explicit condition. In summary, the estimates follow principles described in prospective timing paradigms, although not knowing beforehand when to start timing decreases sensitivity of temporal estimations. Since in naturalistic contexts, we often do not know in advance which durations might be relevant to estimate, the simple task presented here could become a valuable tool for testing models of temporal estimation. PMID- 30029222 TI - The nature of shape constancy mechanisms as revealed by shape priming. AB - Five shape priming experiments are reported in which the target was either a five or six-sided line-drawn figure and participants made a speeded two-alternative forced-choice judgment about the target's number of sides. On priming trials, the target was preceded by a briefly presented smaller line figure (the prime) and performance on these trials was gauged relative to a no-prime condition. In the first two experiments, primes were rendered invisible by the presentation of a backwards visual noise mask, respectively for a short (~40 ms) or long duration (~93 ms). No reliable priming effects arose under masked conditions. When these experiments were repeated without the mask, participants were speeded when the prime and target were related by a rigid through-the-plane rotation but not when the prime was a nonrigid, stretched version of the target. The same pattern of priming effects arose when, in a final experiment, novel irregular shapes were used. Collectively, the data reveal the operation of shape constancy mechanisms that are particularly sensitive to shape rigidity. The findings suggest that the visual system attempts to secure a correspondence between the rapid and successive presentations of the prime and the target by matching shapes according to a rigidity constraint. PMID- 30029219 TI - On spatial attention and its field size on the repulsion effect. AB - We investigated the attentional repulsion effect-stimuli appear displaced further away from attended locations-in three experiments: one with exogenous (involuntary) attention, and two with endogenous (voluntary) attention with different attention-field sizes. It has been proposed that differences in attention-field size can account for qualitative differences in neural responses elicited by attended stimuli. We used psychophysical comparative judgments and manipulated either exogenous attention via peripheral cues or endogenous attention via central cues and a demanding rapid serial visual presentation task. We manipulated the attention field size of endogenous attention by presenting streams of letters at two specific locations or at two of many possible locations during each block. We found a robust attentional repulsion effect in all three experiments: with endogenous and exogenous attention and with both attention field sizes. These findings advance our understanding of the influence of spatial attention on the perception of visual space and help relate this repulsion effect to possible neurophysiological correlates. PMID- 30029224 TI - Ability to identify scene-relative object movement is not limited by, or yoked to, ability to perceive heading. AB - During locomotion humans can judge where they are heading relative to the scene and the movement of objects within the scene. Both judgments rely on identifying global components of optic flow. What is the relationship between the perception of heading, and the identification of object movement during self-movement? Do they rely on a shared mechanism? One way to address these questions is to compare performance on the two tasks. We designed stimuli that allowed direct comparison of the precision of heading and object movement judgments. Across a series of experiments, we found the precision was typically higher when judging scene relative object movement than when judging heading. We also found that manipulations of the content of the visual scene can change the relative precision of the two judgments. These results demonstrate that the ability to judge scene-relative object movement during self-movement is not limited by, or yoked to, the ability to judge the direction of self-movement. PMID- 30029223 TI - Delayed S-cone sensitivity losses following the onset of intense yellow backgrounds linked to the lifetime of a photobleaching product? AB - Thirty years ago, Mollon, Stockman, & Polden (1987) reported that after the onset of intense yellow 581-nm backgrounds, S-cone threshold rose unexpectedly for several seconds before recovering to the light-adapted steady-state value-an effect they called: "transient-tritanopia of the second kind" (TT2). Given that 581-nm lights have little direct effect on S-cones, TT2 must arise indirectly from the backgrounds' effects on the L- and M-cones. We attribute the phenomenon to the action of an unknown L- and M-cone photobleaching product, X, which acts at their outputs like an "equivalent" background light that then inhibits S-cones at a cone-opponent, second-site. The time-course of TT2 is similar in form to the lifetime of X in a two-stage, first-order biochemical reaction A->X->C with successive best-fitting time-constants of 3.09 +/- 0.35 and 7.73 +/- 0.70 s. Alternatively, with an additional slowly recovering exponential "restoring-force" with a best-fitting time-constant 23.94 +/- 1.42 s, the two-stage best-fitting time-constants become 4.15 +/- 0.62 and 6.79 +/- 1.00 s. Because the time constants are roughly independent of the background illumination, and thus the rate of photoisomerization, A->X is likely to be a reaction subsidiary to the retinoid cycle, perhaps acting as a buffer when the bleaching rate is too high. X seems to be logarithmically related to S-cone threshold, which may result from the logarithmic cone-opponent, second-site response compression after multiplicative first-site adaptation. The restoring-force may be the same cone opponent force that sets the rate of S-cone recovery following the unusual threshold increase following the offset of dimmer yellow backgrounds, an effect known as "transient-tritanopia" (TT1). PMID- 30029226 TI - Corrections. PMID- 30029228 TI - Using synchronized eye and motion tracking to determine high-precision eye movement patterns during object-interaction tasks. AB - This study explores the role that vision plays in sequential object interactions. We used a head-mounted eye tracker and upper-limb motion capture to quantify visual behavior while participants performed two standardized functional tasks. By simultaneously recording eye and motion tracking, we precisely segmented participants' visual data using the movement data, yielding a consistent and highly functionally resolved data set of real-world object-interaction tasks. Our results show that participants spend nearly the full duration of a trial fixating on objects relevant to the task, little time fixating on their own hand when reaching toward an object, and slightly more time-although still very little fixating on the object in their hand when transporting it. A consistent spatial and temporal pattern of fixations was found across participants. In brief, participants fixate an object to be picked up at least half a second before their hand arrives at the object and stay fixated on the object until they begin to transport it, at which point they shift their fixation directly to the drop-off location of the object, where they stay fixated until the object is successfully released. This pattern provides additional evidence of a common system for the integration of vision and object interaction in humans, and is consistent with theoretical frameworks hypothesizing the distribution of attention to future action targets as part of eye and hand-movement preparation. Our results thus aid the understanding of visual attention allocation during planning of object interactions both inside and outside the field of view. PMID- 30029227 TI - Human infants can generate vergence responses to retinal disparity by 5 to 10 weeks of age. AB - Vergence is defined as a binocular eye movement during which the two eyes move in opposite directions to align to a target in depth. In adults, fine vergence control is driven primarily by interocular retinal image disparity. Although infants have not typically been shown to respond to disparity until 3 to 5 months postpartum, they have been shown to align their eyes from hours after birth. It remains unclear what drives these responses in young infants. In this experiment, 5- to 10-week-old human infants were presented with a dynamic random noise stimulus oscillating in disparity at 0.1 Hz over an amplitude of 2 degrees for 30 s. Fourier transforms of the horizontal eye movements revealed significant disparity-driven responses at the frequency of the stimulus in over half of the tested infants. Because the stimulus updated dynamically, this experiment precluded the possibility of independent monocular fixations to a sustained target. These data demonstrate cortical binocular function in humans by five weeks, the youngest age tested here, which is as much as two months younger than previously believed. PMID- 30029229 TI - Unsupervised detection of microsaccades in a high-noise regime. AB - Micromovements of the eye during visual fixations provide clues about how our visual system acquires information. The analysis of fixational eye movements can thus serve as a noninvasive means to detect age-related or pathological changes in visual processing, which can in turn reflect associated cognitive or neurological disorders. However, the utility of such diagnostic approaches relies on the quality and usability of detection methods applied for the eye movement analysis. Here, we propose a novel method for (micro)saccade detection that is resistant to high-frequency recording noise, a frequent problem in video-based eye tracking in either aged subjects or subjects suffering from a vision-related pathology. The method is fast, it does not require manual noise removal, and it can work with position, velocity, or acceleration features, or a combination thereof. The detection accuracy of the proposed method is assessed on a new dataset of manually labeled recordings acquired from 14 subjects of advanced age (69-81 years old), performing an ocular fixation task. It is demonstrated that the detection accuracy of the new method compares favorably to that of two frequently used reference methods and that it is comparable to the best of the two algorithms when tested on an existing low-noise eye-tracking dataset. PMID- 30029230 TI - Sustained spatial attention can affect feature fusion. AB - When two verniers are presented in rapid succession at the same location, feature fusion occurs. Instead of perceiving two separate verniers, participants typically report perceiving one fused vernier, whose offset is a combination of the two previous verniers, with the later one slightly dominating. Here, we examined the effects of sustained attention-the voluntary component of spatial attention-on feature fusion. One way to manipulate sustained attention is via the degree of certainty regarding the stimulus location. In the attended condition, the stimulus appeared always in the same location, and in the unattended condition it could appear in one of two possible locations. Participants had to report the offset of the fused vernier. Experiments 1 and 2 measured attentional effects on feature fusion with and without eye-tracking. In both experiments, we found a higher rate of reports corresponding to the offset of the second vernier with focused attention than without focused attention, suggesting that attention strengthened the final percept emerging from the fusion operation. In Experiment 3, we manipulated the stimulus duration to encourage a final fused percept that is dominated by either the first or second vernier. We found that attention strengthened the already dominant percept, regardless of whether it corresponded to the offset of the first or second vernier. These results are consistent with an attentional mechanism of signal enhancement at the encoding stage. PMID- 30029225 TI - Can speed be judged independent of direction? AB - The ability to judge speed is a fundamental aspect of visual motion processing. Speed judgments are generally assumed to depend on signals in motion-sensitive, directionally selective, neurons in areas such as V1 and MT. Speed comparisons might therefore be expected to be most accurate when they use information within a common set of directionally tuned neurons. However, there does not appear to be any published evidence on how well speeds can be compared for movements in different directions. We tested speed discrimination judgments between pairs of random-dot stimuli presented side-by-side in a series of four experiments (n = 65). Participants judged which appeared faster of a reference stimulus moving along the cardinal or oblique axis and a comparison stimulus moving either in the same direction or in a different direction. The bias (point of subjective equality) and sensitivity (Weber fraction) were estimated from individual psychometric functions fitted for each condition. There was considerable between participants variability in psychophysical estimates across conditions. Nonetheless, participants generally made more acute comparisons between stimuli moving in the same direction than those moving in different directions, at least for conditions with an upwards reference (~20% difference in Weber fractions). We also showed evidence for an oblique effect in speed discrimination when comparing stimuli moving in the same direction, and a bias whereby oblique motion tended to be perceived as moving faster than cardinal motion. These results demonstrate interactions between speed and direction processing, thus informing our understanding of how they are represented in the brain. PMID- 30029231 TI - Bone Remodeling under Vibration: A Computational Model of Bone Remodeling Incorporating the Modal Behavior of Bone. AB - Developing precise computational models of bone remodeling can lead to more successful types of orthopedic treatments and deeper understanding of the phenomenon. Empirical evidence has shown that bone adaptation to mechanical loading is frequency dependent and the modal behavior of bone under vibration can play a significant role in remodeling process, particularly in the resonance region. The objective of this study is to develop a bone remodeling algorithm that takes into account the effects of bone vibrational behavior. An extended/modified model is presented based on conventional FE remodeling models. Frequency domain analysis is used to introduce appropriate correction coefficients to incorporate the effect of bone's frequency response into the model. The method is implemented on a bovine bone with known modal/vibration characteristics. The rate and locations of new bone formation depend on the loading frequency and are consistently correlated with the bone modal behavior. The proposed method can successfully integrate the bone vibration conditions and characteristics with the remodeling process. The results obtained support experimental observations in the literature. PMID- 30029232 TI - Engineered Airway Models to Study Liquid Plug Splitting at Bifurcations: Effects of Orientation and Airway Size. AB - Delivery of biological fluids, such as surfactant solutions, into lungs is a major strategy to treat respiratory disorders including respiratory distress syndrome that is caused by insufficient or dysfunctional natural lung surfactant. The instilled solution forms liquid plugs in lung airways. The plugs propagate downstream in airways by inspired air or ventilation, continuously split at airway bifurcations to smaller daughter plugs, simultaneously lose mass from their trailing menisci, and eventually rupture. A uniform distribution of the instilled biofluid in lung airways is expected to increase the treatments success. The uniformity of distribution of instilled liquid in the lungs greatly depends on the splitting of liquid plugs between daughter airways, especially in the first few generations from which airways of different lobes of lungs emerge. To mechanistically understand this process, we developed a bioengineering approach to computationally design three-dimensional bifurcating airway models using morphometric data of human lungs, fabricate physical models, and examine dynamics of liquid plug splitting. We found that orientation of bifurcating airways has a major effect on the splitting of liquid plugs between daughter airways. Changing the relative gravitational orientation of daughter tubes with respect to the horizontal plane caused a more asymmetric splitting of liquid plugs. Increasing the propagation speed of plugs partially counteracted this effect. Using airway models of smaller dimensions reduced the asymmetry of plug splitting. This work provides a step toward developing delivery strategies for uniform distribution of therapeutic fluids in the lungs. PMID- 30029233 TI - Osteoporotic hip fracture prediction: is T-score based criterion enough? A Hip Structural Analysis based model. AB - At present, the current gold-standard for osteoporosis diagnosis is based on bone mineral density measurement, which, however, has been demonstrated to poorly estimate fracture risk. Further parameters in the hands of the clinicians are represented by the Hip Structural Analysis (HSA) variables, which include geometric information of the proximal femur cross-section. The purpose of this study was to investigate the suitability of HSA parameters as additional hip fracture risk predictors. With this aim, twenty-eight three-dimensional patient specific models of the proximal femur were built from CT images and a sideways fall condition was reproduced by finite element analyses. A tensile or compressive predominance based on minimum and maximum principal strains was determined at each volume element and a Risk Factor (RF) was calculated. The power of HSA variables combinations to predict the maximum superficial RF values was assessed by multivariate linear regression analysis. The optimal regression model, identified through the Akaike information criterion, only comprises two variables, the buckling ratio and the neck-shaft angle. In order to validate the study, the model was tested on two additional patients who suffered a hip fracture after a fall. The results classified the patients in the high risk level, confirming the prediction power of the adopted model. PMID- 30029234 TI - The Multi-Axial Failure Response of Porcine Trabecular Skull Bone Estimated Using Microstructural Simulations. AB - The development of a multi-axial failure criterion for trabecular skull bone has many clinical and biological implications. This failure criterion would allow for modeling of bone under daily loading scenarios that typically are multi-axial in nature. Some yield criteria have been developed to evaluate the failure of trabecular bone, but there is a little consensus among them. To help gain deeper understanding of multi-axial failure response of trabecular skull bone, we developed 30 microstructural finite element models of porous porcine skull bone and subjected them to multi-axial displacement loading simulations that spanned three-dimensional (3D) stress and strain space. High-resolution microcomputed tomography (microCT) scans of porcine trabecular bone were obtained and used to develop the meshes used for finite element simulations. In total, 376 unique multi-axial loading cases were simulated for each of the 30 microstructure models. Then, results from the total of 11,280 simulations (approximately 135,360 central processing unit-hours) were used to develop a mathematical expression, which describes the average three-dimensional yield surface in strain space. Our results indicate that the yield strain of porcine trabecular bone under multi axial loading is nearly isotropic and despite a spread of yielding points between the 30 different microstructures, no significant relationship between the yield strain and bone volume fraction is observed. The proposed yield equation has simple format and it can be implemented into a macroscopic model for the prediction of failure of whole bones. PMID- 30029235 TI - Analysis of Spatial and Temporal Step Parameters During Crutch-Assisted Gait as a Dual-Task: A Pilot Study. AB - The main objective was to analyze the changes in the spatial and temporal step parameters during a dual-task: walking with a forearm crutch to partially unload the body weight of the subject. The secondary objective was to determine the influence of the use of the crutch with the dominant or nondominant hand in the essential gait parameters. Seven healthy subjects performed gait without crutches (GWC) and unilateral assisted gait (UAG) with the crutch carried out by dominant hand (dominant crutch (DC)) and nondominant hand (nondominant crutch (NDC)). Gait was recorded using a Vicon System; the GCH System 2.0 and the GCH Control Software 1.0 controlled the loads. The variables were step length, step period, velocity, step width, and step angle. The Wilcoxon signed-rank test compared GWC and UAG while also analyzing the parameters measured for both legs with DC and NDC in general and in each subject. Wilcoxon test only found significant differences in 1 of the 15 general comparisons between both legs. In the analysis by subject, step length, step period, and velocity showed significant differences between GWC and UAG. These parameters obtained less differences in DC. The effect of a forearm crutch on UAG caused a reduction in step length and velocity, and an increase in step period. However, it did not entail changes in step angle and step width. UAG was more effective when the DC carried the crutch. The unloading of 10% body weight produced an assisted gait which closely matched GWC. PMID- 30029238 TI - An Ergonomic Testing System for the First Metatarsophalangeal Joint Stiffness. AB - Osteoarthritis sufferers commonly have first metatarsophalangeal joint (MTPJ) problems in which articular surfaces are changed permanently due to fatigue. Therefore, medical devices for early diagnosis would increase the opportunity for prevention of disease progression. In previous studies on stiffness of the first MTPJ many details, although functionally of great importance, have not been fully considered including: design and size of the device, tribology consideration, and errors from device. Therefore, the motivation of our research was to enhance the device design by reducing the size of the device, and device design was enhanced by minimizing measurement errors through development of a new ergonomic left and right foot instrument located medial to the first MTPJ (instead of beneath the foot). The first MTPJ stiffness (N mm/kg radian) measurement was taken on 28 subjects with two replicates per subject by the same tester. The first MTPJ stiffness ranged from 3.49 to 14.42 N mm/kg radian with the mean (SD) value of 8.28 (3.15) N mm/kg radian for the left feet and 3.91 to 11.90 N mm/kg radian with the mean (SD) value of 7.65 (2.07) N mm/kg radian for the right feet. Reliability evaluation was measured using intraclass correlation coefficient and described an excellent reliability between two tests. PMID- 30029237 TI - A Finite Element Bendo-Tensegrity Model of Eukaryotic Cell. AB - Mechanical interaction of cell with extracellular environment affects its function. The mechanisms by which mechanical stimuli are sensed and transduced into biochemical responses are still not well understood. Considering this, two finite element (FE) bendo-tensegrity models of a cell in different states are proposed with the aim to characterize cell deformation under different mechanical loading conditions: a suspended cell model elucidating the global response of cell in tensile test simulation and an adherent cell model explicating its local response in atomic force microscopy (AFM) indentation simulation. The force elongation curve obtained from tensile test simulation lies within the range of experimentally obtained characteristics of smooth muscle cells (SMCs) and illustrates a nonlinear increase in reaction force with cell stretching. The force-indentation curves obtained from indentation simulations lie within the range of experimentally obtained curves of embryonic stem cells (ESCs) and exhibit the influence of indentation site on the overall reaction force of cell. Simulation results have demonstrated that actin filaments (AFs) and microtubules (MTs) play a crucial role in the cell stiffness during stretching, whereas actin cortex (AC) along with actin bundles (ABs) and MTs are essential for the cell rigidity during indentation. The proposed models quantify the mechanical contribution of individual cytoskeletal components to cell mechanics and the deformation of nucleus under different mechanical loading conditions. These results can aid in better understanding of structure-function relationships in living cells. PMID- 30029236 TI - Statistical Characterization of Human Brain Deformation During Mild Angular Acceleration Measured In Vivo by Tagged Magnetic Resonance Imaging. AB - Understanding of in vivo brain biomechanical behavior is critical in the study of traumatic brain injury (TBI) mechanisms and prevention. Using tagged magnetic resonance imaging, we measured spatiotemporal brain deformations in 34 healthy human volunteers under mild angular accelerations of the head. Two-dimensional (2D) Lagrangian strains were examined throughout the brain in each subject. Strain metrics peaked shortly after contact with a padded stop, corresponding to the inertial response of the brain after head deceleration. Maximum shear strain of at least 3% was experienced at peak deformation by an area fraction (median+/ standard error) of 23.5+/-1.8% of cortical gray matter, 15.9+/-1.4% of white matter, and 4.0+/-1.5% of deep gray matter. Cortical gray matter strains were greater in the temporal cortex on the side of the initial contact with the padded stop and also in the contralateral temporal, frontal, and parietal cortex. These tissue-level deformations from a population of healthy volunteers provide the first in vivo measurements of full-volume brain deformation in response to known kinematics. Although strains differed in different tissue type and cortical lobes, no significant differences between male and female head accelerations or strain metrics were found. These cumulative results highlight important kinematic features of the brain's mechanical response and can be used to facilitate the evaluation of computational simulations of TBI. PMID- 30029239 TI - Finite Element Analysis to Probe the Influence of Acetabular Shell Design, Liner Material, and Subject Parameters on Biomechanical Response in Periprosthetic Bone. AB - The implant stability and biomechanical response of periprosthetic bone in acetabulum around total hip joint replacement (THR) devices depend on a host of parameters, including design of articulating materials, gait cycle and subject parameters. In this study, the impact of shell design (conventional, finned, spiked, and combined design) and liner material on the biomechanical response of periprosthetic bone has been analyzed using finite element (FE) method. Two different liner materials: high density polyethylene-20% hydroxyapatite-20% alumina (HDPE-20%HA-20%Al2O3) and highly cross-linked ultrahigh molecular weight polyethylene (HC-UHMWPE) were used. The subject parameters included bone condition and bodyweight. Physiologically relevant load cases of a gait cycle were considered. The deviation of mechanical condition of the periprosthetic bone due to implantation was least for the finned shell design. No significant deviation was observed at the bone region adjacent to the spikes and the fins. This study recommends the use of the finned design, particularly for weaker bone conditions. For stronger bones, the combined design may also be recommended for higher stability. The use of HC-UHMWPE liner was found to be better for convensional shell design. However, similar biomechanical response was captured in our FE analysis for both the liner materials in case of other shell designs. Overall, the study establishes the biomechanical response of periprosthetic bone in the acetabular with preclinically tested liner materials together with new shell design for different subject conditions. PMID- 30029241 TI - Optimal Estimation of Anthropometric Parameters for Quantifying Multisegment Trunk Kinetics. AB - Kinetics assessment of the human head-arms-trunk (HAT) complex via a multisegment model is a useful tool for objective clinical evaluation of several pathological conditions. Inaccuracies in body segment parameters (BSPs) are a major source of uncertainty in the estimation of the joint moments associated with the multisegment HAT. Given the large intersubject variability, there is currently no comprehensive database for the estimation of BSPs for the HAT. We propose a nonlinear, multistep, optimization-based, noninvasive method for estimating individual-specific BSPs and calculating joint moments in a multisegment HAT model. Eleven nondisabled individuals participated in a trunk-bending experiment and their body motion was recorded using cameras and a force plate. A seven segment model of the HAT was reconstructed for each participant. An initial guess of the BSPs was obtained by individual-specific scaling of the BSPs calculated from the male visible human (MVH) images. The intersegmental moments were calculated using both bottom-up and top-down inverse dynamics approaches. Our proposed method adjusted the scaled BSPs and center of pressure (COP) offsets to estimate optimal individual-specific BSPs that minimize the difference between the moments obtained by top-down and bottom-up inverse dynamics approaches. Our results indicate that the proposed method reduced the error in the net joint moment estimation (defined as the difference between the net joint moment calculated via bottom-up and top-down approaches) by 79.3% (median among participants). Our proposed method enables an optimized estimation of individual specific BSPs and, consequently, a less erroneous assessment of the three dimensional (3D) kinetics of a multisegment HAT model. PMID- 30029242 TI - Laboratory Validation of a Wearable Sensor for the Measurement of Head Acceleration in Men's and Women's Lacrosse. AB - Mild traumatic brain injuries, or concussions, can result from head acceleration during sports. Wearable sensors like the GForceTrackerTM (GFT) can monitor an athlete's head acceleration during play. The purpose of this study was to evaluate the accuracy of the GFT for use in boys' and girls' lacrosse. The GFT was mounted to either a strap connected to lacrosse goggles (helmetless) or a helmet. The assembly was fit to a Hybrid III (HIII) headform instrumented with sensors and impacted multiple times at different velocities and locations. Measurements of peak linear acceleration and angular velocity were obtained from both systems and compared. It was found that a large percent error between the GFT and headform system existed for linear acceleration (29% for helmetless and 123% for helmet) and angular velocity (48% for helmetless and 17% for helmet). Linear acceleration data transformed to the center of gravity (CG) of the head still produced errors (47% for helmetless and 76% for helmet). This error was substantially reduced when correction equations were applied based on impact location (3-22% for helmetless and 3-12% for helmet impacts at the GFT location and transformed to the CG of the head). Our study has shown that the GFT does not accurately calculate linear acceleration or angular velocity at the CG of the head; however, reasonable error can be achieved by correcting data based on impact location. PMID- 30029240 TI - Evaluation and Prediction of Human Lumbar Vertebrae Endplate Mechanical Properties Using Indentation and Computed Tomography. AB - Current implant materials and designs used in spinal fusion show high rates of subsidence. There is currently a need for a method to predict the mechanical properties of the endplate using clinically available tools. The purpose of this study was to develop a predictive model of the mechanical properties of the vertebral endplate at a scale relevant to the evaluation of current medical implant designs and materials. Twenty vertebrae (10 L1 and 10 L2) from 10 cadavers were studied using dual-energy X-ray absorptiometry to define bone status (normal, osteopenic, or osteoporotic) and computed tomography (CT) to study endplate thickness (MUm), density (mg/mm3), and mineral density of underlying trabecular bone (mg/mm3) at discrete sites. Apparent Oliver-Pharr modulus, stiffness, maximum tolerable pressure (MTP), and Brinell hardness were measured at each site using a 3 mm spherical indenter. Predictive models were built for each measured property using various measures obtained from CT and demographic data. Stiffness showed a strong correlation between the predictive model and experimental values (r = 0.85), a polynomial model for Brinell hardness had a stronger predictive ability compared to the linear model (r = 0.82), and the modulus model showed weak predictive ability (r = 0.44), likely due the low indentation depth and the inability to image the endplate at that depth (~0.15 mm). Osteoporosis and osteopenia were found to be the largest confounders of the measured properties, decreasing them by approximately 50%. It was confirmed that vertebral endplate mechanical properties could be predicted using CT and demographic indices. PMID- 30029245 TI - Sensitivity of Arterial Hyperelastic Models to Uncertainties in Stress-Free Measurements. AB - Despite major advances made in modeling vascular tissue biomechanics, the predictive power of constitutive models is still limited by uncertainty of the input data. Specifically, key measurements, like the geometry of the stress-free (SF) state, involve a definite, sometimes non-negligible, degree of uncertainty. Here, we introduce a new approach for sensitivity analysis of vascular hyperelastic constitutive models to uncertainty in SF measurements. We have considered two vascular hyperelastic models: the phenomenological Fung model and the structure-motivated Holzapfel-Gasser-Ogden (HGO) model. Our results indicate up to 160% errors in the identified constitutive parameters for a 5% measurement uncertainty in the SF data. Relative margins of errors of up to 30% in the luminal pressure, 36% in the axial force, and over 200% in the stress predictions were recorded for 10% uncertainties. These findings are relevant to the large body of studies involving experimentally based modeling and analysis of vascular tissues. The impact of uncertainties on calibrated constitutive parameters is significant in context of studies that use constitutive parameters to draw conclusions about the underlying microstructure of vascular tissues, their growth and remodeling processes, and aging and disease states. The propagation of uncertainties into the predictions of biophysical parameters, e.g., force, luminal pressure, and wall stresses, is of practical importance in the design and execution of clinical devices and interventions. Furthermore, insights provided by the present findings may lead to more robust parameters identification techniques, and serve as selection criteria in the trade-off between model complexity and sensitivity. PMID- 30029243 TI - A Thermal and Biological Analysis of Bone Drilling. AB - With the introduction of high-speed cutting tools, clinicians have recognized the potential for thermal damage to the material being cut. Here, we developed a mathematical model of heat transfer caused by drilling bones of different densities and validated it with respect to experimentally measured temperatures in bone. We then coupled these computational results with a biological assessment of cell death following osteotomy site preparation. Parameters under clinical control, e.g., drill diameter, rotational speed, and irrigation, along with patient-specific variables such as bone density were evaluated in order to understand their contributions to thermal damage. Predictions from our models provide insights into temperatures and thresholds that cause osteocyte death and that can ultimately compromise stability of an implant. PMID- 30029244 TI - A New Growth Model for Aortic Valve Calcification. AB - Calcific aortic valve disease (CAVD) is a progressive disease in which minerals accumulate in the tissue of the aortic valve cusps, stiffening them and preventing valve opening and closing. The process of valve calcification was found to be similar to that of bone formation including cell differentiation to osteoblast-like cells. Studies have shown the contribution of high strains to calcification initiation and growth process acceleration. In this paper, a new strain-based calcification growth model is proposed. The model aims to explain the unique shape of the calcification and other disease characteristics. The calcification process was divided into two stages: Calcification initiation and calcification growth. The initiation locations were based on previously published findings and a reverse calcification technique (RCT), which uses computed tomography (CT) scans of patients to reveal the calcification initiation point. The calcification growth process was simulated by a finite element model of one aortic valve cusp loaded with cyclic loading. Similar to Wolff's law, describing bone response to stress, our model uses strains to drive calcification formation. The simulation grows calcification from its initiation point to its full typical stenotic shape. Study results showed that the model was able to reproduce the typical calcification growth pattern and shape, suggesting that strain is the main driving force behind calcification progression. The simulation also sheds light on other disease characteristics, such as calcification growth acceleration as the disease progresses, as well as sensitivity to hypertension. PMID- 30029246 TI - Acute Surgical Injury Alters the Tensile Properties of Thoracolumbar Fascia in a Porcine Model. AB - : Recent work utilizing ultrasound imaging demonstrated that individuals with low back pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia (TLF), an indication that the TLF may play a role in LBP. This study used a porcine injury model (microsurgically induced local injury) shown to produce similar results to those observed in humans with LBP-to test the hypothesis that TLF mechanical properties may also be altered in patients with LBP. Perimuscular TLF tissue was harvested from the noninjured side of vertebral level L3-4 in pigs randomized into either control (n = 5) or injured (n = 5) groups. All samples were tested with a displacement-controlled biaxial testing system using the following protocol: cyclic loading/unloading and stress relaxation tests at 25%, 35%, and then 45% of their resting length. Tissue anisotropy was also explored by comparing responses to loading in longitudinal and transverse orientations. Tissues from injured pigs were found to have greater stretch-stretch ratio moduli (measure of tissue stiffness), less energy dissipation, and less stress decay compared to tissues from control pigs. Responses across these variables also depended on loading orientation. CLINICAL SIGNIFICANCE: these findings suggest that a focal TLF injury can produce impairments in tissue mechanical properties away from the injured area itself. This could contribute to some of the functional abnormalities observed in human LBP. PMID- 30029247 TI - Numerical Parametric Study of Paravalvular Leak Following a Transcatheter Aortic Valve Deployment Into a Patient-Specific Aortic Root. AB - Paravalvular leak (PVL) is a relatively frequent complication after transcatheter aortic valve replacement (TAVR) with increased mortality. Currently, there is no effective method to pre-operatively predict and prevent PVL. In this study, we developed a computational model to predict the severity of PVL after TAVR. Nonlinear finite element (FE) method was used to simulate a self-expandable CoreValve deployment into a patient-specific aortic root, specified with human material properties of aortic tissues. Subsequently, computational fluid dynamics (CFD) simulations were performed using the post-TAVR geometries from the FE simulation, and a parametric investigation of the impact of the transcatheter aortic valve (TAV) skirt shape, TAV orientation, and deployment height on PVL was conducted. The predicted PVL was in good agreement with the echocardiography data. Due to the scallop shape of CoreValve skirt, the difference of PVL due to TAV orientation can be as large as 40%. Although the stent thickness is small compared to the aortic annulus size, we found that inappropriate modeling of it can lead to an underestimation of PVL up to 10 ml/beat. Moreover, the deployment height could significantly alter the extent and the distribution of regurgitant jets, which results in a change of leaking volume up to 70%. Further investigation in a large cohort of patients is warranted to verify the accuracy of our model. This study demonstrated that a rigorously developed patient specific computational model can provide useful insights into underlying mechanisms causing PVL and potentially assist in pre-operative planning for TAVR to minimize PVL. PMID- 30029248 TI - Poly(Propylene Fumarate)-Hydroxyapatite Nanocomposite Can Be a Suitable Candidate for Cervical Cages. AB - A wide range of materials have been used for the development of intervertebral cages. Poly(propylene fumarate) (PPF) has been shown to be an excellent biomaterial with characteristics similar to trabecular bone. Hydroxyapatite (HA) has been shown to enhance biocompatibility and mechanical properties of PPF. The purpose of this study was to characterize the effect of PPF augmented with HA (PPF:HA) and evaluate the feasibility of this material for the development of cervical cages. PPF was synthesized and combined with HA at PPF:HA wt:wt ratios of 100:0, 80:20, 70:30, and 60:40. Molds were fabricated for testing PPF:HA bulk materials in compression, bending, tension, and hardness according to ASTM standards, and also for cage preparation. The cages were fabricated with and without holes and with porosity created by salt leaching. The samples as well as the cages were mechanically tested using a materials testing frame. All elastic moduli as well as the hardness increased significantly by adding HA to PPF (p < 0.0001). The 20 wt % HA increased the moduli significantly compared to pure PPF (p < 0.0001). Compressive stiffness of all cages also increased with the addition of HA. HA increased the failure load of the porous cages significantly (p = 0.0018) compared with nonporous cages. PPF:HA wt:wt ratio of 80:20 proved to be significantly stiffer and stronger than pure PPF. The current results suggest that this polymeric composite can be a suitable candidate material for intervertebral body cages. PMID- 30029249 TI - The Role of the RhoA/ROCK Signaling Pathway in Mechanical Strain-Induced Scleral Myofibroblast Differentiation. AB - Purpose: Biomechanical properties changes and alpha-smooth muscle actin (alpha SMA) overexpression are involved in myopia scleral remodeling. However, interactions between altered tissue biomechanics and cellular signaling that sustain scleral remodeling have not been well defined. We determine the mechanisms of mechanotransduction in the regulation of alpha-SMA expression during myopia scleral remodeling. Methods: Guinea pigs were used to establish a form-deprivation myopia (FDM) model. Protein profiles in myopic sclera were examined using tandem mass spectrometry. Ras homolog gene family member A (RhoA) and alpha-SMA expressions were confirmed using quantitative (q) RT-PCR and Western blotting. Scleral fibroblasts were cultured and subjected to 4% cyclic strain. Levels of RhoA, rho-associated protein kinase-2 (ROCK2), myocardin related transcription factor-A (MRTF-A), serum response factor (SRF), and alpha SMA were determined by qRT-PCR and Western blotting in groups with or without the RhoA siRNA or ROCK inhibitor Y27632. MRTF-A and alpha-SMA were evaluated by confocal immunofluorescent microscopy and myofibroblasts were enumerated using flow cytometry. Results: mRNA and protein levels of RhoA and alpha-SMA were significantly increased in the FDM eyes after 4 weeks of form-deprivation treatment. The 4% static strain increased expressions of RhoA, ROCK2, MRTF-A, SRF, and alpha-SMA as well as nuclear translocalization of MRTF-A in scleral fibroblasts compared to those without strain stimulation. Additionally, the percentage of myofibroblasts increased after strain stimulation. Conversely, inhibition of RhoA or ROCK2 reversed the strain-induced alpha-SMA expression and myofibroblast ratio. Conclusions: Mechanical strain activated RhoA signaling and scleral myofibroblast differentiation. Strain also mediated myofibroblast differentiation via the RhoA/ROCK2-MRTF-A/SRF pathway. These findings provided evidence for a mechanical strain-induced RhoA/ROCK2 pathway that may contribute to myopia scleral remodeling. PMID- 30029252 TI - Diagnostic Accuracy of Three-Dimensional Neuroretinal Rim Thickness for Differentiation of Myopic Glaucoma From Myopia. AB - Purpose: To compare the diagnostic accuracy of three-dimensional neuroretinal rim (3D-NRR) and peripapillary retinal nerve fiber layer (RNFL) thickness for differentiation of myopic glaucoma from myopia. Methods: Healthy myopic individuals (n = 193 eyes) and age-matched myopic glaucoma patients (n = 61 eyes) were enrolled. A 200 * 200-optic disc cube scan was performed with Cirrus HD-OCT. The rates of false-positive errors were compared between RNFL and 3D-NRR thickness measurements. The diagnostic accuracies of RNFL and 3D-NRR thickness for myopic glaucoma were compared by calculating the areas under receiver operating characteristic (AUROC) curves and the partial area under the curve (pAUC) for sensitivity >=90%. Results: The overall false-positive rate was significantly greater for RNFL thickness (26.9%) than for 3D-NRR thickness (2.1%, P < 0.001). False-positive RNFL-thickness errors were prevalent in the nasal peripapillary region. The 3D-NRR thickness relative to RNFL revealed a greater AUROC from the 12 to 6 o'clock and 9 o'clock sectors. Again, comparing 3D-NRR with RNFL thickness, the pAUC for sensitivity >=90% was greater in the nasal quadrant, 12, 3, 4, and 5 o'clock sectors. Also, the sensitivity and specificity, based on the internal normative database, were greater for 3D-NRR than for RNFL thickness. Conclusions: 3D-NRR thickness measurement reduced the false-positive rate for glaucoma diagnosis and demonstrated better accuracy for glaucoma detection in myopic eyes. Measurement of 3D-NRR can be complementary to RNFL thickness measurement for differentiation of myopic glaucoma from myopia. PMID- 30029251 TI - Capn5 Expression in the Healthy and Regenerating Zebrafish Retina. AB - Purpose: Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a devastating inherited autoimmune disease of the eye that displays features commonly seen in other eye diseases, such as retinitis pigmentosa and diabetic retinopathy. ADNIV is caused by a gain-of-function mutation in Calpain-5 (CAPN5), a calcium-dependent cysteine protease. Very little is known about the normal function of CAPN5 in the adult retina, and there are conflicting results regarding its role during mammalian embryonic development. The zebrafish (Danio rerio) is an excellent animal model for studying vertebrate development and tissue regeneration, and represents a novel model to explore the function of Capn5 in the eye. Methods: We characterized the expression of Capn5 in the developing zebrafish central nervous system (CNS) and retina, in the adult zebrafish retina, and in response to photoreceptor degeneration and regeneration using whole-mount in situ hybridization, FISH, and immunohistochemistry. Results: In zebrafish, capn5 is strongly expressed in the developing embryonic brain, early optic vesicles, and in newly differentiated retinal photoreceptors. We found that expression of capn5 colocalized with cone-specific markers in the adult zebrafish retina. We observed an increase in expression of Capn5 in a zebrafish model of chronic rod photoreceptor degeneration and regeneration. Acute light damage to the zebrafish retina was accompanied by an increase in expression of Capn5 in the surviving cones and in a subset of Muller glia. Conclusions: These studies suggest that Capn5 may play a role in CNS development, photoreceptor maintenance, and photoreceptor regeneration. PMID- 30029250 TI - Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage. AB - Purpose: Neovascularization (NV) and retinal vascular leakage are major causes of impaired vision in ocular diseases. The purpose of this study was to identify novel phenylphthalimide analogs with therapeutic effects on NV and vascular leakage and to explore the mechanism of action. Methods: Antiangiogenic activities of novel phenylphthalimide analogs were assessed in vitro by using VEGF ELISA and endothelial cell proliferation assay. Their efficacies on retinal vascular leakage were evaluated using rat models of oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetes. The in vivo antiangiogenic activity was evaluated using topical administration in the alkali burn-induced corneal NV model. The expression of VEGF and intercellular adhesion molecule-1 (ICAM-1) were measured using ELISA. Results: Thalidomide and three novel analogs all showed inhibitory effects on endothelial cell proliferation and VEGF expression in vitro. Through intravitreal injection, all of the compounds reduced retinal vascular leakage in the OIR and STZ-induced diabetic models. Among these compounds, (2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione (DAID) displayed the most potent efficacy and reduced retinal vascular leakage in a dose dependent manner in both the OIR and STZ-diabetes models. Topical administration of DAID also inhibited alkali burn-induced corneal NV. Furthermore, DAID attenuated the overexpression of VEGF and ICAM-1 in the retina of the OIR model. Intravitreal injection of DAID did not result in any detectable side effects, as shown by electroretinogram and retinal histological analysis. Conclusions: DAID is a novel phenylphthalimide analog with potent effects on NV and retinal vascular leakage through downregulation of VEGF and inflammatory factors and has therapeutic potential. PMID- 30029255 TI - Sustained Connexin43 Mimetic Peptide Release From Loaded Nanoparticles Reduces Retinal and Choroidal Photodamage. AB - Purpose: To evaluate the long-term effect on inflammation and inflammasome activation of intravitreally delivered connexin43 mimetic peptide (Cx43MP) in saline or incorporated within nanoparticles (NPs) for the treatment of the light damaged rat eye. Methods: Light-induced damage to the retina was created by exposure of adult albino Sprague-Dawley rats to intense light for 24 hours. A single dose of Cx43MP, Cx43MP-NPs, or saline was injected intravitreally at 2 hours after onset of light damage. Fluorescein isothiocyanate (FITC)-labelled Cx43MP-NPs were intravitreally injected to confirm delivery into the retina. Electroretinogram (ERG) recordings were performed at 24 hours, 1 week, and 2 weeks post cessation of light damage. The retinal and choroidal layers were analyzed in vivo using optical coherence tomography (OCT) and immunohistochemistry was performed on harvested tissues using glial fibrillary acidic protein (GFAP), leukocyte common antigen (CD45), and Cx43 antibodies. Results: FITC was visualized 30 minutes after injection in the ganglion cell layer and in the choroid. Cx43MP and Cx43MP-NP treatments improved a-wave and b wave function of the ERG compared with saline-injected eyes at 1 week and 2 weeks post treatment, and prevented photoreceptor loss by 2 weeks post treatment. Inflammation was also reduced and this was in parallel with downregulation of Cx43 expression. Conclusions: The slow release of Cx43MP incorporated into NPs is more effective at treating retinal injury than a single dose of native Cx43MP in solution by reducing inflammation and maintaining both retinal structure and function. This NP preparation has clinical relevance as it reduces possible ocular complications associated with repeated intravitreal injections. PMID- 30029253 TI - Differences in the Relation Between Perimetric Sensitivity and Variability Between Locations Across the Visual Field. AB - Purpose: Perimetric sensitivities become more variable with glaucomatous functional loss. This study examines the extent to which this relation varies between locations, and whether this can be predicted by eccentricity-related differences in spatial summation. Methods: Longitudinal series of visual fields from standard automated perimetry were obtained from participants with suspected or extant glaucoma. For each location in the 24-2 visual field, heterogeneous fixed-effects models were fit to the data, assuming that variability increased exponentially as sensitivity decreased. The predicted variability at each location was calculated when sensitivity was either 30 dB or 25 dB. Results: Variability significantly increased with damage at all 52 locations. When sensitivity was 30 dB, variability increased with eccentricity, with P = 0.0003. The average SD was 1.54 dB at the four most central locations, versus 1.74 dB at the most peripheral locations. When sensitivity was 25 dB, variability did not vary predictably with eccentricity, with P = 0.340. The average SD was 2.36 dB at the four central locations, versus 2.24 dB at the most peripheral locations. Conclusions: The relation between sensitivity and variability differed by eccentricity. Among healthy locations, variability was lower centrally, where the stimulus size is larger than Ricco's area, than peripherally. Among damaged locations, variability did not systematically vary with eccentricity. This could be because Ricco's area expands in glaucoma, such that stimuli were now smaller than this area at all locations. PMID- 30029256 TI - Peripapillary Choroidal Vascularity Index in Glaucoma-A Comparison Between Spectral-Domain OCT and OCT Angiography. AB - Purpose: To compare the choroidal vascularity index (CVI) determined by spectral domain optical coherence tomography (OCT) between eyes with and without parapapillary deep-layer microvasculature dropout (MvD_P) assessed by OCT angiography in glaucomatous eyes. Methods: A total of 100 open-angle glaucoma patients with and without MvD_P (50 eyes of 50 patients in each group) matched by age and visual field mean deviation were included. Total choroidal area (TCA) and CVI were measured by image binarization of spectral-domain OCT B-scans in order to assess the choroidal vasculature outside beta-zone parapapillary atrophy (betaPPA) at a 3.5-mm distance from the Bruch's membrane opening center. MvD_P was determined by OCT angiography as a deep-layer microvasculature dropout within betaPPA. Global and sectoral (six 60 degrees sectors) TCA and CVI were compared between eyes with and without MvD_P. Results: The CVIs of eyes with MvD_P were significantly lower than those without MvD_P, globally (P = 0.010) as well as in the inferotemporal (TI) (P = 0.003), temporal (P = 0.009), and nasal (P = 0.048) sectors. Eyes with MvD_P, of which the largest portion was located only in the TI sector (n = 33), had significantly lower CVI than those without MvD_P in the corresponding TI and temporal sectors (P < 0.05 for all), whereas TCA did not differ in any areas. Conclusions: Eyes with MvD_P had significantly lower CVIs than did those without MvD_P. Furthermore, CVI reduction was spatially correlated with MvD_P. Further studies investigating the influence of MvD_P on the choroidal vasculature outside betaPPA are warranted. PMID- 30029254 TI - Quantification of Pulse-Dependent Trabecular Meshwork Motion in Normal Humans Using Phase-Sensitive OCT. AB - Purpose: The purpose of this study was to characterize the pulsatile motion of trabecular meshwork (TM) in normal subjects and demonstrate its changes in accommodation with phase-sensitive optical coherence tomography (PhS-OCT). Methods: A new PhS-OCT laboratory prototype was designed to measure pulsatile TM motion in 13 healthy humans. Two sets of images were captured in 10 subjects, first with best corrective refraction and the other with an additional 3.0 diopters of accommodation. In each image, both maximum velocity (MV) and cumulative displacement (CD) in two selected regions of TM, the internal (IMV and ICD) and external (EMV and ECD) region, were measured. Results: For all parameters the intraclass correlation coefficient was >0.75. Neither MV nor CD was significantly different between eyes in individual subjects (PIMV = 0.967, PEMV = 0.391, PICD = 0.603, PECD = 0.482). In 26 eyes, with best corrective refraction, the EMV was higher than the IMV (23.9 +/- 9.8 vs. 18.9 +/- 8.08 MUm/s; P = 0.0001), as was the ECD compared with the ICD (0.340 +/-0.125 vs. 0.264 +/- 0.111 MUm; P = 0.000004). With accommodation, MV and CD significantly increased (PIMV = 0.0003, PEMV = 0.0003, PICD = 0.019, and PECD = 0.007), whereas MV and CD in the external region were still larger than those in the internal area (PEMV vs. IMV = 0.009, PECD vs. ICD = 0.023). Conclusions: This study demonstrates the differences in TM motion between the internal and external regions of TM and displays its change with accommodation. The findings and good reproducibility suggest PhS-OCT helps to understand TM function in regulation of IOP, and, with further refinements, it may be useful in clinical management of glaucoma. PMID- 30029257 TI - Corneal Collagen Cross-Linking With Riboflavin and UVA Regulates Hemangiogenesis and Lymphangiogenesis in Rats. AB - Purpose: The purpose of this study was to determine whether corneal collagen crosslinking (CXL) inhibits hemangiogenesis and lymphangiogenesis during acute corneal inflammation in an in vivo rat model. Methods: Inflammatory corneal neovascularization was induced by suture placement into a rat cornea. At day 3 after suture, a CXL protocol using riboflavin and UVA was administered after mechanical epithelial debridement. Hemangiogenesis and lymphangiogenesis were analyzed morphometrically. CD45 and CD68 immunostaining evaluated corneal leucocyte and macrophage immune cell infiltration, respectively. A TUNEL assay detected stromal cell apoptosis. Quantitative RT-PCR analysis identified angiogenic and lymphangiogenic genes as well as proinflammatory cytokine expression. Western blot analysis characterized vascular endothelial cell CD31 and lymphatic vessel endothelial hyaluronan receptor (LYVE-1) protein expression. Results: CXL treatment significantly reduced corneal pathologic suture-induced hemangiogenesis and lymphangiogenesis 7 days after suture emplacement, but this procedure failed to affect hemangiogenesis and lymphangiogenesis 14 days after suture. Increased cell apoptosis and reduced CD45+ and CD68+ cell infiltration were evident in CXL-treated rats on days 7 and 14 after suture emplacement. CXL treatment significantly decreased angiogenic and lymphangiogenic mRNA expression levels and both CD31 and LYVE-1 protein expression levels, whereas it increased proinflammatory cytokine levels on day 7 after suture emplacement. However, on day 14 after corneal neovascularization, angiogenic and lymphangiogenic mRNA gene expression levels were upregulated along with hematic CD31 and lymphatic LYVE-1 protein expression. Conclusions: CXL treatment only temporarily inhibits corneal inflammatory-associated hemangiogenesis and lymphangiogenesis in vivo. Such insight suggests that future studies are warranted to develop novel CXL strategies with longer-lasting effectiveness in attenuating hemantic- and lymphatic-related corneal diseases. PMID- 30029258 TI - Cyclogram based Joint Symmetry Assessment after Utilization of a Foot Drop Stimulator during Post Stroke Hemiplegic Gait. AB - In the absence of standardized symmetry assessments, quantifying symmetry based on the kinematic evolution of lower extremity joints can elucidate gait irregularities. The objective was to develop a novel cyclogram based symmetry (CBS) method to quantify lower extremity joints' symmetry and assess the effect of 6-month utilization of foot drop stimulator (FDS) on CBS of the lower limbs during hemiplegic gait post stroke. Twenty-four participants (13 stroke and 11 healthy controls (HC)) performed 10 walking trials at a free cadence on level ground. Symmetry values were computed using geometric properties of bilateral cyclograms obtained from normalized sagittal ankle, knee and hip kinematics. CBS and traditional temporospatial symmetry values were compared between the two groups using independent sample t-test. Effect of FDS utilization on symmetry was assessed by paired sample t- test computed at baseline and 6-month follow up. The CBS method successfully showed that the HC group was significantly more symmetrical at the ankle (p=0.001), knee (p=0.001) and hip (p<0.005) compared with the stroke group. The stroke group showed significant increment in hip symmetry with FDS at baseline but did not show any significant CBS changes at follow up. Pearson correlations revealed that hip and knee CBS had a significant influence on overall walking speed. The CBS method presents a unique approach to calculate symmetry based on the kinematics of lower extremities during gait. PMID- 30029259 TI - Force and Contact Location Measurement Errors of the VERASENSE. AB - BACKGROUND: The OrthoSensor VERASENSE knee system is a commercially available instrumented tibial insert that provides real-time intraoperative measurements of tibial contact force and contact location to guide surgeons toward improving outcomes in total knee arthroplasty (TKA). However, the device has been used contrary to the manufacturer's recommendations in several studies and lacks published accuracy data. Therefore, the primary objectives of this study were to evaluate the device's error in tibial contact force when used according to and contrary to the manufacturer's recommendations, and also to evaluate the device's error in anterior-posterior (A-P) and medial-lateral (M-L) contact locations. METHODS: The error in tibial contact force in single compartment distributed loading was evaluated by applying known forces in ranges within and exceeding that recommended by the manufacturer, with rezeroing as recommended by the manufacturer, and without rezeroing. The error in tibial contact location in single compartment concentrated loading was evaluated by applying known forces at known locations on the articular surface. RESULTS: Exceeding the maximum allowable load and not rezeroing did not adversely affect the bias (i.e. average error) (p > 0.05). The maximum absolute bias without rezeroing was 2.9 lbf. Rezeroing more than doubled the bias. The maximum root mean squared error in tibial contact location was 1.5 mm in the A-P direction. CONCLUSION: The device measures tibial contact force with comparable error well above the maximum allowable load and without rezeroing, contrary to the manufacturer's instructions. PMID- 30029260 TI - Residual stresses in titanium spinal rods: effects of two contouring methods and material plastic properties. AB - Posterior spinal fixation based on long spinal rods is the clinical gold standard for the treatment of severe deformities. Rods need to be contoured prior to implantation to fit the natural curvature of the spine. The contouring processes is known to introduce residual stresses and strains which affect the static and fatigue mechanical response of the implant, as determined through time- and cost consuming experimental tests. Finite Element (FE) models promise to provide an immediate understanding on residual stresses and strains within a contoured spinal rods and a further insight on their complex distribution. The present study aims at investigating two rod contouring strategies, French bender (FB) contouring (clinical gold standard) and uniform contouring, through validated FE models. A careful characterization of the elasto-plastic material response of commercial implants is led. Compared to uniform contouring, FB induces highly localized plasticizations in compression under the contouring pin with extensive lateral sections undergoing tensile residual stresses. The sensitivity analysis highlighted that the assumed post-yielding properties significantly affect the numerical predictions, therefore an accurate material characterization is recommended. PMID- 30029261 TI - In vivo quantification of regional circumferential Green strain in the thoracic and abdominal aorta by 2D spiral cine DENSE MRI. AB - INTRODUCTION: Regional tissue mechanics play a fundamental role in patient specific cardiovascular function. Nevertheless, regional assessments of aortic kinematics remain lacking due to the challenge of imaging the thin aortic wall. Herein, we present a novel application of DENSE (Displacement Encoding with Stimulated Echoes) MRI to quantify the circumferential Green strain of the thoracic and abdominal aorta. METHODS: 2D spiral cine DENSE and steady-state free procession (SSFP) cine images were acquired at 3T at the infrarenal aorta (IAA), descending thoracic aorta (DTA), or distal aortic arch (DAA) in a pilot study of 6 healthy volunteers. DENSE data was processed with multiple custom noise reduction techniques to calculate circumferential Green strain across 16 equispaced sectors around the aorta. Each volunteer was scanned twice to evaluate interstudy repeatability. RESULTS: Circumferential strain was heterogeneously distributed in all volunteers and locations. Spatial heterogeneity index by location was 0.37 (IAA), 0.28 (DTA), and 0.59 (DAA). Mean peak strain by DENSE for each cross-section was consistent with the homogenized linearized strain estimated from SSFP cine. The mean difference in peak strain across all sectors following repeat imaging was -0.1+/-2.2%, with a mean absolute difference of 1.7%. CONCLUSIONS: Aortic cine DENSE MRI is a viable non-invasive technique for quantifying heterogeneous regional aortic wall strain and has significant potential to improve patient-specific clinical assessments of numerous aortopathies, as well as to provide the lacking spatiotemporal data required to refine computational models of aortic growth and remodeling. PMID- 30029262 TI - Muscle Function and Coordination of Amputee Stair Ascent. AB - Ascending stairs is challenging following transtibial amputation due to the loss of the ankle muscles, which are critical to human movement. Efforts to improve stair ascent following amputation are hindered by limited understanding of how prostheses and remaining muscles contribute to stair ascent. This study developed a three-dimensional muscle-actuated forward dynamics simulation of amputee stair ascent to identify contributions of individual muscles and passive prosthesis to the biomechanical subtasks of stair ascent. The prosthesis was found to provide vertical propulsion throughout stair ascent, similar to non-amputee plantarflexors. However, the timing differed considerably. The prosthesis also contributed to braking, similar to non-amputee soleus, but to a greater extent. In contrast, the prosthesis was unable to replicate the functions of non-amputee gastrocnemius which contributes to forward propulsion during the second half of stance and leg swing initiation. To compensate, hamstrings and vasti of the residual leg increased their contributions to forward propulsion during the first and second halves of stance, respectively. The prosthesis also contributed to medial control, consistent with the non-amputee soleus but not gastrocnemius. Therefore, prosthesis designs that provide additional vertical propulsion as well as forward propulsion, lateral control and leg swing initiation at appropriate points in the gait cycle could improve amputee stair ascent. However, because non amputee soleus and gastrocnemius contribute oppositely to many subtasks, it may be necessary to couple the prosthesis, which functions most similarly to soleus, with targeted rehabilitation programs focused on muscle groups that can compensate for gastrocnemius. PMID- 30029263 TI - Abdominal aortic aneurysm endovascular repair: profiling post-implantation morphometry and hemodynamics with image-based computational fluid dynamics. AB - Endovascular aneurysm repair (EVAR) has disseminated rapidly as an alternative to open surgical repair for the treatment of abdominal aortic aneurysms (AAAs), because of its reduced invasiveness, low mortality and morbidity rate. The effectiveness of the endovascular devices used in EVAR is always at question as postoperative adverse events can lead to re-intervention or to a possible fatal scenario for the circulatory system. Motivated by the assessment of the risks related to thrombus formation, here the impact of two different commercial endovascular grafts on local hemodynamics is explored through 20 image-based computational hemodynamic models of EVAR-treated patients (N=10 per each endograft model). Hemodynamic features, susceptible to promote thrombus formation, such as flow separation and recirculation, are quantitatively assessed and compared with the local hemodynamics established in image-based infrarenal abdominal aortic models of healthy subjects (N=10). The hemodynamic analysis is complemented by a geometrical characterization of the EVAR-induced reshaping of the infrarenal abdominal aortic vascular region. The findings of this study indicate that: (1) the clinically observed propensity to thrombus formation in devices used in EVAR strategies can be explained in terms of local hemodynamics by means of image-based computational hemodynamics approach; (2) reportedly pro thrombotic hemodynamic structures are strongly correlated with the geometry of the aortoiliac tract postoperatively. In perspective, our study suggests that future clinical follow up studies could include a geometric analysis of the region of the implant, monitoring shape variations that can lead to hemodynamic disturbances of clinical significance. PMID- 30029264 TI - Nonlinear analysis of human movement dynamics offer new insights in the development of motor control during childhood. AB - When aiming at assessing motor control development, natural walking (NW) and tandem walking (TW) are two locomotor tasks that allow analysing different characteristics of motor control performance. NW is the reference locomotor task, expected to become more and more automatic with age. TW is a non-paradigmatic task used in clinics to highlight eventual impairments and to evaluate how a child deals with a new challenging motor experience. This work aims at investigating motor development in school-aged children, by assessing quantitatively their performance during TW and NW. 80 children (6-10 years) participated in the study. Trunk acceleration data and nonlinear measures (recurrence quantification analysis, RQA, and multiscale entropy, MSE) were used to characterize postural control ability and motor complexity. Results were analysed with respect to age and standard clinical assessment of TW (number of correct consecutive steps), by means of Pearson correlation coefficients. RQA and MSE allowed highlighting age-related changes in both postural control stability and motor complexity, while classic standard assessment of TW resulted uniformly distributed in the different age groups. Present results suggest this quantitative approach as relevant when assessing motor development in schoolchildren and complementary to standard clinical tests. PMID- 30029265 TI - A study of the mechanical forces on aphakic iris-fixated intraocular lenses. AB - Iris-fixated aphakic intraocular lenses (IFIOL) are used in cataract surgery, when more common intraocular lenses cannot be adopted because of the absence of capsular bag support. These lenses can be implanted either on the poste- rior or the anterior surface of the iris. In this work we study whether one of these options is preferable over the other from the mechanical point of view. In particular, we focus on the forces that the IFIOL transmits to the iris, which are asso- ciated with the risk of lens dislocation. We study the prob- lem numerically and consider aqueous flow induced by sac- cadic rotations in the cases of an IFIOL in the anterior and posterior side of the iris. The IFIOL considered is the Arti- san Aphakia +30.0 D lens (IFIOL) produced by Ophtec BV. We perform the simulations in OpenFOAM. We find that the forces transmitted by the aphakic IFIOL to the iris are sig- nificantly higher in the case of posterior implantation. This suggests that lens implantation on the posterior surface of the iris might be associated with a higher risk of lens disloca- tion, when an inadequate amount of iris tissue is enclavated during implantation. PMID- 30029266 TI - Distribution of Brain Strain in the Cerebrum for Ice Hockey Goaltender Impacts. AB - Concussions are among the most common injuries sustained by goaltenders. Concussive injuries are characterized by impairment to neurological function which can affect many different brain regions. Understanding how different impact loading conditions (event type and impact site) affect the brain tissue response may help identify what kind of impacts create a high risk of injury to specific brain regions. The purpose of this study was to examine the influence of different impact conditions on the distribution of brain strain for ice hockey goaltender impacts. An instrumented headform was fitted with an ice hockey goaltender mask and impacted under a protocol which was developed using video analysis of real world ice hockey goaltender concussions for three different impact events (collision, puck, and fall). The resulting kinematic response served as input into the University College Dublin Brain Trauma Model, which calculated maximum principal strain in the cerebrum. Strain subsets were then determined and analyzed. Resulting peak strains (0.124 - 0.328) were found to be within the range for concussion reported in the literature. The results demonstrated that falls and collisions produced larger strain subsets in the cerebrum than puck impacts which is likely a reflection of longer impact duration for falls and collisions than puck impacts. For each impact event, impact site was also found to produce strain subsets of varying size and configuration. The results of this study suggest that the location and number of brain regions which can be damaged depend on the loading conditions of the impact. PMID- 30029267 TI - An analytical poroelastic model of a non-homogeneous medium under creep compression for ultrasound poroelastography applications - Part I. AB - An analytical theory for the unconfined creep behavior of a cylindrical inclusion (simulating a soft tissue tumor) embedded in a cylindrical background sample (simulating normal tissue) is presented and analyzed in this paper. Both the inclusion and the background are considered as fluid-filled, porous materials, each of them being characterized by a set of mechanical properties. Specifically, in this paper, the inclusion is considered to be less permeable than the background. The cylindrical sample is compressed using a constant pressure within two frictionless plates and is allowed to expand in an unconfined way along the radial direction. Analytical expressions for the effective Poisson's ratio (EPR) and fluid pressure inside and outside the inclusion are derived and analyzed. The theoretical results are validated using finite element models (FEM). Statistical analysis shows excellent agreement between the results obtained from the developed model and the results from FEM. Thus the developed theoretical model can be used in medical imaging modalities such as ultrasound poroelastography to extract the mechanical parameters of tissues and/or to better understand the impact of the different mechanical parameters on the estimated displacements, strains, stresses and fluid pressure inside a tumor and in the surrounding tissue. PMID- 30029268 TI - The Size of Simulated Lytic Metastases Affects the Strain Distribution on the Anterior Surface of the Vertebra. AB - Metastatic lesions of the vertebra are associated with risk of fracture, which can be disabling and life-threatening. In the literature, attempts are found to identify the parameters that reduce the strength of a metastatic vertebra leading to spine instability. However, a number of controversial issues remain. Our aim was to quantify how the strain distribution in the vertebral body is affected by the presence and by the size of a simulated metastatic defect. Five cadaveric thoracic spine segments were subjected to non-destructive presso-flexion while intact, and after simulation of metastases of increasing size. For the largest defect, the specimens were eventually tested to failure. The full-field strain distribution in the elastic range was measured with digital image correlation (DIC) on the anterior surface of the vertebral body. The mean strain in the vertebra remained similar to the intact when the defects were smaller than 30% of the vertebral volume. The mean strains became significantly larger than in the intact for larger defects. The map of strain and its statistical distribution indicated a rather uniform condition in the intact vertebra and with defects smaller than 30%. Conversely, the strain distribution became significantly different from the intact for defects larger than 30%. A strain peak appeared in the region of the simulated metastasis, where fracture initiated during the final destructive test. This is a first step in understanding how the features of metastasis influence the vertebral strain, and for the construction of a mechanistic model to predicted fracture. PMID- 30029270 TI - Feature integration is unaffected by saccade landing point, even when saccades land outside of the range of regular oculomotor variance. AB - The experience of our visual surroundings appears continuous, contradicting the erratic nature of visual processing due to saccades. A possible way the visual system can construct a continuous experience is by integrating presaccadic and postsaccadic visual input. However, saccades rarely land exactly at the intended location. Feature integration would therefore need to be robust against variations in saccade execution to facilitate visual continuity. In the current study, observers reported a feature (color) of the saccade target, which occasionally changed slightly during the saccade. In transsaccadic change-trials, observers reported a mixture of the pre- and postsaccadic color, indicating transsaccadic feature integration. Saccade landing distance was not a significant predictor of the reported color. Next, to investigate the influence of more extreme deviations of saccade landing point on color reports, we used a global effect paradigm in a second experiment. In global effect trials, a distractor appeared together with the saccade target, causing most saccades to land in between the saccade target and the distractor. Strikingly, even when saccades land further away (up to 4 degrees ) from the saccade target than one would expect under single target conditions, there was no effect of saccade landing point on the reported color. We reason that saccade landing point does not affect feature integration, due to dissociation between the intended saccade target and the actual saccade landing point. Transsaccadic feature integration seems to be a mechanism that is dependent on visual spatial attention, and, as a result, is robust against variance in saccade landing point. PMID- 30029269 TI - Eccentricity dependence of orientation anisotropy of surround suppression of contrast-detection threshold. AB - Both neurophysiological and psychophysical data provide evidence for orientation biases in nonfoveal vision-specifically, a tendency for a Cartesian horizontal and vertical bias close to fixation, changing to a radial bias with increasing retinal eccentricity. We explore whether the strength of surround suppression of contrast detection also depends on retinotopic location and relative surround configuration (horizontal, vertical, radial, tangential) in parafoveal vision. Three visual-field locations were tested (0 degrees , 225 degrees , and 270 degrees , angle increasing anticlockwise from 0 degrees horizontal axis) at viewing eccentricities of 6 degrees and 15 degrees . Contrast-detection threshold was estimated with and without a surrounding annulus. At 6 degrees eccentricity, horizontally oriented parallel center-surround (C-S) configurations resulted in greater surround suppression compared to vertically oriented parallel center-surround configurations (p = 0.001). At 15 degrees eccentricity, radially oriented parallel center-surround stimuli conferred greater suppression than tangentially oriented stimuli (p = 0.027). Parallel surrounds resulted in greater suppression than orthogonal surrounds at both eccentricities (p < 0.05). At 6 degrees the horizontal center was more susceptible to suppression than a vertical center (p < 0.001) for both parallel and orthogonal surrounds, while at 15 degrees a radial center was more susceptible to suppression (relative to a tangential center), but only if the surround was parallel (p = 0.005). Our data show that orientation anisotropy of surround suppression alters with eccentricity, reflecting a link between suppression strength and visual-field retinotopy. PMID- 30029271 TI - When the weaker conquer: A contrast-dependent illusion of visual numerosity. AB - Humans and many nonhuman species have the capacity to perceive the approximate numerosity of a large set of elements. In the visual domain, various factors have been found to affect perceived numerosity, including, as studied here, the effect of luminance contrast. We report a new numerosity illusion in which low-contrast elements appear to be more numerous than high-contrast ones when intermixed in the same display, an effect we have called "the weak conquer the strong." The illusion occurred for both positive and negative contrast disks of the same sign; for example, white disks appeared less numerous than light gray disks when presented on a dark gray field (all positive contrasts). The illusion grew in size as the contrast difference between the two sets of disks became smaller but did not hold for disks with opposite signs, such as white and dark gray disks on a light gray field. The illusion was also eliminated when the disks were segregated spatially, in which case the high-contrast (white) disks and low contrast (gray) disks appeared equally numerous. The illusion is due to the loss of some high-contrast elements; e.g., the perceived numerosity of the white disks was decreased whereas that of gray ones was preserved as shown by matching to isolated sets of white or gray disks. We speculate that failure in segregation coupled with error in contrast normalization may account for the numerosity illusion. PMID- 30029272 TI - Convergent evidence for global processing of shape. AB - There is an ongoing debate over whether there is convincing evidence in support of global contour integration in shape discrimination tasks, particularly when using radial frequency (RF) patterns as stimuli (Baldwin, Schmidtmann, Kingdom, & Hess, 2016). The objection lies in the previous use of high-threshold theory (HTT), rather than signal detection theory (SDT) to model the probability summation estimates of observer thresholds to determine whether integration of information is occurring around the contour. Here we used a discrimination at threshold method to establish evidence of global processing of two frequently used RF patterns (RF3 and RF5) that does not require mathematical modeling. To provide a bridge between current and past research we examined the two proposed methods, finding that HTT produced probability summation estimates that were more conservative than SDT (when an appropriate number of channels was used to generate estimates). We found no difference in observer thresholds when an RF pattern was presented as the only test stimulus in a block of trials or when two RF patterns were interleaved, and no evidence for a decrease in psychometric slopes with increasing numbers of stimulus elements. These findings are contrary to what is predicted by SDT for a stimulus whose detection conforms to probability summation. Therefore, our results find no evidence that supports probability summation, further demonstrating the importance of using random phase RF patterns while measuring integration around a contour and providing strong evidence for global shape processing around low frequency RF patterns. PMID- 30029273 TI - Rewarding objects appear larger but not brighter. AB - Whether reward can accentuate the perception of visual objects, that is, makes them appear larger than they really are, is a long-standing and controversial question. Here, we revisit this issue with a novel two-alternative forced-choice paradigm combining asymmetric reward schedule and task reversal. In a first experiment, participants (n = 27) choose the larger of two unequally rewarded objects in some sessions and the smaller one in other sessions. Response biases toward the most rewarding object differ significantly between the reversed tasks, revealing an influence of reward on perceived sizes. In a second experiment, participants (n = 27) indicate either the brighter or darker object. In contrast with the first experiment, response biases are similar between those reversed tasks, indicating that the perceived luminance is immune to reward manipulation. Together, these results reveal that if two objects are associated with different amounts of reward, participants will perceive the more rewarded object to be slightly larger, but not brighter, than the less rewarded one. PMID- 30029274 TI - Perspective: Can eye movements contribute to emmetropization? AB - During development, the eye tunes its size to its optics so that distant objects are in focus, a state known as emmetropia. Although multiple factors contribute to this process, a strong influence appears to be exerted by the visual input signals entering the eye. Much research has been dedicated to the possible roles of specific features of the retinal image, such as the magnitude of blur. However, in humans and other species, the input to the retina is not an image, but a spatiotemporal flow of luminance. Small eye movements occur incessantly during natural fixation, continually transforming the spatial scene into temporal modulations on the retina. An emerging body of evidence suggests that this space time reformatting is crucial to many aspects of visual processing, including sensitivity to fine spatial detail. The resulting temporal modulations depend not only on ocular dynamics, but also on the optics and shape of the eye, and the spatial statistics of the visual scene. Here we examine the characteristics of these signals and suggest that they may play a role in emmetropization. A direct consequence of this viewpoint is that abnormal oculomotor behavior may contribute to the development of myopia and hyperopia. PMID- 30029275 TI - Construction of analysis suitable vascular models using axis-aligned polycubes. AB - Image-based modeling is an active and growing area of biomedical research that utilizes medical imaging to create patient-specific simulations of physiological function. Under this paradigm, anatomical structures are segmented from a volumetric image, creating a geometric model that serves as a computational domain for physics-based modeling. A common application is the segmentation of cardiovascular structures to numerically model blood flow or tissue mechanics. The segmentation of medical image data typically results in a discrete boundary representation (surface mesh) of the segmented structure. However, it is often desirable to have an analytic representation of the model, which facilitates systematic manipulation. For example, the model then becomes easier to union with a medical device, or the geometry can be virtually altered to test or optimize a surgery. Furthermore, to employ increasingly popular isogeometric analysis methods the parameterization must be analysis suitable. Converting a discrete surface model to an analysis suitable model remains a challenge, especially for complex branched structures commonly encountered in cardiovascular modeling. To address this challenge, we present a framework to convert discrete surface models of vascular geometries derived from medical image data into analysis suitable non uniform rational B-splines representation. This is achieved by decomposing the vascular geometry into a polycube structure that can be used to form a globally valid parameterization. We provide several practical examples and demonstrate the accuracy of the methods by quantifying the fidelity of the parameterization with respect to the input geometry. PMID- 30029276 TI - Biomechanical Properties of Bruch's Membrane-Choroid Complex and Their Influence on Optic Nerve Head Biomechanics. AB - Purpose: The purpose of this study was to measure the rupture pressure and the biomechanical properties of porcine Bruch's membrane (BM)-choroid complex (BMCC) and the influences of BM on optic nerve head (ONH) tissues. Methods: The biomechanical properties of BMCC were extracted through uniaxial tensile tests of 10 BMCC specimens from 10 porcine eyes; the rupture pressures of BMCC were measured through burst tests of 20 porcine eyes; and the influence of BM on IOP induced ONH deformations were investigated using finite element (FE) analysis. Results: Uniaxial experimental results showed that the average elastic (tangent) moduli of BMCC samples at 0% and 5% strain were 1.60 +/- 0.81 and 2.44 +/- 1.02 MPa, respectively. Burst tests showed that, on average, BMCC could sustain an IOP of 82 mm Hg before rupture. FE simulation results predicted that, under elevated IOP, prelamina tissue strains increased with increasing BM stiffness. On the contrary, lamina cribrosa strains showed an opposite trend but the effects were small. Conclusions: BMCC stiffness is comparable or higher than those of other ocular tissues and can sustain a relatively high pressure before rupture. Additionally, BM may have a nonnegligible influence on IOP-induced ONH deformations. PMID- 30029277 TI - Integrated Stress Response and Decreased ECM in Cultured Stromal Cells From Keratoconus Corneas. AB - Purpose: Keratoconus (KC) is a multifactorial disease where progressive thinning and weakening of the cornea leads to loss of visual acuity. Although the underlying etiology is poorly understood, a major endpoint is a dysfunctional stromal connective tissue matrix. Using multiple individual KC corneas, we determined that matrix production by keratocytes is severely impeded due to an altered stress response program. Methods: KC and donor (DN) stromal keratocytes were cultured in low glucose serum-free medium containing insulin, selenium and transferrin. Fibronectin, collagens and proteins related to their chaperone, processing and export, matrix metalloproteinase, and stress response related proteins were investigated by immunoblotting, immunocytochemistry, hydroxyproline quantification, and gelatin zymography. Multiplexed mass spectrometry was used for global proteomic profiling of 5 individual DN and KC cell culture. Transcription of selected proteins was assayed by qPCR. Results: DN and KC cells showed comparable survival and growth. However, immunoblotting of selected ECM proteins and global proteomics showed decreased fibronectin, collagens, PCOLCE, ADAMTS2, BMP1, HSP47, other structural and cytoskeletal proteins in KC. Phosphorylated (p) eIF2alpha, a translation regulator and its target, ATF4 were increased in KC cultured cells and corneal sections. Conclusions: The profound decrease in structural proteins in cultured KC cells and increase in the p eIF2alpha, and ATF4, suggest a stress related blockade in structural proteins not immediately needed for cell survival. Therefore, this cell culture system reveals an intrinsic aggravated stress response with consequent decrease in ECM proteins as potential pathogenic underpinnings in KC. PMID- 30029278 TI - Automated Diagnosis and Grading of Diabetic Retinopathy Using Optical Coherence Tomography. AB - Purpose: We determine the feasibility and accuracy of a computer-assisted diagnostic (CAD) system to diagnose and grade nonproliferative diabetic retinopathy (NPDR) from optical coherence tomography (OCT) images. Methods: A cross-sectional, single-center study was done of type II diabetics who presented for routine screening and/or monitoring exams. Inclusion criteria were age 18 or older, diagnosis of diabetes mellitus type II, and clear media allowing for OCT imaging. Exclusion criteria were inability to image the macula, posterior staphylomas, proliferative diabetic retinopathy, and concurrent retinovascular disease. All patients underwent a full dilated eye exam and spectral-domain OCT of a 6 * 6 mm area of the macula in both eyes. These images then were analyzed by a novel CAD system that segments the retina into 12 layers; quantifies the reflectivity, curvature, and thickness of each layer; and ultimately uses this information to train a neural network that classifies images as either normal or having NPDR, and then further grades the level of retinopathy. A first dataset was tested by "leave-one-subject-out" (LOSO) methods and by 2- and 4-fold cross validation. The system then was tested on a second, independent dataset. Results: Using LOSO experiments on a dataset of images from 80 patients, the proposed CAD system distinguished normal from NPDR subjects with 93.8% accuracy (sensitivity = 92.5%, specificity = 95%) and achieved 97.4% correct classification between subclinical and mild/moderate DR. When tested on an independent dataset of 40 patients, the proposed system distinguished between normal and NPDR subjects with 92.5% accuracy and between subclinical and mild/moderate NPDR with 95% accuracy. Conclusions: A CAD system for automated diagnosis of NPDR based on macular OCT images from type II diabetics is feasible, reliable, and accurate. PMID- 30029279 TI - [Dementia in Adults with Down Syndrome: A Frequent Reason for Admission to Psychiatry]. AB - INTRODUCTION: This study aimed to assess the prevalence and clinical characteristics of dementia in a clinical sample of adults with Down syndrome. Consequences for clinical practice were deduced. METHODS: Patient characteristics and prevalence rates of dementia were evaluated in adults with Down syndrome who were admitted to psychiatry from 2005 to 2012 (N = 75). RESULTS: In every third patient with Down syndrome, dementia was diagnosed in a second assessment 6 to 12 months after initial hospital admission. Patients with dementia were older and more often female, while no association was found with the level of intellectual disability. Thyroid function and calcium values were often abnormal in those with and without dementia. DISCUSSION: In persons with Down syndrome, dementia is a prevalent cause for admission to psychiatry, especially in females and those of advanced age. Services should be adapted to the increased demands. PMID- 30029280 TI - [Assessment of Mental Disorders]. AB - Psychiatric expertise is necessary for a variety of legal expert opinion orders. Psychiatric assessment requires high professional competence and basic knowledge in the relevant areas of law. General conditions for comprehensive psychiatric assessment procedures are outlined. The problem of aggravation and simulation is discussed. PMID- 30029281 TI - [Discussing possible new regulations in german cannabis policy with special regard to the experiences in the Netherlands and Colorado]. AB - In Deutschland wird seit einiger Zeit zunehmend uber eine neue Cannabispolitik nachgedacht. Von vielen Seiten wird die Forderung nach einer Liberalisierung oder Freigabe des Cannabis laut. Der vorliegende Artikel fasst die wichtigsten Erfahrungen der Cannabis-Politik aus den Niederlanden und dem US-Bundesstaat Colorado zusammen und versucht, daraus Schlussfolgerungen fur eine mogliche Neuregulierung der Cannabispolitik in Deutschland abzuleiten. PMID- 30029282 TI - [Inclusion Body Myopathy, Paget's Disease, and Fronto-temporal Dementia: a VCP related Multi-systemic Proteinopathy]. AB - Mutations of the human VCP gene, which encodes the V: alosin C: ontaining P: rotein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively. Based on the clinical findings, a genetic analysis was performed which revealed a heterozygous c.277C>T (p.Arg93Cys) mutation of the VCP gene, thus confirming the diagnosis of IBMPFD (I: nclusion B: ody M: yopathie with P: aget Disease of the Bones and F: ronto-temporal D: ementia). PMID- 30029283 TI - ? PMID- 30029285 TI - Loss of Functional Internal Rotation Following Various Combinations of Bilateral Shoulder Arthroplasty. AB - BACKGROUND: Limited internal rotation (IR) remains a concern for activities of daily living (ADLs) following bilateral shoulder arthroplasty (BSA). The purpose of this study was to evaluate the loss of the ability to perform functional IR tasks following BSA using various combinations of anatomic (TSA) and reverse (RSA) shoulder arthroplasty. METHODS: A retrospective review of an institutional shoulder-surgery database was conducted for patients who underwent BSA with any combination of TSA or RSA with at least a 2-year follow-up. IR range of motion (ROM) and individual American Shoulder and Elbow Surgeons (ASES) score and Simple Shoulder Test (SST) questions specific to IR were used to assess a patient's ability to perform IR tasks with at least one of their shoulders. RESULTS: Seventy-three patients met the inclusion criteria (47 TSA/TSA, 17 RSA/RSA, and 9 TSA/RSA). Average age at surgery was 72.1 years. Average follow-up was 51.4 months. Loss of ability to wash one's back was observed in 30.4% TSA/TSA, 33.3% TSA/RSA, and 52.9% RSA/RSA. Loss of ability to tuck in a shirt was observed in 10.6% TSA/TSA, 11.1% TSA/RSA, and 29.4% RSA/RSA. Loss of ability to manage toileting was observed in no TSA/TSA or TSA/RSA, but in 11.8% RSA/RSA. For each of the tasks, there were no significant differences in the ability to perform the task among the groups (p>0.05). Post-operative IR ROM for TSA/TSA was superior to those for TSA/RSA and RSA/RSA (p<0.01). IR ROM efficacies for both RSA/RSA and TSA/RSA were inferior to that for TSA/TSA (p<0.05). CONCLUSION: Bilateral RSA patients can perform most IR tasks, and their ability to complete these tasks does not differ significantly from those in patients with other BSA. PMID- 30029284 TI - Unilateral Tuberothalamic Artery Ischemia Caused by Pituitary Apoplexy. AB - BACKGROUND AND IMPORTANCE: Pituitary apoplexy (PA) occasionally occurs in patients with pituitary adenoma and may cause severe functional deficits. Headache, pituitary insufficiency, visual impairment, and cranial nerve palsies are the most frequent symptoms in patients with PA. Secondary cerebral ischemia develops in only a limited number of PA patients. Two pathogenic mechanisms were previously proposed. One states that ischemia may be due to major vessel encasement or to vessel compression, as a result of extended tumor growth. The second states that cerebral vasospasm following PA may cause ischemia. We present another mechanism. After PA, a sudden increase in suprasellar tumor volume can lead to compression of perforating arteries causing hypoperfusion and subsequent focal ischemia of the thalamus, basal ganglia, and internal capsule. CLINICAL PRESENTATION: We present the case of a 75-year-old woman who, after having PA, developed cerebral ischemia in the territory of the left anterior thalamus and internal capsule that is primarily supplied by the tuberothalamic artery. Computed tomography and magnetic resonance imaging are used to describe how mechanical compression of the tuberothalamic artery caused this rare phenomenon. The recent literature, vascular anatomy, and pathophysiologic aspects of PA are discussed. CONCLUSION: PA can lead to compression of perforating arteries, for example, the tuberothalamic artery supplying the thalamus or lenticulostriate region, and thus cause hypoperfusion and subsequent focal cerebral ischemia. This may occur when perforating cerebral arteries are affected and compressed by the sudden increase in tumor volume due to hemorrhage or tumor swelling. PMID- 30029286 TI - Cost Savings in a Surgeon-Directed BPCI Program for Total Joint Arthroplasty. AB - BACKGROUND: There are few studies available on the savings generated and strategies employed for cost reduction in total joint arthroplasty. In this study, our organization-a group of private practices partnering with a consultant aimed to analyze the impact of a preoperative protocol on overall cost savings. MATERIALS AND METHODS: Using administrative data from the Medicare Bundled Payments for Care Improvement (BPCI) initiative, 771 consecutive total joint arthroplasty patients from 2009-2014 were compared with 408 consecutive BPCI patients from 2014-2017. The 30-day episode and Medicare part B total cost of care was analyzed. This included inpatient and post-discharge expenditure, laboratory and imaging costs, physician and ER visits, and readmission. RESULTS: Average total episode cost declined by $3,174 or 13% from $23,925 to $20,752 (p<0.001) in the BPCI period. Readmission rate was unchanged (p=0.20), and there was a 48% reduction in the percent of patients presenting to the emergency room (p=.03). There was a decline of $2,647 (78%) in skilled nursing cost per case, which represented the majority of savings. Post-discharge imaging, laboratory test claims, postoperative emergency room visits, primary care physician (PCP) visits, and cost per episode all decreased. The decrease in PCP utilization did not result in increased medical complications or readmissions. CONCLUSION: Our preoperative patient-education protocol has decreased non-home discharge, unnecessary postoperative physician visits, and diagnostic testing resulting in an episode cost savings of 13%. With Advanced BPCI on the horizon, orthopedic surgeon control as the awardee of the bundle, combined with an increasing focus on patient education, will continue to lower costs and improve patient care. PMID- 30029287 TI - Is an Intramedullary Nail a Valid Treatment for Limb-Length Discrepancy After Bone Tumor Resection? Case Descriptions. AB - One of the most frequent outcomes after resection of bone tumors in children is a limb-length discrepancy. An intramedullary nail is a valid method for lengthening the limb. We report our experience with four cases of limb-length discrepancy in the lower limbs several years after the primary treatment of bone tumor resection and subsequent reconstruction. Two femoral PRECICE(r) nails (NuVasive, Inc., San Diego, CA) were introduced retrograde and two were introduced in an anterograde manner. All four cases healed and showed a reduction of the limb-length discrepancy, early loading, and complete bone osteogenesis. In one case, a reduction of the joint ROM recovered after release of the iliotibial band and a quadriceps release according to Judet's arthrolysis. PMID- 30029288 TI - Acromioclavicular Joint Stabilisation Using the Internal Brace Principle. AB - INTRODUCTION: Injury of the acromioclavicular joint (AC joint) is one of the most common conditions affecting the shoulder girdle in athletes, particularly in contact sports. It is generally agreed that surgical management provides superior outcomes in high-grade injuries (Rockwell Grades IV-VI), with nonoperative management preferred in low-grade injuries (Grades I-II). Controversy still exists regarding the optimal treatment for Grade III injuries, with various sources reporting quicker return to activity and reduced complications with nonoperative management, but superior long-term function and satisfaction in cases managed surgically. Mean predicted return to sporting action in surgical cases varies in the literature from four months to 9.5 months. PMID- 30029289 TI - Performance on a Virtual Reality DHS Simulator Correlates with Performance in the Operating Theatre. AB - INTRODUCTION: Dynamic Hip Screw (DHS) fixation of neck of femur fractures is one of the most commonly performed orthopaedic trauma operations. Changes in working practices have impacted surgical training and have resulted in fewer opportunities to perform this procedure. Virtual reality (VR) simulation has been shown to be a valid means of gaining competency, efficiently and safely, without compromising patient safety. OBJECTIVE: The aim of this study is to determine whether performance on a VR DHS simulator correlates with performance in the operating theatre. MATERIALS AND METHODS: All episodes of DHS fixation of neck of femur fractures performed at Royal London Hospital, Barts Health NHS Trust, level 1 major trauma centre between January 2014 and December 2015 were identified using the hip fracture database. The primary surgeon was identified using the electronic operative notes. The intraoperative fluoroscopic images were accessed and the tip-apex distance (TAD) was measured, as well as the probability of cut out. The surgeon then performed DHS fixation on a VR DHS simulator and the TAD achieved in theatre was correlated with the simulated TAD. RESULTS: Twenty-five surgeons, including six novices (core surgical trainees), 12 intermediates (specialist registrars), and seven experts (fellows and consultants), completed the study. There was no overall statistically significant difference in TAD between those achieved in the operating theatre and on the simulator for each participant (p=0.688). CONCLUSION: There is no significant difference between performance on a VR DHS simulator and the operating theatre. This suggests that the simulator is excellent for training in this component of the DHS procedure, but further work is needed to assess whether training on the simulator can improve performance in the operating theatre. PMID- 30029290 TI - Near-Infrared Indocyanine Green-Enhanced Fluorescence and Minimally Invasive Colorectal Surgery: Review of the Literature. AB - BACKGROUND: Leakage of the anastomosis after colonic/rectal surgery is a serious complication. One of the most important causes of anastomotic leakage is impaired vascularization. A microvascular tissue deficit is very often not intraoperatively de visu detectable under white light. Near-infrared indocyanine green (ICG)-enhanced fluorescence is a cutting-edge technology that may be useful for detecting microvascular impairment and potentially preventing anastomotic leakage. AIM: The aim of this narrative review was to evaluate the feasibility and the usefulness of intraoperative assessment of vascular anastomotic perfusion in colorectal surgery using an indocyanine green (ICG) fluorescent tracer. MATERIAL AND METHODS: A PubMed/MedLine, Embase, and Scopus narrative literature review was performed, in which "colorectal surgery" and "indocyanine green" were used as key words. The inclusion criteria were 1) manuscripts written in English; 2) full text is available; 3) topic related to the use of ICG fluorescence for the assessment of tissue perfusion during laparoscopic or robotic colorectal surgery; and 4) sample: adult patients, benign or malignant disease. Exclusion criteria included 1) case reports; 2) topic not related to the use of ICG fluorescence for the evaluation of tissue perfusion during laparoscopic or robotic colorectal surgery; 3) manuscripts that focused solely on other applications of ICG technology; and 4) any study type not showing original data. Results and Critical Discussion: The intraoperative visual assessment of tissue viability under white light may lead to an underestimation of microvascular blood flow impairment. ICG can be safely used in cases of minimally invasive colonic surgery and also low anterior resections. This technology may be useful when deciding whether to intraoperatively change a previously planned resection/anastomotic level, which could decrease theoretically the occurrence of anastomotic leakage. CONCLUSIONS: Near-infrared ICG technology is a very useful approach. Multiple preliminary studies suggest that this technique may be used to predict anastomotic leakage. However, evaluation of the ICG signal is still too subjective. Some reliable scoring/grading parameters related to the ICG signal need to be defined. Additionally, more prospective, randomized, and adequately powered studies are required to completely reveal the true potential of this surgical technological innovation. PMID- 30029291 TI - Capsular Sparing Total Hip Replacement Technique Applied with a Dual-mobility Cup to Reduce Dislocations. AB - Regardless of the surgical approach used, dislocation remains a complication following total hip replacement. In recent years, newer technologies, such as the use of large femoral heads, have reduced the rate of postoperative dislocation. The combination of such technology, together with a soft tissue repair technique, may reduce the dislocation rate even further. A single surgeon performed 513 primary total hip replacements on 505 patients using a posterior approach utilizing a technique designed to spare the capsule. There were 257 males and 248 females. Age ranged from 39 to 92 years. Surgeries were performed from January 2012 to December 2015. Implants used were cementless dual-mobility cups and cementless femoral stems. In all cases, the posterior capsule was incised and retracted, but not excised. Following implant placement, the capsule was repaired using a fiber reinforced suture. The superior border of the capsular incision, just above the piriformis, was sutured to the superior capsule or gluteus minimus muscle. The intent of this repair was to completely incarcerate the femoral head. Patients were followed at two weeks, six weeks, three months, one year, three years, and five years. Follow up was one to five years post-implantation. The dislocation rate was zero. The combination of a large dual-mobility femoral head, combined with a soft tissue repair that spares the deep capsule, has the potential to significantly reduce dislocation rates when using the posterior approach to the hip. PMID- 30029293 TI - [Editorial. The State of Health in Italy and the role of nurses]. PMID- 30029292 TI - Pharmacokinetics and Pharmacodynamics of Anacetrapib in Black and White Healthy Subjects. AB - Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks ( 21.2%) relative to whites (-39.0%). In contrast, there were no apparent race related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of anacetrapib independent of pharmacokinetics. PMID- 30029294 TI - [The Adherence's indicators of cancer patients to oral chemotherapy. A sistematic literature review]. AB - INTRODUCTION: Adherence has a key role in treating patients as influences the effectiveness of therapeutic treatment for improving overall survival, life expectancy, quality of life and reducing healthcare costs. There are gaps in identifying indicators to be used to evaluate adherence and ways in which these indicators should be adopted. The aim of this paper is to identify adherence's indicators in literature. METHODS: Systematic review was carried out in, Cinhal EBSCO, Medline-PUBMED and Scopus including studies of measure patient's adherence in English and published from 2010 to 2016. Inclusion and exclusion criteria were used. The quality of the articles was assessed with the NewCastle Ottawa Scale for observational studies and the Cochrane Collaboration Risk of Bias for experimental studies. RESULTS: Of the 7,368 papers initially retrieved, 15 met the inclusion criteria (11 observational studies, 4 RCTs), for a total of 1,396 patients. The indicators found are: self-report tools, pill counts, drug recharge rate, continuous measures, metabolic dosage. A patient is considered adherent to the treatment if he or she assumes a percentage of drugs >= 80% of the prescribed medications. DISCUSSION: A better adherence rating is obtained by using multiple instruments at the same time. The objective indicators derive from the direct measurement methods of adherence, the subjective ones from the indirect. PMID- 30029295 TI - [Is the Patient Dignity Inventory suitable even for not end of life patients? Factorial structure and invariance in chronic patients]. AB - INTRODUCTION: The sense of dignity is a multifactorial feeling influenced also by the healthcare context. PDI-IT is a tool that measures this construct, but its psychometric characteristics have not been adequately investigated in patients which are not experiencing and End- Of-Life condition. The aim of this study is to examine the psychometric characteristics of PDI-IT in a group of non-terminal chronic patients and to verify the instrument's invariance with respect to the individual characteristics of patients. METHODS: A multicentric study was conducted on 421 patients undergoing ambulatory care or hospitalized in specialized medical, surgical and oncological areas. The study of the PDIIT validity in this population was achieved by structural equation (SEM) models; reliability was assessed by Cronbach's Alpha, whereas invariance was studied through multigroup analysis. RESULTS: Findings show an excellent reliability and confirm the monodimensionality of the theoretical structure. After the model optimization interventions, fit indices point out a good data fitting on the reference model. The instrument is invariant with respect to individual characteristics (sex and age) but does not appear to be appropriate for all chronic patients. DISCUSSION: Although with some cautions about the state of progression of the disease, PDIIT seems to be a valid and reliable tool, useful in measuring the sense of dignity even in populations of chronic patients. Future research should address the development of a short form of the tool. PMID- 30029296 TI - [The linguistic and cultural validation of a tool to evaluate the cultural competence in nurses]. AB - INTRODUCTION: Cultural competence is described as a complex process of elements useful to work in an intercultural context. It could be evaluated with several different tools. In literature different English scales are available, and all of them start from the operator's perception. The Physician's Cultural Competence for Patient Satisfaction (PCCPS), by Ahmed and Bates (2012), is the only scale that consider the perception of the person. OBJECTIVE: validation and linguistic cultural adaptation of the PCCPS at the nursing Italian context. METHOD: the study used Beaton e Valmi's models, that expect five phases to elaborate a pre final version of the tool, this has to be dispensed to a sample of experts and to target population. RESULTS: at the third administration to the expert group, the tool got the face's validity (clearness 70%), the content's validity (I-CVI), and the index of content's validity (S-CVI). The reliability of internal's consistency has been confirmed by an alpha di Cronbach's value of 0.8-0.9. The fidelity of the reliability confirms the tool's stability in the time (correlation inter item 0.8; Sperman- Brown's coefficient 0.9; Guttman's index 0.9). DISCUSSION: the validation path resulted really complex: major problems were related to the adaptation to the nursing context and to the sample population, who has a limited knowledge of the Italian language. These elements have been requested the necessity to reformulate the tool several times, but even working to get clearness, it has been looked to maintain the semantic and conceptual equivalence to the original version. PMID- 30029297 TI - [Reducing drug administration errors using "Do not disturb" tabards and signs]. AB - INTRODUCTION: According to the report published by the Italian Ministry Health on sentinel events collected between 2005-2010, 873 events were reported, of which 4% (about 35) led to mortality, coma or serious functional disorders due to drug administration errors made by nurses. The link between interruptions and patient safety has been emphasized in the USA by the Institute of Medicine as a pivotal variable to improve the quality of nursing care. Airline companies have studied this problem since the 1960s, with a significant reduction of accidents. OBJECTIVE: This study emphasized that nurses who are never interrupted or distracted, by using 'Do not disturb' tabards and signs, reduce errors during the administration of drugs. METHODS: Quasi-experimental study on a convenience sample to explore the cause-effect relationship that reduces errors during drug administration by wearing a 'Do not disturb' tabard and signs. This study was conducted in 8 similar medicine and surgery units within 4 teaching hospitals in Rome. Of these 8 units, 4 were identified for the experimental group and 4 for the control group. Data were collected using the Medication Administration Distraction Observation Sheet tool. Data were analysed using SPSS 10.00 software. RESULTS: In the four hospitals that participated to the research were filled out 688 observational sheets, 356 (51,7%) for the control group and 332 (48,3%) for the experimental group. 132 were completed in the hospital 1, 143 in the hospital 2, 144 in the hospital 3 e 269 in the hospital 4. Analyzing the four hospitals, it emerged that in the experimental cohort some of the distractions calculated by the mean were lower compared with the control group (distractions by nurses and conversation). Yet, some distractions resulted greater in the experimental group respect to the control group (phone calls, other patients, external noise). At last, it did not emerge a significant difference in the distractions connected to variables such as: physicians, other personnel, visitors, and emergency situations. CONCLUSIONS: Distractions can lead to many errors throughout the drug administration phase. Wearing a high visibility vest while administering drugs proved to be very useful. However, this needs to be supported by effective teamwork, 'do not disturb' signs in all the workplace rooms, and by an education program that should not be limited only to those who administer drugs. PMID- 30029298 TI - [Synopses of systematic reviews on effectiveness of heparin to prevent occlusion in central venous access devices]. AB - INTRODUCTION: Prevention of central venous access devices (CVAD) occlusion is crucial to the continuity and quality of care. There is wide consensus on the need to carry out a periodic flushing of the lumen of device in order to ensure its patency. The most commonly used solutions are the heparin solution (HS) and the physiological solution (NaCl 0.9% - PS). There are still controversial opinions on HS's effectiveness over PS. OBJECTIVE: To evaluate the effectiveness of HS compared to PS to prevent occlusion in CVAD. METHODS: A search strategy on four electronic databases (The Cochrane Library, Medline, Embase, CINAHL) was implemented on April 4, 2017. Records returned were independently analyzed; those complying with inclusion criteria were found in full text. They've been included systematic reviews of RCT or quasi-experimental studies that have compared the use of HS with PS. The quality assessment of reviews was done with AMSTAR checklist. RESULTS: Seven moderate-high quality systematic reviews met inclusion criteria. HS is was not superior to PS in preventing CVAD occlusions. DISCUSSION: Reviews included were of high quality methodological. The statistical heterogeneity between RCT was low while the clinical and methodological heterogeneity was high. CONCLUSIONS: HS was no longer effective than PS to prevent CVAD occlusions. Waiting for better quality studies to evaluate the overall DAVC management process, it seems reasonable to recommend using PS. PMID- 30029299 TI - Pain Education in Schools of Nursing: a Survey of the Italian Academic Situation. AB - INTRODUCTION: Proper assessment of pain is imperative for the development of an effective pain management plan and is a core responsibility of nurses and healthcare professionals. This article describes the contents of Italian on-line bachelor's in nursing degree programs, with particular focus on pain management. METHOD: A descriptive study was made on curricula published and available on-line in Italian Nursing Schools, and the concordance with the standards set by the Consensus Curriculum on Pain for Nursing ofthe International Association for the Study of Pain (IASP, 2015) was analyzed. RESULTS: Of all the bachelor programs published on-line, 42.6% offered programs and courses specifically centred on pain education, while in general pain teaching seemed to be delivered as part of other topics. Results showed that the contents of the programs were partially in line with those suggested by the IASP. True is that on-line results may underestimate the actualdiffusion of pain education programs and topics in Italian Universities. CONCLUSION: The Italian academic system does not seem to comply with any specific international standard. Only by interviewing the university administrative staff we may investigate the amount and type of pain education received by Italian healthcare undergraduates and the existing educational curricula and plans, as on-line information may be only partially complete. PMID- 30029300 TI - Erratum. PMID- 30029301 TI - Re: Lazoura et al. Bone Mineral Density Alterations in Upper and Lower Extremities 12 Months After Stroke Measured by Peripheral Quantitative Computed Tomography and DXA (J Clin Densitom 2008;11;511-517). PMID- 30029302 TI - Reply. PMID- 30029303 TI - Reply to the Letter to the Editor by Faulhaber, Schulz, and Furlanetto. PMID- 30029304 TI - Erratum. PMID- 30029305 TI - The need for international benchmark for health care-associated infections. PMID- 30029306 TI - Response to Jentsch et al. PMID- 30029307 TI - Response to Jentsch et al. PMID- 30029308 TI - An assessment of the inhalation bioaccessibility of platinum group elements in road dust using a simulated lung fluid. AB - Metal enrichment of road dust is well characterized but available data on the bioaccessibility of metals in particle size fractions relevant to human respiratory health remain limited. The study goal was to investigate the bioaccessibility of platinum group elements (PGE), which are used as catalysts in automotive exhaust converters, in the inhalable fraction of road dust. Street sweepings were provided by the City of Toronto, Canada, collected as part of its Clean Roads to Clean Air program.The particle size relevance of road dust for inhalation exposures was confirmed using a laser diffraction particle size analyzer (mean Dx(50): 9.42 MUm). Total PGE were determined in both bulk and inhalable fractions using nickel sulfide (NiS) fire-assay and instrumental neutron-activation analysis (INAA). PGE lung solubility was examined for the inhalable fraction using Gamble's extraction. Sample digests were co-precipitated with Te-Sn, to pre-concentrate and isolate PGE, prior to their measurement using inductively coupled plasma mass spectrometry (ICP-MS).Total PGE concentrations were enriched in the inhalable fraction of road sweepings. Geomean concentrations in the inhalable fraction were: palladium (Pd) (152 MUg/kg), platinum (Pt) (55 MUg/kg), rhodium (Rh) (21 MUg/kg) and iridium (Ir) (0.23 MUg/kg). Osmium (Os) concentrations were below the limit of detection (LOD). Bioaccessible PGEs (n = 16) using Gamble's solution were below LOD for Ir and ruthenium (Ru). For the remainder, the geomean % bioaccessibility was highest for platinum (16%), followed by rhodium (14%) and palladium (3.4%). This study provides evidence that PGE in road dust are bioaccessible in the human lung. PMID- 30029309 TI - Perfluorododecanoic acid exposure induced developmental neurotoxicity in zebrafish embryos. AB - Perfluorododecanoic acid (PFDoA), an artificial perfluorochemical, has been widely distributed in different ambient media and has been reported to have the potential to cause developmental neurotoxicity. However, the specific mechanism is largely unknown. In the current study, zebrafish embryos were treated with 0, 0.24, 1.2, and 6 mg/L PFDoA for 120 h. Exposure to PFDoA causes serious decreases in hatching delay, body length, as well as decreased locomotor speed in zebrafish larvae. Additionally, the acetylcholine (ACh) content as well as acetylcholinesterase (AChE) activity were determined to be significantly downregulated in PFDoA treatment groups. The level of dopamine was upregulated significantly after treating with 1.2 and 6 mg/L of PFDoA. Gene expressions related to the nervous system development were also analyzed, with the exception of the gene mesencephalic astrocyte-derived neurotrophic factor (manf), which is upregulated in the 6 mg/L treatment group. All other genes were significantly downregulated in larvae in the PFDoA group in different degrees. In general, the results demonstrated that PFDoA exposure could result in the disruption of the cholinergic system, dopaminergic signaling, and the central nervous system. PMID- 30029310 TI - Fine-grained vehicle emission management using intelligent transportation system data. AB - The increasing adoption of intelligent transportation system (ITS) data in smart city initiatives worldwide has offered unprecedented opportunities for improving transportation air quality management. In this paper, we demonstrate the effective use of ITS and other traffic data to develop a link-level and hourly based dynamic vehicle emission inventory. Our work takes advantage of the extensive ITS infrastructure deployed in Nanjing, China (6600 km2) that offers high-resolution, multi-source traffic data of the road network. Improved than conventional emission inventories, the ITS data empower the strength of revealing significantly temporal and spatial heterogeneity of traffic dynamics that pronouncedly impacts traffic emission patterns. Four urban districts account for only 4% of the area but approximately 30%-40% of vehicular emissions (e.g., CO2 and air pollutants). Owing to the detailed resolution of road network traffic, two types of emission hotspots are captured by the dynamic emission inventory: those in the urban area dominated by urban passenger traffic, and those along outlying highway corridors reflecting inter-city freight transportation (especially in terms of NOX). Fine-grained quantification of emissions reductions from traffic restriction scenarios is explored. ITS data-driven emission management systems coupled with atmospheric models offer the potential for dynamic air quality management in the future. PMID- 30029311 TI - Uptake and transcriptional effects of polystyrene microplastics in larval stages of the Mediterranean mussel Mytilus galloprovincialis. AB - The widespread occurrence of microplastics (MP) in the marine environment is cause of increasing concerns about the safety of the exposed ecosystems. Although the effects associated to the MP uptake have been studied in most marine taxa, the knowledge about their sub-lethal impacts on early life stages of marine species is still limited. Here, we investigated the uptake/retention of 3-MUm polystyrene MP by early stages of the Mediterranean mussel Mytilus galloprovincialis, and the related effects on gut clearance, feeding efficiency, morphological and transcriptional parameters involved in embryo-larval development. Uptake measurements were performed on larvae at 48 h, 3, 6 and 9 days post fertilization (pf) after exposure to a range of 50-10,000 particles mL 1. At all tested pf periods, treatments resulted in a significant and linear increase of MP uptake with increasing concentrations, though levels measured at 48 h pf were significantly lower compared to 3-9 d pf. Ingested MP were retained up to 192 h in larvae's gut, suggesting a physical impact on digestive functions. No change was noted between the consumption of microalgae Nannochloropsis oculata by larvae when administered alone or in the presence of an identical concentration (2000 items mL-1) of MP. The exposure to 50-10,000 MP mL-1 did not alter the morphological development of mussel embryos; however, transcriptional alterations were observed at 50 and 500 MP mL-1, including the up-regulation of genes involved in shell biogenesis (extrapallial protein; carbonic anhydrase; chitin synthase) and immunomodulation (myticin C; mytilin B), and the inhibition of those coding for lysosomal enzymes (hexosaminidase; beta-glucorinidase; catepsin-L). In conclusion, though not highlighting morphological or feeding abnormalities, data from this study revealed the onset of physical and transcriptional impairments induced by MP in mussel larvae, indicating sub-lethal impacts which could increase their vulnerability toward further environmental stressors. PMID- 30029312 TI - Environmental superbugs: The case study of Pedobacter spp. AB - The environment is one of the main reservoirs of antibiotic resistance genes (ARGs) but multidrug resistant (MDR) environmental isolates are barely characterised. As suggested by the name, Pedobacter species have been predominantly isolated from soils, but are also recovered from water (including drinking water), chilled food, fish, compost, sludge, glaciers and other extreme environments. The susceptibility phenotype of Pedobacter lusitanus NL19 (isolated from a deactivated uranium mine), its closely related species and the genus type strain were investigated. All strains are MDR bacteria, resistant to beta lactams, colistin, aminoglycosides and ciprofloxacin. Therefore, Pedobacter spp. are likely intrinsically resistant to beta-lactams (including ertapenem) and to other three classes of antibiotics. 6%-8% of their total protein-encoding genes encode a diverse collection of putative ARGs, including beta-lactamases. These enzymes are highly abundant in all the other Pedobacter strains with sequenced genomes, especially class C, class B3 and class A. LUS-1 and PLN-1 were further characterised in E. coli. LUS-1 is a class A beta-lactamase and it conferred an increase in the MIC of cefotaxime, albeit very low. PLN-1 is a class B3 beta lactamase with carbapenemase activity, conferring resistance to ertapenem and a 66x and 16x increase in the MIC of imipenem and meropenem, respectively. PLN-1 also hydrolyses ampicillin, 1st and 3rd generation cephalosporins, and at a lower extent cephamycins and 4th generation cephalosporins. Therefore, Pedobacter spp. encode a large and diverse arsenal of resistance mechanisms that make them environmental superbugs. PMID- 30029313 TI - Comparison of sensitivity and annoyance to road traffic and community noise between a South African and a Swiss population sample. AB - In developing countries, noise annoyance and noise sensitivity are not commonly investigated. The present study aimed to assess the annoyance and sensitivity to noise in 364 adults living in informal settings in the Western Cape Province, South Africa and to compare with a similar study conducted in Switzerland. Compared to Switzerland, higher percentages of highly noise sensitive individuals (women: 35.1% vs 26.9%; men: 25% vs 20.5%) and people highly annoyed to road traffic noise (women: 20.5% vs 12.4%; men: 17.9% vs 11.1%) were observed in South Africa. While in South Africa women were more annoyed to neighborhood noise than in Switzerland (21.1% vs 9.4%), this was not the case among men (7.1% vs 7.8%). Multivariable logistic regression models showed that in both countries men tended to be less sensitive and less annoyed by noise. Corresponding associations with age and education were somewhat different between the countries, which may be explained by socioeconomic and environmental differences. This study indicates that noise exposure considerably affects people living in informal settlements, and noise should be considered when improving the housing conditions. PMID- 30029314 TI - Halogenated organic pollutants in aquatic, amphibious, and terrestrial organisms from an e-waste site: Habitat-dependent accumulation and maternal transfer in watersnake. AB - Dichlorodiphenyltrichloroethanes (DDTs), Polychlorinated biphenyls (PCBs), and halogenated flame retardants (HFRs) were measured in aquatic, amphibious, and terrestrial wildlife collected from an e-waste contaminated pond and its surrounding region. The species-specific bioaccumulation and maternal transfer of chemicals in the watersnake were investigated. Total concentrations of target chemicals ranged from 1.3 * 103 to 4.8 * 105 ng g-1 lipid weight. PCBs were the predominant (72-95%) contaminants, followed by polybrominated biphenyl ethers (PBDEs, 4-27%). The concentrations of PCBs and HFRs except decabromodiphenyl ethane (DBDPE) were higher in aquatic organisms and terrestrial birds than in amphibians and lizards. Relatively high DDT levels were observed in the terrestrial birds and toads, but high DBDPE was found in the aquatic species except for waterbird eggs. Species-specific congeners profiles for PCB and PBDE and isomeric composition for dechlorane plus were observed. These results indicated a habitat-dependent accumulation among different species. Maternal transfer examined by the ratio of egg to carcass for watersnakes indicated multi linear correlations between maternal transfer potential and octanol-water partition coefficient (log KOW) of chemicals. The same maternal transfer efficiencies were found for chemicals with log KOW between 6 and 8, then the maternal transfer potential rapidly decreased with increasing of log KOW. PMID- 30029316 TI - Microplastic hotspots in the Snake and Lower Columbia rivers: A journey from the Greater Yellowstone Ecosystem to the Pacific Ocean. AB - It is widely understood that microplastics (MPs) are ubiquitous in the marine environment yet less is known about MP abundance in freshwater rivers, particularly those of the western United States. This study documents MP pollution along the Snake River (~1735 km) and from its confluence with the Columbia River to the Pacific Ocean. Grab and plankton net samples (mesh size 100 MUm) were collected from the top 25 cm of surface water every 80.5 river km. MPs were identified if they met visual criteria and were verified with the hot needle test. A small representative subset of MPs from the net samples (16.7%) were selected based on appearance for micro-Raman spectroscopy in effort to provide examples of polymer types found in this study. Seventy-five percent of grab samples and 92.8% of net samples contained MPs, with concentrations ranging from 0 to 5.405 MP L-1 and 0 to 0.014 MP L-1 (0 to 13.7 MP m-3), respectively. The majority of fragments, films and beads were between 100 MUm and 333 MUm. This study identifies potential hotspots of MP pollution along the Snake and Lower Columbia rivers and prioritizes areas where more intensive sampling is needed. Sites with low flow or those further down river had higher numbers and the top two hotspots were located in areas with low population density but high agricultural use. Monitoring MP abundance in freshwater systems is important for establishing baseline levels of MP pollution and can direct laboratory toxicology studies in using more environmentally relevant concentrations for a better indication of how MP pollution affects ecosystems. PMID- 30029315 TI - Insights about sources, distribution, and degradation of sewage and biogenic molecular markers in surficial sediments and suspended particulate matter from a human-impacted subtropical estuary. AB - The molecular markers sterols and linear alkylbenzenes (LABs) were analyzed in the surficial sediments and suspended particulate matter (SPM) of a subtropical estuary in South Atlantic (Paranagua Estuarine System). The purpose of this study was identify the spatial distribution of sewage and the input of biogenic organic matter (OM) and to provide comparative insights about their behavior, compositions, and sources. The concentration of coprostanol ranged from < DL (detection limit) to 2.67 MUg g-1 in SPM and from < DL to 0.94 MUg g-1 in sediments. Total LABs ranged from 43.8 to 480.0 ng g-1 in SPM and from < DL to 21.0 ng g-1 in sediments. LABs homologs composition varied between the two matrices. The local hydrodynamic pattern may promote water column homogenization, dispersion, and dilution of sewage particles, and preferential sedimentation in fluvial and mixture zones. Results suggest that SPM is a good matrix for larger spatial and short time scale evaluation while sediments may help to define hot spot areas of input and final deposition of sewage particles. Marine sterols predominated in SPM while no dominance patterns of marine/terrestrial sterols occurred in surficial sediments. The higher degradation rates of sterols and LABs in the water column must be the main factor for the sharp drop in concentration towards the sediment and the variation of the preferential composition of these markers between compartments. PMID- 30029317 TI - Natural pyrethrins induce autophagy of HepG2 cells through the activation of AMPK/mTOR pathway. AB - Natural pyrethrins, one kind of insects' neural toxin, have been used worldwide for the control of pests of crops, livestock, and human beings. However, their specific mechanisms of action are incompletely understood and hence further investigation is required. Here we used a series of experiments including colony formation, fluorescent staining, western blotting, enzyme activity detection, immunofluorescence analysis, and real-time quantitative PCR (QPCR) to investigate whether natural pyrethrins (0-40 MUg/mL) are able to modulate autophagy process through AMPK/mTOR signaling pathway, in order to reveal their cytotoxic mechanisms. The results showed that natural pyrethrins markedly inhibited the proliferation of HepG2 cells in both concentration- and time-dependent manners. Particularly, natural pyrethrins could induce the resulting autophagosome, and the intensification of LC3-II formation and translocation, the accumulation of Beclin-1 and the reduction of p62 and thus autophagy. We clarified that natural pyrethrins induced the abnormal level of oxidation reduction metabolism, leading to mitochondrial permeability transition pore (mPTP) opening, ATP depletion and mitochondria eliminating by autophagy. Moreover, the phosphorylation levels of AMPK were significantly enhanced, and the mTOR and p70s6k phosphorylation were drastically decreased. These results showed that natural pyrethrins induced autophagy of HepG2 cells and activation of the AMPK/mTOR signaling pathway might have potential risk to human health. PMID- 30029318 TI - Spatiotemporal profile of tetracycline and sulfonamide and their resistance on a catchment scale. AB - Tetracyclines and sulfonamides are the two classes of antibiotics commonly used in the medical, industrial and agricultural activities. Their extensive usage has caused the proliferation and propagation of resistant bacteria (ARB) and resistance genes (ARGs) in the environment. In this study, the occurrence and distribution of tetracyclines (TC, OTC and CTC) and sulfonamides (SMX, SCX and TMP), their associated ARB and ARGs were quantified in water and sediments collected from the mainstream of Liaohe River, northeast China. The average concentration of tetracyclines was higher in May, while the concentration of sulfonamides was slightly higher in October. The highest concentrations of the total tetracyclines and sulfonamides in sediments were 2.7*103 ng/g and 2.1*102 ng/g respectively detected in May. All detected ARGs were found generally with high abundance. The tetA, tetB and tetE genes were dominant (4.4*10-2 to 9.8*10-1 copies of tet genes/copies of 16S rRNA genes) in total communities, and the average abundance of sul genes was expressed above 10-1 in the water samples in May and October. Redundance analysis (RDA) and principle component analysis (PCA) indicated that the antibiotic residue was the most important contributor to the level of tetracycline and sulfonamide resistance genes, and some hydrogeological conditions (e.g. flow rate, intersection settlement) influenced the distribution of resistance genes. Results from this study could help understand the proliferation and propagation of antibiotic resistance on a river catchment scale and mitigate the potential risks to public health. PMID- 30029319 TI - Effects of ambient temperature on myocardial infarction: A systematic review and meta-analysis. AB - Previous studies have suggested that ambient temperature is associated with the mortality and morbidity of myocardial infarction (MI) although consistency among these investigations is lacking. We performed a meta-analysis to investigate the relationship between ambient temperature and MI. The PubMed, Web of Science, and China National Knowledge Infrastructure databases were searched back to August 31, 2017. The pooled estimates for different temperature exposures were calculated using a random-effects model. The Cochran's Q test and coefficient of inconsistency (I2) were used to evaluate heterogeneity, and the Egger's test was used to assess publication bias. The exposure-response relationship of temperature-MI mortality or hospitalization was modeled using random-effects meta regression. A total of 30 papers were included in the review, and 23 studies were included in the meta-analysis. The pooled estimates for the relationship between temperature and the relative risk of MI hospitalization was 1.016 (95% confidence interval [CI]: 1.004-1.028) for a 1 degrees C increase and 1.014 (95% CI: 1.004 1.024) for a 1 degrees C decrease. The pooled estimate of MI mortality was 1.639 (95% CI: 1.087-2.470) for a heat wave. The heterogeneity was significant for heat exposure, cold exposure, and heat wave exposure. The Egger's test revealed potential publication bias for cold exposure and heat exposure, whereas there was no publication bias for heat wave exposure. An increase in latitude was associated with a decreased risk of MI hospitalization due to cold exposure. The association of heat exposure and heat wave were immediate, and the association of cold exposure were delayed. Consequently, cold exposure, heat exposure, and exposure to heat waves were associated with an increased risk of MI. Further research studies are required to understand the relationship between temperature and MI in different climate areas and extreme weather conditions. PMID- 30029320 TI - Research on air pollutant concentration prediction method based on self-adaptive neuro-fuzzy weighted extreme learning machine. AB - In order to improve the prediction accuracy and real-time of the air pollutant concentration prediction, this paper proposes self-adaptive neuro-fuzzy weighted extreme learning machine (ANFIS-WELM) based on the weighted extreme learning machine (WELM) and the adaptive neuro-fuzzy inference system (ANFIS) combined air pollutant concentration prediction method. Firstly, Gaussian membership function parameters are selected to fuzzify the input values and calculate the membership degree of each input variable. Secondly, corresponding fuzzy rules are activated, and the firing strength is normalized to calculate the output matrix of hidden nodes. Then, the optimal parameters (C, M), weights are assigned to weighted ELM by using locally weighted linear regression, and the regularized WELM target formula with equality constraint is optimized by the Karush-Kuhn-Tucker (KKT) conditions, the output weight matrix is calculated, and finally the prediction output matrix is calculated. Based on the air pollutant concentration data collected in Datong, Taiwan, the data on the pollutants containing carbon monoxide (CO), nitric oxide (NO), PM2.5 (particulate matter) and PM10, are selected by different historical time series lengths, using genetic algorithm backpropagation neural network (GA-BPNN), support vector regression (SVR), extreme learning machine (ELM), WELM, ANFIS, regularized extreme learning adaptive neuro-fuzzy inference system (R-ELANFIS) and ANFIS-WELM are built for predict the concentration of each pollutant collected by single monitoring point in single-step time series. The experimental results show that the ANFIS-WELM presented in this paper has better prediction accuracy and real-time performance, realizes the prediction of multi-step time series on the basis of the ANFIS-WELM, and realizes the engineering application of the ANFIS-WELM algorithm package on the self-developed mobile source emissions online monitoring data center software system. PMID- 30029321 TI - Microplastic and soil protists: A call for research. AB - Microplastic is an emerging contaminant of concern in soils globally, probably gradually increasing in soil due to slow degradation. Few studies on microplastic effects on soil biota are available, and no study in a microplastic contamination context has specifically addressed soil protists. Soil protists, a phylogenetically and functionally diverse group of eukaryotic, unicellular soil organisms, are major consumers of bacteria in soils and are potentially important vehicles for the delivery of microplastics into the soil food chain. Here we build a case for focusing research on soil protists by drawing on data from previous, older studies of phagocytosis in protist taxa, which have long made use of polystyrene latex beads (microspheres). Various soil-borne taxa, including ciliates, flagellates and amoebae take up microplastic beads in the size range of a few micrometers. This included filter feeders as well as amoebae which engulf their prey. Discrimination in microplastic particle uptake depended on species, physiological state as well as particle size. Based on the results of the studies we review here, there is now a need to study microplastic effects in a pollution ecology context: this means considering a broad range of particle types under realistic conditions in the soil, and exploring longer-term effects on soil protist communities and functions. PMID- 30029322 TI - Proliferation of low-cost sensors. What prospects for air pollution epidemiologic research in Sub-Saharan Africa? AB - Addressing the worsening urban air quality situation in Sub-Saharan Africa (SSA) is proving increasingly difficult owing to paucity of data on air pollution levels and also, lack of local evidence on the magnitude of the associated health effects. There is therefore the urgent need to expand air quality monitoring (AQM) networks in SSA to enable the conduct of high quality epidemiologic studies to help inform policies aimed at addressing air pollution and the associated health effects. In this commentary, I explore the prospects that the proliferation of low-cost sensors in recent times holds for air pollution epidemiologic research in SSA. This commentary is timely because most SSA governments do not see investments in air pollution control that requires assembling a network of sophisticated and prohibitively expensive instrumentation for AQM as necessary for improving and protecting public health. I conclude that, in a region that is bereft of air pollution data, the growing influx of low-cost sensors represents an excellent opportunity for bridging the data gap to inform air pollution control policies and regulations for public health protection. However, it is essential that only the most promising sensor technologies that performs creditably well in the harsh environmental conditions of the region are promoted. PMID- 30029323 TI - Improving the SoilPlusVeg model to evaluate rhizoremediation and PCB fate in contaminated soils. AB - Tools to predict environmental fate processes during remediation of persistent organic pollutants (POPs) in soil are desperately needed since they can elucidate the overall behavior of the chemical and help to improve the remediation process. A dynamic multimedia fate model (SoilPlusVeg) was further developed and improved to account for rhizoremediation processes. The resulting model was used to predict Polychlorinated Biphenyl (PCB) fate in a highly contaminated agricultural field (1089 ng/g d.w.) treated with tall fescue (Festuca arundinacea), a promising plant species for the remediation of contaminated soils. The model simulations allowed to calculate the rhizoremediation time (about 90 years), given the available rhizoremediation half-lives and the levels and fingerprints of the PCB congeners, to reach the legal threshold, to show the relevance of the loss processes from soil (in order of importance: degradation, infiltration, volatilization, etc.) and their dependence on meteorological and environmental dynamics (temperature, rainfall, DOC concentrations). The simulations showed that the effective persistence of PCBs in soil is deeply influenced by the seasonal variability. The model also allowed to evaluate the role of DOC as a possible enhancer of PCB degradation as a microorganism "spoon feeder" of PCBs in the soil solution. Additionally, we preliminary predicted how the contribution of PCB metabolites could modify the PCB fingerprint and their final total concentrations. This shows that the SoilPlusVeg model could be used in selecting the best choices for a sustainable rhizoremediation of a POP contaminated site. PMID- 30029324 TI - The effect of pyriproxyfen on the motoric activity of rat intestine - In vitro study. AB - The application of pyriproxyfen (PPF) to drinking water and constant exposure of the whole population to this insecticide is an unprecedented action on a world scale and presents a new and serious challenge for toxicology. The aim of the study was to evaluate the potential effect of PPF on the intestine muscle activity. The experiments were performed on isolated duodenum and jejunum strips of rat, in isometric conditions. Doses of PPF in the range of 0.032-100 MUM were used in the experiments. The obtained results indicate that PPF affected significantly the spontaneous activity of duodenum and jejunum strips, PPF caused the muscle relaxation when used in the concentration of 0.8 MUM and higher. The reaction to acetylcholine (ACh) when PPF preceded or followed ACh application was also reduced. It is demonstrated that the reduction of the contraction caused by ACh was stronger when duodenum strips were preincubated in the presence of PPF solution than in case of ACh-precontracted strips. The first significant reaction of duodenal strips appeared in the presence of PPF in a dose of 0.16 MUM and 0.8 MUM when the insecticide application preceded and followed ACh treatment, respectively. Besides, the duodenum turned out to be much more susceptible to the tested insecticide than jejunum. Taking into account PPF kinetic data obtained in animals, the observed disturbances were caused by the insecticide used in relatively high concentrations. However, the full risk estimation requires the kinetic data obtained in human, especially from monitoring studies on general population after long-term exposure to PPF. PMID- 30029325 TI - Cephalosporin antibiotics in the aquatic environment: A critical review of occurrence, fate, ecotoxicity and removal technologies. AB - Due to their widespread occurrence in the aquatic environment, human and veterinary cephalosporin antibiotics have been studied as water pollutants. In order to characterize environmental risks of this compound class, this review evaluates relevant data about physicochemical properties, occurrence, ecotoxicity and degradation of cephalosporins. Although application of cephalosporins is rather low compared to other antibiotics and their environmental life-time is believed to be short (i.e. days), the available data is insufficient to draw conclusions on their environmental relevance. Few studies concerning the fate of cephalosporins in soil are available, while hydrolysis and photo-degradation are suggested as the main attenuation processes in the aquatic environment. Cephalosporins have been detected in different aqueous matrices in concentrations ranging from 0.30 ng L-1 to 0.03 mg L-1, with sewage and wastewater being the main matrices with positive findings. For wastewater treatment purposes, several technologies have been tested for the abatement of cephalosporins, including photolysis and adsorption. In most cases, the technology employed led to complete or significant removal (>95%) of parental drugs but few authors reported on cephalosporins' metabolites and transformation products. Furthermore, the present ecotoxicological data are insufficient for comprehensive ecological risk quotient calculations. Considering the total of 53 cephalosporins, effective values (EC, LC, NOAEC, NOAEL, etc.) are only available for around 30% of parental drugs and are very scarce for cyanobacteria, which is considered to be the most sensitive group of organisms to antibiotics. Furthermore, it has been demonstrated that cephalosporins' transformation products can be more toxic and more persistent than the parental drugs. Few investigations considering this possibility are available. Consequently, more effort on ecotoxicological data generation and verification of biological inactivation of cephalosporins-related products is needed. Likewise, the lack of natural depletion rates and knowledge gaps on mixture effects for cephalosporins' degradation and toxicity have to be overcome. PMID- 30029326 TI - Ecological risk assessment for different macrophytes and fish species in reservoirs using biota-sediment accumulation factors as a useful tool. AB - Metal content was evaluated in the sediment, macrophytes and fish in the Medjuvrsje reservoir (Western Serbia). Concentrations of 16 trace elements (Ag; Al; As; B; Ba; Cd; Co; Cr; Cu; Fe; Li; Mn; Ni; Pb; Sr; Zn) were analysed in the sediment, macrophytes and fish of an aquatic ecosystem. Five macrophyte species and three fish tissues (liver, muscle, gills) from five fish species (freshwater bream, common nase, Prussian carp, chub, wels catfish) were sampled and the metal content was analysed with ICP-OES. The sediment concentrations of Cu, Cd, and Zn exceeded the Canadian sediment quality guidelines while concentrations of Cr and Ni were above the Netherlands' target values. Bioaccumulation factors (BSAF) were calculated for analysed macrophytes and fish tissue. The BSAF had higher values for macrophytes for all investigated elements except for Cu and Zn; Cu had a higher value in the liver of the freshwater bream (0.823) and Zn had a higher value in the liver of freshwater bream (0.914) and chub (0.834) as well as in gills of Prussian carp (2.58) and chub (1.26). Potamogeton pectinatus, Ceratophylum demersum and the root of Phragmites communis showed higher accumulation of elements than Trapa natans and Potamogeton fluitans and the body of P. communis. The highest BSAF values for Ba, Mn, Sr and Ni were recorded in the gills. Cd and Cu had the highest BSAF values in the liver. Results confirmed that particular macrophyte and fish species could be a good indicator of reservoir water and sediment pollution. PMID- 30029327 TI - Finding the conditions for the beneficial use of ZnO nanoparticles towards plants A review. AB - Zinc oxide nanoparticles (ZnO NPs) have a wide range of applications in cosmetics, electrical, and optical industries. The wide range of applications of ZnO NPs, especially in personal care products, suggest they can reach major environmental matrices causing unforeseen effects. Recent literature has shown conflicting findings regarding the beneficial or detrimental effects of ZnO NPs towards terrestrial biota. In this review we carried out a comprehensive survey about beneficial, as well as detrimental aspects, of the ZnO NPs exposure toward various terrestrial plants. A careful scrutiny of the literature indicates that at low concentrations (about 50 mg/kg), ZnO NPs have beneficial effects on plants. Conversely, at concentrations above 500 mg/kg they may have detrimental effects, unless there is a deficiency of Zn in the growing medium. This review also remarks the critical role of the biotic and abiotic factors that may elevate or ameliorate the impact of ZnO NPs in terrestrial plants. PMID- 30029328 TI - Metagenomics reveal triclosan-induced changes in the antibiotic resistome of anaerobic digesters. AB - Triclosan (TCS) is a broad-spectrum antimicrobial used in a variety of consumer products. While it was recently banned from hand soaps in the US, it is still a key ingredient in a top-selling toothpaste. TCS is a hydrophobic micropollutant that is recalcitrant under anaerobic digestion thereby resulting in high TCS concentrations in biosolids. The objective of this study was to determine the impact of TCS on the antibiotic resistome and potential cross-protection in lab scale anaerobic digesters using shotgun metagenomics. It was hypothesized that metagenomics would reveal selection for antibiotic resistance genes (ARGs) not previously found in pure culture studies or mixed-culture studies using targeted qPCR. In this study, four different levels of TCS were continuously fed to triplicate lab-scale anaerobic digesters to assess the effect of TCS levels on the antibiotic resistance gene profiles (resistome). Blasting metagenomic reads against antibiotic/metal resistance gene database (BacMet) revealed that ARG diversity and abundance changed along the TCS concentration gradient. While loss of bacterial diversity and digester function were observed in the digester treated with the highest TCS concentration, FabV, which is a known TCS resistance gene, increased in this extremely high TCS environment. The abundance of several other known ARG or metal resistance genes (MRGs), including corA and arsB, also increased as the concentrations of TCS increased. Analysis of other functional genes using SEED database revealed the increase of potentially key genes for resistance including different types of transporters and transposons. These results indicate that antimicrobials can alter the abundance of multiple resistance genes in anaerobic digesters even when function (i.e. methane production) is maintained. This study also suggests that enriched ARGs could be released into environments with biosolids land application. PMID- 30029329 TI - Occurrences, sources, and transport of hydrophobic organic contaminants in the waters of Fildes Peninsula, Antarctica. AB - As a pristine continent, Antarctica provides a good opportunity to study the spatial transport and temporal accumulation of environmental contaminants and the impacts of anthropogenic activities, both of which have given rise to ongoing public concern. In this research, an approach of coupling aquatic time-integrated passive sampling with chemical analysis and bioassays was used to assess pollution by hydrophobic organic contaminants in Antarctic waters. Passive samplers were deployed in waters of Fildes Peninsula, Antarctica, and their extracts were used for chemical analyses of sixty-six hydrophobic organic contaminants belonging to five groups [organophosphorus flame retardants (PFRs), phthalic acid esters (PAEs), polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polychlorinated biphenyls (PCBs)] and in vitro bioassays for endocrine disruption and genotoxicity. In total, twenty pollutants (six PFRs, one PAE, two PAHs, six OCPs, and five PCBs) were quantified, and six PFRs had concentrations that ranged from ND (not detected) to 44.37 ng L-1 in Antarctic waters. The concentrations detected in the waters were generally low and insufficient to have significant in vitro endocrine disruption potential or genotoxicity. The source and transport pathways of PFRs and PAE in Fildes Peninsula were studied, and multiple local sources (wastewater, air traffic, research stations, and animal feces) for different PFRs were proposed. A spatial and temporal analysis showed slight changes in the exposure of OCPs and PCBs in Antarctic waters. Furthermore, a comparison among a variety of Antarctic water sampling cases revealed that passive sampling can be a tool for aquatic time-integrated investigations in polar regions. PMID- 30029330 TI - Assessment of raw and ozonated oil sands process-affected water exposure in developing zebrafish: Associating morphological changes with gene expression. AB - With the ever-increasing amounts of oil sands process-affected water (OSPW) accumulating from Canada's oil sands operations, its eventual release must be considered. As OSPW has been found to be both acutely and chronically toxic to aquatic organisms, remediation processes must be developed to lower its toxicity. Ozone treatment is currently being studied as a tool to facilitate the removal of organic constituents associated with toxicity. Biomarkers (e.g. gene expression) are commonly used when studying the effects of environmental contaminants, however, they are not always indicative of adverse effects at the whole organism level. In this study, we assessed the effects of OSPW exposure on developing zebrafish by linking gene expression to relevant cellular and whole organism level endpoints. We also investigated whether or not ozone treatment decreased biomarkers and any associated toxicity observed from OSPW exposure. The concentrations of classical naphthenic acids in the raw and ozonated OSPW used in this study were 16.9 mg/L and 0.6 mg/L, respectively. Ozone treatment reduced the total amount of naphthenic acids (NAs) in the OSPW sample by 92%. We found that exposure to both raw and ozonated OSPW had no effect on the survival of zebrafish embryos. The expression levels of biotransformation genes CYP1A and CYP1B were induced by raw OSPW exposure, with CYP1B being more highly expressed than CYP1A. In contrast, ozonated OSPW exposure did not increase the expression of CYP1A and only slightly induced CYP1B. A decrease in cardiac development and function genes (NKX2.5 and APT2a2a) was not associates with large changes in heart rate, arrhythmia or heart size. We did not find any indications of craniofacial abnormalities or of increased occurrence of apoptotic cells. Overall, our study found that OSPW was not overtly toxic to zebrafish embryos. PMID- 30029331 TI - Increased risk of phthalates exposure for recurrent pregnancy loss in reproductive-aged women. AB - Recurrent pregnancy loss (RPL) is the termination of pregnancies, usually before 20 weeks of gestation, and is defined as the loss of two or more pregnancies. In Taiwan, after 2011 di-2-ethylhexyl phthalate (DEHP) exposure episode, more reproductive-aged women still expose to high levels of DEHP and di-butyl phthalate (DBP) than have women of other age groups. Phthalates might be involved in the RPL pathogenesis. This study assessed the association of phthalate exposure with RPL risk in reproductive-aged Taiwanese women. This study recruited 103 patients diagnosed by a physician with RPL of unknown etiology and 76 controls from the Department of Obstetrics and Gynecology at a medical center in southern Taiwan between August 2013 and August 2017. Urine samples were analyzed for 11 phthalate metabolites through liquid chromatography-tandem mass spectrometry; subsequently, principal component analysis (PCA) and hierarchical clustering analysis were performed to determine the main sources of phthalate exposure. Finally, multivariate logistic regression was used to determine the RPL risk. The creatinine-unadjusted median levels of mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) in RPL/control were 9.8/5.3, 27.2/13.1, 11.4/8.1, and 12.9/9.5 ng/mL, respectively; furthermore, SigmaDBPm and SigmaDEHPm in RPL/control were 0.18/0.10 and 0.15/0.12 nmol/mL, respectively. PCA revealed three primary components of phthalate exposure: diethyl phthalates (DEP), DEHP, and DBP. Plastic food container use and medication were identified as the main phthalate exposure sources. After adjustment for potential confounding factors (urinary creatinine, age, age at menarche, education, and plastic food container use), we found that the urinary level of SigmaDBPm was significantly associated with elevated risk for RPL (OR = 2.85, p = 0.045). Our findings supported the hypothesis that exposure to phthalates increases RPL risk. The development of a strategy to reduce phthalate exposure among reproductive aged women should be emphasized. PMID- 30029332 TI - Targeted inactivation of antibiotic-resistant Escherichia coli and Pseudomonas aeruginosa in a soil-lettuce system by combined polyvalent bacteriophage and biochar treatment. AB - High abundances of antibiotic-resistant pathogenic bacteria (ARPB) and antibiotic resistance genes (ARGs) in agricultural soil-plant systems have become serious threats to human health and environmental safety. Therefore, it is crucial to develop targeted technology to control existing antibiotic resistance (AR) contamination and potential dissemination in soil-plant systems. In this work, polyvalent bacteriophage (phage) therapy and biochar amendment were applied separately and in combination to stimulate ARPB/ARG dissipation in a soil-lettuce system. With combined application of biochar and polyvalent phage, the abundance of Escherichia coli K-12 (tetR) and Pseudomonas aeruginosa PAO1 (ampR + fosR) and their corresponding ARGs (tetM, tetQ, tetW, ampC, and fosA) significantly decreased in the soil after 63 days' incubation (p < 0.05). Similar results for endophytic K-12 and PAO1, and ARGs, were also obtained in lettuce tissues following combined treatment. Additionally, high throughput sequencing revealed that biochar and polyvalent phage synergetically improved the structural diversity and functional stability of the indigenous bacterial communities in soil and the endophytic ones in lettuce. Hence, this work proposes a novel biotechnology that combines biochar amendment and polyvalent phage therapy to achieve targeted inactivation of ARPB, which stimulates ARG dissipation in soil lettuce systems. PMID- 30029333 TI - Presence and fate of veterinary antibiotics in age-dated groundwater in areas with intensive livestock farming. AB - The combination of emerging antibiotic resistance and lack of discovery of new antibiotic classes poses a threat to future human welfare. Antibiotics are administered to livestock at a large scale and these may enter the environment by the spreading of manure on agricultural fields. They may leach to groundwater, especially in the Netherlands which has some of the most intensive livestock farming and corresponding excessive manure spreading in the world. This study investigates the presence of antibiotics in groundwater in two regions with the most intensive livestock farming in the Netherlands. If so, the hydrochemical conditions were further elaborated. Ten multi-level wells with in total 46 filters were sampled, focusing on relatively young, previously age-dated groundwater below agricultural fields. Twenty-two antibiotics were analyzed belonging to the following antibiotic groups: tetracyclines, sulfonamides, trimethoprims, beta-lactams, macrolides, lincosamides, quinolones, nitrofurans and chloramphenicol. The samples were analyzed for these antibiotics by LC-MS/MS ESI-POS/NEG (MRM) preceded by solid phase extraction which resulted in importantly low detection limits. Six antibiotics were found above detection limits in 31 filters in seven wells: sulfamethazine, sulfamethoxazole, lincomycin, chloramphenicol, ciprofloxacin, and sulfadiazine. The concentrations range from 0.3 to 18 ng L-1. Sulfonamides were detected at all measured depths down to 23 meters below surface level with apparent groundwater ages up to 40 years old. No antibiotics were detected below the nitrate/iron redox cline, which suggests that the antibiotics might undergo degradation or attenuation under nitrate-reducing redox conditions. This study provides proof that antibiotics are present in groundwater below agricultural areas in the Netherlands due to the spreading of animal manure. PMID- 30029334 TI - The interactions of fullerene C60 and Benzo(alpha)pyrene influence their bioavailability and toxicity to zebrafish embryos. AB - This study aimed to assess the toxicological consequences related to the interaction of fullerene nanoparticles (C60) and Benzo(alpha)pyrene (B(alpha)P) on zebrafish embryos, which were exposed to C60 and B(alpha)P alone and to C60 doped with B(alpha)P. The uptake of pollutants into their tissues and intra cellular localization were investigated by immunofluorescence and electron microscopy. A set of biomarkers of genotoxicity and oxidative stress, as well as functional proteomics analysis were applied to assess the toxic effects due to C60 interaction with B(alpha)P. The carrier role of C60 for B(alpha)P was observed, however adsorption on C60 did not affect the accumulation and localization of B(alpha)P in the embryos. Instead, C60 doped with B(alpha)P resulted more prone to sedimentation and less bioavailable for the embryos compared to C60 alone. As for toxicity, our results suggested that C60 alone elicited oxidative stress in embryos and a down-regulation of proteins involved in energetic metabolism. The C60 + B(alpha)P induced cellular response mechanisms similar to B(alpha)P alone, but generating greater cellular damages in the exposed embryos. PMID- 30029335 TI - The influence of land use in a highly modified catchment: Investigating the importance of scale in riverine health assessment. AB - Riverine landscapes are studied at varying scales, investigating the complex cause-effect pathways between rivers and their physical, chemical and biological attributes. Policy development, management and planning are often formulated and applied at the regional or catchment scale, however the ecological evidence required to inform at this scale is typically collected from the much smaller scale. This research was aimed at determining if patterns in diatom and macroinvertebrate community composition can be attributed to a specific/single land use in a catchment with multiple land uses. The impacts of forest, macadamia, grazing, sugar cane and urban land uses in the Richmond River Catchment of Northern NSW, Australia were investigated at 20 micro-catchment scale sites. A total of 124 diatom species from 43 genera, along with 92 families and three sub-families of macroinvertebrates, were collected and used to calculate the Richmond River Diatom Index (RRDI), AUSRIVAS and SIGNAL2 scores. Statistical analyses showed distinct groupings of land use categories providing evidence of cause-effect pathways attributed to individual land uses. The RRDI, AUSRIVAS and SIGNAL2 scores all showed distinctions between land use categories, though they were clearer in the RRDI. The RRDI indicated that the grazing sites had the poorest health of the land use categories, followed by sugar cane and urban while the macadamia and forest sites were relatively healthy. Signal 2 scores showed similar trends to the RRDI, while the AURIVAS scores did not present clear trends, particularly in the edge habitat of macadamia land use sites. The results indicated that riparian vegetation and instream habitat play an important role in attenuating inputs and that rehabilitation efforts could potentially improve water quality at a micro-catchment scale and subsequently, result in river health improvement at the catchment scale. The research collected at this micro-catchment scale presents new evidence that further informs and affects decisions made at the catchment scale, where policy and planning is developed and implemented. PMID- 30029336 TI - Concentration of soil-transmitted helminth eggs in sludge from South Africa and Senegal: A probabilistic estimation of infection risks associated with agricultural application. AB - The use of sludge in agriculture has been encouraged as a means of increasing soil nutrient content and improving the water holding capacity. On the negative side, major public health concerns with sludge application prevail, mainly due to the high concentration of pathogenic microorganisms. Soil-transmitted helminths (STHs) are of major health concern in this regard, especially in endemic regions, mainly due to the high environmental resistant of the eggs combined with a low infectious dose. In this study the concentration of STH eggs in two months dried sludge from Durban, South Africa and Dakar, Senegal was determined and compared. Sampling was carried out from January to October 2016 and in September 2016 for Dakar. Ascaris spp, hookworm, Trichuris spp, Taenia spp and Toxocara spp were the commonly recorded STH eggs. STH egg concentrations were higher in Dakar than in Durban, with viable STH egg concentrations exceeding both local and international guidelines. Due to the high concentration of viable STH eggs, risks of Ascaris spp infection was very high for farmers applying this sludge on their farms in both Durban (7.9 * 10-1 (+/-1.7 * 10-2)) and Dakar (9.9 * 10-1 (+/-1.3 * 10-5)). Consumption of lettuce grown on sludge amended soil will result in probable infections but harvest after 30 days between sludge application and harvest in Durban gave median probability infection risks with a risk level similar to the WHO tolerable risk value (10-4). This time period need to be prolonged to harvest in Dakar to 40 days to reduce the risks of infection to the tolerable risks values. Further treatment of the sludge either through composting or drying for longer periods of time is thus recommended from a public health perspective. PMID- 30029338 TI - City re-imagined: Multi-stakeholder study on branding Hong Kong as a city of greenery. AB - This study explores the potential to enhance a city's international position and social development through mainstreaming urban greenery in its city branding exercise. The variety of services by urban greenery are theorised to be compatible with the economic and social purposes of city branding. Despite enjoying exceptional green cityscape with the presence of country parks and other green resources, the comparative strength is under-valued under Hong Kong's current brand. This Hong Kong-based study looks into the crucial linkages between city branding and urban greening by factoring in the perception of local residents, overseas investors/workers and tourists. The results from the questionnaire survey (n = 240) reveal that people generally favour incorporating more green elements into the brand, largely due to the positive relationship between urban greenery provision and quality of living. Together with the supplementary focus groups (n = 10) and email interviews, the findings throw light on the significance of these green resources in both projecting a liveable city image and enhancing the living quality for sustainable city development and management, as well as how adopting such brand can facilitate urban greening. The results offer new insights of city governance by highlighting the idea of branding a city green and the challenges in implementation. PMID- 30029337 TI - Influence of artificial drainage system design on the nitrogen attenuation potential of gley soils: Evidence from hydrochemical and isotope studies under field-scale conditions. AB - In North Atlantic Europe intensive dairy farms have a low nitrogen (N) use efficiency, with high N surpluses often negatively affecting water quality. Low feed input systems on heavy textured soils often need artificial drainage to utilise low cost grassland and remain profitable. Heavy textured soils have high but variable N attenuation potential, due to soil heterogeneity. Furthermore, drainage system design can influence the potential for N attenuation and subsequent N loadings in waters receiving drainage from such soils. The present study utilises end of pipe, open ditch and shallow groundwater sampling points across five sites in SW Ireland to compare and rank sites based on N surplus, water quality and "net denitrification", and to develop a conceptual framework for the improved management of heavy textured dairy sites to inform water quality N sustainability. This includes both drainage design and "net denitrification" criterion, as developed within this study.N surplus ranged from 211 to 292 kg N/ha (mean of 252 kg N/sourha) with a common source of organic N across all locations. The predicted soil organic matter (SOM) N release potential from top subsoil layers was high, ranging from 115 to >146 kg N/ha. Stable isotopes analyses showed spatial variation in the extent of specific N-biotransformation processes, according to drainage location and design. Across all sites, nitrate (NO3-N) was converted to ammonium (NH4+-N), which migrated offsite through open ditch and shallow groundwater pathways. Using the ensemble data the potential for soil N attenuation could be discriminated by 3 distinct groups reflecting the relative dominance of in situ N-biotransformation processes deduced from water composition: Group 1 (2 farms, ranked with high sustainability, NH4+ < 0.23 mg N/l, delta15N-NO3- > 50/00 and delta18O-NO3- > 100/00), low NH4+-N concentration coupled with a high denitrification potential; Group 2 (1 farm with moderate sustainability, NH4+ < 0.23 mg N/l, delta15N-NO3- < 80/00 and delta18O-NO3- < 80/00), low NH4+-N concentration with a high nitrification potential and a small component of complete denitrification; Group 3 (2 farms, ranked with low sustainability, NH4+ > 0.23 mg N/l, 140/00 > delta15N-NO3- > 50/00 and 250/00 > delta18O-NO3- > -20/00), high NH4+-N concentration due to low denitrification. The installation of a shallow drainage system (e.g. mole or gravel moles at 0.4 m depth) reduced the "net denitrification" ranking of a site, leading to water quality issues. From this detailed work an N sustainability tool for any site, which presents the relationship between drainage class, drainage design (if present), completeness of denitrification, rate of denitrification and NH4-N attenuation was developed. This tool allows a comparison or ranking of sites in terms of their N sustainability. The tool can also be used pre-land drainage and presents the consequences of future artificial land drainage on water quality and gaseous emissions at a given site. PMID- 30029339 TI - Microbial strategies and biochemical activity during lignocellulosic waste composting in relation to the occurring biothermal phases. AB - Typically, hardly-degradable lignocellulosic waste is a component or a co component of the composted mass. The aim of the work was to present the dynamics and succession of microbial communities during small temperature changes, conditioned by the availability of lignocellulosic polymer and feather waste (the presence of N) in composts with qualitatively and quantitatively different lignocellulosic waste, but most of all, to draw attention to the previously not considered microbial strategies in the composted mass. Decomposition of lignocellulose during composting was similar to the priming effect in the soil, because it was associated with the successive occurrence of two groups of microorganisms. The first group of microorganisms, using easily accessible fraction of the lignocellulose complex, was named the first-strategist group, i.e., non-nutritionally specialized group of microorganisms. The second group, utilizing the hard-to-degrade fraction of lignocellulose, was named second strategist microorganisms, i.e., nutritionally-specialized group of microorganisms. Biodegradation of the lignocellulose complex in compost I enriched with grass (42.86% pine bark, 34.28% grass, 20.0% sawdust and 2.86% chicken feathers) was faster than in compost II that did not contain any grass, but included more hardly degradable components (25.54% pine bark, 10.63% wheat straw, 51.07% sawdust, 12.76% chicken feathers). In compost I, a higher temperature in the thermophilic phase was recorded; larger amounts of non specialized mesophilic and thermophilic bacteria in the first weeks of composting and a higher abundance of ligninolytic, xylanolytic fungi and cellulolytic bacteria were observed already in biothermal phase 3 with limited access to easily available C and energy sources. During this period, phosphatase, dehydrogenase and respiratory activities were higher in compost I than compost II. This work demonstrates that the succession of particular groups of microorganisms may help determine the start of biodegradation of recalcitrant ligninocellulosic components during composting. PMID- 30029340 TI - Constructed wetlands for water quality improvements: Benefit transfer analysis from Ohio. AB - Water resources provide many benefits that generate value for residents and recreation users alike but run-off from agricultural and impervious surfaces can impair water quality, reducing any generated value. A possible solution to this problem is the construction of treatment wetlands to remove excessive nutrients from water bodies. This study uses environmental and economic data to approximate the costs of constructing and operating free surface water wetlands to remove phosphorus and estimates the amenity and recreational benefits of the resulting improvements in water quality for 24 lakes in Ohio. A ten percent improvement in water quality from a decrease in phosphorus loadings generates positive net benefits for all lakes in the sample with a lifetime cost benefit ratio of 2.92. The study also examines the potential use of constructed wetlands as the sole strategy to achieve a reduction goal for phosphorus loadings and find that the costs of doing so are prohibitive. Constructed wetlands can be a cost-effective component of a comprehensive strategy for small-scale nutrient reduction and water quality improvements for surface water bodies, but other treatment methods would be required to achieve any proposed targeted improvements. PMID- 30029341 TI - Beyond the nutrient strategies: Common ground to accelerate agricultural water quality improvement in the upper Midwest. AB - Nutrients in drainage waters from the Upper Mississippi River Basin states have been a well-documented contributor to the Gulf of Mexico hypoxic zone for decades, and in response, twelve states have developed strategies to address this issue, with Iowa, Minnesota, and Illinois performing rigorous science assessments which estimated nitrogen and phosphorus reduction effectiveness for numerous agricultural non-point source conservation practices. The practices identified in these strategies were compared to identify areas of consensus and discord on nutrient load reduction potentials. Additionally, each practice was assessed for (1) the suitability to stack or be layered with other practices (stackability), (2) the ability to track implementation within a state or regionally (trackability), and (3) the level of production system change required to implement the practice. Overall, there was general consensus among the state strategies in the nutrient load reduction effectiveness of most practices with the exception of cover crops (10%-31% nitrogen reduction) and bioreactors (13% 43% nitrogen reduction). The most effective water quality-improvement practices (i.e., land-use change practices) required relatively more production system changes to agronomic management and were the most trackable (scores: 5, 1-5 scale), although they were also less stackable with other practices (scores: 1 to 1.8; 1-5 scale) and were the least cost effective on a unit area basis (generally $15 to $964 per ha). The most cost effective practices tended to be highly stackable (e.g., nitrogen management: (-)$49 per ha and stackability of 4.7), which indicated that stacking a variety of practices may be the most cost effective use of conservation dollars. The practices that were most difficult to track had relatively lower nitrogen loss reduction effectiveness, but these practices were less costly to implement and required relatively less production system change to agronomic management, two factors of importance to many producers. PMID- 30029342 TI - Sequential application of soil washing and phytoremediation in the land of fires. AB - This paper presents an experimental study aimed at verifying the efficiency of a double-stage remediation process to be applied in former agricultural sites contaminated by illegal dumping of industrial wastes. The process, which includes an EDDS (Ethylenediamine-N,N'-disuccinic acid) enhanced washing, followed by a phytoremediation treatment, is applied at the lab scale for the remediation of a soil sampled in a territory known as Land of Fires (Italy) contaminated with Cu (~400 mg kg-1) and Zn (~250 mg kg-1). Phytoremediation is conducted using Lactuca sativa to verify, together with process efficiency, the potential risks due to metal accumulation in edible species. The results of the washing process show the possibility of removing the potential toxic metals from 44% to 77% for Cu and from 18% to 47% for Zn. The removal is well distributed among all soil fractions. There is almost no removal of other components which are fundamental for an agricultural soil. Results of the subsequent phytoremediation treatment indicate that both the contaminants and the residual EDDS/EDDS-chelates adsorbed into the soil generally negatively affect plant growth, reducing the number of germinated seeds up to 43%, and the shoot length up to 63%. Nonetheless, whenever the efficiency of the washing stage is high enough, no adverse effect is obtained on the plants. The efficiency of the phytoremediation stage mainly relies on leaf uptake, which accounts for up to 88% of the total removed Cu and up to 95% of the total removed Zn. Stabilization in the underground part of the plant is more contained because of the limited mass of the roots. PMID- 30029343 TI - Optimizing surface and contributing areas of bioretention cells for stormwater runoff quality and quantity management. AB - Bioretention cells (BCs) have received increasing attention in stormwater quality and quantity management. Selecting a suitable implementation level of BCs to concurrently achieve multiple performance targets (e.g., first flush reduction, peak flow reduction, and runoff volume reduction) is essential and often challenging. This study proposes a method for formulating suitable sizing criteria for multi-objective stormwater management. The performance of BCs of different areas is assessed first using the Storm Water Management Model (SWMM) and then look-up curves (i.e., the performance target versus the required area of BCs) for each of the performance targets and the multi-objective cases are derived. In some cases, the available area of BCs is limited; to account for the multi-objective management interests and maximize the system-wide benefits, an optimal contributing drainage area for BCs should be selected. A method is therefore developed to solve this optimization problem. A case study of Hong Kong shows that the required area of BCs increases non-linearly with increased performance targets. With a limited area of BCs, larger contributing areas are favorable if no special emphasis is placed on the intensive control of peak flow reduction. Design standards (e.g., the intensity of the design storm), evaluation methods (e.g., depth threshold of the initial portion of runoff), and management preference all exert some influence on the resultant sizing criteria and optimization results. Carefully selecting these catchment-specific evaluation methods should lead to more appropriate sizing criteria and thus promote more efficient BC adoption. PMID- 30029344 TI - A habitat-based framework to predict the effects of agricultural drain maintenance on imperiled fishes. AB - One third of the total global land viable for agricultural production has artificial drainage systems. These drainage systems can provide important habitat for fishes and, in some cases, imperiled fish species vulnerable to impact by drainage maintenance activities. A framework to provide quantitative assessments of the effects of maintenance activities on imperiled fish species is needed. In this study, a six-step habitat-based framework was developed to predict suitable habitat for two at-risk species in an agricultural drain: the Endangered Pugnose Shiner (Notropis anogenus) and the Special Concern Blackstripe Topminnow (Fundulus notatus). Using the framework, spatial models were developed to assess the effects of proposed drain maintenance on the overall amount of suitable habitat, habitat patch size, and connectivity of habitat patches. Maintenance had a significant impact on habitat connectivity, but did not significantly reduce the habitat size of isolated patches. The amount of suitable habitat available after maintenance fell below the minimum area for population viability (MAPV) for the Pugnose Shiner, but not the Blackstripe Topminnow. Future impact assessments of drain maintenance should incorporate population viability analysis, coupled with habitat patch analysis (patch size and connectivity), to quantitatively test consequences of proposed alteration to the viability of spatially structured populations. PMID- 30029345 TI - Ecological vulnerability assessment for ecological conservation and environmental management. AB - Identifying ecological vulnerable regions is a significant aspect in ecological conservation and environmental management. This paper presents a first attempt to provide a prototype framework that can assess ecological vulnerability and evaluate potential impacts of natural, social, economic, environmental pollution, and human health elements on ecological vulnerability with integrating spatial analysis of Geographic Information System (GIS) method and multi-criteria decision analysis (MCDA). A general ecological vulnerability index was constructed to describe the vulnerability status in an ecological hotspot of China. The assessment results of this study confirm the poor ecological vulnerability in China that only 1.32% of the China's population lives in not vulnerable ecosystem. A very high percentage (98.68%) of Chinese with 1.34 billion people lives in vulnerable and highly vulnerable area. This situation is mainly caused by increasing population pressure, exhausted nature resources, extensive economic growth, severe environmental pollution, insufficient environmental protection investment, and accelerating population aging. The spatial comparison indicates that spatial disparity existed in China with the central and northwestern provinces showing higher ecological vulnerability than the northeastern and southern provinces. The results of ecological vulnerability assessment can support effective guidance for mid- or long-term ecologic management. The developed framework can be replicated at different spatial and temporal scales using context-specific datasets to support ecological managers and government with decision-making. With available robust climate change models, future research might incorporate climate change into the ecological vulnerability framework. PMID- 30029346 TI - Operating cost reduction of UF membrane filtration process for drinking water treatment attributed to chemical cleaning optimization. AB - This study investigated the cost and CO2 emission reduced as a result of optimizing operating conditions for chemical cleaning in a membrane filtration process used for water treatment. A new protocol was proposed and operating conditions for chemical cleaning of a pilot-scale membrane filtration process were optimized. The critical flux for irreversibility was identified as the permeate flux using a modified flux-step method, and was 100 l m-2 h-1, 20 l m-2 h-1 higher than the vendor recommended permeate flux. NaOCl, which is also the vendor recommended chemical, was selected as the optimal chemical reagent following an examination of the permeability restoration ratios and nature of the irreversible foulants. The optimized operating conditions of enhanced flux maintenance (EFM), determined using response surface methodology (RSM) were: 6.3 d interval, 500 ppm concentration, and 76 min duration, which represented an increase of 4.3 d, 300 ppm, and 36 min, respectively, as opposed to the vendor recommended conditions. As a result, the total operating cost and CO2 emission were $0.1187/m3 and 112.75 g CO2/m3, respectively, and 26.5% lesser compared to the operating cost and CO2 emission based on vendor recommended conditions. This study found that the reductions in operating cost and CO2 emission using the optimization process were excellent. PMID- 30029347 TI - Outcomes of the hydromorphology integration in the Water Framework Directive: A review based on science mapping. AB - The goal of our review was to evaluate scientific outcomes connected to hydromorphology and Water Framework Directive by synthesizing the main themes based on keywords, research domains, and the spatial coverage of high visibility publications. These data were integrated into a social network analysis to understand the structure of science related to our topic. Thus, we investigated 183 articles and conference proceedings from the Web of Science Core Collection. Among the 505 authors keywords, the central ones in our network were Water Framework Directive, hydromorphology, macroinvertebrates, ecological status, water quality, reference conditions, and river. The characteristics of the network of keywords indicated that information developed around a few key concepts linked to numerous peripheral keywords, which highlighted some main themes of research. Hydromorphology appeared mostly in articles with macroinvertebrates and river restoration, suggesting the acceptance of environmental-based paradigm in water bodies' management. Consequently, we expected to count the majority of publications in Environmental Sciences & Ecology research domain. Issues related to the society (e.g. public participation, stakeholders) didn't appear in our analysis. Publications covered especially European Union member states, the network being dominated by Germany, Italy, and UK in terms of both study area and authorship. Besides traditional scientific relations between Western and Northern European states, we also noticed numerous comparisons between Danube countries. To comment the position of these publications in the scientific world, we used the Article Influence Score, which was below the average for the main research domain of Environmental Sciences & Ecology, probably as a consequence of the regional cover and concern of the Water Framework Directive. Further, we recommend more connections between environmental and social sciences, as well as between countries and we encourage funding for open access publications in order to increase the visibility and influence of the topic of hydromorphology and Water Framework Directive both bibliometrically and for decision and policy makers. PMID- 30029348 TI - The importance of landscape characteristics for the delivery of cultural ecosystem services. AB - The importance of Cultural Ecosystem Services (CES) to human wellbeing is widely recognised. However, quantifying these non-material benefits is challenging and consequently they are often not assessed. Mapping approaches are increasingly being used to understand the spatial distribution of different CES and how this relates to landscape characteristics. This study uses an online Public Participation Geographic Information System (PPGIS) to elicit information on outdoor locations important to respondents in Wiltshire, a dynamic lowland landscape in southern England. We analysed these locations in a GIS with spatial datasets representing potential influential factors, including protected areas, land use, landform, and accessibility. We assess these characteristics at different spatial and visual scales for different types of cultural engagement. We find that areas that are accessible, near to urban centres, with larger views, and a high diversity of protected habitats, are important for the delivery of CES. Other characteristics including a larger area of woodland and the presence of sites of historic interest in the surrounding landscape were also influential. These findings have implications for land-use planning and the management of ecosystems, by demonstrating the benefits of high quality ecological sites near to towns. The importance of maintaining and restoring landscape features, such as woodlands, to enhance the delivery of CES were also highlighted. PMID- 30029350 TI - Combinative treatment of phenol-rich retting-pond wastewater by a hybrid upflow anaerobic sludge blanket reactor and solar photofenton process. AB - In this study, recalcitrant rich retting-pond wastewater was treated primarily by anaerobic treatment and subsequently treated with a solar photofenton process to remove phenol and organics. The anaerobic treatment was carried out in a granulated laboratory scale hybrid upflow anaerobic sludge blanket reactor (HUASBR) with a working volume of 5.9 L. It was operated at different hydraulic retention times (HRT) from 40 to 20 h over a period of 140 days. The optimum HRT of the anaerobic reactor was found to be 30 h, with corresponding chemical oxygen demand (COD) and phenol removal of 60% and 47%, respectively. Primary anaerobically treated wastewater was subjected to secondary solar photofenton treatment which was carried out at pH 3.5. Response surface methodology (RSM) was used to design and optimize the performance of the solar photofenton process. Regression quadratic model describing COD removal efficiency of the solar photofenton process was developed and confirmed by analysis of variance (ANOVA). Optimum parameters of the solar photofenton process were found to be: 4 g/L of fenton as catalysts, 25 mL of hydrogen peroxide, and 30 min of reaction time. After the primary anaerobic treatment, solar photofenton oxidation process removed 94% and 96.58% of COD and phenol, respectively. Integration of anaerobic and solar photofenton treatment resulted in 97.5% and 98.4% removal of COD and phenol, respectively, from retting-pond wastewater. PMID- 30029349 TI - Eucalyptus sawdust derived biochar generated by combining the hydrothermal carbonization and low concentration KOH modification for hexavalent chromium removal. AB - In this study, Eucalyptus sawdust was hydrothermally carbonized, and the resulting biochar was modified by a low concentration potassium hydroxide. The morphology and surface property was characterized by SEM-EDS, BET, FTIR and XPS techniques. A series of batch adsorption experiments were conducted to screen out the optimum conditions, and to investigate the isotherm, kinetics and thermodynamic behaviors. The results indicated that a high adsorption capacity of hexavalent chromium (qe 45.88 mg/g) was achieved by the combining of hydrothermal carbonization at 220 degrees C and 0.05 N potassium hydroxide modification, and a high biochar yield (47.61%) was obtained. The isotherm, kinetics and thermodynamic studies suggested that the spontaneously and endothermically chemical adsorption was the main mechanism, which was partially supported by BET, FTIR and XPS results. This finding suggested that the combination of hydrothermal carbonization and a subsequent low alkali modification was an effective method to prepare a high-performance adsorbent for hexavalent chromium removal. PMID- 30029351 TI - One-step synthesis of europium complexes containing polyamino acids through ring opening polymerization and their potential for biological imaging applications. AB - Lanthanide-doped nanoprobes have received significant attentions for utilization in biological sensing and imaging due to their unique optical properties. However, only few works were focused on fabrication of europium complexes based fluorescence polymeric nanoparticles (FPNs) with excellent biocompatibility and biodegradability. In this study, we fabricated the FPNs (named as Eu(TTA)3Phen GluEG FPNs) with encapsulated europium complexes which show low cytotoxicity, high sensitivity and deep penetration. Free amine group present on europium complexes initiated the ring-opening polymerization (ROP) of side-chain modified glutamic acid NCAs, offering a simple and effective method to prepare europium core FPNs with a uniform size distribution. Europium (III) chelates were furnished with a functional polyamino acid shell to fabricate biocompatible and biodegradable FPNs. Biological evaluation results demonstrate that such fabricated FPNs process excellent biocompatibility and dyeing performance. Therefore, we can expect that the fabrication approach will attract much research interest and effort on the preparation of biodegradable probes for various biological applications. PMID- 30029352 TI - Homoarsenocholine - A novel arsenic compound detected for the first time in nature. AB - The arsenic speciation was determined in macrofungi of the Ramaria genus with HPLC coupled to inductively coupled plasma mass spectrometry. Besides arsenic species that are already known for macrofungi, like arsenobetaine or arsenocholine, two compounds that were only known from marine samples so far (trimethylarsoniopropanate and dimethylarsinoylacetate) were found for the first time in a terrestrial sample. An unknown arsenical was isolated and identified as homoarsenocholine. This could be a key intermediate for further elucidation of the biotransformation mechanisms of arsenic. PMID- 30029354 TI - Electrospun nanofibers and spin coated films prepared from side-chain copolymers with chemically bounded platinum (II) porphyrin moieties for oxygen sensing and pressure sensitive paints. AB - Pressure sensitive paints (PSP) containing oxygen probes were primarily used to measure air pressure. In this perspective, a polymerizable methacrylate-derived tetraphenylporphinato platinum(II) (PtTPP-MA) monomer was copolymerized with acrylic/vinyl monomers to produce four different copolymers. Octafluoropentyl methacrylate (OCFPM) and pentafluorophenyl acrylate (PFPA) were used as fluorinated monomers. Methyl methacrylate (MMA) and styrene (S) were used as non fluorinated monomers. The structures and physical properties of the polymers were confirmed by 1H NMR, 19F NMR, GPC, and DSC. Experimental conditions were optimized to get fine nanofibers. Pressure sensing electrospun membranes and spin coated films were fabricated. Nanofibers showed fast response and good sensitivity towards gaseous oxygen. The influence of types of substrate and polymer natures on response time, oxygen sensitivity, and pressure responses were deliberated. Among our synthesized copolymers, poly(PS-co-PFPA-co-OCFPM-co PtTPPMA) (Polymer P3) showed fast response time and good pressure sensitivity both as spin coated films and nanofibers. PMID- 30029353 TI - Nano liquid chromatography-high-resolution mass spectrometry for the identification of metabolites of the two new psychoactive substances N-(ortho methoxybenzyl)-3,4-dimethoxyamphetamine and N-(ortho-methoxybenzyl)-4 methylmethamphetamine. AB - Among the emerging new psychoactive substances (NPS), compounds carrying an N ortho-methoxybenzyl substituent, the so-called NBOMes, represented a highly potent group of new hallucinogens. Recently, 3,4-dimethoxyamphetamine (3,4-DMA) NBOMe and 4-methylmethamphetamine (4-MMA)-NBOMe occurred, but no data on their pharmacokinetics were available. According to other NBOMes, they are expected to be extensively metabolized. For detection and identification of their phase I and II metabolites, nano liquid chromatography coupled to high resolution tandem mass spectrometry (nanoLC-HRMS/MS) was used. Rat urine was prepared by simple dilution and incubation mixtures with pooled human liver S9 fraction by precipitation. Furthermore, the results concerning detectability using the new nanoLC approach were compared to those obtained by conventional ultra-high performance LC (UHPLC). In addition, the detectability of the compounds by standard urine screening approaches (SUSAs) routinely used by the authors with UHPLC-HRMS/MS, LC MSn, and GC-MS was tested. Both NBOMes were extensively metabolized mainly by O demethylation and conjugation with glucuronic acid (3,4-DMA-NBOMe) or oxidation of the tolyl group to the corresponding carboxylic acid (4-MMA-NBOMe). The developed nanoLC-HRMS/MS approach was successfully applied for identification of 38 3,4-DMA-NBOMe metabolites and 33 4-MMA-NBOMe metabolites confirming its detection power. Furthermore, the solvent saving nanoLC system showed comparable results to the UHPLC-HRMS/MS approach. In addition, an intake of an estimated low common user's dose of the compounds was detectable by all SUSAs only via their metabolites. Suggested targets for urine screening procedures were O-demethyl- and O,O-bis-demethyl-3,4-DMA-NBOMe and their glucuronides and carboxy-4-MMA-NBOMe and its glucuronide and N-demethyl-carboxy-4-MMA-NBOMe. PMID- 30029355 TI - Determination of iron in seawater: From the laboratory to in situ measurements. AB - The marine biogeochemistry of iron plays a significant role in regulating climate change. Trace dissolved iron in oceanic surface water can limit phytoplankton growth which in turn limits the carbon dioxide flux at the air/sea interface. To better understand the relationship between iron and its different species with phytoplankton, as well as the biogeochemical cycle of iron in seawater, accurate, sensitive, and in situ methods are needed for iron determination. This paper reviews the methods for determining iron in seawater from the laboratory, shipboard to in situ measurements, including such strategies as atomic spectrometry, spectrophotometry, chemiluminescence, and voltammetry, which will provide the foundation for developing reliable long-term iron monitoring and sensing platforms in the future. PMID- 30029356 TI - Magnetic carbon dots based molecularly imprinted polymers for fluorescent detection of bovine hemoglobin. AB - A simple and effective method was proposed to prepare an imprinted polymer layer at the surface of magnetic carbon dots with dopamine as the functional monomer for selectively and sensitively fluorescent recognizing bovine hemoglobin. The magnetic fluorescence imprinted polymers were investigated by Fourier-transform infrared spectra, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and vibrating sample magnetometer. Under optimum conditions, the fluorescent intensity decreased linearly coincided with the concentration of bovine hemoglobin in the range of 0.05-16.0 MUM with a detection limit of 17.3 nM. The magnetic fluorescence imprinted polymers were used for detecting bovine hemoglobin in real samples with the recoveries of 99.0 104.0%. These results indicated that a convenient method was proposed to develop fluorescent probes for rapid recognition and sensitive detection of trace proteins in real samples. PMID- 30029357 TI - A new suppressor design for low noise performance with carbonate eluents for Ion Chromatography. AB - Carbonate and bicarbonate based eluents have been applied for ion analysis from the inception of ion chromatography. The product of suppression with carbonate and/or bicarbonate eluent is carbonic acid which is weakly dissociated and tends to outgas. While the act of suppression enhanced the signal for fully dissociated ions and lowered the background to a weakly dissociated level, the overall noise performance, however, varied depending on the suppression mechanism. Chemical suppression with a membrane suppressor yielded low noise performance with carbonate and/or bicarbonate eluents. Electrolytic suppression, on the other hand, resulted in a relatively higher noise with carbonate based eluents when compared to chemical suppression. In this work, we investigated the root cause of noise with electrolytic suppressors and carbonate based eluents. Further, a new electrolytic suppressor design based on a three-electrode design is discussed in this paper and provided low noise performance with carbonate and/or bicarbonate eluents. PMID- 30029358 TI - beta-Cyclodextrin functionalization of metal-organic framework MOF-235 with excellent chemiluminescence activity for sensitive glucose biosensing. AB - Herein, we developed a new CL method for the detection of glucose, exhibiting high sensitivity, low limit of detection, good stability and reliability for analysis of real biological samples. The MOF-235/beta-cyclodextrin (beta-CD) hybrids were facilely prepared by a simple method, and characterized by XRD, TGA, FT-IR and SEM. The as-prepared hybrids exhibited highly catalytic activity for the hydrogen peroxide-luminol system, and gave more than 30-fold enhancement in CL response as compared with that of hydrogen peroxide-luminol system, thus could be used for sensitive detection of H2O2 and glucose. The excellent catalytic performance of the MOF-235/beta-CD hybrids is ascribed to the large surface area of MOF-235 as well as the synergistic effect between beta-CD and MOF-235. The proposed sensing strategy coupled with CL detection method showed low detection limits of 5 nM and 10 nM for H2O2 and glucose, respectively. Successful application of the MOF-235/beta-CD hybrid in CL assay of glucose in real human serum samples is demonstrated as an efficient catalyst for sensitive chemiluminescence-based analyses. The success of this work favors to facilitate the future development in CL catalysts via MOF functionalization. PMID- 30029359 TI - Temporal decomposition sampling and chemical characterization of eucalyptus harvest residues using NIR spectroscopy and chemometric methods. AB - Near-infrared (NIR) spectroscopy and chemometric methods were used to predict the chemical properties of decomposing eucalyptus harvest residues to better understand the decomposition process of these materials. Leaves, twigs, branches, and bark from a decomposition experimental set up in commercial plantations were sampled for one year. The contents of carbon (C), nitrogen (N), extractives (EX), acid-soluble lignin (SL), Klason insoluble lignin (KL) and holocellulose (HC) were determined by the reference method in the collected samples. Principal component analysis (PCA) was employed to distinguish the types of harvest residues throughout the decomposition period. Multi-residue regression models were built from the NIR spectra using partial least squares regression (PLS). Two feature selection methods, i.e., ordered predictors selection (OPS) and genetic algorithm (GA), were applied and compared. The OPS and GA did not differ statistically; however, compared with the GA, OPS was more computationally efficient and selected fewer variables. Using the PLS-OPS models, the root mean square errors of prediction (RMSEP) for C, N, EX, SL, KL and HC were 19.70, 0.08, 0.74, 0.39, 28.13 and 33.99, respectively, and the prediction correlations (Rp) for these properties were 0.94, 0.99, 0.99, 0.99, 0.96 and 0.98, respectively. PLS-discriminant analysis (PLS-DA) was used to classify the samples over the decomposition time and provided a good separation. Some mismatches obtained in the modeled classes were explained by the differences in the decomposition rate and changes in the chemical composition of the different harvest residue components that were evaluated. The results showed the feasibility of NIR spectroscopy and chemometric methods to evaluate the chemistry of decomposing eucalyptus harvest residues, indicating that these methods can be used as rapid and inexpensive alternatives to conventional methods to help understand the decomposition process. PMID- 30029360 TI - An integrated strategy to correlate aggregation state, structure and toxicity of Abeta 1-42 oligomers. AB - Despite great efforts, it is not known which oligomeric population of amyloid beta (Abeta) peptides is the main neurotoxic mediator in Alzheimer's disease. In vitro and in vivo experiments are challenging, mainly because of the high aggregation tendency of Abeta (in particular of Abeta 1-42 peptide), as well as because of the dynamic and non covalent nature of the prefibrillar aggregates. As a step forward in these studies, an analytical platform is here proposed for the identification and characterization of Abeta 1-42 oligomeric populations resulting from three different sample preparation protocols. To preserve the transient nature of aggregates, capillary electrophoresis is employed for monitoring the oligomerization process in solution until fibril precipitation, which is probed by transmission electron microscopy. Based on characterization studies by ultrafiltration and SDS-PAGE/Western Blot, we find that low molecular weight oligomers build up over time and form bigger aggregates (> dodecamers) and that the kinetics strongly depends on sample preparations. The use of phosphate buffer results to be more aggregating, since trimers are the smallest species found in solution, whereas monomers and dimers are obtained by solubilizing Abeta 1-42 in a basic mixture. For the first time, attenuated total reflection-Fourier transform infrared spectroscopy is used to assign secondary structure to the separated oligomers. Random coil and/or alpha-helix are most abundant in smaller species, whereas beta-sheet is the predominant conformation in bigger aggregates, which in turn are demonstrated to be responsible for Abeta 1-42 toxicity. PMID- 30029361 TI - A lipid droplet-targeted fluorescence probe for visualizing exogenous copper (II) based on LLCT and LMCT. AB - A simple and sensitive probe, pyridine-based Schiff base (PBSB), is prepared based on the previous studies, which shows a rapid response to copper (II) through a fluorescence enhancement process. On association with copper (II), PBSB immediately presents a large red-shift (130 nm) in emission spectrum simultaneously accompanying with increasing emission intensity. The mechanism and binding sites of PBSB detecting copper (II) have been established by theoretical calculations and 1HNMR study, respectively. More importantly, in the complex biological system, PBSB having an excellent membrane permeability and a great photostability can visualize copper (II) in lipid droplet by bio-imaging, which display so great promising advantages in the issues causing by disorder of copper ions that could be convenient for prevention and control problems with human health and complex bio-system. PMID- 30029362 TI - Imidazolium ionic liquids as dynamic and covalent modifiers of electrophoretic systems for determination of catecholamines. AB - The subject of this study is comparison of imidazolium based dynamic and covalent coatings of the quartz capillary wall on the example of catecholamines determination. A way of synthesis of covalent coatings was proposed. For the first time different type of on-line sample preconcentration techniques (field amplified sample stacking (FASS), head-column field amplified sample stacking (HC FASS), electrostacking, sweeping) were performed for catecholamines determination in N-alkylsubstituted imidazolium coated capillary. It was found that long chain imidazolium ionic liquids (C12MImCl and C16MImCl) in background electrolyte content create a dynamic coating of the quartz capillary walls and generate anode electroosmotic flow. Same is true for covalent coatings based on N alkylsubstituted imidazolium. Both coatings prevent sorption of catecholamines on the internal surface of the quartz capillary. As a result efficiency and peak symmetry are increased. The maximum stacking efficiency factor (SEF) values for dynamic coatings were in range of 70-85, and limits of detection (LODs) were about 0.05 ug/ml under sweeping condition (micelle forming agent - C16MImCl) when the electric conductivity of sample matrix was higher than electric conductivity of BGE. In case of covalent coating, the maximum SEF values were higher than 1000, and LODs were about 1-2 ng/ml under sweeping condition (micelle forming agent - sodium dodecyl sulphate) in combination with electrostacking. PMID- 30029363 TI - Using standard additions to improve extraction and quantification of inositol hexakisphosphate in sediment samples by ion chromatography electrospray ionization mass spectrometry. AB - Several key aspects for the analysis of inositol hexakisphosphate (InsP6) have been investigated in order to establish a suitable method for the study of sediment samples from different aquatic systems. Apparent matrix effects for the ion chromatography electrospray ionization tandem mass spectrometric detection (IC-ESI-MS/MS) method were accounted for with a standard addition approach, which also compensated for variation in extraction efficiency. Several parameters of the extraction method were optimized to improve the extraction efficiency for different sediment types. We observed an improvement in the extraction efficiency between 18% and 720%. Finally, the method was used to gain first insights into the relevance of InsP6 in two aquatic systems located at the German Baltic coastal area. InsP6 was detected in several sediment samples with concentrations between 2.3 and 15.2 ug InsP6-P/g dry weight (DW). PMID- 30029364 TI - Laser-induced breakdown spectroscopy determination of K in biochar-based fertilizers in the presence of easily ionizable element. AB - Laser-induced breakdown spectroscopy is an optical emission technique quite suitable for the analysis of recalcitrant materials as it eliminates complex procedures of sample preparation. However, for some simple LIBS instrumentation the detection limits are still higher compared to those of consolidated spectroscopic techniques. The aim of the present work was to develop a method for the determination of K in new biochar-based fertilizer samples using a simple single pulse LIBS arrangement. Due to the low K detectability, which made impossible to obtain calibration curves, an exploratory qualitative study was performed aiming to evaluate the influence of the addition of easily ionizable elements (EIE) on the sensitivity. To this aim different salts containing EIE (K, Li and Na) and other cations (Cu and Mg) have been evaluated. Results obtained showed that salts containing EIE cations increased the spectral emission signals of some elements in samples previously submitted to charring. In particular, the strategy of using Li+ was applied to the determination of K in biochar-based fertilizers. The addition of Li+ allowed to develop an analytical method for K determination featuring a linear dynamic range from 0.8% to 21.56% K, and limits of detection and quantification of 0.2% and 0.8%, respectively. PMID- 30029365 TI - Intrinsically fluorescent and highly functionalized polymer nanoparticles as probes for the detection of zinc and pyrophosphate ions in rabbit serum samples. AB - Intrinsically fluorescent polymer nanoparticles (F-PNPs) were synthetized from 2 hydroxy-5-methylisophthalaldehyde and melamine by solvothermal method. F-PNPs can emit strong yellow green fluorescence at 542 nm without the conjugation to any external fluorescent agent and surface modification. Owing to the abundant amino and hydroxyl groups on their surface, the F-PNPs possess multiple binding sites, good biocompatibility and excellent water-solubility. Addition of Zn2+ to the F PNPs solution resulted in a blue shift (Deltalambda=40 nm) with obvious enhancement in the fluorescence intensity at 502 nm; while there was negligible change in the presence of other metal ions. The subsequent treatment with pyrophosphate (PPi) can cause fluorescence recovery of F-PNPs by pulling the Zn2+ out of the coordination cavity of F-PNPs-Zn2+ nanocomposites. No interference was observed from other anions and nucleotides, making the F-PNPs-Zn2+ ensembles highly sensitive and selective nanoprobes for PPi. The detection limit is 2.75 * 10-8 M/L and 7.63 * 10-8 M/L for Zn2+ and PPi, respectively. The proposed nanoprobes were then used for detecting the recovery of Zn2+ and PPi in rabbit serum samples, which were found to be 99.4-104.2% and 98.6-104.7%, respectively. The present strategy for the fabrication of nanoparticles may offer a new sight for the preparation of polymer nanostructures. The F-FNPs based probes can provide an accurate method for the detection of Zn2+ and PPi in serum samples. PMID- 30029366 TI - Biomethylation metabolism study of arsenite in SCC-7 cells by reversed phase ion pair high performance liquid chromatography-inductively coupled plasma-mass spectrometry. AB - Arsenite (As(III)) has been considered as a human carcinogen associated with many human cancers especially skin cancer. Elucidation of the transformed species of As(III) during its metabolism in cells is beneficial for evaluation of its bioeffect. In this work, a hyphenated method of reversed phase ion pair high performance liquid chromatography - inductively coupled plasma mass spectrometry (RP-IP-HPLC-ICP-MS) equipped with collision/reaction cell technology (CCT) was developed for speciation of As(III) and its metabolites (arsenate [As(V)], monomethylarsonic acid [MMA(V)], and dimethylarsinic acid [DMA(V)]) in SCC-7 cells. The developed analytical method exhibits low limits of detection for interest arsenic species in the range of 14-27 ng/L and wide linear range up to four orders of magnitude, providing a sensitive tool for arsenic metabolites analysis and further understanding the metabolism of As(III) in SCC-7 cells. The effect of exposure time, exposure concentrations and elimination time on the arsenic species and total arsenic in SCC-7 cells incubated by As(III) were systematically studied. At low exposure concentrations (< 5 MUM), large proportion of intracellular As(III) transformed to methylated metabolites, and the final methylated metabolite DMA(V), which could not be completely removed from the cells in the elimination process, is considered to play as the primary carcinogen. While at high exposure concentrations (> 5 MUM), most of intracellular As(III) probably bound to biomacromolecules rather than followed biomethylation process, exhibiting different metabolism. PMID- 30029367 TI - Highly selective detection of spermine in human urine via a nanometal surface energy transfer platform. AB - As an important biomarker of malignant tumors, spermine is closely related with some diseases. In this work, a nanometal surface energy transfer (NSET) strategy via the positively charged gold nanorods (AuNRs) and the negatively charged tetrakis (4-sulfonatophenyl) porphyrin (TPPS4) was developed to detect spermine in human urine. Under acidic condition, spermine possessed multi-cationic property and a strong affinity towards the anionic phosphate backbone of calf thymus DNA (ctDNA) by electrostatic attraction as well as the groove binding, which enabled to regulate the process of NSET between AuNRs and TPPS4, leading to the fluorescence quenching of TPPS4. Moreover, the quenched fluorescence was proportional to the concentration of spermine, which was applicable to monitor the level of spermine in human urine in the concentration range of 0.5-7.5 MUM. The NSET platform for spemine is simple, selective and time-saving, which has great significance in early cancer diagnosis. PMID- 30029368 TI - Fabrication of a novel and high-performance amperometric sensor for highly sensitive determination of ochratoxin A in juice samples. AB - In the present study, I fabricated a novel amperometric sensor based on step-by step modification of the bare glassy carbon electrode (GCE) by graphene multiwalled carbon nanotubes-chitosan-ionic liquid (Gr-MWCNTs-Ch-IL)/collagen-IL (CG-IL)/NiO nanoparticles (NiO NPs) for ultrasensitive determination of ochratoxin A (OTA) in juice samples. CG has a lot of oxygen and nitrogen atoms which enable it to have good affinity to metal oxide for stabilizing metal oxide NPs and avoiding their aggregation. The modifications applied to the bare GCE to construct the OTA sensor were characterized by electrochemical and microscopic methods. Then, the sensor was electroanalytically characterized by amperometric method towards OTA determination in synthetic samples and our records confirmed that the sensor was able to ultrasensitive determination of OTA in a concentration range of 0.01-10 nM with a limit of detection of 0.5 * 10-11 M and a sensitivity of 36.4 MUA nM-1. Finally, the sensor was successfully applied to determination of OTA in three different grape juice samples. The results of this study introduced a low-cost, sensitive, selective, fast, repeatable and reproducible OTA sensor which can be applied to the routine analysis of real samples towards OTA determination. PMID- 30029369 TI - Label-free and enzyme-free fluorescent isocarbophos aptasensor based on MWCNTs and G-quadruplex. AB - A novel label-free and enzyme-free detection strategy has been developed for the fluorescent detection of isocarbophos (ICP) using multi-walled carbon nanotubes (MWCNTs) and G-quadruplex as the signal transducers. In this work, the split ICP aptamer were attached to a G-quadruplex motif at their respective terminals. In the presence of ICP, the split aptamers could undergo conformational change into a sandwiched-like ternary complex, which prevent them from adsorbing to the MWCNTs due to the increased steric hindrance. As a result, the fluorescence signal of the G-quadruplex probes N-methyl mesoporphyrin IX (NMM) was enhanced significantly. In the absence of ICP, the split aptamer only existed in the form of single-stranded DNA, which could be easily adsorbed by MWCNTs and resulted in a quenched fluorescence signal of NMM. The proposed strategy could selectively and sensitively detect ICP with a detection limit of 10 nM. Furthermore, we have also demonstrated the capability of this strategy in the detection of ICP in real samples from vegetable extract, indicating the potential application of this strategy in food safety issues. PMID- 30029370 TI - Classification analyses for prostate cancer, benign prostate hyperplasia and healthy subjects by SERS-based immunoassay of multiple tumour markers. AB - Prostate cancer (PCa) is a leading cause of cancer-related death among males globally. To date, prostate-specific antigen (PSA), as a typical tumour marker, has been widely used in the early diagnosis of PCa. However, in practical clinical tests, high serum levels of PSA show a high probability for false positive results, leading to misdiagnoses. In this study, we developed a new classification system for PCa, benign prostate hyperplasia (BPH) and healthy subjects by using a surface-enhanced Raman scattering (SERS)-based immunoassay of multiple tumour markers along with a support vector machine (SVM) algorithm. Silver nanoparticles (AgNPs) as immune probes and SiC@Ag@Ag-NPs SERS as immune substrates were constructed into a sandwich structure to serve as an ultrasensitive SERS-based immunoassay platform of tumour markers. With this assay, the limits of detection for PSA, prostate-specific membrane antigen (PSMA) and human kallikrein 2 (hK2) were as low as 0.46 fg mL-1, 1.05 fg mL-1 and 0.67 fg mL-1, respectively. Furthermore, the serum levels of PSA, PSMA and hK2 in clinical samples were successfully detected using the SERS-based immunoassay platform, and correct classifications of PCa, BPH and healthy subjects were feasible with help of the linear SVM algorithm. These results demonstrate the potential for improving the diagnostic accuracy of PCa. Overall, the linear SVM classification model with multiple tumour markers exhibited good classifications of PCa, BPH and healthy subjects, with a PCa diagnostic accuracy of 70% that was significantly superior to that of the linear SVM classification model based only on the serum level of PSA (50%). Therefore, combining the SERS-based immunoassay with pattern recognition technology can allow for comprehensive analyses of the serum levels of multiple tumour markers to effectively improve the diagnostic accuracy of cancer with potential applications in point-of-care testing. PMID- 30029371 TI - Preparation, performance, and application of a stable, sensitive and cost effective microelectrode array. AB - The development of rapid toxicity detection technology has higher requirements for electrode. In this work, a stable, sensitive and cost-effective microelectrode array (MEA) was successfully prepared manually. The advantage of the as-prepared MEA was discussed by means of detecting toxicity of 3,5 Dichlorophenol (3,5-DCP) by contrasting with bulk electrode and single microelectrode, in which mixed microorganisms were selected as biocatalyst, and K3[Fe(CN)6] was adopted as electron mediator. The current reached a stable state in 10 s under the constant potential of 450 mV. The feasibility of rapid detection of toxicity of formaldehyde with the MEA was further verified. The current responses were analyzed over formaldehyde of the final concentrations varied from 0.0036% to 1.0%, and the traditional parameter of 50% inhibitory concentration (IC50) of 0.11% was obtained within 1 h. In brief, the as-prepared MEA has high sensitivity, good stability, strong anti-interference, and well corrosion resistance. It shows a very large application prospects in toxicity detection in water. PMID- 30029372 TI - Simultaneous determination of preservatives and synthetic dyes in cosmetics by single-step vortex extraction and clean-up followed by liquid chromatography coupled to tandem mass spectrometry. AB - A simple methodology based on vortex extraction (VE) followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed for the simultaneous analysis of 22 regulated preservatives and synthetic dyes in cosmetics. The extraction procedure was performed in an Eppendorf tube allowing both extraction and clean-up in a single step, reducing sample and reagents consumption, and resulting in an effective and quick extraction. The method exhibited good linearity (R2 >= 0.9918) and intra and inter-day precision (%RSD <= 13) with LOQs lower than 0.587 ug g-1 for preservatives and 3.437 ug g-1 for synthetic dyes. Quantitative recoveries were obtained at four concentration levels in the range 2-100 ug g-1 in the cosmetic matrices. The method was successfully applied to a broad range of cosmetics, including both leave-on and rinse-off products in which 13 of the target compounds could be quantified at concentrations ranging from 0.39 to 442 ug g-1 in the case of dyes, and from 1.89 to 1335 ug g-1 for the preservatives. It can be highlighted the presence of parabens in 24 out of the 35 analyzed samples at concentrations higher than 1000 ug g-1 in a toothpaste. PMID- 30029373 TI - Cancer cell specific fluorescent methionine protected gold nanoclusters for in vitro cell imaging studies. AB - Benefiting from the excellent photostability and biocompatibility, fluorescent nanoclusters have recently emerged as a highly attractive bio-sensing and imaging material, especially in early diagnosis of cancer. However, their clinic applications were limited by the unsatisfactory specificity and the complex synthesis. In this study, novel methionine coated gold nanoclusters (Met-AuNCs) have been prepared via an easily-achievable one-pot synthetic method. The prepared Met-AuNCs showed high imaging-specificity: after incubating with Met AuNCs for 1 h, cancer cells (including A549, Hela, MCF-7, HepG2) were fluorescent, while the normal cells (WI-38 and CHO) showed no fluorescence. According to a series of controlled experiments, the reason for the high imaging selectivity was proposed to originate from the specific recognition of L-type amino acid transporter overexpressed in cancer cells. PMID- 30029374 TI - A highly sensitive colorimetric probe for Cd2+, Hg2+ and ascorbic acid determination based on trithiocyanuric acid-AuNPs. AB - A highly sensitive and selective colorimetric assay is proposed for the detection of mercury ions (Hg2+), cadmium ions (Cd2+) and ascorbic acid (AA) using trithiocyanuric acid (TMT) functionalized gold nanoparticles (TMT-AuNPs). TMT AuNPs are dispersed in 40 mM NaCl solution, while the presence of Hg2+ and Cd2+ can induce TMT-AuNPs aggregate due to the strong interaction of Hg2+ and Cd2+ with TMT. Then the quantitative detection of Hg2+ and Cd2+can be realized in the linear range from 5 * 10-9 to 1 * 10-6 M and 1 * 10-8 to 3 * 10-7 M, with a lower detection limit of 2.8 nM for Hg2+ and 3.5 nM for Cd2+ (S/N = 3), respectively. To distinguish Hg2+ from Cd2+, a reductive biological small molecule ascorbic acid (AA) was used based on the different redox interaction of AA with Hg2+ and Cd2+. When the mixture of AA and Hg2+ was added into TMT-AuNPs solution, the state of TMT-AuNPs was still dispersed because Hg2+ was reduced by AA. On the contrary, when the mixture of AA and Cd2+ was added into TMT-AuNPs solution, the TMT-AuNPs was aggregated and the color of the solution has no obvious change compared to the system of Cd2+-TMT-AuNPs since the weak interaction between AA and Cd2+. Thus, AA could be detected. A linear correlation exists between the ratio of A640/A520 and the concentration of AA in the range from 1 * 10-8 to 1 * 10-6 M with a detection limit of 4.8 nM (S/N = 3). Importantly, it has been successfully applied to determine Hg2+, Cd2+ in lake water and AA in vitamins C tablet. PMID- 30029375 TI - Single polydiacetylene microtube waveguide platform for discriminating microRNA 215 expression levels in clinical gastric cancerous, paracancerous and normal tissues. AB - MicroRNAs (miRNAs) have emerged as novel biomarkers for human early-phase cancer diagnosis and disease prevention recently. Herein, we reported a novel miRNA-215 targeting biosensor, which was based on single polydiacetylene (PDA) microtube waveguide system integrated with sandwich-type hybridization design and condensing enrichment effect. The target miRNA could be captured by oligonucleotides conjugated on the surface of PDA microtube and Au nanorod (AuNR) respectively, resulting in the out-coupled fluorescence of PDA microtube quenching. In this strategy, the formation of a sandwich structure, as a result of co-hybridization of the target miRNA, enabled simplified preparation process, enhanced reaction efficiency, and increased recyclability and stability of the platform. Based on condensing enrichment effect, the co-hybridization reaction could be enriched on the surface of microtube and the proposed platform could easily achieve highly sensitive detection of miRNA-215 in one step. Remarkably, this platform could be directly applied to discriminate the miRNA-215 expression levels in clinical gastric cancerous, paracancerous and normal tissues samples. This assay offers a simple and convenient method for miRNA quantification in clinical samples, even with the potential for invasive, portable equipment for early clinical diagnosis of diseases. PMID- 30029376 TI - Analysis of children modelling clay (toy) using inductively coupled plasma-based methods. AB - This work proposes the application of a Doehlert design to optimize dilute HNO3 and H2O2 concentrations employed for the digestion of samples of modelling clay for children (used as toy). Inductively coupled plasma-based (ICP) methods were employed to determine 22 inorganic constituents (Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, S, Sb, Se, Sr, V and Zn) in children's modelling clay samples. The limits of quantification (LoQ) obtained were between 0.003 mg kg-1 (Cd, Co and Sb) and 0.54 g kg-1(Ca) employing ICP-based methods. The accuracy and precision of the methods were evaluated by analysing the certified reference materials (CRMs) oyster tissue (NIST 1566b), rice flour (NIST 1568b), peach leaves (NIST 1547) and tomato leaves (NIST 1573a), along with addition and recovery tests. The children's modelling clay samples presented concentrations of As, Ba, Cd, Cr, Pb, Sb and Se in agreement with the maximum values established by National Institute of Metrology, Quality and Technology (Instituto Nacional de Metrologia, Qualidade e Tecnologia - INMETRO). However, for other elements it were obtained concentrations within the following ranges: Al (0.83 +/- 0.12-2.91 +/- 0.04 g kg-1), Ca (16.09 +/- 0.20-24.56 +/- 1.00 g kg-1), Cu (< 0.30-30.01 +/- 2.11 mg kg-1), Fe (< 5.3 - 13.21 +/- 3.94 mg kg-1), K (1.31 +/- 0.33-33.47 +/- 0.75 g kg-1), Mg (0.90 +/- 0.04-1.36 +/- 0.05 g kg-1), Mn (3.32 +/- 0.10-121.05 +/- 1.88 mg kg-1), Na (12.07 +/- 0.88-36.77 +/- 0.50 g kg-1), Sr (4.23 +/- 0.47 22.43 +/- 6.95 mg kg-1), P (1.00 +/- 0.13-57.43 +/- 0.88 g kg-1), V (0.25 +/- 0.07-1.15 +/- 0.19 mg kg-1), S (3.57 +/- 0.77-48.49 +/- 1.02 g kg-1), Zn (< 4.4 11.82 +/- 0.49 mg kg-1), Co (0.020 +/- 0.002-0.060 +/- 0.020 mg kg-1) and Ni (< 0.03-1.33 +/- 0.46 mg kg-1). These elements have no minimum and maximum limits established by legislation for children's modelling clay so, a comparison was not possible. The ICP-based methods presented an efficient routine application in the analysis of modelling clay. PMID- 30029377 TI - Oriented growth of cross-linked metal-organic framework film on graphene surface for non-enzymatic electrochemical sensor of hydrogen peroxide in disinfectant. AB - High-density and cross-linked copper-based metal-organic framework (Cu-MOF) sheets were successfully prepared via a simple oriented growth method on a carboxylated graphene-modified electrode surface. Hydrogen peroxide (H2O2) was selected as a model molecule to examine the performance of the thin film of Cu MOF/graphene. The proposed sensor showed an extended linear detection range from 2.00 * 10-7 to 1.85 * 10-4 mol L-1 (R = 0.998), a high sensitivity of 0.792 A (mol L-1)-1, and a low detection limit of 6.7 * 10-8 mol L-1, due to the synergistic catalysis from the porous structure and favorable electron transfer mediating function of the electroactive Cu-MOFs and the high conductive property of the graphene. The reduction peak current of H2O2 changed less than 3.7% in the presence of 57-fold high concentrations (2.0 * 10-4 mol L-1) of the potential interfering species. The good selectivity of the prepared modified electrode was acquired by the size exclusion (molecular sieving) for H2O2 because of the proper pore shape and pore size of Cu-MOFs. The feasibility of the assay was verified by test of H2O2 in disinfectant samples. The proposed strategy presents valuable information related to the construction of non-enzymatic electrochemical sensors. PMID- 30029379 TI - Method development and validation for total mercury determination in coke oven gas combining a trap sampling method with CVAAS detection. AB - Coke oven gas is one of the by-products of the coal coking process. It is used as a fuel in the coking plant, but also as a raw material in the chemical industry to produce methanol, syngas or environment-friendly, low-CO2 hydrogen fuel. Due to the reasons mentioned above, the knowledge of coke oven gas pollutants such as mercury is a key issue. To determine the mercury in the cleaned coke oven gas a trap sampling method combined with CVAAS mercury detection was developed, optimized and validated. In order to perform the sampling process the traps filled with activated carbon were used. The determination of mercury in the traps material was performed by means of an MA-2 mercury analyzer. During the optimization of the method one selected the trap material, sample volume and flow rate. The optimal volume of the coke oven gas sample was 3 dm3 and the flow rate was 18 dm3/h (per one trap). The developed method was validated according to the Eurachem recommendation and was applied to determine mercury in the clean coke oven gas. The coke oven gas sampling was performed in a coking plant in Poland. The average concentration of mercury in the clean coke oven gas was 3.2 +/- 0.3 MUg/m3N (k = 2) for n = 18. PMID- 30029378 TI - Rapid quantification of honey adulteration by visible-near infrared spectroscopy combined with chemometrics. AB - Honey is a pure product for which the addition of any other substance is prohibited by international regulations. Therefore, it is necessary to develop reliable analytical methods to guarantee its authenticity. Visible-near infrared spectroscopy (Vis-NIRS) combined with chemometric tools, like hierarchical cluster analysis (HCA), principal component analysis (PCA), linear discriminant analysis (LDA), has been used for the discrimination of honey adulterated with high fructose corn syrup (HFCS). Different honey samples from the Granada Protected Designation of Origin (Spain) were adulterated with HFCS at different percentages (10 - 90%). LDA was able to discriminate 100% of the samples. Partial least squares regression (PLS) was used to predict the level of adulteration. The best prediction model used 10 factors with a high coefficient of determination near 1. The developed method showed high precision (coefficient of variation below 4%). Vis-NIRS combined with chemometrics can be used for the rapid and non destructive detection of honey adulteration. The obtained results demonstrate that the application of this technique as a screening method could be a useful tool for quality monitoring analysis in routine laboratories. PMID- 30029380 TI - Phenanthrene metabolites determination in human breast and cow milk by combining elution time-emission fluorescence data with multiway calibration. AB - Phenanthrene is the most released polycyclic aromatic hydrocarbon into the environment by anthropogenic action. Because of the absorption and biotransformation pathways, this compound is metabolized and the most abundant metabolites are hydroxylated derivatives, such as 1-, 2-, 3-, 4- and 9 hydroxyphenanthrene, which are excreted through biological fluids, included mammals milk. For the resolution and quantitation of co-eluted analytes, elution time-emission fluorescence matrices were analysed with different second-order calibration algorithms: n-way and unfolded partial least squares, both coupled with residual bilinearization (N-PLS/RBL and U-PLS/RBL), and multivariate curve resolution-alternative least squares (MCR-ALS). Once optimized the chromatographic parameters, in isocratic mode, the elution time was of 5.5 min. The second-order data were obtained exciting at 250 nm, with an emission range from 330 to 430 nm, each 1 nm, and elution time from 0 to 5.5 min each 5.4 s. The ranges for the second-order multivariate methods in validation samples were from 1.0 to 9.0 ng mL-1 for 1-, 2-, 3- and 4-hydroxyphenanthrene, and from 5.0 to 45.0 ng mL-1 for 9-hydroxyphenanthrene. Root mean square errors of prediction between 0.45 and 1.82 ng mL-1 (relative errors of prediction 7-22%) were obtained. The optimized procedures were applied in the analysis of human breast milk and in whole and semi-skimmed commercial cow milk. N-PLS/RBL and U-PLS/RBL algorithms show satisfactory results for the five metabolites with recoveries ranging between 82% and 115%. PMID- 30029381 TI - Dual-frequency ultrasound assisted-enzyme digestion coupled with atomic fluorescence spectrometry as a green and efficient tool for cadmium detection in rice flour samples. AB - A sample treatment technique based on a duel frequency ultrasonic device for enzymatic digestion of rice is reported. The ultrasonic device combines a high intensity ultrasonic probe and the temperature control function of ultrasonic water bath, which can effectively extract cadmium from rice within only 160 s under the optimized conditions. Compared with the traditional ultrasonic assisted enzymatic digestion, the new method not only shortens the time significantly (e.g., from the 90 min of ultrasonic water bath to the present few minutes), but also increases the extraction efficiency of cadmium (such as ~ 75% from ultrasonic probe to app. 100%). Through the optimization of ultrasonic mode, ultrasonic frequency, power and the type of enzyme, we found that enzyme played a dominant role in ultrasound assisted enzymatic digestion. Compared with a-amylase and pepsin, trypsin is more suitable for the extraction of cadmium from rice. Furthermore, ultrasound energy is beneficial to enzymatic hydrolysis of bimolecular, and this promotion is related to the frequency of ultrasound. The reliability of this method was evaluated by analyzing the content of cadmium in the certified reference materials (CRMs, GBW10045, GBW08510, GBW08511 and GBW08512) based on atomic fluorescence spectrometry combined with a modified chemical vapor generation. The proposed method has been applied satisfactorily in the determination of Cd in several rice samples. PMID- 30029382 TI - A photostable fluorescent probe for long-time imagining of lysosome in cell and nematode. AB - Lysosome fluorescent imaging has been widely used in the field of biological staining and diagnostics, which plays a key role in understanding intracellular metabolism and various physiological processes. However, for most currently used small-molecule lysotrackers, the photostability is often unsatisfactory when used for long-term and real-time visualization of lysosomal dynamics. Herein, we reported a new lysosome-targetable photostable fluorescent probe (i.e. MPL-NPA), and results showed that MPL-NAP possesses superior photostability, appreciable tolerance to pH change, low cytotoxicity and high lysosome targeting ability. These findings confirm that MPL-NAP is a well-suited imaging agent for targeting lysosome and enables long-term and real-time monitor of lysosome morphological changes under physiological processes. PMID- 30029383 TI - Detection of multiple organisms based on the distance-dependent optical properties of gold nanoparticle and dark-field microscopy. AB - Owing to their unique physical and chemical properties like stability, non-toxic, biocompatibility and feasible to modification with various biomolecules, gold nanoparticle has become a versatile nanomaterial in the field of therapeutic, diagnostic and analytical studies. Various surface plasmon resonance based pathogen detection systems, relying on change in colour, have been proposed. However, all the approaches developed so far were designed for the detection of a single pathogen. In the present study, we have designed a new colorimetric approach based on distant-dependent properties of gold nanoparticle for the detection of multiple targets. A modified multiplex asymmetric PCR in which a universal primer amplifies the multiple targets with the same efficiency was performed. The Limit of detection (LOD) of the designed visual assay is 10 pg of Brucella and Leptospira target DNA and 100 pg of Bovine herpes virus-1 (BoHV-1) target DNA. LOD of 0.5 pg, 0.7 pg and 3.8 pg for Brucella, Leptospira and BoHV-1 respectively was obtained spectrophotometrically. A study on dark field microscopy as a qualitative supporting detection system has also been presented in this study. The designed assay has advantages over earlier reports in terms of multiple organisms detection, specificity and sensitivity of the test. PMID- 30029385 TI - Sensitive nonenzymatic detection of hydrogen peroxide at nitrogen-doped graphene supported-CoFe nanoparticles. AB - In this work, a new enzymeless sensor for hydrogen peroxide (H2O2) was constructed by supporting CoFe nanoparticles on the nitrogen-doped graphene (CoFe/NGR). In this preparation, the graphene oxide (GO) is first used as substrate for the growth of CoFe layered double hydroxides (CoFe LDHs) through hydrothermal reaction. Then, the pyrolysis of CoFe LDHs/GO under NH3 produces CoFe/NGR. By supporting CoFe nanoparticles on NGR support, the electrocatalytic performance of CoFe is dramatically improved because of high electric conductivity of NGR. Consequently, the combination of CoFe and NGR allows the nonenzymatic detection of H2O2. Compared with the unsupported CoFe nanoparticles, the CoFe/NGR displays high electrocatalytic activity towards H2O2, enabling a high sensitivity of 435.7 MUA mM-1 cm-2 and low detection limit of 0.28 MUM towards the reduction of H2O2. Especially, the attractive feature of low cost and outstanding analytical performance of CoFe/NGR suggest it great potential in electrochemical sensor and biosensor fabrication. PMID- 30029384 TI - Polyoxometalates as promising enzyme mimics for the sensitive detection of hydrogen peroxide by fluorometric method. AB - Polyoxometalates (POMs) have been proven to possess intrinsic peroxidase-like activity. However, by far, most of POMs with intrinsic peroxidase-like activity are stable at acid aqueous. Herein, we firstly utilized Na10[alpha-SiW9O34] with the peroxidase-like property in basic pH condition to build a CdTe quantum dots (QDs)-based fluorometric method for detection of hydrogen peroxide. In the CdTe QDs stable pH value, Na10[alpha-SiW9O34] can catalyze the decomposition of H2O2 into.OH radicals that could efficiently quench the fluorescence of CdTe QDs. The limit of detection in this system were 3.8 nmol/L. The RSD of detection were range from 0.88% to 2.78%. And the linear range of H2O2 is from 7.8 * 10-9 to 2.5 * 10-7 mol/L. The rate of recovery of sample addition was between 93.99% and 110.02%. The results not only built a simple, sensitive and easy handing assay but also enlarge the POMs' analytic application field. PMID- 30029386 TI - Computer vision-based analytical chemistry applied to determining iron in commercial pharmaceutical formulations. AB - Two different computer vision-based analytical chemistry (CVAC) methods were developed to quantify iron in the commercial pharmaceutical formulations Ferbisol(r) and Ferro sanol(r). The methods involve using a digital camera or a desktop scanner to capture a digital image of a series of Fe2+ standard solutions and the unknown sample upon reaction with o-phenanthroline. The images are processed with appropriate software (e.g., the public domain programme ImageJ, from NIH) to obtain a numerical value (analytical signal) based on colour intensity. The fact that such a value is proportional to the analyte concentration allows one to construct a calibration graph from the standards and interpolate the value for the sample in order to determine its concentration. The results thus obtained were compared with those provided by a spectrophotometric method and the US Pharmacopoeia's recommended method. The differences never exceeded 2%. The two proposed methods are simple and inexpensive; also, they provide an effective instrumental alternative to spectrophotometric methods which can be especially beneficial in those cases where purchasing and maintaining a spectrophotometer is unaffordable. PMID- 30029387 TI - Green synthesis of luminescent graphitic carbon nitride quantum dots from human urine and its bioimaging application. AB - A hydrothermal synthetic approach is developed for the preparation of graphitic carbon nitride quantum dots (g-C3N4 QDs) from human urine. The reported synthetic method is green, simple, low-cost, less time-consuming, and can be used for the large-scale production of the g-C3N4 QDs. The as-prepared g-C3N4 QDs possess a high quantum yield of 15.7% by using quinine sulfate as a reference, and display excitation-wavelength dependent fluorescent emission. In addition, the g-C3N4 QDs exhibit high photostability, low cytotoxicity. and are successfully used as fluorescent probes for cell multicolor imaging. It is believed that the valuable nanomaterials, g-C3N4 QDs, which are transformed from the human bodily wastes, are promising in diverse chemical applications. PMID- 30029388 TI - Colorimetric hydrogen gas sensor based on PdO/metal oxides hybrid nanoparticles. AB - We have synthesized new colorimetric hydrogen-sensing materials, PdO/metal oxide hybrid nanoparticles, in which palladium oxide was loaded upon surface of substrate materials via an acid-base reaction between a H2PdCl4 solution and substrate materials, ZnO, MgO, TiO2, and SiO2 respectively at 25 degrees C. The colorimetric hydrogen gas sensing properties of all the samples, PdO/ZnO, PdO/MgO, PdO/TiO2 and PdO/SiO2, were characterized and compared in order to investigate how hydrogen gas sensitivity would be affected by surface property of substrate materials. It was confirmed that the amount of the loaded PdO, which was thought to be closely related with the colorimetric hydrogen sensitivity, was quite different according to the substrate materials and was increased with increasing of the basicity of substrate materials (ZnO > MgO > TiO2 > SiO2). Consequently, among the PdO/metal oxide hybrid nanoparticles, the largest amount of PdO was observed to be loaded on ZnO substrate nanoparticles due to its highest basicity. The best colorimetric hydrogen gas sensing properties (color difference, DeltaE = 71.57) was observed in PdO/ZnO hybrid nanoparticles, showing the most prominent color change from brown to black, when the sample was exposed to hydrogen gas of 4 vol% balanced with nitrogen for 2 min. PMID- 30029390 TI - A multifunctional two-photon fluorescent probe for detecting H2S in wastewater and GSH in vivo. AB - A novel turn-on fluorescent probe, which coumarin-fused coumarin was used as fluorophore to link with 2, 4- dinitrodiphenyl ether moiety that has high selectivity and sensitivity for H2S and thiols, was designed and synthesized. Our probe YB can sensitively react with H2S and GSH to release free fluorophore with strong fluorescence signals. The probe YB could use as a significant molecular imaging tool to study the endogenous GSH in living cell and a practical detector for H2S in the papermaking wastewater. PMID- 30029389 TI - Solvation characteristics of porous graphitic carbon Hypercarb in subcritical water chromatography. AB - Retention of 17 organic compounds was studied in high-temperature liquid chromatography mode on Hypercarb porous graphitic carbon with subcritical water as an eluent. Three different eluent temperatures were studied: 150, 175 and 200 degrees C. Abraham solvation parameters model was used for quantitative evaluation of retention data. It was found that increase of eluent temperature from 150 to 200 degrees C results in decrease of cavity formation system parameter v from 2.9 to 1.7. No clear tendency can be observed for temperature dependency of other system parameters. PMID- 30029391 TI - Miniaturized point discharge-radical optical emission spectrometer: A multichannel optical detector for discriminant analysis of volatile organic sulfur compounds. AB - In this work, we proposed a miniaturized point discharge-radical optical emission spectrometer (PD-RES) as a multichannel optical detector for discriminant analysis of various volatile organic sulfur compounds (VOSCs). Under appropriate experimental conditions, the unique molecular emission of CS radical in the vicinity of 257.6 nm was recorded, as well as the atomic emission lines of C at 193.1 nm and 247.8 nm, the molecular emission of C2 radical around 231.5 nm and CN radical nearby 384.8 nm. They were utilized as five optical channels for precise qualification and discrimination. Linear discriminant analysis (LDA) and principal component analysis (PCA) further demonstrated the robustness of this detector for discriminant analysis: 95 unknown samples from ten typical VOSCs were classified with accuracy of 98.9%. This proposed detector was further successfully applied to the discrimination of different concentrations of CS2 in air samples and two types of isomers (functional group isomer and carbon-chain isomer). PMID- 30029392 TI - ZrO2 doped magnetic mesoporous polyimide for the efficient enrichment of phosphopeptides. AB - FexOy and ZrO2 nanoparticles co-doped layered porous polyimide, polyimide-FexOy ZrO2 is prepared with a one-step strategy, shortly termed as PI-FexOy-ZrO2. The layered and porous structure of the polymer offers a supported platform for metallic oxide anchoring, exhibiting a mesopore size of 3.93 nm and providing a surface area of 198.47 m2 g-1. The metallic oxides were uniformly and highly dispersed in the PI-FexOy-ZrO2 nanocomposite with percentages of 15.81 and 20.53 wt% for Fe and Zr, respectively. The magnetic FexOy provides driving force for rapid separation. The high doping of ZrO2 facilitates effective enrichment of phosphopeptides, even at a very low mass ratio of 1:1000 for tryptic digest of phosphopeptides/non-phosphopeptides, e.g., beta-casein/BSA in this particular case. In addition, the PI-FexOy-ZrO2 nanocomposite exhibits better adsorption performance to phosphopeptides with respect to commercial titanium dioxide nanoparticles. The effectiveness of low-abundant phosphopeptides isolation and enrichment from human serum is further identified and demonstrated by means of MALDI-TOF MS and LC-ESI-MS/MS. PMID- 30029393 TI - Simultaneous determination of the size and concentration of AgNPs in water samples by UV-vis spectrophotometry and chemometrics tools. AB - The combination of UV-vis spectrophotometry with a chemometric calibration tool based on partial least squares (PLS) has allowed us the development of a multivariate analytical method that simultaneously estimates the concentration and size of mixtures of silver nanoparticles (AgNPs) in environmental water samples. The method is based on changes in the surface plasmon resonance band (SPRB) of AgNPs when they form aggregated/assembled structures with L-cysteine (L cys). Measurementts were performed by employed a fixed-time kinetics method that implies that the final spectra (response) are obtained by subtstracting the solutions spectra at fixed times. Optimization of experimental conditions affecting aggregation such as time, temperature, pH and concentration of aggregating substance was performed by experimental design and response surface methodologies (RSM). A multivariate calibration model using AgNPs of known diameter size ((20 +/- 3), (41 +/- 3), (59 +/- 5) and (79 +/- 7) nm) within a concentration range between 0.62 and 2.5 mg L-1 was constructed by using a mixture experimental design and PLS. The method was finally applied to estimate size and concentration of AgNPs in AgNPs-spiked river and tap water samples. Water samples were spiked with individual, binary and ternary mixtures of AgNPs of different sizes and by using two types of AgNPs: citrate-coated AgNPs (cit AgNPs) and polyvinylpyrrolidone-coated AgNPs (PVP-AgNPs). A good correspondence was obtained between predicted values and the total amount of AgNPs added with recovery values ranged within 80-160% for the individual mixtures, 68-108% for the binary mixtures and 60-64% for the ternary mixtures of AgNPs. Finally, transmission electron microscopy (TEM) measurements were performed for those cases where discrepancies between the expected and the obtained values were observed. TEM micrographs evidenced the presence of agglomerates or aggregates of AgNPs in some of the mixtures or water tested. PMID- 30029394 TI - Near Infra-Red spectroscopy for content uniformity of powder blends - Focus on calibration set development, orthogonality transfer and robustness testing. AB - The aim of this work was to develop and validate a NIR method for the quantification of three active ingredients from powder blends. Calibration set formulations were selected based on a D-optimal experimental design with three factors (ibuprofen, paracetamol, caffeine) and five variation levels (80-90-100 110-120%). NIR spectra were recorded in transmittance mode using a rotating sample configuration. Prior to model development the effect of spectral pre processing was assessed by evaluating its impact over the transfer of orthogonality from concentration space to spectral space. NIR method was validated on the full calibration range with external prediction sets, using the accuracy profile approach. Robustness testing results showed that the accuracy of predictions for the analyte found in lower concentrations (caffeine) was influenced by relative humidity, while paracetamol/ibuprofen predictions were robust to all factors. Redefinition of interfering factor variation level was beneficial to reduce the bias in caffeine content predictions. Also, alternative solutions are provided for ensuring robustness and successful routine use. PMID- 30029395 TI - CO gas sensors based on p-type CuO nanotubes and CuO nanocubes: Morphology and surface structure effects on the sensing performance. AB - Metal oxide nanomaterials have been widely applied in the high-performance gas sensors. For metal oxide semiconductors, high surface-to-volume ratio and the exposed crystal facets are the two key factors for determining their gas sensing performances. In order to study the effect of surface structure on the gas sensing properties, in this work, two types of copper oxide (CuO) nanostructures, CuO nanotubes (CuO NTs) with exposed surface plane of (111) and CuO nanocubes (CuO NCs) with exposed surface plane of (110), were obtained from Cu nanowires (Cu NWs) and Cu2O nanocubes (Cu2O NCs), respectively. The morphologies, crystal and surface structures were characterized by high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The gas-sensing performances of CuO NTs and CuO NCs for CO gas detection were then studied. The results demonstrated that compared to CuO NCs, the CuO NTs exhibited lower optimum working temperature and higher sensitivity for CO gas detection. At the operating temperature of 175 degrees C, the prepared CuO NTs exhibited high sensitivity, good selectivity, fast response and recovery times to CO gas. The present study indicates that for the same semiconductor sensing material, the surface crystal structure has significant influence on the sensing performance. PMID- 30029396 TI - Multivalent aptasensor array and silver aggregated amplification for multiplex detection in microfluidic devices. AB - Herein, we developed a rapid and sensitive aptamers-based sandwich assay in microfluidic devices based on multivalent aptasensor array (MAA) chip and silver aggregated amplification (SAA) strategy for the detection of two biomarkers. Firstly, aptamers-modified silver nanoparticles were dotted in array to form MAA chip. Then PDMS was used to form a microfluidic device. After that, target proteins and two kinds of aptamer-modified silver nanoparticles (Tag-A and Tag-B) were rapidly injected into the microfluidic device. The aptamer on MAA chip recognized target, and the target also bound with Tag-A and Tag-B which could aggregate with each other to amplify fluorescence signal. Based on MAA chip and SAA strategy in microfluidic device, a linear response to PDGF-BB (r = 0.999) was obtained in the concentration range from 16 pg mL-1 to 250 ng mL-1, and the detection limit was 1.4 pg mL-1. In addition, a linear response to PDGF-BB (r = 0.992) was obtained in the concentration range from 16 pg mL-1 to 250 ng mL-1 in 10% blood serum with detection limit of 7.8 pg mL-1. Ultimately, this assay was used to simultaneously detect PDGF-BB and VEGF-165, and the results showed good specificity and sensitivity. This assay can also be expanded to sensitive and high-throughput detection of other protein biomarkers by coupling of various aptamers with nanoparticles. PMID- 30029397 TI - Class specific discrimination of volatile organic compounds using a quartz crystal microbalance based multisensor array. AB - The use of quartz crystal microbalance (QCM) sensor arrays for analyses of volatile organic compounds (VOC) has attracted significant interest in recent years. In this regard, a group of uniformed materials based on organic salts (GUMBOS) has proven to be promising recognition elements in QCM based sensor arrays due to diverse properties afforded by this class of tunable materials. Herein, we examine the application of four novel phthalocyanine based GUMBOS as recognition elements for VOC sensing using a QCM based multisensor array (MSA). These synthesized GUMBOS are composed of copper (II) phthalocyaninetetrasulfonate (CuPcS4) anions coupled with ammonium or phosphonium cations respectively (tetrabutylammonium (TBA), tetrabutylphosphonium (P4444), 3-(dodecyldimethyl ammonio)propanesulfonate (DDMA), and tributyl-n-octylphosphonium (P4448)). These materials were characterized using ESI-MS and FTIR, while thermal properties were investigated using TGA. Vapor sensing properties of these GUMBOS towards a set of common VOCs at three sample flow rate ratios were examined. Upon exposure to VOCs, each sensor generated analyte specific response patterns that were recorded and analyzed using principal component and discriminant analyses. Use of this MSA allowed discrimination of analytes into different functional group classes (alcohols, chlorohydrocarbons, aromatic hydrocarbons, and hydrocarbons) with 98.6% accuracy. Evaluation of these results provides further insight into the use of phthalocyanine GUMBOS as recognition elements for QCM-based MSAs for VOC discrimination. PMID- 30029398 TI - 1H HR-MAS NMR spectroscopy to study the metabolome of the protozoan parasite Giardia lamblia. AB - Knowledge of the metabolic profile and exchange processes in the protozoan parasite Giardia lamblia is of importance for a better understanding of the biochemical processes and for the development of drugs to control diseases caused by G. lamblia. In the current paper, 1H High Resolution Magic Angle Spinning (HR MAS) NMR spectroscopy was directly applied to G. lamblia trophozoite suspensions to analyze the detectable small metabolites with a minimum of intervention. Thirty-one components were identified with main contributions from amino acids such as alanine and ornithine. The reproducibility, variability, and stability of the metabolites were investigated. Citrulline was found to be formed as an intermediate and citrulline levels depended on the stage of cell growth. Glucose 1-phosphate was found to be formed in relatively high amounts after cell harvesting if enzymes were not inactivated. In addition, the metabolic footprint of Giardia trophozoites, i.e. changes in the culture medium induced by G. lamblia, was investigated by liquid state NMR spectroscopy of culture media before and after inoculation. A quantitative comparison of the NMR spectra revealed component changes in the culture media during growth. The results suggested that not glucose but rather arginine serves as main energy supply. Biochemical functions of intracellular components and their metabolic exchange with the culture medium are discussed. The results provide an important basis for the design of HR-MAS NMR based metabolomic studies of G. lamblia in particular and any protozoan parasite samples in general. PMID- 30029399 TI - Lectin affinity based elemental labeling with hybridization chain reaction for the sensitive determination of avian influenza A (H9N2) virions. AB - Avian influenza virus (AIV) as a type of highly pathogenic influenza A virus, can not only cause serious illness and death in poultry but also threat human health and lead to public panic. Rapid, sensitive detection of AIV is urgent and significant for prevention and timely control of influenza epidemics. Herein, we reported an inductively coupled plasma mass spectrometry (ICP-MS) based method for the analysis of AIV virions on the basis of the selective recognition between lectin Con A and glycoproteins on AIV surface and signal amplification of hybridization chain reaction (HCR). With H9N2 as the model AIV, the limit of detection was down to 0.12 ng mL-1 due to the dual amplification effect of AuNPs and HCR, and the linear range was 0.4-50 ng mL-1 with the relative standard deviation of 7.9% for seven replicate detections of 2 ng mL-1 H9N2 virions. Furthermore, the applicability of the method for the analysis of real biological samples was demonstrated by the spiking tests. The proposed approach is highly specific and sensitive for the detection of AIV with good application potential in early diagnosis, which is helpful for the prevention of influenza outbreak. PMID- 30029401 TI - Magnetic solid-phase extraction for the removal of mercury from water with ternary hydrosulphonyl-based deep eutectic solvent modified magnetic graphene oxide. AB - A novel ternary hydrosulphonyl-based deep eutectic solvent (THS-DES) comprised of choline chloride/itaconic acid/3-mercaptopropionic acid (molar ratio 2:1:1) was firstly synthesized. The composition, property and microscopic structure of the new magnetic adsorbent (THS-DES@M-GO) based on the THS-DES modified the magnetic graphene oxide (M-GO) was characterized by the system. Magnetic solid-phase extraction (MSPE) based THS-DES@M-GO was firstly researched for the removal of mercury (Hg2+) from water. Various influencing factors such as the mass of adsorbent, solution pH, initial Hg2+ concentration, the removal time and temperature had been systematically tested. Under optimized conditions the removal efficiency (R%) could achieved 99.91%. The precision, repeatability and stability experiments were investigated in detail to evaluate the presented method. The relative standard deviations (RSD) of the removal efficiency were 0.053%, 1.49% and 1.55%, respectively. The maximum adsorption capacity (Qmax) was 215.1 mg g-1 and the data of the experiment fitted well with Langmuir model. Elution experimental studies shown that 94.94% of Hg2+ could be eluted by ethylenediaminetetraacetic acid (EDTA). After seven cycles of adsorption desorption processes, the THS-DES@M-GO still retained a high removal efficiency of 90.23%. Compared with other adsorbents prepared in this work, THS-DES@M-GO displayed higher removal efficiency for Hg2+. Interference study proved the composites was tolerated and stabled under the complex matrix. What's more, the analysis of mercury contaminated water (from Guizhou, P.R., China) proved that the proposed method could be used to remove Hg2+ in practical application. PMID- 30029400 TI - Coumarin-based, switchable fluorescent substrates for enzymatic bacterial detection. AB - Enzymatically-switchable fluorescent substrates, such as the commercially available 4-methyl umbelliferones (4-MU) are used as standard indicators of enzymatic activity for the detection of various microorganisms and pathogens. However, a major disadvantage of 4-MU is its relatively high pKa leading to only partial dissociation of the fluorescent anion under the conditions where the enzymes are most effective (pH 6-6.5). Here we present a method for new, enzymatically-switchable, fluorescent substrates with improved photo physico/chemical properties. The lead derivative, 4-AAU, shows excellent solubility in aqueous media (0.81 mg/mL) when compared to 4-MU (0.16 mg/mL), significantly improved quantum yield and wider dynamic range of its fluorescence properties. The corresponding bacterial substrate beta-4-AAUG showed superior selectivity in the detection of clinically relevant amounts of E. coli, Enterococcus and K. pneumonia (1 CFU). The fluorescence intensity of beta-4-AAUG was almost 5 times higher than that of the standard, the detection was possible in reasonably short time (~ 2.5 h) and with excellent sensitivity. PMID- 30029402 TI - Microchip gas chromatography columns, interfacing and performance. AB - Almost four decades of investigations have opened up many avenues to explore the production and utilization of planar (i.e., microchip) gas chromatographic columns. However, there remain many practical constraints that limit their widespread commercialization and use. The main challenges arise from non-ideal column geometries, dead volume issues and inadequate interfacing technologies, which all affect both column performance and range of applications. This review reflects back over the years on the extensive developments in the field, with the goal to stimulate future creative approaches and increased efforts to accelerate microchip gas chromatography development toward reaching its full potential. PMID- 30029403 TI - Using ZIF-8 as stationary phase for capillary electrophoresis separation of proteins. AB - Recently, the separation of proteins has received much attention, although many techniques require expensive instrumentation and trained analysts. In this work, a low-cost, effective, and environmental friendship capillary electrophoresis (CE) for proteins separation was first time introduced. The ZIF-8 with outstanding properties of large surface area, and accessible tunnels and cages were coated the inner surface of silica capillary as a separation media by electrostatic interaction. The fast baseline separation of Lys, CC, BSA and RNase A can be obtained within 10 min using the ZIF-8 nanocrystals coated capillary column under the optimum separation conditions. Meanwhile, this system showed good reproducibility and stability. Using L-glutamic acid as the selector ligand, the D- and L-phenylalanine were successfully separated by the ZIF-8 nanocrystals coated capillary column. Furthermore, the method was also applied to separate egg white proteins, and three main proteins were separated in a single run. PMID- 30029405 TI - Disposable electrochemical immunosensor for cortisol determination in human saliva. AB - Cortisol is a steroidal hormone and an important stress marker. Free serum cortisol concentration has been identified to correlate well with free salivary cortisol. In this present work an electrochemical immunosensor was developed to determine cortisol concentration within the physiological concentration range found in human saliva. The immunosensor is based on a direct competitive enzyme linked immunoassay using a home-made cortisol-alkaline phosphatase (AP) conjugate synthesized in our laboratory with disposable graphite screen-printed electrodes (SPEs). 1-nalphtyl phosphate (1-NP) was used as an enzymatic substrate and a square wave voltammetry (SWV) for electrochemical detection. To study method suitability for use with saliva samples, calibration curves were performed both in buffer and saliva. In buffer standard samples showed a limit of detection (LOD) of 0.6 ng/ml and working range (WR) of 0.2-44.6 ng/ml with good reproducibility (RSD 10%). Saliva matrix effect was removed effectively with Salivette Cortisol collection device (polyethylene) and a calibration curve showed similar characteristics as in buffer with LOD 1.7 ng/ml and WR 0.5-55.1 ng/ml (RSD 8%) demonstrating the possibility to determine human salivary cortisol within the desired human physiological range. Spiked saliva samples were analyzed with the developed immunosensor presenting excellent 92-114% recovery. Comparison to liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method showed strong 0.90 correlation between methods indicating good accuracy of the developed immunosensor. PMID- 30029404 TI - Preparation of iminodiacetic acid functionalized silica capillary trap column for on-column selective enrichment of N-linked glycopeptides. AB - In this work, SiO2-IDA microspheres were obtained via a previous method by grafting iminodiacetic acid (IDA) groups onto silica microspheres, then the SiO2 IDA microspheres were packed in capillary columns to prepare SiO2-IDA capillary trap columns for the first time. Based on the trap columns, a novel on-column enrichment method toward glycopeptides was developed as a sample pretreatment step prior to matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) or nano-LC-MS/MS analysis. The preparation procedures of the trap columns are well reproducible. Thanks to outstanding hydrophilicity brought by the grafted zwitterionic IDA groups, the trap columns showed excellent on-column enrichment performance toward glycopeptides by hydrophilic interaction liquid chromatography (HILIC). Experimental results showed that the on-column enrichment method could reach a low detection limit (50 fmol HRP digest) and a high selectivity (molar ratio of HRP digest and BSA digest 1:100). Finally, it was applied to on-column enrichment of glycopeptides from digests of human serum followed by nano-LC-MS/MS analysis. In total, 207 glycopeptides assigned to 78 glycoproteins were identified from 2 MUL human serum. PMID- 30029406 TI - Simultaneous and highly sensitive detection of multiple breast cancer biomarkers in real samples using a SERS microfluidic chip. AB - Accurate and quantitative analysis of breast cancer biomarkers is a particularly requisite in the early diagnosis of breast cancers, especially in real samples. Here, we develop a surface enhanced Raman scattering (SERS) immunoassay biosensor based on a microfluidic chip for the simultaneous detection of multiple breast cancer biomarkers in real samples. In such an immunoassay, immuno-Ag aggregates are labeled with different Raman reporters to detect multiple breast cancer biomarkers in real samples. Moreover, to better enhance the Raman signals, self assembled silver nanoparticles are introduced on the bottom of the microfluidic channels to obtain the SERS active immune-substrate. In order to avoid the crosstalk of SERS signals, we designed a spatially separated detection biosensor by using multi-channels in a microfluidic chip. In the experiments, CA153, CA125 and CEA are selected as the models of breast cancer biomarkers, which can be simultaneously detected of in human serum with an excellently specificity and a high sensitivity. Furthermore, the proposed SERS microfluidic biosensor can be applied to detect the biomarkers in real samples using a linear regression method for the statistical analysis. Our detection results are in agreement with those obtained using commercial ELISA kits, which proves the reliability of our SERS based microfluidic immunoassay. PMID- 30029407 TI - Transverse diffusion of laminar flow profiles as a generic capillary electrophoresis method for in-line nanoreactor mixing: Application to the investigation of antithrombotic activity. AB - Capillary electrophoresis (CE) instrument was used for the generation of a robust and reliable nanoreactor for enzymatic assays in the context of antithrombotic drug screening. The activity of the screened molecules was monitored in a quick and fully automated fashion using only few nanoliters of reactants. To achieve this goal, the targeted enzyme (thrombin) and the chromogenic substrate with or without the screened inhibitor were injected as separate plugs. The mixing of the reactants was then realized using electrophoretically mediated microanalysis (EMMA) or fast transverse diffusion of laminar flow profiles (TDLFP) procedure. The latest provided better mixing performance and was chosen to investigate the inhibitory potency of a fragment library. This very straightforward and fast CE activity assay showed results in good accordance with a previously developed CE affinity assay that confirms the potential of CE at the early stages of drug discovery, providing not only an efficient nanoscale bioreactor but also a selective and integrated separation device. PMID- 30029408 TI - Exploiting the tunable selectivity features of polymeric ionic liquid-based SPME sorbents in food analysis. AB - In this work, the performances of polymeric ionic liquid (PIL) based solid-phase microextraction (SPME) coatings were assessed for applications concerning food safety and quality. Two different polymeric ionic liquid coatings, namely poly(1 4-vinylbenzyl-3-hexadecylimidazolium) bis[(trifluoromethyl)sulfonyl] imide (poly([VBHDIM][NTf2]), PIL 1, and N,N-didecyl-N-methyl-d-glucaminium poly(2 methyl-acrylic acid 2-[1-(3-{2-[2-(3-trifluoromethanesulfonylamino-propoxy) ethoxy]-ethoxy}-propylamino)-vinylamino]-ethyl ester) (poly([DDMGlu][MTFSI]), PIL 2, were evaluated. The PIL-based coatings were compared to commercially available SPME coatings in terms of their performance toward extraction of pesticides and fruit metabolites. The partition coefficients (Kfs) of the tested coatings were calculated, with PIL 1 demonstrating similar or better performance compared to the commercial coatings. Design of experiment (DoE) was applied to optimize the parameters that most influenced SPME extraction, and a quantitative method for determination of 5 organophosphorus pesticides was developed by using PIL-based coatings and commercial SPME fibers. Despite the thin layer of the sorbent coating, PIL 1 achieved limits of quantitation at the low part-per-billion level. Moreover, in a comparative investigation of analyte coverage carried out via HS SPME-GCxGC-ToF/MS with grape homogenate as model matrix, excellent performances were observed for the PIL-based coatings toward the determination of fruit metabolites, demonstrating their capability towards broad extractive coverage of analytes characterized by various physicochemical properties. PMID- 30029409 TI - A novel highly sensitive and selective H2S gas sensor at low temperatures based on SnO2 quantum dots-C60 nanohybrid: Experimental and theory study. AB - In this study, SnO2 quantum dots-fullerene (SnO2 QDs-C60) nanohybrid as novel sensing material was synthesized by a simple hydrothermal method. The structure and morphology of the synthesized sample were studied by using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM). The prepared hybrid was used as gas sensors for detection of different gasses including 70 ppm H2S, 1% methane, and 1% propane at low temperatures of 100-200 degrees C. The results indicated that the SnO2 QDs-C60 nanohybrid has high response and high selectivity to 70 ppm H2S, 1% methane, and 1% propane gasses at low temperatures. The highest response (Rair/Rgas) of 66.0 and 5.4-70 ppm H2S and 1% methane gasses at 150 degrees C and the response of 2.7-1% propane at 200 degrees C were observed for the prepared nanohybrid gas sensor. Moreover, the prepared sensor showed a good selectivity toward H2S gas. Also, DFT calculations were used for studying the interaction of these gases with SnO2-C60. DFT results showed that H2S has the strongest interaction and the highest effect on band-gap variation which is in a good agreement with experimental results. PMID- 30029410 TI - Magnetic fluorescent molecularly imprinted nanoparticles for detection and separation of transferrin in human serum. AB - Transferrin (TrF) is an important glycoprotein and disease biomarker that controls iron ion balance in the human body. Isolation and detection of TrF have important implication for the early detection of disease. Thus, a magnetic fluorescent molecularly imprinted nanoparticles (FMINPs) was prepared for extraction and fluorescence detection of TrF. The FMINPs was prepared with two steps, the first step was the synthesis of magnetic TrF imprinted nanoparticle and the second step was introducing a near-infrared fluorescent compound (CyA) on the imprinted nanoparticles, which has a strong near infrared fluorescence emission at 730 nm while excitation at 690 nm and a large fluorescence signal quenching after adsorption of TrF. The concentration of TrF can be determined by the change of the fluorescence signal. FT-IR, TEM and fluorescence spectrophotometer were used to verify the successful preparation and the fluorescence performance of the FMINPs. Under the optimized experimental conditions, the prepared FMINPs had a great fluorescence performance, offering the lower relative standard deviation (7.7%), good analytical range (0.025-0.175 mg/mL, R2 =0.998) and lower detection limit (0.0075 mg/mL) for TrF. This method provides a new solution for the direct detection and separation of TrF in human serum samples. PMID- 30029411 TI - Improved separation of micro gas chromatographic column using mesoporous silica as a stationary phase support. AB - In this paper, a novel and facile way to improve the separation of micro gas chromatographic column is presented which utilizes the mesoporous silica thin film as the stationary phase support. A serpentine semi-packed column is fabricated based on a micro-electro-mechanical system (MEMS) technology and polydimethylsiloxane is used as the stationary phase. The chromatographic resolution of C6-C7 increases from unseparated to 7.44 after depositing mesoporous silica thin film as the stationary phase support in the separation of a mixture of heavy hydrocarbons (C6-C10), and the separation efficiency is as high as 9290 plates/m. Meanwhile, in the separation of a mixture of benzene series (gas mixtures of benzene, toluene and paraxylene), the chromatographic resolution of benzene and toluene can also be increased by 483%. Those outstanding results indicate that using the mesoporous silica as the stationary phase support is an effective way to improve the separation efficiency of the gas chromatographic column. PMID- 30029412 TI - Detection of Zn2+, Cd2+, Hg2+, and Pb2+ ions through label-free poly-L-glutamic acid. AB - Detection of heavy metal ions in water is important for environmental sustainability and food safety. Current fluorescent sensors interact with metal ions directly through chelation or chemical reactions. Those sensors are expensive to produce and often can detect only one ion at a time. Here we report a fluorescent turn-on sensor that can detect three group IIB metal ions and Pb2+ ions through label-free polypeptides in water. In our sensor-polypeptide mixture, Zn2+, Cd2+, Hg2+, and Pb2+ ions induce helix formation and inter-chain aggregation in poly-L-alpha-glutamic acid (PGA). The acridinium-based sensor molecules incorporate into the polypeptides and emit strongly with characteristic color for each group IIB ion under UV lamp. By adjusting the size of polypeptides or the length of the side chain carboxyl groups, we can selectively turn off or turn on the sensor emission for Hg2+ ions. PMID- 30029413 TI - Development and validation of generic heterogeneous fluoroimmunoassay for bioanalysis of bevacizumab and cetuximab monoclonal antibodies used for cancer immunotherapy. AB - This study describes, for the first time, the development and validation of a highly selective and sensitive heterogeneous fluoroimmunoassay (FIA) for the bioanalysis of two monoclonal antibodies (mAbs) used for cancer immunotherapy: bevacizumab (BEV) and cetuximab (CET). The assay combines reliable non competitive binding of BEV and CET to their specific cell receptor proteins (human vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), respectively) with the highly specific fluorescence activity of the fluorescein isothiocyanate labeled anti-human IgG (FITC-IgG) used as label. The limits of detection were 14.14 and 1.27 * 103 ng mL-1 for BEV and CET, respectively. The accuracy and precision of the assay were demonstrated. The assay is simple, convenient, and requires very small volume (~ 5 uL) of plasma sample for analysis. The assay can offer high throughput analysis in clinical settings when modern microplates of multiplies of 96 (up to 6144-wells) are used and/or integrated as a part of automated robotic system. The proposed assay can be used for routine clinical bioanalysis of mAbs with potential application in pharmacokinetics, pharmacodynamics and therapeutic drug monitoring (TDM). PMID- 30029414 TI - Solid-phase microextraction of heavy metals in natural water with a polypyrrole/carbon nanotube/1, 10-phenanthroline composite sorbent material. AB - A simple and sensitive method for simultaneous microextraction and determination of heavy metals using a new direct immersion solid-phase microextraction (DI SPME) sorbent material combined with inductively coupled plasma mass spectrometry (ICP-MS) was investigated. In this method, sorbent coating composites were prepared by simultaneous electropolymerization of pyrrole on pencil lead in the presence of carbon nanotubes (CNTs) and different metal chelating ligands. Among the coatings evaluated, a polypyrrole coating with entrapped CNTs and the chelator 1, 10 phenanthroline allowed the determination of silver, cadmium, cobalt, iron, nickel, lead, and zinc. Parameters influencing microextraction efficiency including pH, extraction time, and desorption time were optimized. The linear dynamic ranges were 1-1000 MUg L-1 for Ag, 1-750 MUg L-1 for Cd, Pb, and Zn, and 1-500 MUg L-1 for Co, Fe, and Ni with limits of detection of 0.012-0.163 MUg L-1 and limits of quantification of 0.039-0.542 MUg L-1. The relative standard deviations (RSDs, n = 5) ranged from 1.85% to 5.01%. The effect of inorganic interferences on the determination of the heavy metals also was examined and finally, the method was successfully applied for the determination of heavy metals in real water samples. PMID- 30029415 TI - Covalent organic framework as a novel electrochemical platform for highly sensitive and stable detection of lead. AB - A sensitive and selective TAPB-DMTP-COF (TAPB, 1,3,5-tris(4-aminophenyl)benzene; DMTP, 2,5-dimethoxyterephaldehyde; COF, covalent organic framework) modified carbon paste electrode was evaluated as a novel electrochemical sensor for the determination of lead in an aqueous medium. Lead was accumulated on the TAPB-DMTP COF surface by the complexation with the amine groups, and detected by differential pulse anodic stripping voltammetry. Due to the distinct structure features of COF, the resulting sensor revealed a fast electron transfer rate and outstanding adsorption capacity for lead. The influence of various experimental parameters (the content of COF, pH of the electrolyte solution, accumulation potential, and accumulation time) on the peak current were investigated in the overall analysis procedure. Under optimum conditions, the method showed an excellent linearity to the concentration of lead in the range of 0.0050 to 2.0 MUmol/L with a detection limit of 1.9 nmol/L, and the relative standard deviation was 3.1% for 0.50 MUmol/L of lead (n = 11). This method not only displays the feasibility of COF based sensor for trace levels of metal ions detection but also broadens the scope of applications of COF based hybrid materials in electroanalytical chemistry. PMID- 30029416 TI - Three-dimensional Tri-SNSs-layered electrodeposited reduced graphene oxide for ECL biosensing of DNA. AB - In this study,we proposed a triangular silver nanosheets (Tri-SNSs)-layered, Chitosan (CS)-supported three-dimensional of reduced graphene oxide (3D-ERGO) electrochemiluminescence (ECL) biosensing platform using self-designed dual Ru(bpy)32+ scDNA (Ru2-DNA) as capture probe for ECL biosensing of single-chain DNA (scDNA). Based on the different affinity with scDNA and double chain DNA (dcDNA), the biosensor is designed to recognize the target DNA (t-DNA), which leads to the desorption of a hybrid molecule from the surface of the biosensor, further removing the Ru2-DNA and inhibiting the ECL. Analytical results clearly showed that the electrochemical and ECL behaviors of proposed biosensing platform on the glassy carbon electrode (GCE) exhibited outstanding performance, which was due to large specific surface area, high carrier mobility and strong pi-pi non covalent attraction toward single-chain DNA (scDNA) of the stable 3D platform, and ECL amplification of Tri-SNSs. Besides, based on such a system, this strategy can effectively identify full match and mismatched target DNA (M-DNA) with a wide concentration range beyond 7 orders of magnitude and detection limit down to 16.2 aM. Therefore, the 3D biosensing strategy shows potential for the application of bioassays. PMID- 30029417 TI - Towards a spray-coating method for the detection of low-dose compounds in pharmaceutical tablets using surface-enhanced Raman chemical imaging (SER-CI). AB - Surface-enhanced Raman chemical imaging (SER-CI) is a highly sensitive analytical tool recently used in the pharmaceutical field owing to the possibility to obtain high sensitivity along with spatial information. However, the covering method of the pharmaceutical samples such as tablets with metallic nanoparticles is a major issue for SER-CI analyses due to the difficulty to obtain a homogeneous covering of tablet surface with the SERS substrates. In this context, a spray-coating method was proposed in order to fully exploit the potential of SER-CI. A homemade apparatus has been developed from an electrospray ionization (ESI) probe in order to cover the pharmaceutical tablets with the colloidal suspension in a homogeneous way. The silver substrate was pulled through the airbrush by a syringe pump which was then nebulized into small droplets due to the contact of the solution with the gas flow turbulence. A robust optimization of the process was carried out by adjusting experimental parameters such as the liquid flow rate and the spraying time. Besides, the performances of this spraying technique were compared with two others covering methods found in the literature which are drop casting and absorption coating. A homogeneity study, conducted by SER-CI and matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) applied to the different covering techniques was performed. The influence of the metallic nanoparticles deposit on soluble compounds was also investigated in order to highlight the advantages of using this new spray coating approach. PMID- 30029418 TI - An ITO-based point-of-care colorimetric immunosensor for ochratoxin A detection. AB - The accurate and rapid ochratoxin A (OTA) detection at early stage can prevent people from getting cancer to a great extent due to its strong liver toxicity and renal toxicity. The development of an efficient strategy to detect OTA without sophisticated instruments is highly desired, but still remains a severe challenge. In this communication, a sandwich type point-of-care testing (POCT) immunoassay is developed for OTA detection. The 3-aminopropyltrimethoxysilane glutaraldehyde (APTMS-GA) is used as color matrix and Au-N-TiO2 as labels for loading more captured antibodies and glucose oxidases (GOD). When glucose is added, GOD can be catalyzed to produce H2O2 which can weaken the color strength to quantify OTA concentrations. The mean gray values of reacted ITO-based immunosensors can be calculated by the software of Image J. The linear range of OTA is 0.0001-1 ng mL-1 with a low detection limit of 28 fg mL-1 at a signal-to noise ratio of 3 s. This strategy can achieve the excellent performance without sophisticated instruments. This POCT method may has a potential application in the undeveloped countries with only a camera-equipped cellphone. PMID- 30029419 TI - Development of a rapid and accurate method for the determination of sodium in vacuum gas oils (VGOs) by ICP-OES. AB - Sodium in vacuum gas oils (VGOs), even at trace levels, produces corrosion by products in the refinery pipelines and it is a significant catalyst poison, especially for those from atmospheric or vacuum distillation units, thus its concentration in middle-distillate petroleum products needs to be controlled. In addition, sodium contamination was an issue in this study, as sodium might be present even in the dust floating in the air. The use of an ultrapure sodium-free water and the disposal of a clean and dust-free room were the key to be successful on the development of this method. Different sample preparation methods were studied as sample preparation optimisation was an important step in this study. Dry ashing by different processes, wet acid digestion with different acid mixtures, wet acid microwave-assisted digestion, and dilution with a proper solvent were tried to find the appropriate sample preparation method. An accurate and precise method for the determination of sodium in vacuum gas oils (VGOs) by ICP-OES at trace levels has been developed by ashing the sample with a new piece of equipment designed and created by the Instituto de Tecnologia Ceramica (ITC), that permits to calcine the sample in one hour and avoids analyte losses or analyte contamination. The quantification limit achieved by the whole sodium determination method is lower than 1 mg kg-1, which allows it to be used as control method in the petrochemical industry. PMID- 30029420 TI - Chemiluminescence detection with microfluidics for innovative in situ measurement of unbound cobalt ions in dynamic equilibrium with bound ions in binding study with polyethyleneimine and its functionalized nanoparticles. AB - This work reports a novel method for in situ measurement of binding of cobalt ions to polyethyleneimine (PEI) and polyethyleneimine-functionalized poly (methyl methacrylate) nanoparticles (PEI-NPs) using simple microfluidics with a chemiluminescence detection system. The catalytic effect of free cobalt ion in solution on the luminol-hydrogen peroxide chemiluminescence was employed for the detection of unbound cobalt in dynamic equilibrium with cobalt bound to PEI or PEI-NPs. Many binding measurements lead to incorrect estimation of free metal ions due to insufficient separation of bound and free ions. The catalytic activity of only unbound cobalt ion on the luminol reaction was demonstrated by observing that PEI and PEI-NPs alone did not give chemiluminescence. Also, both Co-PEI and Co-PEI-NPs complexes gave no chemiluminescence when cobalt ion is fully bound with excess PEI or PEI-NPs. In addition diethylenetriamine (dien) as a model ligand to completely bind the cobalt ions was also employed as further confirmation. The chemiluminescence measurement employing microfluidics was then successfully applied for the measurement of binding cobalt ion to PEI and PEI NPs. This in situ measurement of binding does not require filtration of the two species. As there is no perturbation of equilibrium, an accurate binding measurement can therefore be successfully performed. Experimental parameters, such as concentrations of polymers and cobalt ions, and equilibration time were investigated. Analysis of the experimental data employed the binding equation derived assuming independent and equivalent binding sites of the polymer for the metal ions. Also the binding constant of cobalt ions with PEI-NPs is first reported employing chemiluminescence detection. This work provides quantitative determination of the binding constant and total binding capacity of PEI and PEI NPs with cobalt ions using chemiluminescence detection and microfluidics as an innovative in situ measurement of the unbound cobalt ions. PMID- 30029421 TI - Selective and sensitive fluorescent and colorimetric chemosensor for detection of CO32- anions in aqueous solution and living cells. AB - A new colorimetric and fluorescent chemosensor for visual determination of carbonate ions was developed by the microwave assisted solvent free synthesis of 7,8-dihydroxy-3-(4-methylphenyl) coumarin (DHMC). The structural characterization of DHMC was confirmed by microanalysis and spectroscopy methods (MALDI-TOF, FT IR, 1H NMR, 13C NMR, and 2D HETCOR). The binding behaviors of DHMC were investigated towards various anions by UV-vis and fluorescence spectroscopy. DHMC showed a selective and sensitive fluorometric and colorimetric responses towards carbonate ion over other anions. The detection limit of CO32- was found to be 1.03 uM. Moreover, the fluorescence imaging in living cells suggests that DHMC has a great potential in the biological imaging application. It has been demonstrated that DHMC can be used as a rapid and reliable sensor for the determination of carbonate anion in a variety of practical applications. PMID- 30029422 TI - A novel ratiometric fluorescence nanoprobe based on aggregation-induced emission of silver nanoclusters for the label-free detection of biothiols. AB - In this work, a novel ratiometric fluorescence nanoprobe based on Au3+-triggered aggregation-induced emission (AIE) behavior of silver nanoclusters (Ag NCs) was designed for the label-free detection of biothiols. The probe was constructed by loading of Au3+ on g-C3N4 nanosheets surface and subsequently aggregating Ag NCs via ion binding. As Au3+ could conversely regulate the emission of g-C3N4 nanosheets and Ag NCs, the remove of Au3+ from nanoprobe by coordination with biothiols would change the emission ratio of nanoprobe that could be used for biothiols detection. The probe provided high sensitivity for glutathione (GSH) determination with the limit of detection as low as 0.8 MUM and showed satisfying performance in human serum samples. This report may offer a new sight for the construction of ratiometric probe based on the AIE behavior of Ag NCs and broaden its applications in biosensing. PMID- 30029423 TI - Silver nanoparticles/activated carbon composite as a facile SERS substrate for highly sensitive detection of endogenous formaldehyde in human urine by catalytic reaction. AB - Most of efforts have been made to prepare high performance surface-enhanced Raman scattering (SERS) substrate for amplifying Raman signals. It still remains a grand challenging task in building a simple, conventional and low-cost SERS substrate with highly dense hotspots for improved sensitivity of the target analytes. Here, we report a very dexterous strategy to fabricate a distinctive SERS substrate with high density hotspots, using common adsorbent activated carbon (AC) as template to assemble silver nanoparticles (Ag NPs). It can be estimated that the enhancement effect of Ag NPs/AC composite is about 6.5-fold that of bare Ag NPs. Different from the resonant dyes, however, formaldehyde (FA) is a Raman-inactive molecule even though enhanced. Considering that, a novel method for quantitative analysis of FA using the Ag NPs/AC composite as SERS sensor has been developed, based on the catalytic effect of trace FA on the oxidation of malachite green (MG) through bromate under acidic condition. The change of MG from reduced form into oxidized leucomalachite green (LMG) results in the quench of Raman signals of MG, responding to 0.07 ppb FA that is about 2 orders of magnitude lower than the limit defined by the Nash's method as a standard procedure recommended in Europe, Japan and China. Moreover, SERS examinations of endogenous FA in human urine signify that the proposed method has high selectivity, reliability and accuracy. Thus, as-fabricated Ag NPs/AC composite is adequate as inexpensive and versatile SERS sensor utilized in the quantification of trace targets in various complicated matrices. PMID- 30029424 TI - Innovative coupling of supercritical fluid extraction with ion mobility spectrometry. AB - This paper describes a pioneer on-line hyphenation between a supercritical fluid extraction (SFE) and an ion mobility spectrometry (IMS) detector through a Tenax TA sorbent trap as retention interface. By means of a simple design, taking advantage of both techniques, this new coupling allows us to extract and preconcentrate analytes and in a second step to determine them. As result, an increase in the accuracy of the analytical process was achieved by elimination of sample transfer from one device to another. In addition, this new coupling reduces the time needed for the optimization of a new SFE method, since the detector can monitor on-line the efficiency of the extraction. The parameters affecting the coupling and its success have been studied in detail via the extraction of benzene and toluene from soil samples. Finally, the suitability of IMS as on-line detector to monitor compounds of industrial interest extracted by SFE was evaluated taking as a model, the extraction and detection of 1,8-cineole (eucalyptol) in rosemary aromatic plants, which could be extrapolated on an industrial scale. PMID- 30029425 TI - Ultrasensitive determination of mercury ions (II) by analysis of the degree of quantum dots aggregation. AB - In this work, an ultrasensitive fluorescence strategy on counting the degree of aggregation (DOA) of QDs aggregates was developed for Hg2+ detection, which is based on thymine-Hg2+-thymine (T-Hg2+-T) coordination chemistry. Oligonucleotides containing 12 thymines are modified on the surface of QDs which could protect QDs effectively from aggregation in the absence of Hg2+. While in the presence of Hg2+, QDs will be made to attach with each other by the structure of "T-Hg2+-T" formed, and then aggregated in the sensing system. The DOA is acquired easily by recording the entire process of the blue shifting and photobleaching of QDs aggregates. First-order spectrum of each QD in the aggregates can be released from the original overlapped spectral image of the aggregates in sequence under continuous illumination because QDs exhibit the asynchronous spectra blue shifting. Employed 0.3 nM functional QDs in the sensing system, an ultralow detection limit of 4.6 pM was reached by the counting DOA-based sensing strategy. Besides, the sensor also shows high selectivity against other 12 metal ions even at high concentrations. At last, the application of the sensing strategy for river water shows that the real samples can be worked well using this method. PMID- 30029426 TI - Sonochemical preparation of gold nanoparticles for sensitive colorimetric determination of nereistoxin insecticides in environmental samples. AB - A simple colorimetric method using gold nanoparticles (AuNPs) was developed as an efficient strategy for specific and sensitive detection of insecticides that are analogs of nereistoxin (NRT). The AuNPs were synthesized by a surfactant-free sonochemical reaction with ultrasonication at 430 kHz. A color change occurred in the presence of NRT because the AuNPs aggregated if they were coated with a small amount of thioctic acid (TA). At a pH of around 5, the TA adsorbed on the AuNPs was deprotonated, whereas NRT was protonated (NRT-H+). Adsorption of NRT-H+ onto the TA-coated AuNPs surface would decrease the surface charge of the AuNPs, and this resulted in aggregation. Because the aggregation of the TA-coated AuNPs could not be induced by amine compounds without thiol groups, this provided a surface-limited aggregation mechanism for specific sensing of NRT. The absorbance at 700 nm was dependent on the concentration of NRT, and the calibration curve was linear over the concentration range 85 nM (12 ng/mL) to 1000 nM (140 ng/mL). The applicability of the proposed method to detection of trace levels of NRT in environmental water samples was successfully demonstrated using a simple liquid liquid reverse extraction technique. PMID- 30029427 TI - Phage-based capacitive biosensor for Salmonella detection. AB - This article reports the detection of Salmonella spp. based on M13 bacteriophage in a capacitive flow injection system. Salmonella-specific M13 bacteriophage was immobilized on a polytyramine/gold surface using glutaraldehyde as a crosslinker. The M13 bacteriophage modified electrode can specifically bind to Salmonella spp. via the amino acid groups on the filamentous phage. An alkaline solution was used to break the binding between the sensing surface and the analyte to allow renewable use up to 40 times. This capacitive system provided good reproducibility with a relative standard deviation (RSD) of 1.1%. A 75 uL min-1 flow rate and a 300 uL sample volume provided a wide linear range, from 2.0 * 102 to 1.0 * 107 cfu mL-1, with a detection limit of 200 cfu mL-1. Bacteria concentration can be analyzed within 40 min after the sample injection. When applied to test real samples (raw chicken meat) it provided good recoveries (100 111%). An enrichment process was also explored to increase the bacteria concentration, enabling a quantitative detection of Salmonella spp. This biosensor opens a new opportunity for the detection of pathogenic bacteria using bacteriophage. PMID- 30029428 TI - Generating lung-metastatic osteosarcoma targeting aptamers for in vivo and clinical tissue imaging. AB - Osteosarcoma (OS) is one of most malignant bone tumors in early adolescence, which is a highly metastatic cancer and pulmonary metastasis is the most common cause of death. Thus, the development of efficient approaches to discover potential compounds that target metastasis of OS remains a topic of considerable interest. In this study, subtractive Cell-SELEX was performed to screen OS metastasis specific DNA aptamers by using cell lines with similar tumorigenic potentials but opposite metastatic aggressiveness (highly metastatic 143B cells and non-metastatic U-2 OS cells as the target and negative cells, respectively). This in vitro selection generated an ssDNA aptamer LP-16 that exhibited high binding affinity to 143B cells with an equilibrium dissociation constant (Kd) of 56.73 +/- 7.750 nM. However, the aptamer LP-16 did not bind to the non-metastatic U-2 OS and normal hFOB 1.19 cells. We further preliminarily presumed the target molecules of aptamer LP-16 was a membrane protein on the cell surface by proteinase treatment. Furthermore, both in vivo fluorescence imaging and clinical tissue imaging also clearly demonstrated that LP-16 could achieve prominently targeting efficiency. Therefore, the ssDNA aptamer LP-16 generated here could be a promising molecular probe for OS metastasis diagnosis. We have developed subtractive Cell-SELEX to screen osteosarcoma metastasis specific DNA aptamers by using cell lines with similar tumorigenic potentials but opposite metastatic aggressiveness (highly metastatic 143B cells and non-metastatic U-2 OS cells as the target and negative cells, respectively). PMID- 30029429 TI - A porous sintered material consisting of Presep PolyChelate as a chelating resin and particulate polyethylene as a thermoplastic binder for solid-phase extraction of trace elements. AB - Cylinder-type and disk-type sintered materials consisting of Presep PolyChelate, which is a commercially available chelating resin immobilizing carboxymethylated polyethyleneimine as a functional group, and particulate polyethylene as a thermoplastic binder were prepared using a polymer sintering technique. The sintered materials had a continuously porous structure. The sintering process at 130 degrees C for 20 min did not affect the ability of the chelating resin in the sintered materials; the selectivity of the sintered material was almost the same as that of the particulate chelating resin which was not sintered. The sintering materials could quantitatively extract 11 kinds of trace elements, namely Cd, Co, Cu, Fe, Mn, Mo, Ni, Pb, Ti, V, and Zn, at pH 5.5. When the disk type sintered material was used, the recoveries of these elements remained almost constant at a flow rate of at least 50 mL min-1; the extracted elements could be eluted using 10 mL of 3 mol L-1 nitric acid at a flow rate of 5 mL min-1. Solid phase extraction using the disk-type sintered material was applied to the separation and preconcentration of trace elements prior to their inductively coupled plasma atomic emission spectrometric determination. The method was applicable to analyses of certified reference materials (EnviroMAT ES-L-1 ground water and EU-L-3 waste water) and a commercially available table salt. PMID- 30029430 TI - Extraction of polycyclic aromatic hydrocarbons from polyhydroxyalkanoates before gas chromatography/mass spectrometry analysis. AB - Among the organic contaminants that could pass from waste to polyhydroxyalkanoates (PHAs), there are the polycyclic aromatic hydrocarbons (PAHs). For this reason, we have developed a rapid analytical method for the determination of sixteen PAHs in PHAs. PAHs were extracted by n-hexane, after matrix dispersion and crumbling into sand; the extract was purified by solid phase extraction using florisil as adsorbent. Recoveries in the range of 89-101% were obtained for the deuterated analytes, except for the two with the lowest molecular weight. Trueness between 92% and 108% and within-laboratory precision (expressed as relative standard deviation) <= 18% were estimated for all the analytes. Gas chromatography/mass spectrometry was used for analyte determination. Method limits of quantification were suitable to assure that PAH presence in PHA biolpolymers is much below the limits set by European law for plastic materials. Indeed, analysis of two different PHA samples showed that contamination is limited to few compounds at non-concerning levels. PMID- 30029431 TI - Near-infrared spectroscopy and X-ray fluorescence data fusion for olive leaf analysis and crop nutritional status determination. AB - Leaf analysis is a useful way of diagnosing the nutritional status of the plants and therefore fast methods of analysis are demanded to aid in fertilization management decisions. In this work, a strategy based on the combined use of near infrared spectroscopy (NIR) and portable energy dispersive X-Ray Fluorescence (EDXRF) is proposed as a suitable cheap and rapid alternative to traditional wet analytical methodologies. The approach has the major benefit of minimal sample preparation since leaves need to be only dried and ground. The ability of both techniques individually and applying two strategies of data fusion for the prediction of the most important plant nutrients, namely N, P, K, Ca, Mg, Mn, Zn, and B was tested. Predictive models were constructed using Partial Least Squares (PLS) to correlate the spectra with the nutrient contents. Models of unequal prediction performance in terms of the ratio of predictive deviation (RPD) were obtained for the different parameters when considering both techniques separately. Low-level data fusion, which consists of a concatenation of the raw data from both techniques, showed little improvement and even decreased the predictive ability for some elements. Better results were obtained with mid-level data fusion, that is, merging data after a feature extraction step performed by means of Principal components analysis (PCA). The results show that a fair quantitative prediction is possible for Ca, K and Mn with RPDs >= 2 for external validation, whereas models for N and P allowed a semiquantitative estimation. Mg and B models were less satisfactory and can be used only for distinguish between low and high levels, while Zn content cannot be predicted. Finally, the potential of the fusion of FT-NIR and EDXRF spectroscopic data for the fast screening of olive crop nutritional status has been tested. Deficiencies in important elements like N and K has been successfully detected. PMID- 30029432 TI - DNA-fueled target recycling-induced two-leg DNA walker for amplified electrochemical detection of nucleic acid. AB - Taking advantage of the homogeneous and heterogeneous electrochemical biosensors, a simple, sensitive, and selective electrochemical biosensor is constructed by combining entropy-driven amplification (EDA) with DNA walker. This electrochemical biosensor realizes the biorecognition and EDA operation in homogeneous solution, which is beneficial to improve the recognition and amplification efficiency. A two-leg DNA walker generated by EDA can walk on the surface of gold electrode for cleaving the immobilized substrate DNA and releasing the electroactive labels, giving rise to a significant decrease of the electrochemical signal. The immobilization of the electroactive labels ensures the reproducibility and reliability of the biosensor. The present cascade amplification assay can be applied to detect target DNA with a detection limit of 0.29 fM, and base mutations can be easily distinguished. Moreover, the proposed electrochemical biosensor shows a satisfactory performance for the detection of target DNA in human serum. Thus, the novel electrochemical biosensor holds promising potential for a future application in disease diagnosis. PMID- 30029434 TI - Fluorescent reversible regulation based on photoinduced electron transfer from DNA to quantum dots and intercalation binding of DNA intercalator to DNA. AB - Based on the fluorescent reversible regulation, a novel sensor platform was designed for the detection of DNA intercalators utilizing the intercalation binding of DNA intercalators to DNA as an inherent exhibition and the fluorescence change of quantum dots (QDs) as an external manifestation. To prove its feasibility, acridine orange (AO) was chosen as an example of DNA intercalator. When different concentrations of herring sperm DNA (hsDNA) were added to cysteamine (CA)-capped ZnSe QDs solution, the hsDNA bound with the QDs through electrostatic interaction due to the photoinduced electron transfer from hsDNA to QDs and formed QDs-hsDNA complexes with 1:1 ratio, leading to the fluorescence quenching of the QDs; and upon addition of different concentrations of AO to the QDs-hsDNA complex system, the AO first caused the release of the hsDNA from the complexes and concomitantly bound with them through intercalation binding and formed AO-hsDNA complexes with 1:3 ratio on account of the fact that the intercalation binding constant between AO and hsDNA (1.932 * 105 L/mol) was greater than the electrostatic interaction constant between QDs and hsDNA (7.874 * 104 L/mol), resulting in the fluorescence recovery of the QDs. Therefore, the detection of AO could be achieved through the relationship between the fluorescence recovery yield of the QDs and the concentration of AO added. The results illustrated that the fluorescence recovery yield of the QDs-hsDNA system was linearly dependent to the concentration of AO in the range of 5.0-75.0 * 10-5 mol/L with a detection limit (3sigma/K) of 1.5 * 10-5 mol/L. This dual directional fluorescent regulation provided a novel method for the detection of DNA intercalators such as polycyclic aromatic hydrocarbons and drugs interfering with DNA-synthesis and possessed some potential applications in the investigation of the interactions between DNA intercalators and DNA. PMID- 30029433 TI - Mitochondria-targeted near-infrared fluorescent probe for the detection of carbon monoxide in vivo. AB - Carbon monoxide is a critical gasotransmitter in the body and related with mitochondrial respiration. To date, various fluorescent probes for CO have been well proposed, but two main problems remain. One is that most of the probes are not mitochondria-targeting, even if the probes claim to be able to detect CO in living cells. The other is that the probes for CO display excitation and emission within the ultraviolet or visible range, which hinders their applications in vivo. Herein, a hemicyanine-based near-infrared (NIR) fluorescent probe named CyAPC is first synthesized and used to detect mitochondrial CO. The characteristics of probe CyAPC are as follows: (1) The fluorescence emission of the sensing system is at 736 nm belonging to NIR region, which is suitable for bioimaging in vivo. (2) CyAPC, a positively charged molecule, would have a high tendency to localize in mitochondria of cells. (3) The fluorescence change of the probe is attributed to the fact that CO with Pd2+ induced cleavage of the allyl formate group from the probe and CyAPC (fluorescence off) is transformed into CyOH (fluorescence on), which is proved by HPLC, MS and DFT calculation. (4) The NIR fluorescent probe is applied for the detection of exogenous and endogenous CO in various biological samples such as cell, tissue and in vivo with satisfactory results. PMID- 30029435 TI - Amperometric immunosensor for prolactin hormone measurement using antibodies loaded on a nano-Au monolayer modified ionic liquid carbon paste electrode. AB - The fabrication of a novel electrochemical immunosensor for rapid and precise determination of prolactin was carried out using carbon paste electrode (CPE) consist of ionic liquid (IL) and graphite. Gold nanoparticles were employed as a modifier on the surface of CPE to immobilize the prolactin antibody (anti-PRL). The immunoassay was set up by sandwiching the antigen between prolactin antibody and the polyclonal anti-human-prolactin antibody labeled with horseradish peroxidase (HRP-labeled anti-PRL) as secondary antibody, on the surface of modified CPE. The reaction between O-aminophenol (OAP) and H2O2 which is catalyzed by labeled HRP on the sandwich immunosensor generate a signal in differential pulse voltammetry (DPV) that is used to determine the concentration of prolactin. This immunosensor provides the measurement of prolactin concentration in a linear range of 25.0-2000.0 mIU L-1 with a detection limit 12.5 mIU L-1. Moreover, it is applicable in the clinical assay of prolactin due to its high sensitivity and acceptable stability. PMID- 30029436 TI - Ratiometric fluorescence sensor based on cholesterol oxidase-functionalized mesoporous silica nanoparticle@ZIF-8 core-shell nanocomposites for detection of cholesterol. AB - A novel ratiometric fluorescence sensing system based on cholesterol oxidase functionalized dual-color mesoporous silica nanoparticles (MSNs)@metal-organic framework core-shell nanocomposite is demonstrated for cholesterol detection. MSNs were first loaded with 5-aminofluorescein (AF) inside pores and then wrapped with red-emission CdTe quantum dots (QDs) on the surface to seal in the dye molecules, forming the signal displaying unit (AF-MSN-QDs). Next, AF-MSN-QDs were encapsulated with zeolitic imidazolate framework (ZIF-8) to form a transition layer with distinct size-selectivity, which not only protected the cores from corrosion but also greatly decreased background interference from large molecules. More significantly, the ZIF-8 shells showed high affinity for most enzymes, which made it possible for cholesterol oxidase (ChOx) to self-organize on the surface of ZIF-8-encapsulated AF-MSN-QDs via chemo-physical adsorption, forming novel core-shell nanocomposites (AF-MSN-QD@ZIF-8-ChOx) as a sensing platform for cholesterol detection. The detectable signal was monitored by enzymatic product-quenching fluorescence of the QDs. The fluorescence changes of I520/I618 showed excellent linearity with H2O2 concentrations in the range of 5 100 nM, with a limit of detection (LOD) as low as 0.89 nM. As a proof-of-concept, cholesterol was selectively detected with beneficial LOD as low as 0.923 MUg/mL, demonstrating the great potential of this biosensor platform for other biologically important molecules with H2O2-producing oxidases. PMID- 30029438 TI - Determination of arsenic in agricultural soil samples using High-resolution continuum source graphite furnace atomic absorption spectrometry and direct solid sample analysis. AB - Soils around coal-fired thermal power plants based on coal combustion can present high concentrations of arsenic. This fact has a direct effect on the food chain. Arsenic can be absorbed by plants and vegetables through the soil, which will then serve as food for different animals, spreading the contamination. A method has been developed using high-resolution continuum source graphite furnace atomic absorption spectrometry (HR-CS GFAAS) for direct determination of arsenic in solid soil samples. Different chemical modifiers were tested to suppress the matrix effects observed. Among them, the modifier that showed the best results was the Zr, used as a permanent modifier. The optimized pyrolysis and atomization temperatures were 1000 degrees C and 2200 degrees C, respectively. A calibration curve was established using aqueous standard solutions which was linear up to 16 ng of arsenic. The characteristic mass and limit of detection were 22 pg and 73 pg As, respectively. The accuracy of the method was verified using two certified reference materials and comparison with results obtained for samples after microwave-assisted digestion. Eleven soil samples were collected around the power plant Complex Jorge Lacerda-Tractebel Suezin, in the south of Santa Catarina, Brazil. The concentration of As ranged from 3.4 mg kg-1 to 9.7 mg kg-1, which is within the limits allowed by Brazilian legislation. PMID- 30029437 TI - Sensitive determination of baicalein based on functionalized graphene loaded RuO2 nanoparticles modified glassy carbon electrode. AB - The nanocomposite of ruthenium oxide (RuO2) loaded on Poly (dimethyldiallylammonium chloride) (PDDA) functionalized reduced graphene oxide (RuO2-PDDA-rGO) was synthesized based on a one-step method. Based on the RuO2 PDDA-rGO modified glassy carbon electrode (GCE), a new electrochemical sensor (RuO2-PDDA-rGO/GCE) was fabricated and used in detection of baicalein for the first time. Compared with other reported electrochemical sensors for the detection of baicalein, the prepared RuO2-PDDA-rGO/GCE had a wider linear range (2-400 nM) and lower detection limit (0.6 nM, S/N = 3). The other advantages were the excellent repeatability of proposed method and good stability of prepared sensor. PMID- 30029439 TI - Label-free electrochemiluminescent immunosensor for detection of prostate specific antigen based on mesoporous graphite-like carbon nitride. AB - In this paper, mesoporous graphite-like carbon nitride (mpg-C3N4) combined with gold nanoparticles (Au NPs) was conducted to construct a luminol-hydrogen peroxide (H2O2) based electrochemiluminescent (ECL) immunosensor for prostate specific antigen (PSA) detection. The mpg-C3N4 exhibited large specific surface area and high porosity was synthesized from a simple precursor, which possessed abundant active sites to load Au NPs and luminol (mpg-C3N4/Au-luminol). After that, Au NPs linked mpg-C3N4 (mpg-C3N4/Au) could hatch with the primary antibody (Ab1) via Au-NH2 bond, which reinforced the sensitivity of immunosensor. The mpg C3N4 and Au shows excellent catalytic enhancement effect on the ECL intensity of luminol. Under optimal conditions, the constructed ECL immunosensor exhibited sensitive response to PSA in a wide linear range of 0.001 ~ 15 ng mL-1 with a lower detection limit of 0.927 pg mL-1. Meanwhile, the proposed ECL immunosensor endows the good reproducibility and stability. Therefore, the results could open another avenue for detection of PSA and other biomarkers. PMID- 30029440 TI - Polymer monolithic capillary microextraction on-line coupled with ICP-MS for determination of inorganic selenium species in natural waters. AB - In this work, ethylenediamine modified poly(glycidyl methacrylate-ethylene dimethacrylate)(poly(GMA-EDMA-NH2)) was prepared for highly selective extraction of Se(VI) with high adsorption capacity of 0.825 mg m-1 (530 um i.d.). Based on it, a novel method of polymer monolithic capillary microextraction (CME) on-line coupling with inductively coupled plasma-mass spectrometry (ICP-MS) was developed for the determination of inorganic selenium species (Se(IV)/Se(VI)) in natural waters. Under the optimized conditions, the analytical performance of the proposed on-line CME-ICP-MS method was evaluated for Se(VI). The limit of detection for Se(VI) was 14.2 ng L-1, and the enrichment factor was 50-fold with the sample throughput of 5 h-1. For Se(IV), the concentration was obtained by subtracting Se(VI) from the total Se(VI) obtained by the proposed method after oxidation of Se(IV) to Se(VI). The accuracy of the method was validated by the analysis of a Certified Reference Materials of GBW(E)080395. The proposed method was applied for the analysis of inorganic selenium species in natural waters with good recoveries. The developed method of monolithic CME-ICP-MS is sensitive, simple and rapid for the analysis of inorganic selenium species in natural waters. PMID- 30029441 TI - Temperature-dependent schlieren effect in liquid flow for chemical analysis. AB - In flow analysis, such as flow injection analysis, liquid lens is formed at the boundary between two adjacent liquid media which have different refractive indices. Light refraction at the liquid interface gives the so-called 'schlieren signal'. Schlieren effect is both concentration-dependent and temperature dependent. In this work, the schlieren signal from temperature difference was quantitatively investigated for application in enthalpimetric measurement. The schlieren phenomena was then exploited for chemical analysis. A thermal insulated single flow line manifold was constructed using deionized water at 23 degrees C as the carrier. Deionized water at various temperatures in the range of 5-85 degrees C was injected into the carrier flow. A correlation between the schlieren signal and sample temperature was observed. A heat exchanger unit (HEU), consisting of a small volume glass-reaction chamber with a surrounding water jacket, was constructed. The unit was thermally insulated in a double layer cylindrical PVC unit. For demonstrating the applicability of temperature dependent schlieren effect in chemical analysis, the exothermic oxidation reaction between acid dichromate and ethanol or ascorbic acid was employed with heat transferring to the surrounding water layer. When an aliquot of water from the HEU is injected into the constant temperature flow line the observed schlieren signal was dependent on the analyte concentration. Linear calibration (r2 > 0.99) were obtained covering the concentration range of ethanol and ascorbic acid as found in samples. The developed flow system provides good precision (RSD < 5%) with sample throughput of 4 sample h-1. The system were applied to the determination of ethanol in Thai white spirit and ascorbic acid in vitamin C tablets, respectively. The quantitative results obtained from the schlieren method were in agreement with the comparative methods. PMID- 30029442 TI - Nano-sized anion-exchangers as a stationary phase in capillary electrochromatography for separation and on-line concentration of carboxylic acids. AB - Nano-sized anion-exchangers (NSAE) are promising materials in electrophoretic separation methods due to their high ion-exchange capacity, large surface-to volume ratios, high adhesion to the quartz surface and pH-independent positive charge. In current research we describe a simple approach for NSAE synthesis, which includes two-step grinding of macroanionite followed by centrifugation. The synthesized stable aqueous suspension of NSAE particles was applied as physically adsorbed modifier of fused-silica capillary walls for CEC separation of carboxylic acids. We proposed fast and simple approach to formation of NSAE-based stationary phase on the internal fused-silica surface, which included 15 min rinsing of the capillary with diluted water suspension of NSAE. Formed physically adsorbed coating turned out to be extremely stable in a wide range of pH (from 2 to 10). NSAE modified capillaries provided high separation efficiency (N = 148 732 *103 t.p./m) and selectivity (Rs = 1.2-5.7) of carboxylic acids. Simultaneous application of NSAE-modified capillaries with various on-line concentration techniques (such as field amplified sample stacking and field amplified sample injection) provided both low detection limits (up to 1-3 ng/mL) and high separation selectivity of carboxylic acids. It was useful for their quantitative determination in wines samples. Physically-adsorbed coatings based on NSAE exhibit higher selectivity and lower detection limits compared to commonly used dynamic modifier of fused-silica capillary walls - cetyltrimethylammonium bromide. NSAE-based coatings do not require equilibrium sustaining to maintain the surface coverage. It makes them appropriate for CE-MS application. PMID- 30029443 TI - Identification of non volatile migrant compounds and NIAS in polypropylene films used as food packaging characterized by UPLC-MS/QTOF. AB - Migration of non volatile compounds from twenty six PP films used as food contact materials has been studied in four simulants (ethanol 95% and 10%, acetic acid 3% and Tenax (r)) and analyzed by UPLC-MS/QTOF. Seventy six compounds have been identified, where 76% of them were non-intentionally added substances (NIAS) coming from degradation of additives used, such as methyl or ethyl or hexyl-3 (3,5-di-tert-butyl-4-hydroxyphenyl) from irganox 1076 and irganox 1010 degradation; or impurities such as N,N-bis(2-hydroxyethyl) amines, or compounds of unknown origin, like hydro-ceramides. The most common compounds found were glyceryl monostearate or monopalmitate, erucamide, irganox 1010, irgafos 168, irgafos 168 OXO, N,N-bis(2-hydroxyethyl) tridecylamine and N,N-bis(2 hydroxyethyl) pentadecylamine. Six films didn't comply with the European Regulation No 10/2011/EU, where irganox 1010 and the group of N,N-bis(2 hydroxyethyl) amines exceeded their SMLs. Other films surpassed the maximum concentration recommended by Cramer for the compounds of class II (degradation products) or III (amide compounds) when ethanol 95% was used as simulant. PMID- 30029444 TI - An optimized solvent extraction and characterization of unidentified flavonoid glucuronide derivatives from spinach by UHPLC-HR-QTOF-MS. AB - A rapid, sensitive analytical method using ultra-high-pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-HR QTOF-MS) was developed for the identification and quantification of flavonoids from spinach. The extraction efficiency of flavonoids was evaluated by different solvents such as acetone, ethanol, methanol, acetone: water (70:30), ethanol: water (70:30) and methanol: water (70:30). Flavonoid identification was achieved by UV spectra, high resolution accurate mass and their fragmentation pattern. The precursor and product ions were recorded by both broadband collision ion dissociation (bbCID) and multiple reaction monitoring (MRM) techniques. Different collision energies (5, 10, 15, 20, 40, and 70 eV) were optimized to obtain the mass spectra of flavonoids in positive and negative ionization modes. For the first time, five minor flavonoid glucuronide derivatives were identified in spinach. MRM and bbCID provided glucuronide fingerprint ions at m/z 175.0278 and m/z 113.0257 respectively in negative ionization mode. The quantification of identified flavonoids was achieved by 5,3',4'-trihydroxy-3-methoxy-6:7-methylen dioxyflavone-4'-beta-D-glucuronide which was purified by semi-preparatory HPLC. The purity of the isolated compound was confirmed by NMR analysis. The identified 5,3',4'-trihydroxy-3-methoxy-6:7-methylen-dioxyflavone-4'-beta-D-(2'-O-feurloyl glucuronide) was the prominent flavonoid and the level was significantly higher in the acetone fraction (2.95 +/- 0.16 ug/g FW). This study demonstrates the systematic identification of potential bioactive compounds especially glucuronide derivatives from spinach. PMID- 30029445 TI - A simple poly(styrene-co-divinylbenzene)-coated glass blood spot method for monitoring of seven antidepressants using capillary liquid chromatography-mass spectrometry. AB - A simple, rapid, selective and sensitive monitoring method for the simultaneous determination of the widely-prescribed antidepressants agomelatine, bupropion, citalopram, fluoxetine, mirtazapine, paroxetine, trazodone in just a human blood drop is here developed and validated. This methodology is based on the use of lab manufactured poly(styrene-co-divinylbenzene)-coated glass (PS-DVB) blood spot for the extraction of the analytes and their subsequent separation and detection by capillary liquid chromatography-mass spectrometry (CLC-MS). Briefly, 10 mm-side squares were punched out from blood spots collected on glass substrate coated by 10 ug of the PS-DVB polymer and eluted with 1.0 mL of 2.0% acetic acid in methanol. The analytes were then separated and detected in less than 20 min by capillary CLC-MS using a Jupiter 4 um Proteo 90 A column and water: acetonitrile (20:80 v/v) and ammonium acetate (5 mM, pH 3.0) as mobile phase. Limit of detection (LOD) ranged from 0.018 to 0.038 ug mL-1, and remarkable precision values for the responses and retention times lower than 5.89% and 1.92% were calculated, respectively. Moreover, accuracy values ranging between 85% and 104% were obtained. PMID- 30029446 TI - Dual range lactate oxidase-based screen printed amperometric biosensor for analysis of lactate in diversified samples. AB - Lactate concentration is studied as an indicator of physical performance in sports activities, and is also analyzed in health care applications, as well as in the food and cosmetic industries. This organic acid is routinely determined in different concentration ranges, depending on the type of samples for analysis. This paper describes the development of a screen-printed lactate oxidase (LOx) based biosensor to determine lactate in broad concentration range. The Cu-MOF (copper metallic framework) crosslinking of 0.25U LOx in a chitosan layer, allows to determine the enzymatic product generated on a platinum modified working electrode, at 0.15 V (vs SPE Ag/AgCl). The biosensor responds linearly in two different concentration ranges: a first catalysis range of 14.65 uA mM-1, from 0.75 uM to 1 mM, followed by a saturation zone from 1 to 4 mM, after which a substrate enzymatic inhibition of 0.207 uA mM-1, is observed up to 50 mM. These two ranges of analysis would allow the biosensor to be used for the determination of lactate in different types of samples, with low and high content of lactate. The method reproducibility was kept below 7% and a limit of detection of 0.75 uM was obtained. The device was successfully used in the determination of lactate in sweat and saliva, as a low cost noninvasive analysis, and also in wine samples. PMID- 30029447 TI - Probing pH variation in living cells and assaying hemoglobin in blood with nitrogen enriched carbon dots. AB - Nitrogen enriched carbon dots (CDs) are prepared by hydrothermal treatment with oxalic acid and ethylenediamine serving as raw materials. The obtained CDs display strong blue fluorescence emission at lambdaex/lambdaem = 320/410 nm, along with a quantum yield of 14%. It is interesting to obtain a linear increase of fluorescence with the variation of pH value within pH 5.01-8.94. Meanwhile, a favorable stability of the fluorescence is achieved in a high saline matrix, i.e., up to 1.0 mol L-1 NaCl, making the CDs particularly suitable for probing pH variation in living cells or real biological systems. In addition, hemoglobin (Hb) significantly quenched the fluorescence of CDs due to the inner filter effect and static quenching, providing a linear relationship between fluorescence and Hb concentration within 20-500 mg L-1. The CDs exhibit favorable selectivity for both pH sensing and hemoglobin detection, which are further demonstrated by selective and sensitive intracellular pH monitoring in living HeLa cells and Hb assay in human blood. PMID- 30029448 TI - Impurity profiling of the most frequently encountered falsified polypeptide drugs on the Belgian market. AB - Advances in biotechnology and the chemical synthesis of peptides have made biopharmaceuticals and synthetic peptide drugs viable pharmaceutical compounds today and an important source for tomorrow's drugs and therapies. Unfortunately, also falsifications and counterfeit versions of these powerful and promising drugs are offered illegally via the internet. Since these falsified preparations are produced outside the legally required quality systems, end-users have no guarantee regarding the efficacy and safety of these products. Although falsified samples of biotherapeutics were already analysed, looking at a specific aspect of their quality or identity, no systematic studies have been performed regarding the presence of different impurities or possible contaminations. Therefore, in order to obtain a better understanding of the potential health risks related to the usage of falsified polypeptide drugs we performed a systematic screening of the ten most frequently encountered falsified peptide drugs on the Belgian market acquired from three different suspected illegal internet pharmacies. The screening incorporated the analysis of the active pharmaceutical ingredient (API), API-related impurities, small molecule contaminants (defined as organic small molecules not belonging to the other categories), elemental impurities and residual solvents. This comprehensive study showed that these type of falsified drugs not only have a high variation in amount of drugs per unit and a low purity (ranging between 5% and 75% for cysteine containing peptides), but also contained the known toxic class one elemental impurities arsenic (As) and lead (Pb). One sample was contaminated with Pb while multiple samples were found with concentrations up to ten times the ICH toxicity limit for parenteral drugs. Subsequent speciation of As confirmed the elevated concentrations for As and demonstrated that all As was present in the more toxic inorganic form. Together with the (sometimes) high amount of peptide impurities and the inherent dangers associated with the use of unauthorized peptide drugs (such as doping peptides or preclinical drugs) this study confirms the reported potential health risks patients/users take when resorting to falsified peptide drugs. Moreover, the presence of the carcinogen As and the known accumulation in human tissues of Pb raises questions about potential sub-acute to chronic toxicity due to the long term administration of these falsified peptide drugs. PMID- 30029449 TI - Advice on chemical weapons sample stability and storage provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons to increase investigative capabilities worldwide. AB - The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice on the long-term storage and stability of samples collected in the context of chemical weapons investigations. The information they compiled and reviewed is beneficial to all laboratories that carry out analysis of samples related to chemical warfare agents and is described herein. The preparation of this report was undertaken on request from the OPCW Director-General. The main degradation products for chemicals on the Schedules in the Annex on Chemicals of the Chemical Weapons Convention are tabulated. The expertise of the 25 scientists comprising the SAB, a review of the scientific literature on environmental and biomedical sample analysis, and answers to a questionnaire from chemists of nine OPCW Designated Laboratories, were drawn upon to provide the advice. Ten recommendations to ensure the long-term storage and stability of samples collected in relation to the potential use of chemical weapons were provided and are repeated here for the consideration of all laboratories worldwide. PMID- 30029450 TI - A novel electrochemical sensor based on Fe3O4-doped nanoporous carbon for simultaneous determination of diethylstilbestrol and 17beta-estradiol in toner. AB - In this paper, Fe3O4-doped nanoporous carbon (Fe3O4-NC) was synthesized through the carbonization of Fe-porous coordination polymer (Fe-PCP), which are also known as metal-organic framework (MOF), and fabricated into an electrochemical sensor for simultaneous analysis of diethylstilbestrol (DES) and 17beta-estradiol (E2) in toner. Fe3O4-NC was characterized by scanning electron microscope (SEM), powder X-ray diffraction (pXRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, N2 adsorption-desorption and so on. It is of great practical significance to achieve the simultaneous determination of the two estrogens because estrogens are co-existing in many real samples. The simultaneous determination of two common estrogens, DES and E2, was achieved through electro catalytically oxidization at a Fe3O4-NC modified glassy carbon electrode (Fe3O4 NC/GCE). The peak currents of DES and E2 increased linearly as their concentrations increasing from 0.01 to 12 MUmol/L and from 0.01 to 20 MUmol/L, with detection limits of 4.6 nmol/L and 4.9 nmol/L (S/N = 3), respectively. This work was focused on the simultaneous determination of the two estrogens in toner. Furthermore, the recoveries of DES and E2 were 91.2-110%, in actual toner samples. The experimental results manifest that the sensor with a stronger anti interference ability can be used for the simultaneous detection of DES and E2 in the actual toner sample. PMID- 30029452 TI - Near-infrared chemical imaging used for in-line analysis of functional finishes on textiles. AB - This paper demonstrates for the first time that near-infrared (NIR) chemical imaging can be used for in-line analysis of textile finishing processes based on impregnation. In particular, it was shown that this analytical method is sufficiently sensitive for the quantitative determination of the application weight of rather thin layers of finishing chemicals. Quantitative analysis of the data recorded by a hyperspectral camera (1320-1900 nm) was based on chemometric approaches using the partial least squares (PLS) algorithm. In this work, a flame retardant and a polyvinyl acetate-based stiffening agent applied to polyester or cotton fabrics, respectively, were studied with application weights in the range between about 1 and 50 g m-2. For both systems, the prediction error (RMSEP) was found to be about 1.5-2 g m-2. Averaging of the predicted individual values of the application weight of the finishes across the complete surface of the fabric resulted in a very close correlation with the corresponding reference values obtained by gravimetry. Furthermore, NIR chemical imaging was used for the detection of remaining traces of a size (a processing agent) after washing, which had to be washed-out before subsequent processing steps. Results of the present investigations prove that even for very thin size layers between 0.4 and 5.5 g m 2 the application weight can be predicted with a precision of about 0.4 g m-2. Apart from the quantitative determination of the application weights, the use of NIR chemical imaging for the analysis of finished textiles was mainly directed towards the investigation of the spatial distribution or the homogeneity of the applied colorless finishes across the surface of the fabrics. It was shown that this method is able to detect and visualize various inhomogeneities on the finished textiles resulting for instance from processing defects or from various technical effects that may influence the drying process and consequently the spatial distribution of the finish. Moreover, the distribution of traces of size that had been sprayed purposely on a washed polyester fabric could be detected. All measurements in the present study were carried under conditions that were very similar to those in typical technical processes (e.g. with respect to line speed). Therefore, the outstanding performance of the method opens an immense potential for application in process and quality control. PMID- 30029453 TI - Use of sequential injection analysis with lab-at-valve and an optical probe for simultaneous spectrophotometric determination of ascorbic acid and cysteine by mean centering of ratio kinetic profiles. AB - Two new, simple, relatively fast and robust methods for the simultaneous kinetic determination of binary mixtures of ascorbic acid (Asc) and cysteine (Cys) were developed using the mean centering of ratio kinetic profiles method. The methods are based on the difference in the reaction rates of Asc and Cys with 18 molybdodiphosphate at pH 5.1. An optical probe as well as the sequential injection analysis lab-at-valve (SIA-LAV) method were used to carry out simultaneous kinetic analysis. The benefits of the mean centering of ratio kinetic profiles method were shown in comparison with other spectrophotometric kinetic methods. Asc and Cys can be determined in the concentration ranges 20-200 and 8-90 umol L-1 with the batch spectrophotometric method and 10-200 and 4-40 umol L-1 with the SI-LAV method, respectively. The method was successfully used to determine Asc and Cys in dietary supplements. PMID- 30029454 TI - Obesity and risk of myocardial infarction: the INTERHEART study - Author's reply. PMID- 30029455 TI - Department of Error. PMID- 30029456 TI - Erratum to: Lee CL, Min H, Befera N, et al. Assessing cardiac injury in mice with dual energy-microCT, 4D-microCT, and microSPECT imaging after partial heart irradiation. Int J Radiat Oncol Biol Phys 2014;88:686-693. PMID- 30029457 TI - Erratum to: Hennequin C, Bossard N, Servagi-Vernat, et al. Ten-year survival results of a randomized trial on irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys 2013;86:860-866. PMID- 30029459 TI - Uncovering Discrete Synaptic Proteomes to Understand Neurological Disorders. AB - The mammalian nervous system is an immensely heterogeneous organ composed of a diverse collection of neuronal types that interconnect in complex patterns. Synapses are highly specialized neuronal cell-cell junctions with common and distinct functional characteristics that are governed by their protein composition or synaptic proteomes. Even a single neuron can possess a wide-range of different synapse types and each synapse contains hundreds or even thousands of proteins. Many neurological disorders and diseases are caused by synaptic dysfunction within discrete neuronal populations. Mass spectrometry (MS)-based proteomic analysis has emerged as a powerful strategy to characterize synaptic proteomes and potentially identify disease driving synaptic alterations. However, most traditional synaptic proteomic analyses have been limited by molecular averaging of proteins from multiple types of neurons and synapses. Recently, several new strategies have emerged to tackle the 'averaging problem'. In this review, we summarize recent advancements in our ability to characterize neuron type specific and synapse-type specific proteomes and discuss strengths and limitations of these emerging analysis strategies. PMID- 30029460 TI - Europium-Doped Sol-Gel SiO2-Based Glasses: Effect of the Europium Source and Content, Magnesium Addition and Thermal Treatment on Their Photoluminescence Properties. AB - Rare-earth doped silica-based glasses lead the optical materials due to their tailorable spectroscopic and optical properties. In this context, we took advantage of the sol-gel process to prepare various Eu-doped silica glasses to study their luminescent properties before and after annealing at 900 degrees C. The effect of magnesium on these properties was studied in comparison with Mg free-glass. Using TEM, nitrogen sorption, XRD and FT-IR, we confirmed that the magnesium modifies the glass structure and the thermal treatment eliminates the aqueous environment, modifying the structure ordering. The emission spectra and the decay time curves show the advantages of the Mg addition and the annealing on the photoluminescent properties. PMID- 30029458 TI - Lyme Disease Transmission Risk: Seasonal Variation in the Built Environment. AB - Seasonal variation in spatial distribution and pathogen prevalence of Borrelia burgdorferi in blacklegged ticks (Ixodes scapularis) influences human population risk of Lyme disease in peri-urban built environments. Parks, gardens, playgrounds, school campuses and neighborhoods represent a significant risk for Lyme disease transmission. From June 2012 through May 2014, ticks were collected using 1 m2 corduroy cloths dragged over low-lying vegetation parallel to walkways with high human foot traffic. DNA was extracted from ticks, purified and presence of B. burgdorferi assessed by polymerase chain reaction amplification. Summer is reported as the time of highest risk for Lyme disease transmission in the United States and our results indicate a higher tick density of 26.0/1000 m2 in summer vs. 0.2/1000 m2 to 10.5/1000 m2 in spring and fall. However, our findings suggest that tick infection rate is proportionally higher during the fall and spring than summer (30.0-54.7% in fall and 36.8-65.6% in spring vs. 20.0-28.2% in summer). Seasonal variation in infected tick density has significant implications for Lyme disease transmission as people are less likely to be aware of ticks in built environments, and unaware of increased infection in ticks in spring and fall. These factors may lead to more tick bites resulting in Lyme infection. PMID- 30029462 TI - Electronic Band Structure Variations in the Ceria Doped Zirconia: A First Principles Study. AB - Using first principle calculations, the effect of Ce with different doping concentrations in the network of Zirconium dioxide (ZrO2) is studied. The ZrO2 cell volume linearly increases with the increasing Ce doping concentration. The intrinsic band gap of ZrO2 of 5.70 eV reduces to 4.67 eV with the 2.08% Ce doping. In 4.16% cerium doped ZrO2, the valence band maximum and conduction band minimum come closer to each other, about 1.1 eV, compared to ZrO2. The maximum band gap reduction of ZrO2 is observed at 6.25% Ce doping concentration, having the value of 4.38 eV. No considerable shift in the band structure is found with further increase in the doping level. The photo-response of the ZrO2 is modulated with Ce insertion, and two distinct modifications are observed in the absorption coefficient: an imaginary part of the dielectric function and conductivity. A 2.08% Ce-doped ZrO2 modeled system reduces the intensities of peaks in the optical spectra while keeping the peaks of intrinsic ZrO2. However, the intrinsic peaks related to ZrO2 completely vanish in 4.16%, 6.25%, 8.33%, and 12.5% Ce doped ZrO2, and a new absorption hump is created. PMID- 30029463 TI - The Nutrition Knowledge of Croatian General Practitioners. AB - Nutrition care delivered in primary health care setting is an effective and necessary preventive health care measure. General practitioners (GPs) nutrition knowledge is related to their nutrition care practice. The aim of this study was to explore the nutrition knowledge of Croatian GPs, and to investigate its connection with the implementation of nutrition care in GPs' offices. A cross sectional study was conducted among 17.0% of randomly selected GPs, from May to July 2013, via an anonymous questionnaire. The study showed that only 35.8% of the Croatian GPs had an adequate level of nutrition knowledge (five or more correct answers to nutrition questions). The study further revealed that females, GPs with additional education in nutrition and GPs who had not suffered from chronic diseases with poor nutrition posing as a risk factor had better nutrition knowledge (p = 0.029, p < 0.001 and p = 0.041, respectively). The Spearman rank correlation between GPs' nutrition knowledge and the implementation of nutrition care in their offices during daily work with patients was rs = -0.190 (p < 0.001). To provide nutrition care in GPs' offices in Croatia, strategies for improving GPs' nutrition knowledge are needed. PMID- 30029461 TI - Short-Term Daily Intake of Polydextrose Fiber Does Not Shorten Intestinal Transit Time in Constipated Adults: A Randomized Controlled Trial. AB - Chronic constipation (CC) remains a common gastrointestinal (GI) disorder that conveys a substantial healthcare burden. Expert guidelines recommend increasing fiber intake, yet the clinical evidence to support this needs strengthening for specific fibers. The aim was to evaluate changes in intestinal transit time and GI symptoms in CC patients who consumed polydextrose. In a randomized, double blind, placebo-controlled trial, 128 adults with CC received 8 g or 12 g polydextrose, or placebo, daily for 4 weeks. Transit time, as primary outcome, was assessed by radiopaque marker distribution after 2-weeks intervention. Bowel habits, GI symptoms and quality of life (QOL) were assessed by questionnaire, including the Patient-Assessment of Constipation (PAC) Symptoms (SYM), and PAC QOL. Following 2-weeks intervention, no reduction was seen in transit time in any group and following 2- or 4-weeks intervention, no improvements were seen in stool frequency or consistency in any group. After 2-weeks intervention with 8 g/day polydextrose an improvement was seen in the PAC-SYM rectal score (p = 0.041). After 4-weeks intervention both rectal (p = 0.049) and stool (p = 0.029) scores improved while improvement in the QOL satisfaction score did not reach significance (p = 0.071). Overall, the results suggest that 2-weeks consumption of 8 or 12 g/day polydextrose does not significantly improve physiological measures of gut function in CC adults. Longer term consumption may improve clinical measures, but further studies will be required to substantiate this. PMID- 30029464 TI - Degradation Characteristics of Color Index Direct Blue 15 Dye Using Iron-Carbon Micro-Electrolysis Coupled with H2O2. AB - Currently, many industrial dyes are discharged into the environment in China, leading to serious water pollution. However, synthetic organic dyes in industrial effluents cannot be degraded by conventional wastewater treatment methods. Consequently, it is necessary to develop new environmentally friendly technologies to completely mineralize these non-biodegradable compounds. In this study, 300 mg/L typical Color Index (CI) Direct Blue 15 (benzidine disazo) in simulated dye wastewater was degraded by iron-carbon micro-electrolysis coupled with H2O2 to explore its decolorization, total organic carbon (TOC) removal rate, and degradation characteristics. Under the optimal degradation conditions (Fe/C = 2:1, pH = 3, 60-min reaction, 2 mL/L H2O2 (added in three aliquots), 300 mg/L dye), the TOC removal rate and the level of dye decolorization attained 40% and 98%, respectively. In addition, the degradation kinetics indicated that the iron carbon micro-electrolysis process coupled with H2O2 followed first-order reaction kinetics. A degradation pathway for CI Direct Blue 15 was proposed based on the analysis results of treated wastewater obtained using UV-Vis spectrophotometry and gas chromatography-mass spectrometry (GC-MS). This study provides an efficient and economical system for the degradation of non-biodegradable pollutants. PMID- 30029465 TI - New Sample Preparation Method for Honey Volatiles Fingerprinting Based on Dehydration Homogeneous Liquid-Liquid Extraction (DHLLE). AB - Qualitative chemical fingerprinting of the honey volatiles by gas chromatography and mass spectrometry (GC-MS) has been an efficient authentication tool that allowed for the classification of the honey botanical origin (strongly related to its medicinal and market value). However, the usage of current sample preparation methods is limited by selectivity of the volatiles extraction from the honey matrix and requires significant solvent volume. Therefore, a new sample preparation method based on dehydrating homogeneous liquid-liquid extraction (DHLLE) involving reduced solvent usage was developed for screening volatiles and semi-volatiles from the honey. The effective extraction was achieved by implementing a miscible liquid extraction system (aqueous honey solution/isopropanol) followed by separation through dehydration with MgSO4 and purification by a solvent polarity change and washing. The method was evaluated by estimating accuracy and precision. The DHLLE method showed satisfactory recoveries (75.2 to 93.5%) for typical honey volatiles: linalool, borneol, terpinen-4-ol, alpha-terpineol, p-anisaldehyde, eugenol, and vanillin. It also showed superior repeatability with percent relative standard deviation (RSD%) 0.8 8.9%. For benzyl alcohol, methyl syringate, and caffeine, the recoveries were 54.3 to 63.9% and 67.3 to 77.7% at lower and higher spiking levels, respectively. Applied to unifloral apple honey, the DHLLE method allowed for the identification of 40 compounds including terpenes, hydrocarbons, phenylpropanoids, and other benzene derivatives, which makes it suitable for fingerprinting and chemical marker screening. The obtained results were comparable or better than those obtained with ultrasonic extraction with dichloromethane. PMID- 30029466 TI - Simple Urea Immersion Enhanced Removal of Tetracycline from Water by Polystyrene Microspheres. AB - Antibiotics pose potential ecological risks in the water environment, necessitating their effective removal by reliable technologies. Adsorption is a conventional process to remove such chemicals from water without byproducts. However, finding cheap adsorbents with satisfactory performance is still a challenge. In this study, polystyrene microspheres (PSM) were enhanced to adsorb tetracycline by surface modification. Simple urea immersion was used to prepare urea-immersed PSM (UPSM), of which surface groups were characterized by instruments to confirm the effect of immersion. Tetracycline hydrochloride (TC) and doxycycline (DC) were used as typical adsorbates. The adsorptive isotherms were interpreted by Langmuir, Freundlich, and Tempkin models. After urea immersion, the maximum adsorption capacity of UPSM at 293 K and pH 6.8 increased about 30% and 60%, achieving 460 mg/g for TC and 430 mg/g for DC. The kinetic data were fitted by first-order and second-order kinetics and Weber-Morris models. The first-order rate constant for TC adsorption on UPSM was 0.41 /h, and for DC was 0.33 /h. The cyclic urea immersion enabled multilayer adsorption, which increased the adsorption capacities of TC on UPSM by two to three times. The adsorption mechanism was possibly determined by the molecular interaction including pi-pi forces, cation-pi bonding, and hydrogen bonding. The simple surface modification was helpful in enhancing the removal of antibiotics from wastewater with similar structures. PMID- 30029469 TI - Tetrel Bonding Interactions in Perchlorinated Cyclopenta- and Cyclohexatetrelanes: A Combined DFT and CSD Study. AB - In this manuscript, we combined DFT calculations (PBE0-D3/def2-TZVP level of theory) and a Cambridge Structural Database (CSD) survey to evaluate the ability of perchlorinated cyclopenta- and cyclohexatetrelanes in establishing tetrel bonding interactions. For this purpose, we used Tr5Cl10 and Tr6Cl12 (Tr = Si and Ge) and HCN, HF, OH- and Cl- as electron donor entities. Furthermore, we performed an Atoms in Molecules (AIM) analysis to further describe and characterize the interactions studied herein. A survey of crystal structures in the CSD reveals that close contacts between Si and lone-pair-possessing atoms are quite common and oriented along the extension of the covalent bond formed by the silicon with the halogen atom. PMID- 30029468 TI - (-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study. AB - Upon acylation of the proteasome by the beta-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-beta-lactonization strategy to construct the bicyclic beta-lactone core, enabled synthesis of (-)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition. PMID- 30029467 TI - Long-Term Dietary Intake of Chia Seed Is Associated with Increased Bone Mineral Content and Improved Hepatic and Intestinal Morphology in Sprague-Dawley Rats. AB - Chia seeds (Salvia hispanica) provide an unusually high content of alpha linolenic acid with several potential health benefits, but few studies have examined the long-term intake of n-3 fatty acid-rich plant foods such as chia. In this work, we investigated some of the effects of a diet containing 10% chia seeds versus a conventional isocaloric diet for 10 and 13 months on body measurements, musculoskeletal system, the liver, and the intestines of 20 male Sprague-Dawley rats assigned into two groups. The n-6/n-3 ratios for the control and chia diets were 7.46 and 1.07, respectively. For the first 10 months of the diet, the body parameters and weights were similar, but at 13 months, the bone mineral content (BMC) of the chia-fed rats was significantly higher than that of the controls whether in total or proximal areas of the left tibia. Also, significant positive correlations were found between the age of the chia group and the bone mineral density, BMC, weight of the musculoskeletal system, final body weight, and skin weight. Liver and intestinal examinations showed improved morphology associated with lower lipid deposit in hepatocytes and increased intestinal muscle layers and crypt size in the chia group. This study provides new data suggesting the potential benefits associated with the long-term intake of chia seeds. PMID- 30029470 TI - Design and Optimization of FBG Implantable Flexible Morphological Sensor to Realize the Intellisense for Displacement. AB - The measurement accuracy of the intelligent flexible morphological sensor based on fiber Bragg grating (FBG) structure was limited in the application of geotechnical engineering and other fields. In order to improve the precision of intellisense for displacement, an FBG implantable flexible morphological sensor was designed in this study, and the classification morphological correction method based on conjugate gradient method and extreme learning machine (ELM) algorithm was proposed. This study utilized finite element simulations and experiments, in order to analyze the feasibility of the proposed method. Then, following the corrections, the results indicated that the maximum relative error percentages of the displacements at measuring points in different bending shapes were determined to be 6.39% (Type 1), 7.04% (Type 2), and 7.02% (Type 3), respectively. Therefore, it was confirmed that the proposed correction method was feasible, and could effectively improve the abilities of sensors for displacement intellisense. In this paper, the designed intelligent sensor was characterized by temperature self-compensation, bending shape self-classification, and displacement error self-correction, which could be used for real-time monitoring of deformation field in rock, subgrade, bridge, and other geotechnical engineering, presenting the vital significance and application promotion value. PMID- 30029473 TI - Development of Validated and Stability-Indicating LC-DAD and LC-MS/MS Methods for Determination of Avanafil in Pharmaceutical Preparations and Identification of a Novel Degradation Product by LCMS-IT-TOF. AB - Avanafil (AVA), one of the most effective drugs prescribed for erectile dysfunction, is a pyrimidine-derivative PDE5 inhibitor. In the current work, new LC methods were developed and validated for quantitative determination of avanafil and qualitative determination of its degradation products. The quantitative determination of avanafil was carried out using liquid chromatography with photodiode array detection (LC-DAD) and liquid chromatography tandem mass spectrometry LC-MS/MS methods, and fully validated according to the ICH Q2 (R1) guideline, while qualitative determination was performed using a liquid chromatography mass spectrometry-ion trap-time of flight (LCMS-IT-TOF) instrument. The separation of avanafil and its degradation products was carried out using the same reversed-phase chromatographic conditions, in which a second generation C18-bonded monolithic silica column (Chromolith(r) High Resolution RP 18e, 100 * 4.6 mm, Merck KGaA) was used as stationary phase. Briefly, the methods enable quantitation of avanafil with high accuracy (recovery > 95%) and precision (RSD% < 2.0), within the ranges of 0.5-20 MUg/mL for LC-DAD and 150-6000 ng/mL for LC-MS/MS. In the forced degradation studies, over and above currently existing data, a new oxidation-based degradation product, whose predicted m/z is 367.1168, was identified and its structure was confirmed by high-resolution mass spectrometric analysis. As the main advantage, either an LC-DAD or LC-MS/MS instrument can be chosen for interference-free quantitation of AVA, according to the facilities in quality-control laboratories. PMID- 30029472 TI - Targeted Molecular Imaging Using Aptamers in Cancer. AB - Imaging is not only seeing, but also believing. For targeted imaging modalities, nucleic acid aptamers have features such as superior recognition of structural epitopes and quick uptake in target cells. This explains the emergence of an evolved new class of aptamers into a wide spectrum of imaging applications over the last decade. Genetically encoded biosensors tagged with fluorescent RNA aptamers have been developed as intracellular imaging tools to understand cellular signaling and physiology in live cells. Cancer-specific aptamers labeled with fluorescence have been used for assessment of clinical tissue specimens. Aptamers conjugated with gold nanoparticles have been employed to develop innovative mass spectrometry tissue imaging. Also, use of chemically conjugated cancer-specific aptamers as probes for non-invasive and high-resolution imaging has been transformative for in vivo imaging in multiple cancers. PMID- 30029474 TI - Intestinal Barrier Function in Chronic Kidney Disease. AB - The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products. The syndrome of uremia equals the altered physiology due to irreversible loss of kidney function that is left uncorrected for, despite therapeutic intervention(s). The intestines and its microbial content are prime contributors to this syndrome. The intestinal barrier separates the self (or the so-called "milieu interior") from the environment. In the large intestine, the intestinal barrier keeps apart human physiology and the microbiota. The enterocytes and the extracellular mucin layer functions form a complex multilayered structure, facilitating complex bidirectional metabolic and immunological crosstalk. The current review focuses on the intestinal barrier in chronic kidney disease (CKD). Loss of kidney function results in structural and functional alterations of the intestinal barrier, contribution to the syndrome of uremia. PMID- 30029475 TI - Analysis of the Active Constituents and Evaluation of the Biological Effects of Quercus acuta Thunb. (Fagaceae) Extracts. AB - We evaluated the antioxidant and antibacterial activity of hexnane, ethyl acetate, acetone, methanol, ethanol, and water extracts of the Quercus acuta leaf. The antioxidant properties were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, reducing power, and total phenolic content. Antibacterial activity was assessed against general infectious pathogens, including antibiotic-resistant clinical isolates. The methanolic extract showed the highest DPPH radical scavenging activity and total phenolic content, while the reducing power was the highest in the water extract. The ethyl acetate extract showed the best antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) strains. Additionally, it displayed antibacterial activity against Staphylococcus aureus KCTC1928, Micrococcus luteus ATCC 9341, Salmonella typhimurium KCTC 1925, Escherichia coli KCTC 1923, and eight MRSA strains. These results present basic information for the possible uses of the ethanolic and ethyl acetate extracts from Q. acuta leaf in the treatment of diseases that are caused by oxidative imbalance and antibiotic-resistant bacterial infections. Six active compounds, including vitamin E, which are known to possess antioxidant and antibacterial activity, were identified from the extracts. To the best of our knowledge, this is the first study that reports the chemical profiling and antibacterial effects of the various QA leaf extracts, suggesting their potential use in food therapy or alternative medicine. PMID- 30029476 TI - A Micellar-Hydrogel Nanogrid from a UV Crosslinked Inulin Derivative for the Simultaneous Delivery of Hydrophobic and Hydrophilic Drugs. AB - Hydrogels are among the most common materials used in drug delivery, as polymeric micelles are too. They, preferentially, load hydrophilic and hydrophobic drugs, respectively. In this paper, we thought to combine the favorable behaviors of both hydrogels and polymeric micelles with the specific aim of delivering hydrophilic and hydrophobic drugs for dual delivery in combination therapy, in particular for colon drug delivery. Thus, we developed a hydrogel by UV crosslinking of a methacrylated (MA) amphiphilic derivative from inulin (INU) (as known INU is specifically degraded into the colon) and vitamin E (VITE), called INVITEMA. The methacrylated micelles were physicochemically characterized and subjected to UV irradiation to form what we called the "nanogrids". The INVITEMA nanogrids were characterized by DSC, SEM, TEM, water uptake and beclomethasone dipropionate (BDP) release. In particular, the release of the hydrophobic drug was specifically assessed to verify that it can spread along the hydrophilic portions and, therefore, effectively released. These systems can open new pharmaceutical applications for known hydrogels or micelle systems, considering that in literature only few examples are present. PMID- 30029477 TI - Impact of the Direct Ageing Procedure on the Age Hardening Response of Al-Mg-Si 6101 Alloy. AB - Al-Mg-Si alloys are used not only as construction material, but also as a material for electrical conductors. For this application, it is crucial for the alloy to achieve a balance between strength and electrical properties. This is achieved in practice by a combination of strain and precipitation hardening. The current paper focuses on a heat treatment procedure in which the EN AW 6101 alloy is cooled by a flowing air stream from the solutionizing temperature down to the artificial ageing temperature. The proposed procedure, unlike the common heat treatment leading to the T6 temper, allowed for the precipitation of the coarser beta" phase with the presence of relatively wide precipitate-free zones. The age hardening response was investigated by Brinell hardness measurements, eddy current testing and microstructural observations using transmission electron microscopy (TEM). The applied heat treatment resulted in slightly lower strength (compared to the T6 temper), but improved electrical performance of the alloy. PMID- 30029471 TI - One-Carbon Metabolism: Biological Players in Epithelial Ovarian Cancer. AB - Metabolism is deeply involved in cell behavior and homeostasis maintenance, with metabolites acting as molecular intermediates to modulate cellular functions. In particular, one-carbon metabolism is a key biochemical pathway necessary to provide carbon units required for critical processes, including nucleotide biosynthesis, epigenetic methylation, and cell redox-status regulation. It is, therefore, not surprising that alterations in this pathway may acquire fundamental importance in cancer onset and progression. Two of the major actors in one-carbon metabolism, folate and choline, play a key role in the pathobiology of epithelial ovarian cancer (EOC), the deadliest gynecological malignancy. EOC is characterized by a cholinic phenotype sustained via increased activity of choline kinase alpha, and via membrane overexpression of the alpha isoform of the folate receptor (FRalpha), both of which are known to contribute to generating regulatory signals that support EOC cell aggressiveness and proliferation. Here, we describe in detail the main biological processes associated with one-carbon metabolism, and the current knowledge about its role in EOC. Moreover, since the cholinic phenotype and FRalpha overexpression are unique properties of tumor cells, but not of normal cells, they can be considered attractive targets for the development of therapeutic approaches. PMID- 30029478 TI - Enhancement of Antibacterial Activity of Orange Oil in Pectin Thin Film by Microemulsion. AB - The purpose of this study was to prepare orange oil microemulsion (ME) and to investigate the antimicrobial activity of film containing orange oil ME. First, surfactants and co-surfactants were screened on their efficiency to form ME using pseudo-ternary phase diagrams. The influences of surfactant and co-surfactant mass ratios were studied and optimized ME-loaded-films were prepared. Then, films containing orange oil ME were characterized by SEM and texture analyzer, and then evaluated for antimicrobial activity against Staphylococcus aureus and Propionibacterium acnes using an agar disc diffusion method. The results showed that Tween 80 as surfactant and propylene glycol as co-surfactant at a 1:1 ratio possessed the maximum ME area. Three ME formulations of ME 20, ME 25, and ME 30, which consisted of 20, 25, and 30% w/v of orange oil were prepared, respectively. All ME formulations showed particle sizes of about 60.26-80.00 nm, with broad a polydispersity index of 0.42. The orange oil ME films exhibited higher elastic values than the control. The diameters of inhibition zones for FME 20, FME 25, and FME 30 against P. acnes were 13.64, 15.18, and 16.10 mm, respectively. Only the FME 30 had an antimicrobial activity against S. aureus with 8.32 mm of inhibition zone. Contrarily, the control film had no antimicrobial activity against both bacteria. In conclusion, the present study found that the antibacterial activity of orange oil in pectin thin film could be enhanced by preparing orange oil as an ME before loading into pectin thin film. PMID- 30029479 TI - Novel T7 Phage Display Library Detects Classifiers for Active Mycobacterium Tuberculosis Infection. AB - Tuberculosis (TB) is caused by Mycobacterium tuberculosis (MTB) and transmitted through inhalation of aerosolized droplets. Eighty-five percent of new TB cases occur in resource-limited countries in Asia and Africa and fewer than 40% of TB cases are diagnosed due to the lack of accurate and easy-to-use diagnostic assays. Currently, diagnosis relies on the demonstration of the bacterium in clinical specimens by serial sputum smear microscopy and culture. These methods lack sensitivity, are time consuming, expensive, and require trained personnel. An alternative approach is to develop an efficient immunoassay to detect antibodies reactive to MTB antigens in bodily fluids, such as serum. Sarcoidosis and TB have clinical and pathological similarities and sarcoidosis tissue has yielded MTB components. Using sarcoidosis tissue, we developed a T7 phage cDNA library and constructed a microarray platform. We immunoscreened our microarray platform with sera from healthy (n = 45), smear positive TB (n = 24), and sarcoidosis (n = 107) subjects. Using a student t-test, we identified 192 clones significantly differentially expressed between the three groups at a False Discovery Rate (FDR) <0.01. Among those clones, we selected the top ten most significant clones and validated them on independent test set. The area under receiver operating characteristics (ROC) for the top 10 significant clones was 1 with a sensitivity of 1 and a specificity of 1. Sequence analyses of informative phage inserts recognized as antigens by active TB sera may identify immunogenic antigens that could be used to develop therapeutic or prophylactic vaccines, as well as identify molecular targets for therapy. PMID- 30029480 TI - Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth. AB - Amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-Type Amino Acid Transporter 1 (LAT1) are coordinately enhanced in human cancers where among other roles, they are thought to drive mechanistic target-of-rapamycin (mTOR) growth signaling. To assess ASCT2 and LAT1 as therapeutic targets, nine unique short hairpin RNA (shRNA) vectors were used to stably suppress transporter expression in human epithelial (Hep3B) and mesenchymal (SK-Hep1) hepatocellular carcinoma (HCC) cell lines. In addition, six unique CRISPR-Cas9 vectors were used to edit the ASCT2 (SLC1A5) and LAT1 (SLC7A5) genes in epithelial (HUH7) and mesenchymal (SK-Hep1) HCC cells. Both approaches successfully diminished glutamine (ASCT2) and leucine (LAT1) initial-rate transport proportional to transporter protein suppression. In spite of profoundly reduced glutamine or leucine transport (up to 90%), transporter suppression or knockout failed to substantially affect cellular proliferation or basal and amino acid-stimulated mTORC1 growth signaling in either HCC cell type. Only LAT1 knockout in HUH7 slightly reduced growth rate. However, intracellular accumulation of radiolabeled glutamine and leucine over longer time periods largely recovered to control levels in ASCT2 and LAT1 knockout cells, respectively, which partially explains the lack of an impaired growth phenotype. These data collectively establish that in an in vitro context, human epithelial and mesenchymal HCC cell lines adapt to ASCT2 or LAT1 knockout. These results comport with an emerging model of amino acid exchangers like ASCT2 and LAT1 as "harmonizers", not drivers, of amino acid accumulation and signaling, despite their long-established dominant role in initial-rate amino acid transport. PMID- 30029481 TI - 3D Carbon Microelectrodes with Bio-Functionalized Graphene for Electrochemical Biosensing. AB - An enzyme-based electrochemical biosensor has been developed with 3D pyrolytic carbon microelectrodes that have been coated with bio-functionalized reduced graphene oxide (RGO). The 3D carbon working electrode was microfabricated using the pyrolysis of photoresist precursor structures, which were subsequently functionalized with graphene oxide and enzymes. Glucose detection was used to compare the sensor performance achieved with the 3D carbon microelectrodes (3DCMEs) to the 2D electrode configuration. The 3DCMEs provided an approximately two-fold higher sensitivity of 23.56 uA.mM-1.cm-2 compared to 10.19 uA mM-1.cm-2 for 2D carbon in glucose detection using cyclic voltammetry (CV). In amperometric measurements, the sensitivity was more than 4 times higher with 0.39 uA.mM-1.cm-2 for 3D electrodes and 0.09 uA.mM-1.cm-2 for the 2D configuration. The stability analysis of the enzymes on the 3D carbon showed reproducible results over 7 days. The selectivity of the electrode was evaluated with solutions of glucose, uric acid, cholesterol and ascorbic acid, which showed a significantly higher response for glucose. PMID- 30029483 TI - Botulinum Toxin for the Treatment of Hand Tremor. AB - The aim of this study is to review our longitudinal experience with onabotulinumtoxinA (onaBoNT-A) injections for medically refractory hand tremor. We performed a retrospective review of our database of patients treated with onaBoNT-A for hand tremor evaluated between 2010 and 2018 in at least 2 sessions with follow-up. The majority were injected into the forearm flexors (FF), although treatment was individualized. During the specified period, 91 patients (53 essential tremor, 31 dystonic tremor, 6 Parkinson's disease tremor, and 1 cerebellar outflow tremor) met our inclusion criteria. The mean age (SD) was 64.8 years (12.8), and mean duration of follow-up was 29.6 months (25.1) with mean of 7.7 (6.3) treatment visits. FF were injected in 89 (97.8%) patients, exclusively in 74 (81.3%), and 15 (16.5%) were injected in FF and other muscles. EMG guidance was used in 5 patients (5.5%). On a 0-4 "peak effect" rating scale (0 = no effect, 4 = marked improvement in severity and function), 80.2% and 85.7% of patients reported moderate or marked improvement (score 3 or 4) at their first and last follow-up visit, respectively. There was no statistically significant difference in the outcomes between first and last visit: average "peak effect" rating score (3.2 versus 3.4), "global" rating score (3.0 versus 3.2), latency of response (4.5 versus 3.8 days), and total duration of response (12.7 versus 12.8 weeks), except onaBoNT-A dose (65.0 versus 78.6 U/limb, p = 0.002). Of 1095 limb injections, there were 134 (12.2%) non-disabling and transient (mean 36 days) adverse events (132 limb weakness, 2 pain). OnaBoNT-A injections are safe and effective in the treatment of hand tremor. PMID- 30029484 TI - Effective Mechanical Properties and Thickness Determination of Boron Nitride Nanosheets Using Molecular Dynamics Simulation. AB - Research in boron nitride nanosheets (BNNS) has evoked significant interest in the field of nano-electronics, nanoelectromechanical (NEMS) devices, and nanocomposites due to its excellent physical and chemical properties. Despite this, there has been no reliable data on the effective mechanical properties of BNNS, with the literature reporting a wide scatter of strength data for the same material. To address this challenge, this article presents a comprehensive analysis on the effect of vital factors which can result in variations of the effective mechanical properties of BNNS. Additionally, the article also presents the computation of the correct wall thickness of BNNS from elastic theory equations, which is an important descriptor for any research to determine the mechanical properties of BNNS. It was predicted that the correct thickness of BNNS should be 0.106 nm and the effective Young's modulus to be 2.75 TPa. It is anticipated that the findings from this study could provide valuable insights on the true mechanical properties of BNNS that could assist in the design and development of efficient BN-based NEMS devices, nanosensors, and nanocomposites. PMID- 30029485 TI - Protective Mechanism of Sulforaphane on Cadmium-Induced Sertoli Cell Injury in Mice Testis via Nrf2/ARE Signaling Pathway. AB - The present study evaluated the mechanism underlying the protective effect of sulforaphane (SFN) on cadmium (Cd)-induced Sertoli cell (TM4 cells) injury in mice. The apoptosis rate of cells in each group was detected by flow cytometry. It was determined the effect of SFN on the expression of downstream molecular targets of Nrf2/ARE axis and on the lipid peroxide content. The related genes involved in the nuclear factor E2-related factor 2(Nrf2)/antioxidant response element (ARE) signaling pathway were evaluated by RT-PCR; for example, the mRNA expression levels of Nrf2, heme oxygenase-1 (HO-1), glutathione peroxidase (GSH Px), quinone oxidoreductase 1 (NQO1), and gamma-glutamylcysteine synthetase (gamma-GCS), while the protein expression levels were assessed by Western blot. Our results showed that the mRNA and protein expression levels of Nrf2, HO-1, NQO1, GSH-Px, and gamma-GCS were increased in various degree when the Sertoli cells were to added different concentrations of SFN. Our results also showed that SFN reduced the apoptosis rate, increased the activity of T-SOD, inhibited the increase of the MDA content caused by Cd. Meanwhile, SFN could increase the mRNA and protein expression levels of Nrf2, HO-1 and NQO1 and reduced the mRNA and protein expression levels of GSH-Px and gamma-GCS caused by Cd in Sertoli cells (p < 0.01). Taken together, SFN could improve the antioxidant capacity of Sertoli cells, and exert a protective effect on the oxidative damage and apoptosis of Cd induced Sertoli cells through the activation of Nrf2/ARE signal transduction pathway. PMID- 30029482 TI - l-Citrulline Supplementation: Impact on Cardiometabolic Health. AB - Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic endothelial protection. Preliminary evidence is also available for l-citrulline induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health. PMID- 30029486 TI - Testing the Feasibility and Preliminary Efficacy of an 8-Week Exercise and Compensatory Eating Intervention. AB - The aim of this study was to evaluate the feasibility and preliminary efficacy of an intervention comprised of regular exercise alongside educational and motivational support for participants' avoidance of unhealthy compensatory eating. Forty-five sedentary individuals were randomized to an 8-week exercise plus compensatory eating avoidance program (CEAP; n = 24), or an 8-week exercise intervention only (control; n = 21). The feasibility and preliminary efficacy of the intervention were assessed using quantitative measures and supplemented with written responses to open-ended questions. The CEAP workshop was well-received; however, self-reported use of some of the included behavior change strategies was lower than expected. Post-intervention, there was evidence of reduced self reported compensatory eating for participants in the CEAP group but not controls, with CEAP participants also reporting greater use of coping plans relative to controls post-intervention. The exercise program had benefits for waist circumference, body fat percentage, blood pressure, and cardiovascular fitness; however, improvements were similar between groups. Taken together, the results of this study indicate that the CEAP is feasible and may reduce compensatory eating around exercise; however, this effect is small. Potential modifications to the CEAP are discussed within the paper. PMID- 30029487 TI - Antiviral Compounds from Myxobacteria. AB - Viral infections including human immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV) pose an ongoing threat to human health due to the lack of effective therapeutic agents. The re emergence of old viral diseases such as the recent Ebola outbreaks in West Africa represents a global public health issue. Drug resistance and toxicity to target cells are the major challenges for the current antiviral agents. Therefore, there is a need for identifying agents with novel modes of action and improved efficacy. Viral-based illnesses are further aggravated by co-infections, such as an HIV patient co-infected with HBV or HCV. The drugs used to treat or manage HIV tend to increase the pathogenesis of HBV and HCV. Hence, novel antiviral drug candidates should ideally have broad-spectrum activity and no negative drug-drug interactions. Myxobacteria are in the focus of this review since they produce numerous structurally and functionally unique bioactive compounds, which have only recently been screened for antiviral effects. This research has already led to some interesting findings, including the discovery of several candidate compounds with broad-spectrum antiviral activity. The present review looks at myxobacteria-derived antiviral secondary metabolites. PMID- 30029489 TI - Recent Advances in Poly(vinylidene fluoride) and Its Copolymers for Lithium-Ion Battery Separators. AB - The separator membrane is an essential component of lithium-ion batteries, separating the anode and cathode, and controlling the number and mobility of the lithium ions. Among the polymer matrices most commonly investigated for battery separators are poly(vinylidene fluoride) (PVDF) and its copolymers poly(vinylidene fluoride-co-trifluoroethylene) (PVDF-TrFE), poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), and poly(vinylidene fluoride cochlorotrifluoroethylene) (PVDF-CTFE), due to their excellent properties such as high polarity and the possibility of controlling the porosity of the materials through binary and ternary polymer/solvent systems, among others. This review presents the recent advances on battery separators based on PVDF and its copolymers for lithium-ion batteries. It is divided into the following sections: single polymer and co-polymers, surface modification, composites, and polymer blends. Further, a critical comparison between those membranes and other separator membranes is presented, as well as the future trends on this area. PMID- 30029488 TI - Integrated Chemical and Transcriptomic Analysis Reveals the Distribution of Protopanaxadiol- and Protopanaxatriol-Type Saponins in Panax notoginseng. AB - Panax notoginseng is famous for its important therapeutic effects and commonly used worldwide. The active ingredients saponins have distinct contents in different tissues of P. notoginseng, and they may be related to the expression of key genes in the synthesis pathway. In our study, high-performance liquid chromatography results indicated that the contents of protopanaxadiol-(Rb1, Rc, Rb2, and Rd) and protopanaxatriol-type (R1, Rg1, and Re) saponins in below ground tissues were higher than those in above ground tissues. Clustering dendrogram and PCA analysis suggested that the below and above ground tissues were clustered into two separate groups. A total of 482 and 882 unigenes were shared in the below and above ground tissues, respectively. A total of 75 distinct expressions of CYPs transcripts (RPKM >= 10) were detected. Of these transcripts, 38 and 37 were highly expressed in the below ground and above ground tissues, respectively. RT-qPCR analysis showed that CYP716A47 gene was abundantly expressed in the above ground tissues, especially in the flower, whose expression was 31.5-fold higher than that in the root. CYP716A53v2 gene was predominantly expressed in the below ground tissues, especially in the rhizome, whose expression was 20.1-fold higher than that in the flower. Pearson's analysis revealed that the CYP716A47 expression was significantly correlated with the contents of ginsenoside Rc and Rb2. The CYP716A53v2 expression was associated with the saponin contents of protopanaxadiol-type (Rb1 and Rd) and protopanaxatriol-type (R1, Rg1, and Re). Results indicated that the expression patterns of CYP716A47 and CYP716A53v2 were correlated with the distribution of protopanaxadiol-type and protopanaxatriol type saponins in P. notoginseng. This study identified the pivotal genes regulating saponin distribution and provided valuable information for further research on the mechanisms of saponin synthesis, transportation, and accumulation. PMID- 30029490 TI - Childhood Asymmetry Labium Majus Enlargement (CALME): Description of Two Cases. AB - Background: Childhood asymmetry labium majus enlargement (CALME) is an uncommon, benign condition that occurs in pre- and early pubertal girls and is characterized by a painless, fluctuating, non-tender labial swelling with normal overlying skin. Recognition of this benign condition is essential. Differentiation with several other diseases that mimic CALME and require different diagnostic and therapeutic approaches is mandatory. Two cases of CALME are described in this report. Differential diagnoses and therapeutic approaches are highlighted. Case presentation: The first case was an 11-year-old Caucasian girl referred to our hospital for the evaluation of right labium majus, which showed a palpable, painless, soft, non-tender, non-erythematous enlargement measuring approximately 2 cm with indistinct borders. Ultrasound showed a mass 23 * 18 * 12 mm in diameter. Surgical excision of the mass was performed and in the histopathological evaluation, the tissue specimens were composed of haphazardly arranged vascular channels, adipose tissue and nervous elements that were components of the vulvar soft tissue and were compatible with the diagnosis of CALME. Case 2 was a 6-year-old Caucasian girl who presented a post-traumatic painless mass of left labium majus swelling that progressively increased in volume. Ultrasound study evidenced an ill-defined heterogeneous echotexture mass 26 * 15 * 10 mm in diameter and magnetic resonance imaging confirmed these findings. Histopathological examination was performed after bioptic sampling evidencing normal constituents of vulvar soft tissue, including fibroblast, collagen, adipose tissue, blood vessels and nerves compatible with CALME. Conclusions: CALME is a particular clinical condition that occurs mainly in pre pubertal girls and has a benign course but poses numerous problems in differential diagnosis that can be solved only with careful clinical observation and with a careful use of radiological imaging techniques. Our cases, in agreement with recent literature, suggest that radical excision is not recommended and that surgical biopsy should be taken into consideration only in cases of doubt. PMID- 30029492 TI - Dynamic Characteristics Study for Surface Composite of AMMNCs Matrix Fabricated by Friction Stir Process. AB - In the present work, Aluminum Metal Matrix Surface Nano Composites (AMMSNCs) were manufactured using Friction Stir Processing (FSP). Moreover, the fabricated surface composite matrix was exposed to a different number of tool passes with different processing parameters. The tensile test and microstructure examinations were used to study the mechanical properties of the composite surface. The dynamic properties were predicted using modal analysis and finite element methods. After this, dynamic characterization was achieved by combining the numerical and experimental methods to investigate the effects of changing the number of passes on the natural frequency and the damping capacity of the AMMSNCs manufactured using FSP. The results indicated that the damping capacity and dynamic behavior improved with an increased number of FSP passes. PMID- 30029491 TI - Strengthening the One Health Agenda: The Role of Molecular Epidemiology in Aspergillus Threat Management. AB - The United Nations' One Health initiative advocates the collaboration of multiple sectors within the global and local health authorities toward the goal of better public health management outcomes. The emerging global health threat posed by Aspergillus species is an example of a management challenge that would benefit from the One Health approach. In this paper, we explore the potential role of molecular epidemiology in Aspergillus threat management and strengthening of the One Health initiative. Effective management of Aspergillus at a public health level requires the development of rapid and accurate diagnostic tools to not only identify the infecting pathogen to species level, but also to the level of individual genotype, including drug susceptibility patterns. While a variety of molecular methods have been developed for Aspergillus diagnosis, their use at below-species level in clinical settings has been very limited, especially in resource-poor countries and regions. Here we provide a framework for Aspergillus threat management and describe how molecular epidemiology and experimental evolution methods could be used for predicting resistance through drug exposure. Our analyses highlight the need for standardization of loci and methods used for molecular diagnostics, and surveillance across Aspergillus species and geographic regions. Such standardization will enable comparisons at national and global levels and through the One Health approach, strengthen Aspergillus threat management efforts. PMID- 30029493 TI - High-Pressure Homogenization Pretreatment before Enzymolysis of Soy Protein Isolate: the Effect of Pressure Level on Aggregation and Structural Conformations of the Protein. AB - The high-pressure homogenization (HPH) treatment of soybean protein isolate (SPI) before enzymatic hydrolysis using bromelain was investigated. Homogenization pressure and cycle effects were evaluated on the enzymatic degree of hydrolysis and the antioxidant activity of the hydrolysates generated. The antioxidant activity of SPI hydrolysates was analyzed by 1,1-dipheny-2-picrylhydrazyl (DPPH). The sizes and structures of the SPI-soluble aggregate after HPH treatment were analyzed using dynamic and static laser light scattering. The changes in the secondary structure, as measured by Fourier transform infrared spectroscopy (FTIR) and the macromorphology of SPI, were measured by scanning electron microscope (SEM). These results suggested that the HPH treatment (66.65%) could increase the antioxidant activities of the SPI hydrolysates compared with the control (54.18%). SPI hydrolysates treated at 20 MPa for four cycles obtained higher DPPH radical-scavenging activity than other samples. The control was predicted to be a hard sphere, and SPI treatment at 10 MPa was speculated to be Gaussian coil, polydisperse, and then the high-pressure treated SPI became a hollow sphere. Changes in the secondary structures showed protein aggregate formation and rearrangements. The image of SPI varied from a globular to a clump structure, as observed by the SEM. In conclusion, combining HPH treatment and enzymolysis could be an effective way to improve the antioxidant activity of the SPI. PMID- 30029494 TI - The Role of Pharmacists in Travel Medicine in South Africa. AB - Worldwide, pharmacists, who are the most accessible health-care providers, are playing an ever increasing role in travel medicine, assisting travelers in taking the necessary precautions to ensure safe and healthy travel. This article looks at the situation in South Africa, and how pharmacists are performing these functions within the legal constraints of the Medicines and Related Substances Act 101 of 1965, which prevents pharmacists from prescribing many of the travel vaccines and medications. The scope of practice in community pharmacies increased since the successful down-scheduling of some of the antimalarials, allowing pharmacists to supply the many travelers who frequently travel to neighboring countries. As in many other countries, travel medicine in South Africa is currently thwart with products that are out of stock, and a number of temporary guidelines were put in place to deal with these. Ways to facilitate expanding the role of pharmacists in travel medicine in South Africa need to be further explored. PMID- 30029496 TI - Dimensions, Dialectic, Discourse. Three Political Perspectives on the Sustainability of the German Healthcare System. AB - This review article deals with the topic of sustainability in the German healthcare system and presents an overview of how the six articles of our research relate to one another. After introducing to the context of the research, its internal principles, and the methods applied, three perspectives are presented, each also discussed in terms of the respective literature in sustainability science and political science. The review concludes by presenting a circular model and by discussing the general limitations as well as the practical implications of our research. PMID- 30029495 TI - Development of Normal and Cleft Palate: A Central Role for Connective Tissue Growth Factor (CTGF)/CCN2. AB - Development of the palate is the result of an organized series of events that require exquisite spatial and temporal regulation at the cellular level. There are a myriad of growth factors, receptors and signaling pathways that have been shown to play an important role in growth, elevation and/or fusion of the palatal shelves. Altered expression or activation of a number of these factors, receptors and signaling pathways have been shown to cause cleft palate in humans or mice with varying degrees of penetrance. This review will focus on connective tissue growth factor (CTGF) or CCN2, which was recently shown to play an essential role in formation of the secondary palate. Specifically, the absence of CCN2 in KO mice results in defective cellular processes that contribute to failure of palatal shelf growth, elevation and/or fusion. CCN2 is unique in that it has been shown to interact with a number of other factors important for palate development, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), epidermal growth factor (EGF), Wnt proteins and transforming growth factor-betas (TGF-betas), thereby influencing their ability to bind to their receptors and mediate intracellular signaling. The role that these factors play in palate development and their specific interactions with CCN2 will also be reviewed. Future studies to elucidate the precise mechanisms of action for CCN2 and its interactions with other regulatory proteins during palatogenesis are expected to provide novel information with the potential for development of new pharmacologic or genetic treatment strategies for clinical intervention of cleft palate during development. PMID- 30029497 TI - Application of Whole Exome and Targeted Panel Sequencing in the Clinical Molecular Diagnosis of 319 Chinese Families with Inherited Retinal Dystrophy and Comparison Study. AB - Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous diseases involving more than 280 genes and no less than 20 different clinical phenotypes. In this study, our aims were to identify the disease-causing gene variants of 319 Chinese patients with IRD, and compare the pros and cons of targeted panel sequencing and whole exome sequencing (WES). Patients were assigned for analysis with a hereditary eye disease enrichment panel (HEDEP) or WES examination based on time of recruitment. This HEDEP was able to capture 441 hereditary eye disease genes, which included 291 genes related to IRD. As RPGR ORF15 was difficult to capture, all samples were subjected to Sanger sequencing for this region. Among the 163 disease-causing variants identified in this study, 73 had been previously reported, and the other 90 were novel. Genes most commonly implicated in different inheritances of IRDs in this cohort were presented. HEDEP and WES achieved diagnostic yield with 41.2% and 33.0%, respectively. In addition, nine patients were found to carry pathogenic mutations in the RPGR ORF15 region with Sanger sequencing. Our study demonstrates that HEDEP can be used as a first-tier test for patients with IRDs. PMID- 30029498 TI - Plant Metabolomics in the Global Scenario of Food Security: A Systems-Biology Approach for Sustainable Crop Production. PMID- 30029500 TI - The HIV-1 Reverse Transcriptase A62V Mutation Influences Replication Fidelity and Viral Fitness in the Context of Multi-Drug-Resistant Mutations. AB - Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance arises from mutation fixation in the viral genome during antiretroviral therapy. Primary mutations directly confer antiviral drug resistance, while secondary mutations arise that do not confer drug resistance. The A62V amino acid substitution in HIV 1 reverse transcriptase (RT) was observed to be associated with multi-drug resistance, but is not known to be a resistance-conferring mutation. In particular, A62V was observed in various multi-dideoxynucleoside resistant (MDR) mutation complexes, including the Q151M complex (i.e., A62V, V75I, F77L, F116Y, and Q151M), and the T69SSS insertion complex, which has a serine-serine insertion between amino acid positions 69 and 70 (i.e., M41L, A62V, T69SSS, K70R, and T215Y). However, what selective advantage is conferred to the virus remains unresolved. In this study, we hypothesized that A62V could influence replication fidelity and viral fitness with viruses harboring the Q151M and T69SSS MDR mutation complexes. A single-cycle replication assay and a dual-competition fitness assay were used to assess viral mutant frequency and viral fitness, respectively. A62V was found to increase the observed lower mutant frequency identified with each of the viruses harboring the MDR mutation complexes in the single-cycle assay. Furthermore, A62V was observed to improve viral fitness of replication-competent MDR viruses. Taken together, these observations indicate an adaptive role of A62V in virus replication fidelity and viral fitness, which would likely enhance virus persistence during drug-selective pressure. PMID- 30029501 TI - Characterization of UDP-Activated Purinergic Receptor P2Y6 Involved in Japanese Flounder Paralichthys olivaceus Innate Immunity. AB - Uridine 5'-diphosphate (UDP)-activated purinergic receptor P2Y6 is a member of a G-protein-coupled purinergic receptor family that plays an important role in mammalian innate immunity. However, the role of the P2Y6 receptor (P2Y6R) in fish immunity has not been investigated. In this report, we characterized a P2Y6R gene from Japanese flounder (Paralichthys olivaceus) and examined its role in fish innate immunity. Sequence analysis reveals that the Japanese flounder P2Y6R protein is conserved and possesses four potential glycosylation sites. Quantitative real-time RT-PCR analysis shows that P2Y6R is broadly distributed in all examined Japanese flounder tissues with dominant expression in the liver. In addition, P2Y6R gene expression was up-regulated in head kidney macrophages (HKMs) upon lipopolysaccharides (LPS) and poly(I:C) stimulations but down regulated by LPS challenge in peripheral blood leukocytes (PBLs). Furthermore, pharmacological inhibition of the endogenous P2Y6 receptor activity by the potently selective P2Y6R antagonist, MRS 2578, greatly up-regulated pro inflammatory cytokine interleukin (IL)-1beta, IL-6 and TNF-alpha gene expression in PBL cells treated with UDP. Moreover, LPS- and poly(I:C)-induced gene expression of IL-1beta and TNF-alpha in Japanese flounder PBL cells was attenuated significantly by inhibition of P2Y6R activity with antagonist MRS 2578. Collectively, we, for the first time, showed the involvement of functional purinergic P2Y6R in fish innate immunity. PMID- 30029499 TI - Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression. AB - In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches. PMID- 30029502 TI - Characteristics, Usability, and Users Experience of a System Combining Cognitive and Physical Therapy in a Virtual Environment: Positive Bike. AB - We present the architecture and usability evaluation of virtual reality system "Positive Bike"-designed for improving cognitive and motor conditions in frail elderly patients. The system consists of a cycle-ergometer integrated in an immersive virtual reality system (CAVE) which allows combining motor and cognitive exercises according to a "dual-task" paradigm. We tested the usability and user's experience of the prototype in a pilot evaluation study that involved five elderly patients. The prototype was tested in one-session training to understand the limitations and areas for improvement of our system. The evaluation consisted in (i) usability assessment using the system usability scale; (ii) evaluation of user's engagement using the flow state scale; and (iii) expert evaluation involving interviews with domain experts. Results showed a good usability, both for system usability scale and the semi-structured interview. The level of flow (i.e., enjoyment with the task at hand) measured using the short flow state scale, was also high. Analysis of semi-structured interview carried out with domain experts provided further indications to improve the system. Overall, these findings show that, despite some limitations, the system is usable and provides an enjoyable user's experience. PMID- 30029504 TI - Dietary Antioxidants and Prevention of Non-Communicable Diseases. PMID- 30029503 TI - How Accurate Are the ISAAC Questions for Diagnosis of Allergic Rhinitis in Korean Children? AB - Background: The aims of this study were to investigate the prevalence of allergic rhinitis (AR) and the accuracy of the International Study of Asthma and Allergies in Childhood (ISAAC) questions for diagnosis of AR, in Korean children. Methods: Students that participated in an allergic disease prevalence survey in 2010-2017 were evaluated (n = 18,425) using questionnaires and a skin prick test (SPT). Age stratified (5-7, 8-10, 11-13, 14-16 years) prevalence of four rhinitis questions, accuracy of the questions for AR, and proportion of comorbidities in the AR and non-AR (NAR) groups were evaluated. Results: The proportion of students responding to the questionnaire that ever had symptoms of AR since birth, that is, the prevalence of "symptom, ever" was 47.6%. Based on the questionnaire and SPT, overall prevalence of AR and NAR were 21% and 26.5%, respectively. The sensitivity, specificity, and accuracy of "symptom, ever" were 57.5%, 58.4%, and 58.1%, respectively, and those of "diagnosis, ever", who had ever been diagnosed with AR, were 39.8%, 76.9%, and 63.4%, respectively. Questionnaire-based asthma, atopic dermatitis, and food allergy were significantly associated with the AR group compared to the NAR group. Conclusions: Since the AR accuracy of the questionnaire is about 60%, it should be considered that the questionnaire based survey overestimates the true prevalence of AR in Korean children. PMID- 30029505 TI - Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models. AB - Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1alpha and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (1) and discorhabdin L (2), with a specific focus on their anti-angiogenic and anti-tumor effects. We demonstrated that only discorhabdin L (2) possesses excellent anti-angiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L (2) significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L (2) represents a promising HIF-1alpha inhibitor worthy of further drug development. PMID- 30029506 TI - Job Satisfaction and Associated Factors among Medical Staff in Tertiary Public Hospitals: Results from a National Cross-Sectional Survey in China. AB - Medical staff in China's tertiary public hospitals are responsible for providing healthcare to a considerable number of patients, and their job satisfaction needs attention. The aim of this study is to investigate the job satisfaction of medical staff in tertiary public hospitals and to explore its associated factors. Based on a national survey conducted in 2016, this study included 43,645 physicians and nurses nested in 136 tertiary public hospitals in 31 provinces of China. Multi-level logistic regression was used to examine job satisfaction and its association with individual characteristics and job-related factors. Results showed that 48.22% respondents were satisfied with their job, and they were least satisfied with their compensation. Individual characteristics including occupation, gender, education background, alcohol drinking and self-reported health status, as well as job-related factors regarding professional title, work years, income, workload, doctor-patient relationship and practice setting were found to be significantly associated with job satisfaction. Given that some of these factors may be amenable to interventions, we suggest that government and hospital administrators could take some measures to promote continuing education, improve personal health, balance workload and compensation for medical staff, in order to improve the job satisfaction of medical staff in tertiary public hospitals. PMID- 30029507 TI - The Use of Qualitative Behaviour Assessment for the On-Farm Welfare Assessment of Dairy Goats. AB - This research investigated whether using qualitative behaviour assessment (QBA) with a fixed list of descriptors may be related to quantitative animal- (ABM) and resource-based (RBM) measures included in the AWIN (Animal Welfare Indicators) welfare assessment prototype protocol for goats, tested in 60 farms. A principal component analysis (PCA) was conducted on QBA descriptors; then PCs were correlated to some ABMs and RBMs. Subsequently, a combined PCA merged QBA scores, ABMs and RBMs. The study confirms that QBA can identify the differences in goats' emotions, but only few significant correlations were found with ABMs and RBMs. In addition, the combined PCA revealed that goats with a normal hair coat were scored as more relaxed and sociable. A high farm workload was related to bored and suffering goats, probably because farmers that can devote less time to animals may fail to recognise important signals from them. Goats were scored as sociable, but also alert, in response to the presence of an outdoor run, probably because when outdoors they received more stimuli than indoors and were more attentive to the surroundings. Notwithstanding these results, the holistic approach of QBA may allow to register animals' welfare from a different perspective and be complementary to other measures. PMID- 30029508 TI - Intersection and Complement Set (IACS) Method to Reduce Redundant Node in Mobile WSN Localization. AB - The majority of the Wireless Sensor Network (WSN) localization methods utilize a large number of nodes to achieve high localization accuracy. However, there are many unnecessary data redundancies that contributes to high computation, communication, and energy cost between these nodes. Therefore, we propose the Intersection and Complement Set (IACS) method to reduce these redundant data by selecting the most significant neighbor nodes for the localization process. Through duplication cleaning and average filtering steps, the proposed IACS selects the normal nodes with unique intersection and complement sets in the first and second hop neighbors to localize the unknown node. If the intersection or complement sets of the normal nodes are duplicated, IACS only selects the node with the shortest distance to the blind node and nodes that have total elements larger than the average of the intersection or complement sets. The proposed IACS is tested in various simulation settings and compared with MSL* and LCC. The performance of all methods is investigated using the default settings and a different number of degree of irregularity, normal node density, maximum velocity of sensor node and number of samples. From the simulation, IACS successfully reduced 25% of computation cost, 25% of communication cost and 6% of energy consumption compared to MSL*, while 15% of computation cost, 13% of communication cost and 3% of energy consumption compared to LCC. PMID- 30029509 TI - Calibration and Noise Identification of a Rolling Shutter Camera and a Low-Cost Inertial Measurement Unit. AB - A low-cost inertial measurement unit (IMU) and a rolling shutter camera form a conventional device configuration for localization of a mobile platform due to their complementary properties and low costs. This paper proposes a new calibration method that jointly estimates calibration and noise parameters of the low-cost IMU and the rolling shutter camera for effective sensor fusion in which accurate sensor calibration is very critical. Based on the graybox system identification, the proposed method estimates unknown noise density so that we can minimize calibration error and its covariance by using the unscented Kalman filter. Then, we refine the estimated calibration parameters with the estimated noise density in batch manner. Experimental results on synthetic and real data demonstrate the accuracy and stability of the proposed method and show that the proposed method provides consistent results even with unknown noise density of the IMU. Furthermore, a real experiment using a commercial smartphone validates the performance of the proposed calibration method in off-the-shelf devices. PMID- 30029510 TI - Software Sensor for Activity-Time Monitoring and Fault Detection in Production Lines. AB - Industry 4.0-based human-in-the-loop cyber-physical production systems are transforming the industrial workforce to accommodate the ever-increasing variability of production. Real-time operator support and performance monitoring require accurate information on the activities of operators. The problem with tracing hundreds of activity times is critical due to the enormous variability and complexity of products. To handle this problem a software-sensor-based activity-time and performance measurement system is proposed. To ensure a real time connection between operator performance and varying product complexity, fixture sensors and an indoor positioning system (IPS) were designed and this multi sensor data merged with product-relevant information. The proposed model based performance monitoring system tracks the recursively estimated parameters of the activity-time estimation model. As the estimation problem can be ill conditioned and poor raw sensor data can result in unrealistic parameter estimates, constraints were introduced into the parameter-estimation algorithm to increase the robustness of the software sensor. The applicability of the proposed methodology is demonstrated on a well-documented benchmark problem of a wire harness manufacturing process. The fully reproducible and realistic simulation study confirms that the indoor positioning system-based integration of primary sensor signals and product-relevant information can be efficiently utilized in terms of the constrained recursive estimation of the operator activity. PMID- 30029511 TI - Identification of Nanocellulose Retention Characteristics in Porous Media. AB - The application of nanotechnology to the petroleum industry has sparked recent interest in increasing oil recovery, while reducing environmental impact. Nanocellulose is an emerging nanoparticle that is derived from trees or waste stream from wood and fiber industries. Thus, it is taken from a renewable and sustainable source, and could therefore serve as a good alternative to current Enhanced Oil Recovery (EOR) technologies. However, before nanocellulose can be applied as an EOR technique, further understanding of its transport behavior and retention in porous media is required. The research documented in this paper examines retention mechanisms that occur during nanocellulose transport. In a series of experiments, nanocellulose particles dispersed in brine were injected into sandpacks and Berea sandstone cores. The resulting retention and permeability reduction were measured. The experimental parameters that were varied include sand grain size, nanocellulose type, salinity, and flow rate. Under low salinity conditions, the dominant retention mechanism was adsorption and when salinity was increased, the dominant retention mechanism shifted towards log-jamming. Retention and permeability reduction increased as grain size decreased, which results from increased straining of nanocellulose aggregates. In addition, each type of nanocellulose was found to have significantly different transport properties. Experiments with Berea sandstone cores indicate that some pore volume was inaccessible to the nanocellulose. As a general trend, the larger the size of aggregates in bulk solution, the greater the observed retention and permeability reduction. Salinity was found to be the most important parameter affecting transport. Increased salinity caused additional aggregation, which led to increased straining and filter cake formation. Higher flow rates were found to reduce retention and permeability reduction. Increased velocity was accompanied by an increase in shear, which is believed to promote breakdown of nanocellulose aggregates. PMID- 30029512 TI - Non-Covalent Associates of siRNAs and AuNPs Enveloped with Lipid Layer and Doped with Amphiphilic Peptide for Efficient siRNA Delivery. AB - Elaboration of non-viral vehicles for delivery of therapeutic nucleic acids, in particular siRNA, into a cell is an actively growing field. Gold nanoparticles (AuNPs) occupy a noticeable place in these studies, and various nanoconstructions containing AuNPs are reported. We aimed our work to the rational design of AuNPs based siRNA delivery vehicle with enhanced transfection efficiency. We optimized the obtaining of non-covalent siRNAs-AuNPs cores: ionic strength, temperature and reaction time were determined. Formation of cores was confirmed using gel electrophoresis. Stable associates were prepared, and then enveloped into a lipid layer composed of phosphatidylcholine, phosphatidylethanolamine and novel pH sensitive lipidoid. The constructions were modified with [Str-(RL)4G-NH2] peptide (the resulting construction). All intermediate and resulting nanoconstructions were analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) to control their physico-chemical properties. To examine the biological effect of the delivery vehicle, green fluorescent protein (GFP) expressing human embryonic kidney (HEK) Phoenix cells were incubated with the resulting construction containing anti-GFP siRNA, with the siRNA effect being studied by flow cytometry and confocal microscopy. Transfection of the cells with the resulting construction reduced the GFP fluorescence as efficiently as Lipofectamin 3000. Thus, siRNA vehicle based on non-covalently bound siRNA-AuNP core and enveloped into a lipid layer provides efficient delivery of siRNA into a cell followed by specific gene silencing. PMID- 30029513 TI - A New Kind of Quinonic-Antibiotic Useful Against Multidrug-Resistant S. aureus and E. faecium Infections. AB - A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC(r) strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1-32 MUg/mL against Gram-positive ATCC(r) strains. The structure-activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 ug/mL and 4/4 ug/mL, respectively, while for vancomycin the MIC50/90 was 256/512 ug/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF. PMID- 30029514 TI - Comparison of the Effect of Melatonin Treatment before and after Brain Ischemic Injury in the Inflammatory and Apoptotic Response in Aged Rats. AB - Aging is associated with an increase in stroke risk. Melatonin, a potent free radical scavenger and broad spectrum antioxidant, has been shown to counteract inflammation and apoptosis in brain injury. However, little is known on the possible protective effects of melatonin in aged individuals affected by brain ischemia. Also, using melatonin before or after an ischemic stroke may result in significantly different molecular outcomes. The objective of the present study was to compare the effects of pre-ischemia vs. post-ischemia melatonin administration in an ischemic lesion in the cortex and hippocampus of senescent Wistar rats. An obstruction of the middle cerebral artery (MCA) to 18-month-old animals was performed. In general, animals treated with melatonin from 24 h prior to surgery until 7 days after the surgical procedure (PrevT) experienced a significant decrease in the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), glial fibrillary acidic protein (GFAP), Bcl-2 associated death promoter (BAD), and Bcl-2-associated X protein (BAX) in both cortex and hippocampus, while hippocampal levels of sirtuin 1 (SIRT1) and B-cell lymphoma 2 (Bcl-2) increased. Treatment of animals with melatonin only after surgery (AT) resulted in similar effects, but to a lesser extent than in the PrevT group. In any case, melatonin acted as a valuable therapeutic agent protecting aged animals from the harmful effects of cerebral infarction. PMID- 30029515 TI - B Regulatory Cells: Players in Pregnancy and Early Life. AB - Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical uterus to a world full of antigens and the rapid microbial colonization of the mucosa. B regulatory (Breg) cells are a recently discovered B cell subset thought to play a pivotal role in different conditions such as chronic infections, autoimmunity, cancer, and transplantation among others in addition to pregnancy. This review focuses on the role of Breg cells in pregnancy and early infancy, two special stages of life in which recent studies have positioned Breg cells as important players. PMID- 30029516 TI - Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery. AB - The amorphous solid state offers an improved apparent solubility and dissolution rate. However, due to thermodynamic instability and recrystallization tendencies during processing, storage and dissolution, their potential application is limited. For this reason, the production of amorphous drugs with adequate stability remains a major challenge and formulation strategies based on solid molecular dispersions are being exploited. Co-amorphous systems are a new formulation approach where the amorphous drug is stabilized through strong intermolecular interactions by a low molecular co-former. This review covers several topics applicable to co-amorphous drug delivery systems. In particular, it describes recent advances in the co-amorphous composition, preparation and solid-state characterization, as well as improvements of dissolution performance and absorption are detailed. Examples of drug-drug, drug-carboxylic acid and drug amino acid co-amorphous dispersions interacting via hydrogen bonding, pi-pi interactions and ionic forces, are presented together with corresponding final dosage forms. PMID- 30029517 TI - Genomic Analysis of 48 Paenibacillus larvae Bacteriophages. AB - The antibiotic-resistant bacterium Paenibacillus larvae is the causative agent of American foulbrood (AFB), currently the most destructive bacterial disease in honeybees. Phages that infect P. larvae were isolated as early as the 1950s, but it is only in recent years that P. larvae phage genomes have been sequenced and annotated. In this study we analyze the genomes of all 48 currently sequenced P. larvae phage genomes and classify them into four clusters and a singleton. The majority of P. larvae phage genomes are in the 38-45 kbp range and use the cohesive ends (cos) DNA-packaging strategy, while a minority have genomes in the 50-55 kbp range that use the direct terminal repeat (DTR) DNA-packaging strategy. The DTR phages form a distinct cluster, while the cos phages form three clusters and a singleton. Putative functions were identified for about half of all phage proteins. Structural and assembly proteins are located at the front of the genome and tend to be conserved within clusters, whereas regulatory and replication proteins are located in the middle and rear of the genome and are not conserved, even within clusters. All P. larvae phage genomes contain a conserved N acetylmuramoyl-l-alanine amidase that serves as an endolysin. PMID- 30029518 TI - FGF2 Dual Warhead Conjugate with Monomethyl Auristatin E and alpha-Amanitin Displays a Cytotoxic Effect towards Cancer Cells Overproducing FGF Receptor 1. AB - In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: alpha-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead FGF2 conjugate may overcome the potential acquired resistance of FGFR1 overproducing cancer cells towards single cytotoxic drugs. PMID- 30029519 TI - GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer. AB - GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305-0.753] and PFS:HR 0.490, [95% CI 0.336-0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy. PMID- 30029520 TI - Aqueous Extract of Perilla frutescens var. acuta Relaxes the Ciliary Smooth Muscle by Increasing NO/cGMP Content In Vitro and In Vivo. AB - The leaves of Perilla frutescens var. acuta (PFA) are commonly used as a traditional medicine in Korea, Japan, and China. We previously showed that PFA attenuates eye fatigue by improving visual accommodation through a clinical study. However, detailed mechanisms and chemical compounds have not been studied. In this study, we analyzed the active compounds in an aqueous extract of PFA involved in ciliary muscle relaxation in vitro and in vivo. NMR and MS analyses showed that the PFA extract contained mainly luteolin-7-O-diglucuronide and apigenin-7-O-diglucuronide. The composition after freeze-drying and spray-drying was similar. Freeze-dried PFA (50 ug/mL, 100 ug/mL, and 200 ug/mL) increased nitric oxide and cGMP levels in ciliary muscle cells isolated from the eyes of rats. [Ca2+]i decreased in a dose-dependent manner. Furthermore, Sprague-Dawley rats treated with freeze-dried PFA (200 mg/kg, orally) showed significantly increased cGMP levels compared with the control group and irradiated with white light. Our results suggest that PFA extract has the potential to reduce eye fatigue by relaxing ciliary muscles. PMID- 30029521 TI - Carapanosins D-F from the Seeds of Andiroba (Carapa guianensis, Meliaceae) and Their Effects on LPS-Activated NO Production. AB - A novel nor-phragmalin-type limonoid, named carapanosin D (1), and two novel mexicanolide-type limonoids, carapanosins E (2) and F (3), were isolated from the seed oil of andiroba (Carapa guianensis Aublet), a traditional medicine in Brazil and Latin American countries. Their structures were unambiguously determined on the basis of spectroscopic analyses using one-dimensional (1D) and two dimensional (2D) NMR techniques and High resolution Fast Atom Bombardment Mass Spectrometry (HRFABMS). Compounds 1-3 were evaluated for their effects on the production of nitric oxide (NO) in Lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. The NO inhibitory assay suggested that compounds 2 and 3 have high potency as inhibitors of macrophage activation. PMID- 30029523 TI - "Benifuuki" Extract Reduces Serum Levels of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Ligands Containing Apolipoprotein B: A Double-Blind Placebo-Controlled Randomized Trial. AB - (1) Background: Arteriosclerosis is associated with high levels of low-density lipoprotein (LDL) cholesterol. O-methylated catechins in "Benifuuki" green tea are expected to reduce cholesterol levels, although there is limited research regarding this topic; (2) Methods: This trial evaluated 159 healthy volunteers who were randomized to receive ice cream containing a high-dose of "Benifuuki" extract including 676 mg of catechins (group H), a low-dose of "Benifuuki" extract including 322 mg of catechins (group L), or no "Benifuuki" extract (group C). Each group consumed ice cream (with or without extract) daily for 12 weeks, and their lipid-related parameters were compared; (3) Results: A significant reduction in the level of lectin-like oxidized LDL receptor-1 ligand containing ApoB (LAB) was detected in group H, compared to groups L and C. No significant differences between the three groups were detected in their levels of total cholesterol, triglycerides, and LDL cholesterol; (4) Conclusions: "Benifuuki" extract containing O-methylated catechins may help prevent arteriosclerosis. PMID- 30029524 TI - ALTEA: A Software Tool for the Evaluation of New Biomarkers for Alzheimer's Disease by Means of Textures Analysis on Magnetic Resonance Images. AB - The current criteria for diagnosing Alzheimer's disease (AD) require the presence of relevant cognitive deficits, so the underlying neuropathological damage is important by the time the diagnosis is made. Therefore, the evaluation of new biomarkers to detect AD in its early stages has become one of the main research focuses. The purpose of the present study was to evaluate a set of texture parameters as potential biomarkers of the disease. To this end, the ALTEA (ALzheimer TExture Analyzer) software tool was created to perform 2D and 3D texture analysis on magnetic resonance images. This intuitive tool was used to analyze textures of circular and spherical regions situated in the right and left hippocampi of a cohort of 105 patients: 35 AD patients, 35 patients with early mild cognitive impairment (EMCI) and 35 cognitively normal (CN) subjects. A total of 25 statistical texture parameters derived from the histogram, the Gray-Level Co-occurrence Matrix and the Gray-Level Run-Length Matrix, were extracted from each region and analyzed statistically to study their predictive capacity. Several textural parameters were statistically significant (p < 0.05) when differentiating AD subjects from CN and EMCI patients, which indicates that texture analysis could help to identify the presence of AD. PMID- 30029522 TI - Infection of Epstein-Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines. AB - Infection of Epstein-Barr virus (EBV), a ubiquitous human gamma herpesvirus, is associated with various malignancies in B lymphocytes and epithelial cells. EBV encodes 49 microRNAs in two separated regions, termed the BART and BHRF1 loci. Although accumulating evidence demonstrates that EBV infection regulates the profile of microRNAs in the cells, little is known about the microRNAs in exosomes released from infected cells. Here, we characterized the expression profile of intracellular and exosomal microRNAs in EBV-negative, and two related EBV-infected Burkitt lymphoma cell lines having type I and type III latency by next-generation sequencing. We found that the biogenesis of exosomes is upregulated in type III latently infected cells compared with EBV-negative and type I latently infected cells. We also observed that viral and several specific host microRNAs were predominantly incorporated in the exosomes released from the cells in type III latency. We confirmed that multiple viral microRNAs were transferred to the epithelial cells cocultured with EBV-infected B cells. Our findings indicate that EBV infection, in particular in type III latency, modulates the biogenesis of exosomes and the profile of exosomal microRNAs, potentially contributing to phenotypic changes in cells receiving these exosomes. PMID- 30029525 TI - Two-Step Magnetization Reversal FORC Fingerprint of Coupled Bi-Segmented Ni/Co Magnetic Nanowire Arrays. AB - First Order Reversal Curve (FORC) analysis has been established as an appropriate method to investigate the magnetic interactions among complex ferromagnetic nanostructures. In this work, the magnetization reversal mechanism of bi segmented nanowires composed by long Co and Ni segments contacted at one side was investigated, as a model system to identify and understand the FORC fingerprint of a two-step magnetization reversal process. The resulting hysteresis loop of the bi-segmented nanowire array exhibits a completely different magnetic behavior than the one expected for the magnetization reversal process corresponding to each respective Co and Ni nanowire arrays, individually. Based on the FORC analysis, two possible magnetization reversal processes can be distinguished as a consequence of the ferromagnetic coupling at the interface between the Ni and Co segments. Depending on the relative difference between the magnetization switching fields of each segment, the softer magnetic phase induces the switching of the harder one through the injection and propagation of a magnetic domain wall when both switching fields are comparable. On the other hand, if the switching fields values differ enough, the antiparallel magnetic configuration of nanowires is also possible but energetically unfavorable, thus resulting in an unstable magnetic configuration. Making use of the different temperature dependence of the magnetic properties for each nanowire segment with different composition, one of the two types of magnetization reversal is favored, as demonstrated by FORC analyses. PMID- 30029526 TI - Novel Type of Complicated Autosomal Dominant Hereditary Spastic Paraplegia Associated with Congenital Distal Arthrogryposis Type I. AB - Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurological disorders. HSP is classified as pure when only a spastic weakness of the lower extremities is present. Complex HSP comes with additional neurological or systemic abnormalities. Complex HSP with skeletal abnormalities is rare and mostly seen in autosomal recessive HSP. Autosomal dominant (AD) complex HSP with skeletal abnormalities are consistently seen only in SPG9 (spastic gait type 9). In this paper, we report a kindred condition with AD HSP among four living affected individuals who had progressive, adult onset spastic paraparesis that was associated with a distal arthrogryposis (DA) in every affected individual. They also had episodes of rhabdomyolysis without any clinical signs of myopathy. Exhaustive genetic analysis including targeted sequencing of known HSP and DA genes and whole exome sequencing did not identify the disease-causing gene. It excluded all known HSP and DA genes. We propose that this is a novel genetic type of complex AD HSP. Elucidation of a genetic cause of this type of HSP will further contribute to our understanding of axonal degeneration and skeletal abnormalities. PMID- 30029527 TI - Combined Supplementation of Pre-Exercise Carbohydrate, Alanine, and Proline and Continuous Intake of Green Tea Catechins Effectively Boost Endurance Performance in Mice. AB - Continuous intake of green tea catechins (GTC) increases fatty acid utilization as an energy source and improves endurance capacity. Conversely, the single pre exercise intake of maltodextrin (MD) as a carbohydrate source and the gluconeogenic amino acids alanine (Ala) and proline (Pro) effectively maintain blood glucose levels and increase endurance performance. In this study, we investigated the synergistic combinational effect of these interventions on endurance performance in mice. Male BALB/c mice were fed a 0.5% GTC diet or Control diet for 8 weeks. Maximum running time was measured every 2 weeks. MD (2 g/kg body weight (B.W.)), MD (1 g/kg B.W.) + AlaPro (9:1, 1 g/kg B.W.), and vehicle were orally administrated 60 mins before measurements in each diet group. The GTC + MD + AlaPro group showed significantly higher endurance performance than the Control-Vehicle group at all measurements. Indirect calorimetry analysis during running exercise at 4 weeks in the Control and GTC groups supplemented with pre-exercise MD + AlaPro administration revealed significantly higher fat oxidation in the GTC groups compared to the Control group. The combined increase in fatty acid utilization through continuous GTC intake and pre-exercise MD + AlaPro carbohydrate energy supplementation synergistically improves endurance capacity. PMID- 30029528 TI - Novel Approaches for BAV Aortopathy Prediction-Is There a Need for Cohort Studies and Biomarkers? AB - Bicuspid aortic valve (BAV) disease is the most common congenital malformation of the human heart with a prevalence of 1-2% in the general population. More than half of patients with a BAV present with a dilated proximal aorta (so-called bicuspid aortopathy) which is associated with an enhanced risk of life threatening aortic complications. Up to now, the pathogenesis of bicuspid aortopathy as well as the risk stratification of aortic complications has not yet been sufficiently clarified. Recent findings have shown that bicuspid aortopathy features phenotypic heterogeneity. Two distinct valvulo-aortic phenotypes, the so called root phenotype, as well as a dilation of the tubular ascending aorta, coincide with a significantly different risk for aortal complications. However, the phenotype-based classification that is only based on these two clinical forms is not sufficient to estimate the risk of aortal complications in a prognostically relevant way. Therefore, there is growing clinical interest to assess novel approaches in BAV research and to introduce circulating biomarkers as an elegant diagnostic tool to improve risk stratification in BAV aortopathy. A large scale epidemiological cohort study, ranking from apparently healthy individuals to disease patients, and comprehensive biobanks provide the opportunity to study BAV disease and its complications and to identify novel biomarkers for BAV aortopathy surveillance and prognosis. Firstly, the data indicate that several protein-based biomarkers and non-coding RNA molecules, in particular circulating microRNAs, can serve as relevant molecular biomarkers to predict the course of BAV-associated aortopathy. Here, we review the current literature and knowledge about BAV from a clinical point of view, and report about novel approaches in BAV biomarker research. PMID- 30029529 TI - Identification and In Silico Prediction of Anticoagulant Peptides from the Enzymatic Hydrolysates of Mytilus edulis Proteins. AB - Mytilus edulis is a typical marine bivalve mollusk. Many kinds of bioactive components with nutritional and pharmaceutical activities in Mytilus edulis were reported. In this study, eight different parts of Mytilus edulis tissues, i.e., the foot, byssus, pedal retractor muscle, mantle, gill, adductor muscle, viscera, and other parts, were separated and the proteins from these tissues were prepared. A total of 277 unique peptides from the hydrolysates of different proteins were identified by UPLC-Q-TOF-MS/MS, and the molecular weight distribution of the peptides in different tissues was investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The bioactivity of the peptides was predicted through the Peptide Ranker database and molecular docking. Moreover, the peptides from the adductor muscle were chosen to do the active validation of anticoagulant activity. The active mechanism of three peptides from the adductor muscle, VQQELEDAEERADSAEGSLQK, RMEADIAAMQSDLDDALNGQR, and AAFLLGVNSNDLLK, were analyzed by Discovery Studio 2017, which also explained the anticoagulant activity of the hydrolysates of proteins from adductor muscle. This study optimized a screening and identification method of bioactive peptides from enzymatic hydrolysates of different tissues in Mytilus edulis. PMID- 30029530 TI - Research and Fabrication of High-Frequency Broadband and Omnidirectional Transmitting Transducer. AB - A wide-band cylindrical transducer was developed by using the wide band of the composite material and the matched matching layer for multimode coupling. Firstly, the structure size of the transducer's sensitive component was designed by using ANSYS simulation software. Secondly, the piezoelectric composite ring shaped sensitive component was fabricated by the piezoelectric composite curved surface forming process, and the matching layer was coated on the periphery of the ring-shaped piezoelectric composite material. Finally, it was encapsulated and the electrodes were drawn out to make a high-frequency broadband horizontal omnidirectional water acoustic transducer prototype. After testing, the working frequency range of the transducer was 230-380 kHz, and the maximum transmission voltage response was 168 dB in the water. PMID- 30029532 TI - Cyclic Octamer Peptoids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides. AB - Cyclic peptoids have recently emerged as an important class of bioactive scaffolds with unique conformational properties and excellent metabolic stabilities. In this paper, we describe the design and synthesis of novel cyclic octamer peptoids as simplified isosters of mycotoxin depsipeptides bassianolide, verticilide A1, PF1022A and PF1022B. We also examine their complexing abilities in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt and explore their general insecticidal activity. Finally, we discuss the possible relationship between structural features of free and Na+-complexed cyclic octamer peptoids and bioactivities in light of conformational isomerism, a crucial factor affecting cyclic peptoids' biomimetic potentials. PMID- 30029531 TI - Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates. AB - Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services. PMID- 30029533 TI - Neuroprotective Effects of Taraxacum officinale Wigg. Extract on Glutamate Induced Oxidative Stress in HT22 Cells via HO-1/Nrf2 Pathways. AB - Oxidative stress-mediated neuron damage is considered an important contributor to the pathogenesis and development of neurodegenerative diseases. Taraxacum officinale has been reported to possess antioxidant activities. However, whether it can protect neurons against oxidative damage and the underlying molecular mechanisms have not been fully determined. In the present study, we examined the neuroprotective effects of ethanol extracts of this plant (ETOW) on glutamate induced oxidative stress in HT22 cells. Both cell viability and reactive oxygen species (ROS) assays showed that ETOW effectively attenuated glutamate-induced cytotoxicity and ROS generation. Furthermore, our results revealed that ETOW increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor-2 (Nrf2). The inhibitory effects of ETOW on glutamate-stimulated cell toxicity and ROS production were partially reversed by tin protoporphyrin (SnPP), an HO activity inhibitor. Taken together, these results demonstrate that ETOW can protect HT22 cells against glutamate-induced oxidative damage by inducing the Nrf2/HO-1 pathways. Our study supports the idea that Taraxacum officinale Wigg. is a promising agent for preventing neurodegenerative diseases. PMID- 30029534 TI - The Inhibitory Effects of Djulis (Chenopodium formosanum) and Its Bioactive Compounds on Adipogenesis in 3T3-L1 Adipocytes. AB - The aim of this study was to provide new insights into the role of the ethanolic extracts of Djulis (Chenopodium formosanum, EECF) and its bioactive compounds in preventing adipogenesis in 3T3-L1 adipocytes. The results demonstrated EECF significantly inhibited oil red O-stained material (OROSM), triglyceride levels and glycerol-3-phosphate dehydrogenase (GPDH) activity in 3T3-L1 adipocytes. The expression of the critical molecules involved in lipid synthesis such as PPARgamma, C/EBPalpha and SREBP-1c was attenuated in EECF-treated cells. According to HPLC-DAD and HPLC-MS/MS analysis, rutin, kaempferol, betanin and another nine compounds were present in EECF. The suppression of lipid accumulation by rutin, kaempferol and betanin occurred by decreasing the gene expression of PPARgamma, C/EBPalpha and SREBP-1c. Taken together, these findings suggest the presence of bioactive compounds in EECF may partly account for the anti-adipogenesis of EECF and EECF is therefore a potentially lipid lowering functional food. PMID- 30029535 TI - Polybrominated Diphenyl Ethers (PBDEs) in a Large, Highly Polluted Freshwater Lake, China: Occurrence, Fate, and Risk Assessment. AB - Polybrominated diphenyl ethers (PBDEs) were extensively investigated in water, sediment, and biota samples collected from Chaohu Lake basin in China. The total concentrations of eight PBDEs (Sigma8PBDEs) were in the ranges of 0.11-4.48 ng/L, 0.06-5.41 ng/g, and 0.02-1.50 ng/g dry weight (dw) in the water, sediment, and biota samples, respectively. The concentrations showed wide variations in the monitoring area, while the congener profiles in all the water, sediment, and biota samples were generally characterized by only a few compounds, such as BDE 47, BDE-99, and/or BDE-209. The spatial analysis depicted a decreasing trend of PBDEs from west to east Chaohu Lake, consistent with regional industrialization degree. The distributions of PBDE congeners in the biota samples were similar to the compositional profiles in the water, which were dominated by BDE-47 and/or BDE-99. Nevertheless, BDE-47 and BDE-153 in the brain tissue showed a higher accumulative potential than PBDEs in other tissues as well as the whole body, with 96% relative contribution of Sigma8PBDEs. The noncarcinogenic risk values estimated for BDE-47, BDE-99, and BDE-153 indicated that the specific risk associated with the studied water and foodstuffs is limited. However, there is a potential mixture ecotoxicity at three trophic levels at some sampling points in the water, which should draw considerable attention. PMID- 30029537 TI - DFT Simulations of the Vibrational Spectrum and Hydrogen Bonds of Ice XIV. AB - It is always a difficult task to assign the peaks recorded from a vibrational spectrum. Herein, we explored a new pathway of density functional theory (DFT) simulation to present three kinds of spectra of ice XIV that can be referenced as inelastic neutron scattering (INS), infrared (IR), and Raman experimental spectrum. The INS spectrum is proportional to the phonon density of states (PDOS) while the photon scattering signals reflect the normal vibration frequencies near the Brillouin zone (BZ) center. Based on good agreements with the experimental data, we identified the relative frequency and made scientific assignments through normal vibration modes analysis. The two hydrogen bond (H-bond) peaks among the ice phases from INS were discussed and the dynamic process of the H bond vibrations was found to be classified into two basic modes. We deduced that two H-bond modes are a general rule among the ice family and more studies are ongoing to investigate this subject. PMID- 30029538 TI - Toughness Enhancement of PHBV/TPU/Cellulose Compounds with Reactive Additives for Compostable Injected Parts in Industrial Applications. AB - Poly(3-hydroxybutyrate-co-3-valerate), PHBV, is a bacterial thermoplastic biopolyester that possesses interesting thermal and mechanical properties. As it is fully biodegradable, it could be an alternative to the use of commodities in single-use applications or in those intended for composting at their end of life. Two big drawbacks of PHBV are its low impact toughness and its high cost, which limit its potential applications. In this work, we proposed the use of a PHBV based compound with purified alpha-cellulose fibres and a thermoplastic polyurethane (TPU), with the purpose of improving the performance of PHBV in terms of balanced heat resistance, stiffness, and toughness. Three reactive agents with different functionalities have been tested in these compounds: hexametylene diisocianate (HMDI), a commercial multi-epoxy-functionalized styrene co-glycidyl methacrylate oligomer (Joncryl(r) ADR-4368), and triglycidyl isocyanurate (TGIC). The results indicate that the reactive agents play a main role of compatibilizers among the phases of the PHBV/TPU/cellulose compounds. HMDI showed the highest ability to compatibilize the cellulose and the PHBV in the compounds, with the topmost values of deformation at break, static toughness, and impact strength. Joncryl(r) and TGIC, on the other hand, seemed to enhance the compatibility between the fibres and the polymer matrix as well as the TPU within the PHBV. PMID- 30029536 TI - In Vivo Performance of Decellularized Vascular Grafts: A Review Article. AB - Due to poor vessel quality in patients with cardiovascular diseases, there has been an increased demand for small-diameter tissue-engineered blood vessels that can be used as replacement grafts in bypass surgery. Decellularization techniques to minimize cellular inflammation have been applied in tissue engineering research for the development of small-diameter vascular grafts. The biocompatibility of allogenic or xenogenic decellularized matrices has been evaluated in vitro and in vivo. Both short-term and long-term preclinical studies are crucial for evaluation of the in vivo performance of decellularized vascular grafts. This review offers insight into the various preclinical studies that have been performed using decellularized vascular grafts. Different strategies, such as surface-modified, recellularized, or hybrid vascular grafts, used to improve neoendothelialization and vascular wall remodeling, are also highlighted. This review provides information on the current status and the future development of decellularized vascular grafts. PMID- 30029540 TI - Synthesis and Properties of Nanosized Stoichiometric Cobalt Ferrite Spinel. AB - Nanoparticles with controllable sizes of ferrite spinel CoFe2O4 were formed by thermal treatment of cobalt-iron glycerolate. Thermal behavior during the heating was studied by differential thermal analysis combined with thermogravimetry. The precursor, as well as the prepared nanoparticles, were analyzed by a broad spectrum of analytic techniques (X-Ray photoelectron spectroscopy (XPS), X-Ray diffraction (XRD), Energy dispersive spectroscopy (EDS), Atomic absorption spectroscopy (AAS), Scanning electron microscopy (SEM), and Raman spectroscopy). The particle size of nanoparticles was obtained from Transmission electron microscopy and also calculated using Scherrer formula. A vibrating sample magnetometer (VSM) in a Physical Property Measurement System was used to analyze the magnetic properties of nanoparticles. PMID- 30029539 TI - A Retrospective Cross-Sectional Population-Based Study on Prenatal Levels of Adherence to the Mediterranean Diet: Maternal Profile and Effects on the Newborn. AB - The Mediterranean diet (MD) is a dietary pattern with important benefits. The objectives of this study were to assess the adherence to the MD among pregnant women in Valencia (Spain) and characterize the pregnant women according to their level of adherence. Finally, we aimed to examine the role of MD adherence during pregnancy in the anthropometric development of the newborn. The study included 492 pregnant women who were followed at La Fe Hospital in 2017. The self administered "Kidmed" questionnaire for data collection on dietary information evaluation was used and a clinical history review of mothers and newborns was performed. Two groups of mothers were identified: those with low adherence (LA) and optimal adherence (OA). The study revealed that 40.2% of the women showed LA to the MD. The newborns born to these women presented a higher risk of being small for gestational age (SGA) {adjusted odds ratio (aOR) = 1.68; 95% confidence interval (CI) 1.02-5.46} when adjusting for parental body mass index (BMI) and multiple gestation, but not when adjusting for all significant possible confounders (aOR = 2.32; 95% CI 0.69-7.78). The association between MD and SGA was not significantly affected by the use of iron and folic acid supplements (aOR = 2.65; 95% CI 0.66-10.65). The profile of the pregnant woman with LA is that of a young smoker, with a low level of education and a low daily intake of dairy products. These results suggest that LA to the MD is not associated with a higher risk of giving birth to a SGA newborn. PMID- 30029542 TI - Conceptual Design of Micro-Bioreactors and Organ-on-Chips for Studies of Cell Cultures. AB - Engineering design of microbioreactors (MBRs) and organ-on-chip (OoC) devices can take advantage of established design science theory, in which systematic evaluation of functional concepts and user requirements are analyzed. This is commonly referred to as a conceptual design. This review article compares how common conceptual design principles are applicable to MBR and OoC devices. The complexity of this design, which is exemplified by MBRs for scaled-down cell cultures in bioprocess development and drug testing in OoCs for heart and eye, is discussed and compared with previous design solutions of MBRs and OoCs, from the perspective of how similarities in understanding design from functionality and user purpose perspectives can more efficiently be exploited. The review can serve as a guideline and help the future design of MBR and OoC devices for cell culture studies. PMID- 30029543 TI - Encapsulation of Citrus By-Product Extracts by Spray-Drying and Freeze-Drying Using Combinations of Maltodextrin with Soybean Protein and iota-Carrageenan. AB - The effect of different combinations of maltodextrin (MD) coating agents (MD, MD + soybean protein, and MD + iota-carrageenan) on the encapsulation of lemon by product aqueous extracts using freeze-drying and spray-drying were investigated. The total phenolic content (TPC), total flavonoid content (TFC), and ferric ion reducing antioxidant power (FRAP) of the microparticles were evaluated. Freeze drying with the mixture of MD + soybean protein resulted in the highest retention of TPC, TFC, and FRAP (1.66 +/- 0.02 mg GAE/g d.b., 0.43 +/- 0.02 mg CE/g d.b., and 3.70 +/- 0.05 mM TE/g, respectively). Freeze-drying resulted in microparticles with lower moisture content (MC) and water activity (aw) than those produced by spray-drying. Specifically, the MC and aw of the microparticles produced by freeze-drying ranged from 1.15 to 2.15% and 0.13 to 0.14, respectively, while the MC and aw of the microparticles produced by spray-drying ranged from 6.06% to 6.60% and 0.33 to 0.40, respectively. Scanning electron microscopy revealed that spray-drying resulted in the formation of spherical particles of different sizes regardless of the type of coating agent. Although freeze-drying resulted in microparticles with amorphous glassy shapes, the mixture of MD + soybean protein resulted in the formation of spherical porous particles. X-ray diffraction revealed a low degree of crystallinity for the samples produced by both techniques. PMID- 30029541 TI - Dual RNA-Seq Analysis of Trichophyton rubrum and HaCat Keratinocyte Co-Culture Highlights Important Genes for Fungal-Host Interaction. AB - The dermatophyte Trichophyton rubrum is the major fungal pathogen of skin, hair, and nails that uses keratinized substrates as the primary nutrients during infection. Few strategies are available that permit a better understanding of the molecular mechanisms involved in the interaction of T. rubrum with the host because of the limitations of models mimicking this interaction. Dual RNA-seq is a powerful tool to unravel this complex interaction since it enables simultaneous evaluation of the transcriptome of two organisms. Using this technology in an in vitro model of co-culture, this study evaluated the transcriptional profile of genes involved in fungus-host interactions in 24 h. Our data demonstrated the induction of glyoxylate cycle genes, ERG6 and TERG_00916, which encodes a carboxylic acid transporter that may improve the assimilation of nutrients and fungal survival in the host. Furthermore, genes encoding keratinolytic proteases were also induced. In human keratinocytes (HaCat) cells, the SLC11A1, RNASE7, and CSF2 genes were induced and the products of these genes are known to have antimicrobial activity. In addition, the FLG and KRT1 genes involved in the epithelial barrier integrity were inhibited. This analysis showed the modulation of important genes involved in T. rubrum-host interaction, which could represent potential antifungal targets for the treatment of dermatophytoses. PMID- 30029544 TI - Nanocomposites of LLDPE and Surface-Modified Cellulose Nanocrystals Prepared by Melt Processing. AB - Cellulose nanocrystals (CNCs) were surface modified by esterification in tetrahydrofuran (THF) at 25 degrees C using different catalysts and anhydrides bearing different alkyl side chain lengths. Unmodified and acetic anhydride (AcAnh)-modified CNCs were studied as potential nanofillers for linear low density poly(ethylene) (LLDPE). Nanocomposites were prepared by melt processing. Determination of the size and size distribution of CNCs in the nanocomposites by SEM revealed an enhanced compatibility of the AcAnh-modified CNCs with the LLDPE matrix, since the average size of the aggregates of the modified CNCs (0.5-5 MUm) was smaller compared to that of the unmodified CNCs (2-20 MUm). Tensile test experiments revealed an increase in the nanocomposites' stiffness and strain at break-by 20% and up to 90%, respectively-at the CNC concentration of 5 wt %, which is close to the critical percolation concentration. Since the CNC nanofiller simultaneously reduced LLDPE crystallinity, the reinforcement effect of CNCs was hampered. Therefore, the molding temperature was increased to 120 degrees C, and, in this way, the greatest increase of the Young's modulus was achieved (by ~45%). Despite the enhanced compatibility of the AcAnh-modified CNCs with the LLDPE matrix, no additional effect on the mechanical properties of the nanocomposites was observed in comparison to the unmodified CNC. PMID- 30029545 TI - Identification of Felis catus Gammaherpesvirus 1 in Tsushima Leopard Cats (Prionailurus bengalensis euptilurus) on Tsushima Island, Japan. AB - Felis catus gammaherpesvirus 1 (FcaGHV1) is a widely endemic infection of domestic cats. Current epidemiological data identify domestic cats as the sole natural host for FcaGHV1. The Tsushima leopard cat (TLC; Prionailurus bengalensis euptilurus) is a critically endangered species that lives only on Tsushima Island, Nagasaki, Japan. Nested PCR was used to test the blood or spleen of 89 TLCs for FcaGHV1 DNA; three (3.37%; 95% CI, 0.70-9.54) were positive. For TLC management purposes, we also screened domestic cats and the virus was detected in 13.02% (95% CI, 8.83-18.27) of 215 cats. Regarding phylogeny, the partial sequences of FcaGHV1 from domestic cats and TLCs formed one cluster, indicating that similar strains circulate in both populations. In domestic cats, we found no significant difference in FcaGHV1 detection in feline immunodeficiency virus infected (p = 0.080) or feline leukemia virus-infected (p = 0.163) cats, but males were significantly more likely to be FcaGHV1 positive (odds ratio, 5.86; 95% CI, 2.27-15.14) than females. The higher frequency of FcaGHV1 detection in domestic cats than TLCs, and the location of the viral DNA sequences from both cats within the same genetic cluster suggests that virus transmission from domestic cats to TLCs is likely. PMID- 30029546 TI - Mapping the Urban Lead Exposome: A Detailed Analysis of Soil Metal Concentrations at the Household Scale Using Citizen Science. AB - An ambitious citizen science effort in the city of Indianapolis (IN, USA) led to the collection and analysis of a large number of samples at the property scale, facilitating the analysis of differences in soil metal concentrations as a function of property location (i.e., dripline, yard, and street) and location within the city. This effort indicated that dripline soils had substantially higher values of lead and zinc than other soil locations on a given property, and this pattern was heightened in properties nearer the urban core. Soil lead values typically exceeded the levels deemed safe for children's play areas in the United States (<400 ppm), and almost always exceeded safe gardening guidelines (<200 ppm). As a whole, this study identified locations within properties and cities that exhibited the highest exposure risk to children, and also exhibited the power of citizen science to produce data at a spatial scale (i.e., within a property boundary), which is usually impossible to feasibly collect in a typical research study. PMID- 30029547 TI - Parents' and Teachers' Views of Food Environments and Policies in Indian Private Secondary Schools. AB - School food environments and policies can play a pivotal role in inculcating healthy food habits among young people. This cross-sectional survey explored teachers' and parents' views of the role of school food environments and policies in promoting healthy food consumption among Indian adolescents. Thirty-two teachers and 280 parents from five private, English-speaking, secondary schools in Kolkata, India took part in a short questionnaire survey which included closed and open answer questions. Descriptive and chi-square analyses were performed to compare the responses of parents and teachers. Thematic data analysis underpinned by Template Analysis Technique was employed to examine the qualitative responses. The easy availability and accessibility of energy-dense, nutrient-poor foods, the limited availability of nutritious foods, the absence of written food policies, and inflated prices of nutritious foods were reported as problems in the Indian school food environment. However, the respondents also noted that schools restricted the sale of sugar-sweetened beverages and adopted hygienic food practices. Novel ideas for creating healthy school food environments and effective school canteen policies were also captured during the survey. These findings point to the need to create effective school food policies in Indian secondary schools to help adolescents eat healthily at school. Future research is required to test the feasibility of the implementation of school food policies. PMID- 30029548 TI - Comparative Evaluation of Indirect Immunofluorescence and NS-1-Based ELISA to Determine Zika Virus-Specific IgM. AB - Differential diagnosis of the Zika virus (ZIKV) is hampered by cross-reactivity with other flaviviruses, mainly dengue viruses. The aim of this study was to compare two commercial methods for detecting ZIKV immunoglobulin M (IgM), an indirect immunofluorescence (IIF) and an enzyme immunoassay (ELISA), using the non-structural (NS) 1 protein as an antigen, both from EuroImmun, Germany. In total, 255 serum samples were analyzed, 203 of which showed laboratory markers of ZIKV infections (PCR-positive in serum and/or in urine and/or positive or indeterminate specific IgM). When tested with IIF, 163 samples were IgM-positive, while 13 samples were indeterminate and 78 were negative. When IIF-positive samples were tested using ELISA, we found 61 positive results, 14 indeterminate results, and 88 negative results. Among the indeterminate cases tested with IIF, ELISA analysis found two positive, two indeterminate, and nine negative results. Finally, 74 of the 78 IIF-negative samples proved also to be negative using ELISA. For the calculations, all indeterminate results were considered to be positive. The agreement, sensitivity, and specificity between ELISA and IIF were 60.2%, 44.9%, and 94.9%, respectively. Overall, 101 samples showed discrepant results; these samples were finally classified on the basis of other ZIKV diagnostic approaches (PCR-positive in serum and/or in urine, IgG determinations using IIF or ELISA, and ZIKV Plaque Reduction Neutralization test-positive), when available. A final classification of 228 samples was possible; 126 of them were positive and 102 were negative. The corresponding values of agreement, sensitivity, and specificity of IIF were 86.0%, 96.8%, and 72.5%, respectively. The corresponding figures for ELISA were 81.1%, 65.9%, and 100%, respectively. The ELISA and IIF methods are both adequate approaches for detecting ZIKV specific IgM. However, considering their respective weaknesses (low sensitivity in ELISA and low specificity in IIF), serological results must be considered jointly with other laboratory results. PMID- 30029549 TI - Urinary Tract Infections among Bladder Outlet Obstruction Patients in Accra, Ghana: Aetiology, Antibiotic Resistance, and Risk Factors. AB - The aim of this study was to investigate urinary tract infections among patients with Bladder Outlet Obstruction (BOO) at the Korle Bu Teaching Hospital (KBTH) in Accra, Ghana, including the prevalence, risk factors, aetiological agents and their antibiogram. Urine specimens were collected from 188 male patients presenting with BOO and cultured for bacteria. The bacterial isolates were identified using standard microbiological methods and tested against a spectrum of antimicrobial agents using the Kirby Bauer method. Demographic information and the clinical history of study participants were also recorded. The prevalence of urinary tract infection among the BOO patients was 76.6% and the main risk factor identified was catheterization (p < 0.0001). A wide range of bacterial organisms was isolated from urine specimens and they were predominantly, Enterobacteriaceae; Escherichia coli was the most frequent cause of bacteriuria (33.3%), followed by Klebsiella (17.3%). Bacterial isolates were most resistant to Augmentin (97.8%) followed by tetracycline (85.8%), nalidixic acid (82.8%) and ciprofloxacin (75%) while 93.6% were multi-drug resistant. The highest susceptibility was observed with amikacin, which had a resistance prevalence of 4.4% resistance. These findings have important implications in the treatment of urinary tract infections among the BOO patients in Ghana. PMID- 30029550 TI - A Hierarchical Voting Based Mixed Filter Localization Method for Wireless Sensor Network in Mixed LOS/NLOS Environments. AB - In recent years, the rapid development of microelectronics, wireless communications, and electro-mechanical systems has occurred. The wireless sensor network (WSN) has been widely used in many applications. The localization of a mobile node is one of the key technologies for WSN. Among the factors that would affect the accuracy of mobile localization, non-line of sight (NLOS) propagation caused by a complicated environment plays a vital role. In this paper, we present a hierarchical voting based mixed filter (HVMF) localization method for a mobile node in a mixed line of sight (LOS) and NLOS environment. We firstly propose a condition detection and distance correction algorithm based on hierarchical voting. Then, a mixed square root unscented Kalman filter (SRUKF) and a particle filter (PF) are used to filter the larger measurement error. Finally, the filtered results are subjected to convex optimization and the maximum likelihood estimation to estimate the position of the mobile node. The proposed method does not require prior information about the statistical properties of the NLOS errors and operates in a 2D scenario. It can be applied to time of arrival (TOA), time difference of arrival (TDOA), received signal (RSS), and other measurement methods. The simulation results show that the HVMF algorithm can efficiently reduce the effect of NLOS errors and can achieve higher localization accuracy than the Kalman filter and PF. The proposed algorithm is robust to the NLOS errors. PMID- 30029551 TI - Cellular Uptake Behaviors of Rigidity-Tunable Dendrimers. AB - Understanding of the interaction between cells and nanoparticles (NPs) is critical. Despite numerous attempts to understand the effect of several parameters of NPs on their cellular uptake behaviors, such as size, shape, surface chemistry, etc., limited information is available regarding NP rigidity. Herein, we investigate the effect of rigidity on cellular uptake behaviors of NPs, using generation 5 poly(amidoamine) dendrimer as a model. By harnessing the abundant inner cavity, their rigidity could be effectively regulated by forming size-tunable gold NPs. The NPs thus formed were well characterized and displayed similar hydrodynamic size, surface potential, fluorescence intensity, and distinct rigidity (owing to differences in the size of the Au core). Flow cytometry analysis revealed a positive correlation between NP rigidity and cellular uptake of NPs. Confocal microscopic evaluation revealed that the entrapped gold NPs may affect the intracellular localization of the internalized dendrimers. The present findings can potentially guide the preparation of suitable NPs for biomedical applications. PMID- 30029552 TI - Differentiated Data Aggregation Routing Scheme for Energy Conserving and Delay Sensitive Wireless Sensor Networks. AB - Data aggregation is a widely adopted method to effectively reduce the data transmission volume and improve the lifetime of wireless sensor networks (WSNs). In the data aggregation networks, some parameters directly determine the delay of aggregation. In industrial applications, the data generated by different sensors have different requirements for delay or other QoS performance. In the previous study, a common strategy is that all kinds of data is aggregated into one frame when the condition is satisfied with a QoS requirement, which causes excessive energy consumption and severely impairs the lifetime of network. A Differentiated Data Aggregation Routing (DDAR) scheme is proposed to reduce energy consumption and guarantee that the delay could be controlled within the corresponding QoS requirement constraint. The primary contributions of the DDAR scheme are the following: (a) The DDAR scheme makes data with different QoS requirement route to the sink along the different paths. The parameters of the aggregators in each path, such as aggregation deadline (Tt) and the aggregation threshold (Nt), are configured according to the QoS requirements. Accordingly, energy consumption can be reduced without degrading the performance of data transmission. (b) Based on DDAR scheme, an improved DDAR scheme is proposed to further improve performance through fully utilize the residual energy in the nodes which are far from the sink. The frequency of aggregation of these nodes increases by reducing the value of Tt and Nt so as to further improve the energy efficiency and reduce delay. Simulation results demonstrate that compared with the previous scheme, this scheme reduces the delay by 25.01%, improves the lifetime by 55.45%, and increases energy efficiency by 83.99%. The improved DDAR scheme improves the energy efficiency by 33.97% and service guarantee rate by 10.11%. PMID- 30029553 TI - Cytoprotective Activities of Milk Thistle Seed Oil Used in Traditional Tunisian Medicine on 7-Ketocholesterol and 24S-Hydroxycholesterol-Induced Toxicity on 158N Murine Oligodendrocytes. AB - The Asteraceae family is economically very important, because many of these plants are grown mainly for their food value, such as lettuce (Lactuca), chicory (Cichorium), and sunflower (Heliantus aminus). One of the typical properties of this family, which includes milk thistle (Sylibum marianum), is the richness of the oil in various compounds (flavonoids, alkaloids, tocopherols, and unsaturated fatty acids). Currently, and for the coming decades, age-related diseases, including neurodegenerative diseases, are a major public health problem. Preventing their appearance or opposing their evolution is a major objective. In this context, the cytoprotective activities of milk thistle seed oil produced in Tunisia were studied on the 158N model using 7-ketocholesterol (7KC) and 24S hydroxycholesterol (24S) as cytotoxic agents. 7KC and 24S were used because they can be increased in the brain and body fluids of patients with major age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. In order to evaluate the cytoprotective properties of milk thistle seed oil, complementary techniques of microscopy, flow cytometry, and biochemistry were used. The chemical composition of milk thistle seed oil has also been determined by various chromatography techniques. Milk thistle seed oils from different area of Tunisia are rich in tocopherols and are strongly antioxidant according to various biochemical tests (KRL (Kit Radicaux Libres), FRAP (Ferric Reducing Antioxidant Power), and DPPH (2,2-diphenyl-1-picrylhydrazyl)). The main fatty acids are linoleic acid (C18:2 n-6) and oleic acid (C18:1 n-9). The main polyphenols identified are homovanillic acid, p-coumaric acid, quercetin, and apigenin, with a predominance of vanillic acid. On 158N cells, milk thistle seed oil attenuates the cytotoxicity of 7KC and 24S including: loss of cell adhesion, increased plasma membrane permeability, mitochondrial dysfunction, overproduction of reactive oxygen species, induction of apoptosis, and autophagy. The attenuation of the cytotoxicity of 7KC and 24S observed with the milk thistle seed oil is in the order of that observed with alpha-tocopherol used as a positive control. In the presence of nigella seed oil, considered potentially cytotoxic, no cytoprotective effects were observed. Given the chemical characteristics, antioxidant properties, and cytoprotective activities of milk thistle seed oil, our results highlight the potential benefit of this oil for human health. PMID- 30029554 TI - Impact of Long-Term RF-EMF on Oxidative Stress and Neuroinflammation in Aging Brains of C57BL/6 Mice. AB - The expansion of mobile phone use has raised questions regarding the possible biological effects of radiofrequency electromagnetic field (RF-EMF) exposure on oxidative stress and brain inflammation. Despite accumulative exposure of humans to radiofrequency electromagnetic fields (RF-EMFs) from mobile phones, their long term effects on oxidative stress and neuroinflammation in the aging brain have not been studied. In the present study, middle-aged C57BL/6 mice (aged 14 months) were exposed to 1950 MHz electromagnetic fields for 8 months (specific absorption rate (SAR) 5 W/kg, 2 h/day, 5 d/week). Compared with those in the young group, levels of protein (3-nitro-tyrosine) and lipid (4-hydroxy-2-nonenal) oxidative damage markers were significantly increased in the brains of aged mice. In addition, levels of markers for DNA damage (8-hydroxy-2'-deoxyguanosine, p53, p21, gammaH2AX, and Bax), apoptosis (cleaved caspase-3 and cleaved poly(ADP ribose) polymerase 1 (PARP-1)), astrocyte (GFAP), and microglia (Iba-1) were significantly elevated in the brains of aged mice. However, long-term RF-EMF exposure did not change the levels of oxidative stress, DNA damage, apoptosis, astrocyte, or microglia markers in the aged mouse brains. Moreover, long-term RF EMF exposure did not alter locomotor activity in aged mice. Therefore, these findings indicate that long-term exposure to RF-EMF did not influence age-induced oxidative stress or neuroinflammation in C57BL/6 mice. PMID- 30029556 TI - Experimental and Numerical Studies on Recrystallization Behavior of Single Crystal Ni-Base Superalloy. AB - The recrystallization (RX) behavior of superalloy during standard solution heat treatment (SSHT) varies significantly with deformation temperature. Single crystal (SX) samples of Ni-base superalloy were compressed to 5% plastic deformation at room temperature (RT) and 980 degrees C, and the deformed samples were then subjected to SSHT process which consists of 1290 degrees C/1 h, 1300 degrees C/2 h, and 1315 degrees C/4 h, air cooling. RT-deformed samples showed almost no RX grains until the annealing temperature was elevated to 1315 degrees C, while 980 degrees C-deformed samples showed a large number of RX grains in the initial stage of SSHT. It is inferred that the strengthening effect of gamma' phases and the stacking faults in them increase the driving force of RX for 980 degrees C-deformed samples. The RX grains nucleate and grow in dendritic arms preferentially when the microstructural inhomogeneity is not completely eliminated by SSHT. A model coupling crystal plasticity finite element method (CPFEM) and cellular automaton (CA) method was proposed to simulate the RX evolution during SSHT. One ({111} <110>) and three ({111} <110>, {100} <110>, {111} <112>) slip modes were assumed to be activated at RT and 980 degrees C in CPFEM calculations, respectively. The simulation takes the inhomogeneous as-cast dendritic microstructure into consideration. The simulated RX morphology and density conform well to experimental results. PMID- 30029555 TI - Bioconversion of Corticosterone into Corticosterone-Glucoside by Glucosyltransferase. AB - Glucosylation of the 21-hydroxyl group of glucocorticoid changes its solubility into hydrophilicity from hydrophobicity and, as with glucocorticoid glucuronides as a moving object in vivo, it is conceivable that it exhibits the same behavior. Therefore, glucosylation to the 21-hydroxyl group while maintaining the 11beta hydroxyl group is particularly important, and glucosylation of corticosterone was confirmed by high-resolution mass spectrometry and 1D (1H and 13C) and 2D (COSY, ROESY, HSQC-DEPT and HMBC) NMR. Moreover, the difference in bioactivity between corticosterone and corticosterone 21-glucoside was investigated in vitro. Corticosterone 21-glucoside showed greater neuroprotective effects against H2O2 induced cell death and reactive oxygen species (ROS) compared with corticosterone. These results for the first time demonstrate that bioconversion of corticosterone through the region-selective glucosylation of a novel compound can present structural potential for developing new neuroprotective agents. PMID- 30029557 TI - Towards an Efficient Identification Process for Large-Scale RFID Systems ?. AB - Radio Frequency Identification (RFID) is one of the most widely used wireless communications technologies nowadays. Among the numerous processes executed within an RFID system, the identification processis the most important one. There have been several proposals to efficiently execute such a mechanism, which are based on the use of an RFID identification method. Besides, one of the most studied scenarios comprises one reader and a set of RFID tags, which we call the centralized approach. Recent work shows that executing the identification process in a distributed or parallel way may be of great benefit for applications with high requirements on time and resources usage, i.e., applications where the time required to execute the identification process needs to be low. In this paper, we focus is on large RFID systems and compare two identification mechanisms, one based on the centralized approach and the other based on the distributed approach. Our aim is to find the advantages and disadvantages of each approach for general RFID scenarios. We observe that the distributed approach is very promising compared to the traditional approach since considerable improvements are found in identification delay, and also the implementation costs would be highly reduced. PMID- 30029558 TI - Accurate Indoor Sound Level Measurement on a Low-Power and Low-Cost Wireless Sensor Node. AB - Wireless sensor networks can provide a cheap and flexible infrastructure to support the measurement of noise pollution. However, the processing of the gathered data is challenging to implement on resource-constrained nodes, because each node has its own limited power supply, low-performance and low-power micro controller unit and other limited processing resources, as well as limited amount of memory. We propose a sensor node for monitoring of indoor ambient noise. The sensor node is based on a hardware platform with limited computational resources and utilizes several simplifications to approximate more complex and costly signal processing stage. Furthermore, to reduce the communication between the sensor node and a sink node, as well as the power consumed by the IEEE 802.15.4 (ZigBee) transceiver, we perform digital A-weighting filtering and non-calibrated calculation of the sound pressure level on the node. According to experimental results, the proposed sound level meter can accurately measure the noise levels of up to 100 dB, with the mean difference of less than 2 dB compared to Class 1 sound level meter. The proposed device can continuously monitor indoor noise for several days. Despite the limitations of the used hardware platform, the presented node is a promising low-cost and low-power solution for indoor ambient noise monitoring. PMID- 30029560 TI - Wasp Size and Prey Load in Cerceris fumipennis (Hymenoptera, Crabronidae): Implications for Biosurveillance of Pest Buprestidae. AB - The relationship between predator and prey size was studied in the buprestid hunting wasp Cerceris fumipennis Say in eight widely distributed nesting aggregations in North Carolina, USA. Initial work indicated a significant linear relationship between wasp head width and wasp wet weight; thus, head width was used to estimate wasp body mass in subsequent studies. Prey loads of hunting females was studied by measuring the head width of the wasp, then identifying and weighing the prey item brought back to the nest. There was significant variation in wasp size among nesting aggregations; the average estimated wasp body mass in one site was double that in another. Prey weight varied with wasp weight, but larger wasps had a slight tendency to carry proportionally larger prey. Beetles captured by large wasps (>=120 mg) were significantly more variable in weight than those taken by small wasps (<80 mg). All but the smallest wasps could carry more than their own body weight. Prey loads ranged from 4.8-150.2% of wasp weight. Evidence suggests that small wasps bring back more of the economically important buprestid genus Agrilus and thus would be most efficient in biosurveillance for pest buprestids. PMID- 30029559 TI - Genome-Wide Comparative Analysis of Aspergillus fumigatus Strains: The Reference Genome as a Matter of Concern. AB - Aspergillus fumigatus is a ubiquitous saprophytic mold and a major pathogen in immunocompromised patients. The effectiveness of triazole compounds, the A. fumigatus first line treatment, is being threatened by a rapid and global emergence of azole resistance. Whole genome sequencing (WGS) has emerged as an invaluable tool for the analysis of genetic differences between A. fumigatus strains, their genetic background, and antifungal resistance development. Although WGS analyses can provide a valuable amount of novel information, there are some limitations that should be considered. These analyses, based on genome wide comparative data and single nucleotide variant (SNV) calling, are dependent on the quality of sequencing, assembling, the variant calling criteria, as well as on the suitable selection of the reference genome, which must be genetically close to the genomes included in the analysis. In this study, 28 A. fumigatus genomes sequenced in-house and 73 available in public data bases have been analyzed. All genomes were distributed in four clusters and showed a variable number of SNVs depending on the genome used as reference (Af293 or A1163). Each reference genome belonged to a different cluster. The results highlighted the importance of choosing the most suitable A. fumigatus reference genome to avoid misleading conclusions. PMID- 30029561 TI - Lower Noise Annoyance Associated with GIS-Derived Greenspace: Pathways through Perceived Greenspace and Residential Noise. AB - Growing amounts of evidence support an association between self-reported greenspace near the home and lower noise annoyance; however, objectively defined greenspace has rarely been considered. In the present study, we tested the association between objective measures of greenspace and noise annoyance, with a focus on underpinning pathways through noise level and perceived greenspace. We sampled 720 students aged 18 to 35 years from the city of Plovdiv, Bulgaria. Objective greenspace was defined by several Geographic Information System (GIS) derived metrics: Normalized Difference Vegetation Index (NDVI), tree cover density, percentage of green space in circular buffers of 100, 300 and 500 m, and the Euclidean distance to the nearest structured green space. Perceived greenspace was defined by the mean of responses to five items asking about its quantity, accessibility, visibility, usage, and quality. We assessed noise annoyance due to transportation and other neighborhood noise sources and daytime noise level (Lday) at the residence. Tests of the parallel mediation models showed that higher NDVI and percentage of green space in all buffers were associated with lower noise annoyance, whereas for higher tree cover this association was observed only in the 100 m buffer zone. In addition, the effects of NDVI and percentage of green space were mediated by higher perceived greenspace and lower Lday. In the case of tree cover, only perceived greenspace was a mediator. Our findings suggest that the potential for greenspace to reduce noise annoyance extends beyond noise abatement. Applying a combination of GIS derived and perceptual measures should enable researchers to better tap individuals' experience of residential greenspace and noise. PMID- 30029562 TI - Analysis and Experimental Validation of a Piezoelectric Harvester with Enhanced Frequency Bandwidth. AB - The use of a single bimorph as a harmonic oscillator aimed at harvesting vibrational energy is not effective due to its inherent narrow frequency bandwidth stemming from the need to adjust the natural frequency of the harvester to the platform excitation frequencies. Therefore, the present research focuses on the development, manufacturing, and testing of an advanced system based on three bimorphs, capable of adjusting their natural frequencies using tip end masses, and interconnected by springs, thus enlarging the system's bandwidth. An analytical model was developed for three bimorphs interconnected by two springs with three end masses. The model can predict the output generated voltage from each bimorph, and then the total output power is measured on a given outside resistor as a function of the material properties, the geometric dimensions of the vibrating beams, the end-masses, and the spring constants. The analytical model was then compared with data in the literature, yielding a good correlation. To further increase the reliability of the model, a test set-up was designed and manufactured that included three bimorphs with three end-masses connected by two springs. The system was excited using a shaker, and the output voltage was measured for each bimorph for various configurations. Then, the analytical model was tuned based on the test results by introducing two factors, the quality and the stiffness factors, and the predictions of the calibrated analytical model were compared with the experimental results, yielding a good correlation. The calibrated analytical model was then used to perform a comprehensive parametric investigation for two and three bimorphs systems, in which the influences of various parameters-like spring constant, mass value, thickness, and width and length of the bimorph and the substrate beam-on the output generated power were investigated. The main conclusion from this parametric investigation was that by correctly choosing the geometric sizes of the cantilevers, the adequate tip end masses, and the ratio between constants of the springs, the frequency bandwidth is expanded yielding a higher harvested power. Typical harvested power of the present designed system can reach up to 20 mW at the first natural frequency and up to 5 mW for the second natural frequency. PMID- 30029563 TI - Pigment cell differentiation in the fire-bellied toad, Bombina orientalis. I. Structural, chemical, and physical aspects of the adult pigment pattern. AB - Wild-collected adults of Bombina orientalis are bright green dorsally and red to red-orange ventrally. As a prelude to an analysis of the differentiation of pigment cells in developing B. orientalis, we describe structural and chemical aspects of the fully differentiated pigment pattern of the "normal" adult. Structurally, differences between dorsal green and ventral red skin are summarized as follows: (1) Dorsal green skin contains a "typical" dermal chromatophore unit comprised of melanophores, iridophores, and xanthophores. Red skin contains predominantly carotenoid-containing xanthophores (erythrophores), and skin from black spot areas contains only melanophores. (2) In ventral red skin, there is also a thin layer of deep-lying iridophores that presumably are not involved in the observed color pattern. (3) Xanthophores of red and green skin are morphologically distinguishable from each other. Dorsal skin xanthophores contain both pterinosomes and carotenoid vesicles; ventral skin xanthophores contain only carotenoid vesicles. Carotenoid vesicles in dorsal xanthophores are much larger but less electron dense than comparable structures in ventral xanthophores. The presence of carotenes in ventral skin accounts for the bright red-orange color of the belly of this frog. Similar pigments are also present in green skin, but in smaller quantities and in conjunction with both colored (yellow) and colorless pteridines. From spectral data obtained for xanthophore pigments and structural data obtained from the size and arrangement of reflecting platelets in the iridophore layer, we attempt to explain the phenomenon of observed green color in B. orientalis. PMID- 30029564 TI - Structure of shells from eggs of kinosternid turtles. AB - Shells from eggs of five species of kinosternid turtle (Sternotherus minor, Kinosternon flavescens, K. baurii, K. Hirtipes, and K. alamosae) were examined with light and scanning electron microscopy. Except for possible differences among species in thickness of eggshells, structure of shells from all eggs was similiar. In general, kinosternid turtles lay eggs having a rigid calcareous layer composed of calcium carbonate in the form of aragonite. The calcareous layer is organized into individual shell units with needlelike crystallites radiating from a common center. Most of the thickness of the eggshell is attributable to the calcareous layer, with the fibrous shell membrane comprising only a small fraction of shell thickness. Pores are found in the calcareous layer, but they are not numereous. The outer surface of the eggshells is sculptured and may have a thick, organic layer in places. The outer surface of the shell membrane of decalcified eggshells is studded with spherical cores which presumably nucleate growth of shell units during shell formation. The shell membrane detaches from eggs incubated to hatching, carrying with it remnants of the calcareous layer. Such changes in shell structure presumably reflect withdrawal of calcium from the eggshell by developing embryos. PMID- 30029565 TI - Morphometric diffusing capacity and functional anatomy of the book lungs in the spider Tegenaria spp. (Agelenidae). AB - The presence of both book lungs and a tracheal system in many spiders raises the question of the functional significance of this double respiratory system. The present physiological and morphometric study of the house spider (Tegenaria spp.) reveals that the diffusing capacity (Dto2 ) of the lungs alone suffices during rest and following exercise to meet measured rates of oxygen consumption (?documentclass{article}?pagestyle{empty}?begin{document}$ ?mathop {?rm V}?limits^{?rm.} $?end{document}o2 ) at driving pressures (DeltaPto2 ) similar to those calculated for vertebrate lungs. During moulting DeltaPto2 may rise to more than double the vertebrate values, implying the possible insufficiency of book lungs during this critical life phase. Resting ?documentclass{article}?pagestyle{empty}?begin{document}$ ?mathop {?rm V}?limits^{?rm .} $?end{document}o2 is greatest (92 mm3 /h . g) during the early morning and lowest (66 mm3 /h . g) near midday: during moulting ?documentclass{article}?pagestyle{empty}?begin{document}$ ?mathop {?rm V}?limits^{?rm .} $?end{document}o2 rises to 278.7 mm3 /h . g. In spiders recovering from exercise ?documentclass{article}?pagestyle{empty}?begin{document}$ ?mathop {?rm V}?limits^{?rm .} $?end{document}o2 is consistently greater than during rest: neither value is significantly reduced by blockage of the tracheal stigmas. Regression calculations of morphometric values for a hypothetical 100-mg Tegenaria yield a total lung volume of 0.578 mm3 , a pulmonary surface area of 69.8 mm2 , and a surface-to-volume ratio of 120.89 mm2 /mm3 . In spite of the similar thickness of the chitinous and hypodermal components of the air-hemolymph barrier (each ca. 0.2 MUm in nonmoulting animals), the low permeability of chitin for oxygen makes this layer the greater barrier to diffusion. For a 100-mg specimen Dto2 is 3.5 mm3 /h . torr: similar to that of a turtle (Pseudemys) on a gram-body weight basis. PMID- 30029566 TI - Spermatogenesis and spermatophore production in the hawaiian red lobster Enoplometopus occidentalis (Randall) (Crustacea, nephropidae). AB - Light microscopy of the male reproductive tract of the Hawaiian red lobster Enoplometopus occidentalis documented the cyclic nature of spermatogenesis and spermatophore formation. Testes are composed of a convoluted collecting tubule bearing many spermatogenic follicles, all within a supporting mesentery. Spermatogonia are restricted to the basal side of the follicular epithelium and proliferate at onset of spermateleosis within the same follicle. Two generations of spermatogenic cells thus occupy each follicle, and accessory cells in the follicle form a basophilic epithelium between them. These accessory cells may detach with the spermatozoa at spermiation. The vas deferens lies outside the testicular mesentery and consists of a coiled proximal portion in which spermatophore production commences. Clusters of spermatozoa are here surrounded by a PAS-positive primary spermatophore layer, and a PAS-negative outer bounding layer is initiated. Completed further distally in the vas deferens, the outer bounding layer is thinner on the side of the spermatophore which adheres to the substratum after ejaculation; the thick side of this layer forms a broad cap. Outer circular and inner longitudinal muscular layers become well developed in the distal loop and descending portions of the vas deferens. The terminal portion of this duct contains no spermatophore prior to ejaculation. It has a longitudinally folded epithelium and an attached tubular gland which produces an extra-spermatophoral, gelatinous secretion. The androgenic gland is associated with this terminal segment of the vas deferens. These features are compared with those reported for other lobsters. PMID- 30029567 TI - Morphology of the intestine of prefeeding and feeding adult lampreys, Petromyzon marinus (L): The mucosa of the posterior intestine and hindgut. AB - The epithelium of the posterior intestine and hindgut of recently metamorphosed adult lampreys (Petromyzon marinus L.) prior to and during spontaneous feeding was examined using light and electron microscopy. These two regions differ slightly in their general morphology but possess the same mucosal cell types. Included are caveolated absorptive and mucous cells, which are not present in more cephalic regions of the intestine, and ciliated and enteroendocrine cells. During feeding, the caveolated cells undergo dramatic transformation in their structure, namely, through the acquisition of numerous heterophagic vacuoles. Due to their morphology and to the fact that there are low amounts of lipid, it is suspected that caveolated cells are primarily involved in the absorption of protein components from the ingested host blood and body fluids. Iron in caveolated cells may result from the degradation of ingested heme or reflect the excretion of bile products at this location in the intestine. Mucous cells are likely responsible for lubrication of the luminal surface and may be important as a stem cell for the mucosal epithelium. PMID- 30029568 TI - Sexually dimorphic muscles in the forelimb of the Japanese toad, Bufo japonicus. AB - During the breeding season, male anurans display clasping behavior by holding females with their forelimbs. This behavior is peculiar to males, and may require specializations in forelimb musculature. The present study revealed that five kinds of forelimb muscles were heavier in the male Japanese toad than in the female: the flexor carpi radialis (FCR), the flexor antibrachii medialis caput superius (FAMsup), the abductor indicis longus (AIL), the extensor carpi radialis caput superius (ECRsup), and the flexor antibrachii lateralis superficialis caput superius (FALSsup). In addition, one breast muscle, the coracoradialis (CR), was also heavier in males than in females. A quantitative analysis of muscle fibers processed for myosin ATPase activity showed that, in such "sexually dimorphic muscles" of the female, both fast (twitch) and slow (tonic) muscle fibers were of smaller diameter than in other forelimb muscles of both sexes (all male muscles plus "nondimorphic muscles" of the female). Moreover, both types of fibers were less numerous than in the corresponding muscles of the male. These results suggest that the "sexually dimorphic muscles" are used especially for clasping by the male and are degenerative or subnormal in the female. Slow muscle fibers were neither peculiar to, nor abundant in, these clasping muscles, although they may well be necessary for tonic and prolonged contractions of the forelimb muscles during clasping. The mechanism of sexual dimorphism may be a direct action of androgens on clasping muscles or an indirect action on clasping muscles via the innervating motoneurons. PMID- 30029569 TI - Morphology of the sternal and tergal glands producing the sexual pheromones and the aphrodisiacs among the cockroaches of the subfamily oxyhaloinae. AB - Among cockroaches in the subfamily of Oxyhaloinae, the adult males produce two essential and successively active chemical signals: the sex pheromone attracting females from a distance secreted by the sternal glands, and the aphrodisiac required for mating which is secreted by the tergal glands. The adult males of the seven species studied, Nauphoeta cinerea, Henschoutedenia flexivitta, Leucophaea maderae, Jagrehnia madecassa, Gromphadorhina portentosa, G. laevigata, and G. chopardi, possess well-developed sternal and tergal glands whose number varies according to the species and methods of mating (three to six sternal glands and four to seven tergal glands). These glands are basically composed of type three glandular units (glandular cell + duct cell) and type 2 cells (modified oenocytes) which exhibit no significant external cuticular modification except for tergite 2 of L. maderae. The extreme variance in development of these glands can be linked to sexual behavior. The hypothesis put forward here is that of a regressive evolution of the tergal glands, related to a modification of the role played by the aphrodisiacs which they secrete. PMID- 30029570 TI - Oral structures and their development in egg-brooding hylid frog embryos and larvae: Evolutionary and ecological implications. AB - Among egg-brooding hylid frogs there is much interspecific variation in the degree of development of the young at hatching. In certain species of Gastrotheca the eggs hatch into free-living tadpoles, whereas in others (and in the genera Amphignathodon, Cryptobatrachus, Stefania and Hemiphractus) the eggs hatch directly into frogs. We examined the oral anatomy of tadpoles and embryos of 22 species of egg-brooding hylids in order to determine the morphological differences between free-living larvae and embryos of species having direct development. All free-living Gastrotheca larvae are morphologically similar and have a large array of oral structures directly associated with a suspension feeding way of life. Among those egg-brooding hylids without free-living larvae there is a complete gradation from those with all of the free-living tadpole oral structures to those with none. Different lineages retain different vestiges of free-living larval morphology, suggesting that direct development has evolved multiple times among these frogs. All of the morphological patterns in the direct developing embryos can be accounted for by simple truncation or acceleration of the normal tadpole developmental program. We explore the possibility that certain Gastrotheca species with tadpoles may have evolved from species that lack larval stages. The development of oral structures in egg-brooding hylids provides insight into the phylogenetic significance of these charactes in other groups of anurans. Most significantly they reinforce the idea that microhylids evolved from ranoidlike ancestors. PMID- 30029571 TI - Morphology of shell formation in eggs of the turtle Kinosternon flavescens. AB - Shells from eggs of the turtle Kinosternon flavescens were examined during different stages of development with light and scanning electron microscopy. Prior to initiation of the calcareous layer, organic spheres or cores appear on the outer surface of the shell membrane. Presumably, these cores nucleate deposition of the mineral layer of the eggshell. Growing shell units of the mineral layer are rounded and nodular in shape, crystallites of adjacent shell units do not interlock, and numerous spaces occur between shell units. As growth continues, most of the spaces between shell units are obliterated, and shell units become more elongate in form. The calcareous layer of partially shelled eggs resembles the calcareous layer of flexible-shelled eggs of emydids and chelydrids. Eggshells assume the morphology typical of rigidshelled chelonian eggs only at an advanced stage of shell formation. These observations indicate that rigid and flexible eggshells may form by fundamentally similar mechanisms, with length of shell growth being the primary determinant of whether shells are flexible or rigid. PMID- 30029572 TI - Morphology of the intestine of prefeeding and feeding adult Lampreys, Petromyzon marinus L.: The mucosa of the diverticulum, anterior intestine, and transition zone. AB - Light and electron microscopy were used to examine the morphology of the mucosa of the diverticulum, anterior intestine, and transition zone in prefeeding and spontaneously feeding adult lampreys (Petromyzon marinus L.). Absorptive (either types A or B), ciliated, and enteroendocrine cells are present in all regions but the diverticulum and anterior intestine also possess zymogen (secretory) cells. Type A absorptive cells are restricted to the diverticulum and the rostral one third of the anterior intestine and are characterized by abundant mitochondria and an extensive smooth tubular network. Type B absorptive cells, in the remainder of the anterior intestine and the transition zone, possess small numbers of these organelles but in the transition zone also have inclusion bodies. During feeding, abundant lipid droplets and lipoprotein (VLDL) accumulate in the cytoplasm of both types of absorptive cells and in the lateral intercellular and the perivascular spaces. Lipid is present to a limited extent in ciliated cells and is encountered only rarely in enteroendocrine and zymogen cells. Although the animals are obligate sanguivores, there is little evidence of iron within these mucosal cells. It is suggested that intestinal efficiency displayed by this animal is due in part to ion transport in osmoregulation in type A cells, lipid absorption in types A and B cells, and digestion through enzymes in zymogen cells. PMID- 30029573 TI - A Graphene-Edge Ferroelectric Molecular Switch. AB - We show that polar molecules (water, ammonia, and nitrogen dioxide) adsorbed solely at the exposed edges of an encapsulated graphene sheet exhibit ferroelectricity, collectively orienting and switching reproducibly between two available states in response to an external electric field. This ferroelectric molecular switching introduces drastic modifications to the graphene bulk conductivity and produces a large and ambipolar charge bistability in micrometer size graphene devices. This system comprises an experimental realization of envisioned memory capacitive ("memcapacitive") devices whose capacitance is a function of their charging history, here conceived via confined and correlated polar molecules at the one-dimensional edge of a two-dimensional crystal. PMID- 30029574 TI - Ligand-Enabled beta-C(sp3)-H Olefination of Free Carboxylic Acids. AB - An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp3)-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp3)-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple beta-C-H bonds. The product gamma-lactone can be readily opened to give either the highly valuable beta-olefinated or gamma-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative. PMID- 30029575 TI - Organoarsine Metal-Organic Framework with cis-Diarsine Pockets for the Installation of Uniquely Confined Metal Complexes. AB - ACM-1 is the first example of an organoarsine metal-organic framework (MOF), prepared using a new pyridyl-functionalized triarylarsine ligand coordinated to Ni(II) nodes. ACM-1 has micropores that are decorated with cis-diarsine coordination pockets. Postsynthetic metalation of ACM-1 with AuCl under facile conditions studied by single-crystal X-ray diffraction reveals the installation of dimeric Au2Cl2 complexes via the formation of As-Au bonds. The Au(I) dimers display exceptionally short aurophilic bonds (2.76 A) induced by the rigidity of the MOF, which acts as a unique solid-state ligand. PMID- 30029576 TI - Effects of freezing on ability to detect Mycobacterium avium subsp. paratuberculosis from bovine tissues following culture. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the bacterium that causes Johne's disease in cattle. Although infected cattle can be identified by examining fecal, blood, or milk samples, the gold standard is identification of MAP in tissue samples postmortem. Although tissue samples are commonly frozen, the ability to detect MAP in frozen-thawed tissue samples has apparently not been reported. We therefore determined the ability to detect MAP in tissue samples following freezing. Tissue samples were collected from calves that were either inoculated (IN) 3 mo prior, or contact-exposed (CE) for 3 mo. Following autopsy, tissues were immediately processed for culture, followed by DNA extraction and detection by qPCR. Samples were categorized as positive or negative based on the cycle threshold (Ct) value. The remaining unprocessed tissue samples were frozen at -80 degrees C. After 18 mo, 50 tissue samples designated MAP-positive were thawed and processed for detection of MAP. Four (8%) samples were qPCR-negative, and Ct values of the remaining 46 samples were higher after freezing. Given the small numerical change in Ct values for MAP-positive samples after 18 mo of frozen storage, freezing and thawing may have had some deleterious effects on MAP detection in tissues. Although the decrease in ability to detect MAP-positive samples was minor for IN calves, there may be a greater effect for CE calves that should be considered when freezing tissue samples. PMID- 30029577 TI - Lead contamination in backyard chicken layer flocks in California. AB - Backyard layer chickens may be exposed to a variety of metals in the environment, including lead. The potential public health concerns associated with lead exposure prompted us to systematically screen liver samples from backyard layers submitted to the diagnostic laboratory to estimate the prevalence of lead exposure. Over a period of 1 y, we tested 1,476 chicken livers, of which 45 were found to have lead concentrations of 0.9-41 ug/g. The lead-positive cases were investigated by follow-up questions to the bird owners on the environment, general management of the flock, and egg consumption of family members. Lead concentrations in 14 pooled egg samples were determined, and a conservative estimate of daily exposure of family members to lead was made based on egg consumption. In some cases, estimated daily lead intake exceeded the recommended limits for lead consumption in children. Analysis of feed, water, and environmental samples did not identify a source of exposure in most cases. Only 34% of owners of lead-positive birds submitted eggs or environmental samples, indicating a lack of interest or financial concerns. In most cases, neither the case history nor postmortem findings were indicative of lead intoxication; without systematically testing all birds, some cases could have been missed. Our study highlights the need for backyard chicken owners, veterinarians, and public health personnel to be aware of the risk of lead exposure and undertake preventive and surveillance measures. PMID- 30029578 TI - Extra-enteric Blastocystis infection in a duck. AB - Cell structures morphologically consistent with Blastocystis were aspirated from a subcutaneous facial swelling in a 13-mo-old pet duck. On PCR analysis and sequencing, the organism was confirmed as Blastocystis sp. subtype 7. Blastocystis is a single-celled protist that is found in the intestinal tract of many species, including mammals, birds, reptiles, amphibians, and insects. A complete understanding of the lifecycle and pathogenesis of the parasite remains elusive. Blastocystis has been implicated in human and animal disease; however, its role is controversial given that it is commonly found among healthy gut microbiota. Infection with Blastocystis outside the intestinal tract has been reported only rarely in humans. Our case of subcutaneous Blastocystis infection in a duck is a novel presentation of a ubiquitous, generally asymptomatic, parasite or commensal of the intestinal tract. PMID- 30029579 TI - Diabetes mellitus and laboratory medicine in sub-Saharan Africa: challenges and perspectives. AB - Diabetes mellitus is an increasing public health problem in sub-Saharan Africa with a substantial socioeconomic burden. Although laboratory medicine has been recognized as one of the six key public health functions, there are still gaps in strengthening of laboratory services in developing countries. In the last decades, a lot of progress has been made in the diagnostic field of infectious diseases, whereas the diagnosis of noncommunicable diseases is still insufficient and uneven. This article analyses the challenges encountered in diagnosing and monitoring of diabetes mellitus in sub-Saharan Africa and explores new alternative diagnostic tools. PMID- 30029580 TI - Injury Surveillance of Nonprofessional Salsa Dance. AB - BACKGROUND: The investigation sought to (1) establish the extent of injuries, (2) determine the odds of sustaining an injury, and (3) calculate the injury incidence rate in nonprofessional salsa dance. METHODS: Salsa dancers completed an anonymous web-based survey containing 11 demographic background and 10 (1 y retrospective) injury history questions. RESULTS: The response rate was 77%. The final sample of respondents included 303 women and 147 men, of which 22% and 14%, respectively, sustained >=1 injury during salsa dance in the past year. The odds of injury was 2.00 (95% confidence interval [CI], 1.14-3.50) times greater (P < .05) for women than for men. Age, body mass index, and salsa dance experience were also found to be significant (all Ps < .05) predictors of injury. The injury incidence rate for women and men was 1.1 (95% CI, 0.9-1.4) and 0.5 (95% CI, 0.3 0.7) injuries per 1000 hours of exposure, respectively. CONCLUSIONS: This is the first study to have described salsa dancers in terms of their injury history profile. Results indicate that the likelihood of sustaining an injury during this physical activity is similar to that of ballroom, but lower than that of Spanish, aerobic, and Zumba(r), dance. PMID- 30029581 TI - Prevalence of Anaplasma phagocytophilum in humans in Belgium for the period 2013 2016. AB - Ticks are vectors for a broad range of pathogens of medical and veterinary importance, such as Borrelia spp., Babesia spp., Anaplasma spp., Rickettsia spp., Bartonella spp. and the tick-borne encephalitis virus. The Gram-negative bacterium Anaplasma phagocytophilum is present worldwide, including Belgium where numerous patients were shown to harbour antibodies against this pathogen as recorded by the Belgian National Reference Center (NRC) for Anaplasma. The clinical presentation of human granulocytic anaplasmosis is an acute, febrile, nonspecific, flu-like illness. Leukopenia, thrombocytopenia and increased hepatic transaminase activities are commonly present early in the disease. Diagnosis early in the course of infection relies on the detection of antibodies or of the bacterium in the blood, as is performed at the NRC for Anaplasma, part of the Clinical Laboratory of the Queen Astrid Military Hospital in Brussels, Belgium. In this article, we discuss diagnostic test results as well as recent clinical and demographic characteristics of patients whose samples were analyzed by the NRC for Anaplasma in a four-year period (2013-2016). PMID- 30029582 TI - Influence of physical activity on hydration state in children with obesity before and after a weight loss program. AB - OBJECTIVE: Evaluate the effect of a 1-year standardized residential slimming program on exercise-induced dehydration in children with obesity. METHOD: At the start (T1) and end (T2) of the program, urine samples, weight, blood pressure and pulse were collected before (TR) and after a Cooper test (TE). Urinary samples were analyzed for volume, Na (UNa), Cl, K (UK), urea, creatinine (Ucreat), protein and osmolality (Uosm). RESULTS: All 66 children (15 +/- 1 years) starting the program were included after informed consent (28 stopped prematurely). The Cooper test induced a significant weight loss at each test moment (p < 0.01). The resting UK/(UNa + UK) % increased significantly from 40 (+/-11) at T1 to 50% (+/ 11) at T2. Only in normal weight patients, exercise induced a significant increase in UK/(UNa + UK) % (T2R: 49 +/- 11; T2E: 56 +/- 12) (p < 0.01) as well as an increase in UNa/Ucreat mmol/mg (T2R: 0.12 +/- 0.07; T2E: 0.1 +/- 0.05) (p < 0.05). CONCLUSION: The significant weight loss after exercise indicated significant dehydration. In patients with obesity, no aldosterone effect measured by UK/(UNa + UK)% was observed in contrast to the normal body mass index patients after the program. PMID- 30029583 TI - Epidemiology of RSV and hMPV in Belgium: a 10-year follow-up. AB - OBJECTIVES: Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are important respiratory pathogens. Both viral pathogens have similar clinical manifestations. The epidemiology of RSV is well known, that of hMPV is less clear. We reviewed the results of 10 consecutive years of molecular testing for RSV and hMPV in respiratory samples of Flemish patients. METHODS: In the laboratory of the OLV hospital Aalst, Belgium, multiplex RT-PCR assays are used for the detection of RSV and hMPV. The lab receives invasive and noninvasive respiratory samples of patients from all over Flanders. RESULTS: Between September 2006 and August 2016, 16,826 respiratory samples were analyzed for RSV and hMPV. Of these samples, 18% tested positive for RSV and 7.3% for hMPV. RSV consistently peaked in November/December each year within a very narrow time frame. The occurrence of hMPV was less predictable and spreaded more widely throughout the winter and spring. Both viruses were mainly found in samples from young children. RSV was most frequently detected in samples from infants <3 months, while hMPV peaked between 6 and 9 months. After the age of 1 year, RSV rapidly dropped. hMPV dropped a little later and slower. Both viruses slightly increased again at older age (>50 years). CONCLUSIONS: Despite their similarities, some of the epidemiologic characteristics of hMPV and RSV differ. The most striking difference is the annual distribution of RSV and hMPV infections. PMID- 30029584 TI - Pitfalls of Conducting and Interpreting Estimates of Energy Availability in Free Living Athletes. AB - The human body requires energy for numerous functions including, growth, thermogenesis, reproduction, cellular maintenance, and movement. In sports nutrition, energy availability (EA) is defined as the energy available to support these basic physiological functions and good health once the energy cost of exercise is deducted from energy intake (EI), relative to an athlete's fat-free mass (FFM). Low EA provides a unifying theory to link numerous disorders seen in both female and male athletes, described by the syndrome Relative Energy Deficiency in Sport, and related to restricted energy intake, excessive exercise or a combination of both. These outcomes are incurred in different dose-response patterns relative to the reduction in EA below a "healthy" level of ~45 kcal.kg FFM-1.day-1. Although EA estimates are being used to guide and monitor athletic practices, as well as support a diagnosis of Relative Energy Deficiency in Sport, problems associated with the measurement and interpretation of EA in the field should be explored. These include the lack of a universal protocol for the calculation of EA, the resources needed to achieve estimates of each of the components of the equation, and the residual errors in these estimates. The lack of a clear definition of the value for EA that is considered "low" reflects problems around its measurement, as well as differences between individuals and individual components of "normal"/"healthy" function. Finally, further investigation of nutrition and exercise behavior including within- and between day energy spread and dietary characteristics is warranted since it may directly contribute to low EA or its secondary problems. PMID- 30029585 TI - Denitrosylate and live longer: how ADH5/GSNOR links mitophagy to aging. AB - Mitochondrial dynamics is required to adapt the manifold functions of mitochondria to cell needs and regulate their turnover by mitophagy. Actually, only if fragmented, mitochondria are engulfed by phagophores, the precursors to autophagosomes, and subsequently degraded. This process is essential to maintain a correct and healthy number of mitochondria that, otherwise, might be harmful. They, indeed, represent the main source of reactive oxygen species that - according to the mitochondrial free radical theory of aging - can cause aging when chronically overproduced. In a recent study, we demonstrated that S nitrosylation, the reversible modification of cysteine residues by nitric oxide (NO), hyperactivates mitochondrial fragmentation by targeting DNM1L/Drp1 (dynamin 1-like) at Cys644, but inhibits mitophagy, the concomitant occurrence of these conditions driving cell senescence. We demonstrated that cell senescence, as well as mouse and human aging are characterized by an epigenetically-driven decrease in ADH5/GSNOR (alcohol dehydrogenase 5 [class III], chi polypeptide), suggesting that ADH5 may act as new longevity gene. PMID- 30029586 TI - Characterization of the histologic appearance of normal gill tissue using special staining techniques. AB - Anatomic pathologists are familiar with stains used in light microscopy to identify cells, storage products, tissue deposits, and pathogens. Assessment of the surrounding tissue with special stains may reveal aspects of interest for the tissue or the species. We illustrate the expected staining characteristics of normal rainbow trout gill tissue with routine hematoxylin and eosin and 18 other histochemical stains. PMID- 30029587 TI - High-throughput profiling of the circulating proteome suggests sexually dimorphic corticosteroid signaling following ischemic stroke. AB - Increasing evidence suggests that there are innate differences between sexes with respect to stroke pathophysiology; however, the molecular mechanisms underlying these differences remain unclear. In this investigation, we employed a shotgun approach to broadly profile sex-associated differences in the plasma proteomes of a small group of male ( n = 6) and female ( n = 4) ischemic stroke patients. Peripheral blood was sampled during the acute phase of care, and liquid chromatography electrospray ionization mass spectrometry was used to quantify plasma proteins. We observed widespread differences in plasma composition, as 77 out of 294 detected proteins were significantly differentially expressed between sexes. Corticosteroid-binding globulin (CBG), a negative acute-phase reactant that inversely regulates levels of bioactive free cortisol, was the most dramatically differentially regulated, exhibiting 16-fold higher abundance in plasma from women relative to men. Furthermore, functional annotation analysis revealed that the remaining differentially expressed proteins were significantly enriched for those involved in response to corticosteroid signaling. Plasma CBG levels were further examined in an additional group of male ( n = 19) and female ( n = 28) ischemic stroke patients, as well as a group of male ( n = 13) and female ( n = 18) neurologically normal controls. CBG levels were significantly reduced in male stroke patients relative to male controls; however, no differences were observed between female stroke patients and female controls, suggesting that women may exhibit an attenuated cortisol response to stroke. Collectively, our findings reinforce the idea that there are sex-associated differences in stroke pathophysiology and suggest that cortisol signaling should be investigated further as a potential molecular mediator. PMID- 30029588 TI - Exploring miRNA-mRNA regulatory network in cardiac pathology in Na+/H+ exchanger isoform 1 transgenic mice. AB - Numerous studies have demonstrated that Na+/H+ exchanger isoform 1 (NHE1) is elevated in myocardial diseases and its effect is detrimental. To better understand the involvement of NHE1, we have previously studied cardiac-specific NHE1 transgenic mice and shown that these mice develop cardiac hypertrophy, interstitial fibrosis, and cardiac dysfunction. The purpose of current study was to identify microRNAs and their mRNA targets involved in NHE1-mediated cardiac injury. An unbiased high-throughput sequencing study was performed on both microRNAs and mRNAs. RNA sequencing showed that differentially expressed genes were enriched in hypertrophic cardiomyopathy pathway by Kyoto Encyclopedia of Genes and Genomes annotation in NHE1 transgenic hearts. These genes were classified as contraction defects (e.g., Myl2, Myh6, Mybpc3, and Actb), impaired intracellular Ca2+ homeostasis (e.g., SERCA2a, Ryr2, Rcan1, and CaMKII delta), and signaling molecules for hypertrophic cardiomyopathy (e.g., Itga/b, IGF-1, Tgfb2/3, and Prkaa1/2). microRNA sequencing revealed that 15 microRNAs were differentially expressed (2-fold, P < 0.05). Six of them (miR-1, miR-208a-3p, miR 199a-5p, miR-21-5p, miR-146a-5p, and miR-30c-5p) were reported to be related to cardiac pathological functions. The integrative analysis of microRNA and RNA sequencing data identified several crucial microRNAs including miR-30c-5p, miR 199a-5p, miR-21-5p, and miR-34a-5p as well as 10 of their mRNA targets that may affect the heart via NFAT hypertrophy and cardiac hypertrophy signaling. Furthermore, important microRNAs and mRNA targets were validated by quantitative PCR. Our study comprehensively characterizes the expression patterns of microRNAs and mRNAs, establishes functional microRNA-mRNA pairs, elucidates the potential signaling pathways, and provides novel insights on the mechanisms underlying NHE1 medicated cardiac injury. PMID- 30029589 TI - A study of outpatient healthcare use by ageing people with HIV. AB - Background Antiretroviral treatment has turned HIV infection into a chronic condition with a near normal life expectancy and an ageing patient population. For a well-defined proportion of these patients, HIV-care could pass from specialty care to primary care, especially for prevention and treatment of additional chronic diseases. A better understanding of the complex health needs of this particular proportion is needed to determine the optimal way to integrate specialist and primary care. Objectives Our objective was to examine the health seeking behaviour of ageing HIV patients. We investigated which physicians they consulted and the reasons for encounter. We also explored patients' participation in preventive healthcare activities. Methods We conducted a retrospective descriptive cohort study among adults, 60 years of age or older living with HIV, who came for a routine consultation visit at the HIV clinic of the Institute of Tropical Medicine (ITM) over a period of 9 months. Those who met the inclusion criteria were offered a self-administered questionnaire. The responses were manually coded, exported into Excel and subsequently imported into SPSS for descriptive statistical analysis. Results We analysed questionnaires from 74 patients, 11 women and 63 men. Since their last consultation visit at the ITM, 48 patients consulted their general practitioner (GP), 35 patients consulted a specialist and 7 went to the emergency department over a period of 6 months. Forty-nine patients (66%) had done a faecal occult blood test and 8 women (73% of female patients) had a screening mammography in the past 2 years, 8 women (73% of female patients) had a PAP smear in the past 3 years. Sixty-three participants (85%) declared that their vaccinations were up-to-date. Thirty-eight patients (51%) take antihypertensive medication, 35 patients (47%) cholesterol medication and 9 participants (12%) are on oral antihyperglycemic medication. Conclusions A large proportion of patients are seeking healthcare from their GP and specialists, other than the HIV specialist. They do so both for curative and preventive health needs. This calls for a more structured collaboration between the various care providers, whereby communication plays a pivotal role. PMID- 30029590 TI - Molecular mechanism of estrogen-mediated neuroprotection in the relief of brain ischemic injury. AB - BACKGROUND: This study aimed to explore the molecular mechanism of estrogen mediated neuroprotection in the relief of cerebral ischemic injury. The gene expression profiles were downloaded from Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified using limma package in R software. Further, DEGs were subjected to Gene Ontology (GO) cluster analysis using online Gene Ontology Enrichment Analysis Software Toolkit and to GO functional enrichment analysis using DAVID software. Using the Gene Set Analysis Toolkit V2, enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways was performed. In addition, protein-protein interaction (PPI) network was constructed using STRING database, and submodule analysis of PPI network. Lastly, the significant potential target sites of microRNAs (miRNAs) were predicted using Molecular Signatures Database, and the function analysis of targets of predicted miRNA was also performed using DAVID software. RESULTS: In total, 321 DEGs were screened in the estrogen-treated sample. The DEGs were mainly associated with intracellular signaling and metabolic pathways, such as calcium channel, calcineurin complex, insulin secretion, low-density lipoprotein reconstruction, and starch or sugar metabolism. In addition, GO enrichment analysis indicated an altered expression of the genes related to starch and sucrose metabolism, retinol metabolism, anti-apoptosis (eg., BDNF and ADAM17) and response to endogenous stimulus. The constructed PPI network comprised of 243 nodes and 590 interaction pairs, and four submodules were obtained from PPI network. Among the module d, four glutamate receptors as Gria4, Gria3, Grin3a and Grik4 were highlighted. Further, 5 novel potential regulatory miRNAs were also predicted. MIR-338 and MIR520D were closely associated with cell cycle, while the targets of MIR-376A and MIR-376B were only involved in cell soma. CONCLUSIONS: The DEGs in estrogen-treated samples are closely associated with calcium channel, glutamate induced excitotoxicity and anti-apoptotic activity. In addition, some functionally significant DEGs such as BDNF, ADAM17, Gria4, Gria3, Grin3a, Grik4, Gys2 and Ugtla2, and new miRNAs like MIR-338 and MIR-376A were identified, which may serve as potential therapeutic targets for the effective treatment of cerebral ischemic injury. PMID- 30029591 TI - Analysis of Brachypodium miRNA targets: evidence for diverse control during stress and conservation in bioenergy crops. AB - BACKGROUND: Since the proposal of Brachypodium distachyon as a model for the grasses, over 500 Bdi-miRNAs have been annotated in miRBase making Brachypodium second in number only to rice. Other monocots, such as switchgrass, are completely absent from the miRBase database. While a significant number of miRNAs have been identified which are highly conserved across plants, little research has been done with respect to the conservation of miRNA targets. Plant responses to abiotic stresses are regulated by diverse pathways many of which involve miRNAs; however, it can be difficult to identify miRNA guided gene regulation when the miRNA is not the primary regulator of the target mRNA. RESULTS: To investigate miRNA target conservation and stress response involvement, a set of PARE (Parallel Analysis of RNA Ends) libraries totaling over two billion reads was constructed and sequenced from Brachypodium, switchgrass, and sorghum representing the first report of RNA degradome data from the latter two species. Analysis of this data provided not only PARE evidence for miRNA guided cleavage of over 7000 predicted target mRNAs in Brachypodium, but also evidence for miRNA guided cleavage of over 1000 homologous transcripts in sorghum and switchgrass. A pipeline was constructed to compare RNA-seq and PARE data made from Brachypodium plants exposed to various abiotic stress conditions. This resulted in the identification of 44 miRNA targets which exhibit stress regulated cleavage. Time course experiments were performed to reveal the relationship between miR393ab, miR169a, miR394ab, and their respective targets throughout the first 36 h of the cold stress response in Brachypodium. CONCLUSIONS: Knowledge gained from this study provides considerable insight into the RNA degradomes and the breadth of miRNA target conservation among these three species. Additionally, associations of a number of miRNAs and target mRNAs with the stress responses have been revealed which could aid in the development of stress tolerant transgenic crops. PMID- 30029593 TI - Shedding of Salmonella Typhimurium in vaccinated and unvaccinated hens during early lay in field conditions: a randomised controlled trial. AB - BACKGROUND: Salmonella vaccination is one of the control measure that farmers can use to reduce bacterial shedding in their flocks. This study aimed to examine the efficacy of the Vaxsafe(r) ST (Strain STM-1) attenuated live vaccine administered as ocular and oral doses followed by an intramuscular (IM) dose in rearing, in reducing contamination by Salmonellae of both eggs and the environment in the commercial multi-age cage layer sheds. A randomised controlled trial was conducted up to 26 weeks post last vaccine on two different multi-age caged egg farms. RESULTS: No clinical symptoms were observed following IM administration of STM-1 during rearing. Following the first two STM-1 doses, both vaccinated and unvaccinated birds exhibited antibody titres below the positive cut-off value, however after IM administration of STM-1, antibody titres in the vaccinated group were above the cut-off value. Wild type Salmonella Typhimurium was not detected during the rearing of pullets. During production, the antibody titres were significantly higher in the vaccinated group at all sampling points during this trial. There was no significant difference in the prevalence of Salmonella (detected by culture and PCR method) between the vaccinated and unvaccinated groups on the egg belt and faeces in early lay. Wild-type Salmonella spp. were consistently found in dust samples. Quantitative PCR (qPCR) assay was able to differentiate between the live vaccine strain and wild type Salmonella. The load of wild-type Salmonella in shed environment was relatively low (1.3 log10 +/- 0.48 CFU/m2 of surface area). CONCLUSION: Given that Salmonella Typhimurium and other serovars are able to survive/persist in the shed environment (such as in dust), regular cleaning and or removal of dust from shed is important. Use of the Vaxsafe(r) ST vaccine in multi-age flocks is "not an ultimate intervention" for reduction of Salmonella Typhimurium because of the complexities involved in achieving control, such as the efficacy of cleaning of sheds, the lack of resting periods between batches and the possible carry over of contamination from existing flocks. Hence implementation of more than one or several interventions strategies is essential. PMID- 30029592 TI - Antennal transcriptome analysis of the chemosensory gene families in Carposina sasakii (Lepidoptera: Carposinidae). AB - BACKGROUND: The peach fruit moth, Carposina sasakii Matsumura (Lepidoptera: Carposinidae), poses a serious threat to a variety of fruits and causes significant economic loss owing to difficulties in its prevention and control. The olfactory sense is generally acknowledged to be a novel target for pest control. However, a systematic study of the olfactory genes expressed in C. sasakii has not been reported yet. Here, we reported the antennal transcriptome of C. sasakii using high-throughput sequencing and annotated the main chemosensory multi-gene families. RESULTS: In the chemosensory gene families, 29 odorant-binding proteins, 13 chemosensory proteins, 1 sensory neuron membrane protein, 52 odorant receptors, 8 ionotropic receptors and 11 gustatory receptors were annotated in the C. sasakii antennal transcriptome. The number of olfactory genes obtained in our transcriptome was consistent with that identified in other lepidopteran insects, confirming that we basically accomplished the annotation of the chemosensory genes of C. sasakii in the adult antennal transcriptome. All sequences were annotated and analyzed by BLAST (basic local alignment search tool), and some chemosensory genes with specific functions were named according to the BLAST results and phylogenetic trees. Based on the expression profile in the transcriptome and phylogenetic analysis, differentially expressed genes (DEGs) were analyzed in both male and female adults. Finally, fluorescence quantitative real-time PCR was used to identify the male-specific or female specific chemosensory genes that were putatively related to odor detection and recognition. Moreover, expression levels of OR33 and PBP2 were significantly higher in males than in females, indicating that these genes may interact with sex pheromones. We found some conserved antennal IRs and GRs involved in detecting sugar compounds (GR2, GR5, GR6, GR8) and carbon dioxide (GR1), which were also identified based on phylogenetic analysis. CONCLUSIONS: There are 114 putative chemosensory proteins expressed in C. sasakii identified in this study. The identification of these proteins will make the molecular mechanism of odor recognition accessible. PMID- 30029594 TI - Plasma small ncRNA pair panels as novel biomarkers for early-stage lung adenocarcinoma screening. AB - BACKGROUND: Lung cancer is a major cause of cancer-related mortality worldwide, and around two-thirds of patients have metastasis at diagnosis. Thus, detecting lung cancer at an early stage could reduce mortality. Aberrant levels of circulating small non-coding RNAs (small ncRNAs) are potential diagnostic or prognostic markers for lung cancer. We aimed to identify plasma small ncRNA pairs that could be used for early screening and detection of lung adenocarcinoma (LAC). RESULTS: A panel of seven small ncRNA pair ratios could differentiate patients with LAC or benign lung disease from high-risk controls with an area under the curve (AUC) of 100.0%, a sensitivity of 100.0% and a specificity of 100.0% at the training stage (which included 50 patients with early-stage LAC, 35 patients with benign diseases and 29 high-risk controls) and an AUC of 90.2%, a sensitivity of 91.5% and a specificity of 80.4% at the validation stage (which included 44 patients with early-stage LAC, 32 patients with benign diseases and 51 high-risk controls). The same panel could distinguish LAC from high-risk controls with an AUC of 100.0%, a sensitivity of 100.0% and a specificity of 100.0% at the training stage and an AUC of 89.5%, a sensitivity of 85.4% and a specificity of 83.3% at the validation stage. Another panel of five small ncRNA pair ratios (different from the first) was able to differentiate LAC from benign disease with an AUC of 82.0%, a sensitivity of 81.1% and a specificity of 78.1% in the training cohort and an AUC of 74.2%, a sensitivity of 70.4% and a specificity of 72.7% in the validation cohort. CONCLUSIONS: Several small ncRNA pair ratios were identified as markers capable of discerning patients with LAC from those with benign lesions or high-risk control individuals. PMID- 30029595 TI - beta-Lactamase production and antibiotic susceptibility pattern of Moraxella catarrhalis isolates collected from two county hospitals in China. AB - BACKGROUND: Moraxella catarrhalis (M. catarrhalis) is an important bacterial pathogen. However, its antibiotic susceptibility patterns in different areas are difficult to compare because of the use of different methods and judgement criteria. This study aimed to determine antimicrobial susceptibility and beta lactamase activity characteristics of M. catarrhalis isolates collected from two county hospitals in China, and to express the results with reference to three commonly used judgement criteria. RESULTS: Nasopharyngeal swabs were obtained from child inpatients with respiratory tract infections at the People's Hospital of Zhongjiang County and Youyang County from January to December 2015. M. catarrhalis strains were isolated and identified from the swabs, and susceptibility against 11 antimicrobials was determined using the E-test method or disc diffusion. Test results were interpreted with reference to the standards of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the Clinical and Laboratory Standards Institute (CLSI), and the British Society for Antimicrobial Chemotherapy (BSAC). Detection of beta-lactamase activity was determined by the chromogenic cephalosporin nitrocefin. M. catarrhalis yield rates were 7.12 and 9.58% (Zhongjiang County, 77/1082 cases; Youyang County, 101/1054 cases, respectively). All isolates were susceptible to amoxicillin clavulanic acid. The susceptibility rate to meropenem was 100% according to EUCAST; no breakpoints were listed in CLSI or BSAC. The non-susceptibility rate to sulfamethoxazole-trimethoprim differed significantly between the two hospitals regardless of the judgemnet criteria used, with isolates from Zhongjiang showing higher susceptibility to those from Youyang (Fisher's exact test, P < 0.05). According to CLSI, the total non-susceptibility rate to erythromycin was 70.8% (Zhongjiang County, 79.2%; Youyang County, 64.3%), and the rate reached 92.1% (Zhongjiang County, 90.9%; Youyang County, 93.1%) on the basis of EUCAST or BSAC. The total positive rate of beta-lactamase was 99.4% (177/178 cases) (Zhongjiang County, 100%, 77/77 cases; Youyang County, 99.0%, 100/101 cases). CONCLUSIONS: Ninety nine percent of M. catarrhalis isolates produce beta-lactamase. The isolates showed poor susceptibility to ampicillin and erythromycin, and high susceptibility to the third- and fourth-generation cephalosporins and amoxicillin clavulanic. Significant discrepancies between different antimicrobial susceptibility judgemnet criteria were noted. PMID- 30029597 TI - Using a cascade approach to assess condom uptake in female sex workers in India: a review of the Avahan data. AB - BACKGROUND: The Avahan India AIDS Initiative was implemented to provide HIV prevention services to key populations including female sex workers (FSWs) who carry the burden of India's concentrated HIV epidemic. Established in 2003 and handed over to the Indian government in 2009, the Initiative included peer-led outreach education, condom promotion and distribution and STI treatment. This study aimed to determine if HIV prevention cascades could be generated using routine monitoring and evaluation data from the Avahan program and to assess their value in identifying and responding to program gaps for FSWs. METHODS: Two data sources were used namely the Integrated Behavioural and Biological Assessment reports and the Centralized Management Information System dataset. Indicators selected for the cascades were: FSWs at risk, belief that HIV can be prevented, condom access and consistent condom use with an occasional partner. Six districts were selected and stratified by HIV prevalence at baseline and two cascades were generated per district reflecting changes over time. RESULTS: Consistent condom use with occasional partners in this population increased in all six districts during program implementation, with statistically significant increases in four of the six. No patterns in the cascades were detected according to HIV prevalence either at baseline (2005) or at follow-up (2009). Cascades were able to identify key programmatic bottlenecks at baseline that could assist with focusing program efforts and direct resources at district levels. In some districts the belief that HIV could not be prevented contributed to inconsistent condom use, while in others, low levels of condom access were a more important barrier to consistent condom use. CONCLUSION: This HIV prevention cascade analysis among FSWs in India suggests that cascades could assist in identifying program gaps, focus intervention efforts and monitor their effect. However, cascades cannot replace a detailed understanding of the multiple factors at individual, community and structural levels that lead to consistent condom use in this key population. Careful indicator selection coupled with innovative data collection methods will be required. Pilot projects are proposed to formally evaluate the value of HIV prevention cascades at district level. PMID- 30029598 TI - Body and mind: retention in antiretroviral treatment care is improved by mental health training of care providers in Ethiopia. AB - BACKGROUND: Ethiopia has achieved a high coverage of antiretroviral treatment (ART), but maintaining lifelong care is still a great challenge. Mental illnesses often co-exist with HIV/AIDS and may compromise the retention on ART. In order to improve prolonged retention in ART care, basic training in mental health care was introduced for ART providers, but this hasn't been evaluated yet. The aim of this study was to examine if this training has improved patient retention in care. METHOD: A retrospective cohort study was employed to compare attrition from ART between clients attended by care provider trained with basic mental health service (exposed) and those in the standard ART follow-up care (unexposed) in public health facilities. A routine patient follow-up electronic database enrolled for ART between 2005 and 2017 was abstracted for the study. The Kaplan Meier plot was used to compare the attrition rates between the two groups. The log-rank test was used to assess differences in the groups. The Cox proportional hazards regression model was used to determine predictors of attrition. We used estimated effect size of hazard ratios (HR) with 95% confidence intervals (CI). RESULT: During the 12 years of observation, 8009 study participants under ART were followed for 33,498 person-years. The incidence of attrition was 6.5 per 100 person-years and 21% higher in the unexposed group (HR 1.21; 95% CI 1.1, 1.3), and retention in care was significantly higher in the mental health exposed group throughout the study period. WHO clinical staging III/IV, tuberculosis coinfection, the male gender, and poor functional status were independent risk factors for attrition. CONCLUSION: We found that clients in the group exposed to mental health care training tended to have better retention in ART care with some variation according to gender, WHO Clinical stage and functional status. Training of ART providers in mental health may be considered in order to strengthen ART retention in low resource settings. PMID- 30029596 TI - RNA-seq assistant: machine learning based methods to identify more transcriptional regulated genes. AB - BACKGROUND: Although different quality controls have been applied at different stages of the sample preparation and data analysis to ensure both reproducibility and reliability of RNA-seq results, there are still limitations and bias on the detectability for certain differentially expressed genes (DEGs). Whether the transcriptional dynamics of a gene can be captured accurately depends on experimental design/operation and the following data analysis processes. The workflow of subsequent data processing, such as reads alignment, transcript quantification, normalization, and statistical methods for ultimate identification of DEGs can influence the accuracy and sensitivity of DEGs analysis, producing a certain number of false-positivity or false-negativity. Machine learning (ML) is a multidisciplinary field that employs computer science, artificial intelligence, computational statistics and information theory to construct algorithms that can learn from existing data sets and to make predictions on new data set. ML-based differential network analysis has been applied to predict stress-responsive genes through learning the patterns of 32 expression characteristics of known stress-related genes. In addition, the epigenetic regulation plays critical roles in gene expression, therefore, DNA and histone methylation data has been shown to be powerful for ML-based model for prediction of gene expression in many systems, including lung cancer cells. Therefore, it is promising that ML-based methods could help to identify the DEGs that are not identified by traditional RNA-seq method. RESULTS: We identified the top 23 most informative features through assessing the performance of three different feature selection algorithms combined with five different classification methods on training and testing data sets. By comprehensive comparison, we found that the model based on InfoGain feature selection and Logistic Regression classification is powerful for DEGs prediction. Moreover, the power and performance of ML-based prediction was validated by the prediction on ethylene regulated gene expression and the following qRT-PCR. CONCLUSIONS: Our study shows that the combination of ML-based method with RNA-seq greatly improves the sensitivity of DEGs identification. PMID- 30029599 TI - Early life vitamin D status and asthma and wheeze: a systematic review and meta analysis. AB - BACKGROUND: Vitamin D deficiency has been linked to an increased risk of asthma. This study aimed to quantify the effect of early life vitamin D status on asthma and wheeze later in life. METHODS: PubMed, Embase, CINAHL, and CNKI databases, the Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 2017. We included randomized controlled trials (RCTs) and cohort studies with vitamin D level in blood (maternal or cord or infant) or intake (maternal intake during pregnancy or infant intake) and asthma and/or wheeze. Two reviewers independently extracted data. Fixed- and random-effects models were used to summarize the risk estimates of comparisons between highest vs. lowest vitamin D categories. RESULTS: Of the 1485 studies identified, three RCTs and 33 cohort studies were included. We did not include the RCTs (1619 participants) in the meta-analysis as the comparators and outcome definitions were heterogenous. Three RCTs reported a non-statistically significant effect of vitamin D supplementation during pregnancy on offspring wheeze/asthma at 3 years of age. Pooled estimates of cohort studies suggest no association between antenatal blood vitamin D levels or vitamin D intake and offspring asthma assessed either > 5 years or <= 5 years. The estimate for blood vitamin D remained unchanged when two studies assessing asthma in adulthood were excluded, but a significant inverse association emerged between vitamin D intake and childhood asthma. We found no association between antenatal vitamin D level and wheeze. On the other hand, vitamin D intake during pregnancy may have a protective effect against wheeze. CONCLUSIONS: The pooled estimates from cohort studies show no association between antenatal blood vitamin D level and asthma/wheeze in later life. Whereas, the pooled estimates from cohort studies suggest that antenatal vitamin D intake may have an effect on childhood asthma > 5 years or childhood wheeze. The inconsistent results from studies assessing vitamin D either in blood or intake may be explained by previously reported non linear association between blood vitamin D3 and childhood asthma. Further trials with enough power and longer follow-up time should be conducted to confirm the results. PMID- 30029601 TI - Fatal interstitial lung disease associated with Crizotinib pathologically confirmed by percutaneous lung biopsy in a patient with ROS1-rearranged advanced non-small-cell lung cancer: a case report. AB - BACKGROUND: Crizotinib is a multi-target inhibitor approved for the treatment of advanced non-small-cell lung cancer patients with a ROS1 rearrangement. However, interstitial lung disease is a rare but severe and fatal side effect of crizotinib that should lead to immediate discontinuation of the drug. Unfortunately, the pathophysiology, molecular mechanism and risk factors for crizotinib-induced interstitial lung disease remain poorly understood. CASE PRESENTATION: We first identified and reported interstitial lung disease induced de novo by crizotinib in a 47-year-old female patient who was diagnosed with advanced lung adenocarcinoma with a ROS1 rearrangement in a malignant pleural effusion. Subsequent next-generation sequencing analysis revealed both ROS1 rearrangement and an EGFR exon 19 deletion mutation in lung biopsy specimens, which were histologically confirmed to be interstitial lung disease. Although crizotinib treatment was ceased immediately and a shock treatment with high-dose methylprednisolone as well as other necessary treatment procedures was applied to reverse the interstitial lung disease process, the patient died. CONCLUSIONS: The present case indicates that while treating non-small-cell lung cancer patients with crizotinib, it is important to constantly monitor any newly emerging respiratory symptoms and unexplained imaging changes, which may suggest an adverse effect related to drug-induced interstitial lung disease or even lethality. Histopathology and molecular pathological examination of lung biopsy specimens may help clinicians understand the development mechanism and exclude other causes. PMID- 30029600 TI - Improving cardiometabolic health through nudging dietary behaviours and physical activity in low SES adults: design of the Supreme Nudge project. AB - BACKGROUND: Initiating and maintaining a healthy lifestyle -including healthy eating and sufficient physical activity- is key for cardiometabolic health. A health-promoting environment can facilitate a healthy lifestyle, and may be especially helpful to reach individuals with a lower socio-economic status (SES). In the Supreme Nudge project, we will study the effects of pricing and nudging strategies in the supermarket - one of the most important point-of-choice settings for food choices - and of a context-specific mobile physical activity promotion app. This paper describes the stepwise and theory-based design of Supreme Nudge, which aims to develop, implement and evaluate environmental changes for a sustained impact on lifestyle behaviours and cardiometabolic health in low SES adults. METHODS: Supreme Nudge uses a multi-disciplinary and mixed methods approach, integrating participatory action research, qualitative interviews, experimental pilot studies, and a randomized controlled trial in a real-life (supermarket) setting. First, we will identify the needs, characteristics and preferences of the target group as well as of the participating supermarket chain. Second, we will conduct a series of pilot studies to test novel, promising and feasible intervention components. Third, a final selection of intervention components will be implemented in a full-scale randomised controlled supermarket trial. Approximately 1000 low SES adults will be recruited across 8-12 supermarkets and randomised at supermarket level to receive 1) no intervention (control); 2) environmental nudges such as food product placement or promotion; 3) nudges and a tailored physical activity app that provides time- and context specific feedback; 4) pricing interventions, nudges, and the physical activity app. The effects on dietary behaviours and physical activity will be evaluated at 3, 6 and 12 months, and on cardiometabolic health at 6 and 12 months. Finally, we will evaluate the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) of the intervention, and we will use insights from System Innovation and Transition Management theories to define the best strategies for implementation and upscaling beyond the study period. DISCUSSION: The Supreme Nudge project is likely to generate thorough evidence relevant for policy and practice on the effects of a mixed method and multi-disciplinary intervention targeting dietary behaviours and physical activity. TRIAL REGISTRATION: The real-life trial has been registered on 30 May 2018, NTR7302 . PMID- 30029602 TI - An exploratory case study of environmental factors related to military alcohol misuse. AB - BACKGROUND: Alcohol misuse has been an ongoing issue for the US Armed Services, with the Marine Corps maintaining the highest levels of problematic drinking. Broad environmental, social, and policy factors play an important role in alcohol misuse but are rarely studied as objective measures. METHODS: This case study used a pattern-matching approach to examine the associations between objective on and off-base community environmental risk and protective factors and 4 objective alcohol-related outcomes at 3 large Marine Corps installations. The study utilized existing aggregated data from Marine Corps electronic data sources and information from internet searches of installation and community services and characteristics. Installation-level alcohol misuse outcomes included the rates of personnel receiving non-medical alcohol services, combined inpatient and outpatient alcohol-related primary diagnoses, alcohol-related domestic violence, and driving under the influence arrests. Installation-level environmental correlates included dollars spent on alcohol sales, density of alcohol outlets, extent of alternative activities, and installation and off-base sociodemographic factors. RESULTS: In general, younger age, enlisted pay grade, and being stationed overseas were related with higher rates of alcohol-related problems among Marines. Greater on-base alcohol sales (both in bars and stores), as well as a greater density of restaurants and bars that serve alcohol, were associated with alcohol misuse outcomes. Several community factors were also associated with alcohol misuse. The hypothesized protective effects of alternative activities were inconsistent. CONCLUSIONS: Findings suggest that environmentally-oriented strategies, particularly restricting on-base sales of alcohol, may help to reduce alcohol-related harm in the Marine Corps. PMID- 30029603 TI - In silico prediction of novel residues involved in amyloid primary nucleation of human I56T and D67H lysozyme. AB - BACKGROUND: Amyloidogenic proteins are most often associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, but there are more than two dozen human proteins known to form amyloid fibrils associated with disease. Lysozyme is an antimicrobial protein that is used as a general model to study amyloid fibril formation. Studies aimed at elucidating the process of amyloid formation of lysozyme tend to focus on partial unfolding of the native state due to the relative instability of mutant amyloidogenic variants. While this is well supported, the data presented here suggest the native structure of the variants may also play a role in primary nucleation. RESULTS: Three-dimensional structural analysis identified lysozyme residues 21, 62, 104, and 122 as displaced in both amyloidogenic variants compared to wild type lysozyme. Residue interaction network (RIN) analysis found greater clustering of residues 112-117 in amyloidogenic variants of lysozyme compared to wild type. An analysis of the most energetically favored predicted dimers and trimers provided further evidence for a role for residues 21, 62, 104, 122, and 112-117 in amyloid formation. CONCLUSIONS: This study used lysozyme as a model to demonstrate the utility of combining 3D structural analysis with RIN analysis for studying the general process of amyloidogenesis. Results indicated that binding of two or more amyloidogenic lysozyme mutants may be involved in amyloid nucleation by placing key residues (21, 62, 104, 122, and 112-117) in proximity before partial unfolding occurs. Identifying residues in the native state that may be involved in amyloid formation could provide novel drug targets to prevent a range of amyloidoses. PMID- 30029604 TI - Cell surface ectodomain integrity of a subset of functional HIV-1 envelopes is dependent on a conserved hydrophilic domain containing region in their C-terminal tail. AB - BACKGROUND: HIV-1 Env gp160 is cleaved to form gp120 and gp41 and the functional HIV-1 Env is a trimer of non-covalently associated heterodimeric subunits, gp120 and gp41. The cleaved, native, trimeric form of Envs expose only broadly neutralizing antibody (bNAb) epitopes while occluding epitopes targeted by non neutralizing antibodies (non-NAbs). We and others have previously observed that efficient cleavage of Envs into their constituent subunits co-relates with specific binding to bNAbs and poor binding to non-neutralizing antibodies (non NAbs). Such Envs have been identified from clades A, B and C which make up a majority of globally circulating HIV-1 strains. Frequently, the C-terminal tail (CT) of Envs is deleted to enhance expression and stabilize soluble Env-based vaccine immunogens. Deletion of CT of efficiently cleaved Indian clade C Env 4 2.J41 results in recognition by both NAbs and non-NAbs. It is to be noted that uncleaved Envs bind to both NAbs and non-NAbs. So we investigated whether altered antigenicity upon CT deletion of efficiently cleaved Envs is due to inefficient cleavage or conformational change as the mechanism by which the CT regulates the ectodomain (ET) integrity is not well understood. RESULTS: We studied the effect of CT deletion in four membrane bound efficiently cleaved Envs, A5 (clade A), 4 2.J41 (clade C), JRFL and JRCSF (clade B). Deletion of CT of the Envs, JRCSF and 4-2.J41, but not JRFL and A5 alter their ET antigenicity/conformation without affecting the cleavage efficiency. We carried out a series of deletion mutation in order to determine the region of the CT required for restoring native-like antigenicity/conformation of the ET of 4-2.J41 and JRCSF. Extending the CT up to aa753 in 4-2.J41 and aa759 in JRCSF, which includes a conserved hydrophilic domain (CHD), restores native-like conformation of these Envs on the plasma membrane. However, CT-deletion in 4-2.J41 and JRCSF at the pseudovirus level has either no or only modest effect on neutralization potency. CONCLUSION: Here, we report that the CHD in the CT of Env plays an important role in regulating the ET integrity of a subset of efficiently cleaved, functional Envs on the cell surface. PMID- 30029605 TI - Early evaluation of experiences of health care providers in reception centers with a patient-held personal health record for asylum seekers: a multi-sited qualitative study in a German federal state. AB - BACKGROUND: The provision of high-quality medical care to asylum seekers represents a key challenge in many countries of the European Union. Especially continuity of care has been difficult to achieve as the migrant trajectory moves asylum seekers across and within European countries. Patient-held personal health records (PHR) have been proposed to facilitate the transfer of medical history between health sectors and providers, but so far there is no data to support its use in the migrant setting. The present paper addresses this knowledge gap by exploring the experiences and practices of healthcare providers in reception centers for asylum seekers using a patient-held PHR as well as the perceived associated benefits and shortcomings. METHODS: Early evaluation by means of a multi-sited qualitative study in six asylum seeker reception centers in five cities in the German state of Baden-Wuerttemberg, conducted between November 2016 and January 2017. The PHR evaluated in this study was implemented in five of these reception centers between February and October 2016; the remaining one only receiving patients with the PHR through transfer from the other facilities. 17 interviews were conducted with physicians and nurses working at these reception centers exploring their experiences, routines, and perspectives regarding the patient-held PHR. The interviews were recorded, transcribed and analyzed following the approach of thematic analysis. RESULTS: Healthcare providers recognise the potential of a patient-held PHR to improve access to medical history. They use the PHR to document their medical consultations and to collect other medical reports. However, physician adherence to the patient-held PHR was described as unsatisfactory, in particular among external doctors, thus limiting its immediate benefit. Reasons given for this low adherence included lack of information before implementation, demanding working conditions with little support, low perceived benefits depending on the degree of fragmentation of settings, parallel existence of other documentation platforms and strained patient relationships. CONCLUSION: A patient-held PHR could improve the availability of health-related information in reception centers if a context sensitive implementation process achieves high adherence to the PHR among physicians as well as high patient compliance and includes guidelines regarding its adequate integration into local routines. PMID- 30029606 TI - GC/MS-based urine metabolomics analysis of renal allograft recipients with acute rejection. AB - BACKGROUND: Acute renal allograft rejection is a common complication after renal transplantation that often leads to chronic rejection and ultimate graft loss. While renal allograft biopsy remains the gold standard for diagnosis of acute rejection, the possibility of biopsy-associated complications cannot be overlooked. The development of noninvasive methods for accurate detection of acute renal allograft rejection is thus of significant clinical importance. METHODS: Gas chromatography-mass spectrometry (GC/MS) was employed for analysis of urine metabolites in 15 renal allograft recipients with acute rejection and 15 stable renal transplant recipients. Partial least squares (PLS) regression and leave-one-out analyses were performed to ascertain whether the metabolites identified could be exploited to distinguish acute rejection from stable groups as well as their sensitivity and specificity. RESULTS: Overall, 14 metabolites were significantly altered in the acute rejection group (11 and 3 metabolites displayed higher and lower levels, respectively) relative to the stable transplant group. Data from PLS and leave-one-out analyses revealed that the differential metabolites identified not only distinguished acute rejection from stable transplant recipients but also showed high sensitivity and specificity for diagnosis of renal allograft recipients with acute rejection. CONCLUSION: Urine metabolites identified with GC/MS can effectively distinguish acute rejection from stable transplant recipients, supporting the potential utility of metabolome analysis in non-invasive diagnosis of acute rejection. PMID- 30029607 TI - Development of a richer measure of health outcomes incorporating the impacts of income inequality, ethnic diversity, and ICT development on health. AB - BACKGROUND: In the literature, measuring health outcomes usually entails examining one dependent variable using cross-sectional data. Using a combination of mortality and morbidity variables, this study developed a new, richer measure of health outcome. Using the health outcome index, this study investigated the impacts of income inequality, levels of ethnic diversity and information and communication technology (ICT) development on health using panel data. METHODS: Partial least squares regression based on a structural equation model is used to construct a health outcome index for 30 OECD countries over the period of 2004 to 2015 using SmartPLS software. Then, panel corrected standard errors estimation and pooled ordinary least square regression with Driscoll and Kraay standard errors approaches were used to investigate the key determinants of health outcomes. Both methods are efficient when the panel data is heteroscedastic and the errors are cross-sectional dependent. RESULTS: Income inequality, level of ethnic diversity and development in ICT access and use have an adverse effect on health outcomes, however, development in ICT skills has a significant positive impact. Moreover, OECD countries with a higher percentage of publicly funded healthcare showed better public health compared to countries where the percentage is smaller. Finally, rising incomes, development of technologies and tertiary education are key determinants for improving health outcomes. CONCLUSIONS: The results indicate that countries with higher levels of income inequality and more ethnically diverse populations have lower levels of health outcomes. Policymakers also need to recognise the adverse effect of ICT use on public health and the benefits of public healthcare expenditure. PMID- 30029608 TI - The adhesion and migration of microglia to beta-amyloid (Abeta) is decreased with aging and inhibited by Nogo/NgR pathway. AB - BACKGROUND: Alzheimer's disease is characterized by progressive accumulation of beta-amyloid (Abeta)-containing amyloid plaques, and microglia play a critical role in internalization and degradation of Abeta. Our previous research confirmed that Nogo-66 binding to Nogo receptors (NgR) expressed on microglia inhibits cell adhesion and migration in vitro. METHODS: The adhesion and migration of microglia isolated from WT and APP/PS1 mice from different ages were measured by adhesion assays and transwells. After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in APP/PS1 transgenic mice, microglial recruitment toward Abeta deposits and CD36 expression were determined. RESULTS: In this paper, we found that aging led to a reduction of microglia adhesion and migration to fAbeta1-42 in WT and APP/PS1 mice. The adhesion and migration of microglia to fAbeta1-42 were downregulated by the Nogo, which was mediated by NgR, and the increased inhibitory effects of the Nogo could be observed in aged mice. Moreover, Rho GTPases contributed to the effects of the Nogo on adhesion and migration of microglia to fAbeta1-42 by regulating cytoskeleton arrangement. Furthermore, blocking the Nogo/NgR pathway enhanced recruitment of microglia toward Abeta deposits and expression of CD36 in APP/PS1 mice. CONCLUSION: Taken together, Nogo/NgR pathway could take part in Abeta pathology in AD by modulating microglial adhesion and migration to Abeta and the Nogo/NgR pathway might be an important target for treating AD. PMID- 30029610 TI - A critical examination of empowerment discourse in medical tourism: the case of the dental tourism industry in Los Algodones, Mexico. AB - BACKGROUND: Medical tourism is a term used to describe the phenomenon of individuals intentionally traveling across national borders to privately purchase medical care. The medical tourism industry has been portrayed in the media as an "escape valve" providing alternative care options as a result of vast economic asymmetries between the global north and global south and the flexible regulatory environment in which care is provided to medical tourists. Discourse suggesting the medical tourism industry necessarily enhances access to medical care has been employed by industry stakeholders to promote continued expansion of the industry; however, it remains unknown how this discourse informs industry practices on the ground. Using case study methodology, this research examines the perspectives and experiences of industry stakeholders working and living in a dental tourism industry site in northern Mexico to develop a better understanding of the ways in which common discourses of the industry are taken up or resisted by various industry stakeholders and the possible implications of these practices on health equity. RESULTS: Interview discussions with a range of industry stakeholders suggest that care provision in this particular location enables international patients to access high quality dental care at more affordable prices than typically available in their home countries. However, interview participants also raised concerns about the quality of care provided to medical tourists and poor access to needed care amongst local populations. These concerns disrupt discourses about the positive health impacts of the industry commonly circulated by industry stakeholders positioned to profit from these unjust industry practices. CONCLUSIONS: We argue in this paper that elite industry stakeholders in our case site took up discourses of medical tourism as enhancing access to care in ways that mask health equity concerns for the industry and justify particular industry activities despite health equity concerns for these practices. This research provides new insight into the ways in which the medical tourism industry raises ethical concern and the structures of power informing unethical practices. PMID- 30029609 TI - Obstetric ultrasound use in low and middle income countries: a narrative review. AB - INTRODUCTION: Although growing, evidence on the impact, access, utility, effectiveness, and cost-benefit of obstetric ultrasound in resource-constrained settings is still somewhat limited. Hence, questions around the purpose and the intended benefit as well as potential challenges across various domains must be carefully reviewed prior to implementation and scale-up of obstetric ultrasound technology in low-and middle-income countries (LMICs). MAIN BODY: This narrative review discusses these issues for those trying to implement or scale-up ultrasound technology in LMICs. Issues addressed in this review include health personnel capacity, maintenance, cost, overuse and misuse of ultrasound, miscommunication between the providers and patients, patient diagnosis and care management, health outcomes, patient perceptions and concerns about fetal sex determination. CONCLUSION: As cost of obstetric ultrasound becomes more affordable in LMICs, it is essential to assess the benefits, trade-offs and potential drawbacks of large-scale implementation. Additionally, there is a need to more clearly identify the capabilities and the limitations of ultrasound, particularly within the context of limited training of providers, to ensure that the purpose for which an ultrasound is intended is actually feasible. We found evidence of obstetric uses of ultrasound improving patient management. However, there was evidence that ultrasound use is not associated with reducing maternal, perinatal or neonatal mortality. Patients in various studies reported to have both positive and negative perceptions and experiences related to ultrasound and lastly, illegal use of ultrasound for determining fetal sex was raised as a concern. PMID- 30029611 TI - Rethinking urinary antibiotic breakpoints: analysis of urinary antibiotic concentrations to treat multidrug resistant organisms. AB - OBJECTIVE: The present study analyzed whether renally eliminated antibiotics achieve sufficient urinary concentrations based on their pharmacokinetic/pharmacodynamic principles to effectively eradicate organisms deemed resistant by automated susceptibility testing. RESULTS: Lower median minimum inhibitory concentrations against enterobacteriaceae were noted for ceftriaxone, cefepime, and doripenem when comparing Etest(r) to Vitek(r). All Pseudomonas aeruginosa isolates were susceptible to cefepime, ciprofloxacin, and doripenem with both susceptibility methods, but higher median minimum inhibitory concentrations were observed with Etest(r). Urine concentrations/time profiles were calculated for standard doses of ceftriaxone, cefepime, doripenem, and ciprofloxacin. The data presented in the current study suggests high urine concentrations of antibiotics may effectively eradicate bacteria which were determined to be resistant per in vitro susceptibility testing. PMID- 30029612 TI - TB Anywhere is TB Everywhere. AB - To control and prevent outbreaks, public health programs in all countries, regardless of tuberculosis (TB) incidence, must maintain the capacity to perform core control and prevention activities. These include diagnosing and treating cases, contact investigations, and infection prevention and control activities. Congregate settings and healthcare facilities demand special attention, because of the potential for outbreaks associated with infectious cases in these settings. Since almost one-fourth of the world population is thought to be infected with Mycobacterium tuberculosis, enhanced efforts to diagnose and treat latent TB infection are needed to prevent future cases and accelerate progress towards TB elimination. PMID- 30029613 TI - Effect of subcutaneous tocilizumab treatment on work/housework status in biologic naive rheumatoid arthritis patients using inverse probability of treatment weighting: FIRST ACT-SC study. AB - BACKGROUND: Following the onset of rheumatoid arthritis (RA), patients experience a functional decline caused by various joint symptoms which affects their activities of daily living and can lead to reduced work productivity. We evaluated the effect of a 52-week treatment with tocilizumab by subcutaneous injection (TCZ-SC) among biologic-naive Japanese house workers (HWs) and paid workers (PWs) with RA in a real-world clinical practice. METHODS: This multicenter, observational, prospective study enrolled 377 and 347 RA patients into TCZ-SC and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)-alone groups, respectively. The primary endpoint was the change in percentage of overall work impairment (OWI) among PWs at week 52 assessed using the Work Productivity and Activity Impairment Questionnaire (WPAI). Inverse probability of treatment weighting analyses were used to compare treatments. The Work Functioning Impairment Scale, disease activity, quality of life (QOL) measures, and safety were also assessed. RESULTS: The weighted change in OWI from baseline for PWs was -18.9% (TCZ-SC group) and -19.0% (csDMARDs group) at week 52, without a significant between-group difference (adjusted treatment difference 0.1, 95% confidence interval (CI) -6.3 to 6.5; P = 0.978). Changes in WPAI activity impairment in the overall group (between-group difference -6.4, 95% CI 10.7 to -2.2; P = 0.003) and HWs (-9.5, 95% CI - 16.0 to -2.9; P = 0.005) were significantly better with TCZ-SC than with csDMARDs at week 52. TCZ-SC-treated HWs showed significant improvement in all QOL assessments (Frenchay Activities Index, EuroQol 5 Dimension (EQ-5D), Japanese Health Assessment Questionnaire Disability Index (HAQ-DI), and 6-item Kessler scale (K6)) at week 52; PWs did not show any between-group differences for these QOL measures. Disease activity (Disease Activity Score 28-erythrocyte sedimentation rate, Clinical Disease Activity Index, and Simplified Disease Activity Index) and QOL measures (EQ-5D, HAQ-DI, and K6) improved over time in the overall group. No new safety concerns were raised with TCZ-SC. CONCLUSIONS: Despite the lack of differences in OWI between groups at week 52, the overall group (particularly HWs) receiving TCZ-SC in addition to csDMARDs showed significant improvements in activity impairment, disease activity, and QOL versus those receiving csDMARDs alone. This study may promote the evaluation of work productivity improvements in HWs and PWs by RA treatment. PMID- 30029614 TI - Risk factors of birth asphyxia among newborns in public hospitals of Central Zone, Tigray, Ethiopia 2018. AB - OBJECTIVE: The aim of study was to identify risk factors of birth asphyxia among newborns in public hospitals of Central Zone Tigray, Ethiopia 2018. RESULTS: A total of 88 cases and 176 controls were included in the study. Thirty (34.1%) cases and 28 (15.9%) of controls were not able to read and write. Twenty-one (23.9%) cases and 9 (5.1%) controls were had meconium stained on pelvic examination. Multivariable logistic regression analysis showed that maternal illiteracy [AOR = 6; 95% CI (1.51, 23.80)], low birth weight [AOR = 6.9; 95% CI (3.01, 15.81)], preterm [AOR = 2.2; 95% CI (1.022, 4.76)], prim parous [AOR = 3.1; 95% CI (1.51, 6.38)], antepartum hemorrhage [AOR = 12; 95% CI (2.29, 63.11)] and meconium stained amniotic fluid [AOR = 7.88; 95% CI (2.92, 21.29)] were independent risk factors of birth asphyxia. PMID- 30029615 TI - Detection of human bocavirus-1 in both nasal and stool specimens from children under 5 years old with influenza-like illnesses or diarrhea in Gabon. AB - OBJECTIVE: Human bocavirus (HBoV) is a viral pathogen which causes respiratory tract diseases and acute gastroenteritis worldwide. This virus mainly affected children under 5 years old. There is little information on HBoV in Gabon. Two first studies was conducted to determine the prevalence of respiratory and enteric viruses in children under 5 years old who visited health centers for influenza-like illness (ILI) or diarrhea in Gabon from March 2010 to June 2011. However, HBoV was not included in the screening. The aim of this retrospective study was to evaluate the prevalence and the HBoV genotype in children under 5 years old with ILI or diarrhea in Gabon. RESULTS: A total of 810 nasal swabs and 317 feces samples collected during the two first study were analyzed among which 32 (4.4%) and 7 (2.2%) were positive for HBoV respectively. While there were no significant differences in prevalence between age groups in children with ILI, all children with diarrhea were under 12 months of age. Moreover, 84.4 and 42.8% were diagnosed in co-infections with at least one other respiratory virus, or enteric viruses respectively. Finally, HBoV subtype 1 has been detected in both respiratory and gastrointestinal tracts with very low variability. PMID- 30029616 TI - Sex-based differences in association between circulating T cell subsets and disease activity in untreated early rheumatoid arthritis patients. AB - BACKGROUND: It is not known if sex-based disparities in immunological factors contribute to the disease process in rheumatoid arthritis (RA). Hence, we examined whether circulating T cell subset proportions and their association with disease activity differed in male and female patients with untreated early rheumatoid arthritis (ueRA). METHODS: Proportions of T cell subsets were analyzed in peripheral blood from 72 ueRA DMARD- and corticosteroid-naive patients (50 females and 22 males) and in 31 healthy age- and sex-matched controls. Broad analysis of helper and regulatory CD4+ T cell subsets was done using flow cytometry. Disease activity in patients was assessed using DAS28, CDAI, swollen joint counts, tender joint counts, CRP, and ESR. RESULTS: Multivariate factor analyses showed that male and female ueRA patients display distinct profiles of association between disease activity and circulating T cell subset proportions. In male, but not female, ueRA patients Th2 cells showed a positive association with disease activity and correlated significantly with DAS28-ESR, CDAI, and swollen and tender joint counts. Likewise, proportions of non-regulatory CTLA-4+ T cells associated positively with disease activity in male patients only, and correlated with DAS28-ESR. In contrast, there was a negative relation between Th1Th17 subset proportions and disease activity in males only. The proportions of Th17 cells correlated positively with DAS28-ESR in males only, while proportions of Th1 cells showed no relation to disease activity in either sex. There were no significant differences in proportions of T cell subsets between the sexes in patients with ueRA. CONCLUSIONS: Our findings show sex-based differences in the association between T cell subsets and disease activity in ueRA patients, and that Th2 helper T cells may have a role in regulating disease activity in male patients. PMID- 30029617 TI - Self-reported prenatal tobacco smoke exposure, AXL gene-body methylation, and childhood asthma phenotypes. AB - BACKGROUND: Epigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Methylation in a gene called AXL was previously reported to differ in response to PTS. METHODS: We investigated the association between PTS and epigenetic changes in AXL and how this was related to childhood asthma phenotypes. We tested the association between PTS and DNA methylation at multiple CpG loci of AXL at birth using Pyrosequencing in two separate study populations, the Children's Health Study (CHS, n = 799) and the Newborn Epigenetic Study (NEST, n = 592). Plasma cotinine concentration was used to validate findings with self-reported smoking status. The inter-relationships among AXL mRNA and miR-199a1 expression, PTS, and AXL methylation were examined. Lastly, we evaluated the joint effects of AXL methylation and PTS on the risk of asthma and related symptoms at age 10 years old. RESULTS: PTS was associated with higher methylation level in the AXL gene body in both CHS and NEST subjects. In the pooled analysis, exposed subjects had a 0.51% higher methylation level in this region compared to unexposed subjects (95% CI 0.29, 0.74; p < 0.0001). PTS was also associated with 21.2% lower expression of miR-199a1 (95% CI - 37.9, - 0.1; p = 0.05), a microRNA known to regulate AXL expression. Furthermore, the combination of higher AXL methylation and PTS exposure at birth increased the risk of recent episodes of bronchitic symptoms in childhood. CONCLUSIONS: PTS was associated with methylation level of AXL and the combination altered the risk of childhood bronchitic symptoms. PMID- 30029618 TI - Resistance to bacteriocin Lcn972 improves oxygen tolerance of Lactococcus lactis IPLA947 without compromising its performance as a dairy starter. AB - BACKGROUND: Lactococcus lactis is the main component of the mesophilic starters used in cheese manufacture. The success of milk fermentation relies on the viability and metabolic activity of the starter bacteria. Therefore, robust strains able to withstand the harsh conditions encountered during cheese manufacture and starter production are demanded. In this work, we have applied adaptive evolution under cell envelope stress imposed by the cell wall active bacteriocin Lcn972 to evolve strains with more robust phenotypes. RESULTS: Consecutive exposure of the starter strain L. lactis IPLA947 to Lcn972 yielded a stable mutant, L. lactis R5, with enhanced survival when challenged with hydrogen peroxide. L. lactis R5 exhibited faster growth rates in aerobic fermentations in broth and was able to acidify milk to a lower pH in aerated milk cultures. The improved behavior of L. lactis R5 in the presence of oxygen did not translate into a better performance in the presence of heme (i.e. respiration metabolism) or into higher survival during storage at cold temperatures or after freeze drying compared to the wild type L. lactis IPLA947. L. lactis R5 retained the same milk acidification rate and no changes in the consumption of lactose and production of organic acids were noticed. However, the profile of volatile compounds revealed a significant increase in 3-hydroxy-2-butanone (acetoin) in curds manufactured with L. lactis R5. CONCLUSIONS: Based on our results, L. lactis R5 can be proposed as a suitable dairy starter with improved survival under oxidative stress and enhanced metabolic traits. The results support the notion that adaptive evolution under cell envelope stress might be useful to generate strain diversity within industrial L. lactis strains. PMID- 30029619 TI - Blue light induces a neuroprotective gene expression program in Drosophila photoreceptors. AB - BACKGROUND: Light exposure induces oxidative stress, which contributes to ocular diseases of aging. Blue light provides a model for light-induced oxidative stress, lipid peroxidation and retinal degeneration in Drosophila melanogaster. In contrast to mature adults, which undergo retinal degeneration when exposed to prolonged blue light, newly-eclosed flies are resistant to blue light-induced retinal degeneration. Here, we sought to characterize the gene expression programs induced by blue light in flies of different ages to identify neuroprotective pathways utilized by photoreceptors to cope with light-induced oxidative stress. RESULTS: To identify gene expression changes induced by blue light exposure, we profiled the nuclear transcriptome of Drosophila photoreceptors from one- and six-day-old flies exposed to blue light and compared these with dark controls. Flies were exposed to 3 h blue light, which increases levels of reactive oxygen species but does not cause retinal degeneration. We identified substantial gene expression changes in response to blue light only in six-day-old flies. In six-day-old flies, blue light induced a neuroprotective gene expression program that included upregulation of stress response pathways and downregulation of genes involved in light response, calcium influx and ion transport. An intact phototransduction pathway and calcium influx were required for upregulation, but not downregulation, of genes in response to blue light, suggesting that distinct pathways mediate the blue light-associated transcriptional response. CONCLUSION: Our data demonstrate that under phototoxic conditions, Drosophila photoreceptors upregulate stress response pathways and simultaneously, downregulate expression of phototransduction components, ion transporters, and calcium channels. Together, this gene expression program both counteracts the calcium influx resulting from prolonged light exposure, and ameliorates the oxidative stress resulting from this calcium influx. Thus, six day-old flies can withstand up to 3 h blue light exposure without undergoing retinal degeneration. Developmental transitions during the first week of adult Drosophila life lead to an altered gene expression program in photoreceptors that includes reduced expression of genes that maintain redox and calcium homeostasis, reducing the capacity of six-day-old flies to cope with longer periods (8 h) of light exposure. Together, these data provide insight into the neuroprotective gene regulatory mechanisms that enable photoreceptors to withstand light-induced oxidative stress. PMID- 30029620 TI - Delivery strategies for malaria chemoprevention with monthly dihydroartemisinin piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years old in Malawi: a protocol for a cluster randomized trial. AB - BACKGROUND: Children initially hospitalized with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No intervention strategy specifically protects children during the post-discharge period. Recent evidence from Malawi shows that 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment with artemether-lumefantrine in children with severe malarial anaemia prevented 31% of deaths and readmissions. While a confirmatory multi-centre trial for PMC with dihydroartemisinin piperaquine is on going in Kenya and Uganda, there is a need to design and evaluate an effective delivery strategy for this promising intervention. METHODS: This is a cluster-randomized trial with 5 arms, each representing a unique PMC delivery strategy. Convalescent children aged less than 5 years and weighing more than 5 kg admitted with severe anaemia and clinically stable are included. All eligible children will receive dihydroartemisinin-piperaquine at 2, 6 and 10 weeks after discharge either: 1) in the community without an SMS reminder; 2) in the community with an SMS reminder; 3) in the community with a community health worker reminder; 4) at the hospital with an SMS reminder; or 5) at the hospital without an SMS reminder. For community-based strategies (1, 2 and 3), mothers will be given all the PMC doses at the time of discharge while for hospital-based strategies (4 and 5) mothers will be required to visit the hospital each month. Each arm will consist of 25 clusters with an average of 3 children per cluster giving approximately 75 children and will be followed up for 15 weeks. The primary outcome measure is uptake of complete courses of PMC drugs. DISCUSSION: The proposed study will help to identify the most effective, cost-effective, acceptable and feasible strategy for delivering malaria chemoprevention for post discharge management of severe anaemia in under-five children in the Malawian context. This information is important for policy decision in the quest for new strategies for malaria control in children in similar contexts. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02721420 . Protocol registered on 29 March 2016.The study was not retrospectively registered but there was a delay between date of submission and the date it first became available on the registry. PMID- 30029621 TI - Comparative study of inverted internal limiting membrane (ILM) flap and ILM peeling technique in large macular holes: a randomized-control trial. AB - BACKGROUND: The anatomical success rate of macular hole surgery ranges around 93 98%. However, the prognosis of large macular holes is generally poor. The study was conducted to compare the anatomical and visual outcomes of Internal Limiting Membrane (ILM) peeling vis-a-vis inverted ILM flap for the treatment of idiopathic large Full-Thickness Macular Holes (FTMH). METHODS: This was a prospective randomized control trial. The study included patients with idiopathic FTMH, with a minimum diameter ranging from 600 to 1500 MUm. The patients were randomized into Group A (ILM peeling) and Group B (inverted ILM flap). The main outcome measures were anatomical and visual outcome at the end of 6 months. Anatomical success was defined as flattening of macular hole with resolution of the subretinal cuff of fluid and neurosensory retina completely covering the fovea. RESULTS: There were 30 patients in each group. The mean minimum diameters in Group A and B were 759.97 +/- 85.01 MUm and 803.33 +/- 120.65 MUm respectively (p = 0.113). The mean base diameter in group A and B was 1304.50 +/- 191.59 MUm and 1395.17 +/- 240.56 MUm respectively (p = 0.112). The anatomical success rates achieved in Group A and B were 70.0 and 90.0% respectively (p = 0.125). The mean best-corrected visual acuity (BCVA) after 6 months was logMAR 0.65 +/- 0.25 (Snellen equivalent, 20/89) in Group A and logMAR 0.53 +/- 0.20 (Snellen equivalent, 20/68) in Group B (p = 0.060). The mean improvement in BCVA was 1.4 lines and 2.1 lines in groups A and B respectively (p = 0.353). BCVA>=20/60 was achieved by 13.3 and 20.0% in group A and B respectively (p = 0.766). CONCLUSION: The anatomical and functional outcome of Inverted ILM flap technique in large FTMH is statistically similar to that seen in conventional ILM peeling. TRIAL REGISTRATION: Clinical Trials Registry - India (Indian Medical Research) CTRI/2017/11/010474 . PMID- 30029622 TI - Gene alterations in monocytes are pathogenic factors for immunoglobulin a nephropathy by bioinformatics analysis of microarray data. AB - BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulopathy worldwide. The study aimed to provide potential molecular biomarkers for IgAN management. METHODS: The public gene expression profiling GSE58539 was utilized, which contained 17 monocytes samples (8 monocytes samples isolated from IgAN patients and 9 monocytes samples isolated from healthy blood donors). Firstly, differentially expressed genes (DEGs) between the two kinds of samples were identified by limma package. Afterwards, pathway enrichment analysis was implemented. Thereafter, protein-protein interaction (PPI) network was constructed and key nodes in PPI network were predicted using four network centrality analyses. Ultimately, gene functional interaction (FI) was constructed according to expressions in each sample, and then module network was extracted from FI network. RESULTS: A total of 678 DEGs were screened out, of these, 72 DEGs were identified as crucial nodes in PPI network that could well distinguish IgAN and healthy samples. In particular, IL6, TNF, IL1B, PRKACA and CCL20 were closely related to pathways such as hematopoietic cell lineage, apoptosis and Toll-like receptor (TLR) signaling pathway. Moreover, 12 genes in the FI network belonged to the 72 identified key nodes, such as CCL20, HDAC10, FPR2 and PRKACA, which were also key genes in 4 module networks. CONCLUSIONS: Several crucial genes were identified in monocytes of IgAN patients, such as IL6, TNF, IL1B, CCL20, PRKACA, FPR2 and HDAC10. These genes might co-involve in pathways such as TLR and apoptosis signaling during IgAN progression. PMID- 30029623 TI - Behavior of hyperreflective foci in non-infectious uveitic macular edema, a 12 month follow-up prospective study. AB - BACKGROUND: Hyperreflective foci have been described in OCT imaging of patients with retinal vascular diseases. It has been suggested that they may play a role as a prognostic factor of visual outcomes in these diseases. The purpose of this study is to describe the presence of hyperreflective foci in patients with non infectious uveitic macular edema and evaluate their behavior after treatment. METHODS: We conducted a multicenter, prospective, observational, 12-month follow up study. Inclusion criteria were age > 18 years and a diagnosis of non infectious uveitic macular edema, defined as central macular thickness of > 300 MUm as measured by OCT and fluid in the macula. Collected data included best corrected visual acuity, central macular thickness and the presence, number and distribution (inner or outer retinal layers) of hyperreflective foci. Evaluations were performed at baseline, and at 1, 3, 6, and 12 months after starting treatment. RESULTS: We included 24 eyes of 24 patients. The frequency of patients with >=11 hyperreflective foci was 58.4% at baseline, falling to 20.8% at 12 months. Further, hyperreflective foci were observed in the outer retinal layers in 50% of patients at baseline and just 28.6% at 12 months. Mean LogMAR visual acuity improved from 0.55 (95% CI 0.4-0.71) at baseline to 0.22 (95% CI 0.08 0.35) at 12 months (p < 0.001). Mean central macular thickness decreased from 453.83 MUm (95% CI 396.6-511) at baseline to 269.32 MUm (95% CI 227.7-310.9) at 12 months (P < 0.001). Central macular thickness was associated with number (p = 0.017) and distribution (p = 0.004) of hyperreflective foci. CONCLUSIONS: We have observed hyperreflective foci in most of our patients with non-infectious uveitic macular edema. During follow-up and after treatment, the number of foci diminished and they tended to be located in the inner layers of the retina. PMID- 30029625 TI - Functional study on new FOXL2 mutations found in Chinese patients with blepharophimosis, ptosis, epicanthus inversus syndrome. AB - BACKGROUND: Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare inheritable disease that mainly affects eyelid development associated with (type I) or without (type II) ovarian dysfunction, resulting in premature ovarian failure (POF). Mutations in the gene forkhead box L2 (FOXL2) have been shown to be responsible for BPES. The aim of this study was to determine and functionally validate the FOXL2 mutation in a Chinese BPES family. METHODS: Twelve individuals including five BPES patients from a Chinese family were enrolled. Genomic DNA was extracted from peripheral blood of enrolled subjects. The coding region of the FOXL2 gene was amplified and mutations were determined by sequencing analyses. Functional analysis was carried out to study changes in expression and transcriptional activity of the mutant FOXL2 protein. RESULTS: A novel mutation in the FOXL2 gene (c.931C > T) was detected in all five BPES patients, which converts a histidine residue into a tyrosine (p.H311Y) in the FOXL2 protein. Functional analysis revealed that this point mutation reduces FOXL2 protein expression, concomitant with decreased transcriptional activity on the steroidogenic acute regulatory (StAR) gene promotor. CONCLUSIONS: Our results expand the mutational spectrum of the FOXL2 gene and provide additional insights to the research on the molecular pathogenesis of FOXL2 in BPES. PMID- 30029624 TI - Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment. AB - BACKGROUND: Digenic inheritance is the simplest model of oligenic disease. It can be observed when there is a strong epistatic interaction between two loci. For both syndromic and non-syndromic hearing impairment, several forms of digenic inheritance have been reported. METHODS: We performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease. RESULTS: We found that this family displays digenic inheritance for two trans heterozygous missense mutations, one in PCDH15 [p.(Arg1034His)] and another in USH1G [p.(Asp365Asn)]. Both of these genes are known to cause autosomal recessive non-syndromic hearing impairment and Usher syndrome. The protein products of PCDH15 and USH1G function together at the stereocilia tips in the hair cells and are necessary for proper mechanotransduction. Epistasis between Pcdh15 and Ush1G has been previously reported in digenic heterozygous mice. The digenic mice displayed a significant decrease in hearing compared to age-matched heterozygous animals. Until now no human examples have been reported. CONCLUSIONS: The discovery of novel digenic inheritance mechanisms in hereditary hearing impairment will aid in understanding the interaction between defective proteins and further define inner ear function and its interactome. PMID- 30029626 TI - Prevalence and type-specific distribution of human papillomavirus infection among women in mid-western rural, Nepal- A population-based study. AB - BACKGROUND: Cervical cancer is the most common cancer among women in Nepal. The prevalence of human papillomavirus (HPV) 16 and or HPV 18 among women with cervical pre-cancer and cancer is higher than the incidence of HPV in the world population. The population-based epidemiological data of HPV in the general population in most parts of the country remains unknown. The objective of this study was to assess the prevalence and type distribution of HPV infection and association of abnormal cytology with high risk HPV infection among women in mid western rural, Nepal. METHODS: A population-based cross sectional study was conducted in Jumla, one of the most remote districts in Nepal. A total of 1050 cervical samples were collected from married and non- pregnant women aged 20-65 years during mobile Cervical Cancer Screening Clinics conducted from May 2016 to January 2017. The presence of HPV DNA was firstly confirmed by HPV consensus PCR using PGMY09/PGMY11 designed primers, then HPV positive samples were further genotyped by the membrane hybridization method to detect the 21 high-risk HPV (HR HPV) and low-risk HPV types. The prevalence of HR-HPV among women with normal and abnormal cytology was calculated. Data were analyzed using SPSS software for Windows. P < 0.05 was considered statistically significant. RESULTS: A total of 998 women were eligible for this study with the mean age 32.6 +/- 8.6 years, and the mean marital age was 16.7 +/- 3.8 years. The overall prevalence of HPV infections was 19.7%. HR-HPV and low-risk HPV were 11.7 and 8.7% respectively. The six most common HR-HPV types were HPV16, 39, 58, 33, 51 and 18. HR-HPV infection among the women with abnormal and normal cytology was of 27.3 and 10.8% respectively. CONCLUSIONS: There was a higher prevalence of HR-HPV infection among women living in Jumla than other parts of Nepal. This study provides preliminary information on overall HPV and type-specific HR-HPV prevalence, HR HPV 16, 39, 58, 33, 51, and 18 are the most prevalent genotypes in this region. The data contribute to the epidemiological knowledge about HPV and type-specific HR-HPV genotypes prevalence in mid-Western Nepal. PMID- 30029627 TI - Computer-based cognitive remediation program for the treatment of behavioral problems in children with intellectual disability: the "COGNITUS & MOI" study protocol for a randomized controlled trial. AB - BACKGROUND: Comorbid psychiatric disorders are frequent in children with intellectual disability (ID). Given the limitations of drugs treatments, cognitive remediation could be a promising tool to reduce these challenging behaviors but evidence is still scarce. Our group recently developed the "COGNITUS & MOI" program that is designed to train the attentional and visuospatial skills in children with ID. This study investigates the efficiency of the "COGNITUS & MOI" program in this condition. METHODS: Children (age: 6.00 13.11) with mild to moderate ID and behavioral problems, will benefit from a therapy during a 16 week randomized controlled trial. One group will be randomly treated with the "COGNITUS & MOI" program and the other with a motor skill and video viewing intervention. All participants will undergo a behavioral, functional and neurocognitive assessment at baseline, post-intervention, and 6 month follow-up. Primary outcome will be the change from the baseline of the score on the "hyperactivity - noncompliance" subscale of the Aberrant Behavior Checklist. DISCUSSION: If the results are conclusive, the "COGNITUS & MOI" program could be added to the therapeutic arsenal against challenging behavior in children with ID. TRIAL REGISTRATION: ClinicalTrials NCT02797418 . Date registered: 8th of June 2016. PMID- 30029629 TI - Bonferroni-Holm and permutation tests to compare health data: methodological and applicative issues. AB - BACKGROUND: Statistical methodology is a powerful tool in the health research; however, there is wide accord that statistical methodologies are not usually used properly. In particular when multiple comparisons are needed, it is necessary to check the rate of false positive results and the potential inflation of type I errors. In this case, permutation testing methods are useful to check the simultaneous significance level and identify the most significant factors. METHODS: In this paper an application of permutation tests, in the medical context of Inflammatory Bowel Diseases, is performed. The main goal is to assess the existence of significant differences between Crohn's Disease (CD) and Ulcerative Colitis (UC). The Sequentially Rejective Multiple Test (Bonferroni Holm procedure) is used to find which of the partial tests are effectively significant and solve the problem of the multiplicity control. RESULTS: Applying Non-Parametric Combination (NPC) Test for partial and combined tests we conclude that Crohn's Disease patients and Ulcerative Colitis patients differ between them for most examined variables. UC patients compared with the CD patients, have a higher diagnosis age, not show smoking status, proportion of patients treated with immunosuppressants or with biological drugs is lower than the CD patients, even if the duration of such therapies is longer. CD patients have a higher rate of re-hospitalization. Diabetes is more present in the sub-population of UC patients. Analyzing the Charlson score we can highlight that UC patients have a more severe clinical situation than CD patients. Finally, CD patients are more frequently subject to surgery compared to UC. Appling of the Bonferroni Holm procedure, which provided adjusted p-values, we note that only nine of the examined variables are statistically significant: Smoking habit, Immunosuppressive therapy, Surgery, Biological Drug, Diabetes, Adverse Events, Re hospitalization, Gender and Duration of Immunosoppressive Therapy. Therefore, we can conclude that these are the specific variables that can discriminate effectively the Crohn's Disease and Ulcerative Colitis groups. CONCLUSIONS: We identified significant variables that discriminate the two groups, satisfying the multiplicity problem, in fact we can affirm that Smoking habit, Immunosuppressive therapy, Surgery, Biological Drug, Diabetes, Adverse Events, Hospitalization, Gender and Duration of Immunosoppressive Therapy are the effectively significant variables. PMID- 30029628 TI - Social determinants of prostate cancer in the Caribbean: a systematic review and meta-analysis. AB - BACKGROUND: Prostate cancer remains the leading cause of cancer deaths among Caribbean men. However, little data exists on the influence of social factors on prostate cancer in the Caribbean setting. This article supports the 2011 Rio Political Declaration on addressing health inequalities by presenting a systematic review of evidence on the role of social determinants on prostate cancer in Caribbean men. It aims to determine the distribution, by known social determinants of health, of the frequency and adverse outcomes of prostate cancer among Caribbean populations. METHODS: Observational studies reporting an association between a social determinant and prostate cancer frequency and outcomes were sought in MEDLINE, EMBASE, SciELO, CINAHL, CUMED, LILACS, and IBECS databases. Fourteen social determinants and 7 prostate cancer endpoints were chosen, providing 98 possible relationship groups exploring the role of social determinants on prostate cancer. Observational studies with > 50 participants conducted in Caribbean territories between 2004 and 2016 were eligible. The review was conducted according to STROBE and PRISMA guidelines. Random-effects meta-analyses were performed. RESULTS: From 843 potentially relevant citations, 13 articles from 9 studies were included. From these included studies, 24 relationships were reported looking at 11 distinct relationship groups, leaving 90 relationship groups (92% of all relationship groups) unexplored. Study heterogeneity and risk of bias restricted results to a narrative synthesis in most instances. Meta-analyses showed more diagnosed prostate cancer among men with less formal education (n = 2 studies, OR 1.60, 95%CI 1.18-2.19) and among men who were married (n = 3 studies, OR 1.54, 95%CI 1.22-1.95). CONCLUSIONS: This review highlights limited evidence for a higher occurrence of diagnosed prostate cancer among Caribbean men with lower levels of education and among men who are married. The role of social determinants on prostate cancer among Caribbean men remains poorly understood. Improvements in study quantity and quality, and reduced variability in outcomes and reporting are needed. This report represents the current evidence, and provides a roadmap to future research priorities for a better understanding of Caribbean prostate cancer inequalities. PMID- 30029631 TI - Reasons for living and dying in suicide attempters: a two-year prospective study. AB - BACKGROUND: The internal suicide debate hypothesis assumes that in a suicidal crisis, individuals are involved in an internal struggle over whether to live or die. Reasons for living (RFL) and Reasons for dying (RFD) are important individual reasons for staying alive (e.g. family) or wanting to die (e.g. hopelessness) and reflect this internal motivational conflict of the suicidal mind. The aim of this study was to explore the association between RFL and RFD of suicide attempters and current and future suicide ideation and behavior. METHOD: The sample consisted of 60 patients who were admitted at a psychiatric emergency unit in Switzerland following an attempted suicide. They received treatment as usual, participated in an assessment interview and completed self-report questionnaires. Additionally, they were instructed to write down up to five individual RFL and RFD. The number of RFL and RFD responses, depressive symptoms, and suicide ideation were assessed at baseline and 6, 12, and 24 months follow up. Outcome measures were suicide ideation and repeated suicide attempts. Multiple imputations were used in order to address missing data. RESULTS: The number of RFD responses was the strongest predictor for increased suicide ideation at baseline. The number of RFL responses was not associated with suicide ideation and reattempts. RFD, depressive symptoms, and baseline suicide ideation predicted subsequent suicide reattempt up to 12 months later in simple regression analyses. Mediation analyses suggested that RFD mediated the effect of depressive symptoms at baseline on suicide ideation at 12-months follow-up. CONCLUSION: RFL were unrelated to the mental health of study participants and did not function as protective factor against suicide risk. RFD may be an important motivational driver in the suicidal process. Clinical interventions should focus more on the reduction of RFD than on RFL in suicidal individuals. PMID- 30029630 TI - Safety monitoring of ROTAVAC vaccine and etiological investigation of intussusception in India: study protocol. AB - BACKGROUND: ROTAVAC, an indigenous rotavirus vaccine, was introduced in the universal immunization program of India in four states in 2016 and expanded to five more states in 2017. The clinical trial on efficacy of ROTAVAC did not detect an increased risk of intussusception, but the trial was not large enough to detect a small risk. This protocol paper describes the establishment and implementation of a surveillance system to monitor the safety of rotavirus vaccine and investigate the potential infectious etiologies of intussusception. METHODS: This is a multi-centric hospital-based active surveillance being conducted at 28 hospitals in nine states of India. Data gathered from surveillance will be used to assess the risk of intussusception after ROTAVAC administration and to determine the infectious etiologies of intussusception. For safety assessment of ROTAVAC vaccine, children aged less than two years with intussusception admitted at the sentinel hospitals are enrolled into surveillance, a case report form completed, and a copy of the vaccination card obtained. The risk of intussusception following rotavirus vaccination will be assessed using a self-controlled case-series design. The investigation for potential infectious etiologies of intussusception is through a matched case control design. Children enrolled for the safety assessment serve as cases and for each case, an age, gender and location matched control is enrolled within 30 days of case enrollment. Stool specimens are obtained from cases and controls. All forms and specimens are sent to the referral laboratory for data entry, analysis, multiplexed molecular testing, and storage. DISCUSSION: Anticipated public health benefits of this surveillance include the generation of information useful to national government on safety of vaccine and to make future decisions on vaccine use through risk-benefit analysis. Investigating infectious agents may help to determine the potential infectious etiologies of intussusception. PMID- 30029632 TI - Use of modified diets to prevent aspiration in oropharyngeal dysphagia: is current practice justified? AB - BACKGROUND: Although modifying diets, by thickening liquids and modifying the texture of foods, to reduce the risk of aspiration has become central to the current management of dysphagia, the effectiveness of this intervention has been questioned. This narrative review examines, and discusses possible reasons for, the apparent discrepancy between the widespread use of modified diets in current clinical practice and the limited evidence base regarding the benefits and risks of this approach. DISCUSSION: There is no good evidence to date that thickening liquids reduces pneumonia in dysphagia and this intervention may be associated with reduced fluid intake. Texture-modified foods may contribute to undernutrition in those with dysphagia. Modified diets worsen the quality of life of those with dysphagia, and non-compliance is common. There is substantial variability in terminology and standards for modified diets, in the recommendations of individual therapists, and in the consistency of diets prepared by healthcare staff for consumption. Although use of modified diets might appear to have a rational pathophysiological basis in dysphagia, the relationship between aspiration and pneumonia is not clear-cut. Clinical experience may be a more important determinant of everyday practice than research evidence and patient preferences. There are situations in the management of dysphagia where common sense and the necessity of intervention will clearly outweigh any lack of evidence or when application of evidence-based principles can enable good decision making despite the absence of robust evidence. Nevertheless, there is a significant discrepancy between the paucity of the evidence base supporting use of modified diets and the beliefs and practices of practitioners. CONCLUSION: The disconnect between the limited evidence base and the widespread use of modified diets suggests the need for more careful consideration as to when modified diets might be recommended to patients. Patients (or their representatives) have a choice whether or not to accept a modified diet and must receive adequate information, about the potential risks and impact on quality of life as well as the possible benefits, to make that choice. There is an urgent need for better quality evidence regarding this intervention. PMID- 30029633 TI - Tumoral BRD4 expression in lymph node-negative breast cancer: association with T bet+ tumor-infiltrating lymphocytes and disease-free survival. AB - BACKGROUND: We previously observed that T-bet+ tumor-infiltrating T lymphocytes (T-bet+ TILs) in primary breast tumors were associated with adverse clinicopathological features, yet favorable clinical outcome. We identified BRD4 (Bromodomain-Containing Protein 4), a member of the Bromodomain and Extra Terminal domain (BET) family, as a gene that distinguished T-bet+/high and T-bet /low tumors. In clinical studies, BET inhibitors have been shown to suppress inflammation in various cancers, suggesting a potential link between BRD4 and immune infiltration in cancer. Hence, we examined the BRD4 expression and clinicopathological features of breast cancer. METHODS: The cohort consisted of a prospectively ascertained consecutive series of women with axillary node-negative breast cancer with long follow-up. Gene expression microarray data were used to detect mRNAs differentially expressed between T-bet+/high (n = 6) and T-bet-/low (n = 41) tumors. Tissue microarrays (TMAs) constructed from tumors of 612 women were used to quantify expression of BRD4 by immunohistochemistry, which was analyzed for its association with T-bet+ TILs, Jagged1, clinicopathological features, and disease-free survival. RESULTS: Microarray analysis indicated that BRD4 mRNA expression was up to 44-fold higher in T-bet+/high tumors compared to T bet-/low tumors (p = 5.38E-05). Immunohistochemical expression of BRD4 in cancer cells was also shown to be associated with T-bet+ TILs (p = 0.0415) as well as with Jagged1 mRNA and protein expression (p = 0.0171, 0.0010 respectively). BRD4 expression correlated with larger tumor size (p = 0.0049), pre-menopausal status (p = 0.0018), and high Ki-67 proliferative index (p = 0.0009). Women with high tumoral BRD4 expression in the absence of T-bet+ TILs exhibited a significantly poorer outcome (log rank test p = 0.0165) relative to other subgroups. CONCLUSIONS: The association of BRD4 expression with T-bet+ TILs, and T-bet+ TIL dependent disease-free survival suggests a potential link between BRD4-mediated tumor development and tumor immune surveillance, possibly through BRD4's regulation of Jagged1 signaling pathways. Further understanding BRD4's role in different immune contexts may help to identify an appropriate subset of breast cancer patients who may benefit from BET inhibitors without the risk of diminishing the anti-tumoral immune activity. PMID- 30029634 TI - Sequela of female genital mutilation on birth outcomes in Jijiga town, Ethiopian Somali region: a prospective cohort study. AB - BACKGROUND: In Ethiopia, female genital mutilation (FGM) remains a serious concern and has affected 23.8 million women and girls, with the highest prevalence in Somali regional state. Even though FGM is reported to be associated with a range of obstetric complications, little is known about its effects on childbirth in the region. Therefore, the objective of this study was to test the hypothesis that FGM is a contributing factor to the increased risk of complication during childbirth. METHODS: Facility based cohort study, involving 142 parturients with FGM and 139 parturients without FGM, was conducted in Jijiga town from October to December, 2014. The study participants were recruited by consecutive sampling technique. Data were collected using a structured interviewer administered questionnaire and observational checklists. Data were analyzed using SPSS version 16 and STATA version 11. RESULTS: The existence of FGM was significantly associated with perinealtear [RR = 2.52 (95% CI 1.26 5.02)], postpartum blood loss [RR = 3.14 (95% CI 1.27-7.78)], outlet obstruction [RR = 1.83 (95% CI 1.19-2.79)] and emergency caesarean section [RR = 1.52 (95% CI 1.04-2.22)]. FGM type I and FGM type II did not demonstrate any association with prolonged 2nd stage of labour, emergency caesarean section, postpartum blood loss, and APGAR score < 7. FGM type III however was significantly associated with prolonged 2nd stage of labour [RR = 2.47 (95% CI 1.06-5.76)], emergency caesarean section [RR = 3.60 (95% CI 1.65-7.86)], postpartum blood loss [RR = 6.37 (95% CI 2.11-19.20] and APGAR score < 7 [RR = 4.41 (95% CI, 1.84-10.60)]. FGM type II and type III were significantly associated with perinealtear [RR = 2.45(95% CI 1.03 5.83)], [RR = 4.91(95% CI 2.46-9.77)] and outlet obstruction [RR = 2.38(95% CI 1.39-4.08)], [RR = 2.94(95% CI 1.84-4.71)] respectively. CONCLUSION: Women with FGM are significantly more likely than those without FGM to have adverse obstetric outcomes. Risks seem to be greater with more extensive form of FGM. Adverse obstetric outcomes can therefore be added to the known harmful immediate and long-term effects of FGM. PMID- 30029635 TI - Reversible cataract after exposure to distilled water: a case report. AB - BACKGROUND: To report a case of a reversible cataract after intracameral infusion of distilled water during full-thickness astigmatic keratotomy. CASE PRESENTATION: A 20-year-old male whose bilateral anterior chambers were exposed to distilled water during astigmatic keratotomy developed bilateral corneal edema, inflammation of the anterior chambers, and an anterior subcapsular cataract in the right eye. After 1 month of topical administration of 0.1% prednisolone acetate and 5% NaCl, the bilateral inflammation of the cornea and anterior chambers cleared; endothelial cell density decreased by 41.1% in the right eye and 12.7% in the left eye. The cataract in the right eye decreased centripetally. Small incision lenticule extraction surgery was performed at 2 months after the astigmatic keratotomy; the patient's uncorrected distance visual acuity 3 months later was 20/25 in both eyes. CONCLUSIONS: This case suggests that a cataract that develops as a result of instantaneous intracameral exposure to distilled water is reversible. PMID- 30029636 TI - A novel splice site mutation in WAS gene in patient with Wiskott-Aldrich syndrome and chronic colitis: a case report. AB - BACKGROUND: Wiskott-Aldrich syndrome is an X-linked recessive immunodeficiency due to mutations in Wiskott-Aldrich syndrome (WAS) gene. WAS gene is encoded for a multifunctional protein with key roles in actin polymerization, signaling pathways, and cytoskeletal rearrangement. Therefore, the impaired protein or its absence cause phenotypic spectrum of the disease. Since identification of novel mutations in WAS gene can help uncover the exact pathogenesis of Wiskott-Aldrich syndrome, the purpose of this study was to investigate disease causing-mutation in an Iranian male infant suspicious of this disorder. CASE PRESENTATION: The patient had persistent thrombocytopenia from birth, sepsis, and recurrent gastrointestinal bleeding suggestive of both Wiskott-Aldrich syndrome and chronic colitis in favor of inflammatory bowel disease (IBD). To find mutated gene in the proband, whole exome sequencing was performed for the patient and its data showed a novel, private, hemizygous splice site mutation in WAS gene (c.360 + 1G > C). CONCLUSIONS: Our study found a novel, splice-site mutation in WAS gene and help consider the genetic counselling more precisely for families with clinical phenotypes of both Wiskott-Aldrich syndrome and inflammatory bowel disease and may suggest linked pathways between these two diseases.